Four-component reaction of N -sulfonylimines, (cyanomethylene) triphenylphosphorane, nitromethane, and formaldehyde for the synthesis of 3-substituted 2-methylene-4-nitrobutanenitriles

Article abstract of DOI:10.1021/jo200483n

An efficient four-component synthesis of 3-substituted 2-methylene-4- nitrobutanenitriles has been developed from N-sulfonylimines, (cyanomethylene)triphenylphosphorane, nitromethane, and formaldehyde in the absence of catalysts and additives at room temperature.

Full text of DOI:10.1021/jo200483n

NOTE
pubs.acs.org/joc
Four-Component Reaction of N-Sulfonylimines,
(Cyanomethylene)triphenylphosphorane, Nitromethane,
and Formaldehyde for the Synthesis of 3-Substituted
2-Methylene-4-nitrobutanenitriles
Yin-Huan Jin, Fan Fang, Xiang Zhang, Qing-Zhou Liu, Hao-Bo Wang, and Shi-Kai Tian*
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China
S Supporting Information
b
ABSTRACT: An efficient four-component synthesis of 3-substituted
2-methylene-4-nitrobutanenitriles has been developed from N-sulfonyli-
mines, (cyanomethylene)triphenylphosphorane, nitromethane, and for-
maldehyde in the absence of catalysts and additives at room temperature.
ulticomponent reactions are very powerful for the con-
struction of complex organic molecules by transforming in
according to the following reaction pathway (Scheme 1). Initial
addition of (cyanomethylene)triphenylphosphorane to N-sulfo-
nylimine 1 results in the formation of betaine 4, which undergoes
rapid proton transfer to give phosphonium ylide 5.5c,7 Elimina-
tion of the sulfonamide group from phosphonium ylide 5 results
in the formation of vinylphosphonium salt 6. Nitromethane is
sufficiently acidic to be deprotonated by the resulting sulfonam-
ide anion and subsequently undergoes Michael addition to
vinylphosphonium salt 6 to give phosphonium ylide 3. Assuming
that phosphonium ylide 3 could undergo the Wittig reaction with
formaldehyde, we envisioned a four-component reaction of N-
sulfonylimines, (cyanomethylene)triphenylphosphorane, nitro-
methane, and formaldehyde leading to 3-substituted 2-methy-
lene-4-nitrobutanenitriles 7, RauhutꢀCurrier-type products that
have not been accessed so far by the corresponding reaction of
nitroalkenes with acryl nitrile.8,9
In continuation of our exploration of new multicomponent
reactions,2d,10 we carried out the following experiments to test
our hypothesis. The mixture of N-sulfonylimine 1aa and (cyano-
methylene)triphenylphosphorane in nitromethane was stirred at
room temperature for 5 min, after which time formalin was
added. The resulting mixture was stirred for 8 h, and 2-methy-
lene-4-nitro-3-phenylbutanenitrile (7a) was obtained in 92%
yield (Table 1, entry 1). Encouraged by this result, we evaluated
a number of N-sulfonyl groups on the imine nitrogen atom in the
four-component reaction (Table 1, entries 2ꢀ6). In general, the
employment of an arenesulfonyl group led to a better yield than
that of an alkanesulfonyl group. Nevertheless, the yield was not
improved further.11
M
a one-pot manner three or more starting materials into a single
product that incorporates portions of all the reactants and exhibit
much higher efficiency relative to the sequential synthesis of the
same targets by conventional bimolecular reactions.1 Owing to
their intrinsic step-economy, multicomponent reactions are
greener than multistep bimolecular reactions through the mini-
mization of the amount of solvents and reagents needed for the
reactions and purifications. Hence, there is an increasing demand
for the development of multicomponent reactions, especially
those with four or more components.2,3
In the course of exploring the synthetic utility of carbonꢀnitrogen
bond cleavage,4,5 we developed a new stereoselective alkene synthesis
through the olefination reaction of N-sulfonylimines with phospho-
nium ylides.5 To our surprise, treatment of N-benzylidene-p-toluene-
sulfonamide (1aa) with (cyanomethylene)triphenylphosphorane in
nitromethane at room temperature did not at all result in the for-
mation of R,β-unsaturated nitrile 2a (eq 1). Instead, phosphonium
ylide 3a was obtained in 93% yield after crystallization from ethyl
acetate/petroleum ether (5:1), and another product was identified as
