Direct halogenation of alcohols with halosilanes under catalyst- and organic solvent-free reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2016.04.083

A chemoselective method for the direct halogenation of different types of alcohols with halosilanes under catalyst- and solvent-free reaction conditions (SFRC) is reported. Various primary, secondary and tertiary benzyl alcohols and tertiary alkyl alcohols were directly transformed to the corresponding benzyl and alkyl halides, respectively, using chlorotrimethylsilane (TMSCl) and bromotrimethylsilane (TMSBr).

Full text of DOI:10.1016/j.tetlet.2016.04.083

Accepted Manuscript
Direct halogenation of alcohols with halosilanes under catalyst- and organic
solvent-free reaction conditions
Njomza Ajvazi, Stojan Stavber
PII:
S0040-4039(16)30457-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.083
TETL 47583
Reference:
Tetrahedron Letters
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Accepted Date:
16 March 2016
8 April 2016
20 April 2016
Please cite this article as: Ajvazi, N., Stavber, S., Direct halogenation of alcohols with halosilanes under catalyst-
and organic solvent-free reaction conditions, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.04.083
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Direct halogenation of alcohols with
halosilanes under catalyst- and organic
solvent-free reaction conditions
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Njomza Ajvazi and Stojan Stavber

1
Tetrahedron Letters
Direct halogenation of alcohols with halosilanes under catalyst- and organic solvent-
free reaction conditions
Njomza Ajvazia and Stojan Stavbera,b 
a Jožef Stefan International Postgraduate School, Jamova 39, 1000 Ljubljana, Slovenia
b Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A chemoselective method for the direct halogenation of different types of alcohols with
halosilanes under catalyst- and solvent-free reaction conditions (SFRC) is reported. Various
primary, secondary and tertiary benzyl alcohols and tertiary alkyl alcohols were directly
transformed to the corresponding benzyl and alkyl halides, respectively, using
chlorotrimethylsilane (TMSCl) and bromotrimethylsilane (TMSBr).
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Halogenation
Alcohols
Halosilanes
Catalyst-free
Solvent-free
———
 Corresponding author. Tel.: +386-1-4773-660; fax: +386-1-423-54-00; e-mail: stojan.stavber@ijs.si

