Rhodium/diene-catalyzed asymmetric arylation of N-sulfonyl indolylimines: A new access to highly optically active α-aryl 3-indolyl-methanamines

Article abstract of DOI:10.1039/c0cc04086j

A new and efficient method for the preparation of highly enantiomerically enriched α-aryl 2- or 3-indolyl-methanamines by rhodium-catalyzed asymmetric arylation of N-sulfonyl indolylimines with arylboronic acids using chiral bicyclo[3.3.0] diene was devel

Full text of DOI:10.1039/c0cc04086j

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Rhodium/diene-catalyzed asymmetric arylation of N-sulfonyl
indolylimines: a new access to highly optically active a-aryl
3-indolyl-methanaminesw
Hong-Yu Yanga and Ming-Hua Xu*ab
Received 26th September 2010, Accepted 19th October 2010
DOI: 10.1039/c0cc04086j
A new and efficient method for the preparation of highly
enantiomerically enriched a-aryl 2- or 3-indolyl-methanamines
by rhodium-catalyzed asymmetric arylation of N-sulfonyl
indolylimines with arylboronic acids using chiral bicyclo[3.3.0]
diene was developed.
3-Indolyl-methanamines (1) and their derivatives represent an
important class of heterocyclic compounds and they are
prevalent in many biologically active natural products
(such as indole alkaloids) and medicinal agents.1 Consequently,
the development of synthetic methods to access 3-indolyl-
methanamines is of great interest to organic and medicinal
chemists.2–7 Despite considerable advances, however, asymmetric
Friedel–Crafts reaction of indoles with arylimines or its
analogues is the only methodology for the synthesis of
chiral 3-indolyl-methanamines (1) reported to date. Among
them, catalytic approaches that use chiral Cu-complexes,3
bifunctional modified cinchona/quinine4 and chiral phosphoric
acids5 as catalysts have attracted much attention. Neverthe-
less, one drawback of the Friedel–Crafts approach is that
feasibility of the reaction and selectivity of the product highly
depend on the electronic nature of the substrates and the
reaction conditions. In some studies, the procedure required
long reaction time and large excess amount of indoles.3,4,5a–c,6
To address these issues, we conceived an alternative methodo-
logy using transition metal-catalyzed asymmetric arylation
strategy8 (Scheme 1). Herein, we describe our successful
development of this approach as a new promising method
for the preparation of highly optically active a-aryl 3-indolyl-
Scheme 2 Catalytic enantioselective arylation of N-tosylarylimines
using bicyclo[3.3.0] diene ligand 2.
methanamines. To our knowledge, this is the first example of
enantioselective catalytic addition of arylboronic acids to
indolylimines.
Asymmetric addition of arylboron reagents to arylimines is
an attractive method for the efficient synthesis of enantio-
enriched diarylmethylamines.9 In the past few years, a number
of chiral diene ligands that formed stable complexes with
metal have emerged for this transformation.10 In 2007, we
reported our design of a new family of C2-symmetric chiral
diene ligands bearing a simple bicyclo[3.3.0] backbone11 and
their successful application in the Rh-catalyzed enantio-
selective arylation of N-tosylarylimines with arylboronic
acids.11a Chiral bicyclo[3.3.0] diene 2 was found to be a super
elegant ligand and gave extremely high enantioselectivities
(98–99% ee) for a broad range of diarylmethylamines
(Scheme 2). Encouraged by this success, we hypothesized
that the preparation of enantioenriched a-aryl 3-indolyl-
methanamines might be achieved with the same diene catalysis
protocol.
