Fe(OTf)3 catalyzed annulation of 2,3-disubstituted indoles with aziridines

Article abstract of DOI:10.1002/cjoc.201400178

A Fe(OTf)₃ catalyzed [3＋2] annulation reaction between 2,3-disubstituted indoles and N-Ts aziridines is described herein. A series of hexahydropyrrolo[3,4-b]indole derivatives bearing two consecutive quaternary carboncenters can be generated efficiently. The reaction features cheap catalyst, mild conditions and operational simplicity.

Full text of DOI:10.1002/cjoc.201400178

FULL PAPER
DOI: 10.1002/cjoc.201400178
Fe(OTf)3 Catalyzed Annulation of 2,3-Disubstituted
Indoles with Aziridines†
Hua Liu, Chao Zheng,* and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A Fe(OTf)3 catalyzed [3＋2] annulation reaction between 2,3-disubstituted indoles and N-Ts aziridines is de-
scribed herein. A series of hexahydropyrrolo[3,4-b]indole derivatives bearing two consecutive quaternary carbon-
centers can be generated efficiently. The reaction features cheap catalyst, mild conditions and operational simplic-
ity.
Keywords annulation, indole, aziridine, Lewis acid, catalysis
Introduction
alization pathway, although with a relatively higher en-
ergetic barrier, dominates and leads to the thermody-
namically more stable products. Based on these findings,
we inferred that the [3＋2] annulation products might be
obtained predominantly by utilizing a weaker Lewis
acid catalyst. Indeed, this hypothesis was recently real-
ized with Fe(OTf)3 as the catalyst (Scheme 1, Eq. 2).
Herein, we report the full account of this study.
Fused polycyclic indole skeletons are attractive
structural motifs as they are frequently found in many
natural products as well as pharmaceutical-relevant
molecules.[1] Therefore, the facile construction of these
privileged targets has been the subject of intensive
studies in recent years.[2] In this regard, the annulation
between indoles and [1,3]-dipolar equivalents received
considerable attention among various methods to access
polycyclic indole derivatives.[3] In 2012, Wu, Zhang and
co-workers[3k] reported a Ni(ClO4)2 catalyzed regio- and
diastereoselective cycloaddition between indoles and
aryl oxiranyldicarboxylates or diketones to afford
furo[3,4-b]indoles. Recently, Tang and co-workers[3m]
developed a highly enantioselective cyclopentannulation
of indoles with donor-acceptor cyclopropanes catalyzed
by a chiral Cu(II)/BOX complex.
Scheme 1 Lewis acid catalyzed reactions between 2,3-disubsti-
tuted indoles and aziridines
R1
R1
Ts
R
N
Sc(OTf)3
Ts
N
R2
R2
+
(1)
R
R
N
H
N
6
Ar
H
R
Ar
Ar
R1
Ts
N
As part of our continuing efforts to exploit the
dearomatization of indoles by diverse catalytic sys-
tems,[4] we envisioned that the annulation between
2,3-disubstituted indoles and donor-acceptor aziridines
might occur with a Lewis acid catalyst,[5] delivering the
hexahydropyrrolo[3,4-b]indole products[6] bearing two
consecutive quaternary carboncenters. Surprisingly, we
recently found that in the presence of a catalytic amount
of Sc(OTf)3, 2,3-disubstituted indoles react with N-Ts
aziridines, affording unprecedented C6 functionalized
indole derivatives (Scheme 1, Eq. 1).[7] Further mecha-
nistic investigation revealed that the originally designed
[3＋2] annulation products are always formed initially
during the course of the reaction. This process is kineti-
cally favored but reversible, whereas the C6 function-
R
N
R2
R
H
R1
Ar
Ts
Ar
R1
R
R
Fe(OTf)3
N
Ts
R2
+
N
R
(2)
N
R
H
N
R2
H
R = CO2Me
Experimental
General methods
Unless stated otherwise, all reactions were carried
out in flame-dried glassware under a dry argon atmos-
*
E-mail: zhengchao@sioc.ac.cn (C. Z.), slyou@sioc.ac.cn (S.-L. Y.)
Received March 24, 2014; accepted April 21, 2014; published online June 5, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400178 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 709—714
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
709

Liu, Zheng & You
FULL PAPER
phere. All solvents were freshly distilled according to
standard methods prior to use. H NMR spectra were
2.20 (s, 3H), 1.82 (s, 3H), 1.47 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 169.1, 167.7, 146.44, 146.42, 146.0,
143.6, 136.8, 131.1, 129.0, 128.9, 128.7, 128.5, 128.0,
124.2, 122.1, 121.8, 119.5, 109.7, 85.0, 80.9, 76.4, 60.4,
53.3, 53.0, 22.1, 21.2, 19.9; IR (thin film) νmax: 3348,
2948, 1756, 1734, 1599, 1517, 1344, 1292, 1144, 940,
857, 756, 672 cm−1; HRMS (ESI-TOF) calcd for
C29H29N3NaO8S [M＋Na]＋: 602.1568; found 602.1583.
