An efficient approach to the synthesis of alkyl 7-hydroxy-1-oxo-1,2,3,4- tetrahydropyrrolo[1,2- a ]pyrazine-8-carboxylates via a one-pot, three-component reaction

Article abstract of DOI:10.1055/s-0034-1378275

An efficient synthesis of alkyl 7-hydroxy-1-oxo-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate derivatives by reaction between diamines, dialkyl acetylenedicarboxylates, and alkyl or aryl glyoxales is reported. Ease of handling, easy purification, and good yields are the main advantages of the presented method. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378275

LETTER
▌1705
lAettner Efficient Approach to the Synthesis of Alkyl 7-Hydroxy-1-oxo-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylates via a One-Pot, Three-Com-
ponent Reaction
Synthesis of Tetrahydropyrrolopyrazines
Abdolali Alizadeh,* Marziyeh Hossein Abadi, Rashid Ghanbaripour
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Received: 22.03.2014; Accepted after revision: 09.05.2014
pyrrolo[1,2-a]pyrazine, they suffer from some disadvan-
Abstract: An efficient synthesis of alkyl 7-hydroxy-1-oxo-1,2,3,4-
tages such as multistep synthesis, tedious workup, and
tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate derivatives by re-
using expensive starting materials, so the development of
action between diamines, dialkyl acetylenedicarboxylates, and al-
kyl or aryl glyoxales is reported. Ease of handling, easy purification,
and good yields are the main advantages of the presented method.
novel strategies for the synthesis of their derivatives is
still required.19
Key words: diamine, dialkyl acetylenedicarboxylate, glyoxale,
alkyl 7-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
8-carboxylate, one-pot, three-component reaction
Accordingly, and as part of our program aimed at devel-
oping new routes for the synthesis of heterocyclic com-
pounds,20 we decided to synthesize alkyl 7-hydroxy-1-
oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbox-
ylate by the reaction of dialkyl acetylenedicarboxylate 1,
glyoxals 2, and aliphatic and aromatic 1,2-diamines in the
presence of p-toluenesulfonic acid (PTSA).
Nitrogen-containing heterocycles are a widespread struc-
tural motif, found as key elements of numerous drugs and
designed medicinal agents in medicinal chemistry.1 Addi-
tionally, they can act as biomimetic and active pharmaco-
phores.2 Among them, pyrroles are heterocycles of great
importance because of their presence in numerous natural
products like the porphyrin ring systems of chlorophyll,
vitamin B12, heme, and various cytochrome enzymes.1
Moreover, polysubstituted pyrroles have biological prop-
erties, such as antitumor,3 antioxidant,4 antifungal,5 and
ionotropic6 activities, and they are poly (ADP-ribose)
polymerase inhibitors 7 and AT1-selective angiotensin II
receptor antagonists.8
O
Br
HN
NH
Br
O
N
N
N
N
H2N
NH
N
O
H
cyclooroidin
phakellstatin
Br
H
N
HO
N
Me
N
H
O
Pyrrole-fused heterocyclic derivatives can be highlighted,
and these compounds are widespread in natural products
and bioactive agents, such as aptazapine and ketorolac.2
Accordingly, the synthesis of new pyrroles and pyrrole-
fused heterocyclic derivatives have been considered by
chemists, and a range of methods have been reported for
their synthesis.9,10
H
N
H
O
H
agelastatin A
Figure 1 Some examples of natural products bearing the 1,2,3,4-tet-
rahydropyrrolo[1,2-a]pyrazine moiety
To optimize the reaction conditions, we chose the reaction
of dimethyl acetylenedicarboxylate (1a), ethylenedi-
amine, and methylglyoxal (2a) as a model reaction. Vari-
ous solvents, catalysts, and amounts of them have been
studied in the model reaction. The best results were ob-
tained by performing the reaction in ethanol in the pres-
ence of PTSA (10 mol%) at reflux for three hours.21 The
results are summarized in Table 1.
