A facile and regioselective synthesis of trans-heterofunctionalized porphyrazine derivatives

Article abstract of DOI:10.1021/jo971683c

New methodology was developed for the selective synthesis of regiochemically defined porphyrazines of the form M[pz(A₂;B₂)] (shown in Chart 1) where A and B represent peripheral functionalization attached to the β-positions of the pyrroles. Specifically, phthalonitriles or derivatives thereof with sterically bulky groups in positions 3 and 6, in particular 4,7- bis(isopropyloxy)-1,3-diiminoisoindoline (3) act as a 'trans director' when macrocyclized with heteroatom-appended maleonitriles under Linstead conditions, the result being preferential formation of the trans- M[pz(A₂;B₂)] pigment where A = SR, NMe₂, OR, as well as R (shown in Chart 2). Linstead crossover macrocyclization of 3 with 4, 11, 15, and 18 gave pigments 10, 14, 17, and 19, respectively. These pigments were characterized by ¹H NMR, ¹³C NMR, UV-visible spectroscopy, mass spectrometry, microanalysis, and 17 was characterized by single-crystal X-ray analysis.

Full text of DOI:10.1021/jo971683c

J . Org. Chem. 1998, 63, 331-336
331
A F a cile a n d Regioselective Syn th esis of
Tr a n s-Heter ofu n ction a lized P or p h yr a zin e Der iva tives
Timothy P. Forsyth,† D. Bradley G. Williams,‡ Antonio Garrido Montalban,‡
Charlotte L. Stern,† Anthony G. M. Barrett,*,‡ and Brian M. Hoffman*,†
Department of Chemistry, Northwestern University, Evanston, Illinois 60208 and Department of
Chemistry, Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AY,
U.K.
Received September 8, 1997
New methodology was developed for the selective synthesis of regiochemically defined porphyrazines
of the form M[pz(A2;B2)] (shown in Chart 1) where A and B represent peripheral functionalization
attached to the â-positions of the pyrroles. Specifically, phthalonitriles or derivatives thereof with
sterically bulky groups in positions 3 and 6, in particular 4,7-bis(isopropyloxy)-1,3-diiminoisoindoline
(3) act as a “trans director” when macrocyclized with heteroatom-appended maleonitriles under
Linstead conditions, the result being preferential formation of the trans-M[pz(A2;B2)] pigment where
A ) SR, NMe2, OR, as well as R (shown in Chart 2). Linstead crossover macrocyclization of 3 with
4, 11, 15, and 18 gave pigments 10, 14, 17, and 19, respectively. These pigments were characterized
1
by H NMR, 13C NMR, UV-visible spectroscopy, mass spectrometry, microanalysis, and 17 was
characterized by single-crystal X-ray analysis.
In tr od u ction
the individual components by common chromatographic
methods.12 Three general methods exist for the prepara-
tion of M[pz(A1;B3)] pigments: the polymer support
route,13-16 subphthalocyanine route,17-19 and statistical
condensation route.20,21 In contrast, fewer methods exist
for the selective preparation of trans-M[pz(A2;B2)] pig-
ments (Chart 1).22-26 We recently published a method
whereby the “cis” and “trans”27 isomers with the formula
M[pz(A2;B2)] can be separated when A and B are chosen
to have disparate polarities. In this case, the cis isomer
with polar groups on adjacent pyrrole subunits is a more
polar molecule than the trans analogue, and the two
macrocycles are separable by chromatography.
Phthalocyanines and related tetraazamacrocycles have
found wide applications in diverse areas such as biomedi-
cal agents for diagnosis and therapy,1,2 chemical sensors,3
liquid crystals,4,5 nonlinear optics,6 Langmuir-Blodgett
films,7 and ladder polymers,8 and are precursors to new
conducting materials. Recently, we reported on the
synthesis and novel physical properties of porphyrazines
(tetraazaporphyrins) with peripheral heteroatom func-
tionalization, including octathiolates,9 octa(dialkyl)-
amines,10 and octaol derivatives.11 Unsymmetrical pe-
ripheral functionalization can fine-tune the molecular
properties, such as UV-visible absorption bands, and
provide precursors to new mutimetallic arrays. However,
the statistical comacrocyclization of two maleo- and/or
phthalonitriles would produce a mixture of the six M[pz-
(An;B4-n)] from which it would be very difficult to purify
In this paper, we show that methodology to prepare
A2;B2 phthalocyanines with a trans configuration23-26
(12) Ikeda, Y.; Konami, H.; Hotano, M.; Mochizuki, K. Chem. Lett.
1992, 763-766.
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Seymour, P.; Lever, A. B. P. J . Org. Chem. 1991, 56, 82-90.
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3026.
† Northwestern University.
‡ Imperial College.
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(2) Rosenthal, I. In Phthalocyanines: Properties and Applications;
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485-507.
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Soc., Chem. Commun. 1995, 467-468.
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Am. Chem. Soc. 1982, 104, 5245-5246.
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Lo´pez, F.; Zyss, J . J . Phys. Chem. 1994, 98, 8761-8765.
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(Berlin) 1990, 74, 41-146.
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Hoffman, B. M. J . Am. Chem. Soc. 1990, 112, 7408-7410.
