Regioselective condensation of alkylidenephosphoranes to N-methoxy-and N-anilino-1 H isoindole-1,3-(2 H)-diones

Article abstract of DOI:10.1080/00397911.2010.551170

Treatment of 2-methoxyisoindoline-1,3-dione with resonance-stabilized alkylidenephosphoranes afforded the corresponding monoalkenes as the sole reaction product, in ～58-63% yields, whereas more than 80% yields of the same monoolefin products were obtained when the reactions were carried out under microwave conditions. Similarly, 2-(phenylamino)isoindoline-1,3-dione reacted under either thermal or microwave conditions to give only the corresponding monoalkene derivatives. The alkene products from both substrates were further reduced to the corresponding isoindoles using Zn-dust in EtOH. Prediction of the designed compounds and the in vivo anti-inflammation activity of the products in the rat adjuvant model were also studied. The work is the first demonstration of the anti-inflammatory activity of phthalimide derivatives.

Full text of DOI:10.1080/00397911.2010.551170

This article was downloaded by: [West Virginia University]
On: 21 October 2014, At: 13:33
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Regioselective Condensation of
Alkylidenephosphoranes to N-Methoxy-
and N-Anilino-1H isoindole-1,3-(2H)-
diones
Wafaa M. Abdou a , Rizk E. Khidre a & Reham F. Barghash a
a Chemical Industries Division, National Research Centre , Giza ,
Egypt
Accepted author version posted online: 27 Oct 2011.Published
online: 26 Mar 2012.
To cite this article: Wafaa M. Abdou , Rizk E. Khidre & Reham F. Barghash (2012) Regioselective
Condensation of Alkylidenephosphoranes to N-Methoxy- and N-Anilino-1H isoindole-1,3-(2H)-diones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:13, 1967-1978, DOI: 10.1080/00397911.2010.551170
To link to this article: http://dx.doi.org/10.1080/00397911.2010.551170
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 42: 1967–1978, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.551170
REGIOSELECTIVE CONDENSATION OF
ALKYLIDENEPHOSPHORANES TO N-METHOXY-
AND N-ANILINO-1H ISOINDOLE-1,3-(2H)-DIONES
Wafaa M. Abdou, Rizk E. Khidre, and Reham F. Barghash
Chemical Industries Division, National Research Centre, Giza, Egypt
GRAPHICAL ABSTRACT
Abstract Treatment of 2-methoxyisoindoline-1,3-dione with resonance-stabilized alkylide-
nephosphoranes afforded the corresponding monoalkenes as the sole reaction product, in
ꢀ58–63% yields, whereas more than 80% yields of the same monoolefin products were
obtained when the reactions were carried out under microwave conditions. Similarly,
2-(phenylamino)isoindoline-1,3-dione reacted under either thermal or microwave conditions
to give only the corresponding monoalkene derivatives. The alkene products from both sub-
strates were further reduced to the corresponding isoindoles using Zn-dust in EtOH. Pre-
diction of the designed compounds and the in vivo anti-inflammation activity of the
products in the rat adjuvant model were also studied. The work is the first demonstration
of the anti-inflammatory activity of phthalimide derivatives.
Keywords Alkylidenephosphoranes; inflammatory inhibition; N-substituted phthali-
mides; olefination
INTRODUCTION
For many years, phthalimides have been a focus of interest as an important class
of organic compounds with medicinal and biological importance.[1–8] We
have precedently described synthesis of various phthalimidophosphor derivatives,
and thus a-aminophosphates, amido-phosphates, and oxoazirdin-1-yl-phosphonic
diamide were prepared by applying different types of P(III) reagents 5a-c to N-phtha-
loylalanylazide (3).[9] The study was extended to the application of some Wittig
Received December 10, 2010.
Address correspondence to W. M. Abdou, Chemical Industries Division, National Research
Centre, El-Bohouth St. D-12622, Dokki, Giza, Egypt. E-mail: wabdou@link.net
1967

1968
W. M. ABDOU, R. E. KHIDRE, AND R. F. BARGHASH
reagents 4a-e on 3, giving the corresponding linear disubstituted 1,2,3-triazoles.[9]
Later on,[10] we showed that N-methoxy- (1) of N-anilinophthalimide (2) behave
differently toward trialkyl phosphites 5a, dialkylphosphonates 5b, and
tris(dialkyl-amino)phosphines 5c, and thereby the respective a-aminophosphonates,
amido-phosphonates, phosphonic acid diamides, and oxadiazaphospholes were suc-
cessfully obtained. The main feature of all reactions investigated in the two articles[9,10]
is the nucleophilic attack on the 2-N-substituents in 1, 2, and 3 by the P(III) 5 and P(V)
4 reagents. On the basis of bioassay results, some of products from the previous two
articles could be considered as lead molecules to be modified in order to improve their
antibiotic properties. Continuing our research work on phthalimides and related phos-
phor derivatives, we herein envisage the importance of the nature of substituents on
the nitrogen atom in isoindole-1,3(2H)-diones 1, 2, and 3 on their reactivity toward
Wittig reagents 4a-e. Different behaviors were observed between 1 or 2 and N-
phthaloyl-alanylazide (3), notably in the susceptibility of nucleophilic attack by alky-
lidenephosphoranes on the 1,3-carbonyl-carbon. The computer-assisted molecular
modeling (CAMM) PASS program was adopted for designing—in silico—the struc-
tures of potentially active molecules for future synthesis. Later on, the in vivo activity
of the synthesized phthalimides in the rat adjuvant model was also studied in terms of
structure–activity relationship (SAR). See Fig. 1.
RESULTS AND DISCUSSION
The behavior of stabilized phosphonium ylides 4a-e toward 2-methoxy-1H-
isoindole-1,3-(2H)-dione (1) was examined to determine the site of attack. Treatment
of 1 with an equivalent amount of alkylidene(triphenyl)phosphoranes, namely meth-
oxycarbonylmethylene (4a), ethoxycarbonyl-methylene (4b), acetylmthylene (4c),
benzoyl-methylene 4d, and cyano-methylenetriphenyl-phosphorane (4e) in dry boiling
toluene containing a few drops (ꢀ0.4 mL) of triethylamine (Et3N) over a period of
ꢁ25 h (monitored by thin-layer chromatography, TLC) afforded the respective mono-
alkene products 6a–e (58–63% yield) as the sole reaction products. The same results
were obtained whether 1 or 2 equiv of the Wittig reagent was employed. Elemental
analyses, infrared (IR), and 1H and 13C NMR spectra as well as mass spectrometry[11]
were the reasons for structure 6 assignments. It is worth mentioning here that even
though compounds 6a–c could be present in Z and =or E-configuration, they are only
Figure 1. Starting substrates 1–3 and reagents 4a–c and 5a–c.

