An efficient synthetic route to ethyl 2-aryl-4-hydroxy-1,3(2H,4H)-dioxoisoquinoline-4-carboxylates

Full text of DOI:10.1021/jo961135j

J . Org. Chem. 1996, 61, 7967-7972
7967
Ta ble 1. Su bstitu en ts a n d Yield s of In ter m ed ia tes 2a -j,
3a -j, 4a -j a n d P r od u cts 5a -j
An Efficien t Syn th etic Rou te to Eth yl
2-Ar yl-4-h yd r oxy-1,3(2H,4H)-
d ioxoisoqu in olin e-4-ca r boxyla tes1
% yield
entry
R1
R2
R3
2
3, methoda
4
5
J . Edward Semple,*,† Robert M. Rydzewski,‡ and
Gary Gardner§
a
b
c
d
e
f
g
h
i
H
H
H
Cl
MeO
H
Me
Me
H
H
CO2Et
Cl
H
H
Me
H
iPr
iPr
H
H
H
H
Cl
MeO
H
H
H
85
80
68
74
53
78
52
80
80
49
A, 51
A, 53; B, 57
A, 43
A, 47; B, 60
A, 30; B, 76
A, 49
A, 26
B, 64
B, 45
B, 62
89
92
92
89
75
72
50
85
78
63
54
45
51
52
47
49
46
61
38
49
Shell Development Company, Biological Sciences Research
Center, P.O. Box 4248, Modesto, California 95352, and Du
Pont Agricultural Products, Stine-Haskell Research Center,
P.O. Box 30, Newark, Delaware 19711
Received J une 14, 1996
H
CF3
j
CF3
Certain 2-aryl-1,3(2H,4H)-dioxoisoquinolines are known
as herbicides and plant growth regulators (PGR’s).2 In
herbicide screens many of these compounds caused
agravitropic behavior of the roots of several test species,
a phenotype characteristic of inhibitors of auxin trans-
port. Most auxin transport inhibitors bind to a specific
site on the plant plasma membrane, which is defined by
its affinity for the herbicide N-1-naphthylphthalamic acid
(NPA).3,4a On the basis of these observations we carried
out in vivo and in vitro studies and concluded that the
mode of action of these aryldioxoisoquinolines is the
inhibition of auxin transport.5a This activity might be a
function of (1) binding of the parent molecule to the NPA
receptor, (2) the propensity toward metabolic ring-open-
ing, yielding more traditional phthalamic acid analogues,
and (3) binding of the metabolite to the receptor.5
With this knowledge in hand, we pursued a series of
target compounds 5a -j (Table 1) as novel auxin transport
inhibitors which proved to be of considerable utility for
the production of hybrid seed as well as for crop yield
enhancement. Thus, molecular modeling and topological
comparisons of a lead compound, 2-[p-(ethoxycarbonyl)-
phenyl]-1,3(2H,4H)-dioxoisoquinoline (2b), with NPA,
DPX-1840 and its ring-opened metabolite,4b morphactin
(chlorflurenol4a), and related auxin transport inhibi-
tors2,4,5 (Scheme 1) led us to design and synthesize the
title compounds. Furthermore, the judicious selection
and placement of aromatic and requisite orthogonal
acidic functionality5b,c were based upon known4,5 and in-
house structure-activity relationships (SAR) in such
families. The 2-aryl substituents in our final targets
were chosen by consideration of the above literature
precedents along with the desire to explore a range of
molecular parameters, such as size and lipophilicity.
Herein, we report an efficient synthetic strategy to 10
such examples, several of which have expressed high
levels of PGR activity.
a
Method A: EtOCOCl, pyridine. Method B: NaH, PhNCO
followed by EtOH, reflux.
Sch em e 1. Exa m p les of Mod er n Au xin Tr a n sp or t
In h ibitor s w ith P GR Activity
the appropriate aniline derivative 1a -j in azeotropically
refluxing xylene5,6 (Scheme 2). It is of interest to note
that the lipophilic aniline used to prepare 2h was
obtained in 35% yield by H2SO4-catalyzed alkylation of
m-toluidine with 2-propanol7 or in ca. 60% yield by AlCl3-
catalyzed Friedel-Crafts alkylation with isopropyl chlo-
ride.8 Aryl substituents and yields for the intermediates
2a -j, 3a -j, a n d 4a -j and final targets 5a -j are
compiled in Table 1.
The 2-aryl-1,3(2H,4H)-dioxoisoquinoline intermediates
2a -j were prepared in 49-85% yield in a conventional
manner by condensation of homophthalic anhydride with
† Current address: Corvas International, Inc., 3030 Science Park
Road, San Diego, CA 92121. E-mail address: ed_semple@corvas.com.
‡ Current address: Arris Pharmaceuticals, 385 Oyster Point Bou-
levard., Suite 3, South San Francisco, CA 94080.
(6) (a) Cheng, C.-Y.; Tsai, H.-B.; Lin, M.-S. J . Heterocycl. Chem.
1995, 32, 73. (b) Murthy, A. R. K.; Chapman, J . M.; Wyrick, S. D.;
Hall, I. H. Pharm. Res. 1986, 3, 286. (c) The condensations may also
be conveniently carried out in toluene or acetic acid at reflux. The
addition of 0.1-0.3 mol equiv of DBU or triethylamine catalyzes the
reaction in the aromatic hydrocarbon solvents.
(7) (a) Private communication from R. J . G. Searle, Shell Research
Limited, Sittingbourne Research Centre, Sittingbourne, Kent, U.K. (b)
Gilkerson, T. (Shell Internationale Research Maatschappij B.V. Neth.).
Neth. Appl., NL 8006568, 1981. (c) Koval’skaya, S. S.; Kozlov, N. G.;
Shavyrin, S. V. Khim. Prir. Soedin. 1991, 29; Chem. Abstr. 1992, 116,
129270. (d) Burmistrov, S. I. Zh. Obsch. Khim. 1965, 1, 1838.
(8) Baardman, F.; van Helden, R.; de Nie-Sarink, M. J . (Shell Oil
Co.). U.S. Patent 4436937, 1984.
§ Current address: University of Minnesota, Department of Horti-
cultural Sciences, 305 Alderman Hall, St. Paul, MN 55108. E-mail
address: ggardner@maroon.tc.umn.edu.
(1) This paper is dedicated to the memory of Geraldine C. Semple.
(2) D’Amico, J . J . (Monsanto Co.). U.S. Patent 4097260, 1978.
(3) Thomson, K. S.; Hertel, R.; Mueller, S.; Tavares, J . E. Planta
1973, 109, 337.
(4) (a) Bures, M. G.; Black-Schaefer, C.; Gardner, G. J . Comput.-
Aided Mol. Des. 1991, 5, 323. (b) Beyer, E. M.; Sweetser, A. L. Plant
Physiol. 1976, 57, 839.
(5) (a) Gardner, G.; Semple, J . E. J . Plant Growth Regul. 1990, 9,
161. (b) Katekar, G. F. Phytochemistry 1976, 15, 1421. (c) Gardner,
G.; Sanborn, J . R. Plant Physiol. 1989, 90, 291.
