Synthesis of Fused-Pyrazines via Palladium-Catalyzed Double Benzyl Isocyanide Insertion and Cross-Dehydrogenative Coupling

Article abstract of DOI:10.1002/adsc.201701202

A palladium-catalyzed cascade reaction has been realized for the synthesis of 5H-pyrrolo[2,3-b]pyrazines and 5H-pyrazino[2,3-b]indoles from benzyl isocyanide by choosing o-pivaloyloximes or o-iodoanilines as a suitable substrate. The key steps involved are (i) oxidative addition of palladium through N–O or C–I cleavage; (ii) migratory double isocyanide insertion; and (iii) cross-dehydrogenative coupling. Notable features are good functional group tolerance as well as formation of three C–C and one C–N bonds. (Figure presented.).

Full text of DOI:10.1002/adsc.201701202

Title: Synthesis of Fused-Pyrazines via Palladium-Catalyzed Double
Benzyl Isocyanide Insertion and Cross-Dehydrogenative
Coupling
Authors: Gopal Chandru Senadi, Bing-Chun Guo, Yu-Ching Chang,
Wan-Ping Hu, and Jeh-Jeng Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701202
Link to VoR: http://dx.doi.org/10.1002/adsc.201701202

10.1002/adsc.201701202
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Fused-Pyrazines via Palladium-Catalyzed Double
Benzyl Isocyanide Insertion and Cross-Dehydrogenative
Coupling
Gopal Chandru Senadi,a Bing-Chun Guo,a Yu-Ching Chang,a Wan-Ping Hub and Jeh-
Jeng Wanga,c*
a
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shiquan 1st Rd, Sanmin
District, Kaohsiung City, 807, Taiwan. Phone: (886)-7-312-1101 Extn. 2275. Email: jjwang@kmu.edu.tw
Department of Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd, Sanmin District, Kaohsiung
b
City, 807, Taiwan.
c
Department of Medical Research, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Rd, Sanmin District,
Kaohsiung City, 807, Taiwan.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A palladium-catalyzed cascade reaction has been palladium through N-O or C-I cleavage; (ii) migratory
realized for the synthesis of 5H-pyrrolo[2,3-b]pyrazines and double isocyanide insertion; and (iii) cross-dehydrogenative
5H-pyrazino[2,3-b]indoles with benzyl isocyanide by coupling. Notable features are good functional group
choosing o-pivaloyloximes or o-iodoanilines as a suitable tolerance, formation of three C-C and one C-N bonds.
substrate. The key steps involved are (i) oxidative addition of
Keywords: Palladium; Benzyl isocyanide; Fused-
Pyrazines; CDC; Catalysis
suitable design in the starting materials and reaction
Introduction
conditions.[4]
In 1981, Vierfond et al developed the synthesis
5H-pyrrolo [2,3-b]pyrazines also known as aloisines of 5H-pyrrolo[2,3-b]pyrazines from methylpyrazines
are important class of N-heterocycles with versatile with aromatic nitriles through a sequence of lithiation,
biological properties. For examples, they are used as condensation and intramolecular cyclization (Scheme
II[3a]
CDKs,[1a,b,d,e] GSK,[1a,c,d] JAK,[2a] Syk,[2b] Topo
1a).[5] In 2004, Hopkins et al developed a palladium-
inhibitors and also as multi-target antimalarial catalyzed heteroannulation process from readily
agents[3b] (Figure 1). Despite its potential bioactivity, accessible
N-(3-chloropyrazin-2-yl)-methane
only a few synthetic strategies have been identified in sulfonamide and commercially available terminal
the literature so far probably due to the lack of
alkynes (Scheme 1b).[6] In 2006, Kasatkin et al
developed two-step process from 2,3-
a
dichloropyrazine with lithiated ketones/esters and
nitriles followed by cyclization with primary amines
(Scheme 1c).[7] In 2012, Keivanloo et al improved the
yield of aloisines by modifying the conditions of
Hopkins using the combination of Pd-Cu in the
presence of SDS surfactant in the water.[8] Recently,
in 2016, Scheidt et al disclosed couple of examples
through an interception of a reactive aza ortho-
azaquinone methide intermediate by an acyl anion
equivalent generated through carbene catalysis
(Scheme 1d).[9]
In spite of these useful methods, some of them
suffer from low yields, limited substrate scopes,
difficult to synthesize starting material and hazardous
reagents. Thus, the development of new synthetic
routes for highly functionalized pyrrolopyrazines is
highly desirable to explore its versatile properties.
Figure 1. Representative examples of bioactive
pyrrolopyrazines
1
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10.1002/adsc.201701202
Advanced Synthesis & Catalysis
Pd(II) with reducing agents also resulted in low yields
(Table 1, entries 10-15) except Pd(dba)2 which
afforded 40% yield of 3aa (Table 1, entry 11). The
effect of solvent was investigated with CH3CN, 1,4-
dioxane, THF, MeOH, DMSO and PhCl (Table 1,
entries 16-21). However, none of them gave better
yield than toluene (Table 1, entry 2). Thus, of the
reaction conditions screened in Table 1, entry 2 was
chosen as the optimum conditions.
Table 1. Screening of the reactions conditionsa)
Catalyst
(mol %)
Yield
(%)b)
Entry
Base
Solvent
1c)
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd(dba)2
DBU
DBU
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
40
50
DABCO
pyridine
Cs2CO3
Na2CO3
NaOAc
K2CO3
CsF
<10
<10
<10
trace
trace
trace
trace
24
Scheme 1. Previous reports and this work fused-pyrazines
Isocyanides are important synthetic precursors in
the synthesis of aza-heterocycles.[10] Among them, -
carbon of the benzyl isocyanides have been recently
involved in synthesis of heterocycles such as
10
11
DBU
DBU
40
oxazoles,[11a]
imidazoles,[11b]
pyrroles[11c]
and
Pd(OAc)2/
PPh3
PdCl2(PPh3)
2/PPh3
PdCl2/PPh3
PdI2/PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
12d)
DBU
DBU
Toluene
Toluene
20
30
imidazo[1,5-a]pyridines[11d] with the aid of intrinsic
-acidity under basic conditions. In this context and
our experience on isocyanides chemistry,[12] herein,
we disclosed the synthesis of pyrrolopyrazines
13d)
14 d)
15 d)
16
17
18
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Toluene
Toluene
CH3CN
Dioxane
THF
MeOH
DMSO
PhCl
31
35
20
22
<10
0
through a sequence of
N-O cleavage, double
isocyanide insertion and cross-dehydrogenative
coupling[13] with o-pivaloyl oximes and benzyl
isocyanide under palladium-catalysis (Scheme 1e).
On the other hand, replacing the o-pivaloyl oximes
with o-iodoanilines under the identical conditions
gave the 5H-pyrazino[2,3-b]indoles (Scheme 1f).
19
20e)
21e)
20
22
a)
Reaction conditions: 1a (0.5 mmol), 2a (1.05 mmol),
catalyst (5.0 mol %), base (1.1 mmol) and solvent (0.5 M)
b)
was stirred at reflux for 24 h unless otherwise noted.