(10) Mani, N. S.; Beall, L. S.; Miller, T.; Anderson, O. P.; Hope, H.;
Parkin, S. R.; Williams, D. J .; Barrett, A. G. M.; Hoffman, B. M. J .
Chem. Soc., Chem. Commun. 1994, 2095-2096.
(11) Cook, A. S.; Williams, D. B. G.; White, A. J . P.; Williams, D. J .;
Lange, S. J .; Barrett, A. G. M.; Hoffman, B. M. Angew. Chem., Int.
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M.; Hoffman, B. M. J . Am. Chem. Soc. 1994, 116, 2639-2640.
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S0022-3263(97)01683-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/03/1998

332 J . Org. Chem., Vol. 63, No. 2, 1998
Forsyth et al.
Ch a r t 1. Tr a n s-F u n ction a lized P or p h yr a zin e
nitrile (18). In each case, the product, containing Mg-
[pz(An;B4-n)], was treated with trifluoroacetic acid or
acetic acid to form the free base, 2H[pz(An;B4-n)] and then
chromatographed to give the desired trans-[pz(A2;B2)]
systems. The degree to which the formation of this
compound was favored was a function of both the ratio
of the two cyclization partners and their relative reac-
tivities.
Dim eth yla m in o P or p h yr a zin e Hybr id s. Magne-
sium-templated cyclization of bis(dimethylamino)maleo-
nitrile 4 and a 3-fold excess of diiminoisoindoline 3
produced three pigments; M[pz(A1;B3)] (5), the cis-M[pz-
(A2;B2)] (6) and trans-M[pz(A2;B2)] (7) in a 2:1:5 ratio. The
metal-free pigments 5, 6, and 7 could be isolated directly,
but it was simpler to purify the nickel(II) chelates. The
1H NMR spectra of the cis- and trans-macrocycles clearly
differentiate between them; in the trans pigment 10, the
protons on the fused aryl rings appeared as a singlet,
while in the cis compound 9, the fused aryl protons gave
rise to an AB quartet.
Ch a r t 2. tr a n s-M[P z(A2;B2)] P igm en ts P r ep a r ed in
Th is Stu d y
Ben zylth io P or p h yr a zin e Hybr id s. Magnesium-
templated cyclization of 2,3-bis(benzylthio)maleonitrile
11 with 3 in a 1:1 stoichiometric ratio yielded M[pz-
(A1;B3)] (13) and trans-M[pz(A2;B2)] (14) in a 2:1 ratio
along with trace amounts of octakis(benzylthio)por-
phyrazine: none of the cis-M[pz(A2;B2)] pigment was
detected. The yield of the trans macrocycle was opti-
mized by the use of only 0.25 equiv of Mg per mole of
combined cyclization partners and by heating the reac-
tion mixture for only 6 h at 100 °C. Longer reaction times
and higher temperatures produced a complex mixture of
pigments with little or no trans-macrocycle. It is possible
that the strongly basic conditions resulted in cleavage of
the carbon-sulfur bonds via an Eschenmoser-type sulfide
contraction.31 Compound 14 provides a convenient entry
into di- and trimetallic arrays since the benzyl groups
attached to the sulfur atoms can be removed via reductive
cleavage and related tetrathiolates have been shown to
bind a variety of metals.32
P r op yl P or p h yr a zin e Hybr id s. Magnesium-tem-
plated cyclization of 15 and 3 in a 1:1 stoichiometric ratio
yielded the M[pz(A1;B3)] (16) and trans-M[pz(A2;B2)] (17)
in a 1:3 ratio. Interestingly, if between 0.25 and 0.5 equiv
of Mg per combined mole of cyclization partners were
employed, only a trace amount of porphyrazine was
obtained. However, if 1 equiv of Mg per combined mole
of cyclization partners was used, the macrocycles could
be obtained in a combined yield of 24%. If a 3:1
stoichiometric ratio of 15 to 3 was used, the ratio of
pigments 16 to 17 obtained was reversed (30% combined
yield).
can be used to preferentially prepare heteroatom-func-
tionalized trans-M[pz(A2;B2)]. We report that phthalo-
nitriles or derivatives thereof with sterically bulky groups
in positions 3 and 6, in particular 4,7-bis(isopropyloxy)-
1,3-diiminoisoindoline (3), act as a “trans director” when
macrocyclized with heteroatom-appended maleonitriles
under Linstead conditions, the result being preferential
formation of the trans-M[pz(A2;B2)] pigment where A )
SR, NMe2, OR, as well as R (shown in Chart 2). When
A ) SR, these pigments have Q-band absorbance red-
shifted beyond those given by the intrinsic trans config-
uration in addition to the red-shift caused by the presence
of alkoxy or other electron donating groups R to the point
of ring fusion in phthalocyanines,28-30 and thus have
potential biomedical applications.
