An efficient synthesis of a (-)-physostigmine's library for identifying potential anti-Alzheimer's agents

Article abstract of DOI:10.1002/hlca.201100020

An efficient route for the synthesis of (-)-physostigmine analogs 1a-1g and 2a-2k is described. Analogs 1a-1g were synthesized via copper(I)-catalyzed cycloaddition between the optically pure azide 10 and a variety of alkynes. Similarly, analogs 2a-2k wer

Full text of DOI:10.1002/hlca.201100020

1496
Helvetica Chimica Acta – Vol. 94 (2011)
An Efficient Synthesis of a (ꢀ)-Physostigmineꢀs Library for Identifying
Potential Anti-Alzheimerꢀs Agents
by Yi Wu, Fusheng Wang, Hao Song, and Yong Qin*
Key Laboratory of Drug Targeting & Drug Delivery Systems of the Ministry of Education, West China
School of Pharmacy, Chengdu 610041, P. R. China
(phone/fax: þ 86-28-85503842; e-mail: yongqin@scu.edu.cn)
An efficient route for the synthesis of (ꢀ)-physostigmine analogs 1a – 1g and 2a – 2k is described.
Analogs 1a – 1g were synthesized via copper(I)-catalyzed cycloaddition between the optically pure azide
10 and a variety of alkynes. Similarly, analogs 2a – 2k were prepared through ꢀthree-component Huisgen
cycloadditionꢁ using various amines, propargyl bromine, and 10 in H2O. Facile preparation of 10 via
MacMillanꢁs organocatalysis has made it possible to generate a great diversity of natural product-like
compounds that can be screened for anti-Alzheimerꢁs effects.
Introduction. – (ꢀ)-Physostigmine was first isolated from the African Calabar bean
seed Physostigma venenosum (Fig. 1) [1]. Possessing a hexahydropyrrolo[2,3-b]indole
ring system, (ꢀ)-physostigmine is one of the earliest compounds to be used as an
inhibitor of acetylcholinesterase and a therapeutic agent against Alzheimerꢁs disease
[2]. However, this drug has the major drawbacks of low bioavailability and a narrow
therapeutic window by its rapid metabolism and inefficient passage across the
bloodꢀbrain barrier [3]. (ꢀ)-Phenserine, a synthetic analog of (ꢀ)-physostigmine with
improved bioavailability, is a more potent and selective inhibitor of acetylcholinester-
ase [4], and it can inhibit the formation of the b-amyloid precursor protein [5].
The five-membered 1,2,3-triazole moiety is a commonly used pharmacophore
associated with anti-HIV [6], anti-allergic [7], antifungal [8], antimicrobial [9], and
other biological activities. The ꢀclick chemistryꢁ [10] to synthesize 1,2,3-triazoles has
been widely used as a powerful tool in generating diverse compound libraries.
Fig. 1. Structure of (ꢀ)-Physostigmine and Its Analogs (ꢀ)-Phenserine, 1, and 2
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 94 (2011)
1497
Given that several physostigmine-like natural alkaloids with different substituents
at C(3a) show a variety of biological activities [11], and that replacing the methyl
carbamate of (ꢀ)-physostigmine at C(5) with a different carbamate improves its
pharmacological activity [12], in this article, we describe the design and synthesis a
series of (ꢀ)-physostigmine analogues with variations at C(5) and C(3a) that can be
screened for anti-Alzheimerꢁs activity.
Results and Discussion. – The synthetic strategy for the preparation of (ꢀ)-
physostigmine analogues 1 and 2 is shown in the Scheme. Although the synthesis of
chiral 3a-substituted hexahydropyrrolo[2,3-b]indoles has been intensively investigated
over the past two decades because of the importance and richness of natural products
with this skeleton [11], a catalytic and reliable procedure involving easy preparation of
Scheme. Synthesis of (ꢀ)-Physostigmine Analogs 1a – 1g and 2a – 2k
a) CH2Cl2/H2O 85 :15, ꢀ 788; 87%. b) LiAlH4, THF, reflux; 86%. c) Raney-Ni, toluene, reflux; 60%. d)
NIS, CH2Cl2, r.t.; 93%. e) NaN3, CuI, N,N’-dimethylethane-1,2-diamine, sodium ascorbate, DMSO/H2O
5 :1, r.t.; 80%. f) CuI, sodium ascorbate, DMF; 50 – 91%. g) CuI, Et3N, H2O; 61 – 80%.

1498
Helvetica Chimica Acta – Vol. 94 (2011)
the starting material, high diastereo- and enatioselectivities, and high yield is still
lacking. Recent advances in organocatalytic reactions [13], such as the highly efficient
procedure of MacMillan and co-workers reported in 2008 [14], have provided easy
access to chiral 3a-substituted hexahydropyrrolo[2,3-b]indoles. With slight modifica-
tions of MacMillanꢁs original conditions with a different starting material, a core
structure of the chiral 3a-ethyl hexahydropyrrolo[2,3-b]indole was prepared from
tryptamine derivative 3 and acrolein (4) in the presence 10 mol-% of imidazolidinone
trifluoroacetic acid salt 5, obtaining aldehyde 6 in 87% yield and with 88% ee. Attempts
to improve the ee value of aldehyde 6 were unsuccessful, because 6 did not easily
crystallize. Fortunately, after reduction of the methyl carbamate and aldehyde groups in
6 with LiAlH4, the resulting alcohol 7 easily recrystallized from a mixture CH2Cl2/Et2O
4 :1 to form a white crystalline solid with 99% ee. The absolute configuration of 7 was
determined by X-ray crystallographic analysis1) (Fig. 2). Compound 8 was obtained in
60% yield by heating 7 with Raney-Ni under reflux in toluene [15]. Reaction of 8 with
N-iodosuccinimide (NIS) in anhydrous CH2Cl2 gave iodide 9 in 93% yield. Iodide
replacement with azide [16] in 9 in the presence of the catalysts CuI and N,N’-
dimethylethane-1,2-diamine in a mixture DMSO/H2O 5 :1 provided the key inter-
mediate azide 10 in 80% yield.
Fig. 2. ORTEP Drawing of Compound 7
In the presence of CuI and sodium ascorbate, analogs 1a – 1g were synthesized in
yields of 50 – 91% by reacting different terminal alkynes 11a – 11g, respectively, with
azide 10 in DMF. The structures of the products 1a – 1g are shown in Table 1. Analogs
2a – 2k were prepared in 61 – 80% yield via a ꢀthree-component Huisgen reactionꢁ using
1
)
A colorless crystal of 7 (C15H22N2O, m.p. 71 – 728) for the X-ray-analysis was obtained by
recrystallization from CH2Cl2 and Et2O (4:1). CCDC-774697 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge from the Cambride
Crystallographic Data Centre, via http://www.ccdc.cam.ac.uk/data_request.cif.

