Syntheses and some chemistry of 1,2- and 1,1-bis(2-pyrrolyl)ethenes

Article abstract of DOI:10.1021/jo961582z

trans-1,2-Bis(2-pyrrolyl)ethenes (e.g. 18-20) are prepared by McMurry-type reductive coupling of the corresponding 2-formylpyrroles. The isomeric 1,1-bis(2-pyrrolyl)ethenes (e.g. 24) are prepared as a minor byproduct in the reaction of 2-unsubstituted pyrroles (e.g. 22) with acetic anhydride under Friedel-Crafts conditions; the major product, as expected is the 2-acetylpyrrole 23. However, 5-(chloromethyl)dipyrromethanes (e.g. 35) can be obtained in high yield by reaction of 2-unsubstituted pyrroles 22 with chloroacetaldehyde diethyl acetal. Base-catalyzed elimination of HCl from 35 affords the 1,1-bis(2-pyrrolyl)ethene 24 along with the trans- and cis-1,2-bis(2-pyrrolyl)-ethenes 18 and 36, respectively. Conditions are optimized to afford a 66% yield of the 1,1-bis(2-pyrrolyl)ethene 24. In neutral organic solvents, 1,1-bis(2-pyrrolyl)ethenes exist in the ethene tautomeric form 2, rather than as the corresponding 5-methyldipyrromethene isomer 3; however, under acidic conditions, the 5-methyldipyrromethene salt 38 is observed, and the 5-methyl group undergoes acid-catalyzed exchange in deuterated solvents. 1,1-Bis(2-pyrrolyl)ethenes (e.g. 24) undergo standard chemistry, such as catalytic hydrogenation (Adams catalyst) of the alkene bond (to give 5-methyldipyrromethane 44), Vilsmeier formylation [to give 2-formyl-1,1-bis(2-pyrrolyl)-ethene 57], and reaction with Eschenmoser's salt (N,N-dimethyl(methylene)ammonium iodide) [to give 2-((N,N-dimethylamino)methyl)-1,1-bis(2-pyrrolyl)ethene 59]. Both the 5-methyldipyrromethane-1,9-dicarboxylic acid 45 and the 1,1-bis(5-carboxy-3,4-dimethyl-2-pyrrolyl)ethene 53 react with the 1,9-diformyldipyrromethane 46, under standard MacDonald conditions, to give 3,5,8-trimethyldeuteroporphyrin IX dimethyl ester 47.

Full text of DOI:10.1021/jo961582z

8508
J . Org. Chem. 1996, 61, 8508-8517
Syn th eses a n d Som e Ch em istr y of 1,2- a n d
1,1-Bis(2-p yr r olyl)eth en es
Hong Xie, David A. Lee, David M. Wallace, Mathias O. Senge,† and Kevin M. Smith*
Department of Chemistry, University of California, Davis, California 95616
Received August 14, 1996X
trans-1,2-Bis(2-pyrrolyl)ethenes (e.g. 18-20) are prepared by McMurry-type reductive coupling of
the corresponding 2-formylpyrroles. The isomeric 1,1-bis(2-pyrrolyl)ethenes (e.g. 24) are prepared
as a minor byproduct in the reaction of 2-unsubstituted pyrroles (e.g. 22) with acetic anhydride
under Friedel-Crafts conditions; the major product, as expected is the 2-acetylpyrrole 23. However,
5-(chloromethyl)dipyrromethanes (e.g. 35) can be obtained in high yield by reaction of 2-unsub-
stituted pyrroles 22 with chloroacetaldehyde diethyl acetal. Base-catalyzed elimination of HCl
from 35 affords the 1,1-bis(2-pyrrolyl)ethene 24 along with the trans- and cis-1,2-bis(2-pyrrolyl)-
ethenes 18 and 36, respectively. Conditions are optimized to afford a 66% yield of the 1,1-bis(2-
pyrrolyl)ethene 24. In neutral organic solvents, 1,1-bis(2-pyrrolyl)ethenes exist in the ethene
tautomeric form 2, rather than as the corresponding 5-methyldipyrromethene isomer 3; however,
under acidic conditions, the 5-methyldipyrromethene salt 38 is observed, and the 5-methyl group
undergoes acid-catalyzed exchange in deuterated solvents. 1,1-Bis(2-pyrrolyl)ethenes (e.g. 24)
undergo standard chemistry, such as catalytic hydrogenation (Adams catalyst) of the alkene bond
(to give 5-methyldipyrromethane 44), Vilsmeier formylation [to give 2-formyl-1,1-bis(2-pyrrolyl)-
ethene 57], and reaction with Eschenmoser’s salt (N,N-dimethyl(methylene)ammonium iodide) [to
give 2-((N,N-dimethylamino)methyl)-1,1-bis(2-pyrrolyl)ethene 59]. Both the 5-methyldipyrromethane-
1,9-dicarboxylic acid 45 and the 1,1-bis(5-carboxy-3,4-dimethyl-2-pyrrolyl)ethene 53 react with the
1,9-diformyldipyrromethane 46, under standard MacDonald conditions, to give 3,5,8-trimethyl-
deuteroporphyrin IX dimethyl ester 47.
In tr od u ction
The synthesis, chemistry, and spectroscopy of trans-
1,2-bis(2-pyrrolyl)ethenes, e.g. 1, have been described.1
In contrast, very little has been published2 on 1,1-bis(2-
pyrrolyl)ethenes, e.g. 2, which are of interest because of
the potentially intriguing tautomeric equilibrium with
meso-5-methyldipyrromethene 3. One example of a BF2-
stabilized complex 4 was reported by Treibs and Kreuzer3
in 1968, and two examples of 10-alkylidene-a,c-biladiene-
1,19-diones, 5 and 6, were reported by Falk et al.4,5 in
1988 and 1989. In 1959, J ohnson and co-workers6
reported the synthesis of 1,2,3,5,7,8,9-heptamethyldi-
pyrromethene 7 and 2,8-bis(2-(methoxycarbonyl)ethyl)-
1,3,5,7,9-pentamethyldipyrromethene 8. They found both
compounds to be unstable and they were characterized
as zinc(II) complexes by elemental analyses alone. In the
present paper we report a new efficient synthesis of 1,2-
bis(2-pyrrolyl)ethenes 1 using low-valent titanium con-
densation methodology, and also describe new syntheses2
and some chemistry of a number of novel 1,1-bis(2-
pyrrolyl)ethenes 2.
Resu lts a n d Discu ssion
Syn th esis of 1,2-Bis(2-p yr r olyl)eth en es via th e
McMu r r y Cou p lin g Rea ction . Fluorescent 1,2-bis(2-
† Present address: Institut fu¨r Organische Chemie (WE 02), Fach-
bereich Chemie, Freie Universita¨t Berlin, Takustrasse 3, 14195 Berlin,
Germany.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) Hayes, A.; J ackson, A. H.; J udge, J . M.; Kenner, G. W. J . Chem.
Soc. 1965, 4385.
(2) Preliminary communication: Lee, D. A.; Xie, H.; Senge, M. O.;
Smith, K. M. J . Chem. Soc., Chem. Commun. 1994, 791.
(3) Treibs, A.; Kreuzer, F. Liebigs Ann. Chem. 1968, 718, 208.
(4) Falk, H.; Wo¨ss, H. Monatsh. Chem. 1988, 119, 1031.
(5) Falk, H.; Mu¨ller, N.; Wo¨ss, H. Monatsh. Chem. 1989, 120, 35.
(6) J ohnson, A. W.; Kay, I. T.; Markham, E.; Price, R.; Shaw, K. B.
J . Chem. Soc. 1959, 3416.
pyrrolyl)ethylenes 9 were first synthesized by Kenner
and co-workers1 in 1965 by the treatment of R-pyridini-
ummethyl- 10 and R-aminomethyl- 11 pyrroles with 2 N
NaOH. Yields were in the range of 10-14%, clearly
S0022-3263(96)01582-4 CCC: $12.00 © 1996 American Chemical Society

Chemistry of 1,2- and 1,1-Bis(2-pyrrolyl)ethenes
J . Org. Chem., Vol. 61, No. 24, 1996 8509
leaving much room for improvement. Vogel and co-
workers based their syntheses of porphycenes7 on the
McMurry reaction8 (TiCl4/Zn) of diformylbipyrroles, and
F igu r e 1. View of the molecular structure of 18 in the crystal.
Hydrogen atoms have been omitted for clarity; ellipsoids show
50% occupancy.
(Figure 1).11 Using the same procedure 1,2-bis(2-
pyrrolyl)ethenes 19 (46% yield from 2-formylpyrrole 13)
and 20 (22% yield from 14) were obtained. The lower
yields for the last two compounds are presumably due to
lability of the tert-butyl and propionic methyl esters in
the presence of the titanium reagent. An attempt to
cross-couple pyrroles 12 and 14 to form the mixed ethene
21 failed to give any useful product; the alkene 18 was
the major product, obtained in 20% yield and once again
demonstrating the lability of the tert-butyl ester to the
McMurry reaction conditions.
we later adapted a similar McMurry reagent [TiCl3-
(DME)1.5 in presence of a Zn/Cu couple] for the coupling
of 5-formyl- and 5-acroleinyl-porphyrins and -chlorins to
give the corresponding pseudo-dimers.9 We therefore
decided to attempt an improvement of the synthesis of
1,2-bis(2-pyrrolyl)ethenes using 2-formylpyrroles and the
same McMurry reagent. 1,2-Bis(2-pyrrolyl)ethenes 1 are
potentially useful intermediates for the syntheses of
expanded porphyrin macrocycles.10
For our pyrrole experiments, we chose three different
but readily available 2-formylpyrroles, namely 12-14.
