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Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin- hydroaminoalkylation

Aaron Trowbridge1, Dominik Reich1 and Matthew J. Gaunt1*

1 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom. CB2

1EW.

There is evidence to suggest that increasing the level of saturation (number of sp3-hybridized carbon

atoms) in small molecules increases the chance of success in the transition from discovery, through

clinical studies, to drugs1. Due to their favorable physical properties, alkylamines have become

ubiquitous features amongst pharmaceutical agents, small-molecule biological probes and pre-clinical

candidates2. Despite their importance, amine synthesis is still dominated by two methods: N-alkylation

and carbonyl reductive amination3. The increasing demand for such saturated polar molecules in drug-

discovery, however, has continued to drive development of practical catalytic methods to synthesize

complex saturated alkylamines4-7. In particular, processes that transform diverse, accessible feedstocks

into structurally diverse sp3-rich architectures provides a strategic advantage in complex alkylamine

synthesis. Here, we report a multicomponent reductive photocatalytic technology that combines

readily-available dialkylamines, carbonyls and alkenes to build architecturally complex and

functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process

involves a visible-light-mediated reduction of in-situ generated iminium ions, selectively furnishing

previously inaccessible alkyl-substituted a-amino radicals, which engage alkenes and lead to C(sp3)–

C(sp3) bond formation. The operationally straightforward reaction exhibits broad functional group

tolerance, facilitates the synthesis of drug-like amines not readily accessible by other methods and is

amenable to late-stage functionalization applications, making it of interest in pharmaceutical research

and other areas.

The physiological properties of tertiary aliphatic amines and their ability to interfere with natural

neurotransmission pathways have rendered them highly effective pharmaceutical agents8, in areas ranging from treatment of neurodegenerative disorders (such as Alzheimer’s disease)9 to metabolic syndromes (such as obesity)10 (Fig 1A). Traditionally, efforts for the synthesis of these molecules require multiple steps and tedious purifications, severely hampering efforts in drug-discovery. Therefore, the development of straightforward methods that enable the construction of complex tertiary amines from simple starting materials would have far-reaching implications in both the synthetic and medicinal chemistry community. While the abundance, diversity and predictable reactivity of sp2-hybridized feedstocks has led to the emergence of new transition-metal catalyzed amine syntheses, namely the Buchwald-Hartwig amination11 and olefin- hydroamination12-14, strategies for more complex alkylamines are more limited13-15. We reasoned that an operationally-simple and mechanistically-distinct catalytic process involving available dialkylamines, olefins, and aliphatic carbonyl feedstocks would expand the capacity of olefin-hydroaminoalkylation-based strategies for the synthesis of tertiary alkylamines.

(a) Cl O N NC Me Me N O O H MeO O O N O OMe O N S O Me OH Me F O2N OCMe3 Me HO Me escitalopram GSK4112 ANAVEX2-73 omacetaxine anti-depressant REV-ERBα agonist phase II trials - Alzheimer’s acute myeloid leukaemia

(b)

O Ir(III) photocatalyst N N + + R R H visible light Hantzsch ester readily available feedstock complex amines and ketones or aldehydes alkene tertiary amine

amine-carbonyl hydrogen atom condensation transfer

N e N R N

SET amino- R alkylation

alkyl-substituted all-alkyl alkyl iminium ion α-amino radical radical

(c) existing photoredox methods for α-amino radical formation

H O N photocatalytic N N H N N SET OH tBuO O tBuO O

selective formation of this useful unfunctionalized oxidation to oxidative radical direct H-atom synthon is difficult via existing photoredox methods radical cation decarboxylation abstraction

Fig 1. (a). Importance of tertiary amines. (b). Multicomponent photocatalytic olefin-hydroaminoalkylation to tertiary alkylamines via the selective formation of alkyl-substituted a-amino radicals. (c). Existing catalytic photoredox methods for the generation of a-amino radicals.