p-toluenesulfonamide. This result is in sharp contrast to the corre-
sponding imine olefination reaction between these two reactants
occurred in many other solvents such as toluene, chloroform, ethyl ace-
tate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl
sulfoxide, and methanol.5c It is clear that the solvent of nitromethane
changes the reaction pathway by acting as a carbon nucleophile.6
A broad range of aromatic, heteroaromatic, and aliphatic N-(p-
toluenesulfonyl)imines smoothly reacted with (cyanomethylene)
triphenylphosphorane, nitromethane, and formaldehyde at room
The efficient three-component synthesis of phosphonium
ylide 3a prompted us to develop a new four-component reaction
Received: March 4, 2011
Published: April 04, 2011
r
2011 American Chemical Society
4163
dx.doi.org/10.1021/jo200483n J. Org. Chem. 2011, 76, 4163–4167
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Proposed Four-Component Reaction of N-Sulfo-
nylimines, (Cyanomethylene)triphenylphosphorane, Nitro-
methane, and Formaldehyde
Scheme 2. Four-Component Reaction of N-Sulfonylimines,
(Cyanomethylene)triphenylphosphorane, Nitromethane,
and Formaldehydea,b
Table 1. Survey of the N-Sulfonyl Groupsa
entry
imine
R
yieldb (%)
1
2
3
4
5
6
1aa
1ab
1ac
1ad
1ae
1af
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
2-O2NC6H4
1-naphthyl
Me
92
90
82
88
90
72
a Reaction conditions: N-sulfonylimine 1a (0.30 mmol), (cyanomethy-
lene)triphenylphosphorane (0.36 mmol), nitromethane (0.30 mL), rt,
5 min; then formaldehyde (0.60 mmol), rt, 8 h. b Isolated yield.
a Reaction conditions: N-sulfonylimine 1aa-oa (0.30 mmol), (cyano-
methylene)triphenylphosphorane (0.36 mmol), nitromethane (0.30 mL),
rt, 5 min; then formaldehyde (37% by mass in water, 0.60 mmol), rt,
temperature to give structurally diverse 3-substituted 2-methy-
lene-4-nitrobutanenitriles 7 in good to excellent yields
(Scheme 2). These RauhutꢀCurrier-type products were char-
acterized by 1H NMR, 13C NMR, IR, and HRMS spectroscopic
analyses, and the structure of product 7f was further confirmed
by single-crystal X-ray analysis (see the Supporting Information).
As demonstrated by the results summarized in Scheme 2,
both electron-withdrawing and electron-donating groups
were successfully introduced into the products by employing
the N-sulfonylimines bearing such groups on the aromatic
rings. Attempts to extend this four-component reaction to an
ester-, an amide-, or a ketone-stabilized phosphonium ylide
were unsuccessful. Moreover, no desired product was ob-
tained from the four-component reaction when nitromethane
and formaldehyde were replaced with nitroethane and ben-
zaldehyde, respectively.
c
6ꢀ30 h. b Isolated yields are shown. The corresponding mixture was
stirred for 30 min before the addition of formaldehyde. d The structure
was confirmed by single-crystal X-ray analysis. e 0.90 mmol of formalde-
hyde was used. f 1.8 mmol of formaldehyde was used.
The four-component reaction with an R,β-unsaturated
N-(p-toluenesulfonyl)imine was found to give a mixture of two
regioisomeric products in moderate yields. For example, the
reaction of N-sulfonylimine 1pa, (cyanomethylene)triphenyl-
phosphorane, nitromethane, and formaldehyde proceeded at
room temperature to afford an inseparable 70:30 mixture of
regioisomers 7pa and 7pb (eq 2). Moreover, the regioselec-
tivity was not enhanced by performing the reaction at lower
temperature.12
In summary, we have developed an unprecedented four-
component synthesis of RauhutꢀCurrier-type products from
readily accessible starting materials through carbonꢀnitrogen
bond cleavage. In the absence of catalysts and additives, the four-
component reaction of N-sulfonylimines, (cyanomethylene)tri-
phenylphosphorane, nitromethane, and formaldehyde proceeds
4164
dx.doi.org/10.1021/jo200483n |J. Org. Chem. 2011, 76, 4163–4167

The Journal of Organic Chemistry
NOTE
smoothly at room temperature to afford structurally diverse
3-substituted 2-methylene-4-nitrobutanenitriles in good to ex-
cellent yields. This study not only adds a useful entry to
increasingly demanding multicomponent reactions but also
significantly extends the synthetic utility of carbonꢀnitrogen
bond cleavage.
