A general synthesis of quinoline-2,5,8(1H)-triones via acylation of 2,5- dimethoxyaniline with S-tert-butyl thioacetates by application of the Knorr cyclization

Article abstract of DOI:10.1055/s-1998-2014

An efficient synthesis of quinoline-2,5,8(1H)-triones bearing alkyl groups at C₃ and/or C₄ is described. The reaction sequence employed involves Knorr cyclization of 2,5-dimethoxyanilides into 5,8- dimethoxyquinoline systems, followed by oxidative demethylation with cerium ammonium nitrate. The starting 2,5-dimethoxyanilides were prepared by chemoselective acylation of 2,5-dimethoxyaniline with a series of β-oxo thioesters obtained by regioselective alkylation of S-tert-butyl acetothioacetate (1) at C₂ and/or C₄. The introduction of electrophiles other than alkyl groups at C₂ on 1 was also studied.

Full text of DOI:10.1055/s-1998-2014

186
Papers
SYNTHESIS
A General Synthesis of Quinoline-2,5,8(1H)-triones via Acylation of 2,5-Dimethoxyaniline
with S-tert-Butyl Thioacetates by Application of the Knorr Cyclization
Pilar López-Alvarado, Carmen Avendaño,* J. Carlos Menéndez
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, ES-28040 Madrid, Spain
Fax +34(91)3941822; E-mail: josecm@eucmax.sim.ucm.es
Received 27 June 1997
Abstract: An efficient synthesis of quinoline-2,5,8(1H)-triones bear-
ing alkyl groups at C3 and/or C4 is described. The reaction sequence
employed involves Knorr cyclization of 2,5-dimethoxyanilides into
cleanly at room temperature with primary alkyl bromides
5,8-dimethoxyquinoline systems, followed by oxidative demethyla-
tion with cerium ammonium nitrate. The starting 2,5-dimethoxyani-
pound 1 with a slight excess of sodium hydride in dry 1,2-
dimethoxyethane yielded a monoanion, which reacted
or iodides to yield the corresponding C2-monosubstituted
derivatives 2–4 in 63–96% yield.13 Primary chlorides and
lides were prepared by chemoselective acylation of 2,5-
dimethoxyaniline with a series of b-oxo thioesters obtained by regio- secondary bromides did not react under these conditions.
selective alkylation of S-tert-butyl acetothioacetate (1) at C2 and/or
C4. The introduction of electrophiles other than alkyl groups at C2 on
1 was also studied.
Regioselective alkylation at C4 was performed using liter-
ature conditions,12 consisting of sequential treatment of 1
with sodium hydride and butyllithium to generate a dian-
ion, followed by addition of the suitable primary halide
and reaction at 0°C for 30–60 min to give compounds 5–
Key words: quinoline-2,5,8(1H)-triones, Knorr cyclization, 2,5-
dimethoxyanilides, b-oxo thioesters, regioselective alkylation
8. These C4-substituted derivatives can be alkylated at C2
Quinoline-2,5,8(1H)-triones have been employed by our
under the same conditions employed for 1, as shown by the
group1 as precursors to antitumor 1,8-diazaanthracene-
easy preparation of the dimethylated derivative 9 from 5.
An attempt to perform a one-pot double alkylation of 1 at
both positions was only partially successful; thus, treat-
ment of the dianion of 1 with an excess of methyl iodide at
2,9,10-triones, designed as analogs of the natural thymid-
ilate synthase inhibitor diazaquinomycin A.2 The methods
currently available for the preparation of these quinones
are restricted to 3-substituted3 or to 4-methyl derivatives,4
room temperature for 12 hours led only to monoalkylation
and this limits the range of structural variations that can be
at C4, affording compound 5 in 91% yield. Under forcing
introduced in the 1,8-diazaanthracene system. We envis-
conditions (60°C for 48 h), the desired product (compound
aged that the acid-promoted cyclization of b-oxo anilides
9) was isolated in moderate yield (39%), together with the
(i.e., the Knorr quinoline synthesis5) might serve as the
2,2,4-trimethylated derivative 10 (38%).
key step of a more general route. However, and in spite of
The reactivity of 1 towards other electrophiles was also
briefly examined. Its reaction with sodium hydride and
acetyl chloride yielded a mixture of the 2-acetyl and 2,2-
diacetyl derivatives 11 (52%) and 12 (46%). Use of p-
tolyllead triacetate,14 an aryl cation equivalent,15 as the
electrophile led to the diarylated derivative 13 in modest
yield (22%), together with unreacted starting material.16
In both cases, the tendency towards introduction of two
molecules of the electrophile must be attributed to the
electron-withdrawing nature of the groups introduced at
C2, which favors deprotonation of the monosubstituted
derivative through proton exchange with the anion of
1.17
the long tradition of this reaction, there are very few ex-
amples of its application to the preparation of 3,4-disub-
stituted quinoline systems,6 probably because of
difficulties in the synthesis of the anilide precursors.
bOxoacylation of amines, which is the most obvious ap-
proach to the required anilides, has been performed by
means of a variety of reagents. Use of b-oxo esters re-
quires the application of high temperatures and long reac-
tion times in order to achieve chemoselective reaction on
the ester group under thermodynamic conditions7 or use
of mixed tin(II) amides as nucleophiles,8 although the
generality of the latter reaction as a b-oxoacylation meth-
od has not been established. Diketene9 is a good ace-
toacetylating reagent, but its volatility, low stability and
high toxicity, and the fact that its derivatives are not easily
available, have stimulated the search for alternatives like
1,3-dioxin-4-one derivatives.10 More recently, it has been
shown11 that b-oxo thioesters react with amines in the
presence of silver trifluoroacetate under exceptionally
mild conditions, and that they may, therefore, be consid-
ered as ideal reagents for the proposed transformation. b-
Oxo thioesters with varied substituents should be avail-
able from S-tert-butyl acetothioacetate (1), since this com-
pound can be regioselectively alk.ylated at C4 by treatment
of its dianion with alkyl halides.12 Introduction of electro-
philes at C2, although little studied, should also be possi-
ble, as well as the combination of both processes.
Finally, the reaction of 1 with N-fluoropyridinium triflate,
an electrophilic fluorinating reagent, which has been suc-
cessfully employed on b-oxo esters,18 was assayed. How-
ever, the reaction failed under neutral conditions18 and use
of the anion of 1 led to a complex mixture from which de-
composition products 14–17 were isolated.
