Dihydroporphyrin synthesis: New methodology

Article abstract of DOI:10.1021/jo980965p

Selective formation of trans-nitrochlorins 16-19, cyclopropylchlorins 14, 15, and 20-23, or functionalized trans-chlorins 5-13 by reaction of 2- nitro-5,10,15,20-tetraphenylporphyrin 1 with 'active' methylene compounds such as malonates or malononitrile in the presence of base has been achieved. Reaction control is accomplished via sequential Michael additions, followed by intra-molecular nucleophilic displacement of a secondary nitro group. Steric as well as thermodynamic effects have been found to govern the selectivity of product formation. Ambient temperature or bulky carbanion substituents lead to nitrochlorins and/or cyclopropylchlorins. Increased reaction temperatures, combined with sterically less encumbered carbanion substituents, favor the formation of disubstituted trans-chlorins. Nucleophilic ring-opening reactions of cyclopropyl-derivative 14 afford disubstituted trans-chlorin products 5 and 25 and provide additional mechanistic evidence for the intermediacy of the cyclopropylchlorin. Use of porphyrins with modified meso-phenyl positions illustrates the generality of this methodology and allows a novel method for the preparation of a wide range of reduced porphyrins, which may find application in fields such as the photodynamic therapy (PDT) of cancer.

Full text of DOI:10.1021/jo980965p

J . Org. Chem. 1998, 63, 7013-7021
7013
Dih yd r op or p h yr in Syn th esis: New Meth od ology†
Kalyn M. Shea, Laurent J aquinod, and Kevin M. Smith*
Department of Chemistry, University of California, Davis, California 95616
Received May 20, 1998
Selective formation of trans-nitrochlorins 16-19, cyclopropylchlorins 14, 15, and 20-23, or
functionalized trans-chlorins 5-13 by reaction of 2-nitro-5,10,15,20-tetraphenylporphyrin 1 with
“active” methylene compounds such as malonates or malononitrile in the presence of base has been
achieved. Reaction control is accomplished via sequential Michael additions, followed by intra-
molecular nucleophilic displacement of a secondary nitro group. Steric as well as thermodynamic
effects have been found to govern the selectivity of product formation. Ambient temperature or
bulky carbanion substituents lead to nitrochlorins and/or cyclopropylchlorins. Increased reaction
temperatures, combined with sterically less encumbered carbanion substituents, favor the formation
of disubstituted trans-chlorins. Nucleophilic ring-opening reactions of cyclopropyl-derivative 14
afford disubstituted trans-chlorin products 5 and 25 and provide additional mechanistic evidence
for the intermediacy of the cyclopropylchlorin. Use of porphyrins with modified meso-phenyl
positions illustrates the generality of this methodology and allows a novel method for the preparation
of a wide range of reduced porphyrins, which may find application in fields such as the photodynamic
therapy (PDT) of cancer.
In tr od u ction
penetration with minimal light scattering. The conver-
sion of tetraarylporphyrins into the corresponding tetra-
arylchlorins is known to increase the long-wavelength
absorbance (>600 nm);4 however, a general synthetic
methodology that would produce a range of highly
functionalized dihydroporphyrins is still needed to fa-
cilitate in-depth studies of the physical and structural
properties of these photosensitizers.
Chemical transformations of natural and synthetic
porphyrin macrocycles and their peripheral substituents
have been an area of intense interest for a number of
years. Development of new methodologies to function-
alize porphyrins and their derivatives can provide a
variety of new compounds that could otherwise only be
obtained by total synthesis.1 Functionalization at the
â-pyrrolic positions of tetrapyrroles is of particular inter-
est due to the potential for additional bond construction
as well as the direct alteration of the properties of the
porphyrin macrocycle.
Presently, effective techniques for the generation of
functionalized meso-tetraarylchlorins (e.g., 5,10,15,20-
tetraphenylchlorin, TPC) from meso-tetraphenylpor-
phyrins (TPP) are limited to a small number of methods
such as the diimide reduction procedure described by
Whitlock et al. in 1969.4 Bonnett et al. recently made
use of this method to prepare a series of meso-tetrakis-
(hydroxyphenyl)chlorins,5 which show promise as second-
generation PDT sensitizers.6 Callot has also demon-
strated that carbenes can be used to functionalize the
TPP macrocycle, affording moderate yields of cyclopro-
panyl-annulated tetraphenylchlorins7 that are similar to
the compounds 14 and 15 described in the present paper.
More recently, meso-arylporphyrins have been shown to
act as dienophiles in the presence of o-benzoquino-
dimethane (a highly reactive diene generated in situ by
exclusion of SO2 from a sulfone) to produce chlorins,
bacteriochlorins, and naphthochlorins.8 Another route
to naphthochlorins involves acid-catalyzed intramolecular
Previous methods for the preparation of reduced por-
phyrins (dihydroporphyrins) have allowed the synthesis
of long-wavelength absorbing chromophores (λmax > 630
nm) that show potential application to the photodynamic
therapy (PDT) modality for treatment of cancer.2 This
therapy makes use of localized, light-absorbing photo-
sensitizer drugs for the treatment of malignant tumors.3
For effectiveness of this treatment, it is important that
the photosensitizer exhibit a strong long-wavelength
absorption in order to minimize the photosensitizer
dosage, reduce side effects, and achieve maximal tissue
† Dedicated to Professor Wolfhart Ru¨diger on the occasion of his 65th
birthday.
(1) Smith, K. M. In Rodd’s Chemistry of the Carbon Compounds;
Sainsbury, M., Ed.; Elsevier: Amsterdam; 1997; Chapter 12, Suppl.
to Vol. IVB.; 1997; pp 277-357.
(2) Kostenic, G. A.; Zhuravkin, I. N.; Zhavrid, E. A. Photochem.
Photobiol. B. Biol. 1994, 22, 211. Bonnett, R.; Benzie, R.; Grahn, M.
F.; Salgado, A.; Valles, M. A. Proc. SPIE 1994, 2078, 178. Leach, M.
W.; Higgins, S. A.; Autrey, S. A.; Boggan, S. E.; Lee, S. J . H.; Smith,
K. M. Photochem. Photobiol. 1993, 58, 653. Ferrario, A.; Kessel, D.;
Gomer, C. J . Cancer Res. 1992, 52, 2890. Morgan, A. R.; Garbo, G. M.;
Keck, R. W.; Eriksen, L. D.; Selman, S. H. Photochem. Photobiol. 1990,
51, 589. Gomer, C. J .; Ferrario, A. Cancer Res. 1990, 50, 3985.
(3) Bonnett, R. Chem. Soc. Rev. 1995, 19. Henderson, B. W.;
Dougherty, T. J . Photochem. Photobiol. 1992, 55, 145.
(4) Whitlock, H. W.; Hanauer, R.; Oester, M. Y.; Bower, B. K. J .
Am. Chem. Soc. 1969, 91, 7485.
(5) Bonnett, R.; White, R. D.; Winfield, U.-J .; Berenbaum, M. C.
Biochem. J . 1989, 261, 277.
(6) Berenbaum, M. C.; Akande, S. L.; Bonnett, R.; Kaur, H.; Ioannou,
S.; White, R. D.; Winfield, U.-J . Br. J . Cancer 1986, 54, 717.
(7) Callot, H. J . Tetrahedron Lett. 1972, 1011.
(8) Tome, A. C.; Lacerda, P. S. S.; Neves, M.; Cavaleiro, J . A. S. J .
Chem. Soc, Chem. Commun. 1997, 1199. Vicente, M. G. H.; Smith, K.
M. Manuscript in preparation.
S0022-3263(98)00965-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/05/1998

7014 J . Org. Chem., Vol. 63, No. 20, 1998
Shea et al.
our recent synthesis of pyrroloporphyrins,14 which in-
volved reactions of metallo-2-nitro-5,10,15,20-tetra-
phenylporphyrin (2-NO2TPP) with isocyanoacetates. Not
only did this reaction provide the desired pyrrolopor-
phyrin product but a Zn(II) cyclopropylchlorin was also
isolated. These results prompted our development of the
new methodology for preparation of dihydroporphyrins
reported herein, based on the conjugate addition of
carbon-centered nucleophiles to nitroalkenes. This ap-
proach offers the means to selectively generate carbon-
carbon bonds for the preparation of novel highly func-
tionalized chlorin systems by reaction of “active” methylene
compounds with readily available â-nitroporphyrin pre-
cursors.
