Efficient Stereoselective Alkenylation through a Homolytic Domino Reaction Involving a 1,5 Sulfur-to-Carbon Translocation

Article abstract of DOI:10.1021/ja031766c

An effective method for cis-stereoselective attachment of functionalized alkenyl appendages to sp³ carbon is reported. This method is based on a free-radical process, involving a sequence of addition?elimination steps, resulting in alkenyl grou

Full text of DOI:10.1021/ja031766c

Published on Web 02/12/2004
Efficient Stereoselective Alkenylation through a Homolytic Domino Reaction
Involving a 1,5 Sulfur-to-Carbon Translocation
Edward E. Korshin, Yaroslav V. Bilokin, Hailin Zheng, and Mario D. Bachi*
Department of Organic Chemistry, The Weizmann Institute of Science, RehoVot 76100, Israel
Received December 17, 2003; E-mail: mario.bachi@weizmann.ac.il
Although being of great power when applied to C(sp2) electro-
Scheme 1
philes, transition metal-catalyzed cross-couplings suffer from basic
limitations in the case of C(sp3) electrophiles, especially of those
possessing â-hydrogen atoms.1 Indeed, while encouraging advance-
ments in the cross-coupling of C(sp2) nucleophiles with primary
alkyl electrophiles have been recently described,1,2 the couplings
of less active secondary alkyl halides or sulfonates were unsuc-
cessful,1 except for a few atypical cases.3,4 Far better results were
obtained by employing homolytic proximal addition-elimination
of secondary carbon-centered radicals to stannyl-,5 sulfonyl-,5a,6a,b
or sulfinylalkenes.6c Methods for intramolecularization via tempo-
rary connection can secure stereoselectivity during C-C bond
formation.7 Combination of temporary silicon connection and
intramolecular free-radical reactions provided an efficient tool for
the stepwise cis-stereoselective attachment of various carbon
appendages, including unsaturated ones.7-10 Of relevance to the
present work is a method for the stereocontrolled C-C bond
formation using temporary sulfur connection in a process combining
homolytic and heterolytic reactions.11 All homolytic translocations12
are widely applied for the preparation of biaryls through intramo-
lecular shift of aryl groups13 but have not been used for stereose-
lective attachment of alkenyl fragments to sp3-stereogenic carbon.14
Herein we report on a novel efficient method for cis-stereose-
lective C-alkenylation through a single homolytic domino reaction
involving a 1,5 translocation of functionalized alkenyl fragments
from divalent sulfur to secondary sp3 carbon. To test the feasibility
of this approach, pyrrolidine derivatives 1-8, bearing a free radical
precursor X (Br or I) at C(4) and an alkenylsulfide radical acceptor
on the side chain attached to stereogenic center C(2), were designed
(Scheme 1a). To minimize secondary reactions due to potentially
reactive products, crude reaction products were treated with acetyl
chloride/pyridine. An early experiment indicated that heating a
benzene solution of iodide 1 (R1 ) R2 ) CO2Et, PG ) Ts, X ) I)
with n-Bu3SnH and a catalytic amount of AIBN, under conditions
commonly used in translocation reactions,12-14 afforded the bridged
bicyclic sulfides 9 (R1 ) R2 ) CO2Et, PG ) Ts) as a mixture of
C(2) epimers in 77% total yield (Scheme 1a). Only traces of
translocation product 10 (R1 ) R2 ) CO2Et, PG ) Ts) were
detected in this experiment. The translocation process was then
generating the thiyl radical C, which is in equilibrium with thiol
D. The latter could also undergo two competitive polar reactions:
boosted by increasing the reaction temperature and decreasing the
hydrogen donor concentration. Indeed, slow addition (4.5 h) of
cyclization to bicyclic sulfide 9 and stannylation to tin sulfide E.
n-Bu3SnH into a solution of bromide 2 (R1 ) R2 ) CO2Et, PG )
Both D and E are eventually acetylated to 2,4-cis-disubstituted
Ts, X ) Br) in toluene at 110 °C increased the yield of translocation
pyrrolidine 10. Formation of bicycles of type 9 by hydrogen transfer
to radical B is accelerated as the reaction proceeds due to an increase
in the combined concentration of the two potent hydrogen donors:
n-Bu3SnH and thiol D. Therefore, to sustain the path leading to
the desired translocation products on account of that leading to the
bridged bicyclic sulfides of type 9, it is necessary to use a tin
mediator which is not a hydrogen donor. Such a mediator should
also act as a thiyl radical trap and thus would make redundant the
product 10 to 35%, although formation of 9 (56%) still prevailed.
