Highly stereoselective dimerization of 3-alkoxyimino-2-aryl-alkylnitriles via oxidative carbon-carbon bond formation

Article abstract of DOI:10.1055/s-0029-1217369

The MnO₂-mediated oxidative dimerization of a series of 3-alkoxyimino-2-aryl-alkylnitriles was investigated. The developed method stereospecifically afforded solely the corresponding C₂-symmetric dl-dimers, with the trans-configurati

Full text of DOI:10.1055/s-0029-1217369

LETTER
1835
Highly Stereoselective Dimerization of 3-Alkoxyimino-2-aryl-alkylnitriles via
Oxidative Carbon–Carbon Bond Formation
Stereoselective
D
im
u
erization of
n
3-Alkoxyim
f
ino-2-ar
e
yl-alkylnitr
i
iles Du,* Yongliang Zhang, Songqing Wang, Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27890968; E-mail: kangzhao@tju.edu.cn
Received 16 March 2009
CN R'
CN CN
R'
[O]
Abstract: The MnO2-mediated oxidative dimerization of a series of
+
Ph
Ph
Ph
Ph
3-alkoxyimino-2-aryl-alkylnitriles was investigated. The developed
method stereospecifically afforded solely the corresponding C2-
symmetric dl-dimers, with the trans-configuration of the C=N dou-
ble bonds, in good to excellent yields under mild conditions. The
alkoxyimino substituents in the substrates and a thermodynamically
controlled mechanism are proposed to be essential for the stereo-
selectivity of this radical dimerization process.
Ph
CN
R' CN
dl
R' R'
meso
achiral
Scheme 1
reaction intrigued us enough to further explore its oxida-
tive condition and stereoselectivity as well as its scope
and generality.
Key words: MnO2, oxidative dimerization, 3-alkoxyimino-2-aryl-
alkylnitriles, dl-dimers, stereoselectivity
We began our investigation with 1a, a mixture of trans
and cis-isomers (trans/cis = 4.7:1), as the model substrate
with which to screen various readily available oxidants
(Scheme 2). It was found that, in addition to K3Fe(CN)6,
MnO2 and Ag2O could also efficiently convert 1a into its
homodimer, while the other oxidants were either unreac-
tive or inefficient for this transformation (see Table 1).
Based on the experimental results, compound 1a in all
cases was found to give solely the dl-isomer rather than a
mixture of dl- and meso-isomers; a distinct feature always
observed for such homocoupling reactions. We finally se-
lected the convenient oxidant MnO2 to transform a series
of 3-alkoximino-2-aryl-alkylnitriles into their corre-
sponding homocoupled dimers.
Oxidative homocoupling of a-substituted benzylcyanides
can result in carbon–carbon bond formation between the
two identical sp3-hybridized benzylic carbon atoms,
which would provide the most straightforward and expe-
dient approach to the synthesis of the substituted 2,3-dia-
rylsuccinonitriles. A large variety of oxidants, for
example tert-butyl peroxide,1 iodine,2 sodium nitrite,3 ox-
ygen,1b H2O2,1b,4 K3Fe(CN)6,3,5 HNO3,6 NiO2,7 KMnO4,3,8
Ag2O,3 PbO2,3 and di-tert-butylhyponitrite9 have been re-
ported for such homocoupling reactions. Generally, these
transformations undergo non-diastereoselective radical
dimerization processes and mixtures of both dl- and meso-
isomers are obtained (Scheme 1). Due to the fact that a
great deal of effort has been devoted to achieving high
diastereoselectivity in many other homocoupling reactions,10
we thought it desirable to realize the stereoselective oxi-
dative dimerization of a-substituted benzylcyanide deriv-
atives. Herein, we report the stereospecific homocoupling
of 3-alkoxyimino-2-aryl-alkylnitriles, a class of highly a-
functionalized benzylcyanides, which affords exclusively
the dl-dimers with no formation of the meso-isomers
(Scheme 1).
OR3
CN
N
R2
R2
NC
R1
oxidant
R1
CH2Cl2
r.t.
R1
N
OR3
CN
R2
R3O
2 dl/trans only
N
1 trans + cis
Scheme 2
We recently reported an efficient and practical FeCl3-
mediated intramolecular cyclization of 3-alkoxyimino-2-
aryl-alkylnitriles that allows the facile preparation of a se-
ries of N-alkoxyindole-3-carbonitriles.11 In an attempt to
elucidate the reaction mechanism, we also applied
K3Fe(CN)6, which is a less potent single-electron oxidant
than FeCl3, to treat substrate 1a, and it was found that the
homodimer of 1a was obtained without any detection of
the cyclized indole products. This oxidative coupling
After optimization,12 the oxidative coupling reaction un-
der study was finally conducted in the presence of four
equivalents of MnO2 in dried CH2Cl2 with stirring at room
temperature. The results shown in Table 2 show that sub-
strates with both electron-withdrawing and electron-
donating groups on the benzene ring could conveniently
furnish the corresponding homodimers in good to excel-
lent yields (84–97%). When the electron-withdrawing
groups were substituted on the benzene ring (entries 4, 5
and 13 in Table 2), the reaction proceeded smoothly to
furnish the coupling dimer in high yields (93–96%) within
shorter periods of time (0.5 h). It is noteworthy that when
SYNLETT 2009, No. 11, pp 1835–1841
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217369; Art ID: W03609ST
© Georg Thieme Verlag Stuttgart · New York

