Evaluation of N-hydroxymethylphthalimide in alkaline medium: Novel entry to the tricyclic [1,3]oxazepine core via an intramolecular π and O-cationic cyclization

Article abstract of DOI:10.1002/jhet.5570400314

Fused isoindolo[1,3]benzo(or thieno)oxazepines 8a,b and one of their positional isomers aromatic tricyclic N,O-acetals 13b are reported to occur efficiently in a three-step sequence from N-hydroxy-methylphthalimide (6). The key step of this methodology is the intramolecular arylation of an endocyclic and/or exocyclic N-acyliminium cation. The mechanism leading to these species, in particular to a tricyclic lactam 13b, is discussed.

Full text of DOI:10.1002/jhet.5570400314

Evaluation of N-Hydroxymethylphthalimide in Alkaline Medium:
Novel Entry to the Tricyclic [1,3]Oxazepine core via
an Intramolecular π and O-Cationic Cyclization
499
May-Jun 2003
a
b
a
Armelle Cul , Abderrahim Chihab-Eddine , Anthony Pesquet ,
ˇ
c
a
Stefan Marchalín and Adam Daïch *
a
Laboratoire de Chimie, URCOM, EA 3221, Faculté des Sciences & Techniques de l’Université du Havre,
B.P: 540, 25 Rue Philippe Lebon, F-76058 Le Havre Cedex, France
b
Laboratoire de Bio-Organique, Département de Chimie, Faculté des Sciences,
Université Ibnou Zohr, B.P:28/S, Agadir, Maroc
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
Received February 20, 2003
c
Fused isoindolo[1,3]benzo(or thieno)oxazepines 8a,b and one of their positional isomers aromatic
tricyclic N,O-acetals 13b are reported to occur efficiently in a three-step sequence from N-hydroxy-
methylphthalimide (6). The key step of this methodology is the intramolecular arylation of an endocyclic
and/or exocyclic N-acyliminium cation. The mechanism leading to these species, in particular to a tricyclic
lactam 13b, is discussed.
J. Heterocyclic Chem., 40, 499 (2003).
the 2-TfO- and 2-MsO-dibenzoxazepine analogues 3
exhibit clinically interesting properties as Clozapine-like
atypical antipsychotics [5]. Other compounds exemplified
by quino[1,4]benzoxazepines 4 which are structurally
closely related to the above, have good inhibitory activity
against the reverse transcriptase of HIV-1 [6]. Because of
the great potential of these types of structures, efforts
continue to be made particularly in the synthesis of a new
class of [1,4]benzoxazepines 5 in which a pyrrolidinone
[7,8] or isoindolone [7] moiety constitutes a nitrogen atom
source.
However, if fused [1,4]benzoxazepines are well
documented, the structurally related [1,3]benzoxazepines
fused to aromatic or non aromatic ring are little known a
fact that is reflected in the few reports in the literature of
their syntheses, uses and biological evaluation. To date,
several synthetic routes for their elaboration have been
described: The most versatile strategy to accede this type
of N,O-heterocycles, is the cyclodehydration reaction
between a dicarbonyl compound and an amino-alcohol [9].
Palladium catalyzed heteroannulation cascades of allenes
[10], and aryl(or alkyl)thio radicals [11] and cationic [12]
cyclizations involving N-acyliminium precursors are other
approaches reported. In all these cases, the reported
[1,3]oxazepines belong to the 7,5-fused bicyclic lactams
commonly known as N,O-acetals which have been used
principally as important synthetic intermediates to accede
Morphan alkaloid cores [9a] and (+)-Adalinine alkaloids
[9b], and as valuable building blocks for peptidomimetics
[12b], respectively.
Introduction.
The development of simple and general synthetic routes
for wide ranges of organic compounds from readily avail-
able reactants constitutes one of the major challenges in
modern organic chemistry. Seven-membered ring systems
containing two heteroatoms (N and O), such as the
oxazepines, are key classes of organic products with
numerous applications in biology. In fact, [1,4]benzox-
azepines with such scaffolds such as the well-established
representatives Loxapine (1) [1] and Amoxapine (2) [2]
are neuroleptics with a general pattern of pharmacological
activity [1], including both neuroleptic [2] and antidepres-
sant activity [3,4], respectively (Scheme 1). Furthermore,
Results and Discussion.
