One-pot synthesis of pyridine derivatives via diels-alder reactions of 2,4-dimethyl-5-methoxyoxazole

Article abstract of DOI:10.1002/hc.20064

A novel series of pyridine derivatives with anticipated biological activity have been synthesized via Diels-Alder reactions of 2,4-dimethyl-5- methoxyoxazole with different types of dienophiles. The regioselectivity of the cycloaddition was inverted from methylacrylate to tert-butylacrylate. The structural elucidation of the new compounds was carried on the basis of spectral and X-ray analyses.

Full text of DOI:10.1002/hc.20064

Heteroatom Chemistry
Volume 16, Number 1, 2005
One-Pot Synthesis of Pyridine Derivatives via
Diels-Alder Reactions of
2,4-Dimethyl-5-methoxyoxazole
Samir Bondock
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
Received 8 August 2004; revised 10 October 2004
alkaloids [13]), the most famous being the synthe-
ABSTRACT: A novel series of pyridine derivatives
with anticipated biological activity have been syn-
thesized via Diels-Alder reactions of 2,4-dimethyl-5-
methoxyoxazole with different types of dienophiles.
The regioselectivity of the cycloaddition was in-
verted from methylacrylate to tert-butylacrylate. The
structural elucidation of the new compounds was
carried on the basis of spectral and X-ray analy-
sis of vitamin B6 [14–16]. Recently, we added the
photochemical cycloaddition of 5-methoxyoxazoles
to aldehydes and ꢀ-keto esters to give bicyclic ox-
etanes that were used as a precursor for the stere-
oselective synthesis of erythro ꢀ-amino-ꢁ-hydroxy
carboxylic acid derivatives [17,18] and erythro ꢁ-
hydroxy dimethyl aspartates [19], respectively. The
present paper deals with the regioselectivity of the
reaction of 2,4-dimethyl-5-methoxyoxazole with dif-
ferent types of acyclic as well as cyclic dienophiles
and with its application to the synthesis of analog of
vitamin B6.
ꢀ
C
ses.
2005 Wiley Periodicals, Inc. Heteroatom Chem
16:49–55, 2005; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20064
INTRODUCTION
RESULTS AND DISCUSSION
The Diels-Alder reaction is one of the most useful
reactions in organic synthesis and is widely stud-
ied for the preparation of six-membered compounds
[1]. Oxazoles have a conjugate azadiene system and
are a versatile ground for investigation as the di-
ene component in Diels-Alder reactions [2–6]. Thus
thermal reaction of oxazoles with acetylenes leads
to furans, while addition to olefins produces sub-
stituted pyridines [7]. In a few instances, the Diels-
Alder adduct was isolated [8,9] but in most cases the
primary adduct was not isolable and instead under-
went rearrangement [10,11]. The methodology was
applied to the synthesis of natural products (e.g. anti-
tumor agent ellipticine [12], pyridoxal and pyridoxyl
In order to test the regioselectivity of the Diels-Alder
reaction, we used 2,4-dimethyl-5-methoxyoxazole
(1) as an electron-rich diene and acrylonitrile,
acrylaldehyde, acrylic acid, methylacrylate, tert-
butylacrylate, E-crotonaldehyde, 2-butene-1,4-diol,
and dimethylmaleate were applied as acyclic
dienophiles. In addition to, maleic anhydride, N-
methylmaleimide, N-(2-methylphenyl) maleimide,
N-(2-carboxylphenyl) maleimide, maleimylglycine,
maleimylalanine, benzoquinone, and naphthoqui-
none were used as cyclic dienophiles. 2,4-Dimethyl-
5-methoxyoxazole (1) was easily synthesized in
75% yield, from the reaction of N-acetylalanine
methylester with phosphorous pentachloride as re-
ported earlier by us in the literature [17,18].
