Synthesis of new tetrahydropyridopyrazine derivatives via continuous flow chemistry approach and their spectroscopic characterizations

Article abstract of DOI:10.1002/jhet.4270

We report here the synthesis of different substituted tetrahydropyridopyrazine derivatives. This approach of synthesis has been designed in a way that in first simple chloro-amine coupling as an alternative of Buchwald coupling followed by heterogeneous h

Full text of DOI:10.1002/jhet.4270

Received: 22 January 2021
DOI: 10.1002/jhet.4270
Revised: 27 March 2021
Accepted: 6 April 2021
A R T I C L E
Synthesis of new tetrahydropyridopyrazine derivatives via
continuous flow chemistry approach and their
spectroscopic characterizations
1
1
1
Nilesh D. Parmar | Sanjay D. Hadiyal | Vimal H. Kapupara
|
2
1
Jaydeep N. Lalpara | Hitendra S. Joshi
1
Department of chemistry, Saurashtra
Abstract
University, Rajkot, India
2
We report here the synthesis of different substituted tetrahydropyridopyrazine
derivatives. This approach of synthesis has been designed in a way that in first
simple chloro-amine coupling as an alternative of Buchwald coupling followed
by heterogeneous hydrogenation of nitro to give amine and further cyclization
of this amine with carboxylic acid was accomplished in a single process with
the help of continuous flow hydrogenation reactor. This processing was a gen-
eration of hydrogen (in situ) by electrolysis of water molecule and using a pre-
packed cartridge of a palladium catalyst. In a further step, LAH was used to
reduce lactam to a yielding product as tetrahydropyridopyrazine (TPP) scaf-
fold. Final adducts were obtained using substituted benzoyl and sulfonyl
derivatives.
SREZ Campus, Saurashtra University,
Rajkot, India
Correspondence
Hitendra S. Joshi, Department of
chemistry, Saurashtra University, Rajkot,
Gujarat, 360005, India.
Email: drhsjoshichem@gmail.com
Funding information
University Grants Commission, Grant/
Award Number: 43-178/2014
1
| INTRODUCTION
potential of TPP, some of the methods for the synthesis
of TPP derivatives are found in the literature [11]. One of
Preparation of nitrogen containing heterocyclic deriva-
tives with a stereo center is a major challenge in stereo
chemistry related synthesis. Out of which one of moiety
is tetrahydropyridopyrazine (TPP) subunits. Nitrogen
containing scaffolds were used as antitubercular (TB) [1],
anaplastic lymphoma kinease (ALK) inhibitor [2], anti-
diabetic [3], anticancer [4], and PARP inhibitor. Various
analogs of pyridopyrazines were part of various pep-
tidomimetic scaffolds [5]. These analogs showed many
biological activities like antimalarial precursor
the most popular methods is the reduction of two ketonic
groups [12]. Most of these methods invite a logical syn-
thesis of one or two isomers of TPP bearing one
stereogenic center [13]. Recently, we have synthesized a
standard three-step synthetic approach for the stereo con-
flicting synthesis of TPP as a scaffold. This approach of
synthesis has been designed with a coupling of both syn-
thons DL-Proline and substituted pyridine [14]. Here, we
have carried out this step with simple Chloro-amine cou-
pling as an alternative of Buchwald coupling, followed by
reduction and cyclization of the isolated intermediate in
a single step via continuous flow hydrogenation reactor,
using palladium as a catalyst to get an intermediate with
one stereocenter. Then reduction of amidic ketone with a
strong base [15] to yield TPP scaffold (Scheme 1).
2
-alkoxycarbonylaminopyridine HIV-1 integrase inhibi-
tors [6], ADP-Ribose polymerase inhibitors (PARP) [7],
and inhibitors of Mycobacterium tuberculosis FtsZ
(Filament temperature-sensitive protein Z) [8]. Some of
the derivatives such as Pyrido [2, 3-d] pyrimidine acted as
adenosine antagonists receptor [9].
In continuation to this, the effective method for new
drug discoveries is the bioisosteric replacement of a func-
tional group [10]. Due to their encouraging biological
The relative configuration of this intermediate at chi-
ral atom (C6) remains constant after reaction with a suit-
able nucleophile and the product will become a
stereospecific product. In this context to the synthesis of
J Heterocyclic Chem. 2021;1–9.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
PARMAR ET AL.
compound (d), continuous flow hydrogenation chemistry
technology presents an interesting alternative to batch
processing. Using H-Cube is promoted due to prepacked
Pd-catalyst cartridge and in situ hydrogen generation that
provide secure and authentic method to perform hydro-
genation under bar pressure [16–18]. In this report, we
explore the reduction and cyclization of compound (c)
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
Our principal focus was to reaction conditions optimiza-
tion for catalytic heterogeneous hydrogenation using the
H-cube mini hydrogenation reactor. The synthesis car-
ried out via preparing 0.05 M stock solution of
(3-nitropyridin-2-yl)proline (c) (Scheme 1) and TPP scaf-
folds (TPP) (d) in methanol. Started pumping this solu-
tion with ensuring that no air was introduced in vessel
and clear solution was passed throughout the system
using a standard Palladium catalyst (5% w/w and 10%
w/w) in sealed cartridge with 1.0 and 2.0 mL/min flow
rate, simultaneously at various temperature and hydro-
gen pressure.
(Scheme 1) under a continuous flow chemistry approach
and create a qualitative comparison with selectivity and
reaction rate, which is newly reported for scale-up hydro-
genation reactions performed by H-cube mini hydrogena-
tion reactor.
