A rare acid-promoted elimination of O-methyl oximes: A practical synthesis of 3-cyano-4-benzopyrones

Full text of DOI:10.1021/jo991031j

8736
J . Org. Chem. 1999, 64, 8736-8740
A Ra r e Acid -P r om oted Elim in a tion of
O-Meth yl Oxim es: A P r a ctica l Syn th esis of
3-Cya n o-4-ben zop yr on es
Richard P. Hsung,* Craig A. Zificsak, Lin-Li Wei,
Luke R. Zehnder, Francis Park,1 Michelle Kim,1 and
Thuy-Trang T. Tran1
Department of Chemistry, The University of Minnesota,
Minneapolis, Minnesota 55455
Received J une 28, 1999
Our interest in natural products containing the oxa-
decalin structural unit has led us to investigate [4 + 2]
cycloaddition reactions involving 4-pyrones as dienophiles
(1 f 2 in Figure 1).2-5 Such a strategy should serve as a
highly convergent approach to the synthesis of natural
products such as arisugacin (3 in Figure 1),4,6-8 pyripy-
ropenes,9 and forskolin.10 However, at this point, a strong
electron-withdrawing group has proven to be essential
for rendering the electron-rich 4-pyrones as reactive
dienophiles in these cycloadditions under thermal or
Lewis acidic conditions.3b,5a Although this specific neces-
sity could hinder the synthetic scope of this strategy,
given the scarce studies of reactions using 4-pyrones as
dienophiles, these initial endeavors have yielded inter-
esting synthetic structures that could serve as entries to
unique natural products and their analogues.
F igu r e 1.
Specifically, we have prepared an array of tetrahy-
droxanthone derivatives (2) via [4 + 2] cycloaddition
reactions using 3-cyano-4-benzopyrones as dieno-
philes.4a-b,11 These tetrahydroxanthone derivatives were
evaluated for their anticholinesterase potential11 because
of the structural resemblance to tacrine (4, Cognex),12 one
of only three available therapeutics for antidementia
diseases. More significantly, 4-benzopyrone derivatives
are known for their pharmacological potential as anti-
bacterial, antitumor, and antiallergy agents,13 and re-
cently, there have been reports indicating their prospects
in demonstrating anti-HIV activity.14 Given these syn-
thetic and medicinal interests, useful preparations of
various 4-benzopyrone derivatives can be significant. We
here report a practical synthesis of 3-cyano-4-benzopy-
rone derivatives via an acid-promoted elimination of the
corresponding O-methyl oximes.
We began our synthesis of 3-cyano-benzopyrones by
focusing on a few reported procedures describing prepa-
rations from the corresponding aldehydes through oxime
intermediates.15 As shown in Scheme 1, when 3-formyl-
4-benzopyrone 5 is refluxed with H2NOH-HCl and a
catalytic amount of concentrated HCl in 95% EtOH, the
corresponding oxime 6 should be formed and undergo
facile dehydration to provide 3-cyano-4-benzopyrone 8.
However, we were not able to isolate any desired 3-cyano-
4-benzopyrones 8 in synthetically useful yields (yield e
2-3%) under these conditions, nor were we able to
intercept the corresponding oxime intermediate 6. We
(1) UMN Undergraduate Research Participants: 1997-1999.
(2) For a recent review see: (a) Ghosh, C. K.; Ghosh, C. Indian J .
Chem. 1997, 968. For the first example of 3-acyl-4-pyrones functioning
as dienophiles see: (b) Groundwater, P. W.; Hibbs, D. E.; Hursthouse,
M. B.; Nyerges, M. J . Chem. Soc., Perkin Trans. 1 1997, 163.
(3) For a recent elegant study on 3-acyl- and 3-cyano-4-pyrones
functioning as dienophiles see: Chen, D.; Wang, J .; Totah, N. I. J . Org.
Chem. 1999, 64, 1776.
(4) For studies on 3-nitrile-4-benzopyrones functioning as dieno-
philes see: (a) Hsung, R. P. J . Org. Chem. 1997, 62, 7904. (b) Hsung,
R. P. Heterocycles 1998, 48, 421. (c) Granum, K. G.; Merkel, G.; Mulder,
J . A.; Debbins, S. A.; Hsung, R. P. Tetrahedron Lett. 1998, 9597.
(5) For the only other examples of benzopyrones functioning as
dienophiles see: (a) Cremins, P. J .; Saengchantara, S. T.; Wallace, T.
W. Tetrahedron 1987, 13, 3075. (b) Ohkata, K.; Kubo, T.; Miyamoto,
K.; Ono, M.; Yamamoto, J .; Akiba, K. Heterocycles 1994, 38, 1483.
(6) Arisugacin has been found to be a potent and selective inhibitor
of acetylcholinesterase. For a leading reference see: Otoguro, K.; Kuno,
F.; O˜ mura, S. Pharmacol. Ther. 1997, 76, 45.
(7) For studies related to arisugacin see: (a) Obata, R.; Sunazuka,
T.; Tian, Z.; Tomoda, H.; Harigaya, Y.; O˜ mura, S.; Smith, A. B. III.
Chem. Lett. 1997, 935. (b) Hua, D. H.; Chen, Y.; Sin, H.-S.; Maroto,
M. J .; Robinson, P. D.; Newell, S. W.; Perchellet, E. M.; Ladesich, J .
B.; Freeman, J . A.; Perchellet, J .-P.; Chiang, P. K. J . Org. Chem. 1997,
62, 6888.
(8) For our other related efforts see: (a) Hsung, R. P.; Shen, H. C.;
Douglas, C. J .; Morgan, C. D.; Degen, S. J .; Yao, L. J . J . Org. Chem.
