Novel preparation of fluorinated isoindoles and their conversion to fluorinated benzoporphyrins

Article abstract of DOI:10.1016/j.tetlet.2007.08.063

4,5,6,7-Tetrafluoroisoindole and their related compounds were prepared directly from the corresponding phthalonitriles by reduction of a hydride reagent such as DIBAL or catalytic hydrogenation in the presence of an acid. 4,5,6,7-Tetrafluoroisoindole was

Full text of DOI:10.1016/j.tetlet.2007.08.063

Tetrahedron Letters 48 (2007) 7512–7515
Novel preparation of fluorinated isoindoles and their conversion
to fluorinated benzoporphyrins
Hidemitsu Uno,a,* Go Masuda,b Marie Tukiji,a Yuiko Nishiokaa and Toshiya Iidab
aDivision of Synthesis and Analysis, Department of Molecular Science, Integrated Center for Sciences,
Ehime University and CREST, Japan Science Technology Agency (JST), Bunkyo-cho 2-5, Matsuyama 790-8577, Japan
bE&I Materials Research Center, Nippon Shokubai Co., Ltd., 5-8 Nishi Otabi-cho, Suita, Osaka 564-8512, Japan
Received 4 July 2007; revised 11 August 2007; accepted 16 August 2007
Available online 22 August 2007
Abstract—4,5,6,7-Tetrafluoroisoindole and their related compounds were prepared directly from the corresponding phthalonitriles
by reduction of a hydride reagent such as DIBAL or catalytic hydrogenation in the presence of an acid. 4,5,6,7-Tetrafluoroisoindole
was converted to fluorinated benzoporphyrins.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Isoindole is a very important 10p aromatic heterocycle
and has attracted much attention from synthetic and
theoretical points of view.1–3 Facile tautomerism of
isoindole between 1H- and 2H-isomers is well known.
The 1- and 3-positions of 2H-isoindole are very reactive
toward electrophiles, while the 3-position of 1H-isoin-
dole is highly electrophilic. Thus, self-condensation of
isoindole between the tautomers easily occurs especially
in solution. The parent isoindole was successfully pre-
pared by flash vapor pyrolysis (600 ꢁC) of the corre-
sponding precursor.4 Stabilization of isoindoles was
effectively achieved by the introduction of substituents
on the five-membered pyrrole moiety. Many successful
methods for the preparation of such isoindole deriva-
tives were reported and their strategies for the stabiliza-
tion are as follows: fixation of the tautomerism to the
2H-isomer by N-substitution, substitution by bulky
groups in order to protect these 1- and 3-positions steri-
cally, and introduction of electron-withdrawing groups
in order to lower the HOMO level.5 Contrarily, success-
ful preparations of 1,2,3-free isoindoles are limited to
5-pivaroyl-2H-isoindole6 and 4,5,6,7-tetrahalo-2H-iso-
indoles.4,7 In the former case, stabilization by hydrogen
bonding in a solid state was suggested,6 and HOMO
levels of the latter were greatly lowered.7
During our continuous studies for the preparation and
application of p-expanded porphyrins,8 we became
interested in the stable isoindoles especially 4,5,6,7-tetra-
fluoro-2H-isoindole9 as a building block10 for the prep-
aration of polyfluorinated benzoporphyrins, because the
polyfluorinated phthalocyanines can be applied to an
n-type field effect transistor (FET).11 Only one prepara-
tion method of 4,5,6,7-tetrafluoroisoindole based on the
retro-Diels–Alder strategy has been reported so far.4,8
This method, however, required multi-step conversion
starting from the rather expensive materials such as
bromopentafluorobenzene and N-benzylpyrrole. Since
pyrroles were prepared by the reduction of malenonitrile
derivative,12 we thought this strategy might be applica-
ble for the synthesis of 4,5,6,7-tetrafluoro-2H-isoindole
from 3,4,5,6-tetrafluorophthalonitrile. This was really
found to be the case. In this Letter, we report this new
preparation method of 4,5,6,7-tetrafluoro-2H-isoindole.
