Phosphono-Substituted Isoindolines and Indoles from 2,3- and 2,4-Benzoxazin-1-ones

Article abstract of DOI:10.1002/hc.10216

Reactions of 2,3-benzoxazinone 1 and 2,4-benzoxazinone 2, with trialkyl phosphites 3a-c provide access to new phosphono-substituted isoindolines 6a-f and indoles 19a-e, respectively. Phosphonosubstituted 2,3-benzoxazines 5a-c were also obtained in the first reaction. Bisisoindolinylidene (7) was, however, isolated in low yields when 1 was heated with triethyl or triisopropyl phosphite at 100°C whereas at 170°C 7 was obtained as the major product (～53%). On the other hand, the reaction of 1 or 2 with dialkyl phosphonates 4a-c proceeded in the presence of aqueous solution of NaOH (5%) to give the respective alkylated product 14a-c or 20a-c.

Full text of DOI:10.1002/hc.10216

Heteroatom Chemistry
Volume 15, Number 1, 2004
Phosphono-Substituted Isoindolines and
Indoles from 2,3- and 2,4-Benzoxazin-1-ones
Wafaa M. Abdou, Azza A. Kamel, and Maha D. Khidre
Department of Pesticide Chemistry, National Research Centre, Dokki, Cairo, Egypt
Received 1 May 2003; revised 21 July 2003
cological value by treating 4-(4-methylphenyl)-2,3-
ABSTRACT: Reactions of 2,3-benzoxazinone 1 and
benzoxazin-1-one (1) with different types of alkyli-
2,4-benzoxazinone 2, with trialkyl phosphites 3a–c
denephosphoranes. This result intrigued us to design
provide access to new phosphono-substituted isoindo-
and to synthesize a series of novel phosphono-
lines 6a–f and indoles 19a–e, respectively. Phosphono-
substituted N-heterocycles from the reactions of 2,3-
substituted 2,3-benzoxazines 5a–c were also obtained
1 and 2,4-benzoxazin-1-ones 2 with trialkyl phos-
in the first reaction. Bisisoindolinylidene (7) was,
phites 3a–c. The study was extended to cover the
however, isolated in low yields when 1 was heated with
reactions of 1 and 2 with dialkyl phosphonates 4a–c.
triethyl or triisopropyl phosphite at 100◦C whereas at
170◦C 7 was obtained as the major product (∼53%).
On the other hand, the reaction of 1 or 2 with dialkyl
phosphonates 4a–c proceeded in the presence of aque-
ous solution of NaOH (5%) to give the respective alky-
ꢀ
C
lated product 14a–c or 20a–c. 2003 Wiley Periodicals,
Inc. Heteroatom Chem 15:77–84, 2004; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.10216
RESULTS AND DISCUSSION
The reaction of 1 with trimethyl phosphite (3a) was
successfully completed (TLC) by using an excess of
INTRODUCTION
Much attention has been given to the preparation of
phosphono-substituted heterocyclic compounds [1–
4] largely because of their possible relevance to the
mechanism of certain enzymatic events [5,6]. The
P O is an important analogue of the carbonyl group
and can serve as a transition state mimic owing to
the additional ligand allowed by sp3 hybridization.
Therefore, the synthesis of phosphono-substituted
heterocycles was extensively studied [7].
the phosphite as solvent and heating the mixture for
15 h at 105◦C. Chromatographic separation of the
product mixture yielded dimethyl 4-(4-methylphe-
nyl)-2,3-benoxazin-1-yl-phosphonate (5a, 30%),
dimethyl 3-(4-methylphenyl)-2-methyl-isoindolyl-
phosphonate (6a, 18%), and dimethyl 3-(4-meth-
ylphenyl)isoindolyl-phosphonate (6b, 22%). Oxa-
zinone 1, when heated with triethyl-or triisopropyl
phosphite (3b,c) at 100–105 ◦C for 12 h, gave a
low yield of bisisoindolinylidene (7) (∼10%), in
addition to the respective phosphonates 5b,c
(18%), 6c,e (∼27%), and 6d,f (∼15%). However,
at higher temperatures, 3b,c reacted with 1 to
give 7 as the major product (∼52%) together with
the phosphonates 6d,f (∼18%). No significant
In a recent study [8], we described the synthe-
sis of several isoquinoline derivatives of pharma-
Correspondence to: Wafaa M. Abdou; e-mail: wabdou@
intouch.com.
c
ꢀ
2003 Wiley Periodicals, Inc.
77

78 Abdou, Kamel, and Khidre
amount of phosphonates 5b,c or 6c,e was detected
(Scheme 1).
Schemes 2 and 3 try to explain the observed
reactions. The primary nucleophilic attack [8,9] of
the phosphite on C-1, with subsequent ring open-
ing of 1, gives the zwitterion 8 [8,9]. Stabilization
of 8 may be attained in two different ways. The first
one is by partial hydrolysis of 8, which affords the
keto phosphonate 9. Deoxygenation followed by cy-
clization of the proposed carbene intermediate 10
gives the phosphonates 5a–c. Formation of the car-
bene intermediate and its transformation into sim-
ilar phosphono-substituted heterocycles has been
previously reported for the reaction of ꢀ-keto phos-
phonates with trialkyl phosphites [10,11].
The second pathway for stabilization of 8 is the
intradeoxygenation of the nitroso function, yielding
3-oxoisoindole 11 (also known as 3-oxoisoindoline)
with concomitant extrusion of trialkyl phosphate.
