Studies on isocyanides and related compounds: A facile synthesis of 1,6-dihydro-6-oxopyrazine-2-carboxylic acid derivatives via Ugi four-component condensation

Article abstract of DOI:10.1055/s-2003-40525

The Ugi four-component condensation (U-4CC) between arylglyoxals 7, amines 6, benzoylformic acid (4) and isocyanides 5 afforded the expected products 8 which were cyclized in a 5+1 fashion with ammonium acetate to give 1,N-disubstituted 4-aryl-1,6-dihydro-6-oxo-5-phenylpyrazine-2-carboxamides 9 in good yields. Evidence for the assigned structures 9 was provided by ¹³C NMR spectra and X-ray analysis of 9a.

Full text of DOI:10.1055/s-2003-40525

PAPER
1553
Studies on Isocyanides and Related Compounds: A Facile Synthesis of 1,6-Di-
hydro-6-oxopyrazine-2-carboxylic Acid Derivatives via Ugi Four-Component
Condensation
S
ynthesis of 1,6-
r
ihydro6
i
-oxop
s
t
carbox
i
ylic
A
c
n
id Derivativ
a
s
Faggi,a María García-Valverde,b Stefano Marcaccini,*c Roberto Pepino,c Ma. Cruz Pozoc
a
b
c
CRIST, Centro Interdipartimentale di Cristallografia, Università di Firenze, via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Dipartimento di Chimica Organica ‘Ugo Schiff’, Università di Firenze, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
E-mail: stefano.marcaccini@unifi.it
Received 8 March 2003; revised 9 May 2003
If an arylglyoxal 76 is employed in place of the cinnamal-
dehyde it is reasonable to presume the formation of the
Ugi 4-CC products 8 the structure of which appears at first
sight suitable for a Davidson type cyclization with ammo-
in nia to give 1,N-disubstituted 4-aryl-1,6-dihydro-6-oxo-5-
phenylpyrazine-2-carboxamides 9 (Scheme 2).
Abstract: The Ugi four-component condensation (U-4CC) be-
tween arylglyoxals 7, amines 6, benzoylformic acid (4) and isocya-
nides 5 afforded the expected products 8 which were cyclized in a
5+1 fashion with ammonium acetate to give 1,N-disubstituted 4-
aryl-1,6-dihydro-6-oxo-5-phenylpyrazine-2-carboxamides
9
good yields. Evidence for the assigned structures 9 was provided by
13C NMR spectra and X-ray analysis of 9a.
We were able to prepare compounds 8 following two dif-
ferent methods: the reaction of preformed anils 10 with
isocyanides and benzoylformic acid and the four-compo-
nent condensation performed in the usual manner. The
yields were similar, so the one-step procedure was the pre-
ferred one. Attempts to perform four-component conden-
sations by employing pyruvic acid as the acid component
failed since tar-like reaction mixtures were obtained.
When pyruvaldehyde 4-methylanil and glyoxal bis(4-me-
thylanil) were used as the starting materials, also intracta-
ble reaction mixtures were obtained.
Key words: Ugi reaction, cyclizations, heterocycles, isocyanides,
pyrazine ring synthesis
Among the various methods that lead to the formation of
the pyrazine ring, those based on the cyclization of C–C–
N–C–C systems with ammonia or its derivatives are note-
worthy.1 In continuation of our studies on the synthesis of
heterocyclic compounds from isocyanides2 we considered
the possibility of obtaining suitable precursors of the pyra-
zine ring by exploiting the multi-component reactions of
isocyanides.3,4
In a previous paper5 we described the synthesis of 1,6-di-
hydro-6-oxopyridine-2-carboxylic acid (acromelic acid)
derivatives 1 by base-induced cyclization of compounds 2
which were in turn obtained by means of a Ugi four-com-
ponent condensation between cinnamaldehyde (3), ben-
zoylformic acid (4), cyclohexyl isocyanide (5a), and
amines 6 (Scheme 1).
The structure of compounds 8 was confirmed by their an-
1
alytical and spectral data (Tables 1–3). The H NMR
spectra of compounds 8a–f,h in CDCl3 showed the exist-
ence of an equilibrium between 8 and the tautomer 11.
The ratio of 8:11 ranged between 1.4 and 4.0. The enol
proton signal was never detected because of the rapid ex-
change with the solvent. By employing the more polar
DMSO-d6 as the solvent no tautomeric equilibrium was
detected.
