Pyrrole and oligopyrrole synthesis by 1,3-dipolar cycloaddition of azomethine ylides with sulfonyl dipolarophiles

Article abstract of DOI:10.1002/chem.201000742

A procedure for the synthesis of functionalized, substituted pyrroles by 1,3-dipolar cycloaddition of azomethine ylides has been developed. This protocol is based on the metal-catalyzed cycloaddition of α-iminoesters with sulfonyl dipolarophiles, followed by the base-promoted elimination of the sulfonyl groups. A wide variety of 2,5-disubstituted and 2,3,5- and 2,4,5trisubstituted pyrroles have been prepared in satisfactory yields from 1,2bis(sulfonyl ethylene), ss-sulfonylenones, and ss- sulfonylacrylates. This method can be applied in an iterative and straightforward manner to the construction of oligopyrroles, from bipyrroles to pentapyrroles. Iterative [n+1] and [n+2] approaches have been devised, the latter involves double 1,3-dipolar cycloaddition from pyrrolylbased bis(iminoesters).

Full text of DOI:10.1002/chem.201000742

DOI: 10.1002/chem.201000742
Pyrrole and Oligopyrrole Synthesis by 1,3-Dipolar Cycloaddition of
Azomethine Ylides with Sulfonyl ACHTNUTRGNEUNGDipolarophiles
Rocꢀo Robles-Machꢀn, Ana Lꢁpez-Pꢂrez, Marꢀa Gonzꢃlez-Esguevillas, Javier Adrio, and
Juan Carlos Carretero*[a]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
Abstract: A procedure for the synthe-
sis of functionalized, substituted pyr-
roles by 1,3-dipolar cycloaddition of
azomethine ylides has been developed.
This protocol is based on the metal-cat-
alyzed cycloaddition of a-iminoesters
with sulfonyl dipolarophiles, followed
by the base-promoted elimination of
the sulfonyl groups. A wide variety of
2,5-disubstituted and 2,3,5- and 2,4,5-
trisubstituted pyrroles have been pre-
pared in satisfactory yields from 1,2-
bis(sulfonyl ethylene), b-sulfonyle-
nones, and b-sulfonylacrylates. This
method can be applied in an iterative
and straightforward manner to the con-
struction of oligopyrroles, from bipyr-
roles to pentapyrroles. Iterative [n+1]
and [n+2] approaches have been de-
vised, the latter involves double 1,3-di-
polar cycloaddition from pyrrolyl-
based bis(iminoesters).
Keywords: cycloaddition · oligome-
rization · pyrroles · sulfones · ylides
Introduction
novel methods for the synthesis of pyrroles. These include
functionalization of simple pyrroles by metal-catalyzed cou-
pling,[14] metal-catalyzed cyclization,[15] ring-contraction and
-expansion procedures,[16] multicomponent reactions,[17] and
[4+1][18] and [3+2] cycloadditions.[19] With regards to the last
approach, very efficient procedures have been developed by
cycloaddition of 1,3-azomethine ylides with activated al-
kynes then straightforward aromatization of the resultant di-
hydropyrrole.[20] In contrast, the related approach based on
the cycloaddition of azomethine ylides with activated al-
kenes has been less explored due to the more difficult direct
aromatization of pyrrolidines to pyrroles.[21] A practical solu-
tion to this limitation could rely on the use of activated al-
kenes, substituted with potential leaving groups, which
would lead to pyrrolidines capable of ready transformation
into the respective pyrroles by base-assisted elimination of
the leaving groups. In this context, there are some successful
examples of the synthesis of pyrroles that employ nitroal-
kenes[22] and activated haloalkenes as dipolarophiles,[23] but
to the best of our knowledge this kind of approach has not
been applied to the more challenging synthesis of bipyrroles
and oligopyrroles. Keeping in mind the excellent ability of
the sulfone unit to act both as an electron-withdrawing and
a leaving group,[24] we envisaged that sulfonyl-substituted al-
kenes could play a dual role 1) as reactive dipolarophiles in
the 1,3-dipolar cycloaddition with azomethine ylides derived
from a-iminoesters (1); 2) by the provision of a leaving
Pyrroles are among the most common heteroaromatic com-
pounds and are present in a vast number of natural prod-
ucts[1] and biologically active compounds.[2] Furthermore,
a,a-linked oligopyrroles are found in important families of
natural products, such as prodigiosins[3] and porphyrins,[4]
and have been the focus of much attention in materials sci-
ence. For example, oligopyrroles have found applications in
anion binding,[5] cation coordination,[6] conducting poly-
mers,[7] liquid crystals,[8] and nonlinear optics.[9]
The interest of the pyrrole unit is exemplified by the great
variety of procedures known for its synthesis,[10] which in-
clude the classical Knorr,[11] Paal–Knorr,[12] and Hantzsch
syntheses.[13] The scope limitations of these classical meth-
ods, especially with regard to the preparation of functional-
ized substituted pyrroles, has prompted the development of
[a] R. Robles-Machꢀn, A. Lꢁpez-Pꢂrez, M. Gonzꢃlez-Esguevillas,
Dr. J. Adrio, Prof. Dr. J. C. Carretero
Departamento de Quꢀmica Orgꢃnica, Facultad de Ciencias
Universidad Autꢁnoma de Madrid, Cantoblanco 28049, Madrid
(Spain)
Fax : (+34)914973966
E-mail: juancarlos.carretero@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000742.
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FULL PAPER
Table 1. One-pot synthesis of 2,5-disubstituted pyrroles 6 from 2.[a,b]
group to assist aromatization to the desired pyrrole product
by basic elimination of the sulfonyl group.
In a previous communication,[25] we applied this strategy
to the synthesis of 2,5-disubstituted pyrroles and a,a-linked
oligopyrroles by using trans-1,2-bis(phenylsulfonylethylene)
(2) as a dipolarophile and base-promoted elimination of
both sulfonyl groups. Herein, we describe in detail the use-
Entry
a-Iminoester
R
Pyrrole 6
Yield [%][c]
fulness of this bisACHTUNGTRENNUNG(sulfonyl) dipolarophile, as well as the
1
1a
1a
1b
1c
1d
1e
1 f
1g
1h
Ph
Ph
6a
6a
6b
6c
6d
6e
6 f
6g
6h
90
27
72
93
72
97
88
80
86
2[d]
3
readily available b-sulfonylenones (3) and b-sulfonylacry-
lates (4),[26] in the synthesis of substituted pyrroles, bipyr-
roles, and a,a-linked oligopyrroles (Scheme 1).