By using bicyclo[3.3.0] diene (R,R)-2 as a chiral ligand,
we first examined the potential of reaction between N-tosyl
3-indolylimine 3a and p-anisylboronic acid (4a) under the
reaction conditions previously reported11a for the arylation
of N-tosylarylimines (Table 1, entry 1). To our disappointment,
most of the 3-indolylimine 3a decomposed and no product was
detected. Same results were observed with several other
aqueous inorganic base additives (entries 2–4). To avoid the
interference of indole NH function in the reaction, we chose
N-Cbz protected 3-indolylimine 3b as substrate and further
screened the conditions. As expected, the addition product 1b
was isolated with excellent enantioselectivity (99% ee), albeit
in only o20% yield in toluene/Et3N and toluene/aqueous
KOH systems (entries 5 and 6). Very gratifyingly, the reactions
with 3-indolylimine 3b proceeded smoothly when performed in
the presence of aqueous KF, K3PO4 or KHF2 and all gave
high yields (95–99%) and great enantioselectivities (99%)
Scheme 1 Synthetic strategies to chiral a-aryl 3-indolyl-methanamines.
a Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 555 Zuchongzhi Road, Shanghai 201203,
People’s Republic of China. E-mail: xumh@mail.shcnc.ac.cn;
Fax: +86 21 5080 7388; Tel: +86 215080 7388
b State key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, People’s Republic of China
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, copies of HPLC, NMR spectra. See
DOI: 10.1039/c0cc04086j
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9223–9225 9223

View Article Online
Table 1 Optimization of the reaction conditionsa
Table 2 Rh-catalyzed enantioselective arylation of N-tosyl 3-indolyl-
imines with arylboronic acidsa
Entry R1
R2
Time/h
1
Yieldb (%) eec (%)
Entry
3
Additive
Time/h
Yieldb (%)
eec (%)
1
2
3
4
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H
5
5
5
5
5
5
12
5
12
5
5
1c
1b 95
1d 88
1e
1f
96
98
99
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3b
3b
3b
3b
3b
3a
3b
3b
Et3N
aq. KOH
aq. KF
aq. K3PO4
Et3N
5
5
5
—
—
—
—
17
13
96
99
95
15
96
98
—
—
—
—
99
97
99
99
99
94
98
99
4-OMe
4-Br
4-CF3
3-Cl
3-Me
3-Me
2-Me
2-F
2-Np
4-OMe
H
H
H
99 (R)d
99
98
91
98
5
5
12
12
6
6
5
12
5
5
6
1g 44
1g 99
1h o20
96
aq. KOH
aq. KF
7e
8
96
NDf
89
aq. K3PO4
aq. KHF2
aq. KHF2
aq. KHF2
H2O
9e
10
11
12
13
14
15
H (3b)
H (3b)
1i
1j
17
98
9
97
97
96
98
97
—
10
11d
12e
4-Br(3c)
5-Br (3d)
5-OMe (3e)
7-Me(3f)
2-Me (3g)
1k 91
1l 99
1m 99
1n 93
5
5
5
5
a
Unless otherwise noted, the reaction was performed with
3
H
—
—
(0.25 mmol), 4a (0.5 mmol), [RhCl(C2H4)2]2 (1.5 mol%), chiral diene
ligand (R,R)-2 (3.3 mol%) in toluene (2 mL) and aqueous inorganic
b
solution (3 M, 0.25 mL). Isolated yield. Determined by HPLC on a
a
The reaction was performed with 3 (0.25 mmol), 4 (0.5 mmol),
[RhCl(C2H4)2]2 (1.5 mol%), chiral diene ligand (R,R)-2 (3.3 mol%) in
c
d
e
b
toluene (2 mL) and aqueous KHF2 (3 M, 0.25 mL). Isolated yield.
c
chiral AD-H column. Phenylboronic acid was used. Potassium
phenyltrifluoroborate was used.
d
Determined by HPLC on a chiral AD-H column. The stereo-
chemistry is assigned by comparison of the HPLC spectrum of its
Cbz-removed product with that reported previously in ref. 3 and 5c.
e
f
(entries 7–9). Since KHF2 in aqueous conditions can react
with organoboronic acids to generate potassium organo-
trifluoroborates,12 we investigated the direct use of PhBF3K
for addition (entry 12). As a result, the yield and enantiomeric
excess were almost identical to those obtained by using
PhB(OH)2 in aqueous KHF2 (compare entries 11 and 12),
suggesting that KHF2 may act as a reagent for generation
of trifluoroborate in situ within the system.13 Particularly
noteworthy is that the KHF2 system is also applicable to
3-indolylimine 3a without NH protection, while no reaction
occurred under other conditions (compare entries 10 and 2–4).
