An acid-catalyzed formal allylic C-H oxidation of aryl cycloalkenes with N-propylthiosuccinimide

Article abstract of DOI:10.1021/ol200261a

A mild acid-catalyzed formal allylic C-H oxidation of aryl cycloalkenes with N-propylthiosuccinimide in the presence of various nucleophiles to generate allylic ethers, esters, and sulfonamides is described. A possible reaction mechanism has been proposed.

Full text of DOI:10.1021/ol200261a

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1548–1551
An Acid-Catalyzed Formal Allylic C-H
Oxidation of Aryl Cycloalkenes with
N-Propylthiosuccinimide
Deshun Huang,† Haining Wang,† Huan Guan,† Hu Huang,† and Yian Shi*,†,‡
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China, and Department of Chemistry, Colorado State University, Fort Collins,
Colorado 80523, United States
yian@lamar.colostate.edu
Received January 26, 2011
ABSTRACT
A mild acid-catalyzed formal allylic C-H oxidation of aryl cycloalkenes with N-propylthiosuccinimide in the presence of various nucleophiles to
generate allylic ethers, esters, and sulfonamides is described. A possible reaction mechanism has been proposed.
Allylic C-H oxidation of olefins provides an important
approach to introduce functionality into molecules.
Various processes have been developed,1 including Pd(II)-
Scheme 1
catalyzed allylic acetoxylation2 and amination,3-5 Cu-
catalyzed allylic oxidation with peresters,6 and selenium
† Chinese Academy of Sciences.
‡ Colorado State University.
(1) For leading reviews, see: (a) Rawlinson, D. J.; Sosnovsky, G.
Synthesis 1972, 1. (b) Rawlinson, D. J.; Sosqovsky, G. Synthesis 1973,
567. (c) Giri, R.; Shi, B. F.; Engle, K. M.; Maugel, N.; Yu, J. Q. Chem.
Soc. Rev. 2009, 38, 3242.
(2) For leading references on Pd(II)-catalyzed acetoxylation, see: (a)
Tsuji, J.; Sakai, K.; Nagashima, H.; Shimizu, I. Tetrahedron Lett. 1981,
based allylic oxidations.7,8 During our studies on the
reactivity of sulfenamides9 toward olefins, we have found
that aryl cycloalkenes can be oxidized at the allylic posi-
tions regioselectively with N-propylthiosuccinimide 3 and
various nucleophiles in the presence of a catalytic amount
of acid to form allylic ethers, esters, and sulfonamides
ꢀ
ꢁ
22, 131. (b) McMurry, J. E.; Kocovsky, P. Tetrahedron Lett. 1984, 25,
˚
4187. (c) Hansson, S.; Heumann, A.; Rein, T.; Akermark, B. J. Org.
€
Chem. 1990, 55, 975. (d) Grennberg, H.; Simon, V.; Backvall, J. E. J.
Chem. Soc., Chem. Commun. 1994, 265. (e) Chen, M. S.; White, M. C. J.
Am. Chem. Soc. 2004, 126, 1346. (f) Chen, M. S.; Prabagaran, N.;
Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970. (g)
Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076. (h)
€
ꢁ
Pilarski, L. T.; Selander, N.; Bose, D.; Szabo, K. J. Org. Lett. 2009, 11,
5518. (i) Thiery, E.; Aouf, C.; Belloy, J.; Harakat, D.; Bras, J. L.;
Muzart, J. J. Org. Chem. 2010, 75, 1771.
(3) For leading references on Pd(II)-catalyzed amination, see: (a)
Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46,
1910. (b) Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem.
Soc. 2009, 131, 11701. (c) Wu, L.; Qiu, S.; Liu, G. Org. Lett. 2009,
11, 2707. (d) Shimizu, Y.; Obora, Y.; Ishii, Y. Org. Lett. 2010, 12,
1372.
(4) For leading reviews on generation of π-allyl Pd complexes from
olefins with PdX2, see: (a) Trost, B. M. Acc. Chem. Res. 1980, 13, 385. (b)
˚
Akermark, B.; Zetterberg, K. In Handbook of Organopalladium Chem-
istry for Organic Synthesis; Negishi, E-i., Ed.; John Wiley & Sons, Inc.:
New York, 2002; p 1875.
r
10.1021/ol200261a
Published on Web 02/24/2011
2011 American Chemical Society

