CaF2 catalyzed SN2 type chlorodehydroxylation of chiral secondary alcohols with thionyl chloride: A practical and convenient approach for the preparation of optically active chloroalkanes

Article abstract of DOI:10.1016/j.tetlet.2013.02.079

A CaF₂ catalyzed chlorodehydroxylation of chiral secondary alcohols with thionyl chloride has been developed. The chlorination reaction is effective for a wide range of alcohols, generating the corresponding chloroalkanes in good yield with high optical purity with inversion of the original configuration of the alcohol.

Full text of DOI:10.1016/j.tetlet.2013.02.079

Tetrahedron Letters 54 (2013) 2261–2263
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Tetrahedron Letters
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CaF2 catalyzed SN2 type chlorodehydroxylation of chiral secondary alcohols
with thionyl chloride: a practical and convenient approach for the
preparation of optically active chloroalkanes
⇑
⇑
Junjie Zhang, Huanxia Wang, Yun Ma, Youming Wang , Zhenghong Zhou , Chuchi Tang
Institute and State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A CaF2 catalyzed chlorodehydroxylation of chiral secondary alcohols with thionyl chloride has been
developed. The chlorination reaction is effective for a wide range of alcohols, generating the correspond-
ing chloroalkanes in good yield with high optical purity with inversion of the original configuration of the
alcohol.
Received 22 November 2012
Revised 28 January 2013
Accepted 22 February 2013
Available online 1 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Optically active alkyl chlorides are commonly used as both very
useful synthetic intermediates and valuable end products.1 For
example, they can be used as electrophiles and are converted, by
nucleophilic displacement, to various valuable chiral synthons
including amines, thiols, or ethers.2 Since alcohols are one of the
most common and versatile compounds for transformation into
other classes of chemicals, an overwhelming approach to the alkyl
chlorides and other halide analogues is the replacement of the hy-
droxyl group of the corresponding alcohols. Consequently, chlori-
nation of alcohols has been accepted as a general and basic
transformation pathway in organic synthesis.3 The conversion
can be accomplished using a two-step procedure where the alcohol
is first converted into a leaving group (generally a sulfonate) fol-
lowed by nucleophilic displacement with the appropriate halide
or in a single flask where both steps are performed in situ. Not sur-
prising, the direct chlorodehydroxylation of alcohols is more pref-
erable than the former. Although the hydroxyl moiety is hardly
substituted due to its lower leaving ability, numerous chlorination
reagents have been developed during the past several decades.
Among them, the most important reagents for such a displacement
of the hydroxyl group by chlorine in a stereospecific manner are
thionyl chloride,4 phosphorus compounds, such as PCl3,5 PCl5,6
chlorination reagent, the concomitant generation of stoichiometric
phosphine oxide by-products impacts severely on the atom effi-
ciency and large-scale applicability of these reactions. Further-
more, purification of the product is not always straightforward.
The use of phosphorus chloride, oxalyl chloride, benzoxazolium
phenylmethyleniminium salt, or N,N0-diisopropylcarbodiimide/
AcCl/CuCl system suffers from some disadvantages with respect
to reaction conditions, availability, or purification issues. Gener-
ally, the use of thionyl chloride demonstrated great advantage on
purification and large-scale applicability because only two gaseous
byproducts were generated in this process. With respect to the ste-
reochemical outcome of the reaction, the reaction proceeds with
retention of the original configuration of the alcohol via an internal
nucleophilic substitution (SNi) when SOCl2 alone was employed as
the chlorination reagent, while the introduction of chlorine oc-
curred with inversion of stereochemistry by an SN2 fashion in the
presence of pyridine.16 The main drawback of the latter process
is the addition of at least stoichiometric odorous pyridine.
Although Kellogg has reported an SN2-type chlorodehydroxylation
of ethyl L-lactate with thionyl chloride in the presence of catalytic
amount of DMF, the generality of the reaction has not been exam-
ined.17 Therefore, the development of an alternative process for the
chlorodehydroxylation of chiral alcohols by thionyl chloride with
inversion of the configuration avoiding the use of pyridine will
be of great interest and remains a challenging task. Herein, we re-
port the development of a practical and convenient approach for
the preparation of optically active chloroalkanes via CaF2 catalyzed
SN2 type chlorodehydroxylation of chiral secondary alcohols with
thionyl chloride.
