Synthesis and Reactions of a Stable o-Quinoid 10-π-Electron System, Furo[3,4-c]pyridine

Article abstract of DOI:10.1021/jo991886w

Methyl 4,6-dichloro-3-(diethylamino)furo[3,4-c]pyridine-1-carboxylate (6), an intermediate in the Hamaguchi-Ibata reaction involving the Rh^II-catalyzed intramolecular reaction of a diazo group with the carbonyl of an adjacent amido group, has been isolated and characterized. PM3 calculations reveal the heat of formation (ΔH_f) of this remarkably stable molecule to be -77.7 kcal/mol. Compound 6 undergoes a facile Diels-Alder cycloaddition with a variety of dienophiles to give polysubstituted isoquinoline derivatives via ring opening of initially formed cycloadducts. In each case the cycloaddition proceeds with high regioselectivity, with the electron-withdrawing group located ortho to the amino group. The most favorable FMO interaction is between the HOMO of the azaisobenzofuran 6 and the LUMO of the dienophile. The atomic coefficient at the ester carbon of the azaisobenzofuran 6 is larger than the amino center, and this nicely accommodates the observed regioselectivity.

Full text of DOI:10.1021/jo991886w

J . Org. Chem. 2000, 65, 3111-3115
3111
Syn th esis a n d Rea ction s of a Sta ble o-Qu in oid 10-π-Electr on
System , F u r o[3,4-c]p yr id in e
Tarun K. Sarkar,*,† Sunil K. Ghosh,† and Tahsin J . Chow‡
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India, and Institute of
Chemistry, Academia Sinica, Taipei, Taiwan
Received December 7, 1999
Methyl 4,6-dichloro-3-(diethylamino)furo[3,4-c]pyridine-1-carboxylate (6), an intermediate in the
Hamaguchi-Ibata reaction involving the RhII-catalyzed intramolecular reaction of a diazo group
with the carbonyl of an adjacent amido group, has been isolated and characterized. PM3 calculations
reveal the heat of formation (∆Hf) of this remarkably stable molecule to be -77.7 kcal/mol.
Compound 6 undergoes a facile Diels-Alder cycloaddition with a variety of dienophiles to give
polysubstituted isoquinoline derivatives via ring opening of initially formed cycloadducts. In each
case the cycloaddition proceeds with high regioselectivity, with the electron-withdrawing group
located ortho to the amino group. The most favorable FMO interaction is between the HOMO of
the azaisobenzofuran 6 and the LUMO of the dienophile. The atomic coefficient at the ester carbon
of the azaisobenzofuran 6 is larger than the amino center, and this nicely accommodates the observed
regioselectivity.
In tr od u ction
The o-quinoid 10-π-electron isobenzofuran system has
remained the subject of intense theoretical, structural,
and reactivity studies, but little work has been done with
the analogous furo[c]pyridines.1,2 The parent furo[3,4-c]-
pyridine 1 was reported as early as 1977 as a white
crystalline solid, stable only at low temperature, but
undergoing rapid polymerization at about room temper-
ature.3 More recently, the 1,3-dimethyl derivative 2 was
also made and was found stable enough to be character-
ized by 1H NMR spectroscopy.4 Although not isolated,
Resu lts a n d Discu ssion
substituted isobenzofurans1 and azaisobenzofuran 35
have been implicated as reactive intermediates in the
synthesis of polyaromatic ring systems by tandem
Hamaguchi-Ibata and Diels-Alder reactions.6,7 In a
preliminary communication, we described the synthesis
of a remarkably stable azaisobenzofuran 6 by a Hamagu-
chi-Ibata reaction.8 In this paper we report the full
details of this work that shows that azaisobenzofuran 6
is simultaneously a functional analogue of labile pyridine
o-quinodimethanes, e.g., 79 as well as 2-amino-substitut-
ed furans, e.g., 810 both of which have rejuvenated
interest in recent years as reactive dienes in Diels-Alder
reactions.
