Tandem radical reactions: Carbon monoxide addition to alkyl radicals and subsequent acyl radical cyclization onto N,N-diphenylhydrazones

Full text of DOI:10.1021/jo960507l

3580
J . Org. Chem. 1996, 61, 3580-3581
Sch em e 1. Ra d ica l Cycliza tion s on to Hyd r a zon es
Ta n d em Ra d ica l Rea ction s: Ca r bon
Mon oxid e Ad d ition to Alk yl Ra d ica ls a n d
Su bsequ en t Acyl Ra d ica l Cycliza tion on to
N,N-Dip h en ylh yd r a zon es
Irina M. Brinza and Alex G. Fallis*
Ottawa-Carleton Chemistry Institute,
Department of Chemistry, University of Ottawa,
10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
Sch em e 2. Rep r esen ta tive Acyl Ra d ica l
Cycliza tion s
Received March 15, 1996
Free-radical cyclizations have received considerable
attention in recent years and have been applied to a
number of synthetic targets with notable success.1
A
liability inherent in the cyclization of classical radical
precursors, such as unsaturated organic halides, is the
net loss of the two participating functional groups. This
severely limits, at an early stage in a synthetic sequence,
the use of conventional radical cyclizations. One solution
employs R-heteroatom radical intermediates, derived
from oxathiolanones, to generate products that retain
synthetically useful functionality for subsequent manipu-
lation.2 Atom transfer reactions also place functional
groups in predetermined positions.1c,d,e,f, 3 Alternatively,
if a heteroatom is present in the addition terminus the
efficiency improves and useful functionality remains in
the product. We have recently established that both halo
and carbonyl hydrazones cyclize directly to hydrazines
under either n-Bu3SnH- or SmI2-mediated conditions
(Scheme 1).4,5 These reactions display a high level of
diastereoselectivity. The carbonylhydrazones provide
rapid access to â-amino alcohols (a type of intramolecular
equivalent of an aza Barbier reaction) after samarium
diiodide-mediated hydrazine reduction of the cyclic prod-
ucts. Kinetic studies, based on an intramolecular com-
petition between alkene and hydrazone, revealed the
hydrazone cyclization rates were quite rapid.6 Thus, the
5-exo cyclization onto a N,N-diphenylhydrazone was
approximately 200 times faster than the intramolecular
capture by an olefin. These studies have also established
that with samarium diiodide these reactions were radical
cyclizations and did not involve anionic organosamarium
intermediates. We now wish to report that alkyl radicals,
generated under tributyltin hydride-mediated conditions
from haloprecursors, are trapped efficiently by carbon
monoxide. The resultant acyl radicals undergo intramo-
lecular cyclization onto N,N-diphenylhydrazones to yield
R-hydrazinocyclopentanones. Selective reduction of the
parent R-hydrazino ketone provides the corresponding
cis- or trans-â-hydrazino alcohols.
salophens, and S-acyl xanthates, which also afford cyclic
ketones upon intramolecular addition to alkenes. These
cyclic ketones are the major products, and usually
decarbonylation does not interfere. Scheme 2 illustrates
representative examples of these procedures.
Recent studies have supplied rate constants for both
the addition of carbon monoxide to primary alkyl radicals7d
and the corresponding decarbonylation reaction. The
rate constant for decarbonylation of a secondary acyl
radical (3.9 × 105 M-1 s-1 at 80 °C) is approximately 30
times faster than that for a primary acyl radical,9 while
the rate constants for the trapping of carbon monoxide
by primary and secondary radicals are similar (2.7 and
1.2 × 105 M-1 s-1 at 50 °C, respectively).7d The rate
constant for the 5-exo cyclization of a secondary alkyl
radical onto a hydrazone is 1.1 × 108 s-1 (80 °C). By
analogy, it appeared likely that acyl radical cyclizations
onto hydrazones should also be relatively rapid and allow
a direct tandem carbonylation-cyclization to yield amino-
and alkyl-substituted cyclic ketones upon trapping of the
initial alkyl radical by carbon monoxide.
The syntheses of the (E)-hydrazones 5-8 are described
in the supporting information. The routes involve either
alkylation of 1,3-dithiane with the appropriate dibromo-
alkene, deacetalization, and hydrazine condensation or
reduction of γ-butyrolactone, hydrazine condensation, oxi-
dation, Grignard addition, and conversion of the resulting
secondary alcohols to the corresponding bromides.
(5) For related hydrazone studies, see: (a) Kim, S.; Kee, I. S.; Lee,
S. J . Am. Chem. Soc. 1991, 113, 9882. (b) Kim, S.; Kee, I. S.
Tetrahedron Lett. 1993, 34, 4213. (c) Kim, S.; Cho, J . R. Synlett 1992,
629. (c) Shono, T.; Kise, N.; Fujimoto, T.; Yamanami, A.; Nomura, R.