Results and Discussion
c)
Yield of isolated product. Reaction was performed with
(E)-1-phenylethan-1-one O-acetyl oxime. 20 mol % of
d)
The systematic investigation of our methodology
e)
began with (E)-1-phenylethan-1-one O-acetyl oxime triphenylphosphine was used.
and benzyl isocyanide 2a using our recently published at 120 °C.
catalytic condition for the synthesis of 2H-pyrrolo-2-
Reaction was carried out
imines using oximes acetates and isocyanide[12b] as
shown in Table 1. To our surprise the desired
compound 3aa was obtained in 40% yield (Table 1,
With the optimized conditions in hand, the scope
and limitations of oximes 1a-t with benzyl isocyanide
entry 1) with its structure confirmed by x-ray analysis 2a has been investigated as shown in Scheme 2. The
(Figure 2).[14] Subsequent reaction by changing acetyl scope of R- functionalities with aryl group containing
oxime to (E)-1-phenylethan-1-one O-pivaloyl oxime various electron-donating and electron-withdrawing
1a with benzyl isocyanide 2a in the presence of 5 groups at o-/m-/p- positions like m-Me-Ph (1b), p-
Me-Ph (1c), 4-MeO-Ph (1d), 3,4-di-MeO-Ph (1e),
3,5-di-MeO-Ph (1f), o-F-Ph (1g), m-F-Ph (1h), p-F-
mol% of Pd(PPh3)4, 2.2 equiv of 1,8-
diazabicyclo(5.4.0)undec-7-ene in toluene at reflux
for 24
h
gave 2,3,6-triphenyl-5H-pyrrolo[2,3- Ph (1i), o-Cl-Ph (1j), p-Cl-Ph (1k), 2,4-di-Cl-Ph (1l),
b]pyrazine 3aa in 50% yield (Table 1, entry 2). p-Br-Ph (1m), and p-CN-Ph (1o) worked well to
Changing the base from DBU to other organic and afford the desired alosines 3aa-ma, oa in 29%-69%
inorganic bases failed to improve the reaction yields yields respectively. However, the reaction gave traces
of 3na along with some other unidentified spots when
(Table 1, entries 3-9). On the other hand Pd(0) and
2
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10.1002/adsc.201701202
Advanced Synthesis & Catalysis
performed with p-I-Ph (1n). The probable reason tetralone (1v) under the standard condition of Table 2.
could be the competitive oxidation addition of iodo The reaction proceeded smoothly to produce the
functionality with Pd(PPh3)4 and leading to complex desired compounds 3ua-va in 52%-55% yields. The
mixture. Subsequently, the scope was evaluated by reaction failed to afford the desired compounds 3ab
replacing aryl functionalilty with heteroaryl groups and 3ac when benzyl isocyanide 2a was replaced by
such as 2-furyl (1p), 2-thiophenyl (1q) and 3-pyridyl TOSMIC 2b as well as ethyl isocyanoacetate 2c. The
(1r). Interestingly, the reaction worked well to afford reason may be high acidity of the -proton leading to
the desired heteroaryl derivatives 3pa-ra in 45%-60% some other transformation under basic conditions.
yields. The reaction also underwent smooth
To understand the preliminary reaction
conversion by changing the R1- functionalities with mechanism few control experiments were carried out
methyl (1s) and phenyl (1t) to afford compounds 3sa- as presented in Scheme 3. Recently, we disclosed that
ta in 48%-79% yields.
In general, reactions oximes can react with isocyanides under palladium
underwent smooth conversion irrespective of catalysis to form 2H-pyrrolo-2-imines.[12b] From this
electronic and steric factors to afford the desired stand point, we carried out reaction with (E)-1-
alosines 3aa-ta in moderate yields. We next evaluated phenylethan-1-one O-pivaloyl oxime 1a and benzyl
the feasibility of the reaction with tetralone (1u) and isocyanide under the standard condition of Table 2 for
6-methoxy-
2 h and examined the formation of 2H-pyrrolo-2,3-
diimine 3aa’ (Scheme 3a). Unfortunately, the desired
Scheme 2. Scope and limitations of oximes with 3aa’ could not be isolated due to the purification and
isocyanidesa),b)
stability difficulties, when the reaction was continued
for longer time the ratio of 3aa was predominant with
traces of 3aa’. By changing the substrate from 1a to
1g also ended in the same problem (Scheme 3b).
In recent past, we also developed the synthesis of
isatins from o-iodo anilines through double
isocyanide insertion via the formation of 3H-indolo-3-
imines.[12d,15] Herein, we used this strategy to
synthesize (E)-N-benzyl-3-(benzylimino)-3H-indol-2-
amine 4aa’ with o-iodo anilines 4a and benzyl
isocyanide 2a under the standard condition of Table 2
for 2 h. The desired intermediate 4aa’ was formed as
a major yellow spot by TLC (Scheme 3c). When this
intermediate was subjected to column purification, we
couldn’t able to isolate 4aa’ rather the conversion of
4aa’ to 6aa was noticed in the aerobic atmosphere. At
the same time, when the reaction was continued for
longer time (~24 h), the intermediate was completely
disappeared to afford 2,3-diphenyl-5H-pyrazino[2,3-
b]indole 5aa as minor product along with 3-benzyl-2-
phenyl-3,4-dihydroimidazo[4,5-b]indole (6aa)
as
major product (Scheme 3d). The structure of
compounds 5aa and 6aa were confirmed by X-ray
analysis (Figure 2).[14]
a)
Scheme 3. Preliminary mechanistic studies
Reaction conditions: 1a-t (0.5 mmol), 2a-c (1.05 mmol),
Pd(PPh3)4 (5.0 mol %), DBU (1.1 mmol) and Toluene (0.5
M) was stirred at reflux for indicated time unless otherwise
noted. Yield of isolated product. Trace refers to no
product isolation.
b)
c)
From these control experiments, we could
rationalize that the regioselective formation of 3 could
3
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10.1002/adsc.201701202
Advanced Synthesis & Catalysis
be due to selective exo (benzylic) isomerization. p-CN-Ph (5ja) and traces of product with m-Me-Ph
Whereas in the case of o-iodoaniline as a substrate, (5ka).
we observed a moderate regioselectivity, this may be
attributed to endo as well as exo isomerization. The Schemes 5 and 6 based on the preliminary
major endo isomerization product observed was due mechanistic studies/previous literature
A plausible reaction mechanism is proposed on
to [1,3-H] proton shift from more acidic nitrogen reports.[12,13,15,17] Oxidative addition of O-pivaloyl
atom. To elucidate our hypothesis, we next focused oximes 1 to Pd(0) would afford the N-O cleaved
on the reaction of N-substituted-o-iodoanilines as intermediate A.[12b] Tautomerization of intermediate A
presented in Scheme 4 under the standard condition of will result in the formation of enamine-derived
Table 2. Interestingly, we observed the regioselective palladium (II) species B.[12b] Migratory double
formation of 5H-pyrazino[2,3-b]indole[16a] derivatives isocyanide insertion of B will produce the imidoyl
through exo (benzylic) isomerization. This high intermediate D.[12b] Base mediated cyclization of
selective could be attributed to the absence of acidic intermediate D will generate the 6-membered
nitrogen atom. The reaction worked well with various palladacycle E.[12b] Reductive elimination of E would
R2-functionalities having electron-donating as well as afford the key intermediate 3’. Furthermore,
withdrawing groups such as p-Me-Ph (5ca), p-tert- intermediate 3’ can undergo carbon-carbon rotation
butyl-Ph (5da), o-MeO-Ph (5ea) and m-CN-Ph (5ea) followed by exo-isomerization rather than endo
derivatives in 45%-68% yields. In addition, the isomerization to get intermediate G. Base promoted
reaction also underwent smooth conversion with cyclization of compound G results in intermediate H.