S0022-3263(96)01135-8 CCC: $12.00 © 1996 American Chemical Society

7968 J . Org. Chem., Vol. 61, No. 22, 1996
Notes
Sch em e 2
Kadin, is applicable to the synthesis of a wide range of
straight- or branched-chain C1-C6 ester derivatives.10b,c
We briefly investigated another approach to 3c,d which
entailed initial enolate O-acylation with ethyl chlorofor-
mate followed by a 1,3-O- to C-acyl shift process (method
C).11 Enolate formation with sodium hydride or LDA
under standard conditions and subsequent trapping with
the above electrophile afforded modest yields of carbonate
derivatives 9c,d along with recovered starting material.
Operationally, it was more convenient and efficient to use
triethylamine in THF or anhydrous potassium carbonate
in DMF as the base/solvent pairs where essentially
quantitative yields of 9c,d could be realized. Unfortu-
nately, thermally induced 1,3-acyl shift of 9d at 30-60
°C in DMF produced 3d in only 14-35% yield. Addition
of DMAP12 did little to alter the course of the reaction,
while other solvents were less satisfactory.
Our initial attempts to install the R-hydroxy group by
direct oxygenation13 of the enolate derived from 3a using
various bases, dry oxygen, and reductive workup condi-
tions led to a complex mixture of products containing the
1,3,4-trione byproducts 10a .14 Although the MoOPH
protocol15 might have succeeded with our substrates, we
were concerned about handling and disposal of the
HMPA produced from this reagent. On the basis of the
precedent of Lawesson and Gronwall,16 the R-hydroxy
group was introduced indirectly by an efficient two-step
process. Treatment of the sodium enolate of 3a -j with
benzoyl peroxide at 0 °C to room temperature afforded
the R-benzoyloxy ester derivatives 4a -j in 70-92% yield
(Scheme 3). Finally, selective alcoholysis of the benzoyl
moiety was effected by treatment of 4a -j with 6-10
equiv of sodium ethoxide at 0 °C and produced the desired
R-hydroxy ester derivatives 5a -j in 38-54% yield. In
addition to very minor amounts of the expected alkoxide-
derived ring-opened amide-ester byproducts, the pre-
dominant byproducts produced during the hydrolysis
stage proved to be the 1,3,4-trione derivatives 10, which
were also detected during the attempted direct oxygen-
ation protocol discussed above.14
C-4 ethoxycarbonylation of 2a -j could be effected by
three complementary methods. The initial one-step
method consisted of acylation with ethyl chloroformate
in pyridine9 and afforded 3a -g in 26-53% yield (Table
1, method A). An indirect but significantly improved two-
step protocol was developed based on the work of Kadin.10
Thus, C-4 enolate formation and reaction with phenyl
isocyanate afforded the N-phenylcarboxamides 6b,d ,e,h -
j. In our hands, use of sodium hydride as base gave
consistently superior yields of product over the triethyl-
amine method employed by Kadin in his work. Alco-
holysis of 6b,d ,e,h -j in refluxing ethanol under neutral
conditions delivered the corresponding ethyl esters
3b,d ,e,h -j in overall yields of 45-76% from 2b,d ,e,h -j
(Table 1, method B). A plausible mechanism for this
latter transformation may involve an addition-elimina-
tion process via the enol-form 7 leading to intermediate
8. Subsequent loss of aniline affords the ester product
3. This neutral alcoholysis method is not limited to the
preparation of ethyl esters and indeed, as reported by
Several of the targets prepared herein expressed potent
auxin transport inhibition activity in selected in vitro
assays. Furthermore, when field tested in Europe,
certain members of this class demonstrated interesting
levels of PGR activity for the production of hybrid wheat
(11) To the best of our knowledge, there exists no literature
precedent for the 1,3-O- to C-acyl shift in the subject isoquinolinedione
systems. However, similar acyl shifts have been successfully executed
in a variety of other systems; cf.: (a) Lu, J . Q.; Wang, S. Y.; Zhang, P.
Chin. Chem. Lett. 1992, 3, 337. (b) Oliver, J . E.; Wilzer, K. R.; Waters,
R. M. Synthesis 1990, 1117. (c) Winkler, D. A.; Liepa, A. J .; Anderson-
McKay, J . E.; Hart, N. K. Pestic. Sci. 1989, 27, 45. (d) For examples of
the synthesis and O- to C-acyl shifts of enol esters to â-keto esters,
see: Larock, R. C. Comprehensive Organic Transformations; VCH Pub-
lishers: New York, 1989; pp 743-744. (e) Seminal O-acylation and O-
to C-acyl migration studies: Eisenhauer, H. R.; Link, K. P. J . Am.
Chem. Soc. 1953, 75, 2044
(12) Scriven, F. V. Chem. Soc. Rev. 1983, 12, 129.
(13) (a) Wasserman, H. H.; Lipshutz, B. Tetrahedron Lett. 1977,
4595. (b) For an excellent compilation of references on the subject of
enolate hydroxylation, see: Larock, R. C. Comprehensive Organic
Transformations; VCH Publishers: New York, 1989; pp 488-490.
(14) 2-Aryl-1,3,4-(2H)-trioxoisoquinolines, also known as phthalon-
imides, have been previously described; see: (a) Peterson, S.; Heitzer,
H. Liebigs Ann. Chem. 1978, 283. (b) Buu-Hoi, N. P.; Saint-Ruf, G.;
Bourgeade, J . C. J . Heterocycl. Chem. 1968, 5, 545. (c) Meyer, A.;
Villenet, R. C. R. Hebd. Seances Acad. Sci. 1931, 193, 531, 1095.
(15) (a) Vedejs, E.; Engler, D. A.; Telschow, J . E. J . Org. Chem. 1978,
43, 188. (b) Vedejs, E. J . Am. Chem. Soc. 1974, 96, 5944. See also ref
13b.
(9) (a) Ethoxycarbonylation of homophthalic anhydride derivatives
with this system is known. However, we are unaware of any reports
describing the direct acylation of 1,3(2H, 4H)-dioxoisoquinolines (ho-
mophthalimides) 2 by this method, cf.: (b) Chatterjea, J . N.; Mukher-
jee, S. K.; Bhakta, H. C. J .; Zilliken, F. Chem. Ber. 1980, 113, 3927. (c)
Hellou, J .; Kingston, J . F.; Fallis, A. G. Synthesis 1984, 1014. (d)
Schnekenburger, J . Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1965, 298,
715.
(10) (a) Kadin, S. (Pfizer, Inc.). U.S. Patent 4569942, 1986. (b) Kadin,
S. (Pfizer, Inc.). U.S. Patent 3998954, 1976. (c) Kadin, S. J . Org. Chem.
1969, 34, 3178. (d) For application of this protocol to antinflammatory
1-acyl-2-oxindole-3-carboxamides, see: Kadin, S. (Pfizer Co.). U.S.
Patent 4730004, 1988.
(16) Lawesson, S. O.; Gronwall, S. Acta Chem. Scand. 1960, 14,
1445.

Notes
J . Org. Chem., Vol. 61, No. 22, 1996 7969
DMSO-d6) δ 1.35 (t, J ) 7 Hz, 3H), 4.10 (s, 2H), 4.36 (q, J ) 7
Hz, 2H), 6.95-8.15 (m, 8H); MS (EI) 309 au. Anal. Calcd for
Sch em e 3
C
18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C, 70.20; H, 4.80;
N, 4.73.
