Refined synthesis of 5-substituted dipyrromethanes

Full text of DOI:10.1021/jo982015+

J . Org. Chem. 1999, 64, 1391-1396
1391
tion of benzaldehyde in excess pyrrole, we found that the
principal reaction products consist of the dipyrromethane
(1), the N-confused dipyrromethane (2,3′-dipyrromethane)
(2) and the tripyrrane (3) (Scheme 1). The presence of
the N-confused dipyrromethane was surprising as this
species had not been detected previously.8 Using GC we
have examined the distribution of these products as a
function of the pyrrole:benzaldehyde ratio and the acid
catalyst. We have developed a purification process based
on bulb-to-bulb distillation followed by recrystallization
that affords analytically pure dipyrromethanes in mul-
tigram quantities. The condensation of pyrrole and
benzaldehyde upon heating without added acids has also
been examined.
Refin ed Syn th esis of 5-Su bstitu ted
Dip yr r om eth a n es
Benjamin J . Littler, Mark A. Miller,
Chen-Hsiung Hung,† Richard W. Wagner,
Donal F. O’Shea,‡ Paul D. Boyle, and
J onathan S. Lindsey*
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
Received October 6, 1998
In tr od u ction
5-Substituted dipyrromethanes are important precur-
sors for the synthesis of meso-substituted porphyrins,1
expanded porphyrins, and porphyrin analogues.2 Several
one-flask methods have been reported for the synthesis
of 5-substituted dipyrromethanes by the condensation of
an aldehyde and pyrrole using various combinations of
acids and solvents.3-14 We previously reported a one-flask
synthesis of dipyrromethanes in which an aldehyde is
dissolved in a 40-fold excess of pyrrole with a catalytic
amount of an acid at room temperature in the absence
of any other solvent.8 This method has afforded good
yields of 5-substituted dipyrromethanes bearing many
types of functional groups.15 However, purification of the
product is typically achieved by flash column chroma-
tography, restricting application to the small-scale prepa-
ration of dipyrromethanes.
Resu lts a n d Discu ssion
In vestiga tion of Rea ction Con d ition s. We first
examined the crude product distribution formed under
our previously reported conditions for the synthesis of
5-phenyldipyrromethane, which involve reaction of pyr-
role and benzaldehyde (40:1) catalyzed by TFA (0.1 equiv)
at room temperature for 15 min.8 Analysis of the crude
product by GC showed three major peaks which were
assigned as 5-phenyldipyrromethane (1), N-confused
5-phenyldipyrromethane (2), and 5,10-diphenyltripyr-
rane (3). Identification of 1 was made by comparison with
pure material prepared by our previously reported
method.8 The N-confused dipyrromethane 2 was assigned
by comparison with an authentic sample (vide infra).
Assignment of tripyrrane 3 was based on GC-MS data
which showed a molecular ion with m/z ) 377 and by
comparison with an impure sample of 3 (ca. 90% pure)
prepared in a manner analogous to that described by
Bru¨ckner et al.16 Minor peaks (typically less than 5% of
the total area) seen in the chromatogram could not be
assigned by GC-MS and were easily removed in the
purification procedure developed (vide infra). Benzalde-
hyde was not detected in any samples, even those
removed 5 min after the addition of acid, hence the rate
of reaction must be rapid.
To optimize the formation of the dipyrromethane, we
initially examined the effect of changing the pyrrole:
benzaldehyde ratio on the crude product distribution
(Figure 1). The product distribution showed little change
with time, indicating that the reaction is essentially
complete within 5 min and that extended reaction did
not lead to the formation of higher oligomers. As the
pyrrole:benzaldehyde ratio increases the dipyrromethane:
tripyrrane (1:3) ratio increased for both TFA and BF3‚
Et2O catalysis. The ratio was much higher under BF3‚
Et2O catalysis because little tripyrrane is formed under
these conditions. TFA catalysis gave a lower 1:3 ratio,
but also gave significantly lower amounts of the N-
confused dipyrromethane 2.
Our objective in this study was to eliminate the use of
chromatography during purification, thereby removing
the major bottleneck to the synthesis of multigram
quantities of dipyrromethanes. Upon examining the
crude reaction mixture from the acid-catalyzed condensa-
† Present address: National Changhua University of Education,
Changhua, Taiwan 50058.
‡ Present address: Eastman Kodak Company, 1999 Lake Avenue,
Rochester, NY 14650.
(1) Lindsey, J . S. In Metalloporphyrins Catalyzed Oxidations; Klu-
wer Academic Publishers: The Netherlands, 1994; pp 49-86.
(2) J asat, A.; Dolphin, D. Chem. Rev. 1997, 22677-2340.
(3) Nagarkatti, J . P.; Ashley, K. R. Synthesis 1974, 186-187.
(4) Casiraghi, G.; Cornia, M.; Rassu, G.; Del Sante, C.; Spanu, P.
Tetrahedron 1992, 48, 5619-5628.
(5) Hammel, D.; Erk, P.; Schuler, B.; Heinze, J .; Mu¨llen, K. Adv.
Mater. 1992, 4, 737-739. See also: Bru¨ckner, C.; Posakony, J . J .;
J ohnson, C. K.; Boyle, R. W.; J ames, B. R.; Dolphin, D. J . Porphyrins
Phthalocyanines 1998, 2, 455-465.
(6) Boyle, R. W.; Xie, L. Y.; Dolphin, D. Tetrahedron Lett. 1994, 35,
5377-5380.
(7) Casiraghi, G.; Cornia, M.; Zanardi, F.; Rassu, G.; Ragg, E.;
Bortolini, R. J . Org. Chem. 1994, 59, 1801-1808.
(8) Lee, C.-H.; Lindsey, J . S. Tetrahedron 1994, 50, 11427-11440.
(9) Mizutani, T.; Ema, T.; Tomita, T.; Kuroda, Y.; Ogoshi, H. J . Am.
Chem. Soc. 1994, 116, 4240-4250.
