Expeditious synthesis of chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines

Article abstract of DOI:10.1016/j.tetlet.2013.02.067

An expeditious one-pot two-step synthesis of chiral 4-substituted-6-methyl- 1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones via reaction between 5-methyl furfurylamine and N-Boc amino acids is described. LiAlH₄-mediated reduction of 4-substituted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones affords respective chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines in excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.02.067

Tetrahedron Letters 54 (2013) 2251–2254
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expeditious synthesis of chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines q
⇑
Subhendu Bhowmik, Anil K. S. Kumar, Sanjay Batra
Medicinal and Process Chemistry Division, CSIR–Central Drug Research Institute, PO Box 173, Lucknow 226001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious one-pot two-step synthesis of chiral 4-substituted-6-methyl-1,2-dihydropyrrolo[1,2-
a]pyrazin-3(4H)-ones via reaction between 5-methyl furfurylamine and N-Boc amino acids is described.
LiAlH4-mediated reduction of 4-substituted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones
affords respective chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines in excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 1 January 2013
Revised 19 February 2013
Accepted 21 February 2013
Available online 27 February 2013
Keywords:
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
Amino acid
Furfurylamine
Reduction
chiral
In order to meet the growing demand of the high throughput
screening against the unexplored/newer molecular targets for the
drug discovery process, chemical libraries of diverse small organic
compounds of biological interest are sought. A set of such com-
pounds can be either bought commercially or prepared by adopt-
H2N
N
NH
O
O
HN
O
X
NH
Br
NH
N
N
X
NH
O
ing different synthetic protocols.
A synthetic protocol for
N
Br
N
Br
OR
obtaining novel compounds is considered productive if it employs
cheap and readily available starting substrates, simple reaction
conditions, atom-economy, generation of complexity in one-pot
and cascade processes.
O
Br
ent-Cyclooroidin
R = Et: Hanishin
X = H: Phakellstatin
R = H: Longamide B X = Br: Dibromophakellin
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazine is considered to be a
scaffold of significant interest as it is found in several natural prod-
ucts including cyclooroidin, hanishin, longamide B, and dibromo-
phakellin (Fig. 1).1 Besides, this class of molecules is endowed
with a variety of bioactivities which include antiamnesic, antihyp-
oxic,2 antiarrhythmic,3 psychotropic,4 antihypersensitive,5 and al-
dose reductase inhibition.6 In addition, compounds incorporating
this subunit are reported as potassium channel ligands,7 serotonin
and noradrenaline reuptake inhibitors,8 and cannabinoid receptor
agonists.9 Given such significance, there is much interest in their
synthesis. Some of the approaches to prepare 1,2,3,4-tetrahydropyr-
rolo[1,2-a]pyrazines include selective hydrogenation or reduction
of 3,4-dihydropyrrolo[1,2-a]pyrazines,5,10 condensation of benzo-
triazole, 2-(pyrrol-1-yl)-1-ethylamine and formaldehyde11, and
chiral catalyst-mediated aza-Friedal–Crafts reaction of 2-(pyrrol-
1-yl)-1-ethylamine with aldehyde.12 Moreover, two different proto-
Figure 1. A few natural products containing 1,2,3,4-tetrahydropyrrolo[1,2-a]pyra-
zine core.
cols for the synthesis of chiral pyrrole-pyrazine-oxazoles, which are
precursors to this fused-system, starting from 2-pyrrolecarbalde-
hyde have been also disclosed.13 We noticed that though a few of
the reported methods lead to chiral 1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazines, they either involve very expensive catalyst, formation
of side-products or issues of diastereoselectivity during the reaction
sequences.12,13 As a consequence we became interested in develop-
ing a simpler straightforward approach to this scaffold. Herein in
this preliminary report we disclose an efficient one-pot synthesis
of chiral 4-substituted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyra-
zin-3(4H)-ones which were smoothly reduced to 4-substituted-6-
methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines.
The 2,5-disubstituted furan ring is susceptible to ring opening
under oxidative conditions especially in the presence of acid to af-
ford a 1,4-diketo system.14 Employing this property, Butin and co-
workers disclosed an acid-catalyzed synthesis of pyrrolo[1,2-
a][1,4]benzodiazepines from N-(furfuryl)anthranilamides which
q
CDRI Communication no. MS no 8413.
