Novel synthesis of 1,3,5-trisubstituted 2-pyrazolines promoted by chlorotrimethylsilane

Article abstract of DOI:10.3184/030823408X287113

1,3,5-Trisubstituted-2-pyrazolines were effectively synthesised by utilising chlorotrimethylsilane as an efficient promoter in the cyclisation addition of Phenylhydrazine to chalcones under nitrogen in acetonitrile. The clean, mild reaction conditions, high yields and a simple workup of target compounds were attractive features of the reaction which enables a facile preparative procedure for building the pyrazoline ring.

Full text of DOI:10.3184/030823408X287113

48 RESEARCH PAPER
JANUARY, 48–49
JOURNAL OF CHEMICAL RESEARCH 2008
Syntheses of (Z)-allyl chlorides from Baylis–Hillman adducts with a
trichlorotriazine/DMF system
Jian Lia,*, Shaoyu Lia, Xueshun Jiaa and Yongmin Zhangb
aDepartment of Chemistry, Shanghai University, Shanghai, 200444, P. R. China
bDepartment of Chemistry, Zhejiang University (Xi-xi Campus), Hangzhou, Zhejiang, 310028, P. R. China
Stereoselective transformation of Baylis–Hillman adducts 1 into corresponding (Z)-allyl chlorides 2 have been
achieved by treatment with 2,4,6-trichloro [1,3,5]triazine and N, N-dimethyl formamide. This novel approach
proceeds readily at room temperature within a few hours with excellent yields and stereoselectivity.
Keywords: Baylis–Hillman adduct, (Z)-allyl chloride, trichlorotriazine/DMF
The Baylis–Hillman reaction is well known as one of the
powerful carbon–carbon bond-forming methods in organic
synthesis.1-3 The adducts of the reactions, 3-hydroxy-2-
methylene-alkanoates (derived from acrylate esters), have
been utilised as important precursors for stereoselective
synthesis of different multifunctional molecules.4-7 Among
these transformations, the preparation of 2-(halomethyl)alk-2-
enoates from Baylis–Hillman adducts has received attention
as these compounds are employed in the synthesis of various
naturally occurring bioactive compounds and their analogues
such as α-methylene-γ-butyrolactone, α-alkylidene-β-lactam
and flavanoids.8,9 The synthesis of the corresponding allyl
bromides and the allylic iodide analogues from Baylis–Hillman
adducts has been studied.11-14 Recently, we have also developed
a novel method to synthesise allylic iodides derivatives.15 In
contrast, the preparations of allylic chlorides has rarely been
reported. Many traditional synthetic methods suffer from
the use of strong acid (HCl) and low yields as well as poor
stereoselectivity.16-18 More recently, a new approach to allylic
chlorides from Baylis–Hillman adducts has been provided by
Krishna et al.19 In the presence of FeCl3, highly steroselective
syntheses of allyl chlorides were obtained in good to excellent
yields. Nevertheless, in such case the Baylis–Hillman adduct
has to be acetylated before use, otherwise a large amount of the
allylic alcohol is formed. As a result, to develop an alternative
synthetic method without the acetylation of BH adduct is highly
desirable. As a continuation of our interest in Baylis–Hillman
reaction,20-23 we report a new strategy to synthesise (Z)-allylic
chlorides 2 from Baylis–Hillman adducts 1 promoted by the