The degree of conversion was monitored using TLC
analysis. Approximately 10% conversion to d (Table 1,
entry 1) was obtained on passing reaction mixture at a
ꢀ
1
2
.0 mL/min flow rate over 5% Pd/C heated to 80 C and
5 bar (ꢁ350 PSI) pressure. Temperature and pressure
ꢀ
will increase conversion growing up to 70% at 100 C and
4
0 bar pressure (Table 1, entry 3). However, an increase
ꢀ
in catalyst concentration to 10% w/w Pd/C at 90 C and
40 bar pressure would give nearly 100% conversion
(
Table 1, entry 4). Due to this phenomenon, we have
ꢀ
increased the temperature 90 to 95 C keeping the pres-
sure same to get 100% conversion (Table 1, entry 5). The
reaction was then performed by using different flow rates
at different temperatures and pressures. Initially, there
was no conversion at 2.0 mL/min flow rate over 5% Pd/C
SCHEME 1 Synthetic route for tetrahydropyridopyrazine
scaffolds (e)
ꢀ
at 60 C and 25 bar pressure (Table 1, entry 6) but the
TABLE 1 Optimization of the reaction conditions
ꢀ
Entry
Catalyst
Flow rate (mL/min)
Temp ( C)
Pressure [bar]
Conversion [%]
1
2
3
4
5
6
7
8
9
Pd/C (5% w/w)
Pd/C (5% w/w)
Pd/C (5% w/w)
Pd/C (10%w/w)
Pd/C (10%w/w)
Pd/C (5% w/w)
Pd/C (5% w/w)
Pd/C (10% w/w)
Pd/C (10%w/w)
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
80
25
30
40
40
40
25
30
30
35
10
30
70
95
100
-
90
100
90
95
60
80
20
60
100
80
100
Note: Bold value indicates final optimal condition and all derivatives were synthesized according to entry 9.

PARMAR ET AL.
3
slight increase in conversion shows the increase in tem-
perature and pressure (Table 1, entry 7). An increase in
catalyst concentration to 10% w/w Pd/C at same flow rate
of 2.0 mL/min gave 60% of conversion and increase in
temperature and pressure to 100 C and 35 bar gave con-
version to 100% product (Table 1, entry 9). Therefore, the
amine coupling reactions and various substituted sulfo-
nyl derivatives 3a-f (Scheme 2).
Further, we undertook the synthesis of (5-[substitu
tedphenyl]sulfonyl)-5,6,6a,7,8,9-hexahydropyrido[3,2-e]p
yrrolo[1,2-a]pyrazine, 3a-f from the corresponding scaf-
fold, TPP. The conversion was completed within 70 to
80 minutes to get brown color crude material as gummy
liquid, which was purified by column chromatography
using 230 to 400 mesh size silica gel using Ethyl acetate:
n-Hexane (1:9, 3:7, and 4:6) as eluent to afford the desired
product as off white to white solid with good yields in all
cases. The nature of the substituent on the benzene sulfo-
nyl chloride did not affect the reaction time.
A single crystal of (4-chlorophenyl)(6a,7,8,9-tetrahydr
opyrido[3,2-e]pyrrolo[1,2-a]pyrazin-5[6H]-yl)methanone,
2a (Figure 1) and (6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazin-5[6H]-yl)(p-tolyl)methanone, 2d crystal-
lized as a colorless block crystal, this species adopted a
lattice type primitive triclinic crystal system containing
P-1 space group. (Figure 2) [19–20]. A single crystal of
(3-bromophenyl)(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazin-5(6H)-yl)methanone, 2h crystallized as a
ꢀ
optimal conditions for the preparation of compound (d)
ꢀ
are catalyst cartridge loading to 10% w/w at 100 C tem-
perature and 35 bar pressure. There were no blockage
issues found in the hydrogenation reaction. A plausible
mechanism was proposed in accordance with previous
literature reports [14–18] as shown in (Scheme 2).
We presume that the aromatic nucleophilic substitu-
tion reaction between compound I and compound II give
intermediate III. This accelerates the intramolecular
cyclization reaction by continuous flow synthesis
approach subsequently reduction of a nitro group (inter-
mediate IV) to form the intermediate V. It then treated
with the strong reducing agent to reduce the amidic
ketone to afford the desired scaffold VI. Then we demon-
strate the possibility of reaction by synthesizing diverse
substituted benzoyl derivatives 2a-o using the chloro-
SCHEME 2 Synthetic route of (4-substituted phenyl)(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-5(6H)-yl)methanone
derivatives (2a-o) & 5-((substituted phenyl)sulfonyl)-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine derivatives (3a-f)

4
PARMAR ET AL.
FIGURE 1 X-ray crystal structure
compound 2a
FIGURE 2 X-ray crystal structure
compound 2d
yellow block crystal, this species adopted a primitive lat-
tice type monoclinic crystal system space group P21/c,
containing an electron-withdrawing group. The simple
benzoyl chloride provided
a
good yield of the
(Figure 3) [21].
corresponding products. All synthesized compounds were
1
characterized by analytical techniques (FT-IR, H NMR,
13
C NMR, Mass, and Elemental analysis). Compound 2a,
3
| CONCLUSION
2d, and 2h were also characterized by single crystal X-ray
diffraction study.
