An unusual route to deoxysugars by hydrogen atom transfer from cyclohexane. Possible manifestation of polar effects in a radical process

Full text of DOI:10.1021/ja9619622

9190
J. Am. Chem. Soc. 1996, 118, 9190-9191
Scheme 1
An Unusual Route to Deoxysugars by Hydrogen
Atom Transfer from Cyclohexane. Possible
Manifestation of Polar Effects in a Radical Process
Be´atrice Quiclet-Sire† and Samir Z. Zard*,†,‡
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-YVette, France
Laboratoire de Synthe`se Organique associe´ au CNRS
Ecole Polytechnique, 91128 Palaiseau, France
lent amount. Clearly, we had stumbled accidentally upon an
unusual radical chain reaction whereby cyclohexane is acting
as a surprisingly effective hydrogen atom donor. Hydrogen
abstraction from cyclohexane by highly reactive radicals (e.g.,
chlorine atoms or alkoxy radicals) has been known for a long
time,6 but as far as we know such a clean and effective hydrogen
atom transfer from cyclohexane to a saturated carbon radical
is unprecedented.
ReceiVed June 11, 1996
We have shown, over the past few years, that xanthates
represent a synthetically useful source of a variety of radical
species.1 As part of this work, we considered the possibility
of obtaining 2-thiosugars by generating an anomeric radical 2
from the corresponding xanthate 1, allowing it, by analogy with
the work of Giese and his collaborators,2,3 to migrate to the
2-position as in 3, and finally letting the transfer of the xanthate
group occur to give the isomeric xanthate 4, as outlined in
Scheme 1. Carbohydrates containing a xanthate group in the
anomeric position are known and readily accessible.4 Com-
pound 5a was therefore prepared from 1-deoxy-1-bromo-2,3,4,6-
tetra-O-acetylglucopyranose and sodium O-neopentylxanthate
and subjected to our usual reaction conditions, which consisted
in simply heating in cyclohexane in the presence of a suitable
peroxide initiator. In much of our work in this area, we have
successfully used cyclohexane alone or in mixtures with toluene
as the solvent for these reactions since benzene, which is the
most commonly used solvent for radical reactions,5 is toxic and
the trend is to replace it whenever possible. However, when a
refluxing solution of 5a in degassed cyclohexane was treated
with a small amount of lauroyl peroxide (6%), a rapid and clean
reaction ensued, but the product, isolated in 90% yield, turned
out to be 2-deoxy-1,3,4,6-tetra-O-acetyl-R-D-glucopyranose (6)
and not the expected rearranged xanthate 4. The other coproduct
was S-cyclohexyl-O-neopentylxanthate, produced in an equiva-
† Institut de Chimie des Substances Naturelles.
‡ Laboratoire de Synthe`se Organique.
(1) (a) Delduc, P.; Tailhan, C.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
1988, 308-310. (b) Mestre, F.; Tailhan, C.; Zard, S. Z. Heterocycles 1989,
28, 171-174. (c) Forbes, J. E. ; Zard, S. Z. Tetrahedron Lett. 1989, 30,
4367-4370. (d) Forbes, J. E.; Zard, S. Z. J. Am. Chem. Soc. 1990, 112,
2034-2035. (e) Forbes, J. E.; Tailhan, C.; Zard, S. Z. Tetrahedron Lett.
1990, 31, 2565-2568. (f) Boivin, J.; Camara, J.; Zard, S. Z. J. Am. Chem.
Soc. 1992, 114, 7909-7910. (g) Forbes, J. E.; Zard, S. Z. Tetrahedron
1993, 49, 8257-8268. (h) Axon, J.; Boiteau, L.; Boivin, J.; Forbes, J. E.;
Zard, S. Z. Tetrahedron Lett. 1994, 35, 1719-1722. (i) For a short review,
see: Zard, S. Z. Actual. Chim. 1993, (3), 10-14.
(2) (a) Giese, B.; Gilges, S.; Gro¨ninger, K. S.; Lamberth, C.; Witzel, T.
Liebiegs Ann. Chem. 1988, 615-617. (b) Giese, B.; Gro¨ninger, K. S. Org.
