A quick synthesis of 1-arylpyrrolopyrazinones from linear alkynylamide derivatives

Article abstract of DOI:10.1055/s-0029-1219218

A rapid synthesis of pyrrolopyrazinone derivatives based on formal double addition across the triple bond of appropriately substituted substrates is presented. The key cyclization step features the formation, mediated by [bis(trifluoroacetoxy)iodo]benzene -(PIFA), of a 5-aroylpyrrolidinone nucleus from appropriately func-t-ionalized N-protected N-(aminoethyl)amides. After removal of the protecting group, the free amino group is used to accomplish a second heterocyclization process onto the newly formed carbonyl group. By appropriate manipulation of these protecting groups and selection of reaction conditions, a series of pyrrolopyrazinones can be obtained in different stages of hydrogenation. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1219218

PAPER
971
A Quick Synthesis of 1-Arylpyrrolopyrazinones from Linear Alkynylamide
Derivatives
S
ynthesis of 1-A
e
rylpyrrolo
t
pyrazin
i
ones cia M. Pardo, Imanol Tellitu,* Esther Domínguez*
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología (ZTF/FCT), Universidad del País Vasco/Euskal Herriko
Unibertsitatea (UPV/EHU), 48940 Leioa, Spain
Fax +34(94)6012748; E-mail: imanol.tellitu@ehu.es
Received 4 November 2009; revised 9 November 2009
Dedicated to Professor Josep Font on the occasion of his 70th birthday
O
H2N
O
Abstract: A rapid synthesis of pyrrolopyrazinone derivatives based
on formal double addition across the triple bond of appropriately
substituted substrates is presented. The key cyclization step features
the formation, mediated by [bis(trifluoroacetoxy)iodo]benzene
(PIFA), of a 5-aroylpyrrolidinone nucleus from appropriately func-
tionalized N-protected N-(aminoethyl)amides. After removal of the
protecting group, the free amino group is used to accomplish a sec-
ond heterocyclization process onto the newly formed carbonyl
group. By appropriate manipulation of these protecting groups and
selection of reaction conditions, a series of pyrrolopyrazinones can
be obtained in different stages of hydrogenation.
N
N
N
O
N
O
H
X
pramiracetam (C)
X = H, piracetam (A)
X = OH, oxiracetam (B)
O
N
H
N
O
Key words: hypervalent iodine, alkynylamides, reductive amina-
tions, pyrazinones, bicyclic compounds
F
nefiracetam (D)
The pharmacological and medical literature uses the term
nootropic to refer to drugs that are used as memory en-
hancers. Since the first studies carried out with piracetam
(A), and its hydroxylated analogue oxiracetam (B)
(Figure 1), a number of structural modifications have
been introduced to maximize the biological activity of this
class of therapeutics and also to elucidate their mechanism
of action.1
O
S
O
N
N
O
O
N
O
N
H
DM232 (unifiram) (E)
dimiracetam (F)
Figure 1 Selected representative and widely used examples of noo-
tropic agents A–F
In addition to A and B, some of their derivatives, e.g.
pramiracetam (C)2 and nefiracetam (D),3 have also been
noted to be nootropic drugs (Figure 1). The vast majority
of these derivatives are structurally characterized by a 2-
pyrrolidinone nucleus substituted at the 1-position by an
aminoethyl group and, in a few cases, this motif is confor-
mationally constrained in a heterocycle fused to the pyr-
rolidinone skeleton. This is the case for both DM232
(unifiram, E), which has been reported to show cognition-
enhancing properties with a potency four orders of magni-
tude greater than piracetam,4 and dimiracetam (F), a pyr-
roloimidazole derivative 10–100 times more potent than
piracetam (Figure 1).5
simple alkyl, aryl, and allyl groups as the amide substitu-
ents was tested.6 Following on this, as the next stage of our
research, we wished to evaluate the actual potential of this
methodology by studying the behavior of more complex
alkynylamides that include an additional amine group
specifically located on the amide fragment of the sub-
strate.
OCOCF3
Ph
I
O
NHX
O
OCOCF3
RHN
O
N
Ar
Ar
(PIFA)
G
TFEA
Recently, our group has discovered a straightforward cy-
clization of linear N-substituted alkynylamides to give 5-
aroylpyrrolidinones, mediated by the hypervalent iodine
R = aryl, alkyl, allyl (ref. 6)
R = functionalized
HN
Ar
amines (this work)
N
O
reagent
[bis(trifluoroacetoxy)iodo]benzene
(PIFA)
H
(Scheme 1). The extension of this preliminary study was
very limited and only the behavior of substrates carrying
Scheme 1 Synthetic design for the preparation of pyrazinones of
type H
SYNTHESIS 2010, No. 6, pp 0971–0978
x
x
.
x
x
.2
0
1
0
Advanced online publication: 04.01.2010
DOI: 10.1055/s-0029-1219218; Art ID: Z23709SS
© Georg Thieme Verlag Stuttgart · New York
Therefore, our synthetic design was conceived to allow a
second intramolecular cyclization between the residual

972
L. M. Pardo et al.
PAPER
amine group and the keto carbonyl group of G to afford cases (the a and b series), the protecting groups had to be
pyrrolopyrazinones of type H (Scheme 1). In this work, removed. Therefore, pyrrolidinones 8a–11a were depro-
we present an original route to a series of derivatives with tected under acidic (TFA) conditions and, without any
the pyrrolopyrazinone skeleton as model compounds that further purification, the resulting non-isolated intermedi-
could potentially show biological activity.7
ates I (resulting from release of the Boc group; confirmed
by 1H NMR, but not isolated) were submitted to a cycliza-
tion process under dehydration conditions (Scheme 3).
