Synthesis of pyrrole derivatives through functionalization of 3,4-bis(lithiomethyl)dihydropyrroles

Article abstract of DOI:10.1002/ejoc.200390120

Bis(2-lithioallyl)amines 2, substituted at the double bonds, undergo intramolecular carbolithiation of a lithiated double bond in different solvents to afford dilithiated dihydropyrroles 3. Treatment of these dianions with electrophiles allows the preparation of functionalized pyrrole derivatives 5 and 6. Interestingly, treatment of these dianions with carboxylic esters selectively affords either keto or hydroxy compounds (9 or 10), depending on the conditions. Several experiments have been carried out in order to clarify the mechanism of this selective transformation. Finally, dilithiated dihydropyrrole 3a could be transformed in a three-step procedure into the corresponding 3,4-bis(bromomethyl) derivative 31, which can easily be converted into bicyclic pyrrole compounds 32-33 by treatment with different nucleophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390120

FULL PAPER
Synthesis of Pyrrole Derivatives through Functionalization of
3,4-Bis(lithiomethyl)dihydropyrroles
[a]
[a]
[b]
[b]
´
´
´
˜
Jose Barluenga,* Francisco J. Fananas, Roberto Sanz, and Jose M. Ignacio
Keywords: Carbanions / Lithiation / Cyclization / Nitrogen heterocycles
Bis(2-lithioallyl)amines 2, substituted at the double bonds,
undergo intramolecular carbolithiation of a lithiated double
have been carried out in order to clarify the mechanism of
this selective transformation. Finally, dilithiated dihydropyr-
bond in different solvents to afford dilithiated dihydropyr- role 3a could be transformed in a three-step procedure into
roles 3. Treatment of these dianions with electrophiles allows
the preparation of functionalized pyrrole derivatives 5 and
6. Interestingly, treatment of these dianions with carboxylic
esters selectively affords either keto or hydroxy compounds
(9 or 10), depending on the conditions. Several experiments
the corresponding 3,4-bis(bromomethyl) derivative 31, which
can easily be converted into bicyclic pyrrole compounds
32−33 by treatment with different nucleophiles.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
bolithiation reactions, we have recently reported the first
intramolecular carbolithiation of lithiated double bonds[16]
and we have applied this methodology to the preparation
of some indole and pyrrole derivatives.[17] Here, in continua-
tion of our research into the preparation of N-heterocycles
through carbolithiation reactions,[18] we would like to re-
port our results in the synthesis of 2,5-unsubstituted 3,4-
functionalized pyrrole derivatives.
The development of carbolithiation reactions[1] as a
methodology for the preparation of heterocyclic systems[2]
has recently emerged as a powerful tool in organic syn-
thesis.[3,4] Moreover, these anionic cyclizations allow the cy-
clized product to be functionalized by treatment with elec-
trophiles, representing an important advantage over radical
cyclizations. This strategy has been used for the preparation
of nitrogen heterocycles such as pyrrolidines,[5] indolines,[6] or
isoquinolines[7] in a diastereoselective and even enantio-
selective way.[8] On the other hand, pyrroles are important
heterocycles widely used in materials science,[9] they are
abundant in nature and are of great interest as subunits for
natural products synthesis.[10] In addition, functionalized
pyrroles often display biological activity. Substantial atten-
tion has therefore been paid to the development of efficient
methods for the synthesis of this kind of heterocycles. Many
procedures, however, are limited in regard to substituents
and substitution patterns. Most known methods for the
synthesis of the pyrrole ring afford 2,5-di-,[11] 2,3-di[12] or
polysubstituted[13] pyrroles. However, methods for the pre-
paration of 2,5-unsubstituted pyrroles are scarce,[14] al-
though α-free pyrroles are very important precursors for
the synthesis of a variety of porphyrinoid dyes and polypyr-
roles.[15] In connection with our interest in the study of car-
Results and Discussion
Intramolecular Carbolithiation of Substituted N,N-Bis(2-
lithioallyl)amines
As we have recently reported,[16,17] treatment of amine 1a
(R1 ϭ R2 ϭ H) with 4 equiv. of tert-butyllithium in Et2O
at Ϫ78 °C gave rise to dianion 2a, which on addition of 4
equiv. of N,N,NЈ,NЈ-tetramethylethylenediamine (TMEDA)
at low temperature and subsequent warming to room tem-
perature afforded 3,4-bis(lithiomethyl)pyrrole derivative 3a,
the methylenepyrrolidine 4a being a likely intermediate in
the reaction. In order to test the scope of this novel trans-
formation with respect to the allyl moieties, we prepared
amines 1bϪe and treated them under the reaction condi-
tions described previously (4 equiv. of tBuLi in Et2O at Ϫ78
°C and then 4 equiv. of TMEDA from Ϫ78 to 20 °C). The
expected dianions 3 were obtained in all cases except for
