Selective reduction of carboxylic acids to aldehydes catalyzed by B(C 6F5)3

Article abstract of DOI:10.1021/ol303296a

B(C₆F₅)₃ efficiently catalyzes hydrosilylation of aliphatic and aromatic carboxylic acids to produce disilyl acetals under mild conditions. Catalyst loadings can be as low as 0.05 mol %, and bulky tertiary silanes are favored to give selectively the acetals. Acidic workup of the disilyl acetals results in the formation of aldehydes in good to excellent yields.

Full text of DOI:10.1021/ol303296a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Selective Reduction of Carboxylic Acids
to Aldehydes Catalyzed by B(C6F5)3
ꢀ
David Bezier, Sehoon Park, and Maurice Brookhart*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
mbrookhart@unc.edu
Received November 30, 2012
ABSTRACT
B(C6F5)3 efficiently catalyzes hydrosilylation of aliphatic and aromatic carboxylic acids to produce disilyl acetals under mild conditions. Catalyst
loadings can be as low as 0.05 mol %, and bulky tertiary silanes are favored to give selectively the acetals. Acidic workup of the disilyl acetals
results in the formation of aldehydes in good to excellent yields.
Aldehydes are an important class of compounds.1 Due
totheir high reactivity, they are useful intermediates for the
synthesis of a wide array of organic chemicals,2 and them-
Scheme 1. Different Reduction Methods from Carboxylic Acids
to Aldehydes
selves have numerous applications, notably in the flavor
and fragrance industry.3 There are several synthetic routes
for the synthesis of aldehydes.4 One of the potentially
most useful routes involves direct reduction of carboxylic
acids to aldehydes via hydrogenation (eq 1, Scheme 1);
however, high pressures and temperatures are required
which makes control of the chemoselectivity difficult due
to the ready reduction of aldehydes to alcohols.5 Alterna-
(1) Kohlpaintner, C.; Schulte, M.; Falbe, J.; Lappe, P.; Weber, J.
Aldehydes, Aliphatic. Ullmann’s Encyclopedia of Industrial Chemistry;
Wiley-VCH: Weinheim, 2008.
(2) Aldehyde. In Houben-Weyl: Methoden der Organischen Chemie;
Falbe, J., Ed.; Georg Thieme: Stuttgart-New York, 1983.
(3) (a) Levrand, B.; Fieber, W.; Lehn, J.-M.; Herrmann, A. Helv.
Chim. Acta 2007, 90, 2281. (b) Surburg, H.; Panten, J. Front Matter,
Common Fragrance and Flavor Materials: Preparation, Properties and
Uses, 5th completely revised and enlarged edition; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, FRG, 2006.
tively, direct transformation from carboxylic acids to
aldehydes has been accomplished by using strong reducing
agents which include lithium in methylamine,6 alane,7
thexylborane,8 i-BuMgBr in combination with a titanocene
catalyst,9 and activated amino-silanes (eq 2).10 A two-step
procedure is usually preferred, involving the transforma-
tion of carboxylic acids to more reactive acid derivatives,
followed by hydrogenation or hydride reduction reactions
(eq 3).11 Despite numerous reports of the synthesis of
aldehydes from carboxylic acids, procedures exhibit poor
chemoselectivities and functional group tolerance and
often require harsh reaction conditions and/or the use
of sensitive reagents. Hydrosilylation is an attractive
methodology for the conversion of carboxylic acids under
(4) Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 8, pp 259ꢀ305.
(5) Yokoyama, T.; Yamagata, N. Appl. Catal. A 2001, 221, 227.
(6) Bedenbaugh, A. O.; Bedenbaugh, J. H.; Bergin, W. A.; Adkins,
J. D. J. Am. Chem. Soc. 1970, 92, 5774.
(7) (a) Muraki, M.; Mukaiyama, T. Chem. Lett. 1974, 3, 1447. (b)
Hubert, T. D.; Eyman, D. P.; Wiemer, D. F. J. Org. Chem. 1984, 49,
2279. (c) Cha, J. S.; Lee, K. D.; Kwon, O. O.; Kim, J. M.; Lee, H. S. Bull.
Korean Chem. Soc. 1995, 16, 561.
(8) (a) Brown, H. C.; Heim, P.; Yoon, N. M. J. Org. Chem. 1972, 37,
2942. (b) Brown, H. C.; Cha, J. S.; Nazer, B.; Yoon, N. M. J. Am. Chem.
Soc. 1984, 106, 8001. (c) Brown, H. C.; Cha, J. S.; Yoon, N. M.; Nazer, B.
J. Org. Chem. 1987, 52, 5400. (d) Cha, J. S.; Kim, J. E.; Lee, K. W. J. Org.
Chem. 1987, 52, 5030. (e) Cha, J. S.; Kim, J. E.; Oh, S. Y. Bull. Korean
Chem. Soc. 1987, 8, 313.
