Versatile Synthesis of Dihydroquinolines and Quinoline Quinones Using Cyclobutenediones. Construction of the Pyridoacridine Ring System

Article abstract of DOI:10.1021/jo970039v

1-BOC-2-lithio-1, 4-dihydropyridines were condensed with 3,4-disubstituted cyclobutenediones to produce 1,2-adducts. Neat thermolysis under oxygen-free conditions produced substituted 1,4-dihydroquinoline hydroquinones in which the tert-butoxy residue of the BOC group was displaced by a phenolic residue, generating an oxazolone ring that functioned to protect both rings of the dihydroquinoline hydroquinone from untimely oxidation. Oxidative aromatization with concomitant loss of the oxazolone ring was achieved using 2 equiv of o-chloranil in acetic acid and provided substituted quinoline quinones in good yields. By use of this strategy, a concise synthesis of the pyridoacridine ring system was achieved.

Full text of DOI:10.1021/jo970039v

4330
J . Org. Chem. 1997, 62, 4330-4338
Ver sa tile Syn th esis of Dih yd r oqu in olin es a n d Qu in olin e Qu in on es
Usin g Cyclobu ten ed ion es. Con str u ction of th e P yr id oa cr id in e
Rin g System
Dawei Zhang, Isidro Llorente,1 and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory University, 1515 Pierce Drive, Atlanta, Georgia, 30322
Received J anuary 6, 1997X
1-BOC-2-lithio-1,4-dihydropyridines were condensed with 3,4-disubstituted cyclobutenediones to
produce 1,2-adducts. Neat thermolysis under oxygen-free conditions produced substituted 1,4-
dihydroquinoline hydroquinones in which the tert-butoxy residue of the BOC group was displaced
by a phenolic residue, generating an oxazolone ring that functioned to protect both rings of the
dihydroquinoline hydroquinone from untimely oxidation. Oxidative aromatization with concomitant
loss of the oxazolone ring was achieved using 2 equiv of o-chloranil in acetic acid and provided
substituted quinoline quinones in good yields. By use of this strategy, a concise synthesis of the
pyridoacridine ring system was achieved.
In tr od u ction
Pyridoacridines are a family of marine alkaloids based
on the 11H-pyrido[4,3,2-mn]acridine skeleton (1) (Figure
1),2 many of which possess the “pyridoacridone” structure
2. These compounds often exhibit an array of biological
activities and a particular chemical behavior that have
attracted the interest of many natural product chemists
and biochemists. Since 1983, when the structure of
amphimedine, the first of these marine alkaloids was
reported,3 many additional examples have been de-
scribed, and a number of papers have appeared describ-
ing synthetic efforts toward and the total synthesis of
pyridoacridine alkaloids.4-14
F igu r e 1.
biologically-active pyridoacridone ring system is depicted
in eq 1. Addition of a suitably protected 4-(2-anilinyl)-
Building upon the well-established chemistry of cy-
clobutenediones 3,15-27 a direct synthetic entry to the
* To whom correspondence should be addressed. Tel.: (404) 727-
6604. Fax: (404) 727-0845. E-mail: CHEMLL1@emory.edu.
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Dr. Isidro Llorente thanks the Spanish Ministerio de Educacio´n
y Ciencia for support in the form of a postdoctoral fellowship.
(2) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(3) Schmitz, F. J .; Agarwal, S. K.; Gunasekera, S. P.; Schmidt, R.
G.; Shoolery, J . N. J . Am. Chem. Soc. 1983, 105, 4835.
(4) Szczepankiewicz, B. G.; Heathcock, C. H. J . Org. Chem. 1994,
59, 3512.
(5) Bishop, M. J .; Ciufolini, M. A. J . Am. Chem. Soc. 1992, 114,
10081.
(1)
(6) Ciufolini, M. A.; Byrne, N. E. J . Am. Chem. Soc. 1991, 113, 8016.
(7) Moody, C. J .; Rees, C. W.; Thomas, R. Tetrahedron 1992, 48,
3589.
(8) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110,
4051.
(9) Gellerman, G.; Rudi, A.; Kashman, Y. Tetrahedron Lett. 1992,
33, 5577.
(10) Alli, N. M.; Chattopadhyay, S. K.; Mckillop, A.; M., P. R.;
Ozturk, T.; Rebelo, R. A. J . Chem. Soc., Chem. Commun. 1992, 1453.
(11) Go´mez-Bengoa, E.; Echavarren, A. M. J . Org. Chem. 1991, 56,
3497.
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1121.
(13) Subramanyam, C.; Noguchi, M.; Weinreb, S. M. J . Org. Chem.
1989, 54, 5580.
2-lithiopyridine to a substituted cyclobutenedione would
provide a 1,2-adduct that could be transformed into the
pyridoacridone ring system 2 upon thermolysis, depro-
tection, and oxidation. However, a wide variety of 1,2-
adducts derived from cyclobutenediones and 2-lithiated
pyridines or other 2-lithiated azaaromatics produced
ring-fused pyridones, exclusively (eq 2), by attack of the
(14) Labarca, C. V.; Mackenzie, A. R.; Moody, C. J .; Rees, C. W.;
Vaquero, J . J . J . Chem. Soc., Perkin Trans. 1 1987, 927.
(15) Koo, S.; Liebeskind, L. S. J . Am. Chem. Soc. 1995, 117, 3389.
(16) Turnbull, P.; Moore, H. W. J . Org. Chem. 1995, 60, 3274.
(17) Turnbull, P.; Moore, H. W. J . Org. Chem. 1995, 60, 644.
(18) Sun, L.; Liebeskind, L. S. J . Org. Chem. 1995, 60, 8194.
(19) Gurski-Birchler, A.; Liu, F.; Liebeskind, L. S. J . Org. Chem.
1994, 59, 7737.
(22) Liebeskind, L. S.; Wang, J . Y. J . Org. Chem. 1993, 58, 3550.
(23) Gurski, A.; Liebeskind, L. S. J . Am. Chem. Soc. 1993, 115, 6101.
(24) Krysan, D. J .; Gurski, A.; Liebeskind, L. S. J . Am. Chem. Soc.
1992, 114, 1412.
(25) Liebeskind, L. S.; Granberg, K. L.; Zhang, J . J . Org. Chem.
1992, 57, 4345.
(20) Edwards, J . P.; Krysan, D. J .; Liebeskind, L. S. J . Am. Chem.
Soc. 1993, 115, 9868.
(26) Moore, H. W.; Yerxa, B. R. ChemtractssOrg. Chem. 1992, 5,
273.
(21) Lee, K. H.; Moore, H. W. Tetrahedron Lett. 1993, 34, 235.
(27) Liebeskind, L. S.; Zhang, J . J . Org. Chem. 1991, 56, 6379.
S0022-3263(97)00039-X CCC: $14.00 © 1997 American Chemical Society

Synthesis of Dihydroquinolines and Quinoline Quinones
J . Org. Chem., Vol. 62, No. 13, 1997 4331
Ta ble 1. Syn th esis of 1,4-Disu bstitu ted 1,4-Dih yd r op yr id in es
entry
RM
R
compd
condnsb 4 f 5
compd
yield (%)
1
2
3
4
5
6
7
NaBH4
H
4a
4b
4c
4d
4e
4f
A
B
B
C
C
C
C
5a 40
5b 28
5c28
5d
5e
5f
41
87
81
85
85
86
78
MeMgCla
Me
nBu
Ph
2-MeOC6H4
2-FC6H4
nBuMgCla
PhMgCla
2-MeOC6H4MgCla
(2-FC6H4)2CuLi
[4-(allyl)2NC6H4]2CuLi
4-(allyl)2NC6H4
4g
5g
a
b
5 mol % CuI. A: THF, rt. B: THF, -20 °C. C: toluene, -78 °C.
electron-rich nitrogen atom upon the ketene intermediate
that is formed during thermolysis.19,23
1,2-dihydropyridines.35-37 However, reaction of 1-acylpy-
ridinium salts with lithium dialkyl- or diarylcuprates
provides the isomeric 4-alkyl(aryl)-1,4-dihydropyridines.38
Comins reported an improved method for the preparation
of 4-substituted 1-acyl-1,4-dihydropyridines via the re-
gioselective addition of Grignard reagents to 1-acylpyri-
dinium salts in the presence of catalytic amounts of CuI.39
A number of 4-substituted 1,4-dihydropyridines were
prepared using both the addition of lithium diarylcu-
prates to 1-(phenoxycarbonyl)pyridinium chloride and the
Comins28 procedure (Table 1). The resulting crude
1-(phenoxycarbonyl)-1,4-dihydropyridines were treated
with potassium tert-butoxide and converted into the more
robust N-BOC derivatives prior to R-metalation with
alkyllithium bases. Using this protocol, the 4-alkyl-1-
(tert-butoxycarbonyl)-1,4-dihydropyridines were prepared
in very good yields as the only isolated regioisomers.
Unexpectedly, however, when 1-(phenoxycarbonyl)-4-
phenyl-1,4-dihydropyridine was treated with potassium
tert-butoxide in THF at various temperatures, a mixture
of the 1,2- and 1,4-regioisomers was obtained in which
the 1,2-dihydropyridine predominated. Since 1,4-dihy-
dropyridines are reported to be more stable than their
1,2-regioisomers (the latter isomerize to the former under
basic conditions),40,41 it is presumed that π-electron
delocalization with the 4-phenyl substituent increases the
thermodynamic stability of the 1,2-isomer relative to the
1,4-isomer. This problem was solved by conducting the
PhOCO to t-BuOCO exchange reaction in toluene at -78
°C. Under these conditions, urethane exchange occurred
to the exclusion of base-catalyzed double-bond isomer-
ization, and the desired 4-aryl-1-(tert-butoxycarbonyl)-
1,4-dihydropyridines were produced in good yields (Table
(2)
In order to circumvent the undesired interaction
between the nucleophilic nitrogen atom and the electro-
philic central carbon atom of the ketene, a cyclobutene-
dione-based route to quinoline quinones demands the use
of a 2-lithiopyridine equivalent that lacks a nucleophilic
nitrogen atom. N-BOC-protected 1,4-dihydropyridines
are easily prepared and are readily lithiated at the
2-position and then functionalized with electrophiles.28,29
These represent appropriate synthetic equivalents of
pyridines for the projected quinoline quinone synthesis.
The BOC protecting group provides activation for the
metalation step and attenuates the nucleophilicity of the
nitrogen atom, thus preventing undesired attack on the
ketene intermediate that is generated during the thermal
ring opening of the cyclobutenone. N-Deprotection is
easily effected, thereby allowing facile aromatization.
Reported herein is an efficient strategy for the prepara-
tion of substituted dihydroquinolines and the medicinally
important quinoline quinone ring system30-32 via the
regioselective addition of 1-BOC-2-lithio-1,4-dihydropy-
ridines to 3,4-disubstituted cyclobutenediones. An ap-
plication of this methodology to the synthesis of the
pyridoacridine ring system is described.
(28) Comins, D. L. Tetrahedron Lett. 1983, 24, 2807.
(29) Schlosser, M.; Schneider, P. Angew. Chem., Int. Ed. Engl. 1979,
18, 489.
(30) Davidson, B. S. Chem. Rev. 1993, 93, 1771.
(31) Thomson, R. H. In Total Synthesis of Natural Products;
Apsimon, J ., Ed.; J ohn Wiley & Sons, Inc.: New York, 1992; Vol. 8; p
311.
(32) Thomson, R. H. Naturally Occurring Quinones III; Chapman
and Hall: London, 1987; Vol. III.
(33) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291.
(34) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
(35) Yamaguchi, R.; Nakazono, Y.; Matsuki, T.; Hata, E.-i.; Kawa-
nisi, M. Bull. Chem. Soc. J pn. 1987, 60, 215.
(36) Yamaguchi, R.; Hata, E.-i.; Utimoto, K. Tetrahedron Lett. 1988,
29, 1785.
