Baylis-Hillman reactions of N-arylidenediphenylphosphinamides with methyl vinyl ketone, methyl acrylate, and acrylonitrile

Article abstract of DOI:10.1016/S0040-4039(02)00813-4

We have found that in the Baylis-Hillman reactions of N-arylidenediphenylphosphinamides 1 with methyl vinyl ketone (MVK), methyl acrylate or acrylonitrile, the Lewis base and solvent can significantly affect the reaction rate. Using PPh₃ as Lewis base in the reaction of 1 with MVK in DMF, THF or MeCN, the normal Baylis-Hillman adduct 2 was formed in very high yield. In the Baylis-Hillman reaction of 1 with methyl acrylate, the Lewis base Ph₂PMe must be used in order to get a high yield of the Baylis-Hillman adduct 3. On the other hand, for the reaction of N-arylidenediphenylphosphinamides 1 with acrylonitrile, DABCO is the best Lewis base giving the corresponding Baylis-Hillman adducts 4 in high yields.

Full text of DOI:10.1016/S0040-4039(02)00813-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4499–4502
Baylis–Hillman reactions of N-arylidenediphenylphosphinamides
with methyl vinyl ketone, methyl acrylate, and acrylonitrile
Min Shi* and Gui-Ling Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 14 March 2002; revised 18 April 2002; accepted 25 April 2002
Abstract—We have found that in the Baylis–Hillman reactions of N-arylidenediphenylphosphinamides 1 with methyl vinyl ketone
(MVK), methyl acrylate or acrylonitrile, the Lewis base and solvent can significantly affect the reaction rate. Using PPh3 as Lewis
base in the reaction of 1 with MVK in DMF, THF or MeCN, the normal Baylis–Hillman adduct 2 was formed in very high yield.
In the Baylis–Hillman reaction of 1 with methyl acrylate, the Lewis base Ph2PMe must be used in order to get a high yield of the
Baylis–Hillman adduct 3. On the other hand, for the reaction of N-arylidenediphenylphosphinamides 1 with acrylonitrile,
DABCO is the best Lewis base giving the corresponding Baylis–Hillman adducts 4 in high yields. © 2002 Elsevier Science Ltd.
All rights reserved.
Since Baylis and Hillman first reported the reactions of
acetaldehyde with ethyl acrylate and acrylonitrile in the
presence of catalytic amounts of a strong Lewis base
such as 1,4-diazabicyclo[2.2.2]octane (DABCO) in
1972,1 the Baylis–Hillman reaction has made great pro-
gress,1 and now includes a catalytic asymmetric ver-
sion.2 However, in this very simple and useful reaction,
only aldehydes1–3 and N-benzylidene-4-methylbenzene-
sulfonamides4 are in general use as the substrates for
reaction with a,b-unsaturated ketones, nitriles or esters.
Herein, we wish to report an unprecedented Baylis–
Hillman reaction of N-arylidenediphenylphosphin-
amides 1 with methyl vinyl ketone (MVK), methyl
acrylate, and acrylonitrile in the presence of various
Lewis bases.5
MVK were systematically examined first (Scheme 1,
Table 1). We found that the Lewis base and solvent
played very important roles in this reaction. For exam-
ple, using 10 mol% of PPh3 as the Lewis base in DMF
or MeCN, the reaction proceeded very well to give the
normal Baylis–Hillman adduct 2a in 81% and 99%
yields, respectively (Table 1, entries 2 and 4). Using
Ph2PMe as the Lewis base, 2a was produced in a
relatively low yield (76%) under the same conditions
(Table 1, entries 5 and 6). Using PBu3 or PhPMe2 as
the Lewis base, only traces of 2a were produced along
with many unidentified products (Table 1, entries 6 and
7). The well established strong Lewis base, DABCO,
gave a lower yield of 2a under the same conditions as
those used for PPh3 (Table 1, entries 8–11). In
dichloromethane, 2a was obtained in moderate yield
(66%) (Table 1, entry 11). In all these cases, the normal
Baylis–Hillman adduct 2a was formed exclusively.
