Stereochemical lability of azatitanacyclopropanes: Dynamic kinetic resolution in reductive cross-coupling reactions with allylic alcohols

Article abstract of DOI:10.1039/c3cc45607b

Azatitanacyclopropanes (titanaziridines) are shown to be stereochemically labile under reaction conditions for reductive cross-coupling. This fundamental property has been employed to realize highly selective asymmetric coupling reactions with allylic alcohols that proceed by dynamic kinetic resolution. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45607b

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Stereochemical lability of azatitanacyclopropanes:
dynamic kinetic resolution in reductive cross-coupling
reactions with allylic alcohols†‡
Cite this: Chem. Commun., 2013,
49, 8857
Received 23rd July 2013,
Dexi Yangab and Glenn C. Micalizio*ab
Accepted 13th August 2013
DOI: 10.1039/c3cc45607b
www.rsc.org/chemcomm
Azatitanacyclopropanes (titanaziridines) are shown to be stereo-
chemically labile under reaction conditions for reductive cross-
coupling. This fundamental property has been employed to realize
highly selective asymmetric coupling reactions with allylic alcohols
that proceed by dynamic kinetic resolution.
While the history associated with metallacycle-mediated cross-
coupling is rich, dating back nearly 70 years ago to the work of
Reppe,1 the broad synthetic utility of reactions that proceed under
this mechanistic paradigm is becoming ever more apparent with
recent contributions.2 Modern advances have greatly increased
substrate scope and have had a substantial impact on the manner
in which this type of reactivity is achieved. For example, inexpensive
and easy to handle metal alkoxides [Ti(Oi-Pr)4] have been identified
as reagent precursors to low-valent species capable of forming
metal–p complexes under reaction conditions that are readily
achieved outside of a glove box,3 and new strategies for reaction
design have emerged that offer fine control over reactivity and
selectivity in intermolecular cross-coupling reactions between
metal–p complexes and substituted alkenes, alkynes, and allenes.4
Building on such advances, recent contributions have included the
realization of Ti-mediated reductive cross-coupling reactions
between metal–imine complexes and allylic alcohols (Fig. 1A,
eqn (1)) – a reaction process that delivers complex homoallylic
Fig. 1 Reductive coupling of Ti–imine complexes with allylic alcohols: stereo-
chemical lability of the complex and development of a dynamic kinetic resolution
en route to homoallylic amines.
amines with control of allylic and homoallylic stereochemistry coupling processes asymmetric (Fig. 1A, eqn (2)).5a–c,6 Here, we
while establishing the geometry of di- and tri-substituted alkenes report that the intermediate organometallic complex in this class
during the course of intermolecular C–C bond formation.5 Reports of reductive cross-coupling undergoes rapid and reversible stereo-
have described the utility of this process in stereoselective synthesis chemical isomerization under the reaction conditions, and that
and a general strategy to accomplish simple kinetic resolution of this behaviour can be employed to realize highly stereoselective
racemic Ti–imine complexes has been employed to render such coupling reactions en route to chiral homoallylic amines that
proceed by dynamic kinetic resolution (Fig. 1B).
Since Kulinkovich’s early reports that described the generation
of vicinal dianion equivalents from the reaction of Ti(Oi-Pr)4 with
Grignard reagents, many new C–C bond-forming reactions have
emerged that take advantage of the organometallic intermediates
presumed to play a central role in this chemistry.3 These processes
have been presumed to proceed by the intermediacy of titana-
cyclopropanes, yet structural work to support this claim remains to
be described (unlike related chemistry associated with Cp2Ti- and
a Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA.
E-mail: glenn.c.micalizio@dartmouth.edu
b Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA
† The authors dedicate this contribution in honor of Ruluan Gao for his lifetime
contributions to the education of young students at Funing Middle School in
Jiangsu, China – Dr Dexi Yang had the great pleasure of being inspired by the
early chemistry teachings of Mr Gao.