Helvetica Chimica Acta – Vol. 94 (2011)
1499
Table 1. Copper(I)-Catalyzed Regioselective Cycloaddition of Azide 10 with Various Alkynes 11a – 11g
Entry
11
R
1
R1
Yield [%]
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
11f
11g
Me3Si
Ph
1a
1b
1c
1d
1e
1f
1g
H
Ph
50
80
61
91
85
84
62
HOꢀCH2
HOꢀC(Me2)
HOꢀ(CH2)2
HOꢀ(CH2)4
EtOOC
HOꢀCH2
HOꢀC(Me2)
HOꢀ(CH2)2
HOꢀ(CH2)4
EtOOC
commercially available amines 13a – 13k, respectively, propargyl bromide 12, and the
azide 10 in the presence of CuI and Et3N in H2O. The structures of the products 2a – 2k
are shown in Table 2. We were pleased to find that the 1,3-dipolar cycloaddition
reaction proceeded regioselectively, affording exclusively the 1,4-disubstituted 1,2,3-
Table 2. Copper(I)-Catalyzed ꢀThree-Component Huisgen Reactionꢁ Involving Amines 13a – 13j, Prop-
argyl Bromine 12, and Azide 10
Entry
13
R1
R2
2
Yield [%]
1
2
3
4
5
6
7
8
9
13a
13b
13c
13d
13e
13f
13g
13h
13i
Me
Bu
Me
Cyclohexyl
Me
Bu
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
61
80
64
70
64
68
74
70
64
61
62
Cyclohexyl
ꢀ(CH2)4ꢀ
ꢀ(CH2)6ꢀ
ꢀ(CH2)2ꢀOꢀ(CH2)2ꢀ
ꢀ(CH2)2ꢀN(Me)ꢀ(CH2)2ꢀ
ꢀ(CH2)2ꢀN(Bn)ꢀ(CH2)2ꢀ
ꢀ(CH2)2ꢀN(COPh)ꢀ(CH2)2ꢀ
ꢀ(CH2)2ꢀN(CH2Bn)ꢀ(CH2)2ꢀ
10
11
13j
13k
2j
2k

1500
Helvetica Chimica Acta – Vol. 94 (2011)
triazole derivatives [10e][10g]. Compounds 1a – 1g and 2a – 2k were fully characterized
by IR, 1H- and 13C-NMR, and HR-MS.
Conclusions. – The (ꢀ)-physostigmine analogs 1a – 1g and 2a – 2k, containing a 3a-
ethyl-5-(1H-1,2,3-triazol-1-yl)hexahydropyrrolo[2,3-b]indole skeleton, have been syn-
thesized via a six-step route with an overall yield of 20 – 30%. Aldehyde 6 with the
hexahydropyrrolo[2,3-b]indole skeleton was prepared in 87% yield and 88% ee
through a highly efficient organocatalytic cascade reaction. The ee value of the core
structure was greatly enhanced to 99% by a single recrystallization of alcohol 7. Easy
preparation of (ꢀ)-azide 10 under mild conditions allowed us to synthesize a diverse
library focusing on the 1,2,3-triazole moiety using reliable ꢀclick chemistryꢁ. Evaluation
of the synthesized library compounds 1a – 1g and 2a – 2k as potent inhibitors of
acetylcholinesterase will be studied in due course.
This work was supported by grants from NSFC (20825207, 20972100, 21021001, and 21002066),
PCSIRT (IRT0846), the National Basic Research Program of China (973 program, 2010CB833200), and
the National S & T Major Project of China (2009ZX09310-002).
Experimental Part
General. All commercially available reagents were used without further purification. All solvents
were dried and distilled before use. THF was distilled from Na/benzophenone; CH2Cl2 and DMF were
distilled from CaH2. Flash column chromatography (FC): silica gel (SiO2; 200 – 300 mesh). IR Spectra: in
KBr; Nicolet 200SXY FT-IR spectrophotometer. HPLC Analysis: Varian ProStar; column, Chiral OD-H
(1.6 ꢁ 25 cm); wavelength 254 nm; flow rate, 1 ml/min; mobile phase: hexane/iPrOH/Et3N 90 :10 :0.3.
1H- and 13C-NMR Spectra: Varian Unity INOVA 400/54 NMR spectrometer at 400 MHz and 100 MHz, in
CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. HR-FAB-MS: Finnigan MAT 90 instrument.
Methyl (3aS,8aS)-3,3a,8,8a-Tetrahydro-8-methyl-3a-(3-oxopropyl)pyrrolo[2,3-b]indole-1(2H)-car-
boxylate (6). A round-bottom flask equipped with a magnetic stir bar, containing (2S,5S)-2-(tert-
butyl)-5-(1H-indol-3-ylmethyl)-3-methylimidazolidin-4-one TFA salt (5; 1.50 g, 5.2 mmol) and methyl
[2-(1-methyl-1H-indol-3-yl)ethyl]carbamate (3; 12.03 g, 51.7 mol) was charged with CH2Cl2 (85 ml) and
H2O (15 ml). The soln. was stirred for 5 min at ꢀ 788 before acrolein (17.38 g, 310.3 mmol) was added.
The resulting suspension was stirred at ꢀ 788 until complete consumption of 5 was observed (TLC).
Then, H2O was added, the mixture was extracted with Et2O, and the org. phase was concentrated in
vacuum. The resulting residue was purified by FCC (in 20% AcOEt/petroleum ether (PE)) to afford 6 as
colorless film (13.02 g, 87% yield). [a]2D0 ¼ ꢀ330.6 (c ¼ 2.5, CHCl3). IR: 2954, 2887, 2828, 1699, 1607, 1493,
1
1448, 1386, 1300, 1223, 1202, 1160, 1105, 1068, 1022, 999, 938, 880, 744. H-NMR: 1.96 – 1.99 (m, 2 H);
2.13 – 2.16 (m, 2 H); 2.20 – 2.28 (m, 1 H); 2.40 – 2.44 (m, 1 H); 2.89 (s, 1 H); 2.98 (s, 3 H); 3.71 (s, 3 H);
3.70 (s, 1 H); 5.27 (s, 1 H); 6.38 (d, J ¼ 7.6, 1 H); 6.68 (t, J ¼ 7.2, 1 H); 6.97 (d, J ¼ 7.2, 1 H); 7.12 (t, J ¼ 7.6,
1 H); 9.64 (s, 1 H). 13C-NMR: 30.2; 32.0; 38.0; 39.7; 45.4; 45.6; 52.2; 85.4; 105.6; 117.3; 122.2; 128.6; 130.4;
151.0; 155.9; 201.1. HR-FAB-MS: 343.1630 (C17H24N2NaOþ4 , [M þ MeOH þ Na]þ; calc. 343.1628).
