Cycloaddition of 3-amino-5-chloro-2(1H)-pyrazinones and olefins: Ring transformation into 3-amino- or 6-cyano-substituted 2-pyridinone systems

Article abstract of DOI:10.1021/jo951016o

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(1H)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-1,2-dihydro-2-oxo-4-pyridinecarboxylates, e.g. 12a,b (loss of amine substituent), or the corresponding 3-amino-6-cyano-1,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates, e.g. 15a,b. From the latter compounds, 3-amino-2-pyridinones can be generated through subsequent loss of HCN. A mechanism accounting for the loss or retention of the amine substituent is based on (1) the effects observed for each reaction mode when varying the substituents in both reaction partners and (2) the exclusive retention of the amine substituent when replacing toluene with the basic solvent pyridine.

Full text of DOI:10.1021/jo951016o

304
J . Org. Chem. 1996, 61, 304-308
Cycloa d d ition of 3-Am in o-5-ch lor o-2(1H)-p yr a zin on es a n d Olefin s:
Rin g Tr a n sfor m a tion in to 3-Am in o- or 6-Cya n o-Su bstitu ted
2-P yr id in on e System s
Stef M. Vandenberghe, Kris J . Buysens, Lieven Meerpoel, Patrick K. Loosen,
Suzanne M. Toppet, and Georges J . Hoornaert*
Laboratorium voor Organische Synthese, Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200 F, B-3001 Leuven, Belgium
Received J une 5, 1995X
The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(1H)-pyrazinones with
methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding
either methyl 6-cyano-1,2-dihydro-2-oxo-4-pyridinecarboxylates, e.g. 12a ,b (loss of amine substitu-
ent), or the corresponding 3-amino-6-cyano-1,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates, e.g.
15a ,b. From the latter compounds, 3-amino-2-pyridinones can be generated through subsequent
loss of HCN. A mechanism accounting for the loss or retention of the amine substituent is based
on (1) the effects observed for each reaction mode when varying the substituents in both reaction
partners and (2) the exclusive retention of the amine substituent when replacing toluene with the
basic solvent pyridine.
Sch em e 1
Several heterocycles containing a 2-aza diene system
are subject to undergo cycloaddition and subsequent
elimination reactions.1 In previous work of our group the
3,5-dichloro-2(1H)-pyrazinones of type 1a -d , easily pre-
pared from R-amino nitriles and oxalyl chloride,2 and
some 3-substituted derivatives were shown to react with
acetylenic compounds in two divergent ways.3 Depending
on the substitution pattern of both the 2(1H)-pyrazinone
and the dienophile, the initially formed cycloadducts 2
gave pyridines 3 and/or 2(1H)-pyridinones 4 (Scheme 1).
Cycloaddition of compounds 1a -d with olefins afforded
stable bicyclic products 6.4,5 The intermediate adducts
2 (R3 ) NEt2) formed from 3-amino-5-chloro-2(1H)-
pyrazinones of type 5a ,b and acetylenic compounds, in
contrast to the reaction of other 3-substituted 2(1H)-
pyrazinones (R3 * NR2), where found6 to undergo ring
transformations resulting in production of compounds 7.
Although ring transformation reactions are common in
heterocyclic chemistry,7 to our knowledge a rearrange-
ment of the type proposed has not been described. An
analogous amino-substituted aza diene system has been
dealt with only in a few papers,8 and only in a single case
could the product obtained after Diels-Alder reaction be
X Abstract published in Advance ACS Abstracts, November 15, 1995.
(1) Boger, D. L. Chem. Rev. 1986, 86, 781. Steglich, W.; J eschke,
R.; Buschmann, E. Gazz. Chim. Ital. 1986, 116, 361. Boger, D. L.;
Weinreb, S. M. In Hetero Diels-Alder Methodology in Organic Syn-
thesis; Wasserman, H. H., Ed.; Academic Press: San Diego, CA, 1987;
Vol. 47. Boger, D. L. Bull. Soc. Chim. Belg. 1990, 99, 599.
(2) Vekemans, J .; Pollers-Wiee¨rs, C.; Hoornaert, G. J . Heterocycl.
Chem. 1983, 20, 919.
(3) Tutonda, M.; Vanderzande, D.; Vekemans, J .; Toppet, S.; Hoor-
naert, G. Tetrahedron Lett. 1986, 27, 2509. Tutonda, M.; Vander-
zande, D.; Hendrix, M.; Hoornaert, G. Tetrahedron 1990, 46, 5715.
(4) Tutonda, M.; Vanderzande, D.; Verschave, P.; Hoornaert, G. In
Bio-Organic Heterocycles 1986: synthesis, mechanism and bioactivity;
Van der Plas, H. C., Simonyi, M., Alderweireldt, F. C, Lepoivre, J . A.,
Eds.; Elsevier Science: Amsterdam, 1986; p 197.
(5) Loosen, P. K.; Tutonda, M. G.; Khorasani, M. F.; Compernolle,
F.; Hoornaert, G. J . Tetrahedron 1991, 47, 9259.
(6) Tutonda, M. G.; Vandenberghe, S. M.; Van Aken, K. J .; Hoor-
naert, G. J . Org. Chem. 1992, 57, 2935.
