A highly stereoselective knoevenagel reaction of N-tosylimines with active methylene compounds in DMSO

Article abstract of DOI:10.1246/cl.2008.1218

In the presence of molecular sieves (MS) 4A in dimethyl sulfoxide (DMSO), a highly stereoselective Knoevenagel reaction of various N-tosylimines with active methylene compounds proceeded smoothly, producing the corresponding Knoevenagel products in high to excellent yields. Copyright

Full text of DOI:10.1246/cl.2008.1218

1218
Chemistry Letters Vol.37, No.12 (2008)
A Highly Stereoselective Knoevenagel Reaction of N-Tosylimines
with Active Methylene Compounds in DMSO
Ryoichi Chiba and Takeshi OriyamaÃ
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received September 18, 2008; CL-080895; E-mail: tor@mx.ibaraki.ac.jp)
In the presence of molecular sieves (MS) 4A in dimethyl
Table 1. Optimization of the reaction conditionsa
sulfoxide (DMSO), a highly stereoselective Knoevenagel reac-
tion of various N-tosylimines with active methylene compounds
proceeded smoothly, producing the corresponding Knoevenagel
products in high to excellent yields.
P(O)(OEt)2
NTs
MS 4A
NC
P(O)(OEt)2
+
DMSO / r t / 2 h
Ph
Ph
CN
Entry
Solvent
Yield/%b
1
2
3
4
DMSO
DMF
MeCN
MeOH
THF
96
92
12
87
5
N-Sulfonyl imines are versatile intermediates in organic
synthesis, they can undergo various reactions such as the
Mannich reactions,1 hetero-Diels–Alder reactions,2 coupling
reactions,3 and the aza-Morita–Baylis–Hillman reaction.4,5 The
Knoevenagel reaction has been widely employed for carbon–
carbon bond formation6 and is generally carried out with carbon-
yl compounds and active methylene compounds having two
electron-withdrawing groups in the presence of a base or a Lewis
acid.7 Moreover, the chemistry of N-sulfonylimine with active
methylene compounds has been established. Zajac et al. have re-
ported that Knoevenagel reaction of N-benzylidenebenzenesul-
fonamide proceeded only in those cases where the active meth-
ylene compound possessed a cyano group.8 Shen and Jiang have
reported a base-catalyzed reaction of phosphonate as an active
methylene compound with N-sulfonylimines,9 and this reaction
differs from the Horner–Wadsworth–Emmons olefination in that
the elimination of phosphonate moiety does not occur. However,
these cases involve some substrate limitations. Hence, a versatile
method in which a wide range of nucleophiles can be employed
was needed.
Recently, we reported a catalyst-free trifluoromethylation of
carbonyl compounds with TMSCF3 in dimethyl sulfoxide
(DMSO)10 and a catalyst-free Henry reaction in DMSO.11 In
contrast to the known methods, these reactions do not need addi-
tional catalysts, demonstrating that the ideal method leading to
the development of a new benign reaction without utilizing cat-
alyst is direct and highly efficient.12 The previous experimental
results encouraged us to investigate the Knoevenagel reaction
of N-sulfonylimine with active methylene compounds involving
elimination of sulfonamide in DMSO. Here we report that the
Knoevenagel reaction of N-tosylimine with active methylene
compounds having various functional groups under the influence
of molecular sieves (MS) 4A in DMSO proceeds smoothly in a
highly stereoselective manner.
5
6
7
8c
9d
CH2Cl2
Hexane
DMSO
DMSO
0
71
96
90
aAll reactions were carried out in a solvent (2 mL) using
an imine (0.3 mmol) and diethyl cyanomethylphospho-
nate (0.33 mmol) in the presence of MS 4A (50 mg).
bIsolated yield of purified product. DMSO (1 mL) was
c
used. dDMSO (0.5 mL) was used.
