Alkylidenephosphoranes in heterocyclic synthesis: Reactivity of benzoxazinones with resonance-stabilized phosphorus ylides

Article abstract of DOI:10.1055/s-2007-977459

2H-3,1-Benzoxazine-2,4(1H)-dione and its N-methyl analogue react with alkylidenephosphoranes to give substituted quinolines and benzazepines as well as indanone and furan derivatives. Reaction mechanisms to explain the formation of products obtained are outlined. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977459

LETTER
1269
Alkylidenephosphoranes in Heterocyclic Synthesis: Reactivity of
Benzoxazinones with Resonance-Stabilized Phosphorus Ylides
A
lkylidenephosph
z
oranes in H
z
eterocyclic
a
S
ynthesis A. Kamel, Wafaa M. Abdou*
Pesticide Chemistry Department, National Research Centre, Dokki, 12622 Cairo, Egypt
E-mail: wabdou@intouch.com
Received 7 December 2006
Dedicated to the memory of one of the greatest contributors to heterocyclic chemistry – Professor Charles W. Rees
in aqueous alkali. Thus, isatoic anhydride is generally
considered unsuitable for chemical reactions and many
research groups have chosen N-methyl isatoic anhydrides
as model compounds. Therefore, a comparative study of
the behavior of 1a in analogy with 1b toward alkylidene-
phosphoranes was herein undertaken.
Abstract: 2H-3,1-Benzoxazine-2,4(1H)-dione and its N-methyl
analogue react with alkylidenephosphoranes to give substituted
quinolines and benzazepines as well as indanone and furan deriva-
tives. Reaction mechanisms to explain the formation of products
obtained are outlined.
Key words: isatoic anhydrides, heteroring transformations, reso-
As early as 1973,3b the first investigation was undertaken
to study the influence of Wittig reagent 6a on 1a and 1b.
The reaction was carried out in dioxane, and led to the
formation of new phosphonium ylides 7a,b. In 1976,
Coppola et al.3e reported that 1b reacted with phosphonyl
carbanion 8 to give phosphono-substituted quinolines 9
(Scheme 2). It has been pointed out that 7 and 9 were
formed via CO2 elimination.
nance-stabilized alkylidenephosphoranes, quinoline derivatives
Benzoxazinone derivatives and related compounds may
undergo ring-opening transformations of the six-mem-
bered heteroring, and serve as precursors of different bio-
logically active heterocycles.1–3 In the course of
investigating the structure–activity relationship of benz-
oxazinones, we have found several unusual ring transfor-
mations in the reactions of 2,3- and 2,4-benzoxazinones
with P(III) and P(V) reagents.4 In this connection, a series
of quinoline derivatives, substituted benzazepines and in-
dolizinones was recently obtained in reasonable yields
from the reactions of 2H-3,1-benzoxazine-2,4(1H)-diones
(also known as isatoic anhydrides) with nonsaturated and
unstabilized phosphonium ylides (e.g. Scheme 1).5
R
N
O
+
Ph3P=CHCOOEt
6a
dioxane, ∆, – CO2, – EtOH
PPh3
1a,b
O
7a,b, R = H, Me
1a,b
O
Me
1b
(EtO) PCH CN
+
2
2
N
NH2
O
As a sequel, we set for ourselves the goal of broadening
the scope of the reaction of isatoic anhydrides with reso-
nance-stabilized alkylidenephosphoranes, and the results
of these studies are summarized in Schemes 4–6.
8
NaH, MeCONH2, CO2
P(OEt)2
O
9
Because of its strongly polar NH group, isatoic anhydride
itself shows only a weak solubility in organic solvents,
and it is almost insoluble in alcohol, although it is soluble
Scheme 2
+
PPh3
OH
N
O
Me
+
CH=CH2 Br–
LiOH (aq), EtOH
N
O
H
O
2
3
1a
CH2
O
N
R
O
+
PPh3
CH2
O
NH2
CH3 Br–
1a, R = H
+
1b, R = Me
NaH, DMF
N
N
R
R
4
5
Scheme 1
SYNLETT 2007, No. 8, pp 1269–1273
1
6.