1836
Y. Du et al.
LETTER
Table 1 Oxidants Screened for the Homocoupling of 1aa
OMe
N
CN
MeO
NC
Ar
Entry Oxidant
(equiv)
Solvent
Temp Time Yield
N
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
100
100
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
(h)
(%)b,c
NR
NR
NR
89
Ar
Ar
CN
oxidant
CN
N
1
2
3
4d
5
6
7
8
9
DDQ (1.5)
CH2Cl2
CH2Cl2
MeCN
MeOH
Acetone
AcOH
2
N
OMe
MeO
I2 (2.0)
2
Ar = 2-naphthyl
3
5
dl-4
CAN (2.5)
2
35%
0%
MnO2
Ag2O
52%
92%
86%
K3Fe(CN)6 (2.0)
KMnO4 (1.5)
Cu(OAc)2·H2O (2.0)
0.5
0.5
1
K3Fe(CN)6
e
0%
–
Scheme 3
30
Mn(OAc)3·3H2O (1.5) AcOH
1
20
We finally turned our attention to a possible explanation
for the stereoselectivity of this radical dimerization pro-
cess. Firstly, we wanted to know whether dl-2 could be
converted into a thermodynamic mixture of both dl- and
meso-isomers. The previous report showed that similar
dimerized products of some benzylcyanides a-substituted
with an ester, could display thermal equilibration of the
dl- and meso-diastereoisomers via a radical dissociation–
recombination process.3,14 Surprisingly, it was found that
no new product was generated when each dimerized dl-2
was heated at reflux temperature in toluene over two
hours. However, heating a mixture of equimolar equiva-
lents of dl-2b and dl-2c in toluene at reflux temperature
over 30 min did afford the cross-dimerized dl-9 as the
only heterocoupling product in 38% yield, in addition to
the recovered dl-2b (60%) and dl-2c (59%). Similarly, the
single cross-heterodimer dl-10 was obtained in 35% yield
from dl-2a and dl-2n under identical conditions, with 61%
of dl-2a and 63% of dl-2n recovered (Scheme 4).
NaNO2 (3.0)
PbO2 (2.0)
Ag2O (2.0)
MnO2 (2.0)
MnO2 (3.0)
MnO2 (4.0)
MnO2 (5.0)
AcOH
2
NR
e
AcOH
1
–
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
94
89
92
97
93
11
12
12
13
4
2.5
1
1
a Reaction conditions: 1a (2.0 mmol), oxidant, solvent (30 mL).
b Isolated yield after silica gel chromatography. c NR: no reaction oc-
curred.
d 10% aq NaOH (7 equiv) was added as additive. e Complex mixture,
no desired product detected.
R2 or R3 were bulkier benzyl, phenyl, or long-chained
alkyl groups (entries 3, 7, 8, 11 and 14 in Table 2), the
reaction also furnished the desired product in good yields
(84–92%), at the expense of requiring relatively longer
reaction times (2–3 h).
OMe
OR3
OR3
N
N
N
R2
R2
NC
Ar
NC
Ar
NC
Ar
toluene
reflux
The products were stable solids whose structures were de-
termined by detailed studies of the spectroscopic data. In
all cases, only one single isomer was observed and the
number of signals in the 1H and 13C NMR spectra clearly
established the symmetry of the molecules. The C2-sym-
metry was further established by the X-ray crystal struc-
ture of the coupling product dl-2n (Figure 1).13 The C=N
double bonds in the dimerized products were assigned the
trans-configuration, regardless of the stereochemistry
(trans or cis) of the substrates employed (for the ratios of
the trans and cis isomers, see Table 2).
Ar
CN
Ar
CN
Ar
CN
+
R2
R3O
N
N
N
MeO
MeO
dl-9 (38% yield): Ar = 4-MePh,
2 = n-Pr, R3 = Me
dl-10 (35% yield): Ar = Ph,
2 = Me, R3 = 3,4-dimethoxybenzyl
dl-2c
or dl-2n
dl-2b
R
or dl-2a
R
Scheme 4
Unfortunately, all attempts to separate the other expected
cross-dimers, for example, the heterocoupling dimers
from dl-2a and dl-2b, dl-2e and dl-2k, dl-2h and dl-2k, or
dl-2h and dl-2j as pure products failed, since the three
dimers, i.e., the two starting homodimers and the expected
heterodimer, always coexisted as a mixture in each case.
When a similar substrate 3, structurally differing from
substrate 1 by the naphthalene ring, was treated with
MnO2 under the same reaction conditions, an intramolec-
ular cyclized product 5 was also obtained in a yield of
35%, in addition to the expected coupling dimer dl-4.
However, if either Ag2O or K3Fe(CN)6 was applied as the
oxidant, only the dimerized dl-4 was obtained in yields of
92% and 86%, respectively, with no formation of the cy-
clized 5 in either case (Scheme 3).