The spectral data of the b-oxo thioesters (Tables 1 and 2)
show the presence of mixtures of the oxo (a) and enol (b)
tautomers for compounds 1–11. The content of enol tau-
tomer was ca. 15% in most cases, and showed little sensi-
tivity to solvent polarity and concentration (Tables 3 and
4). On the other hand, C2-substituted derivatives (com-
pounds 2–4 and 9) exist solely as the oxo tautomer; a sim-
ilar behavior had previously been noted for other b-
dicarbonyl compounds, and is normally ascribed to steric
effects in the C2-substituted enol tautomers.19
The reactions performed by us on S-tert-butyl acetothio-
acetate are summarized in Scheme 1. Treatment of com-

February 1998
SYNTHESIS
187
a) NaH (1.1 equiv), 0°C, 10 min; b) BuLi (1.1 equiv), –20°C, 10 min; c) R–X (1.1 equiv), r.t., 12 h; d) R–X (1.05 equiv), 0°C, 30–60 min; e)
MeI (2.1 equiv), r.t., 12 h; f) MeI (2.5 equiv), 60°C, 48 h; g) MeI (1.1 equiv), r.t., 12 h; h) NaH (1 equiv more), AcCl (1.5 equiv), r.t., 10 h; i)
AcCl (1.1 equiv), r.t., 10 h; j) pyridine (1.1 equiv), p-tolylPb(OAc)3 (1.1 equiv), 40°C, 22 h
Scheme 1
Table 1. 1H NMR Assignments and IR of the Oxo (a) and Enol (b) Tautomers of C2- and C4-Substituted b-Oxo Thioestersa
Com- 1H NMR (CHCl3) d, J (Hz)
IR (NaCl)
pound
n (cm–1)
OH
C2-H
C4-H
C(CH3)3 R3 and/or R4
1a
1b
2a
2b
3a
–
3.58 (s)
5.35 (s)
2.26 (s)
1.90 (s)
1.48 (s)
1.51 (s)
1.52 (s)
1.51 (s)
1.38 (s)
–
–
–
–
12.90 (s)
–
13.97 (br s)
–
3.66 (q, J = 0.5) 2.26 (s)
2.20 (s)
1.36 (d, J = 6.0, C3-CH3)
1.77 (s, C3-CH3)
1723, 1670
–
3.86 (t, J = 7.5) 2.15 (s)
7.27–7.11 (m, C3-Ar-H),
3.12 (dd, J = 2.0 and 9.0 C3-CH2)
2.62 (t, J = 6.5, C3-C1¢-H), 5.80–5.67
(ddt, J = 17.0, 10.0 and 6.5, C2-H),
5.13 (dd, J = 17.5 and 2.0, C3¢-Htrans),
1740, 1684
1720, 1672
4a
–
3.68 (t, J = 6.0) 2.26 (s)
1.50 (s)
5.07 (dd, J = 10.0 and 1.0, C3¢-Hcis
1.07 (t, J = 7.0, C4-CH3)
1.07 (t, J = 7.0, C4-CH3)
)
5a
–
3.56 (s)
2.57 (q, J = 7.0)
1.48 (s)
1.51 (s)
1.40 (s)
1.43 (s)
1.38 (s)
1.43 (s)
1.37 (s)
1724, 1678
1615
5b
6ab
6bb
7a
7b
8a
12.89 (br s) 5.34 (s)
3.48 (s)
12.80 (br s) 5.25 (s)
3.47 (s)
2.18 (q, J = 7.5)
2.44 (t, J = 7.0)
2.03 (t, J = 7.0)
2.80 (br s)
2.17* (m)
2.55 (t, J = 7.5)
–
1.53 (sext, J = 7.5, C4-CH2), 0.84 (t, J = 7.5, CH3) 1732, 1684
1.23–1.14 (m, C5-H), 0.84 (t, J = 7.5, C6-H)
2.80 (br s, C4-CH2), 7.19–7.08 (m, Ar-H)
2.35* (t, J = 7.5, C4-CH2), 7.19–7.08 (m, Ar-H)
2.23 (q, J = 6.5, C5-H), 5.70
1624
1724, 1674
1616
–
12.86 (br s) 5.25 (s)
3.48 (s)
1724, 1674
(ddt, J = 17.0, 10.5 and 6.5, C6-H),
4.99–4.86 (m, J = 17.0, 9.5 and 1.5, C7-H)
1.41 (s) 2.15–2.08 (m, J = 7.5, C5-H), 5.70
(ddt, J = 17.0, 10.5 and 6.5, C6-H),
4.99–4.86 (m, J = 17.0, 9.5 and 1.5, C7-H)
1.28 (dd, J = 7.0 and 0.5, C3-CH3),
1.02 (td, J = 7.0 and 0.5, C4-CH3)
8b
12.78 (br s) 5.24 (s)
2.15–2.08 (m, J = 7.5)
1615
9a
–
–
3.62 (q, J = 7.0) 2.65–2.40 (m)
5.70 (d, J = 1.0) 2.19* (s)
1.43 (s)
1.41 (s)
1728, 1674
1770, 1678
11a
1.91* (d, J = 1.0, CO-CH3)
a Elemental analyses. Compound: calcd (found); 2: C, 57.46 (57.11); H, 8.56 (8.42). 3: C, 68.14 (68.05); H, 7.62 (7.63). 4: C, 61.64 (61.38);
H, 8.46 (8.23). 5: C, 57.44 (57.90); H, 8.51 (8.20). 6: C, 59.36 (58.96); H, 8.96 (8.62). 7: C, 68.15 (68.47); H, 7.63 (7.86). 8: C, 61.64 (61.74);
H, 8.36 (7.97). 9: C, 59.37 (59.15); H, 8.97 (9.12). 11: C, 55.53 (55.14); H, 7.45 (7.61).
b Compound 6 keeps the same numbering used for other b-oxo thioesters in order to facilitate comparison of the data.

188
Papers
SYNTHESIS
Table 2. 13C NMR Assignments of the Oxo (a) and Enol (b) Tautomers of b-Oxo Thioesters (CDCl3)
Com- C1
pound
C2
C3
C4
C(CH3)3 C(CH3)3 R3 and/or R4
1a
1b
2a
3a
4a
5a
5b
6a
6b
7a
7b
8a
8b
9a
11a
192.38
58.95 200.05 29.95
48.77
47.87
48.68
49.18
49.08
48.94
48.10
48.98
48.11
49.17
48.32
48.78
47.93
48.68
29.37
29.94
29.52
29.59
29.51
29.53
30.10
29.64
30.20
29.70
30.26
29.41
29.96
29.53
29.64
–
–
172.76 100.01 195.87 20.84
197.13
195.47
195.44
192.70
177.50
192.65
176.30
192.58
175.04
192.29
175.09
197.20
62.64 202.77 28.16
70.34 201.58 29.48
68.16 201.65 28.85
58.03 202.90 36.39
98.54 196.20 27.96
58.44 202.35 44.99
99.63 196.19 36.88
58.60 201.51 44.70
99.95 196.42 36.87
58.18 201.22 41.88
99.53 196.00 34.06
61.71 205.02 34.50
13.28 (C3-CH3)
137.95 (C1¢), 129.05* (C2¢,6¢), 128.60* (C3¢,5¢), 126.74 (C4¢), 34.84 (C3-CH2)
32.86 (C3-C1¢), 133.79 (C2¢), 117.56 (C3¢)
7.46 (C4-CH3)
10.38 (C4-CH3)
13.59 (C4-CH2), 16.90 (C4-CH2-CH3)
19.68 (C4-CH2), 13.69 (C4-CH2-CH3)
140.69 (C1¢), 128.63* (C2¢,6¢), 128.44* (C3¢,5¢), 126.38 (C4¢), 29.49 (C4-CH2)
140.63 (C1¢), 128.38 (C2¢,6¢,3¢,5¢), 126.30 (C4¢), 32.49 (C4-CH2)
27.15 (C5), 136.43 (C6), 115.29 (C7)
136.48 (C6), 115.46 (C7)
13.48 (C3-CH3), 7.67 (C5)
154.86* (C3-CO-CH3), 20.94** (C3-CO-CH3)
186.95 115.29 167.70* 21.22** 47.94
Table 3. % Enol of Compound 5 in Various Solvents
The isolation of compound 26 is probably due to degrada-
tion of the corresponding b-oxo anilide, since 26 was also
obtained from isolated 23 under the same conditions. The
outcome of this reaction did not change in the absence of
2,5-dimethoxyaniline, which discards a retro-Claisen/ox-
idation mechanism for the loss of the acetyl group, nor
when silver trifluoroacetate was replaced by copper(II)
acetate. Since copper(II) species are commonly employed
for chelating the enol tautomer of b-dicarbonyl com-
pounds,21 this suggests that the enol is the species that un-
dergoes oxidative degradation, probably by addition of
molecular oxygen22 followed by elimination of a mole-
cule of acetic acid (Scheme 3).23
Solvent
% Enol
DMSO MeOD
6.8 11.2
CDCl3 Acetone-d6 Pyridine-d5
12.0 14.1 14.8
Table 4. % Enol of Compound 5 in CDCl3 at Various Concentrations
Concentration
(mol L–1)
0.05
11.3
0.1
0.25
12.0
0.50
14.8
1.0
% Enol
12.0
15.4
NMR data of anilides 18–25 are in Tables 5 and 6. Simi-
larly to b-oxo thioesters, compounds 18–22, which are un-
substituted at C2, show signals assignable to a small
amount (ca. 10%) of the enol tautomer.
