Acid-mediated intramolecular cationic cyclization using an oxygen atom as internal nucleophile: Synthesis of substituted oxazolo-, oxazino- and oxazepinoisoindolinones

Article abstract of DOI:10.1016/S0040-4039(02)00910-3

Efficient assembly of substituted oxazolo-, oxazino-, and oxazepinoisoindolinones (5-7, 12-15 and 19) is described in three steps according to an acidic α-oxoamidoalkylation reaction from ready available phthalic anhydride by successive imidation, sodium borohydride reduction and intramolecular cationic cyclization involving N-acyliminium species. The relative stereochemistry accompanying these reactions was also discussed.

Full text of DOI:10.1016/S0040-4039(02)00910-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4747–4751
Acid-mediated intramolecular cationic cyclization using an
oxygen atom as internal nucleophile: synthesis of substituted
oxazolo-, oxazino- and oxazepinoisoindolinones†,‡
a
a
b,
b
&
Jana Sikoraiova´, Stefan Marchal´ın, Adam Da¨ıch * and Bernard Decroix
aDepartment of Organic Chemistry, Slovak University of Technology, Radlinske´ho 9, Sk-81237 Bratislava, Slovakia
bLaboratoire de Chimie de l’Universite´ du Havre, Faculte´ des Sciences & Techniques, URCOM, EA 3221,
25 Rue Philippe Lebon, B.P. 540, F-76058 Le Havre Cedex, France
Received 6 May 2002; accepted 13 May 2002
Abstract—Efficient assembly of substituted oxazolo-, oxazino- and oxazepinoisoindolinones (5–7, 12–15 and 19) is described in
three steps according to an acidic a-oxoamidoalkylation reaction from ready available phthalic anhydride by successive imidation,
sodium borohydride reduction and intramolecular cationic cyclization involving N-acyliminium species. The relative stereochem-
istry accompanying these reactions was also discussed. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Because of the more potential of theses species, valu-
able efforts continue to be made towards their synthe-
ses and uses. So, known syntheses of these products
include: (i) the cyclodehydration process between an
amino-alcohol and an ketoacid;3,4 (ii) carbonylative
cyclization between an amino-alcohol and 2-bromoben-
zaldehyde using palladium catalysis under controlled
pressure;5 (iii) intramolecular nucleophilic displacement
of halides with oxygen atom as nucleophile;6 and (iv)
cationic cyclization involving N-acyliminium species.7,8
During the last years, numerous groups, notably this of
Meyers,1 have demonstrated the synthetic utility of the
bicyclic N,O-acetal product as a building block for the
construction of a wide variety of natural and unnatural
carbocyclic and azacyclic compounds including simple
and complex alkaloids.1 Also, these acetal intermediates
commonly known as the bicyclic lactams have been
employed in various ways in synthesis of tertiary and
quaternary carbon centres at a-position of a nitrogen
lactam.1,2
As a further development of our search on the synthetic
O
Stereogenic
center R or S
4
O
O
O
5
6
R
5
7
N
4
7
R
R
R
N
N
9
O
N
or
18a
1
9b
9a
14
O
9
2
18
O
11
O
OH
1
16
N
A
D
C
15
R
R = Me, Et, Bn
B
13
O
Scheme 1. Retrosynthetic sequence leading to chiral bicyclic lactam monomers C or D and corresponding chiral dimers B.
Keywords: amino-alcohol; N-acyliminium ion; bicyclic lactam; cationic cyclization; oxazole; oxazine; oxazepine; isoindolinone.
* Corresponding author. Tel.: (+033) 02-32-74-44-03; fax: (+033) 02-32-74-43-91; e-mail: adam.daich@univ-lehavre.fr
† This article is dedicated to our colleague, Professor Jean Morel, for his retirement.
This work was presented in part at JCO ‘Journe´es de Chimie Organique’, Poster A-89, Ecole Polytechnique-Palaiseau, France, 2001, September
‡
´
11–13.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00910-3