(7) Van der Plas, H. C. Ring Transformations of Heterocycles;
Academic Press: New York, 1973; Vol. I. L’Abbe´, G. J . Heterocycl.
Chem. 1984, 21, 627.
(8) Neunhoeffer, H.; Lehmann, B. Liebigs Ann. Chem. 1977, 1413.
Baydar, A. E.; Boyd, G. V. J . Chem. Soc., Chem. Comm. 1979, 178.
Oki, M.; Shimada, S. Chem. Pharm. Bull. 1987, 35, 4705.
interpreted by a similar mechanism.9 We now report on
two alternative modes of ring transformation observed
(9) Sasaki, T.; Kojima, A. Tetrahedron Lett. 1971, 4593.
0022-3263/96/1961-0304$12.00/0 © 1996 American Chemical Society

Cycloaddition of Pyrazinones and Olefins
J . Org. Chem., Vol. 61, No. 1, 1996 305
Sch em e 2
Sch em e 3
in cycloadducts of 3-amino-5-chloro-2(1H)-pyrazinones
5a -g and some olefinic dienophiles.
As a model for our investigations we used the reaction
between methyl acrylate and 5-chloro-3-(diethylamino)-
2(1H)-pyrazinones (5a ,b). Upon reaction with 3 equiv
of methyl acrylate in toluene at 80 °C for about 20 h,
instead of the normally expected adducts of type 8a ,b,
we isolated methyl 6-cyano-1,2-dihydro-2-oxo-4-pyridine-
carboxylate (12a ,b) as the sole reaction product (Scheme
2). The 1H NMR spectra of these compounds show a
peared as two doublets at 3.15 and 2.95 ppm with a J gem
of 17 Hz. Compound 14 was identical to the product
isolated previously in low yield from the reaction of 5c
with methyl propynoate.6 Complete conversion of the
intermediate compound 13 to the final product 14 was
observed when the cycloaddition of 5c with methyl
acrylate was conducted under forcing conditions (toluene,
reflux for 2 d, 83%). Heating of the isolated compound
13 (toluene, reflux for 2 d) also led to a quantitative
conversion. The isolation of 13, the free base analogue
of the salt intermediates 10a ,b provides support for the
mechanism depicted in Scheme 2. Due to the absence of
a hydrogen atom in the 6 position, the loss of diethyl-
amine hydrochloride is prevented; elimination of hydro-
gen cyanide can occur under more forcing conditions.
4
characteristic J coupling of 2 Hz for the protons in the
3 and 5 position. The IR absorptions at about 2225
(nitrile) and 1735 cm-1 (ester) are in agreement with the
structure proposed. Compounds 12a ,b may originate
from a rearrangement similar to that already described
for the acetylene type cycloadducts.6 In the original olefin
type cycloadducts, the 2,5-diazabicyclo[2.2.2]oct-2-ene
compounds 8a ,b, cleavage of the ring C-N bond again
may be assisted by the nitrogen electron pair to form
intermediates 9a ,b. They can be transformed into tau-
tomeric forms 10a ,b and 11a ,b via successive acid-
catalyzed equilibration, resulting in the final loss of the
protonated diethylamino group and formation of com-
pounds 12a ,b.
To clarify the role of the acidic proton in the R position
of the ester group in intermediates 9a ,b, compound 5a
was made to react with methyl methacrylate in toluene
at 80 °C. Not unexpectedly a mixture of tarry products
was formed.
The chlorine atom in the 5 position and the hydrogen
substituent in the 6 position of the 2(1H)-pyrazinones (5)
are crucial factors for the proposed reaction route,
because they are serving as a leaving group and an acidic
proton, respectively. In order to confirm the role of the
5-chlorine substituent, which was essential in the reac-
tion with acetylenic compounds, we tried the addition of
methyl acrylate on the dechlorinated analogue 5d . How-
ever, cycloaddition of 5d proved unsuccessful, as found
already with other 5-dechlorinated 2(1H)-pyrazinones.5
To investigate the role of the 6-H atom, the 6-methyl-
substituted pyrazinone 5c was made to react with methyl
acrylate in toluene at 80 °C for 1 d. After workup and
column chromatography on silica gel, two new products
were isolated, i.e. the 6-cyano compound 13 (41%) and
the corresponding elimination product 14 (13%). In the
1H NMR spectrum of 13, the 5-methylene protons ap-
Since the ring transformation depicted in Scheme 2
involves successive acid-catalyzed tautomerizations re-
sulting in expulsion of diethylamine hydrochloride, a
marked influence on the outcome of the cycloaddition of
5a ,b was to be expected when using a basic solvent, i.e.
dry pyridine. This modification indeed resulted (Scheme
3) in isolation of the unstable 3-amino intermediates
15a ,b when the reaction was conducted at 80 °C for 10
h. When more drastic conditions were applied, i.e. reflux
temperature for 2 d, products 16a ,b corresponding to
further elimination of HCN were isolated in good yield.
On the other hand, ring transformation of the ester
enamine intermediate 15a , to form 12a according to the
reaction sequence depicted in Scheme 2, could be effected
in two different ways. Treatment of 15a with dry HCl
in toluene and further heating of the precipitated salt
(10a )-solvent mixture at 80 °C quickly afforded the

306 J . Org. Chem., Vol. 61, No. 1, 1996
Vandenberghe et al.
