Acetone cyanohydrin as a source of HCN in the Cu-catalyzed hydrocyanation of α-aryl diazoacetates

Article abstract of DOI:10.1021/jo100356d

A procedure for the Cu-catalyzed hydrocyanation of α-aryl diazoesters has been developed using acetone cyanohydrin as a source of hydrogen cyanide (HCN). It was found that the addition of trimethylsilyl cyanide (TMSCN) significantly accelerates the conversion presumably by delivering free cyanide ion in situ, thus producing various types of α-aryl cyanoacetates in high yields under mild conditions.

Full text of DOI:10.1021/jo100356d

pubs.acs.org/joc
SCHEME 1. New Source of Hydrogen Cyanide for the
Acetone Cyanohydrin as a Source of HCN in the
Cu-Catalyzed Hydrocyanation of r-Aryl Diazoacetates
Hydrocyanation of R-Aryl Diazoesters
Eun Ju Park, Seungeon Lee, and Sukbok Chang*
Department of Chemistry and Molecular-Level Interface
Research Center, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 305-701, Republic of Korea
building unit.3 Although hydrogen cyanide (HCN) can be
regarded as the most straightforward reagent for the hydro-
cyanation reaction, its toxic and volatile property makes its
widespread and practical applications in organic synthesis
quite difficult.4
sbchang@kaist.ac.kr
Received February 25, 2010
As a result, there have been investigations of developing
surrogates of hydrogen cyanide.5 Among those candidate
compounds, acetone cyanohydrin can be regarded as one of
mild, cheap, and environmentally friendly species.6 In line
with our recent interest in the development of new reactions
of R-diazocarbonyl compounds,7 we envisioned develop-
ment of a hydrocyanation reaction using acetone cyanohy-
drin as a source of hydrogen cyanide (Scheme 1).
We initiated our study of the hydrocyanation reaction of
methyl R-diazo-R-phenylacetate using acetone cyanohydrin
under various conditions (Table 1). It was immediately
found that while copper(I) chloride catalyzed the reaction
only with low efficiency (entry 2), its cationic species notably
improved the conversion at room temperature (entry 3).
Interestingly, whereas the addition of KCN to the CuCl
catalyst system completely inhibited the reaction (entry 4), a
much increased product yield was obtained upon addition
of the same additive (KCN) to the cationic copper system
(entry 5).8
A procedure for the Cu-catalyzed hydrocyanation of
R-aryl diazoesters has been developed using acetone
cyanohydrin as a source of hydrogen cyanide (HCN). It
was found that the addition of trimethylsilyl cyanide
(TMSCN) significantly accelerates the conversion pre-
sumably by delivering free cyanide ion in situ, thus
producing various types of R-aryl cyanoacetates in high
yields under mild conditions.
Metal-mediated C-H insertion of R-diazoacetates has
been developed as one of the most representative synthetic
tools for the formation of C-C bonds by taking advantage
of excellent reactivity of the resultant carbenoids.1 In more
recent years, insertion reactions of heteroatomic nucleo-
philes X-H (X = N, O, S, etc) into R-diazocarbonyls have
also been actively investigated using various catalytic sys-
tems.2 On the other hand, hydrocyanation of R-diazocarbo-
nyls has been much less investigated although R-cyanoester
products have an important synthetic utility as a bifunctional
The main reason for the additive effects of KCN was
postulated to generate free cyanide ion (CN-) from the
combined copper cocatalyst system, in which in situ gener-
ated cyanide accelerates the hydrocyanation reaction.9 This
reasoning led us to further investigate the optimization
processes. Indeed, whereas the additional coadditive of a
crown ether to the above system of entry 5 resulted in almost
(4) (a) Cornils, B.; Herrmann, W. A. Applied Homogeneous Catalysis with
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Belokon0, Y. N.; North, M.; Parsons, T. Org. Lett. 2000, 2, 1617. (c) Garcıa
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McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with
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Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. (c) Dias, H. V. R.;
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H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(2) For recent reports on the enantioselective X-H (X = N, O, S, etc)
insertion into R-diazocarbonyl compounds, see: (a) Maier, T. C.; Fu, G. C.
J. Am. Chem. Soc. 2006, 128, 4594. (b) Ge, M.; Corey, E. J. Tetrahedron Lett.
2006, 47, 2319. (c) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066.
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1405. (b) Strauss, S. H. Chem. Rev. 1993, 93, 927. (c) Krossing, I.; Raabe, I.
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2760 J. Org. Chem. 2010, 75, 2760–2762
Published on Web 03/25/2010
DOI: 10.1021/jo100356d
r
2010 American Chemical Society

