Regio- and enantioselective N-allylations of imidazole, benzimidazole, and purine heterocycles catalyzed by single-component metallacyclic iridium complexes

Article abstract of DOI:10.1021/ja902243s

Highly regio- and enantioselective iridium-catalyzed N-allylations of benzimidazoles, imidazoles, and purines have been developed. N-Allylated benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity

Full text of DOI:10.1021/ja902243s

Published on Web 05/29/2009
Regio- and Enantioselective N-Allylations of Imidazole,
Benzimidazole, and Purine Heterocycles Catalyzed by
Single-Component Metallacyclic Iridium Complexes
Levi M. Stanley and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue, Urbana, Illinois 61801
Received March 30, 2009; E-mail: jhartwig@illinois.edu
Abstract: Highly regio- and enantioselective iridium-catalyzed N-allylations of benzimidazoles, imidazoles,
and purines have been developed. N-Allylated benzimidazoles and imidazoles were isolated in high yields
(up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from
the reactions of benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the
presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were
also obtained in high yields (up to 91%) with high N9/N7 selectivity (up to 96:4), high branched-to-linear
selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions
encompass a range of benzimidazole, imidazole, and purine nucleophiles, as well as a variety of
unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common
amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustrate the effect of
nucleophile pKa on the rate of iridium-catalyzed N-allylation reactions. Kinetic studies on the allylation of
benzimidazole catalyzed by metallacyclic iridium-phosphoramidite complexes, in combination with studies
on the deactivation of these catalysts in the presence of heterocyclic nucleophiles, provide insight into the
effects of the structures of the phosphoramidite ligands on the stability of the metallacyclic catalysts. The
data obtained from these studies have led to the development of N-allylations of benzimidazoles and
imidazoles in the absence of an exogenous base.
Introduction
(-)-carbovir illustrates the utility of enantioselective N-allyla-
tions of heterocyclic nucleophiles.13 Additional reports detailing
Enantioselective, metal-catalyzed allylic amination is a useful
method to prepare enantiomerically enriched allylic amines from
a variety of nitrogen nucleophiles and allylic electrophiles.1-10
However, metal-catalyzed enantioselective N-allylation of less
nucleophilic reagents, such as nitrogen-containing heterocycles,
remains underdeveloped, despite the synthetic utility of the
products.11,12 Currently, the most prominent catalysts for
enantioselective N-allylation of nitrogen-containing heterocycles
are chiral, nonracemic palladium complexes. A report by Trost
and co-workers on the palladium-catalyzed enantioselective
N-allylation of a guanine equivalent with a cyclic meso-diester
as a key step in the total synthesis of the carbocyclic nucleoside
enantioselective palladium-catalyzed N-allylations of heterocy-
clic nucleophiles have followed, but these processes are limited
by the inability to generate chiral allylic substitution products
selectively from achiral linear allylic esters.14-16
Over the past decade, enantioselective iridium-catalyzed
allylic amination has emerged as a powerful complement to
enantioselective, palladium-catalyzed allylic amination reac-
tions.17-40 Iridium-catalyzed allylic amination reactions make
possible the synthesis of enantioenriched allylic amines from
achiral linear reactants. However, enantioselective reactions that
selectively form branched allylic substitution products from
nitrogen heterocycles, other than phthalimide, and achiral linear
reactants are unknown (eq 1).41 These reactions would create a
direct approach to enantioenriched heterocycles that cannot be
accessed by hydrogenation of a CdN double bond or classical
resolution of racemic material and that can be transformed into
a series of further functionalized materials.42 Access to enan-
tiomerically enriched N-allylated heterocycles from unsym-
(1) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258–297.
(2) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2003, 42, 2580–
2584.
(3) Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837.
(4) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921–2944.
(5) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem.
Res. 2003, 36, 659–667.
(6) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. ReV. 2003, 103,
1875–1916.
(13) Trost, B. M.; Madsen, R.; Guile, S. G.; Elia, A. E. H. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1569–1572.
(7) Trost, B. M. Acc. Chem. Res. 1996, 29, 355–364.
(8) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395–422.
(9) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.; Weinhofen, R.
Chem. Commun. 2007, 675–691.
(14) Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037–3038.
(15) Trost, B. M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc.
2000, 122, 5947–5956.
(10) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349–3366.
(11) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles
in Life and Society; Wiley: New York, 1997.
(16) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054–6055.
(17) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.; Helmchen, G. Angew.
Chem., Int. Ed. 2008, 47, 7652–7655.
(12) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chem-
istry, 2nd ed.; Pergamon: Oxford, 2002.
(18) Bondzic, B. P.; Farwick, A.; Liebich, J.; Eilbracht, P. Org. Biomol.
Chem. 2008, 6, 3723–3731.
9
10.1021/ja902243s CCC: $40.75  2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 8971–8983 8971

A R T I C L E S
Stanley and Hartwig
metrical allylic electrophiles is presently limited to rhodium-
catalyzed reactions of N3-benzoyl thymine or a dihydropyrimidin-
2(3H)-one with enantioenriched secondary allylic carbonates
with retention of configuration.43,44
The products of these reactions are relevant to medicinal
chemistry because of the established biological activity associ-
ated with benzimidazole,45 imidazole,46 and purine derivatives.47
For example, the chiral N-allyl imidazoles are advanced
intermediates to a class of kinase inhibitors,48,49 while the N-allyl
purines are chiral precursors to a family of antiretroviral
drugs.50-53 Furthermore, the N-allyl heterocycle products
contain a terminal olefin that makes possible the straightforward
(19) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org.
Lett. 2007, 9, 3949–3952.
(20) Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 11680–
11681.
(21) Lee, J. H.; Shin, S.; Kang, J.; Lee, S. J. Org. Chem. 2007, 72, 7443–
7446.
Figure 1. Cyclometalated iridium catalyst precursors (1, 2a, and 2b) and
phosphoramidite ligands (L1 and L2).
(22) Spiess, S.; Berthold, C.; Weinhofen, R.; Helmchen, G. Org. Biomol.
Chem. 2007, 5, 2357–2360.
(23) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc.
2007, 129, 7508–7509.
syntheses of R-imidazolyl alcohol, R-purinyl alcohol, ꢀ-imida-
zolyl alcohol, and ꢀ-purinyl alcohol derivatives.
(24) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2007, 46, 3139–3143.
(25) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774–775.
(26) Nemoto, T.; Sakamoto, T.; Matsumoto, T.; Hamada, Y. Tetrahedron
Lett. 2006, 47, 8737–8740.
(27) Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 11770–11771.
(28) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich,
K. Chem.sEur. J. 2006, 12, 3596–3609.
(29) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 15506–15514.
(30) Welter, C.; Moreno, R. M.; Streiff, S.; Helmchen, G. Org. Biomol.
Chem. 2005, 3, 3266–3268.
(31) Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen, G. Chem. Commun.
2005, 3541–3543.
(32) Polet, D.; Alexakis, A. Org. Lett. 2005, 7, 1621–1624.
(33) Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093–1096.
(34) Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y. Org. Lett.
2004, 6, 4631–4634.
(35) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43,
4797–4800.
(36) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int. Ed. 2004,
43, 2426–2428.
(37) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun.
2004, 896–897.
We report the formation of enantioenriched, branched N-allyl
heterocycles from reactions of benzimidazoles, imidazoles, and
purines with achiral linear allylic carbonates in the presence of
single-component iridium catalysts. The new iridium catalysts,
along with the proper base, improve the efficiency of the
allylation process, overcome isomerization of the product to the
enamine, and lead to the formation of products with high
enantioselectivity, high regioselectivity for addition to the more
substituted position of the allyl electrophile, and high selectivity
for the addition to the N9 position over the N7 position of
purines. A combination of competition experiments, kinetic
studies, and experiments on catalyst deactivation create an
improved understanding of the activity and stability of the
metallacyclic iridium catalysts. In addition to revealing a new
class of asymmetric N-allylation reactions, these studies led to
the identification of an appropriate iridium catalyst for base-
free N-allylations of benzimidazole and imidazole nucleophiles.
(38) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 14272–14273.
(39) Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 116–117.
(40) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164–
15165.
(41) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem., Int. Ed.
2006, 45, 5546–5549.
(42) Gandelman, M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
2393–2397.
Results and Disscussion
Catalyst Identification and Optimization of Reaction Condi-
tions. We previously showed that complex 1 (Figure 1), which
is generated from [Ir(COD)Cl]2, phosphoramidite ligand L1 in
Figure 1, and base, catalyzes asymmetric allylic substitutions
with weakly basic nitrogen nucleophiles (arylamines), as well
as basic nitrogen nucleophiles (benzylic amines and alkyl-
amines), to form branched allylic substitution products.38 Thus,
initial studies to develop iridium-catalyzed asymmetric N-
allylations of nitrogen heterocycles containing acidic N-H
bonds were conducted with preformed metallacycle 1 as catalyst.
