Pyrrolodiazines. 2. Structure and chemistry of pyrrolo[1,2-a]pyrazine and 1,3-dipolar cycloaddition of its azomethine ylides

Article abstract of DOI:10.1021/jo9600969

A new synthesis of the pyrrolo[1,2-a]pyrazine system from pyrrole is described. In light of the ab initio calculations carried out on this heterocyclic system some of its basic chemistry was investigated and included electrophilic substitution, addition o

Full text of DOI:10.1021/jo9600969

J . Org. Chem. 1996, 61, 4655-4665
4655
P yr r olod ia zin es. 2. Str u ctu r e a n d Ch em istr y of
P yr r olo[1,2-a ]p yr a zin e a n d 1,3-Dip ola r Cycloa d d ition of Its
Azom eth in e Ylid es
†
†
†
†
J os e´ M. M ´ı nguez, Mar ´ı a I. Castellote, J uan J . Vaquero, J os e´ L. Garc ´ı a-Navio,
,
†
‡
J ulio Alvarez-Builla,* and Obis Casta n˜ o
Departamentos de Qu ´ı mica Org a´ nica and Qu ´ı mica F ´ı sica, Universidad de Alcal a´ ,
2
8871-Alcal a´ de Henares, Madrid, Spain
J os e´ L. Andr e´ s
Institut de Quimica Computacional, Universitat de Girona, C/ Albareda, 3-5, 17071-Girona, Spain
Received J anuary 17, 1996X
A new synthesis of the pyrrolo[1,2-a]pyrazine system from pyrrole is described. In light of the ab
initio calculations carried out on this heterocyclic system some of its basic chemistry was investigated
and included electrophilic substitution, addition of organolithium reagents, metalation with lithium
diisopropylamide and subsequent reaction with electrophiles, and formation of salts by quater-
nization of the nonbridgehead nitrogen. N-ylides obtained from these salts undergo 1,3-dipolar
cycloaddition with suitable dipolarophiles to give dipyrrolo[1,2-a]pyrazines, pyrazolo[1,5-a]-pyrrolo-
[2,1-c]pyrazines, and heterobetaines. Examples of intramolecular 1,3-dipolar cycloadditions are
also reported.
In tr od u ction
Ch a r t 1
Although the chemistry and applications of indolizines
1
as drugs, dyestuffs, and light-screening agents have been
extensively studied, little attention has been paid to some
2
of their aza analogues such as the pyrrolodiazines (Chart
1
). This is probably because of difficulties associated with
their preparation, with the four possible pyrrolodiazine
isomers 1-4 all being prepared by synthetic routes which
are both lengthy and poor yielding. The syntheses of the
3
pyrrolo[1,2-a]pyrimidine 2, the pyrrolo[1,2-c]pyrimidine
4
5
3
, and the pyrrolo[1,2-b]pyridazine 4 are reported in
an overall yield of less than 5% while the pyrrolo[1,2-a]-
6
pyrazine 1 system was prepared in a total yield of 18%.
Moreover, only one of the six possible dihydro derivatives,
7
the 3,4-dihydropyrrolo[1,2-a]pyrazine 5 is known, and
its synthesis has also been reported in low yield.
We became interested in these types of bicyclic systems
because of their potential for use as starting materials
in a simple route to N-bridged heteroaromatics 6 (Chart
derivatives can be obtained by 1,3-dipolar cycloaddition
reactions of azomethine ylides generated from 3,4-dihy-
dropyrrolo[1,2-a]pyrazinium salts.
Following on from these studies we now report an
improved synthesis of the pyrrolo[1,2-a]pyrazine system
1
) in which two azoles are joined through their respective
nitrogens by a carbon link. The resulting tricyclic system
possesses two bridgehead nitrogens, one of which is
eventually quaternized. As demonstrated in an earlier
1
, a study of its structure by ab initio calculations, and
a description of its basic chemistry, including the 1,3-
dipolar cycloaddition of pyrrolo[1,2-a]pyrazinium ylides
of 1.
8
report in this series, the heterocyclic system 5 can be
prepared in an acceptable yield and bridged 2,2′-biazole
†
Departamento de Qu ´ı mica Org a´ nica.
Departamento de Qu ´ı mica F ´ı sica.
Abstract published in Advance ACS Abstracts, J une 15, 1996.
Com p u ta tion a l Meth od s
‡
X
(
1) Flitsch, W. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; 1994; Vol. 4, pp 443-495.
2) For a review of azaindolizines see: (a) Amarnath, V.; Madhav,
The electronic structures of the pyrrolo[1,2-a]pyrazine
and the N-protonated species 1a were studied using
ab initio MO techniques. All geometric optimizations
1
(
R. Synthesis 1974, 837-859. (b) Kuhla, D. E.; Lombardino, J . G. Adv.
Heterocycl. Chem. 1977, 21, 1-63. (c) Blewit, H. L. Chem. Heterocycl.
Compd. 1977, 30, 117-178. (d) Maury, G. Chem. Heterocycl. Compd.
were carried out at the closed shell self-consistent field
9
(
6
SCF) level of theory using Schlegel’s algorithm. The
1
977, 30, 179-24.
-31G*10 basis set was used to optimize the geometries.
(
(
3) Buchan, R.; Fraser, M.; Shand, C. J . Org. Chem. 1977, 42, 2448.
4) Wong, J . L.; Brown, S. M.; Rapoport, H. J . Org. Chem. 1965, 30,
The energies were recalculated by MP2/6-31G*single
2
398.
(
(
(
5) Flitsch, W.; Kr a¨ mer, U. Liebigs Ann. Chem. 1970, 735, 35.
6) Herz, W.; Tocker, S.; J . Am. Chem. Soc. 1955, 77, 6355.
7) Skoldinov, A.; Peresada, B.; Likhosherstov, A. Zh. Org. Khim.
(9) Schlegel, H. B.; J . Comput. Chem. 1982, 3, 214.
(10) (a) Hehre, W. J .; Ditchfield, R.; Pople, J . A. J . Chem. Phys. 1972,
56, 2257. (b) Frisch, M. J .; Pople, J . A.; Binkley, J . S. J . Chem. Phys.
1984, 80, 3265. (c) Clark, T.; Chandrasekhar, J .; Spitznagel, G. W.;
Schleyer, P. V. R. J . Comput. Chem. 1983, 4, 294.
1
983, 19, 450.
8) Pablo, M. S.; Gand a´ segui, T.; Vaquero, J . J .; Garcia Navio, J .
L.; Alvarez-Builla, J . Tetrahedron 1992, 48, 8793.
(
S0022-3263(96)00096-5 CCC: $12.00 © 1996 American Chemical Society

4
656 J . Org. Chem., Vol. 61, No. 14, 1996
M ´ı nguez et al.
Sch em e 1
Ta ble 1. Op tim ized Geom etr ica l P a r a m eter s for
P yr r olo[1,2-a ]p yr a zin e (1)a
bond lengths (HF/6-31G*) bond angles (HF/6-31G*)
C1-N2
N2-C3
C3-C4
C4-N5
N5-C6
C6-C7
C7-C8
C8-C8a
C8a-C1
N5-C8a
1.279
1.379
1.337
1.378
1.355
1.371
1.407
1.374
1.430
1.381
C1-N2-C3
N2-C3-C4
N2-C3-H3
C3-C4-H4
C1-C8a-C8
C6-C7-C8
H6-C6-C7
H7-C7-C6
C7-C8-C8a
H7-C7-C8
C7-C8-H8
H7-C8-C8a
C8a-C1-H1
H1-C1-N2
N5-C8a-C8
117.6
123.5
116.1
124.1
135.3
108.2
130.8
125.2
106.7
126.6
127.3
126.0
118.4
118.0
108.0
point calculations on the HF/6-31G* geometries (MP2/
-31G*//HF/6-31G*level of theory). The charges were
obtained from the Mulliken population analysis of the
HF/6-31G* wave function. All calculations were per-
formed using the GAUSSIAN-9211 series of programs.
a Bond lengths are in angstroms and bond angles in degrees.
6
Ta ble 2. Op tim ized Geom etr ica l P a r a m eter s for
P yr r olo[1,2-a ]p yr a zin e 1a a
bond lengths (HF/6-31G*)
bond angles (HF/6-31G*)
C1-N2
N2-C3
C3-C4
C4-N5
N5-C6
C6-C7
C7-C8
C8-C8a
C8a-C1
N5-C8a
1.318
1.390
1.328
1.387
1.325
1.395
1.379
1.397
1.373
1.407
C1-N2-C3
N2-C3-C4
N2-C3-H3
C3-C4-H4
C1-C8a-C8
C6-C7-C8
H6-C6-C7
H7-C7-C6
C7-C8-C8a
H7-C7-C8
C7-C8-H8
H7-C8-C8a
C8a-C1-H1
H1-C1-N2
C1-N2-H2
121.9
120.3
116.7
123.2
134.4
108.1
129.4
125.0
107.0
127.0
127.4
125.7
121.8
118.1
119.4
Resu lts a n d Discu ssion
The only synthesis of 1 which appears in the literature
6
was reported by Herz and Tocker. This procedure
involves the intermediacy of the pyrrolacetal 7 (Scheme
), which was obtained by the condensation of 2-pyrrole-
1
carboxaldehyde and aminoethylacetal in 90% yield. The
cyclization (21% yield) was carried out by treatment with
polyphosphoric acid and phosphorus oxychloride, and the
method gave an overall yield of 18%. In our hands,
attempts to improve the yield of the cyclization step by
employing different acid media failed. We consequently
considered synthesizing 1 by oxidizing the dihydro de-
a
Bond lengths are in angstroms and bond angles in degrees.
8
rivative 5 which, as we previously reported, could be
tives of azaindolizines.14 When we repeated the bromi-
nation of 1 using 1 equiv of bromine, a 1:1 mixture of
the 8-bromo derivative 8 and the 6,8-dibromopyrrolo[1,2-
prepared in 59% yield (Scheme 1). The oxidation was
carried out with Pd/C in refluxing xylene to give 1 in an
acceptable 65% yield.
a]pyrazine 9 was obtained which essentially is in accord
Complementary to the synthesis, the structure of the
pyrrolo[1,2-a]pyrazine 1 and its N-protonated form 1a
with the earlier reported studies.1
2,15
However, it is
noteworthy that in our hands Vilsmeier-Haack formy-
lation of 1 with dimethylformamide and phosphorous
oxychloride gave a 60% yield of the 8-formyl substituted
derivative 10. These results are broadly in agreement
(
a model of either protonated or N-alkyl derivatives) were
calculated. The geometries and charges on the heavy
atoms of 1 and 1a are presented in Figure 1 and the
calculated geometrical parameters obtained are listed in
Tables 1 and 2. The nitrogen atoms show negative
charges, with N5 being the most negative. From fre-
quency calculations at the RHF/6-31G* level of theory
we obtained a gas phase basicity of 227.4 kcal/mol for 1.
In Figure 2, the HOMO and LUMO and their energy
levels are presented. Only atomic orbitals with coef-
ficients larger than 0.1 are depicted.
with theoretical calculations which indicate C
to be the carbons of greatest electron surplus.
7 8
and C
In the reaction of 1 with 1 equiv of n-butyllithium in
THF at -78 °C the butyl anion adds to the electron
deficient C1 position to give the butylated derivative 11
in 21% yield after quenching. The metalation reaction
of 1 with 1.1 equiv of the lithium diisopropylamide (LDA)
at -78 °C, followed by the addition of several electro-
philes (Scheme 2), afforded the 4-substituted derivatives
12a -d in good yields, with none of the 1-substituted
derivatives being obtained in spite of the charge density
distribution obtained by theoretical calculations being
quite similar for both positions.
