A one-pot method for the efficient conversion of aryl- and acyl-substituted methyl alcohols into chlorides

Article abstract of DOI:10.1081/SCC-120018934

A one-pot and efficient conversion of aryl- and acyl-substituted methyl alcohols into the corresponding chlorides is described, which involved tosylation with tosyl chloride and triethylamine in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in CH₂Cl₂, followed by methanol-facilitated replacement of the tosylates with chloride. This mild method is readily amenable to large-scale synthesis.

Full text of DOI:10.1081/SCC-120018934

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A One-Pot Method for the Efficient Conversion of Aryl-
and Acyl-substituted Methyl Alcohols into Chlorides
Gaifa Lai a , Ping-Zhong Tan b & Pallab Ghoshal a
a Chemo Dynamics, Inc. , Sayreville, New Jersey, USA
b Department of Psychiatry , Yale School of Medicine , West Haven, Connecticut, USA
Published online: 17 Aug 2006.
To cite this article: Gaifa Lai , Ping-Zhong Tan & Pallab Ghoshal (2003) A One-Pot Method for the Efficient Conversion of
Aryl- and Acyl-substituted Methyl Alcohols into Chlorides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:10, 1727-1732
To link to this article: http://dx.doi.org/10.1081/SCC-120018934
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 10, pp. 1727–1732, 2003
A One-Pot Method for the Efficient
Conversion of Aryl- and Acyl-substituted
Methyl Alcohols into Chlorides
2
1
Gaifa Lai,1, Ping-Zhong Tan, and Pallab Ghoshal
*
1Chemo Dynamics, Inc., Sayreville, New Jersey, USA
2Department of Psychiatry, Yale School of Medicine,
West Haven, Connecticut, USA
ABSTRACT
A one-pot and efficient conversion of aryl- and acyl-substituted
methyl alcohols into the corresponding chlorides is described,
which involved tosylation with tosyl chloride and triethylamine in
the presence of a catalytic amount of 4-(dimethylamino)pyridine
(DMAP) in CH2Cl2, followed by methanol-facilitated replacement
of the tosylates with chloride. This mild method is readily amenable
to large-scale synthesis.
The development of mild and one-pot procedures for efficient
functional group conversions is of great significance in organic synthesis.
For the conversion of primary and secondary alcohols into the corre-
*Correspondence: Gaifa Lai, 8-7B Koster Blvd., Edison, NJ 08837, USA;
Fax: þ1-732-422-0156; E-mail: gflai@hotmail.com.
1727
DOI: 10.1081/SCC-120018934
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1728
Lai, Tan, and Ghoshal
sponding chlorides, awide variety of methods have been reported, includ-
ing thionyl chloride,[1] phosphorus trichloride,[2] hydrochloric acid and
zinc chloride (Lucas reagent),[3] triphenylphosphine dichloride,[4] triphe-
nylphosphine and carbon tetrachloride[5] or hexachloroacetone,[6] tosyl
chloride and DMAP,[7] methanesulfonyl chloride and lithium chloride,[8]
and a Vilsmeier reagent.[9] However, many of these methods have
some limitations such as being too drastic to be compatible with other
functionalities, using highly corrosive or toxic reagents, requiring labor-
ious workup, and being difficult to scale up. As a continuation of our
interest in the development of new and simple procedures for functional
group transformations,[10] we now report a mild, scalable, one-pot
procedure for the two-step conversion of aryl- and acyl-substituted
methyl alcohols into chlorides via the intermediate tosylates, as depicted
in Sch. 1.
Thus, tosylation of aryl- and acyl-substituted methyl alcohols was
carried out by treatment with tosyl chloride (1.1 eq.) and triethylamine
(2 eq.) in the presence of a catalytic amount of DMAP (0.02 eq.) in
CH2Cl2 at 0–5ꢀC for 1–2 h. When the starting alcohols were consumed,
methanol (0.4 eq) was added and the mixture was heated at 40–42ꢀC to
afford the desired chlorides in good yields. The results are summarized in
Table 1. The progress of both tosylation and subsequent replacement of
the tosylates by chloride was monitored by TLC and GC or HPLC
analyses. Methanol was found to facilitate the substitution reaction of
tosylates with chloride. Control experiments indicated that without the
use of methanol, the transformation of the tosylates into the chlorides
proceeded slowly or incompletely even after a prolonged reaction time.
One explanation for the effect of methanol is that it may serve to enhance
the nucleophilicity of the chloride ion, which may be freed to a certain
extent when methanol and quaternary ammonium species probably form
acomplex through ahydrogen bond, as shown in Eq. (1). This one-pot
procedure was quite gentle, and functional groups such as epoxide ring,
fluoride, and amide were not affected. Selective reaction of the primary
alcohol functionality in 7a was achieved without affecting the secondary
and tertiary hydroxyl groups and the corresponding chloride 7b was
obtained in 90% yield (Entry 7).
H
þ
À
þ
À
ÀÀÀ*
)ÀÀÀ
Et N À H Á Á Á Cl þ MeOH
Et N À H Á Á Á OMe þ Cl
ð1Þ
3
3
Scheme 1. Reaction conditions: (i) TsCl (1.1 eq.), Et3N (2 eq.), DMAP (0.02
eq.), CH2Cl2, 0–5ꢀC (ii) MeOH (0.4 Equiv.), 40–42ꢀC.