Knorr cyclization of b-oxo anilides 18–25 was carried out
in different acidic media (Scheme 4). Alkyl derivatives
19, 20 and 23 were stirred in 96% sulfuric acid at room
temperature for 1 hour (linear anilides 19 and 20) or 3
hours (C2-substituted compound 23), conditions very sim-
ilar to those previously employed for anilide 18.4 These
conditions caused the sulfonation of phenyl groups on
side chains (e,g., the preparation of 32) and for this reason
the cyclization of anilides 21 and 24 was performed with
35% aqueous HCl at room temperature for 4–7 days. Fi-
nally, allyl anilides 22 and 25 led to complex mixtures in
the presence of mineral acids but could be cyclized, albeit
in moderate yield, by heating in refluxing xylene in the
presence of a catalytic amount of p-toluenesulfonic acid.
Spectral data of carbostyril derivatives thus obtained are
summarized in Tables 7 and 8.
The b-oxo thioesters thus prepared showed three types of
behavior in their reaction with 2,5-dimethoxyaniline in
the presence of silver trifluoroacetate (Scheme 2). C2-Un-
substituted derivatives (compounds 5–8) reacted smooth-
ly at room temperature over 1 hour, affording anilides 18–
2220 in good yields. The reactions of C2-monosubstituted
derivatives, on the other hand, could not normally be com-
pleted even after 48 hours at room temperature, but gave
nevertheless acceptable yields (ca. 60%) of anilides 23–25
together with recovered starting material. An attempt was
made to achieve complete conversion in the reaction of
thioester 2 by raising the temperature to 60°C, but the
only product obtained under these conditions was pyruvic
anilide 26. Finally, 2,2-disubstituted b-oxo thioesters did
not react at all with 2,5-dimethoxyaniline under the con-
ditions assayed.
Finally, oxidative demethylation with cerium ammonium
nitrate of the 5,8-dimethoxycarbostyrils obtained in the
Knorr reaction allowed the preparation of quinones 35–40
(Scheme 5). Spectral data for these compounds can be
found in Tables 9 and 10.
IR spectra were recorded on Perkin–Elmer 283, Perkin–Elmer 577,
and Perkin–Elmer Paragon 1000 spectrophotometers, with all com-

February 1998
SYNTHESIS
189
Scheme 2
pounds compressed into KBr pellets and liquid compounds examined
as films over NaCl. NMR spectra were obtained on Bruker AC-250
(250 MHz for 1H, 63 MHz for 13C) and Varian VXR-300 (300 MHz
for 1H, 75 MHz for 13C) spectrometers (Servicio de Espectroscopìa,
Universidad Complutense). The solvents used were CDCl3, DMSO-
d6, pyridine-d5, and acetone-d6. Exchangeable assignments are
marked with the symbols * and **. Elemental analyses were deter-
mined by the Servicio de Microanálisis, Universidad Complutense.
Microanalyses are expressed as calculated (found). Melting points
were measured in open capillary tubes using a Büchi inmersion appa-
ratus or a “Reichert” hot stage microscope model 723, and are uncor-
rected. Reactions were monitored by TLC, on aluminum plates coated
with silica gel with fluorescent indicator (Scharlau Cf 530), which
were visualized with a UV lamp (Camag UV-II, 254 and 366 nm) and,
occasionally, by use of Draggendorff’s reagent for amines or a solu-
tion of palladium chloride in 5% HCl for sulfur compounds. Separa-
tions by flash chromatography were performed on silica gel (SDS 60
ACC, 230-400 mesh and Scharlau Ge 048). All reagents were of com-
mercial quality (Aldrich, Merck, SDS, Probus, Panreac, Scharlau,
FIuka) and were used as received, unless otherwise stated. S-tert-bu-
tyl acetothioacetate was prepared according to ref 24. Petroleum ether
refers to the fraction boiling at 40–60°C.
Scheme 3
Alkylation of S-tert-Butyl Acetothioacetate on C2; General Proce-
dure:
To a slurry of petroleum ether washed (2 ´ 10 mL) NaH (0.25–0.38 g
of a 60% dispersion in mineral oil, 6.32–9.48 mmol) in anhyd DME
(30–40 mL) under N2 at –20°C, was added dropwise, via cannula, a
solution of 1 (1.0–1.5 g, 5.75–8.62 mmol) in anhyd DME (5 mL). The
solution was left to warm to 0°C for 5–10 min, and the corresponding
alkyl halide (6.03–9.05 mmol, 1.05 equiv) was added. After 14 h at
r.t., the mixture was quenched with sat. aq NH4Cl (50 mL), extracted
with Et2O (2 ´ 100 mL) and washed again with aq NH4Cl (50 mL)
and brine (2 ´ 50 mL), dried (Na2SO4), and concentrated under re-
duced pressure to give an orange oil. Chromatography (99% petro-
leum ether/Et2O) yielded monoalkylated compounds 2–4 as colorless
oils and, in one case (R3 = allyl), a small amount of the secondary
product from the dialkylation of 1.25, 26
Scheme 4

190
Papers
SYNTHESIS
Table 5. 1H NMR, IR and mp Data of C2- and C4-Substituted b-Oxo Anilidesa
Com- 1H NMR (CDCl3) d, J (Hz)
mp (°C) IR (KBr)
pound
n (cm–1)
C2-H
C4-H
2 OCH3¢ C3,-H
C4¢-H
6.54
C6¢-H
8,03
NH R3 or R4
9.24
18b
19b
20b
21b
22
3.55 (s) 2.22 (s) 3.73 and 6.76
71–72e,f
3.82 (2 s) (d, J = 9.0) (dd, J = 9.0, 3.0)(d, J = 3.0) (br s)
3.76 and 6.79 6.57 8.06 9.35 1.10 (t, J = 7.0, C5-H)
(q, J = 7.0)3.87 (2 s) (d, J = 8.5) (dd, J = 8.5, 3.0)(d, J = 3.0) (br s)
3.55 (s) 2.54 3.74 and 6.78 6.55 8.03 9.34 1.64 (m, J = 7.5, 7.2, C5-H), –
(t, J = 7.0) 3.84 (2 s) (d, J = 9.0) (dd, J = 9.0, 3.0)(d, J = 3.0) (br s) 0.92 (t, J = 7.5, C6-H)
3.54 (s) 2.92 (br s) 3.76 and 6.79 6.58 8.05 9.23 2.92 (br s, C5-H),
3.86 (2 s) (d, J = 9.0) (dd, J = 9.0, 3.0)(d, J = 3.0) (br s) 7.30–7.16 (m, Ar²-H)
3.76 and 6.80 6.57 8.05 9.27 2.37 (q, J = 7.0, C5-H),
3.57 (s) 2.62
64–66e 3280, 1720
1680, 1260
3330, 1716,
1684, 1224
–
3330, 1714,
1680, 1221
3.63 (s) 2.69
79–81e 3297, 1715,
1679, 1222
(t, J = 7.0) 3.86 (2 s) (d, J = 9.0) (dd, J = 9.0, 3.0)(d, J = 3.0) (br s) 5.80 (ddt, J = 17.0, 10.5,
6.5, C6-H), 5.05 (dd,
J = 17.0, 1.5, C7-Htrans), 5.00
(dd, J = 10.0, 1.6, C7-Hcis
)
23
3.19
(q, J = 7.0)
3.78c
2.28 (s) 3.75 and 6.77
6.56
8.05
8.51 1.47 (d, J = 7.0,
84–86e 3223, 1720,
1654, 1279
116–118g3320, 1732,
1664, 1240
3.83 (2 s) (d, J = 9.0) (dd, J = 9.0, 3.0)(d, J = 3.0) (br s) C3-CH3)
2.14 (s) 3.75 and 6.75 6.56 8.02 8.46 7.29–7.17 (m, Ar²-H),
3.79 (2 s) (d, J = 9.0) (dd, J = 9.0, 3.0)(d, J = 3.0) (br s) 3.25 (m, C3-CH2)
3.72 and 6.75 6.54 8.00
8.58 2.66 (t, J = 7.0, C3-C1²-H), 79–81e 3276, 1724,
24
25d
3.562.25 (s)
(t, J = 7.5)
3.80 (2 s) (d, J = 9.0) (dd, J = 3.0, 9.0)(d, J = 3.0) (br s) 5.80–5.67 (ddt, J = 17.0,
10.0, 7.0, C2²-H), 5.11 (dd,
1648, 1224
J = 17.0, 1.5, C3²-Htrans),
5.04 (dd, J = 10.0, 1.0, C3²-Hcis
)
a
Elemental analyses. Compound: calcd (found); 19: C, 62.13 (61.98); H, 6.82 (6.70); N, 5.57 (5.47). 20: C, 63.38 (63.67); H, 7.22 (7.28); N,
5.28 (4.83). 21: C, 69.71 (69.39); H, 6.46 (6.53); N, 4.28 (4.20), 22: C, 64.97 (64.98); H, 6.91 (7.11); N, 5.05 (4.89). 23: C, 62.13 (62.04); H,
6.82 (6.68); N, 5.57 (5.84). 24: C, 69.71 (69.75); H, 6.46 (6.32); N, 4.28 (4.62). 25: C, 64.97 (64.57); H, 6.91 (6.73); N, 5.05 (4.74).