Sch em e 1. Syn th esis of Cu (II)
2-Meth yl-5,10,15,20-tetr a p h en ylp or p h yr in fr om th e
Cu (II) 2-Nitr o An a logu e
Resu lts a n d Discu ssion
A preliminary report15 revealed the structure of two
functionalized chlorin compounds prepared by the addi-
tion of “active” methylene compounds (characterized by
X-ray crystallography). To extend this work, we have
examined the reactivity of both metalated and metal-free
2-NO2TPP with a variety of methylene compounds, bases,
and solvents. In contrast to previous reports,13 we find
that metal-free nitroporphyrins can be used as substrates
for nucleophilic reactions under basic conditions, without
formation of a deactivated porphyrin anion.
Rea ction s of 2-Nitr o-5,10,15,20-tetr a p h en ylp or -
p h yr in w ith Ma lon on itr ile a n d Alk ylcya n oa ceta tes.
Reaction of 2-nitro-5,10,15,20-tetraphenylporphyrin 1
with small methylene compounds, such as malononitrile
and alkyl cyanoacetates, produced two chlorin products:
cyclopropylchlorins and disubstituted functionalized trans-
chlorins (Scheme 2).
cyclization of Ni(II) 2-vinyltetraphenylporphyrin.9 Vici-
nal â,â′-dihydroxylation of tetraphenylchlorin and tet-
raphenylporphyrin suffers from the low reactivity of TPP
and the stoichiometric use of expensive and toxic
OsO4.10
2-Nitro-meso-tetraarylporphyrins are versatile starting
materials for efficient incorporation of functionality into
the â-pyrrolic positions of porphyrins through nitrochlo-
rin intermediates.11-13 These intermediates are unstable
and readily eliminate nitrous acid to regenerate â-sub-
stituted porphyrins. For example, conjugate addition of
Grignard and organolithium reagents to 2-nitrotetraphen-
ylporphyrins proceeds through 2-alkyl-2,3-dihydro-3-
nitroporphyrin (chlorin) intermediates. Elimination of
nitrous acid affords 2-alkyltetraphenylporphyrin,11 as
outlined in Scheme 1. Reaction of metallo-2-nitro-5,10,
15,20-tetraphenylporphyrins with sodium borohydride
produces 2,3-dihydro-2-nitro-5,10,15,20-tetraphenylchlo-
rin.12 This chlorin intermediate can either eliminate
nitrous acid to regenerate the porphyrin or undergo
reductive denitration with tributyltin hydride and AIBN
to produce 2,3-dihydroporphyrin. Reaction of copper(II)
2-nitro-5,10,15,20-tetraphenylporphyrin 2 with sodium
methoxide affords the corresponding 2,2-dimethoxy-3-
nitrochlorin via a nucleophilic-substitution nucleophilic-
addition sequence.13 Upon denitration, a blue-green 2,2-
dimethoxychlorin eliminates methanol to afford the
corresponding 2-methoxyporphyrin.
At room temperature (∼22 °C), reaction between 1 and
malononitrile in the presence of K2CO3 produced cyclo-
propylchlorin 14 in 68% yield. A minor second product
with higher polarity was also observed and identified as
the functionalized trans-chlorin 5 (9% yield). Interest-
ingly, by increasing the reaction temperature to 65 °C,
only the trans-chlorin 5 was produced (71% yield).
The structures of the functionalized dihydroporphyrins
5 and 14 were assigned on the basis of their 1H NMR
spectra. The less polar cyclopropylchlorin 14 displayed
a singlet at δ 5.15 characteristic of the reduced â-pyrrolic
protons, as well as two doublets (δ 8.55 and 8.75) and an
additional singlet (δ 8.54) in the â-proton region. The
mass spectrum of compound 14 showed the parent ion
peak at 679.3 (MH
+). The 1H NMR spectrum of the more
polar product 5 revealed a doublet at δ 4.35 correspond-
ing to the malononitrile protons and a doublet at δ 5.38
corresponding to the reduced pyrrole â-protons (C2 and
C3). The mass spectrum of the disubstituted chlorin
showed the appropriate parent ion peak at 744.3 (M+).
The electronic absorbances for both compounds are
characteristic of metal-free chlorins, with a long-wave-
length peak at λmax ) 646 nm.
Although these routes involve chlorin intermediates,
the preparation of stable functionalized dihydroporphyrin
systems from nitroporphyrins has yet to be developed.
In the present paper we report the convenient prepara-
tion of such novel dihydroporphyrins, discuss the versa-
tility of the reaction, and describe the probable mecha-
nism of formation of the products. This work stems from
Stereoselectivity was observed with unsymmetric
methylene compounds such as alkyl cyanoacetates. Re-
action of 1 with methyl cyanoacetate (K2CO3, THF, 14
(9) Faustino, M. A.; Neves, M. G. P. M. S.; Vicente, M. G. H.; Silva,
A. M. S.; Cavaleiro, J . A. S. Tetrahedron Lett. 1995, 36, 5977.
(10) Bru¨ckner, C.; Dolphin, D. Tetrahedron Lett. 1995, 36, 9495.
(11) Crossley, M. J .; Harding, M. M.; Tansey, C. W. J . Org. Chem.
1994, 59, 4433.
(12) Crossley, M. J .; King, L. G. J . Org. Chem. 1993, 58, 4370.
(13) Crossley, M. J .; King, L. G. J . Chem. Soc., Perkin Trans. 1 1996,
1251.
(14) J aquinod, L.; Gros, C.; Olmstead, M. M.; Antolovich, M.; Smith,
K. M J . Chem. Soc, Chem. Commun. 1996, 1475. Gros, C.; J aquinod,
L.; Khoury, R. G.; Olmstead, M. M.; Smith, K. M. J . Porphyrins
Phthalocyanines 1997, 1, 201.
(15) J aquinod, L.; Gros, C.; Khoury, R. G.; Smith, K. M. J . Chem.
Soc., Chem. Commun. 1996, 2581.

Dihydroporphyrin Synthesis: New Methodology
J . Org. Chem., Vol. 63, No. 20, 1998 7015
Sch em e 2. Syn th esis of Cyclop r op ylch lor in s a n d
F u n ction a lized tr a n s-Ch lor in s via Em p loym en t of
Ca r ba n ion s w ith Sm a ll Meth ylen e Su bstitu en ts
Sch em e 3. En a n tiom er ism in
tr a n s-2,3-Bis(cya n om eth yl)ch lor in s
Sch em e 4. Syn th esis of Nitr och lor in s a n d
Cyclop r op ylch lor in s via Em p loym en t of
Ca r ba n ion s w ith Bu lk y Meth ylen e Su bstitu en ts
h) at room temperature produced the exo-cyclopropyl
product 15 exclusively. A steric effect is thought to
control the selective exo orientation of the bulkier group
upon ring closure. Evidence for such stereoselectivity is
1
revealed in the H NMR spectrum, which showed only
one singlet at δ 3.93, corresponding to the ester methoxyl
moiety.
In contrast, addition of alkyl cyanoacetates to both 1
and 3 (K2CO3, THF) at 65 °C afforded a mixture of trans-
chlorin diastereomers 10-13. The 1H NMR spectrum
indicated a mixture of four enantiomeric pairs of com-
pounds. Decarboxymethylation of 10 with NaCl in wet
DMSO at 140 °C yielded 9, quantitatively and as a
racemate. The reduced pyrrole subunit and its cyano-
methyl substituents exhibit an ABX system in the 1H
NMR spectrum, indicating that this compound is both
chiral and C2 symmetric (absence of mirror or inversion
symmetry; Scheme 3).16 The chirality of the functional-
ized trans-chlorin was further confirmed by X-ray crys-
tallography data of compound 6. Indeed, both enanti-
omers were found to be equally present in the crystal
packing.15 Compound 9 can be conveniently prepared in
75% yield by carrying out a one-pot sequential Michael
addition, nitro substitution, and decarboxymethylation
in DMSO.
pounds, such as dimethyl malonate, afforded nitrochlo-
rins and cyclopropylchlorins, but did not lead to disub-
stituted trans-chlorins (Scheme 4). At room temperature,
reaction between 1 and dimethyl malonate in the pres-
ence of K2CO3 afforded the functionalized nitrochlorin 16
(66% yield). The nitrochlorin was surprisingly stable to
warming, chromatography, and even mass spectral analy-
sis. Earlier reports indicated that such stability of
nitrochlorins was not observed, but rather elimination
of HNO2 and decomposition to the porphyrin occurred.11,12
By increasing the temperature to 100 °C, reaction
Rea ction s of 2-Nitr o-5,10,15,20-tetr a p h en ylp or -
p h yr in w ith Bu lk y “Active” Meth ylen e Com p ou n d s.
