Direct NHC-catalysed redox amidation using CO2 for traceless masking of amine nucleophiles

Article abstract of DOI:10.1039/c6cc04639h

The N-heterocyclic carbene (NHC)-catalysed redox amidation reaction is poorly developed and usually requires catalytic co-additives for electron-rich amine nucleophiles. We report a masking strategy (using CO₂) that couples release of the free amine nucleophile to catalytic turnover, and in doing so, enables direct catalytic redox amidation of electron-rich amines.

Full text of DOI:10.1039/c6cc04639h

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Direct NHC-Catalysed Redox Amidation Using CO for Traceless
2
Masking of Amine Nucleophiles
Received 00th January 20xx,
Accepted 00th January 20xx
a
*a
Robert W. M. Davidson, and Matthew J. Fuchter
DOI: 10.1039/x0xx00000x
www.rsc.org/
The N-heterocyclic carbene (NHC)–catalysed redox amidation using electron-rich amines. The most plausible reason for such
reaction is poorly developed and usually requires catalytic co- issues is an inherent incompatibility between the amine
additives for electron-rich amine nucleophiles. We report a nucleophile and the aldehyde substrate, due to their
1
2,13,15
masking strategy (using CO
2
) that couples release of the free propensity for imine formation.
The effect of this side
amine nucleophile to catalytic turnover, and in doing so, enables reactivity is two-fold: 1) imines are typically inactive
direct catalytic redox amidation of electron-rich amines.
electrophiles for the NHC catalyst; 2) the water produced in
the condensation reaction can act as a competing nucleophile
The NHC-catalysed intramolecular-redox formation of acyl
azolium intermediates from α-functionalised aldehydes is a
powerful method for the catalytic formation of acylating
agents as exemplified by numerous examples in the last
1
–6
decade (Scheme 1). The use of oxygen nucleophiles together
with such acyl azoliums to give ester products, has been
2
,3,7–11
thoroughly investigated.
The corresponding amidation
reactions, directly employing amine nucleophiles, have proven
6
,12,13
to be less accessible.
There are a few prevalent
explanations for this divergent reactivity in the literature, with
some suggesting an intrinsic lack of reactivity between acyl
azolium species—the key catalytic acylating agents – with
1
4–16
amine nucleophiles.
However, there are several examples
of catalytically generated acyl azolium species acylating
electron-poor nitrogen nucleophiles (Scheme 1), including
1
2,13,15,17
2
nitrogen-containing heterocycles,
1
anilines,
and
8–21
amides and sulfonamides.
Likewise, the direct reaction of
an acyl azolium with an amine nucleophile has been shown
stoichiometrically on separate occasions by Miyashita and
Studer; both groups also observed that, whilst alcohol
nucleophiles required activation by base or raised
temperatures, amines are acylated at room temperature—
2
2,23
quantitatively in the example presented by Studer.
Therefore while acyl azoliums are clearly capable of acylating
nitrogen nucleophiles, it would seem there are significant
limitations with direct NHC-catalysed amidation substrate
scope and catalytic turnover/side-reactions; especially when
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in the redox acylation resulting in the formation of carboxylic carbamic acid anion (which is proposed to function as the
acid by-products. It is perhaps telling that Owen and initiating base), we selected triazolium cat-1 as the
2
9
coworkers reported stoichiometric acyl azolium salts to “not precatalyst, where the electron poor aromatic substituent
2
4
30–32
react with primary amines unless water is absent”. Current acidifies the C–2 proton.
approaches to overcome such issues rely on the use of co- loading gave the amide 5a as the major product (55%), with
catalytic additives and/or non-aldehyde substrates (e.g. ’- only 20% competing imine 6a formation along with an
hydroxyenones as -unsaturated aldehyde surrogates), as equivalent amount (~20%) of carboxylic acid by-product. The
well as slow addition of the amine nucleophile.
Pleasingly, cat-1 at 10 mol%
α
α
,β
7
4
,12–14,17,25,26
reaction proceeded unexpectedly rapidly, with complete
reaction in under 20 minutes - many similar reactions are
1
2,13,15,17
reported to require reaction times of several hours
.
Given the short reaction time, it was envisaged that the
catalyst loading could be decreased, particularly in order to
further reduce the concentration of free amine released into
solution at any given time, and thus further suppress imine
formation. A loading of 2 mol% pre-catalyst resulted in an
isolated yield of 70% for the desired amide product 5a
.
2
7
Scheme 2: Gravel’s NHC catalyzed redox lactamisation.