This gave the unsaturated pyrrolopyrazinones 13a–d in
33–41% yield, probably as a result of the isomerization of
the imine intermediate. On the other hand, pyrrolidinones
8b–10b were transformed directly (via putative interme-
diate J) into the reduced analogues 14a–c in similar yields
(40–46%) under palladium-catalyzed hydrogenation con-
ditions by a one-pot sequence consisting of Cbz deprotec-
tion and intramolecular reductive amination.14 Extensive
NMR studies led us to conclude that the cyclization took
place with complete syn diastereoselectivity.15 As an ex-
ception, all attempts to transform the 5-(thienylcarbonyl)-
substituted pyrrolidinones 11b and 12b into the desired
bicyclic derivatives 14d and 14e resulted in the complete
recovery of the unchanged starting material.16
Two usual protecting groups (X = Boc, Cbz) for the ter-
minal amino group were selected to evaluate their behav-
ior under the PIFA-mediated cyclization conditions.8
Thus, alkynylamides 3–6 were prepared in a two-step se-
quence as shown in Scheme 2. First, the amide linkages
between the known monoprotected diamines 1a,b and
pentynoic acid were formed in almost quantitative yields
for both cases with the aid of N¢-(3-dimethylaminopro-
pyl)-N-ethylcarbodiimide (EDC) and 1-hydroxybenzotri-
azole (BtOH) as activating agents.9 The aryl groups were
subsequently efficiently inserted (75–90% yield) at the
terminal position of the triple bond by a Sonogashira cou-
pling reaction in which copper(I) iodide and palladium(II)
were used as catalysts.10 The aryl fragments for this reac-
tion were selected on the basis of our preliminary study,6
in which it was found that alkynylamides substituted at
the terminal position by deactivated aryl rings could not
be transformed into the corresponding pyrrolidinone de-
rivatives. Only activated (PMP, thienyl), nonactivated
(Ph), and moderately deactivated (ClC6H4) aryl-substitut-
ed substrates (as in 3–6) were expected to succeed in the
desired heterocyclization step.11,12 Thus, the key cycliza-
tion step took place by treatment of amides 3–6 with a
slight excess (1.25 equiv) of PIFA in trifluoroethanol
(TFEA) as solvent at room temperature; this afforded the
desired pyrrolidinone series 8–11 in good to excellent
yields (53–94%) in a transformation that proceeded to
completion in less than two hours with no noticeable dif-
ference in the behavior of the two protecting groups.
XHN
TFA, CH2Cl2, r.t.
O
H2, Pd/C, r.t.
N
MeOH–HCl
route B:
from 8b–12b
route A:
from 8a–11a
O
Ar
8a–11a, X = Boc
8b–12b, X = Cbz
–
CF3CO2
NH3
N
O
N
N
O
Ar
O
Ar
J
I
4 Å MS
Et3N, r.t.
HN
HN
pentynoic acid, Et3N
XHN
XHN
H
H2
N
O
N
EDC⋅HCl, HOBt
CH2Cl2, r.t.
NH2
HN
O
Ar
O
Ar
CH2Cl2
1a,b
2a (91%)
2b (97%)
14a, Ar = Ph (40%)
14b, Ar = PMP (43%)
14c, Ar = 4-ClC6H4 (46%)
14d, Ar = 2-thienyl (see text)
14e, Ar = 3-thienyl (see text)
13a, Ar = Ph (41%)
13b, Ar = PMP (33%)
13c, Ar = 4-ClC6H4 (34%)
13d, Ar = 2-thienyl (39%)
a X = Boc
b X = Cbz
Et3N
40 °C
(75–90%)
ArI, CuI
Pd(PPh3)2Cl2
Scheme 3 Synthesis of pyrrolopyrazinones 13 and 14
NHX
XHN
Ar
PIFA, TFEA
0 °C
O
In conclusion, this investigation showed that the intramo-
lecular PIFA-mediated alkyne amidation reaction of rela-
tively complex substrates can be an efficient alternative
for the preparation of highly functionalized pyrrolidin-
ones. A demonstration of its usefulness is that when this
transformation is coupled with a second intramolecular
amination step, the overall process results in a simple and
rapid protocol for the synthesis of a series of pyrrolopy-
razinone derivatives of different oxidation states.
HN
O
N
O
Ar
8a/b, Ar = Ph (55/53%)
3a/b, Ar = Ph (95/80%)
9a/b, Ar = PMP (74/68%)
10a/b, Ar = 4-ClC6H4 (54/79%)
11a/b, Ar = 2-thienyl (94/81%)
12b, Ar = 3-thienyl (64%)
4a/b, Ar = PMP (90/75%)
5a/b, Ar = 4-ClC6H4 (80/90%)
6a/b, Ar = 2-thienyl (88/79%)
7b, Ar = 3-thienyl (70%)
Scheme 2 Preparation and reactivity of functionalized alkynyl-
amides 3–7 and synthesis of 5-aroylpyrrolidinones 8–12
All reagents were purchased and used as received. All solvents used
in reactions were dried and purified according to standard proce-
dures. All air- or moisture-sensitive reactions were performed under
At this point, we embarked on our next endeavor to pre-
pare the bicyclic pyrazinones.13 In the first stage, for both
Synthesis 2010, No. 6, 971–978 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Arylpyrrolopyrazinones
973
argon. The glassware was oven-dried (140 °C) overnight and
purged with argon prior to use. Melting points were measured by us-
ing open glass capillaries and are uncorrected. IR spectra of samples
prepared as thin films were recorded on a Perkin-Elmer 1600FT-IR
instrument and only representative absorptions are given. Flash
chromatography was carried out on silica gel 60 (230–400 mesh,
ASTM). NMR spectra were recorded on a Bruker AC-300 spec-
trometer (1H: 300 MHz, 13C: 75.4 MHz) at 20–25 °C unless other-
wise indicated. Chemical shifts (d) were measured relative to CHCl3
(1H: d = 7.26, 13C: d = 77.0) as internal standard. DEPT and several
two-dimensional NMR experiments (COSY, HSQC) were used to
assist with the assignment of the signals and structural determina-
tions. Mass spectra were recorded under EI (70 eV) or CI condi-
tions.
mmol) in Et3N (15 mL) was stirred at 40 °C for 15 min. Then CuI
(8 mg, 0.04 mmol) was added and the mixture was heated at 80 °C
for 2 d. The whole crude was purified by column chromatography
(silica gel, EtOAc); this afforded amide 3a as a white solid, which
was triturated in hexanes.
Yield: 95%; mp 118–120 °C (hexanes).
IR (film): 3284, 2967, 1649, 1549 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.36 (m, 2 H), 7.28–7.25 (m,
3 H), 6.36 (br s, 1 H), 4.93 (br s, 1 H), 3.41–3.26 (m, 4 H), 2.74 (t,
J = 7.3 Hz, 2 H), 2.46 (t, J = 7.3 Hz, 2 H), 1.42 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 171.8, 156.9, 131.6, 127.8, 123.4,
88.4, 81.4, 79.7, 40.8, 40.3, 35.6, 28.3, 15.9.
MS (CI): m/z [M + 1] (%) = 289 (26), 261 (100), 243 (13), 217 (56),
57 (39).
