An unusual oxidation of a benzylic methylene group by thionyl chloride: A synthesis of 1,3-dihydro-2-[2-(dimethyl-amino)ethyl]-1,3-dioxopyrrolo[3,4-c]acridine derivatives

Full text of DOI:10.1021/jo000118y

612
J . Org. Chem. 2001, 66, 612-616
Sch em e 1
An Un u su a l Oxid a tion of a Ben zylic
Meth ylen e Gr ou p by Th ion yl Ch lor id e:
A Syn th esis of 1,3-Dih yd r o-2-[2-(d im eth yl-
a m in o)eth yl]-1,3-d ioxop yr r olo[3,4-c]a cr id in e
Der iva tives
Shixia Feng, Charles A. Panetta, and David E. Graves*
Department of Chemistry, University of Mississippi,
University, Mississippi 38677
graves@olemiss.edu
Received J anuary 29, 2000
In tr od u ction
Although thionyl chloride is routinely used as a chlo-
rinating agent, “atypical” reactions have been reported.
Some examples are the reactions of compounds with an
active methylene group involving O-sulfinylation which
produced gem dichlorides via addition reactions at a
carbonyl group1-3 or C-sulfinylation via the Hell-
Volhard-Zelinsky reaction to give sulfinyl chlorides
which may further undergo a Pummerer-type rearrange-
ment and give various products, including R-chlorosulfe-
nyl chlorides, sulfines, and thiones.4-6 These compounds
can be converted to ketones through acidic hydrolysis.6-8
However, as far as we can determine, the direct oxidation
of a methylene to a carbonyl group by thionyl chloride
has not been reported. We report herein several cases of
the unexpected direct oxidation of such a benzylic me-
thylene in two fused-acridine systems by thionyl chloride.
late12,13 (DPIC) followed by intramolecular cyclization
gave 4 in 30% yield.
Several chlorinating agents including phosphorus oxy-
chloride (POCl3), oxalyl chloride (ClCOCOCl), and thionyl
chloride (SOCl2) were tried for the conversion of 4 to 5.
While the reactions between 4 and POCl3 or ClCOCOCl
gave neither any isolable product nor recovered starting
material, the reaction of 4 and SOCl2 gave a product in
good yield. However, the spectral analysis revealed that
it was not the desired product 5. First, the 1H NMR
showed the absence of the benzylic methylene protons
and the 13C NMR showed the presence of two carbonyl
groups with a very small difference in their chemical
shifts. The two-dimensional HMBC (homonuclear mul-
tiple bond coherence) spectrum showed coupling between
the NCH2 protons and both carbonyl groups. The pres-
ence of one chlorine atom was indicated by GC-MS
analysis which showed a single peak with m/z at 353 (M+•
for C19H16ClN3O2) and 355 (M+• + 2, 39% relative to m/z
353). The formula was confirmed by HRMS. These data
are consistent only with structure 6. However, this
compound is not very stable and undergoes hydrolysis
after being exposed to air and moisture. Obviously,
instead of the expected conversion of acridone to chloro-
acridine, the benzylic methylene group was unexpectedly
oxidized (Scheme 1).
Resu lts a n d Discu ssion
During the course of studies on the synthesis of novel
fused acridine derivatives as potential anticancer agents,9
6-chloroacridine, 5, was needed as a desired intermediate.
As shown in Scheme 1, the acridone 4 was expected to
convert to 5 by treatment with a chlorinating agent such
as thionyl chloride. The preparation of 4 started with
3-aminophthalic acid (1),10 which was heated with N,N-
dimethylethylenediamine (DMEDA) to give the phthal-
imide, 2. Partial reduction of 2 with zinc in acetic acid11,12
gave the isoindole 3. The copper(II) catalyzed coupling
reaction between 3 and diphenyliodonium-2-carboxy-
* To whom correspondence should be addressed. Phone: (662) 915-
7732. Fax: (662) 915-7300.
(1) Newman, M. S.; Sujeeth, P. K. J . Org. Chem. 1978, 43, 4367-
4369.
(2) Oka, K.; Hara, S. Tetrahedron Lett. 1977, 34, 2939-2942.
(3) Scho¨nberg, A.; Ismail, A. F. A. J . Chem. Soc. 1945, 200.