WITTIG OLEFINATION OF PHTHALIMIDES
1969
Table 1. Reactions of the substrates 1 and 2 with Wittig reagents 4 under different conditions
Entry
R1
Conditions
Time
Products
Yield (%)
Mp (ꢃC)
1 þ 4a CO2Me Et3N=toluene=D
30 h 6a (E-isomer)
8 min 6a (E-isomer)
30 h 6b (E-isomer)
8 min 6b (E-isomer)
40 h 6c (E-isomer)
10 min 6c (E-isomer)
40 h 6d (E-isomer)
12 min 6d (E-isomer)
48 h 6e (E-isomer)
12 min 6e (E-isomer)
22 h 8a (E-isomer)
58
84
62
85
53
82
60
80
63
87
58
82
62
85
123–125 (cyclohexane)
128–130 (cyclohexane)
134–136 (Me2Cl2)
120–122 (MeCN)
178–180 (EtOH)
1 þ 4a CO2Me DMSO=microwave oven
1 þ 4b CO2Et Et3N=toluene=D
1 þ 4b CO2Et DMSO=microwave oven
1 þ 4c COMe Et3N=toluene=D
1 þ 4c COMe DMSO=Microwave oven
1 þ 4d COPh Et3N=toluene=D
1 þ 4d COPh DMSO=microwave oven
1 þ 4e CN
1 þ 4e CN
Et3N=toluene=D
DMSO=microwave oven
2 þ 4a CO2Me Et3N=toluene=D
213–215 (acetone)
175–177 (CHCl3)
2 þ 4a CO2Me DMSO=M microwave oven 10 min 8a (E-isomer)
2 þ 4b CO2Et Et3N=toluene=D
20 h 8b (E-isomer)
10 min 8b (E-isomer)
2 þ 4b CO2Et DMSO=microwave oven
obtained in the E-form. In favor of this conclusion are the facts that compounds 6
have sharp melting points and did not show any isomerism in the spectroscopic data,
and it is generally accepted that the geometry of the double bond resulted from olefina-
tion Wittig reactions of stabilized ylides that have electron-withdrawing groups
(CO2R, COR, CN) is usually E. Frequently the Z-alkenes having neighboring
electron-withdrawing group isomerize to the thermodynamically more stable
E-isomers.[12–14]
The enormous growth in the use of microwave irradiation in synthetic organic
chemistry inspired us to perform the same reactions (1 þ 4a–e) to achieve, under
microwave conditions, significantly remarkable rate enhancement and drastic
reduction of the reaction time. Thus, when the substrate 1 and the phosphoranes
4a–e were mixed in dimethylsulfoxide (DMSO) solution and heated in a microwave
oven (1000 W), the olefins 6a–e were obtained after the usual workup (ꢂ 82%) in
8–12 min and in the absence of a base (see Table 1).
Similar sequences were applied to another N-substituted isoindoline-1,3-dione
for obtaining more derivatives of phthalimides like 8a and 8b via applying the Wittig
reagents 4a and 4b on the parent 2-(phenylamino)isoindoline-1,3-dione (2) under
either thermal or microwave conditions (see Table 1). Compounds 8a,b were
assigned to the E-isomer for the same reasons as for compounds 6.
On the other hand, no reaction was observed when compound 2 was caused to
react with either the keto ylides (4c, 4d) or cyanomethylenetriphenylphosphorane
(4e). This behavior is in line with the fact that ketones react sluggishly or not at
all with Wittig reagents (stabilized with an acetyl, benzoyl, or cyno group).[13–17]
As the bioassay results have identified impressively distinct therapeutic charac-
teristics from potassium salts to the olefin counterparts, reduction of the synthesized
olefins was undertaken by treating 6a–e and 8a,b with Zn dust in ethanol to give the
corresponding reduced forms 7a–e and 9a,b, respectively. Compounds 7 and 9
(E-isomers) were obtained in the expected much more stable isoindolin-1-ones form.
Treating the latter compounds with aqueous solution of KOH (5%) afforded the pot-
assium salt 9Aa, 9Ab and 7Aa and 7Ab (Schemes 1 and 2).

1970
W. M. ABDOU, R. E. KHIDRE, AND R. F. BARGHASH
Scheme 1. Reaction of 2-methoxy-1H-isoindole-1,3-(2H)-dione 1 with Wittig reagents 4a–e.
Prediction
Prediction of anti-inflammatory activity was made at the earlier stage of the
designed series 6a–e, 7Aa–e, 8a,b, and 9Aa,b using PASS software.[18,19] The predic-
tion result are expressed (ꢄꢄ) in Table 2 with appropriate Pa and Pi, which are the
estimates of probability to be active and inactive, respectively. The data in Table 2
Scheme 2. Reaction of N-anilino-1H-isoindole-1,3-(2H)-dione 2 with Wittig reagents 4a,b.