(37) Yamaguchi, R.; Otsuji, A.; Utimoto, K. J . Am. Chem. Soc. 1988,
110, 2186.
(38) Piers, E.; Soucy, M. Can. J . Chem. 1974, 52, 3563.
(39) Comins, D. L.; Abdullah, A. H. J . Org. Chem. 1982, 47, 4315.
(40) Sundberg, R. J .; Bloom, J . D. J . Org. Chem. 1981, 46, 4836.
(41) Fowler, F. W. J . Am. Chem. Soc. 1972, 94, 5926.
Resu lts a n d Discu ssion
The chemistry of dihydropyridines has been exten-
sively studied.33,34 Among the various methods known
for their preparation, the nucleophilic addition of orga-
nometallic reagents to pyridinium salts provides good
yields and in some cases occurs with high regioselectivity.
Therefore, the direct addition of organometallic reagents
(Mg, Li, Sn) to 1-acylpyridinium salts usually produces

4332 J . Org. Chem., Vol. 62, No. 13, 1997
Zhang et al.
Ta ble 2. Syn th esis of 1,4-Dih yd r oqu in olin e
Hyd r oqu in on es
Ta ble 3. Oxid a tion of 1,4-Dih yd r oqu in olin e
Hyd r oqu in on es to Qu in olin e Qu in on es
entry
7
R1
R2
R3
compd
yield (%)
1
2
3
4
5
6
7
8
7c
7e
7g
7h
7i
7j
7k
7l
Me
Me
nBu
nBu
Ph
iPrO
Me
iPrO
iPrO
iPrO
iPrO
iPrO
iPrO
iPrO
iPrO
8c
8e
8g
8h
8i
8j
8k
8l
55
47
93
73
62
82
77
82
iPrO
Me
iPrO
Me
Ph
2-MeOC6H4
2-FC6H4
iPrO
iPrO
yield
R3 compd (%)
entry
5
R1
3
R2
3a iPrO
comitant loss of the oxazolone ring and provided the
substituted quinoline quinones 8 in good yields (Table
3).
1
2
3
4
5
6
7
8
9
10
11
12
13
5a
5a
H
H
iPrO
7a
7b
7c
7d
7e
7f
7g
7h
7i
53
44
55
65
42
74
65
55
60
41
57
53
62
3d 4-FC6H4 iPrO
5b Me
5b Me
5b Me
5b Me
5c nBu
5c nBu
5d Ph
5d Ph
3a iPrO
3b Et
iPrO
Et
Con str u ction of th e P yr id oa cr id in e Rin g. Almost
all the members of pyridoacridine family of marine
alkaloids are cytotoxic, and some exhibit specific proper-
ties such as inhibition of topoisomerase II,43 anti-HIV
activity,44 Ca2+ release activity,45 metal-chelating proper-
ties,46 or intercalation into DNA.46 Different approaches
to the synthesis of these polycyclic alkaloids have been
reported in the last few years,4-8 and the efforts toward
the synthesis of their polycyclic skeletons and related
pyridoacridines are considerable.9-14 Because of the
importance that pyridoacridines have acquired since their
discovery, a general synthetic route to pyridoacridines
would be of great interest and potential utility in
medicinal chemistry.
A concise synthesis of the pyridoacridine ring system
that is based on the quinoline quinone synthesis de-
scribed above is depicted in Scheme 1. The key tactical
issue was selection of an appropriate aniline nitrogen-
protecting group that would survive exposure to the
strong nucleophiles and bases (RMgX, RLi) required for
formation of the 4-substituted 1,4-dihydropyridine and
its subsequent metalation. The 2,5-dimethylpyrrole group
fulfilled this role.47
Condensation of 2-bromoaniline with 2,5-hexanedione
in the presence of a catalytic amount of acetic acid
produced N-(2-bromophenyl)-2,5-dimethylpyrrole (9) in
quantitative yield. Copper-mediated addition of the
Grignard reagent derived from 9 to C5H5NCO2Ph+Cl-
provided the protected 4-(2-anilinyl)-1,4-dihydropyridine
10, which was treated with 2 equiv of potassium tert-
butoxide in toluene at -78 °C to produce the protected
4-(2-anilinyl)-1-(tert-butoxycarbonyl)-1,4-dihydropyri-
dine 11 as the only regioisomer in 86% overall yield.
Lithiation of dihydropyridine 11 in the presence of 2
equiv of sec-butyllithium at -78 °C over 5 h followed by
condensation with 3,4-diisopropoxy-3-cyclobutenedione
(3a ) at -78 °C directly afforded the 1,2-adduct as the
3c Me
iPrO
3d 4-FC6H4 iPrO
3a iPrO
3c Me
iPrO
iPrO
iPrO
iPrO
iPrO
iPrO
Et
3a iPrO
3c Me
7j
7k
7l
5e 2-MeOC6H4
5f 2-FC6H4
5g 4-(allyl)2NC6H4 3b Et
3a iPrO
3a iPrO
7m
1, entries 4-7). In the preparation of 4-unsubstituted
1-(tert-butoxycarbonyl)-1,4-dihydropyridine, the base-
catalyzed equilibration between the 1,2- and 1,4-regio-
isomers was employed to advantage. The mixture of 1,4-
and 1,2-dihydropyridines that is formed on reduction of
1-(phenoxycarbonyl)pyridinium chloride with sodium
borohydride was equilibrated in the presence of potas-
sium tert-butoxide in THF at room temperature and
produced compound 5a in 41% yield (Table 1, entry 1).40,42
Because most of the dihydropyridines investigated in
this study were not stable upon standing, 5a -g were
prepared immediately prior to use. Treatment of 4-sub-
stituted 1-(tert-butoxycarbonyl)-1,4-dihydropyridines 5
with sec-butyllithium in THF at -42 °C generated the
2-lithio derivatives, which reacted with a variety of 3,4-
disubstituted 3-cyclobutenediones 3 at the most electro-
philic carbonyl group to produce the 1,2-adducts, 6. The
crude adducts 6 were degassed under vacuum and then
heated neat at 160-165 °C for up to 60 min under an
oxygen-free atmosphere to produce the highly-substituted
1,4-dihydroquinoline hydroquinones 7 in moderate to
good yields (Table 2). Rigorous maintenance of oxygen-
free conditions was essential during the thermolysis in
order to prevent the formation of complex reaction
mixtures. During this process the 4-hydroxyl substituent
on the cyclobutenone ring displaced the tert-butoxy
residue of the BOC group generating an oxazolone ring,
which functioned to protect both rings of the dihydro-
quinoline hydroquinone from untimely oxidation. Re-
sults are summarized in Table 2.
(43) Schmitz, F. J .; Deguzman, F. S.; Hossain, M. B.; Vanderhelm,
D. J . Org. Chem. 1991, 56, 804.
(44) Taraporewala, I. B.; Cessac, J . W.; Chanh, T. C.; Delgado, A.
V.; Schinazi, R. F. J . Med. Chem. 1992, 35, 2744.
(45) Kobayashi, J .; Cheng, J .-f.; Wa¨lchli, M. R.; Nakamura, H.;
Hirata, Y.; Sasaki, T.; Ohizumi, Y. J . Org. Chem. 1988, 53, 1800.
(46) Gunawardana, G. P.; Koelm, F. E.; Lee, A. Y.; Clardy, J .; He,
H. Y.; Faulkner, D. J . J . Org. Chem. 1992, 57, 1523.
(47) Bruekelman, S. P.; Leach, S. E.; Meakins, G. D.; Tirel, M. D.
J . Chem. Soc., Perkin Trans. 1 1984, 2801.
Oxidative aromatization of the N-substituted 1,4-
dihydroquinoline hydroquinones 7 using 2 equiv of o-
chloranil in acetic acid28 proceeded efficiently with con-
(42) Fowler, F. W. J . Org. Chem. 1972, 57, 1321.

Synthesis of Dihydroquinolines and Quinoline Quinones
J . Org. Chem., Vol. 62, No. 13, 1997 4333
Sch em e 1a
Con clu sion s
A general synthesis of 4,6,7-substituted quinoline-5,8-
quinones was developed beginning with the condensation
of 2-lithio-N-BOC-1,4-dihydropyridines with cyclobutene-
diones. The synthesis is completed by thermolysis of the
1,2-adduct followed by oxidation of the resulting dihyd-
roquinoline hydroquinone with chloranil in acetic acid.
By use of this strategy, a concise synthesis of the
pyridoacridine ring system was achieved.
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H and 13C NMR spectra were
recorded at 300 and 75.5 MHz, respectively, in deuteriochlo-
1
roform (CDCl3) using chloroform (7.26 ppm H, 77.00 ppm 13C)
as the internal reference, unless otherwise stated. Analytical
thin-layer chromatography (TLC) was performed on Merck
Kieselgel 60 F254 plates. Visualization was accomplished by
one or more of the following methods: UV light, phosphomo-
lybdic acid stain, vanillin stain, and anisaldehyde stain.
Solvents for extraction and chromatography were reagent
grade and used as received. Chromatographic purification was
conducted by flash column chromatography and Baeckstro¨m
column chromatography49 using 32-63 µm flash silica gel
obtained from EM. Solvents (THF, toluene) were dried over
4 Å molecular sieves before use and had no more than 50 ppm
of H2O as measured by Karl Fischer titration. Reagents
purchased from commercial sources were used directly without
further purification. All reactions were performed under a dry
argon or nitrogen atmosphere in base-washed, flame-dried
glassware. “Brine” refers to a saturated aqueous solution of
NaCl. Unless otherwise specified, solutions of NH4Cl and
NaHCO3 refer to saturated aqueous solutions.
a
Key: (i) Mg, THF, reflux; (ii) C5H5NCO2Ph+Cl-, 5% CuI, -23
°C; (iii) KOtBu, toluene, -78 °C; (iv) BuLi, THF, -78 °C; (v) 3a ,
s
-78 °C; (vi) heat; (vii) NH2OH‚HCl, Et3N, NBS, EtOH:H2O; (viii)
tBuOOH, KOH, EtOH.
Sta r tin g Ma ter ia ls. The following starting materials were
prepared according to literature procedures: 1-(tert-butoxy-
carbonyl)-1,4-dihydropyridine,40 1-(tert-butoxycarbonyl)-4-meth-
yl-1,4-dihydropyridine,28 1-(tert-butoxycarbonyl)-4-n-butyl-1,4-
dihydropyridine,28 3,4-diisopropoxy-3-cyclobutene-1,2-dione,50
3-isopropoxy-4-methyl-3-cyclobutene-1,2-dione,50 3,4-diethyl-
3-cyclobutene-1,2-dione,50 4-(4-fluorophenyl)-3-isopropoxy-3-
cyclobutene-1,2-dione.50
oxazolone 12. The crude reaction product was degassed
under vacuum and heated neat at 160-165 °C for 45 min
under oxygen-free conditions to produce dihydroquinoline
hydroquinone 13 in good yield (66% overall from 11).
Primary amines have been generated from N-substi-
tuted 2,5-dimethylpyrroles by treatment with hydroxy-
lamine hydrochloride under pH-dependent conditions
(Et3N, i-PrOH/water).48 However, attempts to deprotect
the anilino nitrogen of 13 under these and related
conditions resulted in recovery of unreacted pyrrole or
complex reaction mixtures. On the basis of the assump-
tion that hydrolysis of the 2,5-dimethylpyrrole ring
hydrolysis might be facilitated through bromonium ion
formation, the hydroxylamine hydrochloride deprotection
procedure was attempted in the presence of N-bromo-
succinimide as a co-reagent. Using this protocol (20 equiv
of NH2OH‚HCl, 10 equiv of Et3N, 2 equiv of NBS, EtOH/
water), removal of the 2,5-dimethylpyrrole ring of 13
could be achieved in 57% yield. Starting material (30%)
was recovered, but the yield of the desired product, 14,
could not be increased through the use of larger amounts
of NBS and/or longer reaction times.