Upon prolonged heating with a strong excess of ammoni-
um acetate in AcOH, compounds 8 cyclized to 4-aryl-N-
cyclohexyl-1,6-dihydro-6-oxo-5-phenylpyrazine-2-carb-
oxamides 9 in good yields (Table 4). An alternative struc-
ture, namely 1-substituted 4-aryl-2-benzoyl-N-cyclo-
hexyl-1H-imidazole-4-carboxamides 12, could not be ex-
cluded a priori for the cyclized products. With this regard,
it must be underlined that 3-aryl-1,2-dihydropyrazine-2-
ones 13 are isomeric with 2-aroylimidazoles 14 and a
wrong assignation is long-known.7 Fortunately, the 13C
NMR signals of the CO moieties in structures 13 and 14
are well-differentiated. In fact, the CO signals in struc-
tures 13 are found at about 155–164 ppm8 whereas in
structures 14 they appear at about 180 ppm.9 In all of the
13C NMR spectra of the cyclization products the CO sig-
nal was detected at about 160 ppm and this provided evi-
PhCOCO2H (4)
CONHc-C6H11
c-C6H11NC (5a)
RNH2 (6)
CHO
KOH
Ph
Ph
N
O
R
O
3
Ph
CONHc-C6H11
2
Ph
N
O
R
Ph
1
Scheme 1
Synthesis 2003, No. 10, Print: 21 07 2003.
Art Id.1437-210X,E;2003,0,10,1553,1558,ftx,en;T02603SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1554
C. Faggi et al.
PAPER
Figure 1 Crystal structure of 9a
Table 1 Compounds 8a–f Prepared
Producta
Yield (%)
A
Mp (°C)
B
8a
8b
8c
8d
8e
8f
75
72
77
75
77
81
–
70
73
71
72
76
77
42
71
60
66
198–200b
218–219b
210–211b
186–187b
204–205b
195–196b
112–113c
202–203d
163–165d
160–161b
8g
8h
8i
–
–
8j
–
a Satisfactory microanalyses obtained:
C
0.28; H 0.25; N 0.28.
b Solvent: EtOH.
c Solvent: i-PrOH.
d Solvent: DMF–EtOH (1:3).
Cyclohexyl isocyanide (5a),10,11 n-hexyl isocyanide (5b),12 4-meth-
ylphenyl isocyanide (5c),13 and arylglyoxals 7a,14 7b,15 7c,15, 7d15
were prepared according to literature procedures. Mps were deter-
mined in open capillary tubes using a Büchi 512 melting point ap-
Scheme 2
dence for the assigned structures 9 (Table 5). A further
proof was provided by X-ray analysis of 9a (Figure 1).
1
paratus and are uncorrected. H and 13C NMR were recorded on a
Varian Gemini 200 spectrometer. IR spectra (KBr discs) were re-
corded with a Perkin-Elmer 881 spectrophotometer. All the chemi-
cals were used as supplied.
In conclusion, the present method allowed us to obtain, by
means of an experimentally simple two-step procedure, a
series of 1,N-disubstituted 4-aryl-1,6-dihydro-6-oxo-5-
phenylpyrazine-2-carboxamides 9, which can not easily
obtained following other synthetic routes. Furthermore, as
a consequence of the intrinsic features of the multi-com-
ponent reactions, a wide variety of products can be pre-
pared by changing the reactants. Particularly, the
substitution pattern in positions 1- and 5- can be easily
varied by employing commercially available amines and
easily obtainable glyoxals.
3-Aryl-2-(N-benzoylformyl-N-substituted-amino)-3-oxopro-
panoic Acid N-Cyclohexylamides 8
Method A: A solution of arylglyoxal 7 (12 mmol) and amine 6 (12