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Aryl- and Acyl-substituted Methyl Alcohols
1729
Table 1. One-pot conversion of aryl- and acyl-substituted methyl alcohols into
chlorides.
Entry
Alcohol
Chloride
PhCH2Cl
Timea (h)
Yieldb (%)
1
2
PhCH2OH
0.5
2
80c
92d
3
1
83c
4
5
6
2
85d
83c
91d
2
3.5
7
8
4
3
90d
88d
aThe time for the second step, displacement of the toslaytes. bYields refer to single
c
d
runs and are given isolated chlorides. Purified by vacuum distillation. Purified
by column chromatography.
When this procedure was applied to other primary alcohols such as
2-phenylethanol, 5-phenyl-1-pentanol, and 3-(3-pyridyl)propanol, the
results, however, showed incomplete or no conversion of their tosylates
into the expected chlorides after tosylation (Sch. 2). For example,
treatment of 5-phenyl-1-pentanol under the same reaction conditions
only gave 5-phenyl-1-pentyl tosylate (94%) without the corresponding
chloride being detected.

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1730
Lai, Tan, and Ghoshal
Scheme 2. Reaction conditions: (i) TsCl (1.1 eq.), Et3N (2 eq.), DMAP (0.02
eq.), CH2Cl2, 0–5ꢀC (ii) MeOH (0.4 eq.), 40–42ꢀC, 7 h.
In summary, a one-pot and efficient procedure for the conversion of
aryl- and acyl-substituted methyl alcohols into the chlorides is presented.
The distinct advantages of this method are its mild conditions, short
reaction time, operational convenience, high yields, low cost of reagents,
and suitability for scale-up.
EXPERIMENTAL
All reagents and solvents were used without further purification. GC
was performed using a Hewlett-Packard 5890A chromatograph equipped
with a flame ionization detector. HPLC was performed on Nova-Pak C18
column (3.9 Â 150 mm, Waters) with flow rate of 1.5 mL/min, detection at
1
254 nm, and the mobile phase, CH3CN–H2O (46:54). H NMR spectra
were recorded on a Varian Gemini 300 spectrometer. The structures of
1
the products were confirmed by H NMR spectral data and comparison
with those of authentic samples.
General Procedure for the One-Pot Conversion of Aryl- and
Acyl-substituted Methyl Alcohols into Chlorides
To asolution of alcohol (10 mmol) in CH 2Cl2 (25 mL) at 0ꢀC wa s
added tosyl chloride (2.1 g, 11 mmol, 1.1 eq.) in portions with stirring.
A solution of triethylamine (2.79 mL, 20 mmol, 2 eq.) and DMAP (24 mg,
0.2 mmol, 0.02 eq.) in CH2Cl2 (5 mL) was then added dropwise with
stirring at 0–5ꢀC. After addition, the mixture was stirred at 0–5ꢀC
under nitrogen for 1–2 h when the starting alcohol disappeared.
Methanol (0.17 mL, 4 mmol, 0.4 eq.) was added, and the resulting mixture

