An efficient method for chlorination of alcohols using PPh3/Cl3CCONH2

Article abstract of DOI:10.1016/j.tetlet.2006.07.060

A new and convenient method for the chlorination of alcohols utilizing PPh₃/Cl₃CCONH₂ is addressed. Various alcohols could smoothly be converted into their corresponding alkyl chlorides in high yield under mild conditions with short reaction times. A mechanism is disclosed with the evidence of inversion of configuration of the analogous alkyl chloride derived from R-(-)-2-octanol.

Full text of DOI:10.1016/j.tetlet.2006.07.060

Tetrahedron Letters 47 (2006) 6821–6823
An efficient method for chlorination of alcohols
using PPh3/Cl3CCONH2
Wanchai Pluempanupat and Warinthorn Chavasiri*
Natural Products Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan,
Bangkok 10330, Thailand
Received 30 May 2006; revised 6 July 2006; accepted 14 July 2006
Available online 7 August 2006
Abstract—A new and convenient method for the chlorination of alcohols utilizing PPh3/Cl3CCONH2 is addressed. Various alcohols
could smoothly be converted into their corresponding alkyl chlorides in high yield under mild conditions with short reaction times.
A mechanism is disclosed with the evidence of inversion of configuration of the analogous alkyl chloride derived from R-(ꢀ)-2-
octanol.
Ó 2006 Elsevier Ltd. All rights reserved.
Alkyl chlorides are generally used as both synthetically
useful intermediates and valuable end products.1
Although alkyl chlorides can be prepared from various
starting materials, the general and simple protocols
mostly stem from the conversion of alcohols. The main
reasons being due to the uncomplicated process of the
conversion, the variety and good availability of alco-
hols.2 Chlorodehydration has been accepted as a general
and basic transformation pathway using HCl gas,
SOCl2, (COCl)2, PCl3 or TMSCl; nonetheless, the
co-regeneration of HCl often causes undesired side reac-
tions.3 A new methodology with controllable selectivity
is therefore still necessary and is a relevant task for
organic chemists.4
pared with Cl3CCN, however, its cheaper cost and the
ease of work-up make this reagent more practical. We
report herein, the use of PPh3/Cl3CCONH2 for the con-
version of alcohols into their corresponding alkyl
chlorides.
Optimum conditions for the preparation of alkyl
chlorides from alcohols utilizing various chlorinated
reagents coupled with PPh3 were examined (Table 1).
Table 1. Effect of chlorinating agents
PPh3 (1.5 eq)
Chlorinating agent (1.5 eq)
Cl
OH
Ph
Ph
0.25 mmol
CH2Cl2, RT, 30 min
PPh3-halogenated reagents such as PPh3/CCl4, PPh3/
Cl3CCCl3, PPh3/Cl3CCOCCl3 or PPh3/Cl3CCN systems
have been reported as viable routes for the chlorination
of alcohols with high efficiency.5 These reagents are
attractive since reactions can be formed under mild
and acid-free conditions with good yields.
Entry
Chlorinating agent
Yielda (%)
1
2
3
None
CCl4
CHCl3
0
Trace
0
4
5
6
7
Cl3CCCl3
Cl3CCH2OH
CH3CO2CH2CCl3
Cl3CF
Quant
0
0
We have recently introduced Cl3CCONH2 as an alterna-
tive halogenated reagent for conversion of carboxylic
acids to their analogous amides and esters upon its com-
bination with PPh3.6 This reagent is less reactive com-
0
8
9
Cl3CCN
Quant
95
35
82
71
Cl3CCOCCl3
Cl3CCO2H
Cl3CCO2Et
Cl3CCO2 Pr
Cl3CCONH2
10
11
12
13
14
i
Keywords: Chlorination; Alcohols; Triphenylphosphine; Trichloro-
acetamide.
81
80
Cl3CCONHPh
*
Corresponding author. Tel.: +66 2 2187625; fax: +66 2 2187598;
e-mail: warintho@yahoo.com
a Determined by 1H NMR.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.060

6822
W. Pluempanupat, W. Chavasiri / Tetrahedron Letters 47 (2006) 6821–6823
Table 3. Chlorination of alcohols with PPh3/Cl3CCONH2
Variable parameters studied were the types of chlori-
nating agent, ratio of PPh3 and chlorinating agent
and reaction time.7 2-Phenylethanol was chosen as a
model compound to avoid the benzylic effect. A typical
procedure involved the reaction of alcohol (1 equiv),
halogenating reagent (1.5 equiv) and PPh3 (1.5 equiv)
in CH2Cl2 at rt (30 °C) for 30 min.