mmol) in toluene (50 mL) was refluxed in a Dean–Stark apparatus
until the separation of H2O had ceased (ca. 15 min). The reaction
mixture was evaporated to dryness under diminished pressure and
the residue was treated with MeOH (50 mL) and with finely pow-
dered benzoylformic acid (4; 1.80 g, 12 mmol). The resulting sus-
pension was reacted under stirring with a solution of cyclohexyl
isocyanide (5; 1.31 g, 12 mmol) in MeOH (4 mL). The mixture was
Synthesis 2003, No. 10, 1553–1558 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,6-Dihydro-6-oxopyrazine-2-carboxylic Acid Derivatives
1555
Table 2 1H NMR Spectral Data of Compounds 8a–f
Prod-uct
1H NMR (200 MHz, CDCl3)
, J (Hz)
1H NMR (200 MHz, DMSO-d6)
, J (Hz)
8a
0.97–1.97 (m, 10 Hcyclohexane), 3.75 (m, 1 H, 1-Hcyclohexane), 0.86–1.63 (m, 10 Hcyclohexane), 3.36 (m, 1 H, 1-Hcyclohexane),
5.72 (d, J = 8.0, 0.33 H, NH of 11), 6.51–7.97 (m, 14 Harom 6.65 (s, 1 H, NCHCO), 7.25–7.97 (m, 14 Harom), 8.82 (d,
+ 0.67 H, NH of 8 + 0.67 H, CH of 8)
J = 7.2, 1 H, NH)
8b
8c
8d
8e
0.75–2.02 (m, 10 Hcyclohexane), 3.46–3.85 (m, 4 H, OCH3 + 0.92–1.70 (m, 10 Hcyclohexane), 3.34 (m, 1 H, 1-Hcyclohexane),
1-Hcyclohexane), 3.65 (s, OCH3 of 8), 3.85 (s, OCH3 of 11), 3.60 (s, 3H, OCH3), 6.52 (s, 1 H, NCHCO), 6.68–7.95 (m,
5.76 (d, J = 7.6, 0.31 H, NH of 11), 6.05–8.02 (m, 13 Harom 13 Harom), 8.70 (d, J = 7.2, 1 H, NH)
+ 0.69 H, NH of 8 + 0.69 H, CH of 8)a
0.85–1.95 (m, 10 Hcyclohexane), 2.17 (s, 1.02 H, CH3 of 11), 0.92–1.62 (m, 10 Hcyclohexane), 2.12 (s, 3H, CH3), 3.43 (m,
2.39 (s, 1.98 H, CH3 of 8), 3.75 (m, 1 H, 1-Hcyclohexane),
1 H, 1-Hcyclohexane), 6.52 (s, 1 H, NCHCO), 6.95–7.94 (m,
5.75 (d, J = 7.8, 0.34 H, NH of 11), 6.47–7.97 (m, 13 Harom 13 Harom), 8.66 (d, J = 8.0, 1 H, NH)
+ 0.66 H, NH of 8 + 0.66 H, CH of 8)
0.72–2.01 (m, 10 Hcyclohexane), 3.53 (m, 1 H, 1-Hcyclohexane), 0.87–1.65 (m, 10 Hcyclohexane), 3.35 (m, 1 H, 1-Hcyclohexane),
3.79 (s, 0.99 H, OCH3 of 11), 3.83 (s, 2.01 H, OCH3 of 8), 3.85 (s, 3H, OCH3), 6.63 (s, 1 H, NCHCO), 7.10–7.96 (m,
5.66 (d, J = 8.0, 0.33 H, NH of 11), 6.64–8.04 (m, 13 Harom 13 Harom), 8.84 (d, J = 7.6, 1 H, NH)
+ 0.67 H, NH of 8 + 0.67 H, CH of 8)
0.63–2.01 (m, 10 Hcyclohexane), 2.33 (s, 1.23 H, CH3 of 11), 0.90–1.78 (m, 10 Hcyclohexane), 2.38 (s, 3H, CH3), 3.35 (m,
2.37 (s, 1.77 H, CH3 of 8) 3.43 (m, 0.59 H, 1-Hcyclohexane of 1 H, 1-Hcyclohexane), 6.63 (s, 1 H, NCHCO), 7.25–7.95 (m,
8), 3.75 (m, 0.41 H, 1-Hcyclohexane of 11), 5.70 (d, J = 8.0,
0.41 H, NH of 11), 6.76–8.05 (m, 13 Harom + 0.59 H, NH
of 8 + 0.59 H, CH of 8)
13 Harom), 8.82 (d, J = 7.8, 1 H, NH)
8f
0.53–2.00 (m, 10 Hcyclohexane), 3.41 (m, 0.37 H,
1-Hcyclohexane of 11), 3.41 (m, 0.63 H, 1-Hcyclohexane of 8),
0.92–1.65 (m, 10 Hcyclohexane), 3.36 (m, 1 H, 1-Hcyclohexane),
6.63 (s, 1 H, NCHCO), 7.21–7.99 (m, 13 Harom), 8.83 (d,
5.71 (d, J = 7.2, 0.37 H, NH of 11), 6.71–8.04 (m, 13 Harom J = 7.6, 1 H, NH)
+ 0.63 H, NH of 8 + 0.63 H, CH of 8)
