Synthesis of spirodienones by intramolecular ipso-cyclization of N-methoxy-(4-halogenophenyl)amides using [hydroxy(tosyloxy)iodo]benzene in trifluoroethanol

Article abstract of DOI:10.1021/jo034318w

Spirodienones bearing the 1-azaspiro[4.5]decane ring system have been synthesized from N-methoxy-(4-halogenophenyl)amides by the intramolecular ipso attack of a nitrenium ion generated with [hydroxy(tosyloxy)iodo]-benzene in trifluoroethanol.

Full text of DOI:10.1021/jo034318w

Syn th esis of Sp ir od ien on es by
In tr a m olecu la r Ip so-Cycliza tion of
N-Meth oxy-(4-h a logen op h en yl)a m id es
Usin g [Hyd r oxy(tosyloxy)iod o]ben zen e in
Tr iflu or oeth a n ol
Etsuko Miyazawa, Takeshi Sakamoto, and
Yasuo Kikugawa*
Faculty of Pharmaceutical Sciences, J osai University,
1-1 Keyakidai, Sakado, Saitama 350-0295, J apan
kikugawa@josai.ac.jp
Received March 11, 2003
F IGURE 1. Natural products bearing 1-azaspiro[4.5]decane
skeleton.
Abstr a ct: Spirodienones bearing the 1-azaspiro[4.5]decane
ring system have been synthesized from N-methoxy-(4-
halogenophenyl)amides by the intramolecular ipso attack of
a nitrenium ion generated with [hydroxy(tosyloxy)iodo]-
benzene in trifluoroethanol.
TABLE 1. Syn th esis of
1-Meth oxy-1-a za sp ir o[4.5]d eca d ien on e (2a ) Hith er to
Rep or ted
TAN1251A-D,1 FR901483,2 lepadiformine,3 and cylin-
dricine4 isolated by Takeda Industries, by Fujisawa
Pharmaceutical Co., by Biard and co-workers, and by
Blackman and co-workers, respectively, are architectur-
ally interesting natural products which have a novel
1-azaspiro[4.5]decane skeleton (Figure 1). Construction
of the 1-azaspiro[4.5]decane skeleton has been achieved
by oxidative spirocyclizations of phenolic oxazolines,5 of
phenolic sulfonamides,6 and of N-methoxyamides7 via
N-methoxy-N-acylnitrenium ion intermediates using hy-
pervalent iodine compounds.
entry
1
conditions
(1) t-BuOCl
(2) Ag2CO3/TFA, ice cooling
PIFA/CH2Cl2, CH3OH, 0 °C
PIFA/TFEA, ice cooling
yield (%)
83a
2
3
72b
80c
Reference 8. Reference 7a. c Reference 10.
a
b
The last method has been the subject of our own
research. In this earlier work, we developed procedures
for the synthesis of the 1-azaspiro[4.5]decane skeleton
by intramolecular ipso attack of a nitrenium ion gener-
ated from an N-chloro-N-methoxyamide moiety appended
to the 4-methoxybenzene substrate.8 It is generally
accepted that the spirodienones are the major or the
exclusive products whenever the aromatic ring bears a
methoxy group para to the alkyl side chain (Table 1).7-10
This is a very useful transformation since the spiro
compounds so generated have proved to be valuable
intermediates for the synthesis of biologically important
compounds. To make the process even more versatile, we
have investigated the synthesis of substituted spiro-
dienones by this strategy using more readily accessible
starting compounds.
Because 4-halogenophenyl compounds are more readily
accessible than the corresponding methoxy compounds,
we have examined the synthesis of spirodienones using
N-methoxy-(4-halogenophenyl)amides (1) with hyper-
valent iodine compounds. Hypervalent iodine compounds
have low toxicity, are readily available, are easy to
handle, and are environmentally friendly.
