A novel, high-yielding synthesis of meso-substituted porphyrins via the direct arylation of porphine

Article abstract of DOI:10.1016/S0040-4039(02)02339-0

A new method for the synthesis of meso-substituted porphyrins is described: reaction of 5,10,15,20-tetrabromoporphine magnesium complex with aryl or heteroaryl boronic acids in the presence of Pd(PPh₃)₄ gave meso-substituted porphyri

Full text of DOI:10.1016/S0040-4039(02)02339-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9341–9342
A novel, high-yielding synthesis of meso-substituted porphyrins
via the direct arylation of porphine
a,†
b,
Dong-Fang Shi and Richard T. Wheelhouse *
a
College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA
b
School of Pharmacy, The University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK
Received 29 August 2002; accepted 18 October 2002
Abstract—A new method for the synthesis of meso-substituted porphyrins is described: reaction of 5,10,15,20-tetrabromoporphine
magnesium complex with aryl or heteroaryl boronic acids in the presence of Pd(PPh ) gave meso-substituted porphyrins in yields
3
4
up to 70%. © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
direct substitution of porphine. Thus, we envisaged that
meso-tetrabromoporphine, 3, could undergo a Suzuki
7
Interest in cationic porphyrins that modify gene expres-
sion or inhibit human telomerase has led us to design a
number of novel porphyrins that might interact selec-
tively with tetraplex DNA and thereby modify the
growth of tumour cells. Whilst synthesis by the con-
ventional condensation of pyrrole with aryl and het-
eroaryl aldehydes proved adequate where the aldehydes
were readily available, the poor yields encountered in
the porphyrin-forming step (typically in the range 1–
cross-coupling reaction with arylboronic acids in the
presence of a palladium(0) catalyst to yield 5,10,15,20-
tetra aryl—or tetra heteroaryl—porphines, 4 (Scheme
1).
1
–5
2. Results and discussion
1
7%) meant that this approach was unsuitable for the
The selective bromination of porphine at the meso
positions is known but experimental details have not
been reported. Crucially, bromination with N-bro-
moacetamide was directed to the meso positions when
porphine was present as the magnesium complex, whilst
in the absence of magnesium, bromination was
preparation of substituted porphyrins where the corre-
sponding aldehyde was only available after several syn-
thetic steps; yields were particularly low in the case of
1
aldehydes bearing heterocylic groups.
8
The observation that the meso positions of unsubsti-
tuted porphine 1 show more aromatic than olefinic
character in their reactions led us to investigate the
observed solely at the pyrrole b-positions. Magne-
9
sium·porphine complex 2 was prepared by an adapta-
6
10
tion of the method of Lindsey and Woodford; it was
Scheme 1. Reagents and conditions: (i) MgBr ·OEt , Et N, CH Cl , 60°C; (ii) CH CONHBr, CHCl , 0°C; (iii) ArB(OH) ,
2
2
3
2
2
3
3
2
Pd(PPh ) , Na CO , PhCH , MeOH, 70°C; (iv) HCl.
3
4
2
3
3
Keywords: porphyrin; Suzuki coupling reactions; palladium.
*
Corresponding author. Tel.: +44 (1274) 234710; fax: +44 (1274) 235600; e-mail: r.t.wheelhouse@bradford.ac.uk
Present address: Genelabs Technologies, Inc., 505 Penobscot Drive, Redwood City, CA 94063, USA.
†
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02339-0

9
342
D.-F. Shi, R. T. Wheelhouse / Tetrahedron Letters 43 (2002) 9341–9342
extremely acid labile so was purified by careful chro-
matography on basic alumina. Subsequent bromination
with a small excess of N-bromoacetamide yielded the
800 ml of CH Cl in the presence of Et N (1.5 ml) was
2 2 3
stirred at 60°C overnight. The reaction mixture was
washed with 5% aqueous NaHCO (3×150 ml) and water,
3
1
1
desired 5,10,15,20-tetrabromoporhine 3 in 97% iso-
lated yield. Coupling with aryl boronic acids using
standard Suzuki conditions, followed by a final acid
wash to remove the magnesium ion, furnished the
then dried over K CO . The product was purified by
2
3
chromatography on alumina eluting with CH Cl –MeOH
2
2
(50:1) to give red crystals (105 mg, 97%) lH (CDCl , 250
3
MHz) 10.25 (s, 4H), 9.47 (s, 8H); MS (CI) m/z 333
(M+1).
12
desired meso-aryl products, 4, in up to 70% yields.
1
1
0. Lindsey, J. S.; Woodford, J. N. Inorg. Chem. 1995, 34,
The Suzuki coupling reaction has seen wide application
in the preparation of biaryl compounds and its versatil-
ity has resulted in its use in the construction of combi-
natorial libraries, adaptation to solid phase
technologies and a rapid increase in the range of com-
mercially available boronic acids. Herein, its value in
the preparation of substituted porphyrins has been
demonstrated. In the course of this work, conceptually
1063–1069.
1. 5,10,15,20-Tetrabromoporphine magnesium complex (2).
To a solution of compound 2 (60 mg, 0.18 mmol) in 120
ml of CHCl was added dropwise a solution of N-bro-
3
moacetamide (116 mg, 0.846 mmol) in 20 ml of CHCl at
3
0°C over 5 min. The reaction mixture was then stirred at
room temperature for further 10 min, then 20 ml of
acetone and 20 ml of water were added to quench the
reaction. The organic phase was separated and the
aqueous phase was extracted with CHCl3 until no
product was detected by TLC. The combined organic
phases were dried over K CO . The product was purified
1
3,14
similar investigations were reported
using palla-
dium-catalysed reactions to arylate meso-halogenated
porphyrins; none the less, the current report shows the
generality of the method and extends it to the introduc-
tion of heterocyclic substituents.
2
3
by chromatography on alumina using CH Cl –MeOH
2
2
(
8
200:3) as eluent to give a green-purple powder (94.7 mg,
1%) lH (CDCl , 250 MHz) 9.51 (s, 8H); MS (CI) 649
3
Acknowledgements
m/z (M+1).
1
2. General procedure for preparation of 5,10,15,20-tetra-sub-
stituted porphines (4). Magnesium complex 3 (20 mg, 30.8
mmol), aryl or heteroaryl boronic acid (140 mmol) and
Pd(Ph P) (1 mg, 0.8 mmol) were dissolved in a mixture of
The authors would like to associate this communication
with Professor Laurence Hurley in whose laboratory
this project was initiated. We thank Alvin Carter of
Mid-Century Chemicals, Chicago IL, for many helpful
discussions. Mass spectra were obtained from the
EPSRC National Mass Spectrometry Service Centre,
University of Wales, Swansea, UK.
3
4
toluene (2.5 ml) and methanol (0.6 ml) under N2.
Aqueous sodium carbonate (2 M, 0.5 ml) was added via
a syringe and the reaction mixture was stirred at 70°C for
20 h. The mixture was poured into 40 ml of water and
extracted with chloroform (4×30 ml). The combined chlo-
roform extracts were shaken with 1 M HCl (to disrupt
the magnesium complex), washed with 1 M ammonia
solution, dried over Na SO , concentrated to a small
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2
4
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1
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6
6
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48
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,10,15,20-Tetra(thiophen-3-yl)porphine (4c). Yield 52%;
44 27
8
8
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3
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6
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1
(
2
2