We proposed that an electrophilic iminium ion, formed through the well-established union of secondary alkylamines and alkyl-substituted carbonyls, could be susceptible to a catalytic single electron reduction process (Fig 1B). The resulting a-amino radical could then engage a third reaction component, such as an alkene, in a subsequent C(sp3)–C(sp3) cross-coupling process. However, few methods report the generation of ‘all-alkyl’ a-amino radicals from pre-formed iminium ions, and each suffers from issues of practical application16, 17. Moreover, their subsequent addition to alkenes has been limited to specific intramolecular examples. To overcome these problems, we envisioned, firstly, that a visible-light-activated photocatalyst could mediate single-electron transfer (SET) to an in-situ generated alkyl-substituted iminium ion, generating the desired a-amino radical under mild reaction conditions (Fig 1B). Secondly, we considered that a polarity- matched hydrogen atom transfer (HAT) from a suitable reagent could facilitate the cross-coupling to the alkene by intercepting the resulting alkyl-substituted radical. An important feature of this proposed catalytic activation pathway is the regiospecific positioning of the newly formed a-amino radical, made possible by the SET to the iminium ion, regardless of the groups surrounding the reactive center. Selective formation of an ‘all-alkyl’ a-amino radical would not be possible via the related photocatalytic approaches without the use of pre-functionalized starting materials or inherently selective substrates (Fig 1C)18-20.

We were mindful of several factors that could impede the development of the photocatalytic olefin- hydroaminoalkylation process. In contrast to protonated imines and iminium ions conjugated with multiple

red 21 aromatic substituents (E1/2 = –0.8 to –1.2 V vs. SCE in acetonitrile) , which have been shown to partake in a limited range of reductive coupling reactions22, 23, the reduction potential of an ‘all-alkyl’-iminium ion could be up to –2.0 V21 and would require a highly reducing photocatalyst that may be incompatible with resident functionality. Moreover, alkyl-iminium ions are known to exist in (often unfavorable) equilibrium with the corresponding enamines, which can also undergo SET reactions to form radical species, presenting competing pathways24. Finally, the addition of a-amino radicals to simple alkenes is known to be low-yielding due to oligomerization of the resulting radical25. We hereby report a comprehensive strategy for the modular and efficient construction of complex tertiary alkylamines via photocatalytic olefin-hydroaminoalkylation.

The initial evaluation of the proposed amine synthesis focused on a reaction between butyraldehyde 1a, dibenzylamine 2a, butyl acrylate 3a and Hantzsch ester 4a catalyzed by Ir(ppy)3, under the action of visible- light (Fig 2A). Optimized reaction conditions were readily established (for a detailed account of the optimization study: see supplementary materials, S7), using 1mol% Ir(ppy)3 and a 40 W blue-LED for 2 hours at room temperature. Under these conditions, near-equimolar quantities of aldehyde, amine and alkene with

1.5 equivalents of Hantzsch ester in a 0.1 M solution of dichloromethane containing molecular sieves and

20mol% of propionic acid formed desired amine 5a, which was isolated in 84% yield after chromatography

(Fig 2B). We were delighted by the remarkable selectivity displayed in this reaction; only trace quantities of the reductive amination side product were observed, which presumably resulted from HAT to the a-amino radical from 4a26.

(a) 1 mol% Ir(ppy) , 40 W blue LED Bn H H N 3 N O Bn Hantzsch ester 4a EtO2C CO2Et + N + Ir H H 20 mol% propionic acid, 4 Å mol. sieves Me N Me N N CH2Cl2, room temperature, 2 h H

aldehyde 1 dialkyl amine 2 acceptor 3 tertiary amine Hantzsch ester 4a Ir(ppy)3 (b) aldehyde scope

Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn N N N N N N MeO TBSO Me O N O CO Bu CO Bu CO Bu CO Bu CO2Bu CO2Bu 2 2 2 2 Boc Me

5a, 84%a 5b, 59%a 5c, 81%a 5d, 81%a 5e, 81%b,c 5f, 84%b,c

Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn N N N N N N Me F BocN Me BocN O F CO2Bu CO2Bu CO2Bu CO2Bu CO2Bu CO2Bu