With respect to the reactivity of the system, in a very
early paper concerning the chemistry of diazaindenes,
Paudler and Dunham12 reported that 1 undergoes elec-
trophilic bromination and nitration at the 6- and 8-posi-
tions while attempts at Vilsmeier formylation failed to
give the corresponding formyl derivatives, in contrast to
the ready formylation of indolizines13 and some deriva-
(14) (a) Fraser, M. J . Org. Chem. 1972, 37, 3027. (b) Buchan, R.;
Fraser, M.; Shand, C. J . Org. Chem. 1976, 41, 351. (c) Fuentes, O.;
Paudler, W. J . Heterocycl. Chem. 1975, 12, 379. (d) Buchan, R.; Fraser,
M.; Shand, C. J . Org. Chem. 1977, 42, 2448.
(15) For the most recent studies on the chemistry of pyrrolo[1,2-a]-
pyrazine derivatives see: (a) Buchan, R.; Fraser, M. Kong, P. V. S.;
Kong Thoo Lin, K. T. J . Org. Chem. 1989, 54, 1074. (b) Buchan, R.;
Fraser, M.; Kong Thoo Lin, P. V. S. Heterocycles 1989, 28, 857. (c) Kong
Thoo Lin, P. V. S.; Buchan, R.; Fraser, M.; McHattie, D. Heterocycles
1990, 31, 1459.
(
11) GAUSSIAN-92, Frisch, M. J .; Trucks, G. W.; Head-Gordon, M.;
Gill, P. M. W.; Wong, M. W.; Foresman, J . B.; J ohnson, B. G.; Schlegel,
H. B.; Robb, M. A.; Replogle, E. S.; Gomperts, G.; Andr e´ s, J . L.;
Raghavachari, K.; Binkey, J . S.; Gonz a´ lez, C.; Martin, R. L.; Fox, D.
J .; DeFrees, D. J .; Baker, J .; Stewart, J . J . P.; Pople, J . A. Gaussian
Inc., Pittsburgh PA, 1992.
(
(
12) Paudler, W.; Dunham, D. J . Heterocycl. Chem. 1965, 2, 410.
13) Mackenzie, S.; Reid, D. J . Chem. Soc. C 1970, 145.

Structure and Chemistry of Pyrrolo[1,2-a]pyrazine
J . Org. Chem., Vol. 61, No. 14, 1996 4657
F igu r e 1. Optimized geometries and atomic charges for pyrrolo[1,2-a]pyrazine 1 (left) and the N-protonated form 1a (right)
obtained at the HF/6-31G** level.
Sch em e 2
F igu r e 2. HOMO and LUMO of the pyrrolo[1,2-a]pyrazine 1
(above) and the N-protonated form 1a (below) with the orbital
energies and the renormalized HF/6-31G* MO coefficients.
When 1 was treated with alkylating agents the corre-
sponding salts 13, 15, and 16 were obtained in good yields
(
Scheme 3). N-Amination also occurred easily on treat-
ment of 1 with O-(mesitylenesulfonyl)hydroxylamine
MSH) in dichloromethane at 0 °C to give the salt 14 in
7% yield. From these salts the corresponding ylides
Sch em e 3
(
7
were generated which were then subjected to 1,3-dipolar
cycloaddition under various conditions.
The stabilized N-ylides generated from 13a (R ) Ph)
and 13b (R ) OEt) in a two-phase liquid-liquid dichlo-
romethane-potassium carbonate system reacted with
dimethylacetylenedicarboxylate (DMAD) to afford in each
case a mixture of two compounds in combined yield of
5
6% and 47%, respectively. Although complete separa-
1
tion of both components was difficult, H NMR showed
that the major product corresponded to the dihydrodipyr-
rolo[1,2-a:2′,1′-c]pyrazine 18 while the minor component
was the dipyrrolo[1,2-a:2′,1′-c]pyrazine 19 (Scheme 4).
The formation of 18 probably involves a 1,3-hydrogen
shift of the initial cycloadduct 17 to give 18 which is then
oxidized in part to 19. The stereochemistry of 18a and
1
1
8b was established on the basis of their H NMR spectra
which show coupling constants between the H2 and H3
protons of 11.7 Hz for 18a and 11.9 Hz for 18b, consistent
with a trans disposition for these hydrogens. To simplify
product isolation the mixtures of 18 and 19 were readily
aromatized with 2,3-dichloro-5,6-dicyano-1,4-benzoquino-
ne (DDQ) in dichloromethane, giving overall yields from
13a and 13b of 52% and 43% for 19a and 19b, respec-
tively.
As expected, dipolar cycloaddition with unsymetrically

4
658 J . Org. Chem., Vol. 61, No. 14, 1996
M ´ı nguez et al.
Sch em e 4
Sch em e 5
substituted acetylenic or olefinic dipolarophiles was
highly regioselective affording in all cases a single
cycloadduct. Thus, the cycloadditions of 13a ,b with
methyl propiolate, following the same procedure as before
for DMAD, gave the dipyrrolo[1,2-a:2′,1′-c]pyrazine 20
directly.
evidence that showed the double bond on the dihydro-
pyrrole ring to be located between the C1-C10b carbons
and the H3 proton to be coupled to the H2 protons with
coupling constants of J cis ) 6.5 Hz and J trans ) 12.1 Hz.
The derivative 25 was obtained in 59% yield after DDQ
oxidation of the reaction mixture.
When acrylonitrile was reacted for 2 h with the ylide
of 13a in dichloromethane-aqueous potassium carbonate
the endo cycloadduct 21 was the major isolated com-
pound. However, when the reaction was carried out for
A regioisomeric structure for 21 (and hence for 22-
25) was discarded on the basis of chemical shifts and
coupling between H10b (d), H1 (m), H2 (two hydrogens,
td), and H3 (dd) which clearly shows that the cyano and
3
5 h at room temperature in dry acetonitrile using
anhydrous potassium carbonate as base the aromatized
derivative 22 was obtained (Scheme 5). A more complex
mixture containing the tetrahydro derivative 23 as the
major product, the dihydro derivative 24 as a minor
component and a trace of the fully aromatized 25 was
obtained when 13b was reacted with acrylonitrile under
1
two-phase liquid-liquid conditions. H NMR analysis of
the crude mixture lent support to the structures of the
components. Although chromatography failed to fully
separate these three derivatives we were able to isolate
and purify a small amount of 24 and obtain 1H NMR
carbonyl groups are not adjacent to each other. The
coupling constant between H1 and H10b (J ) 6 Hz) and

Structure and Chemistry of Pyrrolo[1,2-a]pyrazine
J . Org. Chem., Vol. 61, No. 14, 1996 4659
Sch em e 6
1
NOE difference H NMR spectra led to the establishment
of the cis arrangement for these hydrogens. The assigned
stereochemistry was supported by the NOE observed
between the H1 and the H2 protons (cis arrangement)
and the NOE observed between the H2′ proton (trans
arrangement with respect to H1) and the H3 proton.
via initial formation of 26, and this supposition was easily
proved by conversion of the ylide 26 into the heterobe-
taine 27 using the same conditions described for the
synthesis of 27.
We also studied the cycloaddition reaction of the
N-amino salt 14 with DMAD and methyl propiolate and
found that a mixture of the dihydro derivative 29 and
the fully aromatized pyrazolo[1,5-a]pyrrolo[2,1-c]pyrazine
The cycloaddition reaction of 13a ,b with heterocumu-
lenes was also tested under the standard two-phase
liquid-liquid conditions using phenyl isothiocyanate as
a dipolarophile (Scheme 5). The reaction led however to
the N-ylides 26 in moderate yield after 4 h at room
temperature. This result was not unexpected since these
ylides seem to be particularly stabilized, not only by
charge delocalization but also by an intramolecular
hydrogen bond. A similar observation has been reported
for some heteroaryl-stabilized cycloimmonium ylides and
isothiocyanate derivatives.16 H NMR evidence consis-
tent with the proposed structure 26 was obtained and
confirmed the presence of the characteristic H1 pyrrolo-
3
0 was formed in the first case while the cycloadduct 31
was the only isolated compound in the latter (Scheme
). In the reaction with DMAD a likely initial transient
6
cycloadduct 28 undergoes a 1,3-sigmatropic hydrogen
shift to give 29 which is in part oxidized to 30. The
mixture can be separated by chromatography on silica
1
gel. The H NMR of the dihydro derivative confirms the
presence of the double bond of the dihydropyrazolo moiety
between the C1 and C10b carbons since the value of the
coupling constant between H2 and NH (J ) 12.5 Hz)
seems to be too high to be assigned to homoallylic H10b
and NH protons which would support an isomeric 3,10b-
dihydropyrazolo[1,5-a]pyrrolo[2,1-c]pyrazine derivative.
DDQ oxidation of the mixture yielded 30 in 45% yield.
1
[
1,2-a]pyrazinium proton at 8.8 ppm and the NH proton
at δ 12-14 ppm. After some effort, we were able to
obtain the desired mesomeric conjugate betaines 27 in
4
0-51% yield using the solid-liquid dry acetonitrile-
Fluoride-induced desilylation of the salt 15 gave the
nonstabilized ylide 32 which underwent cycloaddition
with methyl propiolate to yield the cycloadduct 33 in 16%
yield. Attempts to trap this ylide with other dipolaro-
philes such as DMAD and acrylonitrile failed under
various conditions. The use of a tributylammonium salt
as an alternative source of fluoride also proved unsuc-
cessful. Finally, all our attempts to access benzimidazole-
substituted pyrrolopyrazines 35 by trapping the het-
eroaryl-stabilized N-ylide 34 were fruitless either with
potassium carbonate system and stirring at room tem-
perature for 20-40 h. Under these conditions a small
amount of the ylide is still present as a minor product
(12-20% yield). The formation of 27 probably proceeds
(16) (a) Cuadro, A. M.; Novella, J . L.; Molina, A.; Alvarez-Builla, J .;
Vaquero, J . J . Tetrahedron 1990, 46, 6033. (b) Molina, A.; Cuadro, A.
M.; Alvarez-Builla, J .; Vaquero, J . J .; Garcia Navio, J . L. Heterocycles
1
990, 31, 1451. (c) Minguez, J . M.; Gandasegui, T.; Vaquero, J . J .;
Alvarez-Builla, J . L.; Garcia Navio, J . L.; Gago, F.; Ortiz, A. R.; Gomez-
Sal, P.; Torres, R.; Rodrigo, M. M. J . Org. Chem. 1993, 58, 6030.

4
660 J . Org. Chem., Vol. 61, No. 14, 1996
M ´ı nguez et al.
Sch em e 7
Sch em e 8
acetylenic or olefinic dipolarophiles (hererocumulenes
included) (Scheme 6).
