A novel high-yield synthesis of substituted isoindolequinones

Article abstract of DOI:10.1021/jo971671r

The high-yield, general one-pot synthesis of substituted isoindolequinones, a group of important radiosensitizers which sensitize hypoxic cells to the lethal effect of radiation in cancer radiotherapy, is described. Primary amines react with 2,3-bis[2-(trimethylsilyl)ethynyl]-5,6- dimethylhydroquinone (2) in methanol at room temperature under an inert atmosphere to give substituted isoindolequinones 2-alkyl-1,3,5,6- tetramethylisoindole-4,7-quinone (4) in almost quantitative yields. Moderate yields of 4 are also obtained using 2,3-diethynyl-5,6-dimethylhydroquinone (3) and amines as reactant and solvent under the similar conditions. Tris(2- aminoethyl)amine (TREN) reacts with 2 in MeOH/THF on reflux to produce the isoindolequinone derivative of TREN. Water with 2 on reflux on MeOH forms an isobenzofuranquinone. This indicates that the formation of similar heterocytes from small molecules (e.g., Group VA and VIA hydrides) and 2 is likely. Readily synthesizable starting materials, ease of chromatographic isolation of the product, reaction generality, use of no catalyst, and cost- effective environmentally benign solvents such as MeOH/EtOH make this novel reaction simple and convenient.

Full text of DOI:10.1021/jo971671r

J . Org. Chem. 1997, 62, 8193-8197
8193
A Novel High -Yield Syn th esis of Su bstitu ted Isoin d olequ in on es
Manisha Chakraborty, David B. McConville, Gerald F. Koser, Claire A. Tessier,
Takeshi Saito, Peter L. Rinaldi, and Wiley J . Youngs*
Department of Chemistry, The University of Akron, Akron, Ohio 44325-3601
Received September 8, 1997X
The high-yield, general, one-pot synthesis of substituted isoindolequinones, a group of important
radiosensitizers which sensitize hypoxic cells to the lethal effect of radiation in cancer radiotherapy,
is described. Primary amines react with 2,3-bis[2-(trimethylsilyl)ethynyl]-5,6-dimethylhydroquinone
(2) in methanol at room temperature under an inert atmosphere to give substituted isoindole-
quinones 2-alkyl-1,3,5,6-tetramethylisoindole-4,7-quinone (4) in almost quantitative yields. Moder-
ate yields of 4 are also obtained using 2,3-diethynyl-5,6-dimethylhydroquinone (3) and amines as
reactant and solvent under the similar conditions. Tris(2-aminoethyl)amine (TREN) reacts with 2
in MeOH/THF on reflux to produce the isoindolequinone derivative of TREN. Water with 2 on
reflux in MeOH forms an isobenzofuranquinone. This indicates that the formation of similar
heterocycles from small molecules (e.g., Group VA and VIA hydrides) and 2 is likely. Readily
synthesizable starting materials, ease of chromatographic isolation of the product, reaction
generality, use of no catalyst, and cost-effective environmentally benign solvents such as MeOH/
EtOH make this novel reaction simple and convenient.
In tr od u ction
in the formation of isoindolequinones 4 in almost quan-
titative yields.