2-Formylpyrrole 12 was obtained in high yield by Vils-
meier formylation of the corresponding 2-unsubstituted
pyrrole 15, while pyrroles 13 and 14 were obtained by
sulfuryl chloride oxidation of the corresponding, readily
available 2-methylpyrroles (16 and 17, respectively). For
our first experiment, pyrrole 12 was treated with TiCl3-
(DME)1.5 and 15 equiv of the Zn-Cu couple in DME. A
nonpolar product was characterized by 1H-NMR spec-
troscopy and high resolution mass spectrometry (HRMS)
and found to be the expected alkene 18, obtained in 81%
yield. The unique orientation about the alkene double
1
bond was indicated by overall symmetry in the H-NMR
spectrum, and a singlet (CHdCH) at 6.60 ppm; the trans
configuration was confirmed by X-ray crystallography
Syn th eses of 1,1-Bis(2-p yr r olyl)eth en es. 1,1-Bis-
(2-pyrrolyl)ethenes were first prepared serendipitously
in our laboratory.2 Treatment of pyrrole 22 with acetic
anhydride in the presence of stannic chloride gave the
expected 2-acetylpyrrole 23 (87%), along with a minor,
less polar product in 6-10% yield. This compound was
fully characterized by its 1H and 13C NMR and mass
(7) Vogel, E.; Ko¨cher, M.; Schmickler, H.; Lex, J . Angew. Chem., Int.
Ed. Engl. 1986, 25, 257. Vogel, E.; Balci, M.; Pramod, K.; Koch, P.;
Lex, J .; Ermer, O. Angew. Chem. Int. Ed. Engl. 1987, 26, 928. Vogel,
E.; Grigat, I.; Ko¨cher, M.; Lex, J . Angew. Chem. Int. Ed. Engl. 1989,
28, 1655. Vogel, E.; Ko¨cher, M.; Lex, J .; Ermer, O. Isr. J . Chem. 1989,
29, 257.
(8) (a) McMurry, J . E. Chem. Rev. 1989, 89, 1513. (b) McMurry, J .
E.; Lectka, T.; Rico, J . G. J . Org. Chem. 1989, 54, 3748.
(9) (a) Smith, K. M.; Vicente, M. G. H. J . Org. Chem. 1991, 56, 4407.
(b) Senge, M. O.; Gerzevske, K. R.; Vicente, M. G. H.; Forsyth, T. P.;
Smith, K. M. Angew. Chem., Int. Ed. Engl. 1993, 32, 750. (c) Senge,
M. O.; Vicente, M. G. H.; Gerzevske, K. R.; Forsyth, T. P.; Smith, K.
M. Inorg. Chem. 1994, 33, 5625.
(11) The authors have deposited atomic coordinates and a full
structure description for compounds 18 and 32 with the Cambridge
Crystallographic Data Center. The structures can be obtained, on
request, from The Director, Cambridge Crystallographic Data Center,
12 Union Road, Cambridge CB2 1EZ, UK.
(10) Wallace, D. M. Ph.D. Dissertation, University of California,
Davis, 1992.

8510 J . Org. Chem., Vol. 61, No. 24, 1996
Xie et al.
spectra, as well as elemental analysis and X-ray crystal-
lography2 as 1,1-bis(5-(benzyloxycarbonyl)-3,4-dimethyl-
1H-2-pyrrolyl)ethene 24. At first, it was thought that
the 1,1-bis(pyrrolyl)ethene 24 was formed by nucleophilic
tonation (route A) is much greater than that of intermo-
lecular nucleophilic attack (route B), and compound 23
is isolated in greater quantity (80-87%) than is com-
pound 24 (6-10%). When acetyl chloride with 1 equiv
of SnCl4 was used instead of acetic anhydride with 2
equiv of SnCl4 for the acylation reaction, no 1,1-bis-
(pyrrolyl)ethene was formed. Several attempts to pre-
pare 5-hydroxy-5-methyldipyrromethane 25 were unsuc-
cessful; reduction of dipyrroketone 27 with alkyllithium
attack of the 2-unsubstituted pyrrole 22 at the carbonyl
carbon of the 2-acetylpyrrole 23 followed by dehydration
from the intermediate 25. But when pyrroles 22 and 23
were mixed in the presence of Lewis acids either at 0 °C
or at elevated temperatures, no reaction was observed.
All attempts to synthesize the bis(pyrrolyl)ethene 24 from
2-H- and 2-acetyl-pyrroles under a variety of conditions
failed. These observations suggested that the R-carbonyl
group in 23 was not electrophilic enough to react with
the 2-unsubstituted pyrrole 22. Therefore, the formation
of 24 might involve an activated intermediate rather than
2-acetylpyrrole 23. We propose a mechanism for the
formation of 2-acetylpyrrole 23 and 1,1-bis(2-pyrrolyl)-
ethene 24 as outlined in Scheme 1. An acylium cation
is formed by the reaction of acetic anhydride with stannic
chloride. Nucleophilic attack of the 2-unsubstituted
pyrrole 22 at the acylium ion gives the intermediate 26,
which loses its R-H readily (route A) to give the rearo-
matized R-acetylpyrrole 23. The R-carbonyl group in 26
is highly electrophilic because it does experience the
deactivating effect from the ring, so it may be attacked
by a second molecule of the R-H pyrrole 22 (route B)
before it can lose its R-proton. This leads to formation
of the intermediate 5-hydroxy-5-methyldipyrromethane
25. Subsequent dehydration affords the isolated 1,1-bis-
(2-pyrrolyl)ethene 24. Apparently, the rate of the depro-
or alkyl Grignard (MeMgBr) reagents, and attempted
condensation of R-metallopyrroles with 2-acetylpyrroles
were all unsuccessful.
Using a completely different approach,12 R-free pyrrole
28 (1 equiv) in toluene was treated with commercially
available chloroacetaldehyde diethyl acetal (CADA) (0.6
equiv) and catalytic amounts of TsOH at 100 °C to give
the 5-(chloromethyl)dipyrromethane 29 in 91% yield. The
ethyl ester variant 30 was likewise prepared in 72% yield
from pyrrole 31. 5-(Chloromethyl)dipyrromethanes could
also be prepared at room temperature in good to excellent
yields (72-91%) by using TFA/K-10 (Montmorillonite)
clay as the acid catalyst; the reaction12 can be performed
on a multigram scale, and the products could be directly
crystallized from the reaction mixture.
Sch em e 1. P r op osed Mech a n ism for F or m a tion of
2-Acetylp yr r ole 23 a n d 1,1-Bis(2-p yr r olyl)eth en e 24
We expected that E2 elimination reactions on 5-(chlo-
romethyl)dipyrromethanes should provide the desired
1,1-bis(2-pyrrolyl)ethenes in improved yields (compared
with the Friedel-Crafts route discussed above). 5-(Chlo-
romethyl)dipyrromethane 29 was treated with aqueous
NaOH at 50 °C to give two products. 1H-NMR spectros-
copy of one product indicated a trans-ethylene linkage
of trans-1,2-di(2-pyrrolyl)ethene 32 (resonance at 6.60
ppm, similar to that observed in compound 18). The
second product featured a resonance at 5.43 ppm, indica-
tive of the desired 1,1-bis(2-pyrrolyl)ethene 33. In an
attempt to minimize formation of 32, DBU and lower
temperature conditions (25 °C) were employed; the
5-(chloromethyl)dipyrromethane 29 was treated with 10
equiv of DBU and gave rise to three products. These
were characterized as the trans-1,2-bis(2-pyrrolyl)ethene
32, the 1,1-bis(2-pyrrolyl)ethene 33, and the cis-1,2-bis-
(2-pyrrolyl)ethene 34. X-ray crystallographic analysis of
trans-1,2-bis(2-pyrrolyl)ethene 32 (Figure 2) further con-
firmed the structural assignment.11
5-(Chloromethyl)dipyrromethane 35 was prepared in
91% yield by condensation of the 2-unsubstituted pyrrole
15 with CADA using the TFA/K-10 clay conditions. A
solution of 35 in dichloromethane was then treated with
10 equiv of DBU to again give a mixture of three
(12) Lee, D. A.; Brisson, J . M.; Smith, K. M. Heterocycles 1995, 40,
131.

Chemistry of 1,2- and 1,1-Bis(2-pyrrolyl)ethenes
J . Org. Chem., Vol. 61, No. 24, 1996 8511
Sch em e 2. P r op osed Mech a n ism for F or m a tion of
1,2-Bis(p yr r olyl)eth en e Isom er s 18 a n d 36
F igu r e 2. View of the molecular structure of 32 in the crystal.
