Zinc Mediated Synthesis of Cyclopropylamines

Jessica Bik-Jing Lee

A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto

Jessica Bik-Jing Lee

Master of Science

Department of Chemistry University of Toronto

2017 Abstract The cyclopropylamine motif is often found in both natural and pharmaceutical compounds. Our group has recently developed a synthesis of trans-cyclopropylamines using electrophilic zinc homoenolate intermediates. This thesis describes the attempted extension of this concept to an intramolecular version of this transformation to yield cyclopropanated heterocycles. Despite the successful preparation of the linear precursor for the synthesis of 2,3-methanopyrrolidine, cyclization did not result in any desired product. The second part of this thesis describes a one- pot synthesis of trans-cyclopropylamines from readily available -chloroaldehydes and amines.

Zinc homoenolate intermediates have been reported in the synthesis of cyclopropanols from

-chloroaldehydes, as well as being the key intermediate in our synthesis of trans- cyclopropylamines. Hence, combining both processes would allow the development of a versatile synthetic method to access trans-cyclopropylamines. While products were obtained in excellent yields, diastereomeric ratios remained low, which led us to speculate that this reaction is under thermodynamic control.

Acknowledgments

First of all, I would like to thank my supervisor Professor Sophie Rousseaux for the opportunity to work in her lab. Her passion for chemistry and her guidance has made this a delightful learning experience. I would also like to thank Professor Mark Taylor for his help with this thesis.

Second, I would like to thank the staffs from the NMR and AIMS facility for their hard work in taking such good care of the spectrometers and making sure our chemistry goes 24/7 nonstop.

Third, I would like to thank my lab mates for creating such a friendly, fun and relax working environment. I am very grateful for my fantastic 4-73 peeps, for consistently putting a smile on my face every day almost without failure, making me laugh at the most random thing in the world, tolerating my sassiness (especially on a tiring day coming back from 8:30 am TA), letting me grace the lab with my classical music selections and making this year so very unforgettable!

Very special thanks go to Purvish Patel, whom I share desk space and bench/sink area with, for putting up with my OCD behaviour, it was truly enjoyable working beside you.

Lastly and most importantly, I would like to thank my family in Macau and Hong Kong for believing in me, supporting me and simply being there when I had my ups and downs, I couldn’t imagine this year being possible without you guys.

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Table of Contents

ACKNOWLEDGMENTS ······················································································································ III

TABLE OF CONTENTS ························································································································ IV

LIST OF FIGURES ······························································································································· VI

LIST OF SCHEMES ···························································································································· VII

LIST OF TABLES ······························································································································· VII

LIST OF ABBREVIATIONS ···················································································································· X

CHAPTER 1 ·········································································································································1

AN INTRODUCTION TO CYCLOPROPYLAMINES: PHARMACEUTICAL USES AND SYNTHESIS ············1

1.1 PREVALENCE OF THE CYCLOPROPYLAMINE MOTIF IN THE PHARMACEUTICAL INDUSTRY ································ 1

1.2 LITERATURE PRECEDENT FOR THE SYNTHESIS OF CYCLOPROPYLAMINES ····················································· 3 1.2.1 The Curtius Rearrangement ··························································································· 3 1.2.2 Reduction of 2-Nitrocyclopropanes ··············································································· 4 1.2.3 Cyclopropanation of Enamines ······················································································ 5 1.2.4 The Kulinkovich Reaction································································································ 6 1.2.5 The Simmons-Smith Reaction························································································ 7 1.2.6 Zinc Homoenolates ·········································································································· 9

1.3 THIS WORK ··································································································································· 10

CHAPTER 2 ······································································································································· 12

CIS-CYCLOPROPANES VIA ZINC HOMOENOLATES – SYNTHESIS OF CYCLOPROPANATED HETEROCYCLES ································································································································ 12

2.1 INTRODUCTION ······························································································································ 12

2.2 RESULTS AND DISCUSSION ··············································································································· 13 2.2.1 Synthesis of Linear Starting Material ·········································································· 13 2.2.2 Cyclization ······················································································································· 21

2.3 CONCLUSION AND FUTURE DIRECTIONS ····························································································· 22

CHAPTER 3 ······································································································································· 23

CYCLOPROPYLAMINE SYNTHESIS FROM READILY AVAILABLE -CHLOROALDEHYDES ················· 23

3.1 INTRODUCTION ······························································································································ 23

3.2 RESULTS AND DISCUSSION ··············································································································· 24 3.2.1 Initial Design ···················································································································· 24 3.2.2 Preliminary Results ········································································································ 24 3.2.3 Further Optimization ······································································································ 25 3.2.4 Scope of Cyclopropylamines Prepared from Readily Available -Chloroaldehydes ·························································································································· 31

3.3 CONCLUSION AND FUTURE DIRECTION ······························································································· 32

CHAPTER 4 ······································································································································· 34

EXPERIMENTAL SECTION ·········································································································· 34

List of Figures

Figure 1.1.1 Selected Cyclopropylamine Containing Drugs ······································· 1

Figure 1.1.2 Stereoisomers of 1,2-disubstituted Cyclopropylamines ····························· 2

Figure 2.1.1 a) Selected Members of the Gliptin Family and b) Project Goal ················· 13

Figure 2.2.1.1 gCOSY of 2.4 ············································································· 20

Figure 2.2.1.2 HSQC of 2.4··············································································· 20

List of Schemes

Scheme 1.2.1.1 Curtius Rearrangement to Access Cyclopropylamines ·························· 3

Scheme 1.2.2.1 Synthesis of Cyclopropylamines via Reduction of a Nitro Group ············· 5

Scheme 1.2.4.1 Variants of the Kulinkovich Reaction for the Synthesis of Cyclopropylamines ························································································· 6

Scheme 1.2.5.1 General Scheme of the Simmons-Smith Cyclopropanation ···················· 8

Scheme 1.2.5.2 Diastereoselective Synthesis of Cyclopropylamines by Charette et al. ······· 8

Scheme 1.2.5.3 Preparation of Cyclopropylamides by Motherwell et al. ························ 9

Scheme 1.2.6.1 Cyclopropylamine Formation via Zinc Homoenolate Intermediate ········· 10

Scheme 1.3.1 Formation of Cis-Fused Cyclopropylamines ········································ 10

Scheme 1.3.2 Synthesis of trans-Cyclopropylamines from α-Chloroaldehydes ··············· 11

Scheme 2.2.1.1 Initial Synthetic Route Towards 2,3-Methanopyrrolidines ···················· 14

Scheme 2.2.1.2 Synthesis of 2.2 via DIBAL-H amine complex···································· 15

Scheme 2.2.1.3 Formation of 2.5 from 3-aminopropanol ·········································· 16

Scheme 2.2.1.4 Optimization of the Reaction Conditions for Oxidation of Alcohol 2.5 ····· 16

Scheme 2.2.1.5 Synthesis of Substrate 2.8 ····························································· 17

Scheme 2.2.1.6 Optimization of the Reaction Conditions for Aldehyde Chlorination Using Proline and NCS ··························································································· 17

Scheme 2.2.1.7 Test Reaction of Silyl Enol Ether Synthesis Using Substrate 2.6 ············· 18

Scheme 2.2.1.8 Synthesis of Silyl Enol Ether 2.11 ··················································· 18

Scheme 2.2.1.9 Synthesis of 2.4 using a Simmons-Smith Cyclopropanation ··················· 19

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Scheme 2.2.2.1 Cyclization Test Reaction Using 2.4 ················································ 21

Scheme 2.2.2.2 Formation of Enamine ································································ 21

Scheme 3.1.1 Cyclopropylamine Formation via a Zinc Homoenolate ··························· 23

Scheme 3.1.2 Cyclopropylamine Synthesis from -Chloroaldehydes via Zinc Homoenolate ················································································································· 24

Scheme 3.2.1.1 Synthesis of -Chloroaldehyde 3.8 from Hydrocinnamaldehyde ············ 24

Scheme 3.2.2.1 Prelimiary Reaction Optimization Performed by Reggie Mills ··············· 25

Scheme 3.2.3.1.1 Aqueous Quench prior to Addition of Amine ·································· 26

Scheme 3.2.3.2.1.1 Attempts to Improve the Diastereomeric Ratio by the Addition of Cyanide Salts ······························································································· 27

Scheme 3.2.3.2.2.1 Attempts in Precipitating Iodide by the Addition of Silver Salts ········ 28

Scheme 3.2.3.4.1 Thermodynamic or Kinetic Reaction Probing with the Addition of 3.9 ·· 30

Scheme 3.2.4.1 Synthesis of Cyclopropylamines from Readily Available -Chloroaldehydes ················································································································· 31

Scheme 3.2.4.2 Synthesis of -Chloroaldehydes from Alcohols Using TEMPO/PIDA then Proline/NCS ································································································· 32

Scheme 3.3.1 Synthesis of Enantioenriched Cyclopropylamines From Enantioenriched -Chloroaldehydes ························································································ 33

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List of Tables

Table 2.2.1.1 Optimization of the Reaction Conditions for Oxidation of the Alcohol ······· 16

Table 2.2.1.2 Optimization of the Reaction Conditions for Aldehyde Chlorination Using Proline and NCS ··························································································· 17

Table 3.2.2.1 Preliminary Reaction Optimization Performed by Reggie Mills ··············· 25

Table 3.2.3.1.1 In situ Formation of Cyclopropanols Using Water Quench After 1st Step · 26

Table 3.2.3.2.1.1 Attempt in Improving d.r. by the Addition of Cyanide Salts················ 28

Table 3.2.3.2.2.1 Attempts in Precipitating Iodide by the Addition of Silver Salts ··········· 28

List of Abbreviations

Boc - tert-butyloxycarbonyl LA – Lewis Acid

Bn - Benzyl M – mol/L

C - Degree Celsius Me - methyl d.r. – Diastereomeric ratio NCS – N-chlorosuccinamide

DPPA – Diphenylphosphoryl azide NMR – Nuclear Magnetic Resonance

DIBAL-H – Diisobutylaluminium hydride O/N - Overnight

DMP – Dess-Martin Periodinane Ph - Phenyl eq. - Equivalent PIDA - diacetoxyiodobenzene

Et - Ethyl R – generic organic fragment

GC-MS – Gas-Chromatography Mass r.t – room temperature Spectroscopy gCOSY – gradient Correlation Spectroscopy TCCA – Trichloroisocyanuric acid

HRMS – High Resolution Mass Spectroscopy TEMPO - (2,2,6,6-Tetramethylpiperidin-1- yl)oxyl

HSQC – Heteronuclear Single Quantum Temp. – Temperature Spectroscopy h - hour TFA – Trifluoroacetic acid hrs - hours TMS – trimethylsilyl iPr - isopropyl TIPS - triisopropylsilyl

IBX – 2-iodoxybenzoic acid Tf – triflate

∆ - heat TLC – Thin Layer Chromatography

Chapter 1 An Introduction to Cyclopropylamines: Pharmaceutical Uses and Synthesis 1.1 Prevalence of the Cyclopropylamine Motif in the Pharmaceutical Industry

The cyclopropane motif is often found in natural products and pharmaceutical compounds.1,2,3 One reason for the prevalence of this motif is that its chemical properties largely benefit drug development with respect to drug potency, bioavailability, and receptor selectivity among other things.2,3 Among these bioactive molecules, many contain a cyclopropylamine moiety and selected examples are shown in Figure 1.1.1.2,3

Figure 1.2.1 Selected Cyclopropylamine Containing Drugs

The synthesis of substituted cyclopropylamines (Figure 1.1.1b) is often more challenging compared to the related unsubstituted derivatives (Figure 1.1.1a) since diastereomeric and enantiomeric products can be formed in the former case. For example, 1,2-disubstituted cyclopropylamines can have up to four stereoisomers (Figure 1.1.2).