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J. Sikoraio6a´ et al. / Tetrahedron Letters 43 (2002) 4747–4751
utility and reactivity on polyheterocyclic systems con-
taining an isoindolone moiety fused to oxazaheterocy-
cles,9 we wish to present herein the synthesis of related
oxazolinoisoindolinones 5–7, oxazinoisoindolinones 12–
15 and oxazepinoisoindolinone 19 systems.
(92–96%).13–19 The hydroxylactams 3a–d, were obtained
as a 1/1 mixture of two diastereomers (determined by 1H
NMR study) in a range of 56–95% yields. The separation
of these diastereomers was only performed by chro-
matography on silica gel column for 3a (56%) and 3d
(78%).
2. Results and discussion
According to our previous work in the chiral series,9b
hydrochloric acid (Method I) and trifluoroacetic acid
(Method II) are good catalysts for the intramolecular
a-oxoamidoalkylation. So, subjection of hydroxylactam
3a to hydrochloric acid in chloroform (24 h) or trifl-
uoroacetic acid in dichloromethane (2 h) at room temper-
ature afforded a racemate 5a (R1=H, R2=Me) in 80%
yield. This product, which was identical to D (Scheme
1),9b showed a trans configuration and resulted from an
intramolecular cyclization of the N-acyliminium inter-
mediate 4a in (TS-I) (Scheme 2). During this process, the
oxygen atom attacks the iminium ion when the OH group
is anti to the methyl one to produce the trans racemate
5 in accordance with our previous work in the chiral
series.9 Taking into account that ethyl group (3b) related
to the methyl one (3a) gave same results via 4b in (TS-I)
(Scheme 2), we decided to examine the effect of the
position and the nature of different groups R1 and R2 in
the starting precursors 3c,d on the cyclization step. Thus,
as depicted in Scheme 2 hydroxylactam 3c (R1=Me and
R2=H) upon acidic treatment (Method I or II) gave the
cis/trans mixture of two diastereomers 6c/7c in a 2/1 ratio
in 89% yield. According to the same method, 3d (R1=Ph
and R2=H) produced the 2/1 mixture of 6d/7d in 62%
yield. Compounds 6c and 7c as a racemate have been
previously reported in the same ratio in a 30% yield from
( )-threonine and phthalic anhydride in a six- or seven-
step sequence (two pathways).20
Because we have outlined in our previous paper, using
the N-acyliminium ion chemistry, the best formulation
leading to chiral dimers B or corresponding chiral
monomers C or D as shown above in a retrosynthetic
sense in Scheme 1, we wish to use herein the same
N-acyliminium ion methodology to access a large assem-
bly of the title bicyclic lactams. The key step of this
synthetic sequence was, in an ultimate reaction, an
intramolecular formation of a carbonꢀoxygen bond in an
acidic medium by cationic cyclization with an oxygen
atom as internal nucleophile.
As shown in Scheme 2, the requisite a-hydroxylactam
derivatives 3a–d, as N-acyliminium ion precursors, were
obtained in two steps from phthalic anhydride and
b-amino-alcohol 1a–d, by condensation under azeotropic
removal of water conditions,10 or by thermal amino-
anhydride condensation at 200°C, followed by selective
sodium borohydride reduction under mild conditions. In
all cases, a regular addition of ethanolic hydrogen
chloride solution was necessary to avoid the formation
of the opened amide-alcohol as already mentioned else-
where.11,12
The well known imides 2a–d were isolated by distillation
(2b) or recrystallization (2a,c,d) in comparable yields
R2
O
O
H
H
H
R2
R2
N
O
N
N
R1
OH
O
HO
4a-d
5a,b trans
4a,b (TS-I)
iv
O
O
R2
R2
H2N
R1
R2
1
a
b
c
d
iii
i or ii
N
N
H
H
Me Ph
O
R1
R2
R1
R1
OH
O
Me Et
H
H
HO
H
OH
1a-d
HO
O
2a-d
O
3a-d
iv
+
H
O
O
H
R1
R1
H
O
O
N
N
O
N
N
H
H
OH
OH
O
R1
R1
7c,d trans
Minor
6c,d cis
4c,d (TS-II)
4c,d (TS-III)
1/2
Major
Scheme 2. Reagents and conditions: (i) toluene, reflux, Dean–Stark; (ii) heat at 200°C; (iii) 1.5 equiv. of NaBH4, MeOH, −5 to 0°C
then 10% HCl in ethanol; (iv) Method I: HCl, chloroform, 24 h; Method II: TFA, dichloromethane, 2 h.