(4) Krubsack, A. J .; Higa, T. Tetrahedron Lett. 1968, 49, 5149-5152.
(5) Oka, K.; Hara, S. J . Org. Chem. 1978, 43, 4533-4535.
(6) Oka, K. Synthesis 1981, 9, 661-681 and references therein.
(7) Grøndahl, L.; Hammershoi, A.; Hartshorn, R. M.; Sargeson, A.
M. Acta Chem. Scand. 1995, 49, 781-791.
(8) Oka, K.; Hara, S. Tetrahedron Lett. 1977, 8, 695-698.
(9) Feng, S. Ph.D. Dissertation, The University of Mississippi,
University, MS, 1999.
(10) Omoto, Y.; Miyaka, T.; Ohmon, S.; Sugiyama, N. Bull. Chem.
Soc. J pn. 1967, 40, 899-903.
(11) This is analogous to a reported procedure for the synthesis of
the N,N-diethyl analogue of 3. Da Settimo, A.; Primofiore, G.; Terrarini,
P. L.; Livi, O. Eur. J . Med. Chem. 1981, 16, 59-64.
(12) Scherrer, R. A.; Beatty, H. R. J . Org. Chem. 1980, 45, 2127-
2131.
Confirmation of the structure of 6 was achieved by
direct synthesis from 7, which was prepared by the
coupling reaction between 2 and DPIC in the presence
of a Cu(II) catalyst. When 7 was heated with POCl3 at
(13) Rewcastle, G. W.; Denny, W. A. Synthesis 1985, 220-222.
10.1021/jo000118y CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/29/2000

Notes
J . Org. Chem., Vol. 66, No. 2, 2001 613
Sch em e 2
Sch em e 4
Sch em e 3
Sch em e 5
115 °C, it gave a product in high yield which was identical
in all respects to 6 (Scheme 2).
This unusual oxidation reaction was again observed
when the furoacridone 10 was treated with thionyl
chloride (Scheme 3). 7-Aminophthalide (8)14 was treated
with DPIC and Cu(II) to give the carboxylic acid 9, which
was cyclized in concentrated sulfuric acid to afford 10.
After 10 was heated with SOCl2 under nitrogen, excess
reagent was removed to give a very labile product. Mass
spectrum showed m/z 265 (C15H7NO4), which is consistent
with structure 11. Although no pure product could be
obtained, the formation of this anhydride was confirmed
by its conversion to 12, which was also obtained by either
the hydrolysis of 6 or the cyclization of 7 with concen-
trated H2SO4. It was noted that, during the workup, a
very small amount of insoluble material was obtained
whose total sulfur content was 87% by elemental analy-
sis. This was assumed to be elemental sulfur.
This unusual oxidation was found to be useful in the
synthesis of 1,3-dihydro-2-[2-(dimethylamino)amino]-1,3-
dioxopyrrolo[3,4-c]acridine (16), a potent DNA topoi-
somerase II inhibitor.9 Reduction of 9 using conditions
developed by Sharma15 gave the alcohol 13, which was
oxidized with MnO2 in acetone to afford the aldehyde 14.
Cyclization of 14 in TFA under nitrogen afforded the furo-
[3,4-c]acridine 15. Treatment of 15 with SOCl2 followed
by DMEDA gave the desired product 16, presumably
through an anhydride intermediate. In contrast, the
aldehyde 18, prepared from the carboxylic acid 7 in a two-
step sequence similar to the transformation of 9 to 14,
failed to cyclize to 16 (Scheme 4).
The experimental facts about this oxidation are the
following: (1) the oxidation occurred even under a
nitrogen atmosphere and in the dark; (2) the carbonyl
group formed without acidic hydrolysis; (3) heating at the
refluxing temperature was required; (4) elemental sulfur
was probably a byproduct. On the basis of the above
observations, we propose a possible mechanism for the
thionyl chloride oxidation of the benzylic methylene
groups of 4, 10, and 15. The reaction between 10 and
thionyl chloride is illustrated in Scheme 5.