In conclusion, we developed two series of (4-substituted
phenyl)(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyr
azin-5(6H)-yl)methanone
derivatives
(2a-o)
and
4 | EXPERIMENTAL
4.1 | General
5
-([substituted phenyl]sulfonyl)-5,6,6a,7,8,9-hexahydropy
rido[3,2-e]pyrrolo[1,2-a]pyrazine derivatives (3a-f) by H-
cube hydrogenator via continuous flow chemistry
approach. Different benzoyl chloride containing an
electron-donating group reacted slightly better than those
All chemicals were purchased from Merck, all purchased
chemicals were used without further purification.

PARMAR ET AL.
5
FIGURE 3 X-ray crystal structure
of compound 2h
Reactions were monitored by thin layer chromatography
PhMe (30 mL) solvent after that addition of Potassium
carbonate (5.23 gm, 37.84 mmol). The reaction mixture
was stirred at 110 C for 6 hours. Progress of reaction was
(
0
(
TLC) on silica gel-G plates (G60 F254 [Merck]) of
.5 mm thickness, visualizing with ultraviolet light
254 and 365 nm), or with iodine vapor or aq. KMnO4.
ꢀ
monitored by TLC. After completion of the reaction
excess of solvent was evaporated under reduced pressure,
then add 1 N HCl (40 mL), a yellow precipitate was
observed, which was separated by filtration to give
(3-nitropyridin-2-yl)proline (c) as a yellow solid: yield 2.8
Melting points were determined using a Buchi B-540 cap-
illary apparatus. IR data were recorded on a Shimadzu
FT-IR-8400 instrument using DRS (diffusive reflectance
À1
system) method and are reported in cm (KBr). NMR
ꢀ
ꢀ
1
spectra were recorded on a Bruker Advance 400 MHz
gm (93%); mp 145 C to 146 C; H NMR (400 MHz,
1
spectrometer (400 MHz for H NMR and 101 MHz for
DMSO-d ): δ 12.547 (s, 1H, COOH), 8.351 to 8.336 (q,
6
13
C NMR), respectively, in deuterated solvents like
1H, J = 1.6, 4.4 Hz, ArH), 8.203 to 8.179 (q, 1H, J = 1.6,
8.0 Hz, ArH), 6.849 to 6.818 (q, 1H, J = 4.4, 8.0 Hz, ArH),
4.599 to 4.564 (t, 1H, J = 14.0 Hz, Chiral), 3.211 to 3.167
(qt, 1H, J = 17.6 Hz), 3.056 to 3.002 (m, 1H), 2.335 to
2.288 (m, 1H), 2.022 to 1.940 (m, 3H); Anal. calcd. for
C H N O : C, 50.63; H, 4.67; N, 17.71. Found: C,
DMSO-d6 and CDCl . chemical shifts are referenced to
3
the solvent residual signals with respect to tetra-
methylsilane. Elemental analysis was carried out on Euro
EA 3000 elemental analyzer and the results are in agree-
ment with the structures assigned. The control of reac-
tion temperature was monitored by a ruby thermometer.
Mass spectra were recorded on a Shimadzu GC-MS-QP-
10
11 3 4
50.58; H, 4.68; N, 17.80.
2
010 mass spectrometer in EI (70 eV) model using direct
inlet probe technique and m/z is reported in atomic units
per elementary charge. Single crystal X-Ray was carried
out using Rigaku-SCX Mini Single Crystal X-Ray diffrac-
tometer. Flow hydrogenation reaction was carried out on
ThalesNano, Nanotechnology, H-Cube Mini Plus Hydro-
genation Reactor.
4.1.2 | Synthesis of
6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazin-6(5H)-one (d)
To stir a solution of (3-nitropyridin-2-yl)proline, c (2.8
gm, 11.8 mmol) in methanol (100 mL) in 250 mL conical
flask. Stir it for 5 minutes at room temperature to get a
clear yellow color solution. In the hydrogenator reactor
(H-Cube mini plus) put the vessel containing inlet line
4.1.1 | Synthesis of (3-nitropyridin-2-yl)
proline (c)
into the clear solution and is passed through the system
containing 35 bar pressure of H gas and 90 C tempera-
ꢀ
2
To stir a solution of 2-chloro-3-nitropyridine, a (2.0 gm,
ture using a standard Palladium catalyst (10% w/w) car-
tridge at 2.0 mL/min flow rate. The degree of conversion
1
2.61 mmol), DL-Proline, b (1.44 gm, 12.61 mmol) in

6
PARMAR ET AL.
was established by monitoring on TLC plate. Collect the
product continuously, excess solvent was evaporated
under reduced pressure, to give 6a,7,8,9-tetrahydropyrido
dichloromethane (12 mL) in 50 mL dry RBF, after that
keep into ice bath and dropwise additon of triethyl amine
(1.19 mL, 8.5 mmol). Now, allow to stir the reaction mix-
ꢀ
[
3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (d) as light green
ture at O C for 10 minutes and then add benzoylchloride
ꢀ
ꢀ
1
solid; yield 1.8 gm (80%); mp 129 C to 130 C; H NMR
400 MHz, DMSO-d ): δ 10.473 (s, 1H, NH), 7.712 to
substrate (3.4 mmol), further stir the reaction mass at
room temperature for 2 hours. After completion of reac-
tion (checked by TLC), the reaction mixture was poured
in ice-cooled water (100 mL) and extracted with dic-
hloromethane (3 Â 20 mL). The combined organic layer
was dried over anhydrous Na SO and removed the sol-
(
6
7
.702 (d, 1H, J = 4.0 Hz, ArH), 6.989 to 6.972 (d, 1H
J = 6.8 Hz, ArH), 6.608 to 6.577 (qt, 1H, J = 7.2 Hz,
ArH), 3.996 to 3975 (t, 1H, J = 8.4 Hz), 3.617 to 3.556 (m,
1
H), 3.399 to 3.362 (m, 1H), 2.184 to 2.129 (m, 1H), 1.949
2
4
to 1.869 (m, 3H); Anal. calcd. for C H N O: C, 63.48; H,
vent under vacuum to give crude material, which was
10
11 3
5
.86; N, 22.21. Found: C, 63.41; H, 5.82; N, 22.27.