Correspondence to: S. Bondock; e-mail: Samirbondock@
The reaction of 2,4-dimethyl-5-methoxyoxazole
1 with acrylic acid derivatives in boiling benzene
hotmail.com.
c
ꢀ
2005 Wiley Periodicals, Inc.
49

50 Bondock
afforded 3-hydroxy-2,6-dimethyl-4-substitued
pyridine derivatives (2–5) in quantitative yield
(Scheme 1). In a similar manner, compound 1
reacted with E-crotonalaldehyde under the same
experimental conditions and gave 3-hydroxy-2,5,6-
trimethylpyridine-4-carboxylaldehyde (7) in good
yield. When compound 1 was heated in benzene
with dimethylmaleate, dimethyl 5-hydroxy-2,6-
dimethylpyridine-3,4-dicarboxylate (8) was formed
in moderate yield. Treatment of 2-buten-1,4-diol
with 2,4-dimethyl-5-methoxyoxazole (1) in refluxing
benzene furnished 4,5-bis(hydroxymethyl)-2,6-di-
methylpyridine-3-ol (9) as analog of vitamin B6.
Surprisingly, when compound 1 was heated in ben-
zene with tert-butylacrylate as a bulky dienophile, the
regioselectivity inversed and tert-butyl 5-hydroxy-
2,6-dimethylpyridine-3-carboxylate (6) was formed
in good yield.
played three singlet signals at δ 2.55, 2.59 and 7.64
ppm for two methyl groups (2CH3) and one methine
proton (CH ) of the pyridine ring, respectively. The
mass spectrum of compound 5 revealed a strong
molecular ion peak at 181 M+.
The regioselectivity of compounds 5 and 6
was unambiguously determined by X-ray crystallo-
graphic analysis.
The low wave number of the carbonyl group as-
cribed to the participation in a chelated hydrogen
bond with the 3-hydroxyl group as clearly proved
by single crystal X-ray analysis of compound 5
(see Fig. 1).
Although the number of studies of the regiose-
lectivity of the Diels-Alder reaction of oxazoles with
unsymmetrical olefinic dienophiles is limited, the
generalization has been made that the strongest
electron-withdrawing substituents are found at po-
sition C-4 of the pyridyl products. The deviation of
tert-butylacrylate may be rationalized by the steric
hindrance of tert-butyl group when compared with
CN, CHO, CO2H, and CO2Me groups.
The structural confirmation of compounds 2–9
was accomplished on the basis of the analytical
data and spectroscopic properties. The IR spectra
showed absorption bands at 3455, 1620, 1530 cm−1
corresponding to the OH, C N, C C groups of pyri-
dine ring, respectively. Compounds 3, 4, 5, 7, and 8
showed additional band around 1660 cm−1 charac-
Furthermore, in order to explore the synthetic
utility of the [4 + 2] cycloaddition reactions of 2,4-
dimethyl-5-methoxyoxazole (1), we have also investi-
gated the thermal [4 + 2] cycloaddition of compound
1
teristic for C O group. Their H-NMR spectra dis-
SCHEME 1 Diels-Alder reactions of 2,4-dimethyl-5-methoxyoxazole with acyclic dienophiles.

One-Pot Synthesis of Pyridine Derivatives via Diels-Alder Reactions of 2,4-Dimethyl-5-methoxyoxazole 51
FIGURE 1 X-ray structures of compounds 5 and 6.
1 with a series of cyclic dienophiles aiming to con-
struct a fused heterocycles incorporating pyridine
moiety with anticipated biological activity.
2,4-Dimethyl-5-methoxyoxazole (1) reacted with
maleic anhydride in boiling benzene to form 7-
hydroxy-4,6-dimethylfuro[3,4-c]pyridine-1,3-dione
(10) after cleavage of the oxygen bridge of the
adduct. The IR spectrum of compound 10 shows
two strong bands at 1868 and 1792 cm−1, assign-
able to C O groups of a five-membered cyclic
anhydride. 7-Hydroxy-2,4,6-trimethyl-2H-pyrrolo-
[3,4-c]pyridine-1,3-dione (11) could also be obtained
in a similar manner via the reaction of compound
1 with N-methylmaleimide in 92% yield. In view of
SCHEME 2 Diels-Alder reactions of 2,4-dimethyl-5-methoxyoxazole with cyclic dienophiles.