Sch em e 4
Sch em e 5
expected product 12a . For the analogous conversion of
the free base 15a , prolonged reflux in toluene was
required. These observations strongly support the in-
termediacy of the protonated ester enamine 9a ,b and its
tautomeric forms 10a ,b and 11a ,b. Apparently, depro-
tonation of these intermediates is effected with pyridine,
which retards the elimination of diethylamine (15a ,b f
12a ,b) and favors the loss of HCN (15a ,b f 16a ,b).
The nature of the amine substituent in the 3 position
of the starting 2(1H)-pyrazinone (5) also appears to be
important. Cycloaddition of 3-(ethylamino)- and 3-amino-
2(1H)-pyrazinones (5e,f) (Scheme 4) with methyl acrylate
in toluene proceeded slowly (5 d at 80 °C, 3 d at 110 °C,
respectively), affording the rearranged compounds 17 and
18 which did not lose hydrogen cyanide under these
conditions. Retention of the amine substituent also was
observed in the reaction of ethene with the 3-indolyl-
2(1H)-pyrazinone (5g), wherein the indolyl group can be
considered as a vinylogous amine. The unstable reaction
product 19 was characterized after HPLC purification
(10% ethyl acetate/chloroform). Treatment of a dioxane
solution of compound 19 with aqueous sodium hydroxide
led to complete conversion into the pyridinone elimina-
tion product 20.
26 and 27 have been described scarcely and are not easily
accessible.10
We may therefore conclude that ring transformations
of the cycloadducts from olefins with 3-amino-2(1H)-
pyrazinones proceed with or without loss of the amine
substituent. Expulsion of the amine to produce 6-cyano-
2(1H)-pyridinone systems can occur only if four structural
conditions are fulfilled. For the pyrazinone these are as
follows: (1) a leaving group at position 5, (2) a hydrogen
atom at position 6, and (3) a diethylamino group at
position 3. For the alkene component at least one
hydrogen on each of the original double bond positions
is required to allow for generation of the tautomeric
intermediates 9 and 10. The amine substituent is
retained in the alternative mode of ring transformation.
This occurs when 6-H is replaced with a methyl group
or when an ethylamino or indolyl group is present at the
3 position. Moreover, deprotonation of the iminium ester
intermediate 9, when using pyridine as a solvent instead
of toluene, induces a complete change from the first to
the second mode of ring transformation. This produces
compounds of type 13, 15, 17-19, and 23 which in some
cases may lose HCN to form compounds of type 14, 16,
20, 24, 25, or 27.
To probe the general scope of the rearrangement, we
investigated the reaction of 5a with other olefins, i.e.
styrene and dimethyl maleate, under standard conditions
(toluene, 80 °C, 7 and 3 d, respectively). The expected
cyano-substituted 6-oxopyridine derivatives 21 and 22
were isolated (Scheme 5). For the reaction of 5a with
styrene in pyridine, reflux conditions were required; after
2 d this resulted in a mixture of the 2-pyridinecarbonitrile
derivative 23 (R ) Ph, R′ ) H) and the 3-(diethylamino)-
2(1H)-pyridinone (24). Further reflux for 6 d led to
complete conversion of 23 into 24. The analogous reac-
tion with dimethyl maleate in pyridine (80 °C, 3 d)
afforded 25 (75%).
Exp er im en ta l Section
For general instrument conditions, see ref 6. All crystal-
lizations were carried out in hexane/CHCl3 unless stated
otherwise. The 3,5-dichloro-2(1H)-pyrazinones (1a ,b,d )1 and
the 3-(diethylamino)- and 3-amino-2(1H)-pyrazinones (5a ,b,
and 5f)6 were reported previously.
N-Phenylmaleimide, a powerful cyclic dienophile, re-
acted with 5b in toluene at room temperature to give the
pyrrolopyridine 26. Reaction in dry pyridine afforded the
expected diethylamino derivative 27. Compounds of type
(10) Zaleska, B. J . Prakt. Chem. 1987, 329, 787. Sato, M.; Ogasawara,
H.; Kato, T. J . Heterocycl. Chem. 1983, 20, 87.

Cycloaddition of Pyrazinones and Olefins
J . Org. Chem., Vol. 61, No. 1, 1996 307
3,5-Dich lor o-6-m eth yl-1-p h en yl-2(1H)-p yr a zin on e (1c).
Compound 1c was prepared as reported previously:1 yield 48%;
mp 182-183 °C; IR (KBr) 1670, 1600 cm-1; 1H NMR δ 2.08 (s,
3 H), 7.15-7.60 (m, 5 H); MS m/ z 254 (M+), 226, 77; exact
mass calcd for C11H8Cl2N2O 254.0014, found 254.0032.
5-Ch lor o-3-(d iet h yla m in o)-6-m et h yl-1-p h en yl-2(1H )-
p yr a zin on e (5c). To a solution of 2(1H)-pyrazinone 1c (2.55
g, 10 mmol) in dry dioxane (200 mL) was added freshly
distilled diethylamine (2.08 mL, 20 mmol), and the mixture
was stirred for 2 h at 50 °C under nitrogen. The reaction
mixture was cooled, the solvent was evaporated under reduced
pressure, and the residual oil was dissolved in CHCl3 (250 mL).