(10) Staab, H. A.; Carell, T.; Do¨hling, A. Chem. Ber. 1994, 127, 223-
229.
(11) Vigmond, S. J .; Chang, M. C.; Kallury, K. M. R.; Thompson,
M. Tetrahedron Lett. 1994, 35, 2455-2458.
(12) Nishino, N.; Wagner, R. W.; Lindsey, J . S. J . Org. Chem. 1996,
61, 7534-7544.
(13) Wijesekera, T. P. Can. J . Chem. 1996, 74, 1868-1871.
(14) Setsune, J .; Hashimoto, M.; Shiozawa, K.; Hayakawa, J .; Ochi,
T.; Masuda, R. Tetrahedron 1998, 54, 1407-1424.
(15) For some highly functionalized examples; see: (a) Cornia, M.;
Binacchi, S.; Del Soldato, T.; Zanardi, F.; Casiraghi, G. J . Org. Chem.
1995, 60, 4964-4965. (b) Rudkevich, D. M.; Verboom, W.; Reinhoudt,
D. N. J . Org. Chem. 1995, 60, 6585-6587. (c) Halterman, R. L.; Mei,
X. Tetrahedron Lett. 1996, 37, 6291-6294. (d) Milgrom, L. R.; Yahioglu,
G. Tetrahedron Lett. 1996, 37, 4069-4072.
Next, we examined the effect of different concentra-
tions of BF3‚Et2O and TFA on the distribution of products
for condensations performed at a 25:1 pyrrole:benzalde-
hyde ratio (Figure 2). With 0.316 equiv of acid (relative
to benzaldehyde), the percentage of 3 declined markedly
(16) Bru¨ckner, C.; Sternberg, E. D.; Boyle, R. W.; Dolphin, D. J .
Chem. Soc., Chem. Commun. 1997, 1689-1690.
10.1021/jo982015+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/27/1999

1392 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 1
F igu r e 2. Percentage of the total area of the gas chromato-
gram occupied by 1-3 for the condensation of pyrrole and
benzaldehyde (25:1) catalyzed by a range of TFA (filled
symbols) or BF3‚Et2O (open symbols) equivalents (0.0316
equiv, b; 0.100 equiv, 2; 0.316 equiv, [). Note that the scale
extends only to 10% for 2.
Sch em e 2
of the assignment of 2 was provided by an authentic
sample prepared by the synthetic route shown in Scheme
2. This sample gave GC-MS data identical to the peak
observed by GC-MS of the crude reaction mixture pro-
duced by condensation of benzaldehyde with pyrrole and
1
gave a H NMR spectrum consistent with peaks observed
in a partially purified sample.
F igu r e 1. Percentage of the total area of the gas chromato-
gram occupied by 1-3 for the condensation of pyrrole and
benzaldehyde catalyzed by 0.1 equiv of TFA (filled symbols)
or BF3‚Et2O (open symbols) over a range of pyrrole:benzalde-
hyde ratios (5:1, b; 10:1, 9; 25:1, 2; 40:1, 1; 80:1, [). The
reaction mixture was sampled at 5, 10, 20, and 40 min. Note
that the scale extends only to 10% for 2.
We also prepared N-confused 5-mesityldipyrromethane
(6) as shown in Scheme 3 from mesitaldehyde and the
anion derived from 3-bromo-1-(triisopropylsilyl)pyrrole
(7).19 The authentic sample of 6 obtained in this manner
gave GC-MS and 1H NMR data identical to that of a
byproduct formed in the condensation of mesitaldehyde
with neat excess pyrrole. These two routes provide access
to N-confused dipyrromethanes from either the aldehyde
or the acid chloride.
and a number of broad new peaks appeared in the
chromatogram, making accurate integration difficult.
Reducing the amount of acid from 0.1 to 0.0316 equiv
had little change on the percentage of 1, but the percent-
age of 2 and 3 showed a small increase at the lower acid
concentration. Therefore, all further reactions were run
with 0.1 equiv of acid.
In vestiga tion of Isola tion P r oced u r es. The major
limitation of our previous method for the preparation of
dipyrromethanes was the requirement to purify the
Syn th esis an d Iden tification of N-Con fu sed Dipyr -
r om eth a n es. Identification of the N-confused dipyr-
romethane 2 is noteworthy because such species have not
been previously identified in dipyrromethane condensa-
tions involving unsubstituted pyrrole,17 though acid-
catalyzed acylation of pyrrole is known to give 2-substi-
tution accompanied by some 3-substitution.18 We were
unable to separate a sample of pure 2 from the crude
reaction mixture using chromatography, so confirmation
(17) Production of a 2,3′-dipyrrylmethane from the condensation
between ethyl pyrrole 2-carboxylate and o-nitrobenzaldehyde catalyzed
by TiCl4 in CH2Cl2 has been recently reported in ref 14. However, it
should be noted that the introduction of an electron-withdrawing group
onto the 2-position pyrrole ring is known to promote substitution at
both the 4- and 5-position; see: J ackson, A. H. In Pyrroles, Part One;
J ones, R. A., Ed.; Wiley-Interscience: New York, 1990; Vol. 48, The
Chemistry of Heterocyclic Compounds, pp 295-303.
(18) Anderson, H. J .; Loader, C. E. In Pyrroles, Part One; J ones, R.
A., Ed.; Wiley-Interscience: New York, 1990; Vol. 48, The Chemistry
of Heterocyclic Compounds, pp 397-497.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1393
Sch em e 3
F igu r e 3. Isolated yields of dipyrromethanes (1 and 2)
prepared by the refined procedure (pyrrole and benzaldehyde,
TFA 0.1 equiv, 5 min, followed by distillation) over a range of
pyrrole:benzaldehyde ratios from 5:1 to 80:1.
of ratios from 5:1 to 80:1. Figure 3 shows that the isolated
yields of dipyrromethanes after distillation increased
with the pyrrole:benzaldehyde ratio in a manner consis-
tent with the GC data (Figure 1) but that the isolated
yields showed a greater range than the GC data. This
result is consistent with the hypothesis that a high
pyrrole:benzaldehyde ratio prevents polymerization and
therefore reduces the amount of nonvolatile material that
cannot be examined by GC. As a compromise between
the increased isolated yield of dipyrromethane at high
pyrrole:benzaldehyde ratios and the requirement for
excessive volumes of pyrrole,20 we prefer to use a pyrrole:
benzaldehyde ratio of 25:1 in the condensations.