that of amine 1e (R1 ϭ R2 ϭ Me), in which the intramolec-
ular carbolithiation did not work and decomposition prod-
ucts were obtained (Scheme 1). Moreover, we have found
that while dianion 2a is transformed under these reaction
conditions into the dilithio derivative 3a at Ϫ50 °C,[17] dian-
ions 2b and 2c cyclize at temperatures as low as Ϫ78 °C
[a]
´
´
Instituto Universitario de Quımica Organometalica ‘‘Enrique
Moles’’, Unidad Asociada al C.S.I.C., Universidad de Oviedo,
´
´
Julian Claverıa, 8, 33071 Oviedo, Spain
Fax: (internat.) ϩ 34-985/103450
E-mail: barluenga@sauron.quimica.uniovi.es
[b]
´
´
´
´
Departamento de Quımica, Area de Quımica Organica,
Facultad de Ciencias, Universidad de Burgos,
Pza. Missael Ban˜uelos s/n, 09001 Burgos, Spain
Eur. J. Org. Chem. 2003, 771Ϫ783  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0771 $ 20.00ϩ.50/0
771

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J. Barluenga, F. J. Fan˜anas, R. Sanz, J. M. Ignacio
FULL PAPER
and the transformation of both intermediates even in the
absence of TMEDA takes place at Ϫ40 °C. In contrast,
dianion 2d is only converted into 3d at temperatures over
Ϫ20 °C and it needs to reach room temperature when the
reaction is carried out in the absence of TMEDA. All these
observations support the initial formation of intermediate
4 by a carbolithiation reaction, it being necessary that the
R2 substituent is a hydrogen or a group, such as a phenyl
moiety, able to stabilize the terminal organolithium moiety
in 4.[19] Finally, an allylic rearrangement in 4 would provide
Table 1. Preparation of pyrrole derivatives 5 and 6 from amines 1
Starting R1
amine
R2 Eϩ
Product E/M
Yield
(%)[a]
1b
1b
1b
1c
1c
1c
1d
1d
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
H
H
H
D2O
Me3SiCl
Ph2SiCl2
5a
5b
6a
5c
5d
D
89
86
81
SiMe3
SiPh2
D
SiMe3
SiMe2
D
Ph D2O
Ph Me3SiCl
Ph Me2SiCl2 6b
H
H
91
87[b]
81[c]
85
D2O
Me2CO
5e
5f
Me2C(OH) 71
[a] Isolated yield based on the starting amine 1. [b] A 4:1 mixture of
[c]
diastereoisomers was obtained.
mers was obtained.
A 6:1 mixture of diastereoiso-
that the process worked efficiently in tetrahydropyran. In
THF, however, the cyclic product was obtained only in 45%
yield after 1 h at room temperature, along with unidentified
decomposition products. When toluene or hexane were used
as solvents, no transformation of the starting dianion 2a
was observed at 20 °C. Interestingly, though, when
TMEDA was added to a solution of 2a in toluene or hex-
ane, the cyclization was complete in 1 h at room temper-
ature. We can therefore conclude that TMEDA plays an
important role both in polar and in non-polar solvents. In
the former, the carbolithiation reaction occurs at lower tem-
Scheme 1. Synthesis of functionalized pyrrole derivatives 5 and 6;
reagents and conditions: i) tBuLi (4 equiv.), Et2O, Ϫ78 °C; ii)
TMEDA (4 equiv.), Ϫ78 to 20 °C; iii) Eϩ (2.2 equiv., see Table 1),
Ϫ78 to 20 °C; iv) DDQ (CH2Cl2, 1 equiv., 15 min); v) MCl2 (1 peratures and the yields are generally higher. In the latter,
the reaction only works when TMEDA is present.[20]
equiv.), Ϫ78 to 20 °C
Table 2. Intramolecular carbolithiation reactions of dianion 2a in
dilithiated dihydropyrrole derivatives 3 (Scheme 1). The
presence of an additional phenyl group (R1 ϭ Ph) also fa-
vors the carbolithiation reaction, probably due to extra sta-
bilization in intermediate 3. Dilithiated dihydropyrrole de-
rivatives 3 were trapped with different electrophiles (deuter-
ium oxide, silicon chlorides or acetone), giving rise to func-
tionalized dihydropyrrole derivatives which were
dehydrogenated by treatment with 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ) to give the corresponding
functionalized pyrroles 5 and 6. Interestingly, the func-
tionalized pyrroline intermediates could also be isolated if
a fast purification was carried out.[17] In the case of starting
amine 1c (R1 ϭ R2 ϭ Ph), diastereoisomeric mixtures were
obtained after treatment with electrophiles (Scheme 1 and
Table 1). Compound 5d (R1 ϭ R2 ϭ Ph; E ϭ SiMe3) was
obtained as a 4:1 mixture of diastereoisomers, but we were
unable to establish their stereochemistry. In the case of bi-
cyclic compound 6b (R1 ϭ R2 ϭ Ph; M ϭ SiMe2), however,
different solvents
Solvent
Reaction
Conditions
Time
(min)
Yield
(%)[a]
Et2O
Ϫ78 to 20 °C
Ϫ78 to Ϫ50 °C
Ϫ78 to 20 °C
Ϫ78 to 20 °C
Ϫ78 to 20 °C
Ϫ78 to 20 °C
Ϫ78 to 20 °C
45Ϫ60
60
60
60
60
60
60
91
96
88
45
0
92
93
Et2O-TMEDA
Tetrahydropyran
THF
Toluene
Toluene-TMEDA
Hexane-TMEDA
[a]
Isolated yields of hydrolyzed compound corresponding to 3a
based on the starting amine 1a.
Reactions of Dianions 3 with Carboxylic Esters
To extend the synthetic scope of this carbolithiation reac-
a 6:1 mixture of diastereoisomers was obtained, and we tion we carried out the functionalization of the dilithiated
were able to establish the stereochemistry of the major meso dihydropyrrole derivatives 3 with different carboxylic esters.
diastereoisomer by NOE experiments (Scheme 1).