The solution was washed two times with water (25 mL), dried
over MgSO4, and evaporated. Chromatographic purification
on a silica gel column (10% EtOAc/CHCl3) gave pyrazinone
5c (2.68 g, 92%): mp 92 °C; IR (KBr) 1660, 1600 cm-1; 1H NMR
δ 1.22 (t, 6 H), 1.89 (s, 3 H), 3.70 (q, 4 H), 7.10-7.60 (m, 5 H);
13C NMR δ 13.6, 17.0, 44.2, 120.1, 124.7, 127.6, 128.9, 129.8,
138.5, 148.3, 152.4; MS m/ z 291 (M+), 276, 262, 248; exact
mass calcd for C15H18ClN3O 291.1138, found 291.1144.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
12-19 a n d 21-27. A solution of 3-amino-2(1H)-pyrazinone
(5a -g) (1 mmol) and a dienophile (3 mmol) in freshly distilled
toluene (10 mL) [dry pyridine (10 mL) was used for the
products 15, 16, 23-25, and 27] was stirred under the
conditions (temperature and reaction time) indicated below.
The solvent was evaporated in vacuo, and the residue was
purified by chromatography on a silica gel column (gradient
elution 100% CHCl3 f 10% EtOAc/CHCl3).
Meth yl 6-Cya n o-1,2-d ih yd r o-2-oxo-1-p h en yl-4-p yr id i-
n eca r boxyla te (12a ). Reaction of 5a and methyl acrylate
following the general procedure (toluene 80 °C, 1 d) gave 12a
(201 mg, 79%). Treatment of 15a in toluene with dry HCl and
further heating of the precipitated salt for 5 min also afforded
compound 12a : mp 178-179 °C; IR (KBr) 2225, 1735, 1685
cm-1; 1H NMR δ 4.00 (s, 3 H), 7.26 (d, 1 H, J ) 2 Hz), 7.32 (m,
2 H), 7.50 (d, 1 H, J ) 2 Hz), 7.55 (m, 3 H); 13C NMR δ 53.3,
111.7, 113.5, 122.3, 129.2, 127.4, 129.9, 130.3, 136.8, 139.6,
160.7, 163.1; MS m/ z 254 (M+), 253, 239, 195, 77; exact mass
calcd for C14H10N2O3 254.0691, found 254.0683. Anal. Calcd
for C14H10N2O3: C, 66.14; H, 3.96; N, 11.02. Found: C, 66.04;
H, 3.88; N, 10.97.
3-(Dieth yla m in o)-1-p h en yl-2(1H)-p yr a zin on e (5d ).
A
mixture of compound 1a (554 mg, 2 mmol), 10% palladium on
activated charcoal (100 mg), and NaHCO3 (168 mg, 2 mmol)
in dry methanol (25 mL) was degassed three times and stirred
for 2 h under hydrogen (1 atm) at rt using a gas buret. The
catalyst was removed by filtration over a Millipore filter. After
evaporation of the solvent under reduced pressure, the residue
was dissolved in CHCl3 (100 mL). The solution was washed
two times with water (25 mL), dried over MgSO4, and
evaporated to give compound 6d as an oil (437 mg, 90%): IR
Meth yl 6-Cya n o-1,2-d ih yd r o-1-m eth yl-2-oxo-4-p yr id i-
n eca r boxyla te (12b). Reaction of 5b and methyl acrylate
following the general procedure (toluene, 80 °C, 1 d) gave 12b
(163 mg, 85%): mp 143-144 °C; IR (KBr) 2235, 1740, 1670
1
cm-1; H NMR δ 3.75 (s, 3 H), 3.97 (s, 3 H), 7.22 (d, 1 H, J )
2 Hz), 7.42 (d, 1 H, J ) 2 Hz); MS m/ z 192 (M+), 160, 133;
exact mass calcd for C9H8N2O3 192.0535, found 192.0533.
Anal. Calcd for C9H8N2O3: C, 56.25; H, 4.20; N, 14.58.
Found: C, 55.92; H, 4.22; N, 14.53.
1
1665, 1600 cm-1; H NMR δ 1.25 (t, 6 H), 3.72 (q, 4 H), 6.55
(d, 1 H, J ) 5 Hz), 6.90 (d, 1 H, J ) 5 Hz), 7.40 (m, 5 H); 13C
NMR δ 13.6, 44.2, 117.5, 121.6, 126.0, 128.1, 129.1, 140.3,
151.9, 152.0; MS m/ z 243 (M+), 228, 214, 200; exact mass calcd
for C14H17N3O 243.1372, found 243.1381.