3da White solid, m.p.187－188 ℃, 104 mg, 92%
yield. 1H NMR (400 MHz, CDCl3) δ: 7.27 (d, J＝8.5 Hz,
2H), 7.04 (dd, J＝8.0, 1.9 Hz, 1H), 6.98 (dd, J＝8.1, 1.8
Hz, 1H), 6.86 (d, J＝8.5 Hz, 2H), 6.76 (td, J＝7.6, 1.2
Hz, 1H), 6.36－6.22 (m, 5H), 5.32 (s, 1H), 4.00 (s, 3H),
3.98 (s, 3H), 3.73 (s, 1H), 2.25 (s, 3H), 1.74 (s, 3H),
1.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.4,
167.8, 146.6, 143.0, 137.2, 136.6, 132.6, 131.9, 129.8,
129.5, 128.8, 128.1, 127.9, 127.5, 126.6, 124.4, 119.4,
109.4, 84.8, 80.3, 76.8, 59.8, 53.1, 52.8, 22.5, 21.3, 20.1;
IR (thin film) νmax: 3348, 1758, 1736, 1599, 1487, 1291,
1144, 1083, 945, 811, 746, 678 cm−1; HRMS (ESI-TOF)
calcd for C29H29ClN2NaO6S [M ＋ Na] ＋ : 591.1327;
found 591.1329.
3ea White solid, m.p. 188－189 ℃, 110 mg, 90%
yield. 1H NMR (400 MHz, CDCl3) δ: 7.28 (d, J＝8.4 Hz,
2H), 7.19 (dd, J＝8.1, 2.1 Hz, 1H), 6.92 (dd, J＝8.1, 2.2
Hz, 1H), 6.86 (d, J＝8.6 Hz, 2H), 6.76 (td, J＝7.6, 1.3
Hz, 1H), 6.41 (dd, J＝8.5, 2.1 Hz, 1H), 6.36－6.29 (m,
2H), 6.28－6.20 (m, 2H), 5.30 (s, 1H), 4.00 (s, 3H),
3.98 (s, 3H), 3.74 (s, 1H), 2.26 (s, 3H), 1.74 (s, 3H),
1.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.3,
167.8, 146.6, 143.0, 137.2, 137.1, 131.9, 130.4, 130.2,
129.9, 129.6, 128.8, 128.1, 127.9, 124.4, 120.8, 119.4,
109.4, 84.8, 80.3, 76.9, 59.7, 53.1, 52.8, 22.5, 21.3, 20.1.
IR (thin film) νmax: 3353, 2945, 1755, 1736, 1600, 1487,
1293, 1144, 1065, 813, 748, 667 cm−1. HRMS
(ESI-TOF) calcd for C29H29BrN2NaO6S [M＋Na]＋ :
635.0822; found 635.0825.
1
obtained at 300, 400 or 600 MHz and recorded relative
to tetramethylsilane signal (δ 0) or residual protio-sol-
vent. 13C NMR spectra were obtained at 75 MHz, 100
MHz or 150 MHz, and chemical shifts were recorded
relative to the solvent resonance (CDCl3, 77.0 or
DMSO-d6, 39.5). Data for 1H NMR are recorded as fol-
lows: chemical shift (δ) (multiplicity (s＝singlet, d＝
doublet, t＝triplet, m＝multiplet or unresolved, br＝
broad singlet), coupling constant(s) in Hz, integration).
Data for 13C NMR are reported in terms of chemical
shift (δ).
The aziridines 1a－1h were prepared according to
the reported procedures.[8]
General procedure for the reaction of 2,3-disubsti-
tuted indoles with aziridines by Fe(OTf)3
To a mixture of 2 (0.2mmol), Fe(OTf)3 (10.1 mg,
0.02 mmol) and 4 Å MS (100 mg) in DCM (2 mL), 1
(0.3 mmol) was added while stirring. The reaction mix-
ture was stirred at room temperature and monitored by
TLC. After the reaction was complete, the crude reac-
tion mixture was filtered through a pad of silica gel and
washed with ethyl acetate. The solvents were removed
under reduced pressure. The ratio of 3∶4 or 4∶5 was
1
determined by H NMR of the crude reaction mixture.
