Synthesis of Novel Extremely Sterically Hindered Tertiary Alkylamines

von der Fakultät für Naturwissenschaften der Technischen Universität Chemnitz genehmigte Dissertation zur Erlangung des akademischen Grades

doktor rerum naturalium

(Dr. rer. nat.)

vorgelegt von M.Sc. Tharallah A. Shoker

geboren am 18. April 1985 in Nabi Chit, Lebanon

eingereicht am 17. January 2018

Gutachter:

Prof. Dr. Klaus Banert JP Dr. Evgeny Kataev

Tag der Verteidigung: 16. April 2018

Die vorliegende Arbeit wurde in der Zeit von Oktober 2015 bis Oktober 2017 am Institut für Chemie an der Fakultät für Naturwissenschaften der Technischen Universität Chemnitz unter der Leitung von Prof. Dr. Klaus Banert angefertigt.

Bibliographic Description Synthesis of Novel Extremely Sterically Hindered Tertiary Alkylamines SHOKER, THARALLAH Technische Universität Chemnitz, Fakultät für Naturwissenschaften Dissertation, 2017, 208 pages. Abstract Three advanced methodologies for the preparation of extremely sterically hindered tertiary alkyl amines have been developed. The syntheses of 28 novel tertiary alkylamines that accommodate unusual steric hindrance are detailed. The electrophilic amination of alkyl Grignard reagents with N-chlorodialkylamines, in the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) as a key additive, gives a variety of unprecedentedly sterically hindered tertiary alkylamines in good yields. Alternative strategy to 1-adamantyl-substituted (1-Ad) sterically hindered tertiary amines, which involved instead an SN1 reaction between 1-Ad cation with various secondary amines, is described. A complementary strategy to 1-Ad-based sterically hindered tertiary amines, which involves an iminium salt intermediate, is also reported. Salient features of the three protocols that are detailed here include unusual tolerance of steric hindrance, mild reaction conditions employed, ease of product isolation-purification, and absence of catalysts/transition metals. The molecular structures of two faithful examples of extremely sterically hindered tertiary alkylamines were determined by single crystal X-ray diffraction, and the height “h” of nitrogen pyramid of these compounds were measured. The NMR spectra show a restriction in rotation at room temperature among many hindered tertiary amines, and some of them exhibit two complete sets of peaks for two non-equivalent rotamers at room temperature. 15N NMR has been applied to study the structural changes in highly sterically hindered tertiary amines. Most of these compounds have been shown to undergo Hofmann type elimination reaction upon thermolysis at 100 C in inert solvents, like toluene.

Keywords: Steric hindrance, tertiary amines, 1-adamantyl compounds, N-chloroamines, nucleophilic substitution, N,N,N′,N′-tetramethylethylenediamine, temperature-dependent NMR spectroscopy, pyramidal configuration of nitrogen, nitrogen NMR.

Bibliografische Beschreibung Synthese neuer extrem sterisch gehinderter tertiärer Alkylamine

Abstract

In der vorliegenden Arbeit wurden drei Methoden zur Synthese von tertitären Aminen mit extremer sterischer Hinderung entwickelt und zur Synthese von 28 neuen tertiären Alkylaminen mit entsprechender sterischer Hinderung angewendet. Die elektrophile Aminierung von Grignard-Reagenzien mit N-Chlordialkylaminen, unter Zusatz von N,N,N′,N′-Tetramethylethylendiamin (TMEDA) als Schlüsselkomponente, ermöglicht einen einfachen Zugang zu einer Vielzahl von tertiären Aminen mit extremer sterischer Hinderung mit guten Ausbeuten.

Eine alternative Synthesestrategie unter SN1-Bedingungen führt zu sterisch-gehinderten 1-Adamantyl-substituierten (1-Ad) tertiären Aminen durch die Reaktion eines 1-Ad-Kations mit unterschiedlichen sterisch-gehinderten sekundären Aminen. Angelehnt an die zuvor beschriebene Reaktion können auch sterisch gehinderte Imine über eine Iminium-Salz-Zwischenstufe zu sterisch-gehinderten 1-Ad-substituierten tertiären Aminen umgesetzt werden. Auch in diesen Fall zeichnet sich die Reaktion durch eine bemerkenswerte Toleranz gegenüber sterischer Hinderung, milden Reaktionsbedingungen, leichte Produktisolierbarkeit und die Abwesenheit von Übergangsmetallkatalysatoren aus. Die molekulare Struktur zweier repräsentativer tertiärer Alkylamine mit extremer sterischer Hinderung wurde mittels Röntgeneinkristallstrukturanalyse untersucht und die Höhe “h” ihrer Stickstoff-Pyramide bestimmt. Die NMR-Spektren zeigen bei RT eine Einschränkung der freien Rotation um die N-C-Bindungsachse, teilweise führt dies zu vollständig getrennten Signalsätzen für die einzelnen Rotamere. 15N-NMR-Spektroskopie wurde ebenfalls zur Untersuchung von Strukturveränderungen genutzt. In inerten Lösungsmitteln, wie Toluol, zeigen die Verbindungen bei 100 °C in den meisten Fällen eine Hofmann-Eliminierung.

Stichworte: Sterische Hinderung, tertiäre Amine, 1-Adamantylverbindungen, N-Chloramine, N,N,N′,N′-Tetramethylethylendiamin, Nucleophile Substitution, temperaturabhängige NMR- Spektroskopie, Pyramidale Konfiguration des Stickstoffs, Stickstoff-NMR.

Acknowledgments

Acknowledgment is due to those individuals without whom completion of this body of work would not have been possible: Professor Klaus Banert (advisor), Dr. M. Hagedorn, Dr. A. Ihle,

Dr. M. Müller, M. Heck, T. Pester, E. Gutzeit, M. Hofmann, J. Buschmann, K. Weigand, S.

Bochmann, J. Seifert, Ms. Christiane Dienel, Ms. B. Kempe (for performing elemental analyses),

Dr. R. Buschbeck (for measuring HRMS), Dr. M. Wӧrle (for performing single crystal X-ray diffraction), and Prof. A. D. Boese (for performing the theoretical calculations).

For my parents, my sisters, and my brothers.

Table of Contents

List of Tables ...... 9 List of Figures ...... 9 List of Schemes ...... 10 List of Abbreviations and Symbols ...... 12 List of New Compounds ...... 14 I. Introduction ...... 16 II. Purpose of the Work ...... 22 III. Results and Discussions ...... 23 1. Electrophilic Amination of Alkyl Grignard Reagents with N-Chloroamines...... 23 1.1 Initial Studies ...... 23 1.2 Preparation of Various (tert-Alkyl)-Based Tertiary Amines...... 29 1.3 Preparation of the Novel 2-(tert-Butyl)-1,1,3,3-tetramethylisoindoline (12b), 2-(tert- Butyl)-1,1,3,3-tetraethylisoindoline (12d), and Related Compounds...... 32 1.4 Preparation of Novel Extremely Sterically Hindered Bridgehead-Bonded Tertiary Alkylamines...... 35 1.5 Preparation of N-(tert-Butyl)-N-isopropyladamantan-1-amine (18)...... 45 2. Electrophilic Amination of Alkyl Grignard Reagents with N,N-Dichloroamines...... 50

3. SN1–Type Reaction between Various Secondary Amines and 1-Adamantyl Cation...... 53 3.1 Initial Studies...... 54 3.2 Preparation of Various Novel (1-Ad)-Based N,N,N-Tri(tert-alkyl) Cyclic Amines...... 58 3.3 Attempts for the Preparation of Sterically Hindered Six-Membered Cyclic Amines. ... 60 3.4 Attempts for the Preparation of N,N-Di-tert-Butyladamantan-1-amine (19) and Related Compounds...... 63

4. SN1–Type Reaction between Various Imines and 1-Adamantyl Triflate...... 67 4.1 Initial Studies...... 67 4.2 Preparation of Various Highly Sterically Hindered Enamines...... 68 5. Applications ...... 70 5.1 Non-Planar Structures of Extremely Sterically Hindered Tertiary Alkylamines...... 70 5.2 Preparation of Sequent Series of Sterically Hindered Amines for 15N NMR Studies. .... 72 5.3 Elimination Rate of Some Sterically Hindered Tertiary Amines ...... 74

5.4 Dynamic NMR Studies ...... 75 IV. Conclusion ...... 76 V. Summary……………………………………………………………………………………….....78

VI. Experimental part ...... 81 A. General ...... 81 B. Apparatus ...... 81 C. Chemicals ...... 81 D. Procedures ...... 82 Typical procedure A (General electrophilic amination): ...... 84

Typical procedure B (General SN1 protocol between secondary amines and 1-AdOTf): ...... 85

Typical procedure C (General SN1 protocol between secondary amines and 1-AdOMs): ...... 86

Typical procedure D (General SN1 protocol between secondary amines and 1-AdOAc): ...... 86

Typical procedure E (General SN1 protocol between imines and 1-AdOTf): ...... 87 VII. References ...... 108 VIII. Supporting Information ...... 113 1. 1H NMR and 13C NMR spectra ...... 113 2. X-Ray Data ...... 189 3. Theoretical calculation data ...... 203 IX. Curriculum Vitae ...... 205

List of Tables

Table 1 Scope of secondary amines and N-chlorosuccinimide……………………………………...…..24 Table 2 Effect of solvent in organomagnesium electrophilic amination reaction...... ….27 Table 3 Optimization of reaction temperature using 5b and iPrMgCl…………...…………………..….28 Table 4 Scope of N-chloroamines and alkylmagnesium reagents……………...…………………....…..29 Table 5 The various steric parameters of some alkyl groups…………………………………………....38

Table 6 Effect of the solvent on the SN1 reaction shown in Scheme 30……………………………...…56 Table 7 Scope of 1-Ad–LG………………………..………………………….……………………...….57

List of Figures

Figure 1. Commercially available hindered amine stabilizers...... 17

Figure 2. Height of nitrogen pyramid for some reported tertiary amines...... 18

Figure 3. Relationship between aggregation and reactivity in organolithium chemistry...... 25

Figure 4. 1H NMR spectra of the reaction mixture that show the integration ratio between 6b and 4b. ... 28

Figure 5. Descriptive structures which shows the origin of two rotamers in compounds a) 6e–g; b) 6d. . 31

Figure 6. Conformational equilibrium of monosubstituted cyclohexane...... 38

Figure 7. Molecular structure of compound 15f from single crystal X-ray diffraction...... 41

Figure 8. Molecular structure of compound 18 from single crystal X-ray diffraction...... 46

Figure 9. The two suggestible rotamers of compound 18...... 47

Figure 10. 1H NMR spectrum of compound 18. 1: Major rotamer peaks; 2: Minor rotamer peaks...... 47

1 Figure 11. Sectioned H NMR spectrum (in toluene-d8) of compound 18 at different temperatures...... 48

Figure 12. Decoupled 1H NMR of: a) major rotamer b) minor rotamer of compound 18...... 48

Figure 13. a) Expected major rotamer of compound 18. b) Expected minor rotamer of compound 18. ... 49

Figure 14. NOESY NMR spectrum of compound 18...... 50

Figure 15. Single crystal X-ray diffraction of compounds 18 and 15f ...... 71

Figure 16. 15N NMR chemical shifts of several sterically hindered tertiary amines ...... 73

Figure 17. Half-life of some sterically hindered tertiary amines ...... 75

List of Schemes

Scheme 1. Schematic route for the preparation of two known tertiary amines 1a, b and 2...... 20

Scheme 2. General route for the preparation of some aryl-based tertiary amines...... 21

Scheme 3. Schematic route for the preparation of tertiary amines via SN1 strategy...... 21

Scheme 4. Schematic route for the tertiary amines 6a–g via electrophilic amination strategy...... 24

Scheme 5. Effect of TMEDA on the outcome yield of the electrophilic amination reaction...... 25

Scheme 6. Postulated role of TMEDA in organomagnesium electrophilic amination reaction...... 26

Scheme 7. Attempt of electrophilic amination of Grignard reagent with O-Benzoyl Hydroxylamine 7. .. 29

Scheme 8. Over all synthetic route of compounds 6e–g...... 30

Scheme 9. General thermolysis path of the highly sterically hindered tertiary amines 6c–g...... 32

Scheme 10. Over all synthetic route of compounds 12a–d...... 33

Scheme 11. Schematic route for the tertiary amines 15a–g via the electrophilic amination strategy...... 36

Scheme 12. Synthetic route of compound 15c...... 36

Scheme 13. Attempt for the preparation of compound 15h...... 37

Scheme 14. Synthetic route of compound 15d...... 39

Scheme 15. Synthetic route of compounds 15e, f...... 40

Scheme 16. Synthetic route of compound 15g-exo...... 41

Scheme 17. Attempt for the preparation of compound 15g-endo...... 43

Scheme 18. Attempt for the preparation of compound 6h...... 44

Scheme 19. Decomposition route of compound 15g-exo in protic solvent...... 44

Scheme 20. Over all synthetic route of compound 18...... 45

Scheme 21. Synthetic attempt for the preparation of compound 19...... 50

Scheme 22. The outcome of the electrophilic amination reaction between compound 21 and iPrMgCl. .. 51

Scheme 23. Mechanistic path for the formation of compounds 20, 22, 23...... 52

Scheme 24. Synthetic route of compound 22...... 52

Scheme 25. Outcome products of the reaction between compound 21 and t-BuMgCl...... 53

Scheme 26. General SN1 synthetic route for 1-Ad-based tertiary amines...... 53

Scheme 27. SN1 route between 4a and 25a...... 54

Scheme 28. SN1 route between 4b and 25a...... 54

Scheme 29. Example on Hofmann elimination of sterically hindered tertiary amines...... 55

Scheme 30. SN1 route between 4b and 25a in the presence of K2CO3...... 55

Scheme 31. Postulated SN1 mechanism for the formation of tertiary amines...... 56

Scheme 32. Synthetic route of compound 18 following the SN1 protocol between 4b and 25g...... 58

Scheme 33. Synthetic route to products 26a–d via SN1 method...... 59

Scheme 34. Expected cleavage of the cyclic amine 26c to the acyclic amine 26g or similar compounds. 60

Scheme 35. Attempts for the preparation of compounds 12e and 26e...... 61

Scheme 36. Postulated schematic route toward compounds 26f, h...... 61

Scheme 37. Synthetic route of compound 10f...... 62

Scheme 38. Outcome products of the reaction between 10f and 25g...... 62

Scheme 39. Postulated mechanism for the formation of the unwanted products 27a, b...... 63

Scheme 40. Attempt for the preparation of compound 19 via the SN1 route...... 63

Scheme 41. Source of the formation of the side product 16...... 64

Scheme 42. Source of the side product 29...... 65

Scheme 43. Attempts of SN1 reactions for the preparation of compounds 15h or 30...... 65

Scheme 44. Difference in steric hindrance between 4b and 31...... 66

Scheme 45. Synthetic route to the secondary amines 16 and 31 via the SN1 methodology...... 66

Scheme 46. General reaction between 1-AdOTf and imines to the corresponding tertiary amine...... 67

Scheme 47. New SN1 strategy for the synthesis of compound 18 from imine 33...... 67

Scheme 48. Outcome results of the SN1 protocol of imine 34a...... 68

Scheme 49. Outcome results of the SN1 protocol of imines 34b, c...... 69

Scheme 50. General thermolysis path of highly sterically hindered tertiary amine...... 74

List of Abbreviations and Symbols

ABS acrylonitrile butadiene styrene

Ad adamantane

Ar aryl aq. aqueous br broad t-Bu tert-butyl cat. catalytic amount or catalyst

13C NMR carbon nuclear magnetic resonance spectroscopy cHx cyclohexyl cPn cyclopentyl d doublet equiv. equivalents

Et ethyl

Et2O diethyl ether

FG functional group h hour

1H NMR proton nuclear magnetic resonance spectroscopy

HRMS high resolution mass spectrometry

Hz hertz

J coupling constant

LG leaving group

M molarity, metal m multiplet

Me methyl

12 mg milligram

MHz megahertz min minutes mL milliliter mmol millimole m.p. melting point n.d. no decomposition ppm parts per million iPr isopropyl

R alkyl r.t. room temperature s singlet

Temp. temperature t triplet

OAc acetate

OMs mesylate (methanesulfonate)

OTf triflate (trifluoromethanesulfonate)

SAN styrene acrylonitrile

THF tetrahydrofuran

TMS trimethylsilyl

TMEDA N,N,N’N’-tetramethylethylenediamine

t1/2 half-life

X anionic ligand

δ chemical shift

List of New Compounds

5e 12b

6c 12d

6d 14

6e 15a

6f 15b

6g 15c

11a 15d

11b 15e

12a 15f

15g 31

17 35a

18 35b

22 35c

26a 35d

26b 37a

26c 37b

26d 39b

I. Introduction

Amines are ubiquitous in nature. They are important building blocks in the synthesis of various important organic compounds such as pharmaceuticals, polymers, dyes, xerographic and photographic materials.[1–4] Consequently, the development of new methodologies for their preparations continue to attract the attention of many researchers. [5–9]

Sterically hindered amines represent particularly important class of nitrogen containing compounds. They receive considerable interest from many researchers and prove to be an interesting practical area of study. This is because the steric crowding around the nitrogen results in interesting changes in molecular structure, basicity, and chemical properties.[10–12] Furthermore, the importance of such compounds comes from their well-known applications in the organic synthesis field as well as the industrial ones.

Sterically hindered amines and their metal salts are widely used in chemical reactions as bases, proton scavengers, precious reagents in selective alkylation reactions of carbonyl compounds, and as precursors in the preparations of persistent nitroxyl radicals.[12–20] Indeed, sterically hindered nitrogen bases constitute a family of worthy synthetic reagents, for example, 2,6-di-tert-butylpyridine, 1,8-bis(dimethylamino)naphthalene, 1,1,2,3,3-pentaisopropylguanidine, 2,6-bis(triisopropylsilyl)pyridine, and diisopropylethylamine (Hünig's base), probably the most commonly used of all.[20–22]

Industrially, sterically hindered amines were introduced for market development in the manufacture of polymers as thermo- and photostabilizers.[23–29] Such additives are known as hindered amine light stabilizers (HALS). 2,2,6,6-Tetramethyl-substituted piperidine is the chief component in this area (Figure 1).[30] These compounds are efficient in many polymers and applications, and they show light stabilizing properties superior to many other additives in large number of major polymers especially polypropylene, polyethylene, polystyrene, impact polystyrene, ABS, SAN, polyurethane as well as thermoplastic and thermosetting coatings.[28]

Figure 1. Commercially available hindered amine stabilizers.

Sterically hindered amines are also important agents in gas-treating processes for the removal of carbon dioxide from gas streams.[31–32]

Theoretically, sterically hindered amines are quite interesting for many researchers because the steric effects have proved to alter the geometry about nitrogen atom; therefore, greatly modify the chemical and physical properties of the attached lone pair of electrons. The effect of steric hindrance on the basicity of amines in solution and in gas phase has been intensely studied.[33–36] Correspondingly, steric effects on NMR parameters, namely, 14N NMR and 15N NMR have been considered and correlated with structural features in sterically hindered amines. In fact, it is expected that the geometric and electronic changes around the nitrogen atom would be reflected as changes in parameters observed in the nitrogen NMR of these compounds.[10,37–38]

Researchers are also impressively interested in investigating whether the normal pyramidal geometry of an amine could be deformed to a more planar structure as steric interactions increase. Such deformation would involve a change in the hybridization about the nitrogen atom through which the normal pyramidal sp3 could be expected to change into a trigonal planar sp2; thus, the nitrogen lone pair in the latter case might exhibit significant p-character.[10] Indeed, amines with

17 planar nitrogen are not rare, but there are many examples (Figure 2) in the literature which show partial and complete planarity at nitrogen (represented by “h”: which is the distance from nitrogen to the plane defined by the three carbon atoms to which it is bonded).[39–44]

Figure 2. Height of nitrogen pyramid for some reported tertiary amines.

It is obvious from Figure 2 that there are examples of remarkably planarized trialkylamines that do not appear to have enough substituents of adequate bulk to cause the observed planarity. This can only lead to a consideration of effects other than steric hindrance to account for such structural trends in highly planar trialkylamines. The main cause for such planarity in these cases is proposed by Jie et al. and other authors to be an electronic interaction between the occupied nitrogen p- orbital with the unoccupied side chain orbital as a stabilizing interaction. As the side chain atom is made more electronegative, its orbital move to lower energies resulting in a smaller ΔE; thus, the interaction is stronger and stabilizes the planar form.[11,44–46]

What we want to say, however, is that trialkylamines that hold three tetrahedral carbon atoms, without any heteroatom, are rarely found to be planar at nitrogen. It is still unclear and arouse curiosity whether extreme steric hindrance, as a solitary factor, can account in structural trends that end up with planarity.

Triisopropylamine, was thought for some time to be a planar aliphatic trialkylamine.[10,47] However, it was confirmed from its X-ray crystal structure to be much flatter than an ordinary trialkylamine, but not planar.[39] Is it sensible to consider and study triisopropylamine as an extremely hindered amine? If this is reasonable, then, what should we consider tri(tert-butyl)amine, tri-(1-adamantyl)amine or similar tertiary alkylamines?

Although there are numerous methods for the preparation of hindered secondary amines,[48] there are relatively few general methods available for the synthesis of hindered tertiary amines. Some methods for the preparation of moderately strained tertiary amines include alkylative amination of aldehydes,[49] reductive amination of ketones,[50] alkylation of secondary amines,[51] reduction of hindered 2-chloroalkanamides,[52] reactions between Grignard reagents with α-aminonitriles,[51] reactions between Grignard reagents with formamides,[53] reactions between Grignard reagents with iminium salts,[54–56] and reactions between hindered primary amines with α-halo amides.[57] However, these methods lack the generality, and they are limited to the preparation of hindered amines where one or more substituents are methyl or primary alkyl groups.

Going to a higher degree of steric hindrance among tertiary amines, the methods become rarer and more particular. Talking about highly strained tertiary amines are those that hold two substituents of tert-alkyl groups. These compounds are very rare in the literature when the third substituent is a sec-alkyl group, but they cease when the third substituent is a tert-alkyl group.

In this manner, a successful procedure for the preparation of di-tert-butylamino benzonitrile has been described by Knochel and co-workers.[58] In this procedure, 3- and 4-(di-tert-butylamino) benzonitrile (1a, b) were prepared via the coupling between lithium amidocuprates and N-lithium di-tert-butylamide. However, this method lacks the generality, and it is only applicable for aryl groups (Scheme 1). Another successful method for the preparation of N,N-di(tert-butyl) cyclopropanamine (2) was reported by de Meijere.[59] This involves the reaction of N,N-di(tert- butyl) formamide with ethylmagnesium bromide in the presence of titanium tetra(2-propanolate)

[Ti(OiPr)4] (Scheme 1). Again, this method lacks the generality, and it is only successful for the preparation of compound 2 as the highest sterically hindered outcome product.

According to Boese, tricyclopropylamine shows a height of “N” pyramid = 0.467 Å and C–N–C = 110°; thus, he concluded that tricyclopropylamine is not disordered and being very similar to

Me3N. This means that a cyclopropyl group is a small group, analogous to a methyl group, and by far compound 2 can’t be considered as a highly sterically hindered tertiary amine.[10]

Scheme 1. Schematic routes for the preparation of known tertiary amines 1a, b and 2.

Among modern amination methods, electrophilic amination has been found to be a viable alternative method, and it continues to be a significant method for amine synthesis.[60–61] Various aminating reagents, such as haloamines, hydroxylamines, imines, oxaziridines, oximes, diazonium salts, azodicarboxylates, and azides have been used in the electrophilic amination of various organometallic reagents, such as organomagnesium, organozinc, organocopper, and organolithium.

Haloamines are one of the primary aminating reagent class used for the amination of organomagnesium reagents.[62–65] Unfortunately, reaction of Grignard reagents with haloamines resulted in low yields because of the formation of many side products in parallel with the expected amines.[66–68] For that, haloamines have not received much attention as aminating reagents in the amination of Grignard reagents. Recently, a successful procedure, with marvelous yields, for the electrophilic amination of organomagnesium compounds with N-chloroamines has been described in 2010 by Hatakeyama and co-workers.[69] In this procedure, tertiary amines were prepared by the

20 reaction of aryl- and heteroarylmagnesium bromides with various N-chloroamines in the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) (Scheme 2). Although the desired products are non-sterically hindered aryl amines, the simplicity of the process used and the good yields obtained are quite exciting; hence, it would be taken into consideration in our work.

Scheme 2. General route for the preparation of some aryl-based tertiary amines via electrophilic amination.

Other exciting methodologies have been reported by many authors through which various tertiary amines are prepared from highly reactive electrophiles.[70–71] In these procedures, tertiary amines are prepared by the reaction of alkyl- or aryl triflates with various secondary amines (Scheme 3). In particular, in his paper for the synthesis of di(tert- alkyl)amines, Corey reported the synthesis of N,N-di(tert-butyl)methylamine (3) via the reaction of di(tert-butyl)amine (4c) with methyl fluorosulfonate (Scheme 3).[72] This methodology is noteworthy for its simplicity and its good yield; thus, such highly reactive groups would be taken into consideration in our work.

Scheme 3. Schematic route for the preparation of tertiary amines from secondary amine and highly reactive electrophiles.

II. Purpose of the Work

The aim of this work is to find new, straightforward, and effective routes for the preparation of highly sterically hindered tertiary alkylamines because such compounds and the methods for their preparation are very rare in the literature. Despite the wide varieties of tertiary amines, we will limit our work to the preparation of highly sterically hindered tertiary alkylamines. We are trying to explore the ultimate level of steric hindrance that can be achieved for tertiary alkylamines. Because they are rare in the literature, the physical and chemical properties for such unprecedented compounds must be measured and clarified. This includes basicity, planarity of the nitrogen pyramid, 15N NMR chemical shift, rotational barrier among the N–C bonds, Hoffmann elimination, and stability under various conditions.

