Convenient in situ generation of various dichlorinating agents from oxone and chloride: Diastereoselective dichlorination of allylic and homoallylic alcohol derivatives

Article abstract of DOI:10.1039/c3ob40670a

A safe and convenient protocol was developed for in situ generation of various dichlorinating agents (cf. Cl₂, NCl₃, Et ₄NCl₃, ArICl₂) from oxone and chloride. The synthetic utility of this protocol was demonstrated by diastereoselective dichlorination of a series of allylic and homoallylic alcohol derivatives with excellent yields and diastereoselectivity. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40670a

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Convenient in situ generation of various dichlorinating
agents from oxone and chloride: diastereoselective
dichlorination of allylic and homoallylic alcohol
derivatives†
Cite this: Org. Biomol. Chem., 2013, 11, 4312
Received 4th April 2013,
Accepted 13th May 2013
DOI: 10.1039/c3ob40670a
www.rsc.org/obc
Jingyun Ren and Rongbiao Tong*
A safe and convenient protocol was developed for in situ gen-
eration of various dichlorinating agents (cf. Cl2, NCl3, Et4NCl3,
ArICl2) from oxone and chloride. The synthetic utility of this proto-
col was demonstrated by diastereoselective dichlorination of a
series of allylic and homoallylic alcohol derivatives with excellent
yields and diastereoselectivity.
Naturally-occurring organohalogen compounds are a unique
family of natural products and over 2000 chlorine-containing
natural products have been identified from various sources.1
Many of these organohalogens display potent antibiotic or
cytotoxic activities, which have attracted considerable attention
from synthetic communities.1,2 Particularly, polychlorosulfo-
Scheme 1 In situ generation of various dichlorinating agents from oxone and
chloride.
lipids characterized by the presence of vicinal dichloride protocol for convenient in situ generation of various dichlori-
(sp3C–Cl) have posed formidable synthetic challenges for nating agents (Cl2, NCl3, ArICl2 and Et4NCl3) from low cost
many decades since their discovery in the 1960s.3 One of the and environmentally friendly oxone and chloride sources
most straightforward methods to access such functionality is (Scheme 1). The utility of this method was further demon-
chlorine (Cl2) addition to alkenes.4 Apparently, the use of strated by diastereoselective dichlorination of allylic and
molecular chlorine is less appealing due to the difficult homoallylic alcohol derivatives.
measurement of stoichiometry, incompatibility of many func-
Due to the remarkable stability, simple handling and non-
tional groups and the hazardous laboratory operation. These toxic nature, oxone has been widely used for oxidation in
problems could be alleviated by developing stable chlorine organic synthesis, especially for arene halogenation, epoxi-
complexes or surrogates, which include (i) hypervalent iodine(III) dation and oxidation of alcohols.9 Particularly noteworthy is
dichloride (ArICl2);5 (ii) Mioskowski’s reagent (Et4NCl3);6 that the combination of oxone and chloride has been used for
(iii) Markó–Maguire reagent (KMnO4–TMSCl–BnEt3NCl);7 (iv) olefin functionalizations: 1,2-acetoxychlorination of simple
Yoshimitsu’s method (NCS–PPh3).8 However, the preparation alkenes,10 α-chlorination of α,β-unsaturated ketones or esters11
of Mioskowski’s reagent or ArICl2 still required excessive hazar- and hydroxychlorination of α,β-unsaturated esters12 (Scheme 2,
dous molecular chlorine,5,6 while the Markó–Maguire eqn (1)–(3)). Attracted by this oxidation ability of oxone
method employed stoichiometric KMnO4 and excess of Lewis towards chloride, we were interested in exploration of this
acid trimethylsilyl chloride (TMSCl), which might not be toler- environmentally benign oxone–chloride system for the more
ant of highly functionalized substrates and presented potential challenging vicinal dichlorination of allylic and homoallylic
environmental impacts. Herein, we describe
a
practical alcohol derivatives,13 which served as the indispensable func-
tional groups for the synthesis of vicinal dichlorides and tri-
chlorides and have been elaborated into many chlorosulfolipid
natural products.3 To our delight, our initial studies indicated
that vicinal dichlorination of cinnamyl alcohol using oxone–
NaCl14 was unexpectedly clean (Scheme 2) to give a syn, anti
diastereomeric mixture of vicinal dichloride 2 favoring anti-
diastereomer (∼4 : 1), although the conversion was only 60%.
