Iridium catalyzed asymmetric hydrogenation of cyclic imines of benzodiazepinones and benzodiazepines

Article abstract of DOI:10.1021/ol301620z

Highly enantioselective Ir-catalyzed hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodiazepines was achieved with up to 96% ee. This method provides a direct access to synthesize a range of chiral cyclic amines existing in nume

Full text of DOI:10.1021/ol301620z

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3890–3893
Iridium Catalyzed Asymmetric
Hydrogenation of Cyclic Imines of
Benzodiazepinones and Benzodiazepines
Kai Gao, Bo Wu, Chang-Bin Yu, Qing-An Chen, Zhi-Shi Ye, and Yong-Gui Zhou*
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
ygzhou@dicp.ac.cn
Received June 13, 2012
ABSTRACT
Highly enantioselective Ir-catalyzed hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodiazepines was achieved
with up to 96% ee. This method provides a direct access to synthesize a range of chiral cyclic amines existing in numerous important natural
products and clinical drugs.
Heterocycles containing a tri- or tetracyclic skeleton are
representatives of a major structure typeinnaturalproduct
and medicinal chemistry.1 Dihydrobenzodiazepinone and
-diazepine derivatives containing a pyrrole or an indole
moiety are among an important class of heterocyclic com-
pounds with remarkable biological activities.1 The pyrrolo-
benzodiazepinone skeleton is present in a family of naturally
occurring antitumor antibiotics,2,3 such as anthramycin and
tilivalline, isolated from Streptomyces. Aptazepine with a
pyrrolobenzodiazepine core is a novel antidepressant
agent,4 which is undergoing clinical trials (Figure 1).
Although a great amount of effort has been made to
synthesize the intriguing fused benzodiazepinone and
-diazepine heterocycles via intramolecular cyclization5
and transition metal mediated cascade transformation,6
little attention has been paid to their synthesis through
asymmetric catalysis.7 In this regard, the development of a
simple and flexible asymmetric synthetic method is highly
desirable. We envisaged that asymmetric hydrogenation of
the corresponding cyclic imines would be a convenient and
straightforward route to these chiral dihydrobenzodiaze-
pinone and -diazepine derivatives.
During the past two decades, many kinds of catalyst
systems for the asymmetric hydrogenation8 and transfer
hydrogenation9 of cyclic imines have been developed.
Recently, Zhang et al. reported the highly efficient asym-
metric hydrogenation of a series of cyclic imines using an
iridium/f-binaphane complex.8k Rueping et al. utilized the
organocatalyst for the transfer hydrogenation of hetero-
cyclic imines.9i To our knowledge, there are only a few
(1) (a) Advances in the Study of Pyrrolo[2,1-c][1,4]benzodiazepine
Antitumour Antibiotics, in Molecular Aspects of Anticancer Drug-DNA
Interactions; Neidle, S., Waring, M. J., Eds.; Macmillan: London, 1993. (b)
Antonow, D.; Barata, T.; Jenkins, T. C.; Parkinson, G. N.; Howard, P. W.;
Thurston, D. E.; Zloh, M. Biochemistry 2008, 47, 11818. (c) Leimgruber,
W.; Batcho, A. D.; Schenker, F. J. Am. Chem. Soc. 1965, 87, 5793.
(2) (a) Mostad, A.; Romming, C.; Storm, B. Acta. Chem. Scand. Ser.
B 1978, 32, 639. (b) Komatsu, N.; Kimura, K.; Abe, S.; Kagitani, Y.
J. Antibiot. 1980, 33, 54.
(3) (a) Mohr, N.; Budzikiewicz, H. Tetrahedron 1982, 38, 147.
(b) Hurley, L. H. J. Antibiot. 1977, 30, 349. (c) Mori, S.; Aoyama, T.;
Shioiri, T. Tetrahedron Lett. 1986, 27, 6111.
