Regioselective Synthesis of Indolopyrazines through a Sequential Rhodium-Catalyzed Formal [3+3] Cycloaddition and Aromatization Reaction of Diazoindolinimines with Azirines

Article abstract of DOI:10.1021/acs.joc.8b00115

A regioselective synthetic method for the preparation of indolopyrazines was demonstrated through a sequential Rh-catalyzed formal [3+3] cycloaddition and aromatization reaction of a wide range of diazoindolinimines with azirines. Because the previously reported synthetic methods afforded mixtures of indolopyrazines, the present method using unsymmetrical azirines has a strong advantage from a regioselectivity viewpoint.

Full text of DOI:10.1021/acs.joc.8b00115

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Article
Regioselective Synthesis of Indolopyrazines through a
Sequential Rhodium-Catalyzed Formal [3 + 3] Cycloaddition
and Aromatization Reaction of Diazoindolinimines with Azirines
Yonghyeon Baek, Chanyoung Maeng, Hyunseok Kim, and Phil Ho Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00115 • Publication Date (Web): 21 Jan 2018
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Regioselective Synthesis of Indolopyrazines through a Sequential Rhodium-Catalyzed Formal
[3 + 3] Cycloaddition and Aromatization Reaction of Diazoindolinimines with Azirines
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Yonghyeon Baek,† Chanyoung Maeng,† Hyunseok Kim,† and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
Eꢀmail: phlee@kangwon.ac.kr
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Table of Contents
ABSTRACT: A regioselective synthetic method for the preparation of indolopyrazines was
demonstrated through a sequential Rhꢀcatalyzed formal [3 + 3] cycloaddition and aromatization
reaction of a wide range of diazoindolinimines with azirines. Because the previously reported
synthetic methods afforded mixtures of indolopyrazines, the present method using unsymmetrical
azirines has a strong advantage from a regioselectivity viewpoint.
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INTRODUCTION
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Indolopyrazines possessing both indole and pyrazine moieties are significant structural motifs in a
number of naturally occurring products, show a wide range of biological activities, including
antitumor and antiviral activities and function as fluorescent and host materials (Figure 1).1 In this
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Figure 1. Representative Compounds Bearing Indolopyrazines
regard, the indolopyrazine motif has continuously received the attention of synthetic chemists. Thus,
establishing synthetic approaches for preparing regioselective indolopyrazines from simply
attainable starting materials is highly demanded. To date, a variety of indolopyrazine derivatives
have been prepared by the condensation of isatin with oꢀphenylenediamine in glacial acetic acid
under microwave irradiation (eq 1, Scheme 1),2 condensation of in situ generated diamine with
αꢀ
dicarbonyl compounds (eq 2),3 Pdꢀcatalyzed C–N coupling followed by C–H activation reactions
from secondary aromatic amines and 2,3ꢀdibromoquinoxaline in one pot (eq 3),4 and a twoꢀstep
approach using Pdꢀcatalyzed Suzuki coupling reactions and subsequent annulation by Pdꢀcatalyzed
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twoꢀfold C–N coupling reaction with aromatic and aliphatic amines (eq 4).4,5 Although
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condensation reactions using oꢀphenylenediamines,
dibromoquinoxalines provide efficient synthetic approaches for indolopyrazines, these methods
afford regioisomeric mixtures of indolopyrazines when unsymmetrical oꢀphenylenediamines,
αꢀdicarbonyl compounds, and 2,3ꢀ
αꢀ
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dicarbonyl compounds, or 2,3ꢀdibromoquinoxalines are employed. Given the limitations of these
methods, we were stimulated to develop a selective synthesis of indolopyrazines bearing
unsymmetrical pyrazine skeletons. For this reason, we envisioned that, if azirines6 were employed
to react with diazoindolinimines,7 indolopyrazines could be regioselectively produced. In our
continuing investigations to establish scaffoldꢀbased chemical libraries,6e,8 we were fascinated to
invent an efficient and useful approach for preparing a multitude of heterocyclicꢀfused indols.9
Herein, we demonstrate a regioselective method for the synthesis of the indolopyrazines through a
sequential Rhꢀcatalyzed formal [3 + 3] cycloaddition and aromatization reaction of a wide range of
diazoindolinimines with azirines (eq 5).10
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Scheme 1. Synthetic Methods for Indolopyrazines
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R1 (R2)
R2 (R1)
previous works
O
H2N
H2N
R1
R2
N
cat. acid
MW
+
(1)
(2)
O
N
N
N
PG
N
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PG
R1 (R2)
R2 (R1)
NH2
O
O
R1
R2
N
cat.
heating
+
NH2
N
PG
N
PG
in situ
generated
R1 (R2)
R2 (R1)
cat. Pd
1) C-N coupling
Br
Br
N
N
R1
R2
N
+
(3)
2) C-H activation
NHR
N
N
N
R
R1 (R2)
R2 (R1)
cat. Pd
1) Suzuki reaction
Br
Br
N
N
R1
R2
Br
N
+
(4)
2) two-fold C-N
coupling
B(OH)2
N
R
RNH2
not regioselective
mixtures
this work
R1
N2
N
R2
N
cat. Rh
- N2
-TsH
R3
+
(5)
NTs
R1
R1
R2
N
N
R4
N
R2
regioselective
RESULTS AND DISCUSSION
First, we investigated the reaction of diazoindolinimine (1a) with ethyl 3ꢀ(4ꢀnitrophenyl)ꢀ2Hꢀ
azirineꢀ2ꢀcarboxylate (2a) using a variety of Rh catalysts (Table 1). When Rh2(esp)2 was used in
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dichloroethane (DCE) at 80 oC for 2 h, indolodihydropyrazine (3a) bearing the desired skeleton was
gratifyingly obtained in 8% yield (entry 1). A variety of rhodium catalysts, such as Rh2(TFA)4,
Rh2(OAc)4, and Rh2(oct)4, in DCE were screened to reveal that Rh2(oct)4 was the best performing
catalyst, affording 3a in 63% yield (entries 2, 3, and 4). Then, the desired product indolopyrazine
(4a) was pleasingly accompanied in 16% yield by elimination of 4ꢀmethylbenzenesulfinic acid
(TsH) from 3a. The production of 4a indicates that a Rhꢀcatalyzed formal [3 + 3] cycloaddition
followed by armatization reaction occurred in the present reaction. Thus, we tried to selectively
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o
prepare 4a from the reaction of diazoindolinimine 1a with azirine 2a. Heating at 120 C in DCE
produced indolopyrazine 4a selectively in 68% yield (entry 7). The addition of triethylamine (1.5
equiv) to in situ generated indolodihydropyrazine (3a) increased the yield of 4a up to 79% (entry 8).