b Signals assignable to a small proportion (11%) of enol tautomers were observed. 18: d = 13.54 (br. s, 1 H, OH), 5.00 (s, 1 H, C2-H), 3.78 (s,
3 H, C5¢-OMe), 3.74 (s, 3 H, C2¢-OMe), 1.92 (s, 1 H, C4-H). 19: d = 5.02 (s, 1 H, C2-H). 20: d = 5.01 (s, 1 H, C2-H). 21: d = 4.98 (s, 1 H, C2-H).
c
Partially covered by the methoxy signals.
d This compound keeps the numbering used on other b-oxo anilides.
e
Solvent: Et2O.
f
Lit.4 mp 70–72°C.
g Solvent: 80% petroleum ether/Et2O.
Table 6. 13C NMR Assignments of C2- and C4-Substituted b-Oxo Anilides (CDCl3)
Com- C1
pound
C2
C3
C4
C2¢-OMe C5¢-OMe C1¢
C2¢
C3¢
C4¢
C5¢
C6¢
R3 or R4
18a
19
20
21
163.50 55.84 204.94 31.17 50.83
163.41 49.64 206.99 37.19 55.64
163.49 49.81 206.55 45.70 55.59
163.19 50.18 205.37 45.23 55.61
56.49
56.31
56.27
56.29
128.14 142.63 111.01 108.80 153.81 106.53 –
127.96 142.00 110.76 108.53 153.57 106.26 7.34 (C5)
127.93 142.44 110.77 108.50 153.55 106.32 16.72 (C5), 13.40 (C6)
127.89 142.40 110.78 108.62 153.59 106.30 29.21 (C5), 140.11
(C1²), 128.45*
(C2²,6²), 128.15*
(C3²,5²), 126.18 (C4²)
22
163.28 50.05 205.59 42.82 55.62
56.29
127.92 142.43 110.79 108.57 153.59 106.32 27.20 (C5), 136.21
(C6), 115.65 (C7)
23
24
167.37 56.36* 207.08 28.70 55.88
165.77 64.18 206.32 30.15 55.67
56.43*
56.24
128.03 142.41 110.92 109.11 153.88 106.05 14.80 (CH3)
127.72 142.28 110.77 108.84 153.63 106.03 36.62 (CH2), 137.56
(C1²), 128.66*
(C2²,6²), 128.62*
(C3²,5²), 126.82 (C4²)
127.65 142.34 110.74 108.79 153.57 106.13 34.29 (C1²),
133.60 (C2²),
25b
166.03 61.68 206.03 29.54 55.61
56.19
118.05 (C3²)
a Signals assignable to a small proportion of the enol tautomer of 18 were observed: d = 110.81 (C2), 56.27 (OMe) and 21.58 (C4).
b This compound keeps the numbering used on other b-oxo anilides.

February 1998
SYNTHESIS
191
Table 7. 1H NMR, IR and mp Data of C3- and C4-Substituted Carbostyrilsa
Com- 1H NMR (CDCl3) d, J (Hz)
mp (°C) IR (KBr)
pound
(Solvent) n (cm–1)
NH
C3-H
–
C6-H
C7-H
2 OCH3
R3 and/or R4
27
28
29
9.21
6.38 (d, 6.88 (d,
3.80 and
3.73 (2 s)
2.14 (s, C3-CH3), 2.51 (s, C4-CH3)
182–183 3414,1633,
(br s)
J = 9.0) J = 9.0)
(Et2O)
1251
9.33
(br s)
–
–
6.49 (d, 6.82 (d,
J = 9.0) J = 9.0)
3.89 and
3.79 (2 s)
7.24–7.20 and 7.17–7.01 (m, Ph-H),
4.16 (s, C3-CH2-Ph), 2.62 (s, C4-CH3)
172–174 3410,1632,
(acetone) 1268
8.27
6.51 (d, 6.83 (d,
3.91 and
3.88 (2 s)
3.36 (J = 6.0 C3-C1¢-H), 5.99–5.83 (m, J = 17.0,
10.0 and 6.0, C2¢-H), 4.92 (dd, J = 10.0 and 1.5,
C3¢-Hcis), 5.00 (dd, J = 17,0 and 1.5, C3¢-Htrans),
2.39 (s, C4-CH3)
196–198 3402,1630,
(acetone) 1260
(br s)
J = 9.0) J = 9.0)
30
9.11
(br s) (s)
6.41
6.51 (d, 6.86 (d,
J = 9.0) J = 9.0)
3.83 and
3.88 (2 s)
3.02 (q, J = 7.5, C4-CH2), 1.21 (t, J = 7.5, CH3)
149–151 3160,1690,
(acetone) 1270
31
9.24
(br s) s)
6.39
6.51 (d, 6.86 (d,
J = 9.0) J = 9.0)
3.90 and
3.85 (2 s)
2.94 (t, J = 7.5, C4-CH2), 1.61 (sext, J = 7.5, CH2),
1.00 (t, J = 7.5, CH3)
137–139 3410,1664,
acetone) 1268
c
32b
5.89
(s)
6.12 (d, 6.52 (d,
J = 9.0) J = 9.0)
3.58 and
3.33 (2 s)
2.39 (br s, C4-CH2), 2.00 (br s, C4-CH2- CH2),
7.63 (d, J = 8.0, C3¢5¢-H), 6.89 (d, J = 8.0, C2¢6¢-H)
284–286 3146,1646,
(MeOH) 1401, 1189,
1108
33
34
9.34
(br s) (s)
6.40
6.55 (d, 6.89 (d,
J = 9.0) J = 9.0)
3.90 and
3.88 (2 s)
3.28 (t def., J = 7.5 and 8.5, C4-CH2), 2.88 (t def.,
J = 7.5 and 8.5, C4-CH2-CH2), 7.33–7.20 (m, Ph-H) (acetone) 266
142–144 3414,1654,
8.41
6.18
6.56 (d, 6.89 (d,
3.93 and
2.71 (t, J = 7.0, C4-C1¢-H), 2.46 (dd, J = 7.0 and 7.0, 160–162 3423,1633,
(br s) (s)
J = 9.0) J = 9.0)
3.91 (2 s)
C2¢-H), 5.86 (ddt, J = 17.0, 10.5 and 6.5, C3¢-H),
5.11 (dd, J = 17.0 and 1.5, C4¢-Htrans),
(acetone) 1263
5.05 (dd, J = 10.0 and 1.5, C4¢-Hcis
)
a Elemental analyses. Compound: calcd (found); 27: C, 66.94 (66.50); H, 6.48 (6.39); N, 6.00 (5.94). 28: C, 73.77 (73.52); H, 6.19 (6.05); N,
4.53 (4.12). 29: C, 69.48 (69.09); H, 6.60 (6.39); N, 5.40 (5.06). 30: C, 66.94 (66.97); H, 6.48 (6.43); N, 6.00 (5.90). 31: C, 67.99 (67.63); H,
6.93 (6.74); N, 5.66 (5.11). 32: C, 56.14 (56.18); H, 5.45 (5.63); N, 6.89 (7.05). 33: C, 73.77 (73.48); H, 6.19 (6.10); N, 4.53 (4.16). 34: C,
69.48 (69.32); H. 6.61 (6.61); N, 5.40 (5.62).
b In D2O.
c Not detected.