52 Bondock
have substantial barrier to interconversion of atropi-
somer (20–25 kcal/mol) but these barriers are still
too low for most practical synthetic applications.
All new pyridine derivatives gave satisfactory spec-
tral and microanalytical data and/or high-resolution
mass spectra.
The mechanistic scenario for formation of the
3-hydroxypyridine derivatives (C) may be rational-
ized as follows: olefinic dienophiles cycloadded to
2,4-dimethyl-5-methoxyoxazole to form the initial
cycloadduct (A) that will be cleaved to zwitterion (B)
followed by aromatization. The aromatization takes
place via loss of methanol as depicted in Scheme 3.
In conclusion, we have demonstrated a simple
“one-pot” synthesis of a number of substituted pyri-
dine derivatives of biological significance in excellent
yields via Diels-Alder reactions of 2,4-dimethyl-5-
methoxyoxazole with different types of dienophiles.
The regioselectivity of the cycloaddition was inverted
from methylacrylate to tert-butylacrylate.
FIGURE 2 X-ray structure of compound 17.
the simplicity of the “one-pot” synthesis of pyrrolo
[3,4-c]pyridine derivatives (11), pyrrolo[3,4-c]pyri-
dine derivatives 12 (92%) and 13 (70%) were both
prepared using maleimylglycine and maleimylala-
nine under the same experimental condition. Also,
compound
1 reacted with benzoquinone and
naphthoquinone in benzene at reflux in a “one-pot”
reaction yielding the 4-hydroxy-1,3-dimethylisoqui-
noline-5,8-dione (14) and 4-hydroxy-1,3-dimethyl-
benzo[g]isoquinoline-5,10-dione (15), respectively
in quantitative yields as shown in Scheme 2.
EXPERIMENTAL
All melting points were determined with a Bu¨ chi
melting point apparatus (type Nr. 535) and are un-
corrected. IR spectra were recorded for KBr disk on
1
a Mattson 5000 FTIR spectrophotometer. H-NMR
We have also investigated atroposelective cyclo-
addition of both N-(2-methylphenyl) maleimide and
N-(2-carboxylphenyl) maleimide to 2,4-dimethyl-
5-methoxyoxazole. When compound 1 was heated
in benzene at reflux in the presence of N-(2-methyl-
phenyl) maleimide and/or N-(2-carboxylphenyl)
maleimide, the 7-hydroxy-4,6-dimethyl-2-o-tolyl-
2H-pyrrolo[3,4-c]pyridine-1,3-dione (16) and/or 2-
(7-hydroxy-4,6-dimethyl-1,3-dioxo-1H-pyrrolo[3,4-
c]pyridin-2(3H)-yl)benzoic acid (17) was formed,
respectively in good yield. The chemical structure
of compound 17 was unequivocally determined by
single crystal X-ray analysis as depicted in Fig. 2.
Unfortunately, the optical rotation measurement
of compound 17 was [ꢀ]2D5 = 0◦ (c = 0.05, CHCl3). We
believe that the reaction seems to be nonselective
and hence we have obtained a racemic mixture of
atropisomers of compound (17). These experiments
teach us that compounds 16 and 17 incorporating N-
2-methylphenyl and N-2-carboxylphenyl maleimides
and 13C-NMR spectra were measured on a Bruker
AC 300 (300 MHz) in CDCl3 and/or CD3SOCD3 as sol-
vent, using TMS as an internal standard, and chem-
ical shifts are expressed as δppm. Mass spectra were
determined on Finnigan Incos 500. Elemental anal-
yses were carried out in the Microanalytical Unit of
the Faculty of Science, Cairo University.
2,4-Dimethyl-5-methoxyoxazole (1) [17,18],
maleimylglycine [20], maleimylalanine [20], N-(2-
methylphenyl) maleimide [21], and N-(2-carboxyl-
phenyl)maleimide [21] were prepared according to
the reported methods; the other dienophiles were
commercially available.