Isoindolequinones have been shown to have useful
radiosensitization properties, in that they selectively
sensitize hypoxic cells in some tumors to the lethal effect
of radiation.1,2 Isoindolequinones were first synthesized
by the treatment of rhodium heterocycles, prepared from
diketodiynes and Wilkinson’s catalyst, with nitrosoben-
zene3 in very low yield (5%). Cycloadditions of oxazolium
5-oxides to 1,4-benzoquinones also give isoindole deriva-
tives in moderate yields.4,5 The first reported naturally
occurring isoindolequinone, 2,5-dimethyl-6-methoxyisoin-
dole-4,7-quinone,6 isolated from the sponge Reniera, has
been synthesized in moderate yields from a pyrrole
derivative7 and by the cycloaddition of an ylide to a
quinone.8 Zinc-induced intramolecular cyclizations of bis-
(bromoacetyl)heteroaromatic compounds also give isoin-
dolequinones in good yields.9
The palladium-copper-catalyzed coupling of 2,3-diiodo-
5,6-dimethylhydroquinone10 (1) with (trimethylsilyl)-
acetylene (TMSA) gives precursor 2 in 50% yield. De-
silylation of 2 by potassium fluoride in methanol at rt
gives 2,3-diethynyl-5,6-dimethylhydroquinone (3) in 52%
yield. We first encountered compound 4 (R2 ) isopropyl)
as a side product in a standard palladium-copper-
catalyzed coupling reaction to form an ene-yne cyclic
compound from 3 as one of the starting materials and
diisopropylamine as solvent. The reaction conditions
initially used in exploring the transformation of 3 into 4
involved the use of amines as reactants and solvents and
the presence and absence of Pd(PhCN)2Cl2 and PPh3 to
check the role of catalyst. The production of isoindole-
quinones proceeds with or without the catalyst, but with
increased yields (by about 10-20%) when the catalyst is
present. The trimethylsilyl derivative of 3, 2,3-bis[2-
(trimethylsilyl)ethynyl]-5,6-dimethylhydroquinone (2), un-
dergoes reaction with primary amines using the amine
as both reactant and solvent to produce the same
products as 3 under similar conditions and with ap-
proximately the same yields (37-78%). Surprisingly, a
32% yield of the isopropyl derivative of 4 (R2 ) i-Pr) has
been isolated on reaction of 3 with the secondary amine
i-Pr2NH on reflux, using i-Pr2NH as solvent, but the
formation of 4 is not observed at rt. The formation of 4
(R2 ) i-Pr) from 2 and i-Pr2NH is not observed at rt or
at reflux with MeOH as solvent. Compound 4 (R2 ) i-Pr)
has been structurally characterized by pulsed field gradi-
ent (PFG) heteronuclear multiple bond correlation (HMBC)
and heteronuclear multiple quantum correlation (HMQC)
NMR experiments.11 Neither compound 2 nor 3 reacts
with triethylamine. The production of 4 is not observed
in aprotic solvents such as tetrahydrofuran or toluene
with as much as 5 equiv of a primary amine, but the
reaction does proceed if methanol or ethanol is used as
Resu lts a n d Discu ssion
We report a convenient, novel, high-yield synthesis of
substituted isoindolequinones from a diethynylhydro-
quinone and primary amines by a tandem reaction. The
combination of 2,3-bis[2-(trimethylsilyl)ethynyl]-5,6-di-
methylhydroquinone (2) and 1 molar equiv of a primary
amine in methanol under an inert atmosphere results
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) Myers, J . A. U.S. Patent 4 494 547, 1985.
(2) Radiat. Sensitizers: Their use Clin. Manage. Cancer 1980
(Conference Proceedings); Brady, L. W., Ed.; Masson USA: New York,
1980; pp 497-501.
(3) (a) Mu¨ller, E.; Winter, W. Liebigs Ann. Chem. 1974, 1876. (b)
Mu¨ller, E.; Luppold, E.; Winter, W. Chem. Ber. 1975, 108, 237. (c)
Hambrecht, J .; Straub H.; Mu¨ller E. Tetrahedron Lett. 1976, 21, 1789.
(d) Mu¨ller, V. E.; Dilger, W. Chem.-Ztg. 1973, 97(7), 388.
(4) Matsukubo, H.; Kato H. Bull. Chem. Soc. J pn. 1976, 49, 3333.
(5) Myers, J . A.; Moore, L. D. J r.; Whitter, W. L.; Council, S. L.;
Waldo, R. M.; Lanier, J . L.; Omoji, B. U. J . Org. Chem. 1980, 45, 1202.
(6) Thomson, R. H. Naturally Occuring Quinones III: recent ad-
vances; Chapman and Hall: New York, 1987; pp 657-658.
(7) Frincke, J . M.; Faulkner, D. J . J . Am. Chem. Soc. 1982, 104,
265.
(8) Parker, K. A.; Cohen, I. D.; Padwa, A.; Dent, W. Tetrahedron
Lett. 1984, 25, 4917.
(9) Ghera, E.; Gaoni, Y.; Perry, D. H. J . Chem. Soc., Chem. Commun.
1974, 24, 1034.
(10) Nicolaou, K. C.; Liu, A.; Zeng, Z.; McComb, S. J . Am. Chem.
Soc. 1992, 114, 9279-9282.
