Thiophenol-mediated hydrogen atom abstraction: An efficient tin-free procedure for the preparation of cyclopentane derivatives

Article abstract of DOI:10.1021/ol049162g

(Matrix Presented) An efficient procedure for running a cascade reaction involving 1,5-abstraction of a hydrogen atom followed by a radical cyclization is reported. Alkenyl radicals are generated from easily available terminal alkynes and thiophenol. This procedure eliminates the need of using the toxic tributyltin hydride and gives a greater amount of radical translocation products.

Full text of DOI:10.1021/ol049162g

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2563-2566
Thiophenol-Mediated Hydrogen Atom
Abstraction: An Efficient Tin-Free
Procedure for the Preparation of
Cyclopentane Derivatives
Florent Beaufils, Fabrice De´ne`s, and Philippe Renaud*
Department of Chemistry and Biochemistry, UniVersity of Berne, Freiestrasse 3,
CH-3012 Bern, Switzerland
philippe.renaud@ioc.unibe.ch
Received May 8, 2004
ABSTRACT
An efficient procedure for running a cascade reaction involving 1,5-abstraction of a hydrogen atom followed by a radical cyclization is reported.
Alkenyl radicals are generated from easily available terminal alkynes and thiophenol. This procedure eliminates the need of using the toxic
tributyltin hydride and gives a greater amount of radical translocation products.
Radical reactions represent a very useful tool for synthetic
organic chemistry.1 Their complementarity to ionic or
concerted processes and their ability to be involved in
cascade reactions makes them particularly attractive. The use
of hydrogen atom abstraction is of particular interest since
it has no classical counterpart and allows functionalization
of remote unreactive positions.2 Alkenyl radicals are known
to produce five-membered rings via a hydrogen atom transfer
followed by a cyclization.3 This process, thoroughly inves-
tigated by Curran,4 is depicted in Scheme 1. The alkenyl
radical is generated from the corresponding bromide 1a′ by
reaction with a stannyl radical. After a 1,5-hydrogen atom
abstraction, the translocated radical cyclizes via a 5-exo-trig
mode and is reduced by tin hydride to afford cyclopentane
derivatives 2a′.
To minimize the amount of uncyclized product 3a′ (direct
reduction), tin hydride is generated in situ from a catalytic
amount of tributyltin chloride according to the method
developed by Stork.5 Several applications of this reaction
have been reported.6,7 However, the usefulness of this process
is hampered by the formation of uncyclized product and by
tin contamination of the final products.8
Intermolecular addition of radicals to terminal alkynes
offers an attractive alternative for the generation of alkenyl
(1) For general reviews on radical reactions, see: (a) Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001.
(b) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon
Bonds, Pergamon: Oxford, 1988. (c) Curran, D. P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 715 and 779. (d) Motherwell, W. B.;
Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academic
Press: London, 1992. (e) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in
Organic Synthesis; Wiley: Chichester, 1995. (f) Chatgilialoglu, C.; Renaud,
P. In General Aspects of the Chemistry of Radicals; Alfassi, Z. B., Eds.;
Wiley: Chichester, 1999; p 501.
(2) Feray, L.; Kuznetzov, N.; Renaud, P. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P.; Wiley-VCH: Weinheim, 2001; Vol. 2;
p 246.
(3) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1967, 89, 3772.
(4) (a) Curran, D. P.; Kim, D.; Ziegler, C. Tetrahedron Lett. 1991, 47,
6189. (b) Curran, D. P.; Shen, W. J. Am. Chem. Soc. 1993, 115, 6051.
(5) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303.
(6) (a) Lathbury, D. C.; Parsons, P. J.; Pinto, I. J. Chem. Soc., Chem.
Commun. 1988, 81. (b) Borthwick, A. D.; Caddick, S.; Parsons, P. J.
Tetrahedron 1992, 48, 10655. (c) Brown, C. D. S.; Simpkins, N. S.; Clinch,
K. Tetrahedron Lett. 1993, 34, 131. (d) Bertrand, M. P.; Crich, D.; Nouguier,
R.; Samy, R.; Stien, D. J. Org. Chem. 1996, 61, 3588. (e) Stien, D.; Crich,
D.; Bertrand, M. P. Tetrahedron 1998, 54, 10779. (f) Gimisis, T.;
Chatgilialoglu, C. J. Org. Chem. 1996, 61, 1908. (g) Chatgilialoglu, C.;
Gimisis, T.; Spada, G. P. Chem. Eur. J. 1999, 5, 2866. (h) Robertson, J.;
Peplow, M. A.; Pillai, J. Tetrahedron Lett. 1996, 37, 5825. (i) Kittaka, A.;
Tanaka, H.; Yamada, N.; Kato, H.; Miyasaka, T. Nucleosides Nucleotides
1997, 16, 1423. (j) Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada,
N.; Nakamura, K. T.; Miyasaka, T. J. Org. Chem. 1999, 64, 7081.
(7) Renaud, P.; Beaufils, F.; Feray, L.; Schenk, K. Angew. Chem., Int.
Ed. 2003, 42, 4230.
10.1021/ol049162g CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/25/2004

