Facile synthesis of 1-aryl-2,3-dihydro-1H-isoindoles by cyclization of N-formyliminium ion via geometrically disfavored 5-ENDO-trig process

Article abstract of DOI:10.3987/COM-08-11621

Synthesis of l-aryl-2,3-dihydro-1H-isoindoles (isoindolines) (10) was achieved in a highly effective manner via acid catalyzed cyclization of N-foimyliminium ion (8) obtained from 2,3-dimethoxybenzylamine and carbonyl compounds with acetic-formic anhydride under a one pot procedure. This Pictet-Spengler type reaction provides a convenient method for preparing 1-arylisoindolines.

Full text of DOI:10.3987/COM-08-11621

HETEROCYCLES, Vol. 78, No. 5, 2009
1177
HETEROCYCLES, Vol. 78, No. 5, 2009, pp. 1177 - 1181. © The Japan Institute of Heterocyclic Chemistry
Received, 8th December, 2008, Accepted, 23rd January, 2009, Published online, 27th January, 2009
DOI: 10.3987/COM-08-11621
FACILE SYNTHESIS OF 1-ARYL-2,3-DIHYDRO-1H-ISOINDOLES BY
CYCLIZATION OF N-FORMYLIMINIUM ION VIA GEOMETRICALLY
DISFAVORED 5-ENDO-TRIG PROCESS
Michikazu Kitabatake, Toshiaki Saitoh, Takehiro Sano, and Yoshie
Horiguchi*
Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida,
Tokyo 194-8543, Japan; e-mail: horiguti@ac.shoyaku.ac.jp
Abstract — Synthesis of 1-aryl-2,3-dihydro-1H-isoindoles (isoindolines) (10)
was achieved in a highly effective manner via acid catalyzed cyclization of
N-formyliminium ion (8) obtained from 2,3-dimethoxybenzylamine and carbonyl
compounds with acetic-formic anhydride under a one pot procedure. This
Pictet-Spengler type reaction provides a convenient method for preparing
1-arylisoindolines.
Compounds containing 2,3-dihydro-1H-isoindoles (isoindoline) (1) such as 1-methyl-1-phenyl-(3) and
1-phenyl-derivative (4) are known to be a non-competitive NMDA antagonist1, 2 and a phencyclidine
agonist3 respectively. However, isoindoline derivatives are very rare in spite of biological interest, when
NH
NH
NH
R
2,3-dihydro-1H-isoindole
1,2,3,4-tetrahydroisoquinoline
1
2
3: R=Me
4: R=H
Scheme 1
2,3-Dihydro-1H-isoindoles and related compoundes as a NMDA antagonist
and a phencyclidine agonist

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HETEROCYCLES, Vol. 78, No. 5, 2009
compared to 1,2,3,4-tetrahydroisoquinoline (2) derivatives that constitute the fundamental ring system of
various medicines. Although there are several syntheses of isoindoline in the literature,4-10 only one paper
which deals with a general methodology leading to the isoindoline ring system is reported.10
In this paper we report the synthesis of 1-aryl-2,3-dihydro-1H-isoindole (10) utilizing a simple and
convenient method via a Pictet-Spengler type reaction, that is, the intramolecular cyclization of
N-formyliminium ion (8). We have recently developed this methodology for the synthesis of
tetrahydroisoquinoline (2) producing not only 1-substituted but also 1,1-disubstituted derivatives.11
The N-formyliminium ions (8a~e), substrates of the reaction, were readily prepared by formylation of
imines (7a~e) with acetic-formic anhydride. The imines (7a~e) were obtained by heating a mixture of
3,4-dimethoxybenzylamine (5) and arylaldehydes (6a~d) or acetophenone (6e). The procedures are
shown in Table 1.
The intramolecular cyclization of N-formyliminium ions (8) leading to the isoindoline ring system via
5-endo-trig process was anticipated to be difficult to achieve when compared with the Pictet-Spengler
reaction to 1,2,3,4-tetrahydroisoquinoline via 6-endo-trig; according to the Baldwin rule12 the former
reaction of 5-endo-trig process is geometrically disfavored while the latter 6-endo-trig one is favored.
This disadvantage was overcome by finding reaction conditions using a large excess of trifluoroacetic
acid (TFA) described in Table 1. However, when the process of removing acetic-formic anhydride from
the reaction mixture was omitted or inadequate, the cyclization did not occur in a practical sense. This
fact revealed that the acidity of the reaction solution is critically important to produce this intramolecular
cyclization. Thus, the 1-aryl-2,3-dihydro-2-formyl-1H-isoindoles (9) were obtained in fairly good yields,
as shown in Table 1.13 Hydrolysis of 9 with hydrochloric acid yielded the corresponding
1-aryl-2,3-dihydro-1H-isoindoles (10) in a quantitative yield.13 The direct cyclization of the imine (7) to
the isoindoline (10) did not occur at all even when treated with TFA even under more forced conditions,
indicating that the cyclization is the reaction of N-formyliminium ions (8) activated by N-formyl group.
These experiments clearly demonstrated that the cyclization of the N-formyliminium ion to isoindoline

