Phosphine-catalyzed reaction of cyanohydrins with activated alkynes

Article abstract of DOI:10.1055/s-0029-1216827

A new method for preparing α-cyanoacrylates and α-cyanoenones is described. The procedure uses a phosphine-catalyzed α-C addition of cyanide ion, generated in situ from cyanohydrins, to activated alkynes. An unexpected tandem reaction producing benzyliden

Full text of DOI:10.1055/s-0029-1216827

PAPER
2365
Phosphine-Catalyzed Reaction of Cyanohydrins with Activated Alkynes
R
eaction of Cyano
c
hydrins
w
it
é
h
A
ctivated
t
Alkyn
o
es u Siby, Olivier Loreau,* Frédéric Taran*
CEA, IBITECS, Service de Chimie Bioorganique et de Marquage, Gif sur Yvette 91191, France
Fax +33(1)69087991; E-mail: frederic.taran@cea.fr
Received 29 March 2009; revised 3 April 2009
enones. We have described a series of phosphine-cata-
lyzed a-addition reactions of pronucleophiles on activated
alkynes that allows the formation of polyfunctionalized
activated alkenes.7 We contemplated using this type of
chemistry for the formation of a-cyanoacrylates and a-cy-
anoenones through a-C-addition of cyanide ion to activat-
ed alkynes 1 (Scheme 1). We designed cyanohydrins,
easily prepared from reaction of KCN with aldehydes or
ketones, as cyanide sources.8
Abstract: A new method for preparing a-cyanoacrylates and a-cy-
anoenones is described. The procedure uses a phosphine-catalyzed
a-C addition of cyanide ion, generated in situ from cyanohydrins, to
activated alkynes. An unexpected tandem reaction producing ben-
zylidenecyclopentanones is also described.
Key words: cyanoacrylates, alkynes, catalysis, phosphines
a-Cyanoacrylates and a-cyanoenones are common build-
ing blocks for the synthesis of numerous heterocycles;
their use as monomers in polymer synthesis is also well
established. These products have been mostly synthesized
by the Knoevenagel condensation using active methylene
compounds such as cyanoacetates and a-cyanoketones.1
However, a-cyanoenones may be reactive or unstable to
base, so that classical Knoevenagel conditions are not al-
ways suitable for the preparation of these compounds.2
Only few alternative synthetic approaches to a-cyano-
enones such as isoxazoline oxidation,3 ring opening of
isoxazoles by bases,4 and a-cyanoacylation of aldehydes5
have been described in literature.
Cyanohydrines may indeed react as an indirect pronucleo-
phile upon reaction with the zwitterion intermediate gen-
erated by Michael addition of the phosphine catalyst on
the activated alkyne. H-abstraction of the cyanohydrin by
this intermediate should release cyanide ion that may then
add onto the vinyl phosphonium intermediate. Elimina-
tion of the phosphine after H+ transfer should then afford
the desired acrylonitrile 2. To test the feasibility of this re-
action, various cyanohydrins were reacted with ethyl phe-
nylpropiolate (1a) in the presence of several phosphines
(Table 1).
To our delight, the reaction was found to work through the
desired pathway and afforded ethyl trans-a-cyanocin-
namate (2a) at room temperature in acceptable yield
(Table 1, entry 1). Higher yields and shorter reaction
times are obtained upon heating and by using MePh2P,
During the course of our work on the preparation of 14C-
labeled cyanoacrylates and their polymer derivatives,6 we
have been interested in developing a mild procedure based
on previous work described by our group using labeled
KCN as starting material for the synthesis of a-cyano-
R'
R'
K*CN
R'
R'
R'
R'
O
*CN
HO *CN
O
R
R
R
R
R
P
R
P
Ar
EWG
Ar
EWG
1
Ar
EWG
R3P
α-addition
R'
R'
O
R
R
R3P
R
P
*CN
Ar
*CN
Ar
H+ transfer
*CN
EWG
Ar
EWG
P
EWG
R
2
R
R
Scheme 1 Proposed route to labeled acrylonitrile 2
SYNTHESIS 2009, No. 14, pp 2365–2370
x
x.
x
x
.
