Primary α-tertiary amine synthesis via α-C-H functionalization

Article abstract of DOI:10.1039/c8sc05164j

A quinone-mediated general synthetic platform for the construction of primary α-tertiary amines from abundant primary α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox catalysis enables reactivity with electrophiles, via a nucleophilic α-amino radical intermediate. This efficient, broadly applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the functionalization of drug molecules.

Full text of DOI:10.1039/c8sc05164j

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Primary α-Tertiary Amine Synthesis via α-C–H Functionalization
Dhananjayan Vasu,a Angel L. Fuentes de Arriba,a Jamie A. Leitch,a Antoine de Gombert,a and
Darren J. Dixon*a
Received 00th January 20xx,
Accepted 00th January 20xx
A quinone-mediated general synthetic platform for the construction of primary α-tertiary amines from abundant primary
α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive
ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and
organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox
catalysis enables reactivity with electrophiles, via a nucleophilic α-amino radical intermediate. This efficient, broadly
applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the
functionalization of drug molecules.
DOI: 10.1039/x0xx00000x
www.rsc.org/
quinone co-factors in copper amine oxidases (CuAOs). CuAOs
are a family of metalloenzymes which selectively catalyze the
Introduction
Through direct applications in the modification of biologically
relevant molecules, the construction of challenging building
blocks, and the synthesis of natural products, C(sp3)–H
functionalization has come to the forefront of modern
synthetic methodology development.1 Along these lines, the
persistent need from drug discovery programmes for
elaborate amine containing architectures has led to pioneering
developments in the C(sp3)–H functionalization of amines.2
Elegant use of transition metal catalysis, often in conjunction
with a directing group strategy, has enabled the selective β,3
γ,4 δ,5 and remote6 C(sp3)–H functionalization of amines
through bespoke and meticulously tailored catalyst and/or
reaction systems (Scheme 1A). To date, the α-functionalization
of amines has been widely achieved using primary,7,8
secondary9 and tertiary10 amines, including
a quinone-
mediated α-functionalization of pyrrolidine derivatives
developed by Qu and co-workers.9a However, despite these
advances, there still remains no general protocol to construct
primary α-tertiary amines via C-H functionalization of α-
branched amines. Accordingly, we believed that developing a
practical method to readily access these important primary α-
tertiary amine scaffolds would find widespread utility, owing
to the abundance of α-branched amines as feedstock
chemicals, building blocks for library synthesis, and branch-
point intermediates in drug discovery programmes.
Pioneering studies by Klinman and Mure,11 and Sayre,12
among others13 have elucidated the role and mechanism of
a.Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
12 Mansfield Road, Oxford, UK.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1: (A) C-H functionalization of amines. (B) Copper amine oxidase
mechanism using a quinone co-factor
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oxidation of primary amines into aldehydes (Scheme 1B, R2 = appropriate nucleophiles for efficient carbon-carbon bond
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H) using molecular oxygen through the combination of a formation, a new synthetic platform forDtOhIe: 10g.e10n3e9r/aCt8ioSCn0o51f6α4J-
quinone-based co-factor and a CuII species.14 The mechanism fully substituted primary amines could be realized. Herein we
involves the condensation of a quinone co-factor with the wish to report our findings.
primary amine substrate and a subsequent formal [1,5] H-shift
from the α-position of the amine to generate a reactive imine, Results & Discussion
which is then hydrolyzed to afford the aldehyde product.
We envisaged that the addition of a suitable quinone to an α,α-
disubstituted primary amine would afford the Schiff base
Despite elegant early work on quinone-mediated amine
oxidation by McCoy and Day,15 and Corey,16 the elucidation of
intermediate (Scheme 2A) which would undergo an in situ [1,5] H-
the mechanism of this biotransformation has paved the way
shift creating a reactive intermediary ketimine structure I. It has
for increasing applications in contemporary synthesis17 with
been widely reported previously that such imines exist in
notable contributions from Stahl,18 Kobayashi,19 and Fleury20 in
equilibrium with the corresponding hemiaminal II.17,24 Carbon-
carbon bond formation via nucleophilic addition and subsequent
oxidation of III would allow hydrolytic removal of the quinone
releasing the high value primary α-tertiary amine. From the outset
we considered it important for the procedure to have no inter-step
manipulation or solvent exchange in order to streamline this one-
amine oxidation, from Qu,9a,21 and Clift7a in amine
functionalization, and from Lumb in heterocycle synthesis.22,23
Aligned to this enzymatic process and previous synthetic
reports we hypothesized that if the reactive imine formed by
quinone oxidation (Scheme 1B, R2 ≠ H) could be intercepted by
Scheme 2: (A) Proposed reaction design using quinone mediator. (B) Optimization of allylation of α-branched primary amines
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pot platform for primary α-C-H functionalization of amines.
