Difluorocarbene induced of facile synthesis of chlorohydrins from glycidyl ethers

Article abstract of DOI:10.1139/v04-093

A novel and unusual approach based on a ClCF₂COONa-DMF system has been developed for the synthesis of chlorohydrins via an unexpected mechanism. In a first ever report for the synthesis of chlorohydrins from glycidyl ethers, e.g., CH₂=CH-CH₂-O-Z, CH ₃CH₂-O-Z, C₆H₅-O-Z, C ₆H₄(o-CH₃)-O-Z, CH₂=C(CH ₃)C(=O)-O-Z, etc., (where Z = glycidyl), difluorocarbene-induced facile regioselective ring opening of epoxides has generated the compound in high yield (70%-83%).

Full text of DOI:10.1139/v04-093

1249
Difluorocarbene induced facile synthesis of
chlorohydrins from glycidyl ethers
Sapna Singh, Pinaki S. Bhadury, Mamta Sharma, Meehir Palit, and
Devendra K. Jaiswal
Abstract: A novel and unusual approach based on a ClCF2COONa–DMF system has been developed for the synthesis
of chlorohydrins via an unexpected mechanism. In a first ever report for the synthesis of chlorohydrins from glycidyl
ethers, e.g., CH2=CH-CH2-O-Z, CH3CH2-O-Z, C6H5-O-Z, C6H4(o-CH3)-O-Z, CH2=C(CH3)C(=O)-O-Z, etc., (where Z =
glycidyl), difluorocarbene-induced facile regioselective ring opening of epoxides has generated the compound in high
yield (70%–83%).
Key words: difluorocarbene, sodium chlorodifluoroacetate, chlorohydrins.
Résumé : On a mis au point une nouvelle approche inhabituelle à la synthèse de chlorohydrines qui est basée sur
l’utilization du système ClCF2COONa–DMF et qui implique un mécanisme inattendu. Dans ce travail, on en décrit la
première application à la synthèse de chlorohydrines d’éthers glycidylés de la forme CH2=CH-CH2-O-Z, CH3CH2-O-Z,
C6H5-O-Z, C6H4(o-CH3)-O-Z, CH2=C(CH3)C(=O)-O-Z, etc., (dans lesquels Z = glycidyle) qui ont été générés avec des
rendements élevés (70%–83%) par le biais d’une ouverture de cycle régiosélective et facile d’époxydes, induite par le
difluorocarbène.
Mots clés : difluorocarbène, chlorodifluoroacétate de sodium, chlorohydrines.
[Traduit par la Rédaction] Singh et al. 1253
Introduction
chromyl chloride with simple aliphatic straight chain alkenes
(8–11). The application of these reagents is further limited
due to poor yield and the specific nature of the substrate. In
this paper, we describe a new way to make them based on
the special properties of the sodium chlorodifluoroacetate –
DMF system. The difluorocarbene (:CF2) induced regio-
selective ring opening of epoxides produces chlorohydrins in
high yield with the chlorine atom almost exclusively located
on the primary and (or) less-hindered carbon atom. This
highly facile reaction works particularly well with electron
deficient epoxides and has been successfully employed for
the first time in the ring opening of glycidyl ethers.
Difluorocarbene, a useful synthon (1–3), can be made by
thermal decarboxylation of sodium chlorodifluoroacetate. In
dimethyl formamide (DMF), this salt can act as a source of
hydrogen fluoride (4–7). We showed that this property
enabled the esterification of sodium chlorodifluoroacetate
by fluoroalcohols (5). Here, we attempted to prepare O-
(chlorodifluoroacylated) alcohols by treating various
epoxides with sodium chlorodifluoroacetate in DMF. How-
ever, ring opening occurred to give chlorohydrins. Chloro-
hydrins are an important class of compounds that have
several synthetic and industrial applications, including the
manufacture of dye intermediates, pharmaceuticals, pesti-
cides, and plasticizers. Routes to conventional chlorohydrins
include hypochlorination, enzymatic methods, or reaction of
Results and discussion
We have achieved regioselective synthesis of chlorohydrins
by the reaction of epoxides and sodium chlorodifluoro-
acetate in DMF. This highly facile reaction works particu-
larly well with electron deficient epoxides (e.g., glycidyl
ethers). Furthermore, the reaction proceeds in DMF only,
and no significant product could be detected in other sol-
vents such as diglyme, triglyme, acetonitrile, and dimethyl
sulphoxide.
