A general and efficient palladium-catalyzed intramolecular cyclization reaction of β-brominated porphyrins

Article abstract of DOI:10.1021/jo0609677

A general and efficient synthesis of fused five-membered porphyrins from the readily available β-brominated porphyrins via palladium-catalyzed intramolecular cyclization has been developed, which can be applied for various metal complexes of β-brominated

Full text of DOI:10.1021/jo0609677

A General and Efficient Palladium-Catalyzed Intramolecular
Cyclization Reaction of â-Brominated Porphyrins
Dong-Mei Shen, Chao Liu, and Qing-Yun Chen*
Key laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Road, Shanghai 200032, China
Chenqy@mail.sioc.ac.cn
ReceiVed May 9, 2006
A general and efficient synthesis of fused five-membered porphyrins from the readily available
â-brominated porphyrins via palladium-catalyzed intramolecular cyclization has been developed, which
can be applied for various metal complexes of â-brominated porphyrins or free base ones and generally
results in good yields of the fused five-membered porphyrins.
Introduction
porphyrins from readily available â-brominated porphyrins.3a
However, our method appeared to be limited because it mainly
resulted in reduction products and lower yields of the desired
fused five-membered ones. After many trials, we found a general
and efficient palladium-catalyzed intramolecular cyclization
method for formation of various fused five-membered porphyrin
systems from readily available â-brominated porphyrins. Herein,
the results are presented.
Over the past decade interest in porphyrins with secondary
ring systems fused onto the macrocyclic core has been steadily
on the rise because of their bright prospects, inviting applications
in various branches of optical technology and biomedicine.1
From the structural point of view, the simplest representatives
are those with newly fused five-membered rings joining the
phenyl ortho-position directly to an adjacent â-position. Nev-
ertheless, compared to other secondary ring system fused
porphyrins, the chemistry of this kind of fused five-membered
porphyrins has been little investigated. The main reason for this
might be the lack of general and efficient synthetic methods.
Recently, a practical approach to fused five-membered
porphyrin systems has emerged from the work of Boyle group.2
Their method is based on the intramolecular Pd(0) catalyzed
coupling between the o-iodinated meso-phenyl and â-position
of the porphyrin. Although this method can be successfully
implemented in the synthesis of the newly fused five-membered
porphyrins, the preparation of the precursors themselves is rather
difficult and the yields are lower. In the course of our study on
porphyrin intramolecular cyclization,3 we recently came across
a useful strategy based on Zn-mediated porphyrin radicals, which
enabled us to obtain a variety of the newly fused five-membered
Results and Discussion
The zinc complex of 2-bromo-5,10,15,20-tetraphenylporphy-
rin Zn1a,3a,4 a most readily available brominated porphyrin,5
was employed as a model substrate for the palladium-catalyzed
intramolecular cyclization reaction. The reaction was first
attempted on Zn1a using PdCl2 (10 mol %) as the source of
n
Pd(0), K2CO3 (10 equiv) as base and Bu4NBr (2.0 equiv) as
additive in DMF at 130 °C.6 After only five minutes, the color
of the solution had changed from purple-red to brown-yellow.
TLC of the brown-yellow solution revealed the complete loss
of the starting porphyrin and the formation of two new products.
(3) (a) Shen, D. M.; Liu, C.; Chen, Q. Y. Chem. Commun. 2005, 4982.
(b) Zeng, Z.; Liu, C.; Jin, L. M.; Guo, C. C.; Chen, Q. Y. Eur. J. Org.
Chem. 2005, 306. (c) Liu, C.; Chen, Q. Y. Synlett 2005, 8, 1306. (d) Chen,
L.; Jin, L. M.; Guo, C. C.; Chen, Q. Y. Synlett 2005, 6, 963.
(4) (a) Liu, C.; Shen, D. M.; Chen, Q. Y. Chem. Commun. 2006, 770.
(b) Callot, H. J. Bull. Soc. Chim. Fr. 1974, 1492.
(1) The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
R., Eds.; Academic Press: San Diego, 2000-2003; Vols. 1-20.