Corresponding author. Tel.: +91 522 2612411 18x4234, 4368; fax: +91 522
⇑
2623405.
E-mail addresses: batra_san@yahoo.co.uk, s_batra@cdri.res.in (S. Batra).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.067

2252
S. Bhowmik et al. / Tetrahedron Letters 54 (2013) 2251–2254
Table 1 (continued)
NHBoc
NH
NH
O
NH2
Entry
N-Boc amino acid (2)
Product (4)
NH
Yielda (%)
i
ii
1
N
Ph
O
98%
79%
BocHN
BocHN
CO2H
O
3
4a
O
Ph
N
CO2H
O
Ph
2a
8
89
N
H
NH
Scheme 1. Reagents and conditions- (i) EDCI.HCl (1.05 equiv), NMM (1.05 equiv),
dry CH2Cl2, À15 °C, 1 h; (ii) (a) concd HCl: glacial acetic acid (1:9), rt, 12 h, (b) aq
NaHCO3, reflux, 3 h.
h
i
h
BocHN
BocHN
CO2H
OH
NH
N
N
9
77
O
Table 1
Scope of the protocol for preparing diverse 4-substituted-6-methyl-1,2-dihydropyr-
rolo[1,2-a]pyrazin-3(4H)-ones via one pot reaction
OH
NH
i
CO2H
S
i. EDCI.HCl, NMM,
CH2Cl2, -15 oC, 1 h,
ii. HCl: AcOH (1:9),
rt, 12 h,
iii. Aq. NaHCO3, pH
= 7.0, reflux, 3 h
O
10b
86
85
j
O
NH2
S
1
j
+
NH
O
BocHN
BocHN
BocHN
CO2H
Ph
N
NH
BocHN
O
one-pot
OH
2a-m
N
N
N
R
O
11
R
k
4a-m
Ph
k
Entry
1
N-Boc amino acid (2)
Product (4)
Yielda (%)
CO2H
OH
NH
BocHN
CO2H
Ph
NH
O
12
13
79
86
l
N
O
85
a
OH
NH
l
Ph
NH
a
CO2H
m
BocHN
BocHN
CO2H
CO2H
O
N
N
b
m
2
3
89
92
O
b
c
a
Isolated yields.
b
Product 4j is an oil and hence isolated via column chromatography.
NH
O
c
in turn were prepared from 2-amino aromatic and heteroaromatic
acids.15 They extended this methodology for the synthesis of pyr-
rolo[1,2-a][1,4]diazepine from furfurylamine and b-alanine.16
Influenced by this work we reasoned that coupling of 5-methyl fur-
furylamine with N-Boc amino acids will lead to an amide deriva-
tive which upon acid-promoted simultaneous furan-ring opening
and deprotection of the Boc-group would afford an intermediate
which may cyclize intramolecularly to furnish chiral 4-substi-
tuted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones.
Aiming at this objective, we initiated our study by performing a pi-
lot reaction toward optimization with commercially available 5-
methyl-furfuryl amine (1) and the N-Boc phenyl alanine (2a). The
coupling reaction between the two was carried out in the presence
of EDCIÁHCl and NMM in methylene chloride as the reaction med-
ium chilled in an ice-salt bath. The reaction was found to be com-
plete in 1 h to furnish a product (98% yields) that was characterized
to be the anticipated furfurylamide (3) (Scheme 1). Thereafter
screening experiments to identify the most suitable condition for
the furan-ring opening and subsequent intramolecular ring closing
were carried out. We discovered that treating furfurylamide (3)
with a HCl: AcOH (1:9, v/v) mixture for 12 h at room temperature
followed by neutralization with aqueous NaHCO3 to pH 7.0 and
subsequently heating the mixture for 3 h gave a product (79%)
which was identified as (S)-4-methylphenyl-6-methyl-1,2-dihy-
dropyrrolo[1,2-a]pyrazin-3(4H)-one (4a). At this stage it occurred
BocHN
BocHN
CO2H
NH
N
O
d
4
91
d
e
f
d
CO2H
CO2H
NH
N
5
6
O
90
83
e
BocHN
HO
NH
N
O
HO
f
BocHN
CO2H
NH
N
O
7
88
OH
g
OH
g

S. Bhowmik et al. / Tetrahedron Letters 54 (2013) 2251–2254
2253
O
R
OH
O
H
N
H
O
R
BocHN
EDCI, NMM
coupling
O
NHBoc
2
H+
HN
HN
H
N
H
N
O
R
HN
O
R
N
N
- H2O
O
O
O
O
OH
3
R
R
4
I
II
O
NH2
III
NH3
1
Scheme 2. Plausible mechanism for the formation of the 4-substituted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones from N-Boc amino acids in one-pot.