0
5.
2
0
0
7
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977459; Art ID: D38106ST
© Georg Thieme Verlag Stuttgart · New York

1270
A. A. Kamel, W. M. Abdou
LETTER
were formed from 12 as previously reported3b via carbon
dioxide and alcohol elimination, whereas intramolecular
Wittig reaction yields 13a–d. On the other hand, intermo-
lecular Wittig reaction between 12a–d and a second ylide
species 6a (or 6b) affords the benzazepines 15a–d via
intramolecular cyclization with concomitant loss of tri-
phenylphosphine.
Me
N
O
O
O
O
N
O
1a,b
+
O
O
+
O
P
O
O
(EtO)2
O
10
(E)- and (Z)-11
On repetition6b of the above reaction between 1a,b and
two equivalents of the ylides 6a,b in refluxing ethyl ace-
tate containing a catalytic amount of benzoic acid, benz-
azepines 15a–d were obtained as the major products
together with 13a–d. Efforts to detect or separate the
expected product 7 from the product mixture were un-
successful.
Scheme 3
However, the reaction took a different course when 1a or
1b was allowed to react with a-phosphono-g-butyro-
lactone yielding the corresponding Wittig products 10 or
(E and Z) 11, respectively3f (Scheme 3).
Thus, considering the earlier report,3b the results of the
above reaction (1a,b with 6a,b) show that we are able to
isolate products 7a,b analogous with those of Conner and
Strandtmann, but with 13a–d and 15a–d we have isolated
different condensed products.
Treatment6a of 1a with slight excess (10%) of ethoxycar-
bonylmethylene(triphenyl)phosphorane (6a) or its methyl
ester analogue 6b in boiling dioxane for three days afford-
ed a colorless precipitate (40%), mp >300 °C with proper-
ties corresponding to the known3b ylide 7a. The remaining
soluble materials were purified by chromatography to
give diethyl 2,5-dihydroxybenzazepine-3,4-dicarboxylate
(15a, 18%) together with the known7 ethyl 2,4-dihydroxy-
quinoline-3-carboxylate (13a, 14%), or 7a (36%) together
with the methyl ester analogues 15b (18%) and 13b8
(16%) from the reaction of 1a with 6b (Scheme 4). A sim-
ilar treatment6a of N-methylisatoic anhydride (1b) with 6a
(or 6b) in refluxing dioxane for three days afforded the
parallel products 7b3b (ca. 40%), 13c9 (or 13d,10 ca. 13%)
and 15c (or 15d, ca. 20%; Scheme 4). The spectroscopic
data showed 13a and 13b to be present in the enol form.7,8
We next investigated the reaction of isatoic anhydrides
1a,b with keto ylides 16a,b. Treatment11 of 1a,b with
acetylmethylene(triphenyl)phosphorane (16a,
2 mol
equiv) in refluxing ethyl acetate containing a catalytic
amount of benzoic acid for two days gave, after separation
by column chromatography, substituted quinolinones
18a,b (ca. 28%) and the furan derivatives 21a,b (ca. 50%,
Scheme 5). The formation of these products can be ex-
plained through an initial nucleophilic attack of 16a on
1a,b leading to the intermediates 17a,b. Further Wittig
reaction of 17a,b with the lactone carbonyl of 1a/1b
leads to the formation of 3-acetyl-1-anilinoquinoline-4-
one (18a) or its N-methyl analogue 18b whereas Michael
addition of a second ylide species 16a to 17a,b, followed
by subsequent triphenylphosphine elimination, gives
21a,b.
