Diversity-oriented decoration of pyrrolo[1,2-a]pyrazines

Article abstract of DOI:10.1016/j.tet.2014.08.003

Diversity-oriented synthesis of a chemical library based on a pyrrolo[1,2-a]pyrazine core is described by using palladium-catalyzed direct C6 arylation of pyrrolo[1,2-a]pyrazines with various aryl bromides. The starting materials, pyrrolo[1,2-a]pyrazines, were easily synthesized by the base-mediated N-alkylation of pyrrole-2-carboxaldehyde with several 2-bromoacetophenones followed by dehydrative cyclization with incorporation of nitrogen by the action of ammonium acetate. Introduction of other functional groups on this chemical scaffold is also discussed herein.

Full text of DOI:10.1016/j.tet.2014.08.003

Accepted Manuscript
Diversity-Oriented Decoration of Pyrrolo[1,2-a]pyrazines
Sujin Park, Youngeun Jung, Ikyon Kim
PII:
S0040-4020(14)01166-1
10.1016/j.tet.2014.08.003
TET 25903
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 June 2014
Revised Date: 2 August 2014
Accepted Date: 3 August 2014
Please cite this article as: Park S, Jung Y, Kim I, Diversity-Oriented Decoration of
Pyrrolo[1,2-a]pyrazines, Tetrahedron (2014), doi: 10.1016/j.tet.2014.08.003.
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ACCEPTED MANUSCRIPT
Diversity-Oriented Decoration of Pyrrolo[1,2-a]pyrazines
Sujin Park, Youngeun Jung, and Ikyon Kim*
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University
85 Songdogwahak-ro, Yeonsu-gu, Incheon 406-840, Republic of Korea
*
Corresponding author. Tel.: +82 32 749 4515; fax: +82 32 749 4105; e-mail:
ikyonkim@yonsei.ac.kr
Graphical Abstract
Abstract: Diversity-oriented synthesis of a chemical library based on a pyrrolo[1,2-
a]pyrazine core is described by using palladium-catalyzed direct C6 arylation of pyrrolo[1,2-
a]pyrazines with various aryl bromides. The starting materials, pyrrolo[1,2-a]pyrazines, were
easily synthesized by the base-mediated N-alkylation of pyrrole-2-carboxaldehyde with
several 2-bromoacetophenones followed by dehydrative cyclization with incorporation of
nitrogen by the action of ammonium acetate. Introduction of other functional groups on this
chemical scaffold is also discussed herein.
Keywords: Diversity-oriented synthesis; Pyrrolo[1,2-a]pyrazines; Cyclodehydration; Direct

ACCEPTED MANUSCRIPT
arylation; C-H activation.
Introduction
In the context of drug discovery, design and synthesis of new chemical scaffolds with
potential therapeutic application is highly desirable in early stages of drug discovery research.
In particular, aromatic heterocycles have been employed as basic core skeletons in a number
of medicinal chemistry programs. Among them, a series of 5,6-fused heteroaromatic ring
systems are widely used with several substituents attached around the rings, exhibiting
various pharmacological functions. As part of our research interest to construct novel
chemical libraries for biological screening, we have investigated efficient approaches to
1
nitrogen-fused bicyclic compounds with distinctive substitution patterns. As a continuation
of our efforts, we became interested in the synthesis of pyrrolo[1,2-a]pyrazines as
2
dehydrative cyclization of 2 in the presence of ammonium acetate would give rise to the
pyrrolo[1,2-a]pyrazine 3 from which we wish to introduce additional functionalization
(Scheme 1).
Scheme 1. Strategy for Novel Chemical Library Based on a Pyrrolo[1,2-a]pyrazine Core
3
,4
As a means to install additional functionality, we decided to use direct arylation at C6
position of this motif partly because topologically relevant bicyclic heteroaromatic
compounds with similar substitution patterns such as imidazo[1,2-b]pyridazine, imidazo[1,2-
a]pyridine, imidazo[1,2-a]pyrazine, and imidazo[1,2-a]pyrimidine are known to have a range
of interesting biological activities including antiplasmodial, anti HCV, and anticancer

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5
activities. In addition, pyrrolo[1,2-a]pyrazines with diaryl substituents at C3 and C6 sites
have not been reported to date. Although some pharmacologically active pyrrolo[1,2-
a]pyrazines are disclosed in the literature as shown in Figure 1, this scaffold has been
underevaluated as a drug pharmacophore compared with other nitrogen-fused 5,6-
6
heteroaromatics such as imidazo[1,2-a]pyridine or pyrrolo[1,2-a]pyrimidine.
Figure 1. Pharmacologically Active Pyrrolo[1,2-a]pyrazine Derivatives
Here we report our result on facile construction and chemical diversification of pyrrolo[1,2-
a]pyrazines relying on dehydrative cyclization and Pd-catalyzed direct arylation via C-H
7
activation.
Results and Discussion
Substrates for this study were easily prepared starting from 2-pyrrolecarboxaldehydes and
8
appropriate 2-bromoacetophenones in the presence of base. The resulting compounds were
allowed to cyclize in the presence of ammonium acetate as a nitrogen source to afford the

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corresponding pyrrolo[1,2-a]pyrazines in excellent yields (Scheme 2). 2-Acetylpyrrole was
also employed for this sequence to give 3g in 84% yield.
a
Scheme 2. Preparation of Pyrrolo[1,2-a]pyrazines 3
b
3
a (89%)
3b (74%)
3e (69%)
3c (90%)
3f (71%)
N
N
BnO
3
d (76%)
3
g (84%)
3h (81%)
a
A mixture of 2 (4.69 mmol) and NH OAc (3 equiv) in EtOH (16 mL) was heated at 120 °C
4
b
for 2 h. Isolated yields (%) from 2 to 3.
To optimize the direct arylation conditions, 3a was used as a model substrate. Brief screening
of palladium catalysts with KOAc as base and DMA as solvent at 150 °C revealed
(
PPh ) PdCl to be superior to others (entries 1~3, Table 1). Use of other solvents gave rather
3 2 2
inefficient results compared with that in DMA (entries 4~7). Other inorganic bases or organic
9
,10
base resulted in decreased yields of the desired product 4a (entries 8~12).
a
Table 1. Reaction Optimization of Direct Arylation of 3a

