DMSO-catalyzed chlorination of alcohols using N-phenylbenzimidoyl chloride

Article abstract of DOI:10.1007/s11164-012-0738-z

N-phenylbenzimidoyl chloride has been demonstrated as an efficient chlorination reagent catalyzed by dimethyl sulfoxide (DMSO) in conversion of alcohols to corresponding chlorides. The reaction conditions were mild, and most of the substrates gave satisfactory yields. The configuration inversion of the chlorination was proved using optically active phenyl alcohols. The amount of DMSO can be as low as 0.001 eq without reducing the efficiency of the chlorination. A plausible mechanism for the reaction was proposed and proved by experiments. The reaction is stereoselective and potentially chemoselective among primary benzyl alcohols, secondary benzyl alcohols, and unactivated aliphatic alcohols.

Full text of DOI:10.1007/s11164-012-0738-z

Res Chem Intermed (2013) 39:2071–2076
DOI 10.1007/s11164-012-0738-z
DMSO-catalyzed chlorination of alcohols using
N-phenylbenzimidoyl chloride
•
Qiang Wang Jian Xu Zhou-Qing Xu Ji-Dan Yan
•
•
Received: 1 November 2011 / Accepted: 17 July 2012 / Published online: 3 August 2012
Ó Springer Science+Business Media B.V. 2012
Abstract N-phenylbenzimidoyl chloride has been demonstrated as an efficient
chlorination reagent catalyzed by dimethyl sulfoxide (DMSO) in conversion of
alcohols to corresponding chlorides. The reaction conditions were mild, and most of
the substrates gave satisfactory yields. The configuration inversion of the chlori-
nation was proved using optically active phenyl alcohols. The amount of DMSO can
be as low as 0.001 eq without reducing the efficiency of the chlorination. A plau-
sible mechanism for the reaction was proposed and proved by experiments. The
reaction is stereoselective and potentially chemoselective among primary benzyl
alcohols, secondary benzyl alcohols, and unactivated aliphatic alcohols.
Keywords Alcohols ꢀ Halogenation ꢀ N-phenylbenzimidoyl chloride ꢀ Sulfoxides
Introduction
Transformation of alcohols into corresponding halides plays an important role in
organic synthesis, not only in the laboratory but also at the industrial level. Numerous
methods are available to accomplish this conversion under various reaction
conditions; e.g., hydrochloric acid [1], thionyl chloride [2, 3], phosphorus chloride
[4], N,N–Diphenylchlorophenylmethyleniminium chloride [5], benzoxazolium [6],
Q. Wang (&) ꢀ Z.-Q. Xu
Department of Chemistry, School of Physics-Chemistry, Henan Polytechnic University, Jiao Zuo
454003, People’s Republic of China
e-mail: wangqiang@hpu.edu.cn
J. Xu
Pharmaron Beijing Limited Co., 6 Taihe Road, BDA, Beijing 100176, People’s Republic of China
J.-D. Yan
Junior Section of Tianjin Nankai Xiangyu School, Tianjin 300100, People’s Republic of China
123

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Q. Wang et al.
Vilsmeier Haack [7, 8], Viehe salts [9, 10], PPh3-halogenated reagents [11], (chloro-
phenylthiomethylene)dimethylammonium chloride [12], halide-based ionic liquids
[13], and the complex of 2,4,6-trichloro[1,3,5]triazine and N,N-dimethylformamide
[14] have been reported as viable routes for chlorination of alcohols with high
efficiency.
Organocatalysis can accelerate chemical reactions with a substoichiometric
amount of an organic compound which does not contain any metal atom [15].
Recently, they have received much attention and been successfully applied to
various chemical reactions. DMSO is a common aprotic solvent. It is a favored
solvent for a great variety of reactions. It can also be used as an oxidant in the Swern
oxidation [16–18], Kornblum reaction [16, 19, 20], etc. In 1995, Snyder reported
firstly conversion of alcohols to chlorides by trimethylsilyl chloride (TMSCl) and a
catalytic quantity of DMSO [26].
N-phenylbenzimidoyl chloride is easily and quantitatively prepared by reaction
of N-phenylbenzamide(benzanilide) using thionyl chloride, being isolated as a light-
yellow solid [27] which can react with amines or alcohols under basic conditions.
Herein, we introduce N-phenylbenzimidoyl chloride as a new chlorination
reagent for converting alcohols into corresponding chlorides with DMSO as
organocatalyst.
Results and discussion
A number of potential solvents [chloroform, ethyl acetate, toluene, acetone,
dichloromethane, and tetrahydrofuran (THF)] were tested using chlorination of
1-benzylethanol as a benchmark. Chloroform gave higher yield and was chosen as
the reaction solvent in subsequent experiments. Investigations into the impact of
DMSO on the rates of reactions showed that, without DMSO, no chloride products
were detected, and increasing the quantity of DMSO above 0.1 eq did not improve
the reaction rates or yields. This supports our assumption that DMSO can function
as an organocatalyst. To test the efficiency of the DMSO catalyst, we reduced the
amount of DMSO from 0.05 to 0.001 eq, with only a slight decrease in reaction rate
being observed. This is the most efficient organocatalyst to our knowledge [15].
When other sulfoxides such as tetramethylene sulfoxide and 2-methanesulfinyl-1-
phenylethanone were used to catalyze the chlorination, the reaction rates were about
half that with DMSO.
The procedure was based on the reaction of N-phenylbenzimidoyl chloride with
DMSO in chloroform, followed by addition of the alcohols (Scheme 1). Various
alcohols were all converted to corresponding chlorides in high yields. The reaction
byproduct, N-phenylbenzamide, could be precipitated and filtrated by addition of
petroleum ether.
Cl
Cl
OH
CHCl3, DMSO(cat)
rt or reflux
+
Ph
Ph
N
R
R'
R
R'
Scheme 1 General method for chlorination of alcohols using N-phenylbenzimidoyl chloride
123