13C NMR (75 MHz, CDCl3) δ 135.2, 133.2, 129.9, 129.0, 121.9, 116.5,
76.5, 47.4; IR (film) ν 3055, 2987, 2227, 1620, 1561, 1494, 1376 cmꢀ1
;
HRMS (EI) calcd for C11H9N2O2Cl (M) 236.0353, found 236.0360.
3-(4-Bromophenyl)-2-methylene-4-nitrobutanenitrile (7d):
1
yellowish oil; H NMR (400 MHz, CDCl3) δ 7.58ꢀ7.52 (m, 2H),
7.20ꢀ7.13 (m, 2H), 6.07 (s, 1H), 5.93 (d, J = 0.8 Hz, 1H), 4.92 (dd, J =
13.2, 8.8 Hz, 1H), 4.76 (dd, J = 13.2, 7.2 Hz, 1H), 4.44ꢀ4.37 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 133.7, 133.2, 132.8, 129.2, 123.3, 121.7,
116.4, 76.4, 47.4; IR (film): ν 3023, 2921, 2226, 1621, 1590, 1557, 1490,
1434, 1377 cmꢀ1; HRMS (EI) calcd for C11H9N2O2Br (M) 279.9847,
found 279.9871.
’ EXPERIMENTAL SECTION
1
General Information. H and 13C NMR spectra were recorded
using tetramethylsilane as an internal reference. 31P NMR spectra were
recorded using 85% phosphoric acid as an external reference. Chemical
shifts (δ) and coupling constants (J) were expressed in ppm and Hz,
respectively. Melting points were uncorrected. N-Sulfonylimines and
(cyanomethylene)triphenylphosphorane were prepared according to
known procedures.5
3-(4-Cyanophenyl)-2-methylene-4-nitrobutanenitrile (7e):
yellowish oil; H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz,
1
2H), 7.44 (d, J = 8.4 Hz, 2H), 6.13 (s, 1H), 6.00 (s, 1H), 4.97 (dd, J =
13.2, 8.4 Hz, 1H), 4.82 (dd, J = 13.2, 6.9 Hz, 1H), 4.55ꢀ4.47 (m, 1H);
13C NMR (75 MHz, CDCl3): δ 139.9, 134.0, 133.3, 128.5, 120.9, 118.0,
116.2, 113.1, 76.0, 47.6; IR (film) ν 3023, 2925, 2256, 2232, 1611, 1561,
1508, 1376 cmꢀ1; HRMS (APCI) calcd for C12H10N3O2 (M þ H)þ
228.0773, found 228.0763.
2-Methylene-4-nitro-3-(4-tosyloxyphenyl)butanenitrile (7f):
white solid; mp 98ꢀ100 °C; 1H NMR (400 MHz, CDCl3) δ 7.71ꢀ7.67
(m, 2H), 7.34ꢀ7.30 (m, 2H), 7.24ꢀ7.20 (m, 2H), 7.07ꢀ7.02 (m, 2H),
6.07 (s, 1H), 5.92 (d, J = 0.8 Hz, 1H), 4.90 (dd, J = 13.2, 8.8 Hz, 1H), 4.74
(dd, J = 13.2, 6.8 Hz, 1H), 4.44ꢀ4.38 (m, 1H), 2.46 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 149.9, 145.9, 133.7, 133.3, 132.1, 130.0, 129.0, 128.5,
123.5, 121.7, 116.4, 76.5, 47.3, 21.7; IR (film) ν 3025, 2924, 2226, 1621,
1598, 1557, 1504, 1435, 1376 cmꢀ1; HRMS (EI) calcd for C18H16N2O5S
(M) 372.0780, found 372.0803.
2-Methylene-4-nitro-3-(3-nitrophenyl)butanenitrile (7g):
yellowish oil; 1H NMR (300 MHz, CDCl3) δ 8.30ꢀ8.24 (m, 1H), 8.17
(s, 1H), 7.71ꢀ7.61 (m, 2H), 6.16 (s, 1H), 6.04 (s, 1H), 5.01 (dd, J =
13.5, 8.4 Hz, 1H), 4.87 (dd, J = 13.5, 7.2 Hz, 1H), 4.64ꢀ4.56 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 148.8, 136.8, 134.1, 133.7, 130.8, 124.1,
122.8, 121.0, 116.2, 76.0, 47.3; IR (film) ν 3022, 2925, 2228, 1621, 1562,
1535, 1375, 1352 cmꢀ1; HRMS (ESI) calcd for C11H10N3O4 (M þ H)þ
248.0671, found 248.0667.