Resu lts a n d Discu ssion
Syn th esis. The general synthesis we employ is shown
in Scheme 1. The synthesis of the trans-director begins
with alkylation of inexpensive, commercially available
2,3-dicyanohydroquinone (1) by 2-bromopropane. The
resulting hydroquinone diisopropyl ether (2) is unreactive
under the normal Linstead macrocyclization conditions
(a suspension of magnesium butoxide in refluxing bu-
tanol), thus necessitating its conversion to the corre-
sponding 1,3-diiminoisoindoline (3) by bubbling ammonia
through a solution of ethylene glycol at 140-150 °C
previously treated with a catalytic amount of Na for 4-5
h. Compound 3 was then macrocyclized with bis(di-
methylamino)maleonitrile (4), 2,3-bis(benzylthio)maleo-
nitrile (11), dipropylmaleonitrile (15), and dispiromaleo-
Sp ir a n e P or p h yr a zin e Hybr id s. The reaction of
dispiromaleonitrile 18 with a 5-fold excess of diimi-
noisoindoline 3 in the presence of magnesium butoxide
allowed the isolation of trans-M[pz(A2;B2)] (19) and of
M[pz(A;B3)] (20) in a 3:1 ratio (56% combined yield). The
unusually high yield in this reaction reveals an excep-
tionally good match of the reactivity and stoichiometry
between the two reagents 18 and 3. Maleonitrile 18 has
been employed in other high yielding macrocyclization
reactions.11 The trans geometry of 19 is reflected in both
(28) Cook, M. J .; Dunn, A. J .; Howe, S. D.; Thompson, A. J . J . Chem.
Soc., Perkin Trans. 1 1988, 2453-2458.
(31) Roth, M.; Dubs, P.; Eschenmoser, A. Helv. Chim. Acta 1971,
54, 710-734.
(32) Vela´zquez, C. S.; Baumann, T. F.; Olmstead, M. M.; Hope, H.;
Barrett, A. G. M.; Hoffman, B. M. J . Am. Chem. Soc. 1993, 115, 9997-
10003.
(29) Witkiewicz, Z.; Dabrowski, R.; Waclawek, W. Mater. Sci. II
1976, 1-2, 39-44.
(30) Eberhardt, W.; Hanack, M. Synthesis 1997, 95-100.

Trans-Heterofunctionalized Porphyrazine Derivatives
J . Org. Chem., Vol. 63, No. 2, 1998 333
Sch em e 1. Gen er a l Syn th esis of Tr a n s-F u n ction a lized P or p h yr a zin es
the 1H and 13C NMR spectra of this compound. Of
additional interest is that these spectra highlight the
preferential formation of the trans-M[pz(A2;B2)] isomer.
However, the steric energies of the cis- and trans-M[pz-
(A2;B2)] (A ) Pr) pigments, as calculated using the CS
Chem3D Pro program, were virtually identical (Table 1).
This implies that either a bias toward formation of the
trans isomer occurs in an intermediate or a transition
state, or instead that the trans-M[pz(A2;B2)] is preferred
because the reactivities of the two cyclization partners
1
diastereotopicity of the isopropyl groups: the H NMR
spectrum shows a doublet resonance, and the 13C NMR
spectrum reveals an independent resonance, for each
methyl group of the isopropyl moiety. A similar situation
1
was observed for the NMR spectra of 20: while the H
NMR spectrum provides some indication of the reduced
symmetry of the molecule, the 13C NMR spectrum clearly
exhibits a more complex resonance pattern.
X-r a y Cr ysta llogr a p h y. The X-ray structural analy-
sis of 17 shows it to be the trans-porphyrazine depicted
in Figure 1.33 The macrocyclic 24-atom core of 17 is
planar. There is, however, a very slight saddle distortion
(ca. 0.15 Å) involving the pyrroles fused to the aryl rings
with respect to this plane. The central cavity is sym-
metrical, with the diagonal nonbonded N‚‚‚N distances
virtually identical at 3.84(2) and 3.87(2) Å. The off-
diagonal nonbonded N‚‚‚N distances are also virtually
identical at 2.74(2) and 2.69(2) Å.
It has been shown that peripheral steric congestion
causes nonplanarity in porphyrins,34 while unsymmetri-
cal steric congestion causes elongation of the macrocyclic
core along one of its axes.35 The planar structure of 17
indicates that it does not suffer from steric congestion
at the periphery. This result would appear to support
the idea that steric congestion in the cis isomer leads to
(33) The authors have deposited atomic coordinates and a full
structure description for 17 with the Cambridge Crystallographic Data
Centre. The structure can be obtained upon request from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, U.K.
(34) Nurco, D. J .; Medforth, C. J .; Forsyth, T. P.; Olmstead, M. M.;
Smith, K. M. J . Am. Chem. Soc. 1996, 118, 10918-10919.
(35) Medforth, C. J .; Senge, M. O.; Forsyth, T. P.; Hobbs, J . D.;
Shelnutt, J . A.; Smith, K. M. Inorg. Chem. 1994, 33, 3865-3872.
F igu r e 1. ORTEP diagram of 17 showing the 50% probability
thermal ellipsoids. Hydrogen atoms have been omitted for
clarity.

334 J . Org. Chem., Vol. 63, No. 2, 1998
Forsyth et al.
