Enantioselective and regioselective indium(III)-catalyzed addition of pyrroles to isatins

Article abstract of DOI:10.1021/ol202329s

The indium(III)-catalyzed enantioselective and regioselective addition of pyrroles to isatins is described. The effects of metal and solvent on the reactivity and selectivity are compared and discussed, demonstrating that the indium(III)-indapybox complex

Full text of DOI:10.1021/ol202329s

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5754–5757
Enantioselective and Regioselective
Indium(III)-Catalyzed Addition of Pyrroles
to Isatins
Elisa G. Gutierrez, Casey J. Wong, Aziza H. Sahin, and Annaliese K. Franz*
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States
akfranz@ucdavis.edu
Received August 28, 2011
ABSTRACT
The indium(III)-catalyzed enantioselective and regioselective addition of pyrroles to isatins is described. The effects of metal and solvent on the
reactivity and selectivity are compared and discussed, demonstrating that the indium(III)Àindapybox complex provides the most effective
catalyst. A case of divergent reactivity between pyrroles and indoles is presented.
Oxindoles are significant synthetic targets due to their
biological activity and prevelance in various natural pro-
ducts and medicinal compounds.1 Recent reports highlight
reactions of various nucleophiles that have been investi-
gated for the synthesis of 3-hydroxy-3-oxindoles.2 Work
from our group has previously demonstrated that both
scandium(III) and indium(III) triflates catalyze the nu-
cleophilic addition of indoles to isatin electrophiles to
afford 3-hydroxy-2-oxindoles in high yields and high
enantioselectivity.3 Here we report the first asymmetric
catalytic method for pyrrole addition to isatins catalyzed
by an indium(III)Àpybox complex formed with a 2,6-
bis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazolin-2-
yl]pyridine ligand.4,5
Enantioselective catalysis with chiral indium complexes
is gaining attention due to the catalytic activity and
improved stability under atmospheric conditions that in-
dium offers.6 Recent examples of catalysis with chiral
indium(III) complexes have demonstrated stereoselective
carbonyl ene, MukaiyamaÀMichael, and Mukaiyama
aldol reactions.7,8 While similar in reactivity to indoles,
pyrroles present additional synthetic challenges due to
issues of regioselectivity and oligomerization.9 Mixtures
of C2 and C3 regioisomeric products are often observed
(1) For several examples, see: (a) Kagata, T.; Saito, S.; Shigemori, H.;
Ohsaki, A.; Kubota, H.; Kobayashi, J. J. Nat. Prod. 2006, 69, 1517. (b)
Tokunaga, T.; Hume, W. E.; Nagamine, J.; Kawamura, T.; Taiji, M.;
Nagata, R. Bioorg. Med. Chem. Lett. 2005, 15, 1789. (c) Koguchi, Y.;
Kohno, J.; Nishio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.; Komat-
subara, S. J. Antibiot. 2000, 53, 105. (d) Zhang, H. P.; Kamano, Y.;
Ichihara, Y.; Kizu, H.; Komiyama, K.; Itokawa, H.; Pettit, G. R.
Tetrahedron 1995, 51, 5523.
(2) For selected examples and reviews, see: (a) Yong, S. R.; Ung,
A. T.; Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron 2007, 63,
5579. (b) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854. (c)
Badillo, J. J.; Hanhan, N. V.; Franz, A. K. Curr. Opin. Drug Disc. 2010,
13, 758. (d) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352,
1381. (e) Zheng, K.; Yin, C.; Liu, X.; Lin, L.; Feng, X. Angew. Chem.,
Int. Ed. 2011, 50, 2573. (f) Liu, L.; Zhang, S.-L.; Xue, F.; Lou, G.-S.;
Zhang, H.-Y.; Ma, S.-C.; Duan, W.-H.; Wang, W. Chem.;Eur. J 2011,
17, 7791.
(4) (a) Evans, D. A.; K. R. F.; Song, H.; Scheidt, K. A.; Xu, R. J. Am.
Chem. Soc. 2007, 129, 10029. (b) Hargaden, G. C.; Guiry, P. J. Chem.
Rev. 2009, 109, 2505.
(5) In this study, the (S,R)-indapybox ligand was synthesized using a
modified procedure; see the Supporting Information and: Desimoni, G.;
Faita, G.; Guala, M.; Pratelli, C. Tetrahedron: Asymmetry 2002, 13,
1651.