1999, 64, 690. (b) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas,
C. J .; McLaughlin, M. J .; Mulder, J . A.; Yao, L. J . Org. Lett. 1999, 1,
509. (c) Wei, L.-L.; Xiong, H.; Douglas, C. J .; Hsung, R. P. Tetrahedron
Lett. 1999, 6903. (d) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas,
C. J .; Xiong, H.; Mulder, J . A. Org. Lett. 1999, 1, 1237-1240. (e)
Douglas, C. J .; Sklenicka, H. M.; Shen, H. C.; Mathias, D. S.; Golding,
G. M.; Hsung, R. P.; Degen, S. J .; Morgan, C. D.; Mueller, K. L.; Seurer,
L. M.; Shih, R. A. Tetrahedron 1999, 55, in press.
(11) Degen, S. J .; Mueller, K. L.; Shen, H. C.; Mulder, J . A.; Golding,
G. M.; Wei, L.-L.; Zificsak, C. A.; Hsung, R. P. Bioorg. Med. Chem.
Lett. 1999, 973.
(12) Summers, W. K.; Majovski, L. V.; Marsh, G. M.; Tachiki, K.;
Kling, A. N. Engl. J . Med. 1986, 315, 1241.
(13) For some examples see: (a) Grinberg, L. N.; Newmark, H.;
Kitrossky, N.; Rahamim, E.; Chevion, M.; Rachmilewitz, E. A. Biochem.
Pharmacol. 1997, 54, 973. (b) Leanderson, P.; Faresjo¨, A. O.; Tagesson,
C. Free Radical Biol. Med. 1997, 23, 235. (c) Agullo, G.; Payrastre, L.
G.; Manenti, S.; Viala, C.; Re´sme´sy, C.; Chap, H.; Payraste, B. Biochem.
Pharmacol. 1997, 53, 1649. (d) Fotsis, T.; Pepper, M. S.; Aktas, E.;
Breit, S.; Rasku, S.; Adlercreutz, H.; Wa¨ha¨la¨, K.; Montesano, R.;
Scheweigerer, L. Cancer Res. 1997, 57, 2916. (e) Wright, J . S.;
Carpenter, D. J .; McKay, D. J .; Ingold, K. U. J . Am. Chem. Soc. 1997,
119, 4245.
(14) (a) Mahmood, N.; Piacent, S.; Pizza, C.; Burke, A.; Khan, A. I.;
Hay, A. J . Biochem. Biophys. Res. Commun. 1996, 229, 73. (b) Li, B.
Q.; Fu, T.; Yan, Y. D.; Baylor, N. W.; Ruscetti, F. W.; Kung, H. F. Cell.
Mol. Biol. Res. 1993, 39, 119.
(9) For leading references see: (a) Obata, R.; Sunazuka, T.; Li, Z.
R.; Tian, Z. M.; Harigava, Y.; Tabata, N.; Tomoda, H.; O˜ mura, S. J .
Antibiot. 1996, 49, 1133. (b) Smith, A. B., III; Kinsho, T.; Sunazuka,
T.; O˜ mura, S. Tetrahedron Lett. 1996, 6461. (c) Nagamitsu, T.;
Sunazuka, T.; Obata, R.; Tomoda, H.; Tanaka, H.; Harigaya, Y.;
O˜ mura, S.; Smith, A. B., III. J . Org. Chem. 1995, 60, 8126. (d) Parker,
K. A.; Resnick, L. J . Org. Chem. 1995, 60, 5726.
(10) For total syntheses of forskolin see: (a) Corey, E. J .; J ardine,
P. D. S.; Rohloff, J . C. J . Am. Chem. Soc. 1988, 110, 3672. (b) Ziegler,
F. E.; J aynes, B. H.; Saindane, M. T. J . Am. Chem. Soc. 1987, 109,
8115.
(15) (a) Nohara, A. Tetrahedron Lett. 1974, 1187. (b) Nohara, A.;
Umetani, T.; Sanno, Y. Tetrahedron Lett. 1973, 1995. (c) Goerlitzer,
K.; Dehne, A. Arch. Pharm. (Weinheim, Ger.) 1984, 317, 448.
10.1021/jo991031j CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/22/1999

Notes
J . Org. Chem., Vol. 64, No. 23, 1999 8737
Sch em e 1
Sch em e 2
did, however, isolate the isoxazole 7, in most cases as off-
white solids that are completely insoluble in most organic
solvents except DMSO and EtOH.
The isoxazole 7 has been reported but only as a minor
product,15 and given the aromatic nature of isoxazole, its
formation could be readily rationalized as shown in
Scheme 1. Nevertheless, as suggested by the reported
procedures,15a these isoxazoles (7) were heated in DMSO16
at 85 °C in an attempt to crack open the aromatic
isoxazole ring and force the reaction pathway towards
the desired 3-cyano-4-benzopyrones (8). These efforts also
failed in leading to the desired 3-cyano-4-benzopyrones
(8) in significant yields after taxing chromatographic
purifications. Although we did manage a 67% yield on
one occasion (X ) 6,8-dimethyl), this effort was not again
repeated.
Since literature procedures proved to be unsuccessful
in our hands, we turned our attention to a variety of other
approaches for the synthesis of nitriles.17 For example,
various oxidations of N,N-dimethylhydrazone derivatives
with m-CPBA or MMPP in an attempt to eliminate
N-oxide intermediates (a Cope-like elimination) afforded
the desired 3-cyano-4-benzopyrones in very low yields.18
We also tried to use base-promoted elimination of to-
sylimines and were met with difficulties, especially in
preparations of tosylimines.19 In addition, we attempted
to prepare these 3-cyano-4-benzopyrones using palladium-
catalyzed cross-coupling reactions, but these preliminary
studies were also unsuccessful.20,21
By examining the formation of isoxazole (6 f 9 f 7 in
Scheme 1), we became aware that if the proposed
mechanistic pathway to the isoxazole is feasible, then the
key is to prevent its formation by blocking the hydroxyl
group. Although it was not possible to isolate the oxime
intermediates (6), O-alkyl oximes may be isolated in this
scenario because the initial cyclization could be arrested.