In the literature report, CaF2 has proven to be an efficient cata-
lyst for the chlorination of O,O-dimethyl methylphosphonate with
thionyl chloride, generating the corresponding methylphosphon-
odichloride in excellent yields.18 We envisioned that this
R3PCl2,7 Ph3P/CCl4,8 Ph3P/Cl3CCOCCl3,9 or Ph3P/R2SeCl2 system.
10
Other methods, such as the use of 2-chlorobenzoxazolium salt,11
N,N-diphenylchlorophenyl-methyleniminium chloride,12 or N,N0-
diisopropylcarbodiimide/AcCl/CuCl13 as the chlorination reagents
were also developed. Recently, the first triphenylphosphine
oxide-catalyzed Appel-type chlorination14 reaction has been real-
ized using oxalyl chloride as the chlorination reagent.15 In case of
Ph3P in combination with an electrophilic halogen source as the
⇑
Corresponding authors.
E-mail address: z.h.zhou@nankai.edu.cn (Z. Zhou).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.079

2262
J. Zhang et al. / Tetrahedron Letters 54 (2013) 2261–2263
Table 1
Table 2
Optimization of the reaction conditiona
Catalytic chlorination of hydroxyl substituted carboxylatea
OH
OH
*
Cl
*
Cl
SOCl2/CaF2
70 °C 2h, then reflux
SOCl2(1.1 equiv)/CaF2 (10 mol%)
CO2R1
CO2R1
70 °C 2h, then reflux
CO2Et
R
R
CO2Et
n
n
(n = 0,1)
Entry
CaF2 (mol %)
SOCl2 (equiv)
Time (h)
Yieldb (%)
eec (%)
b,c
Entry
Substrate
OH
CO2Et
OH
CO2Et
Time (h)
7
Yield (%)
85 (81)
eec (%)
1
2
3
4
5
6
10
10
10
5
1
0
1.0
1.1
1.2
1.1
1.1
1.1
4
7
9
8
11
15
74
85
82
80
74
60
94
95
94
94
89
1
2
95 (93)d
92 (88)e
13
78 (72)
ꢀ70
a
b
c
All the reactions are performed on a 20 mmol scale.
Isolated yield.
Determined by chiral GC analysis.
OH
CO2Me
CO2Me
3
6
25
12
86 (81)
77 (74)
85 (80)
95 (91)f
95 (92)h
58 (45)i
MeO2C
4g
5g
OH
OH
chlorination system may be applied for the preparation of the chi-
ral alkyl chloride from optically active secondary alcohols via an
SN2 type displacement of hydroxyl group with chlorine.
Ph
CO2Me
a
b
c
d
e
f
We first optimized the chlorination reaction using ethyl
tate as the test substrate and the selected results are shown in Ta-
ble 1. Screening of an appropriate solvent was first performed upon
L
-lac-
All the reactions are performed on a 20 mmol scale.
Isolated yield.
Data in parenthesis are those obtained from SOCl2/pyridine system.
bDEX120, Rt = 29.8 (minor) and 30.5 min (major).
bDEX120, Rt = 9.42 (major) and 10.60 min (minor).
Chiralpak AS–H column, hexane/2-propanol = 95/5, flow rate = 1 mL/min,
treatment of ethyl L-lactate with 1 equiv thionyl chloride in the
presence of 10 mol % of CaF2. The formation of the corresponding
ethyl (R)-2-chloropropionate was not detected when the reaction
mixture was refluxed for 48 h in conventional solvents, such as
chloroform, 1,2-dichloroethane, and toluene. It was gratifying that
decomposition of the corresponding chlorosulfinic ester preformed
at 70 °C for 2 h was observed at refluxing (appr. 170 °C) under sol-
vent free condition, providing the chlorinated product with inver-
sion of configuration in 74% yield with ee value of 94% (Table 1,
entry 1). Increasing the amount of thionyl chloride from 1.0 to
1.1 equiv gave rise to a slightly increased enantioselectivity and
yield (Table 1, entry 2). The use of 1.2 equiv of chlorination reagent
failed to further improve the optical purity of the product (Table 1,
entry 3). Adjusting the catalyst loading demonstrates an obvious
influence on the reaction. Reducing the amount of CaF2 to
5 mol % led to a slightly decreased yield and ee value. Further
reducing the catalyst loading to 1 mol % resulted in a slower reac-
tion and marked decease in enantioselectivity. In addition, some
control experiments were performed to elucidate the important
role of CaF2 in this transformation. Under indentical conditions,
the chlorodehydroxylation product was obtained in 60% yield with
the retention of stereochemistry in the absence of CaF2 (Table 1,
entry 6, ꢀ70% ee). The use of other calcium salts, such as CaCl2
and CaSO4, resulted in both decrease in yield and enantioselectivity
(CaCl2: 20% yield, 40% ee; CaSO4: 30% yield, 85% ee), while Bu4NF
was not active at all in this process.