WITTIG OLEFINATION OF PHTHALIMIDES
1971
Table 2. Anti-inflammatory activity of phthalimide derivatives 6a,c, 7Aa–e, 8a,b, and 9Aa,b in acute
carrageenin-induced paw edema in rats
Compound
Mean swellinga vol. (mL)
Inhibition of edema %
00.0
Potency (%)
Control
Ab
6a
0.688
0.272
0.574
0.578
0.566
0.576
0.570
0.278
0.377
0.348
0.376
0.381
0.488
0.476
0.189
0.206
—
c
60ꢄꢄꢄ
1.00
0.28
0.29
0.30
0.30
0.23
0.99ꢄ
0.95
0.82
0.76
0.74
0.48
0.51
1.19ꢄ
1.17ꢄ
16.6ꢄꢄꢄ
16.8ꢄꢄꢄ
17.7ꢄꢄꢄ
14.7ꢄꢄꢄ
12.7ꢄꢄꢄ
59.6ꢄꢄ
6b
6c
6d
6e
7Aa
7Ab
7Ac
7Ad
7Ae
8a
57.3ꢄꢄ
49.4
45.3ꢄꢄꢄ
44.6ꢄꢄ
29.0ꢄꢄ
30.8
71.2ꢄ
70.1ꢄ
8b
9Aa
9Ab
aData are means of at least two independent determinations with 6 animals in each group (in a dose of
50 mg=kg body weight), and the deviation in absorbance values was less than 10%.
bA ¼ Indomethacin (used as a reference standard).
c(SEM: standard error of the mean) statistical significance of results was established using the Student’s
t-test (ꢄꢄꢄ) P < 0.001; (ꢄꢄ) P < 0.01; (ꢄ) P < 0.05. The anti-inflammatory activity (prediction results
ꢄ
ꢄꢄ
>
>
ꢄꢄꢄ) was expressed as percentage inhibition of edema volume in treated animals in comparison
with the control group as described in the experimental section.
demonstrates that PASS program[19] has proved 100% accurate in its predictions
between predicted values and experimental results of anti-inflammatory properties
of the tested compounds (i.e., the calculated Pa value is proportional to the potency
of the compound).
Anti-Inflammatory Activity Screening
The anti-inflammatory activity in vivo of the prepared phthalimide derivatives
6a–e, 7Aa–e, 8a,b, and 9Aa,b was determined. Respectively, mice were surgically
implanted with the acute carrageenin-induced paw edema (CPE) standard
method.[20] The anti-inflammatory property of the examined compounds at 50 mg=
Kg body weight is shown in comparison with that of indomethacin (A), in a dose
of 50 mg=kg body weight which used as a reference standard, and the results are col-
lected in Table 2.
Compounds 7Aa and 7Ab both significantly inhibited the granuloma at the
same dose (50 mg=kg) as the reference, while 9Aa and 9Ab exerted the most signifi-
cant inhibition, which was not dose-related, over the same ranges. Compound 7Ac
showed only moderate activity against the carrageenin granuloma at the same dose,
whereas other products showed only low potency.
Finally, the reported activity in vivo in the carrageenin granuloma is the first
demonstration of the anti-inflammatory activity of phthalimide derivatives.

1972
W. M. ABDOU, R. E. KHIDRE, AND R. F. BARGHASH
Toxicity
In acute toxicity experiments, the in vivo compounds were endowed with a 50%
lethal dose of >0.3 mmol=Kg body weight. Thus, toxicological studies of 7Aa,b, 9Aa,
and 9Ab were performed using the LD50 standard method[21] in mice in 500, 750, and
1000 mg=Kg (body weight), that is, 10–20 folds of the used anti-inflammatory effec-
tive dose. However, no toxic symptoms or mortality rates were observed after 24 h
postadministration, demonstrating the safe behavior of the doses.
CONCLUSION
The studied reactions in the previous[9,10] and the present investigations are
offered as easy ways to transform easily available starting materials into a variety
of phthalimide derivatives in satisfactory yields. In addition, our protocol demon-
strates an efficient site-selective method for making novel products in good yields
from N-substituted phthalimides with P(III) and P(V) reagents. In parallel, screening
results showed that the potassium salts of phthalimide derivatives 9Aa and 9Ab
would be good candidates for lead molecules to be modified to improve inflamma-
tory inhibition. Six from 14 compounds tested with carrageenin-induced rat paw
edema were found to be potent anti-inflammatory agents (59.7–87.6%). For most
of these activities, the presence of a saturated substituent moiety and a hydroxyl
group in addition to the phthalimide core seemed to be essential to generate new
derivatives with greater anti-inflammatory activity.
EXPERIMENTAL
Melting points were measured on an Electrothermal melting-point apparatus.
The IR spectra were recorded on a Perkin-Elmer 317 Grating IR spectrophotometer
using KBr pellets. NMR spectra were measured with a Jeol ECA 500-MHz (13C:
1
125, H: 500, 31P: 200 MHz) spectrometer. 31P NMR spectra were recorded with
H3PO4 (85%) as external reference. 1H and 13C NMR spectra were recorded with tri-
methylsilane as internal standard in CDCl3 or DMSO-d6. Chemical shifts (d) are
given in parts per million (ppm). Mass spectra were performed at 70 eV on an
MS-50 Kratos (AEI) spectrometer provided with a data system. Elemental analyses
were carried out at the Microanalysis Laboratory, Cairo University, Cairo, Egypt.
The appropriate precautions in handling moisture-sensitive compounds were con-
sidered. TLC: Merck 0.2-mm silica gel 60 F154 aluminum plates. Column chroma-
tography (CC): silica gel (Kieselgel 60 mesh, particle size 0.2–0.5 mm; E. Merck,
Darmstadt).
Reaction of N-Methoxyphthalimide (1) with Wittig Reagents 4a–e:
Synthesis of 6a–e
Under thermal conditions general procedure A. A mixture of alkoxycar-
bonylmethylene-4a (or 4b), acetylmethylene 4c, benzoylmethylene 4d, or
cyanomethylene(triphenyl)-phosphine (4e) (8.6 mmol) and 1 (1.5 g, 8.5 mmol) in
dry toluene (40 mL) containing triethylamine (TEA) (0.5 mL) was heated under