Intramolecular cyclization was also examined with
acetylenic and olefinic salts 40 and 46. Both salts were
prepared by N-alkylation of 1 with appropriate chains
salt 40 via hydrolysis of the internal ester functionality
occurred. Other attempts to obtain 42 in better yields
by refluxing in toluene or xylene under basic or neutral
conditions also failed. Refluxing salt 46 in xylene for 24
h was found, on the other hand, to be the only way of
generating the chromon-7-one derivative 48, albeit in
only 15% yield. In this case the salt 46 seems to be much
more sensitive to the two-phase system and is extensively
decomposed under such conditions. Under the thermal
conditions the fully aromatized pentacyclic system 48
forms, we believe, via the initial cycloadduct 47. The
intramolecular cycloaddition process was accompanied by
substantial decomposition of the salt 46. Thus after 24
3
9 and 44 which incorporated an acetylenic or olefinic
moiety respectively (Schemes 7 and 8). The methyl
-(iodoacetoxy)-2-butynoate (39a ) and pentynoate 39b
4
were obtained by acylation and subsequent halogen
exchange of the (hydroxyalkyl)propiolates 37, themselves
prepared from the commercially available propynyl and
butynyl alcohols 36 following the method described by
Thomas and Munt.17 Furthermore, the alkylating methyl
1
3
-[2-(iodoacetoxy)phenyl]acrylate (44) was easily pre-
pared from commercial 3-(2-hydroxyphenyl)acrylic acid
43) which after esterification was transformed into 44
h in boiling xylene the H NMR of the crude mixture
suggested it contained a mixture of 48, 1, and methyl
3-(2-hydroxyphenyl)acrylate together with uncharacter-
ized resinous material.
(
using conditions analogous to those described above for
the transformation of 37 into 39.
In conclusion, an alternative synthesis of the pyrrolo-
[1,2-a]pyrazine is reported together with ab initio studies
of its structure and of the derivative protonated at the
nonbridgehead nitrogen. The study of the basic chem-
istry of this heterocyclic system and cycloaddition of some
of its azomethine ylides led to several novel tri- and
tetracyclic systems with two bridgehead nitrogens. We
are continuing to explore alternative syntheses for the
other isomeric pyrrolodiazines and we will report our
additional findings at a later date.
The treatment of salts 40 with potassium carbonate
in dry acetonitrile afforded the corresponding tetracyclic
cycloadducts 42 in moderate yields. Attempts to improve
the yields of these intramolecular cycloadditions using
the aforementioned two-phase liquid-liquid conditions
were not successful, since extensive decomposition of the
(
17) Munt, P. S.; Thomas, E. J . J . Chem. Soc., Chem. Commun. 1989,
8
, 480.

Structure and Chemistry of Pyrrolo[1,2-a]pyrazine
J . Org. Chem., Vol. 61, No. 14, 1996 4661
Exp er im en ta l Section
J ) 4.4 Hz), 9.91 (s, 1H). Anal. Calcd for C
H, 4.14; N, 19.17. Found: C, 65.88; H, 4.43; N, 19.04.
-Bu tylp yr r olo[1,2-a ]p yr a zin e (11). To a solution of 1
8 6 2
H N O: C, 65.75;
All melting points were measured in open capillary tubes
and are uncorrected. Infrared spectra spectral bands are
1
(100 mg, 0.85 mmol) in 5 mL of dry THF was added 0.53 mL
-
1
reported in cm units. NMR spectra were recorded at 300
and 500 MHz, and the chemical shifts are expressed in parts
per million downfield from tetramethylsilane, with multiplic-
ity, coupling constants in hertz, and number of protons.
Elemental analyses were performed in the microanalytical
laboratory of the University. Mass spectra were determined
at an ionizing voltage of 70 eV. Column chromatography was
carried out using silica gel (Merck 60, 230-400 mesh). The
calculations were performed on the Supercomputer FUJ ITSU
VP 2400. All chemicals were of reagent grade and used
without further purification. O-(Mesitylenesulfonyl)hydroxyl-
amine (MSH) was prepared following the literature proce-
(0.85 mmol) of a 1.6 M solution of n-butyllithium in hexane at
-
78 °C under argon. After 90 min, the mixture was hydro-
lyzed with NH
Cl and extracted with EtOAc (2 × 10 mL). The
combined organic extracts were washed with water (3 × 5 mL)
and dried over Na SO , and the solvent was removed under
4
2
4
reduced pressure. Chromatography of the residue using
hexane-EtOAc (7:3) as eluent gave the title compound as a
-1
brown oil (30 mg, 21%): IR (neat) 2957, 1611, 1461, 1077 cm
;
1
H NMR (CDCl ) δ 0.96 (t, 3H, J ) 7.2 Hz), 1.41-1.48 (m,
3
2
1
1
5
1
1
H), 1.79-1.84 (m, 2H), 2.95 (t, 2H, J ) 7.6 H), 6.76-6.78 (m,
H), 6.82 (dd, 1H, J ) 2.5 Hz, J ) 4.0 Hz), 7.37 (dd, 1H, J )
.5 Hz, J ) 2.5 Hz), 7.41 (d, 1H, J ) 5.0 Hz), 7.68 (d, 1H, J )
1
8
dure.
+
.0 Hz); MS m/ z (rel int) 174 (20, M ), 145 (25), 132 (100),
P yr r olo[1,2-a ]p yr a zin e (1). To 2.0 g (16.6 mmol) of 3,4-
18 (94). Anal. Calcd for C11
6.08. Found: C, 76.12; H, 8.14; N, 15.71.
-P yr r olo[1,2-a ]p yr a zin eca r boxa ld eh yd e (12a ). To a
solution of 1 (0.20 g, 1.70 mmol) in 8 mL of dry THF at -78
C under argon was added 0.95 mL (1.90 mmol) of LDA (2 M)
in THF. After stirring for 40 min at -78 °C, DMF (140 mg,
.90 mmol) was added dropwise and stirring was continued
for 4 h at that temperature. The reaction mixture was then
quenched with a solution of NH Cl and extracted with Et O.
The organic phase was washed with water and brine, and dried
over Na SO . The solvent was removed under reduced pres-
14 2
H N : C, 75.82; H, 8.10; N,
7
,8
dihydropyrrolo[1,2-a]pyrazine (5) in xylene (35 mL) was
added 2.24 g of palladium on activated carbon 10%. The
mixture was refluxed for 20 h and then cooled and filtered
through Celite. The solution was concentrated under reduced
pressure to leave an oily residue. Chromatography of this
material using a 1:1 hexane-EtOAc mixture gave 1.20 g (62%)
4
°
1
6
of 1: bp 72 °C, 2 mmHg (lit. bp 71 °C, 2 mmHg). IR (neat)
-
1
1
3
(
(
3
097, 1614, 1458, 1306, 1076 cm ; H NMR (CDCl ) δ 6.78
4
2
d, 1H, J ) 4.2 Hz), 6.87 (dd, 1H, J ) 2.5 Hz, J ) 4.2 Hz), 7.41
d, 1H, J ) 2.5 Hz), 7.47 (d, 1H, J ) 4.9 Hz), 7.79 (d, 1H, J )
2
4
4
1
.9 Hz), 8.78 (s, 1H); 13C NMR (CDCl
) δ 145.0, 128.1, 126.7,
3
sure, and the residue was chromatographed using a mixture
of hexane-EtOAc (7:3) as eluent, to give 140 mg of 12a
17.8, 114.5, 114.2, 103.0; MS m/ z (rel int) 119 (71), 118 (100,
+
M ), 105 (97), 91 (90), 57 (37).
Br om in a tion of 1. To 0.30 g (2.24 mmol) of aluminum
chloride was added a solution of 1 (0.12 g, 1.01 mmol) in CH
Cl (2 mL). After stirring for 15 min, bromine (0.16 g, 1 mmol)
was slowly added and stirring was continued overnight. The
reaction mixture was then poured into cold water and ex-
(
57%): mp 116-117 °C (yellow prisms from EtOH); IR (KBr)
-1
1
1
7
1
3
668, 1606, 1419, 1298, 1088, 1043 cm ; H NMR (CDCl ) δ
2
-
.08-7.15 (m, 2H), 8.19 (s, 1H), 8.94-8.99 (m, 2H), 9.92 (s,
2
H); MS m/ z (rel int) 146 (100, M ), 118 (41), 91 (87), 63 (50).
+
8 6 2
Anal. Calcd for C H N O: C, 65.75; H, 4.14; N, 19.17.
Found: C, 65.31; H, 4.31; N, 18.82.
P h en ylp yr r olo[1,2-a ]p yr a zin -4-ylm eth a n ol (12b). To a
stirred solution of 1 (100 mg, 0.85 mmol) in anhydrous THF
tracted with CH
sively with water (2 × 5 mL) and saturated NaCl solution (2
5 mL) and dried over MgSO . The solvent was evaporated
under reduced pressure and the residue chromatographed.
Elution with CH Cl -acetone (9:1) gave 75 mg (38%) of the
-bromopyrrolo[1,2-a]pyrazine (8) and 120 mg (43%) of the 6,8-
dibromopyrrolo[1,2-a]pyrazine (9).
2 2
Cl . The organic phase was washed succes-
×
4
(5 mL) maintained at -78 °C under an argon atmosphere was
added LDA (2 M) in THF (0.46 mL, 0.93 mmol), and stirring
was continued for 30 min. Then, benzaldehyde (98 mg, 0.93
mmol) was added. After 2 h, the mixture was hydrolyzed with
2
2
8
NH
4
Cl and extracted with EtOAc (3 × 5 mL). The organic
8
-Br om op yr r olo[1,2-a ]p yr a zin e (8): brown powder from
extracts were dried over Na
2
SO and evaporated to give an
4
-
1
EtOH; mp 73-75 °C; IR (KBr) 1651, 1610, 1355, 1303 cm
;
oil that was triturated with a mixture of petroleum ether-
EtOAc (2 mL). Crystallization from EtOH afforded 12b as a
pale brown powder (136 mg, 72%): mp 152-153 °C; IR (KBr)
1
H NMR (CDCl ) δ 6.87 (d, 1H, J ) 2.8 Hz), 7.36 (d, 1H, J )
3
2
1
.8 Hz), 7.52 (d, J ) 4.9 Hz), 7.73 (d, 1H, J ) 4.9 Hz), 8.78 (s,
H). Anal. Calcd for C BrN : C, 42.67; H, 2.56; N, 14.22.
7
H
5
2
-1 1
3
6
167, 2829, 1616, 1450, 1311, 1046 cm ; H NMR (DMSO-d )
Found: C, 42.94; H, 2.73; N, 14.07.
δ 6.03 (d, 1H, J ) 4.7 Hz), 6.41 (d, 1H, J ) 4.7 Hz), 6.84 (bs,
6
,8-Dibr om op yr r olo[1,2-a ]p yr a zin e (9): brown powder
2
7
H), 7.26-7.36 (m, 3H), 7.48 (d, 2H, J ) 7.3 Hz), 7.52 (s, 1H),
1
2
from EtOH; mp 122-123 °C (lit. mp 122 °C, sublimation at
.60 (s, 1H), 8.78 (s, 1H). Anal. Calcd for C14 O: C, 74.98;
12 2
H N
5
5 °C/0.03 mmHg); IR (KBr) 1632, 1606, 1419, 1297, 1233
H, 5.39; N, 12.49. Found: C, 75.15; H, 5.74; N, 12.55.
-
1
1
cm ; H NMR (CDCl
Hz), 7.80 (d, 1H, J ) 5.1 Hz), 8.73 (s, 1H). Anal. Calcd for
Br : C, 30.47; H, 1.46; N, 10.15. Found: C, 30.52; H,
.57; N, 9.86.
