Chemoselective Alpha-Deuteration of Amides via Retro-ene Reaction

Article abstract of DOI:10.1002/chem.202004103

A synthetically convenient approach for the direct α-deuteration of amides is reported. This mechanistically unusual process relies on a retro-ene-type process, triggered by the addition of deuterated dimethyl sulfoxide to a keteniminium intermediate, generated through electrophilic amide activation. The transformation displays broad functional-group tolerance and high deuterium incorporation.

Full text of DOI:10.1002/chem.202004103

Accepted Article
Accepted Article
Title: Chemoselective Alpha-Deuteration of Amides Via Retro-ene
Reaction
Authors: Vincent Porte, Giovanni Di Mauro, Manuel Schupp, Daniel
Kaiser, and Nuno Maulide
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To be cited as: Chem. Eur. J. 10.1002/chem.202004103
Link to VoR: https://doi.org/10.1002/chem.202004103
01/2020

10.1002/chem.202004103
Chemistry - A European Journal
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Chemoselective Alpha-Deuteration of Amides Via Retro-ene
Reaction
Vincent Porte,[a] Giovanni Di Mauro‡,[a] Manuel Schupp‡,[a,b] Daniel Kaiser‡,[a] and Nuno Maulide*[a,b]
[a]
[b]
Vincent Porte, Giovanni Di Mauro, Manuel Schupp, Dr. Daniel Kaiser, and Prof. Dr. Nuno Maulide
Institute of Organic Chemistry, University of Vienna
Wꢀhringer Strasse 38, 1090 Vienna, Austria
Manuel Schupp and Prof. Dr. Nuno Maulide
CeMM – Research Center for Molecular Medicine of the Austrian Academy of Sciences
Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria
E-mail: *Correspondence: nuno.maulide@univie.ac.at (N. Maulide)
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
synthetically convenient approach for the direct
few reports of these valuable compounds as the actual targets.
The -deuteration of amides can be accomplished employing a
MeOD/MeO– system at elevated temperatures. However, this
requires several cycles to achieve high levels of labelling.[30,31] In
addition to thwarting any possibility of chemoselective labelling in
compounds carrying multiple carbonyl functionalities, any
base-sensitive functional groups, or those prone to solvolysis, can
be potentially negatively impacted (Scheme 1A). A further
straightforward approach to α-deuterated amides involves
deprotonation with sec-BuLi and subsequent quenching of the
resulting anion with D2O (Scheme 1B),[32] although the use of a
very strong base once more limits potential functional-group
tolerance. Recently, Atzrodt and Derdau described an iridium-
catalyzed deuteration of aliphatic amides using gaseous D2 that
was even applicable to small peptides (Scheme 1C).[33]
α-deuteration of amides is reported. This mechanistically unusual
process relies on a retro-ene-type process, triggered by the addition
of deuterated dimethyl sulfoxide to a keteniminium intermediate,
generated through electrophilic amide activation. The transformation
displays broad functional-group tolerance and high deuterium
incorporation.
The elucidation of reaction mechanisms has long been at the
heart of organic synthesis. In particular, isotope labelling is a
powerful tool that enables the precise monitoring of specific atoms
by using them as markers during chemical transformations.[1,2]
Moreover, understanding the fate of a drug candidate is of great
importance to drug discovery, especially when studying the
absorption, distribution, metabolism and excretion (ADME)
properties.[3] The introduction of isotopic labels is also one of the
most effective and least invasive methods for monitoring bioactive
substances.[4] While radioactive compounds containing T or 14C
are frequently used for quantification of metabolites and ADME
properties,[5,6] stable isotopes such as D, 13C, 18O or 15N can also
be used as internal standards for bioassays,[7] or for overcoming
matrix effects from sample analysis in LC/MS studies.[8] Moreover,
life sciences can exploit the deuterium kinetic isotope effect to
slow
down
cytochrome
P450
metabolism,
optimize
pharmacokinetic properties or reduce toxicity.[9–11] Expanding the
toolbox to enable cheap, regioselective and mild late-stage
deuterium incorporation is therefore highly desirable. A prime
example of such a transformation was reported by MacMillan,
who developed a photoredox-catalyzed deuteration and tritiation