R1
R1
R2
R3
CN
R2
R3
Reduction
NH
CN
R1
R1
ð1Þ
1a: R1 = R2 = R3 = F
2a: R1 = R2 = R3 = F
1b: R1 = F, R2 = R3 = OC6F5
1c: R1 = R2 = F, R3 = Cl
1d: R1 = R2 = R3 =Cl
2b: R1 = F, R2 = R3 = OC6F5
2c: R1 = R2 = F, R3 = Cl
2d: R1 = R2 = R3 =Cl
Keywords: Fluorinated isoindoles; Phthalonitriles; Catalytic hydro-
genation; Hexadecafluorotetrabenzoporphyrin.
*
Reduction of 3,4,5,6-tetrafluorophthalonitrile (1a) with
DIBAL was conducted in toluene at 95 ꢁC. After acidic
Corresponding author. Tel.: +81 89 927 9660; fax: +81 89 927
9670; e-mail: uno@dpc.ehime-u.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.063

H. Uno et al. / Tetrahedron Letters 48 (2007) 7512–7515
7513
quenching, a black reaction mixture was obtained. From
the 19F NMR, TLC [silica gel, Rf = 0.45 (30% EtOAc/
hexane)] and GC analyses of the reaction mixture,
formation of only one product was suggested (>98%).
Chromatographic separation followed by sublimation,
however, gave 4,5,6,7-tetrafluoro-2H-isoindole (2a) as
colorless crystals in only 23% yield (Table 1, entry 1).
From the sublimation residue, octafluoro-1,10-biisoin-
dole 3 was obtained in a small amount. In order to
improve the yield, we tested other reduction conditions.
The results are summarized in Table 1.
equivalent of sulfuric acid gave a better yield (41%, entry
5). Pentafluorophenoxy- and chloro-substituted fluoro-
phthalonitriles 1b, c were also employed for this conver-
sion, and the corresponding 2H-isoindoles 2b and 2c
were obtained (entries 8 and 9), although the yield of
2c was quite low (13%). In the case of tetrachloro-
phthalonitrile 1d, isoindole 2d was detected immediately
after column chromatography but it deteriorated very
rapidly.
What was formed from the rest of 1a under the reduc-
tion conditions? In order to find other products, the sil-
ica gel used for the separation was thoroughly extracted
with EtOAc and the extracted material was subject to
MALDI-TOF MS. Peaks (m/z > 500) due to oligomeric
products were found from m/z = 561 (corresponding to
trimer) to ca. 2000 with intervals of 187 due to the tetra-
fluoroisoindole part. By the preparative GPC separa-
tion, one by-product was isolated, the structure of
which was assigned as 4 by spectroscopic and finally
X-ray analyses (Fig. 1).21 When the reaction mixture
was treated with acetic anhydride, 3-acetoxy-4,5,6,7-
tetrafluoro-1H-isoindole was obtained in 4% yield. This
by-product was thought to be formed by acetylation of
4,5,6,7-tetrafluorophthalide (5). The possible reaction
routes to isoindole 2 and the by-products are illustrated
in Scheme 1.
Reduction with borane gave a similar result (entry 3).
Catalytic hydrogenation in the presence of one molar
Table 1. Preparation of fluorinated isoindoles
Entry Phthalonitrile Reagents and conditions
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
DIBAL, toluene, 95 ꢁCa
23
20
37
35
DIBAL, toluene, rtb
BH3ÆTHF, toluene, 65 ꢁC
BH3ÆTHF, toluene, rt
H2, Pd/C, H2SO4, MeOH, rt 41
c
H2, Pd/C, MeOH, rt
—
33
34
13
—
H2, Pd/C, TFA, EtOAc, rt
DIBAL, toluene, 95 ꢁC
DIBAL, toluene, 95 ꢁC
H2, Pd/C, H2SO4, MeOH, rt
d
10
Although 4,5,6,7-tetrafluoro-2H-isoindole (2a) was sta-
ble and stored in the dark without any further precau-
tion, it deteriorated during the work-up manipulation.
We decided to carry out X-ray analysis of the sublimed
sample of 2a. The crystal packing diagram of 2a is
shown in Figure 2. The double NH–F interaction
between NH proton and fluorine atoms at 5- and 6-posi-
a Acidic work-up (1.0 M HCl).
b Basic work-up (1.0 M NaOH).
c A complex mixture was obtained.
d See text.