Scop e of Refin ed P r oced u r e. We examined the
scope of the refined procedure developed for 1 by applica-
tion to a range of aldehydes. Examination of the crude
reaction product for each reaction by GC produced a trace
very similar to that seen for the condensation of pyrrole
and benzaldehyde. For every case examined by GC-MS
in this study, a distinct byproduct with a molecular ion
mass identical to the dipyrromethane was observed,
suggesting that the formation of N-confused dipyr-
romethane as a reaction byproduct is universal. We
therefore followed the same purification procedure, in-
volving distillation followed by recrystallization, to pre-
pare analytically pure, multigram batches of 12 dipyr-
romethanes (Table 1). The dipyrromethanes are suf-
ficiently pure to enable the acquisition of X-ray structures
(see the Supporting Information for structures of 1 and
10). Minor modifications to the procedure were required
in four cases:
Sch em e 4
product by column chromatography. In this study we
sought to extend the work of Hammel et al. who first
demonstrated that dipyrromethanes could be purified by
distillation at reduced pressure.5 We found that tripyr-
rane 3 and higher oligomers were easily removed by
distillation, but that removal of the N-confused dipyr-
romethane 2 required recrystallization after distillation
(Scheme 4). This result is relevant to the choice of acid
catalyst because significant amounts of 2 were formed
by reactions catalyzed by BF3‚Et2O (Figure 1) and many
recrystallizations were required for complete removal of
2 (as judged by GC). In contrast, reactions catalyzed by
TFA afforded trace amounts of 2, which were typically
removed by two recrystallizations. Therefore, TFA is the
acid catalyst of choice for the preparation of dipyr-
romethanes. This refined process enabled straightfor-
ward preparation of multigram batches of 5-phenyldipyr-
romethane (1) that are analytically pure and contain
none of the undesired N-confused dipyrromethane 2. A
complete description of studies performed to optimize the
purification procedure is provided in the Supporting
Information.
(1) Mesitaldehyde reacted more slowly with pyrrole
than the other aldehydes examined in this study, requir-
ing 1 h to proceed to completion. (For an assessment of
other methods for preparation and isolation of 10, see
the Supporting Information.)
(2) Paraformaldehyde is relatively insoluble in neat
pyrrole at room temperature, leading to a slow reaction
and poor yields of dipyrromethane.21 Heating the reaction
mixture to 50 °C increased the solubility of the paraform-
aldehyde sufficiently to enable rapid condensation, pro-
viding an expedient synthesis of unsubstituted dipyr-
romethane 22.
To examine how the isolated yields of dipyrromethane
prepared by this refined procedure varied with the
pyrrole:benzaldehyde ratio, we performed a series of
condensations catalyzed by TFA (0.1 equiv) over a range
(19) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T.
T.; Artis, D. R.; Muchowski, J . M. J . Org. Chem. 1990, 55, 6317-6328.
(20) Cost of pyrrole ∼$20/100 cm3 (Aldrich and Acros, 1998).
(21) Wang, Q. M.; Bruce, D. W. Synlett 1995, 1267-1268.

1394 J . Org. Chem., Vol. 64, No. 4, 1999
Ta ble 1. Isola ted Yield a n d Distilla tion Con d ition s of th e 5-Su bstitu ted Dip yr r om eth a n esa
Notes
distillation conditions
aldehyde/ketone
dipyrromethane
yieldb (%)
(°C, mmHg)
benzaldehyde
1
10
11
12
13
14
15
16
17
18
19
20
21
22
53
27
33
41
68
61
57
40
28
65
39
56
53
41
130, 0.03
160-180, 0.03
180, 0.10
mesitaldehydec
p-tolualdehyde
o-tolualdehyde
p-anisaldehyde
o-anisaldehyde
4-iodobenzaldehyde
3-iodobenzaldehyde
4-fluorobenzaldehyde
pentafluorobenzaldehyde
2,6-dichlorobenzaldehyde
4-nitrobenzaldehyde
acetone
180-190, 0.20
200, 0.03
190-210, 0.50
170-180, 0.03
170-180, 0.03
190, 0.08
150-160, 0.03
175-190, 0.03
not distilled
120-130, 0.03
110, 0.04
paraformaldehyde
a
All reactions were performed using a pyrrole:aldehyde ratio of 25:1 with catalysis by TFA (0.1 equiv) for 5 min at room temperature.
Overall yields upon recrystallization of the distilled product. c Reaction was performed for 1 h.
b
(3) p-Nitrophenyldipyrromethane 20 decomposed on
but the isolated yield of 1 fell to 42%. The mechanism of
attempted distillation, but was easily isolated by pre-
cipitation from the crude reaction mixture as described
by Bru¨ckner et al.22
the thermal reaction was not examined in detail, but
catalysis by trace amounts of residual benzoic acid or
adventitious acids cannot be excluded.
(4) 5-(4-Pyridyl)dipyrromethane3 was formed in only
trace amounts using the refined procedure, and no
improvement was achieved with 1.1 equiv of TFA.
The improvement in the synthetic methodology for the
preparation of dipyrromethanes is exemplified by con-
sidering the reported syntheses of 5-(4-methylphenyl)-
dipyrromethane (11): (1) A 6-step synthesis from pyrrole
afforded a brown oil.23 (2) Direct condensation of p-
tolualdehyde and pyrrole in dilute solution gave a solid
(mp 75 °C) after chromatography.11 (3) Direct condensa-
tion in excess pyrrole as the solvent gave a tan solid (mp
110-111 °C)8 or a green solid (mp 114 °C),24 but column
chromatography was required to purify the product, and
in each case less than a gram of material was prepared.
