Metal-catalyzed oxidative cyclizations of a,c-biladiene salts bearing 1- and/or 19-arylmethyl substituents: Macrocyclic products and their chemistry

Article abstract of DOI:10.1021/jo9619138

Several 1-mono- and 1,19-bis(p-arylmethyl)-a,c-biladiene salts were prepared and subjected to either copper(II)- or chromium(III)-assisted oxidative cyclization to yield numerous products in which the 1- or 19- substituent is adapted, eliminated, or rearranged to other points on the tetrapyrrole. For example, cyclization using copper(II) acetate of 19- ((ethoxycarbonyl)methyl)-2,3,7,8,12,13,17,-18-octamethyl-19-(p-tolylmethyl)- a,c-biladiene dihydrobromide (25) yielded the copper(II) 20- ((ethoxycarbonyl)methyl)-1-(p-tolylmethyl)-2,3,7,8,12,13,17,18-octamethyl- 1,20-dihydroporphyrin (42), copper(II) 20-(ethoxycarbonyl)-3-methylidene- 2,3,7,8,12,13,17,18-octamethyl-2-(p-tolylmethyl)-chlorin (44), copper(II) 20- (ethoxycarbonyl)-2-methylidene-2,3,7,8,12,13,17,18-octamethyl-3-(p- tolylmethyl)chlorin (45), and three porphyrins: copper(II) 20- (ethoxycarbonyl)-2,3,7,8,12,13,17,18-octamethylporphyrin (3), copper(II) 2,3,7,8,12,13,17,18-octamethyl-20-p-tolylporphyrin (50), and copper(II) 20- (ethoxycarbonyl)-2,3,7,8,12,13,17,18-octamethyl-5-(p-tolylmethyl)porphyrin (47). Formation of porphyrin 47 and the intermediate chlorins 44 and 45 suggests the stepwise migration of the arylmethyl group from the 1-position in compound. 42. The isolation of products from cyclization reactions of various 1,19-arylmethyl-substituted a,c-biladiene salts provides further insight into the mechanisms of metal-assisted oxidative cyclization of a,c- biladiene salts to give cyclic tetrapyrroles. Macrocyclizations of a,c- biladienes such as 25 using chromium(III) afford good yields of the metal- free 1-substituted compounds such as 43.

Full text of DOI:10.1021/jo9619138

4266
J . Org. Chem. 1997, 62, 4266-4276
Meta l-Ca ta lyzed Oxid a tive Cycliza tion s of a ,c-Bila d ien e Sa lts
Bea r in g 1- a n d /or 19-Ar ylm eth yl Su bstitu en ts: Ma cr ocyclic
P r od u cts a n d Th eir Ch em istr y
J ack J . Lin, Kevin R. Gerzevske, Paul A. Liddell, Mathias O. Senge,† Marilyn M. Olmstead,
Richard G. Khoury, Brent E. Weeth, Stephanie A. Tsao, and Kevin M. Smith*
Department of Chemistry, University of California, Davis, California 95616
Received October 9, 1996X
Several 1-mono- and 1,19-bis(p-arylmethyl)-a,c-biladiene salts were prepared and subjected to either
copper(II)- or chromium(III)-assisted oxidative cyclization to yield numerous products in which
the 1- or 19- substituent is adapted, eliminated, or rearranged to other points on the tetrapyrrole.
For example, cyclization using copper(II) acetate of 19-((ethoxycarbonyl)methyl)-2,3,7,8,12,13,17,-
18-octamethyl-19-(p-tolylmethyl)-a,c-biladiene dihydrobromide (25) yielded the copper(II) 20-
((ethoxycarbonyl)methyl)-1-(p-tolylmethyl)-2,3,7,8,12,13,17,18-octamethyl-1,20-dihydroporphyrin
(42), copper(II) 20-(ethoxycarbonyl)-3-methylidene-2,3,7,8,12,13,17,18-octamethyl-2-(p-tolylmethyl)-
chlorin (44), copper(II) 20-(ethoxycarbonyl)-2-methylidene-2,3,7,8,12,13,17,18-octamethyl-3-(p-tolyl-
methyl)chlorin (45), and three porphyrins: copper(II) 20-(ethoxycarbonyl)-2,3,7,8,12,13,17,18-
octamethylporphyrin (3), copper(II) 2,3,7,8,12,13,17,18-octamethyl-20-p-tolylporphyrin (50), and
copper(II) 20-(ethoxycarbonyl)-2,3,7,8,12,13,17,18-octamethyl-5-(p-tolylmethyl)porphyrin (47). For-
mation of porphyrin 47 and the intermediate chlorins 44 and 45 suggests the stepwise migration
of the arylmethyl group from the 1-position in compound 42. The isolation of products from
cyclization reactions of various 1,19-arylmethyl-substituted a,c-biladiene salts provides further
insight into the mechanisms of metal-assisted oxidative cyclization of a,c-biladiene salts to give
cyclic tetrapyrroles. Macrocyclizations of a,c-biladienes such as 25 using chromium(III) afford good
yields of the metal-free 1-substituted compounds such as 43.
In tr od u ction
the metal salt oxidant used,9 as well as methodology for
generalization of the synthetic route through the prepa-
ration of unsymmetrically substituted a,c-biladienes and
porphyrins therefrom.10,11 Parallel synthetic and mecha-
nistic studies of the synthesis of porphyrins from b-
bilenes have also been reported by Clezy and co-
workers,12-14 and their results are broadly in agreement
with our own conclusions for a,c-biladienes.
In the present paper we describe our results on the
copper(II)-catalyzed cyclization of a,c-biladiene salts
bearing at least one arylmethyl substituent at positions
1 or 19. The presence of the arylmethyl substituent, it
will be shown, results in novel substituent migrations
around the tetrapyrrole macrocycle.
In a recent paper we showed1 that metal ion [e.g.,
copper(II), chromium(III)] promoted oxidative cyclizations
of a,c-biladiene salts substituted at the 1- and 19-
positions (e.g., 1; Scheme 1) with various aliphatic sub-
stituents gave a variety of novel macrocyclic products,
including 1-substituted substances 2, copper(II) porphy-
rins 3, copper(II) chlorins 4, and so-called homoporphy-
rins 5. The chemistry reported paralleled the electro-
chemical synthesis of porphyrins from a,c-biladiene
salts2,3 and enabled a deeper understanding of the
mechanistic pathways4,5 from a,c-biladienes to copper-
(II) porphyrins6,7 and to metal-free porphyrins using the
chromium procedure recently described by Boschi and co-
workers.8 Other studies have also probed the nature of
Resu lts a n d Discu ssion
† Present address: Institut fu¨r Organische Chemie (WE02), Freie
Universita¨t Berlin, Takustrasse 3, D-14195 Berlin, Germany.
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) Liddell, P. A.; Gerzevske, K. R.; Lin, J . J .; Olmstead, M. M.;
Smith, K. M. J . Org. Chem. 1993, 58, 6681.
(2) J eyakumar, D.; Snow, K. M.; Smith, K. M. J . Am. Chem. Soc.
1988, 110, 8562.
(3) Swanson, K. L.; Snow, K. M.; J eyakumar, D.; Smith, K. M.
Tetrahedron Lett. 1991, 47, 685.
P r ep a r a tion of Tr ip yr r en es a n d a ,c-Bila d ien es.
Symmetrical a,c-biladienes bearing 1,19-bis(p-tolyl-
methyl) substituents were prepared by addition of 2
molar equiv of formylpyrrole 7 to a mole of dipyr-
romethanedicarboxylic acid 16 (17 or 18) to give a,c-
biladiene dihydrobromide 19 (20 or 21) in 84% (84% and
78%) yield (Scheme 2).
Unlike the synthesis of a,c-biladienes such as 19, a
stepwise approach was neccessary for the preparation of
the unsymmetrical a,c-biladienes. 2-(Acetoxymethyl)-
(4) Smith, K. M.; Minnetian, O. M. J . Org. Chem. 1985, 50, 2073.
(5) Smith, K. M.; Kehres, L. A. J . Chem. Soc., Perkin Trans. 1 1983,
2329.
(6) J ohnson, A. W.; Kay, I. T. J . Chem. Soc. 1961, 2418.
(7) (a) Smith, K. M. In Porphyrins and Metalloporphyrins; Smith,
K. M., Ed.; Elsevier: Amsterdam, 1975; pp 29-55. (b) Smith, K. M.
In Porphyrins and Metalloporphyrins; Smith, K. M., Ed.; Elsevier:
Amsterdam, 1975; p 764. (c) Smith, K. M. In Porphyrins and Metal-
loporphyrins; Smith, K. M., Ed.; Elsevier: Amsterdam, 1975; p 763.
(d) Improved syntheses of pyrroles 12 and 13 have recently been
reported: Lash, T. D.; Bellettini, J . R.; Bastian, J . A.; Couch, K. B.
Synthesis 1994, 170. Burns, D. H.; J abara C. S.; Burden, M. W. Synth.
Commun. 1995, 25, 379. (e) J ackson, A. H.; Pandey, R. K.; Rao, K. R.
N.; Roberts, E. Tetrahedron Lett. 1985, 26, 793.
(9) Smith, K. M.; Minnetian, O. M. J . Chem. Soc., Perkin Trans. 1
1986, 277.
(10) Almeida, J . A. P. B.; Kenner, G. W.; Rimmer, J .; Smith, K. M.
Tetrahedron 1976, 32, 429.
(11) Smith, K. M.; Craig, G. W. J . Org. Chem. 1983, 48, 4307.
(12) Clezy, P. S.; Ravi, B. N.; Thuc, L. V. Aust. J . Chem. 1986, 39,
419.
(13) Atkinson, E. J .; Brophy, J . J .; Clezy, P. S. Aust. J . Chem. 1990,
43, 383.
(8) Boschi, T.; Paolesse, R.; Tagliatesta, P. Inorg. Chim. Acta 1990,
168, 83.
(14) Clezy, P. S. Aust. J . Chem. 1991, 44, 1163.
S0022-3263(96)01913-5 CCC: $14.00 © 1997 American Chemical Society

Metal-Catalyzed Oxidative Cyclizations of a,c-Biladiene Salts
J . Org. Chem., Vol. 62, No. 13, 1997 4267
Sch em e 1. F or m a tion of Novel Ma cr ocycles fr om
Cop p er (II)-Ca ta lyzed Oxid a tive Cycliza tion of
a ,c-Bila d ien e Dih yd r obr om id e (1)1
Sch em e 2. P r ep a r a tion of Dip yr r om eth a n es 14
a n d 15 a n d a ,c-Bila d ien es 19-21
pyrrole 107c was treated with 2-unsubstituted pyrrole
121,7d in the presence of Montomorillite K-10 Clay7e to
afford the dipyrromethane 141 in 80% yield (Scheme 2).