2-(4-Ch lor oph en yl)-1,3(2H,4H)-dioxoisoqu in olin e (2c): mp
176-177.5 °C; lit.6b mp 166-168 °C; yield 68%; 1H-NMR (60
MHz, DMSO-d6) δ 4.23 (s, 2H), 7.0-8.10 (m, 8H). Anal. Calcd
for C15H10ClNO2: C, 66.31; H, 3.71; N, 5.16. Found: C, 66.65;
H, 3.80; N, 5.13.
2-(3,5-Dich lor op h e n yl)-1,3(2H ,4H )-d ioxoisoq u in olin e
1
(2d ): mp 230.5-232.5 °C, lit.2 mp 241 °C; yield 74%; H-NMR
(300 MHz, DMSO-d6) δ 4.18 (s, 2H), 7.32-7.7 (m, 5H), 8.15 (m,
1H), 8.42 (d, J ) 8.0 Hz, 1H); MS (EI) 305, 307 au. Anal. Calcd
for C15H9Cl2NO2: C, 58.85; H, 2.96; N, 4.58. Found: C, 58.55;
H, 2.90; N, 4.82.
2-(3,5-Dim e t h oxyp h e n yl)-1,3(2H ,4H )-d ioxoisoq u in o-
lin e (2e): mp 178-179.5 °C, lit.2 mp 145-146 °C; yield 64%;
1H-NMR (300 MHz, DMSO-d6) δ 3.71 (s, 6H), 4.10 (s, 2H), 6.42
(m, 2H), 6.63 (m, 1H), 7.13-7.55 (m, 3H), 8.0 (m, 1H); MS (EI)
297 au. Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09; N, 4.71.
Found: C, 69.03; H, 5.11; N, 4.82.
2-(4-Meth ylph en yl)-1,3(2H,4H)-dioxoisoqu in olin e (2f): mp
seed as well as for crop yield enhancement in soybeans,
sugar beets, and cotton. Complete SAR and biological
results will be described in a forthcoming publication.
In conclusion, we have prepared a series of 10 novel
ethyl 2-aryl-4-hydroxy-1,3(2H,4H)-dioxoisoquinoline-4-
carboxylates 5a -j possessing different N-phenyl substit-
uents by a convenient four- or five-step protocol. Espe-
cially noteworthy of this new methodology is the uncon-
ventional introduction of the C-4 ester moiety via neutral
alcoholysis of the phenylcarboxamide precursor 6b,d,e,h -j
as well as the indirect R-hydroxylation of an activated
tertiary center using a benzoyloxyation/hydrolysis strat-
egy. These are both somewhat uncommon yet mild and
potentially useful processes which may find further
application in organic synthesis.
1
170.5-172.5 °C, lit.6b mp 166-168 °C; yield 78%; H-NMR (60
MHz, DMSO-d6) δ 2.50 (s, 3H), 4.15 (s, 2H), 7.0-7.95 (m, 8H);
MS (EI) 251 au. Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21;
N, 5.57. Found: C, 76.80; H, 5.22; N, 5.63.
2-(3-Met h ylp h en yl)-1,3(2H,4H)-d ioxoisoq u in olin e (2g):
1
mp 111.5-113.5 °C, lit.6b mp 108-110 °C; yield 52%; H-NMR
(60 MHz, DMSO-d6) δ 2.40 (s, 3H), 4.12 (s, 2H), 7.0-7.9 (m, 8
H); MS (EI) 251 au. Anal. Calcd for C16H13NO2: C, 76.48; H,
5.21; N, 5.57. Found: C, 76.85; H, 5.38; N, 5.51.
2-(3-Meth yl-4-isopr opylph en yl)-1,3(2H,4H)-dioxoisoqu in -
olin e (2h ): mp 158-160 °C; yield 80%; 1H-NMR (300 MHz,
CDCl3) δ 1.20 (d, J ) 6.8 Hz, 6H), 2.30 (s, 3H), 3.10 (m, 1H),
4.12 (s, 2H), 7.15 (d, J ) 8.0 Hz, 1H), 7.25-7.8 (m, 6H); MS (EI)
293 au. Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77.
Found: C, 77.61; H, 6.63; N, 4.84.
2-(4-Isop r op ylp h e n yl)-1,3(2H ,4H )-d ioxoisoq u in olin e
1
(2i): mp 172-174 °C; yield 82%; H-NMR (300 MHz, CDCl3) δ
1.22 (d, J ) 6.8 Hz, 6H), 3.10 (m, 1H), 4.14 (s, 2H), 7.17 (d, 1H,
J ) 8.0 Hz), 7.25-7.8 (m, 7H); MS (EI) 279 au. Anal. Calcd for
Exp er im en ta l Section
C
18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.38; H, 6.10;
1H-NMR spectra were obtained on spectrometers operating
at 60 and 300 MHz. All melting points are uncorrected and are
reported in degrees centigrade (°C). The elemental microanaly-
ses and low-resolution mass spectral acquisitions were per-
formed by the Shell BSRC Analytical Chemistry Department.
Thin layer chromatography was performed using Merck silica
gel 60 F-254 plates. Visualization was effected with UV and/or
phosphomolybdic acid. All reactions were run under a positive
pressure of nitrogen. All solvents were anhydrous and were used
as purchased from Aldrich. All reagents were purchased from
Aldrich.
N, 5.03.
2-[3,5-Bis(tr iflu or om eth yl)p h en yl]-1,3(2H,4H)-d ioxoiso-
qu in olin e (2j): mp 203-205 °C; lit.2 mp 205-206 °C; yield 49%;
1H-NMR (60 MHz, DMSO-d6) δ 4.10 (s, 2H), 7.2-7.8 (m, 7H);
MS (EI) 373 au. Anal. Calcd for C17H9F6NO2: C, 54.70; H, 2.43;
N, 3.75. Found: C, 55.01; H, 2.65; N, 4.01.
Gen er a l P r oced u r e for th e Eth oxyca r bon yla tion of 2a -
g. Syn th esis of Eth yl 2-Ar yl-1,3(2H,4H)-d ioxoisoqu in olin e-
4-ca r boxyla tes 3a -g. Meth od A. To a solution of 2a -g
(0.020 mol) in 50 mL of anhydrous pyridine was added ethyl
chloroformate (3.26 g, 0.030 mol, 2.90 mL) rapidly dropwise over
5 min. The mixture was stirred at ambient temperature for 16-
24 h. If TLC analysis (ethyl acetate/hexane mixtures) indicated
the presence of unreacted starting material, an additional
portion of ethyl chloroformate was added (generally 0.326 g,
0.0030 mol, 0.29 mL was sufficient to complete the reaction).
After completion of the reaction, the mixture was poured into
an ice-cold solution of acetic acid (45 mL) and water (150 mL).