Secondly, treating the unsubstituted a-phenyl ketonitrile
11 with MnO2 under the described conditions led to a mix-
ture of dl- and meso-12 in a ratio of 1.2:1, determined by
1H NMR analysis (Scheme 5). This result is in general
agreement with previous observations reported in the lit-
erature on the dimerization of substrate 11 with PbO2.3
Synlett 2009, No. 11, 1835–1841 © Thieme Stuttgart · New York

LETTER
Stereoselective Dimerization of 3-Alkoxyimino-2-aryl-alkylnitriles
1837
a
Table 2 Oxidative Dimerization of 3-Alkoxyimino-2-aryl-alkylnitriles Mediated by MnO2
Entry
Substrate (trans/cis)
Dimer
Yield (%)b
Time (h)
OMe
CN
CN
N
NC
1
97
1
N
OMe
N
(4.7:1)
1a
MeO
dl-2a
dl-2b
OMe
CN
N
NC
2
3
4
5
6
93
92
96
93
94
1
N
CN
OMe
N
(3.9:1)
1b
MeO
NC
OMe
CN
N
n-Pr
n-Pr
1
N
CN
OMe
n-Pr
N
(1.1:1)
1c
MeO
dl-2c
Cl
OMe
CN
N
NC
Cl
0.5
0.5
1.5
N
Cl
CN
OMe
N
(25:1)
1d
MeO
NC
dl-2d
Br
OMe
CN
N
Br
N
Br
CN
OMe
N
(4.8:1)
1e
MeO
dl-2e
MeO
OMe
CN
OMe
N
MeO
MeO
NC
OMe
N
CN
OMe
N
MeO
(5.2:1)
1f
MeO
NC
dl-2f
OMe
N
Ph
CN
OMe
OMe
MeO
MeO
Ph
MeO
7
92
2
N
CN
OMe
OMe
N
MeO
(6.3:1)
1g
Ph
dl-2g
Synlett 2009, No. 11, 1835–1841 © Thieme Stuttgart · New York

1838
Y. Du et al.
LETTER
Table 2 Oxidative Dimerization of 3-Alkoxyimino-2-aryl-alkylnitriles Mediated by MnO2a (continued)
Entry
Substrate (trans/cis)
Dimer
Yield (%)b
Time (h)
OMe
CN
OMe
OMe
N
Ph
MeO
Ph
NC
MeO
8
84
3
N
MeO
CN
OMe
Ph
N
MeO
(7.2:1)
1h
MeO
dl-2h
OMe
CN
N
NC
MeO
OMe
9
96
1.5
N
MeO
CN
OMe
N
(5:1)
1i
MeO
NC
dl-2i
OMe
CN
MeO
MeO
MeO
OMe
OMe
OMe
N
MeO
MeO
N
10
11
12
13
14
87
91
90
94
91
1.5
OMe
CN
OMe
N
(5.5:1)
1j
MeO
NC
dl-2j
On-Bu
CN
N
MeO
OMe
2
N
MeO
CN
On-Bu
N
(4.1:1)
1k
n-BuO
dl-2k
OMe
CN
CN
OMe
N
MeO
NC
2
N
OMe
N
MeO
(5.6:1)
1l
MeO
dl-2l
OMe
CN
CN
Cl
N
Cl
NC
0.5
N
OMe
N
Cl
(19:1)
1m
MeO
dl-2m
ODMB
CN
CN
N
N
NC
2
ODMB
N
(4:1)
1n
DMB
dl-2nc
a Reaction conditions: MnO2 (4.0 equiv), r.t., CH2Cl2.
b Isolated yield after silica gel chromatography.
c DMB refers to 3,4-dimethoxybenzyl group.
Synlett 2009, No. 11, 1835–1841 © Thieme Stuttgart · New York

LETTER
Stereoselective Dimerization of 3-Alkoxyimino-2-aryl-alkylnitriles
1839
These experimental observations prompted us to conclude
that the alkoxyimino substituent in substrate 1 should play
an important role in the stereoselective formation of single
dl-dimers and that the stereospecific dimerization should
follow a thermodynamically controlled, rather than an ox-
idant-mediated dynamically controlled pathway.
Alternatively, we tentatively propose that the presence of
the alkoxyimino substituent in substrate 1 might be par-
tially responsible for the stereochemistry of this radical
coupling reaction. Moreover, the weak π–π stacking inter-
action (concluded from the X-ray data) between the two
aryl groups could direct the predominant Re-face (or Si-
face) approach of the radical intermediate A. The forma-
tion of the most preferable transition-state B should then
be responsible for this highly substrate-controlled dia-
stereoselective dimerization process (Scheme 7).
R2
OR3
CN
CN
*
Ar
Ar
N
N
MnO2
N
dl-2
Ar
OR3
1
OR3
R2
R2
NC
A
B
Scheme 7
In conclusion, a class of highly a-substituted benzyl-
cyanides that could undergo oxidative dimerization to
generate the 2,3-diarylsuccinonitriles with complete dias-
tereoselectivity under mild and efficient conditions has
been discovered.15–21 Further studies on the application of
the obtained dl-dimers in organic synthesis are currently
under investigation in our lab.
Figure 1 X-ray crystal structure of dl-2n
O
NC
Ph
CN
Ph
CN
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
NC
Ph
MnO2
+
Ph
CN
Ph
CH2Cl2
O
O
O
O
Acknowledgment
11
meso-12
dl-12
We acknowledge the National Natural Science Foundation of China
(#20802048) and Cultivation Foundation (B) for New Faculty of
Tianjin University (#5110109) for financial support. We also thank
Miss Xiling Zhao, University of California, San Diego, for revising
our English text.