Reaction of 2-NO2TPP 1 with bulky methylene com-
(16) Whitesell, J . K. Chem. Rev. 1989, 89, 1581.

7016 J . Org. Chem., Vol. 63, No. 20, 1998
Shea et al.
Ta ble 1. Effect of Rea ction Tem p er a tu r e on Ch lor in
F or m a tion : Meth od A, Ma lon on itr ile (10 equ iv)/K2CO3/
THF ; Meth od B, Dim eth yl Ma lon a te (10
equ iv)/K2CO3/THF
between 1 and dimethyl malonate (K2CO3, DMSO) af-
forded the cyclopropyl product 20 in 77% yield. Ni(II)
2-NO2TPP 3 reacted similarly with dimethyl malonate
to produce the metalated nitrochlorin 17 at room tem-
perature and the metalated cyclopropyl analogue 21 at
100 °C.
starting
compound time temp
trans-
chlorin
cyclopropyl-
chlorin
nitro-
chlorin
(method)
(h)
12
10
7.5
6
8
3
12
5
(°C)
(% yield)
(% yield)
(% yield)
The structures of nitrochlorins 16 and 17 were as-
1 (A)
1 (A)
1 (A)
1 (A)
2 (A)
2 (A)
1 (B)
1 (B)
1 (B)
22
35
50
65
22
65
22
80
100
5 (9)
14 (68)
14 (41)
14 (27)
1
signed on the basis of H NMR and mass spectral data.
5 (35)
5 (48)
5 (71)
7 (70)
7 (65)
1
The H NMR spectrum of 16 showed singlets at δ 2.40
and 3.71 for the endo and exo methyl ester protons as
well as doublets at δ 4.05 and 5.76 corresponding to the
malonate proton and the C2 proton alpha to the nitro
group, respectively. Similar to the metal-free nitrochlorin
20 (4)
20 (46)
20 (72)
16 (69)
16 (28)
1
3
16, the H NMR spectrum of the Ni(II) nitrochlorin 17
revealed two doublets coupled to each other at δ 3.51
(malonate proton) and 5.40 (C2 proton). In addition, a
singlet at δ 7.02 was observed, corresponding to the
proton geminal to the nitro group (C3). Interestingly,
there is an absence of coupling between the resonances
at δ 5.40 and 7.02, thereby establishing the trans
relationship of the substituents. Mass spectral analysis
of 16 revealed a parent peak at m/z 792.3 and a fragment
peak at 745.3, corresponding to the loss of HNO2. The
electronic absorbances of both compounds are character-
istic of metal-free and metallochlorins, with long-
wavelength peaks at λmax ) 646 nm for 16 and 608 nm
for 17.
Tem p er a tu r e Effects. The selective formation of
trans-nitrochlorins, cyclopropylchlorins, or functionalized
trans-chlorins is highly temperature-dependent. We
found that careful control of reaction temperature and
close monitoring of product formation provided the
desired product in good yield (Table 1). Temperature
effects were studied in reactions of 2-NO2TPP 1 with
malononitrile (method A, Table 1) at 22, 35, 50, and 65
°C. At 22 °C, after 12 h (when all starting material had
been consumed), 68% of the cyclopropylchlorin 14 and
9% of the functionalized trans-chlorin 5 were isolated.
When these reactions were run at temperatures above
room temperature, the combined yields of 14 and 5 were
similar to the yields at room temperature, but the amount
of 5 had increased with elevating temperature. In
refluxing THF, only the functionalized trans-chlorin 5
was obtained.
Temperature effects were also studied in reactions of
2-NO2TPP 1 with a bulky methylene compound, dimethyl
malonate (method B, Table 1), at 22, 80, and 100 °C.
Lower temperatures favored the formation of the nitro-
chlorin 16, whereas at 80 °C, a mixture of the nitrochlorin
16 and cyclopropanylchlorin 20 was obtained. Increasing
the temperature to 100 °C produced the cyclopropylchlo-
rin 20 exclusively.
Use of benzylcyanide as the “active” methylene com-
pound in a reaction with 1 at room temperature also
produced a nitrochlorin 18. Increasing the reaction
temperature to 100 °C afforded the cyclopropylchlorin 22.
Reaction of 1 with di-n-butyl malonamide yielded nitro-
chlorin 19, but only after extended reaction times (36 h)
at elevated temperatures (100 °C). The corresponding
cyclopropyl product was not observed. When malon-
amide was used in a reaction with 1 (50 h, 100 °C), the
cyclopropylchlorin 23 was obtained. Unfortunately, the
more rigorous conditions required to obtain the chlorin
products reduced the yields of 19 and 23 and made
product isolation more difficult.
Cyclop r op yl Rin g Op en in g. To further understand
the mechanism of these reactions cyclopropylchlorins 14
and 20 were subjected to nucleophilic attack in order to
promote ring opening. Treatment of 14 with 10 equiv of
malononitrile, with K2CO3 in THF at 65 °C, led to ring
cleavage, affording the trans-chlorin 5 quantitatively. Use
of 1-thiopropane afforded the highly functionalized prod-
uct 25 in 82% yield. However, subjecting 20 to similar
Cen tr a l Meta l Ion Effects. Reaction of Cu(II), Ni(II),
or Zn(II) 2-nitro-5,10,15,20-tetraphenylporphyrin (2-4,
respectively) with malononitrile in the presence of base
at 65 °C produced functionalized trans-chlorins 6-8 in
similar yields (68, 70, and 63%, respectively). Reaction
times varied from 3 h for the copper and nickel porphy-
rins to 24 h for the zinc porphyrin. Treatment of Ni(II)
2-nitro-5,10,15,20-tetraphenylporphyrin 3 with malono-
nitrile at room temperature afforded exclusively the
trans-chlorin 7. This result is in direct contrast to the
product distribution observed for the reaction of metal-
free 2-NO2TPP 1 at room temperature, which yielded
mainly the cyclopropyl product 14. Similarly, reaction
of 3 with methyl cyanoacetate at room temperature
afforded a diastereomeric mixture of the functionalized
trans-chlorins 11. Zn(II) 2-nitro-5,10,15,20-tetraphenyl-
porphyrin 4 was found to be unreactive under the same
conditions at room temperature, suggesting that moder-
ately electronegative ions such as Cu(II) and Ni(II)
facilitate nucleophilic attack of “active” methylene com-
pounds, whereas less electronegative ions such as Zn(II)
hinder such reactions. This pattern of 2-nitrometallopor-
phyrin reactivity has previously been observed with
oxyanions13 and is in good agreement with the results
presented here.
conditions (malononitrile, K2CO3, DMSO, 100 °C or
1-thiopropane, NaH, THF) did not result in ring opening,
most likely due to steric hindrance by the bulky cyclo-
propyl substituents.
Rea ction s of m eso-Tetr a [3,5-d i(ter t-bu tyl)p h en yl]-
2-n it r op or p h yr in a n d m eso-Tet r a k is(m -m et h oxy-
p h en yl)-2-n itr op or p h yr in w ith “Active” Meth ylen e

Dihydroporphyrin Synthesis: New Methodology
J . Org. Chem., Vol. 63, No. 20, 1998 7017
Sch em e 5. P ossible Mech a n istic P a th w a ys for
F or m a tion of All Th r ee Ch lor in P r od u cts:
Nitr och lor in s, Cyclop r op ylch lor in s, a n d
Disu bstitu ted tr a n s-Ch lor in s
Com p ou n d s. The generality of this methodology was
investigated by modifying meso-aryl substituents. Nitra-
tion of Cu(II) meso-tetra[3,5-di(tert-butyl)phenyl]por-
phyrin 26 with dinitrogen tetraoxide (N2O4), followed by
demetalation in H2SO4, provided meso-tetra[3,5-di(tert-
butyl)phenyl]-2-nitroporphyrin 28. As expected, reaction
of 28 with malononitrile and K2CO3 in THF at 65 °C
produced the functionalized trans-chlorin 30 (in 78%
yield). Likewise, reaction of meso-tetra(m-methoxy-
phenyl)-2-nitroporphyrin 29 (prepared by similar nitra-
tion and demetalation procedures) with malononitrile
afforded the trans-chlorin 31 in 64% yield. Modification
of the six remaining chlorin â positions by exhaustive
bromination provided access to highly nonplanar dodeca-
substituted chlorins for the first time.17
alkanes with base have been shown to result in the
formation of a nitronate anion,18 therefore preventing the
nitro group from serving as a leaving group.
