Concerning the potential reversibility of carbometalation in alkoxide-directed Ti(Oi-Pr)4-mediated reductive cross-coupling of homoallylic alcohols with aromatic imines

Article abstract of DOI:10.1039/b927430h

In an attempt to understand the nature of selectivity in Ti-mediated reductive cross-coupling between homoallylic alcohols and imines, we investigated whether thermodynamic equilibration of the presumed organometallic intermediate plays a role in selectiv

Full text of DOI:10.1039/b927430h

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Concerning the potential reversibility of carbometalation
in alkoxide-directed Ti(Oi-Pr)4-mediated reductive cross-coupling
of homoallylic alcohols with aromatic iminesw
Masayuki Takahashi and Glenn C. Micalizio*
Received 5th January 2010, Accepted 22nd March 2010
First published as an Advance Article on the web 8th April 2010
DOI: 10.1039/b927430h
In an attempt to understand the nature of selectivity in
Ti-mediated reductive cross-coupling between homoallylic alcohols
and imines, we investigated whether thermodynamic equilibra-
tion of the presumed organometallic intermediate plays a role in
selectivity. No evidence could be found for olefin exchange in
preformed azatitanacyclopentanes—an observation that is con-
sistent with a model based on kinetically controlled selective
carbometalation.
Reductive cross-coupling is emerging as a powerful strategy
for bimolecular C–C bond formation.1 This mode of reactivity
has historically been limited to a relatively small substrate
Fig. 2 Stereoconvergence in alkene–imine coupling.
scope as a result of firmly established barriers associated with
the control of reactivity and selectivity in the bimolecular C–C
bond forming event.2 In a program aimed at advancing a suite
of methods for reductive cross-coupling that overcome these
limitations, we recently described highly regio- and stereo-
selective coupling reactions of substituted homoallylic alcohols
with aromatic imines (Fig. 1).3 This process, proceeding with
stoichiometric use of an inexpensive and non-toxic metallic
species (Ti(Oi-Pr)4), was accomplished by: (1) initial conver-
sion of an aromatic imine to an azatitanacyclopropane, (2)
introduction of a homoallylic alkoxide, and (3) protonation of
the presumed bicyclic azametallacyclopentane intermediate. A
mechanistic proposal to account for the enhanced reactivity
and high selectivity observed was put forth based on: (1) rapid
and reversible ligand exchange at titanium, and (2) site- and
stereoselective intramolecular carbometalation under kinetic
control.
During the course of these studies, we observed a stereo-
convergence in reductive cross-coupling between disubstituted
alkenes and aromatic imines. As illustrated in Fig. 2, coupling
of the homoallylic alcohol 7 or 8 with a simple aromatic imine
provided the anti-1,5-amino alcohol 11 in 68 and 73% yield
with very high levels of stereoselection (dr Z 95:5).3 This
observation was consistent with a mechanistic proposal where-
by each alkene underwent selective carbometalation by way of
distinct geometries (I and II). While the number of ligands on
Ti in the transition state for these coupling reactions remains
unclear, we expected that the development of a cis-fused
bicyclo-[3.3.0] system would be favoured.4 Further, minimi-
zation of eclipsing 1,2-interactions about the developing C–C
bond was thought to be important for the control of stereo-
chemistry en route to intermediates 9 and 10. Subsequent
protonation would then furnish the 1,5-amino alcohol 11.
Overall, the high anti-selectivity and stereoconvergence was
consistent with this mechanistic proposal based on kinetic
control.
Previous reports in other laboratories have demonstrated
that a variety of metallacyclopentane intermediates can readily
undergo fragmentation with loss of an alkene ligand
(Fig. 3).5,6 These observations led us to speculate whether
Fig. 1 Reductive cross-coupling of homoallylic alcohols with imines.
Department of Chemistry, The Scripps Research Institute,
Scripps–Florida, Jupiter, FL, USA. E-mail: micalizio@scripps.edu;
Fax: +1 561 228 3092
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data are included for all new compounds. See
DOI: 10.1039/b927430h
Fig. 3 C–C bond cleavage from a preformed azatitanacyclopentane.5
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Fig. 4 Potential equilibria for alkene exchange.