Then the residue was purified by silica gel column
chromatography (petroleum ether∶ethyl acetate＝5∶1)
to afford the desired product 3 (and 4 or 5 in some
cases).
The characterization data of 3aa, 3ab, 3af and com-
pounds 4 and 5 in some cases were reported in our pre-
vious work.[7] All new compounds were characterized as
below.
3ba White solid, m.p. 194－196 ℃, 111 mg, 95%
yield. 1H NMR (400 MHz, CDCl3) δ: 8.22 (d, J＝8.6 Hz,
1H), 7.70 (d, J＝7.9 Hz, 1H), 7.61－7.55 (m, 1H), 7.47
－7.41 (m, 1H), 7.29 (d, J＝8.1 Hz, 1H), 7.07 (d,
J＝8.4 Hz, 2H), 6.84 (d, J＝7.3 Hz, 1H), 6.66 (d, J＝
8.1 Hz, 2H), 6.60－6.55 (m, 1H), 6.46 (t, J＝7.7 Hz,
1H), 6.40 (s, 1H), 6.22 (d, J＝7.8 Hz, 1H), 5.95－5.89
(m, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 3.76 (br, 1H), 2.16 (s,
3H), 1.96 (s, 3H), 1.49 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 169.6, 168.1, 146.5, 142.6, 137.1, 133.5,
132.8, 131.9, 131.4, 128.8, 128.6, 127.74, 127.65, 126.9,
126.7, 126.0, 124.7, 124.5, 123.6, 122.7, 118.5, 109.1,
84.9, 81.1, 71.6, 60.6, 53.2, 52.8, 22.0, 21.2, 20.3; IR
(thin film) νmax: 3360, 3003, 2954, 1767, 1726, 1599,
1491, 1331, 1284, 1134, 1077, 784, 738, 658 cm−1;
HRMS (ESI-TOF) calcd for C33H32N2NaO6S [M＋Na]＋:
607.1873; found 607.1869.
3fa White solid, m.p. 206－207 ℃, 88 mg, 72%
yield. The compound exists as a 70∶30 mixture of two
rotamers in DMSO-d6 at 30 ℃, data for NMR are ob-
1
tained at 100 ℃; H NMR (600 MHz, DMSO-d6) δ:
7.28 (d, J＝8.4 Hz, 2H), 7.04－6.87 (m, 4H), 6.66 (t,
J＝7.5 Hz, 1H), 6.54－6.12 (m, 5H), 5.31 (s, 1H), 5.15
(s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.22 (s, 3H), 1.66 (s,
3H), 1.32 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ:
168.1, 166.3, 147.3, 142.2, 136.8, 131.0, 130.6, 128.8,
127.7, 127.4, 127.1, 126.5, 123.3, 117.2, 108.7, 84.2,
80.1, 76.1, 59.4, 51.88, 51.85, 21.2, 20.2, 18.8; IR (thin
film) νmax: 3340, 2950, 1759, 1597, 1491, 1471, 1333,
1256, 1152, 1062, 869, 748, 693, 657 cm−1; HRMS
(ESI-TOF) calcd for C29H29BrN2NaO6S [M＋Na]＋ :
635.0822; found 635.0824.
3ga White solid, m.p. 227－228 ℃, 70 mg, 57%
yield. 1H NMR (400 MHz, CDCl3) δ: 7.39 (d, J＝7.8 Hz,
2H), 7.16 (d, J＝8.0 Hz, 1H), 6.85－6.80 (m, 3H), 6.78
－6.68 (m, 2H), 6.60 (t, J＝7.6 Hz, 1H), 6.36 (t,
J＝7.5 Hz, 1H), 6.31－6.22 (m, 2H), 5.91 (s, 1H), 4.04
(s, 3H), 3.99 (s, 3H), 3.75 (s, 1H), 2.20 (s, 3H), 1.95 (s,
3ca White solid, m.p. 269－271 ℃, 71 mg, 61%
yield. H NMR (400 MHz, CDCl3) δ: 7.88 (dd, J＝8.3,
2.4 Hz, 1H), 7.37 (d, J＝8.4 Hz, 2H), 7.18－7.11 (m,
2H), 6.83 (d, J＝8.1 Hz, 2H), 6.73 (td, J＝7.8, 1.5 Hz,
1H), 6.67 (dd, J＝8.7, 1.7 Hz, 1H), 6.37－6.27 (m, 3H),
5.41 (s, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.78 (s, 1H),
1
710
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 709—714

Fe(OTf)3 Catalyzed Annulation of 2,3-Disubstituted Indoles with Aziridines
3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.1,
3.77 (s, 1H), 2.64－2.40 (m, 2H), 2.38－2.28 (m, 1H),
168.1, 146.4, 142.8, 137.7, 136.8, 131.9, 131.0, 130.2,
128.7, 128.2, 128.0, 127.9, 126.1, 123.7, 123.6, 119.2,
109.3, 85.0, 81.4, 74.8, 60.7, 53.2, 52.9, 21.4, 21.3, 20.0;
IR (thin film) νmax: 3357, 1768, 1733, 1597, 1443, 1287,
1143, 1068, 877, 750, 667 cm−1; HRMS (ESI-TOF)
calcd for C29H29BrN2NaO6S [M ＋ Na] ＋ : 635.0822;
found 635.0834.