5g, 62%a 5h, 71%b,c 5i, 70%b,c 5j, 79%b,c 5k, 64%b,c 5l, 80%b,c amine scope

Bn Bn Bn CO2Me Bn OMe Bn S Bn N Bn N Ar N N N N N TIPS N O H Me Me F Me Me Me H

CO2Bu CO2Bu CO2Bu CO2Bu CO2Bu CO2Bu

5m, 41%d 5n, 81%a,c 5o, 83%b,c 5p, 79%a 5q, 72%a 5r, Ar = 4-ClPh, 74%b,c

Br Me Bn Br Boc Bn Bn OTIPS Bn Bn N N N N Me Bn N N N N Me N N Me Me Me Me N Me H Me

CO2Bu CO2Bu CO2Bu CO Bu CO2Bu 2 CO2Bu

5s, 63%a 5t, 55%a 5u, 73%b,c 5v, 58%b,c 5w, 65%b,c 5x, 78%a alkene scope O Bn CN Bn Bn Bn Bn Bn Bn Bn N Bn N CO Et N N N N 2 Me Me Me Me Me Me Me

CO2Bu CO2Bu CO2R R CO2R CO2Bu b,c b,c a t a a,c b 5y, 56% 5z, 36% 5aa, 70% 5ab, R = Bu, 84% 5ad, R = SO2Ph, 82% 5ag, R = Me, 42% (1:1 dr) a,e b,c b 5ac, R = Bn, 84% 5ae, R = CN, 88% 5ah, R = CH(CF3)2, 67% (1:1 dr) a 5af, R = PO(OEt)2, 60%

Bn Bn Bn Bn N N Bn Bn Bn Bn Bn Bn Bn Bn N N N N Me Me O Me Me Me Me Me O N N O SO2Ph Me CO2Et Cl

5ai, 54% (1:1 dr)b 5aj, 65% (1:1 dr)b 5ak, 46% (1:1 dr)b,c 5al, 80% (2.3:1 dr)a 5am, 75% (2.3:1 dr)b,c 5an, 37%b,c

Bn Bn Bn Bn Bn Bn N N Bn Bn N N Bn Bn Bn Bn N N Me Me Me H Me N Cbz O Me N CF3 O 7 O H CO2Me N F F CF3 tBu

5ao, 45%a,c 5ap, 42%b,c 5aq, 56% (>20:1 dr)c,d 5ar, 80%a,c 5as, 24%b,c 5at, 66%a,c

Fig 2. (a). Optimized conditions for photocatalytic olefin-hydroaminoalklyation. (b). Scope of photocatalytic olefin-hydroaminoalklyation. aamine/aldehyde/acceptor (1:1.1:1.1) and 4a (1.5 equiv.). bamine/aldehyde/acceptor (1:2:2) and 4a (1.5 equiv.). cconducted using methoxyethyl-Hantzsch ester (1.5 equiv.). dconducted using paraformaldehyde (5 equiv.), preheated for 1 hour. e4 mmol scale. ppy = 2- phenylpyridinato; Boc = t-butyloxycarbonyl; TIPS = triisopropylsilyl; Cbz = benzyloxycarbonyl.

With the optimized conditions, we found that a variety of linear aldehydes reacted efficiently to give amines

5a-5f, including those bearing electron-rich heteroarenes (5e, 5f), in good yields (Fig 2B). Aldehydes displaying a-branching produced the expected amines 5g-5l in good yield; notable examples included saturated heterocycles and strained ring features commonly found in pharmaceutical agents. The a-amino radical formed from formaldehyde and dibenzylamine was effective in the reaction, producing g-aminobutyric acid derivative 5m; unfortunately, benzaldehyde-derived iminium ions failed to deliver the desired cross- coupling products. Next, we found that benzylamine derivatives containing a multitude of functionalized aryl and heteroaryl groups were amenable to the reaction and gave good yields of the corresponding amines (5n-

5u). Amines displaying linear and branched alkyl-substituents, as well as ester, hydroxyl and nitrile functionality, worked well to give amines 5v-5aa. The photocatalytic process was effective with a range of electron-deficient alkenes. A reaction with benzyl acrylate 3c could be adapted to a gram-scale process, delivering 1.4 g of product 5ac in 84% yield. Notably, acrylonitrile (giving 5ae) proved a suitable coupling partner, despite being prone to oligomerization in radical reactions. Substituents at either the a- or b-positions on the alkene (5ag-5ak) could be accommodated despite the lower electrophilicity and greater steric demand of these acceptors, with a diastereoselectivity of 2.3:1 observed in the reaction of methacrylate to form 5al.

