Efficient one-pot regioselective synthesis of 2,3-dibromo-5,10,15,20- tetraarylporphyrins from 5,10,15,20-tetraarylchlorins

Article abstract of DOI:10.1055/s-0029-1217969

2,3-Dibromo-5,10,15,20-tetraarylporphyrins were prepared from easily available 5,10,15,20-tetraarylchlorins in one flask and two steps, namely regioselective dibromination and subsequent oxidation. An improvement in the synthesis of 2,3,12,13-tetrabromo-5

Full text of DOI:10.1055/s-0029-1217969

LETTER
2867
Efficient One-Pot Regioselective Synthesis of 2,3-Dibromo-5,10,15,20-tetra-
arylporphyrins from 5,10,15,20-Tetraarylchlorins
S
ynthesis of 2,3-D
e
ibromo-5,1
-
0,15,20-
L
tetraarylporphy
a
r
ins i Li,a Can-Cheng Guo,*a Qing-Yun Chen*a,b
a
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. of China
E-mail: ccguo@hnu.cn
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: chenqy@mail.sioc.ac.cn
Received 22 June 2009
dro-5,10,15,20-tetraphenylchlorin, which finally elimi-
nated nitrous acid to yield H2(2,3-Br2TPP) (Scheme 1).
This approach was tractable in its operation and efficient
in every step. However, it seemed somewhat troublesome
as there were six reaction steps starting from H2(TPP), in-
cluding metalation, nitration, demetalation, bromination,
reduction, and denitration (Scheme 1). As a consequence,
a more simple and efficient approach to H2(2,3-Br2TPP) is
still in demand.
Abstract: 2,3-Dibromo-5,10,15,20-tetraarylporphyrins were pre-
pared from easily available 5,10,15,20-tetraarylchlorins in one flask
and two steps, namely regioselective dibromination and subsequent
oxidation. An improvement in the synthesis of 2,3,12,13-tetrabro-
mo-5,10,15,20-tetraarylporphyrins has also been achieved.
Key words: bromination, porphyrin, chlorin, regioselective, syn-
thesis
There has been growing interest on bromoporphyrins dur-
ing the last two decades. It is not only because of their in-
teresting physico-chemical properties,1 but also due to
their great utilization as versatile precursors for many
novel and useful porphyrins,2 especially in various cross-
coupling reactions,3 such as Suzuki, Stille, Buchwald–
Hartwig, Negishi, Heck and Sonogashira coupling reac-
tions, as well as trifluoromethylation reaction.4 Since
Callot reported the first b-bromo-meso-tetraphenylpor-
phyrin,5 a large number of methods have been developed
for the synthesis of various brominated porphyrins.1b,6
Among them, 2,3-dibromo-5,10,15,20-tetraphenylpor-
phyrin [H2(2,3-Br2TPP)] has attracted particular attention
due to its special regiochemistry, which can lead to some
interesting compounds.7 For example, starting from
H2(2,3-Br2TPP), after bisallylation via Suzuki coupling
reaction, followed cyclization by the way of olefin met-
athesis and then oxidation, monobenzoporphyrin could be
constructed in a highly efficient manner.7a In another ex-
ample, picenoporphyrins, a novel class of highly p-ex-
tended porphyrins, could also be obtained by using 2,3-
Br2TPP.7d
It is well known that the antipodal b–b¢ double bonds of
b-substituted metal-free porphyrins are more susceptible
to electrophilic reactions than the rest of the macro-
cycles.6a,8 And many regiospecific porphyrins have been
synthesized by using this property.9 For instance, Smith et
al. showed that either a nitro group or a reduced pyrrole
substituent could direct the bromination to the antipodal
pyrrolenic ring, leading to substituted 12,13-dibromo-
porphyrins or 12,13-dibromo-2,3-dihydrochlorins.6g,9d
Therefore, we envisioned that regioselective dibromina-
tion of 5,10,15,20-tetraphenylchlorin [H2(TPC)] would
serve as an excellent platform to access H2(2,3-Br2TPP).
