Dichlorination of olefins with NCS/Ph3P

Article abstract of DOI:10.1039/c3ob27345h

A 2:1 mixture of NCS and Ph₃P successfully promoted the anti-dichlorination of olefins to provide corresponding dichlorides, serving as a molecular chlorine surrogate generated in situ.

Full text of DOI:10.1039/c3ob27345h

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Dichlorination of olefins with NCS/Ph3P†
Cite this: Org. Biomol. Chem., 2013, 11,
Yasumasa Kamada, Yuta Kitamura, Tetsuaki Tanaka and Takehiko Yoshimitsu*
1598
Received 3rd December 2012,
Accepted 14th January 2013
DOI: 10.1039/c3ob27345h
www.rsc.org/obc
A 2 : 1 mixture of NCS and Ph3P successfully promoted the anti-
dichlorination of olefins to provide corresponding dichlorides,
serving as a molecular chlorine surrogate generated in situ.
The increasing interest in bioactive organochlorines widely
distributed in the natural environment has spearheaded
efforts to devise synthetic methodologies for the formation of
carbon–chlorine bonds.1–3 Of particular interest is the class of
organochlorines bearing an sp3C–Cl (sp3carbon–chlorine)
bond as their stereoselective construction still poses a signifi-
cant challenge. Olefin dichlorination with molecular chlorine
(Cl2) is one of the most straightforward approaches for elabor-
ating such a functionality. However, molecular chlorine is
often difficult to handle due to its gaseous state as well as
potential safety problems. Fortunately, those drawbacks are cir-
cumvented by using molecular chlorine surrogates. Examples
of such surrogates include Et4NCl3 (Mioskowski reagent)4 and
BnEt3NCl–KMnO4–TMSCl (Markó–Maguire reagent),5 which
have found successful applications in the preparation of a
variety of organochlorines.6 The stereochemical outcome in
the olefin dichlorinations with those surrogates generally
agrees well with that obtained with molecular chlorine that
installs vicinal chlorine atoms to the double bond in an anti
fashion. In the present study, we demonstrated that the combi-
nation of NCS and Ph3P in a 2 : 1 stoichiometry promoted the
anti-dichlorination of olefins to furnish corresponding dichlor-
ides (2→1), allowing us to expand the versatility of this readily
available chlorination reagent (Scheme 1).
Scheme 1 Dichlorination of olefin 2 with NCS/Ph3P in 2 : 1 stoichiometry.
Scheme 2 Chlorophosphonium complexes generated from NCS/Ph3P.
transformation, the chlorophosphonium complex generated
in situ served as a Lewis acidic activator of the epoxide as well
as a chloride source (Scheme 2). It occurred to us that an
additional ‘chloronium source,’ i.e., NCS, would reasonably
activate the double bond of an olefin to form a chloronium
intermediate, and that intermediate would further undergo
ring opening with a chloride ion generated from the chloro-
phosphonium complex, forming a dichloride.
Our hypothesis was tested by applying 2 : 1 NCS/Ph3P to
various olefins (Table 1). Protected olefin 4 was treated with
2 : 1 NCS/Ph3P to afford corresponding dichloride 10 in 89%
yield (entry 1). Cyclooctene (5) was converted into dichloride
11 in high yield (93%) (entry 2).9 Dichlorination of ethyl
sorbate (6) with 2 : 1 NCS/Ph3P provided regioisomeric dichlor-
ides 12 and 13 in a 3.6 : 1 ratio, favoring the 1,2-adduct (entry
3).10 trans- and cis-Stilbenes 7 and 8 gave a diastereomeric
mixture of dichloride 14 in almost the same ratio (ca. 1 : 1)
(entries 4 and 5).11 In those cases, the anti stereospecificity
was lost probably due to the propensity of the SN1-like substi-
tution via a benzylic cation. Functionalized substrate 9 was
also dichlorinated with 2 : 1 NCS/Ph3P to furnish trans-dichlor-
ide 15 in 96% yield (entry 6).12 The stereochemistry of the
above-mentioned dichlorides 11, 12, and 15 indicated that the
reaction took place via an anti-addition mechanism.
Previous studies in this and other laboratories found that a
1 : 1 mixture of NCS/Ph3P and a combination of cat. Ph3PO/
(COCl)2 were suited for the stereospecific nucleophilic replace-
ment of the oxygen atom of an epoxide with chlorine atoms to
furnish the corresponding dichloride (3→1).7,8 In that
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan. E-mail: yoshimit@phs.osaka-u.ac.jp;
Fax: +81-6-6879-8214; Tel: +81-6-6879-8213
†Electronic supplementary information (ESI) available: Experimental protocols,
spectroscopic and analytical data, and copies of 1H and 13C NMR. See DOI:
10.1039/c3ob27345h
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Table 1 Dichlorination of olefins with NCS/Ph3P in 2 : 1 stoichiometrya
Entry
1c
Substrate
Dichlorideb (%)
2
3
Scheme 4 Chlorination of allylic alcohol derivative 21 with NCS/Ph3P in either
2 : 1 or 1 : 1 stoichiometry.
4e
5g
6
modifying the stoichiometry of the reagent suggested that in
the presence of additional NCS, the double bond was preferen-
tially activated and dichlorinated. Compounds 19 and 20
obtained by 2 : 1 NCS/Ph3P addition were likely to be produced
by anchimeric assistance of the epoxide onto the chloronium