When tertꢀbutyl 3ꢀ(4ꢀnitrophenyl)ꢀ2Hꢀazirineꢀ2ꢀcarboxylate (2b) was employed to the reaction with
o
(1a) in the presence of Rh2(oct)4 in DCE at 80 C for 2 h, indolodihydropyrazine (3b) was
selectively produced in quantitative yield (entry 9). Moreover, when triethylamine was added to 3b,
the elimination reaction of TsH occurred, and the desired indolopyrazine (4b) was selectively
obtained in 96% yield (entry 10). The sequential reaction could be scaled up without difficulty
(entry 11). The structure of 4b was confirmed by Xꢀray crystallography (see the Supporting
Information).
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Table 1. Reaction Optimizationa
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yield (%)b
entry
R
cat.
solvent temp (oC) time (h)
3
8
4
0
1
2
Et
Et
Rh2(esp)2
Rh2(TFA)4
Rh2(OAc)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
DCE
DCE
80
80
80
80
80
80
120
80
80
80
80
2
2
2
2
2
2
6
2
2
2
2
13
61
63
38
17
0
0
3
Et
DCE
9
4
Et
DCE
16
0
5
Et
toluene
EtOAc
DCE
6
Et
0
7
Et
68
79d
0
8c
Et
DCE
0
9
tꢀBu
tꢀBu
tꢀBu
DCE
99
0
10c
11c
DCE
96d
82d,e
DCE
0
aReactions were carried out with 1a (2.0 equiv), 2 (0.2 mmol, 1.0 equiv), and the Rh catalyst (4.0
o
b
mol %) in solvent (1.0 mL) at 80 C for 2 h under a nitrogen atmosphere. NMR yield using
c
o
dibromomethane as an internal standard. After 2 h, Et3N (1.5 equiv) was added at 80 C for 2 h.
dIsolated yield of 4a and 4b. eThis reaction was carried out 1.0 mmol scale of 2b.
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With these optimized reaction conditions, we examined the scope and limitation of the
sequential reaction of diazoindolinimines 1a with azirines 2 (Scheme 2). Likewise, ethyl 3ꢀphenylꢀ
2Hꢀazirineꢀ2ꢀcarboxylate was reacted with 1a to produce indolopyrazine 4c in 40% yield, while
tertꢀbutyl 3ꢀphenylꢀ2Hꢀazirineꢀ2ꢀcarboxylate gave 4d in 83% yield. Next, the substrate scope of a
wide range of azirines 2 in the reaction with diazoindolinimine 1a was investigated. Electronic
modification of the substituents on the aryl group of tertꢀbutyl 3ꢀarylꢀ2Hꢀazirineꢀ2ꢀcarboxylate
slightly influenced the reaction efficiency. An electronꢀdonating 3ꢀmethyl group provided the
desired indolopyrazine 4e in 65% yield. The conditions of the sequential reaction were compatible
with a variety of electronꢀwithdrawing groups, including chloro, iodo, trifluoromethyl, and cyano
groups, affording the corresponding indolopyrazines (4f, 4g, 4h, 4i, and 4j) in good yields varying
from 71% to 89%. tertꢀButyl azirine carboxylate bearing a 2ꢀnaphthyl group was also readily
employed in the Rhꢀcatalyzed formal [3 + 3] cycloaddition followed by the aromatization reaction,
producing 4l in 87% yield. A 2ꢀfurylꢀsubstituted tertꢀbutyl azirine carboxylate tolerated the
optimized reaction conditions and provided the desired 2ꢀfurylꢀsubstituted indolopyrazine 4m in
64% yield. It was notable that a 2ꢀthiophenylꢀsubstituted azirine was also successfully applied to the
sequential Rhꢀcatalyzed cycloaddition and aromatization reaction, affording 4n in 66% yield. The
current approach worked equally well even with methylꢀsubstituted nꢀbutyl and tertꢀbutyl azirine
carboxylates, leading to the formation of indolopyrazines 4o and 4p in 76% and 71% yields,
respectively.
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Scheme 2. Scope of Azirinesa
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R1
N2
1) Rh2(oct)4 (4.0 mol %)
DCE, 80 oC, 2 h
2) Et3N, 80 oC, 2 h
N
CO2R2
N
+
NTs
R1
CO2R2
N
N
N
- N2, -TsH
Me
Me
1a
2
4
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NO2
Me
Ph
N
CO2R
N
N
N
CO2t-Bu
CO2R
N
N
N
Me
N
N
Me
4e (65%)
Me
4a (79%, R = Et)
4c (40%, R = Et)
4b (
R = t-Bu)
4d (
R = t-Bu)
96%,
83%,
Cl
I
Cl
N
N
N
CO2t-Bu
CO2t-Bu
CO2t-Bu
N
N
N
N
Me
N
N
Me
Me
4f (71%)
4g (80%)
4h (83%)
CF3
CN
N
N
N
CO2t-Bu
CO2t-Bu
CO2R
N
N
N
N
N
N
Me
4i (75%)
Me
Me
4j (89%)
4k (42%, R = Et)
4l (
R = t-Bu)
87%,
O
S
N
Me
Ot-Bu
OR
N
N
N
CO2t-Bu
O
O
N
N
N
N
N
Me
Me
Me
4m (64%)
4n (66%)
4o (76%, R = n-Bu)
4p ( R = t-Bu)
71%,
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aAfter the reactions were carried out with 1a (2.0 equiv), 2 (0.2 mmol, 1.0 equiv), and Rh2(oct)4 (4.0
mol %) in DCE (1.0 mL) at 80 oC for 2 h under a nitrogen atmosphere, Et3N (1.5 equiv) was added,
and then, the reaction mixture was stirred at 80 oC for 2 h.
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Next, we examined the substrate scope as well as the functional group tolerance of
diazoindolinimines in the reaction with azirine (2b) (Scheme 3). Modification of the substituents at
the N1 position of diazoindolinimines 1 affected the efficiency of the reaction. NꢀBenzylꢀ and Nꢀ
phenylꢀsubstituted diazoindoloimines were less reactive than Nꢀmethylꢀsubstituted one and afforded
the indolopyrazines 4q and 4r in 58% and 65% yields, respectively. Thus, a variety of Nꢀmethylꢀ
substituted diazoindolimines were employed to the sequential Rhꢀcatalyzed formal [3 + 3]
cycloaddition and aromatization reaction. Electronic modification of the substituents on the aryl
ring of the Nꢀmethylꢀsubstituted diazoindoloimines (1) did not largely influence the reaction
efficiency. For instance, Nꢀmethylꢀsubstituted diazoindoloimines bearing electronꢀdonating 6ꢀ
methyl, 5ꢀmethyl, and 6ꢀmethoxy groups on the phenyl ring were converted to the indolopyrazines
(4s, 4t, and 4u) in good to excellent yields varying from 70% to 96%. Additionally, substrates with
electronꢀwithdrawing 6ꢀfluoro, 6ꢀchloro, and 5ꢀbromo groups on the phenyl ring underwent the
sequential reaction, providing the desired indolopyrazines (4v, 4w, and 4x). The tolerance of halides,
including fluoro, chloro and bromo groups, was significant, as further transformations of these
functional groups are possible.