J. Sikoraio6a´ et al. / Tetrahedron Letters 43 (2002) 4747–4751
4749
These products 6d/7d and their methyl derivatives 6c/
7c, were easily separated by chromatography on a silica
gel column using a mixture of i-hexane/ethyl acetate as
eluent, and their structures were established by spectro-
stability of the transition state (TS-II) in which the
attack of N-acyliminium ion 4c,d by oxygen atom is
being favoured from the anti-direction to the R1
(methyl or ethyl) group. According to same Cram’s
rule, the less stable (TS-III) would lead to minor prod-
ucts 7c,d as trans isomers (Scheme 2).21
scopic analyses, H, 13C NMR and IR. The H NMR
spectra of 5–7 showed a typical H9b proton signals
(l=5.84–7.87 ppm) and H9 aromatic signals (l=7.77–
7.88 ppm as doublet with coupling constant of J=7.2–
7.5 Hz), of the fused isoindolone systems. These
protons were in general shifted downfield compared to
the same of their congeners 3a–d which shifted at
l=5.50–6.04 ppm (H3) and l=7.33–7.56 to 7.58–7.68
ppm (H4), respectively.
1
1
Under the light of these results it seems that the posi-
tion of the substituent group constitutes the key of the
cyclization step. Actually, in the case of an a-substitu-
tion (R1=H; R2=Me, Et) the cyclization leads specifi-
cally to the trans racemate 5a,b while in the case of a
b-substitution (R1=Me, Et; R2=H) the reaction
becomes diastereoselective since a cis (6) and trans (7)
of a mixture product, in a 2/1 ratio, is obtained.
These data, the microanalyses, and the coupling GC–
MS clearly confirmed the proposed structures of prod-
ucts 5–7. Finally, the relative stereochemicals
relationship were established using selective NOE dif-
ference measurements (Scheme 3). In fact, for 6c,d (cis)
as major products (Scheme 2) a strong NOE effect was
observed confirming the cis-orientation of H2 and H9b.
This result can also be explained by assuming the more
To establish the generality and versatility of this syn-
thetic approach, the elaboration of different novel six
and seven N,O-heterocyclic systems, was explored. So,
the requisite a-hydroxylactams 10a–c were obtained
similarly from phthalic anhydride and b-amino-alcohol
8a–c (Scheme 4).
O
O
N
O
5
4
R2
N
N
3
2
H
O
H
O
H
O
9b
H
1
H
H
10-12%
5-7%
5a,b trans
6c cis
6d cis
Scheme 3. NOE difference determination of the relative geometry of 2-substituted oxazolinoisoindolinones 5–7.
Scheme 4. Reagents and conditions: (i) toluene, reflux, Dean–Stark; (ii) heat at 200°C; (iii) 1.5 equiv. of NaBH4, MeOH, −5 to 0°C
then 10% HCl in ethanol; (iv) Method I: HCl, chloroform, 24 h; Method II: TFA, dichloromethane, 2 h.

