NMP-mediated chlorination of aliphatic alcohols with aryl sulfonyl chloride for the synthesis of alkyl chlorides

Article abstract of DOI:10.1080/00397911.2018.1482498

NMP-mediated chlorination of aliphatic alcohols has been developed for the synthesis of alkyl chlorides. This facile, efficient and practical approach used simple and readily available aryl sulfonyl chlorides as the chlorination reagent for the construction of C–Cl bond in good to excellent yields with mild conditions and broad substrate scope.

Full text of DOI:10.1080/00397911.2018.1482498

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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NMP-mediated chlorination of aliphatic alcohols
with aryl sulfonyl chloride for the synthesis of
alkyl chlorides
Dagui Zheng, Liu-Liang Mao, Xian-Hong Zhu & An-Xi Zhou
To cite this article: Dagui Zheng, Liu-Liang Mao, Xian-Hong Zhu & An-Xi Zhou (2018): NMP-
mediated chlorination of aliphatic alcohols with aryl sulfonyl chloride for the synthesis of alkyl
chlorides, Synthetic Communications, DOI: 10.1080/00397911.2018.1482498
To link to this article: https://doi.org/10.1080/00397911.2018.1482498
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https://doi.org/10.1080/00397911.2018.1482498
NMP-mediated chlorination of aliphatic alcohols with aryl
sulfonyl chloride for the synthesis of alkyl chlorides
Dagui Zheng, Liu-Liang Mao, Xian-Hong Zhu, and An-Xi Zhou
Key Laboratory of Applied Organic Chemistry, Higher Institutions of Jiangxi Province, Shangrao Normal
University, Shangrao, PR China
ABSTRACT
ARTICLE HISTORY
NMP-mediated chlorination of aliphatic alcohols has been developed
for the synthesis of alkyl chlorides. This facile, efficient and practical
approach used simple and readily available aryl sulfonyl chlorides as
the chlorination reagent for the construction of C–Cl bond in good
to excellent yields with mild conditions and broad substrate scope.
Received 19 March 2018
KEYWORDS
Alkyl chlorides; aliphatic
alcohols; aryl sulfonyl
chloride; chlorination; NMP
GRAPHICAL ABSTRACT
Introduction
The importance of alkyl chlorides, both in the field of natural products and medical
chemistry, have received extensive attention of investigators owing to their potential bio-
[
1]
logical activities (Fig. 1A). In addition, alkyl chlorides are important synthons in
organic synthesis and have been employed extensively in various synthetic transforma-
[
2]
tions. As a result of this widespread utility, a number of methodologies have been
[
3]
[4]
developed to synthesize alkyl chlorides, Hunsdiecker-type reaction, nucleophilic sub-
[
5]
[6]
stitution reaction, radical coupling reaction of organometallic reagent, reductive
chlorination of carbonyl compound and transition metal-catalyzed C(sp )-H chlorin-
ation reaction are examples of some most commonly used methodologies. Among
which, the most appropriate method is the nucleophilic substitution reaction in trans-
formation of aliphatic alcohols into alkyl chlorides. However, the conversion of alcohols
into the corresponding alkyl chlorides often suffers from a serious limitations due to the
[
7]
3
[
8]
[
9]
use of chlorination reagent, such as HCl, SOCl , CCl , PCl and PCl , which prone to
2
4
3
5
hydrolysis, oxidation and toxic, and even to produce the by-product harmful for the
CONTACT Dagui Zheng
daguizheng@163.com
Key Laboratory of Applied Organic Chemistry, Higher Institutions
of Jiangxi Province, Shangrao Normal University, Shangrao 334001, PR China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
D. ZHENG ET AL.
Figure 1. Selected chloride-containing natural products and pharmaceuticals (A); different chlorination
reagent for the formation of alkyl chlorides from aliphatic alcohols (B); presented method (C).
environment. To overcome these limitations, the stable and elaborate chlorination
[
10]
reagents
such as TCCA, TCT, TCBDA, 3,3-dichloro-1,2-diphenylcyclopropene,
N-phenylbenzimidoyl chloride, (chloro-phenylthiomethylene) dimethylammonium chlor-
0
0
ide, N,N,N ,N -tetrachlorobenzene-1,3-disulfonamide and chloride-based ionic liquids,
have been developed for the synthesis of alkyl chlorides. However, these chlorination
reagents have to be prepared through some complex procedures. These drawbacks still
limits the universality of the nucleophilic chlorination of OH groups. Therefore, the
development of a simple and efficient chlorination reagent for the synthesis of alkyl
chlorides from readily available aliphatic alcohols is still highly desirable.
[
11]
As part of our ongoing work in the field of C–Cl bond formation
opment more useful chlorination reagent,
and for the devel-
[12]
we try to use inherently safer reagent as
chlorination reagent to construct C–Cl bond from the C–OH bond of alcohols. Owing to
the lower volatility and lower reactivity towards water, aryl sulfonyl chloride is less toxic
and hazardous than classical chlorination agents, such as CCl , SOCl , PCl and COCl .
4
2
3
2
To date, only limited methods on the chlorination of allyllic alcohol were reported with
[13]
[14]
toluenesulfonyl chloride
and methanesulfonyl chloride as chlorination reagents.
We herein present a novel and highly efficient method for the NMP-mediated chlor-
ination of aliphatic alcohols employing cheap, safe and readily available aryl sulfonyl
chlorides as the exclusive reagent as shown in Figure 1C.
Results and discussion
We started our investigation by choosing benzylic alcohol (1a) and benzenesulfonyl
chloride (2a) as model substrates. Initially, the reaction of 1a (1.0 equiv.) with 2a

