A rhodium IBiox[(-)-menthyl] complex as a highly selective catalyst for the asymmetric hydroarylation of azabicyles: An alternative route to epibatidine

Article abstract of DOI:10.1021/ol101067d

(Figure Presented) The synthesis and characterization of a new chiral rhodium N-heterocyclic carbene complex, Rh(IBiox[(-)-menthyl](CO)₂Cl, is reported. In addition, the very high enantioselectivity exhibited by this complex, as a catalyst for the asymmetric hydroarylation of azabicycles, is demonstrated and applied to the synthesis of epibatidine.

Full text of DOI:10.1021/ol101067d

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3160-3163
A Rhodium IBiox[(-)-menthyl] Complex
as a Highly Selective Catalyst for the
Asymmetric Hydroarylation of
Azabicyles: An Alternative Route to
Epibatidine
Jason Bexrud and Mark Lautens*
Department of Chemistry, UniVersity of Toronto, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received May 10, 2010
ABSTRACT
The synthesis and characterization of a new chiral rhodium N-heterocyclic carbene complex, Rh(IBiox[(-)-menthyl](CO)2Cl, is reported. In
addition, the very high enantioselectivity exhibited by this complex, as a catalyst for the asymmetric hydroarylation of azabicycles, is demonstrated
and applied to the synthesis of epibatidine.
Among the most important objectives in the field of synthesis
and catalysis is the development of enantioselective methods
Scheme 1. Hydroarylation of Azabicycles
for the formation of C-C bonds. Metal-catalyzed transfor-
mations that can establish the absolute stereochemical
configuration of more than one stereocenter in a given target
molecule are particularly attractive. One such transformation
that has emerged in the past few years involves the
desymmetrization of meso heterobicyclic alkenes such as 1
and 2 via transition-metal-catalyzed hydroarylation (Scheme
1).1 Products such as 3 are potentially valuable intermediates
that can undergo reductive N-N bond cleavage to generate
functionalized cyclopentane-1,3-diamines,1a while the hy-
droarylation of 2 directly produces 7-azabicyclo[2.2.1] hep-
tane derivatives such as the extremely potent analgesic
alkaloid epibatidine.2
Part of the appeal of this method derives from the ease
with which azabicycles 1 and 2 can be prepared. In particular,
(1) (a) Bournaud, C.; Chung, F.; Luna, A. P.; Pasco, M.; Errasti, G.;
Lecourt, T.; Micouin, L. Synthesis 2009, 6, 869. (b) Sajisha, V. S.; Anas,
S.; John, J.; Radhakrishnan, K. V. Synlett 2009, 18, 2885. (c) Menard, F.;
Lautens, M. Angew. Chem., Int. Ed. 2008, 47, 2085. (d) Panteleev, J.;
Menard, F.; Lautens, M. AdV. Synth. Catal. 2008, 350, 2893. (e) Yuan, K.;
Zhang, T. K.; Hou, X. L. J. Org. Chem. 2005, 70, 6085. (f) Yao, M. L.;
Adiwidjaja, G.; Kaufmann, D. T. Angew. Chem., Int. Ed. 2002, 41, 3375.
(g) Storsberg, J.; Nandakumar, M. V.; Sankaranarayanan, S.; Kaufmann,
D. E. AdV. Synth. Catal. 2001, 343, 177.
(2) (a) Carroll, F. I. Heterocycles 2009, 79, 99. (b) Garraffo, M. H.;
Spande, T. F.; Williams, M. Heterocycles 2009, 79, 207.
10.1021/ol101067d  2010 American Chemical Society
Published on Web 06/15/2010