(4) (a) Massa, S.; Artico, M.; Mai, A.; Corelli, F.; Botta, M.; Tafi, A.;
Pantaleoni, G. C.; Giorgi, R.; Coppolino, M. F.; Cagnoto, A.;
Skorupaka, M. J. Med. Chem. 1992, 35, 4533. (b) Boyer, S. K.; Fitchett,
G.; Wasley, J. W. F.; Zaunius, G. J. Heterocycl. Chem. 1984, 21, 833.
(5) (a) Sharma, S. K.; Mandadapu, A. K.; Kumaresan, K.; Arora, A.;
Gauniyal, H. M.; Kundu, B. Synthesis 2010, 4087. (b) Artico, M.; Mai,
A.; Silvestri, R. J. Heterocycl. Chem. 1992, 29, 241. (c) Aranapakam, V.;
Albright, J. D.; Grosu, G. T.; Santos, E. G. D.; Chan, P. S.; Coupet, J.;
Ru, X.; Saunders, T.; Mazandarani, H. Bioorg. Med. Chem. Lett. 1999,
9, 1737.
(6) Zhou, Y.; Li, J.; Ji, X.; Zhou, W.; Zhang, X.; Qian, W.; Jiang, H.;
Liu, H. J. Org. Chem. 2011, 76, 1239.
(7) (a) Nagasaka, T.; Koseki, Y. J. Org. Chem. 1998, 63, 6797. (b)
Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Synthesis 2012, 241. (c)
Pawlowska, J.; Czarnocki, Z.; Wojtasiewicz, K.; Maurin, J. K. Tetra-
hedron: Asymmetry 2003, 14, 3335.
r
10.1021/ol301620z
Published on Web 07/17/2012
2012 American Chemical Society

Table 1. Optimization of Reaction Conditionsa
entry
additive
ligand
conv (%)b
ee (%)c
1
ꢀ
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
93
73
30
74
72
85
87
71
88
87
84
90
93
93
85
95
94
2
I2
>95
65
3
TFA
4
L-CSA
66
5
piperidine HCl
93
3
6
morpholine HCl
78
3
3
3
3
3
3
3
3
Figure 1. Representative dihydrobenzodiazepinone and dihy-
drobenzodiazepine derivatives.
7
morpholine HBr
93
8
9d
morpholine TFA
>95
>95
49
morpholine TFA
10d,e
11d,f
12d,g
13d,h
14d,h
15d,h
16d,h
morpholine TFA
successful examples thus far reported on the asymmetric
reduction of seven-membered cyclic imines,8a,j,9d probably
owing to the relatively rigid and space-demanding features of
these imines. Thereby, an efficient catalyst is highly required
for the hydrogenation of these seven-membered-ring systems
with a unique skeleton. In view of the significance of these
intriguing heterocycles, together with our ongoing programs
directed to the development of an efficient method for the
asymmetric hydrogenation of heteroaromatic compounds10
and cyclic imines,11 we disclosed herein the Ir-catalyzed
asymmetric hydrogenation of seven-membered cyclic imines
of benzodiazepinones and -diazepines (Figure 1).
morpholine TFA
54
morpholine TFA
90
morpholine TFA
>95
10
morpholine TFA
3
3
3
morpholine TFA
>95
>95
morpholine TFA
a Conditions: 1a (0.125 mmol), [Ir(COD)Cl]2 (2 mol %), (R)-SynPhos
(4.4 mol %), additive (20 mol %), H2 (700 psi), DCM (3 mL), rt, 20 h.
b Determined by 1H NMR. c Determined by HPLC. d 10 mol % of
morpholine TFA was used. e EtOAc as solvent. f THF as solvent.
3
g PhMe as solvent. h DCM/PhMe (1:2) as solvent.
(8) (a) Willoughby, C. A.; Buchwald, S. L. J. Org. Chem. 1993, 58, 7627.
(b) Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1995, 6, 2661. (c)
Chang, M.; Li, W.; Hou, G.; Zhang, X. Adv. Synth. Catal. 2010, 352, 3121.