Department of Chemistry, The Hong Kong University of Science and Technology,
Clearwater Bay, Kowloon, Hong Kong, China. E-mail: rtong@ust.hk;
Fax: +(852) 23581594; Tel: +(852) 23587357
†Electronic supplementary information (ESI) available: Experimental procedure
and copies of 1H, 13C-NMR spectra of all major dichlorinated compounds. See
DOI: 10.1039/c3ob40670a
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Scheme 3 Counter ion effects on the generation of dichlorinating agents.
Although it is well documented that oxone is able to oxidize
the chloride ion to produce a mixture of hypochlorous acid
(HOCl) and chlorine (Cl2) in the presence of water,9 we specu-
Scheme 2 Dichlorination of cinnamyl alcohol with oxone and NaCl.
lated that the counter ion (cf. Na+, NH4 and Et4N+) or additive
+
(p-iodotoluene) may exert an influence on chlorinating species
(Scheme 1). In order to verify this hypothetic influence and get
some insights into the active dichlorinating species from
various chloride sources, we designed and performed a series
of experiments as shown in Scheme 3. First of all, we separated
the DCM solution from the excess of oxone, salts and aqueous
phase. The resulting DCM solution was dried over anhydrous
Na2SO4 and then treated with cinnamyl alcohol and trans-
crotyl benzylether (1a and 1e). Not surprisingly, dichlorination
Table 1 Selected conditions for the dichlorination of cinnamyl alcohol with
oxone and chloridea
Oxone MCl
Entry (equiv.) (equiv.)
Temp
(°C)
Time
(min)
Conv.
(%)
Yield
(2, %)
1
2
3
4
5
6
7
8
2
2
4
8
2
4
4
4
NaCl (4)
NaCl (8)
NaCl (4)
NaCl (4)
NH4Cl (4)
NH4Cl (4)
Et4NCl (4)
NaCl (4)/
4-MePhI (2)
0
0
0
0
0
0
30
30
30
30
30
30
8 h
60
65
100
100
54
100
100
42
47
72 (89)b
76
36
74 (93)b with the DCM solution proceeded with very low conversion for
0→rt
0 (0→rt) 30 (24 h)
69
both alkenes 1a and 1e. This result suggested that chlorine
0 (100) 0 (75)
may be the active dichlorinating species11 in the one-pot pro-
cedure. Additional evidence was that chlorine generated in situ
from oxone–NaCl (8/16 equiv.) could be cannulated by nitro-
gen stream into another flask charged with 1e solution in the
anhydrous DCM, which led to the corresponding dichloride 2e
in 81% yield.15 Surprisingly, the DCM solution separated from
a Isolated yield for one-pot dichlorination, the diastereomeric ratio was
about 4 : 1 based on 1H NMR of crude materials. b Overall yield of
2 and 3.
The 1H-NMR spectra of the anti-diastereomer 2 was identical oxone–NH4Cl effectively promoted the dichlorination to give
to that reported in the literature.5b The major side product iso- 2a in 76% yield (dr. = 4 : 1) and 2e in 75% yield (dr. > 20 : 1).
lated in less than 10% yield was alkenyl chloride (3), which This unexpected result indicated that the oxone–NH4Cl may
might be derived from dehydrohalogenation of the desired not produce chlorine as the dichlorinating reagent. It was
dichloride product (2). This encouraging result prompted us to reported that the oxone–NH4Cl could generate HOCl for oxi-
further investigate the reaction conditions and chloride dative chlorination of arenes and α-chlorination of ketones,9,16
sources (Table 1).
but olefin dichlorination could not occur with only HOCl.