Oxidation of the dihydroquinoline hydroquinone 14 and
condensation to the pyridoacridone did not take place
using o-chloranil in acetic acid or other solvents. How-
ever, on treatment of 14 with excess tert-butyl hydro-
peroxide in ethanol/KOH, oxidation and spontaneous
condensation took place, giving the pyridoacridone 15 in
66% yield or 21% overall yield from 2-bromoaniline. A
variety of substituted pyridoacridines should be acces-
sible either by varying the cyclobutenedione or by direct
functionalization of 15.
Dih yd r op yr id in e Syn th esis. Because most of the dihy-
dropyridines investigated in this study were not stable upon
standing, 5a -g were prepared immediately prior to use.
1-(t er t -Bu t oxyca r b on yl)-4-p h e n yl-1,4-d ih yd r op yr i-
d in e (5d ). Pyridine (3.00 mL, 37.09 mmol, 1.50 equiv) and
CuI (235 mg, 1.23 mmol, 0.05 equiv) were dissolved in THF
(50 mL) at -23 °C in a 250 mL round-bottomed flask. Phenyl
chloroformate (3.87 g, 24.72 mmol, 1.00 equiv) was added
dropwise with stirring. After 5 min, phenylmagnesium chlo-
ride (12.36 mL, 2.0 M in THF, 24.73 mmol, 1.00 equiv) was
added via syringe pump over 40 min, and the resulting solution
was stirred at -23 °C for 30 min. After being warmed to room
temperature and stirred at that temperature for another 20
min, the reaction mixture was partitioned between aqueous
NH4Cl (20%, 35 mL) and Et2O (250 mL). The organic layer
was washed with NH4Cl (25 mL), water (25 mL), 10% HCl (2
× 25 mL), and water (3 × 25 mL) and then dried (MgSO4),
filtered, and evaporated, leaving 6.76 g of a yellow solid. A
portion of the crude solid (1.84 g) was dissolved in toluene (45
mL) and cooled to -78 °C in a 100 mL round-bottomed flask.
Potassium tert-butoxide in THF (19.90 mL, 1.00 M, 19.90
mmol, 3.00 equiv) was added dropwise, and the reaction
mixture was stirred at -78 °C for 1.5 h. The reaction mixture
was quenched with water and then partitioned between water
(25 mL) and Et2O (50 mL). The layers were separated, and
the organic layer was washed with 5% NaOH (2 × 25 mL)
and water (3 × 25 mL) and then dried (MgSO4), filtered, and
concentrated to a clear yellow oil. Chromatographic purifica
(49) Purchased from Baeckstro¨m SEPARO AB, Larsbergsva¨gen 24,
S-181 39 Lindingo¨, Sweden.
(48) Macor, J . E.; Chenard, B. L.; Post, R. J . J . Org. Chem. 1994,
59, 7496.
(50) Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J .
Org. Chem. 1988, 53, 2482.

4334 J . Org. Chem., Vol. 62, No. 13, 1997
Zhang et al.
tion (Flash column, silica gel, 2.5 cm × 10 cm, 10% EtOAc/
hexanes) gave 1-(tert-butoxycarbonyl)-4-phenyl-1,4-dihydro-
pyridine as a colorless oil (2.55 g, 8.87 mmol, 85%): TLC (silica
6.96 (m, 5 H), 6.81 (br s, 1 H), 4.91 (br s, 1 H), 4.85 (br s, 1 H),
4.55 (m, 1 H), 1.51 (s, 9 H).
1-(ter t-Bu toxycar bon yl)-4-[4-(N,N-diallylam in o)ph en yl]-
1,4-d ih yd r op yr id in e (5g). n-Butyllithium (1.87 mL, 2.20 M
in hexane, 4.11 mmol, 2.00 equiv) was added dropwise to a
-78 °C solution of 4-bromo-N,N-diallylaniline51 (1.04 g, 4.12
mmol, 2.00 equiv) dissolved in THF (20 mL) in a 50 mL round-
bottomed flask. After 30 min, copper(I) iodide (0.39 g, 2.05
mmol, 1.00 equiv) was added in one portion. The reaction
mixture was allowed to warm to room temperature and then
cannulated into a freshly prepared solution of pyridine (0.25
mL, 3.09 mmol, 1.50 equiv) and phenyl chloroformate (0.26
mL, 2.06 mmol, 1.00 equiv) in THF cooled to -23 °C. After 1
h, the reaction was quenched with NH4Cl (20 mL), and the
organic layer was washed with 1:1 NH4Cl/NH4OH (40 mL),
water (20 mL), 10% HCl (20 mL), and water (2 × 20 mL) and
then dried (MgSO4), filtered, and concentrated to a yellow oil
(0.70 g). The crude product was dissolved in 50 mL of toluene,
cooled to -78 °C, and treated dropwise with a solution of
potassium tert-butoxide in THF (5.60 mL, 1.00 M, 5.60 mmol,
2.72 equiv). After 1.5 h, the reaction mixture was partitioned
between water (35 mL) and Et2O (200 mL). The organic layer
was washed with 5% NaOH (2 × 50 mL) and water (3 × 25
mL) and then dried (MgSO4), filtered, and concentrated to a
yellow oil. Chromatographic purification (flash column, silica
gel, 1.5 cm × 10 cm, 5% EtOAc/hexanes) gave 1-(tert-butoxy-
carbonyl)-4-[4-(N,N-diallylamino)phenyl]-1,4-dihydropyri-
dine as a colorless oil (0.56 g, 1.59 mmol, 78%): TLC (silica
gel, 15% EtOAc/hexanes, Rf ) 0.50); IR (neat, KCl, cm-1) 2967
(m), 2930 (m), 1727 (w), 1603 (m); 1H NMR (CDCl3, 300 MHz)
δ 7.08 (d, J ) 8.4 Hz, 2 H), 6.90-6.76 (m, 2 H), 6.67 (d, J )
8.4 Hz, 2 H), 5.90-5.79 (m, 2 H), 5.21-5.14 (m, 4 H), 4.95-
4.84 (m, 2 H), 4.05-4.04 (m, 1 H), 3.91-3.89 (m, 4 H), 1.53 (s,
9 H).
1,4-Dih yd r oqu in olin es by Con d en sa tion of 2-Lith iod i-
h yd r op yr id in es a n d Cyclobu ten ed ion es. 1,8-(Ca r bon yl-
oxy)-6,7-d iisop r op oxy-5-h yd r oxy-1,4-d ih yd r oq u in olin e
(7a ). sec-Butyllithium (2.29 mL, 1.30 M in cyclohexane, 2.98
mmol, 1.10 equiv) was added dropwise to a -78 °C solution of
1-(tert-butoxycarbonyl)-1,4-dihydropyridine (5a ) (0.49 g, 2.70
mmol, 1.00 equiv) in THF (15 mL). The reaction mixture was
warmed to -42 °C, held at that temperature for 3 h, and then
cannulated into a -78 °C solution of 3,4-diisopropoxy-3-
cyclobutene-1,2-dione (3a ) (0.54 g, 2.72 mmol, 1.01 equiv) in
THF (10 mL). After 2 h, the reaction mixture was quenched
with NH4Cl (35 mL), allowed to warm to room temperature,
and extracted with ether (3 × 25 mL). The combined organic
layers were washed with water (3 × 25 mL), dried (MgSO4),
filtered, and concentrated to a yellow oil. The crude product
was degassed (six cycles, nitrogen-vacuum-nitrogen) and
placed into a hot oil bath (160-165 °C) for 1 h. Chromato-
graphic purification (Baeckstro¨m column, silica gel, 1.5 cm ×
10 cm, gradient from 100% hexanes to 50% EtOAc/hexanes)
gave 1,8-(carbonyloxy)-6,7-diisopropoxy-5-hydroxy-1,4-dihyd-
roquinoline as a white solid (0.44 g, 1.44 mmol, 53%): mp 79-
80 °C (EtOAc/hexane); TLC (silica gel, 10% EtOAc/hexanes,
Rf ) 0.63); IR (CH2Cl2, KCl, cm-1) 3512 (m), 3056 (s), 2989
(s), 1779 (s); 1H NMR (CDCl3, 300 MHz) δ 6.66-6.32 (m, 1 H),
5.81 (s, 1 H), 5.25-5.22 (m, 1 H), 4.83 (sept, J ) 6.0 Hz, 1 H),
4.46 (sept, J ) 6.0 Hz, 1 H), 3.45 (dd, J ) 3.3, 2.4 Hz, 1 H),
1.31 (d, J ) 6.0 Hz, 6 H), 1.25 (d, J ) 6.0 Hz, 6 H); 13C NMR
(CDCl3, 75.5 MHz) δ 150.7, 144.7, 134.3, 132.8, 124.1, 123.0,
118.2, 110.0, 96.7, 76.2, 74.5, 22.6, 22.4, 21.1. Anal. Calcd
for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.81;
H, 6.29; N, 4.57.
gel, 20% EtOAc/hexanes, Rf ) 0.72); IR (neat, KBr pellet, cm-1
)
3060 (w), 3028 (w), 2978 (s), 1718 (s); 1H NMR (CDCl3, 300
MHz) δ 7.38-7.20 (m, 5 H), 6.96 (d, J ) 7.2 Hz, 1 H), 6.80 (d,
J ) 6.6 Hz, 1 H), 4.96 (br s, 1 H), 4.88 (br s, 1 H), 4.20-4.19
(m, 1 H), 1.55 (s, 9 H).
1-(ter t-Bu toxyca r bon yl)-4-(2-m eth oxyp h en yl)-1,4-d ih y-
d r op yr id in e (5e). Magnesium turnings (0.30 g, 12.51 mmol,
1.20 equiv) and I2 (5 mg) were mixed together and flamed
under vacuum for 5-10 s in a 250 mL three-necked, round-
bottomed flask equipped with an addition funnel and con-
denser. 2-Bromoanisole (1.86 mL, 10.46 mmol, 1.00 equiv) was
added dropwise, initially just a few drops neat, and then the
remainder diluted in THF (10 mL). After 5 h, the resulting
black solution was cannulated into a freshly prepared mixture
of pyridine (1.26 mL, 15.58 mmol, 1.49 equiv), copper(I) iodide
(99 mg, 10.44 mmol, 0.05 equiv), and phenyl chloroformate
(1.31 mL, 10.440 mmol, 1.00 equiv) in THF (10 mL) cooled to
-23 °C. After 30 min, the reaction mixture was warmed to
room temperature and stirred for 30 min. The reaction
mixture was partitioned between saturated NH4Cl (20 mL)
and Et2O (50 mL) and the layers were separated. The organic
layer was washed with 1:1 NH4Cl/NH4OH (40 mL), water (20
mL), 10% HCl (20 mL), and water (2 × 20 mL) and then dried
(MgSO4), filtered, and concentrated to a yellow oil (3.20 g).
Potassium tert-butoxide in THF (20.89 mL, 1.00 M, 20.89
mmol, 2.00 equiv) was added dropwise to a solution of the
crude product in toluene (100 mL) at -78 °C. After being
stirred at -78 °C for 1.5 h, the reaction mixture was quenched
with water and then partitioned between water (35 mL) and
ether (100 mL). The layers were separated, and the organic
layer was washed with 5% NaOH (2 × 35 mL) and water (2 ×
25 mL), dried (MgSO4), filtered, and concentrated to a yellow
oil that was purified by chromatography (flash column, silica
gel, 2.5 cm × 10 cm, 10% EtOAc/hexanes) to give 1-(tert-
butoxycarbonyl)-4-(2-methoxyphenyl)-1,4-dihydropyridine as a
colorless oil (2.55 g, 8.87 mmol, 85%): TLC (silica gel, 20%
EtOAc/hexanes, Rf ) 0.49); IR (CDCl3, KCl, cm-1) 2983 (s),
2939 (s), 2250 (m), 1704 (s); 1H NMR (CDCl3, 300 MHz) δ 7.30
(dd, J ) 7.5, 1.5 Hz, 1 H), 7.20 (dt, J ) 7.8, 1.5 Hz, 1 H), 6.98
(app t, J ) 7.5 Hz, 1 H), 6.87-6.78 (m, 3 H), 4.98-4.90 (m, 2
H), 4.62-4.60 (m, 1 H), 3.83 (s, 3 H), 1.52 (s, 9 H).