It seemed therefore that there was an opportunity to develop
a complementary, more direct approach for catalytic redox
amidation using NHCs. The NHC-catalysed rearrangement of
pyrrolidine
1 to lactam 2, depicted in Scheme 2, caught our
2
7
attention. Conceptually this reaction achieves catalytic
amidation through the separation of the amine and aldehyde
components by a chemical rather than physical means: the
amine nucleophile is released as part of the catalytic cycle and
consumed before the catalyst turns over. This coupling of
amine release to turnover likely simulates slow addition of the
amine and limits the concentration of amine that is present in
the reaction at any given time. We sought to develop a
conceptually similar approach—where amine release is
achieved by chemical means—but was not limited to the
formation of cyclic (lactam) products. Treatment of amines
Scheme 3: Initial test reaction for NHC–catalysed amidation. TCP = 2,4,6-
with CO2 reversibly produces ammonium carbamate salts trichlorophenyl
comprising an ammonium cation and a carbamate anion (e.g.
2
4a
in Scheme 3). Notably, both the ammonium cation and Following the success of using an electron-rich propylamine
8
the carbamate anion would have reduced nucleophilicity substrate, the preliminary scope of this methodology was
towards aldehydes and therefore CO2 treatment may investigated (Scheme 4). It was found that reactions with
represent a suitable masking strategy for amines in redox primary carbinylamines (i.e. H
amidation chemistry. Although relatively stable as ammonium afforded products 5a–5d in excellent yield, between 70 and
2 2
NCH R, Series 1) generally
3
3
carbamate salt pairs, protonation of the carbamate anion 84% (Scheme 5, top row). As an exception, the use of benzyl
results in decarboxylation, to return the amine. We amine resulted in the isolation of amide 5c in moderate yield
hypothesised that if this protonation event was coupled to (48%); something we attribute to increased steric bulk of this
deprotonation of the triazolium pre-catalyst (to give the free substrate (vide infra). Notably, the use of ammonium
2 4
NHC catalyst), it would be possible to ensure amine release carbamate (H NCOONH ), a commercially available bench
into the reaction mixture is limited and paired to catalytic stable solid, was also possible, giving the primary amide 5e
turnover.
product in an excellent yield (73%). To the best of our
knowledge, this is the first example of a primary amide
A test reaction was performed using the known redox generated using an NHC-catalysed redox amidation protocol.
acylation substrate
-dichlorohydrocinnamaldehyde (3) The use of more sterically hindered primary amines such as
together with n-propylammonium N-n-propylcarbamate (4a) iso-propylamine and derivatives (Series 2, Scheme 4) led to a
as masked propylamine) (Scheme 3). Since the ammonium large decrease in yield presumably for steric reasons; an
α,α
(
carbamate reagent formally comprises two equivalents of example being N-iso-propyl amide 5f (13%). The steric
amine, no further base should be required: one equivalent of sensitivity of this reaction is attributed to the reasonably bulky
the amine should be acylated, while the other acts as a base in nature of the
the reaction, giving the amine hydrochloride by-product (vide infra). Cyclic amines (c-Hex, c-Pent, c-Bu, c-Pr, Series 2)
Scheme 3). Given the likely weakly basic nature of the also showed a strong trend towards decreasing yield upon
α,α-dichlorohydrocinnamaldehyde substrate
(
2
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increasing steric bulk (% yield 5j
>
5i
>
5h
>
5g). Likewise, the use are present in much greater concentration (see ESI for more
, in an detailed discussion). Ultimately, this would result in the
of even more bulky amines (Series 3), such as t-BuNH
2
attempt to form 5k, resulted solely in imine/carboxylic acid formation of a carboxylic–carbamic mixed anhydride which
byproduct formation. If, however, the steric bulk was moved would subsequently undergo hydrolytic decomposition to give
further from the nucleophilic nitrogen atom (Series 3) the the carboxylic acid and amine.
corresponding yields dramatically increased, such as for 5m
and 5l. Secondary amines generally gave a poor yield, for A less bulky α-monochloro hydrocinnamaldehyde substrate 8
example dimethylamine 5p (10%); however again, reduction in was investigated to provide evidence that a reduction in
steric bulk dramatically improved the yield, such as for substrate bulk would give a corresponding increased tolerance
azetidine 5q (69% yield). Electron-poor amines, such as aniline to amine bulk, and therefore increased (pro)nucleophile scope.
and trifluoroethylamine, were unreactive under the developed Indeed, it was found that by reducing the steric crowding of
conditions. We believe these amines are incapable of forming the substrate, amine nucleophiles that were too hindered for
34
suitably stable ammonium carbamate adducts. We note the di-chlorinated substrate could now be acylated (Scheme
however, that as opposed to electron-rich amines, such 5). For example, while cyclohexylamine gave only trace
electron-poor amines (e.g. aniline) are suitable for direct amounts of product for dichloro substrate
3
(Scheme 4),
gave a significantly
and therefore believe our methodology is complementary to improved yield of 9b (22%). Furthermore, other bulky amines,
2
amidation using alternative NHC-catalysed methodologies, reaction with monochloro substrate
8
those already available.
such as 1-phenylethylamine were suitable nucleophiles using
substrate , giving a highly promising yield of 9a (40%), given
8
the bulky nature of this nucleophile.