(11) Rinaldi, P. L.; Ray, D. G.; Litman, V. E.; Keifer, P. A. Polymer
Int. 1995, 36, 177.
S0022-3263(97)01671-X CCC: $14.00 © 1997 American Chemical Society

8194 J . Org. Chem., Vol. 62, No. 23, 1997
Chakraborty et al.
F igu r e 1. Thermal ellipsoid plot of 4 (R2 ) Bu).
(2)
Sch em e 1
The presence of a small amount of water (0.02% in
commercially available methanol) does not appear to
affect isoindolequinone formation. However, the combi-
nation of 2 with propylamine in 10% water-ethanol gives
a 73% yield of 4 (R2 ) Et). Without water present, a 98%
yield is obtained. The combination of 2 with water in
methanol at reflux affords the isobenzofuranquinone 6
(eq 3) in 56% yield.
cosolvent. The quinonoid form of 2 (5) reacts with ethyl-
and propylamines in methanol to give isoindolequinones
4 in 17% and 11% yields, respectively (eq 1). It is
probable that the quinonoid precursor is reduced to the
hydroquinone form (2) in presence of amine which then
undergoes further reaction.
(3)
(1)
1
All products were characterized by H and 13C NMR,
infrared, and mass spectroscopies and elemental analysis
(C and H). The structure of the butyl derivative 4 (R2 )
Bu) has been confirmed by X-ray crystallography (Figure
1).
The combination of 2 with 1.5-1.7 molar equiv of
methyl-, ethyl-, propyl-, or butylamine in degassed
methanol gives 4 in greater than 97% yield when the
mixtures are stirred at rt for 2 days (Scheme 1). Pure
yellow products were isolated by flash column chroma-
tography eluting with 3% ethyl acetate in petroleum
ether. The combination of ammonium hydroxide with 2
in MeOH gives 1,3,5,6-tetramethylisoindole-4,7-quinone,
4 (R2 ) H), in 88% yield. The combination of the
desilylated derivative 3 and propylamine in methanol
gives a 48% yield of 4 (R2 ) Pr) at room temperature.
This lower yield may be due to the poor solubility of 3
relative to that of 2 in MeOH. Aniline does not react
with 2 at rt in methanol, but when the mixture is heated
at 80 °C for 12 h, 4 (R2 ) Ph) is isolated in 88% yield.
Melamine, adenine, guanine, and cytosine give no reac-
tion when combined with 2 in methanol or in methanol/
H2O/DMSO mixtures at rt or reflux. This is presumably
due to the very low nucleophilicity of these bases. The
combination of 2 with tris(2-aminoethyl)amine, TREN,
in a 1:3 ratio in 1:1 MeOH:THF at reflux gives 6 in 57%
yield (eq 2). When the R1 group in 2 is a phenyl ring, no
reaction with amines is observed.
An important observation, when speculating on the
mechanism of these reactions, is that the best yields are
obtained when protic solvents are employed. The pro-
duction of isoindolequinones 4 from 3 and primary
amines is believed to be the result of anionic tandem
reactions (Scheme 2), comprising base-catalyzed tau-
tomerizations, Michael reactions, and proton transfers.
The series seems to be initiated by base-catalyzed tau-
tomerization (steps i and ii) of the hydroquinone (3) to
ketylallene intermediate 7. Michael addition by amine
on 7 (step iii) and proton transfer (step iv) from solvents
or amine gives 8. Intermolecular Michael addition on
the remaining allene (v) followed by proton transfer gives
(vi) 9. Two steps of base-catalyzed tautomerization (vi)
ultimately yield isoindolequinone 4. In the case of
diisopropylamine (eq 4) it is assumed that the initial
product is a diisopropylammonium ion which undergoes
â elimination with excess amine to give propylene and
the monoisopropylisoindole system 4a (R2 ) i-Pr).
(12) Hartley, F. R. Organomet. Chem. Rev. A 1970, 6, 119.