(Scheme 1). Herein we wish to report our preliminary
results on this subject.
the reaction conditions due to TfOH’s strong acidity.
Among the solvents tested, CH2Cl2 was found to be the
solvent of choice. Treating 1-phenylcyclohexene (1a)
with BnOH (2.0 equiv), N-propylthiosuccinimide 3 (2.2
equiv), and In(OTf)3 (5 mol %) in CH2Cl2 at rt for
1.5 h gave allylic benzyl ether 4a in 81% yield (Table 1,
entry 1). Various substituted 1-phenylcyclohexenes
(1b-f) could also be oxidized (Table 1, entries 2-6),
and more electron-rich substrates were found to be
more reactive. Other aryl cycloalkenes such as 1-nap-
hthyl (1g), 1-(3-thiophenyl)-cyclohexene (1h), 1-phenylcy-
cloheptene (1i), and 1-phenylcyclopentene (1j) were
found to be suitable substrates for the reaction
(Table 1, entries 7-10). For more reactive substrates,
the catalyst loading was decreased to 1 mol % to
minimize any byproduct (Table 1, entries 2-4, 9, 10).
Initial studies with 1-phenylcyclohexene and BnOH
showed that In(OTf)3 gave overall the best result among
various Lewis acids examined. TsOH was also capable of
catalyzing the reaction but with low activity, thus requiring
a longreaction time. WhileTfOH wasfoundtobe anactive
catalyst, the resulting product decomposed quickly under
Table 1. Allylic Oxidation of Aryl Cycloalkenes
Scheme 2
Various other nucleophiles were also investigated with
1-phenylcyclohexene (1a). As shown in Table 2, other
alcohols, carboxylic acids, and sulfonamides could be
employed to give the corresponding allyl ethers, esters,
and sulfonamides in 52-83% yields.
When a weaker Lewis acid InCl3 was used as a catalyst,
compound 5a was formed as the major product along with
allyl ether 4a (Scheme 2). Compound 5a was then isolated
and subjected to various reaction conditions. When 5a was
(5) For a recent book on Pd, see: Tsuji, J. Palladium Reagents and
Catalysts: New Perspective for the 21st Century; John Wiley & Sons Ltd.:
2004.
(6) For a leading review on Cu-catalyzed allylic oxidation, see:
Andrus, M. B.; Lashley, J. C. Tetrhedron 2002, 58, 845.
(7) For a leading reference on allylic oxidation with SeO2, see:
Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
(8) For leading references on oxyselenenylation-elimination reactions
of olefins to generate allylic ethers, see: (a) Sharpless, K. B.; Lauer, R. F. J.
€
Org. Chem. 1974, 39, 429. (b) Wirth, T.; Hauptli, S.; Leuenberger, M.
Tetrahedron: Asymmetry 1998, 9, 547. (c) Tiecco, M.; Testaferri, L.; Santi,
C.; Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A. Tetrahedron:
Asymmetry 2000, 11, 4645. (d) Browne, D. M.; Niyomura, O.; Wirth, T.
Org. Lett. 2007, 9, 3169. (e) Browne, D. M.; Niyomura, O.; Wirth, T.
Phosphorus, Sulfur, and Silicon 2008, 183, 1026. (f) Oshida, M.; Nakamura,
T.; Nakazaki, A.; Kobayashi, S. Chem. Pharm. Bull. 2008, 56, 404. (g)
Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J. Org. Chem. 2009,
1649.
a The reaction was carried out with 1 (1.0 mmol), 3 (2.2 mmol),
BnOH (2.0 mmol), and In(OTf)3 (x mol %) in CH2Cl2 (5 mL) at rt unless
otherwise stated. b Isolated yield. c At 0-4 °C.
(9) For a leading review on sulfenamides, see: Craine, L.; Raban, M.
Chem. Rev. 1989, 89, 689.
Org. Lett., Vol. 13, No. 6, 2011
1549