N-[2-(tert-Butoxycarbonylamino)ethyl]pent-4-ynamide (2a);
Typical Procedure
HRMS (EI): m/z calcd for C18H25N2O3 [M + H]+: 317.1865; found:
A soln of pent-4-ynoic acid (740 mg, 7.2 mmol) in CH2Cl2 (5 mL)
was added to a magnetically stirred soln of EDC·HCl (2.0 g, 10.8
mmol) and BtOH (1.5 g, 10.8 mmol) in the same solvent (20 mL);
the addition of the monoprotected diamine 1a9a (1.74 g, 10.8 mmol)
dissolved in CH2Cl2 (5 mL) followed. The mixture was cooled to 0
°C, Et3N (1.15 g, 10.8 mmol) was added dropwise, and then the
mixture was left to react at r.t. overnight. Then the mixture was di-
luted with CH2Cl2 (25 mL), H2O (25 mL) was added, the mixture
was decanted, and the organic layer was consecutively washed with
5% aq HCl (20 mL), sat. aq NaHCO3 (20 mL), and sat. aq NaCl (20
mL). The organic layer was dried (Na2SO4) and filtered, and the sol-
vent was removed under vacuum. The resultant oil was crystallized
from Et2O; this afforded amide 2a.
317.1860.
N-[2-(tert-Butoxycarbonylamino)ethyl]-5-(p-methoxyphe-
nyl)pent-4-ynamide (4a)
According to the typical procedure, amide 4a was obtained from
amide 2a after purification by column chromatography (silica gel,
EtOAc) followed by crystallization from hexanes.
White solid; yield: 90%; mp 109–111 °C (hexanes).
IR (film): 3296, 2967, 1689, 1643 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.30 (d, J = 8.8 Hz, 2 H),
6.82–6.79 (d, J = 8.8 Hz, 2 H), 6.28 (br s, 1 H), 4.88 (br s, 1 H), 3.80
(s, 3 H), 3.43–3.23 (m, 4 H), 2.72 (t, J = 7.3 Hz, 2 H), 2.48 (t, J = 7.3
Hz, 2 H), 1.43 (s, 9 H).
White solid; yield: 91%; mp 107–108 °C (Et2O).
IR (film): 3284, 2978, 1655 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.24 (br s, 1 H), 4.88 (br s, 1 H),
3.41–3.27 (m, 4 H), 2.53–2.40 (m, 4 H), 2.00 (t, J = 2.6 Hz, 1 H),
1.44 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 172.0, 159.2, 156.9, 132.9, 115.6,
113.8, 86.8, 81.5, 79.5, 56.2, 40.5, 40.3, 35.6, 26.3, 15.9.
MS (CI): m/z [M + 1] (%) = 291 (100), 290 (28), 273 (27), 247 (44),
231 (45), 230 (65).
13C NMR (75 MHz, CDCl3): d = 171.7, 156.9, 82.9, 79.8, 69.3, 40.7,
40.1, 35.3, 28.3, 14.9.
HRMS (EI): m/z calcd for C19H27N2O4 [M + H]+: 347.1971; found:
347.1972.
MS (CI): m/z [M + 1] (%) = 213 (21), 185 (32), 167 (42), 141 (100),
124 (72), 57 (24).
HRMS (EI): m/z calcd for C12H21N2O3 [M + H]+: 241.1552; found:
241.1877.
N-[2-(tert-Butoxycarbonylamino)ethyl]-5-(p-chlorophe-
nyl)pent-4-ynamide (5a)
According to the typical procedure, amide 5a was obtained from
amide 2a after purification by column chromatography (silica gel,
EtOAc) followed by crystallization from hexanes.
N-[2-(Benzyloxycarbonylamino)ethyl]pent-4-ynamide (2b)
According to the typical procedure, amide 2b was obtained from
monoprotected amine 1b9b after purification by crystallization from
hexanes.
Pale yellow solid; yield: 80%; mp 131–132 °C (hexanes).
IR (film): 3296, 2967, 1684, 1637 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32 (d, J = 9.2 Hz, 2 H), 7.23 (d,
J = 9.2 Hz, 2 H), 6.37 (br s, 1 H), 4.90 (br s, 1 H), 3.39–3.25 (m, 4
H), 2.73 (t, J = 7.3 Hz, 2 H), 2.46 (t, J = 7.3 Hz, 2 H), 1.43 (s, 9 H).
White solid; yield: 97%; mp 108–110 °C (hexanes).
IR (film): 3307, 1690, 1643 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.31 (m, 5 H), 6.14 (br s, 1
H), 5.18 (s, 1 H), 5.10 (s, 2 H), 3.39–3.35 (m, 4 H), 2.33–2.49 (m, 4
H), 1.98 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 171.7, 157.0, 133.7, 132.8, 128.5,
122.0, 89.5, 80.3, 79.7, 40.8, 40.3, 35.4, 28.3, 15.9.
MS (CI): m/z [M + 1] (%) = 323 (17), 295 (91), 277 (50), 251 (100),
13C NMR (75 MHz, CDCl3): d = 171.6, 157.2, 136.3, 128.3, 128.2,
128.1, 83.9, 69.3, 66.7, 40.8, 40.2, 35.2, 14.9.
234 (57), 192 (30).
HRMS (EI): m/z calcd for C18H24ClN2O3 [M + H]+: 351.1475;
found: 351.1465.
MS (CI): m/z [M + 1] (%) = 167 (48), 107 (18), 91 (100), 87 (17),
79 (28).
N-[2-(tert-Butoxycarbonylamino)ethyl]-5-(2-thienyl)pent-4-
ynamide (6a)
According to the typical procedure, amide 6a was obtained from
amide 2a after purification by column chromatography (silica gel,
EtOAc) followed by crystallization from hexanes.
HRMS (EI): m/z calcd for C15H19N2O3 [M + H]+: 275.1396; found:
275.1399.
N-[2-(tert-Butoxycarbonylamino)ethyl]-5-phenylpent-4-yn-
amide (3a); Typical Procedure
A soln of iodobenzene (550 mg, 2.7 mmol), PdCl2(PPh3)2 (15 mg,
White solid; yield: 88%; mp 128–130 °C (hexanes).
IR (film): 3284, 2967, 1690, 1649 cm–1.
0.02 mmol), PPh3 (12 mg, 0.04 mmol), and amide 2a (939 mg, 4.0
Synthesis 2010, No. 6, 971–978 © Thieme Stuttgart · New York

974
L. M. Pardo et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.18–7.12 (m, 2 H), 6.99–6.91 (m,
1 H), 6.34 (br s, 1 H), 4.93 (br s, 1 H), 3.39–3.27 (m, 4 H), 2.76 (t,
J = 7.3 Hz, 2 H), 2.64 (t, J = 7.3 Hz, 2 H), 1.43 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 171.7, 156.9, 131.3, 126.8, 126.3,
123.5, 92.5, 79.6, 74.5, 40.7, 40.3, 35.3, 28.3, 16.1.
MS (CI): m/z [M + 1] (%) = 385 (11), 324 (10), 279 (40), 277 (100),
237 (23), 235 (73), 193 (11).
HRMS (EI): m/z calcd for C21H22ClN2O3 [M + H]+: 385.1319;
found: 385.1315.