3-(2-Methoxyphenyl)-2-methylene-4-nitrobutanenitrile
(7h): yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.38ꢀ7.28 (m, 1H),
7.22ꢀ7.15 (m, 1H), 7.01ꢀ6.89 (m, 2H), 6.04 (s, 1H), 5.91 (s, 1H), 4.94
(dd, J = 14.4, 10.8 Hz, 1H), 4.85ꢀ4.75 (m, 2H), 3.86 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 156.8, 132.8, 130.1, 128.2, 123.1, 121.6, 121.2,
117.1, 111.4, 75.8, 55.5, 42.1; IR (film) ν 3022, 2943, 2842, 2226, 1621,
1601, 1589, 1557, 1494, 1438, 1377 cmꢀ1; HRMS (EI) calcd for
C12H12N2O3 (M) 232.0848, found 232.0872.
Three-Component Synthesis of Phosphonium Ylide 3a. A
mixture of N-sulfonylimine 1aa (259 mg, 1.0 mmol) and (cyanomethy-
lene)triphenylphosphorane (361 mg, 1.2 mmol) in nitromethane (1.0 mL)
was stirred under nitrogen at room temperature for 5 min and con-
centrated. The residue was crystallized from ethyl acetate/petroleum
ether (5:1), and the resulting solid was collected by filtration and dried in
vacuum to give phosphonium ylide 3a (420 mg, 93%) as a yellow solid:
mp 172ꢀ175 °C; 1H NMR (400 MHz, CDCl3) δ 7.63ꢀ7.46 (m, 15H),
7.26ꢀ7.14 (m, 5H), 4.99 (dd, J = 12.0, 9.6 Hz, 1H), 4.64ꢀ4.58 (m, 1H),
3.50ꢀ3.42 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 142.7 (d, J =
1.3 Hz), 133.8, 133.7, 133.0 (d, J = 2.8 Hz), 129.2 (d, J = 12.1 Hz), 128.8,
128.5 (d, J = 14.8 Hz), 127.2, 126.9, 125.2 (d, J = 90.6 Hz), 80.4 (d, J =
7.7 Hz), 41.7 (d, J = 12.7 Hz), 12.9 (d, J = 140.2 Hz); IR (film) ν 2925,
2130, 1599, 1587, 1550, 1482, 1453, 1379 cmꢀ1 31P NMR (127 MHz,
;
CDCl3) δ 25.9; HRMS (EI) calcd for C28H23N2O2P (M) 450.1497,
found 450.1502. Anal. Calcd for C28H23N2O2P: C, 74.66; H, 5.15; N,
6.22. Found: C, 74.94; H, 5.13; N, 6.21.
General Procedure for the Four-Component Reaction of
N-Sulfonylimines, (Cyanomethylene)triphenylphosphorane,
Nitromethane, and Formaldehyde. To nitromethane (0.30 mL)
under nitrogen were added N-sulfonylimine 1aaꢀoa (0.30 mmol) and
(cyanomethylene)triphenylphosphorane (109 mg, 0.36 mmol). The
mixture was stirred at room temperature for 5 min (or 30 min as
specified in Scheme 2). To the resulting mixture was added formalin
(37%, 0.045 mL, 0.60 mmol, or another amount as specified in Scheme 2).
The mixture was stirred at room temperature for 8 h (for 7c and 7l, 6 h; for
7f, 10 h; for 7j, 15 h; for 7n, 18 h; for 7m, 24 h; for 7o, 30 h). The mixture
was purified directly by column chromatography on silica gel, eluting with
petroleum ether/ethyl acetate (8:1 to 3:1), to give compound 7.
3-(2-Chlorophenyl)-2-methylene-4-nitrobutanenitrile (7i):
1
yellowish oil; H NMR (300 MHz, CDCl3) δ 7.50ꢀ7.44 (m, 1H),
2-Methylene-4-nitro-3-phenylbutanenitrile (7a): yellowish
1
7.38ꢀ7.28 (m, 3H), 6.12 (s, 1H), 6.03 (d, J = 0.3 Hz, 1H), 5.08ꢀ4.90
(m, 2H), 4.82 (dd, J = 13.2, 6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 134.2, 132.2, 130.8, 130.2, 128.0, 127.9, 120.5, 116.5, 75.6, 44.0; IR
oil; H NMR (300 MHz, CDCl3) δ 7.45ꢀ7.35 (m, 3H), 7.30ꢀ7.25
(m, 2H), 6.06 (s, 1H), 5.93 (s, 1H), 4.96 (dd, J = 13.2, 9.0 Hz, 1H), 4.79
(dd, J = 13.2, 6.6 Hz, 1H), 4.47ꢀ4.39 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 134.7, 133.0, 129.7, 129.1, 127.6, 122.3, 116.7, 76.8, 48.1; IR
(film) ν 3062, 2923, 2226, 1621, 1593, 1557, 1476, 1435, 1376 cmꢀ1
;
(film) ν 3023, 2925, 2228, 1622, 1602, 1559, 1499, 1455, 1377 cmꢀ1
;
HRMS (EI) calcd for C11H9N2O2Cl (M) 236.0353, found 236.0365.