4750
J. Sikoraio6a´ et al. / Tetrahedron Letters 43 (2002) 4747–4751
In the first set of our cationic cyclization with oxygen
atom as internal nucleophile, hydroxylactam 10a was
subjected to trifluoroacetic acid in dichloromethane at
As an extension, hydroxylactam 10c (in which a car-
boxylic acid function is bearing by the Ca adjacent to
the terminal OH function) in a similar manner as above
afforded the exclusive 15 in 89% yield. The cis relative
position of the angular proton H10b with H2 proton was
determined by NOE difference measurements (8%)
(Scheme 5). This can also be rationalized by the oxygen
atom attack of the N-acyliminium ion in 11c as shown
in Scheme 4.
1
room temperature for 2 h (Method II). The H NMR
and GC–MS analysis of crude reaction product indi-
cated the presence of the sole expected 2,3,4,10b-tetra-
hydro[1,3]-oxazino[2,3-a]isoindol-6-one (12) which was
isolated as a solid after recrystallization from dry etha-
nol in 85% yield.
Interestingly, afterwards we decided to study the effect
of the presence of another oxygen atom nucleophile
(compounds 10b (R1=H; R2=OH) and 10c (R1=
CO2H; R2=H)), on the selectivity of the cyclization
process.
The synthesis of the [1,3]oxazepino[2,3-a]isoindol-7-one
19 (Scheme 6) constitutes a generalization of the oxy-
gen-cationic cyclization process. In
a three step
sequence, similarly as outlined above from phthalic
anhydride and 4-aminobutanol (17) we prepared the
bicyclic lactam 19 in an overall of 65% yield.
So, treatment of hydroxylactam 10b according to
Method I or II, gave the 1/2 separable mixture of 13/14
diastereomers in 95% yield. Their relative cis/trans
stereochemistry was confirmed by NOE difference
experiments (Scheme 5). The inversion of the selectivity
of the cyclization reaction, 6c/7c (2/1 ratio) compared
to 13/14 (1/2 ratio), could be probably due to the fact
that the conformation in the transition state (TS-IV)
(Scheme 4) should be more stable than the transition
state in the (TS-V), since an interaction between the
oxygen doublet of the hydroxy function and the N-
acyliminium cation exists in (TS-IV).
3. Conclusion
We have developed a simple and efficient route to the
fused oxazoloisoindolinones 5–7, oxazinoisoindoli-
nones 12–15 and oxazepinoisoindolinone 19 systems
by protic acid induced intramolecular cyclization of
N-acyliminium ion precursors.23 These latter were
obtained easily in two steps from phthalic anhydride
and amino-alcohols. Furthermore, the chemoselectivity
of these reactions is discussed and the probable inter-
mediates leading to stereomers are proposed.
At this stage, it is worth mentioning that we have never
isolated the 2-hydroxymethyl-2,3-dihydrooxazolo[2,3-
a]-9bH-isoindol-5-one (16) which could resulted from a
cyclization with oxygen atom at Cb as internal nucle-
ophile. These results were in accordance with the Bald-
win rules,22 since a 6-endo-trigonal ring forming process
was favoured rather than a 5-endo-trigonal one.
Supplementary material
The data including chemical and physical characteris-
tics of all products may be obtained at the following
e-mail address: adam.daich@univ-lehavre.fr
O
O
O
1%
5
H
4
N
N
N
3
3
2
OH
2
H
10b H
H
O
O
O
9b
1
1
H
CO2H
H
8%
OH
3%
13 cis
15 cis
16
Scheme 5. NOE difference determination of the relative geometry of 2- or 3-substituted oxazinoisoindolinones 13 and 15.
O
O
H2N
8
6
N
1°- i or ii
2°- iii
iv
N
11b
O
OH
18
3
1
HO
OH
17
19
Scheme 6. Reagents and conditions: (i) phthalic anhydride, toluene, reflux, Dean–Stark; (ii) phthalic anhydride, heat at 200°C; (iii)
1.5 equiv. of NaBH4, MeOH, −5 to 0°C then 10% HCl in ethanol; (iv) Method I: HCl, CHCl3, 24 h; Method II: TFA, CH2Cl2,
2 h.

J. Sikoraio6a´ et al. / Tetrahedron Letters 43 (2002) 4747–4751
4751
Acknowledgements
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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.
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Powers, J. C. J. Med. Chem. 1998, 41, 2289.
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General procedure for the synthesis of a-hydroxylactams
(4a–d, 11a–c and 18). To a stirred solution of N-alkylated
phthalimide (10 mmol) in dry methanol (40 mL) at −5 to
0°C was added by portions 1.5 equiv. of sodium borohy-
dride (0.567 g, 15 mmol). After addition of sodium
borohydride, three drops of ethanolic hydrochloric acid
solution was added during 10 min (prepared from one
drop of concentrated hydrochloric acid in 1 mL of etha-
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lactam 4a–d, 11a–c or 18.
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a stirred solution of hydroxylactam (4a–d, 11a–c or 18)
(10 mmol) in 10 mL of chloroform (Method I) or dry
dichloromethane (Method II) was added two to three
drops of concentrated hydrochloric acid (Method I) or 5
mL of trifluoroacetic acid (Method II) and allowed to
react at room temperature for 24 or 2 h, respectively.
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and neutralized carefully with 10% sodium hydroxide
aqueous solution. The solution was extracted twice with
dichloromethane or chloroform (20 mL). The organic
layer was washed with water, brine, separated, dried over
magnesium sulfate and evaporated under reduced pres-
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matography or recrystallization to give the bicyclic
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