3ia White solid, m.p.180－182 ℃, 93 mg, 83%
yield. 1H NMR (400 MHz, CDCl3) δ: 7.25 (d, J＝8.5 Hz,
2H), 7.08－7.03 (m, 2H), 6.87－6.70 (m, 4H), 6.42－
6.18 (m, 5H), 5.37 (s, 1H), 4.66－4.56 (m, 1H), 4.52－
4.34 (m, 3H), 3.73 (s, 1H), 2.20 (s, 3H), 1.76 (s, 3H),
1.56－1.42 (m, 9H); 13C NMR (100 MHz, CDCl3) δ:
169.0, 167.2, 146.7, 142.4, 137.9, 137.6, 132.3, 128.9,
128.34, 128.28, 127.73, 127.70, 127.2, 126.72, 126.66,
124.5, 118.9, 109.1, 84.9, 80.0, 77.6, 62.5, 61.8, 59.9,
22.6, 21.3, 20.4, 14.3, 14.0; IR (thin film) νmax: 3369,
1750, 1601, 1466, 1339, 1242, 1149, 1020, 881, 747,
679 cm−1; HRMS (ESI-TOF) calcd for C31H34N2NaO6S
[M＋Na]＋: 585.2030; found 585.2052.
2.21 (s, 3H), 1.69－1.56 (m, 2H), 1.34－1.19 (m, 2H),
1.12－0.97 (m, 1H); 13C NMR (100 MHz, CDCl3) δ:
169.2, 167.9, 148.1, 142.4, 137.6, 137.5, 130.6, 128.9,
128.7, 128.4, 127.7, 127.1, 126.68, 126.65, 124.3, 119.0,
109.3, 84.6, 78.5, 78.1, 59.7, 52.9, 52.8, 32.6, 31.2, 21.3,
20.1, 18.6; IR (thin film) νmax: 3379, 2950, 1761, 1457,
1335, 1151, 1087, 877, 747, 701 cm−1; HRMS
(ESI-TOF) calcd for C31H32N2NaO6S [M ＋ Na] ＋
:
583.1873; found 583.1867.
Results and Discussion
Our study commenced with the reaction between ra-
cemic N-Ts aziridine 1a and 2,3-dimethylindole 2a (1.5
equiv.) with 10 mol% of Fe(OTf)3 as the catalyst and
toluene as the solvent at room temperature (Table 1,
Entry 1). Since 1a was known to be moisture sensitive,
activated 4 Å molecular sieves (MS) were added.[9] The
desired [3＋2] annulation product 3aa in cis fused con-
figuration was obtained smoothly within 2 h in 76%
3ja White solid, m.p.173－175 ℃, 83 mg, 70%
yield. 1H NMR (400 MHz, CDCl3) δ: 7.30 (d, J＝8.4 Hz,
2H), 7.04 (d, J＝4.9 Hz, 2H), 6.86－6.75 (m, 3H), 6.72
(td, J＝7.8, 1.4 Hz, 1H), 6.39 (d, J＝7.9 Hz, 1H),
6.33–6.18 (m, 4H), 5.46－5.36 (m, 1H), 5.36－5.27 (m,
2H), 3.71 (s, 1H), 2.20 (s, 3H), 1.77 (s, 3H), 1.52－1.43
(m, 15H); 13C NMR (100 MHz, CDCl3) δ: 168.5, 166.5,
146.7, 142.3, 137.9, 137.7, 132.3, 129.0, 128.4, 128.3,
127.7, 127.2, 126.63, 126.57, 124.5, 118.8, 109.0, 85.0,
79.8, 77.5, 70.7, 69.7, 59.9, 22.6, 22.1, 21.9, 21.8, 21.7,
21.3, 20.4; IR (thin film) νmax: 3369, 2989, 1753, 1741,
1600, 1468, 1337, 1245, 1145, 1082, 875, 705, 679 cm−1;
HRMS (ESI-TOF) calcd for C33H38N2NaO6S [M＋Na]＋:
613.2343; found 613.2358.
