Versatile reactivity of 3-chloro-2-phenyl-isoindole-1-carbaldehyde: Hydrolysis and alkylating rearrangement to 1-amino-4-isochromanones

Article abstract of DOI:10.1016/j.tet.2012.06.014

3-Chloro-2-phenyl-isoindole-1-carbaldehyde has been prepared from N-phenylisoindolinone under Vilsmeier-Hack conditions. This electrophilic isoindole proved to be stable under the basic conditions used in the final treatment (KOH/MeOH), and for weeks unde

Full text of DOI:10.1016/j.tet.2012.06.014

Tetrahedron 68 (2012) 6908e6913
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Versatile reactivity of 3-chloro-2-phenyl-isoindole-1-carbaldehyde: hydrolysis
and alkylating rearrangement to 1-amino-4-isochromanonesq
,
b
,
c
a
,
b
,
c
a,
Iaroslav Baglai a , Valerie Maraval
, Zoia V. Voitenko , Carine Duhayon b, Yulian M. Volovenko c,
*
ꢀ
,b,
Remi Chauvin a
*
a CNRS, LCC (Laboratoire de Chimie de Coordination), 205, route de Narbonne, F-31077 Toulouse, France
b
ꢀ
Universite de Toulouse, UPS, INPT, LCC, F-31077 Toulouse, France
c Kiev National Taras Shevchenko University, 60 Volodymlyrska St., 01033 Kiev, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2012
Received in revised form 2 June 2012
Accepted 5 June 2012
Available online 13 June 2012
3-Chloro-2-phenyl-isoindole-1-carbaldehyde has been prepared from N-phenylisoindolinone under
VilsmeiereHack conditions. This electrophilic isoindole proved to be stable under the basic conditions
used in the final treatment (KOH/MeOH), and for weeks under air in the solid state. Nevertheless, the ]
CeCl bond proved highly sensitive to any treatment with reducing or alkylating agents targeted towards
the pendant carbaldehyde group, giving various phthalimide derivatives. This unique reactivity is ex-
ploited for the selective synthesis of new aminoisochromanones.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Carbaldehydes
Chloroalkenes
Electrophilic reactivity
Isochromanones
Isoindoles
1. Introduction
concomitant reactivities of the carbaldehyde and chloroalkene
functions of 3 are hereafter presented.
Since their appearance in the chemical scene in 1951,1 many
isoindoles have been synthesized. Quinoid forms of the isoindole
nucleus are also found in many natural products and their reported
biological activities motivated the search for suitable synthetic
strategies.2 In spite ofdand thanks todtheir relative instability (in
particular for the 2H-isoindole representatives, in equilibrium with
their isoindolenine tautomers),3 the reactivity of isoindoles has
been widely investigated, especially in DielseAlder cycloaddition
and electrophilic substitution processes.3 Only a few examples of
nucleophilic substitution on functional derivatives have been de-
scribed. Halogen replacement in 1,1,3-trichloro-1H-isoindole with
carboxylic hydrazides was thus reported in 2009,4 and more re-
cently, the reactivity of 3-halo-2H-isoindoles 1 and 3-halo-2-
methyl-isoindoles 2 towards carbon, nitrogen, oxygen and sulfur
nucleophiles was described by P. Diana et al.5 As we were at the
same time investigating the reactivity of the related 3-chloro-2-
2. Results and discussion
The title substrate, 3-chloro-2-phenyl-isoindole-1-carbaldehyde
3, was prepared by treatment of the known 1-phenyl-isoindolinone
4 with a POCl3/DMF mixture, thus giving the intermediate iso-
indoleninium 5, which finally afforded 3 in 69% yield over two steps
after basic hydrolysis using KOH in methanol (Scheme 1).6 A strong
infrared (IR) absorption band at 1614 cmꢀ1 is characteristic of the
carbaldehyde function of 3. It is noteworthy that treatment of 4 with
POCl3 afforded the acylated 3-chloroisoindole 3 only when DMF was
used as the solvent, and not as a stoichiometric reactant.6
As no single crystal was suitable for X-ray diffraction analysis,
indirect structural information on the carbaldehyde 3, alternatively
described by its aromaticity-stabilized zwitterionic chloroiminium
form A versus the apolar form B (Scheme 2), were tentatively
gained from a corresponding Schiff base. Treatment of 3 with p-
tolylamine in methanol afforded the iminoeenamine hydrochlo-
ride 6, resulting from a double condensation at both the carbal-
dehyde (the targeted Schiff condensation) and chloroalkene
moieties (Scheme 2). Whatever the amount of p-tolylamine used
(one or 2 equiv), 6 was obtained in 51% yield along with
phenyl-isoindole substrate
3
(Fig. 1), results evidencing
q
Investigations performed within the framework of the GDRI «Groupement
ꢀ
Franco-Ukrainien en Chimie Moleculaire».