In the course of our continuing efforts towards the eval-
uation of N-arylthioalkylimides [13] and N-aryl-
oxoalkylimides [14] functionalities in acidic medium, we
report herein our preliminary findings from our investiga-
tions on N-arylmethyloxomethylphtalimides as N-acyl-
iminium ions precursors under acid conditions. To our

500
Vol. 40
A. Cul, A. Chihab-Eddine, A. Pesquet, Sˇ. Marchalín and A. Daïch
knowledge no work has been done on the chemistry of
these systems, and interestingly, all studies in this area
concern only the N-phenyloxoethylimides [7,8], with the
exception of our previous work dealing with the synthesis
of isoindolo[1,3]benzoxazines using N-chloromethyl-
phthalimide (7) as starting metrial [14].
Attempts to extend this reaction to heteroaromatic, alkyl,
functionalized alkyl, functionalized aromatic and function-
alized heteroaromatic halides was successful and produced
only the corresponding N-alkylated products 9b (75%)
[18], 9c (49%) [19], 9d (58%) [20], 9e (69%) [21], and 9f
(71%) [21], respectively. In light of these results, its seems
that the imidate anion D is more stable than the alcoholate
one C under basic conditions at these temperatures.
Furthermore taking into account that Wada et al. [22],
has esterified alcohol 6, without loss of formalin, with acid
chloride derivative at 0 °C in the presence of triethylamine
as base, the reaction of alcohol 6 with benzyl chloride and
a base was examined again at different temperatures. Even
if at –5 to +60 °C we isolated exclusively the above
N-alkylated product 9a. When the temperature was
decreased at –25 to –20 °C, in contrast, the O-alkylation
occurred leading to the expected product 10a in 65% yield
[23]. It is worth mentioning that under these conditions
more than 48 h of reaction was necessary and, in all runs,
the O-alkylated product 10a was accompanied with small
amounts of the N-alkylated product 9a [24].
As our tricyclic benzoxazepine targets could be obtained
from N-hydroxymethylphthalimide (6) or corresponding
halides 7, via the π-cationic cyclization of the N-acylim-
inium ion intermediates A shown in Scheme 1, our initial
experiments have centred on the evaluation of the reactivity
of N-hydroxymethylphthalimide (6). The behaviour of sub-
strates 6 and 7, in acidic medium, is well-established and
leads to the exocyclic N-acyliminium ion B which can be
trapped by various external aryl systems to furnish
N-aralkylphthalimides 9a-f in good yields (Scheme 2) [15].
Since N-hydroxymethylphthalimide (6) reacts with
amines as a nitrogen base (R R NH) without additional
1
2
co-solvent, to give successfully, via dehydration, only the
N,N-dialkylaminomethylphthalimide [16], the coupling of
alcohol 6 with halide (RX) in the presence of a mineral
base was examined. To our surprise benzyl chloride with
1.2 equiv. of sodium methoxide in dry DMF at room tem-
perature for 6 h of reaction, give only the well-known N-
benzylphthalimide (9a) in appreciable 73% yield [17]. In
spite of the apparent simplicity of this process which
required the transformation of the alkoxide C into the cor-
responding imidate D as the consequence of the extrusion
of formalin (see Scheme 3) followed by a nucleophilic dis-
placement of halide with the nitrogen atom of D, several
experimental parameters were considered. Thus, the varia-
tion of the solvent (THF, 1,4-dioxane) and the nature of the
Application of this procedure to 3-bromomethylthio-
phene, similarly, give a N-(thien-3-yl-methyloxomethyl)-
phthalimide (10b) as the sole reaction product in 79%
base (K CO , NaH) did not change the reaction profile,
2
3
and in all these combinations only the N-alkylated product
9a resulting from a tandem formalin elimination/nucle-
ophilic substitution was isolated in comparable yield.

May-Jun 2003
Evaluation of N-Hydroxymethylphthalimide in Alkaline Medium
501
yield. Mechanistically, it appears that the decomposition of
alcoholate C into imidate D (Scheme 3) is not effective
since the alcoholate, which is required for the O-alkylation
process, is more stable at lower temperature [25].
Having isolated the O-alkylated imides 10a,b, the
regioselective reduction of one carbonyl of imide function
[27] under various conditions afforded in term two
kinds of compounds (Scheme 4) and the results are
summarized in Table 1.