Table 2. Synthesis of (E)-vinylphosphonate from various aro-
matic iminesa
P(O)(OEt)2
CN
NPG
MS 4A
NC
P(O)(OEt)2
+
Ar
DMSO / r t
Ar
Time
/h
Yield
/%b
NRd
NRd
96
Entry
Ar
PG
E:Zc
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
PMP
Ts
Ts
Ts
Ts
Ts
Ts
Ts
2
2
2
2
1
1
18
2
—
—
100:0
100:0
100:0
100:0
100:0
92:8
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-NO2C6H4
1-Naphthyl
2-Naphthyl
94
100
94
83
95
96
2
100:0
aAll reactions were carried out in DMSO (1 mL) using an
imine (0.3 mmol) and diethyl cyanomethylphosphonate
(0.33 mmol) in the presence of MS 4A (50 mg). bIsolated
yield of purified product. cThe ratio of stereoisomers was de-
termined by 1H NMR analysis. dNR indicated no reaction oc-
curred.
We first examined the reaction of N-benzylidene-p-toluene-
sulfonamide with 1.1 molar equivalents of diethyl cyanomethyl-
phosphonate in the presence of MS 4A in various solvents
(Table 1, Entries 1–7). We found that DMSO was the most suit-
able solvent for this reaction and afforded the desired product in
a 96% yield (Entry 1). Acetonitrile, THF, and dichloromethane
were not effective for the present reaction (Entries 3, 5, and 6). A
screening of the amount of DMSO showed that 1 mL of DMSO
was enough to promote the desired reaction (Entry 8).
The reaction was conducted with various aromatic imines as
summarized in Table 2. For imines derived from aniline and p-
anisidine, no reaction occurred (Entries 1 and 2). On the other
hand, N-tosylimines derived from aromatic aldehydes with elec-
tron-donating and electron-withdrawing substituents readily re-
Copyright ꢀ 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.12 (2008)
Table 3. Knoevenagel reaction of N-tosylimines with various active methylene compoundsa
1219
EWG1
NTs
EWG1
EWG2
MS 4A
Ar
+
EWG2
DMSO / r t
Ar
Entry
Ar
EWG1
EWG2
Time/h
Yield/%b,c
E:Zd
1
2
3
4
5
6
7e
8f
9f
Ph
4-MeOC6H4
4-BrC6H4
Ph
4-MeOC6H4
4-BrC6H4
Ph
CO2Et
CO2Et
CO2Et
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO2Me
CO2Et
CO2Me
2.5
2.5
2
2
2
2
24
24
24
85 (91)
94 (88)
95 (90)
85 (84)
95 (93)
93 (78)
88 (0)
85 (0)
76
100:0
100:0
100:0
—
—
—
94:6
96:4
100:0
P(O)(OMe)2
P(O)(OEt)2
SO2Ph
Ph
Ph
aAll reactions were carried out in DMSO (1 mL) using an imine (0.3 mmol) and nucleophile (0.33 mmol) in the presence of MS
4A (50 mg). bIsolated yield of purified product. cFigures in parentheses are yields in the case of reactions carried out without MS
d
f
4A. The ratio of stereoisomers was determined by 1H NMR analysis. eYield was determined by 1H NMR analysis. Reaction
was carried out in DMSO (2 mL) using 1.2 molar equivalents of the nucleophile (0.36 mmol) in the presence of MS 4A (150 mg).
acted with diethyl cyanomethylphosphonate to afford the corre-
sponding (E)-ꢀ-cyanovinylphosphonates in excellent yields,
without any of the Z isomer (Entries 3–7). Although we similarly
performed the reaction of the imine derived from 1-naphthalde-
hyde, the stereoselectivity was slightly lower (E:Z = 92:8,
Entry 8). In contrast to these results, the reaction of benzalde-
hyde in place of N-tosylimine has not occurred under similar
conditions.
In order to determine the scope and limitations of this reac-
tion, we tested various active methylene compounds (Table 3).13
All of the reactions we evaluated with nucleophiles having a cy-
ano group proceeded in a stereospecific manner to yield the cor-
responding (E)-ꢀ-cyano-ꢀ,ꢁ-unsaturated esters (Entries 1–3).