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b
entry
Pd
base
solvent
DMA
DMA
DMA
Dioxane
yield (%)
87
1
2
3
4
5
6
7
8
9
(PPh ) PdCl
KOAc
KOAc
KOAc
3
2
2
Pd(OAc)2
PdCl (CH CN)
2
75
66
2
3
(PPh ) PdCl
KOAc
KOAc
KOAc
KOAc
NaOAc
K CO
34 (98)
44 (59)
66
27 (74)
31 (37)
69
51 (86)
5 (18)
trace
3
2
2
2
2
2
2
2
2
2
2
(PPh ) PdCl
CH CN
3
2
3
(PPh ) PdCl
DMF
toluene
DMA
DMA
DMA
DMA
DMA
3
2
(PPh ) PdCl
3
2
(PPh ) PdCl
3
2
(PPh ) PdCl
3
2
2
3
10
11
12
(PPh ) PdCl
Cs CO
3
2
2
3
(PPh ) PdCl
Li CO
3
2
2
3
(PPh ) PdCl
Et N
3
2
3
a
A mixture of 3a (0.15 mmol), 4-bromonitrobenzene (2.5 equiv), Pd catalyst (5 mol %), and
b
base (2 equiv) in solvent (1 mL) was stirred at 150 °C for 16 h unless otherwise noted.
Isolated yields (%). Yields in parentheses are based on recovered starting materials.
Having identified the optimal direct arylation conditions, we first reacted 3a with several aryl
halides as shown in Table 2. In general, aryl bromides possessing an electron-withdrawing
group provided better results than those having an electron-donating group (entries 2~9 vs.
entries 10~11). Pyridine-containing pyrrolo[1,2-a]pyrazine 4m was also obtained in 61%
yield (entry 12).
a
Table 2. Direct Arylation of 3a with Aryl Bromides
b
entry
ArBr
4
yield (%)

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1
2
4b
4c
62
68
3
4d
68
4
5
4e
4f
45
47
6
7
8
4g
4h
4i
54 (69)
71
N
N
59
F

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F3C
9
4j
72
29
Br
10
4k
1
1
2
4l
55
61
1
4m
a
A mixture of 3a (0.26 mmol), ArBr (2.5 equiv), (PPh ) PdCl (5 mol %), and KOAc (2
3
2
2
b
equiv) in DMA (1 mL) was stirred at 150 °C for 16 h unless otherwise noted. Isolated yields
%). Yields in parentheses are based on recovered starting materials.
(
Reaction scope was further examined with other pyrrolo[1,2-a]pyrazines 3b~3h (Table 3).
2
When R were aryl groups bearing an electron-donating group (3b~3d) or an electron-
withdrawing group (3e and 3f), various C6-arylated products were obtained in good yields
(entries 1~22). In case of 1,3-disubstituted pyrrolo[1,2-a]pyrazine (3g), products having three
substitutents around the bicyclic core were produced (entries 23~28). When 3-
methylpyrrolo[1,2-a]pyrazine (3h) was used under these conditions, however, moderate
yields of the corresponding products were isolated (entries 29 and 30). In addition, compound
arylated at C6 and C8 sites was the major product from the reaction of 3h with ethyl 4-
1
1
bromobenzoate (entry 31).

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a
Table 3. Direct Arylation of 3b-3h with Aryl Bromides
b
entry
1
3
4
yield (%)
4n
4o
88
2
3b
40
3
4
3b
3b
4p
4q
71
64
5
6
3b
3b
4r
4s
68
67

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7
8
4t
67 (69)
82 (95)
3c
3c
4u
9
4v
4w
4x
4y
4z
81
62
35
26
52
1
0
1
2
3
N
N
1
1
1
3d
3d
BnO
CN

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14
15
16
3e
3e
4aa
4ab
4ac
58 (77)
55
77
1
7
8
3f
3f
4ad
4ae
62
28
N
N
1
Cl
CHO
1
9
0
3f
3f
4af
50
2
4ag
46 (57)

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2
1
2
3f
3f
4ah
4ai
65
45
2
2
3
4
4aj
52
58
2
3g
3g
4ak
25
4al
83
2
6
7
3g
3g
4am
4an
53
61
Me
N
N
2
EtO C
2

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2
2
3
8
9
0
3g
4ao
4ap
4aq
52
37
36
3h
3h
31
4ar
34
a
A mixture of 3 (0.26 mmol), ArBr (2.5 equiv), (PPh ) PdCl (5 mol %), and KOAc (2 equiv)
3
2
2
b
in DMA (1 mL) was stirred at 150 °C for 16 h unless otherwise noted. Isolated yields (%).
Yields in parentheses are based on recovered starting materials.
As a means to further decorate the basic pyrrolo[1,2-a]pyrazine core, we have also designed a
strategy where alkylation of 2 and subsequent dehydrative cyclization in the presence of
NH OAc would give rise to more elaborate pyrrolo[1,2-a]pyrazines as outlined in Scheme 3.
4
As such, methyl, allyl, and benzyl groups were installed to give the corresponding products 5
by base-mediated alkylation with 2a and subsequent treatment of 5 with NH OAc afforded
4
1
2
3
,4-disubstituted pyrrolo[1,2-a]pyrazines 6.

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Scheme 3. Additional Introduction of Functional Groups to the Basic Pyrrolo[1,2-
a
a]pyrazine
entry
1
RX
5
6
MeI
b
5
a (50%)
6a (66%)
6b (89%)
6c (100%)
6d (100%)
6e (100%)
2
3
4
5
5
b (82%)
5
c (78%)
5
d (77%)
5
e (77%)
a
To a solution of 2a (0.23 mmol) in THF at 0 °C was added NaOt-Bu (2.5 equiv). After 5

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min stirring at 0 °C, appropriate alkylating agent (1 equiv) was added to the mixture unless
otherwise noted. A mixture of 5 (0.11 mmol) and NH OAc (3 equiv) in EtOH was heated at
4
b
1
20 °C for 2 h. Isolated yields (%) are in parentheses.
Further functionalization was conducted for additional diversification of this scaffold
1
3
(
Scheme 4). While bromination of 4c with NBS produced 7 in quantitative yield, Cu-
promoted decarboxylative acylation of 3a permitted a benzoyl moiety to be installed at C6
1
4
site in 83% yield. Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of 7 with 3,5-
dimethoxyphenyl boronic acid produced 8 with three different substituents at C3, C6, and C8
1
5
positions, respectively.
a
Scheme 4. Further Functionalization of Pyrrolo[1,2-a]pyrazines
a
A solution of 4c (0.1 mmol) and NBS (1 equiv) in CH Cl (2 mL) was stirred at 0 °C for 1 h.
2
2
A mixture of 7 (0.05 mmol), 3,5-dimethoxyphenylboronic acid (3 equiv), Pd(PPh ) (0.02
3
4
equiv), K PO (4 equiv) in toluene/EtOH/H O (1:1:1, 3 mL) was heated at 120 °C for 2 h. A
3
4
2
mixture of 3a (0.15 mmol), phenylglyoxylic acid (3 equiv), and Cu(OAc) (1.2 equiv) in
2
CH CN (1 mL) was stirred at 80 °C for 16 h.
3

