Chlorination of benzylic and allylic alcohols with trimethylsilyl chloride enhanced by natural sodium montmorillonite

Article abstract of DOI:10.1055/s-0034-1379226

A new and practical method for the efficient chlorination of tertiary, secondary, and primary benzylic and allylic alcohols is described. The method is characterized by the formation of hydrogen chloride from trimethylsilyl chloride and trace water, the formation of a carbenium ion through the protonation of an alcohol and subsequent dehydration, and the chlorination of the carbenium ion. During the process, sodium ion-exchanged montmorillonite plays a crucial role in capturing the generated hydrogen chloride, stabilizing the carbenium intermediate as well as promoting the chlorination.

Full text of DOI:10.1055/s-0034-1379226

LETTER
▌2639
lCetther lorination of Benzylic and Allylic Alcohols with Trimethylsilyl Chloride
Enhanced by Natural Sodium Montmorillonite
Chlorination of Benzylic and Allylic Alcohols
Michael Andreas Tandiary,a Yoichi Masui,b Makoto Onaka*b
a
Department of Chemistry, Graduate School of Sciences, The University of Tokyo, Bunkyo-Ku Hongo 7-3-1, Tokyo 113-0033, Japan
b
Graduate School of Arts and Sciences, The University of Tokyo, Meguro-Ku Komaba 3-8-1, Tokyo 153-8902, Japan
Fax +81(3)54546998; E-mail: conaka@mail.ecc.u-tokyo.ac.jp
Received: 30.07.2014; Accepted after revision: 08.09.2014
silane,9 and triethylsilane.10 In these reactions, the alco-
Abstract: A new and practical method for the efficient chlorination
hols first underwent protonation, followed by dehydration
of tertiary, secondary, and primary benzylic and allylic alcohols is
with the aid of Sn-Mont to form benzylic carbenium inter-
mediates, which were trapped between the montmorillon-
described. The method is characterized by the formation of hydro-
gen chloride from trimethylsilyl chloride and trace water, the for-
mation of a carbenium ion through the protonation of an alcohol and ite silicate layers. It is considered that the low nucleophilic
subsequent dehydration, and the chlorination of the carbenium ion.
During the process, sodium ion-exchanged montmorillonite plays a
crucial role in capturing the generated hydrogen chloride, stabiliz-
ating the reactions between the carbenium ions and the
ing the carbenium intermediate as well as promoting the chlorina-
tion.
montmorillonite silicate anions catalyzed the reaction by
not only stabilizing the carbenium ions, but also acceler-
nucleophiles.
Trimethylsilyl chloride has been frequently employed in
various types of organic transformations. For example, al-
cohols were chlorinated with trimethylsilyl chloride with
the aid of dimethylsulfoxide (DMSO),11 BiCl3,12 or
SeO2:13 In the DMSO-catalyzed chlorination, DMSO fa-
cilitated the formation of a critical silicon–oxonium inter-
mediate, followed by the smooth nucleophilic attack of a
chloride ion to afford a chloride product. BiCl3 was con-
sidered to activate the silicon–chloride bond of trimethyl-
silyl chloride to accelerate the chlorination. SeO2 was
converted with trimethylsilyl chloride to produce a reac-
tive chlorinating agent of SeOCl2, which efficiently chlo-
rinated the alcohol.
Key words: hydrous sodium montmorillonite, chlorination, ben-
zylic alcohols, allylic alcohols, trimethylsilyl chloride
The conversion of alcohols into chlorides is one of the
most important functional-group transformations in syn-
thetic organic chemistry. The conversion can be per-
formed using various reagents,1 such as a concentrated
hydrogen chloride aqueous solution,2 gaseous hydrogen
chloride,3 and inorganic acid chlorides, such as SOCl2,4
PCl3, PCl5, and POCl3.5
Passing dry hydrogen chloride (HCl) gas through a solu-
tion of an alcohol in an organic solvent is the simplest
chlorination method of alcohols,3 while handling a speci-
fied amount of toxic HCl gas necessary for the chlorina-
tion is often a troublesome procedure in chemical
laboratories.6 Other chlorination methods using SOCl2 or
the chlorinated phosphorus reagents also coproduce toxic
HCl, SO2, or stoichiometric amounts of residual phospho-
rus components.