1-(ter t-Bu t oxyca r b on yl)-4-(2-flu or op h en yl)-1,4-d ih y-
d r op yr id in e (5f). n-Butyllithium (14.77 mL, 1.60 M in
hexane, 23.63 mmol, 2.20 equiv) was added dropwise to a
solution of 2-fluorobromobenzene (3.76 g, 21.48 mmol, 2.00
equiv) dissolved in THF (50 mL) at -78 °C. After 40 min,
copper (I) iodide (2.05 g, 10.76 mmol, 1.00 equiv) was added
in one portion. The reaction mixture was stirred at -78 °C
for 10 min and then warmed to 0 °C. After 1 h, the green
solution was cannulated into a freshly prepared solution of
pyridine (1.30 mL, 16.07 mmol, 1.50 equiv) and phenyl
chloroformate (1.35 mL, 10.76 mmol, 1.00 equiv) in THF (50
mL) cooled to -23 °C. After 30 min, the reaction mixture was
allowed to warm to room temperature and then quenched with
NH4Cl (50 mL) and extracted with ether (3 × 50 mL). The
combined organic layers were washed with 1:1 NH4Cl/NH4-
OH (100 mL), water (50 mL), 10% HCl (50 mL), and water (2
× 50 mL) and then dried (MgSO4), filtered, and concentrated
to a yellow oil (3.40 g). The crude product was dissolved in
100 mL of toluene, cooled to -78 °C, and treated dropwise with
a solution of potassium tert-butoxide in THF (19.33 mL, 1.00
M, 19.33 mmol, 1.80 equiv). After 1.5 h, the reaction mixture
was quenched with water and then partitioned between water
(35 mL) and Et2O (200 mL). The layers were separated, and
the organic layer was washed with 5% NaOH (2 × 50 mL)
and water (3 × 25 mL) and then dried (MgSO4), filtered, and
concentrated to a yellow oil. Chromatographic purification
(flash column, silica gel, 2.5 cm × 10 cm, 10% EtOAc/hexanes)
gave 1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)-1,4-dihydropy-
ridine as a colorless oil (2.54 g, 9.23 mmol, 86%): TLC (silica
gel, 20% EtOAc/hexanes, Rf ) 0.62); IR (neat, KCl, cm-1) 2978
(s), 2932 (m), 1723 (s); 1H NMR (CDCl3, 300 MHz) δ 7.51-
1,8-(Ca r bon yloxy)-6-(4-flu or op h en yl)-5-h yd r oxy-7-iso-
p r op oxy-1,4-d ih yd r oqu in olin e (7b). Following the proce-
dure for 7a , above, 1-(tert-butoxycarbonyl)-1,4-dihydopyridine
(5a ) (0.34 g, 1.88 mmol, 1.00 equiv) in THF (15 mL) was
metalated at -42 °C for 3 h with sec-butyllithium (1.59 mL,
1.30 M in cyclohexane, 2.07 mmol, 1.10 equiv) and condensed
with 4-(4-fluorophenyl)-3-isopropoxy-3-cyclobutene-1,2-dione
(3d ) (0.44 g, 1.88 mmol, 1.00 equiv) in THF (20 mL) at -78
(51) Tidwell, J . H.; Senn, D. R.; Buchwald, S. L. J . Am. Chem. Soc.
1991, 113, 4685.

Synthesis of Dihydroquinolines and Quinoline Quinones
J . Org. Chem., Vol. 62, No. 13, 1997 4335
°C. Workup, thermolysis neat (160-165 °C, 1 h), and chro-
matographic purification (Baeckstro¨m column, silica gel, 1.5
cm × 10 cm, gradient from 100% hexanes to 50% EtOAc/
hexanes) gave 1,8-(carbonyloxy)-6-(4-fluorophenyl)-5-hydroxy-
7-isopropoxy-1,4-dihydroquinoline as a white solid (0.28 g, 0.82
mmol, 44%): mp 186-187 °C (EtOAc/hexane); TLC (silica gel,
20% EtOAc/hexanes, Rf ) 0.19); IR (CH2Cl2, KCl, cm-1) 3541
300 MHz) δ 6.67 (d, J ) 7.2 Hz, 1 H), 5.22 (dd, J ) 7.2, 4.2
Hz, 1 H), 4.86 (sept, J ) 6.0 Hz, 1 H), 4.65 (br s, 1 H), 3.77-
3.74 (m, 1 H), 2.10 (s, 3 H), 1.39 (d, J ) 6.9 Hz, 3 H), 1.31 (d,
J ) 6.0 Hz, 6 H); 13C NMR (CDCl3, 75.5 MHz) δ 150.9, 148.6,
138.4, 125.1, 124.4, 117.0, 116.5, 110.7, 103.0, 74.1, 27.9, 22.7,
22.6, 9.0. Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N,
5.09. Found: C, 65.19; H, 6.27; N, 5.06.
1
(m), 2983 (m), 1781 (s), 1388 (s); H NMR (CDCl3, 300 MHz)
1,8-(Ca r bon yloxy)-6-(4-flu or op h en yl)-5-h yd r oxyl-7-iso-
p r op oxy-4-m eth yl-1,4-d ih yd r oqu in olin e (7f). 1-(tert-Bu-
toxycarbonyl)-4-methyl-1,4-dihydropyridine (5b) (0.53 g, 2.71
mmol, 1.00 equiv) in THF (15 mL) was metalated -42 °C for
3 h with sec-butyllithium (2.30 mL, 1.30 M in cyclohexane,
2.99 mmol, 1.10 equiv) and condensed with 4-(4-flurophenyl)-
3-isopropoxy-3-cyclobutene-1,2-dione (3d ) (0.64 g, 2.73 mmol,
1.01 equiv) in THF (20 mL) at -78 °C. Workup, thermolysis
neat (160-165 °C, 45 min), and chromatographic purification
(Baeckstro¨m column, silica gel, 1.5 cm × 10 cm, gradient from
100% hexanes to 50% EtOAc/hexanes) gave 1,8-(carbonyloxy)-
6-(4-fluorophenyl)-5-hydroxyl-7-isopropoxy-4-methyl-1,4-dihy-
droquinoline as a white solid (0.71 g, 2.00 mmol, 74%): mp
148-149 °C (EtOAc/hexane); TLC (silica gel, 20% EtOAc/
hexanes, Rf ) 0.69); IR (CH2Cl2, KCl, cm-1) 3535 (w), 2981
δ 7.30-7.25 (m, 2 H), 7.18 (t, J ) 8.1 Hz, 2 H), 6.73 (dt, J )
8.1, 2.1 Hz, 1 H), 5.37-5.32 (m, J ) Hz, 1 H), 4.85 (s, 1 H),
4.75 (sept, J ) 6.0 Hz, 1 H), 3.52 (m, 2 H), 1.15 (d, J ) 6.0 Hz,
6 H); 13C NMR (CDCl3, 75.5 MHz) δ 160.9, 150.7, 147.5, 138.0,
133.0, 132.9, 128.1, 127.9, 124.4, 118.2, 116.3, 116.0, 115.1,
110.6, 97.7, 74.4, 22.4, 21.4. Anal. Calcd for C19H16NO4F: C,
66.86; H, 4.72; N, 4.10; F, 5.57. Found: C, 66.90; H, 4.73; N,
4.08.
1,8-(Ca r bon yloxy)-6,7-d iisop r op oxy-5-h yd r oxy-4-m eth -
yl-1,4-d ih yd r oq u in olin e (7c). 1-(tert-Butoxycarbonyl)-4-
methyl-1,4-dihydropyridine (5b) (0.78 g, 3.99 mmol, 1.00 equiv)
in THF (30 mL) was metalated at -42 °C for 3 h with sec-
butyllithium (3.99 mL, 1.20 M in cyclohexane, 4.79 mmol, 1.20
equiv) and condensed with 3,4-diisopropoxy-3-cyclobutene-1,2-
dione (3a ) (0.79 g, 3.99 mmol, 1.00 equiv) in THF (25 mL) at
-78 °C. Workup, thermolysis neat (160-165 °C, 45 min), and
chromatographic purification (Baeckstro¨m column, silica gel,
1.5 cm × 10 cm, gradient from 100% hexanes to 50% EtOAc/
hexanes) gave 1,8-(6,7-diisopropoxy-5-hydroxy-4-methyl-1,4-
dihydroquinoline as a white solid (0.70 g, 2.19 mmol, 55%):
mp 100-102 °C (EtOAc/hexane); TLC (silica gel, 20% EtOAc/
hexanes, Rf ) 0.32); IR (CH2Cl2, KCl, cm-1) 3509 (m), 3056
1
(s), 1789 (m), 1391 (m); H NMR (CDCl3, 300 MHz) δ 7.28-
7.24 (m, 2 H), 7.16-7.10 (m, 2 H), 6.60 (d, J ) 8.1 Hz, 1 H),
5.24 (dd, J ) 8.1, 4.2 Hz, 1 H), 5.01 (s, 1 H), 4.71 (sept, J )
6.0 Hz, 1 H), 3.80-3.75 (m, 1 H), 1.40 (d, J ) 6.9 Hz, 3 H),
1.11 (d, J ) 6.0 Hz, 6 H); 13C NMR (CDCl3, 75.5 MHz) δ 164.2,
160.9, 150.7, 147.8, 137.9, 133.1, 117.3, 116.5, 116.3, 116.0,
115.3, 102.9, 74.4, 28.2, 22.5, 22.4. Anal. Calcd for C20H17
-
NO4F: C, 67.79; H, 4.84; N, 3.95; F, 5.36. Found: C, 67.55;
H, 5.07; N, 3.94.
1
(m), 1779 (s); H NMR (CDCl3, 300 MHz) δ 6.68 (dd, J ) 4.2,
0.9 Hz, 1 H), 5.89 (s, 1 H), 5.21 (dd, J ) 4.2, 3.6 Hz, 1 H), 4.89
(sept, J ) 6.0 Hz, 1 H), 4.51 (sept, J ) 6.0 Hz, 1 H), 3.83-3.75
(m, 1 H), 1.43 (d, J ) 6.9 Hz, 3 H), 1.36 (d, J ) 6.0 Hz, 6 H),
1.31 (dd, J ) 6.0, 1.8 Hz, 6 H); 13C NMR (CDCl3, 75.5 MHz) δ
150.7, 145.0, 134.2, 132.8, 123.8, 122.3, 116.7, 116.5, 101.8,
4-n -Bu tyl-1,8-(car bon yloxy)-6,7-diisopr opoxy-5-h ydr oxy-
1,4-d ih yd r oqu in olin e (7g). 1-(tert-Butoxycarbonyl)-4-n-bu-
tyl-1,4-dihydropyridine 5c (1.07 g, 4.51 mmol, 1.00 equiv) in
THF (25 mL) was metalated at -42 °C for 3 h with sec-
butyllithium (4.51 mL, 1.20 M in cyclohexane, 5.41 mmol, 1.20
equiv) and then condensed with 3,4-diisopropoxy-3-cyclobutene-
1,2-dione (3a ) (0.89 g, 4.49 mmol, 1.00 equiv) in THF (40 mL)
at -78 °C. Workup, thermolysis neat (160-165 °C, 45 min),
and chromatographic purification (Baeckstro¨m column, silica
gel, 1.5 cm × 10 cm, gradient from 100% hexanes to 50%
EtOAc/hexanes) gave 4-n-butyl-1,8-(carbonyloxy)-6,7-diisopro-
poxy-5-hydroxy-1,4-dihydroquinoline as a white solid (1.05 g,
2.91 mmol, 65%): mp 104-105 °C (diethyl ether/hexane); TLC
(silica gel, 20% EtOAc/hexanes, Rf ) 0.25); IR (CH2Cl2, KCl,
cm-1) 3510 (s), 3060 (w), 2981 (s), 2932 (m), 1777 (s); 1H NMR
(CDCl3, 300 MHz) δ 6.70 (dd, J ) 7.2, 1.2 Hz, 1 H), 5.84 (s, 1
H), 5.19 (dd, J ) 7.2, 3.9 Hz, 1 H), 4.86 (sept, J ) 6.0 Hz, 1
H), 4.47 (sept, J ) 6.0 Hz, 1 H), 3.82-3.79 (m, 1 H), 2.01-
0.82 (m, 9 H), 1.32 (d, J ) 6.0 Hz, 6 H), 1.27 (d, J ) 6.0 Hz, 6
H); 13C NMR (CDCl3, 75.5 MHz) δ 150.8, 144.9, 134.2, 132.7,
123.7, 123.0, 117.6, 114.9, 100.5, 76.1, 74.5, 34.7, 32.8, 27.6,
22.7, 22.6, 22.4, 22.3, 14.0. Anal. Calcd for C20H27NO5: C,
66.46; H, 7.53; N, 3.88. Found: C, 66.54; H, 7.60; N, 3.94.