2
0
0
9
Advanced online publication: 25.05.2009
DOI: 10.1055/s-0029-1216827; Art ID: Z05209SS
© Georg Thieme Verlag Stuttgart · New York

2366
A. Siby et al.
PAPER
We then looked at the scope and limitations of this reac-
tion by employing a panel of activated alkynes starting
materials. As illustrated in Table 2, the presented method-
ology appeared to be amenable on a variety of substrates
affording a straightforward route to polyfunctionalized
acrylonitriles.
Table 1 Optimization of the Reaction of Cyanohydrins with Alkyne
1a
R
R'
(1.1 equiv)
HO CN
R3P (cat.)
CN
CO2Et
CO2Et
2a
1a
The reaction proceeded smoothly on a panel of activated
alkynes affording the desired a-cyanoacrylates 2a–c and
a-cyanoenones 2d–g products in moderate to good yields.
In the case of alkynes activated by a ketone function, the
reaction requires room temperature conditions due to the
thermal instability of the resulting products.
Yield
of 2a
R
R'
Entry
1
R3P (mol%)
Conditions
(%)a
HO CN
Bu3P (20%)
Bu3P (20%)
toluene, r.t., 20 h
66
HO CN
Compounds 2 were fully characterized and their structure
established by NMR and MS experiments as well as by
comparison with published analytical data. By-product 3d
(26% isolated yield) has also been observed when enoliz-
able yne-one starting material 1d was used. The structure
of this by-product (Figure 1) was determined by extensive
spectral analysis. The E-form of the double bound was as-
signed by comparison with the published NMR data.9
2
3
4
5
6
7
toluene, 110 °C, 1 h 63
MePh2P (20%) toluene, 110 °C, 1 h 72
Ph3P (20%)
toluene, 110 °C, 1 h 30
toluene, 110 °C, 6 h 72
MePh2P (5%)
MePh2P (20%) i-PrOH, 90 °C, 7 h 40
MePh2P (20%) CH2Cl2, 40 °C, 24 h 72
O
8
MePh2P (20%) toluene, 110 °C, 7 h 73
NC
O
CN
HO
3d
9
MePh2P (20%) toluene, 110 °C, 5 h 61
MePh2P (20%) toluene, 110 °C, 4 h 74b
Figure 1 Structure of by-product 3d
HO
HO
CN
Control experiments proved that this cyclopentanone
product resulted from a phosphine-catalyzed condensa-
tion of alkyne 1d on cyanoenone 2d (Scheme 2).
10
CN
a Isolated yields.
One possible reaction pathway yielding product 3d from
1d and 2d is shown in Scheme 3.
b A by-product in 17% yield resulting from the a-O-addition of the cy-
anohydrin was isolated in this case.
The zwitterionic intermediate 4 produced by conjugate
which was found the most active catalyst (compare entry addition of the phosphine catalyst undergoes an intramo-
3 with 2 and 4, Table 1). Among the tested cyanohydrins, lecular proton migration (1,3-proton shift) from the meth-
acetone cyanohydrin was found the most efficient (com- yl group. A nucleophilic attack of the resulting enolate 5
pare entries 8, 9, and 10 with 3, Table 1). The other cyano- to cyanoacrylate 2d produces the carbanionic intermedi-
hydrins required longer reaction times; in each cases the ate 6, which then undergoes intramolecular a-C-addition
formation of the corresponding ketone or aldehyde by- on the a,b-unsaturated ketone moiety generating ylide 7.
products were observed in the crude reaction mixture.
Proton transfer followed by phosphine elimination then
produces 3d.