Syn th esis of 6. The synthesis began with readily
available nitrile 911 (Scheme 1) which on reduction with
diisobutylaluminum hydride (DIBAL-H) gave aldehyde
10 in 66% yield. Oxidation12 of 10 gave carboxylic acid
11 (78%) which was transformed to the amide 12 (64%)
via the acid chloride. Treatment of 12 with excess lithium
diisopropylamide (LDA) (2.2 equiv) followed by dimethyl
carbonate yielded 13 (53%). It should be noted that use
of 1 equiv of LDA did not give any lithiated product
(burgundy color) from 12. The substituted diazoacetic
ester 14, the substrate for Hamaguchi-Ibata reaction,
was made from 13 by the Davies protocol via treatment
with 4-acetamidobenzenesulfonyl azide (ABSA) in the
presence of Et3N.13 When 14 was exposed to 1 mol %
Rh2(OAc)4 in CH2Cl2 at room temperature for 1 h the
azaisobenzofuran 6 was obtained in 50% yield as a bright
orange air- and light-stable crystalline solid, which
melted without decomposition at 110-112 °C. In addition
† Indian Institute of Technology.
‡ Academia Sinica.
(1) Rodrigo, R. Tetrahedron 1988, 44, 2093.
(2) Padwa, A. Chem. Commun. 1998, 1417.
(3) Wiersum, U. E.; Eldred, C. D. Tetrahedron Lett. 1977, 18, 1741.
(4) Muller, P.; Schaller, J .-P. Tetrahedron Lett. 1989, 30, 1507.
(5) Chen, C.-W.; Beak, P. J . Org. Chem. 1986, 51, 3325.
(6) Hamaguchi, M.; Ibata, T. Chem. Lett. 1976, 287.
(7) For giving this reaction a name reaction status, see: Peters, O.;
Friedrichsen, W. Tetrahedron Lett. 1995, 36, 8581.
(8) Sarkar, T. K.; Ghosh, S. K.; Nandy, S. K.; Chow, T. J . Tetrahe-
dron Lett. 1999, 40, 397.
1
to its H- and 13C NMR data, the structure of 6 is further
supported by its high reactivity in a Diels-Alder reaction
(Scheme 2). When a dichloromethane solution of 4-phen-
yl-3H-1,2,4-triazoline-3,5-dione (15) (1.2 equiv) was added
(9) Carly, P. R.; Compernolle, F.; Hoornaert, G. J . Tetrahedron Lett.
1995, 36, 2113.
(10) Padwa, A.; Dimitroff, M.; Wasterson, A. G.; Wu, T. J . Org.
Chem. 1997, 62, 4088. See also Padwa, A.; Dimitroff, M.; Wasterson,
A. G.; Wu, T. J . Org. Chem. 1998, 63, 3986.
(11) Bobbitt, J . M.; Scola, D. A. J . Org. Chem. 1960, 25, 560.
(12) J ung, M. E.; D’Amico, D. C. J . Am. Chem. Soc. 1995, 117, 7382.
(13) Baum, J . S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
10.1021/jo991886w CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/15/2000

3112 J . Org. Chem., Vol. 65, No. 10, 2000
Sarkar et al.
Sch em e 1a
Sch em e 3
Sch em e 4
a
(a) DIBALH, CH2Cl2, -78 °C f rt, 2 h, 66%; (b) NaClO2,
tBuOH, H2O, 78%; (c) (COCl)2, PhH, and then Et2NH, py, 64%;
(d) LDA, THF, and then CO(OMe)2, 53%; (e) ABSA, Et3N, 0 °C f
rt, 85%; (f) Rh2(OAc)4, CH2Cl2, rt, 50%.
Sch em e 2
Ta ble 1. Rea ction of Meth yl 4,6-Dich lor o-3-
d ieth yla m in ofu r o[3,4-c]-p yr id in e-1-ca r boxyla te (6)
w ith Dien op h iles
to crystalline 6, a single adduct 16 (65%) was formed as
a white crystalline solid.
The unusual stability of 6 is attributable to resonance
involving the pyridine nitrogen and to electron with-
drawal by that nitrogen as well as the ester group
(Scheme 3). In fact, calculated heats of formation using
the PM3 semiempirical molecular orbital method14 reveal
how thermodynamic parameters change in the series: 1
(27.2 kcal/mol) < 4 (12.9 kcal/mol) < 5 (-67.7 kcal/mol)
< 6 (-77.7 kcal/mol).