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In conclusion, we were able to develop a facile route to novel diverse 3,6-disubstituted
pyrrolo[1,2-a]pyrazines by employing cyclodehydration and Pd-catalyzed direct C-H
arylation. Introduction of other functional groups to the basic pyrrolo[1,2-a]pyrazine core
was also demonstrated for additional diversity. Biological evaluation of these compounds is
in progress and will be reported in due course.
Experimental Section
General Methods
Unless specified, all reagents and starting materials were purchased from commercial sources
and used as received without purification. “Concentrated” refers to the removal of volatile
solvents via distillation using a rotary evaporator. “Dried” refers to pouring onto, or passing
through anhydrous magnesium sulfate followed by filtration. Flash chromatography was
performed using silica gel (230−400 mesh) with hexanes, ethyl acetate, and dichloromethane
as eluent. All reactions were monitored by thin-layer chromatography on 0.25 mm silica
1
13
plates (F-254) visualizing with UV light. H and C NMR spectra were recorded on 400
MHz NMR spectrometer and were described as chemical shifts, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of
protons. HRMS were measured with electrospray ionization (ESI) and Q-TOF mass analyzer.
Representative Procedure for the Synthesis of 3
A mixture of 2a (4.69 mmol) and NH OAc (3 equiv) in EtOH (16 mL) was stirred at 120 °C
4
for 2 h. After the reaction mixture was concentrated in vacuo, the residue was diluted with
dichloromethane (20 mL) and washed with water (20 mL). The water layer was extracted
with dichloromethane (10 mL) one more time. The combined organic layers were dried over

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MgSO and concentrated under reduced pressure. The resulting residue was purified by silica
4
gel column chromatography (hexanes:ethyl acetate:dichloromethane = 20:1:2) to give 3a
(810.7 mg, 89%).
3
-Phenylpyrrolo[1,2-a]pyrazine (3a). Pale green solid, mp 98.5-98.8 °C (810.7 mg, 89%);
−
1 1
IR (ATR) ν = 3089, 1610, 1481, 908, 761, 693 cm ; H NMR (100 MHz, CDCl ) δ 8.90 (s,
3
1
H), 8.23 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.50-7.43 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 6.90
1
3
(
dd, J = 2.8, 4.0 Hz, 1H), 6.81 (dd, J = 0.8, 4.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
1
44.8, 137.7, 137.4, 128.9, 128.1, 127.8, 126.0, 115.5, 115.3, 114.7, 103.4; HRMS (ESI)
+
calcd for C H N 195.0917 ([M+H] ), found 195.0908.
1
3
11
2
3
-(4-Methoxyphenyl)pyrrolo[1,2-a]pyrazine (3b). Pale green solid, mp 133.3-133.6 °C
−
1 1
(
778.3 mg, 74%); IR (ATR) ν = 3092, 1606, 1498, 1309, 1271, 909, 809, 724 cm ; H NMR
(
400 MHz, CDCl ) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.45 (s, 1H), 7.00 (d,
3
13
J = 8.8 Hz, 2H), 6.87 (s, 1H), 6.79 (s, 1H), 3.86 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
1
59.8, 144.7, 137.3, 130.3, 127.7, 127.3, 115.3, 115.2, 114.3, 113.7, 103.3, 55.5; HRMS (ESI)
+
calcd for C H N O 225.1022 ([M+H] ), found 225.1030.
1
4
13
2
3
-(3-Methoxyphenyl)pyrrolo[1,2-a]pyrazine (3c). Pale green solid, mp 77.7-78.1 °C (946.6
−
1 1
mg, 90%); IR (ATR) ν = 3094, 1603, 1483, 1269, 883 cm ; H NMR (400 MHz, CDCl ) δ
3
8
.89 (s, 1H), 8.21 (s, 1H), 7.52-7.49 (m, 1H), 7.47 (s, 1H), 7.45 (dd, J = 1.0, 7.6 Hz, 1H),
1
3
7
.36 (t, J = 7.8 Hz, 1H), 6.94-6.87 (m, 2H), 6.80 (d, J = 4.4 Hz, 1H), 3.89 (s, 3H); C NMR
(
100 MHz, CDCl ) δ 160.2, 144.6, 139.1, 137.1, 129.8, 127.8, 118.2, 115.5, 115.3, 114.8,
3
+
1
14.0 111.4, 103.4, 55.5; HRMS (ESI) calcd for C H N O 225.1022 ([M+H] ), found
1
4
13
2
2
25.1031.

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3
-(4-(Benzyloxy)phenyl)pyrrolo[1,2-a]pyrazine (3d). Pale green solid, mp 165.0-165.4 °C
1
(
1070.6 mg, 76%); H NMR (400 MHz, CDCl ) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 8.8
3
Hz, 2H), 7.49-7.43 (m, 3H), 7.40 (t, J = 6.8 Hz, 2H), 7.35-7.29 (m, 1H), 7.07 (d, J = 8.8 Hz,
1
3
2
H), 6.87 (dd, J = 2.4, 3.6 Hz, 1H), 6.79 (d, J = 4.0 Hz, 1H), 5.13 (s, 2H); C NMR (100
MHz, CDCl ) δ 159.0, 144.7, 137.3, 137.1, 130.6, 128.7, 128.1, 127.6, 127.3, 115.4, 115.3,
3
+
1
15.2, 113.8, 103.3, 70.2; HRMS (ESI) calcd for C H N O 301.1335 ([M+H] ), found
20
17
2
3
01.1333.
3
-(4-Fluorphenyl)pyrrolo[1,2-a]pyrazine (3e). Orange solid, mp 105.2-105.4 °C (686.8 mg,
−
1 1
6
9%); IR (ATR) ν = 3063, 1598, 1155, 1218, 909 cm ; H NMR (400 MHz, CDCl ) δ 8.87
3
(s, 1H), 8.16 (s, 1H), 7.92-7.79 (m, 2H), 7.47 (s, 1H), 7.18-7.07 (m, 2H), 6.89 (d, J = 2.3 Hz,
13
1
H), 6.81 (d, J = 3.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 163.0 (d, J
= 245.7 Hz),
3
C,F
1
44.8, 136.6, 133.8 (d, JC,F = 3.4 Hz), 127.8, 127.7, 115.8 (d, JC,F = 21.5 Hz), 115.6, 115.4,
+
1
14.4, 103.6; HRMS (ESI) calcd for C H FN 213.0823 ([M+H] ), found 213.0811.
1
3
10
2
3
-(4-Chlorophenyl)pyrrolo[1,2-a]pyrazine (3f). Pale green solid, mp 136.3-136.5 °C (761.5
−
1 1
mg, 71%); IR (ATR) ν = 3047, 1609, 1426, 813, 719 cm ; H NMR (400 MHz, CDCl ) δ
3
8
6
1
.88 (s, 1H), 8.20 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H),
1
3
.90 (dd, J = 2.4, 4.0 Hz, 1H), 6.81 (d, J = 4.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 144.8,
3
36.2, 136.2, 134.0, 129.1, 127.7, 127.2, 115.7, 115.5, 114.6, 103.7; HRMS (ESI) calcd for
+
C H ClN 229.0527 ([M+H] ), found 229.0519.
13
10
2
1
-Methyl-3-phenylpyrrolo[1,2-a]pyrazine (3g). Pale green solid, mp 60.7-61.1 °C (820.5
−
1 1
mg, 84%); IR (ATR) ν = 3086, 1445, 1367, 1286, 902 cm ; H NMR (100MHz, CDCl ) δ
3

