Synthesis and spectroscopic properties of 5-tert-butyl-3-(trifluoromethyl) phthalonitrile: A novel precursor for the synthesis of phthalocyanines

Article abstract of DOI:10.1016/j.tetlet.2013.05.145

The synthesis and spectroscopic characterization of the new phthalonitrile 5-tert-butyl-3-(trifluoromethyl)phthalonitrile is reported. A six-step route, which started with a regiospecific iodination, followed by CuI-catalyzed trifluoromethylation, is disc

Full text of DOI:10.1016/j.tetlet.2013.05.145

Tetrahedron Letters 54 (2013) 4388–4391
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and spectroscopic properties
of 5-tert-butyl-3-(trifluoromethyl)phthalonitrile: a novel precursor
for the synthesis of phthalocyanines
⇑
Łukasz Łapok , Arkadiusz Gut, Maria Nowakowska
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and spectroscopic characterization of the new phthalonitrile 5-tert-butyl-3-(trifluoro-
methyl)phthalonitrile is reported. A six-step route, which started with a regiospecific iodination, followed
by CuI-catalyzed trifluoromethylation, is discussed. The title compound is also converted into the more
reactive compound 6-tert-butyl-4-trifluoromethyl-1,3-diiminoisoindoline.
Received 8 April 2013
Revised 16 May 2013
Accepted 30 May 2013
Available online 10 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Phthalonitriles
Electrophilic substitution
Nucleophilic trifluoromethylation
Phthalocyanines
Fluorine-containing motifs, such as fluoro (F-), difluoromethyl
(CHF2-), and trifluoromethyl (CF3-) groups, are present in the struc-
tures of many compounds which are important to the pharmaceu-
tical and agricultural industry.1 For example, a trifluoromethyl
group attached to the aryl ring can be found in many commercially
available medications, such as Prozac (antidepressant), Nexavar
(anticancer), Naturetin (antihypertensive), Emeden (antiemetic),
Viroptic (antiviral), Lariam (antimalarial), and Sensipar (calcimi-
metic).2 Fluorine and fluorine-containing functional groups are
introduced into biologically active compounds in order to improve
their pharmacokinetic, pharmacodynamic, and physicochemical
parameters, for example lipophilicity, stability, or blood circulation
time.3 It has become evident that appropriate positioning of the
fluorine-containing group in a molecule can modify greatly its
physicochemical properties, and its biological activity. The portfo-
lio of commercially available fluorinating agents has expanded
greatly, with many showing high chemoselectivity and regioselec-
tivity. In addition, many ready-to-use fluorine-containing building
blocks have been reported, which facilitate the synthesis of new
biologically active compounds and drug discovery.4
20 years are photosensitizers, such as porphyrins, phthalocyanines,
corroles, and chlorins.5 Photosensitizers, due to their ability to
transfer the energy acquired by absorption of light to molecules
of oxygen resulting in the formation of highly cytotoxic reactive
oxygen species (ROS), have proven to be useful tools in cancer
diagnosis and in photodynamic cancer therapy (PDT). In one of
our current projects, we developed an interest in phthalocyanines
as PDT active agents. Phthalocyanines seem to be better suited,
more than any other group of organic dyes, as perfect candidates
as photosensitizers in PDT. This is mainly due to their intrinsic
properties, viz. efficient absorption of light in the visible and IR
region, high molar extinction coefficients, good photochemical sta-
bility, and above all, an ability to produce efficiently the reactive
oxygen species (ROS). Phthalocyanines are typically prepared from
aromatic ortho-disubstituted derivatives, such as phthalic acids,
phthalimides, or 1,3-diiminoisoindolines.6,7 However, by far the
most versatile precursors for the synthesis of phthalocyanines con-
tinue to be substituted phthalonitriles.8 Despite the fact that many
phthalonitriles are available from commercial sources, the synthe-
sis of phthalonitriles with more sophisticated substitution patterns
is far from trivial and often involves multistep routes. Herein, we
describe a six-step synthesis of a novel trifluoromethyl-containing
phthalonitrile as an important building block for the synthesis of
phthalocyanines with interesting optical and biological properties.
Scheme 1 illustrates the synthesis of the phthalonitrile under
discussion. A tert-butyl group was introduced into ortho-xylene
(1) by modification of a well-established Friedel–Crafts alkylation.
After distillation under reduced pressure, ortho-xylene 1 was
The classes of biologically active compounds which have been
modified by attaching a fluorine-containing group to the parent
structure include hormones, vitamins, antibiotics, carbohydrates,
and small-ring heterocycles. Another group of fluorine-bearing
motifs which have attracted a great deal of attention over the past
⇑
Corresponding author. Tel.: +48 12 6632083; fax: +48 12 6340515.
E-mail address: lapok@chemia.uj.edu.pl (Ł. Łapok).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.145