3-[(3aS,8aR)-2,3,8,8a-Tetrahydro-1,8-dimethylpyrrolo[2,3-b]indol-3a(1H)-yl]propan-1-ol (7). To a
soln. of 6 (10.23 g, 42 mmol) in THF (100 ml) at 08 was added LiAlH4 (9.50 g, 250 mmol). The mixture
was warmed to reflux temp. until complete consumption of 6 (determined by TLC), and quenched with
sat. Na2SO4 soln. The mixture was extracted with AcOEt, filtered through a pad of Celite, and washed
with AcOEt. The combined extracts were concentrated. The residue was purified by SiO2 chromatog-
raphy, eluted with 5 – 10% MeOH in CH2Cl2, to provide 7 as colorless solid (8.80 g, 86% yield with 88%
ee). The ee value was determined by HPLC with Chiral ODꢀH (1.6 ꢁ 25 cm, wave length 254 nm; flow
rate, 1 ml/min; mobile phase: hexane/iPrOH/Et3N 90 :10 :0.3). Compound 7 was recrystallized from a
mixture CH2Cl2/Et2O 4 :1 to form a white crystalline solid (3.96 g, 45 % yield) with 99% ee. The ee value

Helvetica Chimica Acta – Vol. 94 (2011)
1501
was determined by HPLC with Chiral ODꢀH; flow rate, 1 ml/min; mobile phase: hexane/iPrOH/Et3N
90 :10 :0.3). M.p. 71 – 728. [a]2D0 ¼ ꢀ96.5 (c ¼ 0.63, CHCl3). IR: 3284, 3050, 2935, 2866, 2817, 1605, 1492,
1
1463, 1428, 1378, 1344, 1298, 1250, 1157, 1123, 1061, 1022, 937, 842, 793, 742. H-NMR: 1.28 – 1.34 (m,
1 H); 1.44 – 1.50 (m, 1 H); 1.75 (dd, J ¼ 12, 4.4, 1 H); 1.85 (dd, J ¼ 12, 4.4, 1 H); 1.95 – 1.97 (m, 1 H); 2.02 –
2.05 (m, 1 H); 2.51 (s, 3 H); 2.53 – 2.57 (m, 1 H); 2.66 – 2.71 (m, 1 H); 2.94 (s, 3 H); 3.57 (d, J ¼ 8.4, 2 H);
4.19 (s, 1 H); 6.41 (d, J ¼ 8, 1 H); 6.67 (t, J ¼ 7.6, 1 H); 6.96 (d, J ¼ 6.4, 1 H); 7.08 (t, J ¼ 7.6, 1 H).
13C-NMR: 29.2; 36.3; 36.5; 37.7; 39.6; 52.4; 56.7; 62.5; 93.9; 106.6; 117.6; 122.6; 127.7; 134.5; 152.6. HR-
FAB-MS: 247.1812 (C15H23N2Oþ, [M þ H]þ; calc. 247.1805).
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indole (8). To a soln. of 7
(6.0 g, 24.4 mmol) in toluene (100 ml) was added 60 g of Raney-Ni slurry. The suspension was refluxed for
4 – 6 h with vigorous stirring to remove H2O, and cooled to r.t. The mixture was filtered through a pad of
Celite, and washed with AcOEt. The solvent was removed in vacuum to leave a pale residue, which was
purified by chromatography eluted with 1 – 5% MeOH in CH2Cl2, to provide 8 as a colorless film (2.68 g,
51% yield). [a]2D0 ¼ ꢀ71.0 (c ¼ 1.2, CHCl3). IR: 3320, 3049, 2960, 2929, 2875, 2791, 1682, 1605, 1492, 1460,
1
1379, 1346, 1299, 1255, 1207, 1163, 1124, 1031, 968, 919, 786, 740, 635. H-NMR: 0.75 (t, J ¼ 7.2, 3 H);
1.70 – 1.73 (m, 1 H); 1.79 – 1.88 (m, 1 H); 1.89 – 1.94 (m, 1 H); 1.99 – 2.04 (m, 1 H); 2.52 (s, 3 H); 2.53 –
2.57 (m, 1 H); 2.66 – 2.71 (m, 1 H); 2.94 (s, 3 H); 4.16 (s, 1 H); 6.41 (d, J ¼ 7.6, 1 H); 6.67 (t, J ¼ 7.6,
1 H); 6.95 (d, J ¼ 7.6, 1 H); 7.08 (t, J ¼ 7.6, 1 H). 13C-NMR: 10.0; 32.5; 36.4; 37.8; 39.3; 52.6; 57.5; 93.8;
106.5; 117.5; 122.7; 127.6; 134.6; 152.7. HR-FAB-MS: 217.1701 (C14H21Nþ2 , [M þ H]þ; calc. 217.1699).
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-5-iodo-1,8-dimethylpyrrolo[2,3-b]indole (9). To a soln.
of 8 (2.68 g, 12.4 mmol) in dry CH2Cl2 (50 ml) at 08 was added a soln. of N-iodosuccinimide (NIS; 3.35 g,
14.9 mmol) in dry CH2Cl2. The mixture was allowed to warm to r.t., and then stirred for 4 h until
complete consumption of 8 was observed by TLC. Then, sat. Na2SO3 soln. was added, and the mixture
was extracted with CH2Cl2. The combined org. layers were dried (NaSO4), filtered, and concentrated in
vacuum. The residue was purified by CC (3% MeOH in CH2Cl2) to give 9 (3.94 g, 93% yield) as light
yellow film. [a]2D0 ¼ ꢀ77.1 (c ¼ 0.41, CHCl3). IR: 2961, 2929, 2875, 2791, 1680, 1649, 1593, 1490, 1379, 1347,
1271, 1255, 1164, 1127, 1072, 1032, 969, 919, 877, 801, 644, 574. 1H-NMR: 0.75 (t, J ¼ 7.2, 3 H); 1.64 – 1.70
(m, 1 H); 1.75 – 1.84 (m, 1 H); 1.88 – 1.93 (m, 1 H); 1.99 – 2.02 (m, 1 H); 2.51 (s, 3 H); 2.56 – 2.58 (m, 1 H);
2.68 – 2.72 (m, 1 H); 2.91 (s, 3 H); 4.17 (s, 1 H); 6.18 (d, J ¼ 8.4, 1 H); 7.18 (d, J ¼ 1.2, 1 H); 7.33 (dd, J ¼
8.0, 1.6, 1 H). 13C-NMR: 9.9; 32.3; 36.1; 37.5; 39.0; 52.4; 57.6; 78.1; 93.2; 108.7; 131.4; 136.4; 137.4; 152.3.
HR-FAB-MS: 343.2261 (C14H20INþ2 , [M þ H]þ; calc. 343.2259).
(3aS,8aR)-5-Azido-3a-ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indole (10). Under
N2, 9 (296 mg, 0.87 mmol), NaN3 (226 mg, 3.48 mmol), sodium ascorbate (17.2 mg, 0.087 mmol), N,N’-
dimethylethane-1,2-diamine (29.2 mg, 0.348 mmol), and CuI (34.5 mg, 0.174 mmol) were dissolved in a
degassed mixture of DMSO/H2O 5 :1 (50 ml). The mixture was stirred at r.t. for 24 h, then, brine was
added. The mixture was extracted with AcOEt. The combined org. phases were washed with H2O, dried
with anh. NaSO4, filtered, and concentrated in vacuum. The residue was purified by CC to give 10
(358 mg, 80% yield) as light green oil. [a]2D0 ¼ ꢀ74.3 (c ¼ 0.04, MeOH). IR: 2961, 2927, 2876, 2852, 2792,
2101, 1613, 1593, 1498, 1448, 1380, 1347, 1292, 1253, 1164, 1135, 1111, 1033, 967, 928, 869, 802, 655.