PPh3 (2 eq)
Cl3CCONH2 (2 eq)
ROH
RCl
CH2Cl2, RT, 15 min
0.25 mmol
Entry
ROH
RCla (%)
1
2
1-Octanol
1-Dodecanol
96, 95b,c
98
The efficiency of the chlorinating agent greatly depended
on the type of substituent on the chlorinating agents.
The reagents in entries 2–4 have been previously utilized
for conversion of alcohols into alkyl chlorides.5 Under
the specified conditions, the desired product was ob-
tained in low yield except in the case of Cl3CCCl3, which
gave a quantitative yield. No reaction occurred with
a chlorinating agent containing an alkyl group or F
atom on the trichloromethyl group (Cl3C–) (entries
5–7). Cl3CCN and Cl3CCOCCl3 (entries 8–9), reagents
bearing electron-withdrawing groups, gave the desired
products in quantitative yields, while Cl3CCO2H (entry
10) gave only a poor yield of the desired product. This
was probably because of its acidity, which may cause
the reaction medium to become acidic and thus incom-
patible for further reaction to take place. Other elec-
tron-withdrawing group-containing reagents (entries
11–14) were chosen to prove this assumption. For exam-
ple, Cl3CCO2Et, Cl3CCONH2 and Cl3CCONHPh
(entries 11, 13 and 14) furnished the target product in
high yields. Based on the results obtained, Cl3CCONH2
was considered as the most suitable chlorinating agent
for further investigation because it has not been studied
previously, and it is commercially available, cheap and
leads to a simple work-up procedure.
3
4
5
6
7
8
9
10
11
12
13
14
1-Octadecanol
2-Phenylethanol
3-Phenyl-1-propanol
96
Quant, 99b,c
92
(
)-2-Octanol
Quant
56*,d
62*,e
26*,f
76*,g
Quant
68
72*,h
11*,i
Cyclooctanol
Cyclododecanol
(
(
)-2-tert-Butylcyclohexanol
)-4-tert-Butylcyclohexanol
2-Adamantanol
1-Adamantanol
2-Phenyl-2-propanol
1,1-Diphenylethanol
a Determined by 1H NMR.
b Isolated pure product.
c 1 mmol of ROH was used.
d1.40:1.
e 1.44:1.
f
0.33:1.
g 2.71:1.
h 4.50:1.
i
0.12:1.
* RCl:olefin ratio.
primary, secondary and tertiary into their corresponding
alkyl chlorides (Table 3).
Various primary alcohols could be completely converted
into the corresponding alkyl chlorides in high to quanti-
tative yields (entries 1–5).8 The carbon chain length,
perhaps relating to steric hindrance, did not affect this
reaction (entries 1–3). Similarly, secondary alkyl
chlorides could also be obtained in high yield (entry
6). Cyclic compounds, on the other hand, were
converted into cyclic chlorides upon treatment with
PPh3/Cl3CCONH2 in low to moderate yields (entries
7–10) except for 2-adamantanol (entry 11). The olefinic
product was detected in this reaction with an almost
equivalent amount of the alkyl chloride present. This
implied that the reaction may competitively proceed
via two pathways, that is, substitution versus elimina-
tion. The conversion of a tertiary alcohol into its corre-
sponding alkyl chloride could also be accomplished in
high yield (entry 13). In the case of tertiary alcohols with
more phenyl substituents at the tertiary carbon atom,
the chloride product was detected in low yield. Perad-
venture, this alcohol, which was considered to react
via an E2 reaction, also gave an olefin as the main
product (entry 14).
The quantities of PPh3 and Cl3CCONH2 were varied to
find a suitable ratio to provide the maximum yield of
alkyl chloride (Table 2). The use of PPh3 and
Cl3CCONH2 in a 1:1 ratio (based on alcohol) furnished
the corresponding alkyl chloride in moderate yield
(entry 2). Increasing the amount of PPh3 and
Cl3CCONH2 over 1 equiv significantly elevated the yield
of the target product (entries 3–7). A short reaction time
(15 min) was also possible with the production of alkyl
chloride in quantitative yield (entry 6).
