Regio- and stereoselective ring opening of epoxides and aziridines using zirconyl chloride: An efficient approach for the synthesis of β-chlorohydrins and β-chloroamines

Article abstract of DOI:10.1246/cl.2007.82

Zirconyl chloride mediated regio- and stereoselective ring opening of epoxides and aziridines at room temperature affords the corresponding β-chlorohydrins and β-chloroamines, respectively in high yields. Copyright

Full text of DOI:10.1246/cl.2007.82

82
Chemistry Letters Vol.36, No.1 (2007)
Regio- and Stereoselective Ring Opening of Epoxides and Aziridines Using Zirconyl Chloride:
An Efficient Approach for the Synthesis of ꢀ-Chlorohydrins and ꢀ-Chloroamines
Biswanath Das,ꢀ Maddeboina Krishnaiah, and Katta Venkateswarlu
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received August 22, 2006; CL-060962)
Zirconyl chloride mediated regio- and stereoselective ring
opening of epoxides and aziridines at room temperature affords
the corresponding ꢀ-chlorohydrins and ꢀ-chloroamines, respec-
tively in high yields.
a
Table 1. Ring opening of epoxides and aziridines with ZrOCl2
Time
/min
Isolated
yield/%b
Entry
Epoxide/Aziridine 1
Product 2
O
Cl
OH
a
20
98
O
O
O
Ring opening of epoxides and aziridines with nucleophiles
to prepare 1,2-difunctional molecules is an important transfor-
mation in organic synthesis.2 With halide nucleophiles, they
can be converted into vicinal halohydrins and haloamines which
are useful precursors for the synthesis of halogenated natural
products and other bioactive compounds.3 The ring opening of
epoxides to form halohydrins can be accomplished with halo-
gens, hydrogen halides, and metal halides.4 Additionally, some
other chlorides, such as TMSCl,5a,5b SOCl2,5c SiCl4,5d Bu4NCl,
and NH4Cl5e have been used for conversion of epoxides into
ꢀ-chlorohydrins. Aziridine rings can also be cleaved with metal
halides.3b,4d,6 However, many of the earlier methods are associ-
ated with different disadvantages such as high temperature, un-
availability of the reagents, unsatisfactory yields, and low regio-
selectivity. Hence, it is desirable to develop a convenient and ef-
ficient general method for the preparation of vicinal halohydrins
and haloamines from epoxides and aziridines, respectively.
In recent years, ZrIV salts have gained much attention as
reagents and catalysts due to their interesting reactivity, easy
availability, and low toxicity.7 ZrCl4 has already been utilized
in various chemical transformations.8 However, like other metal
oxysalt-based organic reactions, zirconyl chloride (ZrOCl2)-
mediated synthetic transformations are limited.9 The utilities
of the reagent in organic syntheses are yet to be explored. In
continuation of our work8e,8f on the applications of zirconium
compounds for the development of useful synthetic methodolo-
gies, we have recently observed that ZrOCl2 can efficiently be
employed for ring opening of both epoxides and aziridines
(Scheme 1).
Cl
b
c
30
40
82
98
OH
OH
Cl
O
O
O
O
OH
O
O
Cl
d
e
f
40
40
45
95
96
94
F
F
OH
O
O
O
Cl
Cl
Cl
OH
O
O
O
Cl
Cl
Cl
OH
O
O
O
Cl
g
h
70
50
80
81
MeO
MeO
OH
Cl
O
O
O
OH
O
i
j
Cl
30
40
95
89
Cl
Cl
OH
O
Cl
OH
O
k
l
20
25
98
98
Cl
OH
O
Cl
Cl
NTs
Several epoxides and N-tosyl aziridines were treated10 with
ZrOCl2 at room temperature to prepare the corresponding ꢀ-
chlorohydrins and ꢀ-chloroamines, respectively in high yields
(Table 1). The epoxides were converted within short period
but aziridines took somewhat longer times.
NHTs
m
n
30
45
92
90
Cl
NTs
NHTs
NHTs
NTs
o
p
q
7.5c 83(7)
Cl
The ring opening of epoxides and aziridines with ZrOCl2
NHTs
NTs
8c
7c
80(6)
88
Cl
NHTs
Cl
OH
Cl
ZrOCl2
MeCN
O
NTS
NTS
NTS
Cl
OH
80–98%
+
NHTS
20–70 min r. t.
R
R
r
7c
8c
86
R
Cl
ZrOCl2
MeCN
Cl
NHTs
NHTS
NTs
s
85
Cl
NHTs
Cl
0.5–8 h r. t.
