The allylic nucleophilic substitution of Morita-Baylis-Hillman acetates with isocyanides: a facile synthesis of trisubstituted olefins

Article abstract of DOI:10.1016/j.tetlet.2010.02.130

Morita-Baylis-Hillman acetates undergo smooth allylic nucleophilic substitution (S_N2′) with tosylmethyl isocyanide (TosMIC) in the presence of a catalytic amount of BF₃·OEt₂ under mild conditions to furnish trisubstituted olefins in high yields with (E)-stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2010.02.130

Tetrahedron Letters 51 (2010) 2291–2294
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The allylic nucleophilic substitution of Morita–Baylis–Hillman acetates
with isocyanides: a facile synthesis of trisubstituted olefins
*
J. S. Yadav , B. V. Subba Reddy, Ashutosh Pratap Singh, Nilanjan Majumder
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Morita–Baylis–Hillman acetates undergo smooth allylic nucleophilic substitution (SN20) with tosylmethyl
isocyanide (TosMIC) in the presence of a catalytic amount of BF3ꢀOEt2 under mild conditions to furnish
trisubstituted olefins in high yields with (E)-stereoselectivity.
Article history:
Received 23 October 2009
Revised 15 February 2010
Accepted 20 February 2010
Available online 24 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Morita–Baylis–Hillman acetates
SN20 substitution
TosMIC
Alkylation
The ready availability and versatility of Morita–Baylis–Hillman
acetates make them valuable synthetic intermediates for the syn-
thesis of a variety of heterocycles such as quinolines, pyrimidones,
isoxazolines, pyrazolones, pyrrolidines, indolizines, azetidinones,
diazacyclophanes and chromanones as well as biologically active
OAc
CO2Et
.
CO2Et
BF3 OEt2
H
TosMIC
+
N
Ts
°
CH3CN, 0 C-rt
O
1
2
3a
natural products including
a-alkylidene-b-lactams, a-methylene-
c-butyrolactones and mikanecic acids, frontalin, trimethoprim,
Scheme 1. Preparation of 3a from allylic acetate (1) and isocyanide (2).
sarkomycin, ilmofosine nuciferol and many others.1,2 Consequently,
various nucleophiles such as allyl–zinc reagents, metal hydrides, ha-
lides, azides, cyanides, alcohols, amines, arenes, indoles and active
methylene compounds have been used to prepare a wide range of
synthetic intermediates.3–7 However, there have been no reports
on the allylic substitution of Baylis–Hillman acetates with TosMIC
to produce trisubstituted olefins. Lewis acid-catalyzed carbon–car-
bon bond-forming reactions are of great significance in organic syn-
thesis because of their high reactivity, selectivity and mild reaction
conditions.8
In this Letter, we report a versatile approach for the preparation
of trisubstituted olefins by means of allylic nucleophilic substitu-
tion of Baylis–Hillman acetates with tosylmethyl isocyanide using
a catalytic amount of BF3ꢀOEt2. Thus, treatment of the Baylis–Hill-
man acetate derived from benzaldehyde and ethyl acrylate, ethyl
3-acetoxy-2-methylene-3-phenylpropanoate (1) with TosMIC (2)
in the presence of 10 mol % BF3ꢀOEt2 in dry acetonitrile gave the
corresponding trisubstituted olefin 3a in 90% yield (Scheme 1).
The product was obtained as a mixture of E- and Z-isomers in
9:1 ratio favouring E-isomer. The ratio of (E) and (Z) isomers was
determined on the basis of integration ratios of isomeric olefinic
proton and allylic methylene protons in 1H NMR spectra of prod-
ucts. The (E)-stereochemistry of the products was assigned on
the basis of the chemical shift values of vinyl and allylic protons
in the 1H NMR spectra of the products and also by the comparison
of the spectral data with authentic samples.9 In the 13C NMR spec-
tra of trisubstituted olefins, allylic carbon cis- to aryl group appears
up field while the same carbon trans to aryl group appears down
field.10 The structure of 3a was also established by two-dimen-
sional nuclear Overhauser effect spectroscopy (NOESY, Fig. 1).
H
O
H
f
a
b
e
d
1
OEt
H
N
2
O
H2C 3
H
O
c
S
4
O
Me
Figure 1. Characteristic NOEs’ of product 3a.