purified by flash column chromatography using 230 to
400 mesh size silica gel using Ethyl acetate: n-Hexane
(
2:8, 4:6 and 5:5) as eluent to afford the pure product.
Substrate scope for the synthesis of benzoyl deriva-
4
5
.1.3 | Synthesis of
,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo
tives (2a-o) is shown in Supplementary Material file,
Table S2.
[1,2-a]pyrazine (e)
To a stirred solution of 6a,7,8,9-tetrahydropyrido[3,2-e]
pyrrolo[1,2-a]pyrazin-6(5H)-one, d (1.8 gm, 9.5 mmol) in
THF (5 mL) and anhydrous diethyl ether (40 mL)
in 50 mL dry RBF. Stir the reaction mixture to prepare a
4.2.1 | (4-chlorophenyl)
(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazin-5(6H)-yl)methanone (2a)
ꢀ
homogeneous solution, keep RBF in an ice bath at 0 C
temperature followed by added Lithium aluminum
hydride (1.08 gm, 28.5 mmol) quench wise over a time
period of 15 minute. Stir the reaction mass at room tem-
perature for 2 hr. During the progress of the reaction, the
color of reaction mass gradually changes. After comple-
tion of reaction (checked on TLC plate, it shows fluores-
cent spot in the visible light region), the mixture becomes
dark brown in color. The reaction mass quenched in satu-
Synthesized according to the general procedure-I and
then isolated using 7:3 mixture of hexane and ethyl ace-
tate for flash chromatography to get crystalline solid; yield
ꢀ
ꢀ
À1
64%; mp 164 C to 165 C; IR (KBr, νmax, cm ): 3267,
2968, 2883, 1645, 1595, 1450, 1410 (C H bend), 1332,
1
1274, 1209, 1084, 844, 761; H NMR (400 MHz, DMSO-
d6): δ 7.830 to 7.815 (dd, 1H, J = 1.2, 4.8 Hz), 7.487 to
7.423 (qt, 4H, J = 8.4, 17.2 Hz), 6.985 (br, 1H), 6.375 to
6.347 (t, 1H, J = 11.2 Hz), 4.624 (s, 1H), 3.728 to 3.678 (m,
1H), 3.619 to 3.573 (t, J = 9.6, 18.4 Hz), 3.485 to 3.415 (qt,
1H, J = 10.4, 18.0 Hz), 2.700 to 2.645 (m, 1H), 2.159 to
2.102 (m, 1H) 2.049 to 2.984 (m, 1H), 1.926 to 1.862 (m,
rated aqueous NH Cl solution (30 mL). (During the
4
quenching of reaction mass, evolution of H2 gas was
observed) and product was extracted in ethyl acetate
(
3 Â 20 mL). The combined organic layer was dried over
13
anhydrous Na SO and remove the solvent under vacuum
1H), 1.547 to 1.473 (m, 1H); C NMR (100 MHz, DMSO-
d6): δ 167.48, 148.67, 144.81, 135.36, 134.70, 130.65,
130.43, 128.91, 119.89, 110.81, 57.94, 47.31, 30.05, 23.74;
2
4
to give desired 5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo
[
1
7
1,2-a]pyrazine (e) as brown solid; yield 1.1 gm (66%); mp
ꢀ
ꢀ
1
+
12 C to 113 C; H NMR (400 MHz, DMSO-d ): δ 7.346 to
MS: m/z [M ] 313.00; Anal. calcd. for C H ClN O: C,
6
17 16
3
.330 (d, 1H, J = 6.4 Hz, ArH), 6.609 to 6.587 (d, 1H,
65.04; H, 5.14; N, 13.39. Found: C, 65.12; H, 5.10; N, 13.32
J = 8.8 Hz, ArH), 6.322 to 6.291 (t, 1H, J = 12.4 Hz, ArH),
.642 to 5.636 (s, 1H, NH), 3.511 to 3.465 (t, 1H,
J = 18.4 Hz), 3.454 to 3.439 (t, 1H, J = 6.0 Hz), 3.425 to
.345 (m, 2H), 2.632 to 2.570 (t, 1H, J = 24.8 Hz), 2.078
to 2.015 (m, 1H), 1.990 to 1.912 (m, 1H), 1.891 to 1.792 (m,
5
4.2.2 | (3-chlorophenyl)
(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazin-5(6H)-yl)methanone (2b)
3
1
6
H), 1.451 to 1.350 (m, 1H); Anal. calcd. for C H N : C,
10 13 3
8.54; H, 7.48; N, 23.98. Found: C, 68.51; H, 7.51; N, 24.07.