(2) Fox. S.; Boyle, R. W. Chem. Commun. 2004, 1322.
10.1021/jo0609677 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
6508
J. Org. Chem. 2006, 71, 6508-6511

Cyclization Reaction of â-Brominated Porphyrins
SCHEME 1. PdCl2-Catalyzed Intramolecular Cyclization Reaction of Zn1a
TABLE 1. The Palladium-Catalyzed Intramolecular Cyclization Reaction of Zn1aa
yield (%)b
entry
[Pd]
base
additive
T (°C)
t (min)
Zn2a
Zn3a
1
2
3
4
5
6
7
8
PdCl2
PdCl2(PPh3)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
K3PO4
DBU
nBu4NBr
130
130
130
130
130
130
130
130
130
130
130
130
60
5
5
5
5
5
5
5
5
5
5
5
5
120
20
75
70
65
80
85
85
50
35d
85
50
60
0f
10
15
20
10
0
0
40
0
nBu4NBr
PdCl2(CH3CN)2
nBu4NBr
PdCl2(dppf)c
nBu4NBr
Pd2(dba)3‚CHCl3
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
nBu4NBr
nBu4NBr
nBu4NBr
LiCl
9
e
e
e
e
e
e
0
10
11
12
13
14
35
25
0
0
5
K2CO3
K2CO3
0f
100
78
a Reactions were carried out in DMF under N2 with bromoporphyrin (20 mg, 1.0 equiv). Concentration: 5 mg bromoporphyrin/mL of DMF. b Isolated
yields. c dppf ) 1,1′-bis(diphenylphosphino)ferrocene. d The starting material was recovered in 55%. e No additive was used. f No conversion was observed.
Subsequent spectral analysis of them by 1H NMR spectroscopy,
mass spectrometry, and UV-vis spectra demonstrated that the
main product (75%) was the desired fused five-membered
porphyrin Zn2a and the byproduct (10%), the reduction product
Zn3a (Scheme 1).
Encouraged with this result, we decided to optimize the
reaction conditions and the results are shown in Table 1.
Although the reaction proceeded smoothly in the presence of
various palladium sources, Pd(II) precursors generally resulted
in superior results in comparison with Pd(PPh3)4 (Table 1, entries
1-6 vs entry 7). Both Pd2(dba)3‚CHCl3 (dba ) dibenzylide-
neacetone) and Pd(OAc)2 were the most suitable palladium
precursors. The use of additives was unnecessary for the reaction
because the reaction led to similar results in its absence and
lower conversion was observed in the precence of LiCl (Table
1, entries 8 and 9). Among several common bases, K2CO3 as a
mild base stood out (Table 1, entries 9-12). To our surprise,
the organic base DBU was invalid for the reaction (Table 1,
entry 12). An elevated temperature seems to be needed for
effective transformation, as no conversion was observed at low
temperatures even after a longer time (Table 1, entry 13). On
the basis of these preliminary tests, the optimal reaction
conditions were generally conducted in DMF at 130 °C under
N2 with 10 equiv of K2CO3 in the presence of 5 mol % Pd2-
(dba)3‚CHCl3.
(5) For recent and selective reports on porphyrin synthesis via transition
metal-catalyzed cross-coupling reactions of brominated porphyrins, see the
following: (a) Liu, C.; Chen, Q. Y. Eur. J. Org. Chem. 2005, 3680. (b)