As shown in Scheme 2, when 3-formyl-4-benzopyrones
were refluxed in 95% EtOH in the presence of H2NOMe-
HCl and a catalytic amount of concentrated HCl, a
variety of desired O-methyl oximes 10-18 were isolated
quantitatively as a mixture of syn and anti isomers (∼2:1
ratio in favor of the anti isomer). Although the syn and
anti isomers of these O-methyl oximes could be sepa-
rated, such separations were not pursued because we
were interested in the synthesis of nitrile compounds.
Various elimination conditions were examined in the
attempt to prepare 3-cyano-4-benzopyrones from these
O-methyl oximes. Although there are ample precedents
for nitrile synthesis from O-alkyl oximes, it is surprising
to find that most of these involve either base-induced
elimination22 or thermal elimination at an extremely high
temperature.23,24 There are essentially no examples of an
acid-promoted elimination of O-methyl oximes. Because
base-induced elimination was not successful,25 a range
of acids such as p-TsOH, CSA, TFA, HCl, and HNO3 were
examined using various solvents and temperatures. The
(16) Both anhydrous and wet DMSO were used, but neither condi-
tion was fruitful.
(17) For
a
review see: Falbe, J .; Bauer, W. In Methoden Der
(21) (a) Shiao, M.-J .; Shyu, L.-M.; Chen, C.-F. Heterocycles 1990,
31, 523. (b) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.;
Pagh, L. M.; Wepsiec, J . P. J . Org. Chem. 1998, 63, 8224.
(22) For examples of base-promoted elimination of O-methyl oximes
see: (a) Hegarty, A. F.; Tuohey, P. J . J . Chem. Soc., Perkin Trans. 2
1980, 1313. (b) Itsuno, S.; Miyazaki, K.; Ito, K. Tetrahedron 1986, 27,
3033.
(23) For examples of thermal elimination of O-methyl oximes see:
(a) Hickson, C. L.; McNab, H. J . Chem. Soc. Perkin Trans. 1 1984,
1569. (b) Leardini, R.; Mcnab, H.; Nanni, D.; Parsons, S.; Reed, D.;
Tenan, A. G. J . Chem. Soc., Perkin Trans. 1 1998, 1833.
(24) For an example of photochemically induced elimination of
O-methyl oximes see: Pratt, A. C.; Abdul- Majid, Q. J . Chem. Soc.,
Perkin Trans. 1 1987, 359.
Organischen Chemie (Houben-Weyl); Erweiterungs-u. Folgebd. zur 4.
Aufl., Bd.E5. Georg Thieme: Stuttgart, New York, 1985; pp 1322-
1371.
(18) (a) Mlochowski, J .; Giurg, M.; Uher, M.; Korenova, A.; Vegh,
D. J . Prakt. Chem. 1996, 338, 65. (b) Ferna´ndez, R.; Gasch, C.;
Lassaletta, J .-M.; Liera, J .-M.; Va´zquez, J . Tetrahedron Lett. 1993, 141.
(c) D´ıez, E.; Ferna´ndez, R.; Gasch, C.; Lassaletta, J .-M.; Liera, J .-M.;
Mart´ın-Zamora, E.; Va´zquez, J . J . Org. Chem. 1997, 62, 5144.
(19) Glover, E. E.; Rowbottom, K. T. J . Chem. Soc., Perkin Trans. 1
1976, 367.
(20) 3-Bromo- or 3-iodo-4-benzopyrone was reacted with KCN,
CuCN, or NaCN under
conditions, but the only discernible product has been the homo-coupling
product. Regeuiro-Ren, A.; Zificsak, C. A.; Hsung, R. P. Unpublished
results.
a series of palladium-catalyzed coupling
(25) These O-methyl oximes were not very stable under basic
conditions.

8738 J . Org. Chem., Vol. 64, No. 23, 1999
Notes
Sch em e 3
Sch em e 4
We have described here a practical synthesis of a
variety of substituted 3-cyano-4-benzopyrones. Given the
synthetic and medicinal interest of these compounds, this
preparation should be significant in future studies utiliz-
ing these 4-benzopyrone derivatives as dienophiles for
[4 + 2] cycloaddition reactions.
Exp er im en ta l Section
All reagents were obtained from commercial suppliers and
used without further purification unless otherwise indicated.
DMF and benzene were distilled from calcium hydride (CaH2)
under nitrogen. The thin-layer chromatography (TLC) analysis
was done using EM Science silica gel-60 plates (0.25 mm in
thickness) with F254 as the fluorescence indicator. The eluted
plates were developed under UV detector and/or stained with
either an aqueous solution of potassium permanganate (KMnO4)
or an alcoholic solution of phosphomolybdic acid (PMA). Chro-
matographic purifications were performed on EM Science silica
gel (230-400 mesh) by the flash technique.27 All reactions were
carried out under either argon or nitrogen in oven (150 °C)-dried
or flame-dried glassware.
Gen er a l P r oced u r e for P r ep a r a tion of 3-Cya n o-4-ben -
zop yr on es. P r ep a r a tion of O-Meth yl Oxim es. To a hetero-
geneous mixture of 3-formyl-4-benzopyrone (5.0-10.0 mmol) and
H2NOMe-HCl (1.25 equiv) in 20-50 mL of 95% EtOH was
added 1-3 drops of concentrated HCl (∼12 N). The mixture was
refluxed for 3-6 h, and in most cases, a homogeneous pale-yellow
solution was obtained. The progress of the reaction could be
monitored by TLC (5% Et2O in CH2Cl2), but the reaction was
essentially complete within 3 h. In addition, overheating did not
lead to lower yield since these O-methyl oximes are very robust.
