3
036 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Communications to the Editor
the phenyl and amido substituents in the reaction transition state.
Another possible interpretation of the results is that the amido
substituent of 1b, 1d, and 1f coordinates to the bromine atom
involved in the hydrogen atom abstraction [Br∴ NH(tBu)COR],
thereby facilitating reaction. Similar three-electron-bonded
species have been proposed as intermediates, for example, in
the reaction of amino acids with hydroxyl radical [HO∴ NH2-
-
11
CHRCO2 ] and in the radical-induced oxidation of sulfides
Figure 1. Neighboring group participation by the amido group in the
reactions to give the radicals 2b, 2d, and 2f.
1
2
[
RR′S∴ OCOR′′], and sulfide coordination of the bromine
1
3
atom [R2S∴ Br] has been demonstrated. A third alternative
is that the reactions of 1b, 1d, and 1f proceed Via the
corresponding N-bromoamides and involve intramolecular 1,4-
hydrogen transfer to the amidyl radicals. In these cases,
stereoselective loss of the pro-S hydrogen from 1b would be
expected, however, as this would involve less steric interactions
between the phenyl and phthalimido substituents. To confirm
this expectation, the N-bromoamides of 4a and 4b were prepared
by treatment with tert-butylhypobromite and photolyzed at reflux
in CCl4. The bromoamide derived from the (2S,3S)-deuteride
9
reactions, the deuterides 4a and 4b were treated with NBS.
The (2S,3S)-deuteride 4a gave a 1:1 mixture of the diastereomers
of 5, with each diastereomer containing 79% deuterium, whereas
the diastereomer 4b gave 5, with 66% deuterium retention.
4
a gave a mixture of the diastereomers of 5, with each
diastereomer containing 28% deuterium, whereas the bromo-
amide of the diastereomer 4b gave 5, with 85% deuterium
retention. These results correlate with a deuterium isotope effect
of 1.5 for the intramolecular 1,4-hydrogen atom transfer1 and
a stereoselectivity of 3.8 for abstraction of the pro-S hydrogen.
Clearly this stereochemical outcome is different to that observed
in the reactions of 4a and 4b with NBS and precludes the
involvement of amidyl radicals as intermediates in the reactions
of 1b, 1d, and 1f with NBS.
0,14
These results correlate with a deuterium isotope effect of 2.7
for the hydrogen atom transfer10 and a stereoselectivity of 1.4
for abstraction of the pro-R hydrogen. This selectivity is not
1
simply a result of steric effects. The H NMR spectra of 4a
and 4b and the respective coupling constants, JR,â, of 9.8 and
5
.8 Hz indicate that the preferred conformation of the S-
enantiomer of 1b is A. This is the only staggered conformation
which will give rise to the large coupling constant between the
R-proton and the pro-R â-hydrogen. In this conformation, any
steric interactions affecting the hydrogen atom transfer would
be expected to result in stereoselective loss of the pro-S
hydrogen, as this site is the less hindered to the approach of
the bromine atom and loss of this hydrogen would relieve steric
interactions between the phenyl and phthalimido groups. The
stereoselectivity is consistent with neighboring group participa-
tion by the amido substituent. Considering the conformations
B and C of 1b which have the correct orientation to undergo
In conclusion, all of the above evidence indicates that the
reactions of 1a-f with NBS involve anchimeric assistance in
hydrogen atom abstraction by the bromine atom, through
neighboring group participation by an adjacent protected car-
boxyl group. It appears that this may be a more specific
phenomenon than the examples of 1,3-participation in atom
1
-4
transfer reactions reported previously.
While 1,3-participa-
tion occurs in reactions involving either hydrogen or halogen
atom abstraction, with correspondingly electron rich or deficient
transition states, and is also reflected in the bridging of the
product radicals as determined by EPR spectroscopic studies,15
neighboring group effects observed in the present work are
apparently limited to hydrogen transfer reactions and the
stabilization of electron deficient reaction transition states.