Using the refined procedure described herein we pre-
pared an analytically pure 2.22-g batch of 11 as a
colorless crystalline solid (mp 114 °C) within 4 h without
chromatography.
The experimental information given by D’Auria et al.
is insufficient to assess the radiation absorbed by the
reaction mixture as well as the reaction temperature.25
However, given that (1) pyrrole and benzaldehyde readily
form 1 upon heating and (2) illumination by a high-
pressure Hg lamp produces a significant amount of heat,
formation of 1 by a purely photochemical process remains
to be conclusively demonstrated.
Con clu sion
We have developed a refined synthesis of 5-substituted
dipyrromethanes. The procedure is based on condensa-
tion of an aldehyde with neat excess pyrrole catalyzed
by TFA, followed by bulb-to-bulb distillation to remove
oligomeric material and recrystallization to remove the
N-confused dipyrromethane. The production of N-con-
fused dipyrromethane in the one-flask synthesis appears
to be universal. The procedure requires no chromatog-
raphy, has wide scope, and allows synthesis of pure,
multigram batches of 5-substituted dipyrromethanes.
Th er m a l Con d en sa tion of P yr r ole a n d Ben za ld e-
h yd e. During the course of this work, a photochemical
synthesis of 5-phenyldipyrromethane (1) was reported
by D’Auria et al.25 In this procedure a mixture of pyrrole
and benzaldehyde (694:1) was irradiated by a water-
jacketed high-pressure Hg lamp for 3 h to give 1 in 50%
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra and absorption spectra
were collected routinely. Elemental analyses were performed by
Atlantic MicroLab, Inc. Melting points are uncorrected. A
standard-size Kugelrohr short-path distillation apparatus was
purchased from Aldrich. For reactions of 50 mmol of aldehyde,
the distilling bulb was typically 250 mL, and the collection bulb
was typically 100 mL. Column chromatography was performed
on silica (Baker, 40-µm average particle size) and alumina
(Fisher, 80-200 mesh). Pyrrole was distilled from CaH2 under
Ar at atmospheric pressure. CH2Cl2 was distilled from K2CO3.
THF was distilled from sodium chips under argon with ben-
zophenone/ketyl as indicator. Benzaldehyde was freshly distilled
before use. All other chemicals are reagent grade and were used
as obtained. The dipyrromethanes are easily visualized upon
exposure of thin-layer chromatography plates to Br2 vapor.
P r od u ct Qu a n tita tion by GC. Studies on the effect of the
pyrrole:benzaldehyde ratio and the amount of added acid on the
product distribution were performed by removing 250-µL ali-
quots from the reaction mixture which were immediately
quenched by injecting into a solution of ethyl acetate (240 µL)
containing excess triethylamine (10 µL). These were then
examined using a GC system equipped with a FID detector
[temperature gradient temp 1, 35 °C (5 min); temp 2, 270 °C
(10 min); rate 20 °C/min, total runtime 26.75 min]. [GC-MS was
performed using a temperature gradient of temp 1, 100 °C (3
min); temp 2, 270 °C (10 min); rate 10 °C/min, total runtime 30
1
yield. However, the H NMR spectroscopic data given for
the photochemical product are not consistent with 1H
NMR data for pure 1 or 2 prepared in this study.
While reexamining whether a purely photochemical
process could yield dipyrromethanes, we discovered that
a mixture of pyrrole and benzaldehyde (25:1) stirred
under Ar for 24 h at room temperature (ca. 22 °C) in the
absence of light gave 1 in 3% yield, despite no acid being
deliberately added. An identical reaction mixture stirred
at 40 °C for 24 h gave a GC trace analogous to that
obtained from the deliberately acid-catalyzed process.
Distillation of the crude reaction product afforded 1 in
56% yield. Reaction at 90 °C was complete within 90 min,
(22) Bru¨ckner, C.; Karunaratne, V.; Rettig, S. J .; Dolphin, D. Can.
J . Chem. 1996, 74, 2182-2193.
(23) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J .
Org. Chem. 1993, 58, 7245-7257.
(24) Gaud, O.; Granet, R.; Kaouadji, M.; Krausz, P.; Blais, J . C.;
Bolbach, G. Can. J . Chem. 1996, 74, 481-499.
(25) D’Auria, M.; De Luca, E.; Esposito, V.; Mauriello, G.; Racioppi,
R. Tetrahedron 1997, 53, 1157-1166.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1395
min.] We initially attempted to use GC to quantify the yields of
1-3 by constructing calibration curves for the FID detector using
standard solutions of purified material. These studies demon-
strated that the detector had an approximately linear response
to the amount of 1, 2, or 3 present, but the quantitative results
showed too much variance (up to 10%) to be reliable. Therefore,
we present the percentages of the total area of the chromatogram
with no correction for the differential response of the FID
detector to 1, 2, or 3.
P r ep a r a t ion of N-Con fu sed 5-P h en yld ip yr r om et h a n e
(2). A solution of 3-benzoyl-1-(triisopropylsilyl)pyrrole19 (4) (1.01
g, 3.10 mmol) and K2CO3 (71.1 mg, 0.50 mmol) in methanol (15
mL) was stirred under Ar for 3 h.26 The solvent was removed
under vacuum, and then the crude solid product was dissolved
in CH2Cl2, washed with aqueous NaHCO3, and then dried
(MgSO4). Removal of the solvent under vacuum gave 3-ben-
zoylpyrrole19 (5) (520 mg, 98%) as a colorless solid.
