Furan ring opening-pyrrole ring closure. A simple route to 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-ones

Article abstract of DOI:10.1016/j.tetlet.2013.05.066

We report here an application of a furan ring opening-Paal-Knorr pyrrole synthesis sequence for the transformation of furfurylamines into 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-ones.

Full text of DOI:10.1016/j.tetlet.2013.05.066

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
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Furan ring opening–pyrrole ring closure. A simple route
to 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-ones
c
d
d
Igor V. Trushkov a,b, , Tatyana A. Nevolina , Vitaly A. Shcherbinin , Lyudmila N. Sorotskaya ,
⇑
Alexander V. Butin c,d,
⇑
a Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow 119991, Russian Federation
b Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela 1, Moscow 117997, Russian Federation
c Perm State University, Bukireva 15, Perm 614990, Russian Federation
d Research Institute of Heterocyclic Compounds Chemistry, Kuban State Technological University, Moskovskaya St. 2, Krasnodar 350072, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here an application of a furan ring opening-Paal–Knorr pyrrole synthesis sequence for the
transformation of furfurylamines into 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-ones.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 26 March 2013
Revised 6 May 2013
Accepted 17 May 2013
Available online xxxx
Keywords:
Furans
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
Ring opening
Ring closure
Recyclization
Pyrrole derivatives represent a very important class of hetero-
cyclic compounds.1 Among them, pyrroles annulated to other het-
erocycles via a C–N bond can be highlighted due to the broad
spectrum of their bioactivity. The antitumor and antibiotic agent,
mitomycin is a pyrrolo[1,2-a]indole derivative, whilst the anti-
HIV agent castanospermine has an indolizidine scaffold; Erythrina
alkaloids belong to pyrrolo[2,1-a]isoquinoline family; and the pyr-
rolo[1,2-b]isoquinoline fragment is present in Amaryllidaceae alka-
loids. Aptazapine, bretazenil, ketorolac, and other drugs also
contain a pyrrole moiety, the C–N bond of which is annulated to
another ring(s).
various heterocycles based on furan recyclizations,9 we applied
this method for the preparation of 1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazines.10,11 This fragment is present in natural compounds
(e.g., the antibacterial longamide A, the antiprotozoal longamide
B, cytotoxic agelastatin A, and palau’amine, etc.), as well as in syn-
thetic drugs, such as ranirestat which is utilized for the treatment
of diabetic neuropathy (Fig 1).12
Relying on our previous experience,2,6,7 we designed a route to
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-ones 1 as depicted in
Scheme 1. The pyrrolo[1,2-a]pyrazine core can be obtained by an
acid-catalyzed recyclization of N-furfurylamides of
a-amino acids
All syntheses of these compounds can be divided into three
main groups: (a) cyclizations of functionalized pyrroles affording
annulated azaheterocycles; (b) formation of pyrrole rings in com-
pounds containing an azaheterocycle; (c) simultaneous formation
of both rings. The third group includes recyclization of appropri-
ately substituted furans. The last approach was utilized to prepare
5-alkyl-2-aminomethylpyrroles,2 indoles,3 isoindoles,4 pyrrol-
o[2,3-d]pyridazines,5 pyrrolo[1,2-a][1,4]diazepines,6 pyrrolo[1,2-
d][1,4]diazepines,7 and other pyrrole ring-containing polycyclic
systems.8 In continuation of our program on the synthesis of
Br
Br
Br
O
H
N
HO
N
N
X
NH
H3C
O
N
H
O
H
N
H
X = OH: longamide A
H
X = CH2CO2H: longamide B
X = CH2CO2Et: hanishin
agelastatin A
O
H
H
N
HN
N
N
H
N
O
H2N
HO
HN
N
O
O
N
O
⇑
Corresponding authors. Fax: +7 342 237 1480 (A.V.B.).