(9) Sato, F.; Jinbo, T.; Sato, M. Synthesis 1981, 871.
(10) Corriu, R. J. P.; Lanneau, G. F.; Perrot, M. Tetrahedron Lett.
1987, 28, 3941.
r
10.1021/ol303296a
XXXX American Chemical Society

mild conditions to disilyl acetals which can be further
transformed to aldehydes by acid hydrolysis.
Table 1. Effect of Silanes and Catalyst Loading on the Hydro-
silylation Reaction of Hydrocinnamic Acida
Recently hydrosilylation of aliphatic and aromatic car-
boxylic acids to produce aldehydes has been independently
reported by Nagashima and Darcel. Nagashima employed
a ruthenium carbonyl cluster (1 mol %) as a catalyst
together with a specific bis-silane, 1,2-bis(dimethylsilyl)-
benzene.12 Darcel reported an iron-catalyzed hydrosilyla-
tionofcarboxylicacidsinwhich thechemoselectivity of the
product was highly dependent on the types of catalysts and
silanes used; reductions resulted in the formation of alco-
hols or aldehydes.13
Since 1990, tris(pentafluorophenyl)borane has found
many applications in catalysis,14 notably in catalytic hy-
drosilylation reactions of carbonyl-containing substrates
developed by Piers.15 This catalyst enables the reduction of
esters to aldehydes (eq 4)15b and carboxylic acids to silyl
ethers or alkanes (eq 5).16
a Hydrocinnamic acid (0.5 mmol), C6D6 (0.3 mL). b Determined by
1H NMR. c C6D6 (0.6 mL). d C6D6 (1.5 mL).
2a (94%) and alkyl silyl ether 3a as an over-reduction
product (6%) (entry 1). Decreasing the catalyst loading to
0.1 mol % enables quantitative formation of the disilyl ace-
tal without any over-reduction products in 0.5 h (entry 2).
A lower catalyst loading (0.05 mol %) requires a longer
reaction time to achieve full conversion producing the
disilyl acetal in 99% yield (entry 3).
Smaller tertiary silanes, Ph2MeSiH, Me2PhSiH, and
Me2EtSiH, lead to a mixture of 2a, 3a, and/or 4a in 1 h
(entries 4ꢀ6). Hydrosilylation with TMDS (1,1,3,3-
tetramethyldisiloxane) produces only propylbenzene 4a, in 1
h (entry 10). Secondary silanes show high reactivity in hydro-
silylation but result in the formation of over-reduction
products (entries 8, 9). Hydrosilylation using Ph3SiH as
a very bulky silane required a higher catalyst loading
(1 mol %) and longer reaction time (15 h) to produce the
disilyl acetal in an excellent yield (entry 7). Interestingly,
PMHS [poly(methylhydrosiloxane)] is less reactive relative
to TMDS, affording 2a and 3a as well as 4a (entry 11).
Knowing the optimized reaction conditions, we investi-
gated the scope of this catalysis (Table 2).
With0.1 mol % of B(C6F5)3 and Et3SiH, hydrocinnamic
acid 1a undergoes hydrosilylation quantitatively to pro-
duce the disilyl acetal in 0.5 h (entry 1). A gram-scale
hydrosilylation also gives the disilyl acetal in an excellent
yield (entry 2). Using the same conditions, phenylacetic
acid 1b and linear alkyl carboxylic acids from propionic to
decanoic acids have also been successfully transformed to
the corresponding acetals in 1ꢀ3 h (entries 3ꢀ6). With
substrates in which the carboxylic acid group bears an
isopropyl (1f) or cyclohexyl substituent (1g), increases in
catalyst loading and the reaction time are required to
obtain full conversion (1 mol %, 8ꢀ11 h, entries 7, 8).
Following our report of iridium-catalyzed reduction of
esters to aldehydes,17 we report here the selective hydro-
silylation of carboxylic acids to afford the disilyl acetals,
which can subsequently be converted to aldehydes by acid
hydrolysis. This catalysis is operative with low catalyst
loadings and relatively inexpensive silanes at 23 °C.