The promoters and solvents for the Baylis–Hillman
reaction of N-arylidenediphenylphosphinamide 1a with
O
O
Ph2P NH
O
O
10 mol% Lewis base
solvent
+
Ph CH N PPh2
Ph
1a
2a
Scheme 1.
Keywords: N-arylidenediphenylphosphinamide; Lewis base; Baylis–Hillman reaction; methyl vinyl ketone (MVK); methyl acrylate; acrylonitrile.
* Corresponding author. Fax: 86-21-64166128; e-mail: mshi@pub.sioc.ac.cn
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00813-4

4500
M. Shi, G.-L. Zhao / Tetrahedron Letters 43 (2002) 4499–4502
Table 1. Baylis–Hillman reactions of N-benzylidene-
diphenylphosphinamide 1a (1.0 equiv.) with MVK
(1.0 equiv.) in the presence of a Lewis base (10 mol%) at
room temperature
Table 2. Baylis–Hillman reactions of N-arylidene-
diphenylphosphinamide (1.0 equiv.) with MVK in the
presence of PPh3 (10 mol%)
Entry
Ar
Solvent
Time (h)
Yield (%)a, 2
Entry
Lewis base
Solvent
Time (h)
Yield (%)a, 2a
1
2
3
4
5
6
7
8
p-EtC6H4
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4
DMF
DMF
DMF
DMF
DMF
DMF
48
72
48
48
48
4
72
48
48
48
48
36
48
24
48
20
19
76
67
99
60
67
77
90
80
70
99
87
99
99
1
2
PPh3
PPh3
THF
DMF
48
48
52
81
3
4
5
6
7
8
9
10
11
PPh3
PPh3
CH2Cl2
MeCN
MeCN
MeCN
MeCN
THF
DMF
MeCN
CH2Cl2
72
48
72
72
27
99
76
Trace
Trace
30
37
35
Ph2PMe
PhPMe2
PBu3
DABCO
DABCO
DABCO
DABCO
C6H5CHꢀCH DMF
72
p-EtC6H4
p-EtC6H4
p-MeOC6H4
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4
MeCN
THF
MeCN
THF
MeCN
MeCN
MeCN
MeCN
144
144
144
144
9
10
11
12
13
14
15
66
a Isolated yields.
For Baylis–Hillman reactions of other N-aryl-
idenediphenylphosphinamides 1 with MVK using PPh3
as Lewis base under the optimized reaction conditions,
the Baylis–Hillman adducts 2 were obtained in good to
excellent yields (Scheme 2). The results are summarized
in Table 2. For N-arylidenediphenylphosphinamides 1
having an electron-donating group on the phenyl ring,
the corresponding Baylis–Hillman adducts 2b and 2c
were obtained in low yields in DMF (Table 2, entries 1
and 2),6 but in MeCN or THF, 2b and 2c were formed
in 77 and 80% yields (Table 2, entries 8 and 10) or 90
and 70% yields (Table 2, entries 9 and 11), respectively.7
For N-arylidenediphenylphosphinamides 1 having an
electron-withdrawing group on the phenyl ring, the
Baylis–Hillman adducts 2d–h were produced in good
yields (Table 2, entries 3–7, 12–15). In some cases, the
reactions proceeded quantitatively.
a Isolated yields.
For the Baylis–Hillman reactions of other N-aryl-
idenediphenylphosphinamides 1 with methyl acrylate
using Ph2PMe as the Lewis base under the optimized
reaction conditions, the Baylis–Hillman adducts 3 were
obtained in good to excellent yields (Scheme 4). The
results are summarized in Table 4. The aliphatic Baylis–
Hillman adduct 3h was formed in moderate yield
(Table 4, entry 7).
On the other hand, for the reaction of N-aryl-
idenediphenylphosphinamides 1 with acrylonitrile, we
examined many Lewis bases in the same manner as
described above, but we found that only DABCO can
effectively catalyze this reaction to give the correspond-
ing Baylis–Hillman adduct 4 in high yield (Scheme 5,
Table 5). Using Ph2PMe, PhPMe2 or PBu3 as the Lewis
base, the reaction solution immediately became dark in
color giving 4 in lower yields along with many uniden-
tified products.