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazine derivatives are
one of the most important class of pyrrole-fused heterocy-
cles due to their broad biological activities, including an-
tihypersensitive,11 antihypoxic,12 psychotropic,13 and
antiarrhythmic properties.14 Moreover, they are also re-
ported as serotonin and noradrenaline reuptake inhibi-
tors,15 aldose reductase inhibitors,16 and potassium
channel ligands.17 Besides these biological applications,
this skeleton is widely present in natural products, such as
hanishin, dibromophakellin, agelastatin A, longamide B,
and cyclooroidin (Figure 1).18 Although many methods
have been reported for the synthesis of 1,2,3,4-tetrahydro-
According to Table 1, increasing the amount of PTSA
and/or using another catalysts failed to improve the yield
(Table 1, entry 7–9) while decreasing the amount of PTSA
led to reduced yield (Table 1, entry 6). Moreover, we have
also performed the model reaction in the absence of
PTSA, but these conditions suffered from disadvantages
such as long reaction time and lower yield compared to
using PTSA as catalyst (Table 1, entry 10).
SYNLETT 2014, 25, 1705–1708
Advanced online publication: 12.06.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378275; Art ID: st-2014-d0248-l
© Georg Thieme Verlag Stuttgart · New York

1706
A. Alizadeh et al.
LETTER
Table 1 Optimization of the Reaction Conditions
Table 2 Three-Component Synthesis of Alkyl 7-Hydroxy-1-oxo-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate Derivatives
3a–f
H
N
O
CO2Me
+
O
NH2
NH2
O
H
EtOH
H
N
O
+
CO2R1
+
N
Me
O
NH2
reflux, 3 h
O
OMe
PTSA (10 mol%)
EtOH, reflux, 3 h
O
H
CO2Me
+
R2
N
Me
OH
OR1
NH2
O
CO2R1
R2
Entry
Solvent
Acids (mol%)
Yield (%)
OH
1
2
3
1
2
EtOH
THF
PTSA (10)
PTSA (10)
PTSA (10)
PTSA (10)
PTSA (5)
PTSA (15)
FeCl3 (10)
AcOH (10)
–
70a
35a
50a
20a
55a
70a
40a
48a
60b
Entry
Product 3
R1
R2
Yield (%)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Me
Et
Me
Me
Ph
70
74
83
66
76
66
4
MeCN
CHCl3
EtOH
EtOH
EtOH
EtOH
EtOH
5
Me
Et
6
Ph
7
Me
Et
4-ClC6H4
4-ClC6H4
8
9
10
aminopropane and 1,4-diaminobutane instead of
ethylenediamine, a complex mixture was obtained, which
is related to the competition between polymerization and
cyclization of diamines and dialkyl acetylenedicarboxyl-
ates. To expand the product derivatives, we decided to use
1,2-diaminopropane instead of ethylenediamine, but a
complex mixture was obtained, because there are two pos-
sibilities for the reaction between 1,2-diaminopropane
and dialkylacetylenedicarboxylates. These intermediates
have also two possibilities to react with glyoxals. There-
fore, four products can be obtained by the reaction of un-
symmetrical diamines, dialkyl acetylenedicarboxylates,
and glyoxals.
a Reflux, 3 h.
b Reflux, 72 h.
With the optimized reaction conditions in hand, we ex-
tended our study to different dialkyl acetylenedicarboxyl-
ates 1 and methyl- or arylglyoxals 2. The results are
summarized in Table 2.
We also examined o-phenylenediamine instead of ethyl-
enediamine but we did not observe any change in the re-
action mixture probably related to low electron density at
the nitrogen in o-phenylenediamine in comparison to eth-
ylenediamine. In another attempt, when we used 1,3-di-
CO2R1
H
NH2
N
O
O
+
NH2
N
H
OR1
CO2R1
1
4
H
N
O
H
H
N
N
O
O
O
O
O
N
H
OR1
N
N
H
O
tautomerization
OR1
OH
OR1
OH
O
O
R2
H
R2
R2
O
2
5
6
H
N
O
cyclization
O
3
– H2O
N
OR1
R2
H
OH
OH
7
Scheme 1 Proposed mechanism for the formation of 3
Synlett 2014, 25, 1705–1708
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrahydropyrrolopyrazines
1707
(7) Ferraris, D.; Ficco, R. P.; Dain, D.; Ginski, M.; Lautar, S.;