76.1, 74.5, 27.9, 22.7, 22.6, 22.4, 22.3. Anal. Calcd for C17H21
-
NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 64.03; H, 6.51; N,
4.27.
1,8-(Ca r bon yloxy)-6,7-d ieth yl-5-h yd r oxy-4-m eth yl-1,4-
d ih yd r oqu in olin e (7d ). 1-(tert-Butoxycarbonyl)-4-methyl-
1,4-dihydropyridine (5b) (0.59 g, 3.02 mmol, 1.00 equiv) in THF
(15 mL) was metalated at -42 °C for 3 h with sec-butyllithium
(2.56 mL, 1.30 M in cyclohexane, 3.33 mmol, 1.10 equiv) and
condensed with 3,4-diethyl-3-cyclobutene-1,2-dione (3b) (0.42
g, 3.04 mmol, 1.01 equiv) in THF (25 mL) at -78 °C. Workup,
thermolysis neat (160-165 °C, 45 min), and chromatographic
purification (Baeckstro¨m column, silica gel, 1.5 cm × 10 cm,
gradient from 100% hexanes to 50% EtOAc/hexanes) gave 1,8-
(carbonyloxy)-6,7-diethyl-5-hydroxy-4-methyl-1,4-dihydroquin-
oline as a white solid (0.51 g, 1.97 mmol, 65%): mp 132-133
°C (EtOAc/hexane); TLC (silica gel, 20% EtOAc/hexanes, Rf )
0.24); IR (CDCl3, KCl, cm-1) 3612 (m), 2973 (s), 2255 (m), 1769
1
(s); H NMR (CDCl3, 300 MHz) δ 6.71 (dd, J ) 8.1, 1.8 Hz, 1
H), 5.45 (s, 1 H), 5.22 (dd, J ) 8.1, 4.2 Hz, 1 H), 3.86-3.80 (m,
1 H), 2.81-2.63 (m, 4 H), 1.43 (d, J ) 6.9 Hz, 3 H), 1.22 (d, J
) 7.5 Hz, 3 H), 1.17 (d, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3,
75.5 MHz) δ 151.5, 147.9, 134.0, 124.5, 124.1, 123.9, 116.8,
116.7, 107.9, 28.0, 22.6, 19.7, 19.2, 14.8, 14.7. Anal. Calcd
for C15H16NO3: C, 69.75; H, 6.24; N, 5.42. Found: C, 69.31;
H, 6.63; N, 5.43.
4-n -Bu t yl-1,8-(ca r b on yloxy)-5-h yd r oxy-7-isop r op oxy-
6-m eth yl-1,4-d ih yd r oqu in olin e (7h ). 1-(tert-Butoxycarbo-
nyl)-4-n-butyl-1,4-dihydropyridine (5c) (0.35 g, 1.47 mmol, 1.00
equiv) in THF (20 mL) was metalated at -42 °C for 3 h with
sec-butyllithium (1.25 mL, 1.30 M in cyclohexane, 1.62 mmol,
1.10 equiv) and then condensed with 3-isopropoxy-4-methyl-
3-cyclobutene-1,2-dione (3c) (0.23 g, 1.47 mmol, 1.00 equiv)
in THF (15 mL) at -78 °C. Workup, thermolysis neat (160-
165 °C, 45 min), and chromatographic purification (Baeck-
stro¨m column, silica gel, 1.5 cm × 10 cm, gradient from 100%
hexanes to 50% EtOAc/hexanes) gave 4-n-butyl-1,8-(carbony-
loxy)-5-hydroxy-7-isopropoxy-6-methyl-1,4-dihydroquinoline as
a white solid (0.26 g, 0.82 mmol, 55%): mp 90-91 °C (hexane/
diethyl ether); TLC (silica gel, 20% EtOAc/hexanes, Rf ) 0.42);
IR (CH2Cl2, KCl, cm-1) 3595 (w), 2962 (w), 2933 (w), 1777 (s);
1H NMR (CDCl3, 300 MHz) δ 6.72 (d, J ) 7.2 Hz, 1 H), 5.23
(dd, J ) 7.2, 4.2 Hz, 1 H), 5.05 (br s, 1 H), 4.84 (sept, J ) 6.0
Hz, 1 H), 3.79 (m, 1 H), 2.10 (s, 3 H), 1.80-1.66 (m, 2 H), 1.30
(d, J ) 6.0 Hz, 6 H), 1.25-1.08 (m, 4 H), 0.83 (t, J ) 6.6 Hz,
3 H); 13C NMR (CDCl3, 75.5 MHz) δ 151.1, 148.6, 138.4, 125.6,
124.3, 117.5, 111.1, 101.9, 74.1, 35.3, 32.8, 27.6, 22.7, 22.7, 14.0,
1,8-(Car bon yloxy)-4,6-dim eth yl-5-h ydr oxy-7-isopr opoxy-
1,4-d ih yd r oqu in olin e (7e). 1-(tert-Butoxycarbonyl)-4-meth-
yl-1,4-dihydropyridine (5b) (0.78 g, 3.99 mmol, 1.00 equiv) in
THF (25 mL) was metalated at -42 °C for 3 h with sec-
butyllithium (4.36 mL, 1.10 M in cyclohexane, 4.80 mmol, 1.20
equiv) and condensed with 3-isopropoxy-4-methyl-3-cyclobutene-
1,2-dione (3c) (0.74 g, 4.80 mmol, 1.20 equiv) in THF (25 mL)
at -78 °C. Workup, thermolysis neat (160-165 °C, 45 min),
and chromatographic purification (Baeckstro¨m column, silica
gel, 1.5 cm × 10 cm, gradient from 100% hexanes to 50%
EtOAc/hexanes) gave 1,8-(carbonyloxy)-4,6-dimethyl-5-hydroxy-
7-isopropoxy-1,4-dihydroquinoline as a white solid (0.46 g, 1.67
mmol, 42%): mp 147-148 °C (hexane/diethyl ether); TLC
(silica gel, 20% EtOAc/hexanes, Rf ) 0.65); IR (CH2Cl2, KCl,
1
cm-1) 3608 (s), 2981 (m), 1771 (s), 1375 (s); H NMR (CDCl3,

4336 J . Org. Chem., Vol. 62, No. 13, 1997
Zhang et al.
9.2. Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41.
Found: C, 68.72; H, 7.86; N, 3.98.
poxy-3-cyclobutene-1,2-dione (3a ) (0.21 g, 1.06 mmol, 1.22
equiv) in THF (25 mL) at -78 °C. Workup, thermolysis neat
(160-165 °C, 1 h), and chromatographic purification (Baeck-
stro¨m column, silica gel, 1.5 cm × 10 cm, gradient from 100%
hexanes to 50% EtOAc/hexanes) gave 1,8-(carbonyloxy)-6,7-
diisopropoxy-4-(2-fluorophenyl)-5-hydroxy-1,4-dihydroquino-
line as a white solid (185 mg, 0.46 mmol, 53%): mp 147.2-
147.9 °C (EtOAc/hexane); TLC (silica gel, 20% EtOAc/hexanes,
Rf ) 0.35); IR (CH2Cl2, KCl, cm-1) 3504 (s), 3060 (s), 1781 (s),
1389 (s); 1H NMR (CDCl3, 300 MHz) δ 7.22-7.15 (m, 1 H),
7.06-6.70 (m, 3 H), 6.76 (d, J ) 7.8 Hz, 1 H), 5.63 (s, 1 H),
5.31-5.27 (m, 2 H), 4.91 (sept, J ) 6.0 Hz, 1 H), 4.47 (sept, J
) 6.0 Hz, 1 H), 1.37 (d, J ) 6.0 Hz, 6 H), 1.20-1.23 (m, 6 H);
13C NMR (CDCl3, 75.5 MHz) δ 161.5, 158.2, 150.6, 145.0, 135.1,
132.8, 130.3, 130.1, 129.9, 128.5, 128.4, 123.6, 123.0, 116.9,
116.9, 115.5, 115.2, 113.3, 98.3, 74.7, 31.9, 31.8, 22.7, 22.4. 22.4.
Anal. Calcd for C22H22NO5F: C, 66.16; H, 5.55; N, 3.51; F,
4.76. Found: C, 66.40; H, 5.59; N, 3.44.
1,8-(Ca r bon yloxy)-6,7-d iisop r op oxy-5-h yd r oxy-4-p h en -
yl-1,4-d ih yd r oq u in olin e (7i). 1-(tert-Butoxycarbonyl)-4-
phenyl-1,4-dihydropyridine (5d ) (0.48 g, 1.87 mmol, 1.00 equiv)
in THF (15 mL) was metalated at -42 °C for 3 h with sec-
butyllithium (1.78 mL, 1.10 M in cyclohexane, 1.96 mmol, 1.05
equiv) and then condensed with 3,4-diisopropoxy-3-cyclobutene-
1,2-dione (3a ) (0.39 g, 1.97 mmol, 1.05 equiv) in THF (20 mL)
at -78 °C. Workup, thermolysis neat (160-165 °C, 45 min),
and chromatographic purification (Baeckstro¨m column, silica
gel, 1.5 cm × 10 cm, gradient from 100% hexanes to 50%
EtOAc/hexanes) gave 1,8-(carbonyloxy)-6,7-diisopropoxy-5-hy-
droxy-4-phenyl-1,4-dihydroquinoline as a white solid (0.43 g,
1.12 mmol, 60%): mp 115-116 °C (EtOAc/hexane); TLC (silica
gel, 20% EtOAc/hexanes, Rf ) 0.26); IR (CH2Cl2, KCl, cm-1
)
1
3054 (w), 2981 (m), 1781 (s), 1672 (m); H NMR (CDCl3, 300
MHz) δ 7.32-7.17 (H), 6.73 (dd, J ) 7.2, 1.8 Hz, 1 H), 5.64 (s,
1 H), 5.28 (dd, J ) 7.2, 4.2 Hz, 1 H), 4.95-4.87 (m, 2 H), 4.45
(sept, J ) 6.0 Hz, 1 H), 1.36 (dd, J ) 6.0, 1.2 Hz, 6 H), 1.21 (t,
J ) 6.3 Hz, 6 H); 13C NMR (CDCl3, 75.5 MHz) δ 150.7, 145.1,
143.6, 134.9, 132.9, 128.5, 126.9, 123.7, 122.5, 116.4, 99.8, 76.1,
74.7, 39.0, 22.7, 22.5, 22.4. Anal. Calcd for C22H23NO5: C,
69.28; H, 6.08; N, 3.67. Found: C, 69.14; H, 6.10; N, 3.65.