The model reaction of methyl cinnamyl carbonate (3a) with
benzimidazole (4a) was selected to test the viability of metal-
lacycle 1 as a catalyst for allylic substitutions with nitrogen-
containing heterocycles.
(43) Evans, P. A.; Lai, K. W.; Zhang, H.-R.; Huffman, J. C. Chem.
Commun. 2006, 844–846.
(44) Evans, P. A.; Qin, J.; Robinson, J. E.; Bazin, B. Angew. Chem., Int.
Ed. 2007, 46, 7417–7419.
(45) Alamgir, M.; Black, D. S. C.; Kumar, N. Top. Heterocycl. Chem. 2007,
9, 87–118.
(46) De Luca, L. Curr. Med. Chem. 2006, 13, 1–23.
(47) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987–
4006.
(48) Graczyk, P. P.; et al. Bioorg. Med. Chem. Lett. 2005, 15, 4666–4670.
(49) Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490–
491.
(50) Simons, C. Nucleoside Mimetics. Their Chemistry and Biological
Properties.; Gordon and Breach: Australia, 2001.
(51) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.; Schinazi,
R. F.; Chu, C. K. J. Med. Chem. 2001, 44, 3985–3993.
(52) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and L-
Nucleosides; Kluwer Academic: Dordrecht, 1998.
(53) Anastasi, C.; Quelever, G.; Burlet, S.; Garino, C.; Souard, F.; Kraus,
J.-L. Curr. Med. Chem. 2003, 10, 1825–1843.
In contrast to reactions of amines with methyl cinnamyl
carbonate, no reaction occurred between benzimidazole and
methyl cinnamyl carbonate (Table 1, entry 1). The same reaction
with added base did occur, but this reaction conducted without
9
8972 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Ir-Catalyzed N-Allylation of Heterocycles
A R T I C L E S
Table 1. Study of Metallacyclic Iridum Catalyst Precursors and Reaction Conditions for the Allylation of Benzimidazole with Methyl Cinnamyl
Carbonatea
entry
catalyst (mol %)
additive (mol %)
base
time (h)
conversion (%)b
5a/6a/7ab
yield (%)c
ee (%)d
1
2
1 (2)
1 (2)
1 (2)
1 (2)
1 (1)
1 (1)
2a (2)
2b (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (2)
[Ir(COD)Cl]2 (1)
[Ir(COD)Cl]2 (1)
[Ir(COD)Cl]2 (1)
[Ir(COD)Cl]2 (1)
[Ir(COD)Cl]2 (0.5)
[Ir(COD)Cl]2 (0.5)
--
10
4
4
<5
99
88
92
54
74
99
99
99
33
99
99
99
73
48
NDe
0
0
85
73
NDe
NDe
96
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Na3PO4
Li3PO4
KOt-Bu
NaOt-Bu
Cs2CO3
K2CO3
Na2CO3
0:0:100
98:2:0
99:1:0
18:15:67
85:1:14
99:1:0
99:1:0
99:1:0
99:1:0
63:3:34
2:2:96
94:3:3
99:1:0
99:1:0
3
4f,g
5
4
96
16
24
2
2
3
3
3
3
3
(10)h
(64)h
92
NDe
NDe
97
6g,i
7
--
--
--
--
--
--
--
--
--
8
9
90
90
98
97
10
11
12
13
14
15
(32)h
(56)h
(1)h
85
NDe
NDe
NDe
97
3
3
(71)h
(47)h
NDe
NDe
a See Supporting Information for experimental details. b Determined by 1H NMR spectroscopy of the crude reaction mixture. c Isolated yield of 5a.
d Determined by chiral HPLC. e Not determined. f Catalyst 1 (2 mol %) was generated in situ by heating [Ir(COD)Cl]2 (2 mol %) and L1 (4 mol %)
with propylamine (360 mol %) at 50 °C for 20 min. g The excess propylamine was removed under reduced pressure, and the mixture containing catalyst
1 was dissolved in THF (1 mL) and used without further purification. h Yield of 5a was determined by 1H NMR spectroscopy. i Catalyst 1 (1 mol %)
was generated in situ by heating [Ir(COD)Cl]2 (1 mol %) and L1 (2 mol %) with propylamine (180 mol %) at 50 °C for 20 min.
the proper choice of base led to a mixture of N-allylazole and
enamine from isomerization of the initial N-allylazole product
or to the enamine as the exclusive product. For example, the
reaction of methyl cinnamyl carbonate with benzimidazole in
the presence of 2 mol % 1, 1 mol % [Ir(COD)Cl]2 to trap L1
after dissociation, and 1.0 equiv of Cs2CO3 gave enamine 7a
as the only reaction product (entry 2).54 In contrast, the reaction
of methyl cinnamyl carbonate with benzimidazole in the
presence of 1.0 equiv of K3PO4 and 2 mol % 1 and 1 mol %
[Ir(COD)Cl]2 gave the branched N-allylation product 5a in high
yield, branched-to-linear ratio, and enantioselectivity (entry 3).
The reaction catalyzed by 2 mol % 1 generated in situ from 4
mol % L1 and 2 mol % [Ir(COD)Cl]2 also occurred to high
conversion and with high selectivities (entry 4).35 However,
reactions of benzimidazole conducted with lower amounts of
the catalyst precursors (1 mol % 1 and 0.5 mol % [Ir(COD)Cl]2)
formed the branched allylic substitution product 5a in lower
yields due to the formation of substantial amounts of enamine
7a (entry 5). Likewise, substantial isomerization of allylic amine
5a to enamine 7a occurred when the catalyst was generated in
situ from 2 mol % L1 and 1 mol % [Ir(COD)Cl]2 (entry 6).
This isomerization of the allylation product to the enamine was
not observed during studies of the allylation of amines reported
previously.33,35,38,40
iridium-phosphoramidite complex [Ir(COD)(L1)Cl] is not an
active catalyst for the allylic substitution reaction but is a catalyst
for the isomerization process. After 4 h in the presence of 2
mol % [Ir(COD)(L1)Cl], 36% of pure N-allyl benzimidazole
5a in THF solvent converted to the isomeric enamine 7a. This
observation is similar to the known isomerizations of allyl ethers
and allylamides in the presence of the iridium-phosphine
complex [Ir(COD)(PCy3)Cl].54,55 In addition to avoiding the
species that leads to isomerization of 5a to 7a, catalyst 2a would
be simpler to use because an additive is not required to form
the active iridium catalyst prior to addition of the reagents.
Indeed, the reaction of methyl cinnamyl carbonate with
benzimidazole in the presence of 2 mol % of the single-
component catalyst [Ir(COD)(κ2-L1)(ethylene)] (2a), or the
related catalyst [Ir(COD)(κ2-L2)(ethylene)] (2b) generated from
the ortho-anisyl substituted phosphoramidite L2,28,36 occurred
in high yield, branched-to-linear selectivity, and enantioselec-
tivity and without isomerization of the branched substitution
product 5a to the enamine 7a (entries 7 and 8). Furthermore,
the correct choice of base was necessary for the model reaction
catalyzed by 2a to occur with acceptable rates of reaction and
high selectivities. The reaction of methyl cinnamyl carbonate
with benzimidazole in the presence of K3PO4 or Na3PO4 gave
product 5a in high yield and selectivity over 2-3 h reaction
times (entries 7 and 9), but the same reaction in the presence
of Li3PO4 occurred to only 33% conversion after 3 h (entry
10). In contrast, reactions conducted in the presence of alkali
metal alkoxide bases resulted in complete conversion of the
methyl cinnamyl carbonate, but ∼35% of the branched allylation
product 5a converted to the isomeric enamine 7a in the presence
of KOt-Bu (entry 11) and all of 5a converted to 7a during
reactions conducted in the presence of NaOt-Bu (entry 12). The
model reaction catalyzed by 2a also occurred in the presence
of alkali carbonate bases, and the rates of reaction parallel the
To improve the efficiency of the allylation process further,
we investigated reactions catalyzed by the ethylene adduct 2a
of the active metallacyclic catalyst, which was recently identified
as part of mechanistic studies of iridium-catalyzed allylation.20
Catalyst 2a offered the potential for N-allylations of nitrogen
heterocycles to occur with lower amounts of iridium and without
isomerization to the corresponding enamine because [Ir-
(COD)Cl]2 is not necessary to trap the phosphoramidite ligand
L1 after dissociation from metallacycle 1. The four-coordinate
(54) Neugnot, B.; Cintrat, J.-C.; Rousseau, B. Tetrahedron 2004, 60, 3575–
3579.
(55) Higashino, T.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2000, 2, 4193–4195.