HETEROCYCLES, Vol. 78, No. 5, 2009
1179
MeO
O
MeO
MeO
CHO
N
Ti(O-iPr)4 or
neat
N
MeO
MeO
R3
HCO2H-Ac2O
R1
NH2
R3
MeO
R3
+
R1
R1
R2
6
R2
R2
8
5
7
CF3CO2H
N CHO
R1 R2
R3
MeO
MeO
a
b
H
H
H
H
N H
MeO
MeO
OMe OMe
HCl
R3
R3
c
H
H
OMe
R1
R1
R2
H
H
H
d
e
OMe
H
R2
9
10
Me
Scheme 2
Synthesis of 1-aryl-2,3-dihydro-1H-isoindoles
Table 1. Synthesis of 1-Aryl-2,3-dihydro-2-formyl-1H-isoindoles (9) by
Acid Catalyzed Cyclization of N-Formyliminium Ions (8).
N-Formyliminium ion (8)*1
Cyclization*2
Reagent
Run
1
R1
H
R2
H
R3
H
Yields of 9 (%)*3
9a (65)
Temp (℃) Time(h)
8a
TFA
90
3
9b (80)
9c (83)
2
3
8b OMe OMe
H
H
TFA
TFA
90
90
3
3
8c OMe
H
OMe
H
9d (38)
9e (86)
4
5
8d
8e
H
H
H
TFA
TFA
90
90
3
5
Me
*1a) 8a~d were prepared by heating the mixture of 5 (1.2 mol eq.) and 6 (1 mol eq.) without solvent at 80 °C for 1 h,
followed by heating at 70 °C for 1 h in acetic-formic anhydride (100 mol eq.) which was prepared from acetic anhydride
(100 mol eq.) and formic acid (100 mol eq.)
*1b) 8e was prepared as follows: the mixture of 5 (1.2 mol eq.) and 6e (1 mol eq.) was heated in Ti(i-OPr)4 (1.5 mol eq.) at
80 °C for 1 h, and the resulting imine 7e was formylated by acetic-formic anhydride (100 mol eq.) at 70 °C for 1 h
without removing the Ti catalyst.
*2) The reaction was carried out in large excess of TFA (100 mol eq.) after eliminating excess acetic-formic anhydride by
heating in vacuo.
*3) The yields of 9 were calculated based on the quantity of the carbonyl compounds (6).

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HETEROCYCLES, Vol. 78, No. 5, 2009
occurs through the geometrically disfavored 5-endo trigonal process. It is especially noteworthy that the
N-formyliminium ion (8e), in spite of having the congested tetra-substituted C=N+ system, readily caused
the cyclization to give 9e in 86% yield.
The occurrence of this cyclization may be explained in terms of mesomeric effect. The C=N+ bond is
conjugated to the benzene ring. Therefore, the energy of the transition state should be lowered by the
contribution of mesomeric enamino-structure 8B featuring 5-exo trigonal cyclization. Thus, the 5-endo
trig process of the imino-structure 8A to 9, although geometrically disfavored, will be facilitated by the
contribution of 8B that is geometrically favored. The relatively low yield of isoindoline 9d probably is
attributable to the instability of the cation of 8B which is induced by the electron attractive meta OMe
group (R2) .
+
N
MeO
MeO
MeO
MeO
CHO
CHO
5-endo-trig
process
5-exo-trig
N
process
9
9
R3
R3
+
R1
R1
R2
R2
imino-sturutrue 8A
enamino-structure 8B
Mesomeric structure of N-formyliminium ion
Scheme 3
Thus, the Pictet-Spengler type reaction of N-formyliminium ions obtained from
3,4-dimethoxybenzylamine and carbonyl compounds under a one pot procedure provides a convenient
method for preparing 1-arylisoindolines. Investigation concerning the scope and limitation of this
methodology is underway.
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1
13. The structures of 9 and 10 were determined by elementary and spectral analyses (Mass, H-and
13C-NMR data).