With these optimized conditions established, we proceeded
to test the reaction generality. A wide range of arylboronic
acids were reacted with 3-indolylimines under the conditions
using aqueous KHF2 as additive14 at 55 1C (Table 2). In most
cases, the reactions went to completion smoothly in 5 hours.
As shown in Table 2, arylboronic acids bearing different
substituents in meta- and para-positions can be all employed
successfully as the adducts to afford the desired products in
good yields and excellent enantioselectivities. The reaction of
3-MeC6H4B(OH)2 with indolylimine 3b went on slowly at
55 1C (entry 6). Fortunately, excellent yield was provided
without loss of enantioselectivity when we conducted the
transformation at a higher temperature (80 1C) after prolonging
the reaction time to 12 h (entry 7). In addition to 3-indolylimine
3b, imines 3c–3f with either electron-donating or electron-
withdrawing groups (R1) on the benzene ring were found to
be efficient, all giving excellent yields and stereoselectivities
(entries 11–14). Thus, the electronic nature of the aromatic
ring of both 3-indolylimine and boronic acid substrates has no
apparent influence on the reaction reactivity and enantio-
selectivity. In contrast, it is important to note that steric
hinderance significantly retards the accomplishment of the
The reaction was carried out at 80 1C. ND: not determined.
reaction. With sterically encumbered arylboronic acids, a
dramatic decrease in reactivity was observed (entries 8–9).
When o-methyl substituted 3-indolyimine 3g was subjected to
the addition with phenylboronic acid, no product was found
under the same reaction conditions (entry 15).
To further extend the reaction scope, asymmetric arylation
of N-nosyl 3-indolylimine
5 with various arylboronic
acids catalyzed by the rhodium complex of (R,R)-2 under
KHF2/H2O/toluene conditions was carried out (Scheme 3).
Since the removal of the nosyl group is easy, addition to
N-nosylimines is recently of great interest to chemists.9f,g,10e,f,11e
To our delight, the desired N-nosyl a-aryl 3-indolyl-methanamines
1o–1s were obtained in all cases in excellent yields with slightly
lower enantiomeric excesses (94–99%) compared to N-tosyl
3-indolylimines. It is noteworthy that the reaction tolerated
substrates with acid-labile functionalities such as MOM.
Apart from 3-indolyl-methanamines, the current catalytic
system was also applied for the asymmetric addition of N-tosyl
2-indolylimine
6 with p-anisylboronic acid to prepare
the corresponding 2-indolyl-methanamine that is generally
inaccessible by direct Friedel–Crafts reaction.15 Considering
Scheme 3 Asymmetric arylation of N-nosyl 3-indolylimine.
c
9224 Chem. Commun., 2010, 46, 9223–9225
This journal is The Royal Society of Chemistry 2010

View Article Online
Adv. Synth. Catal., 2007, 349, 1863; (c) Q. Kang, Z.-A. Zhao and
S.-L. You, J. Am. Chem. Soc., 2007, 129, 1484; (d) Y.-X. Jia,
J. Zhong, S.-F. Zhu, C.-M. Zhang and Q.-L. Zhou, Angew. Chem.,
Int. Ed., 2007, 46, 5565; (e) G. B. Rowland, E. B. Rowland,
Y. Liang, J. A. Perman and J. C. Antilla, Org. Lett., 2007,
9, 2609.
6 (a) Y. Qian, G. Ma, A. Lv, H.-L. Zhu, J. Zhao and V. H. Rawal,
Chem. Commun., 2010, 46, 3004; (b) Z. Liu and M. Shi,
Tetrahedron: Asymmetry, 2009, 20, 119.
Scheme 4 Asymmetric arylation of N-tosyl 2-indolylimine.