F
F
F
˚
F
tions [2.444(4) A] connected 2H-isoindole molecules lin-
early, and a sheet formation was observed by additional
similar interactions between proton and fluorine atoms
at 1-, 3-, 4-, and 7-positions [2.524(4) A]. Moreover,
F
F
N
˚
F
F
NH2
O
H
the molecules stacked in an anti-parallel fashion, and
˚
the distance of the mean planes was 3.421(5) A. This
4
crystal packing fixes the tautomers to 2H-isoindole
and also prevents the attack of oxygen. Distinctive bond
Figure 1. Chemical and Ortep drawings of by-product 4.
F
F
F
F
HN
HN
F
F
F
F
F
F
H2N
F
F
F
F
F
F
F
F
F
F
F
H2
H2
F
F
N
F
F
1a
NH
NH
NH
F
N
F
F
NH
NH
NH2
NH
7'
7
NH
6
9
8
NH
H2
- NH3
H2O
H2
- NH3
2H2
H2O
F
-2NH3
F
F
F
F
F
F
F
F
F
HN
F
F
F
F
F
F
NH
F
F
F
NH
N
F
F
O
NH
F
O
F
NH2
F
2a
5
4
3
polymeric products
Scheme 1. Possible reaction routes.

7514
H. Uno et al. / Tetrahedron Letters 48 (2007) 7512–7515
Next, we aimed to prepare fluorinated benzoporphyrins.
Remy reported the efficient preparation (57%) of hexa-
decafluorotetrabenzoporphyrin zinc complex 12-Zn by
condensation of 2a and formaldehyde in the presence
of zinc acetate at a high temperature (375 ꢁC).17 How-
ever, he just reported the UV data, and failed to provide
any NMR data and correct MS spectra. He ascribed the
failure to the formation of paramagnetic species during
the reaction. Therefore, we investigated milder reaction
conditions for the preparation of 12 (Scheme 2). The
Vilsmeier reaction of 2a gave 1-(N,N-dimethylaminom-
ethylene)-1H-isoindole 10 in 58% yield. The isoindole-
nine structure (1H-isoindole) of 10 was unambiguously
confirmed by the X-ray analysis.21 Small bond alteration
˚
was observed in the benzo moiety [1.369(2)–1.415(2) A].
Hydrolysis of 10 gave 2H-isoindole-1-carbaldehyde 11
in 81% yield. Reduction of 11 with DIBAL followed
by acid treatment and oxidation afforded hexadec-
afluorotetrabenzoporphyrin 12-H2 in 28% yield. When
isoindole 2a was treated successively with the
Eschenmoser reagent, zinc acetate, and DDQ, hexadec-
afluorotetrabenzoporphyrin zinc complex 12-Zn were
obtained in 27% yield. We also encountered the diffi-
culty in the purification and identification of hexadec-
afluorotetrabenzoporphyrins 12 due to their highly
stacking nature and easy colloidal formation. Purifica-
tion of 12 was performed by washing with ethyl acetate,
chloroform, methanol, and water. In C5D5N, on NMR
spectra of 12-Zn could be taken due to the colloidal
Figure 2. Crystal packing of 4,5,6,7-tetrafluoro-2H-isoindole 2a. (a)
View normal to (001); (b) view normal to (010); (c) view normal to
(100).
alteration is observed even in the benzene ring; C4–
5
6
7
5
6
˚
7
C (C –C ) bonds [1.331(3) A] are shorter than C –C
3a
4
7a
˚
˚
[1.411(4) A] and C –C (C –C ) bonds [1.401(3) A],
and the inner bond (C3a–C7a) is extremely elongated to
˚
be 1.436(3) A. A similar bond alteration was reported
for 2H-isoindoles.13–16
F
F
F
F
F
F
F
F
Me
F
F
F
iv)
v)
NH
n-Bu
Et
F
F
F
F
N
8%
27%
N
F
N
N
N
F
n-Bu
Me
Et
M
Zn
2a
N
N
N
Et
i)
iii)
58%
NH
NH
HN
Me
n-Bu
F
CHO
Et
F
CHO
NH
F
NMe2
F
F
28%
F
F
F
F
F
ii)
n-Bu
14
12-H2: M = H2
12-Zn: M = Zn
CHO
N
Me
81%
F
13
F
F
11
10
Scheme 2. Preparation of F16-porphyrins. Reagents and conditions: (i) DMF, POCl3; CH2Cl2, rt; aq-NaOAc; (ii) NaOH, EtOH, refl.; (iii) DIBAL,
THF; HCl; AcOH, EtOH; Et3N; DDQ; (iv) Me2N+@CH2ÆIꢀ, CH3CN; Zn(OAc)2, air; (v) 13, TFA, CH2Cl2; Zn(OAc)2; air.