Cycloa d d ition /Rin g Op en in g Rea ction s of 6. Aza-
isobenzofuran 6 reacts with various dienophiles in an
intermolecular fashion with high regio- and stereoselec-
tivity (Scheme 4, Table 1). The resultant cycloadducts 17
undergo spontaneous ring opening followed by proton
transfer to yield annulated products 18 as in the case of
2-amino-substituted furans, e.g., 8.10
a
b
20:21 ) ∼1:9 20:21 ) ∼9:1
The structural assignment for 19-23 are based on
interpretations of 1H NMR spectra. For example the 200
MHz 1H NMR spectrum of 19 shows a typical AB pattern
for the allylic hydrogens at δ 2.81 Hz (J AB ) 14.62 Hz)
and δ 2.98 (J AB ) 14.62 Hz). The alternative regioisomer
is ruled out because the 1H NMR spectrum of that
(14) All calculations were done using the semiempirical method PM3
implanted on Spartan with full geometry optimization. Stewart, J . J .
P. J . Comput.-Aided Mol. Des. 1990, 4, 1.

Stable o-Quinoid 10-π-Electron System
J . Org. Chem., Vol. 65, No. 10, 2000 3113
F igu r e 1. Orbital drawing for the LUMO of â-nitrostyrene.
compound should display a doublet vinylic hydrogen
signal. The geometrically isomeric dienophiles dimethyl
maleate and fumarate gave 20 and 21. The major endo-
adduct in the case of dimethyl maleate was unisolable
as it simply eliminated a water molecule on standing to
give the fully aromatic compound 21, which is the minor
product from dimethyl fumarate addition. Stereochemical
assignment for 20, where the two ester groups are trans-
related, is based on an X-ray crystal structure determi-
nation.15 The stereochemical profile of these reactions,
i.e., formation of 20 and 21, mirrors those observed in
the cases of 1-amino-isobenzofurans.5
F igu r e 2. Orbital drawing for the HOMO of 6.
of the ester groups of dimethyl fumarate is located on
the endo side of 6, and it will be oriented closer to the
diethylamino group of 6. A similar reasoning should also
hold for the stereochemical results observed in the cases
of 1-amino-isobenzofurans.5 The endo-selectivity for di-
methyl maleate has been well-analyzed as a result of
secondary orbital interactions, i.e., between C3a and C7a
of 6 and the C(O) of dimethyl maleate.
Similarly, the trans relationship of phenyl and car-
bomethoxy group in 23, the single product from cycload-
dition with trans-â-nitrostyrene was established on the
basis of X-ray crystal structure determination.16
Unfortunately, the reaction of azaisobenzofuran 6 with
2-cyclohexenone or in situ-generated benzyne from 2-bro-
mofluorobenzene17 did not give any cycloaddition product.
F r on tier Or bita ls. The observed regioselectivity in
the cycloaddition of 6 with methyl acrylate is similar to
that of 810 and may be rationalized by FMO theory.10,18
Con clu sion
In conclusion, the product azaisobenzofuran 6 isolated
from a Hamaguchi-Ibata reaction has been found to be
stable and easily characterized. The Diels-Alder reac-
tions of 6 proceed with various dienophiles to furnish
[4 + 2]-cycloadducts that undergo spontaneous transfor-
mation into polysubstituted isoquinoline derivatives. In
this respect, 6 mimics the functions of both aza o-
quinodimethane 7 and 2-amino-substituted furan 8, both
of which have spurred vigorous research activities re-
cently. Further application of this chemistry to intramo-
lecular cycloadditions including the synthesis of confor-
mationally restricted analogues of nicotine and anabasine19
are in progress and will be reported in due course.
This is a normal demand π4 +π2s process with a HOMO-
s
LUMO gap of 8.51 eV between the HOMO of 6 and
LUMO of methyl acrylate. The analogous HOMO-
LUMO gaps for 1, 4, and 5 are 8.62, 7.95, and 8.22 eV,
respectively. In addition, the atomic coefficients of the
interacting orbitals, e.g., 0.27 (ester carbon) and 0.10
(amino carbon) of the π4 system, e.g., 6, match with 0.43
and 0.25 of the π2 acrylate system to provide the product
as shown in Table 1, and the secondary orbital interaction
which leads to assumed endo addition is also favorable.