Liu, C.; Shen, D. M.; Chen, Q. Y. Eur. J. Org. Chem. 2006, 2703. (c) Gao,
G. Y.; Colvin, A. J.; Chen, Y.; Zhang, X. P. J. Org. Chem. 2004, 69, 8886.
(d) Gao, G. Y.; Chen, Y.; Zhang, X. P. Org. Lett. 2004, 6, 1837. (e) Gao,
G. Y.; Colvin, A. J.; Chen, Y.; Zhang, X. P. Org. Lett. 2003, 5, 3261. (f)
Gao, G. Y.; Chen, Y.; Zhang, X. P. J. Org. Chem. 2003, 68, 6215. (g)
Chen, Y.; Zhang, X. P. J. Org. Chem. 2003, 68, 4432. (h) Takanami, T.;
Hayashi, M.; Hino, F.; Suda, K. Tetrahedron Lett. 2003, 44, 7353. (i) Khan,
M. M.; Ali, H.; Van Lier, J. E. Tetrahedron Lett. 2001, 42, 1615. (j) Cheng,
L. L.; Chang, C. J.; Nocera, D. G. J. Org. Chem. 2003, 68, 4075. (k) Vas,
B.; Alvarez, R.; Nieto, M.; Paniello, A. I.; de Lera, A. R. Tetrahedron Lett.
2001, 42, 7409. (l) Deng, Y.; Chang, C. K.; Nocera, D. G. Angew. Chem.,
Int. Ed. 2000, 39, 1066. (m) Iovine, P. M.; Kellett, M. A.; Redmore, N. P.;
Therien, M. J. J. Am. Chem. Soc. 2000, 122, 8717. (n) Shanmugathasan,
S.; Johnson, C. K.; Edwards, C.; Matthews, E. K.; Dolphin, D.; Boyle, R.
W. J. Porphyrins Phthalocyanines 2000, 4, 228. (o) Shi, X.; Amin, R.;
Liebeskind, L. S. J. Org. Chem. 2000, 65, 1650. (p) Sharman, W. M.; Van
Lier, J. E. J. Porphyrins Phthalocyanines 2000, 4, 441 and references therein.
(6) (a) Campear, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (b)
Echavarren, A. M.; Go´mez-Lor, B.; Gonza´lez, J. J.; de Frutos, OÄ . Synlett
2003, 5, 585.
J. Org. Chem, Vol. 71, No. 17, 2006 6509

Shen et al.
SCHEME 2. The Palladium-Catalyzed Intramolecular Cyclization Reaction of Zn4
TABLE 2. The Palladium-Catalyzed Intramolecular Cyclization
SCHEME 3. Proposed Mechanism for the Palladium-
Catalyzed Intramolecular Cyclization Reaction of Various
Reaction of Various â-Brominated Porphyrinsa
â-Brominated Porphyrins
product
entry
M
R
reactant
t (min)
(yield %)b
1
2
3
4
5
6
7
8
Zn
Zn
Zn
Zn
Zn
Cu
Ni
2H
2H
2H
2H
H
Zn1a
Zn1b
Zn1c
Zn1d
Zn1e
Cu1a
Ni1a
1a
5
5
5
30
30
10
10
5
Zn2a (85)
Zn3a (0)
Zn3b (0)
Zn3c (0)
Zn3d (25)
Zn3e (30)
Cu3a (20)
Ni3a (60)
3a (0)
Me
MeO
Cl
CF3
H
H
H
MeO
Cl
CF3
Zn2b (65)
Zn2c (80)
Zn2d (60)
Zn2e (55)
Cu2a (62)
Ni2a (25)
2a (72)
2c (65)
2d (50)
2e (42)
9
10
11
1c
1d
1e
5
30
30
3c (0)
3d (30)
3e (35)
a Reactions were carried out at 130 °C in DMF under N2 with bromo-
porphyrin (50 mg, 1.0 equiv) and K2CO3 (10 equiv) in the presence of
Pd2(dba)3‚CHCl3 (5 mol %). Concentrate: 5 mg bromoporphyrin/mL of
DMF. b Isolated yields.
that the use of a metal ion as an “inorganic protective group”
for the central -NH units was not necessary. For example,
satisfactory yields of the desired fused five-membered products
were achieved when reactions were carried out for the free base
porphyrins 1a and 1c (Table 2, entries 8 and 9). Similarly,
reactions utilizing 1d and 1e as substrates also led to acceptable
yields of the products in addition to the reduction ones as
expected (Table 2, entries 10 and 11).
