Stereoselective Construction of Pyrazinoindoles and Oxazinoindoles via Ring-Opening/Pictet-Spengler Reaction of Aziridines and Epoxides with 3-Methylindoles and Carbonyls

Article abstract of DOI:10.1021/acs.joc.8b02339

A highly efficient and stereoselective route to access 1,3-disubstituted 1,2,3,4-tetrahydropyrazino[1,2-a]indoles and 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indoles with excellent stereoselectivity (de, ee >99%) via base mediated ring opening of aziridines/epoxides with 3-methylindoles followed by BF₃·OEt₂ catalyzed Pictet-Spengler reaction is accomplished. Interestingly, PTSA promoted cyclization led to the formation of oxidized 3,4-dihydropyrazino[1,2-a]indoles in excellent yields via an unprecedented Pictet-Spengler-detosylation cascade.

Full text of DOI:10.1021/acs.joc.8b02339

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Article
Stereoselective Construction of Pyrazinoindoles and
Oxazinoindoles via Ring-Opening/Pictet-Spengler Reaction of
Aziridines and Epoxides with 3-Methylindoles and Carbonyls
Imtiyaz Ahmad Wani, Subhomoy Das, Shobhan Mondal, and Manas K. Ghorai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02339 • Publication Date (Web): 08 Nov 2018
Downloaded from http://pubs.acs.org on November 8, 2018
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Stereoselective Construction of Pyrazinoindoles and Oxazinoindoles
via Ring-Opening/Pictet-Spengler Reaction of Aziridines and
Epoxides with 3-Methylindoles and Carbonyls
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Imtiyaz Ahmad Wani,a,b Subhomoy Das,a Shobhan Mondala and Manas K. Ghorai*a
aDepartment of Chemistry, Indian Institute of Technology, Kanpur, 208016, UP, India
bCurrent Address: Department of Chemistry, Amar Singh College, Srinagar, 190008, J&K, India
mkghorai@iitk.ac.in
Ts
R3
R3
i)
i)
X
N
*
*
R1
R2
R3
R1
R4
R4
NaH, THF, rt
NaH, THF, rt
ii) R4CHO
BF3•OEt2 (20 mol %)
MgSO4 (1.0 equiv)
*
N
N
ii) R4CHO
PTSA (1.0 equiv)
MgSO4 (1.0 equiv)
DCE, 80 °C
N
N
X
X = NTs, O
*
H
R2
*
R1
yield up to 70%
R1
THF, 55 °C
yield up to 86%
de, ee up to >99%
R1, R2 = H, Ph, 4-ClC6H4, 4-BrC6H4, 2-FC6H4, 3-MeC6H4, Bn, Me, n-octyl, -(CH2)3-, -(CH2)4-, -(CH2)5-;
R3 = H, Me, Br; R4 = Ph, 4-NO2C6H4, 4-FC6H4, 4-MeC6H4, cinnamyl, 4-BrC6H4, 4-CNC6H4, 4-ClC6H4,
2-naphthyl, 2-furyl, Et, cyclopentanone
metal-free conditions
one-pot cascade
inexpensive catalysts
wide substrate scope
A
highly efficient and stereoselective route to access 1,3-disubstituted 1,2,3,4-
tetrahydropyrazino[1,2-a]indoles and 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indoles with excellent
stereoselectivity (de, ee >99%) via base mediated ring opening of aziridines/epoxides with 3-
methylindoles followed by BF3·OEt2 catalyzed Pictet-Spengler reaction is accomplished.
Interestingly, PTSA promoted cyclization led to the formation of oxidized 3,4-
dihydropyrazino[1,2-a]indoles in excellent yields via an unprecedented Pictet-Spengler-
detosylation cascade.
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INTRODUCTION
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Among widely distributed fused indole derivatives in natural products and alkaloids,
tetrahydropyrazino[1,2-a]indoles and dihydro-1H-[1,4]oxazino[4,3-a]indoles are found to be of
immense biological significance and pharmacological importance.1,2 Especially,
tetrahydropyrazino[1,2-a]indoles are known to possess 5-HT2C, 5-HT2A and 5-HT4 receptor
agonistic,3 and protein kinase C inhibitors activities;4 whereas, dihydro-1H-[1,4]oxazino[4,3-
a]indoles exhibit potent anti-tumor activities.5 Some of the biologically active alkaloids containing
these two core structures are shown in Figure 1.
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Figure 1. Biologically Active Alkaloids Containing Pyrazino- and Oxazinoindoles
Cl
O
N
N
N
N
N
NH
NH
O
NH
O
N
NH
O
III
, activity against Staphylococcus
II
I
, activity against E.Coli
, CNS agent
Me
OMe
Cl
Me
OH
O
MeO
N
N
NH
N
O
MeO
anti-tumor agents
VI
IV
V
, anti-candida agent
Despite their high medicinal values, only a few reports are available for the
stereoselective synthesis of these indole-based heterocyclic scaffolds.6,7 The interesting
reports available in the literature for the formation of pyrazinoindoles include
intramolecular aza-Michael reaction of α,β-unsaturated esters,6b,c Pd-catalyzed AAA
reaction of indoles with vinyl aziridines,6d and Lewis acid promoted asymmetric iso-Pictet-
Spengler reaction of aminoindoles with α-keto amides.6e Similarly, formation of
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oxazinoindoles via base mediated addition-cyclization reaction of (1H-indole-2-
yl)methanols with vinyl sulfonium salts,7a TMSOTf-mediated intramolecular oxa-Pictet-
Spengler reaction of indoles with N-tethered vinylogous carbonate functionality,7b and
gold-catalyzed asymmetric cascade reactions of functionalized indoles7c are known in the
literature. However, most of these efforts rely on the use of costly metal catalysts and chiral
ligands, super-stoichiometric amount of base and LAs etc. Moreover, some of these
approaches suffer from reduced stereoselectivity and substrate scope. Due to said
limitations, the development of a metal-free, cost-effective and catalytic synthetic route to
such scaffolds with high stereoselectivity is highly desirable. In this context, Pictet-
Spengler (PS) reaction8 is one of the key routes to achieve indole-fused heterocycles.9
Notably, aziridines10 and epoxides11 serve as important building blocks to realise complex
heterocyclic scaffolds. Synthesis of pyrazino[1,2-a]indoles and oxazino[4,3-a]indoles via
ring-opening/transformations of aziridines and epoxides, respectively, is unknown except
one report by Chen et al. for the latter.12 Our ongoing research activities on Lewis acid
catalyzed SN2-type ring-opening transformations of activated aziridines and epoxides13
with indole based nucleophiles14 prompted us to explore (iso/oxa)-Pictet-Spengler reaction
as a tool to achieve synthesis of diastereo- and enantiopure pyrazino[1,2-a]indoles and
oxazino[4,3-a]indoles in a one-pot cascade manner by engaging three components, viz. 3-
methylindoles, aziridine/epoxide and carbonyls. Herein, we wish to report our results in
detail for the synthesis of titular compounds based on the aforementioned proposal as an
article.