These results deserve comment. Contrary to N-aryloxo-
methylamidals which led exclusively to isoindolo[1,3]-
benzoxazines [14], α-hydroxylactam 11a used in this work
gives a mixture of two products which were identified as
the isoindolo[1,3]benzoxazepine 8a and the N,O-diacetal
12a. The ratio and yield of these depend on the reaction
temperature (entries 3, 4), the nature (entries 4, 7) and the
quantity (entries 1, 2, 3 and 5, 6, 7) of the acid used. The
product 8a as the major component is the result of the
intramolecular arylation of the N-acyliminium ion E
(Scheme 5). Furthermore, the stability of a benzyl alcohol
obtained from a tandem cleavage/protonation of the
etheroxyde linkage of 11a in acidic conditions combined
with the good nucleophilicity of the oxygen atom [12,26b]
constitutes a significant intermolecular competing process
leading to 12a to the detriment of the classical π-cationic
proceeded smoothly with a large excess of NaBH
4
(6 equiv.) in methanol and gave the desired α-hydroxylac-
tam 11a after silica gel chromatography with
CH Cl /hexane (9:1) as eluent (82%) and 11b after recrys-
2
2
tallization from dry ethanol (74%). In all these reduction
processes, regular addition of ethanolic hydrogen chloride
solution (10%) was necessary to avoid the formation of the
opened amide-alcohol as already noted [26].
According to our previous work in this field, p-tolue-
nesulfonic acid and trifluoroacetic acid are good cata-
lysts for the intramolecular amidoalkylation. Thus, the
subjection of the above α -hydroxylactam 11a, as a
model of N-acyliminium ion precursor, to these acids
Table 1
Reaction Conditions and Yield of Products Obtained from the Reaction of α-Hydroxylactams 11a,b and Different Acids
Entry
Precursor
11a
"
"
"
"
"
"
11b
"
Acid, quantity
PTSA, 1.0 equiv.
"
PTSA, catalytic
"
Conditions
CH Cl , rt, 3 h
Products
Yield of reaction % [a]
Decomposition [c]
"
37
Ratio of products % [b]
-
-
1.4/1
1.5/1
-
-
2/1
1
2
3
4
5
6
7
8
9
-
-
-
-
-
-
-
-
-
-
2
2
CH Cl , 0 °C, 4 h
-
-
12a
12a
-
2
2
CH Cl , 0 °C, 7 h
8a
8a
-
2
2
CH Cl , rt, 3 h
42
2
2
TFA, neat
rt, 3 h
Decomposition [c]
"
53
34
55
TFA, 1.0 equiv.
TFA, catalytic
PTSA, catalytic
TFA, catalytic
CH Cl , rt, 2 h
-
-
2
2
"
"
"
8a
-
12a
12b [d]
0/1/0
5.5/1.5/1
8b 12b 13b
[a] The reactions were performed on 3-6 mmol using 10 ml of dry CH Cl , and the yield corresponds to the isolated products or purified products
2
2
1
mixture; [b] The ratio of isomers was determined by H NMR spectrum analysis; [c] All starting material was decomposed in acidic conditions;
consequently, only the benzyl alcohol and 3-thiophenemethanol were isolated; [d] Taking into account that two equivalents of starting material 11b were
necessary to form 12b, this product may be obtained at max efficiency in 50% yield.

502
Vol. 40
A. Cul, A. Chihab-Eddine, A. Pesquet, Sˇ. Marchalín and A. Daïch
cyclization leading to the product 8a. The structure of
of two for their hydroxylactam congeners 11a,b. We
1
compounds 8a and 12a have been established by H and/or
found also that H signal on a tertiary carbon of 12a,b
3
13
C-NMR spectroscopy as well as by the coupling GC-
were shifted downfield compared to the same protons in
corresponding alcohols 11a,b (∆δ=+0.12 and +0.07 ppm
respectively). In a similar fashion, the same angular
MS. Moreover, the O-alkylation reaction of hydroxyl-
actam 11a at the hydroxyl group according to our report
[28] (using 1.2 equiv. of NaH, dry DMF and 1 equiv. of
benzyl chloride at 0 °C to rt for 24 h) give 12a in 81%
yield (Scheme 4) thus confirming the structure proposed
for this product 12a [29].
protons H (δ=6.02 ppm for 8a) and H (δ=6.01 ppm
13b
12b
for 8b) appear as singlets without significant change
(δ=5.95 ppm for 11a and 11b). In contrary to product
13b, the angular proton appears at δ=6.11 ppm compara-
13
From these results, it was of interest to investigate this
cyclization in a heterocyclic series. Subjecting the
hydroxylactam 11b to cyclization (conditions (i), entry 8)
gave exclusively product 12b (34%) which was formed in
the same manner as 12a. Its structure was equally con-
firmed by the univocally classical O-alkylation starting
from 11b (Scheme 4, Table 1, 75% yield) [29].
Furthermore, the hydroxylactam 11b was allowed to react
under conditions (ii) as outlined above (entry 9, table 1).
Interestingly, spectroscopic analysis of the crude product
ble to those of 12a,b. Likewise, the C NMR spectra of
13b revealed the presence of an additional quaternary
carbon as the consequence of the cyclization process.