(d) Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, T.; Kataoka, Y.;
^
Ratovelomanana-Vidal, V.; Genet, J.-P.; Mashima, K. Organometallics
2006, 25, 2505. (e) Cobley, J. C.; Henschke, J. P. Adv. Synth. Catal. 2003,
345, 195. (f) Guiu, E.; Claver, C.; Benet-Buchholz, J.; Castillon, S. Tetra-
Initially, catalyst [Ir(COD)Cl]2/(R)-SynPhoswaschosen
to hydrogenate the model substrate 11-(4-chlorophenyl)-
5H-pyrrolo [2,1-c][1,4]benzodiazepin-5-one (1a); moder-
ate enantioselectivity was obtained with high conversion
(Table 1, entry 1). This preliminary result encouraged us to
explore the additive effect on the reactivity and enantio-
selectivity. With the addition of 20 mol % of I2,12 the
reaction gave full conversion, but the ee dropped drama-
tically to 30% (entry 2). Acid additives, such as tri-
fluoroacetic acid, L-camphorsulfonic acid (L-CSA) were
also examined,13 and moderate enantioselectivities were
ꢀ
hedron: Asymmetry 2004, 15, 3365. (g) Oppolzer, W.; Wills, M.; Starkemann,
C.; Bernardinelli, G. Tetrahedron Lett. 1990, 29, 4117. (h) Jackson, M.;
Lenon, I. C. Tetrahedron Lett. 2007, 48, 1831. (i) Li, C. Q.; Xiao, J. L. J . Am.
Chem. Soc. 2008, 130, 13208. (j) Chen, F.; Ding, Z.; Qin, J.; Wang, T.; He, Y.;
Fan, Q.-H. Org. Lett. 2011, 13, 4348. (k) Chang, M.; Li, W.; Zhang, X.
Angew. Chem., Int. Ed. 2011, 50, 10679. (l) Ding, Z.-Y.; Chen, F.; Qin, J.; He,
Y.-M.; Fan, Q.-H. Angew. Chem., Int. Ed. 2012, 51, 5706. (m) Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000.
(9) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 4916. (b) Vedejes, E.; Trapencieris, P.;
Suna, E. J. Org. Chem. 1999, 64, 6724. (c) Mao, J.; Baker, D. C. Org.
Lett. 1999, 1, 841. (d) Rueping, M.; Merino, E.; Koenigs, R. M. Adv.
Synth. Catal. 2010, 352, 2629. (e) Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun,
L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun. 2006, 1766. (f) Canivet, J.;
€
Susss-Fink, G. Green Chem. 2007, 9, 391. (g) Matharu, D. S.; Martins,
J. E. D.; Wills, M. Chem.;Asian J. 2008, 3, 1374. (h) Evanno, L.;
Ormala, J.; Pihko, P. M. Chem.;Eur. J. 2009, 15, 12963. (i) Rueping,
M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45,
6751. (j) Rueping, M.; Brinkmann, C.; Antonchick, A. P.; Atodiresei, L.
Org. Lett. 2010, 12, 4604. (k) Chen, X.; Zheng, Y.; Shu, C.; Yuan, W.;
Liu, B.; Zhang, X. J. Org. Chem. 2011, 76, 9109. (l) Han, Z.-Y.; Xiao, H.;
Gong, L.-Z. Bioorg. Med. Chem. Lett. 2009, 19, 3729.
(10) (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou,
Y.-G. J. Am. Chem. Soc. 2003, 125, 10536. (b) Zhou, Y.-G. Acc. Chem.
Res. 2007, 40, 1357. (c) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-
G. Chem. Rev. 2012, 112, 2557.
(12) (a) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
(b) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 1570. (c) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425.
(d) Chan, Y. N. C.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112, 9400. (e)
€
Dorta, R.; Broggini, D.; Stoop, R.; Ruegger, H.; Spindler, F.; Togni, A.
€
Chem.;Eur. J 2004, 10, 267.