We examined the utility of various silanes in the hydro-
silylation of hydrocinnamic acid using B(C6F5)3 as a
catalyst (Table 1). Generally, the reaction was conducted
in C6D6 at 23 °C with 1 or 0.1 mol % of catalyst loadings
together with 2.3 equiv of the silane. Hydrocinnamic acid
undergoes rapid hydrosilylation with 1 mol % of B(C6F5)3
with Et3SiH to give both the corresponding disilyl acetal
(11) Fromacylchlorides: (a)Four, P.;Guibe, F. J. Org. Chem. 1981, 46,
4439. From esters: (b) Chandrasekhar, S.; Kumar, M. S.; Muralidhar, B.
Tetrahedron Lett. 1998, 39, 909. (c) Fujisawa, T.; Mori, T.; Tsuge, S.; Sato,
T. Tetrahedron Lett. 1983, 24, 1543. (d) Khan, R. H.; Prasada Rao, T. S. R.
J. Chem. Res., Synop. 1998, 402. From amides: (e) Kangani, C. O.; Kelley,
D. E.; Day, B. W. Tetrahedron Lett. 2006, 47, 6289. From anhydrides: (f)
Nagayama, K.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2001, 74,
1803. (g) Goossen, L. J.; Ghosh, K. Chem. Commun. 2002, 836. (h)
Goossen, L. J.; Khan, B. A.; Fett, T.; Treu, M. Adv. Synth. Catal. 2010,
352, 2166. (i) Goossen, L. J.; Khan, B. A.; Fett, T.; Treu, M. Adv. Synth.
Catal. 2010, 352, 2166.
(12) Miyamoto, K.; Motoyama, Y.; Nagashima, H. Chem. Lett.
2012, 41, 229.
(13) Misal Castro, L. C.; Li, H.; Sortais, J.-B.; Darcel, C. Chem.
Commun. 2012, 48, 10514.
(14) For reviews, see: (a) Piers, W. E.; Chivers, T. Chem. Soc. Rev.
1997, 26, 345. (b) Erker, G. Dalton Trans. 2005, 1883. (c) Stephan, D. W.;
Erker, G. Angew. Chem., Int. Ed. 2010, 49, 46. (d) Piers, W. E.; Marwitz,
A. J. V.; Mercier, L. G. Inorg. Chem. 2011, 50, 12252.
(15) (a) Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996, 118, 9440.
(b) Parks, D. J.; Blackwell, J. M.; Piers, W. E. J. Org. Chem. 2000, 65, 3090.
(16) (a) Gevorgyan, V.; Rubin, M.; Liu, J.-X.; Yamamoto, Y. J. Org.
Chem. 2001, 66, 1672. (b) Bajracharya, G. B.; Nogami, T.; Jin, T.;
Matsuda, K.; Gevorgyan, V.; Yamamoto, Y. Synthesis 2004, 2004, 308.
(c) Nimmagadda, R. D.; McRae, C. Tetrahedron Lett. 2006, 47, 3505.
(17) Cheng, C.; Brookhart, M. Angew. Chem., Int. Ed. 2012, 51, 9422.
B
Org. Lett., Vol. XX, No. XX, XXXX

the disilyl acetal products using 2 mol % of B(C6F5)3 over
3 days (entries 11ꢀ12). Furthermore, this reaction is tolerant
of CdC and CtC bonds. Oleic acid 1k, 3-hexenoic acid 1l,
and 9-undecynoic acid 1m are transformed to the desired
disilyl acetals using a low catalyst loading (0.1ꢀ0.2 mol %)
in 1.3ꢀ2 h (entries 13ꢀ15) without reduction of the olefinic
or acetylenic group. No dehalogenation occurred during
the conversion of 9-bromodecanoic acid to the disilyl
acetal (entry 16). The thiophenyl group does not hinder
hydrosilylation under normal reaction conditions (entry 17).
For all these substrates, acidic workup (1 M HCl(aq)/
THF) produced the corresponding aldehydes in good to
excellent yields (65ꢀ95%; see Table 2). However, some
olefin isomerization occurred during the hydrolysis of 1l
resulting in the formation of 83% of trans-3 and 17% of
trans-2 aldehyde. Hydrosilylation of substrates bearing
Lewis basic groups such as4-(dimethylamino)phenylacetic
acid was unsuccesful due to direct inhibition of B(C6F5)3.
Moreover, when using 3-(4-methoxyphenyl)propionic acid
1p, a mixture of three compounds was detected due to the
OꢀMe bond cleavage18 and over-reduction (Scheme 2). A
similar substrate, 3-(4-hydroxyphenyl)propionic acid, also
exhibits over-reduction.
Table 2. Selective Reduction of Aliphatic Carboxylic Acids to
Aldehydes Catalyzed by B(C6F5)3
a
Scheme 2. Reduction of 3-(4-Methoxyphenyl)propionic Acid
The reduction of aromatic carboxylic acids was also
investigated (Table 3). Beginning with the best conditions
for hydrosilylation of aliphatic carboxylic acids (Et3SiH,
0.1 mol % catalyst), benzoic acid 1q was transformed to
the disilyl acetal 2q in 60% yield with formation of 40% of
the over-reduction product 3q (entry 1). Using the bulkier
silane, Ph3SiH (2.5 equiv) in CD2Cl2,19 the disilyl acetal
was quantitatively produced in 92 or 14 h using 1 and 2 mol %
of B(C6F5)3, respectively (entries 2, 3).