naphthyl functionality (5ga). On the other hand, the Isomerization of H would generate the more stable
reaction proceeded well with o-iodoaniline pyrrole ring intermediate I. Finally, oxidation of
derivatives such as p-Me-Ph (5ha) and p-F-Ph (5ia) intermediate I would produce the alosine derivatives
in moderate to good yields. Unfortunately, the 3 via the formation of pyrazine ring (Scheme 5).
reaction failed to provide the desired compound with
Scheme 4. Scope and limitations of 5H-pyrazino[2,3-
b]indole derivatives a),b)
Scheme 5. Plausible reaction mechanism for 5H-
pyrrolo[2,3-b]pyrazines
A similar mechanism was proposed for the
formation of 5H-pyrrolo[2,3-b]indoles and 3-benzyl-
2-phenyl-3,4-dihydroimidazo[4,5-b]indole as shown
in Scheme 6. Oxidative addition of o-iodo aniline
derivatives 4 to palladium (0) would afford the
palladium (II) intermediate J.[12d] Migratory double
isocyanide insertion of intermediate J will produce
the imidoyl intermediate L. Base mediated cyclization
of intermediate L will generate the 6-membered
palladacycle M. Reductive elimination of M would
afford the key intermediate N. Furthermore,
a)
Reaction conditions: 4b-k (0.5 mmol), 2a (1.05 mmol), intermediate N can be transformed into two pathways
Pd(PPh3)4 (5.0 mol %), DBU (1.1 mmol) and Toluene (0.5 depending on the nature of o-iodoanilines 4. In case
M) was stirred at reflux for indicated time unless otherwise of secondary amines, the reaction proceeds via exo
b)
c)
noted. Yield of isolated product. Trace refers to no isomerization intermediate O followed by annulation
product isolation.
intermediate P, isomerization intermediate Q and
oxidation sequence to afford compounds 5aa-ka.
4
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10.1002/adsc.201701202
Advanced Synthesis & Catalysis
Whereas with primary amine the reaction proceeds pyrazino[2,3-b]indoles
when
2-iodo
aniline
via endo isomerization [1,3-H] proton shift from more derivatives was used. The key advantages are broad
acidic nitrogen atom to give intermediate R. functional group tolerance of oximes derivatives and
Intermediate R underwent subsequent transformations construction of two heterocyclic rings from acyclic
such as isomerization/annulation and oxidation to precursors in a cascade way.
afford compound 6aa as major product.
Experimental Section
General Procedure (A) for the Preparation of
Compound 3aa: To an oven dried sealed tube was added
(E)-1-phenylethan-1-one O-pivaloyl oxime 1a (110 mg, 0.5
mmol) in toluene (0.5 M) followed by the sequential
addition of benzyl isocyanide 2a (129 L, 1.05 mmol),
DBU (166 L, 1.1 mmol), and Pd(PPh3)4 (29 mg, 5 mol %).
The reaction mixture was allowed to stir at reflux for
indicated time. After the completion, the reaction mixture
was cooled to room temperature and diluted with 5.0 mL of
water. The water layer was extracted with (3X10 mL) of
ethyl acetate and the combined ethyl acetate layer was
given brine wash (1X10 mL). The final ethyl acetate layer
was dried over sodium sulfate and concentrated under
reduced pressure to get the crude compound. The obtained
crude was purified using column chromatography by
eluting from hexane to 18% ethyl acetate/hexane to afford
pure 2,3,6-triphenyl-5H-pyrrolo[2,3-b]pyrazine (3aa) as a
yellow solid (87 mg, 50%); mp 245-247 °C; 1H NMR (400
MHz, CDCl3) δ 9.71 (s, 1H), 7.65 – 7.61 (m, 2H), 7.48 –
7.36 (m, 7H), 7.31-7.29 (m, 3H), 7.25-7.21 (m, 3H), 7.05
(d, J = 2.1 Hz, 1H); 13C NMR (100 MHz,CDCl3) δ 148.29,
145.95, 143.53, 141.66, 140.30, 139.71, 139.39, 130.93,
130.03, 129.99, 129.24, 128.09, 127.87, 127.67, 125.52,
98.96; HRMS (ESI) calcd for C24H18N3 [M+H]+: 348.1495
found 348.1487.
Scheme 6. Plausible reaction mechanism for 5H-
2,3-diphenyl-6-(m-tolyl)-5H-pyrrolo[2,3-b]pyrazine
pyrrolo[2,3-b]indoles and 3-benzyl-2-phenyl-3,4-
(3ba). Following the general procedure (A) on a 0.5 mmol
dihydroimidazo[4,5-b]indole.
scale giving the desired compound as a light yellow solid
1
(101 mg, 56%); mp 183-185 °C; H NMR (400 MHz,
CDCl3) δ 9.65 (s, 1H), 7.48 – 7.44 (m, 3H), 7.43 – 7.40 (m,
3H), 7.32 – 7.27 (m, 4H), 7.22-7.18 (m, 4H), 7.03 (d, J =
2.0 Hz, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
148.18, 145.85, 143.75, 141.62, 140.34, 139.72, 139.39,
138.94, 130.90, 130.11,130.06, 129.80, 129.13, 128.05,
127.71, 126.24, 122.65, 98.83, 21.52; HRMS (ESI) calcd
for C25H20N3 [M+H]+: 362.1652 found 362.1643.
2,3-diphenyl-6-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazine (3ca).
Following the general procedure (A) on a 0.5 mmol scale
giving the desired compound as a light yellow solid (125
1
mg, 69%); mp 241-243 °C; H NMR (400 MHz, CDCl3) δ
10.59 (s, 1H), 7.47-7.45 (m, 2H), 7.42 (dd, J = 8.0, 1.6 Hz,
2H), 7.37 (d, J = 8.0 Hz, 2H), 7.30-7.27 (m, 3H), 7.12 (d, J
= 7.2 Hz, 3H), 7.06 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 1.7 Hz,
1H), 2.33 (s, 3H); 13C NMR (100 MHz,CDCl3) δ 147.99,
145.27, 144.39, 141.91, 140.41, 139.74, 139.51, 139.08,
130.05, 129.72, 128.05, 127.91, 127.81, 127.56,125.39,
98.10, 21.27; HRMS (ESI) calcd for C25H20N3 [M+H]+:
362.1652 found 362.1644.
Figure 2. X-Ray structure of 3aa, 5aa and 6aa
6-(4-methoxyphenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
b]pyrazine (3da). Following the general procedure (A) on
a 0.5 mmol scale giving the desired compound as a yellow
1
Conclusion
solid (98 mg, 52%); mp ; H NMR (400 MHz, CDCl3) δ
9.71 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.47 – 7.40 (m, 4H),
7.29-7.27 (m, 3H), 7.22 (dd, J = 5.0, 1.9 Hz, 3H), 6.96 –
In conclusions, we have developed an elegant
method for the synthesis of 5H-pyrrolo[2,3-
6.91 (m, 3H), 3.85 (d, J = 4.3 Hz, 3H).; 13C NMR (100
MHz, CDCl3) δ 160.52, 147.97, 145.25, 143.83, 141.67,
b]pyrazines through a reaction sequence of N-O
cleavage/double benzyl isocyanide insertion followed
by cross-dehydrogenative coupling. A plausible
reaction mechanism is proposed based on the control
studies and previous literature studies. At this stage,
only benzyl isocyanide has been used as a proof of
concept. The reaction also produced 2,3-diphenyl-5H-
140.41, 139.80, 139.76, 130.07, 130.01, 128.05, 127.66,
126.96, 114.70, 97.62, 55.42; HRMS (ESI) calcd for
C25H20N3O [M+H]+: 378.1601 found 378.1595.