III. Results and Discussions 1. Electrophilic Amination of Alkyl Grignard Reagents with N-Chloroamines.

In this section, we document the scope and limitations of a non-catalyzed C–N bond construction. Herein, we report an example on electrophilic amination between sterically hindered alkyl Grignard reagents with sterically hindered N,N-dialkyl-N-chloroamines with the aid of N,N,N’,N’-tetramethylethylenediamine (TMEDA) as a key additive. The ease of synthesis and the good stability of N-chloroamines render them attractive starting materials. The results with Grignard reagents in the absence of any additive proved disappointing under all conditions screened. However, the results with TMEDA proved promising through which a dramatic increase in the yield was realized. In all cases, the precursor secondary amine is the major side product. We intentionally limited our search for two key aspects: 1) only those aminating reagents and Grignard reagents allowing for the direct delivery of sp3-hybridized alkyl synthons would be considered; 2) only sterically hindered molecules would be evaluated.

1.1 Initial Studies

We initiated our studies by evaluating the optimal conditions for the non-catalyzed electrophilic amination of organometallic reagents.

N,N-Dialkyl-N-chloroamines were initially investigated as aminating agents. N-Chloroamines 5a–e were synthesized via chlorination of the appropriate secondary amine with N-chlorosuccinimide in DCM at room temperature according to a general literature method (Table 1).[73] Compounds 5a–d are known in the literature,[74–75] but 5e is a new compound.

Table 1. Scope of secondary amines and the corresponding N-chloroamines.

Entry Secondary Amines Product Yield of 5 (%)

1 4a 5a[74] 87 2 4b 5b[75] 85 3 4c 5c[75] 86 4 4d 5d[75] 85 5 4e 5e 83

The reaction of 5a–e with the corresponding Grignard reagent in diethyl ether under N2 in the presence of TMEDA gave the consequential tertiary alkylamines 6a–g along with the side product secondary amines 4a–e (Scheme 4).

Scheme 4. Schematic route for the tertiary amines 6a–g via electrophilic amination strategy.

It is reported in the literature that N,N,N’,N’-tetramethylethylenediamine (TMEDA), as an additive, has played a central role in organometallic coupling reactions.[69,76–78] It dramatically accelerates the reactions rates, improves product yields, and alters product distributions.

To show the effect of such additive in our case, a reaction was conducted first between N-tert- butyl-N-isopropylchloroamine (5b) and isopropylmagnesium chloride at room temperature without any additive. The results proved disappointing under all conditions screened. The NMR spectra confirm the formation of the desired product N,N-diisopropyl-N-tert-butylamine (6b) in 4% yield and N-tert-butyl-N-isopropylamine (4b) as a side product in 20% yield. Indeed, the yield of this reaction is very low. Likewise, other tested organometallic reagents such as RMgBr, RMgI,

RLi, R2CuLi, and R2Zn proved ineffective. The same reaction was conducted between N-tert- butyl-N-isopropylchloroamine (5b) and isopropylmagnesium chloride with 10 equiv. of TMEDA as an additive; then, the results proved promising through which a great enhancement in the yield of the desired tertiary amine 6b has been achieved (46%) (Scheme 5).

Scheme 5. Effect of TMEDA on the outcome yield of the electrophilic amination reaction.

Papers dealing with the effect of TMEDA on Grignard reagents are rare, but that dealing with the effect of TMEDA on organolithium reagents are numerous.[76–80] A study done by Bauer and co-workers on some organolithium compounds shows that most of the alkyl lithium compounds are hexameric-tetrameric in hydrocarbon solvents, dimeric in diethyl ether and dimeric-monomeric in THF.[79] In the same paper, it’s mentioned that the addition of chelating ligands such as TMEDA convert all dimers to monomers. Furthermore, the relation between aggregation and reactivity in organolithium chemistry is represented by Collum[80] in Figure 3.

Figure 3. Relationship between aggregation and reactivity in organolithium chemistry.

In his study, concerning the role of TMEDA in organolithium chemistry, Collum mentions that the detection of lower aggregates foreshadows high reactivity.[80] Such discussion could also be applicable in the case of Grignard reagents in the presence of TMEDA, which lowers aggregations and increases reactivity. Nakamura and co-workers suggest another description for the role of TMEDA in the amination reaction of arylmagnesium compounds with N-chloroamines.[69] They postulated in a published study in 2010 that the Grignard reagents in the absence of TMEDA have two ways to coordinate with N-chloroamine. It could be either nitrogen-coordinated complex A or chloride- coordinated complex B (Scheme 6). Complex A gives rise to electrophilic chlorination via transition state TSA which yields unwanted product, and complex B gives rise to electrophilic amination of Grignard reagent via transition state TSB which yields the target product (Scheme 6). According to this group,[69] the density functional theory calculations suggest that complex A is 8.5 kcal/mol more stable than complex B, which can account for the dominant formation of the unwanted aryl chloride product instead of the desired tertiary amine.

Scheme 6. Postulated role of TMEDA in organomagnesium electrophilic amination reaction.

However, in the presence of TMEDA, the Grignard reagent forms complex C (Scheme 6). Electrophilic amination, thus, can take place predominantly via transition state TSC which can be stabilized by electrostatic interaction between the negatively charged chloride atom of N- chloroamine and the magnesium atom.

Other additives such as N,N,N′,N′-tetramethylpropanediamine (TMPDA), N,N,N',N'- tetramethylnaphthalene-1,8-diamine (proton sponge), diazabicyclo[2.2.2]octane (DABCO), N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDTA), and 1,2-dimethoxyethane (DME) have been tested, but they have not been employed effectively in this electrophilic amination reaction. Hence, in the following study we choose TMEDA as the additive.

To study the effect of solvent in this electrophilic amination reaction, we conducted a reaction between N-tert-butyl-N-isopropylchloroamine (5b) and isopropylmagnesium chloride in different solvents (Table 2). The yield of 6b is practically the same in n-pentane and diethyl ether, but it drops in THF.

Table 2. Effect of solvent in organomagnesium electrophilic amination reaction. Entrya Solventb Yield of 6b (%) Yield of 4b (%)

1 n-pentane 48 13 2 diethyl ether 46 13 3 THF 37 16

a Reaction was carried out between 5b and isopropylmagnesium chloride in the presence of 10 equiv. TMEDA at room temperature. b The commercially available Grignard reagent is a solution in THF. The solvent was removed under vacuum followed by a direct replacement, under N2, of the tested solvent.

Furthermore, n-pentane and diethyl ether are better than THF not only by enhancing the yield of the desired product 6b, but also by suppressing the ratio of the side product 4b over the desired product 6b (Figure 4). The drop in yield of 6b that occurs in the case of THF could be explained by the postulated mechanism given in Scheme 6. Accordingly, THF can compete with TMEDA and favors the formation of TSA which yields the side product 4b instead of the desired product 6b.

a b

Figure 4. . 1H NMR spectra of the reaction mixture that show the integration ratio between 6b (peak at δ = 3.18 ppm) and 4b (peak at δ = 2.78 ppm) with different reaction solvents. a: Reaction in THF; b: Reacton in diethylether.

The reaction between N-tert-butyl-N-isopropylchloroamine (5b) and isopropylmagnesium chloride in diethyl ether was conducted at different temperatures, namely, –70 C, –40 C, –20 C, 0 C, 25 C, and 70 C, for screening the appropriate temperature of the present reaction (Table 3). Indeed, the reaction proceeded sluggishly at –70 C, –40 C and –20 C to give traces of the desired product 6b. However, performing the reaction at 0 C or 25 C considerably improved the formation of 6b and suppressed the undesirable formation of 4b, with no considerable difference to be mentioned between these two temperatures. The reaction at 70 C has been done in an autoclave. Indeed, going up to such temperature was worthless and no enhancement in the yield was observed. Thus, in this study, room temperature is chosen to be the optimum temperature.

Table 3. Optimization of reaction temperature using 5b and isopropylmagnesium chloride. entrya TMEDA (X equiv) Temp (C) Yield of 6b (%) Yield of 4b (%)

1 – –70 <1 <1 2 10 –70 <1 5 3 10 –40 <1 8 4 10 –20 <5 10 5 10 0 46 15 6 – 25 4 10 7 10 25 46 15 8 10 70 40 18 a Reactions were carried out on a 3.7 mmol scale and 2.0 equiv. of Grignard reagent in Et2O.

We assumed that using different aminating agents might provide substantial increase in the yield of the desired product. O-Benzoyl-N,N-diisopropylhydroxylamine (7) was tested instead of N,N-diisopropylchloroamine (5a) as aminating agent for isopropylmagnesium chloride in the

28 presence of TMEDA (Scheme 7). Despite the ease of synthesis and stability of compound 7, this compound proved ineffective in the amination of sterically hindered alkylmagnesium reagents.

Scheme 7. Attempt of electrophilic amination of Grignard reagent with O-benzoyl hydroxylamine 7. 1.2 Preparation of Various (tert-Alkyl)-Based Tertiary Amines.

The present amination reaction is applicable to a variety of sterically hindered N,N-dialkyl- N-chloroamine and sterically hindered alkylmagnesium chlorides (Table 4).

Table 4. Scope of N-chloroamines and alkylmagnesium reagents.

Entry N-Chloroamines Nucleophilea Product Yield of 6 (%) Yield of 4 (%)b

1 5a R3 = iPr 6ac 25 <1 2 5b R3 = iPr 6b 46 14 3 5a R3 = t-Bu 6b 11 9 3 d 4 5c R = iPr 6c 32 16 5 5b R3 = t-Bu 6cd <3 7 6 5d R3 = iPr 6de 26 41 7 5e R3 = iPr 6e 19 35 3 8 5e R = cPn 6f 25 30 9 5e R3 = cHx 6g 22 34

a 2.0 Equiv. of Grignard reagent was used. b The yield of the corresponding secondary amine side product. c Compound 6a is a known compound.[81] d,e Compounds 6c and 6d were synthesized, via other methods, and fully characterized by my colleagues: Mr. T. Pester and Dr. A. Ihle, respectively.

We were successful in synthesizing extremely sterically hindered tertiary amines via this TMEDA- based electrophilic amination protocol. This gave access to wide array of tertiary amine products holding two tert-alkyl groups and one sec-alkyl group, which are readily purified by vacuum condensation (Table 4).

N-Chloro-N,N-diisopropylamine (5a) smoothly reacted with isopropylmagnesium chloride at room temperature to give the corresponding triisopropylamine (6a) in 25% yield as the only product (entry 1). Knowing that 5a is less sterically hindered than 5b, the lower yield observed in the case of 6a than 6b (entries 1, 2) might be explained by the loss due to the high volatility of the starting material 5a as well as the product 6a. The reaction between N-chloro-N,N- diisopropylamine (5a) and tert-butylmagnesium chloride gave the desired product 6b (11% yield) and N,N-diisopropylamine (4a) as a side product (entry 3). Despite the low yield observed, this reaction proves that tert-butylmagnesium chloride, which considered from the highest sterically hindered Grignard reagents, is also utilizable using this methodology. Another point could be observed from Table 4 through which the ratio of the side product to that of the desired product increases sharply with steric hindrance.

N,N-Di(tert-pentyl)amine 4e was synthesized via modified literature procedure (Scheme 8).[82] The hydrogenation step was not as straightforward as anticipated. Indeed, the hydrogenation of such secondary amine cleaves the C–N bond, instead, to yield predominantly tert-pentylamine in parallel with the desired product 4e. The latter was isolated by vacuum condensation.

Scheme 8. Overall synthetic route of compounds 6e–g.

It’s noteworthy to mention that the side product secondary amines 4a–e can be recovered in the purification step via distillation. Indeed, new route toward the tertiary amines 6a–g could be performed from the recovered secondary amines 4a–e, and this makes the overall conversion yield higher. In particular example, the recovered secondary amine 4e increased the overall yield of 6e from 19% to 27% (Scheme 8). The new compounds 6e–g represent considerable examples of reliable open-chained highly sterically hindered tertiary alkylamines. The high steric hindrance among these compounds restricts rotation of the C–N bond at room temperature. Hence, at room temperature, the 1H NMR as well as the 13C NMR spectra of compounds 6e–g exhibit two nonequivalent sets of peaks for the hydrogen and carbon atoms, respectively, for the tert-amyl groups (Supporting Information). The presence of two different tert-amyl groups, in the same compound, can only occur if the rotation is restricted among the C–N bond of the iPr, cPn, or cHx group (Figure 5). This is signifying clearly that these compounds accommodate extreme steric hindrance to the extent that the rotation is restricted at room temperature and even at higher temperatures. The two rotamers in the case of compounds 6e–g are of equivalent energies due to the symmetry that the molecule comprise; thus, they exist in equal ratio 1 : 1, and this can be realized clearly from the integrations in 1H NMR spectrum. When it comes to the tertiary amine 6d, the two rotamers are nonequivalent in energy. In this case, the 1H NMR spectrum is more complicated through which the tert-butyl group shows two nonequivalent peaks, the tert-amyl group shows two nonequivalent sets of peaks, and the isopropyl group shows two nonequivalent sets of peaks. From the integrations in 1H NMR spectrum, the two rotamers of 6d exist in slightly equivalent ratio ̴ 1 : 1 which could be explained by the small difference in bulkiness between the tert-butyl- and the tert-amyl groups.

Figure 5. Descriptive structures which shows the origin of two rotamers in compounds a) 6e–g; b) 6d.

Most sterically hindered tertiary amines undergo Hofmann-type elimination reaction upon thermolysis at 100 C in inert solvents, like toluene. From our experiments in this manner, we deduced that the tert-alkyl groups are the reactive groups that undergo such elimination. Moreover,

31 from these experiments, we deduced that as steric hindrance around the nitrogen increases, the elimination rate increases (t1/2 decreases). Compounds 6c–g undergo such elimination process upon subjecting them to 100 C for several days in toluene, through which a tert-butyl- or tert- amyl group was eliminated from the compounds (Scheme 9). Further details regarding the t1/2 of these compounds as well as other compounds will be described later on in another section.

Scheme 9. General thermolysis path of the highly sterically hindered tertiary amines 6c–g.

1.3 Preparation of the Novel 2-(tert-Butyl)-1,1,3,3-Tetramethylisoindoline (12b), 2-(tert- Butyl)-1,1,3,3-Tetraethylisoindoline (12d), and Related Compounds.

An extreme level of steric tolerance was achieved with this modified electrophilic amination protocol, as evidenced by the coupling of sterically hindered 2-chloro-1,1,3,3-tetraalkylisoindoline 11a, b with the sterically hindered t-BuMgCl. This method shows a straightforward synthetic route for the preparation of two novel extremely sterically hindered N,N,N-tri(tert-alkyl)amines, namely, 2-(tert-butyl)-1,1,3,3-tetramethylisoindoline (12b) and 2-(tert-butyl)-1,1,3,3-tetraethylisoindoline (12d). Herein, the synthesis of these unprecedented tertiary amines as well as other isoindoline- based compounds will be described with their structural features and properties.

N-Benzylphthalimide (8) was obtained quantitatively by refluxing phthalic anhydride and benzylamine in acetic acid for 1 h, according to a literature method.[83] Alkylation of N- benzylphthalimide with Grignard reagents, namely, MeMgI and EtMgI in refluxing toluene under

N2 gave the corresponding 2-benzyl-1,1,3,3-tetramethylisoindoline (9a) and 2-benzyl-1,1,3,3- tetraethylisoindoline (9b) in moderate yields (Scheme 10).[84,85] Debenzylation of 9a, b catalyzed by 10% Pd/C under H2 in AcOH produced 1,1,3,3-tetramethylisoindoline (10a) and 1,1,3,3- tetraethylisoindoline (10b) in good yields.[85,86] The N-chlorination of 10a, b was performed

32 successfully with good yields by using N-chlorosuccinimide to give 2-chloro-1,1,3,3- tetramethylisoindoline (11a) and 2-chloro-1,1,3,3-tetraethylisoindoline (11b), respectively. The N-chloroamines 11a, b are new compounds, which were prepared via the general chlorination method used in this study.[73] The main novel step in this long route is the electrophilic amination of 11a, b to the corresponding tertiary amines. This was accomplished with the appropriate alkyl Grignard reagent, namely, isopropylmagnesium chloride and tert-butylmagnesium chloride in the presence of TMEDA (10 equiv.) at room temperature. The amination step proceeded successfully, and it yielded the desired tertiary amines 12a–d along with the corresponding secondary amines 10a, b as side products (Scheme 10).

Scheme 10. Overall synthetic route of compounds 12a–d.

These results offer a complement to the sterically hindered tertiary amines prepared by this modified electrophilic amination method in the previous part of this chapter. These results prove that the preparation of N,N,N-tri(tert-alkyl)amine is possible using this methodology. Although the yields of 12b, d are low compared to other entries in Table 4, the simplicity of two-step process starting from the corresponding secondary amine represents an attractive route to these unprecedented N,N,N-tri(tert-alkyl)amines. Indeed, it is not surprising that the yield in the case of 12a, c is moderate, but it is low in the case of 12b, d due to the high steric hindrance that these compounds accommodate. Compounds 12a–d are new products and synthesized via a new procedure. Compound 12c was found to be reported by Heidenbluth and co-workers in 1964.[87] However, no sufficient data are reported which really indicate the presence of this product. Indeed, no NMR data, no mass spectroscopy, no complete elemental analysis (only the %N is mentioned) are reported. The reported evidence is just a m.p. of 134 C, but our experimental data proved a m.p. of 145 C!

Compounds 12a–d exhibited appreciable stabilities under high temperatures through which no any decomposition was noticed up to 120 C for 30 days in inert solvents, such as toluene. However, complete loss, which might be due to decomposition, was observed when these compounds were subjected to silica gel chromatography. Purification was only possible via basic aluminum oxide chromatography. Consequently, it is possible that the yields of these products would be higher than what is reported if we consider the loss occurred in the purification step.

Surprisingly, 1,1,2,3,3-pentaethylisoindoline (12e) was obtained as a side product from the reaction between 11b and tert-butylmagnesium chloride in parallel with the desired product 12d in a ratio of 60 : 40, respectively (Scheme 10). This was indicated from the NMR spectra. To verify its formation, compound 12e was synthesized separately from the reaction between 11b and ethylmagnesium chloride in the presence of TMEDA. As expected, the NMR data are fully compatible with that in the mixture. So far, many attempts were done to separate 12d from 12e, but all were unsuccessful due to the comparable hydrophobicity of both compounds.

No clear mechanism explains the formation of 12e. The formation of such side product wasn’t observed with other similar reactions. It seems that the system in this case bears huge steric hindrance; thus, decompositions and side reactions become preferable. Some experiments have been performed to recognize the source of the ethyl group which yields compound 12e or to suppress its formation. a. The reaction was done absolutely in THF, without any trace of diethyl ether. However, compound 12e was still obtained. b. The reaction was done at low temperature (–10 C). The 1H NMR spectrum indicates the formation of compounds 12d, e. c. The reaction was performed by replacing 2-chloro-1,1,3,3-tetraethylisoindoline (11b) with 2-bromo-1,1,3,3-tetraethylisoindoline. Compound 12e was still observed. d. The reaction was performed with tert-butylmagnesium bromide instead of tert- butylmagnesium chloride. Compound 12e was still obtained. e. The reaction was performed with tert-butyllithium, at –78 C, instead of tert- butylmagnesium chloride. The only isolated product was the secondary amine 11b, but compounds 12d, e were not observed.

Thus, the only possible source for the ethyl group is either the reactant 11b or the product 12d. Actually, all the performed effort to suppress the formation of the inseparable side product 12e proved unsuccessful.

To the best of our knowledge, no any example is reported in the literature shows that tert-butylmagnesium halides can be used in electrophilic amination processes. This work shows that tert-butylmagnesium chloride can be used in electrophilic amination as well as in the formation of one of the extremely sterically hindered tertiary amines 12b, d ever known.

1.4 Preparation of Novel Extremely Sterically Hindered Bridgehead-Bonded Tertiary Alkylamines.

The developed TMEDA-based electrophilic amination reaction is quite general. It allows the facile preparation of wide variety of sterically hindered tertiary alkylamines. Likewise, the coupling between various Grignard reagents and sterically hindered 1-adamantane-based

N-chloroamines proceeded extensively in moderate yields. This resulted in the preparation of diverse novel extremely sterically hindered 1-adamantane-based tertiary amine derivatives (Scheme 11). Various structural features and properties of these unprecedented compounds are described. The structures of all newly synthesized products were fully characterized by 1H NMR, 13C NMR, melting point, and elemental analysis/HRMS.

Scheme 11. Schematic route for the tertiary amines 15a–g via the electrophilic amination strategy.

Di(adamantan-1-yl)amine (13) was prepared by a single-step literature method, involving the reaction of 1-bromoadamantane and 1-adamantanamine, in good yield (Scheme 12).[88] The chlorination of 13 was performed successfully in good yield by using N-chlorosuccinimide to give N,N-di(adamantan-1-yl)-N-chloroamine (14) (84% yield). As a preliminary test, N,N-di(adamantan-1-yl)-N-chloroamine (14) was reacted with isopropylmagnesium chloride in the presence of TMEDA. Initial results with such N-chloroamine, accommodating extreme level of steric hindrance, proved encouraging. The reaction gave the desired product 15c in moderate yield (30%) along with the side product 13 (Scheme 12).

Scheme 12. Synthetic route of compound 15c.

Apart from such promising results, N-tert-butyl-N,N-di(adamantan-1-yl)amine (15h) proved difficult to synthesize. Indeed, the reaction of N,N-di(adamantan-1-yl)-N-chloroamine (14) with tert-butylmagnesium chloride in the presence of TMEDA was quite unsuccessful (Scheme 13). This result proved disappointing, and it became clear that the synthesis of an open chained N,N,N-tri(tert-alkyl)amine is not straightforward following this amination protocol.

Scheme 13. Attempt for the preparation of compound 15h.

J. B. Miller[89] alleged in a paper dealing with photoinduced electron-transfer substitution reactions that he synthesized bridgehead tertiary amines, namely, N-tert-butyl-N,N-di(adamantan- 1-yl)amine (15h) and N-methyl-N,N-di(adamantan-1-yl)amine (15a). His method is based on irradiating 1-bromoadamantane and tert-butyl- or methyl amine by using a 1000 W Hg/Xe lamp. Indeed, Miller discussed in his confusing paper that his work is dealing with secondary amines, but he stated in the experimental part that the synthesized products are the tertiary amines 15a, h. However, from our built-up knowledge on sterically hindered tertiary amines, we can surely say that the reported NMR data can’t be matched with compounds 15a, h for the following reasons: 1) the chemical shift of the NMR peaks are comparable to secondary amines; 2) the integrations in the 1H NMR don’t match with the actual number of the hydrogen atoms of 15a, h, but it matches with secondary amines; 3) the reported peak (1H, broad) at 2.3 ppm can’t be matched with any hydrogen in compound 15h. To add further proof, compound 15a was easily synthesized following our amination protocol starting from N,N-di(adamantan-1-yl)-N-chloroamine (14) and methylmagnesium chloride in the presence of TMEDA (Scheme 11). The comparison between the NMR data of our synthesized product 15a with that reported by Miller showed that Miller doesn’t have the tertiary amine 15a. Hence, this description is enough to definitely say that Miller didn’t prepare compounds 15a, h, and his study is ambiguous, and based on unclear compounds.

In an effort aimed at enhancing the practicality of the reported TMEDA-based electrophilic amination protocol and in a way to further increase the steric hindrance around the nitrogen atom, we envisioned to aminate various highly sterically hindered Grignard reagents with the highest sterically hindered N,N-di(adamantan-1-yl)-N-chloroamine (14). In fact, it is not an easy task to compare the bulkiness of various alkyl groups, mainly when it comes to the comparison between an open chain alkyl group and a cyclic one. Four main steric parameters which deal with group bulkiness are reported in the literature, namely,

a steric substituent constant “Es”, Charton’s “υ” values, Meyer’s “V ” values and the axial strain values “A-value” (Table 5).

Table 5. The various steric parameters for some alkyl groups.[90-96] [90] [91,92] [91,92] a 2 [91,92] [93-96] Group Es (Taft) Es (Taft) υ V (x 10 ) A-value(kcal/mol)

H 1.24 0.00 0.00 – 0.00 Methyl 0.00 –1.24 0.52 2.84 1.7 Ethyl – –1.31 0.56 4.31 1.75 Isopropyl –1.08 –1.7 0.76 5.74 2.15 Cyclobutyl –0.67 – – – – Cyclopentyl –1.12 – – – – Cyclohexyl –1.40 –2.03 0.87 6.25 2.15 t-Bu –1.54 –2.78 1.24 7.16 >4 Neopentyl – –2.98 1.34 5.75 2 Ph –2.55 – – – 3 1-Ad – – 1.33 – –

a The first three steric parameters (Es, υ, V ) are functions of the size, the van der waals radii or the volume of the group. The “A-values” are derived from the conformational energy measurements of a monosubstituted cyclohexane ring (Figure 6). As an example, the “A-value” for a methyl group is 1.7 as derived from the chemical equilibrium shown in Figure 6 which means that the molecule requires 1.7 kcal/mol of energy to rotate from the equatorial to the axial position.

Figure 6. Conformational equilibrium of monosubstituted cyclohexane.

All of these parameters give unambiguous picture that the trend of bulkiness goes from methyl- to ethyl- to isopropyl- to tert-butyl group (Table 5). However, what is ambiguous is that according to “Es” and “υ” values the neopentyl group is bulkier than the tert-butyl group, but smaller according to the “Va” and “A-values”. To clarify this, neopentylmagnesium chloride was prepared starting from neopentyl chloride and magnesium turnings following a regular literature procedure.[97] Then, the freshly prepared Grignard reagent was sequentially added to N,N-di(adamantan-1-yl)-N-chloroamine (14) in the presence of TMEDA. Likewise, the reaction proved effective, and N,N-di(adamantan-1- yl)neopentanamine (15d) was obtained successfully in 36% yield (Scheme 14).

Scheme 14. Synthetic route of compound 15d.

The formation of compound 15d in moderate yield (36%), which is even higher than the yield in the case of isopropylmagnesium chloride (15c; 30% yield), means that the neopentyl group can

[91,92] never be bulkier than the tert-butyl group as reported according to “Es” and “υ” values. Accordingly, one might figure out that “Va” and “A-values” could be more reliable in some cases.