4-MeOC6H4
3-FC6H4
2-furyl
2-thienyl
4
5
6
7
8
9
À
Ph CH=CH
tBu
Cy
[a] Conditions (cycloaddition): [CuACHTNURTGENNUG(CH3CN)4]CAHTUNTGRNEN[UGN PF6] (3 mol%), PPh3
(3 mol%), Et3N (18 mol%), THF, RT, 5 h. [b] Conditions (basic elimina-
tion): DBU (2 equiv), THF, RT, 30 min. [c] Isolated yield after silica-gel
chromatography. [d] (Z)-2 was used as the dipolarophile.
bisACTHNUGRTENUNG(sulfone) 2 displays a great tolerance with regard to the
substitution on the a-iminoester precursor. Aromatic
(Table 1, entries 3 and 4), heteroaromatic (Table 1, entries 5
and 6), a,b-unsaturated (Table 1, entry 7), and aliphatic sub-
stituents (Table 1, entries 8 and 9) can be used. The corre-
sponding pyrroles were afforded in good overall yields (72–
97%).
Scheme 1. Strategy for pyrrole synthesis.
Results and Discussion
With these results in hand, we turned to asymmetrically
substituted sulfonyl dipolarophiles, the b-sulfonylenones
Synthesis of pyrroles: Copper and silver Lewis acids are par-
ticularly appropriate catalysts in 1,3-dipolar cycloadditions
with stabilized azomethine ylides derived from a-iminoest-
3.[29] Unlike the bis
ACTHNGUTERNNU(G sulfone) 2, dipolarophile 3 could give
rise to regioisomeric mixtures of pyrroles. Copper-catalyzed
1,3-dipolar cycloaddition with the model ester 1a under the
previous conditions ([CuACTHUNGTREN(NUG CH3CN)4]ACHTGNURTNEN[UNG PF6]/PPh3/Et3N) oc-
ers.[27] We had previously described that [Cu
(CH3CN)4]
G
was a very effective catalyst in the asymmetric 1,3-dipolar
cycloaddition of 2 with the azomethine ylides of a-iminoest-
ers in the presence of chiral 2-(tert-butyl-sulfenyl)-1-(diphe-
nylphosphino)ferrocene (FeSulPhos) ligands.[28] Thus, for the
nonenantioselective version of this process we chose similar
reaction conditions but by using PPh3 as ligand: [Cu-
ACHTUNGTRENNUNG(CH3CN)4]ACHTUNGTRENNUNG[PF6] (3 mol%), PPh3 (3 mol%), and Et3N
(18 mol%). In the model reaction between N-benzylidene
glycine methyl ester (1a) and 2, complete conversion was
curred very rapidly, albeit with a disappointing regioselectiv-
ity. This result was not very surprising because in our previ-
ous studies on the Cu-catalyzed asymmetric version of this
reaction only Segphos-type ligands, such as 7, provided a
high regioselectivity in the cycloaddition.[26b] With these li-
gands, the C4-acetyl-substituted pyrrolidines 8 were selec-
tively obtained as the major regioisomer (mainly as exo iso-
mers), which showed that the regioselectivity is mainly con-
trolled by the acetyl group of the dipolarophile rather than
the sulfonyl group. Thus, we applied these reaction condi-
observed after 5 h and a single bisACTHNUGTRNEUNG(sulfonyl) adduct, 5a, was
isolated by standard silica-gel chromatography.[28] However,
for conversion of 5a to the pyrrole it is more convenient
and efficient to include the direct addition of 1,8-
tions ([CuACHTNGUTREN(NUG CH3CN)4]ACHTNUGTREN[NUNG PF6], DTBM-Segphos (7), Et3N, Et2O,
RT) to the cycloaddition of 1a with 3a, followed by desulfo-
nylation/aromatization by treatment of the crude pyrrolidine
mixture with DBU. Under these conditions, pyrrole 9a was
isolated in 62% yield after chromatographic purification
(Table 2, entry 1).
A good yield was also obtained in the reaction of 1a with
the bulkier isopropyl ketone dipolarophile 3b (Table 2,
entry 9).
Next, we studied the scope of this procedure with regard
to the substitution at the iminoester. Acceptable to good
yields were obtained with aryl- (Table 2, entries 2–5), heter-
oaryl- (Table 2, entries 6 and 7), and alkyl-substituted
(Table 2, entry 8) azomethine ylides.
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU) to the crude reaction
mixture to promote the easy in situ elimination of both sul-
fonyl groups. The expected pyrrole, 6a, was isolated in 90%
yield after final chromatographic purification (Table 1,
entry 1). The stereoisomer of the dipolarophile, (Z)-2, was
also tested under the same reaction conditions (Table 1,
entry 2), but this alkene proved to be much less reactive
than the trans isomer and provided the pyrrole 6a in only
27% yield.
This procedure for the synthesis of 5-substituted pyrrole
2-carboxylic esters 6 by 1,3-dipolar cycloaddition with the
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9865

J. C. Carretero et al.
Table 2. Synthesis of 4-acyl-2,5-disubstituted pyrroles 9 from b-sulfonyl-
enones 3.[a,b]
75:25). Once isolated, this regioisomeric mixture was used
directly in the desulfonylation/aromatization step.
Upon treatment with DBU, the regioisomer 10a[31] was
less prone than 8a to suffer desulfonylation/aromatization
to give the corresponding pyrrole. The best result was ach-
ieved in toluene at 708C, which led to pyrrole 11a in 53%
yield. A more efficient process was achieved by using 4-di-
methylaminopyridine (DMAP) as a base to promote desul-
fonylation and consequent formation of the 2,5-dihydropyr-
role intermediate. This intermediate was readily oxidized to
pyrrole 11a by addition of 2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone (DDQ) to the crude reaction mixture (64% over-
all yield from 3a). As shown in Table 4, application of the
Entry
a-Iminoester
R
R1
Pyrrole 9
Yield [%][c]
1
2
3
4
5
6
7
8
9
1a
1i
1j
1k
1l
1d
1e
1h
1a
Ph
Me
Me
Me
Me
Me
Me
Me
Me
iPr
9a
9i
9j
9k
9l
9d
9e
9h
9m
62
52
63
68
62
68
60
56
79
2-naphthyl
4-BrC6H4
4-ClC6H4
2-MeOC6H4
2-furyl
2-thienyl
Cy
Table 4. Synthesis of 3-acyl-2,5-disubstituted pyrroles 11 from b-sulfony-
lenone 3a.[a,b]
Ph
[a] Conditions (cycloaddition): [Cu
G
G
7
(3.3 mol%), Et3N (18 mol%), Et2O, RT, 5 h. [b] Conditions (basic elimi-
nation): DBU (2 equiv), CH2Cl2, RT, 6–24 h. [c] Overall yield after silica-
gel chromatography.
Entry
a-Iminoester
R
Pyrrole 11
Yield [%][c]
1
2
3
4
5
6
1a
1k
1l
1i
1e
1h
Ph
11a
11k
11l
11i
11e
11h
64
56
59
47
40
49
Silver catalysts, especially AgOAc, have been widely used
in 1,3-dipolar cycloadditions of azomethine ylides. Interest-
ingly, when this catalyst was tested in the model reaction of
enone 3a with the a-iminoester 1a the regioselectivity was
opposite to that observed in the Cu-catalyzed process; the
3-acetyl pyrrolidine 10a is now the major regioisomer (10a/
8a=69:31, Table 3, entry 1). These results show that under
4-ClC6H4
2-MeOC6H4
2-naphthyl
2-thienyl
Cy
[a] Conditions (cycloaddition): AgOAc (10 mol%), TMEDA (10 mol%),
Et3N (20 mol%), THF, RT, 5 h. [b] Conditions (basic elimination/oxida-
tion): 1) DMAP (2 equiv), CH2Cl2, RT, 12 h; 2) DDQ (1.5 equiv),
CH2Cl2, RT, 5 min. [c] Overall yield from 3a after silica-gel chromatogra-
phy.