Ta ble 1. Min im ized Ster ic En er gies of th e M[P z(A2;B2)]
(A ) NMe2, SBn , OR, a n d n -P r Isom er s Ca lcu la ted Usin g
th e CS Ch em 3D P r o P r ogr a m
M[pz(A2;B2)]
kcal/mol
cis-2H[pz{(NMe2)4;B2}]
trans-2H[pz{(NMe2)4;B2}]
cis-2H[pz{(OR)4;B2}]
trans-2H[pz{(OR)4;B2}]
cis-2H[pz{(SBn)4;B2}]
trans-2H[pz{(SBn)4;B2}]
cis-2H[pz{(Pr)4;B2}]
118.6
116.4
122.7
115.1
48.5
47.9
61.2
trans-2H[pz{(Pr)4;B2}]
59.8
are different. Disparate reactivities on different pyrroles
and on phthalonitriles and their derivatives has been
used successfully to prepare porphyrins36 and phthalo-
cyanines22 with D2h symmetry.
Electr on ic Absor p tion Sp ectr a . Porphyrazines, like
phthalocyanines, show an intense B (Soret) band at λ <
400 nm and a Q-band that has its principal absorption
at λ > 600 nm. The Q-band of a 4-fold symmetric
tetraazamacrocycle shows a Q-band with a single origin,
whereas compounds with reduced symmetry typically
show a split Q-band.37 Trans-porphyrazines 7 (539, 747
nm), 14 (656, 798 nm), 17 (638, 718 nm), and 19 (632,
705 nm) all have such split Q-bands (Figure 2). The
introduction of heteroatoms to the periphery of these
trans-M[pz(A2;B2)] pigments may complicate the spectra
by adding n-π* transitions which either broaden the
Q-type absorbances or add additional absorbance bands.
The propyl-substituted compound 17 has its Q-band split
by 1750 cm-1 and has a shoulder (ca. 430 nm) on the B
band that we assign to the n-π* transition from the meso
nitrogens to the macrocycle. The UV-visible spectrum
of oxygen-substituted 19 is very similar to that of 17 with
the Q-band slightly blue-shifted; it contains an additional
band at 451 nm that we assign as the oxygen n-π*
transition. The spectrum of sulfur-substituted 14 has a
red-shifted Q-band with a large splitting (2710 cm-1).
This splitting is comparable to that of a recently reported
trans-substituted porphyrazine.23 The nitrogen-substi-
tuted compound 7 has a Q-band that is less red-shifted
than that of 14 but with an even larger Q-band splitting
(5183 cm-1). The unusual breadth of the individual
Q-bands of 7 is due to the n-π* transitions of the
dimethylamino nitrogens and possibly to multiple con-
formations of the dimethylamino nitrogen groups with
respect to the plane of the macrocyclic core.
F igu r e 2. UV-visible absorption spectra (CH2Cl2) of the
trans-functionalized porphyrazines (from top to bottom) of 17,
19, 14, and 7.
provide a framework upon which metals can be coordi-
nated to the peripheral positions. We are currently
investigating the removal of the isopropyl groups from
compounds 16 and 17 to generate quinone and bis-
quinone macrocycles, respectively. Such work will be
reported in due course.
Exp er im en ta l Section
Gen er a l. Bis(dimethylamino)maleonitrile 4,38 2,3-bis(ben-
zylthio)maleonitrile 11,39 4,5-dicyano-4(Z)-octene 14,40 and
dispiromaleonitrile 1811 were prepared according to literature
procedures.
3,6-Bis(isop r op yloxy)-1,2-ben zen ed in itr ile (2). To a
well stirred slurry of 3,6-dihydroxy-1,2-benzenedinitrile (1) (25
g, 0.156 mol) and K2CO3 (48 g, 0.343 mol) in DMF (500 mL)
was added 2-bromopropane (40 mL), and the solution was
heated at 60 °C for 48 h. At this time an additional portion of
2-bromopropane (10 mL) was added, and the solution was
heated at the same temperature for 12 h. The reaction
contents were poured into water (2 L), and the solution was
vigorously stirred. The resulting white solid was filtered under
reduced pressure and then triturated with hot MeOH to yield
a white crystalline solid 2 (36 g, 0.147 mol, 94%), mp 191-
193 °C; 1H NMR (300 MHz, CDCl3) δ 1.38 (d, J ) 6.1 Hz, 12H),
4.54 (hp, J ) 6.1 Hz, 2H), 7.14 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 21.8, 73.8, 106.7, 113.2, 120.8, 154.5; IR νmax (CH2Cl2)
2232 cm-1; EI MS m/z 244 (M+), 202, 160. Anal. Calcd for
Con clu sion s
We have developed a simple convenient synthesis of
trans-macrocycles 10, 14, 17, and 19 from inexpensive
and readily available starting materials. This method
is sufficiently mild so that a wide range of functionality
and heteroatoms can be tolerated. These trans-por-
phyrazines all have split Q-bands and it is of particular
interest to note that the UV-visible absorption spectrum
of 14 includes an intense long-wavelength absorption at
ca. 800 nm (log ꢀ ) 4.72), a wavelength at which
mammalian tissue is effectively penetrated by light
(potential biomedical agent). These macrocycles will
C
14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.64, H,
6.66; N, 11.50.
4,7-Bis(isop r op yloxy)-1,3-d iim in oisoin d olin e (3). Com-
pound 2 (20 g, 82.0 mmol) was suspended in ethylene glycol
(500 mL), freshly cut Na (0.7 g) was added, and the mixture
(38) Begland, R. W.; Hartter, D. R.; J ones, F. N.; Sam, D. J .;
Sheppard, W. A.; Webster, O. W.; Weigert, F. J . J . Org. Chem. 1974,
39, 2341-2350.