6-(3,4-dimethoxyphenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
b]pyrazine (3ea). Following the general procedure (A) on
a 0.5 mmol scale giving the desired compound as a dark
1
yellow solid (102 mg, 50%); mp 106-108 °C; H NMR
5
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10.1002/adsc.201701202
Advanced Synthesis & Catalysis
(400 MHz, CDCl3) δ 9.43 (s, 1H), 7.47 – 7.40 (m, 4H), 130.82, 129.99, 128.23 – 127.82, 127.58, 102.63; HRMS
7.32 – 7.28 (m, 3H), 7.26 – 7.21 (m, 4H), 7.20 (d, J = 2.1 (ESI) calcd for C24H17ClN3 [M+H]+: 382.1106 found
Hz, 1H), 6.94 (dd, J = 5.2, 4.2 Hz, 2H), 3.96 (s, 3H), 3.94 382.1100.
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.33, 149.61,
148.10, 145.50, 143.73, 141.57, 140.35, 139.71, 130.02,
6-(4-chlorophenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
128.06, 127.70, 123.96, 118.38, 111.69, 108.90, 97.97,
b]pyrazine (3ka). Following the general procedure (A) on
56.07; HRMS (ESI) calcd for C26H22N3O2 [M+H]+:
408.1707 found 408.1697.
a 0.5 mmol scale giving the desired compound as a light
1
yellow solid (101 mg, 53%); mp 260-262 °C; H NMR
(400 MHz, CDCl3) δ 10.09 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H),
6-(3,5-dimethoxyphenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
7.47 – 7.43 (m, 2H), 7.43 – 7.39 (m, 2H), 7.35 – 7.28 (m,
b]pyrazine (3fa). Following the general procedure (A) on a 5H), 7.19 (dd, J = 5.1, 2.0 Hz, 3H), 7.03 (d, J = 2.0 Hz,
0.5 mmol scale giving the desired compound as a dark 1H); 13C NMR (100 MHz, CDCl3) δ 148.56, 146.14,
1
yellow solid (104 mg, 51%); mp 203-205 °C; H NMR 142.48, 141.81, 140.19, 139.47, 139.37, 135.10, 130.04,
(400 MHz, CDCl3) δ 9.52 (s, 1H), 7.47 – 7.42 (m, 2H), 129.99, 129.44, 128.15, 128.08, 128.01, 127.77, 126.69,
7.40 (dd, J = 6.6, 3.0 Hz, 2H), 7.31 – 7.27 (m, 3H), 7.25 – 99.31; HRMS (ESI) calcd for C24H17ClN3 [M+H]+:
7.20 (m, 3H), 7.02 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 2.4 Hz, 382.1106 found 382.1100.
2H), 6.50 (t, J= 2.0 Hz, 1H), 3.85 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 161.38, 148.31, 146.17, 143.35, 141.43,
6-(3,4-dichlorophenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
140.26, 139.67, 139.14, 132.91, 130.05, 129.99, 128.08,
b]pyrazine (3la). Following the general procedure (A) on a
128.03, 127.81, 127.66, 104.03, 101.03, 99.34, 55.50;
0.5 mmol scale giving the desired compound as a light
HRMS (ESI) calcd for C26H22N3O2 [M+H]+: 408.1707
1
yellow solid (102 mg, 49%); mp 220-222 °C; H NMR
found 408.1701.
(400 MHz,CDCl3) δ 10.37 (s, 1H), 7.65 (d, J = 1.1 Hz, 1H),
7.47 – 7.42 (m, 2H), 7.41 – 7.36 (m, 4H), 7.33 – 7.29 (m,
6-(3,5-dimethoxyphenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
3H), 7.16 (dd, J = 5.0, 2.2 Hz, 3H), 7.04 (d, J = 2.0 Hz,
b]pyrazine (3ga). Following the general procedure (A) on 1H); 13C NMR (100 MHz, CDCl3) δ 148.86, 146.58,
a 0.5 mmol scale giving the desired compound as a light 141.88, 141.14, 140.05, 139.23, 133.51, 133.16, 131.11,
yellow solid (97 mg, 53%); mp 221-223 °C; 1H NMR (400 129.98, 128.02, 127.31, 124.56, 100.12; HRMS (ESI) calcd
MHz, CDCl3) δ 9.73 (s, 1H), 7.80 (td, J = 7.8, 1.7 Hz, 1H), for C24H16Cl2N3 [M+H]+: 416.0716 found 416.0708.
7.48 – 7.41 (m, 4H), 7.40 – 7.33 (m, 1H), 7.30-7.29 (m,
3H), 7.28 – 7.24 (m, 4H), 7.22 (ddd, J = 12.1, 3.7, 1.1 Hz,
6-(4-bromophenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
1H), 7.18 – 7.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
b]pyrazine (3ma). Following the general procedure (A) on
159.63 (d, JC-F = 247.0 Hz), 148.51, 146.69, 140.24, 139.78,
a 0.5 mmol scale giving the desired compound as a light
yellow solid (62 mg, 29%); mp 258-260 °C; 1H NMR (400
MHz, CDCl3) δ 10.59 (s, 1H), 7.47 – 7.43 (m, 2H), 7.42 –
7.38 (m, 4H), 7.36 (d, J = 8.8 Hz, 2H), 7.33 – 7.29 (m, 3H),
7.15 (dd, J = 4.8, 2.5 Hz, 3H), 7.03 (d, J = 2.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 148.58, 146.02, 142.80, 141.96,
140.20, 139.41, 132.28, 129.96, 128.11, 127.78, 126.89,
123.21, 99.28; HRMS (ESI) calcd for C24H17BrN3 [M+H]+:
138.11, 130.58 (d, JC-F = 9.0 Hz), 129.99, 128.27 (d, JC-F
=
3.2 Hz), 127.78 (d, JC-F = 18.7 Hz), 125.09 (d, JC-F = 3.1
Hz), 118.67 (d, JC-F = 10.7 Hz), 116.78 (d, JC-F = 22.6 Hz),
100.53 (d, JC-F = 3.1 Hz); HRMS (ESI) calcd for
C24H17FN3 [M+H]+: 366.1401 found 366.1395.