9
J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8973

A R T I C L E S
Stanley and Hartwig
Table 2. Iridium-Catalyzed Allylation of Benzimidazole: Substrate Scopea
entry
3 (R)
catalyst
time (h)
5
yield (%)b
5/6c
ee (%)d
1
2
3
4
5
6
7
8
9
3a (Ph)
2a
2a
2a
2a
2a
2a
2b
2a
2a
2
3
5
3
8
3
3
5
3
5a
5b
5c
5d
5e
5f
5f
5g
5h
92
90
84
92
90
93
97
90
90
99:1
99:1
96:4
98:2
98:2
99:1
99:1
94:6
92:8
97
97
95
97
97
80
92
96
94
3b (4-MeO-C6H4)
3c (4-Br-C6H4)
3d (3-Me-C6H4)
3e (2-naphthyl)
3f (2-MeO-C6H4)
3f (2-MeO-C6H4)
3g (2-furyl)
3h (propyl)
a See Supporting Information for experimental details. b Isolated yield of 5. c Determined by 1H NMR spectroscopy of the crude reaction mixture.
d Determined by chiral HPLC.
Scheme 1. Limitations on the Iridium-Catalyzed Allylation of
Benzimidazole
solubility and ionic charcter of these bases. For example, the
reaction of methyl cinnamyl carbonate with benzimidazole in
the presence of Cs2CO3 occurred to complete conversion after
3 h (entry 13), while the reactions conducted in the presence of
K2CO3 and Na2CO3 occurred to 73% and 48% conversion after
3 h (entries 14 and 15). The high yield, high selectivities, and
absence of isomerization from reactions conducted with catalysts
2a and 2b and the inexpensive base K3PO4 led us to study the
scope of the iridium-catalyzed N-allylation process with a variety
of allylic carbonate electrophiles and benzimidazole nucleophiles
in the presence of complexes 2a and 2b as catalyst and K3PO4
as base.
Enantioselective N-Allylation of Benzimidazoles. Results from
the N-allylation of benzimidazoles with a series of allylic
carbonates under the optimized conditions are summarized in
Table 2. Reactions of benzimidazole with a variety of electron-
rich or electron-neutral cinnamyl carbonates containing meta
or para substituents gave the corresponding chiral benzimidazole
products in high yields with good to excellent regio- and
enantioselectivities (Table 2, entries 1-5). The chiral benzimi-
dazoles produced from the allylations of benzimidazole with
allylic carbonates 3a-3e catalyzed by metallacycle 2a occurred
with 96:4 to 99:1 branched-to-linear regioselectivity, and the
branched isomers were isolated in 84-94% yield with 95-97%
enantiomeric excess.
However, the reaction of methyl ortho-methoxycinnamyl
carbonate 3f with benzimidazole catalyzed by metallacycle 2a
occurred with modest enantioselectivity (80% ee, entry 6). This
with benzimidazole was isolated in 90% yield with 92:8
branched-to-linear selectivity and 94% ee (entry 9).
The allylation of benzimidazole occurred more slowly and
with lower selectivity with cinnamyl carbonates that are
substituted with strongly electron-withdrawing substituents in
the para position. For example, the reaction of benzimidazole
with methyl para-trifluoromethylcinnamyl carbonate in the
presence of 4 mol % 2a occurred to only 21% conversion after
8 h at 50 °C, and the enamine 7i was the only observable product
of the reaction (Scheme 1, eq 1). The allylation of benzimidazole
with methyl para-trifluoromethylcinnamyl carbonate occurred
to completion in the presence of 4 mol % 2b (eq 2). However,
the addition of 1-phenylpropyne was necessary to prevent
complete isomerization of the branched allylic substitution
result is consistent with lower enantioselectivities for iridium-
catalyzed allylic substitution reactions of ortho-substituted
cinnamyl carbonates reported previously.9,35,40 However, the
reaction of benzimidazole with methyl ortho-methoxycinnamyl
carbonate in the presence of 2 mol % 2b, instead of 2a, occurred
with high enantioselectivity (92% ee, entry 7).
Heteroaryl and aliphatic allyl carbonates also reacted selec-
tively with benzimidazole. The chiral N-allylic benzimidazole
produced from the reaction of the 2-furyl-substituted allyl
carbonate 3g with benzimidazole was isolated in 90% yield with
94:6 branched-to-linear selectivity and 96% ee (entry 8). The
product from the reaction of hex-2-enyl methyl carbonate 3h
9
8974 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Ir-Catalyzed N-Allylation of Heterocycles
A R T I C L E S
Table 3. Scope of the Allylation Reaction with Various
Benzimidazole Nucleophilesa
Figure 2. Chiral substructures of biologically active benzimidazoles.
yield due a competing O-allylation process (entry 10). The
selectivity for N- versus O-allylation did not improve when
reactions were conducted at room temperature in the presence
of 2 mol % 2a (entry 11). However, this reaction formed product
5n in 75% yield with high branched-to-linear selectivity (95:
5), N/O selectivity (90:10), and enantioselectivity (96%) when
conducted at room temperature in the presence of 2 mol % of
the ortho-OMe catalyst 2b (entry 12).
Synthetic Utility of N-Allyl Benzimidazoles. Chiral benzimi-
dazoles and the related benzimidazolones, which can be
generated by oxidation of benzimidazoles, exhibit a diverse array
of biological activity. Within these product classes chiral
R-benzimidazolyl alcohols, R-benzimidazolyl acids, R-benz-
imidazolyl amides, ꢀ-benzimidazolyl alcohols, ꢀ-benzimidazolyl
acids, and ꢀ-benzimidazolyl amides are heterocyclic substruc-
tures (Figure 2) present in compounds studied as vanilloid
receptor 1 (VR1) inhibitors,57,58 integrin antagonists,59 farnesoid-
X-receptor (FXR) agonists,60 G-protein coupled receptor (GPCR)
MrgX1 antagonists,61 and kinesin spindle protein (KSP) inhibi-
tors.62 Related benzimidazolones have been studied as vaso-
pressin (AVP) receptor antagonists63 and chymase inhibitors.64
Enantioenriched R-benzimidazolyl alcohol and R-benzimi-
dazolyl acid derivatives have been synthesized previously by a
sequence including the coupling of ortho-nitroaryl halides or
1,2-dihalobenzenes with chiral amino alcohol and amino acid
derivatives to generate ortho-nitroanilines or 1,2-benzenedi-
amines.65,66 These intermediates are readily converted to R-ben-
zimidazolyl alcohol and R-benzimidazolyl acid derivatives by
reduction, in the case of ortho-nitroanilines to form a 1,2-
benzenediamine, and condensation with a formic acid equivalent.
a See Supporting Information for experimental details. b Determined
by 1H NMR spectroscopy of the crude reaction mixture. c Isolated yield
of 5. d Determined by chiral HPLC. e Reaction was run at room
temperature.
product 5i to the enamine 7i,56 and the yield of 5i was only
1
25% by H NMR spectroscopy under optimized conditions.
Additional benzimidazole nucleophiles underwent the allylic
substitution process in moderate to high yield and with high
enantioselectivity. In these cases, the most active and selective
catalyst depended on the nucleophile. Some of these reactions
occurred in higher yields with higher selectivities in the presence
of the ortho-anisyl catalyst 2b. For example, the reaction of
2-phenylbenzimidazole with methyl cinnamyl carbonate in the
presence of 2 mol % of 2b gave product 5j in 96% ee (Table 3,
entry 2), while the reaction conducted with the parent catalyst 2a
formed this product in 86% ee (entry 1). Likewise, reactions of
2-methylbenzimidazole with methyl cinnamyl carbonate 3a and
the hindered aliphatic carbonate 3j occurred to low conversions
when conducted with catalyst 2a (entries 3 and 5) but formed the
chiral benzimidazole 5k and 5l in high yields and with high
selectivities in the presence of catalyst 2b (entries 4 and 6).
However, the reaction of methyl cinnamyl carbonate with 2-chlo-
robenzimidazole to form product 5m was more selective for the
branched substitution product when conducted with parent catalyst
2a. The branched-to-linear ratio for the reaction of methyl cinnamyl
carbonate with 2-chlorobenzimidazole at 50 °C in the presence of
2a was 85:15 (entry 7) but was only 58:42 in the presence of 2b
(entry 8). A further increase in the branched-to-linear selectivity
occurred when this reaction was conducted at room temperature
(5/6 ) 89:11, entry 9).
(57) Besidski, Y.; Kers, I.; Nylof, M.; Rotticci, D.; Slaitas, A.; Swensson,
M. PCT Int. Appl. (2004) WO 04/100865 A2.
(58) Besidski, Y.; Kers, I.; Nylof, M.; Slaitas, A. PCT. Int. Appl. (2006)
WO 06/033620 A1.
(59) Bloxham, J.; Borzillo, G. V.; Collington, E. W.; Sadiq, S.; Sambrook
Smith, C. P.; Waller, C. L.; Wynne, G. M. PCT Int. Appl. (2006)
WO 06/053342 A2.
(60) Benson, G. M.; Bleicher, K.; Chucholowski, A.; Dehmlow, H.; Grether,
U.; Kuhn, B.; Martin, R. E.; Niesor, E. J.; Panday, N.; Richter, H.;
Schuler, F.; Warot, X. M.; Wright, M.; Yang, M. PCT. Int. Appl.