+
R
R
R
aThe structures of the products were established from their spec-
85–92%
tral (1H NMR and MS) and analytical data. Yield reported in
parentheses is for other regioisomer. The reaction time in h.
b
c
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
83
7
8
J. E. Huheey, Inorganic Chemistry, 3rd ed., Roger and Harper
Row, Singapore, 1990.
was found to occur with high regio- and stereoselectivity. 2-Ar-
ylepoxides and N-tosyl-2-arylaziridines formed the products by
nucleophilic attack of the chloride ion at the benzylic position
while 2-alkylepoxides and N-tosyl-2-alkylaziridines afforded
the products by the attack at the terminal position. Only one
regioisomer was obtained by ring opening of chalcone oxide
(Table 1, Entry b) under the present experimental conditions.
Previously, the same reaction using other catalysts provided both
the regioisomers of the corresponding ꢀ-chlorohydrins.4d,5a
Thus, the present method employing ZrOCl2 is more advanta-
geous to the earlier related methods. However, in the case of
N-tosyl-2-alkylaziridines minor amounts of other regioisomers
were also obtained. The ring opening of bicyclic epoxides and
N-tosyl aziridines yielded the corresponding ꢀ-chlorohydrins
and ꢀ-chloroamines, respectively with trans-configuration. The
structures and stereochemistry of the products were character-
ized from their analytical and spectral (1H NMR and MS) data.10
In conclusion, ZrOCl2 has efficiently been utilized for
the first time for regio- and stereoselective ring opening of
epoxides and aziridines at room temperature to produce the
corresponding 2-chlorohydrins and 2-chloroamines, respectively
in high yields.
a) K. P. Chary, S. Raja Ram, D. S. Iyengar, Synlett 2000, 683.
b) J. S. Yadav, B. V. S. Reddy, K. S. Roy, K. B. Reddy,
A. R. Prasad, Synthesis 2001, 2277. c) G. Smitha, Ch. S. Reddy,
Synthesis 2004, 834. d) A. K. Chakraborti, R. Gulhane, Synlett
2004, 627. e) B. Das, V. S. Reddy, Chem. Lett. 2004, 33, 1428.
f) B. Das, M. R. Reddy, V. S. Reddy, R. Ramu, Chem. Lett.
2004, 33, 1526.
a) M. Easwaramurthy, R. Ravikumar, A. J. Lakshmanan, G. J.
Raju, Indian J. Chem., Sect. B 2005, 44, 635. b) T. Yakaiah,
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9
10 General experimental procedure: To a solution of an epoxide
or N-tosylaziridine (1 mmol) in MeCN (5 mL) ZrOCl2 (1.2
mmol) was added and the mixture was stirred at room temper-
ature. After completion of the reaction (TLC) the mixture was
diluted with EtOAc (10 mL) followed by washing with brine
(20 mL) and water (2 ꢁ 10 mL). The organic portion was dried
and concentrated. The crude material was purified by column
chromatography (silica gel, hexane–EtOAc) to furnish pure
ꢀ-chlorohydrin or N-tosyl-ꢀ-chloroamine. The spectral (IR,
1H NMR and MS) and analytical data of some representative
products are given below.
Product 2a: 1H NMR (CDCl3, 200 MHz): ꢁ 7.40–7.28 (5H, m),
4.89 (1H, t, J ¼ 7:0 Hz), 3.88–3.76 (2H, m), 2.83 (1H, brs);
The authors thank CSIR and UGC, New Delhi for financial
assistance.
ꢂ
FABMS: m=z 159, 157 [M + H]þ ; Anal. Calcd for C8H9ClO:
C, 61.34; H, 5.75%. Found: C, 61.46; H, 5.64%.
References and Notes
1
Product 2g: 1H NMR (CDCl3; 200 MHz): ꢁ 7.09 (2H, d,
J ¼ 8:0 Hz), 6.80 (2H, d, J ¼ 8:0 Hz), 4.12 (1H, m), 4.05–
3.98 (2H, m), 3.79–3.62 (2H, m), 3.51 (2H, t, J ¼ 7:0 Hz),
3.31 (3H, s), 2.75 (2H, t, J ¼ 7:0 Hz), 2.72 (1H, brs); FABMS:
Part 97 in the series ‘‘Studies on novel synthetic methodolo-
gies.’’ IICT Communication No. 061117.
2
a) R. E. Parker, N. S. Isaacs, Chem. Rev. 1959, 59, 737. b) J. E.
G. Kemp, in Comprehensive Organic Synthesis, ed. by B. M.
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a) R. E. Moore, in Marine Natural Products, ed. by P. J.
