Chemoselective ruthenium-catalysed reduction of carboxylic acids

Article abstract of DOI:10.1002/adsc.201301088

A very general and efficient catalytic protocol for the selective reduction of carboxylic acids to their corresponding alcohols under mild conditions is described. Various carboxylic acids, including benzoic acids, were reduced in good yields using the presented methodology. The ruthenium-catalysed method yields a highly chemoselective reduction permitting the reduction of a carboxylic acid functionality in the presence of numerous other potentially reducible moieties.

Full text of DOI:10.1002/adsc.201301088

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DOI: 10.1002/adsc.201301088
Chemoselective Ruthenium-Catalysed Reduction of Carboxylic
Acids
Josꢀ A. Fernꢁndez-Salas,a Simone Manzini,a and Steven P. Nolana,*
a
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST, U.K.
Fax : (+44)-(0)1334-463-808; e-mail: snolan@st-andrews.ac.uk
Received: December 5, 2013; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301088.
Abstract: A very general and efficient catalytic pro-
tocol for the selective reduction of carboxylic acids
to their corresponding alcohols under mild condi-
tions is described. Various carboxylic acids, includ-
ing benzoic acids, were reduced in good yields using
the presented methodology. The ruthenium-cata-
lysed method yields a highly chemoselective reduc-
tion permitting the reduction of a carboxylic acid
functionality in the presence of numerous other po-
tentially reducible moieties.
these methodologies involve elegant catalytic meth-
ods [Fe,[7] Ru,[8] and B(C6F5)3[9]] for the hydrosilylation
AHCTUNGTRENNUNG
of carboxylic acids to aldehydes. Regarding the reduc-
tion to the corresponding alcohols, only few catalytic
procedures have been described.[7,10,11,12] The limited
reaction scope[10,11] and the use of light-mediated pro-
tocols[7] can be considered as principal drawbacks in
the above-mentioned reducing procedures. In addi-
tion, an investigation into the chemoselective reduc-
tion of carboxylic acids in the presence of a variety of
functional groups has not yet been undertaken. This
is warranted as it would unequivocally establish the
true potential of the approach. Recently, we reported
Keywords: carboxylic acids; homogenous catalysis;
hydrosilylation; reduction; ruthenium
on the synthesis of [RuClACHTNUTGRNEUNG
(PPh3)2(3-phenylindenyl)][13]
(1), a complex that has proven to be highly efficient
in a number of catalytic transformations, such as alco-
hol racemisation,[13] ketone reduction,[14] alcohol oxi-
The reduction of carboxylic acid derivatives to pro- dation[15] and S S, S Si and S B dehydrogenative
duce the corresponding alcohols has drawn much in- coupling.[16] Moreover, complex 1 can be easily and
terest in organic synthesis and represents a straightfor- inexpensively synthesised starting from a propargylic
À
À
À
2A
Stoichiometric hydride reducing agents (e.g., DIBAL-
Taking into account the interest in developing new
H, LiAlH4 or LiBH4) are most commonly employed catalytic procedures for the reduction of carboxylic
in such reductions. This is despite the protocol being acids and to further extend the utility of 1, we de-
afflicted with several disadvantages such as poor func- scribe here a very general and efficient ruthenium-
tional group tolerance, moisture- and air-sensitivity catalysed hydrosilylation of carboxylic acids under
and often difficulties encountered with product isola- mild conditions, and for the first time, report on
tion and purification.[2] On the other hand, catalytic a highly chemoselective version of this transformation
hydrogenation[3] represents an excellent method to in the presence of other functional groups.
reduce carboxylic acids. In spite of its utility, the re-
At first, we studied the hydrosilylation of benzoic
quired harsh conditions (high pressure and elevated acid (2a) as a model reaction in the presence of
temperatures) represent serious drawbacks in the hy- 1 (1 mol%) (Table 1). The reaction was initially con-
drogenation procedure. Due to its safety and opera- ducted in the presence of PhSiH3 (3 equiv.) while test-
