Chemoselective conversion of α-unbranched aldehydes to amides, esters, and carboxylic acids by NHC-catalysis

Article abstract of DOI:10.1039/c1cc15539c

Depending on the N-heterocyclic carbene catalyst utilized, α-unbranched aldehydes selectively provided amides, esters, or carboxylic acids through oxidation by NCS. The α-unbranched aldehyde underwent these reactions chemoselectively in the presence of an aromatic or α-branched aldehyde.

Full text of DOI:10.1039/c1cc15539c

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COMMUNICATION
Chemoselective conversion of a-unbranched aldehydes to amides, esters,
and carboxylic acids by NHC-catalysisw
¨
Satoru Kuwano, Shingo Harada, Raphael Oriez and Ken-ichi Yamada*
Received 7th September 2011, Accepted 18th October 2011
DOI: 10.1039/c1cc15539c
Depending on the N-heterocyclic carbene catalyst utilized,
a-unbranched aldehydes selectively provided amides, esters, or
carboxylic acids through oxidation by NCS. The a-unbranched
aldehyde underwent these reactions chemoselectively in the
presence of an aromatic or a-branched aldehyde.
Table 1 Survey of oxidant, additive, and catalyst loadinga
Entry Oxidant/equiv.
Additive 2a/mol% Time/h 3a/%yield
N-heterocyclic carbenes (NHCs) are used as organocatalysts
for various transformations.1 NHC-catalyzed esterification and
amidation of a-oxidized aldehydes were demonstrated2 using
a,b-epoxyaldehydes,2a,f a-haloaldehydes,2b,f,g alkenal,2c,f,g and
a-acyloxyaldehydes2k as substrates. Direct conversion of alde-
hydes to esters or amides was also achieved by NHC-catalysis,3
but only aromatic and unsaturated aldehydes were suitable for
the reported direct amidation. Herein, we report a new method
for direct conversion of a-unbranched aldehydes to amides, as
well as esters and carboxylic acids, with NHC-catalysis. The first
report of an NHC-dependent selectivity switch of nucleophiles is
also described.
1b
2
3
4
5
6
7
8
(BzO)2/0.6
(BzO)2/0.6
(BzO)2/0.6
(BzO)2/1
(BzO)2/1
(BzO)2/2
NHPI
NHPI
—
NHPI
HOBt
HOBt
20
20
20
20
20
20
20
20
20
20
20
10
5
19
20
17
19
18
20
20
10
7
6
6
12.5
12.5
12.5
18
20
7
29
45
55
44
20
69
76
96
92
88
79
(3-ClC6H4CO2)2/2 HOBt
NIS/1.3
NBS/1.3
NCS/1.3
NCS/1.3
NCS/1.3
NCS/1.3
NCS/1.3
HOBt
HOBt
HOBt
HOBt
HOBt
HOBt
HOBt
9
10
11c
12c
13c
14c
2
a
The solvent was toluene in entries 1–7 and CH2Cl2 in entries 8–14.
c
Under reflux with Et3N instead of Et2NH. With 1.2 equiv. Et3N.
We unexpectedly found that diethylamide 3a was produced
in 18% yield when hydrocinnamaldehyde (1a) and triethylamine
were heated in refluxing toluene in the presence of benzoyl
peroxide (BPO), N-hydroxyphthalimide (NHPI), and chiral
NHC precursor 2a4 (Fig. 1 and Table 1, entry 1). Although
benzaldehyde failed to undergo amide formation, the reaction
proceeded even at room temperature, and produced 3a in 20%
b
yield when triethylamine was replaced with diethylamine (entry 2).
Without NHPI, the yield of 3a decreased to 7% (entry 3).
These results led us to speculate that the pathway to amide
3a was as follows (Scheme 1). First, aldehyde 1a and diethyl-
amine formed enamine, which was then oxidized by BPO to
give a-benzoyloxy aldehyde 4.5 Diethylamine may have been
produced by the reaction of triethylamine with BPO (entry 1).6
The NHC underwent addition with 4 to form Breslow inter-
mediate 5. Liberation of benzoate followed by tautomerization
gave acyltriazolium 6,2k which was then converted into activated
ester 7 by NHPI, and the diethylamine underwent acylation
to produce amide 3a. The failed reaction with non-enolizable
benzaldehyde is also explained by this enamine-pathway.