Liquid trimethylsilyl chloride is an easy-to-handle substi-
tute for HCl because it is apt to be hydrolyzed upon con-
tact with water to generate in situ a specified amount of
HCl as well as TMSOH that is finally converted into inac-
tive (TMS)2O. We hypothesized that when trimethylsilyl
chloride is mixed with hydrous Na-Mont, it would be hy-
drolyzed with the trace water contained in the Na-Mont to
generate HCl which would be spontaneously trapped by
Na-Mont, because Na-Mont is known as an efficient cat-
ion exchanger. If an alcohol molecule is also present in-
side the Na-Mont, the alcohol would react with the
generated HCl to form a carbenium intermediate, which
would then be attacked by a chloride ion produced during
the hydrolysis of trimethylsilyl chloride, leading to the
formation of a chlorinated product.14
Montmorillonite is one of the abundant naturally occur-
ring clays. It is composed of stacked, negatively charged,
two-dimensional aluminosilicate layers that contain ex-
changeable cationic species, mostly sodium ions, between
the layers. When the sodium ions in the natural montmo-
rillonite are substituted with protons or multivalent metal
ions like tin(IV) ions, the clay becomes strongly acidic.
We were successful in utilizing the acidic tin(IV) mont-
morillonite (Sn-Mont) as an efficient solid-acid catalyst
for various organic transformations. For example, we
were successful in the efficient condensations of second-
ary and tertiary benzylic alcohols with some nucleophiles,
such as allyltrimethylsilane,7 malonates,8 cyanotrimethyl-
Using benzhydrol (1a) as model substrate, we then per-
formed several experiments to confirm our hypothesis.
The results are summarized in Table 1.15
As we expected, when a mixture of hydrous Na-Mont, 1a
and trimethylsilyl chloride in undried dichloromethane
was stirred at room temperature for 40 minutes, benzhy-
dryl chloride (3a) was obtained in 97% yield together with
1% of symmetrical ether 4a (Table 1, entry 6). Compound
4a was likely to be formed from the etherification of 1a
SYNLETT 2014, 25, 2639–2643
Advanced online publication: 15.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379226; Art ID: st-2014-u0641-l
© Georg Thieme Verlag Stuttgart · New York

2640
M. A. Tandiary et al.
LETTER
with a benzhydryl cation derived from 1a. In sharp con- In general, the chlorination system is applicable for vari-
trast, when the reaction was performed without Na-Mont ous secondary benzylic and allylic alcohols. Although the
under the same conditions, 3a was only obtained in 8% chlorination of 1a efficiently proceeded to afford 3a in
yield (Table 1, entry 1). In the presence of other acidic 97% yield, that of benzhydrol bearing an electron-with-
montmorillonites, such as H-Mont and Sn-Mont,16 3a was drawing group, such as a Cl atom 1b produced a 73%
similarly obtained in excellent yields (Table 1, entries 7 yield of 3b together with symmetrical ether 4b in 13%
and 8). On the other hand, when BiCl3, the catalyst used yield.17 This is reasonable as the carbenium ion derived
for the chlorination of various aliphatic and benzyl alco- from 1b is less stable than that derived from 1a due to the
hols in combination with trimethylsilyl chloride,12 was electron-withdrawing effect of a Cl atom. In this reaction,
employed in undried dichloromethane, 3a was only ob- employing four equivalents of trimethylsilyl chloride
tained in 73% yield together with 4a in 13% yield (Table slightly improved the yield of 3b to 80% yield. A benzhy-
1, entry 3). It was also confirmed that using 3.6 equiva- drol derivative bearing a fluorine atom (1c) was suffi-
lents of concentrated aqueous HCl was not efficient for ciently chlorinated to give 3c in 86% yield, and with four
the chlorination of 1a in tetrahydrofuran (Table 1, entry equivalents of trimethylsilyl chloride the yield rose to
2). After the survey on the solvent effects, dichlorometh- 98%. The chlorination of a benzhydrol derivative with an
ane was found to be the solvent of choice (Table 1, entries electron-donating methoxy group 1d gave 3d in a quanti-
6 and 9–12).
tative yield. 1-Phenylethanol (1e) was also chlorinated to
afford 3e in 60% yield. Other 1-arylethanols bearing elec-
tron-donating groups on the benzene ring, such as a meth-
yl (1f) or methoxy (1g), were chlorinated to form products
in higher yields. The chlorination of secondary alcohols
We also investigated the scope and limitations of the chlo-
rination using the trimethylsilyl chloride and Na-Mont
system as shown in Scheme 1.