1 can be synthesized in one high-yielding step involving a
Diels-Alder reaction between a dialkyl azodicarboxylate and
cyclopentadiene,1c while 2 is prepared from 3-cyclohexen-
ecarboxylic acid in four high-yielding steps.3
several of the known Rh-NHC complexes we observed low
reactivity and selectivity.
A survey of the recent literature led us to consider
IBiox[(-)-menthyl] (Figure 1), first prepared by Glorius and
We recently reported the first examples of enantioselective
hydroarylation of bicyclic hydrazines, where arylboronic
acids were coupled to N-Boc 1 with very good selectivities
of up to 99% ee using [Rh(COD)OH]2 in combination with
chiral phosphine ligands such as Josiphos.1c,d A competitive
process that can occur in this system is the rhodium-catalyzed
ring-opening of diazabicycles by ꢀ-nitrogen elimination to
yield cyclopentene derivatives 6 (Scheme 2). It was found
Figure 1. IBiox[(-)-menthyl] NHC ligand devised by Glorius and
co-workers.
Scheme 2
.
Rh-Catalyzed Ring-Opening versus Hydroarylation
of Diazabicycles
co-workers,8 as a potential ligand. The exceeding steric
demand imparted by this ligand resulted in high stereose-
lectivities in the Pd-catalyzed intramolecular R-arylation of
aryl chlorides.
To date, IBiox[(-)-menthyl] has not been employed in
rhodium chemistry, and therefore, we set out to prepare a
discrete complex to ensure that a ligand-Rh species was
possible. Indeed, this proved to be more challenging than
we expected. Our first attempts were to prepare Rh(I-
Biox[(-)-menthyl])(COD)Cl from [Rh(COD)Cl]2 using vari-
ous previously reported methods7a for the preparation of
Rh-NHC compounds, including heating the NHC precursor
IBiox[(-)-menthyl]HOTf with [Rh(COD)Cl]2 in the presence
of t-BuOK and heating IBiox[(-)-menthyl]AgBr with
[Rh(COD)Cl]2. These methods failed to produce any of the
desired complex.
that by choosing the appropriate phosphine ligand and
reaction conditions, either one of the two chemodivergent
products could be favored. A limitation of the Rh(COD)OH]2/
Josiphos system is that ortho-substituted boronic acids are
required for high enantioselectivity. Given that the substituted
cyclopentane-1,3-diamine structural motif can be found in
biologically important compounds such as tRNA ligands4
and enzyme bisubstrate inhibitors,5 stereoselective methods
for the preparation of compounds such as 4 may prove useful.
Therefore, we sought to find an alternative catalyst system
exhibiting improved enantiodiscrimination and greater sub-
strate tolerance.
One such family of catalysts that have not been explored
in addition reactions with unactivated alkenes are complexes
of rhodium that incorporate N-heterocyclic carbenes (NHCs)
as ligands. NHCs have become one of the most widely
studied classes of ligands next to phosphines, primarily due
to their strong σ-donor character, the large steric demand
that they can impose about the metal center, and the high
stability of the metal-NHC bond.6 Chiral Rh-NHC com-
plexes have been successfully applied to asymmetric varia-
tions of the 1,4-addition of organoboron reagents to enones,
the hydrosilylation reaction as well as the hydrogenation of
olefins.7 However, when we subjected the azabicycles to
We suspected that steric interaction between the COD
ligand and the extremely bulky NHC proligand may prevent
complexation. Therefore, we looked to [Rh(CO)2Cl]2 as an
alternative. We found that heating the silver precursor 7 with
an excess of [Rh(CO)2Cl]2 produced an inseparable mixture
of Rh(IBiox[(-)-menthyl])(CO)2Cl (8) and the bimetallic
complex [Rh(IBiox[(-)-menthyl])(CO)Cl]2 (∼4:1, respec-
tively) in good yield as an amorphous solid (Scheme 3,
Scheme 3
.
Synthesis of Rh(IBiox[(-)-menthyl])(CO)2Cl
Complex 8
(3) Gomez-Sanchez, E.; Soriano, E.; Marco-Contelles, J. J. Org. Chem.
2007, 72, 8656.
(4) Chung, F.; Tisne, C.; Lecourt, T.; Dardel, F.; Micouin, L. Angew.
Chem., Int. Ed. 2007, 46, 4489.
Figure 2). Rh-NHC-bis(CO)-chloride complexes are known
to reversibly lose a molecule of CO and undergo dimerization
in solution over a period of time.9 Di-µ-chlorido-RhLn
complexes have been employed numerous times as catalyst
precursors.10 Therefore, the mixture of 8 and the bimetallic
complex was used in all subsequent reactions without further
purification.
(5) Lombes, T.; Begis, G.; Maurice, F.; Turcaud, S.; Lecourt, T.; Dardel,
F.; Micouin, L. ChemBioChem 2008, 9, 1368.
(6) (a) Diez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. ReV 2009,
109, 3612. (b) N-Heterocyclic Carbenes in Transition-Metal Catalysis;
Glorius, F., Ed.; Springer: Berlin, 2007. (c) Gade, L. H.; Bellemin-Laponnaz,
S. Top. Organomet. Chem. 2007, 21, 117. (d) N-Heterocyclic Carbenes in
Synthesis; Nolan, S. P., Ed.; Wiley VCH: Weinheim, 2006. (e) Crudden,
C. M.; Allen, D. P. Coord. Chem. ReV. 2004, 248, 2247.
Org. Lett., Vol. 12, No. 14, 2010
3161