Vinyl pyridine derivatives also proved to be viable acceptors (giving 5am-5ap) allowing facile access to chlorphenamine derivative 5am. By employing a chiral dehydroalanine derivative, the a-amino radical addition to this acceptor led to enantioenriched non-proteogenic amino acid derivative 5aq in good yield. We also found that perfluorinated alkenes, dienes, and electron-deficient alkynes functioned well as acceptors

(giving 5ar-5at); the reaction with methyl propiolate delivered (E)-allylic amine 5at in 66% yield as a single geometric isomer. (a) H O Ph O 3a Ph R Bn Bn Bn 1a OBu Bn H HAT, 4a H photocatalytic N Ph N Ph N N 5a R iminium R R Bn radical addition R (not observed) reduction CO Bu N Ph 2 H H2O iminium ion Int-I α-amino radical Int-II Int-IV CO Bu 2a 2

Bn SET 1,5–HAT (observed) enamine Ph N Int-III R – H [Ir(II)ppy3] [Ir(III)ppy ] (reductant) 3 Ph Bn N oxidation H H EtO C CO Et R red 2 2 E1/2 = – 0.9 V

Me N Me Int-V H CO2Bu H 4a’ 4a’ Bn EtO2C CO2Et N Ph R CO Bu [Ir(III)ppy3]* Me N Me 2 H H (oxidant) H iminium ion Int-VI EtO2C CO2Et

Me N Me Ph H Bn N 4a reduction R 5a

– red – red 40 W blue lamp [Ir(III)ppy3]* / [Ir(II)ppy3] , E1/2 = + 0.31 V [Ir(III)ppy3] / [Ir(II)ppy3] , E1/2 = – 2.1 V CO2Bu

(b) Me O Ph 1 mol% Ir(ppy)3, 40 W blue LED 1 mol% Ir(ppy)3, 40 W blue LED D D Ph Bn amine 2a, 20 mol% propionic acid 4a, 20 mol% propionic acid D N D 1a H Ph N 4 Å mol. sieves, rt, CH2Cl2, 2 h 4 Å mol. sieves, rt, CH2Cl2, 2 h H

Me Me D D O 3a D EtO C CO Et Ph 2 2 D CO Bu D CO Bu 2 OBu 2 d2-4a Ph N d4-2a H d1-5a, 70% Me N Me d4-5a, 67 % D D H

(c) 1 mol% Ir(ppy)3, 40 W blue LED Ph Ph Ph O Bn O Hantzsch ester 4a Bn Boc Bn Bn Int-VII BocHN N N N BocHN N N Ph BocHN H H OBu 20 mol% propionic acid, 4 Å mol. sieves CO2Bu CO2Bu CO2Bu CH2Cl2, 2 h, rt 1n 2a 3a 5au, 29% 6, 22% (d.r. 5.5:1)

Fig 3. (a) Proposed mechanism for the photocatalytic olefin-hydroaminoalkylation. (b). Deuterium-labelling studies. (c). Evidence for iminium ion redox-relay mechanism.

Our mechanistic proposal for the photocatalytic olefin-hydroaminoalkylation is shown in Fig 3A. The reaction

27 begins with visible-light excitation of Ir(ppy)3 to the long-lived photoexcited *Ir(III) species (t = 1.9 µs) .

red 27 While this species may be sufficiently reducing [Ir(IV)/*Ir(III), E1/2 = –1.73 V vs. SCE in acetonitrile] to undergo SET to alkyl-iminium ion Int-I, we recognized that *Ir(III)ppy3 is efficiently quenched by Hantzsch

red 27 – ester 4a [*Ir(III)/Ir(II), E1/2 = +0.31 V vs. SCE in acetonitrile] leading to [Ir(II)ppy3] and the

– corresponding Hantzsch ester-radical cation 4a’. Importantly, [Ir(II)ppy3] is sufficiently reducing

red 27 [Ir(III)/Ir(II), E1/2 = –2.19 V vs. SCE in acetonitrile] to undergo SET with the full range of alkyl-iminium ions21, leading to a-amino radical Int-II. We identified enamine Int-III as the predominant species in the 1H

NMR of the reaction mixture, which we believe is an off-cycle precursor to the iminium ion Int-I; the acid maintains a low concentration of iminium Int-I by protonation of the enamine. The a-amino radical Int-II now engages the polarity-matched acrylate 3a, creating a carbon-carbon bond and a-ester radical Int-IV. Given the propensity for mono-substituted a-ester radical Int-IV to undergo oligomerization25, we anticipated that an intramolecular 1,5-HAT to the benzylic position may act as a kinetic trap to form stabilized radical Int-V28.