For trans-â-nitrostyrene, the regioselectivity is deter-
mined (mainly by primary orbital interactions) by the
relative orbital coefficients on CR and Câ of its LUMO,
the MO coefficient plot of which is shown in Figure 1.
The sum of squares of CR is 0.27, and that of Câ is 0.20.
Threfore, the larger end (CR) of its LUMO will match with
the larger end (ester carbon) of HOMO of 6. It is,
therefore, consistent with the observed result. As for
dimethyl fumarate, the factor that decides which ester
group should be oriented toward the endo side of 6 is the
relative magnitude of C3a and C7a coefficients on HOMO
of 6. The sum of squares of C3a coefficients is 0.039, and
that of C7a is 0.018 (Figure 2). This indicates that the
secondary orbital effect between C3a of 6 and the C(O) of
dimethyl fumarate will be stronger than C7a of 6 and the
C(O) of dimethyl fumarate. In the transition state, one
Exp er im en ta l Section
Melting points were uncorrected. Unless otherwise noted,
all reactions were carried out under argon atmosphere in
flame-dried flasks. Solvents were dried by distillation from
drying agents as follows: THF and benzene (sodium ben-
zophenone ketyl), dichloromethane (P2O5), DMSO, Et3N, ac-
etonitrile, and pyridine (CaH2). Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
residue was flash chromatographed on silica gel (Acme’s,
particle size 230-400 mesh) using an ethyl acetate-petroleum
ether (60-80 °C) mixture as eluent unless specified otherwise.
2,6-Dich lor o-4-m eth yl-3-p yr id in eca r boxa ld eh yd e (10).
To a stirred solution of 3-cyano-2,6-dichloro-4-methylpyridine
(9)11 (6 g, 32.09 mmol) in 100 mL of CH2Cl2 cooled to -78 °C
was added 32 mL of DIBAL-H (1.0 M solution in toluene)
dropwise. Then the resulting solution was allowed to attain
room temperature. It was stirred for another 2 h at room
temperature and quenched by saturated aqueous NH4Cl at 0
°C. This reaction mixture was stirred for another 1 h at 0 °C
and then acidified with 1 N HCl. The organic layer was
(15) Sarkar, T. K.; Ghosh, S. K.; Nigam, G. D.; Chinnakali, K.; Fun,
H.-K. Acta Crystallogr. 1999, C55, 1140.
(16) Sarkar, T. K.; Ghosh, S. K.; Nigam, G. D.; Chinnakali, K.; Fun,
H.-K. Acta Crystallogr. 1999, C55, 1138.
(17) Newman, M. S.; Hung, W. M. J . Org. Chem. 1975, 40, 262.
(18) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(19) Vernier, J .-M.; Holsenback, H.; Cosford, N. D. P.; Whitten, J .
P.; Menzaghi, F.; Reid, R.; Rao, T. S.; Sacaan, A. I.; Lloyd, G. K.; Suto,
C. M.; Chavez-Noriega, L. E.; Washburn, M. S.; Urrutia, A.; Mcdonald,
I. A. Bioorg. Med. Chem. Lett. 1998, 8, 2173.

3114 J . Org. Chem., Vol. 65, No. 10, 2000
Sarkar et al.
separated, and the aqueous layer was extracted with CH2Cl2
(3 × 25 mL). The combined organic fractions were washed with
saturated aqueous NaHCO3 and brine. The organic layer was
dried over Na2SO4 and concentrated under reduced pressure.