of bioactive compounds using D2O or T2O,[12] while more recently
Wasa et al. reported
a frustrated Lewis pair-catalyzed
-per-deuteration of carbonyl compounds.[13] Also, late-stage
hydrogen isotope exchange, often mediated by an organometallic
complex, has been a method of choice to incorporate a
D or T.[14,15]
While other methods for the -deuteration of carbonyls are known,
many of these suffer from low selectivity, owing to the fact that
they are strongly pKa-dependent and therefore only allow for the
deuteration of aldehydes, ketones or esters, using a large excess
of D2O.[16–23] -Deuterated amides have occasionally been
prepared during the course of mechanistic studies,[24–29] with only
Scheme 1. Different approaches to incorporate a deuterium atom in the
α-position of an amide.
1
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Our group has developed research programs centered on the
chemoselective, electrophilic activation of amides,[34–37] as well as
the sigmatropic rearrangement chemistry of aryl and vinyl
sulfoxides.[38–43] During ongoing studies into the reactivity of
keteniminium ions with various classes of sulfoxides, we noticed
that the reaction with the simplest sulfoxide, DMSO (dimethyl
sulfoxide), led to recovery of seemingly unreacted starting
material. Our interest having been sparked by the unexpected
result, we performed the reaction with deuterated dimethyl
sulfoxide (DMSO-d6) and, surprisingly, we observed the -
incorporation of a deuterium atom (Scheme 1D). Eyeing the
aforementioned potential benefits of a mild and chemoselective
-deuteration, we set out to find optimal reaction conditions using
the amide 1a as a model substrate (Table 1).
assumption, when 1a was treated with isotopically labelled
DMS18O (6) after amide activation, 18O incorporation into the
product 1a-[18O] was observed (Scheme 2B). In a further
experiment, 18O-labelled amide 1c-[18O] was treated with
DMSO-d6
following
activation,
and
afforded
the
16O/D combination as the main product 2c (Scheme 2C). These
results confirm unambiguously that the carbonyl oxygen of the
deuterated products stems from DMSO, lending strong support to
our mechanistic hypothesis.
Table 1. Optimization table
Entry
Base
Pyridine
2-F-pyr
2-Cl-pyr
2-Br-pyr
2-I-pyr
2-I-pyr
2-I-pyr
2-I-pyr
D source
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
D2O[b]
Additive
Incorporation (%)[a]
/
/
/
/
/
/
/
43
40
70
72
73
55
40
89
26
90
1
2
3
4
5
6
7
8
9
AcOD
DMSO-d6
DMSO-d6
DMSO-d6
4 Å MS
4 Å MS
4 Å MS
2-I-pyr (1.1 eq)
2-I-pyr (3.3 eq)
10
[a] Reactions were performed on a 0.2 mmol scale and deuterium incorporation
was measured by 1H NMR on the crude mixture after work-up. [b] 5 eq.
Scheme 2. Mechanistic studies. [a] Percentages are relative intensities of the
[M+Na+] ion measured by HRMS.
Our investigations commenced with a broad screening of reaction
conditions (Table 1, see the SI for a complete optimization table).
The influence of a variety of different bases was evaluated
(Table 1, entries 1 to 5), with 2-iodopyridine (2-I-pyr) ultimately
proving most suited. DMSO-d6 was found to be the most effective
source of deuterium, with D2O and acetic acid-d4 (AcOD) affording
considerably lower degrees of incorporation (Table 1, entries 6
and 7). Introduction of molecular sieves (4 Å MS) led to an
increase in deuterium incorporation, while variation of the
stoichiometry of the base did not prove beneficial (Table 1, entries
8 to 10).
To further corroborate the reaction mechanism, we undertook
DFT analysis of the reaction system, which showed the proposed
pathway to be thermodynamically favorable by 51.0 kcal mol–1
(Scheme 3). Starting from 1a, the amide follows a classical amide
activation pathway[52] to yield ion pairs A (AE at 0.7 kcal mol–1 and
AZ at –1.4 kcal mol–1) after addition of dimethyl sulfoxide to the
keteniminium ion 4 (see Scheme 2A). Deuterium transfer takes
place in a concerted fashion through TSE or TSZ (8.4 and 12.0
kcal mol–1, respectively) in a retro-ene-type reaction, generating
product 2a and methylene sulfonium triflate.
Apart from the potential synthetic practicability of this method, the
mechanistic aspects are highly intriguing. Our initial hypothesis
started out with the textbook electrophilic activation of amides with
trifluoromethanesulfonic anhydride (Tf2O) in the presence of