Hydrogen atoms have been omitted for clarity; ellipsoids show
50% occupancy.
products, in approximately a 2:1:1 ratio; these were
structurally assigned as the 1,1-bis(2-pyrrolyl)ethene 24,
the cis-1,2-bis(2-pyrrolyl)ethene 36, and the trans-1,2-
bis(2-pyrrolyl)ethene 18. Subsequent purification af-
Sch em e 3. Alter n a tive Mech a n istic P r op osa l for
F or m a tion of 1,2-Bis(p yr r olyl)eth en e Isom er s 18
a n d 36 In volvin g Neigh bor in g Gr ou p P a r ticip a tion
by th e P yr r ole Nu cleu s
forded 24 in 23% yield, a significant (but not yet
acceptable) improvement over the earlier Friedel-Crafts
approach.
We suspect that the 1,2-bis(pyrrolyl)ethene isomers
were formed by some type of base catalyzed migration,
as proposed in Scheme 2, involving initial base catalyzed
migration followed by base-mediated elimination to afford
the 1,2-bis(pyrrolyl)ethenes. There is literature prece-
dent for similar aryl migration reactions, though they are
generally catalyzed by strong acids.13 The cis and trans
isomers are both obtained as a result of the free rotation
about the tether of the intermediate 37. Alternatively,
intermediate 37 might be formed via a mechanism
(Scheme 3) involving neighboring group participation by
the pyrrole nucleus.14
On the basis of our mechanistic analyses, we predicted
that use of stoichiometric amounts of base, instead of
excess, should minimize the formation of the two side
products, affording a majority of the 1,1-bis(2-pyrrolyl)-
ethene. 5-(Chloromethyl)dipyrromethane 35 was there-
fore treated initially with 1.3 equiv of DBU to afforded
the desired product 24 in 66% yield; the trans-1,2-bis-
(pyrrolyl)ethene 32 was also isolated as a minor product
in 9% yield. The cis-1,2-bis(pyrrolyl)ethene 36 was also
present in small amount but could not be purified. Over
a period of time the cis-1,2-isomer isomerized to the more
thermodynamically stable trans-1,2-isomer.
1,1-Bis(2-p yr r olyl)et h en e vs 5-Met h yld ip yr r o-
m eth en e Ta u tom er ism . The structure of 24 was
confirmed by X-ray crystallography (not shown).2 This
showed the 5-methylidene bond to be 1.333 Å in length,
characteristic for a CdC bond. The molecule is not
planar, the two pyrrole rings being twisted against each
other by 54.9°. We had expected that the fully conju-
gated, presumably planar tautomer, 5-methyldi-
(13) (a) Becker, K. B. Synthesis 1983, 341 and references therein.
(b) Sieber, R. H. Liebigs Ann. Chem. 1969, 730, 31.
(14) (a) Smith, K. M.; Martynenko, Z.; Pandey, R. K.; Tabba, H. D.
J . Org. Chem. 1983, 48, 4296. (b) We thank
a referee for this
suggestion.

8512 J . Org. Chem., Vol. 61, No. 24, 1996
Xie et al.
pyrromethene (e.g. 3) would be more stable than 2, based
on the fact that 5-unsubstituted dipyrromethenes are
quite stable and have been used extensively as interme-
diates in porphyrin syntheses.15 However, compound 24
was easily transformed into the 5-methyldipyrromethene
salt 38 simply by treatment with an acid; when 24 in
dichloromethane was treated with TFA, the solution
turned red, as expected for dipyrromethene salts. UV-
vis and proton NMR spectra confirmed that the red
compound was 5-methyldipyrromethene salt 38. The 1,1-
bis(2-pyrrolyl)ethene 24 has a maximum absorption at
303 nm (ꢀ 39 000), while 5-methyldipyrromethene 38 has
one at 522 nm (ꢀ 79 600); for a figure, see reference 2.
The 5-methyl protons in 38 have a chemical shift of 3.05
ppm, and in presence of deuterated TFA the protons
resonating at 3.05 ppm were exchanged and concomi-
tantly disappeared from the spectrum. All attempts to
crystallize the 5-methyldipyrromethene 38 failed. Upon
contact with protic solvents, such as methanol and water,
the dipyrromethene reverted to the bis(pyrrolyl)ethene
24 form (UV-vis, 1H-NMR). The 5-methyldipyrromethene
could only be observed in aprotic solvents such as CH2-
Cl2 in the presence of excess strong acid, suggesting that
5-substituted dipyrromethene free-bases are not ther-
modynamically stable, and that their nonplanar 1,1-bis-
(2-pyrrolyl)ethene tautomers are the predominant forms
under nonacidic conditions. A plausible explanation
would be that the periphery of the potentially planar
5-methyldipyrromethenes is heavily laden with substit-
uents so that there is not enough room for all of them
without considerable distortion of bond angles or lengths.
On the other hand, the steric compressions in these
systems are relieved when they adopt the geometry of
1,1-bis(2-pyrrolyl)ethenes in which the two pyrrole rings
are tilted against each other.
Ch em istr y of 1,1-Dip yr r olyleth en es. Oxid a tion .
Although
1,1-bis(5-(benzyloxycarbonyl)-4-methyl-2-
pyrrolyl)ethene 39 could be isolated, it was not particu-
larly stable. Attempts to crystallize this oily material
yielded crystalline needles which were fully characterized
as dipyrroketone 43, presumably produced by photo-
oxidation of 39. A characteristic (amide) infrared absorp-
tion band at 1600 cm-1 was observed for the carbonyl
group. In contrast, the fully substituted bis(pyrrolyl)-
ethene 24 was much more stable, and its chemistry was
therefore investigated.
Ca ta lytic Hyd r ogen a tion . The external double bond
in the 1,1-bis(pyrrolyl)ethene 24 was reduced by catalytic
hydrogenation using Adams catalyst, to give dibenzyl
2,3,5,7,8-pentamethyldipyrromethane-1,9-dicarboxy-
late 44. Catalytic hydrogenation using palladium on
activated carbon gave the corresponding 2,3,5,7,8-
pentamethyldipyrromethane-1,9-dicarboxylic acid 45,
which after condensation with 1,9-diformyldipyrromethane
46 in the presence of TsOH afforded the 5-methyl-
porphyrin 47 in 24% yield. The dipyrromethane 46 was
prepared from the corresponding 1,9-dibenzyl ester 48;
catalytic hydrogenation gave the 1,9-dicarboxylic acid 49,
and formylation using TFA/trimethyl orthoformate af-
forded the required 1,9-diformyldipyrromethane 46, usu-
ally along with the 1-formyl-9-(trifluoroacetyl)dipyr-
romethane 50. Compound 50 is presumably produced
by trifloroacetylation of 49 by the TFA used in the
formylation process, and can be avoided by use of the
standard POCl3/DMF Vilsmeier approach.18
In order to provide more information regarding the
equilibrium between 1,1-bis(2-pyrrolyl)ethene 2 and its
dipyrromethene tautomer 3, we synthesized the 3,7-
diunsubstituted bis(pyrrolyl)ethene 39. At the time, our
efficient methodology for bis(pyrrolyl)ethene synthesis
had not been developed, so we employed the Friedel-
Crafts approach by treatment of benzyl 3-methylpyrrole-
2-carboxylate 40 with acetic anhydride in the presence
of stannic chloride. The 2,3-diunsubstituted pyrrole 40
was prepared following a literature procedure16 in 39%
overall yield from toluene-p-sulfonylglycine benzyl ester.
Recently, Lash and Hoehner17 reported an improved
synthesis which gave the pyrrole in a 53% overall yield
from the same starting materials. When pyrrole 40 was
treated with acetic anhydride in the presence of stannic
chloride, three compounds were isolated. The two major
crystalline products were 3- (41, 53%) and 2-acetyl-
pyrroles (42, 12%), and the third (minor) product (<1%)
was characterized as 1,1-bis(5-(benzyloxycarbonyl)-4-
In connection with a separate project involving speci-
ficity of heme oxygenase (HO),19-21 the enzyme which
catalyzes the catabolism of heme into biliverdin, the
5-methylporphyrin 47 was transformed into the 5-me-
thylhemin chloride 51 in 81% yield, after treatment of
the intermediate Fe(III)-µ-oxo dimer with 2 N HCl. 1H-
NMR spectroscopy showed three characteristic singlet
â-methyl resonances at 12.12, 11.84, and 11.59 ppm. The
1
methyl-1H-2-pyrrolyl)ethene 39 by its H-NMR spectrum
and UV-vis spectra. However, like the fully substituted
bis(pyrrolyl)ethene 24, compound 39 turned red in the
presence of TFA with a maximum absorption at 522 nm,
and the color disappeared when water or methanol was
added. Clearly, steric compression is not the only factor
involved in the tautomeric equilibria between 2 and 3,
and electronic factors may also play an important role.
(18) Chong, R.; Clezy, P. S.; Liepa, A. J .; Nichol, A. W. Aust. J . Chem.
1969, 22, 229.
(19) Tomaro, M. L.; Frydman, R. B.; Pandey, R. K.; Smith, K. M.
Biochim. Biophys. Acta 1984, 791, 342.
(20) Herna´ndez, G.; Wilks, A.; Paolesse, R.; Smith, K. M.; Ortiz de
Montellano, P. R.; La Mar, G. N. Biochemistry 1994, 33, 6631.
(21) Torpey, J . W.; Ortiz de Montellano, P. R. J . Org. Chem. 1995,
60, 2195.
(15) Fischer, H.; Orth, H. Die Chemie des Pyrrols; Akademische
Verlag.: Leipzig, 1937; Vol. 2, Part 1.