Park et al.
JOCNote
TABLE 1. Optimization of the Hydrocyanation Reactiona
TABLE 2. Cu-Catalyzed Hydrocyanation of R-Aryl Diazoacetatesa
entry
catalyst system
solvent
yieldb (%)
1
2
3
4
none
CuCl
Cu(CH3CN)4PF6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
<1
15
47
<1
CuCl/KCN
5
Cu(CH3CN)4PF6/KCN
Cu(CH3CN)4PF6/KCN/18-C-6
Cu(CH3CN)4PF6/TMSCN
Cu(CH3CN)4BF4/TMSCN
Cu(CH3CN)4PF6/TMSCN
Rh2(OAc)4
68
4
6c
7
88 (87)d
8
9
10
11
65
5
3
Rh2(OAc)4/TMSCN
3
aMethyl R-diazo-R-phenylacetate (0.5 mmol), acetone cyanohydrin
(1.5 mmol), catalyst (5 mol %), and additive (10 mol %) in solvent
(5.0 mL) at 25 °C for 2 h. bNMR yield of 1a using 1,2-methylenedioxy-
benzene as an internal standard. cEach additive was employed by
10 mol %. dNumber in parentheses is the isolated yield.
complete inhibition (entry 6), substitution of KCN with a
more soluble organic cyanide species, trimethylsilyl cyanide
(TMSCN), provided the product in excellent yield (entry 7).
Interestingly, it turned out that the counteranions of the
ionic copper catalysts also played a role on the reaction
efficiency. For instance, the change of counteranion from
PF6- to BF4- resulted in reduced product yield (entry 8).
After screening various reaction media, dichloromethane
was selected as the solvent of choice. On the other hand,
rhodium catalyst systems which are known to be highly
effective for the X-H insertion into R-diazocarbonyls10
displayed very poor efficiency in this hydrocyanation reac-
tion using acetone cyanohydrin. In fact, almost no product
was obtained when Rh2(OAc)4 catalyst was employed
regardless of the presence of TMSCN coadditive (entries
10 and 11).
With the optimized reaction conditions, we explored the
substrate scope of various R-aryl diazoesters for the hydro-
cyanation with the use of acetone cyanohydrin (3 equiv) as a
hydrogen cyanide source (Table 2). In general, the reaction
proceeded smoothly and was not much effected by the steric
and/or electronic variation on the aryl substituents. Alter-
nation of alkoxy moiety in the R-diazoesters did not much
affect the reaction efficiency. In fact, the hydrocyanation of
methyl, tert-butyl, or benzyl esters of R-diazophenylacetic
acid gave the corresponding R-cyanophenylacetates in high
yields (entries 1, 2, and 3, respectively).
Next, the reaction efficiency was examined upon the
variation of the aryl moiety of diazo substrates. The presence
of various substituents at the para position of methyl
R-diazo-R-phenylacetates displayed little effect on the product
yields (entries 4-6). In addition, halo substituents on the
phenyl moiety were completely tolerated under the present
reaction conditions. However, a trifluoromethyl group de-
creased the reaction rate, and satisfactory product yield could
aR-Aryl diazoacetate (0.5 mmol), acetone cyanohydrin (1.5 mmol),
Cu(CH3CN)4PF6 (5 mol %), and TMSCN (10 mol %) in CH2Cl2
(5.0 mL) at 25 °C for the indicated time. b2.5 mmol of acetone
cyanohydrin was used. c10 mol % of Cu(CH3CN)4PF6 was used.
be obtained only after prolonged reaction time with higher
loading of the copper catalyst (entry 8).
Hydrocyanation reaction of methyl R-diazo-R-phenylace-
tates bearing meta substituents proceeded smoothly to af-
ford the desired products in respectable yields (entries
10-14). Quite interestingly, the reaction efficiency was not
significantly influenced by the steric bulkiness of the phenyl
substituents as evidenced in entries 15-17. Not only simple
phenyl but also condensed R-aryl diazoacetates were facile
substrates for the hydrocyanation (entries 18 and 19). How-
ever, R-diazo-R-alkyl esters did not undergo the hydrocya-
nation under the developed conditions (entry 20).
In order to test a possibility of the diastereoselective
hydrocyanation reaction, optically active R-aryl diazoace-
tates were prepared in high yield by a conventional two-step
procedure starting from phenylacetic acid: esterification of
(10) For recent reports of the rhodium-catalyzed carbenoid formation,
see: (a) Huang, H.; Wang, Y.; Chen, Z.; Hu, W. Adv. Synth. Catal. 2005, 347,
531. (b) Wong, F. M.; Wang, J.; Hengge, A. C.; Wu, W. Org. Lett. 2007, 9,
1663. (c) Hansen, J.; Autschbach, J.; Davies, H. M. L. J. Org. Chem. 2009, 74,
6555.
J. Org. Chem. Vol. 75, No. 8, 2010 2761