the selectivity of our alkene–imine coupling was a result of
thermodynamic, rather than kinetic, control.
Our studies aimed at addressing this question began with an
analysis of the basic reaction process—we accepted that: (1)
Ligand exchange at Ti was readily reversible and fast with
respect to C–C bond formation,7 and (2) azatitanacyclopentane
formation followed from syn-carbometalation across the
alkene. As depicted in Fig. 4, if C–C bond-formation is readily
reversible under the reaction conditions (4 " 5), then rapid
and reversible ligand exchange at Ti should allow for alkene
exchange (4 " 15). Subsequent carbometalation and proto-
nation would then deliver 1,5-amino alcohol 17 from the
preformed azametallacyclopentane 5.
To determine whether such an alkene exchange could occur
under the reaction conditions employed in our reductive cross-
coupling, we explored the general reaction scheme depicted in
Fig. 5A. Here, metallacyclopentane intermediates with similar
steric and electronic properties were sought to avoid biasing
any potential equilibria. With this goal in mind, homoallylic
alcohol 18 was coupled to imine 20 alongside the deuterated
analogs 19 and 21.8,9 After reductive coupling was judged
complete, the reaction mixtures were combined and stirred for
an additional six hours at 0 1C to allow for equilibration.
Subsequent hydrolysis of the presumed organometallic inter-
mediates (H2O) provided two of the four possible products
(Fig. 5B and C–I). Lack of evidence for D5 (M + H = 275.2)
or D2 (M + H = 272.2)-containing products is consistent
with the proposition that the equilibrium discussed in Fig. 4
does not play a role in product distribution.
Fig. 5 Cross-over experiments.
cross-coupling of simple homoallylic alcohols with aromatic
imines.
We gratefully acknowledge financial support of this work by
the National Institutes of Health-NIGMS (GM080266 and
GM080266-04S1).
Notes and references
1 For recent reviews, see: (a) H. A. Reichard, M. McLaughlin,
M. Z. Chen and G. C. Micalizio, Eur. J. Org. Chem., 2009, DOI:
10.1002/ejoc.200901094; (b) S.-S. Ng, C.-Y. Ho, K. D. Schleicher
and T. F. Jamison, Pure Appl. Chem., 2008, 80, 929;
(c) J. Montgomery and G. J. Sormunen, Top. Curr. Chem., 2007,
279, 1; (d) E. Skucas, M.-Y. Ngai, V. Komanduri and M. J. Krische,
Acc. Chem. Res., 2007, 40, 1394.
2 The majority of reductive methods for cross-coupling are limited to
a relatively small subset of coupling partners. See ref. 1 for reviews.
3 M. Takahashi and G. C. Micalizio, J. Am. Chem. Soc., 2007, 129,
7514.
4 For the strain energy of cis- and trans-fused bicyclo-[3.3.0]-octane,
see: (a) S. Chang, R. H. Boyd, D. McNally, S. Sharyteh and
M. J. Hickey, J. Am. Chem. Soc., 1970, 92, 3109. For an example
where a trans-fused bicyclo-[3.3.0] Zr-containing system is preferred,
see: (b) W. A. Nugent and D. F. Taber, J. Am. Chem. Soc., 1989,
111, 6435.
To confirm that the experimental procedure was sufficient for
the conclusion reached, we needed to validate that quenching of
the organometallic intermediates did not occur during the mixing
process. As such, a related experiment was performed where the
organometallic intermediates were quenched with D2O. In this
experiment, only D1 and D8-containing products were identified
(no evidence was found for the D6 or D3-containing cross-over
products; Fig. 5B and C–II).
In conclusion, we provide evidence that alkene exchange in
titanium alkoxide-mediated reductive cross-coupling of imines
with homoallylic alcohols does not occur under the reaction
conditions described. Because rapid and reversible ligand
exchange at Ti would allow for alkene exchange from mixed
titanate esters (i.e. 4 and 15), we conclude that carbometa-
lation under these reaction conditions occurs in an irreversible
manner. While more substituted alkenes may behave differently
in this coupling process, the current study describes conclusive
evidence in support of kinetic selectivity for the reductive
5 J. E. Hill, P. E. Fanwick and I. P. Rothwell, Organometallics, 1992,
11, 1775.
6 For related examples of C–C bond cleavage in metallacyclopentanes,
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7 For a discussion of ligand exchange with titanium alkoxides, see:
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8 In each case, 1.5 eq. of homoallylic alcohol were used to ensure that,
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3338 | Chem. Commun., 2010, 46, 3336–3338