4172
J . Org. Chem. 1998, 63, 4172-4173
Ta ble 1a
Ra tion a l Design of Ben zyl-Typ e P r otectin g
Gr ou p s Allow s Sequ en tia l Dep r otection of
Hyd r oxyl Gr ou p s by Ca ta lytic
Hyd r ogen olysis
Matthew J . Gaunt, J inquan Yu, and
J onathan B. Spencer*
University Chemical Laboratory, Lensfield Road,
Cambridge, CB2 1EW, U.K.
Received May 4, 1998
Benzyl protection of a hydroxyl group is one of the most
frequently used procedures in synthesis because of the mild
conditions involved in its removal by catalytic hydrogen-
olysis.1-3 The synthesis of polyhydroxylated compounds
often requires orthogonal protecting strategies to distinguish
between hydroxyl groups. It would be highly desirable to
develop a range of benzyl-type protecting groups with
different reactivities that can be sequentially removed via
catalytic hydrogenolysis. This requires a detailed under-
standing of the mechanism of the cleavage of the benzyl
oxygen bond by the palladium hydrogen species. Recently,
we have determined the amphipolar nature of the palladium
hydrogen bond (modes a , Mδ+ - Hδ-, or b, Mδ- - Hδ+) in
both homogeneous4 and heterogeneous5 hydrogenation of
alkenes. This has led us to test whether the electronic
properties of the aromatic group can influence the rate of
cleavage, which should in turn guide the development of
hydroxyl protecting groups with different reactivities.
The results in Table 1 show that the rate of debenzylation
can be dramatically affected by the electronic properties of
the aromatic ring. The substitution of the electron-with-
drawing trifluoromethyl group onto the aromatic ring se-
verely retards debenzylation under 1 atm of hydrogen. In
contrast, there is considerable acceleration by electron-
donating substituents, which suggests that the benzylic
carbon bears a partial positive charge in the transition state.
The hydrogenolysis of benzyl alcohols carried out in acetic
acid has shown that protonation of the hydroxyl group is
essential for the cleavage of the carbon-oxygen bond.6
Under the neutral conditions in our study, the reaction may
occur by protonation of the benzyl oxygen atom, through the
operation of mode b, Mδ- - Hδ+, to give a positively charged
benzylic carbon. Alternativly, it is possible that palladium
could act as a Lewis acid and coordinate to the benzyl oxygen
atom to promote the same electron-deficient transition state
(mode a , Mδ+ - Hδ-).
a
The reaction was monitored by 1H NMR, and k was calculated
from changes in concentration.
Sch em e 1
* Yields are based on 75-85% conversion of starting materials.
was proposed.7,8 The results with the linker experiments
(Scheme 1a) seem to contradict those obtained when only
one benzyl group is involved (Table 1).
Surface scientists have determined that the aromatic ring
lies flat on the metal surface for optimal coordination.9,10 It
is possible that substitution on the aromatic ring could have
an adverse steric effect that would interfere with the planar
geometry required for effective binding and thus reduce its
affinity for the metal surface. The linker experiments show
that the limited number of active sites on the palladium
surface could lead to a competition for adsorption sites
between substituted and unsubstituted benzyl groups. This
may explain why the least substituted benzyl group, al-
though not electronically favored, can still be preferentially
cleaved.
It is clear that for the rational design of selective benzyl
type protecting groups both electronic factors and adsorption
must be taken into account. For synthetic purposes, it would
be desirable to find a more labile group than the benzyl
group for protection of the hydroxyl functionality. We
anticipated that the 2-naphthylmethyl (NAP) group would
fulfill these criteria: it is electron rich and should have a
The large difference in reactivity within this range of
substituted benzyl groups suggests that they can be sequen-
tially deprotected, therefore proving useful in multistep
synthesis. To test the synthetic application of these groups,
competition experiments were conducted on model systems
with two differently substituted benzyl groups attached to
ethanediol (Scheme 1a). Surprisingly, the benzyl group was
cleaved first in competition with any of the substituted
benzyl groups. This phenomenon has been observed with
the 4-methoxybenzyl group (PMB); however, no explanation
(1) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis; J ohn Wiley & Sons, Inc.: New York, 1991.
(2) (a) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett.
1976, 3535. (b) Iverson T.; Bundle K. R. J . Chem. Soc., Chem. Commun.,
1981, 1240.
(7) Srikrishna, A.; Viswajanani, J . A.; Sattigeri, J . A.; Vijaykumar, D. J .
Org. Chem. 1995, 60, 5961.
(3) Czech, B. P.; Bartsch, R. A. J . Org. Chem. 1984, 49, 4076.
(4) Yu, J .; Spencer, J . B. J . Am. Chem. Soc. 1997, 119, 5257.
(5) Yu, J .; Spencer, J . B. J . Org. Chem. 1997, 62, 8618.
(6) Kieboom, A. P. G.; De Kreuk, J . F.; Van Berkum, H. J . Catal. 1971,
20, 58.
(8) Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1997, 38, 399.
(9) Lin, R. F.; Koestner, R. J .; Van Hove, M. A.; Somorjai, G. A. Surf.
Sci. 1983, 161.
(10) Held, G.; Bessent, M. P.; Titmuss, S.; King, D. A. J . Chem. Phys.
1996, 11305.
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Published on Web 06/26/1998