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Scheme 3. Scope of 3-Diazoindoline-2-iminesa
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aAfter the reactions were carried out with 1 (2.0 equiv), 2b (0.2 mmol, 1.0 equiv), and Rh2(oct)4
o
(4.0 mol %) in DCE (1.0 mL) at 80 C for 2 h under a nitrogen atmosphere, Et3N (1.5 equiv) was
added, and then, the reaction mixture was stirred at 80 oC for 2 h.
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Based on these results, we next explored the scope of this reaction with respect to a wide range
of unactivated and unsymmetrical azirines (Scheme 4). When phenylazirine was treated with Nꢀ
methyl diazoindolinimine 1a under the optimized conditions, the sequential Rhꢀcatalyzed formal [3
+ 3] cycloaddition and aromatization reaction occurred and afforded the desired indolopyrazine 5a
in 75% yield. 4ꢀMethoxyphenylꢀ and 4ꢀfluorophenylꢀsubstituted azirines were also smoothly
converted to the corresponding indolopyrazines 5b (82%) and 5c (90%), respectively.
Diphenylazirine worked equally well with Nꢀmethyl diazoindolinimine 1a to give indolopyrazine
5d in 80% yield. 3ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀphenylꢀ2Hꢀazirine took part in the reaction with 1a to
afford indolopyrazine 5e in 86% yield. 2,3ꢀBis(4ꢀfluorophenyl)ꢀ2Hꢀazirine was found to couple
with 1a to furnish the corresponding product 5f in 85% yield.
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Scheme 4. Scope of Unactivated and Unsymmetrical Azirinesa
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5
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9
R1
N2
1) Rh2(oct)4 (4.0 mol %)
N
R2
N
DCE, 80 oC, 2 h
+
NTs
R1
R2
N
2) Et3N, 120 oC, 2 h
- N2, -TsH
N
N
Me
1a
3
5
Me
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OMe
F
Ph
N
N
N
N
N
N
N
N
N
5a (75%)
5b (82%)
5c (90%)
Me
Me
Me
OMe
F
Ph
N
N
N
N
F
Ph
N
N
N
N
N
5d (80%)
5e (86%)
5f (85%)
Me
Me
Me
aAfter reactions were carried out with 1a (2.0 equiv), 3 (0.2 mmol, 1.0 equiv), and Rh2(oct)4 (4.0
mol %) in DCE (1.0 mL) at 80 oC for 2 h under a nitrogen atmosphere, Et3N (1.5 equiv) was added,
and then, the reaction mixture was stirred at 120 oC for 2 h.
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Because indolopyrazines (5) are fluorescent, their optical properties in CH2Cl2 solution were
studied (Figure 2). The indolopyrazine fluorophores displayed Stokes shifts ranging from 41 to 146
units. The extinction coefficients were variable from 107,298 to 585,478 Mꢀ1cmꢀ1 (Table 2). The
indolopyrazine (5e) affords high quantum yields and extinction coefficients, which are an attractive
property for biological probes.
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Figure 2. Normalized Absorption (a) and Fluorescence Emission (b) Spectra for Selected
Fluorophores (5a-5f). Observed Fluorescence under UV Excitation (365 nm) (c).
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Table 2. Photophysical Properties of Indolopyrazinesa
3
4
5
6
Compound
λmax,abs
(nm)
λmax,em
(nm)
ε
φ
(Mꢀ1.cmꢀ1)
7
8
9
5a
5b
5c
5d
5e
5f
330
387
378
339
383
340
476
505
419
425
443
426
253,856
343,107
174,025
143,133
585,478
107,298
0.22
0.27
0.13
0.11
0.45
0.08
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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49
50
51
52
53
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55
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57
58
59
60
aAbsorption peaks (λmax,abs) and molar extinction coefficients (ε) were measured in CH2Cl2 (10ꢀ5 M).
To demonstrate the synthetic utility of this cyclization, we next attempted the regioselective
synthesis of indolopyrazines using azirines bearing two unsymmetrical aryl groups (Scheme 5).
Isomeric 3ꢀphenylꢀ2ꢀ(pꢀtolyl)ꢀ2Hꢀazirine and 2ꢀphenylꢀ3ꢀ(pꢀtolyl)ꢀ2Hꢀazirine are applicable to the
present transformation, leading to the regioselective formation of the corresponding indolopyrazines
6a and 6b in 95% and 92% yields, respectively. Likewise, 2ꢀ(4ꢀfluorophenyl)ꢀ3ꢀphenylꢀ2Hꢀazirine
and 3ꢀ(4ꢀfluorophenyl)ꢀ2ꢀphenylꢀ2Hꢀazirine were compatible with the reaction conditions,
affording selectively the desired indolopyrazines 6c (76%) and 6d (78%). In the case of 2ꢀ(4ꢀ
bromophenyl)ꢀ3ꢀphenylꢀ2Hꢀazirine and 3ꢀ(4ꢀbromophenyl)ꢀ2ꢀphenylꢀ2Hꢀazirine, the corresponding
indolopyrazines 6e and 6f were selectively produced in good yield. The structure of 6e and 6f was
confirmed by Xꢀray crystallography (see the Supporting Information). Because the previously
reported synthetic methods afforded mixtures of indolopyrazines, the present approach using
unsymmetrical azirines has a strong advantage from a regioselectivity viewpoint.
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Scheme 5. Regioselective Synthesis of Indolopyrazines Using Unsymmetrical Azirines
3
4
5
6
7
8
9
Ph
N2
N
N
Me
standard conditions
+
Ph
NTs
N
N
N
Me
3g
1a Me
6a (95%
)
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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43
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52
53
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57
58
59
60
Me
N
standard conditions
1a
1a
1a
Ph
+
N
Ph
Me
N
3h
N
6b (92%)
Me
Ph
N
N
F
standard conditions
+
Ph
N
N
F
6c (76%)
Me
3i
F
N
standard conditions
+
Ph
N
Ph
F
N
3j
N
6d
(78%)
Me
Ph
N
N
Br
standard conditions
1a
+
Ph
N
N
Br
6e
Me
6e (80%)
3k
Br
N
standard conditions
1a
+
Ph
N
Ph
Br
N
3l
N
6f
Me
6f (89%)
standard conditions: 1) Rh2(oct)4 (4.0 mol %), DCE, 80 oC, 2 h. 2) Et3N, 120 C, 2 h. - N2, -TsH
o
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3
4
5
6
7
8
Next, we investigated the synthetic application of 5ꢀmethylꢀ2ꢀphenylꢀ5Hꢀpyrazino[2,3ꢀb]indole
(5a) in C–H activation (Scheme 6). When 5a was reacted with TsN3 in the presence of [Cp*IrCl2]2,
AgPF6, and pivalic acid, the sulfonylꢀaminated indolopyrazine 7a was produced in 90% yield.11 The
Rhꢀcatalyzed olefination of 5a with ethyl acrylate was efficient and provided 7b in 86% yield.12 In
addition, the Rhꢀcatalyzed C–H activation of 5a and dioxazolone occurred, and the benzoylꢀ
aminated product 7c was obtained in 86% yield.13
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59
60
Scheme 6. Applications of Indolopyrazine to C–H Activation
[Cp*IrCl2]2 (4.0 mol %)
AgPF6 (16.0 mol %)
NHTs
PivOH (0.5 equiv)
DCE, 80 oC, 1 h
N
N
TsN3
+
N
N
N
N
Me
Me
N
7a (90%)
5a
[Cp*RhCl2]2 (2.5 mol %)
Cu(OAc)2 (1.0 equiv)
DCE, 90 oC, 12 h
5a
+
CO2Et
CO2Et
N
N
Me
7b (86%)
O
O
[Cp*RhCl2]2 (4.0 mol %)
AgSbF6 (16.0 mol %)
DCE, 80 oC, 12 h
N
H
N
+
O
O
Ph
5a
N
N
Ph
N
Me
7c (85%)
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3
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5
6
7
8
A feasible reaction mechanism for the production of indolopyrazine (4, 5, and 6) from
diazoindolinimine 1 and azirine 2 is depicted in the Scheme 7. First, diazoindolinimines by reaction
of a rhodium catalyst affords rhodium carbenoid A together with release of nitrogen molecule.