O
toluene
r.t., 12 h
CN
+
NC
COMe
O
O
1d
2d
3d
MePh2P
none
Yield 3d
(1 equiv)
no reaction
40%
20 mol%
Scheme 2 Control experiment yielding product 3d
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Reaction of Cyanohydrins with Activated Alkynes
2367
Table 2 Phosphine-Catalyzed Reaction of Acetone Cyanohydrin with Activated Alkynesa
(1.1 equiv)
Ar
CN
HO CN
Ar
EWG
EWG
MePh2P (20 mol%)
toluene
1
2
Entry
Conditions
110 °C, 1 h
Product 2, Yield (%)a
Ar
EWG
CN
CO2Et
1
2
CO2Et
1a
2a (72)
MeO
MeO
CO2Et
110 °C, 5 h
CN
1b
CO2Et
2b (81)
Cl
Cl
Cl
3
110 °C, 2 h
CN
Cl
CO2Et
CO2Et
1c
2c (66)
CN
4
5
6
r.t., 20 h
r.t., 20 h
r.t., 2 h
O
1d
O
2d (66)
CN
O
O
1e
2e (66)
S
S
CN
O
1f
O
2f (71)
MeO
CN
MeO
O
7
r.t., 5 h
O
O
O
1g
2g (54)
a Isolated yields.
We therefore decided to take advantage of this new reac- quential addition of 1) cyanohydrin to generate a-cy-
tion for the straightforward synthesis of poly-functional- anoacrylonitrile derivative, and 2) the alkyne-one to
ized benzylidenecyclopentanones. After several attempts, produce cyclopentatones 3 as a mixture of diastereoiso-
we developed a two-step, one-pot process that worked in mers.
reasonable yields (Scheme 4). The process is based on se-
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A. Siby et al.
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R
R
R
P
R
O
R
P
R3P
R
H
Ph
Ph
O
1d
Ph
5
CN
4
O
Ph
P
COMe
2d
R
Ph
R
R
O
R
R
R
O
O
P
H+ transfer
α-C-addition
Ph
3d
Ph
Ph
6
CN
COMe
CN
COMe
7
CN
R3P
Ph
COMe
Ph
Scheme 3 Proposed route to cyclopentanone 3d
In conclusion, we have developed a simple and practical
method for the preparation of a-cyanoacrylates and a-cy-
anoenones starting from activated alkynes and cyanohy-
drins. Besides the practical advantages of the method, this
reaction is interesting for the preparation of labeled acry-
lonitriles. Preliminary investigations conducted in our
laboratory proved that this reaction is highly suitable for
the synthesis of labeled a-cyanoacrylates: reaction of eth-
yl phenylpropiolate (1a) with 13C-labeled cyclohexanone
cyanohydrin, obtained as previously described,10 afforded
product 2h in high yield and isotopic enrichment (IE)
(Scheme 5).
(1.1 equiv)
1)
HO CN
O
MePh2P (20 mol%)
toluene, r.t., 12 h
Ar'
Ar
EWG
NC
Ar
2)
Ar'
(1.1 equiv)
toluene, r.t., 12 h
EWG
O
3
O
O
NC
NC
O
EtO
O
During the course of this work a new construction of ben-
zylidenecyclopentanone from a phosphine-catalyzed cy-
cloaddition of a-cyanoacrylates and a-cyanoenones with
4-arylbut-3-yn-2-ones has also been highlighted. This al-
lowed us to optimize a tandem phosphine-catalyzed one-
pot process that afforded polyfunctionalized cyclopen-
tanones in moderate yields.
3d (39%)
3e (49%)
O
O
NC
NC
Br
MeO
EtO
O
EtO
O
3g (33%)
3f (39%)
All reagents were used directly as obtained commercially, unless
otherwise noted. Melting points were determined on a Büchi 535
capillary melting point apparatus and are uncorrected. Flash chro-
matography was carried out on Merck silica gel (40–63 mm). IR
spectra were obtained on a PerkinElmer system 2000 FT-IR spec-
trophotometer. 1H NMR (400 MHz) and 13C NMR (100 MHz)were
measured on a Bruker Avance 400 MHz spectrometer. Electrospray
mass spectra were obtained using an ESI/TOF Mariner Mass Spec-
trometer.