Table 1 Optimization of Reaction Conditions
Cl
OH
catalyst
O
Me3SiCl
+
+
solvent
r.t.
2
3a
1a
2
4a
1 equiv
2 equiv
Entry
Catalyst
Solvent
Reaction time (min)
Yield of 3a (%)a
Yield of 4a (%)a
1
2b
3c
4d
5e
6
–
CH2Cl2
THF
40
40
40
40
40
40
40
40
40
40
40
40
10
20
8
37
73
18
37
97
99
98
93
53
21
78
49
80
0
2
HCl
BiCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
hexane
acetone
Et2O
13
11
12
1
hydrous Na2SO4
Na-Y
Na-Mont
H-Mont
Sn-Mont
Na-Mont
Na-Mont
Na-Mont
Na-Mont
Na-Mont
Na-Mont
7
0
8
1
9
3
10
11
12
13
14
22
32
7
MeCN
CH2Cl2
CH2Cl2
24
8
a 1H NMR yield based on mesitylene as the internal standard. Reaction conditions: 1a (1 mmol), TMSCl (2 mmol), catalyst (30 mg), solvent (5
mL).
b A mixture of 1a in THF (5 mL) and 37% (v/v) HCl (0.3 mL; approximately 3.6 equiv of HCl) was vigorously stirred without TMSCl at r.t.
for 40 min.
c BiCl3 (10 mol%) was employed as the catalyst.
d See Supporting Information for details on the preparation of hydrous Na2SO4.
e Na-Y (30 mg) was employed as the catalyst.
Synlett 2014, 25, 2639–2643
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chlorination of Benzylic and Allylic Alcohols
2641
1h and 1i efficiently proceeded to give 3h and 3i in quan- cessful, the chlorination of activated benzyl alcohols bear-
titative yields, respectively.
ing polymethyl substituents, such as 1n and 1o, efficiently
proceeded to afford the corresponding chlorides in 94%
and quantitative yields, respectively. This is because the
corresponding carbenium intermediates are more stabi-
lized to form by the electron-donating methyl groups.
The chlorination was also applicable for secondary allylic
alcohols 1j and 1k to yield the corresponding products 3j
and 3k in 93% and 96% yields, respectively. For the chlo-
rination of 1j, 3-chloro-1-phenyl-1-butene was only ob-
tained without its chlorinated regioisomer, 1-chloro-1- An aliphatic tertiary alcohol 1q was not successfully chlo-
phenyl-2-butene, because maintaining a conjugated rinated, but only gave dehydrated alkenes. On the other
phenylvinyl structure in the molecule is thermodynami- hand, trityl alcohol 1r was chlorinated to give trityl chlo-
cally more preferable. An attempt to chlorinate 1l only in- ride in 90% isolated yield because 1r has no β-hydrogen.
duced polymerization. Saturated aliphatic alcohol 1p did
not undergo the chlorination because secondary unstabi-
lized carbocations are hard to produce.
While we optimized the conditions for the Na-Mont-cata-
lyzed chlorination of 1a with trimethylsilyl chloride, we
observed that just after a ten minute reaction, chlorinated
Concerning the chlorination of primary alcohols, although product 3a as well as symmetrical ether 4a were formed
the chlorination of simple benzyl alcohol 1m was not suc- in 49% and 24% yields, respectively (Table 1, entry 13),
OH
Cl
Na-Mont
R
R
+
Me3SiCl
2 equiv
CH2Cl2
1
3
1 equiv
r.t., 40 min
OH
OH
OH
OH
F
F
Cl
Cl
MeO
OMe
1c
1a
1b
1d
quanta
97%a
73%a (80%a,b
)
86%a (98%a,b
)
OH
OH
OH
OH
OH
MeO
1e
60%a
1f
84%a
1g
1h
1i
quanta
quanta
OH
87%a
OH
OH
OH
1m
no reaction
1j
94%a
1l
1k
96%a
polymerization
OH
OH
OH
OH
1n
94%a
1p
no reaction
1q
no productc
1o
quanta
OSiMe3
O
2
Ph
OH
Ph
Ph
1r
90%d
5a
98%a (13%a,e
4a
99%a (7%a,e
)
)
Scheme 1 Scope of substrates. a 1H NMR yield based on mesitylene as the internal standard. Reagents and conditions: 1a (1 mmol), TMSCl
b
c
(2 mmol), substrate (30 mg), solvent (5 mL) of solvent; 4 equiv of TMSCl were employed; dehydration products were formed instead;
d isolated yield; the chlorination was performed at 0 °C; e Na-Mont was activated at 135 °C and 6.58·10–4 bar for 1 h prior to use, CH2Cl2 was
distilled from CaH2 and immediately used.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2639–2643

