Synthesis of α-keto esters by the rhodium-catalysed reaction of cyanoformate with arylboronic acids

Article abstract of DOI:10.1039/b704105e

An arylrhodium(i) species selectively reacts with the cyano group of ethyl cyanoformate to afford the corresponding α-keto ester in good yield. The Royal Society of Chemistry.

Full text of DOI:10.1039/b704105e

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Synthesis of a-keto esters by the rhodium-catalysed reaction of
cyanoformate with arylboronic acids{
Hiroshi Shimizu and Masahiro Murakami*
Received (in Cambridge, UK) 19th March 2007, Accepted 10th April 2007
First published as an Advance Article on the web 26th April 2007
DOI: 10.1039/b704105e
phenylboronic acid (2a, 1.2 equiv.) and [Rh(OH)(cod)]2 (2.5 mol%,
5% of Rh) in dioxane was heated at 80 uC for 3 h. Aqueous work-
up, followed by chromatographic isolation, afforded ethyl
benzoylformate (3a) in 37% yield (Table 1, entry 1). No ethyl
benzoate was detected in the 1H NMR spectrum of the crude
reaction mixture. The selective formation of 3a suggests that the
phenylrhodium intermediate generated by transmetallation under-
goes 1,2-addition to the cyano group in preference to the ester
group. Addition of boric acid (H3BO3, 1.0 equiv.) improved the
yield to 62% yield (Table 1, entry 2). The best yield, of 83%, was
obtained in a reaction at 60 uC using 1.2 equiv. of phenylboronic
acid (2a) and 2.0 equiv. of boric acid (Table 1, entry 4).
An arylrhodium(I) species selectively reacts with the cyano
group of ethyl cyanoformate to afford the corresponding
a-keto ester in good yield.
The rhodium-catalysed reaction of organoboron species with
unsaturated organic compounds has emerged as a powerful
method for carbon–carbon bond formation.1 The reaction
generally proceeds by transmetallation to generate an intermediate
organorhodium species, which then undergoes 1,2-addition to
alkynes,2 alkenes,3 aldehydes,4 imines,5 esters,6 acid anhydrides,7
1,2-dicarbonyl compounds6,8 and nitriles5h,9 in an intermolecular
fashion. We have developed cascade reactions, in which an
organorhodium intermediate adds intramolecularly to a cyano
group,10 and found that, in some cases, the organorhodium species
exhibits a higher propensity to react with a cyano group than with
an ester group. Ethyl cyanoformate is an interesting electrophilic
substrate for comparing the reactivities of its cyano and ester
groups toward nucleophiles (Fig. 1). Since both functionalities are
electron-withdrawing, their electrophilic reactivities are enhanced
relative to isolated ester and nitrile groups. Nucleophiles, such as
organomagnesium11 and organolithium12 compounds, lithium
enolates,13 lithiated amides,14 alcohols15 and amines,16 selectively
attack the ester carbonyl group of ethyl cyanoformate, with the
cyano group acting as a leaving group to afford the corresponding
ethoxycarbonylated products. On the other hand, selective
addition to the cyano group proceeds when ethyl cyanoformate
is reacted under acidic conditions with softer nucleophilic species,
such as active methylene compounds,17 electron-rich benzenes18
and organocadmium compounds.19 Our previous studies on
rhodium-catalysed cascade reactions10 led us to examine the
reaction of ethyl cyanoformate with phenylboronic acid in the
presence of a rhodium catalyst in order to determine which
functionality is more vulnerable to intermolecular attack by a
phenylrhodium species. Thus, a mixture of ethyl cyanoformate (1),
The results obtained with other arylboronic acids are summar-
ized in Table 2.{ The corresponding a-keto esters were produced in
yields ranging from 46 to 87%. Good yields were obtained with
arylboronic acids having a methoxy substituent at either the ortho,
meta or para positions of the phenyl ring (Table 2, entries 2–4).
Although ortho-tolylboronic acid was a suitable substrate (Table 2,
entry 9), ortho-biphenylboronic acid gave only a moderate yield
(Table 2, entry 10). Electron-withdrawing groups at ortho and para
positions decreased the yield (Table 2, entries 8 and 11). Of note is
that a formyl group remained intact under the reaction conditions
(Table 2, entry 12). Formation of considerable quantities of arenes
by protonolysis of arylboronic acids was observed in cases where
the desired products 3 were obtained in moderate yield (Table 2,
entries 10–12).
The mechanism depicted in Scheme 1 is assumed for the
formation of 3. Arylrhodium(I) 4 is generated by transmetallation,
and then undergoes selective 1,2-addition to the cyano group. The
resultant iminorhodium(I) species, 5, is protonated with boric
acid (or 2) to afford imine 6 and rhodium(I) boronate (7), which
is then transmetalated with arylboronic acid 2 to regenerate
Table 1 The effect of boric acid as an additive
Entry
Additive
Temperature/uC
Yield (%)a
Fig. 1 Ambivalent electrophilicity of cyanoformate.
1
2
3
4
5
—
80
80
80
60
40
37
62
78
83
53
Department of Synthetic Chemistry and Biological Chemistry, Kyoto
University, Katsura, Kyoto 615-8510, Japan.
E-mail: murakami@sbchem.kyoto-u.ac.jp; Fax: +81 75 383 2748;
Tel: +81 75 383 2747
H3BO3 (1.0 equiv.)
H3BO3 (2.0 equiv.)
H3BO3 (2.0 equiv.)
H3BO3 (2.0 equiv.)
a
{ Electronic supplementary information (ESI) available: Experimental
details and spectral data for a-keto esters 3. See DOI: 10.1039/b704105e
Isolated yields.
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Chem. Commun., 2007, 2855–2857 | 2855