6-(3-fluorophenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
b]pyrazine (3ha). Following the general procedure (A) on 426.0600 found 426.0592.
a 0.5 mmol scale giving the desired compound as a
1
yellowish- green solid (84 mg, 46%); mp 253-255 °C; H
4-(2,3-diphenyl-5H-pyrrolo[2,3-b]pyrazin-6-
NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 7.49 – 7.43 (m,
2H), 7.43 – 7.37 (m, 2H), 7.31-7.25 (m, 3H), 7.26 (dd, J =
7.4, 5.5 Hz, 2H), 7.21 – 7.14 (m, 1H), 7.14 – 7.07 (m, 3H),
7.06 (d, J = 0.8 Hz, 1H), 6.98 (m, J = 1H); 13C NMR (100
MHz, CDCl3) δ 162.99 (d, JC-F = 245.0 Hz), 147.56, 146.21,
142.54, 141.91, 140.15, 139.31 (d, JC-F = 6.5 Hz), 133.08 (d,
JC-F = 8.2 Hz), 130.68 (d, JC-F = 8.4 Hz), 130.03, 129.96,
128.13, 128.05, 127.96, 127.76, 121.095 (d, JC-F = 2.1 Hz),
115.88 (d, JC-F = 21.2 Hz), 112.46 (d, JC-F = 22.8 Hz),
99.66; HRMS (ESI) calcd for C24H17FN3 [M+H]+:
366.1401 found 366.1391.
yl)benzonitrile (3oa). Following the general procedure (A)
on a 0.5 mmol scale giving the desired compound as a
1
brown solid (97 mg, 52%); mp 192-194 °C; H NMR (400
MHz, CDCl3) δ 10.24 (s, 1H), 7.66-7.62 (m, 3H), 7.46 –
7.40 (m, 3H), 7.36 – 7.25 (m, 6H), 7.21 (dd, J = 5.0, 1.9 Hz,
3H), 7.17 (d, J = 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 149.23, 147.17, 141.95, 140.87, 139.90, 139.24, 138.90,
135.05, 132.91, 129.98, 128.83, 128.26, 128.22, 128.17,
127.99, 127.89, 127.84, 127.50, 125.79, 118.36, 112.23,
101.30, 43.80; HRMS (ESI) calcd for C25H17N4 [M+H]+:
373.1448 found 373.1440.
6-(4-fluorophenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
6-(furan-2-yl)-2,3-diphenyl-5H-pyrrolo[2,3-b]pyrazine
(3pa). Following the general procedure (A) on a 0.5 mmol
scale giving the desired compound as a dark brown solid
b]pyrazine (3ia). Following the general procedure (A) on a
0.5 mmol scale giving the desired compound as a dark
yellow solid (95 mg, 52%); mp 249-251 °C; 1H NMR (400
MHz, CDCl3) δ 10.06 (s, 1H), 7.59 – 7.53 (m, 2H), 7.47 –
7.44 (m, 2H), 7.43 – 7.40 (m, 2H), 7.33 – 7.28 (m, 3H),
7.20 (dd, J = 5.1, 1.9 Hz, 3H), 7.06 (t, J = 8.6 Hz, 2H), 6.99
(d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.18
(d, JC-F = 248.40 Hz), 147.38, 145.85, 142.83, 141.77,
140.23, 139.52 (d, JC-F = 4.2 Hz) , 130.02 (d, JC-F = 4.1 Hz),
128.11 (d, JC-F = 4.8 Hz) 127.83 (d, JC-F = 20.60 Hz),
116.34 (d, JC-F = 21.90 Hz), 98.81; HRMS (ESI) calcd for
C24H17FN3 [M+H]+: 366.1401 found 366.1392.
1
(76 mg, 45%); mp 242-244 °C; H NMR (400 MHz,
CDCl3) δ 9.50 (s, 1H), 7.50 (d, J = 1.4 Hz, 1H), 7.44-7.41
(m, 4H), 7.28-7.23 (m, 7H), 6.93 (d, J = 1.8 Hz, 1H), 6.75
(d, J = 3.4 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 148.34, 146.25, 145.97, 143.39,
140.99, 140.26, 139.74, 138.93, 134.22, 130.03, 127.92,
112.29, 108.59, 97.40; HRMS (ESI) calcd for C22H16N3O
[M+H]+: 338.1288 found 338.1279.
2,3-diphenyl-6-(thiophen-2-yl)-5H-pyrrolo[2,3-
b]pyrazine (3qa). Following the general procedure (A) on
a 0.5 mmol scale giving the desired compound as a dark
6-(2-chlorophenyl)-2,3-diphenyl-5H-pyrrolo[2,3-
1
b]pyrazine (3ja). Following the general procedure (A) on a
0.5 mmol scale giving the desired compound as a beige
solid (109 mg, 57%); mp 223-225 °C; 1H NMR (400 MHz,
CDCl3) δ 9.92 (s, 1H), 7.67 – 7.62 (m, 1H), 7.50 – 7.47 (m,
1H), 7.45 (ddd, J = 4.5, 2.4, 1.5 Hz, 2H), 7.42 (ddd, J = 6.0,
3.5, 1.8 Hz, 2H), 7.35 – 7.32 (m, 2H), 7.30 (dd, J = 6.0, 2.5
Hz, 3H), 7.23 (dd, J = 6.5, 2.8 Hz, 3H), 7.10 (d, J = 2.1 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 148.44, 146.69,
140.91, 140.66, 140.22, 139.67, 138.10, 131.70, 131.06,
brown solid (83 mg, 47%); mp 226-228 °C; H NMR (400
MHz, CDCl3) δ 9.49 (s, 1H), 7.46 – 7.41 (m, 4H), 7.37 (dd,
J = 5.0, 1.1 Hz, 1H), 7.32 – 7.28 (m, 3H), 7.26 – 7.22 (m,
4H), 7.05 (dd, J = 5.0, 3.7 Hz, 1H), 6.92 (d, J = 2.0 Hz,
1H); 13C NMR (100 MHz,CDCl3) δ 148.38, 145.97, 141.43,
140.23, 139.70, 139.26, 137.94, 134.12, 130.03, 128.33,
128.30 – 127.77, 127.70, 126.75, 124.86, 98.95; HRMS
(ESI) calcd for C22H16N3S [M+H]+: 354.1059 found
354.1051.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701202
Advanced Synthesis & Catalysis
2,3-diphenyl-6-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine crude was purified using column chromatography by
(3ra). Following the general procedure (A) on a 0.5 mmol eluting from hexane to ethyl acetate/hexane to afford pure
scale giving the desired compound as a beige solid (105 mg, compounds 5aa as minor and 6aa as major.
1
60%); mp 243-245 °C; H NMR (400 MHz, CDCl3) δ
11.09 (s, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.58 –
8.53 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.48 –
7.37 (m, 5H), 7.33 – 7.27 (m, 3H), 7.17 – 7.09 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 149.57, 148.65,
146.78, 146.37, 142.05, 140.53, 140.08, 139.24, 132.61,
132.11, 130.01, 128.48, 128.33, 128.01, 127.81, 127.25,
123.84, 99.93; HRMS (ESI) calcd for C23H16N4 [M]+:
348.1369 found 348.1489.
2,3-diphenyl-5H-pyrazino[2,3-b]indole (5aa). Following
the general procedure (B) on a 0.5 mmol scale giving the
desired compound as a brown solid (55 mg, 34%); mp 278-
1
280 °C; H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.38
(d, J = 7.9 Hz, 1H), 7.59 (dd, J = 7.7, 1.6 Hz, 2H), 7.52 (dd,
J = 6.5, 3.1 Hz, 2H), 7.45 – 7.25 (m, 9H), 6.63 (d, J = 8.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 147.87, 146.02,
144.36, 140.77, 139.85, 135.17, 130.27, 128.96, 128.49,
128.22, 127.71, 121.79, 120.99, 120.16, 111.80; HRMS
(ESI) calcd for C22H16N3 [M+H]+: 322.1339 found
7-methyl-2,3,6-triphenyl-5H-pyrrolo[2,3-b]pyrazine
(3sa). Following the general procedure (A) on a 0.5 mmol 322.1337.
scale giving the desired compound as a light yellow solid
(87 mg, 48%); mp 211-213 °C;1H NMR (400 MHz,
3-benzyl-2-phenyl-3,4-dihydroimidazo[4,5-b]indole
CDCl3) δ 8.72 (s, 1H), 7.68 – 7.64 (m, 2H), 7.53 (t, J = 7.6
Hz, 2H), 7.47 (dd, J = 6.4, 3.3 Hz, 2H), 7.45 – 7.40 (m, 3H),
7.32 – 7.28 (m, 4H), 7.27 (d, J = 3.0 Hz, 2H), 2.62 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 147.50, 140.61, 140.13,
139.09, 132.12, 130.25, 129.98, 129.14, 128.60, 128.04,
127.63, 108.75, 8.71; HRMS (ESI) calcd for C25H20N3
[M+H]+: 362.1652 found 362.1640.