alkynes, and their efficiency in undergoing a tandem
hydrogen abstraction-cyclization process was examined. For
this purpose, the substrate 1a was investigated (Scheme 2).
Scheme 1
Scheme 2
radicals.3,9 A few examples of sequential reactions involving
intermolecular radical addition to alkyne-hydrogen atom
abstraction-cyclization have been reported.3,9d-i,10 Burke has
reported a radical translocation-cyclization process mediated
by thiophenol.11 However, this particular example involves
the formation of a highly stable captodative radical, and even
with this highly favorable system, the formation of the
nontranslocated product could not be avoided.12 Montevec-
chi13 has investigated the mechanistic aspect of the addition
of the phenylthiyl radical to terminal alkynes, and Broka9a
reported that the reaction of oct-1-en-7-yne with thiophenol
was not leading to any cyclized products either via a direct
6-exo cyclization process or via a translocation-cyclization
reaction. Recently, we reported an isolated example of an
efficient H-abstraction-cyclization process using an acetal
derived from indanol.7 We report here that this method is
applicable to a wide range of substrates for radical translo-
cation-cyclization cascade processes. Activation of un-
reactive C-H bonds is described. A detailed investigation
of the thiophenol method as well as a comparative study
with Curran’s tin hydride procedure is reported.
Benzene, the most common solvent for radical reactions,
is not the best choice for this cascade process. Indeed,
unidentified products resulting from the addition of vinyl
radicals to benzene are observed. The best results are
obtained in refluxing tert-butanol by using syringe pump
addition of thiophenol (2 equiv) over 20 h under AIBN
initiation. Interestingly, the amount of the initiator plays a
crucial role in this process. The use of 2 equiv of AIBN
proved to be the best compromise between conversion and
the ratio of cyclized/uncyclized products 2a/3a (90% yield,
2a/3a 100:0).
A stoichiometric amount of AIBN is required for the
reaction to go to completion, indicating that, under our
reaction conditions, the chain process is not very efficient.
Dimerization of the thiyl radical leading to diphenyl disulfide
could explain this inefficiency.14 Further investigation of the
mechanism is currently underway.
The optimized reaction procedure has been compared with
Curran’s tin hydride procedure. A first series of experiments
with substrates 1a/1a′-1c/1c′ that lead after radical trans-
location to heteroatom stabilized radicals have been per-
formed according to Scheme 3. The results, summarized in
Table 1 (entries 1-3), clearly demonstrate the superiority
of the thiophenol over the tin hydride procedure.15 Indeed,
in all three examples, the thiophenol method leads exclu-
sively to the cyclic compounds 2 in good to excellent yields.
The formation of reduced compounds 3 was not observed.
The tin hydride procedure gives significant amounts of
uncyclized product 3′.
In a first series of experiments, alkenyl radicals were
generated by radical addition of thiophenol to terminal
(8) For review articles on tin-free radical reactions, see: (a) Baguley, P.
A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072. (b) Studer, A.;
Amrein, S. Synthesis 2002, 7, 835.
(9) (a) Broka, C. A.; Reichert, D. E. C. Tetrahedron Lett. 1987, 28, 1503.
(b) Miyata, O.; Naito, T. C. R. Acad. Sci. Paris, Chem. 2001, 4, 401. (c)
Kyoko, N.; Koichiro, O.; Kiitiro, U. Bull. Chem. Soc. Jpn. 1987, 60, 3465.
(d) Bosch, E.; Bachi, M. D. J. Org. Chem. 1993, 58, 5581. (e) Alcaide, B.;
Rodriguez-Campos, I. M. Rodriguez-Lopez, J.; Rodriguez-Vicente, A. J.
Org. Chem. 1999, 64, 5377. (f) Wille, U.; Jargstorff, C. Eur. J. Org. Chem.
2003, 3173. (g) Wille, U. J. Am. Chem. Soc. 2002, 124, 14. (h) Wille, U.
Tetrahedron Lett. 2002, 43, 1239. (i) Wille, U.; Lietzau, L. Tetrahedron
1999, 55, 10119. (j) Wille, U.; Lietzau, L. Tetrahedron 1999, 55, 11465.
(k) Wille, U.; Plath, C. Liebigs Ann. 1997, 111.
(10) More examples involving intramolecular radical addition to alkynes
have been reported: (a) Gross, A.; Fensterbank, L.; Bogen, S.; Thouvenot,
R.; Malacria, M. Tetrahedron 1997, 40, 13797. (b) Bogen, S.; Fensterbank,
L.; Malacria, M. J. Org. Chem. 1999, 64, 819. (c) Bogen, S.; Fensterbank,
L.; Malacria, M. J. Org. Chem. 1999, 64, 819. (d) Martinez-Grau, A.;
Curran, D. P. Tetrahedron Lett. 1997, 53, 5679. (e) Sannigrahi, M.; Mayhew,
D. L.; Clive, D. L. J. Org. Chem. 1999, 64, 2776. (f) Clive, D. L.; Yang,
W.; MacDonald, A. C.; Wang, Z.; Cantin, M. J. Org. Chem. 2001, 66,
1966. See also ref 6c.
A second series of experiments was run with substrates
1d/1d′-1f/1f ′ bearing substituents that stabilize the trans-
located radicals by conjugation. The results are summarized
in entries 4-6 of Table 1. With phenyl (entries 4), cyano
(11) Burke, S. D.; Jung, K. W. Tetrahedron Lett. 1994, 35, 5837.
(12) A rate constant for the reduction of alkyl radicals by thiophenol of
1.3 × 108 M-1 s-1 has been reported: Franz, J. A.; Bushaw, B. A.; Alnajjar,
M. S. J. Am. Chem. Soc. 1989, 111, 268.
(13) (a) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc.,
Perkin Trans. 1 1992, 1659. (b) Capella, L.; Montevecchi, P. C.; Navacchia,
M. L. J. Org. Chem. 1996, 61, 6783.
(14) No reaction takes place between alkynes 1 and PhSSPh with AIBN
as an initiator.
(15) We believe that this is a fair comparison of two optimized methods
since slow addition of tin hydride using a syringe pump does not give
reproducible results with vinyl bromides. Under such conditions, the radical
precursors are partially recovered unreacted: Curran, D. P.; Kim, D.; Liu,
H. T.; Shen, W. J. Am. Chem. Soc. 1988, 110, 5900.
2564
Org. Lett., Vol. 6, No. 15, 2004

