Pivaloyl chloride/DMF: a new reagent for conversion of alcohols to chlorides

Article abstract of DOI:10.1016/j.tetlet.2009.11.131

An efficient procedure for conversion of alcohols into the corresponding chlorides is described. Pivaloyl chloride/DMF complex is employed as a mild and inexpensive reagent. A possible reaction mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2009.11.131

Tetrahedron Letters 51 (2010) 744–746
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Pivaloyl chloride/DMF: a new reagent for conversion of alcohols to chlorides
*
Abhishek Dubey, Arun K. Upadhyay, Pradeep Kumar
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient procedure for conversion of alcohols into the corresponding chlorides is described. Pivaloyl
chloride/DMF complex is employed as a mild and inexpensive reagent. A possible reaction mechanism
is proposed.
Received 29 October 2009
Revised 24 November 2009
Accepted 27 November 2009
Available online 2 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Conversion of alcohols into the corresponding chlorides is one of
the most important and commonly used transformation in organic
synthesis and development of such a procedure is still desirable in
academia as well as in industrial research. A number of reagents have
been employed to carry out this transformation. Some of the methods
developed for this purpose utilize reagents such as thionyl chloride,1
PCl5,2 N,N-diphenylchlorophenylmethyleniminiumchloride,3 2-chlo-
robenzoxazolium salts,4 benzothiazolium salts,5 Vilsmeier–Haack
salt,6 Vieche salts,7 (chloro-phenylthiomethylene)dimethylammoni-
umchloride,8 polymer-supported triphenyl phosphine or a filterable
phosphine source such as 1,2-bis(diphenylphosphino)ethane.9 More
recently, halidebased ionic liquids10 andcomplex of TCT–DMF11 have
been reported to effect this transformation.
During our recent endeavor with HKR (hydrolytic kinetic reso-
lution) mediated synthesis of biologically active compounds, we
required to convert a diol into the required epoxide through piva-
late via a three step-sequence reaction. Interestingly, we observed
an efficient chlorination of alcohol instead of its protection as piv-
alate when reaction was performed in DMF. This could probably be
attributed to the generation of a new reactive species responsible
for chlorination and this observation prompted us to initiate a sys-
tematic investigation of pivaloyl chloride/DMF reagent system for
chlorination of alcohol. Herein we wish to disclose our results for
a very mild and efficient conversion of alcohol to chloride.
In a typical experimental procedure,12 when alcohols were trea-
ted with a pre-formed complex of DMF and pivaloyl chloride in
dichloromethane, it gave the corresponding chloro compounds in
moderate to good yields (Scheme 1).
some cases small amount (5–15% yield) of the pivaloyl ester of
the corresponding alcohol was also obtained as a side product.13
The superiority of this procedure can be clearly visualized in chlo-
rination of b-amino alcohol leading to the corresponding chloro
compound in good yield without formation of any side product
(Table 1, entry 10). The cleavage of acetonide group under the reac-
tion conditions employed was not observed. It should be men-
tioned here that the amino acid based azide thus prepared could
serve as a useful building block to synthesise a new class of unnat-
ural C-glycosyl amino acid featuring a triazole moiety between the
sugar and amino acid entities.15 PMBCl, an important protecting
group in organic synthesis was also synthesized from the corre-
sponding alcohol (Table 1, entry 1). Our method yielded the prod-
uct free from any acidic impurities while the conventional method
of its synthesis using hydrochloric acid generally affords the prod-
uct contaminated with acidic impurities.
In order to examine the stereospecificity of the present method,
we employed (R)-octane-2-ol (Table 1, entry 12) and subjected this
to reaction with pivaloyl chloride/DMF reagent to give (S)-2-chlo-
rooctane, ½a 2D0
ꢀ
+36.0 (c 0.8, ether), lit.4
+36.02. The measurement of optical rotation and its com-
½
a 2D0
+33.0 (c 0.8, ether);
ꢀ
lit.3 ½a 2D0
ꢀ
parison with literature values indicated that the reaction occurs
with inversion of configuration via SN2 displacement leading to
the corresponding chloro product in enantiomerically pure form.
A possible explanation for reaction mechanism is depicted in
Scheme 2. The involvement of Vilsmeier–Haack type complex as
a possible reactive intermediate is invoked which adds on the hy-
droxyl group of the alcohol to form the cationic species followed by
The present procedure is quite general as a wide range of struc-
turally varied alcohols such as primary, secondary, allylic, homoal-
lylic, and benzylic ones underwent smooth conversion with
pivaloyl chloride/DMF into their corresponding chlorides under
mild reaction conditions in moderate to good yields of the corre-
sponding chloride (Table 1). It should be mentioned here that in
Pivaloyl chloride,
R
R
DMF, CH2Cl2, rt
OH
Cl
R'
R'
55-80% yield
R' = 1o, 2o, allyl, benzyl,
1,2-aminoalcohol
* Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.131