1H-NMR: 0.74 (t, J ¼ 7.2, 3 H); 1.63 – 1.72 (m, 1 H), 1.78 – 1.86 (m, 1 H); 1.88 – 1.93 (m, 1 H); 1.97 – 2.03
(m, 1 H); 2.51 (s, 3 H); 2.56 – 2.59 (m, 1 H); 2.68 – 2.70 (m, 1 H); 2.92 (s, 3 H); 4.15 (s, 1 H); 6.36 (d, J ¼
8.4, 1 H); 6.63 (d, J ¼ 2.0, 1 H); 6.75 (dd, J ¼ 8.4, 2.4, 1 H). 13C-NMR: 10.0; 32.4; 36.5; 38.0; 39.3; 52.6;
57.7; 94.2; 107.2; 114.0; 118.4; 136.3; 136.7; 150.5. HR-FAB-MS: 258.1725 (C14H20Nþ5 , [M þ H]þ; calc.
258.1713).
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethyl-5-(1H-1,2,3-triazol-1-yl)pyrrolo[2,3-b]in-
dole (1a). To a soln. of 10 (25.7 mg, 0.10 mmol), CuI (3.8 mg, 0.02 mmol), and sodium ascorbate (4.0 mg,
0.02 mmol) in DMF (1 ml) was added ethynyl(trimethyl)silane (11a; 28 ml, 0.20 mmol) under N2 at r.t.
The mixture was stirred at 608 for 30 h. Then, brine was added, and the mixture was extracted with
AcOEt. The combined org. phases were washed with H2O, dried (Na2SO4), filtered, and concentrated in
vacuum. The residue was purified by FCC to provide 1a (14.2 mg, 50.0% yield) as a colorless film. [a]D20
¼
1
ꢀ49.0 (c ¼ 0.05, CHCl3). IR: 3744, 2960, 2919, 2851, 1694, 1511, 1462, 1260, 1093, 1026, 801. H-NMR:
0.79 (t, J ¼ 7.2, 3 H); 1.71 – 1.76 (m, 1 H); 1.85 – 1.90 (m, 1 H); 2.00 – 2.02 (m, 1 H); 2.05 – 2.07 (m, 1 H);
2.56 (s, 3 H); 2.61 – 2.63 (m, 1 H); 2.65 – 2.72 (m, 1 H); 3.01 (s, 3 H); 4.25 (s, 1 H); 6.42 (d, J ¼ 9.2, 1 H);

1502
Helvetica Chimica Acta – Vol. 94 (2011)
7.32 (d, J ¼ 7.6, 1 H); 7.33 (s, 1 H); 7.80 (s, 1 H); 7.85 (s, 1 H). 13C-NMR: 9.9; 32.3; 35.8; 38.1; 39.0; 52.7;
57.7; 93.9; 105.9; 116.6; 121.1; 121.9; 127.5; 134.0; 136.0; 152.7. HR-FAB-MS: 284.1877 (C16H22Nþ5 , [M þ
H]þ; calc. 284.1870).
General Procedure for the Synthesis of Analogs 1b – 1g. To a soln. of azide (0.10 mmol), CuI
(0.02 mmol), and sodium ascorbate (0.02 mmol) in DMF (1 ml) was added the respective alkyne
(0.15 mmol) under N2 at r.t. The mixture was stirred at r.t. for 4 h, then brine was added, and the mixture
was extracted with AcOEt. The combined org. phases were washed with H2O, dried (Na2SO4), filtered,
and concentrated. The residue was purified by FCC to give 1b – 1g.
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethyl-5-(4-phenyl-1H-1,2,3-triazol-1-yl)pyrro-
lo[2,3-b]indole (1b). Colorless film, 80% yield. [a]2D0 ¼ ꢀ68.9 (c ¼ 0.38, CHCl3). IR: 3415, 2923, 2854,
1615, 1509, 1444, 1383, 1296, 1226, 1036, 810, 760, 702. 1H-NMR: 0.80 (t, J ¼ 7.2, 3 H); 1.73 – 1.79 (m, 1 H);
1.85 – 1.92 (m, 1 H); 2.03 – 2.04 (m, 1 H); 2.08 – 2.10 (m, 1 H); 2.57 (s, 3 H); 2.62 – 2.66 (m, 1 H); 2.75 –
2.77 (m, 1 H); 3.02 (s, 3 H); 4.30 (s, 1 H); 6.45 (d, J ¼ 8.0, 1 H); 7.34 – 7.41 (m, 3 H); 7.45 (t, J ¼ 7.6, 2 H);
7.90 (d, J ¼ 7.2, 2 H); 8.06 (s, 1 H). 13C-NMR: 9.9; 32.3; 35.8; 38.1; 39.0; 52.7; 57.7; 94.0; 105.9; 116.5;
118.0; 121.1; 125.8 ꢁ 2; 128.2 ꢁ 2; 128.9 ꢁ 2; 130.6; 136.0; 147.9; 152.8. HR-FAB-MS: 360.2205 (C22H26Nþ5 ,
[M þ H]þ; calc. 360.2183).
{1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-1,2,3-tria-
zol-4-yl}methanol (1c). Colorless film, 61% yield. [a]2D0 ¼ ꢀ49.8 (c ¼ 0.21, CHCl3). IR: 3394, 2959, 2920,
2851, 1650, 1615, 1508, 1459, 1379, 1260, 1219, 1034, 805, 705. 1H-NMR: 0.78 (t, J ¼ 7.6, 3 H); 1.71 – 1.77
(m, 1 H); 1.83 – 1.90 (m, 1 H); 1.98 – 2.02 (m, 1 H); 2.03 – 2.12 (m, 1 H); 2.56 (s, 3 H); 2.60 – 2.65 (m, 1 H);
2.76 – 2.78 (m, 1 H); 3.01 (s, 3 H); 4.29 (s, 1 H); 4.87 (s, 2 H); 6.43 (d, J ¼ 8.8, 1 H); 7.31 (s, 1 H); 7.32 (d,
J ¼ 8.8, 1 H); 7.84 (s, 1 H). 13C-NMR: 9.7; 31.6; 31.9; 37.3; 41.8; 48.1; 52.6; 56.6; 96.8; 106.2; 116.5; 119.3;
120.2; 121.9; 128.6; 130.9; 136.2. HR-FAB-MS: 314.1985 (C17H24N5Oþ, [M þ H]þ; calc. 314.1975).
2-{1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-1,2,3-
triazol-4-yl}propan-2-ol (1d). White amorphous solid, 91% yield. [a]2D0 ¼ ꢀ65.8 (c ¼ 0.31, CHCl3). IR:
3743, 3384, 3079, 2967, 2923, 2854, 1614, 1508, 1442, 1378, 1287, 1226, 1169, 1039, 806, 754, 705. 1H-NMR:
0.78 (t, J ¼ 7.2, 3 H); 1.74 – 1.77 (m, 1 H); 1.82 – 1.90 (m, 1 H); 1.96 – 2.02 (m, 1 H); 2.04 – 2.09 (m, 1 H);
2.55 (s, 3 H); 2.58 – 2.64 (m, 1 H); 2.67 – 2.74 (m, 1 H); 3.00 (s, 3 H); 4.24 (s, 1 H); 6.43 (d, J ¼ 8.4, 1 H);
7.29 (s, 1 H); 7.32 (d, J ¼ 8.4, 1 H); 7.74 (s, 1 H). 13C-NMR: 9.9; 30.5 ꢁ 2; 32.2; 35.8; 38.0; 38.9; 52.7; 57.7;
68.5; 93.9; 105.9; 116.5 ꢁ 2; 117.8; 121.1; 128.4; 135.8; 152.6. HR-FAB-MS: 342.2290 (C19H28N5Oþ, [M þ
H]þ; calc. 342.2288).