The following experiment exemplifies the successful
outcome of these efforts. To 3-(4-fluorophenyl)-N-meth-
oxypropionamide (1a ) (0.5 mmol) in trifluoroethanol
(TFEA) (5 mL) was added [hydroxy(tosyloxy)iodo]benzene
(HTIB) (1.0 mmol) portionwise over 10 min. The solution
was stirred for 5 min with ice cooling. After usual
workup, 1-methoxy-1-azaspiro[4.5]deca-6,9-diene-2,8-di-
one (2a ) was obtained in 82% yield.
(1) Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. Int. Patent
PCT, WO91/13887, 1991.
(2) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J . Antibiot. 1996, 49, 37.
(3) Biard, J . F.; Guyot, S.; Roussakis, C.; Verbist, J . F.; Vercauteren,
J .; Weber, J . F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.
(4) Blackman, A. J .; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White,
A. H. Tetrahedron 1993, 49, 8645.
(5) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M.
A. J . Am. Chem. Soc. 2001, 123, 7534.
Several halogeno compounds (1) reacted in this way,
and the results are presented in Table 2. Generally
fluorine-substituted starting compounds give good re-
sults. Reactions of 1e and 1f gave the corresponding
spirobenzannulated compounds (2e and 2f) and a com-
plex mixture of benzannulated compounds in which
compound 3 could be isolated by careful column chroma-
tography (Table 2, entry 5).
(6) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M.
A. Tetrahedron Lett. 2002, 43, 5193.
(7) (a) Wardrop, D. J .; Zhang, W. Org. Lett. 2001, 3, 2353. (b)
Wardrop, D. J .; Basak, A. Org. Lett. 2001, 3, 1053.
(8) Kawase, M.; Kitamura, T.; Kikugawa, Y. J . Org. Chem. 1989,
54, 3394.
(9) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J . L.
Tetrahedron 1987, 43, 2577.
(10) Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. Heterocycles 2003,
59, 149.
10.1021/jo034318w CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/03/2003
J . Org. Chem. 2003, 68, 5429-5432
5429

TABLE 2. Syn th esis of Sp ir od ien on es fr om N-Meth oxy-(4-h a logen op h en yl)a m id es w ith HTIB in TF EA
SCHEME 1
Two equivalents of HTIB to 1b were needed to obtain
a high yield of 2b, and the starting compound was
recovered by use of 1.1 equiv of HTIB in 1 h (23%). Use
of phenyliodine(III) bis(trifluoroacetate) (PIFA) (2 equiv)
instead of HTIB gave 2b in low yield (54%). As for
solvents TFEA, (CF3)2CHOH, CHF2CF2CH2OH, and CF3-
COOH were suitable; among them TFEA is the solvent
of choice, while spirodienones were obtained in poor
yields using CH3CN and CHCl3. The reaction proceeds
through a cationic intermediate by the intramolecular
ipso attack of a nitrenium ion.11
A proposed mechanism is illustrated in Scheme 1.
Principally, the spirodienones are obtained whenever
the aromatic ring bears a highly electron-donating meth-
oxy group para to the alkyl side chain.7-10 However, the
influence of para substitution by halogen atoms on the
phenyl ring is of particular interest in view of the
opposing inductive and conjugative effects. Halogens are
considered to be electron-withdrawing groups due to their
electronegativity but at the same time they also have
nonbonded electron pairs, which stabilize the intermedi-
ate (4) through their “back-donation” ability and promote
further reaction.12 The degree of “back-donation” corre-
sponds to the yields of spirodienones and the best results
are obtained in the case of fluorine (Table 2, entry 9).
In conclusion, 2 bearing the 1-azaspiro[4.5]decane ring
system have been synthesized from N-methoxy-(4-halo-
genophenyl)amides with HTIB in TFEA probably because
(12) Olah, G. A.; Singh, B. P.; Liang, G. J . Org. Chem. 1984, 49,
2922; Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. J . Chem. Soc., Perkin
Trans. 2 1998, 7.
(11) Glover, S. A.; Rowbottom, C. A.; Scott, A. P.; Schoonraad, J . L.
Tetrahedron 1990, 46, 7247.