8g
8h
0.84–1.25 (m, 11 Hhexane), 2.90 (m, 2 H, CH2NH), 3.97 (d, 0.81 (t, J = 7.1, 3 H, CH3), 0.97–1.19 (m, 8 H, CH2, hex-
J = 13.8, 1 H, CH2N), 5.29 (m, 1 H, NH), 5.54 (d,
J = 13.8, 1 H, CH2Ph), 7.18–7.60 (m, 14 H, 14 H, 13 Harom CH2N), 4.62 (d, J = 17.1, 1 H, CH2N), 6.32 (s, 1 H, NCH-
+ CHN) CO), 7.17–7.93 (m, 13 Harom), 8.57 (t, J = 5.3, 1 H, NH)
ane), 2.58–2.82 (m, 2 H, CH2NH), 4.57 (d, J = 17.1, 1 H,
0.66–2.11 (m, 17 H, 10 Hcyclohexane + CH(CH3)2], 2.81 (dd, 0.66–1.72 [m, 16 H, 10 Hcyclohexane + CH(CH3)2], 3.24–
J = 4.0, J = 12.8, 1 H, CH2N), 3.75 (m, 1 H, 1-Hcyclohexane), 3.20 [m, 1 H, CH(CH3)2], 3.50–3.61 (m, 1 H,
4.10 (dd, J = 10.6, J = 13.2, 1 H, CH2N), 5.82 (s, 0.80 H, 1-Hcyclohexane), 6.06 (s, 1 H, NCHCO), 7.55–7.90 (m, 9
CH of 8), 6.05 (d, J = 7.2, 0.20 H, NH of 11), 6.14 (d,
J = 8.0, 0.80 H, NH of 8)
Harom), 8.56 (d, J = 7.0, 1 H, NH)
8i
8j
1.00 (d, J = 6.6, 3 H, CH3), 1.13 (d, J = 6.6, 3 H, CH3),
1.93 [m, 1 H, CH(CH3)2], 2.25 (s, 3 H, CH3), 2.96 (dd,
J = 4.4, J = 13.2, 1 H, CH2N), 4.23 (dd, J = 10.6,
J = 13.2, 1 H, CH2N), 6.19 (s, 1 H, NCHCO), 6.94–8.11
(m, 13 Harom), 9.65 (s, 1 H, NH)
0.67 (d, J = 6.7, 3 H, CH3), 0.71 (d, J = 6.7, 3 H, CH3),
1.70–1.77 [m, 1 H, CH(CH3)2], 2.23 (s, 3 H, CH3), 3.34–
3.36 (m, 2 H, CH2N), 6.15 (s, 1 H, NCHCO), 7.06–7.95
(m, 13 Harom), 10.5 (s, 1 H, NH)
0.18–1.46 (m, 10 Hcyclohexane), 2.93 (m, 1 H, 1-Hcyclohexane), 0.78–1.56 (m, 10 Hcyclohexane), 3.04–3.07 (m, 1 H,
4.68 (d, J = 17.0, 1 H, CH2N), 6.59 (s, 1 H, NCHCO),
7.18–8.17 (m, 14 H, 13 Harom + NH)
1-Hcyclohexane), 4.58 (m, 2 H, CH2N), 6.31 (s, 1 H, NCH-
CO), 7.15–8.55 (m, 15 H, 14 Harom + NH)
a The multiplet signals of the 1-H of cyclohexane and singlet signals of the methoxyl groups of compounds 8 and 11 are overlapped.
stirred at r.t. for 3 d and then cooled and filtered. The collected solid
was washed with cold Et2O (20 mL) to give 8. The product was pure
enough to perform the successive reaction.
lected solid was washed with cold Et2O (20 mL) to give 8. The prod-
uct was pure enough to perform the successive reaction.
1-Substituted 4-Aryl-N-cyclohexyl-1,6-dihydro-6-oxo-5-phe-
nylpyrazine-2-carboxamides 9
Method B: A solution of the arylglyoxal (7, 12 mmol) in anhyd Et2O
(30 mL) was treated with a solution of the amine (6, 12 mmol) in
anhyd Et2O (20 mL). The resulting suspension was treated with
finely powdered benzoylformic acid (4, 1.80 g, 12 mmol) and then
with a solution of the isocyanide (5, 12 mmol) in anhyd Et2O (10
mL). The mixture was stirred at r.t. for 3 d and then filtered. The col-
A mixture of 8 (4.0 mmol) and NH4OAc (7.71 g, 100 mmol) in
AcOH (50 mL) was refluxed for 3 h. The resulting solution was al-
lowed to cool to r.t. and filtered to give 9. The mother liquors were
evaporated to dryness and the residue stirred with H2O (50 mL) to
give another crop of 9. The crude product was recrystallized from a
Synthesis 2003, No. 10, 1553–1558 © Thieme Stuttgart · New York