The formation of the reaction products 7, 13 and 15 can be
explained by the mechanism suggested in Scheme 4. The
initial nucleophilic attack of the carbanion center in 6a,b
on the C(1)=O group with subsequent ring cleavage of 1
leads to the formation of the betaine 12, which is the key
intermediate for subsequent transformations. Thus, 7a,b
R
N
O
Ph3P=CHCOOR1
+
O
6a, R1 = Et
6b, R1 = Me
O
1a,b
R
N
R
O
R
N
– CO2
– R1OH
O
N
O
C
– Ph3PO
O–
C CHCOOR1
+
PPh3
COOR1
O
O
PPh3
OH
13a–d
7a, R = H, 7b, R = Me
12a–d
R
R
N
-
OH
O
N
C=CHCOOR1
+ 6a,b
– Ph3P
12
COOR1
C CHCOOR1
PPh3
COOR1
OH
O
+
12–15a, R = H, R1 = Et
12–15b, R = H, R1 = Me
12–15c, R = Me, R1 = Et
12–15d, R = Me, R1 = Me
15a–d
14
Scheme 4
Synlett 2007, No. 8, 1269–1273 © Thieme Stuttgart · New York

LETTER
Alkylidenephosphoranes in Heterocyclic Synthesis
1271
R
R
N
+
Ph3P CHPh2Br–
N
O
O
Ph3P=CHCOR2
EtOAc, benzoic acid
22
+
+
– HBr
O
O
16a, R2 = Me
16b, R2 = Ph
O
O
Ph3P CPh2
1a, R = H
1b, R = Me
1a, R = H
1b, R = Me
23
R
N
NaOEt, EtOH
NRH
O
+ 1a/1b
R
N
–
NHR
COR2
NHR
C
CC R2
Ph
Ph
– Ph3PO
+
O
O
PPh3
+
18a, R = H, R2 = Me
18b, R = Me, R2 = Me
18c, R = H, R2 = Ph
18d, R = Me, R2 = Ph
17a–d
COOEt
O
only 17a and 17b
– Ph3PO
24a, R = H
24b, R = Me
25a, R = H
25b, R = Me
+
Scheme 6
NHR
PPh3
NRH
–CHCOR2
CH–CMe
–O
O
-
On treatment12 of 1a,b with diphenylmethylene(tri-
phenyl)phosphorane (23), prepared in situ from the
corresponding bromophosphonium salt 22 by addition of
C CH=C=CH2
C
+
CMe
Ph3P
O
20a,b
19a,b
NHR
O
sodium ethoxide in absolute
ethanol, substituted
– PPh3
indanones 24a13 (46%) and 24b14 (53%) were obtained
along with the anthranilate 25a (or 25b, ca. 15%;
Scheme 6).
COMe
Me
19–21a, R = H
19–21b, R = Me
21a,b
The structures suggested for all new compounds are in
agreement with their analytical and spectral data (see
Table 1).
Scheme 5
When11 1a,b and an equimolar amount (or 2 equiv) of
benzoylmethylene(triphenyl)phosphorane (16b) were
heated in ethyl acetate containing benzoic acid for two
days, 2-(2-anilino)-3-benzoylquinoline-4-one (18c, or its
N-methyl analogue 18d) was the only product (isolated in
ca. 69% yield), as shown in Scheme 5.
In summary, the reactions studied are offered as an easy
way for the transformation of commercially available
starting compounds to biologically important N-hetero-
cycles. The results of the present work also show marked
resemblance between 1a and 1b in their chemical behav-
ior toward phosphonium ylides under similar conditions.