Received 20 April 2004. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 22 October 2004.
S. Singh, P.S. Bhadury,1 M. Sharma, M. Palit, and
D.K. Jaiswal. Synthetic Chemistry Division, Defence
Research and Development Establishment, Gwalior 474 002,
India.
1Corresponding author (e-mail: drpsb2003@yahoo.co.in).
Can. J. Chem. 82: 1249–1253 (2004)
doi: 10.1139/V04-093
© 2004 NRC Canada

1250
Can. J. Chem. Vol. 82, 2004
Table 1. Synthesis of chlorohydrins.
Compound no.
R
Isolated yield (%)
CH2=CH-CH2-O-CH2
C6H5-O-CH2
I
II
72
75
75
77
83
70
81
0
III
IV
V
C6H4(o-CH3)-O-CH2
C6H4(p-OCH3)-O-CH2
C6H4(p-NO2)-O-CH2
CH3CH2-O-CH2
CH2=C(CH3)C(=O)-O-CH2
CH3(CH2)2CH2
CH3(CH2)4CH2
HO-CH2
VI
VII
VIII
IX
X
0
27
1
Synthesis of a series of chlorohydrins has been achieved
by heating 1 mol of monoepoxides with 2 mol of sodium
chlorodifluoroacetate in DMF under a nitrogen atmosphere
at a temperature of 150 °C. The compounds synthesized
are listed in Table 1. With diepoxide 1,4 butanediol digly-
cidyl ether, under similar conditions, the reaction required
4 mol of sodium chlorodifluoroacetate. The ring opening
occurs at both epoxide centers giving rise to
ClCH2CH(OH)CH2O(CH2)4OCH2CH(OH)CH2Cl (XI) in
71% yield.
Fig. 1. Representative H NMR pattern of CH2Cl in the product
chlorohydrin.
All compounds synthesized have been characterized on
1
the basis of IR spectra, H and 13C NMR, and mass spectral
data. Purity of the products (>98%) was confirmed by
1H NMR and GC–MS studies. IR showed strong bands in
1
the region 3360–3446 (OH) and 725–752 (C-Cl) cm–1. H
NMR data were consistent with the assigned structures and
chemical shift values were assigned on the basis of observed
splitting patterns and shielding and (or) deshielding effects
exerted by neighboring groups or atoms (Table 2). This as-
signment was further confirmed from two-dimensional homo
correlation spectroscopy (1H–1H HOMOCOSY) by observ-
ing contours indicative of characteristic coupling among all
nonequivalent protons. The characteristic pattern of the
chlorohydrins and described in Table 3. Physical characteris-
tics (bp and (or) mp) of product chlorohydrins are also given
in Table 3. Analytical data for elemental analysis (C and H
for I–IV, VI, VII, and XI) and (C, H, and N for V) were
found to be in agreement with calculated values.
Formation of difluorocarbene from the present system
(ClCF2COONa–DMF) and its participation in several syn-
thetic transformations has been noted by several groups of
workers (5, 12, 13). To account for the formation of chloro-
hydrins, we presume that under the influence of :CF2, ob-
tained by heating ClCF2COONa, the solvent DMF probably
generates an active fluoro Vilsmeier–Haack intermediate
[Me2N–+CHF]F– (i, Scheme 1).
Proof of the formation of this strong Lewis acid interme-
diate (i) has been provided by Burton and Wiemers (4). It is
probably that this coordinates with the epoxide oxygen
atom. Any possibility of protonation on the β-oxygen (in the
alkyl group R) and its subsequent participation in the reac-
tion is ruled out on the ground that in the end, the product
alkyl group has been found to remain intact. The SN2 attack
on the primary carbon atom by the chlorodifluoroacetate an-
ion, electrophilically assisted by protonation of epoxide ring
(14), generates the intermediates O-(chlorodifluoroacylated)
alcohols (ii) (5). The nucleophilic attack occurs almost ex-
clusively at the less-hindered carbon atom probably due to a
1
starting epoxide ring was absent in H NMR, confirming the
complete ring opening. The integration ratio for all the
1
protons in their respective H NMR corresponds to the as-
signed structures. The representative and distinctive patterns
of two magnetically nonequivalent protons of CH2Cl moiety
in product chlorohydrin after ring opening is shown in
Fig. 1. Mass spectral data were recorded both in electron
ionization (EI) and chemical ionization (CI) modes. The
spectra were also obtained on silyl derivatives of chloro-
hydrins
obtained
through
silylation
with
N,O-
bis(trimethylsilyl)trifluoroacetamide (BSTFA); these were
particularly useful in cases where M+ was not detectable in
the original sample (Table 2). The presence of the
chloromethyl moiety in the chlorohydrins is further sup-
ported by the fragmentation pattern showing the characteris-
tic loss of CH2Cl (m/z 49/51) from the molecular ion in their
respective mass spectra. For unequivocal structural assess-
ment of products, 13C NMR data were obtained for all the
© 2004 NRC Canada

Singh et al.
