Photocatalytic α-Tertiary Amine Synthesis via C?H Alkylation of Unmasked Primary Amines

Article abstract of DOI:10.1002/anie.202005294

A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C?H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 percent atom-economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.

Full text of DOI:10.1002/anie.202005294

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Photocatalytic α-Tertiary Amine Synthesis via C–H Alkylation of
Unmasked Primary Amines
Authors: Alexander James Cresswell, Alison Ryder, William
Cunningham, George Ballantyne, Tom Mules, Anna Kinsella,
Jacob Turner-Dore, Catherine Alder, Lee Edwards, Blandine
McKay, and Matthew Grayson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202005294
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10.1002/anie.202005294
Angewandte Chemie International Edition
RESEARCH ARTICLE
Photocatalytic α-Tertiary Amine Synthesis via C–H Alkylation of
Unmasked Primary Amines
Alison S. H. Ryder,[a] William B. Cunningham,[b] George Ballantyne,[b] Tom Mules,[b] Anna G. Kinsella,[b]
Jacob Turner-Dore,[b] Catherine M. Alder,[c] Lee J. Edwards,[c] Blandine S. J. McKay,[c] Matthew N.
Grayson,[b] and Alexander J. Cresswell*[b]
Dedicated to the memory of Professor Jonathan M. J. Williams (deceased on 03/08/2019)
ABSTRACT: A practical, catalytic entry to α,α,α-trisubstituted
(α-tertiary) primary amines by C–H functionalisation has long been
recognised as a critical gap in the synthetic toolbox. We report a
simple and scalable solution to this problem that does not require any
in situ protection of the amino group and proceeds with 100% atom-
economy. Our strategy, which uses an organic photocatalyst in
could be transformative. Despite isolated reports of non-catalytic
α-C–H alkylations of primary aliphatic amines,[6] including an
amine dehydrogenation sequence with stoichiometric quinones,[7]
catalytic protocols to directly access C-alkylated primary amines
have proven elusive, especially for non-benzylic amines.[8]
Indirect methods reliant on N-protection, catalytic C–H
combination with azide ion as a hydrogen atom transfer (HAT) catalyst, alkylation[9a,b] or arylation,[9b] and subsequent N-deprotection have
provides a direct synthesis of α-tertiary amines, or their corresponding
γ-lactams. We anticipate that this methodology will inspire new
retrosynthetic disconnections for substituted amine derivatives in
organic synthesis, and particularly for challenging α-tertiary primary
amines.
been realised, but the triflamide or benzamide groups that are
required suffer from harsh deprotection protocols. Notably, a
recent study from Rovis, Schoenebeck and co-workers showed
that in situ N-protection of aliphatic primary amines with CO2
enables a catalytic α-C–H alkylation process, leading to γ-lactam
products (Figure 1A).[10]
Introduction
Aliphatic amines and their simple derivatives are pervasive in
bioactive molecules, and their centrality in medicinal chemistry is
evidenced by their occurrence in over 40% of drug candidates.[1]
Saturated azacyclic motifs such as piperidines and pyrrolidines[2]
– as well as more conformationally-constrained analogues such
as azaspirocycles[3] – are now a mainstay in drug discovery
programmes, where their high fraction of saturated carbon (Fsp3)
can markedly reduce compound attrition rates. Unsurprisingly, the
growing demand for functionalised aliphatic amines and saturated
azacycles in drug design has continued to spur the development
of practical, catalytic methods for their synthesis.[4] The alkylation
of α-C–H bonds in aliphatic amines provides a powerful
alternative to established C–N bond-forming strategies,[5] but
novel methods for the synthesis of α-tertiary amines via C–H
functionalisation are still urgently needed.[1] Given that primary
alkyl amines offer the greatest potential for diversification, and are
prevalent in pharmaceutical compound libraries (e.g., >2,700 non-
benzylic primary amines in GSK’s internal chemical inventory),
methods for the α-C–H alkylation of this particular amine class
Figure 1. [A] Prior art for catalytic α-C–H alkylation of primary amines using in
situ N-protection; [B] This work. EWG = electron-withdrawing group.