(16) Terry, W. G.; J ackson, A. H.; Kenner, G. W.; Kornis, G. J . Chem.
Soc. 1965, 4389.
(17) Lash T. D.; Hoehner, M. C. J . Heterocycl. Chem. 1991, 28, 1671.

Chemistry of 1,2- and 1,1-Bis(2-pyrrolyl)ethenes
J . Org. Chem., Vol. 61, No. 24, 1996 8513
resonance for the 5-methyl substituent appeared as a
singlet at 46.75 ppm. This extreme deshielding effect is
an interesting and unique result. The singlet H-NMR
aldehydes, employing formamides (N-methylformanilide,
dimethylformamide, etc.) as formylating agents, usually
in the presence of POCl3. Although the Vilsmeier reac-
tion was originally designed for aromatic ring formyla-
tion, it has been extended to the formylation of olefins.26
For example, the formylation of styrene and its deriva-
tives was carried out by heating with DMF in the
presence of POCl3, producing substituted acroleins.27
Moreover, vinylporphyrins and chlorins have been shown
to formylate preferentially at the terminal carbon of the
vinyl group, in preference to the macrocyclic meso-
position.28,29 Like other olefins bearing aryl groups, the
vinyl group in 1,1-bis(pyrrolyl)ethene 24 can be easily
formylated using the Vilsmeier reagent. Treatment of
the bis(pyrrolyl)ethene with POCl3/DMF, followed by
basic hydrolysis, afforded 3,3-bis(5-(benzyloxy)carbonyl-
3,4-dimethyl-2-pyrrolyl)acrolein 57 in 90% yield. Such
compounds may well prove to be valuable as starting
materials for the synthesis of novel meso-substituted
porphyrins and meso-linked porphyrin dimers.9,30 At-
tempts to acylate the vinyl group in 24 using acetic
anhydride/SnCl4 failed.
1
resonances for the three meso-protons, two being chemi-
cally equivalent, appeared at -11.52 and -18.59 ppm.
Novel results using 51 and a recombinant, truncated
version of human HO-122 will be reported elsewhere.23
We were interested to see if a methylidene phlorin 52
would form when 1,1-bis(5-carboxy-3,4-dimethyl-2-pyr-
rolyl)ethene 53 was condensed with 1,9-diformyldipyr-
romethane 46 under acid-catalyzed MacDonald condi-
tions.24,25 The dicarboxylic acid 53 was derived from the
corresponding diethyl ester 54 by basic hydrolysis; bis-
(pyrrolyl)ethene 54 was synthesized from ethyl 3,4-
dimethylpyrrole-2-carboxylate 55 in 12% yield (along
with the 2-acetylpyrrole byproduct 56) using the un-
optimized Friedel-Crafts approach. Condensation of 53
with 1,9-diformyldipyrromethane 46 in the presence of
TsOH gave the 5-methylporphyrin 47 as the only mac-
rocyclic product, indicating that the exocyclic double bond
migrated in to the macrocycle after the cyclization
occurred.
Rea ction of 1,1-Dip yr r olyleth en es w ith Esch en -
m oser ’s Sa lt. Eschenmoser’s salt,31,32 dimethyl(meth-
ylene)ammonium iodide CH2dNMe2+I-, 58, is highly
electrophilic, and has found applications in pyrrole33 and
porphyrin/chlorin34 chemistry. It is commercially avail-
able from Aldrich. There is no report on the reaction of
Eschenmoser’s salt with CdC double bonds in olefins and
aromatic systems. When 1,1-bis(pyrrolyl)ethene 24 or 54
was treated with a large excess of Eschenmoser’s salt 58
the novel compounds 1,1-bis(5-(benzyloxycarbonyl)-3,4-
dimethyl-1H-2-pyrrolyl)-3-(dimethylamino)propene 59 or
1,1-bis(5-(ethoxycarbonyl)-3,4-dimethyl-1H-2-pyrrolyl)-3-
(dimethylamino)propene 60, respectively, were isolated
in almost quantitative yield. We suspect that these
products were formed via the dipyrromethene intermedi-
ate 61. Quaternization of 59 or 60, followed by reactions
with nucleophiles, should provide access to a number of
interesting dipyrrole species, and well as potential por-
phyrin precursors.
Exp er im en ta l Section
General details are as previously described.35 Mass spectra
were measured at the Mass Spectrometry Facility, University
of California, San Francisco.
Cr ysta l Str u ctu r e Deter m in a tion s: For techniques and
programs used, see reference 9c.
(26) Olah, G. A.; Kuhn, S. J . In Friedel-Crafts and Related
Reactions; Olah, G. A., Ed.; Interscience: New York; 1964; Vol. 3, part
2, pp 1214-19.
(27) Schmidle, C. J .; Barnett, P. G. J . Am. Chem. Soc. 1956, 78,
3209.
(28) Nichol, A. W. J . Chem. Soc. (C) 1970, 903.
(29) Smith, K. M.; Bisset, G. M. F.; Bushell, M. J . J . Org. Chem.
1980, 45, 2218.
(30) Paolesse, R.; Pandey, R. K.; Forsyth, T. P.; J aquinod, L.;
Gerzevske, K. R.; Nurco, D. J .; Senge, M. O.; Liccocia, S.; Boschi, T.;
Smith, K. M. J . Am. Chem. Soc. 1996, 118, 3869.
(31) Schreiber, J .; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330.
(32) Bryson, T. A.; Bonitz, G. H.; Reichel, C. J .; Dardis, R. E. J . Org.
Chem. 1980, 45, 524.
Vilsm eier F or m yla t ion of 1,1-Bis(2-p yr r olyl)-
eth en es. The Vilsmeier reaction is used to prepare
(22) Wilks, A.; Black, S, M.; Miller, W. L.; Ortiz de Montellano, P.
R. Biochemistry 1995, 34, 4421.
(23) Torpey, J . W.; Lee, D. A.; Smith, K. M.; Ortiz de Montellano,
P. R. J . Am. Chem. Soc. 1996, 118, 9172.
(24) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J . Am. Chem.
Soc. 1960, 82, 4384.
(33) Nguyen, L. T.; Senge, M. O.; Smith, K. M. Tetrahedron Lett.
1994, 35, 7581; J . Org. Chem. 1996, 61, 998.
(34) Pandey, R. K.; Smith, N. W.; Shiau, F.-Y.; Dougherty, T. J .;
Smith, K. M. J . Chem. Soc., Chem. Commun. 1991, 1637. Pandey, R.
K.; Shiau, F.-Y.; Smith, N. W.; Dougherty T. J .; Smith, K. M.
Tetrahedron 1992, 48, 7591.
(25) Cavaleiro, J . A. S.; Gonsalves, A. M. d’A. R.; Kenner, G. W.;
Smith, K. M. J . Chem. Soc., Perkin Trans. 1 1974, 1771.
(35) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J .
Org. Chem. 1993, 58, 7245.

8514 J . Org. Chem., Vol. 61, No. 24, 1996
Xie et al.
Anal. Calcd for C24H34N2O4‚1/2H2O: C, 68.08; H, 8.33; N, 6.62.
Found: C, 68.57; H, 8.22; N, 6.52.
Ben zyl 5-Acetyl-3,4-dim eth ylpyr r ole-2-car boxylate (23)
a n d 1,1-Bis(5-(b en zyloxyca r b on yl)-3,4-d im et h yl-1H -2-
pyr r olyl)eth en e (24) (Fr iedel-Cr afts Appr oach ). A stirred
solution of pyrrole 22 (3.42 g; 14.9 mmol), in dichloromethane
(56 mL) and acetic anhydride (2.0 mL; 21.1 mmol) was cooled
to 0 °C under nitrogen, and stannic chloride (3.5 mL; 30.0
mmol) was added dropwise over 3 min. The mixture was
stirred at 0 °C for 10 min. The cherry red solution was poured
into a mixture of ice-water and dichloromethane; the organic
layer was separated and washed with cold water. It was then
washed with saturated sodium bicarbonate solution and dried
over anhydrous sodium sulfate. Evaporation and chromatog-
raphy on silica gel (elution with 1:3 ethyl acetate/cyclohexane)
afforded 3.49 g (12.9 mmol, 87%) of the 5-acetylpyrrole 23 as
the major product, mp 101.5-103 °C (lit.38 mp 103 °C); 1H-
NMR: δ, ppm, 2.28 (s, 6H), 2.49 (s, 3H), 5.32 (s, 2H, 7.4 (m,
5H), 9.5 (bs, 1H); LRMS: m/ z (%) 271 (20), 91 (100). 1,1-Bis-
(2-pyrrolyl)ethene 24 was isolated in 6-10% yield, mp 135-
136 °C; λmax: 251 nm (ꢀ 17 000), 303 (39 000); 1H-NMR: δ,
ppm, 1.98, 2.27 (each s, 6H), 5.19 (s, 4H), 5.46 (s, 2H), 7.3-
7.4 (m, 10H), 9.34 (bs, 2H). 13C-NMR: δ, ppm, 10.6, 10.9, 65.6,
116.0, 118.2, 119.6, 127.5, 127.8, 128.2, 128.6, 130.7, 132.5,
136.2, 161.6. LRMS: m/ z (%) 482.2 (100). Anal. Calcd for
C30H30N2O4: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.52; H,
6.30; N, 5.87. HRMS: Calcd for C30H30N2O4: 482.2205; Found
482.2201. Dipyrrolylethene 24 was converted into the 5-me-
thyldipyrromethene 38 when treated with excess TFA, result-
ing in a red solution; λmax: 522 nm (ꢀ 79 600); 1H-NMR: δ,
ppm, (CDCl3 + TFA) 2.23, 2.34 (each s, 6H), 3.05 (s, 3H), 5.50
(s, 4H), 7.43 (s, 10H), 10.87 (bs, 2H). When deuterated TFA
was used, 38 was formed but the 5-methyl peak at 3.05 ppm
was either partially or completely absent.