Table 1 Physical Properties and Spectral Data for Products 15a–d, 18a–d and 21a,b
Product,a color, Mp (°C),b IR (v, cm–1)e
MS: m/z (%), [M+],
1H NMR (CDCl3),
13C NMR (CDCl3),
d (ppm)
yield (%)c,d
solvent
and relevant fragmentsf d (ppm)
15a,
pale yellow,
46
215–217, 3410–3337 (2
acetone
318 (11) [M+ – 1], 316 1.32, 1.41 (2 t, JHH = 6.7 Hz, 6 14.2, 14.4 (2 ×OCCH3), 59.7, 61.7
OH, NH), 1716, (17), 301 (48), 290 H, 2 × CH3), 4.37, 4.42 (2 q, (2 × OCH2), 90.6 (C-3), 99.6 (C-4-
1689 [2 C(O),
ester]
(22), 255 (53), 138
(100), 107 (68), 77
(34)
JHH = 6.7 Hz, 4 H, 2 × OCH2), ester), 114.7, 118.4, 121.6, 123.4,
7.40, 7.91 (2 d, JHH = 6.7 Hz, 4 131.1, (C=C, Ph), 151.5 (C-2-OH),
H, H-Ph), 8.88 (s, br, 1 H, HN), 156.2 (C-5-OH), 162.9, 164.4 (2
11.79–12.0 (br, 2 H, 2 × OH)
C=O)
15b,
239–241, 3400, 3356 (2
290 (14) [M+ – 1], 288 3.40, 3.53 (2 s, 6 H, 2 × OCH3), 50.6, 51.7 (2 × OCH3), 90.2 (C-3),
straw yellow, acetone
51
OH), 1722, 1706 (21), 276 (16), 258
[2 C(O), ester]
7.43, 7.99 (2 d, JHH = 6.7 Hz, 4 99.4 (C-4), 114.8, 118.6, 121.5,
H, H-Ph), 8.82 (s, br, 1 H, HN), 122.6, 123.4, 131.4, 137.9, (C=C,
11.72, 11.92 [2 s (br), 2 H, 2 × Ph), 153.6, 156.3 (C-2 and C-5),
(36), 226 (56), 226
(63), 138 (100), 107
(54), 77 (26)
OH)
169.5, 171.3 (2 C=O).
15c,
pale yellow,
44
113–114, 3430 (2 OH),
332 (15) [M+ – 1], 231 3.15 (s, 3 H, N-CH3), 1.25,
14.1, 14.3 (2 ×OCCH3), 32.1
CH2Cl2
1710, 1695
(19), 318 (28), 286
(36), 240 (48), 138
(100), 107 (46), 77
(41)
1.42 (2 t, JHH = 6.4 Hz, 6 H, 2 (NCH3), 57.9, 61.7 (2 ×OCH2);
[2 C(O), ester]
× CH3), 4.38, 4.41 (2 q, JHH
=
83.8 (C-3-ester), 110.4 (C-4-ester),
6.4 Hz, 4 H, 2 × OCH2), 7.45, 114.9, 118.4, 121.6, 127.8, 132.8,
8.05 (2 d, JHH = 6.4 Hz, 4 H, H- (C=C, Ph), 153.7 (C-2-OH), 156.5
Ph), 11.93–12.21 (br, 2 H, 2 × (C-5-OH), 160.9, 164.2 (2 C=O)
OH)
Synlett 2007, No. 8, 1269–1273 © Thieme Stuttgart · New York

1272
A. A. Kamel, W. M. Abdou
LETTER
Table 1 Physical Properties and Spectral Data for Products 15a–d, 18a–d and 21a,b (continued)
Product,a color, Mp (°C),b IR (v, cm–1)e
MS: m/z (%), [M+],
1H NMR (CDCl3),
13C NMR (CDCl3),
d (ppm)
yield (%)c,d
solvent
and relevant fragmentsf d (ppm)
15d,
142–144, 3415 (2 OH),
304 (21) [M+ – 1], 303 3.23 (s, 3 H, N-CH3), 3.37,
32.2 (NCH3), 51.7, 57.8 (2 ×
straw yellow, benzene
48
1713, 1705
[2 C(O), ester]
(22), 290 (18), 287
(31), 275 (23), 258
(41), 226 (76), 138
(100), 107 (73), 77
(38)
3.46 (2 s, 6 H, 2 × OCH3), 7.40, OCH3), 83.9 (C-3), 110.1 (C-4),
7.95 (2 d, JHH = 6.7 Hz, 4 H, H- 114.9, 124.1, 122.6, 123.4, 127.7,
Ph), 11.80 [2 s (br), 2 H, 2 ×
OH)
131.7, 132.8, (C=C, Ph), 153.6,
157.6 (C-2 and C-5), 169.5, 171.3
(2 C=O)
18a,
201–205, 3340–3324 (NH, 277 (18) [M+ – 1], 276 2.55 [s, 3 H, C(O)CH3], 5.56 [s 28.8 (CH3), 107.7 (C-3), 118.2,
pale yellow,
29
EtOAc
NH2), 1772
[C-4(O)], 1673
[C(O), acetyl]
(29), 261(36), 185
(100), 107 (28), 77
(42)
(br), 2 H, NH2], 7.38, 7.68,
8.21 (3 m, 8 H, H-Ph), 8.94 (br 133.7 (C=C, Ph), 144.3 (CNH2),
s, 1 H, N-1-H).
