Direct, efficient NHC-catalysed aldehyde oxidative amidation:: In situ formed benzils as unconventional acylating agents

Article abstract of DOI:10.1039/c7cc05561g

A new N-heterocyclic carbene-catalysed oxidative amidation of aldehydes has been developed which converts the aldehyde to a benzil acylating agent in situ. The process uses an air-recyclable oxidant and a nucleophilic co-catalyst and does not require the use of a large excess of either one coupling partner or catalyst.

Full text of DOI:10.1039/c7cc05561g

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Direct, efficient NHC-catalysed aldehyde oxidative
amidation: in situ formed benzils as
Cite this:DOI: 10.1039/c7cc05561g
unconventional acylating agents†
Received 18th July 2017,
Accepted 24th August 2017
Vikas Kumar and Stephen J. Connon
*
DOI: 10.1039/c7cc05561g
rsc.li/chemcomm
A new N-heterocyclic carbene-catalysed oxidative amidation of
aldehydes has been developed which converts the aldehyde to a
benzil acylating agent in situ. The process uses an air-recyclable
oxidant and a nucleophilic co-catalyst and does not require the use
of a large excess of either one coupling partner or catalyst.
The ubiquity and importance of amide bonds in natural product
and pharmaceutical chemistry is not easily understated,1 and
thus new methods for their formation involving unconventional
coupling partners are highly prized. The most common methodol-
ogy for the formation of amides involves the transformation of a
carboxylic acid into a more electrophilic derivative (or its in situ
activation using a coupling agent) followed by reaction with an
amine. A relatively underexplored approach involves the use of an
amine in conjunction with an aldehyde with concomitant oxidation
in the presence of an N-heterocyclic carbene (NHC) catalyst.2 There
are a plethora of methodologies for the analogous reaction leading
to esters, however progress towards amides has been considerably
slower.3,4
In 2007 two groups independently demonstrated the concept
of ‘internal redox’ amidation of aldehydes. Rovis and Vora
disclosed that a,a-dichloro aldehydes (inter alia) such as 1 could
be converted to a-chloro amides 2 in the presence of an amine,
a base, a triazolium ion precatalyst 3, HOAt and tert-butanol.5
Contemporaneously, Bode and John6 reported that cyclopropyl
aldehydes 4 could be transformed into amides of general type 6
with cleavage of the cyclopropyl ring balancing (from a redox
standpoint) the oxidative coupling of an aldehyde with an amine
(Fig. 1A).7,8 Studer and De Sarkar9 were the first to carry out
NHC-mediated oxidative coupling between simple aldehydes 7
Fig. 1 NHC catalysed oxidative amination of aldehydes.
and amines in the presence of a stoichiometric quinone-based triazolium ion precatalyst 10 the initially formed active ester
oxidant 8 (Fig. 1B). This process is an oxidative esterification:10 12 is subsequently reacted with an amine in one pot to give
in the presence of stoichiometric alcohol additive 9 and amides 11. Yields are high to excellent; however a substantial
excess of amine (2.5 eq.) and only amidations involving primary
amines and pyrrolidine were reported.
School of Chemistry Trinity Biomedical Sciences Institute, Trinity College Dublin
Very recently Brown et al.11 published an innovative study
152-160 Pearse Street, Dublin 2, Ireland. E-mail: connons@tcd.ie;
involving the use of anodic oxidation in flow to bring about the
Tel: +35 318961306
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc05561g synthesis of amides 11 from aldehydes – often with excellent
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yield – in the presence of stoichiometric loadings of thiazolium
ion precatalyst 13 and primary amines, while Biju et al.12 have
just reported oxidative amidations of aldehydes (in two-fold
excess) using oxidant 8 and the specialised amine 2-amino-
benzothiazole 14 (Fig. 1C). Maheswari et al. have also recently
reported aldehyde amidations with NBS (3.0 eq.) as a stoichiometric
oxidant. Amide yields were high, with obvious restrictions on
substrate scope given the reactivity of NBS.13,14
Herein we report the development of an efficient, general
oxidative amidation methodology of wide scope with respect to
the amine component (used in only slight excess) utilising a
cheap recyclable oxidant in conjunction with the cooperation
of nucleophilic and NHC-based catalysis. The mechanism is
unconventional and involves neither internal redox nor the
intermediacy of an acylazolium ion (Fig. 1D).