There are two possible routes for conversion of unsym-
metrically substituted dipyrromethanes into tripyrrenes
and then on to a,c-biladienes; these involve selective and
sequential cleavage of either the tert-butyl or the benzyl
ester on the dipyrromethane. Catalytic debenzylation of
dipyrromethane 14 followed by acid-catalyzed condensa-
tion with formylpyrrole 7 afforded the tripyrrene hydro-
bromide 22 in 81% yield. Treatment of tripyrrene 22
with acid followed by addition of 2-formylpyrrole 8 gave
the a,c-biladiene 25 (Scheme 3). The alternative pathway
through tripyrrene required the removal of the tert-butyl
ester from dipyrromethane 15 (or 14) with acid. The
dipyrromethane was condensed with 1 molar equiv of
pyrrole 7 under acidic conditions to give tripyrrene 24
(or 23). Hydrolysis and decarboxylation of the benzyl
ester with 30% HBr/acetic acid and trifluoroacetic acid11
gave the tripyrrene hydrobromide 24 (or 23) which
readily underwent condensation with another 2-formylpyr-
role (8) to give the unsymmetrical a,c-biladiene dihydro-
bromide 28 in yields ranging from 76 to 85%.
DMF at 145 °C in the presence of copper(II) acetate
(Scheme 4) afforded the copper(II) porphyrin 36 as the
major product (characterized as 37 after demetalation),
together with a very small amount of a copper(II) chlorin
which was shown, by X-ray crystallography (Figure 1),
to be the 2-methylidene compound 33 rather than the
isomer 41; presumably, steric congestion between the 1-
and 20-substituents in 41 caused it to be unstable, under
the reaction conditions, compared with its further migra-
tion product, compound 33. When the reaction was
performed in DMF with copper(II) acetate at 120 °C, the
copper(II) porphyrin was again the major product, but
the 1-substituted copper(II) complex 30 was also isolated,
thereby demonstrating its intermediacy in the reaction
at 145 °C; the milder reaction conditions resulted in none
of the copper(II) chlorins 33 or 41 being observed or
isolated. Figure 2 shows the X-ray structure of the
copper(II) 1-(p-tolylmethyl)-20-p-tolyl macrocycle 30.
Copper(II)-catalyzed cyclization of a,c-biladiene dihy-
drobromide 20 in DMF at room temperature resulted in
formation of the copper(II) 1-substituted compound 29
Cop p er (II)-P r om oted Oxid a tive Cycliza tion of
a ,c-Bila d ien e Sa lts. Heating of a,c-biladiene 19 in

4268 J . Org. Chem., Vol. 62, No. 13, 1997
Lin et al.
Sch em e 3. Syn th etic Ap p r oa ch es to
Un sym m etr ica l a ,c-Bila d ien es 25-28
Sch em e 4. P r od u cts fr om Cop p er (II)-Ca ta lyzed
Oxid a tive Cycliza tion of a ,c-Bila d ien e
Dih yd r obr om id es 19, 20, a n d 21
as the major product, in 81% yield. Its structure was
confirmed by X-ray crystallography (not shown, but
deposited with CCDC). When the same reaction was
performed at 120 °C, several products were isolated,
including copper(II) compound 29 (8%), the copper(II)
2-methylidenechlorin 32 (4%), and the copper(II) por-
phyrins 34 (30%) and 38 (3%) (both characterized by
NMR spectroscopy after demetalation in sulfuric/trifluo-
roacetic acids to give 35 and 39, respectively). The
regiochemistry of the migrated p-tolylmethyl group was
assigned on the basis of the structure of the similar
chlorin 33, determined by X-ray crystal analysis as
previously reported.15 Perhaps the most surprising
product was the copper(II) porphyrin 38 in which the
p-tolylmethyl substituent had migrated from the 1-posi-
tion in 29 (presumably) completely across the macrocyclic
A ring to the 5-position. Further examples elucidating
the migratory effect of the p-tolylmethyl moiety will be
seen with cyclization of a,c-biladiene 25 (vide infra).
The roles as intermediates, in the migration process,
of the 1-substituted compound 29 and chlorin 32 were
further investigated. Compound 29 was subjected to
cyclization conditions (copper acetate and N,N-dimeth-
ylformamide) for 15 min at 140 and 120 °C. At 140 °C,
29 provided copper(II) porphyrin 34 as the major product.
In addition, porphyrin 38 and chlorin 32 were isolated
in 3% and 1% yields, respectively. The product distribu-
tion is comparable to the yield of these macrocycles
isolated by cyclizing a,c-biladiene 20 at 120 °C, further
substantiating product 29 as the intermediate that
provides the migration products. Heating of compound
29 under similar conditions at 120 °C provided an
increase in yield of the chlorin 32 over porphyrins 34 and
38, from 1% to 11%. When the copper(II) 2-meth-
ylidenechlorin 32 was heated in o-dichlorobenzene (at 140
°C for 120 min), a mixture of the copper(II) porphyrins
34 and 38 was obtained, with porphyrin 38 as the major
product (78% yield). Table 1 summarizes the results
obtained from 29 and 32.
When a,c-biladiene 25 was treated with copper(II)
acetate in DMF at 120 °C, the 1-p-tolylmethyl-substituted
copper(II) complex 42 was isolated, along with three
copper(II) porphyrins and two copper(II) chlorins (Scheme
5). The pathway for this migration became clearer once
the two copper(II) chlorins were isolated, purified, and
characterized as the migration intermediates 44 and 45,
along with porphyrin 47; compounds 42, 44, 45, and 47
(and experiments described above with 19 and 20)
(15) Liddell, P. A.; Olmstead, M. M.; Smith, K. M. Tetrahedron Lett.
1990, 31, 2685.

Metal-Catalyzed Oxidative Cyclizations of a,c-Biladiene Salts
J . Org. Chem., Vol. 62, No. 13, 1997 4269
Sch em e 5. P r od u cts fr om Cop p er (II)-Ca ta lyzed
Oxid a tive Cycliza tion of a ,c-Bila d ien e
Dih yd r obr om id e 25
F igu r e 1. Molecular structure of copper(II) chlorin 33.
Hydrogen atoms have been omitted for clarity.
F igu r e 2. Molecular structure of the copper(II) complex 30.
Hydrogen atoms have been omitted for clarity.
Ta ble 1. Resu lts fr om Rea r r a n gem en t Exp er im en ts
Usin g Com p ou n d s 29 a n d 32
product yield (%)
temp
(°C)
1-subd
prod
porphyrin
chlorin
32
porphyrin
compd
34
38
29
140
120
100
33
21
29
1
11
1
3
2
1
42
32
140
12
21
78
confirmed the stepwise migration of p-tolylmethyl from
the 1-positon to positions 2, 3, and 5. Figure 3A shows
the X-ray structure for chlorin 45, while the crystal
structure of chlorin 44 is shown in Figure 3B. The second
copper(II) porphyrin was identified as the 20-p-tolylpor-
phyrin 50 by demetalation and characterization of the
metal-free product 51. This led us to the conclusion that
the 1-(ethoxycarbonyl)methyl compound 49 must also
have been a product from the cyclization of a,c-biladiene
25 since the methylene carbon in the 1-p-tolylmethyl
group had been used to provide the 20-carbon in 49 (and
50); cleavage of acetic side chains from such 1-substituted
substances is not uncommon,1 and the fact that we had
not isolated compound 49 suggests that it was so labile
under the reaction conditions that it was transformed
into 50 in situ. Even during chromatography the 1-sub-
stituted compound 42 could be observed to decompose
into the two chlorins 44 and 45, and when the compound
42 (obtained from reaction of 6 at 100 °C in DMF, and
therefore presumably contaminated with some 49) was
heated above 145 °C, copper(II) porphyrins were pro-
duced. Instability of the copper(II) complex 49 could be
attributed to the presence of the acetic side chain as
indictated by the results obtained in cyclizations of the
19-propionic 1-((ethoxycarbonyl)methyl)-a,c-biladiene 1.1
Copper(II)-promoted cyclization of 27 at 120 °C, af-
forded four products, namely, two copper(II) porphyrins
and two copper(II) 1-substituted compounds. The major
product was identified as the 1-propionic 20-p-tolyl
copper(II) complex 52 (Scheme 6); Figure 4 shows the
X-ray structure of 52. The less abundant 1-substituted
compound was deduced (from mass spectral data) to be
the 20-acetic 1-p-tolylmethyl isomer 54 of compound 52.
The most abundant porphyrin was identified as the
copper(II) 20-arylporphyrin 50. Although not enough
material was isolated for complete characterization, the
second porphyrin isolated was deduced to be copper(II)
porphyrin 55, obtained by aryl elimination from the
corresponding copper(II) 1-substituted compound. Table
2 shows the results obtained under variable conditions

4270 J . Org. Chem., Vol. 62, No. 13, 1997
Lin et al.
F igu r e 3. Molecular structure of (A) copper(II) chlorin 45 and (B) copper(II) chlorin 44. Hydrogen atoms have been omitted for
clarity.
Sch em e 6. P r od u cts fr om Cop p er (II)-Ca ta lyzed
Oxid a tive Cycliza tion of a ,c-Bila d ien e
Dih yd r obr om id e 27
F igu r e 4. Molecular structure of the copper(II) complex 52.
Hydrogen atoms have been omitted for clarity.
Ta ble 2. Su m m a r y of a ,c-Bila d ien es Stu d ied , Rea ction
Con d ition s, a n d P r od u cts
product and yield (%)
temp 1-subd
a,c-biladiene (°C) prod
porphyrin
(mono-meso-) chlorin (di-meso-)
porphyrin
19
20
25
27
28
120 30 (71) 36 (4)
145 30 (45) 36 (14)
25 29 (81) 34 (<1)
33 (0)
33 (2.5)
32 (a)
32 (4)
44 (0.5)
45 (1)
a
a
a
38 (a)
38 (3)
47 (1)
120 29 (8)
34 (30)
120 42 (33) 50 (3)
3 (7)
120 52 (41) 50 (1)
a
54 (4)
55 (<1)
25 58 (--) 34 (9)
100 58 (18) 34 (47)
60 (12)
a
a
a
a
125 58 (<1) major product
a
a
during cyclization reactions of a,c-biladienes 19, 20, 25,
27, and 28.
a
No product isolated.
Low-temperature/room temperature cyclization of a,c-
biladiene 28 gave two porphyrins, 34 and 60, in yields
of 8% and 2%, respectively; no significant amounts of
1-substituted intermediates 57 and 58 were isolated. At
125 °C, cyclization of 28 afforded porphyrin 34 as the
major product, with again an insignificant amount of
1-substituted compound. Cyclization was then carried
out at 100 °C, and this afforded three products, the two
porphyrins (34, 60) and a 1-substituted intermediate,
believed to be 58 (Scheme 7). The identity of 60 was
further confirmed by demetalation to give 61. The
precise structure of 58 was established using X-ray
crystallography (Figure 5). At room temperature, copper-
(II) cyclization of 28 afforded only copper(II) porphyrins,
with no 1-substituted products being isolated. Significant
amounts of 1-substituted compounds were only observed
at higher temperature (100 °C); at this temperature,
some 1-(p-tolyl)-20-methyl macrocycle 57 appeared to be
produced, but it decomposed during chromatography to
give copper (II) porphyrin 60.