1 For reviews see: (a) Salaün, J. Top. Curr. Chem. 2000, 207, 1-67. Gnad, F.; (b) Reiser, O. Chem. Rev. 2003, 103, 1063-1623 2 Talele, T. T., J. Med. Chem. 2016, 59, 8712- 8756 3 Miyamura, S., Itami, K.; Yamaguchi, J. Synthesis, 2017, 49, 1131-1149

Figure 1.1.2 Stereoisomers of 1,2-disubstituted Cyclopropylamines

There are many synthetic routes to access cyclopropylamines. These include the Curtius rearrangement of cyclopropyl acyl azides3, the reduction of 2-nitrocyclopropanes 4 , 5 , 6 , the cyclopropanation of enamines7,8,9,10 the Kulinkovich-de Meijere11 and Kulinkovich-Szyomoniak reactions12, and the Simmons-Smith cyclopropanation13,14,15,16. Our group has also recently

4 Asunskis, J.; Schechter, H. J. Org. Chem. 1968, 33, 1164-1168 5 Rh: Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv. Chem. Acta. 2002, 85, 4468-4484. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2005, 65, 9252-9254. Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262- 1269 Cu: Charette, A. B.; Wurz, R. P. J. Mole. Cat. A. 2003, 196, 83-91 6 Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327-2329. Wurz, R. P.; Charette, A. B. J. Am. Soc. Chem. 2005, 127, 18014-18015 7 Xie, M.-S.; Zhou, P.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2016, 18, 4344-4347 8 Davies, H. M. L.; Panaro, S. A. Tetrahedron, 2000, 56, 4871-4880 9 Aggarwal, V. K.; de Vincente, J.; Bonnert, R. V. Org. Lett. 2001, 3, 2785-2788 10 Tsai, C.-C.; Hsieh I.-L.; Cheng, T.-T.; Tsai P.-K.; Lin, K.-W.; Yan, T.-H. Org. Lett. 2006, 8, 2261-2263 11 For a review see: de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. J. Organomet. Chem. 2004, 689, 2033- 2055 12 (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792-1793; (b) Bertus, P.; Szymoniak, J. Synlett, 2007, 9, 1346-1356; (c) Bertus, P.; Szymoniak, J. J. Org. Chem. 2003, 68,7133-7136.

13 Simmons, H. E.; Smith, R. D. J. Am. Soc. Chem. 1958, 80, 5323-5324 14 Charett, A. B.; Côté, B.; Marcoux, J.-F. J. Am. Soc. Chem. 1991, 113, 8166-8167 15 Charette, A. B.; Côté, B. J. Am. Soc. Chem. 1995, 117, 12721-12732

reported that cyclopropylamines can be prepared using zinc homoenolates 17 . Despite the abundance of synthetic methods to access cyclopropylamines, there remains room for improvement with respect to synthetic methods that yield products in high levels of diastereo- and enantioselectivity.

1.2 Literature Precedent for the Synthesis of Cyclopropylamines

1.2.1 The Curtius Rearrangement

The Curtius rearrangement is widely used for the preparation of carbamates, ureas and primary amines as these functional groups can be generated via a common reaction intermediate, an isocyanate. 18 Acyl azides release nitrogen gas upon thermal decomposition to generate isocyanates, which can be quenched with various nucleophiles such as alcohols, amines and water to yield carbamates, ureas and primary amines, respectively (Scheme 1.2.1.1).

Scheme 1.2.1.1 Curtius Rearrangement to Access Cyclopropylamines

Many biologically active molecules containing the cyclopropylamine motif are prepared using a Curtius rearrangement as the final step to install the amino group.3 In these cases, the installation

16 (a) Bégis, G.; Cladingboel, D.; Motherwell, W. B. Chem. Commun. 2003, 2656-2657; (b) Motherwell, W. B.; Bégis, G.; Cladingboel D.; Joreme, L.; Sheppard T. D. Tetrahedron, 2007, 63, 6462-6476 17 Mills, L. R.; Barrera Arbelaez, L. M.; Rousseaux, S. A. L. J. Am. Soc. Chem. 2017, 139, 11357-11360.

18 Franklin, E. C. Chem. Rev., 1934, 14, 219-250

of the cyclopropane ring occurs upstream to the Curtis rearrangement. Most of the reported methods involve the cyclopropanation of an alkene with a metal carbene based on Cu, Pd, Rh, or Ru.19 Other cyclopropanation strategies such as the Corey-Chaykovsky reaction, involving the reaction of sulfur ylides with electron deficient olefins such as α,β-unsaturated esters, have also been reported.20 Upon installation of the cyclopropane ring, hydrolysis is required to obtain the cyclopropylcarboxylic acid which can then be converted into the corresponding acyl azide required for the Curtius rearrangement. Quenching the reaction with water yields the cyclopropylamine. Despite being frequently used, this strategy involves numerous synthetic steps and the explosive nature of acyl azides poses certain limitations for large scale applications.

1.2.2 Reduction of 2-Nitrocyclopropanes

The reduction of nitro-substituted cyclopropanes has also been used to access cyclopropylamines (Scheme 1.2.2.1). These methods tend to require fewer synthetic steps compared to the aforementioned Curtius rearrangement (Section 1.2.1) as the amino group is imbedded in the starting material in the form of a nitro functionality.

The Corey-Chaykovsky reaction can be used to cyclopropanate nitro alkenes as the presence of the nitro group fulfills the requirement for an electron deficient olefin for this type of transformation (Scheme 1.2.2.1, route a). Although the yields of these reactions tend to be modest, it is a common strategy used in synthesizing bioactive cyclopropylamines.2,3

Other reported methods include using metal carbenes generated from diazo derivatives containing a nitro functional group (Scheme 1.2.2.1, route b).5 A related strategy was developed by Charette et al.5 to avoid safety concerns with the use of α-nitro-α-diazo reagents.6 Instead of using these reagents to generate the cyclopropane ring, iodonium ylides, generated from methyl nitroacetate and iodine(III) species, were used (Scheme 1.2.2.1, route c). This method was originally developed using a Rh(II) catalyst however the second generation reaction conditions

19 For reviews on cyclopropanations using metal carbenes see: Brookhart, M.; Studabaker, W. B. Chem. Rev. 1987, 87, 411-432 20 For a review see Gololobov, Y. G.; Nesmeyanov, A. N.; Iysenko, V. P., Boldeskul, I.E. Tetrahedron. 1987, 43, 2609-2651

involving a Cu(I) catalyst leads to higher diastereoselectivity and, for the first time, enantioselectivity.6

Scheme 1.2.2.1 Synthesis of Cyclopropylamines via Reduction of a Nitro Group

1.2.3 Cyclopropanation of Enamines

As mentioned above, diazo compounds are widely used in the cyclopropanation of alkenes to yield cyclopropane derivatives. Thus, a possible route to directly access cyclopropylamines would involve the reaction of metal carbenes with enamines. However, there are few reported methods based on this bond disconnection as the stability of enamines poses certain challenges.

Previously reported synthetic routes that use this strategy include the metal catalyzed cyclopropanation of vinylpthalimide7 or vinyl acetamide8 using diazoesters or diazo derivatives released in situ from tosylhydrazones.9 Furthermore, cyclopropanation of enamines via 10 electrophilic carbenes generated from TiCl4-Mg-CH2Cl2 has also been reported.

Despite the fact that these methods give moderate to good diastereoselectivities, and even excellent enantioselectivity in the case of vinyl acetamide,7 the pre-installed amide moiety leaves little room for post-cyclopropanation modifications.

1.2.4 The Kulinkovich Reaction

The Kulinkovich reaction (Scheme 1.2.4.1, route a) is frequently used in the synthesis of cyclopropanols. This method employs a titanium IV catalyst (Scheme 1.2.4.1).21 Titanacycle 1.1 which is equivalent to metal-coordinated alkene intermediate 1.2, reacts with ester 1.3 to generate a five-membered ring intermediate 1.4. Titanium coordinated cyclopropanol 1.5 is then obtained after ring-closure. With the addition of excess Grignard reagent, titanacycle 1.1 is re- generated after -hydride elimination and cyclopropanol 1.6 is obtained upon aqueous work up.21

Scheme 1.2.4.1 Variants of the Kulinkovich Reaction for the Synthesis of Cyclopropylamines

21 For a review see: Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789-2834

Variations of the Kulinkovich reaction such as the Kulinkovich-de Meijere reaction11 (Scheme 1.2.4.1, route b) and the Kulinkovich-Szymoniak reaction12 (Scheme 1.2.4.1, route c) are used to prepare cyclopropylamines. Replacing the ester starting material by an amide 1.7 or nitrile derivative 1.11 affords tertiary and primary cyclopropylamine products, respectively (Scheme 1.2.4.1).21 Despite the similarities between these methods, these cyclopropylamine syntheses often require stoichiometric amounts of titanium to obtain high yields and limit the formation of unwanted side products such as ketones and alkyl amines in the case of Kulinkovich-Szymoniak reaction.11,12

Both the Kulinkovich-de Meijere and the Kulinkovich-Szymoniak transformations are efficient methods to prepare 1,1-disubstituted cyclopropylamines. More diverse substitution patterns can be achieved through ligand exchange of alkenes with intermediate 1.2 (Scheme 1.2.4.1).21,12 For example, using 1,2-disubstituted alkenes and Grignard reagents such as cyclohexyl magnesium bromide, cyclopropanes bearing substitutions at all three carbons can be prepared. However, the reported diastereoselectivities for these reactions are often low.11,12 Other aspects of these methods also pose limitations, for example the generation of substituted amines in the Kulinkovich-de Meijere reaction restricts further modification of the amine.11 Furthermore, in the Kulinkovich-Szymoniak transformation, side products such as ketones 1.15 and alkyl amines 1.16 can be generated upon the addition of water or excess Grignard reagent to intermediate 1.12, respectively (Scheme 1.2.4.1).12

1.2.5 The Simmons-Smith Reaction

The Simmons-Smith reaction is a commonly used strategy for the synthesis of cyclopropanes, involving the use of diiodomethane and diethylzinc to generate a zinc carbenoid in situ.13 The concerted addition of the zinc carbenoid to the olefin allows the geometry of the olefin to be preserved.13 Despite its frequent use in cyclopropanation reactions, very few applications of the Simmons-Smith reaction have been reported for the synthesis of cyclopropylamines.

Scheme 1.2.5.1 General Scheme of the Simmons-Smith Cyclopropanation

Charette et al. have reported one such method,14,15 using D-glucose as a chiral auxiliary. Coordination of the unprotected O-2 and zinc carbenoid in 1.17 allows the exclusive attack to the front face of the alkene and results in a highly diastereoselective cyclopropanation reaction (Scheme 1.2.5.2). Upon cleavage of the carbohydrate and a series of modifications including the installation of the amino functionality via a Curtius rearrangement, a Boc-protected cyclopropylamine was obtained with excellent diastereomeric excess (>99%).15

Scheme 1.2.5.2 Diastereoselective Synthesis of Cyclopropylamines by Charette et al.

Another method that employs the Simmons-Smith strategy was reported by Motherwell et al.16 Using N-diethoxymethyl 2-pyrrolidinone as a starting material, cyclopropylamides can be prepared via an organozinc diethoxymethylamide carbenoid 1.18 (Scheme 1.2.5.3). Upon addition of an alkene to the zinc carbenoid, a cyclopropylamide is formed. This transformation however, is largely affected by the electronic properties of the starting alkene, with electron rich alkenes giving diastereoselectivities as high as 95:5 whereas electron poor alkenes gave little to no selectivity.