Ł. Łapok et al. / Tetrahedron Letters 54 (2013) 4388–4391
4389
Scheme 1. Reagents and conditions: (a) H5IO6, I2, CH3COOH, H2SO4, H2O, 60–65 °C, 6 h, 81%; (b) CF3COONa, CuI, NMP, 160 °C, 24 h, 41%; (c) KMnO4, py/H2O, 11 days, 100 °C,
96%; (d) formamide, 190 °C, 1 h, 96%; (e) NH3, H2O, MeOH, 80 °C, 1 h; (f) POCl3, py, 0 °C to rt, 2 h, 23%; (g) MeOH, NH3, NaOMe, rt, 24 h.
isolated in 85% yield.9,10 Iodine was then introduced regiospecifi-
cally into 1 by a previously described route.11
centered at –60.19 ppm confirmed the presence of the trifluoro-
methyl group (see Supplementary data, Fig. S3).
The most synthetically useful method for the introduction of a
trifluoromethyl (CF3) group into an aromatic/heteroaromatic ring
system is via coupling of the corresponding aryl/heteroaryl halide
with a trifluoromethyl-copper species.12 In this work, the trifluo-
romethyl group was introduced regiospecifically into 1 by utiliz-
ing sodium trifluoroacetate and copper(I) iodide in the dipolar
aprotic solvent, NMP.13,14 Care was taken to ensure strictly anhy-
drous reaction conditions to avoid reduction of the aromatic ha-
lide 2 into the corresponding aromatic hydrocarbon. It was
found that the use of one equivalent of sodium trifluoroacetate
and copper(I) iodide resulted in a 29% reaction yield, while the
use of two equivalents of sodium trifluoroacetate and copper(I) io-
dide gave a 41% yield. Interestingly, a further increase in the
amount of sodium trifluoroacetate and copper(I) iodide did not re-
sult in an improved reaction yield. The separation of the reaction
product 3 from the unreacted substrate 2 proved to be a very
arduous task. Three vacuum distillations were needed to obtain
the product in sufficient purity (as judged by GC–MS). The regio-
specific introduction of the CF3 group to 2 was corroborated by
mass spectrometry, IR, 1H NMR, 13C NMR, and 19F NMR spectros-
copy. In the 13C NMR spectrum the three fluorine atoms attached
directly to the carbon atom resulted in a quartet centered at about
125 ppm with a coupling constant of ca. 274 Hz (see Supplemen-
tary data, Fig. S2). This large coupling constant is typical for direct
one-bond coupling of the 19F nucleus to a 13C nucleus (1J). More-
over, another quartet centered at around 128 ppm was discernible
in the 13C NMR spectrum with a coupling constant of 28 Hz,
resulting from the coupling of the 19F nucleus with the 13C atom
adjacent to the trifluoromethyl group. In this case, the coupling
constant measured was defined as a two-bond coupling constant
(2J). Another quartet was evident at ca. 120 ppm with a coupling
constant of 5.8 Hz. Here, the 19F atoms of the trifluoromethyl
group split the signal of the C-4 of the aromatic ring giving rise
to the three-bond coupling (3J).15 In the 1H NMR spectrum, two
doublets were observed in the aromatic region of the spectrum
with equal intensities and coupling constants of ca. 2.2 Hz (see
Supplementary data, Fig. S1). The measured coupling constant
clearly indicated that both aromatic protons were located in meta
positions, thereby the 1,2,3,5-substitution pattern was unambigu-
ously corroborated. Moreover, in the 19F NMR spectrum a signal
Oxidation of the methyl groups in 3 was carried out in order to
obtain phthalic acid derivative 4, which could be converted into a
phthalonitrile 7 by a classical route (see Scheme 1). This was
achieved by using KMnO4 in water/pyridine mixture at 100 °C for
11 days. Compared to the other ortho-xylenes investigated in our
laboratory, the oxidation of 3 proceeded very slowly and a very
long reaction time was needed, phthalic acid 4 was eventually ob-
tained in 95% yield. The IR spectrum of 4 was dominated by a sharp
absorption band at 1699 cmÀ1 (C@O) and a broad absorption band
spanning 3300 to 2500 cmÀ1 (–OH), while the 1H NMR spectrum
revealed a broad signal centered at 13.51 ppm accounting for the
two protons of the carboxylic groups. The negative mode ESI mass
spectrum revealed a peak at m/z 289 that was attributed to the [M-
H+]À ion (see Supplementary data, Figs. S6, S9 and S10).
In the next step, phthalic acid 4 was converted into phthalimide
5. Simple heating of 4 in formamide at 190 °C for 1 h provided
phthalimide 5 in a high 96% yield.16,17 The product obtained was
purified chromatographically using silica gel. A strong absorption
in the IR spectrum at 3218 cmÀ1 indicated the presence of an
N–H stretching vibration, while two strong absorption bands at
1776 cmÀ1 and 1722 cmÀ1 were assigned to C@ O stretching vibra-
tions. The ESI mass spectrum of phthalimide 5 was dominated by a
peak at m/z 270 [MÀH+]À. In addition, in the 1H NMR spectrum a
broad peak centered at 7.89 ppm was observed for the N–H hydro-
gen of phthalimide 5 (see Supplementary data, Figs. S11, S14 and
S15).
The main hurdle in the synthesis of phthalonitrile 7 was the
very strong tendency of the phthalamide 6 to undergo basic hydro-
lysis to diammonium phthalate and/or ammonium 2-(aminocar-
bonyl)benzoate. This resulted in a low concentration of the
phthalamide 6 in the crude product, which in turn resulted in a
low reaction yield of the target phthalonitrile 7. For example, when
the ammonolysis of phthalimide 5 was carried out at 80 °C for 1 h,
it was found that the reaction mixture consisted of around 40% of
phthalamide 6 and 60% of diammonium phthalate and/or ammo-
nium 2-(aminocarbonyl)benzoate (as judged by the corresponding
proton signals intensities in the 1H NMR spectrum, see Supplemen-
tary data Fig. S16).
In the final step, phthalamide 6 was converted into the
corresponding phthalonitrile 7 by treatment with phosphorus