After stirring for 20 min at 0 °C, the resultant solid was collected
by suction filtration, washed with ice/water, dried, and recrystal-
lized from ethanol/acetone mixtures to afford the following
products 3a -g as nearly colorless, tiny needles. Range of
principal IR bands for 3a -g in KBr: ∼3400 (br), 2965-2975,
Gen er a l P r oced u r e for th e Syn th esis of 2-Ar yl-1,3-
(2H,4H)-d ioxoisoqu in olin es 2a -j. A mixture of homophthalic
anhydride (16.21 g, 0.10 mol) and the appropriate aniline
derivative (0.11 mol) in 250 mL of xylene was rapidly stirred
and azeotropically heated at reflux using a Dean-Stark trap
for 4-72 h until water evolution ceased and TLC monitoring
(hexanes/ethyl acetate/THF, 4/1/1 to 2/1/1 mixtures) suggested
completion of the reaction. The solvent was removed, and the
residue was purified either by recrystallization from 2-propanol,
ethanol, methanol, or ethyl acetate/hexane mixtures or by flash
chromatography using ethyl acetate, hexane or ethyl acetate/
methylene chloride gradient systems to afford the products 2a -j
as nearly colorless solids. Range of principal IR bands for 2a -j
1660-1700, 1600-1615, 1575-1595 cm-1
.
in KBr: 1705-1715, 1665-1670, 1590-1595 cm-1
.
Eth yl 2-p h en yl-1,3(2H,4H)-d ioxoisoqu in olin e-4-ca r box-
yla te (3a ): mp 155-157 °C; yield 51%; 1H-NMR (60 MHz,
DMSO-d6) δ 1.50 (t, J ) 7 Hz, 3H), 4.53 (q, J ) 7 Hz, 2H), 7.10-
8.60 (m, 9H); MS (EI) 309 au. Anal. Calcd for C18H15NO4: C,
69.89; H, 4.89; N, 4.53. Found: C, 70.25; H, 4.90; N, 4.55.
Eth yl 2-[4-(eth oxyca r bon yl)p h en yl]-1,3(2H,4H)-dioxoiso-
qu in olin e-4-ca r boxyla te (3b): mp 175-177 °C; yield 53%; 1H-
NMR (60 MHz, DMSO-d6) δ 1.40 (t, J ) 7 Hz, 3H), 1.53 (t, J )
7 Hz, 3H), 4.41 (q, J ) 7 Hz, 2H), 4.55 (q, J ) 7 Hz, 2H), 7.25-
8.6 (m, 8H); MS (EI): 381 au. Anal. Calcd for C21H19NO6: C,
66.14; H, 5.02; N, 3.67. Found: C, 66.25; H, 5.00; N, 3.73.
2-P h en yl-1,3(2H,4H)-d ioxoisoqu in olin e (2a ): mp 188-189
1
°C, lit.6b mp 181-184 °C; lit.17 mp 190-192 °C; yield 87%; H-
NMR (60 MHz, DMSO-d6) δ 4.20 (s, 2H), 7.04-8.25 (m, 9H).
Anal. Calcd for C15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found:
C, 76.25; H, 4.40; N, 6.00.
2-[4-(Eth oxyca r bon yl)p h en yl]-1,3(2H,4H)-d ioxoisoqu in -
olin e (2b): mp 170-172 °C; yield 80%; 1H-NMR (60 MHz,
(17) (a) Modi, A. R.; Usgaonkar, R. N. Indian J . Chem. 1979, 18B,
304. (b) Gerald, R.; Popp, F. J . Heterocycl. Chem. 1969, 6, 12.

7970 J . Org. Chem., Vol. 61, No. 22, 1996
Notes
Eth yl 2-(4-ch lor op h en yl)-1,3(2H,4H)-d ioxoisoqu in olin e-
4-ca r boxyla te (3c): mp 174-176 °C; yield 43%; H-NMR (60
MHz, DMSO-d6) δ 1.52 (t, J ) 7 Hz, 3H), 4.52 (q, J ) 7 Hz, 2H),
ethyl acetate/hexanes; yield 81%; 1H-NMR (300 MHz, DMSO-
d6) δ 1.25 (d, J ) 7.0 Hz, 6H), 2.35 (s, 3H), 3.15 (m, 1H), 5.30 (s,
1H), 6.90-7.22 (m, 3H), 7.35 (m, 4H), 7.41 (m, 4H), 7.75 (m, 1H),
8.12 (m, 1H), 10.7 (s, 1H); MS (EI) 412 au. Anal. Calcd for
1
7.0-8.6 (m, 8H); MS (EI) 342, 344 au. Anal. Calcd for C18H14
-
ClNO4: C, 62.89; H, 4.10; N, 4.07. Found: C, 63.25; H, 4.13; N,
4.10.
C
26H24N2O3: C, 75.71; H, 5.86 N, 6.79. Found: C, 75.53; H, 5.79;
N, 6.86.
N-P h en yl 2-(4-isop r op ylp h en yl)-1,3(2H ,4H )-d ioxoiso-
Eth yl 2-(3,5-d ich lor op h en yl)-1,3(2H,4H)-d ioxoisoqu in o-
lin e-4-ca r boxyla te (3d ): mp 191-193 °C; yield 47%; 1H-NMR
(300 MHz, DMSO-d6) δ 1.19 + 1.44 (2t, J ) 7.0 Hz, 3H), 4.23 +
4.53 (2q, J ) 7 Hz, 2H), 5.41 (s, ∼1H, C-4 methine), 7.37-7.85
(m, 5H), 8.17 (m, 1H), 8.52 (d, J ) 8.2 Hz, 1H); MS (EI) 377,
379 au. Anal. Calcd for C18H13Cl2NO4: C, 57.16; H, 3.46; N,
3.70. Found: C, 56.77; H, 3.39; N, 3.61.
qu in olin e-4-ca r boxa m id e (6i): mp 217-219 °C from acetone
or acetone/hexanes; yield 55%; 1H-NMR (300 MHz, DMSO-d6)
δ 1.30 (d, J ) 7.0 Hz, 6H), 3.00 (m, 1H), 5.35 (s, 1H), 7.15 (m,
3H), 7.42 (m, 3H), 7.63 (m, 5H), 7.75 (m, 1H), 8.10 (m, 1H), 11.0
(s, 1H); MS (EI) 398 au. Anal. Calcd for C25H22N2O3: C, 75.36;
H, 5.57; N, 7.03. Found: C, 75.46; H, 5.69; N, 7.09.
Eth yl 2-(3,5-d im eth oxyp h en yl)-1,3(2H,4H)-d ioxoisoqu in -
olin e-4-ca r boxyla te (3e): mp 161-163 °C; yield 52%; 1H-NMR
(300 MHz, DMSO-d6) δ 1.40 (t, J ) 7.0 Hz, 3H), 3.70 (s, 6H),
4.50 (q, J ) 7 Hz, 2H), 7.40-7.65 (m, 5H), 7.95 (m, 1H), 8.45 (d,
J ) 8.2 Hz, 1H); MS (EI) 369 au. Anal. Calcd for C20H19NO6:
C, 65.03; H, 5.18; N, 3.79. Found: C, 65.37; H, 5.09; N, 4.01.
Eth yl 2-(4-m eth ylp h en yl)-1,3(2H,4H)-d ioxoisoqu in olin e-
4-ca r boxyla te (3f): mp 164-166 °C; yield 56%; 1H-NMR (300
MHz, CDCl3) δ 1.25 + 1.55 (2t, J ) 7.0 Hz, 3H), 2.40 + 2.50 (2s,
3H), 4.25 + 4.55 (2q, J ) 7.0 Hz, 2H), 7.12-7.84 (m, 6H), 7.95
(m, 1H), 8.40 (dd, J ) 8.2, 2.1 Hz, 1H), 8.55 (dd, J ) 8.2, 2.1 Hz,
1H); MS (EI) 323 au. Anal. Calcd for C19H17NO4: C, 70.58; H,
5.30; N, 4.33. Found: C, 70.67; H, 5.65; N, 4.29.