Scheme 1.2.5.3 Preparation of Cyclopropylamides by Motherwell et al.

1.2.6 Zinc Homoenolates

Our group recently reported a strategy for the synthesis of trans-cyclopropylamines via zinc homoenolate intermediates (Scheme 1.2.6.1).17 This strategy utilizes cyclopropanol 1.19 as a starting material. Addition of a zinc source and base to cyclopropanol leads to ring-opening via C-C bond cleavage between C1 and C3 to form zinc homoenolate intermediate 1.20. With the addition of a nucleophilic amine, intermediate 1.21 is formed after the condensation of the amine and aldehyde. Subsequent nucleophilic attack of C3 onto C1 generates the ring closed trans- cyclopropylamine product 1.22 (Scheme 1.2.6.1).

This method provides access to trans-cyclopropylamines generally in good yields and excellent diastereoselectivities. Furthermore, this strategy allows flexibility in amine selection since the amine functionality is not inherited from the cyclopropane-containing starting materials. Therefore, besides primary and acyclic secondary amines, cyclopropylamines bearing cyclic secondary amines can also be synthesized.

Scheme 1.2.6.1 Cyclopropylamine Formation via Zinc Homoenolate Intermediate

1.3 This Work

The work presented in this thesis has two foci. First, taking the aforementioned cyclopropylamine synthesis via zinc homoenolates that was developed in our group17, an intramolecular variant of this transformation was explored in an effort to develop a method to synthesize cyclopropane fused cyclic amines (Scheme 1.3.1). The efforts towards synthesizing the linear starting material and the result of a test reaction will be presented.

Scheme 1.3.1 Formation of Cis-Fused Cyclopropylamines

In the second part of this thesis, a one-pot methodology to access cyclopropylamines via zinc homoenolates prepared from readily available starting materials was further explored. Zinc homoenolate 1.21 has been reported as an intermediate in the synthesis of cyclopropanols and cyclopropylamines by Walsh et al. 22 and Rousseaux et al.17, respectively (Scheme 1.3.2). Combining both processes would enable the preparation of trans-cyclopropylamines from readily available -chloroaldehydes. Preliminary results suggest that the diastereomeric ratio of

22 Cheng, K.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2011, 13, 2346-2349

the cyclopropylamine products is significantly lower when both processes are combined. Efforts towards further optimizing this one-pot protocol and a preliminary reaction scope will be presented in the second half of this thesis.

Scheme 1.3.2 Synthesis of trans-Cyclopropylamines from α-Chloroaldehydes

Walsh et al. (2011)

R O + IZn ZnI R OH THF, 0˚C Cl d.r. 10:1

R OZnI

1.21 Rousseaux et al. (2017) Zn(CN)2, Na2CO3 R’ or Et2Zn HN R' + R N R OH R’’ 1,4-Dioxane 110 ˚C, 18h R'' d.r. >20:1

combine both processes

This Work R’ HN R R’’ O (1 equiv.) R’ IZn ZnI R N Cl THF, 0˚C, 1h R OZnI 90 ˚C , 18h R” ( 2 equiv.)

Chapter 2 Cis-Cyclopropanes via Zinc Homoenolates – Synthesis of Cyclopropanated Heterocycles 2.1 Introduction

Trans-cyclopropylamines can be synthesized from cyclopropanols and nucleophilic amines in a highly diastereoselective fashion using electrophilic zinc homoenolate intermediate (Section 1.2.6). Employing the same concept, an intramolecular version of this transformation was envisioned. Unlike the intermolecular version, which gives trans-cyclopropylamines, cis-fused cyclopropylamines would be generated in an intramolecular reaction. The development of this intramolecular methodology would increase the synthetic value of our zinc-mediated synthesis of cyclopropylamines since both trans- and cis-cyclopropylamines could be accessed via intermolecular or intramolecular reactions, respectively.

The cis-fused cyclopropylamine motif is also found in pharmaceutical compounds such as Saxagliptin. Saxagliptin is a biologically active compound used in the treatment of diabetes and is marketed under the name of Onglyza®. Compared to other molecules in the gliptin family, which all contain the same proline-like cyanopyrrolidine group, Saxagliptin was reported to have increased potency due to the cyclopropane moiety (Figure 2.1.1a).2,23

23 Simpkins, L. M.; Bolton, S.; Pi, Z.; Sutton, J. C.; Kown, C.; Zhao, G.; Magnin, D. R.; Augeri, D. J.; Gungor, T.; Rotella, D. P.; Sun, Z.; Liu, Y.; Slusarchyk, W. S.; Marcinkeyiciene, J.; Robertson, J. G.; Wang, A.; Robl, J. A.; Atwal, K. S.; Zahler, R. L.; Parker, R. A.; Kirby, M. S.; Hamann, L. G. Bioorg. Med. Chem. Lett. 2007, 17, 6476- 6480

Figure 2.1.1 a) Selected Members of the Gliptin Family and b) Project Goal

Based on our interest in exploring the intramolecular reactivity of zinc homoenolates, we chose to explore the synthesis of the cyclopropane fused pyrrolidine core present in Saxagliptin, 2,3- methanopyrrolidine (highlighted in blue in Figure 2.1.1a), as a project goal. This Chapter presents my efforts towards the synthesis of the linear starting material required for the formation of 2,3-methanopyrrolidine from a zinc homoenolate and the result of a cyclization test reaction (Figure 2.1.1.b).

2.2 Results and Discussion

2.2.1 Synthesis of Linear Starting Material

To be able to access 2,3-methanopyrrolidines in an intramolecular fashion using the zinc homoenolate synthesis of cyclopropylamines mentioned above (Section 1.2.6), a linear substrate that contains both the cyclopropanol and amine motifs 2.4 was needed (Scheme 2.2.1.1).

The initial synthetic route to access molecule 2.1 involved the use of a nucleophilic amine such as benzylamine to ring open butyrolactone to obtain linear amide 2.2 (Scheme 2.2.1.1). Upon amide reduction using LiAlH4, molecule 2.2, which contains both an amine and an alcohol, would be obtained. The alcohol could be converted into -chloroaldehyde 2.3 using oxidative

chlorination conditions 24 From 2.3, the cyclopropane ring could be installed through cyclopropanation using bis(iodozinco)methane to form linear precursor 2.4.22 The relative stereochemistry of the resulting cyclopropanol would be ablated during the cyclization process since formation of the zinc homoenolate intermediate leads to the loss of stereochemical information at C1 (Figure 1.2.6.1). With the linear starting molecule 2.4 and the cyclopropylamine synthesis conditions developed in our group, 2,3-methanopyrrolidine could be obtained after deprotection of the benzyl group. However, this short synthetic sequence presents many challenges as we originally hoped to limit the use of protecting groups for the amine moiety due to the potential instability of cyclopropane fragment under harsh deprotection conditions. Furthermore, the TEMPO/TCCA oxidation and chlorination method tends to give mixtures of products due to the strong oxidizing nature of TEMPO.

Scheme 2.2.1.1 Initial Synthetic Route Towards 2,3-Methanopyrrolidines

The opening of butyrolactone using benzylamine proceeded cleanly to give 2.1 in quantitative yield. However, reduction of the amide using LiAlH4 was sluggish and the results obtained from each trial were inconsistent. The reduction often did not go to completion. Unfortunately, larger amounts of LiAlH4 (10 equiv.) and longer reaction times (up to 3 days) did not lead to consistent results.

24 Jing, Y.; Daniliuc, C. G.; Studer, A. Org. Lett. 2014, 16, 4932-4935

Resorting to another strategy, compound 2.2 was successfully synthesized using a DIBAL-H amine complex developed by Deng et al.25 Using the same starting material and an excess of DIBAL-H (6.0 equiv.), compound 2.2 was synthesized in 90 % yield. From an economical and scalability point of view, the large amounts of DIBAL-H required for this transformation remains a limitation. However, decreasing the amount of DIBAL-H resulted in incomplete reduction of the amide leaving a mixture of 2.1 and 2.2 (Scheme 2.2.1.2).

Scheme 2.2.1.2 Synthesis of 2.2 via DIBAL-H amine complex

With access to 2.2, direct oxidation and chlorination to obtain -chloroaldehyde 2.3 using TEMPO and TCCA was attempted. However, this reaction led to unproductive decomposition of the starting material to benzaldehyde. Due to the strong oxidative nature of TEMPO, we chose to investigate a milder oxidation and chlorination sequence.

Aldehydes can be chlorinated at the -position via a proline-catalyzed chlorination using NCS.26 Thus, access to the corresponding aldehyde of 2.2 was investigated. Unfortunately, attempts to oxidize 2.2 with Dess-Martin periodinane also resulted in failure; formation of benzaldehyde was once again observed. The choice of a benzyl protecting group for the amine, while beneficial for mild deprotection at the end of our reaction sequence, is incompatible with these oxidation conditions. In fact, aliphatic amines are readily oxidized to imines due to the nucleophilicity of the nitrogen atom, forming the corresponding aldehydes upon aqueous work-up. Therefore, the use of an alternative amine protecting group was investigated to avoid this issue.

25 Huang, P.-Q.; Zheng, X.; Deng, X.-M. Tetrahedron, 2001, 42, 9039 26 Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen K. A. J. Am. Chem. Soc., 2004, 126, 4790-4791

Scheme 2.2.1.3 Formation of 2.5 from 3-aminopropanol

Due to the large excess of DIBAL-H used in the synthesis of 2.2, a three-carbon model substrate 2.5 was synthesized via Boc protection of 3-aminopropanol and was used to optimize the reaction conditions for oxidation of the alcohol to the aldehyde (Scheme 2.2.1.4, Table 2.2.1.1)

Scheme 2.2.1.4 Optimization of the Reaction Conditions for Oxidation of Alcohol 2.5

Table 2.2.1.1 Optimization of the Reaction Conditions for Oxidation of the Alcohol

Entry Oxidant (eq.) Solvent (M) Temp. (°C) Time (h) Yield (%) a 1 TEMPO, PIDA CH2Cl2 (0.1) 25 24 30 (0.10, 1.10) 2 IBX (1.5) MeCN (0.2) 90 2 99b b 3 DMP (1.5) CH2Cl2 (0.1) 25 4 99 a 1H NMR yield using trimethoxybenzene as internal standard; b Pure product obtained

Employing the TEMPO/PIDA oxidation condition, 30% of the desired product was observed in the 1H NMR spectrum of the crude reaction mixture while no remaining starting material could be detected. The loss of material is perhaps due to decomposition caused by the strong oxidizing nature of TEMPO (Table 2.2.1.1, entry 1). Using hypervalent iodine oxidizing reagents such as IBX and DMP, the desired aldehyde is obtained in quantitative yield, however oxidation with IBX required heating at reflux whereas the DMP oxidation can be carried out at room temperature (Table 2.2.1.1, entries 2-3). Therefore, DMP was selected as the optimal oxidizing reagent for this transformation. Substrate 2.2 was Boc protected to yield 2.7 in 86% yield. Oxidation using Dess-Martin periodinane afforded 2.8 in quantitative yield (Scheme 2.2.1.5).