The lack of a practical and scalable catalytic entry to α-tertiary
primary amines by C–H functionalisation was recently stressed as
a key unsolved problem for synthetic chemistry.[1a,7] To address
this challenge, our lab has initiated a research programme on the
use of unprotected aliphatic primary amines as formal
C-nucleophiles in catalytic C–C bond-formation, seeking to avoid
N-protection strategies altogether. With carbon electrophiles as
reactants, a critical issue is to outcompete the innate background
reactivity of the free amines, leading to N-alkylation, and to steer
the reactions towards an unconventional (‘umpolung’)
C-alkylation. In this work, we report a practical and scalable
solution to this problem, based on photoredox catalysis,[11] for the
catalytic generation of unprotected α-amino radicals[12] 2 from
primary amines 1, and their interception with electrophilic Michael
[a]
[b]
A. S. H. Ryder
Centre for Sustainable Chemical Technologies, 1 South, University
of Bath, Claverton Down, Bath, BA2 7AY (UK)
Dr W. B. Cunningham, G. Ballantyne, T. Mules, A. G. Kinsella, J.
Turner-Dore, Dr A. J. Cresswell, Dr M. N. Grayson
Department of Chemistry, 1 South, University of Bath, Claverton
Down, Bath, BA2 7AY (UK)
a.j.cresswell@bath.ac.uk
[c]
Dr C. M. Alder, L. J. Edwards, Dr B. McKay
Medicines Design, GSK Medicines Research Centre, Gunnels
Wood Rd, Stevenage, SG1 2NY (UK)
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.202005294
Angewandte Chemie International Edition
RESEARCH ARTICLE
acceptors 3 to give α-tertiary amines 4 (Figure 1B). We also
demonstrate that these products can be readily elaborated – in a
telescoped process
– to N-functionalised α-tertiary amine
derivatives[13] or pharmacologically-valuable γ-lactams.[3]
Yield[a]
85%
Results and Discussion
Entry Deviation from standard conditions
1
none
We began our investigations by using cyclohexylamine 5
(Ep/2 = +1.53 V vs SCE, in MeCN) and butyl acrylate 6 as model
substrates (Figure 2A). By irradiating 5 and 6 in MeCN with 34 W
Kessil blue LEDs, in the presence of various photoredox catalysts
(PCs) and hydrogen atom transfer (HAT) catalysts (Figure 2B-
C),[14] we found that α-C–H alkylation could be cleanly effected in
85% NMR yield using 4CzIPN[15] as the photocatalyst (PC) and
2
[Ir(ppy)2(dtbbpy)]PF6 as PC
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 as PC 83%[b]
79%
3
4
10 as HAT catalyst
70%
42%[b]
5
11 as HAT catalyst
6
12 or 13 as HAT catalyst
DMF as solvent (0.075 M)
EtOAc as solvent (0.075 M)
concentration of 0.2 M in MeCN
concentration of 0.4 M in MeCN
no 4CzIPN or no Bu4NN3 or no light 0%[b]
no drying or degassing of MeCN
24%[b]
<1%
7
46%
–
tetrabutylammonium azide (Bu4N+N3 ) as the HAT catalyst (Ep/2 of
8
74%
–
N3 = +0.87 V vs SCE in MeCN[16]). Surprisingly, azide ion
11[10]
(42%)
and
9
84%[b,c]
44%[b,d]
outperformed
both
quinuclidine
10
11
12
tri(isopropyl)silanethiolate 10 (70%), despite the well-established
pedigree of these species as HAT catalysts. Control experiments
verified that 4CzIPN, visible light, and azide catalyst are all
necessary components for reactivity. To determine the optimal
wavelength of light to use in the reaction, we tested a series of
pseudo-monochromatic LED light sources (405–475 nm), and
used flow NMR spectroscopy[17] to monitor the reaction (Figure
2D). A 425 nm light source proved to be optimal, consistent with
the absorption maximum of 4CzIPN at λmax = 435 nm. These NMR
experiments also revealed that lactamisation proceeds to a
negligible extent under the reaction conditions (at 25 °C), such
that α-tertiary amines are the primary products.
With optimised conditions in hand, we next investigated the
scope of the reaction with respect to the amine partner 1 (Figure
3A). Methyl acrylate 14 [or in some cases 2-methoxyethyl acrylate
15[18]] was used as the alkylating agent, and a 1:1 stoichiometry
of amine:acrylate was employed in all cases (except 1f and 1p).