85% (dl/meso = 1.2:1, determined by 1H NMR)
Scheme 5
Furthermore, a mixture of equimolar amounts of 12 (dl +
meso) and dl-2n, upon being refluxed in toluene for 30
min, afforded the cross-dimerized product dl-13 as a sole
heterodimer in 25% yield, together with 68% of 12 (dl +
meso) and 72% of recovered dl-2n (Scheme 6).
References and Notes
(1) (a) Huang, R. L.; Kum-Tatt, L. J. Chem. Soc. 1954, 2570.
(b) Kharasch, M. S.; Sosnowsky, G. Tetrahedron 1958, 3,
105. (c) Frenette, M.; Aliaga, C.; Font-Sanchis, E.; Scaiano,
J. C. Org. Lett. 2004, 6, 2579.
(2) (a) Chalanay, L.; Knoevenagel, E. Chem. Ber. 1892, 25,
297. (b) Villemin, D.; Alloum, A. B. Synth. Commun. 1992,
22, 3169.
(3) De Jongh, H. A. P.; De Jonge, C. R. H. I.; Mijs, W. J. J. Org.
Chem. 1971, 36, 3160; and references cited therein.
(4) Barber, H. J.; Slack, R. J. Chem. Soc. 1944, 612.
(5) Hartzler, H. D. J. Org. Chem. 1966, 31, 2654.
(6) Hitomi, S.; Hideki, K.; Takuji, O. Bull. Chem. Soc. Jpn.
1988, 61, 501.
ODMB
N
NC
toluene
Ph
Ph
CN
(dl + meso) + dl-2n
12
reflux
O
DMB = 3,4-dimethoxybenzyl
dl-13
31%
Scheme 6
Synlett 2009, No. 11, 1835–1841 © Thieme Stuttgart · New York

1840
Y. Du et al.
LETTER
After cooling to room temperature, the mixture was
evaporated to remove the solvent. The residue was passed
through silica gel column using a mixture of PE and EtOAc
as eluent, to give the heterodimerized dl-9. Unreacted dl-2b
and dl-2c were also recovered.
(7) Yin, Z.; Zhang, Z.; Kadow, J. F.; Meanwell, N. A.; Wang, T.
J. Org. Chem. 2004, 69, 1364.
(8) (a) Kaiser, E. M. J. Am. Chem. Soc. 1967, 89, 3659.
(b) Mieczyslaw, M.; Krzysztof, S. Tetrahedron 1998, 54,
8797.
(9) Protasiewicz, J.; Mendenhall, G. D. J. Org. Chem. 1985, 50,
3220.
(18) Substrates 1a, 1c, 1d, 1f and 1m were synthesized and
characterized in our previous work (see reference 11). The
others substrates were characterized as follows: (1b) White
solid; mp 55–57 °C; 1H NMR (500 MHz, CDCl3): d(trans) =
7.29–7.18 (m, 4 H), 4.70 (s, 1 H), 3.93 (s, 3 H), 2.36 (s, 3 H),
1.77 (s, 3 H); d(cis) = 7.29–7.18 (m, 4 H), 5.78 (s, 1 H), 3.93
(s, 3 H), 2.36 (s, 3 H), 1.91 (s, 3 H); HRMS (ESI): m/z [M +
H+] calcd for C12H15N2O: 203.1179; found: 203.1180. (1e)
White solid; mp 74–75 °C; 1H NMR (500 MHz, CDCl3):
d(trans) = 7.55–7.52 (m, 2 H), 7.30–7.26 (m, 2 H), 4.70 (s,
1 H), 3.93 (s, 3 H), 1.78 (s, 3 H); d(cis) = 7.55–7.52 (m, 2 H),
7.30–7.26 (m, 2 H), 5.77 (s, 1 H), 3.94 (s, 3 H), 1.92 (s, 3 H);
HRMS (ESI): m/z [M + H+] calcd for C11H12BrN2O:
267.0128; found: 267.0112. (1g) White solid; mp 86–87 °C;
1H NMR (500 MHz, CDCl3): d(trans) = 7.25–6.54 (m, 8 H),
4.51 (s, 1 H), 4.04 (s, 3 H), 4.00 (d, J = 14.5 Hz, 1 H), 3.87
(s, 3 H), 3.82 (s, 3 H), 3.19 (d, J = 15 Hz, 1 H); d(cis) = 7.25–
6.54 (m, 8 H), 5.54 (s, 1 H), 4.01 (s, 3 H), 3.85 (s, 3 H), 3.71
(s, 3 H), 3.58 (d, J = 6 Hz, 2 H); HRMS (ESI): m/z [M + H+]
calcd for C19H21N2O3: 325.1547; found: 325.1555. (1h)
White solid; mp 101–102 °C; 1H NMR (500 MHz, CDCl3):
d(trans) = 7.52–6.76 (m, 8 H), 6.10 (s, 1 H), 4.11 (s, 3 H),
3.87 (s, 3 H), 3.84 (s, 3 H); d(cis) = 7.52–6.76 (m, 8 H), 4.98
(s, 1 H), 3.95 (s, 3 H), 3.87 (s, 3 H), 3.80 (s, 3 H); HRMS
(ESI): m/z [M + H+] calcd for C18H19N2O3: 311.1390; found:
311.1397. (1i) White solid: mp 80–81 °C; 1H NMR (500
MHz, CDCl3): d(trans) = 7.32–7.28 (m, 2 H), 6.93–6.90 (m,