Herein we present the results.
The starting material, H2(TPC) (2a), was prepared from
H2(TPP) (1a) in 73% yield according to the literature
method9i with a slight modification that the product was
recrystallized from CH2Cl2–MeOH rather than benzene
(Scheme 1). After refluxing 2a with 2.2 equivalents NBS
in ethanol-free chloroform under nitrogen for four hours,
4.0 equivalents DDQ were added, and refluxing was con-
tinued for one hour. After being cooled to room tempera-
ture, the reaction mixture was filtrated under suction
through a sintered glass funnel containing silica gel to re-
move succinimide impurities. We noted that besides the
purple filtrate, a green band appeared at the top of the col-
umn. The purple filtrate was evaporated to dryness and
purified by chromatography to afford H2(2,3-Br2TPP)
Since direct dibromination of metal-free meso-tetraphe-
nylporphyrin [H2(TPP)] using NBS/CHCl3 produced a re-
gioisomeric mixture of H2(Br2TPP),5 which were difficult
to separate, Smith et al. developed a regioselective syn-
thetic method for H2(2,3-Br2TPP).6g Their method in-
volved the dibromination of 2-nitro-5,10,15,20-
tetraphenylporphyrin [H2(2-O2NTPP)] with NBS to give
12,13-dibromo-2-nitro-5,10,15,20-tetraphenylporphyrin,
followed by reducing the b–b¢ double bond with sodium
borohydride to afford 12,13-dibromo-2-nitro-2,3-dihy-
1
(4a) in 56% yield. The observed H NMR and MS data
were identical as the reported literature values.6g
The facts that the yield of H2(2,3-Br2TPP) was somewhat
low motivated us to find the reason. Since the conversion
of 2a and the selectivity of the reaction were both high by
judging from TLC analysis, it might be attributed to the
loss of part of the products during the workup. Associated
with N-protonated porphyrins being green and more po-
larized, we suspected that the green band at the top of the
SYNLETT 2009, No. 17, pp 2867–2871
x
x
.x
x
.2
0
0
9
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217969; Art ID: W09709ST
© Georg Thieme Verlag Stuttgart · New York

2868
K.-L. Li et al.
LETTER
Ph
NO2
Ph
Ph
NO2
NH
N
N
N
N
N
N
N
N
N
N2O4
NBS
Ph
Ph
Ph
M
M
Ph
Br
Ph
Ph
CH2Cl2
88%
CHCl3
82%
HN
N
Br
Ph
Ph
Ph
M = 2 H
M = Cu
M = Cu
M = 2 H
Cu(OAc)2
98%
concd HCl
98%
NaBH4
THF
84%
Ph
NO2
Ph
NH
N
N
NH
N
N
SiO2
Ph
Ph
Ph
Br
Ph
Br
CHCl3
98%
HN
HN
overall yield of H2(2,3-Br2TPP)
from H2(TPP): 57%
Br
Ph
Br
Ph
Scheme 1 Synthesis of H2(2,3-Br2TPP) via Smith’s method
Ph
Ph
Ph
TsNHNH2
NH
N
NH
N
N
N
NH
N
N
K2CO3
NBS
Ph
Ph
Ph
Ph
Ph
Ph
pyridine
73%
CHCl3
98%
HN
HN
HN
Br
Ph
1a
Ph
2a
Br
Ph
3a
Zn(OAc)2
pyridine
72%
DDQ
CHCl3
(1) NBS, CHCl3
(2) DDQ
96%
98%
Ph
Ph
NH
N
N
N
N
N
Ph
Ph
Zn
Ph
Ph
Ph
Br
HN
N
Br
overall yield of H2(2,3-Br2TPP) (4a)
from H2(TPP) (1a): 70%
Br
Ph
4a
Br
Zn3a
Scheme 2 Synthesis of H2(2,3-Br2TPP) via ‘reduction–oxidation’ protection
column contained the N-protonated products. So, the The
intermediate,
12,13-dibromo-2,3-dihydro-
green band was dug out and immersed in CH2Cl2, and to 5,10,15,20-tetraphenylchlorin [H2(12,13-Br2TPC)] (3a)
which several drops of triethylamine were added, the could also be isolated by recrystallization in 98% yield.11
green solution turned into purple immediately. After puri- A single-crystal X-ray diffraction study was performed on
fication by chromatography, another portion of H2(2,3- its zinc complex Zn3a (Figure 1),12,13 which provided the
Br2TPP) was indeed obtained in 40% yield. The phenom- ultimate proof of the proposed structure. Compound 3a
enon indicated that the green band truly contained desired can be easily converted into 4a by oxidation with DDQ in
N-protonated products. These N-protonated porphyrins refluxing chloroform in nearly quantitative yield
might be formed through acidification by HBr generated (Scheme 2).