TCT/DMF system (Scheme 1).
Cl
N
Cl
H
O
Me
N
,
N
N
OH
Me
COOR
Cl
COOR
Cl
Ar
Ar
CH2Cl2, r. t.
2
1
Scheme 1
Table 1 Stereospecific syntheses of (Z)-allyl chlorides 2 from
Baylis–Hillman adducts 1a
Entry
Ar
R
Product
Yield/%b,c
1
2
3
4
5
C6H5
Me
Me
Me
Me
Me
2a
2b
2c
2d
2e
89
91
94
90
85
2-ClC6H4
4-ClC6H4
4-CH3C6H4
O
6
7
8
9
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
C6H5
Me
Me
Me
Et
2f
2g
2h
2i
95
96
97
91
92
10
2-ClC6H4
Et
2j
aAll reactions were carried out with 1 mmol Baylis–Hillman
adduct 1 at room temperature and finished within 1.5 h.
bIsolated yields based on substrate 1.
cAll new products were characterised by 1H NMR, MS and IR.
The reaction mechanism, may follow the pathway depicted in
Scheme 2. As suggested, the reactive Vilsmeier–Haack type
complex A was firstly formed, which then combines with
the hydroxyl oxygen of substrate 1 to give the resonance-
stabilised cation intermediate.24 Subsequent nucleophilic
attack of a chloride anion toward the methylene carbon
and the cleavage of C–O bond resulted in the formation of
corresponding chlorides 2.
In conclusion, we have provided a new method to synthesise
(Z)-allylic chlorides 2 from the Baylis–Hillman adducts 1.25
The cheap reagents, experimental simplicity together with
the excellent yields and good stereoselectivity make present
method a good alternative to traditional methods.
In a typical procedure, the 2,4,6-trichloro[1,3,5]triazine
(TCT) and DMF was mixed first, followed by the addition
of CH2Cl2 solution of 1 equiv. Baylis–Hillman adduct 1. As
shown by Scheme 1 and Table 1, blending of BH adducts 1
with this system essentially led to the quantitative conversion
to the corresponding allyl chlorides (Table 1). A series of
substrates were examined to establish the generality, of
the reaction. Most reactions proceeded smoothly under
similar conditions. The experimental results showed that the
present method was effective for substrates bearing either
electron-donating or electron-withdrawing groups. Besides
affording good yields, this process also exhibited excellent
stereoselectivity. The Z-stereoconfiguration of the product was
Experimental
All reactions were conducted in the air. 1H NMR spectra were
recorded on a Bruker AC-400 instrument in CDCl3 solutions using
TMS as an internal standard. Chemical shifts (d) were reported in
ppm and coupling constants J are given in Hz. IR spectra were taken
as thin films with a Bruker Vector-22 infrared spectrometer. EIMS
spectra were obtained on a HP 5989B mass spectrometer. Melting
points were uncorrected. Elemental analyses were performed on an
EA-1110 instrument. All solvents were purchased from commercial
sources and were used without further purification. All Baylis–
Hillman adducts are prepared according to the literature.
1
assigned by comparing the chemical shifts in H NMR with
reported ones and no E-isomer was observed from the spectra.
Generally, the chemical shift value of the olefinic proton in
1H NMR appears downfield to the aromatic ring proton, while
the corresponding olefinic proton of E-isomer often mixes
with aromatic ring proton or appears upfield.
* Correspondent. E-mail: lijian@shu.edu.cn
PAPER: 07/4987