Novel Synthesis of Substituted Isoindolequinones
J . Org. Chem., Vol. 62, No. 23, 1997 8195
(4)
When the reaction of 2 and excess butylamine was
carried out in CD3OD, 80% deuterium incorporation in
the methyl groups adjacent to the nitrogen was observed
(trimethylsilyl)acetylene (Aldrich), propylamine (Lancaster),
triphenylphosphine (J anssen Chimica), aniline, methanol,
ethanol, carbon tetrachloride, acetonitrile, magnesium sulfate
(Fisher), and deuterated chloroform (Cambridge Isotope Labo-
ratory) were used as received. Tetrahydrofuran and toluene
(Fisher) were distilled from sodium and benzophenone under
nitrogen. Isopropylamine (Lancaster) and diisopropylamine
(J anssen Chimica) were distilled from BaO and KOH, respec-
tively.
1
by H NMR and 4 (D6, R2 ) Bu) was obtained. When 3
Gen er a l Tech n iqu es. Field desorption mass spectra
(FDMS) were obtained by Dr. Robert Lattimer at BF Goodrich
in Brecksville, OH. High-resolution mass spectra (HRMS)
were obtained by the Nebraska Center for Mass Spectrometry.
Unless specified otherwise, all reactions were conducted under
argon by standard Schlenk techniques. The amines and
methanol used in reactions were degassed by three freeze-
pump-thaw cycles. Reaction temperatures were monitored
externally. All reactions were monitored by thin-layer chro-
matography (TLC) on E. Merck silica gel plates (60F-254)
using UV light. Flash column chromatography was performed
on silica gel (Baker: 40 µm). Elemental analyses were
performed by Midwest Microlab in Indianapolis, IN, and
Schwarzkopf Microanalytical Laboratory, NY.
was refluxed for 8 h in CD3OD, the quantitative conver-
sion to 11 was observed (eq 5). This is consistent with
the reversible formation of ketoallenes such as 7 from 3
as in Scheme 2.
(5)
2,3-Bis[2-(tr im eth ylsilyl)eth yn yl]-5,6-d im eth ylh yd r o-
qu in on e (2). To a solution of 2,3-diiodo 5,6-dimethylhydro-
quinone10 (1, 3.60 g, 9.23 mmol), PdII(PhCN)2Cl2 (176 mg, 0.46
mmol), PPh3 (278 mg, 1.06 mmol), and CuI (297 mg, 1.56
mmol) in toluene (110 mL) were added diisopropylamine (2.50
mL, 18.5 mmol), and (trimethylsilyl)acetylene (4.00 mL, 28.6
mmol). After being stirred at room temperature for a day, the
reaction mixture was opened to air, filtered, and concentrated
in vacuo. Flash column chromatography of the crude solid
with 7% ethyl acetate in petroleum ether gave 2 as a yellow
solid: yield, 1.53 g (50.2%); mp 79-80 °C; 1H NMR (CDCl3) δ
0.29 (s, 18 H, 2 SiMe3), 2.18 (s, 6 H, 2 CH3), 5.63 (s, 2 H, 2
OH); 13C NMR (CDCl3) δ 0.01,12.42, 98.04, 104.68, 106.81,
125.67, 149.02; IR (Nujol solution) ν 3483 (s, OH), 2957 (s, CH3
on benzene ring), 2141 (s, CtC) cm-1; UV-vis (CH3CN) λmax
(log ꢀ) 236 (4.13), 262 (s, 3.53), 278 (3.71), 288 (3.76), 348 (3.45),
358 (3.46) nm; HRMS (EI) calcd for C18H26O2Si2 330.1471,
found 330.1472 (err 0.43 ppm).
2,3-Dieth yn yl-5,6-d im eth ylh yd r oqu in on e (3). A solu-
tion of 2 (375 mg, 1.14 mmol), KF (198 mg, 3.40 mmol), MeOH
(35 mL), and H2O (2.9 mL) was stirred in air at room
temperature for 1 h. The reaction was monitored by TLC
every 10 min after the first half hour had elapsed. When the
starting material spot on the TLC disappeared (after 20 min),
the mixture was quenched with water (20 mL). Otherwise the
product was found to polymerize. The reaction mixture was
then extracted with CH2Cl2 (3 × 20 mL), and the combined
extracts were washed thoroughly with H2O (3 × 20 mL), dried
over MgSO4, and concentrated in vacuo. Flash column chro-
matography of the crude solid with 7% ethyl acetate in
Con clu sion s
Readily synthesizable starting materials, one-pot con-
versions, high-yields, and ease of chromatographic isola-
tion of products make this isoindolequinone synthesis
simple and convenient. In addition the reaction requires
no catalyst and uses environmentally benign solvents
(MeOH or EtOH). This reaction can be expected to have
potential use in the high-yield synthesis of substituted
isoindolequinone systems. We are in the process of
further investigation of this reaction and its extension
to other amines and substrate systems. We are also
exploring the synthesis and reaction chemistry of vari-
ously substituted 2-(2-(R5)ethynyl)-3-(2-(R6)ethynyl)-5-
(R3)-6-(R4)hydroquinones 12 with amines, water, H2S,
and other small molecules.