2642
M. A. Tandiary et al.
LETTER
and that 4a was gradually converted into 3a over time (Ta- We demonstrated the synthetic applicability of this proto-
ble 1, entries 6, 13 and 14), suggesting that 4a is an inter- col for the gram-scale chlorination of 1a and 1n as shown
mediate in this reaction. To gain a better insight into the in Scheme 3. In both examples, chlorination products
reaction mechanism, we used 4a as a reactant for the chlo- were obtained in almost quantitative yields in very high
rination under anhydrous conditions using activated Na- purity based on an NMR analysis.
Mont and dried dichloromethane and were surprised to
find that 3a was formed in only 7% yield (the chlorination
Cl
OH
of 4a in Scheme 1). On the other hand, when the reaction
was performed under the standard hydrous conditions, 3a
Na-Mont
Me3SiCl
+
CH2Cl2
was obtained in almost quantitative yield. Similar results
were also observed in the chlorination of 5a (a trimethyl-
silyl ether of 1a, Scheme 1). Under the anhydrous condi-
tions, the yield of 3a was only 13%, while under the
standard conditions, 3a was obtained in almost quantita-
tive yield. These results indicate that a trace amount of
water included in the reaction system is crucial to perform
the efficient chlorination of alcohols with trimethylsilyl
chloride.
1a
1.84 g
r.t., 40 min
3a
1.91 g (94% isolated yield)
OH
Na-Mont
Cl
+
Me3SiCl
CH2Cl2
r.t., 40 min
1n
1.50 g
3n
1.61 g (95% isolated yield)
We also confirmed the stabilization effects of Na-Mont on
carbenium ions as follows. We tested the chlorination of
1a with trimethylsilyl chloride using hydrous Na2SO4 and
hydrous sodium exchanged zeolite NaY instead of Na-
Mont, which resulted in the low efficiencies of 18% and
37% yields, respectively. The bulky aluminosilicate an-
ions of Na-Mont are much less nucleophilic, so they can
stabilize and hold the unstable carbenium ions in much
higher concentrations in their interlamellar space than the
sulfate ions in Na2SO4. Zeolite NaY is also made of an
aluminosilicate framework, but its small cavity size is not
adequate for the effective chlorination.
Scheme 3 Gram-scale chlorination of benzylic alcohols
In conclusion, we developed a novel and practical method
for the chlorination of various tertiary, secondary, and pri-
mary benzylic and allylic alcohols using hydrous Na-
Mont as the catalyst and trimethylsilyl chloride as the hy-
drogen chloride source. Trimethylsilyl chloride is not only
a cheap and easy-to-handle liquid reagent, but a conve-
nient reagent for small-scale organic synthesis to safely
generate in situ a specified amount of hydrogen chloride,
simply by contacting it with trace water. In addition, Na-
Mont is an abundant natural clay and commercially avail-
We proposed a plausible mechanism for the chlorination able. Not having to pay special attention to anhydrous
as shown in Scheme 2: The reaction was initiated by the conditions for Na-Mont, and the reaction solvent is anoth-
hydrolysis of trimethylsilyl chloride with a small amount er great advantage over conventional chlorination proto-
of water included in the reaction system to produce a spec- cols.
ified amount of hydrogen chloride. An alcohol undergoes
protonation by the HCl and subsequent dehydration to
Supporting Information for this article is available online
generate a carbenium ion that is stabilized between the an-
at
http://www.thieme-connect.com/products/ejournals/journal/
ionic aluminosilicate layers of Na-Mont. The carbenium
ion then smoothly reacts with the liberated chloride ion to
yield the chlorinated product. The released water also re-
acts with the remaining trimethylsilyl chloride to generate
HCl, and two molecules of the generated TMSOH are eas-
ily condensed into more stable (TMS)2O and water. This
assertion was supported by the facts that the chlorination
of 4a or 5a with trimethylsilyl chloride yielded 3a in very
low yields under anhydrous conditions, but in almost
quantitative yields under the standard hydrous conditions.