Surprisingly, treatment of 3a with 2 equiv. of ethyl isobutyr-
We have also studied the role played by the solvent in ate gave rise to a mixture of compounds that was analyzed
this novel transformation, carrying out different experi- by GC-MS to show that the major product had incorpor-
ments with dianion 2a in several solvents (Table 2). In Et2O ated only one equivalent of ester. We therefore treated 3a
the cyclization was complete in 45 min at room temper- with 1 equiv. of ethyl isobutyrate at Ϫ78 °C, the mixture
ature, whereas in Et2O/TMEDA the process was complete then being allowed to come to room temperature and
in 1 h at temperatures ranging between Ϫ78 and Ϫ50 °C. stirred for 1 h. The formation of a mixture of the β,γ-unsat-
With respect to other ethereal solvents, we also observed urated ketone 7e and the bicyclic alcohol 8e was observed,
772
Eur. J. Org. Chem. 2003, 771Ϫ783

Synthesis of Pyrrole Derivatives
FULL PAPER
but these were isolated as the oxidized pyrrole derivatives
9e and 10e (Scheme 2). With the goal of achieving selective
formation of each product, several experiments were carried
out under different reaction conditions. Finally, we found
that the hydroxy bicyclic derivative 8e was generated exclus-
ively when the reaction mixture was allowed to stir over-
night at 20 °C, the corresponding bicyclic pyrrole 10e being
isolated in 77% yield after dehydrogenation of the crude
product and further purification by column chromato-
graphy (Scheme 2 and Table 3). Moreover, we also observed
that if the reaction mixture was stirred for only 1 h at Ϫ78
Table 3. Preparation of keto and hydroxy pyrrole derivatives 7؊10
from reactions between dianion 3a and ethyl carboxylates
Ester
Product
R
Oxidant
Yield (%)[a]
cϪC3H5CO2Et
c-C3H5CO2Et
c-C3H5CO2Et
MeCO2Et
EtCO2Et
nPrCO2Et
7a
c-C3H5
c-C3H5
c-C3H5
Me
82
80
69
68
75
69
78
69
65
64
75
68
77
66
8a
9a
DDQ
DDQ
Air
DDQ
Air
DDQ
DDQ
DDQ
Air
DDQ
Air
9b
9c
Et
9d
nPr
iPrCO2Et
PhCO2Et
9e
iPr
Ph
c-C3H5
Me
9f
°C, the pyrrole derivative 9e could be isolated in 78% yield c-C3H5CO2Et
10a
10b
10c
10d
10e
10f
MeCO2Et
after hydrolysis and further oxidation in air (Scheme 2). It
EtCO2Et
is interesting to note that, despite the strong tendencies of
nPrCO2Et
Et
nPr
β,γ-unsaturated ketones towards prototropic rearrange-
iPrCO2Et
iPr
Ph
ments, producing conjugated α,β-unsaturated ketones,[21]
PhCO2Et
DDQ
no isomerization was observed in our case. In view of the
[a]
Isolated yields based on the starting amine 1a.
interesting functionalized moieties in the synthesized pyr-
role derivatives 7؊10, several carboxylic esters were tested
as electrophiles with dianion 3a (Table 3). In all the cases
the expected keto or hydroxy derivatives were obtained, de-
pending on the reaction conditions (Ϫ78 °C for ketones 7
and 9 or room temperature for alcohols 8 and 10). With
ethyl cyclopropanecarboxylate the dihydropyrroles 7a and
8a could be isolated and purified, although they could also
be further dehydrogenated to their aromatic counterparts
9a and 10a by DDQ.
so the completion of the reaction needed several hours at
room temperature. Moreover, if THF was added after the
initial reaction between 3a and the ester, a different pathway
occurred and the results were consistent with a transloca-
tion of the lithium atom in organolithium 11 to form a
more stable lithium enolate 13 (Scheme 3). This process is
probably favored by the polar character of THF, which can
promote a higher basicity of anion 11.[23]
Scheme 2. Synthesis of functionalized pyrrole derivatives 7؊10; re-
agents and conditions: i) Et2O, Ϫ78 °C, 1 h; ii) MeOH, Ϫ78 to 20
°C; iii) DDQ (CH2Cl2, 1 equiv., 15 min) or air (CH2Cl2, 24 h); iv)
Et2O, Ϫ78 to 20 °C, 12 h; v) H2O, 20 °C
A detailed suggested mechanism for the reactions be-
tween intermediate 3a and carboxylic esters is presented in
Scheme 3. The initial attack of 3a on the ester carbonyl
group, followed by elimination of ethoxide anion, would
yield monoanion 11. This is partially supported by the
isolation of the deuterated (Ͼ90% deuterium incorporated)
ketone 9e(D), obtained after dehydrogenation, when the re-
action mixture was quenched with MeOD at Ϫ78 °C after
Scheme 3. Proposed mechanism for the selective formation of ke-
tones 7 and alcohols 8
Synthesis of Pyrrole Derivatives 14
In order to verify the formation of enolate 13 we carried
1 h. To explain the difference in outcome of the reaction out some experiments. Deuteriolysis of the THF solution
depending on the conditions, several experiments were car- of 11e at Ϫ78 °C gave, after oxidation, compound 9e(D).
ried out. Surprisingly, we observed that anion 11 was rela- However, when the THF solution was allowed to warm to
tively inert towards conventional electrophiles[22] and that 0 °C before the addition of deuterium oxide, 14a was ob-
its closure to bicyclic alkoxide 12 took place slowly at 0 °C, tained exclusively (after air oxidation). Although several ex-
Eur. J. Org. Chem. 2003, 771Ϫ783
773

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J. Barluenga, F. J. Fan˜anas, R. Sanz, J. M. Ignacio
FULL PAPER
periments at different temperatures were performed, we
were not able to determine the exact temperature at which
the translocation reaction takes place. Addition of elec-
trophiles other than deuterium oxide, such as allyl bromide
or benzyl chloride, to the THF solution of 11 at Ϫ78 °C
and subsequent warming to room temperature and then
heating at reflux gave pyrrole derivatives 14b and 14c after
oxidation and purification. It is interesting to note that
functionalized pyrrole derivatives 14b and 14c were ob-
tained from the simple amine 1a, with the formation of
three new CϪC bonds in a regioselective way, in good yields
without isolation of any intermediates. We also found that
if THF was added to 11 and the temperature was then al-
lowed to come to 20 °C, the bicyclic alcohol 8 was not
formed but the corresponding ketone 7 was then isolated.