Furthermore, an important deshielding of the angular
carbon of component 13b was observed (δ=89.7 ppm
instead of the range 80.7 to 86.4 ppm for other products
8a,b, 11a,b and 12a,b) which is due to the proximity of
the oxymethylene group [12a].
As depicted mechanistically in Scheme 5, [1,3]benzox-
azepines 8a,b are obtained classically through arylation of
the N-acyliminium ion E generated in acidic medium from
11a,b. Formation of tricyclic lactam 13b, could be
explained by isomerization of the endocyclic cation E into
the exocyclic one G via the azaoxonium ion F, followed
ultimately by intramolecular π-cationic cyclization.
Interestingly, related cations which are in equilibrium via a
cyclic aza-sulfonium ion obtained from an atypical
intramolecular α-thioamidoalkylation and leading to
isomeric [1,3]benzothiazines are put in evidence recently
by us [13b]. Otherwise, the only report concerning similar
phenomenon which using a tandem as aza-Cope
isomerization/intramolecular O-cationic cyclization was
pointed in literature [30].
1
by H NMR revealed the product to be a 5.5:1.5:1 mixture
of three components as [1,3]thienoxazepine 8b, N,O-diac-
etal 12b and tricyclic lactam 13b, respectively (55%).
Attempts of separation by chromatography give only 13b
as a solid in pure form while 8b and 12b remain insepara-
ble, whatever the attempts for their separation, in a ratio of
approximatively 4:1.
The assignment of these structures was made on the
basis of coupling GC-MS, elemental analyses and other
spectroscopic properties. The IR spectra of a mixture of
8a+12a and 8b+12b or pure products 12a, 12b and 13b
1
indicated the absence of an O-H stretch. The H NMR
spectra of 12a,b showed three methylene groups instead

May-Jun 2003
Conclusion.
Evaluation of N-Hydroxymethylphthalimide in Alkaline Medium
503
General Procedure for O-Alkylation of N-Hydroxymethyl-
phthalimide (6).
We have shown that N-hydroxymethylphthalimide (6) in
alkaline medium and depending essentially on the reaction
temperature give selectively the N- or O-alkylated phthal-
imide products in good yields. These latter, as N-acylim-
inium ion precursors, lead to fused [1,3]oxazepines 8 and
to a tricyclic lactam 13 through an intramolecular arylation
of an endocyclic E and exocyclic G N-acyliminium ions,
respectively. These species are in aquilibrium via the
newly cyclic azaoxonium ion F.
This reaction was performed in a similar manner as above
except that the reaction temperature was maintained at –25 to
–20°. After 52 h, the mixture was poured onto crushed ice and the
small amount of precipitate was extracted with diethyl ether
several times. After the classical work up of the organic layer, the
residue obtained was purified by chromatography on silica gel
column using a mixture of dichloromethane/hexane (4:1) as
eluent to give the O-alkylated product 10a and 10b. Product 10a
was accompanied with the N-alkylated 9a in a small amount (<
8% yield).
N-(Benzyloxymethyl)phthalimide (10a).
EXPERIMENTAL
This product was obtained as a white solid in 65 % yield; mp
84-85° (ethanol) (lit. [23], mp 80-81° (isopropyl ether)); IR
(KBr): ν 3016, 2090, and 1708 cm ; H NMR: δ 4.61 (s, 2H,
All melting points were measured on a Boetius micro hot-
stage and are uncorrected. The infrared spectra of solids (potas-
sium bromide) and liquids (neat) were recorded on a Perkin
-1
1
O-CH ), 5.16 (s, 2H, CH -O), 7.15-7.34 (m, 5H, H
),
);
2
2
aromatic
1
13
7.68-7.75 (m, 2H, H
13
), 7.80-7.86 (m, 2H, H
Elmer FT-IR paragon 1000 spectrometer. The H and C NMR
spectra were recorded on a Bruker AC-200 (200 MHz) instru-
ment in deuteriochloroform unless otherwise indicated and
chemical shifts (δ) are expressed in ppm relative to TMS as
internal standard. Ascending thin layer chromatography was
performed on precoated plates of silica gel 60 F 254 (Merck)
and the spots visualised using an ultraviolet lamp or iodine
vapour. Mass spectral measurements were recorded on an AEI
MS 902 S spectrophotometer. Elemental analyses were carried
out by the microanalysis laboratory of INSA, F-76130 Mt. St.
Aignan, France.
phthalimide phthalimide
C NMR: δ 66.9 (CH ), 71.5 (CH ), 123.8 (2CH), 127.8 (2CH),
2
2
128.1 (CH), 128.5 (2CH), 131.9 (C), 134.5 (2CH), 137.4 (2C),
+
168.1 (2C=O); MS (m/z) 267 (M ).