Table 8. 13C NMR Assignments of C3- and C4-Substituted Carbostyrils (CDCl3)
Com- C2
pound
C3
C4
C4a
C5
C6
C7
C8
C8a
2 OMe
R4
27a
28a
30
161.33 126.91 139.37 111.79 151.36 102.19 108.38 144.69 127.85 55.89, 55.49 19.54 (CH3)
161.49 130.13 139.60 112.83 151.92 102.44 109.13 146.63 128.59 56.17, 55.66 20.10
161.74 120.20 139.97 111.11 156.52 102.35 110.04 151.87 130.39 56.39, 55.76 30.01 (C1¢), 14.62 (C2¢)
161.33 120.87 139.68 110.70 158.30 102.06 109.76 151.50 130.00 56.07, 55.47 38.84 (C1¢), 23.45 (C2¢),
13.93 (C3¢)
(CH3)
31
32b
33
164.58 120.21 143.20 113.31 157.49 105.93 112.82 152.49 130.79 58.19, 57.45 40.25 (C1¢), 38. 19 (C2¢), 147.17
(C1²), 130.87* (C2²,6²),
128.17* (C3²,5²), 142.27 (C4²)
161.33 121.37 139.81 110.57 153.24 102.15 109.95 151.26 130.25 56.11, 55.53 38.89 (C1¢), 36.95 (C2¢), 141.46
(C1²), 128.29* (C2²,6²),
128.17* (C3²,5²), 125.91 (C4²)
110.96 152.73 102.91 110.20 151.25 129.33 56.50, 56.12 32.33 (C1¢), 29.68 (C2¢), 136.29
(C3¢), 116.37 (C4¢)
c
34
161.75 117.04
a Compound 27: R3, d = 12.62 (CH3). Compound 28: R3, d = 31.97 (CH2), 139.94 (C1¢), 128.20* (C2²,6²), 128.12* (C3²,5²), 125.63 (C4²).
b In D2O.
c Not detected.
Alkylation of S-tert-ButylAcetothioacetate on C4; GeneralProce-
dure:
1.1 equiv) was added dropwise, and the solution turned from yel-
low to dark red. The reaction was warmed to –20 °C in order to
complete anion formation. After stirring for 10 min more at this
temperature, it was cooled again to –40 °C, and the suitable alkyl
halide (6.03–18. 10 mmol, 1.05 equiv) was added. After 30 min to
0 °C, the mixture was quenched with sat. aq NH4Cl (50 mL), ex-
tracted with Et2O (2 ´ 100 mL) and washed again with aq NH4Cl
(50 mL) and brine (2 ´ 50 mL), dried (Na2SO4), and concentrated
under reduced pressure to give an orange oil. Chromatography
To a slurry of petroleum ether washed (2 ´ 10 mL) NaH (0.253–
0.758 g of a 60% dispersion in mineral oil, 6.32–18.97 mmol, 1.1
equiv) in anhyd DME (30–70 mL) under N2 at –20 °C, was added
dropwise, via cannula, a solution of 1 (1.0–3.0 g, 5.75–17.24 mmol)
in DME (50 mL). The solution was left to warm to 0 °C for 5–10
min, and then was cooled to –40 °C. After 15 min at this tempera-
ture, 1.6 M BuLi in hexanes (3.95–11.85 mL, 6.32–18.97 mmol;

192
Papers
SYNTHESIS
Table 9. 1H NMR, IR and mp Data of C3- and C4-Substituted Carbostyrilquinonesa
Com- 1H NMR (CDCl3) d, J (Hz)
mp (°C)b IR (KBr)
pound
n (cm–1)
NH
C3-H C6-H
C7-H
6.86
R3 and/or R4
35
36
37
38
39
40
10.35
(br s)
–
–
6.80
2.23 (s, C3-CH3), 2.58 (s, C4-CH3)
183–185 3419, 1637
(d, J = 10.2) (d, J = 10.2)
6.78 6.85
(d, J = 10.0) (d, J = 10.0)
6.68 6.83 6.90
(s) (d, J = 10.0) (d, J = 10.0)
6.60 6.75 6.84
(s)
6.60 6.82
(s) (d, J = 10.0) (d, J = 10.0) 7.29–7.19 (m, Ar-H)
6.98 6.95 7.05 2.98 (t, J = 7.5, C4-C1¢-H), 2.50 (dd, J = 7.5 and 7.0, C2¢-H),
(s) (d, J = 10.4) (d, J = 10.4) 5.82 (ddt, J = 17.0, 10.5 and 6.5, C3¢-H), 5.03 (dd, J = 17.0
and 1.5, C4¢-Htrans), 4.98 (dd, J = 10.0 and 1.5, C4¢-Hcis
8.87
(br s)
7.32–7.18 (m, Ph-H), 4.09 (s, C3-CH2-Ph), 2.60 (s, C4-CH3) 172–174 3402, 1699,
1632
9.85
(br s)
3.03 (q, J = 7.5, C4-CH2), 1.15 (t, J = 7.5, C4-CH2-CH3)
2.89 (t, J = 7.0, C4-C1¢-H), 1.51 (sext, J = 7.5, C2¢-H),
149–151 3450, 1670,
1660
11.39
(br s)
166–168 450, 1660,
1641
(d, J = 10.0) d, J = 10.0) 0.95 (t, J = 7.5, C3¢-H)
10.35
(br s)
6.90 3.25 (t, J = 8.0, C1¢-H), 2.83 (t, J = 8.0, C2¢-H),
163–l65
3414, 1651
11.72
(br s)
–
1642
)
a Elemental analyses. Compound: calcd (found); 35: 65.02 (65.01); H, 4.46 (4.75); N, 6.89 (6.67). 36: C, 73.11 (73.49); H, 4.69 (4.60); N, 5.01
(4.96). 37: C, 65.02 (65.40); H, 4.46 (4.80); N, 6.89 (6.59). 38: C, 66.35 (66.68); H, 5.10 (5.14); N, 6.45 (6.81). 39: C, 73.11 (73.49); H, 4.69
(4.70); N, 5.01 (4.86).
b Solvent: Et2O.
Table 10. 13C NMR Assignments of C3- and C4-Substituted Carbostyrilquinones (CDCl3)
Com- C2
pound
C3
C4
C4a
C5
C6
C7
C8
C8a
R3 and/or R4
35
36
160.94 135.12* 145.94 114.56 179.57 140.19 132.67 184.23 135.74* 12.82 (C3-CH3), 17.39 (C4-CH3)
160.94 136.16* 147.54 114.76 179.35 140.54 132.66 184.04 137.77* 32.02 (C3-CH2), 138.37 (C1¢),
128.60** (C2²,6²), 128.56**
(C3²,5²), 126.37 (C4²), 17.85 (C4-CH3)
37
38
39
161.41 125.24 157.12 113.90 179.58 140.24 132.96 183.49 138.74 27.22 (C4-C1¢), 13.31 (C2¢)
161.36 126.14 155.62 113.92 179.54 140.19 132.96 183.43 138.85 35.95 (C4-C1¢), 22.50 (C2¢), 13.86 (C3¢)
160.79 126.27 154.43 113.68 179.37 140.24 132.94 183.32 138.75 36.20 (C4-C1¢), 35.72 (C2’), 140.44 (C1²),
128.45* (C2²,6²),
128.40* (C3²,5²), 126.70 (C4²)
38.04 (C4-C1¢), 33.59 (C2¢), 136.65 (C3¢),
115.41* (C4¢)
40
166.63 115.75* 147.94 113.25 169.52 139.31 137.43 182.86a
a Not detected.
NaH (45 mg of a 60% dispersion in mineral oil, 1.12 mmol, 1.05
equiv), and MeI (0.159 g, 1.12 mmol; 1.05 equiv) in DME (20 mL),
a yield of0.200 g (93%) of 9 as a colorless oil was obtained, following
the General Procedure for the alkylation of S-tert-butyl acetothioace-
tate (1) at C2.