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
References and Notes
(1) For a list of chlorinating agents, see: Larock, R. C.
Comprehensive Organic Transformations; Wiley-VCH:
New York, 1999, 2nd ed., 689–697.
(2) Tertiary chlorides are easily prepared from tertiary alcohols
using a concentrated HCl solution, while primary and
secondary alcohols are slow to react with concentrated HCl.
Thus an adequate catalyst is required.
(3) The synthesis of chlorides from alcohols using gaseous
hydrogen chloride: (a) Rule, H. G.; Bain, J. J. Chem. Soc.
1930, 1894. (b) Denegri, B.; Streiter, A.; Juric, S.; Ofial, A.
R.; Kronja, O.; Mayr, H. Chem. Eur. J. 2006, 12, 1648.
(4) For a review of SOCl2, see: Pizey, J. S. Synthetic Reagents;
Vol. 1; Wiley: New York, 1974, 321–357.
(5) For a review, see: Salomaa, P.; Kankaanpera, A.; Pihlaja, K.
In The Chemistry of the Hydroxyl Group; Patei, S., Ed.;
Wiley: New York, 1971, Part 1, 595–622.
(Me3Si)2O
Me3SiCl
Me3SiOH
Na-Mont
H2O
HCl
(6) Hydrogen chloride gas is not only commercially available,
but can also be prepared in laboratories. For the laboratory-
scale preparation of hydrogen chloride gas, see: (a) Maurya,
RCl
ROH
Scheme 2 Plausible mechanism
Synlett 2014, 25, 2639–2643
© Georg Thieme Verlag Stuttgart · New York

LETTER
M. R. J. Chem. Educ. 1990, 67, 974. (b) Arnaiz, F. J.
J. Chem. Educ. 1995, 72, 1139.
(7) Wang, J.; Masui, Y.; Onaka, M. Tetrahedron Lett. 2010, 51,
3300.
Chlorination of Benzylic and Allylic Alcohols
2643
mixture was stirred at r.t. for 40 min. The solid material was
filtered off, and the filtrate was concentrated. Compound 3a
was isolated by Kugelrohr distillation under vacuum in 90%
yield as a colorless liquid.
(8) Wang, J.; Masui, Y.; Onaka, M. Synlett 2010, 2493.
(9) Wang, J.; Masui, Y.; Onaka, M. ACS Catal. 2011, 1, 446.
(10) Tandiary, M. A.; Masui, Y.; Onaka, M. Tetrahedron Lett.
2014, 55, 4160.
NMR Data of 3a
1H NMR (500 MHz, CDCl3): δ = 7.42–7.18 (m, 10 H), 6.08
(s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 141.1, 128.6,
128.1, 127.8, 64.3.
(11) Synder, D. C. J. Org. Chem. 1995, 60, 2638.
(12) (a) Le Roux, C.; Gaspard-Iloughmane, H.; Dubac, J. J. Org.
Chem. 1994, 59, 2238. (b) Labrouillere, M.; Le Roux, C.;
Gaspard-Iloughmane, H.; Dubac, J. Synlett 1994, 723.
(13) Lee, J. G.; Kang, K. K. J. Org. Chem. 1988, 53, 3634.
(14) Hydrous Na-Mont was obtained from Kunimine Industries,
Japan, and contains 14 wt% H2O.
(16) H-Mont and Sn-Mont were prepared from Na-Mont by an
ion exchange and contain 8 wt% and 18 wt% water,
respectively. See Supporting Information.
(17) Although a mixture of 3b and 4b was obtained after the
reaction, 3b can be easily separated from the mixture by
distillation due to the significant difference in boiling points
of these two compounds.
(15) A Representative Procedure for the Chlorination of 1a
with TMSCl in the Presence of Na-Mont
NMR Data of 3b
1H NMR (500 MHz, CDCl3): δ = 7.29 (s, 8 H), 6.03 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 139.2, 134.3, 129.2, 128.9,
62.7.
In a flask was placed Na-Mont (30 mg), 1a (1 mmol, 0.18 g),
TMSCl (2 mmol, 0.22 g, 0.25 mL), and CH2Cl2 (5 mL). The
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2639–2643

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