Synthesis of β-chlorohydrins in water

Article abstract of DOI:10.1002/hlca.200790008

2,4,6-Trichloro-1,3,5-triazine (TCT, cyanuric chloride) was found to mediate the regio- and stereoselective ring opening of epoxides in H ₂O in the presence of morpholine at room temperature to afford the corresponding β-chlorohydrins in excellent yields (Table). The transformation is very simple, fast, efficient, and ecologically beneficial.

Full text of DOI:10.1002/hlca.200790008

Helvetica Chimica Acta – Vol. 90 (2007)
149
Synthesis of b-Chlorohydrins in Water1)
by Biswanath Das*, Katta Venkateswarlu, and Maddeboina Krishnaiah
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(phone: +91-40-7193434; fax: +91-40-7160512; e-mail: biswanathdas@yahoo.com)
2,4,6-Trichloro-1,3,5-triazine (TCT, cyanuric chloride) was found to mediate the regio- and stereose-
lective ring opening of epoxides in H2O in the presence of morpholine at room temperature to afford the
corresponding b-chlorohydrins in excellent yields (Table). The transformation is very simple, fast, effi-
cient, and ecologically beneficial.
Introduction. – The ring opening of epoxides by halide nucleophiles produces vici-
nal halohydrins, which are useful intermediates for the synthesis of halogenated marine
natural products and various other bioactive compounds [1]. This transformation can
be carried out with halogens, hydrogen halides, and metal halides in organic solvents
such as MeCN or CH2Cl2 [2]. However, many of these methods are associated with sev-
eral disadvantages, including harsh reaction conditions, unsatisfactory yields, and poor
selectivity. Thus, an improved protocol for the conversion of epoxides into the corre-
sponding vicinal halohydrins is essential.
Cyanuric chloride, i.e., 2,4,6-trichloro-1,3,5-triazine (TCT), is a safe and inexpensive
reagent being used in various chemical transformations in organic media [3]. In contin-
uation of our work on the development of useful synthetic methodologies [4], we
recently observed that the ring opening of epoxides can efficiently be carried out
with TCT in the presence of morpholine in H2O at room temperature to form the cor-
responding b-chlorohydrins (Scheme 1). Herein, we report the results and synthetic
details of this useful transformation.
Scheme 1
1
)
Part 108 in the series ꢀStudies on Novel Synthetic Methodologiesꢁ; IICT Communication No. 061227.
ꢂ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 90 (2007)
Results and Discussion. – As can be seen from the Table, chlorohydrin formation
readily took place by simply stirring a mixture of TCT (2 mmol), morpholine (5
mmol), and epoxide (5 mmol) in H2O at ambient temperature for 5–45 min. With sty-
rene oxide (Entry 1), the reaction took only 5 min, affording 2-chloro-2-phenylethanol
in 99% yield. The reaction was highly efficient, both for aromatic and aliphatic or ali-
cyclic substrates. Even sterically hindered epoxides, derived from trisubstituted olefins
(Entry 8), underwent the cleavage smoothly.
The conversion of epoxides into b-chlorohydrins took place with high regio- and
stereoselectivity. In 2-aryl epoxides (Entries 1 and 2), nucleophilic attack of ClÀ occur-
red at the benzylic position. In contrast, 2-alkyl or 2-aryloxy epoxides gave rise to prod-
ucts derived by attack at the terminal 3-position. The ring opening of bicyclic epoxides
(Entries 11 and 12) occurred with anti selectivity to form the trans-configured products
exclusively. The structures of the b-chlorohydrins were settled by spectroscopic (IR, 1H-
NMR), spectrometric (MS), and elemental analyses.
From a mechanistic point of view, the present conversion possibly takes place as fol-
lows. Reaction between morpholine and TCT liberates HCl in situ, as indicated by gas
evolution upon mixing of these two components, before addition of H2O (Scheme 2).
Then, HCl protonates the epoxide O-atom, followed by nucleophilic ring opening. In
the absence of morpholine, the reaction between epoxide and TCT in H2O afforded
a mixture of products, including b-chlorohydrins and 1,2-dihydroxy compounds. Note
that morpholine derivatives have been used earlier together with TCT in other organic
syntheses [3b].
Scheme 2
In conclusion, we have synthesized a number of b-chlorohydrins by regio- and ster-
eoselective ring opening of epoxides applying cyanuric chloride (TCT) in the presence
of morpholine in H2O. The efficiency, and the economic and environmental benefits of
this reaction are the notable features of our synthetic protocol.
We thank CSIR and UGC, New Delhi, for financial assistance.
Experimental Part
General. IR Data are reported in cmÀ1. 1H-NMR Chemical shifts d and coupling constants Jare given
in ppm (rel. to Me4Si) and in Hz, resp. Mass-spectrometric (MS) data are reported in m/z.
Synthetic Procedure. To a mixture of TCT (2 mmol), morpholine (5 mmol), and an epoxide (5 mmol)
was added H2O (5 ml), and the mixture was stirred at r.t. (TLC control). After completion of the reaction,