(6aa). Following the general procedure (B) on a 0.5 mmol
scale giving the desired compound as a brown solid (73 mg,
1
45%); mp 208-210 °C; H NMR (400 MHz, CDCl3) δ 8.34
(s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 7.5, 1.9 Hz,
2H), 7.42 – 7.35 (m, 3H), 7.32 – 7.23 (m, 4H), 7.19 – 7.09
(m, 4H), 5.30 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
147.10, 139.43, 135.24, 129.26, 128.80, 128.44, 126.92,
121.47, 120.57, 119.70, 118.00, 112.20, 49.56; HRMS
2,3,6,7-tetraphenyl-5H-pyrrolo[2,3-b]pyrazine
(3ta). (ESI) calcd for C22H18N3 [M+H]+: 324.1495 found
Following the general procedure (A) on a 0.5 mmol scale 324.1489.
giving the desired compound as a light yellow solid (167
1
mg, 79%); mp 203-205 °C; H NMR (400 MHz, CDCl3) δ
5-benzyl-2,3-diphenyl-5H-pyrazino[2,3-b]indole (5ba).
9.16 (s, 1H), 7.68 (dd, J = 8.3, 1.3 Hz, 2H), 7.50 – 7.42 (m,
6H), 7.38 – 7.32 (m, 5H), 7.29 – 7.24 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 148.25, 146.41, 140.58, 140.30,
140.00, 139.22, 137.83, 132.41, 131.85, 130.37, 130.02,
128.99, 128.40, 128.11, 127.88, 127.58, 126.65, 113.56;
HRMS (ESI) calcd for C30H22N3 [M+H]+: 424.1808 found
424.1795.
Following the general procedure (B) on a 0.5 mmol scale
giving the desired compound as a light yellow solid (123
1
mg, 60%); mp 203-205 °C; H NMR (400 MHz, CDCl3) δ
8.44 (d, J = 7.8 Hz, 1H), 7.52 (m, 5H), 7.41 (d, J = 8.2 Hz,
1H), 7.30 (m, 13H), 5.73 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 148.41, 145.91, 144.26, 141.61, 140.32, 139.89,
136.82, 134.01, 130.29, 128.79, 128.31, 127.88, 127.61,
127.28, 121.99, 120.95, 120.04, 110.29, 45.09; HRMS
(ESI) calcd for C29H22N3 [M+H]+: 412.1808 found
8,9-diphenyl-6,11-dihydro-5H-benzo[g]pyrazino[2,3-
b]indole (3ua). Following the general procedure (A) on a 412.1814.
0.5 mmol scale giving the desired compound as a yellow
1
solid (97 mg, 52%); mp 234-236 °C; H NMR (400 MHz,
5-(4-methylbenzyl)-2,3-diphenyl-5H-pyrazino[2,3-
CDCl3) δ 9.51 (s, 1H), 7.46-7.41 (m, 4H), 7.31-7.18 (m,
10H), 3.20 – 3.06 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
147.74, 145.40, 142.01, 140.47, 139.98, 138.79, 137.64,
137.12, 130.10, 128.74, 128.49, 128.07, 127.85 – 127.06,
126.90, 120.76, 110.94, 29.08, 18.46; HRMS (ESI) calcd
for C26H20N3 [M+H]+: 374.1652 found 374.1641.
b]indole (5ca). Following the general procedure (B) on a
0.5 mmol scale giving the desired compound as a pale
1
yellow solid (96 mg, 45%); mp 181.6-183.3 °C; H NMR
(400 MHz, CDCl3) δ 8.43 (ddd, J = 7.8, 1.2, 0.7 Hz, 1H),
7.56 – 7.48 (m, 5H), 7.42 (dt, J = 8.3, 0.8 Hz, 1H), 7.36 –
7.27 (m, 7H), 7.23 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz,
2H), 5.69 (s, 2H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 148.35, 145.81, 144.23, 141.61, 140.34, 139.92,
3-methoxy-8,9-diphenyl-6,11-dihydro-5H-
benzo[g]pyrazino[2,3-b]indole (3va). Following the 137.29, 133.99, 133.79, 130.33, 130.23, 129.38, 128.80,
general procedure (A) on a 0.5 mmol scale giving the 128.15, 128.02, 127.97, 127.56, 127.29, 121.94, 120.86,
desired compound as a yellowish-green solid (111 mg, 120.00, 110.30, 44.84, 21.08 ; HRMS (ESI) calcd for
55%); mp 233-235 °C; 1H NMR (400 MHz, CDCl3) δ 9.74 C30H24N3 [M+H]+: 426.1964 found 426.1962.
(s, 1H), 7.50 – 7.43 (m, 4H), 7.33 – 7.26 (m, 3H), 7.25 –
7.17 (m, 3H), 7.05 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.5 Hz,
5-(4-(tert-butyl)benzyl)-2,3-diphenyl-5H-pyrazino[2,3-
1H), 6.64 (dd, J = 8.4, 2.6 Hz, 1H), 3.82 (s, 3H), 3.16 –
b]indole (5da). Following the general procedure (B) on a
3.10 (m, 2H), 3.06 (d, J = 7.5 Hz, 2H); 13C NMR (100
0.5 mmol scale giving the desired compound as a pale
1
MHz,CDCl3) δ 159.94, 147.45, 144.46, 142.08, 140.64,
yellow solid (159 mg, 68%); mp 207-209 °C; H NMR
140.06, 139.73, 139.39, 137.50, 130.14, 128.05, 127.57,
(400 MHz, CDCl3) δ 8.43 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H),
122.22, 120.54, 114.87, 111.85, 108.94, 55.35, 29.56,
7.57 – 7.49 (m, 5H), 7.46 (dt, J = 8.2, 0.8 Hz, 1H), 7.37 –
18.47; HRMS (ESI) calcd for C27H22N3O [M+H]+:
404.1757 found 404.1748.
7.25 (m, 11H), 5.70 (s, 2H), 1.27 (s, 9H).; 13C NMR (100
MHz, CDCl3) δ 150.53, 148.35, 145.80, 144.22, 141.65,
140.36, 139.91, 133.97, 133.82, 130.35, 130.23, 128.78,
General experimental Procedure (B) for the Synthesis 128.15, 128.02, 127.96, 127.56, 127.07, 125.61, 121.95,
of 2,3-diphenyl-5H-pyrazino[2,3-b]indole (5aa) and 3- 120.84, 119.98, 110.32, 109.96, 44.71, 34.48, 31.28;
benzyl-2-phenyl-3,4-dihydroimidazo[4,5-b]indole (6aa). HRMS (ESI) calcd for C33H30N3 [M+H]+: 468.2434 found
To an oven dried sealed tube was added 2-iodoaniline 4a 468.2433.