2
Tetrahedron
1. Introduction
Bromotrimethylsilane (TMSBr) has been employed for
alcohol bromination under SFRC in the presence of BiBr3 as a
catalyst.16 The catalyst-free transformation of alcohols into
bromides was also achieved using a high molar excess of TMSBr
in CHCl3.24
The development of protocols for the transformation of
organic compounds using environmentally friendly methods
while still achieving high atom economy, selectivity and
efficiency is currently one of the main trends in organic
synthesis. Therefore, planning organic reactions and processes in
accordance with the principles of green chemistry is a major
challenge in organic chemistry.1 Because increasing numbers of
organic solvents are restricted due to their damaging effects on
human health and the environment, performing organic reactions
under solvent-free reaction conditions (SFRC)2 is highly
desirable. As a result, catalyst- and solvent-free synthetic
protocols have attracted significant interest and have become
increasingly important in organic chemistry research and
development because of their simplicity and cost efficiency.
The aforementioned methods suffer some disadvantages, such
as the need for a catalyst; the use of environmentally undesirable
solvents, such as CCl4, CHCl3 and CH2Cl2; the requirement of a
high number of equivalents of TMSCl or TMSBr; and low atom
economy and selectivity. Thus, the development of an efficient
and environmentally benign methodology for C-X bond
construction using halotrimethylsilanes as a halogen source
remains an attractive research subject. On the basis of our
research group’s continuing interest in developing greener
methods for the efficient and selective halo-functionalization of
organic compounds,25-32 we report, to the best of our knowledge,
the first example of the direct halogenation of alcohols using
chloro- and bromotrimethylsilane under catalyst- and SFRC.
The hydroxyl functional group is one of the most abundant
functional groups in organic compounds, thus, hydroxyl
transformations under green reaction conditions represent a
considerable challenge and have attracted the interest of organic
chemists. Because of their lower leaving group ability, hydroxyl
moieties are rarely substituted under mild conditions and must
often be activated before treatment with nucleophiles.3
2. Result and discussion
Initially, we chose phenyl(p-tolyl)methanol 1a as the model
compound to investigate the reactions of alcohols in the presence
of 10% excess TMSCl under catalyst- and SFRC. After 30 min
stirring at room temperature, we observed that the reaction
resulted in the formation of 1-(chloro(phenyl)methyl)-4-
methylbenzene 2a in 97% yield (entry 1, Table 1). We further
evaluated the reaction of diphenylmethanol 1b, a less reactive
analogue, under the same reaction conditions and observed the
formation of the corresponding chloride 2b in 96% yield (entry
3), however, a longer reaction time was necessary. Both reactions
performed in CH2Cl2 gave negative results (entries 2 and 4),
revealing that SFRC were critical for a successful reaction.
The halogenation of alcohols via nucleophilic substitution is
an important transformation in organic chemistry that has
attracted significant interest in recent years.4 Halogenated organic
compounds play significant roles in chemistry and are used as
starting compounds and synthetic intermediates for various
coupling reactions in organic, pharmaceutical and agrochemical
syntheses.5
The most frequently used reagent for the selective
transformation of alcohols into alkyl chlorides is thionyl
chloride.6 Another classical approach is the use of gaseous or
aqueous HCl, however, these approaches are limited by many
factors (e.g. poor selectivity, low yields, and harsh reaction
conditions) making them frequently unsuitable in modern organic
synthesis.7 Other chlorination and bromination methods have also
been reported including aromatic tropylium cation activation,8
2,4,6-trichloro-1,3,5-triazine catalysed by dimethyl sulfoxide,9
improved classical Appel halogenation reactions10 and other
similar modern approaches.11-14
Encouraged by these results, we further extended the scope of
the transformation to additional classes of secondary benzyl
alcohols including derivatives of 1-phenylethanol carrying
electron-donating or electron-withdrawing substituents on the
aromatic ring 1c-f. These alcohols were quantitatively converted
under SFRC, however, the high-yielding formation of the
corresponding chlorides 2c-f was accompanied by 10-17% of the
dimeric ether (R-O-R) side products (entries 5-8). In contrast, the
analogous benzo-cycloalkan-1-ols 1g and 1h were quantitatively
and selectively converted into the corresponding chlorides 2g and
2h (entries 9 and 10). In the case of primary benzyl alcohols, a
quantitative and chemoselective reaction was observed for 4-
methoxybenzyl alcohol 1j (entry 11) while the 4-methyl-
substituted derivative 1k underwent quantitative conversion but
exhibited only moderate selectivity (2k, entry 13). Benzyl
alcohol 1i and its p-Cl analogue 1l were transformed under the
described reaction conditions to chlorides 2i and 2l in 65% and
63% yield, respectively, but were accompanied by the formation
of symmetric ethers in 10% and 16% yield respectively (entries
11 and 14).
Numerous accounts of transformations of alcohols into halides
using halosilanes have been reported in the literature. The
methods for chlorination using chlorotrimethylsilane (TMSCl)
demand the use of various catalysts or co-reagents such as
20
K2CO3,15 BiCl3,16 DMSO,17 SeO2,18 TeO2,19 or K2CrO4 to
convert TMSCl in situ into the corresponding terminal
chlorinating agent (SeOCl2, TeOCl2 or CrO2Cl2). The authors of
these previous reports claimed that, in the absence of a catalyst,
TMSCl does not produce alkyl chlorides, even after prolonged
heating with alcohols. Indeed, the conversion of tertiary alcohols
into their corresponding chlorides using these methods was
negatively affected by competing elimination.
Table 1. Chlorination of benzyl and tertiary alkyl alcohols
with TMSCla
Furthermore, the use of HSiMe2Cl requires
substoichiometric amount of InCl3 in the presence of an
equimolar amount of benzil21 or gallium trichloride/tartrate.22
a
A
more recently developed method for alcohol chlorination with
silanes utilizes TMSCl and natural sodium montmorillonite as the
catalyst in CH2Cl2.23 In the absence of catalyst, the efficiency of
the transformation was reported to be very low (8%) and the
scope of this reaction was limited to secondary benzyl alcohols
and strongly activated primary benzyl alcohols.
Side
Yield
Entry
Chlorides 2
product
(%)b
(%)c