Scheme 2.2.1.5 Synthesis of Substrate 2.8

Substrate 2.6 was also used as a model substrate in the optimization of the reaction conditions for chlorination using the aforementioned proline and NCS method (Table 2.2.1.2). However, despite obtaining good ratios of 2.9:2.9’, the overall reaction yield (7%) was relatively poor (Scheme 2.2.1.6, Table 2.2.1.2). It is likely that both chlorinated products are poorly soluble in pentane, a solvent that was added at the end of the reaction to precipitate the succinimide by- product and excess NCS.

Scheme 2.2.1.6 Optimization of the Reaction Conditions for Aldehyde Chlorination Using Proline and NCS

Table 2.2.1.2 Optimization of the Reaction Conditions for Aldehyde Chlorination Using Proline and NCS

Entry L-Proline NCS Reaction Time 2.9:2.9’b (eq.) (eq.) (h) 1a 0.2 1.3 18 1:0 2a 0.2 1.3 1.5 1.0:0.09 a Low yield (7%) was obtained due to poor solubility of product in pentane. See the supporting information for full experimental details. b Calculated by using aldehyde proton peak integration

Scheme 2.2.1.7 Test Reaction of Silyl Enol Ether Synthesis Using Substrate 2.6

This unfortunate result led us to explore another alternative for the synthesis of the cyclopropanol precursor via cyclopropanation of a silyl enol ether intermediate. Aldehydes can 27 be converted to silyl enol ethers in the presence of TMSCl, Et3N and NaI. Thus, model substrate 2.6 was used to investigate these reaction conditions. In the 1H NMR spectrum of the crude reaction mixture, two peaks were observed between 6.20-6.40 ppm. Based on the coupling constants, these peaks are believed to correspond to the trans- and cis-silyl enol ethers 2.10 and 2.10’, which have J = 11.9 Hz and 5.9 Hz, respectively (Scheme 2.2.1.7). To further support these assignments, coupling constants of 11.5 Hz and 5.8 Hz, respectively, have been previously reported in the literature for trans- and cis-silyl enol ethers derived from other propanal derivatives.27

Based on the successful test reaction with substrate 2.6, a reaction using 2.8 was attempted in the hope of preparing its corresponding silyl enol ether. Unfortunately, initial reactions were not successful. Incomplete conversion of aldehyde to silyl enol ether was observed, potentially due to the presence of trace water and/or acid in the NMR solvent. Since the TMS group is highly sensitive, trace acid from in the deuterated chloroform solvent would readily convert the desired silyl enol ether back to the aldehyde starting material, hence giving these results.

Scheme 2.2.1.8 Synthesis of Silyl Enol Ether 2.11

27 Cazeau, P.; Duboulin, F.; Moulines, F.; Babot, O.; Dunogues, J. Tetrahedron. 1987, 43, 2075-2088

After taking extra care with the purity of the NMR solvent, including the use of molecular sieves and K2CO3 to remove any residual water and acid in deuterated chloroform, silyl enol ether 2.11 was detected by 1H NMR. Based on the 1H NMR spectrum, both cis- and trans-silyl enol ethers were observed (Scheme 2.2.1.8).

From silyl enol ether 2.11, cyclopropanols were synthesized using a Simmons-Smith cyclopropanation reaction, however only 26% of the cis-cyclopropanol 2.4 was isolated post- TMS deprotection using TMSCl and methanol, this low isolated yield could due to the unexpected polar nature of these cyclopropanols (Scheme 2.2.1.9). Since the cyclopropane ring undergoes ring opening to form the key zinc homoenolate intermediate, the relative stereochemistry of the resulting cyclopropylamine should not be affected by the stereochemistry of the starting cyclopropanol. One interesting result is that the Boc group was removed during the reaction since the tert-butyl protons were not observed in the 1H NMR spectrum of the crude reaction mixture. This reaction however was found to be irreproducible. In repeated attempts at this reaction, the Boc group remained intact, even after treatment of the crude material with TFA.

Scheme 2.2.1.9 Synthesis of 2.4 using a Simmons-Smith Cyclopropanation

Selected 2D NMR spectra (gCOSY and HSQC) of 2.4 are presented below. The formation of cis-cyclopropanol further supports that the geometry of 2.11 is the cis-silyl enol ether since the Simmons-Smith cyclopropanation allows the alkene geometry to be preserved.

Figure 2.2.1.1 gCOSY of 2.4

Figure 2.2.1.2 HSQC of 2.4

2.2.2 Cyclization

With the limited amount of linear precursor 2.4 prepared, a test reaction was set up using diethyl zinc (Scheme 2.2.2.1). Diethyl zinc was chosen as a source of zinc for the reaction since it has previously been used in challenging intermolecular reactions.17 Analysis of the crude reaction mixture showed a match for the mass of the desired product on GC-MS, however no cyclopropane protons were observed in the 1H NMR spectrum of the crude reaction mixture. The lack of cyclopropane protons could result from the small scale of this test reaction, therefore further investigation is required.

Scheme 2.2.2.1 Cyclization Test Reaction Using 2.4

H H HO N Et2Zn (2.0 equiv.) HO N 1,4-Dioxane 2.4 rt 2.4’

Another explanation to the lack of cyclopropane protons could be the formation of enamine product 2.15 (Scheme 2.2.2.2). Upon the ring-opening of cyclopropane, iminium intermediate 2.13 is formed after the condensation of aldehyde and amine, 2.13 can then tautomerize to its enamine form 2.14 (Scheme 2.2.2.2).

Scheme 2.2.2.2 Formation of Enamine

2.3 Conclusion and Future Directions

Several synthetic routes were investigated in the preparation of the linear cyclization precursor, cyclopropanol 2.4. Due to a lack of reproducibility in the synthesis of silyl enol ether and the subsequent cyclopropanation reaction, only one cyclization test reaction was performed. The results of this reaction were inconclusive since no cyclopropane protons were observed in the 1H NMR spectrum of the crude reaction mixture however the desired mass for the cyclized product was detected by GC-MS.

Future efforts in this area should involve synthesizing larger quantities of the linear precursor in order to conduct the test reaction on a larger scale. This will provide better insight as to whether this transformation will work in an intramolecular fashion.

Chapter 3 Cyclopropylamine Synthesis from Readily Available - Chloroaldehydes 3.1 Introduction

Our group has demonstrated that trans-cyclopropylamines can be synthesized via electrophilic zinc homoenolates.17 Combining cyclopropanol starting materials with nucleophilic amines, in the presence of a zinc source and base, provides access to trans-cyclopropylamines in high yields and excellent diastereomeric ratios (Section 1.2.6).

Upon addition of a zinc source and base to cyclopropanol 3.1, the ring strain present in the cyclopropane motif leads to the formation of a zinc homoenolate 3.2 (Scheme 3.1.1). With the addition of amine and after condensation to form an iminium 3.3, the nucleophilic -carbon can then undergo ring closing C–C bond formation via nucleophilic attack onto the carbonyl carbon forming the trans-cyclopropylamine product.

Scheme 3.1.1 Cyclopropylamine Formation via a Zinc Homoenolate

Zinc homoenolate intermediates have also been invoked in the synthesis of cyclopropanols using bis(iodozinco)methane and -chloroaldehydes by Walsh et al.22 Since both methods share the same intermediate, we sought to develop a method that would allow the synthesis of trans- cyclopropylamines from readily available -chloroaldehydes (Scheme 3.1.2). Furthermore, with this one-pot methodology, trans-cyclopropylamines could potentially be synthesized in an

enantiospecific fashion as both the transformations of enantioenriched -chloroaldehydes to trans-cyclopropanols and enantioenriched trans-cyclopropanols to trans-cyclopropylamines have been shown to be enantiospecific by Walsh et al.22 and Rousseaux et al.,17 respectively. This Chapter will present the preliminary results towards this goal, which involve work carried out by Reggie Mills, and further optimization studies and preliminary reaction scope that I performed.

Scheme 3.1.2 Cyclopropylamine Synthesis from -Chloroaldehydes via Zinc Homoenolate

3.2 Results and Discussion

3.2.1 Initial Design

Based on our previous results in the development of a synthesis of cyclopropylamines from zinc homoenolates derived from cyclopropanols,17 -chloroaldehyde 3.8 and morpholine were chosen for reaction optimization. -Chloroaldehyde 3.8 was made from hydrocinnamaldehyde using the proline catalyzed chlorination method described in Chapter 2.26 Product 3.8 was obtained in high yield however care must be taken when using it as it tends to decompose within a week, even when stored in the freezer and under argon (Scheme 3.2.1.1).

Scheme 3.2.1.1 Synthesis of -Chloroaldehyde 3.8 from Hydrocinnamaldehyde

3.2.2 Preliminary Results

The results presented in this section were obtained by Reggie Mills, who is responsible for the initial design and optimization of this methodology. Optimization studies included modifying the

ratio of -chloroaldehyde, bis(iodozinco)methane and amine, and varying the reaction temperature. Selected entries are presented in Table 3.2.2.1.

Scheme 3.2.2.1 Prelimiary Reaction Optimization Performed by Reggie Mills

Table 3.2.2.1 Preliminary Reaction Optimization Performed by Reggie Mills

a,b a Entry CH2(ZnI)2 (equiv.) Temperature (°C) Yield (%) d.r. 1 2.2 80 38 4.7:1 2 3.0 80 49 4.7:1 3 3.0 110 0 - 4c 4.0 110 27 4.8:1 5 4.0 90 77 4.4:1 a Determined by GC-MS using dodecane as an internal standard; b Combined yield for cis- and trans- cyclopropylamines; c THF was replaced with 1,4-dioxane after the first step

With a 4:2:1 ratio of bis(iodozinco)methane:3.8:morpholine, cyclopropylamine 3.9 was obtained in 77% yield and 4.4:1 d.r. favouring the trans-cyclopropylamine product (Table 3.2.2.1, Entry 5). This one-pot sequence however, was shown to give olefin 3.10 as by-product, presumably due to the excess bis(iodozinco)methane reacting with -chloroaldehyde (Table 3.2.2.1).

3.2.3 Further Optimization 3.2.3.1 Use of Protic Quenches

Since the preliminary reaction conditions developed by Reggie Mills gave good yields but poor diastereoselectivities, we decided to explore different protic quenches between the two reaction steps in order to mimic the sequential reaction conditions for the synthesis of cyclopropylamines

as closely as possible. Protic solvents such as water and isopropanol were tested to generate cyclopropanol in situ prior to the formation of cyclopropylamine.

Quenching the reaction with water results in the formation of cyclopropanol but this protic quench seems to be detrimental to the subsequent transformation since no cyclopropylamine product was observed. The large amount of precipitate observed upon aqueous quench was thought to be the reason that caused reaction termination, therefore, conditions involving the addition of MgSO4, Zn(CN)2 and Na2CO3 to the mixture after the aqueous quench were explored. Initially, no conversion of cyclopropanol to cyclopropylamine was observed after 18 hours of reaction time. However, 27% of cyclopropylamine was detected by GC-MS with a d.r. of 7.0:1 after 42 hours while 58% cyclopropanol remained (Scheme 3.2.3.1.1, Table 3.2.3.1.1).

Scheme 3.2.3.1.1 Aqueous Quench prior to Addition of Amine

Table 3.2.3.1.1 In situ Formation of Cyclopropanols Using Water Quench After 1st Step

3.9 3.11 Entry Yield (%)a,b d.r.a Yield (%)a,b d.r.a 1 - - 86 2.3:1 2c 28 7.0:1 58 2.5:1 3d >99 4.4:1 - - a Determined by GC-MS using dodecane as an internal standard; b Combined yield for cis- and trans- cyclopropylamines; c Reaction was heated at 90 ºC for 42 hours; d Using isopropanol as protic quench

On the other hand, an isopropanol quench was found to drastically increase the reaction yield to quantitative yield with no trace of cyclopropanol detected. Unfortunately, although the isopropanol quench led to an increase in yield (approx. 20%) relative to the original conditions developed by Reggie Mills, the d.r. of the reaction mixture remained the same (Table 3.2.3.1.1,

entry 3). Furthermore, using protic quenches completely eliminates the formation of by-product 3.10 (Scheme 3.2.2.1). One other notable change in these studies is that the isopropanol quench does not lead to visible formation of precipitate in the reaction flask whereas salts were observed using the aqueous quench protocol.