General Procedure for the Preparation
of the Pyridine Derivatives
A mixture of 2,4-dimethyl-5-methoxyoxazole (0.64 g,
0.005 mole) and dienophiles (0.005 mole) in 25 mL
SCHEME 3 Mechanistic scenario for the formation of 3-hydroxy-4-substituted pyridine derivatives.

One-Pot Synthesis of Pyridine Derivatives via Diels-Alder Reactions of 2,4-Dimethyl-5-methoxyoxazole 53
1H-NMR (300 MHz, CDCl3): δppm = 1.55 (s, 9H, 3CH3),
1.61 (bs, 1H, OH), 2.49 (s, 3H, CH3), 2.79 (s, 3H, CH3),
7.52 (s, 1H, CH ); 13C-NMR (75.5 MHz, CDCl3):
δppm = 18.8, 23.6, 28.2 (3C), 81.9, 123.9, 125.4, 148.3,
149.1, 150.1, 165.9; MS: m/z = 223 (M+). Calcd for
C12H17NO3 (223.27): C, 64.55; H, 7.67, N, 6.27%.
Found: C, 64.48; H, 7.61; N, 6.25%.
benzene in a round bottom flask was refluxed for
4 h. Allowed to cool, then filtered the products and
recrystallized from benzene.
3-Hydroxy-2,6-dimethylpyridine-4-carbonitrile(2).
White powder; yield 0.48 g (65%); mp 176–177◦C;
IR (KBr): ν˜ (cm−1) = 3550 (OH), 2986 (CH-aliph.),
1
2218 (CN), 1590 (C N), 1538 (C C); H-NMR (300
MHz, CDCl3): δppm = 2.53 (s, 3H, CH3), 2.55 (s, 3H,
CH3), 3.59 (bs, 1H, OH), 7.86 (s, 1H, CH ); 13C-NMR
(75.5 MHz, CDCl3): δppm = 14.0, 21.8, 108.1, 117.3,
123.8, 150.8, 153.7; MS: m/z = 148 (M+). Calcd for
C8H8N2O (148.16): C, 64.85; H, 5.44, N, 18.91%.
Found: C, 64.79; H, 5.48; N, 18.86%.
3-Hydroxy-2,5,6-trimethylpyridine-4-carboxylal-
dehyde (7). White powder; yield 0.7 g (65%); mp
75–76◦C; IR (KBr):ν˜ (cm−1) = 3457 (OH), 2975
(CH-aliph.), 1673 (CO), 1592 (C N), 1538 (C C);
1H-NMR (300 MHz, CDCl3): δppm = 2.42 (s, 3H,
CH3), 2.45 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.21 (bs,
1H, OH), 9.27 (s, 1H, CHO); 13C-NMR (75.5 MHz,
CDCl3): δppm = 14.9, 15.2, 17.9, 131.1, 143.7, 149.3,
155.2, 168.9, 190.1; MS: m/z = 165 (M+). Calcd for
C9H11NO2 (165.19): C, 65.44; H, 6.71, N, 8.48%.
Found: C, 65.43; H, 6.64; N, 8.42%.
3-Hydroxy-2,6-dimethylpyridine-4-carboxylalde-
hyde (3). White powder; yield 0.45 g (60%); mp
>300◦C; IR (KBr): ν˜ (cm−1) = 3545 (OH), 2980
(CH-aliph.), 1670 (CO), 1584 (C N), 1532 (C C);
1H-NMR (300 MHz, CDCl3): δppm = 2.50 (s, 3H,
CH3), 2.52 (s, 3H, CH3), 3.54 (bs, 1H, OH), 7.82
(s, 1H, CH ), 9.43 (s, 1H, CHO); 13C-NMR (75.5
MHz, CDCl3): δppm = 11.4, 19.4, 123.1, 129.3, 149.3,
150.2, 151.4, 195.7; MS: m/z = 151 (M+). Calcd
for C8H9NO2 (151.16): C, 63.56; H, 6.00, N, 9.27%.