2-Methylene-3-(1-naphthyl)-4-nitrobutanenitrile (7j): yel-
lowish oil; H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H),
HRMS (EI) calcd for C11H10N2O2 (M) 202.0742, found 202.0738.
1
3-(4-Methoxyphenyl)-2-methylene-4-nitrobutanenitrile
(7b): yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.22ꢀ7.16 (m, 2H),
6.95ꢀ6.88 (m, 2H), 6.02 (s, 1H), 5.89 (s, 1H), 4.92 (dd, J = 13.2, 9.0 Hz,
1H), 4.74 (dd, J = 13.2, 6.9 Hz, 1H), 4.41ꢀ4.33 (m, 1H), 3.80 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 160.0, 132.4, 128.7, 126.4, 122.5, 116.8,
114.9, 76.9, 55.4, 47.3; IR (film) ν 3022, 2963, 2938, 2841, 2228, 1612,
1585, 1560, 1515, 1465, 1377 cmꢀ1; HRMS (EI) calcd for C12H12N2O3
(M) 232.0848, found 232.0860.
7.96ꢀ7.85 (m, 2H), 7.66ꢀ7.40 (m, 4H), 6.13 (s, 1H), 6.02 (s, 1H), 5.34
(dd, J = 9.0, 5.7 Hz, 1H), 5.07 (dd, J = 13.5, 9.3 Hz, 1H), 4.91 (dd, J =
13.5, 5.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 134.3, 133.5, 130.7,
130.2, 129.8, 129.6, 127.5, 126.5, 125.5, 124.8, 121.9, 116.8, 76.5, 42.9;
IR (film): ν 3055, 2920, 2225, 1620, 1598, 1557, 1512, 1435, 1376 cmꢀ1
;
HRMS (EI) calcd for C15H12N2O2 (M) 252.0899, found 252.0916.
3-(2-Furyl)-2-methylene-4-nitrobutanenitrile (7k): yellow-
1
3-(4-Chlorophenyl)-2-methylene-4-nitrobutanenitrile (7c):
yellowish oil; H NMR (300 MHz, CDCl3) δ 7.45ꢀ7.38 (m, 2H),
ish oil; H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 1.2 Hz, 1H),
1
6.40ꢀ6.37 (m, 1H), 6.33 (d, J = 3.3 Hz, 1H), 6.12 (s, 1H), 5.98 (s, 1H),
4.94ꢀ4.79 (m, 2H), 4.60ꢀ4.52 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 147.4, 143.6, 134.5, 119.7, 116.2, 111.0, 108.9, 75.0, 42.4; IR (film) ν
7.30ꢀ7.21 (m, 2H), 6.09 (s, 1H), 5.95 (d, J = 0.6 Hz, 1H), 4.95 (dd, J =
13.2, 8.7 Hz, 1H), 4.78 (dd, J = 13.2, 6.9 Hz, 1H), 4.48ꢀ4.40 (m, 1H);
4165
dx.doi.org/10.1021/jo200483n |J. Org. Chem. 2011, 76, 4163–4167

The Journal of Organic Chemistry
NOTE
3059, 2924, 2228, 1622, 1565, 1556, 1504, 1433, 1376 cmꢀ1; HRMS
(EI) calcd for C9H8N2O3 (M) 192.0535, found 192.0550.
’ ACKNOWLEDGMENT
We are grateful for the financial support from the National
Natural Science Foundation of China (20972147 and 20732006),
the National Basic Research Program of China (973 Program
2010CB833300), and the Chinese Academy of Sciences.