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RESULTS AND DISCUSSION
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Our study commenced with the reaction of 2-phenyl-N-tosylaziridine (2a) and 3-
methylindole (1a) in the presence of NaH as the base in DMF at rt to obtain the ring-opening
product (3a) in 88% yield as a single regioisomer (Scheme 1).14d,15 It is noteworthy that the
nucleophile being strong and bulky attacks the aziridine at the unsubstituted side to afford 3a as
the only product. 3a was then subject to BF3·OEt2 (10 mol %) catalyzed PS reaction with 4-
nitrobenzaldehyde (4a) in presence of 1.0 equiv of MgSO4 in toluene at 50 °C, and the
corresponding tetrahydropyrazino[1,2-a]indole derivative (5a) was formed in 80% yield as a
single diastereomer (Scheme 1). Both 3a and 5a were characterized by spectroscopic data and the
structure of 5 was further confirmed by single crystal X-ray analysis.16
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Scheme 1. Ring-Opening/Pictet-Spengler Reaction of 2-Phenyl-N-tosylaziridine (2a) with 3-
Methylindole (1a) and 4-Nitrobenzaldehyde (4a)
OHC
NO2
4a
BF3•OEt2 (10 mol %)
MgSO4 (1.0 equiv)
NO2
Ts
N
NaH (1.5 equiv)
DMF, rt, 3 h
+
N
N
N
Toluene, 2 h, 50 °C
Ph
NTs
H
NHTs
Ph
3a
(88%)
1a
2a
(1.5 equiv) (1.0 equiv)
5a
(80%)
Ph
Next, to increase the efficiency of our protocol for the synthesis of 5a, we switched the
two-step synthetic strategy to one-pot stepwise fashion comprising of base-mediated ring opening
of 2a with 1a followed by PS reaction of the ring-opening product with 4a by using 10 mol %
BF3·OEt2 catalyst in toluene at 50 °C and the corresponding cyclic product 5a was obtained in
48% overall yield as a single diastereomer (entry 2, Table 1). To improve the yield, various
reaction parameters including Lewis acid, base, solvent, and temperature were screened. Altering
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the Lewis acid to PTSA even lowered the yield of one-pot process drastically (entry 3). Slightly
5
6
better yield
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8
9
Table 1. Optimization Studies for the One-Pot Stepwise Synthesis of 1,2,3,4-
Tetrahydropyrazino[1,2-a]indole (5a)a
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NO2
4a
Ts
N
reaction conditions
N
+
NTs
N
Ph
2a
1a
5a
H
Ph
entry
reaction conditions
5ab
1
i) NaH (1.2 equiv), toluene, rt, 2 h
25
ii) 4a, BF3·OEt2 (20 mol %), MgSO4, toluene, rt, 10 h
i) NaH (1.2 equiv), toluene, rt, 2 h
2
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10
ii) 4a, BF3·OEt2 (10 mol %), MgSO4, toluene, 50 °C, 4 h
i) NaH (1.2 equiv), toluene, rt, 2 h
ii) 4a, PTSA (10 mol %), MgSO4, toluene, 50 °C, 6 h
i) NaH (1.2 equiv), diethyl ether, rt, 3 h
3c
4
58
ii) 4a, BF3·OEt2 (10 mol %), MgSO4, diethyl ether, rt, 7 h
i) NaH (1.2 equiv), THF, rt, 2 h
5
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ii) 4a, BF3·OEt2 (20 mol %), MgSO4, THF, 55 °C, 2 h
i) tBuOK (1.2 equiv), toluene, rt, 4 h
6
53
ii) 4a, BF3·OEt2 (20 mol %), MgSO4, toluene, 55 °C, 4 h
i) tBuOK (1.2 equiv), THF, rt, 3.5 h
7
42
ii) 4a, BF3·OEt2 (20 mol %), MgSO4, THF, 55 °C, 4.5 h
i) K2CO3 (1.2 equiv), THF, rt, 3 h
8
34
ii) 4a, BF3·OEt2 (20 mol %), MgSO4, THF, 55 °C, 5 h
i) tBuOK (1.2 equiv), DMF, rt, 3 h
9
NRd
NR
ii) 4a, BF3·OEt2 (20 mol %), MgSO4, DMF, 100 °C, 9 h
i) NaH (1.2 equiv), DMF, rt, 2 h
10
ii) 4a, BF3·OEt2 (20 mol %), MgSO4, DMF, 100 °C, 10 h
aUnless otherwise noted, 0.12 mmol of 1a, 0.10 mmol of 2a, 0.12 mmol of base, 0.11 mmol of
b
4a, 0.02 mmol of BF3·OEt2 and 0.10 mmol of MgSO4 were reacted. Yield of the isolated
c
product. Along with 5a, the oxidized product 3,4-dihydropyrazino[1,2-a]indole was obtained
in 30% yield. dNR = No reaction.
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was observed when NaH in diethyl ether was employed along with BF3·OEt2 as catalyst (entry 4).
The best result was obtained by using 20 mol % BF3·OEt2 in THF at 55 °C affording 5a in 72%
overall yield (Entry 5). When tBuOK and K2CO3 were used as bases in the ring-opening reaction,
they resulted in poorer yields of the desired product (entries 6–8). Further, use of DMF, as a polar
aprotic solvent, proved futile for desired product formation and the starting material was recovered
back (entries 9 and 10). All results are summarized in Table 1.
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To generalize our approach, a wide range of racemic 2-(aryl/alkyl)-N-tosylaziridines 2a–l
were reacted with 3-methylindole 1a and 4-nitrobenzaldehyde 4a under optimized reaction
conditions (Table 2). Both electron withdrawing groups, like halides (Cl, Br, F), and donating
group like -CH3, in the benzene ring of 2-aryl-N-tosylaziridines were well tolerated under the
reaction conditions to yield 5b–e in good to excellent yields as single diastereomers (entries 2–5).
Among activated alkyl aziridines, 2-benzyl-N-tosylaziridine and 2-methyl-N-tosylaziridine
underwent smooth transformations to produce 5f and 5g in good yields (entries 6,7). Interestingly,
Table 2. One-Pot Cascade Synthesis of Tetrahydropyrazino[1,2-a]indoles (5a–l)a
NO2
i) NaH, THF, rt, 2 h
Ts
N
N
+
4a
ii) 4-NO2C6H4CHO (
BF3•OEt2, MgSO4
THF, 55 °C, 2-3 h
)
R1
R2
N
NTs
5a-l
R1
2a-l
1a
H
R2
de >99%
entry 1a
aziridine (2)
4a
4a
pyrazinoindole (5)
yield (%)b
drc
NO2
Ts
N
N
1
1a
72
>99:1
NTs
Ph
2a
5a
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NO2
Ts
N
5
6
7
N
2
1a
4a
74
>99:1
NTs
8
9
2b
Cl
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5b
Cl
NO2
N
Ts
N
NTs
3
1a
4a
78
>99:1
2c
Br
5c
Br
NO2
N
Ts
F
N
NTs
4
5
1a
1a
4a
4a
58
60
>99:1
>99:1
F
2d
5d
NO2
Ts
N
N
Me
NTs
2e
5e
Me
NO2
N
Ts
N
6
1a
4a
68
>99:1
NTs
2f
5f
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NO2
Ts
N
5
6
N
7
8
1a
1a
4a
4a
67
75
>99:1
>99:1
NTs
5g
7
8
9
Me
2g
Me
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NO2
Ts
N
N
NTs
2h
5h
NO2
Ts
N
N
9
1a
4a
65
>99:1
NTs
Me
Me
2i
5i
Ts
NO2
N
N
N
10
11
1a
1a
4a
4a
72
75
>99:1
>99:1
NTs
2j
5j
Ts
N
NO2
NTs
2k
5k
Ts
N
NO2
N
12
1a
4a
86
>99:1
NTs
2l
5l
aUnless otherwise noted, 0.12 mmol of 1, 0.10 mmol of 2, 0.12 mmol of base, 0.11 mmol of 4a,
b
0.02 mmol of BF3·OEt2, and 0.10 mmol of MgSO4 were reacted. Yields of isolated products.
cDiastereomeric ratios have been determined by 1H NMR analysis of the crude reaction mixture.
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2-n-octyl-N-tosylaziridine (2h), with a long-tethered alkyl chain, and trans-disubstituted activated
aziridine (2i), when reacted under the same reaction conditions, the desired
tetrahydropyrazino[1,2-a]indoles, 5h and 5i, were obtained as single diastereomers, respectively
(entries 8,9). When five to seven membered cycloalkyl-fused activated aziridines were reacted
with 1a and 4a, the corresponding tetracyclic core of pyrazino[1,2-a]indoles 5j–l were obtained as
single diastereomers in excellent yields (entries 10–12). All the results are described in Table 2.
The synthetic significance of the methodology was further demonstrated by the formation
of optically pure tetrahydropyrazino[1,2-a]indoles, (1R,3S)-5a,m–q (de, ee >99%), from
enantiopure 2-phenyl-N-tosylaziridine (S)-2a (ee >99%), 3-methylindole 1a and different
aldehydes 4a–d under optimized one-pot reaction conditions in good yields (Table 3). The
formation of the products with enantiospecificity (ee >99%) could be rationalized by the fact that
the stereocenter of enantiopure aziridine remains unperturbed during base-mediated ring-opening
Table 3. One-Pot Stereospecific Synthesis of Tetrahydropyrazino[1,2-a]indoles (5)a
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R1
i) NaH (1.2 equiv)
THF, r.t.