Figure 3. UV–vis spectra of 12-Zn (bold line) in THF and 14 (solid line) in chloroform.

H. Uno et al. / Tetrahedron Letters 48 (2007) 7512–7515
7515
formation. Finally, fine 19F NMR spectra of 12-Zn was
obtained in THF-d8 [d = ꢀ143.6 (8F, m) and ꢀ154.8
(8F, m)]. The inverse [3+1] porphyrin synthesis18 of 2a
with tripyrranedicarbaldehyde 1319 afforded tetrafluoro-
benzoporphyrin 14 in 8% yield. The UV–vis spectra of
fluorinated benzoporphyrin zinc complexes 12-Zn and
14 are shown in Figure 3. The Soret bands of 12-Zn
and 14 showed bathochromical shifts (5 nm for 12-Zn
and 12 nm for 14) compared to the corresponding
non-fluorinated benzoporphyrins.20 Similar shifts were
also observed in Q band absorptions.
8. Anderson, P. S.; Christy, M. E.; Engelhardt, E. L.;
Lundell, G. F.; Ponticello, G. S. J. Heterocycl. Chem.
1977, 14, 213.
9. For a recent example, see: Uno, H.; Nakamoto, K.;
Kuroki, K.; Fujimoto, A.; Ono, N. Chem. Eur. J. 2007, 13,
5773–5784.
10. Warrener, R. N.; Butler, D. N. Aldrichim. Acta 1997, 30,
119.
11. Huang, C.; Katz, H.; West, J. E. J. Appl. Phys. 2006, 100,
114512/1–114512/9; de Oteyza, D. G.; Barrena, E.; Osso,
J. O.; Dossch, H.; Meyer, S.; Pflaum, J. Appl. Phys. Lett.
2005, 87, 183504/1–183504/3.
12. Schwenninger, R.; Ramondenc, V.; Wurst, K.; Schlo¨l, J.;
Kra¨utler, B. Chem. Eur. J. 2000, 6, 1214.
13. Bonnett, R.; Hursthouse, M. B.; North, S. A.; Trotter, J.
J. Chem. Soc., Perkin Trans. 2 1984, 833.
14. Bonnett, R.; Hursthouse, M. B.; North, S. A.; Trotter, J.
J. Chem. Soc., Perkin Trans. 2 1985, 293.
15. Murashima, T.; Tamai, R.; Nishi, K.; Nomura, K.; Fujita,
K.; Uno, H.; Ono, N. J. Chem. Soc., Perkin Trans. 1 2000,
995.
In conclusion, we achieved the facile preparation of
benzene-ring-fluorinated 2H-isoindoles by reduction of
the corresponding phthalonitriles in one step, although
the yields were rather low. Distinctive stability of
4,5,6,7-tetrafluoro-2H-isoindole in solid was rationali-
zed by X-ray analysis. Utilization of 4,5,6,7-tetra-
fluoro-2H-isoindole for benzoporphyrin synthesis was
done, and fluorinated benzoporphyrins were prepared.
16. Takahashi, I.; Tsuzuki, M.; Keumi, T.; Kitajima, H.; Isa,
K.; Hosoi, S.; Tsuda, Y. Chem. Pharm. Bull. 1994, 42,
947.
17. Remy, D. E. Tetrahedron Lett. 1983, 24, 1451.
18. Uno, H.; Masumoto, A.; Ono, N. J. Am. Chem. Soc. 2003,
125, 12082; Sessler, J. L.; Johnson, M. R.; Lynch, V. J.
Org. Chem. 1987, 52, 4394; Shevchuk, S. V.; Davis, J. M.;
Sessler, J. L. Tetrahedron Lett. 2001, 42, 2447.