Scheme 2 Oxidative amidation of benzoin and benzil.
amidation (Scheme 2A), while its replacement with 2517 led to the
In 2013 we reported that benzaldehydes underwent efficient formation of amide 29 in greatly improved yield (Scheme 2B). The
oxidative esterification in the presence of a carbene catalyst in magnitude of the product yields seemed to support a hypothesis
alcoholic media using air as the terminal oxidant.15 A precis of involving efficient amidation from the benzil stage of the catalytic
the extended catalytic cycle is shown in Scheme 1A.16 The process cycle forwards, but problematic conversion of benzoin to benzil
is distinct from analogous literature processes in that the species under these conditions,18 despite the fact it occurs without
which is oxidised is neither the Breslow intermediate nor its problems in the analogous esterification chemistry (albeit in
1,2-catalyst-aldehyde adduct precursor, but aldehyde-derived alcoholic media).13,14 The inferiority of the amine nucleophile
benzoin. Addition of the carbene 21 to benzaldehyde (22) in these processes was underlined by a competition experiment
generates the Breslow intermediate 23. This reacts with 22 to in which 22 was amidated with pyrrolidine in the presence of
form benzoin (24), which, in the presence of oxygen and base stoichiometric benzyl alcohol (Scheme 2C): not only was 31 formed
oxidises to benzil (25). This electrophilic diketone is attacked by in preference to 29 – the major salt side product 32 identified in
carbene 21 to afford 26, which, in the crucial step, is attached the reactions summarised in Scheme 2A and B was completely
by the alcohol nucleophile – most likely under the influence of absent.15,19 It is noteworthy that rigorous drying of reagents/
general base catalysis – to give the sterically hindered 27, which solvents (even the air) failed to lead to suppress the formation of
collapses to form the product ester 28 and regenerates the 23. 32; indicating that it does not derive from a hydrolytic process.
When amidation in the presence of precatalyst 17 was
It is clear that in the case of the amidation reaction, sluggish
attempted under similar conditions using the more nucleophilic (relative to esterification) amide formation allows the interven-
but less acidic pyrrolidine nucleophile (2.5 eq.), yields reduced tion of an alternative, deleterious, aerobic oxidation pathway
dramatically (Scheme 1B). Therefore our study began with an which leads to the formation of 32. Focus therefore shifted to
attempt to optimise the reaction conditions. Variation of the the use of oxidant additives under an inert atmosphere
solvent, concentration, temperature, base, catalyst structure (both (Table 1). We began with the use of the quinone-like oxidant
triazolium and thiazolium salt precatalysts) and loading of the 8 at stoichiometric levels used successfully by Studer.9 Using
amine nucleophile failed to lead to significant improvements in 2.5 equivalents of pyrrolidine the amide 29 was obtained in
product yield. We therefore endeavoured to pinpoint the step(s) 43% yield (entry 1). This was higher than that in the presence of air
in the catalytic cycle which were proving problematic (Scheme 2). (Scheme 1B) but is some way short of being synthetically useful.
These experiments were instructive: use of 24 led to inefficient Azobenzene (33) had previously been shown to be a serviceable
added oxidant in an aldehyde esterification methodology,20 but
was ineffective here (entry 2) Acridine (34) and its N-methylated
analogue 35 (entries 3–4) were less efficacious oxidants than 8.
Use of the inexpensive phenazine (18) however, allowed smooth
amidation to occur in 86% yield (entry 5). While increasing the
oxidant loading proved ineffectual (entry 6), the reaction could
be carried out using just 1.2 equivalents of the amine in 83%
yield (entry 7). Importantly, we observed that on exposure to air,
the dihydrophenazine (detected by 1H NMR spectroscopy)
oxidised rapidly to 18, and we could recover the oxidant in
98% isolated yield after column chromatography. Thus while
the process is inefficient in air due to side reactions, air can be
used to recycle the oxidant – thereby lowering the cost of the
process considerably. Lowering the loading of the oxidant to
Scheme 1 NHC-Catalysed aerobic oxidative esterification and amidation. 25 mol% led to only a 5% reduction in product yield (entry 8).
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Table 1 Influence of added oxidant under an argon atmosphere
Scheme 3 Intervention of nucleophilic co-catalysis.
of active esters generated amide 29 in 91% yield. It seems likely
that the conjugate base of 48 is the active co-catalyst, as the
N-methylated analogue 49 failed to promote amidation. Of the
other similar heterocycles (50–53) evaluated, only 1,2,3-triazole
was comparable in efficacy to 48.
