Selective selenocatalytic allylic chlorination

Article abstract of DOI:10.1021/ol036525o

Ene-chlorination of olefins by N-chlorosuccinimide is catalyzed by phenylselenenyl chloride. This reaction demonstrates the catalytic conversion of C-H bonds into more reactive C-Cl bonds.

Full text of DOI:10.1021/ol036525o

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1205-1207
Selective Selenocatalytic Allylic
Chlorination
Jon A. Tunge* and Shelli R. Mellegaard
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
tunge@ku.edu
Received December 30, 2003
ABSTRACT
Ene-chlorination of olefins by N-chlorosuccinimide is catalyzed by phenylselenenyl chloride. This reaction demonstrates the catalytic conversion
of C−H bonds into more reactive C−Cl bonds.
The selective conversion of C-H bonds into more reactive
functional groups represents a frontier in synthetic organic
methodology.1 We have chosen to focus on the selective
catalytic conversion of C-H bonds into carbon-halogen
bonds because transformations of the latter play a central
role in synthetic chemistry. Recent research has shown that
catalytic generation of enolates in the presence of electro-
philic halogen sources is a successful strategy toward
selective halogenation.2 In contrast to R-halogenation of
carbonyl compounds, allylic halogenation requires substitu-
tion of a weakly acidic proton, and selective catalysis of this
reaction is not well-studied.3 This is likely due to the
propensity of typical halogenating agents to generate free
radicals.4 Herein we report that selective allylic chlorination
can be achieved through selenocatalytic ene-type oxidation
of olefins with N-chlorosuccinimide.
On the basis of our desire to develop catalysts for oxidative
halogenation, we identified two criteria for initial catalyst
investigation: (i) the catalyst should be capable of stereo-
specific addition of halogens to olefins through reagent-
bound intermediates so that the addition step might be
controlled by changes in the reagent coordination sphere,
and (ii) the catalyst should have an accessible 2 e- oxida-
tion-reduction cycle. These criteria are both met by aryl-
selenium halides.5,6 In fact, Sharpless communicated that
diphenyldiselenide catalyzes the halogenation of olefins with
N-chlorosuccinimide (NCS); however, the study was limited
in scope and the reaction lacked selectivity. Specifically,
reaction of simple olefins with NCS in the presence of
diselenide catalysts provided mixtures of allyl halides, vinyl
halides, and dihalides.7,8
(5) (a) Organoselenium Chemistry; Back, T. G., Ed.; Oxford: New York,
1999. (b) Selenium in Natural Products Synthesis; Nicolaou, K. C., Petasis,
N. A., Eds.; CIS: Philadelphia, 1984.
(6) (a) Back, T. G.; Moussa, Z. J. Am. Chem. Soc. 2002, 124, 12104-
12105. (b) Mugesh, G.; Panda, A.; Singh, H. B.; Punekar, N. S.; Butcher,
R. J. J. Am. Chem. Soc. 2001, 123, 839-850. (c) Abe, M.; You, Y.; Detty,
M. R. Organometallics 2002, 21, 4546-4551. (d) Francavilla, C.; Drake,
M. D.; Bright, F. V.; Detty, M. R. J. Am. Chem. Soc. 2001, 123, 57-67.
(e) Leonard, K. A.; Zhou, F.; Detty, M. R. Organometallics 1996, 15, 4285-
4292.
(7) Hori, T.; Sharpless, K. B. J. Org. Chem. 1979, 44, 4204-4208. (b)
Hori, T.; Sharpless, K. B. J. Org. Chem. 1979, 44, 4208-4210.
(8) Recent selenium-catalyzed oxidations: (a) Wirth, T.; Hauptli, S.;
Leuenberger, M. Tetrahedron: Asymmetry 1998, 9, 547-550. (b) Tiecco,
M.; Testaferri, L., Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.;
Temperini, A. Chem. Eur. J. 2002, 8, 1118-1124.
(1) (a) ActiVation of UnreactiVe Bonds and Organic Synthesis; Murai,
S., Ed.; Springer: New York, 1999. (b) Shilov, A. E.; Shul’pin, G. B. Chem.
ReV. 1997, 97, 2879-2932. (c) Arndtsen, B. A.; Bergman, R. G.; Mobley,
T. A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154-162.
(2) (a) Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Lectka, T.
J. Am. Chem. Soc. 2001, 123, 1531-1532. (b) Hintermann, L.; Togni, A.
Angew. Chem., Int. Ed. 2000, 39, 4359-4362. (c) El-Qisairi, A. K.; Qaseer,
H. A.; Katsigras, G.; Lorenzi, P.; Trivedi, U.; Tracz, S.; Hartman, A.; Miller,
J. A.; Henry, P. M. Org. Lett. 2003, 5, 439-441. (d) El-Qisairi, A.; Hamed,
O.; Henry, P. M. J. Org. Chem. 1998, 63, 2790-2791.
(3) (a) Yamanaka, M.; Arisawa, M.; Nishida, A.; Nakagawa, M.
Tetrahedron Lett. 2002, 43, 2403-2406. (b) Moreno-Dorado, F.; Javier,
F. J.; Guerra, F. M.; Francisco M.; Manzano, F. L.; Aladro, F. J.; Jorge, Z.
D.; Massaner, G. M. Tetrahedron Lett. 2003, 44, 6691-6693.
(4) Walling, C.; Thaler, W. J. Am. Chem. Soc. 1961, 83, 3877-3884.
10.1021/ol036525o CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/19/2004

