Organocatalytic synthesis of dipyrromethanes by the addition of N-methylpyrrole to aldehydes

Article abstract of DOI:10.1016/j.tet.2006.09.104

The reaction of aldehydes with N-methylpyrrole carried out in the presence of catalytic pyrrolidinium tetrafluoroborate at room temperature affords the corresponding dipyrromethanes and minor amounts of tripyrranes. This new, mild, and convenient process

Full text of DOI:10.1016/j.tet.2006.09.104

Tetrahedron 62 (2006) 12375–12379
Organocatalytic synthesis of dipyrromethanes
by the addition of N-methylpyrrole to aldehydes
a
a,b
Cinzia Biaggi,a Maurizio Benaglia,a, Laura Raimondi and Franco Cozzi
*
aDipartimento di Chimica Organica e Industriale, Centro di Eccellenza CISI, Universita’ degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
bCNR-ISTM, Universita’ degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
Received 21 June 2006; revised 8 September 2006; accepted 28 September 2006
Available online 25 October 2006
Abstract—The reaction of aldehydes with N-methylpyrrole carried out in the presence of catalytic pyrrolidinium tetrafluoroborate at room
temperature affords the corresponding dipyrromethanes and minor amounts of tripyrranes. This new, mild, and convenient process represents
the first organocatalytic synthesis of dipyrromethanes. The products are obtained in chemical yields similar to those obtained with existing
methods, which, however, require either a much larger excess of heterocycle (when aldehydes are employed as starting materials), or more
drastic reaction conditions (when aldehyde equivalents are used as starting materials) than those employed here. A mechanism is proposed to
explain the course of this reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
The present method improves the previous protocols in that
the products are obtained directly from the aldehydes under
mild reaction conditions, with a relatively small excess of
N-methylpyrrole, and in the presence of a substoichiometric
amount of promoter.
In the context of organic catalysis,1a iminium ion formation
by reaction of a carbonyl compound with a secondary amine
in acidic medium is a ubiquitous mode of activation of car-
bonyl substrates toward addition of electrophiles.1b Based on
this approach we here disclose a new, mild synthesis of di-
pyrromethanes by addition of N-methylpyrrole to aldehydes
catalyzed by the tetrafluoroborate salts of pyrrolidines.
2. Results and discussion
The reaction of N-methylpyrrole with benzaldehyde
(1 mmol) in the presence of 10 mol % of pyrrolidinium tetra-
fluoroborate salt6 in aqueous THF afforded after 24 h at
room temperature N-methyl-2-[1-phenyl-1-(20-N-methyl-
pyrrolyl)-methyl]-pyrrole 1 in 57% yield (Scheme 1, and
entry 1 of Table 1). ‘Tripyrrane’ 2, the major by-product
usually observed in these dipyrromethane syntheses,4,5 was
also isolated in 25% yield as a 1:1 mixture of meso- and
d,l-diastereoisomers.
Dipyrromethanes are important compounds used, inter alia,
as building blocks for the synthesis of porphyrins and cal-
ix[n]phyrins.2 Some dipyrromethanes have applications as
flavors or food additives.3 These compounds are generally
obtained by acid-catalyzed addition of pyrroles and pyrrole
derivatives to aldehydes4 or aldehyde equivalents such as
oxazines.5 However, in the case of the reaction involving
aldehydes (generally carried out at room temperature), a
very large excess of heterocycle is necessary (typically,
50–100 mol equiv with respect to the aldehyde; sometimes
the heterocycle is used as the reaction solvent); when
oxazines are involved, the excess of heteroaromatic com-
pound can be drastically reduced to 4 mol equiv, but much
harsher reaction conditions (300 mol % of acidic promoter,
high reaction temperatures) are required for the reaction to
proceed in acceptable yields (28–62%).5
N
H H
BF4
PhCHO
+
N
R
N
R
N
R
N
R
n
Ph
Ph
1, R = Me, n = 0 2, R = Me, n =1
6, R = H, n = 0 7, R = H, n =1
8, R = H, n = 2 9, R = H, n =3
Ph
COOMe
BF4
CHPh2
BF4
N
N
H
H
3
H
H
4
NMe
MeN
Keywords: Catalysis; Organocatalysis; Heterocycles; Dipyrromethanes;
Nucleophilic addition.