R1
Ts
N
+
4
ii) ArCHO ( , 1.1 equiv)
BF3•OEt2 (20 mol %)
MgSO4 (1.0 equiv)
THF, 55 °C
Ar
NTs
Ph
Ph
2a
N
N
)-
(S
H
1a-c
(1.2 equiv)
ee >99%
(1.0 equiv)
5
(1R,3S)-
de, ee >99%
entry 3-methylindole aziridine aldehyde
pyrazinoindole (5)
yielda deb/ee
(1)
(S)-2a
(4)
(%)
(%)
CHO
NO2
Ts
N
1c
72
>99/99
N
Ph
2a
N
1a
H
(S)-
NTs
5a
NO2
4a
Ph
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CHO
2d
63
76
>99/99
>99/99
1a
1a
(S)-2a
(S)-2a
N
NTs
4b
5m
Ph
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F
CHO
3d
N
NTs
F
4c
5n
Ph
CHO
Me
4d
1a
(S)-2a
(S)-2a
56
72
>99/99
>99/99
N
NTs
Me
4d
5o
Ph
Br
Br
5d
4a
4a
NO2
N
H
1b
N
NTs
5p
Ph
Me
Me
6d
(S)-2a
74
>99/99
NO2
N
1c
H
N
NTs
5q
Ph
aYields of isolated products. The products were obtained as single diastereomers. As a
b
c
d
representative example, the ee was determined by chiral HPLC analysis. Since, ring-opening
doesn’t disturb the chiral center, the formation of single diastereomeric product confirms that de
equals ee.14d
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5
6
7
8
9
with 1a.14d Successful implementation of both electron-deficient and electron-rich aldehydes to
obtain desired products in enantiopure forms indicates little or no significant electronic influence
on PS reaction outcomes (entries 1-4). Further, 5-bromo-3-methyl-1H-indole (1b) and 3,5-
dimethylindole (1c) were investigated as nucleophiles with (S)-2a (ee >99%) and 4-
nitrobenzaldehyde 4a to obtain (1R,3S)-5p,q in high yields with excellent stereospecificities (de,
ee >99%, entries 5,6).17 The absolute configuration of 5 has been determined as (1R,3S) based on
the crystal structure of 5n.16
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The synthetic utility of this strategy was further realized by the formation of another
class of biologically important compounds, 3,4-dihydropyrazino[1,2-a]indoles 6,18 via a
one-pot unprecedented detosylation of tetrahydropyrazino[1,2-a]indoles. We observed that
while optimizing reaction conditions for one-pot synthesis of 5a, PTSA-promoted PS
reaction in toluene at 50 °C (entry 3, Table 1) produced 5a only in 10% yield, along with
the detosylated oxidized product dihydropyrazino[1,2-a]indole derivative 6 in 30% yield.
Table 4. PTSA-Promoted One-Pot Synthesis of 3,4-dihydropyrazino[1,2-a]indoles
(6a–e)a
i) NaH (1.2 equiv)
THF, rt
Ts
N
Ar
+
N
4
ii) ArCHO ( , 1.1 equiv)
R1
2a g
(1.0 equiv)
N
PTSA (1.0 equiv)
MgSO4 (1.0 equiv)
DCE, 80 °C, 12 h
N
H
1a
,
6a-e
R1
(1.2 equiv)
entry
1
1a
aziridine
aldehyde (4)
3,4-dihydropyrazinoindole
yielda
(%)
(2)
(6)
CHO
Ts
N
NO2
57
1a
Me
N
2g
N
NO2
6a
4a
Me
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Ts
N
F
CHO
6
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9
1a
1a
1a
1a
2
3
4
5
62
67
70
60
Ph
2a
N
N
F
4c
6b
Ph
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Br
CHO
2a
N
N
Br
4e
6c
Ph
CN
CHO
2a
2a
N
N
CN
4f
6d
Ph
CHO
N
N
4g
6e
Ph
aYields of isolated products.
To increase the yield of dihydropyrazino[1,2-a]indole moiety, a set of reaction conditions
were screened. The best result was obtained when ring-opening product was treated with
1.1 equiv. of aldehyde in presence of 1.0 equiv PTSA in DCE at 80 °C for overnight (Table
4). Under the optimal reaction conditions, when alkyl and aryl N-tosylaziridines (2a,g,
respectively) were treated with 3-methylindole 1a, the ring-opening products were formed
which further underwent ring-closing transformations with various aldehydes to produce
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the corresponding oxidized dihydropyrazino[1,2-a]indole derivatives 6a–e in good yields
5
6
(Table 4, Entries 1–5).
7
8
9
Inspired by our success for the synthesis of pyrazino[1,2-a]indoles, we next explored the
synthesis of dihydro-1H-[1,4]oxazino[4,3-a]indoles employing 2-phenyl-oxirane (7a) under
identical reaction conditions (Table 5). When, 2-phenyloxirane 7a was treated with 3-methylindole
1a under basic reaction conditions followed by BF3·OEt2 catalyzed PS reaction with 4a, to our
great pleasure, the desired product dihydro-1H-[1,4]oxazino[4,3-a]indole (8a) was obtained in
excellent yield, although, as a mixture of diastereomers (dr 3:1, entry 1). The structure of 8a was
confirmed by single crystal X-ray analysis.16 Generalization of this method was made by studying
Table 5. One-Pot Stepwise Synthesis of Dihydro-1H-[1,4]oxazino[4,3-a]indoles (8a–d)a,b
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i) NaH (1.2 equiv)
THF, rt
O
R
+
N
4
ii) RCHO ( , 1.1 equiv)
BF3•OEt2 (20 mol %)
MgSO4 (1.0 equiv)
THF, 55 °C
N
Ph
O
7a
(1.0 equiv)
H
1a
8a-d
(1.2 equiv)
Ph
major diastereomer
entry
1a
1a
7a
aldehyde (4)
oxazinoindole (8)
yielda
(%)
drb
3:1
CHO
NO2
1
7a
7a
74
N
O
NO2
4a
8a
Ph
F
CHO
2
1a
73
1.5:1
N
O
F
4c
8b
Ph
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O
O
CHO
3
4
1a
1a
7a
7a
68
65
5:1
5:1
N
4h
O
9
8c
Ph
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CHO
N
4i
O
8d
Ph
aYields of isolated products. bDiastereomeric ratios have been determined by 1H NMR analysis
of the crude reaction mixture.
a series of aromatic, heteroaromatic, and alkyl aldehydes (4) under optimized reaction
conditions to produce the corresponding oxazinoindoles derivatives 8b–d in good yields
with diastereomeric ratio up to 5:1 (Entries 2–4). All the results are described in Table 5.
Moreover, we were delighted to observe that cyclic ketone, such as cyclopentanone
(9), underwent smooth transformation after being introduced as an electrophile in the
second step under optimal Pictet-Spengler reaction condition, to form spiro-dihydro-1H-
[1,4]oxazino[4,3-a]indole (8e) in 72% yield (Scheme 2). Notably, such spiro compounds
with heterocyclic scaffolds are important in drug design and delivery due to their inherent
three-dimensional structures.19
Scheme 2. One-Pot Synthesis of Spiro-dihydro-1H-[1,4]oxazino[4,3-a]indole 8e
i) NaH (1.2 equiv)
THF, rt
O
+
ii)
N
O
N
Ph
O
H
1a
7a
(1.0 equiv)
9
( , 1.1 equiv)
8e
(72%)
(1.2 equiv)
Ph
BF3•OEt2 (20 mol %)
MgSO4 (1.0 equiv)
THF, 55 °C, 4 h
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9
To demonstrate the synthetic utility of our approach, we attempted a short synthesis
of pyrazinoindole derivative IV (Figure 1), used as anti-candida agent.2a One-pot synthesis
of 5r was carried out via ring-opening/Pictet-Spengler reaction of unsubstituted activated
aziridine 2m with 3-methylindole (1a) and 4-chlorobenzaldehyde (4j) under the optimized
reaction conditions. However, 5r, upon detosylation,14e,20 produced only the more stable
oxidized product, dihydropyrazino[1,2-a]indole (6f), probably due to its extended
conjugation (Scheme 3).