Table 3. Ag-catalyzed 1,3-dipolar cycloaddition of a-iminoester 1a with
b-sulfonylenone 3a.[a]
Ag-catalyzed 1,3-dipolar cycloaddition and the two-step aro-
matization procedure gave acceptable overall yields (40–
64%) for the formation of 3-acetyl pyrroles 11 from a varie-
ty of aryl-, heteroaryl-, and alkyl-substituted iminoesters 1.
With the aim of applying the methodology described
above to the preparation of pyrroles with electron-rich sub-
stituents,[32] we examined the conversion of 3-acetylpyrrole
11a into 3-acetoxypyrrole 12 by Baeyer–Villiger oxidation.
The reaction under standard conditions (m-chloroperbenzo-
ic acid (m-CPBA), CH2Cl2, RT) was very slow and afforded
the ester 12 in low yield after 24 h (22%). Gratifyingly, a
much faster and cleaner reaction occurred in the presence
of an acid, such as p-toluenesulfonic acid (PTSA) and the 3-
acetoxypyrrole 12 was produced in nearly quantitative yield
(Scheme 2).
Entry
Ligand
Time [min]
10a/8a[b]
1
2
3
4
–
105
10
10
69:31
69:31
71:29
75:25
PPh3
phenanthroline
TMEDA
10
[a] Conditions: AgOAc (10 mol%), ligand (10 mol%), Et3N (20 mol%),
THF, 5 h, RT. [b] Determined by 1H NMR spectroscopy of the crude re-
action mixture.
Ag-catalyzed reaction conditions the regioselectivity of the
process is mainly controlled by the sulfonyl group rather
than the ketone unit.[30] A significant increase in the reactivi-
ty and a similar regioselectivity were observed in the pres-
ence of ligands such as PPh3, phenanthroline, or N,N,N’,N’-
tetramethyl-1,2-ethane (TMEDA) (Table 3, entries 2–4).
The optimal regioselectivity was obtained with AgOAc/
TMEDA as the catalyst system (Table 3, entry 4, 10a/8a=
With regard to the 1,3-dipolar cycloaddition of b-sulfony-
lacrylates, we had previously studied the catalytic asymmet-
ric reaction of (Z)-4 with a-iminoesters (Cu/Segphos as the
catalyst system). We found that the reaction occurred with
complete exo selectivity and that the regioselectivity was
mainly controlled by the sulfonyl group.[26a] This regiochemi-
cal outcome is in agreement with the higher activation
effect of the phenylsulfonyl group relative to the ester
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1,3-Dipolar Cycloaddition of Azomethine Ylides with Sulfonyl Dipolarophiles
FULL PAPER
mainly based on Vilsmeier condensations,[40] Paal–Knorr
cyclizations,[41] couplings of pyrrolinones with pyrroles,[42]
Ullmann couplings,[43] and other metal-catalyzed coupling
processes.[44]
The procedure for the synthesis of pyrroles by 1,3-dipolar
cycloaddition of azomethine ylides with sulfonyl dipolaro-
philes and further desulfonylation/aromatization could be
straightforwardly applied to the synthesis of bipyrroles by
using a pyrrolyl-substituted a-iminoester as azomethine
ylide precursor. To verify this assumption, we first studied
the cycloaddition/aromatization strategy with the bis-
Scheme 2. Baeyer–Villiger oxidation of pyrrole 11a.
moiety, evidenced in the Diels–Alder reactions of b-
sulfonyl
a-iminoester 1a a high regioselectivity was also observed
when [Cu(CH3CN)4][PF6]/PPh3 was used as the catalyst
ACHTUNGTRENNUNG
acrylates.[33] In the reaction of (Z)-4 with the model
A
U
ACHTUNGTRENN(UNG sulfonyl) dipolarophile 2 (Table 6).
system, exo-13a was isolated as the major regioisomer in
81% yield.[34] Aromatization of 13a to the equivalent pyr-
role was achieved with the procedure previously developed
for b-sulfonylenones; DMAP-mediated desulfonylation and
in situ aromatization of the resulting dihydropyrrole by
treatment with DDQ provided pyrrole 14a in 58% yield
after purification (47% overall yield from 4).
Table 6. One-pot synthesis of a,a-linked bipyrroles 15 from 2.[a]
As shown in Table 5 pyrroles 14, with electronically
varied aromatic and heteroaromatic substitution at C-5,
were obtained with reasonable overall yields from the sulfo-
Entry
a-Iminoester
R
Bipyrrole 15
Yield [%][b]
1
2
3
4
1n
1o
1p
1q
H
Boc
Ts
–
–
15o
15p
15q
67
61
78
Table 5. Synthesis of pyrrole 2,3-dicarboxylate esters 14 from (Z)-4.[a,b]
Bn
[a] Conditions (cycloaddition): 1) [CuACHTNURTGNENUG(CH3CN)4]CAHTUNTGRNEN[UGN PF6] (3 mol%), PPh3
(3 mol%), Et3N (18 mol%), THF, RT, 5 h; 2) DBU (2 equiv), RT,
30 min. [b] Isolated yield after silica-gel chromatography.
Entry
a-iminoester
Ar
Pyrrole 14
Yield [%][c]
Under the standard reaction conditions ([Cu
AHCTNUTGERGUN[NN PF6], PPh3, Et3N, CH2Cl2; then DBU), a complex mixture
ACHTUGNERTN(NUNG CH3CN)4]-
1
2
3
4
5
6
1a
1k
1l
1m
1i
Ph
14a
14k
14l
14m
14i
47
61
51
51
42
57
4-ClC6H4
2-MeOC6H4
4-N-(Boc)2C6H4
2-naphthyl
2-furyl
À
of products was obtained from the N H unprotected pyrro-
lylimino glycinate 1n (Table 6, entry 1), which is likely to be
À
due to competitive coordination of the pyrrole N H unit
1d
14d
with the copper catalyst. Gratifyingly, the protected N-Boc,
N-tosyl (N-Ts), and N-benzyl (N-Bn) pyrrolylimino glyci-
nates 1o, 1p, and 1q (Table 6, entries 2–4) provided the ex-
pected bipyrroles 15o–q in good overall yields. The best
result (78%) was obtained with the N-Bn-protected imino-
pyrrole 1q.