Finally, we expected that the Hantzsch ester or its radical cation 4a/4a’ would participate in a HAT reaction with Int-V, to form amine 5a. A reaction using deuterium-labelled Hantzsch ester d2-4a (Fig 3B) confirmed our hypothesis; deuterium was incorporated exclusively at the benzylic position of amine d1-5a, showing that

1,5-HAT occurred prior to interception with 4a/4a’. This theory was further corroborated using labelled dibenzylamine d4-2a, wherein a deuterium was transferred to the position adjacent to the ester in amine d4-5a.

We also found that an aldehyde bearing a b-nucleophilic group (1n) underwent cyclization onto the benzylic position to form 6, as a side reaction in the formation of 5au (Fig 3C). This result suggests that the a-

red 29 aminobenzyl radical (Int-V) can undergo oxidation [E1/2 = –0.9 V vs. SCE in acetonitrile] to iminium Int-

VI, which is accessible to a range of oxidants, such as *Ir(III)27. Notably, selective reduction of benzaldiminium ion Int-VI, over the initially formed iminium Int-I, can be accounted for by its inability to form a stable enamine intermediate compared to the interconversion between Int-I and Int-III. The reduction of Int-VI could proceed by a 2-electron process with 4a or photocatalytic SET and HAT. Interestingly, a pathway whereby iminium Int-I is translated into a new iminium species Int-VI represents an overall mechanism that can be described as a redox-relay of iminium ions, which, to the best of our knowledge, has not been previously reported.

In this context, benzylamines not only overcome the inherent challenges posed by the addition of a-amino radicals to electron-deficient alkenes, but also act as a protecting group for primary and secondary alkylamines. Nonetheless, we reasoned that use of an alkene which would produce a less-electrophilic radical should favor direct reaction with the Hantzsch ester-radical cation 4a’, obviating the need for the 1,5-HAT process, and hence permitting the use of a variety of dialkylamines. To test this, 1,1-diphenylethylene was combined with aldehyde 1a and 4-phenyl piperidine under the standard conditions. Pleasingly,

O 1 mol% Ir(ppy) , 40 W blue LED 3 N (a) + N + Hantzsch ester 4a H H Me 20 mol% propionic acid, 4 Å mol. sieves CH2Cl2, room temperature, 2 h

aldehyde 1 dialkyl amine 2 acceptor 3 tertiary amine

Ph CF3 Boc Me O Me H H N H H N Ph N Ph N Ph N Ph N Ph N Ph Me Ph Me Ph Me Ph Me Ph Me Ph Me Ph

7a, 51%a,c 7b, 54%a,d 7c, 38%a,c 7d, 60%a 7e, 25%a,c,d 7f, 38%a,c,d

O Me OMe OMe Me Me Me Me N N O Me N Ph Me Me N Ph N Ph N Ph Me Ph O Ph N Me Ph Cbz Me Ph Me Ph Me Ph tBu

7g, 34%a,c,d 7h, 81%a,d 7i, 69%a 7j, 86%a 7k, 88%a 7l, 61% (>20:1 d.r.)b,c,e

(b) 1mol% Ir(ppy) , 40 W blue LED O N 3 Hantzsch ester 4a N N + + H 20 mol% propionic acid, 4 Å mol. sieves X X X CH2Cl2, room temperature, 2 h di-alkylamine 2 ketone 8 enamine 9 acceptor 3 complex amine 10