118.8, 121.9, 123.7, 127.6, 129.3,
148.4 (C-2), 180.7 (4-C=O), 192.8
[C(O), acetyl]
18b,
yellow,
25
148–149, 3322 (NH), 1772 305 (16) [M+ – 1], 291 2.25 [s, 3 H, C(O)CH3], 2.96
28.6 (CH3, acetyl), 30.5, 37.6 (2
NCH3), 110.3 (C-3), 118.2, 118.6,
121.7, 122.3, 123.8, 126.7, 127.8,
128.3, 133.0 (C=C, Ph), 144.2 (C-
2), 146.4 (CNHCH3), 180.5 (4-
C=O), 193.9 [C(O), acetyl]
EtOH
[C-4(O)], 1672
[(C(O), acetyl]
(28), 275 (82), 271
(33), 209 (55), 185
(100), 107 (51), 77
(33)
(d, JHH = 4.5 Hz, CH3NH),
3.13 (N-1-CH3), 5.86 [q (ill-
defined), NHMe], 7.38, 7.68,
8.21 (3 m, 8 H, H-Ph).
18c,
284–286, 3333–3325 (NH, 339 (12) [M+ – 1], 338 5.67 (s, 2 H, NH2), 7.37–8.21 102.2 (C-3), 114.0, 118.1, 118.6,
yellow,
72
EtOH
NH2), 1770
[C-4(O)], 1654
[C(O)Ph]
(21), 262 (36), 247
(49), 185 (100), 107
(43), 77 (62)
(m, 13 H, H-Ph), 9.08 (br s, 1 122.9, 123.7, 127.1, 127.4, 127.6,
H, HN)
129.63, 132.76, 134.4, 134.8 (C=C,
Ph), 144.9 (CNH2), 147.6 (C-2),
179.8 (4-C=O), 192.8 [C(O), ben-
zoyl]
18d,
yellow,
69
176–178, 3326 (NH), 1773 367 (35) [M+ – 1], 353 2.76 (d, JHH = 4.5 Hz,
30.5, 37.6 (2 NCH3), 104.7 (C-3),
EtOH
[C-4(O)], 1646
[C(O)Ph]
(30), 338 (24), 261
(38), 185 (100), 107
(46), 77 (64)
CH3NH), 3.06 (N-1-CH3), 5.44 114.7, 118.6, 119.7, 122.3, 123.8,
(q, 1 H, NHMe), 7.37–8.21 (m, 125.o, 126.9, 127.8, 129.6, 132.7,
13 H, H-Ph)
133.7, 134.4 (C=C, Ph), 143.3 (C-
2), 146.2 (CNH), 179.7 (4-C=O),
193.7 [C(O), benzoyl]
21a,
168–171, 3342 (br, NH2),
214 (57) [M+ – 1], 200 2.18 (s, 3 H, C-3-CH3), 2.54 [s, 15.5 (CH3, furyl), 26.6 (CH3,
colorless,
49
EtOH
1675 [(C(O),
acetyl], 1110
(C=C, furan)
(35), 184 (100), (12), 3 H, C(O)CH3], 5.67 (s, 2 H,
acetyl), 108.1 (C-4-furyl), 117.3,
120.7, 124.7, 129.8 (C=C, Ph and
91 (62), 77 (16), 68
(17)
NH2), 6.56 (s, 1 H, H-furan),
7.34, 7.98 (2 d, JHH = 6.5 Hz, 4 C-3-furyl), 140.1 (CNH2), 148.6
H, H-Ph)
(C-5, furyl), 152,2 (C-2, furyl),
187.2 [C(O), acetyl]
21b,
colorless,
52
106–108, 3322 (br, NH),
228 (16) [M+ – 1], 213 2.15 (s, 2 × 3 H, C-3-CH3),
15.5 (CH3, furyl), 26.5 (CH3,
acetyl), 30.7 (NCH3), 106.8 (C-4-
furyl), 114.9, 117.8, 119.8, 120.7,
