Tin-free and catalytic radical cyclizations

Article abstract of DOI:10.1021/ja0673276

H? transfer from CpCr(CO)₃H to the kinetically favored double bond of a 1,6-diene can be used to initiate a radical cyclization. The CpCr(CO)₃H can be regenerated by a hydrogen atmosphere, making the reaction catalytic as well as tin

Full text of DOI:10.1021/ja0673276

Published on Web 01/09/2007
Tin-Free and Catalytic Radical Cyclizations
Deborah M. Smith, Mary E. Pulling, and Jack R. Norton*
Department of Chemistry, Columbia UniVersity, 3000 Broadway, New York, New York 10027
Received October 12, 2006; E-mail: jrn11@columbia.edu
Table 1. Rates of H• Transfer to Alkenes from CpCr(CO)3H
Radical cyclization (eqs 1-3), invaluable for natural product
synthesis in the laboratory,1 has not been industrially useful because
of its reliance on toxic organotin reagents. Special procedures are
required to handle trialkyltin hydrides and the waste they generate,
and standard purification techniques often leave toxic levels of tin
compounds in the product.2 Methods catalytic in tin have been
developed,3 along with tin hydride reagents modified to make their
removal easier,4 but the need for alternatives to tin remains.5
Substitutes such as (Me3Si)3SiH,6 (Me3Si)3GeH,7 HGaCl2,8 and
HInCl29 contain a bond to hydrogen stronger than that in Bu3SnH10
and are therefore likely to be less reactive at H• transfer (eq 1).
Furthermore, these methods are stoichiometric in some other heavy
element, typically iodine, bromine, selenium, or sulfur, which is
abstracted by tin to generate the organic radical species (eq 2).
1
compound
kH1
(×
10-3) (M-1 s-
)
observed
1a: R1 ) R2 ) Ph, R3 ) Me
1b: R1 ) Ph, R2 ) R3 ) H
0.59
15.8
14
1a
3b
1c
1c: R1 ) CO2Me, R2 ) Me, R3 ) H
Scheme 1
rapidly than the b double bond, so the principal product of H•
transfer to 4 will be 5 (Scheme 1). Not only will 5 cyclize quickly
(kcycl for its carboethoxy analogue is 3.3 × 105 s-1 at 20 °C)19 but,
because it is tertiary, it will resist the transfer of a second H• leading
to 6, that is, its kH4 will be relatively small.
The diene 4 was synthesized from the iodoalkene 8 and commer-
cially available methyl 3-(dimethylamino)propionate in three steps
(eq 7).
Studer has remarked that “transition metal based hydrides are
promising alternatives to the tin hydrides.”11 The use of Cp2Zr-
(H)Cl as a tin hydride analogue in cyclizations of halo acetals has
been reported.12 However, the difference in strength between
transition metal-hydrogen bonds (typically 60 kcal/mol)13 and
Sn-H bonds (78 kcal/mol)10 allows a different approach to
generating radicals. The weaker M-H bond can transfer H• directly
to olefins. The transfer in eq 4 was reported by Sweany and Halpern
in 1977,14 and the transfer in eq 5 is essential in the catalysis of
chain transfer during the radical polymerization of MMA.15
The reaction of 4 with a catalytic quantity of CpCr(CO)3H was
disappointing, showing low turnover and only a small amount of
the carbocycle 9 along with the isomerization product 10 (eq 8).
In order to know which radicals are accessible via H• transfer,
we have looked at the reaction of various alkenes with CpCr(CO)3H
(Table 1),16 which has a Cr-H BDE of 61.5 kcal/mol.17 The extent
of hydrogenation per H• transfer for each alkene measures the ratio
of kH2 to ktr1 (eq 6), while the observed values of kH1 measure the
relative reactivity of these alkenes toward H• transfer. The data in
Table 1 for compounds 1a and 1b show that only alkenes with a
single substituent on the incipient radical center are extensively
hydrogenated, implying that a secondary radical is appreciably more
receptive to a second H• than a tertiary one.
The fact that 9 is reduced indicates that the cyclized radical 7
has accepted a H• from CpCr(CO)3H rather than donating a H• to
CpCr(CO)3• to afford the exocyclic alkene 11 (eq 9). Presumably,
the tertiary C-H bond in 7 is too hindered to permit approach of
the metalloradical and H• transfer (ktr3).