[a] Conditions (cycloaddition): [CuACHTNURTGENNUG(CH3CN)4]CAHTUNTGRNEN[UGN PF6] (5 mol%), PPh3
(5 mol%), Et3N (18 mol%), CH2Cl2, RT, 5 h. [b] Conditions (basic elimi-
nation/oxidation): 1) DMAP (2 equiv), CH2Cl2, RT, 12 h; 2) DDQ
(1.5 equiv), CH2Cl2, RT, 5 min. [c] Overall isolated yield from 4. Both the
pyrrolidine intermediate 13 (see the Supporting Information for isolated
yields) and the pyrrole 14 were purified by silica gel chromatography.
We extended this methodology to cycloadditions with the
b-sulfonylenone dipolarophile 3a (Scheme 3). In this case,
the cycloaddition/aromatization strategy would provide easy
access to trisubstituted bipyrroles with a 2,4,5- or 2,3,5-sub-
stitution pattern. This kind of substitution is present, for in-
stance, in the bipyrrole core of prodigiosin and marineosin
natural products.[3]
However, under the optimized conditions for the Cu-cata-
lyzed process, the reaction from 1q provided 16q in very
low yield (15%, Scheme 3). Interestingly, the N-Boc pyrrolyl
analogue 1o proved to be a suitable substrate and afforded
the 4-acetyl bipyrrole 16o in 49% overall yield. A similar
reactive behavior was detected in the case of the Ag-cata-
lyzed cycloaddition process (AgOAc/TMEDA); the N-Boc
substrate 1o was much more effective than the N-Bn ana-
logue 1q. In accordance with the usual regiochemical out-
nyl dipolarophile 4 (42–61%) (Table 5, entries 1–6), and in-
cluded N-tert-butoxycarbonyl (N-Boc) protected-aniline de-
rivative 14m (Table 5, entry 4).
Synthesis of bipyrroles: The preparation of a,a-linked bipyr-
roles deserves special consideration because they have
served as precursors for the synthesis of prodigiosin[3a] and
marineosin[3b] natural products, expanded porphyrins,[35] and
for conductive oligopyrroles, polymers, and related struc-
tures.[7] Symmetrical bipyrroles can be efficiently prepared
by oxidative coupling,[36] coupling of halopyrroles,[37] and de-
sulfurization of thienodipyrroles.[38] In comparison, only a
handful of methods have been reported for the synthesis of
asymmetrically substituted bipyrroles and oligopyrroles,[39]
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J. C. Carretero et al.
methyl ester to afford the key bipyrrole a-iminoesters 24,
25, and 26. Once isolated, these azomethine ylide precursors
were immediately submitted to 1,3-dipolar cycloaddition
with the bisACTHNUGRTNEUNG(sulfone) 2 under the standard Cu-catalyzed re-
action conditions. In situ DBU-promoted desulfonylation af-
forded the terpyrroles 28 and 29 and the related compound
27 in good overall yields (61–69% from the aldehydes 21–
23). Interestingly, this modular approach for the introduc-
tion of the pyrrole units allows the selective construction of
orthogonally protected terpyrroles, such as 28, as well as
mixed heterocyclic systems, such as the thienylbipyrrole 27.
In addition, these terpyrroles could be used as building
blocks in the preparation of highly valuable, substituted
polypyrroles and expanded porphyrins.[35]
Scheme 3. Synthesis of a,a-linked bipyrroles from b-sulfonylenone 3a:
a) [Cu(CH3CN)4][PF6] (3 mol%), 7 (3 mol%), Et3N (18 mol%), Et2O,
RT, 5 h; b) DBU (2 equiv), CH2Cl2, RT, 30 min; c) AgOAc (10 mol%),
TMEDA (10 mol%), Et3N (20 mol%), THF, RT, 5 h; d) 1) DMAP
(2 equiv), CH2Cl2, RT, 12 h; 2) DDQ (1.5 equiv), CH2Cl2, RT, 5 min.
G
ACHTUNGTRENNUNG
AHCTUNGTREG[NNUN n+2] strategy: To accelerate the process of construction of
higher-order oligoheterocycles, we envisaged the possibility
for the generation of two pyrrole rings in a single synthetic
operation from a bis(a-iminoester) as double azomethine
ylide precursor. This [1+2] and [1+2+2] approach from N-
benzyl pyrrole 2,5-dicarbaldehyde (30) and thiophene 2,5-di-
carbaldehyde (31) is shown in Scheme 5.
come of the Ag-catalyzed process, the cycloaddition/aroma-
tization process from 1o led selectively to the 3-acetyl bipyr-
role 17o (62% overall yield, Scheme 3).
Synthesis of oligopyrroles
The formation of the bis(a-iminoester) precursor proved
to be more of a challenge than expected. Under the usual
conditions, the condensation of the pyrrole dialdehyde 30[45]
ACHTUNGTRENNUNG[n+1] strategy: Encouraged by the efficiency of this proce-
dure for the synthesis of bipyrroles, we sought to examine
the preparation of terpyrroles through iterative application
of the pyrrole ring construction sequence. To test this ap-
proach, we chose thienylpyrrole 6e and bipyrroles 15p and
15q as model substrates (Scheme 4). The benzylation of the
free-NH group in bipyrroles 15p and 15q under usual condi-
tions (BnBr, NaH, DMF) afforded the fully protected bipyr-
roles 19 and 20. Subsequent conversion of the methyl ester
moiety to the formyl derivative by application of a straight-
forward reduction (LiAlH4)/oxidation (MnO2) sequence
provided the aldehydes 21, 22, and 23 in good yields. These
aldehydes were then subjected to condensation with glycine
Scheme 4. Synthesis of the terpyrroles 28 and 29 and the thienylbipyrrole
27: a) BnBr, NaH, DMF, RT, 12 h; b) LiAlH4, THF, 08C, 3 h; c) MnO2,
acetone, RT, 14 h; d) glycine methyl ester hydrochloride (1.3 equiv),
Scheme 5. Synthesis of the pentaheterocycles 40 and 41: a) glycine
methyl ester hydrochloride (4 equiv), Et3N, EtOH, SiO2, RT, 2 h; b) 2
(4 equiv), [CuACTHNUGTRENNG(U CH3CN)4]AHCTUNGTRENN[GUN PF6] (3 mol%), PPh3 (3 mol%), Et3N
Et3N, MgSO4, RT, 15 h; e) 2 (1.5 equiv), [Cu
PPh3 (3 mol%), Et3N (18 mol%), THF, RT, 5 h; then DBU (2 equiv),
RT, 30 min.
(CH3CN)4]
E
(18 mol%), CH2Cl2, 4 ꢅ molecular sieves, RT, 5 h; then DBU (4 equiv),
RT, 30 min; c) BnBr, NaH, DMF, RT, 12 h; d) LiAlH4, THF, 08C, 3 h;
e) MnO2, acetone, RT, 14 h.