3.2.3.2 Additive Studies

3.2.3.2.1 Cyanide Salt as Additives

We hoped to overcome the poor levels of diastereoselectivity by the addition of various cyanide sources to the reaction mixture since Zn(CN)2 proved to be crucial in our original report for the formation of cyclopropylamines in high diastereoselectivity.17 With the addition of a cyanide source, we hypothesized that ROZnI species 3.12 could undergo ion exchange, substituting the iodide for a cyanide anion. The resulting ROZnCN species should lead to trans- cyclopropylamine product in high d.r. as in our preliminary report. Different cyanide sources such as NaCN, KCN, CuCN, Zn(CN)2 and AgCN were used (Table 3.2.3.2.1.1). Most of these salts did not affect the reaction yield or diastereoselectivity. In the case of CuCN, copper metal plating around the reaction vial was observed, which was detrimental to the reaction as no product was formed. We were surprised by the inefficiency of Zn(CN)2 and AgCN to improve the diastereoselectivity of the reaction. As previously mentioned, Zn(CN)2 was found to be the best source of zinc for highly diastereoselective cyclopropylamine formation in our previous report. AgCN was also used in this experiment, since silver is known to bind strongly to halides and could therefore accelerate the ion exchange process. However, none of these cyanide salts showed any visible positive effects on the diastereomeric ratio of the product.

Scheme 3.2.3.2.1.1 Attempts to Improve the Diastereomeric Ratio by the Addition of Cyanide Salts

Table 3.2.3.2.1.1 Attempt in Improving d.r. by the Addition of Cyanide Salts

Entry Additive Yield (%)a,b d.r.a 1 KCN >99 4.3:1 2 NaCN >99 4.2:1 3 CuCN - -

4 Zn(CN)2 87 4.9:1 5 AgCN 97 3.8:1 a Determined by GC-MS using dodecane as an internal standard; b Combined yield of cis- and trans- cyclopropylamines

3.2.3.2.2 Silver Salts as Additives

Before ruling out the possibility of ion exchange on zinc using silver salts, additional experiments were performed using silver salts and Zn(CN)2 as additives (Scheme 3.2.3.2.2.1).

Unfortunately, results for a wide range of silver salt additives including Ag2CO3, AgCl, AgOTf, AgF and AgCN showed no significant changes in the diastereomeric ratio of the final product.

Scheme 3.2.3.2.2.1 Attempts in Precipitating Iodide by the Addition of Silver Salts

Table 3.2.3.2.2.1 Attempts in Precipitating Iodide by the Addition of Silver Salts

Entry Additives Yield (%)a,b d.r.a

1 Ag2CO3 97 4.3:1 2 AgCl >99 4.1:1 3 AgOTf 98 4.3:1 4 AgF 73 4.3:1 5 AgCN 97 3.8:1 a Determined by GC-MS using dodecane as an internal standard, b Combined yield of cis- and trans- cyclopropylamines

3.2.3.3 Filtration and Aqueous Work up

Due to the lack of success in the additive studies, alternative methods to improve the reaction diastereoselectivity were explored. The result from the protic quench studies suggested that a slightly higher d.r. was obtained when water was used to quench the reaction compared to isopropanol (Table 3.2.3.1.1, entry 2). However, the conversion of cyclopropanol to cyclopropylamine remains low in these reactions despite longer reaction times. Due to the significant amount of precipitate formed after water quench, it was speculated that these salts may be detrimental to the reaction. Therefore, filtration of the reaction mixture after aqueous quench and fast aqueous work up were explored as an alternative. The results demonstrated that filtration of the reaction mixture through a Celite plug did not improve the diastereomeric ratio. However, aqueous work up significantly increases the d.r. up to 20:1, although the obtained product yield was extremely low. This is perhaps due to the additional volume of diethyl ether (used in extractions) and mechanical losses. Despite the excellent d.r. obtained via aqueous work up, this modification was viewed as incompatible with our research goal of developing a one-pot method to access cyclopropylamines from readily available starting materials.

3.2.3.4 Thermodynamic vs. Kinetic Control

With efforts devoted to improving the d.r. of this transformation and no promising results, we began to wonder if this reaction was perhaps under thermodynamic control, meaning that the cis- and trans-cyclopropylamines could equilibrate under this set of reaction conditions, presumably via ring-opening, and result in the constant d.r. of approximately 4.5:1.This idea was not speculated before since we had demonstrated in our previous report that the transformation of cyclopropylpropanol to cyclopropylamine via a zinc homoenolate was under kinetic control.17

To probe this idea, experiments were performed where trans-cyclopropylamine 3.9 (>20:1 d.r.) was added to the reaction post isopropanol quench. Results showed that the trans- cyclopropylamine 3.9 does indeed equilibrate to the cis-isomer under these reaction conditions to give diastereomeric ratios of approximately 4.5:1. The reaction was repeated with another amine and a similar result (d.r.= 4.7:1) was obtained. These results suggest that the one-pot transformation of α-chloroaldehydes to cyclopropylamines is under thermodynamic control under these reaction conditions.

Scheme 3.2.3.4.1 Thermodynamic or Kinetic Reaction Probing with the Addition of 3.9

3.2.4 Scope of Cyclopropylamines Prepared from Readily Available -Chloroaldehydes

Scheme 3.2.4.1 Synthesis of Cyclopropylamines from Readily Available -Chloroaldehydes

Despite the moderate levels of diastereoselectivity of this one-pot cyclopropylamine synthesis, this method still allows the transformation of -chloroaldehydes to cyclopropylamines in moderate to good yields (Scheme 3.2.4.1). Secondary amines are well-tolerated although the reaction of a primary amine such as benzylamine showed no product formation. -Chloroaldehydes can be synthesized from their corresponding alcohols or aldehydes using the TEMPO/TCCA method (Chapter 2.2.1) or proline catalyzed chlorination method (Chapter 2.2.1), respectively.24,26

Scheme 3.2.4.2 Synthesis of -Chloroaldehydes from Alcohols Using TEMPO/PIDA then Proline/NCS

Although the TEMPO/TCCA method requires fewer synthetic steps, this reaction tends to lead to over-chlorinated products, which are difficult to separate from the desired mono-chlorinated aldehydes. Since this one-pot method is very sensitive to the quality of the starting material, the proline-catalyzed chlorination protocol is preferred to access the starting material. Through an oxidation and chlorination sequence using TEMPO/PIDA and proline/NCS, pure mono- chlorinated -chloroaldehydes are obtained (Scheme 3.2.4.2).28,26

3.3 Conclusion and Future Direction

To conclude, a method for the synthesis of trans-cyclopropylamines from readily available -chloroaldehydes has been developed. This method generally gives moderate to good yields and moderate diastereoselectivities for the trans-cyclopropylamine product. The moderate level of d.r. is due to the fact that this reaction is under thermodynamic control; both cis- and trans- cyclopropylamine products can ring-open under the reaction condition to equilibrate to a d.r. of around 4.5:1. Regardless, despite the moderate diastereoselectivity, this method offers a short synthetic route to access cyclopropylamines, especially when compared to more conventional cyclopropylamine syntheses (Chapter 1).

28 De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem., 1997, 62, 6974-6977

Scheme 3.3.1 Synthesis of Enantioenriched Cyclopropylamines From Enantioenriched -Chloroaldehydes

Future work on this project should involve exploring an enantiospecific variant of this transformation. Walsh et. al. reported that the formation of cyclopropanols from -chloroaldehydes occurs in high levels of enantiospecificity with inversion of stereochemistry and our group has reported that conversion of cyclopropanols to cyclopropylamines occurs with retention of stereochemistry in high enantiospecificity.22,17 Therefore, by combining both processes, enantioenriched cyclopropylamines could be synthesized from enantioenriched -chloroaldehydes, which can be readily accessed using organocatalytic methods developed by MacMillan et al. and Jørgensen et al. (Scheme 3.3.1).29,26

29 Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Soc. Chem. 2004, 126, 4108-4109

Chapter 4 Experimental Section

General Information

All reactions were performed using anhydrous solvents in oven-dried flasks unless otherwise specified. Anhydrous DCM and THF were purchased from Sigma-Aldrich and was used as received. All other chemicals were purchased from Sigma-Aldrich, Fisher Scientific and Combi-Blocks, and were used without further purification.

NMR solvents (CDCl3) were purchased from Cambridge Isotope Laboratories, Inc. or

Sigma-Aldrich. Proton chemical shifts are reported in ppm with respect to CDCl3 (δ 7.26). Carbon chemical shifts were internally referenced to the solvent resonances in CDCl3 (δ 77.2 ppm). Peak multiplicities are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; J, coupling constant in Hz. Complex multiplicities were reported as a combination of the above abbreviations to provide an appropriate descriptor for the observed pattern (i.e., dt –doublet of triplets).

All synthesized compounds were characterized by 1H, and 13C NMR, HRMS, IR and melting point (when applicable). 1H, 13C NMR were recorded on Varian MercuryPlus 400 MHz, Bruker AvanceIII-400 MHz, Agilent DD2-500 with one NMR probe and Agilent DD2-600 MHz spectrometers. Mass spectra were obtained by the University of Toronto Advanced Instrumentation for Molecular Structure (AIMS) mass spectrometry facility; high resolution mass spectra (HRMS) were recorded on a JEOL AccuTOF model JMS-T1000LC mass spectrometer equipped with an IONICS Direct Analysis in Real Time (DART) ion source.

Flash chromatography on silica gel (60 Å, 230-400 mesh, from Silicycle) was performed. Solvent ratios for chromatography are reported as v/v ratios. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 pre-coated plates and visualized with a UV lamp and KMnO4 stain.

The following compound was prepared using a literature procedure.30

Benzylamine (5.0 mmol, 1.0 equiv.) and butyrolactone (5.0 mmol, 1.0 equiv.) were added to a round bottom flask and left to stir for 18 hours at 80 °C. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled down to room temperature to obtain the desired product.

N-Benzyl-4-hydroxybutanamide: White solid (99%, 97 mg). 1H NMR (400 MHz, CDCl3, 298K): δ 7.37–7.27 (m, 5H), 5.90 (s, 1H), 4.45 (d, J = 5.7 Hz, 2H), 3.85–3.64 (m, 2H), 2.39 (dd, J = 7.4, 6.1 13 Hz, 2H), 1.97–1.82 (m, 2H). C NMR (100 MHz, CDCl3, 298K) δ 173.9, 138.3, 128.6, 127.6, 127.3, 61.7, 43.5, 33.4, 28.4. Melting Point: 65-68 °C. Experimental spectra match with literature reports.31

The following procedure was modified from a literature protocol.25,32

A DIBAL-H solution (1.0 M in toluene, 2.0 mmol, 1.0 equiv., 2.0 mL) was added to benzylamine (2.0 mmol, 1.0 equiv., 0.22 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h before butyrolactone (2.0 mmol, 1.0 equiv., 0.15 mL) was added to the flask. The mixture was stirred for another 30 minutes and cooled to 0 °C before slow addition of a DIBAL-H solution (1.0 M in toluene, 10.0 mmol, 5.0 equiv, 10 mL). The resulting mixture was left to stir until the reaction was judged to be complete as indicated by TLC. To quench the excess DIBAL-H, the reaction mixture was diluted with diethyl ether and cooled down to 0 °C. Water (0.10 mL) was added to the mixture, then 15% NaOH (0.10 mL) followed by another portion of water (0.20 mL). The mixture was warmed to room temperature, dried with magnesium sulfate, filtered through a pad of Celite and concentrated in vacuo.

