Novel cobalt-mediated regio- and strereoselective radical cyclization

Full text of DOI:10.1021/ja971852a

J. Am. Chem. Soc. 1997, 119, 9053-9054
9053
Scheme 1
Novel Cobalt-Mediated Regio- and Stereoselective
Radical Cyclizations
Karen L. Salazar, Masood A. Khan, and
Kenneth M. Nicholas*
Department of Chemistry and Biochemistry
UniVersity of Oklahoma, Norman, Oklahoma 73019
ReceiVed June 5, 1997
The discovery of efficient, radical-based carbon-carbon
bond-forming reactions has provided a powerful new array of
tools for organic synthesis.1 Especially valuable are intramo-
lecular radical additions to carbon-carbon double bonds as
typified by the 5-hexenyl radical cyclization (eq 1).2
A
distinctive and useful feature of this reaction is the kinetically-
controlled, highly regioselective formation of five-membered
rings. The levels of stereoselectivity for such reactions,
however, are less useful, e.g., 1-substituted 5-hexenyl radicals
undergo cyclization generally with only a modest preference
for cis-1,2-disubstituted cyclopentanes.3
treatmentof alcohol 4a7,8 with excess HBF4‚Et2O at -30 ° C in
ether precipitated salt 3a which reacted with Zn powder in CH2-
Cl2 to produce a single cyclized product 5a (38%). NMR
analysis of 5a indicated the presence of only one isomer,
established as the trans cyclopentane derivative by X-ray
diffraction (Scheme 1).8,9
The unusual trans stereoselectivity of this reaction, coupled
with its modest yield, prompted us to seek a more efficient and
general method for cyclization. Accordingly, little known, labile
propargyl bromide-Co2(CO)6 complexes,10 i.e., 6a-d, were
prepared by treatment of the alcohols 4a-d (CH2Cl2, 0 °C) with
2Br2‚(Ph2PCH2CH2PPh2)11 (Scheme 1).8 A CH2Cl2 solution of
6a (R ) CO2Me) reacted with Et3B and Bu3SnH or Ph2SiH2 at
20 °C, producing a 1.0:1.8 separable mixture (70% yield from
4a) of the expected trans 5a and a compound suspected to be
the Br-atom transfer product 7a based on its spectroscopic
properties (Vide infra).
Serendipitously, it was discovered that neat samples (or a
benzene solution) of oily cis/trans-6b (R ) Ph) left in laboratory
sunlight or briefly irradiated with a 300 W sunlamp were
conVerted exclusiVely to the atom transfer product trans-7b
(76% from 4b; Scheme 2).9 This remarkably facile photo-
cyclization appears to be quite general as the bromides 6a, c,
and d (R′ ) CO2Me, Me, and H) also underwent ready
conversion to cycloisomerized products.12 The regiochemical
course of these reactions depends dramatically on the C-6
substituent. Irradiation of the ester trans-6a, like the phenyl
derivative 6b, caused its smooth conversion to trans 7a (56%
from 4a). However, the bromide 6c (R ) Me) afforded a
We recently initiated a program to investigate the chemistry
of carbon-centered organotransition metal radicals, wondering
whether sterically and electronically influential organometallic
units, which have powerful effects on carbocation5 and carban-
ion reactivity,6 can induce extraordinary radical reactivity.
Indeed, initial studies of (propargyl)Co2(CO)6-radicals (1)4 have
uncovered some of the highest diastereoselectivities known for
radical dimerizations.4b We now report that cyclizations of
1-(alkynyl)Co2(CO)6-5-hexenyl radicals (2) not only proceed
with exceptionally high trans-1,2-stereoselectivity in the 5-exo
mode but also exhibit novel regioselectivity that is remarkably
sensitive to the 6-position substituent.
Initially, we sought to generate the radicals 2 by reduction
of the cobalt-stabilized cations, e.g., 3a (Scheme 1). Thus,
(7) Complexes 4 were prepared in good yield by addition of lithium
phenylacetylide to glutaraldehyde, reaction of the resulting hemiacetal with
Ph3PCHR′ (R ) CO2Me, Ph, Me, H) and complexation of the en-yn-ol
with Co2(CO)8.
(1) Reviews: (a) Curran, D. P. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon: London, 1991; Vol. 4, Chapters 4.1 and 4.2.
(b) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon
Bonds; Pergamon: London, 1986. (c) Giese, B. Vol. 18 of Houben-Weyl’s
Methoden der Organischen Chemie, C-Radikale; Verlag: Stuttgart, 1989.
(2) (a) Giese, B.; Kopping, B. Gobel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K. J.; Trach, F. Radical Cyclization Reactions. In Organic
Reactions; Paquette, L., Ed.; Wiley: New York, 1996; pp 301-856. (b)
Beckwith, A. L. J.; Ingold, K. U. Free Radical Rearrangments. In
Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic
Press: New York, 1980; Vol. 1, pp 162-310.