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.130

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J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2291–2294
The cis orientation of the two aromatic substituents across the
hyde, the corresponding product was obtained in 85% yield with
(2E,4E)-selectivity (Table 1, entry h). Allylic acetates derived from
heteroaromatic aldehydes were also equally effective for this
transformation (Table 1, entries k and l). The reaction conditions
were compatible with various functionalities such as olefins, ha-
lides, aryl methyl ethers and esters (Table 1). The products were
characterized by 1H NMR, IR and mass spectroscopy. In the absence
of BF3ꢀOEt2, no allylic substitution occurred even after long reac-
tion times (6–12 h) under reflux conditions. Various Lewis acids
such as InCl3, FeCl3 and CeCl3ꢀ7H2O were screened and none gave
desired product. Furthermore, metal triflates such as Sc(OTf)3,
double bond was inferred from a strong NOE cross peak between
CH2 (C-3) and Hb. Additional support for the proposed structure
came from a weak NOE correlation between CH2 (C-3) and CH
(C-1), being trans to each other.
These results encouraged us to examine the reactivity of various
substituted Baylis–Hillman acetates. Interestingly, Baylis–Hillman
acetates derived from both aliphatic and aromatic aldehydes par-
ticipated well in this reaction (Table 1). In all cases, the reactions
were clean and stereoselective affording the trisubstituted olefins
in good yields with complete (E)-selectivity. In case of cinnamalde-
Table 1
Allylic nucleophilic substitution of Baylis–Hillman acetates with isocyanides using BF3ꢀOET2
Entry
Substrate
OAc
Isocyanide
Product (3)a
Reaction time (h)
Yieldb (%)
Me
CO2Et
O
S
CO2Et
H
N
Me
a
2.0
90
O
O
O S O
NC
Me
OAc
CO2Et
O
S
CO2Et
H
N
Me
Cl
b
c
d
e
f
Cl
3.0
2.0
4.0
3.0
5.0
4.0
4.0
95
92
85
88
78
84
85
O
O
O S O
NC
Me
OAc
CO2Et
O
S
CO2Et
H
N
Me
MeO
MeO
O
O
O S O
NC
Me
OAc
CO2Et
CO2Et
O
H
N
Me
S
Me
Me
O
O
O S O
NC
Me
OAc
CO2Et
O
S
CO2Et
H
N
Me
F
F
O
O
O S O
NC
Me
OAc
CO2Et
Br
Br
CO2Et
O
H
N
Me
S
O
O
O S O
NC
Me
OAc
CO2Et
PhO
O
S
CO2Et
PhO
H
N
Me
g
h
O
O
O S O
NC
Me
OAc
CO2Et
O
CO2Et
H
N
Me
S
O
O
O S O
NC

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2291–2294
2293
Table 1 (continued)
Entry
Substrate
Isocyanide
Product (3)a
Reaction time (h)
Yieldb (%)
OAc
Me
CO2Et
CO2Et
O
S
H
N
Me
i
3.0
78
77
84
88
O
O
O S O
NC
Me
OAc
CO2Et
CO2Et
O
S
H
N
Me
Me
Me
j
4.0
5.0
3.0
O
O
O S O
NC
Me
OAc
OAc
CO2Me
O
S
O
S
CO2Me
O
H
N
S
k
O
O
O S O
NC
Me
CO2Me
O
CO2Me
H
N
S
l
O
O
O S O
NC
OAc
CO2Et
CO2Et
H
m
n
4.0
3.0
74
76
N
Cl
F
NC
NC
Cl
O
OAc
CO2Et
CO2Et
H
N
F
O
OAc
CO2Et
CO2Et
H
o
3.5
3.5
72
70
N
Cl
F
Cl
NC
Me
O
OAc
Me
CO2Et
CO2Et
p
H
F
N
NC
O
a
The product was characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
b
Yb(OTf)3 and In(OTf)3 also failed to give the desired product under
similar conditions. Interestingly, various isonitriles such as cyclo-
hexyl, benzyl and p-methylbenzyl isocyanides also participated
in this reaction (Table 1, entries m–p). As a solvent, acetonitrile
gave the best results. The scope of the BF3.OEt2-promoted allylic
substitution was investigated with respect to various Baylis–Hill-
man acetates and the results are presented in Table 1.11 Further-
more, the reactions were carried out with Baylis–Hillman
adducts (hydroxy compounds) instead of acetates. Even though,
the reactions succeeded with hydroxy compounds, low conver-
sions (20–45%) were obtained even after long reaction times. High
conversions were obtained only with Baylis–Hillman acetates.