Anal. Calcd. for C
H NO : C, 71.89; H, 4.90; N, 5.24.
16 13 3
Found: C, 71.77; H, 4.82; N, 5.22 .
N-(Thien-3-yl-methyloxymethyl)phthalimide (10b).
This product was obtained as a white-yellow solid in 79 % yield;
mp 115-118° (ethanol/water); IR (KBr): ν 3018, 2095, and 1702
-1 1
cm ; H NMR: δ 4.67 (s, 2H, O-CH ), 5.23 (s, 2H, CH -O), 7.05
2
2
(d, J=4.7 Hz, 1H, H -thiophene), 7.18-7.35 (dd, J=3.1 and 2.3 Hz,
4
General Procedure for N-Alkylation of N-Hydroxymethyl-
phthalimide (6).
2H, H -thiophene), 7.68-7.78 (m, 2H, H
), 7.81-7.94 (m,
2,5
phthalimide
13
2H, H
); C NMR: δ 66.8 (CH ), 67.2 (CH ), 123.6
phthalimide
2
2
(CH), 124.0 (2CH), 126.4 (CH), 127.5 (CH), 132.1 (2C), 134.7
(2CH), 138.6 (C), 168.3 (2C=O); MS (m/z) 273 (M ).
To a stirred solution under an atmosphere of dry argon of
N-hydroxymethylphthalimide (6) (1.77 g, 10 mmol) in 10 mL
of dry DMF was added 0.65 g (12 mmol) of sodium
methoxide. After stirring for 20 min at –5 to +60°, 10 mmol of
halide RX (see text for details) dissolved in 10 mL of dry
DMF was added dropwise over a period of 15 min. The
mixture was then allowed to react at the same temperature for
6 h and hydrolyzed. The resulting solid was collected by
filtration and recrystallized from ethanol to give the expected
imide 9a-f in 49 to 75% yield. In the case of 9c, the solution
after hydrolysis was concentrated under reduced pressure,
extracted with dichloromethane, dried over magnesium sulfate
and evaporated to give 9c as an oil in 49% yield. The data of
these products correspond to that reported in literature (see
text).
+
Anal. Calcd. for C H NO S: C, 61.52; H, 4.06; N, 5.12.
14 11
3
Found: C, 61.48; H, 3.98; N, 4.99.
General Procedure for Reduction of Imides (10a,b).
To a mixture of 5 mmol of imide 10a (or 10b) in dry methanol
(40 mL) at -5-0° was added sodium borohydride (1.13 g,
30 mmol) by portions during 5 min. To this mixture was added
5 drops of ethanolic hydrochloric acid solution (prepared by
addition of 9 drops of concentrated hydrochloric acid into 5 mL
of dry ethanol) at regular intervals of 10 min. The reaction was
monitored by TLC using CH Cl as eluent. At the end of the
2
2
reaction (90 min), the excess of sodium borohydride was decom-
posed by careful addition of cold water (15 mL) and 10 %
hydrochloric acid until pH = 4. Sodium hydrogen carbonate was
added and the solvent was evaporated. The resulting residue was
triturated with water and dichloromethane and the organic layer
was separated, washed with water, brine, dried over magnesium
sulfate and concentrated in vacuo. The resulting product was
purified by chromatography on silica gel column or by recrystal-
lization to give 11a or 11b, respectively.
N-(2-Methoxycarbonylfur-3-yl-methyl)phthalimide (9f).
This product was isolated in a yield of 71 % as a white solid;
mp 147-149° (ethanol); IR (KBr): ν 3026, 2096, 1715, and 1702
-1 1
cm ; H NMR: δ 3.93 (s, 3H, OMe), 5.10 (m, 2H, CH -N), 6.39
2
(d, J=1.5 Hz, 1H, H -furane), 7.41 (d, J=1.5 Hz, 1H, H -furane),
4
7.69-7.74 (m, 2H, H
13
5
), 7.81-7.86 (m, 2H, H
);
phthalimide
phthalimide
N-(Benzyloxymethyl)-2,3-dihydro-3-hydroxy-1H-isoindol-1-
one (11a).
C NMR: δ 33.5 (CH ), 52.1 (OCH ), 112.9 (CH), 123.6 (2CH),
2
3
129.9 (C), 132.0 (C), 134.3 (2CH), 140.5 (2C), 145.5 (CH), 159.4
+
(C=O), 167.9 (C=O); MS (m/z) 285 (M ).