Scheme 4 Phosphine-catalyzed reaction yielding benzylidene-
cyclopentanones 3
O
K
13CN
H2O
MePh2P-Catalyzed Synthesis of a-Cyanoacrylates and a-Cya-
noenones; General Procedure
To a solution of ethyl arylpriopiolate 1 (1 mmol) and acetone cyano-
hydrin (100 mL, 1.1 mmol) in anhyd toluene (5 mL) was added
diphenylmethylphosphine (37.3 mL, 0.2 mmol) under argon. The
mixture was heated at reflux and then evaporated under reduced
pressure. The residue was purified by flash chromatography on a
silica gel column to give a-cyanoacrylates as the final product (Ta-
ble 2). Identical procedure, but at r.t., was applied to 4-arylbut-3-yn-
2-one for the preparation of a-cyanoenones (Table 2).
(73%)
HO 13CN
13CN
CO2Et
CO2Et
MePh2P (20 mol%)
toluene, reflux, 7 h
2h (77%)
IE : 99%
Scheme 5 Synthesis of 13C-labeled cyanoacrylate 2h
(E)-2-Cyano-3-phenylacrylic Acid Ethyl Ester (2a)
Purified by column chromatography (CH2Cl2–hexane, 50:50);
beige solid; mp 50–51 °C.
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Reaction of Cyanohydrins with Activated Alkynes
2369
IR (KBr): 3030, 2981, 2223, 1727, 1607, 1572, 1496, 1465, 1444,
1386, 1367, 1301, 1258, 1202, 1089, 1010, 970, 887, 849, 768, 683,
579, 524 cm–1.
IR (KBr): 3360, 3064, 3020, 2973, 2935, 2876, 2210, 1968, 1897,
1689, 1583, 1565, 1497, 1478, 1446, 1396, 1367, 1343, 1321, 1294,
1214, 1134, 1075, 1035, 1035, 1002, 984, 956, 939, 834, 795, 761,
733, 685, 625, 600, 570, 523 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.25 (s, 1 H), 8 (d, J = 7.2 Hz, 2
H), 7.55 (m, 3 H), 4.4 (q, J = 7.1 Hz, 2 H), 1.4 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.23 (s, 1 H), 8.0 (d, J = 7.2 Hz, 2
H), 7.5 (m, 3 H), 1.4 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 162.4, 154.9, 133.2, 131.4, 131.0,
129.2, 115.4, 102.9, 62.6, 14.1.
13C NMR (100 MHz, CDCl3): d = 198.9, 156.1, 132.9, 131.9, 131.1,
129.1, 113.2, 107.31, 44.54, 26.4.
MS (ESI): m/z = 202 [M + H]+.
MS (EI, 70 eV): m/z (%) = 213 (30, [M+]), 185 (34), 170 (12), 157
(63), 129 (98), 102 (41), 77 (21), 57 (100), 41 (47), 29 (23).
(E)-2-Cyano-3-(4-methoxyphenyl)acrylic Acid Ethyl Ester (2b)
Purified by column chromatography (CH2Cl2–hexane, 70:30); yel-
low solid; mp 81–82 °C.
3-Oxo-2-[1-thiophen-2-ylmeth-(E)-ylidene]butyronitrile (2f)
Purified by column chromatography (CH2Cl2–heptane, 80:20); yel-
low solid; mp 79–81 °C.
IR (KBr): 3415, 3084, 3025, 2993, 2943, 2844, 2577, 2215, 1968,
1912, 1748, 1586, 1562, 1513, 1461, 1431, 1364, 1320, 1263, 1211,
1182, 1127, 1089, 1018, 984, 894, 837, 817, 763, 737, 723, 625, 586
cm–1.
IR (KBr): 3443, 3082, 3046, 2364, 2330, 2212, 1833, 1717, 1695,
1676, 1579, 1504, 1413, 1360, 1268, 1243, 1201, 1054, 976, 948,
858, 786, 742, 635, 600, 567, 518 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.2 (s, 1 H), 8 (d, J = 8.9 Hz, 2 H),
7 (d, J = 8.9 Hz, 2 H), 4.4 (q, J = 7.1 Hz, 2 H), 3.9 (s, 3 H), 1.4 (t,
J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.3 (s, 1 H), 7.8 (dd, J = 3.7, 15.8
Hz, 2 H), 7.3 (q, J = 4.1 Hz, 1 H), 2.6 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.7, 163.0, 154.3, 133.6, 124.3,
116.1, 55.5, 14.1.