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Scheme 3. Oxidative Detosylation of Tetrahydropyrazinoindole (5r): Synthesis of
Dihydropyrazino[1,2-a]indole (6f)
Cl
Cl
Ts
N
i) NaH, THF, r.t.
Na (10.0 equiv)
+
4j
ii) 4Cl-C6H4CHO (
)
N
H
C10H8 (10.0 equiv)
THF, 78 °C, 2 h
N
N
2m
BF3•OEt2 (10 mol %)
MgSO4 (1.0 equiv)
THF, 3 h, 55 °C
1a
NTs
N
5r
(84%)
6f
(67%)
MECHANISM
A plausible mechanism is shown in Scheme 4. Based on our experimental observations, we
believe that the ring opening of activated aziridines and epoxides follows an SN2-type
pathway.14d Under basic reaction conditions, 1 attacks 2 and 7 from less substituted side
through its N-1 site in an SN2 fashion to produce 3. BF3·OEt2 activates 4 to initiate
nucleophilic attack by the ring opening product to generate the corresponding iminium and
oxonium ion boat like TS A. A subsequent favorable re- face intramolecular nucleophilic
attack through C-2 center of the indole ring on C=X bond in 6-endo-trig fashion then leads
to the more stable species B, where bulky 1,3-substituents are present at pseudo-equatorial
orientations to avoid possible destabilizing 1,3-diaxial interactions, producing the exclusive
or major 1,3-cis diastereomers in (5,8). The exclusive formation of 5 in case of aziridines
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Scheme 4. Plausible Mechanism for the Formation of Pyrazino[1,2-a]indoles and
Oxazino[4,3-a]indoles
7
8
9
H
H
R1
R1
N
N
Na
N
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R
O
SN2-type
X
X
4
X
R1 ring opening
BF3•OEt2
R
O
Me
1
Na
2 7
,
Me
Me
3
Na
BF3
10
X = NTs, O
R1 = aryl, alkyl
H
R1
R = aryl, heteroaryl, alkyl
NaOBF3
N
X
R
Me
A
H
R
H
H
H
R1
N
R1
X
N
N
re-face attack
6-endo-trig
R1
si-face attack
X
X
6-endo-trig
H
H
R
H
R
Me
disfavoured
Me
Me
1,3-diaxial interaction
between two C-H bonds,
less destabilising
1,3-diaxial interaction
between R and H,
more destabilising
C
B
favoured
A
X
H
R
H
H
R
N
R1
N
R1
N
N
R1
X
X
R1
X
X
X
R
R
5 8
H
H
H
5' 8'
,
,
Me
(not formed, X = NTs)
(minor diastereomer, X = O)
Me
Me
Me
(single diastereomer, X = NTs)
(major diastereomer, X = O)
is due to the presence of bulky tosyl group in between two aryl groups which pushes them to 1,3-
pseudo-diequatorial orientation to alleviate steric strain. The absence of such type of steric
hinderance in case of epoxides explains the formation of minor 1,3-trans diastereomer 8' through
species C.
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CONCLUSION
We have successfully developed a simple and efficient route for the synthesis of three
important heterocycles, viz. tetrahydropyrazino[1,2-a]indoles, dihydro-1H-
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[1,4]oxazino[4,3-a]indoles and dihydropyrazino[1,2-a]indoles in high yields with excellent
diastereo- and enantiomeric excess via Lewis acid catalyzed three component one-pot
cascade reaction of activated aziridines and epoxides with 3-methyl indoles and carbonyl
compounds under metal-free condition. We do believe that the developed strategy would
find tremendous utility in synthetic organic chemistry towards the synthesis of polycyclic
indole-fused heterocycles.
EXPERIMENTAL SECTION
Analytical thin layer chromatography (TLC) was carried out using silica gel 60 F254 pre-coated
plates. Visualization was accomplished with UV lamp or I2 stain. Silica gel 230-400 mesh size
were used for column chromatography using the combination of ethyl acetate and petroleum ether
as an eluent. Unless otherwise noted, all reactions were carried out in oven-dried glassware under
an atmosphere of nitrogen using anhydrous solvents. Where appropriate, solvents and all reagents
were purified prior to use following the guidelines of Perrin, Armarego21 and Vogel.22 2-aryl-N-
tosylaziridines were prepared from different styrene derivatives following a reported procedure.23
Chiral 2-phenyl-N-tosylaziridine was prepared from corresponding amino alcohol following a
reported procedure.24 All commercial reagents were used as received without prior purification
unless mentioned. IR spectra were recorded in potassium bromide (KBr) pellet for solid
compounds. Proton nuclear magnetic resonance (1H NMR) were recorded at 500 MHz and 400
MHz. The chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethyl silane
(δ 0.00) as internal standard. 1H NMR splitting patterns are designated as singlet (s), doublet (d),
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doublet of doublet (dd), triplet (t), triplet of doublets (td), quartet (q), multiplet (m) etc. Carbon
nuclear magnetic resonance (13C{1H} NMR) spectra were recorded at 100 MHz and 125 MHz.
HRMS were obtained using (ESI) mass spectrometer (TOF). The melting point measurements
were made using a hot stage apparatus and are reported as uncorrected. The enantiomeric excess
(ee) were determined by HPLC using Chiralcel OD-H column (detection at 254 nm). Optical
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25
rotations were measured using a 6.0 mL cell with a 1.0 dm path length and are reported as [α]D
(c in gm per 100 mL solvent) at 25 ºC.
General experimental procedure for the synthesis of 1,2,3,4-tetrahydropyrazino[1,2-
a]indoles/3,4-dihydro-1H-[1,4]oxazino[4,3-a]indoles (2A): A clean and dried double neck round
bottom flask under argon was charged with NaH (0.120 mmol, 1.2 equiv) and 3-methylindole
(0.120 mmol, 1.2 equiv) dissolved in (1.0 mL) of THF and was allowed to stir at rt for 1 h followed
by the addition of aziridine (0.100 mmol, 1.0 equiv)/epoxide (0.100 mmol, 1.0 equiv) dissolved in
(2.0 mL) of THF. The reaction mixture was then allowed to stir at the same temperature for 0.5 h.
After complete consumption of starting compound, the formation of ring opening product was
monitored by TLC. To this reaction mixture containing ring opening product was added the
aldehyde (0.110 mmol, 1.1 equiv), BF3·OEt2 (0.020 mmol, 0.2 equiv), MgSO4 (0.100 mmol, 1.0
equiv) and then again stirred at 55 °C for appropriate time. The formation of product and the
progress of reaction was monitored by TLC. The aqueous layer was extracted with ethyl acetate
(3 × 10.0 mL) and dried over anhydrous Na2SO4. The crude product was purified by flash column
chromatography on silica gel (230−400 mesh) using diethyl ether in petroleum ether as the eluent
to provide the pure products.
General experimental procedure for the synthesis of 3,4-dihydropyrazino[1,2-a]indoles
(2B): A clean and dried double neck round bottom flask under argon was charged with NaH (0.120
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mmol, 1.2 equiv) and 3-methyl indole (0.120 mmol, 1.2 equiv) dissolved in (1.0 mL) of THF and
stirred at rt for 0.5 h followed by the addition of aziridine (0.100 mmol, 1.0 equiv.) dissolved in
(2.0 mL) of THF. The reaction mixture was then allowed to stir at the same temperature for 0.5 h.
The formation of ring opening product was monitored by TLC, after complete consumption of
starting compound. To this reaction mixture containing ring opening product was added the
aldehyde (0.110 mmol, 1.1 equiv) dissolved in DCE (2.0 mL), PTSA (0.100 mmol, 1.0 equiv),
MgSO4 (0.100 mmol, 1.0 equiv) and then again stirred at 80 °C for appropriate time. The formation
of product and the progress of reaction was monitored by TLC. The aqueous layer was extracted
with ethyl acetate (3 × 10.0 mL) and dried over anhydrous Na2SO4. The crude product was purified
by flash column chromatography on silica gel (230−400 mesh) using ethyl acetate in petroleum
ether as the eluent to give the pure products.