We reasoned that the allyl/vinyl selectivity could be
increased by differentiating the acidity of the hydrogens
capable of syn-elimination from hypothetical selenium ad-
dition intermediates 2 and 3 (Scheme 1). Toward this end,
the limits of NMR detection. It is noteworthy that the
catalytic production of allyl halides is in contrast to the
reaction of â,γ-unsaturated acids with stoichiometric PhSeCl,
which results in lactonization.9
Protecting the acids as methyl esters substantially reduced
the required reaction time. Thus, â,γ-unsaturated esters (1d-
g) provided high yields of chloro-enoates when treated with
5-10 mol % PhSeCl and 1.1 equiv NCS (added by addition
funnel or syringe pump) in under 4 h. Disubstituted olefins
(1d-f) produced the E-allyl halides exclusively, and the
cyclic olefin (1g) provided the trisubstituted allyl halide with
good E/Z selectivity (g9:1, Scheme 2).
Scheme 1
Scheme 2
the halogenation of â,γ-unsaturated acids was investigated.
Indeed, treatment of vinyl acetic acid (1a) with 5 mol %
PhSeCl and 1.1 equiv of NCS in CD2Cl2 produced the allyl
chloride in 70% yield with no evidence for the production
of vinyl halides or dihalides. No product was formed in the
absence of PhSeCl, demonstrating that PhSeCl is a catalyst
or precatalyst for allylic halogenation. Switching the solvent
to acetonitrile proved beneficial, and allyl halide was obtained
in 82% isolated yield. However, the rates were rather erratic;
seemingly identical reactions were complete at varying times
(within 1-3 days) at room temperature with some reactions
stopping at <60% conversion. Addition of molecular sieves
(MS4Å) solved this problem and allowed complete conver-
sion to the allyl halide in 24 h. Qualitatively, it was observed
that reactions with higher NCS concentration proceeded more
slowly. On the basis of the idea that the reaction was
inhibited by NCS, we investigated reactions where the NCS
concentration was minimized. It was found that the rates of
the reaction could be increased by slow addition of an NCS
solution by syringe pump, supporting the idea of some
inhibition by NCS. Thus, under optimized conditions vinyl
acetic acid was halogenated in 16 h at 25 °C in the presence
of 10 mol % PhSeCl, 1.1 equiv NCS, and MS4Å.
Other electron-withdrawing groups, such as phenyl and
cyano, also provided allyl halides selectively. However,
allylbenzene and pentenenitrile both required higher catalyst
loadings for reasonable rates of conversion to the allyl halide.
Furthermore, the E/Z selectivity for allylic halogenation of
3-pentenenitrile (3:1) was lower than that observed for the
corresponding acids and esters but was improved to 9:1 upon
chromatographic separation.
Selectivity for allyl halides could also be realized by
sterically differentiating the protons capable of elimination.
Thus prenyl olefins, where syn-elimination to form vinyl
chloride requires an unfavorable eclipsed conformation,
provide good yields of allyl halides (Scheme 3, Table 2).
Scheme 3
The halogenation of substituted allylic acids provided
similarly high yields of γ-halo-R,â-unsaturated acids in 16
h at room temperature (Table 1). Importantly, the reactions
selectively produced the E-isomer as the only isomer within
Table 1. Allylic Chlorination of Allylic Acids, Esters, Arenes,
and Nitriles
The oxidative halogenation of prenyl olefins was more rapid
than the â,γ-unsaturated acids previously described, so slow
addition of NCS was not necessary. For example, 2-methyl-
2-heptene reacts to give allyl halide in 82% isolated yield in
3 h upon treatment with PhSeCl and NCS in CH2Cl2.10 Prenol
(6c) reacted much more sluggishly to produce the halohydrin
8c in 68% yield after 1 day at 35 °C.
substrate
R1
EWG
time
% yield
1a
1b
1c
1d
1e
1f
H
CO2H
CO2H
CO2H
CO2Me
CO2Me
CO2Me
Ph
16 h
16 h
16 h
4 h
4 h
8 h
82
83
75
88
89
77
66
62b
Et
Bu
Et
Bu
Ph
H
1h a
1ia
48 h
48 h
Me
CN
(9) Nicolaou, K. C.; Seitz, S. P.; Sipio, W. J.; Blount, J. F. J. Am. Chem.
Soc. 1979, 101, 3884-3893.
(10) CH2Cl2 proved a more convenient solvent for halogenation of prenyl
olefins as a result of its volatility and lower water content.
a 20 mol % PhSeCl. b Isolated as a 9:1 E/Z mixture
1206
Org. Lett., Vol. 6, No. 8, 2004