Addition of azirine 2 to the carbene center of A provides the rhodiumꢀbond zwitterionic
intermediate B. Next, a ringꢀopening reaction via the release of an electron pair from anionic
rhodium of B furnishes dihydroindolopyrazine 3 (pathway b). Finally, elimination of 4ꢀ
methylphenylsulfinic acid (TsH) from 3 affords indolopyrazine (4, 5, and 6). 6ꢀElectrocyclization
(pathway a) of 1,4ꢀdiazatriene C might be involved to the production of dihydroindolopyrazine 3.
Because regioisomeric indolopyrazine G are not detected from the present reaction, an
intramolecular hydrogen transfer (pathway c) can be ruled out. In fact, this postulation is provided
by Xꢀray structure of indolopyrazine 6e and 6f.
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Scheme 7. A Plausible Mechanism
3
4
5
6
7
8
9
R3
R3
TsH
N
N
R4
H
R4
pathway a
N
N
R3
Ts
N
N
R2
R1
R1
R2
4, 5, 6
3
N
R4
N2
10
11
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pathway b
NTs
NTs
N
R1
N
[Rh2L4]
R2
R1
C
R2
1
N2
R3
[Rh]
R4
R4
NTs
[Rh]
N
N
NTs
R3
N
R2
R1
N
N
R2
A
R1
N
R2
B
R1
N
G
not observed
R3
R4
2
pathway c
TsH
R4
H
R4
R3
Ts
R4
[Rh]
R3
NTs
[Rh]
N
N
N
R3
N
H
Ts
N
N
R2
N
N
R2
R1
R1
R1
R2
D
E
F
CONCLUSION
In summary, we developed a regioselective synthetic method to prepare indolopyrazines through a
sequential Rhꢀcatalyzed formal [3 + 3] cycloaddition and aromatization reaction of a wide range of
diazoindolinimines with azirines. Because the previously reported synthetic methods afforded
mixtures of indolopyrazines, the present method using unsymmetrical azirines has the an excellent
merit from a regioselectivity standpoint.
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Experimental Section
3
4
5
6
7
8
9
General: Commercial available reagents were used without purification. All reaction mixtures were
stirred magnetically and were monitored by thinꢀlayer chromatography using silica gel preꢀcoated
glass plates, which were visualized with UV light and then, developed using either iodine or a
solution of anisaldehyde. Flash column chromatography was carried out using silica gel (230ꢀ400
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1
mesh). H NMR (400 MHz), 13C{1H} NMR (100 MHz), and 19F NMR (377 MHz) spectra were
recorded on NMR spectrometer. Deuterated chloroform was used as the solvent and chemical shift
values (
δ
) are reported in parts per million relative to the residual signals of this solvent [δ 7.26 for
1H (chloroformꢀd), δ 2.05 for H (acetoneꢀd6), δ 77.2 for 13C{1H} (chloroformꢀd) and δ 29.84,
1
206.26 for C{1H} (acetoneꢀd6)]. Infrared spectra were recorded on FTꢀIR spectrometer as either a
13
thin film pressed between two sodium chloride plates or as a solid suspended in a potassium
bromide disk. High resolution mass spectra (HRMS) were obtained by fast atom bombardment
(FAB) using a double focusing magnetic sector mass spectrometer and electron impact (EI)
ionization technique (magnetic sector ꢀ electric sector double focusing mass analyzer) from the
KBSI (Korea Basic Science Institute Daegu Center). Melting points were determined in open
capillary tube.
Synthetic procedure of azirines
Preparation of substrates
Azirines were prepared by reported method.14,15,16,17
General procedure for azirines ester14
To a mixture of βꢀketoester (2.2 mmol, 1.0 equiv), NH2OH·HCl (160 mg, 2.2 mmol, 1.0 equiv) and
sodium acetate (210 mg, 2.2 mmol, 1.0 equiv) was added methanol (15 mL) and water (0.7 mL).
After being stirred at room temperature for 4 h, the solvent was removed in vacuo. The reaction
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mixture was partitioned between Et2O and water. After saperation, the organic extract was washed
with saturated aqueous NaHCO3, brine, and dried over anhydrous MgSO4. The solvents were
removed in vacuo, and the resulting crude was used directly in the next reaction. To an ice cold
solution of crude oxime and Et3N (0.9 mL, 6.6 mmol, 3.0 equiv) in DCM (20 mL) was slowly
added TsCl (500 mg, 2.6 mmol, 1.2 equiv), and the mixture was stirred at the same temperature for
2.5 h. The reaction was quenched with water, and the organic material was extracted three times
with ethyl acetate. The combined extracts were washed with water, brine, and dried over anhydrous
MgSO4. The solvents were removed in vacuo, and the resulting crude materials were used
immediately for the next step without further purification. To an ice cold solution of crude ketoxime
tosylate in DCM (8 mL) was slowly added DBU (0.4 mL, 2.6 mmol, 1.2 equiv), and the mixture
was stirred at the same temperature for 1 h. The reaction was quenched with water, and the organic
materials were extracted with DCM. The combined extracts were washed with brine, and dried over
anhydrous MgSO4. After the solvents were removed in vacuo, the residue was purified by column
chromatography to give the corresponding azirines ester.