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(2-thienyl)pent-4-yn-
amide (6b)
According to the typical procedure, amide 6b was obtained from
amide 2b after purification by column chromatography (silica gel,
EtOAc) followed by crystallization from hexanes.
MS (CI): m/z [M + 1] (%) = 267 (100), 249 (23), 223 (44), 206 (50),
180 (26).
HRMS (EI): m/z calcd for C16H23N2O3S [M + H]+: 323.1429; found:
323.1440.
White solid; yield: 79%; mp 127–128 °C (hexanes).
IR (film): 3296, 3070, 1690, 1637 cm–1.
N-[2-(Benzyloxycarbonylamino)ethyl]-5-phenylpent-4-yn-
amide (3b)
According to the typical procedure, amide 3b was obtained from
amide 2b after purification by column chromatography followed by
crystallization of the resultant oil in hexanes.
1H NMR (300 MHz, CDCl3): d = 7.36–7.33 (m, 5 H), 7.17–7.11 (m,
2 H), 6.93–6.90 (m, 1 H), 6.17 (br s, 1 H), 5.13–5.07 (m, 3 H), 3.41–
3.34 (m, 4 H), 2.70 (t, J = 7.1 Hz, 2 H), 2.43 (t, J = 7.2 Hz, 2 H).
White solid; yield: 80%; mp 151–152 °C (hexanes).
IR (film): 3296, 3070, 1690, 1637 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.26 (m, 10 H), 6.17 (br s, 1
H), 5.17–5.07 (m, 3 H), 3.38 (m, 4 H), 2.72 (t, J = 7.2 Hz, 2 H), 2.44
(t, J = 7.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 171.8, 157.2, 136.3, 131.4, 128.5,
128.2, 128.1, 126.9, 126.3, 123.4, 92.4, 74.7, 66.9, 40.9, 40.4, 35.3,
16.1.
MS (CI): m/z [M + 1] (%) = 296 (11), 249 (39), 248 (30), 208 (14),
207 (100), 164 (16), 108 (22).
13C NMR (75 MHz, CDCl3): d = 171.9, 157.2, 136.3, 131.5, 128.5,
128.3, 128.1, 127.9, 123.4, 88.3, 81.5, 66.9, 41.0, 40.9, 40.3, 35.6,
15.9.
HRMS (EI): m/z calcd for C19H21N2O3S [M + H]+: 357.1273; found:
357.1289.
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(3-thienyl)pent-4-yn-
amide (7b)
According to the typical procedure, amide 7b was obtained from
amide 2b after purification by column chromatography (silica gel,
EtOAc) followed by crystallization from hexanes.
MS (CI): m/z [M + 1] (%) = 351 (20), 286 (100), 266 (18), 243 (23),
91 (61), 79 (19).
HRMS (EI): m/z calcd for C21H23N2O3 [M + H]+: 351.1709; found:
351.1708.
White solid; yield: 70%; mp 150–151 °C (hexanes).
IR (film): 3300, 3078, 1685, 1641 cm–1.
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(p-methoxyphe-
nyl)pent-4-ynamide (4b)
According to the typical procedure, amide 4b was obtained from
amide 2b after purification by column chromatography (silica gel,
EtOAc) followed by crystallization from hexanes.
1H NMR (300 MHz, CDCl3): d = 7.37–7.30 (m, 6 H), 7.21–7.19 (m,
1 H), 7.06–7.02 (m, 1 H), 6.34 (br s, 1 H), 5.30 (br s, 1 H), 5.07 (s,
2 H), 3.42–3.30 (m, 4 H), 2.69 (t, J = 7.2 Hz, 2 H), 2.33 (t, J = 7.2
Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 172.0, 157.2, 136.4, 125.2, 129.9,
128.6, 128.1, 123.4, 122.3, 87.9, 66.9, 40.9, 40.3, 35.5, 15.9.
White solid; yield: 75%; mp 124–125 °C (hexanes).
IR (film): 3296, 1684, 1637 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.29 (m, 7 H), 6.80–6.77 (d,
J = 8.8 Hz, 2 H), 6.17 (br s, 1 H), 5.13–5.07 (m, 3 H), 3.78 (s, 3 H),
3.41–3.34 (m, 4 H), 2.70 (t, J = 7.1 Hz, 2 H), 2.43 (t, J = 7.1 Hz, 2
H).
HRMS (EI): m/z calcd for C19H21N2O3S [M + H]+: 357.1273; found:
357.1289.
5-Benzoyl-N-[2-(tert-butoxycarbonylamino)ethyl]pyrrolidin-2-
one (8a); Typical Procedure
13C NMR (75 MHz, CDCl3): d = 172.0, 159.3, 157.0, 136.4, 132.9,
128.5, 128.2, 128.1, 115.5, 113.9, 86.7, 81.3, 66.8, 56.2, 41.0, 40.3,
35.7, 15.9.
A soln of alkynylamide 3a (250 mg, 0.8 mmol) in CF3CH2OH
(TFEA; 12 mL) was stirred and cooled to 0 °C, and then a soln of
PIFA (526.8 mg, 1.2 mmol) in the same solvent (6 mL) was added
dropwise. The reaction mixture was stirred at that temperature for 2
h. For the workup, 10% aq Na2CO3 (20 mL) was added and the mix-
ture was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with brine (3 × 20 mL) and dried (Na2SO4), and
the solvent was evaporated. Purification of the crude by flash chro-
matography (silica gel, EtOAc) gave the desired product 8a.
MS (CI): m/z [M + 1] (%) = 381 (22), 273 (65), 272 (44), 231 (100),
91 (78), 79 (29).
HRMS (EI): m/z calcd for C22H25N2O4 [M + H]+: 381.1814; found:
381.1818.
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(p-chlorophenyl)pent-
4-ynamide (5b)
According to the typical procedure, amide 5b was obtained from
amide 2b after purification by column chromatography (silica gel,
EtOAc) followed by crystallization from hexanes.
Yellowish oil; yield: 55%.
IR (film): 3331, 2967, 1690, 1519 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.99 (d, J = 7.1 Hz, 2 H), 7.64–
7.63 (m, 1 H), 7.55–7.50 (m, 2 H), 5.39–5.35 (m, 1 H), 4.90 (br s, 1
H), 3.80–3.77 (m, 1 H), 3.49–3.40 (m, 1 H), 3.11–3.02 (m, 2 H),
2.44–2.30 (m, 3 H), 2.11–2.01 (m, 1 H), 1.41 (s, 9 H).
Pale yellow solid; yield: 90%; mp 169–170 °C (hexanes).