during bromination.3f Being aware of this, an excess of tri-
After having been successfully established a convenient
ethylamine was added to adjust the reaction solution to
route to H2(2,3-Br2TPP), we next examined other easily
basic after the oxidation was completed. Consequently,
available tetraarylchlorins14 bearing different substituents
the yield of 4a could be achieved to 96%.10
at the meso-phenyl groups. Under similar conditions, 2,3-
Synlett 2009, No. 17, 2867–2871 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3-Dibromo-5,10,15,20-tetraarylporphyrins
2869
when the chromatography was completed if triethylamine
was added, while the Kieselguhr was gray in the case that
triethylamine was not added, which gave further evidence
that part of the products had remained on the top of the
column. When other tetraarylporphyrins were used, the
similar results were obtained (Table 1).17 It is worth to
note that the increased degree of the yield of 2,3,12,13-tet-
rabromo-5,10,15,20-tetrakis(p-methoxyphenyl)porphy-
rin (5e, Table 1, entry 3) is much higher than the others.
We thought it could be ascribed to the strong electro-do-
nating property of the four methoxy groups, which makes
the porphyrin more basic and hence more easily to be N-
protonated, and therefore more products remained on the
top of the column if no base was added.
Figure 1 Top view (solvated molecules are omitted for clarity) of
the X-ray crystal structures of Zn3a; thermal ellipsoids are shown at
the 50% probability level
Table 1 Improvement on the Synthesis of H2(2,3,12,13-Br4TArP)
by Adding Et3N
Ar
Br
Ar
dibromo-5,10,15,20-tetra(p-chlorophenyl)porphyrin (4b)
and 2,3-dibromo-5,10,15,20-tetra(p-trifluoromethylphen-
yl)porphyrin (4c) could also be obtained in excellent
yields from the corresponding chlorins (Scheme 3).15
Br
Ar
NBS
CHCl3
NH
N
N
NH
N
N
Ar
Ar
Br
Ar
reflux, 4 h
HN
HN
Thus, an efficient route to 2,3-dibromo-5,10,15,20-tet-
raarylporphyrins has been developed. As compared with
the method using a nitro group as the directing group,6g
our method seems more concise. It only needs three steps
(reduction, bromination, and oxidation) starting from
H2(TPP) (Scheme 2), and the last two steps can be con-
ducted in one flask. Moreover, starting from the same ma-
terial H2(TPP), the overall yield of this approach (70%,
Scheme 2) is higher than that of literature6g (57%,
Scheme 1).
Br
Ar
Ar
1
5
Entry Substrate Ar
Yield (%, lit.6f Yield (%, this
method)
work)
1
2
3
4
1a
1d
1e
1f
Ph
65
83
4-MeC6H4
54
80
4-MeOC6H4
15
66
On the other hand, after realizing that the acid generated
in the bromination would bring loss to free-base porphyrin
products during chromatography, we turned our attention
to the synthesis of 2,3,12,13-tetrabromo-5,10,15,20-tet-
raphenylporphyrin [H2(2,3,12,13-Br4TPP)] (5a),16 where-
in a similar matter existed. Two comparative experiments
were carried out. One experiment was carried out as the
same as the literature procedure.6f The other was per-
formed in a similar manner with the only difference that
an excess of triethylamine was added when the reaction
was completed. The results revealed that the yield of 5a
increased from 65% to 83% by adding triethylamine
(Table 1, entry 1).17 Notably, the Kieselguhr absorbed
crude product turned black to its original white color
3,5-(t-Bu)2C6H3 44
61
In conclusion, a simple and efficient method for the syn-
thesis of 2,3-dibromo-5,10,15,20-tetraarylporphyrins has
been developed by using a reduced pyrrole substituent to
direct the bromination on the antipodal pyrrolic ring,
which will provide an alternative and practical approach.