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4-Methyl-N-(2-(3-methyl-1H-indol-1-yl)-1-phenylethyl)benzenesulfonamide (3a). To
the suspension of NaH (10.9 mg, 0.273 mmol, 1.5 equiv) in dry DMF (1.0 mL) taken in a double
necked round bottom flask under argon atmosphere was added a solution of 3-methylindole 1a
(35.8 mg, 0.273 mmol, 1.5 equiv) in dry DMF (0.5 mL) and stirred at room temperature for 10
min. Subsequently, a solution of 2-phenyl-N-tosylziridine 2a (50.0 mg, 0.182 mmol, 1.0 equiv) in
dry DMF (0.5 mL) was added to the reaction mixture and stirred at room temperature for 3 h. After
the complete consumption of aziridine, the reaction mixture was quenched with saturated aqueous
NH4Cl solution. The organic layer was extracted with ethyl acetate (5 × 10.0 mL). Combined
extracts were washed with brine and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the crude product was purified by flash column chromatography on
silica gel (230–400 mesh) using 15% ethyl acetate in petroleum ether to afford ring-opening
product 3a (35.6 mg, 0.088 mmol) as a thick colorless liquid in 88% yield: Rf 0.42 (20% ethyl
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acetate in petroleum ether); IR ṽmax (neat, cm–1) 3278, 3029, 2922, 1598, 1495, 1481, 1466, 1386,
1329, 1184, 1158, 1119, 1092, 1068, 1015, 957, 811, 739, 700, 665; 1H NMR (400 MHz, CDCl3)
 2.18 (s, 3H), 2.32 (s, 3H), 4.28 (dd, 1H, J = 11.5, 5.0 Hz), 4.30–4.35 (m, 1H), 4.57–4.61 (m, 1H),
4.91 (d, 1H, J = 4.6 Hz), 6.45 (s, 1H), 7.00 (d, 2H, J = 6.4 Hz), 7.06–7.13 (m, 5H), 7.21–7.24 (m,
3H), 7.38 (d, 2H, J = 6.9 Hz), 7.48 (d, 1H, J = 6.0 Hz); 13C{1H} NMR (100 MHz, CDCl3)  9.5,
21.6, 52.3, 58.0, 109.0, 111.3, 119.0, 119.1, 122.0, 125.4, 126.7, 126.9, 128.3, 128.9, 129.0, 129.4,
136.3, 136.4, 138.5, 143.4; HRMS (ESI-TOF) calcd for C24H25N2O2S (M+H)+ 405.1637, found
405.1633.
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(1R,3S)-10-Methyl-1-(4-nitrophenyl)-3-phenyl-2-tosyl-1,2,3,4-tetrahydropyrazino[1,2-
a]indole (5a). The general method 2A described above was followed when aziridine 2a (27.3 mg,
0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH (4.8
mg, 0.12 mmol) in THF at room temperature for 1.5 h followed by addition of 4-nitrobenzaldehyde
4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4 (11.9 mg, 0.10
mmol) at 55 °C for 2.5 h to afford 5a (38.7 mg, 0.072 mmol) as a white solid in 72% yield: Rf 0.5
(10% ethyl acetate in petroleum ether), mp 178–180 °C; IR ṽmax (KBr, cm–1) 3059, 2924, 2851,
1739, 1569, 1598, 1520, 1493, 1422, 1387, 1347, 1303, 1245, 1163, 1095, 1011, 997, 928, 862,
1
814, 745, 700, 654; H NMR (400 MHz, CDCl3)  2.03 (s, 3H), 2.32 (s, 3H), 3.75 (dd, 1H, J =
13.3, 5.5 Hz), 4.29 (dd, 1H, J = 13.3, 4.6 Hz), 5.22–5.25 (m, 1H), 6.67 (s, 1H), 6.97–7.10 (m, 5H),
7.17–7.23 (m, 5H), 7.26–7.29 (m, 2H), 7.59 (d, 1H, J = 7.8 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.87 (d,
13
2H, J = 9.1 Hz); C{1H} NMR (100 MHz, CDCl3)  7.7, 20.6, 41.1, 53.0, 55.2, 107.7, 107.9,
118.2, 119.2, 121.2, 122.2, 125.8, 126.2, 126.8, 127.1, 127.39, 127.44, 128.0, 129.1, 134.9, 135.2,
136.3, 143.4, 145.8, 146.0; HRMS (ESI-TOF) calcd for C31H28N3O4S (M+H)+ 538.1801, found
538.1806. [α]25 = 79.26 (c 0.16, CHCl3) for a >99% ee sample. The enantiomeric excess was
D
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determined by chiral HPLC analysis (OD-H column), n-hexane/i-propanol = 95:5, flow rate = 1
mL/min, tR (1) = 15.30 min (minor), tR (2) = 18.49 min (major).
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3-(4-Chlorophenyl)-10-methyl-1-(4-nitrophenyl)-2-tosyl-1,2,3,4-
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tetrahydropyrazino[1,2- a]indole (5b). The general method 2A described above was followed
when aziridine 2b (30.7 mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol)
in presence of NaH (4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition
of 4-nitrobenzaldehyde 4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and
MgSO4 (11.9 mg, 0.10 mmol) at 55 °C for 2 h to afford 5b (42.3 mg, 0.074 mmol) as a white solid
in 74% yield: Rf 0.4 (10% ethyl acetate in petroleum ether), mp 193–195 °C; IR ṽmax (KBr, cm–1)
2923, 2854, 1596, 1520, 1492, 1460, 1347, 1250, 1163, 1093, 1012, 963, 855, 815, 746, 716; 1H
NMR (500 MHz, CDCl3)  2.04 (s, 3H), 2.32 (s, 3H), 3.78 (dd, 1H, J = 13.0, 5.4 Hz), 4.18 (dd,
1H, J = 13.0, 5.4 Hz), 5.15 (t, 1H, J = 5.4 Hz), 6.65 (s, 1H), 7.01 (dd, 4H, J = 15.3, 8.4 Hz), 7.17
(d, 2H, J = 8.4 Hz), 7.21–7.29 (m, 5H), 7.59 (d, 1H, J = 8.4 Hz), 7.66 (d, 2H, J = 8.5 Hz), 7.95 (d,
13
2H, J = 9.2 Hz); C{1H} NMR (125 MHz, CDCl3)  8.7, 21.6, 42.4, 54.1, 56.2, 108.8, 108.9,
119.3, 120.2, 122.3, 123.3, 126.6., 127.2, 128.4, 128.5, 128.9, 129.1, 130.1, 132.9, 134.2, 135.8,
136.1, 144.6, 146.6, 147.1; HRMS (ESI-TOF) calcd for C31H27ClN3O4S (M+H)+ 572.1411, found
572.1415.
3-(4-Bromophenyl)-10-methyl-1-(4-nitrophenyl)-2-tosyl-1,2,3,4-
tetrahydropyrazino[1,2-a]indole (5c). The general method 2A described above was followed
when aziridine 2c (35.1 mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol)
in presence of NaH (4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition
of 4-nitrobenzaldehyde 4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and
MgSO4 (11.9 mg, 0.10 mmol) at 55 °C for 2.5 h to afford 5c (48.1 mg, 0.078 mmol) as a white
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solid in 78% yield: Rf 0.4 (10% ethyl acetate in petroleum ether), mp 204–206 °C; IR ṽmax (KBr,
cm–1) 2927, 2923, 2854, 2851, 1739, 1696, 1598, 1569, 1520, 1464, 1431, 1427, 1367, 1345, 1309,
1295, 1163, 1093, 1035, 1017, 964, 921, 865, 818, 745, 702, 642; 1H NMR (400 MHz, CDCl3) 
2.04 (s, 3H), 2.32 (s, 3H), 3.77 (dd, 1H, J = 13.3, 5.5 Hz), 4.18 (dd, 1H, J = 13.3, 5.5 Hz), 5.12–
5.15 (m, 1H), 6.65 (s, 1H), 6.96 (d, 2H, J = 8.7 Hz), 7.14–7.28 (m, 9H), 7.59 (d, 1H, J = 7.8 Hz),
7.66 (d, 2H, J = 8.2 Hz), 7.95 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (100 MHz, CDCl3)  8.7, 21.6,
42.2, 54.1, 56.2, 108.8, 108.9, 119.3, 120.3, 122.3, 123.4, 126.6, 127.2, 127.9, 128.9, 129.4, 130.1,
131.5, 132.6, 132.9, 135.8, 140.9, 142.5, 146.6, 147.0; HRMS (ESI-TOF) calcd for
C31H27BrN3O4S (M+H)+ 616.0906, found 616.0910.