Ch r om iu m (III)-P r om oted Oxid a tive Cycliza tion
of a ,c-Bila d ien e Sa lts. Boschi and co-workers8 have
shown that metal-free porphyrins can be obtained from
the cyclization of a,c-biladienes using chromium(III)
acetate in hot buffered ethanol or DMF. In the same
study they concluded that when the 1,19 groups are other
than methyl (e.g., ethyl or propionic methyl ester) an
alternative mechanism to that established for copper(II)-
promoted cyclization must be dominant. We have shown
that if a modification of Boschi’s method using mild
chromium(III) cyclization conditions is employed, then
intermediates (such as the metal free analogue of 2) were
isolated.16 Our original studies concentrated on a,c-

Metal-Catalyzed Oxidative Cyclizations of a,c-Biladiene Salts
J . Org. Chem., Vol. 62, No. 13, 1997 4271
Sch em e 7. P r od u cts fr om Cop p er (II)-Ca ta lyzed
Oxid a tive Cycliza tion of a ,c-Bila d ien e
Dih yd r obr om id es 26 a n d 28
F igu r e 5. Molecular structure of chlorin 58. Hydrogen atoms
have been omitted for clarity.
observable (TLC), the major product isolated (but in only
4% overall yield) was a blue green compound identified
as the metal-free analogue 53 of compound 52. The
structure of the product was determined by proton NMR
spectroscopy (comparing three singlets in the meso region
at 6.23, 5.42, and 4.81 ppm with earlier decoupling
experiments2). This result provided further evidence for
the similarity in cyclization mechanisms between the
traditional copper(II) and newer chromium(III) methods.
Interestingly, none of the isomeric 1-(p-tolylmethyl)-20-
((methoxycarbonyl)methyl) compound 54 was isolated. As
in other examples of compounds containing a 1- or 19-
propionic methyl ester,1 the chromium(III) cyclization
method resulted in a product in which the alkyl ester is
situated in the 1-position. Steric interactions may play
a role in the cyclization with the chromium(III) method;
in contrast, however, the copper(II) method yielded a
small amount of isomer 54 (vide supra).
Chromium-assisted cyclization of a,c-biladiene 25 un-
der conditions similar to those used for synthesis of
compound 21 resulted only in decomposition products.
A reaction at 0 °C gave metal-free 1-substituted com-
pound 43 as the only product, in 13% yield. a,c-Biladiene
26 was also oxidized under the same conditions as used
for a,c-biladiene 21 to provide the 1-substituted com-
pound 59 as the only product. Table 3 summarizes the
products observed in the chromium(III) cyclizations of
a,c-biladienes.
biladienes with alkyl groups in the terminal 1,19-posi-
tions. In the present study the a,c-biladienes chosen for
cyclization are again extended to substances with at least
one arylmethyl group in the two terminal positions. The
results clearly demonstrate mechanistic similarities be-
tween the copper(II)- and chromium(III)-promoted cy-
clizations.
The main advantage of the chromium(III) method over
the copper(II) approach is the formation of metal-free
intermediates and porphyrins during the cyclization
process. Many of the 1-substituted cyclized intermedi-
ates which we have isolated as copper(II) complexes have
proven unstable to the harsh acidic (H2SO4/TFA) condi-
tions of demetalation,1 and we have needed to depend
upon X-ray diffraction analysis of the copper(II) com-
plexes to accurately characterize the products; however,
the chromium(III) reaction offers an attractive alterna-
tive because metal-free reaction intermediates and por-
phyrins are isolated, and proton NMR characterization
is therefore available.
To initiate this study, a,c-biladiene 21 was chosen as
the substrate for cyclization (due to the simplicity of its
proton NMR spectrum). Cyclization at 100 °C in DMF
for 60 min unexpectedly provided the metal-free 1-p-
tolylmethyl compound 31 as the only product, in 52%
yield.
Chromium(III)-promoted cyclization of a,c-biladiene 27
in DMF at 100 °C also yielded the 1-substituted com-
pound as the major product. Although decomposition
was evident, with several trace decomposition products
Con clu sion s
a,c-Biladienes bearing 1- and/or 19-(p-tolylmethyl)
substituents can be cyclized using copper(II) oxidation
methodology to give numerous products in which the 1-
or 19-substituents are adapted, eliminated, or rearranged
to other points on the tetrapyrrole macrocycle. Copper-
(II)-assisted cyclization of a,c-biladiene 25 provided the
most impressive example of the overall phenomenon;
after cyclization to give a 1-p-tolylmethyl macrocycle,
stepwise migration of the 1-substituent to adjacent
carbons gives the chlorins 44 and 45 and finally the 5-(p-
tolylmethyl)-substituted porphyrin 47. a,c-Biladienes 19
and 20 demonstrated product distribution upon copper-
(II)-promoted cyclization; for example, a,c-biladiene 20
afforded the copper(II) 1-(p-tolylmethyl)-20-p-tolyl mac-
rocycle 29, the copper(II) 2-methylidenechlorin 32, and
copper(II) porphyrins 34 and 38.
19-((Methoxycarbonyl)ethyl)-1-(p-tolylmethyl)-a,c-bila-
diene 27 afforded four products upon copper(II)-promoted
(16) Gerzevske, K. R.; Lin, J . J .; Smith, K. M. Heterocycles 1994,
37, 207.

4272 J . Org. Chem., Vol. 62, No. 13, 1997
Ta ble 3. Str u ctu r es of a ,c-Bila d ien es Stu d ied , w ith Rea ction Con d ition s a n d P r od u ctsa
Lin et al.
a,c-biladiene
reaction conditions
temp (°C) solvent
products
R20
compd
R1
R19
compd
R1
yield (%)
21
26
PX
PX
PX
Me
100
140
100
100
0
DMF
DMF
31
59
59
53
43
PX
Me
Me
PMe
PX
p-C6H4Me
p-C6H4Me
p-C6H4Me
p-C6H4Me
CO2Et
50
51
40
13
30
27
25
PX
PX
PMe
DMF
EtOH aq
AEE
a
PX ) CH2(C6H4)-p-Me; AEE ) CH2CO2Et; PMe ) CH2CH2CO2Me.
Dip yr r om eth a n e. ter t-Bu tyl 9-((Ben zyloxy)ca r bon yl)-
3,7-d ie t h yl-2,8-d im e t h yl-d ip yr r om e t h a n e -1-ca r b oxy-
late (15). tert-Butyl 5-(acetoxymethyl)-4-ethyl-3-methylpyrrole-
2-carboxylate7c (1.15 g, 4.09 mmol) and benzyl 4-ethyl-3-
methylpyrrole-2-carboxylate17 (1.96 g, 8.06 mmol) under N2
were stirred with dichloromethane (100 mL) and Montmorillite
K-10 clay (3.00 g) for 24 h at rt. The clay was then filtered
off and rinsed with dichloromethane (600 mL). Evaporation
gave a brownish oil which was flashed-chromatographed on
silica gel, eluting with dichloromethane, to give an oily residue
which solidified to afford 1.52 g (80% yield) of the title di-
pyrromethane: mp 58-60 °C; δ (CDCl3) 8.47, 8.34 (each br s,
1H), 7.38 (m, 5H), 5.27, 3.84 (each s, 2H), 2.40 (m, 4H), 2.29,
2.25 (each s, 3H), 1.53 (s, 9H), 1.05 (m, 6H). Anal. Calcd for
C28H36N2O4: C, 72.37; H, 7.81; N, 6.03. Found: C, 72.43; H,
7.70; N, 6.04.
Tr ip yr r en es. ter t-Bu tyl 1-(p-Tolylm eth yl)-2,3,7,8,12,-
13-h exa m eth yl-5-tr ip yr r en e-14-ca r boxyla te Hyd r obr o-
m id e (22). tert-Butyl 9-((benzyloxy)carbonyl)-2,3,7,8-tetra-
methyldipyrromethane-1-carboxylate (14)1 (6.0 g, 13.7 mmol)
in dry THF (100 mL) containing 10% Pd-C (500 mg) was
hydrogenated at rt and atmospheric pressure overnight. The
catalyst was filtered off through a bed of Celite which was
washed with distilled THF. The filtrate was evaporated to
give a white solid which was dried under high vacuum. The
dipyrromethanecarboxylic acid and formylpyrrole 7 (3.16 g,
15.12 mmol) were dissolved in distilled CH2Cl2 (200 mL).
Next, TsOH (5.75 g) in distilled MeOH (20 mL) was added over
a period of 15 min, and the mixture was stirred at rt for 45
min (solution turned from clear to a deep yellow orange). The
mixture was diluted with CH2Cl2 (200 mL) and washed with
aqueous saturated NaHCO3 (200 mL), and the organic phase
was dried over anhydrous sodium sulfate. The solvent was
immediately removed (at 30 °C) using a benzene chaser to
eliminate any residual water and MeOH. The residue was
placed under high vacuum for several hours before being
dissolved in dichloromethane (40 mL) and (after cooling to 0
°C) having a slow stream of HBr(g) pass through the solution
for 5 s (solution turned bright orange). The solvent was
removed immediately over low heat, and a benzene chaser was
added and removed. The residue was dissolved in dichlo-
romethane (130 mL) and MeOH (10 mL) before addition of
ether (200 mL). The solution was placed at -20 °C and then
at -40 °C before being filtered to give the title compound (4.85
g, 81% yield). Proton NMR integration indicated an ap-
proximate 10% loss of the tert-butyl protecting group; there-
fore, a portion was subjected to further HBr(g) treatment and
crystallized as the monocarboxylic acid for analysis: mp 192-
211 °C; λmax (CH2Cl2) 277 nm (ꢀ 28 500), 372 (14 000), 500
(88 700); δ (CDCl3) 13.32, 13.23, 10.42 (each br s, 1H), 7.27,
7.10 (d, J ) 8.0 Hz, 4H), 7.07 (s, 1H), 4.41 (s, 2H), 4.31 (s,
2H), 2.29, 2.23, 1.90 (each s, 3H), 2.21, 2.04 (each 6H, s), 1.55
(s, 9H). Anal. Calcd for C33H42BrN3O2: C, 66.68; H, 7.16; N,
7.11. Found: C, 66.68; H, 7.02; N, 6.97.
oxidation, and none of them showed any substituent
migration; the major products are macrocycles with the
p-tolylmethyl contributing a carbon atom to form the
bridge in 52 and in porphyrin 50. Thus, the p-tolyl-
methyl group showed more tendency to contribute its
methylene to become the macrocyclic bridging carbon
than did the propionic side chain. Similarly, 19-methyl-
1-(p-tolylmethyl)-a,c-biladiene 28 showed the same dis-
tribution of products as did a,c-biladiene 27, again
indicating that the p-tolylmethyl group is also more likely
than methyl to contribute the interpyrrolic carbon atom
in the cyclization process. The results of the earlier
copper(II)-promoted cyclization studies using only alkyl
groups1 and data from the present work complement the
chromium(III) cyclization results, which concluded that
the 1- or 19-substituent most likely to provide the
interpyrrolic (20-) carbon follows the order (ethoxycar-
bonyl)methyl > p-tolylmethy > methyl > (methoxycar-
bonyl)ethyl.16 Finally, metal-free 1-substituted macro-
cycles (e.g., 31, 43, 53, 59) can be prepared from oxidative
cyclization of a,c-biladienes using the Boschi chromium-
(III) procedure.