The crude residue was purified by flash silica gel chromatog-
raphy to give 3.96 g (66%) of aldehyde 10 as a snow white
crystalline solid: mp 58-59 °C; IR (KBr) 1697, 1567 cm-1; 1H
NMR (200 MHz, CDCl3) δ 2.62 (s, 3H), 7.20 (s, 1H), 10.54 (s,
1H); 13C NMR (50 MHz, CDCl3) δ 20.7, 126.0, 126.4, 153.3,
154.2, 154.9, 190.0. Anal. Calcd for C7H5NOCl2: C, 44.21; H,
2.63; N, 7.37. Found: C, 44.23; H, 2.46; N, 7.48.
mmol) in acetonitrile at 0 °C was added triethylamine (1.5 mL,
11.1 mmol). The reaction mixture was allowed to warm to room
temperature and stirred for another 12 h. The solvent was
evaporated under reduced pressure. The residue was tritu-
rated with ether/petroleum ether (1:1) and filtered, and the
solvent was evaporated under reduced pressure. This gave the
crude diazo product, which was further purified by chroma-
tography over a short silica gel column with ether/petroleum
ether (1:4) as eluent to give 1.1 g (85%) of diazo compound 14
as a light yellow crystalline solid: mp 112-114 °C; IR (KBr)
1
2113, 1714, 1634 cm-1; H NMR (200 MHz, CDCl3) δ 1.09 (t,
2,6-Dich lor o-4-m eth yl-3-p yr id in eca r boxylic Acid (11).
To a 10 °C solution of 2,6-dichloro-4-methyl-3-pyridinecarbox-
aldehyde (10) (3 g, 15.7 mmol) in 16 mL tert-butyl alcohol were
added NaClO2 (80%, technical, 4.6 g, 40.66 mmol) and NaH2-
PO4‚2H2O (6.6 g, 47.14 mmol) in 11.9 mL of water over 25 min.
The temperature was allowed to warm to 25 °C over 1 h. The
reaction mixture was stirred at room temperature for 3 h, and
then it was concentrated in vacuo to approximately half its
volume. The concentrate was diluted to 20 mL with water and
washed with pentane (2 × 10 mL). The water layer was
acidified to pH 2.0 with 1 M HCl, saturated with NaCl, and
extracted with ether (10 × 3 mL). The ether extracts were
washed with brine, dried over Na2SO4, and concentrated.
Heating to 40 °C at 0.03 mmHg (to remove the excess tert-
butyl alcohol) afforded 2.54 g (78%) of acid 11 as an oil which
solidified on standing as a white solid: mp 138-139 °C; IR
3H, J ) 7.18 Hz), 1.25 (t, 3H, J ) 7.17 Hz), 3.11-3.29 (m,
3H), 3.66-3.80 (m, 1H), 3.84 (s, 3H), 7.93 (s, 1H); 13C NMR
(50 MHz, CDCl3) δ 12.0, 13.5, 39.1, 42.8, 52.5, 62.1, 119.6,
124.9, 136.8, 147.2, 150.1, 163.0, 163.2. Anal. Calcd for
C13H14N4O3Cl2: C, 45.23; H, 4.08; N, 16.23. Found: C, 45.31;
H, 3.89; N, 16.27.
Meth yl 4,6-Dich lor o-3-(d ieth yla m in o)fu r o[3,4-c]p yr i-
d in e-1-ca r boxyla te (6). A mixture of diazo compound 14 (1
g, 2.9 mmol) and 1 mol % Rh2(OAc)4 in CH2Cl2 (3 mL) was
stirred for 1 h at room temperature. Solvent was removed
under reduced pressure, and the residue was purified by
passing through a short silica column to give 450 mg (50%) of
azaisobenzofuran 6 as a bright orange crystalline solid: mp
1
110-112 °C; IR (KBr) 1679, 1609, 1568 cm-1; H NMR (300
MHz, CDCl3) δ 1.35 (t, 6H, J ) 7.0 Hz), 3.76 (q, 4H, J ) 7.0
Hz), 3.90 (s, 3H), 7.41 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
12.9, 46.3, 50.9, 102.1, 108.8, 122.6, 135.0, 144.6, 145.9, 157.1,
158.4; MS (EI) m/e (relative intensity) 318/316 (75/92, M+), 289/
287 (75/92, M-C2H5), 261/259 (15/22), 233/231 (23/47), 201/
199 (88/100). Anal. Calcd for C13H14N2O3Cl2: C, 49.23; H, 4.45;
N, 8.83. Found: C, 49.38; H, 4.62; N, 8.66.