5430 J . Org. Chem., Vol. 68, No. 13, 2003

22.3), 169 (34.0), 141 (38.0), 127 (100). Anal. Calcd for C10H11
NO2F2: C, 55.81; H, 5.15; N, 6.51. Found: C, 55.73; H, 5.14; N,
6.44.
-
a halogen atom has a cation stabilizing effect and is a
good leaving group. These spirodienones, themselves of
potential synthetic interest, can be converted into 7-ox-
ygenated quinolone derivatives in acidic conditions through
the dienone-phenol rearrangement.13
3-(3,4-Diflu or op h en yl)-N-m et h oxyp r op ion a m id e (1e):
white crystals; mp 81-82 °C (Et2O); IR (KBr) 3230, 1660, 1520,
1280 cm-1; 1H NMR (DMSO-d6) δ 2.26 (t, J ) 7.5 Hz, 2H), 2.82
(t, J ) 7.5 Hz, 2H), 3.53 (s, 3H), 6.98-7.13 (m, 1H), 7.20-7.40
(m, 2H), 10.99 (br s, 1H); 13C NMR (DMSO-d6) δ 29.7, 33.5, 63.1,
117.0 (dd, J C-F ) 16.2, 5.0 Hz), 124.9 (dd, J C-F ) 6.1, 3.3 Hz),
138.4 (dd, J C-F ) 5.9, 3.2 Hz), 147.4 (dd, J C-F ) 242.4, 12.5 Hz),
148.9 (dd, J C-F ) 243.9, 12.8 Hz), 167.7; EI-MS m/z 215 (M+,
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. NMR
spectra were recorded at 270 MHz (1H) and 68 MHz (13C) with
TMS as the internal reference. Mass spectra were measured with
direct inlet system at 70 eV. Elemental analyses were performed
in the Microanalytical Laboratory of this University.
35.7), 169 (34.0), 141 (58.4), 127 (100). Anal. Calcd for C10H11
NO2F2: C, 55.81; H, 5.15; N, 6.51. Found: C, 55.74; H, 5.12; N,
6.49.
-
Ma ter ia ls. Compounds 1a ,b,d ,e were prepared by the Schot-
ten-Baumann reaction of the corresponding carboxylic acid
chlorides with methoxyamine hydrochloride in diethyl ether-
H2O.8 These carboxylic acids, except for commercially available
3,4-difluorophenylpropionic acid, were prepared by catalytic
hydrogenation (Pd/C) of the corresponding cinnamic acid deriva-
tives. Compounds 1c,g,h were prepared by catalytic hydrogena-
tion (Pd/C) of the corresponding N-methoxycinnamamides, which
were synthesized by the Schotten-Baumann reaction of the
corresponding cinnamic acid chlorides with methoxyamine
hydrochloride in diethyl ether-H2O. Compound 1f was prepared
similarly from 3-methyl-4-fluorocinnamic acid which was syn-
thesized from 2-fluoro-3-methylbenzaldehyde with malonic acid
in pyridine.14 Compounds 1i and 1j were prepared similarly from
the corresponding acids which were synthesized from the
corresponding ketones by Zn-NH4OH reduction.15
3-(4-F lu or o-3-m et h ylp h en yl)-N-m et h oxyp r op ion a m id e
(1f): white crystals; mp 58-59 °C (AcOEt/hexane); IR (KBr)
1
3230, 1660, 1515, 1210 cm-1; H NMR (DMSO-d6) δ 2.16-2.26
(m, 5H), 2.75 (t, J ) 7.6 Hz, 2H), 3.52 (s, 3H), 6.98-7.14 (m,
3H), 10.95 (br s, 1H); 13C NMR (DMSO-d6) δ 14.2 (d, J C-F ) 3.3
Hz), 29.8, 34.0, 63.0, 114.4 (d, J C-F ) 21.8 Hz), 123.5 (d, J C-F
)
17.3 Hz), 127.8 (d, J C-F ) 7.8 Hz), 132.0 (d, J C-F ) 4.5 Hz), 136.4,
159.0 (d, J C-F ) 239.9 Hz), 167.8; EI-MS m/z 211 (M+, 20.2),
165 (14.7), 137 (18.8), 123 (100). Anal. Calcd for C11H14NO2F:
C, 62.55; H, 6.68; N, 6.63. Found: C, 62.44; H, 6.64; N, 6.59.