(36) Nguyen, L. T.; Senge, M. O.; Smith, K. M. J . Org. Chem. 1996,
61, 998-1003.
(37) Kobayashi, N.; Konami, H. In Phthalocyanines: Properties and
Applications; Leznoff, C. C., Lever, A. B. P., Eds.; VCH: New York,
1996; Vol. 4; pp 343-404.
(39) Vela´zquez, C. S.; Fox, G. A.; Broderick, W. E.; Andersen, K. A.;
Anderson, O. P.; Barrett, A. G. M.; Hoffman, B. M. J . Am. Chem. Soc.
1992, 114, 7416-7424.
(40) Fitzgerald, J .; Taylor, W.; Owen, H. Synthesis 1991, 686-688.

Trans-Heterofunctionalized Porphyrazine Derivatives
J . Org. Chem., Vol. 63, No. 2, 1998 335
was heated to 130 °C under a positive pressure of N2. At this
time NH3(g) was bubbled through the solution for 5 h while
maintaining the temperature between 140 °C and 150 °C. The
solution was allowed to cool to room temperature and was
poured into water (1 L). The solid obtained was filtered and
dried under vacuum to yield a pale brown solid which was
recrystallized from MeOH to yield 3: (18 g, 68.6 mmol, 85%),
mp 144-148 °C; 1H NMR (300 MHz, CDCl3) δ 1.37 (d, J ) 6.1
Hz, 12H), 4.62 (hp, J ) 6.1 Hz, 2H), 6.92 (s, 2H), 8.1 (v br s,
3H); 13C NMR (75 MHz, CDCl3) δ 22.0, 71.4, 117.5, 123.6,
147.9, 168.2; EI MS m/z 261 (M+); IR νmax (CH2Cl2) 1641, 1611
cm-1. Anal. Calcd for C14H19N3O2: C, 64.35; H, 7.33; N, 16.08.
Found: C, 63.97; H, 7.53; N, 15.69.
N12NiO4: C, 60.35; H, 6.45; N, 19.19. Found: C, 60.15; H,
6.55; N, 19.03.
Ben zylth io P or p h yr a zin e Hybr id s 13 a n d 14. Magne-
sium turnings (78 mg, 3.2 mmol) were added to PrOH (30 mL),
and the suspension was heated under reflux for 16 h under
N2. At this time a mixture of 11 (1.73 g, 5.36 mmol) and
diiminoisoindoline 3 (1.42 g, 5.36 mmol) were added, and the
solution was heated under reflux for 6 h. The solution
immediately turned a dark brown color and after 5 min to
green-black. The PrOH was removed under reduced pressure,
the green-black residue was dissolved in CH2Cl2 (100 mL), and
TFA (20 mL) was added. The solution was stirred for 30 min
and then poured onto crushed ice containing a large excess of
NH4OH. The mixture was stirred vigorously for 1 h. At this
time the organic and aqueous layers were separated, and the
aqueous layer was extracted with CH2Cl2 until the washings
were colorless. The organic layers were then dried over
Na2SO4, and the solution was concentrated under reduced
pressure. The resulting residue was chromatographed (silica
gel, 80/20 CH2Cl2/hexanes eluant). The pigments eluted in the
order 12, 13, and 14. Octa k is(ben zylth io)p or p h yr a zin e
(12): (50 mg, 0.039 mmol, 3%); mp > 250 °C.39 3:1 Ben -
zylth io P or p h yr a zin e (13): (250 mg, 0.205 mmol, 11%); mp
175-176 °C dec; UV-vis (CH2Cl2) λmax (log ꢀ) 346 (4.66), 488
N,N-Dim eth ylam in o P or ph yr azin e Hybr ids 7-10. Mag-
nesium turnings (170 mg, 7.02 mmol) were added to BuOH
(100 mL), and the suspension was heated under reflux for 24
h under N2. At this time 3 (2.3 g, 8.79 mmol) and dinitrile 4
(0.48 g, 2.92 mmol) were added, and the solution was heated
under reflux for an additional 24 h. During this time the
solution slowly turned from an orange color to brown and
finally to blue-black. The BuOH was removed under reduced
pressure, and the remaining blue-black residue was dissolved
in CH2Cl2 (100 mL), cooled to 0 °C with an ice bath and AcOH
(20 mL) was added. The solution was stirred at 0 °C for 30
min while being shielded from ambient lighting and poured
onto crushed ice containing an excess of NH4OH. The layers
were separated, and the aqueous layer was washed with
CH2Cl2 until the washings were clear. The organic layers were
combined, dried over Na2SO4, and concentrated to yield a black
residue containing a mixture of 5, 6, and 7. The black residue