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc45607b
c
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Chem. Commun., 2013, 49, 8857--8859 8857

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Cp2Zr-based systems). In the subset of reactions most relevant to the
current study, exposure of an imine to the reagent combination
of Ti(Oi-Pr)4–2RMgX or Ti(Oi-Pr)4–2RLi is presumed to generate
azatitanacyclopropanes (or titanaaziridines; i.e. 2, Fig. 1A) and
subsequent addition of an alkene, alkyne, or allene results in C–C
bond formation by intermolecular carbometalation.7 Titanaaziri-
dines proposed to play a role in these processes have not been
structurally characterized, yet gross reactivity patterns are consistent
with their proposed intermediacy.
Cognizant of the uncertainty associated with the nature of the
reactive organometallic species in Ti(Oi-Pr)4–2RMet-promoted
reactions of imines, we began an investigation aimed at explor-
ing the configurational stability of the presumed titanaaziridine
intermediates. Our first pursuit was designed to investigate
whether a racemic mixture of titanaaziridines could be resolved
in a manner to deliver an optically active organometallic complex
for use in a subsequent stereoselective coupling reaction. A
reaction scheme with this goal in mind is depicted in Fig. 2
(eqn (4)). Treatment of the TMS–imine 98 with Ti(Oi-Pr)4–2c-
C5H9MgCl was thought to result in the formation of a racemic
mixture of azatitanacyclopropanes 6 [depicted as 6(R) and 6(S)].
Given our previous success in attaining high levels of stereo-
selection in reductive cross-coupling reactions with cyclic allylic
alcohols, we added a single equivalent of the terpene-derived
chiral allylic alkoxide 10 to the mixture of enantiomeric Ti–imine
complexes 6 to achieve selective engagement of 6(S) in reductive
cross-coupling en route to 11. In this manner, 6(S) would be
selectively removed from the reaction mixture leaving the
resolved azametallacyclopropane 6(R) available for a distinct
stereoselective coupling process. Moving on, one equivalent of
benzophenone was added to engage 6(R) in a metallacycle-
mediated coupling reaction en route to oxazametallacyclo-
pentane 12. Finally, addition of water resulted in the formation
of the two chiral products: homoallylic amine 13 (62% from 10;
dr Z 20: 1) and aminoalcohol 14 (81% from benzophenone). On
further analysis of the aminoalcohol product, 14 was found to be
racemic – an observation that supports the conclusion that the
organometallic intermediate 6(R) undergoes rapid and reversible
stereochemical equilibration under the reaction conditions for
reductive cross-coupling.
Fig. 3 Dynamic kinetic resolution in reductive cross-coupling reactions of
titanium–imine complexes with allylic alcohols. * = ee determined by 1H NMR
analysis of the (+)-MTPA amide.
Recognizing that such stereochemical lability may be a
useful property in the design of new reactions that proceed by
Fig. 2 Observing the dynamic stereochemical behaviour of a presumed azatitanacyclopropane intermediate. Note: equivalents depicted below each reactive
intermediate are estimates based on assuming complete conversion of 9 to 6 (R and S), and conversion of 6(S) to 11.
c
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dynamic kinetic resolution (DKR), we explored the reductive cross-
coupling of achiral aromatic imines with suitably substituted chiral
allylic alcohols. As illustrated at the top of Fig. 3, conversion of one
equivalent of an imine to a presumed equilibrating mixture of
titanaaziridines was followed by addition of an excess of a chiral
allylic alkoxide (1.3–2.0 equivalents) to consume as much of the
equilibrating mixture as possible. Aqueous work up then delivered
stereodefined homoallylic amine products. In all cases, these reduc-
tive cross-coupling reactions proceeded with exceptional levels of
stereochemical control and in up to 87% yield – an efficiency that is
based on the imine and due to the dynamic stereochemical
behaviour of the organometallic intermediate.
From a synthetic perspective, we note that this DKR is compatible
with a range of substrates that include TMS- and Bn-substituted
aromatic imines (eqn (5) and (6)), as well as coupling partners
harbouring cyclic and acyclic allylic alcohols, di- and trisubstituted
alkenes, as well as vinyl bromides (eqn (7)–(9)).