All these experiments seem to rule out the possibility of the
formation of a lithium cyclopropanolate intermediate such
as 15, generated by intramolecular addition of the allylic
organolithium 11 to the ketone carbonyl. These kind of in-
termediates were proposed by Rieke et al. for the reaction
between substituted (2-butene-1,4-diyl)magnesium com-
plexes and carboxylic esters[24] to generate cyclopentenols
or β,γ-unsaturated ketones. Those authors also found that
soft carbon electrophiles such as imines, ketones and esters
reacted regioselectively at the 2-position of the 1,4-diylmag-
nesium complex, whereas we always found that soft or
harder (silicon or tin chlorides) electrophiles reacted at the
1-position in our 3,4-bis(lithiomethyl)dihydropyrrole deriv-
atives.
Furthermore, when a functionalized carboxylate such as
ethyl 5-bromovalerate was used as electrophile in the reac-
tion with dianion 3a and the reaction mixture was
quenched at low temperature, the expected ketone derivat-
ive 16 was obtained in 69% yield after exposure of the crude
product to air in CH2Cl2 for 24 h (Scheme 4). According to
our proposed mechanism, if THF were added to the reac-
tion mixture after the reaction between intermediate 3a and
the ethyl 5-bromovalerate, cyclic ketone 17 should be gener-
ated by intramolecular trapping of the bromide by the inter-
mediate enolate 13 [R ϭ (CH2)4Br]. Indeed, 17 was ob-
tained in 61% yield after oxidation of the crude product,
supporting the pathways outlined in Scheme 3. On the
other hand, when the reaction between the ester and the
dianion 3a was carried out at temperatures ranging between
Ϫ78 and 20 °C, the alcohol 18 was obtained in 45% yield
after oxidation and purification, along with the spiro deriv-
Scheme 4. Preparation of pyrroles 16؊19 by treatment of 3a with
ethyl 5-bromovalerate; reagents and conditions: i) Et2O, Ϫ78 °C,
1 h; ii) MeOH, Ϫ78 to 20 °C; iii) air (CH2Cl2, 24 h); iv) THF, Ϫ78
to 20 °C; v) Et2O, Ϫ78 to 20 °C, 12 h; vi) NaH (1.5 equiv.), THF,
reflux, 24 h.
gave rise to a mixture of four compounds: regioisomeric
ketones 20 and 21, diketone 22 and the hydroxy derivative
23. When the quenching of the reaction was carried out at
Ϫ78 °C the overall yield was 58% and the expected mono-
ketone 20 was the main product. When the temperature was
allowed to reach 20 °C before quenching, however, the dike-
tone 22 was obtained as the major product and only a small
amount of the expected alcohol 23 was generated, with a
similar overall yield. Although the process was not useful
from a synthetic point of view, the formation of diketone
22 provided additional support for the intermediacy of an
anion such as 11, which in this case mainly reacted inter-
molecularly with another molecule of ester instead of re-
acting intramolecularly to afford 23.
Treatment of dianion 3c with ethyl isobutyrate, on the
other hand, gave rise to a mixture of three diastereoisomeric
hydroxy derivatives 24, 25 and 26 in a 75% overall yield. In
this case, the same ratio of isomers was obtained irrespect-
ive of the quenching conditions (Ϫ78 °C or room temper-
ature). The three diastereoisomers could be separated by
column chromatography and their stereochemistry deter-
mined by NOESY experiments. Compound 24, with the
two phenyl and the hydroxy groups in a cis arrangement,
was the major diastereoisomer (53% isolated yield).
Synthesis of Dibromide 31
We had previously reported that treatment of dianions 3
ative 19 (15%), derived from intramolecular alkylation of with some electrophiles such as diphenyl disulfide or 1,2-
the corresponding alkoxide derivative 12 [R ϭ (CH2)4Br]. diphenylethanedione did not afford the expected func-
However, compound 19 was obtained in 56% yield when tionalized dihydropyrrole derivatives because a competing
compound 18 was treated with NaH in refluxing THF.
conjugated elimination in 27 gave rise to diene 28
(Scheme 6).[17] In addition, we had also observed that the
same result was obtained when 1,2-dibromethane or iodine
were used as electrophiles. In view of the potential interest
of a dibromide compound like 31, we considered alternative
Reactions between Dianions 3b and 3c and Ethyl
Isobutyrate
When we extended the reaction to other dianions 3 and ways to obtain it, and so a three-step sequence was estab-
other carboxylic esters such as ethyl isobutyrate, different lished. Firstly, 3a was treated with trimethyl borate at tem-
results were obtained, depending on the substituents on the peratures ranging between Ϫ78 and 20 °C. The crude bor-
double bonds. Thus, treatment of 3b with ethyl isobutyrate ate 29 was oxidized in situ with alkaline hydrogen peroxide
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Synthesis of Pyrrole Derivatives
FULL PAPER
Scheme 6. Transformation of dianion 3a into dibromide 31 and
further functionalization with nucleophiles; synthesis of com-
pounds 32؊34; reagents and conditions: i) Et2O, Ϫ78 to 20 °C; ii)
B(OMe)3 (2 equiv.), Et2O, Ϫ78 to 20 °C; iii) NaOH/H2O2 (4
equiv.), 0 °C and then reflux, 30 min; iv) HBr (48%); v) RNH2 (1
equiv.), K2CO3 (2 equiv.), CH3CN, reflux; vi) catechol (1 equiv.),
K2CO3 (2 equiv.), (CH3)2CO, reflux; vii) PhSH (2 equiv.), NaOH
(0.7 ), H2O/THF, 20 °C.