A. Dubey et al. / Tetrahedron Letters 51 (2010) 744–746
745
Me
Me
Cl
Me
Me
O
N
N
O
H
Me
Me
N
O
Cl
O
Cl
O
O
Vilsmeier-Haack complex
OH
Me
O
Me
Me
O
Me
Me
O
Me
Cl
N
R
N
N
H
R'
H
R
R
R
H
H
H
R'
R'
R'
Cl
Cl
R'
H
Me
Me
R
H
N
O
Cl
Scheme 2. Proposed mechanism for chlorination of alcohol.
Table 1
Dimethylformamide/pivaloyl chloride mediated conversion of alcohols to chlorides
Entry
Alcohol
Product
Reaction time
20 min
Yielda (%)
Cl
Cl
OH
1
80
MeO
MeO
OH
2
3
4
30 min
30 min
20 min
70
80
80
Cl
OH
7
7
OH
Cl
OH
Cl
5
6
2 h
2 h
70
70
Cl
OH
H3CO
H3CO
OH
Cl
7
8
1 h
5 h
75
60
13
13
OH
Cl
9
1 h
4 h
65
Cl
OH
OH
Cl
O
O
NBoc
10
55
NBoc
(continued on next page)

746
A. Dubey et al. / Tetrahedron Letters 51 (2010) 744–746
Table 1 (continued)
Entry
Alcohol
Product
Reaction time
4 h
Yielda (%)
60
OH
Cl
11
OH
Cl
12
1 h
60
5
5
a
Crude yield of the chloro products.
7. Benazza, M.; Uzan, R.; Beaupe‘re, D.; Demailly, G. Tetrahedron Lett. 1992, 33,
3129–3132.
8. Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C. Tetrahedron Lett. 2000, 41,
6049–6052.
9. Pollastri, M.; Sagal, J. F.; Chang, G. Tetrahedron Lett. 2001, 42, 2459–2460.
10. Ren, R. X.; Xin Wu, J. Org. Lett. 2001, 3, 3727–3728.
subsequent nucleophilic attack of chloride ion in SN2 fashion to
produce the corresponding chloride.
Some of the crude chloro compounds which were found to be
volatile and unstable were subsequently treated with sodium azide
in DMF at 60 °C to afford the corresponding azide in good yield.14
In conclusion, a mild, general and efficient conversion of alco-
hols into chlorides has been developed. The noteworthy feature
of the present method is the use of pivaloyl chloride/DMF as a mild,
non-toxic and inexpensive reagent coupled with simple operation
and ease of work-up. We believe this will present a better and
more practical alternative to the existing methodologies.
11. Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553–555.
12. Representative procedure. Chlorination of p-methoxybenzyl alcohol: A mixture of
pivaloyl chloride (1.30 g, 10.86 mmol) and DMF (5 mL) was stirred at room
temperature for 1 h. To the mixture was first added CH2Cl2 (25 mL) followed by
alcohol (1 g, 7.24 mmol). The reaction was monitored (TLC) until the complete
disappearance of starting material. Water (20 mL) was added, and then the
organic phase was washed with 15 mL of a saturated solution of Na2CO3,