Reductive cyclization of the nitroso function with
phosphites has been reported [11a]. The reaction
of 11 with a second phosphite species would lead
to the formation of the ylidic phosphonate 13a–c
via the carbene intermediate 12. Trialkyl phosphites
are known to be efficient traps for carbenes, leading
to ylide formation [12]. While the trismethoxyphos-
phonium ylide 13a tended to rearrange to the cor-
responding phosphonate 6a under the conditions
needed for this formation, trisethoxy- and trisiso-
propoxy ylide analogs 13b,c were much more re-
sistant to such rearrangement. Therefore, a compet-
ing side reaction was observed for the case of 13b,c,
leading to the formation of 7. This arose because of
the ability of 13b,c to function as Wittig reagents
and to intercept the 3-oxoisoindole 11. At relatively
SCHEME 2
◦
high temperature (160–170 C), the Wittig reaction
between 13b,c and 11 predominates to give 7 as
the major product. Notwithstanding, an alternative
pathway for the formation of 7 by direct dimeriza-
tion [10c] of the carbene 12 cannot be ruled out. The
attack by three-valence phosphorus on the carbonyl-
oxygen of cyclic anhydrides, phthalyl anhydride, was
previously reported by Ramirez et al. [10b,c]. The re-
action resulted in a deoxygenation coupling of the
substrate through the carbene intermediate.
Finally, the hypothesis that a carbene 12 is gen-
erated during the reaction of trialkyl phosphites with
oxazinone 1 is sufficient to explain the formation
of isoindolinyl-1-phosphonates 6b,d,f (R1 = H). It
SCHEME 1
SCHEME 3

Phosphono-Substituted Isoindolines and Indoles from 2,3- and 2,4-Benzoxazin-1-ones 79
seemed likely that such products resulted from a
or hydrolyzed to dimethyl phosphonate. However,
yields are lower and the side-reactions (formation
of 5a and 6b) are more noticeable.
small amount of water or of dialkyl phosphonates
4a–c being present in the reaction mixture. It is
noteworthy that, the formation of 6 in 1,2-addition
rather than the expected 1,1-addition is consistent
with the literature. Thus, stabilization of isoindolines
by steric protection, particularly in the presence of
substituents at the 1- and 3-positions, is well estab-
lished [13].
In the absence of trialkyl phosphite, the reac-
tion of 1 with dialkyl phosphonates 4a–c proceeded
only when a trace amount of aqueous solution NaOH
(5%) was present in the medium, giving the respec-
tive 4-(4-methylphenyl)-3-alkyl-4H-2,3-benzoxazin-
1-one 14a–c as a sole reaction product in 60–70%
yield (Scheme 4).
In summary, the findings from the reactions of
2,3-oxazinone 1 with alkyl phosphites, which have
been reported in the present investigation, or with
alkylidene phosphoranes that were reported in the
earlier work [8], highlight the initial attack by the nu-
cleophilic tri- and pentavalent phosphorus reagents
on the carbonyl-carbon in 1. However, the mode of
further transformations would vary with the elec-
tronic characteristics of the phosphorus reagent.
Considering the previous report [8], the common
feature of the reactions of phosphorus ylides with
1 seemed to be proceeding via an ionic mecha-
nism. Conversely, the involvement of the carbene
intermediate in the reactions of 1 with TAP is the
driving force for the formation of the final prod-
ucts 5–7. Furthermore, the formation of only the di-
alkyl phosphonates 6b,d,f, only from the reaction
of 1 with TAP is a conclusive evidence for the in-
volvement of the carbene intermediate 12. Dialkyl
phosphonates themselves acted as reducing agents
[10c] toward 1 (Scheme 4). Other features of inter-
est in the results of the reactions of 1 and 3a–c are
(a) The bisisoindolinyl condensation required ele-
vated temperatures and (b) TMP was a very poor
reagent. This was attributed to a lower reaction
temperature and to a relatively rapid disappear-
ance of the phosphite, which had been converted
into dimethyl methyl phosphonate [P(O)Me(OMe)2]
We next studied the reactions between 2 and
alkyl phosphites 3 and 4, and the products obtained
are depicted in Schemes 5 and 6. Thus, oxazinone
2 and trimethyl phosphite (TMP, 3a), when heated
at 100–105 ◦C for 12 h, gave dimethyl 2-phenyl-
N-methylindolyl-3-phosphonate (19a) and dimethyl
2-phenylindolyl-3-phosphonate (19b) in equal yields
(∼32%). Similarly, the reaction products of 2 with
triethyl phosphite (TEP, 3b) were assigned analo-
gous structures 19c (42%) and 19d (28%). Con-
versely, the reaction of 2 with triisopropyl phosphite
(3c) afforded only the vinyl phosphonate 19e (68%).
Treatment of 19b with methyl iodide in acetone, in
the presence of anhydrous potassium carbonate, af-
forded the expected product 19a (Scheme 5).
The formation of 19a–e resulted from the initial
production of the dipolar species 15 [14,15], which
is an analog to the intermediate 8 (Scheme 2). Fur-
ther intramolecular group translocation gave the in-
termediate 16, whereas a partial hydrolysis yielded
17. The absence of N-isopropyl derivative was not
unexpected since the bulky isopropyl group could
impede the Arbusov reaction. Reaction of 16 with
a second phosphite species 3 afforded the epox-
ide intermediate 18 [11a]. Deoxygenation of 18 by
further phosphite molecule yielded the products
19a,c. Deoxygenation of epoxides to olefins with
phosphites has been reported [16]. In the same man-
ner, the phosphonates 19b,d,e (R1 = H) were derived
from the intermediate 17.