5
* Corresponding author. Tel.: +39 0250314171; fax: +39 0250314159;
e-mail: maurizio.benaglia@unimi.it
Scheme 1. Reaction of N-methylpyrrole and N-methylindole with benz-
aldehyde.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.104

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C. Biaggi et al. / Tetrahedron 62 (2006) 12375–12379
Table 1. Synthesis of dipyrromethane 1 and tripyrrane 2 from benzaldehyde and N-methylpyrrole (NMP) catalyzed by pyrrolidine/HBF4 (P/HBF4) and other
catalysts at room temperature
Entry
PhCHO
(mol equiv)
NMP
(mol equiv)
Catalyst
Catalyst
(mol %)
THF/H2O
t (h)
% Yield
of 1
% Yield
of 2
1
2
3
4
5
6
7
8
9
1
3
1
1
1
1
1
1
1
5
1
1
10
5
5
5
5
5
P/HBF4
P/HBF4
P/HBF4
P/HBF4
P/HBF4
P/HBF4
P/HBF4
3/HBF4
4/HBF4
10
20
20
10
20
10
10
20
20
20:3
20:3
20:3
20:3
20:3
100:0
50:50
20:3
20:3
24
48
48
24
24
24
24
48
48
57
—
—
66
54
35
54
49
40
25
—
—
19
25
23
28
27
31
The influence exerted by reagent stoichiometry on the reac-
tion outcome was examined by varying the amounts of benz-
aldehyde, N-methylpyrrole, and catalyst (entries 2–5 of
Table 1). It was discovered that a small excess of heterocycle
was necessary for the reaction to occur, and that, as ex-
pected, the higher the heterocycle/aldehyde molar ratio the
better the yield of dipyrromethane 1. Indeed with a 1:3 or
1:1 pyrrole/aldehyde ratio (entries 2 and 3), the dipyrro-
methane derivative was not formed in significant yield, even
if 20 mol % was used. However, by employing 10 mol equiv
of N-methylpyrrole, in the presence of 10 mol % of catalyst,
the yield of 1 was increased to 66% (entry 4).
A possible reaction mechanism accounting for the formation
of dipyrromethane 1 is proposed in Scheme 2. Iminium ion
A, formed by condensation of the catalyst with benzalde-
hyde, undergoes addition of N-methylpyrrole to afford
adduct B. Aromatization of the pyrrole nucleus occurs
through deprotonation by the lone pair of the pyrrolidine
nitrogen to afford intermediate C (this step can also be
mediated by the water present in the reaction medium and
acting as proton shuttle). Adduct C can then release the
pyrrolidine precatalyst and the relatively stable carbenium
ion D. The latter undergoes attack of a second molecule
of N-methylpyrrole to afford adduct E. Deprotonation
by pyrrolidine (to aromatize the second heterocyclic unit)
generates product 1 and the catalytically active protonated
pyrrolidine.
Doubling the amount of catalyst did not improve the yield
or the 1/2 ratio (54% yield of 1 vs 57% yield, entry 5 vs
entry 1). Increasing the water content in the solvent from
13 to 50% did not affect the reaction outcome, while the
use of anhydrous THF led to a decrease in the yields of 1
and 2, and in the 1/2 ratio (entries 6 and 7 of Table 1), pos-
sibly pointing to the role of water in the reaction mechanism
(see below).
H
N
N
N
Me
H
B
Ph
Ph
H
A
N
Me
Other catalysts having pyrrolidine-related structure such as
the tetrafluoroborate salts of methyl prolinate 3 and 2-(di-
phenylmethyl)pyrrolidine 4 were also shown to promote
the reaction (entries 8 and 9).
MeN
H
Ph
N
N
Me
Ph
H
H
However, while catalyst 3/HBF4 behaved very similarly to
pyrrolidine, the use of the much more sterically hindered cat-
alyst 4/HBF4 depressed the yields of 1 and 2 and the 1/2
ratio. Finally, it was found that the catalysts obtained by
reacting pyrrolidine with other strong acids (HCl, HClO4,
CF3SO3H) were much less effective, if at all, than the pyrro-
lidine/HBF4 combination.7
D
C
N
Me
HN
H
+
1
N
N
N
Me
Me
H
H
Ph
E
The pyrrolidinium tetrafluoroborate-catalyzed reaction was
then extended to other heterocyclic compounds (Scheme 1).
Scheme 2. Proposed mechanism for the reaction of N-methylpyrrole with
benzaldehyde.
