An efficient route to alkyl chlorides from alcohols using the complex TCT/DMF

Article abstract of DOI:10.1021/ol017168p

(formula presented) Efficient conversion of alcohols and β-amino alcohols to the corresponding chlorides (and bromides) can be carried out at room temperature in methylene chloride, using 2,4,6-trichloro[1,3,5]triazine and N,N-dimethyl formamide. This procedure can also be applied to optically active carbinols.

Full text of DOI:10.1021/ol017168p

ORGANIC
LETTERS
2002
Vol. 4, No. 4
553-555
An Efficient Route to Alkyl Chlorides
from Alcohols Using the Complex
TCT/DMF
Lidia De Luca, Giampaolo Giacomelli,* and Andrea Porcheddu
Dipartimento di Chimica, UniVersita` degli Studi di Sassari, Via Vienna 2,
I-07100 Sassari, Italy
ggp@ssmain. uniss.it
Received December 4, 2001
ABSTRACT
Efficient conversion of alcohols and â-amino alcohols to the corresponding chlorides (and bromides) can be carried out at room temperature
in methylene chloride, using 2,4,6-trichloro[1,3,5]triazine and N,N-dimethyl formamide. This procedure can also be applied to optically active
carbinols.
The transformation of alcohols into the corresponding alkyl
halides is one of the most studied reactions in organic
synthesis, and many reagents can be usually used. Often the
conversion requires elaborate reagents and quite drastic
reaction conditions. Most of the methods employed utilize
reagents such as thionyl chloride,1 phosphorus halides,2
phenylmethyleniminium,3 benzoxazolium,4 Vilsmeier-Haack,5
and Viehe salts.6 In this context, the development of efficient
reagents to use in mild conditions has interested organic
chemists. The procedure based on the use of triphenylphos-
phine-carbon tetrahalides seems to meet these requirements
but suffers the inconvenience of generating stoichiometric
triphenylphosphine oxide as byproduct. To resolve these
drawbacks, (chloro-phenylthiomethylene)dimethylammonium
chloride was reported as a mild reagent for selective
chlorination and bromination of primary alcohols.7 However,
the reagent has to be prepared through a two-step procedure
that requires flash- chromatography workup. Other solutions
may be the use of polymer-supported triphenyl phosphine
or a filterable phosphine source such as 1,2-bis(diphe-
nylphosphino)ethane.8 More recently, a mild conversion of
alcohols to alkyl halides using halide-based ionic liquids was
reported.9
A search of the literature revealed that the treatment of
cyanuric chloride, a very cheap reagent, with alcohols
furnished the corresponding chlorides.10 The reported pro-
cedure implied heating of the mixture to 10-20 °C below
the boiling point of the alcohol and the use of excess cyanuric
chloride for the complete conversion. Indeed, this method
did not seem suitable for obtaining complex organic chlo-
rides, such as those derived from amino alcohols. An accurate
examination of a former report11 showed that the treatment
of the adduct formed by cyanuric chloride and dimethyl
formamide with ethanol resulted in the quantitative formation
of HCl and ethyl chloride.
(1) For a review, see: Larock, R. C. ComprehensiVe Organic Transfor-
mations, 2nd ed.: John Wiley & Sons: 1999; p 689.
(2) Weiss, R. G.; Snyder, E. I. J. Chem. Soc., Chem. Commun. 1968,
1358; J. Org. Chem. 1972, 36, 403.
On this basis and following our recent interest in the use
of [1,3,5]triazine derivatives in organic synthesis,12 we report
(3) Fujisawa, T.; Iida, S.; Sato, T. Chem. Lett. 1977, 1173.
(4) Mukaiyama, T.; Shoda, S. I.; Watanabe, Y. Chem. Lett. 1977,
383.
(5) Benazza, T.; Uzan, R.; Beaupe`re, D.; Demailly, G. Tetrahedron Lett.
1992, 33, 4901.
(6) Benazza, T.; Uzan, R.; Beaupe`re, D.; Demailly, G. Tetrahedron Lett.
1992, 33, 3129.
(7) Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C. Tetrahedron
Lett. 2000, 41, 6049.
(8) Pollastri, M.; Sagal, J. F.; Chang, G. Tetrahedron Lett. 2001, 42,
2459.
(9) Ren, R. X.; Xin Wu, J. Org. Lett. 2001, 3, 3027.
(10) Sandler, S. R. J. Org. Chem. 1970, 35, 3967.
(11) Gold, H. Angew. Chem. 1960, 72, 956.
10.1021/ol017168p CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/17/2002