CH2Cl2
1110 (C=C,
furan), 1665
[(C(O), acetyl]
(26), 198 (46), 183
(100), 91 (64), 77
(25), 68 (21)
2.55 [s, 3 H, C(O)CH3], 2.87
(d, JHH = 5.7 Hz, 3 H,
NHCH3), 5.77 [q (ill-defined), 124.7, 126.8, 127.2 (C=C, Ph and
1 H, HNMe], 6.76 (s, 1 H, H- C-3-furyl), 143.3 (CNH2), 149.2
furan), 7.34, 7.98 (2 d,
JHH = 6.5 Hz, 4 H, H-Ph).
(C-5, furyl), 152.2 (C-2, furyl),
187.2 [C(O), acetyl]
a Satisfactory elemental analyses were obtained for all new compounds.
b All melting points are uncorrected.
c Yields are approximate.
d Yields were considered from the catalytic reactions (ref. 7).
e The IR spectra were recorded, in KBr, on a Jasco FT/IR 300 E.
f Mass spectra were determined on a Finnigan SSQ 7000 (EI 70 eV) spectrometer.
g NMR spectra were recorded on a Joel-270 MHz instrument using SiMe4 as an internal reference.
h The 1H and 13C NMR spectra were run in CDCl3 or DMSO.
(2) (a) Witt, A.; Bergman, J. Tetrahedron 2000, 56, 7245.
(b) Coppola, G. M. Tetrahedron Lett. 1998, 39, 8233. (c)de
Silva, J. F. M.; Gorden, S. J.; Pinto, A. C. J. Braz. Chem. Soc.
2001, 12, 273. (d) Kovalenko, S. M.; Bylov, I. E.; Sytnik, K.
M.; Chernykh, V. P.; Bilokin, Y. V. Molecules 2000, 5,
1146.
References and Notes
(1) (a) El-Hashash, M. A.; Sayed, M. A. Egypt. J. Chem. 1979,
2, 115. (b) Dash, B.; Dora, E. K.; Panda, C. S. J. Indian
Chem. Soc. 1980, 57, 835. (c) Fahmy, A. F. M.; Aly, N. F.
Bull. Chem. Soc. Jpn. 1976, 49, 1391. (d) Baddar, F. G.;
Fahmy, A. F. M.; Aly, N. F. J. Chem. Soc., Perkin Trans. 1
1973, 2448.
Synlett 2007, No. 8, 1269–1273 © Thieme Stuttgart · New York

LETTER
Alkylidenephosphoranes in Heterocyclic Synthesis
1273
(3) (a) Coppola, G. M. Synthesis 1980, 505; and references cited
therein. (b) Connor, D. T.; von Strantmann, M. J. Org.
Chem. 1973, 38, 1047. (c) McIntosh, J. M.; Steevensz, R. S.
Can. J. Chem. 1974, 52, 1934. (d) McIntosh, J. M.;
Steevensz, R. S. Can. J. Chem. 1977, 55, 2442.
(e) Coppola, G. M.; Hardtmann, G. E.; Pfister, O. R. J. Org.
Chem. 1976, 41, 825. (f) Minami, T.; Matsumoto, M.;
Suganuma, H.; Agawa, T. J. Org. Chem. 1978, 43, 2149.