3ac White solid, m.p. 190－192 ℃, 63 mg, 55%
yield. 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, J＝6.0 Hz,
1H), 7.21 (t, J＝7.3 Hz, 1H), 7.10 (d, J＝8.2 Hz, 2H),
6.97 (t, J＝7.2 Hz, 1H), 6.84－6.75 (m, 3H), 6.41 (d,
J＝7.9 Hz, 1H), 6.26 (t, J＝7.6 Hz, 1H), 6.14 (t, J＝7.4
Hz, 1H), 5.92 (d, J＝7.7 Hz, 1H), 5.52 (d, J＝7.5 Hz,
1H), 5.40 (s, 1H), 4.01 (s, 3H), 3.96 (s, 3H), 3.70 (s, 1H),
2.58 (dd, J＝14.8, 9.1 Hz, 1H), 2.43 (t, J＝13.6 Hz, 1H),
2.23 (s, 3H), 2.16 (dd, J＝14.9, 5.3 Hz, 1H), 1.78 (dd,
J＝14.6, 10.7 Hz, 1H), 1.66－1.47 (m, 3H), 1.29－0.90
(m, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.0, 167.7,
148.5, 142.6, 137.8, 136.3, 130.8, 130.3, 129.0, 128.9,
127.8, 127.6, 127.2, 127.0, 126.7, 126.3, 118.0, 107.9,
86.3, 82.2, 78.7, 65.1, 52.8, 52.5, 36.4, 36.0, 31.0, 24.8,
21.9, 21.3; IR (thin film) νmax: 3379, 2948, 1769, 1728,
1599, 1491, 1264, 1151, 965, 746, 701, 656 cm−1;
HRMS (ESI-TOF) calcd for C32H35N2O6S [M＋H]＋:
575.2210; found 575.2202.
Table 1 Optimization of reaction conditionsa
Me
Ts
R
R
Fe(OTf)3 (x mol%)
N
+
Me
molecular sieves
solvent
N
Ph
H
1a, R = CO2Me
2a
Ph
Me
Ts
N
R
R
N
H
Me
3aa
Me
R
Ph
Me
Ts
Me
R
N
R
N
N
Me
H
Ts
N
R
Ph
H
4aa
experimentally not observed
5aa
Entry Solvent
x
MS
4 Å
4 Å
4 Å
5 Å
3 Å
None
4 Å
4 Å
4 Å
4 Å
Time/h
2
Yield/%
1
PhMe
DCE
10
10
10
10
10
10
10
10
5
76
2
0.5
0.5
24
79
3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
83
4
16
5
0.5
1
75
6
57
7b
8c
9c
10c
0.5
0.5
1.5
24
73
95
84
2
Low conv.
3ad White solid, m.p. 192－194 ℃, 23 mg, 22%
yield. 1H NMR (400 MHz, CDCl3) δ: 7.22 (d, J＝8.3 Hz,
2H), 7.08－6.99 (m, 2H), 6.86－6.77 (m, 3H), 6.73 (t,
J＝7.5 Hz, 1H), 6.39 (d, J＝7.8 Hz, 1H), 6.34－6.26 (m,
3H), 6.19 (d, J＝7.3 Hz, 1H), 5.33 (s, 1H), 4.00 (s, 6H),
a 1a (0.2 mmol), 2a (0.3 mmol), Fe(OTf)3 and activated MS (100
mg) in anhydrous solvent (2 mL) at room temperature. b 1a (0.2
mmol) and 2a (0.2 mmol) were used. c 1a (0.3 mmol) and 2a (0.2
mmol) were used.
Chin. J. Chem. 2014, 32, 709—714
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
711

Liu, Zheng & You
FULL PAPER
yield. The structure and the relative configuration of
3aa were determined unambiguously by single crystal
X-ray diffraction analysis.[7] The C5 or C6 functional-
ized product (4aa or 5aa) was not observed even with
elongated reaction time. Examination of solvent effect
revealed that the reaction proceeds better in a chlorin-
ated solvent in terms of yield and reaction time, with
DCM as the optimal choice (83% yield) (Entries 2 and
3). Varied types of MS were found to affect the reaction
significantly (Entries 4－6). The use of 3 Å MS instead
of 4 Å MS led to comparable results (75% yield), while
switching to 5 Å MS only resulted in remarkably re-
tarded reaction rate and modest yield (16%) of the
product. The reaction without adding MS gave rise to
diminished results (57% yield) compared with that ob-
tained using 4 Å MS. Next, the ratio of the two sub-
strates was examined (Entries 7 and 8), indicating an
excess amount of N-Ts aziridine (1a∶2a＝1.5∶1) was
beneficial for getting an enhanced yield (95%) of the
product. Reducing the catalyst loading to 5 mol% or 2
mol% led to slightly lowered yield (84%) or completely
suppressed reactivity (Entries 9 and 10). Finally, the
optimal reaction conditions were identified as described
in Entry 8, Table 1.