This product was isolated as an colorless oil in 82 % yield after
chromatography on silica gel column (CH Cl /hexane, 9:1); IR
Anal. Calcd. for C H NO : C, 63.16; H, 3.88; N, 4.91.
15 11
3
2
2
-1
1
Found: C, 63.02; H, 4.00; N, 4.78.
(neat): ν 3259, 3008, 2094, and 1700 cm ; H NMR: δ 3.1

504
Vol. 40
A. Cul, A. Chihab-Eddine, A. Pesquet, Sˇ. Marchalín and A. Daïch
(d, J=10.2 Hz, 1H, OH, exchangeable with D O), 4.49 (s, 2H,
N-(Benzyloxymethyl)-3-benzyloxy-2,3-dihydro-1H-isoindol-1-
one (12a).
2
O-CH ), 4.88 (d, J= 10.9 Hz, 1H, CH -O), 5.04 (d, J=10.9 Hz,
2
2
1H, CH -O), 5.94 (d, J=10.2 Hz, 1H, CH), 7.20-7.34 (m, 5H,
2
This product was isolated as a white solid; mp 57-59° (diethyl
ether/hexane); IR (KBr): ν 3006, 2989, and 1695 cm ; H NMR:
H
H
), 7.44-7.52 (m, 1H, H
), 7.54-7.60 (m, 2H,
aromatic
phthalimide
-1 1
13
), 7.72 (d, J=8.1 Hz, 1H, H
); C NMR: δ
phthalimide
phthalimide
δ 4.12 (d, J=10.9 Hz, 1H, CH -O), 4.26 (d, J=10.9 Hz, 1H,
2
69.9 (CH ), 71.5 (CH ), 81.6 (CH), 124.5 (CH), 124.8 (CH),
2
2
CH -O), 4.60 (s, 2H, CH -O), 4.87 (d, J=11.0 Hz, 1H, O-CH -
2
2
2
128.5 (CH), 128.9 (2CH), 129.2 (2CH), 130.8 (CH), 131.3 (C),
134.1 (CH), 138.3 (C), 145.2 (C), 168.7 (C=O); MS (m/z) 269
N), 5.32 (d, J=11.0 Hz, 1H, O-CH -N), 6.17 (s, 1H, O-CH-N),
2
7.20-7.35 (m, 10H, H
7.89 (d, J=9.4 Hz, 1H, H
), 7.53-7.62 (m, 3H, H
),
aromatic
phthalimide
+
(M ).
13
); C NMR: δ 66.5 (CH ),
phthalimide
2
Anal. Calcd. for C
H NO : C, 71.36; H, 5.61; N, 5.20.
16 15 3
70.1 (CH ), 71.9 (CH ), 86.4 (CH), 124.8 (CH), 125.1 (CH),
2
2
Found: C, 71.26; H, 5.51; N, 5.09.
128.7 (CH), 128.8 (2CH), 128.9 (2CH), 129.0 (CH), 129.3
(2CH), 129.5 (2CH), 131.3 (CH), 132.5 (C), 133.4 (CH), 137.8
2,3-Dihydro-3-hydroxy-N-(thien-3-yl-methyloxymethyl)-1H-
isoindol-1-one (11b).
+
(C), 138.3 (C), 141.7 (C), 167.7 (C=O); MS (m/z) 359 (M ).
Anal. Calcd. for C
Found: C, 76.59; H, 5.71; N, 3.79.
H NO : C, 76.86; H, 5.89; N, 3.90.
23 21 3
This product was isolated as a white-yellow solid in 74 % yield
after recrystallization from ethanol; mp 83-85°; IR (KBr): ν
-1
1
2,3-Dihydro-3-(thien-3-yl-methyloxy)-N-(thien-3-yl-methyl-
oxymethyl)-1H-isoindol-1-one (12b).