19. Uno, H.; Nakamoto, K.; Kuroki, K.; Fujimoto, A.; Ono,
N. Chem. Eur. J. 2007, 13, 5773.
Acknowledgment
This work was partially supported by Grant-in-Aid for
Scientific Research B (17350022) from the Ministry of
Education, Culture, Science, Sports and Technology,
Japan.
20. Ito, S.; Ochi, N.; Murashima, T.; Uno, H.; Ono, N.
Heterocycles 2000, 52, 399; Itoh, T.; Murashima, T.; Uno,
H.; Ono, N. J. Chem. Soc., Chem. Commun. 1998, 1661.
21. Crystallographical data for 4: C16H4F8N2O; FW = 392.21,
colorless prisms, 0.20 · 0.15 · 0.05 mm, monoclinic, P21/c
References and notes
1. For reviews, see: ‘Comprehensive Heterocyclic Chemistry’,
Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4,
Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996; Vol. 2.
2. Bird, C. W. Tetrahedron 1992, 58, 335.
3. Chacko, E.; Bornstein, J.; Sadella, D. J. Tetrahedron 1979,
35, 1055.
˚
(#14), Z = 4 in a cell of dimensions a = 4.6394(17) A,
˚
˚
b = 24.603(8) A, c = 11.746(4) A, b = 98.349(3)ꢁ, V =
1326.5(8) A , Dcalc = 1.964 g cmꢀ3, Mo Ka, F(000) =
3
˚
776, T = 150, 2997 unique reflections, 2342 with
F2 > 2r(F2). The final R1 = 0.084, wR2(all) = 0.211, good-
ness-of-fit = 1.013 for 259 parameters refined on F2,
CCDC No. 635797. 2a: C8H3F4N; FW = 189.11, colorless
blocks,
0.50 · 0.16 · 0.16 mm,
monoclinic,
C2/c
˚
(#15), Z = 4 in a cell of dimensions a = 13.297(10) A,
4. Bornstein, J.; Remy, D. E.; Shield, J. E. J. Chem. Soc.,
Chem. Commun. 1972, 1149; Bornstein, J.; Remy, D. E.;
Shields, J. E. Tetrahedron Lett. 1974, 4247.
˚
˚
b = 8.546(6) A,
c = 7.204(5) A,
b = 117.305(4)ꢁ,
Mo Ka,
V = 727.4(9) A , Dcalc = 1.727 g cmꢀ3
,
3
˚
F(000) = 376, T = 298, 832 unique reflections, 341 with
F2 > 2r(F2). The final R1 = 0.062, wR2(all) = 0.143, good-
ness-of-fit = 1.00 for 67 parameters refined on F2, CCDC
No. 635798. 10: C11H8F4N2; FW = 244.19, grey platelet,
0.50 · 0.50 · 0.20 mm, monoclinic, P21/c (#14), Z = 4 in a
5. Donohoe, T. J. 1H- and 2H-isoindoles. In Hetarenes and
Related Ring Systems, Fused Five-Membered Hetarenes
with One Heteroatom; Thomas, E. J., Ed.; Science of
Synthesis; George Thieme Verlag: Stuttgart, 2000; Vol.
10.14, p 654.
6. Kreher, R.; Kohl, N.; Use, G. Angew. Chem., Int. Ed.
Engl. 1982, 21, 621.
7. Babudri, F.; Farinola, G. M.; Naso, F.; Ragni, R. Chem.
Commun. 2007, 1003, From our simple calculation
(MOPAC PM3), the HOMO levels of indole and tetraflu-
oroisoindole 1a were ꢀ8.02 and ꢀ8.75 eV, respectively.
˚ ˚
cell of dimensions a = 6.681(2) A, b = 19.699(7) A,
3
˚
˚
c = 7.723(3) A, b = 101.598(2)ꢁ, V = 995.6(6) A , Dcalc
=
1.629 g cmꢀ3
, Mo Ka, F(000) = 376, T = 150, 2280
unique reflections, 2073 with F2 > 2r(F2). The final
R1 = 0.038, wR2(all) = 0.103, goodness-of-fit = 1.05 for
155 parameters refined on F2, CCDC No. 652719.