The initial step was perhaps the tautomerization of 10
to form the enol ester 19. Thionyl chloride then adds to
the enol double bond to give 20, in a way much like the
Hell-Volhard-Zelinsky reaction.6 Subsequent attack of
the oxygen anion to the CdO+ double bond yields a four-
(14) Wamser, C. C.; Phillips, R. B. J . Org. Chem. 1976, 41, 2929-
2931.
(15) Sharma, R.; Voymov, G. H.; Ovaska, T. V.; Marquez, V. E.
Synlett 1995, 8, 839-840.

614 J . Org. Chem., Vol. 66, No. 2, 2001
Notes
GC-MS using electron-impact (EI) ionization mode (70 eV).
HRMS spectra were recorded using the electrospray ionization
(ESI) method. Elemental analyses were performed by either
Galbraith Laboratories, Inc., Knoxville, Tennessee, or Atlantic
Microlabs, Inc., Norcross, Georgia.
Sch em e 6
3-Am in o-N-[2-(d im et h yla m in o)et h yl]p h t h a lim id e (2).
3-Aminophthalic acid (4.0 g, 0.017 mole) and 3.5 mL of N,N-
dimethylethylenediamine were heated in a 165 °C oil bath for
2.5 h. After the mixture was cooled to room temperature,
methylene chloride was added until the solid mass had dissolved.
The solution was passed through an alumina column (50 g) and
eluted with methylene chloride. The fraction containing the
product (2) was collected, and the solvent was evaporated to give
4.9 g (95% yield) of a yellow solid: mp 103-103.5 °C; GC-MS
membered ring intermediate.16 Loss of a proton and the
cleavage of the S-O bond gave 22, which proceeds to
form 11 with the loss of a molecule of SOCl2 and
elemental sulfur. The strain of the four-membered ring
and the strong polarization of the S-O bond due to the
positive charge on sulfur atom were, perhaps, the driving
forces for the cleavage of the S-O bond.
m/z 233 (M+); IR (KBr) 3466, 3436, 3360, 3288, 1748, 1694 cm-1
;
1H NMR (CDCl3) 7.38 (t, 1H, J ) 7.2 Hz), 7.11 (d, 1H, J ) 7.2
Hz), 6.80 (d, 1H, J ) 7.2 Hz), 5.22 (br s, 2H), 3.74 (t, 2H, J ) 6.6
Hz), 2.57 (t, 2H, J ) 6.5 Hz), 2.29 (s, 6H). Anal. Calcd for
C12H15N3O2: C, 61.80; H, 6.44; N, 18.02. Found: C, 62.06; H,
6.41; N, 18.06.
Compound 2 (5.2 g, 0.022 mole) was dissolved in 50 mL of
acetone. Concentrated HCl (3.8 mL) was added, and the solid
formed was filtered and washed with acetone-ethyl acetate (2:
1). The monohydrochloride was obtained as a yellow solid (5.9
g, 98% yield): mp 239-241 °C. Anal. Calcd for C12H15N3O2‚
HCl: C, 53.43; H, 5.94; Cl, 13.17; N, 15.58. Found: C, 53.35; H,
5.99; Cl, 13.37; N, 15.54.
Alternatively,17 19 could form 11 directly by an internal
oxidation which involves a simple, smooth transforma-
tion through
(Scheme 6).
a six-membered ring transition state
Interestingly, treatment of 10 with SOCl2 only facili-
tates the benzylic oxidation to form 11 but does not
convert 11 to the corresponding chloroacridine. This is
in contrast to the reaction of 4 with SOCl2 to give 6 in
which both oxidation and chlorination are involved. As
to the chlorination, it is not necessary to postulate a
tautomeric enol intermediate because 10-methyl-9-acri-
done gives 9-chloro-10-methyl-acridinium dichlorophos-
phate in refluxing POCl3 as reported by Gleu et al.18 As
compared to POCl3, SOCl2 is a relatively weaker chlori-
nating agent and it is known that many acridones are
reluctant to undergo chlorination under the same condi-
tions. In many cases, a catalytic amount of DMF is added
to facilitate the chlorination with SOCl2. In the case of 4
going to 6 with SOCl2, it appears that the oxidation
occurs before the chlorination because 4 does not convert
to 5 with POCl3.