Lee-Wisdom, K.; Liang, S.; Lin, Q.; Lu, M. X. C.; Morgan,
L.; Thomas, B.; Williams, L. R.; Zhang, J.; Zhou, Y.; Kalish,
V. J. Bioorg. Med. Chem. 2003, 11, 3695.
(8) Bovy, P. R.; Reitz, D. B.; Collins, J. T.; Chamberlain, T. S.;
Olins, G. M.; Corpus, V. M.; McMahon, E. G.; Palomo, M.
A.; Koepke, J. P.; Smits, G. J.; McGraw, D. E.; Gaw, J. F.
J. Med. Chem. 1993, 36, 101.
The molecular structures of all products 3a–f were as-
signed by IR, mass, 1H NMR, and 13C NMR spectra, and
1
their elemental analyses, as described for 3a. The H
NMR spectrum of 3a exhibited four singlet signals at δ =
2.20, 3.94, 7.28, and 8.39 ppm which are related to Me,
OMe, NH, and OH groups. One multiplet and one triplet
signal at δ = 3.65–3.68, and 3.95 ppm are related to CH2
1
groups. The H-decoupled 13C NMR spectrum of 3a
(9) Trushkov, I. V.; Nevolina, T. A.; Shcherbinin, V. A.;
Sorotskaya, L. N.; Butin, A. V. Tetrahedron Lett. 2013, 54,
3974.
showed ten distinct signals in agreement with the suggest-
ed structure. The most important peak is related to the pyr-
role ring which appeared at δ = 103.4, 114.4, 118.2, and
145.9 ppm.
(10) (a) Smith, N. D.; Huang, D.; Cosford, N. D. P. Org. Lett.
2002, 4, 3537. (b) Suryavanshi, P. A.; Sridharan, V.;
Menéndez, J. C. Tetrahedron 2013, 69, 5401. (c) Chong, Q.;
Xin, X.; Wang, C.; Wu, F.; Wan, B. Tetrahedron 2014, 70,
490. (d) Butin, A. V.; Nevolina, T. A.; Shcherbinin, V. A.;
Uchuskin, M. G.; Serdyuk, O. V.; Trushkov, I. V. Synthesis
2010, 2969. (e) El Kaim, L.; Grimaud, L.; Wagschal, S.
Chem. Commun. 2011, 47, 1887. (f) Stroganova, T. A.;
Butin, A. V.; Vasilin, V. K.; Nevolina, T. A.; Krapivin, G.
D. Synlett 2007, 1106. (g) Hashmi, A. S. K.; Pankajakshan,
S.; Rudolph, M.; Enns, E.; Bander, T.; Rominger, F.; Frey,
W. Adv. Synth. Catal. 2009, 351, 2855. (h) Petronijevic, F.
R.; Wipf, P. J. Am. Chem. Soc. 2011, 133, 7704.
A plausible mechanism for the synthesis of product 3a–f
is proposed in Scheme 1.
Initial addition of ethylenediamine to dialkyl acetylenedi-
carboxylate leads to intermediate 4, and subsequent attack
of the resulting reactive intermediate 4 onto the glyoxal 2
results in the formation of intermediate 6. Finally, cycliza-
tion and dehydration of this intermediate affords the de-
sired product 3.
(11) Peresada, V. P.; Medvedev, O. S.; Likhosherstov, A. M.;
Skoldinov, A. P. Khim. Farm. Zh. 1987, 21, 1054; Chem.
Abstr. 1988, 108, 68298g.
(12) Seredenin, S. B.; Voronina, T. A.; Beshimov, A.; Peresada,
V. P.; Likhosherstov, A. M. RU 2099055, 1997; Chem.
Abstr. 1998, 128, 290245j
(13) Seredenin, S. B.; Voronina, T. A.; Likhosherstov, A. M.;
Peresada, Y. P.; Molodavkin, G. M.; Halikas, J. A. US
5378846, 1995; Chem. Abstr. 1995, 123, 83350w
(14) Likhosherstov, A. M.; Filippova, O. V.; Peresada, V. P.;
Kryzhanovskii, S. A.; Vititnova, M. B.; Kaverina, N. V.;
Reznikov, K. M. Pharm. Chem. J. 2003, 37, 6.