wavelengh = 220 nm: Rt = 10.19 (minor) and 11.20 (major).
g
The reaction is conducted at 70 °C.
h
c
-DEX225, Rt = 43.9 (minor) and 44.9 min (major).
i
Chiralpak OD–H column, hexane/2-propanol = 99/1, flow rate = 1 mL/min,
wavelengh = 220 nm: Rt = 7.40 (major) and 11.20 (minor).
chloro-ester was obtained both with higher yield and optical purity
than those obtained from SOCl2/pyridine system.
To further extend the scope of this catalytic chlorination proto-
col, a plethora of optically active simple secondary alcohol were
prepared from the ring-opening of (S)-2-methyloxirane with Grig-
nard reagent and subjected to the CaF2 catalyzed chlorodehydroxy-
lation with thionyl chloride. The results are collected in Table 3.
In the case of simple secondary alcohols, the optimal tempera-
ture of the decomposition of the chlorosulfinic ester is 70 °C.19
Either increasing or decreasing the temperature will lead to a de-
crease of the specific rotation value of the chloroalkane. As shown
in Table 3, the reaction tolerated alkyl, branched alkyl, phenyl and
alkenyl substituted chiral secondary alcohols, generating the corre-
sponding alkyl chloride with inversion of the original configuration
of the alcohol. Compared with the results obtained for SOCl2/pyri-
dine system, better or comparable yields and stereochemistry out-
comes were obtained for this newly developed CaF2 catalyzed
chlorination system.
To demonstrate the potential of this method for preparative
purposes, the chlorodehydroxylation of (S)-ethyl lactate is also car-
ried out on a large scale giving (R)-ethyl 2-chloropropionate with-
out any erosion in both chemical yield and optical purity
(Scheme 1). In view of the latter being the key intermediate for
With a protocol for catalytic chlorination in hand we examined
a range of optically active hydroxyl substituted carboxylate sub-
strates, such as (S)-methyl 3-methyl-2-hydroxybutanoate, (S)-di-
methyl 2-hydroxysuccinate, (R)-methyl 3-hydroxybutanoate, and
(S)-methyl mandelate, under the optimal conditions (Table 2).18
In general, the corresponding configuration inversed chlorination
products can be obtained in good yields with high optical purity
for chiral alkyl substituted acetate regardless of the hydroxyl
group’s location (Table 2, entries 1–4). In the case of the aryl
substituted substrate, (S)-methyl mandelate, the reaction occurred
with partial racemization, which indicated that the existence of a
competition of the type SN1 versus SNi in the decomposition pro-
cess of the chlorosulfinic ester (Table 2, entry 5). This may be
attributed to the unusual stability of the benzylic carbocation. Nev-
ertheless, it is noteworthy that, in all cases, the corresponding
the synthesis of L-alanyl-L-glutamide which is currently used as
part of total parenteral nutrition protocols in hospital settings, this
efficient and environmental benign stereoselective chlorodehydr-
oxylation process will be of great importance for the synthesis of
L-alanyl-L-glutamide and related fine chemicals.
In conclusion, a CaF2 catalyzed chlorodehydroxylation of chiral
secondary alcohols with thionyl chloride has been developed. The
stereochemistry outcome indicates that the SN2 process leading to
the inversion of configuration is involved in this developed reagent
system. Compared with the literature reported SOCl2/pyridine

J. Zhang et al. / Tetrahedron Letters 54 (2013) 2261–2263
2263
Table 3
2. Nelson, J. D. In Practical Synthetic Organic Chemistry: Reactions, Principles, and
Techniques; Caron, S., Ed.; John Wiley & Sons: Hoboken, 2011. and references
therein.
Catalytic chlorination of chiral secondary alcoholsa
3. Bohlmann, R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 6, pp 203–223.
4. Young, W. G.; Caserio, F. F., Jr.; Brandon, D. D., Jr. J. Am. Chem. Soc. 1960, 82,
6163.
OH
Cl
SOCl2(1.1 equiv)/CaF2 (10 mol%)
70 °C
R
R
5. Goodwin, D. G.; Hudson, H. R. J. Chem. Soc. 1968, 1333.
6. Cowdrey, W. A.; Hughes, E. D.; Ingold, C. K.; Masterman, S.; Scott, A. D. J. Chem.
Soc. 1937, 1252.