* Corresponding authors. E-mail addresses: vmaraval@lcc-toulouse.fr (V. Mar-
aval), chauvin@lcc-toulouse.fr (R. Chauvin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.014

I. Baglai et al. / Tetrahedron 68 (2012) 6908e6913
6909
X
Cl
Cl
NH
N CH3
N
R
CH3
O
H
O
O
X = Cl or Br, R = H or CH3
1
2
3
Fig. 1. 1-Acyl-3-halo-isoindole derivatives susceptible to nucleophilic attack.
Cl
O
Cl
X
N
KOH
POCl3/DMF
MeOH
N
N
N
r.t., 1h
0°C then 80°C, 6 h
H
O
H
4
5
3, 69 %
Scheme 1. Synthesis of 3-chloro-2-phenyl-isoindole-1-carbaldehyde 3.
H
Tol
Tol
NH2
Cl
Cl
N Ph
Cl
N Ph
N
Cl
H2N
MeOH
N Ph
N Ph
H
r.t., 24 h
51 %
Me
H
H
H
HN
O
O
N
Tol
6b
(Tol-NH2)
Tol
6a
A
3
B
6
Scheme 2. Preparation of the iminoeenamine hydrochloride 6.
unidentified side-products, thus revealing a peculiar sensitivity of
the CeCl bond.
Both the tautomers 6a and 6b were observed by 1H NMR
spectroscopy in solution, but mono-crystals could be obtained by
slow evaporation of a methanol solution of the mixture. X-ray
diffraction analysis confirmed the proposed structure under the
exclusive tautomeric form 6a in the crystal state
ꢁ
ꢁ
(C13eN3z1.36 A>C1eN2z1.33 A: Fig. 2), thus suggesting a sig-
nificant mesomeric contribution of the form A for the parent
chloroisoindole 3.
Prior to an attempt at metal-halogen exchange of the CeCl bond
of 3, protection of the carbaldehyde group was first envisaged by
acid-catalyzed formation of an acetal using 2,2-dimethylpropane-
1,3-diol in toluene at room temperature (Scheme 3). These condi-
tions indeed resulted in the protection of the aldehyde function, but
induced concomitant hydrolysis of the CeCl bond, thus giving the
isoindolinone 7a in 65% yield. The formation of the amide function
was clearly evidenced by the appearance of an intense C]O
stretching vibration band at 1687 cmꢀ1 in the IR spectrum of 7a,
and by a mass spectrum (MS), which isotopic patterns corre-
sponded to a non-chlorinated product. Attempts at acidic hydro-
lysis of 7a (using either PTSA or HCl) failed to generate the non-
conjugated aldehyde 7b, while 7a was recovered unreacted.
Acetalization of 3 was then attempted under ‘neutral’ conditions
by treatment with triethyl orthoformate in refluxing ethanol
(Scheme 4). Two products were formed in almost equal amounts,
which, after separation by chromatography, were respectively at-
tributed to the acetal 8 and the enolic ether derivative 9. Both of
Fig. 2. Cameron diagram of the X-ray crystal structure of 6a (Scheme 2). R¼5.5%. Se-
ꢁ
lected bond lengths in A: C1eN1: 1.3499(11), C2eN1: 1.4381(12), C1eC8: 1.4514(12),
C2eC3: 1.4420(13), C3eC4: 1.4020(13), C4eC5: 1.3880(16), C5eC6: 1.4036(16), C6eC7:
1.3883(13), C7eC8: 1.3981(13), C1eN2: 1.3280(11), C2eC13: 1.3663(13), C13eN3:
1.3575(13). Selected bond angles in degrees: C1eN2eC19: 128.50(8), C2eC13eN3:
126.51(10), N1eC1eN2: 128.11(8), C13eC2eN1: 119.69(9).

6910
I. Baglai et al. / Tetrahedron 68 (2012) 6908e6913
Cl
O
O
HO
HO
PTSA cat.
acid
H2O
N
N
N
+
toluene
r.t., 16 h
H
O
O
O
O
H
3
7a, 65 %
7b
Scheme 3. Acid-catalyzed acetalization of the carbaldehyde function of 3, with concomitant hydrolysis of the CeCl bond.