(15) Merla, B.; Christoph, T.; Oberboersch, S.; Schiene, K.;
Bahrenberg, G.; Frank, R.; Kuehnert, S.; Schroeder, W. WO
2008046581, 2008; Chem. Abstr. 2009, 148, 495982g
(16) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.;
Kuromiya, A.; Komiya, M.; Suzuki, K.; Matsumoto, J. I.
J. Med. Chem. 1998, 41, 4118.
To investigate the proposed mechanism, intermediate 4a
was synthesized separately, and it was added to methylg-
lyoxal 2a in solution in the presence PTSA, and the same
product 3a was obtained.
In summary, we have presented a powerful and efficient
method to the synthesis of alkyl 7-hydroxy-1-oxo-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate deriva-
tives by the reaction of diamines, dialkyl acetylenedicar-
boxylates, and alkyl or aryl glyoxals. This is a simple
method in comparison to the other methods. Good yields,
easy purification, and use of simple and inexpensive start-
ing materials are advantages of this method. Due to the
importance of this class of compounds, the products can
be considered for biological applications in the near fu-
ture.
(17) Merla, B.; Christoph, T.; Oberboersch, S.; Schiene, K.;
Bahrenberg, G.; Frank, R.; Kuehnert, S.; Schroeder, W. WO
2008046582, 2008; Chem. Abstr. 2008, 148, 472076a
(18) (a) Tilvi, S.; Moriou, C.; Martin, M. T.; Gallard, J. F.;
Sorres, J.; Patel, K.; Petek, S.; Debitus, C.; Ermolenko, L.;
Al-Mourabit, A. J. Nat. Prod. 2010, 73, 720. (b) Al-
Mourabit, A.; Zancanella, M. A.; Tilvic, S.; Romo, D. Nat.
Prod. Rep. 2011, 28, 1229. (c) Papeo, G.; Gómez-Zurita
Frau, M. A.; Borghi, D.; Varasi, M. Tetrahedron Lett. 2005,
46, 8635.
(19) (a) Hewlett, N. M.; Tepe, J. J. Org. Lett. 2011, 13, 4550.
(b) Cheng, G.; Wang, X.; Bao, H.; Cheng, C.; Liu, N.; Hu,
Y. Org. Lett. 2012, 14, 1062. (c) Bhowmik, S.; Kumar, A. K.
S.; Batra, S. Tetrahedron Lett. 2013, 54, 2251. (d) Bandini,
M.; Bottoni, A.; Eichholzer, A.; Miscione, G. P.; Stenta, M.
Chem. Eur. J. 2010, 16, 12462. (e) Voskressensky, L. G.;
Titov, A. A.; BorisovaT, N.; Listratova, A. V.; Borisov, R.
S.; Kulikova, L. N.; Varlamov, A. V. Tetrahedron 2010, 66,
5140. (f) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem.
Soc. 2010, 132, 15800. (g) Mukherjee, S.; Sivappa, R.;
Yousufuddin, M.; Lovely, C. J. Org. Lett. 2010, 12, 4940.
(h) Imaoka, T.; Akimoto, T.; Iwamoto, O.; Nagasawa, K.
Chem. Asian J. 2010, 5, 1810. (i) Trost, B. M.; Osipov, M.;
Dong, G. Org. Lett. 2010, 12, 1276.
References and Notes
(1) (a) Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996. (b) Craig, P. N. In Comprehensive Medicinal
Chemistry; Vol. 8; Drayton, C. J., Ed.; Pergamon: New
York, NY, 1991.
(2) (a) Hansch, C.; Sammes, P. G.; Taylor, J. B. Comprehensive
Medicinal Chemistry; Vol. 2; Chapt. 7.; Pergamon: Oxford,
1990. (b) Erlanson, D. A.; McDowell, R. S.; O’Brien, T.