The substrate scope of this reaction was then evalu-
ated (Table 2). Generally, the N-Ts aziridines with vari-
ous aryl groups or diester moieties can be converted to
the corresponding [3＋2] annulation products (3aa－
3ga, 3ia and 3ja) in reasonable yields. In some cases
(the reactions of 1c, R1＝4-NO2C6H4; 1g, 2-BrC6H4 and
1j, R2＝CO2i-Pr, respectively), a small amount of their
corresponding C6 functionalization products 4 was gen-
Table 2 Substrate scopea
R5
Ts
N
R4
R2
R1
R5
N
R3
R5
Fe(OTf)3
(10 mol%)
Ts
R2 R1
R2
R2
Ts
N
R4
N
4
+
4o MS
R2
+
N
R3
A
R1
R2 R1
N
R3
3
R4
R2
R5
DCM, r.t.
1
2
R2
N
R4
Ts
N
R3
5
NO2
Br
Cl
Ph
Me
Me
Me
Me
Me
Ts
Ts
Ts
N
N
N
Ts
Ts
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
H
N
N
H
CO2Me
CO2Me
N
H
Me
Me
Me
N
H
H
Me
Me
3cab
24 h, 61% yield
3ca : 4ca = 10 : 1
3aa
3ba
3ea
3da
1 h, 92% yield
0.5 h, 95% yield
0.5 h, 95% yield
0.75 h, 90% yield
Br
Ph
Ph
Me
Me
Ts
N
Br
Ts
N
Me
Me
Me
Ts
N
i
Ts
Ts
CO2Et
CO2Et
CO2 Pr
N
N
N
N
i
Me
Me
CO2 Pr
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
Me
Me
Me
H
H
H
3ja
3ia
1 h, 70% yield
3ja : 4ja = 10 : 1
0.75 h, 83% yield
3hab
No reaction
3fa
3ga
24 h, 57% yield
3ga : 4ga = 5 : 1
2.5 h, 72% yield
Ph
Ph
Ph
Ph
Ph
Me
Ts
N
Ts
N
Ts
Ts
N
Ts
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
N
N
H
H
H
H
Me
3abc
1 h, < 5%
3ac
3aed
24 h, no 3ae
3afe
3ad
3 h, 55% yield
3ac : 4ac = 4 : 1
2 h, 50% yield
dr = 2.5 : 1
2 h, 22% yield
3ad : 4ad = 1 : 1
a 1 (0.3 mmol), 2 (0.2 mmol), Fe(OTf)3 (10 mol%) and activated 4 Å MS (100 mg) in anhydrous DCM (2 mL) at room temperature. Iso-
1
b
lated yield of 3 is reported. The ratio of 3∶4 or 4∶5 was determined by H NMR of the crude reaction mixture. The reaction was re-
fluxed for 24 h with 20 mol% of Fe(OTf)3. c The yield of 4ab is 52%. d The total yield of 4ae and 5ae (1.5∶1) is 20% e Combined yield
of the two diastereomers of 3af is reported.
712
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 709—714

Fe(OTf)3 Catalyzed Annulation of 2,3-Disubstituted Indoles with Aziridines
erated, with the ratio of 3∶4 as 5∶1 to 10∶1. Proba-
bly due to the introduction of a nitro group on the
phenyl ring, the reactivity of 1c was largely reduced in
that the reaction required 20 mol% of Fe(OTf)3 and was
refluxed in DCM for 24 h to deliver the annulation
product 3ca in 62% yield. The reaction of 1g also re-
sulted in a moderate yield of 3ga (57%) with a much
longer time, which might be explained with the in-
creased steric congestion raised by an ortho-bromo sub-
stituent. To be noted, the product 3fa exists as a mixture
of a pair of rotamers at room temperature, according to
occurs. The C3 position of 2a attacks the N-Ts iminium
carbon to deliver intermediate III. The following ring
closing process gives rise to a Fe(OTf)3 coordinated
hexahydropyrrolo[3,4-b]indole intermediate IV. The
final ligand exchange with 1a liberates the desired [3＋
2] annulation product 3aa and furnishes the catalytic
cycle.