(2008) WO 08/000643 A1.
(61) Olsson, R.; Knapp, A. E.; Eskildsen, J. PCT. Int. Appl. (2008) WO
08/052072 A2.
(62) Shipps, G. W., Jr.; Ma, Y.; Lahue, B. R.; Seghezzi, W.; Herbst, R.;
Chuang, C.; Annis, D. A.; Kirtley, M. PCT. Int. Appl. (2008) WO
08/153701 A1.
(63) Arndt, T.; Oost, T.; Lubisch, W.; Wernet, W.; Hornberger, W.; Unger,
L.; Ruiz Caro, J. PCT. Int. Appl. (2006) WO 08/025736 A1.
(64) Abeywardane, A.; Cook, B. N.; Delombaert, S.; Emmanuel, M. J.;
Guo, X.; Kim, J. M.; Hao, M.-H.; Lo, H. Y.; Man, C. C.; Morwick,
T.; Nemoto, P. A.; Qian, K. C.; Takahashi, H.; Taylor, S. J. PCT. Int.
Appl. (2008) WO 08/147697 A1.
The reactions of 2-hydroxylmethylbenzimidazole 4e with
methyl cinnamyl carbonate 3a were also affected by N- versus
O-allylation. In the presence of 2 mol % 2a, this reaction
occurred with 88:12 branched-to-linear selectivity and 93% ee,
but the N-allylated product 5n was isolated in a modest 53%
(65) Lee, J.; Doucette, A.; Wilson, N. S.; Lord, J. Tetrahedron Lett. 2001,
42, 2635–2638.
(66) Rivas, F. M.; Giessert, A. J.; Diver, S. T. J. Org. Chem. 2002, 67,
1708–1711.
(56) Ueno, S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 1928–1931.
9
J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8975

A R T I C L E S
Stanley and Hartwig
catalysts.68-70 However, enantioselective N-allylations of imi-
dazole nucleophiles catalyzed by metal complexes that generate
branched substitution products from the linear allylic esters have
not been reported. Thus, we sought conditions to conduct the
enantioselective allylation of imidazoles with the metallacylic
iridium catalyst. The reaction of methyl cinnamyl carbonate with
imidazole in the presence of 2 mol % of the parent catalyst 2a
occurred with high branched-to-linear selectivity and enanti-
oselectivity but gave product 12a in a moderate 76% yield
(Table 4, entry 1). The lower yield of product from the allylation
of imidazole with methyl cinnamyl carbonate than from the
allylation of benzimidazole (compare Table 2, entry 1 with Table
4, entry 1) resulted from partial isomerization of the N-allyl
imidazole product 12a to the corresponding achiral enamine.
However, the reaction of imidazole with methyl cinnamyl
carbonate in the presence of 2 mol % ortho-OMe catalyst 2b
occurred without isomerization to the enamine (entry 2). This
reaction formed product 12a in 87% yield with excellent
branched-to-linear selectivity and enantioselectivity. Based on
these results, catalyst 2b was chosen for further studies on the
allylation of imidazole nucleophiles.
Scheme 2. Synthesis of Chiral R-Benzimidazolyl Alcohols,
ꢀ-Benzimidazolyl Alcohols, and ꢀ-Benzimidazolyl Acids
4,5-Diphenylimidazole, 2-phenylimidazole, and 4-phenylimi-
dazole reacted with allylic carbonates in the presence of catalyst
2b to form N-allylation products. The reaction of 4,5-diphe-
nylimidazole with methyl cinnamyl carbonate formed product
12b in good yield with high selectivities (entry 3). The reaction
of 2-phenylimidazole with methyl cinnamyl carbonate occurred
with high enantioselectivity, but the yield and regioselectivity
for the formation of product 12c were lower than those of the
reactions of other imidazole nucleophiles (entry 4). The reaction
of 4-phenyl imidazole occurred with nearly complete branched-
to-linear selectivity to form N1-allylated imidazole 12d in 75%
isolated yield with 98% ee. Moreover, the reaction of this
unsymmetrical imidazole with methyl cinnamyl carbonate
occurred with good N1/N3 selectivity (83:17, entry 5).
Formal Synthesis of a JNK3 Inhibitor. The bicyclic bisarylim-
idazole 16 is a c-jun N-terminal kinase 3 (JNK3) inhibitor that
was originally synthesized in 6% overall yield in 14 linear
steps.48 Bergman, Ellman, and co-workers subsequently reported
an improved synthesis of 16 in 13% overall yield and 11 linear
steps (Figure 3)49 using a rhodium-catalyzed C-H bond
functionalization of the 1-(1-(tert-butyldiphenylsilyloxy)but-3-
en-2-yl)-4-(4-fluorophenyl)-1H-imidazole 18. Imidazole 18, the
substrate for the rhodium-catalyzed C-H bond functionalization
to form the key bicyclic imidazole 17, was synthesized from
2-(tert-butyldimethylsilyloxy)acetaldehyde and (SS)-tert-butane-
sulfinamide in 53% yield over five steps. Our ability to conduct
iridium-catalyzed allylations at the N1 position of an unsym-
metrical 4-arylimidazole selectively led us to study this process
as a simplified route to compound 18. After optimization of
conditions, we found that the reaction of (E)-4-(tert-butyldiphe-
nylsilyloxy)but-2-enyl methyl carbonate 19 with 4-(4-fluorophe-
nyl)-1H-imidazole 11e at room temperature in the presence of
4 mol % of ortho-MeO catalyst 2b occurred to high conversion
with nearly complete branched-to-linear selectivity and useful
N1/N3 selectivity (Scheme 3). The key N-allyl imidazole 18
was isolated from this reaction in 64% yield with 91% ee. This
These coupling strategies are practical methods to synthesize
chiral, nonracemic benzimidazoles when the intermediate 1,2-
benzenediamine is generated from an amino acid or an amino
alcohol derived from naturally occurring, enantioenriched amino
acids. However, these approaches require longer synthetic
sequences when the intermediate 1,2-benzenediamine is to be
derived from unnatural R-amino acids, ꢀ-amino acids, or the
corresponding amino alcohols.
Our iridium-catalyzed synthesis of enantiomerically enriched
benzimidazoles can overcome these limitations because a variety
of allylic carbonates are suitable electrophiles in the allylic
substitution reaction. Thus, we investigated the transformation
of our chiral N-allylated benzimidazole products to the chiral,
nonracemic R- and ꢀ-benzimidazolyl alcohols (Scheme 2),
which could be used to synthesize the corresponding carboxylic
acid and amide derivatives. Ozonolysis of N-allyl benzimida-
zoles 5a and 5h, followed by reduction of the resulting ozonides
with NaBH4, formed (S)-2-(1H-benzo[d]imidazol-1-yl)-2-phe-
nylethanol 8a67 and (S)-2-(1H-benzo[d]imidazol-1-yl)pentan-
1-ol 8b in 84% and 93% yield, respectively (eq 3). The sequence
of oxidation and reduction occurs with full retention of the
enantiomeric excess of the starting N-allylated benzimidazoles.
Hydroboration of N-allyl benzimidazoles 5a and 5h, followed
by oxidation of the resulting alkylborane in the presence of basic
hydrogen peroxide, gave (R)-3-(1H-benzo[d]imidazol-1-yl)-3-
phenylpropan-1-ol 9a and (S)-3-(1H-benzo[d]imidazol-1-yl)-
hexan-1-ol 9b in 85% and 91% yield, respectively, with full
retention of the enantiomeric excess (eq 4). Furthermore, the
ꢀ-benzimidazolyl acid 10, which is an integrin antagonist,59 was
readily synthesized by oxidation of the optically active ꢀ-ben-
zimidazolyl alcohol in the presence of iodobenzene diacetate,
TEMPO, and sodium bicarbonate (eq 5). This reaction formed
ꢀ-benzimidazolyl acid 10 in 97% ee prior to recrystallization,
and product 10 was isolated in 74% yield and 99% ee after
recrystallization from dichloromethane.
Enantioselective N-Allylation of Imidazole Nucleophiles.
N-Allylation reactions between imidazole nucleophiles and
allylic electrophiles are known to occur in the presence of Pd(0)
(68) Saville-Stones, E. A.; Lindell, S. D.; Jennings, N. S.; Head, J. C.;
Ford, M. J. J. Chem. Soc., Perkin Trans. 1 1991, 2603–2604.
(69) Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett. 1992, 33, 2481–
2484.
(67) The absolute configuration of 8a was assigned after conversion to the
corresponding methyl ether. See the Supporting Information for
additional details.
(70) Arnau, N.; Moreno-Manas, M.; Pleixats, R.; Villarroya, M. J. Het-
erocycl. Chem. 1995, 32, 1325–1334.