Improvement on the synthesis of 2,3,12,13-tetrabromo-
5,10,15,20-tetraarylporphyrins was also achieved during
this study.
Ar
Ar
Ar
TsNHNH2
K2CO3
NH
N
NH
N
N
N
NH
N
N
(1) NBS, CHCl3
(2) DDQ
Ar
Ar
Ar
Ar
Br
Ar
Ar
pyridine
HN
HN
HN
Br
Ar
Ar
1b, Ar = 4-ClC6H4
1c, Ar = 4-(F3C)C6H4
Ar
2b, 60%;
2c, 85%
4b, 95%;
4c, 96%
Scheme 3 Synthesis of other 2,3-dibromotetraarylporphyrins
Synlett 2009, No. 17, 2867–2871 © Thieme Stuttgart · New York

2870
K.-L. Li et al.
LETTER
(6) For reviews, see: (a) Jaquinod, L. In The Porphyrin
Supporting Information for this article is available online at
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Acknowledgment
The authors are grateful to Professor Min-Qin Chen (Fudan Univer-
sity) for the resolution of the X-ray crystal structures. We also thank
for financial support from the National Natural Science Foundation
of China (Nos. 20272076, 20772146 and D20032010).
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(10) Typical Procedure for the Synthesis of 2,3-Dibromo-
5,10,15,20-tetraarylporphyrins 4
5,10,15,20-Tetraarylchlorin 2 (0.2 mmol) and NBS (80 mg,
0.44 mmol) were added to a Schlenk flask (50 mL). The
flask was then evacuated and backfilled with nitrogen (three
Synlett 2009, No. 17, 2867–2871 © Thieme Stuttgart · New York

LETTER
cycles). Then dry CHCl3 (EtOH free, 20 mL) was charged
Synthesis of 2,3-Dibromo-5,10,15,20-tetraarylporphyrins
2871
(13) C44H28Br2N4Zn·C5H5N×0.5CHCl3 (Zn3a) crystallized by
diffusion of MeOH into a CHCl3–pyridine (100:1) solution.
Crystal Data
with a syringe. The reaction mixture was stirred and heated
under reflux for 4 h. After being slightly cooled, a solution
of DDQ (184 mg, 0.8 mmol) in toluene (2 mL) was added,
and the mixture was refluxed for further 1 h. After being
cooled to r.t., Et3N (1 mL) was added to neutralize the acids
produced in the reaction. Then the reaction mixture was
filtered through a short silica plug (300–400 mesh, eluting
with CH2Cl2). The filtrate was evaporated to dryness, and the
resulting solid was purified by flash chromatography (silica
gel, 300–400 mesh, PE–CH2Cl2 as eluent) to yield the
products 4.
M = 976.68, monoclinic, space group P2(1)/c, a = 13.330
(4), b = 19.918 (6), c = 17.843 (6) Å, a = 90.00, b = 109.285
(4), g = 90.00°, V = 4472 (2) Å3, T = 293 (2) K, Z = 4,
Dc = 1.451 g cm–3, m (Mo Ka) = 2.466 mm–1, 21287
reflections measured, 9543 unique which were used in all
calculations. R1 (all data) = 0.1106. R1 = 0.0551. CCDC
689519.