Fig. 1 NHC precursors 2a–f.
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
E-mail: yamak@pharm.kyoto-u.ac.jp; Fax: +81 75 753 4604;
Tel: +81 75 753 4573
w Electronic supplementary information (ESI) available: Experimental
details, characterization data and NMR charts of products, HPLC
traces of 3g, and results of DFT calculations. See DOI: 10.1039/
c1cc15539c
Scheme 1 Working hypothesis.
c
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Chem. Commun., 2012, 48, 145–147 145

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Based on this hypothesized pathway, the reaction condi-
tions were optimized. First, the reaction was performed with a
stoichiometric amount of BPO, and 3a was obtained in 29%
yield after 19 h (entry 4). The use of 1-hydroxybenzotriazole
(HOBt) instead of NHPI made the reaction cleaner, and gave
3a in 45% yield (entry 5). Although other NHC precursors
2b–f were tested, less satisfactory results were obtained.
Then, the reaction was performed with an increased amount
of BPO (2 equiv.), and the yield of 3a slightly improved to 55%
(entry 6). No improvement was observed when m-chlorobenzoyl
peroxide was used in place of BPO, and 3a was obtained in
44% yield (entry 7). Then, NCS was tested as the oxidant,
replacing BPOs. The reaction of 1a with NCS (1.3 equiv.) in
dichloromethane produced 3a in 76% yield (entry 10), though
NIS and NBS gave less satisfactory results (entries 8 and 9).
Finally, when the reaction was conducted with triethylamine
(1.2 equiv.) to neutralize the hydrogen chloride liberated during
the reaction, 3a was obtained in excellent yield after 6 h (entry 11).
When the reaction was quenched after 30 min, 3a was produced
in 32% yield and a-chlorohydrocinnamaldehyde was mainly
obtained in 60% yield. The chloroaldehyde and diethylamine
were then converted into 3a in 94% yield after 6 h in the presence
of 2a and triethylamine in dichloromethane at room temperature.
These results indicate that the reaction proceeds mainly through
the a-chlorination of aldehyde followed by NHC-catalyzed acyla-
tion of nucleophiles, and not through oxidation of a Breslow
intermediate. Thus, the reaction was best performed by pre-
mixing 1a and NCS in the presence of diethylamine before the
addition of 2a, triethylamine, and HOBt, and catalyst loading of
2a was reducible (2–10 mol%) with only a slight decrease in the
product yield (entries 12–14).
Scheme 2 Reaction of benzotriazolyl ester 11 with diethylamine in
the presence of water and 2c-derived NHC.
dibenzylamine gave N,N-dibenzyl amide 3d in 49% yield along
with N-benzyl amide 3e in 11% yield. The production of 3e
indicates that dibenzylamine was debenzylated by the action
of NCS. To avoid the reaction of the amine and NCS, an
a-chlorination step was performed using L-proline as a catalyst;
a solution of 2a, triethylamine, HOBt, and dibenzylamine was
added to a solution of 1a, NCS, and L-proline (5 mol%) in
dichloromethane pre-mixed for 9 h, and 3d was obtained in
71% yield (entry 4). The use of L-proline was effective for the
reactions of other amines. In the reaction of benzylamine,
however, slow addition of the amine over 3 h was important
to obtain 3e in 72% yield (entry 5), and adding the amine in one
portion decreased the yield to 39%. Formation of Weinreb
amide efficiently proceeded, and the reaction of 1a with methoxy-
amine hydrochloride salt provided 3f in 81% yield (entry 6). An
amino acid was also a good reaction partner; the reaction of 1a
and phenylalanine tert-butyl ester hydrochloride salt produced
N-acyl amino acid 3g without racemization (entry 7). The
reaction rates of the amino acid enantiomers, however, were
not significantly different, suggesting that amidation proceeded
via an achiral intermediate such as 11 as shown in Scheme 2.
