Convenient and efficient stereoselective synthesis of (2Z)-2-(chloromethyl) alk-2-enoates using iron(III) or indium(III) chloride

Article abstract of DOI:10.1016/j.tetlet.2004.01.101

The stereoselective synthesis of (2Z)-2-(chloromethyl)alk-2-enoates has been achieved efficiently and in high yields and in short reaction times from Baylis-Hillman adducts, 3-hydroxy-2-methylene-alkanoates, by treatment with FeCl₃ or InCl

Full text of DOI:10.1016/j.tetlet.2004.01.101

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2425–2426
Convenient and efficient stereoselective synthesis of (2Z)-2-
(chloromethyl)alk-2-enoates using iron(III) or indium(III) chlorideq
Biswanath Das,* Joydeep Banerjee, Nasi Ravindranath and Bollu Venkataiah
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 14 October 2003; revised 7 January 2004; accepted 16 January 2004
Abstract—The stereoselective synthesis of (2Z)-2-(chloromethyl)alk-2-enoates has been achieved efficiently and in high yields and in
short reaction times from Baylis–Hillman adducts, 3-hydroxy-2-methylene-alkanoates, by treatment with FeCl3 or InCl3 at room
temperature.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Baylis–Hillman
adducts,
3-hydroxy-2-methylene-
FeCl3 (reaction time: 3 h) showed somewhat better
activity than InCl3 (reaction time: 3.5–4 h). However,
the work-up procedure with the latter was easier.4 The
products were characterized by their spectral (1H NMR
and MS) data.5 The 1H NMR spectra of the crude
products showed the formation of the (2E)-isomers of 2
in very small amounts (<5%). With InCl3 the yields of
the (2E)-isomers were less than with FeCl3.
alkanoates, have recently been utilized1 as important
precursors for stereoselective synthesis of different
multifunctional molecules. These adducts can be con-
verted into (2Z)-2-(halomethyl)alk-2-enoates, which are
employed for the synthesis of various naturally occur-
ring bioactive compounds and their analogues such as a-
methylene-c-butyrolactones,2a a-alkylidene-b-lactams,2b
and flavanoids.2c This conversion has been carried out in
a single step using hydrogen halides together with strong
acids (HBr–H2SO4, HI–H3PO4),2a;3a–c organic acid
halides (oxalyl chloride, MsCl)3d;e and other reagents
including the HCA–PPh3 complex3c and NCS/NBS-
Me2S.3fꢀh However, most of the reported methods suffer
from certain drawbacks, which include the use of con-
centrated acids, long reaction times, incompatibility
with other functional groups and a requirement for
complex experimental procedures. Here we describe a
simple and efficient process for the one-step conversion
of Baylis–Hillman adducts, 1 into the corresponding
allyl chlorides, 2 using FeCl3 or InCl3. 3-Hydroxy-2-
methylidenoalk-2-enoates 1 were treated with FeCl3 or
InCl3 in CH2Cl2 at room temperature to afford (2Z)-2-
(chloromethyl)alk-2-enoates 2 in high yields (Table 1).
FeCl3 or InCl3
OH
CH2Cl2
COOR'
COOR'
R
R
r.t, 3-4 h
Cl
71-88%
R = alkyl or aryl; R' =alkyl
2
1
The reaction using either FeCl3 or InCl3 was found to be
equally applicable to both 3-aryl or 3-alkyl-3-hydroxy-2-
methylidenoalkanoates 1. However, the yields of the
products from 1 (R ¼ alkyl) were somewhat lower. The
present reaction conditions tolerate several functional-
ities such as halogen, nitro and ether groups. The pres-
ence of electron-donating or electron-withdrawing
groups in the aromatic ring did not affect the reaction.
Increasing the solvent polarity led to decreased yields of
the allyl chlorides. Thus, the reaction of methyl 3-phe-
nyl-3-hydroxy-2-methylidenopropionate (Table 1, entry
a) carried out in CH2Cl2 using FeCl3 afforded the cor-
responding allyl chloride in a yield of 88% but when
conducted in CH3CN, the yield was only 72%; CH2Cl2
was therefore preferred as a solvent for the present
conversion.
Keywords:
(2Z)-2-(Chloromethyl)alk-2-enoates;
Baylis–Hillman
adducts; 3-Hydroxy-2-methylene-alkanoates; FeCl3; InCl3.
q Part 34 in the series, ÔStudies on novel synthetic methodologiesÕ, for
part 33 see Srinivas, K. V. N. S.; Mahender, I.; Das, B. Chem. Lett.
2003 (submitted).
* Corresponding author. Tel.: +91-40-7173874; fax: +91-40-7160512;
e-mail: biswanathdas@yahoo.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.101