3-(2,4-Dich lor op h en yl)-N-m et h oxyp r op ion a m id e (1g):
white crystals; mp 59.5-60 °C (AcOEt/hexane); IR (KB) 3170,
1
1650, 1540, 1480, 1080, 1050 cm-1; H NMR (DMSO-d6) δ 2.26
(t, J ) 7.6 Hz, 2H), 2.91 (t, J ) 7.6 Hz, 2H), 3.54 (s, 3H), 7.28-
7.42 (m, 2H), 7.57 (s, 1H), 11.02 (br s, 1H); 13C NMR (DMSO-d6)
δ 27.9, 31.7, 63.1, 127.2, 128.4, 131.5, 131.7, 133.6, 137.1, 167.4;
EI-MS m/z 251 (M+ + 4, 0.31), 249 (M+ + 2, 0.68), 247 (M+, 0.50),
212 (51.4), 173 (51.0), 159 (100); FAB-MS (matrix NBA) m/z 248
(M+ + 1, 100). Anal. Calcd for C10H11NO2Cl2: C, 48.41; H, 4.47;
N, 5.65. Found: C, 48.45; H, 4.45; N, 5.66.
3-(4-F lu or op h en yl)-N-m eth oxyp r op ion a m id e (1a ): white
crystals; mp 55.5-56 °C (AcOEt/hexane); IR (KBr) 3150, 1650,
1510, 1220, 1070 cm-1 1H NMR (DMSO-d6) δ 2.23 (t, J ) 7.5
;
Hz, 2H), 2.81 (t, J ) 7.5 Hz, 2H), 3.53 (s, 3H), 7.09 (t, J H-F)H-H
) 8.9 Hz, 2H), 7.22 (dd, J H-H ) 7.6 Hz, J H-F ) 6.1 Hz, 2H),
10.96 (br s, 1H); 13C NMR (DMSO-d6) δ 29.8, 34.0, 63.0, 114.8
3-(3,4-Dich lor op h en yl)-N-m et h oxyp r op ion a m id e (1h ):
white crystals; mp 97-98 °C (Et2O); IR (KBr) 3240, 1660, 1525,
1475, 1140 cm-1; 1H NMR (DMSO-d6) δ 2.26 (t, J ) 7.3 Hz, 2H),
2.82 (t, J ) 7.3 Hz, 2H), 3.53 (s, 3H), 7.20 (d, J ) 8.0 Hz, 1H),
7.47 (s, 1H), 7.53 (d, J ) 8.0 Hz, 1H), 10.97 (br s, 1H); 13C NMR
(DMSO-d6) δ 29.4, 33.1, 62.9, 128.3, 128.5, 130.0, 130.1, 130.4,
141.8, 167.4; EI-MS m/z 251 (M+ + 4, 3.8), 249 (M+ + 2, 22.4),
247 (M+, 35.4), 201 (28.8), 173 (56.1), 159 (100). Anal. Calcd for
(d, J C-F ) 21.2 Hz), 129.9 (d, J C-F ) 7.8 Hz), 136.7 (d, J C-F
2.8 Hz), 160.5 (d, J C-F ) 240.4 Hz), 167.8; EI-MS m/z 197 (M+,
24.7), 151 (25.9), 123 (28.4), 109 (100). Anal. Calcd for C10H12
)
-
NO2F: C, 60.91; H, 6.13; N, 7.10. Found: C, 60.80; H, 6.12; N,
7.07.