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3-(2-Fluorophenyl)-10-methyl-1-(4-nitrophenyl)-2-tosyl-1,2,3,4-
tetrahydropyrazino[1,2-a]indole (5d). The general method 2A described above was followed
when aziridine 2d (29.1 mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol)
in presence of NaH (4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition
of 4-nitrobenzaldehyde 4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and
MgSO4 (11.9 mg, 0.10 mmol) at 55 °C for 2.5 h to afford 5d (32.2 mg, 0.058 mmol) as a white
solid in 58% yield: Rf 0.5 (10% ethyl acetate in petroleum ether), mp 171–173 °C; IR ṽmax (KBr,
cm–1) 2956, 2925, 2855, 1598, 1521, 1492, 1459, 1348, 1165, 1092, 963, 844, 747, 706, 686, 665;
1H NMR (500 MHz, CDCl3)  2.13 (s, 3H), 2.30 (s, 3H), 3.86 (dd, 1H, J = 13.0, 8.6 Hz), 4.20 (dd,
1H, J = 13.5, 5.5 Hz), 5.25 (dd, 1H, J = 8.5, 5.5 Hz), 6.57 (s, 1H), 6.89–6.97 (m, 2H), 7.06–7.09
(m, 1H), 7.15–7.26 (m, 6H), 7.41 (d, 2H, J = 8.5 Hz), 7.58 (d, 1H, J = 10.9 Hz), 7.68 (d, 2H, J =
8.2 Hz), 8.07 (d, 2H, J = 8.9 Hz); 13C{1H} NMR (100 MHz, CDCl3)  8.6, 21.6, 43.6, 53.6, 54.4,
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108.6, 108.8, 115.6 (d, JC–F = 22.0 Hz), 119.4, 119.9, 122.3, 123.7, 124.4 (d, JC–F = 3.8 Hz),
3
126.3, 127.1, 127.6, 128.1, 128.8, 129.9 (d, JC–F = 8.6 Hz), 130.1, 134.4, 135.3, 144.6, 146.9,
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147.5, 159.9 (d, 1JC–F = 267.3 Hz); HRMS (ESI-TOF) calcd for C31H27FN3O4S (M+H)+ 556.1706,
found 556.1703.
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10-Methyl-1-(4-nitrophenyl)-3-(m-tolyl)-2-tosyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole
(5e). The general method 2A described above was followed when aziridine 2e (28.7 mg, 0.10
mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH (4.8 mg,
0.12 mmol) in THF at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde 4a
(16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4 (11.9 mg, 0.10 mmol)
at 55 °C for 2 h to afford 5e (33.1 mg, 0.060 mmol) as a colorless liquid in 60% yield: Rf 0.5 (10%
ethyl acetate in petroleum ether); IR ṽmax (neat, cm–1) 2956, 2925, 2854, 1597, 1520, 1490, 1461,
1347, 1245, 1163, 1094, 1014, 963, 928, 845, 776, 736, 687, 655; 1H NMR (400 MHz, CDCl3) 
2.04 (s, 6H), 2.31 (s, 3H), 3.73 (dd, 1H, J = 12.8, 5.5 Hz), 4.27 (dd, 1H, J = 13.3, 4.6 Hz), 5.22 (t,
1H, J = 5.0 Hz), 6.67 (s, 1H), 6.82–6.92 (m, 4H), 7.15–7.22 (m, 5H), 7.26–7.29 (m, 2H), 7.59 (d,
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1H, J = 7.8 Hz), 7.67 (d, 2H, J = 8.7 Hz), 7.87 (d, 2H, J = 9.2 Hz); C{1H} NMR (100 MHz,
CDCl3)  8.7, 21.2, 21.6, 42.0, 54.0, 56.1, 108.6, 108.9, 119.1, 120.1, 122.1, 123.0, 124.2, 126.7,
127.2, 128.3, 128.4, 128.7, 128.9, 129.0, 130.1, 135.9, 136.2, 137.0, 138.0, 144.4, 146.7, 146.9;
HRMS (ESI-TOF) calcd for (C32H30N3O4S) (M+H)+ 552.1957, found 552.1955.
3-Benzyl-10-methyl-1-(4-nitrophenyl)-2-tosyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole
(5f). The general method 2A described above was followed when aziridine 2f (28.7 mg, 0.10
mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH (4.8 mg,
0.12 mmol) in THF at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde 4a
(16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4 (11.9 mg, 0.10 mmol)
at 55 °C for 3 h to afford 5f (37.5 mg, 0.068 mmol) as a white solid in 68% yield: Rf 0.55 (10%
ethyl acetate in petroleum ether), mp 174–176 °C; IR ṽmax (KBr, cm–1) 3059, 3028, 2925, 2855,
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1598, 1521, 1493, 1457, 1348, 1258, 1163, 1095, 1015, 966, 856, 813, 742, 703, 670; H NMR
(400 MHz, CDCl3)  2.09 (s, 3H), 2.22 (s, 3H), 2.48–2.54 (m, 1H), 3.07–3.11 (m, 1H), 3.47–3.58
(m, 2H), 4.30–4.37 (m, 1H), 6.55 (s, 1H), 7.00–7.05 (m, 5H), 7.13–7.18 (m, 2H), 7.23–7.29 (m,
3H), 7.53–7.60 (m, 5H), 8.17 (d, 2H, J = 9.2 Hz); 13C{1H} NMR (125 MHz, CDCl3)  8.6, 21.3,
41.2, 41.8, 53.5, 56.3, 108.7, 108.9, 118.9, 119.9, 122.0, 123.8, 126.8, 126.9, 127.1, 128.1, 128.80,
128.84, 129.1, 129.6, 135.7, 136.1, 137.0, 144.1, 147.1, 147.6; HRMS (ESI-TOF) calcd for
C32H30N3O4S (M+H)+ 552.1957, found 552.1956.
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3,10-Dimethyl-1-(4-nitrophenyl)-2-tosyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (5g).
The general method 2A described above was followed when aziridine 2g (21.1 mg, 0.10 mmol)
was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH(4.8 mg, 0.12 mmol)
in THF at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde 4a (16.7 mg, 0.11
mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4 (11.9 mg, 0.10 mmol) at 55 °C for 2.5
h to afford 5g (31.9 mg, 0.067 mmol) as a white solid in 67% yield: Rf 0.4 (10% ethyl acetate in
petroleum ether), mp 155–157 °C; IR ṽmax (KBr, cm–1) 3055, 2962, 2925, 2857, 1601, 1573, 1519,
1485, 1469, 1455, 1422, 1387, 1348, 1327, 1314, 1303, 1242, 1209, 1184, 1108, 1057, 1000, 866,
857, 837, 808, 743, 732, 704; 1H NMR (400 MHz, CDCl3)  1.25 (d, 3H, J = 6.4 Hz), 2.11 (s, 3H),
2.22 (s, 3H), 3.40 (dd, 1H, J = 12.8, 7.4 Hz), 3.84 (dd, 1H, J = 13.0, 6.2 Hz), 4.24 (td, 1H, J = 13.3,
6.6 Hz), 6.48 (s, 1H), 7.03 (d, 2H, J = 8.2 Hz), 7.12–7.16 (m, 2H), 7.18–7.22 (m, 1H), 7.51–7.57
(m, 5H), 8.17 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (100 MHz, CDCl3)  8.6, 21.5, 22.0, 44.1, 51.1,
53.7, 108.7, 119.1, 119.8, 122.0, 123.9, 126.9, 127.2, 128.1, 128.7, 129.4, 129.6, 135.6, 135.8,
144.1, 147.4, 147.7; HRMS (ESI-TOF) calcd for C26H26N3O4S (M+H)+ 476.1644, found 476.1649.