IR (film): 3284, 1684, 1637 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.21 (m, 9 H), 6.22 (br s, 1
H), 5.18 (br s, 1 H), 5.07 (s, 2 H), 3.40–3.34 (m, 4 H), 2.70 (t, J = 7.2
Hz, 2 H), 2.43 (t, J = 7.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 197.1, 176.3, 156.3, 134.0, 129.0,
128.4, 79.2, 61.8, 42.2, 33.2, 29.3, 28.3, 23.5.
13C NMR (75 MHz, CDCl3): d = 171.7, 157.2, 136.3, 133.8, 132.8,
128.5, 128.2, 126.9, 126.3, 121.9, 89.4, 80.4, 66.9, 40.9, 40.5, 35.4,
15.9.
MS (EI): m/z (%) = 332 (36), 317 (31), 305 (100), 287 (26), 277
(16).
HRMS (EI): m/z calcd for C18H24N2O4 332.1736; found: 332.1731.
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Synthesis of 1-Arylpyrrolopyrazinones
975
N-[2-(tert-Butoxycarbonylamino)ethyl]-5-(p-methoxyben-
zoyl)pyrrolidin-2-one (9a)
According to the typical procedure, pyrrolidinone 9a was obtained
from amide 4a after purification by column chromatography (silica
gel, EtOAc) followed by crystallization from EtOAc.
1H NMR (300 MHz, CDCl3): d = 7.92–7.80 (m, 2 H), 7.60–7.55 (m,
1 H), 7.48–7.43 (m, 1 H), 7.26–7.23 (m, 5 H), 5.83–5.76 (m, 1 H),
5.35–5.29 (m, 1 H), 5.06 (d, J = 12.3 Hz, 1 H), 4.94 (d, J = 12.3 Hz,
1 H), 2.97–2.74 (m, 4 H), 2.40–2.19 (m, 3 H), 1.89–1.83 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 197.2, 176.5, 156.9, 136.8, 134.1,
132.1, 129.0, 128.4, 128.0, 127.9, 66.4, 62.0, 42.1, 38.9, 29.3, 23.5.
White solid; yield: 74%; mp 111–113 °C (EtOAc).
IR (film): 3331, 2967, 1684, 1596, 1508 cm–1.
MS (CI): m/z [M + 1] (%) = 259 (75), 216 (40), 215 (100), 214 (75),
153 (29), 108 (35).
HRMS (EI): m/z calcd for C21H23N2O4 [M + H]+: 367.1658; found:
367.1653.
1H NMR (300 MHz, CDCl3): d = 7.97 (d, J = 8.7 Hz, 2 H), 6.99 (d,
J = 8.7 Hz, 2 H), 5.34–5.30 (m, 1 H), 4.92 (br s, 1 H), 3.89 (s, 3 H),
3.80–3.76 (m, 1 H), 3.51–3.33 (m, 1 H), 3.11–3.06 (m, 2 H), 2.50–
1.97 (m, 4 H), 1.41 (s, 9 H).
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(p-methoxyben-
zoyl)pyrrolidin-2-one (9b)
According to the typical procedure, pyrrolidinone 9b was obtained
from amide 4b after purification by column chromatography (silica
gel, EtOAc).
13C NMR (75 MHz, CDCl3): d = 195.7, 176.4, 164.2, 156.3, 130.8,
127.1, 114.2, 79.1, 61.5, 55.5, 42.2, 38.2, 29.4, 28.3, 23.7.
MS (CI): m/z [M + 1] (%) = 246 (15), 245 (83), 244 (100), 215 (5).
HRMS (EI): m/z calcd for C19H27N2O5 [M + H]+: 363.1920; found:
363.1877.
Yellowish oil; yield: 68%.
IR (film): 3331, 2943, 1684, 1596, 1514 cm–1.
N-[2-(tert-Butoxycarbonylamino)ethyl]-5-(p-chloroben-
zoyl)pyrrolidin-2-one (10a)
According to the typical procedure, pyrrolidinone 10a was obtained
from amide 5a after purification by column chromatography (silica
gel, EtOAc).
1H NMR (300 MHz, CDCl3): d = 7.92 (d, J = 8.6 Hz, 2 H), 7.33–
7.30 (m, 5 H), 6.97 (d, J = 8.6 Hz, 2 H), 5.31–5.24 (m, 2 H), 5.10
(d, J = 12.2 Hz, 1 H), 5.03 (d, J = 12.2 Hz, 1 H), 3.89 (s, 3 H), 3.80–
3.75 (m, 1 H), 3.60–3.49 (m, 1 H), 3.24–3.09 (m, 2 H), 2.43–2.25
(m, 3 H), 1.95–1.74 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 195.6, 176.5, 164.3, 156.8, 136.7,
128.1, 128.0, 127.9, 127.0, 114.2, 66.6, 61.7, 56.6, 42.2, 39.1, 29.4,
23.9.
Yellowish oil; yield: 54%.
IR (film): 3343, 2967, 1690, 1588, 1519 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.91 (d, J = 8.4 Hz, 2 H), 7.47 (d,
J = 8.4 Hz, 2 H), 5.35–5.28 (m, 1 H), 5.00 (br s, 1 H), 3.87–3.75 (m,
1 H), 3.50–3.27 (m, 1 H), 3.12–2.94 (m, 2 H), 2.49–2.32 (m, 3 H),
2.02–1.86 (m, 1 H), 1.39 (s, 9 H).
MS (CI): m/z [M + 1] (%) = 290 (14), 289 (100), 246 (26), 245 (13),
153 (13).
HRMS (EI): m/z calcd for C22H25N2O5 [M + H]+: 397.1763; found:
397.1767.
13C NMR (75 MHz, CDCl3): d = 196.0, 176.1, 156.4, 140.6, 132.4,
129.9, 129.4, 79.3, 61.6, 42.1, 30.0, 28.3, 28.2, 23.4.
MS (CI): m/z [M + 1] (%) = 294 (20), 280 (15), 267 (21), 266 (91),
238 (100), 194 (17), 180 (19).
HRMS (EI): m/z calcd for C18H24ClN2O4 [M + H]+: 367.1425;
found: 367.1317.
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(p-chlorobenzoyl)pyr-
rolidin-2-one (10b)
According to the typical procedure, pyrrolidinone 10b was obtained
from amide 5b after purification by column chromatography (silica
gel, EtOAc).
N-[2-(tert-Butoxycarbonylamino)ethyl]-5-(2-thienylcarbon-
yl)pyrrolidin-2-one (11a)
According to the typical procedure, pyrrolidinone 11a was obtained
from amide 6a after purification by column chromatography (silica
gel, EtOAc).
Yellowish oil; yield: 79%.