was not purified but instead converted to the nickel(II) chelates
by dissolving the residue in a mixture of 25 mL of chloroben-
zene and 25 mL of DMF, adding an excess of Ni(OAc)2‚4H2O
(1.0 g, 4.0 mmol) and heating the resulting solution at 100 °C
for 10 h under N2. The solvent was removed under reduced
pressure to yield a black residue. This was purified by column
chromatography (alumina, Brockmann grade III, 70/30 CH2Cl2/
hexanes eluant) to yield three pigments which eluted in the
order 8, 9, and 10. tr a n s-Am in o P or p h yr a zin e (7):41 mp
190-191 °C dec; UV-vis (CH2Cl2) λmax (log ꢀ) 327 (4.75), 548
1
(4.21), 661 (sh), 703 (4.65), 752 (sh) nm; H NMR (300 MHz,
CDCl3) δ -0.29 (br s, 2H), 1.77 (d, J ) 6.0 Hz, 12H), 5.08 (s,
4H), 5.12 (s, 4H), 5.21 (s, 4H), 5.28 (hp, J ) 6.0 Hz, 2H), 7.01-
7.35 (m, 30H), 7.68 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 22.6,
39.4, 39.9, 72.5, 119.2, 126.5, 126.9, 127.1, 128.2, 128.3, 128.4,
128.9, 129.1, 137.9, 138.0, 138.3, 139.0, 141.6, 150.2, 151.4,
151.6, 151.8, 154.2, 154.4, 154.7; FABMS m/z 1215 (M + H+),
Calcd for C68H61N8O2S6: 1215. Anal. Calcd for C68H60N8-
O2S6: C, 67.30; H, 4.98; N, 9.23. Found: C, 67.34; H, 4.95; N,
8.88. tr a n s-Ben zylth io P or p h yr a zin e (14): (120 mg, 0.105
mmol, 5%); mp 201-205 °C dec; UV-vis (CH2Cl2) λmax (log ꢀ)
344 (4.72), 434 (4.23), 656 (4.70), 718 (4.36), 798 (4.72) nm; 1H
NMR (300 MHz, CDCl3) δ -0.56 (br s, 2H), 1.76 (d, J ) 6.0
Hz, 24H), 5.27 (hp, J ) 6.0 Hz, 4H), 5.24 (s, 8H), 7.01 (m, 12H),
7.19-7.25 (m, 8H), 7.56 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
22.7, 36.6, 72.3, 118.3, 126.8, 128.2, 128.4, 129.9, 138.4, 147.1,
147.6, 156.3, 156.8; FABMS m/z 1137 (M + H+), Calcd for
1
(4.68), 747 (4.63) nm; H NMR (300 MHz, CDCl3) δ -0.86 (s,
C
64H63N8O4S4: 1137. Anal. Calcd for C64H62N8O4S4‚H2O: C,
2H), 1.72 (d, J ) 6.0 Hz, 24H), 3.95 (s, 24H), 5.38 (hp, J ) 6.0
Hz, 4H), 5.38 (s, 4H); FABMS m/z 819 (M+), Calcd for
C44H58N12O4: 819. Anal. Calcd for C44H58N12O4: C, 64.53; H,
7.14; N, 20.52. Found: C, 64.97; H, 7.24; N, 20.32. Ni(II)
3:1 Am in o P or p h yr a zin e (8): (47 mg, 0.058 mmol, 6%); mp
250-253 °C dec; UV-vis (CH2Cl2) λmax (log ꢀ) 315 (4.68), 519
(4.31), 709 (4.50) nm; 1H NMR (300 MHz, CDCl3) δ 1.72 (d, J
) 6.1 Hz, 12H), 3.66 (s, 12H), 3.69 (s, 12H), 3.88 (s, 12H), 5.16
(hp, J ) 6.1 Hz, 2H), 7.40 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 22.6, 44.8, 44.9, 45.2, 70.9, 113.7, 127.0, 136.8, 139.0, 140.6,
142.9, 143.7, 144.0, 144.3, 148.1; FABMS m/z 796 (M+), Calcd
for C38H52N14NiO2: 796. Anal. Calcd for C38H52N14NiO2: C,
57.37; H, 6.59; N, 24.65. Found: C, 57.71; H, 6.71; N, 24.50.
Ni(II) cis-Am in o P or p h yr a zin e (9): (38 mg, 0.044 mmol,
3%); mp 203-205 °C dec; UV-vis (CH2Cl2) λmax (log ꢀ) 318
(4.70), 718 (4.65) nm; 1H NMR (300 MHz, CDCl3) δ 1.50 (d, J
) 6.2 Hz, 12H), 1.74 (d, J ) 6.1 Hz, 12H), 3.68 (s, 12H), 3.87
(s, 12H), 5.02 (hp, J ) 6.2 Hz, 2H), 5.19 (hp, J ) 6.1 Hz, 2H),
7.44 (dd, J ) 8.8 Hz and J ) 8.6 Hz, 4H); 13C NMR (75 MHz,
CDCl3) δ 22.6, 44.8, 45.1, 70.9, 75.1, 113.1, 122.7, 126.5, 129.5,
137.1, 140.3, 143.4, 144.2, 144.3, 144.9, 148.1, 149.8; FABMS
m/z 876 (M+), Calcd for C44H56N12NiO4: 876. Anal. Calcd for
66.64; H, 5.59; N, 9.71. Found: C, 66.58; H, 5.67; N, 9.68.
P r op yl P or p h yr a zin e Hybr id s 16 a n d 17. Magnesium
turnings (200 mg, 8.22 mmol) were added to BuOH (70 mL),
and the solution was heated at reflux for 24 h under N2. At
this time dinitrile 15 (0.67 g, 4.11 mmol) and 3 (1.08 g, 4.11
mmol) were added, and the solution was heated under reflux
for an additional 24 h. The solvent was removed under
reduced pressure, the remaining blue-green residue was
dissolved in CH2Cl2 (200 mL), and TFA (25 mL) was added.