Scheme 5. Reactions between dianions 3b and 3c and ethyl isobu-
tyrate; obtention of compounds 20؊26
Experimental Section
General Remarks: All reactions were carried out under nitrogen in
oven-dried glassware. Temperatures are reported as bath temper-
atures. Diethyl ether, tetrahydrofuran, toluene, hexane and tetrahy-
dropyran were heated continuously at reflux and freshly distilled
under nitrogen from sodium or sodium/benzophenone. N,N,NЈ,NЈ-
Tetramethylethylenediamine was distilled from potassium/benzo-
phenone in vacuo. Solvents used in extraction and purification were
distilled prior to use. TLC was performed on aluminium-backed
plates coated with silica gel 60 with F254 indicator (Merck) and
compounds were viewed by use of UV light (254 nm) or iodine.
Flash column chromatography was carried out on silica gel 60,
230Ϫ400 mesh (Merck). Melting points were measured on a
BüchiϪTottoli apparatus with open capillary tubes and are uncor-
rected. 1H NMR and 13C NMR spectra were recorded at 400
(100.6) and 200 (50.3) MHz on Varian spectrometers with CDCl3
(δ ϭ 7.26 ppm in 1H NMR spectra and δ ϭ 76.95 ppm in 13C
to afford the diol 30, which was isolated and purified. This
compound was transformed into the dibromide 31 by treat-
ment with concentrated HBr (Scheme 6). Surprisingly, diol
30 was stable to all the oxidation conditions attempted (air,
DDQ and hydrogen peroxide) and the corresponding pyr-
role derivative was not obtained. With dibromide 31 to
hand, we were able to prepare interesting bicyclic or
tricyclic dihydropyrrole derivatives 32 and 33 by treatment
of 31 with different nucleophiles such as amines and cate-
chol. It is also interesting to note that treatment of 31 with
thiophenol yielded the disulfide 34, which had been unob-
tainable by direct treatment of 3a with diphenyl disulfide.[17]
1
NMR spectra), C6D6 (δ ϭ 7.15 ppm in H NMR spectra and δ ϭ
Conclusion
128.02 ppm in 13C NMR spectra), [D6]DMSO (δ ϭ 2.50 ppm in
1H NMR spectra and δ ϭ 39.43 ppm in 13C NMR spectra) and
[D6]acetone (δ ϭ 2.05 ppm in 1H NMR spectra and δ ϭ 30.83 ppm
in 13C NMR spectra) as internal standards by use of the DEPT
pulse sequence. Low-resolution electron impact mass spectra (EI-
LRMS) were obtained at 70 eV on an HP-5987 A instrument and
the intensities are reported as percentages relative to the base peak
after the corresponding m/z value. Elemental analyses were per-
formed with PerkinϪElmer and LECO elemental analysers. All
commercially available reagents were used without further purifica-
tion unless otherwise indicated and were purchased from Aldrich
Chemical Co. or Acros Organics. tBuLi was used as 1.5  solution
in pentane. BuLi was used as 2.5  solution in hexane.
In summary, we have extended the scope of our previ-
ously reported intramolecular carbolithiation reaction of
lithiated double bonds. We have also demonstrated a new
and unexpected reactivity of the resulting dianions with
carboxylic esters, selectively affording β,γ-unsaturated ke-
tone or bicyclic cyclopentenol derivatives, depending on the
reaction conditions. With this methodology, it was possible
to form up to three new CϪC bonds selectively in a one-
pot process, to afford functionalized pyrrole derivatives
from simple and easily available bis(2-bromoallyl)amines.
Finally, the reactivity of the 3,4-bis(lithiomethyl)dihydro-
pyrroles is completed by their conversion into the corres-
ponding dibromides, which allow further functionalization
with nucleophiles to give heterofused polycyclic com-
pounds.
General Procedure for the Preparation of N,N-Bis(2-bromoallyl)am-
ines 1a, 1c and 1e: A mixture of 4-methylaniline (2.68 g, 25 mmol),
K2CO3 (6.9 g, 50 mmol), NaI (0.75 g, 5 mmol), and 2 equiv. of the
corresponding substituted alkene (2,3-dibromopropene, (Z)-2-bro-
Eur. J. Org. Chem. 2003, 771Ϫ783
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J. Barluenga, F. J. Fan˜anas, R. Sanz, J. M. Ignacio
FULL PAPER
mocinnamyl chloride and (Z)-methanesulfonic acid 2-bromo-2-bu-
45 mmol), NaI (0.68 g, 4.5 mmol) and the corresponding substi-
tenyl ester) in CH3CN (50 mL) was heated at reflux overnight. The tuted alkene [(Z)-2-bromocinnamyl chloride and (Z)-methanesul-
mixture was extracted with EtOAc (3 ϫ 30 mL), and the combined fonic acid 2-bromo-2-butenyl ester] in CH3CN (50 mL) was stirred
organic layers were washed with saturated aqueous Na2CO3 and under reflux overnight. The mixture was extracted with EtOAc (3
dried over anhydrous Na2SO4. The solvents were removed under
vacuum, and the residue was purified by flash column chromato-
graphy to afford amines 1a and 1e. In the case of amine 1c, on the
other hand, the solid amine crystallized after the refluxing of the
mixture and cooling to room temperature. It was filtered and
washed with water to remove the inorganic salts, affording pure 1c.