Conclusions
In conclusion, we have developed a Fe(OTf)3 cata-
lyzed [3＋2] annulation reaction between N-Ts aziridi-
nes and 2,3-disubstituted indoles to furnish the fused
polycyclic indole derivatives with two consecutive qua-
ternary carboncenters. This reaction features cheap
catalyst, mild conditions and operational simplicity.
Complex indole scaffolds which might find further ap-
plications can be accessed in a concise and efficient
manner.
1
its H NMR spectrum. In addition, the cyclohexyl-sub-
stituted N-Ts aziridine 1h was found completely inac-
tive under the optimal conditions. On the other hand,
different indole derivatives led to quite varied results.
When skatole 2b was utilized as the substrate, only C6
functionalized product 4ab was afforded in 52% yield.
In the cases of hexahydrocyclohepta[b]indole 2c and
tetrahydrocarbazole 2d, the desired annulation products
3ac and 3ad were obtained in moderate yields (55% and
22%), in combination with the corresponding C6 func-
tionalized product 4ac and 4ad, respectively. The N-Me
tetrahydrocarbazole 2e could not be converted to the
annulation product under the optimal conditions with
prolonged reaction time. Instead, a mixture of C6 and
C5 functionalization products 4ae and 5ae were deliv-
ered with a ratio of 1.5∶1. As to tetrahydrocyclopenta-
[b]indole 2f, the annulation reaction led to a pair of di-
astereomers in a combined yield of 50% with 2.5∶1 dr.
Based on our previous results of Sc(OTf)3 catalyzed
analogous reaction,[7] a plausible mechanism of
Fe(OTf)3 catalyzed [3＋2] annulation reaction was
proposed (Scheme 2). To take the reaction between N-Ts
aziridine 1a and 2,3-dimethylindole 2a as an example,
1a first coordinates to Fe(OTf)3 to form intermediate I,
which undergoes ring opening to generate azomethine
ylide II. Subsequently, a stepwise [3＋2] annulation
Acknowledgement
We thank the National Basic Research Program of
China (No. 2010CB833300) and the National Natural
Science Foundation of China (Nos. 21025209,
21121062, 21332009, and 21302209) for generous fi-
nancial support.
References
[1] (a) Sundberg, R. J. The Chemistry of Indoles, Academic Press, New
York, 1970; (b) Indoles, Ed.: Sundberg, R. J., Academic Press, San
Diego, CA, 1996; (c) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004,
21, 278; (d) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23,
532; (e) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489; (f) Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F.;
Álvarez, M. Chem. Eur. J. 2011, 17, 1388.
[2] For selected recent reviews: (a) Crich, D.; Banerjee, A. Acc. Chem.
Res. 2007, 40, 151; (b) Bandini, M.; Eichholzer, A. Angew. Chem.,
Int. Ed. 2009, 48, 9608; (c) Bartoli, G.; Bencivenni, G.; Dalpozzo, R.
Chem. Soc. Rev. 2010, 39, 4449; (d) Shiri, M. Chem. Rev. 2012, 112,
3508; (e) Repka, L. M.; Reisman, S. E. J. Org. Chem. 2013, 78,
12314; For a recent study on the synthesis of pyrrolo[1,2-a]indoles:
(f) Zeng, M.; Zhang, W.; You, S.-L. Chin. J. Chem. 2012, 30, 2615.
[3] (a) Nakagawa, M.; Kawahara, M. Org. Lett. 2000, 2, 953; (b) Eng-
land, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem.
2001, 66, 4704; (c) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J.
Am. Chem. Soc. 2007, 129, 9631; (d) Barluenga, J.; Tudela, E.;
Ballesteros, A.; Tomás, M. J. Am. Chem. Soc. 2009, 131, 2096; (e)
Lian, Y.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440; (f)
Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132,
14418; (g) Benkovics, T.; Guzei, I. A.; Yoon, T. P. Angew. Chem.,
Int. Ed. 2010, 49, 9153; (h) Lucarini, S.; Bartoccini, F.; Battistoni, F.;
Diamantini, G.; Piersanti, G.; Righi, M.; Spadoni, G. Org. Lett. 2010,
12, 3844; (i) Cera, G.; Crispino, P.; Monari, M.; Bandini, M. Chem.
Commun. 2011, 47, 7803; (j) Cera, G.; Chiarucci, M.; Mazzanti, A.;
Mancinelli, M.; Bandini, M. Org. Lett. 2012, 14, 1350; (k) Zhang, J.;
Chen, Z.; Wu, H.-H.; Zhang, J. Chem. Commun. 2012, 48, 1817; (l)
Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6802;
(m) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc.