2 H), 4.68 (s, 1 H), 3.93 (s, 3 H), 3.81 (s, 3 H), 1.77 (s, 3 H);
d(cis) = 7.32–7.28 (m, 2 H), 6.93–6.90 (m, 2 H), 5.75 (s,
1 H), 3.94 (s, 3 H), 3.81 (s, 3 H), 1.92 (s, 3 H). HRMS (ESI):
m/z [M + H+] calcd for C12H15N2O2: 219.1128; found:
219.1135. (1j) White solid; mp 89–90 °C; 1H NMR (500
MHz, CDCl3): d(trans) = 6.59 (s, 2 H), 4.67 (s, 1 H), 3.96 (s,
3 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 1.82 (s, 3 H); d(cis) = 6.59
(s, 2 H), 5.77 (s, 1 H), 3.97 (s, 3 H), 3.87 (s, 3 H), 3.85 (s,
3 H), 1.94 (s, 3 H); HRMS (ESI): m/z [M + H+] calcd for
C14H19N2O4: 279.1339; found: 279.1345. (1k) Colorless oil;
1H NMR (400 MHz, CDCl3): d(trans) = 7.31–7.29 (d, 2 H),
6.93–6.89 (m, 2 H), 4.68 (s, 1 H), 4.13 (t, J = 8.0 Hz, 2 H),
3.80 (s, 3 H), 1.78 (s, 3 H), 1.70–1.63 (m, 2 H), 1.44–1.26 (m
2 H), 0.95 (t, J = 9.0, 3 H); d(cis) = 7.31–7.29 (d, 2 H), 6.93–
6.89 (m, 2 H), 5.77 (s, 1 H), 4.13 (t, J = 8.0 Hz, 2 H), 3.80 (s,
3 H), 1.91 (s, 3 H), 1.70–1.63 (m, 2 H), 1.44–1.26 (m, 2 H),
0.95 (t, J = 9.0 Hz, 3 H); HRMS (ESI): m/z [M + H+] calcd
for C15H21N2O2: 261.1598; found: 261.1610. (1n) White
solid: mp 54–56 °C; 1H NMR (500 MHz, CDCl3): d(trans) =
7.38–7.34 (m, 5 H), 6.95–6.85 (m, 3 H), 5.11 (s, 2 H), 4.73
(s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 1.81 (s, 3 H); d(cis) =
7.38–7.34 (m 5 H), 6.95–6.85 (m, 3 H), 5.83 (s, 1 H), 5.10 (s,
2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 1.93 (s, 3 H); HRMS (ESI):
m/z [M + H+] calcd for C19H21N2O3: 325.1547; found:
325.1553.
(10) (a) Arai, S.; Takita, S.; Nishida, A. Eur. J. Org. Chem. 2005,
5262. (b) Barrero, A. F.; Quilez del Moral, J. F. E.; Sánchez,
M.; Arteaga, J. F. Org. Lett. 2006, 8, 669. (c) Kozlowski,
M. C.; DiVirgilio, E. S.; Malolanarasimhan, K.; Mulrooney,
C. A. Tetrahedron: Asymmetry 2005, 16, 3599. (d) Clerici,
A.; Pastori, N.; Porta, O. J. Org. Chem. 2005, 70, 4174.
(e) Matsumura, Y.; Nishimura, M.; Hiu, H.; Watanabe, M.;
Kise, N. J. Org. Chem. 1996, 61, 2809. (f) Nguyen, P. Q.;
Schäfer, H. J. Org. Lett. 2001, 3, 2993. (g) Mazzega, M.;
Fabris, F.; Cossu, S.; Lucchi, O. D.; Lucchini, V.; Valle, G.
Tetrahedron 1999, 55, 4427. (h) Gansauer, A.; Bauer, D.
J. Org. Chem. 1998, 63, 2070. (i) Hirao, T.; Asahara, M.;
Muguruma, Y.; Ogawa, A. J. Org. Chem. 1998, 63, 2812.
(j) Takenaka, N.; Xia, G.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 3198. (k) Bagal, S. K.; Adlington, R. M.;
Baldwin, J. E.; Marquez, R. J. Org. Chem. 2004, 69, 9100.
(11) Du, Y.; Chang, J.; Reiner, J.; Zhao, K. J. Org. Chem. 2008,
73, 2007.
(12) (a) CaH2-dried EtOAc, THF and MeCN were also tested as
solvents, but were not superior to CH2Cl2. (b) An excess of
MnO2 (4 equiv) was used for a complete conversion of 1a
into dimerized dl-2a within a shorter period of time (1 h)
although two equivalents of MnO2 was enough for the total
consumption of 1a.
(13) Compound dl-2n: Crystallized in the monoclinic space
group P2 (1) with cell dimensions: a = 8.0723 (11) Å,
b = 26.531 (4) Å, c = 16.356 (2) Å, a = 90°, b = 92.325 (2)°,
g = 90°, V = 3499.9 (8) Å3, Dc = 1.227 g/cm3, Z = 2. CCDC:
712678.
(14) De Jongh, H. A. P.; De Jonge, C. R. H. I.; Sinnige, H. J. M.;
De Klein, W. J.; Huysmans, W. G. B.; Mijs, W. J.; Van Den
Hoek, W. J.; Smidt, J. J. Org. Chem. 1972, 37, 1960.