3263, 3022, 2086, and 1695 cm ; H NMR: δ 4.48 (s, 2H,
O CH ), 4.77 (dd, J=10.9 and 10.2 Hz, 2H, OH and O-CH ), 4.94
2
2
(d, J=10.9 Hz, 1H, O-CH ), 5.95 (d, J=10.2 Hz, 1H, CH), 7.03 (d,
2
This product was isolated as an colorless oil; IR (neat): ν 3010,
J=4.7 Hz, 1H, H -thiophene), 7.19-7.32 (m, 2H, H -thiophene an
-1
1
4
2
2983, and 1681 cm ; H NMR: δ 4.14 (d, J=11.7 Hz, 1H,
CH -O), 4.27 (d, J=11.7 Hz, 1H, CH -O), 4.58 (s, 2H, CH -O),
H
), 7.43-7.55 (m, 1H, H
), 7.57-7.69 (d+d,
phthalimide
phthalimide
2
2
2
13
J=7.8 and J=3.9 Hz, H -thiophene and H
); C NMR: δ
5
phthalimide
4.83 (d, J=10.9 Hz, 1H, O-CH -N), 5.27 (d, J=10.9 Hz, 1H,
2
66.0 (CH ), 68.6 (CH ), 80.7 (CH), 123.5 (CH), 123.8 (CH),
2
2
O-CH -N), 6.12 (s, 1H, O-CH-N), 6.13-6.97 (dd, J=1.5 and 4.7
2
123.9 (CH), 126.3 (CH), 127.5 (CH), 130.0 (CH), 130.7 (C),
133.2 (CH), 138.5 (C), 144.4 (C), 168.6 (C=O); MS (m/z) 275
Hz, 1H, H
), 7.02-7.09 (m, 2H, H
), 7.23-7.28 (m,
thiophene
thiophene
3H, H
Hz, 1H, H
), 7.50-7.62 (m, 3H, H
), 7.86 (d, J=7.3
thiophene
phthalimide
+
(M ).
13
); C-NMR: δ 60.7 (CH ), 65.9 (CH ), 69.3
phthalimide
2 2
Anal. Calcd. for. C H NO S: C, 61.07; H, 4.76; N, 5.08.
14 13
3
(CH ), 85.4 (CH), 123.8 (CH), 124.1 (CH), 124.6 (CH), 124.8
2
Found: C, 60.95; H, 4.68; N, 5.00.
(CH), 126.8 (CH), 127.1 (CH), 127.9 (CH), 128.1 (CH), 130.9
(CH), 132.5 (C), 133.7 (CH), 138.9 (C), 139.5 (C), 142.0 (C),
General Procedure for Treatment of Hydroxylactams (11a,b)
with Trifluoroacetic Acid or para-Toluenesulfonic Acid.
+
165.2 (C=O); MS (m/z) 371 (M ).
Anal. Calcd. for C H NO S : C, 61.43; H, 4.61; N, 3.77.
19 17
3 2
A solution of 6 mmol of hydroxylactam 11a (or 11b) in 15 mL
of dry dichloromethane was stirred at required temperature (see
text and table in the text part for more details) with pure
trifluoroacetic acid (TFA) or paratoluenesulfonic acid (PTSA).
At the end of the reaction (the reaction was monitored by TLC
using dichloromethane/hexane (4:1) as eluent), the solution was
concentrated in vacuo, diluted with CH Cl , washed successively
with a saturated sodium hydrogen carbonate solution, then with
water and was dried over magnesium sulfate and filtered. The
solution was concentrated under reduced pressure and the residue
was recrystallized and/or chromatographed to furnish 8a,b,
12a,b, and/or 13b.
Found: C, 61.31; H, 4.48; N, 3.56.
4,12-Dihydrothieno[2’,3’:5,6][1,3]oxazepino[2,3-a]isoindol-
10(5bH)-one (13b).
This product was isolated as white-yellow crystals after
chromatography and recrystallization; mp 89-91°
(ethanol/water); IR (KBr): ν 3010, 2951, and 1689 cm ; H
NMR: δ 4.42 (d, J=14.9 Hz, 1H, CH -O), 4.52 (d, J=16.4 Hz, 1H,
-1
1
2
2
2
CH -N), 4.64 (d, J= 14.9 Hz, 1H, CH -O), 5.47 (d, J=16.4 Hz,
2
2
CH -N), 6.11 (s, 1H, O-CH-N), 6.67 (d, J=5.4 Hz, 1H, H
2
4-thio-
), 7.49-7.61 (m, 3H,
), 7.05 (d, J=5.4 Hz, 1H, H
phene
5-thiophene
13
H
), 7.79 (d, J=7.05 Hz, 1H, H
); C NMR: δ
phthalimide
phthalimide
38.9 (CH ), 63.0 (CH ), 89.7 (CH), 122.8 (CH), 123.0 (CH),
2
2
4,7-Dihydroisoindolo[2,1-d][2,4]benzoxazepin-9-(13bH)-one (8a).
126.3 (CH), 129.8 (CH), 131.9 (CH), 132.1 (CH), 134.8 (C),
139.0 (C), 143.6 (C), 147.5 (C), 168.5 (C=O); MS (m/z) 257
1
This product was not isolated in pure form; HNMR: δ 4.58 (s,
+
2H, O-CH ), 4.83 (d, J=10.1 Hz, 1H, CH -N), 5.31 (d, J=10.1
(M ).