5 (a) M. Takahashi, M. McLaughlin and G. C. Micalizio, Angew. Chem., Int.
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2010, 75, 8048–8059; (d) see also: ref. 2s.
While dynamic kinetic resolution of Cp2Zr–imine complexes has
been studied by Tunge and Norton and employed as a strategy to
prepare chiral a-amino acids,9 to our knowledge these studies
describe the first observations consistent with stereochemical lability
of titanaaziridine intermediates derived from Ti(Oi-Pr)4, the first
dynamic kinetic resolution of metal–imine complexes derived from
Ti(IV)–alkoxides,6,10,11 and establish a convenient method for the
convergent asymmetric synthesis of highly substituted chiral homo-
allylic amines. Notably, the facile stereochemical isomerization of
the organometallic intermediate observed here should prove useful
for asymmetric metallacycle-mediated cross-coupling reactions
of precious imines, where readily accessible chiral allylic alcohols
can be used to dictate the absolute stereochemical course of C–C
bond-formation.12
6 In ref. 5b, experiments were conducted with a slight excess of imine
(1.2 eq.), and yields for highly selective reactions were reported from
60–65%. This efficiency, where yields are reported >60% reflects an
observation consistent with DKR of the presumed Ti–imine complex.
Details regarding efficiency associated with the DKR cannot be
extracted from the results reported, as simple kinetic resolution can
be envoked to explain the vast majority of product formation.
7 For reactions with aromatic imines, see: (a) G. Yao, Y. Yoshida and
F. Sato, Synlett, 1997, 1353–1354. For reactions with aliphatic imines,
see: (b) M. A. Tarselli and G. C. Micalizio, Org. Lett., 2009, 11, 4596–4599.
8 TMS–imine 9 was generated in situ from treatment of benzaldehyde
with LiHMDS. For examples of the use of this process in
Ti-mediated reductive cross-coupling reactions with allylic alcohols,
see ref. 2s.
9 (a) J. A. Tunge, D. A. Gately and J. R. Norton, J. Am. Chem. Soc., 1999,
121, 4520–4521; (b) S. A. Cummings, J. A. Tunge and J. R. Norton,
J. Am. Chem. Soc., 2008, 130, 4669–4679.
10 The conclusions made from this study assume the intermediacy of
racemic Ti–imine complexes similar to that which has been
observed in related chemistry of Cp2Zr–imine complexes (see
ref. 9). The mechanism for interconversion between these presumed
chiral intermediates may include that based on radical homolysis of
the sTi–C bond and subsequent reformation of the metallacycle.
Such a mechanism would imply that aryl imines would be superior
substrates to aliphatic imines in this DKR due to an enhanced
stability of the resulting benzylic radical. While not presented in the
body of the current manuscript, we have explored the potential
utility of aliphatic imines in this resolution process. Unfortunately,
when an aliphatic imine is employed as limiting reagent, we have
not been able to achieve yields of the homoallylic amine product
over 25%. The reasons associated with the divergent efficiency of
this process could be related to a number of factors that include the
different reaction conditions required for aliphatic imines (see
ref. 7b) and the stability of radical intermediates derived from
homolysis of the sTi–C bond of the presumed titanaaziridne
intermediate.
This work was supported by the National Institutes of Health
(GM080266).
Notes and references
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11 For
a report focused on the rate of enantiomer conversion
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12 The current contribution is of great synthetic value when the cost of
the imine far outweighs the cost of the allylic alcohol, as 1.3–2
equivalents of the chiral allylic alcohol are employed to engage the
Ti–imine complex in an efficient dynamic kinetic resolution. In cases
where the chiral allylic alcohol is significantly more expensive than
the imine coupling partner, potential users of this imine–allylic
alcohol coupling process should purse simple kinetic resolution
using the allylic alcohol coupling partner as limiting reagent. Such
a procedure has been described earlier (see ref. 5).
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c
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