ϫ 30 mL), and the combined organic layers were dried over anhyd-
rous Na2SO4. The solvents were removed under vacuum and the
residue was purified by flash column chromatography to afford
amines 1b and 1d.
N-(2-Bromoallyl)-N-[(Z)-2-bromocinnamyl]-4-methylaniline
(1b):
Treatment of N-(2-bromoallyl)-4-methylaniline (10.1 g, 45 mmol),
K2CO3 (6.21 g, 45 mmol), NaI (0.68 g, 4.5 mmol) and (Z)-2-brom-
ocinnamyl chloride (10.42 g, 45 mmol) as above, workup and puri-
fication by column chromatography (hexane/EtOAc, 40:1) afforded
amine 1b (13.27 g, 70%) as a white solid. M.p. 65Ϫ67 °C. 1H NMR
(200 MHz, CDCl3): δ ϭ 2.32 (s, 3 H), 4.27 (s, 2 H), 4.36 (s, 2 H),
5.63Ϫ5.68 (m, 1 H), 5.75Ϫ5.80 (m, 1 H), 6.68Ϫ6.77 (m, 2 H), 6.91
(s, 1 H), 7.07Ϫ7.16 (m, 2 H), 7.28Ϫ7.46 (m, 3 H), 7.57Ϫ7.66 (m,
2 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.2, 58.5, 60.1,
112.3, 116.2, 122.1, 126.3, 127.3, 127.9, 128.0, 128.8, 128.9, 129.8,
135.0, 144.5 ppm. LRMS (70 eV, EI): m/z (%) ϭ 423 (5) [Mϩ ϩ 4],
421 (13) [Mϩ ϩ 2], 419 (6) [Mϩ], 220 (100). C19H19Br2N (421.2):
calcd. C 54.18, H 4.55, N 3.33; found C 54.01, H 4.49, N 3.37.
N,N-Bis(2-bromoallyl)-4-methylaniline (1a): Data are in agreement
with our previous report.[17]
N,N-Bis[(Z)-2-bromocinnamyl]-4-methylaniline (1c): 4-Methylanil-
ine (2.68 g, 25 mmol) was treated with K2CO3 (6.9 g, 50 mmol),
NaI (0.75 g, 5 mmol) and (Z)-2-bromocinnamyl chloride (11.5 g,
50 mmol) in CH3CN (50 mL). Workup as above yielded amine 1c
1
(8.08 g, 65%) as a clear brown solid. M.p. 137Ϫ139 °C. H NMR
(400 MHz, CDCl3): δ ϭ 2.31 (s, 3 H), 4.44 (s, 4 H), 6.76Ϫ6.81 (m,
2 H), 6.92 (s, 2 H), 7.09Ϫ7.14 (m, 2 H), 7.29Ϫ7.41 (m, 6 H),
7.59Ϫ7.64 (m, 4 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ
20.2, 60.1, 112.5, 122.1, 126.4, 127.3, 127.9, 128.0, 128.9, 135.0,
144.7 ppm. LRMS (70 eV, EI): m/z (%) ϭ 116 (100). C25H23Br2N
(497.3): calcd. C 60.38, H 4.66, N 2.82; found C 60.55, H 4.62,
N 2.84.
N-(2-Bromoallyl)-N-[(Z)-2-bromo-2-butenyl]-4-methylaniline (1d):
Treatment of N-(2-bromoallyl)-4-methylaniline (10.1 g, 45 mmol),
K2CO3 (6.21 g, 45 mmol), NaI (0.68 g, 4.5 mmol), and (Z)-meth-
anesulfonic acid 2-bromo-2-butenyl ester (10.31 g, 45 mmol) as
above, followed by workup and purification by column chromato-
graphy (hexane), afforded amine 1d (11.96 g, 74%) as a colorless
oil. Rf ϭ 0.27 (hexane). 1H NMR (400 MHz, CDCl3): δ ϭ 1.75
(dt, J ϭ 6.6, 1.8 Hz, 3 H), 2.24 (s, 3 H), 4.09Ϫ4.11 (m, 2 H),
4.13Ϫ4.16 (m, 2 H), 5.54Ϫ5.56 (m, 1 H), 5.66Ϫ5.68 (m, 1 H), 5.84
(tq, J ϭ 6.6, 1.7 Hz, 1 H), 6.58Ϫ6.61 (m, 2 H), 7.00Ϫ7.03 (m, 2
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ16.2, 20.2, 58.4, 58.6,
112.1, 116.0, 122.8, 123.6, 126.9, 128.9, 129.7, 144.5 ppm. LRMS
(70 eV, EI): m/z (%) ϭ 361 (15) [Mϩ ϩ 4], 359 (39) [Mϩ ϩ 2], 357
(19) [Mϩ], 158 (100). C14H17Br2N (359.1): calcd. C 46.83, H 4.77,
N 3.90; found C 46.89, H 4.73, N 3.94.