(4) (a) Kamel, A. A. Phosphorus, Sulfur Silicon Relat. Elem.
2007, 182, 765. (b) Abdou, W. M.; Fahmy, A. F. M.; Kamel,
A. A. Eur. J. Org. Chem. 2002, 1696. (c) Abdou, W. M.;
Kamel, A. A.; Khidre, M. D. Synth. Commun. 2004, 34,
4119. (d) Abdou, W. M.; Kamel, A. A.; Khidre, M. D.
Heteroat. Chem. 2004, 15, 77.
(b) In EtOAc with benzoic acid: The same reaction between
ester ylides 6a,b (7.5 mmol) and 1a,b (4.9 mmol) was
repeated in EtOAc containing benzoic acid (0.3 g), heating
under reflux for 2 d. After the usual workup, yellow crystals
of 13a (313 mg, 28% yield) and 15a (720 mg, 46%, from 6a
and 1a), 13b (279 mg, 28% yield) and 15b (728 mg, 51%,
from 6b and 1a), 13c (334 mg, 30% yield) and 15c (662 mg,
44%, from 6a and 1b), and 13d (263 mg, 25% yield) and 15d
(662 mg, 48%, from 6b and 1b) were obtained. All products
were identified by mixed mp as well as comparison of IR and
mass spectral data with those of the materials previously
obtained. Compounds 7a,b were not isolated from this
reaction.
(7) Grundon, M. F.; McCrokinale, N. J. J. Chem. Soc. 1955,
4284.
(8) Koller, G. Ber. Dtsch. Chem. Ges. 1927, 60, 1108.
(9) Coppola, G. M.; Hardtmann, G. E. J. Heterocycl. Chem.
1979, 16, 1605.
(5) Abdou, W. M.; Kamel, A. A. Synth. Commun. 2007,
accepted for publication.
(6) Typical Procedure for the Reaction of Isatoic
Anhydrides 1a,b with Ester Ylides 6a,b
(a) In dioxane: A mixture of alkoxycarbonylmethylene
(triphenyl)phosphorane 6a (or 6b, 5.2 mmol) and 1a (or 1b,
4.9 mmol) in 40 mL dry dioxane was heated under reflux for
3 d. After removal of the solvent, EtOAc (30 mL) was added.
The material that precipitated was collected and crystallized
from EtOAc–CH2Cl2 to give the known ylide 7a (from the
reaction of 6a,b with 1a; ca. 38%), mp >300 °C (from
acetone; lit.3b mp 320 °C), or 7b (from the reaction of 6a,b
with 1b; ca. 40%), mp 252–254 °C [from acetone–Et2O
(2:1); lit.3b mp 252–253 °C, from EtOAc–CH2Cl2].
Components present in the filtrate were separated by column
chromatography on silica gel.
Compounds 1a and 6a: Elution with n-hexane–EtOAc (3:7
v/v) gave colorless needles of ethyl 2,4-dihydroxyquinoline-
3-carboxylate (13a, 156 mg, 14%), mp 206–208 °C (from
CHCl3; lit.7 mp. 208 °C, from EtOAc]. The second fraction
(n-hexane–EtOAc, 1:9 v/v) gave straw-colored crystals of
diethyl 2,5-dihydroxybenzazepine-3,4-dicarboxylate (15a,
282 mg, 18%), mp 215–217 °C (from acetone).
Compounds 1a and 6b: Elution with n-hexane–EtOAc (3:7
v/v) gave yellow crystals of methyl 2,4-dihydroxyquinoline-
3-carboxylate (13b, 172 mg, 16%), mp 202–204 °C (from
MeOH; lit.8 mp 203–204 °C, from Et2O]. The second
fraction (n-hexane–EtOAc, 1:9 v/v) gave straw-colored
crystals of dimethyl 2,5-dihydroxybenzazepine-3,4-
dicarboxylate (15b, 300 mg, 21%), mp 239–242 °C (from
acetone).
