A new reagent for the synthesis of [26]hexaphyrin: N-sulfonyl aldimine

Article abstract of DOI:10.1016/j.tetlet.2013.11.101

The selective synthesis of [26]hexaphyrin(1.1.1.1.1.1) has been achieved by the reaction of meso-substituted tripyrrane and N-sulfonyl aldimine. The protocol is simple and requires only a catalytic amount of copper(II) triflate under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2013.11.101

Tetrahedron Letters 55 (2014) 544–547
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new reagent for the synthesis of [26]hexaphyrin: N-sulfonyl
aldimine
⇑
Seda Cinar, Baris Temelli, Canan Unaleroglu
Hacettepe University, Department of Chemistry, 06800 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2013
Revised 5 November 2013
Accepted 26 November 2013
Available online 1 December 2013
The selective synthesis of [26]hexaphyrin(1.1.1.1.1.1) has been achieved by the reaction of meso-substi-
tuted tripyrrane and N-sulfonyl aldimine. The protocol is simple and requires only a catalytic amount of
copper(II) triflate under mild reaction conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Expanded porphyrin
Hexaphyrin
Tripyrrane
N-sulfonyl aldimine
Expanded porphyrins as a class of macrocyclic molecules have
attracted much attention because of their unique optical, electro-
chemical, and coordination properties.1 The number of pyrrolic
units and their linkages designate the structures of expanded por-
thesis of hexaphyrin by copper(II) triflate catalyzed [3+3] condensa-
tion of meso-pentafluorophenyl substituted tripyrrane 1 and N-
sulfonyl aldimine 2. Herein, we report our results in detail.
The reactivity of pyrroles with N-sulfonyl aldimines in the pres-
ence of metal triflate catalysts was first discovered during our
previous studies on the synthesis of 2-substituted pyrrole sulfona-
mides, meso-substituted dipyrromethanes, and porphyrins.6 These
results prompted us to investigate further the synthesis of ex-
panded porphyrins, especially meso-substituted hexaphyrins from
meso-pentafluorophenyl substituted tripyrrane 1 and N-sulfonyl
aldimine 2. In initial experiments, we compared the reactivity of tri-
pyrrane 1 toward aldehyde 3 and N-sulfonyl aldimine 2 (Scheme 1).
Condensation reactions were carried out in the presence of
10 mol % of copper(II) triflate as the catalyst at room temperature
in dichloromethane for two hours, and the condensation products
were oxidized by adding DDQ. N-Sulfonyl aldimine 2 afforded
meso-pentafluorophenyl substituted [26]hexaphyrin(1.1.1.1.1.1) 5
in a promising 19% yield and in 14% yield with pentafluorobenzal-
dehyde. The spectroscopic data of hexaphyrin were in agreement
with the literature values. Both reactions gave porphyrin and some
expanded porphyrins (heptaphyrin, octaphyrin, and nonaphyrin) as
side products, and scrambling of expanded porphyrinogen precur-
sors, which is typically encountered in porphyrin synthesis could
be the main reason for the formation of these side products.7 These
compounds were separated by column chromatography and identi-
fied by MALDI-TOF-MS.
phyrins, the ring size of which and number of
p electrons influence
their properties. Their complexing ability with transition metals
also makes them important precursors in the field of biomedical
applications such as photodynamic therapy (PDT) and magnetic
resonance imaging (MRI).2 Among expanded porphyrins, hexapyrr-
olic systems have drawn attention due to their structural stability,
flexibility, high molecular symmetry, and variable metallation
behavior. The first meso-hexaphenylhexaphyrin was reported by
Dolphin et al., but the poor stability of this compound prevented
spectroscopic characterization.3 Cavaleiro et al. obtained stable
meso-hexa(pentafluorophenyl)hexaphyrin during Rothemund syn-
thesis of meso-tetra(pentafluorophenyl)porphyrin.4 They charac-
terized the structure by using spectroscopic techniques and
reported the X-ray structure. Osuka and co-workers have made sig-
nificant contributions, especially on the synthesis and characteriza-
tion of hexaphyrin and higher analogues.5 Their pioneering work on
the ring size selective synthesis of expanded porphyrins indicated
that dipyrromethane or tripyrromethane in place of pyrrole was
suitable starting material. The reaction conditions and catalyst are
also very important in the synthesis of the target molecules.6 It is
still challenging for organic chemists to develop more convenient
synthetic routes for ring size selective hexaphyrin synthesis. In this
context, we have successfully developed the ring size selective syn-
In order to optimize this procedure, a variety of catalysts were
screened (Table 1). Among the triflates, only Cu(OTf)2 showed cat-
alytic activity by producing hexaphyrin 5 with high selectivity
(19% yield) (Table 1, entries 1–4). BF3ÁOEt2 and TfOH gave porphyrin
⇑
Corresponding author. Tel.: +90 312 297 7962; fax: +90 312 299 2163.