WITTIG OLEFINATION OF PHTHALIMIDES
1973
reflux for ffi25 h. After removal of the solvent, the residue was chromatographed on
silica gel using n-hexane=CHCl3 as eluents to give the respective olefins 6a-e
(Table 1). Triphenylphosphine oxide (TPPO) was isolated (6:4 v=v) and identified
from all described reactions.
Methyl 2-(2-methoxy-3-oxoisoindolin-1-ylidene)acetate (6a). IR (KBr):
1
n ¼ 1733, 1713 (C O, cyclicimide & ester), 1636 (C C, olefin) cmÀ1; H NMR
=
=
~
(500.6 MHz, CDCl3): d ¼ 3.73 (s, 3H, MeO, ester), 3.94 (s, 3H, MeON), 5.98 (s,
1H, CH, olefin), 7.76, 7.87 (2d, JH-H ¼ 6.8 Hz, 2 Â 2H, H-Ar) ppm; 13C NMR
=
=
=
(125.7 MHz, CDCl3): d ¼ 170.2 (C O, ester), 168.3 (C O, imide), 146.9 [C(1)],
=
138.7, 135.2, 127.8, 126.1, 125.8, 125.2 (C-Ar), 86.6 ( CH), 62.4 (MeON), 52.3
(OMe, ester) ppm; MS (EI, 70 eV): m=z (%) ¼ 233 (100) [Mþ], 203 (28) [Mþ
À31(OMe], 190 (25) [Mþ À45 (NOMe)], 173 (22) [Mþ À62(2 Â OMe)], 160 (46),
146 (34), 130 (71), 77 (13). C12H11NO4 (233.2): calcd. C, 61.80; H, 4.75; N, 6.01.
Found: C, 61.87; H, 4.69; N, 5.96%.
Ethyl 2-(2-methoxy-3-oxoisoindolin-1-ylidene)acetate (6b). IR (KBr):
1
n ¼ 1728, 1715 (C O, cyclicimide & ester), 1632 (C C, olefin) cmÀ1; H NMR
=
=
~
(500.6 MHz, CDCl3): d ¼ 1.44 (t, JHH ¼ 5.8 Hz, 3H, MeC.O, ester), 3.94 (s, 3H,
=
MeON), 4.24 (q, JH-H ¼ 5.8 Hz, 2H, H2C.O, ester), 6.08 (s, 1H, CH, olefin), 7.76,
7.87 (2d, JH-H ¼ 6.8 Hz, 2 Â 2H, H-Ar) ppm; 13C NMR (125.7 MHz, CDCl3):
=
=
d ¼ 170.4 (C O, ester), 168.2 (C O, imide), 146.7 [C(1)], 138.3, 135.2, 133.6,
=
127.8, 126.8, 125.2 (C-Ar), 85.6 ( CH), 62.4 (MeON), 59.6 (OCH2, ester), 15.3
(OMe, ester) ppm; MS (EI, 70 eV): m=z (%) ¼ 247 (100) [Mþ], 203 (36) [Mþ
À45(OEt)], 189 (15), 173 (20), 160 (51), 146 (42), 130 (51), 77 (18). C13H13NO4
(247.25): calcd. C, 63.15; H, 5.30; N, 5.67. Found: C, 63.23; H, 5.26; N, 5.58%.
2-Methoxy-3-(2-oxoproylidene)isoindolin-1-one
=
(6c). IR
(KBr):
1
n ¼ 1723, 1684 (C O, cyclicimide & acetyl), 1590 (C C, olefin) cmÀ1; H NMR
=
~
(500.6 MHz, CDCl3): d ¼ 2.48 (s, 3H, Me, acetyl), 4.07 (s, 3H, MeON), 6.32 (s,
1H, CH, olefin), 7.78, 7.84 (2d, JH-H ¼ 6.8 Hz, 2 Â 2H, H-Ar) ppm; 13C NMR
=
=
=
(125.7 MHz, CDCl3): d ¼ 173.6 (C O, acetyl), 168.6 (C O, imide), 145.8 [C(3)],
=
136.8, 133.2, 127.6, 121.2, 127.8 (C-Ar), 89.5 ( CH), 62.2 (MeON), 32.6 (Me, acetyl)
ppm; MS (EI, 70 eV): m=z (%) ¼ 217 (62) [Mþ], 203 (9) [Mþ À15 (CH3)], 174 (100)
[Mþ À45 (NOCH3)], 146 (18), 130 (17), 77 (11). C12H11NO3 (217.22): calcd. C,
66.35; H, 5.10; N, 6.45. Found C, 66.42; H, 5.05; N, 6.53%.
2-Methoxy-3-(2-oxo-2-phenylethylidene)isoindolin-1-one
=
(6d). IR
=
=
~
(KBr): n ¼ 1730 (C O, cyclicimide), 1654 (C O, benzoyl), 1610 (C C, olefin)
1
cmÀ1; H NMR (500.6 MHz, CDCl3): d ¼ 4.12 (s, 3H, MeON), 7.24 (s, 1H, CH,
=
olefin), 7.64–7.89 (m, 9H, H-Ar & H-Ph) ppm; 13C NMR (125.7 MHz, CDCl3):
=
=
d ¼ 193.2 (C O, benzoyl), 167.6 (C O, imide), 144.8 [C(3)], 138.7, 137.2, 138.3,
135.3, 134, 132.5, 128.6, 128.2, 127.9, 125.8, 124.6, 122.6 (C-Ar & þC-Ph), 84.þ6
=
( CH), 62.8 (MeON) ppm; MS (EI, 70 eV): m=z (%) ¼ 279 (72) [M ], 249 [M
À31(OCH3)], 236 (18) [Mþ À45(NOCH3)], 106 (100) [C(O]Ph), 77 (52). C17H13NO3
(279.29): calcd. C, 73.11; H, 4.69; N, 5.02. Found: C, 73.19; H, 4.61; N, 5.12%.
2-(2-Methoy-3-oxoisoindolin-1-ylidene)acetonitrile
=
(6e).À1IR (KBr):
;
1H NMR
=
~
n ¼ 2218 (CN), 1727 (C O, cyclicimide), 1622 (C C, olefin) cm