2013, 135, 7851; (n) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc.
2014, DOI: 10.1021/ja412435b.
Scheme 2 A plausible mechanism
Fe(OTf)3
1a
+
R = MeO
[Fe] = Fe(OTf)n
R
Ts
O
O
N
Ph
[Fe]
3aa
R
I
1a
R
R
Ts
R
Ts
O
N
O
O
Ph
N
Ph
[Fe]
-
+
[Fe]
O
R
N
IV
II
H
R
Ts
O
O
N
Ph
-
[Fe]
2a
R
N
+
H
[4] (a) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc.
III
Chin. J. Chem. 2014, 32, 709—714
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
713

Liu, Zheng & You
FULL PAPER
2010, 132, 11418; (b) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew.
Chem., Int. Ed. 2012, 51, 1680; (c) Wu, K.-J.; Dai, L.-X.; You, S.-L.
Org. Lett. 2012, 14, 3772; (d) Liu, C.; Zhang, W.; Dai, L.-X.; You,
S.-L. Org. Lett. 2012, 14, 4525; (e) Liu, C.; Zhang, W.; Dai, L.-X.;
You, S.-L. Org. Biomol. Chem. 2012, 10, 7177; (f) Zhang, X.; Yang,
Z.-P.; Liu, C.; You, S.-L. Chem. Sci. 2013, 4, 3239; (g) Zhang, X.;
Liu, W.-B.; Wu, Q.-F.; You, S.-L. Org. Lett. 2013, 15, 3746; (h)
Zhang, X.; Han, L.; You, S.-L. Chem. Sci. 2014, 5, 1059; (i) Han, L.;
Liu, C.; Zhang, W.; Shi, X.-X.; You, S.-L. Chem. Commun. 2014,
50, 1231.
Kamaishi, R.; Hirotaki, K.; Furuno, H.; Hanamoto, T. Org. Lett.
2011, 13, 6240; (i) Li, L.; Wu, X.; Zhang, J. Chem. Commun. 2011,
47, 5049; (j) Wu, X.; Li, L.; Zhang, J. Chem. Commun. 2011, 47,
7824; (k) Jiang, Z.; Wang, J.; Lu, P.; Wang, Y. Tetrahedron 2011,
67, 9609; (l) Li, X.; Yang, X.; Chang, H.; Li, Y.; Ni, B.; Wei, W.
Eur. J. Org. Chem. 2011, 3122; (m) Wei, L.; Zhang, J. Chem. Com-
mun. 2012, 48, 2636; (n) Griffin, K.; Montagne, C.; Hoang, C. T.;
Clarkson, G. J.; Shipman, M. Org. Biomol. Chem. 2012, 10, 1032;
(o) Wu, X.; Zhang, J. Synthesis 2012, 44, 2147; (p) Ghorai, M. K.;
Tiwari, D. P. J. Org. Chem. 2013, 78, 2617.
[5] For a recent review on aziridines in formal [3＋2] annulation, see: (a)
Cardoso, A. L.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2012,
6479; For selected recent examples, see: (b) Pohlhaus, P. D.; Bow-
man, R. K.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 2294; (c)
Yadav, V. K.; Sriramurthy, V. J. Am. Chem. Soc. 2005, 127, 16366;
(d) Wu, J.; Sun, X.; Xia, H.-G. Tetrahedron Lett. 2006, 47, 1509; (e)
Wender, P. A.; Strand, D. J. Am. Chem. Soc. 2009, 131, 7528; (f)
Fan, J.; Gao, L.; Wang, Z. Chem. Commun. 2009, 5021; (g) Li, L.;
Zhang, J. Org. Lett. 2011, 13, 5940; (h) Maeda, R.; Ishibashi, R.;
[6] (a) Gribble, G. W.; Fraser, H. L.; Badenock, J. C. Chem. Commun.
2001, 805; (b) Roy, S.; Kishbaugh, T. L. S.; Jasinski, J. P.; Gribble,
G. W. Tetrahedron Lett. 2007, 48, 1313; (c) Ivachtchenko, A. V.;
Frolov, E. B.; Mitkin, O. D.; Tkachenko, S. E.; Khvat, A. V. Chem.
Heterocycl. Compd. 2010, 46, 170.
[7] Liu, H.; Zheng, C.; You, S.-L. J. Org. Chem. 2014, 79, 1047.
[8] Fan, R.; Ye, Y. Adv. Synth. Catal. 2008, 350, 1526.
[9] Aziridine 1a is moisture sensitive and decomposes in the presence of
Lewis acid without molecular sieves. See ref. 5i.
(Lu, Y.)
714
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 709—714