By reacting benzaldehyde with N-methylindole under the re-
action conditions of entry 1, Table 1, N-methyl-3-[1-phenyl-
1-(30-N-methylindolyl)methyl]-indole 5 was isolated as the
only product in 33% yield.8 On the other hand, the reaction
of benzaldehyde with pyrrole led to a mixture of adducts
featuring two (6, 20% yield), three (7, 30% yield), four (8,
20% yield), and five (9, 23% yield) pyrrole units, readily
separated by flash chromatography, and identified by mass
spectrometry and comparison of their 1H NMR spectra with
those reported in the literature.4
This is transformed into iminium ion A by reaction with
the aldehyde to start a new catalytic cycle. Tripyrrane 2
can arise from addition of dipyrromethane 1 to carbenium
ion D.
On the basis of this mechanism, it was anticipated that aro-
matic aldehydes should react better than aliphatic aldehydes
in this process, since, in the case of the aromatic substrates,
the formation of carbenium ion D would be favored by

C. Biaggi et al. / Tetrahedron 62 (2006) 12375–12379
12377
delocalization of the positive charge on the phenyl ring. This
turned out to be the case.
4. Experimental
4.1. General methods
Indeed, when cyclohexane carboxaldehyde and phenylpro-
panal were used instead of benzaldehyde, dipyrromethanes
10 and 11 were isolated in 33 and 13% yields, respectively
(Scheme 3).9,10 In both cases no traces of the corresponding
tripyrranes were detected. On the contrary, 4-nitrobenzalde-
hyde and 2-thiophene carboxyaldehyde reacted nicely with
N-methylpyrrole to afford the corresponding dipyrro-
methanes 125a and 1310 in 61 and 59% isolated yields,
respectively. These products were accompanied by the cor-
responding tripyrranes 14 and 15,10 obtained in 11 and
30% yields, respectively, after a straightforward chromato-
graphic separation.
TLC was performed on Merck silica gel 60 TLC plates F254
and visualized using UV or phosphomolybdic acid. Flash
chromatography was carried out on silica gel (230–400
mesh).
1H NMR spectra were recorded on Bruker instruments at
300 or 500 MHz in chloroform-d (CDCl3) unless otherwise
stated, and were referenced to tetramethylsilane (TMS) at
0.00 ppm; 13C NMR spectra were recorded at 75 or
125 MHz and were referenced to 77.0 ppm in CDCl3.
IR spectra were recorded on thin film or as solution in
CH2Cl2 or as KBr pellet.
N
N
N
N
Products 1,5a 2,5a 5,8 6,4d 12,5a 16,11 are known compounds,
completely characterized; they had physical and spectral
properties in agreement with literature data.
N
Me
Me
Me
Me
Me
R
R
R
10, R = c-C6H11
11, R = PhCH2CH2
12, R = 4-NO2Ph
13, R = 2-thienyl
14, R = 4-NO2Ph
15, R = 2-thienyl
Products 7,4f 8,4f 9,4f and 1812b are known compounds but
NMR data are not reported in the original works; the charac-
terization of those compounds is reported in Section 4 of the
present work.
17, R = (E)-PhCH=CH
NMe
NMe
Ph
Ph
MeN
CHO
16
4.2. Synthesis of the catalysts
18
Scheme 3. Reaction of N-methylpyrrole with different aldehydes.
To a stirred solution of pyrrolidine (0.18 ml, 2.2 mmol) in
dry Et2O (8 mL) a 54% w/w solution of HBF4 in diethyl-
ether (0.37 ml, 2.7 mmol) was added at 0 ꢀC. After the reac-
tion mixture was allowed to stir at room temperature for
30 min, the solvent was evaporated to give a very thick oil.
Treatment with pentane afforded a waxy, low melting point
Finally, the reaction of cinnamaldehyde with N-methylpyr-
role was investigated. It was recently reported by MacMillan
and co-workers that, in the presence of the trifluoroacetate
salt of a chiral pyrrolidine derived from phenylalanine,
cinnamaldehyde underwent exclusively conjugate addition
of N-methylpyrrole to afford 3-(2-N-methylpyrrolyl)-3-
phenylpropanal 16 (THF/water 20:3, room or low tempera-
ture, 3–72 h) in a highly stereoselective fashion.11 However,
when the reaction was repeated in the presence of pyrroli-
dine/HBF4 (0.1 mmol) as catalyst, no traces of adduct 16
were observed, even by analysis of the crude reaction mix-
ture performed at different reaction times. Rather, dipyrro-
methane 17 was isolated as the major reaction product in
30% yield (Scheme 3). It was accompanied by minor
amounts of other compounds, among which adduct 18
could be detected.12 We do not have at present any rational-
ization to explain why our reaction follows this unusual
course, which however is in agreement with our mechanistic
hypothesis.