O
O
O
Cl
N Ph
moist air
EtOH
N Ph
N Ph
N Ph
HC(OEt)3
+
+
O
O
H
H
O
O
O
3
10
8, 40 %
9, 40 %
Scheme 4. Reactivity of 3 with triethyl orthoformate under ‘neutral’ conditions.
them proved to contain the amide function again (as indicated by
strong IR absortion bands at 1697 cmꢀ1), thus confirming the high
sensitivity of the CeCl bond, even under non- or weakly acidic
conditions. The enol ether 9 was obtained as a mixture of Z and E
isomers in a 3/1 ratio (without assignment). This product proved
sensitive to oxidation and/or hydrolysis, giving N-phenyl-
phthalimide 10 after being kept under air for a few days at room
temperature (the structure of 10 was confirmed by X-ray diffraction
analysis of a single crystal).7
Attempts at reducing the carbaldehyde function of 3 by various
methods (NaBH4/MeOH, LiAlH4/THF, Canizzaro conditions in the
presence of paraformaldehyde) afforded intractable mixtures,
which attempted partial analyses were not conclusive. Irreversible
masking of the carbaldehyde group of 3 was finally attempted by
Wittig reaction with methylenetriphenylphosphorane, but the
expected alkene could not be isolated from the reaction mixture.
Although the 1H NMR spectrum of the crude mixture gave evidence
for the formation of an ethenyl moiety, MS analysis clearly in-
dicated that the chlorine atom was removed.
Facing the high sensitivity of the CeCl bond of 3 in either acidic
or ‘neutral’ protic medium (acetalization reactions can indeed not
be performed under strictly basic conditions), metallation of the
chlorinated carbon atom was finally investigated without pre-
liminary protection of the carbaldehyde group. Inspired by a recent
report by L. Jiao et al. dealing with the reactivity of benzo-fused
BODIPYs bearing a chlorine atom at the equivalent 3-position of
the isoindole motif,8 a Pd(II)/Cu(I)-mediated Sonogashira coupling
between the 3-chloro-isoindole 3 and tri-(isopropyl)silylacetylene
in the presence of a base (triethylamine or potassium carbonate)
was first attempted in THF and toluene solutions, but no coupling
product could be detected and the starting material 3 was re-
covered in each case. Under more daring conditions, direct treat-
ment of 3 with magnesium turnings in THF also proved non-
productive, even after activation with I2, mainly affording the
unreacted starting material.
of 3 at ꢀ78 ꢁC. After hydrolysis, the expected C-3-unsubstituted
products 11 and 12 were not obtained. Instead, the unexpected 4-
isochromanones 13 and 14 were observed as major products in
the 1H NMR spectra of the crude materials (in ca. 75e80 % esti-
mated crude yields). Their purification proved quite problematic,
but allowed 13 and 14 to be isolated in ca. 30% yield as 2/1 mixtures
of diastereoisomers (Scheme 5).
As, in principle, the generation of 13 and 14 requires a single
equivalent of alkylmetal reagents only, a mechanistic rationale is
proposed in Scheme 5. It first involves the addition of the alkyl-
metal to the carbaldehyde, thus generating the alkoxide adduct 15,
which, in the absence of water molecule, might attack the chlori-
nated C-3 atom. The driving force of this process could be attributed
to the aromatization of the benzoquinodimethane ring. The
resulting fused pyrrolidine ring would then be opened by cleavage
of the CeN bond with concomitant formation of a benzylic met-
alcarbenium centre and stabilization of the negative charge at the
nitrogen atom of the anilide 16. Elimination of the chloride ion
would then give a carbenoid-iminoester 17 (M0¼M, X¼Cl), which
upon hydrolysis would afford the 1-amino-4-isochromanones 13
and 14 (Scheme 5). Alternatively, invokation of the carbenoid in-
termediate might be avoided by considering that the primary alk-
oxide 15 would be stable in solution until the hydrolytic treatment,
and that the rearrangement would be lately induced by a water
molecule, through a benzylic carbenium intermediate 16 (M0¼H)
and a benzylic alcohol 17 (M0¼H, X¼OH).
The structure of 14 was confirmed by X-ray diffraction analysis
of crystals deposited by slow evaporation of a 1/1 Et2O/CH2Cl2 so-
lution at room temperature (Fig. 3). Only the isomer bearing the
butyl and the anilinyl substituents in trans position crystallized,
whereas both isomers were present in solution, as indicated by the
presence of two multiplets for the C-2eH signals at 4.32 and
4.43 ppm in the 1H NMR spectrum of 14.