SCHEME 4
SCHEME 5

80 Abdou, Kamel, and Khidre
using hexane-CHCl3 as the eluent to give compounds
6a, 5a, and 6b, respectively.
Dimethyl 3-(4-methylphenyl)-N-methylisoindoly-
l-phosphonate (6a) was obtained (9:1 v/v) as color-
less crystals (250 mg, 18%), m.p. 110–112◦C (from
pentane). Found: C, 65.53; H, 6.05; N, 4.19; P, 9.34.
C18H20NO3P (329.35) requires C, 65.64; H, 6.12; N,
4.25; P, 9.41%; νmax (KBr) (cm−1) 2920 (H3C N),
1252 (P O), 1080 (P O C); δH (CDCl3): 2.42 (s, 3H,
H C Ph), 3.27 (s, 3H, H C N), 3.89 (d, JH.H 11.2 Hz,
SCHEME 6
3
3
In a systematic study, the reaction of 2 with di-
alkyl phosphonates 4a–c was completed in the pres-
ence of a trace amount of aqueous solution (5%
NaOH) to give the respective 3-alkyl-4-phenyl-4H-
2,4-benzoxazin-1-one 20a–c (50–60%) (Scheme 6),
similar as in Scheme 4.
The structures suggested for all new compounds
are in good agreement with their analytical and spec-
troscopic data.
Finally, the present work describes an efficient
and simple synthesis of a variety of phospho-
nate derivatives in satisfactory yields. This general
method consists of suitable application of the ap-
propriate phosphite ester with benzoxazinones. Fur-
thermore, the new isoindole-phosphonates 6a–f and
indole-phosphonates 19a–e might be useful for phar-
maceutical and biological purposes as it is widely
realized that the activity of certain natural products,
drugs, and pesticides owes much to the presence of
an isoindoline nucleus [17,18] or indole species in
their molecules [19].
6H, H COP), 7.42-7.48 (m, 3H, H Ph), 7.52–7.58 (m,
3
3H, H Ph), 7.95, 8.25 (2dd, JH.H 2.7 Hz, 2H, H Ph);
δc (CDCl3): 22.2 (CH3 Ph), 31.2 (CH3 N), 55.4 (d,
JC.P 6.6 Hz, CH3O P), 127.31 (d, JC.P 145 Hz, 1-C P),
123.5, 124.2, 126.7, 127.3, 129.6, 131.5, 136.8 (3-
C Ar, C6H4, and C6H4 Me); δp (CDCl3) 29.77; m/z
(EI) (%): 329 (33) [M+], 314 (22), 223 (36), 205 (100),
109 (64), 91 (16).
Dimethyl 4-(4-methylphenyl)-1H-benzoxazin-1-
yl-phosphonate (5a) was obtained (7:3 v/v) as col-
orless needles (419 mg, 30%), m.p. 122–124◦C (from
cyclohexane). Found: C, 61.69; H, 5.41; N, 4.14; P,
9.28. C17H18NO4P (331.3) requires C, 61.63; H, 5.48;
N, 4.23; P, 9.35%; νmax (KBr) (cm−1) 1610 (C N),
1256 (P O), 1082 (P O C); δH (CDCl3): 2.41 (s, 3H,
H C Ph), 3.88 (d, JHP 11.2 Hz, 6H, H COP), 4.39 (d,
3
3
JHP 18 Hz, 1H, 1-CH P), 7.44–7.49 (m, 3H, H Ph),
7.53–7.61 (m, 3H, H Ph), 7.98, 8.34 (2dd, J 2.5, 3.6
Hz, 2H, H Ph); δC (CDCl3): 22.4 (CH3 Ph), 42.4 (d,
JC.P 136.8 Hz, 1-C P), 55.8 (d, JC.P 7.5 Hz, CH3O),
124.3, 124.8, 126.3, 127.8, 128.9, 131.5 (C6H4 and
C6H4 Me), 133.4 (4-C Ar); δp (CDCl3): 29.47; m/z
(EI) (%): 331 (42) [M+], 330 (27), 314 (36), 223 (18),
221 (17), 205 (100), 109 (68), 91 (13).
EXPERIMENTAL
Dimethyl 3-(4-methylphenyl)isoindolyl-1-phos-
phonate (6b) was obtained as colorless crys-
tals (290 mg, 22%), m.p. 136–138◦C (CHCl3-light
petroleum, 1:1). Found: C, 64.83; H, 5.61; N, 4.47;
P, 9.72. C17H18NO3P (315.3) requires C, 64.76; H,
5.75; N, 4.44; P, 9.82%; νmax (KBr) (cm−1) 3267 (NH),
1262 (P O), 1081 (P O C); δH (CDCl3): 2.43 (s,
3H, H C Ph), 3.88 (d, JHH 11.2 Hz, 6H, H COP),
7.27–7.35 (m, 3H, H Ph), 7.44–7.68 (m, 3H, H Ph),
7.93, 8.36 (2dd, JHH 2.7 Hz, 2H, H Ph), 12.26 (s br,
1H, NH, deuterium exchangeable); δC (CDCl3) 22.2
(CH3 Ph), 55.6 (d, JC.P 7.5 Hz, CH3 O P), 127.5
(d, JC.P 143 Hz, 1-C P), 123.5, 124.3, 126.4, 127.1,
129.5, 131.2, 136.2 (3-C Ar, C6H4, and C6H4 Me); δp
(CDCl3) 29.92; m/z (EI) (%): 315 (62) [M+], 314 (24),
223 (55), 205 (100), 109 (60), 91 (20).