At the end of the reaction, the mixture was concentrated to
dryness under reduced pressure. The crude solid was filtered
through a small pad of silica gel using 2-3% Et2O in CH2Cl2 as
the eluting solvent system. After the solvent was evaporated
under reduced pressure and the solids were dried on a high-
vacuum pump, an off-white solid was obtained and characterized
as the desired syn/anti isomeric O-methyl oximes (yield g 95%
in all cases).
P r ep a r a tion of 3-Cya n o-4-ben zop yr on es. To a homoge-
neous solution of the O-methyl oxime prepared above (0.5-1.0
mmol) in anhydrous benzene (80-160 mL) was added concen-
trated H2SO4 (195.0-240.0 mg or 100.0-130.0 µL with d )
∼1.84). The reaction mixture was refluxed vigorously, and the
resulting methanol byproduct was removed by using a Dean-
Stark apparatus filled with anhydrous 4 Å molecular sieves. The
reaction progress was monitored carefully with TLC analysis
(25% or 50% EtOAc in hexane). The product has a lower Rf,
whereas the starting material has a higher Rf (one spot in 25%
EtOAc in hexane but two spots in 5% Et2O in CH2Cl2 for both
syn and anti isomers). When the starting material was mostly
consumed and a decomposition (close to the baseline) occurred
according to the TLC analysis, the reaction was terminated by
optimized condition would eventually involve refluxing
a benzene solution of an appropriate O-methyl oxime in
the presence of 195.0-240.0 mg (100.0-130.0 µL) of
concentrated H2SO4 per 1.0 mmol of the starting O-
methyl oxime and a Dean-Stark trap packed with 4 Å
sieves to trap out the methanol (Scheme 3).
The reaction progress should be monitored closely by
TLC. It was found that prolonged refluxing can reduce
the yield significantly because a slow decomposition of
the nitrile product did occur under these conditions.
These reactions were routinely terminated when there
were still small amounts of starting materials left. Hence,
isolated yields for these elimination reactions were
consistently within the range of 45%-75% depending
upon the termination point. Nevertheless, we were able
to achieve preparations of 3-cyano-4-benzopyrones 19-
27 (Scheme 3) through this protocol in a consistent
manner. Both syn and anti isomers of O-methyl oximes
undergo this acid-promoted elimination with relatively
similar ease.
Given this preparation of 3-cyano-4-benzopyrones from
3-formyl-4-benzopyrones via the corresponding O-methyl
oxime derivatives, it is then possible to construct many
3-cyano-4-benzopyrones with various substitution pat-
terns on the aromatic ring because the starting 3-formyl-
4-benzopyrones can be readily prepared from available
hydroxyacetophenones.15b As shown in Scheme 4, the
starting 2′-hydroxy-1′-acetonaphthone could be converted
into the 3-formyl-4-naphthopyrone 29 in 96% yield under
the Vilsmeier conditions. Following another quantitative
formation of the O-methyl oxime 30, the desired 3-cyano-
4-naphthopyrone 31 was obtained in 62% yield under the
elimination conditions described above and 86% yield
based on recovered starting material. The compound 31
is an important intermediate to a class of therapeutics
that exhibit potent antiallergic activity.26
(26) (a) Nohara, A.; Kuriki, H.; Saijo, T.; Sugihara, H.; Kanno, M.;
Sanno, Y. J . Med. Chem. 1977, 20, 0, 141. (b) Nohara, A.; Ishiguro, T.;
Ukawa, K.; Sugihara, H.; Maki, Y.; Sanno, Y. J . Med. Chem. 1985,
20, 559.
(27) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Notes
J . Org. Chem., Vol. 64, No. 23, 1999 8739
cooling to room temperature. If necessary, 1H NMR analysis was
also useful to determine the extent of desired elimination and
decomposition promoted by the acid. The reaction duration
usually falls in the range of 8-36 h. If severe precipitation or
gummy residue occurs, the final yield would likely be low. After
cooling to room temperature, the mixture was first filtered
through a small bed of silica gel using 25% EtOAc in hexane as
the eluting solvent. The solvent was concentrated under reduced
pressure, and the residue was purified by flash silica gel column
chromatography27 (gradient solvent system, 0-25% EtOAc in
hexane) to provide the desired pyrones.
Ch a r a cter iza tion s of O-Meth yl Oxim es 10-18 a n d 30.
6-Isop r op yl-4-oxo-4H-1-ben zop yr a n -3-ca r boxa ld eh yd e 3-O-
m eth yl oxim e (10): Rf ) 0.46 (25% EtOAc in hexane); 1H NMR
(300 MHz, CDCl3) syn δ 1.29 (d, 6 H, J ) 6.9 Hz), 3.03 (septet,
1 H, J ) 6.9 Hz), 4.05 (s, 3 H), 7.40 (dd, 1 H, J ) 2.4, 8.7 Hz),
7.57 (dd, 1 H, J ) 1.8, 8.7 Hz), 7.82 (s, 1 H), 8.08 (d, 1 H, J ) 2.1
Hz), 9.36 (s, 1 H); anti δ 1.29 (d, 6 H, J ) 6.9 Hz), 3.03 (septet,
1 H, J ) 6.9 Hz), 3.94 (t, 3 H, J ) 0.9 Hz), 7.57 (dd, 1 H, J )
1.8, 8.7 Hz), 8.08 (d, 1 H, J ) 2.1 Hz), 8.38 (d, 1 H, J ) 0.9 Hz);
13C NMR (75 MHz, CDCl3) δ 23.9, 33.8, 62.1, 62.8, 117.0, 118.2,
122.8, 123.0, 123.8, 133.0, 133.2, 136.9, 141.4, 146.8, 152.8, 160.2,
175.7, (missing 11 signals because of overlap); IR (neat) cm-1
2962m, 1652s, 1619m; MS (EI) m/e (% relative intensity) 245
(7) M+, 215 (19), 216 (100). Anal. Calcd for C14H15NO3: C 68.56,
H 6.16, N 5.71. Found: C 68.70, H 6.28, N 5.64.