Among the known functional 4-isochromanones (1H-2-
benzopyran-4(3H)-ones), most of them are oxygenated at the C-1
position, in particular in the tricyclic series,9 where 1-amino,1-oxy
derivatives have also been described.10 Representatives with hy-
Finally, in an attempt at performing addition to the carbalde-
hyde group and metal-chlorine exchange in one pot, 2 equiv of
ethylmagnesium bromide or butyllithium were added to a solution
drogenated C-1 positions (i.e., with
a CHeOR vertex) are

I. Baglai et al. / Tetrahedron 68 (2012) 6908e6913
6911
HN
O
HN
Cl
1) RLi, THF
-78°C, 2 h
1) 2 RM
2) H+
O
O
N
N
or RMgBr, Et2O
-78°C, 1 h
R
R
R
H
OH
Then r.t., 16 h
O
H
HO
M = Li, MgBr
RM
R = Et, 13, 31 %
R = n-Bu, 14, 33 %
2) H+
R = Et, 11
R = n-Bu, 12
3
H2O
O
H
N
O
N
Cl
Cl
N
Cl
R
(H2O)
O
N
R
R
M
H
M'
M'
X
M'
16
O
R
15
M' = M and X = Cl (or M' = H and X = OH)
17
Scheme 5. Reaction of 3 with organolithium and organomagnesium nucleophiles, and proposed mechanism for the rearrangement of the isoindole core of 3 to the 4-
isochromanone core of 13 and 14.
4. Experimental section
4.1. General
THF and diethylether were dried and distilled over sodium/
benzophenone, pentane and dichloromethane over P2O5. All other
reagents were used as commercially available. In particular, com-
mercial solutions of n-BuLi were 2.5 M in hexane and EtMgBr were
3 M in diethylether. All reactions were carried out under nitrogen or
Argon using Schlenk and vacuum line techniques. Column chro-
matography was carried out on silicagel (60 P, 70e200 mm). Silica
gel thin-layer chromatography plates (60F254, 0.25 mm) were
revealed under UV. The following analytical instruments were
used. 1H and 13C NMR: Bruker DPX 300, Avance 300 or Avance 400
spectrometers. Mass spectrometry: Quadrupolar Nermag R10-10H
spectrometer. NMR chemical shifts
d are in parts per million, with
Fig. 3. Cameron diagram of the X-ray crystal structure of the trans-1-phenylamino-1H-
ꢁ
positive values to high frequency relative to the tetramethylsilane
reference; coupling constants J are in Hertz. IR: 0.1 mm CaF2 cell,
PerkineElmer GX FTIR. Absorption spectra: PerkineElmer UVevis
Win-Lab Lambda 35. Emission spectra: FluoroMax-4 Spectrofluo-
rometer HoribaJobinYvon.
2-benzopyran-4(3H)-one trans-14 (Scheme 5). R¼4.4%. Selected bond lengths in A:
C1eO1: 1.4329(10), O1eC2: 1.4289(10), C2eC3: 1.5186(12), C3eO2: 1.2243(10), C3eC4:
1.4775(12), C4eC9: 1.4007(12), C1eC9: 1.5084(12), C1eN1: 1.4380(11). Selected angles
in degrees: C1eO1eC2: 113.40(6), O1eC1eN1: 114.09(7), O1eC1eC9: 109.40(6),
O2eC3eC4: 122.26(8), O2eC3eC2: 120.13(8).
exemplified,11 but to the best of our knowledge, 13 and 14 (with
a CHeNHPh C-1 vertex) are the first examples of 1-amino
representatives.
4.2. Crystallographic data and structural refinement
parameters for compounds 6 and 14
Intensity data for compound 14 were collected on an Agilent
3. Conclusion
Gemini diffractometer using a Cu K
were collected on a Bruker Apex2 diffractometer using a graphite-
monochromated Mo K radiation source. Structures were solved by
a radiation source. Data for 6
The peculiar electrophilic character of the 3-chloro-2-
a
phenylisoindole-1-carbaldehyde 3 can be related with
p
-elec-
direct methods using SIR92,12 or SHELXS,13 and refined by full-
matrix least-squares procedures on F using the programs of the
PC version of CRYSTALS.14 For compound 14, a non-merohedral
twin (0.93/0.07) was detected. Data were treated using the Crysa-
lisPro program,15 and permitted to improve the final results. Atomic
scattering factors were taken from the International Tables for X-
ray Crystallography.16 All non-hydrogen atoms were refined an-
isotropically. Hydrogen atoms were refined using a riding model.
CCDC-862026 and 862027 contain the supplementary
tron-richness and reactivity of the isoindole core. The high sensi-
tivity of the CeCl bond, which was systematically cleaved whatever
the experimental conditions used is however key for the un-
precedented rearrangement of the isoindole core to the iso-
chromanone core induced by nucleophilic addition of alkylmetals
to the carbaldehyde group of 3. Generalization of this reactivity
would allow the investigation of chemical and biological properties
of 1-amino-4-isochromanones.

