First synthesis of dioxadithiaporphycene with a benzene ring fused onto the double bond

Article abstract of DOI:10.1016/S0040-4039(00)01846-3

Dioxadithiaporphycenes 5 and 5' were synthesized by using the Suzuki cross-coupling and McMurry coupling reactions as the key steps. This approach provided an access to the first dioxadithiaporphycene derivative 15 with a benzene ring fused onto the double bond. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01846-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10277–10280
First synthesis of dioxadithiaporphycene with a benzene ring
fused onto the double bond
Wei-Min Dai* and Wing Leung Mak
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong SAR, China
Received 15 August 2000; revised 13 October 2000; accepted 19 October 2000
Abstract
Dioxadithiaporphycenes 5 and 5% were synthesized by using the Suzuki cross-coupling and McMurry
coupling reactions as the key steps. This approach provided an access to the first dioxadithiaporphycene
derivative 15 with a benzene ring fused onto the double bond. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: porphyrins and analogues; coupling reactions; furans; thiophenes.
Porphycene (1), a planar and aromatic nitrogen-containing [18]annulene, was first synthesized
in 1986 by Vogel and co-workers.1 It possesses an N4 coordination site and porphyrin-like
properties. Some expanded porphycene derivatives are known as promising candidates for
photodynamic therapy (PDT) in cancer treatment.2 In recent years, numerous attempts have
been made, with great success, to synthesize novel hetero-atom bridged annulenes related to
porphyrin ring systems.3 Replacement of pyrrole units by other heterocycles is an attractive
approach. For example, tetraoxaporphycene (2),4 tetrathiaporphycene (3)5 and dithiaporphycene
isomers (4 and 4%)6 have been synthesized via reductive dimerization of the corresponding
dialdehydes under the McMurry coupling conditions using low-valent titanium.7 We report here
on the first synthesis of dioxadithiaporphycenes 5 and 5% and the benzo derivative 15 possessing
a benzene ring fused onto the double bond. The Suzuki cross-coupling8 and McMurry coupling
reactions are the key steps in these syntheses.
N
H
N
Y
X
Y
Y
N
H
N
X
Y
X
X
2: X = Y = O
3: X = Y = S
4: X = NH, Y = S
5: X = O, Y = S
4': X = NH, Y = S
5': X = O, Y = S
1: porphycene
* Corresponding author. Fax: +852 2358 1594; e-mail: chdai@ust.hk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01846-3

10278
As outlined in Scheme 1,9 dialdehyde 9 possessing both furan and thiophene rings is required
for synthesis of [20]annulenes 5 and 5% through the McMurry coupling reaction. We attempted
two cross-coupling procedures, both catalyzed by Pd(0), in the formation of the 2,2%-furanthio-
phene 8. The Stille cross-coupling10 of 2-(tributylstannyl)furan with 2-iodothiophene (7) in the
presence of 5 mol% Pd(PPh3)4 (toluene, reflux, 26 h) gave compound 8. However, complete
removal of the tributyltin by-product from 8 by column chromatography proved difficult.
Therefore, the Suzuki cross-coupling of 2-furanboronic acid (6)11 with 7 was adopted. Refluxing
a solution of 6 and 7 in mixed toluene and methanol (1:1) in the presence of 20 mol% Pd(PPh3)4
and Na2CO3 (4 equiv.) provided 8 in 98% yield. Compound 8 was then deprotonated by using
2.2 equiv. of nBuLi in THF at −78°C to give the 5,5%-dilithiated species which reacted with
DMF to furnish 5,5%-diformyl-2,2%-furanthiophene (9) in 44% yield. Reductive dimerization of 9
was carried out under the conditions reported for porphycene synthesis.1a,12 A THF solution of
dialdehyde 9 (0.014 M final concentration) was slowly added to a slurry of the titanium reagent
generated from 10 equiv. of TiCl4 and 20 equiv. of activated zinc dust in THF containing 0.1
equiv. of pyridine followed by heating at reflux for 2.5 h. Two lower molecular weight
compounds, 21,23-dioxa-22,24-dithiaporphycene (5) and 21,24-dioxa-22,23-dithiaporphycene
(5%), were isolated in 2.6 and 7.2% yield, respectively.13 Their structures were assigned based on
1H NMR data. For compound 5, the two olefinic protons on the same double bond are
chemically non-equivalent with a coupling constant of ca. 13 Hz. In contrast, the adjacent
olefinic protons in compound 5% are chemically equivalent and they appear as singlet peaks at l
6.63 and 5.78 ppm, respectively. We assume that the formation of 5% began with an intermolec-
ular coupling of formyl groups on the furan rings in 9 because of the relatively small size of
oxygen compared to sulfur. This is then followed by an intramolecular carbonyl coupling on the
side of the thiophene rings. We believe this is the reason why the distorted and less stable isomer
5% was formed preferentially over 5.
Pd(PPh3)4, Na2CO3
+
B(OH)2
I
O
S
O
S
PhMe-MeOH (1:1)
reflux, 10 h (98%)
6
7
8
nBuLi, DMF
THF, -78 °C
(44%)
1
TiCl4, Zn, Py
S
S
S
O
S
O
O
20
19
9
21 22
24 23
+
OHC
CHO
10
THF, reflux,
2.5 h
O
S
O
9
5 (2.6%)
5' (7.2%)
Scheme 1.
Next, we designed a scheme for synthesis of the first benzo porphycene analogue 15 by taking
advantage of the Suzuki cross-coupling reaction (Scheme 2).9 The commercially available
1,2-diiodobenzene (10) underwent double cross-coupling with 2-furanboronic acid (6)11 to give
11 in 37% yield. Lithiation of the furan rings in 11 with nBuLi (3 equiv.) followed by reaction
with B(OMe)3 (6 equiv.) and acidic hydrolysis produced bis-boronic acid 12. The latter
compound is not stable after removal of solvent to dryness and was used, without purification,