the PhSeSePh-catalyzed chlorination of â-pinene; however,
in that case PhSeCl was ruled out as the active catalyst.7b
The observed catalysis can be adequately described by the
catalytic cycle shown in Scheme 5. Phenylselenenyl chloride
Table 2. Allylic Chlorination of Prenyl Olefins
Scheme 5
1
a Based on H NMR.
The observation that oxidative halogenation is more rapid
than alcohol oxidation is interesting in light of the recent
report on sulfenamide-catalyzed alcohol oxidation utilizing
NCS as the terminal oxidant.11 As a result of the suspicion
that alcohol oxidation may be contributing to the somewhat
lower yield, the alcohol was protected as the benzyl ether.12
This proved successful, reducing the reaction time to 3 h,
and pure 8d was isolated in 84% yield. Reaction of the prenyl
ketone 6e under our standard conditions resulted in the
formation of 8e in low (20-50%) yields along with other
products presumably formed by competitive R-selenylation.13
In line with this assumption, the protected ketone 6f reacted
smoothly to give the allyl halide in 85% yield.
is well-known to undergo 1,2-addition to olefins.5 This
addition is only moderately regioselective for prenyl olefins
and â,γ-unsaturated esters14 but is reversible. Oxidation of
the alkylselenide with NCS followed by elimination of
succinimide completes the cycle. The observation that a
regioisomeric mixture of addition intermediates provides a
single product indicates that the oxidation of the alkyl
selenides is also reversible. Thus, product allyl halide will
result from the regioisomeric intermediate that most rapidly
undergoes elimination.
The observed inhibition by NCS can be explained by
reversible oxidation of the catalyst, which will sequester
some catalyst in an inactive complex 11. The likely role of
the molecular sieves is to protect complexes 10 and 11, which
are expected to be hydrolytically labile.
The tert-butyl-substituted olefin 6b did not give the
expected product of allylic transposition 8b as the major
product, but rather it reacted to produce a 4.8:1 mix of 9:8b
(Scheme 4). Prolonged heating of the product resulted in a
Scheme 4
In conclusion, we have described a practical method for
selective allylic halogenation using readily available reagents
NCS and PhSeCl. Details concerning the mechanism of this
transformation and its extension to asymmetric halogenation
will be reported in due course.
Acknowledgment. We thank the Kansas NSF-EPSCoR
program for support of this research and Dr. David Vander-
Velde and Sarah Neuenswander for valuable NMR as-
sistance. J.T. thanks Professors Jack Norton and Charles
Casey for valuable mentoring.
1:1.2 equilibrium ratio of 9:8b, showing that 9 is the kinetic
product of catalytic halogenation. This is the only case where
we have observed halogenation without allylic transposition.
Interestingly, this substrate was also the most reactive of
those studied, with the reaction occurring in <10 min at room
temperature. Sharpless noted similar anomalous behavior in
Supporting Information Available: Complete experi-
mental details and characterization of all new compounds
prepared in this work. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) Mukaiyama, T.; Matsuo, J.-I.; Iida, D.; Kitagawa, H. Chem. Lett.
2001, 30, 846-847.
(12) A referee correctly pointed out that ether formation could also
account for the reduced yield.
OL036525O
(13) (a) Engman, L.; Persson, J.; Tilstam, U. Tetrahedron Lett. 1989,
30, 2665-2668. (b) Cossy, J.; Furet, N. Tetrahedron Lett. 1993, 34, 7755-
7756.
(14) Reaction of PhSeCl with 1d gives 3.6:1 ratio of regioisomers after
5 min at 25 °C. Similarly. the regioselectivity with 6a is 3:1.7a
Org. Lett., Vol. 6, No. 8, 2004
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