2-Methylene-4-nitro-3-(2-thienyl)butanenitrile (7l): yel-
lowish oil; 1H NMR (300 MHz, CDCl3) δ 7.35ꢀ7.30 (m, 1H),
7.05ꢀ7.00 (m, 2H), 6.08 (s, 1H), 5.99 (s, 1H), 4.93 (dd, J = 13.2, 9.0
Hz, 1H), 4.82 (dd, J = 13.2, 6.3 Hz, 1H), 4.71 (dd, J = 9.0, 6.3 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 136.5, 133.5, 127.8, 126.4, 121.9, 116.2,
77.0, 43.6; IR (film) ν 3022, 2229, 1622, 1561, 1432, 1377 cmꢀ1; HRMS
(EI) calcd for C9H8N2O2S (M) 208.0306, found 208.0331.
’ REFERENCES
(1) For recent reviews, see: (a) Ganem, B. Acc. Chem. Res. 2009,
42, 463–472. (b) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006,
39, 451–463. (c) D€omling, A. Chem. Rev. 2006, 106, 17–89.(d) Multi-
component Reactions; Zhu, J., Bienaymꢀe, H., Eds.; Wiley-VCH:
Weinheim, 2005. (e) Ramꢀon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005,
44, 1602–1634.
2-Methylene-3-(nitromethyl)nonanenitrile (7m): yellowish
oil; 1H NMR (400 MHz, CDCl3) δ 6.02 (s, 1H), 5.88 (d, J = 0.4 Hz,
1H), 4.52ꢀ4.42 (m, 2H), 3.15ꢀ3.07 (m, 1H), 1.64ꢀ1.50 (m, 2H),
1.40ꢀ1.25 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 134.0, 122.1, 116.0, 77.8, 43.9, 31.5, 30.1, 28.8, 26.6, 22.6,
14.1; IR (film) ν 2930, 2225, 1623, 1556, 1463, 1434, 1379 cmꢀ1
;
(2) For recent examples of the reactions with four different
components, see: (a) Song, W.; Lei, M.; Shen, Y.; Cai, S.; Lu, W.; Lu,
P.; Wang, Y. Adv. Synth. Catal. 2010, 352, 2432–2436. (b) Husmann, R.;
Na, Y. S.; Bolm, C.; Chang, S. Chem. Commun. 2010, 46, 5494–5496.
(c) Kielland, N.; Catti, F.; Bello, D.; Isambert, N.; Soteras, I.; Luque, F. J.;
Lavilla, R. Chem.—Eur. J. 2010, 16, 7904–7915. (d) Yang, B.-L.; Weng,
Z.-T.; Yang, S.-J.; Tian, S.-K. Chem.—Eur. J. 2010, 16, 718–723.
(e) Matiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010, 75, 1674–1683.
(f) Song, W.; Lu, W.; Wang, J.; Lu, P.; Wang, Y. J. Org. Chem. 2010,
75, 3481–3483. (g) Sun, J.; Xia, E.-Y.; Wu, Q.; Yan, C.-G. Org. Lett. 2010,
12, 3678–3681. (h) Ramazani, A.; Rezaei, A. Org. Lett. 2010,
12, 2852–2855. (i) Borisov, R. S.; Polyakov, A. I.; Medvedeva, L. A.;
Khrustalev, V. N.; Guranova, N. I.; Voskressensky, L. G. Org. Lett. 2010,
12, 3894–3897. (j) Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.;
Hajishaabanha, F. Tetrahedron 2010, 66, 4040–4042. (k) Alizadeh, A.;
Rezvanian, A.; Zhu, L.-G. Tetrahedron 2010, 66, 6924–6927. (l) Sun, J.;
Xia, E.-Y.; Wu, Q.; Yan, C.-G. Tetrahedron 2010, 66, 7794–7798.
(m) Sridharan, V.; Maiti, S.; Menꢀendez, J. C. Chem.—Eur. J. 2009,
15, 4565–4572. (n) Yan, C. G.; Wang, Q. F.; Song, X. K.; Sun, J.
J. Org. Chem. 2009, 74, 710–718. (o) Mumford, P. M.; Tarver, G. J.;
Shipman, M. J. Org. Chem. 2009, 74, 3573–3575. (p) Yoo, E. J.; Park,
S. H.; Lee, S. H.; Chang, S. Org. Lett. 2009, 11, 1155–1158. (q) Airiau, E.;
Girard, N.; Mann, A.; Salvadori, J.; Taddei, M. Org. Lett. 2009,
11, 5314–5317. (r) Han, F.; Ge, Z.; Cheng, T.; Li, R. Synlett
2009, 648–650. (s) Nagarajan, A. S.; Reddy, B. S. R. Synlett
2009, 2002–2004. (t) Zhang, X.; Zhang, N.; Guo, X.; Yang, L.; Hu,
W. Tetrahedron 2009, 65, 8277–8282. (u) Shaabani, A.; Seyyedhamzeh,
M.; Maleki, A.; Behnam, M.; Rezazadeh, F. Tetrahedron Lett. 2009,
50, 2911–2913. (v) Zhou, H.; Jin, H.; Ye, S.; He, X.; Wu, J. Tetrahedron
Lett. 2009, 50, 4616–4618.