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tert-Butyl 3-(m-tolyl)-2H-azirine-2-carboxylate (2e): Yield: 104 mg (20%); Rf = 0.5
(EtOAc:Hexane = 1:10); Red oil; 1H NMR (400 MHz, CDCl3)
= 6.3 Hz, 2H), 2.45 (s, 3H), 1.47 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 7.68 (d, J = 8.1 Hz, 2H), 7.45 (d, J
δ
171.1, 159.0, 139.4,
134.7, 130.9, 129.3, 127.7, 122.6, 81.7, 30.7, 28.2, 21.4; IR (film) 2976, 2928, 1729, 1584, 1367,
1152, 787, 689 cmꢀ1; HRMS (FAB) m/z: [M + H]+ Calcd for C14H18NO2 232.1338; Found 232.1335.
tert-Butyl 3-(4-chlorophenyl)-2H-azirine-2-carboxylate (2g): Yield: 208.3 mg (55%); Rf = 0.3
o
(EtOAc:Hexane = 1:5); Yellow solid; Melting point: 55ꢀ57 C; 1H NMR (400 MHz, CDCl3)
δ 7.82
(d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 2.77 (s, 1H), 1.47 (s, 9H) ; 13C{1H} NMR (100 MHz,
CDCl3) 170.7, 158.5, 140.3, 131.6, 130.0, 121.3, 82.0, 30.9, 28.2; IR (film) 2979, 2933, 1991,
δ
1725, 1594, 1485, 1157, 835, 556 cmꢀ1; HRMS (FAB) m/z: [M + H]+ Calcd for C13H15ClNO2
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252.0791; Found 252.0794.
3
4
5
tert-Butyl 3-(4-iodophenyl)-2H-azirine-2-carboxylate (2h): Yield: 256 mg (30%); Rf = 0.3
6
7
o
(EtOAc:Hexane = 1:5); Yellow solid; Melting point: 74ꢀ76 C; 1H NMR (400 MHz, CDCl3)
δ 7.95
8
9
(d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 2.76 (s, 1H), 1.46 (s, 9H) ; 13C{1H} NMR (100 MHz,
CDCl3) 170.6, 152.4, 135.2, 135.2, 128.6, 125.2, 81.9, 31.5, 28.2; IR (film) 2977, 1942, 1723,
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δ
1651, 1342, 1156, 824, 554 cmꢀ1; HRMS (FAB) m/z: [M + H]+ Calcd for C13H15INO2 344.0147;
Found 344.0145.
tert-Butyl 3-(4-(trifluoromethyl)phenyl)-2H-azirine-2-carboxylate (2i): Yield: 85.5 mg (25%);
1
Rf = 0.6 (EtOAc:Hexane = 1:5); Ivory oil; H NMR (400 MHz, CDCl3)
δ
8.02 (d, J = 8.0 Hz, 2H),
170.4,
7.85 (d, J = 8.1 Hz, 2H), 2.84 (s, 1H), 1.47 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
159.1, 135.3(q, J = 33.1 Hz), 130.6, 126.5(q, J = 3.7 Hz), 126.2, 122.1(t, J = 272.9 Hz), 82.2, 31.2,
28.2; IR (film) 2982, 2936, 1867, 1725, 1636, 1328, 1132, 1064, 847 cmꢀ1; HRMS (FAB) m/z: [M +
H]+ Calcd for C14H15F3NO2 286.1055; Found 286.1053.
tert-Butyl 3-(4-cyanophenyl)-2H-azirine-2-carboxylate (2j): Yield: 502 mg (34%); Rf = 0.4
o
(EtOAc:Hexane = 1:10); White solid; Melting point: 94ꢀ96 C; 1H NMR (400 MHz, CDCl3)
δ 8.01
(d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 2.86 (s, 1H), 1.48 (s, 1H) ; 13C{1H} NMR (100 MHz,
CDCl3) 170.1, 159.1, 133.1, 130.6, 126.8, 117.7, 117.1, 82.3, 31.4, 28.1; IR (film) 2979, 2232,
δ
1722, 1347, 1157, 845, 566 cmꢀ1; HRMS (FAB) m/z: [M + H]+ Calcd for C14H15N2O2 243.1134;
Found 243.1136.
General procedure for azirines ester15
To a solution of NH2OH·HCl (2.0 equiv) in pyridine (12.0 equiv) was added βꢀketoester (1.0 equiv)
dropwise. The solution was stirred for 1ꢀ20 h and the solvent was removed under reduced pressure.
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The residue was extracted twice with ethyl acetate. The combined organic layers were dried over
MgSO4 and concentrated in vacuo to give ketoxime, which was used for the next step without
purification. To the ketoxime was added TsCl (1.2 equiv) and pyridine (12.0 equiv). The solution
was stirred for 20 h and quenched with saturated aqueous NH4Cl. The mixture was extracted three
times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo.
The crude material was purified by column chromatography using ethyl acetate : hexane (1:4). To a
solution of ketoxime tosylate in DCM was added Et3N dropwise, and the mixture was stirred at
room temperature for 3 h. Upon completion of the reaction as indicated by TLC, the reaction
mixture was quenched with H2O and the layers were separated. The aqueous layer was extracted
with DCM and the combined layers were washed with water and brine, and dried over anhydrous
MgSO4. The crude material was purified by column chromatography using ethyl acetate : hexane
(1:6).
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Butyl 3-methyl-2H-azirine-2-carboxylate (2o): Yield: 1050 mg (83%); Rf = 0.5 (EtOAc:Hexane =
1:5); White Yellow oil; 1H NMR (400 MHz, CDCl3)
1.66ꢀ1.59 (m, 2H), 1.43ꢀ1.34 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 4.18ꢀ4.07 (m, 2H), 2.53 (s, 3H), 2.43 (s, 1H),
δ
172.2, 159.2, 65.0, 30.7, 28.9, 19.1, 13.7, 12.6; IR (film) 2961, 2874, 1909, 1728, 1637, 1337,
1192, 961, 638 cmꢀ1; HRMS (FAB) m/z: [M + H]+ Calcd for C8H14NO2 156.1025; found 156.1026.
General procedure for synthesis of unsubstituted 2H-azirine16
To a stirred solution of ICl (2.2 mmol) in MeCN (4 mL) was added NaN3 (4 mmol) at rt, 1.5 h later,
the reaction mixture was cooled to 0℃, a solution of alkene (2 mmol) in MeCN (4 mL) was added.
After 5 h later, the mixture was partitioned between Ether and H2O, the organic phase was separated,
then dried (MgSO4) and concentrated. The crude was dissolved in Et2O (6 mL), KOtBu (3.1 mmol)
was added. The reaction was stirred for 5 h at rt, then partitioned between ethyl acetate and H2O,
the organic phase was separated, then dried (MgSO4) and concentrated. The solvent was removed in
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vacuo, and the resulting crude materials were purified by silicagel flash column chromatography
(eluant : hexane) to give the corresponding vinyl azide. To a solution of vinyl azide (3 mmol) in
toluene was heated in reflux and until completion was showed by TLC. The reaction was allowed to
cool to room temperature and toluene was evaporated. The crude residue was purified by flash
column chromatography (in pentane) to give 2Hꢀazirine.