One-Pot Double Methylation of S-tert-Butyl 3-Oxobutanethioate
on C2 and C4:
The method for alkylation at C4 was used, using MeI (2.05 equiv). Af-
ter 30 min at 0 °C, the mixture was slowly heated to 60°C. After 24 h,
more MeI (0.12 mL, 0.28 equiv) was added followed by further addi-
tion of MeI (0.10 mL, 0.25 equiv) 12 h later. The solution was stirred
for 12 h at 60°C and was quenched. Chromatography (99% petroleum
ether/Et2O) yielded 0.224 g (39%) of S-tert-butyl 2-methyl-3-oxo-
pentanethioate (9) and 0.236 g (38%) of S-tert-butyl 2,2-dimethyl-3-
oxopentanethioate (10), as colorless oils.
Scheme 5
10:
IR (NaCl): n = 1721 (C=O), 1673 (t-BuS-C=O) cm–1.
1H NMR (CDCl3, 250 MHz): d = 2.44 (c, 2H, J = 7.0 Hz, C4-H), 1.40
(s, 9H, t-Bu), 1.31 [s, 6H, (CH3)2-C2], 1.00 (t, 3H, J = 7.0 Hz, C5-H).
13C NMR (CDCl3, 63 MHz): d = 208.59 (C3), 201.93 (C1), 63.81 (C2),
48.27 [C(CH3)3], 31.39 (C4), 29.79 [C(CH3)3], 22.31 [(CH3)2-C2],
8.40 (C5).
(99% petroleum ether/Et2O) yielded monoalkylated compounds 5–
8 as colorless oils.
Alkylation on C2 of a b-Oxo Thioester Previously Substituted at
C4. Preparation of S-tert-Butyl 2-Methyl-3-oxopentanethioate (9):
StartingfromS-tert-butyl3-oxopentanethioate(5)(0.20g, 1.06mmol),

February 1998
SYNTHESIS
193
Acetylation of S-tert-Butyl Acetothioacetate at C2:
= 7.0 and 5.0 Hz, C5-H), 6.81 (d, 1H, J = 8.5 Hz, C3-H), 4.47 (t, 2H,
J = 4.5 Hz, C2¢-H), 3.75 (t, 2H, J = 4,5 Hz, C1¢-H), 3.44 (s, 3H, OCH3).
13C NMR (CDCl3, 63 MHz): d = 163.50 (C2), 146.60 (C6), 138.48
(C4), 116.75 (C3), 111.34 (C5), 71.00 (C1¢), 64.76 (C2¢), 59.03 (OCH3).
Method A; Using Two Equivalents ofNaH: To a slurry of petroleum
ether washed (2 ´ 10 mL) NaH (47 mg, 1.18 mmol, 2.05 equiv of a
60% dispersion in mineral oil), in anhyd DME (17 mL) under N2 at
–20°C, was added dropwise, via cannula, a solution of 1 (100 mg,
0.58 mmol, 1 equiv) in DME (2 mL). The solution was left to warm
to 0°C for 5–10 min, and AcCl (68 mg, 0.86 mmol, 1.5 equiv) was
added. After 10 h at r.t., the mixture was quenched with sat. aq NH4Cl
(25 mL), extracted with Et2O (2 ´ 50 mL) and washed again with aq
NH4Cl (25 mL) and brine (2 ´ 25 mL), dried (Na2SO4), and concen-
trated under reduced pressure to give an orange oil. Chromatography
(80% petroleum ether/Et2O) yielded 64 mg (52%) of S-tert-butyl 2,2-
diacetylthioacetate (11) and 51 mg (46%) of S-tert-butyl 2,2,2-tri-
acetylthioacetate (12), both as colorless oils.
15:
1H NMR (CDCl3, 250 MHz): d = 8.58 (dd, 1H, J = 5.0 and 1.0 Hz,
C6¢-H), 7.66 (td, 1H, J = 7.5 and 2.0 Hz, C4¢-H), 7.30 (d, 1H, J = 7.5
Hz, C3¢-H), 7.20 (ddd, 1H, J = 7.5, 5.0 and 1.0 Hz, C5¢-H), 3.97 (s, 2H,
C2-H), 1.46 (s, 9H, t-Bu).
3C NMR (CDCl3, 63 MHz): d = 196.76 (C1), 154.30 (C2¢), 149.66
(C6¢), 136.71 (C4¢), 124.16 (C3¢), 122.26 (C5¢), 53.53 (C2), 48.55
[C(CH3)3], 29.79 [C(CH3)3].
16:
1H NMR (CDCl3, 250 MHz): d = 8.65 (d, 1H, J = 4.0 Hz, C6¢-H), 7.77
(td, 1H, J = 7.5 and 1.5 Hz, C4¢-H), 7.50 (d, 1H, J = 8.0 Hz, C3¢-H),
7.32 (dd, 1H, J = 7.5 and 5.0 Hz, C5¢-H), 5.84 (d, 1H, J = 47.5 Hz, C2-
H), 1.48 (s, 9H, t-Bu).
12:
IR (NaCl): n = 1770 (C=O), 1698 (t-BuS-C=O) cm–1.
1H NMR (CDCl3, 250 MHz): d = 2.27, 2.26 and 2.13 (3 s, 3 ´ 3H, 3
CO-CH3), 1.49 (s, 9H, t-Bu).
13C NMR (CDCl3, 63 MHz): d = 196.17 (C1), 154.14 (C2¢), 149.72
13C NMR (CDCl3, 63 MHz): d = 194. 14 (C1), 192.45, 167.50 and
160.84 (3 CO-CH3), 131.42 (C2), 49.29 [C(CH3)3], 29.45 [C(CH3)3],
29.73, 20.82 and 19.32 (3 CO-CH3).
(C6¢), 137. 17 (C4¢), 124.20 (C3¢), 121.34 (C5¢), 95.56 (d, C2, JC-F
760.0 Hz), 48.72 [C(CH3)3], 29.79 [C(CH3)3].
=
19F NMR (CDCl3, 235 MHz): d = –182.19 (d, 1F, J = 47.0 Hz, C2-F).
Method B; Using one equivalent of NaH: Starting from 1 (174 mg,
1.00 mmol), NaH (44 mg of a 60% dispersion in mineral oil, 1.10
mmol, 1.1 equiv), and AcCl (86 mg, 1.10 mmol, 1.1 equiv) in DME
(19 mL), a yield of 41 mg (29%) 12, as a colorless oil, was obtained,
together with 100 mg of recovered 1.
17:
1H NMR (CDCl3, 250 MHz): d = 8.71 (d, 1H, J = 4.0 Hz, C6¢-H), 8.02
(d, 1H, J = 8.0 Hz, C3¢-H), 7.82 (td, 1H, J = 7.5 and 1.5 Hz, C4¢-H),
7.46 (dd, 1H, J = 7.0 and 5.0 Hz, C5¢-H), 1.56 (s, 9H, t-Bu).
13C NMR (CDCl3, 63 MHz): d = 194.04 (C2), 187.75 (C1), 150.48
(C2¢), 150.01 (C6¢), 137.23 (C4¢), 127.95 (C3¢), 124.89 (C5¢), 50.20
[C(CH3)3], 30.04 [C(CH3)3].
Arylation of S-tert-Butyl Acetothioacetate on C2; General Proce-
dure:
Method A: To a solution of 1 (0.10 g, 0.58 mmol) in anhyd CHCl3 (5
mL) under N2 at r.t., was added dropwise pyridine (45 mg, 0.63
mmol; 1.1 equiv). The solution was stirred for 5–10 min, and p-tolyl-
lead triacetate (0.301 g, 0.63 mmol, 1.1 equiv) was added. After 22 h
at 40°C, the mixture was quenched with sat. aq NH4Cl (10 mL), ex-
tracted with CHCl3 (2 ´ 20 mL) and washed again with aq NH4Cl (10
mL) and brine (2 ´ 10 mL), dried (Na2SO4), and concentrated under
reduced pressure to give an orange oil. Chromatography (99% petro-
leum ether/Et2O) yielded 45 mg of 1 and 22 mg (20%) of S-tert-butyl
3-oxo-2,2-bis(p-tolyl)butanethioate (13).