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8
.09 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.48-7.39 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 6.83 (dd, J
1
3
=
2.4, 4.0 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 2.74 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
1
53.0, 138.0, 137.0, 128.9, 127.9, 127.4, 126.1, 115.6, 114.6, 113.3, 102.7, 22.0; HRMS (ESI)
+
calcd for C H N 209.1073 ([M+H] ), found 209.1083.
1
4
13
2
3
-Methylpyrrolo[1,2-a]pyrazine (3h). Brown solid, mp 82.3-82.6 °C (502.1 mg, 81%); IR
−1 1
(
ATR) ν = 3076, 2920, 1620, 1422, 916 cm ; H NMR (400 MHz, CDCl ) δ 8.74 (s, 1H),
3
7
.64 (s, 1H), 7.34-7.30 (m, 1H), 6.81 (dd, J = 2.4, 4.0 Hz, 1H), 6.73 (d, J = 4.0 Hz, 1H), 2.40
1
3
(
s, 3H); C NMR (100 MHz, CDCl ) δ 144.5, 135.4, 127.5, 115.0, 114.6, 114.2, 103.0, 20.9;
3
+
HRMS (ESI) calcd for C H N 133.0760 ([M+H] ) found 133.0764.
8
9
2
Representative Procedure for the Synthesis of 4
A mixture of 3a (0.26 mmol), 4-bromonitrobenzene (2.5 equiv), (PPh ) PdCl (5 mol %), and
3
2
2
KOAc (2 equiv) in DMA (1 mL) was stirred at 150 °C for 16 h. After the reaction mixture
was complete, the residue was diluted with ethyl acetate (2 mL) and washed with water (2
mL). The water layer was extracted with ethyl acetate (2 mL) one more time. The combined
organic layers were dried over MgSO and concentrated under reduced pressure. The
4
resulting residue was purified by silica gel column chromatography (hexanes:ethyl
acetate:dichloromethane = 30:1:2 to 10:1:2) to give 4a (71.3 mg, 87%).
6
-(4-Nitrophenyl)-3-phenylpyrrolo[1,2-a]pyrazine (4a). Orange solid, mp 176.0-176.2 °C
−
1 1
(
71.3 mg, 87%); IR (ATR) ν = 2919, 1587, 1338, 901, 687 cm ; H NMR (400 MHz, CDCl )
3
δ 9.00 (s, 1H), 8.52 (s, 1H), 8.41 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 7.6 Hz, 2H), 7.81 (d, J = 8.8
Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H) 7.39 (t, J = 7.2 Hz, 2H), 7.11 (d, J = 4.4 Hz, 1H), 6.97 (d, J
1
3
=
4.4 Hz, 1H); C NMR (100 MHz, CDCl ) δ 145.6, 139.3, 137.6, 137.4, 129.6, 129.1,
3

ACCEPTED MANUSCRIPT
1
28.6, 128.2, 126.3, 126.0, 124.9, 117.5, 111.4, 105.5; HRMS (ESI) calcd for C H N O
2
1
9
14
3
+
3
16.1081 ([M+H] ), found 316.1085.
3
,6-Diphenylpyrrolo[1,2-a]pyrazine (4b). Yellow solid, mp 97.3-97.4 °C (43.6 mg, 62%);
−
1 1
IR (ATR) ν = 3049, 1601, 1405, 901, 693 cm ; H NMR (400 MHz, CDCl ) δ 8.94 (s, 1H),
3
8
7
.49 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 2H), 7.47-
13
.39 (m, 3H), 7.35 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 4.0, 1H), 6.91 (d, J = 4.0 Hz, 1H); C
NMR (100 MHz, CDCl ) δ 145.2, 138.1, 138.0, 131.2, 129.4, 128.9, 128.5, 128.4, 128.3,
3
+
1
28.1, 126.2, 116.0, 111.6, 104.5; HRMS (ESI) calcd for C H N 271.1230 ([M+H] ),
1
9
15
2
found 271.1231.
4
-(3-Phenylpyrrolo[1,2-a]pyrazine-6-yl)benzonitrile (4c). Yellow solid, mp 156.0-156.3 °
−
1 1
C (52.2 mg, 68%); IR (ATR) ν = 3032, 2217, 1598, 1423, 901, 698 cm ; H NMR (400
MHz, CDCl ) δ 8.99 (d, J = 1.6 Hz, 1H), 8.48 (s, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.83 (d, J =
3
8
.4 Hz , 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.05
13
(
d, J = 4.0 Hz, 1H), 6.95 (d, J = 4.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 145.5, 139.1,
3
1
37.5, 135.7, 133.2, 129.4, 129.0, 128.5, 128.2, 126.3, 118.7, 117.1, 111.4, 111.3, 105.3;
+
HRMS (ESI) calcd for C H N 296.1182 ([M+H] ), found 296.1188.
2
0
14
3
4
-(3-Phenylpyrrolo[1,2-a]pyrazine-6-yl)benzaldehyde (4d). Yellow solid, mp 127.6-128.0 °
−1 1
C (52.7 mg, 68%); IR (ATR) ν = 3068, 1738, 1594, 1424, 901 cm ; H NMR (400 MHz,
CDCl ) δ 10.07 (s, 1H), 8.97 (s, 1H), 8.53 (s, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 7.2
3
Hz, 2H), 7.80 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.08 (s,
1
3
1
H), 6.94 (s, 1H); C NMR (100 MHz, CDCl ) δ 191.4, 145.4, 138.9, 137.5, 137.1, 135.5,
3

ACCEPTED MANUSCRIPT
1
30.8, 129.3, 129.0, 128.4, 128.1, 126.9, 126.2, 117.0, 111.5, 105.2; HRMS (ESI) calcd for
+
C H N O 299.1179 ([M+H] ), found 299.1181.
20
15
2
3
-(3-Phenylpyrrolo[1,2-a]pyrazine-6-yl)benzaldehyde (4e). Yellow solid, mp 109.5-110.0 °
−1 1
C (34.9 mg, 45%); IR (ATR) ν = 3062, 1690, 1572, 1405, 904 cm ; H NMR (400 MHz,
CDCl ) δ 10.12 (s, 1H), 8.98(s, 1H), 8.44 (s, 1H), 8.13 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.89
3
(d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.73 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H),
1
3
7
.37 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 6.95 (d, J = 4.0 Hz, 1H); C NMR (100
MHz, CDCl ) δ 191.9, 145.4, 138.6, 137.6, 137.4, 133.7, 132.3, 130.2, 129.4, 129.1, 128.9,
3
1
28.8, 128.3, 126.8. 126.2, 116.5, 111.3, 104.9; HRMS (ESI) calcd for C H N O 299.1179
20 15 2
+
(
[M+H] ), found 299.1179.
2
-(3-Phenylpyrrolo[1,2-a]pyrazine-6-yl)benzaldehyde (4f). Yellow solid, mp 97.2-97.4 °C
−
1
1
(
36.5 mg, 47%); IR (ATR) ν = 3062, 1682, 1597, 1486, 902 cm ; H NMR (400 MHz,
CDCl ) δ 9.90 (s, 1H), 9.00 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J = 7.6 Hz,
3
2
7
H), 7.77 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.4 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.34 (t, J =
13
.2 Hz, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.97 (d, J = 4.0 Hz, 1H); C NMR (100 MHz, CDCl )
3
δ 191.6, 145.2, 138.8, 137.5, 134.9, 134.5, 133.7, 131.1, 129.5, 129.1, 128.9, 128.7, 128.4,
+
1
26.3, 123.1, 119.0, 111.5, 104.5; HRMS (ESI) calcd for C H N O 299.1179 ([M+H] ),
2
0
15
2
found 299.1181.
Ethyl 4-(3-phenylpyrrolo[1,2-a]pyrazine-6-yl)benzoate (4g). Brown solid, mp 126.8-
−
1 1
1
27.0 °C (48.1 mg, 54%); IR (ATR) ν = 3062, 1682, 1597, 1486, 902 cm ; H NMR (400
MHz, CDCl ) δ 8.97 (s, 1H), 8.52 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 7.2 Hz, 2H),
3