Eth yl 2-(3-m eth ylp h en yl)-1,3(2H,4H)-d ioxoisoqu in olin e-
4-ca r boxyla te (3g): mp 130-132 °C; yield 26%; 1H-NMR (300
MHz, CDCl3) δ 1.30 + 1.55 (2t, J ) 7.0 Hz, 3H), 2.40 (s, 3H),
4.24 + 4.54 (2 q, J ) 7.0 Hz, 2H), 7.00-7.82 (m, 6H), 7.95 (m,
1H), 8.42 (dd, J ) 7.4, 2.0 Hz, 1H), 8.58 (dd, J ) 7.4, 2.0 Hz,
1H); MS (EI) 323 au. Anal. Calcd for C19H17NO4: C, 70.58; H,
5.30; N, 4.33. Found: C, 70.46; H, 5.46; N, 4.51.
N-P h en yl 2-[3,5-bis(tr iflu or om eth yl)p h en yl]-1,3(2H,4H)-
d ioxoisoqu in olin e-4-ca r boxa m id e (6j): mp 188-190 °C (dec)
from acetone or acetone/hexanes; yield 95%; 1H-NMR (300 MHz,
DMSO-d6) δ 5.40 (s, 1H), 7.15 (t, J ) 7.0 Hz, 1H), 7.40 (t, J )
7.0 Hz, 2H), 7.65 (m, 4H), 7.70 (t, J ) 7.0 Hz, 1H), 8.10 (br s,
2H), 8.22 (d, J ) 7.0 Hz, 1H), 8.3 (br s, 1H), 11.0 (s, 1H); MS
(EI) 492 au. Anal. Calcd for C24H14F6N2O3: C, 58.55; H, 2.87;
N, 5.69. Found: C, 58.47; H, 2.63; N, 5.47.
Meth od B-2. Gen er a l P r oced u r e for th e Alcoh olysis of
th e C-4 N-P h en ylca r boxa m id e Der iva tives 6b,d ,e,h -j To
Affor d Eth yl 2-Ar yl-1,3(2H,4H)-d ioxoisoqu in olin e-4-ca r -
boxyla tes 3b,d ,e,h -j. A suspension of 6b,d ,e,h -j (0.020 mol)
in 300-400 mL of ethanol was stirred and heated at reflux for
12-36 h, reaction progress being monitored by TLC (EtOAc/
hexane mixtures) as well as by complete dissolution of the
starting material. The solution was cooled to ambient temper-
ature and then refrigerated overnight at 0-4 °C. The resultant
products were collected by suction filtration and dried to afford
nearly colorless crystalline products 3b,d ,e,h -j which were
usually obtained in analytically pure form. Where appropriate,
recrystallization from ethanol afforded 3b,d ,e,h -j as colorless
solids.
Eth yl 2-[4-(eth oxyca r bon yl)p h en yl]-1,3(2H,4H)-dioxoiso-
qu in olin e-4-ca r boxyla te (3b): mp 176-177 °C; yield 87%;
same physical properties and spectra as material prepared above
via the ethyl chloroformate protocol.
Eth yl 2-(3,5-Dich lor op h en yl)-1,3(2H,4H)-d ioxoisoqu in o-
lin e-4-ca r boxyla te (3d ): mp 192-194 °C; yield 87%; same
physical properties and spectra as material prepared above via
the ethyl chloroformate protocol.
Eth yl 2-(3,5-d im eth oxyp h en yl)-1,3(2H,4H)-d ioxoisoqu in -
olin e-4-ca r boxyla te (3e): mp 176-177 °C; yield 88%; same
physical properties and spectra as material prepared above via
the ethyl chloroformate protocol.
Eth yl 2-(3-m eth yl-4-isop r op ylp h en yl)-1,3(2H,4H)-d iox-
oisoqu in olin e-4-ca r boxyla te (3h ): mp 135-137 °C; yield 79%;
1H-NMR (300 MHz, CDCl3) δ 1.30 (d, J ) 7.0 Hz, 6H), 1.55 (t,
J ) 7.0 Hz, 3H), 2.40 (s, 3H), 3.21 (m, 1H), 4.25 + 4.55 (2 q, J
) 7.0 Hz, 2H), 7.00-7.73 (m, 5H), 8.41 (dd, J ) 7.2, 2.1 Hz, 1H),
Syn th esis of Eth yl 2-Ar yl-1,3(2H,4H)-d ioxoisoqu in olin e-
4-ca r boxyla tes 3b,d ,e,h -j via Alcoh olysis of th e C-4 N-
P h en ylca r boxa m id e Der iva tives 6b,d ,e,h -j. Meth od B-1.
Gen er a l P r oced u r e for th e Syn th esis of th e N-P h en ylca r -
boxa m id e Der iva tives 6b,d ,e,h -j. To a suspension of sodium
hydride (0.26 g, 0.011 mol, from 0.44 g of 60% dispersion in oil,
washed three times with dry hexane) in 50 mL of anhydrous
THF at 0 °C was added with good stirring a solution of
2b,d ,e,h -j (0.010 mol) in 50 mL of dry THF over about 30 min.
After 15 min, the solution was briefly warmed to ambient
temperature and recooled to 0 °C, and then phenyl isocyanate
(1.31 g, 0.0110 mol, 1.20 mL) was added rapidly dropwise over
1 min. After 30 min at 0 °C, the mixture was stirred at ambient
temperature for 2-12 h (TLC monitoring; THF/H2O/EtOAc, 10/
1/39 or EtOAc/hexane mixtures). The solution was poured into
500-600 mL of ice/water and acidified to pH ∼1-2 with 12 N
HCl. After stirring at 0 °C for 30 min, the resultant solid was
collected by suction filtration, washed with several portions of
ice/water, dried, and recrystallized from the appropriate solvents
indicated below to afford 6b,d ,e,h -j as nearly colorless, volu-
minous solids. Principal IR bands (KBr): 3275, 1715-1720,
8.55 (d, J ) 7.2 Hz, 1H); MS (EI) 365 au. Anal. Calcd for C22H23
-
NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.65; H, 6.63; N,
3.76.
1670, 1645, 1590, 1250 cm-1
.
N-P h en yl 2-[4-(eth oxyca r bon yl)p h en yl]-1,3(2H,4H)-d i-
oxoisoqu in olin e-4-ca r boxa m id e (6b): mp 220.5-222.5 °C
Eth yl 2-(4-isop r op ylp h en yl)-1,3(2H,4H)-d ioxoisoqu in o-
lin e-4-ca r boxyla te (3i): mp 160-161.5 °C; yield 81%; 1H-NMR
(300 MHz, CDCl3) δ 1.30 (d, J ) 8.0 Hz, 6H), 1.55 (t, J ) 7.4
Hz, 3H), 3.00 (m, 1H), 4.60 (q, J ) 7.4 Hz, 2H), 7.12-7.62 (m,
5H), 7.70 (m, 1H), 8.40 (dd, J ) 7.2, 2.1 Hz, 1H), 8.55 (dd, J )
7.2, 2.1 Hz, 1H); MS (EI) 351 au. Anal. Calcd for C21H21NO4:
C, 71.78; H, 6.02; N, 3.99. Found: C, 71.59; H, 5.83; N, 3.94.