1556
C. Faggi et al.
PAPER
Table 3 IR and 13C NMR Spectral Data of Compounds 8a–f
Product
IR (KBr) (cm–1)
13C NMR (50 MHz, DMSO-d6)
8a
3293 (NH), 1686,
1668, 1635 (C=O)
24.11, 25.06, 31.56, 31.67 (CH2), 47.89 (CHcyclohexane), 66.54 (NCHCO), 127.79, 128.62, 129.01,
129.15, 131.96, 132.36, 133.50, 133.94, 134.91, 135.16, 135.27 (CHarom, Carom), 162.51 (CCON),
166.55 (CCONH), 190.02, 191.66 (C=O)
8b
8c
8d
8e
8f
3277 (NH), 1680,
1629 (C=O)
24.15, 25.10, 31.67, 31.94 (CH2), 47.89 (CHcyclohexane), 55.23 (OCH3), 66.66 (NCHCO), 113.60,
128.64, 129.01, 129.12, 129.57, 131.54, 132.48, 133.87, 134.92, 138.64, 158.99 (CHarom, Carom),
162.60 (CCON), 166.97 (CCONH), 190.22, 190.87 (C=O)
3319 (NH), 1684,
1627 (C=O)
20.55 (CH3), 24.13, 25.10, 31.65, 31.96 (CH2), 47.86 (CHcyclohexane), 66.68 (NCHCO), 129.04, 129.17,
129.57, 129.77, 132.47, 133.76, 133.89, 134.96, 138.38, 138.62 (CHarom, Carom), 162.60 (CCON),
166.84 (CCONH), 190.00, 190.88 (C=O)
3283 (NH), 1668,
1631 (C=O)
24.15, 25.08, 31.69, 31.89 (CH2), 47.86 (CHcyclohexane), 55.69 (OCH3), 66.17 (NCHCO), 114.28,
127.71, 128.93, 129.13, 130.03, 130.23, 130.41, 132.37, 135.18, 137.62, 163.64 (CHarom, Carom),
162.62 (CCON), 166.44 (CCONH), 189.86, 190.02 (C=O)
3288 (NH), 1671,
1631 (C=O)
21.27 (CH3), 24.15, 25.08, 31.60, 31.91 (CH2), 47.87 (CHcyclohexane), 66.43 (NCHCO), 127.91, 128.59,
129.13, 129.50, 132.03, 132.38, 132.43, 133.50, 135.14, 135.25, 144.52 (CHarom, Carom), 162.60
(CCON), 166.51 (CCONH), 190.06, 191.08 (C=O)
3280 (NH), 1700,
1672, 1634 (C=O)
24.13, 25.06, 31.61, 31.83 (CH2), 47.95 (CHcyclohexane), 66.55 (NCHCO), 128.88, 129.13, 129.24,
129.66, 130.17, 132.34, 132.52, 133.56, 135.21, 137.60, 138.89 (CHarom, Carom), 162.27 (CCON),
166.44 (CCONH), 189.86, 190.84 (C=O)
8g
8h
8i
3407 (NH), 1678,
1661 (C=O)
14.61 (CH3), 22.72, 26.74, 28.87, 31.62 (CH2), 39.66 (CH2NH), 50.17 (CH2Ph), 64.03 (NCHCO),
128.55, 129.79, 129.91, 130.17, 130.25, 130.34, 133.01, 133.12, 134.37, 135.39, 136.17, 139.42
(CHarom, Carom), 164.21 (CCON), 168.87 (CCONH), 191.44, 191.92 (C=O)
3267 (NH), 1696,
1672, 1614 (C=O)
20.32, 20.47 [CH(CH3)2], 24.73, 24.86, 25.82 (CH2), 27.76 [CH(CH3)2], 32.47, 32.53 (CH2), 48.75
(CHcyclohexane), 55.32 (CH2N), 65.63, (NCHCO), 129.77, 129.95, 130.15, 130.33, 130.34, 133.47,
135.08, 135.98, 139.03 (CHarom, Carom), 164.27 (CCON), 168.31 (CCONH), 190.93, 192.29 (C=O)
3313 (NH), 1701,
1684, 1620 (C=O)
20.44, 21.12 (CH3), 27.88 [CH(CH3)2], 56.17 (CH2N), 66.55 (NCHCO), 120.17, 129.73, 129.81,
130.04, 130.33, 133.37, 133.82, 135.44, 135.92, 136.57, 139.03, (CHarom, Carom), 163.87 (CCON),
168.38 (CCONH), 190.61, 192.47 (C=O)
8j
3279 (NH), 1696,
1667, 1626 (C=O)
24.51, 24.73, 25.72, 31.77, 32.26 (CH2), 48.55 (CHcyclohexane), 50.03 (CH2N), 64.15 (NCHCO), 128.53,
128.96, 129.77, 129.85, 130.03, 130.12, 130.26, 130.49, 133.07, 134.14, 135.56, 136.17, 139.51
(CHarom, Carom), 163.32 (CCON), 168.81 (CCONH), 191.55, 191.72 (C=O)
suitable solvent to give pure 9.
Table 4 Compounds 9a–f Prepared
X-Ray Structural Analysis of Compound 9a
Mp (°C)
Producta
9a
Yield (%)
C29H26ClN3O2, MW = 483.98, orthorhombic, space group P 21ab,
a = 9.589(2), b = 11.341(2), c = 22.819(3) Å, V = 2841.5(8) Å3,
73
69
71
70
78
85
67
75
80
82
288–290b
252–253c
259–260b
248–250c
246–248b
287–288b
145–146c
186–188c
247–248b
240–241b
Z = 4 Dc = 1.295, = 1.610 mm–1, F(000) = 1016.