13C NMR (100 MHz, CDCl3): d = 190.9, 144.8, 137.9, 136.2, 135.7,
128.8, 117.5, 106.1, 27.9.
MS (EI, 70 eV): m/z (%) = 231 (100, [M+]), 216 (7), 203 (37), 186
(53), 158 (22), 143 (9), 115 (11), 77 (8), 29 (9).
MS (EI, 70 eV): m/z (%) = 177 (100, [M]+), 162 (65), 135 (42), 108
(18), 90 (13), 63 (14), 43 (99).
HRMS: m/z calcd for C9H7NOS + Na: 200.0146; found: 200.0150.
(E)-3-(3,4-Dichlorophenyl)-2-cyanoacrylic Acid Ethyl Ester
(2c)
Purified by column chromatography (CH2Cl2–hexane, 70:30);
beige solid; mp 118–120 °C.
(E)-3-(4-Methoxyphenyl)-2-(3-methylbenzofuran-2-carbon-
yl)acrylonitrile (2g)
Purified by column chromatography (CH2Cl2–heptane, 80:20); or-
ange solid; mp 102.7–104.6 °C.
IR (KBr): 3424, 3087, 3065, 3037, 2985, 2938, 2905, 2225, 1921,
1804, 1720, 1611, 1585, 1548, 1473, 1445, 1396, 1366, 1354, 1281,
1261, 1209, 1136, 1094, 1029, 1014, 973, 904, 826 cm–1.
IR (KBr): 2958, 2838, 2219, 1726, 1650, 1567, 1488, 1465, 1434,
1385, 1363, 1339, 1292, 1260, 1221, 1196, 1176, 1150, 1098, 1048,
977, 940, 902, 872, 787, 746, 725, 683 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.15 (s, 1 H), 8 (d, J = 2.0 Hz, 1
H), 7.9 (dd, J = 2.0, 8.4 Hz, 1 H), 7.7 (d, J = 8.4 Hz, 1 H), 4.4 (q,
J = 7.1 Hz, 2 H), 1.4 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.3 (s, 1 H), 7.7 (m, 3 H), 7.5 (m,
3 H), 7.4 (t, J = 8.1 Hz, 1 H), 7.3 (t, J = 7.1 Hz, 1 H), 7.1 (dd,
J = 1.98, 8.2 Hz, 1 H), 3.9 (s, 3 H), 2.6 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.7, 151.8, 137.5, 133.7, 132.6,
131.3, 131.1, 129.2, 114.7, 104.8, 62.9, 14.0.
13C NMR (100 MHz, CDCl3): d = 177.6, 159.9, 155, 154.3, 146.6,
133.2, 130.1, 129.1, 120.0, 116.2, 114.5, 112.5, 110.2, 55.4, 9.9.
MS (EI, 70 eV): m/z (%) = 273 (12, [M (2 37Cl)]+), 271 (68, [M
(37Cl, 35Cl)]+), 269 (100, [M (2 35Cl)]+), 245 (9), 243 (50) 241 (75),
228 (7), 226 (41), 224 (63), 196 (39), 161 (63), 124 (20), 75 (18), 50
(9), 29 (56).
MS (EI, 70 eV): m/z (%) = 317 (100, [M+]), 302 (19), 286 (69), 274
(10), 251 (11), 210 (18), 159 (57), 103 (29), 77 (37).
HRMS: m/z calcd for C20H15NO3 + Na: 340.0950; found: 340.0943.
HRMS: m/z calcd for C12H935Cl2O2 + Na: 291.9908; found:
291.9901; m/z calcd for C12H935Cl37ClO2 + Na: 293.9879; found:
293.9885.
(E)-2-13C-Cyano-3-phenylacrylic Acid Ethyl Ester (2h)
1H NMR (400 MHz, CDCl3): d = 8.3 (d, J = 13.9 Hz, 1 H), 8 (d,
J = 7.4 Hz, 2 H), 7.5 (m, 3 H), 4.4 (q, J = 7.1 Hz, 2 H), 1.5 (t, J = 7.1
Hz, 3 H).