Exp er im en ta l Section
Ma t er ia ls. All chemicals were reagent grade materials.
The compounds 2,3-diiodo-5,6-dimethylhydroquinone (1)10 and
bis(benzonitrile)palladium dichloride12 were prepared by lit-
erature procedures. Methylamine in methanol (2 M), ethy-
lamine in ethanol (2 M), butylamine, deuterated methanol
(CD3OD), potassium fluoride, copper iodide, barium oxide, and
Sch em e 2

8196 J . Org. Chem., Vol. 62, No. 23, 1997
Chakraborty et al.
petroleum ether gave the title compound as a creamy white
solid: yield, 111 mg (52%); mp, gets darker after 133 °C and
for C13H15O2N 217 (M+). Anal. Calcd for C13H15O2N: C, 71.86;
H, 6.95; N, 6.44. Found: C, 71.60; H, 6.90; N, 6.24.
1
2-Eth yl-1,3,5,6-tetr a m eth ylisoin d ole-4,7-qu in on e, 4 (R2
) Et). A 2 M solution of EtNH2 in EtOH was used as received.
Using procedure A, the 2 M solution of EtNH2 in EtOH (9.0
mL, 18 mmol) was added to 2 (59.4 mg, 0.18 mmol) via syringe.
Column chromatography (3% ethyl acetate in petroleum ether)
gave the ethyl derivative as a yellow solid in 98% yield (40.8
mg): mp 166 °C; 1H NMR (CDCl3) δ 2.05 (s, 6 H, 2 CH3), 2.58
(s, 6 H, 2 CH3), 3.85 (q, 2 H, J ) 7.2 Hz, CH2), 1.30 (t, 3 H, J
) 7.1 Hz, CH3); 13C NMR (CDCl3) δ 11.01, 12.66, 15.38, 38.04,
116.83, 134.96, 144.05, 183.16; IR (CCl4) ν 1640 (s, CdO), 2928
(w, CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 200 (3.81), 222
(3.70), 264 (3.57), 398 (3.02, br) nm; HRMS (EI) calcd for
C14H17O2N 231.1259, found 231.1259 (err 0.02 ppm).
melts between 151 and 152 °C; H NMR (CDCl3) δ 2.21 (s, 6
H, 2 CH3), 3.65 (s, 2 H, 2 alkynyl H), 5.59 (s, 2 OH); 13C NMR
(CDCl3) δ 12.70, 86.88, 95.70, 105.95, 126.70, 149.80; IR (CCl4)
ν 2099 (w, CtC), 2931 (w, CH3 on benzene ring), 3308 (s,
CtCH), 3533 (m, OH) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 346
(4.05), 272 (4.24), 264 (4.22), 224 (4.68) nm; FDMS found for
C12H10O2 186 (M+). Anal. Calcd for C12H10O2: C, 77.36; H,
5.37. Found: C, 77.20; H, 5.34.
Gen er a l P r oced u r e A: Syn th esis of Isoin d olequ in on es
4 fr om 2,3-Bis[(tr im eth ylsilyl)eth yn yl]-5,6-d im eth ylh y-
d r oqu in on e (2) in Meth a n ol. All the compounds except the
isopropyl derivative have been synthesized using this proce-
dure. To a colorless solution of 2 in methanol was added an
amine via syringe (1.2-1.4 molar equiv) under argon, and the
solution was stirred at room temperature. The solution
immediately assumed an orange yellow color that turned into
bright yellow within half an hour and was stirred for 2 days
at room temperature. After the reaction vessel was opened
to air, the volatiles were removed in vacuo. Flash column
chromatography of the residual materials gave pure yellow
isoindolequinones in 97-98% yield in most cases.