Exp er im en ta l Section
General details are as previously described.17 Mass spectra
were measured at the Mass Spectrometry Facility, University
of California, San Francisco.
P yr r ole. 2-F or m yl-3,4-d im eth yl-5-(p-tolylm eth yl)p yr -
r ole (7). Benzyl 3,4-dimethyl-5-(p-tolylmethyl)pyrrole-2-car-
boxylate18,19 (3.0 g, 0.90 mol) in THF (110 mL) containing 10%
Pd-C (229 mg) and triethylamine (2 drops) was hydrogenated
at rt overnight. The catalyst was filtered off through a bed of
Celite which was rinsed with a small amount of DMF and
THF, and the filtrate was evaporated to give an oil. After the
solution was cooled to 0 °C under N2, cold TFA (8.7 mL) was
added. After 10 min, triethyl orthoformate (8.7 mL) was
added, and the mixture was stirred for 0.5 h before being
diluted with CH2Cl2 and treated with 10% aqueous sodium
carbonate. The organic layer was washed with 10% aqueous
sodium carbonate and brine before being dried over anhydrous
sodium sulfate. The organic phase was filtered through an
anhydrous sodium sulfate plug and then evaporated. Crystal-
lization from CH2Cl2/n-hexane afforded 1.35 g (66% yield) of
the title pyrrole: mp 136-137 °C; δ (CDCl3) 9.45 (s, 1H), 8.65
(br s, 1H), 7.12, 7.04 (each d, J ) 7.8 Hz, 2H), 3.87 (s, 2H),
2.32, 2.25, 1.97 (each s, 3H). Anal. Calcd for C15H17NO: C,
79.25; H, 7.54; N, 6.17. Found: C, 78.92; H, 7.36; N, 6.11.
(17) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J .
Org. Chem. 1993, 58, 7245.
(18) Gerzevske, K. R. Ph.D. Dissertation, University of California,
Davis, 1994.
Ben zyl 2,3,7,8,12,13-Hexa m et h yl-1-(p-t olylm et h yl)-5-
tr ip yr r en e-14-ca r boxyla te Hyd r obr om id e (23). tert-Butyl
(19) Gribble, G. W.; Kelly, W. J .; Emery, S. E. Synthesis 1978, 763.

Metal-Catalyzed Oxidative Cyclizations of a,c-Biladiene Salts
J . Org. Chem., Vol. 62, No. 13, 1997 4273
9-((benzyloxy)carbonyl)-2,3,7,8-tetramethyldipyrromethane-1-
carboxylate1 (15) (769 mg, 1.76 mmol) was dissolved in cold
TFA (4.4 mL) and stirred under dry nitrogen in an ice bath
for 30 min before formylpyrrole 7 (444 mg, 1.95 mmol) in
MeOH (21 mL) was introduced. The solution was stirred for
an additional 1 h before a slow stream of HBr gas was passed
through the solution for 10 s, followed by addition of diethyl
ether to precipitate out the product. Isolation of the title
compound (792 mg, 72%) was achieved through suction filtra-
tion and washing the product with cold ether: mp 193-5 °C;
and the flask was placed at -20 °C overnight before the
product was filtered off, washed with cold ether, and dried to
give the title compound (365 mg, 76%): mp > 250 °C dec; λmax
(CH2Cl2) 456 nm (ꢀ 144 000), 532 (90 000); δ (CDCl3) 13.45,
13.31 (each br s, 2H), 7.32, 7.10 (each d, J ) 8.0 Hz, 2H), 7.11
(s, 2H), 5.21 (s, 2H), 4.41 (s, 4H), 2.29, 2.23, 2.22, 1.93, 1.92
(each s, 6H). Anal. Calcd for C43H50Br2N4: C, 65.99; H, 6.44;
N, 7.16. Found: C, 65.72; H, 6.40; N, 6.96.
1-((E t h oxyca r b on yl)m et h yl)-2,3,7,8,12,13,17,18-oct a -
m eth yl-19-(p-tolylm eth yl)-a ,c-bila d ien e Dih yd r obr om id e
(25). Tripyrrene 22 (3.20 g, 5.40 mmole) was dissolved in dry
TFA (30 mL) under N2 and stirred at rt for 5 min before being
cooled to 0 °C and then the addition of formylpyrrole 61 (1.36
g, 6.48 mmol) in EtOH (25 mL). After 3 min of stirring, HBr
gas was bubbled into the solution for 1 min, and stirring was
continued at rt for 4 h. The solvent was removed under
vacuum, and the residue was azeotropically distilled with a
portion of benzene (200 mL). The solid was redissolved in
dichloromethane (35 mL) and treated with diethyl ether (300
mL). The solid was collected and recrystallized again from
CH2Cl2 (30 mL) and MeOH (15 mL) and ether to afford the
title a,c-biladiene (3.30 g, 80%) after filtering, washing with
cold ether, and drying under vacuum: mp >195 °C dec; λmax
(CH2Cl2) 454 nm (ꢀ 116 000), 530 (82 000); δ (CDCl3) 13.47,
13.41, 13.30, 13.21 (each br s, 1H), 7.32, 7.09 (each d, J ) 7.8
Hz, 2H), 7.16 (each s, 1H), 5.20 (s, 2H), 4.41 (s, 2H), 4.23 (s,
2H), 4.20 (q, J ) 7.2 Hz, 2H), 2.30, 2.29, 2.10, 1.98, 1.93, 1.92,
1.90 (each s, 3H), 2.23 (s, 6H), 1.28 (t, J ) 7.2 Hz, 3H). Anal.
Calcd for C38H48Br2N4O2: C, 60.64; H, 6.43; N, 7.44. Found:
C, 60.41; H, 6.12; N, 7.55.
19-((Met h oxyca r b on yl)et h yl)-2,3,7,8,12,13,17,18-oct a -
m eth yl-1-(p-tolylm eth yl)-a ,c-bila d ien e Dih yd r obr om id e
(27). This compound was prepared similarly to a,c-biladiene
25 from benzyl 1-(p-tolylmethyl)-2,3,7,8,12,13-hexamethyl-5-
tripyrrene-14-carboxylate hydrobromide (23) (370 mg, 0.590
mmol); the tripyrrene was first treated with 30% HBr/CH3-
CO2H (5 mL) for 1 h at 0 °C and then with TFA (10 mL) for 1
h. The mixture was stirred at rt for an additional 1 h, before
being cooled in an ice bath and then addition of formylpyrrole1
9 (200 mg, 0.956 mmol) in MeOH (12 mL). The product (378
mg, 84%) was obtained after filtering, washing with cold ether,
and drying under vacuum, mp > 200 °C dec; λmax (CH2Cl2) 454
nm (ꢀ 122 000), 530 (84 000); δ (CDCl3) 13.46, 13.41, 13.32,
13.07 (each br s, 1H), 7.32, 7.10 (each d, J ) 7.8 Hz, 2H), 7.12,
7.11 (each s, 1H), 5.20 (s, 2H), 4.42 (s, 2H), 3.67 (s, 3H), 3.28
(t, J ) 7.3 Hz, 2H), 3.00 (t, J ) 7.3 Hz, 2H), 2.29, 2.28, 2.23,
2.22, 2.21, 2.05, 1.90 (each s, 3H), 1.91 (s, 6H). Anal. Calcd
for C38H48Br2N4O2: C, 60.64; H, 6.43; N, 7.44. Found: C,
60.80; H, 6.33; N, 7.52.
8,12-Diet h yl-1,2,3,7,13,17,18-h ep t a m et h yl-19-(p -t olyl-
m eth yl)-a ,c-bila d ien e Dih yd r obr om id e (28). Under N2,
tripyrrene 24 (0.396 g, 0.607 mmol) was dissolved in 30% HBr/
acetic acid (5 mL) and stirred at 0 °C for 1 h. TFA (10 mL)
was added, and the solution was stirred for another 1 h at 0
°C. The solution was then stirred at rt for an additional 1 h
while being warmed up to rt. Finally the solution was cooled
again (0 °C), formylpyrrole 84 (0.110 g, 0.803 mmol) in MeOH
(13 mL) was added, and the mixture was stirred for 90 min
before being treated for 10 s with a stream of HBr gas.
Precipitation with ether gave the title compound (338 mg; 85%)
after filtering, washing with cold ether, and drying, mp > 210
°C dec; λmax (CH2Cl2) 454 nm (ꢀ, 115 000), 530 (91 000); δ
(CDCl3) 13.43, 13.36 13.22 13.19 (each br s, 1H), 7.32, 7.11
(each d, J ) 7.5 Hz, 2H), 7.10, 7.08 (each s, 1H), 5.20 (s, 2H),
4.42(s, 2H), 2.68 (s, 3H), 2.28, 2.29 (each s, 3H each), 2.23 (s,
9H), 2.56 (m, 4H), 2.00 (s, 3H), 1.93 (s, 3H), 0.646 (m, 6H).
Anal. Calcd for C38H48Br2N4‚1.5H2O: C, 61.19; H, 6.90; N,
7.52. Found: C, 61.12; H, 6.43; N, 7.35.
2,3,7,8,12,13,17,18,19-Non a m eth yl-1-(p-tolylm eth yl)-a ,c-
bila d ien e Dih yd r obr om id e (26). This compound was pre-
pared using a method similar to that used for a,c-biladiene
28 from benzyl 2,3,7,8,12,13-hexamethyl-1-(p-tolylmethyl)-5-
tripyrrene-14-carboxylate hydrobromide (23) (248 mg, 0.396
mmol) in 30% HBr/HOAc (7 mL) with TFA (8 mL) and
2-formyl-3,4,5-trimethylpyrrole (8) (62 mg, 0.452 mmol) in
MeOH (12 mL). The title a,c-biladiene (208 mg, 76% yield)
26 was filtered off, washed with cold ether, and dried under
λ
max (CH2Cl2) 280 nm (ꢀ, 28 800), 376 (12 900), 500 (91 600); δ
(CDCl3) 13.25, 13.18, 10.58 (each br s, 1H), 7.48, 7.08 (each d,
J ) 7.5 Hz, 2H), 7.32 (m, 5H), 7.07 (s, 1H), 5.29, 4.38, 4.33-
(each s, 2H), 2.21 (s, 6H), 2.28, 2.24, 2.03, 2.00, 1.91 (each s,
3H). Anal. Calcd for C36H40BrN3O2: C, 69.09; H, 6.45; N, 6.72.