(15) General Procedure for the Synthesis of the
Homocoupling Dimers dl-2: To a solution of 3-
alkoxyimino-2-aryl-alkylnitriles 1 (4 mmol) in CH2Cl2 (30
mL) was added, in one portion, the dried MnO2 (16 mmol)
powder with stirring at room temperature. TLC was used to
monitor the reaction process until the total consumption of 1
was observed. The insoluble materials were removed via
filtration and the filtrate was evaporated in vacuum to
remove the solvent. The residue was then purified by flash
silica gel chromatography, using a mixture of petroleum
ether (PE) and EtOAc as eluent, to afford the desired
homodimers 2. The synthesis of 12 (dl + meso) from 11 was
conducted under similar reaction conditions.
(16) Procedures for the Synthesis of dl-4 and 5: Case 1: When
either MnO2 or Ag2O was used as the oxidant, the reactions
were conducted following the procedure described for the
synthesis of dimers dl-2. Case 2: When K3Fe(CN)6 was used
as the oxidant: A mixture of 3 (5 mmol), K3Fe(CN)6 (20
mmol), and aq 10% NaOH (35 mmol) in MeOH (20 mL)
was stirred at r.t. for 0.5 h. The reaction mixture was then
extracted with EtOAc (3 × 20 mL) and the combined organic
layer, after drying over anhydrous Na2SO4, was evaporated
to remove the solvent. The residue was purified by silica gel
column to give the homodimerized dl-4 in 86% yield, with
no separation of 5.
(19) (dl-2a) White solid; mp 185–186 °C; 1H NMR (400 MHz,
CDCl3): d = 7.36–7.33 (m, 1 H), 7.23 (d, J = 7.5 Hz, 2 H),
7.13 (d, J = 7.5 Hz, 2 H), 4.06 (s, 3 H), 1.91 (s, 3 H). 13
C
NMR (125 MHz, CDCl3): d = 150.1, 131.8, 129.8, 129.7,
128.3, 118.0, 62.8, 59.8, 14.1; HRMS (ESI): m/z [M + Na+]
calcd for C22H22N4NaO2: 397.1635; found: 397.1639. (dl-
2b) White solid; mp 144–146 °C; 1H NMR (500 MHz,
CDCl3): d = 7.06–7.00 (m, 4 H), 4.04 (s, 3 H), 2.33 (s, 3 H),
1.90 (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 150.4, 139.7,
129.8, 129.0, 128.8, 118.2, 62.7, 59.6, 21.3, 14.1; HRMS
(17) General Procedure for the Synthesis of Heterodimerized
dl-Dimers: A mixture of dl-2b (0.30 mmol) and dl-2c (0.30
mmol) in toluene (20 mL) was stirred at reflux for 30 min.
Synlett 2009, No. 11, 1835–1841 © Thieme Stuttgart · New York

LETTER
Stereoselective Dimerization of 3-Alkoxyimino-2-aryl-alkylnitriles
1841
(ESI): m/z [M + Na+] calcd for C24H26N4NaO2: 425.1948;
calcd for C24H26N4NaO4: 457.1846; found: 457.1852. (dl-2l)
White solid; mp 142–143 °C; 1H NMR (500 MHz, CDCl3):
d = 7.33–7.30 (t, 1 H), 7.19–7.16 (t, 2 H), 7.05–6.99 (m,
4 H), 6.88 (d, J = 8.0 Hz, 1 H), 5.79 (d, J = 12 Hz), 5.10 (d,
found: 425.1953. (dl-2c) White solid; mp 176–177 °C; 1H
NMR (500 MHz, CDCl3): d = 7.05–7.01 (t, 4 H), 4.04 (s,
3 H), 2.54–2.48 (m, 1 H), 2.34 (s, 3 H), 1.83–1.74 (m, 2 H),
1.69–1.61 (m, 1 H), 0.88 (t, J = 7.0 Hz, 3 H); 13C NMR (125
MHz, CDCl3): d = 153.4, 139.6, 130.0, 129.1, 128.9, 118.1,
62.6, 59.0, 31.9, 21.3, 19.6, 14.8; HRMS (ESI): m/z [M +
Na+] calcd for C28H34N4NaO2: 481.2574; found: 481.2577.
(dl-2d) White solid; mp 143–144 °C; 1H NMR (500 MHz,
CDCl3): d = 7.27 (d, J = 11.5 Hz, 2 H), 7.09 (d, J = 11.5 Hz,
2 H), 4.05 (s, 3 H), 1.90 (s, 3 H); 13C NMR (125 MHz,
CDCl3): d = 149.8, 136.4, 131.2, 130.1, 128.7, 117.5, 62.9,
59.2, 14.1; HRMS (ESI): m/z [M + Na+] calcd for
J = 12.5 Hz), 3.93 (s, 3 H), 3.89 (s, 3 H), 1.85 (s, 3 H); 13
C
NMR (125 MHz, CDCl3): d = 150.8, 148.9, 131.3, 130.5,
129.6, 129.5, 128.0, 121.4, 117.9, 112.0, 111.0, 59.8, 56.0,
55.9, 14.3; HRMS (ESI): m/z [M + Na+] calcd for
C38H38N4NaO6: 669.2684; found: 669.2689. (dl-2m) White
solid; mp 163–164 °C; 1H NMR (500 MHz, CDCl3): d =
7.39 (d, J = 7.5 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.11 (d,
J = 4.5 Hz, 1 H), 4.06 (s, 3 H), 1.93 (s, 3 H); 13C NMR (125
MHz, CDCl3): d = 149.4, 134.7, 133.6, 130.3, 130.0, 129.7,
127.7, 117.2, 62.9, 59.4, 14.2; HRMS (ESI): m/z [M + Na+]
calcd for C22H20Cl2N4NaO2: 465.0856; found: 465.0862.