These kinetic data have enabled us to design a diene substrate 4
that can be cyclized by the H• transfer agent CpCr(CO)3H.18 Table
1 predicts that the a double bond in 4 will accept H• 25 times more
The formation of the isomerization product 10 in eq 8 suggested
that significant CpCr(CO)3• (which can abstract H• as in eq 10)
9
770
J. AM. CHEM. SOC. 2007, 129, 770-771
10.1021/ja0673276 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
was present. CpCr(CO)3• is formed as a byproduct of any
hydrogenation, such as that of 7, and is unavoidably present as an
impurity in CpCr(CO)3H.20
Reactions 11 and 14 illustrate an approach to radical cyclizations
that is both tin-free and catalytic, with the stoichiometric reductant
being hydrogen gas. These results suggest a mechanism involving
H• transfer for the cyclizations recently reported by van der Donk
and co-workers, with Ti(III) citrate as a reducing agent and vitamin
B12 as a catalyst.24
Acknowledgment. We are grateful to G. Abramo, E. Papish, M.
Arribas-Layton, and S. Cummings for preliminary work, to the Sames
group for use of their HPLC, to DOE Grant DE-FG02-97ER14807
for financial support, and to L. Tang, J. Choi, James Franz (PNNL),
and Marc Greenberg (Johns Hopkins) for helpful discussions.
As H2 is known to regenerate CpCr(CO)3H from CpCr(CO)3•,21
we carried out the reaction between CpCr(CO)3H and 4 under 30
psi of H2 at 22 °C (eq 11, Table 2). Filtration of the reaction mixture
through silica gel gave the cyclization products 9 and the
hydrogenation product 6, along with a small amount of the
isomerization product 10. Both diastereomers of 9 are formed, with
the major product reflecting the preference of the methyl substituent
for an equatorial position in a chair transition state (eq 12).22
Increasing the concentrations of CpCr(CO)3H and 4, or heating the
reaction to 50 °C, shortened the reaction time but increased the
extent of hydrogenation (Table 2).
Note Added after ASAP Publication. A correction was made
in the last paragraph and published ASAP on January 16, 2007.
Supporting Information Available: Experimental procedures,
spectroscopic data for all compounds, and spectra of cyclization
substrates and products. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon: New York, 1986. (b) Curran, D. P. Synthesis
1988, 417-439. (c) Stork, G.; Sher, P. M.; Chen, H.-L. J. Am. Chem.
Soc. 1986, 108, 6384-6385. (d) Parker, K. A.; Fokas, D. J. Am. Chem.
Soc. 1992, 114, 9688-9689. (e) Jasperse, C. P.; Curran, D. P.; Fevig, T.
L. Chem. ReV. 1991, 91, 1237-1286.
(2) (a) Boyer, I. J. Toxicology 1989, 55, 253-298. (b) Ingham, R. K.;
Rosenberg, S. D.; Gilman, H. Chem. ReV. 1960, 60, 459-539.
(3) (a) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 2554-2555. (b)
Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303-304. (c) Tormo,
J.; Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 5296-5297.
(4) (a) Curran, D. P.; Hadida, S.; Kim, S.-Y.; Luo, Z. J. Am. Chem. Soc.
1999, 121, 6607-6615. (b) Salomon, C. J.; Danelon, G. O.; Mascaretti,
O. A. J. Org. Chem. 2000, 65, 9220-9222. (c) Clive, D. L. J.; Wang, J.
J. Org. Chem. 2002, 67, 1192-1198. (d) Curran, D. P.; Yang, F.; Cheong,
J. J. Am. Chem. Soc. 2002, 124, 14993-15000. (e) Stien, D.; Gastaldi, S.
J. Org. Chem. 2004, 69, 4464-4470.
Table 2. Cyclization of 4 with CpCr(CO)3H
temp (
°
C)
[4] (M)
days
9:6:10a
22
22
50
50
0.13
0.30
0.13
0.06
10
4
4
72:21:7
63:29:8
62:26:11
62:23:15
(5) (a) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072-
3082. (b) Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108-1111. (c)
Gilbert, B. C.; Parsons, A. F. J. Chem. Soc., Perkin Trans. 2 2002, 367-
387. (d) Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Org. Biomol.