10-Methyl-1-(4-nitrophenyl)-3-octyl-2-tosyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole
(5h). The general method 2A described above was followed when aziridine 2h (30.9 mg, 0.10
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mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH (4.8 mg,
0.12 mmol) in THF at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde 4a
(15.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4 (11.9 mg, 0.10 mmol)
at 55 °C for 2.5 h to afford 5h (43.0 mg, 0.075 mmol) as a white solid in 75% yield: Rf 0.35 (10%
ethyl acetate in petroleum ether), mp 180–182 °C; IR ṽmax (KBr, cm–1) 3210, 2924, 2854, 1614,
1595, 1524, 1462, 1436, 1416, 1348, 1267, 1157, 1119, 1092, 1017, 953, 852, 813, 789, 749, 731,
715, 670; 1H NMR (400 MHz, CDCl3)  0.87–0.91 (m, 3H), 1.24–1.35 (m, 11H), 1.48–1.51 (m,
1H), 1.68–1.74 (m, 2H), 1.91 (s, 3H), 2.13 (s, 3H), 3.81–3.89 (m, 1H), 4.08–4.12 (m, 1H), 4.20–
4.26 (m, 1H), 6.60 (d, 2H, J = 8.2 Hz), 6.76 (brs, 1H), 7.11–7.17 (m, 4H), 7.36 (t, 1H, J = 7.8 Hz),
7.48 (d, 1H, J = 8.2 Hz), 7.94 (d, 2H, J = 8.7 Hz), 8.35 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (100
MHz, CDCl3)  11.8, 14.1, 21.5, 22.7, 25.1, 29.3, 29.5, 29.7, 31.9, 35.3, 47.8, 53.6, 110.3, 120.7,
121.2, 122.0, 123.9, 125.8, 127.2, 127.5, 128.5, 130.8, 132.1, 137.2, 138.9, 141.8, 144.5, 150.3;
HRMS (ESI-TOF) calcd for C33H43N4O4S (M+NH4)+ 591.3005, found 591.3011.
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4,10-Dimethyl-1-(4-nitrocyclohexa-1,5-dien-1-yl)-3-phenyl-2-tosyl-1,2,3,4-
tetrahydropyrazino[1,2-a]indole (5i). The general method 2A described above was followed when
aziridine 2i (28.7 mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in
presence of NaH (4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition of
4-nitrobenzaldehyde 4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4
(11.9 mg, 0.10 mmol) at 55 °C for 3 h to afford 5i (35.9 mg, 0.065 mmol) as colorless liquid in
65% yield: Rf 0.55 (10% ethyl acetate in petroleum ether); IR ṽmax (neat, cm–1) 3480, 2956, 2925,
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2855, 1598, 1522, 1461, 1346, 1259, 1157, 1088, 1014, 910, 860, 813, 741, 700, 681; H NMR
(400 MHz, CDCl3)  1.78 (s, 3H), 1.87 (d, 3H, J = 6.4 Hz), 2.27 (s, 3H), 4.97–5.02 (m, 1H), 5.52
(d, 1H, J = 3.2 Hz), 6.06 (s, 1H), 6.88 (d, 2H, J = 8.2 Hz), 7.05 (d, 2H, J = 7.3 Hz), 7.10 (d, 2H, J
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= 8.2 Hz), 7.14 (d, 1H, J = 7.8 Hz), 7.17–7.24 (m, 4H), 7.31 (d, 1H, J = 8.2 Hz), 7.35 (d, 2H, J =
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8.7 Hz), 7.47 (d, 1H, J = 7.8 Hz) 7.87 (d, 2H, J = 8.2 Hz); C{1H} NMR (100 MHz, CDCl3) 
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8.5, 21.3, 21.5, 51.8, 57.3, 62.5, 107.1, 109.0, 118.8, 119.9, 121.9, 122.9, 126.7, 127.9, 128.3,
128.75, 128.80, 128.9, 129.1, 131.0, 134.9, 137.3, 138.7, 143.3, 145.5, 147.2; HRMS (ESI-TOF)
calcd for C32H32N3O4S (M+H)+ 554.2114, found 554.2119.
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6-Methyl-5-(4-nitrophenyl)-4-tosyl-2,3,3a,4,5,11a-hexahydro-1H-
cyclopenta[5,6]pyrazino[1,2-a]indole (5j). The general method 2A described above was followed
when aziridine 2j (23.7 mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol)
in presence of NaH (4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition
of 4-nitrobenzaldehyde 4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and
MgSO4 (11.9 mg, 0.10 mmol) at 55 °C for 2 h to afford 5j (36.1 mg, 0.072 mmol) as a yellow
solid in 72% yield: Rf 0.5 (10% ethyl acetate in petroleum ether), mp 164–166 °C; IR ṽmax (KBr,
cm–1) 2956, 2924, 2854, 1745, 1605, 1524, 1463, 1377, 1349, 1260, 1165, 1088, 1025, 993, 909,
815; 1H NMR (400 MHz, CDCl3)  1.88–1.97 (m, 3H), 2.10–2.17 (m, 1H), 2.28 (s, 3H), 2.35 (s,
3H), 2.54–2.63 (m, 2H), 2.87–2.94 (m, 1H), 3.79–3.87 (m, 1H), 6.38 (s, 1H), 7.07–7.15 (m, 2H),
7.22–7.30 (m, 3H), 7.48 (d, 2H, J = 9.2 Hz), 7.56 (d, 1H, J = 7.5 Hz), 7.67 (d, 2H, J = 8.1 Hz),
13
8.13 (d, 2H, J = 8.7 Hz); C{1H} NMR (100 MHz, CDCl3)  8.6, 19.3, 21.5, 25.8, 29.5, 56.2,
58.7, 65.3, 108.4, 110.6, 118.9, 119.7, 122.2, 123.8, 127.4, 127.8, 127.9, 129.9, 130.2, 133.6,
134.9, 144.4, 147.4, 148.3; HRMS (ESI-TOF) calcd for (C28H28N3O4S) (M+H)+ 502.1801, found
502.1806.
7-Methyl-6-(4-nitrophenyl)-5-tosyl-1,2,3,4,4a,5,6,12a-octahydroindolo[1,2-
a]quinoxaline (5k). The general method 2A described above was followed when aziridine 2k (25.1
mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH
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(4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition of 4-
nitrobenzaldehyde 4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4
(11.9 mg, 0.10 mmol) at 55 °C for 2 h to afford 5k (38.7 mg, 0.075 mmol) as a yellow solid in
75% yield: Rf 0.5 (10% ethyl acetate in petroleum ether), mp 167–169 °C; IR ṽmax (KBr, cm–1)
2964, 2934, 2896, 2812, 1735, 1698, 1567,1473, 1446, 1398, 1358, 1259, 1189, 1112, 1035, 965,
940, 849, 742, 634; 1H NMR (400 MHz, CDCl3)  1.36–1.42 (m, 2H), 1.47 (dt, 1H, J = 13.3, 3.2
Hz), 1.74–1.78 (m, 1H), 1.90–1.93 (m, 1H), 2.02 (s, 3H), 2.14–2.21 (m, 4H), 2.72–2.76 (m, 1H),
2.93–2.97 (m, 1H), 3.50–3.59 (m, 2H), 6.18 (s, 1H), 6.94 (d, 2H, J = 8.2 Hz), 7.04–7.11 (m, 2H),
7.42–7.48 (m, 4H), 7.56 (d, 2H, J = 8.7 Hz), 8.18 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (100 MHz,
CDCl3)  8.3, 21.4, 24.5, 24.8, 30.9, 35.0, 54.5, 58.5, 64.5, 111.3, 119.0, 122.1, 124.0, 126.96,
127.03, 128.0, 129.2, 130.3, 132.7, 133.8, 133.9, 134.6, 143.9, 147.0, 147.7; HRMS (ESI-TOF)
calcd for C29H30N3O4S) (M+H)+ 516.1957, found 516.1954.
