A mild and efficient method for chlorination of Baylis-Hillman adducts using PPh3/Cl3CCONH2

Article abstract of DOI:10.1002/hlca.200790211

A new and convenient stereoselective synthesis of (Z)-2-(chloromethyl)alk- 2-enoates has been achieved from Baylis - Hillman adducts by treatment with PPh₃/Cl₃CCONH₂ at room temperature. The synthesis can proceed under mil

Full text of DOI:10.1002/hlca.200790211

Helvetica Chimica Acta – Vol. 90 (2007)
2037
A Mild and Efficient Method for Chlorination of Baylis – Hillman Adducts
1
Using PPh /Cl CCONH )
3
3
2
by Biswanath Das*, Nikhil Chowdhury, Kongara Damodar, and Bommena Ravikanth
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(
phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
A new and convenient stereoselective synthesis of (Z)-2-(chloromethyl)alk-2-enoates has been
achieved from Baylis – Hillman adducts by treatment with PPh /Cl CCONH at room temperature. The
3
3
2
synthesis can proceed under mild and acid-free conditions to form the products in high yields.
Introduction. – Baylis – Hillman adducts [1] have recently been utilized as
important building blocks for stereoselective synthesis of different multifunctional
molecules [2]. These adducts can be converted into (Z)-2-(halomethyl)alk-2-enoates,
which are valuable synthons for the synthesis of a variety of important bioactive
molecules such as micanecic acid, kizanolide, rennin inhibitor A-72517, b-lactams, a-
methylene-g-butyrolactones, and flavonoids [3]. The conversion of the Baylis – Hill-
man adducts to the corresponding halides has earlier been carried out using hydrogen
halides along with strong protic acids (HBrÀH SO , HIÀH PO ) [4], organic acid
2
4
3
4
halides (oxalyl chloride, MsCl) [5], NCS/NBS-Me S [6], and Na-halides/KSF clay
2
under microwaves [7]. However, many of the procedures have limitations in terms of
yield, selectivity, reaction time, and also the quantity of the catalyst used. Therefore, the
developments of new reagents, which are more efficient and lead to convenient
procedures with better yields, are highly useful.
Results and Discussion. – In continuation of our of work [8] on the application of
Baylis – Hillman adducts, we describe herein a simple and efficient process for the one-
step conversion of Baylis – Hillman adducts, 3-hydroxy-2-methylidenalkanoates 1 into
the corresponding (chloromethyl)alkenoates 2 using PPh /Cl CCONH reagent. The
3
3
2
adducts were treated with this reagent in CH Cl at room temperature to afford (Z)-2-
2
2
(
chloromethyl)alk-2-enoates 2 in high yields (Scheme 1). The products were charac-
1
terized on the basis of their spectral (IR, H-NMR, and MS) data. The reaction was
found to be equally applicable to both 3-aryl- and 3-alkyl-3-hydroxy-2-methylidenal-
kanoates. However, with 3-alkyl-3-hydroxy-2-methylidenalkanoates, the yields were
lower. Baylis – Hillman adducts having electron-withdrawing groups in the aromatic
ring also led to the products with somewhat lower yields.
The present reaction conditions tolerated several functionalities such as halogen,
NO , and ether groups. The method is highly stereoselective. The desired products were
2
1)
Part 151 in the series, ꢁStudies on novel synthetic methodologiesꢂ.
ꢀ
2007Verlag Helvetica Chimica Acta AG, Zürich

2
038
Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 1
1
formed with excellent (Z)-selectivity (94 – 100%) as suggested by the H-NMR spectra
1
of the crude products. In the H-NMR spectrum of a trisubstituted alkene, the b-vinylic
H-atom, cis and trans to the ester group are known to resonate at ca. d 7.5 and d
6.5 ppm, respectively, when R is aryl, while the signals of the same H-atoms cis and
trans to the ester group appear at ca. d 6.8 and 5.7ppm, respectively, when R is alkyl
1
[
9]. These reported H-NMR values were useful to determine the configuration of the
products.
PPh /Cl CCONH has recently been utilized for the conversion of alcohols into the
3
3
2
corresponding alkyl chlorides, and the mechanism has been mentioned [10]. We
consider that this conversion operates similarly (Scheme 2). PPh3 reacts with
Cl CCONH to give the intermediate 3, which then reacts with a Baylis – Hillman
3
2
adduct to give alkoxyphosphonium salt 4, which subsequently decomposes to form allyl
chloride and Ph PO.
3
The stereochemistry of the present conversion can be explained by considering the
transition state models A and B (Fig.). Model A is more favored than B, and (Z)-
products are formed predominantly.
Scheme 2