ACCEPTED MANUSCRIPT
7
.71 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 4.4 Hz,
13
1
H), 6.93 (d, J = 4.0 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); C NMR
(
100 MHz, CDCl ) δ 166.2, 145.4, 138.6, 137.7, 135.5, 130.6, 129.8, 129.1, 129.0, 128.3,
3
1
27.7, 127.3, 126.2, 116.7, 111.6, 105.0, 61.3, 14.5; HRMS (ESI) calcd for C H N O
22 19 2 2
+
3
43.1441 ([M+H] ), found 343.1446.
Ethyl 3-(3-phenylpyrrolo[1,2-a]pyrazine-6-yl)benzoate (4h). Yellow gum (63.2 mg, 71%);
−1 1
IR (ATR) ν = 3030, 1703, 1603, 1422, 903 cm ; H NMR (400 MHz, CDCl ) δ 8.96 (s, 1H),
3
8
.46 (s, 1H), 8.31 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 8.0
Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.02 (d, J
13
=
4.0 Hz, 1H), 6.93 (d, J = 4.0 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz, CDCl ) δ 166.2, 145.3, 138.4, 137.8, 132.3, 131.8, 131.5, 129.5, 129.3,
3
1
29.2, 128.9, 128.7, 128.2, 127.3, 126.2, 116.3, 111.4, 104.7, 61.4, 14.5; HRMS (ESI) calcd
+
for C H N O 343.1441 ([M+H] ), found 343.1446.
2
2
19
2
2
6
-(4-Fluorophenyl)-3-phenylpyrrolo[1,2-a]pyrazine (4i). Yellow solid, mp 129.7-130.2 °C
−
1
1
(
44.2 mg, 59%); IR (ATR) ν = 3056, 1605, 1469, 1322, 901 cm ; H NMR (400 MHz,
CDCl ) δ 8.94 (s, 1H), 8.38 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.61-7.54 (m, 2H), 7.44 (t, J =
3
7
.2 Hz , 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 6.4 Hz, 2H), 6.93 (d, J = 4.0 Hz, 1H), 6.91
13
(
d, J = 4.0Hz, 1H); C NMR (100 MHz, CDCl ) δ 145.3, 138.2, 137.8, 130.22 (d, J
= 8.2
3
C,F
Hz), 128.9, 128.4, 128.2, 127.29, 127.26, 126.2, 116.5 (d, JC,F = 21.5 Hz), 116.0, 111.4,
+
1
04.5; HRMS (ESI) calcd for C H FN 289.1136 ([M+H] ), found 289.1141.
1
9
14
2
3
-Phenyl-6-(3-trifluoromethyl)phenyl)pyrrolo[1,2-a]pyrazine (4j). Yellow solid, mp 82.5-
−
1 1
8
2.9 °C (63.3 mg, 72%); IR (ATR) ν = 3057, 1069, 1485, 1118, 903 cm ; H NMR (400

ACCEPTED MANUSCRIPT
MHz, CDCl ) δ 8.96 (s, 1H), 8.41 (s, 1H), 7.85 (s, 2H), 7.83 (s, 1H), 7.79 (d, J = 6.4 Hz, 1H),
3
7
6
1
.70-7.62 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.6, 1H), 7.00 (d, J = 4.0 Hz, 1H),
13
.92 (d, J = 4.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 145.4, 138.6, 137.6, 132.1, 132.0,
3
31.8, 131.1, 129.9, 129.0, 128.8, 128.3, 126.6, 126.2, 125.2 (q, JC,F = 3.8 Hz), 124.9 (q, JC,F
+
=
3.8 Hz), 116.5, 111.2, 104.8; HRMS (ESI) calcd for C H F N 339.1104 ([M+H] ), found
20
14
3
2
3
39.1103.
6
-(4-Methoxyphenyl)-3-phenylpyrrolo[1,2-a]pyrazine (4k). Yellow gum (22.6 mg, 29%);
−
1
1
IR (ATR) ν = 2920, 1600, 1469, 1244, 1173, 901, 827, 768 cm ; H NMR (400 MHz,
CDCl ) δ 8.92 (s, 1H), 8.41 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.43 (t,
3
J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.90 (s, 2H), 3.90 (s, 3H);
1
3
C NMR (100 MHz, CDCl ) δ 159.7, 145.1, 138.0, 137.9, 129.8, 128.9, 128.3, 128.2, 128.1,
3
1
26.2, 123.5, 115.6, 114.8, 111.6, 104.4, 55.6; HRMS (ESI) calcd for C H N O 301.1335
20
17
2
+
(
[M+H] ), found 301.1335.
6
-(2,5-Dimethoxyphenyl)-3-phenylpyrrolo[1,2-a]pyrazine (4l). Yellow solid, mp 100.6-
01.0 °C (47.2 mg, 55%); IR (ATR) ν = 3029, 1610, 1478, 1457, 1376, 1016, 902, 802, 768
1
−
1 1
cm ; H NMR (400 MHz, CDCl ) δ 8.94 (s, 1H), 7.95 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.42
3
(t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.04-6.96 (m, 3H), 6.95 (d, J = 4.0 Hz, 1H), 6.92
1
3
(
d, J = 4.4 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H); C NMR (100 MHz, CDCl ) δ 153.9, 151.4,
3
1
44.4, 138.2, 137.1, 128.8, 128.4, 127.9, 126.1, 125.5, 120.6, 117.5, 116.7, 115.1, 114.0,
+
1
12.7, 103.9, 56.3, 56.0; HRMS (ESI) calcd for C H N O 331.1441 ([M+H] ), found
21
19
2
2
3
31.1443.
3
-Phenyl-6-(pyridine-3-yl)pyrrolo[1,2-a]pyrazine (4m). Pale yellow solid, mp 86.4-86.7 °