6912
I. Baglai et al. / Tetrahedron 68 (2012) 6908e6913
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
126.8(2s), 128.8(2s), 129.8(2s), 130.0(2s), 130.5(2s), 130.9, 131.4,
132.5, 132.8, 133.1, 133.3, 133.8, 138.6, 139.0, 151.8. UVevis: lmax
(MeOH): 432 nm (
3
¼38,904 L molꢀ1 cmꢀ1). Fluo (lex¼432 nm):
lEm¼497 nm. MS (ESI>0): m/z 416.21 [M]þ; HRMS (ESI>0): m/z
calcd for C29H26N3: 416.2127; found: 416.2119.
6
14
4.3.3. 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-2-phenyl-2,3-dihydro-1H-
Chemical formula
M (g molꢀ1
C
29H26ClN3
C19H21NO2
295.38
Triclinic
P-1
8.8753(4)
10.0547(4)
10.6142(4)
64.768(3)
67.583(4)
79.728(3)
791.94(6)
2
isoindol-1-one 7a. A mixture of
3 (255 mg, 1 mmol), 2,2-
)
452.00
Triclinic
P-1
dimethylpropane-1,3-diol (105 mg, 1 mmol), and PTSA (40 mg,
0.2 mmol) in toluene (5 mL) was stirred for 16 h at rt. After cooling,
thesolventwas removed underreduced pressure. Thecrudeproduct
was purified by silicagel chromatography (pentane/EtOAc 6/4, v/v)
to give 7a as a white powder (210 mg, 65%). Rf (heptane/EtOAc 1/1, v/
Crystal system
Space group
ꢁ
a (A)
10.4531(5)
10.6908(5)
11.1744(5)
96.211(2)
103.656(2)
97.933(2)
1188.92(10)
2
ꢁ
b (A)
ꢁ
c (A)
a
b
g
(ꢁ)
(ꢁ)
(ꢁ)
v)¼0.37. Mp¼168 ꢁC. IR (ATR):
n
C]O¼1687 cmꢀ1 1H NMR (CDCl3):
d
¼0.63 (s, 3H, CH3), 0.97 (s, 3H, CH3), 3.17 (d, J¼11.2 Hz,1H, CH2), 3.39
3
ꢁ
V (A )
Z
(d, J¼11.2 Hz, 2H, CH2), 3.68 (d, J¼11.2 Hz,1H, CH2), 4.74 (d, J¼2.1 Hz,
1H, CH(O)2), 5.27 (d, J¼2.1 Hz, 1H, CHeN), 7.24 (t, J¼7.6 Hz, 1H, p-
NePh), 7.52 (m, 6H, o-,m-NePh, H-5, H-6), 7.83 (d, J¼7.6 Hz,1H, H-4),
rcalcd
1.263
0.183
34.75
1.239
0.632
60.63
m
(mmꢀ1
)
7.92 (d, J¼7.6 Hz, 1H, H-7). 13C{1H} NMR (CDCl3):
¼21.5, 22.9, 30.3,
d
Өmax (ꢁ)
63.2, 76.5, 77.6, 98.6, 123.7, 124.1, 124.6, 125.8, 128.6, 129.1, 131.6,
132.9, 137.5, 141.1, 167.8. MS (DCI/NH3): m/z¼324.1 [MH]þ, 341.1
[MþNH4]þ. Elemental anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N,
4.33; found: C, 74.38; H, 6.52; N, 4.32.
Crystal size (mm)
0.20ꢂ0.20ꢂ0.30
0.20ꢂ0.20ꢂ0.25
ꢁ
l
(A)
0.71073 (MoKa)
1.54180 (CuKa)
Scan mode
T(K)
F
180
58,484
9703
and U scans
F and U scans
180
4795
2372
Refl. measured
Refl. unique
Rint
Refl. with I>3s(I)
Nb. parameters
0.019
8411
298
0.0521
0.0565
ꢀ0.33/0.88
0.026
4126
200
0.0444
0.0305
ꢀ0.26/0.21
4.3.4. 3-(Diethoxymethyl)-2-phenyl-2,3-dihydro-1H-isoindol-1-one
8. A mixture of 3 (255 mg, 1 mmol), triethyl orthoformate (225 mg,
1.5 mmol), in EtOH (5 mL) was refluxed for 4 h. After cooling to
room temperature, ethanol was removed under reduced pressure.
The crude product was purified by silicagel chromatography
(pentane/EtOAc 6/4, v/v) to give 8 as a yellow powder (0.125 g, 40%).