Synth. 1990, 69, 66-71. (c) Korth, H.-G.; Sustmann, R.; Gro¨ninger, K. S.;
Leising, M.; Giese, B. J. Org. Chem. 1988, 53, 4364-4369. (d) Giese, B.;
Kopping, B.; Chatgilialoglu, C. Tetrahedron Lett. 1989, 30, 681-684. (e)
Koch, A.; Lamberth, C.; Wetterich, F.; Giese, B. J. Org. Chem. 1993, 58,
1083-1089. (f) Koch, A.; Giese, B. HelV. Chim. Acta 1993, 76, 1687-
1701.
(3) Formal 1,2-migrations of acyloxy (Surzur, J.-M.; Tessier, P. C. R.
Acad. Sci. Fr. Ser. C 1967, 264, 1981-1984; Bull. Soc. Chim. Fr. 1970,
3060-3070) and related groups have been studied extensively, although a
coherent mechanistic picture has not yet emerged, see inter alia: (a) Crich,
D.; Filzen, G. F. J. Org. Chem. 1995, 60, 4834-4837. (b) Beckwith, A. L.
J.; Duggan, P. J. J. Chem. Soc., Perkin Trans. 2 1992, 1777-1783 and
references there cited.
(4) (a) Horton, D.; Hutson, D. H. AdV. Carbohydr. Chem. 1963, 18, 123-
199. For some recent examples, see: (b) Martichonok, V.; Whitesides, G.
M. J. Org. Chem. 1996, 61, 1702-1706. (c) Marra, A.; Shun, L. K. S.;
Gauffeny, F.; Sinay¨, P. Synlett 1990, 445-448. (d) Paulsen, H.; Rauwald,
W.; Weichert, U. Liebiegs Ann. Chem. 1988, 75-86. (e) Lundt, I.; Skelbæk-
Pedersen, B. Acta Chim. Scand. B 1981, B35, 637-642.
(5) (a) Curran, D. P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, pp 715-831. (b)
Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon
Bonds; Pergamon Press: Oxford, 1986. (c) Motherwell, W. B.; Crich, D.
Free Radical Chain Reactions in Organic Synthesis; Academic Press:
London, 1991.
In the same way, the benzoylated galactose xanthate 7a
furnished the corresponding 2-deoxy product 8 in 90% yield.
This conversion could also be accomplished using the ethyl
analogues 5b and 7b, but the yield (65 and 61%, respectively)
was lower. In the former case, a small amount (17%) of
ethylthio glycoside 5c, probably of ionic origin,4c was isolated.
A number of other carbohydrate neopentyl xanthate derivatives
were successfully reduced under similar conditions. Thus,
xanthate 9, derived from peracetylated methyl glucuronate, and
xanthates 11 and 13, from D-xylose and D-arabinose (ring flip
occurred in the latter case), respectively, produced compounds
10, 12, and 14 in high yield (80, 96, and 93%). The xanthate
group need not be in the anomeric position as illustrated by
example 15, a derivative of arabinose, which showed the same
reactivity and was easily converted into 16 (85%). No ben-
(6) (a) Nonhebel, D. C.; Tedder, J. M.; Walton, J. C. Radicals; Cambridge
University Press: Cambridge, 1979; Chapter 8. (b) Tedder, J. M. Quart.
ReV. 1960, 336-356.
S0002-7863(96)01962-2 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9191
Scheme 2
Scheme 3a
a Conditions: (i) 1,2-dichloroethane, di-lauroyl peroxide (5 mol %)
(ii) cyclohexane, di-lauroyl peroxide (4 mol %).
zoyloxy group migration occurs in this case. We also found
that it was possible to use the 1-bromo precursors as substrates
but the reaction was relatively inefficient and a much greater
amount of peroxide was needed to drive the reaction to
completion. Bromine atom abstraction by the cyclohexyl radical
to give the same anomeric radical 2 is apparently slower than
the equivalent, two-step transfer of the xanthate group (addition
to the thiocarbonyl then fragmentation).
A plausible mechanism for these transformations is portrayed
in Scheme 2. The success of the process hinges on at least
two considerations. The first is the fact that the reaction of
radical 3 with its xanthate precursor 1 is redundant,1a and
consequently this radical has a sufficiently long lifetime to be
able to react with cyclohexane. The second is of course the
hydrogen abstraction step which in this case must be especially
favored, since ordinary secondary radicals do not react with
cyclohexane to any significant extent under similar conditions.