7 X.-L. Qiu, J. Zhu, G. Wu, W.-H. Lee and A. R. Chamberlin,
J. Org. Chem., 2009, 74, 2018.
8 For an excellent review on catalyzed asymmetric arylation
reactions, see: C. Bolm, J. P. Hildebrand, K. Muniz and
N. Hermanns, Angew. Chem., Int. Ed., 2001, 40, 3284.
the steric hinderance of the o-Cbz substituent on N atom,
2-indolylimine could be a relatively challenging substrate.
After some experiments, we were pleased to find that
2-indolylimine 6 showed the similar reactivity as 3-indolylimine
3b at a higher temperature (80 1C), and the resulting product
was obtained in 72% yield with an extremely high enantio-
selectivity (98.5% ee) (Scheme 4). This result indicates a
substantial expansion of the reaction scope.
9 For selected examples of Rh(I)-catalyzed arylation, see:
(a) M. Kuriyama, T. Soeta, X. Hao, Q. Chen and K. Tomioka,
J. Am. Chem. Soc., 2004, 126, 8128; (b) D. J. Weix, Y. Shi and
J. A. Ellman, J. Am. Chem. Soc., 2005, 127, 1092; (c) H.-F. Duan,
Y.-X. Jia, L.-X. Wang and Q.-L. Zhou, Org. Lett., 2006, 8, 2567;
(d) H. Nakagawa, J. C. Rech, R. W. Sindelar and J. A. Ellman,
Org. Lett., 2007, 9, 5155; (e) X. Hao, M. Kuriyama, Q. Chen,
Y. Yamamoto, K. Yamada and K. Tomioka, Org. Lett., 2009, 11,
4470; (f) K. Kurihara, Y. Yamamoto and N. Miyaura, Adv. Synth.
Catal., 2009, 351, 260; (g) J. A. Bishop, S. Lou and S. E. Schaus,
Angew. Chem., Int. Ed., 2009, 48, 4337. For selected examples of
Pd(II)-catalyzed arylation, see: (h) P. He, Y. Lu and Q.-S. Hu,
Tetrahedron Lett., 2007, 48, 5283; (i) H.-X. Dai and X.-Y. Lu,
Tetrahedron Lett., 2009, 50, 3478; (j) G.-N. Ma, T. Zhang and
M. Shi, Org. Lett., 2009, 11, 875.
10 For leading reviews on chiral diene ligands in asymmetric catalysis,
see: (a) F. Glorius, Angew. Chem., Int. Ed., 2004, 43, 3364;
(b) C. Defieber, H. Grutzmacher and E. M. Carreira, Angew.
Chem., Int. Ed., 2008, 47, 4482; (c) R. Shintani and T. Hayashi,
Aldrichimica Acta, 2009, 42, 31. For representative Rh/diene
catalysis on arylation: (d) N. Tokunaga, Y. Otomaru,
K. Okamoto, K. Ueyama, R. Shintani and T. Hayashi, J. Am.
Chem. Soc., 2004, 126, 13584; (e) Y. Otomaru, N. Tokunaga,
R. Shintani and T. Hayashi, Org. Lett., 2005, 7, 307;
(f) K. Okamoto, T. Hayashi and V. H. Rawal, Chem. Commun.,
2009, 4815; (g) C. Shao, H.-J. Yu, N.-Y. Wu, C.-G. Feng and
G.-Q. Lin, Org. Lett., 2010, 12, 3820.
In summary, we have reported the first example of catalytic
asymmetric arylation of N-sulfonyl indolylimines by using
Rh(I) and bicyclo[3.3.0] diene ligand. The reaction works well
with a variety of N-tosyl or nosyl indolylimines and arylboronic
acids under mild conditions, affording the N-sulfonyl-
protected methanamine products in good yields and with high
enantiomeric excesses (94–99%). This protocol provides a new
enantioselective approach to the synthesis of a-aryl 2- or
3-indolyl-methanamines. Compared to the known asymmetric
Friedel–Crafts reaction of indoles with arylimines, the current
asymmetric arylation shows no dependence on the electronic
nature of the substrates, it represents a great alternative. Given
the importance of optically active a-aryl 2- or 3-indolyl-
methanamines, this methodology should find wide applica-
tions in asymmetric synthesis and medicinal chemistry.