1974
W. M. ABDOU, R. E. KHIDRE, AND R. F. BARGHASH
=
(500.6 MHz, CDCl3): d ¼ 4.07 (s, 3H, MeON), 5.63 (s, 1H, CH, olefin), 7.78, 7.84
(2d, JH-H ¼ 6.8 Hz, 2 Â 2H, H-Ar) ppm; 13C NMR (125.7 MHz, CDCl3): d ¼ 167.8
=
=
(C O, imide), 148.2 [C(1)], 137.7, 135.4, 127.2, 126.5, 122.6 (C-Ar), 63.2 ( CH-CN),
62.7 (MeON) ppm; MS (EI, 70 eV): m=z (%) ¼ 200 (90) [Mþ], 186 (100) [Mþ À15
(CH3)], 170 (64), 157 (55), 143 (9), 129 (44), 77 (16). C11H8N2O2 (200.2): calcd. C,
66.00; H, 4.03; N, 13.99. Found: C, 66.04; H, 4.11; N, 13.89%.
Reduction of 6a–e. To a mixture of the olefins 6a–e (2.72 mmol) in EtOH
(26 mL) and zinc dust (4.76 g, 73.0 mmol), 6.5 mL of NH4OAc (1 M) was added
slowly into the slurry over a period of 3 min. After 45 min of stirring at rt, a solution
of 10 (N) NaOH (0.92 mL) was added to the reaction mixture. The product mixture
was filtered through the celite, washed with CH2Cl2, and brine was added. The
organic phase was separated, and the water phase was extracted with CHCl3. The
combined organic phases were dried over Na2SO4 and evaporated under reduced
pressure. The residue was collected and crystallized from the proper solvent to give
7a–e.
Methyl 2-(2-methoxy-3-oxoisoindol-1-yl)acetate (7a). Pure E-isomer,
as pale yellow crystals (486 mg, 76%); mp. 142–143 ꢃC (MeCN); IR (KBr):
n ¼ 1728, 1713 (2C O, cyclicimide & ester); 1H NMR (500.6 MHz, CDCl3):
=
~
d ¼ 3.64 (d, JH-H ¼ 6.3 Hz, 2H, H2C-Ar), 3.88 (s, 3H, MeO, ester), 4.09 (s, 3H,
13
MeON), 4.54 (t, JH-H ¼ 6.3 Hz, 1H, C(1)H), 7.77, 7.88 (2d, JH-H ¼ 6.5 Hz, 2 Â 2H,
=
H-Ar) ppm; d ¼ C NMR (125.7 MHz, CDCl3): d ¼ 168.6 (C O, imide), 161.7
=
(C O, ester), 131.1, 128.4, 126.7, 124.2, 114.8, 94.8 (C-Ar), 62.8 (MeON), 52.5
(OMe, ester), 42.3 (CH2-Ar), 38.6 [C(1)] ppm; MS (EI, 70 eV): m=z (%) ¼ 234 (28)
[Mþ À1], 209 (100) [Mþ À28(CO)], 177 (35), 147 (53) [Mþ À90 (CO þ 2 Â OMe)],
127 (22), 130 (44), 116 (34), 77 (23). C12H13NO4 (235.2): calcd C, 61.27; H, 5.57;
N, 5.95: Found C, 61.33; H, 5.51; N, 6.02%.
Ethyl 2-(2-methoxy-3-oxoisoindol-1-yl)acetate (7b). Pure E-isomer, as
ꢃ
~
pale yellow crystals (542 mg, 80%); mp 148–150 C (MeCN); IR (KBr): n ¼ 1725,
1
1714 (2C O, cyclicimide & ester) cmÀ1; H NMR (500.6 MHz, CDCl3): d ¼ 1.37
=
(t, JH-H ¼ 6.6 Hz, 3H, MeCO, ester), 3.76 (d, JH-H ¼ 8.2 Hz, 2H, H2C-Ar), 3.88 (s,
3H, MeON), 4.32 (q, JHH ¼ 6.6 Hz, 2H, H2CO, ester), 4.57 (t, JH-H ¼ 8.2 Hz, 1H,
C(1)H), 7.76, 7.87 (2d, JH-H ¼ 6.5 Hz, 2 Â 2H, H-Ar) ppm; 13C NMR (125.7 MHz,
=
CDCl3): d ¼ 167.6, 160.8 (2C O, cyclicimide & ester), 131.6, 127.8, 126.7, 124.2,
116.8, 94.8 (C-Ar), 63.2 (MeON), 62.3 (OCH2), 41.4 (CH2-Ar), 38.3 [C(1)], 14.7
(OCMe, ester) ppm; MS (EI, 70 eV): m=z (%) ¼ 248 (37) [Mþ À1], 223 (100) [Mþ
À28(CO)], 193 (42) [Mþ À59 (CO þOMe], 149 (53), 127 (28), 130 (21), 116 (48),
77 (33). C13H15NO4 (249.26): calcd. C, 62.64; H, 6.04; N, 5.65. Found: C, 62.69;
H, 5.98; N, 5.72%.
1-(2-Methoxy-3-oxoisoindol-1-yl)propan-2-one (7c). Pure E-isomer, as
colorless crystals (464 mg, 78%); mp 158–160 ꢃC (CHCl3); IR (KBr): 158–160
& ;
acetyl) cmÀ1 1H NMR
=
~
(CHCl3); n ¼ 1719, 1682 (2C O, cyclicimide
(500.6 MHz, CDCl3): d ¼ 2.48 (s, 3H, Me.acetyl), 3.78 (d, JH-H ¼ 7.2 Hz, 2H,
H2C-Ar), 4.07 (s, 3H, MeON), 4.72 [t, JH-H ¼ 7.2 Hz, 1H, C(1)H], 7.78, 7.84 (2d,
JH-H ¼ 6.8 Hz, 2 Â 2H, H-Ar) ppm; 13C NMR (125.9 MHz, CDCl3): d ¼ 205.7
=
=
(C O, acetyl),168.4 (C O, imide), 129.6, 128.4, 126.7, 124.2, 118.8, 94.2 (C-Ar),

