C O M M U N I C A T I O N S
Scheme 3. Substitution of (R)-(-)-35 with 4
Scheme 1. Proposed Mechanism for Substitution
Scheme 2. Secondary Kinetic Isotope Effect Studies
addition, the unfavorable steric interaction depicted between one
of the Cp* ligands and axial substituent of a Z-allylic chloride (see
(R) in 37) is consistent with our observation that reaction of Z-1-
chloro-2-hexene with 4 was less regioselective than that of the
corresponding E-isomer.
In conclusion, we have discovered a new mode of reactivity for
zirconium oxo complexes that results in the regio- and stereospecific
SN2′ substitution of E-allylic chlorides. We have also found that
the oxo complexes exhibit excellent substrate scope and functional
group compatibility, and that the initially formed zirconium
alkoxides could be efficiently trapped with TBSOTf to furnish TBS
protected allylic ethers in a single flask. Finally, we have carried
out detailed kinetic, isotope labeling and stereochemical experiments
that allow us to propose a mechanism for the overall reaction,
involving a concerted “closed” transition state for rate-determining
C-O bond formation. These results provide insight into the
reactivity of zirconium oxo complexes and may aid in the
development of alternative transition metal-mediated SN2′ reactions.
alkene, alkyl chloride, allylic TBS ether, dithiane, and dimethyl
acetal functionality (Table 1, entries 6-10).5
Motivated to further understand the elementary steps associated
with the SN2′ reaction, we next initiated a kinetic study by moni-
toring the homogeneous reaction of oxo complex 27 with 7 by 1H
NMR spectroscopy.6 In the presence of excess 4-trifluorometh-
ylpyridine (4-CF3pyr) and 7, the substitution exhibited pseudo-first-
order kinetics with no observable intermediates, indicating the
overall reaction is first-order in 27.7 In addition, the first-order rate
constant for the reaction (kobs ) (1.4 ( 0.1) × 10-3 s-1 at 27 °C)
was found to be independent of the initial concentration of 27, while
the kobs values obtained in the presence of 7 and various concentra-
tions of 4-CF3pyr established that the overall reaction is inverse
first-order in [4-CF3pyr].6 Based on these data, and in analogy to
complexes 1 and 2,1 we propose that the SN2′ reaction is initiated
by rapid and reversible dissociation of the pyridine ligand, followed
by rate-limiting C-O bond formation (Scheme 1). Consistent with
the rate law predicted by this mechanism, we observed that the
substitution reaction exhibited saturation kinetics at high concentra-
tions of 7.6 By measuring kobs at different [4-CF3pyr]/[7] ratios,
Acknowledgment. This work was supported by the NIH
through grant No. GM-25459 to R.G.B.
Supporting Information Available: Experimental procedures and
spectral data for products (PDF). This material is available free of charge
References
(1) (a) Sweeney, Z. K.; Polse, J. L.; Andersen, R. A.; Bergman, R. G. J. Am.
Chem. Soc. 1998, 120, 7825. (b) Lalic, G.; Blum, S. A.; Bergman, R. G.
J. Am. Chem. Soc. 2005, 127, 16790.
(2) For the in situ formation and trapping of Cp*2ZrdO and Cp*2ZrdS, see:
(a) Carney, M. J.; Walsh, P. J.; Hollander, F. J.; Bergman, R. G. J. Am.
Chem. Soc. 1989, 111, 8751. (b) Carney, M. J.; Walsh, P. J.; Bergman,
R. G. J. Am. Chem. Soc. 1990, 112, 6426. (c) Carney, M. J.; Walsh, P. J.;
Hollander, F. J.; Bergman, R. G. Organometallics 1992, 11, 761.
(3) (a) Howard, W. A.; Waters, M.; Parkin, G. J. Am. Chem. Soc. 1993, 115,
4917. (b) Howard, W. A.; Parkin, G. J. Am. Chem. Soc. 1994, 116, 606.
(c) Howard, W. A.; Trnka, T. M.; Waters, M.; Parkin, G. J. Organomet.
Chem. 1997, 528, 95. For reactions involving the corresponding titanium
analogue, see: (d) Polse, J. L.; Andersen, R. A.; Bergman, R. G. J. Am.
Chem. Soc. 1995, 117, 5393.
we were able to extract values for k1 ) (8.40 ( 0.01) × 10-4 (s-1
)
and k-1/k2 ) 3.1 ( 0.1 at 10 °C.6
To provide support for rate-limiting C-O bond formation we
also conducted competition experiments between E-1-chloro-2-
hexene (7) and deuterated analogues 29, 30, and 31 (Scheme 2).
As expected based on hybridization changes,8 we observed the
averaged secondary isotope effects (kH/kD) of 1.16, 1.055, and 0.571,
respectively, shown in Scheme 2.6
(4) Both 3 and 4 furnished similar SN2′/SN2 ratios with all substrates,
demonstrating that the SN2′ selectivity for allylic chlorides was not the
result of the pyridine substituent or homogenicity.
(5) 4-(Trifluoromethyl)phenol was substituted for TBSOTf in entry 10 due
to incompatibility of TBSOTf with the dimethyl acetal moiety.
(6) For details of kinetics and kinetic isotope effect experiments, see the
Supporting Information.
Following our kinetic studies, we sought to determine the
stereochemical outcome of the SN2′ reaction for a chiral allylic
chloride. We subjected allylic chloride (-)-35 to reaction with 4,
followed by quenching with 4-(trifluoromethyl)phenol, to furnish
allylic alcohol (-)-36 in 96% yield (Scheme 3). Importantly, the
substitution proceeded with essentially complete syn selectivity.9
Based on this stereochemical outcome, we propose transition state
37 for C-O bond formation. Cyclic transition states such as 37
have previously been postulated to rationalize syn stereochemistry
in allylic substitutions,1,10 as well as for the formation of Cp2*Zr-
(I)(OH) via reaction of Cp2*(pyr)ZrdO with tert-butyl iodide.3c In
(7) 4 was replaced with 27 for the kinetic studies since minor amounts of
SN2 substitution were detected when the reaction between 4 and 7 was
run in the presence of excess 4-(3-phenylpropyl)pyridine and 7. The
increased electron-withdrawing nature of 4-(trifluoromethyl)pyridine
presumably enhances the rate of ligand dissociation.
(8) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry;
University Science Books: Sausalito, CA, 2006; Chapter 8.
(9) The absolute stereochemistry of (-)-36 was verified by Kakisawa-Mosher
ester analysis. See the Supporting Information for details.
(10) Morrill, C.; Beutner, G. L.; Grubbs, R. H. J. Org. Chem. 2006, 71, 7813.
JA075967I
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