(6) For a recent review of indium in organic synthesis, see: Yadav,
J. S.; Antony, A.; George, J.; Subba Reddy, B. V. Eur. J. Org. Chem.
2010, 591.
(7) (a) Zhao, J.-F.; Tsui, H.-Y.; Wu, P.-J.; Lu, J.; Loh, T.-P. J. Am.
Chem. Soc. 2008, 130, 16492. (b) Zhao, J.-F.; Tan, B.-H.; Loh, T.-P.
Chem. Sci. 2011, 2, 349. (c) Chua, S.-S.; Alni, A.; Chan, L.-T. J.;
Yamane, M.; Loh, T.-P. Tetrahedron 2011, 67, 5079.
(8) (a) Hayashi, R.; Cook, G. R. Org. Lett. 2007, 9, 1311. (b) Giera,
D. S.; Schneider, C. Org. Lett. 2010, 12, 4884.
(3) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.;
Franz, A. K. Angew. Chem., Int. Ed. 2010, 49, 744.
r
10.1021/ol202329s
Published on Web 10/11/2011
2011 American Chemical Society

with an inherent bias for the C2 regioisomer based on
resonance stabilization.10 Methods for regio- and enantio-
selective pyrrole additions have been previously reported,
often utilizing highly activated electrophiles and low
temperatures.11
Table 1. Optimization for Pyrrole Additiona
We initially screened various Lewis acidic metal com-
plexes for activation of isatin 1a to optimize the enantio-
selective addition of N-methylpyrrole (Table 1). Using the
scandium(III)Àindapybox catalyst afforded the desired
3-hydroxy-2-oxindole product 3 with excellent enantios-
electivity (93À98% ee) under various conditions (entries
1À5); however, a mixture of C2- and C3-substituted
regioisomers 3 and 4 was consistently observed. Reactions
were performed using an excess (2À3 equiv) of pyrrole
nucleophile in order to overcome oligomerization and
increase the rate of the reaction. Yttrium(III) triflate was
also investigated and shown to proceed with good regio-
selectivity, but lower yield and enantioselectivity were
observed (entries 6À9). Further investigations showed that
the indium(III) triflate complex is also effective in promot-
ing pyrrole additions with high enantioselectivity, up to
99% ee (entries 10À13).12 Indium(III) chloride showed
very low reactivity in all cases (entries 14À17).
metal
salt
temp time ratio
yieldc
(%) (major)d
% ee
entry
solvent (°C) (h)
3:4b
1
2
Sc(OTf)3 DCM
Sc(OTf)3 DCM
Sc(OTf)3 DCM
rt
4
24 77:23
24 70:30
48 77:23
36 78:22
36 80:20
120 nd
90
99
89
91
17
<5
45
21
24
78
98
74
32
<5
<5
10
<5
98
93
97
98
98
nd
63
32
60
99
97
96
67
nd
nd
14
nd
3
À20
4
Sc(OTf)3 MeCN À20
5
Sc(OTf)3 MeCN
Y(OTf)3 DCM
Y(OTf)3 MeCN
Y(OTf)3 DCM
4
4
4
6
7
72 80:20
Varying the temperature and solvent with indium(III)
triflate catalyst allowed us to identify optimal conditions
for the single addition of N-methylpyrrole with 98:2 re-
gioselectivity and 99% ee (entry 11). Generally, oligomer-
ization was minimized and conversion increased by using
acetonitrile at lower temperatures. Although previous
reports have shown that Lewis acids can catalyze the
condensation of isatin and pyrroles for the synthesis of
3,3-dipyrrolyloxindoles,13 the addition of a second pyrrole
was not observed here using these optimized conditions.
Formation of such diaryloxindole structures could still be
induced under slightly modified conditions in other cases
(see Scheme 2). Through this optimization process, it was
established that (1) regioselectivity is influenced by both
metal and solvent effects, (2) oligomerization can be miti-
gated by using acetonitrile solvent at lower reaction tem-
peratures, and (3) high enantioselectivity is maintained with
the In(OTf)3Àpybox complex under a variety of conditions.
Proceeding with the optimized indium(III) conditions,
thescope ofisatins wasinvestigated(Table2). First, aseries
of various N-alkylated isatins was investigated and shown
to maintain high enantioselectivity and regioselectivity.
