Direct and efficient N-heterocyclic carbene-catalyzed hydroxymethylation of aldehydes

Article abstract of DOI:10.1039/c0cc02416c

The N-heterocyclic carbene-catalyzed coupling of several aldehydes with paraformaldehyde is reported, directly providing the corresponding valuable hydroxymethyl ketones. Results of first mechanistic experiments for this remarkably selective transformation are also provided.

Full text of DOI:10.1039/c0cc02416c

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Direct and efficient N-heterocyclic carbene-catalyzed hydroxymethylation
of aldehydeswz
Nadine Kuhl and Frank Glorius*
Received 7th July 2010, Accepted 13th September 2010
DOI: 10.1039/c0cc02416c
The N-heterocyclic carbene-catalyzed coupling of several
aldehydes with paraformaldehyde is reported, directly providing
the corresponding valuable hydroxymethyl ketones. Results of
first mechanistic experiments for this remarkably selective
transformation are also provided.
Table 1 Initial optimization study for the hydroxymethylation of
benzaldehydea
The hydroxymethyl ketone moiety is an important motif
of synthetic precursors and biologically active compounds.1
Consequently, many methods for its preparation have
been reported. However, most of these methods are rather
simple hydrolyses2 or oxidations3 and do not form any new
C–C bonds.
Entry
NHCꢀHX
Base
Solvent
Yielda (%)
1b
1
2
3
4
5
6
6
6
6
6
6
6
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
N(iPr)2Et
DBU
THF
THF
THF
THF
THF
THF
THF
THF
0
0
9
2b
3b
4b
15
26
66
53
74
53
66
68
57
5b
6b
An attractive alternative strategy is based on the
N-heterocyclic carbene (NHC)4 catalyzed umpolung of aldehydes
by the formation of the Breslow-intermediate and the addition
of this nucleophilic species to electrophiles as found in the
well-known Benzoin condensation5,6 and related reactions.5,7,8
In these transformations, many selectivity issues arise and the
recent interest into and progress in the field of NHCs has
allowed the development of new, efficient and highly selective
processes. In this respect, the NHC-catalyzed addition of
aldehydes to formaldehyde seems to be straightforward and
an efficient route for the formation of hydroxymethyl ketones.
Thus, it comes as a surprise that this strategy has only rarely
been applied.9,10 In these remarkable pioneering reports by
Inoue et al.9 using an NHC-organocatalyst and Demir et al.10a
7c
8c
9c
THF
10c
11c
12c
N(iPr)2Et
N(iPr)2Et
N(iPr)2Et
tAmylOH
DMF
Toluene
a
Yield determined by 1H NMR (mesitylene as internal standard).
b
c
2 eq. (CH2O)n, CPhCHO = 0.5 mol Lꢁ1
.
1 eq. (CH2O)n, CPhCHO
=
0.5 mol Lꢁ1
.
and Muller et al.10b employing an enzyme as the catalyst, the
¨
validity of this approach was impressively shown. However, all
of these reports have significant drawbacks, including low
isolated yields (ranging from 6–17% for the work of
Inoue et al.9) or high dilution (o0.02 M10a), a large
excess of formaldehyde (e.g. 32 eq.10a) or long reaction time
(e.g. 4 days10a).
choice of NHC has been crucial,5 we started off by screening
different classes of NHC-organocatalysts (entries 1–6).
Whereas imidazolylidenes and benzimidazolylidenes failed
completely (entries 1 and 2), thiazolylidenes derived from 3
and 49 resulted in the formation of small amounts of product
(entries 3 and 4). This could be somewhat improved by the use
of the thiazolylidene derived from 5, commonly applied in
NHC-organocatalysis5 (entry 5). Interestingly, however, the
major improvement came with employing the NHC derived
from 6 (entry 6), which was designed by us for dual organo-/
metal-catalysis.11 Further optimization of base and solvent
proved N(iPr)2Et in THF to be the best combination (entry 8),
providing the hydroxymethylated product in 74% yield (based
An improved preparative method that builds up hydroxy-
methyl ketones from readily available aldehydes and formal-
dehyde, increasing the complexity of the carbon skeleton,
would be highly desirable. Herein, we report the NHC-
catalyzed direct coupling of aldehydes with formaldehyde
resulting in hydroxymethyl ketones in good isolated yields.
We commenced our investigation with the hydroxy-
methylation of benzaldehyde, employing paraformaldehyde
(Table 1) as the CH2O source. Since in many recent studies the
Organisch-Chemisches Institut der Westfalischen Wilhelms-Universitat
¨ ¨
Munster, Corrensstraße 40, 48149 Munster, Germany.
¨
¨
E-mail: glorius@uni-muenster.de; Fax: +49 251 8333202;
Tel: +49 251 8333248
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
1
on H NMR).
After additional optimization,12 we investigated the scope of
this potentially useful hydroxymethylation reaction, employing
3 eq. of paraformaldehyde (Table 2).13 Several different classes
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c0cc02416c
c
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Chem. Commun., 2011, 47, 573–575 573