1,8-(Ca r bon yloxy)-5-h yd r oxy-7-isop r op oxy-6-m eth yl-4-
p h en yl-1,4-d ih yd r oqu in olin e (7j). 1-(tert-Butoxycarbonyl)-
4-phenyl-1,4-dihydropyridine (5d ) (0.89 g, 3.46 mmol, 1.00
equiv) in THF (25 mL) was metalated at -42 °C for 3 h with
sec-butyllithium (3.30 mL, 1.10 M in cyclohexane, 3.63 mmol,
1.05 equiv) and then condensed with 3-isopropoxy-4-methyl-
3-cyclobutene-1,2-dione (3c) (0.56 g, 3.63 mmol, 1.05 equiv)
in THF (25 mL) at -78 °C. Workup, thermolysis neat (160-
165 °C, 45 min), and chromatographic purification (Baeck-
stro¨m column, silica gel, 1.5 cm × 10 cm, gradient from 100%
hexanes to 50% EtOAc/hexanes) gave 1,8-(carbonyloxy)-5-
hydroxy-7-isopropoxy-6-methyl-4-phenyl-1,4-dihydroquino-
line as a white solid (0.48 g, 1.42 mmol, 41%): mp 155-156
°C (EtOAc/hexane); TLC (silica gel, 20% EtOAc/hexanes, Rf )
0.69); IR (CH2Cl2, KCl, cm-1) 3541 (m), 2934 (m), 1773 (s); 1H
NMR (CDCl3, 300 MHz) δ 7.34-7.23 (m, 5 H), 6.74 (d, J ) 7.2
Hz, 1 H), 5.23 (dd, J ) 7.2, 3.6 Hz, 1 H), 4.92-4.88 (m, 2 H),
4.72 (br s, 1 H), 2.02 (s, 3 H), 1.34 (d, J ) 4.5 Hz, 6 H); 13C
NMR (CDCl3, 75.5 MHz) δ 150.8, 148.7, 143.0, 139.3, 129.3,
128.1, 127.6, 124.9, 124.2, 116.4, 115.0, 112.2, 100.5, 74.2, 39.4,
22.8, 9.2. Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N,
4.15. Found: C, 70.91; H, 5.63; N, 4.11.
1,8-(Ca r bon yloxy)-4-[4-(N,N-d ia llyla m in o)p h en yl]-6,7-
d ieth yl-5-h yd r oxy-1,4-d ih yd r oqu in olin e (7m ). 1-(tert-Bu-
toxycarbonyl)-4-[4-(N,N-diallylamino)phenyl]-1,4-dihydropy-
ridine (5b) (0.45 g, 1.28 mmol, 1.00 equiv) in THF (15 mL)
was metalated at -42 °C for 3 h with sec-butyllithium (1.08
mL, 1.30 M in cyclohexane, 1.40 mmol, 1.09 equiv) and then
condensed with 3,4-diethyl-3-cyclobutene-1,2-dione (3b) (0.18
g, 1.30 mmol, 1.02 equiv) in THF (15 mL) at -78 °C. Workup,
thermolysis neat (160-165 °C, 1 h), and chromatographic
purification (Baeckstro¨m column, silica gel, 1.5 cm × 10 cm,
gradient from hexanes to 50% EtOAc/hexanes) gave 1,8-
(carbonyloxy)-4-[4-(N,N-diallylamino)phenyl]-6,7-diethyl-5-hy-
droxy-1,4-dihydroquinoline as a white solid (0.33 g, 0.79 mmol,
62%): mp 132-133 °C (EtOAc/hexane); TLC (silica gel, 15%
EtOAc/hexanes, Rf ) 0.26); IR (CH2Cl2, KCl, cm-1) 3514 (m),
1
2973 (m), 1775 (s); H NMR (CDCl3, 300 MHz) δ 7.09 (d, J )
8.4 Hz, 2 H), 6.73 (dd, J ) 7.8, 1.5 Hz, 1 H), 6.66 (dd, J ) 8.4
Hz, 1 H), 5.88-5.76 (m, 2 H), 5.16-5.12 (m, 4 H), 4.77 (br s,
1 H), 4.53 (br s, 1 H), 3.89 (d, J ) 5.7 Hz, 4 H), 2.71 (q, J ) 7.5
Hz, 2 H), 2.58 (q, J ) 7.5 Hz, 2 H), 1.24 (t, J ) 7.5 Hz, 3 H),
1.05 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 150.7.
Anal. Calcd for C26H28N2O3: C, 74.98; H, 6.78; N, 6.73.
Found: C, 74.90; H, 6.81; N, 6.77.
Qu in olin e Qu in on e Syn th esis. 6,7-Diisop r op oxy-4-
m eth ylqu in olin e-5,8-d ion e (8c). 1,8-(Carbonyloxy)-6,7-di-
isopropoxy-5-hydroxy-4-methyl-1,4-dihydroquinoline (7c) (194
mg, 0.61 mmol, 1.00 equiv) in 1 mL of acetic acid was treated
with o-chloranil (329 mg, 1.34 mmol, 2.20 equiv) at room
temperature. After 5 h, the reaction mixture was quenched
with ice-cold NaOH (20% aqueous) to a pH near 7.0. Ether
(100 mL) was added, and the organic layer was washed with
water (5 × 25 mL) and then dried (MgSO4) and passed through
a pad of neutral alumina. The eluent was concentrated to a
red oil that was chromatographed (preparative TLC plate,
alumina, 0.25 mm, 50% EtOAc/hexanes) to give 6,7-diisopro-
poxy-4-methylquinoline-5,8-dione as a yellow oil (96.2 mg, 0.33
mmol, 55%): TLC (silica gel, 50% EtOAc/hexanes, Rf ) 0.18);
1,8-(Ca r b on yloxy)-6,7-d iisop r op oxy-5-h yd r oxy-4-(2-
m eth oxyp h en yl)-1,4-d ih yd r oqu in olin e (7k ). 1-(tert-Bu-
toxycarbonyl)-4-(2-methoxyphenyl)-1,4-dihydropyridine (5e)
(0.95 g, 3.32 mmol, 1.00 equiv) in THF (30 mL) was metalated
at -42 °C for 3 h with sec-butyllithium (2.81 mL, 1.30 M in
cyclohexane, 3.65 mmol, 1.10 equiv) and then condensed with
3,4-diisopropoxy-3-cyclobutene-1,2-dione 3a (0.79 g, 3.99 mmol,
1.20 equiv) in THF (25 mL) at -78 °C. Workup, thermolysis
neat (160-165 °C, 1 h), and chromatographic purification
(Baeckstro¨m column, silica gel, 2.5 cm × 10 cm, gradient from
100% hexanes to 50% EtOAc/hexanes) gave 1,8-(carbonyloxy)-
6,7-diisopropoxy-5-hydroxy-4-(2-methoxyphenyl)-1,4-dihydro-
quinoline as a white solid (0.78 g, 1.90 mmol, 57%): mp 129-
130 °C (EtOAc/hexane); TLC (silica gel, 15% EtOAc/hexanes,
Rf ) 0.25); IR (CH2Cl2, KCl, cm-1) 3504 (s), 3062 (s), 2981 (s),
1779 (s); 1H NMR (CDCl3, 300 MHz) δ 7.23-7.18 (m, 1 H),
6.93-6.87 (m, 3 H), 6.72 (d, J ) 7.5 Hz, 1 H), 5.83 (s, 1 H),
4.94 (sept, J ) 6.0 Hz, 1 H), 4.48 (sept, J ) 6.0 Hz, 1 H), 3.89
(s, 3 H), 1.39 (d, J ) 6.0 Hz, 6 H), 1.25 (dd, J ) 6.0, 2.1 Hz, 6
H); 13C NMR (CDCl3, 75.5 MHz) δ 155.8, 150.8, 145.0, 134.9,
133.0, 131.3, 129.0, 128.0, 123.8, 123.3, 121.1, 116.2, 114.3,
110.7, 99.4, 76.1, 74.6, 55.6, 22.7, 22.5, 22.4. Anal. Calcd for
C23H25NO6: C, 67.14; H, 6.12; N, 3.40. Found: C, 67.24; H,
5.90; N, 3.41.
1
IR (CH2Cl2, KCl, cm-1) 3058 (w), 2983 (s), 1667 (s); H NMR
(CDCl3, 300 MHz) δ 8.74 (d, J ) 4.8 Hz, 1 H), 7.35 (d, J ) 4.8
Hz, 1 H), 5.00-4.93 (m, 2 H), 2.76 (s, 3 H), 1.35 (d, J ) 3.6
Hz, 6 H), 1.33 (d, J ) 3.6 Hz, 6 H); 13C NMR (CDCl3, 75.5
MHz) δ 183.5, 181.0, 152.6, 150.1, 148.2, 148.1, 147.1, 76.4,
76.1, 22.7, 22.0; HRMS (EI) calcd for C16H19NO4 289.1314,
found 289.1313.
4,6-Dim eth yl-7-isopr opoxyqu in olin e-5,8-dion e (8e). Fol-
lowing the procedure for 8c, 1,8-(carbonyloxy)-4,6-dimethyl-
5-hydroxy-7-isopropoxy-1,4-dihydroquinoline (7e) (60 mg, 0.22
mmol, 1.00 equiv) and o-chloranil (110 mg, 0.45 mmol, 2.05
equiv) gave after workup and chromatographic purification
(preparative TLC plate, alumina, 0.25 mm, 33% EtOAc/
hexanes) 4,6-dimethyl-7-isopropoxyquinoline-5,8-dione as a
yellow oil (25 mg, 0.102 mmol, 47%): IR (CH2Cl2, KCl, cm-1
)
1,8-(Car bon yloxy)-6,7-diisopr opoxy-4-(2-flu or oph en yl)-
5-h yd r oxy-1,4-d ih yd r oqu in olin e (7l). 1-(tert-Butoxycarbo-
nyl)-4-(2-fluorophenyl)-1,4-dihydropyridine (5f) (0.24 g, 0.87
mmol, 1.00 equiv) in THF (10 mL) was metalated -42 °C for
3 h with sec-butyllithium (0.81 mL, 1.30 M in cyclohexane,
1.05 mmol, 1.21 equiv) and then condensed with 3,4-diisopro-
3060 (m), 2986 (m), 1684 (s), 1652 (s), 1621 (m); 1H NMR
(CDCl3, 300 MHz) δ 8.75 (d, J ) 4.8 Hz, 1 H), 7.38 (d, J ) 4.8
Hz, 1 H), 5.08 (sept, J ) 6.0 Hz, 1 H), 2.80 (s, 3 H), 2.10 (s, 3
H), 1.35 (d, J ) 6.0 Hz, 6 H); 13C NMR (CDCl3, 75.5 MHz) δ
187.2, 180.0, 156.3, 152.4, 150.0, 148.4, 133.9, 130.9, 127.2,

Synthesis of Dihydroquinolines and Quinoline Quinones
J . Org. Chem., Vol. 62, No. 13, 1997 4337
53.4, 23.0, 22.2, 9.8; HRMS (EI) calcd for C14H15NO3 245.1052,
found 245.1047.
7.2, 1.8 Hz, 1 H), 7.01 (t, J ) 7.2 Hz, 1 H), 6.89 (d, J ) 8.4 Hz,
1 H), 4.94 (sept, J ) 6.4 Hz, 1 H), 4.86 (sept, J ) 6.0 Hz, 1 H),
3.62 (s, 3 H), 1.34-1.21 (m, 2 H); 13C NMR (CDCl3, 75.5 MHz)
δ 181.5, 181.0, 155.6, 153.0, 148.4, 148.4, 147.4, 147.3, 130.1,
130.0, 128.6, 127.9, 126.7, 120.9, 110.5, 76.2, 75.9, 55.3, 22.8,
22.7, 22.6; HRMS (EI) calcd for C22H23NO5 381.1563, found
381.1576.