2-{1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-1,2,3-
triazol-4-yl}ethanol (1e). Colorless film, 85% yield. [a]2D0 ¼ ꢀ82.9 (c ¼ 0.14, CHCl3). IR: 3744, 3359, 3079,
2962, 2926, 2856, 1612, 1586, 1507, 1440, 1383, 1346, 1261, 1218, 1120, 1037, 804, 755, 704. 1H-NMR: 0.78 (t,
J ¼ 7.2, 3 H); 1.70 – 1.77 (m, 1 H); 1.84 – 1.91 (m, 1 H); 1.96 – 2.01 (m, 1 H); 2.04 – 2.09 (m, 1 H); 2.55 (s,
3 H); 2.58 – 2.64 (m, 1 H); 2.69 – 2.74 (m, 1 H); 3.00 (s, 3 H); 3.02 (t, J ¼ 5.6, 2 H); 4.00 (t, J ¼ 6, 2 H); 4.24
(s, 1 H); 6.41 (d, J ¼ 8.4, 1 H); 7.30 (s, 1 H); 7.31 (d, J ¼ 8.4, 1 H); 7.70 (s, 1 H). 13C-NMR: 9.8; 28.7; 32.1;
35.7; 37.8; 38.7; 52.6; 57.6; 61.5; 93.8; 106.0; 116.3 ꢁ 2; 120.2; 121.0; 128.4; 135.7; 152.4. HR-FAB-MS:
328.2155 (C18H26N5Oþ, [M þ H]þ; calc. 328.2132).
4-{1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-1,2,3-
triazol-4-yl}butan-1-ol (1f). Colorless film, 84 % yield. [a]2D0 ¼ ꢀ62.5 (c ¼ 0.12, CHCl3). IR: 3368, 2964,
1
2926, 2798, 1614, 1508, 1459, 1378, 1288, 1228, 1169, 1042, 962, 807, 754, 706. H-NMR: 0.78 (t, J ¼ 7.2,
3 H); 1.66 – 1.76 (m, 3 H); 1.80 – 1.90 (m, 3 H); 1.98 – 2.02 (m, 1 H); 2.05 – 2.07 (m, 1 H); 2.53 (s, 3 H);
2.58 – 2.64 (m, 1 H); 2.72 – 2.74 (m, 1 H); 2.83 (t, J ¼ 7.2, 2 H); 2.94 (s, 3 H); 3.71 (t, J ¼ 5.4, 2 H); 4.25 (s,
1 H); 6.41 (d, J ¼ 8.8, 1 H); 7.30 (s, 1 H); 7.31 (d, J ¼ 7.2, 1 H); 7.60 (s, 1 H). 13C-NMR: 9.9; 25.3; 25.6;
30.5; 32.3; 35.8; 39.0; 50.7; 52.7; 57.7; 62.4; 93.9; 105.9; 116.4; 116.5 ꢁ 2; 120.9; 121.1; 135.9; 152.7. HR-
FAB-MS: 356.2424 (C20H30N5Oþ, [M þ H]þ; calc. 356.2445).
Ethyl 1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-
1,2,3-triazole-4-carboxylate (1g). Compound 1g was prepared at ꢀ 208 as described for 1b. Colorless
film, 62 % yield. [a]2D0 ¼ ꢀ65.9 (c ¼ 0.085, CHCl3). IR: 3419, 2961, 2919, 2851, 1733, 1613, 1509, 1460,
1440, 1376, 1259, 1149, 1038, 804, 753, 705. 1H-NMR: 0.78 (t, J ¼ 7.2, 3 H); 1.43 (t, J ¼ 7.2, 3 H); 1.68 – 1.77
(m, 1 H); 1.82 – 1.91 (m, 1 H); 1.95 – 2.02 (m, 1 H); 2.04 – 2.09 (m, 1 H); 2.55 (s, 3 H); 2.58 – 2.64 (m, 1 H);
2.68 – 2.73 (m, 1 H); 2.83 (t, J ¼ 7.2, 2 H); 3.00 (s, 3 H); 4.24 (s, 1 H); 4.45 (q, J ¼ 7.2, 2 H); 6.41 (d, J ¼ 8.4,

Helvetica Chimica Acta – Vol. 94 (2011)
1503
1 H); 7.31 (s, 1 H); 7.34 (d, J ¼ 8.4, 1 H); 8.35 (s, 1 H). 13C-NMR: 9.8; 14.4; 32.2; 35.6; 38.0; 38.8; 52.7; 57.7;
61.3; 93.8; 105.9; 116.5; 121.3; 125.5; 136.0; 140.3; 153.0; 160.9; 186.3. HR-FAB-MS: 356.2092
(C19H26N5Oþ2 , [M þ H]þ; calc. 356.2081).
General Procedure for the Synthesis of Analogs 2a – 2k. To a mixture of amine 13 (2 mmol),
propargyl bromide 12 (2 mmol), and Et3N (3.3 mmol) in H2O (2 ml) was added azide 10 (1.0 mmol) and
CuI (0.2 mmol). The mixture was stirred vigorously for 2 h at r.t. and then was added brine. The mixture
was extracted with AcOEt. The combined org. phases were washed with brine, dried over anh. Na2SO4,
filtered, and concentrated. The residue was purified by FCC to give the desired analog 2.
1-{1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-1,2,3-
triazol-4-yl}-N,N-dimethylmethanamine (2a). Colorless film, 61% yield. [a]2D0 ¼ ꢀ26.4 (c ¼ 0.125,
CHCl3). IR: 3413, 2957, 2920, 2851, 1726, 1662, 1613, 1509, 1465, 1381, 1259, 1123, 1030, 807.
1H-NMR: 0.77 (t, J ¼ 7.6, 3 H); 1.69 – 1.74 (m, 1 H); 1.83 – 1.89 (m, 1 H); 1.96 – 1.99 (m, 1 H); 2.00 – 2.02
(m, 1 H); 2.36 (s, 6 H); 2.54 (s, 3 H); 2.60 – 2.63 (m, 1 H); 2.69 – 2.73 (m, 1 H); 2.99 (s, 3 H); 3.73 (s, 2 H);
4.24 (s, 1 H); 6.40 (d, J ¼ 8.4, 1 H); 7.30 (s, 1 H); 7.31 (d, J ¼ 7.2, 1 H); 7.82 (s, 1 H). 13C-NMR: 9.8; 32.3;
35.6; 38.4; 39.1; 45.0 ꢁ 2; 52.6; 54.3; 57.5; 94.0; 105.6; 116.3; 120.7; 120.8; 128.8; 136.1; 145.0; 152.7. HR-
FAB-MS: 341.2440 (C19H29Nþ6 , [M þ H]þ; calc. 341.2448).