Compounds 1b and 6a): Elution with n-hexane–EtOAc (8:2
v/v) gave yellow crystals of ethyl 4-hydroxy-1-methyl-2-
oxoquinoline-3-carboxylate (13c, 145 mg, 13%), mp 100–
103 °C (from cyclohexane; lit.9 mp 100–102 °C, from Et2O].
The second fraction (n-hexane–EtOAc, 7:3 v/v) gave straw-
colored crystals of diethyl 2,5-dihydroxy-1-methylbenz-
azepine-3,4-dicarboxylate (15c, 270 mg, 18%), mp 113–
114 °C (from CH2Cl2).
(10) Zikou, G.; Athanasellis, G.; Detsi, A.; Zografos, A.; Mitsos,
C.; Igglessi-Markopoulou, O. Bull. Chem. Soc. Jpn. 2004,
77, 1505.
(11) Typical Procedure for the Reaction of Isatoic
Anhydrides 1a,b with Keto Ylides 16a,b
A solution of acetylmethylene(triphenyl)phosphorane (4.9
mmol) and 1a (or 1b, 5.2 mmol) in 40 mL EtOAc containing
benzoic acid was refluxed for 2 d. After usual workup, the
products 18a and 21a or 18b and 21b were obtained (see
Table 1).
Compounds 18c or 18d were likewise obtained upon
reacting 1a (or 1b) with an equimolar amount of
benzoylmethylene(triphenyl)phosphorane under the same
conditions as mentioned above and workup (data for 18c and
18d are listed in Table 1).
(12) Typical Procedure for the Reaction of Isatoic
Anhydrides 1a,b with Phosphonium Salt 22
Diphenylmethylene(triphenyl)phosphonium bromide (22,
5.2 mmol) was added dropwise to a solution of abs. EtOH
(50 mL) containing Na metal (0.4 g). The reaction mixture
was stirred at r.t. for 1 h followed by addition of 1a (or 1b,
4.9 mmol), and then heated under reflux for 15 h. The
product mixture was concentrated and diluted with a small
amount of distilled H2O, followed by solvent extraction
(EtOAc), drying, and evaporation. The resulting residue was
purified by chromatography on silica gel, gradient eluting
using CHCl3–EtOAc to yield compounds 24a and 25a, or
24b and 25b, respectively. Compound 25a was obtained as
pale yellow needles (130 mg, 16%), mp 36–38 °C (from
pentane); mp and mixed mp, as well as IR and mass spectral
data were comparable to those of an available sample.
Compound 24a was obtained as colorless plates (643 mg,
46%), mp 212–214 °C (from EtOH; lit.13 mp 212–214 °C,
from acetone). Compound 25b was obtained as pale yellow
liquid (105 mg, 13%), with IR and mass spectral data
comparable to those of an available sample. Compound 24b
was obtained as colorless plates (716 mg, 53%), mp 176–
177 °C (from EtOH).14
Compounds 1b and 6b: Elution with n-hexane–EtOAc (4:6
v/v) gave yellow crystals of methyl 4-hydroxy-1-methyl-2-
oxoquinoline-3-carboxylate (13d, 126 mg, 12%), mp 164–
166 °C (from benzene; lit.10 mp. 166–167 °C, from
benzene]. The second fraction (n-hexane–EtOAc, 3:7 v/v)
gave straw-colored crystals of diethyl 2,5-dihydroxy-1-
methylbenzazepine-3,4-dicarboxylate (15d, 303 mg, 22%),
mp 142–144 °C (from benzene). Percentage yields, physical
and spectral data of the new products 15a–d are listed in
Table 1.
(13) Sheehan, J. C.; Frankenfeld, J. W. J. Am. Chem. Soc. 1961,
83, 4792.
(14) Bruni, P.; Conti, C.; Tosi, G. J. Mol. Struct. 1997, 408/409,
477.
Synlett 2007, No. 8, 1269–1273 © Thieme Stuttgart · New York

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