2-halopyridines to form a keteniminium ion 4 and its stabilized
adduct 3 (Scheme 2A). In analogy to the previously described
methodologies, we then assumed that addition of DMSO-d6 to the
keteniminium intermediate 4 generates intermediate 5. At this
point, we proposed the latter to undergo a retro-ene fragmentation
to yield the deuterated product 2 through simultaneous cleavage
of the C–D and the S–O bonds.[44–50] In studies reported during
the preparation of this manuscript, Movassaghi and co-workers
proposed a similar mechanistic pathway.[51]
Scheme 3. Computed reaction profile for the amide deuteration through
retro-ene-type reaction at the PBE0/def-2SVP level including solvation factor
SMD(CH2Cl2) at 298.15 K. Free energies are reported using 1a as the reference
point.
In this mechanistic proposal, the oxygen atom is ultimately
transferred from DMSO to the amide. In support of this
2
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Having established optimized reaction conditions and with a
better understanding of the mechanistic intricacies of this
transformation, the applicability of this reaction to different amides
was explored (Scheme 4). Initial focus was placed on the
substitution patterns tolerated at the amide nitrogen with different
carbon chains. A broad range of tertiary amides derived from
dimethyl- (2b), diethyl- (2c), diallyl- (2d) and dibenzylamine (2e),
as well as pyrrolidine (2a and 2i), piperidine (2f) and azepane (2g)
were successfully deuterated. Notably, deuterated lactam 2h was
also formed in excellent yield and with a high level of deuterium
incorporation. We then turned our attention to the carbon chain
and the tolerance of reactive functional groups. We were pleased
to find that the reaction displayed good functional-group tolerance,
leaving alkyne (2j), alkene (2k), ester (2l), methyl ketone (2m),
nitrile (2n), halide (2o and 2p) and trifluoromethyl (2q) moieties
untouched. Satisfyingly, the amide obtained from the natural
product dehydrocholic acid (2r) also afforded the desired product
with high levels of deuterium incorporation and no noticeable
labelling around the ketone functionalities. In terms of limitations,
we found that amides bearing bulkier substituents on either side
of the central sp2 carbon, such as 2s and 2t, were less amenable
to this protocol.
Herein, we have presented the highly chemoselective
α-deuteration of amides via a retro-ene reaction triggered by the
addition of DMSO-d6 to activated amides. Experimental
mechanistic probing and DFT analysis shed light on this intriguing
process that is able to tolerate a broad range of functional groups
and tertiary amides. Good yields and high levels of deuterium
incorporation were obtained throughout. The possibility to perform
chemoselective bisdeuteration was established, adding to the
potential applicability of this method in the study of reaction
mechanisms and in life sciences.
Acknowledgements
This work was supported by the FWF (Project P32206) and the
European Research Council Horizon 2020 (ERC CoG 682002
VINCAT). G.D.M. is a fellow of the FWF-funded Doctoral Program
MolTag, funded by the FWF (W1232). We acknowledge strong
financial support from the Christian-Doppler Society (CDLab
EnODD) and the Center for Molecular Medicine of the Austrian
Academy of Sciences (CeMM). D.K. thanks the FWF for an Erwin-
Schrödinger Fellowship (J 4202-N28). We additionally thank the
University of Vienna for continued support of our research
programs and its mass spectrometry department for
measurements. We acknowledge C. R. Gonçalves, M. Lemmerer,
I. Klose, Dr. M. Riomet, Dr. M. Vayer and Dr. B. Maryasin for
stimulating and helpful discussions.
Keywords: amide activation • deuteration • sulfoxide isotopic
labelling • chemoselectivity
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4
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Entry for the Table of Contents
Label me softly: We have developed a facile method for the α-deuteration of amides via a retro-ene reaction. The process is triggered
by the addition of DMSO-d6 to activated amides and tolerates a broad-range of functional groups, affording products in good yields and
with high levels of deuterium incorporation throughout.
Institute and/or researcher Twitter usernames: @MaulideLab
5
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