-P yr r olo[1,2-a ]p yr a zin eca r boxa ld eh yd e (10). To a
suspension of POCl (143 mg, 0.93 mmol) in dry Et O (2 mL)
3
) δ 6.92 (s, 1H), 7.68 (d, 1H, J ) 5.1
4
-(Tr im eth ylsilyl)p yr r olo[1,2-a ]p yr a zin e (12c). To a
solution of 1 (100 mg, 0.85 mmol) in anhydrous THF (5 mL)
was added, at -78 °C under argon, 0.46 mL (0.93 mmol) of
LDA (2 M) in THF. After 45 min chlorotrimethylsilane (106
mg, 0.93 mmol) was added dropwise. Stirring was continued
for 90 min. After hydrolysis, the mixture was extracted with
C
7
H
4
2 2
N
1
8
3
2
cooled to 0 °C was added DMF (68 mg, 0.93 mmol). The
mixture was stirred until an insoluble oil formed (about 10
min). The oil was then dissolved in CH Cl , and a CH Cl
2 2 2 2
Et
2
O (3 × 5 mL). The ethereal phase was washed with water
and brine (3 × 10 mL) and dried over Na
2
SO . The solvent
4
was removed to give a brown oil that was chromatographed
solution (4 mL) containing 1 (100 mg, 0.85 mmol) was added.
The reaction mixture was then stirred for 3 h at room
temperature followed by 1 h at reflux. The solvent was
evaporated under reduced pressure, and the residue was
treated with cold water (10 mL), neutralized with NaOAc, and
extracted with EtOAc (3 × 5 mL). The organic phase was
using hexane-EtOAc (7:3) as eluent to afford 12c (93 mg,
5
8%). White powder from petroleum ether: mp 67-69 °C; IR
-1
1
(
(
6
KBr) 1590, 1414, 1336, 1302, 1251, 1040, 950 cm ; H NMR
CDCl ) δ 0.45 (s, 9H), 6.80 (dd, 1H, J ) 1.5 Hz, J ) 4.2 Hz),
.88 (dd, 1H, J ) 2.5 Hz, J ) 4.2 Hz), 7.48 (dd, 1H, J ) 1.5
Hz, J ) 2.5 Hz), 7.52 (s, 1H), 8.80 (s, 1H); MS m/ z (rel int)
3
dried over Na
2
SO
4
, the solvent evaporated under reduced
+
1
90 (91, M ), 175 (100), 145 (18), 105 (30). Anal. Calcd for
Si: C, 63.11; H, 7.41; N, 14.72. Found: C, 62.69; H,
.30; N, 14.81.
-Meth ylp yr r olo[1,2-a ]p yr a zin e (12d ). To a solution of
(0.20 g. 1.70 mmol) in anhydrous THF (10 mL) at -78 °C
pressure, and the residue chromatographed. Elution with
CH Cl -acetone (9:1) gave the formyl derivative 10 which was
10 14 2
C H N
7
2
2
recrystallized from EtOH to give yellow prisms (75 mg, 60%):
4
mp 115-117 °C; IR (KBr) 1646, 1603, 1465, 1364, 1103, 1018
1
-
1 1
cm ; H NMR (CDCl ) δ 6.85 (d, 1H, J ) 4.8 Hz), 7.50 (d, 1H,
3
and under argon was added LDA (2 M) (0.95 mL, 1.90 mmol)
in THF. After 30 min methyl iodide (240 mg, 1.7 mmol) was
added and the reaction mixture was allowed to warm to room
temperature and stirring was continued overnight. The
J ) 4.4 Hz), 7.95 (d, 1H, J ) 4.8 Hz), 9.06 (s, 1H), 9.38 (d, 1H,
(18) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1.

4
662 J . Org. Chem., Vol. 61, No. 14, 1996
M ´ı nguez et al.
mixture was hydrolyzed with NH
3 × 10 mL). The organic phase was washed with water and
brine and dried over Na SO . After evaporating the solvent,
2d was obtained as a dark oil (176 mg, 79%): IR (neat) 1612,
4
Cl and extracted with Et
2
O
Rea ction of 13a w ith DMAD. To a suspension of 0.20 g
(
(0.63 mmol) of 13a in 15 mL of CH
2
Cl
2
were added 0.22 g (1.60
CO (6 mL,
2
4
mmol) of DMAD and an aqueous solution of K
2
3
1
50%). The mixture was stirred for 5 h at room temperature,
and then the organic phase was separated, washed with water
-
1
1
1
3
425, 1256, 1045 cm ; H NMR (CDCl ) δ 2.49 (s, 3H), 6.85
(
dd, 1H, J ) 1.1 Hz; J ) 4.0 Hz), 6.94 (dd, 1H, J ) 2.8 Hz, J
4.0 Hz), 7.31 (d, 1H, J ) 2.8 Hz), 7.38 (s, 1H), 8.75 (s, 1H).
Anal. Calcd for C : C, 72.70; H, 6.10; N, 21.20. Found:
C, 72.98; H, 5.99; N, 21.61.
-P h en a cylp yr r olo[1,2-a ]p yr a zin iu m Br om id e (13a ).
(3 × 10 mL), and dried over Na
2 4
SO . After removing the
)
solvent under reduced pressure, the oily residue was chro-
matographed. Elution with hexane-EtOAc (9:1) allowed the
separation of the dihydro derivative 18a as a dark oil and the
fully aromatized 19a as a yellow solid. When the crude
mixture containing 18a and 19a was treated with 74 mg (0.32
8
8 2
H N
2
A mixture of 1 (1.06 g, 9.0 mmol) and phenacyl bromide (1.77
g, 9.0 mmol) was refluxed in acetone (20 mL) for 4 h. The
yellow precipitate that appeared was filtered off to afford a
solid which was recrystallized from EtOH to give 2.5 g (88%)
of the title compound as pale yellow crystals: mp 179-181
2 2
mmol) of DDQ in 5 mL of CH Cl and stirred at room
temperature for 1 h, compound 19a was obtained. Recrystal-
lization from EtOH afforded 123 mg (52%) as yellow needles.
3-Ben zoyl-1,2-bis(m eth oxyca r bon yl)-2,3-d ih yd r od ip yr -
r olo[1,2-a ;2′,1′-c]p yr a zin e (18a ): IR (KBr) 1773, 1678, 1598,
-
1
1
°
(
C; IR (KBr) 1696, 1652, 1348, 1231, 759 cm
DMSO-d ) δ 6.22 (s, 2H), 7.49 (dd, 1H, J ) 2.4 Hz, J ) 4.4
Hz), 7.65 (t, 2H, J ) 7.8 Hz), 7.73 (d, 1H, J ) 5.9 Hz), 7.74-
.76 (m, 1H), 7.82 (d, 1H, J ) 4.2 Hz), 8.06 (d, 2H, J ) 8.4
Hz), 8.51-8.52 (m, 1H), 8.84 (d, 1H, J ) 5.8 Hz), 9.45 (s, 1H).
Anal. Calcd for C15 O: C, 56.80; H, 4.13; N, 8.83.
Found: C, 56.48; H, 4.46; N, 8.69.
-[(E t h oxyca r b on yl)m e t h yl]p yr r olo[1,2-a ]p yr a zin i-
; H NMR
-
1 1
6
3
1316, 1155 cm ; H NMR (CDCl ) δ 3.43 (s, 3H), 3.87 (s, 3H),
4.55 (d, 1H, J ) 11.7 Hz), 5.50 (d, 1H, J ) 11.7 Hz), 5.79 (d,
1H, J ) 5.8 Hz), 6.13-6.19 (m, 1H), 6.22 (dd, 1H, J ) 2.9 Hz,
J ) 3.3 Hz), 6.27 (d, 1H, J ) 5.8 Hz), 6.62-6.68 (m, 1H), 7.52
(t, 2H, J ) 7.3 Hz), 7.65 (t, 1H, J ) 7.3 Hz), 8.00 (d, 2H, J )
7
H
13BrN
2
7.3 Hz). Anal. Calcd for C21
18 2 5
H N O : C, 66.66; H, 4.79; N,
2
7.40. Found: C, 66.39; H, 5.27; N, 7.79.
u m Br om id e (13b). To a solution of 1 (1.0 g, 8.50 mmol) in
EtOAc (20 mL) was added 1.50 g (9.0 mmol) of ethyl bromoac-
etate, and the mixture was refluxed for 4 h. The resulting
precipitate was filtered off, washed with EtOAc, and recrystal-
lized from acetonitrile to give 1.95 g (81%) of the title salt as
a pale yellow powder: mp 182-183 °C; IR (KBr) 1751, 1648,
3-Ben zoyl-1,2-bis(m eth oxycar bon yl)dipyr r olo[1,2-a ;2′,1′-
c]p yr a zin e (19a ): mp 142-144 °C; IR (KBr) 1736, 1696, 1682,
-
1 1
1627, 1493, 1234, 1214 cm ; H NMR (CDCl ) δ 3.25 (s, 3H),
3
3.87 (s, 3H), 6.75 (dd, 1H, J ) 3.9 Hz, J ) 2.7 Hz), 7.30 (dd,
1H, J ) 2.7 Hz, J ) 1.5 Hz), 7.45 (t, 2H, J ) 7.3 Hz), 7.46 (d,
1H, J ) 6.3 Hz), 7.57 (t, 1H, J ) 7.3 Hz), 7.72 (d, 2H, J ) 8.7
Hz), 7.79 (d, 1H, J ) 3.9 Hz), 8.33 (d, 1H, J ) 6.3 Hz); MS
-
1
1
1
6
207, 1149 cm ; H NMR (DMSO-d ) δ 1.24 (t, 3H, J ) 7.2
+
Hz), 4.22 (q, 2H, J ) 7.2 Hz), 5.43 (s, 2H), 7.47 (dd, 1H, J )
m/ z (rel int) 376 (100, M ), 345 (18), 313 (25), 258 (10), 105
2
1
.4 Hz, J ) 4.5 Hz), 7.79 (d, 1H, J ) 6.0 Hz), 7.80-7.82 (m,
(45). Anal. Calcd for C21
Found: C, 66.82; H, 4.05; N, 7.27.
Rea ction of 13b w ith DMAD. To 0.20 g (0.70 mmol) of
the salt 13b in 17 mL of CH Cl were added 0.25 g (1.75 mmol)
of DMAD and 7 mL of an aqueous solution (50%) of K CO
16 2 5
H N O : C, 67.02; H, 4.28; N, 7.44.
H), 8.52-8.53 (m, 1H), 8.85 (d, 1H, J ) 6.0 Hz), 9.55 (s, 1H);
+
MS m/ z (rel int) 206 (31, M ), 177 (36), 133 (55), 110 (100).
Anal. Calcd for C11
Found: C, 45.90; H, 4.56; N, 9.92.
-Am in opyr r olo[1,2-a ]pyr azin iu m Mesitylen esu lfon ate
14). To a solution of MSH (0.45 g, 2.10 mmol) in 5 mL of dry
CH Cl was added 0.25 g (2.10 mmol) of 1, and the mixture
was stirred at room temperature for 1 h. The precipitate was
filtered off and washed with Et O to give 0.54 g (77%) of a
white solid: mp 167-169 °C (white powder from EtOH-Et O);
H
13BrN
2
O: C, 46.34; H, 4.60; N, 9.82.
2
2
2
3
.
2
The mixture was stirred at room temperature for 6 h. The
(
organic phase was separated and washed with water (3 × 10
2
2
2 4
mL) and dried over Na SO . The solvent was removed under
reduced pressure, and the residue was chromatographed.
Elution with hexane-EtOAc (9:1) allowed the separation of
18b (green oil) and 19b. Treatment of the mixture with DDQ
(65 mg, 0.30 mmol) in CH Cl (5 mL) for 1 h afforded the fully
2 2
aromatized derivative 19b (105 mg, 43%).