J . Org. Chem. 1994, 59, 1730. (d) Kim, S.; Cheong, J . H.; Yoon, K. S.
Tetrahedron Lett. 1995, 36, 6069. (e) Bowman, W. R.; Stephenson, P.
T.; Terrett, N. K.; Young, A. R. Tetrahedron 1995, 51, 6069.
(6) Fallis, A. G.; Sturino, C. F. J . Org. Chem. 1994, 59, 6514.
(7) For leading references, see: (a) Ryu, I.; Kusano, K.; Ogawa, A.;
Kambe, N.; Sonoda, N. J . Am. Chem. Soc. 1990, 112, 1295. (b) Ryu, I.;
Kusano, K.; Hasegawa, M.; Kambe, N.; Sonoda, H. J . Chem. Soc.,
Chem. Commun. 1991, 1018. (c) Tsunoi, S.; Ryu, I.; Sonoda, H. J . Am.
Chem. Soc. 1994, 116, 5473. (d) Nagahara, K.; Ryu, I.; Kambe, N.;
Komatsu, M.; Sonoda, H. J . Org. Chem. 1995, 60, 7384. For a recent
review see: Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96,
177.
(8) For leading references on acyl radical reactions, see: (a) Pfen-
ninger, J .; Heuberger, C.; Graf, W. Helv. Chim. Acta 1980, 63, 2328.
(b) Boger, D. L.; Mathvink, R. J . J . Org. Chem. 1988, 53, 3377. (c) Crich,
D.; Fortt, S. M. Tetrahedron 1989, 45, 6581. (d) Schwartz, C. E.;
Curran, D. P. J . Am. Chem. Soc. 1990, 112, 9272. (e) Boger, D. L.;
Mathvink, R. J . J Org. Chem. 1992, 57, 1429. (f) Betty, D.; Crich, D.
J . Chem. Soc., Perkin Trans. 1 1992, 3193. (g) Crich, D.; Chen, C.;
Hwang, J .-H.; Yuan, H.; Papadatos, A.; Walter, R. I. J . Am. Chem.
Soc. 1994, 116, 8937. (h) Hayes, C. J .; Pattenden, G. Tetrahedron Lett.
1996, 37, 271. (i) Chen, L.; Gill, G. B.; Pattenden, G.; Simonian, H. J .
Chem. Soc., Perkin Trans. 1 1996, 31.
Recent years have witnessed an increased interest in
the free-radical carbonylation of alkyl radicals. The acyl
radicals generated in this manner afford cyclopentanones
by intramolecular addition to an alkene or lead to varied
products by multicomponent coupling depending upon
the nature of reactants selected.7 Previous studies have
demonstrated the utility of a variety of other acyl radi-
cal precursors,8 including selenides, tellurides, cobalt
* To whom correspondence should be addressed. Phone: (613)
562-5732. FAX: (613) 562-5170. E mail: AFALLIS@OREO.CHEM.
UOTTAWA.CA.
(1) For reviews, see: (a) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Pergamon Press: New York,
1986. (b) Curran, D. P. Synthesis 1988, 417. (c) Curran, D. P. Synthesis
1988, 489. (d) J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev.
1991, 91, 1237. (e) Fossey, J .; Lefort, D.; Sorba, J . Free Radicals in
Organic Chemistry; J ohn Wiley & Sons: New York, 1995.
(2) Yadav, V.; Fallis, A. G. Tetrahedron Lett. 1988, 29, 897;
Tetrahedron Lett. 1989, 30, 3283; Can. J . Chem. 1991, 69, 779.
(3) (a) Curran, D. P. In Free Radicals in Synthesis and Biology;
Minisci, F., Ed.; Kluwer: Dordrecf, 1989; p 37. (b) Curran, D. P.;
Tamine, J . J . Org. Chem. 1991, 56, 2746.
(9) (a) Chatgilialoglu, C.; Lucarini, M. Tetrahedron Lett. 1995, 36,
1299. (b) Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.; Pedrielli, P.;
Pedulli, G. F. Organometallics 1995, 14, 2672.
(4) Fallis, A. G.; Sturino, C. F. J . Am. Chem. Soc. 1994, 116, 7447.
S0022-3263(96)00507-5 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 11, 1996 3581
Ta ble 1. Ta n d em Ra d ica l-Ca r bon yla tion -Cycliza tion s
Ta ble 2. Cyclop en ta n on e Red u ction s
entry substrate
R
product yield,a
%
ratio cis/transb
1
2
3
4
5
6
7
8
H
9
69
75
71
67
Me
i-Pr
Cy
10/11
12/13
14/15
1:1
1:1.1
1:1.2
9
a
Yields are for isolated chromatographically homogeneous
16/17
material. Ratios were determined from 1H NMR analysis of total
b
product mixture.