9868
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Chem. Eur. J. 2010, 16, 9864 – 9873

1,3-Dipolar Cycloaddition of Azomethine Ylides with Sulfonyl Dipolarophiles
FULL PAPER
with an excess of glycine methyl ester in the presence of the
usual dehydrating agents, such as MgSO4, NaSO4, or molec-
ular sieves, was accompanied by incomplete conversion or
the formation of side products. Interestingly, the bis(a-imi-
noester) was cleanly formed in high yield when silica gel
was used as a dehydrating agent under sonication in etha-
meier formylation[48] of the previously prepared bipyrrole al-
dehyde 23 provided the symmetrical bipyrrole dialdehyde
44 (76% yield), suitable for the two-directional sequence.
The formation of bis(a-iminoester) 45, followed by 1,3-dipo-
lar cycloaddition of 45 with 2 and DBU-promoted desulfo-
nylation, afforded the quaterpyrrole 46 in 51% yield. A
minor amount (7%) of the terpyrrole 47, a result of the
monocycloaddition process, was also isolated.
nol.[46] Once isolated, crude bis
treated with an excess of bis(sulfone) 2 under the usual Cu-
ACHTUNGERTN(NUNG imine) 32 was immediately
AHCTUNGTRENNUNG
catalyzed reaction conditions, but in the presence of molecu-
lar sieves to minimize the imine hydrolysis side-reaction. In
situ DBU-mediated desulfonylation then chromatographic
purification afforded the expected symmetrical terpyrrole 34
as the main product (53% yield from dialdehyde 30), along
with a minor amount of the bipyrrole aldehyde 36 (11%
yield)—the result of a monocycloaddition process and hy-
drolysis of the second imine unit.[47] The conversion of the
terpyrrole diester 34 into the N-protected terpyrrole dialde-
hyde 38, required for the further preparation of the penta-
pyrrole derivative, was efficiently performed in three steps,
as previously developed in the iterative [n+1] strategy (N-
benzylation, ester reduction, MnO2 oxidation of the alco-
hol). The dialdehyde 38 was then submitted to double pyr-
role ring construction, by 1,3-dipolar cycloaddition of its
Conclusion
We have described a novel process for the preparation of
substituted pyrroles based on the metal-catalyzed 1,3-dipolar
cycloaddition of a-iminoesters with readily available sulfo-
nyl dipolarophiles, such as bis(sulfonylethene), b-sulfonyl
acrylates, and b-sulfonylenones, followed by base-promoted
sulfone elimination and aromatization. This methodology
provides access to 2,5-disubstituted and 2,3,5- and 2,4,5-tri-
substituted pyrroles. Furthermore, this pyrrole construction
protocol can be iteratively applied to the preparation of
a,a-linked bipyrroles, oligopyrroles, and related oligohetero-
cycles by conversion of the ester moiety of the pyrrole unit
into an a-iminoester functionality. Both [n+1] and [n+2]
strategies, in which the latter case involves a double cycload-
dition process, have been developed and allow the prepara-
tion of bipyrroles, terpyrroles, quaterpyrroles, and pentapyr-
roles.
bis(a-iminoester) with bisACHTNUTRGNE(NUG sulfone) 2, to provide pentapyr-
role 40 as the main product (47% overall yield). In this re-
action, the quaterpyrrole aldehyde 42 (from the competitive
monocycloaddition process) was also isolated as a minor
product (14% yield). Additionally, the application of this
[1+2+2] strategy to thiophene dialdehyde 31 provided the
triheterocycle 35 (47% yield) and subsequently the pentahe-
terocycle 41 (44% yield from dialdehyde 39), which illus-
trates the generality of this iterative method for the synthe-
sis of a,a-linked oligoheterocycles.
To complement the previous syntheses of odd-numbered
oligopyrroles, we applied a similar strategy to the synthesis
of even-numbered oligopyrroles, such as quaterpyrroles, by
means of a [2+2] construction approach (Scheme 6). Vils-
Experimental Section
Typical procedure for the synthesis of 2,5-disubstituted pyrroles (6a): A
solution of 1a (60 mg, 0.34 mmol) in dry THF (1 mL) and Et3N (13 mL,
0.09 mmol) was successively added to
a solution of PPh3 (2.8 mg,
0.01 mmol) and [Cu(CH3CN)4][PF6] (3.8 mg, 0.01 mmol) in dry THF
G
ACHTUNGTRENNUNG
(1 mL) under nitrogen atmosphere at RT. The resulting solution was
added to a suspension of 2 (193 mg, 0.51 mmol) in dry THF (1 mL). The
mixture was then stirred for 5 h before DBU (93 mL, 0.68 mmol) was
added. After 30 min, the mixture was filtered through a plug of Celite
with the aid of CH2Cl2 (5 mL) and the solvent was removed under re-
duced pressure. The residue was purified by silica-gel flash chromatogra-
phy (hexane/EtOAc 5:1) to afford the pyrrole 6a[49] (148 mg, 90%,
yellow solid). 1H NMR (300 MHz, CDCl3): d=9.58 (brs, 1H), 7.46 (d,
J=7.6 Hz, 2H), 7.28–7.23 (m, 2H), 7.18–7.11 (m, 1H), 6.84–6.82 (m,
1H), 6.42–6.39 (m, 1H), 3.73 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=161.9, 137.2, 131.1, 128.9, 127,6, 124.8, 122.8, 116.9, 107.9, 51.6 ppm.
Typical procedure for the synthesis of 2,4,5-trisubstituted pyrroles (9a):
A solution of 1a (61 mg, 0.34 mmol) in Et2O (1 mL) and Et3N (8 mL,
0.057 mmol) were successively added to a solution of 7 (11.1 mg, 9.4ꢆ
10À3 mmol) and [Cu [PF6] (3.2 mg, 8.5 10À3 mmol) in Et2O
ACTHNUGTRENN(UG CH3CN)4]ACHUTNGTRENNGUN
(1 mL) under nitrogen atmosphere at RT. The resulting solution was
added to a suspension of 3a (60 mg, 0.28 mmol) in Et2O (1 mL). The
mixture was stirred for 10 min, filtered through a plug of Celite with the
aid of CH2Cl2 (5 mL), and the solvent was removed under reduced pres-
sure. The residue was dissolved in CH2Cl2 (2 mL) and DBU (120 mL,
0.86 mmol) was added. After stirring for 6 h, CH2Cl2 (10 mL) and satu-
rated aqueous solution of NH4Cl (10 mL) were added. The organic phase
was separated and the aqueous phase was extracted with CH2Cl2 (2ꢆ
5 mL). The combined organic phases were dried over MgSO4 and evapo-
rated under reduced pressure. The residue was purified by flash chroma-
tography (hexane/EtOAc 3:1) to afford 9a (43 mg, 62%, white solid).
Scheme 6. Synthesis of the quaterpyrrole 46: a) POCl3, DMF, 08C to RT,
12 h; b) glycine methyl ester hydrochloride (4 equiv), Et3N (4 equiv),
EtOH, SiO2, RT, 2 h; c) 2 (3 equiv), [CuACHTNUTGRNNEUG(CH3CN)4]HCAUTNTGREN[NGUN PF6] (3 mol%), PPh3
(3 mol%), Et3N (18 mol%), CH2Cl2, 4 ꢅ molecular sieves, RT, 5 h; then
DBU (4 equiv), RT, 30 min.