A more feasible mechanistic route would rely on the
formation of the less hindered trans-nitrochlorin, 34
(Scheme 5), followed by deprotonation to form 35. Per-
haps even more likely would be initial formation of 35
via intramolecular proton exchange, as illustrated in the
conversion of 33 to 35. Ring closure via intramolecular
displacement of the nitro group would then produce the
cyclopropylchlorin 36. This type of intramolecular dis-
placement of a nitro group has been reported previously
by Tamura et al.19 during cyclopropanation of R-nitro-
alkenes with cyanoacetate and malononitrile. The stable
cyclopropyl intermediate 36 either can be isolated or can
undergo a ring-opening reaction with a second equivalent
of nucleophile to produce the functionalized disubstituted
trans-chlorin 37.
Support for path b (Scheme 5) was obtained by isola-
tion, characterization, and further reactions of certain
key intermediates. Heating nitrochlorin 16 in the pres-
ence of base promoted ring closure and intramolecular
nitro group displacement to produce the cyclopropylchlo-
rin 20. Additionally, nucleophilic ring opening of cyclo-
propylchlorin 14 afforded disubstituted trans-chlorin
products 5 and 25. These results suggest that the
functionalized trans-chlorins are obtained via a cyclo-
propylchlorin intermediate (path b) and not through an
intermolecular displacement of a nitro group as il-
lustrated by path a.
Mech a n ism . Two primary mechanisms may describe
the reactions between “active” methylene compounds and
either metal-free or metallo 2-nitro-5,10,15,20-tetra-
phenylporphyrins to produce the observed dihydropor-
phyrins. After initial Michael addition of a carbanion at
the â-pyrrolic position adjacent to the carbon bearing the
nitro group, the resulting nitronate 33 undergoes a
protonation step via either path a or path b (Scheme 5),
or perhaps a combination of these two pathways. In path
a, protonation of nitronate 33 from the less crowded face
would lead to the unlikely formation of the crowded
stereoisomer, cis-nitrochlorin 38. The nitro group, being
then pseudobenzylic, could function as an electrophile to
yield, via an intermolecular displacement of the nitro
group by a second equivalent of carbanion, trans-chlorin
37 (as a racemic mixture). However, such intermolecular
nucleophilic substitution of a nitro group is extremely
rare. Indeed, reactions of primary and secondary nitro-
It can thus be seen that Michael addition of a carban-
ion at the â-pyrrolic position adjacent to the carbon
bearing the nitro group followed by intramolecular proton
exchange, intramolecular nitro group displacement, and
ring opening of the cyclopropyl intermediate can account
for formation of all three chlorin products: nitrochlorins,
cyclopropylchlorins, and disubstituted trans-chlorins.
(18) Ono, N. In Nitro Compounds: Recent Advances in Synthesis
and Chemistry; Feuer, H., Nielsen, A. T., Eds.; VCH Publishers: New
York, 1990; Chapter 1.
(17) Shea, K. M.; J aquinod, L.; Khoury, R. G.; Smith, K. M.Chem.
Commun. 1998, 759.
(19) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423.

7018 J . Org. Chem., Vol. 63, No. 20, 1998
Shea et al.
Na2SO4, filtered, and evaporated to dryness. The crude chlorin
was purified by chromatography on a short silica gel column
eluted with dichloromethane/cyclohexane (2:1), and the red
band was collected. Recrystallization from dichloromethane/
n-hexane afforded the title product in 71% yield (161 mg), mp
>300 °C; λmax (CH2Cl2) 408 nm (ꢀ 227 000), 516 (29 000), 544
(30 000), 590 (22 000), 642 (40 000); δ (CDCl3) -1.82 (br s, 2
H), 4.35 (d J 3.9 Hz, 2 H), 5.38 (d J 3.9 Hz, 2 H), 7.8 (m, 12
H), 8.04 (m, 8 H), 8.31 (d J 4.8 Hz, 2 H), 8.52 (s, 2 H), 8.71 (d
J 4.8 Hz, 2 H); MS (LSIMS) m/z 744.3 (M+). Anal. Calcd for
Con clu sion s
New methodology based on the conjugate addition of
carbon-centered nucleophiles with nitroalkenes as a new
route to the selective preparation of a variety of 5,10,15,20-
tetraaryldihydroporphyrin compounds is reported. Prod-
uct distribution can be controlled by altering the size of
the carbanion substituents or varying reaction time and/
or temperature, as well as the absence or presence of a
chelated metal in the starting material. Increased tem-
peratures, combined with smaller carbanion substituents,
favor the formation of the disubstituted trans-chlorins,
whereas ambient temperatures or bulky carbanion sub-
stituents afford trans-nitrochlorins and cyclopropylchlo-
rins. Furthermore, it is shown that this methodology can
be adapted to nitrotetraphenylporphyrins with other
meso-phenyl substituents, thereby providing a general
method for the preparation of new sensitizers for PDT
of tumors.
C
50H32N8: C, 80.63; H, 4.33; N, 15.04. Found: C, 80.49; H,
4.50; N, 14.91.
Cop p er (II) tr a n s-2,3-Dih yd r o-2,3-bis(d icya n om eth yl)-
5,10,15,20-tetr a p h en ylp or p h yr in 6. Sodium hydride (80%
dispersion in mineral oil, 26 mg, 1.12 mmol) was placed in a
two-neck flask equipped with a rubber septum and condenser.
Sodium hydride was washed (3 ×) with pentane and removed
through the septum with a syringe. DMF (2 mL) was added,
followed by malononitrile (88 µL, 1.39 mmol), and the mixture
was allowed to stir for 1 h at 60 °C. The mixture was cooled
to room temperature, and compound 2 (100 mg, 0.139 mmol)
was added; the mixture was then stirred for 6 h. The reaction
mixture was diluted with dichloromethane, washed with H2O
(6 ×), filtered, and evaporated to dryness. The crude copper
chlorin was purified by chromatography on a short silica gel
column eluted with dichloromethane, and the blue band was
collected. Recrystallization from dichloromethane/n-hexane
afforded the title product in 68% yield (76 mg), mp 298-300
°C; λmax (CH2Cl2) 412 nm (ꢀ 300 000), 514 (27 000), 606 (56
Exp er im en ta l Section
General experimental conditions were as described previ-
ously.20 Mass spectra were obtained at the University of
California, San Francisco, Mass Spectrometry Resource.
Tetraarylporphyrins were prepared via condensation of an
aldehyde (benzaldehyde, 3,5-di-tert-butylbenzaldehyde,21 or
3-methoxybenzaldehyde) with pyrrole in refluxing propionic
acid according to Adler and Longo.22
000); MS (LSIMS) m/z 806.2 (M+). Anal. Calcd for C50H30
-
CuN8‚0.5H2O: C, 73.69; H, 3.84; N, 13.76. Found: C, 73.87;
H, 4.01; N, 13.54.
Nitr a tion of Cu (II) Tetr a a r ylp or p h yr in s. P r ep a r a tion
of N2O4. N2O4 gas was prepared by dropwise addition of
concentrated HNO3 (150 mL) from a dropping funnel into a
500 mL three-neck flask (with an argon inlet) containing zinc
metal (50 g). The gas was pushed by a slow stream of argon
toward a trap containing P2O5 to remove any water or HNO3.
The P2O5 trap was connected to a hose leading to a container
of petroleum ether (∼150 mL, cooled by liquid N2), and N2O4
was bubbled through the cold ether. The petroleum ether
dissolved N2O4 quickly, producing a blue-colored solution at
low temperatures and a dark orange color at room tempera-
ture.