This is further shown by the sluggish, relatively unclean, and
clearly non chain reaction of nucleoside derivative 171f when it
was subjected to the same conditions. The special behavior in
the present situation appears thus to be due to the electron-
attracting acetate or benzoate groups flanking the radical center,
which are absent in compound 17.
obtained by comparing the behavior of xanthates 19 and 20
under the usual reaction conditions. These substrates were easily
prepared in high yield (88 and 82%, respectively) by reacting
xanthate 18 with 1-decene and heptadecafluorodecene in 1,2-
dichloroethane in the presence of a small amount (4%) of lauroyl
peroxide (Scheme 3). In the event, when an equimolar mixture
of 19 and 20 in refluxing cyclohexane was treated with lauroyl
peroxide (4%), only the latter underwent reduction to 21 in 76%
yield. It is difficult to invoke steric effects in this instance,
whereas enhancement of the electrophilic character of the radical
arising from cleavage of the xanthate group by the powerful
electron-withdrawing perfluorinated chain must be quite sig-
nificant. This results in a considerable acceleration in the rate-
determining hydrogen abstraction step.11 Notice also that
precursor 20 was prepared in 1,2-dichloroethane which, because
of the presence of the electronegative chlorine atoms, does not
act as a hydrogen atom donor in this case, even though from a
thermodynamic stance, the stability of the ensuing radical would
have been easily comparable to that of a cyclohexyl radical.
This new reduction process illustrates what appears to be a
manifestation of polar effects in a hydrogen abstraction process
that is clearly not limited to carbohydrates. The preliminary
results presented here open the way to a number of synthetic
possibilities for exploiting the subtle factors that control the rates
and hence the selectivity of such radical reactions. But beyond
the more enduring fundamental aspects uncovered by this work,
it is perhaps worth underlining the extreme simplicity (and
cheapness) of the method from a preparative point of view.12
Barton and co-workers had noted the effect of an alkoxy or
acyloxy group in the â-position in lowering the temperature
required for deoxygenating certain thiocarbonyl ester type
derivatives and termed this the “â-oxygen effect”.7 Later studies
by Beckwith did not indicate a significant stabilization of the
ensuing radical by such substituents,8 and some uncertainty
remains as to whether this phenomenon is due essentially to
steric9 or polar10,11 effects. Our present work is strongly in favor
of the latter as the dominating factor. Further evidence was
Acknowledgment. We wish to thank Dr. Ge´rard Mignani of Rhoˆne-
Poulenc for a generous gift of heptafluorodecene.
(7) Barton, D. H. R.; Hartwig, W.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1982, 447-448.
Supporting Information Available: Experimental procedures for
the preparation and reduction of the xanthates, as well as a compilation
of spectral and analytical data of all new compounds (5 pages). See
any current masthead page for ordering and Internet access instructions.
(8) Beckwith, A. L. J. Chem. Soc. ReV. 1993, 22, 143-151 and references
cited.
(9) Crich, D.; Beckwith, A. L. J.; Chen, C.; Yao, Q.; Davison, I. G. E.;
Longmore, R. W.; Anaya de Parrodi, C.; Quintero-Cortes, L.; Sandoval-
Ramirez, J. J. Am. Chem. Soc. 1995, 117, 8575-8768.
(10) Jenkins, I. D. J. Chem. Soc., Chem. Commun. 1994, 1227-1228.
(11) (a) Busfield, W. K.; Grice, I. D.; Jenkins, I. D.; Monteiro, M. J. J.
Chem. Soc., Perkin Trans. 2 1994, 1071-1079. (b) Busfield, W. K.; Grice,
I. D.; Jenkins, I. D. J. Chem. Soc., Perkin Trans. 2 1994, 1079-1086. (c)
Kaushal, P.; Mock, L. H.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 2
1990, 1663-1670 and references cited. For reviews on the polar effects in
radical reactions, see: (d) Tedder, J. M. Angew. Chem., Int. Ed. Engl. 1982,
21, 401-410; Tetrahedron 1982, 38, 313-329. (e) Russell, G. A. In Free
Radicals; Kochi, J. K., Ed.; Wiley: New York, 1973; Vol. 1, Chapter 7.
JA9619622
(12) Typical experimental procedure: A solution of the xanthate (1 mmol)
in degassed cyclohexane (7 mL) or a 9:1 mixture of cyclohexane and 1,2-
dichloroethane was heated under reflux and lauroyl peroxide was added
portionwise (2% every 2 h) until the starting material was consumed (6-
15% was needed depending on the substrate). The solvents were evaporated
under reduced pressure, and the residue purified by chromatography on a
silica gel column to afford the deoxygenated derivative.