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76, 1259. b) C. Einhorn, J. L. Luche, J. Chem. Soc., Chem.
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Turos, Tetrahedron Lett. 1992, 33, 7093. d) I. Shibata, N.
Yoshimura, A. Baba, H. Matsuda, Tetrahedron Lett. 1992, 33,
7149. e) M. Shimizu, A. Yoshida, T. Fujisawa, Synlett 1992,
204. f) H. Kotsuki, T. Shimanouchi, Tetrahedron Lett. 1996,
37, 1845. g) N. Iranpoor, T. Tarrian, Z. Movahedi, Synthesis
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ꢂ
m=z 247, 245 [M + H]þ ; Anal. Calcd for C12H17ClO3: C,
58.90; H, 6.95%. Found: C, 58.82; H, 6.91%.
Product 2h: 1H NMR (CDCl3, 200 MHz): ꢁ 7.33–7.21 (5H, m),
4.54 (2H, s), 3.81 (1H, dd, J ¼ 11:0, 2.0 Hz), 3.70 (1H, d,
J ¼ 9:0 Hz), 3.29 (1H, d, J ¼ 9:0 Hz), 2.50 (1H, brs), 2.12
3
4
(1H, m), 1.51 (1H, m), 1.16 (3H, s), 1.08 (3H, d, J ¼ 7:0 Hz);
ꢂ
FABMS: m=z 245, 243 [M + H]þ
; Anal. Calcd for
C13H19ClO2: C, 64.33; H, 7.83; Cl, 14.64%. Found: C, 64.38;
H, 7.79; Cl, 14.69%.
Product 2l: 1H NMR (CDCl3; 200 MHz): ꢁ 3.68 (1H, ddd, J ¼
9:8, 9.1, 3.8 Hz), 3.46 (1H, ddd, J ¼ 9:5, 9.1, 3.8 Hz), 2.51 (1H,
brs), 2.30–2.06 (2H, m), 1.85–1.52 (4H, m), 1.41–1.22 (2H, m);
ꢂ
FABMS: m=z 137, 135 [M + H]þ ; Anal. Calcd for C6H11ClO:
C, 53.53; H, 8.18%. Found: C, 53.46; H, 8.24%.
1
Product 2m: H NMR (CDCl3, 200 MHz): ꢁ 7.73 (2H, d, J ¼
8:0 Hz), 7.39–7.25 (7H, m), 4.92 (1H, t, J ¼ 7:0 Hz), 4.87
(1H, t, J ¼ 7:0 Hz), 3.48–3.34 (2H, m), 2.45 (3H, s); FABMS:
ꢂ
m=z 312, 310 [M + H]þ ; Anal. Calcd for C15H16ClNO2S: C,
58.16; H, 5.17; N, 4.52%. Found: C, 58.28; H, 5.24; N, 4.45%.
Product 2o: 1H NMR (CDCl3, 200 MHz): ꢁ 7.75 (2H, d, J ¼
8:0 Hz), 7.24 (2H, d, J ¼ 8:0 Hz), 5.32 (1H, d, J ¼ 6:0 Hz),
3.48–3.33 (2H, m), 3.20 (1H, m), 2.39 (3H, s), 1.52–1.30
(2H, m), 1.22–1.01 (4H, m), 0.82 (3H, t, J ¼ 7:0 Hz); FABMS:
ꢂ
m=z 292, 290 [M + H]þ ; Anal. Calcd for C13H20ClNO2S: C,
5
6
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5, 2543. c) K. Surendra, N. S. Krishnaveni, Y. D. V. Nageswar,
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a) J. S. Yadav, B. V. S. Reddy, G. M. Kumar, Synlett 2001,
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53.89; H, 6.91; N, 4.84%. Found: C, 53.94; H, 6.95; N, 4.81%.
Product 2r: 1H NMR (CDCl3, 200 MHz): ꢁ 7.82 (2H, d,
J ¼ 8:0 Hz), 7.31 (2H, d, J ¼ 8:0 Hz), 5.85 (1H, d, J ¼ 6:0
Hz), 4.05 (1H, ddd, J ¼ 9:5, 9.0, 3.7 Hz), 3.54 (1H, m), 2.42
(3H, s), 2.22–2.01 (2H, m), 1.85–1.69 (2H, m), 1.63–1.32
ꢂ
(4H, m); FABMS: m=z 290, 288 [M + H]þ ; Anal. Calcd for
C13H18ClNO2S: C, 54.26; H, 6.26; N, 4.87%. Found: C,
54.38; H, 6.32; N, 4.81%.
Published on the web (Advance View) November 29, 2006; doi:10.1246/cl.2007.82