On the peculiar reactivity of a C,N-annelated isoindole core

Article abstract of DOI:10.3906/kim-1306-58

C-, N-, and/or O-methylation products were generated from 11H-isoindolo[2,1-a]quinazoline-5-one upon treatment with NaH followed by iodomethane under air, and possible recrystallization from methanol. Two products were fully characterized by NMR and X-ray diffraction analysis. In accordance with the HSAB principle, this soft methylating agent (MeI) leads mainly to the C,C-dimethylated product 11,11-dimethyl-11H-isoindolo[2,1-a] quinazoline-5-one, which was previously not observed, beside the N-methylated product, in a procedure using methyl tosylate as a hard methylating agent of the same substrate in the initial absence of a base. A mechanism is finally proposed for the formation of methyl 2-(3-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)benzoate as an oxidation side product. TUeBITAK.

Full text of DOI:10.3906/kim-1306-58

Turk J Chem
Turkish Journal of Chemistry
(2014) 38: 121 – 126
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1306-58
Research Article
On the peculiar reactivity of a C,N-annelated isoindole core
Iaroslav BAGLAI1,2,3, Val´erie MARAVAL1,2, Zoia Vsevolodivna VOITENKO3,
Carine DUHAYON1,2, Yulian Mikhailovich VOLOVENKO3, Remi CHAUVIN1,2,∗
1CNRS, LCC (Laboratoire de Chimie de Coordination), Toulouse, France
2University of Toulouse, Toulouse, France
3Kiev National Taras Shevchenko University, Kiev, Ukraine
Received: 24.06.2013
•
Accepted: 11.07.2013
•
Published Online: 16.12.2013
•
Printed: 20.01.2014
Abstract: C-, N-, and/or O-methylation products were generated from 11H -isoindolo[2,1-a]quinazoline-5-one upon
treatment with NaH followed by iodomethane under air, and possible recrystallization from methanol. Two products
were fully characterized by NMR and X-ray diffraction analysis. In accordance with the HSAB principle, this soft
methylating agent (MeI) leads mainly to the C,C-dimethylated product 11,11-dimethyl-11H -isoindolo[2,1-a]quinazoline-
5-one, which was previously not observed, beside the N-methylated product, in a procedure using methyl tosylate as a
hard methylating agent of the same substrate in the initial absence of a base. A mechanism is finally proposed for the
formation of methyl 2-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate as an oxidation side product.
Key words: Isoindoles, methylation processes, oxidative ring opening, quinazolines
1. Introduction
The chemistry of isoindoles remains a blooming topic from both the standpoints of fundamental organic re-
activity (aromaticity-driven processes)1 and target-oriented synthesis of biologically active compounds (het-
erocyclic drug design). This is particularly prevalent in the annelated isoindole series, where derivatives of
11H -isoindolo[2,1-a]quinazoline-5-one (1) have been shown to exhibit various activities in vitro.2 Examples of
chemical variations of 1 were based on its treatment with a hard electrophile to give a quaternary ammonium
salt, followed by addition of an alkali metal base leading to a locked N-methylated isoindole form.3,4 The direct
transformation of 1 into the isoindole form is hereafter addressed.
2. Results and discussion
Treatment of 1 with sodium hydride and then with iodomethane afforded 11,11-dimethyl-11H -isoindolo[2,1-
a]quinazoline-5-one (2) as the major product in 43% yield (Scheme 1).
The structure of 2 was ascertained by NMR and IR spectroscopic analyses and mass spectrometry, and
confirmed by X-ray diffraction analysis of a single crystal deposited from diethylether (Figure 1). Therefore,
whereas methylation of various derivatives of 1 under hard (in the initial HSAB sense)5 and harsh conditions
(in the absence of a base with methyl tosylate, at 125–130 ◦ C) afforded the N-methylated isoindole products,
e.g., 4 from 1 itself,3,4 the use of softer and milder conditions (in the presence of a base with MeI at room
temperature) was found to afford the C-dimethylated iminoisoindole derivative 2 as the major product.
∗Correspondence: chauvin@lcc-toulouse.fr
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BAGLAI et al./Turk J Chem
O
N
H
O
N
N
N
H
H
H
1b
1
1a
1) NaH
2) MeI
DMF, air
16 h
MeOTs
130 °C
6 h
O
O
Me
Me
O
N
N
N
+
N
N
N
Me
(43%)
Me
H
CO2Me
(5%)
3
4
2
Scheme 1. Reaction of the C,N-annelated isoindole 1 with hard (left) and soft (right) methylating reagents.
Figure 1. ORTEP view of the X-ray crystal structure of C,C-dimethylated product 2 (Scheme 1). R = 4.2%. Selected
˚
bond lengths in A: N1-C2: 1.5022(10), N1-C5: 1.3624(10), C2-C3: 1.5136(12), C4-C5: 1.4595(11), C5-N6: 1.3099(11),
N6-C7: 1.3821(12), C7-O20: 1.2341(10).
Minor amounts of a side-product were isolated (in 5% yield) from the reaction mixture and assigned to
the ester structure of methyl 2-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate 3 (Scheme 1), which was
confirmed by X-ray diffraction analysis of a single crystal deposited from methanol (Figure 2).
The intense IR stretching vibration bands of the nonequivalent ester and amide carbonyl groups of 3 were
observed at 1722 cm−1 and 1667 cm−1 , respectively. The presence of 2 different methyl groups was confirmed
by 1 H (δNCH3 = 3.33 ppm, δOCH3 = 3.78 ppm) and 13 C (δNCH3 = 32.8 ppm, δOCH3 = 52.6 ppm) NMR
spectroscopy. The amido-ester 3 formally results from concomitant oxidative opening of a ring of the pyrrole
ring of 1 and N-,O-dimethylation.
In a previous report on the formation of such amido-esters, the proposed mechanism was based on
oxidation of 1 by SOCl2 , followed by the formation of amino-hemi-ortho esters generated from aliphatic alcohols,
and subsequent ring-opening to the corresponding esters.6 In the present procedure, no oxidative auxiliary is
added, except the oxygen of air. Although autoxidation by oxygen-derived hydroperoxide radicals cannot be
ruled out, an alternative mechanism, based on previous reports on oxidative pyrrole ring-opening (also annelated
in an isoindole core),7−9 is proposed (Scheme 2).
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BAGLAI et al./Turk J Chem
Figure 2. ORTEP view of the X-ray crystal structure of the amidoester 3. R = 3.4%. Selected bond lengths in
˚
A: N1-C2: 1.2943(11), N31-C32: 1.2901(11), C2-C11: 1.5067(11), C32-C41: 1.5050(11), C2-N3: 1.3750(11), C32-N33:
1.3801(11), N3-C4: 1.3979(11), N33-C34: 1.3954(11), C4-O18: 1.2230(11), C34-O48: 1.2257(11).
3O2 (air)
in situ
E
O
O
E
photosensitizer
(e.g. 1)
O
E
N
N
N
O
NaH
1O2
N
N
O
1
N
O
6a
6
6b
E = Na (5) E = Me (4)
O
MeI
O
O
O
E
N
E
Me
N
O
N
MeOH
MeI
N
H
N
N
6
OH
OMe
recrystallization
O
O
O
7
3
Scheme 2. Proposed mechanism for the oxidative conversion of 1 into the amidoester 3.
After deprotonation of 1 with NaH, the anion of the sodium salt 5 might undergo either primary N-
methylation to 4 (a rather slow process),4 or oxidation by the aerobic atmosphere. Thus 4, or more specifically
5, would react with singlet oxygen that would be generated by some photosensitizer in situ, such as 1 or
one of its heteroaromatic derivatives.10 The process would thus consist of an allowed asynchronous [4 + 2]
cycloaddition process leading to an endo-peroxide structure of type 6a,6−8 which would instantly rearrange
into the zwitterionic peroxide 6b (possibly even directly, without the intermediacy of any cyclo-adduct 6a of
123