P r ep a r a tion of 2-Nitr otetr a a r ylp or p h yr in s. A suspen-
sion of Cu(II) tetraarylporphyrin (e.g., CuTPP, 25.0 g) in
dichloromethane (2.0 L) was stirred vigorously. The N2O4
solution was added dropwise over 2-3 h. The addition was
performed rapidly at the beginning, but was slowed near
completion of the reaction to avoid over-nitration. Close
reaction monitoring by TLC (Al2O3, CHCl3/cyclohexane 1:2)
was crucial. If done properly, all Cu(II) tetraarylporphyrin
was converted into the mononitro product with minimal dinitro
product formation. The reaction mixture was filtered to
remove any unreacted CuTPP. The mixture was then evapo-
rated to 100 mL, and the product (2-NO2CuTPP,23 22.0 g, 88%)
was precipitated by addition of methanol.
tr a n s-2,3-Dih yd r o-2,3-b is(d icya n om et h yl)-5,10,15,20-
tetr a p h en ylp or p h yr in 5. A mixture of K2CO3 (336 mg, 2.43
mmol) and malononitrile (200 µL, 3.03 mmol) in dry THF (5
mL) was stirred for 1 h at reflux under argon. The reaction
mixture was cooled to room temperature, and 2-NO2TPP 1 (200
mg, 0.303 mmol) was added to the mixture. The temperature
was slowly increased to 65 °C and the mixture was allowed to
stir for 6 h until all starting material and intermediate
cyclopropylchlorin had disappeared (monitored by TLC). The
reaction mixture was cooled, diluted with dichloromethane
(200 mL), washed with H2O (3 ×), dried over anhydrous
Nick el(II) tr a n s-2,3-Dih yd r o-2,3-b is(d icya n om et h yl)-
5,10,15,20-tetr a p h en ylp or p h yr in 7. A solution of K2CO3
(155 mg, 1.12 mmol) and malononitrile (88 µL, 1.40 mmol) in
dry THF (5 mL) was stirred under argon for 1 h at reflux. The
reaction mixture was cooled to room temperature, and com-
pound 3 (100 mg, 0.140 mmol) was added; the mixture was
then stirred for 6 h. The mixture was diluted with dichloro-
methane, washed with H2O (3 ×), filtered, and evaporated to
dryness. The crude nickel chlorin was purified by chroma-
tography on a short silica gel column eluted with dichloro-
methane, and the blue band was collected. Recrystallization
from dichloromethane/n-hexane afforded the nickel chlorin in
70% yield (79 mg), mp 245-248 °C; λmax (CH2Cl2) 414 nm (ꢀ
181 000), 504 (22 000), 604 (45 000); δ (CDCl3) 3.88 (d J 4.5
Hz, 2 H), 5.03 (d J 4.5 Hz, 2 H), 7.15 (d J 7.8 Hz, 2 H), 7.63
(m, 10 H), 7.83 (m, 8 H), 8.2 (s, 2 H), 8.35 (d J 4.8 Hz, 2 H),
8.40 (d J 4.8 Hz, 2 H); MS (LSIMS) m/z 801.6 (M+). Anal.
Calcd for C50H30N8Ni.0.5H2O: C, 74.15; H, 3.86; N, 13.84.
Found: C, 73.99; H, 3.75; N, 13.63.
Zin c(II)
tr a n s-2,3-Dih yd r o-2,3-bis(d icya n om eth yl)-
5,10,15,20-tetr a p h en ylp or p h yr in 8. Sodium hydride (31.8
mg, 1.106 mmol) was prepared as described above. DMSO (2
mL) and malononitrile (87.6 µL, 1.38 mmol) were added, and
the mixture was allowed to stir for 1 h at 60 °C. Compound 4
(100 mg, 0.138 mmol) was added, and stirring was continued
for an additional 24 h at 80 °C. The mixture was cooled,
diluted with dichloromethane (100 mL), washed with H2O (3
×), dried over anhydrous Na2SO4, filtered, and evaporated to
dryness. The crude zinc chlorin was purified by chromatog-
raphy on a short silica gel column eluted with dichloro-
methane. Recrystallization of the green band from dichloro-
methane/n-hexane afforded the title chlorin product in 63%
yield (70 mg), mp >300 °C; λmax (CH2Cl2) 414 nm (ꢀ 245 000),
514 (9000), 582 (15 000) 608 (44 000); δ (CDCl3) 4.38 (d J 3.9
Hz, 2 H), 5.27 (d J 3.9 Hz, 2 H), 7.72-8.15 (m, 20 H), 8.23 (d
J 4.8 Hz, 2 H), 8.45 (s, 2 H), 8.58 (d J 4.8 Hz, 2 H); MS (LSIMS)
m/z 809 (M+). Anal. Calcd for C50H30N8Zn: C, 74.31; H, 3.74;
N, 13.86. Found: C, 73.95; H, 3.93; N, 13.49.
(20) Nguyen, L. T.; Senge, M. O.; Smith, K. M. J . Org. Chem. 1996,
61, 998.
(21) Newman, M. S.; Lee, L. F. J . Org. Chem. 1972, 37, 4468.
(22) Adler, A. D.; Longo, F. R.; Finarelli, J . D.; Goldmacher, J .;
Assour, J .; Korsakoff, L. J . Org. Chem. 1967, 32, 476.
(23) Girardeau, A.; Callot, H. J .; J ordan, J .; Ezhar, I.; Gross, M. J .
Am. Chem. Soc. 1979, 101, 3857.
tr a n s-2,3-Dih yd r o-2,3-bis(cya n om eth yl)-5,10,15,20-tet-
r a p h en ylp or p h yr in 9. Sodium hydride (35.1 mg, 1.22 mmol)
was washed as described above. DMSO (5 mL) and methyl
cyanoacetate (108 µL, 1.52 mmol) was added, and the mixture
was allowed to stir for 1 h at 60 °C. Compound 1 (100 mg,

Dihydroporphyrin Synthesis: New Methodology
J . Org. Chem., Vol. 63, No. 20, 1998 7019
0.152 mmol) was added with stirring at 80 °C for 3 h. Eight
drops of H2O and NaCl (89 mg, 1.52 mmol) were added, and
the temperature was increased to 140 °C for 14 h. The mixture
was cooled, diluted with dichloromethane (200 mL), washed
with H2O (6 ×), dried over anhydrous Na2SO4, filtered, and
evaporated to dryness. The crude chlorin was purified on a
silica gel column eluted with 20% cyclohexane in dichloro-
methane. Recrystallization from dichloromethane/n-hexane
afforded the title product in 75% yield (79 mg), mp >300 °C;
λmax (CH2Cl2) 410 nm (ꢀ 168 000), 516 (13 800), 544 (13 400),
592 (6700), 644 (26 000); δ (CDCl3) -1.81 (br s, 2 H), 2.54 (dd
J 17.1 Hz, J 8.1 Hz, 2 H), 2.81 (dd J 17.1 Hz, J 4.2 Hz, 2 H),
4.98 (dd J 8.1 Hz, J 4.2 Hz, 2 H), 7.61-8.23 (m, 22 H), 8.51 (s,
2 H), 8.67 (d J 4.8 Hz, 2 H). Anal. Calcd for C48H34N6: C,
82.96, H, 4.94 N, 12.10. Found: C, 83.11; H, 4.82; N, 11.97.
5,10,15,20-Tetr a p h en yl-[2:3]-d icya n om eth a n op or p h y-
r in 14. A solution of K2CO3 (3.34 g, 24.2 mmol) and malono-
nitrile (1.9 mL, 30.3 mmol) in dry THF (100 mL) was stirred
for 1 h at reflux under argon. The mixture was cooled to -20
°C, followed by addition of compound 1 (2.0 g, 3.03 mmol), and
the mixture was stirred for 1 h. The reaction mixture was
allowed to slowly warm to room temperature and stirred for
an additional 12 h. Close monitoring by TLC was necessary
to isolate the cyclopropyl product before the reaction proceeded
to give the disubstituted trans-chlorin 5. The mixture was
diluted with dichloromethane (400 mL), washed with H2O (3
×), dried over anhydrous Na2SO4, filtered, and evaporated to
dryness. The crude chlorin was purified on a silica gel column
eluted with dichloromethane/cyclohexane (2:1). The first red
band was collected, and the residue after evaporation was
recrystallized from dichloromethane/n-hexane, affording the
title product in 68% yield (1.40 g), mp >300 °C; λmax (CH2Cl2)
414 nm (ꢀ 251 000), 522 (15 300), 592 (7000), 646 (16 000); δ
(CDCl3) -2.11 (br s, 2 H), 5.15 (s, 2 H), 7.74-8.17 (m, 20 H),
8.54 (s, 2 H), 8.55 (d J 5.1 Hz, 2 H), 8.75 (d J 5.1 Hz, 2 H); MS
(LSIMS) m/z 679.3 (MH+). Anal. Calcd for C47H30N6: C, 83.15;
H, 4.46; N, 12.39. Found: C, 83.30; H, 4.61; N, 12.23. A more
polar red band was isolated and identified as 5 (in 9% yield).