This oxidation has thus far only worked effectively for
acridine derivatives, including the 10-methyl-substituted
analogue of 15 (unpublished result). Phthalide did not
react with SOCl2 at all, and only the starting material
was recovered. Although the reaction of 2(5H)-furanone
with SOCl2 for 1 h at refluxing temperature did produce
maleic anhydride, the conversion rate was only about 1%
by GC-MS analysis, the major component was the
unchanged starting material.
1,6-Dioxo-2-[2-(d im et h yla m in o)et h yl]-1,3,6,11-t et r a h y-
d r op yr r olo[3,4-c]a cr id in e (4). A suspension of 3 (2.92 g, 13.3
mmol), diphenyliodonium-2-carboxylate (5.17 g, 16.0 mmol), and
cupric acetate (0.121 g, 0.665 mmol) in 21 mL of 2-propanol was
heated under reflux for 72 h. The solvent was removed in vacuo
until dryness. The brown oily residue was triturated with hexane
(50 mL) to precipitate a yellow solid. It was filtered, and the
filter cake was immediately dried in a vacuum desiccator to give
5.75 g of an amorphous powder (the solid material was extremely
hygroscopic). It was added to 30 mL of concentrated sulfuric acid,
and the resulting mixture was heated at 100 °C for 2 h. The
mixture was cooled to room temperature and poured slowly into
ice (300 g) with stirring. Concentrated NH4OH was added until
a pH of 9 resulted while the temperature was kept below 10 °C.
The mixture was extracted with CHCl3 (6 × 80 mL). The
combined organic layers were washed with brine and dried over
MgSO4. The solvent was removed to give an oily residue which
was chromatographed (CHCl3-MeOH, 9:1) to give a total of 1.27
g (30% yield) of 4: mp 178-180 °C; GC-MS m/z 321 (M+); IR
(KBr) 3328, 1672, 1654, 1606 cm-1 1H NMR (CDCl3) 8.53 (d,
;
1H, J ) 8.2 Hz), 8.46 (d, 1H, J ) 8.0 Hz), 8.12 (br s, 1H), 7.69
(m, 1H), 7.40 (d, 1H, J ) 8.3 Hz), 7.28 (m, 1H), 7.22 (d, 1H, J )
8.2 Hz), 4.58 (s, 2H), 3.71 (t, 2H, J ) 6.3 Hz), 2.61 (t, 2H, J )
6.3 Hz), 2.31 (s, 6H); 13C NMR (CDCl3) 177.5, 168.9, 147.8, 139.7,
137.9, 133.8, 131.1, 127.2, 122.2 (C-6a, C-8), 120.6, 117.4, 117.1,
115.2, 57.8, 51.3, 45.4, 39.8. HRMS calcd for C19H20N3O2 (MH+),
322.1551; found, 322.1525.
3-(o-Ca r boxyp h en yl)a m in o-N-[2-(d im eth yla m in o)eth yl]-
p h th a lim id e (7). A mixture of 1.4 g (4.3 mmol) of diphenyli-
odonium carboxylate (DPIC), 1.0 g (4.3 mmol) of 2, and 40 mg
(0.22 mmol) of cupric acetate in 10 mL of 2-propanol was heated
under reflux for 12 h. Another portion of DPIC (0.70 g, 2.2 mmol)
was added, and the mixture continued to be heated under reflux
temperature for another 12 h. The mixture was filtered while it
was still hot, and the yellow solid was washed successively with
hot 2-propanol (15 mL) and warm water (30 mL). The solid was
dried to give 1.2 g (77% yield) of 7: mp 263-265 °C dec.
Con clu sion
A novel oxidation reaction of a benzylic methylene to
a carbonyl group, in pyrroloacridone or furoacridone ring
systems, has been observed. This oxidation reaction is
useful in the synthesis of 1,3-dihydro-2-[2-(dimethylami-
no)amino]-1,3-dioxopyrrolo[3,4-c]acridine derivatives which
are potential anticancer agents.