of L and D N-Boc amino acids (2a–m). As illustrated in Table 1, it
was gratifying to note that all amino acids afforded the corre-
sponding 4-substituted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyra-
zin-3(4H)-ones (4a–m) in excellent yields. It is worthwhile to
mention that in most of the cases the major part of the total
yields of products was isolated without any chromatographic
purification.
Table 2
Results of reduction of 4-substituted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-
3(4H)-ones to 4-substituted-6-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines
LiAlH4 (1.0 eq),
dry THF, 70 oC, 1 h
NH
NH
N
N
∗
∗
O
A plausible mechanism for the formation of the product is illus-
trated in Scheme 2. The initial coupling reaction between 1 and 2 is
followed by the acid-catalyzed ring opening of the furan ring and
in situ deprotection of the N-Boc group of the amino acid in 3 to
afford the free amine I. Subsequent sequential intramolecular
cyclizations between the amino and the keto groups in I and II re-
sult in the intermediate III which undergoes dehydration to yield
the observed product 4. It may be noted that reaction was unsuc-
cessful with furfurylamine indicating that substitution on the 5-
position is necessary for the success of the reaction.
Finally some of the 4-substituted-6-methyl-1,2-dihydropyrrol-
o[1,2-a]pyrazin-3(4H)-ones were transformed into their corre-
sponding 4-substituted-6-methyl-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazines via amide reduction. Treating compounds 4a–c,g,k,m
with LiAlH4 in THF for 1 h at reflux temperature gave the reduced
products 5a-c,g,k,m, respectively (Table 2).18
In summary we have developed a facile approach for the syn-
thesis of chiral substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyra-
zines. The commercially available cheap starting materials,
simple reaction conditions, excellent yields are some of the attrac-
tive features of this protocol. Further experiments for exploring the
scope of this protocol and utility of the prepared 4-substituted-6-
methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines for synthesizing
natural products are underway and will be subject of future
communication.
R
R
5a-c,g,k,m
4a-c,g,k,m
Entry
1
4
5
Yielda (%)
NH
NH
N
N
O
94
Ph
a
b
Ph
NH
a
NH
N
N
N
2
3
96
94
O
b
NH
NH
NH
N
O
c
c
NH
N
N
O
4
96
OH
OH
g
g
NH
NH
N
N
N
Acknowledgments
O
5
6
95
92
Ph
Ph
k
k
One of the authors (S.B.) acknowledges the CSIR, New Delhi for
the financial support in the form of fellowship. Authors also
acknowledge SAIF, CDRI for providing the spectral and analytical
data.
NH
NH
N
O
m
m
a
Isolated yields.
Supplementary data
Supplementary data (spectroscopic data and copies of 1H and
13C NMR data for all compounds is provided) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.02.067.
to us that instead of isolating the furfurylamide we can perform the
two step-process in one pot. To investigate this feasibility after
pursuing the coupling reaction for 1 h, HCl: AcOH mixture was
added to the same flask and the reaction was allowed to stir for
12 h. The contents were neutralized to pH 7.0 with aqueous NaH-
CO3 and then heated to reflux for 2 h to afford the product as solid
which was identical to the product isolated in two steps.17 Since
the yields were comparable in both processes, we considered to
conduct the sequence as a one-pot process.
References and notes
1. (a) Al-Mourabit, A.; Zancanella, M. A.; Tilvic, S.; Romo, D. Nat. Prod. Rep. 2011,
28, 1229–1260. and references cited therein; (b) Papeo, G.; Gómez-ZuritaFrau,
M. A.; Borghi, D.; Varasi, M. Tetrahedron Lett. 2005, 46, 8635–8638.
2. Seredenin, S. B.; Voronina, T. A.; Beshimov, A.; Peresada, V. P.; Likhosherstov, A.
M. RU 2,099,055, 1997; Chem. Abstr. 1998, 128, 290245j.
To investigate the scope of the protocol, in the next stage 5-
methyl-furfurylamine was subjected to reactions with a variety
3. 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, 6–9.