Eth yl 2-[3,5-bis(tr iflu or om eth yl)p h en yl]-1,3(2H,4H)-d i-
oxoisoqu in olin e-4-ca r boxyla te (3j): mp 161-163 °C; yield
1
from THF or acetone; yield 66%; H-NMR (60 MHz, DMSO-d6)
δ 1.35 (t, J ) 7 Hz, 3H), 4.37 (q, J ) 7 Hz, 2H), 5.43 (s, 1H),
6.95-8.15 (m, 13H), 10.8 (br s, 1H); MS (EI) 428 au. Anal.
Calcd for C25H20N2O5: C, 70.09; H, 4.71; N, 6.54. Found: C,
70.42; H, 4.80; N, 6.64.
N-P h en yl 2-(3,5-d ich lor op h en yl)-1,3(2H ,4H )-d ioxoiso-
qu in olin e-4-ca r boxa m id e (6d ): mp 252-254 °C from acetone;
yield 69%; 1H-NMR (300 MHz, DMSO-d6) δ 5.37 (s, 1H), 7.14 (t,
J ) 8.0 Hz, 1H), 7.38 (m, 4H), 7.62 (m, 4H), 7.80 (m, 2H), 8.16
(d, J ) 8.0 Hz, 1H), 10.8 (br s, 1H); MS (EI) 424, 426 au. Anal.
Calcd for C22H14Cl2N2O3: C, 62.14; H, 3.32; N, 6.59. Found: C,
62.48; H, 3.28; N, 6.55.
1
62%; H-NMR (300 MHz, CDCl3) δ 1.30 + 1.60 (2t, J ) 7.2 Hz,
3H), 4.32 + 4.60 (2q, J ) 7.2 Hz, 2H), 7.31-8.10 (m, 5H), 8.40
(m, 1H), 8.55 (d, J ) 7.2 Hz, 1H); MS (EI) 445 au. Anal. Calcd
for C20H13F6NO4: C, 53.94; H, 2.94; N, 3.15. Found: C, 54.17;
H, 3.08; N, 3.37.
N-P h en yl 2-(3,5-d im eth oxyp h en yl)-1,3(2H,4H)-d ioxoiso-
qu in olin e-4-ca r boxa m id e (6e): mp 211-213 °C from acetone;
yield 86%; 1H-NMR (300 MHz, DMSO-d6) δ 3.75 (s, 6H), 5.35
(s, 1H), 6.43 (br, 2H), 6.63 (m, 1H), 7.15 (m, 1H), 7.35 (m, 2H),
7.61 (m, 4H), 7.75 (m, 1H), 8.15 (m, 1H), 10.9 (s, 1H); MS (EI)
416 au. Anal. Calcd for C24H20N2O5: C, 69.22; H, 4.84; N, 6.73.
Found: C, 69.51; H, 5.02; N, 6.65.
Gen er a l P r oced u r e for th e Ben zoyloxya tion of 3a -j.
Syn th esis of Eth yl 2-Ar yl-4-(ben zoyloxy)-1,3(2H,4H)-d iox-
oisoqu in olin e-4-ca r boxyla tes 4a -j. To a magnetically stirred
suspension of sodium hydride (0.26 g, 0.011 mol, from 0.43 g of
60% oil dispersion, washed three times with dry hexane) in 50
mL of anhydrous THF at 0 °C was added intermediate 3a-j
(0.010 mol) portionwise over 10-15 min. After stirring at 0 °C
for 1 h, a solution of benzoyl peroxide (2.67 g, 0.011 mol) in 25
mL of anhydrous THF was added dropwise over 15 min. The
N-P h en yl 2-(3-m eth yl-4-isop r op ylp h en yl)-1,3(2H,4H)-d i-
oxoisoqu in olin e-4-ca r boxa m id e (6h ): mp 200-202 °C from

Notes
J . Org. Chem., Vol. 61, No. 22, 1996 7971
ice bath was removed, and the mixture was stirred at ambient
temperature for 6-24 h, reaction progress being monitored by
TLC (EtOAc/hexane or methylene chloride/ethyl acetate mix-
tures). The solvent was evaporated, and the residue was
dissolved in 300 mL of methylene chloride and extracted with 2
× 50 mL portions each of saturated sodium bicarbonate solution
and water. Drying over anhydrous MgSO4, filtration, and
solvent removal afforded the crude product, which was purified
either by recrystallization from ethanol/acetone or ethyl acetate/
hexane mixtures or by flash chromatography using ethyl acetate/
hexane or ethyl acetate/methylene chloride gradient systems to
afford the products 4a -j as nearly colorless solids. Range of
principal IR bands for 4a -j in KBr: 1755-1765, 1715-1720,
1670-1680, 1585-1590 cm.-1
Eth yl 2-p h en yl-4-(ben zoyloxy)-1,3(2H,4H)-d ioxoisoqu in -
olin e-4-ca r boxyla te (4a ): mp 232-234 °C; yield 89%; 1H-NMR
(60 MHz, DMSO-d6) δ 1.23 (t, J ) 7 Hz, 3H), 4.25 (dq, each J )
7 Hz, 2H), 7.12-8.43 (m, 14H); MS (EI) 429 au. Anal. Calcd
for C25H19NO6: C, 69.92; H, 4.46; N, 3.26. Found: C, 69.73; H,
4.50; N, 3.34.
7.65 (m, 4H), 7.81 (s, 2H), 8.00 (s, 1H), 8.23 (dd, J ) 7.2, 2.1 Hz,
2H), 8.35 (d, J ) 7.2 Hz, 1H); MS (EI) 565 au. Anal. Calcd for
C
27H17F6NO6: C, 57.35; H, 3.03; N, 2.48. Found: C, 57.18; H,
2.97; N, 2.76.
Gen er a l P r oced u r e for th e Clea va ge of th e C-4 Ben zoyl-
oxy In ter m ed ia tes 4a -j. Syn th esis of Eth yl 2-Ar yl-4-
h yd r oxy-1,3(2H,4H)-Dioxoisoqu in olin e-4-ca r boxyla tes 5a-
j. To a magnetically stirred solution of intermediate 4a -j (7.5
mmol) in 50 mL of anhydrous ethanol at 0 °C was added slowly
over 20 min a solution of sodium ethoxide freshly prepared from
sodium (0.045-0.075 mol) and 15-25 mL of anhydrous ethanol.