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General procedure for unsymmetrical azirines17
The mixture of ketone (1.0 equiv), NH2OH·HCl (1.5 equiv) and sodium acetate were dissolved in
MeOH/H2O (20:1) at room temperature and monitored by TLC. After the reaction completed, the
solution was sequentially washed with sat. NaHCO3 and brine. The organic layer was dried over
MgSO4. Concentration led to the oxime which was used directly for the next step. Triethylamine
(1.5 equiv) and methanesulfonyl chloride (1.5 equiv) was added sequentially to the solution of
o
oxime (1 equiv) in dry THF at rt or 0 C. The solution got cloudy after the addition of
methanesulfonyl chloride. Then, the resulting mixture was stirred for 30 min and DBU (1.5 equiv)
was added over 10 min. After stirring for additional 30 min, the reaction mixture was passed
through a pad of silica gel and washed with ethyl acetate. The mixture was concentrated in vacuo
and the resulting residue was purified by column chromatography on silica gel to give the
unsymmetrical azirines.
2-(4-bromophenyl)-3-phenyl-2H-azirine (3k): Yield: 1401 mg (58%); Rf = 0.4 (EA:Hexane =
o
1
1:10); White solid; Melting point: 43ꢀ45 C; H NMR (400 MHz, CDCl3)
δ 7.89ꢀ7.87 (m, 2H),
7.63ꢀ7.53 (m, 3H), 7.41ꢀ7.38 (m, 2H), 7.03ꢀ7.00 (m, 2H), 3.28 (s, 1H) ; 13C{1H} NMR (100 MHz,
CDCl3)
δ 163.4, 140.1, 133.5, 131.5, 130.0, 129.5, 127.8, 123.8, 121.0, 34.0; IR (film) 2987, 1896,
1743, 1487, 1069, 759, 519 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C14H1079BrN 270.9997,
C14H1081BrN 272.9977; Found 270.9999, 272.9993.
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Synthetic procedure of diazoindoloimines18
3
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7
To an ovenꢀdried 10 mL Schlenk tube equipped with a magnetic stirring bar were added
sequentially indole (0.25 mmol), sulfonyl azide (0.5 mmol), and DMSO (0.5 mL). The reaction
8
9
o
mixture was stirred at 50 C for 12 h. Then, the reaction was quenched by H2O (10 mL) and
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extracted with CH2Cl2 (15 mL × 3). The combined organic layers were dried over anhydrous
MgSO4 and concentrate+d in vacuo. The crude product was purified by column chromatography on
silica gel (petroleum ether : EtOAc = 3:1).
Synthetic procedure of indolopyrazines
To a test tube were added 3ꢀdiazoindolinꢀ2ꢀimines (1) (2.0 equiv, 0.4 mmol), azirines (2) (1.0 equiv,
0.2 mmol), and [Rh2(oct)4]2 (4.0 mol %) in DCE (1.0 mL). The resulting mixture was stirred at 80
oC for 2 h under nitrogen after 2 h, Et3N (1.5 equiv) was added in oneꢀpot, and the solution was
stirred at 80 °C for 2 h. The mixture was cooled to room temperature, filtered through a pad of
Celite, and concentrated under reduced pressure. The residue was then purified by flash column
chromatography to give indolopyrazines 4.
Ethyl 5-methyl-2-(4-nitrophenyl)-4-tosyl-4,5-dihydro-3H-pyrazino[2,3-b]indole-3-carboxylate
(3a): Yield: 67 mg (63%); Rf = 0.3 (DCM:Hexane = 2:1); Red solid; Melting point: 134ꢀ136 oC; 1H
NMR (400 MHz, CDCl3)
δ 8.22 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 7.8 Hz,
1H), 7.45 (d, J = 8.3 Hz, 1H), 7.39ꢀ7.35 (m, 1H), 7.28ꢀ7.25 (m, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.79
(d, J = 8.0 Hz, 2H), 5.98 (s, 1H), 4.12ꢀ4.08 (m, 1H), 4.02 (s, 3H), 4.00ꢀ3.95 (m, 1H), 2.20(s, 3H),
1.06 (t, J = 7.1 Hz, 3H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 165.9, 148.0, 145.6, 144.9, 142.2,
136.0, 133.1, 129.4, 127.6, 126.8, 125.5, 123.7, 123.5, 122.2, 121.7, 120.4, 118.5, 110.4, 62.9, 58.2,
31.4, 21.6, 14.0; IR (film) 2985, 2941, 1843, 1750, 1645, 1342, 1170, 747 cmꢀ1; HRMS (EI) m/z:
[M]+ Calcd for C27H24N4O6S 532.1417; Found 532.1414.
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tert-Butyl
5-methyl-2-(4-nitrophenyl)-4-tosyl-4,5-dihydro-3H-pyrazino[2,3-b]Indole-3-
3
4
5
6
carboxylate (3b): Yield: 78 mg (99%); Rf = 0.3 (DCM:Hexane = 2:1); Red solid; Melting point:
265ꢀ267 oC; 1H NMR (400 MHz, CDCl3)
δ
8.21 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.80
7
8
9
(d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.28ꢀ7.24 (m, 1H), 7.08 (d, J
= 8.1 Hz, 2H), 6.78 (d, J = 8.2 Hz, 2H), 5.88 (s, 1H), 4.03 (s, 3H), 2.20(s, 3H), 1.20 (s, 9H) ;
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13C{1H} NMR (100 MHz, CDCl3)
δ 164.4, 147.8, 145.5, 145.4,142.3, 135.9, 133.2, 129.3, 127.7,
126.8, 125.6, 123.5, 123.3, 122.1, 121.6, 120.2, 118.4, 110.3, 84.4, 58.6, 31.4, 27.8, 21.6; IR (film)
2924, 1852, 1626, 1598, 1169, 1143, 1010, 812 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C29H28N4O6S
560.1730; Found 560.1726.
Ethyl 5-methyl-2-(4-nitrophenyl)-5H-pyrazino[2,3-b]indole-3-carboxylate (4a): Yield: 59.5 mg
o
1
(79%); Rf = 0.2 (DCM:Hexane = 2:1); White Yellow solid; Melting point: 190ꢀ192 C; H NMR
(400 MHz, CDCl3) 8.43 (d, J = 7.8 Hz, 1H), 8.37ꢀ8.34 (m, 2H), 7.89ꢀ7.85 (m, 2H), 7.77ꢀ7.73 (m,
δ
1H), 7.57 (d, J = 8.3 Hz, 1H), 7.46ꢀ7.42 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 1.19 (t, J
= 7.1 Hz, 3H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
167.1, 147.8, 145.8, 143.8, 143.6, 143.6, 139.6,
137.1, 130.9, 130.1, 123.6, 122.7, 121.8, 119.1, 110.0, 62.4, 28.1, 13.9; IR (film) 2978, 2936, 1730,
1517, 1345, 1330, 1190, 749 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C20H16N4O4 376.1172; Found
376.1174.
tert-Butyl 5-methyl-2-(4-nitrophenyl)-5H-pyrazino[2,3-b]indole-3-carboxylate (4b): Yield: 78
mg (96%); Rf = 0.2 (DCM:Hexane = 2:1); Yellow solid; Melting point: 188ꢀ190 C; 1H NMR (400
o
MHz, CDCl3)
δ 8.41 (d, J = 7.9 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.73 (d,
J = 7.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 4.05 (s, 3H), 1.40 (s, 9H) ;
13C{1H} NMR (100 MHz, CDCl3)
δ
166.1, 147.8, 146.3, 143.8, 143.6, 143.3, 141.0, 136.7, 130.6,
130.3, 123.6, 122.6, 121.7, 119.2, 110.0, 83.6, 28.1, 27.8; IR (film) 2977, 2933, 1730, 1519, 1144,
846, 749 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C22H20N4O4 404.1485; Found 404.1484.