We also examined the Baylis–Hillman reactions of N-
arylidenediphenylphosphinamides 1 with methyl acryl-
ate in the presence of various Lewis bases (Scheme 3).
Using PPh3 or DABCO as the Lewis base, the reaction
was very sluggish (Table 3, entries 1–7), but we were
pleased to find that using Ph2PMe as the Lewis base in
dichloromethane gave the corresponding Baylis–Hill-
man adduct 3a in 71% yield (Table 3, entry 10).8 It
should be emphasized that when using PBu3 or PhPMe2
as the Lewis base, 3a was obtained only in traces along
with many unidentified products (Table 3, entries 8 and
9).
In conclusion, we have found that in the Baylis–Hill-
man reaction of N-arylidenediphenylphosphinamides 1
with MVK, methyl acrylate or acrylonitrile, the Lewis
base and solvent can significantly affect the reaction.
Using PPh3 as the Lewis base in the reaction of 1 with
MVK in DMF, THF or MeCN, the normal Baylis–
Hillman adduct 2 was formed in very high yields. In the
O
Ph2P NH
O
O
O
10 mol% PPh3
+
Ar CH N PPh2
Ar
DMF, THF or MeCN
1
2
b: Ar= p-EtC6H4, c: Ar= p-MeOC6H4, d: Ar= p-FC6H4, e: Ar= p-ClC6H4,
f: Ar= p-BrC6H4, g: Ar= p-NO2C6H4, h: Ar= C6H5-CH=CH.
Scheme 2.

M. Shi, G.-L. Zhao / Tetrahedron Letters 43 (2002) 4499–4502
4501
O
O
O
Ph2P NH O
Ph
10 mol% Lewis base
solvent
Ph CH N PPh2
+
OMe
OMe
1a
3a
Scheme 3.
Table 3. Baylis–Hillman reactions of N-benzylidene-
diphenylphosphinamide 1a (1.0 equiv.) with methyl
acrylate (1.0 equiv.) in the presence of a Lewis base (10
mol%) at room temperature
Table 4. Baylis–Hillman reactions of N-arylidene-
diphenylphosphinamide (1.0 equiv.) with methyl acrylate
in the presence of Ph2PMe (10 mol%)
Entry
Ar
Time (h)
Yield (%)a, 3
Entry
Lewis base
Solvent
Time (h)
Yield (%)a,
3a
1
2
3
4
5
6
7
p-EtC6H4
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4
C6H5CHꢀCH
96
96
42
48
48
4
50
78
92
50
60
63
40
1
PPh3
DMF
48
Trace
480 (20 days) 12
2
3
4
5
6
7
8
9
10
11
12
13
PPh3
CH2Cl2
THF
DMF
CH2Cl2
MeCN
MeCNb
MeCN
CH2Cl2
CH2Cl2
THF
DABCO
DABCO
DABCO
DABCO
DABCO
PhPMe2
PBu3
Ph2PMe
Ph2PMe
Ph2PMe
Ph2PMe
120
120
120
120
120
72
12
12
Trace
26
58
Trace
Trace
71
42
a Isolated yields.
72
42
in high yield. Efforts are underway to elucidate mecha-
nistic details of this reaction and the key factors
required from the Lewis base for the different sub-
strates for the Baylis–Hillman reactions. Work along
these lines is currently in progress.
42
42
42
39
36
30
MeCN
DMF
a Isolated yields.
b The reaction was carried out at 60°C.
Acknowledgements
Baylis–Hillman reaction of 1 with methyl acrylate, the
Lewis base Ph2PMe must be used in order to give 3 in
high yields. On the other hand, for the reaction of
We thank the State Key Project of Basic Research
(Project 973) (No. G2000048007) and the National
Natural Science Foundation of China for financial sup-
port (20025206). We also thank the Inoue Photochiro-
genesis Project (ERATO, JST) for chemical reagents.