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9869

J. C. Carretero et al.
M.p. 130.0–132.08C; 1H NMR (300 MHz, CDCl3): d=9.43 (brs, 1H),
7.60–7.57 (m, 2H), 7.45–7.43 (m, 3H), 7.35 (d, J=2.6 Hz, 1H), 3.85 (s,
3H), 2.37 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=193.7, 161.2,
139.8, 131.0, 129.4, 129.1, 128.4, 123.1, 121.9, 117.9, 51.9, 28.9 ppm; MS
(FAB+): m/z (%): 244.0 [M+H]+ (80); HRMS (FAB+): m/z: calcd for
C14H14NO3: 244.0974; found: 244.0978.
HRMS (FAB+): m/z: calcd for C14H14NO4: 260.0923 [M+H]+; found:
260.0922.
Typical procedure for the synthesis of bipyrroles (15q): Compound 1q
(143 mg, 0.56 mmol) in dry THF (2 mL) and Et3N (14 mL, 0.10 mmol)
were successively added to a solution of PPh3 (4.0 mg, 0.017 mmol) and
[CuACHTUNGTRENNUG(CH3CN)4]AHCUTNGTRNEN[GUN PF6] (6.0 mg, 0.016 mmol) in dry THF (2 mL) under a ni-
trogen atmosphere at RT. The resulting solution was added to a suspen-
sion of 2 (260 mg, 0.84 mmol) in dry THF (2 mL). The resulting mixture
was stirred for 5 h before DBU (0.18 mL, 1.12 mmol) was added. After
30 min, the mixture was filtered through a plug of Celite with the aid of
CH2Cl2 (5 mL) and the solvent was removed under reduced pressure.
The residue was purified by silica-gel flash chromatography (hexane/
EtOAc 5:1) to afford the bipyrrole 15q (122 mg, 78%, white solid). M.p.
116–1178C; 1H NMR (300 MHz, CDCl3): d=9.30 (brs, 1H), 7.30–7.22
(m, 3H), 6.99–6.96 (m, 2H), 6.82 (dd, J=3.8, 2.5 Hz, 1H), 6.72 (dd, J=
2.7, 1.8 Hz, 1H), 6.40 (dd, J=3.8, 2.5 Hz, 1H), 6.22 (dd, J=3.7, 2.7 Hz,
1H), 6.02 (dd, J=3.8, 2.6 Hz, 1H), 5.18 (s, 2H), 3.78 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=161.5, 138.2, 129.1, 128.8, 127.5, 126.1,
125.4, 123.8, 122.0, 116.2, 109.3, 108.9, 108.6, 51.4, 50.9 ppm; MS (EI+):
m/z (%): 280 (100) [M]+, 248 (33), 219 (23), 189 (81), 171 (28),157 (54),
129 (25), 102 (15), 91 (61), 65 (18); HRMS (EI+): m/z: calcd for
C17H16N2O2: 280.1211 [M]+; found: 280.1210.
Typical procedure for the synthesis of 2,3,5-trisubstituted pyrroles (11a):
A solution of 1a (60 mg, 0.34 mmol) in THF (1 mL) and Et3N (8 mL,
0.06 mmol) were successively added to a solution of TMEDA (4 mL,
0.03 mmol) and AgOAc (5.0 mg, 0.03 mmol) in THF (1 mL) under a ni-
trogen atmosphere at RT. The resulting solution was added to a suspen-
sion of 3a (60 mg, 0.28 mmol) in THF (1 mL). The mixture was stirred
for 15 h, filtered through a plug of Celite with the aid of CH2Cl2 (5 mL),
and the solvent was removed under reduced pressure. The crude material
was filtered through a short pad of SiO2 (hexane/EtOAc 3:1) and the sol-
vent was removed under reduced pressure. The residue was dissolved in
CH2Cl2 (3 mL) and DMAP (93 mg, 0.77 mmol) was added. After stirring
for 12 h, CH2Cl2 (10 mL) and saturated aqueous solution of NH4Cl
(10 mL) were added. The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (2ꢆ5 mL). The combined organic
phases were washed with brine (5 mL), dried over MgSO4, and evaporat-
ed under reduced pressure. The residue was dissolved in CH2Cl2 (5 mL)
and DDQ (87 mg, 0.38 mmol) was added. After stirring for 5 min at RT,
CH2Cl2 (10 mL) and a saturated aqueous solution of NaHCO3 (10 mL)
were added, the organic phase was separated, and the aqueous phase was
extracted with CH2Cl2 (2ꢆ5 mL). The combined organic phases were
dried over MgSO4 and evaporated under reduced pressure. The residue
was purified by flash chromatography (hexane/EtOAc 3:1) to afford 11a
(44 mg, 64%, yellow oil). 1H NMR (300 MHz, CDCl3): d=9.56 (brs,
1H), 7.58–7.54 (m, 2H), 7.45–7.40 (m, 2H), 7.37–7.31 (m, 1H), 6.87 (d,
J=3.2 Hz, 1H), 3.92 (s, 3H), 2.65 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=196.7, 160.4, 135.0, 131.4, 130.2, 129.1, 128.4, 124.9, 121.0,
109.9, 52.1, 30.7 ppm; MS (FAB+): m/z (%): 244.1 [M+H]+ (40); HRMS
(FAB+): m/z: calcd for C14H14NO3: 244.0974; found: 244.0971.
Typical procedure for the [n+1] strategy–-conversion of bipyrrole 19 into
terpyrrole 28: LiAlH4 (2.0m in THF, 63 mL, 0.12 mmol) was added drop-
wise to a solution of 19 (18 mg, 0.04 mmol) in dry THF (2 mL) at 08C.
After 10 min at 08C, MeOH (3 mL) and a 1:1 saturated aqueous solution
of sodium tartrate/EtOAc (10 mL) were added. The organic phase was
separated, dried over anhydrous MgSO4, and evaporated under reduced
pressure to afford the bipyrrole alcohol as a yellow oil, which was used
without further purification in the next step. MnO2 (73 mg, 0.84 mmol)
was added to
a solution of the crude bipyrrole alcohol (17 mg,
0.04 mmol) in acetone (3 mL) at RT and the suspension was stirred for
12 h. The mixture was filtered through a plug of Celite with the aid of
acetone and evaporated under reduced pressure. The residue was puri-
fied by silica-gel flash chromatography (hexane/EtOAc 6:1) to afford al-
dehyde 22 (17 mg, 99% from 19, red oil). 1H NMR (300 MHz, CDCl3):
d=9.57 (s, 1H), 7.52–7.51 (m, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.22–7.17
(m, 5H), 6.98 (d, J=3.9 Hz, 1H), 6.78–6.76 (m, 2H), 6.23 (t, J=3.3 Hz,
1H), 6.16 (d, J=3.9 Hz, 1H), 6.03–6.02 (m, 1H), 5.04 (s, 2H), 2.42 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=179.5, 145.4, 138.2, 135.2, 132.2,
132.1, 129.6, 128.3, 127.4, 127.0, 126.0, 124.5, 122.9, 122.6, 119.3, 115.2,
111.5, 49.2, 21.7 ppm; MS (FAB+): m/z: 405.1 [M+H]+; HRMS (FAB+):
m/z: calcd for C23H21N2O3S: 405.1273 [M+H]+; found: 405.1276.