Once more to Table 5, the “Es” values show that the cyclopentyl group as well as the cyclohexyl group are bulkier than the isopropyl group. Moreover, all the other steric parameters (υ, Va, A-values) show that the cyclohexyl group is comparable or bulkier than the isopropyl group. For that, it is precious to conduct the amination of these Grignard reagents with N,N-di(adamantan- 1-yl)-N-chloroamine (14).

Consequently, the amination reaction of 14 with cyclopentyl- or cyclohexylmagnesium bromide in the presence of TMEDA gave the corresponding N,N-di(adamantan-1- yl)cyclopentanamine (15e) and N,N-di(adamantan-1-yl)cyclohexanamine (15f), respectively, along with the side product secondary amine 13 (Scheme 15).

Scheme 15. Synthetic route of compounds 15e, f.

Unless at very low temperatures or other complicated conditions, it is not an easy task to perform X-ray crystallography for tertiary alkylamines because these compounds are usually of low melting point. Reliable highly sterically hindered tertiary alkylamines as well as their X-ray crystallography are very rare and even invalid in the literature. Accordingly, we are interested in performing X-ray crystallography for some of our synthesized extremely sterically hindered amines to study thoroughly some features of these unprecedented compounds. Fortunately, the presence of one or two adamantyl groups in our synthesized products increase considerably the melting point of these products. This makes it easier to crystallize such compounds. Then, we were successful in growing up some crystals of compound 15f suitable for X-ray crystallography course (X-ray diffraction was performed by Dr. M. Wӧrle, ETH, Zürich) (Figure 7). A distinguishing feature could be noticed in this X-ray. The X-ray just shows one conformer through which N1C1H1 is in the same plane of N1C17C19 and N1C7C9. The three inplane arcs are oriented in an anticlockwise direction (Figure 7). This could happen to minimize the steric hindrance among the various substituents in the molecule.

a As mentioned previously, all the steric parameters (Es, υ, V , A-values) show that the cyclohexyl group is comparable or more sterically hindered than the isopropyl group. Without any doubt, the replacement of the cyclohexyl group with 2-norbornyl group will further increase the steric hindrance around the amino group. Hence, the reaction was extended to such higher level of

40 steric hindrance by aminating 2-norbornylmagnesium bromide with N,N-di(adamantan-1-yl)-N- chloroamine (14).

Figure 7. Molecular structure of compound 15f from single crystal X-ray diffraction.

2-Norbornylmagnesium bromide was prepared via a literature procedure staring from exo- 2-bromonorbornane and magnesium turnings (Scheme 16).[97] This general method yields a mixture of endo and exo-2-norbornylmagnesium bromide. Subsequently, the freshly prepared 2-norbornylmagnesium bromide solution was added to N,N-di(adamantan-1-yl)-N-chloroamine (14) in the presence of TMEDA (Scheme 16).

Scheme 16. Synthetic route of compound 15g-exo.

It is expected that the outcome of such reaction will yield two stereoisomers, namely, exo and endo N,N-di(adamantan-1-yl)bicyclo[2.2.1]heptan-2-amine (15g-exo, 15g-endo). However, the NMR data verify the formation of one stereoisomer of compound 15g. As known about the norbornane system, the exo side is less sterically hindered and more likely to react, mainly with highly sterically hindered substrates, than the endo side. Hence, it was suggested that our formed product is the N,N-di(adamantan-1-yl)exo-bicyclo[2.2.1]heptan-2-amine (15g-exo) (Scheme 16).

Indeed, it is not an easy task to prove the stereoisomerism of compound 15g from the NMR data due to the complex number of hydrogen atoms in the molecule (41 hydrogen atoms) and the overlap between all of these protons. However, the multiplicity of the peak at 3.26 ppm might be useful. According to Jensen,[98] endo-2-norbornylmagnesium bromide shows a multiplet peak in the 1H NMR spectrum for the deshielded hydrogen near the magnesium atom. Whereas, the same hydrogen shows a triplet peak in the 1H NMR spectrum for the case of exo-2-norbornylmagnesium bromide. If this is applicable in our case, then, the formed isomer of 15g is the exo isomer because the deshielded hydrogen shows a triplet peak in the 1H NMR spectrum.

Moreover, according to Jensen’s method,[98] endo-2-norbornylmagnesium bromide can be obtained as pure isomer by reacting the mixture of 2-norbornylmagnesium bromide with benzophenone at low temperature. Then, the endo-isomer was prepared according to this method followed by its addition to N,N-di(adamantan-1-yl)-N-chloroamine (14) in the presence of TMEDA, under the same previous reaction conditions (Scheme 17). No traces of the expected product (15g-endo) was obtained. Hence, this could be a further proof that 15g-endo is difficult to be formed from this aminating protocol, and that compound 15g was obtained as the exo-isomer.

Scheme 17. Attempt for the preparation of compound 15g-endo.

Compound 15g-exo was obtained in 16% yield (Scheme 16). Despite the moderate yield, compound 15g-exo is a novel compound accommodating extreme steric hindrance around the amino group. Up to now, we can say that compound 15g-exo is the most sterically hindered tertiary-acyclic-alkylamine ever known. Furthermore, as the case with all the previously isolated products, the secondary amines 13 is recovered from the reaction in considerable amount. This can be used again in a new recycling route which makes the overall conversion yield higher. If we consider the case of compound 15g-exo, a recycling process increases the yield from 16% to 22%.

Compounds 15a–g proved good stability under high temperatures through which no any decomposition was noticed up to 120 C for 30 days in inert solvents, such as toluene. Unlike some other tert-butyl or tert-amyl-based tertiary amines, this class of (1-adamantyl)-based tertiary amines illustrates high thermal stability.

By the way, in an attempt to synthesize the extremely sterically hindered N,N-di-tert- pentylbicyclo[2.2.1]heptan-2-amine (6h), the isolated product was the secondary amine 4g instead of the expected product 6h. Compound 4g could be formed from the decomposition of compound 6h, or as a result from small impurity of the tert-pentylamine which form the corresponding chloroamine (Scheme 18). Such impurity might exist throughout the synthetic route for the preparation of di-tert-pentylamine.

Scheme 18. Attempt for the preparation of compound 6h. In polar protic solvents, such as methanol or water, compounds 15c–g proved unstable under high temperatures. The decomposition rate is proportional to steric hindrance and temperature. To exemplify, compound 15g showed complete decomposition after 1 hour in refluxed methanol according to the reaction shown in Scheme 19. 1-Methoxyadamantane and compound 4h were separated by acid/base extraction and characterized by NMR spectroscopy.

Scheme 19. Decomposition route of compound 15g-exo in MeOH. Compounds 15a–g can be acidified then neutralized without showing any significant decomposition; however, complete lose was observed when these compounds were subjected to silica gel chromatography or acidic aluminum oxide chromatography. Due to the high hydrophobicity of these compounds, washing with warm methanol is sufficient to yield analytically pure products.

At room temperature, the 1H NMR as well as the 13C NMR spectra of compounds 15c, e–g exhibit two nonequivalent sets of peaks for the hydrogen and carbon atoms for the 1-adamantyl groups (Supporting Information). The asymmetry in these compounds can only occur when the rotation around the C–N bond for the iPr, cPn, cHx, or norbornyl group is restricted. Indeed, these compounds accommodate extreme steric hindrance to the extent that the C–N bond is restricted

44 from rotation at room temperature and even at higher temperatures. This is signifying clearly that these compounds reside as two rotamers at room temperature. In this case, the two rotamers are of equivalent energies, and they exist in equal ratio 1 : 1.

1.5 Preparation of N-(tert-Butyl)-N-isopropyladamantan-1-amine (18).

Because of the fact that the tert-butyl group as well as the 1-admantyl group are two of the bulkiest groups, we carried on a synthetic course for the preparation of N-(tert-butyl)-N- isopropyladamantan-1-amine (18) through which the nitrogen atom holds three diverse groups, and at the same time it still shows high steric hindrance. The asymmetry in this molecule would be interesting for NMR studies which will be discussed later on.

Following our aminating protocol, compound 18 was prepared via the sequential addition of N- (tert-butyl)-N-chloroadamantan-1-amine (17) to a solution of isopropylmagnesium chloride and TMEDA. N-chloroamine (17) was synthesized successfully via the N-chlorination of N-(tert- butyl)adamantan-1-amine (16) by N-chlorosuccinimide. The secondary amine 16 was prepared in moderate yield (46% yield) following a literature procedure,[99] via the reaction between tert- butylmagnesium chloride and 1-nitroadamantane followed by a reduction step (Scheme 20).

Scheme 20. Overall synthetic route of compound 18.

The structure of the synthesized product 18 was characterized by 1H NMR, 13C NMR, melting point, and HRMS.

As mentioned previously, we are interested in performing X-ray crystallography for some of our synthesized extremely sterically hindered tertiary amines to study thoroughly some features of these unprecedented compounds. Fortunately, we were successful in growing up crystals of compound 18 suitable for X-ray crystallography course (X-ray diffraction was performed by Dr. M. Wӧrle, ETH Zürich) (Figure 8). Furthermore, the molecular structure of 18 shows the same feature which was discussed for the structure of 15f in page 40, through which the inplane arcs formed by N1C15H15, N1C1C6 and N1C11C12 are all oriented in a clockwise direction (Figure 8).

Figure 8. Molecular structure of compound 18 from single crystal X-ray diffraction. As the case with some previously reported highly sterically hindered tertiary amines, compound 18 exhibits a restriction in C–N bond rotation at room temperature, owing to the high steric hindrance that it gathers. However, what is more interesting in this case is that this restriction in rotation gives rise to two rotamers with different energy content. These two non-equivalent rotamers of compound 18 are most likely arisen from the constrained rotational barrier of the isopropyl group, through which the “isopropyl-hydrogen” (CH(CH3)2) can be oriented either in the direction of the tert-butyl group or toward the admantyl group (Figure 9).

Figure 9. The two suggestible rotamers of compound 18.

The 1H NMR and 13C NMR spectra show clearly the presence of two complete sets of peaks (Figure 10). The 1H NMR spectrum shows a major septet at δ = 3.52 ppm and a minor septet at δ

= 3.44 ppm, which corresponds to “CH(CH3)2”. The spectrum shows a major singlet at δ = 1.38 ppm and a minor singlet at δ = 1.29 ppm, which corresponds to “C(CH3)3”. The same for the doublet peak of “CH(CH3)2”, the spectrum shows one major doublet at δ = 1.32 ppm and one minor doublet at δ = 1.37 ppm. It’s difficult to differentiate the two sets of the admantane’s hydrogen atoms due to the broadness of these peaks, but the integrations of these peaks confirm the overlapping of the two sets.

1 Figure 10. Sectioned H NMR spectrum (600 MHz, toluene-d8) of compound 18. 1: Major rotamer peaks (assigned as H1, H2, H3); 2: Minor rotamer peaks (assigned as H1’, H2’, H3’).

To verify that these two sets of peaks are corresponded to two rotamers, but not to other isomers, the 1H NMR spectrum of compound 18 was taken at higher temperatures. The peaks broaden, coalesce, and finally one set of peaks was observed at elevated temperature (99 C) (Figure 11). This indicates a conformational exchange which yields a chemical shift equivalence of the average structure at high temperatures.

99 °C 99 °C

75 °C 75 °C

50 °C 50 °C

r.t. r.t.

1 Figure 11. Sectioned H NMR spectrum (400 MHz, toluene-d8) of compound 18 at different temperatures.

Furthermore, decoupled 1H NMR spectrum gives further evidence through which it indicates that the suggested peaks of the major or minor rotamer are correlated. Indeed, an irradiation for the septet peak (CH(CH3)2) at δ = 3.52 ppm of the major rotamer converted the doublet peak (of the coupled CH(CH3)2) at δ = 1.32 ppm to a singlet peak (Figure 12a). The same was observed when the septet peak CH(CH3)2 at δ = 3.44 ppm was irradiated to yield a singlet peak at δ = 1.37 ppm instead of a doublet (of the coupled CH(CH3)2) (Figure12b).

1 Figure 12. Decoupled H NMR (400 MHz, toluene-d8) of: a) major rotamer b) minor rotamer of compound 18. 1: decoupled spectrum; 2: original spectrum. All the previously mentioned tertiary amines that show restriction in rotation exist as two equivalent rotamers (1 : 1) or nearly equivalent as the case with 6d (1 : 0.95). However, in the case of compound 18, the integrations in 1H NMR spectrum indicates the presence of two nonequivalent rotamers with big different ratio (5 : 1). This indicates the small bulkiness difference between a tert-butyl group compared to tert-amyl group, but the faraway difference in bulkiness between a tert-butyl group compared to 1-adamantyl group.

If we consider that 1-adamantly group is bulkier than tert-butyl group, then we can assign the following structures for the major and minor rotamers of compound 18 (Figure 13). This is because the hydrogen atom (CH(CH3)2) in the isopropyl group prefers to be oriented in the direction of the bulkier 1-admantyl group, and the larger methyl group (CH(CH3)2) to be oriented in the direction of the less bulky tert-butyl group.

Figure 13. a) Expected major rotamer of compound 18. b) Expected minor rotamer of compound 18.

In fact, many evidences provide that the 1-adamantly group is bulkier than tert-butyl group as well as the suggested structures in Figure 13 are accurate. 1- The comparison of the Charton steric parameter “υ” given in Table 5 for the 1-Ad group (1.33) to the t-Bu group (1.24) indicates that 1-Ad group is bulkier than t-Bu group.[91] 2- A study was performed by our group member (J. Seifert-PhD work), based on reactivity and yields of secondary amines with allenyl isothiocyanate, showed that amines with tert- butyl group are more reactive than those with 1-adamantly group (factor of reactivity is around 120 : 72) just because the latter group is bulkier. 3- Logically, the X-ray crystallography must detect the structure of the major rotamer when the minor rotamer exists in tiny amount. Indeed, the X-ray structure is compatible with the suggested structure of the major rotamer “a” (compare Figures 8 to Figure 13). 4- NOESY NMR experiment can assist in clarifying such problem, but such experiment is not straightforward in our case due to the interference of the peaks of the two rotamers. However, after an extensive effort, we were able to suggest that rotamer “a” is the major rotamer and “b” is the minor rotamer. Figure 14 shows the NOESY 1H NMR spectrum of compound 18. Figure 14-a shows the spectrum when the septet peak of the major rotamer at 3.52 is irradiated. When the major septet peak is irradiated (H1), the singlet peak at 1.38

ppm (H2) shows a small intensity. This means that the isopropyl-hydrogen CH(CH3)2 is not oriented in the direction of the tert-butyl group, in the case of the major rotamer. Figure 14-b shows the spectrum when the septet peak of the minor rotamer at 3.45 is irradiated.

When the minor septet peak is irradiated (H1’), the singlet peak at 1.29 ppm (H2’) shows

a high intensity. This means that the isopropyl-hydrogen CH(CH3)2 is oriented in the direction of the tert-butyl group, in the case of the minor rotamer. This proves again that the assigned structures for the major and minor rotamers shown in Figure 13 are accurate.

2 2

1 1

Figure 14. NOESY 1H NMR (600 MHz) spectrum of compound 18. a: Irradiation of H1 (the septet large peak at 3.52 ppm). b: Irradiation of H1’ (the septet small peak at 3.45 ppm). 1: Main spectrum; 2: Irradiated spectrum. Because of the fact that N-(tert-butyl)-N-chloroadamantan-1-amine (17) is a useful precursor for the synthesis of N,N-di-tert-butyladamantan-1-amine (19), we applied the same reaction conditions to carry out an attempt to synthesize such considerable product. However, an electrophilic amination reaction analogous to that used in the preparation of compound 18 failed in giving compound 19 (Scheme 21).

Scheme 21. Synthetic attempt for the preparation of compound 19.

2. Electrophilic Amination of Alkyl Grignard Reagents with N,N-Dichloroamines.

In 1876, in a study for the structure of ethyldichloroamine, Tcherniak reported the formation of a small quantity of triethylamine upon reacting ethyldichloroamine with diethylzinc.[100] Another study dealing with alkyldichloroamines was reported by Coleman.[67] In his paper, he mentioned the reaction of ethyldichloroamine with various alkylmagnesium chlorides

50 of low steric hindrance. The reaction yielded mainly the corresponding primary and secondary amines, but the desired tertiary amine was obtained in very low yield. Thus, the formation of tertiary amines from alkyldichloroamines is known in the literature; however, no any reported example, in this manner, is dealing with sterically hindered ones.

Such route, starting from alkyldichloroamine, might be considered as the most straightforward path for the preparation of symmetrical tertiary amines from primary amines. We initiated our study by conducting a reaction between N,N-dichloroadamantan-1-amine (21) with isopropylmagnesium chloride in the presence of TMEDA, and under the same conditions applied previously in the electrophilic aminating protocol of N-chloroamines. The results proved promising through which the desired tertiary amine N,N-diisopropyladamantan-1-amine (22) was obtained with some side products (Scheme 22). Compound 21 was prepared from 1-adamantylamine and calcium hypochlorite following a literature procedure (Scheme 22).[101]

Scheme 22. The outcome of the electrophilic amination reaction between compound 21 and iPrMgCl.

Although compound 22 was obtained in low yield (12% yield), the simplicity of two step process starting from primary amine represents an attractive route to this unprecedented tertiary amine which is difficult to be prepared by other methods. The formation of 1,2-di(adamantan-1-yl)diazene (23) as a side product was not expected. It is a known compound, and it’s formation was verified by comparing the experimental melting point and the NMR data to that in the literature.[102] The mechanistic path for the formation of the various outcome products is described in Scheme 23.

Scheme 23. Mechanistic path for the formation of compounds 20, 22, 23.

By the way, compound 22 was prepared by analogous route starting from N-chloro-N,N- diisopropylamine (5a) via the sequential addition of 1-adamantylmagnesium bromide in the presence of TMEDA (Scheme 24). Compound 22 was obtained successfully but in low yield (7% yield). Without any doubt, 1-adamantylmagnesium bromide could be considered as one of the highest sterically hindered Grignard reagents, and this explains the obtainable low yield of compound 22 via this method.

Scheme 24. Synthetic route of compound 22 via electrophilic amination between compound 5a and 1-AdMgBr.

In a similar manner, and in an attempt to synthesize the desired N,N-di-tert- butyladamantan-1-amine (19), we carried out an analogous reaction between N,N-dichloroadamantan-1-amine (21) and tert-butylmagnesium chloride in the presence of

TMEDA. However, the reaction proved unsuccessful, and the only isolated products were the azo compound 23, the secondary amine 16, and 1-adamantylamine (Scheme 25).

Scheme 25. Outcome products of the reaction between compound 21 and t-BuMgCl.

3. SN1–Type Reaction between Various Secondary Amines and 1-Adamantyl Cation.

Herein, we report a direct nucleophilic substitution “SN1–type” reaction for the preparation of sterically hindered tertiary amines. This method is based on reacting various secondary amines with 1-Ad cation. The latter was produced in situ from the corresponding 1-adamantyl acetate, 1-adamantyl mesylate or 1-adamantyl triflate (Scheme 26). Salient features of the protocol that will be detailed here include: 1) remarkable tolerance of steric hindrance in the molecules undergoing the reaction; 2) mild reaction conditions (0 °C, 3 h); 3) ease of product isolation/purification (acid-base extractive workup, recrystallization); 4) simple SN1 reaction without the aid of any ligand or transition metal catalysts.

Scheme 26. General SN1 synthetic route for the preparation of (1-Ad)-based tertiary amines.

3.1 Initial Studies.

The idea was initiated from a study described by Carrow and co-workers in 2016.[103] They reported a successful method for the preparation of tri(1-adamantyl)phosphine via an alternative strategy involving an SN1 reaction between di-1-adamantylphosphine and 1-adamantyl acetate. Regardless the big difference between nitrogen and phosphorus atoms such as nucleophilicity, bond length, and size, the success achieved by Carrow in the preparation of extremely sterically hindered phosphine motivated us to develop analogous SN1 reaction for synthesizing sterically hindered tertiary amines. We initiated our study by evaluating the optimum conditions for the reaction under investigation. To start with, a reaction was performed under the same conditions used by Carrow in the production of tri(1-Ad)phosphine.[103] Hence, a reaction was conducted between N,N-diisopropylamine (4a) with 1-AdOAc (25a) and trimethylsilyl trifluoromethanesulfonate

(Me3SiOTf) in dichloromethane (Scheme 27). The results with 4a proved promising, with an unprecedented moderate yield (66%) of the desired sterically hindered tertiary amine.

Scheme 27. SN1 route between 4a and 25a.

To study the performance of the reaction with increasing steric hindrance of the secondary amine, a reaction was conducted between N-tert-butyl-N-isopropylamine (4b) with the same latter mentioned reagents and conditions (Scheme 28).

Scheme 28. SN1 route between 4b and 25a.

The NMR spectra confirm the formation of the desired product N-(tert-butyl)-N- isopropyladamantan-1-amine (18, 24% yield) along with the side product N-isopropyladamantan- 1-amine (20, 20% yield). The formation of the side product 20 was not expected, but not surprising in the case of highly sterically hindered tertiary amine holding a tert-butyl group. Indeed, the formation of compound 20 can only be described as a result of the decomposition of the desired product 18 via Hofmann elimination. Such elimination is favored with heating, in protic solvents, or in the presence of an acid (Scheme 29). Thus, the acidic medium of the reaction, owing to the formation of trifluoromethanesulfonic acid (HOTf), boosts Hofmann elimination of the tertiary amine 18 to yield the secondary amine 20.

Scheme 29. Example on Hofmann elimination of sterically hindered tertiary amines.

So far, many attempts were done to suppress the elimination of the tert-butyl group in compound 18 and to find the optimum conditions of this reaction. The trouble is to quench the acid in the reaction, but at the same time not to quench the reaction itself. As a result, the addition of some soluble bases such as triethylamine, pyridine, and proton-sponge quenched the reaction itself, and we observed a sharp decrease in the yield of compound 18. Ultimately, the addition of 5 equivalents of dry potassium carbonate as well as using 1.5 equivalents of the starting secondary amine showed an auspicious result. Actually, under these condition, the NMR spectra didn’t show the formation of any trace of the decomposed product 20, and a considerable increase in the yield of the desired product 18 was realized (Scheme 30).

Scheme 30. SN1 route between 4b and 25a in the presence of K2CO3.

To study the effect of the solvent, we conducted an analogous reaction to that shown in Scheme 30 between 4b and 25a in different solvents (Table 6).

Table 6. Effect of the solvent on the SN1 reaction shown in Scheme 30. Entrya Solventb Yield of 18 (%)

1 n-hexane 0 2 diethyl ether 4 3 THF 22 4 DCM 46 a Reaction was carried out between 4b (1.5 equiv) and 25a in the presence of 5 equiv. K2CO3 and Me3SiOTf at r.t. b All the used solvents are dry and freshly distilled. n-Hexane seems to be the worst solvent, and this is not surprising as SN1 reactions disfavor non- polar solvents. Moreover, protic solvents can’t be used in such reaction due to their substitution behavior. In fact, DCM is a key solvent in this reaction, and it could be the only practical solvent.

Mechanistically, compound 25a reacts with Me3SiOTf to generate a good leaving group which enhances the formation of 1-Ad cation. The latter can readily reacts with the secondary amine via an SN1 mechanism (Scheme 31).

Scheme 31. Postulated SN1 mechanism for the formation of tertiary amines.

The formation of the carbocation is the rate determining step in an SN1 mechanism. Hence, using better leaving groups rather than the acetate group might improve the viability and the yield of the reaction, by enhancing the formation of 1-Ad cation.

For this issue, compounds 25b–g were prepared following modified literature procedures,[104–107] and their efficacy were compared to compound 25a. This was achieved by conducting analogous

SN1 reactions between 4b and 25a–g (Table 7).

Table 7. Scope of 1-Ad–LG.

entry 1-Ad–LG LG moiety Yield of 18 (%)

1 25a OAca 46 a 2 25b OCOCCl3 0 3 25c OBza 0 a 4 25d OCOC6H3-3,5-(NO2)2 0 5 25e OTs 0 6b 25f OMs 54 7c 25g OTf 63 a These reagents were prepared following the same procedure used to prepare the acetate 25a starting from 1-adamantanol and the corresponding acetyl or benzoyl chloride. b Completion of the reaction was achieved after 3 h. c Me3SiOTf wasn’t added, and completion of the reaction was achieved after 3 h at 0 °C.

Results with 1-Ad–LGs 25b–e (entries 2–5) proved ineffective. However, a dramatic increase in yield was realized when OMs and OTf were employed as leaving groups (entries 6, 7). Indeed, compounds 25f, g engender a higher level of efficiency to the process; thus, we next set out to prepare novel sterically hindered tertiary amines following this protocol by using compounds 25f, g as effective electrophiles.

1-AdOTf (25g) has been prepared following a modified literature procedure by reacting 1-bromoadamantane and silver trifluoromethanesulfonate (AgOTf) in dichloromethane at 0 °C for 3 hours in the dark.[106,107] Without isolation or purification of the unstable product 25g, various secondary amines were added directly to the reaction mixture (Scheme 32). It is noteworthy to

57 mention that Me3SiOTf isn’t necessary to be added to the reaction mixture when 1-AdOTf (25g) is used as electrophile, and the reaction reached completion in 3 h at 0 °C.

Scheme 32. Synthetic route of compound 18 following the SN1 protocol between 4b and 25g. Knowing that a simple acid-base treatment of the reaction mixture can give analytically pure products, and talking about 63% yield in the preparation of sterically hindered tertiary amines such as compound 18 is tremendous in this field.

3.2 Preparation of Various Novel 1-Adamantyl-Based N,N,N-tri(tert-alkyl) Cyclic Amines.

We have described previously the synthetic route of the highly sterically hindered 2-(tert- butyl)-1,1,3,3-tetramethylisoindoline (12b) and 2-(tert-butyl)-1,1,3,3-tetraethylisoindoline (12d) following the electrophilic amination of tert-butylmagnesium chloride with 2-chloro-1,1,3,3- tetramethylisoindoline (11a) and 2-chloro-1,1,3,3-tetraethylisoindoline (11b) in the presence of TMEDA. Compound 12b was obtained in around 5% yield; whereas, compound 12d was obtained in <3% yield with a parallel formation of inseparable side product 12e (Scheme 10). Furthermore, we have verified previously on page 49 that 1-Ad group is considerably bulkier than the tert-butyl group. This suggests that the insertion of 1-Ad group into the secondary amines 10a–d should add further steric hindrance if compared to tert-butyl group added to the same amines.