3-(4-Ch lor op h en yl)-N-m eth oxyp r op ion a m id e (1b): white
crystals; mp 73-75 °C (Et2O/petroleum ether); IR (KBr) 3250,
1660, 1520, 1495, 1100 cm-1; 1H NMR (DMSO-d6) δ 2.23 (t, J )
7.5 Hz, 2H), 2.80 (t, J ) 7.5 Hz, 2H), 3.52 (s, 3H), 7.22 (d, J )
8.4 Hz, 2H), 7.33 (d, J ) 8.4 Hz, 2H), 10.96 (br s, 1H); 13C NMR
(DMSO-d6) δ 29.9, 33.7, 63.1, 128.1, 130.0, 130.4, 139.7, 167.7;
EI-MS m/z 215 (M+ + 2, 10.8), 213 (M+, 32.8), 167 (25.7), 139
(38.3), 125 (100). Anal. Calcd for C10H12NO2Cl: C, 56.21; H, 5.66;
N, 6.56. Found: C, 56.05; H, 5.62; N, 6.48.
3-(4-Br om op h en yl)-N-m eth oxyp r op ion a m id e (1c): white
crystals; mp 82-85 °C (Et2O); IR (KBr) 3240, 1655, 1520, 1490,
1075 cm-1; 1H NMR (DMSO-d6) δ 2.23 (t, J ) 7.4 Hz, 2H), 2.79
(t, J ) 7.4 Hz, 2H), 3.53 (s, 3H), 7.16 (d, J ) 7.8 Hz, 2H), 7.46
(d, J ) 7.8 Hz, 2H), 10.97 (br s, 1H); 13C NMR (DMSO-d6) δ
30.0, 33.6, 63.1, 118.9, 130.4, 130.9, 140.1, 163.7; EI-MS m/z 259
(M+ + 2, 33.5), 257 (M+, 34.1), 211 (37.2), 185 (38.6), 169 (100),
104 (38.7). Anal. Calcd for C10H12NO2Br: C, 46.53; H, 4.69; N,
5.43. Found: C, 46.64; H, 4.54; N, 5.34.
3-(2,4-Diflu or op h en yl)-N-m et h oxyp r op ion a m id e (1d ):
white crystals; mp 82-83 °C (Et2O); IR (KBr) 3150, 1660, 1500,
1095 cm-1; 1H NMR (DMSO-d6) δ 2.24 (t, J ) 7.6 Hz, 2H), 2.83
(t, J ) 7.6 Hz, 2H), 3.53 (s, 3H), 7.01 (td, J H-F)H-H ) 8.1, 2.4
Hz, 1H), 7.17 (td, J H-F ) 9.9 Hz, J H-H ) 2.4 Hz, 1H), 7.31 (q,
J H-F)H-H ) 8.1 Hz, 1H), 11.02 (br s, 1H); 13C NMR (DMSO-d6)
δ 23.6 (d, J C-F ) 1.9 Hz), 32.4, 63.1, 103.5 (t, J C-F ) 25.9 Hz),
111.1 (dd, J C-F ) 20.6, 3.3 Hz), 123.4 (dd, J C-F ) 16.1, 3.6 Hz),
131.5 (dd, J C-F ) 9.7, 6.4 Hz), 160.1 (dd, J C-F ) 211.3, 12.0 Hz),
160.7 (dd, J C-F ) 227.8, 12.0 Hz), 167.6; EI-MS m/z 215 (M+,
C
10H11NO2Cl2: C, 48.41; H, 4.47; N, 5.65. Found: C, 48.45; H,
4.51; N, 5.44.
2-(4-Flu or oben zyl)-N-m eth oxyben za m id e (1i): white crys-
tals; mp 115-115.5 °C (AcOEt/hexane); IR (KBr) 3140, 1640,
1520, 1235, 1045 cm-1; 1H NMR (CDCl3) δ 3.69 (s, 3H), 4.12 (s,
2H), 6.92 (t, J H-F)H-H ) 8.8 Hz, 2H), 7.11 (dd, J H-H ) 8.6 Hz,
J H-F ) 5.4 Hz, 2H), 7.17-7.27 (m, 2H), 7.28-7.42 (m, 2H), 8.55
(br s, 1H); 13C NMR (CDCl3) δ 37.9, 64.4, 115.0 (d, J C-F ) 21.2
Hz), 126.3, 127.4, 130.3 (d, J C-F ) 7.9 Hz), 130.7, 130.9, 132.4,
136.0 (d, J C-F ) 3.3 Hz), 139.8, 161.2 (d, J C-F ) 243.8 Hz), 167.4;
EI-MS m/z 259 (M+, 7.3), 227 (17.7), 213 (100), 183 (31.6). Anal.