16/17
16/17
16/17
Sch em e 3. Ca r bon Mon oxid e Tr a p p in g a n d
Cycliza tion on to Hyd r a zon es
16/17
16/17
19
10
18
18/19
18/19
21
20
20/21
20/21
9
3
4
presence of tris(triphenylphosphine)ruthenium(II) chlo-
ride catalyst.14 The selectivity of the reductions varied
with the substitution pattern of the parent ketone. Thus,
the use of L-Selectride also gave the cis isomer 18 upon
reduction of the ketone 10 (Table 2, entry 7). Mixtures
were obtained in the other methyl-substituted cyclopen-
tanone examples; however, the alcohol products were
separated cleanly by flash chromatography. Thus, all the
possible diastereomers could be prepared depending upon
the method selected.
In conclusion, hydrazones are useful acyl radical ac-
ceptors for intramolecular cyclization reactions to afford
cyclopentanones15 in which the initial alkyl radicals are
trapped with carbon monoxide. Subsequent ketone
reduction provides direct access to the corresponding
cyclopentyl â-hydrazino alcohols.
The results of the trapping-cyclization studies are
summarized in Table 1, and the products arise from the
pathway illustrated in Scheme 3. The desired R-hydazino
ketones were produced in reasonable yields but with a
disappointing level of stereoselectivity. However, the
isomers can be separated readily by flash chromatogra-
phy. In addition to the ketone products, 10-12% of
reduced alkylhydrazone substrates were also isolated.
Similar products were observed previously during carbon
monoxide-trapping studies of cyclizations onto alkenes.7b
However, there was no evidence of any aldehyde that
would have arisen from direct quenching of the interme-
diate acyl radical. Both the experimental procedure and
the structural assignments of the products were straight-
forward.10,11 Neither the yields nor the stereoselectivity
of the cyclic ketones were altered significantly upon
varying the pressure from 800 to 1100 psi.
In view of the current interest in the synthesis of
â-amino alcohols as potential glycosidase and chitinase
inhibitors,12 a series of carbonyl reductions to prepare the
corresponding hydrazino alcohols were performed. As
tabulated (Table 2), ketone 9 (Table 2, entry 4) afforded
only the cis isomer 16 upon reduction with L-Selectride.13
In contrast, the trans isomer 17 was generated exclu-
sively (Table 2, entry 6) upon hydrogenation of 9 in the
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
for financial support of this research.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data (25 pages).
J O960507L
(12) For leading references, see: (a) Trost, B. M.; VanVranken, D.
L. J . Am. Chem. Soc. 1993, 115, 444. (b) Simpkins, N. S.; Stokes, S.;
Whittle, A. J . Tetrahedron Lett. 1992, 33, 793. (c) King, S. B.; Ganem,
B. J . Am. Chem. Soc. 1994, 116, 562. (d) Corbett, D. F.; Dean, D. K.;
Robinson, S. R. Tetrahedron Lett. 1994, 35, 459. (e) Goering, B. K.; Li,
J .; Ganem, B. Tetrahedron Lett. 1995, 36, 8905. (f) Nishimura, Y.;
Umezawa, Y.; Adachi, H.; Kondo, S.; Takeuchi, T. J . Org. Chem. 1996,
61, 480.
(13) (a) Tanis, S. P.; Chuang, Y.-H.; Head, D. B. J . Org. Chem. 1988,
53, 4929. (b) Knapp, S.; Levorse, A. T. J . Org. Chem. 1988, 53, 4006.
(14) (a) Devlin, J . A.; Robins, D. J . J . Chem. Soc., Chem. Commun.
1981, 1272. (b) Zonan, A.; Sasson, Y. J . Org. Chem. 1981, 46, 255.
(15) A reviewer has recommended that this study be extended to
six-membered rings. However, this would be a rather dubious under-
taking as the rate for the 5-exo cyclization onto the hydrazone exceeds
the rate of addition of a secondary radical onto carbon monoxide by
approximately 103.
(10) A 0.05 M benzene solution of hydrazone containing 5-10 mol
% AIBN and tributyltin hydride (1.2 equiv) was placed in a glass-
lined steel autoclave and heated at 80 °C under an atmosphere of
carbon monoxide at a pressure of 1100 psi for 5 h. The autoclave was
cooled to 21 °C, the pressure released, and the benzene evaporated.
Ether addition followed by a saturated aqueous potassium fluoride
wash (4 mL), filtration, drying, and flash chromatography (60/40
dichloromethane/petroleum ether) afforded the cyclopentanone
products.
(11) The relative stereochemistries were established by NOE 1H
NMR experiments. As has been observed previously, the 13C NMR
resonances for both methine carbons in the cis isomer appeared at
higher field than those for the trans isomer.4 Ley, G. C.; Lichter, R.
L.; Nelson, A. L. Carbon-13 Nuclear Magnetic Resonance for Organic
Chemists, 2nd ed.; J . Wiley and Sons; New York, 1980. Bartlett, P. A.;
McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc. 1988, 110, 1633.