The melting points are uncorrected. The IR spec-
tra were recorded on a Perkin Elmer spectropho-
tometer model 297 (Grating), using KBr discs. The
1H and 13C NMR spectra were run in CDCl3 or
DMSO-d6 as solvents on a Jeol-270 MHz instru-
ment, using SiMe4 as an internal reference. The
31P NMR spectra were recorded relative to exter-
nal H3PO4 (85%) with a Varian CFT-20 instrument.
The mass spectra were performed at 70 eV on a
Shimadzu GCS-QP 1000 EX spectrometer provided
with a data system. The appropriate precautions
in handling moisture-sensitive compounds were ob-
served. Solvents were dried by standard techniques.
Light petroleum refers to the fraction 40–60◦C.
3
3
Reaction of 1 with Trimethyl Phosphite (3a)
A mixture of 1.00 g (4.21 mmol) 1 [20] and 5 ml
3a was heated at 100–105◦C for 15 h. After removal
of the volatile materials under reduced pressure, the
residue was purified by chromatography on silica gel
Reaction of 1 with Triethyl Phosphite (3b)
A mixture of 1.00 g (4.21 mmol) 1 and 5 ml 3b
was heated at 100–105◦C for 12 h (TLC). Excess of

Phosphono-Substituted Isoindolines and Indoles from 2,3- and 2,4-Benzoxazin-1-ones 81
the phosphite was removed under reduced pressure
126.7, 127.3, 129.5, 131.3, 136.4 (3-C Ar, C6H4, &
C6H4 Me); δp (CDCl3): 30.62; m/z (EI) (%): 343 (39)
[M+], 342 (14), 251 (22), 205 (100), 137 (66), 91 (11).
Bisisoindolinylidene (7) was obtained (1:9 v/v) as
yellow leaflets (155 mg, 9%), m.p. 188–190◦C (from
C2H5OH). Found: C, 87.87; H, 5.43; N, 6.88. C30H22N2
(410.50) requires C, 87.78; H, 5.40; N, 6.82%; νmax
(KBr) (cm−1) 1624 (C C, exocyclic), 1595 (C N); δH
and the residue was chromatographed on silica gel,
gradient eluting from 1% to 10% CHCl3 in hexane,
yielded compounds 6c, 5b, 6d, and 7, respectively.
Diethyl 3-(4-methylphenyl)-N-ethylisoindolyl-1-
phosphonate (6c) was obtained (9:1 v/v) as colorless
crystals (438 mg, 28%), m.p. 98–100◦C (from cyclo-
hexane). Found: C, 67.98; H, 7.11; N, 3.72; P, 8.25.
C21H26NO3P (371.41) requires C, 67.91; H, 7.05; N,
3.77; P, 8.34%; νmax (KBr) (cm−1) 2915 ( N Et), 1255
(P O), 1055 (P O C); δH (CDCl3): 1.35 (dt, JH.H 7.5,
(d6-DMSO) 2.32, 2.40 (2s, 2 × 3H, H C Ph), 7.27–
3
7.95 (m, 16H, H Ph); m/z (EI) (%): 410 (100) [M+],
319 (24), 228 (38), 205 (71), 182 (14).
JH.P 2.7 Hz, 6H, H C C OP), 1.44 (t, JH.H 6.5 Hz,
When the same reaction (1 + 3b) was repeated
in boiling triethyl phosphite for 10 h, only 6d and 7
were isolated in 20 and 50% yields, respectively.
3
3H, H C C N), 2.49 (s, 3H, H C Ph), 3.56 (q, JHH
3
3
6.5 Hz, 2H, H C N), 3.89 (dq, JHH 7.5 Hz, JH.P 3.5
2
Hz, 4H, H C OP), 7.41–7.49 (m, 3H, H Ph), 7.50–
2
7.53 (m, 3H, H Ph), 7.93, 8.28 (2dd, JHH 2.4, 2.8 Hz,
2H, H Ph); δC (CDCl3): 15.8 (CH3CH2N), 16.2 (d, JC.P
5.5 Hz, CH3-C O P), 22.3 (CH3 Ph), 40.7 (CH2N),
61.5 (d, JC.P 7.5 Hz, CH2OP), 121.6 (d, JC.P 145 Hz, 1-
C P), 123.5, 124.4, 126.7, 127.6, 129.2, 131.8, 136.8
(3-C Ar, C6H4, & C6H4-Me); δp (CDCl3) 29.77; m/z
(EI) (%): 371 (29) [M+], 342 (47), 251 (27), 205 (100),
137 (58), 91 (18).
Diethyl 4-(4-methylphenyl)-1H-benzoxazin-1-yl-
phosphonate (5b) was obtained (7:3 v/v) as color-
less needles (242 mg, 16%), m.p. 115–117◦C (from
benzene-pentane, 1:2 v/v). Found: C, 63.59; H, 6.11;
N, 3.84; P, 8.55. C19H22NO4P (359.36) requires C,
63.50; H, 6.17; N, 3.90; P, 8.62%; νmax (KBr) (cm−1)
1605 (C N), 1258 (P O), 1100 (P O C); δH (CDCl3)
Reaction of 1 with Triisopropyl Phosphite (3c)
Similarly compounds 6e, 5c, 6f, and 7 were isolated
upon heating a mixture of 1.00 g (4.21 mmol) 1 and
5 ml 3c at 105–110◦C for 12 h; followed by the usual
working up.