2
2
Anal. Calcd. for C H NO S: C, 65.35; H, 4.31; N, 5.44.
Hz, 1H, CH -N), 6.02 (s, 1H, O-CH-N), 7.24-7.32 (m, 4H,
14 11
2
2
Found: C, 65.12; H, 4.27; N, 5.27.
H
H
), 7.52-7.57 (m, 3H, H
), 7.84 (d, J=7.2 Hz, 1H,
aromatic
phthalimide
+
); MS (m/z) 251 (M ).
phthalimide
Other Method for Preparation of 3-Arylmethyloxylactams
(12a,b).
4,6-Dihydrothieno[2’,3’:5,6][1,3]oxazepino[4,3-a]-isoindol-
8(12bH)-one (8b).
To a stirred solution under an atmosphere of dry argon α-
hydroxylactam 11a (or 11b) (10 mmol) in 20 mL of dry THF at
0° was added by portions 0.48 g (12 mmol) of sodium hydride
(60 % in mineral oil). After stirring for 30 min at room tempera-
ture, 10 mmol of benzyl chloride (or 3-bromomethylthiophene)
dissolved in 25 mL of dry THF was added dropwise over a period
of 10 min. The mixture was then allowed to react at the same
1
This product was not isolated in pure form; HNMR: δ 4.57 (s,
2H, O-CH ), 4.83 (d, J=10.2 Hz, 1H, CH -N), 5.32 (d, J=10.2
Hz, 1H, CH -N), 6.01 (s, 1H, O-CH-N), 6.94 (d, J=4.2 Hz, 1H,
2
2
2
H
), 7.09 (d, J=4.2 Hz, 1H, H
), 7.55-7.62 (m,
); MS (m/z)
4-thiophene
5-thiophene
3H, H
), 7.80 (d, J=8.1 Hz, 1H, H
phthalimide
phthalimide
+
257 (M ).

May-Jun 2003
Evaluation of N-Hydroxymethylphthalimide in Alkaline Medium
505
[13a] N. Hucher, A. Daïch and B. Decroix, Org. Lett., 2, 1201
(2000); [b] N. Hucher, B. Decroix and A. Daïch, J. Org. Chem., 66, 4695
(2001); [c] A. Chihab-Eddine, A. Daïch, A. Jilale and B. Decroix,
Tetrahedron Lett., 42, 573 (2001).
[14] N. Hucher, A. Daïch and B. Decroix, J. Heterocyclic Chem.,
35, 1477 (1998).
[15a] H. E. Zaugg, Synthesis, 49 (1970); [b] H. E. Zaugg, Synthesis,
85 (1984); [c] H. E. Zaugg, Synthesis, 181 (1984); [d] The same N-acyli-
minium ion B was also generated from N-chloromethylphthalimide (7) in
the presence of Brönsted or Lewis acid. For this end, see for example:
[e] I. Iley, T. Calheiros and R. Moreira, Bioorg. Med. Chem. Lett., 8, 955
(1998), and [f] B. Venugopalan, P. J. Karnik and S. Shinde, J. Chem. Soc.,
Perkin Trans. 1, 1015 (1996), respectively.
temperature for 24 h and carefully hydrolysed with cold water.
The reaction mixture was extracted with dichloromethane and the
organic layer was washed with water, brine, dried over
magnesium sulfate and concentrated in vacuo. The resulting
crude product was purified by recystallization (diethyl
ether/hexane) or chromatography on silica gel column
(dichoromethane/hexane, 4:1) to give 12a (81 %) or 12b (75 %)
identical to 3-arylmethyl-oxylactams described above.
Acknowledgements.
The authors thank the Scientific Council of University of Le
Havre, France, and the Slovak Grant Agency (Grant Number:
1/9249/2002), Slovak Republic for their financial support. We
thank also Professor Bernard Decroix from the University of Le
Havre for critical review of this manuscript.
[16] In this area, see for example: J. D. Coyle and G. L. Newport,
J. Chem. Soc., Perkin Trans. 1, 93 (1980).
[17] S-D. Cho, H-J. Kim, C. Ahn, J. R. Falck and D-S. Shin,
Tetrahedron Lett., 40, 3215 (1999).
[18] P. Pigeon and B. Decroix, J. Heterocyclic Chem., 33, 129
(1996).
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chromatography on a silica gel column using a mixture of CH Cl /hexane
(4:1) as eluent and its yield did not exceed 8% whatever the reaction
conditions.
[25] When the reaction was performed at -40 to –35°, the reaction
times increase to 2.5-3 days.
2
2
[26a] A. Mamouni, A. Daïch and B. Decroix, J. Heterocyclic
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