The resulting mixture was stirred for 1 h and then poured into
ice containing an excess of aqueous NH4OH. The organic layer
was separated from the aqueous layer, and the aqueous layer
was washed with CH2Cl2 until the washings were clear. The
combined organic washings were dried over Na2SO4, and the
solvent was concentrated under reduced pressure. The result-
ing residue was chromatographed (silica gel, 90/10 CH2Cl2/
hexanes eluant) to yield two pigments eluting in the order 16
and 17. 3:1 P r op yl P or p h yr a zin e (16): (60 mg, 0.08 mmol,
6%); mp 168-172 °C dec; UV-vis (CH2Cl2) λmax (log ꢀ) 333
(4.77), 568 (sh), 600 (4.67), 673 (4.55) nm; 1H NMR (300 MHz,
CDCl3) δ -1.84 (br s, 2H), 1.26 (dt, J ) 7.3 Hz and J ) 1.2
Hz, 18H), 1.83 (d, J ) 6.1 Hz, 6H), 2.39 (m, 12H), 3.80 (t, J )
7.7 Hz, 4H), 4.00 (t, J ) 7.7 Hz, 4H), 4.09 (t, J ) 7.6 Hz, 4H),
5.37 (m, 2H), 7.55 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 14.1,
14.6, 14.7, 22.8, 25.2, 25.4, 25.5, 27.9, 28.1, 28.2, 71.7, 118.2,
121.9, 140.8, 141.6, 141.7, 145.1, 145.8, 149.2, 158.9, 161.4;
FABMS m/z 733 (M+), Calcd for C44H60N8O2: 733. Anal.
Calcd for C44H60N8O2: C, 72.10; H, 8.25; N, 15.29. Found: C,
71.76; H, 8.48; N, 15.17. tr a n s-P r op yl P or p h yr a zin e (17):
(300 mg, 0.37 mmol, 18%); mp 260 °C dec; UV-vis (CH2Cl2)
C
44H56N12NiO4: C, 60.35; H, 6.45; N, 19.19. Found: C, 60.64;
H, 6.51; N, 18.84. Ni(II) tr a n s-Am in o P or p h yr a zin e (10):
(190 mg, 0.22 mmol, 15%); mp 215-217 °C; UV-vis (CH2Cl2)
λmax (log ꢀ) 321 (4.75), 727 (4.68) nm; 1H NMR (300 MHz,
CDCl3) δ 1.73 (d, J ) 6.0 Hz, 24H), 3.86 (s, 24H), 5.18 (m,
4H), 7.41 (s, 4H); 13C NMR (75 MHz, CDCl3) δ 22.6, 45.1, 70.9,
113.8, 126.9, 138.6, 143.5, 145.0, 149.2; FABMS m/z 876 (M+),
Calcd for C44H56N12NiO4: 876. Anal. Calcd for C44H56
-
λ
max (log ꢀ) 333 (4.85), 596 (4.59), 638 (4.88), 718 (4.59) nm; 1H
NMR (300 MHz, CDCl3) δ -1.60 (br s, 2H), 1.28 (t, J ) 7.3
Hz, 12H), 1.81 (d, J ) 6.1 Hz, 24H), 2.39 (sextet, J ) 7.3 Hz,
(41) Because of the difficulty associated with the purification of
compound 7, no effort was made to quantitate the yield at this stage.

336 J . Org. Chem., Vol. 63, No. 2, 1998
Forsyth et al.
8H), 4.09 (t, J ) 7.1 Hz, 8H), 5.36 (hp, J ) 6.1 Hz, 4H), 7.51
(s, 4H); 13C NMR (75 MHz, CDCl3) δ 14.6, 22.8, 25.1, 27.9, 71.7,
118.1, 130.0, 141.1, 145.1, 149.1, 158.3; FABMS m/z 815 (M+),
Calcd for C48H62N8O4: 815. Anal. Calcd for C48H62N8O4: C,
70.73; H, 7.67; N, 13.75. Found: C, 70.68; H, 7.76; N, 13.63.