(110 mg, 0.5 mmol) in toluene (0.5 M) followed by the
sequential addition of benzyl isocyanide 2a (129 L, 1.05
mmol), DBU (166 L, 1.1 mmol), and Pd(PPh3)4 (29 mg, 5
mol %). The reaction mixture was allowed to stir at reflux
for indicated time. After the completion, the reaction
mixture was cooled to room temperature and diluted with
5.0 mL of water. The water layer was extracted with (3X10
mL) of ethyl acetate and the combined ethyl acetate layer
was given brine wash (1X10 mL). The final ethyl acetate
layer was dried over sodium sulfate and concentrated under
reduced pressure to get the crude compound. The obtained
5-(2-methoxybenzyl)-2,3-diphenyl-5H-pyrazino[2,3-
b]indole (5ea). Following the general procedure (B) on a
0.5 mmol scale giving the desired compound as a pale
1
yellow solid (122 mg, 56%); mp 176-178 °C; H NMR
(400 MHz, CDCl3) δ 8.44 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H),
7.57 – 7.46 (m, 6H), 7.37 – 7.20 (m, 8H), 6.98 (dd, J = 7.6,
1.6 Hz, 1H), 6.92 (dd, J = 8.2, 0.8 Hz, 1H), 6.79 (td, J = 7.5,
1.0 Hz, 1H), 5.75 (s, 2H), 3.92 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 156.91, 148.30, 145.66, 144.47, 141.93,
140.40, 139.99, 134.06, 130.35, 130.24, 128.74, 128.58,
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701202
Advanced Synthesis & Catalysis
128.29, 128.13, 127.95, 127.93, 127.52, 124.87, 121.78,
120.74, 120.52, 119.86, 110.59, 110.22, 55.35, 39.91;
HRMS (ESI) calcd for C30H24ON3 [M+H]+: 442.1913
found 442.1912.
Seeliger, L. -H. Tsai, L. Meijer, A. Musacchio, J. Med.
Chem. 2005, 48, 671-679; c) M. Zeng, Y. Jiang, B.
Zhang, K. Zheng, N. Zhang, Q. Yu, Bioorg. Med. Chem.
Lett. 2005, 15, 395–399; (d) G. G. Dubinina, M. O.
Platonov, S. M. Golovach, P. O. Borysko, A. O.
Tolmachov, Y. M. Volovenko, Eur. J. Med. Chem.
2006, 41, 727–737; (e) C. Corbel, R. Haddoub, D.
Guiffant, O. Lozach, D. Gueyrard, J. Lemoine, M.
Ratin, L. Meijer, S. Bach, P. Goekjian, Bioorg. Med.
Chem. 2009, 17, 5572–5582.
3-((2,3-diphenyl-5H-pyrazino[2,3-b]indol-5-
yl)methyl)benzonitrile (5fa). Following the general
procedure (B) on a 0.5 mmol scale giving the desired
compound as a light yellow solid (127 mg, 58%); mp 206-
1
208 °C; H NMR (400 MHz, CDCl3) δ 8.44 (ddd, J = 8.0,
1.2, 0.8 HZ, 1H), 7.63 – 7.48 (m, 8H), 7.44 – 7.29 (m, 9H),
5.73 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 148.61,
146.48, 144.03, 141.11, 140.07, 139.66, 138.41, 134.07,
131.64, 131.43, 130.79, 130.23 (d, J = 3.3 Hz), 129.66,
129.10, 128.12 (d, J = 13.0 Hz), 127.73, 122.26, 121.41,
120.21, 118.46, 112.95, 109.73, 44.33; HRMS (ESI) calcd
for C30H21N4 [M+H]+: 437.1760 found 437.1761.
[2] a) J. de Vicente, R. Lemoine, M. Bartlett, J. C.
Hermann, M. Hekmat-Nejad, R. Henningsen, S. Jin, A.
Kuglstatter, H. Li, A. J. Lovey, J. Menke, L. Niu, V.
Patel, A. Petersen, L. Setti, A. Shao, P. Tivitmahaisoon,
M. D. Vu, M. Soth, Bioorg. Med. Chem. Lett. 2014, 24,
4969–4975; b) F. Padilla, N. Bhagirath, S. Chen, E.
Chiao, D. M. Goldstein, J. C. Hermann, J. Hsu, J. J.
Kennedy-Smith, A. Kuglstatter, C. Liao, W. Liu, L. E.
Lowrie, K. C. Luk, S. M. Lynch, J. Menke, L. Niu, T.
D. Owens, C. O-Yang, A. Railkar, R. C. Schoenfeld, M.
Slade, S. Steiner, Y. -C. Tan, A. G. Villaseꢀor, C.
Wang, J. Wanner, W. Xie, D. Xu, X. Zhang, M. Zhou,
M. C. Lucas, J. Med. Chem. 2013, 56, 1677−1692.
5-(naphthalen-2-ylmethyl)-2,3-diphenyl-5H-
pyrazino[2,3-b]indole (5ga). Following the general
procedure (B) on a 0.5 mmol scale giving the desired
compound as a yellow solid (127 mg, 55%); mp 211-
213 °C; 1H NMR (400 MHz, CDCl3) δ 8.45 (td, J = 7.2, 1.2
Hz, 1H), 7.80 – 7.72 (m, 4H), 7.55 – 7.51 (m, 4H), 7.49 (dd,
J = 7.1, 1.2 Hz, 1H), 7.43 (m, 4H), 7.36 – 7.27 (m, 7H),
5.88 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 148.45,
145.98, 144.33, 141.68, 140.31, 139.90, 134.17 (d, J = 17.9
Hz), 133.28, 132.82, 130.29 (d, J = 9.1 Hz), 128.89, 128.66,
128.26 – 127.92, 127.92 – 127.46, 126.29, 125.98 (d, J =
2.4 Hz), 125.25, 121.98, 121.00, 120.09, 110.36, 45.34;
HRMS (ESI) calcd for C33H24N3 [M+H]+: 462.1965 found
462.1960.
[3] a) P. -H. Li, P. Zeng, S. -B. Chen, P. -F. Yao, Y. -W.
Mai, J. -H. Tan, T. -M. Ou, S. -L. Huang, D. Li, L. -Q.
Gu, Z. -S. Huang, J. Med. Chem. 2016, 59, 238−252; b)
D. Reker, M. Seet, M. Pillong, C. P. Koch, P. Schneider,
M. C. Witschel, M. Rottmann, C. Freymond, R. Brun,
B. Schweizer, B. Illarionov, A. Bacher, M. Fischer, F.
Diederich, G. Schneider, Angew. Chem. Int. Ed. 2014,
53, 7079 –7084.
5-benzyl-8-methyl-2,3-diphenyl-5H-pyrazino[2,3-
b]indole (5ha). Following the general procedure (B) on a
0.5 mmol scale giving the desired compound as a pale
1
yellow solid (149 mg, 70%); mp 172-174 °C; H NMR
(400 MHz, CDCl3) δ 8.25 – 8.23 (m, 1H), 7.54 – 7.49 (m,
4H), 7.37 – 7.23 (m, 13H), 5.70 (s, 2H), 2.52 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 148.17, 145.63, 144.39, 140.41,
139.96, 139.87, 136.93, 133.89, 130.45, 130.32, 130.22,
130.20, 128.69, 128.12, 127.98, 127.95, 127.53, 127.50,
127.23, 121.78, 120.07, 109.99, 109.96, 45.05, 21.31;
HRMS (ESI) calcd for C30H24N3 [M+H]+: 426.1964 found
426.1963.