This work was generously supported by the National
Natural Science Foundation of China (20632060, 20721003,
20972172), the Chinese Academy of Sciences, the State key
Laboratory of Drug Research, SIMM and National Science &
Technology Major Project (2008ZX09401-004, 2009ZX09301-
001). The authors thank Professor Guo-Qiang Lin at SIOC for
helpful discussion.
11 (a) Z.-Q. Wang, C.-G. Feng, M.-H. Xu and G.-Q. Lin, J. Am.
Chem. Soc., 2007, 129, 5336; (b) C.-G. Feng, Z.-Q. Wang, P. Tian,
M.-H. Xu and G.-Q. Lin, Chem.–Asian J., 2008, 3, 1511;
(c) C.-G. Feng, Z.-Q. Wang, C. Shao, M.-H. Xu and G.-Q. Lin,
Org. Lett., 2008, 10, 4101; (d) Z.-Q. Wang, C.-G. Feng,
S.-S. Zhang, M.-H. Xu and G.-Q. Lin, Angew. Chem., Int. Ed.,
2010, 49, 5780; (e) L. Wang, Z.-Q. Wang, M.-H. Xu and G.-Q. Lin,
Synthesis, 2010, 3263.
12 For recent reviews on organotrifluoroborates, see: (a) E. Vedejs,
R. W. Chapman, S. C. Fields, S. Lin and M. R. Schrimpf, J. Org.
Chem., 1995, 60, 3020; (b) G. A. Molander and R. Figueroa,
Aldrichimica Acta, 2005, 38, 49; (c) G. A. Molander and
N. M. Ellis, Acc. Chem. Res., 2007, 40, 275; (d) H. A. Stefani,
R. Cella and A. S. Vieira, Tetrahedron, 2007, 63, 3623; (e) S. Darses
and J. P. Genet, Chem. Rev., 2008, 108, 288.
13 For our recent discovery of the use of KHF2 under similar
conditions for successful asymmetric conjugate addition of organo-
boronic acids to nitroalkenes, see ref. 11d.
Notes and references
1 (a) M. Somei and F. Yamada, Nat. Prod. Rep., 2004, 21, 278;
(b) D. J. Faulkner, Nat. Prod. Rep., 2002, 19, 1; (c) J. Bosch and
M. L. Bennasar, Synlett, 1995, 587.
2 For recent reviews on asymmetric Friedel–Crafts reactions, see:
(a) S.-L. You, Q. Cai and M. Zeng, Chem. Soc. Rev., 2009, 38,
2190; (b) T. B. Poulsen and K. A. Jørgensen, Chem. Rev., 2008,
108, 2903; (c) M. Bandini, A. Melloni and A. Umani-Ronchi,
Angew. Chem., Int. Ed., 2004, 43, 550.
3 Y.-X. Jia, J.-H. Xie, H.-F. Duan, L.-X. Wang and Q.-L. Zhou,
Org. Lett., 2006, 8, 1621.
4 (a) Y.-Q. Wang, J. Song, R. Hong, H. Li and L. Deng, J. Am.
Chem. Soc., 2006, 128, 8156; (b) P. Yu, J. He and C. Guo, Chem.
Commun., 2008, 2355.
14 Considering the better reaction performance with KHF2 to both
indolylimines with/without NH protection (entries 9 and 10), we
used it for further generality.
15 For a one-pot procedure involving the Friedel–Crafts reaction
of 4,7-dihydroindoles with imines followed by oxidation of the
products, see: Q. Kang, X.-J. Zheng and S.-L. You, Chem.–Eur. J.,
2008, 14, 3539.
5 (a) M. Terada and K. Sorimachi, J. Am. Chem. Soc., 2007, 129,
292; (b) M. Terada, S. Yokoyama, K. Sorimachi and D. Uraguchi,
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9223–9225 9225