Compound
7 was converted to its HCl salt as follows:
2-Propanol (5 mL) was added to a solution of 7 (100 mg, 0.283
mmol) in 2 mL of 0.3 N HCl. The precipitate was filtered and
washed with 2-propanol and ethyl acetate and was then dried
in vacuo to give 86 mg (74% yield) of a yellow solid: mp 175-
Exp er im en ta l Section
Gen er a l. 1H NMR and 13C NMR spectra were recorded at
500 and 125 MHz, respectively. Mass spectra were obtained by
1
177 °C; H NMR (D2O) 7.63 (d, 1H, J ) 7.8 Hz), 7.55 (d, 1H, J
) 8.6 Hz), 7.34 (t, 1H, J ) 7.8 Hz), 7.28 (m, 2H), 7.01 (d, 1H, J
) 7.1 Hz), 6.84 (m, 1H), 3.86 (t, 2H, J ) 6.2 Hz), 3.41 (t, 2H, J
) 6.2 Hz), 3.00 (s, 6H); 13C NMR (D2O) 173.3, 172.3, 171.7, 144.4,
142.6, 138.7, 136,3, 134.9, 134.6, 123.9, 123.8, 119.8, 119.5, 118.0,
115.9, 58.1, 46.0, 35.5. Anal. Calcd for C19H19N3O4‚HCl‚H2O: C,
55.95; H, 5.44; Cl, 8.69; N, 10.38. Found: C, 56.04; H, 5.42; Cl,
8.74; N, 10.30.
(16) Such four-membered ring intermediates have been proposed
to explain the products from the reaction of enols and SOCl2 by the
following: Effenberger, F.; Daub, J . Chem. Ber. 1969, 102, 104-111.
(17) We thank one of the reviewers for this excellent suggestion.
(18) Gleu, K.; Nitzsche, S.; Schubert, A. Chem. Ber. 1939, 72, 1093-
1097.

Notes
6-Ch lor o-1,3-d ih yd r o-2-[2-(d im eth yla m in o)eth yl]-1,3-d i-
J . Org. Chem., Vol. 66, No. 2, 2001 615
sion of 9 (57 mg, 0.21 mole) in 1.5 mL of dry THF. The mixture
was stirred at room temperature for 24 h. It was added dropwise
to NaBH4 (55 mg, 1.5 mmol) in 4 mL of THF-H2O (1:1). The
resulting mixture was stirred for 20 min. The excess reagent
was decomposed by the addition of 6 N HCl until a pH of 5
resulted. It was basified again with saturated NaHCO3 solution
until it attained a pH of 8. The product was precipitated by
removing the THF in vacuo. Filtration followed by recrystalli-
zation from acetone-H2O gave a white solid (42 mg, 78%
oxop yr r olo[3,4-c]a cr id in e (6). 1. Meth od A. A suspension of
4 (19 mg, 0.059 mmol) in 0.5 mL of thionyl chloride was heated
under nitrogen for 1.5 h. It was cooled to room temperature and
slowly added to a vigorously stirring mixture of CHCl3 (2 mL)
and concentrated NH4OH (1 mL) with ice cooling. The mixture
was filtered, and the CHCl3 layer was separated and washed
with brine and dried over MgSO4. The solvent was removed in
vacuo, and the residue was purified by column chromatography
(CHCl3-MeOH, 97:3) to give 14 mg (67% yield) of yellow solid:
mp 206-208 °C dec; GC-MS m/z 353 (M+), 355 (M+ + 2, 39%
1
yield): mp 145-147 °C; H NMR (CDCl3) δ 8.67 (s, 1H), 7.03-
7.51 (m, 6H), 6.75 (d, 1H, J ) 7.3 Hz), 5.26 (s, 2H), 4.74 (s, 2H),
2.24 (br s, 1H). Anal. Calcd for C15H13NO3: C, 70.59; H, 5.10;
N, 5.49. Found: C, 70.21; H, 5.10; N, 5.78.
1
relative to m/z 353); IR (KBr) 1773, 1709, 1625 cm-1; H NMR
(CDCl3) 8.72 (d, 1H, J ) 8.7 Hz), 8.34 (d, 2H, J ) 9.8 Hz), 7.88
(d, 1H, J ) 8.8 Hz), 7.83 (m, 1H), 7.64 (m, 1H), 3.85 (t, 2H, J )
6.5 Hz), 2.62 (t, 2H, J ) 6.6 Hz), 2.25 (s, 6H); 13C NMR (CDCl3)
168.2, 167.4, 151.1, 142.7, 142.6, 136.5, 132.7, 132.1, 131.1, 128.7,
127.5, 126.9, 124.7 (C-6a, C-7), 118.8, 57.2, 45.5, 36.1. HRMS
calcd for C19H17ClN3O2 (MH+), 354.1006; found, 354.0979.
