Rhodium catalyzed enantioselective cyclization of substituted imidazoles via C-H bond activation

Article abstract of DOI:10.1039/b902878a

The enantioselective intramolecular alkylation of substituted imidazoles with enantiomeric excesses up to 98% has been accomplished by rhodium catalyzed C-H bond functionalization with (S,S′,R,R′)TangPhos as the chiral ligand.

Full text of DOI:10.1039/b902878a

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Rhodium catalyzed enantioselective cyclization of substituted imidazoles
via C–H bond activationwz
Andy S. Tsai,b Rebecca M. Wilson,b Hitoshi Harada,b Robert G. Bergman*a
and Jonathan A. Ellman*b
Received (in College Park, MD, USA) 11th February 2009, Accepted 1st May 2009
First published as an Advance Article on the web 2nd June 2009
DOI: 10.1039/b902878a
The enantioselective intramolecular alkylation of substituted
imidazoles with enantiomeric excesses up to 98% has been
accomplished by rhodium catalyzed C–H bond functionalization
with (S,S0,R,R0)TangPhos as the chiral ligand.
which were successful in asymmetric imine directed alkylations,
were not active for this system.2b,c Previous work on the
alkylations of imidazoles established that electron rich
phosphines were required.5 Indeed, trialkyl phosphine L4
provided the desired product in good yield, but in racemic form.
Given the limited number of chiral, monodentate electron
rich phosphines that are commercially available, hemilabile
bidentate ligands were explored (L5–8). Though from past
studies, bidentate ligands consistently inhibited the reaction
most likely by blocking a necessary metal coordination site,5d
we hoped that the weaker coordination of the nitrogen or
oxygen heteroatom on the hemilabile ligands would allow
partial dissociation. This hypothesis seemed to be operative
as some ligands in this class (L8) did generate the cyclized
product, albeit in nearly racemic form.6
Carbon–hydrogen and carbon–carbon bonds represent the
two most common linkages in organic chemistry. Thus,
the formation of C–C bonds via catalytic activation of
C–H bonds has the potential to be highly general, practical
and atom economical. Great progress has been achieved in
this area from fundamental study to chemical application.1
However, only a limited number of catalytic enantioselective
transformations have been reported to date. The two most
common methods for asymmetric C–H functionalization have
been via chelation-assistance2 and carbenoid insertion.3,4 Our
group previously disclosed a unique C-2 functionalization of
benzimidazoles that proceeds through an N-heterocyclic-carbene
intermediate obtained via C–H activation.5 Herein, we disclose
a catalytic asymmetric benzimidazole functionalization that
provides remarkably high enantioselectivities (up to 98%)
despite the elevated temperatures (135 1C) of the reaction.
Investigation into the catalytic asymmetric alkylation of
imidazoles began with N-allylic benzimidazole 1 as the model
substrate. Reaction parameters were adapted from previously
reported conditions for the alkylation of this substrate with
achiral catalysts.5a With [RhCl(coe)2]2 (coe ¼ cis-cyclooctene)
as the rhodium pre-catalyst, a variety of chiral ligands were
screened to explore reactivity and enantioselectivity.
Although we were encouraged by the reactivity of some
hemilabile ligands, the chiral induction was still deficient and
therefore more rigid chiral bidentate phosphines were explored
in hopes of improving ee. Indeed, L9, the bidentate analog
of L4, did provide the cyclized product with moderate
enantioselectivity. However, the bidentate ligand architecture
suppressed the reaction, possibly by occupying a metal
coordination site necessary for the reaction. Next, the
Results obtained using a representative subset of screened
chiral ligands are summarized in Scheme 1. Monodentate
ligands were initially explored (L1–4) because only this type
of ligand architecture provided successful reactions in past
alkylation studies.5 Phosphoramidites and phosphites (L1–2),
a Division of Chemical Sciences, Lawrence Berkeley National
Laboratory and Department of Chemistry, University of California,
Berkeley, CA 94720-1460, USA. E-mail: rbergman@berkeley.edu;
Fax: þ1 510 642 7714; Tel: þ1 510 642 2156
b Department of Chemistry, University of California, Berkeley,
CA 94720-1460, USA. E-mail: jellman@berkeley.edu;
Fax: þ1 510 666 2504; Tel: þ1 510 642 4488
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details, analytical data, HPLC chromatograms, NMR spectra, and
X-ray crystallographic data. CCDC 727522. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI:
10.1039/b902878a
Scheme 1 Representative chiral ligands screened for enantioselective
cyclization of 1.
ꢀc
This journal is The Royal Society of Chemistry 2009
3910 | Chem. Commun., 2009, 3910–3912