Chem. 2004, 2, 585-592.
10
a As determined by 1H NMR analysis of the products relative to an
internal standard. All conversions >95%.
(6) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194.
(7) Chatgilialoglu, C.; Ballestri, M.; Escudie, J.; Pailhous, I. Organometallics
1999, 18, 2395-2397.
(8) Mikami, S.; Fujita, K.; Nakamura, T.; Yorimitsu, H.; Shinokubo, H.;
Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 1853-1855.
(9) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002,
124, 906-907.
Consideration of the Thorpe-Ingold effect23 suggested construc-
tion of the substrate 13, with geminal substituents on the carbon
chain. The diene 13 was made from the alkene 12 in one step (eq 13).
(10) Laarhoven, L. J. J.; Mulder, P.; Wayner, D. D. M. Acc. Chem. Res. 1999,
32, 342-349.
(11) Studer, A.; Amrein, S. Synthesis 2002, 835-849.
(12) Fujita, K.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2001, 123, 3137-3138.
(13) Halpern, J. Acc. Chem. Res. 1982, 15, 238-244.
(14) Sweany, R. L.; Halpern, J. J. Am. Chem. Soc. 1977, 99, 8335-8337.
(15) (a) Gridnev, A. A.; Ittel, S. D. Chem. ReV. 2001, 101, 3611-3659. (b)
Tang, L.; Papish, E. T.; Abramo, G. P.; Norton, J. R.; Baik, M.-H.;
Friesner, R. A.; Rappe´, A. J. Am. Chem. Soc. 2003, 125, 10093-10102.
(16) Choi, J. W.; Tang, L.; Norton, J. R. J. Am. Chem. Soc. 2007, 129, 234-240.
(17) (a) Kiss, G.; Zhang, K.; Mukerjee, S. L.; Hoff, C. D.; Roper, G. C. J.
Am. Chem. Soc. 1990, 112, 5657-5658. (b) Tilset, M.; Parker, V. D. J.
Am. Chem. Soc. 1989, 111, 6711-6717.
Treatment of diene 13 with CpCr(CO)3H at 50 °C for 10 days
afforded the cyclization product 14 exclusively (eq 14, Table 3);
higher concentrations of 13 and CpCr(CO)3H led to clean cycliza-
tion after 1.5 days. The substituents may not only increase the rate
of cyclization (kcycl) but also decrease the rates of the competing
hydrogenation (kH4) and isomerization (kisom) reactions, although
they make the initial H• transfer slower.
(18) We are aware of no evidence that low-valent organochromium compounds
are significantly toxic.
(19) Newcomb, M.; Horner, J. H.; Filipkowski, M. A.; Ha, C.; Park, S.-U. J.
Am. Chem. Soc. 1995, 117, 3674-3684.
(20) See footnote 53 in reference 15b above.
(21) This reaction was originally reported by Fischer (Fischer, E. O.; Hafner,
W.; Stahl, H. O. Z. Anorg. Allgem. Chem. 1955, 47, 282), and later used
by Kondo (Miyake, A.; Kondo, H. Angew. Chem., Int. Ed. Engl. 1968, 7,
631-632) and Hoff (Kubas, G. J.; Kiss, G.; Hoff, C. D. Organometallics
1991, 10, 2870-2876). Related chromium hydrides have also been
prepared from H2: (a) Cooley, N. A.; Watson, K. A.; Fortier, S.; Baird,
M. C. Organometallics 1986, 5, 2563-2565. (b) Capps, K. B.; Bauer, A.;
Kiss, G.; Hoff, C. D. J. Organomet. Chem. 1999, 586, 23-30. (c) ref 17a.
(22) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc., Chem.
Commun. 1980, 482-483.
Table 3. Cyclization of 13 with CpCr(CO)3H
temp (
°
C)
[13] (M)
days
(23) Kaneti, J.; Kirby, A. J.; Koedjikov, A. H.; Pojarlieff, I. G. Org. Biomol.
Chem. 2004, 2, 1098-1103.
22
50
50
0.13
0.13
0.30
NR
10
1.5
(24) McGinley, C. M.; Relyea, H. A.; van der Donk, W. A. Synlett 2006,
211-214.
JA0673276
9
J. AM. CHEM. SOC. VOL. 129, NO. 4, 2007 771