We found that the solvents (DCM–H2O) were critical to the Therefore, we proposed that oxone–NH4Cl may generate a
success of the dichlorination and the optimal stoichiometry of different active dichlorinating agent: trichloramine,17 which
oxone and chloride was 4/4 with respect to the cinnamyl was supported by a comparison of a DCM solution of trichlor-
alcohol.15 Under this condition, dichlorination was complete amine prepared according to the literature procedure.18 In
in 30 min at 0 °C to afford the dichloride (2) in 72% isolated addition, UV-vis spectra indicated the presence of NCl3 from a
yield (entry 3, Table 1). Noteworthy is that the water for DCM solution of oxone–NH4Cl.15 However, we cannot rule
dissolution of oxone did not compete with chloride for nucleo- out the possibility of formation of a mixture of chloramine,
philic addition (substitution), since only trace amount of 4 was dichloramine and trichloramine.19 When Et4NCl was used as
detected in the 1H-NMR of the crude materials. Screening of the chloride source, the dry DCM solution obtained, surpris-
other halide salts led us to identify NH4Cl (entries 5 and 6) as ingly, only led to a lower conversion of 1a with 44% yield of 2a
another competent chloride source.16 When Et4NCl was used, even with a longer reaction time, but it gave excellent yield of
dichlorination of cinnamyl alcohol also gave good yield (69%) dichloride 2e (77%) as a single diastereomer. We speculated
after an extended reaction time at room temperature (entry 7). that Mioskowski’s reagent (Et4NCl3), not chlorine or hypo-
Interestingly, aryliodide completely suppressed the dichlorina- chlorous acid, was generated as the active chlorinating agent,
tion of cinnamyl alcohol with oxone–NaCl at the initial stage although more efforts are needed for its confirmation.15
(30 min), but reaction with a prolonged time (24 h) at ambient Lastly, when stoichiometric 4-iodotoluene was added to the
temperature afforded dichloride 2 in 75% yield (entry 8, in solution of oxone–NaCl in DCM–H2O, the resulting dry DCM
parentheses).
solution could promote effective dichlorination with good
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hexachlorosulfolipid.3 Homoallylic alcohol (1i) and its benzyl-
ether (1j) were also suitable substrates for dicholorination,
affording the corresponding dichlorides (2i and 2j) in excellent
yields (82% and 87%) and diastereoselectivity (>20 : 1),
respectively. Remarkably, trans-butene-1,4-diol and cis-butene-
1,4-diol derivatives, substrates used in total synthesis of some
polychlorosulfolipids, underwent smooth and clean vicinal
dichlorination to give the corresponding highly functionalized
anti-dichloride (2k, 80% yield) and syn-dichloride (2l, 87%
yield) with exclusive diastereoselectivity. For secondary allylic
alcohols and their TBS ethers, high yields and exclusive
diastereoselectivity of vicinal dichlorides (2m–2p, anti for
trans-alkene, syn for cis-alkene) could be achieved, but with
poor facial selectivity of the alkene controlled by A1,3-strain.13
Terminal alkenes, including styrene that is easily polymerized
under some dichlorination conditions, underwent smooth
dichlorination with oxone and NaCl or NH4Cl (2q–2t).
Table 2 Substrate scope of dichlorination of allylic and homoallylic alcohol
derivatives using oxone and NaCla
In summary, a convenient method was developed for in situ
generation of various active dichlorinating agents from an
environmentally friendly oxone and various cheap chloride
sources. The counter ion of the chloride has a tremendous
effect on the generation of different dichlorinating species
using oxone as the oxidant. The synthetic utility of this proto-
col was demonstrated by diastereoselective dichlorination of a
series of allylic and homoallylic alcohol derivatives with excel-
lent yields and diastereoselectivity. The active chlorinating
species generated from oxone–chloride by this method may be
exploited in the synthesis of other chlorinated organic
compounds.
This work was financially supported by HKUST and Hong
Kong RGC (ECS HKUST605912 and DAG12CS03).
a Conditions: The reaction was run in 1.0 mmol of alkene, oxone
(4.0 mmol), NaCl (4.0 mmol), DCM (10 mL), H2O (2 mL); isolated
yield (yield in parentheses including dehydrochlorination); the
diastereomeric ratio was determined by 1H NMR of the crude Notes and references
materials.
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Finally, the optimized oxone–NaCl system was demon-
strated by diastereoselective dichlorination of various allylic
and homoallylic alcohol derivatives (Table 2). Electron-with-
drawing pivalate (1c) gave lower dichlorination yield of 2c than
that of benzylether (1b). The low diastereoselectivity for 2a–2c
might be due to the competing SN1/SN2 chloride substitution
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drochlorination was not observed for all aliphatic alkenes such
as trans-crotyl alcohol (1d) and its derivatives (1e–1h), which
gave higher dichlorination yields (64%–89%) with remarkably
excellent anti-diastereoselectivity (2d–2h). In addition, a gram-
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