1
solid. H NMR analysis showed that this compound was
a single species, which did not contain either free HBF4
(whose proton resonates in CDCl3 at 11.5 ppm) or unproto-
nated pyrrolidine. 1H NMR (300 MHz, CDCl3): d 6.4 (br s,
2H), 3.20 (m, 4H), 1.95 (m, 4H).
Following a similar procedure catalysts 3 and 4 were
prepared.
Catalyst 3: 1H NMR (300 MHz, acetone d6): d 4.77 (m, 1H),
3.86 (s, 3H), 3.70 (m, 2H), 2.58 (m, 1H), 2.20 (m, 3H).
1
Catalyst 4: H NMR (300 MHz, CDCl3): d 7.30 (m, 10H),
6.3 (br s, 2H), 4.40 (br s, 1H), 4.10 (m, 1H), 3.30 (m, 4H),
2.00 (m, 3H), 1.90 (m, 1H).
4.3. General procedure for the synthesis of dipyrro-
methanes
3. Conclusion
In conclusion the first organocatalytic synthesis of dipyrro-
methanes has been achieved by the reaction of aldehydes
with N-methylpyrrole in the presence of catalytic amounts
of pyrrolidinium tetrafluoroborate. This convenient method
represents an improvement with respect to previous proto-
cols because the products are obtained directly from the
aldehydes under mild reaction conditions, with a relatively
small excess of N-methylpyrrole, and in the presence of a
catalytic amount of promoter.
In a typical experiment benzaldehyde (1 mmol) was added
to a stirred solution of pyrrolidine/HBF4 (0.1 mmol) in
3.0 mL of THF/water 20:3. After 10 min N-methylpyrrole
(5 mmol) was added and the mixture was stirred at room
temperature for 24 h. Aqueous work-up followed by purifi-
cation by flash chromatography with a hexane/ethyl acetate
mixture allowed the isolation of N-methyl-2-[1-phenyl-1-
(20-N-methylpyrrolyl)-methyl]-pyrrole 1 in 57% yield and
‘tripyrrane’ 2 in 25% yield.

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C. Biaggi et al. / Tetrahedron 62 (2006) 12375–12379
4.3.1. Compound 1.5a LC–ESI-MS 251 (M+1), H NMR
(300 MHz, CDCl3): d 7.35–7.20 (m, 3H), 7.19–7.10 (m,
2H), 6.60 (m, 2H), 6.06 (t, J¼8.5 Hz, 2H), 5.55 (m, 2H),
5.31 (s, 1H), 3.40 (s, 6H), yellow solid, mp 85–86 ꢀC
(lit.,5a 86.5 ꢀC).
4.3.9. Compound 14. H NMR (300 MHz, CDCl3): d 8.15
1
1
(d, J¼10 Hz, 4H), 7.30 (d, J¼10 Hz, 4H), 6.58 (m, 2H),
6.05 (m 2H), 5.45 (m, 2H), 5.35 (m, 2H), 3.38 (s, 6H),
3.10 (s, 3H). 13C NMR (75 MHz, CDCl3): d 155.0, 147.2,
142.5, 137.6, 128.9, 126.9, 121.2, 108.0, 107.0, 106.3,
55.2, 33.9, 30.7. (Found: C, 68.37; H, 5.35; N, 13.73.
C29H27N5O4 requires C, 68.36; H, 5.34; N, 13.74%.) LC–
ESI-MS 510 (M+1), yellow solid, mp 191–193 ꢀC.
1
4.3.2. Compound 2.5a LC–ESI-MS 419 (M+1), H NMR
(300 MHz, CDCl3): d 7.33–7.21 (m, 6H), 7.19–7.12 (m,
4H), 6.57 (m, 2H), 6.02 (t, J¼9.5 Hz, 2H), 5.45 (m, 2H),
5.35 (m, 2H), 5.23 (s, 2H), 3.40 (s, 6H), 3.10 (s, 3H), yellow
solid.