Though the reaction was successful with cyclohexyl isocyanide,
the yields were low compared to those of TosMIC (Table 1, entries
m and n).
uted to the formation of chelated structure, in the case of ester,
leading to (E)-product (Scheme 2).12
In conclusion, we have described a novel method for the prepara-
tion of trisubstituted olefins from Morita–Baylis–Hillman acetates
and tosylmethyl isocyanide via SN20 type allylic substitution. The
method has several advantages such as operational simplicity, mild
reaction conditions, clean reaction profiles, simple experimental
B(III)
O
O
Ac
OAc O
O
BF3.OEt2
Ar
OR
Nu
3a
Ar
OR
Ar
OR
(-)
Nu
The reaction may proceed via the activation of allylic acetate by
the Lewis acid. A preferential attack of isonitrile across the olefin
gave the trisubstituted olefin. The stereochemistry may be attrib-
SN2'
Scheme 2. A plausible reaction mechanism.

2294
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2291–2294
10. (a) Mandal, S. K.; Paira, M.; Roy, S. C. J. Org. Chem. 2008, 73, 3823; (b) Basavaiah,
D.; Sarma, P. K. S.; Bhavani, A. K. D. J. Chem. Soc., Chem. Commun. 1994, 1091.
11. General procedure: A mixture of Baylis–Hillman acetate (1.0 mmol), TosMic
(1.2 mmol) and BF3ꢀOEt2 (0.1 mmol) in dry acetonitrile (5 mL) was stirred at
0 °C until complete reaction took place. The mixture was then diluted with
saturated NaHCO3 solution (10 mL) and extracted with ethyl acetate
(3 ꢁ 10 mL). The combined organic layers were washed with water
(2 ꢁ 10 mL), brine (10 mL) and dried over anhydrous Na2SO4. Removal of the
solvent was followed by purification by silica gel column chromatography
eluting with hexane/ethyl acetate (6:4) gave the pure product. Spectral data
and work-up procedures and the use of inexpensive and readily
available reagents which makes it a useful and attractive process
for the preparation of trisubstituted olefins.
Acknowledgement
A.P.S. and N.M. thank CSIR, New Delhi for the award of
fellowships.
(3b): white solid, mp 87–89 °C; IR (neat):
1644, 1557, 1490, 1442, 1370, 1287, 1232, 1088, 1012, 924, 846, 816, 765,
721 cmꢂ1 1H NMR (CDCl3, 300 MHz): d 1.37 (t, 3H, J = 7.5 Hz), 1.97 (s, 3H), 2.04
m 3288, 3089, 2982, 2934, 1711,
References and notes
.
(d, 2H, J = 6.7 Hz), 4.05–4.17 (m, 2H), 4.25–4.32 (m, 2H), 6.19 (s, 1H, NH), 7.18
(d, 2H, J = 8.3 Hz), 7.24 (d, 2H, J = 8.3 Hz), 7.40 (d, 2H, J = 8.3 Hz), 7.51 (d, 2H,
J = 9.0 Hz), 7.65 (s, 1H). 13C NMR (CDCl3, 75 MHz): d 185.6, 169.5, 167.5, 140.5,
135.2, 132.5, 130.9, 128.8, 128.5, 127.6, 127.5, 61.2, 61.0, 60.3, 54.2, 36.6, 29.5,
23.2, 20.9, 14.1, 13.9; ESIMS: m/z: 436.3 (M+H); HRMS calcd for
C21H22ClNO5SNa: 458.0805, found: 458.0807. Compound 3d: colourless solid,
1. Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
2. (a) Basavaiah, D.; Rao, P. D.; Suguna, H. R. Tetrahedron 1996, 52, 8001; (b)
Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
3. (a) Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2003, 44, 6737; (b) Lee, K. Y.;
Kim, J. M.; Kim, J. N. Tetrahedron 2003, 59, 385; (c) Im, Y. J.; Lee, K. Y.; Kim, T. H.;
Kim, J. N. Tetrahedron Lett. 2002, 43, 4675.
4. (a) Kim, J. N.; Kim, J. M.; Lee, K. Y. Synlett 2003, 821; (b) Kim, J. N.; Kim, H. S.;
Gong, J. H.; Chung, Y. M. Tetrahedron Lett. 2001, 42, 8341.