E-mail address: canan@hacettepe.edu.tr (C. Unaleroglu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.101

S. Cinar et al. / Tetrahedron Letters 55 (2014) 544–547
545
C6F5
C6F5
C6F5
C6F5
N
H
N
H
Ts
C6F5CHO
C6F5
N
+
+
NH
NH
HN
HN
3
1
2
1
1. Cu(OTf)2 (10 mol%)
2. DDQ
C6F5
C6F5
N
porphyrin
N
HN
NH
N
heptaphyrin
octaphyrin
nonaphyrin
C6F5
+
C6F5
N
C6F5
C6F5
5
Scheme 1. Synthesis of expanded porphyrins.
Table 1
Effect of the catalyst on the reaction of tripyrrane 1 and N-sulfonyl aldimine 2
C6F5
C6F5
C6F5
n=1 porphyrin (4)
n=3 hexaphyrin (5)
n=4 heptaphyrin (6)
n=5 octaphyrin (7)
n=6 nonaphyrin (8)
N
H
NH
N
Ts
N
1. Cu(OTf)2, rt, CH2Cl2, 2 h
2. DDQ, rt , 1 h
C6F5
N
+
HN
NH
C6F5
C6F5
HN
1
2
n
C6F5
Entryb
Catalyst
Yielda (%)
4
5
6
7
8
1
2
3
4
5
6
7
Y(OTf)3
Yb(OTf)3
Sc(OTf)3
Cu(OTf)2
TFA
—
—
—
12
8
—
—
—
19
15
—
—
—
—
1
5
—
—
—
—
—
5
—
—
—
—
—
—
4
—
—
—
BF3ÁOEt2
21
35
TfOH
—
a
Isolated yield after column chromatography.
Reactions were carried out at 45 mM concentration.
b
4 as the sole product in 21% and 35% yields, respectively (Table 1,
entries 5 and 6). Only TFA which is a commonly used catalyst in
the synthesis of porphyrins and expanded porphyrins afforded hex-
aphyrin (5) (15%) in a comparable yield to Cu(OTf)2.
4, hexaphyrin 5, heptaphyrin 6, and nonaphyrin 8 products were
obtained in almost the same yields (ꢀ2–5%) at 30 mM. The
reaction showed similar behavior at 60 mM and 90 mM for all
the products and the yield of hexaphyrin 5 was reduced to 9%.
The tendency for the polymerization of oligopyrroles at higher con-
centrations caused a decrease in the yield of hexaphyrin.
Next, we investigated the effect of the solvent on the reaction
(Table 2, entries 1–5). Among the examined solvents, the best
result was obtained in dichloromethane. While porphyrins were
formed in chloroform with comparable yields to dichloromethane,
no products were obtained in acetonitrile or toluene. The effect of
catalyst loading on the reaction was also tested (Table 2, entries
6–8). When 1% of the catalyst was used, no products were ob-
tained; 5% and 20% catalyst loadings led to a decrease in the yield
of hexaphyrin (5). However, there was a significant increase in the
yield of heptaphyrin (6) (9%) with a high Cu(OTf)2 loading (Table 2,
entry 6).