Found: C, 68.86; H, 6.36; N, 6.71.
Ben zyl 8,12-Diet h yl-2,3,7,13-t et r a m et h yl-1-(p -t olyl-
m eth yl)-5-tr ip yr r en e-14-ca r boxyla te Hyd r obr om id e (24).
tert-Butyl 9-((benzyloxy)carbonyl)-3,7-diethyl-2,8-dimethyl-
dipyrromethane-1-carboxylate (14) (498 mg, 1.07 mmol) was
dissolved in cold TFA (3.4 mL) and stirred under nitrogen and
in an ice bath for 20 min before formylpyrrole 7 (279 mg, 1.22
mmole) in MeOH (14 mL) was added. The mixture was stirred
for an additional 1 h before being treated with a slow stream
of HBr gas for 10 s, followed by precipitation with cold ether
to give 483 mg (69%) of the title compound: mp 200-205 °C;
λ
max (CH2Cl2) 500 nm (ꢀ, 100 000); δ (CDCl3) 13.26, 13.23, 10.53
(each br s, 1H), 7.48, 7.06 (each d, J ) 8.1 Hz, 2H), 7.31 (m,
5H), 7.22 (s, 1H), 5.30 (s, 2H), 4.39, 4.33 (each s, 2H), 2.33,
2.49 (each q, J ) 7.5 Hz, 2H), 2.28, 2.21, 2.17, 2.02 (each s,
3H), 1.91 (s, 3H), 1.14, 1.03 (each t, J ) 7.5 Hz, 3H). Anal.
Calcd for C38H44BrN3O2‚H2O: C, 68.85; H, 6.85; N, 6.34.
Found: C, 69.06; H, 6.59; N, 6.24.
a ,c-Bila d ien e Sa lt s. 8,12-Diet h yl-2,3,7,13,17,18-h exa -
m et h yl-1,19-b is(p -t olylm et h yl)-a ,c-b ila d ien e Dih yd r o-
br om id e (20). 3,7-Diethyl-2,8-dimethyldipyrromethane-1,9-
dicarboxylic acid7b (17) (500 mg, 1.00 mmol) in THF (30 mL)
was hydrogenated over 10% Pd-C (70 mg). After uptake of
hydrogen ceased, the catalyst was filtered off through a bed
of Celite, and the filtrate was concentrated (at 40 °C) under
vacuum. The resulting white solid (31) was dissolved in TFA
(6 mL) and stirred at rt for 15 min before being cooled to 0 °C
followed by rapid addition of formylpyrrole 7 (620 mg, 2.7
mmol) over a 3 min period. After the solution was stirred for
1 h, a slow stream of HBr gas was passed for 10 s through the
solution; then ether (100 mL) was added dropwise to initiate
precipitation. The flask was placed at -20 °C for 4 h before
the product was filtered, washed with cold ether, and dried
(683 mg, 84%): mp > 300 °C; λmax (CH2Cl2) 456 nm (ꢀ 136 000),
534 (103 000); δ (CDCl3) 13.44, 13.37 (each br s, 2H), 7.33, 7.10
(each d, J ) 7.8 Hz, 2H), 7.12 (s, 2H), 5.24 (s, 2H), 4.42 (s,
4H), 2.57 (q, J ) 7.2 Hz, 4H), 2.29 (s, 6H), 2.24 (s, 12H), 1.93
(s, 6H), 0.67 (t, J ) 7.5 Hz, 3H); HRMS calcd for [C45H54BrN4]+
729.353, found 729.354. Anal. Calcd for C45H54Br2N4: C,
66.81 ; H, 6.73; N, 6.91. Found: C, 66.87; H, 6.73; N, 6.91.
8,12-Bis((m eth oxyca r bon yl)m eth yl)-2,3,7,13,17,18-h ex-
a m eth yl-1,19-bis(p-tolylm eth yl)-a ,c-bila d ien e Dih yd r o-
br om id e (19). The title a,c-biladiene was prepared in 84%
yield from 3,7-bis((methoxycarbonyl)methyl)-2,8-dimethyl-
dipyrromethane-1,9-dicarboxylic acid7b (16) (2.28 g, 4.57 mol)
in THF (100 mL) with 10% Pd-C (400 mg) and treatment with
TFA (20 mL) and formylpyrrole 7 (2.20 mg, 9.68 mmol) in
MeOH (30 mL), followed by HBr gas and ether (250 mL)
precipitation, to give (3.75 g): mp >290 °C dec; λmax (CH2Cl2)
452 nm (ꢀ 90 000), 528 (131 000); δ (CDCl3) 13.56, 13.50 (each
br s, 2H), 7.34, 7.11 (each d, J ) 8.0 Hz, 2H), 7.15 (s, 2H),
5.26 (s, 2H), 4.45(s, 4H), 3.80 (s, 4H), 3.30 (s, 6H), 2.30, 2.27,
2.24, 1.93 (each s, 6H). Anal. Calcd for C47H54Br2N4O4‚H2O:
C, 62.30; H, 6.12; N, 6.19. Found: C, 62.01; H, 5.88; N, 6.09.
2,3,7,8,12,13,17,18-Octa m eth yl-1,19-bis(p-tolylm eth yl)-
a ,c-bila d ien e Dih yd r obr om id e (21). 2,3,7,8-Tetramethyl-
dipyrromethane-1,9-dicarboxylic acid3 (18) (178 mg, 0.613
mmol) was dissolved in TFA (2.4 mL) and stirred at rt for 5
min before rapid addition of formylpyrrole 7 (350 mg, 1.53
mmol) in MeOH (4 mL). Stirring was continued for a further
1 h before HBr gas was bubbled into the solution for 10 s.
Ether (50 mL) was added dropwise to initiate precipitation,

4274 J . Org. Chem., Vol. 62, No. 13, 1997
Lin et al.
vacuum, mp > 185 °C dec; λmax (CH2Cl2) 452 nm (ꢀ, 139 000),
530 (71 800); δ (CDCl3) 13.41, 13.28, 13.22, 13.11 (each br s,
1H), 7.32, 7.10 (each d, J ) 7.8Hz, 2H), 7.11, 7.09 (each s, 1H),
5.17 (s, 2H), 4.22 (s, 2H), 2.67, 2.29, 2.28, 2.23, 1.99, 1.93 (each
s, 3H), 2.22, 1.92 (each s, 6H). Anal. Calcd for C36H44Br2N4‚
0.5H2O: C, 61.95; H, 6.45; N, 8.20. Found: C, 61.63; H, 6.47;
N, 7.99.
(41 700)], and the most polar band gave 12 mg of copper(II)
20-(eth oxyca r bon yl)-2,3,7,8,12,13,17,18-octa m eth yl-5-(p-
tolylmethyl)porphyrin (47) [mp 240-242 °C dec; λmax (CH2Cl2)
408 nm (ꢀ, 221 500), 538 (15 500), 572 (16 300); LRMS calcd
for [C39H40CuN4O2]+ 659.2, found 659.2. Anal. Calcd for
C39H40CuN4O2‚0.5H2O: C, 70.33; H, 6.18; N, 8.38. Found: C,
70.19; H, 6.01; N, 8.34]. Using the standard demetalation
protocol, 10 mg of 47 was used to obtain 6 mg of the metal-
free product, 20-(ethoxycarbonyl)-2,3,7,8,12,13,17,18-octa-
methyl-5-(p-tolylmethyl)-porphyrin (48) [mp > 217 °C dec; λmax
(CH2Cl2) 408 nm (ꢀ, 158 900), 508 (16 200), 540 (12 000), 582
(11 800), 630 (8200); δ (CDCl3) 9.80, 9.74 (each s, 1H), 6.97,
6.94 (each d, J ) 8.4 Hz, 2H), 6.19 (s, 2H), 5.00 (m, 2H), 3.46
(s, 6H), 3.45, 3.38, 3.26, 3.16, 3.11, 3.08 (each s, 3H), 2.27 (s,
3H), 1.67 (t, J ) 7.2 Hz, 3H), -3.15 (br s, 2H). Anal. Calcd
for C39H42N4O2Cu‚2/3H2O: C, 76.68; H, 7.16; N, 9.18. Found:
C, 76.38; H, 6.79; N, 9.22.