As a result, we carried on a synthetic course for the preparation of novel extremely sterically hindered tertiary amines, namely, 2-(adamantan-1-yl)-1,1,3,3-tetramethylisoindoline (26a), 2-(adamantan-1-yl)-1,1,3,3-tetraethylisoindoline (26b), 1-(adamantan-1-yl)-2,2,5,5- tetramethyl-2,5-dihydro-1H-pyrrole (26c), and 1-(adamantan-1-yl)-2,2,5,5-tetramethylpyrrolidine

(26d) from the corresponding secondary amine 10a–d in one-step using this SN1 methodology (Scheme 33). The obtainable moderate yields, the ease of preparation, the high level of steric tolerance achieved, and the simplicity of one step process represent an attractive route to these unprecedented extremely sterically hindered tertiary amines 26a–d.

Scheme 33. Synthetic route to products 26a–d via SN1 method.

Up to now, compounds 26a–d can be considered as the highest sterically hindered N,N,N-tri(tert- alkyl)-cyclic-amines ever known in this field. This methodology provides a simple and straightforward access to valuable extremely sterically hindered tertiary amines in moderate yields. In fact, the preparation of extremely sterically hindered tertiary amines in moderate yields

(63-68% in some cases) is considered uncommon in this field, and for the first time such exciting results could be obtained. Compound 26b could be considered as a “world record” in the field of sterically hindered tertiary amines, and the extreme steric hindrance that it accommodates describes the obtainable low yield.

No strong evidence describes the low yield observed in the case of compound 26c if compared to 26d. One might expect that a side reaction on the double bond could occur; however, no any corresponding side product has been detected. This could lead to the postulation that there is an interaction between the π*-orbital of the double bond with the lone pair of the nitrogen; thus, such interaction orients the lone pair in a disfavored direction making it less available to react. The importance of compound 26c is based on the functionality that exists in the ring. Indeed, we supposed that the double bond could be cleaved under mild conditions to yield the desired open- chained N,N,N-tri(tert-alkyl)amine (Scheme 34). This will be studied separately by my colleagues.

Scheme 34. Expected cleavage of the cyclic amine 26c to the acyclic amine 26g or similar compounds.

3.3 Attempts for the Preparation of Sterically Hindered Six-Membered Cyclic Amines.

Several attempts have been conducted for the preparation of 1-(tert-butyl)-2,2,6,6- tetramethylpiperidine (12e) or 1-(adamantan-1-yl)-2,2,6,6-tetramethylpiperidine (26e), via the electrophilic amination method or the nucleophilic SN1 method, respectively, but all ended up with no success (Scheme 35).

Scheme 35. Attempts for the preparation of compounds 12e and 26e.

The only speculation that could explain the failure of the reactions on going from pyrrolidine 10d to piperidine 10e is the enlargement of the ring, which increases the steric hindrance around the nitrogen. However, it is still unclear whether this is the only reason that sharply drops down the yield from 65% in the case of 26d to 0% in the case of 26e.

Another attempt was done by using 3,3,5,5-tetramethylmorpholin-2-one (10f) because we suggested that an sp2 hybridized carbon as well as an oxygen atom might form shorter bonds in the case of 10f than an sp3 carbon in the case of 10e; thus, we might have ring contraction in the case of 10f. Moreover, if the reaction works properly as expected, the lactone functionality in compound 26f could be hydrolyzed or reduced in a next step to the desired acyclic N,N,N-tri(tert- alkyl)amine 26h or related products (Scheme 36).

Scheme 36. Postulated schematic route toward compounds 26f, h.

Lactone 10f was synthesized following a literature procedure, by reacting 2-amino-2- methylpropan-1-ol with acetone and chloroform followed by a cyclization step with the aid of concentrated hydrochloric acid (Scheme 37).[108]

Scheme 37. Synthetic route of compound 10f.

The reaction of lactone 10f with 1-AdOTf (25g) was performed, and two main products were isolated after purification. The NMR data of the first product prove the presence of an adamantyl group connected to the amino lactone 10f moiety; whereas, the NMR data of the second product prove the presence of two adamantyl groups connected to the amino lactone 10f moiety. According to the first product, the chemical shift and the integration of all the peaks in the 1H NMR spectrum fit completely with that expected for the desired product 26f. Likewise, the chemical shift and the number of peaks in the 13C NMR spectrum fit completely with that expected for the desired product 26f except one peak at δ = 80.2 ppm. Nothing can explain the extra deshielding of this peak unless a carbon atom is connected to an oxygen. In another way, it’s expected that the 13C NMR of compound 26f show three quaternary carbon atoms attached to a nitrogen in the region of δ = 50– 65 ppm; however, only two of them are observed at the mentioned region and one is observed at δ = 80.2 ppm. Unfortunately, such discussion can only come to a conclusion that this product is not the desired product 26f, but the opened-ring secondary amine 27a. The same discussion could be applied for the second product, and this can end up with a conclusion that such data fit with the ring-opened secondary amine 27b (Scheme 38).

Scheme 38. Outcome products of the reaction between 10f and 25g.

Indeed, it was not expected that a lactone functionality would cleave out under acidic condition. However, mechanistically, it seems that the highly reactive 1-AdOTf (25g) reacts with the lone pair of the oxygen, but not with the sterically hindered nitrogen (Scheme 39).

Scheme 39. Postulated mechanism for the formation of the unwanted products 27a, b. 3.4 Attempts for the Preparation of N,N-Di-tert-butyladamantan-1-amine (19) and Related Compounds.

The optimization of the reaction conditions and the promising results from the SN1 methodology drive us to conduct a synthetic attempt toward the desired extremely sterically hindered N,N-di(tert-butyl)adamantan-1-amine (19). The reaction was directed by reacting di-tert- butylamine (4c) with various 1-Ad–LG (25a, f, g). However, the results proved disappointing under all conditions screened, and no any trial for its preparation was successful (Scheme 40).

Scheme 40. Attempt for the preparation of compound 19 via the SN1 route.

As a preliminary view, one more methyl group is added by going from the secondary amine 4a to 4b to 4c. Then, the sensible manner that could be expected is a slight drop in the yield of the applied SN1 reaction by going from 4a to 4b to 4c. This is proper by going from 4a to 4b through which a slight decrease in the yield was observed; however, a sharp drop from 63% yield in the case of 4b to 0% yield in the case of 4c is quite doubtful and unconvincing! In fact, it is still unclear whether we are dealing only with steric hindrance problematic issue in the case of compound 19, or other geometrical and instability issues are involved. It is noteworthy to mention the formation of two undesirable products, as an outcome from this reaction, to be aware of any doubt. The first side product is N-(tert-butyl)adamantan-1-amine (16) which was isolated in trivial amount. We thought first that such side product resulted out from the decomposition of the desired product 19 (Scheme 41). However, after several experiments, we concluded that this compound is formed as a result of the reaction between tert-butylamine with the electrophile 25g (Scheme 41). tert-Butylamine is present as an impurity with di-tert- butylamine (4c), and it is a difficult task to remove it completely.

Scheme 41. Source of the formation of the side product 16.

The second side product is O-(adamantan-1-yl)-N,N-di(tert-butyl)hydroxylamine[121] (29) which shows very close analysis data to that expected for the desired product 19.

Indeed, compound 29 shows comparable 1H NMR and 13C NMR spectra with those expected for compound 19. They can only be differentiated by means of the chemical shift of the quaternary carbon attached to an oxygen in the case of 29, which appears at δ = 77.5 ppm; however, the alternative one connected to a nitrogen in the case of 19 must appear around δ = 55–65 ppm.

The formation of compound 29 can be explained as a result of the reaction between the 1-Ad cation and N,N-di-tert-butylamine-N-oxyl (28). The latter is a precursor intermediate in the preparation of N,N-di-tert-butylamine (4c), and might exist as an impurity in the substrate (Scheme 42).

Scheme 42. Source of the side product 29.

1-Adamantyl group is characterized by its rigidity and resistance to decomposition processes. Thus, we have conducted a reaction between N-(tert-butyl)adamantan-1-amine (16) or di(1- adamantyl)amine (13) with 1-AdOTf (25g). However, neither of the two reactions yielded the desired products 15h or 30, respectively (Scheme 43).

Scheme 43. Attempts of SN1 reactions for the preparation of compounds 15h or 30.

Another attempt which can really expose the further bulkiness of the adamantly group in comparison with other groups was performed. As we described previously, a reaction between N-tert-butyl-N-isopropylamine (4b) with 1-AdOTf (25g) proceeded successfully to afford compound 18 in good yield (63%). However, an alternative reaction between N-(adamantan-2- yl)adamantan-1-amine (31) and 1-AdOTf (25g) did not yield the desired product N,N-di- (adamantan-1-yl)adamantan-2-amine (32) (Scheme 44).

Scheme 44. Difference in steric hindrance between 4b and 31. Knowing that the 2-adamantyl group is a secondary group, only one explanation can describe the unsuccessful formation of compound 32 which is the extra bulkiness of the 1-adamantly- or the 2-adamantly groups, if compared to the tert-butyl- or the isopropyl groups, respectively.

Although the synthesis of secondary amines is not our target, but they are the main substrates in our reactions. The syntheses for many of these secondary amines are not straightforward and involve many steps with low yields. Hence, it’s noteworthy to mention here that sterically hindered 1-Ad secondary alkylamines are also accessible using this methodology. For instance, N-(tert-butyl)adamantan-1-amine (16) and N-(adamantan-2-yl)adamantan-1-amine

(31) could be prepared in a simple straightforward way via this SN1 methodology in good yields (Scheme 45).

Scheme 45. Synthetic route to the secondary amines 16 and 31 via the SN1 methodology.

4. SN1–Type Reaction between Various Imines and 1-Adamantyl Triflate.

From our studies for the SN1 methodology, we discovered that 1-AdOTf is a highly reactive electrophile which can react with any lone pair under mild conditions. With a convenient means of preparing this reagent, we next set out to test the generality of its reaction with imines. The strategy is based on reacting various imines with 1-AdOTf followed by the addition of excess alkyl lithium (Scheme 46). Unlike the previously discussed protocols, this methodology adds lastly a methyl group indirectly to the system, namely, on the electrophilic sp2 hybridized iminium carbon. Imines were prepared from various modified literature procedures.[109–111]

Scheme 46. General imine-based SN1 reaction between 1-AdOTf and imines to the corresponding tertiary amine.

4.1 Initial Studies.

To achieve our desires, we will limit the various “R” groups shown in Scheme 46 to those that we are interested in. Then, R1 and R2 could be variable alkyl groups, R3 is limited to the tert-butyl group, and R4 is limited to the methyl group.

To start with, a reaction was performed under the same conditions used in the SN1 protocol between the secondary amines and 1-AdOTf (25g). Hence, a reaction was conducted between N-ethylidene- tert-butylamine (33) and 1-AdOTf (25g) followed by the addition of MeLi (Scheme 47).

Scheme 47. Imine-based SN1 strategy for the synthesis of compound 18 from imine 33.

Such reagents have been chosen to start with because they yield the sterically hindered tertiary amine 18 which was fully characterized previously, and this helps in following the reaction progress. The reaction proved effective through which the NMR spectra confirm the formation of the desired product 18 in moderate yield (42%). Furthermore, it’s noteworthy to mention that analogous reaction was performed between imine 33 with 1-AdOTf (25g) followed by the addition of MeMgCl, instead of MeLi, at 0 °C for 12 h. However, the expected product 18 was not observed. The formation of the desired product 18, which accommodates high steric hindrance, via two step protocol in moderate yield represents an attractive route, and this might allow a facile preparation of wide variety of analogous sterically hindered tertiary amines.

4.2 Preparation of Various Highly Sterically Hindered Enamines.

While this method led to in successful results for the preparation of compound 18, we next set out an attempt to prepare compound 19 or any similar N,N,N-tri(tert-alkyl)amine. Then, the same protocol was applied to N-(tert-butyl)propan-2-imine (34a). Unfortunately, while the reaction worked uniformly well for the preparation of compound 18, the expected desired product 19 failed to come out from the present reaction. The NMR spectra confirm the formation of enamine 35a in moderate yield (Scheme 48).

Scheme 48. Outcome results of the imine-based SN1 protocol of imine 34a.

To prove the generality of the reaction, other attempts were conducted using analogous imines 34b, c. Similar results were obtained through which enamines 35b–d were isolated, but the expected desired tertiary amines 36a, b were not observed (Scheme 49).

Furthermore, it’s noteworthy to mention that analogous reaction was performed between imine 34c with 1-AdOTf (25g) followed by the addition of MeMgI or MeMgCl.LiCl, instead of MeLi, at 0 °C for 12 h. However, the expected tertiary amine 36b was not observed, and the enamines 35c, d were obtained as traces. Indeed, the outcome of such attempt is mainly the imine 34c and some related compounds. This means that the iminium salt intermediate doesn’t react properly with Grignard reagents, which decomposed later in the work up steps.

Scheme 49. Outcome results of the imine-based SN1 protocol of imines 34b, c.

While these results proved fruitless regarding the desired tertiary amines, we could surmise that the synthesis of open-chain N,N,N-tri(tert-alkyl)amines is not a straightforward task, and even impossible. All the discovered methodologies are very effective for the preparation of extremely sterically hindered tertiary amines, but suddenly fail in the case of open-chain N,N,N-tri(tert- alkyl)amines, as a special case. Indeed, the secret behind that is still unclear.

Although the unsuccessful formation of the desired compounds 19 or 36a, b is disappointing, the presented imine-based SN1 protocol would provide easy access to sterically hindered tertiary enamines. These compounds are even rare in the literature, and they lack to an efficient synthetic route. Sterically hindered tertiary enamines represent a curious class which

69 could show various interesting spectroscopic and geometrical characteristics. The structures of the synthesized enamines 35a–d were characterized by 1H NMR, 13C NMR, and HRMS.

5. Applications

Herein, we will illustrate some features of the synthesized extremely sterically hindered tertiary amines. However, we will not go so deeply in discussions because this could be detailed in separate correspondence papers.

5.1 Non-Planar Structures of Acyclic Extremely Sterically Hindered Tertiary alkylamines.

Researchers are impressively interested in investigating whether the normal pyramidal geometry of an amine could be deformed to a more planar structure as steric interactions increase. There are some examples in the literature of remarkably partial or complete planarized tertiary amines, but such planarity arises from electronic interaction between the occupied nitrogen p- orbital with the unoccupied side chain orbital.[44–46] It is still unclear and arouses curiosity whether extreme steric hindrance, as a solitary factor, can account in structural trends that end up with planarity.

For this purpose, we were successful in growing up some crystals of two extremely sterically hindered tertiary alkylamines, namely, compounds 18 and 15f suitable for single crystal X-ray diffraction course (single crystal X-ray diffraction was performed by Dr. M. Wӧrle at ETH Zürich). With the aid of some calculations (done by Prof. A. D. Boese at the University of Graz) for the molecular crystal data, it was confirmed that extremely sterically hindered tertiary alkylamines are not planar (Figure 15). To exclude the possibility that the nonplanar structures of 18 and 15f may be enhanced by the crystal field effect, the calculations were done also in the gas phase; however, no significant difference was obtained. Indeed, the calculations based on these crystal structures show that the height of “N” pyramid (h) is (0.22–0.23 Å) for compound 15f and (0.24–0.26 Å) for compound 18 which could be considered far away from complete planarity. In comparison with the structures of trimethylamine (h ̴ 0.45 Å) and triisopropylamine (h = 0.27–

0.29 Å)[39] the height of nitrogen pyramid (h) in our cases are much smaller than the former but with insignificant difference from the latter. Finally, we can say that our X-ray related studies cut- off the earlier suggestions that extremely sterically hindered tertiary amines tend toward planarity. (Further X-ray details concerning bond length and angles could be checked in supporting information).

15f

Figure 15. Single crystal X-ray diffraction of compounds 18 and 15f which shows pseudo pyramidal geometry.

5.2 Preparation of Sequent Series of Sterically Hindered Amines for 15N NMR Studies.

Steric effects on 15N NMR have been considered and correlated with structural features in sterically hindered amines.[10] In fact, it is expected that the geometric and electronic changes around the nitrogen atom would be reflected in changes in parameters observed in the nitrogen NMR of these compounds.[37–38]

Generally, the chemical shifts in the 15N NMR are sensitive to the variation of steric hindrance around the nitrogen atom. As branching increases, the chemical shift of the nitrogen moves toward downfield (β-effects). From the measurements of 15N NMR for series of tertiary amines with moderate steric hindrance, Wong has come into a conclusion that triisopropylamine has a trigonal planar geometry because it deviates from the correlation of the series under study![10] According to Wong, the chemical shift of the nitrogen moves toward downfield as branching increases, following the expected trend. However, when steric hindrance reaches high level, namely, at di- tert-butyl methylamine and triisopropylamine the trend reverses, and such compounds show deviation from the role. If this is convincing, then, all the tertiary amines that accommodate steric hindrance more than di-tert-butyl methylamine or triisopropylamine must move toward upfield in the 15N NMR!

To perform an absolute study which clarify the relation between steric hindrance and chemical shift in the 15N NMR, sequent series of (1-adamantyl)-based tertiary amines have been prepared, in a way that the branching increases by one methyl group added to the α-position (to the first carbon attached on the nitrogen), and their 15N NMR were measured (measured by Dr. M. Hagedorn, TU Chemnitz) (Figure 16).

Compounds 15a–c and 39a, b have been prepared via the electrophilic amination protocol, whereas compounds 18, 22, 37a, b, 38 have been prepared via the SN1 protocol from the corresponding secondary amines. Compounds 38 and 39a are known in the literature,[74,112] but all the other compounds are new and fully characterized.

Figure 16. 15N NMR chemical shifts of several sterically hindered tertiary amines measured in benzene.

General view on Figure 16 shows that the chemical shift of the nitrogen moves toward downfield as β-branching increases, following the general trend. However, such results couldn’t fit to a linear correlation, and even in some examples the trend reverses toward upfield shift as the case between compound 38 and 39a.

By going from compound 15a to 15b, the difference in chemical shift is 20 ppm; whereas, by going from compound 15b to 15c, the difference in chemical shift is just 6.6 ppm (Figure 16). This could be explained by major geometrical and electronical characteristic changes around the nitrogen by going from 15a to 15b, but minor geometrical and electronical characteristic changes occur by going from 15b to 15c. This explanation could be approved by the results obtained from the X-ray study in the previous section (section 5.1) through which a major change in the height

73 of “N” pyramid occur by going from non-sterically hindered tertiary amines to moderately sterically hindered ones; whereas, a minor change in the height of “N” pyramid occurs by going from moderately sterically hindered tertiary amines to highly sterically hindered ones.

When it comes to group 1 (Figure 16), the analysis becomes more complicated. Then, each structure must be considered separately because many factors might involve in the outcome 15N NMR results. For instance, if the β-carbon atoms are added to the same α-position, they yield absolutely different values from the case when they are added to different α-positions. This is not easy to be discussed without the aid of other experiments that assist in understanding some structural features of these compounds. Restriction of the rotational conformers in case of strong steric hindrance may explain special effects on 15N NMR values. Further detailed discussion for these results could be done separately, with the aid of other results from complementary compounds and other experiments, such as dynamic NMR spectroscopy.

5.3 Elimination Rate of Some Sterically Hindered Tertiary Amines

Most sterically hindered tertiary amines undergo Hofmann type elimination reaction upon thermolysis at 100 C in inert solvents, like toluene (Scheme 50). The instability among these systems arises from the high energy in these molecules which resulted from steric strains. Thus, as steric hindrance around the nitrogen increases, the elimination rate increases (t1/2 decreases). From our experiments in this manner, we deduce that tert-alkyl groups undergo such elimination, but 1-Ad group resists such elimination process.

Scheme 50. General thermolysis path of highly sterically hindered tertiary amine holding various groups.

Based on this, we have conducted some measurements to calculate the t1/2 for some of these sterically hindered tertiary amines. This might give extra information in recognizing the steric hindrance and the stability among these compounds (Figure 17).

Figure 17. Half-life of some sterically hindered tertiary amines measured in toluene at 100 °C based on 1H NMR measurements. n.d: no decomposition observed after 60 days.

It’s noteworthy to mention that this elimination increases sharply when polar solvent is added. For that, a very dilute sample can’t be precise for such measurement because the traces of water in toluene and humidity are sufficient to catalyze the elimination process of such trivial amount in a short time (few hours in the case of compound 18).

The vast variation in t1/2 between compounds 18, 6e, and 6c can only be explained in term of the difference in steric hindrance. Obviously, compound 6e is more sterically hindered than 6c, and this can be shown clearly in the t1/2 listed in Figure 17. Compounds 6e or 6c hold two tert-amyl or two tert-butyl groups, respectively, which increase twice the probability of elimination; however, compound 18, which holds only one tert-butyl group, still shows lower t1/2. The picture is clearer if we compare compound 18 to compound 6c through which they differentiate by just one group. The lower t1/2 for compound 18 can only means that this compound is more sterically hindered than compound 6c, and the 1-adamantyl group is far bulkier than the tert-butyl group. It’s not surprising that compound 26d doesn’t undergo any decomposition because it doesn’t hold a free tert-butyl group, and the five membered ring seems to be resistant toward elimination. However, it is difficult to believe that compound 12b doesn’t undergo Hofmann elimination on its tert-butyl group, after a period of 60 days. This means that the tert-butyl group in this case is free to rotate and not strained. This could happen in the case of 12b because the small five membered pyrrolidine ring leaves a free space from the external side of the nitrogen atom available for the tert-butyl group to reduce steric strain.

5.4 Dynamic NMR Studies

Increasing steric congestion around the nitrogen atom in tertiary amines leads to lower barriers to nitrogen inversion[113] but potentially to higher barriers in C–N rotation.[114] Brois

75 demonstrates that steric factors do indeed accelerate the nitrogen inversion process in 1- alkylaziridines.[113] It is unclear whether Brois study could be considered as a general role for all tertiary amines, or it is only applicable to alkylaziridines. Much elegant recent dynamic NMR work has probed such inversion processes in trialkylamines, and many researchers are interested in studying these processes for actual extremely sterically hindered tertiary amines.[115–116] In the search for rotation dominated process, we have previously described briefly the NMR spectra of some sterically hindered tertiary amines which show restriction in rotation at room temperature, and even at high temperatures, such as compound 18. Detailed features on dynamic NMR and calculations of rotational barrier “∆G” of some sterically hindered tertiary amines are under study by my colleague (M. Heck).

IV. Conclusion

In conclusion, we have developed mild and broadly applicable three methodologies for the preparation of wide variety of extremely sterically hindered tertiary amines. The protocols are also useful for the preparation of some hindered secondary amines as well.

The first method is based on electrophilic amination reaction for alkyl Grignard reagents with various N-chloroamines and N,N-dichloroamines in the presence of TMEDA, as a key additive. The N-chloroamine aminating reagents employed are easily prepared with high yields in one step from the corresponding secondary amine and show good stability. The reaction shows good substrate scope in terms of the steric of the coupling partners. The immediate practical value of this reaction is exemplified by the straightforward syntheses of many sterically hindered tertiary amines that can never be obtained by other methods. Isolation of analytically pure material is possible in most instances via vacuum condensation or washing with hot methanol; thus, making this reaction operationally convenient.

The second novel method provides rapid access to extremely sterically hindered tertiary amines under exceptionally mild conditions without any catalyst. The method is based on an alternative strategy concerning an SN1 reaction between various secondary amines and 1-Ad cation. This methodology provides results far superior to the first method, through which various extremely

76 sterically hindered N,N,N-tri(tert-alkyl)amines were prepared from the corresponding secondary amine with 1-Ad cation in one-step. This protocol is noteworthy for the mild reaction conditions employed and the ease of product purification through which an analytically pure material is obtained by simple acid/base extractive work. The feature of this method is its good yield, which could compete with other methods, and its wide applicability to many systems.

The third method employed is based on SN1 strategy between imines and 1-AdOTf followed by the addition of alkyllithium without prior isolation and/or purification. The reaction yields the desired tertiary amines with comparable level of steric hindrance as the previous two methods. However, when the level of steric hindrance in imines goes higher, the reaction route deviates to yield interesting sterically hindered tertiary enamines.

We have reported the preparation and full characterization of 28 newly synthesized sterically hindered tertiary amines all of which are difficult to access otherwise. Up to now, we can say that compound 15g-exo is the most sterically hindered acyclic tertiary alkylamine, and compound 26b is the most sterically hindered cyclic tertiary alkylamine ever known.

We are successful in grow up some viable crystals of two compounds 18 and 15f for performing X-ray crystallography. This helps in putting an end to the doubt about planarity in extremely sterically hindered tertiary amines. With the aid of special theoretical calculations based on these X-ray structures, we end up that extremely sterically hindered amines are not planar and even not much flatter than triisopropylamine.

15N NMR parameters are sensitive to the effects of steric hindrance around the nitrogen atom among the highly strained tertiary amines. This is studied deeply via sequent series of 1-adamantyl-based sterically hindered tertiary amines that exhibit an increasing order of β-branching.

Many other structural features including thermal stability, chemical stability, half-life, and rotational barrier of these unprecedented compounds are detailed.

V. Summary:

Three advanced methodologies for the preparation of extremely sterically hindered tertiary alkyl amines have been developed. The syntheses of 28 novel tertiary alkylamines that accommodate unusual steric hindrance are described.

The electrophilic amination of alkyl Grignard reagents with N-chlorodialkylamines, in the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) as a key additive, gives a variety of unprecedentedly sterically hindered tertiary alkylamines in good yields. The reaction is noteworthy for the unusual tolerance of steric hindrance, mild reaction conditions employed, ease of product isolation/purification, and absence of catalysts/transition metals.

An alternative strategy to 1-adamantyl-substituted (1-Ad) sterically hindered tertiary amines, which involved instead an SN1 reaction, is described. The nucleophilic substitution of 1-Ad cation, using various hindered secondary amines as nucleophilic nitrogen, provides novel sterically hindered tertiary amines in generally good yields. Salient features of the protocol that is detailed here include unusual tolerance of steric hindrance, mild reaction conditions employed, ease of product isolation-purification, and absence of catalysts/transition metals.