E-mail addresses: trush@phys.chem.msu.ru (I.V. Trushkov), alexander_butin@
H2N
N
NH2
Br
F
Cl
mail.ru (A.V. Butin).
palau'amine
ranirestat
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.066
Fig. 1. Several bioactive 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines.
Please cite this article in press as: Trushkov, I. V.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.05.066

2
I. V. Trushkov et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
2, which, in turn, can be prepared by acylation of furfurylamines 3
with -phthalimidoacyl chlorides 4.
To realize this approach, we prepared a number of furfurylam-
Synthesis of N-furfuryl-2-phthalimidoamides
a]pyrazines 1
9 and 1,2,3,4-tetrahydropyrrolo[1,2-
a
Entry
R1
R2
R3
R4
Yielda (%)
ines 3 bearing various substituents on nitrogen, C5, and the
a-C
atoms (Scheme 2).13,14
9
1
The acylation of 3a–n with a-phthalimidoacyl chlorides 4 affor-
b
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
H
Me
Et
H
H
H
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
i-Pr
79
82
90
88
82
80
88
81
79
84
91
95
76
85
82
84
—
ded the corresponding N-furfurylamides 9 in good to excellent
yields (Scheme 3, Table 1). Removal of the phthaloyl group under
treatment with hydrazine hydrate produced amines 2, which
underwent acid-catalyzed transformation into tetrahydropyrrol-
o[1,2-a]pyrazines 1 via a furan ring opening-Paal–Knorr cyclization
sequence.15–17
Deprotection of 9 followed by recyclization of 2 into 1 pro-
ceeded with reasonable yields with a few exceptions. Namely, all
attempts to recyclize 2a failed due to the well-known polymeriza-
tion of 5-unsubstituted furans under acidic conditions. Moreover,
67
65
73
32
15
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
b
3,4-(MeO)2C6H3
—
H
H
H
H
H
H
H
H
H
2-FC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-F3CC6H4
3-F3CC6H4
H
74
69
62
69
67
70
59
65
57
we need to point out that introduction of a substituent at the a-po-
sition of furfurylamine was accompanied by a significant decrease
in the yield of the recyclization product (entries e-g, Table 1). This
effect was earlier demonstrated for various furan recyclizations
and was rationalized by the increased stability of the furfuryl cat-
ion which can eliminate under the reaction conditions via the
amide group protonation.6a At the same time, both N-unsubstitut-
H
a
Isolated yield.
b
Significant polymerization precluded isolation of the target products.
ed and N-substituted pyrrolopyrazines 1 were efficiently formed
by this reaction. Moreover, quite different functional groups on
the arene substituent were compatible with the reaction condi-
tions. Similarly, not only glycine-derived 4, but also other amino
acid derivatives could participate in the discussed transformation
(entries o and p in Table 1).11
To conclude, we have developed a simple and efficient approach
to differently substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-
3-ones. Easy functionalization of these compounds allows for prep-
aration of pyrrolopyrazines with other substitution patterns. The
scope of the applications and restrictions of the method are cur-
rently under investigation.
R2
R1
O
3
R2
R3
O
NH
Cl
R2
R3
R1
R1
O
N
R3
N
+
O
N
R4
NH2
O
O
R4
N
R4
1
2
O
4
Scheme 1. Retrosynthetic analysis of 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines.
Acknowledgments
R2
R2
.
R2
NH2OH HCl
Zn
NaOH
R1
R1
R1
O
O
Py, EtOH
O
O
NOH
Financial support was provided by the Russian Foundation for
Basic Research (grant 13-03-96024) and the Ministry of Education
of the Perm Krai.
NH2
3b-g
5
6
ArNH2
NaBH4
H
H
H3C
H3C
H3C
benzene,
reflux
EtOH, rt
O
O
O
References and notes
N
HN
Ar
O
Ar
8
3h-n
7
1. (a)The Chemistry of Heterocyclic Compounds: Pyrroles. Part 1; Jones, R. A., Ed.;
Wiley: New York, 1990; Vol. 48,
p 742; (b)The Chemistry of Heterocyclic
Scheme 2. Synthesis of furfurylamines 3b–n.