A solution of 5 (456 mg, 2.20 mmol) in CH2Cl2 (2 mL) was
added to a solution of DIBAL-H (1.0 M in CH2Cl2, 4.0 mL, 4.0
mmol) cooled to 0 °C under Ar. After 30 min TLC showed
incomplete reduction, so an additional aliquot of DIBAL-H (1.0
M in CH2Cl2, 0.5 mL, 0.5 mmol) was added. After a further 10
min, no starting material remained. The reaction was quenched
with H2O and diluted with CH2Cl2. The organic phase was
washed with H2O and dried (MgSO4), and the solvent was
removed under vacuum. On the basis of a route for the directed
synthesis of dipyrromethanes,8 the crude reaction product was
immediately dissolved in pyrrole (30 mL, 432 mmol) and
degassed by a stream of Ar for 5 min. TFA (39 µL, 0.51 mmol)
was added, and the reaction mixture was stirred for 10 min;
then 0.1 M aqueous NaOH and CH2Cl2 were added. The organic
phase was dried (MgSO4), concentrated under vacuum, and then
purified by flash column chromatography [Al2O3; hexanes:ethyl
acetate (5:1)], giving 2 (260 mg, 44%) as a brown oil: 1H NMR
(CDCl3) δ 5.34 (s, 1 H), 5.87 (s, 1 H), 6.07 (m, 1 H), 6.13 (q, J )
2.9 Hz, 1 H), 6.39 (m, 1 H), 6.63 (m, 1 H), 6.68 (m, 1 H), 7.23 (m,
5 H), 7.91 (br s, 2 H); 13C NMR (CDCl3) δ 43.2, 106.5, 108.0,
108.7, 116.3, 116.5, 118.2, 125.7, 126.3, 128.3, 128.5, 134.9, 144.5;
MS (EI+) m/z 222 (M+, 86%), 145 (100) [found (HRMS) m/z
222.1159, C15H14N2 requires 222.1157].
by TLC [SiO2; CH2Cl2:hexanes (1:1); I2 chamber detection]. The
reaction mixture was diluted with water, and the aqueous layer
was extracted with ethyl acetate. The combined extracts were
washed with brine, dried (Na2SO4), and concentrated under
vacuum giving a light yellow oil. Column chromatography [Al2O3;
CH2Cl2:hexanes (1:1, then steadily enriched with CH2Cl2)] gave
6 (320 mg, overall yield 11% from 7) as an oil that solidified
upon standing in the freezer: mp 106-107 °C; 1H NMR (CDCl3)
δ 2.08 (s, 6 H), 2.26 (s, 3 H), 5.81 (s, 1 H), 5.95 (m, 1 H), 6.18 (m,
1 H), 6.14 (m, 1 H), 6.50 (s, 1 H), 6.61 (m, 1 H), 6.75 (m, 1 H),
6.76 (s, 2 H), 7.91 (br s, 1 H), 8.02 (br s, 1 H); found (HRMS)
m/z 264.1623, C18H20N2 requires 264.1626.
P r ep a r a tion of th e Dip yr r om eth a n es. Gen er a l P r oce-
d u r e for th e P r ep a r a tion of 5-Su bstitu ted Dip yr -
r om eth a n es. Pyrrole (25 equiv) and the aldehyde (1.0 equiv)
were added to a dry round-bottomed flask and degassed with a
stream of Ar for 5 min. TFA (0.10 equiv) was then added, and
the solution was stirred under Ar at room temperature for 5
min and then quenched with 0.1 M NaOH. Ethyl acetate was
then added. The organic phase was washed with water and dried
(Na2SO4), and the solvent removed under vacuum to afford an
orange oil. Bulb-to-bulb distillation typically gave an oil which
crystallized upon standing. Crystallization of the oil was slow,
so the oil was washed into a round-bottomed flask with ethyl
acetate. Removal of the solvent under vacuum gave a solid that
was recrystallized two times from ethanol or ethanol/water to
give pure dipyrromethane as a crystalline solid.
5-P h en yld ip yr r om eth a n e (1). Pyrrole (87.0 mL, 1.25 mol)
and benzaldehyde (5.00 mL, 50.0 mmol) were reacted by the
general procedure (distilled at 130 °C (0.03 mmHg); recrystal-
lized from ethanol) giving 1 (5.93 g, 53%) as pale yellow
crystals: mp 100-101 °C; 1H NMR (CDCl3) δ 5.48 (s, 1 H), 5.92
(s, 2 H), 6.15-6.18 (m, 2 H), 6.70 (m, 2 H), 7.21-7.33 (m, 5 H),
7.92 (br s, 2 H); 13C NMR (CDCl3) δ 44.6, 107.9, 109.3, 117.8,
127.6, 128.9, 129.3, 133.2, 142.7; MS (EI+) m/z 222 (M+, 100%),
156 (42), 145 (89). Anal. Calcd. for C15H14N2: C, 81.05; H, 6.35;
N, 12.6. Found: C, 80.8; H, 6.3; N, 12.6.
5-Mesityld ip yr r om eth a n e (10). Pyrrole (50.0 mL, 720
mmol) and mesitaldehyde (4.27 g, 28.8 mmol) were added to a
dry 250-mL round-bottomed flask and degassed with a stream
of Ar for 5 min. TFA (222 µL, 5.00 mmol) was then added, and
the solution was stirred under Ar at room temperature for 1 h
and then quenched with triethylamine (1.00 mL). Toluene (200
mL) was then added, and the organic phase was washed with
brine (2 × 150 mL) and dried (Na2SO4). The solvent was removed
under vacuum to give a black oil.27 Bulb-to-bulb distillation at
160-180 °C (0.03 mmHg) gave a highly colored solid that was
washed into a round-bottomed flask with ethyl acetate. The
solvent was evaporated under vacuum until a solid began to
form, and then cyclohexanes (100 mL) were added to precipitate
a yellow solid that was filtered and recrystallized from ethanol/
water (10:1) giving 10 (2.04 g, 27%) as pale yellow crystals: mp
170-171 °C; 1H NMR (CDCl3) δ 2.06 (s, 6 H), 2.28 (s, 3 H), 5.93
(s, 1 H), 6.01 (m, 2 H) 6.17-6.19 (m, 2 H), 6.67 (m, 2 H), 6.87 (s,
1 H), 7.97 (br s, 2 H); 13C NMR (CDCl3) δ 20.6, 20.8, 38.3, 106.5,
108.7, 116.2, 130.4, 131.3, 134.6, 136.6, 137.6; MS (EI+) m/z 264
(M+, 100%), 196 (42), 145 (53). Anal. Calcd. for C18H20N2: C,
81.8; H, 7.6; N, 10.6. Found: C, 81.7; H, 7.7; N, 10.6.