4.3.10. Compound 13. 1H NMR (300 MHz, CDCl3): d 7.20
(d, J¼6 Hz, 1H), 6.90 (dd, J¼6 Hz, J¼4 Hz, 1H), 6.70 (d,
J¼4 Hz, 1H), 6.52 (m, 2H), 6.05 (m, 2H), 5.65 (m, 2H),
5.55 (s, 1H), 3.39 (s, 6H). 13C NMR (75 MHz, CDCl3):
d 142.5, 138.5, 137.1, 128.9, 126.9, 120.2, 108.6, 106.3,
49.2, 33.6. (Found: C, 70.31; H, 6.31; N, 10.89.
C15H16N2S requires C, 70.27; H, 6.29; N, 10.93%.) LC–
ESI-MS 257 (M+1), yellow solid, mp 110–111 ꢀC.
1
4.3.3. Compound 7. H NMR (300 MHz, CDCl3): d 7.90
(br s, 2H), 7.70 (br s, 1H), 7.20 (m, 10H), 6.61 (m, 2H),
6.10 (m, 2H), 5.80 (m, 2H), 5.70 (m, 2H), 5.35 (m, 2H).
13C NMR (75 MHz, CDCl3): d 142.0, 133.6, 128.5, 128.4,
125.9, 121.2, 118.2, 108.0, 107.0, 106.3, 50.1. (Found: C,
82.70; H, 6.13; N, 11.18. C26H23N3 requires C, 82.73; H,
6.14; N, 11.13%.) LC–ESI-MS 378 (M+1), viscous solid.
4.3.11. Compound 15. 1H NMR (300 MHz, CDCl3): d 7.20
(d, J¼5 Hz, 2H), 6.90 (t, J¼5 Hz, 2H), 6.65 (d, J¼5 Hz, 2H),
6.53 (m, 2H), 6.02 (m, 2H), 5.65 (m, 2H), 5.55 (m, 2H), 5.50
(s, 2H), 3.41 (s, 6H), 3.19 (s, 3H). 13C NMR (75 MHz,
CDCl3): d 142.5, 141.5, 138.5, 137.1, 128.9, 127.0, 126.9,
120.2, 108.6, 106.3, 47.2, 33.6, 32.7. (Found: C, 69.53; H,
5.81; N, 9.77. C25H25N3S2 requires C, 69.57; H, 5.84; N,
9.74%.) LC–ESI-MS 432 (M+1), yellow solid, mp 157–
159 ꢀC.
1
4.3.4. Compound 8. H NMR (300 MHz, CDCl3): d 7.90
(br s, 2H), 7.65 (br s, 2H), 7.20 (m, 15H), 6.60 (m, 2H),
6.10 (m, 2H), 5.85 (m, 2H), 5.70 (m, 4H), 5.30 (m, 2H),
5.25 (m, 1H). 13C NMR (75 MHz, CDCl3): d 142.6, 141.1,
133.6, 132.0, 128.5, 128.1, 126.4, 125.7, 121.2, 119.2,
118.1, 108.0, 107.2, 107.0, 106.3, 106.1, 53.1, 50.1. (Found:
C, 83.51; H, 6.08; N, 10.48. C37H32N4 requires C, 83.43; H,
6.06; N, 10.52%.) LC–ESI-MS 533 (M+1), low melting
point solid.
4.3.12. Compound 17. 1H NMR (300 MHz, CDCl3):
d 7.50–7.18 (m, 6H), 6.66 (m, 2H), 6.25 (d, J¼19 Hz, 1H),
6.12 (m, 2H), 5.87 (m, 2H), 4.87 (m, 1H), 3.52 (s, 6H).
13C NMR (75 MHz, CDCl3): d 143.1, 137.6, 131.5, 128.9,
126.9, 123.2, 111.2, 107.0, 106.3, 102.3, 47.7, 33.8. (Found:
C, 82.61; H, 7.31; N, 10.11. C19H20N2 requires C, 82.57; H,
7.29; N, 10.14%.) LC–ESI-MS 277 (M+1), waxy solid.
