Reductions of aldehydes and ketones with a readily available N-heterocyclic carbene borane and acetic acid

Article abstract of DOI:10.3762/bjoc.9.76

Acetic acid promotes the reduction of aldehydes and ketones by the readily available N-heterocyclic carbene borane, 1,3-dimethylimidazol-2-ylidene borane. Aldehydes are reduced over 1-24 h at room temperature with 1 equiv of acetic acid and 0.5 equiv of the NHC-borane. Ketone reductions are slower but can be accelerated by using 5 equiv of acetic acid. Aldehydes can be selectively reduced in the presence of ketones. On a small scale, products are isolated by evaporation of the reaction mixture and direct chromatography.

Full text of DOI:10.3762/bjoc.9.76

Reductions of aldehydes and ketones with a readily
available N-heterocyclic carbene borane
and acetic acid
Vladimir Lamm, Xiangcheng Pan, Tsuyoshi Taniguchi*§
and Dennis P. Curran*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 675–680.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA
doi:10.3762/bjoc.9.76
15260 USA
Received: 31 January 2013
Accepted: 18 March 2013
Published: 08 April 2013
Email:
Tsuyoshi Taniguchi* - tsuyoshi@p.kanazawa-u.ac.jp;
Dennis P. Curran* - curran@pitt.edu
Associate Editor: D. Y.-K. Chen
*
Corresponding author
§
Current address: School of Pharmaceutical Sciences, Institute of
© 2013 Lamm et al; licensee Beilstein-Institut.
License and terms: see end of document.
Medical, Pharmaceutical and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
Keywords:
NHC-borane; N-heterocyclic carbene borane; reduction
Abstract
Acetic acid promotes the reduction of aldehydes and ketones by the readily available N-heterocyclic carbene borane, 1,3-
dimethylimidazol-2-ylidene borane. Aldehydes are reduced over 1–24 h at room temperature with 1 equiv of acetic acid and
0
.5 equiv of the NHC-borane. Ketone reductions are slower but can be accelerated by using 5 equiv of acetic acid. Aldehydes can
be selectively reduced in the presence of ketones. On a small scale, products are isolated by evaporation of the reaction mixture and
direct chromatography.
Introduction
Reduction of carbonyl compounds is a common, fundamental and aqueous workup are essential steps along the way to isola-
chemical transformation. Among the numerous hydride tion of the product. Although many borohydride reagents are
reagents available for such reductions, boron reductants are relatively stable solids, their contact with moisture can cause
widely used in the field of synthetic chemistry due to their decomposition with the release of hydrogen gas. Therefore,
availability and favorable reaction profiles [1-3]. For instance, appropriate precautions are required for larger scale reactions as
sodium borohydride (NaBH4) is an inexpensive salt that is one well as during transport and storage [5].
of the most popular hydride sources for the reduction of alde-
hydes and ketones [4]. Reactions with NaBH4 are usually N-Heterocyclic carbene boranes (NHC-boranes) have emerged
performed in a protic solvent such as methanol, and quenching in recent years as a useful class of synthetic reagents, which
675

Beilstein J. Org. Chem. 2013, 9, 675–680.
have interesting chemistry in their own right [6,7]. Most NHC cheap, soluble and volatile. A pilot reduction of 3-phenyl-
complexes of borane (NHC-BH3) are white solids that are con- propanal 2 (0.5 mmol), 1 (0.5 equiv), and acetic acid (1.0 equiv)
venient to handle because they are stable to air, water, strong in ethyl acetate (EtOAc) was complete in 30 min and gave
bases, and weak acids [8]. Unlike amine-boranes such as R3N- 3-phenylpropanol (3) in 86% yield after evaporation and flash
BH3 or pyridine-BH3 [9-11], carbene-boranes (NHC-BH3) do chromatography (Scheme 2). Other acids including pyridinium
not decomplex easily to release reactive borane (BH3) to solu- p-toluenesulfonate, benzohydroxamic acid, and 2,2-dimethyl-
tion under typical thermal reaction conditions. Perhaps because 1,3-dioxane-4,6-dione (Meldrum’s acid) also promoted this
of their stability, the potential use of carbene-boranes as hydride reduction, but offered no clear advantages over acetic acid. No
sources has been largely overlooked. Lindsay and McArthur reduction occurs over 24 h when 1 and 2 are stirred in EtOAc
reported that strong Lewis acids such as BF3 and Sc(OTf)3 acti- without acid under these conditions.