(13) (a) Blaser, H.-U. Adv. Synth. Catal. 2002, 344, 17. (b) Li, Z.-W.;
Wang, T.-L.; He, Y.-M.; Wang, Z.-J.; Fan, Q.-H.; Pan, J.; Xu, L.-J. Org.
Lett. 2008, 10, 5265. (c) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J.
Angew. Chem., Int. Ed. 2009, 48, 6524. (d) Tadaoka, H.; Cartigny, D.;
^
Nagano, T.; Gosavi, T.; Ayad, T.; Genet, J.-P.; Ohshima, T.;
(11) (a) Gao, K.; Yu, C.-B.; Li, W.; Zhou, Y.-G.; Zhang, X. Chem.
Commun. 2011, 7845. (b) Gao, K.; Yu, C.-B.; Wang, D.-S.; Zhou, Y.-G.
Adv. Synth. Catal. 2012, 354, 483. (c) Wang, Y.-Q.; Lu, S.-M.; Zhou,
Y.-G. J. Org. Chem. 2007, 72, 3729. (d) Yu, C.-B.; Wang, D.-W.; Zhou,
Y.-G. J. Org. Chem. 2009, 74, 5633.
Ratovelomanana-Vidal, V.; Mashima, K. Chem.;Eur. J 2009, 15,
9990. (e) Imwinkelried, R. Chimia 1997, 51, 300. (f) Hou, G.; Li, W.;
Ma, M.; Zhang, X.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12844. (g)
Pautigny, C.; Jeulin, S.; Ayad, T.; Zhang, Z.; Genet, J.-P.; Ratovelo-
manana-Vidal, V. Adv. Synth. Catal. 2008, 350, 2525.
^
Org. Lett., Vol. 14, No. 15, 2012
3891

fused benzodiazepinones 1aꢀj was explored (Table 2).
In general, aryl substituted substrates bearing electron-
withdrawing and -donating groups gave high yields and
excellent ee’s (entries 1ꢀ6). Interestingly, for alkyl sub-
stituents, the additive should be changed to the piperidi-
nium hydrochloride to maintain high enantioselectivity
(entries 7ꢀ10). The absolute configuration of 2f was
determined by X-ray diffraction analysis as an R isomer.16
Table 2. Asymmetric Hydrogenation of Pyrrole Fused Benzo-
diazepinonesa
entry
R
yield (%)b
ee (%)c
Table 3. Asymmetric Hydrogenation of Indole Fused Benzo-
diazepinonesa
1
p-ClC6H4
Ph
95 (2a)
97 (2b)
97 (2c)
92 (2d)
97 (2e)
99 (2f)
96 (2g)
96 (2h)
97 (2i)
92 (2j)
95 (þ)
95 (þ)
94 (þ)
95 (þ)
96 (þ)
96 (R)d
91 (þ)
91 (þ)
93 (þ)
90 (þ)
2
3
m-MeC6H4
p-MeC6H4
p-FC6H4
p-BrC6H4
Me
4
5
6
7e
8e
9e
10e
Et
n-Pr
Bn
entry
R1
R2
R3
yield (%)b
ee (%)c
a Conditions: 1 (0.125 mmol), [Ir(COD)Cl]2 (2 mol %), (S,S,R)-C3*-
TunePhos (4.4 mol %), morpholine TFA (10 mol %), H2 (700 psi),
1
Ph
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
F
98 (4a)
95 (4b)
98 (4c)
98 (4d)
96 (4e)
96 (4f)
98 (4g)
98 (4h)
97 (4i)
98 (4j)
95 (ꢀ)
94 (ꢀ)
94 (ꢀ)
95 (ꢀ)
94 (ꢀ)
95 (ꢀ)
96 (ꢀ)
96 (ꢀ)
90 (ꢀ)
83 (ꢀ)
3
DCM/PhMe (1:2, 3 mL), rt, 20 h. b Isolated yield. c Determined by
HPLC. d Determined by X-ray diffraction analysis. e 10 mol % of
piperidine HCl was used.