N,N-Bis[(Z)-2-bromo-2-butenyl]-4-methylaniline (1e): Treatment of
4-methylaniline (2.68 g, 25 mmol), K2CO3 (6.9 g, 50 mmol), NaI
(0.75 g, 5 mmol) and (Z)-methanesulfonic acid 2-bromo-2-butenyl
ester (11.4 g, 50 mmol) as above in CH3CN (50 mL), followed by
workup and purification by column chromatography (hexane/
EtOAc, 40:1), yielded amine 1e (7.05 g, 76%) as a 15:1 Z/E mixture
and as a white solid. M.p. 83Ϫ85 °C. 1H NMR (400 MHz, CDCl3):
δ ϭ 1.74 (dt, J ϭ 6.6, 1.7 Hz, 6 H), 2.25 (s, 3 H), 4.11Ϫ4.14 (m, 4
H), 5.82 (tq, J ϭ 6.6, 1.5 Hz, 2 H), 6.55Ϫ6.60 (m, 2 H), 7.00Ϫ7.05
(m, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 16.2, 20.2,
58.4, 112.0, 122.6, 123.7, 126.7, 129.6, 144.8 ppm. LRMS (70 eV,
EI): m/z (%) ϭ 375 (10) [Mϩ ϩ 4], 373 (23) [Mϩ ϩ 2], 371 (13)
[Mϩ], 220 (100). C15H19Br2N (373.1): calcd. C 48.28, H 5.13, N
3.75; found C 48.14, H 5.08, N 3.77.
General Procedure for the Preparation of Pyrrole Derivatives 5 and
6: A solution of the starting amine 1bϪd (2 mmol) in diethyl ether
(15 mL) was treated at Ϫ78 °C with 4 equiv. of tBuLi (5.33 mL of
a 1.5  solution in pentane, 8 mmol), and the resulting mixture was
stirred at this temperature for 30 min. TMEDA (4 equiv., 1.2 mL,
8 mmol) was then added. The mixture was stirred at Ϫ78 °C for
1 h, except in the case of amine 1d, in which the cooling bath was
removed and stirring was continued for 1 h. The ethereal suspen-
sion of the corresponding dianion 3 was again cooled to Ϫ78 °C
and either 2.1 equiv. (4.2 mmol) of neat electrophile (deuterium ox-
ide, chlorotrimethylsilane, acetone) or 1.0 equiv. (2 mmol) of
metallodichloride (dichlorodiphenylsilane, dichlorodimethylsilane)
were added. The mixture was allowed to come to room temperature
and the reaction mixture was stirred for 3 h. The mixture was hy-
drolyzed with water and extracted with EtOAc (3 ϫ 20 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
the solvents were removed under vacuum, yielding the correspond-
ing dihydropyrrole derivatives. The solutions of these compounds
in CH2Cl2 (20 mL) were each treated with dichlorodicyanobenzo-
quinone (DDQ, 1.0 equiv., 0.46 g, 2 mmol). After the mixture had
been stirred for 15 min at room temperature, aqueous NaOH (1 ,
20 mL) was added (alternatively, oxidation was carried out by stir-
ring the solution exposed to the air for 24 h). The mixture was
extracted with CH2Cl2 (3 ϫ 20 mL), the combined organic layers
Preparation of N-(2-Bromoallyl)-4-methylaniline: A solution of 4-
methylaniline (16.05 g, 150 mmol) in THF (50 mL) was treated at
Ϫ40 °C with BuLi (20 mL of a 2.6  solution in hexanes, 50 mmol).
The reaction mixture was stirred for 15 min at this temperature
and was then allowed to come to room temperature, stirring being
continued for 45 min. The reaction mixture was cooled to Ϫ60 °C,
and 2,3-dibromopropene (10 g, 50 mmol) was added. After 15 min
at this temperature, the reaction mixture was allowed to warm and
stirring was continued for 3 h. The mixture was hydrolyzed with
water and extracted with EtOAc (3 ϫ 30 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4 and the solvents
were removed under vacuum. The residue was purified by silica
gel column chromatography (hexane/EtOAc, 30:1) to afford N-(2-
bromoallyl)-4-methylaniline (10.1 g, 90%) as a clear brown oil.
Rf ϭ 0.21 (hexane/EtOAc, 30:1). 1H NMR (200 MHz, CDCl3): δ ϭ
2.26 (s, 3 H), 3.98 (s, 2 H), 4.08 (br. s, 1 H), 5.54Ϫ5.58 (m, 1 H),
5.84Ϫ5.88 (m, 1 H), 6.51Ϫ6.60 (m, 2 H), 6.97Ϫ7.06 (m, 2 H) ppm.
13C NMR (50.3 MHz, CDCl3): δ ϭ 20.3, 52.1, 112.9, 116.4, 127.1,
129.6, 131.2, 144.1 ppm. LRMS (70 eV, EI): m/z (%) ϭ 227 (30)
[Mϩ ϩ 2], 225 (31) [Mϩ], 120 (100). C10H12BrN (226.1): calcd. C
53.12, H 5.35, N 6.19; found C 53.27, H 5.41, N 6.12.
Preparation of N-(2-Bromoallyl)amines 1b and 1d: A mixture of N-
(2-bromoallyl)-4-methylaniline (10.1 g, 45 mmol), K2CO3 (6.21 g, were dried over anhydrous Na2SO4, and the solvents were removed
776 Eur. J. Org. Chem. 2003, 771Ϫ783

Synthesis of Pyrrole Derivatives
under vacuum. The resulting residue was purified by flash column 1-(4-Methylphenyl)-3,4-bis[phenyl(trimethylsilyl)methyl]-1H-pyrrole
FULL PAPER
chromatography (silica gel, hexane/EtOAc) to afford pyrrole deriv-
atives 5 and 6.