J. Med. Chem. 2004, 4, 3463. (c) Butler, M. S. J. Nat. Prod.
2004, 67, 2141.
(3) Denny, W. A.; Rewcastle, G. W.; Baguley, B. C. J. Med.
Chem. 1990, 33, 814.
(4) Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.;
Piriou, A.; Vierfond, J. M. Eur. J. Med. Chem. 1999, 34, 991.
(5) Del Poeta, M.; Schell, W. A.; Dykstra, C. C.; Jones, S.;
Tidwell, R. R.; Czarny, A.; Bajic, M.; Kumar, A.; Boykin,
D.; Perfect, J. R. Antimicrob. Agents Chemother. 1998, 4,
2495.
(6) (a) Jonas, R.; Klockow, M.; Lues, I.; Pruecher, H.; Schliep,
H. J.; Wurziger, H. Eur. J. Med. Chem. 1993, 28, 129.
(b) von der Saal, W.; Hoelck, J. P.; Kampe, W.; Mertens, A.;
Mueller-Beckmann, B. J. Med. Chem. 1989, 32, 1481.
© Georg Thieme Verlag Stuttgart · New York
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A. Alizadeh et al.
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(20) (a) Alizadeh, A.; Ghanbaripour, R.; Zhu, L. G. Synlett 2013,
24, 2124. (b) Alizadeh, A.; Ghanbaripour, R.; Zhu, L. G.
Synth. Commun. 2013, 43, 2575. (c) Alizadeh, A.;
Ghanbaripour, R. Helv. Chim. Acta 2013, 96, 473.
(d) Alizadeh, A.; Sedighian, H.; Bayat, F. Synlett 2014, 24,
389. (e) Alizadeh, A.; Ghanbaripour, R.; Zhu, L. G.
Tetrahedron 2014, 70, 2048. (f) Alizadeh, A.; Zohreh, N.
ACS Comb. Sci. 2013, 15, 278.
(21) To a solution of ethylenediamine (1 mmol) in EtOH (2 mL),
dimethyl acetylenedicarboxylate (1 mmol) was added
dropwise at r.t. After 30 min, methylglyoxal (1 mmol) and
PTSA (0.1 mmol) were added to the reaction mixture, and
the solution was stirred for 2.5 h at reflux conditions. Upon
completion (3 h), monitored by TLC, the solvent was cooled
at an ice bath, and the precipitate was filtered to afford the
pure products 3a–f.
(CO2Me), 167.6 (NCO). MS: m/z = 287 [M+ + 1], 287 [M+],
279, 262, 254, 219, 205, 167, 149, 132, 121, 113, 104, 93,
83, 71, 57. Anal. Calcd (%) for C15H14N2O4: C, 62.93; H,
4.93, N, 9.79. Found: C, 62.97; H, 5.01; N, 9.86.
Ethyl 7-Hydroxy-1-oxo-6-1,2,3,4-tetrahydrophenyl-
pyrrolo[1,2-a]pyrazine-8-carboxylate (3d)
Pale yellow powder; 0.198 g 66% yield; mp 213–214 °C. IR
(KBr): 3184 (NH), 3064 (OH), 1708 (CO2Et), 1665 (NCO),
1580 and 1481 (Ar), 1300, 1239 and 1197 (CO) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.45 (t, 3JHH = 7.2 Hz, 3H,
CH2CH3), 3.10–3.64 (m, 2 H, CH2NH), 4.11 (t, 3JHH = 5.6
Hz, 2 H, CH2N), 4.45 (q, 3JHH = 7.2 Hz, 2 H, CH2CH3), 7.12
(s, 1 H, NH), 7.36–7.40 (m, 1 H, CHpara of Ph), 7.46–7.51
(m, 4 H, 2 × CHortho and 2 × CHmeta of Ph), 8.75 (s, 1 H, OH).