Calcd for C15H14NO2F: C, 69.49; H, 5.44; N, 5.40. Found: C,
69.56; H, 5.37; N, 5.32.
2-(4-Ch lor oben zyl)-N-m eth oxyben za m id e (1j): white crys-
tals; mp 111-112 °C (AcOEt); IR (KBr) 3140, 1640, 1500, 1325,
1045 cm-1; 1H NMR (CDCl3) δ 3.69 (s, 3H), 4.12 (s, 2H), 7.08 (d,
J ) 8.6 Hz, 2H), 7.15-7.45 (m, 6H), 8.60 (br s, 1H); 13C NMR
(CDCl3) δ 38.0, 64.4, 126.4, 127.4, 128.3, 130.3, 130.8, 130.9,
131.8, 132.4, 138.8, 139.5, 167.4; EI-MS m/z 277 (M+ + 2, 3.5),
275 (M+, 10.2), 244 (22.3), 229 (100), 194 (66.5), 165 (43.9). Anal.
Calcd for C15H14NO2Cl: C, 65.34; H, 5.12; N, 5.08. Found: C,
65.55; H, 5.15; N, 5.08.
R ea ct ion of 3-(4-F lu or op h en yl)-N-m et h oxyp r op ion -
a m id e (1a ) w ith HTIB in TF EA. Typ ica l P r oced u r e. To 1a
(100 mg, 0.51 mmol) in TFEA (5 mL) was added HTIB (399 mg,
1.02 mmol) portionwise over 10 min under ice cooling in an argon
atmosphere. After the reaction mixture was stirred for 5 min,
10% Na2CO3 (20 mL) was added under cooling. The aqueous
layer was extracted with AcOEt (30 mL × 2), and the combined
organic layer was washed with brine (30 mL), dried over Na2-
(13) Kikugawa, Y.; Kitamura, T.; Kawase, M. J . Chem. Soc., Chem.
Commun. 1989, 525.
(14) Newman, M. S.; Zahm, H. V. J . Am. Chem. Soc. 1943, 65, 1097.
(15) Bradley, W.; Watkinson, L. J . J . Chem. Soc. 1956, 319.
J . Org. Chem, Vol. 68, No. 13, 2003 5431

SO4, and concentrated. The residue was chromatographed on a
column of silica gel with AcOEt as an eluent to give 2a (80 mg,
82%).
2.32-2.80 (m, 3H), 3.84 (s, 3H), 6.39 (dd, J ) 9.8, 1.8 Hz, 1H),
6.66 (d, J ) 1.8 Hz, 1H), 6.90 (d, J ) 9.8 Hz, 1H); 13C NMR
(CDCl3) δ 26.0, 27.1, 64.6, 64.9, 129.4, 130.5, 147.5, 154.6, 171.4,
182.8; EI-MS m/z 229 (M+ + 2, 2.6), 227 (M+, 6.9), 197 (53.2),
162 (100), 142 (47.5), 134 (54.1). Anal. Calcd for C10H10NO3Cl:
C, 52.76; H, 4.43; N, 6.15. Found: C, 52.60; H, 4.42; N, 6.00.
1-Meth oxy-1-a za sp ir o[4.5]d eca -6,9-d ien e-2,8-d ion e (2a ):
mp 129-131 °C (AcOEt) (lit.10 mp 130-132 °C).