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Ł. Łapok et al. / Tetrahedron Letters 54 (2013) 4388–4391
Figure 1. 1H NMR spectrum (upper left), 13C NMR spectrum (upper right), and 19F NMR spectrum (bottom) of 5-tert-butyl-3-(trifluoromethyl)phthalonitrile (7).
oxychloride in dry pyridine as a dehydrating agent.18 After chro-
matographic separation on silica gel, 5-tert-butyl-3-(trifluoro-
methyl)phthalonitrile (7) was obtained in a 23% yield (based on
the phthalimide 5). The 1H NMR spectrum confirmed unambigu-
ously the assigned structure of 7 (Fig. 1). The integration of the sig-
nals observed for the tert-butyl group and an aromatic ring gave, as
expected, a 9:2 ratio. In the 19F NMR spectrum a single peak at
À62.09 ppm was attributed to the trifluoromethyl group attached
to the aromatic ring (Fig. 1). The IR spectrum of the product
showed a sharp peak at 2237 cmÀ1 clearly indicating the presence
of the CN groups (aromatic nitriles). The presence of a peak at m/z
275 [M+Na]+ in the mass spectrum confirmed that the product had
been obtained (see Supplementary data, Figs. S21 and S22).
It is worth noting that phthalonitrile 7 could be easily trans-
formed into its more reactive form, namely 6-tert-butyl-4-trifluo-
romethyl-1,3-diiminoisoindoline (8). Diiminoisoindolines are
very useful precursors for the synthesis of phthalocyanine com-
plexes of less reactive metals, where simple phthalonitriles fail to
give the corresponding dye.7,8 Moreover, 1,3-diiminoisoindolines
have found application as precursors for the synthesis of phthalo-
cyanine homologues, viz. subphthalocyanines. Ammonia gas was
passed through a methanolic solution of 7 at room temperature
with sodium methoxide as the catalyst to afford 1,3-diiminoisoind-
oline 8 quantitatively. The ESI mass spectrum of 8 was dominated
by two peaks: one at m/z 270 [M+H]+ and the other at m/z 292
[M+Na]+ (see Supplementary data, Figs. S23 and S24).
under discussion was converted into its more reactive form,
namely 6-tert-butyl-4-trifluoromethyl-1,3-diiminoisoindoline 8.
Acknowledgments
This work operated within the Foundation for Polish Science
Team Programme, co-financed by the EU European Regional Devel-
opment Fund. PolyMed, TEAM/2008-2/6. We would like to thank
Professor Jerzy Silberring’s team (Department of Biochemistry
and Neurobiology, AGH) for performing ESI mass spectra.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
145.
References and notes
1. Chemistry of Organic Fluorine compounds II, ACS Monograph 187; Hudlick, M.,
Pavlath, A. E., Eds.; Washington: DC, 1995.
2. Roy, S.; Gregg, B. T.; Gribble, G. W.; Van-De, Le; Roy, S. Tetrahedron 2011, 67,
2161–2195.
3. Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11.
4. Sigma–Aldrich has as many as 3787 fluorinated building blocks available.
5. Goslinski, T.; Piskorz, J. J. Photochem. Photobiol. C. 2011, 12, 304–321.
6. Phthalocyanines in Properties and Applications; Leznoff, C. C., Lever, A. B. P., Eds.;
VCH: Weinheim, 1989–1996. vols. 1–4.
7. McKeown, N. The Synthesis of Symmetrical Phthalocyanines In The Porphyrin
Handbook; Academic Press, 2003; Vol. 15.
In conclusion, we have described a six-step synthesis of a novel
CF3 group containing phthalonitrile. Phthalonitriles are known
precursors for the synthesis of phthalocyanines. The phthalonitrile
8. Synthesis of Phthalocyanine Precursors in The Porphyrin Handbook; Sharman, W.
M., van Lier, J. E., Eds.; Academic Press, 2003. vol. 15.