N-Butyl-N-({1-[(3aS,8aR)-3a-ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-
1H-1,2,3-triazol-4-yl}methyl)butan-1-amine (2b). White amorphous solid, 80% yield. [a]2D0 ¼ ꢀ42.5 (c ¼
0.36, CHCl3). IR: 3396, 2958, 2928, 2871, 1614, 1507, 1460, 1380, 1297, 1258, 1162, 1124, 1044, 969, 923, 887,
807. 1H-NMR: 0.78 (t, J ¼ 7.6, 3 H); 0.90 (t, J ¼ 7.2, 6 H); 1.25 – 1.36 (m, 4 H); 1.47 – 1.54 (m, 4 H); 1.69 –
1.77 (m, 1 H); 1.82 – 1.86 (m, 1 H); 1.95 – 2.01 (m, 1 H); 2.03 – 2.06 (m, 1 H); 2.49 (t, J ¼ 7.2, 4 H); 2.54 (s,
3 H); 2.57 – 2.63 (m, 1 H); 2.67 – 2.71 (m, 1 H); 2.99 (s, 3 H); 3.84 (s, 2 H); 4.23 (s, 1 H); 6.40 (d, J ¼ 9.2,
1 H); 7.31 (s, 1 H); 7.32 (d, J ¼ 6.8, 1 H); 7.77 (s, 1 H). 13C-NMR: 9.9; 13.9 ꢁ 2; 20.5 ꢁ 2; 28.1; 32.3; 35.7;
38.4; 39.1; 48.7; 52.7; 53.0 ꢁ 2; 53.3; 57.6; 94.0; 105.7; 116.3 ꢁ 2; 120.7; 121.8; 128.1; 136.1; 152.8. HR-FAB-
MS: 425.3378 (C25H41Nþ6 , [M þ H]þ; calc. 425.3387).
N-({1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-1,2,3-
triazol-4-yl}methyl)-N-methylaniline (2c). Colorless film, 64% yield. [a]2D0 ¼ ꢀ20.0 (c ¼ 0.06, CHCl3). IR:
3395, 2959, 2924, 2856, 1730, 1604, 1503, 1460, 1379, 1262, 1081, 1024, 801, 699. 1H-NMR: 0.75 (t, J ¼ 7.2,
3 H); 1.68 – 1.82 (m, 1 H); 1.86 – 1.91 (m, 1 H); 1.98 – 2.04 (m, 1 H); 2.08 – 2.12 (m, 1 H); 2.56 (s, 3 H);
2.59 – 2.62 (m, 1 H); 2.76 – 2.82 (m, 1 H); 3.00 (s, 3 H); 3.05 (s, 3 H); 4.35 (s, 1 H); 4.70 (s, 2 H); 6.41 (d,
J ¼ 8.4, 1 H); 6.75 (t, J ¼ 7.2, 1 H); 6.83 (d, J ¼ 8.0, 2 H); 7.23 – 7.29 (m, 4 H); 7.58 (s, 1 H). 13C-NMR: 9.9;
32.2; 35.2; 38.7; 40.0; 48.8 ꢁ 2; 52.6; 59.5; 93.7; 112.8 ꢁ 2; 116.3; 117.1; 119.8; 120.5; 121.1; 129.3 ꢁ 2; 131.3;
143.2; 147.9; 152.8; 165.6. HR-FAB-MS: 403.2617 (C24H31Nþ6 , [M þ H]þ; calc. 403.2605).
N-Cyclohexyl-N-({1-[(3aS,8aR)-3a-ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-
5-yl]-1H-1,2,3-triazol-4-yl}methyl)cyclohexanamine (2d). Colorless film, 70% yield. [a]2D0 ¼ ꢀ33.3 (c ¼
0.18, CHCl3). IR: 3380, 3080, 2930, 2854, 1584, 1507, 1439, 1381, 1349, 1216, 1123, 1069, 1032, 994, 924,
891, 757, 703, 666, 605. 1H-NMR: 0.78 (t, J ¼ 7.2, 3 H); 1.05 – 1.10 (m, 4 H); 1.47 – 1.49 (m, 2 H); 1.57 – 1.68
(m, 4 H); 1.72 – 1.87 (m, 10 H); 1.98 – 2.06 (m, 4 H); 2.50 (s, 3 H); 2.54 – 2.63 (m, 3 H); 2.88 – 2.90 (m,
1 H); 2.99 (s, 3 H); 3.92 (s, 2 H); 4.23 (s, 1 H); 6.40 (d, J ¼ 8.0, 1 H); 7.32 (d, J ¼ 7.2, 1 H); 7.33 (s, 1 H); 7.72
(s, 1 H). 13C-NMR: 9.9; 24.7; 25.5 ꢁ 2; 25.8 ꢁ 4; 32.2 ꢁ 2; 35.8; 38.0; 39.0; 42.6 ꢁ 2; 52.7 ꢁ 2; 53.5; 53.8;
57.8; 93.9; 105.9; 116.2 ꢁ 2; 121.1; 127.9; 128.8; 135.9; 152.8. HR-FAB-MS: 477.3707 (C29H45Nþ6 , [M þ H]þ;
calc. 477.3700).
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethyl-5-[4-(pyrrolidin-1-ylmethyl)-1H-1,2,3-tria-
zol-1-yl]pyrrolo[2,3-b]indole (2e). Colorless film, 64% yield. [a]2D0 ¼ ꢀ34.2 (c ¼ 0.18, CHCl3). IR: 3397,
2959, 2918, 2850, 1613, 1583, 1508, 1460, 1439, 1380, 1348, 1259, 1216, 1122, 1070, 1031, 922, 806, 752, 704,
1
664, 605. H-NMR: 0.78 (t, J ¼ 7.2, 3 H); 1.69 – 1.75 (m, 1 H); 1.84 – 1.89 (m, 5 H); 1.96 – 1.99 (m, 1 H);
2.01 – 2.04 (m, 1 H); 2.52 (s, 3 H); 2.68 – 2.71 (m, 5 H); 3.00 (s, 3 H); 3.92 (s, 2 H); 4.23 (s, 1 H); 6.40 (d,
J ¼ 8.0, 1 H); 7.30 (s, 1 H); 7.33 (d, J ¼ 6.4, 1 H); 7.89 (s, 1 H). 13C-NMR: 9.9; 23.4 ꢁ 2; 32.3; 35.6; 38.4;
39.1; 50.3; 52.7; 53.6 ꢁ 2; 57.6; 94.0; 105.7; 116.3; 120.9; 121.7; 128.0; 130.9; 136.1; 152.9. HR-FAB-MS:
367.2613 (C21H31N6þ, [M þ H]þ; calc. 367.2605).
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethyl-5-[4-(piperidin-1-ylmethyl)-1H-1,2,3-tria-
zol-1-yl]pyrrolo[2,3-b]indole (2f). Colorless film, 68% yield. [a]2D0 ¼ ꢀ48.0 (c ¼ 0.215, CHCl3). IR: 3395,
2922, 2852, 1612, 1584, 1508, 1440, 1382, 1344, 1257, 1220, 1112, 1035, 922, 806, 754, 704, 665, 606.