N-arylidenediphenylphosphinamides
nitrile, DABCO is the best Lewis base giving the corre-
1 with acrylo-
sponding Baylis–Hillman adduct 4 as the sole product
O
O
Ph2P NH
O
10 mol% Ph2PMe
CH2Cl2
O
OMe
+
Ar CH N PPh2
Ar
OMe
1
3
b: Ar= p-EtC6H4, c: Ar= p-MeOC6H4, d: Ar= p-FC6H4, e: Ar= p-ClC6H4,
f: Ar= p-BrC6H4, g: Ar= p-NO2C6H4, h: Ar= C6H5-CH=CH.
Scheme 4.
O
Ph2P NH
O
10 mol% Lewis base
DMF
CN
+
CN
Ph CH N PPh2
Ph
1a
4a
Scheme 5.

4502
M. Shi, G.-L. Zhao / Tetrahedron Letters 43 (2002) 4499–4502
Table 5. Baylis–Hillman reactions of N-benzylidenediphenyl-
phosphinamide 1a (1.0 equiv.) with acrylonitrile (1.0 equiv.)
in the presence of a Lewis base (10 mol%) at room temper-
ature
M.; Jiang, J.-K.; Feng, Y.-S. Org. Lett. 2000, 2, 2397; (u)
Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406; (v) Shi,
M.; Jiang, J.-K.; Cui, S.-C.; Feng, Y.-S. J. Chem. Soc.,
Perkin Trans. 1 2001, 390; (w) Shi, M.; Jiang, J.-K.
Tetrahedron 2000, 56, 4793; (x) Shi, M.; Li, C.-Q.; Jiang,
J.-K. J. Chem. Soc., Chem. Commun. 2001, 833.
Entry
Lewis base
Time (h)
Yield (%)a, 4a
3. Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama,
1
2
3
4
5
PPh3
24
24
24
10
24
Trace
80
24
60
50
S. J. Am. Chem. Soc. 1999, 121, 10219.
DABCO
PhPMe2
PBu3
4. (a) Perlmutter, P.; Teo, C. C. Tetrahedron Lett. 1984, 25,
5951; (b) Takagi, M.; Yamamoto, K. Tetrahedron 1991,
47, 8869; (c) Bertenshow, S.; Kahn, M. Tetrahedron Lett.
1989, 30, 2731; (d) Shi, M.; Xu, Y.-M. J. Chem. Soc.,
Chem. Commun. 2001, 1876; (e) Shi, M.; Xu, Y.-M. Eur. J.
Org. Chem. 2002, 696.
Ph2PMe
a Isolated yields.
5. N-Arylidenediphenylphosphinamide
1
was prepared
References
according to the literature: (a) Jennings, W. B.; Lovely, C.
J. Tetrahedron 1991, 47, 5561; (b) Yamada, K.; Harwood,
S. J.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 3504.
1. (a) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. 1972,
2,155,113; Chem. Abstr. 1972, 77, 34174q; Hillman, M. E.
D.; Baylis, A. B. US Patent, 1973, 3,743,669; (b) Morita,
K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815.
6. Typical reaction procedure for the Baylis–Hillman reac-
tion of 1a with MVK: To a Schlenk tube with 1a (76 mg,
0.25 mmol) and triphenylphosphine (13.1 mg, 0.050 mmol)
in DMF (0.5 mL) was added MVK (25.8 mg, 24 mL, 0.30
mmol) under an argon atmosphere and the reaction mix-
ture was stirred for 48 h at room temperature (20°C). The
reaction mixture was washed with water (3×10 mL) and
extracted with dichloromethane (2×10 mL). The organic
layer was dried over anhydrous Na2SO4, the solvent
removed under reduced pressure and the residue purified
by silica gel column chromatography (eluent: EtOAc/
petroleum=1/4) to give 2a (72 mg, 81%) as a colorless
solid.
2. (a) Ciganek, E. Org. React. 1997, 51, 201; (b) Basavaiah,
D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001;
(c) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653; (d) Brzezinski, L. J.; Rafel, S.; Leahy, J. M. J. Am.
Chem. Soc. 1997, 119, 4317; (e) Miyakoshi, T.; Saito, S.
Nippon Kagaku Kaishi 1983, 1623; Chem. Abstr. 1984, 100,
156191g; (f) Marko, I. E.; Giles, P. G.; Hindley, N. J.