4-n -Bu tyl-6,7-diisopr opoxyqu in olin e-5,8-dion e (8g). 4-n-
Butyl-1,8-(carbonyloxy)-6,7-diisopropoxy-5-hydroxy-1,4-dihy-
droquinoline (7g) (330 mg, 0.91 mmol, 1.00 equiv) and o-chlo-
ranil (494 mg, 2.01 mmol, 2.20 equiv) gave after workup and
chromatographic purification (preparative TLC plate, alumina,
0.25 mm, 50% EtOAc/hexanes) 4-n-butyl-6,7-diisopropoxyquin-
oline-5,8-dione as a red oil (282 mg, 0.85 mmol, 93%): TLC
(silica gel, 50% EtOAc/hexanes, Rf ) 0.33); IR (CDCl3, KCl,
cm-1) 2965 (m), 2935 (m), 2242 (w), 1667 (s); 1H NMR (CDCl3,
300 MHz) δ 8.76 (d, J ) 5.4 Hz, 1 H), 7.37 (d, J ) 5.4 Hz, 1
H), 5.02-4.94 (m, 2 H), 3.17 (t, J ) 7.5 Hz, 2 H), 1.62-1.39
(m, 4 H), 1.37 (d, J ) 6.0 Hz, 6 H), 1.35 (d, J ) 6.3 Hz, 6 H),
0.96 (t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 183.2,
180.9, 154.7, 152.5, 148.3, 148.2, 146.8, 129.7, 125.5, 76.3, 76.0,
6,7-Diisop r op oxy-4-(2-flu or op h en yl)q u in olin e-5,8-d i-
on e (8l). 1,8-(Carbonyloxy)-6,7-diisopropoxy-4-(2-fluorophe-
nyl)-5-hydroxy-1,4-dihydroquinoline (7l) (92 mg, 0.23 mmol,
1.00 equiv) and o-chloroanil (102 mg, 0.42 mmol, 1.80 equiv)
gave after workup and chromatographic purification (prepara-
tive TLC plate, alumina, 0.25 mm, 50% EtOAc/hexanes) 6,7-
diisopropoxy-4-(2-fluorophenyl)quinoline-5,8-dione as a yellow
oil (70.2 mg, 0.19 mmol, 82%): TLC (silica gel, 50% EtOAc/
hexanes, Rf ) 0.44); IR (CH2Cl2, KCl, cm-1) 3060 (s), 2987 (s),
1671 (m), 1607 (m); 1H NMR (CDCl3, 300 MHz) δ 8.93 (d, J )
5.1 Hz, 1 H), 7.42-7.40 (m, 2 H), 7.24-7.12 (m, 2 H), 7.00 (t,
J ) 2.7 Hz, 1 H), 4.96 (sept, J ) 6.0 Hz, 1 H), 4.90 (sept, J )
6.0 Hz, 1 H), 1.36 (d, J ) 6.0 Hz, 6 H), 1.27 (d, J ) 6.0 Hz, 6
H); 13C NMR (CDCl3, 75.5 MHz) δ 181.5, 180.7, 160.6, 157.3,
148.3, 147.7, 147.5, 144.4, 130.7, 130.6, 130.1, 129.2, 126.4,
126.2, 126.0, 124.5, 124.4, 115.5, 115.2, 76.4, 76.3, 22.8, 22.7;
HRMS (EI) calcd for C21H20NO4F 369.1376, found 369.1380.
Con st r u ct ion of t h e P yr id oa cr id on e R in g Syst em .
1-(2-Br om op h en yl)-2,5-d im eth ylp yr r ole (9). A solution of
2-bromoaniline (10.0 g, 58.13 mmol, 1.0 equiv), 2,5-hexanedi-
one (6.848 g, 60 mmol, 1.03 equiv), and AcOH (1.00 mL, 17.47
mmol, 0.30 equiv) in toluene (70 mL) was heated at reflux for
48 h with removal of water. The solution was cooled, diluted
with EtOAc (100 mL), washed with 2 M HCl (100 mL), brine
(100 mL), 1 M NaHCO3 (100 mL), and brine (100 mL), and
dried (MgSO4). After filtration and removal of solvents the
resulting brown oil (14.5 g) was purified by chromatography
(Baeckstro¨m column, silica gel, 2.5 cm × 12 cm, gradient from
100% hexanes to 5% EtOAc/hexanes) or short-path distillation
and gave a yellow oil in 97% yield: bp 105 °C (1.7 mmHg);
TLC (silica gel, 5% EtOAc/hexanes, Rf ) 0.36); IR (CHCl3, KCl,
cm-1) 3064 (w), 2991 (m), 2918 (w), 1590 (w), 1483 (s), 1398
(m); 1H NMR (CDCl3, 300 MHz) δ 7.72 (m, 1 H), 7.44 (m, 1 H),
7.32 (m, 2 H), 5.94 (s, 2 H), 1.97 (s, 6 H); 13C NMR (CDCl3,
75.5 MHz) δ 138.7 (s), 133.5 (d), 130.8 (d), 130.0 (d), 128.5 (s),
33.9, 32.2, 22.7, 22.6, 22.6, 13.7; HRMS (EI) calcd for C19H25
NO4 331.1783, found 331.1796.
-
4-n -Bu t yl-7-isop r op oxy-6-m et h ylq u in olin e-5,8-d ion e
(8h ). 4-n-Butyl-1,8-(carbonyloxy)-5-hydroxy-7-isopropoxy-6-
methyl-1,4-dihydroquinoline (7h ) (65 mg, 0.21 mmol, 1.00
equiv) and o-chloranil (101 mg, 0.41 mmol, 2.00 equiv) gave
after workup and chromatographic purification (preparative
TLC plate, alumina, 0.25 mm, 20% EtOAc/hexanes) 4-n-butyl-
7-isopropoxy-6-methylquinoline-5,8-dione as a yellow oil (43
mg, 0.15 mmol, 73%): TLC (silica gel, 20% EtOAc/hexanes,
Rf ) 0.11); IR (CH2Cl2, KCl, cm-1) 3058 (m), 2935 (s), 2875
(m), 1685 (s), 1652 (s), 1623 (s); 1H NMR (CDCl3, 300 MHz) δ
8.76 (d, J ) 3.9 Hz, 1 H), 7.34 (d, J ) 3.9 Hz, 1 H), 5.04 (q, J
) 6.0 Hz, 1 H), 3.14 (t, J ) 7.5 Hz, 2 H), 2.05 (s, 3 H), 1.57-
1.48 (m, 2 H), 1.46-1.36 (m, 2 H), 1.31 (d, J ) Hz, 6 H), 0.93
(t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ 186.9, 179.9,
156.1, 154.6, 152.4, 148.7, 133.9, 129.9, 126.7, 34.1, 32.3, 30.3,
23.0, 22.9, 13.9, 9.8; HRMS (EI) calcd for C17H21NO3 287.1521,
found: 287.1516.
6,7-Diisopr opoxy-4-ph en ylqu in olin e-5,8-dion e (8i). 1,8-
(Carbonyloxy)-6,7-diisopropoxy-5-hydroxy-4-phenyl-1,4-dihy-
droquinoline (7i) (67 mg, 0.18 mmol, 1.00 equiv) and o-chlo-
ranil (86 mg, 0.35 mmol, 1.99 equiv) gave after workup and
chromatographic purification (preparative TLC plate, alumina,
0.25mm, 50% EtOAc/hexanes) 6,7-diisopropoxy-4-phenylquino-
line-5,8-dione as a yellow oil (38.7 mg, 0.11 mmol, 62%): TLC
(silica gel, 50% EtOAc/hexanes, Rf ) 0.47); IR (CH2Cl2, KCl,
cm-1) 2983 (m), 2250 (m), 1671 (s); 1H NMR (CDCl3, 300 MHz)
δ 8.88 (d, J ) 4.8 Hz, 1 H), 7.42-7.38 (m, 4 H), 7.25-7.23 (m,
2 H), 5.02-4.86 (m, 2 H), 1.34 (d, J ) 6.0 Hz, 6 H), 1.26 (d, J
) 6.0 Hz, 6 H); 13C NMR (CDCl3, 75.5 MHz) δ 181.6, 180.8,
152.8, 152.7, 151.4, 148.2, 147.3, 138.5, 130.1, 128.4, 128.2,
127.8, 76.3, 76.3, 22.8, 22.7; HRMS (EI) calcd for C21H21NO4
351.1470, found 351.1455.
7-Isopr opoxy-6-m eth yl-4-ph en ylqu in olin e-5,8-dion e (8j).
1,8-(Carbonyloxy)-5-hydroxy-7-isopropoxy-6-methyl-4-phenyl-
1,4-dihydroquinoline (7j) (54 mg, 0.16 mmol, 1.00 equiv) and
o-chloranil (80.7 mg, 0.33 mmol, 2.05 equiv) gave after workup
and chromatographic purification (preparative TLC plate,
alumina, 0.25 mm, 50% EtOAc/hexanes) 4-phenyl-6-methyl-
7-isopropoxyquinoline-5,8-dione as a yellow oil (40.4 mg, 0.131
mmol, 82%): TLC (alumina, 50% EtOAc/hexanes, Rf ) 0.32);
IR (CH2Cl2, KCl, cm-1) 3058 (m), 2939 (m), 1685 (s), 1657 (s);
1H NMR (CDCl3, 300 MHz) δ 8.86 (d, J ) 4.8 Hz, 1 H), 7.42-
7.36 (m, 4 H), 7.23-7.20 (m, 2 H), 5.08 (sept, J ) 6.0 Hz, 1 H),
1.97 (s, 3 H), 1.32 (d, J ) 6.0 Hz, 6 H); 13C NMR (CDCl3, 75.5
MHz) δ 185.0, 179.7, 156.4, 152.5, 151.3, 148.5, 138.8, 133.9,
130.2, 128.3, 128.1, 127.7, 126.1, 76.3, 23.1, 15.3; HRMS (EI)
calcd for C19H17NO3 307.1208, found 307.1203.
6,7-Diisop r op oxy-4-(2-m et h oxyp h en yl)q u in olin e-5,8-
d ion e (8k ). 1,8-(Carbonyloxy)-6,7-diisopropoxy-5-hydroxy-4-
(2-methoxy-phenyl)-1,4-dihydroquinoline (7k ) (100 mg, 0.24
mmol, 1.00 equiv) and o-chloroanil (120 mg, 0.49 mmol, 2.00
equiv) gave after workup and chromatographic purification
(preparative TLC plate, alumina, 0.25 mm, 50% EtOAc/
hexanes) 6,7-diisopropoxy-4-(2-methoxyphenyl)quinoline-5,8-
dione as a yellow oil (72 mg, 0.19 mmol, 77%): TLC (alumina,
50% EtOAc/hexanes, Rf ) 0.23); IR (CH2Cl2, KCl, cm-1) 3060
(s), 2983 (m), 1671 (s), 1605 (s); 1H NMR (CDCl3, 300 MHz) δ
8.86 (d, J ) 4.8 Hz, 1 H), 7.93-7.32 (m, 2 H), 7.11 (dd, J )
128.4 (d), 124.6 (s), 105.9 (d), 12.8 (q). Anal. Calcd for C12H12
-
BrN: C, 57.62; H, 4.84; Br, 31.95; N, 5.60. Found: C, 57.77;
H, 4.86; N, 5.59.