1504
Helvetica Chimica Acta – Vol. 94 (2011)
1H-NMR: 0.78 (t, J ¼ 7.6, 3 H); 1.46 – 1.47 (m, 2 H); 1.60 – 1.66 (m, 4 H); 1.70 – 1.75 (m, 1 H); 1.84 – 1.90
(m, 1 H); 1.98 – 2.03 (m, 1 H); 2.04 – 2.05 (m, 1 H); 2.55 (s, 3 H); 2.55 – 2.60 (m, 4 H); 2.59 – 2.64 (m,
1 H); 2.68 – 2.72 (m, 1 H); 3.00 (s, 3 H); 3.76 (s, 2 H); 4.23 (s, 1 H); 6.41 (d, J ¼ 8.0, 1 H); 7.31 (s, 1 H); 7.33
(d, J ¼ 8.4, 1 H); 7.85 (s, 1 H). 13C-NMR: 9.8; 23.7; 25.2 ꢁ 2; 32.3; 35.6; 38.3; 39.1; 52.6; 53.6; 54.0 ꢁ 2; 57.5;
93.9; 105.6; 116.2; 120.8; 121.6; 128.0; 136.0; 143.6; 152.7. HR-FAB-MS: (C22H33Nþ6 þ, [M þ H]þ; calc.
381.2761) 381.2762.
(3aS,8aR)-3a-Ethyl-1,8-dimethyl-5-[4-(morpholin-4-ylmethyl)-1H-1,2,3-triazol-1-yl]-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (2g). Colorless film, 74% yield. [a]2D0 ¼ ꢀ63.8 (c ¼ 0.66, CHCl3). IR:
3421, 2959, 2920, 2852, 1613, 1509, 1456, 1381, 1346, 1288, 1261, 1221, 1116, 1046, 1032, 1005, 918, 864, 807,
1
753, 705. H-NMR: 0.77 (t, J ¼ 7.2, 3 H); 1.73 – 1.75 (m, 1 H); 1.82 – 1.90 (m, 1 H); 1.97 – 2.01 (m, 1 H);
2.04 – 2.09 (m, 1 H); 2.51 (s, 3 H); 2.55 – 2.63 (m, 5 H); 2.65 – 2.75 (m, 1 H); 3.00 (s, 3 H); 3.66 – 3.73 (m,
4 H); 3.73 (s, 2 H); 4.24 (s, 1 H); 6.41 (d, J ¼ 8.0, 1 H); 7.31 (s, 1 H); 7.32 (d, J ¼ 9.2, 1 H); 7.80 (s, 1 H).
13C-NMR: 9.9; 32.3; 35.7; 38.3; 39.1; 52.7; 53.4 ꢁ 2; 53.7; 57.6; 66.7 ꢁ 2; 94.0; 105.7; 116.4; 120.9; 121.1;
128.1; 136.1; 144.1; 152.8. HR-FAB-MS: 383.2561 (C21H31N6Oþ, [M þ H]þ; calc. 383.2554).
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethyl-5-{4-[(4-methylpiperazin-1-yl)methyl]-
1H-1,2,3-triazol-1-yl}pyrrolo[2,3-b]indole (2h). Colorless film, 70% yield. [a]2D0 ¼ ꢀ57.1 (c ¼ 0.07,
CHCl3). IR: 3408, 2958, 2918, 2850, 1613, 1585, 1508, 1460, 1439, 1380, 1346, 1286, 1217, 1163, 1146,
1124, 1046, 1031, 922, 809, 752, 705, 664, 605. 1H-NMR: 0.77 (t, J ¼ 7.2, 3 H); 1.70 – 1.76 (m, 1 H); 1.84 –
1.89 (m, 1 H); 1.98 – 2.02 (m, 1 H); 2.04 – 2.08 (m, 1 H); 2.38 (s, 3 H); 2.55 (s, 3 H); 2.57 – 2.64 (m, 5 H);
2.72 – 2.74 (m, 5 H); 3.00 (s, 3 H); 3.79 (s, 2 H); 4.27 (s, 1 H); 6.41 (d, J ¼ 8.4, 1 H); 7.30 (s, 1 H); 7.32 (d,
J ¼ 8.4, 1 H); 7.82 (s, 1 H). 13C-NMR: 9.9; 32.3; 35.7; 38.3; 39.1; 45.5; 52.1 ꢁ 2; 52.7; 53.0; 54.5 ꢁ 2; 57.7;
94.0; 105.8; 114.4; 116.4; 121.0; 121.3; 128.2; 143.7; 152.7. HR-FAB-MS: 396.2877 (C22H34Nþ7 , [M þ H]þ;
calc. 396.2870).
(3aS,8aR)-5-{4-[(4-Benzylpiperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}-3a-ethyl-1,2,3,3a,8,8a-hexa-
hydro-1,8-dimethylpyrrolo[2,3-b]indole (2i). Colorless film, 64% yield. [a]2D0 ¼ ꢀ50.2 (c ¼ 0.285, CHCl3).
IR: 3396, 2920, 2850, 1613, 1508, 1457, 1379, 1345, 1291, 1216, 1127, 1030, 1008, 922, 808, 748, 702.
1H-NMR: 0.77 (t, J ¼ 7.2, 3 H); 1.69 – 1.78 (m, 1 H); 1.82 – 1.90 (m, 1 H); 2.00 – 2.03 (m, 1 H); 2.04 – 2.09
(m, 1 H); 2.55 (s, 3 H); 2.57 – 2.62 (m, 5 H); 2.65 – 2.71 (m, 4 H); 2.73 – 2.78 (m, 1 H); 3.00 (s, 3 H); 3.55
(s, 2 H); 3.81 (s, 2 H); 4.29 (s, 1 H); 6.41 (d, J ¼ 7.6, 1 H); 7.27 – 7.34 (m, 7 H); 7.85 (s, 1 H). 13C-NMR: 9.9;
32.3; 35.8; 38.1; 39.0; 52.4 ꢁ 2; 52.5 ꢁ 2; 52.6; 53.0; 57.7; 62.7; 93.8; 105.8; 116.3; 120.9; 121.4; 127.2;
128.3 ꢁ 3; 129.3 ꢁ 2; 135.9; 137.3; 143.6; 152.7. HR-FAB-MS: 472.3186 (C28H38Nþ7 , [M þ H]þ; calc.
472.3183).
[4-({1-[(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethylpyrrolo[2,3-b]indol-5-yl]-1H-1,2,3-
triazol-4-yl}methyl)piperazin-1-yl](phenyl)methanone (2j). Colorless film, 61% yield. [a]2D0 ¼ ꢀ53.8 (c ¼
0.24, CHCl3). IR: 3434, 2960, 2918, 2850, 1620, 1577, 1508, 1436, 1380, 1345, 1279, 1260, 1227, 1161, 1125,
1045, 1023, 999, 923, 886, 807, 752, 710, 664. 1H-NMR: 0.77 (t, J ¼ 7.2, 3 H); 1.73 – 1.77 (m, 1 H); 1.85 – 1.88
(m, 1 H); 2.01 – 2.03 (m, 1 H); 2.05 – 2.09 (m, 1 H); 2.50 – 2.53 (m, 2 H); 2.56 (s, 3 H); 2.60 – 2.64 (m,
3 H); 2.76 – 2.77 (m, 1 H); 3.01 (s, 3 H); 3.45 (br. s, 2 H); 3.73 (s, 2 H); 3.78 (br. s, 2 H); 4.32 (s, 1 H); 6.43
(d, J ¼ 8.0, 1 H); 7.32 (s, 1 H); 7.34 (d, J ¼8.4, 1 H); 7.40 (s, 5 H); 7.79 (s, 1 H). 13C-NMR: 9.9; 29.3; 32.3;
35.7; 38.1; 38.9; 52.7 ꢁ 2; 53.1 ꢁ 3; 57.7; 93.9; 105.9; 116.4; 120.9; 121.1; 127.0 ꢁ 2; 128.5 ꢁ 2; 129.7; 135.7;
143.9 ꢁ 2; 150.3; 152.5; 170.3. HR-FAB-MS: 486.2976 (C28H36N7Oþ, [M þ H]þ; calc. 486.2976).