Investigation for the best NHC catalyst under the condi-
tions using NCS revealed that 2a was the best among 2a–f, and
also led to an interesting NHC-dependent selectivity switching
of the nucleophilic partner. When the reaction was conducted in
the presence of triazolium 2b, instead of 2a, along with amide 3a
in 67% yield, carboxylic acid 8a was obtained in 14% yield
(Table 3, entry 2). With triazolium 2c, 8a and 3a were obtained
in similar amounts (31–38% and 23–37%, respectively) (entry 3),
while complex mixtures were produced using 2d–f. The varying
yields of 3a and 8a in the reaction with 2c indicate that the
formation of the carboxylic acid is due to a reaction of inter-
mediate 6 or 11 with exogenous water. Indeed, additional water
(2 equiv.) increased the yield of the carboxylic acid, and we
obtained 8a in 83% yield and 3a in 10% yield (entry 5). In
contrast, the reaction with NHC derived from 2a preferentially
produced amide 3a even in the presence of water (entry 4).
Other aldehydes and amines were applied to the reaction
(Table 2). Linear aliphatic aldehyde 1b was a good substrate,
and amide 3b was obtained in 91% yield (entry 2). A siloxy
group was compatible with this transformation, and the
reaction with aldehyde 1c provided 3c in 87% yield using
10 mol% 2a (entry 3), though the yield was decreased to 56%
with 5 mol% 2a. a-Branched aldehyde was not suitable; the
reaction of cyclohexanecarbaldehyde gave the corresponding
diethylamide in only 25% yield. The reaction of 1a and
Table 2 NHC-catalyzed amidation of aldehydes with aminesa
Entry
1/R1
Amineb R2, R3
Time/h
3/%yield
Table 3 NHC-dependent selectivity between formation of 3a and 8a
1c
2
1a/Ph(CH2)2
1b/Me(CH2)5
1c/TBSO(CH2)3
1a/Ph(CH2)2
1a/Ph(CH2)2
1a/Ph(CH2)2
Et, Et
Et, Et
Et, Et
Bn, Bn
H, Bn
H, OMe
12.5
12
9
20
23
23
3a/88
3b/91
3c/87
3d/71
3e/72
3f/81
3d
4
5e
6f
7f
Entry
2
Time/h
3a/%yield
8a/%yield
3g/76g
1a
2
2a
2b
2c
2a
2c
6
6
6
7
6
96
67
0
14
1a/Ph(CH2)2
19
23–37b
90
10
31–38b
a
3
Entries 1–3 were conducted without L-proline, while entries 4–7 were
b
conducted with L-proline. Used 2 equiv. in entries 1–3 and 1.5 equiv.
4c
5c
6
83
c
d
in entries 4–7. From Table 1, entry 13 for comparison. With
10 mol% 2a. BnNH2 was added over 3 h. HCl salt of R2R3NH
e
f
a
b
From Table 1, entry 11 for comparison. Range of three reactions.
In the presence of 2 equiv. H2O.
g
was added instead of free amine. Without racemization.
c
c
146 Chem. Commun., 2012, 48, 145–147
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with diethylamine and water gave amide 3h in 82% yield and
carboxylic acid 8d in 73% yield. The reaction of benzylamine
also proceeded in a chemoselective manner using proline as a
co-catalyst to give a-unbranched amide 3i in 65% yield and no
amidation of the aromatic aldehyde moiety was observed. The
reaction of diethylamine and 1e having both a-branched and
a-unbranched aldehyde moieties proceeded selectively at the
a-unbranched moiety to provide mono-amide 3j in 89% yield.
Partial isomerization (trans only to trans : cis 83 : 17) was
observed at the a-position of the branched aldehyde moiety in
the reaction of 1e, suggesting reversible enamine formation of the
a-branched aldehyde moiety. Therefore, the selectivity is likely
due to the slower chlorination of the more hindered enamine.