30 Meyers, C. F. L.; Borch, R. F. Org. Lett., 2001, 3, 3765-3768 31 Decker, M.; Nuyen, T. T. H.; Lehmann, J. Tetrahedron., 2004, 60, 21, 4567- 4578 32 Wang, Y.-H.; Ye, J.-L.; Wang, A.-E.; Huang P.-Q. Org. Biomol. Chem., 2012, 10, 6504-6511

4-(Benzylamino)butan-1-ol: Light-yellow oil (90 % yield, 0.16 g). 1 H NMR (400 MHz, CDCl3, 298K): δ 7.40 – 7.30 (m, 5H), 3.82 (s, 2H), 3.67–3.60 (m, 2H), 2.80–2.67 (m, 2H), 1.71 (m, 4H). 13C NMR (100 MHz, CDCl3, δ 128.6, 128.6, 128.4, 127.4, 62.7, 53.8, 49.2, 32.5, 28.6. IR (neat): 3309, 3087, 3065, 3029, 2930, 2866 cm-1. HRMS (DART, ESI+) calcd: 180.13884; found: 180.13822

General procedure A for the preparation of Boc-protected amines:

This procedure was adapted from a literature protocol.33

In an oven-dried, argon-filled round bottom flask, amine (1.0 mmol, 1.0 equiv.) was dissolved in THF (0.80 mL) and the mixture was cooled down to 0 °C before a solution of Boc2O (0.95 mmol, 0.95 equiv.) in THF (0.80 mL) was added dropwise. The reaction was stirred at room temperature overnight. Upon completion of the reaction as indicated by TLC, the reaction mixture was washed with saturated NH4Cl, NaHCO3, water and brine. The collected organic layer was dried over sodium sulfate and filtered through a pad of Celite, concentrated in vacuo to obtained product.

tert-Butyl benzyl(4-hydroxybutyl)carbamate: This compound was synthesized from 4-(benzylamino)butan-1-ol (3.5 mmol scale) and pure product was obtained as a colourless oil (86 %, 0.84 g). 1H NMR (400 MHz, CDCl3, 298K) δ 7.36–7.29 (m, 2H), 7.25–7.19 (m, 3H), 4.43 (br s, 2H), 3.63 13 (br s, 2H), 3.22 (br s, 2H), 1.81–1.21 (m, 13H). C NMR (100 MHz, CDCl3, 298K) δ 156.0, 138.5, 128.4, 127.6, 127.1, 79.8, 62.1, 50.5, 46.3, 29.8, 28.4, 24.3. FTIR (cm-1): 3437, 2976, 2933, 2870, 1674. HRMS (DART, ESI+) calcd: 280.19127; found: 280.19197

tert-Butyl (3-hydroxypropyl)carbamate: This compound was synthesized from 3-aminopropanol (10.5 mmol scale) and pure product was obtained as 1 a colourless oil (93 %, 1.6 g). H NMR (400 MHz, CDCl3, 298K): δ 4.75 (br s, 1H), 3.66 (q, J = 5.9 Hz, 2H), 3.29 (q, J = 6.3 Hz, 2H), 2.94 (t, J = 6.5 Hz, 1H), 1.66 (p, J = 13 5.9 Hz, 2H), 1.44 (s, 9H). C NMR (100 MHz, CDCl3, 298K) δ 157.1, 79.5, 59.3, 37.0, 32.8, 28.4. Experimental spectra match with literature reports.34

33 Vo, C.-V. T.; Luescher, M.U.; Bode, J. W. Nat. Chem., 2014, 6, 310-314 34 Majik, M. S.; Parameswaran, P. S., Tilve, S. G. J. Org. Chem., 2009, 74, 6378–6381

Optimization of Alcohol Oxidation

Entry Oxidant (eq.) Solvent (M) Temp. (°C) Time (h) Yield (%) a 1 TEMPO, PIDA CH2Cl2 25 24 30 (0.10, 1.10) (0.1) 2 IBX MeCN 90 2 99c (1.5) (0.20) c 3 DMP CH2Cl2 25 4 99 (1.5) (0.1) a 1H NMR yield using trimethoxybenzene (aromatic protons) as internal standard; b Reaction was under reflux; c Pure product obtained

Procedure:

Oxidation of aldehyde using TEMPO/PIDA: This procedure was adapted from a literature protocol.28

Alcohol 2.5 (1.0 mmol, 1.0 equiv., 018 g) and TEMPO (0.10 mmol, 0.1 equiv., 16 mg) were dissolved in dichloromethane (10 mL, 0.10 M) before the addition of PIDA (1.1 mmol, 1.1 equiv., 0.35 g). The reaction mixture was stirred at room temperature until the reaction was judged to have reached completion by TLC. To quench the reaction, 10 mL of saturated Na2S2O3 was added to the reaction flask and left to stir for 15 minutes. The aqueous layer was then extracted with dichloromethane twice. The combined organic layers were washed with a 15% NaOH solution, water, brine and then dried with sodium sulfate. The crude mixture was then filtered, concentrated in vacuo and 1H NMR yield was obtained using trimethoxybenzene as internal standard.

Oxidation of aldehyde using IBX: This procedure was adapted from a literature protocol.35

Alcohol 2.5 (1.0 mmol, 1.0 equiv., 018 g) was dissolved in acetonitrile (5.0 mL, 0.20 M) before the addition of IBX (1.5 mmol, 1.5 equiv., 0.42 g). The reaction mixture was refluxed at 90 C until the reaction was judged to have reached completion by TLC. The reaction mixture was cooled down to room temperature, filtered through a plug of Celite, concentrated in vacuo and 1H NMR yield was obtained using trimethoxybenzene as internal standard.

Oxidation of aldehyde using DMP:

Alcohol 2.5 (1.0 mmol, 1.0 equiv., 018 g) and DMP (1.5 mmol, 1.5 equiv., 0.67 g) were dissolved in dichloromethane (10 mL, 0.10 M). The reaction mixture was stirred at room temperature until the reaction was judged to have reached completion by TLC. To quench the

35 More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003

reaction, 10 mL of saturated Na2S2O3 was added to the reaction flask and left to stir for 15 minutes. The aqueous layer was then extracted with dichloromethane twice. The combined organic layers were washed with a 15% NaOH solution, water, brine and then dried with sodium sulfate. The crude mixture was then filtered, concentrated in vacuo and 1H NMR yield was obtained using trimethoxybenzene as internal standard.

Optimization of Chlorination Using Proline and NCS

Entry L-Proline NCS Reaction Time 2.9:2.9’b (eq.) (eq.) (h) 1a 0.2 1.3 18 1:0 2a 0.2 1.3 1.5 1.0:0.09 a Low yield (7 %) due to product solubility; b Calculated by using aldehyde proton peak integration

Procedure: Aldehyde 2.6 (1.0 mmol, 1.0 equiv., 0.18 g), L-proline (0.20 mmol, 0.20 equiv., 23 mg) and anhydrous CH2Cl2 (2.0 mL, 0.50 M) were added to an oven-dried, argon filled round bottom flask, the mixture was cooled down to 0 °C before the slow addition of NCS (1.3 mmol, 1.3 equiv., 0.17 g). Upon completion of reaction indicated by TLC, pentane was added to the mixture to precipitate out any succinimide and excess NCS. The mixture was then filtered through a plug of Celite, and the plug was rinsed with pentane (2x 10mL). The filtrate was then concentrated in vacuo to obtain 1H NMR yield the ratio of 2.9:2.9’.

General procedure B for the oxidization of alcohols to aldehydes:

In a round bottom flask, alcohol (1.0 mmol, 1.0 equiv.) was dissolved in dichloromethane (2.0 mL, 0.50 M) and DMP (1.5 mmol, 1.5 equiv.) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction as indicated by TLC, the mixture was washed twice with saturated Na2SO3, NaHCO3, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.

tert-butyl (3-oxopropyl)carbamate: This compound was synthesized according general procedure B from tert-butyl (3-hydroxypropyl)carbamate (1.65 mmol scale) to afford a colourless oil (99%, 0.28 g). 1H NMR (400 MHz, CDCl3, 298K δ 9.80 (t, J = 1.1 Hz, 1H), 4.89 (br s, 1H), 3.42 (q, J = 6.0 Hz, 2H), 2.70 (t, J 13 = 5.8 Hz, 2H), 1.42 (s, 9H). C NMR (100 MHz, CDCl3, 298K) δ 201.4, 155.9, 44.3, 34.0, 28.4, 28.0. Experimental spectra match with literature reports.36

36 Freeman, N. S.; Hurevich, M.; Gilon. C. Tetrahedron, 2009, 65, 1737-1745

tert-Butyl benzyl(4-oxobutyl)carbamate: This compound was prepared according to general procedure B from tert-Butyl benzyl(4- hydroxybutyl)carbamate. The product was obtained as a colourless 1 oil in quantitative yield. H NMR (400 MHz, CDCl3, 298K): δ 9.73 (d, J = 1.4 Hz, 1H), 7.36– 7.20 (m, 5H), 4.42 (br s, 2H), 3.21 (br s, 2H), 2.41 (br s, 2H), 1.82 (br s, 2H), 1.47 (s, 9H). 13C NMR (100 MHz, CDCl3, 298K) δ 201.5, 155.8, 138.3, 128.5, 127.7, 127.2, 79.9, 50.5, 45.7, 41.0, 28.4, 20.5. IR (neat) 3089, 3064, 3031, 3004, 2976, 2933, 2821, 2722, 1686 cm-1. HRMS (DART, ESI+) calcd.: 278.17562; found: 278.17649

This compound was prepared according to a literature procedure.37 tert-Butyl (Z)-benzyl(4-((trimethylsilyl)oxy)but-3-en-1-yl)carbamate: TMSCl (0.54 mmol, 3.0 equiv., 69 L) was added to an oven-dried round bottom flask. In another flask, a mixture of tert-butyl benzyl(4-oxobutyl)carbamate (0.18 mmol, 1.0 equiv., 50 mg), Et3N (0.54 mmol. 1.5 equiv.,75 L) and NaI (0.030 mmol, 0.10 equiv., 3.0 mg) in anhydrous MeCN (0.18 mL) was prepared. The mixture was then added dropwisely to the flask that contained TMSCl, the mixture was then heated at 80 °C overnight. The reaction mixture was cooled down to room temperature, diluted with diethyl ether and washed with saturated NH4Cl. The aqueous layer was then washed with diethyl ether three times and the combined organic layer was then dried with sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a brown oil in quantitative yield.

tert-butyl (Z)-benzyl(4-((trimethylsilyl)oxy)but-3-en-1-yl)carbamate: 1 H NMR (600 MHz, CDCl3, 243K, mixture of rotamers): δ 7.32–7.23 (m, 5H), 6.20–6.16 (m, 1H), 4.51–4.34 (m, 3H), 3.19 (t, J = 7.4 Hz, 1H), 3.06 (t, J = 7.7 Hz, 1H), 2.27 (dq, J = 22.0, 7.4 Hz, 2H), 1.48–1.39 (m, 9H), 0.15 (s, 9H). 13C NMR (150 MHz, CDCl3, 243K, mixture of rotamers) δ 139.5, 139.4, 128.6, 128.5, 127.7, 127.6, 127.2, 107.3, 107.1, 49.8, 49.4, 45.8, 45.5, 28.5, 28.5, 22.5, 22.2, -0.4. IR (neat): 2955, 1961, 1958 cm-1. HRMS (DART ESI+) calcd: 350.21653; found: 350.21637

tert-Butyl (Z)-benzyl(4-((trimethylsilyl)oxy)but-3-en-1-yl)carbamate (0.30 mmol, 1.0 equiv., 0.11 g) was dissolved in anhydrous dichloromethane (1.5 mL, 0.20 M) in an oven-dried, argon- filled round bottom flask followed by the addition of diiodomethane (0.45 mmol, 1.50 equiv., 36

37 Cazeau, P.; Duboulin, F.; Moulines, F.; Babot, O.; Dunogues, J. Tetrahedron. 1987, 43, 2075-2088

L). Et2Zn (1M in hexanes, 0.45 mmol, 1.50 equiv., 0.45 mL) was added to the flask dropwise, the mixture was left to stir at room temperature overnight. The reaction was quenched with saturated NH4Cl solution. The aqueous layer was then extracted with dichloromethane, and the collected organic layer was then dried with sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel using ethyl acetate:methanol 9:1 with 2 % Et3N to afford a light-yellow oil (26 %, 15 mg).