followed by 1 N HCl and brine. The organic layers were dried over Na2SO4, and
the solvent evaporated to yield p-methoxybenzyl chloride (0.91 g, 80%).
13. Heptadecyl pivalate (entry 7): 1H NMR (CDCl3, 200 MHz): 0.88 (t, 3H, J = 6.0 Hz),
1.2 (s, 9H), 1.26 (br s, 26H), 1.51–1.65 (m, 2H), 4.04 (t, 2H, J = 6.8 Hz); dC 13C
NMR (CDCl3, 50 MHz): 14, 22.6, 25.9, 27.1, 28.6, 29.2, 29.7, 31.9, 38.6, 64.3,
178.4.
Acknowledgments
14. (a) 1-(Azidomethyl)-2-octylcyclopropane (entry 3): 1H NMR (CDCl3, 200 MHz):
0.34–0.48 (m, 2H), 0.62–0.74 (m, 1H), 0.77–0.98 (m, 4H), 1.21–1.44 (m, 14 H),
2.99–3.18 (2H, m); dC 13C NMR (CDCl3, 50 MHz): 10.6, 14.1, 17.3, 17.8, 22.7,
29.3, 29.4, 29.5, 31.9, 33.52, 55.5. Anal. Calcd for C12H23N3 (209.33): C, 68.85; H,
11.07; N, 20.07. Found: C, 68.55; H, 11.38; N, 20.0.
A.D. thanks CSIR, New Delhi for the award of Senior Research
Fellowship. We thank Dr. Ganesh Pandey, Head, organic division,
NCL for his support and encouragement.
(b) (2-Azidopent-4-enyl)benzene (entry 8): 1H NMR (CDCl3, 200 MHz): 2.85–3.05
(m, 2H), 3.26–3.55 (m, 3H), 5.21–5.33 (m, 2H), 6.82–6.92 (m, 1H), 7.17–7.35
(m, 5H); dC 13C NMR (CDCl3, 50 MHz): 33.1, 37.4, 52.3, 113.71, 127.1, 128.7,
129.3, 135.7, 160.1. Anal. Calcd for C11H13N3 (187.24): C, 70.56; H, 7.00; N,
22.44. Found: C, 70.32; H, 6.95; N, 22.60.
References and notes
1. For a review, see: Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
John Wiley & Sons, 1999. pp 689–702.
2. Weiss, R. G.; Snyder, E. I. J. Chem. Soc., Chem. Commun. 1968, 1358–1359. J. Org.
Chem. 1971, 36, 403–406.
3. Fujisawa, T.; Iida, S.; Sato, T. Chem. Lett. 1984, 1173–1174.
4. Mukaiyama, T.; Shoda, S. I.; Watanabe, Y. Chem. Lett. 1977, 383–386.
5. Hojo, K.; Mukaiyama, T. Chem. Lett. 1976, 619–622.
6. Benazza, M.; Uzan, R.; Beaupe‘re, D.; Demailly, G. Tetrahedron Lett. 1992, 33,
4901–4904.
(c) (E)-(2-(3-Azidobut-1-enyl)cyclopropyl)benzene (entry 11): 1H NMR (CDCl3,
200 MHz): 0.85–0.94 (m, 2H), 1.19–1.33 (m, 5H), 2.51–2.60 (m, 1H), 5.38–5.72
(m, 1H), 5.94–6.05 (m, 1H), 7.17–7.43 (m, 5H); dC 13C NMR (CDCl3, 50 MHz):
11.1, 11.4, 21, 21.4, 64.6, 122, 122.6, 125.3, 128.4, 128.7, 131.2. Anal. Calcd for
C13H15N3 (213.28): C, 73.21; H, 7.09; N, 19.70. Found: C, 73.01; H, 7.16; N,
19.65.
15. Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett. 2004, 6, 2929–2932.