9
8976 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Ir-Catalyzed N-Allylation of Heterocycles
A R T I C L E S
Table 4. Iridium-Catalyzed Allylation of Imidazolesa
entry
catalyst (mol %)
11
time (h)
12
N1/N3b,c
yield (%)d
12/13b
ee (%)e
1
2
3
4
5
2a (2)
2b (2)
2b (2)
2b (2)
2b (2)
11a
11a
11b
11c
11d
3
2
3
5
3
12a
12a
12b
12c
12d
NAf
NAf
NAf
NAf
83:17
73
87
83
68
75
98:2
99:1
95:5
88:12
99:1
96
98
98
95
98
a See Supporting Information for experimental details. b Determined by 1H NMR spectroscopy of the crude reaction mixture. c N1/N3 ratio indicates
the ratio of N1 allylation to N3 allylation (12+13)/(14+15). d Isolated yield of 12. e Determined by chiral HPLC. f Not applicable.
philes is striking when compared to analogous enantioselective
palladium-catalyzed allylic substitution reactions that often result
in N9/N7 selectivities of less than 9:1.13-15
Similar yields of the N9 allylation products 21 and levels of
regio- and enantioselectivity were observed for the reactions of
6-chloropurine with a series of cinnamyl carbonates (entries
3-6).72 With few exceptions, the N9/N7 selectivities were
>93:7, the N9 branched-to-linear ratios were >90:10, and the
Figure 3. Bergman and Ellman’s retrosynthesis of JNK3 inhibitor 16.
N9 substitution products 21 were isolated in >75% yield with
>90% ee. One exception to these trends was the reaction of
6-chloropurine with methyl ortho-methoxycinnamyl carbonate
3f, which formed the N-allylated purine product 21f with
moderate enantioselectivity in the presence of either catalyst
2a or catalyst 2b (entries 7 and 8, 2af78% ee, 2bf81% ee).
The reaction of 6-chloropurine with aliphatic carbonate 3k in
the presence of 4 mol % 2a occurred with poor N9/N7
selectivity (74:26, entry 9). However, the same reaction
conducted with 4 mol % 2b as the catalyst occurred with high
regio- and enantioselectivity (N9/N7 ) 93:7, entry 10). The
difference in N9/N7 selectivity for the reaction of 6-chloropurine
with 3k in the presence of parent catalyst 2a and ortho-OMe
catalyst 2b is probably due to a faster decomposition of catalyst
2a than of catalyst 2b. The relative rates of catalyst decomposi-
tion are discussed in greater detail later in this paper.
Several other purines underwent the allylation process in high
yields and with high selectivities (Table 6). For example,
reactions of 6-(methylthio)purine 20b and adenine 20c with
methyl cinnamyl carbonate occurred to form products 21h and
21i with high N9/N7 and N9 branched-to-linear selectivities
(entries 1 and 2). From these reactions, the branched allylated
purine derivatives 21h and 21i were isolated in high yields with
high enantioselectivities. The reaction of adenine conducted with
a lower 2 mol % loading of parent catalyst 2a occurred with a
similar yield and selectivity for formation of 21i as the reaction
conducted with 4 mol % 2a (entry 3). In contrast, the allylations
of bis-Boc-adenine 20d and 2-amino-6-chloropurine 20e, a
guanine equivalent, with methyl cinnamyl carbonate occurred
with higher selectivities when conducted with ortho-OMe
catalyst 2b than with the parent catalyst 2a. The reaction of
bis-Boc-adenine 20d with methyl cinnamyl carbonate to form
product 21j proceeded to low conversion (entry 4) in the
presence of 2 mol % 2a but occurred to high conversion with
reaction is a more direct approach to 18 than the previously
reported five-step sequence and occurs in slightly higher yield.
Rhodium-catalyzed cyclization of 18 gave bicyclic imidazole
17 in 63% yield with 88% ee. Bergman, Ellman, and co-workers
have developed efficient conditions to synthesize the JNK3
inhibitor 16 from compound 17 in 49% yield over five steps.
Enantioselective N-Allylation of Purine Nucleophiles. Having
developed conditions for the enantioselective allylation of
benzimidazoles and imidazoles, we tested these procedures for
the more complex, but related, N-allylation of purines (Scheme
4). Such reactions would create a rapid route to a variety of
chiral non-natural nucleotides, a class of compounds that have
been widely studied as potential antiviral drugs.50-53 However,
the N-allylation of these reagents is complicated by the potential
that allylation could occur at N9 or N7 and that it could occur
at the exocyclic nitrogen of adenine or the guanine surrogate,
2-amino-6-chloropurine.
Our effort to develop the allylation of purines initially focused
on reactions of 6-chloropurine 20a with a variety of allylic
carbonates in the presence of the parent catalyst 2a (Table 5).
The allylation of 6-chloropurine with methyl cinnamyl carbonate
3a in the presence of 2 mol % 2a occurred with incomplete
conversion of 3a, but with excellent selectivities (entry 1). The
reaction of 6-chloropurine with 3a did, however, occur to high
conversion with a high branched-to-linear ratio (21a/22a )
93:7) in the presence of 4 mol % of 2a as catalyst, and the
N9-branched product was isolated in 83% yield with 93% ee
(entry 2). Furthermore, the N9/N7 selectivity for this reaction
was 94:6.71 Although purine nucleophiles are known to react
preferentially at the N9-position, the observed N9/N7 selectivity
for iridium-catalyzed allylic substitution with purine nucleo-
(71) The reaction of 20a with 3a in the presence of 4 mol % 2b also
occurred with high branched-to-linear selectivity (90:10) and enanti-
oselectivity (92% ee). However, the N9/N7 selectivity is reduced to
83:17.
(72) The preference for N9-selectivity was confirmed by NMR spectroscopy
(HMBC) for compound 21e. See the Supporting Information for
additional details.
9
J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8977

A R T I C L E S
Stanley and Hartwig
Scheme 3. Direct Synthesis of 18 by Iridium-Catalyzed Allylic Substitution as a Formal Synthesis of JNK3 Inhibitor 16
Scheme 4. Potential Products from an Iridium-Catalyzed Allylation
of Purine Nucleophiles
enine derivatives 26a and 26b, followed by oxidation of the
resulting alkylboranes in the presence of basic hydrogen
peroxide, gave MMTr-protected (R)-3-(6-amino-9H-purin-9-yl)-
3-phenylpropan-1-ol) 27a and MMTr-protected (S)-3-(6-amino-
9H-purin-9-yl)hexan-1-ol 27b in 82% and 77% yield (eq 7).
Thus, iridium-catalyzed allylation, followed by a combination
of ozonolysis and reduction or a combination of hydroboration
and oxidation, provides a new route to chiral, nonracemic
derivatives of adenine that are related to FDA approved reverse
transcriptase inhibitors.
Competition between Azole and Amine Nucleophiles. After
developing methods for the regio- and enantioselective N-
allylation of benzimidazoles, imidazoles, and purines, we
conducted a series of competition experiments to develop an
understanding of the relative nucleophilicities of these hetero-
cycles and other common nitrogen nucleophiles toward iridium-
catalyzed allylic substitution reactions (Scheme 6). These
experiments were designed to provide a basis to rationalize the
high yields for reactions of the imidazole, benzimidazole, and
purine reagents, which are typically weaker nucleophiles than
amines, toward metal-catalyzed allylic substitution reactions.
Mayr’s scale of nucleophilicity for nitrogen nucleophiles
provides benchmark reactivities of benzylamine, aniline, and
imidazole with S-methyldibenzothiophenium ion and a variety
of benzhydrylium ions as electrophiles.79,80 The nucleophilicity
and nucleophile-specific slope parameters for these nucleophiles
show that benzylamine reacts twice as fast as aniline and 20
times faster than imidazole with the activated electrophiles
studied by Mayr and co-workers. We conducted competition
experiments between imidazole and benzylamine, aniline,
benzimidazole, and bis-BOC-adenine to determine whether this
trend in nucleophilicity, based on reactions of nitrogen nucleo-
philes with S-methyldibenzothiophenium ion and benzhydrylium
ions as electrophiles, holds for iridium-catalyzed N-allylation
reactions.
Reactions of imidazole (2 equiv) and either benzylamine,
aniline, benzimidazole, or bis-Boc-adenine (2 equiv) with methyl
cinnamyl carbonate 3a (1.0 equiv) were performed in the
presence of K3PO4 (1.0 equiv) and 4 mol % 2b. The reaction
of 3a with benzylamine and imidazole gave the N-allylamine
and imidazole products 28 and 11a in a 74:26 ratio (eq 8). Thus,
benzylamine reacts faster than imidazole in this iridium-
catalyzed process, as expected, but the 3:1 ratio of relative rates
was much smaller than the 20:1 ratio that would be expected
based on Mayr’s nucleophile parameters for benzyl amine (N
) 13.46, s ) 0.62) and imidazole (N ) 10.41, s ) 0.70). The
discrepancy is best explained by a contribution from the reaction
high N9/N7 selectivity, branched-to-linear selectivity, and
enantioselectivity when conducted in the presence of 2 mol %
2b (entry 5). Likewise, the reaction of 2-amino-6-chloropurine
20e with methyl cinnamyl carbonate occurred with modest N9/
N7 selectivity (82:18, entry 6) in the presence of 2 mol % 2a
but occurred with excellent N9/N7 selectivity when conducted
in the presence of 2 mol % 2b (entry 7).