Compounds: Pyrroles. Part 2; Jones, R. A., Ed.; Wiley: New York, 1990; Vol. 48, p
628; (c) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39,
4402–4421.
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Trushkov, I. V. Synthesis 2010, 2969–2978.
R2
3. (a) Yin, B.; Cai, C.; Zeng, G.; Zhang, R.; Li, X.; Jiang, H. Org. Lett. 2012, 14, 1098–
1101; (b) Petronijevic, F.; Timmons, C.; Cuzzupe, A.; Wipf, P. Chem. Commun.
2009, 104–106; (c) Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.; Bender, W.;
Krapivin, G. D. Tetrahedron 2007, 63, 474–491; (d) Butin, A. V.; Smirnov, S. K.
Tetrahedron Lett. 2005, 46, 8443–8445; (e) Rashatasakhon, P.; Padwa, A. Org.
Lett. 2003, 5, 189–191.
R1
O
O
O
O
R4
N
R3
R2
+
N
R1
benzene
O
R4
Cl
R3
NH
N
O
O
4. (a) Hashmi, A. S. K.; Rudolph, M.; Bats, J. W.; Frey, W.; Rominger, F.; Oeser, T.
Chem. Eur. J. 2008, 14, 6672–6678; (b) Hashmi, A. S. K.; Schaefer, S.; Bats, J. W.;
Frey, W.; Rominger, F. Eur. J. Org. Chem. 2008, 4891–4899; (c) Hashmi, A. S. K.;
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6. (a) Butin, A. V.; Nevolina, T. A.; Shcherbinin, V. A.; Trushkov, I. V.; Cheshkov, D.
A.; Krapivin, G. D. Org. Biomol. Chem. 2010, 8, 3316–3327; (b) Stroganova, T. A.;
Butin, A. V.; Vasilin, V. K.; Nevolina, T. A.; Krapivin, G. D. Synlett 2007, 1106–
1108.
7. (a) Nevolina, T. A.; Shcherbinin, V. A.; Serdyuk, O. V.; Butin, A. V. Synthesis 2011,
3547–3551; (b) Shcherbinin, V. A.; Nevolina, T. A.; Butin, A. V. Chem. Heterocycl.
Compd. 2010, 46, 1542–1544.
8. (a) Petronijevic, F. R.; Wipf, P. J. Am. Chem. Soc. 2011, 133, 7704–7707; (b) Trost,
B. M.; McDougall, P. J. Org. Lett. 2009, 11, 3782–3785; (c) Hashmi, A. S. K.;
Pankajakshan, S.; Rudolph, M.; Enns, E.; Bander, T.; Rominger, F.; Frey, W. Adv.
Synth. Catal. 2009, 351, 2855–2875; (d) Butin, A. V.; Tsiunchik, F. A.; Abaev, V.
O
3a-n
4
9a-p
N2H4 H2O
EtOH
.
R2
R2
R1
R1
R2
R1
R3
O
N
3
N
HCl, AcOH
rt, 24 h
AcOH
reflux
O
N
O
R
N
NH2
R3
R4
NH2
O
O
R4
2a-p
R4
O
1b-f,h-p
Scheme 3. Transformation of furfurylamines 3 into 1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazines.
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I. V. Trushkov et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
T.; Zavodnik, V. E. Synlett 2008, 1145–1148; (e) Zhang, H.; Boonsombat, J.;
Padwa, A. Org. Lett. 2007, 9, 279–282.
