Thionyl chloride-benzotriazole in methylene chloride: A convenient solution for conversion of alcohols and carboxylic acids expeditiously into alkyl chlorides and acid chlorides by simple titration

Article abstract of DOI:10.1055/s-1999-2943

A solution of 1:1 equivalent of thionyl chloride and benzotriazole in dry methylene chloride efficiently transforms alcohols and carboxylic acids into the corresponding alkyl chlorides and acid chlorides respectively at room temperature, with excellent yields by simple titration.

Full text of DOI:10.1055/s-1999-2943

LETTER
1763
Thionyl Chloride-Benzotriazole in Methylene Chloride: A Convenient
Solution for Conversion of Alcohols and Carboxylic Acids Expeditiously into
Alkyl Chlorides and Acid Chlorides by Simple Titration
Sachin S. Chaudhari, Krishnacharya G. Akamanchi*
Pharmaceuticals and Fine Chemicals Division, Department of Chemical Technology, University of Mumbai, Matunga, Mumbai-400 019,
India
Fax (91)22 414 5614, E-mail: kga@udct.ernet.in
Received 23 August 1999
Abstract: A solution of 1:1 equivalent of thionyl chloride and ben-
zotriazole in dry methylene chloride efficiently transforms alcohols
and carboxylic acids into the corresponding alkyl chlorides and acid
chlorides respectively at room temperature, with excellent yields by
simple titration.
Key words: benzotriazole, thionyl chloride, chlorination, alcohols,
carboxylic acids
Transformation of alcohols and carboxylic acids to the
corresponding alkyl chlorides1 and acid chlorides2 respec-
tively are two of the basic functional group transforma-
tions in organic synthesis. A plethora of reagents and
systems with varying generality are available for these
transformations. Commonly used classical reagents are
thionyl chloride,3a phosphorous trichloride3b and phos-
phorous pentachloride.3c These are used as such or in
combination with a base. Though these transformations
are routine ones, newer systems continue to be developed
as reflected by the recent reports where TMSCl / DMSO,4a
CCl4 / Cu / Fe / CuBr(Phen)2,4b TMSCl / K2Cr2O4,4c TPP /
dichloroselenurate,4d trichloroisocyanuric acid / TPP4e
were used for the conversion of alcohols to alkyl chlorides
and trichloroacetonitrile / TPP4f was used for the conver-
sion of carboxylic acids to acid chlorides. The present let-
ter describes an alternative and cost effective system.
,
Thionyl chloride can be used alone2e 3a or in combination
with bases such as pyridine2f, 3d and triethylamine.5 How-
ever, the reactions are invariably slow and often require
reflux temperature. There are some modifications to over-
come these difficulties e.g. use of DMF.2b Recently, we
have reported an efficient transformation of aldoximes to
the corresponding nitriles at room temperature, in high
yields using thionyl chloride-benzotriazole combination.6
We have further explored this combination for the chlori-
nation of alcohols and carboxylic acids. The exploitable
features of benzotriazole are that it is a mild base as well
as acid which leaves options to use either acid or alkali
wash for its ready removal from the reaction mixture. It is
a solid and water insoluble, nonodoriferous and more im-
portantly it is a good leaving group. These are some ad-
vantages over commonly used bases like triethylamine
and pyridine. Moreover, benzotriazole (1 mol) dissolves
readily in thionyl chloride (1 mol) at room temperature
giving a clear viscous solution, the dissolution is slightly
Synlett 1999, No. 11, 1763–1765 ISSN 0936-5214 © Thieme Stuttgart · New York