1251
1
Table 2. H NMR and mass spectral data of the chlorohydrins.a
Compound No.
1H NMR δ (ppm), J (Hz)
Mass (m/z) EI (CI)
5.86 (1H, m, CH2=CH-CH2), 5.23, 5.10 (2H, m, CH2=CH-CH2), 4.27(1H, bs,
OH), 4.0 (2H, td, J = 5.2, 1.2, CH-CH2-O-), 3.88 (1H, m, CH-OH), 3.63, 3.61
(2H, m, CH2Cl), 3.45 (2H, d, J = 5.6, O-CH2-CHOH)
I
150/152, 109/111, 101, 93/95,
79/81,71, (151/153)
II
7.11 (5H, m, Ar), 4.55 (1H, bs, OH), 4.18 (1H, m, CH-OH), 4.06 (2H, d, J =
5.6, O-CH2-CH), 3.79, 3.76 (2H, m, CH2Cl)
186/188, 137, 109/111, 107,
93/95, 79/81,77, (187/189)
III
IV
6.97 (4H, m, Ar), 4.23 (1H, m,CH-OH), 4.08, 4.06 (2H, m, Ar-O-CH2-), 3.94
(1H, bs, OH), 3.76, 3.78 (2H, m, CH2Cl), 2.21 (3H, s, CH3)
200/202, 151, 109/111, 107,
93/95, 79/81,91, (201/203)
6.80 (4H, m, Ar), 4.13 (1H, m, CH-OH), 4.0, 3.96 (2H, m, Ar-O-CH2-), 3.66,
3.64 (2H, m, CH2Cl), 3.72 (3H,s, OCH3), 2.88 (1H, bs, OH)
As the silyl derivative:
288/290, 239, 181/183,
165/167, 151/153, 137, 123,
107, 73, (289/291)
V
7.0, 8.2 (4H, 2xd, Ar), 4.29 (1H, m, CH-OH), 4.20 (2H, d, J = 5.6, Ar-O-CH2 -), As the silyl derivative:
3.78, 3.76 (2H, m, CH2Cl), 2.90 (1H, bs, OH)
303/305, 254, 181/183,
165/167, 152, 151/153, 138,
122, 73, (304/306)
VI
3.65 (1H, m,CH-OH), 3.56 (1H, bs, OH), 3.34, 3.32 (2H, m, CH2Cl), 3.21 (4H,
m, CH2-O-CH2), 0.82 (3H, t, CH3CH2)
138/140, 109/111, 93/95, 89,
79/81, 59, (139/141)
VII
6.03 (2H, m, =CH2), 4.29 (2H, d, J = 5.8, -O-CH2), 4.13 (1H, m, CH-OH), 3.75
(1H, bs, OH), 3.67, 3.65 (2H, m, CH2Cl), 1.99 (3H, s, CH3)
As the silyl derivative:
250/252, 235/237, 201,
181/183, 165/167,151/153,
99, 85, 73, 69, (251/253)
X
4.31 (2H, d, J = 5.6, CH2OH), 4.13 (1H, m, CHOH), 3.77, 3.75 (2H, m, CH2Cl)
As the silyl derivative:
182/184, 165/167, 151/153,
133, 73, (183/185)
aWith 1,4 butanediol diglycidyl ether, a diepoxide, the ring opening occurs at both epoxide centers giving rise to
1
ClCH2CH(OH)CH2O(CH2)4OCH2CH(OH)CH2Cl (XI). H NMR (ppm) δ: 3.92 (2H, m, CHOH), 3.57, 3.54 (4H, m, CH2Cl), 3.48 (8H, m, CH2-O-CH2),
2.10 (1H, bs, OH), 1.60 (4H, m, CH2-CH2). Mass spectra EI (CI), m/z as the silyl derivative: 418/420/422, 369/371, 267/269, 253/255, 237/239,116,73
(419/421/423).