P r ep a r a t ion of N-Con fu sed 5-Mesit yld ip yr r om et h a n e
(6). On the basis of a procedure described by Bray et al.,19
a
sample of 3-bromo-1-(triisopropylsilyl)pyrrole19 (7) (3.50 g, 11.6
mmol) was dissolved in THF (50 mL) at room temperature under
Ar and then cooled to -78 °C in a dry ice-acetone bath.
n-Butyllithium (1.6 M in hexanes, 11.6 mmol, 7.25 mL) was
added dropwise via a syringe. After 15 min mesitaldehyde (1.70
mL, 11.6 mmol) was added dropwise via syringe. Upon the final
addition of mesitaldehyde the reaction mixture was allowed to
warm to room temperature, and then H2O was added. The
aqueous layer was extracted with diethyl ether. The combined
extracts were washed with brine and then dried (Na2SO4).
Removal of the solvent under reduced pressure gave a dark
yellow oil (4 g). Flash column chromatography [SiO2; CH2Cl2:
hexanes (1:1)] gave crude 3-[R-hydroxy-2,4,6-trimethylbenzyl]-
1-(triisopropylsilyl)pyrrole (8) as the third major product eluted.
TLC [CH2Cl2:hexanes (1:1); I2 chamber detection] showed several
minor impurities, and GC-MS showed a mixture of 8 (tR ) 20.5
min, m/z ) 371) and an uncharacterized material (tR ) 11.7 min,
m/z ) 206). The clear yellow oil was used in the next step without
further purification.
5-(4-Meth ylp h en yl)d ip yr r om eth a n e (11). Pyrrole (50.0
mL, 720 mmol) and p-tolualdehyde (3.46 g, 28.8 mmol) were
reacted by the general procedure (distilled at 180 °C (0.1 mmHg);
crystallized from ethyl acetate:hexanes; recrystallized from
ethanol:water 4:1) giving 11 (2.22 g, 33%) as colorless crystals:
Crude 8 (1.00 g, 2.70 mmol) was dissolved in pyrrole (4.7 mL,
67 mmol) at room temperature, and then TFA (21 µL, 0.27 mmol)
was added. After 5 min GC-MS analysis showed complete
consumption of 8. After 30 min of stirring the pyrrole was
removed under vacuum. Flash column chromatography [SiO2;
hexanes:CH2Cl2 (2:1)] gave 9 (500 mg) as the first major band
eluted. GC-MS analysis showed the product to be >98% pure
[tR (product) ) 23.5 min, m/z ) 420]. The TIPS group was
removed by treatment of 9 with powdered KOH (1.2 g) in
methanol/THF (10:1, 11 mL). After the reaction was stirred at
room-temperature overnight, no starting material was detected
1
mp 114 °C; H NMR (CDCl3) δ 2.33 (s, 3 H), 5.44 (s, 1 H), 5.92
(m, 2 H), 6.15 (q, J ) 2.9 Hz, 2 H), 6.68 (m, 2 H), 7.08-7.14 (m,
4 H), 7.91 (br s, 2 H); 13C (CDCl3) δ 21.0, 43.6, 107.1, 108.4, 117.1,
128.2, 129.3, 132.7, 136.5, 139.1; MS (EI+) m/z 236 (M+, 100%),
170 (42), 145 (83). Anal. Calcd for C16H16N2: C, 81.3; H, 6.8; N,
11.85. Found: C, 81.25; H, 6.8; N, 11.8.
(27) The isolation of 10 on a larger scale (4-10 g) is most effective
with the following modifications: (1) The black oil produced on removal
of pyrrole is filtered through a short pad of silica (eluted with CH2Cl2),
affording a brown oil upon removal of CH2Cl2 via rotary evaporation.
(2) The bulb-to-bulb distillation is performed with a dry ice-cooled bulb
inserted between the collection bulb and the Kugelrohr motor to collect
a yellow oil that distills prior to 10.
(26) Attempted removal of the TIPS group with tetrabutylammo-
nium fluoride as described in ref 19 failed, so K2CO3 in methanol was
used instead, see: Austin, W. B.; Bilow, N.; Kelleghan, W. J .; Lau, K.
S. Y. J . Org. Chem. 1981, 46, 2280-2286.

1396 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
5-(2-Meth ylp h en yl)d ip yr r om eth a n e (12). Pyrrole (50.0
mL, 720 mmol) and o-tolualdehyde (3.46 g, 28.8 mmol) were
reacted by the general procedure (distilled at 180-190 °C (0.2
mmHg); crystallized from CH2Cl2:hexanes; recrystallized from
ethanol:water) giving 12 (2.77 g, 41%) as colorless crystals: mp
(EI+) m/z 312 (M+, 100%), 246 (53), 145 (79), 67 (32). Anal. Calcd.
for C15H9N2F5: C, 57.7; H, 2.9; N, 9.0. Found: C, 57.45; H, 2.7;
N, 8.9.
5-(2,6-Dich lor op h en yl)d ip yr r om et h a n e (19). Pyrrole
(25.0 mL, 360 mmol) and 2,6-dichlorobenzaldehyde (2.58 g, 14.4
mmol) were reacted by the general procedure (distilled at 175-
190 °C (0.03 mmHg)) giving 19 (1.63 g, 39%) as yellow crystals:
1
118 °C; H NMR (CDCl3) δ 2.27 (s, 3 H), 5.62 (s, 1 H), 5.88 (m,
2 H), 6.15 (q, 2 H, J ) 2.9 Hz), 6.66 (m, 2 H), 6.94 (m, 1 H),
7.11-7.17 (m, 3 H), 7.83 (br s, 2 H); 13C NMR (CDCl3) δ 19.3,
40.3, 107.2, 108.3, 117.0, 126.2, 126.9, 127.9, 130.5, 131.9, 136.3,
140.5; MS (EI+) m/z 236 (M+, 100%), 168 (54), 145 (85). Anal.