Attention now turned to substrate scope (Scheme 4). Under
optimised conditions a range of benzaldehydes could be amidated
with pyrrolidine (1.2 eq.) in the presence of precatalyst 17, DBU,
co-catalyst 48 and recyclable oxidant 18 to form amides 29 and
56–67 in good to excellent isolated yields. Electron rich, electron
deficient and heterocyclic variants were all compatible. The
lower (but still synthetically useful) yield of the o-substituted
product 67 supports the rationale that the mechanism involves
oxidation of the corresponding benzoin (the formation of which
is sterically sensitive24) and not the formation of an acyl azolium
ion (much less sterically sensitive18) and highlights the contribution
from the nucleophilic co-catalyst 48.
Pyrrolidine DBU loading
Entry loading (eq.) (mol%)
Oxidant loading
Oxidant (eq.)
Yielda (%)
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.5
2.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
8
1.00
1.00
1.00
1.00
1.00
1.50
1.00b
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
43
45
21
33
86
86
83
78
68
44
70
67
68
64
46
33
34
35
18
18
18
18
36
37
38
49
40
41
42
9
10
11
12
13
14
15
The scope was also broad with respect to the amine component
(Scheme 5): 22 could be efficiently amidated by 1.2 equivalents of
Determined by 1H NMR spectroscopy using styrene as an internal straight chain-, benzylic-, allylic- and propargylic primary amines
a
b
standard. Recovered in 98% yield after chromatography.
to give amides 70–73. b-Branching is also tolerated (i.e. product
74), while both functionalised and unfunctionalised secondary
amines could also be used – leading to amides 75–77. One of the
distinct advantages associated with this process is that large
Variation of the electronic characteristics (i.e. 36–40, entries
9–13) and the solubility21 (i.e. 41–42, entries 14–15) of the
excesses of either coupling partner are not required. To demon-
phenazine core failed to provide further improvements.
strate the potential utility of the methodology, we prepared the
We now attempted to influence the other (putative) challenging
MAO-inhibitor drug moclobemide (Hoffman-La Roche) from the
step in the catalytic cycle – the attack of the amine on the catalyst-
benzil adduct (i.e. 29a, Scheme 3). It had hypothesised that (vide
supra) this step was both general base catalysed and – as it forms a
product with adjacent quaternary carbon centres – exquisitely
sensitive to steric bulk in the nucleophile. We therefore sought
to establish if this step could be accelerated by nucleophilic
catalysis. Initial attempts involved the use of alcohols (known to
be good nucleophiles in this step) 43–45 incorporating a hydrogen
bond-donating unit to facilitate subsequent amidation of the ester
product by pyrrolidine to release the catalyst. Addition of these
alcohols at 20 mol% loading led to decreased product yields. The
guanidine base TBD had been shown to serve as an effective
catalyst ester amidation processes,22 but had little effect on the
NHC catalysed process either in the presence or absence of an
added alcohol nucleophile (i.e. 46ÁCF3CO2H and 47). Gratifyingly,
use of 1,2,4-triazole (48) – who Birman et al.23 had reported served
Scheme 4 Substrate scope: aldehyde component.
as an efficient catalyst (in the presence of DBU) for the amidation
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3 For reviews on NHC-catalysed oxidative transformations see: (a) C. E. I.
Knappke, A. Imami and A. Jacobi von Wangelin, ChemCatChem, 2012,
4, 937; (b) S. De Sarkar, A. Biswas, R. C. Samanta and A. Studer, Chem. –
Eur. J., 2013, 19, 4664.
4 Selected recent reviews on NHC catalysis: (a) M. H. Wang and
K. A. Scheidt, Angew. Chem., Int. Ed., 2016, 55, 14912; (b) D. M. Flanigan,
F. Romanov-Michailidis, N. A. White and T. Rovis, Chem. Rev., 2015,
115, 9307; (c) R. S. Menon, A. T. Biju and V. Nair, Chem. Soc. Rev., 2015,
44, 5040; (d) M. N. Hopkinson, C. Richter, M. Schedler and F. Glorius,
Nature, 2014, 510, 485; (e) J. Mahatthananchai and J. W. Bode, Acc. Chem.
Res., 2014, 47, 696; ( f) A. Grossmann and D. Enders, Angew. Chem., Int.
Ed., 2012, 51, 314; (g) X. Bugaut and F. Glorius, Chem. Soc. Rev., 2012,
41, 3511; (h) S. R. Yetra, A. Patra and A. T. Biju, Synthesis, 2015, 1357;
(i) H. U. Vora and T. Rovis, Aldrichimica Acta, 2011, 44, 3.