When the zinc complex of 2,3,12,13-tetrabromotetraphe-
nylporphyrin Zn4 was used as a substrate under similar
conditions, the double-cyclization isomers Zn6 and Zn7 instead
of the expected highly symmetrical tetracyclization Zn5 were
also obtained in high yield (80%) (Scheme 2). By contrast, the
zinc-mediated intramolecular cyclization of Zn4 only resulted
in 42% yield of the desired products.3a It should be mentioned
that no partly reduction and cyclizated products were observed,
which were the main products in the zinc-mediated intramo-
lecular cyclization reaction of Zn4.3a
Under the optimal reaction conditions, a variety of different
â-brominated porphyrins could be subjected to smooth cycliza-
tion. As illustrated in Table 2, the zinc complexes of â-bromi-
nated porphyrins with an electron-donating group were effec-
tively intramolecularly cyclizated to afford the fused five-
membered porphyrins in higher yields without reduction products
(Table 2, entries 2 and 3). On the contrary, for substrates with
an electron-withdrawing group, yields of the desired products
decreased, and the reduction products were obtained in signifi-
cant yield (Table 2, entries 4 and 5). The catalytic reaction could
also be applied for the copper and nickel complexes of
â-brominated porphyrins, although lower yields of fused five-
membered porphyrins and higher yields of reduction products
were obtained (Table 2, entries 6 and 7). The potential utility
of this method was further enhanced with our later discovery
6510 J. Org. Chem., Vol. 71, No. 17, 2006

Cyclization Reaction of â-Brominated Porphyrins
502 (2.4), 588 (1.0). Anal. Calcd for C48H22N4F12Zn: C, 60.24; H,
2.42; N, 5.85. Found: C, 60.64; H, 2.85; N, 5.35.
Cu2a: 62% yield. MS (MALDI) m/z: 673.1 (M+). UV-vis,
CH2Cl2, λmax nm (relative intensity): 400 (9.7), 439 (sh, 17.5), 460
(28.7), 496 (4.6), 581 (2.2), 667 (1.3), 731 (1.0). Anal. Calcd for
C44H26N4Cu: C, 78.38; H, 3.89; N, 8.31. Found: C, 78.14; H, 4.14;
N, 7.93.
All the results may be rationalized by the mechanism similar
to that which is recently proposed by Maseras et al. for the
palladium-catalyzed intramolecular arylation reaction of simple
aromatic halides.7 As shown in Scheme 3, oxidative addition
of active Pd(0) species A generated under the reaction conditions
with bromoporphyrin provides porphyrin Pd(II) bromide B,
which undergoes cyclocarbopalladation with its adjacent meso-
phenyl ring followed by replacement of bromine ion with
carbonate to form porphyrin Pd(II) complex C. The subsquent
proton abstraction by the carbonate provides porphyrin Pd(II)
complex D. Reductive elimination of intermediate D results in
the formation of the desired product and the regeneration of
the active species A, which continues the catalytic cycle.
1
Ni2a: 25% yield. H NMR (300 MHz, CDCl3) δ: 6.95 (t, J )
7.5 Hz, 1H), 7.05(t, J ) 7.5 Hz, 1H), 7.31-7.26 (1H, overlapping
with the signal of CHCl3), 7.64-7.73 (m, 13H), 7.88 (s, 1H), 7.92-
7.99 (m, 8H), 8.32 (d, J ) 5.1 Hz, 1H), 8.37 (d, J ) 5.1 Hz, 1H),
8.62 (d, J ) 4.8 Hz, 1H), 9.03 (d, J ) 4.8 Hz, 1H). MS (MALDI)
m/z: 668.2 (M+). UV-vis, CH2Cl2, λmax nm (relative intensity):
370 (11.8), 382 (11.7), 430 (35.2), 462 (sh, 25.1), 530 (2.6), 564
(3.2), 653 (1.6), 714 (1.0). Anal. Calcd for C44H26N4Ni‚THF: C,
77.75; H, 4.62; N, 7.56. Found: C, 78.11; H, 4.53; N, 7.44.