5,10,15,20-Tetr a p h en yl-[2:3]-[(cya n o)(m eth oxyca r bon -
yl)m eth a n o]p or p h yr in 15. A solution of K2CO3 (155 mg,
1.12 mmol) and methyl cyanoacetate (152 µL, 1.70 mmol) in
dry THF (5 mL) was stirred for 1 h at reflux under argon. The
mixture was cooled to room temperature, followed by addition
of compound 1 (100 mg, 0.152 mmol), and the solution was
allowed to stir for 14 h. Close monitoring by TLC was
necessary to isolate the cyclopropyl product before it proceeded
to the disubstituted trans-chlorin 10. The mixture was diluted
with dichloromethane, washed with H2O (3 ×), filtered, and
evaporated to dryness. The crude chlorin was purified on a
silica gel column eluted with dichloromethane/cyclohexane (2:
1). Recrystallization of the material from the major band using
dichloromethane/n-hexane afforded the title compound in 63%
yield (68 mg), mp >300 °C; λmax (CH2Cl2) 416 nm (ꢀ 249 000),
518 (16 000), 548 (11 200), 592 (7000), 646 (15 700); δ (CDCl3)
-2.03 (br s, 2 H), 3.93 (s, 3 H), 4.98 (s, 2 H), 7.73 (m, 12 H),
7.97 (m, 2 H), 8.13 (m, 6 H), 8.51 (d J 4.8 Hz, 2 H), 8.52 (s, 2
H), 8.72 (d J 4.8 Hz, 2 H); MS (LSIMS) m/z 712.3 (MH+). Anal.
8.36 (d J 4.8 Hz, 1 H) 8.52 (m, 2 H), 8.69 (m, 2 H); MS (LSIMS)
m/z 792.3 (MH+, 40), 745.3 (-HNO2, 100). Anal. Calcd for
C49H37N5O6‚H2O: C, 72.66; H, 4.86; N, 8.65. Found: C, 72.71;
H, 4.72; N, 8.77.
Nick el(II) tr a n s-2,3-Dih yd r o-2-[bis(m eth oxyca r bon yl)-
m et h yl]-3-n it r o-5,10,15,20-t et r a p h en ylp or p h yr in 17.
A
solution of K2CO3 (310 mg, 2.25 mmol) and dimethyl malonate
(320 µL, 2.79 mmol) in dry THF (10 mL) was stirred for 1 h at
reflux under argon. The mixture was cooled to room temper-
ature, followed by addition of Ni(II) 2-NO2TPP 3 (200 mg, 0.279
mmol), and the solution was allowed to stir for 12 h. The
mixture was diluted with dichloromethane (200 mL), washed
with H2O (3 ×), filtered, and evaporated to dryness. The crude
chlorin was purified on
a silica gel column eluted with
dichloromethane. Recrystallization from dichloromethane/n-
hexane afforded the title compound in 61% yield (144 mg), mp
194-197 °C; λmax (CH2Cl2) 416 nm (ꢀ 156 000), 532 (5600), 608
(19 200); δ (CDCl3) 2.14 (s, 3 H), 3.51 (d J 4.5 Hz, 1 H), 3.68
(s, 3 H), 5.40 (d J 4.5 Hz, 1 H), 7.02 (s, 1 H), 7.63-7.85 (m, 20
H), 7.98 (d J 4.8 Hz, 2 H), 8.21 (s, 2 H), 8.34 (d J 4.8 Hz, 2 H);
MS (LSIMS) m/z 848.3 (M+, 30), 801.1 (-HNO2, 100). Anal.
Calcd for C49H35N5NiO6‚0.5 H2O: C, 68.68; H, 4.24; N, 8.18.
Found: C, 68.68; H, 4.11 N, 8.05.
tr a n s-2,3-Dih yd r o-2-[(cya n o)(p h en yl)m eth yl]-3-n itr o-
5,10,15,20-tetr a p h en ylp or p h yr in 18. A solution of K2CO3
(168 mg, 1.22 mmol) and benzylcyanide (175 µL, 1.52 mmol)
in dry THF (5 mL) was stirred for 1 h at reflux under argon.
The mixture was cooled to room temperature, followed by
addition of compound 1 (100 mg, 0.152 mmol), and the solution
was allowed to stir for 48 h. The reaction mixture was diluted
with dichloromethane (100 mL), washed with H2O (3 ×),
filtered, and evaporated to dryness. The crude chlorin was
purified on a silica gel column eluted with dichloromethane/
cyclohexane (2:1). Recrystallization from dichloromethane/n-
hexane afforded the title product in 61% yield (72 mg), mp
187-189 °C; λmax (CH2Cl2) 410 nm (ꢀ 174 000), 571 (13 200),
546 (15 300), 592 (7800), 642 (22 900); δ (CDCl3) -1.75 (br s,
2 H), 4.58 (d J 3.6 Hz, 1 H), 5.45 (dd J ) 3.6, 0.6 Hz, 1 H),
6.95 (d J 7.8 Hz, 2 H), 7.03 (s, 1 H), 7.40 (m, 3 H), 7.75 (m, 12
H), 8.04 (m, 4 H), 8.27 (m, 4 H), 8.36 (d J 4.8 Hz, 1 H), 8.44 (d
J 4.8 Hz, 1 H), 8.52 (m, 2H), 8.69 (d J 4.8 Hz, 1 H), 8.75 (d J
4.8 Hz, 1 H); MS (LSIMS) m/z 777.2 (MH+, 45), 730.2 (-HNO2,
25). Anal. Calcd for C52H36N6O2‚H2O: C, 78.56; H, 4.82; N,
10.58. Found: C, 78.61; H, 4.89 N, 10.61.
tr a n s-2,3-Dih yd r o-2-[bis(n -bu tyla m in oca r bon yl)m eth -
yl]-3-n itr o-5,10,15,20-tetr a p h en ylp or p h yr in 19. A solution
of K2CO3 (168 mg, 1.22 mmol) and di(n-butyl)malonamide (326
mg, 1.52 mmol) in DMSO (5 mL) was stirred for 1 h at 60 °C
under argon. 2-NO2TPP 1 (100 mg, 0.152 mmol) was added,
the temperature was raised to 100 °C, and the solution was
stirred for 36 h. The reaction mixture was diluted with
dichloromethane, washed with H2O (3 ×), filtered, and evapo-
rated to dryness. The crude chlorin was purified on a silica
gel column eluted with 2% methanol in dichloromethane.
Recrystallization from dichloromethane/n-hexane afforded the
title chlorin in 19% yield (25 mg), mp 221-224 °C; λmax
(CH2Cl2) 412 nm (ꢀ 180 000), 516 (8000), 546 (10 000), 594
(7000); δ (CDCl3) -1.91 (br s, 2 H), -1.51 (m, 1 H), -1.32 (m,
2 H), -1.13 (t J 7.2 Hz, 3 H), -0.93 (m, 1 H), -0.78 (m, 1 H),
0.88 (t J 7.2 Hz, 3 H), 1.2-1.6 (m, 4 H), 2.99 (m, 2 H), 3.38 (m,
2 H), 4.52 (m, 1 H,), 5.72 (d J 3.6 Hz, 1 H), 7.41-8.23 (m, 22
H), 8.38 (m, 3 H), 8.56 (d J 4.8 Hz, 1 H), 8.63 (d J 4.8 Hz, 1
H); MS (LSIMS) m/z 874.3 (M+). Anal. Calcd for C55H51N7O4‚
2H2O: C, 72.59; H, 6.09; N, 10.21. Found: C, 72.42; H, 6.03
N, 10.21.