(dl-2n) White solid; mp 142–143 °C; 1H NMR (500 MHz,
CDCl3): d = 7.33–7.30 (t, 1 H), 7.19–7.16 (t, 2 H), 7.05–6.99
(m, 4 H), 6.88 (d, J = 8.0 Hz, 1 H), 5.79 (d, J = 12 Hz), 5.10
(d, J = 12.5 Hz, 1 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 1.85 (s,
3 H); 13C NMR (125 MHz, CDCl3): d = 150.8, 148.9, 131.3,
130.5, 129.6, 129.5, 128.0, 121.4, 117.9, 112.0, 111.0, 76.7,
59.8, 56.0, 55.9, 14.3; HRMS (ESI): m/z [M + Na+] calcd for
C38H38N4NaO6: 669.2684; found: 669.2689.
C22H20Cl2N4NaO2: 465.0856; found: 465.0861. (dl-2e)
White solid; mp 160–161 °C; 1H NMR (500 MHz, CDCl3):
d = 7.43 (d, J = 8.5 Hz, 2 H), 7.03 (d, J = 8.5Hz, 2 H), 4.05
(s, 3 H), 1.90 (s, 3 H); 13C NMR (125 MHz, CDCl3): d =
149.7, 131.7, 131.4, 130.6, 124.7, 117.4, 62.9, 59.3, 14.1;
HRMS (ESI): m/z [M + Na+] calcd for C22H20Br2N4NaO2:
552.9845; found: 552.9850. (dl-2f) White solid; mp 186–
187 °C; 1H NMR (500 MHz, CDCl3): d = 6.77 (s, 2 H), 6.61
(s, 1 H), 4.05 (s, 3 H), 3.88 (s, 3 H), 3.67 (s, 3 H), 1.94 (s,
3 H); 13C NMR (125 MHz, CDCl3): d = 150.2, 149.7, 148.1,
123.8, 122.3, 118.0, 112.8, 110.2, 62.5, 59.5, 55.9, 55.7,
13.9; HRMS (ESI): m/z [M + Na+] calcd for C26H30N4NaO6:
517.2058; found: 517.2065. (dl-2g) White solid; mp 189–
190 °C; 1H NMR (500 MHz, CDCl3): d = 7.26 (d, J = 7.5 Hz,
2 H), 7.19–7.11 (m, 3 H), 6.70–6.60 (m, 3 H), 3.94 (s, 3 H),
3.93 (d, J = 14.0 Hz, 1 H), 3.85 (s, 3 H), 3.62 (s, 3 H), 3.47
(d, J = 14.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3): d =
151.6, 149.9, 148.1, 135.7, 129.6, 128.2, 126.5, 124.0,
122.8, 118.1, 113.2, 110.3, 62.7, 59.7, 56.1, 55.9, 35.2;
HRMS (ESI): m/z [M + Na+] calcd for C38H38N4NaO6:
669.2684; found: 669.2689. (dl-2h) White solid; mp 198–
199 °C; 1H NMR (500 MHz, CDCl3): d = 7.36–7.29 (m,
3 H), 6.84–6.82 (m, 5 H), 4.14 (s, 3 H), 3.90 (s, 3 H), 3.69
(s, 3 H); 13C NMR (125 MHz, CDCl3): d = 152.0, 150.2,
148.2, 131.9, 129.8, 128.4, 128.3, 123.5, 118.0, 113.7,
110.5, 63.4, 61.4, 56.2, 55.9; HRMS (ESI): m/z [M + Na+]
calcd for C36H34N4NaO6: 641.2371; found: 641.2377. (dl-2i)
White solid; mp 146–147 °C; 1H NMR (500 MHz, CDCl3):
d = 7.05 (d, J = 8.5 Hz, 2 H), 6.78 (d, J = 9.0 Hz, 2 H), 4.04
(s, 3 H), 3.80 (s, 3 H), 1.91 (s, 3 H); 13C NMR (125 MHz,
CDCl3): d = 160.5, 150.4, 131.2, 123.5, 118.3, 113.6, 62.7,
59.5, 55.5, 14.1; HRMS (ESI): m/z [M + Na+] calcd for
C24H26N4NaO4: 457.1852; found: 457.1854. (dl-2j) White
solid; mp 180–182 °C; 1H NMR (500 MHz, CDCl3): d =
6.42 (s, 1 H), 4.05 (s, 3 H), 3.84 (s, 3 H), 3.71 (s, 6 H), 1.97
(s, 3 H); 13C NMR (125 MHz, CDCl3): d = 152.7, 150.2,
138.9, 127.1, 118.1, 107.1, 62.8, 61.1, 60.1, 56.3, 14.2;
HRMS (ESI): m/z [M + Na+] calcd for C28H34N4NaO8:
577.2269; found: 577.2273. (dl-2k) White solid; mp 67–
70 °C; 1H NMR (500 MHz, CDCl3): d = 7.04 (d, J = 8.0 Hz,
2 H), 6.77 (d, J = 9.0 Hz, 2 H), 4.27–4.19 (m, 2 H), 3.79 (s,
3 H), 1.91 (s, 3 H), 1.76 (quin, J = 7.0 Hz, 2 H), 1.45 (sext,
J = 7.5 Hz, 2 H), 1.00 (t, J = 7.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3): d = 160.5, 149.9, 131.2, 123.8, 118.4, 113.6,
74.6, 59.6, 55.5, 31.8, 19.2, 14.2, 14.1; HRMS (ESI): m/z [M
+ Na+] calcd for C30H38N4NaO4: 541.2785; found: 541.2792.