9b
Analysis on prismatic transparent single crystal was carried out with
a Siemens P4 X-Ray diffractometer at room temperature. Graphite
monochromated Cu K radiation was used for cell parameter deter-
mination and data collection. The intensities of three standard re-
flections were monitored during data collection to check the
stability of the crystal: no loss of intensity was recognized. The in-
tegrated intensities, measured using the /2 scan mode, were cor-
rected for Lorentz and polarization effects.16
9c
9d
9e
9f
9g
The reflections collected were 2201 with a 3.5 < 2 < 130° range;
1858 reflections were independent and the final R index was 0.0559
for reflections having I > 2 I, and 0.0875 for all data. The non-hy-
drogen atoms were refined anisotropically; the hydrogen atoms
were assigned in calculated position and were refined as isotropic
with an overall isotropic temperature factor of 0.05 Å2. This struc-
ture was solved by direct methods of SIR9717 and refined using the
full-matrix least squares on F2 provided by SHELXL97.18,19
9h
9i
9j
a Satisfactory microanalyses obtained: C 0.25; H 0.25; N 0.27.
b Solvent: DMF–EtOH (1:3).
c Solvent: EtOH.
Synthesis 2003, No. 10, 1553–1558 © Thieme Stuttgart · New York

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Synthesis of 1,6-Dihydro-6-oxopyrazine-2-carboxylic Acid Derivatives
1557
Table 5 Spectral Data of Compounds 9a–f
Product
IR (KBr) (cm–1)
1H NMR (200 MHz, CDCl3)
, J (Hz)
13C NMR (50 MHz, CDCl3)
9a
3304 (NH), 1669, 1629 0.66–1.62 (m, 10 Hcyclohexane), 3.44
24.37, 25.13, 31.79 (CH2), 48.57 (CHcyclohexane), 128.08,
128.23, 128.51, 128.58, 129.22, 129.36, 129.41, 130.64,
(C=O)
(m, 1 H, 1-Hcyclohexane), 5.69 (d,
J = 8.4, 1 H, NH), 7.24–8.44 (m, 14
131.66, 135.20, 135.38, 135.59, 136.08 (CHarom, Carom
Cpyr), 153.08, 153.76 (Cpyr), 159.91, 160.03 (C=O)
,
Harom
)
9b
9c
3300 (NH), 1666, 1640 0.69–1.70 (m, 10 Hcyclohexane), 3.44
24.45, 25.12, 31.82 (CH2), 48.61 (CHcyclohexane), 55.52
(C=O)
(m, 1 H, 1-Hcyclohexane), 3.80 (s, 3 H,
(OCH3), 114.42, 128.09, 128.57, 128.91, 128.99, 129.30,
129.47, 130.57, 132.60, 134.39, 134.73, 135.43 (CHarom
Carom, Cpyr), 152.80, 154.09 (Cpyr), 159.94, 160.16 (C=O)
OCH3), 5.73 (d, J = 8.4, 1 H, NH),
,
6.89–8.42 (m, 13 Harom
)
3241 (NH), 1664, 1633 0.68–1.63 (m, 10 Hcyclohexane), 2.37 (s, 21.29 (CH3), 24.43, 25.12, 31.78 (CH2), 48.61
(C=O)
3 H, CH3), 3.44 (m, 1 H,
1-Hcyclohexane), 5.63 (d, J = 8.6, 1 H,
NH), 7.12–8.43 (m, 13 Harom
(CHcyclohexane), 127.45, 128.09, 128.57, 128.97, 129.32,
129.50, 129.88, 130.59, 132.32, 133.91, 134.42, 134.76,
135.43, 139.74 (CHarom, Carom, Cpyr), 152.88, 153.89
(Cpyr), 159.91, 160.24 (C=O)
)
9d
3233 (NH), 1658, 1635 0.64–1.58 (m, 10 Hcyclohexane), 3.43
24.36, 25.07, 31.77 (CH2), 48.54 (CHcyclohexane), 55.33
(OCH3), 113.76, 126.36, 127.75, 127.89, 128.33, 129.17,
129.35, 129.51, 129.89, 130.13, 130.44, 134.50, 135.19,
137.62 (CHarom, Carom, Cpyr), 152.62, 153.27 (Cpyr),