2. Meth od B. A mixture of the carboxylic acid 7 (50 mg, 0.14
mmol) and 0.5 mL of phosphorus oxychloride (0.82 g, 5.4 mmol)
was heated at 115 °C for 24 h. After the mixture was cooled to
room temperature, it was added dropwise with vigorous stirring
to a mixture of 6 mL of 30% ammonium hydroxide and 10 g of
crushed ice. The temperature was kept below 5 °C during the
addition. After the addition, the resulting mixture was extracted
with chloroform (3 × 10 mL). The organic layers were combined,
washed with brine, and dried over MgSO4. The solvent was
evaporated to give a solid residue which was recrystallized from
CHCl3-EtOH to give 44 mg (88% yield) of 6 as a yellow solid:
mp 206 °C dec; this material was identical in all respects to the
sample obtained from method A.
7-(o-Ca r boxyp h en yl)a m in op h th a lid e (9). A mixture of 5.0
g (0.034 mole) of 8, 13 g (0.040 mole) of diphenyliodonium-2-
carboxylate (DPIC), and 0.30 g (1.65 mmol) of cupric acetate in
70 mL of 2-propanol was heated under reflux for 24 h. The
precipitate was filtered and washed with 2-propanol and water.
The crude 9 (8.4 g, 93% yield) was obtained as a green powder.
A portion of this crude product was converted to its sodium salt
as follows: 1 g of it was added to a stirred solution of 19 mL of
0.2 N NaOH and heated to 45 °C. It was filtered, and the filtrate
was concentrated to a small volume. The product precipitated
upon addition of 2-propanol. The solid was filtered and washed
with H2O-2-propanol (1:2) to give 0.92 g (85% yield) of a sodium
salt of 9 as a white solid: mp >300 °C; 1H NMR (d6-DMSO)
12.13 (s, 1H), 7.95 (d, J ) 7.6 Hz, 1H), 7.39-7.52 (m, 3H), 7.26
(m, 1H), 6.89 (m, 2H), 5.29 (s, 2H). Anal. Calcd for C15H10NO4-
Na‚1/2H2O: C, 60.00; H, 3.67; N, 4.67. Found: C, 59.83; H, 3.57;
N, 4.74.
7-(o-F or m yl)p h en yla m in op h th a lid e (14). MnO2 (2.6 g) was
added to a solution of 13 (0.85 g, 3.3 mmol) in 50 mL of acetone,
and the mixture was stirred at room temperature for 4 days.
The MnO2 was filtered, and the filter cake was washed with hot
chloroform. The filtrate was evaporated in vacuo to give 0.84 g
of a yellow solid which was recrystallized from acetone to give
0.79 g (94% yield) of 14 as a yellow solid: mp 204-205 °C; GC-
MS m/z 253 (M+); 1H NMR (CDCl3) 10.88 (s, 1H), 10.00 (s, 1H),
7.47-7.71 (m, 5H), 7.09 (dd, 1H, J ) 7.8, 7.8 Hz), 6.96 (br d,
1H, J ) 6.4 Hz), 5.28 (s, 2H); 13C NMR (CDCl3) 193.3, 170.9,
148.3, 143.0, 141.5, 136.3, 135.2, 134.9, 123.2, 120.7, 116.3, 114.8,
113.5, 112.7, 69.1. Anal. Calcd for C15H11NO3: C, 71.15; H, 4.35;
N, 5.53. Found: C, 71.00; H, 4.43; N, 5.67.