Analysis of the reaction mechanism indicates that the incipient
carbon-centered radical A undergoes a 6-exo-trig cyclization to
carbon-centered radical B. Due to the bridged-bicyclic nature of
radical B, it is imperative that a new C(1)-C(2) bond is formed
with absolute stereoselectivity. Hydrogen transfer to B gives the
bicyclic sulfide 9. In a competing monomolecular step, carbon-
centered radical B undergoes â-scission of the C(2)-S bond,
9
2708
J. AM. CHEM. SOC. 2004, 126, 2708-2709
10.1021/ja031766c CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
pendages to an sp3 carbon atom through a new 1,5 S(II) f C
translocation.16 This method takes advantage of the particular
properties of the C-S bond and thiyl radicals. The intramolecular
cyclization to the bridged-bicyclic key radical intermediate B
guaranties an exclusive cis-stereochemistry of the products. Reaction
conditions are mild and are tolerated by a variety of functional
groups. Facile conversion of the styrylsulfanylmethyl group into
an aldehyde function opens an additional avenue for further
synthetic applications.
Table 1. Tri-n-butylstyryltin (11)-Mediated Homolytic 1,5 S f C
Translocation of Alkenyl Groups (Scheme 1)
substrate
product,
1
2
entry
R ; R
(E : Z)
X
PG
Ts
time/ha
yield (%)b
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8E
8Z
CO2Et; CO2Et
Ph; H
Br
I
Br
I
Br
I
Br
Br
7
4
7
4
7
4
7
7
12, 89
13, 82
14, 84
14, 86
15, 78
15, 69
16, 86
16, 89
(2:1)
(2:3)
(2:3)
(2:3)
(4:5)
Ts
CO2Me; H
CO2Me; H
CO2Me; H
CO2Me; H
H; Ts
Boc
Boc
Ts
Ts
Boc
Boc
Acknowledgment. This research was supported by the Israel
Science Foundation, founded by the Israel Academy of Sciences
and Humanities, and by Minerva Science Foundation, Germany.
E. E. K. thanks the Israel Ministry of Absorption for Giladi and
Kamea fellowships.
Ts, H
a A solution of substrate, styryltin 11 (3-4 equiv), and 1,1′-azobis(cy-
clohexanecarbonitrile) (ACN) (0.1 equiv) in toluene was heated for the
indicated time at 105 °C. b Isolated yields.
Scheme 2
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-387. (b) Luh,
T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. ReV. 2000, 100, 3187-3204.
(2) (a) Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 3718-3719. (b)
Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910-
3912.
(3) Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2002, 124, 6514-6515.
(4) (a) Thottathil, J. K.; Moniot, J. L. Tetrahedron Lett. 1986, 27, 151-154.
(b) Normant, J. F.; Mulamba, T.; Scott, F.; Alexakis, A.; Cahiez, G.
Tetrahedron Lett. 1978, 19, 3711-3712.
extra step of sulfur protection. These properties are known to be
characteristic for tri-n-butylstyryltin (11).15
(5) (a) Rosenstein, I. J. In Radicals in Organic Synthesis. Vol. 1: Basic
Principles; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
pp 50-71. (b) Baldwin, J. E.; Kelly, D. R. Chem. Commun. 1985, 682-
684. (c) Russell, G. A.; Ngoviwatchai, P.; Tashtoush, H. I. Organometallics
1988, 7, 696-702. (d) An, H.; Wang, T.; Maier, M. A.; Manoharan, M.;
Ross, B. S.; Cook, P. D. J. Org. Chem. 2001, 66, 2789-2801.
(6) (a) Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed. 1999,
38, 1943-1946. (b) Kalai, C.; Tate, E.; Zard, S. Z. Chem. Commun. 2002,
1430-1431. (c) Delouvrie´, B.; Fensterbank, L.; Lacoˆte, E.; Malacria, M.