3-Oxo-2-[1-phenylmeth-(E)-ylidene]butyronitrile (2d)
Purified by column chromatography (CH2Cl2–hexane, 70:30);
white solid; mp 81–82 °C.
13C NMR (100 MHz, CDCl3): d = 162.4, 155, 133.2, 131.4, 131,
129.2, 115.4, 102.9 (d, J = 84 Hz), 62.7, 14.1.
IR (KBr): 3380, 3030, 3008, 2216, 1697, 1586, 1567, 1494, 1450,
1419, 1363, 1317, 1294, 1243, 1200, 1186, 1081, 1026, 980, 960,
761, 687, 637, 561, 547, 522 cm–1.
MS (ESI): m/z = 203 [M + H]+.
MePh2P-Catalyzed Construction of Polyfunctionalized Cyclo-
pentanones; General Procedure
1H NMR (400 MHz, CDCl3): d = 8.25 (s, 1 H), 8 (d, J = 7.3 Hz, 2
H), 7.55 (m, 3 H), 2.66 (s, 3 H).
To a solution of the activated alkyne (1 mmol) and acetone cyano-
hydrin (100 mL, 1.1 mmol) in anhyd toluene (5 mL) was added
diphenylmethylphosphine (37.3 mL, 0.2 mmol) under argon. The
mixture was stirred at r.t. for 12 h, then 4-arylbut-3-yn-2-one (1
mmol, 1 equiv) dissolved in anhyd toluene (5 mL) was added drop-
wise over 5 h (syringe pump, 0.2 equiv/h). After the complete addi-
tion, the mixture was further stirred overnight at r.t. and then
concentrated under reduced pressure. The residue was purified by
flash chromatography on a silica gel column to give the final prod-
uct.
13C NMR (100 MHz, CDCl3): d = 191.11, 153.1, 133.48, 131.39,
131.26, 129.28, 117.18, 109.64, 27.81.
MS (ESI): m/z = 172 [M + H]+
.
4,4-Dimethyl-3-oxo-2-[1-phenylmeth-(E)-ylidene]pentane-
nitrile (2e)
Purified by column chromatography (CH2Cl2–hexane, 50:50); yel-
low solid; mp 69–72 °C.
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1-Acetyl-2-benzylidene-3-oxo-5-phenylcyclopentanecarbo-
nitrile (3d)
1256, 1229, 1179, 1155, 1108, 1077, 1031, 953, 930, 902, 852, 834,
759, 738, 696, 653, 620, 604, 571 cm–1.
Purified by column chromatography (CH2Cl2–hexane, 70:30); col-
orless oil.
1H NMR (400 MHz, CDCl3): d = 7.9 (s, 1 H), 7.6 (m, 2 H), 7.5 (m,
3 H), 7.3 (d, J = 8.7 Hz, 2 H), 6.9 (d, J = 8.7 Hz, 2 H), 3.9 (m, 6 H),
3.1 (dd, J = 3.7, 17.5 Hz, 1 H), 2.9 (dd, J = 7.1, 17.5 Hz, 1 H), 1 (t,
J = 7.2 Hz, 3 H).
IR (film): 3428, 3062, 3032, 2925, 2855, 2240, 1963, 1720, 1619,
1575, 1494, 1450, 1410, 1360, 1312, 1287, 1234, 1180, 1146, 1108,
1080, 1029, 1001, 966, 927, 827, 759, 736, 698, 662, 619, 606 cm–1.
13C NMR (100 MHz, CDCl3): d = 199.3, 166.1, 160, 139.8, 132.9,
132.7, 130.8, 130.1, 129.1, 128.7, 126.2, 115.8, 114.2, 63.1, 56.6,
55.2, 50, 40.4, 13.6.
1H NMR (400 MHz, CDCl3): d = 7.9 (s, 1 H), 7.4 (m, 9 H), 7.3 (dd,
J = 1.8, 5.2 Hz, 2 H), 3.7 (dd, J = 7.2, 12.9 Hz, 1 H), 3.1 (dd,
J = 12.9, 17.6 Hz, 1 H), 2.9 (dd, J = 7.3, 17.6 Hz, 1 H), 2.05 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 375 (61, [M]+), 329 (36), 302 (21), 241
(19), 213 (48), 195 (23), 134 (100), 119 (13), 91 (15).