2-P r op yl-1,3,5,6-t et r a m et h ylisoin d ole-4,7-qu in on e, 4
(R2 ) P r ). Following procedure A, MeOH (0.80 mL) and
n-propylamine (0.02 mL, 0.24 mmol) were added to 2 (46.2 mg,
0.14 mmol). Column chromatography with 3% ethyl acetate
in petroleum ether gave the title compound as a yellow solid:
yield, 33.3 mg (97%); mp 163-164 °C; 1H NMR (CDCl3) δ 2.05
(s, 6 H, 2 CH3), 2.57 (s, 6 H, 2 CH3), 0.97 (t, 3 H, J ) 7.0 Hz,
CH3), 1.69 (tq, 2 H, J ) 7.4 Hz, CH2), 3.79 (t, 2 H, J ) 7.4 Hz,
CH2); 13C NMR (CDCl3) δ 11.27, 12.66, 14.16, 23.59, 44.80,
116.76, 135.34, 144.06, 183.17; IR (CCl4) ν 1641 (s, CdO), 2927
(m, CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 208 (4.42), 222
(4.46), 264 (4.33), 396 (3.88, br) nm; FDMS found for C15H19O2N
245 (M+). Anal. Calcd for C15H19O2N: C, 73.46; H, 7.75; N,
5.71. Found: C, 73.20; H, 7.61; N, 5.70.
1,3,5,6-Tetr a m eth ylisoin d ole-4,7-qu in on e, 4 (R2 ) H).
General procedure A was followed using 2 (39.6 mg, 0.12
mmol) and 2 mL of MeOH saturated with ammonia. The
mixture was stirred at room temperature for 12 h. Column
chromatography (20% ethyl acetate in petroleum ether) gave
the title compound as a yellow solid: yield, 21.4 mg (88%);
mp, turns black after 290 °C and becomes totally black until
360 °C without melting; 1H NMR (CDCl3) δ 2.06 (s, 3 H, CH3),
2.55 (s, 3 H, CH3
) 8.15 (s, H, br); 13C NMR (in DMSO,
referenced at δ 39.51) δ 12.01, 12.27, 115.95, 134.08, 143.29,
181.82; IR (CCl4) νmax 1641 (m, CdO), 2927 (m, CH3), 3244
(m, N-H) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 208 (4.06), 216
(4.04), 260 (3.95), 394 (3.47, br) nm; HRMS (FAB) calcd for
C12H14O2N (M + H) 204.1025, found 204.1026 (err -0.7 ppm).
Com p ou n d 6. To a solution of 2 (201 mg, 0.61 mmol) in
MeOH:THF (20 mL:20 mL) was added tris(2-aminoethyl)-
amine or TREN (0.03 mL, 0.2 mmol, d ) 0.97) via syringe.
The mixture was stirred at room temperature for 12 h and
refluxed for 24 h. After the reaction mixture was opened to
air, the volatiles were removed in vacuo. Flash column
chromatography (with 55% ethyl acetate in petroleum ether)
gave the TREN derivative of 4, a yellow solid, in 57% yield
(81.5 mg): mp, melts with decomposition within 270-278 °C;
1H NMR (CDCl3) δ 2.04 (s, 18 H, 6 CH3), 2.55 (s, 18 H, 6 CH3),
2.79 (t, 6 H, J ) 7.1 Hz, 3 CH2), 3.77 (t, 6 H, J ) 7.1 Hz 3
CH2); 13C NMR (CDCl3) δ 11.27, 12.66, 41.69, 55.05, 117.14,
134.36, 144.25, 182.92; IR (CCl4) ν 1632 (m, CdO), 2928 (m,
CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 202 (4.65), 224 (4.61),
260 (4.50), 394 (4.10) nm; HRMS (FAB) calcd for C42H49O6N4
(M+H) 705.3653, found 705.3661 (err -1.3 ppm).