J. Am. Chem. Soc. 1999, 121, 11395-11401.
Indeed, upon treatment of 4-bromopyrrolidines 2, 4, 6, and 8 or
4-iodopyrrolidines 3, 5, and 7 with tri-n-butylstyryltin (11) (3-4
equiv) and a radical initiator (ACN, 5-10%) in toluene at 105 °C,
a smooth reaction took place, furnishing the corresponding 2,4-
cis-disubstituted 4-alkenyl-2-(styrylsulfanyl)methylpyrrolidines 12-
16 in high yields (Scheme 1b, Table 1). In the final products 12-
16, the composition and connectivity of alkenyl appendages at C(4)
are the same as those in the alkenyl substituent on the sulfur atom
of the starting compounds 2-8. Irrespective of the CdC bond
geometry in precursors 2-8, migration of the unsaturated append-
ages resulted in E-alkenyl substituents at C(4) of pyrrolidines 12-
16. The CdC bond geometry of the C(2)-styrylsulfanylmethyl side
chain in 12-16 accounts for about 90% of E-isomer.
To widen the scope of this methodology, it was proved that the
styrylsulfanylmethyl group is a viable synthetic equivalent of the
formyl group. Since styrylsulfoxides are vinylogues of phenylsul-
foxides, it was expected that they should undergo a similar
Pummerer rearrangement to aldehydes. So far, Pummerer-type
transformations of alkenylsulfoxides to carbonyl compounds have
not been reported. We were pleased to find that selective low-
temperature (-30 °C) oxidation of sulfides 13-15 to sulfoxides
17-19, followed by treatment of the latter with TFAA and 2,6-
lutidine, afforded the aldehydes 20-22 in good yields (Scheme
2).
(7) (a) Cox, L. R.; Ley, S. V. In Templated Organic Synthesis; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 2000; pp 276-393. (b)
Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54, 2238-
2289. (c) Fensterbank, L.; Malacria, M.; Sieburth, S. McN. Synthesis 1997,
813-854. (d) Bols, M.; Skrydstrup, T. Chem. ReV. 1995, 95, 1253-1277.
(8) Pearce, A. J.; Mallet, J.-M.; Sinay, P. In Radicals in Organic Synthesis.
Vol. 2: Applications; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; pp 538-577.
(9) (a) Stork, G.; Suh, H. S.; Kim, G. J. Am. Chem. Soc. 1991, 113, 7054-
7056. (b) Mazeas, D.; Skrydstrup, T.; Doumeix, O.; Beau, J.-M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1383-1386.
(10) Sugimoto, I.; Shuto, S.; Matsuda, A. J. Org. Chem. 1999, 64, 7153-
7157.
(11) (a) Bachi, M. D.; Bar-Ner, N.; Melman, A. J. Org. Chem. 1996, 61, 7116-
7124. (b) Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 62, 1896-
1898. (c) Bachi, M. D.; Bilokin, Y. V.; Melman, A. Tetrahedron Lett.
1998, 39, 3035-3038.
(12) Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc. ReV. 2001, 30, 94-103.
(13) Reviewed in: Studer, A.; Bossart, M. Tetrahedron 2001, 57, 9649-9667.
(14) Related examples: (a) low-yielding desulfonylative 1,4 translocation of
styryl fragment from S(VI) to a primary sp3 carbon; Ko¨hler, J. J.;
Speckamp, W. N. Tetrahedron Lett. 1977, 18, 635-638. (b) Desulfony-
lative 1,4 S(VI) f sp2 C styryl shift: Godfrey, C. R. A.; Hegarty, P.;
Motherwell, W. B.; Uddin, M. K. Tetrahedron Lett. 1998, 39, 723-726.
(15) Russell, G. A.; Ngoviwatchai, P. Tetrahedron Lett. 1985, 26, 4975-4978.
(16) For a recent cis-stereoselective 1,4 Si f sp3 C transfer of some alkenyl
fragments through a Heck/sila-Stille sequence, see: Quan, L. G.; Cha, J.
K. J. Am. Chem. Soc. 2002, 124, 12424-12425.
In summary, we have elaborated an effective method for cis-
stereoselective attachment of various functionalized alkenyl ap-
JA031766C
9
J. AM. CHEM. SOC. VOL. 126, NO. 9, 2004 2709