2
m-MeC6H4
p-MeC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
Ph
3
3
4
5
achieved yet with limited conversions (entries 3 and 4).
Ammonium salts were successfully introduced as effective
cocatalysts or additives in organic reactions.14 Hence the
effect of ammonium salt on the reactivity and enantioselec-
tivity was investigated. Delightedly, when piperidinium
6
7
8
Ph
9d
10d
n-Pr
H
H
Phenethyl
hydrochloride (piperidine HCl) was used, the enantiomeric
3
a Conditions: 3 (0.125 mmol), [Ir(COD)Cl]2 (2 mol %), (S,S,R)-C3*-
TunePhos (4.4 mol %), morpholine TFA (10 mol %), H2 (700 psi),
excess was enhanced to 85% (entry 5). Subsequently, several
kinds of the salt of morpholine were screened, and morpho-
linium trifuoroacetate (morpholine TFA) gave the highest
3
DCM/PhMe (1:2, 3 mL), rt, 20 h. b Isolated yield. c Determined by
HPLC. d 10 mol % of piperidine HCl was used.
3
3
ee (entries 6ꢀ8). Lowering the amount of salt resulted in a
slight drop in enantioselectivity (entry 9). Further investiga-
tion on the solvent effect suggested the combination of
dichloromethane and toluene in a ratio of 1:2 was the best
choice (entries 10ꢀ13). The influence of a chiral ligand was
studied through a brief screening of some commercially
available diphosphine ligands (entries 14ꢀ16). To our de-
light, C3*-TunePhos, developed by the Zhang group,15
showed the highest enantioselectivity.
Next, we examined the extension of the hydrogenation
procedure to indole fused benzodiazepinones 3. Gratify-
ingly, the hydrogenation proceeded well with excellent
enantioselectivity, as shown in Table 3. When R1 is an aryl
group, 94ꢀ96% ee and excellent yields were achieved
regardless of the position and electronic effect of substituents
on the phenyl ring (entries 1ꢀ6); besides, both the methyl
and fluoro group on the 5- and 6-position of the indole core
were compatible (entries 7 and 8). When R1 is an alkyl
group, high ee’s were still obtained by switching the additive
to piperidinium hydrochloride (entries 9 and 10).
With the optimized conditions in hand, the scope of the
iridium catalyzed asymmetric hydrogenation of pyrrole
Having established a general and highly enantioselective
hydrogenation of pyrrolobenzodiazepinones 1 and indo-
lobenzodiazepinones 3, we also decided to apply this
efficient catalyst system to hydrogenate pyrrole fused
benzodiazepines 5 as this would lead to valuable pharma-
ceutical intermediates. In complete contrast, when the
additive was added in the reaction, the enantioselectivity
deteriorated (see the Supporting Information for details).
No intermolecular H-bond formed, as that was formed
between the additive and carbonyl group in substrate 1
or 3, which may be responsible for this unexpected
(14) (a) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.;
Keck, G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031. (b)
Takahashi, A.; Shibasaki, M. Tetrahedron Lett. 1987, 28, 1893. (c)
Roush, W. R.; Barda, D. A. Tetrahedron Lett. 1997, 38, 8785. (d) Nahm,
S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (e) Cavill, J. L.;
Peters, J. L.; Tomkinson, N. C. O. Chem. Commun. 2003, 728. (f) Yang,
J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004,
43, 6660. (g) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C. Acc.
ꢁ ꢀ
Chem. Res. 2007, 40, 1327. (h) Mrsic, N.; Lefort, L.; Boogers, J. A. F.;
Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Adv. Synth. Catal. 2008,
350, 1081.
(15) (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem.
2000, 65, 6223. (b) Sun, X.; Zhou, L.; Li, W.; Zhang, X. J. Org. Chem.
2008, 73, 1143. (c) Qiu, L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.;
Yu, W.-Y.; Li, Y.-M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem.