(3aS,8aR)-3a-Ethyl-1,2,3,3a,8,8a-hexahydro-1,8-dimethyl-5-(4-{[4-(2-phenylethyl)piperazin-1-yl]-
methyl}-1H-1,2,3-triazol-1-yl)pyrrolo[2,3-b]indole (2k). Colorless film, 62% yield. [a]2D0 ¼ ꢀ40.0 (c ¼
1
0.18, CHCl3). IR: 2919, 2850, 1583, 1508, 1459, 1439, 1377, 1260, 1217, 1030, 804, 752, 703. H-NMR:
0.78 (t, J ¼ 7.2, 3 H); 1.73 – 1.77 (m, 1 H); 1.84 – 1.90 (m, 1 H); 1.99 – 2.06 (m, 2 H); 2.51 (s, 3 H); 2.55 –
2.74 (m, 10 H); 2.79 – 2.83 (m, 2 H); 3.00 (s, 3 H); 3.79 (s, 2 H); 4.25 (s, 1 H); 6.41 (d, J ¼ 8.4, 1 H);
7.20 (d, J ¼ 6.0, 2 H); 7.21 (s, 1 H); 7.28 – 7.34 (m, 3 H); 7.42 (br. s, 1 H); 7.82 (s, 1 H). 13C-NMR: 9.9; 32.4;
33.6; 35.7; 38.4; 39.2; 52.7; 52.8 ꢁ 2; 53.0 ꢁ 2; 53.3; 57.6; 60.5; 94.0; 105.7; 116.4; 120.9; 121.1; 126.1; 128.1;
128.4 ꢁ 2; 128.7 ꢁ 2; 136.2; 140.2; 144.2; 152.8. HR-FAB-MS: 486.3343 (C29H40Nþ7 , [M þ H]þ; calc.
486.3340).

Helvetica Chimica Acta – Vol. 94 (2011)
1505
REFERENCES
[1] J. Jobst, O. Hesse, Justus Liebigs Ann. Chem. 1864, 129, 115.
[2] P. Williams, A. Sorribas, M.-J. R. Howes, Nat. Prod. Rep. 2011, 28, 48; N. H. Greig, X.-F. Pei, T. T.
Soncrant, D. K. Ingram, A. Brossi, Med. Res. Rev. 1995, 15, 3; M. Sano, K. Bell, K. Harder, L. Stricks,
Y. Stern, R. Mayeux, Clin. Neuropharmacol. 1993, 16, 61.
[3] A. A. Al-Jafari, M. A. Kamal, N. H. Greig, A. S. Alhomida, E. R. Perry, Biochem. Biophys. Res.
Commun. 1998, 248, 180, and refs. cit. therein.
[4] Q.-S.Yu, H. W. Holloway, J. L. Flippen-Anderson, B. Hoffman, A. Brossi, N. H. Greig, J. Med.
Chem. 2001, 44, 4062.
[5] K. T. Y. Shaw, T. Utsuki, J. Rogers, Q.-S. Yu, K. Sambamurti, A. Brossi, Y.-W. Ge, D. K. Lahiri, N. H.
Greig, Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7605.
[6] R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E. De Clercq, C. F. Perno, A. Karlsson, J.
Balzarini, M. J. Camarasa, J. Med. Chem. 1994, 37, 4185.
[7] D. R. Buckle, C. J. M. Rockell, H. Smith, B. A. Spicer, J. Med. Chem. 1986, 29, 2262.
[8] C. B. Vicentini, V. Brandolini, M. Guarneri, P. Giori, Farmaco 1992, 47, 1021; J. C. Fung-Tomc, E.
Huczko, B. Minassian, D. P. Bonner, Antimicrob. Agents Chemother. 1998, 42, 313.
[9] M. J. Genin, D. A. Allwine, D. J. Anderson, M. R. Barbachyn, D. E. Emmert, S. A. Garmon, D. R.
Graber, K. C. Grega, J. B. Hester, D. K. Hutchinson, J. Morris, R. J. Reischer, C. W. Ford, G. E.
Zurenko, J. C. Hamel, R. D. Schaadt, D. Stapert, B. H. Yagi, J. Med. Chem. 2000, 43, 953.
´
[10] a) Y. Bourne, H. C. Kolb, Z. Radic, K. B. Sharpless, P. Taylor, P. Marchot, Proc. Natl. Acad. Sci.
´
U.S.A. 2004, 101, 1449; b) W. G. Lewis, L. G. Green, F. Grynszpan, Z. Radic, P. R. Carlier, P. Taylor,
M. G. Finn, K. B. Sharpless, Angew. Chem., Int. Ed. 2002, 41, 1053; c) S. Kamijo, T. Jin, Z. Huo, Y.
Yamamoto, J. Org. Chem. 2004, 69, 2386; d) S. Kamijo, T. N. Jin, Z. Huo, Y. Yamamoto, Tetrahedron
Lett. 2002, 43, 9707; e) P. Appukkuttan, W. Dehaen, V. V. Fokin, E. Van der Eycken, Org. Lett. 2004,
6, 4223; f) A. K. Feldman, B. Colasson, V. V. Fokin, Org. Lett. 2004, 6, 3897; g) Z.-Y. Yan, Y.-B.
Zhao, M.-J. Fan, W.-M Liu, Y.-M. Liang, Tetrahedron 2005, 61, 9331.
[11] J. S. Carle, C. Christophersen, J. Am. Chem. Soc. 1979, 101, 4012; J. S. Carle, C. Christophersen, J.
Org. Chem. 1981, 46, 3440; T. F. Spande, M. W. Edwards, L. K. Pannell, J. W. Daly, V. Erspamer, P.
Melchiorri, J. Org. Chem. 1988, 53, 1222; J. W. Daly, H. M. Garraffo, L. K. Pannell, T. F. Spande, C.
Severini, V. Erspamer, J. Nat. Prod. 1990, 53, 407.
[12] L. A. Sorbera, J. Castaner, Drugs Future 2003, 28, 18, and references cited therein; S. S. Chaudhaery,
K. K. Roy, N. Shakya, G. Saxena, S. R. Sammi, A. Nazir, C. Nath, A. K. Saxena, J. Med. Chem. 2010,
53, 6490.
[13] S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; A. G. Doyle, E. N.
Jacobsen, Chem. Rev. 2007, 107, 5713; M. J. Gaunt, C. C. C. Johansson, Chem. Rev. 2007, 107, 5596.
[14] J. F. Austin, S.-G. Kim, C. J. Sinz, W.-J. Xiao, D. W. C. MacMillan, Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5482.
[15] M. E. Krafft, W. J. Crooks III, B. Zorc, S. E. Milczanowski, J. Org. Chem. 1988, 53, 3158.
[16] J. Andersen, U. Madsen, F. Bjçrkling, X. Liang, Synlett 2005, 14, 2209.
Received January 13, 2011