Synthesized according to the general procedure-I and
then isolated using 7:3 mixture of hexane and ethyl ace-
tate for flash chromatography to get isolated crystalline
ꢀ
ꢀ
4
.2 | General procedure-I for the
solid; yield 59%; mp 161 C to 162 C; IR (KBr, νmax,
À1
synthesis of compounds (2a-o)
cm ): 3277, 2966, 2875, 1647, 1597, 1498, 1402, 1330,
1
1
261, 1207, 1082, 742, 688; H NMR (400 MHz, DMSO-
To a stirred solution of 5,6,6a,7,8,9-hexahydropyrido
d6): δ 7.838 to 7.828 (d, 1H, J = 4.0 Hz), 7.541 to 7.503 (t,
2H, J = 15.2 Hz), 7.450 to 7.412 (t, 1H, J = 15.2 Hz),
[
3,2-e]pyrrolo[1,2-a]pyrazine, e (0.5 gm, 2.8 mmol) in

PARMAR ET AL.
7
7
(
3
.359 (s, 1H), 7.015 to 6.939 (br, 1H), 6.370 (s, 1H), 4.609
br, 1H), 3.716 (s, 1H), 3.626 to 3.579 (t, 1H, J = 18.8 Hz),
.473 to 3.402 (m, 1H), 2.674 (s, 1H), 2.137 to 2.110 (t, 1H,
J = 10.8 Hz, 1H), 2.046 to 1.982 (m, 1H), 1.923 to 1.861
4.2.5 | (2,3-dichlorophenyl)
(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazin-5(6H)-yl)methanone (2e)
(
qt, 1H, J = 8.0, 17.2 Hz), 1.513 to 1.468 (qt, 1H, J = 7.6,
Synthesized according to the general procedure-I and iso-
lated using 8:2 mixture of hexane and ethyl acetate for
flash chromatography to get crystalline solid; yield 54%;
13
1
1
1
0.4 Hz); C NMR (100 MHz, DMSO-d ): δ 166.48,
6
48.18, 144.42, 137.54, 133.03, 130.26, 130.05, 129.96,
ꢀ
ꢀ
À1
27.88, 126.66, 119.14, 110.26, 57.28, 46.81, 29.52, 23.23.
mp 158 C to 159 C; IR (KBr, νmax, cm ): 3273, 2968,
+
MS: m/z [M ] 313.00; Anal. calcd. for C H ClN O: C,
6
5
2856, 1645, 1595, 1491, 1404, 1329, 1269, 1205, 1080,
17
16
3
+
5.04; H, 5.14; N, 13.39. Found: C, 65.08; H,
.19; N, 13.42.
796, 765, 684; MS: m/z [M ] 347.00; Anal. calcd. for
C H Cl N O: C, 58.64; H, 4.34; N, 12.07. Found: C,
17
15
2 3
58.60; H, 4.31; N, 12.13.
4
.2.3 | (4-nitrophenyl)
(
[
6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
1,2-a]pyrazin-5(6H)-yl)methanone (2c)
4.2.6 | (2,6-difluorophenyl)
(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[
1,2-a]pyrazin-5(6H)-yl)methanone (2f )
Synthesized according to the general procedure-I and iso-
lated using 8:2 mixture of hexane and ethyl acetate for
flash chromatography to get crystalline solid; yield 61%;
Synthesized according to the general procedure-I and iso-
lated using 8:2 mixture of hexane and ethyl acetate for
flash chromatography to get crystalline solid; yield 56%;
ꢀ
ꢀ
À1
mp 152 C to 153 C; IR (KBr, νmax, cm ): 3281, 2877,
1
ꢀ
À1
1
651, 1597, 1492, 1410, 1330, 1267, 1201, 1085, 826; H
mp 155 to 156 C; IR (KBr, νmax, cm ): 3282, 2928, 2872,
NMR (400 MHz, DMSO-d ): δ 8.262 to 8.243 (d, 2H,
J = 7.6 Hz), 7.843 (s, 1H) 7.705 (s, 2H), 6.354 (s, 1H),
1653, 1593, 1498, 1410, 1371, 1273, 1209, 1085, 1002, 756;
6
1
H NMR (400 MHz, DMSO-d ): δ 7.790 to 7.308 (m, 8H),
6
3
3
1
1
.757 to 3.322 (m, 3H), 2.718 (s, 1H), 2.134 to 1.910 (m,
6.540 (s, 1H), 6.184 (s, 1H), 5.001 (s, 1H), 3.595 to 3.574
13
H), 1.507 (s, 1H); C NMR (100 MHz, DMSO-d ): δ
(m, 2H) 3.447 to 3.363 (m, 2H), 1.994 (m, 4H); MS: m/z
6
+
48.23, 147.98, 144.68, 141.74, 130.09, 129.50, 123.58,
[M ] 315.00; Anal. calcd. for C H F N O: C, 64.75; H,
17
15 2 3
+
10.30, 57.32, 46.80, 29.51, 23.24; MS: m/z [M ] 324.00;
4.80; N, 13.33. Found: C, 64.79; H, 4.86; N, 13.22.
Anal. calcd. for C H N O : C, 62.95; H, 4.97; N, 17.27.
17
16 4 3
Found: C, 63.01; H, 5.02; N, 17.32.