intermediate, followed by ring opening of the resultant
oxonium intermediate13 with a chloride, although the intramo-
lecular chloroetherification of a chlorohydrin generated from
the epoxide might also be operative.
The preferential activation of a hydroxy group over a double
bond was generally observed irrespective of the reagent stoichi-
ometry (Scheme 4). Thus, a 1 : 1 mixture of NCS/Ph3P efficien-
tly promoted the Appel-type allylic chlorination to afford
chloride 22 in 94% yield. In contrast, the 2 : 1 combination
afforded trichloride 23 as the major product (57%) along with
allylic chloride 22 (24%). Trichloride 23 was likely produced
via dichlorination of allylic chloride 22 because, in another
experiment, treatment of 22 with the 2 : 1 reagent system
promptly gave 23 in 92% yield. It should be noted that trichlo-
ride 23 was predominantly produced when more reagents were
used, i.e., 6 equiv. of NCS and 3 equiv. of Ph3P. The trichlorina-
tion of the allylic alcohol represented a unique property of the
2 : 1 reagent; neither the 1 : 1 NCS/Ph3P reagent nor molecular
chlorine facilitated such a transformation.
Under the present conditions, TBS-protected olefin 24 was
cleanly transformed into anti-dichloride 26 in 77% yield
(Table 2, entry 1). In contrast, treatment of pivalate 25 with
2 : 1 NCS/Ph3P afforded the expected dichloride 27 (66%) along
with ester-migrated product 28 (12%) (entry 2). The migration
strongly suggested the intermediacy of a chloronium ion,
which likely suffered from anchimeric assistance by the neigh-
boring ester functionality. This was further supported by the
observation that the dichlorination of olefin 25 with molecular
chlorine (Cl2) afforded 28 (30%), 27 (24%), and recovered
olefin 25 (27%) (Scheme 5). The distinct product ratio observed
for the 2 : 1 NCS/Ph3P system and molecular chlorine reflected
the concentration of chloride ions in the reaction media, i.e.,
the higher the chloride ion concentration was, the less often
the migration took place: the 2 : 1 system promptly produced a
high concentration of chloride ions necessary for intermolecu-
lar nucleophilic chlorination, whereas molecular chlorine
concomitantly generated a limited number of chloride ions
a All reactions were carried out in CH2Cl2 at room temperature using
olefin (1 equiv.), Ph3P (1.5 equiv.) and NCS (3.0 equiv.). b Isolated yield
after chromatographic purification. c Regioisomeric chlorohydrins (ca.
1 : 1) were produced as a minor product (7%). d Stereochemistry has yet
to be determined. e Chlorohydrin (7%) was produced. f 1 : 1 syn : anti
dichloride was obtained. g Chlorohydrin (6%) was produced. h 1 : 1
syn : anti dichloride was obtained.
Further application of the present dichlorination system to
bifunctional substrate 16 provided insights into its unique
reaction scope (Scheme 3). With the addition of a 1 : 1 mixture
of NCS/Ph3P, epoxy cyclooctene 16 was cleanly and smoothly
converted into dichloride 17 with the double bond remaining
intact. This outcome indicated that the chlorophosphonium
reagent was rapidly generated in situ to preferentially undergo
deoxydichlorination over double bond activation. In contrast,
the 2 : 1 combination of NCS/Ph3P afforded epoxy dichloride
18 (41%) and ring-opened isomeric products 19 (7%) and 20
(33%). The production of such chlorides in the latter case by
Scheme 3 Dichlorination of cyclooctene 16 with NCS/Ph3P in either 2 : 1 or
1 : 1 stoichiometry.
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Organic & Biomolecular Chemistry
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Table 2 Dichlorination of olefins 24 and 25 with NCS/Ph3P in 2 : 1
stoichiometrya
Entry
1
Substrate
Dichlorideb (%)
2
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Scheme 5 Dichlorination of olefin 25 with molecular chlorine (Cl2).
via chloronium intermediate formation. Therefore, with the
2 : 1 reagent that had a high concentration of nucleophilic
chloride ions, the migration was relatively suppressed. It
should be noted that such neighboring participation was not
observed in the deoxydichlorination of epoxides bearing a
pivalic ester functionality.14
In conclusion, we have demonstrated that the NCS/Ph3P
system, a well-known source of the chlorophosphonium ion, is
a readily available dichlorination reagent for olefins by modify-
ing the reagent stoichiometry. This simple combination is
expected to expand its scope in further chlorination reactions
of organic molecules.
Acknowledgements
This work was partially supported by the Hoansha Foundation
and a Grant-in-Aid for Scientific Research on Innovative Areas
[No. 22136006] from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (MEXT). The authors
thank Mr Hirotaka Yonemoto and Mr Yusuke Satake for their
technical assistance in the preliminary part of this study.
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1600 | Org. Biomol. Chem., 2013, 11, 1598–1601
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