1-(ter t-Bu toxyca r bon yl)-4-[2-(2,5-d im eth ylp yr r ol-1-yl)-
p h en yl]-1,4-d ih yd r op yr id in e (11). A solution of 1-(2-bro-
mophenyl)-2,5-dimethylpyrrole (9) (5.0 g, 20 mmol, 1.0 equiv)
in dry THF (25 mL) was heated at reflux with magnesium
turnings (0.535 g, 22 mmol, 1.1 equiv) and iodine (0.02 g, 0.06
mmol) until the magnesium had reacted. The resulting black
solution was cooled to room temperature and cannulated into
a freshly prepared mixture of pyridine (2.4 mL, 30 mmol, 1.5
equiv), phenyl chloroformate (2.5 mL, 20 mmol, 1.0 equiv), and
cuprous iodide (0.19 g, 1.0 mmol, 0.05 equiv) in 100 mL of THF
at -23 °C. After 30 min, the reaction mixture was allowed to
warm to room temperature and then quenched with NH4Cl
(200 mL) and extracted with EtOAc (100 mL). After removal
of solvent, the resulting yellow oil was dissolved in 200 mL of
dry toluene, cooled to -78 °C, and treated dropwise with
potassium tert-butoxide in THF (40 mL, 1.0 M in THF, 40
mmol, 2.0 equiv). After 3 h, the reaction mixture was warmed
to room temperature, quenched with water (200 mL), and
extracted with EtOAc (100 mL), and the organic layer was
dried (MgSO4), filtered, and concentrated to a yellow oil.
Crystallization from methanol gave a white solid (6.03 g,
86%): mp 104-105 °C; TLC (silica gel, 5% EtOAc/hexanes, Rf
) 0.24); IR (CHCl3, KCl, cm-1) 3025 (w), 2985 (w), 2924 (w),
1708 (m), 1685 (m), 1488 (w), 1370 (s), 1337 (s), 1320 (s), 1207
(m), 1128 (m), 976 (m); 1H NMR (CDCl3, 300 MHz) δ 7.57 (m,
1 H), 7.47 (m, 1 H), 7.32 (m, 1 H), 7.13 (m, 1 H), 6.92 (m, 1 H),
6.75 (m, 1 H), 5.92 (s, 2 H), 4.74 (m, 1 H), 4.64 (m, 1 H), 3.71
(m, 1 H), 1.94 (s, 6 H), 1.53 (s, 9 H); 13C NMR (CDCl3, 75.5
MHz) δ 150.0 (s), 144.7 (s), 135.8 (s), 131.1 (d), 129.3 (d), 128.7
(d), 128.5 (s), 127.3 (d), 122.9 (d), 122.7 (d), 108.2 (d), 107.9
(d), 105.8 (d), 82.1 (s), 33.2 (d), 28.2 (q), 12.9 (q). Anal. Calcd

4338 J . Org. Chem., Vol. 62, No. 13, 1997
Zhang et al.
for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.28;
H, 7.45; N, 7.92.
7.03-7.09 (m, 2 H), 6.89 (dd, J ) 8.1, 1.7 Hz, 1 H), 6.81 (br t,
J ) 7.3 Hz, 1 H), 6.74 (br d, J ) 8.1 Hz, 1 H), 6.48 (br s, 1 H),
5.28 (dd, J ) 8.1, 4.1 Hz, 1 H), 5.02 (dd, J ) 4.1, 1.7 Hz, 1 H),
4.90 (sept, J ) 6.1 Hz, 1 H), 4.45 (sept, J ) 6.2 Hz, 1 H), 3.94
(br s, 2 H), 1.37 (d, J ) 6.1 Hz, 3 H), 1.35 (d, J ) 6.1 Hz, 3 H),
1.24 (d, J ) 6.2 Hz, 3 H), 1.23 (d, J ) 6.2 Hz, 3 H); 13C NMR
(CDCl3, 75.5 MHz) δ 150.6 (s), 145.1 (s), 142.3 (s), 134.9 (s),
133.3 (s), 129.8 (d), 129.6 (s), 127.6 (d), 123.9 (s), 122.0 (s),
120.4 (d), 117.8 (d), 117.3 (d), 113.3 (d), 100.1 (s), 75.8 (d), 74.5
(d), 32.9 (d), 22.6 (q), 22.5 (q), 22.4 (q), 22.2 (q); HRMS (EI)
calcd for C22H24N2O5 396.1685, found 396.1696. Anal. Calcd
for C22H24N2O5: C, 66.65; H, 6.10; N, 7.07. Found: C, 66.75;
H, 6.15; N, 7.05.
1,8-(Ca r b on yloxy)-6,7-d iisop r op oxy-4-[2-(2,5-d im et h -
ylpyr r ol-1-yl)ph en yl]-5-h ydr oxy-1,4-dih ydr oqu in olin e (13).
1-(tert-Butoxycarbonyl)-4-[2-(2,5-dimethylpyrrol-1-yl)phenyl]-
1,4-dihydropyridine (11) (3.50 g, 10 mmol, 1.0 equiv) was
dissolved in 50 mL of dry THF and cooled to -78 °C. To this
solution was added sec-butyllithium (9.3 mL, 1.3 M in cyclo-
hexane, 12.02 mmol, 1.2 equiv) dropwise. After 5 h, the
solution was cannulated into 3,4-diisopropoxy-3-cyclobutene-
1,2-dione (2.376 g, 12.0 mmol, 1.2 equiv) in dry THF (50 mL)
at -78 °C. After 2 h, the reaction mixture was quenched with
NH4Cl (100 mL), allowed to warm, and extracted with EtOAc
(3 × 50 mL). The combined organic layers were washed with
water (2 × 50 mL), dried (MgSO4), filtered, and concentrated
to a brown oil. From this crude oil, the unreacted dihydropy-
ridine was removed by chromatography (Baeckstro¨m column,
silica gel, 3.5 cm × 15 cm, 5% EtOAc/hexanes, Rf ) 0.24; 0.56
g, 16%). The remainder of the chromatographed material was
degassed (six cycles, nitrogen-vacuum-nitrogen) and then
thermolyzed neat at 160-165 °C for 45 min. Chromatographic
purification (Baeckstro¨m column, silica gel, 3.5 cm × 15 cm,
10% EtOAc/hexanes) gave a white solid that was recrystallized
from methanol (3.128 g, 6.6 mmol, 66%): mp 169-170 °C; TLC
(silica gel, 20% EtOAc/hexanes, Rf ) 0.42); IR (CHCl3, KCl,
cm-1) 3508 (br, w), 3025 (w), 2979 (m), 1775 (s), 1384 (m), 1106
(m), 1020 (m); 1H NMR (CDCl3, 300 MHz) δ 7.30 (m, 2 H),
7.16 (m, 1 H), 6.98 (m, 1 H), 6.56 (dd, J ) 8.1, 1.7 Hz, 1 H),
5.94 (s, 2 H), 5.69 (br s, 1 H), 4.97 (dd, J ) 8.1, 4.2 Hz, 1 H),
4.94 (sept, J ) 6.1 Hz, 1 H), 4.71 (dd, J ) 4.2, 1.7 Hz, 1 H),
4.50 (sept, J ) 6.2 Hz, 1 H), 2.12 (s, 3 H), 1.97 (s, 3 H), 1.38
(app t, J ) 6.1 Hz, 6 H), 1.23 (d, J ) 6.2 Hz, 6 H); 13C NMR
(CDCl3, 75.5 MHz) δ 150.5 (s), 145.0 (s), 141.9 (s), 136.7 (s),
135.0 (s), 132.8 (s), 129.6 (d), 129.4 (d), 129.1 (s), 129.0 (d),
128.1 (s), 127.6 (d), 123.6 (s), 123.5 (s), 116.4 (d), 113.1 (d),
106.4 (d), 106.1 (d), 98.4 (s), 76.1 (d), 74.6 (d), 34.3 (d), 22.8
(q), 22.4 (q), 13.2 (q), 12.6 (q). Anal. Calcd for C28H30N2O5:
C, 70.87; H, 6.37; N, 5.90. Found: C, 70.75; H, 6.40; N, 5.89.
1,8-(Car bon yloxy)-6,7-diisopr opoxy-4-(2-am in oph en yl)-
5-h yd r oxy-1,4-d ih yd r oqu in olin e (14). A mixture of pro-
tected aniline 13 (2.845 g, 6 mmol, 1.0 equiv), hydroxylamine
hydrochloride (8.339 g, 120 mmol, 20.0 equiv), triethylamine
(8.363 mL, 60 mmol, 10.0 equiv), and N-bromosuccinimide
(2.136 g, 12 mmol, 2.0 equiv) in EtOH (80 mL) and water (20
mL) was refluxed for 4 days. After this time, the dark solution
was cooled, quenched with 50 mL of water, and extracted with
EtOAc (3 × 50 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated. Purification of the residue
by chromatography (Baeckstro¨m column, silica gel, 2 cm × 12
cm, from 20% to 50% EtOAc/hexanes) gave 0.853 g (30%) of
starting material and a brown solid that was recrystallized
from hexane/E2O (1.354 g, 3.42 mmol, 57%): mp 111-113 °C;
TLC (silica gel, 50% EtOAc/hexanes, Rf ) 0.45); IR (CHCl3,
NaCl, cm-1) 3504 (br, w), 3395 (br, w), 3062 (w), 2981 (m),
2936 (w), 1779 (s), 1684 (m), 1616 (m), 1493 (m), 1481 (m),
1389 (s), 1107 (m), 1026 (m); 1H NMR (CDCl3, 300 MHz) δ
5,6-Diisop r op oxyp yr id o[2,3,4-kl]a cr id in -4-on e (15). A
solution of dihydroquinoline 14 (356 mg, 0.9 mmol, 1.0 equiv)
in ethanol (5 mL) was treated with tert-butyl hydroperoxide
(1.0 mL, aqueous solution 70%, 10.43 mmol, 11.59 equiv) and
potassium hydroxide (112 mg, 2.0 mmol, 2.22 equiv) for 7 h.
The reaction mixture was quenched with water (25 mL) and
extracted with EtOAc (3 × 25 mL). The combined organic
layers were dried (MgSO4), filtered, and condensed to a solid
residue that was washed with cold Et2O and recrystallized
from hot Et2O to give a bright yellow solid (207 mg, 0.59 mmol,
66%): mp 174-176 °C; TLC (silica gel, 50% EtOAc/hexanes,
Rf ) 0.23); IR (CHCl3, NaCl, cm-1) 2986 (m), 2935 (w), 1659
1
(s), 1607 (m), 1574 (m), 1383 (w), 1098 (s), 1005 (s); H NMR
(CDCl3, 300 MHz) δ 9.19 (d, J ) 5.5 Hz, 1 H), 8.52 (br d, J )
8.1 Hz, 1 H), 8.50 (d, J ) 5.5 Hz, 1 H), 8.31 (br d, J ) 8.1 Hz,
1 H), 7.87 (br t, J ) 8.1 Hz, 1 H), 7.76 (br t, J ) 8.1 Hz, 1 H),
5.20 (sept, J ) 6.2 Hz, 1 H), 4.88 (sept, J ) 6.2 Hz, 1 H), 1.49
(d, J ) 6.2 Hz, 6 H), 1.39 (d, J ) 6.2 Hz, 6 H); 13C NMR (CDCl3,
75.5 MHz) δ 181.2 (s), 153.3 (s), 149.9 (d), 149.0 (s), 146.4 (s),
146.3 (s), 145.8 (s), 136.9 (s), 131.9 (d), 131.5 (d), 129.3 (d),
122.8 (d), 121.5 (s), 119.3 (d), 115.8 (s), 77.7 (d), 75.8 (d), 22.9
(q), 22.7 (q); HRMS (EI) calcd for C21H21N2O3 (M + H)+
349.1552, found 349.1562. Anal. Calcd for C21H20N2O3: C,
72.40; H, 5.79; N, 8.04. Found: C, 72.13; H, 5.88; N, 8.01.
Ack n ow led gm en t . This investigation was sup-
ported by Grant No. CA40157, awarded by the National
Cancer Institute, DHHS. We acknowledge the use of a
VG 70-S mass spectrometer purchased through funding
from the National Institutes of Health, S10-RR-02478,
and a 300 MHz NMR and 360 MHz NMR purchased
through funding from the National Science Foundation,
NSF CHE-85-16614 and NSF CHE-8206103, respec-
tively.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 5d -g; 1H and 13C NMR spectra of compounds
8c,e-l (20 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O970039V