159.74, 159.87 (C=O)
(C=O)
(m, 1 H, 1-Hcyclohexane), 3.83 (s, 3 H,
OCH3), 5.66 (d, J = 8.4, 1 H, NH),
6.91–8.43 (m, 13 Harom
)
9e
9f
3257 (NH), 1659, 1634 0.60–1.51 (m, 10 Hcyclohexane), 2.37 (s, 21.26 (CH3), 24.38, 25.13, 31.78 (CH2), 48.58
(C=O)
3 H, CH3), 3.43 (m, 1 H,
(CHcyclohexane), 128.07, 129.19, 129.36, 130.59, 131.17,
1-Hcyclohexane), 5.63 (d, J = 8.6, 1 H,
133.17, 135.24, 135.42, 135.54, 138.54 (CHarom, Carom
Cpyr), 152.97, 153.72 (Cpyr), 159.80, 160.05 (C=O)
,
NH), 7.18–8.43 (m, 13 Harom
)
3292 (NH), 1661, 1639 0.80–1.59 (m, 10 Hcyclohexane), 3.47
24.40, 25.12, 31.85 (CH2), 48.69 (CHcyclohexane), 126.53,
127.96, 128.15, 128.68, 129.35, 129.50, 129.89, 130.22,
(C=O)
(m, 1 H, 1-Hcyclohexane), 5.60 (d,
J = 8.4, 1 H, NH), 7.24–8.42 (m, 13
130.82, 131.56, 134.48, 134.68, 134.82, 137.52 (CHarom,
Harom
)
Carom, Cpyr), 153.34, 153.48 (Cpyr), 159.67, 159.97 (C=O)
9g
3302 (NH), 1660, 1637 0.82–1.18 (m, 11 Hhexane), 3.01 (q,
14.27 (CH3), 22.75, 26.61, 28.44, 31.56, 40.43 (CH2),
(C=O)
J = 6.8, 2 H, CH2NH), 5.39–5.55 (m, 47.92 (CH2NH), 102.47, 128.41, 128.96, 129.02, 129.55,
3 H, NH + CH2N), 7.23–8.39 (m, 13 129.85, 130.11, 130.66, 130.96, 131.52, 134.28, 134.61,
Harom
)
135.07, 135.69 (CHarom, Carom, Cpyr), 153.23, 154.29
(Cpyr), 161.92 (C=O)
9h
3243 (NH), 1655, 1632 0.85–1.65 (m, 10 Hcyclohexane), 0.94 [d, 20.55 (CH3), 24.67, 25.42, 28.12, 32.16, (CH2), 49.27,
(C=O) J = 6.6, 6 H, CH(CH3)2], 2.25–2.32 CHcyclohexane), 53.28 (NCH2CH), 102.47, 128.33, 128.81,
[m, 1 H, CH(CH3)2], 3.75–3.77 (m, 1 129.55, 129.91, 130.27, 130.65, 132.63, 134.71, 135.37,
H, 1-Hcyclohexane), 4.04–4.05 (m, 2 H, 135.86 (CHarom, Carom, Cpyr), 154.35, 161.01 (C=O)
NCH2CH), 5.70 (br s, 1 H, NH),
7.25–7.58 (m, 9 Harom
)
9i
9j
3284 (NH), 1652, 1634 0.93 (d, J = 6.6, 6 H, CH3), 2.30–
28.38 (CH), 53.51 (CH2), 102.56, 120.87, 128.43,
128.91, 129.57, 129.72, 130.05, 130.83, 132.15, 134.06,
134.77, 134.85, 135.61, 136.12 (CHarom, Carom, Cpyr),
(C=O)
2.38 [m, 1 H, CH(CH3)2], 2.32 (s, 3
H, CH3), 4.03–4.05 (m, 2 H, CH2),
7.12–7.48 (m, 11 Harom), 8.03 (br s, 1 152.41, 154.33 (Cpyr), 159.82 (C=O)
H, NH), 8.34–8.36 (m, 2 Harom
)
3279 (NH), 1648, 1637 0.63–1.47 (m, 10 Hcyclohexane), 3.57–
24.57, 25.33, 31.82, 47.99 (CH2), 49.27 (CHcyclohexane),
102.55, 128.44, 128.91, 129.03, 129.55, 129.92, 130.13,
130.66, 130.94, 131.67, 134.21, 134.50, 134.96, 135.03,
135.68 (CHarom, Carom, Cpyr), 153.27, 154.28 (Cpyr),
161.09 (C=O)
(C=O)
3.68 (m, 1 H, 1-Hcyclohexane), 5.30 (d,
J = 8.1, 1 H, NH), 5.44 (s, 2 H,
CH2N), 7.24–8.38 (m, 13 Harom
)
Synthesis 2003, No. 10, 1553–1558 © Thieme Stuttgart · New York

1558
C. Faggi et al.
PAPER
(6) Arylglyoxals are useful starting products in isocyanide-
References
based multi-component reactions: (a) Beck, B.; Magnin-
Lachaux, M.; Herdtweck, E.; Dömling, A. Org. Lett. 2001,
3, 2875. (b) Zhang, C.; Moran, E. J.; Woiwode, T. F.; Short,
K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 751.