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compounds, including triphenylmethanol and benzophenone
Table 2 Reaction of ethyl cyanoformate (1) with arylboronic acids 2
(eqn. 2). The selective formation of a-keto esters in the present
reaction is in sharp contrast to the results obtained with
phenylmagnesium bromide and phenyllithium.
Entry
2
Ar
Product 3
Yield (%)a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
83
80
74
87
82
73
81
46
83
50
58
50
4-MeO–C6H4
3-MeO–C6H4
2-MeO–C6H4
4-Br–C6H4
4-F–C6H4
3-Cl–C6H4
2-Cl–C6H4
2-Me–C6H4
2-Ph–C6H4
4-MeO2C–C6H4
3-CHO–C6H4
ð2Þ
In conclusion, the rhodium-catalysed reaction of ethyl cyano-
formate with arylboronic acids provides a convenient method for
the synthesis of arylated a-keto esters. It has been demonstrated
that arylrhodium(I) species preferentially add to the cyano group
of 1 rather than to the ester carbonyl group.
10
11
12
a
2j
2k
2l
3j
3k
3l
Isolated yields.
Notes and references
{ General procedure: A mixture of arylboronic acid 2 (0.6 mmol, 1.2 equiv.),
H3BO3 (1.0 mmol, 2.0 equiv.), [Rh(OH)(cod)]2 (0.0125 mmol, 2.5 mol%)
and ethyl cyanoformate (1, 0.5 mmol, 1.0 equiv.) in 1,4-dioxane (1 ml) was
stirred for 30 min at room temperature, and then at 60 uC for 3 h under an
Ar atmosphere. The reaction mixture was cooled and diluted with AcOEt
(10 ml) and citric acid (10% aq., 5 ml). The organic layer was separated,
and the aqueous layer was extracted with AcOEt (3 6 5 ml). The
combined extracts were washed with water and brine, and dried over
Na2SO4. The solvent was removed under reduced pressure and the residue
was purified by preparative thin layer chromatography (hexane : AcOEt) to
give the product 3, which was characterized by 1H and 13C NMR, and/or
HRMS (see ESI{).
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Boric acid is presumed to facilitate the release of rhodium from the
iminorhodium(I) intermediate 5 by protonolysis. The effect of the
acidic proton of boric acid is apparent from the contrasting results
of the reaction of 1 with phenylboroxine (9), both with and
without boric acid (eqn. 1).
ð1Þ
The selective reaction of the cyano group of
1 with
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2856 | Chem. Commun., 2007, 2855–2857
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