1i′ using both methods (entries 9). The formation of
benzothiophene derivatives such as 4i and 4h demonstrates
that thiophenol does not allow running of a very slow
hydrogen atom transfer. The only reaction that takes place,
at least partially under tin hydride conditions, is performed
with thiophenol.
Scheme 3
It was, however, possible to generate a nonstabilized
primary alkyl radical using the thiophenol method starting
from dimethyl 2-tert-butyl-2-propargylmalonate 5 (Scheme
4). The cyclized product 6 is isolated as a single product in
48% yield.
(entries 5), and ester (entries 6) substituents, a clear enhance-
ment of the amount cyclized versus uncyclized products is
observed when using the thiophenol-mediated process. For
the phenyl and the cyano group, the overall yield is also
improved with thiophenol relative to tin hydride. In the case
of the ester group, only a moderate yield (57%) of cyclized
product is obtained.16
Scheme 4
Table 1. Thiophenol versus Tin Hydride for the Generation of
Radicals via 1,5-Hydrogen Transfer According to Scheme 3
substrate
PhSH 2/3
Bu3SnHa (2′/3′)
1 or 1′:Y,Z
(yield)
(yield)
1
2
3
4
5
6
7
8
9
a : OCH2CH2O
b: OTBS, H
c: PhS, H
d : Ph, H
100:0 (90%)
100:0 (89%)b
100:0 (88%)c
100:0 (85%)d
100:0 (70%)e,f
100:0 (57%)g
100:0 (83%)
57:17h,i (-)
0:90k (54%)
58:42 (81%)
88:12 (87%)
Substrates bearing an alkyl substituent at the propargylic
position were investigated next (Scheme 5).17 Interestingly,
78:22 (76%)
69:31 (61%)
76:24 (83%)
87:13 (65%)
48:52 (73%)j
e: CN, H
f: CO2Et, H
g: Me, Me
h : Et, H
Scheme 5
i: H, H
d
a Taken from ref 4b. b Dr 62:38. c Dr 69:31. Dr 78:22. e gem-Diethyl
esters were used. f Dr 69:31. g Dr 76:24. h Benzothiophenyl derivative 4a
(26%). i Dr not determined. j Y ) Me, Z ) H. k Benzothiophenyl derivative
4i (10%).
Finally, the generation of simple alkyl radicals bearing no
extra stabilizing group was examined with substrates 1g/
1g′-1i/1i′ (entries 7-9, Table 1). The generation of a tertiary
alkyl radical from 1g/1g′ proves again to be more efficient
with the thiophenol method than with the tin hydride method
(entry 7). However, when attempting to generate secondary
alkyl radicals from 1h (entry 8), some reduced compound
3h is obtained together with the benzothiophene derivative
4h resulting from an intramolecular addition of the alkenyl
radical to the aryl moiety.13 The tin hydride method starting
from 1h′ was also described to be inefficient for this process.
Not surprisingly, very similar results are obtained when
attempting to generate a primary alkyl radical from 1i and
most of these substrates give very high yields of hydrogen
transfer. For instance, the generation of tertiary alkyl radicals
from 7a affords the cyclic compounds 8a in 90% yield.
Secondary alkyl radicals are efficiently generated from 7b
with this system, and the cyclized product 8b is isolated in
90% yield without formation of the benzothiophene deriva-
(17) For the stereochemistry nomenclature used in this paper, see: Panico,
R.; Powell, W. H.; Richer, J.-C. A Guide to IUPAC Nomenclature of
Organic Compounds, Recommendation 1993; Blackwell: Oxford, 1993.
(16) Fragmentation of the translocated radical to ethyl acrylate and a
malonyl radical cannot be excluded for this system.
Org. Lett., Vol. 6, No. 15, 2004
2565