Copper (II)-P r om oted Oxidative Cyclization s. Cycliza-
tion of 1-((Eth oxyca r bon yl)m eth yl)-2,3,7,8,12,13,17,18-
octa m eth yl-19-(p-tolylm eth yl)-a ,c-bila d ien e Dih yd r obr o-
m id e (25). Copper(II) acetate (3.10 g, 0.017 mol) was added
to DMF (40 mL) under N2. The mixture was heated at 120
°C for 5 min before the a,c-biladiene 25 (0.765 g, 1.00 mmol)
was added all at once and stirred an additional 3 min before
cooling. The mixture was diluted with a biphasic mixture of
iced water and dichloromethane. After the two layers were
separated, the aqueous layer was washed with more dichlo-
romethane (2 × 100 mL). The combined organic layer was
washed with brine (100 mL) and dried over anhydrous sodium
sulfate before being filtered and concentrated. Residual DMF
was removed under high vacuum. The reaction was repeated
under the same conditions with identical amounts of reactants,
and the crude mixtures were combined for separation. To
remove the base-line impurities, a flash silica gel column,
eluting with 10% cyclohexane and 0.05% MeOH in dichlo-
romethane, afforded the mixture of products. Further flash
silica gel chromatography, eluting with a solvent gradient from
33% cyclohexane in toluene to pure toluene, afforded 84 mg
of the least polar porphyrin copper(II) 2,3,7,8,12,13,17,18-
octamethyl-20-(p-tolylmethyl)porphyrin (50) [mp 292-295 °C
dec; λmax (CH2Cl2) 330 nm (ꢀ 19 200), 402 (207 000), 528
(16 600), 564 (20 400); LRMS calcd for [C35H34CuN4]+ 573.207,
found 573.6. Anal. Calcd for C35H34CuN4‚0.5H2O: C, 72.14;
H, 6.06; N, 9.62. Found: C, 72.59; H, 6.10; N, 9.62], a mixture
of chlorins and porphyrins, and 436 mg of copper(II) 20-
(ethoxycarbonyl)-2,3,7,8,12,13,17,18-octamethyl-1-(p-tolylmethyl)-
1,20-dihydroporphyrin (42) [mp 242-245 °C dec to porphyrin;
Cycliza tion of 19-((Meth oxyca r bon yl)eth yl)-2,3,7,8,12,-
13,17,18-octa m eth yl-1-(p-tolylm eth yl)-a ,c-bila d ien e Di-
h yd r obr om id e (27). This reaction was repeated three times
(with identical quantities of reactants and solvents) to obtain
sufficient quantities of material. It was performed as for a,c-
biladiene 25, using the a,c-biladiene 27 (0.765 g, 1.00 mmol)
and copper(II) acetate (3.10 g, 17.0 mmol) in DMF (40 mL) at
120 °C for 3 min. The combined residue of the three reactions
was purified by flash silica gel chromatography, eluting with
1-10% ethyl acetate in cyclohexane. The least polar band was
21 mg of copper(II) 20-p-tolylporphyrin 50 [LRMS calcd for
[C35H34CuN4]+ 573.208, found 573.6]. The second band iso-
lated was 84 mg of copper(II) 2,3,7,8,12,13,17,18-octamethyl-
20-((methoxycarbonyl)methyl)-1-(p-tolylmethyl)-1,20-dihydro-
porphyrin (54) [mp 224-225 °C; λmax (CH2Cl2) 420 nm (ꢀ,
34 300), 750 (8100), 828 (13 900); LRMS calcd for [C39H43
-
CuN4O2]+ 661.3, found 661.3], the isomer of copper(II) 1-(2-
(methoxycarbonyl)ethyl)-2,3,7,8,12,13,17,18-octamethyl-20-p-
tolyl-1,20-dihydroporphyrin (52) which was obtained in 41%
yield (819 mg) [mp 235-238 °C dec to porphyrin; λmax (CH2-
Cl2) 322 nm (ꢀ 24 100), 421 (42 400), 753 (8600), 832 (16 500);
LRMS calcd for [C47H46CuN4O4]+ 661.260, found 661.2 (see
Figure 2)]. The most polar compound isolated was a trace
of copper(II) 2,3,7,8,12,13,17,18-octamethyl-5-(2-(methoxy-
carbonyl)ethyl)porphyrin (55) [mp > 300 °C; λmax (CH2Cl2) 399
nm (ꢀ 165 800), 524 (14 600), 560 (23 800). Anal. Calcd for
C31H32CuN4O2: C, 67.01; H, 5.81; N, 10.09. Found: C, 67.30;
H, 5.57; N, 10.48]. A small amount of porphyrin 55 was taken
through standard TFA/H2SO4 demetalation protocols, but
yielded a mixture of porphyrins. One of these porphyrins was
identified as 2,3,7,8,12,13,17,18-octamethyl-20-((methoxycar-
λmax (CH2Cl2) 321 nm (ꢀ 23 700), 416 (45 200), 764 (8500), 837
(14 100). Anal. Calcd for C39H41CuN4O2: C, 70.83; H, 6.25,
N, 8.47; Found: C, 70.63; H, 6.39; N, 8.33]. Finally, 40 mg of
the most polar compound copper(II) 2,3,7,8,12,13,17,18-octa-
methyl-20-(ethoxycarbonyl)porphyrin (3) was obtained [mp >
300 °C; λmax (CH2Cl2) 332 nm (ꢀ, 15 500), 399 (154 400), 526
(100 200), 564 (14 300). Anal. Calcd for C31H32N4O2Cu‚
H2O‚CH3OH: C, 63.45; H, 6.33; N, 9.25. Found: C, 63.40; H,
5.95; N, 8.95]. Removal of the copper from 50 was ac-
complished using the standard method of H2SO4/TFA, to yield
the metal-free porphyrin 2,3,7,8,12,13,17,18-octamethyl-20-p-
tolylporphyrin (51) [mp > 300 °C; λmax (CH2Cl2) 400 nm (ꢀ
175 000), 501 (22 000), 534 (14 500), 570 (13 400), 622 (9700);
δ (CDCl3) 10.11 (s, 2H), 9.88 (s, 1H), 7.91, 7.54 (each d, J )
7.8 Hz, 2H), 3.59, 3.56, 3.52 (each s, 3H), 2.73 (s, 3H), 2.47 (s,
6H), -3.20 (br s, 2H); LRMS calcd for [C35H36N4]+ 512.294,
found 512.5. Anal. Calcd for C35H36N4: C, 81.98 H, 7.08; N,
10.93. Found: C, 81.69; H, 6.94; N, 10.99]. Removal of copper
(H2SO4/TFA) from a small amount of porphyrin 3 gave 2,3,7,8,-
12,13,17,18-octamethyl-20-(ethoxycarbonyl)porphyrin (46) [mp
> 300 °C; λmax (CH2Cl2) 398 nm (ꢀ, 106 100), 500 (15 000), 532
(12 400), 568 (10 300), 622 (9700); δ (CDCl3) 10.36 (s, 2H),
10.29 (s, 1H), 5.04 (q, J ) 7.2 Hz, 2H), 3.51 (s, 12H), 3.41,
3.16 (each s, 6H), 1.76 (t, J ) 7.2 Hz, 3H), -1.80 (br s, 2H).
Anal. Calcd for C31H34N4O2‚H2O: C, 72.62, H, 7.08, N, 10.93.
Found: C, 72.88, H, 6.86, N, 10.88]. Further separation of
the mixed porphyrin/chlorin band (above) was accomplished
by flash silica gel chromatography, eluting first with a solvent
gradient (33% CH2Cl2 in cyclohexane to 33% cyclohexane in
CH2Cl2) and then using a second column eluting with 2% ethyl
acetate in cyclohexane. The least polar band gave 6 mg of the
copper(II) 3-methylidenechlorin copper(II) 20-(ethoxycarbonyl)-
2,7,8,12,13,17,18-heptamethyl-3-methylidene-2-(p-tolylmethyl)-
chlorin (44) [mp 224-226 °C; λmax (CH2Cl2) 310 nm (ꢀ, 17 100),
410 (133 400), 514 (9400), 552 (12 400), 582 (10 800), 628
(38 400)], the band of medium polarity gave 12 mg of the
copper(II) 2-methylidenechlorin copper(II) 20-(ethoxycarbonyl)-
2,7,8,,12,13,17,18-heptamethyl-2-methylidene-3-(p-tolylmethyl)-
chlorin (45) [mp 216-8 °C; λmax (CH2Cl2) 310 nm (ꢀ, 19 000),
406 (146 700), 508 (9000), 548 (12 000), 582 (12 400), 626
bonyl)methyl)porphyrin (56) using MS [HRMS calcd for [C31H34
-
CuN4O2]+ 494.2682, found 494.2674]. Because of the low
solubilities of the porphyrins in the mixture, further analysis
was not pursued.
Cycliza t ion of 8,12-Bis((m et h oxyca r b on yl)m et h yl)-
2,3,7,13,17,18-h exa m eth yl-1,19-bis(p-tolylm eth yl)-a ,c-bi-
la d ien e Dih yd r obr om id e (19). The reaction was performed
as for a,c-biladiene 27, using a,c-biladiene 19 (450 mg; 0.50
mmol) and copper(II) acetate (1.56 g, 8.60 mmol) in DMF (30
mL) at 120 °C for 3 min. The products were separated by flash
silica gel chromatography, eluting with 20-30% ethyl acetate
in cyclohexane. Two products were isolated. The least polar
compound isolated was 285 mg of copper(II) 8,12-bis((methoxy-
carbonyl)methyl)-2,3,7,13,16,17-hexamethyl-1-(p-tolylmethyl)-
20-(p-tolyl)-1,20-dihydroporphyrin (30) [mp 190-198 °C dec
to porphyrin; λmax (CH2Cl2) 325 nm (ꢀ 26 800), 419 (50 000),
749 (9500), 825 (17 100); HRMS calcd for [C47H49CuN4O4]+
796.305, found 796.308. Anal. Calcd for C47H48CuN4O4: C,
70.88; H, 6.07; N, 7.03. Found: C, 71.03; H, 6.13; N, 6.99].
The most polar compound isolated was 14 mg of copper(II)
8,12-bis((methoxycarbonyl)methyl)-2,3,7,13,16,17-hexamethyl-
20-(p-tolyl)porphyrin (36) [mp 296 °C dec; λmax (CH2Cl2) 402
nm (ꢀ 341 000), 528 (25 700), 564 (28 000); HRMS calcd for
[C39H38CuN4O4]+ 689.219, found 689.222. Anal. Calcd for
C39H38CuN4O4‚2/3H2O: C, 66.74; H, 5.65; N, 7.99. Found: C,
66.76; H, 5.65; N, 7.85]. The whole sample of porphyrin was
demetalated using standard acidic conditions, affording 10 mg
of 8,12-bis((methoxycarbonyl)methyl)-2,3,7,13,16,17-hexamethyl-
20-p-tolylporphyrin (37) [mp 297 °C dec; λmax (CH2Cl2) 404 nm

Metal-Catalyzed Oxidative Cyclizations of a,c-Biladiene Salts
J . Org. Chem., Vol. 62, No. 13, 1997 4275
(ꢀ, 199 000), 502 (26 000), 536 (18 000), 572 (17 800), 624
(13 200); δ (CDCl3) 10.15 (s, 2H), 10.00 (s, 1H), 7.90, 7.54
(each d, J ) 7.8 Hz, 2H), 5.04 (s, 2H), 3.79, 3.65, 3.51, 2.47
(each s, 6H), 2.73 (s, 3H), -3.22 (br s, 2H). Anal. Calcd for
N2 for 15 min. The solution was then poured into a biphasic
mixture of ether and ice-water. The organic products were
extracted with diethyl ether (4 × 50 mL), and the combined
organic layers were washed with deionized water and then
brine (100 mL), dried over anhydrous sodium sulfate, and
evaporated to dryness. The residue was chromatographed on
a column of Brockmann Grade II alumina (elution with 1:1
petroleum ether/CH2Cl2). The least polar band contained the
copper(II) 5,20-disubstituted porphyrin 38, followed by the
copper(II) 2-methylidenechlorin 32, and finally the 20-p-
tolylporphyrin 34. At 140 °C: compound 29 (110 mg, 0.155
mmol) yielded 3.4 mg of porphyrin 38, 1.4 mg of chlorin 32,
and 30.4 mg of porphyrin 34. At 120 °C: compound 29 (123
mg, 0.173 mmol) afforded 6.0 mg of 38, 14.0 mg of chlorin 32,
and 22.0 mg of 20-p-tolylporphyrin 34.
Rea r r a n gem en t Stu d ies Usin g Cop p er (II) 8,12-Di-
eth yl-3,7,13,17,18-p en ta m eth yl-2-m eth ylid en e-20-p-tolyl-
3-(p-tolylm eth yl)ch lor in (32). The copper(II) chlorin 32
(13.0 mg) was combined with 10 mL of o-dichlorobenzene
under dry N2 and then heated at 140 °C for 2 h. The solvent
was evaporated, and the residue was chromatographed on a
Brockmann Grade II alumina column (elution with 1:1 petro-
leum ether/CH2Cl2). The least polar compound was identified
as porphyrin 38 (8 mg, 78%), and this was followed by the
starting material 32 (2.8 mg). Finally, the 20-p-tolylporphyrin
34 (1.3 mg) was collected.