tional simplicity, the catalytic hydrosilylation of car-
bonyl moieties has recently become an important al-
ternative as a reduction strategy.[4] Metal-catalysed
hydrosilylations of carboxylic acid derivatives such as
esters[5] or amides[6] to the corresponding alcohols and
amines have been widely developed. In contrast, only
a limited number of systems has been described for
the hydrosilylation of carboxylic acids.[7–12] Most of Scheme 1. Synthesis of 1.
308
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Chemoselective Ruthenium-Catalysed Reduction of Carboxylic Acids
Table 1. Optimization of the conditions for the reduction of
benzoic acid 2a.[a]
Table 2. Reduction of carboxylic acids (2a–l) catalysed by
1.[a]
Entry
Acid
PhSiH3
[equiv.]
Conv.
[%][b]
Yield
[%][c]
Entry
Silane [equiv.]
Solvent
Conv. 3a [%][b]
1
2
3
4
5
6
7
8
PhSiH3 (3)
PhSiH3 (3)
PhSiH3 (3)
PhSiH3 (3)
PhSiH3 (3)
PhSiH3 (3)
PhSiH3 (3)
Ph2SiH2 (3)
Ph2MeSiH (3)
PhMe2SiH (3)
Et3SiH (3)
PMHS (3)
MeOH
i-PrOH
CH3CN
toluene
toluene[c]
THF
THF
THF
THF
THF
THF
THF
THF
THF
50
60
64
45
55
>98
0[d]
0
0
0
0
0
1
2
3
4
5
6
7
2a 2
2b 2
2c
>98
>98
92
84 (3a)
80 (3b)
77 (3c)
79 (3d)
73 (3e)
78 (3f)
–
3
9
2d 3
2e 3
>98
93
10
11
12
13
14
15
A
0
PhSiH3 (2)
PhSiH3 (1)
>98
70
THF
2f
3
>98
[a]
Reaction conditions: 1 (1 mol%), 2a (0.25 mmol) and
silane (1–3 equiv.). Hydrolysis was performed using HCl
(1 mL, 1M) in THF (0.5 mL).
Conversion determined by H NMR spectroscopy.
At 808C.
[d]
2g 2
2h 2
–
[b]
[c]
[d]
1
8
9
>98
>98
65 (3h)
60 (3i)
In the absence of catalyst (1).
2i
2
10
11
12
2j 3[e]
2k 3[e]
2l 3[e]
>98
>98
>98
80 (3j)
79 (3k)
78 (3l)
ing different solvents. Moderate conversions were ob-
tained with polar (Table 1, entries 1–3) or non-polar
(Table 1, entries 4 and 5) solvents. Interestingly, THF
shows an enormous beneficial effect on the reaction,
leading to complete conversion of benzoic acid to the
corresponding benzyl alcohol (3a) (Table 1, entry 6).
In absence of complex 1, the reaction does not take
place (Table 1, entry 7). In addition to PhSiH3, several
other silanes were also evaluated for this reaction
(Table 1, entries 8–13). However, the unchanged start-
ing material was recovered in all the cases. It is note-
worthy that the amount of PhSiH3 can be decreased
to 2 equiv. without any loss in the conversion to the
desired benzyl alcohol (Table 1, entry 14).
[a]
Reaction conditions: 1 (1 mol%), carboxylic acid (2)
(0.25 mmol) and silane (2–3 equiv.). Hydrolysis was per-
formed using HCl (1 mL, 1M) in THF (0.5 mL).
[b]
[c]
[d]
[e]
1
Conversion determined by H NMR spectroscopy.
Isolated yields.
Complex mixture.
2 mol% of 1.
process can be achieved even in the presence of
After optimizing the reaction conditions, the scope a free hydroxy group in the ortho position with
of the reduction of carboxylic acids with PhSiH3 was a good isolated yield (Table 2, entry 6). It should be
examined using 1 (1 mol%) and THF as a solvent highlighted that the catalytic system displays a good
(Table 2). Several aromatic carboxylic acids were efficiency for the reduction of substituted benzoic
tested (Table 2, entries 1–6). Substituted benzoic acids acid derivatives, which are not easily obtained using
with an electron-donating or electron-withdrawing the previously reported hydrosilylation methodolo-
group in either the ortho or para position were suc- gies.[7,10,11] Heteroaromatic carboxylic acids were also
cessfully reduced to the corresponding alcohols in studied. Furoic (2h) and thiophene (2i) acids can be
good yields (73–84%) (Table 2, entries 1–6). However, reduced to the corresponding alcohols in moderate
ortho- or electron-donating substituted benzoic acids isolated yields (60–65%) (Table 2, entries 8 and 9).
showed a slightly lower reactivity and 3 equiv. of With respect to the 2-picolinic acid (2g), the desired
PhSiH3 were required to efficiently yield the desired product cannot be isolated and a complex mixture of
products (Table 2, entries 3–5). Notably, the reduction products was obtained (Table 2, entry 7). The system
Adv. Synth. Catal. 2014, 356, 308 – 312
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309