(c) Sung, K.; Wu, S.-H.; Chen, P.-I. Tetrahedron 2002, 58,
5599.
(1) Barlin, G. B. In The Pyrazines; Weissberger, A.; Taylor, E.
C., Eds.; Wiley-Interscience: New York, 1982, 49–52.
(2) Reviews: (a) Marcaccini, S.; Torroba, T. Org. Prep. Proc.
Int. 1993, 25, 141. (b) Bossio, R.; Marcaccini, S.; Pepino, R.
Synthesis 1994, 765. (c) Bossio, R.; Marcaccini, S.; Pepino,
R. Tetrahedron Lett. 1995, 36, 2325. (d) Bossio, R.;
Marcaccini, S.; Pepino, R.; Torroba, T. J. Org. Chem. 1996,
61, 2202. (e) Bossio, R.; Marcaccini, S.; Pepino, R.;
Torroba, T. J. Chem. Soc., Perkin Trans. 1 1996, 229.
(f) Bossio, R.; Fernández Marcos, C.; Marcaccini, S.;
Pepino, R. Tetrahedron Lett. 1997, 38, 2519. (g)Bossio,R.;
Fernández Marcos, C.; Marcaccini, S.; Pepino, R. Synthesis
1997, 1389. (h) Bossio, R.; Marcaccini, S.; Pepino, R.;
Torroba, T. Heterocycles 1999, 50, 463. (i) Marcaccini, S.;
Pepino, R.; Polo, C.; Pozo, M. C. Synthesis 2001, 85.
(j) Marcaccini, S.; Pepino, R.; Pozo, M. C. Tetrahedron Lett.
2001, 42, 2727.
(3) Reviews: (a) Ugi, I.; Dömling, A.; Hörl, W. Endeavour
1994, 18, 115. (b) Armstrong, R. W.; Combs, A. P.;
Tempest, P.; Brown, S. D.; Keating, T. A. Acc. Chem. Res.
1996, 29, 123. (c) Ugi, I.; Dömling, A. Angew. Chem., Int.
Ed. 2000, 39, 3168. (d) Dömling, A. Comb. Chem. High
Throughput Screening 1998, 1, 1. (e)Bienaymé, H.; Hulme,
C.; Oddon, G.; Schmitt, P. Chem.–Eur. J. 2000, 6, 3321.
(4) (a) Janvier, P.; Bienaymé, H.; Zhu, J. Angew. Chem. Int. Ed.
2002, 41, 4291. (b) Owens, T. D.; Semple, J. E. Org. Lett.
2001, 3, 3301. (c) Tempest, P.; Pettus, L.; Gore, V.; Hulme,
C. Tetrahedron Lett. 2003, 44, 1947.
(7) Gastaldi, C.; Princivalle, E. Gazz. Chim. Ital. 1928, 58, 412.
(8) (a) Nishio, T.; Tokunaga, N.; Kondo, M.; Omote, Y. J.
Chem. Soc., Perkin Trans. 1 1988, 2921. (b) Devys, M.;
Barbier, M.; Kollmann, A.; Bousquet, J.-F. Tetrahedron
Lett. 1982, 23, 5409. (c) Nishio, T. J. Heterocycl. Chem.
1998, 35, 655.
(9) Kong, Y. C.; Kim, K. J. Heterocycl. Chem. 1999, 36, 911.
(10) Gokel, G. W.; Widera, R. P.; Weber, W. P. Org. Synth. 1976,
55, 96.
(11) Ugi, I.; Meyr, R.; Lipinsky, M.; Bodesheim, F.; Rosendahl,
F. Org. Synth., Coll. Vol. 5; Wiley: New York, 1973, 300.
(12) Lipp, M.; Dallaker, F.; Köcker, I. M. Monatsh. Chem. 1959,
90, 48.
(13) Ugi, I.; Meyr, R. Org. Synth. 1961, 41, 101.
(14) Riley, H. A.; Gray, A. R. Org. Synth., Coll. Vol. 2; Wiley:
New York, 1948, 509.
(15) Venien, F.; Brault, A.; Kerfanto, M. C. R. Acad. Sci. Paris.
Ser. C 1968, 266, 1650.
(16) Walker, N.; Stuart, D. Acta Crystallogr., Sect. A 1983, 39,
158.
(17) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G.; Polidori,
G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115.
(18) Sheldrick, G. M. SHELXL97: Program for Crystal Structure
Refinement; University of Göttingen: Germany, 1997.
(19) Crystallographic data have been deposited at Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK and are available from there under the
deposition number CCDC179438.
(5) Bossio, R.; Fernández Marcos, C.; Marcaccini, S.; Pepino,
R. Heterocycles 1997, 45, 1589.
Synthesis 2003, No. 10, 1553–1558 © Thieme Stuttgart · New York