6-Flu or o-1-m eth oxy-1-a za sp ir o[4.5]d eca -6,9-d ien e-2,8-d i-
on e (2d ): white crystals; mp 110-112 °C (AcOEt/hexane); IR
(KBr) 1730, 1680, 1655, 1365, 1165 cm-1;1H NMR (CDCl3) δ
2.12-2.70 (m, 4H), 3.78 (s, 3H), 6.04 (dd, J H-F ) 13.5 Hz, J H-H
7-Ch lor o-1-m et h oxy-1-a za sp ir o[4.5]d eca -6,9-d ien e-2,8-
d ion e (2h ): white crystals; mp 135-138 °C (AcOEt/hexane);
IR (KBr) 1720, 1680, 1315 cm-1;1H NMR (CDCl3) δ 2.24 (t, J )
7.9 Hz, 2H), 2.57 (t, J ) 7.9 Hz, 2H), 3.80 (s, 3H), 6.47 (d, J )
10.0 Hz, 1H), 6.87 (dd, J ) 10.0, 2.8 Hz, 1H), 7.01 (d, J ) 2.8
Hz, 1H); 13C NMR (CDCl3) δ 25.9, 27.4, 63.8, 65.4, 129.9, 134.7,
142.9, 147.4, 171.4, 177.3; EI-MS m/z 229 (M+ + 2, 14.9), 227
(M+, 43.9), 196 (94.1), 167 (65.8), 162 (70.5), 140 (83.4), 132 (100).
) 1.6 Hz, 1H), 6.32 (dt, J H-H ) 10.0 Hz, J H-F
) 1.3 Hz,
H-H
)
1H), 6.70 (t, J H-F)H-H ) 10.3 Hz, 1H); 13C NMR (CDCl3) δ 25.7,
25.8 (d, J C-F ) 1.7 Hz), 61.8 (d, J C-F ) 22.3 Hz), 64.8, 111.0 (d,
J C-F ) 9.5 Hz), 130.1 (d, J C-F ) 1.6 Hz), 143.7 (d, J C-F ) 5.0
Hz), 171.6, 172.7 (d, J C-F ) 287.9 Hz), 185.7 (d, J C-F ) 15.6
Hz); EI-MS m/z 211 (M+, 8.5), 181 (39.3), 153 (100), 126 (32.5),
124 (30.1), 109 (28.6), 96 (27.5). Anal. Calcd for C10H10NO3F:
C, 56.87; H, 4.77; N, 6.63. Found: C, 56.76; H, 4.71; N, 6.63.
7-Flu or o-1-m eth oxy-1-a za sp ir o[4.5]d eca -6,9-d ien e-2,8-d i-
on e (2e): white crystals; mp 116-118 °C (Et2O/petroleum
ether); IR (KBr) 1730, 1690, 1185 cm-1;1H NMR (CDCl3) δ 2.26
(t, J ) 8.0 Hz, 2H), 2.57 (t, J ) 8.0 Hz, 2H), 3.80 (s, 3H), 6.34-
6.46 (m, 2H), 6.86 (dd, J H-H ) 10.0, 2.7 Hz, 1H); 13C NMR
(CDCl3) δ 25.8, 27.6, 63.7 (d, J C-F ) 1.6 Hz), 65.4, 112.9 (d, J C-F
) 13.4 Hz), 129.7 (d, J C-F ) 3.9 Hz), 147.9 (d, J C-F ) 2.8 Hz),
154.3 (d, J C-F ) 269.4 Hz), 171.4, 177.2 (d, J C-F ) 22.3 Hz);
EI-MS m/z 211 (M+, 50.5), 180 (100), 151 (78.3), 137 (65.6), 124
(99.0), 109 (86.3), 96 (69.0). Anal. Calcd for C10H10NO3F: C,
56.87; H, 4.77; N, 6.63. Found: C, 56.76; H, 4.78; N, 6.58.