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Josꢀ A. Fernꢁndez-Salas et al.
Table 3. Chemoselective reduction of carboxylic acids.[a]
Entry
1
Acid
Alcohol
Conv. [%][b]
Yield [%][c]
80
2m
2n
3m
3n
>98
>98
2
3
73
81
77
2o
2p
3o
3p
>98
4
90
[a]
Reaction conditions: 1 (1 mol%), carboxylic acid (2) (0.25 mmol) and silane (0.5 mmol). Hydrolysis was performed using
HCl (1 mL, 1M) in THF (0.5 mL).
Conversion determined by H NMR spectroscopy.
Isolated yields.
[b]
[c]
1
permitted benzyl carboxylic acid (2j) to be converted trile (2m), a tertiary amide (2n), an ester (2o) or even
to the desired alcohol in a good yield (80%) (Table 2, a ketone (2p), which are well known to be much
entry 10). Linear (2k) or even highly hindered (2l) more reactive under any other hydrosilylation or re-
alkyl carboxylic acids can be efficiently reduced to duction reaction conditions. It should be noted that
the corresponding alcohols (Table 2, entries 11 and the reduction products of these extra functional
12). It must be noted that under these hydrosilylation groups were never observed.
reaction conditions terminal double bonds are also
tolerated (Table 2, entry 11).
To further study the chemoselectivity of the reduc-
tion, a few competitive reactions were carried out.
After demonstrating the general applicability of The reduction under the optimised reaction condi-
this hydrosilylation system, and with the aim to fur- tions of the benzoic acid (2a) in presence of various
ther extend the generality and the activity of 1, we ketones takes place with full conversion. Surprisingly,
studied more challenging carboxylic acids with poten- the benzophenone and the cyclohexanone were recov-
tially reactive groups such as nitrile or carbonyl moi- ered unchanged, and only the acetophenone was
eties (Table 3). Surprisingly, and to our delight, we slightly reduced (15% conversion) (Scheme 2).
found that carboxylic acids can be chemoselectively
Several experiments were conducted to gain insight
reduced to the desired alcohols in the presence of a ni- into the reaction mechanism. Using dimethylphenylsi-
Scheme 2. Competitive reactions.
310
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Chemoselective Ruthenium-Catalysed Reduction of Carboxylic Acids
Scheme 3. a) Formation of silyl ester 4. b) Proposed mechanism of the ruthenium-catalysed reduction of carboxylic acids.
lane in the presence of 1, the silyl ester 4 can be acid group reduction is targeted. The method is
easily obtained (Scheme 3, reaction a).[18] Unfortu- straightforward, is more atom- and step-economical
nately, due to its high moisture-sensitivity, the possi- than existing protocols where protection/deprotection
ble formation of poly-dehydrogenative coupled prod- steps are oftentimes required. The exploration of the
ucts and the observed redistribution associated with activity of 1 and its congeners in the catalytic land-
the phenylsilane,[19] the analogous silyl ester inter- scape is ongoing in our laboratories.
mediate A cannot be easily detected. At short reac-
tion times (15 min), and after the hydrolysis of the
disilylacetals (B), the corresponding aldehyde was de- Experimental Section
tected by 1H NMR spectroscopy. On the basis of
these results, we propose that the reduction of the car- General Procedure for Hydrosilylation of Carboxylic
boxylic acids with phenylsilane in the presence of 1, Acids
takes place in three steps (Scheme 3, reaction b).[8]
The desired primary alcohols are proposed to be pro-
In a vial fitted with a screw cap, in the glove box, 1 (1 mol%
or 2 mol%) and the corresponding carboxylic acid
duced by (i) a dehydrogenative coupling between the
(0.25 mmol) were dissolved in THF (0.5 mL). Then, outside
carboxylic acid and the silane, (ii) a reduction of the
of the glove box, the PhSiH3 was added (2–4 equiv.) and
then, an empty balloon was placed in the vial cap. The re-
sulting mixture was stirred 16 h at 608C. The reaction was
hydrolyzed with aqueous HCl (1 mL, 1M) in THF (0.5 mL)
at room temperature for 1 h. Then, the aqueous phase was
extracted with Et2O (3ꢃ5 mL). The organic layer was
washed with brine and dried over MgSO4. The solvent was
removed under reduced pressure. The residue was purified
by flash chromatography on silica gel.
À
silyl ester derivative (A) by an Si H addition in the
C=O bond, followed by (iii) reductive cleavage of
À
a C O bond of the disilylacetal intermediate (B), and
the final hydrolysis of the corresponding silyl ether
(C). It is generally assumed that the silane is activated
by the metal complex via oxidative addition to pro-
duce a metal silyl complex able to transfer the silyl
.[6c,20]
group to a carbonyl moiety
However, we were
unable to observe the desired ruthenium species in
the corresponding stoichiometric reactions. Further
investigations are currently ongoing in our laboratory,
in order to better understand the mechanism of the
hydrosilylation reaction.
In conclusion, we have described an efficient meth-
odology for the reduction of carboxylic acids to the
corresponding alcohols, under mild conditions, cata-
Acknowledgements
We thank the ERC (Advanced Investigator Award
ꢀFUNCATꢁ to SPN) and the EPSRC for funding. SPN is
a Royal Society Wolfson Merit Award holder.
lysed by [RuClACHTUNGTRENNUNG(PPh3)2(3-phenylindenyl)] (1). The de-
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