Application of the Enantioselective N-Allylation of Purine
Nucleophiles. (9H-Purin-9-yl)alcohols are key substructures of
the commercial antivirals adefovir and tenofovir, which are
adenine analogues (Figure 4). Adefovir is FDA approved for
treatment of hepatitis B infections, while tenofovir is FDA
approved for treatment of HIV and hepatitis B infections.73-76
Analogues of current antiviral compounds are important for
addressing the spread of viral resistance. Thus, we sought to
illustrate how chiral N-allylated adenine derivatives could be
converted to R-adeninyl alcohols and ꢀ-adeninyl alcohols, which
are optically active R-substituted analogues of the antiretrovirals
adefovir and tenofovir (Scheme 5). Ozonolysis of bis-BOC-
protected adenine derivatives 21j and 21l, followed by reduction
of the resulting ozonides with NaBH4, formed bis-Boc-protected
(S)-2-(6-amino-9H-purin-9-yl)-2-phenylethanol 25a and bis-
Boc-protected (S)-2-(6-amino-9H-purin-9-yl)pentan-1-ol 25b in
89% and 88% yield, respectively, without erosion of enantio-
meric purity (eq 6). Standard procedures for hydroboration and
oxidation gave complex product mixtures from reactions of bis-
BOC-protected adenine derivatives 21j and 21l.77,78 However,
hydroboration of the monomethoxytrityl(MMTr)-protected ad-
(73) De Clercq, E. Med. Res. ReV. 2008, 28, 929–953.
(74) De Clercq, E. Future Virol. 2006, 1, 709–715.
(75) Cihlar, T.; Delaney, W. E., IV.; Mackman, R. Modified Nucleosides
2008, 601–630.
(76) Tillmann, H. L. Therapeut. Clin. Risk. Manag. 2008, 4, 797–802.
(77) Brown, H. C.; Chen, J. J. Org. Chem. 1981, 46, 3978–3988.
(78) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem. 1989,
54, 5930–5933.
(79) Phan, T. B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2006, 45,
3869–3874.
(80) Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org. Chem. 2007, 72, 3679–
3688.
9
8978 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Ir-Catalyzed N-Allylation of Heterocycles
A R T I C L E S
Table 5. Iridium-Catalyzed Allylation of 6-Chloropurinea
entry
catalyst (mol %)
3 (R)
time (h)
21
N9/N7b,c
yield (%)d
21/22b
ee (%)e
1
2
3
4
5
6
7
8
9
10
2a (2)
2a (4)
2a (4)
2a (4)
2a (4)
2a (4)
2a (4)
2b (4)
2a (4)
2b (4)
3a (Ph)
3a (Ph)
8
5
5
5
5
5
4
4
5
2
21a
21a
21b
21c
21d
21e
21f
21f
21g
21g
94:6
94:6
96:4
94:6
89:11
93:7
95:5
94:6
74:26
93:7
63
83
91
76
75
77
60
84
68
85
93:7
93:7
98:2
91:9
95:5
93:7
95:5
90:10
92:8
91:9
94
93
92
95
90
92
78
81
96
94
3b (4-MeO-C6H4)
3c (4-Br-C6H4)
3d (3-Me-C6H4)
3e (2-Naphthyl)
3f (2-MeO-C6H4)
3f (2-MeO-C6H4)
3k (Heptyl)
3k (Heptyl)
a See Supporting Information for experimental details. b Determined by 1H NMR spectroscopy of the crude reaction mixture. c N9/N7 ratio indicates
the ratio of N9 allylation to N7 allylation (21+22)/(23+24). d Isolated yield of 21. e Determined by chiral HPLC.
Table 6. Allylation of Various Purine Nucleophiles with Methyl Cinnamyl Carbonatea
entry
catalyst (mol %)
20
time (h)
21
N9/N7b,c
yield (%)d
21/22b
ee (%)e
1
2
3
4
5
6
7
2a (4)
2a (4)
2a (2)
2a (2)
2b (2)
2a (2)
2b (2)
20b (R1 ) SMe, R2 ) H)
20c (R1 ) NH2, R2 ) H)
20c (R1 ) NH2, R2 ) H)
20d (R1 ) N(Boc)2, R2 ) H)
20d (R1 ) N(Boc)2, R2 ) H)
20e (R1 ) Cl, R2 ) NH2)
20e (R1 ) Cl, R2 ) NH2)
5
5
5
6
6
8
4
21h
21i
21i
21j
21j
21k
21k
96:4
96:4
95:5
90:10
92:8
82:18
96:4
91
81
88
29
82
75
83
98:2
93:7
94:6
92:8
92:8
95:5
94:6
92
96
96
93
96
97
98
a See Supporting Information for experimental details. b Determined by 1H NMR spectroscopy of the crude reaction mixture. c N9/N7 ratio indicates
the ratio of N9 allylation to N7 allylation (21+22)/(23+24). d Isolated yield of 21. e Determined by chiral HPLC.
Scheme 5. Synthesis of New Chiral Derivatives of Adenine
Analogue Antivirals
Figure 4. Adenine derivatives that are reverse transcriptase inhibitors.
of imidazolate, rather than imidazole. The imidazolate would
be generated by deprotonation of the heterocycle by K3PO4 or
the counterion of the iridium-allyl intermediate, which could
be the methyl carbonate or methoxide after decarboxylation of
the carbonate. If so, then the observed selectivity would result
from a competition between benzylamine and the imidazolate
or, more precisely, between benzylamine and an equilibrium
mixture of the neutral imidazole and the anionic imidazolate.
The competition experiment between aniline and imidazole
provides further evidence to support this hypothesis. N-Allyl
aniline and imidazole products 29 and 11a were formed in a
46:54 ratio favoring the imidazole product 11a (eq 9). This ratio
is, again, much smaller than the 10:1 ratio of rates for aniline
versus imidazole that would be expected from the nucleophile
parameters for these two nucleophiles (N ) 12.64, s ) 0.68
for aniline and N ) 10.41, s ) 0.70 for imidazole). Furthermore,
competition experiments between imidazole and either benz-
imidazole or bis-Boc-adenine favor the formation of the
benzimidazole product 5a (eq 10, 11a/5a ) 29:71) or the bis-
Boc-adenine product 21j (eq 11, 11a/21j ) 15:85), resulting
from allylation of the more acidic of the two nucleophiles in
9
J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8979

A R T I C L E S
Stanley and Hartwig
Scheme 6. Competition Experiments between Imidazole and
Amine or Heterocyclic Nitrogen Nucleophiles
Scheme 7. Allylation of Benzimidazole with 3a in the Absence of
Exogenous Base
heterocycle species, we studied the reaction of benzimidazole
with methyl cinnamyl carbonate catalyzed by 4 mol % 2a or 2
mol % 2b in the absence of K3PO4 at room temperature and at
50 °C (Scheme 7).
Two sets of data lead to several conclusions about the relative
importance of the potassium phosphate and the counterions of
the allyl complex as base. First, the reaction of 3a with 4a in
the presence of 4 mol % of the parent catalyst 2a was 68%
complete after 5 h at room temperature, while the same reaction
conducted at 50 °C was only 52% complete after 5 h (eq 12).
The reaction of 3a with 4a catalyzed by 2 mol % of the ortho-
OMe catalyst 2b was 85% complete after 4 h at room
temperature, while the same reaction conducted at 50 °C was
77% complete after 4 h (eq 13). Because these reactions
proceeded in the absence of added K3PO4, we conclude that
the methyl carbonate or methoxide generated in situ can serve
as the base to form the benzimidazolate nucleophile and that
base-free allylations of heterocyclic nucleophiles can be devel-
oped. Because higher conversions were observed for reactions
conducted in the absence of K3PO4 at room temperature than
from those at 50 °C, we conclude that increasing catalyst
deactivation occurs during the reactions with increasing
temperature.