C
39H40N4O4‚H2O: C, 73.43; H, 6.48; N, 8.79. Found: C, 73.25;
H, 6.37; N, 8.70]. The reaction was repeated at 145 °C giving
a different distribution of products: after a similar workup
as in the previous reaction, the products were separated by
flash silica gel chromatography, eluting with 60:10:30 mixture
of cyclohexane:ethyl acetate:CH2Cl2. Three products were
isolated, and the least polar was 184 mg of compound 30. The
product from the band of medium polarity was 10 mg of
copper(II)
8,12-bis((methoxycarbonyl)methyl)-3,7,13,17,18-
pentamethyl-2-methylidene-3-(p-tolylmethyl)-20-p-tolylchlo-
rin (33) [mp 118-120 °C; λmax (CH2Cl2) 414 nm (ꢀ, 186 500),
516 (5700), 554 (7300), 582 (7800), 628 (33 500); LRMS calcd
for [C47H46CuN4O4]+ 793.282, found 793.6. Anal. Calcd for
C
47H46CuN4O4‚H2O: C, 69.52; H, 5.96; N, 6.90. Found: C,
69.41; H, 5.98; N, 6.99].
Cycliza tion of 8,12-Dieth yl-2,3,7,13,17,18-h exa m eth yl-
1,19-bis(p-tolylm eth yl)-a ,c-biladien e Dih ydr obr om ide (20).
This reaction was performed as for a,c-biladiene 27, using the
a,c-biladiene 20 (0.618 g, 0.762 mmol) and copper(II) acetate
(4.59 g, 25.4 mmol) in DMF (35 mL) at 120 °C for 6 min. The
products were separated by chromatography on Brockmann
Grade II alumina (eluting with 1:1 petroleum ether/CH2Cl2).
Four fractions were separated and products were isolated.
Fraction 1 contained 18 mg of copper(II) 8,12-diethyl-2,3,7,-
13,17,18-hexamethyl-20-p-tolyl-1-(p-tolylmethyl)-1,20-dihydro-
porphyrin (29) [mp 210-212 °C; λmax (CH2Cl2) 416 nm (ꢀ
28 200), 750 (5800), 812 (10 000). Anal. Calcd for C45H48CuN4‚
0.5H2O: C, 75.33; H, 6.88; N, 7.81. Found: C, 75.43; H, 6.76;
N, 7.92]. Fraction 2 contained 17 mg of copper(II) 8,12-diethyl-
2,3,7,13,17,18-hexamethyl-20-p-tolyl-5-(p-tolylmethyl)porphy-
rin (38) [mp 226-227 °C; λmax (CH2Cl2) 412 nm (ꢀ 250 300),
540 (25 500), 571 (22 000); LRMS calcd for C45H46CuN4
705.3018, found 705.3. Anal. Calcd for C45H46CuN4‚0.5H2O:
C, 71.95; H, 6.85; N, 7.25. Found: C, 71.97; H, 6.85; N, 7.47].
A small portion of 38 was demetalated in acid for proton NMR
confirmation of the metal-free porphyrin 8,12-diethyl-2,3,7,-
13,17,18-hexamethyl-20-p-tolyl-5-(p-tolylmethyl)porphyrin (39)
[mp 140-142 °C dec to porphyrin 35; λmax (CH2Cl2) 418 nm (ꢀ
129 400), 516 (16 900), 554 (12 400), 590 (13 000), 644 (9900);
δ (CDCl3) 9.67, 9.64 (each s, 1H), 7.95, 7.54 (each d, J ) 7.2
Hz, 2H), 6.95, 6.93 (each d, J ) 8.1 Hz, 2H), 6.30 (s, 2H), 3.91
(m, 4H), 3.48, 3.33, 3.16, 2.94, 2.70, 2.03 (each s, 3H), 2.27,
2.26 (each s, 3H), 1.18, 1.65 (each t, J ) 7.5 Hz, 3H), -2.66 (s,
2H). Porphyrin 39 was found to decompose when heated to
give porphyrin 34; thus, this compound could not be subjected
to normal thermal preparation prior to elemental analysis.
HRMS: calcd for C45H48N4 644.3879, found 644.3901]. Frac-
tion 3 provided 10 mg of copper(II) 8,12-diethyl-3,7,13,-
17,18-pentamethyl-2-methylidene-20-p-tolyl-3-(p-tolylmeth-
yl)chlorin (32) [mp 223-225 °C; λmax (CH2Cl2) 412 nm (ꢀ
185 700), 513 (23 300), 552 (24 000), 630 (55 100). Anal. Calcd
for C45H46CuN4‚0.5H2O: C, 75.60; H, 6.63; N, 7.84. Found:
C, 75.46; H, 6.56; N, 7.63]. Fraction 4 contained 193 mg of
copper(II) 8,12-diethyl-2,3,7,13,17,18-hexamethyl-20-p-tolylpor-
phyrin (34) [mp >296 °C dec; λmax (CH2Cl2) 400 nm (ꢀ 276 500),
526 (19 700), 562 (23 800). Anal. Calcd for C37H40CuN4: C,
73.85; H, 6.37; N, 9.32. Found: C, 73.85; H, 6.62; N, 9.19].
For proton NMR characterization, a small portion of 34 was
demetalated in acid to give 8,12-diethyl-2,3,7,13,17,18-hexa-
methyl-20-p-tolylporphyrin (35) [mp > 300 °C; λmax (CH2Cl2)
402 nm (ꢀ 123 400), 501 (16 300), 531 (14 000), 568 (14 200); δ
(CDCl3) 10.16 (s, 2H), 9.95 (s, 1H), 7.91, 7.54 (each d, J ) 7.8
Hz, 2H), 4.08 (q, J ) 7.5 Hz, 4H), 3.64, 3.53, 2.48 (each s, 6H),
2.73 (s, 3H), 1.89 (t, J ) 7.5 Hz, 6H), -3.17, -3.30 (each s,
1H); LRMS calcd for [C37H40N4]+ 540.3, found 540.0. Anal.
Calcd for C37H40N4: C, 82.17; H, 7.46; N, 10.37. Found: C,
81.91; H, 7.54; N, 10.47].
Cyclization of 8,12-Dieth yl-1,2,3,7,13,17,18-h eptam eth yl-
19-(p-tolylm eth yl)-a ,c-bila d ien e Dih yd r obr om id e (28). At
100 °C: the a,c-biladiene 28 (338 mg, 0.469 mmol) and copper-
(II) acetate (3.24 g, 16.2 mmol) in DMF (35 mL) were heated
for 5 min. After the usual workup the crude product was
chromatographed on a Brockmann Grade II alumina column
(elution with 1:1 petroleum ether/CH2Cl2). Three fractions
were isolated: the first fraction yielded 53 mg of copper(II)
8,12-diethyl-2,3,7,13,17,18-hexamethyl-1-(p-tolylmethyl)-1,20-
dihydroporphyrin (58) (see Figure 5) [mp 241-242 °C dec; λmax
(CH2Cl2) 416 nm (ꢀ 47 600), 742 (11 700), 820 (18 800); LRMS
calcd for [C38H42CuN4]+ 617.27, found 617.3]. The second
fraction contained 133 mg of copper(II) 8,12-diethyl-2,3,7,13,-
17,18-octamethyl-20-p-tolylporphyrin (34). The most polar
fraction provided 29 mg of copper(II) 3,7-diethyl-2,8,12,13,17,-
18-hexamethylporphyrin (60) [mp dec > 280 °C; λmax (CH2Cl2)
397 nm (ꢀ 336 500), 524 (32 600), 560 (41 700). Anal. Calcd
for C30H32CuN4‚0.5H2O: C, 69.20; H, 6.39; N, 10.77. Found:
C, 68.98; H, 6.40; N, 10.54]. A small quantity of compound
60 was demetalated for proton NMR analysis, to give 8,12-
diethyl-2,3,7,13,17,18-hexamethylporphyrin (61) [mp > 300 °C;
λmax (CH2Cl2) 397 nm (ꢀ 88 400), 496 (10 200), 530 (8800), 566
(7400), 620 (6200), δ (CDCl3) 10.52 (s, 4H), 4.04 (q, J ) 7.2
Hz, 4H), 3.06 (s, 18H), 1.96 (t, J ) 7.2 Hz, 6H), -2.70 (br s,
1H); HRMS calcd for [C30H34N4]+ 450.2783, found 450.2783.
Anal. Calcd for C30H34N4‚0.5H2O: C, 78.38; H, 7.68; N, 12.20.
Found: C, 78.61; H, 7.43; N, 12.22]. At 20 °C: a,c-biladiene
28 (78.3 mg, 0.109 mmol) and copper(II) acetate (1.00 g, 5.01
mmol) in DMF (15 mL) were stirred under N2 for 20 h. After
chromatography, three major products were isolated. The first
fraction contained 58 (< 1 mg), the second fraction provided
copper(II) porphyrin 34 (5.8 mg), and the most polar band
provided copper(II) porphyrin 60 (1 mg).
Ch r om iu m (III)-P r om oted Oxid a tive Cycliza tion s. Cy-
cliza t ion of 2,3,7,8,12,13,17,18-Oct a m et h yl-1,19-b is(p -
tolylm eth yl)-a ,c-bila d ien e Dih yd r obr om id e (21). Dry
DMF (50 mL) and triethylamine (0.5 mL) were heated at 100
°C under nitrogen for 5 min before a,c-biladiene dihydrobro-
mide 21 (48.6 mg, 0.0621 mmol) and Cr3(OAc)7(OH)2 (55.8 mg,
0.0925 mmol) were added simultaneously. The reaction was
protected from light during the 3 h reaction time. After
cooling, the mixture was diluted with CH2Cl2 (100 mL) and
water (100 mL) before being separated and extracted with
CH2Cl2. The combined organic layer was evaporated, and the
residue was diluted with ether (100 mL) and washed with
water (4 × 100 mL) and then brine (100 mL) to drive off
remaining DMF. After drying over anhydrous sodium sulfate
and filtering, the solution was concentrated. Alumina chro-
matography (Brockmann Grade III; elution with 1:1 CH2Cl2
and petroleum ether) afforded (20 mg, 52%) of 20-p-tolyl-
2,3,7,8,12,13,17,18-octamethyl-1-p-tolyl-1,20-dihydroporphy-
Rea r r a n gem en t Stu d ies Usin g Cop p er (II) 8,12-Di-
e t h yl-2,3,7,13,17,18-h e xa m e t h yl-20-p -t olyl-1-(p -t olyl-
m eth yl)-1,20-d ih yd r op or p h yr in (29). Apart from the dif-
ference in reaction temperatures (140 °C, 120 °C) conditions
were the same for each reaction; compound 29 and copper(II)
acetate (1.0 g, 5 mmol) in DMF (15 mL) were heated under

4276 J . Org. Chem., Vol. 62, No. 13, 1997
Lin et al.
rin (31), mp ∼180 °C dec to give compound with λmax 442
nm; λmax (CH2Cl2) 304 nm (ꢀ 19 000), 383 (48 000), 655 (7900),
711 (9700); δ (CDCl3) 14.35, 13.58 (each br s, 1 H), 7.54, 7.12,
6.96, 6.89 (each d, J )7.8 Hz, 2H), 6.28, 5.46, 4.67 (each s,
1H), 4.04, 2.99 (each d, J ) 13.2 Hz, 1H), 3.75 (each s, 1H),
2.23, 2.22, 2.03, 1.98, 1.72, 1.18 (each s, 3H), 1.96, 1.83 (each
s, 6H); HRMS calcd for [C43H46N4+] 618.3723, found 618.3710;
calcd for [C43H47N4]+ 619.3801, found 619.3830. Anal. Calcd
for C43H46N4‚H2O: C, 81.09; H, 7.60; N, 8.80. Found: C, 81.46;
H, 7.55; N, 8.82.
tolyl-1,20-dihydroporphyrin (53), mp ∼165 °C dec to porphyrin;
λ
max (CH2Cl2) 304 nm (ꢀ 20 700), 383 (50 300), 654 (8500), 716
(10 100); δ (CDCl3) 14.24, 13.47 (each br s, 1 H), 7.51, 6.97
(each d, J ) 7.8 Hz, 2H), 6.23, 5.42, 4.81 (each s, 1H), 3.61 (s,
3H), 3.59 (s, 1H), 3.23, 2.32 (each m, 2H), 2.24, 1.99, 1.93, 1.92,
1.91, 1.85, 1.75, 1.71, 1.43 (each s, 3 H); HRMS calcd for
[C39H45N4O2]+ 601.3542, found 601.3541. Anal. Calcd for
C39H44N4O2‚0.5H2O: C, 76.82; H, 7.44; N, 9.19. Found: C,
76.98; H, 7.32; N, 8.95.