(3) Curran, D. P.; Porter, N. A.; Geise, B. In Stereochemistry of Radical
Reactions; VCH: Weinheim, 1996; pp 30-76, and references therein.
(4) (a) Melikyan, G. G.; Vostrowsky, O.; Bauer, W.; Bestmann, H. J.;
Khan, M. A.; Nicholas, K. M. J. Org. Chem. 1994, 59, 222. (b) Melikyan,
G. G.; Combs, R. C.; Lamirand, J.; Khan, M. A.; Nicholas, K. M.
Tetrahedron Lett. 1994, 35, 363. (c) Melikyan, G. G.; Khan, M. A.;
Nicholas, K. M. Organometallics 1995, 14, 2170.
(8) Preparative procedures and spectroscopic and analytical data for new
compounds are provided in the Supporting Information.
(9) The structures of 5a, 7b, and 8d were established by X-ray diffraction;
crystal data and collection details are provided in the Supporting Information.
(10) Examples of (propargyl halide)Co2(CO)6 are few and poorly
characterized. (a) Tirpak, M. R.; Hollingsworth, C. A.; Wotiz, J. H. J. Org.
Chem. 1960, 25, 687. (b) Melikyan, G. G.; Mkrtchyan, V. M.; Atanesyan,
K. A.; Asaryan, G. K.; Badanyan, S. O. Bioorg. Khim. 1990, 16, 1000. (c)
Vizniowski, C. S.; Green, J.; Breen, T. L.; Dalacu, A. V. J. Org. Chem.
1995, 60, 7496.
(11) Schmidt, S. P.; Brooks, D. W. Tetrahedron Lett. 1987, 28, 767.
(12) General procedure for 4 f 6 f 7, 8: Under N2 0.21 mmol of Ph2-
PCH2CH2PPh2 dissolved in 14 mL of CH2Cl2 was treated with bromine
(0.24 mmol) in 3 mL of CH2Cl2 at 0 °C followed by 0.21 mmol of the
alcohol 4 in 3 mL of CH2Cl2; the mixture was stirred for an hour. Addition
of pentane and diethyl ether (1:2:4 CH2Cl2:Et2O:pentane) produced a white
precipitate. The mixture was filtered through Celite under N2 and
concentrated under vacuum, and crude 6 was then placed under a 300 W
GE Halogen Floodlight (ca. 0.5 m) for an hour. The products 7 and 8 were
purified by column chromatography over silica gel or deactivated alumina.
(5) Watts, W. E. Ferrocenyl Carbocations and Related Species. J.
Organometal. Chem. Lib. 1979, 7, 399. Nicholas, K. M. Acc. Chem. Res.
1987, 20, 207.
(6) Davies, S. G. Organotransition Metal Chemistry: Applications to
Organic Synthesis; Pergamon: Oxford, 1982; pp 209-214.
S0002-7863(97)01852-0 CCC: $14.00 © 1997 American Chemical Society

9054 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Communications to the Editor
Scheme 2
Scheme 3
mixture of isomeric products (60% from 4c), comprised of the
trans cyclopentyl compound 7c (2:1 stereoisomeric at C-6) and
a comparable amount of the cyclohexyl derivative 8c (isomeric
mixture). This rare 6-endo-trig pathway became the exclusive
one when the parent complexed bromide 6d was irradiated, the
stereoisomeric cyclohexyl derivatives 8d being the sole products
(2:1 trans/cis, 73% from 4d).9
The ready cyclization of 6 having either electron-rich or
-deficient double bonds is both synthetically promising and
consistent with an intervening radical process. That the special
reactivity of the radicals 2 derives from the -Co2(CO)6 unit is
apparent since the uncomplexed bromide 9d was unchanged
after being irradiated neat for 3 h or 24 h in the presence of
Sn2Bu6 (cf. reaction of 6 in Scheme 2).13 The exclusive trans
stereoselectivity observed in the cyclizations of 6 stands in
contrast to the moderate cis preference typical of most 1-sub-
stituted hexenyl substrates.3,14 Even more striking, however,
is the extent to which the ring size depends on the 6-substituent,
ranging from exclusively 5-exo (when R ) Ph, CO2Me) to
6-endo (with R ) H).15
The distinctive regio- and stereoselectivity of the reactions
of 6 can be rationalized in terms of an atom transfer mechanism
having a late, product-like, transition state for cyclization
(Scheme 3). This process is presumably initiated by cobalt-
assisted photoinduced homolysis of the C-Br bond to generate
radical 2 which may be stabilized by metal coordination.17 As
such, the transition states for the cyclization of 2 (A vs B) would
involve significant C-C bond making (and breaking) as well
as the development of radical character at the original olefinic
carbons. With a strongly radical-stabilizing group at C-6 (e.g.,
Ph or CO2R) the 5-exo transition state A is favored because it
allows delocalization of the developing radical at C-6. More-
over, steric interactions between the bulky (alkyne)Co2(CO)6
unit and the -CHR group would be amplified in this later,
probably “boat-like” transition state,3 which could account for
the high trans stereoselectivity. The 6-endo transition state B
may be preferred for R ) H since it develops secondary radical
character at C-5 (vs primary C-6 radical character as in A).