JA953021F
(
11) M o¨ nig, J.; Chapman, R.; Asmus, K.-D. J. Phys. Chem. 1985, 89,
3
139-3144.
(
12) Glass, R. S.; Hojjatie, M.; Wilson, G. S.; Mahling, S.; G o¨ bl, M.;
Asmus, K.-D. J. Am. Chem. Soc. 1984, 106, 5382-5383. Asmus, K.-D.;
hydrogen atom transfer with direct interaction between the amide
group and the developing electron deficient center, the con-
former B would be preferred on steric grounds and stereose-
lective loss of the pro-R hydrogen from this conformer would
be expected.
G o¨ bl, M.; Hiller, K.-O.; Mahling, S.; M o¨ nig, J. J. Chem. Soc., Perkin Trans.
2
1985, 641-646. Mahling, S.; Asmus, K.-D.; Glass, R. S.; Hojjatie, M.;
Wilson, G. S. J. Org. Chem. 1987, 52, 3717-3724. Glass, R. S.; Petsom,
A.; Hojjatie, M.; Coleman, B. R.; Ducheck, J.; Klug, J.; Wilson, G. S. J.
Am. Chem. Soc. 1988, 110, 4772-4778.
(
13) Asmus, K.-D.; Bahnemann, D.; Bonifacic, M.; Gillis, H. A. Faraday
Several alternative explanations for the kinetic effects ob-
served in the reactions of 1a-f and 3a-f were considered, but
these are inconsistent with the stereoselectivity observed in the
reactions of 4a and 4b. In principal, the phthalimido group of
Discuss. 1978, 63, 213-225.
(
14) Although examples of intramolecular 1,4-hydrogen atom transfer
17
are rare, the reactions of the N-bromoamides of 1b, 4a, and 4b were shown
to be intramolecular by carrying out the photolyses to give the bromides
3b and 5 in the presence of other potentially reactive substrates.
1
a-f could be involved in neighboring group participation, but
(15) Krusic, P. J.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 846-860.
Cooper, J.; Hudson, A.; Jackson, R. A. Tetrahedron Lett. 1973, 831-834.
Lyons, A. R.; Symons, M. C. R. J. Chem. Soc., Faraday Trans. 2 1972,
this would be expected to result in stereoselective loss of the
pro-S hydrogen from 1b. This would occur from the conformer
A, whereas loss of the pro-R hydrogen would involve the
conformer C. Not only is the conformer C of much higher
ground-state energy, reaction Via that conformer would also
involve the development of additional steric interactions between
6
8, 622-630. Norman, R. O. C.; Storey, P. M. J. Chem. Soc. B 1971,
1009-1013. Griller, D.; Ingold, K. U. J. Am. Chem. Soc. 1973, 95, 6459-
6
460; 1974, 96, 6715-6720.
(
16) Easton, C. J.; Hutton, C. A. J. Chem. Soc., Perkin Trans. 1 1994,
3
545-3548.
(17) For examples, see: Brunton, G.; Griller, D.; Barclay, L. R. C.;
Ingold, K. U. J. Am. Chem. Soc. 1976, 98, 6803-6811. Brunton, G.; Gray,
J. A.; Griller, D.; Barclay, L. R. C.; Ingold, K. U. J. Am. Chem. Soc. 1978,
100, 4197-4200. Casarini, D.; Grossi, L.; Lunazzi, L.; Placucci, G. J.
Org. Chem. 1985, 50, 703-705. Gilbert, B. C.; Parry, D. J.; Grossi, L. J.
Chem. Soc., Faraday Trans. 1 1987, 83, 77-83. Vener, E. J.; Cohen, T.
J. Org. Chem. 1992, 57, 1072-1073.
(
9) Compounds 4a and 4b were prepared as previously described for
16
the corresponding methyl esters, each in approximately 98% diastereomeric
excess and with approximately 99% D1 incorporation.
(10) Based on the assumption that the isotope effects for loss of the pro-R
and pro-S hydrogens are identical.