A complementary strategy to 1-Ad-based sterically hindered tertiary amines, which involves an iminium salt intermediate, is described. The easily prepared and handled imines react with 1-adamantyl triflate followed by the addition of excess methyllithium to provide novel 1-Ad-based sterically hindered tertiary amines/enamines in moderate yields.

The molecular structures of N,N-di(adamantan-1-yl)cyclohexanamine (15f) and N-(tert-butyl)- N-isopropyladamantan-1-amine (18) were determined by single crystal X-ray diffraction. The height “h” of nitrogen pyramid of 15f is 0.22–0.23 Å and that of 18 is 0.24–0.26 Å. The corresponding out-of-plane measurement for triisopropylamine is 0.27–0.29 Å and ̴ 0.4 Å for non- hindered trialkylamines as determined in literature. Both structures 15f and 18 represent faithful examples of extremely sterically hindered tertiary alkylamines; nevertheless, they have traditional pyramidal configuration of the nitrogen atom. This could be an end for the historical theoretical suggestions about the planarity of extremely sterically hindered tertiary alkylamines.

Restricted rotation about N–C bonds for some extremely sterically hindered tertiary amines were studied by variable temperature dynamic NMR (DNMR) spectroscopy. The 1H NMR and 13C NMR show a restriction in rotation at room temperature among many of these hindered tertiary amines, and some of them, such as 18, exhibit two complete sets of peaks for two non-equivalent rotamers at room temperature.

15N NMR parameters are sensitive to the effects of steric hindrance around the nitrogen atom among the highly strained tertiary amines. This is studied deeply via sequent series of

1-adamantyl-based sterically hindered tertiary amines that exhibit an increasing order of β-branching.

Most of these compounds have been shown to undergo Hofmann type elimination reaction upon thermolysis at 100 C in inert solvents, like toluene. This elimination reaction could be used to calculate the half-life (t1/2) and the stability of these compounds. Furthermore, the t1/2 could be used to compare the steric hindrance among these compounds because the rate of such elimination should correlate with steric hindrance.

VI. Experimental part

A. General

All the reactions dealing with air- or moisture-sensitive compounds were carried out in a dry reaction vessel under a positive pressure of nitrogen. Air- and moisture-sensitive liquids and solutions were transferred via a syringe. Organic solvents were removed by simple or vacuum distillation/condensation.

B. Apparatus

NMR spectra were recorded with a UNITY INOVA 400 FT spectropmeter (Varian Inc., Palo Alto, CA, USA) operating at 400 MHz for 1H NMR (and 600 MHz in few cases), 100 MHz for 13C NMR, and 40.5 MHz for 15N NMR. 1H NMR and 13C NMR signals were referenced with the help 15 of the solvent signals and recalculated relative to TMS. N NMR were referenced to external

MeNO2 (δ = 0). Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, sept = septet, m = multiplet, br = broad), coupling constant in Hertz (Hz) followed by the number of hydrogen atoms. Melting points (m.p.) were measured on a heated metal-block using mercury thermometer. Mass spectra were obtained from micrOTOF QII spectrometer from BRUKER utilizing Electrospray-Ionization technique (ESI). Quantitative elementary analyses were performed on a Vario Micro Tube from ELEMENTAR ANALYSENSYSTEME GMBH HANAU.

C. Chemicals

All reactions were carried out with freshly distilled, dry solvents. Anhydrous solvents were distilled immediately before use. AgOTf was obtained commercially and kept away from light and stored under argon. MeLi, MeMgCl, EtMgCl, iPrMgCl, t-BuCH2MgCl, cHxMgCl, and t-BuMgCl were obtained commercially and used as received. EtMgBr, cPnMgBr, t-BuMgBr, 1-AdMgBr, and 2-norbornylmagnesium bromide were prepared from the corresponding alkylbromide and magnesium turnings following a general literature procedure and used immediately after preparation.[97]

D. Procedures

Preparation of N-chloro-2-methyl-N-(tert-pentyl)butan-2-amine (5e)

General procedure for the preparation of N-chloroamines: N,N-di(tert-pentyl)amine[82] (4e) (5.1 g, 32.2 mmol) and N-chlorosuccinimide (5.0 g, 37.6 mol) were stirred in methylene chloride (50 mL) at room temperature for 4 h. The solvent was then removed at 0 °C and 100 mbar. The residue was extracted with n-pentane (3 x 50 mL). The organic layer was isolated, dried over magnesium sulfate, and the solvent was evaporated. The residue was then recondensed at room temperature and 1 mbar into a liquid nitrogen trap to afford N-chloro-N,N-di(tert-pentyl)amine 1 3 (5e) as colorless oil (5.3 g, 83% yield). H NMR (400 MHz, toluene-d8): δ = 0.96 (t, J = 8 Hz, 3 13 6H, CH2CH3), 1.15 (s, 12H, C(CH3)2), 1.56 (q, J = 8 Hz, 4H, CH2CH3). C NMR (100 MHz,

C6D6): δ = 8.4 (q, CH2CH3), 27.4 (q, C(CH3)2), 38.4 (t, CH2), 66.2 (s, CN). HRMS m/z calcd for + C10H24N (M–Cl+2H ) 158.1903; found 158.1887. This compound is new but synthesized via literature known procedure.[73]

Preparation of 2-chloro-1,1,3,3-tetramethylisoindoline (11a)

The titled compound was prepared in the same way as compound 5e by using 1,1,3,3- tetramethylisoindoline[85] (10a) (2.0 g, 11.4 mmol) and N-chlorosuccinimide (1.6 g, 12.0 mmol). After extraction, 2-chloro-1,1,3,3-tetramethylisoindoline (11a) was obtained as pure low melting colorless solid, and it can be used directly without distillation or further purification (2.1 g, 88% 1 yield). m.p. = 35–36 °C. H NMR (400 MHz, CDCl3): δ = 1.45 (s, 12H, CH3), 7.13–7.15 (m, 2H, 13 CH), 7.25–7.27 (m, 2H, CH). C NMR (100 MHz, C6D6): δ = 26.8 (q, CH3), 69.0 (s, C(CH3)2),

+ 121.4 (d, CH), 127.3 (d, CH), 144.7 (s, C). HRMS m/z calcd for C12H18N (M–Cl+2H ) 176.1434; found 176.1495. This compound is new but synthesized via literature known procedure.[73]

Preparation of 2-chloro-1,1,3,3-tetraethylisoindoline (11b)

The titled compound was prepared in the same way as compound 5e by using 1,1,3,3- tetraethylisoindoline[85] (10b) (4.0 g, 17.3 mmol) and N-chlorosuccinimide (2.4 g, 18.0 mmol). After extraction, 2-chloro-1,1,3,3-tetraethylisoindoline (11b) was obtained as pure low melting colorless solid, and it can be used directly without distillation or further purification (4.2 g, 91%

1 3 yield). m.p. = 42–43 °C. H NMR (400 MHz, C6D6): δ = 0.81 (t, J = 6 Hz, 12H, CH2CH3), 1.72–

1.81 (m, 4H, CH2CH3), 1.95–2.05 (m, 4H, CH2CH3), 6.83–6.85 (m, 2H, CH), 7.03–7.05 (m, 2H, 13 CH). C NMR (100 MHz, C6D6): δ = 9.0 (q, CH2CH3), 29.5 (t, CH2CH3), 74.0 (s, C(CH2CH3)2),

123.2 (d, CH), 126.3 (d, CH), 142.1 (s, C). Anal. Calcd. for C16H24ClN (265.16): C, 72.29; H, 9.10; N, 5.27; found: C, 72.14; H, 9.22; N, 5.19. This compound is new but synthesized via literature known procedure.[73]

Preparation of N-chloro-N,N-di(adamantan-1-yl)amine (14)

The titled compound was prepared in the same way as compound 5e by using di(adamantan-1- yl)amine[88] (13) (1.0 g, 3.5 mmol) and N-chlorosuccinimide (0.5 g, 4.0 mmol). After extraction, N-chloro-N,N-di(adamantan-1-yl)amine (14) was obtained as pure white solid, and it can be used

83 directly without further purification (0.9 g, 84% yield). m.p. = 172–173 °C. 1H NMR (400 MHz, 13 C6D6): δ = 1.47–1.55 (m, 12H), 1.96 (bs, 6H), 2.21 (bs, 12H). C NMR (100 MHz, C6D6):

δ = 30.7 (d, CH), 36.4 (t, CH2), 43.3 (t, CH2), 66.6 (s, C). Anal. Calcd. for C20H30ClN (319.21): C, 75.09; H, 9.45; N, 4.38; found: C, 75.20; H, 9.48; N, 4.34. This product is new but synthesized via literature known procedure.[73]

N-(tert-butyl)-N-chloroadamantan-1-amine (17)

The titled compound was prepared in the same way as compound 5e by using N-(tert- butyl)adamantan-1-amine[99] (16) (1.00 g, 4.83 mmol) and N-chlorosuccinimide (0.69 g, 5.31 mmol). After extraction, N-(tert-butyl)-N-chloroadamantan-1-amine (17) was obtained as pure white solid, and it could be used directly without further purification (0.93 g, 80% yield). 1 m.p. = 140–142 °C. H NMR (400 MHz, C6D6): δ = 1.35 (s, 9H, C(CH3)3), 1.47 (bs, 6H), 1.93 13 (bs, 3H), 2.08 (bs, 6H). C NMR (100 MHz, C6D6): δ = 30.4 (d, CH), 31.5 (q, CH3), 36.3

(t, CH2), 42.4 (t, CH2), 64.7 (s, C), 66.1 (s, C). Anal. Calcd. for C14H24ClN (241.80): C, 69.54; H, + 10.00; N, 5.79; found: C, 69.02; H, 10.04; N, 5.68. HRMS m/z calcd for C14H25ClN (M+H ) 242.1670; found 242.1660. This product is new but synthesized via literature known procedure.[73]

N-(tert-butyl)-N-isopropyladamantan-1-amine (18)

Typical procedure A (General electrophilic amination): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen, N-(tert-butyl)-N- chloroadamantan-1-amine (17, 0.24 g, 1.00 mmol) was added to a solution of isopropylmagnesium chloride (0.75 mL, 2 M in THF, 1.5 mmol) and TMEDA (3.00 g, 26.0 mmol) in diethyl ether

(10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with n-pentane (3 x 25 mL). The organic layer was washed with water (2 x 20 mL), dried over potassium carbonate, and the solvent was evaporated. The crude product, which contains the secondary amine 16 (37% yield), was added to cold MeOH (5 mL) and stirred for 5 min. The desired product 18 was collected by filtration as pure white solid (59.51 mg, 24% yield). Further purification can be achieved by dissolving in minimum quantity 1 of methanol at 50°C, and left to crystalize at –20 °C. m.p. = 55–56 °C. H NMR (400 MHz, C6D6): (signals for the major rotamer where distinguishable are marked as “*”; signals for the minor ** * 3 rotamer where distinguishable are marked as “**”) δ = 1.24 (s, 1.8H, C(CH3)3), 1.26 (d, J = 7.2 ** 3 * Hz, 6H, CH(CH3)2), 1.31 (d, J = 7.2 Hz, 1.2H, CH(CH3)2), 1.33 (s, 9H, C(CH3)3), 1.50–1.57 ** 3 * 3 (m, 7.2H), 1.87–2.07 (m, 10.8H), 3.41 (sept, J = 7.2 Hz, 0.2H, CH(CH3)2), 3.47 (sept, J = 7.2 13 * ** * Hz, 1H, CH(CH3)2). C NMR (100 MHz, C6D6): δ = 26.5 (q, CH3), 27.0 (q, CH3), 30.4 (d, ** ** * * ** * CH), 30.7 (d, CH), 33.4 (q, CH3), 35.0 (q, CH3), 36.7 (t, CH2), 36.8 (t, CH2), 43.8 (t, CH2), ** * ** * ** ** * 44.4 (t, CH2), 45.8 (d, CH), 48.3 (d, CH), 57.0 (s, C), 59.0 (s, C), 59.4 (s, C), 60.0 (s, C). + HRMS m/z calcd for C17H32N (M+H ) 250.2529; found 250.2506.

Typical procedure B (General SN1 protocol between secondary amines and 1-AdOTf): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen and dark, 1-bromoadamantane (0.25 g, 1.16 mmol) and silver trifluoromethanesulfonate (AgOTf, 0.30 g, 1.16 mmol) were dissolved in 20 mL dry methylene chloride at 0 °C. The reaction mixture was stirred at 0 °C for at least 4 h. Anhydrous potassium carbonate (0.60 g, 5.79 mmol) was added followed by the addition of N-tert-butyl-N-isopropylamine (16, 0.20 g, 1.74 mmol). The mixture was stirred at 0 °C for 4 h under dark. After cooling to –10 °C, the reaction mixture was quenched with saturated solution of sodium bicarbonate (20 mL). The neutralized reaction mixture was extracted with more DCM (2 x 25 mL). The organic layers were collected, dried over potassium carbonate, and the solvent was removed under vacuum. The residue was dissolved in ether, and the formed solid, if any, was filtered off. The clear ether solution was cooled down to –10 °C, and HCl(g) was bubbled inside the solution for 20 seconds. The formed amine hydrochloride salt was filtered and washed well with diethyl ether. The salt was dissolved in dichloromethane, cooled to –10 °C, and a cold saturated solution of sodium

85 bicarbonate, or NaOH (5%), was added slowly. The neutralized mixture was transferred to a separatory funnel and extracted using dichloromethane and water. The organic phase was collected, dried over K2CO3, and the solvent was removed under vacuum. Further purification was achieved by washing with methanol to yield compound 18 as pure white solid (0.18 g, 63% yield).

Typical procedure C (General SN1 protocol between secondary amines and 1-AdOMs): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.26 g, 1.17 mmol) and anhydrous potassium carbonate (0.60 g, 5.79 mmol) were added to a solution of 1-adamantyl mesylate[104,117] (25f) (0.27 g, 1.16 mmol) in 20 mL dry methylene chloride. The reaction mixture was stirred at 0 °C for 30 minutes followed by the addition of N-tert-butyl-N-isopropylamine (16, 0.20 g, 1.74 mmol). The reaction mixture was stirred at r.t. for 3 h. After cooling to –10 °C, the reaction was quenched with saturated solution of sodium bicarbonate (20 mL). The neutralized reaction mixture was extracted, worked up, and purified as mentioned in the typical procedure B to yield compound 18 as pure white solid (0.16 g, 54% yield).

Typical procedure D (General SN1 protocol between secondary amines and 1-AdOAc): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.26 g, 1.17 mmol) and anhydrous potassium carbonate (0.60 g, 5.79 mmol) were added to a solution of 1-adamantyl acetate[118] (25a, 0.23 g, 1.16 mmol) in 20 mL dry methylene chloride. The reaction mixture was stirred at 0 °C for 30 minutes followed by the addition of N-tert-butyl-N-isopropylamine (16, 0.20 g, 1.74 mmol). The mixture was stirred at r.t. for 12 hrs. After cooling to –10 °C, the reaction was quenched with saturated solution of sodium bicarbonate (20 mL). The neutralized reaction mixture was extracted, worked up, and purified as mentioned in the typical procedure B to yield compound 18 as pure white solid (0.13 g, 46% yield).

Typical procedure E (General SN1 protocol between imines and 1-AdOTf): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen and dark, silver trifluoromethanesulfonate (AgOTf, 0.30 g, 1.16 mmol) and 1-bromoadamantane (0.25 g, 1.16 mmol) were dissolved in dry methylene chloride (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for at least 4 h. Anhydrous potassium carbonate (0.60 g, 5.79 mmol) was added followed by the addition of N-ethylidene-tert-butylamine[110] (33) (0.11 g, 1.16 mmol), and the reaction mixture was stirred at 0 °C for 4 h under dark. The reaction mixture was cooled to –78 °C followed by the dropwise addition of methyllithium (0.75 mL, 3.10 M in diethoxymethane, 2.32 mmol). The reaction mixture was stirred at –78 °C for 2 h. The reaction was quenched with saturated solution of ammonium chloride (20 mL). The reaction mixture was extracted, worked up, and purified as mentioned in the typical procedure B to yield compound 18 as pure white solid (0.12 g, 42% yield). Product 18 and the five methods of preparation are new.

Preparation of triisopropylamine (6a)

The titled compound was prepared in the same way as compound 18 following typical procedure A by using N-chloro-N,N-diisopropylamine[73,74] (5a, 0.50 g, 3.68 mmol), isopropylmagnesium chloride (3.7 mL, 2.0 M in THF, 7.4 mmol), and TMEDA (5.0 g, 43.11 mmol). After extraction, 1 compound 6a was obtained as colorless liquid (0.12 g, 25% yield). H NMR (400 MHz, CDCl3): 3 3 13 δ = 0.97 (d, J = 6 Hz, 18H, CH3), 3.09 (sept, J = 6 Hz, 3H, CH). C NMR (100 MHz, CDCl3):

δ = 23.0 (q, CH3), 44.0 (d, CH).

This compound is known,[51] but the method of preparation is new.

Preparation of N,N-diisopropyl-2-methylpropan-2-amine (6b)

Method A: The titled compound was prepared in the same way as compound 18 following typical procedure A by using N-chloro-N-isopropyl-2-methylpropan-2-amine[73,75] (5b, 0.50 g, 3.34 mmol), TMEDA (5.0 g, 43.11 mmol), and isopropylmagnesium chloride (3.3 mL, 2.0 M in THF, 6.6 mmol). The crude product was recondensed at 25 °C and 0.05 mbar to yield a mixture of the titled compound 6b (0.25 g, 46% yield) and the side product 4b (0.05 g, 14% yield) as colorless 1 3 liquid. H NMR (400 MHz, toluene-d8): δ = 1.08 (d, J = 6 Hz, 12H, CH(CH3)2), 1.12 (s, 9H, 3 13 C(CH3)3), 3.15 (sept, J = 6 Hz, 2H, CH(CH3)2). C NMR (100 MHz, C6D6): δ = 24.4

(q, CH(CH3)2), 30.8 (q, C(CH3)3), 46.2 (d, CH(CH3)2), 58.0 (s, C(CH3)3).

Method B: The titled compound was prepared in the same way as compound 18 following typical procedure A by using N-chloro-N,N-diisopropylamine[73,74] (5a, 0.5 g, 3.7 mmol), TMEDA (5.0 g, 43.1 mmol), and tert-butylmagnesium chloride (4.3 mL, 1.7 M in diethyl ether, 7.4 mmol). The crude product was recondensed at 25 °C and 0.05 mbar to yield a mixture of the title compound 6b (70.0 mg, 11% yield) and the side product 4a (30.0 mg, 9% yield) as a colorless liquid.

Preparation of N-isopropyl-N,N-di(tert-pentyl)amine (6e)

The reaction was carried out following typical procedure A for the synthesis of compound 18 by using N-chloro-N,N-di(tert-pentyl)amine (5e, 0.5 g, 2.6 mmol), TMEDA (5.0 g, 43.1 mmol), and isopropylmagnesium chloride (2.5 mL, 2.0 M in THF, 5.0 mmol). The crude product was subjected to recondensation method via liquid nitrogen trap. The side product di-tert-pentylamine (4e) was collected first at 60 °C and 10 mbar for a period of 4 h, and the desired product 6e was collected at 60 °C and 1 mbar as pure colorless oil (0.1 g, 19% yield) m.p. = 6–7 °C. 1H NMR (400 MHz,

3 3 toluene-d8): δ = 0.90 (t, J = 8 Hz, 3H, CH2CH3), 0.92 (t, J = 8 Hz, 3H, CH2CH3), 1.13 (s, 6H, 3 3 C(CH3)2), 1.22 (d, J = 8 Hz, 6H, CH(CH3)2), 1.24 (s, 6H, C(CH3)2), 1.40 (q, J = 8 Hz, 2H, 3 3 13 CH2CH3), 1.57 (q, J = 8 Hz, 2H, CH2CH3), 3.29 (sept, J = 8 Hz, 1H, CH(CH3)2). C NMR (100

MHz, CDCl3): δ = 9.6 (q, CH2CH3), 10.0 (q, CH2CH3), 26.6 (q, CH(CH3)2), 29.0 (q, C(CH3)2),

31.6 (q, C(CH3)2), 37.2 (t, CH2), 37.7 (t, CH2), 47.6 (d, CH(CH3)2), 60.2 (s, C(CH3)2), 61.4 (s, + C(CH3)2). HRMS m/z calcd for C13H30N (M+H ) 200.2373; found 200.2385. The product and the method of preparation are new.

N,N-di(tert-pentyl)cyclopentanamine (6f)

The reaction was carried out following typical procedure A for the synthesis of compound 18 by using N-chloro-N,N-di(tert-pentyl)amine (5e, 0.50 g, 2.62 mmol), cyclopentylmagnesium bromide (7.85 mL, 0.5 M in diethyl ether, 3.93 mmol), and TMEDA (5.00 g, 43.11 mmol). The crude product was subjected to recondensation method via liquid nitrogen trap. The side product di-tert- pentylamine (4e) was collected at 50 °C and 10 mbar for a period of 3 h (30% yield), and the desired product 6f was collected at 50 °C and 1 mbar as pure colorless oil (0.15 g, 25% yield). 1 3 H NMR (400 MHz, C6D6): δ = 0.96 (t, J = 7.6 Hz, 6H, CH2CH3), 1.22 (bs, 12H, C(CH3)2), 3 13 1.35–1.84 (m, 12H), 3.44 (quint, J = 9.6 Hz, 1H, CH). C NMR (100 MHz, C6D6): δ = 9.21

(q, CH2CH3), 9.39 (q, CH2CH3), 23.9 (t, CH2), 24.0 (t, CH2), 29.8 (bq, CH3), 32.7 (q, CH3), 32.8

(t, CH2), 37.1 (bt, CH2), 59.3 (d, CH), 59.6 (s, C), 60.2 (bs, C). HRMS m/z calcd for C15H32N (M+H+) 226.2529; found 226.2509. The product and the method of preparation are new.

N,N-di(tert-pentyl)cyclohexanamine (6g)

The reaction was carried out following typical procedure A for the synthesis of compound 18 by using N-chloro-N,N-di(tert-pentyl)amine (5e, 0.50 g, 2.62 mmol), TMEDA (5.0 g, 43.1 mmol), and cyclohexylmagnesium chloride (1.96 mL, 2 M in THF, 3.93 mmol). The crude product was subjected to recondensation method via liquid nitrogen trap. The side product di-tert-pentylamine (4e) was collected first at 50 °C and 10 mbar for a period of 4 hours (34% yield), and the desired product 6g was collected at 50 °C and 1 mbar as pure colorless oil (0.14 g, 22% yield). 1 3 H NMR (400 MHz, C6D6): δ = 0.95 (t, J = 7.6 Hz, 6H, CH2CH3), 1.19 (s, 6H, C(CH3)2), 1.20– 3 1.23 (m, 2H, CH2), 1.29 (s, 6H, C(CH3)2), 1.48 (q, J = 7.6 Hz, 2H, CH2CH3), 1.53–1.86 (m, 10H), 3 3 13 2.78 (tt, J1 = 11.6 Hz, J2 = 2.8 Hz, 1H, CH). C NMR (100 MHz, C6D6): δ = 9.4 (q, CH2CH3),

9.7 (q, CH2CH3), 26.6 (t, CH2), 28.5 (q, C(CH3)), 28.8 (q, C(CH3)), 31.6 (t, CH2), 36.8 (t, CH2),

37.1 (t, CH2), 37.4 (t, CH2), 59.4 (d, CH), 59.6 (s, C(CH3)2), 61.4 (s, C(CH3)2). HRMS m/z calcd + for C16H34N (M+H ) 240.2686; found 240.2668. The product and the method of preparation are new.

Preparation of 2-isopropyl-1,1,3,3-tetramethylisoindoline (12a)

The reaction was carried out following typical procedure A for the synthesis of compound 18 by using 2-chloro-1,1,3,3-tetramethylisoindoline (11a, 0.5 g, 2.4 mmol), TMEDA (5.0 g, 43.1 mmol), and isopropylmagnesium chloride (2.4 mL, 2 M in THF, 4.8 mmol). The crude product was subjected to column chromatography using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed

90 under vacuum to yield the desired product 12a as white solid (0.16 g, 26% yield). Further purification can be done by recrystallization from methanol. m.p. = 41–42 °C. 1H NMR (400 MHz, 3 3 C6D6): 1.26 (d, J = 6 Hz, 6H, CH(CH3)2), 1.41 (s, 12H, C(CH3)2), 3.36 (sept, J = 6 Hz, 1H, 13 CH(CH3)2), 6.97–6.98 (m, 2H, CH), 7.12–7.14 (m, 2H, CH). C NMR (100 MHz, C6D6):

δ = 24.1 (q, CH(CH3)2), 30.1 (q, C(CH3)2), 43.8 (d, CH(CH3)2), 64.4 (s, C(CH3)2), 120.0 (d, CH),

125.7 (d, CH), 147.5 (s, C). Anal. Calcd. for C15H23N (217.18): C, 82.89; H, 10.67; N, 6.44; found: C, 82.44; H, 10.67; N, 6.16. This compound is unknown, and the method used here for its preparation is new.

Preparation of 2-(tert-butyl)-1,1,3,3-tetramethylisoindoline (12b)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using 2-chloro-1,1,3,3-tetramethylisoindoline (11a, 0.5 g, 2.4 mmol), TMEDA (5.0 g, 43.1 mmol), and tert-butylmagnesium chloride (2.8 mL, 1.7 M in diethyl ether, 4.8 mmol). The crude product was subjected to column chromatography using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 12b as pure white solid (30.0 mg, 5.5% yield). Further purification can be done by washing with methanol. m.p. = 70–72 °C. 1H NMR (400 MHz,

(CD3)2CO): δ = 1.47 (s, 9H, C(CH3)3), 1.59 (s, 12H, C(CH3)2), 7.10–7.13 (m, 2H, CH), 7.17–7.20 13 (m, 2H, CH). C NMR (100 MHz, (CD3)2CO): δ = 33.4 (q, C(CH3)3), 33.6 (q, C(CH3)2), 54.8 (s,

C(CH3)3), 66.9 (s, C(CH3)2), 121.0 (d, CH), 126.5 (d, CH), 148.5 (s, C). HRMS m/z calcd for + C16H26N (M+H ) 232.2087; found 232.2117.