Found: C, 63.52; H, 5.98; N, 9.26%.
Dimethyl 5-hydroxy-2,6-dimethylpyridine-3,4-
dicarboxylate (8). White crystals; yield 0.84 g (70%);
mp 113–114◦C; IR (KBr):ν˜ (cm−1) = 3543 (OH), 2987
(CH-aliph.), 1670 (CO), 1724 (CO), 1583 (C N), 1535
(C C); 1H-NMR (300 MHz, CDCl3): δppm = 2.42 (s, 3H,
CH3), 2.44 (s, 3H, CH3), 3.12 (bs, 1H, OH), 3.62 (s,
3H, OCH3), 3.69 (s, 3H, OCH3), 7.42 (s, 1H, CH );
13C-NMR (75.5 MHz, CDCl3): δppm = 15.1, 18.7, 52.7,
52.9, 129.3, 143.2, 149.5, 155.1, 167.6, 170.2, 172.1;
MS: m/z = 239 (M+). Calcd for C11H13NO5 (239.22):
C, 55.23; H, 5.48, N, 5.86%. Found: C, 55.19; H, 5.46;
N, 5.84%.
3-Hydroxy-2,6-dimethylpyridine-4-carboxylic acid
(4). White crystals; yield 0.7 g (84%); mp 294–295◦C
(lit [22], 290–291◦C); IR (KBr): ν˜ (cm−1) = 3553
(OH), 2959 (CH-aliph.), 1665 (CO), 1580 (C N), 1525
(C C); 1H-NMR (300 MHz, DMSO-d6): δppm = 2.46 (s,
3H, CH3), 2.48 (s, 3H, CH3), 3.40 (bs, 1H, OH), 7.67
(s, 1H, CH ); 13C-NMR (75.5 MHz, DMSO-d6): δppm
=
4,5-Bis(hydroxymethyl)-2,6-dimethylpyridine-3-ol
(9). White crystals; yield 0.6 g (65%); mp 105–
106◦C; IR (KBr):ν˜ (cm−1) = 3540 (OH), 2976
(CH-aliph.), 1585 (C N), 1530 (C C); 1H-NMR (300
MHz, CDCl3): δppm = 2.49 (s, 3H, CH3), 2.51 (s, 3H,
CH3), 3.40 (bs, 1H, OH), 4.67 (s, 4H, 2CH2OH);
13C-NMR (75.5 MHz, CDCl3): δppm = 11.7, 15.4, 52.7,
56.1, 131.2, 134.9, 145.7, 149.9, 151.4; MS: m/z =
183 (M+). Calcd for C9H13NO3 (183.20): C, 59.00; H,
7.18, N, 7.65%. Found: C, 59.11; H, 7.13; N, 7.69%.
14.7, 18.4, 123.3, 143.3, 149.9, 154.3, 165.9, 197.3;
MS: m/z = 167 (M+). Calcd for C8H9NO3 (167.16): C,
57.48; H, 5.43, N, 8.38%. Found: C, 57.39; H, 5.41; N,
8.32%.
Methyl 3-hydroxy-2,6-dimethylpyridine-4-car-
boxylate (5). White crystals; yield 0.8 g (90%);
mp 90–91◦C; IR (KBr):ν˜ (cm−1) = 3542 (OH), 2981
(CH-aliph.), 1660 (CO), 1585 (C N), 1530 (C C);
1H-NMR (300 MHz, CDCl3): δppm = 1.60 (bs, 1H,
OH), 2.49 (s, 3H, CH3), 2.68 (s, 3H, CH3), 3.69 (s,
3H, OCH3), 7.52 (s, 1H, CH ); 13C-NMR (75.5 MHz,
CDCl3): δppm = 18.8, 23.6, 52.5, 123.8, 125.4, 148.3,
149.1, 150.0, 164.6; MS: m/z = 181 (M+). Calcd for
C9H11NO3 (181.19): C, 59.66; H, 6.12, N, 7.73%.