Me O O N

N N N N N N O Bn Cbz N Ph Cl O Ph Ph Ph O N O N tBu

10a, 53%f 10b, 59%f 10c, 32%f 10d, 83%f 10e, 60%b,c,e,f

(c) OH Cl Cl F O N O

O N N Cbz N N Cbz O N N tBu F N N O O Me N N tBu O O O O N O O Cbz tBu F F MeO O 11, 44% (d.r. 1:1)a,c,d from paroxetine 12, 32%e,c from desloratidine 13, 55% (d.r. 1:1)a,b from amoxapine 14, 64% (d.r. 1:1)a,b from ciprofloxacin

Fig 4. (a). Scope of non-benzylic amines for photocatalytic olefin-hydroaminoalkylation (b). The synthesis of alkyl substituted a-tertiary amines from dialkyl ketones. (c). Late-stage photocatalytic olefin- hydroaminoalkylation with pharmaceutical agents. aconducted using amine/aldehyde/acceptor (1:2:2), and 4a (1.5 equiv.). bconducted using acceptor (1.5 equiv.). cconducted using methoxyethyl-Hantzsch ester (1.5 d e equiv.). using amine hydrochloride and Et3N (1 equiv.). conducted using paraformaldehyde (5 equiv.), preheated for 1 hour. fconducted using enamine (1 equiv.) and acceptor (2 equiv.).

the desired tertiary amine 7a was formed in 51% yield (Fig 4A). Other amine heterocycles were also compatible with this alkene acceptor, giving the amine products (7b-7k) in good yield; 1,1-diarylpropylamines

30 are key motifs commonly found in H1-antihistamines . Among these examples, a number of amines found in pharmaceuticals formed the corresponding complex tertiary amines (7c-7h), demonstrating the potential to forge ‘drug-like’ molecules in a single step from readily available materials. The use of non-benzylic amines was not restricted to reactions with 1,1-diarylethenes; the union of tetramethylpiperidine, formaldehyde and a dehydroalanine acceptor proceeded smoothly to form amine 7l as a single diastereomer.

We envisioned that the use of dialkylketones would be an important extension to the photocatalytic process, since these reactions would give rise to a-tertiary amine products31. Conscious that the formation of ketiminium ions often require more forcing conditions, we reasoned that protonation of a pre-formed enamine

9 would provide a more accessible source of alkyl-ketiminium ions, since alkyl-enamines can be readily prepared on gram scale in one step (Fig 4B). Under the standard conditions, a range of alkyl enamines underwent smooth cross-coupling with alkene acceptors to form a-tertiary amines (10a-10e). The olefin- hydroaminoalkylation method was able to generate complex a-tertiary alkylamines scaffolds, in a single step, which would be difficult to assemble via classical methods.

Given that dialkylamine motifs are present in a range of small molecule drugs and pre-clinical candidates, late-stage functionalization of such molecules would be a powerful demonstration of the utility of this process.

To confirm this strategy, we selected four pharmaceutical agents and subjected them to the photocatalytic reaction (Fig 4C). Each of these architecturally complex amines underwent smooth olefin- hydroaminoalkylation with a variety of aldehydes to furnish the tertiary amine products (11-14). In particular, the combination of desloratidine with formaldehyde and a chiral dehydroalanine acceptor forms a single diastereomer of the tertiary amine derivative (12), constituting a potentially useful linker-strategy through which further functionalization of drug scaffolds could be realized.

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Acknowledgments: We are grateful to Dr. Andrew Bond for x-ray crystallographic analysis and the EPSRC

UK National Mass Spectrometry Facility at Swansea University for HRMS analysis; we thank Dr. Manuel

Nappi, Dr. John C. K. Chu and Dr. Thomas Hunt (AstraZeneca) for useful discussion. Funding: We are grateful to the Herschel Smith Scholarship Scheme and AstraZeneca for studentships (to A.T. and D.R. respectively) and the Royal Society for a Wolfson Merit Award (M.J.G.). Author Contributions: M.J.G.,

A.T. and D.R. designed the experiments. A.T. and D.R. performed and analyzed the experiments. M.J.G.,

A.T. and D.R prepared the manuscript. Competing Interests: Authors declare no competing interests. Data and Materials: Materials and methods, experimental procedures, useful information, mechanistic studies, optimization studies, 1H NMR spectra, 13C NMR spectra and MS data are available in the Supplementary

Materials. Crystallographic data are available free of charge from the Cambridge Crystallographic Data

Centre under the reference number CCDC 1819790.