Ł. Łapok et al. / Tetrahedron Letters 54 (2013) 4388–4391
4391
9. Nightingale, D.; Janes, J. R. J. Am. Chem. Soc. 1944, 66, 154.
10. Contractor, R. B.; Peters, A. T. J. Chem. Soc. 1949, 1314.
11. Suzuki, H.; Nakamura, K.; Goto, R. Bull. Chem. Soc. Jpn. 1966, 39, 128–131.
12. Roy, S.; Gregg, B. T.; Gribble, G. W.; Van-De, Le; Roy, S. Tetrahedron 2011, 67,
2161–2195.
13. Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981, 1719–1720.
14. Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker,, D. G. J. Chem. Soc., Perkin
Trans. 1 1988,, 921–926.
15. Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Vyvyan, J. R. Introduction to
Spectroscopy, 4th edition; Brooks/Cole, Cengage Learning, 2009.
16. Kaneko, T.; Sakamoto, M. Jpn. Kokai Tokkyo Koho, 06065200, 08/03/1994, 4 pp.
Heisei. Chemical Abstract Number: P 85717d.
1 h at room temperature. The mixture was quenched by pouring onto crushed
ice and stirred for 10 min, followed by extraction with CH2Cl2 (3 Â 30 mL). The
organic phase was washed with 5% HCl solution (2 Â 50 mL) to remove the
pyridine and then with water until neutral pH was obtained. After solvent
evaporation the residue was subjected to column chromatography (silica gel,
acetone/hexane, 2:8). The first colorless fraction was collected and identified as
the product. Yield: 50 mg, 23%. 1H NMR (300 MHz, CDCl3) d [ppm]: 1.40 (s, 9H,
t-Bu), 7.98 (m, 2H). 13C NMR (75 MHz, CDCl3) d [ppm]: 158.83, 133.57, 127.75
(q, 2J = 4.1 Hz), 123.59, 119.95, 118.91, 116.89 (q, 1J = 293.0 Hz), 112.47, 36.17,
30.73. 19F NMR (282 MHz, CDCl3, fluorobenzene was used as an internal
standard) d [ppm]: À62.09. ESI-MS: m/z = 275 [M+Na]+. FT-IR:
m = 3426 (m),
3089 (m, Ar–H), 2975 (s, C–H), 2959 (s, C–H), 2917 (m, C–H), 2879 (m, C–H),
2237 (s, CN), 1603 (s), 1571 (m), 1480 (s), 1462 (s), 1419 (m), 1402 (m), 1372
(s), 1336 (vs), 1273 (vs), 1249 (s), 1214 (s), 1190 (vs), 1142 (vs), 1094 (s), 909
(s), 873 (m) cmÀ1. Anal. Calcd for C13H11N2F3: C, 61.90; H , 4.40; N, 11.10.
Found: C, 61.80; H, 4.59; N, 10.73.
17. Vagin, S.; Hanack, M. Eur. J. Org. Chem. 2004, 600–606.
18. 5-tert-Butyl-3-(trifluoromethyl)phthalonitrile (7): Anhydrous pyridine (10 mL)
was added to the phthalamide 6 (obtained from 230 mg of phthalimide 5).
Next, POCl3 (0.25 mL, 2.68 mmol) was transferred to the flask via a syringe. The
mixture was stirred under an inert gas atmosphere for 1 h at 0 C, and then for