[4] a) S. Klutchko, H. V. Hansen, R. I. Meltzer, J. Org.
Chem. 1965, 30, 3454–3457; b) C. Martin, J. -M.
Vierfond, Y. Mettey, M. Miocque, Tetrahedron Lett.
1989, 30, 935–936; c) M. L. Davis, B. J. Wakefield, J.
A. Wardellt, Tetrahedron, 1992, 48, 939-952; d) S. W.
Schneller, J. -H. Sun, Heterocycles, 1977, 6, 137-142.
5-benzyl-8-fluoro-2,3-diphenyl-5H-pyrazino[2,3-
b]indole (5ia). Following the general procedure (B) on a
0.5 mmol scale giving the desired compound as a pale
1
[5] J. -M. Vierfond, Y. Mettey, L. Mascrier-Demagny, M.
yellow solid (136 mg, 63%); mp 205-207 °C; H NMR
(400 MHz, CDCl3) δ 8.09 (dd, J = 8.4, 2.3 Hz, 1H), 7.51
(m, 4H), 7.38 – 7.21 (m, 13H), 5.72 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 159.33, 156.96, 149.14, 146.13, 144.84,
139.89 (d, JC-F = 38.5 Hz), 137.75, 136.56, 133.45 (d, JC-F
= 4.2 Hz), 130.30, 130.17, 128.79, 128.21, 128.19, 128.01,
127.72, 127.22, 127.18, 120.62 (d, JC-F = 9.2 Hz), 116.72
(JC-F = 25.5 Hz), 111.19 (JC-F = 8.8 Hz), 107.64 (JC-F = 24.1
Hz), 45.19; HRMS (ESI) calcd for C29H21FN3 [M+H]+:
430.1714 found 430.1711.
Miocque, Tetrahedron Lett. 1981, 22, 1219–1222.
[6] C. R. Hopkins, N. Collar, Tetrahedron Lett. 2004, 45,
8087–8090.
[7] D. S. Chekmarev, S. V. Shorshnev, A. E. Stepanov, A.
N. Kasatkina, Tetrahedron, 2006, 62, 9919–9930.
[8] A. Keivanloo, M. Bakherad, H. Nasr-Isfahani, S.
Esmaily, Tetrahedron Lett. 2012, 53, 3126–3130.
[9] H. A. Sharma, M. T. Hovey, K. A. Scheidt, Chem.
Commun. 2016, 52, 9283-9286.
Acknowledgements
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for Re-
search and Development of Kaohsiung Medical University for
400 MHz NMR, LC-MS and GC-MS analyzes.
[10]For recent review on isocyanides, see: a) G. Qiu, Q.
Ding, J. Wu, Chem. Soc. Rev. 2013, 42, 5257-5269; b)
V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin, V. Y.
Kukushkin, Chem. Rev. 2015, 115, 2698–2779; c) B.
Song, B. Xu, Chem. Soc. Rev. 2017, 46, 1103-1123; d)
M. Giustiniano, A. Basso, V. Mercalli, A. Massarotti,E.
Novellino, G. C. Tron, J. Zhu, Chem. Soc. Rev. 2017,
46, 1295-1357.
References
[1] a) Y. Mettey, M. Gompel, V. Thomas, M. Garnier, M.
Leost, I. Ceballos-Picot, M. Noble, J. Endicott, J. -M.
Vierfond, L. Meijer, J. Med. Chem. 2003, 46, 222-236;
b) M. Mapelli, L. Massimiliano, C. Crovace, M. A.
[11] a) L. El Kaım, L. Grimaud, A. Schiltz, Tetrahedron
Lett. 2009, 50, 5235–5237; b) B. Pooi, J. Lee, K. Choi,
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701202
Advanced Synthesis & Catalysis
H. Hirao, S. H. Hong, J. Org. Chem. 2014, 79,
9231−9245; c) X. Qi, H. Xiang, Y. Yang, C. Yang,
RSC Adv. 2015, 5, 98549-98552; d) Y. Li, A. Chao, F.
F. Fleming, Chem. Commun. 2016, 52, 2111-2113.
[12] a) G. C. Senadi, M. R. Mutra, T. –Y. Liu, J. –J. Wang,
Green Chem. 2017, 19, 4272-4277; b) G. C. Senadi, T.
-Y. Lu, G. K. Dhandabani, J. -J. Wang, Org. Lett. 2017,
19, 1172-1175; c) G. C. Senadi, W. -P. Hu, T. -Y. Lu,
A. M. Garkhedkar, J. K. Vandavasi, J. -J. Wang, Org.
Lett. 2015, 17, 1521-1524; d) G. C. Senadi, W. -P. Hu,
S. S. K. Boominathan, J. -J. Wang, Chem. Eur. J. 2015,
21, 998-1003.
2014, ch. 9, pp 197-218; e) A. S.-K. Tsang, S. J. Park,
M. H. Todd, in Mechanisms of Cross-Dehydrogenative-
Coupling Reactions, C. -J. Li, RSC Green Chemistry,
2014, ch. 11, pp 254-294.
[14] CCDC number for compound 3aa CCDC 1553782,
5aa CCDC 1557739, 6aa CCDC 1557738.
[15] Direct synthesis of 3H-indolo-3-imines was also
developed by Jiang et al, however, we both didn’t
perform the reaction with benzyl isocyanide, see Y. -Y.
Pan, Y. -N. Wu, Z. -Z. Chen, W. -J. Hao, G. Li, S. -J.
Tu, B. Jiang, J. Org. Chem. 2015, 80, 5764–5770.
[13] For recent reviews on cross-dehydrogenative coupling,
see: a) C. -J. Li, Acc. Chem. Res. 2009, 42, 335-344; b)
S. A. Girard, T. Knauber, C. -J. Li, in The Evolution of
the Concept of Cross-Dehydrogenative-Coupling
Reactions, ed. C. -J. Li, RSC Green Chemistry, 2014,
ch. 1, pp 1-32; c) H. Ito, K. Ueda, K. Itami, in Cross-
Dehydrogenative-Coupling Reactions without Metals,
ed. C. -J. Li, RSC Green Chemistry, 2014, ch. 8, pp
153-196; d) O. Baslé, in Cross-Dehydrogenative-
Coupling Reactions with Molecular Oxygen as the
Terminal Oxidant, ed. C. -J. Li, RSC Green Chemistry,
[16] P. Z. Mannes, E. O. Onyango, G. W. Gribble. J. Org.
Chem. 2016, 81, 12478-12481.
[17] a) W. P. Hong, A. V. Iosub, S. S. Stahl, J. Am. Chem.
Soc. 2013, 135, 13664-13667; b) M. Zheng, P. Chen, W.
Wu, H. Jiang, Chem. Commun. 2016, 52, 84-87.
9
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FULL PAPER
Synthesis of Fused-Pyrazines via Pd-Catalyzed
Double Benzyl Isocyanide Insertion and Cross-
Dehydrogenative Coupling
Adv. Synth. Catal. Year, Volume, Page – Page
G. C. Senadi, B. –C. Guo, Y. –C. Chang, W. –P.
Hu, J. –J. Wang*
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