1
(KBr) 1721, 1563 cm-1; H NMR (200 MHz, CDCl3) δ 2.46 (s,
3H), 7.21 (s, 1H) and 7.50-7.70 (bs, 1H); 13C NMR (50 MHz,
CDCl3) δ 19.7, 124.5, 127.7, 147.1, 150.8, 151.3, 169.5. Anal.
Calcd for C7H5NO2Cl2: C, 40.78; H, 2.43; N, 6.79. Found: C,
40.75; H, 2.21; N, 6.52.
N,N-Dieth yl-2,6-dich lor o-4-m eth yl-3-pyr idin am ide (12).
To a stirred suspension containing 2,6-dichloro-4-methyl-3-
pyridinecarboxylic acid (11) (2.5 g, 12.13 mmol) in benzene (25
mL) was added 1.5 mL (17.34 mmol) of oxalyl chloride. Then
the solution was refluxed for 3 h and concentrated under
reduced pressure. The crude acid chloride was dissolved in 20
mL of dry CH2Cl2, and to this solution was added dropwise
1.5 mL (14.54 mmol) of diethylamine followed by 1 mL (12.3
mmol) of pyridine at 0 °C under argon. After being stirred at
room temperature for 2 h, the mixture was washed succes-
sively with water and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The re-
sidual oil was purified by flash silica gel chromatography to
give 2.02 g (64%) of amide 12 as a colorless oil: IR (neat) 1638
cm-1; 1H NMR (200 MHz, CDCl3) δ 1.09 (t, 3H, J ) 7.22 Hz),
1.25 (t, 3H, J ) 7.09 Hz), 2.28 (s, 3H), 3.12 (q, 2H, J ) 7.16
Hz), 3.43-3.69 (m, 2H) and 7.12 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 12.3, 13.9, 18.9, 38.9, 42.6, 124.3, 124.4, 131.4, 146.2,
149.7, 164.4.
Meth yl 2,6-Dich lor o-3-(N,N-d ieth yla m id o)p yr id in e-4-
a ceta te (13). To a solution of LDA (16.7 mmol) (prepared from
11.9 mL of 1.4 M n-BuLi in hexane and 2.4 mL, 16.7 mmol of
diisopropylamine) in THF (50 mL) at -78 °C under argon
atmosphere was added by syringe injection a solution of N,N-
diethyl-2,6-dichloro-4-methyl-3-pyridinamide (12) (2 g, 7.6
mmol) in THF (5 mL). After being stirred for 1 h, the burgundy
red solution was treated with dimethyl carbonate (0.7 mL, 8.3
mmol) and HMPA (1.4 mL, 8.3 mmol). The cooling bath was
removed after 2 h, and stirring was continued for 1 h at room
temperature. Then the reaction mixture was quenched by
saturated aqueous NH4Cl and extracted with Et2O. The
combined ether extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue
was purified by flash silica gel chromatography to give 1.27 g
(53%) of acetate 13 as a colorless oil: IR (neat) 1743, 1636
cm-1; 1H NMR (200 MHz, CDCl3) δ 1.12 (t, 3H, J ) 7.17 Hz),
1.22 (t, 3H, J ) 7.18 Hz), 3.07-3.20 (m, 2H), 3.45-3.64 (m,
4H), 3.69 (s, 3H) and 7.27 (s, 1H); 13C NMR (50 MHz, CDCl3)
δ 11.9, 13.3, 37.1, 38.5, 42.5, 52.2, 124.6, 131.3, 145.5, 146.1,
149.6, 163.6, 168.5.
Gen er a l P r oced u r e for th e Diels-Ald er Cycloa d d ition
Sequ en ces. A dichloromethane (5 mL) solution of the methyl
4,6-dichloro-3-(diethylamino)furo[3,4-c]pyridine-1-carboxyl-
ate (6), and a 2-fold excess of dienophile was stirred at room
temperature for 2-3 h. The mixture was then concentrated
under reduced pressure to give the crude adducts, which was
separated by column chromatography on silica gel (particle
size 100-200 mesh) with various ratios of EtOAc/petroleum
ether as eluant. Repeated recrystallization from EtOAc/
petroleum ether was done to provide analytically pure prod-
ucts.