1,1-Bis(5-(ben zyloxycar bon yl)-3,4-dim eth yl-2-pyr r olyl)-
eth en e (24) (Elim in a tion Ap p r oa ch ). To a solution of
dipyrromethane 35 (1.004 g, 1.934 mmol) in freshly distilled
dichloromethane (240 mL), under argon, was added DBU
(0.350 mL, 2.321 mmol, 1.2 equiv). The reaction mixture was
stirred at rt in the dark for 7 h, after which time additional
DBU (0.040 mL, 0.268 mmol) was added. After 25 h all the
starting material was consumed (TLC analysis). The solvent
was evaporated to afford a yellow oil that was purified by silica
gel flash chromatography (elution with 1% methanol/dichlo-
romethane), to afford the title ethene 24 (611 mg, 66%) as a
crystalline yellow solid, mp 133-135 °C, identical in all
respects with the material obtained using the Friedel-Crafts
approach. A minor product trans-1,2-bis(5-(benzyloxycarbo-
nyl)-3,4-dimethyl-2-pyrrolyl)ethene 18 (88 mg, 9%) was iso-
lated as yellow crystals (mp 210-212 °C; identical in all
respects with the material described above, synthesized using
the McMurry approach.). A very minor product cis-1,2-bis(5-
(benzyloxycarbonyl)-3,4-dimethyl-2-pyrrolyl)ethene 36 was not
quantified, [1H-NMR: δ, ppm, 1.90 (s, 6H), 2.25 (s, 6H), 5.26
(s, 4H), 6.30 (s, 2H), 7.30-7.43 (m, 10H), 8.78 (bs, 2H).
HRMS: Calcd for C30H30N2O4: 482.2205. Found 482.2224].
Dib en zyl 5-(Ch lor om et h yl)-3,7-d iet h yl-2,8-d im et h yl-
d ip yr r om eth a n e-1,9-d ica r boxyla te (29). To a rt solution
of pyrrole 28 (1.035 g, 4.256 mmol) and TsOH (0.201 g, 1.057
mmol) in freshly distilled toluene (25.0 mL), under argon, was
added 2-chloroacetaldehyde diethyl acetal (0.395 mL, 2.639
mmol). The reaction mixture was heated at 100 °C for 40 min,
after which time water and dichloromethane were added. The
organic layer was separated, the aqueous layer was extracted
with dichloromethane, and the combined organic layer was
washed with brine and then dried over anhydrous sodium
sulfate. Evaporation gave a deep brown oil which was purified
by silica gel flash column chromatography (elution with 1%
methanol/dichloromethane) to give the title product (1.06 g,
91%) as a light brown foam, which was recrystallized from
dichloromethane/n-hexane to give a tan powder, mp 178-180
°C. 1H-NMR: δ, ppm, 1.03 (t, J ) 7.5 Hz, 6H), 2.26 (s, 6H),
2.43 (q, J ) 7.5 Hz, 4H), 4.01 (d, J ) 7.5 Hz, 2H), 4.59 (t, J )
(18) C30H30N2O4, at 130 K, (Mo KR radiation λ ) 0.71069Å,
2θmax ) 48°), monoclinic, space group P2/c, a ) 19.987(11), b
) 10.117(7), c ) 13.423(8) Å, â ) 107.94(4)°, V ) 2582(2) Å3,
Z ) 4, R ) 0.059, wR ) 0.076, s ) 1.06 for 2457 reflections
with F > 4.0σ(F) and 325 parameters.
(32) C32H34N2O4, at 130 K, (Mo KR radiation λ ) 0.71069Å,
2θmax ) 55°), monoclinic, space group P21/c, a ) 12.720(8), b
) 17.94(3), c ) 12.145(8) Å, â ) 103.27(5), V ) 2697(4) Å3, Z
) 4, R ) 0.087, wR ) 0.065, s ) 1.49 for 2441 reflections with
F > 4.0σ(F) and 343 parameters.
tr a n s-1,2-Bis(5-(b en zyloxyca r b on yl)-3,4-d im et h yl-2-
p yr r olyl)eth en e (18). TiCl3(DME)1.5 (5.2 g; 17.9 mmol) and
Zn-Cu couple (4.9 g; 69 mmol) were added to a dry nitrogen-
filled flask in a dry box. DME (100 mL) was added to the
reaction flask, and the resulting mixture was refluxed for 2 h
under an atmosphere of N2 to yield a black suspension.
Formylpyrrole 12 (1.12 g; 4.36 mmol) in dry DME (10 mL) was
added, and the mixture was refluxed for 8 h. After being
cooled to rt, the reaction mixture was filtered through a bed
of neutral alumina (CH2Cl2 elution). The filtrate was evapo-
rated, yielding 0.853 g (81%) of the title ethene, mp 208-210
°C.
λ
max: 268 nm (ꢀ 14 100) and 389 (27 500); 1H-NMR: δ,
ppm, 2.06 (s, 6H), 2.27 (s, 6H), 5.33 (s, 4H), 6.60 (s, 2H), 7.38
(m, 10H), 8.79 (bs, 2H); 13C-NMR: δ, ppm, 9.2, 10.6, 65.8,
114.3, 128.1, 128.6, 161.4. LRMS: m/ z (%) 482 (70), 359 (30),
256 (10), 211 (13), 91 (100). HRMS: Calcd for C30H30N2O4:
482.2205. Found 482.2184. Anal. Calcd for C30H30N2O4: C,
74.65; H, 6.27; N, 5.81. Found: C, 74.64; H, 6.17; N, 5.71.
tr a n s-1,2-Bis(5-(ben zyloxyca r bon yl)-4-(2-m eth oxyca r -
bon yleth yl)-3-m eth yl-2-pyr r olyl)eth en e (19). TiCl3(DME)1.5
(4.31 g; 14.9 mmol), Zn-Cu couple (4.0 g; 56.7 mmol), dry DME
(100 mL), and formylpyrrole 1336 (1.20 g; 3.63 mmol) in dry
DME (10 mL) were mixed as described above and then refluxed
for 8 h. After workup as above, the title compound was
obtained as bright yellow crystals (0.521 g, 45.8%), mp 186-
188 °C. 1H-NMR: δ, ppm, 2.29 (s, 6H), 2.46 (t, 4H), 2.85 (t,
4H), 3.62 (s, 6H), 5.34 (s, 4H), 6.68 (s, 2H), 7.38 (m, 10H), 9.00
(bs, 2H). LRMS: m/ z (%) 626 (16), 448 (9), 151 (19), 113 (20),
91 (100). HRMS: Calcd for C36H38N2O8: 626.2628. Found
626.2618. Anal. Calcd for C36H38N2O8: C, 68.98; H, 6.12; N,
4.47. Found: C, 69.28; H, 6.03; N, 4.29.
1,2-Bis(5-(ter t-bu toxyca r bon yl)-3,4-d im eth yl-2-p yr r o-
lyl)eth en e (20). TiCl3(DME)1.5 (5.5 g; 19.1 mmol), Zn-Cu
couple (5.2 g; 72.8 mmol), dry DME (100 mL), and formylpyr-
role 1437 (1.04 g; 4.66 mmol) in dry DME (10 mL) were mixed
as described above and then refluxed for 8 h. After workup,
as above, 0.210 g (21.7%) of the title ethene, mp (unobserved
due to slow decomposition). 1H-NMR: δ, ppm, 1.01 (s, 18H),
1.51 (s, 6H), 1.62 (s, 6H), 6.55 (s, 2H), 10.13 (bs, 2H). LRMS:
m/ z (%) 414 (22), 358 (14), 302 (100), 284 (25), 269 (34).
HRMS: Calcd for C24H34N2O4: 414.2518. Found 414.2497.
(36) Clezy, P. S.; Liepa, A. J .; Nichol, A. W.; Smythe, G. A. Aust. J .
Chem. 1970, 23, 589.
(37) Paine, J . B., III; Woodward, R. B.; Dolphin, D. J . Org. Chem.
1976, 41, 2826.
(38) Smith, K. M.; Miura, M.; Tabba, H. D. J . Org. Chem. 1983, 48,
4779.

Chemistry of 1,2- and 1,1-Bis(2-pyrrolyl)ethenes
J . Org. Chem., Vol. 61, No. 24, 1996 8515
7.5 Hz, 1H), 5.22 (s, 4H), 7.20-7.35 (m, 10H), 9.61 (bs, 2H).
HRMS: Calcd for C32H35ClN2O4: 546.2285. Found 546.2307.
Anal. Calcd for C32H35ClN2O4: C, 70.30; H, 6.46; N, 5.13.
Found: C, 70.12; H, 6.42; N, 4.96.