Scheme 5 Substrate scope: amine component.
5 H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2007, 129, 13796.
6 J. W. Bode and S. S. Sohn, J. Am. Chem. Soc., 2007, 129, 13798.
7 For
a modification using CO2 to supress imine formation see:
R. W. M. Davidson and M. J. Fuchter, Chem. Commun., 2016, 52, 11638.
8 For a related report involving the generation of the a-substituted
aldehyde in situ see: S. Kuwano, S. Harada, R. Oriez and K.-I. Yamada,
Chem. Commun., 2012, 48, 145.
9 S. De Sarkar and A. Studer, Org. Lett., 2010, 12, 1992.
10 (a) S. De Sarkar, S. Grimme and A. Studer, J. Am. Chem. Soc., 2010,
Scheme 6 Synthesis of moclobemide.
¨
132, 1190; (b) R. C. Samanta, S. De Sarkar, R. Frohlich, S. Grimme
and A. Studer, Chem. Sci., 2013, 4, 2177; (c) D. L. Cramer, S. Bera and
A. Studer, Chem. – Eur. J., 2016, 22, 7403.
11 R. A. Green, D. Pletcher, S. G. Leach and R. C. D. Brown, Org. Lett.,
2016, 18, 1198.
12 S. Premaletha, A. Ghosh, S. Joseph, S. R. Yetra and A. T. Biju, Chem.
Commun., 2017, 53, 1478.
13 A. Alanthadka and C. U. Maheswari, Adv. Synth. Catal., 2015, 357, 1199.
14 For related oxidative amidations involving sulfoximines using 8 as
the oxidant see: (a) S. Dong, M. Frings, H. Cheng, J. Wen, D. Zhang,
G. Raabe and C. Bolm, J. Am. Chem. Soc., 2016, 138, 2166;
(b) A. Porey, S. Santra and J. Guin, Asian J. Org. Chem., 2016, 5, 870.
15 E. G. Delany, C.-L. Fagan, S. Gundala, A. Mari, T. Broja, K. Zeitler
and S. J. Connon, Chem. Commun., 2013, 49, 6510.
16 E. G. Delany, C.-L. Fagan, S. Gundala, K. Zeitler and S. J. Connon,
Chem. Commun., 2013, 49, 6513.
17 We had previously shown that 1,2-diketones could be cleaved in the
presence of either water or alcohols under the influence of NHC
catalysis: S. Gundala, C.-L. Fagan, E. G. Delany and S. J. Connon,
Synlett, 2013, 1225.
oxidative amidation of p-chlorobenzaldehyde (78) with the
commercially available amine 79 in 92% yield (Scheme 6).
In conclusion, a new NHC-catalysed oxidative amidation of
aldehydes has been developed. The methodology is mechanistically
distinct (involving benzils as acylating agents) and unique among
such methodologies in that a large excess of neither the amine,
aldehyde nor catalyst are required. Phenazine proved superior to the
often used 8, and could be recycled and recovered efficiently after
the reaction by exposure to air. A carbene catalyst and a nucleophilic
co-catalyst operate synergistically to allow the smooth amidation of
a range of aromatic aldehydes with either primary or secondary
amines in good-excellent yields, and the utility of the technology was
demonstrated through the efficient synthesis of an anti-depression
drug. Efforts to further explore the scope and mechanism of
this reaction are underway.
18 Because 23 is formed from the amidation of 25 in equimolar amounts,
reversion of 23 to 21 and 22 ensures that 24 is also a product from the
amidation of 25. Hypothetically speaking, if 25 were amidated smoothly
it would account for 50% yield, but if the 24 formed is only amidated at
26% levels, the theoretical yield is (50 Â 1.0) + (50 Â 0.26) = 63%, a value
very close to the 66% obtained.
We are grateful to Science Foundation Ireland the Solid State
Pharmaceutical Centre (12/RC/2275) for financial support.
19 Rigorous drying of all reagents/solvents (even the air) utilised failed
to suppress the formation of 32 in amidation reactions involving
pyrrolidine, indicating that it does not derive from a hydrolytic
process. We also exposed 31 to amidation conditions: 29 does not
emanate from 31.
Conflicts of interest
There are no conflicts to declare.
20 (a) C. Noonan, L. Baragwanath and S. J. Connon, Tetrahedron Lett.,
2008, 49, 4003; (b) C. A. Rose and K. Zeitler, Org. Lett., 2010, 12,
4552.
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