ACCEPTED MANUSCRIPT
−
1 1
C (43.0 mg, 61%); IR (ATR) ν = 3031, 1611, 1484, 902, 715, 693 cm ; H NMR (400 MHz,
CDCl ) δ 8.97 (s, 1H), 8.91 (s, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.41 (s, 1H), 7.91 (d, J = 7.6 Hz,
3
1
1
1
H), 7.85 (d, J = 8.0 Hz, 2H), 7.50-7.46 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 3.8 Hz,
1
3
H), 6.94 (d, J = 3.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ 149.21, 149.17, 145.4, 138.7,
3
37.5, 135.3, 129.0, 128.9, 128.3, 127.4, 126.2, 124.7, 124.0, 116.5, 111.1, 104.8; HRMS
+
(
ESI) calcd for C H N 272.1182 ([M+H] ), found 272.1180.
1
8
14
3
3
-(4-Methoxyphenyl)-6-(4-nitrophenyl)pyrrolo[1,2-a]pyrazine (4n). Orange solid, mp
1
70.9-171.5 °C (79.0 mg, 88%); IR (ATR) ν = 3077, 1588, 1495, 1460, 1397, 1337, 902,
−
1 1
8
2
1
1
03, 696 cm ; H NMR (400 MHz, CDCl ) δ 8.98 (s, 1H), 8.45 (s, 1H), 8.40 (d, J = 8.0 Hz,
3
H), 7.81-7.79 (m, 4H), 7.08 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 4.0 Hz,
1
3
H), 3.86 (s, 3H); C NMR (100 MHz, CDCl ) δ 160.2, 145.4, 139.1, 137.7, 129.9, 129.5,
3
28.1, 127.5, 125.8, 124.9, 117.3, 114.5, 110.4, 105.4, 55.5; HRMS (ESI) calcd for
+
C H N O 346.1186 ([M+H] ), found 346.1265.
20
16
3
3
4
-(3-(4-Methoxyphenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzonitrile (4o). Yellow solid, mp
20.2-220.7 °C (33.8 mg, 40%); IR (ATR) ν = 3052, 2224, 1602, 1497, 1369, 1244, 900,
2
−
1 1
8
7
38, 709 cm ; H NMR (400 MHz, CDCl ) δ 8.96 (s, 1H), 8.40 (s, 1H), 7.87-7.76 (m, 4H),
3
.74 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 3.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 3.6
13
Hz, 1H), 3.86 (s, 3H); C NMR (100 MHz, CDCl ) δ 160.1, 145.4, 138.9, 135.8, 133.2,
3
1
30.0, 129.3, 128.2, 127.5, 126.0, 118.8, 116.9, 114.4, 111.2, 110.3, 105.2, 55.5; HRMS (ESI)
+
calcd for C H N O 326.1288 ([M+H] ), found 326.1284.
2
1
16
3
Ethyl 4-(3-(4-methoxyphenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzoate (4p). Yellow solid,

ACCEPTED MANUSCRIPT
mp 121.4-121.8 °C (68.7 mg, 71%); IR (ATR) ν = 3077, 2926, 1704, 1602, 1499, 1368, 901,
−
1 1
8
2
8
08, 707 cm ; H NMR (400 MHz, CDCl ) δ 8.93 (s, 1H), 8.44 (s, 1H), 8.20 (d, J = 8.2 Hz,
3
H), 7.79 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.97 (d, J =
.6 Hz, 2H), 6.90 (d, J = 4.0 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.43 (t, J = 7.1
1
3
Hz, 3H); C NMR (100 MHz, CDCl ) δ 166.2, 159.9, 145.2, 138.4, 135.6, 130.6, 130.2,
3
1
29.7, 129.0, 127.6, 127.4, 127.1, 116.5, 114.3, 110.5, 104.8, 61.3, 55.5, 14.5; HRMS (ESI)
+
calcd for C H N O 373.1547 ([M+H] ), found 373.1545.
2
3
21
2
3
Ethyl 3-(3-(4-methoxyphenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzoate (4q). Yellow gum
62.0 mg, 64%); IR (ATR) ν = 3065, 2920, 1713, 1604, 1464, 1375, 1234, 902, 817, 750
(
−
1 1
cm ; H NMR (400 MHz, CDCl ) δ 8.93 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.10 (d, J = 7.8
3
Hz, 1H), 7.82-7.77 (m, 3H), 7.62 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 6.97 (d, J = 8.6
Hz, 2H), 6.91 (d, J = 4.0 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.43 (t, J = 7.1 Hz,
1
3
3
1
H); C NMR (100 MHz, CDCl ) δ 166.1, 159.7, 145.0, 138.1, 132.1, 131.6, 131.4, 130.2,
3
29.3, 129.1, 129.0, 128.5, 127.3, 126.9, 116.0, 114.2, 110.2, 104.4, 61.3, 55.4, 14.3; HRMS
+
(
ESI) calcd for C H N O 373.1547 ([M+H] ), found 373.1544.
2
3
21
2
3
3
-(4-Methoxyphenyl)-6-(3-trifluoromethyl)phenyl)pyrrolo[1,2-a]pyrazine (4r). Yellow
solid, mp 103.6-104.0 °C (65.1 mg, 68%); IR (ATR) ν = 3033, 2999, 16909, 1499, 1375,
−
1 1
1
7
1
1
310, 1119, 904, 809, 709 cm ; H NMR (400 MHz, CDCl ) δ 8.93 (s, 1H), 8.34 (s, 1H),
3
.86 (s, 1H), 7.81-7.74 (m, 3H), 7.69-7.63 (m, 2H), 7.01-7.64 (m, 3H), 6.90 (d, J = 4.1 Hz,
1
3
H), 3.84 (s, 3H); C NMR (100 MHz, CDCl ) δ 159.9, 145.3, 138.5, 132.1, 131.8, 131.1,
3
30.2, 129.9, 128.7, 127.4, 126.4, 125.4, 125.1 (q, JC,F =3.6 Hz), 124.7 (q, JC,F = 3.7 Hz),
+
1
16.3, 114.4, 110.1, 104.7, 55.5; HRMS (ESI) calcd for C H F N O 369.1209 ([M+H] ),
2
1
16
3
2
found 369.1207.