1-Met h oxy-7-m et h yl-1-a za sp ir o[4.5]d eca -6,9-d ien e-2,8-
d ion e (2f): white crystals; mp 113-115 °C (AcOEt/hexane); IR
(KBr) 1730, 1675, 1640, 1170 cm-1;1H NMR (CDCl3) δ 1.95 (d,
J ) 1.4 Hz, 3H), 2.15 (t, J ) 7.8 Hz, 2H), 2.54 (t, J ) 7.8 Hz,
2H), 3.78 (s, 3H), 6.36 (d, J ) 9.7 Hz, 1H), 6.58-6.63 (m, 1H),
6.80 (dd, J ) 9.7, 3.1 Hz, 1H); 13C NMR (CDCl3) δ 16.0, 26.1,
27.7, 62.3, 65.2, 130.8, 137.8, 142.2, 146.9, 171.6, 185.0; EI-MS
m/z 207 (M+, 31.4), 176 (100), 147 (36.3), 133 (60.2), 120 (42.8),
91 (32.2). Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76.
Found: C, 63.51; H, 6.23; N, 6.76.
Anal. Calcd for
C10H10NO3Cl: C, 52.76; H, 4.43; N, 6.15.
Found: C, 52.59; H, 4.30; N, 6.13.
1-Oxo-2-m eth oxyl-3,4-d ih yd r o-2H-isoqu in olin e-3-sp ir o-
1′-(cycloh exa -2′,5′-d ien -4′-on e) (2i): white crystals; mp 133-
135 °C (AcOEt/hexane); IR (KBr) 1670, 1635, 1325, 1020 cm-1;1H
NMR (CDCl3) δ 3.32 (s, 2H), 3.90 (s, 3H), 6.35 (d, J ) 10.2 Hz,
2H), 6.96 (d, J ) 10.2 Hz, 2H), 7.18 (d, J ) 7.5 Hz, 1H), 7.41 (t,
J ) 7.5 Hz, 1H), 7.53 (td, J ) 7.5, 1.4 Hz, 1H), 8.19 (dd, J ) 7.5,
1.4 Hz, 1H); 13C NMR (CDCl3) δ 39.9, 63.7, 64.9, 127.2, 127.4,
127.8, 128.5, 130.6, 133.2, 133.9, 146.7, 164.5, 184.1; EI-MS m/z
255 (M+, 4.3), 225 (30.4), 118 (100), 90 (26.7). Anal. Calcd for
C
15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.48; H, 4.91;
N, 5.28.
6,7-Diflu or o-1-m eth oxy-1H-qu in olin -2-on e (3): white crys-
tals; mp 137-139 °C (AcOEt/hexane); IR (KBr) 1665, 1610, 1410,
1260 cm-1;1H NMR (CDCl3) δ 4.11 (s, 3H), 6.75 (d, J H-H ) 9.6
Hz, 1H), 7.36-7.50 (m, 2H), 7.58 (d, J H-H ) 9.6 Hz, 1H); 13C
NMR (CDCl3) δ 63.1, 101.2 (d, J C-F ) 23.5 Hz), 115.8 (dd, J C-F
) 18.4, 1.7 Hz), 116.0 (dd, J C-F ) 5.9, 3.0 Hz), 123.2 (d, J C-F
)
3.3 Hz), 135.3 (dd, J C-F ) 10.6, 1.1 Hz), 137.0 (t, J C-F ) 2.1 Hz),
146.6 (dd, J C-F ) 246.5, 14.0 Hz), 152.3 (dd, J C-F ) 254.3, 14.5
Hz), 157.3; EI-MS m/z 211 (M+, 71.2), 181 (100), 166 (30.1), 153
(59.1), 152 (56.1), 125 (29.5). Anal. Calcd for C10H7NO2F2: C,
56.88; H, 3.34; N, 6.63. Found: C, 56.81; H, 3.40; N, 6.59.
6-Ch lor o-1-m et h oxy-1-a za sp ir o[4.5]d eca -6,9-d ien e-2,8-
d ion e (2g): white crystals; mp 179-180 °C (AcOEt); IR (KBr)
1730, 1665, 1345 cm-1;1H NMR (CDCl3) δ 2.03-2.31 (m, 1H),
J O034318W
5432 J . Org. Chem., Vol. 68, No. 13, 2003