1
4.3.5. Compound 9. H NMR (300 MHz, CDCl3): d 7.90
(br s, 2H), 7.60 (br s, 3H), 7.20 (m, 20H), 6.60 (m, 2H),
6.10 (m, 2H), 5.80 (m, 2H), 5.70 (m, 6H), 5.25 (m, 2H),
5.20 (m, 2H). 13C NMR (75 MHz, CDCl3): d 142.6, 141.4,
134.1, 133.0, 129.5, 128.1, 126.7, 125.1, 122.2, 119.2,
118.1, 109.4, 108.0, 107.5, 107.1, 106.9, 106.3, 106.0,
53.1, 50.1. (Found: C, 83.77; H, 5.99; N, 10.23. C48H41N5
requires C, 83.81; H, 6.01; N, 10.18%.) LC–ESI-MS 688
(M+1), low melting point solid.
4.3.13. Compound 18. 1H NMR (300 MHz, CDCl3):
d 7.50–7.20 (m, 6H), 6.63 (m, 2H), 6.35 (m, 2H), 6.15 (m,
3H), 4.83 (m, 1H), 3.53 (s, 3H), 3.45 (s, 3H). 13C NMR
(75 MHz, CDCl3): d 143.6, 142.9, 137.8, 131.4, 131.0,
128.8, 126.9, 123.2, 111.2, 107.3, 107.0, 106.8, 106.1,
102.3, 48.1, 34.1, 33.0. (Found: C, 82.55; H, 7.27; N,
10.16. C19H20N2 requires C, 82.57; H, 7.29; N, 10.14%.)
LC–ESI-MS 277 (M+1), waxy solid.
1
4.3.6. Compound 10. H NMR (300 MHz, CDCl3): d 6.45
(m, 2H), 6.04 (t, J¼6.5 Hz, 2H), 5.94 (m, 2H), 3.70 (d,
J¼10 Hz, 1H), 3.55 (s, 6H), 2.08 (m, 1H), 1.80–1.50 (m,
6H), 1.20 (m, 2H), 0.90 (m, 2H). 13C NMR (75 MHz,
CDCl3): d 133.4, 121.0, 107.1, 106.3, 42.6, 42.0, 34.0,
32.3, 26.6, 26.5. (Found: C, 79.71; H, 9.47; N, 10.88.
C17H24N2 requires C, 79.64; H, 9.44; N, 10.93%.) LC–
ESI-MS 257 (M+1), low melting point solid.
Acknowledgements
This work was supported by University of Milan, Italy and
MIUR.
4.3.7. Compound 11. 1H NMR (300 MHz, CDCl3): d 7.30–
7.10 (m, 5H), 6.50 (m, 2H), 6.03 (t, J¼4.5 Hz, 2H), 5.92 (m,
2H), 3.90 (t, J¼11 Hz, 1H), 3.35 (s, 6H), 2.65 (t, J¼12 Hz,
2H), 2.25 (m, 2H). 13C NMR (75 MHz, CDCl3): d 142.0,
133.6, 128.5, 128.4, 125.9, 121.2, 107.0, 106.3, 36.2, 34.8,
33.9, 33.7. (Found: C, 81.93; H, 7.96; N, 10.08. C19H22N2
requires C, 81.97; H, 7.97; N, 10.06%.) LC–ESI-MS 279
(M+1), low melting point solid.
References and notes
1. For a general overview on organic catalysis see: (a) Berkessel,
A.; Groger, H. Asymmetric Organic Catalysis; Wiley-VCH:
Weinheim, 2005; For a recent review on aminocatalysis see:
(b) List, B. Chem. Commun. 2006, 819–824.
2. Burrell, A. K.; Officer, D. L.; Plieger, P. G.; Reid, D. C. W.
Chem. Rev. 2001, 101, 2751–2796 and reference cited therein.
3. (a) Stoll, M.; Winter, M.; Gautschi, F.; Flamment, I.; Willhalm,
B. Helv. Chim. Acta 1967, 50, 628–689; (b) Frattini, C.; Bicchi,
C.; Barettini, C.; Nano, G. M. J. Agric. Food Chem. 1977, 25,
1
4.3.8. Compound 12.5a LC–ESI-MS 296 (M+1), H NMR
(300 MHz, CDCl3): d 8.15 (d, J¼11 Hz, 2H), 7.30 (d,
J¼11 Hz, 2H), 6.60 (m, 2H), 6.01 (t, J¼5.5 Hz, 2H), 5.45
(m, 2H), 5.35 (s, 1H), 3.40 (s, 6H), yellow solid, mp 119–
121 ꢀC (lit.,5a 123 ꢀC).