Ben zyl 4-Acetyl-3-m eth ylp yr r ole-2-ca r boxyla te (41),
Ben zyl 5-Acetyl-3-m eth ylp yr r ole-2-ca r boxyla te (42), a n d
1,1-Bis(5-(b e n zyloxyca r b on yl)-4-m e t h yl-2-p yr r olyl)-
eth en e (39). Stannic chloride (10 mL, 85.6 mmol) was added
over 5-6 min to a well stirred mixture of pyrrole 4016 (11.63
g, 54.0 mmol), dichloromethane (100 mL), and acetic anhydride
(5.6 mL, 59.2 mmol) at 0 °C, under N2. The resulting brick
red suspension was kept at 0 °C for 6 min before being poured
into ice-water/dichloromethane. The organic layer was sepa-
rated, washed with water several times, with aqueous sodium
bicarbonate twice, and then once with brine. The yellow
solution was dried with anhydrous sodium sulfate and evapo-
rated, and the orange-yellow oily residue was crystallized from
25% ethyl acetate/cyclohexane to give benzyl 4-acetyl-3-me-
thylpyrrole-2-carboxylate 41 as the major product in 53% yield,
mp 110-113 °C, 1H-NMR: δ, ppm, 2.39, 2.63 (each s, Me),
5.33 (s, 2H), 7.3 (m, 5H), 7.40 (s, 1H), 9.8 (bs, 1H). A second
crystallization of the mother liquor from 25% ethyl acetate/
cyclohexane gave benzyl 5-acetyl-3-methylpyrrole-2-carboxy-
late 42 in ca. 12% yield, mp 86-88 °C; 1H-NMR: δ, ppm, 2.35,
2.42 (each s, 3H), 5.32 (s, 2H), 6.65 (d, 1H), 7.4 (m, 5H), 9.6
(bs, 1H). Chromatography of the final mother liquor on silica
gel (elution with 25% ethyl acetate/cyclohexane) gave the
desired 1,1-bis(pyrrolyl)ethene 39 as an oil (<1%). λmax: 298
nm; λmax: (CH2Cl2 + TFA) 522 nm; 1H-NMR: δ, ppm, 2.29 (s,
6H), 5.12 (s, 4H), 5.47 (s, 2H), 6.32 (s, 2H), 7.3-7.4 (m, 10H),
10.64 (bs, 2H).
Diet h yl 5-(Ch lor om et h yl)-3,7-d iet h yl-2,8-d im et h yld i-
p yr r om eth a n e-1,9-d ica r boxyla te (30). Pyrrole 31 (1.397
g, 7.708 mmol), TsOH (0.367 g, 1.927 mmol), toluene (30.0 mL),
and 2-chloroacetaldehyde diethylacetal (0.715 mL, 4.779 mmol)
were mixed as above and heated at 100 °C for 75 min, after
which time water and dichloromethane were added. After
workup as above, the solid was purified by successive silica
gel flash columns, the first column being eluted with 1%
methanol/dichloromethane, and the second with 0.5% methanol/
dichloromethane, to give the title compound (1.18 g, 72%) as
a tan/brown foam. Recrystallization from dichloromethane/
n-hexane gave colorless prisms, mp 151-152 °C. 1H-NMR:
δ, ppm, 1.02 (t, J ) 7.5 Hz, 6H), 1.27 (t, J ) 7.5 Hz, 6H), 2.27
(s, 6H), 2.42 (q, J ) 7.5 Hz, 4H), 4.06 (d, J ) 7.2 Hz, 2H), 4.24
(q, J ) 7.5 Hz, 4H), 4.59 (t, J ) 7.2 Hz, 1H), 9.39 (bs, 2H).
HRMS: Calcd for C22H31ClN2O4: 422.1972. Found 422.1977.
Anal. Calcd for C22H31ClN2O4: C, 62.53; H, 7.40; N, 6.63.
Found: C, 62.34; H, 7.37; N, 6.52.
1,1-Bis(5-(b e n zyloxyc a r b on yl)-3-e t h yl-4-m e t h yl-2-
p yr r olyl)eth en e (33). To a solution of 5-(chloromethyl)-
dipyrromethane 29 (503 mg, 0.919 mmol) in freshly distilled
dichloromethane (35 mL), under argon, was added DBU (0.185
mL, 1.241 mmol, 1.35 equiv). The reaction mixture was stirred
at rt in the dark for 22 h, after which time additional DBU
(0.040 mL, 0.268 mmol, 0.29 equiv) was added. After 24 h
(46 h total) all the starting material was consumed (TLC
analysis), so the mixture was purified using a silica gel plug
column (elution with 1% methanol/dichloromethane) to afford
a mixture of products (33, 32, 34) (412 mg, 88%) as a yellow
foam, which was recrystallized from dichloromethane/n-hexane
to give a crystalline yellow powder. Yield data is approxi-
mated, based on the 1H-NMR spectrum of the chromato-
graphed product mixture [approximately 2.5 parts 33 (187 mg,
40%) to 2 parts 32 (87 mg, 19%) to 1 part 34 (137 mg, 29%)].
[Title compound, 33: 1H-NMR: δ, ppm, 0.99 (s, 6H), 2.30 (q,
J ) 7.5 Hz, 4H), 2.31 (s, 6H), 5.26 (s, 4H), 5.43 (s, 2H), 7.35-
7.45 (m, 10H), 9.10 (bs, 2H). HRMS: Calcd for C32H34N2O4:
510.2518. Found 510.2512. trans-1,2-Bis(5-(benzyloxy-
carbonyl)-3-ethyl-4-methyl-2-pyrrolyl)ethene (32): 1H-NMR: δ,
ppm, 1.10 (t, J ) 7.5 Hz, 6H), 2.30 (s, 6H), 2.52 (q, J ) 7.5 Hz,
4H), 5.35 (s, 4H), 6.60 (s, 2H), 7.35-7.45 (m, 10H), 8.84 (bs,
2H). HRMS: Calcd for C32H34N2O4: 510.2518. Found 510.2502.
cis-1,2-Bis(5-(benzyloxycarbonyl)-3-ethyl-4-methyl-2-pyrro-
lyl)ethene (34): 1H-NMR: δ, ppm, 1.06 (t, J ) 7.5 Hz, 6H),
2.28 (s, 6H), 2.44 (q, J ) 7.5 Hz, 4H), 5.20(s, 4H), 6.31 (s, 2H),
7.32 (s, 10H), 8.75 (bs, 2H). HRMS: Calcd for C32H34N2O4:
510.2518; Found 510.2517].
Diben zyl 5-(Ch lor om eth yl)-2,3,7,8-tetr a m eth yld ip yr -
r om eth a n e-1,9-d ica r boxyla te (35). To a rt solution of
pyrrole 22 (2.075 g, 9.050 mmol) and a suspension of Mont-
morillonite K-10 clay (15.0 g) in dichloromethane (150 mL),
under argon, were added 2-chloroacetaldehyde diethyl acetal
(0.865 mL, 5.792 mmol), and then TFA (5.35 mL, 69.685 mmol,
15.4 equiv). This solution was stirred at rt for 90 min, after
which time the solids were filtered off and rinsed several times
with dichloromethane. The combined organic layer was
poured into saturated aqueous sodium bicarbonate and shaken
carefully until effervescence ceased. The aqueous layer was
extracted with dichloromethane, and the combined organic
layer was washed with brine and then dried over anhydrous
sodium sulfate. Evaporation gave a crude product which was
crystallized from dichloromethane/n-hexane to give the title
dipyrromethane (1.69 g, 72%) as a crystalline tan solid. The
mother liquor from the crystallization, after silica gel flash
column chromatography (elution with 1% methanol/dichlo-
romethane), afforded another 0.435 g (18.5%), to give an
overall yield of 91% (2.13 g), mp 158-162 °C. 1H-NMR: δ,
ppm, 1.94 (s, 6H), 2.24 (s, 6H), 4.01 (d, J ) 6.9 Hz, 2H), 4.58
(t, J ) 6.9 Hz, 1H), 5.25 (s, 4H), 7.25-7.40 (m, 10H), 9.25 (bs,
2H). HRMS: Calcd for C30H31ClN2O4: 518.1972. Found
518.1967. Anal. Calcd for C30H31ClN2O4: C, 69.47; H, 6.03;
N, 5.40. Found: C, 69.40; H, 6.13; N, 5.40.
Dib en zyl 2,8-Dim et h yld ip yr r ok et on e-1,9-d ica r b oxy-
la te (43). Attempts to crystallize the foregoing oily 1,1-bis-
(2-pyrrolyl)ethene from ethyl acetate/cyclohexane yielded the
1
title dipyrroketone as needles, mp 203-205 °C; H-NMR: δ,
ppm, 2.39 (s, 6H), 5.35 (s, 4H), 6.88 (d, 2H), 7.3-7.5 (m, 10H),
9.81 (bs, 2H). HRMS: Calcd for C27H24N2O5: 456.16852.
Found 456.16789. Anal. Calcd for C27H24N2O5: C, 71.04; H,
5.30; N, 6.14. Found C, 70.99; H, 5.33; N, 6.17.