Using our optimized conditions, we further examined the effect
of concentration, temperature and time on the reaction. The
substrate concentration has a profound effect on the formation of
porphyrins.7a For this reason, the reaction was performed at differ-
ent concentrations (Table 3, entries 1–4). The highest yield of hex-
aphyrin 5 was obtained at 45 mM. When the concentration was
decreased to 30 mM, or increased to 60 mM or 90 mM, formation
of hexaphyrin 5 in high yields was no longer selective. Porphyrin
Temperature is known to be an important parameter in the
synthesis of expanded porphyrins and reactions in the literature
are generally carried out at low temperatures such as 0 °C.5b,8 Tak-
ing into account this importance, the reaction was repeated at 0
and 50 °C (Table 3, entries 5 and 6). The reaction at 0 °C gave hex-
aphyrin 5 in 7% yield with the same yield of porphyrin 4. At 50 °C,
the amount of hexaphyrin 5 was reduced dramatically to 5% and a
large increase in the amount of porphyrin 4 resulted (20% yield).
Interestingly, no other expanded products (heptaphyrin, octaphy-
rin, or nonaphyrin) were observed at lower or higher temperatures.
We finally examined the effect of the reaction time before DDQ
addition using the optimized conditions (Table 3, entries 7–11).
When the reaction time was reduced to one hour, the yield of
hexaphyrin 5 decreased to 10%. However, when the reaction time
was extended to eight hours, size selective hexaphyrin formation
was successfully achieved raising the yield to 25%. In the literature,
hexaphyrin is known to be synthesized in up to 30% yield along

546
S. Cinar et al. / Tetrahedron Letters 55 (2014) 544–547
Table 2
Effect of the solvent and catalyst loading on the reaction of tripyrrane 1 and N-sulfonyl aldimine 2
C6F5
n=1 porphyrin (4)
n=3 hexaphyrin (5)
n=4 heptaphyrin (6)
n=5 octaphyrin (7)
n=6 nonaphyrin (8)
C6F5
C6F5
N
H
NH
N
N
Ts
1. Cu(OTf)2, rt, 2 h
2. DDQ, rt, 1 h
C6F5
N
+
C6F5
C6F5
HN
NH
HN
1
2
n
C6F5
Entryb
Solvent
Catalyst (%)
Yielda (%)
4
5
6
7
8
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
THF
Toluene
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
10
10
10
10
10
20
5
12
12
2
—
—
7
19
18
9
—
—
14
4
1
5
14
—
—
9
5
6
2
—
—
—
5
4
2
3
—
—
—
—
—
4
—
1
—
1
—
—
a
Isolated yield after column chromatography.
Reactions were carried out at 45 mM concentration.
b
Table 3
Effect of the concentration, temperature and reaction time on the Cu(OTf)2-catalyzed
reaction of tripyrrane 1 and N-sulfonyl aldimine 2 in CH2Cl2
In summary, we have developed an efficient reaction protocol
for the synthesis of hexaphyrin based on the Cu(OTf)2-catalyzed
reaction of tripyrrane with N-sulfonyl aldimine. The reaction
conditions were optimized to give the highest yield of hexaphyrin
with high selectivity. The method requires a catalytic amount of
Entry
1 (mM)
Temp (°C)
Timeb (h)
Yielda (%)
4
5
6
7
8
1
2
3
4
5
6
7
8
9
30
45
60
90
45
45
45
45
45
45
45
rt
rt
rt
rt
0
50
rt
rt
rt
rt
rt
2
2
2
2
2
2
1
4
8
4
12
5
3
7
20
8
9
11
12
12
4
19
9
9
7
2
1
3
4
5
5
5
4
4
Cu(OTf)2 as
inexpensive.
a water-stable catalyst, which is reusable and
3
5
5
—
—
14
11
1
—
—
—
2
3
5
—
—
—
5
7
5
Acknowledgment
5
10
21
25
22
22
This work was supported by the Scientific and Technological
Research Council of Turkey (TUBITAK), under Grant 110T777.
10
11
16
24
4
5
7
4
Supplementary data
a
Isolated yield after column chromatography.
The reaction time before addition of DDQ.
b
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.11
.101.
with high yields of other expanded porphyrins.9 A suggested reac-
tion pathway for hexaphyrin synthesis is shown in Scheme 2.
C6F5
C6F5
H
N
C6F5
C6F5
2
C6F5
C6F5
HN
HN
N
H
NH
NH
N
H
Ts
C6F5
N
Cu(OTf)2, CH2Cl2
8 h, rt
C6F5
+
C6F5
NH
HN
NH
HN
2
1
TsHN
N
H
C6H5
C6F5
C6F5
C6F5
DDQ, rt , 2 h
C6F5
N
N
NH
N
C6F5
C6F5
HN
N
C6F5
C6F5
5
Scheme 2. Suggested reaction pathway.