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Ethyl 5-methyl-2-phenyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4c): Yield: 26.5 mg (40%); Rf
3
4
o
= 0.2 (DCM:Hexane = 2:1); Brown solid; Melting point: 134ꢀ136 C; 1H NMR (400 MHz, CDCl3)
5
6
7
δ
8.43 (d, J = 7.8 Hz, 1H), 7.71ꢀ7.67 (m, 3H), 7.54ꢀ7.44 (m, 4H), 7.41ꢀ7.37 (m, 1H), 4.26 (q, J = 7.1
Hz, 2H), 4.01 (s, 3H), 1.09 (s, 3H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
167.9, 146.0, 143.5, 143.3,
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139.9, 139.3, 136.8, 130.3, 129.1, 128.5, 122.6, 121.3, 119.4, 109.8, 62.1, 28.0, 13.8; IR (film) 2938,
2792, 1853, 1728, 1631, 1187, 778 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C20H17N3O2 331.1321;
Found 331.1319.
tert-Butyl 5-methyl-2-phenyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4d): Yield: 59.6 mg
(83%); Rf = 0.3 (DCM:Hexane = 2:1); Yellow solid; Melting point: 165ꢀ167 oC; 1H NMR (400 MHz,
CDCl3)
δ 8.41 (d, J = 7.8 Hz, 1H), 7.69ꢀ7.65 (m, 3H), 7.52ꢀ7.45 (m, 4H), 7.39ꢀ7.35 (m, 1H), 4.01 (s,
3H), 1.35 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
166.8, 145.9, 143.4, 143.3, 141.0, 139.7,
136.3, 130.0, 129.3, 128.4, 128.3, 122.5, 121.2, 119.4, 109.7, 83.0, 28.0, 27.7; IR (film) 2672, 2641,
1861, 1723, 1641, 1144, 832 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C22H21N3O2 359.1634; Found
359.1636.
tert-Butyl 5-methyl-2-(m-tolyl)-5H-pyrazino[2,3-b]indole-3-carboxylate (4e): Yield: 48.5 mg
o
1
(65%); Rf = 0.2 (DCM:Hexane = 2:1); White Yellow solid; Melting point: 148ꢀ150 C; H NMR
(400 MHz, CDCl3)
δ 8.42 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 8.2 Hz, 1H), 7.52ꢀ7.46 (m, 3H), 7.37 (t, J
= 7.56 Hz, 2H), 7.27ꢀ7.25 (m, 1H), 4.01 (s, 3H), 2.44 (s, 3H), 1.36 (s, 9H) ; 13C{1H} NMR (100
MHz, CDCl3)
δ 166.9, 146.1, 143.4, 143.3, 141.1, 139.6, 137.9, 136.3, 130.0, 129.1, 128.4, 126.5,
122.5, 121.2, 119.5, 109.7, 82.9, 28.0, 27.7, 21.6; IR (film) 2670, 2629, 1889, 1637, 1141, 780, 687
cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C23H23N3O2 373.1790; Found 373.1792.
tert-Butyl 2-(2-chlorophenyl)-5-methyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4f): Yield:
o
1
55.8 mg (71%); Rf = 0.3 (DCM:Hexane = 2:1); Red solid; Melting point: 177ꢀ179 C; H NMR
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(400 MHz, CDCl3)
δ
8.41 (d, J = 7.8 Hz, 1H), 7.70ꢀ7.66 (m, 1H), 7.53ꢀ7.48 (m, 3H), 7.43ꢀ7.35 (m,
3
4
5
3H), 4.04 (s, 3H), 1.29 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 165.2, 144.6, 143.9, 143.5,
6
7
8
9
140.4, 139.7, 136.6, 133.8, 131.3, 130.4, 129.5, 129.3, 126.9, 122.6, 121.3, 119.1, 109.8, 82.6, 28.0,
27.6; IR (film) 3068, 2977, 1828, 1725, 1445, 1147, 740 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C22H20ClN3O2 393.1244; Found 393.1241.
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tert-Butyl 2-(4-chlorophenyl)-5-methyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4g): Yield:
o
62.9 mg (80%); Rf = 0.3 (DCM:Hexane = 2:1); Yellow solid; Melting point: 149ꢀ151 C; 1H NMR
(400 MHz, CDCl3)
δ 8.37 (d, J = 7.8 Hz, 1H), 7.67ꢀ7.61 (m, 3H), 7.49ꢀ7.45 (m, 3H), 7.38ꢀ7.34 (m,
1H), 3.98 (s, 3H), 1.40 (s, 1H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
166.5, 144.4, 143.4, 143.3,
140.8, 138.2, 136.3, 134.5, 130.6, 130.1, 128.5, 122.4, 121.3, 119.2, 109.7, 83.2, 28.0, 27.8; IR
(film) 3059, 2977, 1845, 1725, 1450, 1144, 850, 740 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C22H20ClN3O2 393.1244; Found 393.1244.
tert-Butyl 2-(4-iodophenyl)-5-methyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4h): Yield: 80.5
o
1
mg (83%); Rf = 0.3 (DCM:Hexane = 2:1); Pink solid; Melting point: 175ꢀ177 C; H NMR (400
MHz, CDCl3)
δ 8.35 (d, J = 7.8 Hz, 1H), 7.84ꢀ7.81 (m, 2H), 7.65ꢀ7.61 (m, 1H), 7.46ꢀ7.42 (m, 3H),
7.35 (t, J = 7.5 Hz, 1H), 3.96 (s, 3H), 1.40 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
166.4,
144.5, 143.3, 143.2, 140.7, 139.2, 137.4, 136.3, 131.1, 130.1, 122.3, 121.2, 119.1, 109.6, 94.3, 83.1,
27.9, 27.7; IR (film) 2977, 1844, 1717, 1636, 1143, 785, 603 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C22H20IN3O2 485.0600; Found 485.0603.
tert-Butyl
5-methyl-2-(4-(trifluoromethyl)phenyl)-5H-pyrazino[2,3-b]indole-3-carboxylate
(4i): Yield: 64.1 mg (75%); Rf = 0.2 (DCM:Hexane = 2:1); White Yellow solid; Melting point: 194ꢀ
196 oC; 1H NMR (400 MHz, CDCl3)
δ
8.40 (d, J = 7.7 Hz, 1H), 7.78 (t, J = 8.9 Hz, 4H), 7.72ꢀ7.68
(m, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 4.02 (s, 3H), 1.36 (s, 9H) ; 13C{1H}
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NMR (100 MHz, CDCl3)
δ
166.3, 144.4, 143.7, 143.5, 143.5, 140.9, 136.5, 130.4 (q, J = 32.5 Hz),
3
4
5
6
7
8
9
130.4, 129.7, 124.4 (q, J = 272.2 Hz), 125.3 (q, J = 3.7 Hz), 122.5, 121.5, 119.3, 109.8, 83.3, 28.0,
27.7; IR (film) 1853, 1833, 1640, 1475, 1145, 772, 631 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C23H20 F3N3O2 427.1508; Found 427.1511.