13C NMR (100 MHz, CDCl3): d = 199, 198.5, 140.12, 134, 132.99,
131.0, 129.9, 129.03, 129.15, 128.07, 107, 62.04, 50.11.
MS (EI, 70 eV): m/z (%) = 315 (13, [M]+), 273 (100), 244 (22), 230
(15), 196 (13), 167 (6), 140 (9), 103 (8), 77 (10), 43 (73).
Acknowledgment
We warmly thank Dr. E. Zekri, E. Leonce, and D. Buisson for ex-
perimental assistance with NMR, IR, and MS measurements.
HRMS: m/z calcd for C21H17NO2 + Na: 338.1157; found: 338.1158.
2-Benzylidene-1-cyano-3-oxo-5-phenylcyclopentanecarboxylic
Acid Ethyl Ester (3e)
Purified by column chromatography (EtOAc–heptane, 75:25), yel-
low oil.
References
(1) (a) Clark, J. H. Chem. Rev. 1980, 80, 429. (b) Gugelchuk,
M. M.; Hart, D. J.; Tsai, Y. M. J. Org. Chem. 1981, 46,
3671. (c) Brunskill, J. S. K.; De, A.; Ewing, D. F. J. Chem.
Soc., Perkin Trans. 1 1978, 629.
IR (film): 3446, 3082, 3003, 2935, 1744, 1729, 1625, 1575, 1493,
1469, 1452, 1404, 1367, 1316, 1264, 1230, 1177, 1108, 933, 909,
853, 779, 762, 694, 649, 623, 604, 546, 524 cm–1.
(2) (a) Yoshimatsu, M.; Yamaguchi, S.; Matsubara, Y. J. Chem.
Soc., Perkin Trans. 1 2001, 2560. (b) Brillon, D.; Sauvé, G.
J. Org. Chem. 1992, 57, 1838.
(3) Padwa, A.; Kline, D. N.; Perumattam, J. Tetrahedron Lett.
1987, 28, 913.
1H NMR (400 MHz, CDCl3): d = 7.9 (s, 1 H), 7.2–7.6 (m, 10 H), 3.9
(m, 3 H), 3.1 (dd, J = 13.6, 17.6 Hz, 1 H), 2.9 (dd, J = 7, 17.6 Hz, 1
H), 1 (t, J = 7.15 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 199.2, 166.05, 139.9, 143.3,
132.84, 132.6, 130.83, 130.15, 129.0, 128.9, 128.7, 127.93, 115.7,
63.2, 56.4, 50.4, 40.2, 13.6.
(4) Ciller, J. A.; Martin, N.; Seoane, C.; Soto, J. L. J. Chem.
Soc., Perkin Trans. 1 1985, 2581.
(5) Yoshimatsu, M.; Timura, Y. J. Org. Chem. 2002, 67, 5678.
(6) (a) Garcia-Garcia, E.; Gil, S.; Andrieux, K.; Desmaële, D.;
Nicolas, V.; Taran, F.; Georgin, D.; Andreux, J. P.; Roux, F.;
Couvreur, P. Cell. Mol. Life Sci. 2005, 62, 1.
MS (EI, 70 eV): m/z (%) = 345 (36, [M]+), 299 (12), 272 (35), 241
(91), 213 (100), 195 (35), 168 (24), 141 (46), 114 (16), 103 (17), 91
(9), 77 (20), 29 (35).
HRMS: m/z calcd for C22H19NO3 +Na: 368.1263; found: 368.1259.
(b) Ryoung Kim, H.; Gil, S.; Andrieux, K.; Nicolas, V.;
Appel, M.; Chacun, H.; Desmaële, D.; Taran, F.; Georgin,
D.; Couvreur, P. Cell. Mol. Life Sci. 2007, 64, 356. (c)Kim,
H. R.; Andrieux, K.; Gil, S.; Taverna, M.; Chacun, H.;
Desmaële, D.; Taran, F.; Georgin, D.; Couvreur, P.