4
.2.7 | (2-fluorophenyl)
(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
4
.2.4 | (6a,7,8,9-tetrahydropyrido[3,2-e]
[1,2-a]pyrazin-5(6H)-yl)methanone (2g)
pyrrolo[1,2-a]pyrazin-5(6H)-yl)(p-tolyl)
methanone (2d)
Synthesized according to the general procedure-I and iso-
lated using 9:1 mixture of hexane and ethyl acetate for
flash chromatography to get crystalline solid; yield 63%;
Synthesized according to the general procedure-I and iso-
lated using 6:4 mixture of hexane and ethyl acetate for
flash chromatography to get crystalline solid; yield 76%;
ꢀ
À1
mp 157 to 158 C; IR (KBr, νmax, cm ): 3277, 2970, 2872,
1651, 1595, 1496, 1408, 1327, 1255, 1203, 1084, 1037, 769;
ꢀ
ꢀ
À1
1
mp 160 C to 161 C; IR (KBr, νmax, cm ): 3267, 2968,
887, 1649, 1595, 1454, 1408, 1334, 1276, 1209, 1107, 831;
H NMR (400 MHz, DMSO-d ): δ 7.793 (s, 1H) 7.505 (s,
6
2
2H) 7.303 (s, 1H), 7.096 (s, 1H), 6.526 (s, 1H), 6.183
(s, 1H), 5.012 (s, 1H), 3.616 to 3.342 (m, 5H), 2.931 (s, 1H),
1.522 (br, 2H); Anal. calcd. for C H FN O: C, 68.67; H,
1
H NMR (400 MHz, DMSO-d ): δ 7.818 to 7.802 (dd, 1H,
6
J = 1.6, 4.8 Hz), 7.318 to 7.298 (d, 2H, J = 8.0 Hz), 7.223
to 7.204 (d, 2H, J = 7.6 Hz), 6.973 (br, 1H), 6.366 to 6.336
17
16
3
5.42; N, 14.13. Found: C, 68.62; H, 5.49; N, 14.21.
(
(
(
2
1
t, 1H, J = 12.0 Hz), 3.692 to 3.655 (m, 1H), 3.626 to 3.579
t, 1H, J = 18.8 Hz), 3.482 to 3.412 (m, 1H), 2.688 to 2.633
t, J = 22.0 Hz), 2.330 (s, 3H), 2.156 to 2.099 (m, 1H),
4.2.8 | (3-bromophenyl)
(6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazin-5(6H)-yl)methanone (2h)
.032 to 1.985 (q, 1H, J = 5.6, 12.0 Hz), 1.933 to 1.886 (m,
13
H), 1.526 to 1.471 (m, 1H); C NMR (100 MHz, DMSO-
d6): δ 168.09, 148.15, 144.02, 140.06, 132.46, 129.77,
1
2
28.80, 128.25, 119.79, 110.34, 57.53, 46.84, 29.54, 23.23,
0.93. MS: m/z [M ] 293.00; Anal. calcd. for
Synthesized according to the general procedure-I and iso-
lated using 7:3 mixture of hexane and ethyl acetate for
flash chromatography to get crystalline solid; yield 73%;
+
C H N O: C, 73.69; H, 6.53; N, 14.32. Found: C,
18
19 3
ꢀ
ꢀ
À1
7
3.73; H, 6.58; N, 14.26.
mp 169 C to 170 C; IR (KBr, νmax, cm ): 3269, 2866,

8
PARMAR ET AL.
1
3
1
645, 1597, 1460, 1500, 1327, 1261, 1199, 1087, 759, 686;
1.683 (m, 1H), 1.380 to 1.336 (m, 1H); C NMR
1
H NMR (400 MHz, DMSO-d ): δ 7.838 to 7.827 (d, 1H,
(100 MHz, DMSO-d ): δ 148.33, 145.37, 138.53, 137.39,
6
6
J = 4.0 Hz), 7.672 to 7.623 (t, 2H, J = 19.6 Hz), 7.381 to
130.50, 129.80, 128.77, 116.39, 111.05, 54.52, 46.91, 46.26,
40, 29.76, 22.71; MS: m/z [M ] 349.00; Anal. calcd. for
+
7
.343 (t, 2H, J = 15.2 Hz), 6.976 (br, 1H), 6.372 (s, 1H),
4
.596 (s, 1H), 3.717 (s, 1H), 3.626 to 3.579 (t, 1H,
C H ClN O S: C, 54.93; H, 4.61; N, 12.01; Found: C,
16
16
3 2
J = 18.8 Hz), 3.477 to 3.407 (m, 1H), 2.671 (s, 1H), 2.134
54.99; H, 4.55; N, 12.08.
13
to 1.865 (m, 3H), 1.547 to 1.473 (m, 1H); C NMR
100 MHz, DMSO-d ): δ 148.19, 144.43, 137.74, 132.95,
(
6
1
4
30.70, 130.49, 129.98, 127.05, 121.47, 110.26, 57.27,
6.81, 29.52, 23.22; MS: m/z [M ] 357.00; Anal. calcd. for
4.3.2 | 5-((4-fluorophenyl)sulfonyl)-
5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazine (3b)
+
C H BrN O: C, 57.00; H, 4.50; N, 11.73. Found: C,
5
17
16
3
7.09; H, 4.57; N, 11.66.