2-(2-(Benzylamino)ethyl)cyclopropan-1-ol: 1H NMR (400 MHz, CDCl3, 298K): δ 7.28– 7.19 (m, 5H), 3.85–3.66 (m, 2H), 3.26 (tdd, J = 6.5, 3.3, 1.4 Hz, 1H), 2.80 (dddd, J = 12.4, 4.4, 2.9, 1.3 Hz, 1H), 2.65–2.53 (m, 1H), 2.07 – 2.00 (m, 1H), 1.38 – 1.26 (m, 1H), 0.71– 13 0.57 (m, 2H), 0.22 (tt, J = 5.6, 4.2 Hz, 1H). C NMR (100 MHz, CDCl3, 298K) δ 138.6, 128.6, 128.4, 127.4, 60.4, 54.0, 48.3, 47.8, 17.5, 14.2. IR (neat): 3004, 2995, 2961, 2925, 2859 cm-1. HRMS (DART ESI+) calcd: 192.13884; found:192.13872

The following compound was prepared using a literature prepartaion.28

Dodecanol (3.0 mmol, 1.0 equiv., 0.67 mL) and TEMPO (0.30 mmol, 0.1 equiv., 47 mg) were dissolved in dichloromethane (6.0 mL, 0.50 M) before the addition of PIDA (3.3 mmol, 1.1 equiv., 1.1 g). The reaction mixture was stirred at room temperature until the reaction was judged to have reached completion by TLC. To quench the reaction, 6.0 mL of saturated Na2S2O3 was added to the reaction flask and left to stir for 15 minutes. The aqueous layer was then extracted with dichloromethane twice. The combined organic layers were washed with a 15% NaOH solution, water, brine and then dried with sodium sulfate. The crude mixture was then filtered and concentrated in vacuo. The product was isolated by flash column chromatography on silica gel using 9:1 hexanes:diethyl ether to afford a colourless oil (80 % yield, 0.44 g).

1 Dodecanal: H NMR (400 MHz, CDCl3, 298K) δ 9.76 (t, J = 1.9 Hz, 1H), 2.42 (td, J = 7.4, 1.9 Hz, 2H), 1.62 (p, J = 7.4 13 Hz, 2H), 1.31–1.24 (m, 16H), 0.94–0.82 (m, 3H). C NMR (100 MHz, CDCl3, 298K) δ 203.0, 43.9, 31.9, 29.6, 29.6, 29.4, 29.3, 29.3, 29.2, 22.7, 22.1, 14.1. Experimental spectra match with literature reports.38

General Procedure B for the synthesis of -chloroaldehydes:

38 Hodgson, D.; Fleming, M.J.; Stanway, S. J. J. Org. Chem., 2007, 72, 4763-4773

The following procedure was modified from a literature preparation.26

Aldehyde (1.0 mmol, 1.0 equiv.) and L-proline (0.10 mmol, 0.10 equiv.) were added to an oven- dried flask followed by the addition of anhydrous dichloromethane (2.0 mL, 0.50 M). The reaction mixture was cooled to 0-C followed by slow addition of NCS (0.90 mmol, 0.90 equiv.). The reaction mixture was stirred at room temperature for 18 hours until the reaction was judged to have reached completion as indicated by the disappearance of starting material by TLC. Upon completion, hexanes were added to the mixture to precipitate out the succinamide which was removed by filtration. The crude mixture was then concentrated in vacuo and purified by flash column chromatography on silica gel.

2-Chloro-3-phenylpropanal: This compound was synthesized from hydrocinnamaldehyde (0.40 mmol scale) using general procedure B and was purified on silica gel using 8:2 hexanes:ethyl Acetate to afford a light-yellow 1 oil (87% yield, 58 mg). H NMR (400 MHz, CDCl3, 298K) δ 9.47 (d, J = 2.2 Hz, 1H), 7.29– 7.20 (m, 3H), 7.18–7.13 (m, 2H), 4.31 (ddd, J = 8.1, 5.7, 2.1 Hz, 1H), 3.31 (dd, J = 14.5, 5.7 Hz, 13 1H), 3.01 (dd, J = 14.5, 8.3 Hz, 1H). C NMR (100 MHz, CDCl3, 298K) δ 194.4, 135.3, 129.4, 128.7, 127.3, 63.9, 38.3. IR (neat): 3088, 3065, 3030, 3007, 2928, 2837, 1731 cm-1. Experimental spectra match with literature reports.39

2-Chlorododecanal: This compound was synthesized from dodecanal (2.4 mmol scale) using general procedure B. The product was purified on silica gel using 8:2 hexanes:ethyl 1 acetate to afford a light yellow oil. (91% yield, 0.48g). H NMR (400 MHz, CDCl3, 298K) δ 9.48 (d, J = 2.5 Hz, 1H), 4.15 (ddd, J = 8.2, 5.5, 2.5 Hz, 1H), 2.01 – 1.87 (m, 1H), 1.87 – 1.75 (m, 13 1H), 1.55 – 1.20 (m, 16H), 0.90 – 0.85 (m, 3H). C NMR (100 MHz, CDCl3, 298K) δ 195.4, 64.0, 32.1, 31.9, 29.5, 29.4, 29.3, 28.9, 25.5, 22.6, 14.1. Experimental spectra match with literature report.40

39 Borg, T.; Danielsson, J.; Somfai, P. Chem. Commun., 2010, 46, 1281-1283 40 Shinoyama, M.; Shirokawa, S.; Nakaaki, A.; Kobayashi, S. Org. Lett., 2009, 11,1277–1280

bis(iodozinco)methane: Activated zinc dust (184 mmol, 2.30 equiv., 12.0 g), lead (II) chloride (0.800 mmol, 0.0100 equiv., 222 mg) and THF (16 mL) were added to an oven-dried, argon- filled flask followed by the addition of diiodomethane (8.00 mmol, 0.100 equiv., 0.645 mL). The mixture was then sonicated at room temperature for 1 hour before it was cooled to 0 C. THF (154 mL) was added to the flask before slow addition of the remaining diiodomethane (72 mmol, 9.9 equiv., 5.8 mL). The mixture was stirred at 0 C for 2 hours and then warmed to room temperature and left to stand overnight for the zinc dust to settle.

Use of Protic Quenches Optimization

3.9 3.11 Entry Yield (%)a d.r.a Yield (%)a,b d.r.a 1 - - 86 2.3:1 2c 28 7.0:1 58 2.5:1 3d >99 4.4:1 - - a Determined by GC-MS using dodecane as internal standard; b Combined cis-and trans-cyclopropylamines; c Reaction ran for 42 hours; d Using isopropanol as protic quench

Procedure: -Chloroaldehyde (0.20 mmol, 2.0 equiv., 34 mg) was added to an oven-dried, argon filled vial followed by the addition of bis(iodozinco)methane (0.40 mmol, 4.0 equiv.). After the reaction mixture was stirred at 0 C for 1 hour, the reaction mixture was brought to room temperature before the addition of water (1.0 mmol, 10 equiv. 18 L), MgSO4, Zn(CN)2 (0.2 mmol, 2.0 equiv, 24 mg) and Na2CO3 (0.2 mmol, 2.0 equiv., 21 mg). The reaction was left to stir for 18 hours at 90 C. The reaction mixture was cooled down to room temperature, diluted with diethyl ether and quenched with saturated NaHCO3. The aqueous layer was washed with diethyl ether three times. The combined organic layer was filtered through plug of Celite and magnesium sulfate mixture and was used in GC-MS analysis.

Cyanide Salts as Additives Optimization

Entry Additive Yield (%)a,b d.r.a 1 KCN >99 4.3:1 2 NaCN >99 4.2:1 3 CuCN - - 4 Zn(CN)2 87 4.9:1 5 AgCN 97 3.8:1 a Determined by GC-MS using dodecane as internal standard; b Combined cis- and trans-cyclopropylamines

Procedure:

-Chloroaldehyde (0.20 mmol, 2.0 equiv., 34 mg) was added to an oven-dried, argon filled vial followed by the addition of bis(iodozinco)methane (0.40 mmol, 4.0 equiv.). After the reaction mixture was stirred at 0 C for 1 hour, the reaction mixture was brought to room temperature before the addition of isopropanol (0.80 mmol, 8.0 equiv. 60 L), followed by the addition of cyanide salt (0.20 mmol, 2.0 equiv.). The reaction was left to stir for 18 hours at 90 C. The reaction mixture was cooled down to room temperature, diluted with diethyl ether and quenched with saturated NaHCO3. The aqueous layer was washed with diethyl ether three times. The combined organic layer was filtered through plug of Celite and magnesium sulfate mixture and was used in GC-MS analysis.

Silver Salts as Additives Optimization

Entry Additives Yield (%)a,b d.r.a 1 Ag2CO3 97 4.3:1 2 AgCl >99 4.1:1 3 AgOTf 98 4.3:1 4 AgF 73 4.3:1 5 AgCN 97 3.8:1 a Determined by GC-MS using dodecane as internal standard; b Combined cis- and trans-cyclopropylamines

Procedure:

-Chloroaldehyde (0.20 mmol, 2.0 equiv., 34 mg) was added to an oven-dried, argon filled followed by the addition of bis(iodozinco)methane (0.40 mmol, 4.0 equiv.). After the reaction mixture was stirred at 0 C for 1 hour, the reaction mixture was brought to room temperature before the addition of isopropanol (0.80 mmol, 8.0 equiv. 60 L), followed by the addition of Zn(CN)2 (0.20 mmol, 2.0 equiv.). and silver salts. The reaction was left to stir for 18 hours at 90 C. The reaction mixture was cooled down to room temperature, diluted with diethyl ether and quenched with saturated NaHCO3. The aqueous layer was washed with diethyl ether three times. The combined organic layer was filtered through plug of Celite and magnesium sulfate mixture and was used in GC-MS analysis.

