Simple and efficient synthesis of pyrazole-fused porphyrins

Article abstract of DOI:10.1016/j.tetlet.2016.02.020

A simple and efficient method for the synthesis of pyrazole-fused porphyrins from readily available N-tosylhydrazones and 2-nitroporphyrins has been developed. This catalyst-free method can be applied to a wide range of substrates and demonstrate excellen

Full text of DOI:10.1016/j.tetlet.2016.02.020

Tetrahedron Letters xxx (2016) xxx–xxx
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Simple and efficient synthesis of pyrazole-fused porphyrins
⇑
⇑
Lei-Lei Yang, Xiao-Fang Li , Xiao-Lian Hu, Xian-Yong Yu
Key Laboratory of Theoretical Organic Chemistry and Functional Molecules, Ministry of Education, Hunan Province College Key Laboratory of QSAR/QSPR, School of Chemistry
and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient method for the synthesis of pyrazole-fused porphyrins from readily available
N-tosylhydrazones and 2-nitroporphyrins has been developed. This catalyst-free method can be applied
to a wide range of substrates and demonstrate excellent tolerance to a variety of substituents.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 28 December 2015
Revised 31 January 2016
Accepted 3 February 2016
Available online xxxx
Keywords:
Porphyrin
2
-Nitroporphyrins
Fused-pyrazole
N-Tosylhydrazones
Heterocycles
Porphyrins are an important and interesting class of molecules
in nature and have shown wide applications in catalysts, molecular
sensing, artificial photosynthesis, nonlinear optical materials,
N-Tosylhydrazones have emerged as useful reagents in many
1
5
organic reactions.
Among these reactions, Tang’s group
developed a simple method for the synthesis of pyrazoles from
1
16
molecular wires, medicine, and so forth. The derivatization step
N-tosylhydrazones and nitroalkenes.
This reaction and the
2
is particularly important for the applications of porphyrin. Thus,
property of 2-nitroporphyrins make it possible to synthesize
pyrazole-fused porphyrins derivatives with N-tosylhydrazones.
As part of our endeavor to synthesize porphyrin derivatives based
considerable efforts have been made to develop selective methods
for allowing the effective functionalization of porphyrin. Up to
now, there are some important methods that have been developed
to modify porphyrin as a useful reaction platform such as bromina-
1
3
on 2-nitroporphyrins, we herein report a simple method for the
synthesis of a series of new porphyrin derivatives by the reaction
of 2-nitroporphyrins and N-tosylhydrazones under basic condition
(Scheme 1).
3
4
5
tion, nitration, and borylation.
4
a
2
-Nitroporphyrin, an easily accessible product by nitration of
porphyrin, has attracted considerable attention in recent years
because of their high versatility as intermediate for further
derivatization. On the one hand, the nitro group can be
converted to amino and diazonium groups, both of them are
In the initial study, we investigated the influence of the differ-
ent base to the reaction of 2-nitroporphyrin 1a and 4-methyl-N -
0
(4-nitrobenzylidene)benzenesulfonohydrazide 2a (Table 1). In
each case the experiment was conducted for 2 h with 1.5 equiv
N-tosylhydrazone 2a and 2 equiv base in N,N-dimethylformamide
(DMF) at 80 °C. The progress of this reaction was monitored by
TLC and the target products were purified by flash column chro-
matography on silica gel. As shown in Table 1, after 2 h, all tested
bases could precede the reaction and provide the desired product
6
important synthetic tools for porphyrin derivatization. On the
other hand, the peripheral double bonds of meso-tetraarylpor-
phyrins can be partially isolated from the macrocyclic conjugation
pathway. So the 2-nitro substituted double bond has the similar
reactivity of normal nitroalkenes. With this property, extensive
researches have been made on 2-nitroporphyrins in nucleophilic
substitution reactions. For example, 2-nitro group can be nucle-
3a except triethylamine (entry 1). We found that Cs
best base for this reaction (70% yield, entry 6), and K
2
CO
3
was the
CO and
2
3
7
ophilically substituted by other groups including thiolates,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were also both suitable
bases with 61% and 65% yield, respectively (entries 2 and 4). The
other bases such as NaH (entry 3) and t-BuOK (entry 5) were also
tested with lower yields from 10% to 23%. Then we improved the
reaction temperature to 100 °C to test the influence of temperature
to this reaction (entry 7). The result showed the yield could not be
markedly increased when improving the reaction temperature. We
Grignard or organolithium reagents, alkoxides,9 1,3-dicarbonyl
compounds, or azide ion. Additionally, many other interesting
reactions also have been investigated such as Diels–Alder cycload-
8
1
0
11
dition, sulfa-Michael/aldol cascade reaction,13 and so on.