When R ) Me, the choice (A vs B) is between two incipient
(and similarly energetic) secondary radicals.18
Our studies to date of the propargyl-cobalt radicals 1 and 2
presage that new and unusual reaction selectivity will be
associated with carbon-centered organometallic radicals. Efforts
to further elucidate the origin of this selectivity and to exploit
it in organic synthesis are underway.
Acknowledgment. We are grateful for partial financial support by
the Petroleum Research Fund of the American Chemical Society
(27375AC) and a Patricia Roberts-Harris Fellowship to K.L.S.
Supporting Information Available: Characterizational data for
4-8 and details of crystal structure determinations, diagrams, listings
of bond distances, bond angles, hydrogen atom coordinates, and thermal
parameters for 5a, 7b, and 8d (54 pages). See any current masthead
page for ordering and Internet access instructions.
JA971852A
(13) Atom transfer cyclizations of typical hexenyl halides require radical
initiators and bromides react inefficiently. (a) Curran, D. P. Synthesis 1988,
489. (b) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986,
108, 2489. (c) Giese, B.; Horler, H.; Leising, M. Chem. Ber. 1986, 119,
444. (d) Curran, D. P. Chang, C.-T. Tetrahedron Lett. 1987, 28, 2477. (e)
Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong, C. M.; Chang, C.-T. J.
Am. Chem. Soc. 1989, 111, 8872. (f) Curran, D. P.; Chang, C.-T. J. Org.
Chem. 1989, 54, 3140.
(14) The trans stereoselectivity exceeds that of substrates with bulky or
heteroatomic groups. (a) Beckwith, A. L. J.; Cliff, M. D.; Schiesser, C. H.
Tetrahedron 1992, 48, 4641. (b) Keck, G. E. Tafesh, A. M. Synlett 1990,
257. (c) Curran, D. P. Shen, W. J. Am. Chem. Soc. 1993, 115, 6051. (d)
Ueno, Y.; Khare, R. K.; Okawara, M. J. Chem. Soc., Perkin Trans. 1 1983,
2637.
(17) There are scattered reports of dimerizations presumed to involve
metal-complexed organic radicals, but the stability and structure of these
species are essentially unknown. (a) Baker, C.; Horspool, W. H. J. Chem.
Soc., Perkin Trans. I 1979, 1862, 2294, 2298. (b) Forrester, A. R.; Hepburn,
S. P.; Dunlop, R. S.; Mills, H. H. J. Chem. Soc., Chem. Commun. 1969,
698. (d) Creary, X.; Mehrsheikh-Mohammadi, M. E.; McDonald, S. J. Org.
Chem. 1989, 54, 2904. (e) Top, S.; Jaouen, G. J. Organomet. Chem. 1987,
336, 143. (f) Schmalz, H.-G.; Siegel, S.; Bats, J. W. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2383. (g) Le Berre-Cosquer, N.; Kergoat, R.; L’Haridon,
P. Organometallics 1992, 11, 721. (h) Meyer, A.; McCabe, D. J.; Curtis,
M. D. Organometallics 1987, 6, 1491. (i) Sapienza, R. S.; Riley, P. E.;
Davis, R. E.; Pettit, R. J. Organomet. Chem. 1976, 121, C35. (j) Pearson,
A. J.; Chen, Y.-S.; Daroux, M. L.; Tanaka, A. A.; Zettler, M. J. Chem.
Soc., Chem. Commun. 1987, 155. (k) Casty, G. L.; Stryker, J. M. J. Am.
Chem. Soc. 1995, 117, 7814.
(15) Substrates which previously have exhibited appreciable 6-endo
selectivity either have been 5-substituted (sterically blocking the 5-exo mode,
ref 13f) or conformationally biased (e.g., R-halo carbonyl compounds, ref
13f) or produce radicals which cyclize reversibly (under thermodynamic
control, ref 16).
(18) We cannot exclude the possibility that the product distribution is
determined by a thermodynamically controlled (i.e., reversibly formed) ratio
of the radicals 9 and 10. However, product formation from 9 or 10 apparently
is not reversible since irradiation of 7c in the presence of a trace of 6c as
initiator gave no NMR-detectable amount of the isomeric 8c.
(16) Julia, M. Acc. Chem. Res. 1971, 4, 386.