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a
Table 1. Optimization of the reaction conditions.
ꢀ
b
Entry
Promoter
NMP
–
DMF
DMAc
DEF
DMPr
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Chloride source
Temp. ( C)
Yield (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
80
80
80
80
80
80
60
100
80
80
80
80
80
80
80
97
0
90
80
88
20
59
95
62
75
90
68
51
54
90
c
9
d
1
1
1
1
1
1
0
1
2
3
4
5
e
f
a
ꢀ
Reaction conditions: 1a (10 mmol), 2a (13 mmol), promoter (2.5 equiv.), DCE (3.0 mL) at 80 C under air for 1.5 h.
Isolated yield.
b
c
NMP (1.0 equiv.).
d
e
NMP (1.5 equiv.).
NMP (2.0 equiv.).
Without DCE.
f
ꢀ
1.3 equiv.) was performed in DCE (3.0 mL) at 80 C for 1.5 h under air in the presence
(
of NMP (2.5 equiv.) as promoter. Fortunately, the desired product (chloromethyl)ben-
zene (3a) was obtained in yield of 97% (Table 1, entry 1). Then, control experiment was
examined, and the reaction was totally shut down in the absence of NMP (Table 1, entry
2). Subsequently, various accelerating agents were screened (Table 1, entries 3–6), and
the results showed that the yield of the desired product were more or less suppressed.
ꢀ
Then, the influence of temperature were screened (Table 1, entries 7–8), and 80 C was
found to be the ideal reaction temperature. In order to enhance the reaction efficiency,
then the loading of the promoter were examined (Table 1, entries 9–11), and the results
indicated that the yield of the 3a was decreased with the reducing of the loading of
the promoter.
Next, we expected that changing the electronic properties of substituents on the aryl
ring would have a significant impact on the efficiency of the reaction. Therefore, we
screened a range of aryl sulfonyl chloride bearing electron-withdrawing substituent (m-
NO ) or electron-donating substituents (p-Me, p-Br), and found that the reaction was
2
depressed in the absence of either the electron-withdrawing substituent or the electron-
donating substituents on the aryl ring of the aryl sulfonyl chloride (Table 1, entries
12–14). Interestingly, we found that the chlorinations proceed efficiently to afford the
desired products in 90% yield even in the absence of any solvent (Table 1, entry 15).
Thus, the optimization of the reaction condition was acquired with benzylic alcohol (1a)

4
D. ZHENG ET AL.
a
Table 2. Chlorination of various alcohols.
a
ꢀ
Reaction conditions: 1 (10 mmol), 2a (1.3 equiv.), promoter (2.5 equiv.), DCE (3.0 mL) at 80 C under air for 1.5 h.
Isolated yield.
b
(
8
1.0 equiv.), benzenesulfonyl chloride (2a) (1.3 equiv.) and NMP (2.5 equiv.) in DCE at
0 C under air (Table 1, entry 1).
ꢀ
With the optimal reaction conditions in hand, we proceeded to investigate the scope
of aliphatic alcohols. As shown in Table 2, various benzylic alcohol bearing electron-
withdrawing substituents (X¼Cl, Br, NO ) or electron-donating substituents (X¼H,
2
i
Pr, OMe) at the para-position of the aryl ring all worked smoothly and produced the
desired product in excellent yields (92–97%, 3a–3f). Then, substituents such as bromo-
(1g), methyl-(1h) and methoxy-(1i) on the more sterically encumbered position (ortho-
position of the aryl ring) produced the expected product in excellent yields (3g–3i).
Additionally, substrates containing bromine at the meta-position of the aryl ring (1j)