of the boronic acid and the extremely bulky IBiox[(-)-
menthyl] ligand, which is in direct contrast with the Rh-P
catalysts where the ortho-substituent was required. To the
best of our knowledge, these are the highest ee’s reported
to date for the hydroarylation of a bicyclic hydrazine.
The reaction of N-Boc-3-pyrrolylpinacolboronic ester11 10
with N-boc-diazabicycle 1 unexpectedly produced the ring-
opened product in moderate yield and very high enantiose-
lectiviy (Scheme 4). This is a somewhat surprising result
Scheme 4
.
Ring-Opening with N-Boc-3-pyrrolylpinacolboronic
Figure 2
complex 8.
. ORTEP depiction of Rh(IBiox[(-)-menthyl])(CO)2Cl
Ester
With 8 in hand, we first examined the desymmetrization
of diazabicycles with arylboronic acids (Table 1). Using
Table 1. Hydroarylation of N-Boc-diazabicycle 1 with Various
Boronic Acids
given the high yield of hydroarylation product observed when
3-thienylboronic acid was used. Use of the unprotected
3-pyrrolylpinacolboronic ester resulted in no conversion,
which we propose to be due to catalyst poisoning by the
free amine.
When hydroarylation with phenylboronic acid was carried
out in THF/D2O, a monodeuterated product 9a was isolated,
wherein the deuterium was located on the aromatic ring. This
is consistent with the proposal that the reaction proceeds
through a 1,4-Rh migration, analogous to the process that
we have described previously for the Rh/Josiphos-catalyzed
hydroarylation of diazabicycles (Scheme 5). The reaction is
slow to initiate in the absence of water, suggesting conversion
of LnRh-Cl 8 to a LnRh-OH species (A) likely precedes
transmetalation with the boron reagent. It is known that the
transmetalation of boronic acids occurs more readily with
LnRh-OH than with LnRh-Cl complexes.10 Following alkene
coordination and insertion into the resulting Rh-Ar bond,
1,4-Rh migration occurs via a Rh3+ intermediate (D) to
generate the Rh-Ar species (E), which then reacts with 1
equiv of water to liberate the product and regenerate the
LnRh-OH complex (A). Incorporation of deuterium occurs
upon hydrolysis of the Rh-Ar species (E) immediately
following the migration step.
In the interest of expanding the scope as well as demon-
strating the synthetic potential of this method, we also looked
a Isolated yield. b Determined by chiral HPLC.
(7) (a) Praetorius, J. M.; Crudden, C. M. Dalton Trans. 2008, 4079. (b)
Gade, L. H.; Cesar, V.; Bellemin-Laponnaz, S. Angew. Chem., Int. Ed. 2004,
43, 1014. (c) Bappert, E.; Helmchen, G. Synlett 2004, 10, 1789. (d) Ma,
Y.; Song, C.; Ma, C.; Sun, Z.; Chai, Q.; Andrus, M. B. Angew. Chem., Int.
Ed. 2003, 42, 5871.
reaction conditions similar to those utilized in the Rh-P
catalyzed system, it was found that, in general, 8 produced
the hydroarylation product in good yield with only trace
amounts of the ring-opened cyclopentene being detected by
TLC. Most importantly, the reaction proceeded with high
ee, all in excess of 90% even in the cases where boronic
acids devoid of ortho-substituents were used. The low yields
obtained for 9c and 9e are likely due to unfavorable steric
interactions between the o-chloro or o-methoxy substituent
(8) (a) Wu¨rtz, S.; Lohre, C.; Fro¨hlich, R.; Bergander, K.; Glorius, F.
J. Am. Chem. Soc. 2009, 131, 8344. (b) Wu¨rtz, S.; Glorius, F. Acc. Chem.
Res. 2008, 41, 1523. (c) Altenhoff, G.; Goddard, R.; Lehmann, C. W.;
Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195. (d) Glorius, F.; Altenhoff,
G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704.
(9) Bittermann, A.; Harter, P.; Herdweck, E.; Hoffmann, S. D.; Herrman,
W. A. J. Organomet. Chem. 2008, 693, 2079.
(10) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169.
(11) The pinacolborane ester was used rather than the boronic acid due
to the inherent instability of 3-pyrrolylboronic acids.
3162
Org. Lett., Vol. 12, No. 14, 2010