Diisopropyl 3-(4-methylphenyl)-N-isopropyliso-
indolyl-1-phosphonate (6e) was obtained (9:1 v/v)
as colorless crystals (435 mg, 24%), m.p. 92–94◦C
(from diethyl ether-light petroleum, 1:1 v/v). Found:
C, 69.77; H, 7.72; N, 3.32; P, 7.58. C24H32NO3P
(413.45) requires C, 69.72; H, 7.79; N, 3.39; P,
7.49%; νmax (KBr) (cm−1) 2915 ( N CHMe2), 1248
(P O), 1050 (P O C); δH (CDCl3): 0.88 (d, JH.H
6.3 Hz, 6H, (H C)2CHN), 1.26 (d, JH.H 6.3 Hz, 12H,
3
1.38 (dt, JH.H 7.5, JH.P 2.7 Hz, 6H, H C C OP), 2.38
(H C)2CO), 2.42 (s, 3H, H C Ph), 3.51 (sept, JHH
3
3
3
(s, 3H, H C Ph), 3.95 (dq, JHH 7.5, JH.P 3.4 Hz, 2H,
6.3 Hz, 1H, NCHMe2), 3.87–3.98 (d.sept, JH.P 7.5 Hz,
2H, OCHMe)2), 7.47–7.49 (m, 3H, H Ph), 7.51–7.52
(m, 2H, H Ph), 7.96, 8.29 (2dd, JH.H 2.5 Hz, 2H,
H Ph); δp (CDCl3): 27.43; m/z (EI) (%): 413 (15) [M+],
470 (36), 279 (14), 205 (100), 165 (55), 91 (33).
Diisopropyl 4-(4-methylphenyl)-1H-benzoxazin-
1-yl-phosphonate (5c) was obtained (8:2 v/v) as col-
orless needles (295 mg, 18%), m.p. 109–110◦C (from
cyclohexane). Found: C, 55.19; H, 6.70; N, 3.54; P,
8.08. C21H26NO4P (387.41) requires C, 55.11; H, 6.76;
N, 3.62; P, 8.00%; νmax (KBr) (cm−1) 1587 (C N),
1258 (P O), 1080 (P O C); δH (CDCl3): 1.32, 1.37
3
H COP), 4.47 (d, JH.P 18 Hz, 1H, 1-CH P), 7.47–7.49
2
(m, 3H, H Ph), 7.50–7.51 (m, 3H, H Ph), 7.97, 8.31
(2dd, JHH 2.5 Hz, 2H, H Ph); δC (CDCl3): 16.4 (d,
JC.P 5.5 Hz, CH3 C O), 22.4 (CH3 Ph), 44.3 (d, JC.P
139.3 Hz, 1-C P), 61.4 (d, JC.P 7.4 Hz, CH2 OP),
123.7, 124.2, 126.3, 127.6, 128.3, 131.5, 136.7 (4-
C Ar, C6H4, & C6H4 Me); δp (CDCl3): 30.41; m/z (EI)
(%): 359 (21) [M+], 358 (11), 251 (40), 221 (20), 205
(100), 137 (22), 91 (19).
Diethyl 3-(4-methylphenyl)isoindolyl-1-phosph-
onate (6d) was obtained as colorless crystals
(245 mg, 17%), m.p. 128–130◦C (from CH2Cl2).
Found: C, 66.55; H, 6.42; N, 4.03; P, 9.10. C19H22NO3P
(343.36) requires C, 66.46; H, 6.46; N, 4.08; P, 9.02%;
νmax (KBr) (cm−1) 3245 (NH), 1245 (P O), 1085
(P O C); δH (CDCl3): 1.38 (dt, JH.H 7.2, JH.P 2.9 Hz,
6H, H C C OP), 2.39 (s, 3H, H C Ph), 4.01 (dq,
(2d, JH.H 6.3 Hz, 12H, (H C)2CHOP), 4.16–4.22 (d
3
sept, JH.P 7.5 Hz, 2H, OCHMe2), 4.46 (d, JH.P 15.6
Hz, 1H, 1-CH P), 7.38–7.40 (m, 3H, H Ph), 7.49–
7.51 (m, 3H, H Ph), 7.90, 8.28 (2dd, JH.H 2.4 Hz,
2H, H Ph); δC (CDCl3): 20.6, 20.9 (2d, JC.P 6.0 Hz,
(CH3)2C O), 22.77 (CH3 Ph), 46.3 (d, JC.P 156 Hz, 1-
C P), 123.1, 124.8, 126.5, 129.2, 130.7, 131.3, 137.6
(4-C Ar, C6H4, and C6H4 Me); δp (CDCl3): 29.5; m/z
(EI) (%): 387 (37) [M+], 386 (23), 370 (14), 221 (20),
205 (100), 165 (58), 91 (15).