5. (a) Drewes, S. E.; Emslie, N. D. J. Chem. Soc., Perkin Trans. 1 1982, 2079; (b)
Hoffmann, H. M. R.; Rabe, J. Helv. Chim. Acta 1984, 67, 413; (c) Hoffmann, H. M.
R.; Rabe, J. J. Org. Chem. 1985, 50, 3849.
mp 85–87 °C. IR (neat):
m
3275, 2982, 2926, 1706, 1653, 1540, 1447, 1369,
1288, 1229, 1185, 1109, 1025, 815, 756 cmꢂ1
.
1H NMR (CDCl3, 300 MHz): d
1.36 (t, 3H, J = 7.5 Hz), 1.96 (s, 3H), 2.01 (d, 2H, J = 5.2 Hz), 2.36 (s, 3H), 4.04–
4.12 (m, 2H), 4.23–4.31 (m, 2H), 6.20 (s, 1H, NH), 7.20 (d, 4H, J = 7.5 Hz), 7.39
(d, 4H, J = 7.5 Hz), 7.69 (s, 1H). 13C NMR (CDCl3, 75 MHz): d 198.7, 188.3, 177.2,
166.5, 155.8, 144.0, 143.4, 133.7, 129.6, 127.9, 106.7, 95.5, 92.8, 90.6, 73.1,
69.2, 48.3, 47.1, 29.6, 24.5, 21.3, 14.0; ESIMS: m/z: 438 (M+Na); HRMS calcd for
C22H25NO5SNa: 438.1351, found: 438.1354. Compound 3e: white solid, mp 84–
6. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94; (b)
Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta 1991, 74, 1213; (c) Ameer, F.;
Drewes, S. E.; Hoole, R. F. A.; Kaye, P. T.; Pitchford, A. T. J. Chem. Soc., Perkin
Trans. 1 1985, 2713.
86 °C; IR (neat):
m
3282, 3067, 2984, 2925, 1708, 1651, 1601, 1510, 1371, 1288,
1229, 1110, 1023, 837, 761, 517 cmꢂ1
.
1H NMR (CDCl3, 300 MHz): d 1.36 (dt,
3H, J = 9.0 Hz), 1.96 (d, 3H, J = 1.5 Hz), 2.01 (s, 2H), 4.07–4.16 (m, 2H), 4.26 (dq,
2H, J = 6.7, 8.3 Hz), 6.35 (s, 1H, NH), 6.94 (dt, 1H, J = 8.3 Hz), 7.08 (dt, 3H,
J = 9.8 Hz), 7.20 (t, 1H, J = 7.5 Hz), 7.56 (t, 3H, J = 6.7 Hz), 7.66 (s, 1H). 13C NMR
(CDCl3, 75 MHz): d 169.6, 164.6, 140.7, 131.7, 131.6, 128.1, 128.0, 127.8, 127.1,
115.8, 115.5, 115.4, 115.1, 61.1, 60.9, 54.1, 36.6, 29.5, 23.2, 14.2, 13.8; ESIMS:
m/z: 420; HRMS calcd for C21H22ClNO5SNa: 442.1100, found: 442.1103.
12. (a) Gowrisankar, S.; Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2004, 45,
6141; (b) Ranu, B. C.; Chattopadhyay, K.; Jana, R. Tetrahedron Lett. 2007, 48,
3847.
7. (a) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.; Prabhakar, A.;
Jagadesh, B. Tetrahedron Lett. 2005, 46, 639; (b) Srihari, P.; Singh, A. P.; Basak, A.
K.; Yadav, J. S. Tetrahedron Lett. 2007, 48, 5999.
8. Kobayashi, S. Eur. J. Org. Chem. 1999, 15–27.
9. (a) Yadav, J. S.; Reddy, B. V. S.; Singh, A. P.; Basak, A. K. Tetrahedron Lett. 2007,
48, 7546; (b) Yadav, J. S.; Reddy, B. V. S.; Singh, A. P.; Basak, A. K. Tetrahedron
Lett. 2007, 48, 4169; (c) Yadav, J. S.; Gupta, M. K.; Pandey, S. K.; Reddy, B. V. S.;
Sharma, A. V. S. Tetrahedron Lett. 2005, 46, 2761; (d) Yadav, J. S.; Reddy, B. V. S.;
Madan, C. New J. Chem. 2001, 25, 1114; (e) Yadav, J. S.; Reddy, B. V. S.; Basak, A.
K.; Narsaiah, A. V.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2005, 46, 639.