Similar conditions using 2 mol % of B(C6F5)3 were
used to selectively reduce other aromatic carboxylic acids.
Reduction of p-toluic acid, 1r, containing an electron-
donating group in the para-position was fully converted
to the disilyl acetal but required a longer reaction time
(18h, entry 4). Using similar conditions, noconversion was
detected with the sterically hindered o-toluic acid, 1s;
however use of Et3SiH produced the disilyl acetal in ex-
cellent yield (entries 5, 6). In contrast to electron-donating
groups, electron-withdrawing groups in the para-position
of the phenyl ring accelerate the reaction rate (entries 7ꢀ10).
Indeed, 4-phenyl-, 1t, 4-bromo-, 1u, and 4-chloro-, 1v,
a Reaction conditions: RCO2H (0.5 mmol), silane (2.3 equiv), B-
(C6F5)3 (0.1ꢀ2 mol %), C6D6 (0.3 mL), rt. Acidic workup: 1 M HCl(aq)/
THF. b Yields of 2 determined by 1H NMR. The numbers in parentheses
are the yields of isolated 5. c RCO2H (5 mmol), C6D6 (3 mL). d Isolated as
the 2,4-dinitrophenylhydrazone adducts. e 83% of 3-trans and 17% of
2-trans hydrazones were isolated.
More sterically hindered 2-phenylpropionic acid 1h was
completely converted to the disilyl acetal 2h with 1 mol %
catalyst in 5 days (entry 9). Using Me2PhSiH as an
alternative silane for hydrosilylation of bulky substrates
permitted reduction of the catalyst loading and reaction
time (0.5 mol %, 10 h) and yet avoided any over-reduction
(entry 10). The same procedure allowed the transformation
of pivalic acid 1i and 1-adamantanecarboxylic acid 1j to
(18) Gevorgyan, V.; Liu, J.-X.; Rubin, M.; Benson, S.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 8919.
(19) CD2Cl2 was used in place of C6D6 to improve the solubility of
Ph3SiH.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Selective Reduction of Aromatic Carboxylic Acids to
Aldehydes Catalyzed by B(C6F5)3
Scheme 3. Proposed Mechanism for the Reduction of
Carboxylic Acids to Disilyl Acetals
a
After the rapid generation of the silyl ester 5 with the
release of hydrogen, the silane is activated by B(C6F5)3
through reversible coordination to the SiꢀH bond and
transfers R3Siþ to the carbonyl oxygen generating the ion
pair 6. Hydride transfer from HB(C6F5)3ꢀ to the carbonyl
carbon forms the disilyl acetal and regenerates the catalyst,
B(C6F5)3.
In summary, we have developed a selective and con-
venient one-pot procedure for the reduction of aliphatic
and aromatic carboxylic acids to aldehydes. B(C6F5)3
catalyzes the hydrosilylation of carboxylic acids to give
disilyl acetals which can be hydrolyzed in situ to generate
the corresponding aldehydes. Attractive features of this
process include use of common tertiary silanes, near-
quantitativeyields of disilylacetals with noover-reduction,
low catalyst loadings (0.05ꢀ2.0 mol %), and mild condi-
tions (23 °C).
a Reaction conditions: RCO2H (0.5 mmol), Ph3SiH (2.5 equiv),
B(C6F5)3 (2 mol %), CD2Cl2 (0.6 mL), rt. Acidic workup: CF3CO2H/
Et2O. b Yields of 2 determined by 1H NMR. The numbers in parentheses
are the yields of isolated 5. c C6D6 (0.3 mL). Acidic workup: 1 M
HCl(aq)/THF. d Yields of 5 determined by 1H NMR of the crude
mixture using EtOAc as an internal standard.
benzoic acids were selectively converted to disilyl acetals
with traces of over-reduction products detected (entries
7ꢀ9). Using 4-(trifluoromethyl)benzoic acid, 1w, as the
substrate, the reaction was complete in 6 h with a small
decrease in selectivity (6% of silyl ether product detected,
entry 10). For these aromatic substrates, acidic workup
(TFA/Et2O) furnished the corresponding aldehydes in
good yields (68ꢀ87%, Table 3). Attempts to reduce 4-ni-
trobenzoic acid were unsuccessful due to deactivation of
the catalyst after a few minutes.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the National Science Foundation as
part of the Center for Enabling New Technologies through
Catalysis (CENTC, CHE-0650456).
Supporting Information Available. Typical experimen-
tal procedures and characterizations for all products.
This material is available free of charge via the Internet
at http://pubs.acs.org.
The proposed mechanism of reduction is shown in
Scheme 3 and based on the previous work of Piers.14d,15b
The authors declare no competing financial interest.
D
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