1,3-Dih ydr o-2-[2-(dim eth ylam in o)eth yl]-1,3-dioxopyr r olo-
[3,4-c]a cr id in e (16). A mixture of 15 (50 mg, 0.21 mmol) and
thionyl chloride (2 mL) was heated at 80 °C under nitrogen for
1.5 h. The excess reagent was removed in vacuo to give a residue
which was dissolved in dry chloroform (2 mL). N,N-Dimethyl-
ethylenediamine (75 mg, 0.85 mmol) in dry chloroform (1 mL)
was added. The resulting mixture was stirred at room temper-
ature for 30 min. Chloroform (20 mL) was added, and the
solution was washed with 10 mL of 1.5% NH4OH and brine and
dried over MgSO4. The solvent was evaporated to give a residue
which was chromatographed (CHCl3-MeOH, 95:5) to give 32
mg (47% yield) of pure 16: mp 206-208 °C; GC-MS m/z 319
(M+); IR (KBr) 1764, 1716, 1627 cm-1; 1H NMR (CDCl3) 8.87 (s,
1H), 8.43 (d, 1H, J ) 8.9 Hz), 8.35 (d, 1H, J ) 8.4 Hz), 8.02 (d,
1H, J ) 8.5 Hz), 7.88 (m, 2H), 7.63 (t, 1H, J ) 7.5 Hz), 3.92 (t,
2H, J ) 6.5 Hz), 2.69 (t, 2H, J ) 6.5 Hz), 2.32 (s, 6H); 13C NMR
(CDCl3) 169.2, 168.3, 151.8, 143.3, 137.8, 136.8, 136.7, 132.3,
131.2, 129.8, 128.9, 127.9, 127.7, 127.4, 118.3, 57.7, 45.9, 36.4.
Anal. Calcd for C19H17N3O2‚1/2H2O: C, 69.51; H, 5.49; N, 12.80.
Found: C, 69.78; H, 5.31; N, 12.74.
3-(o-Hydr oxym eth yl)ph en ylam in o-N-[2-(dim eth ylam in o)-
eth yl]p h th a lim id e (17). A suspension of the carboxylic acid 7
(100 mg, 0.283 mmol) in 1 mL of thionyl chloride was heated
under reflux for 30 min. The excess of reagent was removed in
vacuo. The residue was suspended in 4 mL of dry THF and 76
mg (0.752 mmol) of triethylamine. Imidazole (40 mg, 0.59 mmol)
was added, and the resultant mixture was refluxed for 24 h. It
was cooled to 5 °C. Cold water (5 °C) (1.5 mL) was added, and
the mixture became clear. NaBH4 (a total of 24 mg, 0.63 mmol)
was added in three equal portions every 5 min. The mixture was
stirred vigorously during the addition and for a further 10 min
after the addtion was completed. The excess of reagent was
decomposed by addition of 6 N HCl until a pH of 5 was attained.
The pH was then adjusted to 9 by concentrated NH4OH. The
THF was evaporated in vacuo, and the residue was extracted
with CHCl3 (3 × 10 mL). The combined organic layers were
washed with brine and dried over MgSO4. The solvent was
removed in vacuo, and the residue was chromatographed
(CHCl3-acetone, 9:1) to give 45 mg (47% yield) of 17 as a yellow
solid product: mp 133-134 °C; GC-MS m/z 339 (M+); 1H NMR
(CDCl3) 8.76 (br s, 1H), 7.11-7.48 (m, 7H), 4.74 (s, 2H), 4.06 (t,
2H, J ) 7.5 Hz), 3.04 (t, 2H, J ) 7.6 Hz), 2.70 (s, 6H), 2.27 (br
s, 1H); 13C NMR (CDCl3) 169.5, 167.9, 143.1, 138.5, 135.5, 132.9,
132.7, 129.7, 128.8, 124.4, 121.7, 118.8, 113.5, 112.2, 63.3, 61.1,
51.9, 32.7. Anal. Calcd for C19H21N3O3‚5/4H2O: C, 63.07; H, 6.50;
N, 11.62. Found: C, 62.92; H, 6.67; N, 11.49.
Pure 9 was obtained by acidifing the aqueous solution of its
sodium salt. It melted at 258-259 °C.