JOURNAL OF CHEMICAL RESEARCH 2008 49
Me
Me
Cl
Me
Me
O
N
N
N
Cl
N
Cl
H
O
Me
A
O
N
N
+
N
N
Cl
Me
N
N
N
Cl
Cl
Cl
N
Cl
Cl
OH
Me
Me
Me
Me
Me
O
Me
COOR
N
N
N
Ar
-HCl
1
H
O
O
Cl
COOR
COOR
COOR
Ar
Cl
Ar
Ar
B
Cl
COOR
Cl
H
Me
Ar
+
N
O
Me
2
Scheme 2
General procedure for the synthesis of (Z)-allylic chloride (2)
2,4,6-Trichloro [1,3,5]triazine (2.5 mmol) was added to DMF (0.5 ml)
at room temperature. After the formation of a white solid, the
reaction was monitored (TLC) until the disappearance of the TCT.
Then CH2Cl2 (10 ml) was added as solvent, followed by the addition
of the Baylis–Hillman adduct (1 mmol). After completion of the
reaction, the reaction mixture was quenched with 0.1 M hydrochloric
acid (5 ml) and extracted with ether (3 × 20 ml). The organic phase
was successively washed with brine (15 ml) and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure to give the
crude products, which were purified by preparative TLC using ethyl
acetate and cyclohexane (1:5) as eluent.
(Z)-methyl 2-(chloromethyl)-3-phenylacrylate (2a): Oil. IR (film)/
cm-1: 1721, 1625; 1H NMR (400 MHz, CDCl3): d 7.81 (1H, s),
7.41–7.55 (5H, m), 4.46 (2H, s), 3.88 (3H, s); MS: m/z (%) 196 (M+,
100), 198 (M+ + 2, 52), 261 (M+–Cl, 64), 102 (31); Anal: Calcd.for
C11H11ClO2 C, 62.72; H, 5.26; Found C, 62.85; H, 5.37%.
(Z)-methyl 2-(chloromethyl)-3-(4-nitrophenyl)acrylate (2h): Yellow
solid, m.p. 118–119°C. IR (film)/cm-1: 1718, 1631, 1591, 1490, 1437;
1H NMR (400 MHz, CDCl3): d 8.32 (2H, d, J = 8.0 Hz), 7.89 (1H,
s), 7.71 (2H, d, J = 8.0 Hz), 4.41 (2H, s), 3.92 (3H, s); MS: m/z (%)
255 (M+, 56), 220 (M+–Cl, 42), 174 (85), 160 (100); Anal: Calcd.for
C11H10ClNO4 C, 51.68; H, 3.94; Found C, 51.55; H, 3.82%.
(Z)-ethyl 2-(chloromethyl)-3-phenylacrylate (2i): Oil (lit.19).
1
IR (film)/cm-1: 1718, 1628, 1591, 1457, 1056; H NMR (400 MHz,
CDCl3): d 7.82 (1H, s), 7.58–7.42 (5H, m), 4.45 (2H, s), 4.34 (2H, q,
J = 7.0 Hz), 1.40 (3H, t, J = 7.1 Hz); MS: m/z (%) 224 (M+, 12), 189
(M+–Cl, 100), 129 (31).
(Z)-ethyl 2-(chloromethyl)-3-(2-chlorophenyl)acrylate (2j): Oil
(lit.19). IR (film)/cm-1: 1724, 1648, 1590, 1437; 1H NMR (400 MHz,
CDCl3): d 7.74 (1H, s), 7.61–7.22 (4H, m), 4.38 (2H, q, J = 7.6 Hz),
4.30 (2H, s), 1.38 (3H, t, J = 7.6 Hz); MS: m/z (%) 258 (M+, 100),
224 (M+–Cl, 42), 136 (45), 111 (21).
(Z)-methyl 2-(chloromethyl)-3-(2-chlorophenyl)acrylate (2b): White
solid, m.p. 41–42°C. IR (KBr)/cm-1: 1709, 1630, 1359; 1H NMR
(400 MHz, CDCl3): d 7.94 (1H, s), 7.63-7.31 (4H, m), 4.33 (2H, s), 3.87
(3H, s); MS: m/z (%) 244 (M+, 5.1), 209 (M+–Cl, 100), 149 (12); Anal:
Calcd.for C11H10Cl2O2 C, 53.90; H, 4.11; Found C, 54.05; H, 4.12%.
(Z)-methyl 2-(chloromethyl)-3-(4-chlorophenyl)acrylate (2c): Oil.
We thank the National Natural Science Foundation of China
(Project No. 20572068) and Innovation Fund of Shanghai
University for financial support.
Received 10 December 2007; accepted 31 January 2008
Paper 07/4987
doi: 10.3184/030823408X287113
1
IR (film)/cm-1: 1718, 1631, 1591, 1490, 1437; H NMR (400 MHz,
CDCl3): d 7.82 (1H, s), 7.50 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.4 Hz),
4.44 (2H, s), 3.89 (3H, s); MS: m/z (%) 244 (M+, 100), 246 (M+ + 2,
52), 248 (M+ + 4, 10), 209 (M+–Cl, 76), 149 (67); Anal: Calcd.for
C11H10Cl2O2 C, 53.90; H, 4.11; Found C, 53.97; H, 4.26%.
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1
2
3
4
5
6
7
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(Z)-methyl 2-(chloromethyl)-3-(2-nitrophenyl)acrylate (2f): Yellow
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1H NMR (400 MHz, CDCl3): d 8.24 (1H, d, J = 8.0 Hz), 8.12 (1H, s),
7.79 (1H, t, J = 7.6 Hz), 7.68 (1H, t, J = 7.6 Hz), 7.63 (1H, d, J = 8.0 Hz),
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PAPER: 07/4987