ACCEPTED MANUSCRIPT
3
-(4-Methoxyphenyl)-6-(pyridine-3-yl)pyrrolo[1,2-a]pyrazine (4s). Yellow solid, mp
1
00.0-100.5 °C (52.5 mg, 67%); IR (ATR) ν = 3098, 2960, 1609, 1460, 1393, 905, 800, 709
−
1 1
cm ; H NMR (400 MHz, CDCl ) δ 8.95 (s, 1H), 8.91 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.34
3
(s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.48 (dd, J = 4.8 Hz, 7.6 Hz, 1H),
1
3
7
.00 (d, J = 4.2 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 4.2 Hz, 1H), 3.85 (s, 3H); C
NMR (100 MHz, CDCl ) δ 160.0, 149.18, 149.15, 145.3, 138.6, 135.3, 130.1, 128.9, 127.5,
3
1
27.4, 124.5, 124.1, 116.4, 114.3, 110.1, 104.8, 55.5; HRMS (ESI) calcd for C H N O
19 16 3
+
3
02.1288 ([M+H] ), found 302.1287.
3
-(3-(3-Methoxyphenyl)-6-nitrophenylpyrrolo[1,2-a]pyrazine (4t). Orange solid, mp 89.1-
−
1 1
8
9.6 °C (52.3 mg, 67%); IR (ATR) ν = 3049, 1601, 1405, 901, 693 cm ; H NMR (400
MHz, CDCl ) δ8.94 (s, 1H), 8.49 (s, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H),
3
7
6
1
.48-7.38 (m, 3H), 7.34 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 4.2 Hz, 1H), 6.92 (d, J = 4.2 Hz, 1H),
1
3
.91-6.88 (m, 1H), 3.88 (s, 3H); C NMR (100 MHz, CDCl ) δ 160.2, 145.1, 139.4, 137.9,
3
31.1, 129.9, 129.4, 128.6, 128.33, 128.30, 118.5, 116.1, 113.9, 111.9, 104.6, 55.6; HRMS
+
(
ESI) calcd for C H N O 301.1335 ([M+H] ), found 301.1336.
2
0
17
2
3
-(3-(3-Methoxyphenyl)-6-(4-nitrophenyl)pyrrolo[1,2-a]pyrazine (4u). Orange solid, mp
1
55.3-155.8 °C (73.6 mg, 82%); IR (ATR) ν = 3088, 2997, 1590, 1487, 1333, 850, 772, 686
−
1 1
cm ; H NMR (400 MHz, CDCl ) δ9.00 (s, 1H), 8.51 (s, 1H), 8.41 (d, J = 8.8 Hz, 2H), 7.81
3
(d, J = 8.8 Hz, 2H), 7.48 (s, 1H), 7.43-7.33 (m, 2H), 7.11 (d, J = 4.4 Hz, 1H), 6.97 (d, J = 4.4
1
3
Hz, 1H), 6.96-6.91 (m, 1H), 3.89 (s, 3H); C NMR (100 MHz, CDCl ) δ 160.3, 145.5, 139.8,
3
1
39.0, 138.9, 137.8, 137.6, 130.0, 128.2, 124.9, 118.4, 117.5, 114.2, 112.0, 111.6, 105.5, 55.6;

ACCEPTED MANUSCRIPT
+
HRMS (ESI) calcd for C H N O 346.1186 ([M+H] ), found 346.1185.
2
0
16
3
3
4
-(3-(3-Methoxyphenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzonitrile (4v). Yellow solid, mp
1
1
47.9-148.3 °C (68.5 mg, 81%); H NMR (400 MHz, CDCl ) δ8.98 (s, 1H), 8.47 (s, 1H),
3
7
.83 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.47 (s, 1H), 7.42-7.33 (m, 2H), 7.05 (d, J
1
3
=
4.0 Hz, 1H), 6.95 (d, J = 4.0 Hz, 1H), 6.94-6.90 (m, 1H), 3.89 (s, 3H); C NMR (100 MHz,
CDCl ) δ 160.3, 145.5, 139.0, 138.9, 135.7, 133.2, 130.0, 129.4, 128.2, 126.3, 118.4, 117.1,
3
1
14.1, 112.0, 111.5, 111.4, 105.3, 55.6; HRMS (ESI) calcd for C H N O 326.1282
21 16 3
+
(
[M+H] ), found 326.1288.
3
-(4-(Benzyloxy)phenyl)-6-(4-nitrophenyl)pyrrolo[1,2-a]pyrazine (4w). Orange solid, mp
1
75.2-175.9 °C (67.9 mg, 62%); IR (ATR) ν = 3032, 2920, 2851, 1590, 1454, 1230, 900,
−
1 1
7
2
7
29, 694 cm ; H NMR (400 MHz, CDCl ) δ 8.98 (s, 1H), 8.44 (s, 1H), 8.40 (d, J = 8.8 Hz,
3
H), 7.83-7.76 (m, 4H), 7.48-7.43 (m, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H),
1
3
.08 (d, J = 4.4 Hz, 1H), 7.07-7.04 (m, 2H), 6.95 (d, J = 4.4 Hz, 1H), 5.13 (s, 2H); C NMR
(
100 MHz, CDCl ) δ 159.3, 146.8, 145.4, 139.1, 137.7, 134.9, 130.2, 129.5, 128.8, 128.2,
3
1
28.1, 127.6, 127.5, 124.9, 117.3, 115.4, 110.4, 105.4, 70.2; HRMS (ESI) calcd for
+
C H N O 422.1499 ([M+H] ), found 422.1501.
26
20
3
3
4
-(3-(4-(Benzyloxy)phenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzonitrile (4x). Yellow solid,
mp 183.8-184.2 °C (57.4 mg, 55%); IR (ATR) ν = 3031, 2921, 2888, 2221, 1600, 1496,
−
1 1
1
173, 903, 806, 723 cm ; H NMR (400 MHz, CDCl ) δ 8.94 (s, 1H), 8.39 (s, 1H), 7.80-
3
7
.76 (m, 4H), 7.72 (d, J = 8.4 Hz, 2H), 7.47-7.42 (m, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.33 (t, J
=
7.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 4.3 Hz, 1H), 6.92 (d, J = 4.3 Hz, 1H),

ACCEPTED MANUSCRIPT
1
3
5
.11 (s, 2H); C NMR (100 MHz, CDCl ) δ 159.2, 145.4, 138.9, 136.9, 135.8, 133.2, 130.2,
3
1
29.3, 128.7, 128.2, 128.1, 127.6, 127.5, 126.0, 118.7, 116.9, 115.3, 111.2, 110.3, 105.1, 70.2;
+
HRMS (ESI) calcd for C H N O 402.1601 ([M+H] ), found 402.1599.
2
7
20
3
4
-(3-(4-(Benzyloxy)phenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzaldehyde (4y). Yellow solid,
mp 139.2-139.8 °C (27.3 mg, 26%); IR (ATR) ν = 3035, 2919, 1689, 1595, 1494, 1452,
−
1 1
1
167, 808 cm ; H NMR (400 MHz, CDCl ) δ 10.08 (s, 1H), 8.95 (s, 1H), 8.47 (s, 1H), 8.04
3
(d, J = 8.0 Hz, 2H), 7.82-7.77 (m, 4H), 7.48-7.42 (m, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.33 (t, J
=
7.2 Hz, 1H), 7.09-7.06 (m, 2H), 7.05 (d, J = 4.4 Hz, 1H), 6.93 (d, J = 4.4 Hz, 1H), 5.12 (s,
1
3
2
1
H); C NMR (100 MHz, CDCl ) δ 191.5, 159.2, 145.3, 138.8, 137.2, 136.9, 135.4, 130.8,
3
30.4, 129.3, 128.8, 128.2, 128.1, 127.6, 127.5, 126.8, 116.9, 115.4, 110.6, 105.1, 70.2;
+
HRMS (ESI) calcd for C H N O 405.1598 ([M+H] ), found 405.1594.
2
7
21
2
2
4
-(3-(4-Fluorophenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzonitrile (4z). Yellow solid, mp
2
19.4-219.8 °C (42.4 mg, 52%); IR (ATR) ν = 3000, 2919, 2220, 1598, 1493, 901, 814, 774
−
1 1
cm ; H NMR (400 MHz, CDCl ) δ 8.97 (s, 1H), 8.42 (s, 1H), 7.87-7.80 (m, 4H), 7.74 (d, J
3
13
=
8.4 Hz, 2H), 7.15 (t, J = 8.4 Hz, 2H), 7.05 (d, J = 4.2 Hz, 1H), 6.96 (d, J = 4.2 Hz, 1H); C
NMR (100 MHz, CDCl ) δ 145.5, 138.3, 135.64, 133.6 (d, J = 3.2 Hz), 133.3, 129.3,
3
C,F
1
28.2, 128.0 (d, JC,F = 8.2 Hz), 126.3, 118.7, 117.1, 115.9 (d, JC,F = 21.5 Hz), 111.5, 111.0,
+
1
05.4; HRMS (ESI) calcd for C H FN 314.1088 ([M+H] ), found 314.1090.
2
0
13
3
Ethyl 4-(3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzoate (4aa). Yellow gum (54.3
−
1 1
mg, 58%); IR (ATR) ν = 3042, 2984, 1710, 1603, 1497, 1268, 1096, 902, 812, 701 cm ; H
NMR (400 MHz, CDCl ) δ 8.94 (s, 1H), 8.46 (s, 1H), 8.22 (d, J = 7.2 Hz, 2H), 7.83 (dd, J =
3
5
.6, 7.2 Hz, 2H), 7.70 (d, J = 7.2 Hz, 2H), 7.13 (t, J = 8.4 Hz , 2H), 7.05 (d, J = 4.0 Hz, 1H),