effective substrates for the allylation platform (18-30), with larger
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DOI: 10.1039/C8SC05164J
ring and heterocyclic systems achieving good to excellent yields,
In order to assess feasibility, a selection of substituted quinones
was studied in the allylation of α-methyl-p-methoxybenzylamine as
a model system (Scheme 2B). Toluene was identified as the
preferred reaction solvent and following condensation of the
quinone and amine, sequential addition of excess allyl Grignard
reagent was required for full conversion of ketimine, which in turn
aided product purification. A simple, oxidative hydrolytic work-up
and even challenging cyclobutane units affording α-functionalized
products (18). Pleasingly heteroaryl substituted amine (31) granted
access to the α-functionalized product effectively. It should be
noted that in this study the quinone can be isolated and reused
with no detriment to reaction efficiency.
Having established the scope with respect to the amine
using iodine and NaOH (1M)9a was sufficient to detach the component it was of interest to study the performance of diverse
hydroxyarene from the desired α-allylated 1°-amine product 1. organometallic reagents28 using 1-(4-methoxyphenyl)ethan-1-amine
Following this sequential procedure, whereas quinones A & B led to as a model α-branched amine (Scheme 3B). Initial studies using
complex product mixtures (for full optimization details see aliphatic organomagnesium reagents were disappointing (with and
supporting information), quinones C & D did indeed provide access without TMEDA additive). Despite this, a survey of organometallic
to the α-allylated product 1 in good yields over the three-stage, alternatives identified simple aliphatic organolithium reagents as
one-pot sequence. Pleasingly, the inclusion of TMEDA (1 eq) in the effective coupling partners. To this end, methyl (32), n-butyl (33), s-
nucleophilic alkylation step resulted in cleaner addition leading to a butyl (34), and t-butyl (35) alkyl groups were installed using their
significant increase in the product yield (81%).25 Quinones E & F corresponding organolithium with good to excellent efficiency. The
were found to be ineffective in this protocol due to their poor tert-butylation demonstrates that the steric profile of this
solubility in the reaction medium and a solvent change provided no methodology can easily accommodate the construction of
improvement in comparison to quinone D.
neighbouring quaternary centres. We were pleased to find that the
general protocol was effectively applied to a range of aryllithiums
with varied electronic profiles (37, 39-47).
With an efficient protocol in hand, we sought to establish the
scope with a variety of primary α-branched amine substrates.
Investigations began using the model allylation procedure described
In addition to organometallic reagents we were keen to identify
above with a wide range of α-substituted benzylamine structures other nucleophilic species that could intercept the reactive ketimine
(Scheme 3A, 1-14).26 Pleasingly, the use of the unsubstituted phenyl intermediate. Due to the synthetic versatility of nitrile substituents,
ring (2) gave excellent yields of the α-allylated amine product, and we decided to investigate their incorporation at the α position of
benzhydrylamine (3) also proceeded efficiently in the reaction. The primary α-branched amines.29 Pleasingly, we found that the use of
chemistry was tolerant of methoxy substituents in the ortho or TMSCN as a nucleophilic source of cyanide and in MeOH as solvent
meta positions (4-5). Substrates possessing alkyl (6), hydroxyl (7) in the initial ketimine forming step, led to near quantitative addition
and halogen (8-12) functionality present on the aromatic ring all to the imine (Scheme 4). Despite this, the conditions for oxidative
performed efficiently in the reaction thereby demonstrating its cleavage used previously were ineffective (see supporting
tolerance to electronic variation. Interestingly, when 2-amino-2-(4- information for details), however orthoperiodic acid (H5IO6) was
fluorophenyl)acetonitrile was employed as a substrate, it was identified as an excellent replacement. This modified protocol
observed that the allylated amine intermediate (III, with respect to allowed, after a basic work-up, the clean isolation of the α-
Scheme 2A) underwent an in situ elimination of cyanide followed by aminonitrile product in 95% yield (48). We then expanded the
a second addition of the Grignard reagent, affording diallylated scope of this methodology to electron rich (49) and electron
structure 11 after oxidation. The biologically relevant 1-indanamine deficient (50) arenes, as well as linear (51-52) and cyclic (53-56)
scaffold (relevant to compounds for early onset Parkinson’s amines with excellent yields for the one-pot multi-step process.
treatment)27 was shown to partake in this chemistry in good yield Over the course of establishing the scope, α-aminonitrile addition
(15). The transition from benzylic to aliphatic amines was achieved intermediate was isolated and characterized via single crystal X-ray
with remarkable success, with excellent yields on branched analysis (57), thus confirming our proposed reaction pathway.
aminoheptane derivatives (16-17). Cyclic systems were shown to be
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DOI: 10.1039/C8SC05164J
c
Scheme 3. Substrate scope for primary amine α-functionalization using organometallic reagents. a: 3 eq oxidant used. b: THF:PhMe (5:1) used as solvent for step (i). :
2-amino-2-(4-fluorophenyl)acetonitrile used as starting material and step (i) carried out at 80 °C. d: 10 eq coupling partner used. e: DCE used as solvent for step (i) and
f
i
j
exchanged to toluene before organolithium addition. : isolated as HCl salt. g: isolated as benzoylated product. h: 2 eq oxidant used. : pyrrolidine (1.2 eq) added. : 5
eq oxidant used.