Dim eth yl (5SR)-1,3-Dich lor o-8-(N,N-d ieth yla m in o)-5,6-
d ih yd r o-5-h yd r oxy-5,7-isoqu in olin ed ica r boxyla te (19).
The reaction was carried out with 200 mg (0.63 mmol) of 6
and 108 mg (1.26 mmol) of methyl acrylate. Column chroma-
tography afforded 234 mg of 19 in 92% yield as a yellow
crystalline solid: mp 150 °C; IR (KBr) 3408, 1742, 1674, 1571
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.00 (t, 6H, J ) 7.1 Hz),
2.81 (1H, J AB ) 14.62 Hz), 2.98 (1H, J AB ) 14.62 Hz), 2.93-
3.05 (m, 3H), 3.15-3.26 (m, 2H), 3.52 (s, 1H), 3.66 (s, 3H), 3.72
(s, 3H), 7.47 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.3, 37.9,
45.7, 51.5, 53.5, 74.2, 104.6, 119.0, 126.1, 147.3, 148.1, 150.1,
156.1, 167.4, 172.5; MS (EI) m/e (relative intensity) 404/402
(20/30, M+), 389/387 (8/14, M - CH3), 375/373 (9/27, M -
C2H5), 369/367 (42/100, M - Cl), 345/343 (42/82, M - CO2-
Me). Anal. Calcd for C17H20N2O5Cl2: C, 50.63; H, 5.00; N, 6.95.
Found: C, 50.62; H, 4.98; N, 6.97.
Tr im eth yl (5SR,6SR)-1,3-Dich lor o-8-(N,N-d ieth yla m i-
n o)-5,6-d ih yd r o-5-h yd r oxy-5,6,7-isoqu in olin etr ica r boxyl-
ate (20) an d Tr im eth yl 1,3-Dich lor o-8-(N,N-dieth ylam in o)-
5,6,7-isoqu in olin etr ica r boxyla te (21). The reaction was
carried out with 200 mg (0.63 mmol) of 6 and 180 mg (1.25
mmol) of dimethyl maleate. Column chromatography afforded
25 mg of 20 (8.5%) and 214 mg of 21 (76.5%) as yellow
crystalline solids: 20: mp 150 °C; IR (KBr) 3361, 1742, 1674,
1569 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.00 (t, 6H, J ) 7.07
Hz), 3.04-3.29 (m, 4H), 3.56 (s, 3H), 3.66 (s, 3H), 3.74 (s, 3H),
4.22 (s, 1H), 7.60 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.5,
46.6, 49.3, 51.6, 52.9, 53.4, 103.5, 120.1, 124.8, 147.8, 148.2,
150.9, 156.5, 166.0, 168.9, 172.9. Anal. Calcd for C19H22N2O7-
Cl2: C, 49.47; H, 4.81; N, 6.07. Found: C, 49.50; H, 4.80; N,
6.10. 21: mp 158 °C; IR (KBr) 1731, 1579, 1524 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.09 (t, 6H, J ) 4.7 Hz), 3.19-3.35 (m,
Dia zo Com p ou n d 14. To a stirred solution of methyl 2,6-
dichloro-3-(N,N-diethylamido)pyridine-4-acetate (13) (1.2 g, 3.7
mmol) and p-acetamidobenzenesulfonyl azide (1.06 g, 4.4

Stable o-Quinoid 10-π-Electron System
J . Org. Chem., Vol. 65, No. 10, 2000 3115
2H), 3.39-3.50 (m, 2H), 3.88 (s, 6H), 3.93 (s, 3H), 7.97 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 12.8, 48.5, 53.0, 53.1, 53.2, 117.5,
121.6, 124.0, 128.1, 135.9, 140.2, 145.4, 149.3, 149.6, 165.9,
166.6, 167.2. Anal. Calcd for C19H22N2O7Cl2: C, 51.48; H, 4.55;
N, 6.32. Found: C, 51.50; H, 4.52; N, 6.30.
Diels-Ald er Rea ction of 6 w ith Dim eth yl F u m a r a te.