tive (compare with substrate 1h, entry 8 in Table 1). It is
also worth mentioning that hydrogen atom abstraction
starting from 7a and 7b is completely regioselective. The
regioselectivity is explained by the presence of gem-diester
substituents (Thorpe-Ingold effect18) in the cyclic transition
state leading to 8a and 8b. Even the product 8c, resulting
from the cyclization of a primary alkyl radical generated from
7c could be observed. However, in this particular case, the
major product is the noncyclized product 9c. The ester-
subtituted substrate 7d gives the expected translocation-
cyclization product 8d in much better yield than 1f, the
substrate nonsubstituted at the propargylic position (Table
1, entry 6). The four examples of Table 2 demonstrate clearly
is at the origin of a rate acceleration similar to the one
observed by Jung in related Vic-disubstituted systems.19
In summary, we have developed an efficient procedure
for running cascade reactions involving 1,5-abstraction of a
hydrogen atom followed by a radical cyclization. Such
reactions are classically run under tin hydride conditions
starting from haloalkenes. In the procedure presented here,
alkenyl radicals are generated from easily available terminal
alkynes and thiophenol. This procedure eliminates the need
of using the toxic tributyltin hydride and gives a greater
amount of radical translocation products. Finally, the products
bear a phenylthio substituent that offers many opportunities
for further transformation. By proper design of gem- and
Vic-disubstituents effects, it is possible to generate efficiently
nonstabilized radicals via 1,5-hydrogen transfers. We believe
that this procedure strongly enhances the synthetic potential
of the translocation-cyclization reaction developed by
Curran. Application of this procedure for the preparation of
natural products containing fused and spirocycles is currently
under investigation.
Table 2. Effect of the Propargylic Effect on the
Thiophenol-Mediated H-Abstraction-Cyclization Process
According to Scheme 5
starting material
R
Y
Z
ratio
yield
7a
7b
7c
7d
nC5H11
nC5H11
iC3H7
CH3
nC5H11
H
CH3
H
H
100:0
100:0
20:80
100:0
90%a
90%b
c
Acknowledgment. This work was supported by the Swiss
National Science Foundation (Grant 21-67106.01) and by
the Roche Research Foundation (Grant to F.D.).
iC3H7
CO2Et
H
97%d
Supporting Information Available: Experimental pro-
cedures and characterizations of compounds 1-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a (r-2,t-3)/(r-2,c-3) 88:12.16 b Mixture (45:45:5:5) of diastereomers; (r-
2,t-3,c-4 and t-4)/(r-2,c-3,c-4 and t-4) 90:10. c Yield not determined. d (r-
2,t-3,c-4/(r-2,t-3,t-4) 85:15.
OL049162G
that a propargylic substituent has a very beneficial effect on
the rate of hydrogen transfer. The presence of vicinal
substituents (the propargylic substituent and the gem-diesters)
(18) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080. (b) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.
(19) Jung, M. E. Synlett 1999, 843.
2566
Org. Lett., Vol. 6, No. 15, 2004