Calcd. for C16H16N2: C, 81.3; H, 6.8; N, 11.85. Found: C, 81.3;
H, 6.8; N, 11.8.
1
mp 102-103 °C; H NMR (CDCl3) δ 6.06 (m, 2 H), 6.19 (q, J )
3.0 Hz, 2 H), 6.49 (s, 1 H), 6.72-6.73 (m, 2 H), 7.11-7.16 (t, J
) 7.9 Hz, 1 H), 7.31-7.34 (d, J ) 7.9 Hz, 2 H), 8.28 (br s, 2 H);
13C NMR (CDCl3) δ 40.0, 107.4, 108.6, 116.9, 128.5, 129.3, 129.6,
135.8, 137.1; MS (EI+) m/z 290 (M+, 68%), 188 (29), 145 (100).
Anal. Calcd. for C15H12N2Cl2: C, 61.9; H, 4.15; N, 9.6. Found:
C, 61.7; H, 4.1; N, 9.6.
5-(4-Meth oxyp h en yl)d ip yr r om eth a n e (13). Pyrrole (50.0
mL, 720 mmol) and p-anisaldehyde (3.92 g, 28.8 mmol) were
reacted by the general procedure (distilled at 200 °C (0.3 mmHg);
recrystallized from diethyl ether:hexanes) giving 13 (4.96 g, 68%)
5-(4-Nitr op h en yl)d ip yr r om eth a n e (20). Pyrrole (25.0 mL,
360 mmol) and 4-nitrobenzaldehyde (2.23 g, 14.4 mmol) were
reacted by the general procedure. However, the crude product
was not distilled but was crystallized from ethyl acetate-
hexanes and then recrystallized from ethanol giving 20 (2.16 g,
56%) as green crystals: mp 159-160 °C; 1H NMR (CDCl3) δ 5.58
(s, 1 H), 5.87 (s, 2 H), 6.17 (q, J ) 2.9 Hz, 2 H), 6.74 (m, 2 H),
7.36 (AA′BB′m, 2 H), 8.01 (br s, 2 H), 8.15 (AA′BB′m, 2 H); 13C
NMR (CDCl3) δ 43.7, 107.8, 108.7, 117.9, 123.8, 129.2, 130.8,
146.9, 149.6; MS (EI+) m/z 267 (M+, 89%), 201 (34), 145 (100),
67 (31). Anal. Calcd. for C15H13N3O2: C, 67.4; H, 4.9; N, 15.7.
Found: C, 67.1; H, 4.95; N, 15.5.
1
as a colorless powder: mp 99 °C; H NMR (CDCl3) δ 3.79 (s, 3
H), 5.42 (s, 1 H), 5.91 (m, 2 H), 6.15 (q, J ) 2.9 Hz, 2 H), 6.68
(m, 2 H), 6.85 (AA′BB′m, 2 H), 7.12 (AA′BB′m, 2 H), 7.91 (br s,
2 H); 13C NMR (CDCl3) δ 43.0, 55.2, 107.0, 108.3, 113.9, 117.1,
129.3, 132.8, 134.1, 158.4; MS (EI+) m/z 252 (M+, 100%), 186
(33), 170 (27), 145 (74). Anal. Calcd. for C16H16N2O: C, 76.2; H,
6.4; N, 11.1. Found: C, 75.9; H, 6.35; N, 11.1.
5-(2-Meth oxyp h en yl)d ip yr r om eth a n e (14). Pyrrole (50.0
mL, 720 mmol) and o-anisaldehyde (3.92 g, 28.8 mmol) were
reacted by the general procedure (distilled at 190-210 °C (0.5
mmHg); recrystallized from CH2Cl2:hexanes) giving 14 (4.40 g,
61%) as a colorless powder: mp 115 °C; 1H NMR (CDCl3) δ 3.77
(s, 3 H), 5.81 (s, 1 H), 5.89 (m, 2 H), 6.13 (q, J ) 2.9 Hz, 2 H),
6.65 (m, 2 H), 6.88-6.92 (m, 2 H), 7.09 (m, 1 H), 7.23 (m, 1 H),
8.06 (br s, 2 H); 13C NMR (CDCl3) δ 37.5, 55.7, 106.6, 108.1,
111.2, 116.7, 120.8, 128.0, 129.4, 130.8, 132.5, 156.6; MS (EI+)
m/z 252 (M+, 100%), 145 (67). Anal. Calcd. for C16H16N2O: C,
76.2; H, 6.4; N, 11.1. Found: C, 76.0; H, 6.35; N, 10.9.
5,5-Dim eth yld ip yr r om eth a n e (21). Pyrrole (87.0 mL, 1.25
mol) and acetone (3.70 mL, 50.0 mmol) were reacted by the
general procedure (distilled at 120-130 °C (0.03 mmHg)) giving
21 (4.57 g, 53%) as colorless crystals: mp 56 °C; 1H NMR (CDCl3)
δ 1.65 (s, 6 H), 6.10 (m, 2 H), 6.14 (m, 2 H), 7.78 (br s, 2 H); 13
C
NMR (CDCl3) δ 29.3, 35.3, 103.7, 107.7, 117.1, and 139.1; MS
5-(4-Iod op h en yl)d ip yr r om eth a n e (15). Pyrrole (25.0 mL,
360 mmol) and 4-iodobenzaldehyde (3.30 g, 14.4 mmol) were
reacted by the general procedure (distilled at 170-180 °C (0.03
mmHg)) giving 15 (2.86 g, 57%) as colorless crystals: mp 145-
(EI+) m/z 174 (M+, 41%), 159 (100), 92 (47). Anal. Calcd. for
C
11H14N2: C, 75.8; H, 8.1; N, 16.1. Found: C, 75.5; H, 8.1; N,
15.9.