3
1
2d
3
R1=Me
R1=Me
R1=H
100 (97)
/
42
/
2a
2a
2b
2b
Table 2. Bromination of benzyl and tertiary alkyl alcohols
with TMSBra
18
100 (96)
/
4e
R1=H
/
5
6
7
8
83 (79)
90 (86)
89 (85)
86 (82)
17
10
11
14
2c
2d
2e
2f
R2=H
R2=Me
R2=F
R2=Cl
Yield
Entry
1
Bromides 3
(%)b
9
10
n=1
n=2
100 (99)
100 (98)
/
/
2g
2h
100 (98)
3a
3b
11
12
13
14
15
16
R3=H
69 (65)
100 (98)
78 (74)
68 (63)
/
10
/
22
16
/
2i
2j
2k
2l
2m
2n
R3=p-OMe
R3=p-Me
R3=p-Cl
100 (98)
2
R3=m-NO2
R3=m-CF3
3
4
R1=H
100 (99)
100 (98)
92
13
100 (98)
100 (99)
3c
3d
3d
3d
3e
3f
/
/
R1=p-Me
R1=p-Me
R1=p-Me
R1=p-F
5c
6d
7
69 (65)
26
/
2o
2p
17
18
8
R1=m-NO2
100 (98)
100 (99)
3g
9
10
100 (99)
3h
19
100 (99)
/
2q
11
12
100 (98)
/
3i
3j
100 (98)
/
/
/
2r
2s
20
21
13
/
3k
22
/
/
2t
14
100 (99)
3l
aReaction conditions: Alcohol 1 (0.5 mmol), TMSBr (0.55 mmol),
rt, 1.30-24 h. Detailed reaction conditions are given in the ESI.
23
95 (90)
/
2u
bDetermined from the 1H NMR spectra of the crude reaction
mixture. Yield calculated relative to alcohol; values in parentheses
refer to purified products.
aReaction conditions: Alcohol 1 (0.5 mmol), TMSCl (0.55 mmol), rt or
(70-75 °C), 0.5-24 h. Detailed reaction conditions are given in the ESI.
bDetermined from the 1H NMR spectra of the crude reaction mixture.
Yield calculated relative to alcohol; values in parentheses refer to
purified products.
cCH2Cl2 (2 mL).
d2-MeTHF (2 mL).
cSide product: R-O-R.
dCH2Cl2 (2 mL).
To expand the utility of the halosilane-mediated
transformation of alcohols, we studied the reaction of TMSBr
with benzyl and tertiary alkyl alcohols under catalyst- and SFRC
(Table 2). In all cases, quantitative and chemoselective
transformations were observed. TMSBr efficiently and
selectively converted secondary benzyl alcohols 1a and 1b into
the corresponding bromides 3a and 3b (entries 1 and 2). Efficient
and chemoselective transformations were observed, unlike the
TMSCl-mediated transformations, in the reactions with primary
benzyl alcohols bearing electron-withdrawing or electron–
donating substituents 3c-f (entries 3-8). The corresponding
reactions performed in CH2Cl2 gave good results (entry 5),
whereas those performed in the greener solvent, 2-
methyltetrahydrofuran, were unsuccessful (entry 6). Therefore, in
the case of TMSBr, the SFRC protocol was observed to be the
best choice. Moreover, tertiary benzyl and alkyl alcohols 1g-i
were selectively converted under SFRC to afford the
corresponding bromides 3g-i (entries 9-11). In contrast,
secondary and primary alkyl alcohols 1j and 1k could not be
transformed into the corresponding bromides under the examined
reaction conditions (entries 12 and 13).
eTMSCl (1 mmol), CH2Cl2 (2.5 mL), 40 min.
Conversely, primary benzyl alcohols bearing strongly
deactivated aromatic rings 1m and 1n were not transformed into
the corresponding chlorides using TMSCl under catalyst- and
SFRC (entries 15 and 16). Electron-donating substituents on the
phenyl ring considerably enhanced the reaction efficiency,
whereas nitro and trifluoromethyl groups, which are strongly
electron withdrawing, suppressed the transformation.
Naphthalen-2-ylmethanol 1o was transformed into the
corresponding chloride 2o in good yield (entry 17). Similar to
secondary and primary benzyl alcohols, effective transformations
were observed in the reactions of tertiary benzyl and alkyl
alcohols. 2-Phenylpropan-2-ol 1p was selectively converted into
(2-chloropropan-2-yl)benzene 2p in 98% yield (entry 18), while
α,α-dimethylbenzenepropanol 1q and 3-ethylpentan-3-ol 1r were
converted into their corresponding chlorides 2q and 2r,
respectively (entries 19 and 20). In contrast, the secondary and
primary alkyl alcohols 1s and 1t were not transformed into their
corresponding chlorides under the examined reaction conditions
(entries 21 and 22).