WITTIG OLEFINATION OF PHTHALIMIDES
1975
62.8 (MeON), 33.6 (CH2-Ar), 40.6 [C(1)], 22.6 (Me, acetyl) ppm; MS (EI, 70 eV): m=
z (%) ¼ 218 (47) [Mþ À1], 193 (100) [Mþ À28(CO)], 163 (18), 148 (65), 127 (18), 130
(44), 116 (46), 77 (37). C12H13NO3 (219.24): calcd. C, 65.74; H, 5.98; N, 6.39. Found:
C, 65.80; H, 6.03; N, 6.32%.
2-(2-Methoxy-3-oxoisoindol-1-yl)-1-phenylethanone (7d). Pure E-iso-
mer, as colorless crystals (610 mg, 80%); mp 144–145 ꢃC; (MeCN); IR (KBr):
n ¼ 1732, 1656 (2C O, cyclicimide & benzoyl) cmÀ1; 1H NMR (500.6 MHz, CDCl3):
d ¼ 3.75 (d, JH-H ¼ 6.8 Hz, 2H, H2C-Ar), 4.16 (s, 3H, MeON), 4.66 (t, JH-H ¼ 6.8 Hz,
1H, C(1)H), 7.64–7.89 (m, 9H, H-Ar & H-Ph) ppm; 13C NMR (125.7 MHz, CDCl3):
=
~
=
=
d ¼ 196.3 (C O, benzoyl), 165.5 (C O, imide), 133.8, 131.2, 130.6, 129.2, 128.2, 127.9,
123.8, 1156, 91.6 (C-Ar & C-Ph), 63.2 (MeON), 36.6 [C(1)], 28.6 (CH2-Ar) ppm; MS
(EI, 70 eV): m=z (%) ¼ 280 (22) [Mþ À1], 255 (56) [Mþ À28(CO)], 210 (42) [Mþ
À73(CO þNOCH3)], 105 (100) (C(O)Ph), 77 (55). C11H8N2O2 (200.2): C17H15NO3
(281.31): calcd. C, 72.58; H, 5.37; N, 4.98. Found: C, 72.64; H, 5.32; N, 5.03%.
2-(2-Methoxy-3-oxoisoindol-1-yl)acetonitrile (7e). Pure E-isomer, as pale
yellow crystals (mg, 76%); mp (395 mg, 72%);Àm1 p 194–196 ꢃC; (EtOH); IR (KBr):
;
1H NMR (500.6 MHz, CDCl3):
=
~
n ¼ 2220 (CN), 1721 (C O, cyclicimide) cm
d ¼ 3.85 (d, JH-H ¼ 7.8 Hz, 2H, H2C-Ar), 4.17 (s, 3H, MeON), 4.55 [t, JH-H ¼ 7.8 Hz,
Hz, 1H], C(1)H), 7.78, 7.87 (2d, JH-H ¼ 6.5 Hz, 2 Â 2H, H-Ar) ppm; 13C NMR
=
(125.7 MHz, CDCl3): d ¼ 169, 164.3 (2C O, cyclicimide & ester), 130.6, 129.4,
126.7, 125.2, 122.4, 96.3 (C-Ar), 114.6 (CN), 63.5 (MeON), 38.6 [C(1)] ppm; MS
(EI, 70 eV): m=z (%) ¼ 201 (60) [Mþ À1], 174 (66) [Mþ À28 (CO)], 148 (100), 118
(55), 111 (9), 77 (16). C11H10N2O2 (202.21): calcd. C, 65.34; H, 4.98; N, 13.85.
Found: C, 65.44; H, 4.94; N, 13.91%.
Reaction of 1 with two molar amounts of 4a–e under the previous experimental
conditions yielded only the same products 6a–e.
Under microwave condition, general procedure B. Compound
1
(2.8 mmol), 0.5 g was added to a solution mixture of 8 mL dry dimethylsulfoxide
(DMSO) and ꢁ 2.85 mmol of 4a, 4b, 4c, 4d or 4e) in a Pyrex glass beaker. Microwave
irradiation (MW domestic type oven 1000 W with a frequency 2450 of MHz,
National Jp) was applied for 8–10 min (each pulse of 2 min). After the completion
of the reaction and the usual workup, the resulting residue was chromatographed
on silica gel (n-hexane=CHCl3) to give the respective olefin as the sole reaction
products 6a (84), 6b (85), 6c (82), 6d (78), or 6e (87%).
Reaction of N-Anilinophthalimide (2) with Wittig Reagents 4a,b:
Synthesis of 8a,b
Under thermal conditions. A mixture of 6.4 mmol of 4a or 4b and 1.5 g
(6.3 mmol) of 2 in 40 mL of dry toluene was heated under reflux for ffi20 h (TLC). After
removal of the solvent, the residue was chromatographed on silica gel using n-hexane=
CHCl3 as eluents to give the respective product 8a or 8b (see Table 1). Triphenylphos-
phine oxide (TPPO) was also isolated (6:4 v=v) and identified from both reactions.
Methyl 2-(3-oxo-2-(phenylamino)isoindolin-1-ylidene)acetate (8a). IR
1
(KBr): n ¼ 1732, 1710 (C O, cyclicimide & ester), 1618 (C C, olefin) cmÀ1; H
=
=
~