2¢,5¢-Dimethoxy-3-oxoanilides; General Procedure:
To a solution of the suitable b-oxo thioester (0.750–0.300 g, 1.60–
3.71 mmol) and 2,5-dimethoxyaniline (0.256–0.625 g, 1.68–4.08
mmol; 1.05–1. 1 equiv) in DME (5–15 mL) was added freshly pre-
pared silver trifluoroacetate27 (0.282–0.656 g, 1.28–2.97 mmol). Af-
ter 10 min at r.t., more silver salt (0.141–0.328 g, 0.64–1.49 mmol,
totalling 1.2 equiv) was added, and the suspension was stirred over-
night at r.t.28 The dark-brown suspension was decanted from the pre-
cipitate of silver salts, which was washed with petroleum ether
(3 ´ 20–50 mL). The combined organic phases were concentrated un-
der reduced pressure to give a black oil. Chromatography (CH2Cl2 to
Et2O) yielded the corresponding 2¢,5¢-dimethoxy-3-oxoanilides as
white solids (compounds 18,4a 19 and 22–25) or syrups (compounds
20 and 21).
1H NMR (CDCl3, 60 MHz): d = 7.20 (d, 4H, J = 8.0 Hz, C3¢,5¢), 6.90
(d, 4H, J = 8.0 Hz, C2¢,6¢), 2.35 (s, 9H, 2 Ar-CH3 and CO-CH3), 1.30
(s, 9H, t-Bu).
Method B: The general method for alkylation at C2 was used, starting
from 1 (0.250 g, 1.44 mmol) and p-tolyllead triacetate (0.750 g,
1.58 mmol; 1.1 equiv), and using anhyd CH2Cl2 (8 mL) as solvent.
Chromatography (90% petroleum ether/Et2O) yielded 170 mg of 1
and 61 mg (22%) of 13.
N-(2,5-Dimethoxyphenyl)-2-oxopropanamide (26):
Method A: To a solution of S-tert-butyl 2-methyl-3-oxobutanethioate
(2) (0.40 g, 2.13 mmol) and 2,5-dimethoxyaniline (0.340 g, 2.23
mmol, 1.05 equiv) in DME (7 mL) at 60°C, four portions of silver tri-
fluoroacetate (1.412 g, 6.39 mmol, 3 equiv) were added at 10-min in-
tervals. After 1.5 h, the dark brown suspension was decanted from the
precipitate of silver salts, and concentrated under reduced pressure to
give a black oil. Chromatography (CH2Cl2 to CHCl3) yielded 0.422 g
(89%) of 26; mp 91–93 °C (Et2O).
Reaction of S-tert-Butyl Acetothioacetate with N-Fluoropyridini-
um Triflate:
To a slurry of petroleum ether washed (2 ´ 10 mL) NaH (81 mg of a
60% dispersion in mineral oil, 2.11 mmol; 1.05 equiv), in anhyd DME
(12 mL) under N2 at –20°C, was added dropwise, via cannula, a solu-
tion of S-tert-butyl acetothioacetate (1) (0.350 g, 2.01 mmol) in DME
(3 mL). The solution was left to warm to 0°C for 5–10 min, and N-
fluoropyridinium triflate (0.521 g, 2.11 mmol, 1.05 equiv) was added.
After 2.5 h at r.t., the mixture was quenched with sat. aq NH4Cl (25
mL), extracted with Et2O (2 ´ 50 mL) and washed again with aq
NH4Cl (50 mL) and brine (2 ´ 25 mL), dried (Na2SO4), and concen-
trated under reduced pressure to give an orange oil. Chromatography
(90% petroleum ether/Et2O) yielded 83 mg (20%) of 2-(2-methoxy-
ethoxy)pyridine (14), S-tert-butyl 2-(2-pyridyl)thioacetate (15), and
24 mg (5%) of S-tert-butyl 2-fluoro-2-(2-pyridyl)thioacetate (16).
Compound 16 is unstable, and during its purification by chromatog-
raphy on silica gel gave S-tert-butyl 2-oxo-2-(2-pyridyl)thioacetate
(17).
IR (KBr): n = 3415 (NHassoc.), 3375 (NHfree), 1725 (C=O), 1694 (CO-
N), 1221 (OCH3) cm–1.
1H NMR (CDCl3, 250 MHz): d = 9.38 (sa, 1H, NH), 8.12 (d, 1H, J =
3.0 Hz, C6¢-H), 6.82 (d, 1H, J = 9.0 Hz, C3¢-H), 6.64 (dd, 1H, J = 3.0
and 9.0 Hz, C4¢-H), 3.86 (s, 3H, C5¢-OMe), 3.80 (s, 3H, C2¢-OMe), 2.57
(s, 3H, C3-H).
13C NMR (CDCl3, 75 MHz): d = 197.03 (C2), 157.64 (C1), 153.78
(C5¢), 143.14 (C2¢), 126.58 (C1¢), 111.01 (C3¢), 110.01 (C4¢), 105.86
(C6¢), 56.29 (C5¢-OMe), 55.84 (C2¢-OMe), 24.19 (C3).
Method B: A suspension of N-(2,5-dimethoxyphenyl)-2-methyl-3-
oxobutanamide (23) (35 mg, 0.14 mmol) and Cu(OAc)2 (28 mg, 0.15
mmol; 1.1 equiv) or silver trifluoroacetate (34 mg, 0.15 mmol; 1. l
equiv) in DME (3 mL) was stirred for 2 h at 70°C and then concen-
trated under reduced pressure. Chromatography of the reaction crude
(CH2Cl2) gave 20 mg (64%; 86% based on recovered starting materi-
al) of 26.
14:
1H NMR (CDCl3, 250 MHz): d = 8.13 (dd, 1H, J = 5.0 and 2.0 Hz,
C6-H), 7.77 (ddd, 1H, J = 8.5, 7.0 and 2.0 Hz, C4-H), 6.86 (dd, 1H, J

194
Papers
SYNTHESIS
5,8-Dimethoxycarbostyrils; General Procedures:
(7) Benetti, S.; Romagnoli, R.; De Risi, C,; Spalluto, G. Chem. Rev.
1995, 95, 1065.
(8) Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101.
(9) CIemens, R. J. Chem. Rev. 1986, 86, 241.
Method A: Cyclization with H2SO4: A solution of N-(2,5-dimethoxy-
phenyl)-3-oxobutanamide 18, 19, 20 or 23 (0.30–0.15 g, 1.20–0.54
mmol) in 96% H2SO4 (2–3 mL) was stirred at r.t. for 50 min–3 h, and
was then quenched with ice, made basic with 25% aq NH4OH and ex- (10) Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431.
tracted with CHCl3 (3 ´ 25–50 mL). The combined organic layers (11) Ley, S. V.; Woodward, P. R. Tetrahedron Lett. 1987, 32, 2431.
were washed with brine (25–50 mL), dried (Na2SO4) and concentrat- (12) Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. Chem. Soc., Perkin
ed under reduced pressure to give an off-white solid. Chromatogra-
phy (50% Et2O/EtOAc to EtOAc) afforded the corresponding 4-mono
or 3,4-disubstituted 5,8-dimethoxyquinolin-2(1H)-ones as white sol-
ids (compounds 27, 30 and 31).
Trans. 1 1987, 121.
Ley, S. V.; Trudell, M.; Wadsworth, D. J. Tetrahedron 1991,
47, 8285.
Booth, P. M.; Broughton, H. B.; Ford, M. J.; Fox, C. M. J.; Ley,
S. V.; Slawin, A. M. Z.; Williams, D. J.; Woodward, P. R.
Tetrahedron 1991, 47, 2005.
Method B: Cyclization with HCl: A suspension of amide 21 or 24
(0.30 g; 0.92 mmol) in 35% HCl (25 mL) was vigorously stirred at r.t.
for 4–7 d. The product was isolated following Method A and the chro-
matography was performed using Et2O as the mobile phase (com-
pounds 28 and 33).
(13) Compounds 2 and 4 had been previously obtained using this
methodology in 46% and 65% yields, respectively: Booth, P.
M.; Fox, C. M. J.; Ley, S. V. Tetrahedron Lett. 1983, 24, 5143.
(14) Bell, H. C.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979, 32,
1521.
