C O M M U N I C A T I O N S
Scheme 1
Figure 1. Postulated transition state for the second step of the substitution
reaction.
step.14 The interaction between the zirconium atom and the leaving
group in the proposed transition state provides an explanation for
the unusual propensity of allylic ethers to undergo the substitution
reaction and is in agreement with the established Lewis acidity and
oxophilicity of zirconium imido complexes.12 Furthermore, the
presence of an unfavorable steric interaction between the TBS group
and R3 (see Figure 1) in the proposed transition state is consistent
with the lower reactivity of E-substituted allylic ethers.
Scheme 2
In conclusion, we have discovered a new reaction of zirconium
imido complexes that allows regio- and stereospecific transforma-
tion of allylic ethers directly into Cbz-protected allylic amines. We
have also proposed a mechanism that is consistent with our studies
of reaction kinetics, the measured secondary kinetic isotope effect,
and the observed regio- and stereospecificity of the reaction. These
results provide further insight into the reactivity of zirconium imido
complexes and may facilitate the development of practical methods
for the SN2′ substitution reactions.
Another important feature of the substitution reactions with 2 is
complete chirality transfer observed in the reactions with enan-
tioenriched 1,3-disubstituted allylic ethers. The reaction of (R)-4
with 2 resulted in the regio- and stereospecific formation of (R)-5
in 91% yield (Scheme 1). Similarly, the reaction with (R)-6
produced only the rearranged product (R)-7 as a single diastereo-
isomer. These experiments demonstrated the use of the SN2′
substitution reaction in a highly stereoselective synthesis of
enantioenriched allylic amines and also allowed us to determine
the stereochemistry of the reaction. The absolute configuration of
5 revealed that the substitution proceeds with syn stereochemistry.
Intrigued by this stereospecificity and the regiospecificity observed
with all other substrates, regardless of their structure, we decided
to study the mechanism of the reaction between 2 and the allyl
tert-butyldimethylsilyl (TBS) ether in more detail.
Acknowledgment. This work was supported by the NIH
through Grant No. GM-25459 to R.G.B., and by the NSF through
a graduate fellowship to S.A.B.
Supporting Information Available: Experimental procedures and
spectral data for products (PDF). This material is available free of charge
References
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1
The reaction with TBS allyl ether was monitored by H NMR
spectroscopy. In the presence of excess THF and substrate, the
reaction exhibits pseudo-first-order behavior with no observable
intermediates.11 The first-order rate constant for the reaction (kobs
) (5.47 ( 0.01) × 10-4 s-1, at 21.5 °C) is independent of the
initial concentration of 2, indicating that the overall reaction is first
order in 2. From the pseudo-first-order rate constants obtained in
the presence of various concentrations of THF, we also established
that the overall reaction is inverse first order in THF. On the basis
of these results and the mechanisms of related reactions of
zirconium imido complexes,12 we propose that the substitution
reaction involves reversible dissociation of THF, followed by the
rate-limiting substitution step (Scheme 2). In agreement with the
rate law (Scheme 2), we observed that at a high ratio of allylic
substrate and THF concentrations kobs becomes independent of their
concentrations. By measuring kobs at different concentrations of THF
and allylic ether, we were able to extract values for k1 ) (1.4 (
0.1) × 10-3 s-1 and k2/k-1 ) (2.2 ( 0.2) × 10-2 at -7.55 °C.
Consistent with the C-N bond formation in the rate-determining
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the measured pseudo-first-order rate constants for the reactions with
TBS allyl ether and (E)-1-(tert-butyldimethylsiloxy)-3-deuterioprop-
2-ene (kH/kD ) 0.88 ( 0.01 at 20.6 °C).
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(11) For details of kinetics and kinetic isotope effect experiments, see
Supporting Information.
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(14) An alternative mechanism that involves chelation-assisted 2 + 2 cycload-
dition followed by the fragmentation of the bicyclic intermediate has been
proposed by one of the reviewers and is consistent with the results of the
kinetics and kinetic isotope effect experiments presented in the paper.
More insight into the second step of the reaction can be obtained
from the stereochemistry of the substitution. In the literature, syn
stereochemistry of allylic substitutions has been interpreted as a
strong indication of a cyclic transition state.13 Consistent with these
precedents and the observed regio- and stereospecificity of the
reaction, we propose 9 (Figure 1) as the transition state for this
JA056132F
9
J. AM. CHEM. SOC. VOL. 127, NO. 48, 2005 16791