In summary, we developed a new one-pot transformation of
a-unbranched aldehydes to amides, esters, and carboxylic acids
with NHC-catalysis. It is advantageous that selective conversion
of a-unbranched aldehydes is possible and isolation of unstable
a-chloroaldehyde intermediates is unnecessary. The observed
NHC-dependent nucleophile-selectivity shows that chemo-
selectivity can be controlled by the selection of the NHC-catalyst.
We thank financial support by a Grant-in-Aid for Young
Scientist (B) from JSPS, Targeted Protein Research Program
from JST, and Uehara Memorial Foundation.
Scheme 3 Reaction of 1a with O-nucleophiles.
In this reaction, amides were likely formed via activated
esters 11, because acylazoliums, such as 6, react predominantly
with water and alcohols over amines,7 and indeed, the yield of
amide 3a was poor without NHPI and HOBt (Table 1, entry 3).
Recently, activation of O-nucleophiles by hydrogen bonding with
NHC was proposed to explain the O-preference of acylazoliums;3e,8
thus, a competitive reaction of water and diethylamine with
benzotriazolyl ester 11 was conducted in the presence of
20 mol% 2c (Scheme 2). Although 11 was slowly added over
6 h, no activation of water over amine was observed, and amide
3a was quantitatively produced. This result also indicates that
carboxylic acid 8a was directly produced by the reaction of
acyltriazolium 6 with water.
As expected from the pKa values (HOBt 4.6,9 water 15.7),
DFT calculations suggested higher stability of an NHC–HOBt
hydrogen-bond complex, in which the O–H bond of HOBt
was more elongated and thus activated, than an NHC–water
complex.10 The reaction of HOBt was, however, faster than
that of water with more bulky 2a-derived NHC (entry 4), and
became slower with less bulky 2c-derived NHC (entry 5). In
contrast to entry 5, using 5 mol% 2c, 3a was produced in 43%
yield with 8a in 53% yield. These results are contradictory
to the hydrogen-bond activation model, and seem to suggest that
a hydrogen bond with NHC is not an important factor of the
chemoselectivity of acylazoliums, at least in this reaction, although
acyltriazolium 6 reacts with HOBt or water, depending on the
choice of the NHC catalyst.
Notes and references
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Thus, the reaction of O-nucleophiles was best performed
with 1.1 equiv. of diethylamine in the absence of HOBt. In the
presence of 5 mol% 2c, carboxylic acid 8a was obtained in
85% yield without production of amide 3a (Scheme 3). Alcohols
such as benzyl and allyl alcohols were also good nucleophiles,
and aldehyde 1a was converted into the corresponding esters 9
and 10, respectively, in good yields.
Taking advantage of this reaction, chemoselective conversion
of dialdehydes 1d and 1e was demonstrated (Scheme 4). With 1d
having both aliphatic and aromatic formyl groups, the reaction
6 K. Gambar’jan, Zh. Obshch. Khim., 1933, 3, 222.
7 (a) T. C. Bruice and N. G. Kundu, J. Am. Chem. Soc., 1966,
88, 4098; (b) T. C. Owen and A. Richards, J. Am. Chem. Soc.,
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Bode, Angew. Chem., Int. Ed., 2011, 50, 1673.
8 M. Movassaghi and M. A. Schmidt, Org. Lett., 2005, 7, 2453.
9 I. Koppel, J. Koppel, I. Leito, V. Pihl, L. Grehn and U. Ragnarsson,
J. Chem. Res., Miniprint, 1993, 11, 3008.
10 A complex of 1,3,4-trimethyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene
with 1-hydroxy-1H-1,2,3-triazole was more stable by 8 kcal molÀ1
and elongation of its H–O bond was larger by 0.07 A than a complex
with H2O at the B3LYP/6-311+G** level of theory with counterpoise
corrections, which would be sufficient for qualitative discussion. For
the H-bond activation by NHC, see ref. 3e and 8.
Scheme 4 Chemoselective conversion of a-unbranched aldehydes to
amides and carboxylic acids.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 145–147 147