1976
W. M. ABDOU, R. E. KHIDRE, AND R. F. BARGHASH
=
NMR (500.6 MHz, CDCl3): d ¼ 3.78 (s, 3H, MeO, ester), 6.18 (s, 1H, CH, olefin),
7.36–7.88 (m, 9H, H-Ar), 8.86 (s, 1H, HN, exch with D2O) ppm; 13C NMR
=
=
(125.7 MHz, CDCl3): d ¼ 172.2 (C O, imide), 169.6 (C O, ester), 144.8 [C(1)],
139.7, 136.5, 133.2, 130.2, 129.6, 126.1, 125.8, 125.2, 124.7, 122.6, 114.2 (C-Ar &
=
C-Ph), 84.6 (Ar CH), 52.3 (OMe, ester) ppm; MS (EI, 70 eV): m=z (%) ¼ 294
(100) [Mþ], 280 (16) [Mþ À15 (Me)], 264 (100) [Mþ À31(OMe)], 203 (22) [Mþ
À
92 (NHPh], 179 (14), 129 (14), 92 (20), 77 (46). C17H14N2O3 (294.3): calcd. C,
69.38; H, 4.79; N, 9.52. Found: C, 69.51; H, 4.77; N, 9.43%.
Ethyl 2-(3-oxo-2-(phenylamino)isoindolin-1-ylidene)acetate (8b). IR
1
(KBr): n ¼ 1732, 1718 (C O, cyclicimide & ester), 1614 (C C, olefin) cmÀ1; H
=
=
~
NMR (500.6 MHz, CDCl3): d ¼ 1.34 (t, JHH ¼ 6.8 Hz, 3H, MeC.O, ester), 4.28 (q,
=
JH-H ¼ 6.8 Hz, 2H, H2CO, ester), 6.34 (s, 1H, CH, olefin), 7.45–7.87 (m, 9H, H-
Ar), 9.26 (s, 1H, HN, exch with D2O) ppm; 13C NMR (125.7 MHz, CDCl3):
=
d ¼ 173.2, 169.4 (2C O, imide, ester), 144.7 [C(1)], 138.1, 135.6, 134.1, 129.8, 129.6,
=
126.3, 125.2, 124.7, 124.1, 121.6, 115.7 (C-Ar & C-Ph), 85.6 (Ar CH), 62.4 (CH2O)
ppm; MS (EI, 70 eV): m=z (%) ¼ 308 (100) [Mþ], 264 (72) [Mþ À45(OEt))], 217 (18)
[Mþ À92 (NHPh], 179 (14), 129 (20), 92 (13), 77 (16). C18H16N2O3 (308.34): calcd.
C, 70.12; H, 5.23; N, 9.09. Found: C, 70.17; H, 5.31; N, 8.98%.
Compounds 8a and 8b in 82 and 85% yields were obtained by carrying out these
two reactions under the microwave conditions. On the other hand, no reaction was
observed when 2 was allowed to react, under the same conditions, with 4c, 4d, or 4e.
Preparation of 9a, 9b. These compounds were prepared from 8a, b by apply-
ing the same protocol adopted for the preparation of 7a–e from 6a–e.
Methyl 2-(2-(phenylamino)-3-oxoisoindol-1-yl)acetate (9a). Pure E-iso-
mer, as pale yellow crystals (660 mg, 82%); mp 231–233 ꢃC (CHCl3); IR (KBr):
1
n ¼ 1722, 1715 (2C O, cyclicimide & ester) cmÀ1; H NMR (500.6 MHz, CDCl3):
=
~
d ¼ 3.82 (d, JH-H ¼ 6.8 Hz, 2H, H2C-Ar), 3.85 (s, 3H, MeO, ester), 4.72 (t, JH-H
-
¼ 6.8 Hz, 1H, C(1)H), 7.36–7.88 (m, 9H, H-Ar), 9.46 (s, 2 Â 1H, HN, exch with
D2O) ppm; MS (EI, 70 eV): m=z (%) ¼ 295 (38) [Mþ À1]. ÀC18H18N2O3 (310.35):
calcd. C, 69.66; H, 5.85; N, 9.03. Found: C, 70.01; H, 5.91; N, 9.09.
Ethyl 2-(2-(phenylamino)-3-oxoisoindol-1-yl)acetate (9b). Pure E-isomer,
as pale yellow crystals (715 mg, 85%); mp 189–190 ꢃC (CHCl3); IR (KBr):
1
n ¼ 1728, 1713 (2C O, cyclicimide & ester) cmÀ1; H NMR (500.6 MHz, CDCl3):
d ¼ 1.23 (t, JH-H ¼ 7 Hz, 3H, MeCO, ester), 3.87 (d, JH-H ¼ 7.6 Hz, 2H, H2C-Ar),
4.22 (q, JH-H ¼ 7 Hz, 2H, H2CO, ester), 4.72 [t, JH-H ¼ 7.6 Hz, 1H, C(1]H),
7.45–7.87 (m, 9H, H-Ar), 9.26 (s, 1H, HN, exch. D2O) ppm; MS (EI, 70 eV): m=z
(%) ¼ 309 (33) [Mþ À1], -C17H16N2O3 (296.3): calcd. C, 68.91; H, 5.44; N, 9.45.
Found: C, 69.01; H, 5.37; N, 9.51%.
=
~
Anti-Inflammatory Activity Experiments In Vivo: Carrageenin-
Induced Edema
All compounds tested were dispersed in sterilized saline with a concentration of
0.11 mmol=kg, stabilized by 0.05% Tween-80 (vehicle solution) and administered
intraperitoneally. Fisher 344 male and female rats (pregnant excluded) weighing