Recently our group and others have demonstrated that intermediate, could expand the capability of the synthetic platform
photoredox catalysis can reverse the polarity of an imine moiety to (Scheme 5). Indeed, when the ketimine intermediate was treated
enable new reactivity.30 Proton coupled electron transfer (PCET) with
a
photocatalyst ([Ir(dF(CF3)ppy)2(dtbpy)]PF6, [Ir]), the
reduction of an imine can generate a nucleophilic α-amino radical commercial Hantzsch ester (HE), an electrophilic radical acceptor
which can be intercepted by electrophiles.31 We recognized that (tert-butyl 2-((phenylsulfonyl)methyl)acrylate) in DMSO and
applying this umpolung concept to the quinone-generated ketimine irradiated with blue light, we were delighted to observe α-allylated
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DOI: 10.1039/C8SC05164J
Scheme 5. Substrate scope for photocatalytic reverse polarity primary
a
amine α-functionalization. : ethyl 2-((phenylsulfonyl)methyl)acrylate used
as coupling partner.
Scheme 4. Substrate scope for primary amine α-functionalization using
Furthermore, the utility of this methodology was also highlighted
in the one-step synthesis of the anorectic drug phentermine (64),
where previous reports utilize Strecker and Henry chemistry
respectively and require multiple steps (Scheme 6C).33 A prominent
advantage of this mild protocol is the potential application to
derivatization of biologically relevant molecules for inter alia drug
discovery. To demonstrate this, we were pleased to obtain α-
allylated (65) and α-cyanated (66) derivatives of rimantadine, an α-
allylated derivative of mexiletine (67) and α-cyanated amphetamine
analogue (68) in good to excellent yields (Scheme 6D).
cyanide. a: 10 eq coupling partner used.b: oxidation (1 h).
product in moderate to good yields for the overall process despite a
challenging photocatalytic step (58-62). Interestingly, when the
ethyl ester derivative of the coupling partner was employed, an in
situ lactamization took place on addition of NaOH (63).
For the organometallic addition stage, at least four equivalents of
the organometallic reagent are required, as three equivalents are
necessarily consumed in sequestering the water (produced in the
first step) and the intermediary phenol. Despite this, addition of 6
equivalents of the organometallic was found to be optimal and
reliable throughout the scope. However, using a modified protocol
– where azeotropic removal of water after the first step was carried
out – 2.5 equivalents of the nucleophile could be employed to
achieve comparable yields to the streamlined platform (Scheme
6A).
Conclusions
In conclusion, a new synthetic platform for the ready
construction of primary α-tertiary amines from primary α-
branched amine substrates has been realized. This quinone-
mediated chemistry has enabled α-allylation, α-alkylation, α-
arylation, α-cyanation and photocatalytic reverse polarity α-
allylation reactions to be carried out creating a quaternary
center in the α-position of various amine structures. The new
protocol is broad in scope, scalable and has been applied to a
one-step synthesis of phentermine and in the functionalization
of drug molecules. This new α-functionalization platform of α-
branched primary amines should find widespread future
applications ranging from complex amine diversification to
drug molecule synthesis.
We also found that this methodology could be applied on gram-
scale, where the α-allylation of 30 mmol of 4-aminopyran using four
equivalents of allylmagnesium bromide (Scheme 6B) was
achieved.32 Pleasingly, the reaction proceeded smoothly and
afforded over 4 g of α-functionalized product 27.
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Thompson and Dr Kirsten E. Christensen (Oxford Chemical
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Crystallography Service) for X-ray mentorDinOgI:a1n0d.10h3e9l/pC.8SC05164J
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Acknowledgements
D.V. and A.L.F.A. acknowledge funding from the European
Union’s Horizon 2020 research and innovation framework
programme under the Marie Skłodowska-Curie grant
agreement No 703789 and 660125. J.A.L. thanks the
Leverhulme Trust (RPG-2017-069) for a research fellowship.
A.d.G. is supported by the EPSRC Centre for Doctoral Training
in Synthesis for Biology and Medicine, generously supported
by AstraZeneca, Diamond Light Source, Defence Science and
Technology Laboratory, Evotec, GlaxoSmithKline, Janssen,
Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. We thank
Heyao Shi for X-ray structure determination and Dr Amber L.
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