7. (a) Wiley, G. A.; Hershkovitz, R. L.; Rein, B. M.; Chung, B. C. J. Am. Chem. Soc.
1964, 86, 964; (b) Caregg, P. J.; Johansson, R.; Samuelsson, B. Synthesis 1984,
168.
8. (a) Snyder, E. I. J. Org. Chem. 1972, 37, 1466; (b) Jones, L. A.; Sumner, C. E., Jr.;
Franzus, B.; Huang, T. T. S.; Snyder, E. I. J. Org. Chem. 1978, 43, 2281.
9. (a) Magid, R. M.; Fruchey, O. S.; Johnson, W. L. Tetrahedron Lett. 1977, 18, 2999;
(b) Magid, R. M.; Fruchey, O. S.; Johnson, W. L.; Allen, T. G. J. Org. Chem. 1979, 44,
359.
10. Drabowicz, J.; Luczak, J.; Mikolajczyk, M. J. Org. Chem. 1998, 63, 9565.
11. Mukaiyama, T.; Shoda, S.-I.; Watanabe, Y. Chem. Lett. 1977, 383.
12. Fujisawa, T.; Iida, S.; Sato, T. Chem. Lett. 1984, 1173.
½ ꢁ
a 2D5 (c 1.0 CHCl3)c
Entry
Substrate
Time (h)
Yieldb,c (%)
1
2
3
4
5
6
7
8
9
Et
3
3
4
4
5
2.5
3
3
3
82 (77)
86 (84)
87 (83)
82 (81)
89 (85)
68 (74)
71 (80)
74 (78)
65
ꢀ33.6 (ꢀ32.8)d
ꢀ28.9 (ꢀ28.7)e
ꢀ34.2 (ꢀ33.6)
ꢀ34.8 (ꢀ32.5)
ꢀ27.4 (ꢀ26.7)f
ꢀ32.9 (ꢀ33.8)g
ꢀ43.8 (ꢀ42.6)
ꢀ35.7 (ꢀ36.4)
ꢀ22.7h
Pr
iBu
Pentyl
Octyl
Bn
BnCH2
BnCH2CH2
Allyl
10
CH2@CHCH2CH2
3
68
ꢀ23.6i
13. Crosignani, S.; Nadal, B.; Li, Z.; Linclau, B. Chem. Commun. 2003, 260.
14. Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801.
a
b
c
d
e
f
All the reactions are performed on a 20 mmol scale.
Isolated yield.
15. Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010, 46, 3025.
16. Hughes, E. D.; Ingold, C. K.; Whitfield, I. C. Nature 1941, 147, 206.
17. Hof, R. P.; Kellogg, R. M. J. Chem. Soc., Perkin Trans. 1 1995, 1247.
18. (a) He, Z. J.; Wang, Y. M.; Tang, C. C. Phosphorus, Sulfur Silicon 1997, 127, 59; (b)
Wojtowicz, J. A. U.S. 4,871,486, 1989 (Chem. Abstr. 1990, 112, 98835e).; (c)
Grosse, J.; Pieper, W.; Neumaier, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 542;
(d) Vasu, K.; Roy, N. K. Agric. Biol. Chem. 1983, 47, 2657.
Data in parenthesis are those obtained from SOCl2/pyridine system.20
½
½
½
½
½
½
a 2D0
a 2D0
a 2D0
ꢁ
ꢀ31.2 (neat).21
ꢁ
ꢀ38.1 (methanol).22
ꢁ
+33.0 (c 0.97, CH2Cl2) for S enantiomer.23
a 2D5
ꢁ
ꢀ20.0 (c 5, CHCl3)24 and ½a D16
ꢁ
ꢀ22.6 (neat).25
g
h
i
25
a
ꢁ
ꢀ5.1 (calculated value).26
ꢀ61.8 (calculated value).27
587:5
a 2D5
ꢁ
19. General procedure for the CaF2 catalyzed chlorodehydroxylation of chiral
secondary alcohols: To a mixture of thionyl chloride (1.6 mL, 22 mmol) and
CaF2 (156 mg, 2 mmol) was added dropwise the chiral secondary alcohols at
room temperature. After stirring at 70 °C for 2 h, the reaction mixture was
heated to refluxing or maintain the same temperature for the depicted time.