M+, 191 (16), 192 (100). Anal. Calcd for C11H8FNO3: C 59.73, H
3.65, N 6.33. Found: C 59.60, H 3.75, N 6.08.
6-Ch lor o-7-m et h yl-4-oxo-4H -1-b en zop yr a n -3-ca r b oxa l-
d eh yd e 3-O-m eth yl oxim e (15): Rf ) 0.44 (25% EtOAc in
hexane); mp 150-153 °C; 1H NMR (300 MHz, CDCl3) syn δ 2.49
(s, 3 H), 4.05 (s, 3 H), 7.35 (s, 1 H), 7.76 (s, 1 H), 8.36 (s, 1 H),
9.32 (s, 1 H); anti δ 2.49 (s, 3 H), 3.95 (s, 3 H), 7.36 (s, 1 H), 8.15
(s, 1 H), 8.25 (s, 1 H), 8.36 (s, 1 H); 13C NMR (75 MHz, CDCl3)
δ 21.0, 62.3, 63.1, 115.5, 117.3, 120.3, 123.1, 123.2, 125.8, 126.0,
132.6, 132.7, 136.5, 141.0, 143.6, 143.9, 152.9, 154.1, 154.6, 160.3,
174.4 (missing three signals because of overlap); IR (neat) cm-1
3070w, 1649s, 1620m; MS (EI) m/e (% relative intensity) 251
(5) M+, 222 (34), 221 (19), 220 (100). Anal. Calcd for C12H10
-
ClNO3: C 57.27, H 4.01, N 5.57. Found: C 57.43, H 4.14, N 5.55.
6,8-Dim e t h yl-4-oxo-4H -1-b e n zop yr a n -3-c a r b oxa ld e -
h yd e 3-O-m eth yl oxim e (16): Rf ) 0.41 (25% EtOAc in hexane);
mp 103-106 °C; 1H NMR (300 MHz, CDCl3) syn δ 2.37 (s, 3 H),
2.40 (s, 3 H), 4.02 (s, 3 H), 7.29 (s, 1 H), 7.76 (s, 1 H), 8.38 (s, 1
H), 9.34 (s, 1 H); anti δ 2.37 (s, 3 H), 2.40 (s, 3 H), 3.92 (s, 3 H),
7.29 (s, 1 H) 7.79 (s, 1 H), 8.25 (s, 1 H), 8.38 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 15.4, 15.5, 21.0, 62.2, 62.9, 115.2, 116.8, 123.0,
123.2, 123.7, 123.8, 127.6, 135.2, 135.3, 136.4, 136.6, 137.1, 141.6,
152.6, 153.2, 153.2, 160.0, 175.8 (missing three signals because
of overlap); IR (neat) cm-1 3064w, 2971w, 1650s, 1620m; MS
(EI) m/e (% relative intensity) 231 (7) M+, 201 (17), 200 (100).
Anal. Calcd for C13H13NO3: C 67.52, H 5.67, N 6.06. Found: C
67.50, H 5.78, N 5.95.
4-Oxo-4H-1-ben zop yr a n -3-ca r boxa ld eh yd e 3-O-m eth yl
oxim e (11): Rf ) 0.36 (25% EtOAc in hexane); mp 75-77 °C;
1H NMR (300 MHz, CDCl3) syn δ 4.05 (s, 3 H), 7.40-7.49 (m, 2
H), 7.67-7.72 (m, 1 H) 7.80 (s, 1 H),8.24 (m, 1 H), 9.37 (s, 1 H);
anti δ 3.95 (s, 3 H), 7.40-7.49 (m, 2 H), 7.67-7.72 (m, 1 H),
8.24 (m, 1 H), 8.29 (s, 1 H), 8.41 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 62.1, 62.9, 115.5, 117.2, 118.3, 124.0, 125.7, 126.0,
126.2, 134.0, 134.2, 136.7, 141.09, 141.13, 152.9, 155.7, 156.2,
160.2, 160.3, 175.4, (missing two signals because overlap); IR
(neat) cm-1 2941w, 1661s, 1622m; MS (EI) m/e (% relative
intensity) 203 (7) M+, 173 (16), 172 (100). Anal. Calcd for C11H9-
NO3: C 65.02, H 4.46, N 6.89. Found: C 65.11, H 4.60, N 6.86.
6-Ch lor o-4-oxo-4H-1-ben zop yr a n -3-ca r boxa ld eh yd e 3-O-
m eth yl oxim e (12): Rf ) 0.43 (25% EtOAc in hexane); mp 97-
100 °C; 1H NMR (300 MHz, CDCl3) syn δ 4.05 (s, 3 H), 7.44 (dd,
1 H, J ) 2.1, 9.0 Hz), 7.64 (dd, 1 H, J ) 2.4, 9.9 Hz), 7.77 (s, 1
H), 8.20 (d, 1 H, J ) 2.4 Hz), 9.37 (s, 1 H); anti δ 3.95 (s, 3 H),
7.44 (dd, 1 H, J ) 2.1, 9.0 Hz), 7.63 (dd, 1 H, J ) 2.4, 9.0 Hz),
8.20 (d, 1 H, J ) 2.4 Hz), 8.26 (s, 1 H), 8.41 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 62.2, 63.0, 115.5, 117.4, 120.0, 120.1, 124.9,
125.4, 125.7, 131.8, 134.3, 134.5, 136.3, 136.2, 140.7, 152.9, 154.0,
154.5, 160.2, 160.3, 174.2 (missing one signal because overlap);
IR (neat) cm-1 2937w, 1651s, 1616m; MS (EI) m/e (% relative
intensity) 237 (6) M+, 208 (32), 207 (100). Anal. Calcd for C11H8-
ClNO3: C 55.60, H 3.39, N 5.89. Found: C 55.31, H 3.60, N 5.83.