Meth yl 6-Cya n o-3-(d ieth yla m in o)-1,2,5,6-tetr a h yd r o-6-
m eth yl-2-oxo-1-p h en yl-4-p yr id in eca r boxyla te (13) a n d
Meth yl 3-(Dieth yla m in o)-1,2-d ih yd r o-6-m eth yl-2-oxo-1-
p h en yl-4-p yr id in eca r boxyla te (14). Reaction of 5c and
methyl acrylate following the general procedure (toluene, 80
°C, 1 d) gave 13 (140 mg, 41%) as a colorless and unstable oil:
IR (film) 2225, 1710, 1665 cm-1; 1H NMR δ 1.10 (t, 6 H), 1.42
(s, 3 H), 2.95 (d, 1 H, J ) 17 Hz), 3.15 (d, 1 H, J ) 17 Hz), 3.25
(q, 4 H), 3.82 (s, 3 H), 7.40 (m, 5 H); 13C NMR δ 13.8, 26.3,
38.5, 47.2, 51.8, 112.2, 120.6, 127.5, 128.8, 129.6, 137.6, 145.7,
163.1, 166.1; MS m/ z 341 (M+), 326, 310, 299; exact mass calcd
for C19H23N3O3 341.1740, found 341.1736.
When the reaction was carried out at reflux (toluene, 2 d),
compound 14 was obtained in 83% yield calculated on the basis
of 5c. The isolated compound 13 was subjected to the same
conditions (toluene, reflux for 2 d) to afford compound 14 in
quantitative yield. The spectral characteristics of 14 were
identical to those of the product obtained from the reaction of
5c with methyl propynoate.6
5-Ch lor o-3-(et h yla m in o)-1-m et h yl-2(1H )-p yr a zin on e
(5e). A solution of compound 1b (1.55 g, 8.7 mmol), ethyl-
amine hydrochloride (1.4 g, 17.4 mmol), and freshly distilled
triethylamine (3 mL, 21.7 mmol) in dry CHCl3 (125 mL) was
stirred at rt for 1 week and then heated at 70 °C for 12 h. The
reaction mixture was cooled, diluted with CHCl3 (150 mL), and
washed with 0.5 N HCl (2 × 20 mL) and water (20 mL). The
organic layer was dried over MgSO4 and concentrated in vacuo.
The crude pyrazinone 5e was chromatographed on an alumina
column (gradient elution CHCl3 f 5% EtOAc/CHCl3). Crys-
tallization from ethanol afforded the pure product 5e (1.38 g,
85%): mp 92-93 °C; IR (KBr) 3350, 1670, 1605 cm-1; 1H NMR
δ 1.20 (t, 3 H), 3.45 (s, 3 H), 3.50 (qd, 2 H), 6.55 (s, 1 H), 6.75
(s (br), 1 H); MS m/ z 187 (M+, 100), 172, 158, 144; exact mass
calcd for C7H10ClN3O 187.0512, found 187.0512. Anal. Calcd
for C7H10ClN3O: C, 44.81; H, 5.37; N, 22.40. Found: C, 44.78;
H, 5.42; N, 22.51.
Meth yl 6-Cya n o-3-(d ieth yla m in o)-1,2,5,6-tetr a h yd r o-1-
p h en yl-2-oxo-4-p yr id in eca r boxyla te (15a ). Reaction of 5a
with methyl acrylate following the general procedure (pyridine,
80 °C, 10 h) gave 15a (235 mg, 72%) as an unstable oil: IR
(film) 1725, 1680 cm-1; 1H NMR δ 1.15 (t, 6 H), 3.01 (dd, 1 H,
J ) 17, 3 Hz), 3.18 (dd, 1 H, J ) 17, 5 Hz), 3.15-3.45 (m, 4
H), 3.80 (s, 3 H), 4.65 (dd, 1 H, J ) 5, 3 Hz), 7.20-7.60 (m, 5
H); 13C NMR δ 13.6, 29.6, 47.0, 50.0, 51.7, 111.1, 117.7, 125.8-
129.5, 140.5, 145.9, 161.6, 165.8; MS m/ z 327 (M+), 312, 255,
77; exact mass calcd for C18H21N3O3 327.1582, found 327.1576.
Meth yl 6-Cya n o-3-(d ieth yla m in o)-1,2,5,6-tetr a h yd r o-1-
m eth yl-2-oxo-4-p yr id in eca r boxyla te (15b). Reaction of 5b
with methyl acrylate following the general procedure gave 15b
(207 mg, 78%) as an unstable oil: IR (film) 2240, 1700, 1670
5-C h lo r o -3-(1H -in d o l-3-y l)-1-b e n zy l-2(1H )-p y r a zi-
n on e (5g). A 2 M solution of ethylmagnesium bromide (6 mL,
12 mmol) in THF was added under nitrogen to a stirred
solution of indole (1.4 g, 12 mmol) in dry toluene (200 mL).
The resulting mixture was heated at reflux for 2 h. The
reaction mixture was cooled to rt, and a solution of 1-benzyl-
3,5-dichloro-2(1H)-pyrazinone (1d ) (2 g, 8 mmol) in dry toluene
(50 mL) was added. The mixture was heated at reflux for 2 h
and subsequently stirred overnight at rt. A 10% NH4Cl
solution (100 mL) was added, and the mixture was extracted
with CHCl3 (3 × 100 mL). The combined organic fractions
were washed with water (2 × 50 mL) and brine (50 mL) and
dried over MgSO4. The solvent was evaporated, and the crude
product 5g was chromatographed on a silica gel column using
gradient elution (10% EtOAc/CHCl3 f 40% EtOAc/CHCl3).