4
Tetrahedron
To improve the synthetic value of the reported methodology,
We are grateful to the Slovene Human Resources
Development and Scholarship Fund (contract: 11011-9/2011),
Slovenian Research Agency (contract: Programme P1-0134) for
the financial support. National NMR Centre at the National
Institute of Chemistry, Ljubljana, Slovenia, is acknowledged for
the use of NMR instrumentation.
the following reactions were performed on the 10-mmol scale:
chlorination of 3-ethylpentan-3-ol 1r and bromination of 4-
methylbenzyl alcohol 1d. The conversion of the starting
materials into halides 2r and 3d was achieved in 95% and 99%
yields respectively. NMR analysis of the reaction mixtures
revealed that they contained only halides and (TMS)2-O in a 2:1
molar ratio. We could thus define the stoichiometry of the
process as follows:
References and notes
1.
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3.
The products were easily separated by distillation, where
(TMS)2-O was collected as the first fraction and R-X as the
second (experimental details are given in the ESI). (TMS)2-O
could be further used as the reagent or regenerated to give the
trimethylhalosilane (TMSX).33, 34
4.
Michael B. Smith, J. M. March's Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure; John Wiley & Sons, Inc.,
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The results support the assumption that the reaction course is
related to the stability of the carbocation intermediates formed
after the dehydroxylation of alcohols 1, which is characteristic of
SN1-type nucleophilic substitution processes. To verify this
assumption, we also tested 1-phenyl-1,2-ethanediol and observed
the quantitative and chemoselective formation of 2-chloro- (2u,
entry 23, Table 1) or 2-bromo-2-phenylmethanol (3l, entry 14,
Table 2) after treatment with TMSCl or TMSBr under SFRC,
confirming that this substitution likely proceeds via a SN1
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secondary alkyl alcohols were resistant to transformations under
the aforementioned reaction conditions, the SN1 reaction course
was confirmed as the most likely reaction pathway. The
formation of carbocation intermediates can be explained by at
least two mechanisms. The first explanation assumes the initial
hydrolysis of TMSX with a small amount of water present in the
reaction system to produce HCl. In this process, the alcohol
undergoes protonation by HX with subsequent dehydration to
form a carbocation that further reacts with the released chloride
ion to produce the chlorinated product. The released water also
reacts with the remaining TMSX to form HX, and two molecules
of the generated TMSOH are easily condensed into the more
stable molecules (TMS)2O and water.23 The second explanation
is related to catalysis caused by the ‘halogen bonding’
phenomenon, which is defined as ‘non-covalent interaction of the
halogen atom (X) in one molecule with a negative site in another.
This phenomenon has been theoretically evaluated,35,36 and
several organo-halogen compounds have been used as organo-
Lewis acid catalysts in organic syntheses.37,38 Therefore, in our
case, TMSX could play a dual role, acting as both a ‘halogen
bonding’ catalyst, thereby accelerating the formation of
carbocation intermediates, and as the halogen source.
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We have demonstrated a chemoselective and scalable method
for the direct conversion of benzyl, allyl and tertiary alkyl
alcohols into their corresponding chlorides or bromides via the
direct nucleophilic substitution of hydroxyl groups using
trimethylhalosilanes as halogen sources under catalyst- and
SFRC. Under these reaction conditions, we investigated the
method’s limitations by studying benzyl alcohols with strongly
deactivated aromatic rings and primary and secondary alkyl
alcohols. The development of catalyst- and SFRC protocols will
increase the green chemical profile of this type of organic
transformation.
Supplementary Material
Detailed experimental information, spectroscopic and other
characterisation data for compounds 2a-2u and 3a-3l as well as
copies of the corresponding 1H, 13C and 19Fspectra.
Acknowledgments

6
Tetrahedron
Direct halogenation of alcohols with
halosilanes under catalyst- and organic
solvent-free reaction conditions
HIGHLIGHTS
- Halogenation of alcohols were
performed under solvent-free reaction
conditions
- The value of such a green chemical
approach was verified by scale-up
experiments
- The method includes primary,
secondary, tertiary benzyl and tertiary
alkyl alcohols