Diben zyl 2,3,5,7,8-P en ta m eth yld ip yr r om eth a n e-1,9-d i-
ca r boxyla te (44). 1,1-Dipyrrolylethene 24 (1.13 g, 2.34 mmol)
in THF (2l mL) was hydrogenated over Adams catalyst (39
mg; 7 mol%) using a hydrogen balloon at rt. The reaction was
1
monitored by H-NMR spectroscopy. After 17 h, the reaction
was only about 30% completed, so more Adams catalyst (ca.
12 mg) was added. When the total reaction time reached 5
1
days, H-NMR spectra indicated negligible starting material
to be present, so the catalyst was filtered off and the solvent
was evaporated under reduced pressure. The brownish resi-
due was chromatographed on silica gel (elution with 1:3 ethyl
acetate/cyclohexane) to remove debenzylated product and base
line material. Recrystallization of the residue from ethyl
acetate/cyclohexane afforded 0.82 g (1.69 mmol, 72%) of the
1
title product as a white solid, mp 159.5-161.5 °C; H-NMR:
δ, ppm, 1.56 (d, 3H), 1.86 (s, 6H), 2.24 (s, 6H), 4.27 (q, 1H),
5.28 (s, 4H), 7.3 (m, 10H), 8.69 (bs, 2H); LRMS: m/ z (%) 484.2
(66), 91.0 (100). Anal. Calcd for C30H32N2O4: C, 74.36; H, 6.66;
N, 5.78. Found: C, 74.31; H, 6.56; N, 5.71.
1,9-Difor m yl-3,7-b is(2-(m et h oxyca r b on yl)et h yl)-2,8-
d im eth yld ip yr r om eth a n e (46) a n d 3,7-Bis(2-(m eth oxy-
car bon yl)eth yl)-2,8-dim eth yl-1-for m yl-9-(tr iflu or oacetyl)-
d ip yr r om eth a n e (50). Dipyrromethane 4818 (1.0 g; 1.63
mmol), in THF (56 mL), triethylamine (0.1 mL), and absolute
ethanol (20 mL) was hydrogenated over 10% Pd-C (100 mg)
at rt overnight, before being filtered through Celite to remove
the catalyst. The solvent was evaporated to give the dicar-
boxylic acid 49 as a yellow solid, which was dissolved in TFA
(46 mL) under N2 and stirred for 45 min. The mixture was
cooled to -5 °C (ice water/NaCl) while separately and simul-
taneously triethyl orthoformate (28 mL) was also cooled. The
triethyl orthoformate was added to the cold mixture and
stirred for 8 min before removing the ice/NaCl bath and
stirring for another 2 min. The mixture was poured into
aqueous sodium bicarbonate/CH2Cl2 mixture, and the organic
layer was separated, washed with water, dried over Na2SO4,
and evaporated to give a dark orange oil. The oil was
chromatographed on a silica gel flash column [elution with
cyclohexane/ethyl acetate (70/30)]. The appropriate fractions
were combined and the solvent was evaporated to give the title
dipyrromethane as a white solid (311.7 mg, 48%), mp 179-

8516 J . Org. Chem., Vol. 61, No. 24, 1996
Xie et al.
181 °C (lit.18 180-181 °C). 1H-NMR: δ, ppm, 2.28 (s, 6H), 2.50
(t, 4H), 2.78 (t, 4H), 3.68 (s, 6H), 4.04 (s, 2H), 9.42 (s, 2H),
10.46 (bs 2H). The 9-(trifluoroacetyl)dipyrromethane 50 was
also isolated from the column as a light tan solid (27%), mp
136-138 °C. 1H-NMR: δ, ppm, 2.30 (s, 3H), 2.32 (s, 3H), 2.56
(m, 4H), 2.80 (m, 4H), 3.69 (s, 3H), 3.70 (s, 3H), 4.11 (s, 2H),
9.48 (s, 1H), 10.21 (bs, 1H), 10.34 (bs, 1H). 13C-NMR: δ, ppm,
8.9, 11.2, 18.9, 19.0, 22.7, 34.0, 34.2, 51.8, 117.0 (CaF3 [J 19F-a
) 285.26 Hz]), 121.5, 128.9, 133.0, 133.2 (5R-Cc [J 19F-c ) 6.29
Hz]), 135.7, 136.6, 168.3 (-CbOCF3 [J 19F-b ) 35.73 Hz]), 173.4,
173.5, 177.0. LRMS: m/ z (%) 470 (100), 441 (33), 395 (42),
321 (28), 113 (50). HRMS: Calcd for C22H25F3N2O6: 470.1665.
Found 470.1679. Anal. Calcd for C22H25F3N2O6: C, 56.17; H,
5.36; N, 5.95. Found: C, 55.55; H, 5.24; N, 5.90.
13,17-Bis(2-(m eth oxycar bon yl)eth yl)-2,3,5,7,8,12,18-h ep-
ta m eth ylp or p h yr in (47). Meth od A: A mixture of 1,1-bis-
(pyrrolyl)ethene 24 (224.5 mg, 0.465 mmol), THF (5.8 mL), and
10% Pd-C (44 mg, 9 mol %) was stirred under hydrogen
(under a balloon) at rt for 3.5 h. The catalyst was filtered off
and washed with MeOH/THF (1:1). The filtrate was evapo-
rated under vacuum at 40-50 °C to give 2,3,5,7,8-pentameth-
yldipyrromethane-1,9-dicarboxylic acid 45, which was imme-
diately treated with TFA (2 mL) and stirred at rt under
nitrogen for 30 min. A solution of 1,9-diformyldipyrromethane
46 (183.5 mg, 0.456 mmol) in dry dichloromethane (30 mL)
was added and rinsed with more dichloromethane (15 mL).
The red reaction mixture was stirred at rt under oxygen (via
a balloon) for 42 h. It was then poured into dichloromethane/
water. The organic layer was separated and washed succes-
sively with water, saturated sodium bicarbonate solution, and
brine, dried over anhydrous sodium sulfate, and evaporated
to dryness. The residue was purified by column chromatog-
raphy (neutral alumina, Brockmann Grade III; elution with
1% MeOH/dichloromethane) to provide the 5-substituted por-
phyrin 47 as the fastest-running band. Crystallization from
CH2Cl2/hexane afforded 74 mg (0.127 mmol, 28%) of the title
porphyrin, mp > 300 °C; λmax: 404 nm (ꢀ 174 000), 504 (14
000), 538 (5800), 576 (5800), 628 (1900); 1H-NMR: δ, ppm,
-3.14 (bs, 2H), 3.27 (t, 4H), 3.46, 3.53 (each s, 6H), 3.60, 3.68
(each s, 6H), 4.35 (s and overlapping t, 7H), 9.82 (s, 1H), 9.98
(s, 2H). LRMS: m/ z (%) 580.3 (100). HRMS: Calcd for
C35H40N4O4: 580.3049. Found 580.3037. Anal. Calcd for
C35H40N4O4: C, 72.39; H, 6.94; N, 9.65. Found: C, 72.28; H,
6.89; N, 9.28.
Met h od B: A mixture of 1,9-dicarboxylic acid 53 (made
from 231 mg, 0.644 mmol, of the corresponding diethyl ester)
and 1,9-diformyldipyrromethane 46 (284 mg, 0.706 mmol) was
stirred in the presence of TsOH (436 mg, 2.29 mmol) for 20 h
at rt under nitrogen. The reaction was monitored by spectro-
photometry. An absorption around λmax 618 nm was observed
shortly after the reaction was initiated and its intensity
decreased with time. After being exposed to air, a Soret
absorption around λmax 404 nm was observed and its intensity
increased with time. The final reaction mixture was washed
with aqueous sodium bicarbonate and saturated sodium
chloride solution. After drying over anhydrous sodium sulfate,
the solvent was evaporated and the residue was chromato-
graphed (neutral alumina, Brockmann Grade III; elution with
1% MeOH in dichloromethane) to give the 5-methylporphyrin
47 as the major product in low yield. 1H-NMR and analytical
TLC indicated that this product was identical to that obtained
by the method A.