14. General procedure for the synthesis of N-arylfurfurylamines 3h–n. A solution of 5-
methylfurfural (7) (5.0 g, 45.45 mmol) and aniline (41.3 mmol) in benzene
(50 mL) was refluxed using a Dean-Stark trap for 2 h, and then evaporated to
dryness. The obtained imine 8 was dissolved in EtOH (30 mL) and treated
portionwise with NaBH4 (1.56 g, 41.3 mmol). The mixture was stirred for 1–2 h
until completion (TLC monitoring). The reaction was poured into H2O
(100 mL), neutralized with 10% AcOH until pH 7, and extracted with CH2Cl2
(4 Â 40 mL). The combined organic fractions were dried with Na2SO4 and
evaporated under reduced pressure to dryness. The residue was passed
9. (a) Uchuskin, M. G.; Pilipenko, A. S.; Serdyuk, O. V.; Trushkov, I. V.; Butin, A. V. Org.
Biomol. Chem. 2012, 10, 7262–7265; (b) Uchuskin, M. G.; Molodtsova, N. V.; Abaev,
V. T.; Trushkov, I. V.; Butin, A. V. Tetrahedron 2012, 68, 4252–4258; (c) Pilipenko, A.
S.; Mel’chin, V. V.; Trushkov, I. V.; Cheshkov, D. A.; Butin, A. V. Tetrahedron 2012,
68, 619–627; (d) Butin, A. V.; Tsiunchik, F. A.; Kostyukova, O. N.; Uchuskin, M. G.;
Trushkov, I. V. Synthesis 2011, 2629–2638; (e) Butin, A. V.; Tsiunchik, F. A.;
Kostyukova, O. N.; Trushkov, I. V. Chem. Heterocycl. Compd. 2010, 46, 1539–1541;
(f) Butin, A. V.; Uchuskin, M. G.; Pilipenko, A. S.; Tsiunchik, F. A.; Cheshkov, D. A.;
Trushkov, I. V. Eur. J. Org. Chem. 2010, 920–926.
10. For examples of pyrrolopyrazine syntheses, see: (a) Cheng, G.; Wang, X.; Bao,
H.; Cheng, C.; Liu, N.; Hu, Y. Org. Lett. 2012, 14, 1062–1065; (b) Hewlett, N. M.;
Tepe, J. J. Org. Lett. 2011, 13, 4550–4553; (c) He, Y.; Lin, M.; Li, Z.; Liang, X.; Li,
G.; Antilla, J. C. Org. Lett. 2011, 13, 4490–4493; (d) Gualandi, A.; Cerisoli, L.;
Monari, M.; Savoia, D. Synthesis 2011, 909–918; (e) Bandini, M.; Bottoni, A.;
Eichholzer, A.; Miscione, G. P.; Stenta, M. Chem. Eur. J. 2010, 16, 12462–12473;
(f) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010, 132, 15800–15807;
(g) Mukherjee, S.; Sivappa, R.; Yousufuddin, M.; Lovely, C. J. Org. Lett. 2010, 12,
4940–4943; (h) Imaoka, T.; Akimoto, T.; Iwamoto, O.; Nagasawa, K. Chem. Asian
J. 2010, 5, 1810–1816; (i) Trost, B. M.; Osipov, M.; Dong, G. Org. Lett. 2010, 12,
1276–1279.
through
a pad of Al2O3 using petroleum ether (3h–j, l–n) or benzene–
petroleum ether (3k) mixture as the eluent. Amine 3k was recrystallized from
petroleum ether below 0 °C (86% yield). Other amines were used in the
following transformations without additional purification (3h, 82%; 3i, 91%; 3j,
92%; 3l, 84%; 3m, 92%; 3n, 80% yield).
15. General procedure for the synthesis of amides 9. A solution of a-phthalimidoacyl
chloride (4) (6.0 g, 26.9 mmol) in benzene (50 mL) was added dropwise over
30 min to a solution of amine 3 (24.4 mmol) in benzene (50 mL). The mixture
was stirred for 1 h at room temperature (TLC monitoring), then saturated aq
NaHCO3 solution was added, and the mixture was stirred vigorously for
30 min. The resulting precipitate was removed by filtration and the organic
layer was separated and the aqueous phase extracted with EtOAc (3 Â 50 mL).