that the pyridylboronic acid may be more susceptible to
proto-deboronation than phenylboronic acid. We therefore
tried increasing the number of equivalents of boronic acid,
but this failed to improve the yield. Potassium organotrif-
luoroborates are known to be less prone to undergo pro-
todeboronation and have been used in various rhodium-
catalyzed C-C bond-forming processes.15 Utilizing 8 equiv
of potassium trifluoroborate 13 produced the desired N-Boc-
epibatidine 14 in 45% isolated yield and 93% ee (Scheme
6). Although the yield of 14 is modest, the good selectivity
Scheme 5
.
Proposed Mechanism for the Rh-Catalyzed
Hydroarylation Reaction
Scheme 6.
Synthesis of N-Boc Epibatidine16
and yield obtained using phenylboronic acid is promising,
and further optimization with 13 is underway.
at N-Boc-protected 7-azanorbornene 2 as a substrate. Asym-
metric hydroarylation of this compound with 2-chloropyri-
dine-5-boronic acid would lead directly to the N-Boc-
protected alkaloid epibatidine 5.
When this reaction was performed in THF/D2O, a ∼50:
50 mixture of 14 having deuterium incorporated in the 4-
and 6-positions of the pyridyl ring was produced, which is
consistent with a 1,4-Rh migration. Therefore, further
elaboration of the epibatidine core in one pot may be possible
by taking advantage of this migration.
In summary, we have described the first rhodium complex
incorporating IBiox[(-)-menthyl] as a ligand. In addition,
we have demonstrated the impressive stereoselectivity that
this system provides for the hydroarylation of azabicycles,
and as a proof of principle, we have shown that this method
can be used to prepare the N-Boc-protected alkaloid epiba-
tidine, thus providing an alternative route to this molecule
that may be useful for SAR studies. Future investigations
will involve expanding the scope of the hydroarylation
reaction to other strained alkenes and investigating the
application of complex 8 with other Rh-catalyzed reactions.
Epibatidine is an alkaloid isolated from the skin of a
poisonous frog, Epipedobates tricolor, and is known to be
200-400 times more potent than morphine.12 It has been
the subject of a number of structure-activity relationship
(SAR) studies13 and total syntheses.14 Among the most direct
and widely applied routes to this molecule and its derivatives
is the Pd-catalyzed reductive arylation of substrates such as
2 with aryl iodides.2,14g While an asymmetric variant has
been reported, the highest observed ee was 81% with a yield
of 50%.14f
Reaction of N-Boc-7-azanorbornene with 2 equiv of
phenylboronic acid produced the desired exo-hydroarylation
product in 69% yield and 93% ee. Unfortunately, reaction
with 2-chloropyridine-5-boronic acid generated less than 12%
of the N-Boc-protected epibatidine, albeit with good enan-
tioselectivity (93% ee). On the basis of the detection of
2-chloropyridine in the crude reaction mixture, it is suspected
Acknowledgment. We thank NSERC and the University
of Toronto for funding of this research. We also thank Dr.
Alan Lough of the University of Toronto for X-ray analysis.
(12) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.;
Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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2005, 44, 5516. (c) Lee, C. L. K.; Loh, T. P. Org. Lett. 2005, 7, 2965. (d)
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OL101067D
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Pucheault, M.; Darses, S.; Genet, J. P. Eur. J. Org. Chem. 2002, 3552. (c)
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(16) Conversion of 14 to epibatidine in 89% yield has been reported;
see ref 14a.
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