3
3
JHH 7.2, JH.P 3.4 Hz, 6H, H COP), 7.42–7.44 (m, 3H,
2
H Ph), 7.48–7.49 (m, 3H, H Ph), 7.97, 8.28 (2dd,
JHH 2.7 Hz, 2H, H Ph), 12.22 (s br, 1H, NH, deu-
terium exchangeable); δC (CDCl3): 15.95 (d, JC.P 5.5
Hz, CH3 C O), 22.37 (CH3 Ph), 62.8 (d, JC.P 7.2 Hz,
CH2OP), 127.2 (d, JC.P 145.8 Hz, 1-C P), 122.4, 124.1,
Diisopropyl 3-(4-methylphenyl)isoindolyl-1-ph-
osphonate (6f) was isolated (7:3 v/v) as colorless

82 Abdou, Kamel, and Khidre
crystals (200 mg, 13%), m.p. 112–113◦C (from di-
ethyl ether). Found: C, 67.85; H, 7.01; N, 3.71; P,
8.42. C21H26NO3P (371.43) requires C, 67.91; H, 7.06;
N, 3.77; P, 8.34%; νmax (KBr) (cm−1) 3260 (NH),
1252 (P O), 1060 (P O C); δH (CDCl3): 1.36 (d,
3.82 (q, JH.H 6.4 Hz, 2H, H C N), 4.65 (s, 1H, 4-CH),
2
7.42–7.45 (m, 3H, H Ph), 7.48–7.49 (m, 3H, H Ph),
7.92, 8.26 (2dd, JH.H 2.5 Hz, 2H, H Ph); δC (CDCl3):
15.8 (CH3CH2 N), 22.1 (CH3 Ph), 43.6 (CH2 N),
47.2 (4-CHAr), 121.7, 122.4, 124.9, 126.1, 127.2,
130.6, 131.7 (C6H4 & C6H4 Me), 178.6 (1-C O); m/z
(EI) (%): 267 (100) [M+], 266 (29), 237 (22), 221
(36), 205 (67), 91 (18).
4-(4-Methylphenyl)-N-isopropyl-4H-2,3-benzox-
azin-1-one (14c) was obtained as pale yellow
crystals (685 mg, 58%), m.p. 122–124◦C (from ace-
tone). Found: C, 76.89; H, 6.86; N, 4.92. C18H19NO2
(281.35) requires C, 76.84; H, 6.81; N, 4.98%;
νmax (KBr) (cm−1) 2935 (N C3H7), 1770 (C O);
JH.H 6.3 Hz, JH.P 2.7 Hz, 12H, (H C)2CHOP), 2.39 (s,
3
3H, H C Ph), 4.03–4.08 (d sept, JH.P 10.3 Hz, 2H,
3
OCHMe2), 7.41–7.44 (m, 3H, H Ph), 7.48–7.49 (m,
3H, H Ph), 7.93, 8.32 (2dd, JH.H 2.6 Hz, 2H, H Ph),
12.28 (s.br, 1H, HN, deuterium exchangeable); δp
(CDCl3): 30.20; m/z (EI) (%): 371 (40) [M+], 370 (21),
279 (18), 205 (100), 165 (55), 91 (18).
Bisisoindolinylidene (7) was next obtained
(1:9 v/v) in a pure form (170 mg, 10%), m.p., and
mixed m.p., and comparative IR and mass spectra
with that previously obtained.
δH (CDCl3) 1.58 (d, JH.H 7.2 Hz, 6H, (CH )2-CHN),
3
2.42 (s, 3H, H C Ph), 3.98 (sept., JH.H 7.2 Hz, 1H,
3
When the same reaction (1 + 3c) was repeated
at the boiling temperature of triisopropyl phosphite
for 10 h, only 6f and 7 were isolated in 18 and 55%
yields, respectively.
HCMe2N), 4.68 (s, 1H, 4-CH), 7.45–7.47 (m, 3H,
H Ph), 7.48–7.49 (m, 3H, H Ph), 7.92, 8.31 (2dd,
JH.H 2.7 Hz, 2H, H Ph); m/z (EI) (%): 281 (100)
[M+], 280 (20), 237 (26), 221 (30), 205 (60), 91 (22).
Reaction of 2 with Trialkyl Phosphites 3a–c
Reaction of 1 with Dialkyl Phosphonates 4a–c
A mixture of 1.00 g (4.48 mmol) 2 [21] and 5 ml tri-
alkyl phosphite (trimethyl-, triethyl, or triisopropyl
phosphite (3a–c) was heated at 100–110◦C for 12 h.
After removal of the excess phosphite, the residue
was chromatographed on silica gel using hexane-
CHCl3 as the eluent.
To a mixture of 1.00 g (4.21 mmol) 1 and
dimethyl-, diethyl or diisopropyl phosphonate
(4a–c) (6.00 mmol) in 20 ml toluene was added 2 ml
of freshly prepared NaOH solution (5%). The reac-
tion mixture was refluxed for 10 h. After the removal
of the volatile materials in vacuo, the oily residue
left behind was treated with light petroleum ether.
The solid product, thus obtained was crystallized
from the appropriate solvent to give 14a, 14b, or
14c.
Reaction with 3a
Dimethyl 3-phenyl-N-methylindolyl-1-phosphonate
(19a) was obtained (9:1 v/v) as colorless crystals
(438 mg, 31%), m.p. 98–100◦C (from diethyl ether).
Found: C, 64.84; H, 5.73; N, 4.38; P, 9.91. C17H18NO3P
(315.32) requires C, 64.76; H, 5.75; N, 4.44; P, 9.82%;
νmax (KBr) (cm−1) 2918 (Me-N), 1235 (P O), 1086
(P O C); δH (CDCl3): 3.65, 3.69 (2d, JH.H 10 Hz,
4-(4-Methylphenyl)-N-methyl-4H-2,3-benzoxa-
zin-1-one (14a) was isolated as pale yellow crystals
(675 mg, 72%), m.p. 132–134◦C (from n-hexane).