Chlorination of alcohols using N-phenylbenzimidoyl chloride
2073
The scope and limitations of the chlorination reaction were explored with various
alcohols, and the results are summarized in Table 1. With the primary and
secondary alcohols at 70 °C (entries 1, 4–7, and 16; Table 1), the reaction rates are
usually faster, requiring ca. 1.5 h for completion. Although benzyl alcohols can also
be chlorinated at room temperature (entries 1–12 and 16; Table 1), longer reaction
times are required for primary benzyl alcohols (from 6 to 24 h, entries 1–5; Table 1)
and secondary alcohols (from 2 to 4 days, entries 6–13; Table 1). Chlorination of
aliphatic alcohols (entries 13–15; Table 1) must be performed under reflux
conditions of chloroform, indicating that benzyl alcohols have higher reactivity
than aliphatic alcohols. However, tertiary alcohol, for example, 1-phenyl-1-(4-
methylphenyl)ethanol, only gave elimination product at room temperature. Primary
benzyl alcohols with electron-releasing groups are usually superior to electron-
withdrawing ones in terms of reaction time at room temperature, but no notable
difference in yield was found at either room temperature or 70 °C. The effect of
substituting groups to the secondary benzyl alcohols is not remarkable. Optically
active alcohol, a sample of (R)-1-phenylethanol {[a]2D5 ?36.19 (c 1, CHCl3),
86.9 %ee}, under the above reaction conditions gave (S)-1-phenylethyl chloride
{[a]2D5 -18.53 (neat), Lit. [25] [a]2D5 -23.7 (neat) (entry 16; Table 1)}, correspond-
ing to 96 % inversion of the configuration. Analogously, (R)-1-phenyl-1-propanol
and (R)-1-phenyl-1-butanol gave the corresponding (S)-chlorides with over 95 %
Table 1 Conversion of alcohols into corresponding chlorides by N-phenylbenzimidoyl chloride and
DMSO
Entry
R
R0
Yield (time)a
Yield (time)b
Ref.
1
Ph
H
H
68 (24 h)
75 (6 h)
80 (6 h)
90 (12 h)
87 (24 h)
75 (4 days)
54 (4 days)
82 (4 days)
82 (3 days)
65 (4 days)
73 (4 days)
77 (2 days)
–
70 (1 h)
[21]
[21]
[21]
[21]
[21]
[22]
[21]
[21]
[21]
[21]
[21]
[21]
[23]
[24]
2
4-MeOPh
Piperonyl alcohol
4-ClPh
–
3
–
4
H
90 (1 h)
85 (1.5 h)
73 (1.5 h)
56 (1.5 h)
–
5
3-O2NPh
Ph
H
6
CH3
CH3
CH3
CH3
CH3
CH3
CH3
7
4-FPh
8
4-ClPh
9
4-BrPh
–
10
11
12
13
14
15
16c
a, b
4-MePh
–
4-n-BuOPh
2-BnOPh
Cholesterol
Cyclohexanol
–
–
90 (1.5 h)
66 (12 h)
84 (1.5 h)
78 (1.5 h)
–
4-(6-Methoxynaphthalen-2-yl)butan-2-ol
Ph CH3
–
76 (4 days)
[25]
Yields refer to pure isolated products in mass %, time is in hours or days
Reaction temperature refers to room temperature
Reaction temperature refers to reflux conditions of chloroform
(R)-1-phenylethanol
a
b
c
123