Park et al.
JOCNote
SCHEME 2. Diastereoselective Hydrocyanation
that a reaction of TMSCN with hexafluorophosphate coun-
teranion generates a free cyanide ion that can be involved in
the catalytic cycle.15,16 It can next be suggested that the
initially formed copper carbenoid from the reaction of R-
diazoester with copper species reacts with the in situ generated
cyanide anion to afford an alkylcyano copper intermediate,
and then a hydrogen transfer takes place from acetone cyano-
hydrin into the copper intermediate upon the regeneration of
Cu(I) and cyanide species for the next catalytic cycle.9
In summary, we have developed a mild and efficient
protocol of hydrocyanation of R-aryl diazoesters with the
use of acetone cyanohydrin as a hydrogen cyanide surrogate
under the copper catalyst system. The addition of TMSCN
as a cocatalyst significantly improves the reaction efficiency,
thus allowing a broad range of substrates to react leading
to R-aryl cyanoacetates in satisfactory yields under mild
conditions.
the acid with chiral alcohols followed by a diazo transfer with
p-(acetamido)benzenesulfonyl azide.11 When (-)-menthyl
R-diazo-R-phenylacetate was allowed to react with acetone
cyanohydrin under the Cu-catalytic conditions, only a low
level of diastereoselectivity (60:40) was observed (Scheme 2).
A more promising result was obtained by the introduction of
a phenyl group at the menthyl auxiliary, thus providing
improved diastereoselectivity up to 73:27. Importantly,
optically pure (-)-menthyl R-cyanophenylacetate could be
isolated in 48% yield after a simple recrystallization of the
crude reaction mixture.12
Experimental Section
Representative Procedure for the Cu-Catalyzed Hydrocyana-
tion of r-Aryl Diazoacetates. To a Schlenk tube was added
Cu(CH3CN)4PF6 (9.3 mg, 0.025 mmol) followed by CH2Cl2 (5.0
mL) and TMSCN (6.3 μL, 0.05 mmol) under nitrogen atmo-
sphere. After the reaction mixture was stirred for 5 min at room
temperature, acetone cyanohydrin (137 μL, 1.5 mmol) and then
methyl R-diazo-R-phenylacetate (88 mg, 0.5 mmol) were then
added dropwise. The resulting mixture was stirred for 1 h at
room temperature and filtered through a pad of Celite. After an
organic solvent was removed under reduced pressure, flash
column chromatography on silica gel (hexane/ethyl acetate,
7:1) afforded methyl (2-cyano-2-phenyl)acetate (1a, 77 mg,
88%): Rf 0.20 (hexane/ethyl acetate, 7:1); yellow oil; 1H NMR
(400 MHz, CDCl3) δ 7.45-7.38 (m, 5H), 4.73 (s, 1H), 3.77 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 129.8, 129.3, 129.2,
127.9, 115.5, 53.9, 43.4; IR (NaCl) ν 3035, 2957, 2848, 2252,
1751, 1436, 1311, 1237, 1210, 1079 cm-1; HRMS (EI) calcd for
C10H9NO2 [M]þ 175.0633, found 175.0635.
The obtained products in this study, R-aryl cyanoesters,
are a key precursor of β-cyano alcohols which can be
regarded as an important building motif in organic synth-
esis.13 R-Aryl cyanoesters could be readily reduced to the
corresponding aryl-substituted hydroxylpropane nitrile in
high yield upon treatment with magnesium borohydride
under mild conditions (eq 1).14
Although detailed mechanistic studies are required to
describe the exact catalytic pathway, some preliminary ob-
servations give mechanistic clues. For example, the fact that
the addition of TMSCN accelerates the hydrocyanation
most significantly in the case of using Cu(CH3CN)4PF6
catalyst and that the type of counteranion species of the
copper catalysts influences the reaction efficiency indicates
Acknowledgment. This research was supported by the
Korea Research Foundation (KRF-2008-C00024, Star
Faculty Program) and MIRC (SRC). We acknowledge the
Korea Basic Science Institute (KBSI) for the mass analysis.
(11) See the Supporting Information for the detailed experimental pro-
cedures.
Supporting Information Available: Experimental details and
1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Taber, D. F.; Berry, J. F.; Martin, T. J. J. Org. Chem. 2008, 73, 9334.
(13) (a) Shia, K.-S.; Jan, N.-W.; Zhu, J.-L.; Ly, T. W.; Liu, H.-J.
Tetrahedron Lett. 1999, 40, 6753. (b) Garcıa Ruano, J. L.; Cifuentes Garcıa,
M.; Martın Castro, A. M.; Rodrıguez Ramos, J. H. Org. Lett. 2002, 4, 55. (c)
Im, D. S.; Cheong, C. S.; Lee, S. H. J. Mol. Catal. B: Enz. 2003, 26, 131.
(14) For an example of a selective reduction using Ca(BH4)2, see:
Narasimhan, S.; Ganeshwar Prasad, K.; Madhavan, S. Synth. Commun.
1995, 25, 1689.
(15) (a) Ong, C. W.; Chien, C. J. Organometallics 1993, 12, 241. (b)
Faragalla, J.; Heaton, A.; Griffith, R.; Bremner, J. B. Synlett 2009, 306.
(16) One reviewer suggested an alternative mechanistic pathway where
TMSCN would be in equilibrium with TMSNC and this isocyanide can
accelerate the reaction rate, acting as a similar way to cyanide ion.
2762 J. Org. Chem. Vol. 75, No. 8, 2010