6,8-D ib r o m o -4-o x o -4H -1-b e n zo p y r a n -3-c a r b o x a ld e -
h yd e 3-O-m eth yl oxim e (17): Rf ) 0.53 (25% EtOAc in hexane);
mp 148-150 °C; 1H NMR (300 MHz, CDCl3) syn δ 4.07 (s, 3 H),
8.03 (d, 1 H, J ) 2.4 Hz), 8.30 (d, 1 H, J ) 2.4 Hz), 8.48 (s, 1 H),
9.46 (s, 1 H); anti δ 3.96 (s, 3 H), 8.03 (d, 1 H, J ) 2.4 Hz), 8.22
(s, 1 H), 8.30 (d, 1 H, J ) 2.4 Hz), 8.48 (s, 1 H); 13C NMR (75
MHz, CDCl3) δ 62.5, 63.3, 113.30, 113.33, 115.8, 117.9, 119.2,
119.3, 126.2, 126.3, 128.2, 128.5, 135.9, 140.0, 140.1, 140.3, 153.0,
160.3, 173.8 (missing three signals because of overlap); IR (neat)
cm-1 3070w, 2940w, 1659s, 1614w; MS (EI) m/e (% relative
intensity) 363 (5), 361 (11), 359 (5) M+, 332 (49), 331 (20), 330
(100). Anal. Calcd for C11H7Br2NO3: C 36.60, H 1.95, N 3.88.
Found: C 36.73, H 1.86, N 3.88.
6,8-D ic h lo r o -4-o x o -4H -1-b e n zo p y r a n -3-c a r b o x a ld e -
h yd e 3-O-m eth yl oxim e (18): Rf ) 0.56 (25% EtOAc in hexane);
mp 146-149 °C; 1H NMR (300 MHz, CDCl3) syn δ 4.05 (s, 3 H),
7.70 (d, 1 H, J ) 2.4 Hz), 8.06 (d, 1 H, J ) 2.4 Hz), 8.45 (s, 1 H),
9.42 (s, 1 H); anti δ 3.94 (s, 3 H), 7.71 (d, 1 H, J ) 2.4 Hz), 8.06
(d, 1 H, J ) 2.4 Hz), 8.19 (s, 1 H), 8.45 (s, 1 H); 13C NMR (75
MHz, CDCl3) δ 62.5, 63.2, 115.8, 117.9, 124.3, 124.8, 125.8, 125.9,
131.5, 131.6, 134.3, 134.5, 135.8, 140.3, 150.7, 152.9, 160.1, 173.8,
173.9 (missing three signals because of overlap); IR (neat) cm-1
3073w, 2946w, 1665s; MS (EI) m/e (% relative intensity) 271 (6)
M+, 242 (65), 240 (100). Anal. Calcd for C11H7Cl2NO3: C 48.56,
H 2.59, N 5.15. Found: C 48.35, H 2.66, N 5.02.
6-Meth oxy-4-oxo-4H-1-ben zopyr an -3-car boxaldeh yde 3-O-
m eth yl oxim e (13): Rf ) 0.33 (25% EtOAc in hexane); mp 119-
1-Oxo-1H-n a p h t h o[2,1-b]p yr a n -2-ca r b oxa ld eh yd e (29).
The aldehyde 29 was prepared according to literature procedures:
15b Rf ) 0.51 (5% Et2O in CH2Cl2); mp 188-190 °C; lit. mp 192-
1
121 °C; H NMR (300 MHz, CDCl3) syn δ 3.94 (d, 3 H, J ) 2.7
1
Hz), 4.04 (s, 3 H), 7.27 (dd, 1 H, J ) 3.0, 8.9 Hz), 7.41 (d, 1 H,
J ) 9.3 Hz), 7.60 (d, 1 H, J ) 3.0 Hz), 7.82 (s, 1 H), 9.35 (s, 1 H);
anti δ 3.90 (s, 3 H), 3.94 (d, 3 H, J ) 2.7 Hz), 7.27 (dd, 1 H, J )
3.0, 9.0 Hz), 7.42 (d, 1 H, J ) 9.0 Hz), 7.59 (d, 1 H, J ) 3.0 Hz),
8.31 (s, 1 H), 8.40 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 56.0,
62.1, 62.8, 105.1, 105.2, 105.3, 105.4, 114.8, 116.5, 119.7, 124.1,
124.7, 136.9. 137.0, 141.3, 141.4, 151.1, 152.7, 157.4, 159.9, 160.0,
175.3 (missing two signals because of overlap); IR (neat) cm-1
3085w, 2940w, 1651s, 1615m; MS (EI) m/e (% relative intensity)
233 (12) M+, 202 (100). Anal. Calcd for C12H11NO4: C 61.80, H
4.75, N 6.01. Found: C 62.00, H 4.87, N 6.11.
194 °C; H NMR (300 MHz, CDCl3) δ 7.56 (d, 1 H, J ) 9.0 Hz),
7.65-7.71 (m, 1 H), 7.78-7.84 (m, 1 H), 7.95 (dd, 1 H, J ) 1.3,
8.1 Hz), 8.16 (d, 1 H, J ) 9.0 Hz), 8.56 (s, 1 H), 10.00 (dd, 1 H,
J ) 0.6, 8.6 Hz), 10.51 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ
117.3, 118.9, 122.2, 126.9, 127.4, 128.4, 129.8, 130.3, 131.0, 136.6,
157.5, 158.1, 177.7, 189.3; IR (neat) cm-1 2853w, 1697m, 1651s;
MS (EI) m/e (% relative intensity) 224 (14) M+, 196 (100). Anal.