(3) For recent examples of the reactions with five or more different
components, see: (a) Brauch, S.; Gabriel, L.; Westermann, B. Chem.
Commun. 2010, 46, 3387–3389. (b) Al-Tel, T. H.; Al-Qawasmeh, R. A.;
Voelter, W. Eur. J. Org. Chem. 2010, 5586–5593. (c) Bararjanian, M.;
Balalaie, S.; Rominger, F.; Movassagh, B.; Bijanzadeh, H. R. J. Org. Chem.
2010, 75, 2806–2812. (d) Marcaccini, S.; Neo, A. G.; Marcos, C. F.
J. Org. Chem. 2009, 74, 6888–6890.
(4) (a) Liu, C.-R.; Yang, F.-L.; Jin, Y.-Z.; Ma, X.-T.; Cheng, D.-J.; Li,
N.; Tian, S.-K. Org. Lett. 2010, 12, 3832–3835. (b) Yang, B.-L.; Tian, S.-
K. Chem. Commun. 2010, 46, 6180–6182. (c) Liu, C.-R.; Li, M.-B.; Yang,
C.-F.; Tian, S.-K. Chem.ꢀEur. J. 2009, 15, 793–797. (d) Liu, C.-R.; Li,
M.-B.; Cheng, D.-J.; Yang, C.-F.; Tian, S.-K. Org. Lett. 2009,
11, 2543–2545. (e) Liu, C.-R.; Li, M.-B.; Yang, C.-F.; Tian, S.-K. Chem.
Commun. 2008, 1249–1251.
HRMS (ESI) calcd for C11H19N2O2 (M þ H)þ 211.1447, found
211.1436.
2-Methylene-3-(nitromethyl)-5-phenylpentanenitrile (7n):
1
yellowish oil; H NMR (300 MHz, CDCl3) δ 7.28ꢀ7.05 (m, 5H),
6.00 (s, 1H), 5.80 (s, 1H), 4.48ꢀ4.32 (m, 2H), 3.10ꢀ3.00 (m, 1H),
2.75ꢀ2.62 (m, 1H), 2.56ꢀ2.43 (m, 1H), 1.92ꢀ1.74 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 139.7, 134.8, 128.9, 128.4, 126.7, 121.7, 115.9, 77.7,
43.2, 32.7, 31.6; IR (film) ν 3026, 2928, 2225, 1621, 1604, 1557, 1497,
1455, 1379 cmꢀ1; HRMS (EI) calcd for C13H14N2O2 (M) 230.1055,
found 230.1051.
3-Cyclohexyl-2-methylene-4-nitrobutanenitrile (7o): yel-
lowish oil; 1H NMR (300 MHz, CDCl3) δ 6.02 (s, 1H), 5.81 (s, 1H),
4.65 (dd, J = 12.6, 4.5 Hz, 1H), 4.50 (dd, J = 12.6, 11.1 Hz, 1H),
2.94ꢀ2.82 (m, 1H), 1.84ꢀ1.50 (m, 6H), 1.36ꢀ0.96 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 134.5, 121.6, 116.5, 76.4, 49.7, 38.1, 30.8, 30.4, 29.8,
26.0, 25.9; IR (film) ν 3022, 2931, 2855, 2225, 1622, 1555, 1450,
1379 cmꢀ1; HRMS (EI) calcd for C11H16N2O2 (M) 208.1212, found
208.1221.
Four-Component Reaction of r,β-Unsaturated N-Sulfo-
nylimine 1pa, (Cyanomethylene)triphenylphosphorane, Ni-
tromethane, and Formaldehyde. To nitromethane (0.30 mL)
under nitrogen were added N-sulfonylimine 1pa (85.5 mg, 0.30 mmol),
and (cyanomethylene)triphenylphosphorane (109 mg, 0.36 mmol).
The mixture was stirred at room temperature for 30 min. To the
resulting mixture was added formalin (37%, 0.045 mL, 0.60 mmol).