10279
1. nBuLi, B(OMe)3
THF, -78 °C
I
I
O
O
Pd(PPh3)4, Na2CO3
+
(HO)2B
O
THF, reflux,
10 h (37%)
2. HCl, 25 °C, 3 h
6
10
11
Br
CHO
B(OH)2
B(OH)2
S
13
O
S
S
O
O
CHO
CHO
Pd(PPh3)4, Na2CO3,
PhMe-MeOH (1:1),
reflux, 2.5 days
O
12
14 (37% from 11)
TiCl4, Zn, Py
THF, reflux, 5 h
d
d
1
1
20
9
S
S
O
S
9
O
O
20
19
21 22
21 22
24 23
s
i
24 23
10
O
S
19
10
n
n
15 (18%)
16
Scheme 2.
for the second Suzuki cross-coupling with 5-bromothiophene-2-carboxaldehyde (13). Thus,
dialdehyde 14 was synthesized in 37% yield from 11 in two steps. Intramolecular McMurry
coupling within 14 in the presence of a slurry of the titanium reagent generated from 5 equiv.
of TiCl4 and 10 equiv. of activated zinc dust in THF containing 0.05 equiv. of pyridine (THF,
reflux, 5 h) furnished benzo[s]21,24-dioxa-22,24-dithiaporphycene (15)14 in 18% yield. As
1
expected, the olefinic protons of 15 appear at l 6.78 ppm as a singlet peak in the H NMR
spectrum.
We tried to synthesize benzo[i ]21,24-dioxa-22,24-dithiaporphycene 16 with a benzene ring
fused onto the C9 and C10 positions. Unfortunately, the Suzuki cross-coupling of 1,2-diiodoben-
zene (10) with 2-thiopheneboronic acid failed to form the mono- and bis-coupled compounds.
The severe steric interaction between the iodine and thiophene ring in the mono-coupled product
may render its formation difficult via the reductive elimination step in the catalytic cycle.
In summary, we have developed a novel strategy for synthesis of the first benzo porphycene
analogue 15. Our approach takes advantage of the Suzuki cross-coupling to fuse a benzene ring
onto the double bond. The synthetic scheme is flexible and should be useful for synthesis of
related compounds. For example, replacement of 5-bromothiophene-2-carboxaldehyde (13) in
Scheme 2 by 5-bromo-2-furaldehyde should lead to synthesis of benzo tetraoxaporphycene. Use
of 2,3-bis{[(trifluoromethane)sulfonyl]oxy}naphthalene15 for coupling with 2-furanboronic acid
(6) in Scheme 2 should provide an access to 21,24-dioxa-22,24-dithiaporphycene fused with a
naphthalene ring. Syntheses of these novel chromophores are underway in our laboratory.