IR (film): 3319, 2943, 1690, 1590, 1525 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.88 (d, J = 8.4 Hz, 2 H), 7.47 (d,
J = 8.4 Hz, 2 H), 7.32–7.25 (m, 5 H), 5.42–5.36 (m, 1 H), 5.30–5.28
(m, 1 H), 5.09 (d, J = 12.2 Hz, 1 H), 5.02 (d, J = 12.2 Hz, 1 H),
3.86–3.77 (m, 1 H), 3.49–3.30 (m, 1 H), 3.20–2.96 (m, 2 H), 2.32–
2.20 (m, 2 H), 1.87–1.80 (m, 1 H).
Yellowish oil; yield: 94%.
IR (film): 3331, 2967, 1684, 1514 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79–7.70 (m, 2 H), 7.19–7.14 (m,
1 H), 5.18–5.09 (m, 2 H), 3.75–3.72 (m, 1 H), 3.41–3.37 (m, 1 H),
3.11–2.88 (m, 2 H), 2.44–2.27 (m, 3 H), 2.12–2.10 (m, 1 H), 1.35
(s, 9 H).
13C NMR (75 MHz, CDCl3): d = 190.8, 176.3, 156.2, 141.1, 135.2,
132.9, 128.6, 79.1, 62.3, 42.2, 38.2, 29.4, 28.3, 24.0.
13C NMR (75 MHz, CDCl3): d = 196.0, 176.3, 156.8, 140.7, 136.6,
132.3, 129.8, 129.4, 128.5, 128.1, 127.9, 66.6, 61.8, 42.1, 38.7,
29.2, 23.4.
MS (CI): m/z [M + 1] (%) = 295 (33), 293 (100), 252 (10), 250 (84),
289 (77), 153 (95), 108 (26).
HRMS (EI): m/z calcd for C21H22ClN2O4 [M + H]+: 401.1268;
found: 401.1261.
MS (CI): m/z [M + 1] (%) = 265 (4), 222 (20), 221 (93), 220 (100),
191 (11).
HRMS (EI): m/z calcd for C16H23N2O4S [M + H]+: 339.1379; found:
339.1334.
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(2-thienylcarbon-
yl)pyrrolidin-2-one (11b)
According to the typical procedure, pyrrolidinone 11b was obtained
from amide 6b after purification by column chromatography (silica
gel, EtOAc).
5-Benzoyl-N-[2-(benzyloxycarbonylamino)ethyl]pyrrolidin-2-
one (8b)
According to the typical procedure, pyrrolidinone 8b was obtained
from amide 3b after purification by column chromatography (silica
gel, EtOAc).
Yellowish oil; yield: 81%.
IR (film): 3319, 3072, 1678, 1590 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.75–7.67 (m, 2 H), 7.27–7.22 (m,
5 H), 7.14–7.11 (m, 1 H), 5.79–5.73 (m, 1 H), 5.13–5.10 (m, 1 H),
Yellowish oil; yield: 53%.
IR (film): 3331, 2931, 1690, 1525, 1449 cm–1.
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976
L. M. Pardo et al.
PAPER
5.03 (d, J = 12.2 Hz, 1 H), 4.96 (d, J = 12.2 Hz, 1 H), 3.76–3.68 (m,
1 H), 3.49–3.30 (m, 1 H), 3.20–2.96 (m, 2 H), 2.30–2.14 (m, 3 H),
1.97–1.90 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 190.8, 176.5, 156.8, 141.0, 135.3,
128.7, 128.4, 128.0, 127.9, 66.4, 62.7, 42.0, 38.7, 29.4, 24.0.
Yellowish solid; yield: 33%; mp 131–132 °C (MeOH).
IR (film): 3355, 1696 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.96 (d, J = 9.0 Hz, 2 H), 6.93 (d,
J = 9.0 Hz, 2 H), 4.14–4.02 (m, 2 H), 3.87 (s, 3 H), 3.70–3.58 (m, 1
H), 3.22–3.12 (m, 1 H), 2.75–2.66 (m, 1 H), 2.48–2.34 (m, 2 H),
2.14–2.04 (m, 1 H), 1.64 (br s, 1 H).
MS (CI): m/z [M + 1] (%) = 329 (8), 256 (34), 222 (38), 221 (100),
220 (69), 108 (34).
HRMS (EI): m/z calcd for C19H21N2O4S [M + H]+: 373.1222; found:
13C NMR (75 MHz, CDCl3): d = 172.8, 163.9, 161.2, 129.7, 128.3,
113.6, 84.0, 55.3, 48.0, 32.8, 32.7, 29.3.
373.1224.
MS (CI): m/z [M + 1] (%) = 261 (43), 245 (71), 244 (100), 243 (53),
242 (42).
N-[2-(Benzyloxycarbonylamino)ethyl]-5-(3-thienylcarbon-
yl)pyrrolidin-2-one (12b)
According to the typical procedure, pyrrolidinone 12b was obtained
from amide 7b after purification by column chromatography (silica
gel, EtOAc).
HRMS (EI): m/z calcd for C14H17N2O2 [M + H]+: 245.1290; found:
245.1288.
1-(p-Chlorophenyl)-3,4,7,8-tetrahydropyrrolo[1,2-a]pyrazin-
6(2H)-one (13c)
According to the typical procedure, pyrrolidinone 13c was obtained
from amide 10a after purification by column chromatography (sili-
ca gel, EtOAc–MeOH, 95:5).
Yellowish oil; yield: 64%.
IR (film): 3315, 3088, 1685, 1528 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.14 (br s, 1 H), 7.56–7.54 (m, 1
H), 7.39–7.33 (m, 1 H), 5.39 (br s, 1 H), 5.12–5.00 (m, 3 H), 3.85–
3.76 (m, 1 H), 3.52–3.45 (m, 1 H), 3.19–3.04 (m, 2 H), 2.42–2.22
(m, 3 H), 2.00–1.93 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 191.8, 176.5, 156.8, 139.1, 136.5,
133.3, 128.5, 128.1, 128.0, 127.2, 127.0, 66.6, 62.9, 42.0, 38.8,
29.3, 23.7.
Yellowish oil; yield: 34%.
IR (film): 3302, 1678 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.92 (d, J = 8.7 Hz, 2 H), 7.37 (d,
J = 8.7 Hz, 2 H), 4.10–3.99 (m, 2 H), 3.70–3.57 (m, 1 H), 3.48 (s, 1
H), 3.25–3.14 (m, 1 H), 2.74–2.62 (m, 1 H), 2.38–2.27 (m, 2 H),
2.05–1.98 (m, 1 H).
HRMS (EI): m/z calcd for C19H21N2O4S [M + H]+: 373.1222; found:
373.1224.
13C NMR (75 MHz, CDCl3): d = 173.0, 163.9, 136.4, 134.2, 129.5,
128.6, 83.8, 48.2, 32.7, 32.6, 29.3.
MS (CI): m/z [M + 1] (%) = 265 (16), 250 (36), 249 (58), 248 (100),
213 (11).