ACCEPTED MANUSCRIPT
1
3
6
.94 (d, J = 4.0 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); C NMR (100
MHz, CDCl ) δ 166.2, 164.3, 161.8, 145.4, 137.8, 135.4, 133.8 (d, J = 3.2 Hz), 130.7, 129.9,
3
1
29.0, 127.9 ((d, JC,F = 8.1 Hz), 127.7, 127.4, 116.7, 115.9 (d, JC,F = 21.5 Hz), 111.3, 105.1,
+
6
1.4, 14.5; HRMS (ESI) calcd for C H FN O 361.1347 ([M+H] ), found 361.1344.
2
2
18
2
2
Ethyl 3-(3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzoate (4ab). Yellow solid, mp
1
1
00.2-100.6 °C (51.5 mg, 55%); H NMR (400 MHz, CDCl ) δ 8.93 (s, 1H), 8.40 (s, 1H),
3
8
.31 (s, 1H), 8.11 (d, J = 7.7 Hz, 2H), 7.87-7.80 (m, 2H), 7.79 (d, J = 7.7 Hz, 1H), 7.62 (t, J =
.7 Hz, 1H), 7.12 (t, J = 8.6 Hz, 2H), 7.02 (d, J = 4.0 Hz, 1H), 6.93(d, J = 4.0 Hz, 1H), 4.43
7
1
3
(
q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl ) δ 166.2, 164.2,
3
1
61.8, 145.3, 137.6, 133.9, 132.3, 131.8, 131.4, 129.5, 129.2 (d, JC,F = 2.5 Hz), 128.6, 127.9
(d, JC,F = 8.1 Hz), 127.3, 116.4, 115.8 (d, JC,F = 21.5 Hz), 111.1, 104.8, 61.5, 14.5; HRMS
+
(
ESI) calcd for C H FN O 361.1347 ([M+H] ), found 361.1342.
2
2
18
2
2
3
-(4-Chlorophenyl)-6-(4-nitrophenyl)pyrrolo[1,2-a]pyrazine (4ac). Orange solid, mp
2
29.2-229.6 °C (70.0 mg, 77%); IR (ATR) ν = 3061, 2917, 1587, 1427, 1503, 1335, 804,
−
1 1
7
7
23 cm ; H NMR (400 MHz, CDCl ) δ 8.99 (s, 1H), 8.49 (s, 1H), 8.41 (d, J = 8.0 Hz, 2H),
3
.90-7.37 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 3.9 Hz, 1H), 6.98 (d, J = 3.9 Hz, 1H);
1
3
C NMR (100 MHz, CDCl ) δ 147.0, 145.6, 138.1, 137.5, 135.8, 134.6, 129.5, 129.2, 128.2,
3
1
27.4, 126.1, 124.9, 117.6, 111.3, 105.7; HRMS (ESI) calcd for C H ClN O 350.0691
1
9
13
3
2
+
(
[M+H] ), found 350.0696.
4
-(3-(4-Chlorophenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzonitrile (4ad). Yellow solid, mp
03.0-203.4 °C (53.2 mg, 62%); IR (ATR) ν = 3045, 2980, 2223, 1602, 1487, 902, 809, 787,
2

ACCEPTED MANUSCRIPT
−
1 1
7
7
25 cm ; H NMR (400 MHz, CDCl ) δ 8.97 (s, 1H), 8.45 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H),
3
.81 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 4.2
13
Hz, 1H), 6.96 (d, J = 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 145.6, 138.0, 135.9, 135.6,
3
1
34.5, 133.3, 129.2, 128.29, 128.26, 127.4, 118.7, 117.2, 111.5, 111.3, 110.8, 105.5; HRMS
+
(
ESI) calcd for C H ClN 330.0787 ([M+H] ), found 330.0789.
2
0
13
3
4
-(3-(4-Chlorophenyl)pyrrolo[1,2-a]pyrazine-6-yl)benzaldehyde (4ae). Yellow solid, mp
64.8-165.3 °C (24.2 mg, 28%); IR (ATR) ν = 2920, 1600, 1469, 1244, 1173, 901, 827, 768
1
−
1 1
cm ; H NMR (400 MHz, CDCl ) δ 10.09 (s, 1H), 8.96 (s, 1H), 8.52 (s, 1H), 8.06 (d, J = 8.2
3
Hz, 2H), 7.85-7.77 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 4.2 Hz, 1H), 6.96 (d, J =
1
3
4
1
.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 191.5, 145.5, 137.8, 137.0, 136.0, 135.6, 134.4,
3
30.8, 130.5, 129.3, 129.1, 128.2, 127.4, 127.2, 117.2, 111.5, 105.5; HRMS (ESI) calcd for
+
C H ClN O 333.0789 ([M+H] ), found 333.0787.
20
14
2
Ethyl 4-(3-(4-chlorophenyl)pyrrolo[1,2-a]pyrazin-6-yl)benzoate (4af). Yellow solid, mp
−1
1
29.3-129.7 °C (49.0 mg, 50%); IR (ATR) ν = 3034, 2985, 1720, 1425, 1269, 902, 806 cm ;
1
H NMR (400 MHz, CDCl ) δ 8.91 (s, 1H), 8.46 (s, 1H), 8.20 (d, J = 8.2 Hz, 2H), 7.78 (d, J
3
=
8.4 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 4.0 Hz, 1H),
1
3
6
.92 (d, J = 4.0 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); C NMR (100
MHz, CDCl ) δ 166.1, 145.4, 137.4, 136.1, 135.3, 134.2, 130.6, 129.9, 129.02, 128.95, 127.7,
3
1
27.4, 127.3, 116.8, 111.5, 105.2, 61.3, 14.5; HRMS (ESI) calcd for C H ClN O 377.1051
22 18 2 2
+
(
[M+H] ), found 377.1059.
Ethyl 3-(3-(4-chlorophenyl)pyrrolo[1,2-a]pyrazin-6-yl)benzoate (4ag). Yellow solid, mp