13C NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 39.6
(CH2NH), 43.1 (CH2N), 61.1 (OCH2), 104.1 (C6), 118.6
(C8), 119.8 (C8a), 127.9 (CHpara of Ph), 128.4 (Cipso), 128.7
(2 × CHortho of Ph), 129.4 (2 × CHmeta of Ph), 146.4 (COH),
159.2 (CO2Et), 166.9 (NCO). MS: m/z = 301 [M+ + 1], 300
[M+], 254, 225, 211, 198, 183, 169, 155, 141, 128, 115, 104,
95, 77, 67, 53. Anal. Calcd (%) for C16H16N2O4: C, 63.99; H,
5.37, N, 9.33. Found: C, 64.01; H, 5.49; N, 9.30.
Methyl 7-Hydroxy-6-methyl-1-oxo-1,2,3,4-tetrahydro-
pyrrolo[1,2-a]pyrazine-8-carboxylate (3a)
Pale orange powder; 0.156 g, 70% yield; mp 187–189 °C. IR
(KBr): 3211 (NH), 3099 (OH), 1715 (CO2Me), 1675 (NCO),
1219 and 1146 (CO) cm–1. 1H NMR (400 MHz, CDCl3): δ =
2.20 (s, 3 H, CH3), 3.65–3.68 (m, 2 H, CH2NH), 3.94 (s, 3 H,
OMe), 3.95 (t, 3JHH = 5.6 Hz, 2 H, CH2N), 7.28 (s, 1 H, NH),
8.39 (s, 1 H, OH). 13C NMR (100 MHz, CDCl3): δ = 7.9
(CH3), 39.3 (CH2NH), 41.6 (CH2N), 52.1 (OMe), 103.4 (C6),
114.4 (C8), 118.2 (C8a), 145.9 (COH), 159.3 (CO2CH3),
167.5 (NCO). MS: m/z = 225 [M+ + 1], 224 [M+], 192, 164,
136, 123, 107, 95, 79, 66, 53. Anal. Calcd (%) for
C10H12N2O4: C, 53.57; H, 5.39; N, 12.40. Found: C, 53.51;
H, 5.46; N, 12.38.
Methyl 7-Hydroxy-1-oxo-6-(4-chlorophenyl)-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate (3e)
Pale beige powder; 0.245 g, 86% yield; mp 203–204 °C. IR
(KBr): 3325 (NH), 3200 (OH), 1710 (CO2Me), 1660 (NCO),
1574 and 1481 (Ar), 1299, 1233 and 1138 (C–O) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 3.63–3.68 (m, 2 H, CH2NH),
3.99 (s, 3 H, OMe), 4.10 (t, 3JHH = 5.8 Hz, 2 H, CH2N), 6.84
(s, 1 H, NH), 7.41 (d, 3JHH = 8.8 Hz, 2 H, 2 × CH of Ar), 7.46
Ethyl 7-Hydroxy-6-methyl-1-oxo-1,2,3,4-tetrahydro-
pyrrolo[1,2-a]pyrazine-8-carboxylate (3b)
(d, 3JHH = 8.4 Hz, 2 H, 2 × CH of Ar), 8.85 (s, 1 H, OH). 13
C
NMR (100 MHz, CDCl3): δ = 39.6 (CH2NH), 43.1 (CH2N),
52.3 (OMe), 103.7 (C6), 117.5 (C8), 120.0 (C8a), 126.7
(Cipso), 129.0 (2 × CH of Ar), 130.7 (2 × CH of Ar), 133.9
(CipsoCl), 146.8 (COH), 158.9 (CO2Me), 167.5 (NCO). MS:
m/z = 322 [M+ + 2], 321 [M+ + 1], 320 [M+], 288, 262, 253,
232, 189, 175, 162, 151, 137, 123, 111, 95, 80, 67, 53. Anal.
Calcd (%) for C15H13ClN2O4: C, 66.02; H, 5.30; N, 13.39.
Found: C, 65.98; H, 5.45; N, 13.43.