Found: C, 75.94; H, 5.92; N, 5.44. C17H17NO2 (253.3)
requires C, 75.87; H, 5.97; N, 5.53%; νmax (KBr)
(cm−1) 2920 (N-Me), 1758 (C O); δH (CDCl3): 2.47
(s, 3H, H C Ph), 3.17 (s, 3H, H C N), 4.64 (s, 1H,
6H, (H CO)2P), 7.48–7.57 (m, 3H, H Ph), 7.68–7.82
3
(m, 3H, H Ph), 8.23, 8.46 (2d, JH.H 2.7 Hz, H Ph);
δC (CDCl3): 33.2 (N CH3), 54.72, 55.3 (2 × CH3OP),
105.7 (d, JC.P 136.8 Hz, 2-C P), 122.2, 122.6, 124.1,
124.5, 126.6, 126.9, 129.1, 131.8 (C6H5 & C6H4), 142.5
(2-C Ph); δp (CDCl3) 33.41; m/z (EI) (%): 315 (15)
[M+], 300 (11), 206 (23), 191 (38), 109 (24), 105
(100).
Dimethyl 3-phenylindolyl-1-phosphonate (19b)
was obtained (8:2 v/v) as colorless crystals (445 mg,
33%), m.p. 147–149◦C (from C2H5OH). Found: C,
63.72; H, 5.28; N, 4.60; P, 10.34. C16H16NO3P (301.29)
requires C, 63.78; H, 5.35; N, 4.65; P, 10.28%;
νmax (KBr) (cm−1) 3279 (NH), 1248 (P O), 1028
(P O C); δH (CDCl3): 3.74, 3.78 (2d, JH.H 10.6 Hz,
3
3
4-CH), 7.41–7.42 (m, 3H, H Ph), 7.48–7.50 (m, 3H,
H Ph), 7.92, 8.28 (2dd, JH.H 2.5 Hz, 2H, H Ph); δC
(CDCl3): 24.4 (CH3 Ar), 31.4 (CH3 N), 42.6 (4-C),
121.8, 122.6, 124.2, 124.6, 126.8, 130.9, 133.4 (C6H4
& C6H4 Me), 182.4 (1-C O); m/z (EI) (%): 253
(100) [M+], 252 (13), 237 (29), 221 (55), 205 (37), 91
(13).
4-(4-Methylphenyl)-N-ethyl-4H-2,3-benzoxazin-
1-one (14b) was obtained as pale yellow crystals
(766 mg, 68%), m.p. 115–117◦C (from cyclohex-
ane). Found: C, 76.32; H, 6.33; N, 5.18. C17H17NO2
(267.32) requires C, 76.38; H, 6.41; N, 5.24%; νmax
(KBr) (cm−1) 2915 (N Et), 1764 (C O); δH (CDCl3):
1.33 (t, JH.H 6.4 Hz, CH C N), 2.44 (s, 3H, H C Ph),
6H, (H CO)2P), 7.47–7.57 (m, 3H, H Ph), 7.66–7.84
3
3
3

Phosphono-Substituted Isoindolines and Indoles from 2,3- and 2,4-Benzoxazin-1-ones 83
(m, 3H, H Ph), 8.15, 8.46 (2d, JH.H 2.75 Hz, 2H,
68%), m.p. 147–149◦C (from acetone). Found: C,
67.28; H, 6.71; N, 3.84; P, 8.65. C20H24NO3P (357.4) re-
quires C, 67.21; H, 6.77; N, 3.92; P, 8.67%; νmax (KBr)
(cm−1) 3278 (NH), 1228 (P O), 1008 (P O C); δH
H Ph), 11.84 (s, 1H, HN, deuterium exchangeable);
δp (CDCl3): 33.26; m/z (EI) (%): 301 (42) [M+], 192
(23), 109 (24), 105 (100).
(CDCl3): 1.16, 1.18 (2d, JH.H 6.2 Hz, 12H, (H C)2CH),
3
4.73–4.79 (d.sept, JH.H 6.2 Hz, JH.P 7.5 Hz, 2H,
OCHMe2), 7.54–7.58 (m, JH.H 4 Hz, 3H, H Ph), 7.79–
7.95 (m, 3H, H Ph), 8.69, 8.72 (2d, JH.H 4 Hz, 2H,
H Ph); δC (CDCl3): [21.6 (d, JC.P 6.5 Hz), 22.8 (d, JC.P
5 Hz, OCH(CH3)2], 70.6 (dd, JC.P 5.5 Hz, OCH(CH3)2),
110 (d, JC.P 145 Hz, 3-C), 122.4, 125.2, 125.7, 126.1,
131.6, 139.4, 144.5 (2-C, C6H4, and C6H5); δp (CDCl3):
31.81; m/z (EI) (%): 357 (52) [M+], 356 (18), 191 (43),
166 (33), 105 (100).
Methylation of the Phosphonate 19b
To a stirred solution of 0.5 g (1.58 mmol) 19b in
20 ml dry acetone was added 1.00 g of anhydrous
K2CO3. Stirring was continued at room temperature
for 1 h. Freshly distilled 0.3 g CH3I (2.16 mmol) was
then added and the mixture was gently heated un-
der reflux for 8 h. The inorganic and volatile materi-
als were removed to give a semi-solid, which solidi-
fied after being triturated with cold pentane to give
272 mg (52%) 19a, m.p. and mixed m.p. and com-
parative IR and mass spectra with that previously
obtained.
IV-Reaction of 2 with Dialkyl Phosphonates
4a–c
To a mixture of 1.00 g (4.48 mmol) 2 and dimethyl-,
diethyl-, or diisopropyl phosphonate (4a–c) (6.00
mmol) in 20 ml toluene, was added 2 ml of freshly
prepared NaOH solution (5%). The reaction mixture
was refluxed for 10 h. After the removal of the volatile
materials in vacuo, the residue was crystallized from
the appropriate solvent to give 20a, 20b, or 20c,
respectively.