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Aryl- and Acyl-substituted Methyl Alcohols
1731
was then heated at 40–42ꢀC with stirring under nitrogen until the con-
version of the tosylate to the chloride was complete. The mixture was
cooled to room temperature, and CH2Cl2 (50 mL) and water (50 mL)
were added. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (2 Â 50 mL). The combined organic layers
were washed with brine (2 Â 50 mL), dried over sodium sulfate, and con-
centrated under reduced pressure. The crude product was purified by
vacuum distillation or column chromatography on silica gel.
The chemical names, 1H NMR, and elemental analytical data of
compounds 6b–8b are listed below.
21-Chloro-9b,11b-epoxy-17a-hydroxy-16a-methylpregna-1,4-diene-3,20-
1
dione (6b): H NMR (DMSO-d6): ꢀ 7.32 (d, J ¼ 10.7Hz, 1H), 6.25 (d,
J ¼ 10.6 Hz, 1H), 6.08 (s, 1 H), 4.54 (s, 2H), 2.90–2.86 (m, 1H), 1.99–1.96
(m, 3H), 1.74–1.73 (m, 1H), 1.52–1.49 (m, 2H), 1.43–1.40 (m, 2H),
1.39–1.37 (m, 1H), 1.36 (s, 3H), 1.29–1.27 (m, 2H), 1.16 (s, 3H), 0.84 (d,
J ¼ 7.1 Hz, 3H). Anal. calcd. for C22H27ClO4: C, 67.60; H, 6.96; Cl, 9.07.
Found: C, 67.56; H, 7.05; Cl, 9.11.
21-Chloro-11a,17a-dihydroxy-16a-methylpregna-1,4-diene-3,20-dione (7b):
1H NMR (DMSO-d6): ꢀ 7.82 (d, J¼ 10.7 Hz, 1H), 6.00-5.97 (m, 2 H), 5.31 (s,
1 H), 4.74 (d, J¼ 16.8 Hz, 1H), 4.73 (d, J¼ 7.0 Hz, 1H), 4.42 (d, J¼ 16.8 Hz,
1H), 3.90–3.84 (m, 1H), 2.95–2.89 (m, 1H), 2.50–2.43 (m, 1H), 2.35–2.29 (m,
1H), 1.87–1.70 (m, 3H), 1.69–1.53 (m, 1H), 1.24 (s, 3H), 1.12–1.06 (m, 1H),
1.05–0.94 (m, 2H), 0.79 (d, J¼ 7.1 Hz, 3H), 0.65 (s, 3H). Anal. calcd. for
C22H29ClO4: C, 67.25; H, 7.44; Cl, 9.02. Found: C, 67.15; H, 7.49; Cl, 9.07.
21-Chloro-9a-fluoro-11b-hydroxy-16a-methylpregna-1,4-diene-3,20-
1
dione (8b): H NMR (CDCl3): ꢀ 7.21 (d, J ¼ 10.7 Hz, 1H), 6.38 (d, J ¼
10.7 Hz, 1H), 6.14 (s, 1H), 4.36 (m, 1H), 4.07 (s, 2H), 2.80–2.56 (m, 2H),
2.48–2.24 (m, 3H), 2.09–2.01 (m, 1H), 1.95–1.78 (m, 3H), 1.63–1.57 (m,
1H), 1.56 (s, 3H), 1.39–1.25 (m, 1H), 1.00 (d, J ¼ 7.1 Hz, 3H), 0.98 (s, 3H).
Anal. calcd. for C22H28ClFO4: C, 66.91; H, 7.15. Found: C, 66.98; H, 7.11.
REFERENCES
1. Lewis, E.S.; Boozer, C.E. J. Am. Chem. Soc. 1952, 74, 308.
2. Wiley, G.A.; Rein, B.M.; Hershkowitz, R.L. Tetrahedron Lett. 1964,
2509.
3. Copenhaver, J.E.; Whaley, A.M. Org. Synth. I 1941, 142.
4. Wiley, G.A.; Hershkowitz, R.L.; Rein, B.M.; Chung, B.C. J. Am.
Chem. Soc. 1964, 86, 964.
5. MacKenzie, B.D.; Angelo, M.M.; Wolinsky, J. J. Org. Chem. 1979,
44, 4042.

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1732
Lai, Tan, and Ghoshal
6. Magid, R.M.; Fruchey, O.S.; Johnson, W.L.; Allen, T.G. J. Org.
Chem. 1979, 44, 359.
7. Hwang, C.K.; Li, W.S.; Nicolaou, K.C. Tetrahedron Lett. 1984,
25, 2295.
8. Collington, E.W.; Meyers, A.I. J. Org. Chem. 1971, 36, 3044.
9. (a) Chen, F.-E.; Meng, G.; He, Y.-P.; Cheng, Y.; Ling, X.-H. Org.
Prep. Proc. Inter. 2001, 33, 311; (b) Hepburn, D.R.; Hudson, H.R.
J. Chem. Soc. Perkin 1 1976, 754.
10. (a) Lai, G.; Bhamare, N.K.; Anderson, W.K. Synlett 2001, 230;
(b) Lai, G.; Anderson, W.K. Synth. Commun. 1997, 27, 1281.
Received in the USA February 21, 2002