Tetrahedron 1997, 53, 1015; (g) Richter, H.; Jung, G.
Tetrahedron Lett. 1998, 39, 2729; (h) Barrett, A. G. M.;
Cook, A. S.; Kamimura, A. J. Chem. Soc., Chem. Com-
mun. 1999, 2533; (i) Kunidig, E. P.; Xu, L. H.; Romanens,
P.; Bernardinelli, G. Tetrahedron Lett. 1993, 34, 7049; (j)
Aggarwal, V.; Mereu, A.; Tarver, G. J.; MaCague, R. J.
Org. Chem. 1998, 63, 7183; (k) Kawamura, M.;
Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539; (l)
Kataoka, T.; Iwama, T.; Tsujiyama, S.; Iwamura, T.;
Watanabe, S. Tetrahedron 1998, 54, 11813; (m) Kataoka,
T.; Iwama, T.; Kinoshita, S.; Tsujiyama, Y.; Iwamura, T.;
Watanabe, S. Synlett 1999, 197; (n) Kataoka, T.; Iwama,
T.; Tsujiyama, S.; Kanematsu, K.; Iwamura, T.; Watan-
abe, S. Chem. Lett. 1999, 257; (o) Kataoka, T.; Iwama, T.;
Tsujiyama, S. J. Chem. Soc., Chem. Commun. 1998, 197;
(p) Ono, M.; Nishimura, K.; Nagaoka, Y.; Tomioka, K.
Tetrahedron Lett. 1999, 40, 1509; (q) Li, G.-G.; Wei,
H.-X.; Gao, J. J.; Caputo, T. D. Tetrahedron Lett. 2000,
41, 1; (r) Kataoka, T.; Kinoshita, H.; Iwama, T.; Tsu-
jiyama, S.; Iwamura, T.; Watanabe, S.; Muraoka, O.;
Tanabe, G. Tetrahedron 2000, 56, 4725; (s) Li, G.-G.; Gao,
J.; Wei, H.-X.; Enright, M. Org. Lett. 2000, 2, 617; (t) Shi,
7. The spectral data of 2e: mp 161–164°C; IR (KBr) w 1674
cm−1 (CꢀO); 1H NMR (CDCl3, 300 MHz, TMS) l 2.28
(3H, s, CH3), 3.37 (1H, dd, JCHꢁNH=11.1 Hz, JPꢁNꢁH=8.4
Hz, NH), 4.87 (1H, t, JCHꢁNH=11.1 Hz, JPꢁNꢁCH=11.1
Hz, CH), 6.11 (1H, s, ꢀCH), 6.21 (1H, s, ꢀCH), 7.20–7.31
(4H, m, Ar), 7.37–7.56 (6H, m, Ar), 7.80–7.90 (4H, m, Ar);
MS (EI) m/e 409 (M+, 4.82), 340 (M+−69, 12.31), 208
(M+−201, 100); [found: C, 67.44; H, 5.36; N, 3.38%.
C23H21ClNO2P requires: C, 67.40; H, 5.17; N, 3.42%].
8. The spectral data of 3e: mp 173–175°C; IR (KBr) w 1719
cm−1 (CꢀO); 1H NMR (CDCl3, 300 MHz, TMS) l 3.65
(3H, s, OCH3), 4.33 (1H, dd, JCHꢁNH=11.4 Hz, JPꢁNꢁH
=
8.4 Hz, NH), 5.04 (1H, t, JCHꢁNH=11.4 Hz, JPꢁNꢁCH=11.4
Hz, CH), 5.86 (1H, s, ꢀCH), 6.34 (1H, s, ꢀCH), 7.20–7.31
(4H, m, Ar), 7.37–7.56 (6H, m, Ar), 7.80–7.95 (4H, m, Ar);
MS (EI) m/e 425 (M+, 9.54), 356 (M+−69, 18.65), 224
(M+−201, 100); [found: C, 64.67; H, 5.00; N, 3.16%.
C23H21ClNO3P requires: C, 64.87; H, 4.97; N, 3.29%].