As the initially-formed γ-amino esters 16 are prone to
lactamisation on heating, we chose to purposefully convert them
to their γ-lactams 17 in a subsequent lactamisation step, though
other manipulations of the amino group are possible (Figure 4A).
Under these generalised conditions, an array of primary amines 1
were assessed, providing C–H alkylated products 17 in yields
ranging from 32–84%. Cyclic primary amines with 5–7-membered
ring sizes delivered the corresponding azaspirocycles (17a–c) in
60–68% yield. Unsurprisingly, cyclobutyl amine 1d proved more
challenging – a consequence of the stronger α-C–H bond (see
Supporting Information) – although the alkylated product 17d
could still be isolated in 49% yield. A range of acyclic amines
(17e–j) were also surveyed, and we found that tertiary (1f,g) or
quaternary carbons (1h) β- to the amino group are tolerated. For
Figure 2. [A] Reaction optimisation. [a] Measured by GC (gas chromatography)
against dodecane as an internal standard; note that lactamisation occurs under
the analysis conditions. [b] Measured by 1H NMR against mesitylene as an
internal standard. [c] <1% of the aza-Michael adduct was formed. [d] 4% of the
aza-Michael adduct was formed. [B] Selected photocatalysts. [C] HAT
catalysts. [D] Concentration-time plots, at different irradiation wavelengths, for
formation of the α-tertiary amine product 8 (using methyl acrylate).
of benzylic hydrogens elsewhere in the molecule poses no issue,
as evidenced by the successful α-alkylation of amine 1j.
Diastereoselective α-alkylation of norbornyl amine 1k also proved
possible, with the radical intercepting the acrylate species on the
expected exo face. We also tested functionalised amines
containing acetal (1l,m), hydroxyl (1n,v), ether (1o,p,w),
carbamate (1q–s), thioether (1t), sulfone (1u), and ester moieties
(1x). In several cases, competitive HAT at other ‘hydridic’ C–H
bonds is thought to be operative, including tertiary C–H (17f–h)
and C–H bonds α- to hydroxyl (17n,v), ether (17m,o,p,w), and
carbamate moieties (17q–s). Though all of these C–H bonds are
α-monosubstituted amine 1f,
a mixture of α-mono and
α-dialkylated products was evident on using a 1:1 amine:acrylate
stoichiometry, due to overalkylation of the intermediate γ-amino
ester 16f (see Supporting Information). However, after some re-
optimisation (i.e., photocatalyst, amine equiv), α-monosubstituted
γ-lactam 17f could be isolated in 49% yield. One notable limitation
is the lack of reactivity of benzylamine 1i, which may arise from
the increased stability of the α-amino radical, rendering the
addition step to the acrylate reversible. That said, the presence
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10.1002/anie.202005294
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RESEARCH ARTICLE
Figure 3. [A] Scope for α-C–H alkylation of primary amines. [a] Used methyl acrylate 14 as the acceptor. [b] Used 2-methoxyethyl acrylate 15 as the acceptor, and
performed the lactamisation step with Et3N (4.0 equiv) in MeCN at 100 °C for 24 h. [c] ~20% unreacted amine 1d. [d] Used 2.0 equiv of amine 1f, 1.0 equiv of
acrylate 15, and Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 (1 mol%) as the photocatalyst. [e] A 59:42 ratio of 17n to unreacted amine 1n was observed. [f] 3.0 equiv of amine
1p was used (N.B. 26% yield with only 1.0 equiv of 1p, with >50% unreacted 1p). [g] ~25% unreacted amine 1s. [h] The amine hydrochloride salt was used and
Cs2CO3 (1.0 equiv) was added. [B] Transition states and experimental rate ratio for α-NH2 versus α-OH C–H abstraction by azidyl radical. [C] Scope for α-C–H
dialkylation of primary amines. [i] Used 4CzIPN (1 mol%) as the photocatalyst. [g] Used acrylate 15. Boc = tert-butoxycarbonyl; Tol = 4-tolyl. [D] Scope with respect
to the alkene acceptor.