These optimized reaction conditions were extended to
investigate the conversion of various alcohols including
Table 2. Effect of PPh3 and Cl3CCONH2 ratio
PPh3, Cl3CCONH2
Cl
OH
Ph
Ph
CH2Cl2, RT, Time
0.25 mmol
Entry
PPh3
(equiv)
Cl3CCONH2
(equiv)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
0.5
1.0
1.2
1.5
1.5
2.0
2.0
0.5
1.0
1.2
1.5
1.5
2.0
2.0
15
15
15
15
30
15
30
15
53
73
75
81
Quant
Quant
Further examination of this method was performed
using an optically active substrate, R-(ꢀ)-2-octanol (1)
(Scheme 1). Under the standard protocol, chiral alcohol
25
17
1 (½aꢁD ꢀ9.6, c 0.97, CHCl3) (lit. ½aꢁD ꢀ9:9)9 was suc-
25
cessfully transformed into the alkyl chloride 2 (½aꢁD
+26.9, c 0.58, CHCl3) (lit. [a]D +26.1)4d,9 in good iso-
a Determined by 1H NMR.
lated yield with complete inversion of configuration.8,10

W. Pluempanupat, W. Chavasiri / Tetrahedron Letters 47 (2006) 6821–6823
6823
References and notes
PPh3 (2 eq)
OH
Cl
Cl3CCONH2 (2 eq)
1. (a) Hatakeyama, T.; Ito, S.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 2005, 127, 14192–14193; (b)
Braddock, D. C.; Peyralans, J. J.-P. Tetrahedron 2005,
61, 7233–7240; (c) Evans, W. J.; Workman, P. S. Organo-
metallics 2005, 24, 1989–1991.
CH2Cl2, RT, 15 min
1, 2.0 mmol
2, 76%, 100% ee
Scheme 1. Chlorination of R-(ꢀ)-2-octanol.
2. Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A.
J. Org. Chem. 2001, 66, 7741–7744.
O
O
Cl2
3. (a) Comprehensive Organic Transformations; 2nd ed.;
Larock, R. C., Ed., Wiley-VCH: New York, 1999; pp
689–702; (b) Organic Syntheses; Copenhaver, J. E.,
Whaley, A. M., Eds.; Wiley and Sons: New York, 1941;
Vol. 1, pp 144–145; (c) Lewis, E. S.; Boozer, C. E. J. Am.
Chem. Soc. 1952, 74, 308–311; (d) Ireland, R. E.; Norbeck,
D. W.; Mandel, G. S.; Mandel, N. S. J. Am. Chem. Soc.
1985, 107, 3285–3294; (e) Lee, J. G.; Kang, K. K. J. Org.
Chem. 1988, 53, 3634–3637.
C NH2
Cl
C
Cl PPh3
+
PPh3
Cl2C C NH2
3
O
ROH
+
Cl
RCl + O=PPh3
R O PPh3
Cl2HC C NH2
4
Scheme 2. Proposed mechanism.
4. (a) Lepore, S. D.; Bhunia, A. K.; Mondal, D.; Cohn, P. C.;
Lefkowitz, C. J. Org. Chem. 2006, 71, 3285–3286; (b)
Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A. J. Am.
Chem. Soc. 2004, 126, 7186–7187; (c) Gomez, L.; Gelli-
bert, F.; Wagner, A.; Mioskowski, C. Tetrahedron Lett.
2000, 41, 6049–6052; (d) Drabowicz, J.; Luczak, J.;
Mikolajczyk, M. J. Org. Chem. 1998, 63, 9565–9568.
5. (a) Slagle, J. D.; Huang, T. T.-S.; Franzus, B. J. Org. Chem.
1981, 46, 3526–3530; (b) Downie, I. M.; Holmes, J. B.
Chem. Ind. (London) 1966, 900–901; (c) Hooz, J.; Gilani, S.
S. H. Can. J. Chem. 1968, 46, 86–87; (d) Bringmann, G.;
Schneider, S. Synthesis 1983, 139–141; (e) Magid, R. M.;
Fruchey, O. S.; Johnson, W. L.; Allen, T. G. J. Org. Chem.
1979, 44, 359–363; (f) Jang, D. O.; Park, D. J.; Kim, J.