Calcd for C14H8O3: C 75.00, H 3.60. Found: C 75.19, H 3.71.
Chemical Abstracts Registry Number: 23469-50-3 (supplied by
author).
1-Oxo-1H-n a p h th o[2,1-b]p yr a n -2-ca r boxa ld eh yd e 3-O-
m eth yl oxim e (30). Rf ) 0.62 (5% Et2O in CH2Cl2); mp 102-
6-F lu or o-4-oxo-4H-1-ben zop yr a n -3-ca r boxa ld eh yd e 3-O-
m eth yl oxim e (14): Rf ) 0.38 (25% EtOAc in hexane); mp 144-
147 °C; 1H NMR (300 MHz, CDCl3) syn δ 4.05 (s, 3 H), 7.38-
7.53 (m, 2 H), 7.88 (dd, 1 H, J ) 2.4, 8.1 Hz), 7.78 (s, 1 H), 9.39
(s, 1 H); anti δ 3.95 (s, 3 H), 7.38-7.53 (m, 2 H), 7.88 (dd, 1 H,
J ) 2.7, 8.1 Hz), 8.27 (d, 1 H, J -) 0.6 Hz), 8.42 (d, 1 H, J ) 0.3
Hz); 13C NMR (75 MHz, CDCl3) δ 62.2, 63.0, 110.9 (d, J ) 24.2
Hz), 111.0 (d, J ) 23.6 Hz), 114.9, 116.7, 120.6, 122.4, 125.2,
136.4, 136.3, 140.8, 140.8, 153.0, 158.2, 160.4, 161.5 (d, J ) 247.7
Hz), 174.7 (missing four signals because of overlap); IR (neat)
cm-1 2940w, 1652s; MS (EI) m/e (% relative intensity) 221 (7)
1
105 °C; H NMR (300 MHz, CDCl3) δ syn 3.95 (s, 3 H), 7.08 (d,
1 H, J ) 9.0 Hz), 7.42-7.36 (m, 1 H), 7.56-7.50 (m, 1 H), 7.59
(d, 1 H, J ) 8.0 Hz), 7.71 (d, 1 H, J ) 8.9 Hz), 7.73 (s, 1 H), 9.00
(s, 1 H), 9.68 (d, 1 H, J ) 8.6 Hz); anti 3.88 (s, 3 H), 7.10 (d, 1
H, J ) 9.1 Hz), 7.42-7.36 (m, 1 H), 7.56-7.50 (m, 1 H), 7.59 (d,
1 H, J ) 8.0 Hz), 7.71 (d, 1 H, J ) 8.9 Hz), 8.10 (s, 1 H), 8.19 (s,
1 H), 9.73 (d, 1 H, J ) 8.6 Hz); 13C NMR (75 MHz, CDCl3) δ
62.0, 62.7, 117.1, 117.5, 119.5, 126.8, 128.3, 128.4, 129.3, 129.4,
130.3, 130.7, 135.7, 135.9, 136.8, 141.4, 150.4, 156.9, 157.5, 157.8,
176.6, 176.7 (missing eight signals because of overlap); IR (neat)

8740 J . Org. Chem., Vol. 64, No. 23, 1999
Notes
cm-1 3079w, 2960w, 2932w, 1641s, 1610m; MS (EI) m/e (%
6,8-Dim eth yl-4-oxo-4H-1-ben zop yr a n -3-ca r bon itr ile (25):
Rf ) 0.22 (25% EtOAc in hexane); mp 182-184 °C; lit. mp 196-
198 °C; 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3 H), 2.46 (s, 3 H),
7.43 (s, 1 H), 7.87 (s, 1 H), 8.42 (s, 1 H). Chemical Abstracts
Registry Number: 50743-40-3 (supplied by author).
relative intensity) 253 (6) M+, 222 (100). Anal. Calcd for C15H11
-
NO3: C 71.14, H 4.38, N 5.53. Found: C 70.92, H 4.47, N 5.66.
Ch a r a cter iza tion s for 3-Cya n o-4-ben zop yr on es 19-27
a n d 31. 6-Isop r op yl-4-oxo-4H-1-ben zop yr a n -3-ca r bon itr ile
(19): Rf ) 0.24 (25% EtOAc in hexane); mp 119-120 °C; lit. mp
118-120 °C; 1H NMR (300 MHz, CDCl3) δ 1.30 (dd, 6 H, J )
1.2, 6.9 Hz), 3.05 (octet, 1 H, J ) 6.8 Hz), 7.46 (dd, 1 H, J ) 0.9,
8.4 Hz), 7.65 (ddd, 1 H, J ) 0.6, 1.5, 8.8 Hz), 8.08 (d, 1 H, J )
2.1 Hz), 8.37 (d, 1 H, J ) 1.2 Hz). Chemical Abstracts Registry
Number: 50743-32-3 (supplied by author).
4-Oxo-4H-1-ben zop yr a n -3-ca r bon itr ile (20): Rf ) 0.37
(50% EtOAc in hexane); mp 177-179 °C; lit. mp 177-178 °C;
1H NMR (300 MHz, CDCl3) δ 7.53 (t, 1 H, J ) 7.2 Hz), 7.54 (d,
1 H, J ) 8.4 Hz), 7.79 (m, 1 H), 8.26 (dd, 1 H, J ) 1.8, 8.4 Hz),
8.40 (d, 1 H, J ) 0.6 Hz). Chemical Abstracts Registry Number:
50743-17-4 (supplied by author).