vate ketones towards reduction by achiral and chiral carbene
boranes [12], and we showed that some high-temperature reduc-
tions of halides were probably occurring by ionic rather than
radical pathways [13].
Recently, we discovered in collaboration with Mayr that NHC-
boranes are good hydride sources by measurement of the nucle-
ophilicity parameter, N [14]. By this measure, NHC-boranes are
Scheme 2: Pilot reduction of aldehyde 2 with 1 and acetic acid.
among the best neutral hydride donors known, more reactive
than distant relatives such as silanes, stannanes, and dihydropy-
ridines, and more reactive even than their amine-borane cousins We next conducted a series of experiments to look at the boron
[
15-19]. Despite being neutral, 1,3-dimethylimidazol-2-ylidene products of such reactions by 11B NMR spectroscopy, and these
borane (diMe-Imd-BH3, 1, see Scheme 1) has an N value (N = results are summarized in Figure 1. A control experiment
2) that is roughly comparable to the anion cyanoborohydride showed that the direct acid/base reaction of 1 with acetic acid
NaBH3CN) in DMSO. Unlike NaBH3CN, diMe-Imd-BH3 (1) (aldehyde omitted) was very slow at rt (entry 1). Evolution of
1
(
is freely soluble in many organic solvents, including most hydrogen gas was not evident (no bubbling), and boryl acetate
aprotic solvents. Unaided reductions of aldehydes and ketones 4a was present in only trace amounts (<<5%) after 24 h.
by 1 are not practical (little or no reaction occurs, depending on Evidently then, the acetic acid functions as a Brønsted acid to
the substrate). However, addition of silica gel causes reductions activate the carbonyl group towards attachment by 1. This is
to occur at ambient temperatures (Scheme 1) [20]. In a different from NaBH4, which reacts quickly with acetic acid to
preferred small-scale procedure, 0.5 mmol of an aldehyde or liberate H2 and form a modified reducing agent, NaBH(OAc)3
ketone can be reduced by 0.25 mmol of 1 and 500 mg of added [21,22].
silica gel over periods ranging from 1–24 h.
Even with heating, the direct acid/base reaction of 2 and acetic
acid was rather slow [23]. After one day (entry 2), about 18% of
2
was converted to the known boryl acetate 4a (−14 ppm) [14].
After three days (entry 3), the major component was still the
starting NHC-borane 2, but now there was 22% of 4a and 19%
of a new product that exhibited a broad doublet at −3 ppm. We
could not isolate this product by flash chromatography, but we
tentatively assign it as boryl diacetate 4b. For comparison, the
known ditriflate dipp-Imd-BH(OTf)2 resonates at −2 ppm [24].
Scheme 1: Aldehydes and ketones are reduced by 1 when silica gel is
added.
Next we reduced hydrocinnamaldehyde 2 (1 equiv) under the
Results and Discussion
standard procedure (AcOH, 1 equiv) but varying the amount of
DiMe-Imd-BH3 (1) does not react with silica gel, so it seems NHC-borane 1. Alcohol 3 is the reduction product, and the
likely that silica gel serves as a weak acid to activate carbonyl soluble boron products [25] were identified by 11B NMR spec-
groups toward reduction by 1. Based on this analysis, we troscopy of the crude product mixture. Each product spectrum
decided to replace the silica gel with weak acids in order to gave the same four resonances, but in different ratios. With
extend the practicality of reductions with NHC-boranes. We 1 equiv of 1 (entry 4), there was 55% of the starting NHC-
specifically targeted acetic acid because it is a weak acid that is borane 1, 24% boryl monoacetate 4a, 4% boryl diacetate 4b,
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Beilstein J. Org. Chem. 2013, 9, 675–680.