Cr ysta llogr a p h ic Str u ctu r e Deter m in a tion .20 All crys-
tals were grown from CH2Cl2/n-hexane. 29: crystal data for
C45H48N4Cu at 130 K (Cu KR radiation, λ ) 1.541 78 Å, 2θmax
) 115°), triclinic, space group P1h, a ) 13.672(2) Å, b ) 14.475-
(3) Å, c ) 18.968(4) Å, R ) 84.67(2)°, â ) 87.22(2)°, γ ) 82.30-
(2)°, V ) 3701.1(12) Å3, Z ) 4, R ) 0.0541, wR ) 0.069, S )
0.94 for 8643 reflections with F > 4.0σ(F) and 896 parameters.
30: crystal data for C53H62CuN4O4 at 130 K (Mo KR radiation,
λ ) 0.710 73 Å, 2θmax ) 50°), monoclinic, space group P21/n, a
) 14.966(4) Å, b ) 16.786(3) Å, c ) 19.608(3) Å, â ) 110.97-
(2)°, V ) 4599.7(16) Å3, Z ) 4, R ) 0.067, wR ) 0.0966, S )
0.82 for 3955 reflections with F > 4.0σ(F) and 395 parameters.
33: crystal data for C47H46CuN4O4 at 130 K (Cu KR radiation,
λ ) 1.541 78 Å, 2θmax ) 115°), triclinic, space group P1h, a )
11.104(4) Å, b ) 13.138(4) Å, c ) 14.681(5) Å, R ) 65.55(2)°, â
) 84.18(3)°, γ ) 76.03(2)°, V ) 1892(1) Å3, Z ) 2, R ) 0.0579,
wR ) 0.079, S ) 1.52 for 4750 reflections with F > 4.0σ(F)
and 415 parameters. 44: crystal data for C39H44CuN4O2 at
130 K (Cu KR radiation, λ ) 1.541 78 Å, 2θmax ) 115°), triclinic,
space group P1h, a ) 7.438(2) Å, b ) 14.857(4) Å, c ) 14.830(3)
Å, R ) 96.03(2)°, â ) 97.64(2)°, γ ) 103.66(2)°, V ) 1562.4(7)
Å3, Z ) 2, R ) 0.0524, wR ) 0.0689, S ) 1.12 for 3865
reflections with F > 4.0σ(F) and 415 parameters. 45: crystal
data for C39H40CuN4O2 at 130 K (Mo KR radiation, λ ) 0.710 73
Å, 2θmax ) 42°), monoclinic, space group P21/c, a ) 9.200(6) Å,
b ) 14.220(11) Å, c ) 25.514(9) Å, â ) 103.20(4)°, V ) 3249(3)
Å3, Z ) 4, R ) 0.0823, wR ) 0.08, S ) 1.53 for 1790 reflections
with F > 4.0σ(F) and 190 parameters. 52: crystal data for
C39H42CuN4O2 at 130 K (Mo KR radiation, λ ) 0.710 73 Å,
2θmax ) 55°), monoclinic, space group P21/c, a ) 12.591(9) Å,
b ) 18.03(2) Å, c ) 14.726(10) Å, â ) 101.070(1)°, V ) 3329(5)
Å3, Z ) 4, R ) 0.0892, wR ) 0.1244, S ) 1.50 for 3510
reflections with F > 4.0σ(F) and 320 parameters. 58: crystal
data for C38H42CuN4 at 130 K (Cu KR radiation, λ ) 1.541 78
Å, 2θmax ) 114°), monoclinic, space group P21/c, a ) 18.285(4)
Å, b ) 13.324(3) Å, c ) 13.177(3) Å, R ) 65.55(2)°, â ) 84.18-
(3)°, γ ) 76.03(2)°, V ) 3179.4(11) Å3, Z ) 4, R ) 0.047, wR )
0.1191, S ) 1.063 for 3875 reflections with F > 4.0σ(F) and
387 parameters.
Cycliza tion of 1-((Eth oxyca r bon yl)m eth yl)-2,3,7,8,12,-
13,17,18-octa m eth yl-19-(p-tolylm eth yl)-a ,c-bila d ien e Di-
h yd r obr om id e (25). Ethanol, (95% 25 mL) was degassed
with N2 in an ice bath before sodium acetate (259 mg, 3.15
mmol) and Cr3(OAc)7(OH)2 (109 mg, 0.180 mmol) were added
all at once. The a,c-biladiene 25 (51.8 mg, 0.0688 mmol) was
added, and the mixture was stirred, in the dark at 0 °C. The
reaction was completed after 3.5 h (spectrophotometry). CH2Cl2
(50 mL) and water (50 mL) were added, and the organic layer
was separated. The organic layer was washed with water (2
× 100 mL) and aqueous saturated sodium bicarbonate (100
mL) and then brine (100 mL). After being dried over anhy-
drous sodium sulfate and filtered, the solution was concen-
trated, and the residue was quickly chromatographed on an
alumina column (Brockmann Grade III, elution with 30%
CH2Cl2 in petroleum ether). The major band isolated (13.9
mg, 40%) was 20-(ethoxycarbonyl)-2,3,7,8,12,13,17,18-octa-
methyl-1-(p-tolylmethyl)-1,20-dihydroporphyrin (43), mp >180
°C dec to compound with λmax 436 nm; λmax (CH2Cl2) 304 nm
(ꢀ 17 600), 380 (47 200), 653 (8100), 703 (8600); δ (CDCl3) 14.6,
14.2 (each br s, 1H), 7.11, 6.90 (each d, J ) 7.8 Hz, 2H each),
6.15, 5.22, 4.66 (each s, 1H), 4.17, 4.04 (each m, 1H), 3.99, 2.76
(each d, J ) 12.6 Hz, 1H), 3.50 (s, 1H), 2.22, 2.00, 1.97, 1.86,
1.39 (each s, 3H), 1.87, 1.79 (each s, 6H), 1.19 (t, J ) 7.2 Hz,
3H); HRMS calcd for [C39H45N4O2]+ 601.3542, found 601.3548.
Anal. Calcd for C39H44N4O2‚0.5H2O: C, 76.82; H, 7.44; N, 9.19.
Found: C, 76.42; H, 7.43; N, 8.92.
Cycliza tion of 2,3,7,8,12,13,17,18,19-Non a m eth yl-1-(p-
tolylm eth yl)-a ,c-bila d ien e Dih yd r obr om id e (26). The a,c-
biladiene 26 (49.4 mg, 0.0713 mmol) and Cr3(OAc)7(OH)2 (97.2
mg, 0.0161 mmol) in DMF (25 mL) and triethylamine (0.5 mL)
were refluxed for 5 min. The crude product was subjected to
chromatography on an alumina column (Brockmann Grade III;
elution with 1:1 CH2Cl2/petroleum ether), to give 18 mg (50%)
of 1,2,3,7,8,12,13,17,18-nonamethyl-20-p-tolyl-1,20-dihydro-
porphyrin (59): mp > 180 °C dec; λmax (CH2Cl2) 304 nm (ꢀ
19 400), 381 (47 100), 655 (7900), 708 (9800); δ (CDCl3) 14.25,
13.50 (each br s, 1H), 7.52, 6.97 (each d, J ) 7.8 Hz, 2H),
6.26, 5.44, 4.84 (each s, 1H), 3.61 (s, 1H), 2.24, 2.01, 1.96, 1.85,
1.79, 1.77, 1.66, 1.45 (each s, 3H), 1.93 (s, 6 H); HRMS calcd
for [C36H41N4]+ 529.3331, found 529.3348. Anal. Calcd for
C36H40N4‚0.5H2O: C, 80.41; H, 7.69; N, 10.42. Found: C,
80.67; H, 7.55; N, 10.32. When the reaction was repeated at
100 °C the identical compound was isolated in 40% yield (1H
NMR data).
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (HL-22252), the National Science Foun-
dation (CHE-96-23117), and the Deutsche Forschungs-
gemeinschaft for support of this research. Mass spec-
trometric analyses were performed by the UCSF Mass
Spectrometry Facility (A. L. Burlingame, Director)
supported by the Biomedical Research Technology
Program of the National Center for Research Resources,
NIH NCRR BRTP 01614.
Cycliza tion of 19-((Meth oxyca r bon yl)eth yl)-2,3,7,8,12,-
13,17,18-octa m eth yl-1-(p-tolylm eth yl)-a ,c-bila d ien e Di-
h yd r obr om id e (27). Cr3(OAc)7(OH)2 (319 mg, 0.529 mmol)
and a,c-biladiene 27 (152 mg, 0.202 mmol) in DMF (75 mL)
and triethylamine (1.5 mL) were heated at 100 °C for 1 h
(spectrophotometric monitoring). After an aqueous workup the
residue was chromatographed on alumina (Brockmann grade
III, elution with 1:1 CH2Cl2/petroleum ether) followed by
chromatography on a silica gel column, eluting with 1%
acetone in CH2Cl2. Many minor decomposition bands were
observed, but the major product (5.0 mg, 4% yield) was 1-(2-
(methoxycarbonyl)ethyl)-2,3,7,8,12,13,17,18-octamethyl-20-p-
J O9619138
(20) For experimental procedures and programs used, see: Senge,
M. O.; Hope, H.; Smith, K. M. J . Chem. Soc., Perkin Trans. 2 1993,
11. The authors have deposited atomic coordinates and a full structure
description for 29, 30, 33, 44, 45, 52, and 58 with the Cambridge
Crystallographic Data Centre. The structrues can be obtained, upon
request, for the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, U.K.