Tetrahedron Lett. 1999, 40, 5323–5326; (g) Matveeva, E.
D.; Kurts, A. L.; Yalovskaya, A. I.; Nikishova, N. G.;
Bundel, Y. G. Zh. Org. Khim. 1989, 25, 652–653.
The mechanism for the conversion of alcohols into their
corresponding alkyl chlorides using PPh3/CCl4 has been
addressed.5a,11 We considered that the reaction using
PPh3/Cl3CCONH2 should proceed similarly (Scheme
2). PPh3 reacts with Cl3CCONH2 to give intermediate
3, which then reacts with the alcohol to give alkoxyphos-
phonium salt 4, which decomposes to give the alkyl
chloride and triphenylphosphine oxide.
The effect of external nucleophiles such as NaCl, tri-
methylsilyl azide (TMSN3) was also carefully exam-
ined.12 Surprisingly, external chloride did not increase
the % yield of the corresponding alkyl chloride. Simi-
larly, the alkyl chloride was still the predominant
product without concomitant formation of an alkyl
azide when external azide was added. This strongly
implies that the ion pair formed (4) is tightly bound such
that it does not react with added nucleophiles.5a,13
6. Chaysripongkul, S.; Pluempanupat, W.; Jang, D. O.;
Chavasiri, W., submitted for publication.
7. Only alkyl chloride and recovered alcohol were obtained
from varying the halogenated reagent, PPh3/Cl3CCONH2
ratio and reaction time.
1
8. (a) 2-Phenethyl chloride: H NMR (CDCl3): d 7.20–7.25
In summary, we have described a very efficient and con-
venient method for the preparation of alkyl chlorides
from alcohols using a combination of PPh3 and
Cl3CCONH2 as the reagent system.
(m, 5H), 3.63 (t, J = 7.4 Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H).
1
(b) 1-Octyl chloride: H NMR (CDCl3): d 3.53 (t, J = 6.7
Hz, 2H), 1.77 (m, 2H), 1.20–1.48 (m, 10H), 0.89 (t, J =
6.7 Hz, 3H). (c) S-(+)-2-octyl chloride: 1H NMR (CDCl3):
d 4.01 (sex, J = 6.5 Hz, 1H), 1.69 (m, 2H), 1.28–1.50 (m,
11H), 0.89 (t, J = 6.7 Hz, 3H).
A typical experimental procedure is as follows: to
a stirred solution of alcohol (0.25 mmol) and PPh3
(0.5 mmol) in dry CH2Cl2 (0.5 mL) was added
Cl3CCONH2 (0.5 mmol) at rt (30 °C) under an N2
atmosphere. After 15 min, the reaction was quenched
with cold water and the presence of the corresponding
product in the crude mixture was determined by 1H
NMR utilizing toluene as an internal standard or alter-
natively was isolated by purification through silica gel
column chromatography.
9. Filippo, J. S.; Silbermann, J., Jr. J. Am. Chem. Soc. 1981,
103, 5588–5590.
10. The stereochemistry was determined by comparison with
S-(+)-2-octyl chloride by HPLC using commercially
available chiral columns (column cyclobond I 2000).
11. (a) Appel, R.; Halstenberg, M. In Organophosphorus
Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.;
Academic Press: London, 1979, Chapter 9; (b) Tomo-
skoozi, I.; Gruber, L.; Radics, L. Tetrahedron Lett. 1975,
16, 2473–2476.
12. Conditions: (a) alcohol (1 equiv), PPh3 (1 equiv),
Cl3CCONH2 (1 equiv) and NaCl (5 equiv) at rt (30 °C)
or 40 °C, 1 h; (b) Alcohol (1 equiv), PPh3 (2 equiv),
Cl3CCONH2 (2 equiv) and TMSN3 (1.5 equiv) at rt
(30 °C) or 40 °C, 1 h.
13. (a) Jones, L. A.; Sumner, C. E.; Franzus, B., Jr.; Huang,
T. T.-S.; Snyder, E. I. J. Org. Chem. 1978, 43, 2821–2827;
(b) Weiss, R. G.; Snyder, E. I. J. Org. Chem. 1970, 35,
1627–1632.
Acknowledgements
Financial support from the Graduate school, Chu-
lalongkorn University is acknowledged. W.P. is grateful
to Chulalongkorn University for the HM. King Rama
IX 72th Anniversary scholarship.