HRMS (EI): m/z calcd for C13H1435ClN2O [M + H]+: 249.0795;
found: 249.0783.
1-Phenyl-3,4,7,8-tetrahydropyrrolo[1,2-a]pyrazin-6(2H)-one
(13a); Typical Procedure
A soln of pyrrolidinone 8a (170 mg, 0.5 mmol) in TFA–CH2Cl2
(1:1, 20 mL) was stirred for 30 min. An aliquot was taken to confirm
1
(by H NMR) that the protecting group was completely released.
Then both solvents were removed under vacuum, and the residue
was taken up in CH2Cl2 (50 mL); the mixture was cooled to 0 °C and
treated with Et3N (0.7 mL, 5 mmol). After stirring for 20 min, 4 Å
MS were added and the stirring was continued for an additional 15
min. The mixture was then filtered through Celite, washed with sat.
aq NaHCO3 (20 mL), and finally extracted with EtOAc (3 × 25 mL).
The combined organic extracts were dried (Na2SO4) and evaporated
under reduced pressure, and the resulting residue was purified by
column chromatography (silica gel, EtOAc–MeOH, 95:5); this af-
forded pyrazinone 13a as a yellowish oil, which was finally crystal-
lized from MeOH.
1-(2-Thienyl)-3,4,7,8-tetrahydropyrrolo[1,2-a]pyrazin-6(2H)-
one (13d)
According to the typical procedure, pyrrolidinone 13d was obtained
from amide 11a after purification by column chromatography (sili-
ca gel, EtOAc–MeOH, 95:5) followed by crystallization from
MeOH.
Yellowish solid; yield: 39%; mp 131–132 °C (MeOH).
IR (film): 3296, 1690 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64–7.39 (m, 2 H), 7.08–7.06 (m,
1 H), 4.12–3.93 (m, 2 H), 3.91–3.79 (m, 1 H), 3.66–3.58 (m, 1 H),
3.18–2.80 (m, 1 H), 2.79–2.56 (m, 2 H), 2.42–2.22 (m, 1 H), 1.68
(br s, 1 H).
Yield: 41%; mp 127–128 °C (MeOH).
IR (film): 3236, 1667 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.95 (d, J = 8.0 Hz, 2 H), 7.43–
7.36 (m, 3 H), 5.14 (br s, 1 H), 4.05–3.95 (m, 2 H), 3.68–3.57 (m, 1
H), 3.23–3.16 (m, 1 H), 2.71–2.59 (m, 1 H), 2.37–2.25 (m, 2 H),
2.09–1.96 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 173.0, 160.3, 141.4, 129.2, 129.1,
127.7, 83.9, 48.1, 33.6, 32.9, 29.3.
MS (CI): m/z [M + 1] (%) = 237 (99), 221 (67), 220 (100), 153 (13),
127 (14).
HRMS (EI): m/z calcd for C11H13N2OS [M + H]+: 221.0749; found:
221.0739.
13C NMR (75 MHz, CDCl3): d = 173.1, 165.2, 135.9, 130.2, 128.3,
128.1, 83.9, 48.1, 32.6, 32.5, 29.4.
MS (CI): m/z [M + 1] (%) = 231 (12), 215 (72), 214 (100), 213 (14),
185 (10).
HRMS (EI): m/z calcd for C13H15N2O [M + H]+: 215.1184; found:
215.1191.
(1R,8aS)-1-Phenylhexahydropyrrolo[1,2-a]pyrazin-6(2H)-one
(14a); Typical Procedure
A soln of pyrrolidinone 8b (209.5 mg, 0.6 mmol) in MeOH (6 mL)
and 1 M aq HCl (0.5 mL) was hydrogenated (70 psi) overnight in
the presence of Pd/C (21 mg). The catalyst was removed by filtra-
tion through Celite and the soln was treated with 20% aq Na2CO3
(15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL), the
combined organic extracts were dried (Na2SO4), and the solvent
was evaporated under vacuum. The resulting oil was purified by
column chromatography (silica gel, MeOH); this afforded pyrazine
14a.
1-(p-Methoxyphenyl)-3,4,7,8-tetrahydropyrrolo[1,2-a]pyrazin-
6(2H)-one (13b)
According to the typical procedure, pyrrolidinone 13b was obtained
from amide 9a after purification by column chromatography (silica
gel, EtOAc–MeOH, 70:30) followed by crystallization from
MeOH.
Synthesis 2010, No. 6, 971–978 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Arylpyrrolopyrazinones
977
Yellowish oil; yield: 40%.
IR (film): 3350, 1655 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.61 (d,
J = 8.0 Hz, 1 H), 3.79–3.77 (m, 1 H), 3.71–3.68 (m, 1 H), 3.47–3.44
(m, 1 H), 3.38–3.36 (m, 1 H), 2.93–2.90 (m, 1 H), 2.45–2.38 (m, 1
H), 2.26–2.19 (m, 1 H), 1.90–1.83 (m, 1 H), 1.72–1.68 (m, 1 H).
Government (GIU 06/87), and the Spanish Ministry of Science and
Innovation (CTQ2007-64501/BQU) is gratefully acknowledged.
The authors gratefully acknowledge PETRONOR, S. A. (Muskiz,
Bizkaia) for the generous gift of hexanes.
References
13C NMR (75 MHz, CDCl3): d = 177.5, 141.4, 128.5, 127.9, 127.0,
77.1, 66.6, 46.8, 39.2, 30.1, 22.6.
(1) For a review on pharmacological properties and clinical uses
of piracetam, see: Winblad, B. CNS Drug Rev. 2005, 11,
169.
MS (CI): m/z [M + 1] (%) = 259 (74), 216 (39), 215 (100), 214 (76),
(2) Pramiracetam (C) has shown improved efficacy in patients
with senile or presenile cognitive impairment. See: Manetti,
D.; Ghelardini, C.; Bartolini, A.; Bellucci, C.; Dei, S.;
Galeotti, N.; Gualtieri, F.; Romanelli, M. N.; Scapecchi, S.;
Teodori, E. J. Med. Chem. 2000, 43, 1969.
(3) Nefiracetam (D) has been shown to modulate receptor
systems such as the cholinergic and/or glutamatergic ones.
See: (a) Moriguchi, S.; Shioda, N.; Maejima, H.; Zhao, X.;
Marszalec, W.; Yeh, J. Z.; Fukunaga, K.; Narahashi, T. Mol.
Pharmacol. 2007, 71, 580. (b) Zhao, X.; Kuryatov, A.;
Lindstrom, J. M.; Yeh, J. Z.; Narahashi, T. Mol. Pharmacol.
2001, 59, 674.