10280
Acknowledgements
We thank the Department of Chemistry, HKUST and the Research Grants Council of the
Hong Kong Special Administrative Region, China (HKUST676/96P) for financial support.
References
1. (a) Vogel, E.; Ko¨cher, M.; Schmickler, H.; Lex, J. Angew. Chem., Int. Ed. Engl. 1986, 25, 257. Also see: (b) Vogel,
E.; Balci, M.; Pramod, K.; Koch, P.; Lex, J.; Ermer, O. Angew. Chem., Int. Ed. Engl. 1987, 26, 928. (c) Vogel,
E.; Grigat, I.; Ko¨cher, M.; Lex, J. Angew. Chem., Int. Ed. Engl. 1989, 28, 1655.
2. (a) Martire, D. O.; Jux, N.; Aramendia, P. F.; Negri, R. M.; Lex, J.; Braslavsky, S. E.; Schaffner, K.; Vogel, E.
J. Am. Chem. Soc. 1992, 114, 9969. Also see: (b) Bonnett, R. Chem. Soc. Rev. 1995, 19. (c) Frank, B.; Nonn, A.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1795. (d) Sternberger, E. D.; Dolphin, D. Tetrahedron 1998, 54, 4151. (e)
Wo¨hrle, D.; Hirth, A.; Bogdahn-Rai, T.; Schnurpfeil, G.; Shopova, M. Russ. Chem. Bull. 1998, 47, 807.
3. (a) Vogel, E. Pure Appl. Chem. 1990, 62, 557. (b) Vogel, E. J. Heterocyclic Chem. 1996, 33, 1461. (c) Sessler, J.
L.; Weghorn, S. J. Expanded, Contracted and Isomeric Porphyrins; Pergamon: Oxford, 1997. (d) Jasant, A.;
Dolphin, D. Chem. Rev. 1997, 97, 2267.
4. (a) Vogel, E.; Sicken, M.; Ro¨hrig, P.; Schmickler, H.; Lex, J.; Ermer, O. Angew. Chem., Int. Ed. Engl. 1988, 27,
411. (b) Bachmann, R.; Gerson, F.; Gescheidt, G.; Vogel, E. J. Am. Chem. Soc. 1993, 115, 10286.
5. (a) Ellinger, F.; Gieren, A.; Hu¨bner, T.; Lex, J.; Lucchesini, F.; Merz, A.; Neidlein, R.; Salbeck, J. Monatsh.
Chem. 1993, 124, 931. (b) Hu, Z.; Atwood, J. L.; Cava, M. P. J. Org. Chem. 1994, 59, 8071. Also see: (c)
Dahlmann, U.; Krieger, C.; Neidlein, R. Eur. J. Org. 1988, 525.
6. De Munno, G.; Lucchesini, F.; Neidlein, R. Tetrahedron 1993, 49, 6863.
7. Reviews, see: (a) McMurry, J. Chem. Rev. 1989, 89, 1513. (b) Fu¨rstner, A.; Bogdanovic, B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2442.
8. Reviews, see: (a) Suzuki, A. Acc. Chem. Res. 1982, 15, 178. (b) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749. (c)
Suzuki, A. Pure Appl. Chem. 1986, 58, 629. (d) Suzuki, A. Pure Appl. Chem. 1991, 63, 419. (e) Suzuki, A. Pure
Appl. Chem. 1994, 66, 213. (f) Snieckus, V. Chem. Rev. 1990, 90, 879. (g) Matteson, D. S. Tetrahedron 1989, 45,
1859.
1
9. All new compounds are fully characterized by IR, H NMR, 13C NMR, MS and HRMS.
10. (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (c)
Mitchell, T. N. Synthesis 1992, 803.
11. Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237.
12. Lenoir, D. Synthesis 1977, 553.
1
13. Spectroscopic data for 5: IR (KBr) 2971, 1098 cm−1; H NMR (400 MHz, CDCl3) l 6.19 (d, J=3.42 Hz, 2 H),
6.14 (d, J=3.91 Hz, 2 H), 5.62 (d, J=3.42 Hz, 2 H), 5.52 (d, J=3.42 Hz, 2 H), 5.34 (d, J=13.19 Hz, 2 H,
olefinic), 4.95 (d, J=12.69 Hz, 2 H, olefinic); 13C NMR (100 MHz, CDCl3) l 153.3, 151.6, 140.2, 134.9, 130.7,
122.5, 119.9, 114.9, 114.6, 106.8; MS (+CI) m/z (relative intensity) 348 (M+, 100); HRMS (FAB+) m/z calcd for
1
C20H12O2S2 (M+) 348.0279, found 348.0288. For 5%: IR (KBr) 2924, 2854, 1464, 1378 cm−1; H NMR (400 MHz,
CDCl3) l 7.09 (d, J=3.41 Hz, 2 H), 6.91 (d, J=3.42 Hz, 2 H), 6.63 (s, 2 H, olefinic), 6.36 (d, J=3.42 Hz, 2 H),
6.23 (d, J=3.41 Hz, 2 H), 5.78 (s, 2 H, olefinic); 13C NMR (100 MHz, CDCl3) l 153.0, 149.8, 141.5, 136.4, 129.3,
127.1, 125.8, 114.8, 112.0, 109.0; MS (+CI) m/z (relative intensity) 348 (M+, 100); HRMS (FAB+) m/z calcd for
C20H12O2S2 (M+) 348.0279, found 348.0283.
14. Spectroscopic data for 15: IR (neat) 2924, 2857, 1462, 1378 cm−1 1H NMR (300 MHz, CDCl3) l 7.54–7.47
;
(AA%BB%, 2 H), 7.43–7.34 (AA%BB%, 2 H), 7.16 (d, J=3.63 Hz, 2 H), 6.90 (d, J=3.66 Hz, 2 H), 6.78 (s, 2 H,
olefinic), 6.47 (s, 4 H, furan ring protons); 13C NMR (75 MHz, CDCl3) l 154.2, 149.5, 142.1, 137.8, 131.2, 129.5,
129.4, 128.6, 125.6, 124.7, 111.3, 107.1; MS (+CI) m/z (relative intensity) 399 (M+H+, 100); HRMS (+FAB) calcd
for C24H14O2S2 (M+) 398.0435, found 398.0441.
15. Nicolaou, K. C.; Dai, W.-M.; Hong, Y. P.; Tsay, S.-C.; Baldridge, K. K.; Siegel, J. S. J. Am. Chem. Soc. 1993,
115, 7944.
.