The mixture was stirred at 0 °C for 15-60 min; progress of the
reaction was monitored by TLC analysis (EtOAc/hexane or
methylene chloride/ethyl acetate mixtures). Upon completion,
the reaction was neutralized at 0 °C with the theoretical amount
of acetic acid (0.045-0.075 mol). The solvent was evaporated,
and the residue was dissolved in 300 mL of ethyl acetate, mixed
with MgSO4 (to assist with the filtration of colloidal NaOAc),
filtered, and evaporated. The crude product was purified by
flash chromatography, employing methylene chloride/hexane to
methylene chloride/ethyl acetate gradient systems to afford the
pure products 5a -j. Analytical samples, usually appearing as
colorless needles, were obtained by recrystallization from ether/
hexane mixtures. Range of principal IR bands for 5a -j in
KBr: 3200-3320, 1745-1755, 1685-1690, 1660-1665, 1595-
1605 cm.-1
Eth yl 2-[4-(eth oxyca r bon yl)p h en yl]-4-(ben zoyloxy)-1,3-
(2H,4H)-d ioxoisoqu in olin e-4-ca r boxyla te (4b): glass; yield
92%; 1H-NMR (60 MHz, DMSO-d6) δ 1.25 (t, J ) 7 Hz, 3H), 1.38
(t, J ) 7 Hz, 3H), 4.38 (dq, each J ) 7 Hz, 4H), 7.20-8.45 (m,
13H); MS (EI) 501 au. Anal. Calcd for C28H23NO8: C, 67.06;
H, 4.62; N, 2.79. Found: C, 67.40; H, 4.95; N, 3.12.
Eth yl 2-(4-ch lor op h en yl)-4-(ben zoyloxy)-1,3(2H,4H)-d i-
oxoisoqu in olin e-4-ca r boxyla te (4c): mp 232-235 °C; yield
92%; 1H-NMR (60 MHz, DMSO-d6) δ 1.23 (t, J ) 7 Hz, 3H), 4.27
(dq, each J ) 7 Hz, 2 H), 7.05-8.45 (m, 13H); MS (EI) 462, 464
au. Anal. Calcd for C25H18ClNO6: C, 64.73; H, 3.91; N, 3.02.
Found: C, 65.01; H, 3.94; N, 3.14.
Eth yl 2-p h en yl-4-h yd r oxy-1,3(2H,4H)-d ioxoisoqu in olin e-
4-ca r boxyla te (5a ): mp 97.5-98.5 °C; yield 54%; 1H-NMR (60
MHz, CDCl3) δ 1.00 (t, J ) 7 Hz, 3H), 4.03 (dq, each J ) 7 Hz,
2H), 5.10 (br s, 1H), 7.20-8.05 (m, 9H); MS (EI) 325 au. Anal.
Calcd for C18H15NO5: C, 66.46; H, 4.65; N, 4.31. Found: C,
66.85; H, 5.03; N, 4.58.
Eth yl 2-(3,5-d ich lor op h en yl)-4-(ben zoyloxy)-1,3(2H,4H)-
d ioxoisoqu in olin e-4-ca r boxyla te (4d ): mp 181-183 °C; yield
89%; 1H-NMR (300 MHz, CDCl3) δ 1.27 (t, J ) 7.0 Hz, 3H), 4.30
(m/overlapping q, 2H), 7.25 (m, 2H), 7.50 (m, 3H), 7.66 (m, 4H),
8.18 (m, 2H), 8.33 (d, J ) 8.0 Hz, 1H); MS (EI) 497, 499 au.
Anal. Calcd for C25H17Cl2NO6: C, 60.26; H, 3.44; N, 2.81.
Found: C, 59.89; H, 3.41; N, 2.75.
E t h yl
2-[4-(E t h oxyca r b on yl)p h en yl]-4-h yd r oxy-1,3-
(2H,4H)-d ioxoisoqu in olin e-4-ca r boxyla te (5b): mp 110-111
°C; yield 45%; 1H-NMR (60 MHz, CDCl3) δ 0.98 (t, J ) 7 Hz,
3H), 1.37 (t, J ) 7 Hz, 3H), 4.07 (dq, each J ) 7 Hz, 2H), 4.37
(q, J ) 7 Hz, 2H), 5.20 (s, 1H), 7.40-8.25 (m, 8H); MS (EI) 397
au. Anal. Calcd for C21H19NO7: C, 63.47; H, 4.82; N, 3.52.
Found: C, 63.75; H, 5.00; N, 3.50.
Eth yl 2-(3,5-dim eth oxyph en yl)-4-(ben zoyloxy)-1,3(2H,4H)-
d ioxoisoqu in olin e-4-ca r boxyla te (4e): mp 166-167 °C; yield
75%; 1H-NMR (300 MHz, CDCl3) δ 1.25 (t, J ) 7.0 Hz, 3H), 3.80
(s, 6H), 4.20 (m, 1H), 4.35 (m, 1H), 6.45 (d, J ) 2.1 Hz, 2H),
7.40-7.73 (m, 6H), 8.21 (m, 2H), 8.35 (m, 1H); MS (EI) 489 au.
Anal. Calcd for C27H23NO8: C, 66.25; H, 4.74; N, 2.86. Found:
C, 66.31; H, 4.95; N, 3.04.
Eth yl 2-(4-m eth ylp h en yl)-4-(ben zoyloxy)-1,3(2H,4H)-d i-
oxoisoqu in olin e-4-ca r boxyla te (4f): mp 243-245 °C; yield
72%; 1H-NMR (300 MHz, CDCl3) δ 1.25 (t, J ) 7.0 Hz, 3H), 2.40
(s, 3H), 4.11-4.43 (overlapping q, J ) 7.0 Hz, 2H), 7.23-7.70
(m, 10H), 8.10-8.43 (m, 3H); MS (EI) 443 au. Anal. Calcd for
Eth yl 2-(4-ch lor op h en yl)-4-h ydr oxy-1,3(2H,4H)-dioxoiso-
qu in olin e-4-ca r boxyla te (5c): mp 113.5-115 °C; yield 51%;
1H-NMR (60 MHz, CDCl3) δ 1.02 (t, J ) 7 Hz, 3H), 4.08 (dq,
each J ) 7 Hz, 2 H), 5.12 (s, 1H), 7.13-8.05 (m, 8H); MS(EI)
358, 360 au. Anal. Calcd for C18H14ClNO5: C, 60.09; H, 3.92;
N, 3.89. Found: C, 60.33; H, 4.21; N, 4.20.
E t h yl 2-(3,5-d ich lor op h en yl)-4-h yd r oxy-1,3(2H,4H)-d i-
oxoisoqu in olin e-4-ca r boxyla te (5d ): mp 148-150 °C; yield
52%; 1H-NMR (300 MHz, CDCl3) δ 1.09 (t, J ) 7.0 Hz, 3H), 4.17
(m, 2H), 4.95 (s, 1H), 7.32 (m, 1H), 7.47-7.70 (m, 5H), 7.92 (d,
J ) 8.2 Hz, 1H); MS(EI) no molecular ion. Anal. Calcd for
C
18H13Cl2NO5: C, 54.84; H, 3.32; N, 3.55. Found: C, 54.96; H,
C
26H21NO6: C, 70.42; H, 4.77; N, 3.16. Found: C, 70.26; H, 4.68;
N, 3.27.
Eth yl 2-(3-m eth ylp h en yl)-4-(ben zoyloxy)-1,3(2H,4H)-d i-
3.64; N, 3.80.