Helvetica Chimica Acta – Vol. 90 (2007)
Table. Preparation of b-Chlorohydrins
Time [min] Product
151
Entry Epoxide
Isolated yield [%] Ref.
1
5
99
87
98
97
98
[2c]
[2f]
[2c]
–
2
3
4
5
15
20
30
25
[2e]
6
7
25
30
96
98
–
[2g]
8
9
45
25
81
92
–
[2d]
10
20
96
[2d]
11
12
15
15
98
98
[2d]
[2d]
H2O (10ml) was added, and the mixture was filtered. The filtrate was extracted with AcOEt (3”5 ml),
dried (Na2SO4), and concentrated in vacuo. The crude residue was subjected to column chromatography
(SiO2, hexane/AcOEt) to afford the pure b-chlorohydrin. Selected anal. data are presented below.

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Helvetica Chimica Acta – Vol. 90 (2007)
1-Chloro-3-(3-chlorophenoxy)propan-2-ol (Table, Entry 4). Colorless liquid. IR (KBr): 3416, 1607,
1384. 1H-NMR (200 MHz, CDCl3): 7.32 (dd, J=8.0, 2.0, 1 H); 7.28–7.16 (m, 1 H); 6.97–6.86 (m, 2 H);
4.20( m, 1 H); 4.18–4.05 (m, 2 H); 3.88–3.71 (m, 2 H); 2.65 (d, J=6.5, 1 H). FAB-MS: 221/223/225
([M+H]+). Anal. calc. for C9H10Cl2O2: C 48.89, H 4.56; found: C 48.82, H 4.58.
1-Chloro-3-(4-fluorophenoxy)propan-2-ol (Table, Entry 6). Pale-yellow liquid. IR (KBr): 3414, 1618,
1491. 1H-NMR (200 MHz, CDCl3): 7.22 (d, J=8.0, 2 H); 6.83 (d, J=8.0, 2 H); 4.15 (m, 1 H); 4.07–3.98
(m, 2 H); 3.74–3.67 (m, 2 H); 2.68 (br. s, 1 H). FAB-MS: 205/207 ([M+H]+). Anal. calc. for C9H10ClFO2:
C 52.83, H 4.93; found: C 52.88, H 4.82.
(2S,3R)-1-(Benzyloxy)-3-chloro-2-methylpentan-2-ol (Table, Entry 8). Colorless liquid. IR (KBr):
3418, 1617, 1512, 1496. 1H-NMR (200 MHz, CDCl3): 7.33–7.21 (m, 5 H); 4.54 (s, 2 H); 3.81 (dd,
J=11.0, 2.0, 1 H); 3.70 (d, J=9.0, 1 H); 3.29 (d, J=9.0, 1 H); 2.50 (br. s, 1 H); 2.12 (m, 1 H); 1.51 (m,
1 H); 1.16 (s, 3 H); 1.08 (d, J=7.0, 3 H). FAB-MS: 243/245 ([M+H]+). Anal. calc. for C13H19ClO2: C
64.32, H 7.89; found: C 64.38, H 7.79.
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Received October 3, 2006