2426
B. Das et al. / Tetrahedron Letters 45 (2004) 2425–2426
Table 1. Synthesis of (2Z)-2-(chloromethyl)alk-2-enoates 2a
Entry
R
R0
Time (h)
Isolated yield (%)
With FeCl3 With InCl3
With FeCl3
With InCl3
a
b
c
d
e
f
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
3
3
3
3
3
3
3
3
3
3
3
3
3
88
80
86
77
75
86
84
83
4-O2NC6H4
2-O2NC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
3.5
3.5
3
78
86
3
85
84
3.5
3.5
4
g
h
i
2-ClC6H4
8280
75
CH3(CH2)7CH2
PhCH2CH2
a-Naphthyl
4-ClC6H4
72
71
76
77
4
76
78
j
3.5
3
k
l
80
C6H5
4-MeOC6H4
Et
Et
3
8276
78
m
3
73
a The structures of all the products were established from their spectral (1H NMR and MS) data.
Engl. 1983, 22, 795–796; (h) Hoffmann, H. M. R.; Rabe, J.
J. Org. Chem. 1985, 50, 3849–3859.
In conclusion, we have developed a simple and efficient
one-pot synthesis of (2Z)-2-(chloromethyl)alk-2-enoates
in high yields using the readily available reagents, FeCl3
and InCl3 in CH2Cl2 at room temperature. The reaction
conditions are mild and compatible with several func-
tional groups. The method is highly stereoselective. We
feel the present procedure will find important synthetic
applications.
4. (a) Reaction with FeCl3: To a solution of 3-hydroxy-2-
methylidenoalkanoates 1 (1 mmol) in dry CH2Cl2 (10 mL)
anhydrous FeCl3 (0.35 equiv) was added. The mixture
was stirred at room temperature for 3 h. The solvent was
removed under reduced pressure and the residue
was extracted with EtOAc (3 · 10 mL). The extract was
concentrated and subjected to column chromatography
over silica gel using hexane–EtOAc (4:1) as eluent to obtain
the (2Z)-2-(chloromethyl)alk-2-enoates 2. (b) Reaction with
InCl3: To a solution of 3-hydroxy-2-methylidenoalkanoates
1 (1 mmol) in dry CH2Cl2 (10 mL), InCl3 (0.35 equiv) was
added. The mixture was stirred at room temperature and
the reaction was monitored by TLC. After completion the
solution was decanted, concentrated and subjected to
column chromatography over silica gel using hexane–
EtOAc (4:1) as eluent to yield the (2Z)-2-(chlorom-
ethyl)alk-2-enoates 2.
Acknowledgements
The authors thank CSIR and UGC, New Delhi for
financial assistance.
References and notes
5. The 1H NMR and MS data for the new products are given
below. 2d: 1H NMR (CDCl3, 200 MHz): d 7.77 (1H, s), 7.45
(2H, d, J ¼ 8:0 Hz), 6.84 (2H, d, J ¼ 8:0 Hz), 4.20 (2H, s),
3.84 (3H, s), 3.79 (3H, s); EIMS: m=z 240, 242 (Mþ), 205
1. (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001–8053, and references cited therein; (b)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811–891, and references cited therein.
1
(Mþ)Cl) 2g: H NMR (CDCl3, 200 MHz): d 7.84 (1H, s),
2. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.
Engl. 1985, 24, 94–110; (b) Buchholz, R.; Hoffmann, H. M.
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Dreiding, A. S. Helv. Chim. Acta 1976, 59, 1904–1910;
(g) Rabe, J.; Hoffmann, H. M. R. Angew. Chem., Int. Ed.
7.63–7.34 (2H, m), 7.40 (1H, t, J ¼ 8:0 Hz), 7.22 (1H, t,
J ¼ 8:0 Hz), 4.23 (2H, s), 3.84 (3H, s); EIMS: m=z 211, 209
(Mþ)Cl), 155, 149, 127, 115. 2h: 1H NMR (CDCl3,
200 MHz): d 6.95 (1H, t, J ¼ 7:0 Hz), 4.28 (2H, s), 3.82
(3H, s), 2.35–2.28 (2H, m), 1.44–1.23 (14H, m), 0.98 (3H, t,
J ¼ 7:0 Hz); EIMS: m=z 227, 225 (Mþ)Cl), 193, 165, 149,
135, 109. 2i: 1H NMR (CDCl3, 200 MHz): d 7.20–7.02 (5H,
m), 6.82(1H, t, J ¼ 7:0 Hz), 3.78 (2H, s), 3.72 (3H, s), 2.98
(2H, t, J ¼ 7:0 Hz), 2.58–2.42 (2H, m); EIMS: m=z 202
(Mþ)HCl), 143, 128, 115. 2j: 1H NMR (CDCl3, 200 MHz):
d 8.32 (1H, s), 7.92–7.38 (7H, m), 4.26 (2H, s), 3.88 (3H, s);
EIMS: m=z 262, 260 (Mþ), 224, 165, 85. 2m: 1H NMR
(CDCl3, 200 MHz): d 7.78 (1H, s), 7.44 (2H, d, J ¼ 8:0 Hz),
6.82(2H, d, J ¼ 8:0 Hz), 4.18 (2H, s), 3.88 (3H, s), 3.58
(2H, q, J ¼ 7:0 Hz), 1.26 (3H, t, J ¼ 7:0 Hz); EIMS: m=z
254, 256 (Mþ), 219.