N-Methyl-3-phenyl-3H-2,4-benzoxazin-1-one
(20a) was obtained as colorless needles (568 mg,
53%), m.p. 105–107◦C (from cyclohexane). Found: C,
75.35; H, 5.41; N, 5.79. C15H13NO2 (239.28) requires
C, 75.30; H, 5.48; N, 5.85%; νmax (KBr) (cm−1) 2920
(N-Me), 1764 (C O); δH (CDCl3): 3.31 (d, JH.H 2.2 Hz,
Reaction with 3b
Diethyl 3-phenyl-N-ethylindolyl-1-phosphonate (19c)
was obtained (9:1 v/v) as colorless crystals (672 mg,
42%), m.p. 62–64◦C (from pentane). Found: C, 67.11;
H, 6.72; N, 3.84; P, 8.74. C20H24NO3P (357.4) requires
C, 67.21; H, 6.77; N, 3.92; P, 8.67%; νmax (KBr) (cm−1)
1922 (Et N), 1238 (P O), 1080 (P O C); δH (CDCl3):
1.23 (t, JH.H 6.5 Hz, 3H, H C CN), 1.40–1.45 (m,
3
6H, H C C OP), 3.9 (q, 2H, H C N), 4.24–4.28 (2q
3
2
(m), 4H, H C OP), 7.58–7.63 (m, 3H, H Ph), 7.79–
2
8.05 (m, 3H, H Ph), 8.69, 8.72 (2d, JH.H 2.5 Hz,
2H, H Ph); δC (CDCl3): 15.7, 16.2, 16.5 [CH3-C N
& (H3C CO)2], 44.3 (H2C N), 59.4, 61.8 (POCH2),
98.9 (3-C P), 118.2, 121.2, 122.2, 124.8, 125.9, 129.6,
133.6, 137.4 (2-C Ph), C6H4, and C6H5); δp (CDCl3):
32.85; m/z (EI) (%): 357 (22) [M+], 328 (13), 220 (55),
191 (30), 137 (18), 105 (100).
Diethyl 3-phenylindolyl-1-phosphonate (19d)
was obtained (8:2 v/v) as colorless crystals (410 mg,
27%), m.p. 108–110◦C (from cyclohexane). Found: C,
65.71; H, 6.07; N, 4.17; P, 9.49. C18H20NO3P (329.35)
requires C, 65.64; H, 6.12; N, 4.25; P, 9.41%; νmax
(KBr) (cm−1) 3260 (NH), 1240 (P O), 1110 (P O C);
δH (CDCl3): 1.41, 1.44 (2dt, JH.H 6.7 Hz, JH.H 3.1 Hz,
3H, H C N), 5.01 (q, 1H, 3-CH Ph), 7.47–7.96
3
(m, 8H, H Ph); δC (CDCl3): 32.2 (H3C N), 49.5
(3-CH Ph), 118.6, 120.9, 121.2, 123.5, 125.4, 125.9,
126.28, 133.47 (C6H4 and C6H5), 205.6 (1-C O); m/z
(EI) (%): 239 (78) [M+], 224 (26), 162 (50), 147 (32),
77 (100).
N-Ethyl-3-phenyl-3H-2,4-benzoxazin-1-one (20b)
was obtained as colorless needles (680 mg, 60%),
m.p. 85–86◦C (from pentane). Found: C, 75.82; H,
5.90; N, 5.47. C16H15NO4 (253.30) requires C, 75.82;
H, 5.97; N, 5.53%; νmax (KBr) (cm−1) 2915 (N C2H5),
1764 (C O); δH (CDCl3): 1.55 (t, JH.H 7 Hz, 3H,
H C CH2 N), 3.92 (q, JH.H 7 Hz, 2H, CH N), 5.03
6H, (H C CH2O)2P), 4.22, 4.25 (2q, JH.P 11.2 Hz, 4H,
3
3
2
H C O), 7.53–7.56 (m, 3H, H Ph), 7.62–7.66 (m, 3H,
(s, 1H, 3-CH Ph), 7.47–7.98 (m, 8H, H Ph); m/z (EI)
(%): 253 (100) [M+], 237 (18), 224 (12), 208 (30), 176
(40), 147 (55), 77 (82).
N-isopropyl-3-phenyl-3H-2,4-benzoxazin-1-one
(20c) was obtained as colorless crystals (590 mg,
50%), m.p. 98–100◦C (from light petroleum). Found:
C, 76.43; H, 6.33; N, 5.17. C17H17NO2 (267.33)
requires C, 76.38; H, 6.41; N, 5.24%; νmax (KBr)
(cm−1) 2933 (N C3H7), 1760 (1-C O); δH (CDCl3):
2
H Ph), 8.11, 8.12 (2d, JH.H 2.5 Hz, 2H, H Ph), 12.06
(s, 1H, HN, deuterium exchang.); δp (CDCl3): 31.31;
m/z (EI) (%): 329 (36) [M+], 328 (16), 191 (29), 138
(18), 105 (100).
Reaction with 3c
Diisopropyl 3-phenylindolyl-1-phosphonate (19e)
was obtained (7:3 v/v) as colorless crystals (1.00 g,
1.62 (d, JH.H 8.0 Hz, 6H, i-H C C N), 4.40 (sept,
3

84 Abdou, Kamel, and Khidre
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JH.H 8.0 Hz, 1H, CH N), 7.45–8.11 (m, 8H, H Ph);
m/z (EI) (%): 267 (100) [M+], 251 (11), 237 (42), 190
(31), 177 (22), 160 (9), 77 (78).
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