1
2
14
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2016.02.020
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Yang, L.-L.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.02.020

2
L.-L. Yang et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Ar
Table 2
Ph
Ph
N
Synthesis of pyrazole-fused porphyrins 3a–q
NH
Ts
HN
NO
Ph
2
Ar
2
NH
N
N
NH
N
N
Ar1
M
N
Cs
CO
Ar1
N
NH
2
3
Ph
+
Ph
Ph
H
Ar
DMF
HN
NO2
Ar
Ts
HN
HN
N
N
N
N
N
N
N
N
Cs
2
CO
3
Ar
1
Ar
1
M
1
+
Ar
1
Ph
Ph
H
Ar2
DMF
N
Scheme 1. Reaction of 2-nitroporphyrins with N-tosylhydrazone under catalyst-
free conditions.
Ar
1
1
Ar
1
2
3
Entrya
Ar
Ar
2
M
Product
Yield (%)
Table 1
1
Optimization of the reaction conditions
1
2
3
4
5
6
7
8
9
1
11
12
1
14
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-NO
2-NO
2
-Ph
-Ph
2H
2H
2H
2H
2H
2H
2H
2H
2H
2H
2H
2H
2H
2H
Cu
Cu
Cu
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
85
60
75
65
61
67
90
58
62
54
55
69
58
85
68
65
78
2
4
2
-NO Ph
4-CN-Ph
4-Cl-Ph
2-Cl-Ph
2,4-di-Cl-Ph
2,6-di-Cl-Ph
4-F-Ph
Ph
Ph
N
NH
NO
Ph
2
Ts
HN
NH
N
N
NH
N
N
N
Base
Ph
+
Ph
Ph
H
4-NO
2
Ph Solvent
HN
HN
4-Br-Ph
Ph
0
Ph
Ph
3a
4-CH
3-OCH
3
-Ph
1a
2a
3
-Ph
3
4-tBu-Ph
4-Py
Entrya
Base
Et
Solvent
Hydrazone (equiv) t (h) T (°C) Yield (%)
15
16
17
4-NO
4-NO
4-NO
2
2
2
-Ph
-Ph
-Ph
1
2
3
4
5
6
7
8
9
1
1
1
1
1
3
N
DMF
DMF
DMF
DMF
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
2
2
2
2
2
2
2
2
2
2
2
2
1
80
80
80
80
80
80
100
80
80
80
80
60
80
80
—
61
10
65
23
70
4-OCH
4-CH -Ph
3
-Ph
K
2
CO
3
3
NaH
DBU
t-BuOK DMF
a
Reactions were performed with 2-nitroporphyrins 1 (0.05 mmol), N-tosylhy-
drazones 2 (0.35 mmol), and Cs CO (0.45 mmol) in DMF (3 ml) at 80 °C.
2 3
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
3
3
DMF
DMF
THF
Toluene
Benzene 1.5
Dioxane 1.5
72
28
Trace
Trace
—
4-NO Ph
2
i, TsNHNH2
MeOH, RT, 3h
ii, 2-nitro-tetraphenylporphyrin
°
2 3
DMF, Cs CO , 80
Ph
N
NH
0
1
2
3
4
O
NH
N
N
CHCl
DMF
DMF
3
1.5
3
7
—
76
85
H
C, 2h
Ph
Ph
O
2
N
one pot
5%
HN
6
a
Unless otherwise specified, all reactions were carried out on 0.015 mmol of 2a
Ph
in 0.5 mL of solvent.