Table 2. Allylic Oxidation of 1-Phenylcyclohexene with Various
Nucleophiles
Scheme 3
deuterium-labeled 1-phenylcyclohexene (1k:1l
=
78:22) was treated with 5 mol % In(OTf)3, 1.1 equiv of
3, and 0.5 equiv of BnOH in CH2Cl2 at rt for 25 min,
compounds 7 and 8 were obtained as a 1:1 mixture with
the remaining 1k and 1l being 72:28 (only a slight
decrease from the initial 78:22).
Scheme 4. A Proposed Reaction Pathway
Based on the aforementioned observations, a plausi-
ble reaction mechanism for the allylic C-H oxidation is
proposed in Scheme 4. Thiiranium 9 generated from 1
undergoes an elimination to form allyl sulfide 1110-13 or
a nucleophilic opening to form compound 10, which is
then converted to allyl sulfide 11 directly or via thiir-
anium 9. At the end, allyl cation 12 generated from 11 by
acid and N-propylthiosuccinimide 3 reacts with the
nucleophile to form product 4. The involvement of allyl
cation 12 is supported by the fact that a 1:1 mixture of 7
and 8 was obtained in Scheme 3.
In summary, we have developed a mild and efficient acid-
catalyzed formal allylic C-H oxidation of aryl cycloalk-
enes with N-propylthiosuccinimide. Various nucleophiles
including alcohols, carboxylic acids, and sulfonamides can
be employed to give corresponding allyl ethers, esters, and
a The reaction was carried out with 1a (1.0 mmol), 3 (2.2 mmol), NuH
(2.0 mmol), and In(OTf)3 (x mol %) in CH2Cl2 (5 mL) at rt unless
otherwise stated. b Isolated yield. c The reaction was carried out with
NsNH2 (1.2 mmol) in 1,4-dioxane (5 mL).
treated with In(OTf)3 (5 mol %), allyl sulfide 6a was
formed along with allyl ether 4a and 1-phenylcyclohexene
(1a). However, when N-propylthiosuccinimide 3 was
added, allyl ether 4a was formed predominately. When
allyl sulfide 6a was treated with In(OTf)3 (5 mol %), N-
propylthiosuccinimide 3, and BnOH, it was converted to
allyl ether 4a cleanly. All these results suggest that com-
pounds 5a and 6a are likely to be the intermediates
involved in the reaction pathway.
(10) For leading reviews on thiiranium ions, see: (a) Mueller, W. H.
Angew. Chem., Int. Ed. 1969, 8, 482. (b) Fox, D. J.; House, D.; Warren, S.
Angew. Chem., Int. Ed. 2002, 41, 2462.
(11) For a leading review on seleniranium ions, see: Wirth, T. Angew.
Chem., Int. Ed. 2000, 39, 3740.
To further probe the reaction mechanism, deuterium-
labeled 1-phenylcyclohexene was prepared and investi-
gated for the reaction. It was found that compound 1k
was slowly converted to 1l under the acidic reaction
conditions (Scheme 3). Therefore, the reaction was then
carried out for a partial conversion to determine the
ratio of the remaining 1k and 1l in addition to the ratio of
products 7 and 8. As shown in Scheme 3, when
(12) For leading references on acid-promoted addition of RS or
RSe to olefins with RS-N or RSe-N reagents, see: (a) Nicolaou,
K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J. Am. Chem. Soc.
1979, 101, 3704. (b) Caserio, M. C.; Kim, J. K. J. Am. Chem. Soc.
1982, 104, 3231. (c) Brownbridge, P. J. Chem. Soc., Chem. Commun.
1987, 1280.
(13) For a leading reference on the generation of allylic sulfide
with PhSCl, see: Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978, 43,
1208.
1550
Org. Lett., Vol. 13, No. 6, 2011

sulfonamides. Importantly, the reaction occurs selectively
at one allylic carbon. Mechanistic studies show that the
sulfenamide plays an important role in converting the allyl
sulfide intermediate into the products. Further efforts will
be devoted to the development of a more effective system to
expand the substrate scope and to reduce sulfur reagents to
catalytic amounts as well as an asymmetric process possibly
with chiral counteranions.
Acknowledgment. We gratefully acknowledge the Na-
tional Basic Research Program of China (973 program,
2010CB833300) and CAS for the financial support.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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