Rf (heptane/EtOAc 1/1, v/v)¼0.4. Mp¼70e71 ꢁC. IR (ATR):
R
Rw
ꢁꢀ3
ꢂ
Residual electron density (e A
)
n
C]O¼1697 cmꢀ1 1H NMR (CDCl3):
¼1.03 (t, J¼6.9 Hz, 3H, CH3),
d
4.3. Synthesis procedures
1.22 (t, J¼6.9 Hz, 3H, CH3), 3.30 (dq, J¼7.0 Hz, J¼2.0 Hz, 1H, CH2),
3.43 (dq, J¼7.0 Hz, J¼2.0 Hz, 1H, CH2), 3.56 (dq, J¼7.0 Hz, J¼2.0 Hz,
1H, CH2), 3.69 (dq, J¼7.0 Hz, J¼2.0 Hz, 1H, CH2), 4.58 (d, J¼4.0 Hz,
1H, CH(O)2), 5.32 (d, J¼4.0 Hz, 1H, CHeN), 7.26 (t, J¼7.5 Hz, 1H, p-
NePh), 7.57 (m, 6H, o-,m-NePh, H-5, H-6), 7.79 (d, J¼7.5 Hz, 1H, H-
4.3.1. 3-Chloro-2-phenyl-2H-isoindole-1-carbaldehyde
3. POCl3
(1.53 g, 10 mmol) was added dropwise to DMF (0.73 g, 10 mmol) at
0 ꢁC. The mixture was stirred for 30 min at room temperature. After
cooling down the solution back to 0 ꢁC, a suspension of 1-
phenylisoindolinone 4 (0.7 g, 3.3 mmol) in DMF (2 mL) was added.
Subsequently, the reaction mixture was heated at 80 ꢁC for 6 h. Then,
after cooling to room temperature, chloroform (10 mL) and ice were
added. The organic layer was collected and the chloroform was re-
moved under reduced pressure. Then, KOH (4 M, 5 mL) and MeOH
(5 mL) were added to the crude residue, and the mixture was stirred
for 1 h at room temperature. The precipitate was filtered, washed
with water, and recrystallized from i-PrOH, to give 3 as a light yellow
4), 7.92 (d, J¼7.5 Hz, 1H, H-7). 13C{1H} NMR (CDCl3):
¼15.0, 15.3,
d
63.4, 64.6, 65.6, 102.7, 123.5, 123.7, 124.8, 125.4, 128.6, 129.0, 131.8,
132.8, 137.9, 168.0. MS (DCI/NH3): m/z¼312.1 [MH]þ, 329.1
[MþNH4]þ. Elemental anal. Calcd for C19H21NO3: C, 73.29; H, 6.80;
N, 4.50; found: C, 73.15; H, 6.57; N, 4.57.
4.3.5. 3-(Ethoxymethylidene)-2-phenyl-2,3-dihydro-1H-isoindol-1-
one 9. The product 9 was isolated by purification on silicagel of the
reaction mixture obtained in the preparation of 8. Rf (heptane/
solid (0.58 g, 69%). Mp¼98e99 ꢁC. IR (ATR):
n
C]O¼1614 cmꢀ1 1H
EtOAc 1/1, v/v)¼0.32. Mp¼136e140 ꢁC. IR (ATR):
n
C]O¼1697 cmꢀ1
NMR (acetone-d6):
d
¼7.36 (t, J¼7.8 Hz,1H, H-5), 7.49 (t, J¼7.8 Hz,1H,
1H NMR (CDCl3):
d
¼1.07, 1.14 (2t, J¼6.9 Hz, 3H, CH3), 3.85, 4.00 (2q,
H-6), 7.72 (m, 6H, H-4, NePh), 8.33 (d, J¼7.8 Hz,1H, H-7), 9.46 (s,1H,
J¼6.9 Hz, 2H, CH2), 6.37, 6.63 (2s, 1H,¼CH), 7.45e8.09 (m, 9H, o-,m-
CHO). 13C{1H} NMR (acetone-d6):
d¼118.6, 120.5, 122.2, 124.4, 128.2,
,p-NePh, H-4, H-5, H-6, H-7).13C{1H} NMR (CDCl3):
d
¼14.7, 59.2,
128.4, 129.4, 130.2, 135.3, 176.1. UVevis: lmax (CHCl3): 379 nm
123.3, 123.7, 124.7, 126.6, 128.1, 129.1, 129.3, 131.7, 132.7, 134.4, 136.1,
¼22,060 L molꢀ1 cmꢀ1). Fluo (lex¼379 nm): lEm¼409 nm. MS (DCI/
137.7, 167.3. MS (DCI/NH3): m/z¼266.1 [MH]þ.
(
3
NH3): m/z¼256.0 [MH]þ. HRMS (DCI/CH4): m/z calcd for
C15H11NOCl: 256.0529; found: 256.0529.