C. Biaggi et al. / Tetrahedron 62 (2006) 12375–12379
12379
1238–1241; (c) Shimoda, M.; Shibamoto, T. J. Agric. Food
Chem. 1990, 38, 802–804.
effective than HBF4 (1, 43%; 2, 21%); pyrrolidine/HClO4 did
not promote any reaction at all.
4. For leading references to the acid-catalyzed synthesis of
dipyrromethanes from aldehydes and pyrroles see: (a)
Vigmond, S. J.; Chang, M. C.; Kallury, K. M. R.; Thompson, M.
Tetrahedron Lett. 1994, 35, 2455–2458; (b) Lee, C.-H.;
Lindsey, J. S. Tetrahedron 1994, 50, 11427–11440; (c)
Br€uckner, C.; Sternberg, E. D.; Boyle, R. W.; Dolphin, D.
Chem. Commun. 1997, 1689–1690; (d) Littler, B. J.; Miller,
M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle,
P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391–1396; (e)
Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S.
J. Org. Chem. 2000, 65, 7323–7344; (f) Laha, J. K.;
Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S.
Org. Process Res. Dev. 2003, 7, 799–812; For a recent synthesis
of dipyrromethanes in water see: (g) Kral, V.; Vasek, P.;
Dolensky, B. Collect. Czech. Chem. Commun. 2004, 69,
1126–1128.
8. For a recently reported example of addition of N-methylindole
to aldehydes catalyzed by gold(III) chloride and leading to
product 5 see: Nair, V.; Abhilash, K. G.; Vidya, N. Org. Lett.
2005, 7, 5857–5859.
9. The possibility that these aliphatic aldehydes can also undergo
formation of the corresponding unreactive enamines under the
reaction conditions can also be invoked to explain the observed
low yields. In agreement with this hypothesis is the observation
that 3-phenylpropanal reacts more sluggishly than cyclohexane
carboxyaldehyde, because the latter is less prone to enamine
formation than the former.
10. Known compounds had physical and spectral properties in
agreement with literature data. New compounds gave analyti-
cal and spectral data in agreement with the proposed structure
(see Section 4).
11. (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370–4371; (b) Austin, J. F.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 1172–1173; (c) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894–
7895; For an example of conjugate addition of N-methyl-
indoles to a,b-unsaturated ketones catalyzed by pyrrolidinium
perchlorate see: (d) Li, D.-P.; Guo, Y.-C.; Xiao, W.-J. Chem.
Commun. 2006, 799–801.
12. (a) Renard, M.; Hevesi, L. J. Chem. Soc., Chem. Commun.
1986, 688–689; (b) Hevesi, L.; Proess, G.; Lazarescu-
Grigore, A. Synth. Met. 1993, 59, 201–210; The formation of
products structurally related to 17 and 18 was also observed
in some Lewis acid-catalyzed addition of heterocycles to
enals and enones: (c) Shi, M.; Cui, S.-C.; Li, Q.-J.
Tetrahedron 2004, 60, 6679–6684; (d) Li, Z.; Shi, Z.; He, C.
J. Organomet. Chem. 2005, 690, 5049–5054; (e) Ko, S.; Lin,
C.; Tu, Z.; Wang, Y.-F.; Wang, C.-C.; Yao, C.-F. Tetrahedron
Lett. 2006, 47, 487–492.
5. For leading references to the acid promoted synthesis of dipyr-
romethanes from oxazines and pyrroles see: (a) Singh, K.;
Behal, S.; Singh Hundal, M. Tetrahedron 2005, 61, 6614–
6622 and references cited therein; (b) Singh, K.; Behal, S.;
Deb, P. K. Synth. Commun. 2005, 35, 929–934.
6. The catalyst was prepared by adding a commercially available
54% solution of HBF4 in diethylether to an equimolar amount
of pyrrolidine also dissolved in dry diethylether. After 30 min
stirring at room temperature under nitrogen, the solvent was
1
evaporated under vacuum. H NMR analysis showed that this
compound was a single species, which did not contain either
free HBF4 or unprotonated pyrrolidine. The catalyst was used
as obtained.
7. This different behavior of the pyrrolidine salts as catalysts was
only partially matched by that of the free acids employed for
catalyst preparation. For instance, HBF4 behaved almost iden-
tically to pyrrolidine/HBF4 (1, 60%; 2, 24%); HClO4 was less