2
2
-
1
1
IR (KBr) 3229, 3137, 1601, 1556, 1219, 1169, 1012 cm ; H
NMR (DMSO-d ) δ 2.15 (s, 3H), 2.48 (s, 6H), 6.71 (s, 2H), 7.33
dd, 1H, J ) 2.2 Hz, J ) 4.4 Hz), 7.51 (d, 1H, J ) 4.4 Hz), 7.62
d, 1H, J ) 5.9 Hz), 7.70 (bs, 2H), 8.25-8.30 (m, 1H), 8.70 (d,
H, J ) 5.9 Hz), 9.30 (s, 1H). Anal. Calcd for C16 SO
C, 57.64; H, 5.74; N, 12.60. Found: C, 57.59; H, 5.93; N, 12.83.
-[(Tr im eth ylsilyl)m eth yl]pyr r olo[1,2-a ]pyr azin iu m Tr i-
6
(
(
3-(E t h oxyca r b on yl)-1,2-b is(m et h oxyca r b on yl)-2,3-d i-
h yd r op yr r olo[1,2-a ]p yr a zin e (18b): IR (KBr) 1742, 1691,
-
1 1
1
H
19
N
3
3
:
3
1596, 1434, 1023 cm ; H NMR (CDCl ) δ 1.38 (t, 3H, J ) 7.1
Hz), 3.67 (s, 3H), 3.82 (s, 3H), 4.39 (q, 2H, J ) 7.2 Hz), 4.44
(d, 1H, J ) 11.9 Hz), 5.36 (d, 1H, J ) 11.9 Hz), 6.01 (d, 1H, J
) 5.7 Hz), 6.08-6.13 (m, 1H), 6.17-6.21 (m, 1H), 6.33 (d, 1H,
J ) 5.7 Hz), 6.65 (dd, 1H, J ) 2.5 Hz, J ) 1.3 Hz); MS m/ z
2
flu or om eth a n esu lfon a te (15). A mixture of 1 (0.20 g, 1.70
mmol) and (trimethylsilyl)methyl trifluoromethanesulfonate
+
(0.40 g, 1.70 mmol) in 8 mL of dry CH
2
Cl
2
was stirred at room
(rel int) 346 (100, M ), 315 (40), 287 (65). Anal. Calcd for
temperature under argon for 3 h. The solvent was removed
under reduced pressure to leave a solid which was filtered off
17 18 2 6
C H N O : C, 58.96; H, 5.24; N, 8.09. Found: C, 58.74; H,
5.29; N, 8.24.
and washed with Et
gave 0.38 g (64%) of a pale brown powder: mp 104-105 °C;
2
O. Recrystallization from hexane-EtOAc
3-(Eth oxycar bon yl)-1,2-bis(m eth oxycar bon yl)dipyr r olo-
[1,2-a ]p yr a zin e (19b): mp 129-130 °C (white needless,
-
1
1
-1 1
IR (KBr) 3106, 1653, 1342, 1278, 1256, 859 cm ; H NMR
DMSO-d ) δ 0.12 (s, 9H), 4.13 (s, 2H), 7.38 (dd, 1H, J ) 2.5
Hz, J ) 4.4 Hz), 7.57-7.59 (m, 2H), 8.34 (d, 1H, J ) 2.5 Hz),
.75 (d, 1H, J ) 5.8 Hz), 9.34 (s, 1H). Anal. Calcd for
SO SSi: C, 40.67; H, 4.83; N, 7.90. Found: C,
0.66; H, 4.69; N, 7.86.
-(Ben zim id a zol-2-ylm et h yl)p yr r olo[1,2-a ]p yr a zin i-
u m Ch lor id e (16). A mixture of 1 (0.11 g, 0.93 mmol) and
-(chloromethyl)benzimidazole (0.17 g, 1.0 mmol) was refluxed
EtOH); IR (KBr) 1746, 1707, 1502, 1221, 1172 cm ; H NMR
(
6
3
(CDCl ) δ 1.37 (t, 3H, J ) 7.2 Hz), 3.90 (s, 3H), 3.95 (s, 3H),
4.34 (q, 2H, J ) 7.2 Hz), 6.74 (dd, 1H, J ) 2.7 Hz, J ) 4.0 Hz),
7.28 (dd, 1H, J ) 2.7 Hz, J ) 1.7 Hz), 7.44 (d, 1H, J ) 6.2 Hz),
7.86 (dd, 1H, J ) 1.3 Hz, J ) 4.0 Hz), 8.60 (d, 1H, J ) 6.2 Hz);
8
C
12
H
17
F
3
N
2
3
+
4
MS m/ z (rel int) 344 (100, M ), 313 (16), 272 (30), 241 (77).
2
16 2 6
Anal. Calcd for C17H N O : C, 59.30; H, 4.68; N, 8.14.
Found: C, 59.48; H, 4.83; N, 8.08.
3-Ben zoyl-1-(m eth oxyca r bon yl)d ip yr r olo[1,2-a :2′,1′-c]-
p yr a zin e (20a ). To a solution containing 0.20 g (0.63 mmol)
2
in EtOAc (4 mL) for 6 h. The solvent was then evaporated
under reduced pressure and the solid residue washed with
of the salt 13a in CH
(0.13 g, 1.58 mmol) and an aqueous solution of K
2
Cl
2
(15 mL) were added methyl propiolate
CO (50%, 6
Et
2
O (3 × 3 mL) and recrystallized to give 154 mg (58%) of
2
3
the title compound: mp 197-198 °C (brown powder from
mL), and the reaction mixture was stirred at room tempera-
ture for 3 h. The organic phase was then separated, and the
-
1
1
EtOH); IR (KBr) 3208, 1625, 1535, 1193 cm
DMSO-d ) δ 4.20 (bs, 1H), 6.09 (s, 2H), 7.33-7.36 (m, 2H),
.48 (dd, 1H, J ) 2.5 Hz, J ) 4.4 Hz), 7.64-7.68 (m, 2H), 7.82
d, 1H, J ) 4.4 Hz), 7.94 (d, 1H, J ) 5.8 Hz), 8.50 (d, 1H, J )
.5 Hz), 8.83 (d, 1H, J ) 5.8 Hz), 9.80 (s, 1H). Anal. Calcd
for C15 : C, 63.27; H, 4.60; N, 19.68. Found: C, 63.43;
H, 4.46; N, 19.97.
; H NMR
(
6
aqueous layer was extracted with CH
combined organic phases were washed with water and satu-
rated NaCl solution. The organic phase was dried over Na
SO and concentrated under reduced pressure to give 20a .
2
Cl
2
(3 × 5 mL). The
7
(
2
2
-
4
H
13ClN
4
Recrystallization from EtOH gave 150 mg (77%) of yellow
needles: mp 174-175 °C; IR (KBr) 1722, 1612, 1472, 1223

Structure and Chemistry of Pyrrolo[1,2-a]pyrazine
J . Org. Chem., Vol. 61, No. 14, 1996 4663
cm- ; H NMR (CDCl
Hz, J ) 4.1 Hz), 7.35 (dd, 1H, J ) 2.6 Hz, J ) 1.4 Hz), 7.48-
.51 (m, 2H), 7.53 (d, 1H, J ) 6.1 Hz), 7.56 (s, 1H), 7.57-7.60
m, 1H), 7.82 (d, 1H, J ) 6.9 Hz), 8.00 (d, 1H, J ) 4.1 Hz),
1
1
) δ 3.89 (s, 3H), 6.79 (dd, 1H, J ) 2.6
compound 25. When this mixture was treated with DDQ (115
3
mg, 0.5 mmol) in 10 mL of CH
obtained.
2 2
Cl , 129 mg (59%) of 25 were
7
(
8
1-Cya n o-3-(eth oxyca r bon yl)-2,3-d ih yd r od ip yr r olo[1,2-
+
-1
.87 (d, 1H, J ) 6.1 Hz); MS m/ z (rel int) 318 (100, M ), 287
32), 241 (7), 213 (13). Anal. Calcd for C19 : C, 71.69;
H, 4.43; N, 8.80. Found: C, 71.56; H, 4.38; N, 8.86.
-(Eth oxycar bon yl)-1-(m eth oxycar bon yl)dipyr r olo[1,2-
a ;2′,1′-c]p yr a zin e (20b). To 0.15 g (0.52 mmol) of 13b in 12
mL of CH Cl were added 0.11 g (1.30 mmol) of methyl
propiolate and an aqueous solution of K CO (50%, 5 mL). The
a :2′,1′-c]p yr a zin e (24): IR (neat) 2177, 1723, 1592, 1118 cm ;
1
(
H
14
N
2
O
3
3
H NMR (CDCl ) δ 1.30 (t, 3H, J ) 7.0 Hz), 3.12 (dd, 1H, J )
6.5 Hz, J ′ ) 14.5 Hz), 3.32 (dd, 1H, J ) 14.5 Hz, J ) 12.5 Hz),
4.23-4.26 (m, 2H), 4.69 (dd, 1H, J ) 6.5 Hz, J ) 12.5 Hz),
6.24 (d, 1H, J ) 6.0 Hz), 6.49 (dd, 1H, J ) 2.5 Hz, J ) 4.0 Hz),
6.61 (d, 1H, J ) 6.0 Hz), 6.95 (dd, 1H, J ) 1.0 Hz, J ) 2.5 Hz),
7.14 (d, 1H, J ) 4.0 Hz).
3
2
2
2
3
mixture was stirred at room temperature for 3 h. The organic
phase was separated, and the aqueous layer was extracted
1-Cyan o-3-(eth oxycar bon yl)dipyr r olo[1,2-a :2′,1′-c]pyr a-
zin e (25): white prisms (from hexane-EtOAc); mp 152-154
-1 1
with CH
washed with water and brine (3 × 10 mL) and dried over Na
SO . After removing the solvent, the residue was chromato-
2
Cl
2
(3 × 5 mL). The combined organic extracts were
°C; IR (KBr) 2219, 1702, 1488, 1403, 1235, 1105 cm ; H NMR
2
-
3
(CDCl ) δ 1.40 (t, 3H, J ) 7.1 Hz), 4.37 (q, 2H, J ) 7.1 Hz),
4
6.77 (t, 1H, J ) 3.3 Hz), 7.25-7.28 (m, 2H), 7.42 (d, 1H, J )
6.2 Hz), 7.49 (s, 1H), 8.54 (d, 1H, J ) 6.2 Hz). Anal. Calcd
graphed using a mixture of hexane-EtOAc (9:1) as eluent to
give 20b. Recrystallization from EtOH afforded 90 mg (61%)
of white prisms: mp 158-160 °C; IR (KBr) 1698, 1488, 1228,
for C14
11 3 2
H N O : C, 66.40; H, 4.38; N, 16.59. Found: C, 66.08;
H, 4.44; N, 16.36.
2-(1-Ben zoyl-2-(p h en yla m in o)-2-su lfid ovin yl)p yr r olo-
[1,2-a ]p yr a zin -2-iu m (26a ). To a mixture of 0.20 g (0.63
-
1
1
1
(
)
7
182 cm ; H NMR (CDCl
s, 3H), 4.36 (q, 2H, J ) 7.2 Hz), 6.73 (dd, 1H, J ) 2.7 Hz, J
4.2 Hz), 7.25 (d, 1H, J ) 2.7 Hz), 7.40 (d, 1H, J ) 6.0 Hz),
.75 (s, 1H), 7.91 (d, 1H, J ) 4.1 Hz), 8.60 (d, 1H, J ) 6.0 Hz).
Anal. Calcd for C15 C, 62.93; H, 4.93; N, 9.79.