BAGLAI et al./Turk J Chem
local minimum energy). The latter would then spontaneously evolve into a carboxylic acid of type 7 via a
carbonyl oxide (and/or a putative dioxirane isomer).11 The latter would finally react with MeI and MeOH
(during recrystallization) to give 3 (not observed by TLC in the crude material).
3. Conclusion
The disclosed results and interpretations provide a further rationale in the scope of the versatile reactivity of
isoindole cores, in particular of C,N-annelated representatives, and open new horizons for the design of either
new structures or new preparative schemes in the field of hetero-aromatic chemistry.
4. Experimental
4.1. General
The following analytical instruments were used. 1 H and 13 C NMR: Bruker DPX 300, Avance 400 or Avance 500
spectrometers. Mass spectrometry: Quadrupolar Nermag R10-10H spectrometer. NMR chemical shifts (δ) are
in parts per million, with positive values to high frequency relative to the tetramethylsilane reference; coupling
constants (J) are in hertz. IR: 0.1 mm CaF2 cell, PerkinElmer GX FTIR. 11H -isoindolo [2,1-a]quinazoline-5-
one was prepared by a previously described procedure.12,13
4.2. Crystallographic data and structural refinement parameters for compounds 2 and 3 (Table).
Intensity data were collected at low temperature on an Agilent Gemini diffractometer or on a Bruker Apex2
diffractometer. Structures were solved by direct methods using SIR9214 or SUPERFLIP,15 and refined by
full-matrix least-squares procedures using the programs of CRYSTALS.16 Atomic scattering factors were taken
from the International Tables for X-ray Crystallography.17 All nonhydrogen atoms were refined anisotropically.
Hydrogen atoms were refined using a riding model. Absorption corrections were introduced using the program
MULTISCAN.18
4.3. Synthesis procedure
A solution of 11H -isoindolo[2,1-a]quinazoline-5-one (0.5 g, 2.1 mmol) in DMF (3 mL) was added dropwise to
a suspension of NaH (100 mg, 2.5 mmol) in DMF (5 mL). The mixture was stirred for 30 min at 0◦ -before
dropwise addition of iodomethane (0.15 mL, 2.35 mmol). Stirring was continued for another 16 h at room
temperature; then chloroform (10 mL) and water (20 mL) were added, and the organic layer was collected,
dried, and concentrated under reduced pressure. The crude residue was recrystallized from Et2 O to give 2 as
a light yellow solid (0.24 g, 43%). The filtrate was then concentrated under reduced pressure and the residue
was stirred in water for 16 h at room temperature. The precipitate was then recovered and recrystallized from
methanol, to give 3 as a white solid (35 mg, 5%).
11,11-dimethyl-11H -isoindolo[2,1-a]quinazoline-5-one (2). mp 219–220◦ . IR: ν (cm−1) 1649
(C=O). 1 H NMR (300 MHz, CDCl3)δ 1.99 (s, 6 H, 2 CH3), 7.84–7.45 (m, 6 H, arom. CH), 8.27 (d, J = 7.6
Hz, 1 H, H 7), 8.54 (d, J = 8.0 Hz, 1 H, H 4). 13 C NMR (101 MHz, CDCl3)δ 26.2 (–H3), 69.6 (C Me2), 115.0,
120.6, 124.7, 125.4, 129.3, 130.1, 133.3, 133.4 (arom C H), 120.2, 130.2, 138.1, 151.6 (quaternary arom.C), 159.7
(C =N), 170.5 (C =O). MS (DCI/NH3): m/z 263.1 ([MH]+), 280.1 ([MNH4 ]+). HRMS (DCI/CH4): m/z
calcd for C17 H15 N2 O [MH]+ : 263.1184; found: 263.1190.
124