WITTIG OLEFINATION OF PHTHALIMIDES
1977
180–220 g were used. The animals were divided into 12 groups of 6 animals each and
housed under standard conditions. Indomethacin, A (0.11 mmol=kg body weight)
was administered as a standard drug.
Acute anti-inflammatory activity[20] (Table 1) was measured after 3.5 h by
reduction of rat paw carrageenin edema, induced by injection of 0.1 mL carrageenin
2% (K100, commercially available) in sterilized saline, intradermally into the right
foot pad. The examined compounds (previously prepared in the vehicle solution)
were administered simultaneously to the animals. Paw volumes were measured volu-
metrically after 3.5 h with plethysmometer 7150 (UGO BASILE, Italy) and com-
pared with the initial hind paw volume of each rat for determining the edema
volume. Data were collected, checked, revised, and analyzed. Quantitative variables
from normal distribution were expressed as means ÆSE. The significant difference
between groups was tested by using one-way (ANOVA) followed by least significiant
difference (LSD) test (P).
The anti-inflammatory activity was expressed as percentage inhibition of
edema volume in treated animals in comparison with the control group, and the data
are collected in Table 2.
ðVc À VtÞ
% Inhibition of edema ¼
 100
Vc
where Vc and Vt are the volumes of edema for the control and drug-treated animal
groups, respectively, while potency of the tested compounds was calculated regard-
ing indomethacin, reference standard, in the treated group according to the follow-
ing equation:
% Edema inhibition of tested compound treated group
Potency ¼
% Edema inhibition of Indomethacin treated group
Toxicity of the Evaluated Phosphorus Heterocycles
The LD50 determination of the most promising synthesized anti-inflammatory
active agents (7Aa,b, 9Aa, and 9Ab) was determined the standard known LD50
method in mice.[21] Albino mice weighing 20–25 g were divided into 6 groups of 8
mice each. Administrations of the tested compounds (7Aa,b, 9Aa, and 9Ab) dis-
solved in the same vehicle solution in 500, 750, and 1000 mg=kg (body weight) were
given intraperitoneally. The control groups were given in buffer solution only. The
toxic symptoms, mortality rates, and postmortem findings in each group were
recorded 24 h postadministration.
LD50 of the tested compounds were calculated according to the following
formula:
LD50 ¼ Dm À Rðz  dÞ=n
where Dm is the largest dose that kills all animals, z is mean of dead animals between
two successive groups, d is the constant factor between two successive doses, n is the
number of animals in each group, and R is the sum of (z  d).

1978
W. M. ABDOU, R. E. KHIDRE, AND R. F. BARGHASH
ACKNOWLEDGMENTS
Financial support from the Egyptian Academy of Scientific Research and
Technology is gratefully acknowledged. We thank the National Central Laboratory
of Toxicology, Cairo, Egypt, for carrying out the pharmacological screening.
REFERENCES
1. Fahmy, A. F. Arkivoc. 2006, 7, 395–415.
2. Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. Chem. Rev. 1970, 70, 439–469.
3. Achinami, K.; Ashizawa, N.; Kobayashi, F. I 03,133,955, Chem. Abstr. 1991, 115, 255977.
4. Kato, Y.; Ebiik, H.; Achiwa, K.; Kurihara, T.; Kobayashi, F. Chem. Pharm. Bull. 1990,
38, 2060–2062.
5. Laboratori Baldacci DPA. Jpn. Patent JP 59 46, 268, 1984; Chem. Abstr. 1984, 101, 54922.
6. Weiss, I.; Fidous, S.; Freyer, A. J.; Shamma, M.; Urzua, A.; Fayardo, V. Tetrahedron
1984, 40, 3957–4962.
7. Priestap, H. A. Phytochemistry 1985, 24=44, 849–852.
8. Shaikhiev, I. G.; Fridland, S. V.; Mukhutdinova, G. M. Russ. J. Gen. Chem. 1999, 69,
557–559.
9. Abdou, W. M.; Ganoub, N. A.; Sabry, E. Z. Naturforschung 2009, 46b, 1057–1064.
10. Abdou, W. M.; Khidre, R. E. Montsh. Chem. 2010, 141, 219–228.
11. Silverstein, R. M.; Webster, F. X. W.; Kiemle, D. J. (eds). Spectrometric Identification of
Organic Compounds; John Wiley and Sons: New York, 2005.
12. Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron 1997, 53, 10313–10330.
13. Maryanoff, B. E.; Reitz, A. R. Chem. Rev. 1989, 89, 863–927.
14. Johnson, A. W. Ylides and Imines of Phosphorus; John Wiley & Sons: New York, 1993.
15. Gosney, I.; Rowley, A. G. In Organophosphorus Reagents in Organic Synthesis; Academic
Press: London, 1979; chapter 2: pp. 17–153.
16. Bobbitt, J. M.; Katrizky, A. R.; Boulton A. L. (Eds.); Advances in Heterocyclic Chemistry
1973; Elsevier: New York, vol. 15, pp. 122–129.
17. (a) Sugasawa, S.; Matsuo, H. Chem. Pharm. Bull. Jp. 8, 819–826; (b) Chem. Absr. 1961; 55,
20901.
18. http://www.ibmc.msk.ru/PASS
19. Poroikov, V. V.; Filimonov, D. A.; Ihlenfeld, W. D.; Gloriozova, T. A.; Lagunin, A. A.;
Borodina, Y. V.; Stepanchikova, A. V.; Nicklaus, M. C. J. Chem. Inf. Comput. Sci. 2003,
43, 228–236.
20. Hadjipavlou-Litina, D. Res. Commun. Chem. Pathol. Pharmacol. 1993, 81, 1091–1102.
21. Ka¨rber, C. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1931, 162, 480–487.