2-Bu tyl-1,3,5,6-tetr a m eth ylisoin d ole-4,7-qu in on e, 4 (R2
) Bu ). Procedure A was followed using 2 (49.50 mg, 0.15
mmol), butylamine (0.02 mL), and MeOH (2 mL). Column
chromatography (3% ethyl acetate in petroleum ether) gave
the butyl derivative as a yellow solid: yield, 38.1 mg (98%);
1
mp 172 °C; H NMR (CDCl3) δ 2.04 (s, 6 H, 2 CH3), 2.56 (s, 6
H, 2 CH3), 0.97 (t, 3 H, J ) 7.2 Hz, CH3), 1.38 (m, 2 H, CH2),
1.6 (m, 2 H, CH2), 3.78 (t, 2 H, J ) 7.4 Hz, CH2); 13C NMR
(CDCl3) δ 11.22, 12.65, 13.79, 20.14, 32.36, 43.12, 116.74,
135.27, 144.02, 183.13; IR (CCl4) ν 1642 (s, CdO), 2928 (m,
CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 202 (4.22), 222 (4.19),
266 (4.01), 396 (3.52, br) nm; FDMS found for C16H21O2N 259
(M+). Anal. Calcd for C16H21O2N: C, 74.09; H, 8.16; N, 5.40.
Found: C, 73.81; H, 8.46; N, 5.33.
1,3,5,6-Tetr a m eth ylisoben zofu r a n -4,7-qu in on e (7). To
a solution of 2 (201 mg, 0.61 mmol) in MeOH was added H2O
(5 mL), and the mixture was refluxed for a day. Removal of
the solvents and column chromatography of the solid residue
with 1% ethyl acetate in petroleum ether gave the title
compound as a yellow product in 56% yield (69.6 mg): mp
1
145-147 °C; H NMR (CDCl3) δ 2.07 (s, 6 H, 2 CH3), 2.60 (s,
2-P h en yl-1,3,5,6-tetr a m eth ylisoin d ole-4,7-qu in on e, 4
(R2 ) P h ). This compound was prepared (procedure A) from
2 (49.5 mg, 0.15 mmol), aniline (0.02 mL), and MeOH (2 mL).
The residue, after column chromatography with 3% ethyl
acetate in petroleum ether, gave the phenyl derivative (yellow
solid): yield, 36.8 mg (88%); mp, melts with blackening
6 H, 2 CH3); 13C NMR (CDCl3) δ 12.80, 13.43, 116.75, 145.91,
156.23, 182.19; IR (CCl4) ν 1620 (s, CdO), 2928 (m, CH3) cm-1
;
UV-vis (CH3CN) λmax (log ꢀ) 214 (4.00), 248 (4.04), 298 (3.51),
364 (3.46) nm; FDMS found for C12H12O3 204 (M+). Anal.
Calcd for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.61; H,
6.01.
1
between 239 and 241 °C; H NMR (CDCl3) δ 2.09 (s, 6 H, 2
CH3), 2.34 (s, 6 H, 2 CH3), 7.21, 7.55, (two sets of m, 5 H, Ph);
13C NMR (CDCl3) δ 12.07, 12.74, 116.88, 128.19, 129.78,
130.13, 136.06, 136.46, 144.35, 183.28; IR (CCl4) ν 1643 (m,
CdO), 2927 (m, CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 206
(4.21), 226 (4.16), 258 (4.02), 394 (3.52, br) nm; HRMS (EI)
calcd for C18H17O2N 279.1259, found 279.1257 (err -0.55 ppm).
2-Meth yl-1,3,5,6-tetr a m eth ylisoin d ole-4,7-qu in on e, 4
(R2 ) Me). A 2 M solution of MeNH2 in MeOH was used as
received. The 2 M solution of MeNH2 in MeOH (9.0 mL, 18
mmol) was added via syringe to 2 (59.4 mg, 0.18 mmol) under
argon and procedure A was followed. Column chromatography
of the residual solid with 4% ethyl acetate in petroleum ether
gave the product, a yellow solid, in 97% yield (37.9 mg): mp
Gen er a l P r oced u r e B: Syn th esis of Isoin d olequ in on es
4 fr om Am in e a s Solven t a n d Rea cta n t a n d 2 or 2,3-
Dieth yn y1-5,6-d im eth ylh yd r oqu in on e (3). A series of
reactions were carried out using 2 or 3 and excess amines as
reactants. In some of the cases a palladium catalyst was used.
In a typical reaction in the presence of catalyst, 2 or 3 was
combined with 5% bis(benzonitrile)palladium dichloride (PdII-
(PhCN)2Cl2), 12% triphenylphosphine (PPh3), and excess amine
and stirred at room temperature for a day, followed by
refluxing for 8-12 h (depending upon the requirement).