3a
Scheme 3. One-pot reaction of 4-nitrobenzaldehyde to form 3a. Reaction condi-
Ar
tion: (i) 4-nitrobenzaldehyde (0.35 mmol), TsNHNH
ii) 2-nitro-tetraphenylporphyrin (0.05 mmol), Cs CO
2
(0.35 mmol), MeOH, rt, 3 h;
(0.45 mmol), DMF, 80 °C, 2 h.
NNHTs
(
2
3
H
Ar
Ph H
Ph
N
N
tested (entries 9 and 10), but just with trace product 3a. The other
solvents such as dioxane and CHCl could not get any product
NO2
Ph
NH
N
N
NH
N
N
NO2
3
N
N
1,3-dipolar cycloaddition
+
Ph
Ph
Ph
under the same reaction condition (entries 11 and 12). Inspired
by the excellent results, we also investigated the quantity of used
N-tosylhydrazone. The reaction yield was surprisingly improved
when the amount of N-tosylhydrazone was increased (entries 13
and 14). Up to 85% yield was achieved using 7 equiv of N-tosylhy-
drazone and the reaction time was decreased to 1 h (entry 14).
The structure of product 3a was unambiguously established
HN
HN
Ar
H
Ph
Ph
A
-HNO2
Ar
Ar
Ph
N
NH
Ph
N
N
1
13
from its spectroscopic data, especially HRMS, H, and C. The mass
NH
N
N
spectrometry of product 3a displayed the molecular ion peak at
NH
N
N
Ph
1,3-H-shift
+
Ph
Ph
Ph
m/z 776.2769 (calcd 776.2768 for [M+H] ), which indicated the
HN
HN
desired pyrazole-fused product was produced in the reaction.
The UV–Vis absorption spectra of 3a demonstrated the sort band
accompanied by Q bands. These were consistent with our NMR
Ph
Ph
B
3
results ( H and C) of 3a (Supporting information). The 1H NMR
1
13
Scheme 2. Possible reaction mechanism.
3
spectrum of 3a (298 K, CDCl ) was characterized by the inner NH
signal (22, 24 NH) of the pyrrole at d ꢀ2.74 and ꢀ2.72 ppm, and
six b-pyrrole proton signals in the region of d 8.66–8.98 ppm. The
broad peak at d 9.29 ppm was assigned to the proton of NH which
was located on the pyrazole segment, which was confirmed by the
next examined the effect of solvent to the reaction (entries 8–12),
and the best solvent was DMF. Tetrahydrofuran (THF) turned out to
be a fair solvent in this reaction and afforded relatively low yield
(
28%). Aromatic solvents containing toluene and benzene were also
2
deuterium exchange experiment with D O.
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L.-L. Yang et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
A plausible mechanism for the formation of pyrazole-fused
porphyrin is outlined in Scheme 2. The first step was the classic
of Hunan Provincial Education Department (No. 13A026,
12C0116, 14C0463).
1
,3-dipolar cycloaddition reaction of 2-nitroporphyrin and diazo
dipolar which generated in situ by the reaction of tosylhydrazone
and base, the resulting pyrazoline-fused chlorin intermediate A
was transformed into pyrazole-fused porphyrin intermediate B
via elimination of nitrous acid. The final product 3 was formed
by [1,3]-H-migration of pyrazole-fused porphyrin intermediate B.
Next, under the above optimized conditions, we then proceeded
to synthesize a variety of pyrazole-fused porphyrins to test the
generality and scope of the method (Table 2). At first, we examined
the substrate scope of the N-tosylhydrazones, which were derived
from aromatic aldehydes. For example, the N-tosylhydrazones
bearing a range of electron-withdrawing and electron-donating
substituents were successfully converted to the corresponding
products in moderate to high yields (3a–3m). In addition, the
N-tosylhydrazones derived from heteroaromatic aldehyde also
worked well to give the corresponding product in moderate yields
Supplementary data
Supplementary data (a description of the synthesis and charac-
terization of all new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2
016.02.020.