Figure 1: 11B NMR studies of boron products from 1 and acetic acid with and without aldehyde 2. aIn C6D6; bunreacted aldehyde remained.
and 17% of a broad resonance at about +18 ppm. This is not in 11 were also reduced to the corresponding primary alcohols 17
the region expected for an NHC-borane, but is instead where and 18 in 85% and 84% yield, respectively (entries 6 and 7).
boric acid and similar molecules resonance. Thus, it might be
B(OAc)3, but it could also be boric acid itself (the solvent was To be consistent with the prior silica gel reductions, ketones
not dried) or some intermediate product. We write this simply (Table 2) were reduced in dichloromethane, and the molar ratio
as B(OR)3. With 0.5 equiv 1 (entry 5), there was 32% of the of ketone to 1 was 1/1. Under the standard conditions for reduc-
starting 1, 39% 4a, 4% 4b and 25% B(OR)3. The final reaction tion of aldehydes (25 °C, 1 equiv acetic acid), the reaction of
with 0.33 equiv of 1 was considerably slower (entry 6). Alde- 1-(4-bromophenyl)ethanone (19) was very slow. Heating of 19
hyde 2 still remained after 6 h, and the 11B NMR spectrum (1 equiv), 1 (1 equiv) and acetic acid (1 equiv) at 40 °C for 24 h
shows 2% starting 1, 46% 4a, 14% 4b and 38% B(OR)3. These gave a moderate yield (68%) of secondary alcohol 26, but unre-
results demonstrate that the reaction is complex on the boron acted ketone remained. This problem was solved by increasing
side, with the second and third hydride transfers competing with the amount of acetic acid to 5 equiv. Now ketone 19 was
the first. This makes little difference when the alcohol is the consumed in 24 h and alcohol 26 was isolated in 93% yield
target product because all the other boron and NHC products (Table 2, entry 1). The excess of acetic acid was removed prior
are held back on the silica gel during flash chromatography.
to chromatography during evaporation, so the simple isolation
procedure was not changed. Under these conditions, ketones
To compare the acid-promoted reductions with the silica-gel- 20–25 were reduced to the corresponding secondary alcohols
promoted reactions, we tested the scope of this reaction on 27–33 in good yields (Table 2). Reductions of 4-tert-butylcy-
many of the same aldehydes and ketones (Table 1 and Table 2). clohexanone (21) and 4-phenyl-2-butanone (22) needed only
The typical procedure is convenient, and no precautions were 1 equiv of acetic acid (as with aldehydes), while the other
taken to exclude moisture or air. For aldehyde reductions substrates were reduced with 5 equiv.
(
Table 1), the reactants were mixed in EtOAc that was taken
from the bottle without drying. The standard ratio of aldehyde Reduction of 4-tert-butylcyclohexanone (21) gave the cis-
to 1 was 1:0.5, so two of the three hydride equivalents of 1 are alcohol 28 in 65% yield and the trans-alcohol in 24% yield
consumed. After completion of the reaction, the solvent was (89% combined yield). The major product results from axial
removed on a rotary evaporator, and the residue was directly attack and is seen with borohydride reagents [26,27] as well as
purified by silica gel chromatography.
with the combination of 1 and silica gel. Reaction of (E)-4-
phenylbut-3-en-2-one (23) gave the 1,2-reduction product 31
Aromatic aldehydes 5–8 gave the corresponding benzylic alco- along with a small amount of doubly reduced, saturated alcohol
hols 12–15 in yields of 79–93% (Table 1, entries 1–4). 30 (90:10). The combined yield of these inseparable products
Cinnamaldehyde underwent exclusive 1,2-reduction to give was 79%. Reductions of hindered ketones 24 and 25 were
allyl alcohol 16 in 86% (entry 5). Branched aldehydes 10 and slower even with 5 equiv of acetic acid, but gave the corres-
677

Beilstein J. Org. Chem. 2013, 9, 675–680.