Conclusion
1
2a: 72% yield. H NMR (300 MHz, CDCl3) δ: -0.22 (br s,
2H), 6.88 (t, J ) 7.5 Hz, 1H), 7.01 (t, J ) 7.5 Hz, 1H), 7.19 (d, J
) 7.5 Hz, 1H), 7.62 (s, 1H), 7.68-7.73 (m, 9H), 7.94 (d, J ) 7.5
Hz, 1H), 8.02-8.08 (m, 6H), 8.24-8.38 (m, 4H), 8.60 (d, J ) 5.1
Hz, 1H), 9.04 (d, J ) 5.1 Hz, 1H). MS (MALDI) m/z: 613.2 (M+
+ 1). UV-vis, CH2Cl2, λmax nm (relative intensity): 417 (43.6),
446 (39.6), 468 (45.6), 499 (15.6), 549 (2.2), 613 (3.0), 648 (3.2),
767 (1.0). Anal. Calcd for C44H28N4‚0.5H2O: C, 85.00; H, 4.72;
N, 9.01. Found: C, 85.24; H, 5.09; N, 8.94.
In summary, a general and efficient synthesis of fused five-
membered porphyrins from the readily available â-brominated
porphyrins via palladium-catalyzed intramolecular cyclization
has been developed. The method can be applied for various
metal complexes of â-brominated porphyrins or free base ones
and generally results in good yields of the fused five-membered
porphyrins. In view of efficiency and convenience of the reaction
and ready accessibility of the starting porphyrins, this method
will permit quick entrance to various fused five-membered
porphyrins which might find applications in areas such as
medicine, materials, and biomimetics.
1
2c: 65% yield. H NMR (300 MHz, CDCl3) δ: -0.11 (br s,
2H), 3.88(s, 3H), 4.07-4.08 (t, 9H), 7.18-7.25 (m, 6H), 7.54-
7.57 (m, 1H), 7.63 (s, 1H), 7.72-7.75 (m, 1H), 7.78-7.81 (m,
1H), 7.92-7.98 (m, 6H), 8.24-8.36 (m, 4H), 8.57 (d, J ) 5.4 Hz,
1H), 8.95 (d, J ) 5.4 Hz, 1H). MS (MALDI) m/z: 733.3 (M+
+
1). UV-vis, CH2Cl2, λmax nm (relative intensity): 414 (15.3), 449
(14.4), 473 (21.6), 508 (7.4), 614 (1.0), 661 (1.4). Anal. Calcd for
C48H36N4‚0.5H2O: C, 77.71; H, 5.03; N, 7.55. Found: C, 78.01;
H, 5.37; N, 7.46.
Experimental Section
General Procedure for the Palladium-Catalyzed Intramo-
lecular Cyclization Reaction of â-Brominated Porphyrins. An
oven-dried Schlenk flask was charged with porphyrin (50 mg, 1.0
equiv), K2CO3 (10 equiv), and Pd2(dba)3‚CHCl3 (5 mol %). The
flask was then evacuated and backfilled with N2 (three cycles). DMF
(5 mg porphyrin/mL of DMF) was charged at room temperature.
The resulting mixture was stirred at 130 °C for 5-30 min and then
allowed to reach room temperature. CH2Cl2 was added, and the
reaction mixture was washed with water three times. The organic
layer was passed through dry silica gel and evaporated to dryness.
The resulting solid was purified by flash chromatography (silica
gel, 300-400 mesh, CH2Cl2/PE or THF/PE as eluent) to provide
the desired product M2 in good yields. An analytical sample was
recrystallized from CH2Cl2/MeOH or THF/MeOH.