(14) 5,10,15,20-Tetraarylchlorins were synthesized according to
the literature method.9i
(11) Synthesis of 12,13-Dibromo-2,3-dihydro-5,10,15,20-
5,10,15,20-Tetra(p-chlorophenyl)chlorin (2b)
tetraphenylchlorin 3a
Purple crystals, 736 mg, yield 60%. 1H NMR (300 MHz,
CDCl3): d = 8.56 (d, J = 4.5 Hz, 2 H, b-H), 8.40 (s, 2 H, b-
H), 8.18 (d, J = 4.5 Hz, 2 H, b-H), 8.02 (d, J = 7.8 Hz, 4 H,
o-PhH), 7.80 (d, J = 7.8 Hz, 4 H, o-PhH), 7.67 (d, J = 7.5
Hz, 8 H, m-PhH), 4.15 (s, 4 H, CH2), –1.52 (s, 2 H, NH). UV/
vis (CH2Cl2): lmax (rel. int.) = 419 (1.00), 519 (0.09), 545
(0.06), 599 (0.04), 652 (0.19) nm. MS (MALDI): m/z =
754.1 [M+]. Anal. Calcd for C44H28Cl4N4×0.5H2O (from
CH2Cl2–wet MeOH): C, 69.21; H, 3.83; N, 7.34. Found: C,
69.35; H, 3.68; N, 7.34.
5,10,15,20-Tetraphenylchlorin (2a, 124 mg, 0.2 mmol) and
NBS (80 mg, 0.44 mmol) were added to a Schlenk flask (50
mL). The flask was then evacuated and backfilled with
nitrogen (three cycles). Then dry CHCl3 (EtOH free, 20 mL)
was charged with a syringe. The reaction mixture was stirred
and heated under reflux for 4 h. After being cooled to r.t.,
Et3N (1 mL) was added to neutralize the acids produced in
the reaction. Then the reaction mixture was quickly filtered
through a short silica plug (300–400 mesh, eluting with
CH2Cl2). The filtrate was concentrated and recrystallized
from CH2Cl2–MeOH to give pure products 3a.
(15) For the details of the synthesis of 4b and 4c, see ref. 10.
2,3-Dibromo-5,10,15,20-tetrakis(p-chlorophenyl)-
porphyrin (4b)
12,13-Dibromo-2,3-dihydro-5,10,15,20-
tetraphenylchlorin (3a)
Purple crystals, 172 mg, yield 95%. 1H NMR (300 MHz,
CDCl3): d = 8.85 (s, 4 H, b-H), 8.68 (s, 2 H, b-H), 8.11 (d,
J = 6.0 Hz, 4 H, o-PhH), 8.05 (d, J = 6.6 Hz, 4 H, o-PhH),
7.74–7.76 (m, 8 H, m-PhH), –2.93 (s, 2 H, NH). UV/vis
(CH2Cl2): lmax (rel. int.) = 425 (1.00), 522 (0.06), 599 (0.02),
687 (0.05) nm. MS (MALDI): m/z = 909.9 [M+]. Anal. Calcd
for C44H24Br2Cl4N4×0.5H2O (from CH2Cl2–wet MeOH): C,
57.49; H, 2.74; N, 6.09. Found: C, 57.39; H, 2.60; N, 6.16.
(16) H2(2,3,12,13-Br4TPP) was first synthesized by Callot5a in
1974, but its structure was misassigned as 2,7,12,17-
tetrabromo-5,10,15,20-tetraphenylporphyrin. In 1991, work
by Crossley et al.6n revealed the antipodal nature of the
bromination reaction of metal-free tetraarylporphyrins, and
H2(2,3,12,13-Br4TPP) was prepared by refluxing H2(TPP)
with NBS in 80% yield, but no detail operation was reported.
In 1994, Xu et al.6i obtained H2(2,3,12,13-Br4TPP) using the
same method by directly recrystallized from CH2Cl2–MeOH
after the reaction mixture was concentrated, but no yield was
reported. In 2003, Bhyrappa et al.6f reported the synthetic
procedure of H2(2,3,12,13-Br4TPP) in detail, in which the
crude product was purified by chromatography and the yield
was 65%.