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Scheme 1. Application studies.
Scheme 2. Proposed mechanism.
and one naphthalene moiety (1k), even substrates such as aliphatic alcohols with long-
chain (1l–1m), all reacted smoothly and afforded the corresponding product in excellent
yields (3j–3m). Then, substrates bearing heteroatom and double bond could all generate
the corresponding alkyl chloride in good yields (3n–3o). What’s more, substrates includ-
ing diol and secondary alcohol could also well compatible with this reaction system, and
to afforded the corresponding product (3p–3u). Moreover, to enrich the scope of sub-
strates, a tertiary alcohol was investigated in this reaction system. Although the corre-
sponding alkyl chloride was not obtained, the simple alkene was obtained (3v), which
may be due to the rate of elimination of tertiary alcohol is much faster than its chlorin-
[
15]
ation.
Finally, a range of heterocyclic substrates, such as 2,5-dimethylolfuran, furfuryl
alcohol and 2-thiophene methanol were screened under the optimized conditions,

6
D. ZHENG ET AL.
unfortunately, none of them could produce desired product. To our delight, 3-pyridine-
methanol yield corresponding product (3w) in 41% yield.
It is noteworthy that the NMP-mediated chlorination of aliphatic alcohols with aryl
sulfonyl chloridefor the synthesis of alkyl chlorides could be effectively scaled up, which
will meet the demands of the industry. For example, 1a (500 mmol), 2a (600 mmol) and
ꢀ
NMP (2.5 equiv.) in the presence or absence of DCE at 80 C for 12 h, the correspond-
ing product 3a was obtained with 93% and 81% yields, respectively (Scheme 1).
[
11,16]
Based on the above experimental results and previous studies,
a plausible reac-
tion mechanism was proposed in Scheme 2. Initially, a resonance balance between NMP
and active species A exists, and then the interaction of benzenesulfonyl chloride 2a with
active species A to afford Vilsmeier–Haack type complex B. Next, aliphatic alcohol 1
was added, and the hydroxyl group of the alcohol interacts with B to produce the inter-
mediate C and 4a. Finally, C reacted with chloride ion in S 2 fashion to produce the
N
corresponding alkyl chloride 3, and regenerate the NMP, which could be interacts with
4a to regulate the pH of the reaction system.
Conclusions
In conclusion, we have developed a highly efficient and practical NMP-mediated nucleo-
philic substitution reaction for the transformation of aliphatic alcohols into alkyl chlor-
ides. In the reaction, simple, readily available and inherently safe aryl sulfonyl chloride
emerged as efficient chlorination reagent, and the reaction takes advantage of mild reac-
tion conditions, broad substrate scope and high functional group tolerance, even
expected to find broad application in both academia and industry.
Experimental
General procedures for the synthesis of alkyl chlorides
In a round-bottom flask, benzylic alcohol 1a (10 mmol, 2.0 equiv.), benzenesulfonyl
chloride 2a (13 mmol, 1.3 equiv.) and NMP (2.5 equiv.). Then, DCE (3 mL) were added.
ꢀ
The mixture was stirred at 80 C for 1.5 h. After completion of the reaction (monitored
by TLC), water (10 mL) was added and the mixture was extracted with ethyl acetate
(
3 ꢁ 10 mL). The combined organic phase was dried over anhydrous Na SO , filtered,
2
4
and evaporated under reduced pressure. The crude product was purified by flash chro-
matography on silica gel to give the desired alkyl chlorides 3a.
1
About 97% yield, colorless oil; H NMR (400 MHz, CDCl ) d: 7.34–7.29 (m, 5H), 4.53
3
1
3
(
(
s, 2H). C NMR (100 MHz, CDCl ) d: 137.60, 128.83, 128.69, 128.49, 46.37. GC–MS
%): 126.0 (M , 52.58), 91.2 (100).
3
þ
Funding
The research work was supported by the financial support from the Science and Technology
Research Projects of the Jiangxi Provincial Education Department [Nos. GJJ161059, GJJ151062
and GJJ14716].

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ORCID
An-Xi Zhou
http://orcid.org/0000-0002-2143-0988
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