Biomacromolecules 2007, 8, 793. (d) Kim, H. R.; Andrieux,
K.; Chacun, H.; Appel, M.; Desmaële, D.; Taran, F.;
Georgin, D.; Couvreur, P.; Taverna, M. Electrophoresis
2007, 28, 2252.
2-(4-Bromobenzylidene)-1-cyano-3-oxo-5-phenylcyclopentane-
carboxylic Acid Ethyl Ester (3f)
Purified by column chromatography (CH2Cl2–heptane, 80:20), yel-
low oil.
IR (film): 3417, 3091, 3033, 2985, 2930, 2363, 2242, 1888, 1736,
1719, 1618, 1582, 1562, 1543, 1487, 1455, 1402, 1363, 1305, 1264,
1226, 1178, 1152, 1108, 1072, 1050, 1025, 1007, 946, 922, 852,
820, 769, 727, 697, 672, 631, 606, 562, 521 cm–1.
(7) (a) Lecerclé, D.; Sawicki, M.; Taran, F. Org. Lett. 2006, 8,
4283. (b) Gabillet, S.; Lecerclé, D.; Loreau, O.; Dézard, S.;
Gomis, J.-M.; Taran, F. Synthesis 2007, 515. (c) Gabillet,
S.; Lecerclé, D.; Loreau, O.; Carboni, M.; Dézard, S.;
Gomis, J.-M.; Taran, F. Org. Lett. 2007, 9, 3925.
(d) Hanedanian, M.; Loreau, O.; Taran, F.; Mioskowski, C.
Tetrahedron Lett. 2004, 45, 7035. (e) Hanedanian, M.;
Loreau, O.; Sawicki, M.; Taran, F. Tetrah edron 2005, 61,
2287.
(8) Cyanohydrins have been successfully used as a cyanide
source in palladium-catalyzed cyanation reactions, for
example: Sundermeier, M.; Zapf, A.; Beller, M. Angew.
Chem. Int. Ed. 2003, 42, 1661.
1H NMR (400 MHz, CDCl3): d = 7.8 (s, 1 H), 7.6 (d, J = 8.4 Hz, 2
H), 7.4 (m, 5 H), 7.3 (m, 2 H), 3.9 (m, 3 H), 3.1 (dd, J = 13.4, 17.2
Hz, 1 H), 2.9 (dd, J = 7.2, 17.2 Hz, 1 H), 1.1 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 199, 166, 134.5, 134.2, 133.3,
132, 131.6, 131.5, 129.1, 128.9, 127.9, 125.5, 115.4, 63.4, 56.3,
50.4, 13.6.
MS (EI, 70 eV): m/z (%) = 425 (33, [M (81Br)]+), 423 (34, [M
(79Br) ]+), 379 (17), 377 (16), 352 (35), 350 (35), 321 (77), 319 (77),
293 (60), 291 (60), 270 (13), 243 (11), 229 (41), 212 (100), 202
(16), 167 (13), 139 (24), 104 (37), 78 (27), 29 (55).
(9) (a) Zhu, J.-L.; Ko, Y.-C.; Kuo, C.-W.; Shia, K.-S. Synlett
2007, 1274. (b) Kreher, U. P.; Rosamilia, A. E.; Raston,
C. L.; Scott, J. L.; Strauss, C. R. Org. Lett. 2003, 5, 3107.
(10) Carr, G.; Whittaker, D. J. Chem. Soc., Perkin Trans. 2 1989,
359.
1-Cyano-2-(4-methoxybenzylidene)-3-oxo-5-phenylcyclopen-
tanecarboxylic Acid Ethyl Ester (3g)
Purified by column chromatography (CH2Cl2–heptane, 80:20); yel-
low oil.
IR (film): 3548, 3059, 2961, 2934, 2872, 2840, 2242, 2099, 1889,
1728, 1664, 1621, 1577, 1516, 1494, 1463, 1448, 1391, 1367, 1293,
Synthesis 2009, No. 14, 2365–2370 © Thieme Stuttgart · New York