Sp ir a n e P or p h yr a zin e Hybr id s 19 a n d 20. To Mg
turnings (5 mg, 0.21 mmol) in BuOH (4 mL) was added a small
crystal of I2, and the suspension was heated under reflux for
12 h. To the cooled solution were added isoindoline 3 (131
mg, 0.50 mmol) and dinitrile 18 (28 mg, 0.10 mmol), after
which the mixture was heated under reflux for 16 h. Removal
of the solvent in vacuo, dissolution of the residue in CH2Cl2
(15 mL), and filtration through Celite allowed removal of most
of the magnesium salts. After solvent removal, AcOH (7 mL)
was added to the remaining solid material, and the solution
was stirred for 12 h, poured into ice (ca. 50 mL), and
neutralized with 1 N NaOH. Suction filtration afforded a dark
green solid material which was subjected to column chroma-
tography (silica gel, 70/30 hexanes/ethyl acetate and, subse-
quently, 95/5 toluene/acetone eluants), eluting the pigments
in the order 19 and 20. When making use of stoichiometric
amounts of the starting materials, 19 and 20 were obtained
in ca. 1:2 ratio (66% combined yield). tr a n s-Sp ir a n e P or -
p h yr a zin e (19): (22 mg, 21.1 µmol, 42%); mp 270-272 °C
dec; IR νmax (CH2Cl2) 1031, 1079, 1104, 1135, 1230, 1299, 1501,
1623, 2856, 2928, 2960, 3601, 3686 cm-1; UV-vis (CH2Cl2) λmax
(log ꢀ) 230 (4.50), 327 (4.74), 380 (4.15), 451 (4.20), 586 (4.36),
632 (4.79), 705 (4.51) nm; 1H NMR (300 MHz, CDCl3) δ -2.34
(s, 2H), 1.86-1.94 (m, 8H), 1.87 (d, J ) 6.0 Hz, 12H), 1.92 (d,
J ) 6.0 Hz, 12H), 2.09 (d, J ) 12.5 Hz, 4H), 2.21 (td, J ) 13.2
Hz and J ) 4.7 Hz, 4H), 2.62 (d, J ) 14.0 Hz, 4H), 2.74 (dd, J
) 12.8 Hz and J ) 4.0 Hz, 4H), 3.76 (dd, J ) 10.3 Hz and J )
2.9 Hz, 4H), 4.31 (td, J ) 11.6 Hz and J ) 2.6 Hz, 4H), 5.42
(hp, J ) 6.1 Hz, 4H) 7.54 (s, 4H); 13C NMR (75 MHz, CDCl3)
δ 18.2, 23.01, 23.05, 24.8, 28.7, 62.5, 74.5, 100.2, 121.8, 131.2,
134.8, 136.2, 150.3, 157.6; FABMS m/z 1043 (M+); HRFABMS
Calcd for C56H67N8O12 (M + H+) 1043.488. Found: 1043.490.
3:1 Sp ir a n e P or p h yr a zin e (20): (5 mg, 4.7 µmol, 14%); mp
231-232 °C dec; IR νmax (CH2Cl2) 1079, 1103, 1135, 1230, 1244,
1299, 1502, 1603, 1624, 2938, 2959, 2976, 3362 cm-1; UV-vis
(CH2Cl2) (log ꢀ) λmax 230 (4.25), 331 (4.78), 447 (4.24), 591
) 6.0 Hz, 6H), 2.07-2.24 (m, 12H), 2.54-2.76 (m, 12H), 3.63-
3.82 (m, 6H), 4.16-4.38 (m, 6H), 5.44 (hp, J ) 6.0 Hz, 2H),
7.58 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 18.2, 18.4, 22.99,
23.05, 24.8, 25.0, 28.7, 28.9, 29.0, 62.4, 62.5, 62.7, 74.5, 99.8,
100.1, 100.3, 122.3, 131.0, 135.2, 136.0, 136.3, 136.6, 138.1,
150.2, 150.4, 157.9; FABMS m/z 1075 (M+); HRFABMS Calcd
for C56H66N8NaO14 (M + Na+) 1097.460. Found 1097.468.
Cr ysta l Str u ctu r e Deter m in a tion of 17. Compound 17
was grown by diffusion of methanol into a solution of 17 in
toluene. All measurements were made on an Enraf-Nonius
CAD4 diffractometer. Crystal data for C48H62N8O4 (MW )
815.01) at 153 K (Mo-KR radiation, λ ) 0.710 69 Å, 2θmax
)
49.9°, ω-θ scan technique), orthorhombic, space group P212121
(no. 19), a ) 9.599(3) Å, b ) 20.902(3) Å, c ) 22.349(3) Å, V )
4484(1) Å3, Z ) 4, R ) 0.095, wR ) 0.0730, GOF ) 2.39 for
1559 reflections with I > 3.00σ(I) and 242 parameters. The
structure was solved by direct methods (SIR92),42 expanded
using Fourier techniques, and refined by the full-matrix least-
squares technique. Due to the paucity of data, the non-
hydrogen atoms were refined isotropically. Hydrogen atoms
on the carbon atoms were included in idealized positions but
not refined. The Flack parameter supports the proposed
model. All calculations were performed using the TEXSAN
crystallographic software package of the Molecular structure
Corporation (TEXSAN 5.0).
Ack n ow led gm en t. We thank the Glaxo Group
Research Ltd. for the generous endowment (A.G.M.B.),
the Wolfson Foundation for establishing the Wolfson
Centre for Organic Chemistry in Medical Science at
Imperial College, the Engineering and Physical Sciences
Research Council, the National Science Foundation
(CHE-9408651), NATO, and the Foundation for Re-
search and Development (South Africa) for generous
support of our studies.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
(300 MHz, CDCl3) and 13C (75 MHz, CDCl3) NMR spectra of
compounds 19 and 20 and X-ray data of 17 (31 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of this journal, and
can be ordered from the ACS; see any current masthead page
for information.
1
(4.58), 667 (4.49) nm; H NMR (300 MHz, CDCl3) δ -2.79 (s,
2H), 1.75-1.97 (m, 12H), 1.88 (d, J ) 6.0 Hz, 6H), 1.93 (d, J
(42) Altomare, A.; Cascarano, G.; Guaglinard, A.; Burla, M. C.;
Polidori, G.; Camalli, M. J . Appl. Crystallogr. 1994, 27, 435.
J O971683C