The reaction was carried out with 254 mg (0.80 mmol) of 6
and 230 mg (1.60 mmol) of dimethyl fumarate. Column
chromatography afforded 266 mg of 20 (72%) and 28 mg of 21
(8%) as yellow crystalline solids.
2106, 1732, 1676, 1632 cm-1; 1H NMR δ 1.15 (t, 6H, J ) 7.02
Hz), 3.10-3.30 (bs, 2H), 3.40-3.54 (m, 2H), 3.78 (s, 3H), 4.70
(s, 1H), 6.97-7.02 (m, 2H), 7.21-7.24 (m, 3H), 7.35 (s, 1H);
13C NMR (50 MHz, DMSO-d6) δ 12.3, 46.6, 50.6, 52.5, 119.7,
123.7, 126.8, 127.3, 128.3, 128.5, 132.9, 143.0, 147.2, 150.5,
155.6, 170.8. Anal. Calcd for C21H21N3O5Cl2: C, 54.09; H, 4.54;
N, 9.01. Found: C, 54.10; H, 4.53; N, 9.04.
Com p ou n d 16. The reaction was carried out with 250 mg
(0.79 mmol) of 6 and 175 mg (1.0 mmol) of 4-phenyl-3H-1,2,4-
triazoline-3,5-dione. Column chromatography afforded 232 mg
of 16 in (65%) yield as a white crystalline solid: mp 204-205
Meth yl (5SR)-7-Cya n o-1,3-d ich lor o-8-(N,N-d ieth yla m i-
n o)-5,6-dih ydr o-5-h ydr oxy-5-isoqu in olin ecar boxylate (22).
The reaction was carried out with 300 mg (0.95 mmol) of 6
and 100 mg (1.9 mmol) of acrylonitrile. Column chromatog-
raphy afforded 250 mg of 22 in (72%) yield as a yellow
crystalline solid: mp 184 °C; IR (KBr) 3326, 2191, 1738, 1568
cm-1; 1H NMR (200 MHz, CDCl3) δ 1.05-1.35 (bs, 6H), 2.69-
°C; IR (KBr) 1810, 1750, 1561 cm-1 1H NMR (200 MHz,
;
CDCl3) δ 1.17 (t, 6H, J ) 7.15 Hz), 2.77-3.03 (m, 4H), 3.82 (s,
3H), 7.44-7.56 (m, 5H), 7.96 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 16.1, 46.4, 54.5, 90.1, 118.5, 122.3, 126.3, 129.2, 129.3,
129.9, 145.6, 151.6, 152.2, 152.4, 154.5, 155.0, 164.9. Anal.
Calcd for C21H19N5O5Cl2: C, 51.23; H, 3.89; N, 14.22. Found:
C, 51.30; H, 3.84; N, 13.90.
2.87 (m, 2H), 3.25-3.50 (m, 4H), 3.83 (s, 3H), 7.50 (s, 1H); 13
C
NMR (50 MHz, CDCl3) δ 12.5, 37.7, 45.8, 53.9, 73.6, 81.3,
119.4, 120.1, 124.6, 147.7, 151.0, 153.1, 155.2, 171.6. Anal.
Calcd for C16H17N3O3Cl2: C, 51.89; H, 4.59; N, 11.35. Found:
C, 51.80; H, 4.61; N, 11.24.
Ack n ow led gm en t. Financial support from CSIR &
DST, Government of India, is gratefully acknowledged.
We are also thankful to Dr. S. Djuric (Abbott, Chicago,
IL), Dr. C. Fehr (Firmenich, Geneva), Prof. T. Gallagher
(Bristol, UK), and Dr. A. Sarkar (NCL, Pune) for
continuing help and support.
Meth yl (5SR,6SR)-1,3-Dich lor o-8-(N,N-d ieth yla m in o)-
5,6-d ih yd r o-5-h yd r oxy-6-p h en yl-7-n it r o-5-isoq u in olin e-
ca r boxyla te (23). The reaction was carried out with 200 mg
(0.63 mmol) of 6 and 188 mg (1.26 mmol) of trans-â-nitrosty-
rene. Column chromatography afforded 185 mg of 23 in (63%)
yield as a yellow crystalline solid: mp 137 °C; IR (KBr) 3439,
J O991886W