The product and the method of preparation are new.

Preparation of 1,1,3,3-tetraethyl-2-isopropylisoindoline (12c)

The reaction was carried out following typical procedure A for the synthesis of compound 18 by using 2-chloro-1,1,3,3-tetraethylisoindoline (11b, 0.5 g, 1.9 mmol), TMEDA (5.0 g, 43.1 mmol), and isopropylmagnesium chloride (1.9 mL, 2 M in THF, 3.8 mmol). The crude product was subjected to column chromatography using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 12c as white solid (0.10 g, 22% yield). Further purification can be done by recrystallization from methanol. m.p. = 144–145 °C. 1H NMR (400 3 3 MHz, CD2Cl2): δ = 0.76 (t, J = 6 Hz, 12H, CH2CH3), 1.33 (d, J = 6 Hz, 6H, CH(CH3)2), 1.77 2 3 2 3 (dq, J = 15 Hz, J = 6 Hz, 4H, CH2CH3), 1.98 (dq, J = 15 Hz, J = 6 Hz, 4H, CH2CH3), 3.49 3 13 (sept, J = 6 Hz, 1H, CH(CH3)2), 7.01–7.04 (m, 2H, CH), 7.15–7.18 (m, 2H, CH). C NMR (100

MHz, CD2Cl2): δ = 9.9 (q, CH2CH3), 25.3 (q, CH(CH3)2), 32.9 (t, CH2CH3), 44.8 (d, CH(CH3)2),

72.1 (s, C(CH2CH3)2), 122.7 (d, CH), 125.2 (d, CH), 145.0 (s, C). Anal. Calcd. for C19H31N (273.25): C, 83.45; H, 11.43; N, 5.12; found: C, 82.68; H, 11.35; N, 5.04. HRMS m/z calcd for + C19H32N (M+H ) 274.2529; found 274.2514. This compound is known,[87] but the method used here for its preparation is new.

Preparation of 2-(tert-butyl)-1,1,3,3-tetraethylisoindoline (12d)

92 crude product was subjected to thick layer chromatography using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected. The solvent was removed under vacuum to yield a mixture of the desired product 12d (20.0 mg, 3% yield) and 1,1,2,3,3-pentaethylisoindoline (12e) as an inseparable side product. 1H NMR (400 3 3 MHz, C6D6): δ = 0.84 (t, J = 6 Hz, 12H, CH2CH3), 1.41 (s, 9H, C(CH3)3), 1.98 (q, J = 6 Hz, 8H, 13 CH2CH3), 6.87–6.89 (m, 2H, CH), 7.09–7.11 (m, 2H, CH). C NMR (100 MHz, C6D6): δ = 10.5

(q, CH2CH3), 33.9 (q, (CH3)3), 36.2 (t, CH2), 55.6 (s, C), 75.1 (s, C), 121.8 (d, CH), 126.5 (d, CH), + 145.9 (s, C). HRMS m/z calcd for C20H34N (M+H ) 288.2613; found 288.2646. The product and the method of preparation are new.

Preparation of 1,1,2,3,3-pentaethylisoindoline (12e)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using 2-chloro-1,1,3,3-tetraethylisoindoline (11b, 0.6 g, 2.4 mmol), TMEDA (5.0 g, 43.1 mmol), and ethylmagnesium chloride (2.4 mL, 2 M in diethyl ether, 4.8 mmol). The crude product was subjected to thick layer chromatography using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected. The solvent was removed under vacuum to yield the desired product 12e as crystalline solid (0.4 g, 64% yield). [87] 1 3 m.p. = 85–86 °C (lit. m.p = 85 °C). H NMR (400 MHz, C6D6): δ = 0.84 (t, J = 6 Hz, 12H, 3 C(CH2CH3)2), 1.15 (t, J = 6 Hz, 3H, NCH2CH3), 1.53–1.62 (m, 4H, C(CH2CH3)2), 1.81–1.90 (m, 3 4H, C(CH2CH3)2), 2.79 (q, J = 6 Hz, 2H, NCH2CH3), 6.95–6.97 (m, 2H, CH), 7.10–7.13 (m, 2H, 13 CH). C NMR (100 MHz, C6D6): δ = 9.5 (q, CH3)2), 16.8 (q, CH3), 30.9 (t, CH2), 35.3 (t, NCH2),

70.5 (s, C(CH2CH3)2), 122.8 (d, CH), 125.7 (d, CH), 145.0 (s, C). This compound is known,[87] but the method of preparation is new.

N,N-di(adamantan-1-yl)-N-methylamine (15a)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-chloro-N,N-di(adamantan-1-yl)amine (14, 0.32 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and methylmagnesium chloride (0.50 mL, 3 M in THF, 1.50 mmol). The crude product was added to MeOH (5 mL) and stirred for 5 min at room temperature. The desired product 15a was collected by filtration as pure white solid (0.17 g, 57% yield). m.p. = 136–137 °C. 1 H NMR (400 MHz, C6D6): δ = 1.49 (bs, 12H, CH2), 1.91 (bs, 6H, CH), 1.92 (bs, 12H, CH2), 13 2.21 (s, 3H, CH3). C NMR (100 MHz, CDCl3): δ = 31.0 (d, CH), 37.1 (t, CH2), 43.4 (t, CH2), + 47.3 (q, CH3), 58.6 (s, C). HRMS m/z calcd for C21H34N (M+H ) 300.2686; found 300.2703. The product and the method of preparation are new.

N,N-di(adamantan-1-yl)-N-ethylamine (15b)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-chloro-N,N-di(adamantan-1-yl)amine (14, 0.32 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and ethylmagnesium bromide (3.0 mL, 0.50 M in diethyl ether, 1.50 mmol). The crude product was added to MeOH (30 mL), heated at 40 °C, and the product filtered off while hot. The desired product 15b was collected as pure white solid (0.12 g, 37% yield). m.p. = 105–106 °C. 1 3 H NMR (400 MHz, C6D6): δ = 1.13 (t, J = 8 Hz, 3H, CH2CH3), 1.61 (bs, 12H), 2.01 (bs, 12H), 3 13 2.11 (bs, 6H), 2.71 (q, J = 8 Hz, 2H, CH2CH3). C NMR (100 MHz, C6D6): δ = 22.9 (q, CH3),

30.5 (d, CH), 36.8 (t, CH2), 43.9 (t, CH2), 46.7 (t, CH2), 59.2 (s, C). HRMS m/z calcd for C22H36N (M+H+) 314.2842; found 314.2851. The product and the method of preparation are new.

Preparation of N,N-di(adamantan-1-yl)-N-isopropylamine (15c)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-chloro-N,N-di(adamantan-1-yl)amine (14) (0.3 g, 1.0 mmol), TMEDA (3.0 g, 26.2 mmol), and isopropylmagnesium chloride (1 mL, 2 M in THF, 2.0 mmol). The crude product was dissolved in MeOH (20 mL), heated at 50 °C, and the product filtered off while hot. The desired product 15c was collected as pure white solid (92.0 mg, 30% yield). m.p. = 160–162 °C. 1 3 H NMR (400 MHz, C6D6): δ = 1.42 (d, J = 6 Hz, 6H, CH(CH3)2), 1.56–1.69 (m, 12H), 2.02 (bs, 3 13 6H), 2.07 (bs, 6H), 2.22 (bs, 6H), 3.61 (sept, J = 6 Hz, 1H, CH(CH3)2). C NMR (100 MHz,

C6D6): δ = 28.2 (q, CH(CH3)2), 31.2 (d, CH), 31.3 (d, CH), 37.2 (t, CH2), 37.3 (t, CH2), 45.3 (t,

CH2), 45.4 (t, CH2), 46.4 (d, CH(CH3)2), 60.3 (s, C), 62.0 (s, C). Anal. Calcd. for C23H37N (327.29): C, 84.34; H, 11.39; N, 4.28; found: C, 84.02; H, 11.31; N, 4.30. The product and the method of preparation are new.

N,N-di(adamantan-1-yl)neopentanamine (15d)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-chloro-N,N-di(adamantan-1-yl)amine (14, 0.32 g, 1.00 mmol), neopentylmagnesium chloride (1.50 mL, 1 M in diethyl ether, 1.50 mmol), and TMEDA (3.00 g, 26.20 mmol). The crude product was dissolved in MeOH (20 mL), heated at 50 °C, and the product filtered off while hot. The desired product 15d was collected as pure white solid (0.12 g, 36% yield). m.p. = 123– 1 125 °C. H NMR (400 MHz, C6D6): δ = 1.10 (s, 9H, C(CH3)3), 1.56–1.63 (m, 12H), 1.98–2.07 13 (m, 18H), 2.75 (s, 2H, CH2C(CH3)3), C NMR (100 MHz, C6D6): δ = 30.65 (d, CH), 30.84 (q,

CH2C(CH3)3), 31.08 (s, CH2C(CH3)3), 36.75 (t, CH2), 44.36 (t, CH2), 51.75 (t, CH2C(CH3)3), 58.16

(s, C). Anal. Calcd. for C25H41N (355.32): C, 84.44; H, 11.62; N, 3.94; found: C, 84.12; H, 11.53; N, 3.87. The product and the method of preparation are new.

N,N-di(adamantan-1-yl)cyclopentanamine (15e)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-chloro-N,N-di(adamantan-1-yl)amine (14, 0.32 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and cyclopentylmagnesium bromide (3.0 mL, 0.50 M in diethyl ether, 1.50 mmol). The crude product was added to MeOH (30 mL), heated at 50 °C, and the product filtered off while hot. The desired product 15e was collected as pure white solid (0.09 g, 27% yield) m.p. = 124–125 1 °C. H NMR (400 MHz, C6D6): δ = 1.40–1.72 (m, 18H), 1.97 (bs, 8H), 2.01 (bs, 6H), 2.16 (bs, 3 13 6H), 3.52 (quint, J = 9.6 Hz, 1H, CH). C NMR (100 MHz, C6D6): δ = 24.0 (t, CH2), 30.6 (d,

CH), 30.9 (d, CH), 34.1 (t, CH2), 36.8 (t, CH2), 36.9 (t, CH2), 44.7 (t, CH2), 44.9 (t, CH2), 58.5 (d, + CH), 59.7 (s, C), 61.1 (s, C). HRMS m/z calcd for C25H40N (M+H ) 354.3155; found 354.3135. The product and the method of preparation are new.

N,N-di(adamantan-1-yl)cyclohexanamine (15f)

96 product was added to MeOH (30 mL), heated at 50 °C, and the product filtered off while hot. The desired product 15f was collected as pure white solid (0.09 g, 25% yield). m.p. = 201–202 °C. 1 H NMR (400 MHz, C6D6): δ = 1.00–1.13 (m, 1H), 1.25–1.38 (m, 2H), 1.55–1.81 (m, 15H), 1.85– 3 3 2.08 (m, 10H), 2.10 (bs, 6H), 2.21 (bs, 6H), 3.02 (tt, J1 = 11.6 Hz, J2 = 2.8 Hz, 1H, CH). 13 C NMR (100 MHz, C6D6): δ = 26.6 (t, CH2), 28.6 (t, CH2), 30.7 (d, CH), 30.9 (d, CH), 36.8 (t,

CH2), 36.9 (t, CH2), 38.8 (t, CH2), 45.1 (t, CH2), 45.6 (t, CH2), 58.0 (d, CH), 59.5 (s, C), 61.7 (s, + C). HRMS m/z calcd for C26H42N (M+H ) 368.3312; found 368.3367. The product and the method of preparation are new.

N,N-di(adamantan-1-yl)(exo-bicyclo[2.2.1]heptan-2-yl)amine (15g-exo)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-chloro-N,N-di(adamantan-1-yl)amine (14, 0.32 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and 2-norbornylmagnesium bromide[97] (1.50 mL, 1 M in diethyl ether, 1.50 mmol). The crude product was added to MeOH (30 mL), heated at 50 °C, and the product filtered off while hot. The desired product 15g-exo was collected as pure white solid (60.83 mg, 16% yield). 1 3 m.p. = 225–226 °C. H NMR (400 MHz, C6D6): δ = 1.12 (d, J = 9.5 Hz, 1H), 1.17–1.24 (m, 1H), 1.40–1.48 (m, 1H), 1.53–1.68 (m, 15H), 1.97–2.27 (m, 22H), 3.26 (t, 3J = 9.5 Hz, 1H, CHN). 13 C NMR (100 MHz, C6D6): δ = 27.5, 30.1, 30.8, 33.5, 36.7, 36.8, 38.3, 44.9, 45.4, 45.6, 45.7,

46.7, 58.7 (s, C), 59.7 (d, CH), 61.2 (s, C). Anal. Calcd. for C27H41N (379.32): C, 85.42; H, 10.89; N, 3.69; found: C, 85.35; H, 10.81; N, 3.62. The product and the method of preparation are new.

N,N-diisopropyladamantan-1-amine (22)

Method A: The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-chloro-N,N-diisopropylamine (5a, 0.50 g, 3.70 mmol), TMEDA (3.00 g, 26.20 mmol), and 1-adamantylmagnesium bromide[119] (11.11 mL, 0.50 M in diethyl ether, 5.55 mmol). After extraction, the solvent and the side product diisopropylamine were removed under vacuum. The crude product was dissolved in ether, and HCl(g) was bubbled inside the solution for 20 seconds. The formed amine hydrochloride salts were filtered and washed well with ether. The salt was dissolved in dichloromethane, and a cold saturated solution of sodium bicarbonate, or NaOH (5%), was added slowly. The neutralized mixture was transferred to a separatory funnel and extracted using dichloromethane and water. The organic phase was collected, dried over

K2CO3, and the solvent was removed under vacuum to yield the desired product 22 as yellowish 1 3 oil (60.92 mg, 7% yield). H NMR (400 MHz, C6D6): δ = 1.17 (d, J = 8 Hz, 12H, CH(CH3)2), 3 1.59 (bs, 6H, CH2), 1.82 (bs, 6H, CH2), 1.99 (bs, 3H, CH), 3.27 (sept, J = 8 Hz, 2H, CH(CH3)2). 13 C NMR (100 MHz, C6D6): δ = 25.5 (q, CH(CH3)2), 30.5 (d, CH), 37.2 (t, CH2), 43.4 (t, CH2), + 45.4 (d, CH(CH3)2), 56.9 (s, C). HRMS m/z calcd for C16H30N (M+H ) 236.2373; found 236.2378.

Method B: The reaction was carried out following typical procedure A for the preparation of compound 18 by using N,N-dichloroadamantan-1-amine[101] (21, 0.50 g, 2.28 mmol), TMEDA (3.00 g, 26.20 mmol), and isopropylmagnesium chloride (2.85 mL, 2 M in THF, 5.70 mmol). The crude product was added to MeOH (15 mL) and stirred for 5 min at 40 °C. The side product 1,2-di(adamantan-1-yl)diazene (23) was removed as white solid by filtration (35% yield). The mother liquor was collected, concentrated under vacuum, and purified over column chromatography using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 22 as yellowish oil (64.38 mg, 12% yield).

Method C: The reaction was carried out following typical procedure D for the preparation of compound 18 by using N,N-diisopropylamine (4a, 0.20 g, 1.98 mmol), TMSOTf (0.29 g, 1.32 mmol), and 1-adamantyl acetate[118] (25a) (0.26 g, 1.32 mmol). After the acid/base extraction, the desired product 22 was collected as yellowish oil (0.20 g, 66% yield). Compound 22 can also be prepared in a similar manner to compound 18 following typical procedures B, C, E. The product and the methods of preparation are new.

2-(adamantan-1-yl)-1,1,3,3-tetramethylisoindoline (26a)

Method A: The reaction was carried out following typical procedure B for the preparation of compound 18 by using 1,1,3,3-tetramethylisoindoline[85] (10a, 0.11 g, 0.65 mmol), AgOTf (0.17 g, 0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). After acid/base extraction, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 26a as white solid (0.14 g, 68% yield). m.p. = 117–118 °C (soften at 110°C). 1H NMR (400 MHz,

C6D6): δ = 1.58–1.68 (m, 18H), 1.98–2.05 (m, 3H), 2.15–2.21 (m, 6H), 6.92–6.97 (m, 2H), 7.11– 13 7.15 (m, 2H). C NMR (100 MHz, C6D6): δ = 30.6 (d, CH), 34.8 (q, CH3), 36.7 (t, CH2), 44.8 (t,

CH2), 57.3 (s, C), 67.0 (s, C), 120.9 (d, CH), 126.5 (d, CH), 148.7 (s, C). Anal. Calcd. for C22H31N (309.24): C, 85.38; H, 10.10; N, 4.53; found: C, 84.77; H, 10.15; N, 4.47.

Method B: The reaction was carried out following typical procedure C for the preparation of compound 18 by using 1,1,3,3-tetramethylisoindoline[85] (10a, 0.20 g, 1.14 mmol), TMSOTf (0.17 g, 0.76 mmol), and 1-adamantyl mesylate[104,117] (25f, 0.18 g, 0.76 mmol). After acid/base extraction, the excess secondary amine 10a in this case can’t be removed by evaporation under

99 vacuum. Then, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 26a as white solid (0.12 g, 51% yield). Compound 26a is unknown, and the methods of preparation are new.

2-(adamantan-1-yl)-1,1,3,3-tetraethylisoindoline (26b)

Method A: The reaction was carried out following typical procedure B for the preparation of compound 18 by using 1,1,3,3-tetraethylisoindoline[85] (10b, 0.15 g, 0.65 mmol), AgOTf (0.17 g, 0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). After acid/base extraction, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 26b as white solid (42.66 mg, 18% yield). m.p. = 126–128 °C. 1 3 H NMR (400 MHz, C6D6): δ = 0.89 (t, J = 7.6 Hz, 12H, CH2CH3), 1.56–1.69 (m, 6H), 1.99– 2.16 (m, 11H), 2.25–2.30 (m, 6H), 6.86–6.91 (m, 2H), 7.09–7.13 (m, 2H). 13C NMR (100 MHz,

C6D6): δ = 10.9 (q, CH2CH3), 30.6 (d, CH), 36.2 (t, CH2), 36.9 (t, CH2), 43.8 (t, CH2), 58.6 (s, C),

74.6 (s, C), 122.2 (d, CH), 125.8 (d, CH), 145.2 (s, C). Anal. Calcd. for C26H39N (365.30): C, 85.42; H, 10.75; N, 3.83; found: C, 85.01; H, 10.20; N, 3.56

Method B: The reaction was carried out following typical procedure C for the preparation of compound 18 by using 1,1,3,3-tetraethylisoindoline[85] (10b, 0.20 g, 0.86 mmol), TMSOTf (0.13 g, 0.57 mmol), and 1-adamantyl mesylate[104,117] (25f, 0.13 g, 0.57 mmol). After acid/base extraction, the excess secondary amine 10b in this case can’t be removed by evaporation under vacuum. Then, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide as the stationary phase and n-hexane as the

100 mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 26b as white solid (25.28 mg, 12% yield). Compound 26b is unknown, and the methods of preparation are new.

1-(adamantan-1-yl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole (26c)

The reaction was carried out following typical procedure B for the preparation of compound 18 by using 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole[122] (10c, 0.08 g, 0.65 mmol), AgOTf (0.17 g, 0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). After acid/base extraction, the desired 1 product 26c was obtained as thick oil (25.25 mg, 15% yield). H NMR (400 MHz, C6D6):

δ = 1.42 (s, 12H, CH3), 1.60–1.63 (m, 6H), 1.99–2.03 (m, 3H), 2.07–2.10 (m, 6H), 5.14 (s, 2H). 13 C NMR (100 MHz, C6D6): δ = 30.3 (q, CH3), 32.5 (d, CH), 36.9 (t, CH2), 44.8 (t, CH2), 57.0 + (s, C), 69.0 (s, C), 135.7 (d, CH). HRMS m/z calcd for C18H30N (M+H ) 260.2370; found 260.2373. Compound 26c is unknown, and the method of preparation is new.

1-(adamantan-1-yl)-2,2,5,5-tetramethylpyrrolidine (26d)

Method A: The reaction was carried out following typical procedure B for the preparation of compound 18 by using 2,2,5,5-tetramethylpyrrolidine[123] (10d, 0.08 g, 0.65 mmol), AgOTf (0.17 g, 0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). Further purification was achieved by washing with MeOH. The desired product (26d) was collected as white solid (0.11 g, 65% yield).

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1 m.p. = 92–93 °C. H NMR (400 MHz, C6D6): δ = 1.29 (s, 12H, CH3), 1.51 (s, 4H, CH2CH2), 13 1.52–1.58 (m, 6H), 1.93–2.01 (m, 9H). C NMR (100 MHz, C6D6): δ = 30.5 (q, CH3), 33.2 (d,

CH), 36.8 (t, CH2), 42.7 (t, CH2), 44.9 (t, CH2), 56.6 (s, C), 63.3 (s, C). Anal. Calcd. for C18H31N (261.24): C, 82.69; H, 11.95; N, 5.36; found: C, 81.87; H, 11.31; N, 4.94. Method B: The reaction was carried out following typical procedure C for the preparation of compound 18 by using 2,2,5,5-tetramethylpyrrolidine[123] (10d, 0.20 g, 1.57 mmol), TMSOTf (0.23 g, 1.05 mmol), and 1-adamantyl mesylate[104,117] (0.24 g, 1.05 mmol). After acid base/extraction, further purification was done by washing with MeOH. The desired product (26d) was collected as white solid (0.13 g, 48% yield). Compound 26d is unknown, and the methods of preparation are new.

Attempt for the preparation of 4-(adamantan-1-yl)-3,3,5,5-tetramethylmorpholin-2-one (26f)

The reaction was carried out following typical procedure B for the preparation of compound 18 by using 3,3,5,5-tetramethylmorpholin-2-one[108] (10f, 0.27 g, 1.74 mmol), AgOTf (0.29 g, 1.16 mmol), and 1-bromoadamantane (0.25 g, 1.16 mmol). Unfortunately, the desired product 26f was not observed, and the isolated amines were 27a and 27b in approximate ratio of 1:1 as yellowish 1 oil (20% and 23% yield respectively). Compound 27a: H NMR (400 MHz, C6D6): δ = 1.07 (s,

6H, CH3), 1.26 (s, 6H, CH3), 1.42–1.52 (m, 6H), 1.99 (bs, 3H), 2.09 (bs, 6H), 3.23 (s, 2H, CH2), 13 NH and OH labile hydrogens are difficult to be remarked. C NMR (100 MHz, C6D6): δ = 25.5

(q, CH3), 27.8 (q, CH3), 30.8 (d, CH), 36.0 (t, CH2), 41.0 (t, CH2), 55.2 (s, C), 58.2 (s, C), 69.4 (t, 1 CH2), 80.2 (s, C), 177.8 (s, CO). Compound 27b: H NMR (400 MHz, C6D6): δ = 1.32 (s, 6H,

CH3), 1.41–1.55 (m, 18H), 1.75 (bs, 6H), 1.96 (bs, 6H), 2.10 (bs, 0.6H, NH), 2.22 (bs, 6H), 3.19 13 (s, 2H, CH2). C NMR (100 MHz, C6D6): δ = 25.7 (q, CH3), 28.8 (q, CH3), 30.4 (d, CH), 30.8

(d, CH), 36.1 (t, CH2), 36.6 (t, CH2), 41.1 (t, CH2), 41.7 (t, CH2), 53.9 (s, C), 58.1 (s, C), 70.1 (t,

CH2), 71.2 (s, C), 79.2 (s, C), 177.8 (s, CO). Compounds 27a, b are unknown, and the method of preparation is new.

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Attempt for the preparation of N,N-di-tert-butyladamantan-1-amine (19)

The reaction was carried out following typical procedure B for the preparation of compound 18 by using di-tert-butylamine[73] (4c, 1.50 g, 11.63 mmol), AgOTf (1.99 g, 7.75 mmol), and 1-bromoadamantane (1.66 g, 7.75 mmol). Unfortunately, the desired product 19 was not isolated, and the isolated amine was O-(adamantan-1-yl)-N,N-di(tert-butyl)hydroxylamine 29 which was 1 collected as colorless waxy solid. H NMR (400 MHz, C6D6): δ = 1.33 (s, 18H, CH3), 1.52 (bs, 13 6H), 1.99 (bs, 3H), 2.40 (bs, 6H). C NMR (100 MHz, C6D6): δ = 31.1 (q, CH3), 31.6 (d, CH),

36.4 (t, CH2), 42.3 (t, CH2), 60.8 (s, C), 77.5 (s, C). Compound 29 is known, [121] but the method of preparation is new.

N-(adamantan-2-yl)adamantan-1-amine (31)

The reaction was carried out following typical procedure B for the preparation of compound 18 by using 2-adamantanamine (1.0 g, 6.53 mmol), 1-bromoadamantane (1.41 g, 6.53 mmol), and AgOTf (1.68 g, 6.53 mmol). The desired product 31 was collected as white solid (1.36 g, 73% 1 yield). m.p. = 174–175 °C. H NMR (400 MHz, C6D6): δ = 1.47–1.64 (m, 14H), 1.64–1.71 (m, 2H), 1.72–1.87 (m, 8H), 1.96–2.02 (m, 3H), 2.14–2.21 (m, 2H), 2.94 (s, 1H), NH labile hydrogen 13 is difficult to be detected. C NMR (100 MHz, C6D6): δ = 27.5 (d, CH), 27.7 (d, CH), 29.9 (d,

CH), 31.6 (t, CH2), 36.1 (d, CH), 36.8 (t, CH2), 37.9 (t, CH2), 38.0 (t, CH2), 43.9 (t, CH2), 50.8 (s,

C), 53.5 (d, CH). Anal. Calcd. for C20H31N (285.24): C, 84.15; H, 10.95; N, 4.91; found: C, 83.37; H, 10.23; N, 4.71. Compound 31 is unknown, and the method of preparation is new.