The mixture was stirred at room temperature for 36 h and purified
directly by column chromatography on silica gel, eluting with petroleum
ether/ethyl acetate (5:1), to give an inseparable 70:30 mixture of
regioisomers 7pa and 7pb (32.0 mg, 47%) as a yellowish oil. Major
isomer 7pa: 1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.20 (m, 5H), 6.65
(d, J = 16.0 Hz, 1H), 6.07 (dd, J = 16.0, 8.0 Hz, 1H), 6.08 (s, 1H), 5.98
(d, J = 1.2 Hz, 1H), 4.72 (dd, J = 12.8, 8.4 Hz, 1H), 4.63 (dd, J = 12.8, 6.8
Hz, 1H), 4.03ꢀ3.96 (m, 1H). Minor isomer 7pb: 1H NMR (400 MHz,
CDCl3): δ 7.42ꢀ7.20 (m, 5H), 6.32 (dd, J = 15.6, 8.0 Hz, 1H), 6.13
(d, J = 15.6 Hz, 1H), 5.92 (s, 1H), 5.82 (s, 1H), 4.69 (d, J = 7.2 Hz, 2H),
4.36ꢀ4.29 (m, 1H); HRMS (EI) calcd for C13H12N2O2 (M) 228.0899,
found 228.0924.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
(5) (a) Dong, D.-J.; Li, H.-H.; Tian, S.-K. J. Am. Chem. Soc. 2010,
132, 5018–5020. (b) Dong, D.-J.; Li, Y.; Wang, J.-Q.; Tian, S.-K. Chem.
Commun. 2011, 47, 2158–2160. (c) Fang, F.; Li, Y.; Tian, S.-K. Eur. J.
Org. Chem. 2011, 1084–1091.
spectra for products and crystal data of compound 7f. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(6) For comparison, the corresponding Wittig reaction of benzalde-
hyde with (cyanomethylene)triphenylphosphorane was carried out in
nitromethane at room temperature for 16 h. This reaction afforded R,
β-unsaturated nitrile 2a (85% yield, 20:80 Z/E) rather than phospho-
nium ylide 3a. This result suggests a different reaction pathway from that
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tiansk@ustc.edu.cn.
4166
dx.doi.org/10.1021/jo200483n |J. Org. Chem. 2011, 76, 4163–4167

The Journal of Organic Chemistry
NOTE
for the reaction with an N-sulfonyl imine. For recent mechanistic studies
on the Wittig reaction, see: Robiette, R.; Richardson, J.; Aggarwal, V. K.;
Harvey, J. N. J. Am. Chem. Soc. 2006, 128, 2394–2409.
(7) For examples on the addition of ester-stabilized phosphonium
ylides to N-Boc imines, see: Zhang, Y.; Liu, Y.-K.; Kang, T.-R.; Hu, Z.-K.;
Chen, Y.-C. J. Am. Chem. Soc. 2008, 130, 2456–2457.
(8) For a review, see: Aroyan, C. E.; Dermenci, A.; Miller, S. J.
Tetrahedron 2009, 65, 4069–4084.
(9) To our knowledge, they have also not been accessed by other
methods.
(10) (a) Li, H.-H.; Jin, Y.-H.; Wang, J.-Q.; Tian, S.-K. Org. Biomol.
Chem. 2009, 7, 3219–3221. (b) Liu, D.-N.; Tian, S.-K. Chem.ꢀEur. J.
2009, 15, 4538–4542. (c) Li, H.-H.; Dong, D.-J.; Tian, S.-K. Eur. J. Org.
Chem. 2008, 3623–3626. (d) Yang, B.-L.; Tian, S.-K. Eur. J. Org. Chem.
2007, 4646–4650. (e) Song, Q.-Y.; Yang, B.-L.; Tian, S.-K. J. Org. Chem.
2007, 72, 5407–5410.
(11) Product 7a was obtained in 20% yield when N-sulfonylimine
1aa was replaced with PhCHdNPMP (PMP = 4-methoxyphenyl) in the
four-component reaction. The mixture of PhCHdNPMP and (cyano-
methylene)triphenylphosphorane in nitromethane was stirred at room
temperature for 1.5 h before the addition of formaldehyde.
(12) A 63:37 mixture of regioisomers 7pa and 7pb was obtained in
51% yield from the four-component reaction carried out at 0 °C.
4167
dx.doi.org/10.1021/jo200483n |J. Org. Chem. 2011, 76, 4163–4167