The combined organic layers were washed with H2O (30 mL), dried with
Na2SO4 and evaporated to dryness under reduced pressure. The residue was
combined with the obtained precipitate after treatment of the reaction mixture
with NaHCO3 and passed through a pad of silica gel or Al2O3 followed by
recrystallization.
11. When this manuscript was in preparation, Batra and co-workers reported the
analogous preparation of 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines from
furfurylamines and optically active
a-amino acids, see: Bhowmik, S.; Kumar,
A. K. S.; Batra, S. Tetrahedron Lett. 2013, 54, 2251–2254.
12. For examples of the bioactivity of 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines,
see: (a) Scala, F.; Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O.; Tierney, M.;
Kaiser, M.; Tasdemir, D. Mar. Drugs 2010, 8, 2162–2174; (b) 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, 720–723; (c) Zhu, B.;
Marinelli, B. A.; Goldschmidt, R.; Foleno, B. D.; Hilliard, J. J.; Bush, K.; Macielag,
M. J. Bioorg. Med. Chem. Lett. 2009, 19, 4933–4936; (d) Wiscount, C. M.;
Williams, P. D.; Tran, L. O.; Embrey, M. W.; Fisher, T. E.; Sherman, V.; Homnick,
C. F.; Staas, D. D.; Lyle, T. A.; Wai, J. S.; Vacca, J. P.; Wang, Z. Q.; Felock, P. J.;
Stillmock, K. A.; Witmer, M. V.; Miller, M. D.; Hazuda, D. J.; Day, A. M.;
Gabryelski, L. J.; Ecto, L. T.; Schleif, W. A.; DiStefano, D. J.; Kochansky, C. J.;
Anari, M. R. Bioorg. Med. Chem. Lett. 2008, 18, 4581–4583; (e) Kurono, M.;
Itogawa, A.; Noguchi, H.; Sanjoba, M. J. Pharm. Sci. 2008, 97, 1468–1483.
13. Furfurylamine 3a is commercially available. Furfurylamines 3b–g were
synthesized from the corresponding oximes by the published method: Kuo,
Y.-H.; Shih, K.-S. Chem. Pharm. Bull. 1991, 39, 181–183; N-Furfurylanilines 3h–n
were obtained using a modified10 literature procedure, see: Sarang, P. S.;
Yadav, A. A.; Patil, P. S.; Krishna, U. M.; Trivedi, G. K.; Salunkhe, M. M. Synthesis
2007, 1091–1095.
16. General procedure for the preparation of N-furfuryl-a-aminoacylamides 2.
Hydrazine hydrate (6.0 mL) was added to a solution of amide 9 (6.0 g) in
EtOH (30 mL). The reaction mixture was refluxed for 5 min (TLC monitoring)
and cooled to room temperature. The resulting precipitate was removed by
filtration and washed with cold EtOH. The mother liquor was evaporated to
dryness under reduced pressure, treated with H2O (100 mL), and carefully
extracted with Et2O (5 Â 30 mL). The organic phases were combined, dried
with Na2SO4 and evaporated to dryness under reduced pressure. Compounds
2g, 2m, and 2n were recrystallized from EtOH, petroleum ether–CH2Cl2
mixture, and from petroleum ether below 0 °C, respectively. Other amines 2
were used for further transformations without additional purification.
17. General procedure for the recyclization of aminofurans
2 into 1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazin-3-ones 1. A mixture of amine 2 (1.0 g), glacial
AcOH (20 mL), and concd HCl (3 mL) was stirred for 24 h at room temperature
(TLC monitoring). Then NaHCO3 (3.0 g) was added portionwise, the reaction
mixture was refluxed for 3 min, poured into H2O (100 mL) and neutralized to
pH 7. The formed precipitate was filtered, washed with H2O, dried, and passed
through a pad of silica gel or Al2O3. The solvent was evaporated to dryness and
the product recrystallized.
Please cite this article in press as: Trushkov, I. V.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.05.066