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N-(tert-butyl)-N-(prop-1-en-2-yl)adamantan-1-amine (35a)

The reaction was carried out following typical procedure E for the preparation of compound 18 by using N-(tert-butyl)propan-2-imine[120] (34a, 0.74 g, 6.53 mmol), 1-bromoadamantane (1.41 g, 6.53 mmol), AgOTf (1.67 g, 6.53 mmol), and methyllithium (4.21 mL, 3.10 M in diethoxymethane, 13.06 mmol). Further purification was achieved via thick layer chromatography by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The 1 titled compound 35a was collected as thick oil (0.37 g, 23% yield). H NMR (400 MHz, C6D6): 2 δ = 1.36 (s, 9H, CH3), 1.55–1.58 (m, 6H), 1.82 (s, 3H, CH3), 1.99–2.02 (m, 9H), 4.71 (d, J = 2 13 Hz, 1H), 5.07 (m, 1H). C NMR (100 MHz, C6D6): δ = 29.9 (q, CH3), 30.6 (d, CH), 33.5 (q,

CH3), 36.6 (t, CH2), 44.4 (t, CH2), 55.3 (s, C), 56.6 (s, C), 115.6 (d, CH2), 150.2 (s, C). HRMS + m/z calcd for C17H30N (M+H ) 248.2379; found 248.2373. Compound 35a is unknown, and the method of preparation is new.

N-(tert-butyl)-N-(cyclopent-1-en-1-yl)adamantan-1-amine (35b)

The reaction was carried out following typical procedure E for the preparation of compound 18 by using N-(tert-butyl)cyclopentanimine[109] (34b, 0.91 g, 6.53 mmol), AgOTf (1.67 g, 6.53 mmol), 1-bromoadamantane (1.41 g, 6.53 mmol), and methyllithium (4.21 mL, 3.10 M in diethoxymethane, 13.06 mmol). Further purification was achieved via thick layer chromatography by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The 1 titled compound 35b was collected as thick oil (0.61 g, 34% yield). H NMR (400 MHz, C6D6):

104

3 δ = 1.33 (s, 9H, CH3), 1.59 (bs, 6H), 1.78 (quint, J = 7.2 Hz, 2H, CH2), 2.00 (bs, 9H), 2.17–2.29 3 13 (m, 4H, CH2), 5.30 (t, J = 2 Hz, 1H). C NMR (100 MHz, C6D6): δ = 22.6 (t, CH2), 29.9 (t,

CH2), 30.5 (d, CH), 33.3 (q, CH3), 36.6 (t, CH2), 41.0 (t, CH2), 44.3 (t, CH2), 55.9 (s, C), 57.0 (s, + C), 127.1 (d, CH), 150.2 (s, C). HRMS m/z calcd for C19H32N (M+H ) 274.2529; found 274.2529. Compound 35b is unknown, and the method of preparation is new.

1-(adamantan-1-yl)-2,2,4-trimethyl-6-methylenepiperidine (35c) and 1-(adamantan-1-yl)- 2,2,4,6-tetramethyl-1,2,3,4-tetrahydropyridine (35d)

The reaction was carried out following typical procedure E for the preparation of compound 18 by using 2,2,4,6-tetramethyl-2,3,4,5-tetrahydropyridine[111] (34c, 0.91 g, 6.53 mmol), AgOTf (1.67 g, 6.53 mmol), 1-bromoadamantane (1.41 g, 6.53 mmol), and methyllithium (4.21 mL, 3.10 M in diethoxymethane, 13.06 mmol). Further purification was achieved via thick layer chromatography by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The titled compounds 35c and 35d were collected as thick oil mixture (0.69 g, 22% and 17% yield, 1 3 3 respectively). H NMR (400 MHz, C6D6): δ = 0.85 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.4 Hz, 2.3H), 1.12–1.17 (m, 2H), 1.27 (s, 3H), 1.33 (s, 2.3H), 1.34 (s, 2.3H), 1.45 (s, 3H), 1.53–1.58 (m, 11H), 1.70–1.82 (m, 2H), 1.86–1.94 (m, 6H), 1.95–2.02 (m, 7H), 2.03–2.11 (m, 7H), 2.14–2.26 (m, 2H), 4.69 (d, 2J = 2.4 Hz, 1H), 4.84–4.85 (m, 1H), 5.27 (d, 3J = 3.2 Hz, 0.74H). 13C NMR (100

MHz, C6D6): δ = 22.7, 22.8, 27.0, 28.7, 30.0, 30.5, 30.7, 31.3, 31.5, 32.0, 33.1, 36.5, 36.6, 41.4, 43.5, 43.8, 45.2, 46.2, 55.3, 56.8, 57.2, 59.2, 110.6, 124.9, 142.4, 151.5. HRMS m/z calcd for + C19H32N (M+H ) 274.2529; found 274.2519. Compounds 35c, d are unknown, and the method of preparation is new.

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N-isopropyl-N-methyladamantan-1-amine (37a)

The reaction was carried out following typical procedure B for the preparation of compound 18 by using N-isopropylmethylamine (0.13 g, 1.74 mmol), AgOTf (0.29 g, 1.16 mmol), and 1-bromoadamantane (0.25 g, 1.16 mmol). The desired product (37a) was collected as yellowish 1 3 oil (0.13 g, 55% yield). H NMR (400 MHz, C6D6): δ = 1.01 (d, J = 8 Hz, 6H, CH(CH3)2), 1.54 2 2 (d, J = 12 Hz, 3H), 1.60 (d, J = 12 Hz, 3H), 1.68 (bs, 6H), 1.99 (bs, 3H), 2.17 (s, 3H, CH3), 3.27 3 13 (sept, J = 8 Hz, 1H, CH(CH3)2). C NMR (100 MHz, C6D6): δ = 21.5 (q, CH3), 26.0 (q, CH3),

30.1 (d, CH), 37.1 (t, CH2), 40.2 (t, CH2), 44.1 (d, CH), 54.1 (s, C). HRMS m/z calcd for C14H26N (M+H+) 208.2060; found 208.2058. Compound 37a is unknown, and the method of preparation is new.

N-ethyl-N-isopropyladamantan-1-amine (37b)

The reaction was carried out following typical procedure B for the preparation of compound 18 by using N-ethylisopropylamine (0.15 g, 1.74 mmol), AgOTf (0.29 g, 1.16 mmol), and 1-bromoadamantane (0.25 g, 1.16 mmol). The desired product (37b) was collected as yellowish 1 3 oil (0.14 g, 53% yield). H NMR (400 MHz, C6D6): δ = 1.03 (d, J = 8 Hz, 6H, CH(CH3)2), 1.11 3 3 (t, J = 8 Hz, 3H, CH2CH3), 1.57 (bs, 6H), 1.70 (bs, 6H), 1.99 (bs, 3H), 2.58 (q, J = 8 Hz, 2H, 3 13 CH2CH3), 3.37 (sept, J = 8 Hz, 1H, CH(CH3)2). C NMR (100 MHz, C6D6): δ = 21.5 (q, CH3),

23.0 (q, CH3), 30.2 (d, CH), 33.9 (t, CH2), 37.1 (t, CH2), 41.8 (t, CH2), 44.8 (d, CH), 55.3 (s, C). + HRMS m/z calcd for C15H28N (M+H ) 222.2216; found 222.2228. Compound 37b is unknown, and the method of preparation is new.

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N-(tert-butyl)-N-ethyladamantan-1-amine (39b)

The reaction was carried out following typical procedure A for the preparation of compound 18 by using N-(tert-butyl)-N-chloroadamantan-1-amine (17, 0.24 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and ethylmagnesium bromide (3.0 mL, 0.50 M in diethyl ether, 1.50 mmol). Further purification was achieved via thick layer chromatography by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The desired product (39b) was collected as 1 3 colorless oil (0.08 g, 36% yield). H NMR (400 MHz, C6D6): δ = 1.11 (t, J = 8 Hz, 3H, CH2CH3), 13 1.25 (s, 9H, (CH3)3), 1.59 (bs, 6H), 1.91 (bs, 6H), 1.99 (bs, 3H), 2.60 (bs, 2H, CH2CH3). C NMR

(100 MHz, C6D6): δ = 22.2 (q, CH3), 30.3 (d, CH), 32.5 (q, CH3), 36.9 (t, CH2), 38.1 (t, CH2), + 43.2 (t, CH2), 57.1 (s, C), 58.8 (s, C). HRMS m/z calcd for C16H30N (M+H ) 236.2373; found 236.2383. Compound 39b is unknown, and the method of preparation is new.

N-(bicyclo[2.2.1]heptan-2-yl)adamantan-1-amine (4h)

N,N-di(adamantan-1-yl)-N-(exo-bicyclo[2.2.1]heptan-2-yl)amine (15g-exo, 0.20 g, 0.53 mmol) was refluxed in MeOH for 1 h. The solvent was evaporated under vacuum. The crude product was purified via thick layer chromatography, by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The desired product (4h) was collected as white solid (0.10 g, 1 77% yield). m.p. = 162–164 °C. H NMR (400 MHz, C6D6): δ = 0.99–1.12 (m, 4H), 1.37–1.45 3 3 (m, 2H), 1.54–1.66 (m, 14H), 1.95–2.02 (m, 4H), 2.15 (bs, 1H), 2.72 (dd, J1 = 8 Hz, J2 = 4 Hz, 13 1H), NH labile hydrogen is difficult to be remarked. C NMR (100 MHz, C6D6): δ = 26.9, 28.6,

29.8, 35.1, 35.7, 36.8, 44.0, 44.3, 45.2, 50.6, 53.5. Anal. Calcd. for C17H27N (245.41): C, 83.20; H, 11.09; N, 5.71; found: C, 82.68; H, 11.25; N, 5.04. Compound 4h is unknown, and the method of preparation is new.

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VII. References

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2. X-Ray Data

Compound 15f:

Table 1 Crystal data and structure refinement for wit_sol05o10.

Identification code wit_sol05o10 Empirical formula C26H41N Formula weight 367.60 Temperature/K 100 Crystal system monoclinic Space group P21/n a/Å 16.46750(10) b/Å 6.46350(10) c/Å 19.8240(2) α/° 90 β/° 102.7450(10) γ/° 90 Volume/Å3 2058.03(4) Z 4 3 ρcalcg/cm 1.186 μ/mm-1 0.493 F(000) 816.0 Crystal size/mm3 0.168 × 0.129 × 0.074

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Radiation CuKα (λ = 1.54184) 2Θ range for data collection/° 6.33 to 160.578 Index ranges –20 ≤ h ≤ 20, –8 ≤ k ≤ 7, –25 ≤ l ≤ 25 Reflections collected 232051 Independent reflections 4451 [Rint = 0.0756, Rsigma = 0.0128] Data/restraints/parameters 4451/0/409 Goodness-of-fit on F2 1.114 Final R indexes [I>=2σ (I)] R1 = 0.0579, wR2 = 0.1342 Final R indexes [all data] R1 = 0.0585, wR2 = 0.1346 Largest diff. peak/hole / e Å-3 0.38/–0.24

Table 2 Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement 2 3 Parameters (Å ×10 ) for wit_sol05o10. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) N1 2591.5(9) 3043(2) 5471.7(7) 17.2(3) C1 3461.2(10) 2339(3) 5757.4(9) 17.1(4) C2 3645.6(11) 31(3) 5942.1(10) 20.4(4) C3 4581.3(12) -362(3) 6015.6(11) 26.6(4) C4 5107.9(12) 1050(3) 6558.9(12) 29.3(5) C5 4899.2(12) 3337(3) 6405.7(11) 25.3(4) C6 3964.9(11) 3728(3) 6331.8(10) 22.0(4) C7 1919(1) 2489(3) 5841.8(9) 15.9(3) C8 1250.1(11) 4224(3) 5761.8(9) 19.2(4) C9 2278.9(11) 2404(3) 6633.1(9) 19.4(4) C10 1489.0(11) 392(3) 5621.4(9) 18.4(4) C11 574.2(11) 3739(3) 6165.5(9) 20.1(4) C12 951.2(12) 3569(3) 6938.4(10) 22.2(4) C13 1612.3(11) 1868(3) 7042.0(9) 21.2(4) C14 1201.8(12) -202(3) 6794.1(9) 21.6(4) C15 805.2(11) -54(3) 6019.8(9) 20.3(4) C16 155.6(11) 1687(3) 5897(1) 22.0(4) C17 2442.8(10) 3229(3) 4690.9(9) 16.5(3) C18 2986.6(11) 5062(3) 4531.4(9) 19.1(4) C19 1545.9(11) 3814(3) 4312.0(9) 18.9(4) C20 2673.8(11) 1231(3) 4338.5(9) 18.3(4) C21 2921.5(12) 5330(3) 3751.2(9) 20.8(4) C22 2021.4(12) 5825(3) 3390.7(10) 22.4(4) C23 1463.0(11) 4053(3) 3524.6(9) 20.3(4) C24 1711.3(11) 2059(3) 3208.3(9) 21.1(4) C25 2609.3(11) 1542(3) 3558.1(9) 20.0(4) C26 3193.1(12) 3318(3) 3452.1(10) 21.6(4)

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Table 3 Anisotropic Displacement Parameters (Å2×103) for wit_sol05o10. The Anisotropic 2 2 2 displacement factor exponent takes the form: -2π [h a* U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 N1 14.2(7) 20.9(8) 16.4(7) 1.6(6) 3.0(5) 1.0(6) C1 14.7(8) 16.7(8) 19.5(8) -0.3(7) 2.6(6) 0.3(6) C2 16.8(8) 17.7(9) 25.7(9) 1.8(7) 2.8(7) 0.6(7) C3 19.1(9) 21.5(10) 38.5(11) 4.3(8) 4.9(8) 2.7(7) C4 17.2(9) 30.4(11) 37.6(11) 7.3(9) 0.4(8) -1.0(8) C5 18.9(9) 25(1) 30.6(10) 1.9(8) 2.2(7) -4.0(7) C6 19.3(9) 20.6(9) 24.7(9) -2.1(7) 2.0(7) -2.7(7) C7 14.6(7) 15.5(8) 17.6(8) -1.2(6) 3.3(6) -1.1(6) C8 19.0(8) 18.0(9) 21.3(9) 0.7(7) 5.8(7) 1.7(7) C9 18.9(8) 20.4(9) 18.5(8) -0.2(7) 3.1(7) -0.3(7) C10 19.1(8) 15.1(8) 21.3(9) -0.4(7) 5.2(7) -1.3(7) C11 18.4(8) 20.6(9) 21.8(9) 0.2(7) 5.6(7) 2.3(7) C12 22.7(9) 22.4(9) 22.9(9) -2.3(7) 7.8(7) 0.4(7) C13 21.7(9) 23.1(9) 18.5(8) 0.5(7) 3.7(7) 0.2(7) C14 24.6(9) 19.9(9) 21.0(9) 1.7(7) 6.8(7) -0.3(7) C15 20.3(8) 17.8(9) 22.8(9) -0.8(7) 5.0(7) -4.1(7) C16 17.3(8) 26.4(10) 22.3(9) 1.2(7) 4.4(7) -1.9(7) C17 17.1(8) 15.2(8) 17.0(8) 0.2(6) 3.4(6) 0.4(6) C18 20.9(9) 14.2(8) 22.2(9) 0.1(7) 5.2(7) -1.0(7) C19 19.0(8) 19.2(9) 18.3(8) 0.9(7) 3.9(6) 1.5(7) C20 19.1(8) 15.0(8) 20.7(8) 0.3(7) 4.2(7) -0.1(7) C21 24.1(9) 16.2(9) 23.6(9) 1.2(7) 8.5(7) -0.7(7) C22 26.7(9) 18.9(9) 22.1(9) 3.0(7) 6.4(7) 3.4(7) C23 19.6(8) 22.0(9) 19.3(8) 2.3(7) 4.0(7) 3.5(7) C24 22.8(9) 21.2(9) 19.2(9) -0.9(7) 4.3(7) -1.2(7) C25 23.0(9) 17.0(9) 20.5(8) -1.4(7) 6.0(7) 0.5(7) C26 23.6(9) 20.0(9) 23.2(9) -0.3(7) 9.3(7) -0.4(7)

Table 4 Bond Lengths for wit_sol05o10. Atom Atom Length/Å Atom Atom Length/Å N1 C1 1.490(2) C12 C13 1.529(3) N1 C7 1.500(2) C13 C14 1.530(3) N1 C17 1.518(2) C14 C15 1.533(2) C1 C2 1.550(2) C15 C16 1.534(3) C1 C6 1.541(2) C17 C18 1.559(2) C2 C3 1.537(2) C17 C19 1.549(2) C3 C4 1.527(3) C17 C20 1.555(2)

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C4 C5 1.533(3) C18 C21 1.536(2) C5 C6 1.534(3) C19 C23 1.544(2) C7 C8 1.555(2) C20 C25 1.540(2) C7 C9 1.551(2) C21 C22 1.531(3) C7 C10 1.547(2) C21 C26 1.536(3) C8 C11 1.540(2) C22 C23 1.528(3) C9 C13 1.541(2) C23 C24 1.528(3) C10 C15 1.539(2) C24 C25 1.525(3) C11 C12 1.525(3) C25 C26 1.541(3) C11 C16 1.535(3)

Table 5 Bond Angles for wit_sol05o10. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ C1 N1 C7 119.49(13) C13 C14 C15 109.10(15) C1 N1 C17 109.70(13) C14 C15 C10 109.10(15) C7 N1 C17 123.17(13) C14 C15 C16 109.45(15) N1 C1 C2 120.37(14) C16 C15 C10 110.18(15) N1 C1 C6 114.72(14) C15 C16 C11 109.54(15) C6 C1 C2 109.93(14) N1 C17 C18 107.24(13) C3 C2 C1 108.75(15) N1 C17 C19 115.85(13) C4 C3 C2 111.70(17) N1 C17 C20 113.07(14) C3 C4 C5 111.65(16) C19 C17 C18 104.21(14) C4 C5 C6 110.74(16) C19 C17 C20 106.64(14) C5 C6 C1 109.85(16) C20 C17 C18 109.36(14) N1 C7 C8 111.15(14) C21 C18 C17 111.97(14) N1 C7 C9 110.15(13) C23 C19 C17 112.14(14) N1 C7 C10 114.34(14) C25 C20 C17 111.92(14) C9 C7 C8 103.47(14) C22 C21 C18 109.81(15) C10 C7 C8 109.46(14) C22 C21 C26 109.35(15) C10 C7 C9 107.66(14) C26 C21 C18 109.38(15) C11 C8 C7 112.17(15) C23 C22 C21 108.66(15) C13 C9 C7 112.49(14) C22 C23 C19 109.15(15) C15 C10 C7 111.12(14) C24 C23 C19 111.01(15) C12 C11 C8 110.86(15) C24 C23 C22 109.59(15) C12 C11 C16 109.79(15) C25 C24 C23 108.57(15) C16 C11 C8 108.45(15) C20 C25 C26 109.10(15) C11 C12 C13 107.85(15) C24 C25 C20 109.29(14) C12 C13 C9 109.65(15) C24 C25 C26 110.25(15) C12 C13 C14 109.56(15) C21 C26 C25 109.53(15) C14 C13 C9 110.07(15)

192

Table 6 Torsion Angles for wit_sol05o10. A B C D Angle/˚ A B C D Angle/˚ N1 C1 C2 C3 163.53(16) C10 C7 C9 C13 -55.45(19) N1 C1 C6 C5 -160.2(15) C10 C15 C16 C11 -61.46(19) N1 C7 C8 C11 -177.3(14) C11 C12 C13 C9 58.50(19) N1 C7 C9 C13 179.27(15) C11 C12 C13 C14 -62.40(19) N1 C7 C10 C15 -179.6(14) C12 C11 C16 C15 -60.22(19) N1 C17 C18 C21 177.05(14) C12 C13 C14 C15 61.67(19) N1 C17 C19 C23 177.70(15) C13 C14 C15 C10 61.40(19) N1 C17 C20 C25 -173.7(14) C13 C14 C15 C16 -59.23(19) C1 N1 C7 C8 147.03(15) C14 C15 C16 C11 58.52(19) C1 N1 C7 C9 33.0(2) C16 C11 C12 C13 61.54(19) C1 N1 C7 C10 -88.42(18) C17 N1 C1 C2 -98.91(18) C1 N1 C17 C18 -67.95(17) C17 N1 C1 C6 126.28(16) C1 N1 C17 C19 176.20(14) C17 N1 C7 C8 -66.6(2) C1 N1 C17 C20 52.69(18) C17 N1 C7 C9 179.30(15) C1 C2 C3 C4 57.2(2) C17 N1 C7 C10 57.9(2) C2 C1 C6 C5 60.38(19) C17 C18 C21 C22 61.70(19) C2 C3 C4 C5 -55.4(2) C17 C18 C21 C26 -58.30(19) C3 C4 C5 C6 54.8(2) C17 C19 C23 C22 -62.61(19) C4 C5 C6 C1 -57.3(2) C17 C19 C23 C24 58.3(2) C6 C1 C2 C3 -59.75(19) C17 C20 C25 C24 -62.10(19) C7 N1 C1 C2 51.6(2) C17 C20 C25 C26 58.52(19) C7 N1 C1 C6 -83.24(19) C18 C17 C19 C23 60.15(18) C7 N1 C17 C18 142.87(15) C18 C17 C20 C25 -54.26(18) C7 N1 C17 C19 27.0(2) C18 C21 C22 C23 -59.20(19) C7 N1 C17 C20 -96.50(18) C18 C21 C26 C25 61.45(19) C7 C8 C11 C12 61.6(2) C19 C17 C18 C21 -59.61(18) C7 C8 C11 C16 -58.95(19) C19 C17 C20 C25 57.86(18) C7 C9 C13 C12 -63.2(2) C19 C23 C24 C25 -58.96(19) C7 C9 C13 C14 57.4(2) C20 C17 C18 C21 54.09(19) C7 C10 C15 C14 -62.05(19) C20 C17 C19 C23 -55.48(19) C7 C10 C15 C16 58.13(19) C20 C25 C26 C21 -61.47(19) C8 C7 C9 C13 60.38(18) C21 C22 C23 C19 59.20(19) C8 C7 C10 C15 -54.16(18) C21 C22 C23 C24 -62.56(19) C8 C11 C12 C13 -58.3(2) C22 C21 C26 C25 -58.83(19) C8 C11 C16 C15 61.04(19) C22 C23 C24 C25 61.68(19) C9 C7 C8 C11 -59.12(18) C23 C24 C25 C20 60.39(19) C9 C7 C10 C15 57.66(18) C23 C24 C25 C26 -59.52(19) C9 C13 C14 C15 -58.97(19) C24 C25 C26 C21 58.56(19) C10 C7 C8 C11 55.42(19) C26 C21 C22 C23 60.82(19)

193

Table 7 Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for wit_sol05o10. Atom x y z U(eq) H1 3742(12) 2550(30) 5361(10) 14(5) H2A 3499(13) -390(30) 6400(11) 22(5) H2B 3329(14) -840(40) 5581(12) 27(6) H3A 4740(12) 10(30) 5550(10) 17(5) H3B 4702(16) -1910(40) 6132(13) 39(7) H4A 4996(15) 700(40) 7029(13) 34(6) H4B 5732(16) 700(40) 6594(13) 37(7) H5A 5224(14) 4220(40) 6766(12) 26(6) H5B 5075(13) 3820(40) 5944(11) 23(5) H6A 3803(14) 3440(40) 6790(12) 29(6) H6B 3813(14) 5250(40) 6227(12) 30(6) H8A 953(12) 4370(30) 5283(11) 17(5) H8B 1571(14) 5480(40) 5939(12) 28(6) H9A 2535(13) 3860(30) 6784(11) 19(5) H9B 2732(14) 1360(40) 6748(11) 26(6) H10A 1918(12) -750(30) 5715(10) 13(5) H10B 1217(13) 440(40) 5095(11) 24(6) H11 180(13) 4800(40) 6072(11) 19(5) H12A 505(13) 3200(30) 7204(11) 19(5) H12B 1207(13) 5010(40) 7111(11) 22(5) H13 1886(14) 1760(40) 7545(12) 28(6) H14A 1608(14) -1360(40) 6873(12) 27(6) H14B 761(13) -500(40) 7058(11) 24(6) H15 528(13) -1410(30) 5856(11) 19(5) H16A -296(14) 1320(40) 6154(11) 27(6) H16B -90(13) 1800(40) 5389(12) 24(6) H18A 3602(13) 4880(30) 4765(10) 19(5) H18B 2768(14) 6390(40) 4707(12) 29(6) H19A 1116(13) 2770(40) 4391(11) 23(5) H19B 1415(13) 5170(30) 4504(11) 18(5) H20A 3269(13) 800(30) 4548(10) 16(5) H20B 2253(14) 140(40) 4411(12) 29(6) H21 3323(14) 6520(40) 3681(12) 29(6) H22A 1843(14) 7140(40) 3572(12) 30(6) H22B 1971(13) 5980(40) 2877(11) 23(5) H23 870(13) 4360(30) 3314(11) 19(5) H24A 1656(14) 2220(40) 2710(12) 25(6) H24B 1312(14) 880(40) 3298(12) 29(6) H25 2787(14) 180(40) 3368(12) 27(6)

194

H26A 3791(14) 3000(40) 3673(11) 23(5) H26B 3188(14) 3490(40) 2937(12) 30(6)

Experimental:

Single crystals of C26H41N [wit_sol05o10] were crystallized from dibutylether/ethanole mixture. A suitable crystal was selected and [tip-mounted] on a XtaLAB Synergy, Dualflex, Pilatus 300K diffractometer. The crystal was kept at 100 K during data collection. Using Olex2, the structure was solved with the ShelXT structure solution program using Intrinsic Phasing and refined with the ShelXL refinement package using Least Squares minimisation.

Crystal structure determination of [wit_sol05o10]

Crystal Data for C26H41N (M =367.60 g/mol): monoclinic, space group P21/n (no. 14), a = 16.46750(10) Å, b = 6.46350(10) Å, c =19.8240(2) Å, β = 102.7450(10)°, V = 2058.03(4) Å3, Z = 4, T = 100 K, μ(CuKα) = 0.493 mm-1, Dcalc = 1.186 g/cm3, 232051 reflections measured (6.33° ≤

2Θ ≤ 160.578°), 4451 unique (Rint = 0.0756, Rsigma = 0.0128) which were used in all calculations.