8
À20 168 86:14
9
Y(OTf)3 MeCN À20 168 93:7
10
In(OTf)3 DCM
À20
60 69:31
48 98:2
48 70:30
48 71:29
11e In(OTf)3 MeCN À20
12
13
14
15
16
17
In(OTf)3 tol
In(OTf)3 tol
4
À20
InCl3
InCl3
InCl3
InCl3
DCM
À20 168 nd
MeCN À20 168 nd
DCM
rt 168 nd
rt 168 nd
MeCN
a All reactions performed under argon with 10 mol % catalyst
loading, using 2À3 equiv of pyrrole, with activated 4 A MS. b Based
˚
on 1H NMR analysis of unpurified product; regioisomers are separable
by column chromatography. c Represents total yield isolated for both
isomers after separation. d Determined by HPLC analysis of unpurified
sample with AD-H stationary phase; minor regioisomer is g95% ee.
e Reported as an average of two or more reactions.
Substitution with methoxy and various halogen groups
affords consistently high yields, regioselectivity (g90:10),
and enantioselectivity (94À99% ee). While the 5-chloro N-
methylisatin proceeded with high yield and selectivity
(entry 2), shifting the chloro substituent to the 4-position
had a detrimental effect on the reactivity, and only the
isatin starting material was recovered (entry 3).
The intolerance of the 4-chloro group suggests that the
4-positionisclose enoughtothe electrophiliccarboncenter
to prevent nucleophilic addition due to steric or electronic
interference with either the pyrrole nucleophile or the
metalÀligand complex. Our previous studies have shown
that the 4-chloro group of isatin 1c is still well-tolerated for
the enantioselective addition of indoles to isatins with
chiral Sc(OTf)3 catalysts,3 which would indicate that the
interaction is specific to the case of the pyrrole. Here we
have performed a direct comparison for the addition of
N-methylpyrrole and N-methylindole with 4-chloro-N-
methylisatin (Scheme 1). We have observed that the source
(9) (a) For information on pyrrole polymer formation, see: Can, M.;
€
€
€
Ozaslan, H.; Ildak, O.; Pekmez, N. O.; Yıldız, A. Polymer 2004, 45, 7011.
(b) For information on pyrrole regioisomers, see: Voldhardt, P.; Schore,
N. Organic Chemistry: Structure and Function; W. H. Freeman and Co.:
New York, 2011. (c) For relative pyrrole reactivities, see: Nigst, T. A.;
Westermaier, M.; Ofial, A. R.; Mayr, H. Eur. J. Org. Chem. 2008, 2369.
(10) Yadav, J. S.; Reddy, B. V. S.; Abraham, S.; Sabitha, G. Tetra-
hedron Lett. 2002, 43, 1565.
(11) For recent examples of stereoselective pyrrole additions with
other metals, see: (a) Huang, Y.; Suzuki, S.; Shiro, M.; Shibata, N. Org.
Lett. 2010, 12, 1136. (b) Singh, P. K.; Singh, V. K. S. Org. Lett. 2010, 12,
80.
(12) The regiochemistry and absolute configuration was assigned and
confirmed on the basis of X-ray crystallography (anomalous dispersion
method) of 3b (see the Supporting Information).
(13) Yadav, J. S.; SubbaReddy, B. V.; Gayathri, K. U.; Meraj, S.;
Prasad, A. R. Synthesis 2006, 4121.