2254
S. Bhowmik et al. / Tetrahedron Letters 54 (2013) 2251–2254
4. Seredenin, S. B.; Voronina, T. A.; Likhosherstov, A. M.; Peresada, Y. P.;
Molodavkin, G. M.; Halikas, J. A. U.S. 5,378,846, 1995; Chem. Abstr. 1995, 123,
83350w.
5. Peresada, V. P.; Medvedev, O. S.; Likhosherstov, A. M.; Skoldinov, A. P. Khim.
Farm. Zh. 1987, 21, 1054–1059. Chem. Abstr. 1988, 108, 68298g.
6. Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.;
Suzuki, K.; Matsumoto, J.-I. J. Med. Chem. 1998, 41, 4118–4129.
7. Merla, B.; Christoph, T.; Oberboersch, S.; Schiene, K.; Bahrenberg, G.; Frank, R.;
Kuehnert, S.; Schroeder, W. WO 2008046582, 2008; Chem. Abstr. 2008, 148,
472076a.
consumed, the reaction was treated with conc. HCl (3 mL) and glacial acetic
acid (27 mL) at 0 °C and the reaction was continued at room temperature for
12 h. Thereafter the reaction mixture was poured into water (100 mL) and
neutralized to pH ꢀ7 with aq saturated NaHCO3. The resulting aqueous
solution was heated to reflux for 3 h and cooled to room temperature. Upon
cooling, the product separates out as a precipitate which was filtered off,
washed with water and air-dried (0.32 g). To recover additional product from
the filtrate, it was extracted with EtOAc (2 Â 20 mL), the organic layers were
combined, washed with brine (25 mL) and subsequently dried over anhydrous
Na2SO4. Evaporation of ethyl acetate in vacuo gave a residue which after
purification via silica-gel column chromatography (hexane/EtOAc, 7:3)
afforded the desired product, as a brown solid 4a (0.06 g, total = 85%). (S)-4-
Benzyl-6-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one: mp = 122–124 °C;
8. Merla, B.; Christoph, T.; Oberboersch, S.; Schiene, K.; Bahrenberg, G.; Frank, R.;
Kuehnert, S.; Schroeder, W. WO 2008046581, 2008; Chem. Abstr. 2009, 148,
495982g.
9. Gahman, T. C.; Zhao, C.; Lang, H.; Massari, M. E. U.S. 20,090,062,253, 2009;
Chem. Abstr. 2009, 150, 283093j.
[
a]
D = +135.3 (c 0.05, CHCl3); Rf = 0.39 (hexanes/EtOAc, 60:40, v/v); mmax (KBr)
1677 (CO) cmÀ1 1H NMR (300 MHz, CDCl3) d = 2.13 (s, 3H, CH3), 3.20–3.33 (m,
;
10. (a) Skoldinov, A. P.; Likhosherstov, A. M.; Peresada, V. P. Brit. UK Pat. Appl.
2,025,936, 1980, Chem Abstr. 1981, 93, 186406k.; (b) Skoldinov, A. P.;
Likhosherstov, A. M.; Peresada, V. P. Ger.Offen. 2,832,488, 1980; Chem. Abstr.
1980, 93, 46720h.; (c) Skoldinov, A. P.; Likhosherstov, A. M.; Peresada, V. P.
USSR 798,104, 1981; Chem. Abstr. 1981, 95, 7337k.
11. Katritzky, A. R.; Jain, R.; Xu, Y.-J.; Steel, P. J. J. Org. Chem. 2002, 67, 8220–8223.
12. He, Y.; Lin, M.; Li, Z.; Liang, X.; Li, G.; Antilla, J. C. Org. Lett. 2011, 13, 4490–4493.
Also refer to Li, G.; Rowland,G. B.; Rowland, E. B.; Antilla, J. C. Org. Lett. 2007, 9,
4065–4068..