6,8-Dibr om o-4-oxo-4H-1-ben zop yr a n -3-ca r bon itr ile (26):
Rf ) 0.49 (25% EtOAc in hexane); mp 191-194 °C; 1H NMR
(300 MHz, CDCl3) δ 8.13 (d, 1 H, J ) 2.4 Hz), 8.32 (d, 1 H, J )
2.4 Hz), 8.51 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 103.6, 111.5,
113.6, 121.0, 125.6, 128.3, 141.4, 151.8, 162.3, 170.8; IR (neat)
cm-1 3071w, 2224w, 1660s; MS (EI) m/e (% relative intensity)
331 (49), 329 (100), 327 (49) M+, 280 (43), 278 (83), 276 (43).
Anal. Calcd for C10H3NO2Br2: C 36.51, H 0.92, N 4.26. Found:
C 36.70, H 1.06, N 4.08.
6,8-Dich lor o-4-oxo-4H-1-ben zop yr a n -3-ca r bon itr ile (27).
Rf ) 0.21 (10% EtOAc in hexane); mp 166-168 °C; 1H NMR
(300 MHz, CDCl3) δ 7.82 (d, 1 H, J ) 2.4 Hz), 8.11 (d, 1 H, J )
2.4 Hz), 8.49 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 103.5, 111.3,
124.3, 125.1, 125.2, 133.2, 135.5, 150.2, 161.9, 170.7; IR (neat)
cm-1 3074w, 2241m, 1671s; MS (EI) m/e (% relative intensity)
241 (50), 240 (15) M+, 239 (75), 188 (100). Anal. Calcd for C10H3-
NO2Cl2: C 50.04, H 1.26, N 5.84. Found: C 49.94, H 1.16, N
5.69.
6-Ch lor o-4-oxo-4H-1-ben zop yr a n -3-ca r bon itr ile (21): Rf
) 0.35 (50% EtOAc in hexane); mp 211-213 °C; lit. mp 210-
1
213 °C; H NMR (300 MHz, CDCl3) δ 7.51 (d, 1 H, J ) 9.0 Hz),
7.73 (ddd, 1 H, J ) 0.6, 2.7, 8.7 Hz), 8.22 (d, 1 H, J ) 2.4 Hz),
8.40 (d, 1 H, J ) 0.6 Hz). Chemical Abstracts Registry Number:
50743-20-9 (supplied by author).
6-Meth oxy-4-oxo-4H-1-ben zop yr a n -3-ca r bon itr ile (22): Rf
) 0.24 (25% EtOAc in hexane); mp 184-186 °C; lit. mp 194-
1-Oxo-1H-n a p h th o[2,1-b]p yr a n -2-ca r bon itr ile (31): Rf )
0.40 (50% EtOAc in hexane); mp 182-184 °C, lit. mp 194.5-
195.5 °C; 1H NMR (300 MHz, CDCl3) δ 7.54 (d, 1 H, J ) 9.1
Hz), 7.68-7.73 (m, 1 H), 7.81-7.84 (m, 1 H), 7.97 (d, 1 H, J )
8.0 Hz), 8.20 (d, 9.1 Hz, 1 H), 8.46 (s, 1 H), 9.82 (dd, 0.6 Hz, 9.2
Hz, 1 H). Chemical Abstracts Registry Number: 50743-28-7
(supplied by author).
1
195 °C; H NMR (300 MHz, CDCl3) δ 3.92 (s, 3 H), 7.33 (dd, 1
H, J ) 3.0, 9.0 Hz), 7.36 (d, 1 H, J ) 9.0 Hz), 7.59 (d, 1 H, J )
3.0 Hz), 8.39 (s, 1 H). Chemical Abstracts Registry Number:
50743-21-0 (supplied by author).
6-F lu or o-4-oxo-4H-1-ben zop yr a n -3-ca r bon itr ile (23): Rf
1
) 0.34 (50% EtOAc in hexane); mp 172-174 °C; H NMR (300
MHz, CDCl3) δ 7.47-7.60 (m, 2 H), 7.90 (dd, 1 H, J ) 3.0, 7.7
Hz), 7.41 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 35.8, 102.7, 111.7,
121.1 (d, J ) 8.2 Hz), 123.8 (d, J ) 25.2 Hz), 125.0, 138.6, 152.2,
160.6 (d, J ) 250.6 Hz), 162.3, 171.9; IR (neat) cm-1 3070w,
2240w, 1660s, 1628m; MS (EI) m/e (% relative intensity) 189
(100) M+, 188 (14), 161 (20). Anal. Calcd for C10H4NO2F: C 63.50,
H 2.13, N 7.41. Found: C 63.49, H 2.36, N 7.28.
6-Ch lor o-7-m et h yl-4-oxo-4H -1-b en zop yr a n -3-ca r b on i-
tr ile (24): Rf ) 0.43 (50% EtOAc in hexane); mp 232-235 °C;
1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3 H), 7.43 (s, 1 H), 8.19 (s,
1 H), 8.36 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 20.7, 101.5,
113.5, 121.7, 122.4, 124.8, 132.8, 145.0, 154.3, 166.0, 172.0; IR
(neat) cm-1 3066w, 2247w, 1663s, 1621m; MS (EI) m/e (%
relative intensity) 219 (100) M+, 218 (10), 217 (26), 170 (24), 168
(74). Anal. Calcd for C11H6NO2Cl: C 60.16, H 2.75, N 6.38.
Found: C 59.94, H 2.91, N 6.14.
Ack n ow led gm en t. The authors would like to thank
the University of Minnesota for financial support in the
forms of Start-up Funds and Grant-in-Aid of Research,
Artistry and Scholarship (CUFS 1003-519-5984). C.A.Z.
thanks the University of Minnesota for a Departmental
Fellowship.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
O-methyl oximes 10-18 and 30 and 3-cyano-4-benzopyrones
19-27 and 31. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O991031J