Synthesized according to the general procedure-II and
isolated using 5:5 mixture of hexane and ethyl acetate for
flash chromatography to get amorphous solid; yield 58%;
4
.3 | General procedure-II for the
ꢀ
ꢀ
À1
synthesis of compounds (3a-f )
mp 99 C to 100 C; IR (KBr, νmax, cm ): 3097, 2974,
856, 1591, 1492, 1338, 1284, 1203, 1168, 1080, 1055, 842;
2
To a stirred solution of 5,6,6a,7,8,9-hexahydropyrido
1H NMR (400 MHz, CDCl3): δ 8.025 to 8.015 (d, 1H,
J = 4.0 Hz), 7.898 to 7.880 (d, 1H, J = 7.2 Hz), 7.646 to
7.612 (qt, 2H, J = 5.2, 8.4 Hz), 7.139 to 7.097 (t, 2H,
J = 16.8 Hz), 6.621 to 6.589 (qt, 1H, J = 5.2, 7.6 Hz), 4.508
to 4.464 (dd, 1H, J = 4.0, 14.0 Hz), 3.586 to 3.438 (m, 1H),
2.989 to 2.916 (m, 1H), 2.675 to 2.614 (qt, 1H, J = 10.8,
13.6 Hz), 2.083 to 1.975 (m, 2H), 1.859 to 1.764 (m, 1H),
1.406 to 1.267 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
166.57, 164.02, 148.65, 145.66, 135.41, 135.38, 131.84,
129.87, 129.78, 129.61, 128.51, 117.06, 116.71, 116.49,
111.48, 54.58, 47.06, 46.85, 30.53, 23.22; MS: m/z [M+]
333.00; Anal. calcd. for C16H16FN3O2S: C, 57.64; H,
4.84; N, 12.60; Found: C, 57.58; H, 4.89; N, 12.68.
[
3,2-e]pyrrolo[1,2-a]pyrazine, e (0.5 g, 2.8 mmol) in
dimethylformamide (15 mL) solvent after that addition of
potassium carbonate (0.9 g, 7.1 mmol). Now, allow to stir
the reaction mixture to prepare a homogeneous solution
then add benzene sulfonyl chloride substrate (3.9 mmol).
ꢀ
Further stir the reaction mixture at 90 C temperature for
1
.5 hours. After completion of reaction (checked by
TLC), the mixture becomes dark in color. Then cool the
reaction mass to room temperature and pour into ice-
cooled water (150 mL), and extract with ethyl acetate
(
3 Â 20 mL). The combined organic layer is dried over
anhydrous Na SO and remove the solvent under vacuum
2
4
to give crude material, which was purified by flash col-
umn chromatography using 230 to 400 mesh size silica
gel using Ethyl acetate: n-Hexane (2:8, 4:6 and 5:5) as elu-
ent to afford the pure product.
Substrate scope for the synthesis of sulfonyl deriva-
tives (3a-f) is shown in Supplementary Material file,
Table S3.
4.3.3 | 5-((4-bromophenyl)sulfonyl)-
5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo
[1,2-a]pyrazine (3c)
Synthesized according to the general procedure-II and
isolated using 5:5 mixture of hexane and ethyl acetate for
flash chromatography to get amorphous solid; yield 49%;
ꢀ
ꢀ
4
5
.3.1 | 5-((4-chlorophenyl)sulfonyl)-
,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo
mp 100 C to 101 C; IR (KBr, νmax, cm-1): 3086, 2970,
2875, 1595, 1496, 1336, 1284, 1203, 1165, 1084, 840, 756;
1H NMR (400 MHz, CDCl3): δ 8.017 to 8.007 (d, 1H,
J = 4.0 Hz), 7.889 to 7.869 (t, 1H, J = 8.0 Hz), 7.580 to
7.559 (d, 2H, J = 8.4 Hz), 7.475 to 7.454 (d, 2H,
J = 8.4 Hz), 6.611 to 6.579 (qt, 1H, J = 5.2, 8.0 Hz), 4.503
to 4.459 (qt, 1H, J = 3.6, 13.6 Hz), 3.587 to 3.428 (m, 2H),
3.008 to 2.934 (m, 1H), 2.670 to 2.609 (qt, 1H, J = 10.8,
13.6 Hz), 2.083 to 1.970 (m, 2H), 1.871 to 1.777 (m, 3H),
1.403 to 1.299 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
148.69, 145.88, 138.37, 132.58, 131.70, 128.58, 128.24,
116.92, 111.51, 54.61, 47.12, 46.84, 30.53, 23.21; MS: m/z
[M+] 393.00; Anal. calcd. for C16H16BrN3O2S: C,
48.74; H, 4.09; N, 10.66; Found: C, 48.69; H,
4.18; N, 10.72.
[1,2-a]pyrazine (3a)
Synthesized according to the general procedure-II and
isolated using 5:5 mixture of hexane and ethyl acetate for
flash chromatography to get amorphous solid; yield 56%;
ꢀ
ꢀ
À1
mp 95 C to 96 C; IR (KBr, νmax, cm ): 3084, 2875, 1591,
1
1
491, 1354, 1282, 1203, 1165, 1080, 833, 759; H NMR
400 MHz, DMSO-d6): 7.937 to 7.927 (d, 1H,
J = 4.0 Hz), 7.734 to 7.715 (d, 1H, J = 7.6 Hz), 7.654 (s,
(
δ
4H), 6.628 to 6.597 (qt, 1H, J = 5.2, 7.6 Hz), 4.467 (dd,
1H, J = 3.2, 13.6 Hz), 3.436 to 3.284 (m, 4H), 2.996 to
2.961 (m, 1H), 2.767 to 2.706 (qt, 1H, J = 11.2, 13.6 Hz),
2.049 to 2.021 (m, 1H), 1.902 to 1.873 (m, 1H), 1.724 to

PARMAR ET AL.
9
4
.3.4 | (mesitylsulfonyl)-
,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo
[5] J. Bulicz, D. C. G. Bertarelli, D. Baumert, F. Fülle, C. E.