Con ver sion of 10 t o 2-[2-(Dim et h yla m in o)et h yl]-1,3,6-
tr ioxo-11H-1,3,6,11-tetr a -h yd r op yr r olo[3,4-c]a cr id in e (12)
by Sequ en tia l Tr ea tm en t w ith Th ion yl Ch lor id e a n d N,N-
Dim eth yleth ylen ed ia m in e. A suspension of 10 (100 mg, 0.398
mmol) in thionyl chloride (1.5 mL) was heated to the reflux
temperature under nitrogen for 1.5 h. The excess thionyl chloride
was removed under reduced pressure to give an orange solid
residue (m/z 256) which was suspended in dry chloroform (30
mL). N,N-Dimethylethylenediamine (67 mg, 0.76 mmol) and 3
mL of dry chloroform were added. The resulting mixture was
stirred at room temperature for 1 h. Water (10 mL) was added,
and the mixture was stirred for an additional 5 min. The mixture
was filtered, and the chloroform layer was washed with brine
and dried over MgSO4. The solvent was evaporated, and the
residue was chromatographed (CHCl3-MeOH, 97:3). A yellow
band (Rf ) 0.4, CHCl3-MeOH 4:1) was collected to give 40 mg
(30% yield) of a solid: mp 204-205 °C; m/z 335 (M+); IR (KBr)
3370, 1764, 1701, 1636, 1600 cm-1 1H NMR (CDCl3) 9.60 (s,
;
1H), 8.69 (d, 1H, J ) 7.9 Hz), 8.39 (d, 1H, J ) 10.0 Hz), 7.70 (t,
1H, J ) 8.3 Hz), 7.55 (d, 1H, J ) 7.9 Hz), 7.31 (m, 2H), 3.82 (t,
2H, J ) 6.4 Hz), 2.62 (t, 2H, J ) 6.4 Hz), 2.30 (s, 6H); 13C NMR
(CDCl3) 176.8, 169.5, 167.5, 139.9, 136.5, 136.0, 134.8, 134.6,
127.4, 125.3, 123.0, 122.1, 117.0, 115.8, 114.9, 57.1, 45.5, 36.1.
HRMS calcd for C19H18N3O3 (MH+), 336.1344; found, 336.1319.
3-(o-F or m yl)p h en yla m in o-N-[2-(d im eth yla m in o)eth yl]-
p h th a lim id e (18). A mixture of 17 (400 mg, 1.18 mmol) and
activated MnO2 (435 mg) in 40 mL of acetone was stirred at room
temperature for 48 h. After two additional portions of MnO2 (435
mg each) were added at 24 h intervals, a TLC indicated that
7-(o-Hyd r oxym eth yl)p h en yla m in op h th a lid e (13). 1,1′-
Carbonyldiimidazole (51 mg, 0.32 mmol) was added to a suspen-

616 J . Org. Chem., Vol. 66, No. 2, 2001
Notes
the starting material has disappeared. The mixture was filtered,
and the filter cake was washed with hot acetone. The combined
filtrate was evaporated to give 356 mg (89% crude yield) of a
yellow solid: mp 132-134 °C dec. An analytical sample was
obtained by recrystalliztion from MeOH-H2O: mp 132-133 °C
dec; GC-MS m/z 337 (M+); 1H NMR (CDCl3) 11.02 (br s, 1H),
9.99 (s, 1H), 7.82 (d, 1H, J ) 8.4 Hz), 7.72 (dd, J ) 7.6, 1.3 Hz),
7.51-7.61 (m, 3H), 7.38 (d, 1H, J ) 7.1 Hz), 7.13 (t, 1H, J ) 6.9
Hz), 4.10 (t, 2H, J ) 7.5 Hz), 3.07 (t, 2H, J ) 7.6 Hz), 2.72 (s,
6H); 13C NMR (CDCl3) 193.7, 168.3, 167.4, 142.5, 139.7, 136.6,
135.2, 135.0, 133.1, 122.8, 121.6, 121.0, 116.0, 115.9 (C-5, C-6),
61.0, 51.9, 32.9. Anal. Calcd for C19H19N3O3‚3/4H2O: C, 65.04;
H, 5.89; N, 11.98. Found: C, 64.88; H, 6.28; N, 11.85.
Ack n ow led gm en t. This work was supported by the
National Science Foundation Grant MCB-9728720
(D.E.G).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 4, 6, 7, 9, 12, 16, 17, and 18, and 13C NMR spectra
of compounds of 4, 6, 7, 12, 16, 17, and 18. This information
is available free of charge via the Internet at http://pubs.acs.org.
J O000118Y