General procedure C for the synthesis of cyclopropylamines from -chloroaldehydes:

-Chloroaldehyde (0.20 mmol, 2.0 equiv.) was added to an oven-dried, argon-filled vial followed by the addition of bis(iodozinco)methane (0.40 mmol, 4.0 equiv.). After the reaction mixture was stirred at 0 C for 1 hour, the reaction mixture was brought to room temperature before the addition of isopropanol (0.80 mmol, 8.0 equiv., 60 L) followed by amine (0.10 mmol, 1.0 equiv.). The reaction was left to stir for 18 h at 90 C. The reaction mixture was then diluted with diethyl ether and quenched with saturated NH4Cl.The aqueous layer was washed with diethyl ether three times. The combined organic layer was washed with brine then dried with sodium sulfate and concentrated in vacuo. The product was obtained via flash column chromatography, and d.r. was obtained by GC-MS analysis pre-purification.

4-(2-benzylcyclopropyl)morpholine: This compound was synthesized according to general procedure C from 2-chloro-3-phenylpropanal and morpholine (0.40 mmol scale) and was purified on silica gel using 8:2 hexanes:ethyl acetate to afford a clear oil (61% yield, 53 mg, d.r = 3.7:1). 1H NMR (400 MHz, CDCl3, 298K) δ 7.35 – 7.17 (m, 5H), 3.61 (t, J = 4.7 Hz, 4H), 2.65 (dd, J = 14.5, 6.4 Hz, 1H), 2.59 – 2.36 (m, 5H), 1.55 (dt, J = 6.8, 3.4 Hz, 1H), 1.16 – 1.05 (m, 1H), 0.70 13 (ddd, J = 8.9, 4.9, 3.7 Hz, 1H), 0.46 (dt, J = 6.8, 5.3 Hz, 1H). C NMR (100 MHz, CDCl3, 298K) δ 141.5, 128.3, 128.3, 125.9, 66.9, 53.4, 45.9, 38.5, 21.0, 13.1. IR (neat): 3027, 3000, 2957, 2928, 2913, 2895, 2852, 2805, 2759, 2736 cm-1. Experimental spectra match with literature report.17

1-(2-benzylcyclopropyl)-1,2,3,4-tetrahydroquinoline: This compound was synthesized according to general procedure C from 2-chloro-3- phenylpropanal and 1,2,3,4-tetrahydroquinoline (0.10 mmol scale) and was purified on silica gel using 99:1 hexanes:diethyl ether to afford a light 1 yellow oil (74 % yield, 19 mg, d.r. = 5.1:1) H NMR (400 MHz, CDCl3, 298K) δ 7.27 – 7.13 (m, 5H), 6.95 – 6.83 (m, 3H), 6.55 (td, J = 7.2, 1.3 Hz, 1H), 3.08 – 2.97 (m, 2H), 2.75 (dd, J = 14.4, 6.6 Hz, 1H), 2.63 (t, J = 6.6 Hz, 2H), 2.55 (dd, J = 14.5, 7.4 Hz, 1H), 2.09 (dt, J = 6.8, 3.5 Hz, 1H), 1.85 – 1.73 (m, 2H), 1.25 – 1.13 (m, 1H), 0.83 – 0.74 (m, 1H), 13 0.73 – 0.66 (m, 1H). C NMR (100 MHz, CDCl3, 298K) δ 146.7, 140.9, 128.8, 128.6, 128.4, 126.6, 126.1, 123.4, 117.0, 112.6, 48.5, 38.9, 38.5, 27.6, 22.9, 22.7, 15.7. IR (neat): 3025, 2927, 2842 cm-1. HRMS (DART, ESI+): calc.:264.17522, found:264.17559

1-(2-benzylcyclopropyl)indoline: This compound was synthesized according to general procedure C from 2-chloro-3-phenylpropanal and indoline (0.10 mmol scale) and was purified on silica gel using 100% Hexanes to afford a light yellow oil (91 % yield, 23 mg, d.r. = 4.4:1). The 1 product was isolated as a mixture of diastereomers. H NMR (400 MHz, CDCl3, 298K) δ 7.35 – 7.27 (m, 5H), 7.06 (dd, J = 7.2, 1.3 Hz, 1H), 7.00 (tt, J = 7.7, 1.0 Hz, 1H), 6.68 (td, J = 7.4, 1.0 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 3.32 – 3.22 (m, 2H), 2.92 – 2.83 (m, 2H), 2.70 (dd, J = 7.1, 5.1 Hz, 2H), 2.03 (dt, J = 6.7, 3.3 Hz, 1H), 1.33 (dtdd, J = 8.9, 7.1, 5.7, 3.0 Hz, 1H), 0.94 (ddd, J = 13 8.8, 5.0, 3.6 Hz, 1H), 0.69 (dt, J = 6.7, 5.2 Hz, 1H). C NMR (100 MHz, CDCl3, 298K) δ 141.0, 130.4, 128.6, 128.4, 128.3, 127.1, 126.1, 124.3, 118.3, 108.4, 54.0, 38.4, 37.0, 28.5, 20.6, 13.3. Experimental spectra match with literature report.17

8-(2-benzylcyclopropyl)-1,4-dioxa-8-azaspiro[4.5]decan: This compound was synthesized according to general procedure C from 2- chloro-3-phenylpropanal and 1,4-dioxa-8-azaspiro[4.5]decane (0.10 mmol scale) and was purified on silica gel using 8:2 hexanes:ethyl acetate to afford a colourless oil (77 % yield, 19mg, d.r. = 4.2:1). 1H NMR (400 MHz, CDCl3, 298K) δ 7.29 – 7.19 (m, 5H), 3.93 (s, 4H), 2.58 (dtd, J = 32.9, 13.0, 11.7, 6.0 Hz, 5H), 2.40 (dd, J = 14.5, 7.9 Hz, 1H), 1.65 (t, J = 5.8 Hz, 4H), 1.55 (dt, J = 6.9, 3.4 Hz, 1H), 1.09 (ttd, J = 8.8, 5.8, 3.0 Hz, 1H), 0.68 (ddd, J = 8.9, 4.9, 3.8 Hz, 1H), 0.45 (dt, J = 6.8, 5.2 Hz, 13 1H). C NMR (100 MHz, CDCl3, 298K) δ 141.7, 128.4, 128.3, 125.9, 107.4, 64.2, 51.2, 45.2, 38.7, 34.7, 21.5, 13.7. Experimental spectra match with literature report.17

N,N-diallyl-2-benzylcyclopropan-1-amine: This compound was synthesized according to general procedure C from 2-chloro-3- phenylpropanal and diallylamine (0.10 mmol scale) and was purified on silica gel using 8:2 hexanes:ethyl acetate to afford a light yellow oil (35 % 1 yield, 8.0 mg, d.r. = 3.2:1). H NMR (400 MHz, CDCl3, 298K) δ 7.36 – 7.25 (m, 2H), 7.20 (dt, J = 7.8, 1.9 Hz, 3H), 5.84 (ddt, J = 17.0, 10.2, 6.8 Hz, 2H), 5.21 – 4.96 (m, 4H), 3.25 – 3.04 (m, 4H), 2.61 (dd, J = 14.6, 6.6 Hz, 1H), 2.46 (dd, J = 14.6, 7.5 Hz, 1H), 1.68 (dt, J = 6.9, 3.5 Hz, 1H), 1.14 (h, J = 6.1, 5.5 Hz, 1H), 0.71 (dt, J = 8.9, 13 4.3 Hz, 1H), 0.46 (dt, J = 6.8, 5.3 Hz, 1H). C NMR (100 MHz, CDCl3, 298K) δ 141.4, 135.2, 128.4, 128.2, 125.8, 117.3, 57.3, 42.9, 38.3, 22.1, 14.5. IR (neat): 3071, 3027, 2918 cm-1 HRMS (DART ESI+) calc.: 228.17522 found: 228.17499

N-(2-benzylcyclopropyl)-N-methylaniline: This compound was synthesized according to general procedure C from 2-chloro-3- phenylpropanal and N-methylaniline (0.10 mmol scale) and was purified on silica gel using 100% hexanes to afford a light yellow oil (72 % yield, 17 mg, d.r. = 6.9:1). The product was isolated as a mixture of diastereomers. 1H NMR (400 MHz, CDCl3, 298K) δ 7.38 – 7.27 (m, 5H), 7.23 – 7.18 (m, 2H), 6.92 – 6.86 (m, 2H), 6.75 (tt, J = 7.3, 1.1 Hz, 1H), 2.87 (s, 3H), 2.86 – 2.80 (m, 1H), 2.66 (dd, J = 14.4, 7.4 Hz, 1H), 2.31 – 2.26 (m, 1H), 1.36 – 1.26 (m, 1H), 0.89 (ddd, J = 9.0, 5.1, 3.8 Hz, 1H), 0.84 – 0.77 (m, 1H). 13C NMR (100 MHz, CDCl3, 298K) δ 149.5, 139.8, 127.8, 127.6, 127.4, 125.1, 116.2, 112.6, 39.0, 37.7, 37.3, 22.5, 15.2. Experimental spectra match with literature report.17

N-(2-dibenzyl)-N-methylcyclopropan-1-amine: This compound was synthesized according to general procedure C from 2-chloro-3- phenylpropanal and N-methylbenzylamine (0.10 mmol scale) and was purified on silica gel using 100% hexanes to afford a light yellow oil (55 % yield, 13 mg, d.r. = 5.3:1). The product was isolated as a mixture of diastereomers 1H NMR (400 MHz, CDCl3, 298K) δ 7.51 – 7.04 (m, 12H), 3.66 – 3.52 (m, 2H), 2.52 (d, J = 7.1 Hz, 2H), 2.17 (s, 3H), 1.62 (ddd, J = 6.7, 3.7, 3.0 Hz, 1H), 1.12 (dtdd, J = 8.7, 7.1, 5.5, 3.0 Hz, 1H), 0.71 13 (ddd, J = 9.0, 4.8, 3.7 Hz, 1H), 0.47 (ddd, J = 6.8, 5.5, 4.8 Hz, 1H). C NMR (101 MHz, CDCl3, 298K) δ 141.63, 138.52, 129.31, 128.38, 128.24, 128.03, 126.82, 125.85, 62.06, 45.58, 41.81, 38.50, 22.42, 14.47. Experimental spectra match with literature report.17

N-(2-decylcyclopropyl)-N-methylaniline: This compound was synthesized according to general procedure C from 2-chlorododecanal and N- methylaniline (0.10 mmol scale) and was purified on silica gel using 100% hexanes to afford a light yellow oil (63 % yield, 18 mg, d.r. = 9.7:1). 1H NMR (400 MHz, CDCl3, 298K) δ 7.30 – 7.20 (m, 2H), 6.97 – 6.91 (m, 2H), 6.76 (tt, J = 7.3, 1.1 Hz, 1H), 2.96 (s, 3H), 2.10 (dt, J = 6.7, 3.4 Hz, 1H), 1.63 – 1.54 (m, 1H), 1.46 (q, J = 7.5 Hz, 2H), 1.33 – 1.26 (m, 14H), 1.19 (dq, J = 12.9, 7.6 Hz, 1H), 1.03 – 0.93 (m, 1H), 0.93 – 0.86 (m, 13 3H), 0.76 (ddd, J = 8.9, 4.8, 3.7 Hz, 1H), 0.68 – 0.57 (m, 1H). C NMR (101 MHz, CDCl3, 298K) δ 150.7, 128.8, 117.2, 113.7, 40.3, 38.8, 32.6, 32.0, 29.7, 29.7, 29.7, 29.6, 29.4, 29.1, 22.7, 22.5, 16.2, 14.1. IR (neat): 2955, 2922, 2853 cm-1. HRMS (DART ESI+) calc.: 288.26912 found: 288.26943

With 40% trans-silyl enol ether and its rotamers

Compound is prone to decomposition