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tert-Butyl 2-(4-cyanophenyl)-5-methyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4j): Yield:
o
68.43 mg (89%); Rf = 0.2 (DCM:Hexane = 2:1); Yellow solid; Melting point: 221ꢀ223 C; 1H NMR
(400 MHz, CDCl3)
δ 8.40 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 1.8 Hz, 4H), 7.74ꢀ7.70 (m, 1H), 7.55 (d,
J = 8.3 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 4.03 (s, 3H), 1.39 (s, 9H) ; 13C{1H} NMR (100 MHz,
CDCl3)
δ 166.1, 144.4, 143.7, 143.6, 140.8, 136.6, 132.1, 130.6, 130.1, 122.6, 121.6, 119.2, 119.0,
112.0, 109.9, 83.5, 28.1, 27.8; IR (film) 2933, 2227, 1725, 1397, 1144, 749, 557 cmꢀ1; HRMS (EI)
m/z: [M]+ Calcd for C23H20N4O2 384.1586; Found 384.1589.
Ethyl 5-methyl-2-(naphthalen-2-yl)-5H-pyrazino[2,3-b]indole-3-carboxylate (4k): Yield: 32 mg
(42%); Rf = 0.3 (DCM:Hexane = 2:1); Green solid; Melting point: 109ꢀ111 oC; 1H NMR (400 MHz,
CDCl3)
δ 8.46 (d, J = 7.8 Hz, 1H), 8.17 (s, 1H), 7.97ꢀ7.89 (m, 3H), 7.85ꢀ7.83 (m, 1H), 7.72ꢀ7.68
(m, 1H), 7.54ꢀ7.50 (m, 3H), 7.41 (t, J = 7.5 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.01 (t, J
= 7.1 Hz, 3H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
167.9, 145.7, 143.4, 143.2, 140.0, 136.8, 136.5,
133.3, 133.2, 130.2, 128.4, 128.3, 128.1, 127.7, 126.7, 126.4, 126.3, 122.6, 121.3, 119.3, 109.7,
62.0, 27.9, 13.7; IR (film) 2981, 2936, 1728, 1624, 1473, 1398, 1187, 1143, 746 cmꢀ1; HRMS (EI)
m/z: [M]+ Calcd for C24H19N3O2 381.1477; Found 381.1479.
tert-Butyl 5-methyl-2-(naphthalen-2-yl)-5H-pyrazino[2,3-b]indole-3-carboxylate (4l): Yield:
71.2 mg (87%); Rf = 0.3 (DCM:Hexane = 2:1); White Yellow solid; Melting point: 191ꢀ193 oC; 1H
NMR (400 MHz, CDCl3)
δ 8.42 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.91ꢀ
7.87 (m, 3H), 7.66ꢀ7.62 (m, 1H), 7.51 (q, J = 3.2 Hz, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.38ꢀ7.34 (m,
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1H), 3.99 (s, 3H), 1.27 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 166.9, 145.7, 143.4, 143.2,
3
4
5
6
7
8
9
140.0, 136.8, 136.5, 133.3, 133.2, 130.2, 128.4, 128.3, 128.1, 127.7, 126.7, 126.4, 126.3, 122.6,
121.3, 119.3, 109.7, 62.0, 27.9, 13.7; IR (film) 2263, 2629, 1883, 1834, 1642, 1141, 772 cmꢀ1;
HRMS (EI) m/z: [M]+ Calcd for C26H23N3O2 409.1790; Found 409.1787.
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tert-Butyl 2-(furan-2-yl)-5-methyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4m): Yield: 44.7
o
mg (64%); Rf = 0.2 (DCM:Hexane = 2:1); Brown solid; Melting point: 155ꢀ157 C; 1H NMR (400
MHz, CDCl3)
δ 8.42 (d, J = 7.8 Hz, 1H), 7.69ꢀ7.65 (m, 1H), 7.57ꢀ7.57 (m, 1H), 7.50 (d, J = 8.2
Hz, 1H), 7.41ꢀ7.37 (m, 1H), 7.06 (dd, J = 1.4 Hz, 1H), 6.59 (q, J = 1.7 Hz, 1H), 3.98 (s, 3H), 1.62 (s,
9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
166.6, 152.2, 143.2, 143.1, 140.2, 136.0, 134.7, 130.0,
122.5, 121.3, 119.3, 112.1, 109.7, 109.7, 109.7, 83.3, 28.1, 28.0; IR (film) 2978, 2936, 1861, 1725,
1625, 1157, 738 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C20H19N3O3 349.1426; Found 349.1428.
tert-Butyl 5-methyl-2-(thiophen-2-yl)-5H-pyrazino[2,3-b]indole-3-carboxylate (4n): Yield: 48.2
mg (66%); Rf = 0.3 (DCM:Hexane = 2:1); White Yellow solid; Melting point: 144ꢀ146 oC; 1H NMR
(400 MHz, CDCl3)
δ 8.37 (d, J = 7.8 Hz, 1H), 7.65ꢀ7.61 (m, 1H), 7.48ꢀ7.44 (m, 2H), 7.39ꢀ7.33 (m,
2H), 7.12 (q, J = 2.9 Hz, 1H), 3.95 (s, 3H), 1.52 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ
166.9, 143.2, 143.1, 141.6, 140.9, 138.2, 136.0, 130.0, 127.6, 127.4, 127.4, 122.5, 121.3, 119.2,
109.7, 83.4, 28.0, 27.9; IR (film) 2979, 2936, 1771, 1720, 1645, 1263, 1128, 953 cmꢀ1; HRMS (EI)
m/z: [M]+ Calcd for C20H19N3O2S 365.1198; Found 365.1201.
Butyl 2,5-dimethyl-5H-pyrazino[2,3-b]indole-3-carboxylate (4o): Yield: 42.2 mg (71%); Rf = 0.3
(DCM:Hexane = 2:1); White Yellow solid; Melting point: 117ꢀ119 oC; 1H NMR (400 MHz, CDCl3)
δ
8.39 (d, J = 7.8 Hz, 1H), 7.70ꢀ7.66 (m, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H),
4.47 (t, J = 6.8 Hz, 1H), 3.97 (s, 1H), 2.97 (s, 1H), 1.89ꢀ1.82 (m, 2H), 1.58ꢀ1.49 (m, 2H), 1.02 (t,
J = 7.4 Hz, 3H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 167.1, 145.9, 143.6, 143.3, 138.2, 137.1,
29
ACS Paragon Plus Environment