Crystallization from ethanol gave pure 5g (1.49 g, 56%): mp
1
cm-1; H NMR δ 1.09 (t, 6 H), 2.91 (dd, 1 H, J ) 17, 6 Hz),
3.03 (dd, 1 H, J ) 17, 7 Hz), 3.13 (s, 3 H), 3.11-3.38 (m, 4 H),
3.79 (s, 3 H), 4.30 (dd, 1 H, J ) 5, 3 Hz); 13C NMR δ 13.5,
28.6, 34.6, 46.9, 48.8, 51.7, 111.8, 117.1, 145.6, 162.5, 166.2;
MS m/ z 265 (M+), 250, 219, 190; exact mass calcd for
C13H19N3O3 265.1426, found 265.1424.
188 °C; IR (KBr) 1645, 1575 cm-1 1H NMR δ 5.10 (s, 2 H),
;
7.00 (s, 1 H), 7.20-7.40 (m, 8 H), 8.75 (m, 2 H), 8.95 (s, 1 H);
13C NMR δ 52.5, 111.5, 112.5, 120.3, 122.0, 123.2, 123.4, 127.1,
126.1, 128.3, 128.6, 129.1, 132.2, 134.8, 136.0, 150.4, 154.0;
Meth yl 3-(Dieth yla m in o)-1,2-d ih yd r o-2-oxo-1-p h en yl-
4-p yr id in eca r boxyla te (16a ). Reaction of 5a with methyl
acrylate following the general procedure (pyridine, reflux, 2
d) gave 16a (210 mg, 70%): mp 91-92 °C; IR (KBr) 1740, 1660
cm-1; 1H NMR δ 1.06 (t, 6 H), 3.23 (q, 4 H), 3.90 (s, 3 H), 6.28
(d, 1 H, J ) 7.5 Hz), 7.10 (d, 1 H, J ) 7.5 Hz), 7.35-7.50 (m,
MS m/ z 335 (M+), 244, 216, 91; exact mass calcd for C19H14
ClN3O 335.0825, found 335.0827. Anal. Calcd for C19H14
-
-
ClN3O: C, 67.96; H, 4.20; N, 12.51. Found: C, 67.57; H, 4.10;
N, 12.31.

308 J . Org. Chem., Vol. 61, No. 1, 1996
Vandenberghe et al.
5 H); 13C NMR δ 13.9, 46.3, 52.2, 104.5, 126.6, 128.4, 129.2,
131.3, 133.6, 140.7, 140.8, 161.4, 167.5; MS m/ z 300 (M+), 285,
271, 257, 230, 77; exact mass calcd for C17H20N2O3 300.1474,
found 300.1480.
Meth yl 3-(Dieth yla m in o)-1,2-d ih yd r o-1-m eth yl-2-oxo-
4-p yr id in eca r boxyla te (16b). Reaction of 5b with methyl
acrylate following the general procedure (pyridine, reflux, 2
d) gave 16b (oil, 180 mg, 75%): IR (film) 1737, 1650 cm-1; 1H
NMR δ 1.03 (t, 6 H), 3.20 (q, 4 H), 3.55 (s, 3 H), 3.85 (s, 3 H),
6.20 (d, 1 H, J ) 7 Hz), 7.05 (d, 1 H, J ) 7 Hz); 13C NMR δ
13.8, 37.5, 46.1, 52.0, 104.0, 132.0, 134.7, 139.6, 161.8, 167.4;
MS m/ z 238 (M+), 223, 209; exact mass calcd for C12H18N2O3
238.1317, found 238.1316.
Dim eth yl 2-Cya n o-1,6-d ih yd r o-6-oxo-1-p h en yl-3,4-p y-
r id in ed ica r boxyla te (22). Reaction of 5a and dimethyl
maleate following the general procedure (toluene, 80 °C, 3 d)
gave 22 (275 mg, 88%): mp 157-158 °C; IR (KBr) 2230, 1730,
1
1680 cm-1; H NMR δ 3.85 (s, 6 H), 7.10 (s, 1 H), 7.50 (m, 5
H); MS m/ z 312 (M+), 297, 281, 253; exact mass calcd for
C16H12N2O5 312.0746, found 312.0747. Anal. Calcd for
C16H12N2O5: C, 61.54; H, 3.87; N, 8.97. Found: C, 61.54; H,
3.80; N, 8.91.
5-(Dieth ylam in o)-1,2,3,6-tetr ah ydr o-1,4-diph en yl-6-oxo-
2-p yr id in eca r bon itr ile (23). Reaction of 5a with styrene
following the general procedure (pyridine, reflux, 2 d) gave a
mixture of 23 (163 mg, 50%) and 24 (32 mg, 10%). Compound
23 was obtained as an unstable oil after purification on a silica
gel preparative plate, eluting with CH2Cl2: IR (film) 1663
cm-1; 1H NMR δ 0.97 (t, 6 H), 2.78-3.05 (m, 4 H), 2.83 (dd, 1
H, J ) 17, 2 Hz), 3.52 (dd, 1 H, J ) 17, 5 Hz), 4.72 (dd, 1 H,
J ) 5, 2 Hz), 7.20-7.60 (m, 10 H); 13C NMR δ 13.8, 34.1, 47.2,
50.1, 118.2, 125.9, 127.6, 127.6, 128.0, 128.1, 129.5, 137.8,
137.9, 138.7, 140.7, 162.8; MS m/ z 345 (M+), 330, 316; exact
mass calcd for C22H23N3O 345.1842, found 345.1846.