Table 1: Reductions of aldehydes by diMe-Imd-BH3 (1) and acetic
Table 2: Reductions of ketones by diMe-Imd-BH3 (1) and acetic acid.a
acid.a
entry
ketone
alcohol
yield
entry
aldehyde
alcohol
yield
92%
1
93%
1
1
9
26
27
5
6
12
13
2
3
88%
2
79%
20
3
4
89%b
93%
6
2
5%b
4%b
2
8
9
7
14
21
2
4
5
88%b
8
9
15
16
2
2
3
30
31
5
6
86%
85%
79%c
(90:10)
+
30
2
6
7
83%d
97%e
1
0
1
17
18
24
32
33
7
84%b
25
1
aConditions: ketone (0.5 mmol), 1 (0.5 mmol), and AcOH (2.5 mmol) in
CH2Cl2 (2 mL) at 40 °C for 24 h; bonly 1 equiv of acetic acid was used;
cminor product 30 could not be separated; dreaction time was 48 h;
ereaction time was 72 h.
aConditions: aldehyde (0.5 mmol), 1 (0.25 mmol), and AcOH
0.5 mmol) in EtOAc (2 mL) at room temperature for 24 h; breaction
time was 1 h.
(
ponding alcohols 32 and 33 in 83% and 97% after 48–72 h. For
comparison, the yield of the reaction of 24 using silica gel was Conclusion
3% after 96 h [20]. Overall, the reductions of aldehydes and In summary, we have shown that acetic acid is a good activator
ketones with the combination of 1 and acetic acid gave compa- for the reductions of aldehydes and ketones by stable NHC-
7
rable yields to the silica procedure.
borane 1. DiMe-Imd-BH3 (1), and by implication related
carbene-boranes, are convenient reagents for small-scale reduc-
Chemoselective reductions were also readily achieved under the tions, because their ease of handling allows simple reaction and
present reaction conditions (Scheme 3). Treatment of a mixture separation procedures.
of aldehyde 6 (0.5 mmol) and ketone 19 (0.5 mmol) with 1
(
0.25 mmol) and acetic acid (1 equiv) in EtOAc exclusively The results of control experiments suggest that the acetic acid
provided the primary alcohol 13 in 95% yield, while the ketone activates the carbonyl component, not the NHC-borane. Thus,
1
9 was intact (<5% conversion to 26). The reduction of the acid does not consume a hydride equivalent of NHC-BH3,
-acetylbenzaldehyde (34) was also chemoselective and and a stoichiometric amount of H2 gas (a safety hazard on a
4
afforded only 4-acetylbenzyl alcohol (35) in 79% yield. large scale) is not produced.
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Beilstein J. Org. Chem. 2013, 9, 675–680.
(
hexane/EtOAc, 2:1) to give 1-(4-bromophenyl)ethanol (26,
9
4.2 mg, 93%) as a colorless oil.
Supporting Information
Supporting Information File 1
contains copies of the 1H NMR spectra of all the products
from Figure 1, Scheme 2 and Scheme 3, and Table 1 and
Table 2.
NMR spectra of all products.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-76-S1.pdf]
Acknowledgements
We thank the U.S. National Science Foundation for support of
this work. TT also warmly thanks Kanazawa University, the
Mochida Memorial Foundation for Medical and Pharmaceu-
tical Research, and the Yoshida Foundation for Science and
Technology for underwriting his stay at the University of Pitts-
Scheme 3: Chemoselective reductions of aldehydes with 1 and acetic
acid. aDetermined by 1H NMR spectroscopic analysis of the
crude product; bisolated yield after flash chromatography.
Further research and process-development work are needed burgh.
before one can conclude that diMe-Imd-BH3 and related
carbene boranes are generally attractive reagents on larger References
scales [5,21]. However, based on the established physical and
chemical properties of 1 and its relatives and on the conve-
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gel and acetic acid, NHC-boranes deserve serious consideration
as candidates for large-scale reductions.
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