Found: C, 59.69; H, 6.11; N, 7.68%.
7-Hydroxy-4,6-dimethylfuro[3,4-c]pyridine-1,3-
dione (10). Brown powder; yield 0.89 g (92%); mp
235–236◦C; IR (KBr):ν˜ (cm−1) = 3453 (OH), 2976
(CH-aliph.), 1868 (CO), 1792 (CO), 1596 (C N),
1
1534 (C C); H-NMR (300 MHz, DMSO-d6): δppm
=
2.44 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.43 (bs, 1H,
OH); 13C-NMR (75.5 MHz, DMSO-d6): δppm = 12.4,
14.3, 123.9, 127.9, 149.8, 151.3, 153.6, 162.1, 162.5;
MS: m/z = 193 (M+). Calcd for C9H7NO4 (193.16): C,
55.96; H, 3.65, N, 7.25%. Found: C, 55.60; H, 3.63;
N, 7.23%.
tert-Butyl 5-Hydroxy-2,6-dimethylpyridine-3-car-
boxylate (6). White crystals; yield 0.94 g (84%); mp
205–206◦C; IR (KBr):ν˜ (cm−1) = 3340 (OH), 2982
(CH-aliph.), 1716 (CO), 1582 (C N), 1528 (C C);

54 Bondock
IR (KBr):ν˜ (cm−1) = 3545 (OH), 2965 (CH-aliph.),
7-Hydroxy-2,4,6-trimethyl-2H-pyrrolo[3,4-c]pyri-
1
dine-1,3-dione (11). Orange crystals; yield 0.93 g
(90%); mp 105–106◦C; IR (KBr):ν˜ (cm−1) = 3553
(OH), 2960 (CH-aliph.), 1750 (CO), 1720 (CO), 1664
(C N), 1538 (C C); 1H-NMR (300 MHz, CDCl3):
δppm = 2.57 (s, 3H, CH3), 2.72 (s, 3H, CH3), 3.12 (s,
3H, CH3), 3.61 (bs, 1H, OH); 13C-NMR (75.5 MHz,
CDCl3): δppm = 19.2, 20.1, 23.9, 119.6, 128.3, 145.4,
147.1, 155.7, 167.9, 169.2; MS: m/z = 206 (M+).
Calcd for C10H10N2O3 (206.20): C, 58.25; H, 4.89, N,
13.59%. Found: C, 58.21; H, 4.86; N, 13.64%.
1723 (CO), 1610 (C N), 1540 (C C); H-NMR (300
MHz, DMSO-d6): δppm = 1.43 (d, J = 7.5 Hz, 3H,
CH3), 2.43 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.42 (bs,
1H, OH), 4.67 (q, J = 7.5 Hz, 1H, CH); 13C-NMR
(75.5 MHz, DMSO-d6): δppm = 13.6, 14.2, 18.1, 49.4,
126.5, 131.6, 146.4, 149.8, 154.1, 165.9, 166.1; MS:
m/z = 264 (M+). Calcd for C12H12N2O5 (264.23): C,
54.55; H, 4.58, N, 10.60%. Found: C, 54.52; H, 4.52;
N, 10.62%.
4-Hydroxy-1,3-dimethylisoquinoline-5,8-dione
(14). Violet crystals; yield 0.97 g (96%); mp >300◦C;
IR (KBr):ν˜ (cm−1) = 3560 (OH), 2986 (CH-aliph.),
1735 (CO), 1600 (C N), 1545 (C C); 1H-NMR
(300 MHz, DMSO-d6): δppm = 2.47 (s, 3H, CH3), 2.49
(s, 3H, CH3), 3.48 (bs, 1H, OH), 7.12 (d, J = 9.9 Hz,
1H, CH ) 7.15 (d, J = 9.9 Hz, 1H, CH ); 13C-NMR
(75.5 MHz, DMSO-d6): δppm = 14.5, 18.2, 128.1,
129.6, 141.3, 141.6, 149.9, 153.8, 154.3, 187.3, 187.9;
MS: m/z = 203 (M+). Calcd for C11H9NO3 (203.19):
C, 65.02; H, 4.46, N, 6.89%. Found: C, 65.17; H, 4.37;
N, 6.74%.