Meth yl 6-Cya n o-3-(eth yla m in o)-1,2,5,6-tetr a h yd r o-1-
m eth yl-2-oxo-4-p yr id in eca r boxyla te (17). Reaction of 5e
with methyl acrylate following the general procedure (toluene,
80 °C, 5 d) gave 17 (190 mg, 80%) as an unstable oil: IR 2250,
1
1730, 1675 cm-1; H NMR δ 1.21 (t, 3 H), 2.85 (dd, 1 H, J )
18, 6 Hz), 3.00 (dd, 2 H, J ) 18, 3 Hz), 3.13 (s, 3 H), 3.40-3.80
(m, 4 H), 3.75 (s, 3 H), 4.32 (dd, 1 H, J ) 6, 3 Hz), 8.30 (s, 1
H); 13C NMR δ 16.1, 26.0, 34.2, 40.2, 49.1, 51.1, 91.3, 117.2,
146.6, 160.3, 168.9; MS m/ z 237 (M+), 220, 205, 190, 177; exact
mass calcd for C11H15N3O3 237.1113, found 237.1116.
3-(Dieth yla m in o)-1,4-d ip h en yl-2(1H)-p yr id in on e (24).
Reaction of 5a and styrene following the general procedure
(pyridine, reflux, 8 d) gave 24 (127 mg, 40%): mp 99-101 °C;
Meth yl 3-Am in o-6-cya n o-1,2,5,6-tetr a h yd r o-1-m eth yl-
2-oxop yr id in e-4-ca r boxyla te (18). Reaction of 5f and meth-
yl acrylate following the general procedure (toluene, 110 °C,
3 d) gave 18 (134 mg, 64%): mp 134-135 °C; IR 2240, 1730,
1665 cm-1; 1H NMR δ 2.90 (dd, 1 H), 3.00 (dd, 1 H), 3.18 (s, 3
H), 3.79 (s, 3 H), 4.38 (dd, 1 H), 8.00 (s, 2 H); 13C NMR δ 25.1,
34.6, 49.1, 51.4, 91.3, 116.9, 143.0, 161.2, 168.8; MS m/ z 209
(M+), 178, 150, 141; exact mass calcd for C9H11N3O3 209.0800,
found 209.0802. Anal. Calcd for C9H11N3O3: C, 51.67; H, 5.30;
N, 20.09. Found: C, 51.30; H, 5.25; N, 19.90.
IR (KBr) 1647 cm-1 1H NMR δ 0.91 (t, 6 H), 3.02 (q, 4 H),
;
6.21 (d, 1 H, J ) 7 Hz), 7.20 (d, 1 H, J ) 7 Hz), 7.45 (m, 10 H);
13C NMR δ 13.8, 46.4, 108.5, 126.7, 127.6, 127.9, 128.1, 128.6,
129.2, 132.4, 138.0, 139.3, 141.1, 146.9, 162.2; MS m/ z 318
(M+), 303, 289; exact mass calcd for C21H22N2O 318.1732, found
318.1729.
Dim eth yl 5-(Dieth yla m in o)-1,6-d ih yd r o-6-oxo-1-p h en -
yl-3,4-p yr id in ed ica r boxyla te (25). Reaction of 5a and
dimethyl maleate following the general procedure (pyridine,
80 °C, 3 d) gave 25 (268 mg, 75%). This compound showed
the same spectral characteristics as the product isolated from
the reaction of 5a with dimethyl butynedioate.6
3-(6-Cya n o-1,2,5,6-tetr a h yd r o-2-oxo-1-ben zylp yr id in -3-
yl)in d ole (19). A solution of 2(1H)-pyrazinone 5g (200 mg,
0.6 mmol) in dry toluene (30 mL) was made to react with
ethene (25 atm) in a steel vessel. The mixture was stirred at
110 °C for 3 d. The gas was removed carefully, and the solvent
was evaporated under reduced pressure. Flash chromatog-
raphy and subsequent HPLC chromatography on silica gel
(10% EtOAc/CHCl3) gave 19 (135 mg, 70%) as an unstable oil.