a very mild, efficient, and chemoselective procedure for the
quantitative conversion of alcohols into the corresponding
alkyl chlorides (Scheme 1).
Table 1. Conversion of Aliphatic Alcohols into the
Corresponding Alkyl Halides
Scheme 1
The procedure is based on the reaction of 2,4,6-trichloro-
[1,3,5]triazine (TCT) with DMF, followed by the addition
of a CH2Cl2 solution of 1 mol equiv of the alcohol. At 25
°C this system effects rapidly the quantitative conversion of
the alcohols to the corresponding chlorides (Table 1), which
can be recovered chemically pure after a simple aqueous
workup that removes the triazine byproducts. The reaction
is generally fast, requiring from 10-15 min to 4 h for
completion in most of the cases. Reduced rates were observed
with sterically constrained alcohols, such as borneol and
neopentyl alcohol. As in other cases, 2-phenylsulfanyl-1-
ethanol reacts very slowly (ca. 72 h). Reaction of diols gave
monochlorination using 1 mol equiv of the diol, and the
conversion to dichloride is complete only using 0.5 mol
equiv. At least with the optically active alcohols we have
tested, the data collected show that the reaction occurs with
inversion of configuration at the chiral center. In fact, a
sample of (R)-1-phenyl-2-methyl-1-propanol, [R]25D + 42.1
(c 2, ether), gave (S)-1-phenyl-2-methyl-1-chloropropane,
[R]25 -40.8 (c 1, ether).13,14 Analogously, (S)-1-phenyl-1-
D
propanol, [R]22 - 20.2 (neat), gave (R)-1-phenyl-1-chlo-
D
ropropane, [R]25 + 24.9 (neat).
D
Alkyl bromides can be obtained by addition of sodium
bromide and the alcohol to the TCT/DMF mixture in CH2-
Cl2. However, in this case, a noticeable amount of the alkyl
chloride may be recovered as byproduct.15 Use of sodium
iodide did not lead to the formation of alkyl iodide.16
Most interestingly, the reaction is applicable for the
synthesis of N-protected â-amino chlorides. Under the usual
conditions, N-protected â-amino alcohols are in fact con-
verted to the corresponding chlorides, with slightly reduced
rates (Table 2); however, the reaction is complete within 4
a For complete conversion of the alcohol. b The corresponding chloride
is formed also.
h. Moreover, the method is compatible with the common
N-protecting groups, and no deprotection was noted even
with N-Boc-protected amino acids, if working in the presence
of NaHCO3.
(12) (a) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett. 1999,
40, 4395. (b) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J.
Org. Chem. 1999, 64, 8962. (c) Falchi, A.; Giacomelli, G.; Porcheddu, A.;
Taddei, M. Synlett 2000, 275. (d) De Luca, L.; Giacomelli, G.; Taddei, M.
J. Org. Chem. 2001, 66, 2534. (e) De Luca, L.; Giacomelli, G.; Porcheddu,
A. Org. Lett. 2001, 3, 1519. (f) De Luca, L.; Giacomelli, G.; Porcheddu,
A. Org. Lett. 2001, 3, 3041. (g) De Luca, L.; Giacomelli, G.; Porcheddu,
A. J. Org. Chem. 2001, 66, 7907.
(13) Giacomelli, G.; Lardicci, L. J. Org. Chem. 1981, 46, 3116.
(14) Kwart, H.; Givens, E. N.; Collins, C. J. J. Am. Chem. Soc. 1969,
91, 5532.
(15) The bromide can be recovered by accurate distillation or flash
chromatography.
The stereochemical results indicate the occurrence of a
Sn2 reaction that may be consistent with the mechanism
(17) Representative Procedure. Chlorination of (S)-(1-Hydroxy-
methyl-3-methylbutyl)-carbamic Acid Benzyl Ester. 2,4,6-Trichloro-
[1,3,5]triazine (1.83 g, 10.0 mmol) was added to DMF (2 mL), maintained
at 25 °C. After the formation of a white solid, the reaction was monitored
(TLC) until complete disappearance of TCT, and CH2Cl2 (25 mL) was
added, followed by the alcohol (2.39 g, 9.5 mmol). After the addition, the
mixture was stirred at room temperature and monitored (TLC) until
completion (4 h). 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 (Na2SO4), and the solvent
evaporated to yield (S)-(1-chloromethyl-3-methylbutyl)-carbamic acid benzyl
ester, which was isolated without other purifications (2.28 g, 89%).
(16) No result was obtained even with the addition of tetrabutylamonium
iodide. The presence of tetrabutylammonium bromide causes the formation
of the alkyl bromide in low yields.
554
Org. Lett., Vol. 4, No. 4, 2002

Scheme 2
Table 2. Conversion of Diols and Unsaturated and â-amino
Alcohols into the Corresponding Alkyl Halides
In conclusion, the procedure reported here is operationally
simple and allows a rapid and high-yielding conversion of
alcohols to the corresponding chlorides and bromides under
very mild conditions. The method seems to be more
convenient with respect to other reports and can be used as
a valid alternative to other methods, so avoiding tedious
purifications or the use of more toxic reagents.
Acknowledgment. This work was financially supported
by the University of Sassari (Fondi ex-60%).
Note Added after ASAP: There was a nitrogen omitted
from the second reagent above the arrow in the abstract in
the version posted ASAP on 1/17/02. The print and final
Web version was posted (1/23/02).
a For complete conversion of the alcohol. b The corresponding chloride
is formed also.
Supporting Information Available: Physical and spec-
troscopic data for all unknown compounds and experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
depicted in Scheme 2. The Vilsmeier-Haack-type complex
should add the hydroxyl group of the alcohol to form the
cationic species 3; subsequent nucleophilic attack of halide
ion should produce the corresponding halide.17
OL017168P
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