Zn2a: 85% yield. Anal. Calcd for C44H26N4Zn: C, 78.17; H,
3.88; N, 8.29. Found: C, 77.92; H, 4.36; N, 8.10. Other analytical
data are consistent with literature values.3a
Zn2b: 65% yield. Anal. Calcd for C48H34N4Zn‚1.5H2O: C,
75.93; H, 4.91; N, 7.38. Found: C, 76.11; H, 4.71; N, 6.98. Other
analytical data are consistent with literature values.3a
1
2d: 50% yield. H NMR (300 MHz, CDCl3) δ: -0.32 (br s,
2H), 6.93-6.97 (m, 1H), 7.14 (s, 1H), 7.56 (s, 1H), 7.66-7.71
(m, 6H), 7.77 (d J ) 8.7 Hz, 1H), 7.93-7.96 (m, 6H), 8.21-8.36
(m, 4H), 8.56 (d, J ) 5.1 Hz, 1H), 8.95 (d, J ) 5.1 Hz, 1H). MS
(MALDI) m/z: 749.1 (M+ + 1). UV-vis, CH2Cl2, λmax nm (relative
intensity): 421 (28.1), 445 (9.7), 468 (13.6), 501 (3.7), 549 (1.6),
585 (1.1), 642 (1.0). Anal. Calcd for C44H24N4Cl4: C, 70.42; H,
3.22; N, 7.47. Found: C, 70.08; H, 3.68; N, 7.23.
1
2e: 42% yield. H NMR (300 MHz, CDCl3) δ: -0.34 (br s,
2H), 7.31-7.34 (m, 1H), 7.45 (s, 1H), 7.67 (s, 1H), 7.95-8.06
(m, 7H), 8.13-8.37 (m, 10H), 8.59 (d, J ) 5.4 Hz, 1H), 9.10 (d,
J ) 5.4 Hz, 1H). 19F (282 MHz, CDCl3) δ: -63.16 (t, 9F), -64.97
(s, 3F). MS (MALDI) m/z: 885.2 (M+ + 1). UV-vis, CH2Cl2,
λmax nm (relative intensity): 415 (28.9), 448 (39.6), 470 (45.0),
498 (13.6), 614 (2.6), 649 (2.9), 755 (1.0). Anal. Calcd for
C48H24N4F12‚0.5MeOH: C, 64.67; H, 2.91; N, 6.22. Found: C,
65.00; H, 3.30; N, 6.22.
Zn6 + Zn7: 80% yield. MS (MALDI) m/z: 672.1 (M+). UV-
vis, CH2Cl2, λmax nm (relative intensity): 353 (2.2), 438 (6.4), 460
(28.7), 475 (4.7), 534 (3.9), 576 (1.0). Anal. Calcd for C44H24N4-
Zn‚1.5THF: C, 76.77; H, 4.64; N, 7.16. Found: C, 76.40; H, 4.96;
N, 7.50.
Zn2c: 80% yield. Anal. Calcd for C48H34N4O4Zn‚0.5H2O: C,
71.55; H, 4.44; N, 6.95. Found: C, 71.86; H, 4.64; N, 6.80. Other
analytical data are consistent with literature values.3a
Zn2d: 60% yield. Anal. Calcd for C44H22N4Cl4Zn‚H2O: C,
63.53; H, 2.91; N, 6.73. Found: C, 63.06; H, 3.23; N, 6.27. Other
analytical data are consistent with literature values.3a
Acknowledgment. We thank the Natural Science Foundation
of China (Nos. 20272026, D20032010, and 20532040) for
supporting this work.
Zn2e: 55% yield. 1H NMR (300 MHz, CDCl3) δ: 7.39 (s, 2H),
7.78 (d, 2H,), 7.99-8.16 (m, 12H), 8.35-8.50 (m, 5H), 8.76 (br s,
1H). 19F NMR (282 MHz, CDCl3) δ: -62.10 (m, 9F, CF3), -63.78
(s, 3F, CF3). MS (MALDI) m/z: 946.1 (M+). UV-vis, CH2Cl2,
λmax nm (relative intensity): 396 (4.7), 440 (sh, 8.4), 464 (17.8),
Supporting Information Available: General methods and
copies of typical 1H NMR and UV-vis spectra of fused five-
membered porphyrins Zn2a, Ni2a, and 2a. This material is available
free of charge via the Internet at http://pubs.acs.org.
(7) Garc´ıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Ichavarren, A.
M. J. Am. Chem. Soc. 2006, 128, 1066.
JO0609677
J. Org. Chem, Vol. 71, No. 17, 2006 6511