steric factor. However, the ester intermediate is short lived
and in the presence of an electron attracting environment
decarboxylates readily to generate chlorodifluoromethide ion
(CF2Cl–), which decomposes to regenerate :CF2 and Cl–
ions. The simultaneous attack of the Cl ion on the primary
positive carbon yields the desired chlorohydrins. As with
most other SN2 displacements, the method works well with
electron-poor epoxides like alkyl, allyl, and aryl glycidyl
ethers and with glycidyl methacrylate and 1,4 butanediol
diglycidyl ether, but fails to take place with 1,2-epoxyoctane
and butyloxirane. A similar observation was noted earlier
when O-(chlorodifluoroacylated) alcohols were formed from
electron-deficient alcohols using this system (5). With mod-
erately electron-deficient epoxides containing active alco-
holic (-OH) functionality (e.g., glycidol), the yield of the
desired chlorohydrin (X) is poor.
Taking o-cresyl glycidyl ether as the model epoxide, the
reaction was carried out at different time intervals with so-
dium chlorodifluoroacetate in DMF. The intermediate O-
(chlorodifluoroacylated) species (ii, Scheme 1) was detected
(EI-MS m/z: 294/296 (M+), 187/189,108, 85/87) along with
the product chlorohydrin (iii), after heating the reaction mix-
ture for 0.5 h at 150 °C. On further heating for 1 h, the inter-
mediate disappeared and chlorohydrin was detected as the
main product in solution. If the heating was continued fur-
ther (e.g., after 3 h), the chlorodifluoroacylated derivative of
chlorohydrin, (o-CH3)C6H4OCH2CH(OCOCF2Cl)CH2Cl, EI-
MS m/z: 312/314/316 (M+), 205/207/209, 91, δ CF2 –61.6),
similar to our earlier observation with fluoroalcohols (5),
started appearing. A similar observation including in situ de-
tection of an O-(chlorodifluoroacylated) intermediate was
noted with other epoxides. These observations support our
proposed mechanism as shown in Scheme 1.
Conclusion
In summary, the ClCF2COONa–DMF mixture works as a
facile reagent system for the preparation of chlorohydrins
from electron-deficient epoxides. The difluorocarbene (:CF2)
induced regioselective ring opening reported for the first
time on glycidyl ethers is simple, facile, does not require any
prior reagent preparation and is devoid of any appreciable
side reaction products. Using a similar system, fluoro-
hydrins, volatile CFC alternatives, and perfluoroolefins have
been obtained, which wwill be subsequently communicated.
Experimental
Reactions were monitored by GC–MS and the mass spec-
tra were recorded on a TSQ 7000 mass spectrometer
© 2004 NRC Canada

1252
Can. J. Chem. Vol. 82, 2004
Table 3. 13C NMR and physical characteristic data of the chlorohydrins.
Boiling point or
[melting point] (°C)
138–140 (2 mmHg)a
Chlorohydrin
13C NMR (δ ppm)
157.2 (C4), 129.5 (C8 and C6),
120.0 (C7), 115.1 (C9 and
C5), 69.7 (C3), 68.7 (C2),
46.0 (C1)
156.4 (C4), 130.9 (C6), 127.0
(C8), 126.8 (C5), 121.4 (C7),
111.5 (C9), 69.4 (C3), 68.6
(C2), 46.1 (C1) 16.1 (C10)
143–145 (0.5 mmHg)a
154.1 (C7), 151.6 (C4), 115.8
(C5 and C9), 114.5 (C8 and
C6), 70.3 (C3), 68.9 (C2),
56.9 (C10), 46.4 (C1)
[68–70]
165.3 (C4), 140.5 (C7), 125.3
(C8 and C6), 116.0 (C9 and
C5), 70.8 (C3), 70.1 (C2),
47.0 (C1)
[97–99]
68.6 (C3), 67.9 (C2), 61.8 (C4),
46.0 (C1), 14.2 (C5)
64–66 (4 mmHg)a
123–125 (16 mmHg)a
164.5 (C4), 138.7 (C5), 122.0
(C6), 68.5 (C3), 67.9 (C2),
45.9 (C1), 17.9 (C7)
137.2 (C5), 115.2 (C6), 69.0
(C3), 68.6 (C4), 68.2 (C2),
46.3 (C1)
110–112 (20 mmHg)a
119–121 (0.8 mmHg)a
68.8 (C3), 67.6 (C4), 67.1 (C2),
46.2 (C1), 27.5 (C5)
a1 mmHg = 133.3224 Pa.