Pale brown powder; 0.178 g, 74%; mp 178–179 °C. IR
(KBr): 3393 (NH), 3193 (OH), 1710 (CO2Et), 1668 (NCO),
1335, 1225 and 1150 (CO) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.34 (t, 3JHH = 7.0 Hz, 3 H, CH2CH3), 2.12 (s, 3
H, CH3), 3.56–3.59 (m, 2 H, CH2NH), 3.87 (t, 3JHH = 5.7 Hz,
2 H, CH2N), 4.32 (q, 3JHH = 7.0 Hz, 2 H, CH2CH3), 7.01 (s,
1 H, NH), 8.28 (s, 1 H, OH). 13C NMR (100 MHz, CDCl3):
δ = 7.9 (CH3), 14.2 (CH3), 39.3 (CH2NH), 41.6 (CH2N), 60.9
(OCH2), 103.9 (C6), 114.3 (C8), 118.3 (C8a), 145.8 (COH),
159.2 (CO2Et), 166.9 (NCO). MS: m/z = 239 [M+ + 1], 238
[M+], 192, 164, 136, 123, 107, 95, 80, 67, 53. Anal. Calcd
(%) for C11H14N2O4: C, 55.46; H, 5.92; N, 11.76. Found: C,
55.36; H, 5.87; N, 11.82.
Ethyl 7-Hydroxy-1-oxo-6-(4-chlorophenyl)-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate (3f)
Yellow powder; 0.223 g, 66% yield; mp 243–244 °C. IR
(KBr): 3181 (NH), 3073 (OH), 1713 (CO2Et), 1677 (NCO),
1566 and 1476 (Ar), 1302, 1224 and 1150 (CO) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.45 (t, 3JHH = 7.0 Hz, 3 H,
CH2CH3), 3.63–3.68 (m, 2 H, CH2NH), 4.10 (t, 3JHH = 5.8
Hz, 2 H, CH2N), 4.46 (q, 3JHH = 7.0 Hz, 2 H, CH2CH3), 6.51
(s, 1 H, NH), 7.41 (d, 3JHH = 8.8 Hz, 2 H, 2 × CH of Ar), 7.46
Methyl 7-Hydroxy-1-oxo-6-1,2,3,4-tetrahydrophenyl-
pyrrolo[1,2-a]pyrazine-8-carboxylate (3c)
Pale yellow powder; 0.238 g, 83% yield; mp 90–92 °C. IR
(KBr): 3350 (NH), 3235 (OH), 1706 (CO2Me), 1664 (NCO),
1580 and 1481 (Ar), 1348, 1225 and 1141 (CO) cm–1. 1H
NMR (300.13 MHz, CDCl3): δ = 3.69–3.65 (m, 2 H,
CH2NH), 3.98 (s, 3 H, OMe), 4.11 (t, 3JHH = 5.9 Hz, 2 H,
CH2N), 6.59 (s, 1 H, NH), 7.35–7.39 (m, 1 H, CHpara of Ph),
7.44–7.50 (m, 4 H, 2 × CHortho and 2 × CHmeta of Ph), 8.80 (s,
1 H, OH). 13C NMR (75 MHz, CDCl3): δ = 39. 7 (CH2NH),
43.1 (CH2N), 52.2 (OMe), 103.7 (C6), 118.7 (C8), 119.6
(C8a), 128.0 (CHpara of Ph), 128.3 (Cipso), 128.7 (2 × CHortho
of Ph), 129.4 (2 × CHmeta of Ph), 146.6 (COH), 158.9
(d, 3JHH = 8.8 Hz, 2 H, 2 × CH of Ar), 8.84 (s, 1 H, OH). 13
C
NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 39.7 (CH2NH),
43.1 (CH2N), 61.3 (OCH2), 104.2 (C6), 117.4 (C8), 120.1
(C8a), 126.8 (Cipso), 129.0 (2 × CH of Ar), 130.5 (2 × CH of
Ar), 133.9 (CipsoCl), 146.7 (COH), 158.7 (CO2Et), 166.9
(NCO). MS: m/z = 336 [M+ + 2], 335 [M+ + 1], 334 [M+],
288, 259, 245, 232, 203, 189, 175, 162, 138, 123, 111, 95,
80, 67, 53. Anal. Calcd (%) for C16H15ClN2O4: C, 57.41; H,
4.52; N, 8.37. Found: C, 57.32; H, 4.47; N, 8.31.
Synlett 2014, 25, 1705–1708
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