Typical procedure for the synthesis of pyrrole 2,3-dicarboxylate esters
(14a): A solution of 1a (468 mg, 2.6 mmol) in CH2Cl2 (5 mL), Et3N
(83 mL, 0.59 mmol), and a solution of 4 (500 mg, 2.2 mmol) in CH2Cl2
(5 mL) were sequentially added to a solution of PPh3 (29 mg, 0.11 mmol)
and [CuACHTUNGTRENNUNG(CH3CN)4]ACHTUNGTRENNUNG[PF6] (41 mg, 0.11 mmol) in CH2Cl2 (5 mL) under a ni-
trogen atmosphere at RT. The mixture was stirred for 5 h, filtered
through a plug of Celite with the aid of CH2Cl2 (10 mL), and the solvent
was removed under reduced pressure. The residue was purified by silica-
gel flash chromatography (hexane/EtOAc 2:1) to afford the pyrrolidine
13a (569 mg, 81%, white solid). M.p.156–1578C; 1H NMR (300 MHz,
CDCl3): d=7.83–7.80 (m, 2H), 7.64–7.60 (m, 1H), 7.52–7.47 (m, 2H),
7.19–7.15 (m, 3H), 7.09–7.06 (m, 2H), 5.00 (d, J=3.4 Hz, 1H), 4.61 (d,
J=9.0 Hz, 1H), 3.91 (dd, J=7.4, 3.4 Hz, 1H), 3.77 (s, 3H), 3.68 (dd, J=
9.0, 7.4 Hz, 1H), 3.58 (s, 3H), 2.74 ppm (brs, 1H); 13C NMR (75 MHz,
CDCl3): d=172.5, 168.8, 141.2, 138.4, 134.0, 129.2, 128.5, 128.4, 127.6,
126.1, 72.9, 62.1, 60.7, 52.5, 52.4, 47.1 ppm; HRMS (FAB+): m/z: calcd
for C20H22NO6S: 404.1158 [M]+; found: 404.1134.
Et3N (28 mL, 0.2 mmol) was added to a suspension of methyl glycinate
hydrochloride (25 mg, 0.20 mmol) and microwave-activated 4 ꢅ molecu-
lar sieves (385 mg) in dry toluene (5 mL). The mixture was stirred at RT
for 30 min before 22 (52 mg, 0.13 mmol) was added. After 12 h at RT the
mixture was filtered off and water (10 mL) was added. The organic layer
was separated and the aqueous phase was extracted with CH2Cl2
(10 mL). The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and evaporated under reduced pressure to
afford 25, which was used in the next step without further purification
(55 mg, 89%, yellow oil). 1H NMR (300 MHz, CDCl3): d=8.06 (s, 1H),
7.48 (dd, J=3.4, 1.7 Hz, 1H), 7.39–7.15 (m, 7H), 6.78–6.73 (m, 2H), 6.66
(d, J=3.9 Hz, 1H), 6.19–6.14 (m, 1H); 6.05 (d, J=3.9 Hz, 1H), 5.95 (dd,
J=3.4, 1.7 Hz, 1H), 5.04 (brs, 2H), 4.18 (s, 2H), 3.67 (s, 3H), 2.41 ppm
(s, 3H).
DMAP (480 mg, 3.33 mmol) was added to a solution of 13a (150 mg,
0.37 mmol) in CH2Cl2 (8 mL). The mixture was stirred for 12 h at RT and
CH2Cl2 (10 mL) and saturated aqueous solution of NH4Cl (10 mL) were
added. The organic phase was separated and the aqueous phase was ex-
tracted with CH2Cl2 (2ꢆ5 mL). The combined organic phases were
washed with brine (5 mL), dried over MgSO4, and evaporated under re-
duced pressure. The residue was dissolved in dry CH2Cl2 (4 mL) under
nitrogen atmosphere at RT and DDQ (126 mg, 0.55 mmol) was added.
After 5 min, the mixture was filtered through a plug of Celite with the
aid of CH2Cl2 (5 mL) and the solvent was removed under reduced pres-
sure. The residue was purified by silica-gel flash chromatography
(hexane/EtOAc 3:1) to afford the pyrrole 14a (56 mg, 58%, white solid).
M.p. 133–1348C; 1H NMR (300 MHz, CDCl3): d=9.69 (brs, 1H), 7.58–
7.56 (m, 2H), 7.45–7.40 (m, 2H), 7.36–7.32 (m, 1H), 6.93 (s, 1H), 3.93 (s,
3H), 3.89 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=164.3, 160.6,
134.8, 130.3, 129.1, 128.4, 124.8, 122.7, 121.5, 110.7, 52.2, 51.9 ppm;
A solution of a-iminoester 25 (55 mg, 0.12 mmol) in dry THF (0.5 mL)
and Et3N (5 mL, 0.035 mmol) were successively added to a solution of
PPh3 (1.0 mg, 0.0038 mmol) and [CuACHTUNTGRNNEUG(CH3CN)4]ACHTUTGNREN[NNGU PF6] (1.4 mg,
0.0037 mmol) in dry THF (0.5 mL) under a nitrogen atmosphere at RT.
The resulting solution was added to a suspension of 2 (57 mg, 0.18 mmol)
in dry THF (0.5 mL). The resulting mixture was stirred for 5 h and DBU
(55 mL, 0.37 mmol) was added. After 30 min, the mixture was filtered
through a plug of Celite with the aid of CH2Cl2 (5 mL) and the solvent
was removed under reduced pressure. The residue was purified by silica-
gel flash chromatography (hexane/EtOAc 5:1) to afford the terpyrrole 28
(41 mg, 69%, yellow oil). 1H NMR (300 MHz, CDCl3): d=8.82 (brs,
9870
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Chem. Eur. J. 2010, 16, 9864 – 9873

1,3-Dipolar Cycloaddition of Azomethine Ylides with Sulfonyl Dipolarophiles
FULL PAPER
1H), 7.46 (dd, J=3.3, 1.8 Hz, 1H), 7.40 (d, J=8.3 Hz, 2H), 7.23–7.17 (m,
5H), 6.78–675 (m, 2H), 6.38 (d, J=3.7 Hz, 1H); 6.18–6–16 (m, 2H),
6.04–6.00 (m, 3H); 4.80 (s, 2H), 3.82 (s, 3H), 2.37 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=161.0, 145.5, 138.7, 136.9, 135.2, 133.3, 129.6, 129.4
128.7, 127.6, 127.2, 125.5, 124.2, 123.8, 122.0, 118.7, 116.9, 113.5, 111.3,
109.2, 108.3 51.4, 48.7, 21.6 ppm; MS (FAB+): m/z: 499.1 [M]+; HRMS
(FAB+): m/z: calcd for C28H25N3O4S: 499.1565 [M]+; found: 499.1572.
b) L. Naumovski, J. Ramos, M. Sirisawad, J. Chen, P. Thieman, P.