References and notes
1. (a)Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.;
World Scientific Publishing: Singapore, 2010; Vol. 4, (b)The Handook of
Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World
Scientific Publishing: Singapore, 2010; Vol. 12, (c) Urbani, M.; Grätzel, M.;
Nazeeruddin, M. K.; Torres, T. Chem. Rev. 2014, 114, 12330.
2
.
(a) Senge, M. O. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
R., Eds.; Academic Press: San Diego CA, 2000; Vol. 1, (b) Mack, J.; Shen, Z.;
Kobayashi, N. In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; World Scientific: Publishing, Singapore, 2012; Vol. 23,.
(a) Shen, D. M.; Liu, C.; Chen, Q. Y. Chem. Commun. 2005, 4982; (b) Liu, C.; Shen,
D. M.; Chen, Q. Y. Chem. Commun. 2006, 770; (c) Callot, H. J. Bull. Soc. Chim. Fr.
(
3n). And then, we also tested the scope of the porphyrin, 2-nitro-
tetraphenylporphyrin Cu(II) was tested and also afforded the
desired product in moderate yields (3o). Moreover, 4-OCH Ph
and 4-CH Ph-substituted 2-nitroporphyrins Cu(II) were also suit-
3
.
3
1
974, 1492; (d) Jaquinod, L.; Khoury, R. G.; Shea, K. M.; Smith, K. M. Tetrahedron
1999, 55, 13151; (e) Kumar, D. K.; Bhyrappa, P.; Varghese, B. Tetrahedron Lett.
003, 40, 4849.
(a) Giraudeau, A.; Callot, H. J.; Jordan, J.; Ezhar, I.; Gross, M. J. Am. Chem. Soc.
979, 101, 3857; (b) Hombrecher, H. K.; Gherdan, V. M.; Cavaleiro, J. A. S.;
3
2
able substrates to this reaction and afforded the corresponding
products (3p and 3q) in moderate yields. It is noteworthy that
the reaction proceeded with a high level of regioselectivity and
no isomer was detected in all substituents.
4.
1
Neves, M. G. P. M. S.; Condesso, M. F. Tetrahedron 1993, 49, 8569.
Hata, H.; Shinokubo, H.; Osuka, A. J. Am. Chem. Soc. 2005, 127, 8264.
(a) Hombrecher, H. K.; Gherdan, V. M.; Ohm, S.; Cavaleiro, J. A. S.; Neves, M. G.
P. M. S.; Condesso, M. F. Tetrahedron 1993, 49, 8569; (b) Alonso, C. M. A.; Neves,
M. G. P. M.; Tom e´ , A. C.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2004,
3233; (c) Alonso, C. M. A.; Neves, M. G. P. M. S.; Tomé, A. C.; Silva, A. M. S.;
Cavaleiro, J. A. S. Tetrahedron 2005, 61, 11866; (d) Shen, D.-M.; Liu, C.; Chen, Q.-
Y. Eur. J. Org. Chem. 2007, 9, 1419–1422.
5
6
.
.
It is worthy to note that we also developed a one-pot procedure
to perform this reaction. The 1:1 stoichiometry reaction of
0
4
-nitrobenzaldehyde and tosylhydrazide to produce 4-Methyl-N -
(
4-nitrobenzylidene)benzenesulfonohydrazide was completed in
MeOH for 3 h. After removal of the solvent, subjection of the result-
ing residue to the porphyrins synthesis conditions with 2-nitro-
tetraphenylporphyrin generated 3a with 65% yield which was just
a little diminished compared with the separate steps (Scheme 3).
This one-pot method is a viable option, and in most cases, N-tosylhy-
drazones can be prepared without purification in a similar manner.