S. Cinar et al. / Tetrahedron Letters 55 (2014) 544–547
547
4. Neves, M. G. M. S.; Martins, R. M.; Tome, A. C.; Silvestre, A. J. D.; Silva, A. M. S.;
Felix, V.; Drew, M. G. B.; Cavalerio, J. A. S. Chem. Commun. 1999, 385–386.
5. (a) Shin, J. Y.; Furuta, H.; Yoza, K.; Igarashi, S.; Osuka, A. J. Am. Chem. Soc. 2001,
123, 7190–7191; (b) Taniguchi, R.; Shimizu, S.; Suzuki, M.; Shin, J.-Y.; Furuta, H.;
Osuka, A. Tetrahedron Lett. 2003, 44, 2505–2507; (c) Suzuki, M.; Osuka, A. Org.
Lett. 2003, 5, 3943–3946; (d) Shimizu, S.; Taniguchi, R.; Osuka, A. Angew. Chem.,
Int. Ed. 2005, 44, 2225–2229.
6. (a) Temelli, B.; Unaleroglu, C. Tetrahedron Lett. 2005, 46, 7941–7943; (b) Temelli,
B.; Unaleroglu, C. Tetrahedron 2006, 62, 10130–10135; (c) Temelli, B.;
Unaleroglu, C. Tetrahedron 2009, 65, 2043–2050.
7. (a) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.; Marguerettaz, A. M. J.
Org. Chem. 1987, 52, 827–836; (b) Littler, B. J.; Ciringh, Y.; Lindsey, J. S. J. Org.
Chem. 1999, 64, 2864–2872.
8. (a) Tanaka, Y.; Shin, J. Y.; Osuka, A. Eur. J. Org. Chem. 2008, 1341–1349; (b) Lim, J.
M.; Shin, J. Y.; Tanaka, Y.; Saito, S.; Osuka, A.; Kim, D. J. Am. Chem. Soc. 2010, 132,
3105–3114.
References and notes
1. (a) Jasat, A.; Dolphin, D. Chem. Rev. 1997, 97, 2267–2340; (b) Saito, S.; Osuka, A.
Angew. Chem., Int. Ed. 2011, 50, 4342–4373; (c) Rath, H.; Sankar, J.; PrabhuRaja,
V.; Chandrashekar, T. K.; Nag, A.; Goswami, D. J. Am. Chem. Soc. 2005, 127,
11608–11609; (d) Yoon, Z. S.; Kwon, J. H.; Yoon, M. C.; Koh, M. K.; Noh, S. B.;
Sessler, J. L.; Lee, J. T.; Seidel, D.; Aguilar, A.; Shimizu, S.; Suzuki, M.; Osuka, A.;
Kim, D. J. Am. Chem. Soc. 2006, 128, 14128–14134; (e) Kang, S.; Hayashi, H.;
Umeyama, T.; Matano, Y.; Tkavhenko, N. V.; Lemmetyinen, H.; Imahori, H. Chem.
Asian J. 2008, 3, 2065–2074.
2. (a) Sessler, J. L.; Miller, R. A. Biochem. Pharmacol. 2000, 59, 733–739; (b) Sessler, J.
L.; Tvermoes, N. A.; Davis, J.; Anzenbacher, P., Jr.; Jursikova, K.; Sato, W.; Seidel,
D.; Lynch, V.; Black, C. B.; Try, A.; Andrioletti, B.; Hemmi, G.; Mody, T. D.; Magda,
D. J.; Kral, V. Pure Appl. Chem. 1999, 71, 2009–2018; (c) Young, S. W.; Qing, F.;
Harriman, A.; Sessler, J. L.; Dow, W. C.; Mody, T. D.; Hemmi, G. W.; Hao, Y.;
Miller, R. A. Proc. Natl. Acad. Sci. USA 1996, 93, 6610–6615.
9. Kamimura, Y.; Shimizu, S.; Osuka, A. Chem. Eur. J. 2007, 13, 1620–1628.
3. Brückner, C.; Sternberg, E. D.; Boyle, R. W.; Dolphin, D. Chem. Commun. 1997,
1689–1690.