Lecane, D. Magda, Z. Wang, C. Cortez, G. Boswell, D. G. Cho, J. L.
Sessler, R. A. Miller, Mol. Cancer Ther. 2005, 4, 968; c) A. Hall, S.
Atkinson, S. H. Brown, I. P. Chesell, A. Chowdhury, G. M. P. Gibin,
P. Goldsmith, M. P. Healy, K. S. Jandu, M. R. Johnson, A. D. Michel,
A. Naylor, J. A. Sweeting, Bioorg. Med. Chem. Lett. 2007, 17, 1200.
[3] a) A. Fꢇrstner, Angew. Chem. 2003, 115, 3706; Angew. Chem. Int.
Ed. 2003, 42, 3582; for a recent reference, see: b) L. N. Aldrich, E. S.
Dawson, C. W. Lindsley, Org. Lett. 2010, 12, 1048.
Typical procedure for the [n+2] strategy–-conversion of terpyrrole dia-
ldehyde 38 into pentapyrrole 40: A suspension of methyl glycinate hydro-
chloride (27 mg, 0.22 mmol) and Et3N (30.6 mL, 0.22 mmol) in EtOH
(1 mL) was stirred for 30 min at RT. The resulting solution was added to
a mixture of 38 (28 mg, 0.054 mmol) and silica (43 mg) in EtOH (0.5 mL)
and sonicated at RT for 2 h. The mixture was diluted with CH2Cl2 (5 mL)
and filtered. The resulting solution was washed with water (5 mL), dried
over anhydrous MgSO4, and evaporated under reduced pressure to
afford the crude bis(a-iminoester) (35.5 mg, 98%, yellow oil), which was
immediately used in the next step without further purification. 1H NMR
(300 MHz, [D6]benzene): d=7.65 (t, J=1.1 Hz, 2H), 7.07–6.92 (m, 13H),
6.60 (m, 2H), 6.43 (d, J=3.96 Hz, 2H), 6.20 (d, J=3.96 Hz, 2H), 6.18 (s,
2H), 5.65 (s, 4H), 4.44 (s, 2H), 3.87 (s, 4H), 3.27 ppm (s, 6H).
[4] A. R. Battersby, C. J. R. Fookes, G. W. J. Matcham, E. McDonald,
Nature 1980, 285, 17.
[5] For recent reviews, see: a) J. L. Sessler, P. A. Gale, W.-S. Cho, Anion
Receptor Chemistry, RSC, Cambridge, 2006; b) J. L. Sessler, S. Ca-
miolo, P. A. Gale, Coord. Chem. Rev. 2003, 240, 17; c) P. A. Gale,
Acc. Chem. Res. 2006, 39, 465; for a recent example, see: d) E. A.
Katayev, N. V. Boev, E. Myshkovskaya, V. N. Khrustalev, Y. A. Usty-
nyuk, Chem. Eur. J. 2008, 14, 9065.
[6] For a recent reference, see: P. Plitt, D. E. Gross, V. M. Lynch, J. L.
Sessler, Chem. Eur. J. 2007, 13, 1374.
[7] For some recent references, see: a) S. L. Hung, T. C. Wen, A. Copa-
lan, Mater. Lett. 2002, 55, 165; b) J. M. Nadeau, T. M. Swager, Tetra-
hedron 2004, 60, 7141; c) M. R. Abidian, J. M. Corey, D. R. Kipke,
D. C. Martin, Small 2010, 6, 421.
A solution of the freshly prepared bis(a-iminoester) (27 mg, 0.042 mmol)
in dry CH2Cl2 (0.5 mL) and Et3N (2 mL, 0.015 mmol) were successively
added to a solution of PPh3 (0.6 mg, 0.002 mmol), [CuACHTNUTRGENNUG(CH3CN)4]ACHTUGNTERN[NGUN PF6]
(0.9 mg, 0.002 mmol) and microwave-activated 4 ꢅ molecular sieves
(480 mg) in dry CH2Cl2 (0.5 mL) under a nitrogen atmosphere at RT.
´
[8] For recent references, see: a) M. Ste˛pien, B. Donnio, J. L. Sessler,
Angew. Chem. 2007, 119, 1453; Angew. Chem. Int. Ed. 2007, 46,
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The resulting solution was added to
a suspension of 2 (38 mg,
0.125 mmol) in dry CH2Cl2 (0.5 mL). The resulting mixture was stirred
for 5 h before DBU (25.1 mL, 0.17 mmol) was added. After 30 min, the
mixture was filtered through a plug of Celite with the aid of CH2Cl2
(5.0 mL) and the solvent was removed under reduced pressure. The resi-
due was purified by silica gel flash chromatography (hexane/EtOAc 6:1)
to afford a mixture of the pentapyrrole 40 (14 mg, 47%, yellow solid)
and the corresponding quaterpyrrole aldehyde 42 (3.6 mg, 12%, yellow
solid). The products were kept at À208C, under nitrogen atmosphere,
and protected from the light. M.p. 80–828C (decomposed); 1H NMR
(300 MHz, CDCl3): d=8.74 (brs, 2H), 7.31–7.21 (m, 6H), 7.17–7.15 (m,
3H), 6.85–6.81 (m, 4H), 6.79 (dd, J=3.8, 2.6 Hz, 2H), 6.68–6.65 (m, 2H),
6.38 (d, J=3.8 Hz, 2H), 6.17 (d, J=3.8 Hz, 2H), 6.03 (s, 2H), 6.00 (dd,
J=3.8, 2.6 Hz, 2H), 4.86 (s, 4H), 4.67 (s, 2H), 3.80 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=161.2, 139.2, 139.1, 129.1, 128.8, 128.2,
127.3, 127.2, 126.9, 126.4, 126.2, 125.7, 125.5, 122.1, 116.1, 111.7, 111.1,
109.1, 108.9, 51.4, 48.3, 48.1 ppm; MS (FAB+): m/z: 713.1 [M]+; HRMS
(FAB+): m/z: calcd for C45H39N5O4: 713.1997 [M]+; found: 713.3002.
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Acknowledgements
This work was supported by the Ministerio de Ciencia e Innovaciꢁn
(MICINN, grants CTQ2006-01121 and CTQ2009-07791), Consejerꢀa de
Educaciꢁn de la Comunidad de Madrid (programme AVANCAT; S2009/
PPQ-1634), and Universidad Autꢁnoma de Madrid (UAM/CAM grant
CCG08-UAM/PPQ-4454). R.R. and A.L.P. thank the MICINN and CAM
respectively for predoctoral fellowships.
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Chem. Eur. J. 2010, 16, 9864 – 9873

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Received: March 24, 2010
Published online: June 22, 2010
Chem. Eur. J. 2010, 16, 9864 – 9873
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9873