Second, competition experiments that are analogous to those
shown in Scheme 6, but conducted in the absence of K3PO4,
generate product ratios that contain more of the species derived
from the less acidic nitrogen nucleophile.82 This observation,
along with the observation of reaction in the absence of
exogenous base suggest that both the methyl carbonate (or
methoxide) generated in situ and K3PO4 contribute to the
formation of the azolate nucleophile. Although we are cognizant
of the limited solubility of K3PO4 in THF solvent and the close
proximity of the counterions to the allyliridium intermediate,
we suggest that reactions conducted with added K3PO4 contain
a higher concentration of azolate anion than reactions conducted
without added K3PO4. An increase in the concentration of
azolate anion would increase the rate of the N-allylation of
each case. The combination of these results suggests that
imidazole, benzimidazole, and adenine nucleophiles undergo
facile iridium-catalyzed N-allylation reactions because of the
contributions from reaction of the deprotonated species. The
competition experiments also show that an increased acidity of
the heterocycle, rather than increased basicity, leads to faster
rates for allylation of these heterocycles (10a: pKa ) 18.6;
5a: pKa ) 16.4; 20d: pKa ≈ 15 in DMSO).81
The results from the competition experiments displayed in
Scheme 6 suggest that imidazolate, benzimidazolate, and
adeninate anions are the form of the heterocycles that undergo
the N-allylation reactions. To test whether the methyl carbonate
or methoxide anion formed upon generation of the intermediate
allyliridium complex or exogenous K3PO4 acted as the base
primarily responsible for the formation of the deprotonated
(82) Product ratios for competition experiments in the absence of potassium
phosphate base are as follows: 18:82 (11a/28) for the competition
reaction between imidazole and benzyl amine; 40:60 (11a/29) for the
competition reaction between imidazole and aniline; 50:50 (11a/5a)
for the competition reaction between imidazole and benzimidazole;
and 30:70 (11a/21k) for the competition reaction between imidazole
and bis-BOC-adenine.
(81) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
9
8980 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Ir-Catalyzed N-Allylation of Heterocycles
A R T I C L E S
Figure 5. A comparison of catalysts [Ir(COD)(κ2-L1)(L1)] (1) and
[Ir(COD)(κ2-L2)(L2)] (30) for the reaction of methyl cinnamyl carbonate
with benzimidazole in the presence and absence of K3PO4. All reactions
were conducted in THF solvent at room temperature. Catalysts and
conditions: 9, 2 mol % 1 + 1 mol % [Ir(COD)Cl]2 (no base); 2, 2 mol %
30 + 1 mol % [Ir(COD)Cl]2 (no base); b, 2 mol % 1 + [Ir(COD)Cl]2 +
1.0 equiv of K3PO4; [, 2 mol % 30 + 1 mol % [Ir(COD)Cl]2 + 1.0 equiv
of K3PO4.
Figure 6. A comparison of catalysts [Ir(COD)(κ2-L1)(ethylene)] (2a) and
[Ir(COD)(κ2-L2)(ethylene)] (2b) for the reaction of methyl cinnamyl
carbonate with benzimidazole in the presence and absence of K3PO4. All
reactions were conducted in THF solvent at room temperature. Catalysts
and conditions: 9, 2 mol % 2a (no base); 2, 2 mol % 2b (no base); b, 2
mol % 2a + 1.0 equiv of K3PO4; [, 2 mol % 2b + 1.0 equiv of K3PO4.
Scheme 8. Cyclometallation to Form Iridium Metallacycles 2a and
2b and Ring Opening in the Presence of a Protic Acid
nucleophiles containing more acidic N-H bonds, and this
prediction is consistent with the larger amounts of product
derived from the more acidic nitrogen nucleophiles in reactions
conducted with added K3PO4.
Studies of the Relative Activity and Stability of Catalysts
2a and 2b. Kinetic studies of the reactions of benzimidazole
with methyl cinnamyl carbonate catalyzed by bis-phosphora-
midite complexes [Ir(COD)(κ2-L1)(L1)] (1) and [Ir(COD)(κ2-
L2)(L2)] (30) were conducted to gauge the effect of substituents
on the phosphoramidite ligand on catalyst stability and activity
in the presence and absence of K3PO4. A comparison of
reactions in the presence and absence of K3PO4 catalyzed by
the combination of [Ir(COD)Cl]2 (to bind the κ1-phosphoramidite
after dissociation) and complex 1 or 30 is shown in Figure 5.
As previously observed during the development of conditions
for the reaction of benzimidazole with methyl cinnamyl carbon-
ate (see Table 1, entry 1), the reactions catalyzed by bis-
phosphoramidite complexes 1 and 30 occurred to low conver-
sions in the absence of K3PO4. However, analogous reactions
at room temperature occurred to high conversions when
conducted in the presence of 1.0 equiv of K3PO4. These data
show that deactivation of either the metallacyclic catalysts 1
and 30 or the [Ir(COD)Cl]2 occurred rapidly in the absence of
exogenous base. Furthermore, these data suggest that substit-
uents on the arylethyl group of the phosphoramidite ligand have
minimal impact on the stability and activity of metallacyclic
bis-phosphoramidite catalysts 1 and 30.
tion of the catalyst and that the rates of the sets of reactions
within the catalytic cycle involving the species generated from
the ethylene adducts 2a and 2b are similar to each other. The
latter conclusion contrasts a previous claim that the ortho-anisyl
phosphoramidite ligand L2 generates a more active metallacyclic
iridium catalyst than does phosphoramidite ligand L1.32
We propose that the metallacyclic catalysts undergo decom-
position by protonation of the metallacyclic unit to form an
inactive acyclic species. Metallacyclic iridium complexes 2a
and 2b are formed from the four-coordinate iridium complexes
31a and 31b and ethylene in the presence of an amine base,
and opening of the metallacycle occurs upon addition of a protic
acid, such as acetic acid or excess amine hydrochloride (Scheme
8).17 Thus, metallacyclic iridium catalysts 2a and 2b would be
expected to be stable during allylic substitution reactions of basic
nitrogen nucleophiles but to undergo ring opening as a side
reaction during allylic substitution reactions of the acidic
nitrogen nucleophiles studied in this work.
In contrast to the reactions catalyzed by bis-phosphoramidite
complexes 1 and 30, the reactions catalyzed by metallacyclic
ethylene adducts [Ir(COD)(κ2-L1)(ethylene)] (2a) and [Ir-
(COD)(κ2-L2)(ethylene)] (2b) (Figure 6) were significantly
affected by the substituents on the arylethyl group of the
phosphoramidite ligand. The reaction of methyl cinnamyl
carbonate with benzimidazole in the presence of parent catalyst
2a without added K3PO4 occurred to modest conversion, but
the same reaction catalyzed by ortho-OMe catalyst 2b occurred
to nearly complete conversion. This result implies that the
metallacyclic iridium complex 2b generated from the ortho-
anisyl phosphoramidite ligand L2 is more stable toward
decomposition than the metallacyclic iridium complex 2a
generated from the parent phosphoramidite L1. In contrast, the
kinetic profile of the reactions catalyzed by complexes 2a and
2b are similar to each other in the presence of added K3PO4.
This result implies that the phosphate base prevents decomposi-
To assess this proposal for the mechanism of decomposition
of the iridium metallacycles in the presence of the imidazole
nucleophiles, we studied the stoichiometric reactions of catalysts
2a and 2b with excess benzimidazole (pKa ) 16.4, DMSO) and
bis-BOC-adenine (pKa ≈ 15, DMSO). Consistent with our
conclusion about the relative stabilities of catalysts 2a and 2b,
parent catalyst 2a reacted with the two azoles more rapidly than
did the ortho-OMe catalyst 2b. The half-life of catalyst 2a in
THF at 50 °C in the presence of 25 equiv of benzimidazole
was ∼60 min, while the half-life of catalyst 2b was greater than
4 h under identical conditions. Furthermore, the half-life of
catalyst 2a in the presence of 25 equiv of bis-BOC adenine
was less than 20 min, while the half-life of catalyst 2b was
∼40 min. Analogous reactions of 2a and 2b with N-methyl
benzimidazole and 9-methyl-bis-BOC-adenine resulted in mini-
mal decomposition of 2a or 2b.
9
J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8981

A R T I C L E S
Stanley and Hartwig
Scheme 9. Mechanism for the Deactivation of
Table 7. Base-Free N-Allylation of Benzimidazole and Imidazole
[Ir(COD)(κ2-L1)(Ethylene)] (2a) in the Presence of Benzimidazole
Nucleophilesa
entry
azole (R)
time (h)
product
yield (%)b
5/6 or 12/13c
ee (%)d
1
2
3
4
5
4a (H)
7
7
4
20
5
5a
5j
5m
12a
12b
87
87
84
92
86
97:3
96:4
92:8
99:1
95:5
98
98
97
98
99
4b (Ph)
4d (Cl)
11a (H)
11b (Ph)
Scheme 10. Independent Generation of
[Ir(COD)(L1)(benzimidazolate)] 32 and Its Rapid Decomposition to
Free Phosphoramidite Ligand L1 and [Ir(COD)(benzimidazolate)]3
a See Supporting Information for experimental details. b Isolated yield
c
1
of 5 or 12. Determined by H NMR spectroscopy of the crude reaction
mixture. d Determined by chiral HPLC.