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8-Methyl-7-(4-nitrophenyl)-6-tosyl-2,3,4,5,5a,6,7,13a-octahydro-1H-
cyclohepta[5,6]pyrazino[1,2-a]indole (5l). The general method 2A described above was followed
when aziridine 2l (26.5 mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol)
in presence of NaH (4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition
of 4-nitrobenzaldehyde 4a (16.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and
MgSO4 (11.9 mg, 0.10 mmol) at 55 °C for 2 h to afford 5l (45.5 mg, 0.086 mmol) as a white solid
in 78% yield: Rf 0.5 (10% ethyl acetate in petroleum ether), mp 171–173 °C; IR ṽmax (KBr, cm–1)
3047, 2925, 2855, 1708, 1598, 1521, 1490, 1454, 1412, 1377, 1347, 1264, 1184, 1164, 1090, 1032,
1015, 981, 943, 877, 856, 812, 738, 705, 688, 665; 1H NMR (400 MHz, CDCl3)  1.26–1.34 (m,
1H), 1.38–1.47 (m, 1H), 1.56–1.75 (m, 4H), 1.78–1.86 (m, 1H), 2.03 (d, 6H, J = 2.3 Hz), 2.11–
2.22 (m, 1H), 2.38–2.43 (m, 1H), 2.92–2.99 (m, 1H), 3.58 (td, 1H, J = 10.5, 4.6 Hz), 3.84–3.89
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(m, 1H), 6.26 (s, 1H), 6.76 (d, 2H, J = 8.2 Hz), 7.05 (t, 2H, J = 5.0 Hz), 7.32 (d, 2H, J = 8.2 Hz),
7.39–7.43 (m, 4H), 7.59 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (100 MHz, CDCl3)  8.3, 21.2, 23.4,
23.9, 25.2, 32.2, 35.9, 54.2, 61.4, 63.9, 109.5, 112.3, 118.8, 119.1, 122.0, 124.0, 126.6, 128.4,
128.8, 130.3, 134.6, 135.1, 143.7, 146.4, 147.8; HRMS (ESI-TOF) calcd for C30H32N3O4S (M+H)+
530.2114, found 530.2116.
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(1R,3S)-10-Methyl-1,3-diphenyl-2-tosyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (5m).
The general method 2A described above was followed when aziridine 2a (27.3 mg, 0.10 mmol)
was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH(4.8 mg, 0.12 mmol)
in THF at room temperature for 2 h followed by addition of benzaldehyde 4b (11.2 μL, 11.7 mg,
0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4 (11.9 mg, 0.10 mmol) at 55 °C
for 2 h to afford 5m (31.0 mg, 0.063 mmol) as a white solid in 63% yield: Rf 0.6 (10% ethyl acetate
in petroleum ether), mp 163–165 °C; IR ṽmax (KBr, cm–1) 3059, 2919, 1598, 1493, 1467, 1451,
1
1349, 1248, 1184, 1163, 1095, 1010, 961, 925, 894, 842, 813, 740, 698; H NMR (400 MHz,
CDCl3)  2.08 (s, 3H), 2.28 (s, 3H), 3.96 (dd, 1H, J = 13.3, 8.7 Hz), 4.04 (dd, 1H, J = 13.5, 5.7
Hz), 4.88–4.92 (m, 1H), 6.58 (s, 1H), 7.09–7.22 (m, 15H), 7.55 (d, 1H, J = 7.8 Hz), 7.61 (d, 2H, J
13
= 7.8 Hz); C{1H} NMR (100 MHz, CDCl3)  8.4, 21.4, 44.0, 54.9, 59.8, 107.8, 108.4, 119.0,
119.3, 121.5. 127.27, 127.31, 127.6, 127.7, 127.8, 128.2, 128.3, 128.4, 128.9, 129.5, 135.0, 135.5,
139.2, 139.6, 143.8; HRMS (ESI-TOF) calcd for C31H29N2O2S (M+H)+ 493.1950, found 493.1955.
[α]D25 = +139.00 (c 0.10, CHCl3) for a 99% ee sample.
(1R,3S)-1-(4-Fluorophenyl)-10-methyl-3-phenyl-2-tosyl-1,2,3,4-
tetrahydropyrazino[1,2-a]indole (5n). The general method 2A described above was followed
when aziridine 2a (27.3 mg, 0.10 mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol)
in presence of NaH (4.8 mg, 0.12 mmol) in THF at room temperature for 2 h followed by addition
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of 4-fluorobenzaldehyde 4c (11.8 μL, 13.7 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol
%) and MgSO4 (11.9 mg, 0.10 mmol) at 55 °C for 2 h to afford 5n (38.8 mg, 0.076 mmol) as a
white solid in 76% yield: Rf 0.55 (10% ethyl acetate in petroleum ether), mp 166–168 °C; IR ṽmax
(KBr, cm–1) 3058, 2919, 1602, 1506, 1461, 1348, 1225, 1163, 1095, 1010, 962, 927, 895, 860,
838, 788, 740, 698, 678, 655, 599; 1H NMR (400 MHz, CDCl3)  2.05 (s, 3H), 2.30 (s, 3H), 3.94
(dd, 1H, J = 13.3, 5.5 Hz), 4.09 (dd, 1H, J = 13.3, 7.3 Hz), 4.99–5.02 (m, 1H), 6.56 (s, 1H), 6.82
(t, 2H, J = 8.7 Hz), 7.08–7.19 (m, 10H), 7.22 (d, 2H, J = 4.6 Hz), 7.56 (d, 1H, J = 7.8 Hz), 7.63
(d, 2H, J = 8.2 Hz); 13C{1H} NMR (100 MHz, CDCl3)  8.5, 21.6, 43.4, 54.3, 58.5, 108.0, 108.6,
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115.1 (d, JC-F = 21.9 Hz), 119.1, 119.7, 121.7, 127.3, 127.4, 127.9, 128.3, 128.5 (d, JC-F = 3.8
Hz), 129.8 (d, 3JC-F = 9.5 Hz), 135.3, 135.41, 135.44, 135.8, 135.9, 138.7, 144.0, 162.1 (d, 1JC-F
246.0 Hz); HRMS (ESI-TOF) calcd for C31H28FN2O2S (M+H)+ 511.1856, found 511.1855. [α]D
= ‒48.00 (c 0.15, CHCl3) for a >99% ee sample.
=
25
(1R,3S)-10-Methyl-3-phenyl-1-(p-tolyl)-2-tosyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole
(5o). The general method 2A described above was followed when aziridine 2a (27.3 mg, 0.10
mmol) was reacted with 3-methylindole 1a (15.7 mg, 0.12 mmol) in presence of NaH (4.8 mg,
0.12 mmol) in THF at room temperature for 2 h followed by addition of 4-methylbenzaldehyde 4d
(13 μL, 13.2 mg, 0.11 mmol) along with BF3·OEt2 (2.5 μL, 20 mol %) and MgSO4 (11.9 mg, 0.10
mmol) at 55 °C for 2 h to afford 5o (28.4 mg, 0.056 mmol) as a white solid in 56% yield: Rf 0.6
(10 % ethyl acetate in petroleum ether), mp 164–166 °C; IR ṽmax (KBr, cm–1) 3028, 2957, 2924,
2854, 1739, 1598, 1510, 1494, 1464, 1378, 1349, 1260, 1185, 1163, 1095, 1019, 927, 894, 874,
812, 739, 699; 1H NMR (400 MHz, CDCl3)  2.08 (s, 3H), 2.29 (d, 6H, J = 9.2 Hz), 3.93 (dd, 1H,
J = 13.5, 9.4 Hz), 4.07 (dd, 1H, J = 13.5, 5.7 Hz), 4.84 (dd, 1H, J = 9.2, 5.5 Hz), 6.53 (s, 1H), 7.03
(d, 2H, J = 8.2 Hz), 7.08 (d, 3H, J = 9.2 Hz), 7.11–7.21 (m, 9H), 7.54 (d, 1H, J = 7.8 Hz), 7.60 (d,
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