Found: C, 63.04; H, 4.82; N, 9.55.
-Ben zoyl-1-cya n o-1,2,3,10b-tetr a h yd r od ip yr r olo[1,2-
a ;2′,1′-c]p yr a zin e (21). To a suspension of 200 mg (0.63
mmol) of 13a in 15 mL of CH Cl were added 85 mg (1.60
mmol) of acrylonitrile and 6 mL of an aqueous solution of K
CO (50%). The yellow orange-mixture was stirred at room
temperature for 2 h. The organic phase was separated,
washed with water and brine (3 × 10 mL), and dried over Na
SO . The solvent was removed under reduced pressure, and
3
) δ 1.40 (t, 3H, J ) 7.2 Hz), 3.92
mmol) of 13a in 15 mL of CH
2 2
Cl and 6 mL of an aqueous
solution of K CO (50%) was added 100 mg (0.75 mmol) of
2
3
H
14
N
2
O
4
:
phenyl isothiocyanate. The yellow solution was stirred at room
temperature for 2 h, and the organic phase was separated,
3
washed with water and brine (3 × 10 mL), and dried over Na
2
-
SO . The solvent was evaporated and the residue chromato-
4
2
2
graphed using hexane-EtOAc (7:3) as eluent to give the title
compound as an orange powder after recrystallization from
hexane (98 mg, 42%): mp 169-171 °C; IR (KBr) 3061, 1646,
2
-
3
-
1
1
1564, 1499, 1395, 1188 cm ; H NMR (CDCl ) δ 7.12-7.17
3
2
-
(m, 6H), 7.29-7.38 (m, 5H), 7.72 (d, 1H, J ) 2.2 Hz), 7.78 (d,
1H, J ) 5.5 Hz), 7.82 (d, 2H, J ) 8.0 Hz), 8.76 (s, 1H), 14.32
(bs, 1H). Anal. Calcd for C22H N OS: C, 71.14; H, 4.61; N,
17 3
4
the residue was chromatographed using hexane-EtOAc (8:2)
as eluent to give 65 mg (36%) of the tetrahydro derivative 21
as a yellow oil. Traces of the dihydro derivative and the fully
aromatized compound were also separated: IR (neat) 2236,
11.31. Found: C, 71.45; H, 4.68; N, 11.08.
3-Ben zoyl-1-ph en ylim idazo[1,2-a ]pyr r olo[2,1-c]pyr azin -
4-iu m -2-th iola te (27a ). To 100 mg (0.31 mmol) of 13a in 6
mL of dry acetonitrile were added 51 mg (0.37 mmol) of phenyl
isothiocyanate and 174 mg (1.23 mmol) of anhydrous K CO .
2 3
The mixture was stirred at room temperature for 40 h. The
potassium carbonate was filtered off, the solvent removed
1
678, 1481, 1223, 1065 cm-1; 1H NMR (CDCl
3
) δ 2.54 (td, 1H,
J ) 13.5 Hz, J ) 5.7 Hz, J ) 2.5 Hz), 2.67 (td, 1H, J ) 13.5
Hz, J ) 8.5 Hz, J ) 2.5 Hz), 3.43-3.47 (m, 1H,), 4.84 (d, 1H,
J ) 6.0 Hz), 5.21 (dd, 1H, J ) 5.7 Hz, J ) 8.5 Hz), 5.83 (d, 1H,
J ) 5.9 Hz), 6.07 (d, 1H, J ) 2.4 Hz), 6.14 (d, 1H, J ) 5.9 Hz),
under reduced pressure, and the residue dissolved in CH
The organic layer was washed with water (3 × 5 mL) and dried
over Na SO . After removing the solvent, chromatography of
2 2
Cl .
6
.20-6.21 (m, 1H), 6.66 (dd, 1H, J ) 3.3 Hz, J ) 1.5 Hz), 7.51
(t, 2H, J ) 7.7 Hz), 7.61 (d, 1H, J ) 7.3 Hz), 7.98 (d, 2H, J )
2
4
+
7
1
5
.9 Hz); MS m/ z (rel int) 289 (16, M ), 235 (72), 184 (100),
57 (53), 105 (65). Anal. Calcd for C18 O: C, 74.72; H,
.23; N, 14.52. Found: C, 74.60; H, 5.43; N, 14.39.
-Ben zoyl-1-cya n od ip yr r olo[1,2-a :2′,1′-c]p yr a zin e (22).
the residue using hexane-EtOAc (8:2) as eluent gave 23 mg
(20%) of the ylide 26a and 60 mg (51%) of 27a as orange
prisms: mp 281-283 °C (from EtOH); IR (KBr) 1664, 1576,
15 3
H N
-
1
1
3
3
1511, 1339, 1123 cm ; H NMR (CDCl ) δ 5.70 (d, 1H, J )
To 0.20 g (0.63 mmol) of 13a in 12 mL of dry acetonitrile were
added 85 mg (1.60 mmol) of acrylonitrile and 0.34 g (2.50
4.4 Hz), 6.63-6.67 (m, 1H), 7.43-7.52 (m, 6H), 7.63-7.67 (m,
3H), 7.70 (d, 1H, J ) 6.1 Hz), 7.97 (d, 2H, J ) 7.1 Hz), 8.78 (d,
mmol) of anhydrous K
at room temperature for 35 h. The potassium carbonate was
filtered off and washed with CH Cl . The combined organic
extracts were washed with water and brine (3 × 10 mL). After
drying with Na SO , the solvent was removed and the residue
2
CO
3
. The orange mixture was stirred
15 3
1H, J ) 6.1 Hz). Anal. Calcd for C22H N OS: C, 71.52; H,
4.09; N, 11.37. Found: C, 71.26; H, 3.87; N, 11.45.
2
2
2-(1-(Eth oxycar bon yl)-2-(ph en ylam in o)-2-su lfidovin yl)-
p yr r olo[1,2-a ]p yr a zin -2-iu m (26b). To 200 mg (0.70 mmol)
2
4
of 13b in 17 mL of CH
2 2
Cl were added 7 mL of an aqueous
was chromatographed using hexane-EtOAc (7:3) as eluent to
give 22 as the main compound together with minor amounts
of dihydro and tetrahydro compounds. Treatment of the
solution of K CO (50%) and 115 mg (0.84 mmol) of phenyl-
isothiocyanate. The mixture was stirred at room temperature
for 4 h. The organic phase was separated, washed with water
2
3
mixture with DDQ (45 mg, 0.2 mmol) in CH
afforded the title compound which after recrystallization from
EtOH-Et O gave 0.32 g (68%) of yellow prisms: mp 167-
68 °C; IR (KBr) 2224, 1732, 1612, 1472, 1336, 1242 cm-1; 1H
NMR (CDCl ) δ 6.83 (t, 1H, J ) 3.5 Hz), 7.33-7.36 (m, 3H),
.49-7.54 (m, 3H), 7.59-7.61 (m, 1H), 7.79 (d, 2H, J ) 7.0
Hz), 8.80 (d, 1H, J ) 6.2 Hz). Anal. Calcd for C18 O: C,
5.78; H, 3.89; N, 14.73. Found: C, 76.01; H, 3.81; N, 14.82.
Rea ction of 13b w ith Acr ylon itr ile. To 0.25 g (0.87
mmol) of 13b in 20 mL of CH Cl were added 115 mg (2.30
mmol) of acrylonitrile and an aqueous solution of K CO (8
mL, 50%). The mixture was stirred at room temperature for
h. The organic phase was separated, washed with water
. The solvent
2
Cl
2
(4 mL)
and brine (3 × 10 mL), and dried over Na
was removed under reduced pressure and the residue chro-
matographed using CH Cl
2 4
SO . The solvent
2
2
2
-acetone (19.5:0.5) as eluent to give
1
the title compound (91 mg, 38%): mp 142-144 °C (orange
3
powder from hexane-EtOAc); IR (KBr) 3166, 1735, 1632, 1587,
-
1 1
7
3
1549, 1370, 1263, 1034 cm ; H NMR (CDCl ) δ 1.15 (t, 3H,
H
11
N
3
J ) 7.1 Hz), 4.12 (q, 2H, J ) 7.1 Hz), 7.08-7.11 (m, 1H), 7.20-
7.33 (m, 4H), 7.42 (d, 1H, J ) 4.1 Hz), 7.71 (d, 2H, J ) 7.7
Hz), 7.83 (dd, 1H, J ) 2.2 Hz, J ) 1.1 Hz), 8.00 (d, 1H, J ) 5.9
Hz), 8.81 (s, 1H), 11.8 (bs, 1H). Anal. Calcd for
7
2
2
2
3
18 17 3 2
C H N O S: C, 63.70; H, 5.05; N, 12.38. Found: C, 63.97;
H, 5.07; N, 12.47.
3-(E t h oxyca r b on yl)-1-p h en ylim id a zo[1,2-a ]p yr r olo-
[2,1-c]p yr a zin -4-iu m -2-th iola te (27b). To a mixture of 0.15
g (0.52 mmol) of 13b, 10 mL of dry acetonitrile and 0.29 g (2.1
2
and brine (3 × 10 mL), and dried over MgSO
4
was removed under reduced pressure, and the residue was
chromatographed using hexane-EtOAc (8:2) as eluent to give
an oily mixture containing the tetrahydro derivative 23, the
dihydro compound 24, and traces of the fully aromatized
mmol) of anhydrous K
phenylisothiocyanate. The dark red mixture was stirred for
48 h. The K CO was filtered off, the acetonitrile removed
2 3
CO was added 85 mg (0.63 mmol) of
2
3

4
664 J . Org. Chem., Vol. 61, No. 14, 1996
M ´ı nguez et al.
under reduced pressure, and the oily residue dissolved in CH
Cl
. The organic solution was washed with water (3 × 10 mL),
dried over Na SO , and evaporated. The dark oily residue was
chromatographed using hexane-EtOAc (3:7) as eluent to give
2 mg (12%) of the ylide 27a and 71 mg (40%) of 27b which
after crystallization from EtOH afforded yellow prisms: mp
2
-
CH
2
Cl
2
(50 mL) at 0 °C were added 4-hydroxy-2-butynoic acid
1
7
2
methyl ester (2.0 g, 17.54 mmol) and Et
mmol) in CH Cl (12 mL). The solution was stirred at room
temperature for 3 h. The solvent was removed under reduced
pressure and the residue purified by column chromatography
using hexane-EtOAc (8:2) as eluent to yield 38a (3.01 g, 90%)
as an orange oil: IR (neat) 2957, 2250, 1760, 1724, 1654, 1435,
1264, 1160, 1022 cm ; H NMR (CDCl
(s, 2H), 4.90 (s, 2H). Anal. Calcd for C
3.70. Found: C, 44.15; H, 3.90.
5-(Ch lor oacetoxy)-2-pen tyn oic Acid Meth yl Ester (38b).
Starting from 37b17 (2.0 g, 15.61 mmol) and following the same
procedure described for the preparation of 38a , column chro-
matography (hexane:EtOAc, 9:1) gave 38b (2.39 g, 75%) as a
yellow oil: IR (neat) 2959, 2242,1751, 1714, 1435, 1261, 1166,
3
N (4.9 mL, 35.08
2
4
2
2
2
-
1
2
41-242 °C; IR (KBr) 3087, 1733, 1666, 1513, 1336, 1236 cm ;
1
-1
1
H NMR (CDCl
7
)
8
6
3
) δ 1.49 (t, 3H, J ) 7.0 Hz), 4.49 (q, 2H, J )
3
) δ 3.79 (s, 3H), 4.12
.0 Hz), 5.65 (dd, 1H, J ) 4.4 Hz, J ) 0.8 Hz), 6.63 (dd, 1H, J
7
H
7
ClO : C, 44.12; H,
4
2.6 Hz, J ) 4.4 Hz), 7.42-7.45 (m, 3H), 7.64-7.68 (m, 4H),
S: C,
.88 (d, 1H, J ) 6.2 Hz). Anal. Calcd for C18
H
15
N
3
O
2
4.08; H, 4.48; N, 12.45. Found: C, 63.81; H, 4.77; N, 12.61.