2-(7-Hydroxy-4,6-dimethyl-1,3-dioxo-1H-pyrrolo-
[3,4-c]pyridin-2(3H)-yl) Acetic Acid (12). Yellowish
white crystals; yield 1.15 g (92%); mp 252–253◦C;
IR (KBr):ν˜ (cm−1) = 3555 (OH), 2973 (CH-aliph.),
1750 (CO), 1702 (CO), 1695 (CO), 1610 (C N), 1538
1
(C C); H-NMR (300 MHz, DMSO-d6): δppm = 2.49
(s, 3H, CH3), 2.61 (s, 3H, CH3), 3.42 (bs, 1H, OH),
4.24 (s, 2H, CH2); 13C-NMR (75.5 MHz, DMSO-d6):
δppm = 19.1, 19.6, 38.3, 119.6, 119.8, 144.9, 156.8,
165.1, 166.7, 168.3; MS: m/z = 250 (M+). Calcd for
C11H10N2O5 (250.21): C, 52.80; H, 4.03, N, 11.20%.
Found: C, 52.78; H, 4.01; N, 11.17%.
4-Hydroxy-1,3-dimethylbenzo[g]isoquinoline-
5,10-dione (15). Violet crystals; yield 1.21 g (96%);
mp >300◦C; IR (KBr):ν˜ (cm−1) = 3565 (OH), 2974
(CH-aliph.), 1738 (CO), 1595 (C N), 1528 (C C);
(S)-2-(7-Hydroxy-4,6-dimethyl-1,3-dioxo-1H-
pyrrolo[3,4-c]pyridin-2(3H)-yl) Propanoic Acid (13).
White crystals; yield 0.92 g (70%); mp = 127–128◦C;
TABLE 1 Crystal Structure Data for Compounds 5, 6, and 17
Compound
5
6
17
Empirical formula
Formula mass
Color
C9H11NO3
181.19
Colorless
293 (2)
C12H17NO3
223.27
Colorless
293 (2)
C16H12N2O5
312.28
Green
293 (2)
0.71073
Temperature (K)
˚
Wavelength (A)
0.71073
0.71073
Size (mm)
0.25 × 0.15 × 0.15
0.15 × 0.15 × 0.10
0.30 × 0.30 × 0.20
˚
a (A)
4.831 (10)
9.329 (1)
7.3706 (3)
˚
b (A)
11.381 (10)
8.634 (10)
90
105.17
90
458.17 (12)
2
25.068 (1)
11.165 (1)
21.1124 (13)
11.3856 (5)
90 (1)
127.521 (3)
90 (1)
1405.21 (12)
4
˚
c (A)
α (◦)
β (◦)
γ (◦)
90
90
90
3
˚
V (A )
2611.0 (4)
8
Z
dcalcd. (g/cm3)
Crystal system
Space group
No. refl. meas.
No. uni. Refl.
No. obs. Refl.a
R
1.270
Monoclinic
P21/m
1022
1022
815
0.0373
0.0746
0.123/−0.111
1.136
Orthorhombic
Pccn
1.476
Monoclinic
P21/c
11044
3063
1570
0.0382
0.1062
0.262/−0.180
8532
2613
1112
0.0548
0.1350
Rw
−3
˚
Largest diff. Peak/hole (e/A
)
0.170/−0.168
aFor I > 2σ(I ).