5,10,15,20-Tet r a p h en yl-[2:3]-[b is(m et h oxyca r b on yl)-
m eth a n o]p or p h yr in 20. A solution of K2CO3 (310 mg, 2.25
mmol) and dimethyl malonate (320 µL, 3.40 mmol) in DMSO
(10 mL) was stirred for 1 h at 60 °C under argon. 2-NO2TPP
1 (200 mg, 0.303 mmol) was added, and the solution was
stirred for 3 h at 100 °C. The mixture was cooled, diluted with
dichloromethane (200 mL), washed with H2O (6 ×), dried over
anhydrous Na2SO4, filtered, and evaporated to dryness. The
crude chlorin was purified on a silica gel column eluted with
dichloromethane; the first red band was collected and evapo-
Calcd for
Found: C, 78.98; H, 4.84; N, 9.60.
C48H33N5O2‚H2O: C, 79.17; H, 4.71; N, 9.52.
tr a n s-2,3-Dih yd r o-2-[bis(m eth oxyca r bon yl)m eth yl]-3-
n itr o-5,10,15,20-tetr a p h en ylp or p h yr in 16. A solution of
K2CO3 (169 mg, 1.22 mmol) and dimethyl malonate (143 µL,
1.52 mmol) in dry THF (5 mL) was stirred for 1 h at reflux
under argon. The mixture was cooled to room temperature,
followed by addition of compound 1 (100 mg, 0.152), and then
stirred for 12 h. The mixture was diluted with dichloro-
methane (100 mL), washed with H2O (3 ×), filtered, and
evaporated to dryness. The crude chlorin was purified on a
silica gel column eluted with dichloromethane/cyclohexane (2:
1). Recrystallization from dichloromethane/n-hexane afforded
the title product in 66% yield (79 mg), mp 209-211 °C; λmax
(CH2Cl2) 410 nm (ꢀ 182 000), 516 (16 300), 544 (17 500), 592
(9400), 642 (24 400); δ (CDCl3) -192 (s, 1 H), -186 (d, 1 H),
2.40 (s, 3 H), 3.79 (s, 3 H), 4.05 (d J 4.2 Hz, 1 H), 5.76 (d J 4.2
Hz, 1 H), 7.71 (m, 13 H), 8.20 (m, 8 H), 8.32 (d J 4.8 Hz, 1 H),

7020 J . Org. Chem., Vol. 63, No. 20, 1998
Shea et al.
rated to dryness. Recrystallization from dichloromethane/n-
hexane afforded the title product in 77% yield (174 mg), mp
271-273 °C; λmax (CH2Cl2) 416 nm (ꢀ 266 000), 518 (15 800)
548 (12 900), 592 (6000), 644 (18 000); δ (CDCl3) -2.02 (br s,
2 H), 2.45 (s, 3 H), 3.80 (s, 3 H), 4.75 (s, 2 H), 7.70 (m, 12 H),
8.13 (m, 8 H), 8.53 (s, 2 H), 8.62 (d J 4.8 Hz, 2 H), 8.71 (d J
4.8 Hz, 2 H); MS (LSIMS) m/z 744.3 (M+). Anal. Calcd for
(s, 1 H), -1.80 (s, 1 H), 0.778 (t J 7.2 Hz, 3 H), 1.2 (m, 2 H),
2.15 (m, 1 H), 2.47 (m, 1 H), 4.14 (d J 3.9 Hz, 1 H), 5.36 (d J
3.9 Hz, 1 H), 5.67 (s, 1 H), 7.65-8.30 (m, 20 H), 8.34 (d J 4.8
Hz, 2 H), 8.50 (m, 2 H), 8.66 (d J 4.8 Hz, 2 H); MS (LSIMS)
m/z 756.0 (MH+). Anal. Calcd for C50H38N6S: C, 79.55; H,
5.07; N, 11.13. Found: C, 79.25; H, 5.10; N, 10.90.
Cop p er (II) 5,10,15,20-Tetr a [3,5-d i(ter t-bu tyl)p h en yl]-
2-n itr op or p h yr in 26. The nitration of copper(II) 5,10,15,20-
tetra[3,5-di(tert-butyl)phenyl]porphyrin (3.0 g) in 150 mL of
CH2Cl2 was performed as described above. Recrystallization
of the nitrated porphyrin in CH2Cl2/MeOH produced the title
compound in 89% yield (2.70 g), mp >300 °C; λmax (CH2Cl2)
426 nm (ꢀ 247 000), 548 (28 000), 590 (23 000); MS (LSIMS)
m/z 1169.5 (M+). Anal. Calcd for C76H91CuN5O2: C, 78.01;
H, 7.84; N, 5.98. Found: C, 77.70; H, 7.76; N, 5.94.
Cop p er (II) 5,10,15,20-Tetr a k is(m -m eth oxyp h en yl)-2-
n itr op or p h yr in 27. Nitration of copper(II) 5,10,15,20-tet-
rakis(m-methoxyphenyl)nitroporphyrin (5.0 g) in CH2Cl2 (500
mL) was performed as described above. Recrystallization of
the nitrated porphyrin in CH2Cl2/MeOH produced the title
compound in 88% yield (4.7 g), mp 197-200 °C; λmax (CH2Cl2)
424 nm (ꢀ 175 000), 548 (12 000), 590 (8000); MS (LSIMS) m/z
841.1 (M+). Anal. Calcd for C48H35CuN5O6: C, 68.52; H, 4.19;
N, 8.32. Found: C, 68.55; H, 4.27; N, 8.46.
5,10,15,20-Tetr akis[3,5-di(ter t-bu tyl)ph en yl]-2-n itr opor -
p h yr in 28. Demetalation of 26 (2.65 g) in 100 mL of
concentrated H2SO4 and recrystallization of the nitrated
porphyrin from CH2Cl2/MeOH gave the title compound in 85%
yield (2.15 g), mp >300 °C; λmax (CH2Cl2) 430 nm (ꢀ 185 000),
528 (19 000), 562 (9000), 604 (7000), 664 (13 000); δ (CDCl3)
-2.57(br s, 2 H), 1.51 (s, 72 H), 7.80 (m, 4 H), 8.06 (m, 8 H),
8.78 (m, 2 H), 8.95 (m, 2 H), 9.06 (s, 1 H), 9.08 (m, 2 H); MS
(LSIMS) m/z 1108.6 (M+). Anal. Calcd for C71H93N5O2: C,
82.34; H, 8.46; N, 6.32. Found: C, 82.24; H, 8.45; N, 6.41.
5,10,15,20-Tetr a k is(m -m eth oxyp h en yl)-2-n itr op or p h y-
r in 29. Demetalation of 27 (2.0 g) in TFA/H2SO4 (4:1) and
recrystallization from CH2Cl2/MeOH produced the title com-
pound in 76% yield (1.4 g), mp 290-293 °C; λmax (CH2Cl2) 430
nm (ꢀ 144 000), 526 (14 000), 602 (6000), 662 (7000); δ (CDCl3)
-2.60 (br s, 2 H), 4.00 (s, 12 H), 7.34-7.84 (m, 16 H), 8.75-
9.01 (m, 7 H); MS (LSIMS) m/z 779.3 (M+). Anal. Calcd for
C
49H36N4O4: C, 79.00; H, 4.87; N, 7.53. Found: C, 78.72; H,
5.12; N, 7.23.
Nick el(II) 5,10,15,20-Tetr a p h en yl-[2:3]-[bis(m eth oxy-
ca r bon yl)m eth a n o]p or p h yr in 21. A solution of K2CO3 (155
mg, 1.38 mmol) and dimethyl malonate (160 µL, 1.40 mmol)
in DMSO was stirred for 1 h at 60 °C under argon. Compound
3 (155 mg, 0.138 mmol) was added, and the solution was
stirred for 2 h at 100 °C. The mixture was cooled, diluted with
dichloromethane (100 mL), washed with H2O (6 ×), dried over
anhydrous Na2SO4, filtered, and evaporated to dryness. The
crude chlorin was purified on a silica gel column eluted with
dichloromethane. Recrystallization from dichloromethane/n-
hexane afforded the desired product in 76% yield (85 mg), mp
237-240 °C; λmax (CH2Cl2) 416 nm (ꢀ 195 000), 526 (7400), 568
(7400), 602 (24 000);); δ (CDCl3) 2.36 (s, 3 H), 3.84 (s, 3 H),
4.71 (s, 2 H), 7.61 (m, 12 H), 7.87 (m, 8 H), 8.17 (d J 4.8 Hz,
2 H), 8.29 (s, 2 H), 8.41 (d J 4.8 Hz, 2 H); MS (LSIMS) m/z
800.2 (M+). Anal. Calcd for C49H34N4NiO4: C, 73.43; H, 4.39;
N, 6.99. Found: C, 73.36; H, 4.39; N, 7.11.