Method C: Cyclization with TsOH: Compound 22 or 25 (70–90 mg;
0.25–0.33 mmol) was cyclized by heating in refluxing xylene at 185 °C
for 3–4 h in the presence of a catalytic amount of TsOH (50–60 mg,
1.0 equiv). The mixture was washed with H2O (2 ´ 30–50 mL), dried
(Na2SO4), and concentrated under reduced pressure to give a dark oil,
and chromatographed (EtOAc) (compounds 29 and 34).
(15) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353.
(16) Aryllead triacetates give 2,2-disubstituted derivatives by treat-
ment with the anions derived from several types of b- dicarbo-
nyl compounds. See, for example:
Rowe, B. A.; Pinhey, J. T. Aust. J. Chem. 1979, 32, 1561.
May, G. L.; Pinhey, J. T. Aust. J. Chem. 1982, 35, 1859.
(17) Dialkylation through this mechanism is a common problem in
the reaction of enolate anions and alkyl halides. See:
Jackman, L. M. Tetrahedron 1977, 33, 2737.
Caine, D. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford 1991; Vol. 3, p 1.
(18) Umemoto, T.; Tomita, K.; Kawada, K. Org. Synth. 1991, 69,
129.
Quinoline-2,5,8(1H)-triones from 5,8-Dimethoxycarbostyrils;
General Procedure:
Method A: To a solution of 5,8-dimethoxyquinolin-2(1H)-one 27, 28,
30, 31, 33 or 34 (20–184 mg, 0.07–0.70 mmol) in a mixture of
CH3CN and H2O (2:1), cerium ammonium nitrate (CAN) (0.106–
1.159 g, 0. 19–0.21 mmol; 3 equiv) was added. The solution was
stirred at r.t. for 30 min–5 h, and was then diluted with H2O (10–20
mL) and extracted with CHCl3 (3 ´ 20–50 mL). The CHCl3 layer was
washed with H2O (2 ´ 25–50 mL), dried (Na2SO4) and concentrated
under reduced pressure to give an orange-red solid. Quick chromatog-
raphy (Et2O) or sublimation (compounds 35–40) was used to purify
the quinones, which were isolated as dark-orange or red solids.
Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986,
27, 4465.
(19) Rogers, M. T.; Burdett, J. L. Can. J. Chem. 1965, 43, 1516.
Allen, G.; Dwek, R. A. J. Chem. Soc. (B) 1966, 161.
(20) Compound 18 had been previously prepared from 2,5-di-
methoxyaniline and 2,2,6-trimethyl-l,3-dioxin-4-one. See ref 4a.
(21) Kettrup, A. Monatsch. Chem. 1975, 106, 55.
(22) Similar oxygen additions to other enols and enolates are describ-
ed: Jones, A. B. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon: Oxford 1991; Vol. 7, p 151.
(23) We have observed a similar oxidative degradation in the ab-
sence of metals for 3-aryl-b- oxo anilides, which exist predomi-
nantly as enol tautomers. López-Alvarado, P.; Avendano, C.;
Menéndez, J. C. J. Org. Chem. 1996, 61, 5865.
Method B: To a solution of 5,8-dimethoxyquinolin-2(1H)-one 28 or
33 (20–155 mg, 0.065–0.501 mmol) in MeCN (2–10 mL), a solution
of cerium ammonium nitrate (CAN) (0.071–0.549 g, 0.13–
1.00 mmol; 2 equiv) in H2O (1–5 mL) was added. If necessary, slight
heating can be applied to dissolve completely the starting material,
but the addition of the oxidant should be carried out at r.t. Compounds
36 and 39 were isolated following Method A. In the case of the oxi-
dation of compounds 29 and 32, the quinones could not be isolated
from the aqueous phase.
(24) López-Alvarado, P.; Avendaño, C.; Menéndez, J. C. Synth.
Commum. 1992, 22, 2329.
(1) Gesto, C.; de la Cuesta, E.; Avendano, C. Tetrahedron 1989, 45,
4477.
(25) S-tert-Butyl 2-acetyl-2-allylpent-4-enethioate: Anal. calcd. for
C14H22SO2, M = 254: C, 66.10 H, 8.71. Found: C, 66.23; H,
8.51. IR (NaCl): n = 1721 (C=O), 1672 (t-BuS-C=O) cm–1, 1H
NMR (CDCl3, 300 MHz): d = 5.60–5.46 (ddt, 2H, J = 17.0; 9.5
and 7.5 Hz, C2¢-H), 5.04 (d, 2H, J = 17.5 Hz, C3¢-Htrans), 5.03 (d,
2H, J = 9.5 Hz, C3¢-Hcis), 2.58 (m, 4H, C1¢-H), 2.13 (s, 3H, C4-
H), 1.46 (s, 9H, t-Bu).13C NMR (CDCl3, 75 MHz): d = 203.71
(C3), 199.47 (C1), 131.70 (C2¢), 119.36 (C3¢), 70.82 (C2), 48.86
[C(CH3)3], 35.42 (C2-CH2), 29.66 [C(CH3)3], 26.68 (C4).
(26) Dialkylation is favored by the use of more concentrated solu-
tions. For example, starting from S-tert-butyl acetothioacetate
(1) (1.50 g, 8.62 mmol), MeI (1.281 g, 9.05 mmol) and NaH
(379 mg of a 60% dispersion in mineral oil, 9.48 mmol) in DME
(13 mL) a yield of 1.118 g (69%) of 2 and 278 mg (16%) of S-
tert-butyl 2,2-dimethyl-3-oxobutanethioate was obtained. IR
Pérez, J. M.; Vidal, L.; Grande, M. T.; Menéndez, J. C.; Aven-
dano, C. Tetrahedron 1994, 50, 7923.
Villacampa, M.; Pérez, J. M.; Avendano, C.; Menéndez, J. C.
Tetrahedron 1994, 50, 10047.
Pérez, J. M.; Avendano, C.; Menéndez, J. C. Tetrahedron 1995,
51, 6573.
Blanco, M. M;. Alonso, M. A.; Avendano, C.; Menéndez, J. C.
Tetrahedron 1996, 52, 5933.
(2) Omura, S.; Iwai, Y.; Hinotozawa, K.; Tanaka, H.; Takahashi,
Y.; Nakagawa, A. J. Antibiot. 1982, 35, 1425.
(3) Friedländer reaction: Blanco, M. M.; Avendano, C.; Cabezas,
N.; Menéndez, J. C. Heterocycles 1993, 36, 1387.
Vilsmeier–Haack reaction: Alonso, M. A.; Blanco, M. M.;
Avendano, C.; Menéndez, J. C. Heterocycles 1993, 36, 2315.
lntramolecular Wittig reaction: Ferrer, P.; Avendano, C.; Söll-
huber, M. Liebigs Ann. Chem. 1995, 1895.
(4) a)Avendano, C.; de la Cuesta, E.; Gesto, C. Synthesis 1991, 727.
b) Martín, O.; de la Cuesta, E.; Avendano, C. Tetrahedron 1995,
51, 7547.
(5) Jones, G. Adv. Heterocycl. Chem. 1977, 32, 137.
Manske, R. H. Chem. Rev. 1942, 30, 121.
1
(NaCl): n = 1724 (C=O), 1671 (t-BuS-C=O) cm–1. H NMR
(CDCl3, 250 MHz): d = 2.16 (s, 3H, C4-H); 1.47 (s, 9H, t-Bu);
1.37 [s, 6H, (CH3)2-C2].13C NMR (CDCl3, 63 MHz): d = 205.78
(C3), 201.79 (C1), 64.06 (C2), 48.30 [C(CH3)3], 29.61
[C(CH3)3], 25.83 (C4), 22.07 [( CH3)2-C2].
(27) Janssen, D. E.; Wilson, C. V. Org. Synth. 1956, 36, 47.
(28) The reaction was complete after 1.5 h in most cases. However,
if the mixture is quenched in this moment, the yield obtained is
lower because silver species in solution interfere during the pu-
rification process.
(6) For an example see: Kelly, T. R.; Field, J. A.; Li, Q. Tetrahe-
hedron Lett. 1988, 29, 3545.