Scheme 5. Examples of direct NHC-catalysed amidation using substrate 8.
Given the success of the above chemistry for intermolecular redox
amidation, and the steric limitations in substrate scope that are
caused by the use of the α,α-dichloroaldehyde susbtrate, an
alternative α-carbamate aldehyde substrate was considered (see
Scheme 6). Conceptually, such carbamate substituents could act as
the leaving group, giving rise to a less bulky acyl azolium and a
carbamate anion, which could subsequently engage in the
methodology developed above. Surprisingly, there are only a few
examples in the literature of the related carbonates being used as
3
5-38
leaving groups,
and of these, only one utilises the displaced
Scheme 4: Substrate scope for direct NHC-catalysed amidation. *Substrate
commercially available as pre-formed ammonium carbamate species (1.1 eq.
used).
38
alcohol as a nucleophile. To the best of our knowledge there are
no examples of carbamates being used as leaving groups in related
chemistry. A morpholine α-O-carbamoyl aldehyde substrate 10a
Whilst it would seem that our masking strategy allows for the was therefore synthesised (see ESI) and tested, using a range of
direct NHC-catalysed amidation using a range of amino
pro)nucleophiles, clearly steric bulk of the amine limits
productive reactivity. The main by-product observed in all
cases utilising bulky amines was the -reduced carboxylic acid
, which we attribute, not to reaction of advantageous water
triazolium precatalysts, sub-stoichiometric bases and solvents (see
ESI for details). Pleasingly, a preliminary isolated yield of 57% was
obtained for the amidation product 12a (Scheme 6). This result
clearly shows that it is possible to mediate direct redox amidation
through coupling of amine release to cleavage of an α-leaving
group. Through masking of the amine nucleophile as a synthetically
accessible carbamate with a concomitant reduction of steric bulk at
(
α
7
with the acyl azolium, but instead from hindered amine
nucleophiles being outcompeted by the carbamate anions that
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the acyl azolium, secondary amines become viable nucleophiles
5
6
7
J. Mahatthananchai and J. W. Bode, Acc. Chem. Res., 2014,
, 696–707.
H. U. Vora, P. Wheeler and T. Rovis, Adv. Synth. Catal., 2012,
54, 1617–1639.
S. S. Sohn and J. W. Bode, Angew. Chem. Int. Ed. Engl., 2006,
, 6021–6024.
S. S. Sohn and J. W. Bode, Org. Lett., 2005,
J. Douglas, G. Churchill and A. Smith, Synthesis (Stuttg).,
012, 44, 2295–2309.
0 S. Iwahana, H. Iida and E. Yashima, Chemistry, 2011, 17
009–8013.
4
7
(57% yield of 12a vs 0% yield of 5o in Scheme 4).
3
4
5
8
9
7, 3873–3876.
2
1
1
1
1
,
8
1 N. T. Reynolds and T. Rovis, J. Am. Chem. Soc., 2005, 127
16406–16407.
,
Scheme 6: Intramolecular variant of direct redox amidation.
2 J. W. Bode and S. S. Sohn, J. Am. Chem. Soc., 2007, 129
3798–13799.
3 H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2007, 129, 13796–
3797.
,
While NHC-catalysed redox esterification has been extensively
optimised to encompass a wide substrate scope including
chiral variants, the corresponding amidation reaction is
1
1
dramatically underdeveloped. Herein we have developed an 14 M. Binanzer, S.-Y. Hsieh and J. W. Bode, J. Am. Chem. Soc.,
2
011, 133, 19698–19701.
amine masking strategy that couples release of the free amine
nucleophile to catalytic turnover, and in doing so, enables
direct catalytic redox amidation. We predict that this approach
should enable the large number of known chiral NHC
precursors to now be successfully employed in the field of
redox amidation; something that is not possible when
1
1
5 C. Gondo and J. Bode, Synlett, 2013, 24, 1205–1210.
6 P. Wheeler, H. U. Vora and T. Rovis, Chem. Sci., 2013,
4
,
1
674–1679.
7 P.-C. Chiang, Y. Kim and J. W. Bode, Chem. Commun., 2009,
1
1
4566–4568.
8 A. Chan and K. a Scheidt, Org. Lett., 2005,
7
, 905–908.
3
9
19 G.-Q. Li, Y. Li, L. Dai and S. You, Org. Lett., 2007,
521.