(Finigan MAT, USA) using a Varian 3400 GC inlet with a
BP-5 column (30 m × 2.5 mm (i.d.) × 0.25 µm (film thick-
ness) with a temperature program of 50 °C (2 min) – at
10 °C/min – 280 °C (5 min) using helium as carrier gas at a
flow rate of 1.2 mL/min. The injector temperature was
250 °C and the transfer line was heated to 280 °C. EI-MS
was performed at 70 eV with the ion source temperature
180 °C and an emission current of 400 mA. The CI-MS ex-
periments were performed using methane as a reagent gas at
pressure 2500 mtorr (1 torr = 133.3224 Pa), source tempera-
storing on a 4 Å Linde molecular sieve followed by distilla-
tion under vacuum.
Synthesis of chlorohydrins
Sodium salt of chlorodifluoroacetic acid (6.1 g, 0.04 mol
for all cases; except for compound No. XI, 12.2 g, 0.08 mol)
in 50 mL of dry DMF was placed in a 250 mL three-necked
flask, containing a stirring bar and a dry nitrogen inlet, at
room temperature. Epoxide (0.02 mol) was then added
slowly through a dropping funnel to the well-stirred mixture.
The temperature of the reaction mixture was raised to
150 °C and was further refluxed for 1 h. The course of the
reaction was followed by withdrawing a small aliquot of the
reaction mixture and subjecting it to GC–MS analysis. Ini-
tially the salt was soluble making a homogeneous solution in
DMF. On heating, the reaction mixture turned brown with
the deposition of a solid at the bottom of the flask, which in-
1
ture 200 °C, and emission current 300 mA. The H and 13C
NMR spectra of the chlorohydrins were recorded on a
Bruker Avance DPX-400 spectrometer in CDCl3 solution for
all except compound No. I, which was run in DMF-d7, using
TMS as the internal reference. 19F NMR of the intermediate
O-(chlorodifluoroacylated) derivatives was obtained using
CFCl3 as the internal standard. The epoxides were obtained
commercially and distilled before use. DMF was dried by
© 2004 NRC Canada

Singh et al.
1253
Scheme 1. A probable mechanism for the formation of chlorohydrins.
3. T. Taguchi, T. Takigawa, Y. Tawara, T. Morikawa, and Y.
Kobayashi. Tetrahedron Lett. 25, 5689 (1984).
4. D.J. Burton and D.M. Wiemers. J. Am. Chem. Soc. 107, 5014
(1985).
dicated completion of the reaction. The reaction mixture was
then filtered and the bulk of DMF was removed by distilla-
tion under vacuum. The residue, which still contained some
traces of solid, was separated by centrifugation. It was then
washed with excess water to remove the remaining DMF
and extracted into diethyl ether. The ether layer was dried
and then removed by distillation. The chlorohydrins were
obtained either by distillation under vacuum (compound
Nos. I–III, VI, VII, X, and XI) or by crystallization from
hexane (compound Nos. IV and V).
5. P.S. Bhadury, M. Palit, M. Sharma, S.K. Raza, and D.K.
Jaiswal. J. Fluorine Chem. 113, 47 (2002).
6. P.S. Bhadury, M. Palit, M. Sharma, S.K. Raza, and D.K.
Jaiswal. J. Fluorine Chem. 116, 75 (2002).
7. P.S. Bhadury. Ph.D. thesis, Jiwaji University, Gwalior, India,
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10. J.M. Klunder and G.H. Posner. In Comprehensive organic syn-
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p. 224.
Acknowledgement
We thank Mr. K. Sekhar, Director, D.R.D.E., Gwalior for
his keen interest in this work.
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© 2004 NRC Canada