Similar reactions without catalyst were carried out using
amines as received. The yields of the products in these cases
were moderate to good (40-78%). This procedure has been
found to be exclusive for the synthesis of the isopropyl
derivative of 4 from diisopropylamine.
1
228-229 °C; H NMR (CDCl3) δ 2.04 (s, 6 H, 2 CH3), 2.56 (s,
6 H, 2 CH3), 3.43 (s, 3 H, CH3); 13C NMR (CDCl3) δ 11.25, 12.65,
29.82, 116.58, 135.65, 144.02, 183.09; IR (CCl4) ν 1643 (m,
CdO), 2926 (m, CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 202
(3.88), 222 (3.82), 262 (3.70), 396 (3.21, br) nm; FDMS found
2-I s o p r o p y l-1,3,5,6-t e t r a m e t h y lis o in d o le -4,7-q u i-
n on e, 4 (R2 ) i-P r ). To a mixture of 3 (50.2 mg, 0.27 mmol),
Pd(PhCN)2Cl2 (4.00 mg, 0.01 mmol), and PPh3 (10.4 mg, 0.04

Novel Synthesis of Substituted Isoindolequinones
J . Org. Chem., Vol. 62, No. 23, 1997 8197
mmol) was added isopropylamine (12 mL) and the solution was
stirred overnight at room temperature. Column chromatog-
raphy (3% ethyl acetate in petroleum ether) gave the product,
a yellow solid, in 49% yield (32.5 mg): mp 162-163 °C; 1H
NMR (CDCl3) δ 1.54 (d, 6 H, J ) 7.1 Hz, 2 CH3), 2.05 (s, 6 H,
2 CH3), 2.67 (s, 6 H, 2 CH3), 4.52 (h, 1 H, J ) 7.1 Hz, isopropyl);
13C NMR (CDCl3) δ 12.58, 12.79, 21.83, 47.72, 116.98, 135.58,
Hea tin g 3 in CD3OD (11). Two NMR tubes were as-
sembled having 3 (10 mg) in CD3OD in the presence and
absence of air at rt, and the 1H NMR spectrum was monitored
every half hour. The spectrum remained unchanged at rt but
upon reflux for 8 h the alkyne hydrogens were completely
exchanged with deuterium under both conditions.
143.94, 183.03; IR (CCl4) ν 1643 (s, CdO), 2930 (m, CH3) cm-1
;
Ack n ow led gm en t. We thank the National Institute
of General Medicine, National Institutes of Health
(Grant 1R15GM54294-01), and the National Science
Foundation (DMR-9310642 and DMR-9617477) for fi-
nancial support. We also thank Dr. Robert Lattimer of
BF Goodrich for providing FDMS data and the Ne-
braska Center for Mass Spectrometry for HRMS data.
UV-vis (CH3CN) λmax (log ꢀ) 202 (4.03), 224 (4.01), 264 (3.87),
398 (3.40, br) nm; FDMS found for C15H19O2N 245 (M+). Anal.
Calcd for C15H19O2N: C, 73.46; H, 7.41; N, 5.71. Found: C,
73.50; H, 7.07; N, 5.42.
Deu ter a tion Stu d y. Rea ction of Bu tyla m in e a n d 2 in
CD3OD, 4 (D6, R2 ) Bu ). An NMR tube was assembled with
2 (10.0 mg, 0.03 mmol), butylamine (0.01 mL), and 0.5 mL
deuterated methanol (CD3OD) in the drybox. The 1H NMR
spectrum was monitored at rt every half hour for the first 5 h
and every 10 h after that. The peak at δ 2.04 (due to the
methyls on the quinone ring) remained unchanged but the
peak at δ 2.56 (corresponding to the methyls adjacent to the
nitrogen) appeared as a small multiplet after 2 days. Integra-
tion showed 80% deuterated product containing D in the two
methyls on the pyrrole ring distributed in the products of
molecular weight (FDMS) 261 (1%), 262 (9%), 263 (28%), 264
(40%), 265 (22%).
Su p p or tin g In for m a tion Ava ila ble: HMQC and HMBC
data for compound 4 (R2 ) i-Pr), and the X-ray crystal data
for compound 4 (R2 ) Bu) (17 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 O971671R