4.3.6. 3-Ethyl-1-(phenylamino)-3,4-dihydro-1H-2-benzopyran-4-
one 13. A EtMgBr solution (0.13 mL, 1 mmol) was added dropwise
to a solution of 3 (255 mg, 1 mmol) in diethylether (15 mL) at
ꢀ78 ꢁC. The reaction mixture was stirred for 1 h at ꢀ78 ꢁS, and then
for 16 h at rt. The mixture was then hydrolyzed with saturated
aqueous NH4Cl, washed with brine, and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure. The
crude product was purified by silicagel chromatography (pentane/
EtOAc 6/4, v/v) to give 13 as a brown solid (94 mg, 35%). Rf (heptane/
EtOAc 1/1, v/v)¼0.31. Mp¼92e93 ꢁC. IR (ATR): nNeH¼3372,
4.3.2. N-(4-methylphenyl)-3-{[(4-methylphenyl)amino]methyl-
idene}-2-phenyl-2,3-dihydro-1H-isoindol-1-imine
hydrochloride
6a. A solution of 3 (255 mg, 1 mmol) and 4-methylaniline (107 mg,
1 mmol) in MeOH (5 mL) was stirred at room temperature for 24 h.
The resulting precipitate was filtered and washed with MeOH
(3ꢂ1 mL) to give 6a as a yellow solid (115 mg, 51%). 1H NMR
(CD3OD):
d
¼2.28 (s, 3H, Me), 2.44 (s, 3H, Me), 6.86 (s, 1H, C]CH),
6.95 (d, J¼8.0 Hz, 2H, Nþ-o-Ar), 7.13 (m, 3H, C]N-m-Ar, N-p-Ph),
7.29e7.35 (m, 5H, eC]N-o-Ar, Nþ-m-Ar), (1H, H-5), 7.66e7.88 (m,
6H, N-o, m-Ph, H-4, H-6), 8.42 (d, J¼8.0 Hz, 1H, H-7). 13C{1H} NMR
n
C]O¼1697 cmꢀ1 1H NMR (CDCl3):
¼1.00, 1.09 (2t, J¼7.5 Hz, 3H,
d
CH3), 1.86e2.22 (m, 2H, CH2), 4.25, 4.45 (2m, 1H, CH(C]O)), 4.59,
4.62 (2m, 1H, NH), 6.22 (m, 1H, CHeN), 6.88e6.98 (m, 3H, o-,p-
(CD3OD):
d
¼19.3, 19.7, 116.3, 121.2, 121.3, 124.4, 126.1, 126.6(2c),

I. Baglai et al. / Tetrahedron 68 (2012) 6908e6913
6913
NePh), 7.26e7.65 (m, 5H, m-NePh, H-5, H-6, H-7), 8.07 (m, 1H, H-
8). 13C{1H} NMR (CDCl3):
123.6, 124.6, 129.3, 131.0, 134.1, 141.2, 145.6, 196.7. MS (DCI/NH3): m/
z¼268.1 [MH]þ. HRMS (DCI/CH4): m/z calcd for C17H18NO2 [MH]þ:
268.1338; found: 268.1340.
References and notes
d
¼9.7, 23.4, 74.5, 80.4, 114.1, 114.9, 119.6,
1. Wittig, G.; Tenhaeff, H.; Schoch, W.; Koenig, G. Justus Liebigs Ann. Chem. 1951,
572, 1.
2. (a) Claessens, S.; Jacobs, J.; Van Aeken, S.; Abbaspour Tehrani, K.; De Kimpe, N. J.
Org. Chem. 2008, 73, 7555; (b) Deblander, J.; Van Aeken, S.; Jacobs, J.; De Kimpe,
N.; Abbaspour Tehrani, K. Eur. J. Org. Chem. 2009, 4882.
3. See, for examples: (a) Voitenko, Z. V.; Halaev, O. I.; Samoylenko, V. P.; Kolotilov,
S. V.; Donnadieu, B.; Lepetit, C.; Chauvin, R. Tetrahedron 2010, 66, 8214 and
references therein; (b) Voitenko, Z. V.; Kysil, A. I.; Turov, A. V.; Wolf, J. G. Zhurnal
Organichnoi ta Farmatsevtichnoi Khimii 2006, 4, 36; (c) Voitenko, Z. V.; Sa-
moylenko, V. P. Chem. Heterocycl. Comp. 2002, 38, 197; (d) Kovtunenko, V. A.;
Kucherenko, T. T.; Voitenko, Z. V. Ukrainskii Khimicheskii Zhurnal (Russian Edi-
tion) 1992, 58, 1035; (e) Kreher, R. P.; Seubert, J.; Schmitt, D.; Use, G.; Kohl, N.;
Muleta, T. Chem. Ber. 1990, 123, 381; (f) Kovtunenko, V. A.; Kucherenko, T. T.;
Voitenko, Z. V.; Tyltin, A. K.; Babichev, F. S. Ukrainskii Khimicheskii Zhurnal
(Russian Edition) 1989, 55, 64; (g) Bonnett, R.; North, S. A. Adv. Heterocycl. Chem.