3H, 2 Â CH2), 3.99 (dd, 1H, J1 = 14.6 HZ, J2 = 3.4 Hz, CH2), 4.84 (s, 1H, CH), 5.72
(s, 1H, ArH), 5.92 (s, 1H, ArH), 6.63 (br s, 1H, NH), 6.81 (d, 3H, J = 7.0 HZ, ArH),
7.15–7.26 (m, 3H, ArH); 13C NMR (75 MHz, CDCl3) d = 11.5, 39.1, 40.1, 58.5,
101.9, 107.9, 121.9, 126.3, 127.5, 128.4, 130.0, 135.0, 170.4; mass (ES+) m/
z = 241.1(M++1); ES-HRMS calcd. for C15H17N2O 241.1341, found 241.1339.
18. General procedure for the synthesis of 4-substituted-6-methyl-1,2-
dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones from chiral 4-substituted-6-methyl
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines as exemplified for 5c. At 0 °C LiAlH4
powder (0.02 g, 0.49 mmol) was added to
a solution of 4-substituted-6-
13. (a) Demir, A. S.; Subasia, N. T.; Sahin, E. Tetrahedron: Asymmetry 2006, 17,
2625–2631; (b) Gualandi, A.; Cerisoli, L.; Monari, M.; Savoia, D. Synthesis 2011,
909–918.
14. A few citations only (a) Pilipenko, A. S.; Mel’chin, V. V.; Trushkov, I. V.;
Cheshkov, D. A.; Butin, A. V. Tetrahedron 2012, 68, 619–627; (b) Okada, T.;
Sakaguchi, K.; Shinada, T.; Ohfune, Y. Tetrahedron Lett. 2011, 52, 5744–5746.
and references cited therein.
methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one 4c (0.1 g, 0.49 mmol) in
dry THF (20 mL) and then the reaction mixture was heated to reflux. Upon
consumption of starting material (as monitored by TLC) the reaction mixture
was cooled to 0 °C and excess LiAlH4 was quenched with ethyl acetate and
water. The resulting white precipitate was filtered off and the filtrate was
concentrated under reduced pressure to obtain the crude product which is
purified by silica-gel column chromatography (hexane/EtOAc, 3:2) to afford 4-
substituted-6-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones as brown
oil 5c (0.08 g, 94%). (S)-4-Isobutyl-6-methyl-1,2,3,4-tetrahydropyrrolo[1,2-
15. Stroganova, T. A.; Butin, A. V.; Vasilin, V. K.; Nevolina, T. A.; Krapivin, G. D.
Synlett 2007, 1106–1108.
16. 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.
a]pyrazine: [
a
]
À44.0 (c 0.1 CHCl3);Rf = 0.23 (hexanes/EtOAc, 50:50, v/v);
D
mmax (Neat) 3412 (NH) cmÀ1
;
1H NMR (300 MHz, CDCl3) d = 0.95 (d, 3H, J = 6.4
17. General procedure for the one pot synthesis of 4-substituted-6-methyl-1,2-
HZ, CH3), 1.02 (d, 3H, J = 6.4 HZ, CH3), 1.31–1.42 (m, 1H, CH), 1.80–1.89 (m, 1H,
NH), 2.22 (s, 3H, CH3), 3.08–3.25 (m, 2 H, CH2), 3.92 (t, 1H, J = 11.1 Hz, CH),
4.00–4.13 (m, 2H, CH2), 5.72 (s, 1H, ArH), 5.84 (s, 1H, ArH); 13C NMR (75 MHz,
CDCl3) d = 14.3, 21.5, 24.0, 25.3, 42.0, 43.9, 49.7, 60.5, 101.4, 106.1, 125.8,
126.0; mass (ES+) m/z = 193.1(M++1); ES-HRMS calcd for C12H21N2 193.1705,
found 193.1707.
dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones as exemplified for 4a. To
a stirred
solution of N-Boc- -Phenyl alanine 2a (0.5 g, 1.89 mmol) in dry CH2Cl2
L
(20 mL) was added 5-methyl furfuryl amine (0.22 mL, 1.98 mmol) at À15 °C
(chilled in an ice-salt mixture) followed by EDCI.HCl (0.38 g, 1.98 mmol) and N-
methyl morpholine (0.22 mL, 1.98 mmol) and the reaction was allowed to
continue at the same temperature. After 1 h when the entire amino acid was