(4) (a) Martini, E.; Ghelardini, C.; Bertucci, C.; Dei, S.;
Gualtieri, F.; Guandalini, L.; Manetti, D.; Scapecchi, S.;
Teodori, E.; Romanelli, M. N. Med. Chem. 2005, 1, 473.
(b) See also ref. 2.
(5) (a) Farina, C.; Gagliardi, S.; Ghelardini, C.; Martinelli, M.;
Norcini, M.; Parini, C.; Petrillo, P.; Ronzoni, S. Bioorg.
Med. Chem. 2008, 16, 3224. (b) Pinza, M.; Farina, C.; Cerri,
A.; Pfeiffer, U.; Riccaboni, M. T.; Banfi, S.; Biagetti, R.;
Pozzi, O.; Magnani, M.; Dorigotti, L. J. Med. Chem. 1993,
36, 4214.
(6) (a) Tellitu, I.; Serna, S.; Herrero, M. T.; Moreno, I.;
Domínguez, E.; SanMartin, R. J. Org. Chem. 2007, 72,
1526. (b) Serna, S.; Tellitu, I.; Domínguez, E.; Moreno, I.;
SanMartin, R. Org. Lett. 2005, 7, 3073.
(7) The pyrrolopyrazinone (1,4-diazabicyclo[4.3.0]nonane)
skeleton has also been identified as the bicyclic constituent
of the recently isolated natural product tunicyclin A. See:
(a) Tian, J.-M.; Shen, Y.-H.; Yang, X.-W.; Liang, S.; Tang,
J.; Shan, L.; Zhang, W.-D. Org. Lett. 2009, 11, 1131.
(b) See also: Macías, A.; Alonso, E.; Del Pozo, C.;
González, J. Tetrahedron Lett. 2004, 45, 4657.
(8) In previous unpublished results from our group, we found
that the presence of free amino and also hydroxy groups is
not compatible with the PIFA-assisted intramolecular
heterocyclization of unsaturated amides.
(9) For the synthetic and spectroscopic details of monoprotected
diamines 1a,b, see, respectively: (a) Guy, J.; Caron, K.;
Dufresne, S.; Michnick, S. W.; Skene, W. G.; Keillor, J. W.
J. Am. Chem. Soc. 2007, 129, 11969. (b) Krivickas, S. J.;
Tamanini, E.; Todd, M. H.; Watkinson, M. J. Org. Chem.
2007, 72, 8280.
153 (29), 108 (35).
HRMS (EI): m/z calcd for C13H17N2O [M + H]+: 217.1341; found:
217.1348.
(1R,8aS)-1-(p-Methoxyphenyl)hexahydropyrrolo[1,2-
a]pyrazin-6(2H)-one (14b)
According to the typical procedure, pyrrolidinone 14b was obtained
from amide 9b after purification by column chromatography (silica
gel, EtOAc).
Yellowish oil; yield: 43%.
IR (film): 3425, 1667 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27 (d, J = 8.7 Hz, 2 H), 6.85 (d.
J = 8.7, 2 H), 4.09–4.04 (m, 1 H), 3.76 (s, 3 H), 3.48–3.43 (m, 1 H),
3.22 (d, J = 9.3 Hz, 1 H), 3.13–3.10 (m, 1 H), 2.97–2.91 (m, 1 H),
2.82–2.76 (m, 1 H), 2.46–2.26 (m, 3 H), 1.84–1.77 (m, 1 H), 1.64–
1.56 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 173.7, 159.5, 131.6, 128.8, 114.0,
79.7, 61.9, 55.2, 45.4, 40.2, 30.1, 21.6.
MS (CI): m/z [M + 1] (%) = 275 (15), 258 (15), 247 (100), 246 (66),
230 (28), 161 (13).
HRMS (EI): m/z calcd for C14H19N2O2 [M + H]+: 247.1447; found:
247.1440.
(1R,8aS)-1-(p-Chlorophenyl)hexahydropyrrolo[1,2-a]-pyrazin-
6(2H)-one (14c)
According to the typical procedure, pyrrolidinone 14c was obtained
from amide 10b after purification by column chromatography (sili-
ca gel, MeOH).
Yellowish oil; yield: 46%.
IR (film): 3387, 1667.
1H NMR (300 MHz, CDCl3): d = 7.42–7.33 (m, 4 H), 4.12–4.09 (m,
1 H), 3.54–3.49 (m, 1 H), 3.30 (d, J = 9.2 Hz, 1 H), 3.17–3.14 (m, 1
H), 3.00–2.96 (m, 1 H), 2.86–2.80 (m, 1 H), 2.42–2.29 (m, 2 H),
1.98 (br s, 1 H), 1.84–1.80 (m, 1 H), 1.66–1.62 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 173.7, 139.6, 128.7, 128.5, 127.7,
68.3, 61.9, 45.4, 40.3, 30.1, 21.6.
MS (CI): m/z [M + 1] (%) = 245 (10), 218 (14), 217 (100), 216 (60),
200 (23).
HRMS (EI): m/z calcd for C13H16ClN2O [M + H]+: 251.0951; found:
251.0953.
(10) For some recent reviews on the Sonogashira reaction, see:
(a) Heravi, M. M.; Sadjadi, S. Tetrahedron 2009, 65, 7761.
(b) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
(c) Doucet, H.; Hierso, J. C. Angew. Chem. Int. Ed. 2007, 46,
834.
(11) These results led us to propose a mechanism in which the
activated triple bond easily coordinates with the iodine(III)
reagent and, hence, assisting the nucleophilic attack of the
amidic nitrogen. In addition, alkyl-substituted alkynes also
failed in the PIFA-mediated cyclization step.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
Financial support from the University of the Basque Country (UPV
41.310-13656 and a fellowship granted to L.M.P.), the Basque
Synthesis 2010, No. 6, 971–978 © Thieme Stuttgart · New York

978
L. M. Pardo et al.
PAPER
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(14) Additional attempts to hydrogenate unsaturated pyrrolo-
pyrazinone 13a to afford 14a resulted in the recovery of the
unchanged starting material. Hydrogenation of the imine
intermediate J appears to proceed much faster than the
isomerization process that would lead to its enamine
tautomer.
(15) Diastereomers 14 showed a significant NOE between the H1
and H8a protons, indicating that they are located on the same
face of the heterocyclic ring.
(m) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108,
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(13) For previous alternative approaches to the synthesis of this
skeleton, see: (a) Scapecchi, S.; Martini, E.; Manetti, D.;
Ghelardini, C.; Martelli, C.; Dei, S.; Galeotti, N.;
(16) It is known that, in some cases, thiophene-containing olefins
can be unreactive under palladium-catalyzed hydrogenation
conditions.
Synthesis 2010, No. 6, 971–978 © Thieme Stuttgart · New York