Dip yr r om eth a n e (22). A suspension of paraformaldehyde
1
146 °C; H NMR (CDCl3) δ 5.42 (s, 1 H), 5.89 (m, 2 H), 6.16 (q,
J ) 3.0 Hz, 2 H), 6.70-6.72 (m, 2 H), 6.95-6.98 (AA′BB′m, 2
H), 7.62-7.65 (AA′BB′m, 2 H), 8.65 (br s, 2 H); 13C NMR (CDCl3)
δ 43.5, 92.3, 107.4, 108.5, 117.5, 130.4, 131.8, 137.7, 141.9; MS
(EI+) m/z 348 (M+, 100%), 282 (36), 145 (93). Anal. Calcd. for
C15H13N2I: C, 51.7; H, 3.8; N, 8.05. Found: C, 51.7; H, 3.8; N,
8.1.
(1.73 g, 57.7 mmol) in pyrrole (100 mL, 1.44 mol) was placed in
a 250-mL two-necked round-bottomed flask equipped with an
internal thermometer and a water condenser in the reflux
position. The solution was heated to 50 °C, and then the heat
source was removed and TFA (444 µL, 5.77 mmol) was added
immediately. A sharp increase in the temperature of the solution
was observed (to ca. 70 °C), and the solution rapidly became clear
and dark. After 5 min the reaction was quenched and the product
was purified following the general procedure (distilled at 110
°C (0.04 mmHg); recrystallized from ethanol:water 1:1) giving
22 (3.48 g, 41%) as colorless crystals: mp 75 °C; 1H NMR (CDCl3)
δ 3.96 (s, 2 H), 6.03 (m, 2 H), 6.15 (q, J ) 2.9 Hz, 2 H), 6.64 (m,
2 H), 7.81 (br s, 2 H); 13C NMR (CDCl3) δ 26.1, 106.4, 108.1,
117.3, 129.1; MS (EI+) m/z 146 (M+, 100%), 80 (40), 67 (27). Anal.
Calcd. For C9H10N2 C, 73.9; H, 6.9; N, 19.2. Found: C, 73.6; H,
6.9; N, 19.1.
5-(3-Iod op h en yl)d ip yr r om eth a n e (16). Pyrrole (25.0 mL,
360 mmol) and 3-iodobenzaldehyde (3.30 g, 14.4 mmol) were
reacted by the general procedure (distilled at 170-180 °C (0.03
mmHg); crystallized from ethyl acetate/hexanes; recrystallized
from ethanol) giving 16 (1.97 g, 40%) as yellow crystals: mp
102-103 °C; 1H NMR (CDCl3) δ 5.41 (s, 1 H), 5.90 (m, 2 H),
6.16 (m, 2 H), 6.71 (m, 2 H), 7.02-7.07 (m, 1 H), 7.17 (m, 1 H),
7.58-7.61 (m, 2 H), 7.93 (br s, 2 H); 13C NMR (CDCl3) δ 43.4,
94.5, 107.4, 108.4, 117.5, 127.6, 130.3, 131.6, 136.0, 137.2, 144.4;
MS (EI+) m/z 348 (M+, 68%), 282 (24), 145 (100). Anal. Calcd.
for C15H13N2I: C, 51.7; H, 3.8; N, 8.05. Found: C, 51.7; H, 3.6;
N, 7.9.
5-(4-F lu or op h en yl)d ip yr r om eth a n e (17). Pyrrole (50.0
mL, 720 mmol) and 4-fluorobenzaldehyde (3.57 g, 28.8 mmol)
were reacted by the general procedure (distilled at 190 °C (0.08
mmHg); recrystallized from ethanol) giving 17 (1.93 g, 28%) as
Ack n ow led gm en t. This work was supported by the
NIH (GM36238) and by Aeolus, Inc. Mass spectra were
obtained at the NC State University Mass Spectrometry
Laboratory for Biotechnology. Partial funding for the
Facility was obtained from the North Carolina Biotech-
nology Center and the National Science Foundation.
1
colorless crystals: mp 81 °C; H NMR (CDCl3) δ 5.44 (s, 1 H),
5.88 (m, 2 H), 6.15 (q, J ) 2.8 Hz, 2 H), 6.67 (m, 2 H), 6.98 (m,
2 H), 7.17 (m, 2 H), 7.90 (br s, 2 H); 13C NMR (CDCl3) δ 43.1,
107.2, 108.4, 115.1, 115.4, 117.4, 129.7, 129.8, 132.3, 137.7, 160.1,
163.3; MS (EI+) m/z 240 (M+, 100%), 174 (54), 145 (87). Anal.
Calcd. for C15H13FN2 C, 75.0; H, 5.45; N, 11.7. Found: C, 74.8;
H, 5.55; N, 11.6.
Su p p or tin g In for m a tion Ava ila ble: A gas chromato-
gram of the crude reaction mixture from the condensation of
pyrrole and benzaldehyde; a full description of the study into
factors affecting the purification procedure; X-ray structural
data for 1 and 10 including complete atomic coordinates and
thermal parameters, bond distances and angles. This material
is available free of charge via the Internet at http://pubs.acs.org.
5-(P en ta flu or op h en yl)d ip yr r om eth a n e (18). Pyrrole (25.0
mL, 360 mmol) and pentafluorobenzaldehyde (1.76 mL, 14.4
mmol) were reacted by the general procedure (distilled at 150-
160 °C (0.03 mmHg)) giving 18 (2.92 g, 65%) as colorless
crystals: mp 131-132 °C; 1H NMR (CDCl3) δ 5.90 (s, 1 H), 6.02
(m, 2 H), 6.16 (q, J ) 2.9 Hz, 2 H), 6.72-6.75 (m, 2 H), 8.15 (br
s, 2 H); 13C NMR (CDCl3) δ 33.0, 107.6, 108.6, 118.1, 128.1; MS
J O982015+