Org. Lett., Vol. 13, No. 21, 2011
5755

regioselectivity (Table 3). It was noted that reactions contain-
ing NH isatins demonstrated a greater sensitivity to air and
moisture because the reduced reactivity allowed time for
moisture to diminish the reactivity of hygroscopic indium-
(III) complex. Using more rigorous air-free techniques or
adding catalytic NaSbF6 was effective to promote the reac-
tion and maintain high enantioselectivity (entries 4À6).7b,14,15
Table 2. Scope of Isatins with N-Methylpyrrolesa
time
(d)
ratio
yield
eed
(%)
R1
product 3:4b of 3c (%)
Table 3. Scope of NH Isatins with N-Methylpyrrole
entry
R
1
2
CH3
CH3
CH3
CH3
CH3
CH3
5-Br
5-Cl
4-Cl
5-F
3
3
5
3
4
4
4
3
4
3
4
3a
3b
3c
3d
3e
3f
98:2
98:2
98
97
94
95
3
no rxn
94
4
98:2
>99:1
>99:1
95:5
97
98
5
H
83
6
OCH3
82
99
7
C3H3 5-Br
C3H3 5-F
C3H3 OCH3
PMB 5-Br
PMB 5-F
3g
3h
3i
83
98
time
(d)
ratio
yield
eec
8
90:10 80
99
entry
R1
5-F
product 3:4a of 3b (%)
(%)
9
99:1
94:6
93:7
91
88
84
>99
>99
>99
10
11
3j
1
3
3
4
3
3
4
3l
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
86
96
87
45
63
65
>99
98
3k
2
5-Cl
3m
3n
3o
3p
3q
3
5-OCF3
H
>99
95
a All reactions performed under argon using 2À3 equiv of pyrrole.
b Determined upon 1H NMR analysis of unpurified product. c Isolated
yield of major product. Most yields reported as an average of two or
more reactions. d Determined by HPLC analysis on chiral stationary phase.
4d
5d
6
5-Br
99
5-OMe
96
a Determined using 1H NMR spectroscopy for analysis of unpurified
product. b Isolated yield of major product. c Determined by HPLC
analysis on chiral stationary phase of unpurified sample. d Reactions
performed with 10 mol % NaSbF6.
of metal does not influence the reaction because the indole
reaction proceeds withboth scandium(III) and indium(III)
conditions, and the pyrrole addition does not proceed with
either metal. When the indole and pyrrole nucleophiles are
both added to a reaction, the indole addition still proceeds
to completion in less than1 day. The success of these indole
reactions (e.g., 5b and 5c) confirms that the effect is not
based on an interaction of the metalÀligand complex with
the 4-chloro substituent but rather that the distinction in
reactivity is attributed solely to the nucleophilic species
(i.e., pyrrole vs indole).
The addition of NaSbF6 may facilitate the removal of
triflate ions and generate a more cationic catalyst com-
plex that would exhibit increased catalytic activity. This
outcome is supported by 19F NMR studies for both the
In(OTf)3Àpybox and Sc(OTf)3Àpybox catalyst com-
plexes. In both CD2Cl2 and CD3CN, the 19F NMR spectra
show a single peak at À79 ppm for the M(OTf)3Àpybox
complex, indicating that the triflate ligands are partially or
totally dissociated for the metalÀligand complex. The
uncoordinated triflate anions are typically observed near
À78 ppm, while the coordinated triflate ligand are known
to be shifted downfield.16 The coordinating ability of
acetonitrile also assists in displacing weakly coordinating
triflate ligands. It should be noted that the lack of a signal
for the bound triflate cannot be perceived as an indication
that all triflate ligands are uncoordinated; bound triflate
may not be present in solution in sufficient quantities to be
visible by NMR spectroscopy. The Sc(OTf)3 salt alone is
insoluble in CD2Cl2, and the In(OTf)3 salt alone is inso-
luble in both CD2Cl2 and CD3CN.
Scheme 1. Divergent Reactivity of Indoles and Pyrroles
(14) (a) Zhao, J.-F.; Tjan, T.-B. W.; Loh, T.-P. Tetrahedron Lett.
2010, 51, 5649. (b) Zhao, J.-F.; Tjan, T.-B. W.; Tan, B.-H.; Loh, T.-P.
Org. Lett. 2009, 11, 5714.
(15) While investigating various additives, it was discovered that the
˚
use and efficient activation of 4 A molecular sieves was critical for
optimal catalyst performance, affording faster and more efficient con-
version. Further investigation into the role of molecular sieves in this
reaction is required. See: Posner, G. H.; Dai, H.; Bull, D. S.; Lee, J.;
Eydoux, F.; Ishihara, Y.; Welsh, W.; Pryor, N.; Petr, S. J. Org. Chem.
1996, 61, 671.