(dl-2l) White solid; mp 101–102 °C; 1H NMR (500 MHz,
CDCl3): d = 9.18 (t, J = 8.0 Hz, 1 H), 6.89 (dd, J = 8.0, 2.5
Hz, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.65 (s, 1 H), 4.05 (s,
3 H), 3.64 (s, 3 H), 1.93 (s, 3 H); 13C NMR (125 MHz,
CDCl3): d = 159.3, 150.1, 133.3, 129.3, 121.9, 118.0, 115.9,
115.1, 62.8, 59.7, 55.4, 14.1; HRMS (ESI): m/z [M + Na+]
(20) (dl-4) White solid; mp 202–204 °C; 1H NMR (500 MHz,
CDCl3): d = 7.80 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.5 Hz,
1 H), 7.59–7.50 (m, 3 H), 7.44–7.41 (m, 1 H), 7.20–7.18 (t,
1 H), 4.14 (s, 3 H), 1.98 (s, 3 H); 13C NMR (125 MHz,
CDCl3): d = 150.3, 133.5, 132.5, 130.3, 129.1, 128.9, 128.0,
127.6, 127.6, 126.8, 126.3, 118.1, 62.9, 60.0, 14.3; HRMS
(ESI): m/z [M + Na+] calcd for C30H26N4NaO2: 497.1948;
found: 497.1949.(5) White solid; mp 100–101 °C; 1H NMR
(500 MHz, CDCl3): d = 8.51 (d, J = 8.5 Hz, 1 H), 7.95 (d,
J = 8.0 Hz, 1 H), 7.70–7.61 (m, 3 H), 7.54–7.50 (m, 1 H),
4.14 (s, 3 H), 2.70 (s, 3 H). This compound was well
characterized in our previous report (see reference 11).
(21) (dl-9) White solid; mp 166–168 °C; 1H NMR (500 MHz,
CDCl3): d = 7.06–6.99 (m, 8 H), 4.05 (s, 3 H), 4.03 (s, 3 H),
2.54–2.46 (m, 1 H), 2.34 (s, 6 H), 1.90 (s, 3 H), 1.84–1.78
(m, 1 H), 1.76–1.62 (m, 2 H), 0.88 (t, J = 7.5 Hz, 3 H); 13
C
NMR (125 MHz, CDCl3): d = 153.4, 150.4, 139.7, 139.6,
130.0, 129.9, 129.8, 129.0, 128.9, 128.9, 128.8, 118.3,
118.0, 62.7, 62.6, 59.5, 59.1, 31.9, 21.3, 19.6, 19.5, 14.8,
14.1; HRMS (ESI): m/z [M + Na+] calcd for C26H30N4NaO2:
453.2261; found: 453.2268. (dl-10) White solid; mp 126–
129 °C; 1H NMR (500 MHz, CDCl3): d = 7.35–7.31 (m,
2 H), 7.24–7.17 (m, 4 H), 7.07–7.03 (m, 5 H), 6.90 (d,
J = 8.0 Hz, 1 H), 5.21 (q, 2 H), 3.93–3.92 (t, 9 H, 3 × OMe),
1.95 (s, 3 H), 1.78 (s, 3 H); 13C NMR (125 MHz, CDCl3):
d = 151.1, 149.7, 149.1, 131.9, 131.5, 131.0, 129.8, 129.7,
129.6, 128.3, 128.2, 121.7, 118.1, 118.0, 112.4, 111.3, 77.0,
62.6, 59.9, 59.8, 56.2, 56.2, 14.6, 13.0; HRMS (ESI):
m/z [M + Na+] calcd for C30H30N4NaO4: 533.2159; found:
533.2165.(12) White solid; mp 161–162 °C; 1H NMR (500
MHz, CDCl3): d(dl) = 7.46–7.33 (m, 3 H), 7.03–7.01 (q,
2 H), 2.47 (s, 3 H); d(meso) = 7.46–7.33 (m, 5 H), 2.31 (s,
3 H). For previous characterization of this compound, see
reference 3. (dl-13) White solid; mp 139–141 °C; 1H NMR
(500 MHz, CDCl3): d = 7.42–7.23 (m, 7 H), 7.10 (d, J = 7.5
Hz, 2 H), 6.70–6.96 (t, 4 H), 6.91 (d, J = 7.5 Hz, 1 H); 13
C
NMR (125 MHz, CDCl3): d = 196.3, 151.4, 149.3, 149.2,
130.9, 130.3, 130.1, 129.9, 129.5, 129.4, 128.9, 128.5,
128.2, 120.9, 118.1, 117.3, 111.5, 111.2, 77.0, 64.4, 60.0,
56.2, 56.2, 28.4 (CH3), 14.5 (CH3); HRMS (ESI): m/z [M +
Na+] calcd for C29H27N3NaO4: 504.1894; found: 504.1899.
Synlett 2009, No. 11, 1835–1841 © Thieme Stuttgart · New York