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10.1002/anie.202005294
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RESEARCH ARTICLE
generally stronger or less ‘hydridic’ than those α- to the
unprotected amine, statistical effects (i.e., relative number of
C–H bonds) and the impact of reaction conversion on kinetic
partitioning will influence this competition. Isolation of the minor
by-products in these cases proved fruitless, but the ~3.6 ppm
region in the crude NMR spectra did evidence complex mixtures
We next sought to access the prospect of an unprecedented
α-C–H dialkylation of primary amines 1f,y–ab bearing two α-C–H
bonds, to generate α-tertiary amines 19 directly (Figure 3C). This
transformation proved more challenging – possibly due to side-
reactions (e.g., telomerisation, aza-Michael) promoted by the
higher acrylate concentration – but dialkylated γ-lactams 20 could
of minor (<5%) singlets (i.e., methyl ester-containing by-products), still be isolated in yields of 27–55%.[21] The scope of the α-C–H
supportive of acrylate addition to sites other than the amine
α-C–H bond. To further our understanding, we attempted to
quantify the relative ease of α-C–H abstraction by azidyl radical
monoalkylation process with respect to the alkene acceptor (21)
was also evaluated (Figure 3D). Acrylates 21a–e bearing α- or
β-substituents, including methyl, phenyl, and -N(Boc)2 were all
tolerated, as was an unsaturated γ-lactone acceptor (giving 23f).
The use of tert-butyl acrylate (21g) led to a γ-amino ester product
(22g) that proved substantially more resistant to lactamisation.
Preliminary examination of non-acrylate partners was also carried
out, with vinyl pyridines 21h,i successfully delivering α-alkylated
products. No reactivity was observed with unactivated alkenes
(i.e., 1-hexene) as the acceptor.
To validate the fact that our chemistry is useful for the rapid
and modular assembly of α-tertiary amine derivatives, we next
effected a series of N-functionalisations of the γ-amino ester
products, in lieu of lactamisation (Figure 4A). In order to reduce
reaction times and facilitate scale-up, we conducted the reactions
in continuous flow,[22] using a Vapourtec UV-150 reactor equipped
with a 54 W output 420 nm LED lamp. With cyclohexylamine 5 as
a representative amine, this led to a straightforward preparation
of a series of α-tertiary amine derivatives 24a–f. To assess the
scalability of our α-C–H alkylation process, we ran the reaction of
cyclohexylamine 5 with methyl acrylate 14 on a decagram-scale
•
(N3 ) from primary amines versus alcohols, as a representative
example. DFT calculations using the M06-2X functional indicate
that the barrier to HAT is approximately doubled from
cyclohexylamine 5 to cyclohexanol 18, and an intermolecular
competition experiment between 5 and 18 gave a relative rate
ratio of >20:1 (Figure 3B). In
a standalone experiment,
cyclohexanol 18 itself was α-C–H alkylated in only 12% yield
under our conditions, with the remaining mass balance being
mainly unreacted 18 (see Supporting Information). Despite this
low reactivity of alcohols, we observed incomplete conversion in
the case of 4-hydroxycyclohexylamine 1n (i.e., 59:42 ratio of 17n
to unreacted 1n), which may be due to intramolecular hydrogen-
bonding[19] in the syn-diastereomer, raising the barrier to HAT. In
some other cases, such as the 4-membered ring substrates
1d,p,s (bearing α-C–H bonds strengthened by ring strain),
incomplete conversion of the amine was also primarily
responsible for the lower (<50%) isolated yields, as opposed to
extensive by-product formation. Finally, a robustness screen[20]
with 15 different functional group additives was performed,
including ketones, alkynes, bromoarenes, nitriles, amides,
benzofurans, imidazoles, and pyridines (see Supporting
Information), though it should be qualified that these results are
only strictly diagnostic of intermolecular competitions.
in continuous flow, using
a
prototype of the recently
commercialised Uniqsis PhotoSyn reactor (Figure 4B). Although
the centre wavelength of 455 nm was sub-optimal for our
purposes, a space-time yield (STY) of 0.74 mol L–1 h–1 for γ-amino
ester 8 still proved possible, and we were able to isolate 10.1 g of
Figure 4. [A] Continuous flow synthesis of α-tertiary primary amine derivatives 24. Yields reported for products 24 are w.r.t. the γ-amino ester 8/22g. Fmoc,
fluorenylmethoxycarbonyl. [B] Decagram-scale reaction in continuous flow.