L1 then reacts with ethylene adduct 2a to form [Ir(COD)(κ2-
L1)(L1)] (1), which is known to catalyze the allylic substitution
reaction with slow rates in the absence of an additive to sequester
the κ1-bound phosphoramidite ligand.38
The ortho-OMe catalyst 2b is more stable toward benz-
imidazole than the parent catalyst 2a. After 4 h at 50 °C, the
only decomposition product (ca. 30%) observed by 31P{1H}
NMR spectroscopy from the stoichiometric reaction of 2b with
excess benzimidazole was the free phosphoramidite ligand L2
at 155.4 ppm. [Ir(COD)(κ2-L2)(L2)] (30), the ortho-anisyl
analogue of [Ir(COD)(κ2-L1)(L1)] (1), was not observed in the
reaction of 2b with benzimidazole. This result implies that the
increased stability of ortho-OMe catalyst 2b, relative to the
parent catalyst 2a, results from two factors. First, the rate of
ring opening of the metallacycle in ortho-OMe catalyst 2b is
slower than that for parent catalyst 2a. Second, ortho-OMe
catalyst 2b does not readily react with free phosphoramidite
ligand L2 to form the less active catalyst [Ir(COD)(κ2-L2)(L2)]
(30). These factors result in a concentration of 2b that is greater
than that of 2a in catalytic reactions of azole nucleophiles with
allylic carbonates in the absence of K3PO4. Furthermore, these
results are consistent with rates of reactions of benzimidazole
with methyl cinnamyl carbonate in the absence of K3PO4 base
that are faster when catalyzed by ortho-OMe complex 2b than
when catalyzed by parent complex 2a (Figure 6).
Base-Free N-Allylation of Benzimidazole and Imidazole
Nucleophiles. The stability of catalyst 2b toward deactivation
in the presence of benzimidazole led us to study reactions of
benzimidazole and imidazole nucleophiles in the absence
of added K3PO4 (Table 7). The room temperature reactions of
methyl cinnamyl carbonate with benzimidazole, 2-phenylben-
zimidazole, and 2-chlorobenzimidazole in the presence of 2
mol % of the ortho-OMe catalyst 2b occurred to high conver-
sions and formed products 5a, 5j, and 5m in high yields (>84%)
with high selectivities (branched-to-linear >92:8 and >97% ee)
(entries 1-3). Imidazole nucleophiles, which contain a less
acidic N-H bond than the benzimidazoles, also reacted
selectively with 3a (entries 4 and 5). Products 12a and 12b were
formed in greater than 86% yield with >95:5 branched-to-linear
selectivity and >98% ee.
The stoichiometric reaction of parent catalyst 2a with excess
benzimidazole was studied in further depth to develop a more
detailed understanding of the reactions leading to catalyst
decomposition (Scheme 9). Three major new species were
observed by 31P{1H} NMR spectroscopy from this reaction. Two
sets of doublets that correspond to [Ir(COD)(κ2-L1)(L1)] (1)
were observed at 153.5 ppm (J ) 47 Hz) and 128.5 ppm (J )
47 Hz), and a singlet corresponding to the free phosphoramidite
ligand L1 was observed at 151.2 ppm. In addition, a singlet at
120.0 ppm, which we propose to correspond to [Ir(COD)(L1)-
(benzimidazolate)] (32), was observed transiently. Attempts to
independently synthesize complex 32 from the reaction of
[Ir(COD)(L1)Cl] (31a) with sodium benzimidazolate led to rapid
formation of free phosphoramidite ligand L1 and the known
complex [Ir(COD)(benzimidazolate)]3 as a yellow precipitate
(Scheme 10).83
Based on these data, we propose that catalyst 2a reacts with
benzimidazole to form benzimidazolate complex 32 as a
transient intermediate, either by direct protonation of the
metallacycle or by oxidative addition of the azole N-H bond,84
followed by reductive elimination to form a C-H bond.
Complex 32 decomposes to form free phosphormidite L1 and
[Ir(COD)(benzimidazolate)]3. The free phosphoramidite ligand
(83) Ramaswamy, Y. S.; Halesha, R.; Gowda, N. M. N.; Reddy, G. K. N.
Indian J. Chem., Sec. A 1991, 30A, 393–399.
(84) Cuenca, T.; Padilla, A.; Royo, P.; Parra-Hake, M.; Pellinghelli, M. A.;
Tiripicchio, A. Organometallics 1995, 14, 848–854.
9
8982 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Ir-Catalyzed N-Allylation of Heterocycles
A R T I C L E S
Scheme 11. Base-Free N-Allylation of Bis-BOC-adenine 20d with
lead to the ability to conduct the N-allylation of azole nucleo-
philes, even though they are much weaker nucleophiles than
benzylamines, alkylamines, and arylamines in stoichiometric
reactions with organic electrophiles. More specifically, the ratio
of rates from competition reactions of amines versus azoles is
much smaller than that for reaction of the two types of neutral
nucleophiles toward organic electrophiles. Because this ratio
of rates depended on the presence or absence of added base,
we suggest that the deprotonated forms of imidazole, benzimi-
dazole, and adenine nucleophiles react, at least in part, as the
nucleophile in the iridium-catalyzed N-allylation reactions. This
hypothesis also rationalizes the preferential reaction of the more
acidic azoles in competition studies conducted in the presence
of base. The same trend is not observed when comparing the
rates of separate allylation reactions of the different classes of
azoles because the more acidic heterocycles led to faster catalyst
decomposition.
Kinetic studies of reactions catalyzed by metallacyclic
complexes 2a and 2b show that the rates of reactions catalyzed
by the parent catalyst 2a and the ortho-OMe-substituted catalyst
2b are similar but that catalyst 2b is more stable to acidic
benzimidazole, imidazole, and purine nucleophiles than catalyst
2a. Stoichiometric reactions of the metallacyclic complexes 2a
and 2b with azoles show that ring opening of the metallacycles
occurs in the presence of the azoles to form [Ir(COD)(azolate)]n
and free phosphoramidite ligand L1 or L2 and that ring opening
of the metallacycle in the ortho-OMe-substituted complex 2b
is slower than that of the metallacycle in parent complex 2a. In
addition, complex 2a reacts with free ligand L1 to generate the
less active catalyst [Ir(COD)(κ2-L1)(L1)] (1). This process is
not observed in stoichiometric reactions of complex 2b with
azole nucleophiles, and the absence of this process provides
further evidence of the improved stability of ortho-OMe-
substituted catalyst 2b, relative to that of parent catalyst 2a.
Efforts to develop more robust iridium catalysts that will extend
the method to additional azole nucleophiles and other acidic
nitrogen nucleophiles are currently underway.
3a
The instability of catalyst 2b to bis-BOC adenine in the
absence of K3PO4 implied that base-free N-allylations of purine
nucleophiles would not occur to the same high conversions as
were observed for reactions of the benzimidazoles and imda-
zoles. Indeed, the reaction of bis-Boc-adenine with methyl
cinnamyl carbonate occurred to only 63% conversion, and
product 21k was isolated in only 49% yield (Scheme 11). Thus,
base-free, iridium-catalyzed N-allylations of benzimidazole and
imidazole nucleophiles with allylic carbonates occur in high
yield and selectivity with catalyst 2b, but allylations of purine
nucleophiles should be conducted with added K3PO4 to prevent
deactivation of metallacyclic iridium catalysts 2a and 2b.
Conclusions
In summary, we have developed the first catalytic enantiose-
lective allylation of benzimidazole, imidazole, and purine
nucleophiles with achiral acyclic allylic electrophiles to form
chiral N-allylated azoles. These reactions are enabled by the
use of single-component ethylene catalysts 2a and 2b. Reactions
with these single-component catalysts occur with less isomer-
ization and with less iridium than those with previous metal-
lacyclic iridium catalysts. The N-allylated benzimidazoles and
purines generated from these reactions are readily converted to
substructures, such as R-benzimidazolyl alcohols, ꢀ-benzimi-
dazolyl alcohols, ꢀ-benzimidazolyl acids, R-purinyl alcohols,
and ꢀ-purinyl alcohols, present in a variety of biologically
important compounds. Furthermore, a formal synthesis of a
JNK3 inhibitor demonstrates that iridium-catalyzed allylation
provides rapid access to N-allylated imidazoles that can be
transformed into enantiomerically enriched annulated products
by intramolecular addition of an imidazole C(2)-H bond across
the pendant alkene. In addition, base-free N-allylation of
benzimidazole and imidazole nucleophiles occurs readily in the
presence of 2b as catalyst.
Acknowledgment. We thank the NIH for financial support of
this work (NIH GM55382 to J.F.H. and GM84584 to L.M.S.) and
Johnson-Matthey for gifts of [Ir(COD)Cl]2 and IrCl3. We thank Dr.
Klaus Ditrich and BASF for a gift of both enantiomers of 1-(2-
methoxyphenyl)ethylamine. We thank Mark Pouy and Dr. Dan
Weix for experimental assistance and insightful discussions.
Supporting Information Available: Experimental procedures,
characterization data, and complete ref 48. This material is
available free of charge via the Internet at http://pubs.acs.org.
Competition experiments between azole nucleophiles and
common amine nucleophiles helped elucidate the factors that
JA902243S
9
J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8983