5,10,15,20-Tetr a p h en yl-[2:3]-[(cya n o)(p h en yl)m eth a n o]-
p or p h yr in 22. A solution of K2CO3 (168 mg, 1.22 mmol) and
benzylcyanide (175 µL, 1.52 mmol) in DMSO was stirred for 1
h at 60 °C under argon. 2-NO2TPP 1 (155 mg, 0.138 mmol)
was added, and the solution was stirred for 12 h at 100 °C.
The mixture was cooled, diluted with dichloromethane (100
mg), washed with H2O (6 ×), filtered, and evaporated to
dryness. The crude chlorin was purified on a silica gel column
eluted with ethyl acetate/cyclohexane (1:3). Recrystallization
from dichloromethane/n-hexane afforded the desired product
in 58% yield (58 mg), mp >300 °C; λmax (CH2Cl2) 420 nm (ꢀ
218 000), 520 (15 000), 548 (10 000), 596 (6000), 650 (20 000);
δ (CDCl3) -1.81 (br s, 2 H), 4.67 (s, 2 H), 7.37 (m, 5 H), 7.72
(m, 12 H), 8.16 (m, 8 H), 8.45 (d J 4.8 Hz, 2 H), 8.51 (s, 2 H),
8.71 (d J 4.8 Hz, 2 H); MS (LSIMS) m/z 730.3 (M+). Anal.
Calcd for
Found: C, 84.43; H, 4.96; N, 9.36.
C
52H35N5‚0.5H2O: C, 84.53; H, 4.91; N, 9.48.
C48H37N5O6: C, 73.93; H, 4.78; N, 8.98. Found: C, 73.74; H,
4.91; N, 7.82.
5,10,15,20-Tetr a p h en yl-[2:3]-[bis(a m in oca r bon yl)m eth -
a n o]p or p h yr in 23. A solution of K2CO3 (168 mg, 1.22 mmol)
and malonamide (155 mg, 1.52 mmol) in DMSO (5 mL) was
stirred for 1 h at 60 °C under argon. 2-NO2TPP 1 (100 mg,
0.152 mmol) was added, and the solution was stirred for 50 h
at 100 °C. The mixture was cooled, diluted with dichloro-
methane (100 mL), washed with H2O (6 ×), dried over
anhydrous Na2SO4, and evaporated to dryness. The crude
chlorin was purified on a silica gel column, eluted with 3%
methanol in dichloromethane, to yield the title product in 25%
yield (31 mg), mp >300 °C; λmax (CH2Cl2) 418 nm (ꢀ 165 000),
520 (13 000), 548 (11 000), 594 (7000), 650 (16 000); δ (CDCl3)
-1.95 (br s, 2 H), 4.02 (br s, 1 H), 4.33 (br s, 1 H), 4.96 (s, 2
H), 5.49 (br s, 1 H), 7.59-8.21 (m, 21 H), 8.42 (d J 4.8 Hz, 2
H), 8.51 (s, 2 H), 8.72 (d J 4.8 Hz, 2 H); MS (LSIMS) m/z 715.2
(M+).
tr a n s-2,3-Dih yd r o-2-(d icya n om eth yl)-3-(S-th iop r op yl)-
5,10,15,20-tetr a p h en ylp or p h yr in 25. Sodium hydride (3.5
mg, 0.110 mmol) was treated as described above. THF (5 mL)
was added, followed by addition of propane-1-thiol (13.3 µL,
0.147 mmol), and the mixture was stirred for 1 h at 60 °C.
The mixture was then transferred to a dropping funnel and
added dropwise to a stirring solution of compound 13 (50 mg,
0.0736 mmol) in THF at 0 °C under argon. The mixture was
allowed to stir for 12 h and was then diluted with dichloro-
methane (50 mL), washed with H2O (3 ×), dried over anhy-
drous Na2SO4, and evaporated to dryness. The crude chlorin
was purified on a silica gel column eluted with 25% ethyl
acetate in cyclohexane. Recrystallization from dichloromethane/
n-hexane afforded the title compound in 78% yield (43 mg),
mp 196-198 °C; λmax (CH2Cl2) 412 nm (ꢀ 188 000), 518 (13
000), 546 (13 000), 594 (6000), 646 (23 000); δ (CDCl3) -1.69
tr a n s-2,3-Dih yd r o-2,3-b is(d icya n om et h yl)-5,10,15,20-
tetr a k is[3,5-d i(ter t-bu tyl)p h en yl]p or p h yr in 30. Sodium
hydride (52 mg, 1.81 mmol) was prepared as described above;
THF (10 mL) and malononitrile (143 µL, 2.26 mmol) were
added, and the mixture was stirred for 1 h at 60 °C.
Compound 28 (250 mg, 0.226 mmol) was added, and the
mixture was stirred for an additional 5 h at 60 °C. The
mixture was cooled, diluted with dichloromethane (200 mL),
washed with H2O (3 ×), filtered, and evaporated to dryness.
The crude chlorin was purified on a silica gel column eluted
with dichloromethane/cyclohexane (2:3). Recrystallization
from dichloromethane/methanol afforded the title product in
78% yield (140 mg), mp >300 °C; λmax (CH2Cl2) 412 nm (ꢀ 204
000), 518 (12 000), 550 (17 000) 592 (9000), 642 (22 000); δ
(CDCl3) -1.79 (br s, 2 H), 1.7 (s, 72 H), 4.30 (d J 3.9 Hz, 2 H),
5.31 (d J 3.9 Hz, 2 H), 7.84 (m, 12 H), 8.14 (m, 8 H), 8.43 (d J
5.1 Hz, 2 H), 8.59 (s, 2 H), 8.75 (d J 5.1 Hz, 2 H); MS (LSIMS)
m/z 1193.8 (M+). Anal. Calcd for C82H96N8‚H2O: C, 81.53;
H, 8.01; N, 9.33. Found: C, 81.28; H, 8.15; N, 9.25.
tr a n s-2,3-Dih yd r o-2,3-b is(d icya n om et h yl)-5,10,15,20-
tetr a k is(m -m eth oxyp h en yl)p or p h yr in 31. A solution of
K2CO3 (425 mg, 3.08 mmol) and malononitrile (244 µL, 3.85
mmol) in dry THF (15 mL) was stirred under argon for 1 h at
reflux. Compound 29 (300 mg, 0.385 mmol) was added, and
the solution was allowed to stir for an additional 10 h. The
mixture was cooled, diluted with dichloromethane, washed
with H2O (3 ×), dried over anhydrous Na2SO4, filtered, and
evaporated to dryness. The crude chlorin was chromato-
graphed on a short silica gel column eluted with dichloro-
methane. Recrystallization from dichloromethane/n-hexane
afforded the title product in 56% yield (187 mg), mp 205-208
°C; λmax (CH2Cl2) 410 nm (ꢀ 165 000), 514 (15 000), 544 (14

Dihydroporphyrin Synthesis: New Methodology
J . Org. Chem., Vol. 63, No. 20, 1998 7021
000), 590 (9000), 642 (24 000); δ (CDCl3) -1.92 (br s, 2 H),
3.52 (s, 3 H), 3.94 (s, 3 H), 4.02 (s, 6 H), 4.47 (d J 3.9 Hz, 1 H),
4.53 (d J 3.9 Hz, 1 H), 5.46 (d J 3.9 Hz, 1 H), 5.48 (d J 3.9 Hz,
1 H), 7.30-7.95 (m, 16 H), 8.40 (d J 4.8 Hz, 2 H), 8.57 (s, 2 H),
8.78 (d J 4.8 Hz, 2 H); MS (LSIMS) m/z 865.3 (M+). Anal.
Calcd for C54H40N8O4: C, 74.99; H, 4.66; N, 12.95. Found: C,
74.86; H, 4.61; N, 12.85.
23117) and the National Institutes of Health (HL-
22252). Mass spectrometric analyses were performed by
the UCSF Mass Spectrometry Facility (A. L. Burlin-
game, Director) supported by the Biomedical Research
Technology Program of the National Center for Re-
search Resources, NIH NCRR BRTP 01614.
Ack n ow led gm en t. This work was supported by
grants from the National Science Foundation (CHE-96-
J O980965P