In conclusion, we have developed a facile method for the prepa-
ration of pyrazole-fused porphyrins from N-tosylhydrazones and
7
.
Baldwin, J. E.; Crossley, M. J.; DeBernardis, J. Tetrahedron 1982, 38, 685.
8. Crossley, M. J.; Harding, M. M.; Tansey, C. W. J. Org. Chem. 1994, 59, 4433.
9
.
(a) Crossley, M. J.; King, L. G. J. Chem. Soc., Perkin Trans. 1 1996, 1251; (b)
Crossley, M. J.; King, L. G.; Simpson, J. L. J. Chem. Soc., Perkin Trans. 1 1997, 3087.
1
1
1
0. Giuntini, F.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Tomé, A. C.; Silva, A. M. S.;
Cavaleiro, J. A. S. Tetrahedron 2005, 61, 10454.
1. Lacerda, P. S. S.; Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.;
Cavaleiro, J. A. S.; Llamas-Saiz, A. Angew. Chem., Int. Ed. 2006, 45, 5487.
2. Ostrowski, S.; Wyr e˛ bek, P. Tetrahedron Lett. 2006, 47, 8437.
13. Yang, L. L.; Hu, X. L.; Tang, Z. Q.; Li, X. F. Chem. Lett. 2015, 44. http://dx.doi.org/
0.1246/cl.150711.
1
2
-nitroporphyrins. The efficient and simple reaction shows
1
4. (a) Jaquinod, L. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
R., Eds.; Academic: New York, 2000; Vol. 1, pp 215–218; (b) Shea, K. M.;
Jaquinod, L.; Khoury, R. G.; Smith, K. M. Tetrahedron 2000, 56, 3139; (c)
Crossley, M. J.; King, L. G. J. Org. Chem. 1993, 58, 4370; (d) Knapp, S.; Vasudevan,
J.; Emge, T. J.; Arison, B. H.; Potenza, J. A.; Schugar, H. J. Agnew. Chem., Int. Ed.
excellent tolerance to a variety of substituents, including both
electron-donating and electron-withdrawing groups. The reaction
provides moderate-to-excellent yields of a wide variety of prod-
ucts, and can be performed as a one-pot procedure without
transition-metal catalysts. The pyrazole-fused porphyrins can be
used as reagent of photodynamic therapy and as derivatization
platform due to the bioactivity and reactivity of pyrazole. Further
studies on the properties of these new and potentially valuable
porphyrins are currently under investigation.
1998, 37, 2368; (e) Gros, C. P.; Jaquinod, L.; Khoury, R. G.; Olmstead, M. M.;
Smith, K. M. J. J. Porphyrins Phthalocyanines 1997, 1, 201; (f) Krattinger, B.;
Nurco, D. J.; Smith, K. M. J. Chem. Soc. 1998, 757; (g) Jaquinod, L.; Gros, C.;
Khoury, R. G.; Smith, K. M. J. Chem. Soc., Chem. Commun. 1996, 2581.
5. (a) Valdés, C.; Barluenga, J. Angew. Chem., Int. Ed. 2011, 50, 7486; (b) Shao, Z.;
Zhang, H. Chem. Soc. Rev. 2012, 41, 560; (c) Xiao, Q.; Zhang, Y.; Wang, J. Acc.
Chem. Res. 2013, 46, 236; (d) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew.
Chem., Int. Ed. 2012, 51, 775; (e) Liu, Z.; Wang, L.; Tan, H.; Zhou, S.; Fu, T.; Xia,
Y.; Zhang, Y.; Wang, J. Chem. Commun. 2014, 50, 5061. 1.
1
1
Acknowledgments
6. Tang, M.; Zhang, W.; Kong, Y. F. Org. Biomol. Chem. 2013, 11, 6250.
This work was supported by National Natural Science
Foundation of China (No. 21371054), the Scientific Research Fund
Please cite this article in press as: Yang, L.-L.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.02.020