1764
S. S. Chaudhari, K. G. Akamanchi
LETTER
endothermic.7 This solution can be readily diluted with
dry DCM and the stock solution of known concentration
can be prepared for use whenever needed.
The reactions were performed by following the general
procedure.8 The required amount of reagent (1.25 mmol
equivalent) was added directly from the burette to a solu-
tion of substrate (1 mmol) in dry DCM with stirring. The
reaction was fast and before the addition was complete
benzotriazole hydrochloride started separating out as a
solid indicating the progress of the reaction.
Under the reaction conditions primary, (Table 1, entries 1
and 10) secondary, (Table 1, entries 4 and 9 ) and tertiary
alcohols (Table 1, entry 11) were converted into their cor-
responding alkyl chlorides efficiently. Substrates carrying
electron donating (Table 1, entry 2) and electron with-
drawing groups (Table 1, entry 3) had practically no effect
on the overall transformation. Sensitive alcohols such as
furfuryl alcohol, (Table 1, entry 7) tetrahydrofurfuryl al-
cohol (Table 1, entry 8) and a,b-unsaturated alcohol (Ta-
ble 1, entry 5) were transformed into the corresponding
chlorides without any difficulties. It is noteworthy that
acid sensitive methoxy group, (Table 1, entry 2) and ace-
tonide group (Table 1, entry 13) were compatible under
the reaction conditions employed. As expected, alcohols
protected as trimethyl silyl ether (Table 1, entry 1-ii) were
recovered completely unaffected.
References and Notes
(1) a) Lee, J. B.; Nolan, T. J. Can. J. Chem. 1966, 44, 1331;
b) Yoshihara, M.; Eda, T.; Sakaki, K.; Maeshima, T. Synthesis
1980, 746; c) Itoh, H.; Saito, T.; Oshima, K.; Nozaki, J. Bull.
Chem. Soc. Jpn. 1981, 54, 1456; d) Hwang, C. K.; Li, W. S.;
Nicolaou, K. C. Tetrahedron Lett. 1984, 25, 2295; e) Ireland,
R. E.; Norbeck, D. W.; Mandel, G. S.; Mandel, N. S. J. Am.
Chem. Soc. 1985, 107, 3285; f) Blame, G.; Gore, J.; Fournet,
G. Tetrahedron Lett. 1986, 27, 1907; g) Camps, F.; Gasol, V.;
Guerrero, A. Synthesis 1987, 511; h) Lee, J. G.; Kang, K. K.
J. Org. Chem. 1988, 53, 3634; i) Ioe, E. M.; Jones, C. J.
Polyhedron 1992, 11, 3123.
(2) a) Ottenheijm, H. C. J.; DE Man, J. H. M. Synthesis 1975, 163;
b) Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, H. Helv.
Chim. Acta. 1959, 42, 1653; c) Venkataraman, K.; Wagle, D.
R. Tetrahedron Lett. 1979, 32, 3037; d) Cainelli, G.;
Contento, M.; Manescalchi, F.; Plessi, L.; Panunzio, M.
Synthesis 1983, 306 and references cited therein; e) Hwang, Y.
C.; Fowler, F. W. J. Org. Chem. 1985, 50, 2719; f) Wolfe, S.;
Godfrey, J. C.; Holdrege, C. T.; Perron, Y. G. Can. J. Chem.
1968, 46, 2549; g) Masuhika, F.; Hitoshi, N. JP 92,117,344,
1992; Chem. Abstr. 1992, 117, 150719q.
(3) a) Brown, G. W., In The Chemistry of the Hydroxyl Group,
Patai, S., Ed.; Interscience; London, 1971, Part 1, pp. 592-622;
b) Newkome, G. R.; Theriot, K. J.; Majestic, V. K.; Spruell, P.
A.; Baker, G. R. J. Org. Chem. 1990, 55, 2838; c) Ansell, M.
F., In The Chemistry of Acyl Halides, Patai, S.; Ed.;
Interscience; London, 1972, Chapter 2, pp. 35-68; d) Ward, A.
M. OSC, 1943, 2, 159.
(4) a) Snyder, D. C. J. Org. Chem. 1995, 60, 2638; b) Leonel, E.;
Paugam, J. P.; Nedelec, J. Y. J. Org. Chem. 1997, 62, 7061;
c) Dong Soo, H.; Hyeung Ae, K. Bull. Korean Chem. Soc.
1998, 19, 1303; d) Drabowicz, J.; Luczak, J.; Mikolajczyk, M.
J. Org. Chem. 1998, 63, 9565; e) Hiegel, G. A.; Ramirez, J.;
Barr, R. K. Synth. Commun. 1999, 29, 1415; f) Jang, D. O.;
Park, D. J.; Kim, J. Tetrahedron Lett. 1999, 40, 5323.
(5) a) See reference 1a; b) Darzenes, G. Compt. Rend. 1911, 152,
1601.
In the case of butene-1,4-diol a 2.5 mole equivalent of the