When ethyl cyanoacetate and malononitrile were used as active
methylene compounds, both 4-methoxy- and 4-bromo-substi-
tuted imines reacted more readily than nonsubstituted imine
(Entries 1–6). Furthermore, we performed the reaction with nu-
cleophiles having no cyano group. Although we found that they
could also react without a base such as triethylamine or sodium
hydride, the reaction needed a longer reaction time. Moreover,
the yield and stereoselectivity of the product were somewhat
lower than the others. Increasing the amount of DMSO, MS
4A, and equivalents of nucleophile improved the chemical yield
(Entries 8 and 9). Interestingly, the reactions using active meth-
ylene compounds not possessing cyano group barely proceeded
in the absence of MS 4A (Entries 7 and 8).
tions of Carbon Resources’’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
References and Notes
1
2
3
H. Hagiwara, D. Iijima, B. Z. S. Awen, T. Hoshi, T. Suzuki,
Synlett 2008, 1520.
´
O. G. Manchen˜o, R. G. Arrayas, J. C. Carretero, J. Am. Chem.
Soc. 2004, 126, 456.
Y. Matsuya, K. Hayashi, A. Wada, H. Nemoto, J. Org. Chem.
2008, 73, 1987.
4
5
K. Matsui, S. Takizawa, H. Sasai, Synlett 2006, 761.
For other reactions of N-tosylimines, see: D.-D. Chen, X.-L.
Hou, L.-X. Dai, J. Org. Chem. 2008, 73, 5578; K. Yamada,
Y. Yamamoto, M. Maekawa, T. Akindele, H. Umeki, K.
Tomioka, Org. Lett. 2006, 8, 87.
6
7
8
9
E. Knoevenagel, Ber. 1894, 27, 2345; E. Knoevenagel, Ber.
1896, 29, 172.
W. Lehnert, Tetrahedron Lett. 1970, 11, 4723; J. Han, Y. Xu,
Y. Su, X. She, X. Pan, Catal. Commun. 2008, 9, 2077.
W. W. Zajac, T. R. Walters, J. Buzby, J. Gagnon, M. Labroli,
Synth. Commun. 1994, 24, 427.
Y. Shen, G.-F. Jiang, Synthesis 2000, 99.
10 K. Iwanami, T. Oriyama, Synlett 2006, 112.
11 T. Oriyama, M. Aoyagi, K. Iwanami, Chem. Lett. 2007, 36,
612.
12 For other catalyst-free reactions in DMSO developed by our
group, see: T. Watahiki, M. Matsuzaki, T. Oriyama, Green
Chem. 2003, 5, 82; T. Watahiki, S. Ohba, T. Oriyama, Org.
Lett. 2003, 5, 2679; K. Iwanami, Y. Hinakubo, T. Oriyama,
Tetrahedron Lett. 2005, 46, 5881.
13 Typical experimental procedure is as follows: Diethyl cyano-
methylphosphonate (52 mL, 0.33 mmol) was added to a
solution of N-benzylidene-p-toluenesulfonamide (78.0 mg,
0.30 mmol) in DMSO (1 mL) in the presence of MS 4A
(50 mg) at room temperature under an argon atmosphere. After
stirring for 2 h, the reaction mixture was quenched with satu-
rated NaHCO3. The organic materials were extracted with
EtOAc, washed with brine, and dried over MgSO4. The solvent
was evaporated and (E)-1-cyano-2-phenylvinylphosphonate
(76.8 mg, 96%) was isolated by TLC on silica gel.
In conclusion, we have developed a simple and stereoselec-
tive Knoevenagel reaction using N-tosylimine in DMSO. The
present reaction has the following synthetic advantages: (1) in
contrast to the known methods, this procedure does not need
an additional base or Lewis acid, (2) a wide range of active meth-
ylene compounds with and without cyano groups can be em-
ployed, (3) this method produces high yields with high to excel-
lent stereoselectivities, and (4) the reaction proceeds smoothly
and conveniently.
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘‘Advanced Molecular Transforma-
Published on the web (Advance View) November 1, 2008; doi:10.1246/cl.2008.1218