BAGLAI et al./Turk J Chem
Table. Crystallographic data from X-ray diffraction analysis of 2 and 3.
Compound nos.
3
2
Chemical formula
C17H14N2O3
294.31
Triclinic
P-1
C17H14N2O
262.31
Othorhombic
Pbca
M (g mol−1
)
Crystal system
Space group
˚
a (A)
10.4664(3)
11.1901(3)
12.5314(4)
83.001(2)
75.099(3)
88.381(2)
1407.75(8)
4
14.2706(7)
12.7347(6)
14.7793(7)
90
90
90
˚
b (A)
˚
c (A)
α (◦)
β (◦)
γ (◦)
3
˚
V (A )
2685.9(2)
8
1.297
0.082
33.30
Z
ρcalcd
µ (mm−1
Θmax (◦)
1.389
0.794
71.71
)
Crystal size (mm)
˚
λ (A)
Scan mode
T (K)
0.20 × 0.20 × 0.25 0.20 × 0.20 × 0.25
1.54180 (CuKα)
Φ and Ω scans
180
0.71073 (MoKα)
Φ and Ω scans
100
Refl. measured
Refl. unique
Rint
Refl. with I > 3σ(I)
Nb. parameters
R
27,384
5458
0.014
5182
397
0.0345
66,121
4989
0.031
3811
181
0.0418
Rw
0.0472
–0.17/0.23
0.0470
–0.18/0.51
−3
˚
Residual electron density (¯e A
)
Methyl 2-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate (3: see Scheme 3). mp 162–
163◦ . IR: ν (cm−1) 1722 (O=C(OMe)), 1667 (O=C(NH)). 1 H NMR (300 MHz, CDCl3)δ 3.33 (s, 3 H,
NCH3), 3.78 (s, 3 H, OCH3), 7.43–7.78 (m, 6 H, arom. CH), 8.20 (d, J = 7.7 Hz, 1 H, C10H), 8.39 (d,
O
17
4
10
7
N
2
5
6
9
8
16
13
15
14
11
12
N
O
19
O
22
Scheme 3. Numbering of the carbon atoms for NMR assignment of the amidoester 3.
125

BAGLAI et al./Turk J Chem
J = 7.1 Hz, 1 H, C13H).13 C NMR (101 MHz, CDCl3)δ 32.8 (NC H3), 52.6 (OC H3), 126.9 (2 C), 127.3,
129.0, 129.9, 131.0, 133.3, 134.1 (arom. C H), 120.8, 128.4, 136.7 (quaternary arom. C), 147.5 (C6), 156.2 (C2),
162.2, 165.8 (2 C =O). MS (DCI/NH3): m/z 295.1 ([MH]+). HRMS (DCI/CH4):m/z calcd for C17 H15 N2 O3
[MH]+ : 295.1083; found: 295.1072.
Acknowledgements
The purchase of supplies and costs of analyses were supported by the ANR (11-BS07-016-01). IB was supported
by the French Embassy in Kiev, Ukraine, the investigations having been performed within the framework of
the GDRI (Groupement Franco-Ukrainien en Chimie Mol´eculaire) funded by the CNRS. The ANR, the French
Embassy in Kiev, and the CNRS are thus sincerely acknowledged.
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