This was crystallized from a hexane/CHCl3 mixture: mp 58
2,3,5,6-Tetr a h yd r o-5-m eth yl-2-p h en yl-1,3,6-tr ioxo-1H-
p yr r olo[3,4-c]p yr id in e-4-ca r bon itr ile (26). Reaction of 5b
and N-phenylmaleimide following the general procedure (tolu-
ene, 80 °C, 15 h) gave 26 (254 mg, 91%): mp 258-259 °C
(hexane/acetone); IR (KBr) 2240, 1725, 1650 cm-1 1H NMR
;
(DMSO-d6) δ 3.80 (s, 3 H), 7.30 (s, 1 H), 7.50 (m, 5 H); 13C
NMR (DMSO-d6) δ 35.0, 109.6, 114.0, 118.7, 119.4, 127.1,
128.7, 128.9, 131.2, 139.6, 161.0, 162.1, 163.2; MS m/ z 279
(M+), 250, 223; exact mass calcd for C15H9N3O3 279.0644, found
279.0635. Anal. Calcd for C15H9N3O3: C, 64.52; H, 3.25; N,
15.05. Found: C, 64.10; H, 3.10; N, 14.73.
1
°C; IR (KBr) 3295, 1650, 1610 cm-1; H NMR δ 2.75 (ddd, 1
H, J ) 17.5, 6.25, 2.2 Hz), 2.90 (ddd, 1 H, J ) 17.5, 6.25, 2.8
Hz), 4.15 (d, 1 H, J ) 15 Hz), 4.40 (ddd, 1 H, J ) 6.25, 2.2, 0.9
Hz), 5.55 (d, 1 H, J ) 15 Hz), 6.92 (ddd, 1 H, J ) 6.25, 2.8, 0.9
Hz), 7.1-7.45 (m, 8 H), 7.78 (m, 1 H), 7.82 (d, 1 H, J ) 4.5
Hz), 8.35 (br s, 1 H); 13C NMR δ 28.1, 46.0, 49.2, 110.7, 111.4,
117.2, 119.6, 120.5, 122.3, 126.1, 128.3, 128.5, 128.6, 129.1,
129.1, 130.1, 136.1, 163.8; MS m/ z 327 (M+), 300, 91; exact
mass calcd for C21H17N3O 327.1370, found 327.1370.
7-(Dieth yla m in o)-5-m eth yl-2-p h en yl-1H-p yr r olo[3,4-c]-
p yr id in e-1,3,6(2H,5H)-tr ion e (27). Reaction of 5b and N-
phenylmaleimide following the general procedure (pyridine,
20 °C, 15 h) gave 27 (283 mg, 87%): mp 140-141 °C; IR (KBr)
3-(1,2-Dih yd r o-2-oxo-1-ben zylp yr id in -3-yl)in d ole (20).
The crude compound 19 was treated with an aqueous 1 N
NaOH/dioxane solution (40 mL, 1:1), and the mixture was
further stirred for 3 h. Water (40 mL) was added, and the
mixture was extracted with CHCl3 (3 × 100 mL). The
combined organic fractions were dried over MgSO4 and
concentrated under reduced pressure. The residue was puri-
fied by using preparative TLC (silica gel, 10% EtOAc/CHCl3).
Crystallization from CCl4 gave the analytical sample 20 (155
1
1710, 1650 cm-1; H NMR δ 1.20 (s, 6 H), 3.50 (s, 3 H), 3.70
(q, 4 H), 7.40 (m, 5 H), 7.70 (s, 1 H); MS m/ z 325, 310, 296,
282, 267; exact mass calcd for C18H19N3O3 325.1426, found
325.1419. Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N,
12.91. Found: C, 66.32; H, 5.83; N, 12.79.
Ack n ow led gm en t. The authors are indebted to the
FKFO and the “Ministerie voor Wetenschapsbeleid”,
IUAP16, for financial support and to the Katholieke
Universiteit Leuven (K.B.) and IWONL (P.L., S.V., and
L.M.) for a fellowship. They wish to thank Dr. P.
Delbeke, R. De Boer, and P. Valvekens for technical
assistance and the J anssen Pharmaceutica Co. for the
elemental analyses.
mg, 86%): mp 174 °C; IR (KBr) 3280, 1645, 1585 cm-1 1H
;
NMR δ 5.30 (s, 2 H), 6.33 (t, 1 H, J ) 7 Hz), 7.10-7.40 (m, 9
H), 7.91 (m, 2 H), 8.20 (d, 1 H, J ) 2.8 Hz), 8.75 (br s, 1 H);
13C NMR δ 52.7, 106.5, 111.2, 111.6, 119.6, 120.2, 122.0, 125.9,
126.8, 126.9, 127.8, 128.1, 128.8, 133.4, 134.0, 136.1, 161.5;
MS m/ z 300 (M+), 209, 181, 91; exact mass calcd for C20H16N2O
300.1262, found 300.1270.
1,6-Dih yd r o-1,4-d ip h e n yl-6-oxo-2-p yr id in e ca r b on i-
tr ile (21). Reaction of 5a and styrene following the general
procedure (toluene, 80 °C, 7 d) gave 21 (207 mg, 76%): mp
180-181 °C; IR (KBr) 2235, 1670 cm-1; 1H NMR δ 7.20-7.50
(m, 12 H); 13C NMR δ 112.3, 115.2, 121.7, 123.0, 125.2, 126.5,
127.7, 128.6, 129.4, 129.7, 130.0, 135.2, 137.1, 150.5; MS m/ z
272 (M+), 244, 77; exact mass calcd for C18H12N2O 272.0950,
found 272.0941. Anal. Calcd for C18H12N2O: C, 76.40; H, 4.44;
N, 10.29. Found: C, 76.76; H, 4.35; N, 9.95.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra for 5c, 5d , 15a , 15b, 16a , 16b, 17, 19, 20, 23, and 24
(22 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O951016O