reagent gave 1,4-dichlorobutane and 1.2 mole equivalent
gave cyclic sulfite. Cyclic sulfite was formed while at-
tempting selective chlorination in 1,2-isopropylidene xy-
lofuranoside (Table 1, entry 13). Reaction with (-)-
menthol ended in formation of dimenthyl sulfite9 instead
of menthyl chloride (Table 1, entry 14).
Varieties of carboxylic acids like aromatic, aliphatic, and
a,b-unsaturated such as cinnamic acid were transformed
into acid chlorides rapidly without any difficulties (Table
2). The crude products obtained were sufficiently pure
and can be directly used in the next step without further
purifications. Amides can also be converted into the cor-
responding nitriles using this combination, but the yields
are poor even after the use of 5 equivalent of the reagent
combination.
In conclusion, the new reaction system described here of-
fers a quick, convenient, and inexpensive alternative to
other methods for the synthesis of alkyl chlorides and acid
chlorides. In addition, the transformation using reactive
thionyl chloride-benzotriazole combination in methylene
chloride can be carried out simply by titration at room
temperature in high yields, which may have wide synthet-
ic applicabilty.
Acknowledgement
We gratefully acknowledge the UGC of India for fellowship to
SSC.
Synlett 1999, No. 11, 1763–1765 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Thionyl Chloride-Benzotriazole in Methylene Chloride
1765
(6) Chaudhari, S. S.; Akamanchi, K. G. Synth. Commun. 1999,
29, 1741.
(7) Bases such as pyridine, triethylamine, and imidazole react
exothermically / violently with thionyl chloride at room
temperature unlike benzotriazole, where dissolution is slightly
endothermic
used. It was further purified by column chromatography (15%
EA/Hexane). In case of acid chlorides, the filtrate was stirred
with MgSO4.7H2O (~ 0.5 g) to destroy excess reagent. The
solids were filtered off. The filtrate can be used as such or the
acid chloride can be recovered by removal of solvent.
(9) a) Rebiere, F.; Samual, O.; Ricard, L.; Kagan, H. B. J. Org.
Chem. 1991, 56, 5991.
(8) General procedure: A stock solution (1.5 M) was prepared
by making up volume of a viscous clear solution of thionyl
chloride (5.46 mL, 0.075 mol) and benzotriazole (8.93 g,
0.075 mol) with dry DCM up to 50 mL and transferred to 50
mL graduated burette. Reaction was carried out by adding the
stock solution (1.25 mmol equivalent) intermittantly from the
burette to a stirred solution of alcohol (1 mmol) or carboxylic
acid (1 mmol) in dry DCM (20 mL). Before the addition is
complete, benzotriazole hydrochloride started separating out
as a solid. Reaction mixture was swirled or stirred further for
5-10 min. At the end solid was filtered off.10 In case of alkyl
chlorides, the filtrate was washed with water (25 mL)
followed by 2% NaOH solution (25 mL). The organic layer
was separated and passed through anhydrous sodium sulfate.
Removal of solvent gave crude product that can be directly
b) Dimenthyl sulfite, White crystalline solid, mp: 49-50°C
(Lit.9a m.p.: 49°C), [a]D: -59 (c = 1, CHCl3 ) (Lit.9a [α]D:
-60), 1H NMR (60 MHz, CDCl3): d 0.8-2.1 (m, 36H), 4.3 (m,
2H, -OCH=).
(10) Benzotriazole was recovered as follows: To a cooled solution
of benzotriazole hydrochloride salt in water was added
gradually a cold solution of 2% NaOH till pH was just neutral
and precipitated benzotriazole was filtered off and dried. It
was sufficiently pure (mp. 98°C) and can be reused.
Article Identifier:
1437-2096,E;1999,0,11,1763,1765,ftx,en;L12999ST.pdf
Synlett 1999, No. 11, 1763–1765 ISSN 0936-5214 © Thieme Stuttgart · New York