2074
Q. Wang et al.
Scheme 2 Plausible
mechanism for chlorination
of alcohols using
N-phenylbenzimidoyl
chloride
OH
S
H
R'
R
O
R
R'
H
Ph
N
Ph
Cl
O
Cl
Ph
Ph
N
I
S
H
N
O
Ph
II
Ph
O
Cl
S
Cl
R'
Cl
H
R
O
R
R'
Ph
H
O
Ph
N
H
S
III
inversion of configuration. This is comparable to the classical conditions using a
combination of SOCl2 and pyridine [2, 3].
Mechanism
The stereochemical results indicate the occurrence of an SN2 reaction that may be
consistent with the mechanism depicted in Scheme 2. The reactions are exothermal
and fast in the DMSO-involved Swern oxidation [19, 20] and Snyder chlorination
[4] because very reactive sulfonium intermediates are generated. In our case, the
reaction is not that fast, most probably because intermediate I is relatively
unreactive, which forms II and generates a better nucleophile alcoholate from the
alcohol. The alcoholate reacts with II to yield III. After attack by chloride anion, III
yields the product with configuration inversion. The lower reactivity of the
intermediates makes it possible to differentiate various types of alcohols according
to the reaction rates (Table 1), whereas in the Swern oxidation [19, 20] and Snyder
chlorination [4] rates of different types of alcohols are about the same.
Experimental
General
Chloroform was distilled over P2O5. All reagents were purchased commercially and
used without further purification. Thin-layer chromatography (TLC) was performed
on HG/T2354-92 GF254 silica gel precoated plates. 1H nuclear magnetic resonance
(NMR) [0.00 ppm for tetramethylsilane (TMS) as internal standard] spectra were
recorded on a Varian Oxford 500 (500 MHz) instrument. Coupling constants are
measured in Hertz. Infrared (IR) spectra were recorded using a Bio-Rad Excalibur
123

Chlorination of alcohols using N-phenylbenzimidoyl chloride
2075
FTS3000 spectrometer. Elemental analyses for C, H, and N were performed on a
Yanaco CHNCORNER MF-3 elemental analyzer, and the analytical results were
within 0.3 % of the theoretical values. The chiral alcohols were prepared
according to Xie, J. etc. [28], and optical rotation was recorded on a PerkinElmer
model 341 polarimeter (wavelength of light: 589 nm, temperature: room temper-
ature). The products were separated by isolation method using column chromatog-
raphy using a 40-cm column packed with silica gel 60 (Merck, 0.063–0.200 l) and
the product eluted with mixture solvents of hexane and ethers. All products reported
here are known compounds, and their identity was determined with IR, 1H-NMR or
gas chromatography–mass spectrometry (GC–MS).
Typical procedure for chlorination of alcohols
To a mixture of N-phenylbenzimidoyl chloride (1.5 mmol) and DMSO (0.05 mmol)
in dry chloroform was added an alcohol (1.0 mmol). The reaction mixture was
stirred at room temperature for the time periods specified in Table 1 (refluxing was
required for aliphatic alcohols). After completion of the reaction, the chloroform
was removed under vacuum and petroleum ether was added, then filtrated. The
filtrate was evaporated to give corresponding chlorides. After bulb-to-bulb
distillation or filtration through silica gel, data for 4-(6-methoxynaphthalen-2-
yl)butan-2-ol were as follows: IR (KBr). m 3,008, 2,930, 1,634, 1,606, 1,455, 1,230,
1
1,029, 854 cm-1; H NMR (500 Hz, CDCl3): d 7.67 (m, 2H), 7.57 (s, 1H), 7.31
(d, 1H, J = 8.0 Hz), 7.12 (m, 2H), 3.91 (s, 3H), 3.84 (m, 1H), 2.85 (m, 2H), 1.90
(m, 2H), 1.25 (m, 3H). Elem. Anal. Calc. for C15H17OCl (248.7) C 72.42, H 6.88, O
6.43, Cl 14.25; found C 72.60, H 6.71.
Conclusions
The reported procedure can effect conversion of alcohols to corresponding chlorides
efficiently under mild conditions and be operated simply. We have demonstrated the
application of N-phenylbenzimidoyl chloride in chlorination of alcohols with
catalytic quantity of DMSO. The reaction is stereoselective and potentially
chemoselective among primary benzyl alcohols, secondary benzyl alcohols, and
unactivated aliphatic alcohols.
Acknowledgments This work was supported by the Natural Science Research Program from Education
Department of Hean Province (2011A150015), the Hean Polytechnic University Foundation for Doctor
Teachers (B2010-65), and Hean Polytechnic University Foundation for the Youth (P051102).
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