13,17-Bis(2-ca r boxyeth yl)-2,3,5,7,8,12,18-h ep ta m eth yl-
h em in Ch lor id e (51). A solution of porphyrin 47 (33 mg,
0.057 mmol) in chloroform (20 mL) was degassed with a
nitrogen purge for 30 min. Iron(II) chloride (525 mg, 2.709
mmol) was added to degassed methanol (10 mL), which was
degassed an additional 30 min, after which time the solution
of 47 in chloroform was added. The mixture was heated at
50 °C for 80 min in the dark under argon and then poured
into water; dichloromethane was added, and the organic layer
was separated. The aqueous layer was extracted with dichlo-
romethane, and the combined organic layer was washed with
water and with brine and then dried over anhydrous sodium
sulfate. The solvent was evaporated to afford a deep brown
solid [Fe(III) µ-oxo-dimer] which was used for the next step
without further purification [λmax (rel absorbance) 394 nm
(17.43), 501 (2.10), 533 (1.67), 638 (1.00).] To a solution of the
above product in THF (28 mL) and methanol (15 mL), under
argon, was added 1 N potassium hydroxide (6 mL). The
mixture was stirred vigorously at rt in the dark for 24 h. The
reaction mixture was poured into water, chloroform was added,
and the aqueous layer was separated. The aqueous layer was
acidified with 2 N HCl (2-3 mL) to pH 3, and the resulting
flocculant precipitate was extracted with 30% THF in diethyl
ether. The solvent was evaporated to afford the crude product
which was recrystallized from THF/n-hexane to afford the
desired product 3,7-bis(2-carboxyethyl)-2,3,5,7,8,12,18-hep-
tamethylhemin chloride 51 (30 mg, 81%) as a brown precipi-
tate. The purity of the hemin chloride dicarboxylic acid was
confirmed by low-spin 1H-NMR spectroscopy. [1H-NMR: δ,
ppm, (D2O) 46.75 (bs, 3H), 12.12 (s, 6H), 11.84 (s, 6H), 11.59
(s, 6H), 6.87 (s, 4H), 4.02 (s, 4H) -11.52 (s, 1H), -18.59 (s,
2H)]. This material has been used23 in studies of biliverdin
formation by a recombinant, truncated human HO-1.21
1,1-Bis(5-(et h oxyca r b on yl)-3,4-d im et h yl-2-p yr r olyl)-
eth en e (54). Stannic chloride (10 mL, 85.6 mol) was added
over 10 min to a well-stirred mixture of pyrrole 55 (9.97 g,
59.6 mmol), dichloromethane (120 mL), and acetic anhydride
(4.0 mL, 42.3 mmol) at 0 °C under nitrogen. After the addition
was complete, the dark red solution was stirred at 0 °C under
nitrogen for an additional 5 min. An additional 1.6 mL of
acetic anhydride (total amount: 59.2 mmol) was added drop-
wise. The mixture was stirred for a further 10 min before it
was poured in ice water. The organic layer was separated,
washed with cold water, aqueous sodium bicarbonate, and
brine, and then dried over anhydrous sodium sulfate. Evapo-
ration and chromatography on silica gel (elution with 25%
ethyl acetate/cyclohexane) gave 1.28 g (12%) of the title 1,1-
bis(pyrrolyl)ethene 54 from the minor, fast running band, mp
1
154-156 °C; H-NMR: δ, ppm, 1.28 (t, 6H), 2.06, 2.26 (each
s, 6H), 4.06 (q, 4H), 5.44 (s, 2H), 9.99 (bs, 2H). HRMS: Calcd
for C20H26N2O4; 358.1893. Found 358.1888. Anal. Calcd for
C20H26N2O4: C, 67.00; H, 7.32; N, 7.82. Found C, 67.03; H,
7.37; N, 7.83. Ethyl 5-acetyl-3,4-dimethylpyrrole-2-carboxylate
56 was isolated as the major product (slow running band), but
the yield was not determined, mp 102-104 °C, (lit.39 mp 106
°C and 106-108 °C); 1H-NMR: δ, ppm, 1.30 (t, 3H), 2.21, 2.22,
2.42 (each s, 3H), 4.26 (q, 2H), 9.5 (s, 1H).
2,3,7,8-Tetr a m eth yl-5-m eth ylen ed ip yr r om eth a n e-1,9-
d ica r boxylic Acid (53). A solution of KOH (0.879 g; 15.7
mmol, 4 equiv) in 95% ethanol (16 mL) was added to a mixture
of 54 (0.728 g; 2.03 mmol) in 95% ethanol (30 mL). The
suspension turned into a solution upon heating. The resulting
orange-red solution was refluxed for 4 h. Most of the solvent
was removed at reduced pressure. The solid residue was
dissolved in enough water to give a yellow-brown solution
which, after extraction with dichloromethane, was acidified
to pH 2 with 1 N HCl. An olive green precipitate was collected,
washed with water several times, and dried in vacuum oven
at 70 °C overnight, to afford 0.460 g (1.52 mmol; 75%) of the
title product, mp >180 °C dec; 1H-NMR: δ, ppm, (CDCl3
+
DMSO-d6) 1.56, 1.98 (each s, 6H), 5.15 (s, 2H), 9.12 (bs, 2H).
3,3-Bis(5-(ben zyloxyca r bon yl)-3,4-d im eth yl-1H-2-p yr -
r olyl)a cr olein (57). Vilsmeier reagent was prepared by
mixing dry DMF (0.46 mL; 5.94 mmol) and POCl3 (0.35 mL;
3.75 mmol) at 0 °C under nitrogen. The mixture was kept at
0 °C for 5 min before addition of 34 (573.7 mg; 1.19 mmol) in
dry carbon tetrachloride (26 mL) over 10 min. The mixture
was warmed to 50 °C and maintained at this temperature for
3 h before being cooled slightly and addition of saturated
sodium acetate solution (40 mL). The two-phase mixture was
stirred at rt for 1.5 h. The organic layer was separated, and
the aqueous layer was extracted with dichloromethane, which
was washed successively with sodium bicarbonate solution,
water, and then brine. It was dried over anhydrous sodium
sulfate and then evaporated under reduced pressure. The
residue was chromatographed on silica gel (elution with 25%
ethyl acetate/cyclohexane). The desired product was collected
(39) Fisher, H.; Ho¨felmann, H. Liebigs Ann. Chem. 1938, 533, 216.
Moon, M. W.; Wade, R. A. J . Org. Chem. 1984, 49, 2663.

Chemistry of 1,2- and 1,1-Bis(2-pyrrolyl)ethenes
J . Org. Chem., Vol. 61, No. 24, 1996 8517
and crystallized from dichloromethane/hexane to give 547 mg
(1.07 mmol, 90%) of the title compound as a yellow solid, mp
178.5-180.5 °C; 1H-NMR: δ, ppm, 2.08, 2.18, 2.27, 2.30 (each
s, 3H), 5.07, 5.09 (each s, 2H), 6.35 (d, 1H), 7.33 (bd, 10H),
9.44 (d, 1H), 10.18, 10.70 (each bs, 1H,); 13C-NMR: δ, ppm,
10.8, 10.9, 11.8, 66.3, 121.7, 121.9, 124.4, 125.6, 126.0, 127.2,
127.6, 128.0, 128.2, 128.5, 131.2, 135.3, 135.3, 139.9, 161.4,
161.9, 192.6. LRMS: m/ z (%) 511.1 (100, MH+), 91.0 (71).
Anal. Calcd for C31H30N2O5: C, 72.92; H, 5.92; N, 5.49.
Found: C, 72.81; H, 5.83; N, 5.37.
Calcd for C33H37N3O4: C, 73.44; H, 6.91; N, 7.79. Found: C,
73.20; H, 6.82; N, 7.63.
1,1-Bis(5-(eth oxycar bon yl)-3,4-dim eth yl-1H-2-pyr r olyl)-
3-(d im eth yla m in o)p r op en e (60). 1,1-Dipyrrolylethene 54
(232 mg; 0.647 mmol) and Eschenmoser’s salt (946 mg; 5.11
mmol, 8 equiv) was stirred at rt for 20 h, as described above.
Chromatography gave 255 mg (95%) of the title product as
pale flaky solid, mp 101-103 °C; 1H-NMR: δ, ppm, 1.28 (t,
6H), 1.71, 1.80, 2.17, 2.20 (each s, 3H), 2.67 (s, 6H), 2.59 (d,
2H), 4.14 (q, 4H), 6.25 (t, 1H), 9.71, 10.49 (each bs, 1H). Anal.
Calcd for C23H33N3O4: C, 66.48; H, 8.00; N, 10.11. Found: C,
66.44; H, 8.03; N, 10.00.
1,1-Bis(5-(ben zyloxyca r bon yl)-3,4-d im eth yl-1H-2-p yr -
r olyl)-3-d im eth yla m in op r op en e (59). A mixture of 1,1-bis-
(pyrrolyl)ethene 24 (215 mg; 0.446 mmol) and Eschhenmoser’s
salt 58 (670 mg; 3.62 mmol, 8 equiv) in dry dichloromethane
(50 mL) was stirred at rt for 20 h. The yellow suspension was
diluted with dichloromethane, washed with water and then
with brine, and then dried over anhydrous sodium sulfate and
evaporated. The residue was chromatographed (neutral alu-
mina, Brockmann Grade III; elution with 0-2% MeOH/
dichloromethane) to afford 215 mg (0.398 mmol, 90%) of the
Ack n ow led gm en t. This work was supported by
grants from National Institutes of Health (HL 22252),
the National Science Foundation (CHE 93-05577), the
Deutsche Forschungsgemeinschaft, and the Fonds der
Chemischen Industrie. Mass spectrometric analyses
were performed by the UCSF Mass Spectrometry Facil-
ity (A. L. Burlingame, Director) supported by the
Biomedical Research Technology Program of the Na-
tional Center for Research Resources, NIH NCRR BRTP
01614.
1
title product as pale flaky solid, mp 57-59 °C; H-NMR: δ,
ppm, 1.51, 1.94, 2.32, 2.34 (each s, 3H), 2.19 (s, 6H), 2.86 (d,
2H), 5.31, 5.33 (each s, 2H), 5.87 (t, 1H), 7.4 (m, 10H), 8.77,
12.80 (each bs, 1H); 13C-NMR: δ, ppm, 9.0, 9.5, 10.31, 10.6,
44.0, 56.2, 65.4, 65.5, 117.6, 118.9, 119.1, 120.5, 126.1, 127.9,
128.2, 128.4, 128.4, 129.5, 130.7, 132.6, 136.4, 136.5, 161.3.
LRMS: m/ z (%) 539.3 (18, M+), 495.2 (100), 91.1 (31). Anal.
J O961582Z