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Table
investigation of substrate scope
2
Hydroxymethylation of different classes of aldehydes:
(entry 10) also represents an interesting competition experiment,
since this substrate is known to undergo an NHC-catalyzed
hydroacylation of the alkyne moiety.7d Under standard
conditions, however, only the desired hydroxymethylation
product was observed.
Moreover, the smooth hydroxymethylation of 2-furyl-
carbaldehyde and the mono-hydroxymethylation/cyclization
of benzene-1,2-dicarbaldehyde are remarkable (entries 11
and 12). The benzopyranone, formed in the latter reaction in
64% yield, is difficult to obtain with alternative methods.14
In addition, non-aromatic aldehydes can also be hydroxy-
methylated (entries 13 and 14).
Entry Product
Yielda (%) Entry Product
Yielda (%)
77e
1
70b,c
8
9
2
3
77d
33
50
A
straightforward mechanistic scenario is shown in
Scheme 1. The sequence involves the nucleophilic attack of
the NHC onto the aldehyde group (step 1), proton transfer
giving the Breslow intermediates A or B (step 2), and finally
the addition to an electrophilic aldehyde group, followed by
proton transfer and elimination of the NHC catalyst (step 3).
Under the optimized reaction conditions and utilizing
thiazolium salt 6 as the NHC precursor, 7 and 9 are formed,
with 7 being the predominant product. In addition, small
amounts of 8 could be found, whereas 10 was not detectable
at all.15 Considering the high electrophilicity and steric
accessibility of CH2O, it is reasonable that the Breslow inter-
mediates A and B preferentially attack formaldehyde, resulting
in the observed product distribution.
74
86
10
11
4
5
6
57
60
12
64f
32
13
14
57e
29
In order to shed some light on the mechanism, the following
experiments were run. First, the reversibility of the formation
of benzoin 8 under hydroxymethylation conditions was
demonstrated by employing 8 (R = Ph) as a substrate,
resulting in the formation of 27% of the corresponding
product 7.13 Second, on the contrary, hydroxymethylation
product 7 (R = Ph) was found to be stable under reaction
conditions.13,16 Finally, a simple competition experiment was
insightful (Scheme 2). Treatment of an electron-rich and an
electron-poor benzaldehyde derivative in the same flask under
standard conditions strikingly showed the superior reactivity
of more electrophilic aldehydes, resulting in the rapid formation
of hydroxymethyl ketone 7b. 7a and dihydroxyacetone (9) are
formed at approximately the same rate but significantly slower
than 7b. This seems to indicate that the addition of the Breslow
intermediate to formaldehyde is not the rate-determining step of
this transformation. Finally, it should be noted that a low
equilibrium concentration of free CH2O might also play a role
for the observed product distribution.
7
85c
a
Isolated yield after column chromatography. Reactions were run on
b
c
a 1 mmol scale. Yield determined after 6 h. On a 10 mmol scale, a
d
similar yield of 70% was obtained. Yield determined after 20 h.
e
f
Yield determined by 1H NMR; reaction on 0.25 mmol scale. Yield
determined after 12 h.
of aldehydes proved suitable. First, the hydroxymethylation of
benzaldehyde provided 70% of the desired product, on a
1 mmol as well as on a 10 mmol scale (entry 1).y However,
generally, 1H NMR analysis of the crude reaction mixture
indicates a significantly higher yield. Some of the product
might be lost upon column chromatography. This notion was
validated by a simple control experiment: reduction of the
crude reaction product with NaBH4 resulted in the formation
of the corresponding diol product, which could be isolated
in an improved yield of 79%.13 Several para-substituted
benzaldehyde derivatives were smoothly hydroxymethylated
in good yields, with electron-poor aldehydes leading to higher
yields than electron-rich ones (entries 2–6). Although o-chloro
benzaldehyde reacts well (entry 8), ortho-substitution results in
reduced yields in some cases (entries 9 and 10). This kind of
deterioration is often observed in NHC-catalyzed umpolung
chemistry due to the increased steric shielding of the
aldehyde moiety of these substrates. Several halide-containing
hydroxymethyl ketones can readily be formed (entries 2, 3, 7
and 8), allowing further functionalization by standard cross-
coupling methodology. The use of o-propargyloxy-benzaldehyde
Scheme 1 Plausible mechanistic pathways.
c
574 Chem. Commun., 2011, 47, 573–575
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Scheme 2 Competition experiment.
In conclusion, we have developed a direct NHC-catalyzed
hydroxymethylation of aldehydes that tolerates several important
functional groups. In addition, some light is shed on the
mechanistic intricacies of this remarkably selective trans-
formation. The rather broad scope and the attractive features
of this transformation should result in ample application of
this method.
Financial support by the Deutsche Forschungsgemeinschaft
(SPP 1179) is gratefully acknowledged. The research of
F.G. was supported by the Alfried Krupp Prize for Young
University Teachers of the Alfried Krupp von Bohlen und
Halbach Foundation. We also thank Dr A. T. Biju and I. Piel
for helpful discussions.
Notes and references
y General hydroxymethylation procedure: in an oven-dried Schlenk-
flask sealed with a rubber septum, thiazolium salt 6 (37 mg, 0.1 mmol,
0.1 eq.), paraformaldehyde (90 mg, 3.0 mmol, 3.0 eq.) and the
aldehyde (1.0 mmol, 1.0 eq.) were suspended in dry THF (4 mL).
N(iPr)2Et (33 mL, 0.2 mmol, 0.2 eq.) was added and the resulting
mixture was heated to 60 1C. In the case of aliphatic aldehydes, the
aldehyde was added after stirring the other reactants for 5 min at room
temperature. After a maximum reaction time of 24 h, the solvent was
evaporated and the crude product pre-adsorbed on Celite. Flash
chromatography on silica gel afforded the pure product.
9 T. Matsumoto, M. Ohishi and S. Inoue, J. Org. Chem., 1985, 50,
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dehyde and base, showed 10 mol% of the catalyst precursor 6,
3 eq. of the paraformaldehyde and a ratio of base (N(iPr)2Et) to
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16 However, (ir)reversibility seems to depend on the electronic
nature of the R substituent: whereas 7 (R = Ph) was stable under
reaction conditions, the compound
7 substituted with an
electron-withdrawing ester group (R = 4-CO2Me–C6H4) was not
(ref. 13).
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 573–575 575