Soc. 2006, 128, 5955. (d) Qiu, L.; Wu, J.; Chan, S.; Au-Yeung, T.; Ji,
J.-X.; Guo, R.; Pai, C.-C.; Zhou, Z.; Li, X.; Fan, Q.-H.; Chan, A. S. C.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5815.
(16) See Supporting Information for details.
3892
Org. Lett., Vol. 14, No. 15, 2012

(Table 4). Excellent ee’s were obtained for substrates
bearing alkyl chains (entries 1ꢀ5). For aryl substituted
compounds, high to excellent enantioselectivities were also
achieved under the standard conditions (entries 6ꢀ8).
Furthermore, indole fused benzodiazepines 7 could also
be hydrogenated with the [Ir(COD)Cl]2/(R)-C4-Tune-
Phos catalyst system (Table 5). The reaction proceeded
well with high yields, but slightly lower enantioselectivities
were observed (entries 1ꢀ6).
Table 4. Asymmetric Hydrogenation of Pyrrole Fused Benzo-
diazepinesa
entry
R
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Me
Et
98 (6a)
96 (6b)
96 (6c)
97 (6d)
97 (6e)
96 (6f)
97 (6g)
97 (6h)
96 (ꢀ)
92 (ꢀ)
91 (ꢀ)
93 (ꢀ)
87 (ꢀ)
92 (ꢀ)
82 (ꢀ)
91 (ꢀ)
Scheme 1. Asymmetric Hydrogenation of 1a on a Gram Scale
n-Pr
Phenethyl
Bn
Ph
p-MeC6H4
p-FC6H4
a Conditions: 5 (0.125 mmol), [Ir(COD)Cl]2 (2 mol %), (R)-C4-
TunePhos (4.4 mol %), H2 (700 psi), benzene (3 mL), rt, 20 h. b Isolated
yield. c Determined by HPLC.
To test the practicality of the current method, the
asymmetric hydrogenation of the standard substrate 1a
on a gram scale (1.227 g, 4.0 mmol of 1a) was carried out
with 1 mol % of iridium catalyst [Ir(COD)Cl]2/(S,S,R)-
C3*-TunePhos at room temperature (Scheme 1), giving the
chiral product 2a in 99% yield and 95% ee.
Table 5. Asymmetric Hydrogenation of Indole Fused Benzo-
diazepinesa
In summary, an efficient iridium catalyst for the highly
enantioselective hydrogenation of a series of pyrrole and
indole fused benzodiazepinones and -diazepines has been
successfully developed with up to 96% ee. Due to the high
enantioselectivity and readily available starting materials,
this method provides a direct and facile access to a broad
scope of corresponding chiral dihydrobenzodiazepinone
and -diazepine derivatives existing in numerous important
natural products and clinical drugs. Further investigation
will be directed toward the extension of this strategy to
other synthetically interesting compounds and a mechan-
ism study.
entry
R1
R2
R3
yield (%)b
ee (%)c
1
2
3
4
5
6
Me
Et
H
H
H
H
H
H
F
97 (8a)
94 (8b)
97 (8c)
95 (8d)
97 (8e)
97 (8f)
89 (þ)
83 (þ)
85 (þ)
77 (þ)
89 (þ)
88 (þ)
H
n-Pr
Bn
H
Acknowledgment. We are grateful for the financial
support from the National Science Foundation of China
(21032003 and 20921092) and the National Basic Research
Program of China (2010CB833300).
H
Me
Me
Me
H
a Conditions: 7 (0.125 mmol), [Ir(COD)Cl]2 (2 mol %), (R)-C4-
TunePhos (4.4 mol %), H2 (700 psi), benzene (3 mL), rt, 20 h. b Isolated
yield. c Determined by HPLC.
Supporting Information Available. Experimental, spec-
troscopic, and crystallographic details. This material is
available free of charge via the Internet at http://pubs.acs.
org.
phenomenon. After a simple optimization of the reaction,
excellent enantioselectivity was recovered with (R)-C4-
TunePhos as the ligand and benzene as the solvent
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
3893