1981, 29, 341.
4.3.7. 3-Butyl-1-(phenylamino)-3,4-dihydro-1H-2-benzopyran-4-
one 14. A n-BuLi solution (0.4 mL, 1 mmol) was added dropwise to
the solution of 3 (255 mg, 1 mmol) in THF (15 mL) at ꢀ78 ꢁC. The
reaction mixture was stirred for 2 h at ꢀ78 ꢁS, and then, the
mixture was hydrolyzed with saturated aqueous NH4Cl, washed
with brine, and dried over anhydrous MgSO4. Then, the solvent was
removed under vacuum. The crude product was purified by silica-
gel chromatography (pentane/EtOAc 6/4, v/v) to give 14 as a brown
solid (109 mg, 37%). Rf (heptane/EtOAc 1/1, v/v)¼0.38.
4. Hordiyenko, O. V.; Rudenko, I. V.; Biitseva, A. V.; Turov, A. V.; Arrault, A.; Brosse,
ꢃ
Mp¼88e89 ꢁC. IR (ATR): nNeH¼3374,
n
C]O¼1682 cmꢀ1 1H NMR
N.; Fabre, O.; Jamart-Gregoire, B.; Zubatyuk, R. I.; Shishkin, O. V. Tetrahedron
2009, 65, 6218.
(CDCl3):
d
¼0.90 (m, 3H, CH3), 1.29e2.07 (m, 6H, 3ꢂCH2), 4.32, 4.43
5. Diana, P.; Martorana, A.; Barraja, P.; Montalbano, A.; Carbone, A.; Cirrincione, G.
Tetrahedron 2011, 67, 2072.
(2m, 1H, CH(C]O)), 4.65 (m, 1H, NH), 6.21 (m, 1H, CHeN),
6.90e6.97 (m, 3H, o-,p-NePh), 7.25e7.77 (m, 5H, m-NePh, H-5, H-6,
6. (a) Von Dobeneck, H.; Reinhard, H.; Deubel, H.; Wolkenstein, D. Chem. Ber. 1969,
102, 1357; (b) Messerschmitt, T.; von Specht, U.; von Dobeneck, H. Liebigs Ann.
Chem. 1971, 751, 50.
7. Magomedova, M. S.; Neigauz, M. Z.; Zavodnik, V. E. Kristallografiya 1981, 26, 841.
8. Jiao, L.; Yu, C.; Liu, M.; Wu, Y.; Cong, K.; Meng, T.; Wang, Y.; Hao, E. J. Org. Chem.
2010, 75, 6035.
H-7), 8.06 (m, 1H, H-8). 13C{1H} NMR (CDCl3):
d
¼13.9, 22.4, 27.4,
29.7, 73.3, 81.6, 114.1, 114.9, 119.6, 126.5, 127.0, 129.3, 134.2, 141.2,
144.9, 145.6. MS (DCI/NH3): m/z¼296.1 [MH]þ. HRMS (DCI/CH4): m/
z calcd for C19H22NO2: 296.1651; found: 296.1656.
9. Padwa, A.; Carter, S. P.; Nimmesgern, H.; Stull, P. D. J. Am. Chem. Soc. 1988, 110,
2894.
10. See, for example: (a) Padwa, A.; Carter, S. P.; Nimmesgern, H. J. Org. Chem. 1985,
51, 1157; (b) Suga, H.; Ebiura, Y.; Fukushima, K.; Kakehi, A.; Baba, T. J. Org. Chem.
2005, 70, 10782.
11. (a) Sammes, P. G.; Whitby, R. J. Perkin Trans. 1 1987, 195; (b) Kuhl, N.; Glorius, F.
Chem. Commun. 2011, 573.
Acknowledgements
12. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori,
The authors wish to thank the French Embassy in Kiev for the
financial support of I.B., the Centre National de la Recherche Sci-
entifique for funding the GDRI «Groupement Franco-Ukrainien en
G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
13. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.
14. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl.
Crystallogr. 2003, 36, 1487.
ꢀ
Chimie Moleculaire», and both the Paul Sabatier University and the
15. Oxford Diffraction; CrysAlisPro: 2010.
Taras Shevchenko University for general support of the Toulouse-
Kiev collaboration.
16. International Tables for X-ray Crystallography; Kynoch: Birmingham, England,
1974; vol. IV; 1.