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10.1002/anie.202005294
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RESEARCH ARTICLE
product 17b from a single 5.3 h run, post-lactamisation. Notably,
followed by a short radical chain, where quantum yields can be
<1.0.
this chemistry provides
a scalable access to spirocyclic
pyrrolidine building blocks for drug discovery that outcompetes
the current most practical synthetic routes for process-scale work
(5–7 steps).[3a]
Conclusion
Our proposed catalytic cycle for the α-C–H alkylation process
–
is outlined in Figure 5A. Initial oxidation of azide ion (Ep/2 of N3
=
In summary, we have developed the first visible-light
photocatalysed α-C–H alkylation of primary aliphatic amines with
electrophilic alkenes that does not rely on in situ masking of the
amino group’s intrinsic reactivity. Our dual catalytic approach,
which uses azide ion as a HAT catalyst, is amenable to the
decagram-scale preparation of hitherto difficult-to-access
α-tertiary amines and aza(spiro)cyclic building blocks.[3a] We
anticipate that this technology will open up new retrosynthetic
strategies for the disconnection of substituted amine derivatives
in organic synthesis, and find immediate application in
conventional and fragment-based lead identification programmes.
+0.87 V vs SCE, in MeCN) by the photoexcited 4CzIPN [E
½
•
(PC*/PC•–) = +1.35 V vs SCE] generates the azidyl radical, N3
–
a potent oxidant that is capable of hydrogen atom abstraction
even from unactivated alkanes.[23] This reductive quenching step
is supported by cyclic voltammetry and Stern-Volmer
luminescence
quenching
experiments
(Figure
5B).[24]
Subsequent HAT from the relatively weak α-C–H bond of the
primary amine (BDE = 89–91 ± 2 kcal mol–1)[25,26] is thought to
occur selectively, possibly augmented by a polarity-matching
effect between the electrophilic N3• radical and the ‘hydridic’ C–H
bond.[4d] The resultant α-amino radical 25 can undergo a rapid and
polarity-matched addition to the acrylate acceptor to give an
α-carboxy stabilised radical 26 [E ~ −0.63 V vs SCE[27]].
½
Acknowledgements
Reduction of this radical to the corresponding enolate 27 (pKaH
~24 in H2O) by the [4CzIPN]•– radical anion (E = –1.21 V vs SCE,
½
This work was supported by the Engineering and Physical
Sciences Research Council EP/L016354/1. A.J.C. thanks the
Royal Society for a University Research Fellowship (UF150533)
and a PhD studentship (G.B.), the University of Bath for generous
financial support and a PhD studentship (A.G.K.), the Centre for
Sustainable Chemical Technologies (CSCT) for an EPSRC CDT
PhD studentship (A.S.H.R.), the EPSRC and AstraZeneca for an
iCASE PhD studentship (T.M.), and the Dial-a-Molecule network
for proof-of-concept funding. We thank Dr Catherine Lyall for
assistance with flow NMR, Dr Adam Noble for assistance with
quantum yield measurements, and Dr Josh Tibbetts for assisting
with experiments. We also thank Duncan Guthrie at Vapourtec for
the loan of a high-powered LED lamp unit, and Mark Ladlow from
Uniqsis Ltd for the loan of a PhotoSyn reactor.
in MeCN) is presumably followed by proton transfer from HN3
(pKa = 4.72 in H2O) to give the γ-amino ester product and
regenerate the azide ion. Alternatively, a chain process involving
Keywords: Amines • Photocatalysis • C-H activation • Radicals •
Spiro compounds
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10.1002/anie.202005294
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
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Catalytic strategies for the α-C–H functionalisation of primary amines are a major challenge in organic synthesis. We report a
photocatalytic protocol for the α-C–H alkylation of unprotected primary amines that is amenable to the direct synthesis of α-tertiary
primary amines. This process is readily scalable in continuous flow to provide access to decagram quantities of valuable γ-lactams and
azaspirocycles, for application in drug discovery.
Institute and/or researcher Twitter usernames: @UniofBath, @UniofBathSci, @BathChem, @csctbath
This article is protected by copyright. All rights reserved.