One-Pot Synthesis of Pyridine Derivatives via Diels-Alder Reactions of 2,4-Dimethyl-5-methoxyoxazole 55
1H-NMR (300 MHz, DMSO-d6): δppm = 2.49 (s, 3H,
ACKNOWLEDGMENTS
CH3), 2.52 (s, 3H, CH3), 3.44 (bs, 1H, OH), 7.64–8.00
(m, 4H, Ar.H); 13C-NMR (75.5 MHz, DMSO-d6):
δppm = 14.2, 18.8, 129.7, 129.9, 130.2, 132.2, 132.9,
134.8, 135.2, 148.8, 150.9, 154.3, 186.7, 187.3; MS:
m/z = 253 (M+). Calcd for C15H11NO3 (253.25): C,
71.14; H, 4.38, N, 5.53%. Found: C, 71.08; H, 4.32;
N, 5.47%.
We wish to thank Prof. A. G. Griesbeck, Institute of
Organic Chemistry,University of Cologne, Germany,
for advice and for helpful discussions. We are also
indebted to Dr. J. Lex and Dr. J. Neudo¨rf, university
of Cologne, Germany, for X-ray measurements.
REFERENCES
7-Hydroxy-4,6-dimethyl-2-o-tolyl-2H-pyrrolo[3,4-
c]pyridine-1,3-dione (16). Yellow crystals; yield
1.19 g (85%); mp = 190–191◦C; IR (KBr):ν˜ (cm−1) =
3553 (OH), 2964 (CH-aliph.), 1708 (CO), 1584 (C N),
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1527 (C C); 1H-NMR (300 MHz, CDCl3): δppm
=
2.19 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.77 (s, 3H,
CH3), 3.49 (bs, 1H, OH), 7.14 (d, J = 7.5 Hz, 1H,
Ar.H), 7.31–7.37 (m, 3H, Ar.H); 13C-NMR (75.5 MHz,
CDCl3): δppm = 18.0, 19.2, 20.2, 126.9, 128.6, 129.7,
131.3, 136.4, 145.9, 147.8, 156.0, 168.3, 181.3; MS:
m/z = 282 (M+). Calcd for C16H14N2O3 (282.16): C,
68.07; H, 5.00, N, 9.92%. Found: C, 67.95; H, 5.01;
N, 9.86%.
2-(7-Hydroxy-4,6-dimethyl-1,3-dioxo-1H-pyrrolo-
[3,4-c]pyridin-2(3H)-yl)benzoic Acid (17). Green
crystals; yield 1.36 g (87%); mp 255–256◦C; IR
(KBr):ν˜ (cm−1) = 3543 (OH), 2974 (CH-aliph.), 1716
(CO), 1695 (CO), 1600 (C N), 1535 (C C); 1H-NMR
(300 MHz, DMSO-d6): δppm = 2.45 (s, 3H, CH3),
2.58 (s, 3H, CH3), 3.34 (bs, 1H, OH), 7.41–7.44
(dd, J = 7.8, 3.12 Hz, 1H, Ar.H), 7.52–7.57 (ddd,
J = 15.3, 7.5, 3.12 Hz, 1H, Ar.H), 7.67–7.72 (ddd,
J = 15.3, 3.12, 1.92 Hz, 1H, Ar.H), 7.95–7.98 (dd,
J = 7.8, 1.47 Hz, 1H, Ar.H), 11.01 (s, 1H, CO2H);
13C-NMR (75.5 MHz, DMSO-d6): δppm = 19.7, 20.1,
120.4, 120.6, 129.3, 129.4, 130.7, 131.1, 131.4, 133.1,
145.1, 145.5, 157.1, 165.6, 166.1, 167.2; MS: m/z =
312 (M+). Calcd for C16H12N2O5 (312.28): C, 61.54;
H, 3.87, N, 8.97%. Found: C, 61.48; H, 3.79; N,
8.93%.
[10] Johnsen, B. A.; Undheim, K. Acta Chem Scand 1983,
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B37, 907–910.
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R. R.; Cross, F. J.; Currie, R. B.; Monaco, M.; Peterson,
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Tetrahedron 1969, 25, 3527–3553.
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2079c.
X-ray Crystallographic Studies
All data sets were collected with an Enraf Nonius
CACD-4 diffractometer. Hydrogen atoms were calcu-
lated and refined as riding atoms. Crystal structure
data and details are listed in Table 1.