Eth yl 2-(3,5-d im eth oxyp h en yl)-4-h yd r oxy-1,3(2H,4H)-d i-
oxoisoqu in olin e-4-ca r boxyla te (5e): mp 124-125 °C; yield
47%; 1H-NMR (300 MHz, CDCl3) δ 1.11 (t, J ) 7.0 Hz, 3H), 3.82
(s, 6H), 4.10-4.43 (2 overlapping q, J ) 7.0 Hz, 2H), 4.91 (s,
1H), 6.45 (m, 1H), 6.70 (m, 2H), 7.53 (m, 1H), 7.65 (m, 2H), 7.93
(m, 1H); MS(EI) 385 au. Anal. Calcd for C20H19NO7: C, 62.33;
H, 4.97; N, 3.63. Found: C, 62.57; H, 5.15; N, 3.87.
E t h yl 2-(4-m et h ylp h en yl)-4-h yd r oxy-1,3(2H ,4H )-d iox-
oisoqu in olin e-4-ca r boxyla te (5f): mp 118-120 °C; yield 49%;
1H-NMR (300 MHz, CDCl3) δ 1.10 (t, J ) 6.5 Hz, 3H), 2.41 (s,
3H), 4.00-4.32 (m, 2H), 4.85 (s, 1H), 7.20-8.02 (m, 8H); MS-
(EI) 339 au. Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N,
4.13. Found: C, 67.08; H, 5.00; N, 4.25.
E t h yl 2-(3-m et h ylp h en yl)-4-h yd r oxy-1,3(2H ,4H )-d iox-
oisoqu in olin e-4-ca r boxyla te (5g): mp 144-145 °C; yield 46%;
1H-NMR (300 MHz, CDCl3) δ 1.15 (t, J ) 7.0 Hz, 3H), 2.44 (s,
3H), 4.03-4.38 (m, 2H), 5.00 (s, 1H), 7.15-7.92 (m, 8H); MS-
(EI) 339 au. Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N,
4.13. Found: C, 67.19; H, 5.07; N, 4.36.
E t h yl 2-(3-m et h yl-4-isop r op ylp h en yl)-4-h yd r oxy-1,3-
(2H,4H)-d ioxoisoqu in olin e-4-ca r boxyla te (5h ): mp 164-166
°C; yield 61%; 1H-NMR (300 MHz, CDCl3) δ 1.12 (t, J ) 7.1 Hz,
3H), 1.25 (d, J ) 8.0 Hz, 6H), 2.30 (s, 3H), 3.14 (m, 1H), 4.24 (2
overlapping q, J ) 7.1 Hz, 2H), 4.83 (br s, 1H), 7.15-7.35 (m,
3H), 7.42-7.70 (m, 3H), 7.92 (dd, J ) 8.1, 2.1 Hz, 1H); MS(EI)
oxoisoqu in olin e-4-ca r boxyla te (4g): mp 214-217 °C; yield
50%; 1H-NMR (300 MHz, CDCl3) δ 1.25 (t, J ) 7.5 Hz, 3H), 2.42
(s, 3H), 4.13-4.40 (2 overlapping q, J ) 7.5 Hz, 2H), 7.10-7.83
(m, 10H), 8.10-8.44 (m, 3H); MS (EI) 443 au. Anal. Calcd for
C
26H21NO6: C, 70.42; H, 4.77; N, 3.16. Found: C, 70.53; H, 4.91;
N, 3.34.
E t h yl 2-(3-m et h yl-4-isop r op ylp h en yl)-4-(b en zoyloxy)-
1,3(2H,4H)-d ioxoisoqu in olin e-4-ca r boxyla te (4h ): mp 149-
1
151 °C; yield 85%; H-NMR (300 MHz, CDCl3) δ 1.25 (m, 9H),
2.20 (s, 3H), 3.11 (m, 1H), 4.25 (2 overlapping q, J ) 7.0 Hz,
2H), 7.12 (m, 2H), 7.32-7.71 (m, 7H), 8.15 (m, 2H), 8.21 (m, 1H);
MS(EI) 485 au. Anal. Calcd for C29H27NO6: C, 71.74; H, 5.61;
N, 2.88. Found: C, 71.97; H, 5.87; N, 3.14.
Eth yl 2-(4-isop r op ylp h en yl)-4-(ben zoyloxy)-1,3(2H,4H)-
d ioxoisoqu in olin e-4-ca r boxyla te (4i): mp 165-167 °C; yield
1
78%; H-NMR (300 MHz, CDCl3) δ 1.32 (m, 9H), 3.02 (m, 1H),
4.20 (q, J ) 7.2 Hz, 1H), 4.35 (q, J ) 7.2 Hz, 1H), 7.23-7.72 (m,
10H), 8.21 (dd, J ) 8.2, 2.1 Hz, 2H), 8.35 (d, J ) 7.0 Hz, 1H);
MS(EI) 471 au. Anal. Calcd for C28H25NO6: C, 71.33; H, 5.34;
N, 2.97. Found: C, 71.47; H, 5.39; N, 3.04.
Eth yl 2-[3,5-bis(tr iflu or om eth yl)p h en yl]-4-(ben zoyloxy)-
1,3(2H,4H)-d ioxoisoqu in olin e-4-ca r boxyla te (4j): mp 164-
166 °C; yield 63%; 1H-NMR (300 MHz, CDCl3) δ 1.30 (t, J ) 7.2
Hz, 3H), 4.25 (m, 1H), 4.40 (m, 1H), 7.50 (t, J ) 8.2 Hz, 2H),

7972 J . Org. Chem., Vol. 61, No. 22, 1996
Notes
381 au. Anal. Calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67.
Found: C, 69.47; H, 6.26 ; N, 3.90.
1H), 8.10 (s, 2H); MS(EI) 461 au. Anal. Calcd for C20H13F6-
NO5: C, 52.07; H, 2.84; N, 3.04. Found: C, 52.39; H, 3.17; N,
3.33.
Eth yl 2-(4-isop r op ylp h en yl)-4-h yd r oxy-1,3(2H,4H)-d iox-
oisoqu in olin e-4-ca r boxyla te (5i): mp 133-134 °C; yield 38%;
1H-NMR (300 MHz, DMSO-d6) δ 1.00 (t, J ) 7.2 Hz, 3H), 1.25
(d, J ) 8.1 Hz, 6H), 2.92 (m, 1H), 3.97 (q, J ) 7.2 Hz, 1H), 4.13
(q, J ) 7.2 Hz, 1H), 7.20-7.81 (m, 8H); MS(EI) 367 au. Anal.
Calcd for C21H21NO5: C, 68.65; H, 5.76; N, 3.81. Found: C,
68.97; H, 5.95; N, 4.04.
Eth yl 2-[3,5-bis(tr iflu or om eth yl)p h en yl]-4-h yd r oxy-1,3-
(2H,4H)-d ioxoisoqu in olin e-4-ca r boxyla te (5j): mp 123-125
°C; yield 49%; 1H-NMR (300 MHz, CDCl3) δ 1.05 (t, J ) 7.1 Hz,
3H), 4.05 (m, 1H), 4.25 (m, 1H), 5.02 (s, 1H), 7.55 (d, J ) 7.0
Hz, 1H), 7.62-7.81 (m, 3H), 7.85 (s, 1H), 7.95 (d, J ) 7.0 Hz,
Ack n ow led gm en t. The authors thank the Shell
BSRC analytical chemistry department for providing
analytical and spectral data. Drs. G. D. Berger, T. K.
Brunck, W. D. Kollmeyer, and J . E. Powell are also
acknowledged for stimulating and helpful discussions
during the course of this work.
J O961135J