Helvetica Chimica Acta – Vol. 90 (2007)
2039
a
Table. Synthesis of( Z)-2-(Chloromethyl)alk-2-enoates 2 ) Using PPh /Cl CCONH
3
3
2
1
R
R’
Time [h]
Yield [%]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
89
85
77
88
84
77
74
83
76
74
75
76
77
76
80
4-ClÀC H
3.5
3.5
3
6
4
2-NO ÀC H
2
6
4
4-MeOÀC H
6
4
4-MeÀC
6
H
4
3
4-NO ÀC H
3.5
3.5
3.5
4
4
4
3.5
3
3
2
6
4
3-NO ÀC H
2
6
4
2-ClÀC H
6
4
Me(CH ) CH
2
5
2
Me(CH ) CH
PhCH CH
Naphthalen-1-yl
2
7
2
2
2
4-ClÀC H
6
4
Ph
Et
Et
4-MeOÀC H
3
6
4
a) The structures of all the products were established on the basis of their spectral (IR, H-NMR, and
1
MS) and analytical data (see Exper. Part). The yields refer to isolated material.
In conclusion, we have described a simple and convenient method for the
stereoselective synthesis of (Z)-2-(chloromethyl)alk-2-enoates using a combination of
readily available PPh and Cl CCONH as a reagent system at room temperature. The
3
3
2
mild and acid-free conditions, application of cheaper reagents, easy experimental
procedure, and high yields are the notable advantages of the present protocol.
The authors thank CSIR, New Delhi, for financial support.
Experimental Part
General Procedure for the Preparation of Alkenoates 2. To a stirred soln. of a 3-hydroxy-2-
methylidenalkanoate 1 (2 mmol) and PPh (4 mmol) in dry CH Cl (10 ml), Cl CCONH (4 mmol) was
3
2
2
3
2
added under N . The mixture was stirred at r.t., and the reaction was monitored by TLC. After
2
completion, the reaction was quenched with cold water (10 ml), and the mixture was extracted with
CH Cl (3 Â 10 ml). The org. layer was dried (anh. Na SO ) and concentrated. The crude product was
2
2
2
4
purified by column chromatography (CC) over silica gel with hexane/AcOEt 9 :1 as eluent to yield the
corresponding (Z)-2-(chloromethyl)alk-2-enoate 2.

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Helvetica Chimica Acta – Vol. 90 (2007)
1
The spectral (IR, H-NMR, and MS) and analytical data of some representative products are given
below.
Methyl (Z)-2-(Chloromethyl)-3-(4-chlorophenyl)prop-2-enoate (2b): IR (KBr): 2926, 1720, 1466,
1
1
290, 770. H-NMR: 7.78 (s , 1 H); 7 .48 (d , J ¼ 8.0, 2 H); 7.35 (d, J ¼ 8.0, 2 H); 4.36 (s, 2 H); 3.84 (s, 3 H).
þ
EI-MS: 211, 209 ([M À Cl] ), 155, 149, 127, 115. Anal. calc. for C H Cl O : C 54.10, H 4.10; found: C
11
10
2
2
5
4.03, H 4.07.
Methyl (Z)-2-(Chloromethyl)-3-(3-nitrophenyl)prop-2-enoate (2g): IR (KBr): 2962, 1727, 1463,
1
1
1
295, 778. H-NMR: 8.39 (s, 1 H); 8.27( d, J ¼ 8.0, 1 H); 7.90 (d, J ¼ 8.0, 1 H); 7.85 (s, 1 H); 7 .66 (t , J ¼ 8.0,
þ
H); 4.38 (s, 2 H); 3.91 (s, 3 H). EI-MS: 257, 255, 220 ([M À Cl] ). Anal. calc. for C H ClNO : C 51.7 6,
11
10
4
H 3.92; found: C 51.88, H 4.02.
1
Methyl (Z)-2-(Chloromethyl)dec-2-enoate (2i): IR (KBr): 2942, 2853, 1728, 1452, 759. H-NMR: 6.95
(
0
t, J ¼ 7.0, 1 H); 4.28 (s, 2 H); 3.7 9 (s , 3 H); 2.31 (q, J ¼ 7.0, 2 H); 1.56 – 1.46 (m, 2 H); 1.39 – 1.24 (m, 8 H);
þ
.89 (t, J ¼ 7.0, 3 H). EI-MS: 234, 232, 197 ( [M À Cl] ), 195. Anal. calc. for C H ClO : C 62.09, H 9.05;
12
21
2
found: C 62.17, H 9.12.
1
Methyl (Z)-2-(Chloromethyl)dodec-2-enoate (2j): IR (KBr): 2929, 2853, 1720, 1442, 768. H-NMR:
.95 (t, J ¼ 7.0, 1 H); 4.28 (s, 2 H); 3.82 (s, 3 H); 2.35 – 2.28 (m, 2 H); 1.44 – 1.23 (m, 14 H); 0.98 (t, J ¼ 7.0,
6
3
þ
H). EI-MS: 227, 225 ([M À Cl] ), 193, 165, 149, 135, 109. Anal. calc. for C H ClO : C 64.61, H 9.61;
14
25
2
found: C 64.71, H 9.66.
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Received June 21, 2007