The final R1 was 0.0579 (I > 2σ(I)) and wR2 was 0.1346 (all data).

Compound 18:

195

Table 1 Crystal data and structure refinement for amin10p06. Identification code amin10p06 Empirical formula C17H31N Formula weight 249.43 Temperature/K 100.0 Crystal system monoclinic Space group P21/c a/Å 18.776(5) b/Å 6.4752(18) c/Å 24.315(6) α/° 90 β/° 90.017(4) γ/° 90 Volume/Å3 2956.2(14) Z 8 3 ρcalcg/cm 1.121 μ/mm-1 0.063 F(000) 1120.0 Crystal size/mm3 0.711 × 0.216 × 0.086 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/° 1.674 to 50.816 Index ranges –22 ≤ h ≤ 22, –7 ≤ k ≤ 7, –29 ≤ l ≤ 29 Reflections collected 33220 Independent reflections 5434 [Rint = 0.0607, Rsigma = 0.0371] Data/restraints/parameters 5434/0/336 Goodness-of-fit on F2 1.034 Final R indexes [I>=2σ (I)] R1 = 0.0435, wR2 = 0.0987 Final R indexes [all data] R1 = 0.0556, wR2 = 0.1044 Largest diff. peak/hole / e Å-3 0.26/–0.19

Table 2 Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement 2 3 Parameters (Å ×10 ) for amin10p06. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) N1 1694.7(9) 7134(2) 4472.8(7) 16.4(4) C1 1177(1) 7742(3) 4022.6(9) 15.0(4) C2 1129.8(11) 5927(3) 3610.9(8) 16.0(4) C3 636.2(11) 6407(3) 3122.4(9) 17.5(5) C4 -116.1(11) 6768(3) 3326.5(9) 21.3(5) C5 -100.7(11) 8554(3) 3735.3(9) 19.6(5) C6 409.6(11) 8070(3) 4218.0(9) 18.3(5)

196

C7 1395.6(10) 9730(3) 3713.5(8) 16.3(4) C8 889.9(11) 10176(3) 3230.5(8) 18.1(4) C9 139.5(11) 10517(3) 3441.9(9) 20.8(5) C10 897.0(12) 8360(3) 2831.4(8) 19.3(5) C11 1611.0(13) 7808(3) 5055.6(9) 23.4(5) C12 2209.4(13) 6878(4) 5415.5(10) 29.5(6) C13 1625.3(13) 10171(3) 5142.1(9) 29.3(5) C14 935.0(13) 6934(4) 5320.4(10) 30.1(6) C15 2426.9(11) 6968(3) 4251.2(9) 19.0(5) C16 2948.8(11) 8762(3) 4341.2(10) 25.4(5) C17 2784.9(12) 4891(3) 4370.8(10) 26.9(5) N1A 6698.0(9) 8117(2) 3020.9(7) 16.7(4) C1A 6167.3(11) 7807(3) 3473.0(9) 14.0(4) C2A 6161.8(11) 9811(3) 3821.3(8) 16.3(4) C3A 5652.2(11) 9650(3) 4306.0(9) 19.0(5) C4A 4896.1(11) 9323(3) 4094.7(9) 20.6(5) C5A 4875.9(11) 7350(3) 3751.4(9) 18.3(4) C6A 5395.5(10) 7526(3) 3271.7(9) 16.0(4) C7A 6343.9(10) 5965(3) 3854.7(8) 15.7(4) C8A 5830.2(11) 5835(3) 4337.1(9) 19.3(5) C9A 5076.9(12) 5518(3) 4117.2(9) 21.4(5) C10A 5871.0(12) 7825(3) 4670.8(9) 19.0(5) C11A 6588.5(12) 7248(3) 2456.5(9) 22.1(5) C12A 7209.5(13) 7884(4) 2090.3(10) 30.7(6) C13A 6524.4(13) 4883(3) 2431.5(9) 29.8(5) C14A 5940.1(12) 8204(3) 2163.3(9) 26.7(5) C15A 7437.5(11) 8193(3) 3254.7(9) 20.0(5) C16A 7892.8(12) 6230(3) 3239.3(10) 25.5(5) C17A 7868.5(12) 10068(3) 3074.1(10) 28.3(5)

Table 3 Anisotropic Displacement Parameters (Å2×103) for amin10p06. The Anisotropic 2 2 2 displacement factor exponent takes the form: -2π [h a* U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 N1 15.7(9) 15.1(8) 18.5(9) 1.7(7) -1.1(8) 0.9(7) C1 13.8(10) 9.4(9) 21.9(12) 1.5(8) -1.7(9) 0.1(8) C2 13.9(10) 9.7(9) 24.2(11) 0.4(8) 0.1(9) 0.5(7) C3 20.4(11) 12.5(10) 19.7(11) -3.3(8) -3.3(9) 0.1(8) C4 15.4(11) 17.1(10) 31.2(12) 1.9(9) -5.4(10) -1.4(8) C5 12.4(10) 18.2(10) 28.3(12) 1.2(9) 1.3(9) 1.7(8) C6 19.7(11) 14(1) 21.2(12) 0.0(8) 1.9(10) 0.1(8)

197

C7 17.9(11) 10.4(9) 20.6(10) -0.7(8) 0.6(9) 0.4(7) C8 22.0(11) 11.1(9) 21.2(11) 5.8(8) -2.0(9) -0.5(8) C9 21.4(11) 16.8(10) 24.1(11) -1.3(8) -4.8(9) 4.8(9) C10 21.8(12) 17.3(10) 18.8(11) 0.7(8) -2.7(10) 1.2(8) C11 26.4(12) 22.2(11) 21.6(12) 1.2(9) 2.7(10) 1.4(9) C12 33.5(15) 32.5(13) 22.5(12) 0.7(10) -3.0(11) 2.1(11) C13 34.4(13) 28.2(12) 25.2(12) -5.9(10) 2.1(11) 3.1(10) C14 33.9(14) 33.9(13) 22.5(13) 7.7(10) 5.2(11) 0.1(10) C15 16.9(11) 17(1) 23.2(11) -1.8(8) -0.9(9) 2.5(8) C16 17.5(11) 26.2(12) 32.6(13) -1.8(10) 0.8(10) 1.2(9) C17 27.2(13) 23.0(11) 30.4(12) -4.3(10) -3.9(11) 8.5(10) N1A 14.6(9) 16.8(8) 18.9(9) 1.6(7) 2.5(8) 1.0(7) C1A 15.1(11) 9.1(9) 17.8(11) -0.2(7) 1.3(9) -0.4(7) C2A 14.8(10) 9.8(9) 24.3(11) -0.8(8) -1.1(9) -0.4(8) C3A 23.3(11) 12.7(10) 21.1(11) -4.5(8) 3.2(10) 1.2(8) C4A 17.0(11) 18.2(10) 26.6(11) -2.5(9) 5.7(9) 3.2(8) C5A 10.3(10) 19.5(10) 25.1(12) -3.0(9) 0.7(9) -1.4(8) C6A 17.6(11) 11.9(9) 18.6(11) -2.2(8) -1.7(9) -0.3(8) C7A 17.4(11) 9.6(9) 20.1(10) -0.1(8) 0.7(9) 1.5(8) C8A 24.1(11) 10.0(9) 23.9(11) 3.7(8) 1.8(10) -1.1(8) C9A 25.0(12) 16(1) 23.1(11) -1.7(8) 5.7(10) -6.0(9) C10A 18.3(11) 20.4(11) 18.3(11) -0.3(8) 3.6(10) -1.9(8) C11A 25.1(13) 21.9(11) 19.2(12) 0.9(8) 2.3(10) 5.6(9) C12A 31.2(14) 39.0(14) 21.9(13) 0.5(10) 4.6(11) 5.6(11) C13A 37.9(14) 27.4(12) 24.0(12) -8.9(9) -2.9(11) 6.7(11) C14A 29.3(13) 31.3(13) 19.5(12) 1.7(9) -2.5(11) 4.1(10) C15A 16.5(11) 17.3(10) 26.1(12) 1.4(9) 1.4(10) 0.5(8) C16A 20.5(11) 26.5(12) 29.5(12) 2.4(10) 2.1(10) 3.2(9) C17A 25.3(12) 23.9(11) 35.6(13) 2.5(10) 2.5(11) -4.5(10)

Table 4 Bond Lengths for amin10p06. Atom Atom Length/Å Atom Atom Length/Å N1 C1 1.516(3) N1A C1A 1.497(3) N1 C11 1.491(3) N1A C11A 1.497(3) N1 C15 1.481(3) N1A C15A 1.501(3) C1 C2 1.546(3) C1A C2A 1.549(3) C1 C6 1.532(3) C1A C6A 1.540(3) C1 C7 1.546(3) C1A C7A 1.547(3) C2 C3 1.538(3) C2A C3A 1.522(3) C3 C4 1.515(3) C3A C4A 1.524(3)

198

C3 C10 1.529(3) C3A C10A 1.534(3) C4 C5 1.525(3) C4A C5A 1.527(3) C5 C6 1.547(3) C5A C6A 1.525(3) C5 C9 1.526(3) C5A C9A 1.530(3) C7 C8 1.537(3) C7A C8A 1.521(3) C8 C9 1.516(3) C8A C9A 1.526(3) C8 C10 1.525(3) C8A C10A 1.524(3) C11 C12 1.546(3) C11A C12A 1.524(3) C11 C13 1.545(3) C11A C13A 1.538(3) C11 C14 1.532(3) C11A C14A 1.540(3) C15 C16 1.535(3) C15A C16A 1.532(3) C15 C17 1.531(3) C15A C17A 1.524(3)

Table 5 Bond Angles for amin10p06. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ C11 N1 C1 122.86(17) C1A N1A C15A 110.00(16) C15 N1 C1 110.57(15) C11A N1A C1A 122.11(17) C15 N1 C11 117.71(18) C11A N1A C15A 119.09(17) N1 C1 C2 107.87(15) N1A C1A C2A 107.09(15) N1 C1 C6 114.52(17) N1A C1A C6A 114.12(17) N1 C1 C7 113.39(15) N1A C1A C7A 113.64(15) C2 C1 C7 109.47(17) C6A C1A C2A 105.44(15) C6 C1 C2 104.62(16) C6A C1A C7A 107.52(16) C6 C1 C7 106.55(15) C7A C1A C2A 108.61(17) C3 C2 C1 112.37(15) C3A C2A C1A 111.74(16) C4 C3 C2 109.87(17) C2A C3A C4A 109.53(17) C4 C3 C10 108.83(16) C2A C3A C10A 109.40(16) C10 C3 C2 109.37(16) C4A C3A C10A 109.70(17) C3 C4 C5 108.22(16) C3A C4A C5A 108.87(16) C4 C5 C6 110.64(17) C4A C5A C9A 108.96(18) C4 C5 C9 109.43(18) C6A C5A C4A 109.84(16) C9 C5 C6 109.89(16) C6A C5A C9A 110.18(16) C1 C6 C5 112.04(17) C5A C6A C1A 111.59(17) C8 C7 C1 111.33(16) C8A C7A C1A 111.67(16) C9 C8 C7 109.99(17) C7A C8A C9A 108.98(17) C9 C8 C10 109.65(17) C7A C8A C10A 109.39(16) C10 C8 C7 109.62(16) C10A C8A C9A 110.29(17) C8 C9 C5 108.19(16) C8A C9A C5A 109.14(16) C8 C10 C3 109.90(17) C8A C10A C3A 109.26(18) N1 C11 C12 110.31(18) N1A C11A C12A 109.22(18)

199

N1 C11 C13 114.67(17) N1A C11A C13A 114.90(18) N1 C11 C14 112.25(19) N1A C11A C14A 112.43(17) C13 C11 C12 107.23(19) C12A C11A C13A 107.81(19) C14 C11 C12 102.74(18) C12A C11A C14A 103.05(18) C14 C11 C13 108.85(19) C13A C11A C14A 108.67(19) N1 C15 C16 119.07(17) N1A C15A C16A 118.67(17) N1 C15 C17 113.72(17) N1A C15A C17A 114.10(17) C17 C15 C16 110.93(18) C17A C15A C16A 110.94(18)

Table 6 Torsion Angles for amin10p06. A B C D Angle/˚ A B C D Angle/˚ N1 C1 C2 C3 -177.9(15) N1A C1A C2A C3A -178.4(16) N1 C1 C6 C5 -176.4(15) N1A C1A C6A C5A -176.5(15) N1 C1 C7 C8 175.13(16) N1A C1A C7A C8A 174.69(16) C1 N1 C11 C12 178.20(16) C1A N1A C11A C12A 178.39(16) C1 N1 C11 C13 -60.6(3) C1A N1A C11A C13A -60.3(3) C1 N1 C11 C14 64.3(2) C1A N1A C11A C14A 64.6(2) C1 N1 C15 C16 100.2(2) C1A N1A C15A C16A 98.0(2) C1 N1 C15 C17 -126.1(18) C1A N1A C15A C17A -128.3(18) C1 C2 C3 C4 -62.2(2) C1A C2A C3A C4A -61.5(2) C1 C2 C3 C10 57.2(2) C1A C2A C3A C10A 58.8(2) C1 C7 C8 C9 61.7(2) C1A C7A C8A C9A 61.1(2) C1 C7 C8 C10 -58.9(2) C1A C7A C8A C10A -59.6(2) C2 C1 C6 C5 -58.59(19) C2A C1A C6A C5A -59.3(2) C2 C1 C7 C8 54.6(2) C2A C1A C7A C8A 55.6(2) C2 C3 C4 C5 58.5(2) C2A C3A C4A C5A 59.0(2) C2 C3 C10 C8 -60.1(2) C2A C3A C10A C8A -60.9(2) C3 C4 C5 C6 -58.1(2) C3A C4A C5A C6A -59.0(2) C3 C4 C5 C9 63.2(2) C3A C4A C5A C9A 61.8(2) C4 C3 C10 C8 60.0(2) C4A C3A C10A C8A 59.2(2) C4 C5 C6 C1 60.9(2) C4A C5A C6A C1A 61.2(2) C4 C5 C9 C8 -62.2(2) C4A C5A C9A C8A -61.0(2) C6 C1 C2 C3 59.7(2) C6A C1A C2A C3A 59.7(2) C6 C1 C7 C8 -58.0(2) C6A C1A C7A C8A -58.0(2) C6 C5 C9 C8 59.5(2) C6A C5A C9A C8A 59.6(2) C7 C1 C2 C3 -54.1(2) C7A C1A C2A C3A -55.3(2) C7 C1 C6 C5 57.3(2) C7A C1A C6A C5A 56.4(2) C7 C8 C9 C5 -60.6(2) C7A C8A C9A C5A -60.4(2) C7 C8 C10 C3 61.3(2) C7A C8A C10A C3A 61.2(2) C9 C5 C6 C1 -60.0(2) C9A C5A C6A C1A -58.8(2)

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C9 C8 C10 C3 -59.5(2) C9A C8A C10A C3A -58.6(2) C10 C3 C4 C5 -61.3(2) C10A C3A C4A C5A -61.1(2) C10 C8 C9 C5 60.0(2) C10A C8A C9A C5A 59.7(2) C11 N1 C1 C2 -146.3(18) C11A N1A C1A C2A -144.4(17) C11 N1 C1 C6 -30.3(2) C11A N1A C1A C6A -28.1(2) C11 N1 C1 C7 92.3(2) C11A N1A C1A C7A 95.7(2) C11 N1 C15 C16 -48.2(3) C11A N1A C15A C16A -50.2(3) C11 N1 C15 C17 85.5(2) C11A N1A C15A C17A 83.5(2) C15 N1 C1 C2 67.19(19) C15A N1A C1A C2A 68.54(18)

-175.2(15) C15 N1 C1 C6 -176.7(16) C15A N1A C1A C6A C15 N1 C1 C7 -54.2(2) C15A N1A C1A C7A -51.4(2) C15 N1 C11 C12 -37.5(2) C15A N1A C11A C12A -37.4(2) C15 N1 C11 C13 83.7(2) C15A N1A C11A C13A 83.9(2)

C15 N1 C11 C14 -151.4(18) C15A N1A C11A C14A -151.1(18)

Table 7 Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for amin10p06. Atom x y z U(eq) H2A 1613 5611 3471 19 H2B 951 4686 3805 19 H3 640 5222 2859 21 H4A -300 5506 3507 26 H4B -433 7108 3014 26 H5 -592 8770 3884 24 H6A 398 9226 4484 22 H6B 243 6811 4410 22 H7A 1389 10912 3972 20 H7B 1888 9576 3573 20 H8 1054 11447 3034 22 H9A -185 10827 3132 25 H9B 131 11699 3700 25 H10A 1387 8140 2692 23 H10B 585 8666 2514 23 H12A 2188 5368 5398 44 H12B 2147 7328 5797 44 H12C 2673 7350 5280 44 H13A 2081 10724 5013 44 H13B 1568 10482 5534 44 H13C 1236 10808 4934 44

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H14A 524 7774 5211 45 H14B 984 6961 5722 45 H14C 864 5507 5198 45 H15 2355 6949 3844 23 H16A 2706 10074 4269 38 H16B 3354 8616 4090 38 H16C 3120 8740 4722 38 H17A 2945 4860 4754 40 H17B 3195 4713 4126 40 H17C 2443 3771 4308 40 H2AA 6649 10086 3960 20 H2AB 6019 10987 3586 20 H3A 5672 10955 4526 23 H4AA 4748 10516 3867 25 H4AB 4563 9205 4408 25 H5A 4383 7141 3605 22 H6AA 5260 8719 3039 19 H6AB 5365 6265 3043 19 H7AA 6321 4666 3641 19 H7AB 6836 6118 3996 19 H8A 5964 4640 4576 23 H9AA 4738 5408 4427 26 H9AB 5054 4221 3902 26 H10C 6363 8031 4807 23 H10D 5549 7733 4992 23 H12D 7243 9394 2080 46 H12E 7132 7357 1717 46 H12F 7653 7311 2238 46 H13D 6968 4256 2562 45 H13E 6435 4453 2051 45 H13F 6129 4431 2665 45 H14D 5506 7489 2280 40 H14E 5997 8061 1765 40 H14F 5905 9671 2259 40 H15A 7358 8433 3656 24 H16D 7603 5045 3353 38 H16E 8297 6383 3491 38 H16F 8069 6007 2865 38 H17D 8062 9826 2706 42 H17E 8260 10296 3333 42 H17F 7560 11288 3067 42

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Experimental:

Single crystals of C17H31N [amin10p06]. A suitable crystal was selected and [tip- mounted] on a Bruker SMART Platform with a Apex I-detector diffractometer. The crystal was kept at 100.0 K during data collection. Using Olex2, the structure was solved with the ShelXS structure solution program using Direct Methods and refined with the ShelXL refinement package using Least Squares minimisation.

Crystal structure determination of [amin10p06]

Crystal Data for C17H31N (M =249.43 g/mol): monoclinic, space group P21/c (no. 14), a = 18.776(5) Å, b = 6.4752(18) Å, c = 24.315(6) Å, β = 90.017(4)°, V = 2956.2(14) Å3, Z = 8, T = 100.0 K, μ(MoKα) = 0.063 mm-1, Dcalc = 1.121 g/cm3, 33220 reflections measured (1.674° ≤ 2Θ

≤ 50.816°), 5434 unique (Rint = 0.0607, Rsigma = 0.0371) which were used in all calculations. The final R1 was 0.0435 (I > 2σ(I)) and wR2 was 0.1044 (all data).

3. Theoretical calculation data

Pyramidenhöhen Trimethylamin (Gasphase) BLYPD3: 0.436 PBED3: 0.438 SCS-MP2: 0.469 MP2: 0.472

Triethylamin (Gasphase) BLYPD3: 0.346 PBED3: 0.391

tert-Butyl-diisopropylamin (Molekülkristall) experimenteller: 0.250 BLYPD3: 0.241 optB88-vdW: 0.248 PBED3: 0.245 PBE-TS: 0.223 PBE-MBD: 0.234 RPBE-D3: 0.250 vdW-DF2: 0.248

203 tert-Butyl-diisopropylamin (Gasphase) BLYPD3: 0.229 optB88-vdW: 0.230 PBED3: 0.232 PBE-TS: 0.207 PBE-MBD: 0.233 RPBE-D3: 0.245 vdW-DF2: 0.233 SCS-MP2: 0.255 MP2: 0.264

1-Adamantyl-tert-butyl-isopropylamin (18) (Molekülkristall) experimenteller: 0.259 BLYPD3: 0.256 optB88-vdW: 0.256 PBED3: 0.253 PBE-TS: 0.243 RPBE-D3: 0.266 vdW-DF2: 0.260

1-Adamantyl-tert-butyl-isopropylamin (18) (Gasphase) BLYPD3: 0.241 optB88-vdW: 0.242 PBED3: 0.240 PBE-TS: 0.228 RPBE-D3: 0.255 vdW-DF2: 0.248

Di-(1-adamantyl)cyclohexylamin (15f) (Molekülkristall) experimenteller: 0.241 BLYPD3: 0.223 optB88-vdW: 0.230 PBED3: 0.228 PBE-TS: 0.200 RPBE-D3: 0.247 vdW-DF2: 0.229

Di-(1-adamantyl)cyclohexylamin (15f) (Gasphase) BLYPD3: 0.247 optB88-vdW: 0.247 PBED3: 0.246 PBE-TS: 0.231 RPBE-D3: 0.260 vdW-DF2: 0.250

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IX. Curriculum Vitae

EDUCATION

2015-2017 Technische Universität Chemnitz Chemnitz, Germany PhD in Organic Chemistry Faculty of Natural Sciences

2008-2011 American University of Beirut Beirut, Lebanon MA in Organic Chemistry Faculty of Arts and Sciences

2003-2007 Lebanese University Beirut, Lebanon BS in Chemistry Faculty of Arts and Sciences

WORK EXPERIENCE

2008-2015 American University of Beirut Beirut, Lebanon

Research assistant in organic chemistry labs Teaching assistant in organic and analytical labs Trainee at the Chemistry Department Report/paper writing experience Analyzed research studies Learned new research techniques Learned new laboratory skills

ACADEMIC PROJECTS

2015-2017 PhD project Organic synthesis of Novel High Sterically Hindered Tertiary Amines by Various Method.

2011-2015 Research project Organic synthesis and the Photophysical studies of new classes of cyclometalated Ruthenium-Osmium complexes dyes and organic electrolytes for dye sensitized solar cells.

2008-2011 Master thesis Synthesis of novel drugs based on quinoxaline, quinoline and cinnoline moieties and investigate their effects as anticancer drugs.

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PUBLICATIONS AND PATENTS

1- Quinoxalino[2,3-c]cinnolines and their 5-N-oxide: alkoxylation of methyl-substituted quinoxalino[2,3-c]cinnolines to acetals and orthoesters. Makhluf J Haddadin, Mirna El-Khatib, Tharallah A Shoker, Christine M Beavers, Marilyn M Olmstead, James C Fettinger, Kelli M Farber, Mark J Kurth J. Org. Chem. 2011, 76 (20), pp 8421–8427.

2- Unusual Friedlander Reactions: A Route to Novel Quinoxaline-Based Heterocycles. Tharallah A Shoker, Khaled I Ghattass, James C Fettinger, Mark J Kurth, Makhluf J Haddadin Org. Lett. 2012, 14(14), 3704–3707.

3- Photophysical properties of new cyclometalated ruthenium complexes and their use in dye sensitized solar cells. Hawraa Kisserwan, Amanda Kamar, Tharallah Shoker, Tarek H Ghaddar Dalton Trans. 2012, 41(35), 10643–10651.

4- Investigation of carbon nanotube webs as counter electrodes in a new organic electrolyte based dye sensitized solar cell. Dalal Noureldine, Tharallah Shoker, Mustafa Musameh, Tarek H. Ghaddar J. Mater. Chem. 2012, 22, 862–869.

5- Novel poly-pyridyl ruthenium complexes with bis- and tris-tetrazolate mono-dentate ligands for dye sensitized solar cells. Tharallah A. Shoker, Tarek H. Ghaddar RSC Adv., 2014, 4, 18336–18340

6- A Universal Low Temperature MWCNT-COOH Based Counter Electrode and a New Thiolate/Disulfide Electrolyte System for Dye Sensitized Solar Cells. Abdulla Hilmi, Tharallah Shoker, Tarek H. Ghaddar ACS Applied Materials & Interfaces, 2014, 6(11), 8744–53.

7- Highly robust tetrazolate based complexes for efficient and long-term stable dye sensitized solar cells. Tharallah A. Shoker, Ralph Tanios, Remi Fayad, Tarek H. Ghaddar. RSC Adv., 2015, 5, 66047–66056 8- Ghaddar, Tarek, Shoker, Tharallah. 2015. Photosensitizers, Method of Making Them And Their Use In Photoelectric Conversion Devices. U.S. Patent 20150187513, filed Dec 26, 2013, and issued Jul 02, 2015.

9- Turning the Heat on Conjugated Polyelectrolytes: An Off-On ratiometric Nanothermometer. Ghinwa H. Darwish, Ali Koubeissi, Tharallah Shoker, Pierre Karam. Chem. Commun. 2016, 52, 823–826.

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10- High photo-currents with a zwitterionic thiocyanate-free dye in aqueous-based dye sensitized solar cells. Remi Fayad, Tharallah A. Shoker, Tarek H. Ghaddar. Dalton Trans., 2016, 45, 5622–5628.

AWARDS

2011 “Makhlouf Haddadin Award” for Outstanding Chemistry Graduate Student.

TALKS DELIVERED

2011 Conference on Innovative Materials and Applications (CIMA). Beirut, March 2011. 2010 First Kamal A. Shair (KAS) Central Research Science Laboratory (CRSL), American University of Beirut (AUB). Beirut, June 2010.

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Selbstständigkeitserklärung

Hiermit erkläre ich an Eides statt, dass ich die vorliegende Arbeit selbstständig und nur unter Verwendung der angegebenen Quellen und Hilfsmittel angefertigt habe.

Tharallah Shoker,

Tharallah Shoker Chemnitz 15.01.2018 Unterschrift Ort Datum

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