Then the reaction mixture was cooled to room temperature, neutralized with
saturated aqueous NaHCO3 solution, extracted with methylene chloride, and
dried over anhydrous MgSO4. After removal of solvent in vacuum, the crude
product was purified either by column chromatograph on silica gel or
distillation under reduced pressure. 2-Methyl-4-chloropentane: 1H NMR
(CDCl3, 300 MHz): d 0.91 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H), 1.40–
1.47 (m, 1 H), 1.51 (d, J = 6.6 Hz, 3 H), 1.64–1.74 (m, 1 H), 1.83–1.88 (m, 1 H),
OH
CO2Et
100 g
Cl
SOCl2 (1.1 equiv)/CaF2 (10 mol%)
70 °C 2h, then reflux
CO2Et
104 g
(90% yield, 97% ee)
Scheme 1. Large-scale preparation of (R)-ethyl 2-chloropropionate.
4.03–4.15 (m,
1
H). 2-Chloroheptane: 1H NMR (CDCl3, 400 MHz): 0.90 (t,
J = 6.4 Hz, 3 H), 1.26–1.35 (m, 4 H), 1.37–1.43 (m, 1 H), 1.45–1.50 (m, 1 H), 1.51
(d, J = 6.4 Hz, 3 H), 3.99–4.07 (m, 1 H). 1-(3-Chlorobutyl)benzene: 1H NMR
(CDCl3, 400 MHz): 1.54 (d, J = 6.4 Hz, 3 H), 1.99–2.06 (m, 2 H), 2.72–2.79 (m, 1
H), 2.83–2.90 (m, 1 H), 3.96–4.05 (m, 1 H). 7.21–7.22 (m, 3 Harom), 7.29–7.32
(m, 2 Harom). 1-(4-Chloropentyl)benzene: 1H NMR (CDCl3, 400 MHz): 1.50 (d,
J = 6.4 Hz, 3 H), 1.74–1.78 (m, 3 H), 1.82–1.89 (m, 1 H), 2.63–2.68 (m, 2 H),
4.01–4.09 (m, 1 H), 7.18–7.21 (m, 3 Harom), 7.27–7.31 (m, 2 Harom).
method, the great advantage of this chlorination system is that
only catalytic amount of CaF2 is sufficient to ensure the conversion
of the alcohol into the corresponding alkyl chloride with high opti-
cal purity in an SN2 fashion, avoiding the use of at least stoichiom-
etric environmentally hazardous pyridine. Moreover, the new
reaction described here offers a practical and inexpensive method
20. General procedure for the chlorodehydroxylation of chiral secondary alcohols with
Py/SOCl2: To
a solution of alcohol (0.02 mol) and pyridine (0.022 mol) in
for the synthesis of the key intermediate for the synthesis of
nyl- -glutamide.
L-ala-
chloroform (20 mL) was added dropwise a solution of SOCl2 (0.022 mol) in
chloroform (10 mL) at 0 °C. Then resulting mixture was heated to 60 °C until
the full conversion of the alcohol. After cooling to room temperature, the
reaction mixture was neutralized with saturated aqueous NaHCO3 solution.
The organic phase was separated and dried over anhydrous MgSO4. After
removal of the solvent under reduced pressure, the crude product was purified
either by column chromatograph on silica gel or distillation under reduced
pressure.
L
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Nos. 20972070, 21121002), the National Basic research Pro-
gram of China (973 program 2010CB833300), Program for New
Century Excellent Talents in University (NCET-11-0265) and the
Key laboratory of Elemento-Organic Chemistry for generous finan-
cial support for our programs.
21. Stevens, C. L.; Morrow, D.; Lawson, J. J. Am. Chem. Soc. 1955, 77, 2341.
22. Chaudri, B. A.; Goodwin, D. G.; Hudson, H. R.; Barlett, L.; Scopes, P. M. J. Chem.
Soc. 1970, 1329.
23. Braddock, D. C.; Pouwer, R. H.; Burton, J. W.; Broadwith, P. J. Org. Chem. 2009,
74, 6042.
24. Masuda, S.; Nakajima, T.; Suga, S. Bull. Chem. Soc. Jpn. 1983, 56, 1089.
25. Gerrard, W.; Shepherd, B. D. J. Chem. Soc. 1953, 2069.
26. Levene, P. A.; Rothen, A. J. Chem. Phys. 1937, 5, 980.
References and notes
27. Friederang, A. W.; Tarbell, D. S. J. Org. Chem. 1968, 33, 3797.
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Eds.; John Wiley & Sons: Chichester, 1995; (b) Larock, R. C. Comprehensive
Organic Transformations, 2nd ed.; Wiley-VCH: New York, 1999. pp 689–702.