(17) Typical Procedure for the Synthesis of 2,3,12,13-
Tetrabromo-5,10,15,20-tetraarylporphyrins 5
5,10,15,20-Tetraarylporphyrin 1 (0.5 mmol) and NBS (580
mg, 3.25 mmol) were dissolved in CHCl3 (EtOH free, 60
mL). The reaction mixture was stirred and heated under
reflux for 4 h. After being cooled to r.t., Et3N (3 mL) was
added to neutralize the acids produced in the reaction. Then
the reaction mixture was filtered through a short silica plug
(300–400 mesh, eluting with CH2Cl2). The filtrate was
evaporated to dryness, and the resulting solid was purified
by flash chromatography (silica gel, 300–400 mesh, CH2Cl2
as eluent) to yield the products 5. The spectroscopic data
were in agreement with literature values.2g,6f
Purple crystals, 151 mg, yield 98%. 1H NMR (300 MHz,
CDCl3): d = 8.51 (d, J = 2.7 Hz, 2 H, b-H), 8.08 (d, J = 2.7
Hz, 2 H, b-H), 8.02 (d, J = 6.0 Hz, 4 H, o-PhH), 7.82 (d,
J = 6.0 Hz, 4 H, o-PhH), 7.67–7.70 (m, 12 H, m-PhH and p-
PhH), 4.07 (s, 4 H, CH2), –1.40 (s, 2 H, NH). UV/vis
(CH2Cl2): lmax (rel. int.) = 428 (1.00), 529 (0.08), 598 (0.05),
650 (0.10) nm. MS (MALDI): m/z = 774.1 [M+]. Anal. Calcd
for C44H30Br2N4×2H2O (from CH2Cl2–wet MeOH): C,
65.20; H, 4.23; N, 6.91. Found: C, 65.00; H, 4.01; N, 6.90.
(12) Synthesis of Zinc 12,13-Dibromo-2,3-dihydro-
5,10,15,20-tetraphenylchlorin Zn3a
Zn3a was synthesized according to the literature method.18
12,13-Dibromo-2,3-dihydro-5,10,15,20-tetraphenylchlorin
(3a, 77 mg, 0.1 mmol) and zinc acetate dihydrate (66 mg, 0.3
mmol) were added to a Schlenk flask (20 mL). The flask was
then evacuated and backfilled with nitrogen (three cycles).
Then pyridine (10 mL) was charged with a syringe. The
reaction mixture was stirred and heated at 100 °C under
nitrogen for 1 h. To the cooled reaction mixture, benzene (20
mL) and distilled H2O (20 mL) were added. The organic
layer was quickly washed with distilled H2O and brine and
then filtered through a short silica plug (300–400 mesh,
eluting with CH2Cl2). The filtrate was concentrated and
recrystallized from CH2Cl2–MeOH to give monopyridinate
complex of Zn3a.
Zinc 12,13-Dibromo-2,3-dihydro-5,10,15,20-
tetraphenylchlorin (Zn3a)
Purple crystals, 66 mg, yield 72%. 1H NMR (300 MHz,
CDCl3): d = 8.36 (d, J = 4.2 Hz, 2 H, b-H), 7.96 (d, J = 4.2
Hz, 2 H, b-H), 7.86 (d, J = 7.2 Hz, 4 H, o-PhH), 7.77 (d,
J = 7.2 Hz, 4 H, o-PhH), 7.59–7.61 (m, 12 H, m-PhH and p-
PhH), 3.97 (s, 4 H, CH2). UV/vis (CH2Cl2): lmax (rel. int.) =
424 (1.00), 553 (0.05), 619 (0.08) nm. MS (MALDI): m/z =
836.0 [M+]. Anal. Calcd for C44H28Br2N4Zn·C5C5N×4H2O
(from CH2Cl2–wet MeOH–pyridine): C, 59.50; H, 4.18; N,
7.08. Found: C, 59.68; H, 3.86; N, 7.08.
(18) Whitlock, H. W.; Oester, M. Y. J. Am. Chem. Soc. 1973, 95,
5738.
Synlett 2009, No. 17, 2867–2871 © Thieme Stuttgart · New York

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