Rea ction of 14 w ith DMAD. To a suspension of 0.16 g
(0.48 mmol) of 14 in 10 mL of dry acetonitrile were added 0.26
g (1.92 mmol) of anhydrous K CO and 0.17 g (1.20 mmol) of
2
3
-
1
1
DMAD. The yellow mixture was stirred at room temperature
for 24 h, and the potassium carbonate was filtered off and
1080, 1017 cm ; H NMR (CDCl
3.75 (s, 3H), 4.09 (s, 2H), 4.32 (t, 2H, J ) 6.6 Hz). Anal. Calcd
for C ClO : C, 46.96; H, 4.43. Found: C, 47.10; H, 4.26.
3
) δ 2.73 (t, 2H, J ) 6.6 H),
washed with CH
2
Cl
2
. The organic extracts were washed with
SO The
8
H
9
4
water and brine (3 × 10 mL) and dried over Na
2
4
.
4-(Iod oa cetoxy)-2-bu tyn oic Acid Meth yl Ester (39a ).
To a solution of NaI (0.79 g, 5.27 mmol) in dry acetone (10
mL) was added 38a (1.0 g, 5.27 mmol). The mixture was
stirred at room temperature for 2 h. The precipitated NaCl
was filtered off, and the solvent was removed under reduced
pressure. The residue was dissolved in EtOAc, and a satu-
rated Na
separated, washed with a saturated Na
dried (MgSO ). The solvent was evaporated under reduced
pressure, and the residue was purified by chromatography
(hexane:EtOAc, 9:1) to give 39a (1.32 g, 89%) as a yellow oil:
IR (neat) 2957, 2250, 1756, 1722, 1654, 1436, 1263, 1161, 1023,
993, 792, 751 cm ; H NMR (CDCl
3H), 4.84 (s, 2H). Anal. Calcd for C
Found: C, 30.08; H, 2.69.
solvent was removed and chromatography of the residue using
hexane-EtOAc (9:1) as eluent gave 13 mg (10%) of the dihydro
derivative 29 as a yellow solid and 47 mg (36%) of 30 as a
brown solid. Treatment of the mixture with DDQ (65 mg, 0.30
mmol) in CH
,2-Bis(m eth oxyca r bon yl)-2,3-d ih yd r op yr a zolo[1,5-a ]-
p yr r olo[2,1-c]p yr a zin e (29): mp 123-124 °C (hexane-
2 2
Cl (5 mL) afforded 30 in 45% yield.
1
2
S
2
O
3
solution was added. The organic layer was
2
2 3
S O
solution, and
-
1
1
EtOAc); IR (KBr) 1742, 1682, 1431, 1177 cm
CDCl ) δ 3.84 (s, 3H), 3.86 (s, 3H), 4.57 (d, 1H, J ) 12.5 Hz),
.48 (d, 1H, J ) 12.5 Hz), 6.08 (dd, 1H, J ) 1.5 Hz, J ) 3.3
Hz), 6.21 (t, 1H, J ) 3.3 Hz), 6.36 (d, 1H, J ) 5.8 Hz), 6.56 (d,
H, J ) 5.8 Hz), 6.68 (dd, 1H, J ) 1.5 Hz, J ) 2.2 Hz). Anal.
Calcd for C13 : C, 56.72; H, 4.76; N, 15.27. Found: C,
6.38; H, 4.69; N, 14.93.
,2-Bis(m et h oxyca r bon yl)p yr a zolo[1,5-a ]p yr r olo[2,1-
c]p yr a zin e (30): mp 126-128 °C (hexane-EtOAc); IR (KBr)
;
H NMR
4
(
3
5
-
1
1
1
3
) δ 3.73 (s, 2H), 3.77 (s,
H
13
N
3
O
4
7
H
7
IO : C, 29.81; H, 2.50.
4
5
1
5-(Iod oa cetoxy)-2-p en tyn oic Acid Meth yl Ester (39b).
This was prepared from NaI (0.73 g, 4.89 mmol) and 38b (1.0
g, 4.89 mmol), using the procedure described above for 39a ,
to give 39b (1.30 g, 90%) as a colorless oil: IR (neat) 2958,
1
1
739, 1706, 1248, 1217 cm-1; H NMR (CDCl
CH), 4.00 (s, 3H), 6.75 (dd, 1H, J ) 2.9 Hz, J ) 4.0 Hz), 7.31
dd, 1H, J 8-9 ) 2.9 Hz, J ) 1.4 Hz), 7.46 (d, 1H, J ) 6.2 Hz),
.52 (d, 1H, J ) 6.2 Hz), 7.56 (dd, 1H, J ) 4.0 Hz, J ) 1.4 Hz).
Anal. Calcd for C13 C, 57.14; H, 4.06; N, 15.38.
Found: C, 56.89; H, 4.25; N, 15.57.
-(Meth oxycar bon yl)pyr azolo[1,5-a ]pyr r olo[2,1-c]pyr a-
3
) δ 3.95 (s, 3H,
-1 1
(
7
2244, 1738, 1716, 1434, 1335, 1258, 1082, 1016 cm ; H NMR
(CDCl ) δ 2.71 (t, 2H, J ) 6.6 Hz); 3.71 (s, 2H); 3.76 (s, 3H);
3
H
11
N
3
O
4
:
8 9 4
4.27 (t, 2H, J ) 6.6 Hz). Anal. Calcd for C H IO : C, 32.46;
H, 3.06. Found: C, 32.05; H, 3.16.
1
2-[[[[3-(Meth oxyca r bon yl)-2-p r op yn yl]oxy]ca r bon yl]-
m eth yl]p yr r olo[1,2-a ]p yr a zin iu m Iod id e (40a ). A solution
of 1 (200 mg, 1.69 mmol) and 4-(iodoacetoxy)-2-butynoic acid
methyl ester (470 mg, 1.69 mmol) in EtOAc (10 mL) was
stirred under reflux for 24 h. The reaction mixture was cooled,
and the resulting precipitate was filtered off to give the title
zin e (31). To 0.20 g (0.60 mmol) of the salt 14 in 12 mL of
dry acetonitrile were added 0.33 g (2.40 mmol) of anhydrous
K
2
CO
mixture was stirred at room temperature for 35 h. The
potassium carbonate was filtered off and washed with CH
Cl
(3 × 5 mL). The combined organic extracts were washed
with water and brine (3 × 10 mL) and dried over Na SO . After
removing the solvent, the residue was chromatographed using
CH Cl as eluent to give the title compound as white needles
after recrystallization from ethanol (63 mg, 49%): mp 160-
62 °C; IR (KBr) 1702, 1570, 1536, 1401, 1272, 1237, 1157
3
and 0.12 g (1.50 mmol) of methyl propiolate. The
2
-
2
compound. Recrystallization from EtOH-Et
2
O afforded yellow
2
4
crystals (567 mg, 84%): mp 205-207 °C; IR (KBr) 3066, 2249,
-
1
1
1753, 1714, 1653, 1340, 1261, 1193, 1148 cm
; H NMR
2
2
(DMSO-d ) δ 3.69 (s, 3H), 5.11 (s, 2H), 5.47 (s, 2H), 7.49 (dd,
6
1H, J ) 4.4 Hz, J ) 2.2 Hz), 7.74 (d, 1H, J ) 6.1 Hz,), 7.84 (d,
1H, J ) 4.4 Hz), 8.48-8.52 (m, 1H), 8.79 (d, 1H, J ) 5.9 Hz),
1
-
1
1
cm ; H NMR (CDCl
Hz, J ) 3.8 Hz), 7.29 (dd, 1H, J ) 1.5 Hz, J ) 2.6 Hz), 7.41 (d,
H, J ) 6.0 Hz), 7.53 (d, 1H, J ) 6.0 Hz), 7.74 (d, 1H, J ) 3.8
Hz), 8.18 (s, 1H). Anal. Calcd for C11 : C, 61.39; H,
.22; N, 19.53. Found: C, 61.21; H, 4.49; N, 19.05.
-(Met h oxyca r b on yl)d ip yr r olo[1,2-a ;2′,1′-c]p yr a zin e
33). To 0.16 g (0.45 mmol) of the salt 15 in 8 mL of DME
were added 68 mg (0.45 mmol) of cesium fluoride and 40 mg
0.49 mmol) of methyl propiolate under an argon atmosphere.
The mixture was refluxed for 20 h and then cooled and poured
into cold water and extracted with CH Cl
(3 × 10 mL). The
organic phase was dried over Na SO , the solvent removed,
3
) δ 3.93 (s, 3H), 6.76 (dd, 1H, J ) 2.6
2 4
9.47 (s, 1H). Anal. Calcd for C14H13IN O : C, 42.02; H, 3.27;
N, 7.00. Found: C, 42.21; H, 3.56; N, 7.11.
1
2-[[[[4-(Met h oxyca r b on yl)-3-b u t yn yl]oxy]ca r b on yl]-
m eth yl]p yr r olo[1,2-a ]p yr a zin iu m Iod id e (40b). A mixture
of 1 (200 mg, 1.69 mmol) and 5-(iodoacetoxy)-2-pentynoic acid
methyl ester (500 mg, 1.69 mmol) in EtOAc (10 mL) was
stirred at room temperature for 5 h. The precipitate was
filtered off to give a brown solid which was recrystallized from
9 3 2
H N O
4
1
(
(
EtOH-Et
2
O to give the title compound (601 mg, 86%): mp
212-214 °C; IR (neat) 2951, 2242, 1751, 1708, 1655, 1565,
-
1
1
2
2
6
1339, 1264, 1201, 1152 cm ; H NMR (DMSO-d ) δ 2.84 (t,
2
4
2H, J ) 6.0 Hz), 3.69 (s, 3H), 4.30 (t, 2H, J ) 6.2 Hz), 5.41 (s,
2H), 7.48 (dd, 1H, J ) 2.4 Hz, J ) 4.6 Hz), 7.74 (dd, 1H, J )
1.5 Hz, J ) 5.9 Hz), 7.82 (d, 1H, J ) 4.7 Hz), 8.46-8.51 (m,
1H), 8.78 (d, 1H, J ) 5.9 Hz), 9.45 (s, 1H). Anal. Calcd for
and the brown oily residue chromatographed using hexane-
EtOAc (8:2) as eluent to give 15 mg (16%) of 33 as a yellow
-
1
1
oil: IR (CDCl
3
) 1697, 1444, 1228, 1127, 1041 cm ; H NMR
(
6
CDCl ) δ 3.90 (s, 3H), 6.65 (dd, 1H, J ) 2.8 Hz, J ) 4.0 Hz),
3
15 2 4
C H15IN O : C, 43.50; H, 3.65; N, 6.76. Found: C, 43.17; H,
4.01; N, 6.82.