(16) Britovsek, G. J. P.; England, J.; Spitzmesser, S. K.; White,
A. J. P.; Williams, D. J. Dalton Trans. 2005, 945.
Further investigation of scope shows that NH isatins
also afford products with excellent enantioselectivity and
5756
Org. Lett., Vol. 13, No. 21, 2011

Next, the scope of pyrrole substrates for nucleophilic
addition to isatins was investigated (Table 4). For all cases,
enantioselectivity remains high (98À99% ee), but different
reactivity was observed based on pyrrole substitution.9
The NH pyrrole (2b) reacts readily to form regioisomer 3r
in high 98:2 regioselectivity, but this pyrrole also poly-
merizes quickly under the reaction conditions to afford
only a 60% yield (entry 2). In order to maintain suitable
yields with the NH pyrrole substrate, four equivalents of
nucleophile were typically employed. The addition of N-
benzylpyrrole (2c) also proceeded with a lower conversion
(entry 3). The reaction with 2,4-dimethylpyrrole (2d) pro-
ceeds quickly, and product 3t was observed by ESI-MS;
however, product 3t was not stable to silica gel and degraded
under purification conditions (entry 4). The reaction with
2-ethylpyrrole (2e) also proceeds quickly; full consumption
of starting material is observed in less than 1 day, affording
50% of the single addition product 3u (entry 5). For the
more reactive pyrroles 2d and 2e,9c the product selectivity
can be shifted to favor the diaryloxindole product (6t and
6u) by using excess pyrrole (see Scheme 2).
either the 3-hydroxy-2-oxindole, such as 3u, or the 3,
3-dipyrrolyloxindole product, such as 6u. Similar 3,
3-diaryloxindole structures have shown biological activity
and thus provide targets of interest.17 Product selectivity
for either 3u or 6u is achieved by controling the equivalents
of pyrrole nucleophile and temperature (Scheme 2). When
only one equivalent of pyrrole 2e is utilized, the reaction
affords the 3-hydroxy-2-oxindole product 3u as the major
product. However, the diaryloxindole product 6u can be
isolated in 52% yield using three equivalents of pyrrole
2e. Likewise, the diaryloxindole product 6t, derived
from pyrrole 2d, can be isolated in 95% yield when five
equivalents of pyrrole are utilized.
Scheme 2. Conditions Controlling Product Formation
Table 4. Scope of Pyrroles with 5-Chloro-N-methylisatin
In conclusion, we have developed the first enantioselec-
tive addition ofpyrroles toisatins. The indium(III)Àpybox
catalyst provides sufficient catalytic activation of isatins
while also controlling the regio- and enantioselectivity for
the addition. It was also observed that interactions with a
4-chloro substituent hinder the pyrrole addition in this
system, leading to a case of divergent reactivity for indoles
and pyrroles.
time
(d)
ratio yield of eeb
entry
R
R1
R2
product 3:4a
3 (%)
(%)
1
2c
CH3
H
H
H
3
2
2
4
1
3b
3r
3s
3t
98:2
>99:1
>99:1
>99:1
nd
98
97
H
H
H
H
60
99
Acknowledgment. We acknowledge the University of
California, Davis, the donors of the American Chemical
Society Petroleum Research Fund, and NIH/NIGMS
(P41-GM0089153) for support of this research. A.K.F. is
the recipient of a 3M Nontenured faculty grant, and E.G.
G. acknowledges the United States Department of Educa-
tion for a GAANN fellowship. Special thanks to Ngon
Tran (UC Davis) for solving the X-ray structure of 3b.
3
Bn
H
45
99
4d
5d
CH3 CH3
Et
nde
50f
n/a
>99
H
H
3u
a Determined upon 1H NMR analysis of unpurified reaction. b De-
termined by HPLC analysis with chiral stationary phase. c Performed
using 4 equiv of pyrrole. d Performed using 1.1 equiv of pyrrole.
e Isolated 95% of the 3,3-diaryl product 6t with 5 equiv of pyrrole.
f Isolated 52% of the 3,3-diaryl product 6u using 5 equiv of pyrrole.
For pyrroles substituted in the 2-position (e.g., 2d and
2e), reaction conditions can control selective formation of
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds; X-ray
crystal structure coordinates and files in CIF format for
3b. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Paira, P.; Hazra, A.; Kumar, S.; Paira, R.; Sahu, K. B.; Naskar,
S.; Saha, P.; Mondal, S.; Maity, A.; Banerjee, S.; Mondal, N. B. Bioorg.
Med. Chem. Lett. 2005, 15, 1789.
Org. Lett., Vol. 13, No. 21, 2011
5757