electron rich diphosphine L12 ((S,S0,R,R0)-TangPhos) was
evaluated.7 Not only was high reaction conversion observed,
but exceptional enantioselectivity was also achieved, which
is notable considering the elevated reaction temperature
(135 1C). Interestingly, the close analog (S,S0,R,R0)-DuanPhos
(L11) showed no activity for the alkylation of 1. Furthermore,
a less bulky isopropyl analog of L12 resulted in only trace
reaction.
factors that determine the degree of chiral induction are
unclear. Of the ligands that were evaluated, only TangPhos
incorporated all of the characteristics necessary for a successful
and highly enantioselective transformation.
With the identification of TangPhos as an active and
selective ligand, reaction optimization was performed to
establish THF as the optimal solvent and a slight excess
of rhodium to TangPhos as the optimal stoichiometry
(Table 1, entry 1). With these optimized conditions identified,
substrate scope was next explored. The reaction conditions
accommodated the alkylation of isomerizable and aryl sub-
strates (entries 2 and 3). Electronic effects of the aryl sub-
stituted alkene and of the benzimidazole ring were also
examined (entries 4–9). Both electron-poor and -rich substrates
required higher temperatures for satisfactory reaction rates,
leading to an erosion of enantioselectivity. Finally, the
4,5-diphenyl substituted imidazole could also be alkylated
with high enantioselectivities (entry 10), although alkylation
was not observed for the corresponding 4,5-dimethyl
imidazole (not shown). Yields were high for most of the
substrates; starting material and products arising from hydro-
genation of the starting alkene comprised the remaining mass
balance. Alkylation could also be successfully carried out with
2.5% of [RhCl(coe)2]2 and 4.9% of TangPhos. Comparable
yields (95% by NMR) and only a slight reduction in enantio-
selectivity (90%) were obtained by performing the cyclization
of 1 with this catalyst loading at 175 1C for 36 h.
Considering the results from the ligand screen, electron rich
phosphines seem to be necessary for activity though it is not
the only requirement. Partial ligand dissociation to form a
monodendate diphosphine may be occurring with L12 to
allow for the formation of an open coordination site necessary
to provide catalytic activity.8 This process may be slow for L9
and inaccessible for L11 or the L12 analog. Moreover, the
Table 1 Substrate scope for the catalytic, asymmetric alkylation of
imidazolesa
Entry Product
1
Temp./1C Time/h Yieldbc (%) eed (%)
135
135
20
60
89
71
98
90
In summary, a method for the catalytic asymmetric
cyclization of substituted imidazoles via C–H bond activation
has been achieved. A ligand screen identified TangPhos (L12)
as a highly active ligand for the asymmetric cyclization of
N-allylic imidazoles to yield products with moderate to high
enantioselectivities even at elevated temperatures.
2
3
4
135
175
46
24
91
83
97
87
We acknowledge the support by the National Institutes of
Health under Grant GM069559 (JAE) and the Office of Basic
Energy Sciences, Chemical Sciences Division, US Department
of Energy, under Contract DE-AC02-05CH11231 (RGB).
5
175
24
87
79
Notes and references
1 (a) For reviews on C–H bond functionalization see the following
leading references: D. Alberico, M. E. Scott and M. Lautens,
Chem. Rev., 2007, 107, 174–238; (b) K. Godula and D. Sames,
Science, 2006, 312, 67–72; (c) F. Kakiuchi and T. Kochi, Synthesis,
2008, 3013–3039; (d) V. Ritleng, C. Sirlin and M. Pfeffer, Chem.
Rev., 2002, 102, 1731–1769.
2 (a) N. Fujii, F. Kakiuchi, A. Yamada, N. Chatani and S. Murai,
Chem. Lett., 1997, 425–426; (b) R. K. Thalji, J. A. Ellman and
R. G. Bergman, J. Am. Chem. Soc., 2004, 126, 7192–7193;
(c) H. Harada, R. K. Thalji, R. G. Bergman and J. A. Ellman,
J. Org. Chem., 2008, 73, 529–531; (d) B. F. Shi, N. Gaugel,
Y. H. Zhang and J. Q. Yu, Angew. Chem., Int. Ed., 2008, 47,
4882–4886.
6
7
8
175
175
175
36
24
24
89
92
83
71
81
53
9
175
135
24
98
81
90
71
95
3 (a) For leading references on enantioselective carbenoid insertions
see: H. M. L. Davies and J. R. Manning, Nature, 2008, 451,
417–424; (b) H. M. L. Davies and R. E. J. Beckwith, Chem. Rev.,
2003, 103, 2861–2904.
10
4 (a) For examples of asymmetric C–H functionalization occurring
through other methods see: X. Han and R. A. Widenhoefer, Org.
Lett., 2006, 8, 3801–3804; (b) Z. Li and C. J. Li, Org. Lett., 2004, 6,
4997–4999.
5 (a) K. L. Tan, R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc.,
2001, 123, 2685–2686; (b) K. L. Tan, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2002, 124, 13964–13965;
a
Absolute configuration of the HCl salt of 2 (entry 1) was determined
by X-ray crystallography (see ESIz). Remaining products are assigned
b
by analogy. Reactions were carried out on 0.15 mmol scale.
c
d
Isolated yield after chromatography. Determined by chiral HPLC
analysis (see ESIz).
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(c) K. L. Tan, R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc.,
2002, 124, 3202–3203; (d) S. H. Wiedemann, J. C. Lewis,
J. A. Ellman and R. G. Bergman, J. Am. Chem. Soc., 2006, 128,
2452–2462.
6 A more sterically demanding di-isopropyl analog of L8 also showed
activity but no improvement in ee.
7 (a) W. Tang and X. Zhang, Angew. Chem., Int. Ed., 2002, 41,
1612–1614; (b) W. Tang and X. Zhang, Chem. Rev., 2003, 103,
3029–3069.
8 (a) I. D. Gridnev and T. Imamoto, Organometallics, 2001, 20,
545–549; (b) B. R. James and D. Mahajan, J. Organomet. Chem.,
1985, 279, 31–48.
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This journal is The Royal Society of Chemistry 2009
3912 | Chem. Commun., 2009, 3910–3912