1-(Met h oxyca r b on yl)-4-oxo-2-d ih yd r ofu r a n [4′,3′:4,5]-
p yr r olo[1,2-c]p yr r olo[1,2-a ]p yr a zin e (42a ). A solution of
2 3
the salt 40a (0.50 g, 1.25 mmol) and K CO (0.18 g, 1.25 mmol)
.90 (d, 1H, J ) 3.3 Hz), 6.95 (d, 1H, J ) 3.3 Hz), 7.04 (d, 1H,
J ) 5.9 Hz), 7.13 (dd, 1H, J ) 1.4 Hz, J ) 2.8 Hz), 7.24 (d, 1H,
J ) 5.9 Hz), 7.72 (d, 1H, J ) 4.0 Hz); MS m/ z (rel int) 214
+
(
100, M ), 204 (17), 183 (28). Anal. Calcd for C12
H
10
N
2
O
2
: C,
6
7.28; H, 4.71; N, 13.08. Found: C, 66.91; H, 4.35; N, 12.95.
-(Ch lor oa cetoxy)-2-bu tyn oic Acid Meth yl Ester (38a ).
To a solution of chloroacetyl chloride (1.4 mL, 17.54 mmol) in
in dry acetonitrile (12 mL) was stirred at room temperature
for 24 h. The reaction mixture was filtered, and the filtrate
was concentrated under reduced pressure to give a residue
4

Structure and Chemistry of Pyrrolo[1,2-a]pyrazine
J . Org. Chem., Vol. 61, No. 14, 1996 4665
which was chromatographed (hexane:EtOAc, 8:2) to yield 42a
(5 mL) was added a solution of NaI (0.59 g, 3.93 mmol) in dry
acetone (5 mL). The reaction mixture was stirred at room
temperature for 24 h. The precipitated NaCl was filtered off,
and the filtrate was concentrated. The residue was dissolved
(
80 mg, 24%): mp 212-214 °C (white prisms from EtOAc); IR
-
1
(
KBr) 2925, 2857, 1748, 1439, 1360, 1276, 1096, 1029 cm ;
1
H NMR (CDCl
3
) δ 3.91 (s, 3H), 5.36 (s, 2H), 6.79 (dd, 1H, J )
.6 Hz, J ) 4.0 Hz), 7.33 (dd, 1H, J ) 1.5 Hz, J ) 2.60 Hz),
.47 (d, 1H, J ) 6.2 Hz), 7.58 (d, 1H, J ) 5.9 Hz), 7.97 (d, 1H,
2
7
in EtOAc, and the solution was washed with saturated Na
SO solution, dried (MgSO ), and concentrated. The residue
2
-
4
4
J ) 4.0 Hz); MS m/ z (relat. int.) 272 (15), 271 (100), 270 (13),
was chromatographed (hexane:EtOAc, 8:2) to give the title
compound which was recrystallized from petroleum ether
affording white needles (1.36 g, 76%): mp 57-59 °C; IR (KBr)
2
3
55 (1), 239 (2). Anal. Calcd for C14
.73; N, 10.37. Found: C, 61.99; H, 4.01; N, 10.06.
-(Meth oxyca r bon yl)-5-oxo-2,3-d ih yd r op yr a n [4′,3′:2,3]-
p yr r olo[1,2-c]p yr r olo[1,2-a ]p yr a zin e (42b). A solution of
the salt 40b (0.80 g, 1.93 mmol) and K CO (0.28 g, 1.93 mmol)
10 2 4
H N O : C, 62.22; H,
-1 1
1
2951, 1751, 1712, 1637, 1322, 1210, 1176, 1093 cm ; H NMR
(DMSO-d
6
) δ 3.70 (s, 3H), 4.11 (s, 2H), 6.67 (d, 1H, J ) 16.1Hz),
2
3
7.18 (d, 1H, J ) 8.1 Hz), 7.33 (t, 1H, J ) 7.5 Hz), 7.49 (t, 1H,
J ) 7.7 Hz), 7.74 (d, 1H, J ) 16.1 Hz), 7.91 (d, 1H, J ) 7.7
in dry acetonitrile (18 mL) was stirred at room temperature
for 24 h. The reaction mixture was filtered, and the filtrate
was concentrated. The residue was chromatographed (hexane:
EtOAc, 9:1) to give the title compound as white needles after
recrystallization from AcOEt (165 mg, 30%): mp 205-207 °C;
IR (neat) 1717, 1693, 1546, 1502, 1453, 1436, 1423, 1241, 1093
Hz). Anal. Calcd for C12
C, 41.55; H, 3.22.
4
H11IO : C, 41.64; H, 3.20. Found:
2-[[[2-[2-(Meth oxyca r bon yl)vin yl]p h en oxy]ca r bon yl]-
m eth yl]p yr r olo[1,2-a ]p yr a zin iu m Iod id e (46). A mixture
of 1 (200 mg, 2.69 mmol) and 3-[2-(iodoacetoxy)phenyl]acrylic
acid methyl ester (584 mg, 1.69 mmol) in EtOAc (10 mL) was
stirred at room temperature for 24 h. The precipitate formed
was filtered off and recrystallized from EtOAc-CH Cl to give
-
1 1
cm ; H NMR (CDCl ) δ 3.32 (t, 2H, J ) 6.2 Hz), 3.93 (s, 3H),
3
4
7
7
.58 (t, 2H, J ) 6.2 Hz), 6.76 (dd, 1H, J ) 2.6 Hz, J ) 4.0 Hz),
.31 (dd, 1H, J ) 1.5 Hz, J ) 2.6 Hz), 7.45 (d, 1H, J ) 5.9 Hz),
.91(dd, 1H, J ) 1.1 Hz, J ) 4.0 Hz), 8.42 (d, 1H, J ) 5.9 Hz);
2
2
46 (0.70 g, 89%) as yellow needles: mp 127-129 °C; IR (KBr)
-1 1
MS m/ z (rel int) 284 (100), 253 (18), 226 (15), 225 (37), 168
3054, 1763, 1712, 1634, 1334, 1281, 1238, 1145 cm ; H NMR
(
21), 167 (14). Anal. Calcd for C15
N, 9.85. Found: C, 63.41; H, 4.69; N, 9.62.
-(2-(Ch lor oa cetoxy)p h en yl)a cr ylic Acid Meth yl Ester
44). To a stirred solution of 43 (1.0 g, 6.10 mmol) in MeOH
5 mL) was added H SO (0.1 mL). The resulting reaction
H
12
N
2
O
4
: C, 63.38; H, 4.25;
(DMSO-d ) δ 3.74 (s, 3H), 5.77 (s, 2H), 6.67 (d, 1H, J ) 16.1Hz),
6
7.33-7.41 (m, 2H), 7.49-7.55 (m, 2H), 7.76 (d, 1H, J ) 16.1
Hz), 7.88-7.95 (m, 3H), 8.52 (m, 1H), 8.83 (d, 1H, J ) 5.9 Hz),
9.58 (s, 1H). Anal. Calcd for C H IN O : C, 49.16; H, 3.69;
3
(
(
1
9
17
2
4
2
4
N, 6.03. Found: C, 49.07; H, 3.62; N, 6.12.
mixture was refluxed for 2 h and then concentrated in vacuo,
and the residue was dissolved in Et O and washed with water,
and the organic layer was dried (MgSO ). Evaporation of the
solvent and column chromatography of the residue (hexane:
EtOAc, 8:2) gave 3-(2-hydroxyphenyl)acrylic acid methyl ester.
[
1]Ben zop yr a n o[3′,4′:2,3]p yr r olo[1,2-c]p yr r olo[1,2-a ]-
2
p yr a zin -6-on e (48). A solution of the salt 46 (0.66 g, 1.42
mmol) in xylene (3 mL) was heated at reflux for 24 h, and
then the reaction mixture was filtered. Removal of the solvent
in vacuo and purification of the residue by chromatography
4
The product was recrystallized from Et
2
O to afford white
(
hexane:EtOAc, 9:1) afforded a solid which after recrystalli-
needles (0.97 g, 80%): mp 131-133 °C; IR (KBr) 3392, 1693,
zation from EtOAc yielded 48 (60 mg, 15%) as white crystals:
mp 293-295 °C; IR (KBr) 3104, 1712, 1487, 1452, 1411, 1085,
-
1 1
1
(
1
626, 1603, 1455, 1327, 1227, 1197, 1174, 988 cm ; H NMR
DMSO-d ) δ 3.70 (s, 3H), 6.61 (d, 1H, J ) 16.1 Hz), 6.82 (t,
H, J ) 7.6 Hz), 6.90 (d, 1H, J ) 8.3 Hz), 7.23 (t, 1H, J ) 7.7
-1 1
6
1
3
066, 1042 cm ; H NMR (CDCl ) δ 6.72 (dd, 1H, J ) 3.9, 2.7
Hz); 6.90 (d, 1H, J ) 3.7 Hz); 6.99 (s, 1H); 7.32-7.37 (m, 2H);
Hz), 7.60 (d, 1H, J ) 7.8 Hz), 7.86 (d, 1H, J ) 16.1 Hz), 10.26
s, 1H).
A solution of chloroacetyl chloride (0.57 mL, 7.05 mmol) in
7
7
2
1
1
.39 (d, 1 H, J ) 5.9 Hz); 7.45-7.43 (m, 2H); 7.91(d, 1H, J )
.7 Hz); 8.46 (d, 1H, J ) 5.9 Hz); MS m/ z (rel int) 275 (19),
74 (100), 245 (8), 218 (8), 217 (14), 216 (6), 164 (6), 163 (5),
(
toluene (10 mL) was slowly added to a cooled solution of 3-(2-
hydroxyphenyl)acrylic acid methyl ester (1.0 g, 5.61 mmol) in
toluene (10 mL) and pyridine (1.14 mL.) The reaction mixture
was stirred at room temperature for 2 h. The solid was filtered
off, and the solvent was removed from the filtrate under
reduced pressure. The residue was purified by chromatogra-
phy (hexane:EtOAc, 8:2) to give 44 (1.34 g, 94%) as a colorless
oil: IR (neat) 2955, 1775, 1715, 1635, 1436, 1177, 1135, 1092
37 (7). Anal. Calcd for C17
0.21. Found: C, 74.39; H, 3.80; N, 10.08.
10 2 2
H N O : C, 74.45; H, 3.67; N,
Ack n ow led gm en t. The authors acknowledge sup-
port of this work from the Comisi o´ Interdepartamental
de Recerca i Innovaci o´ T e´ cnologica (CIRIT) through the
project QFN94-4619 and a grant from the Ministerio
de Educaci o´ n y Ciencia (J .M.M.). We thank Profs. R.
Carb o´ and M. Dur a´ n and the Centro de Computaci o´ n
de Galixia (CESGA) for providing the computing facili-
ties. We also thank Prof. J . Elguero for careful reading
of the manuscript and helpful discussions.
-
1 1
cm ; H NMR (DMSO-d
H, J ) 16.1 Hz), 7.27 (d, 1H, J ) 8.1 Hz), 7.35 (t, 1H, J ) 7.5
Hz), 7.51 (t, 1H, J ) 7.7 Hz), 7.65 (d, 1H, J ) 16.1 Hz), 7.93
d, 1H, J ) 7.7 Hz). Anal. Calcd for C12 : C, 56.60; H,
.35. Found: C, 56.62; H, 4.77.
-(2-(Iod oa cet oxy)p h en yl)a cr ylic Acid Met h yl E st er
45). To a stirred solution 44 (1.0 g, 3.93 mmol) in dry acetone
6
) δ 3.71 (s, 3H), 4.77 (s, 2H), 6.69 (d,
1
(
4
H11ClO
4
3
(
J O9600969