0 N. Duguet, C. D. Campbell, A. M. Z. Slawin and A. D. Smith,
Org. Biomol. Chem., 2008, , 1108–1113.
9
, 3519–
employing a co-catalytic additive. The success of our
methodology stems from the fact that only low
concentration of amine is present at any one time, which in
3
a
2
6
turn limits an important competing side reaction: imine 21 K. Thai, L. Wang, T. Dudding, F. Bilodeau and M. Gravel, Org.
Lett., 2010, 12, 5708–5711.
formation. Previous efforts towards NHC-catalysed redox
2
2
2 A. Miyashita, Y. Suzuki, I. Nagasaki, C. Ishiguro, K. Iwamoto
and T. Higashino, Chem. Pharm. Bull., 1997, 45, 1254–1258.
3 R. C. Samanta, S. De Sarkar, R. Fröhlich, S. Grimme and A.
amidation (usually in the presence of co-catalyts) have been
seen to employ slow or delayed addition of the amine
substrate as a physical means of limiting imine formation. Not
Studer, Chem. Sci., 2013, 4, 2177–2184.
only is our approach operationally simpler, it likely also better 24 T. C. Owen and A. Richards, J. Am. Chem. Soc., 1987, 109
,
2
520–2521.
balances amine presence in the reaction (via in situ generation
vs slow addition) to formation of the key acyl azolium catalytic
intermediate and therefore results in fast reactions. Although
clear limitations are present in our methodology, particularly
the (substrate and amine) steric sensitivity of the chemistry,
we believe this proof of concept work provides an enhanced
mechanistic understanding of direct NHC-catalysed redox
amidation chemistry that should enable further development
2
2
5 S. De Sarkar and A. Studer, Org. Lett., 2010, 12, 1992–1995.
6 B. Zhang, P. Feng, Y. Cui and N. Jiao, Chem. Commun., 2012,
48, 7280–7282.
7 K. Thai, L. Wang, T. Dudding, F. Bilodeau and M. Gravel, Org.
Lett., 2010, 12, 5708–5711.
8 D. E. Penny and T. J. Ritter, J. Chem. Soc. Faraday Trans. 1,
2
2
2
1
983, 79, 2103–2109.
9 Another electron-poor triazolium pre-catalyst, replacing the
trichlorophenyl aromatic N-substituent with a
pentafluorophenyl group was found to give approximately
equivalent reactivity in this chemistry.
0 X. Zhao, D. a DiRocco and T. Rovis, J. Am. Chem. Soc., 2011,
to
a level comparable with that observed for redox
esterification. Such efforts to expand substrate scope, based
on the mechanistic understanding gained herein are ongoing
and will be reported in due course.
3
3
3
3
1
33, 12466–12469.
1 J. Mahatthananchai and J. W. Bode, Chem. Sci., 2012,
97.
3
, 192–
1
2 R. S. Massey, C. J. Collett, A. G. Lindsay, A. D. Smith and A. C.
O. Donoghue, J. Am. Chem. Soc., 2012, 134, 20421–20432.
3 A lower pre-catalyst loading of 0.25 mol% was additionally
examined for benzylamine (to give product 5c) and was
found to give a comparable yield, suggesting that even lower
loadings should be possible in this reaction.
Acknowledgements
We would like to acknowledge Cancer Research UK for funding
(grant C21484A6944).
3
3
4 M. Aresta and E. Quaranta, Tetrahedron, 1992, 48, 1515–
1530.
5 Y.-M. Zhao, M. S. Cheung, Z. Lin and J. Sun, Angew. Chem.
Int. Ed. Engl., 2012, 51, 10359–10363.
6 X. Dong and J. Sun, Org. Lett., 2014, 16, 2450–2453.
7 X.-Y. Chen, F. Xia, J.-T. Cheng and S. Ye, Angew. Chem. Int.
Ed. Engl., 2013, 52, 10644–10647.
8 X. Dong, Y.-M. Zhao and J. Sun, Synlett, 2013, 24, 1221–1224.
9 D. M. Flanigan, F. Romanov-Michailidis, N. a. White and T.
Rovis, Chem. Rev., 2015, 115, 9307–9387.
Notes and references
1
2
K. Zeitler, Angew. Chem. Int. Ed. Engl., 2005, 44, 7506–7510.
N. T. Reynolds, J. Read de Alaniz and T. Rovis, J. Am. Chem.
Soc., 2004, 126, 9518–9519.
3
3
3
4
K. Y.-K. Chow and J. W. Bode, J. Am. Chem. Soc., 2004, 126
126–8127.
K. B. Ling and A. D. Smith, Chem. Commun., 2011, 47, 373–
75.
,
3
3
8
3
4
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