Müller, D. Heber, Bioorg. Med. Chem. 2006, 14, 2837.
5
[
[
6] C. J. Creighton, C. W. Zapf, J. H. Bu, M. Goodman, Org. Lett.
999, 1, 1407.
[1,2-a]pyrazine (3d)
1
7] J. S. Wai, B. Kim, T. E. Fisher, L. Zhuang, M. W. Embrey,
P. D. Williams, D. D. Staas, C. Culberson, T. A. Lyle, J. P.
Vacca, D. J. Hazuda, P. J. Felock, W. A. Schleif, L. J.
Gabryelski, L. Jin, I. W. Chen, J. D. Ellis, R. Mallai, S. D.
Young, Bioorg. Med. Chem. Lett 2007, 17, 5595.
Synthesized according to the general procedure and iso-
lated using 5:5 mixture of hexane and ethyl acetate for
flash chromatography to get amorphous solid; yield 63%;
ꢀ
ꢀ
À1
mp 98 C to 99 C; IR (KBr, νmax, cm ): 3290, 2958,
[
8] B. Mathew, S. Srivastava, L. J. Ross, W. J. Suling, E. L. White,
L. K. Woolhiser, A. J. Lenaerts, R. C. Reynolds, Bioorg. Med.
Chem. 2011, 19, 7120.
2
874, 1591, 1487, 1342, 1284, 1205, 1161, 1076, 862, 746;
1
H NMR (400 MHz, CDCl3): δ 7.972 to 7.957 (dd, 1H,
J = 1.2, 4.8 Hz), 6.989 (s, 2H), 6.896 to 6.875 (dd,
[9] C. G. Bonde, N. J. Gaikwad, Bioorg. Med. Chem. 2004, 12,
1
7
3
2
1
1
5
H, J = 0.8, 7.2 Hz), 6.396 to 6.364 (qt, 1H, J = 5.2,
.6 Hz), 4.421 to 4.378 (dd, 1H, J = 3.6, 13.6 Hz), 3.774 to
.531 (m, 3H), 2.580 to 2.520 (t, 8H, J = 24.0 Hz), 2.197 to
.140 (m, 2H), 2.117 to 1.857 (m, 3H), 1.455 to 1.370 (m,
H); 13C NMR (100 MHz, CDCl3): δ 149.42, 145.22,
43.28, 140.39, 133.33, 132.25, 130.66, 118.24, 110.83,
6.41, 46.88, 45.86, 30.61, 23.48, 22.90, 21.08; MS: m/z [M
2
151.
[
[
10] L. Trnka, J. Kuška, A. Havel, Chemotherapy 1964, 9, 158.
11] R. Chicharro, S. de Castro, J. Reino, V. Ar ꢀa n, Eur. J. Org.
Chem. 2003, 2003, 2314.
[12] R. Dunn, T. M. Nguyen, W. Xie, A. Tehim, PCT Int. Appl.
WO2008101247, PCT/US2008/054309, A2 Aug 21, 2008.
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14] M. I. Hamada, A. A. A. Wael, B. Haider, RSC Adv. 2018, 8, 66.
15] M. Abou-Gharbia, M. E. Freed, R. J. McCaully, P. J. Silver,
R. L. Wendt, J. Med. Chem. 1984, 27, 1743.
[
[
[
+
] 357.00; Anal. calcd. for C19H23N3O2S: C, 63.84; H,
6
.49; N, 11.76; Found: C, 63.91; H, 6.55; N, 11.71.
[16] R. V. Jones, L. Godorhazy, N. Varga, D. Szalay, L. Urge, F.
ACKNOWLEDGMENTS
Darvas, J. Comb. Chem. 2006, 8, 110.
Nilesh D Parmar is thankful to the University Grants
Commission (UGC, New Delhi, India) for providing fel-
lowship under UGC-MRP Major Research Project (UGC
F. No. -43-178/2014[SR]) and also thankful to Prof. H. S.
Joshi for providing his valuable support and Department
of Chemistry, Saurashtra University, Rajkot for providing
synthesis and analytical support.
[17] K. R. Knudsen, J. Holden, S. V. Ley, M. Ladlow, Adv. Synth.
Catal. 2007, 349, 535.
[
18] B. Clapham, N. S. Wilson, M. J. Michmerhuizen, D. P.
Blanchard, D. M. Dingle, T. A. Nemcek, J. Y. Pan, D. R. Sauer,
J. Comb. Chem. 2008, 10, 88.
[
19] CCDC 1587326 contains the supplementary crystallographic
data for compound 2a. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/getstructures.
CONFLICT OF INTEREST
No potential conflict of interest was reported by the
authors.
[20] CCDC 1836511 contains the supplementary crystallographic
data for compound 2d. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/getstructures.
[
21] CCDC 1587328 contains the supplementary crystallographic
data for compound 2h. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/getstructures.
DATA AVAILABILITY STATEMENT
Data openly available in a public repository that issues
datasets with DOIs The data that support the findings of
this study are openly available in “figshare” at https://
doi.org/10.6084/m9.figshare.14123582.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
ORCID
Hitendra S. Joshi https://orcid.org/0000-0003-2212-
1
199
REFERENCES
How to cite this article: Parmar ND, Hadiyal SD,
Kapupara VH, Lalpara JN, Joshi HS. Synthesis of
new tetrahydropyridopyrazine derivatives via
continuous flow chemistry approach and their
spectroscopic characterizations. J Heterocyclic
Chem. 2021;1–9. https://doi.org/10.1002/jhet.4270
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