(5d): Treatment of amine 1c (1.0 g, 2 mmol) with tBuLi (5.33 mL
of a 1.5  solution in pentane, 8 mmol) and TMEDA (1.2 mL,
4 mmol) was followed by addition of chlorotrimethylsilane
(0.53 mL, 4.2 mmol). Treatment with DDQ (0.46 g, 2 mmol) in
CH2Cl2 (20 mL) at 20 °C and workup as above, followed by puri-
fication by column chromatography (hexane/EtOAc, 40:1), yielded
5d (0.84 g, 87%), which was isolated as a 4:1 mixture of diastereo-
isomers. 1H NMR (200 MHz, CDCl3) for the mixture of the two
diastereoisomers: δ ϭ 0.16 (s, 9 H maj.), 0.05 (s, 9 H min), 2.36 (s,
3 H min), 2.39 (s, 3 H maj.), 3.12 (s, 2 H maj.), 3.29 (s, 2 H min.),
6.77Ϫ7.33 (m, 16 H) ppm. 13C NMR (50.3 MHz, CDCl3) for the
mixture of the two diastereoisomers: δ ϭ Ϫ2.0 (maj.), Ϫ1.8 (min.),
20.8, 33.9 (maj.), 34.4 (min.), 116.4 (min.), 117.0 (maj.), 119.4
(min.), 119.5 (maj.), 124.0 (min.), 124.1 (maj.), 125.6 (min.), 125.8
(maj.), 127.6 (min.), 127.7 (maj.), 128.0, 129.9 (min.), 130.0 (maj.),
134.1 (min.), 134.2 (maj.), 138.5, 143.5 (min.), 143.6 (maj.) ppm.
LRMS (70 eV, EI): m/z (%) ϭ maj.: 481 (31) [Mϩ], 408 (100); min:
481 (31) [Mϩ], 408 (100). C31H39NSi2 (481.8): calcd. C 77.28, H
8.16, N 2.91; found. C 77.42, H 8.11, N 2.87.
3-(Deuteriomethyl)-4-[(deuteriophenyl)methyl]-1-(4-methylphenyl)-
1H-pyrrole (5a): Amine 1b (0.84 g, 2 mmol) was treated with tBuLi
(5.33 mL of a 1.5  solution in pentane, 8 mmol) and TMEDA
(1.2 mL, 8 mmol). Addition of deuterium oxide (excess) was fol-
lowed by treatment with DDQ (0.46 g, 2 mmol) in CH2Cl2 (20 mL).
Workup as above and purification by column chromatography
(hexane/EtOAc, 40:1) yielded 5a (0.47 g, 89%) as a colorless oil.
Rf ϭ 0.27 (hexane/EtOAc, 30:1). 1H NMR (200 MHz, CDCl3): δ ϭ
2.11 (s, 2 H), 2.41 (s, 3 H), 3.90 (s, 1 H), 6.78Ϫ6.81 (m, 1 H),
6.90Ϫ6.94 (m, 1 H), 7.19Ϫ7.44 (m, 4 H) ppm. 13C NMR
(50.3 MHz, CDCl3): δ ϭ 10.0 (t, JC/D ϭ 19.4 Hz), 20.7, 31.5 (t, JC/
D ϭ 19.2 Hz), 117.1, 117.3, 119.4, 119.9, 124.2, 125.6, 128.2, 128.6,
129.8, 134.2, 138.3, 141.3 ppm. LRMS (70 eV, EI): m/z (%) ϭ 263
(87) [Mϩ], 186 (100). C19H17D2N (263.4): calcd. C 86.65, H/D 8.03,
N 5.32; found C 86.54, H/D 7.95, N 5.28.
1-(4-Methylphenyl)-3-[phenyl(trimethylsilyl)methyl]-4-(trimethyl-
silylmethyl)-1H-pyrrole (5b): Amine 1b (0.84 g, 2 mmol) was treated
with tBuLi (5.33 mL, 8 mmol) and TMEDA (1.2 mL, 8 mmol).
Chlorotrimethylsilane (0.53 mL, 4.2 mmol) was added before treat-
ment with DDQ (0.46 g, 2 mmol) in CH2Cl2 (20 mL) at 20 °C.
Workup as above and purification by column chromatography
(hexane) yielded 5b (0.70 g, 86%) as a colorless oil. Rf ϭ 0.22 (hex-
ane). 1H NMR (200 MHz, CDCl3): δ ϭ 0.00 (s, 9 H), 0.13 (s, 9 H),
1.73 (s, 2 H), 2.42 (s, 3 H), 3.41 (s, 1 H), 6.75Ϫ6.79 (m, 1 H),
7.06Ϫ7.39 (m, 10 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ
Ϫ1.8, Ϫ1.5, 13.5, 20.7, 34.4, 115.2, 116.4, 119.2, 122.5, 124.1, 124.4,
127.8, 128.0, 129.8, 133.9, 138.5, 143.4 ppm. LRMS (70 eV, EI):
m/z (%) ϭ 405 (32) [Mϩ], 332 (100). C25H35NSi2 (405.7): calcd. C
74.01, H 8.70, N 3.45; found. C 74.20, H 8.81, N 3.41.
2,4,5,6-Tetrahydro-5,5-dimethyl-2-(4-methylphenyl)-4,6-diphenyl-
silolo[3,4-c]pyrrole (6b): Amine 1c (1.0 g, 2 mmol) was treated with
tBuLi (5.33 mL of a 1.5  solution in pentane, 8 mmol) and
TMEDA (1.2 mL, 8 mmol). Addition of dichlorodimethylsilane
(0.24 mL, 2 mmol) was followed by treatment with DDQ (0.46 g,
2 mmol) in CH2Cl2 (20 mL). Workup as above and purification by
column chromatography (hexane/EtOAc, 40:1) yielded 6b (0.64 g,
81%) as a mixture of diastereoisomers cis/trans ϭ 6:1. 1H NMR
(400 MHz, CDCl3) for the mixture of diastereoisomers: δ ϭ Ϫ0.46
(s, 3 H cis), 0.00 (s, 6 H trans), 0.50 (s, 3 H, cis), 2.38 (s, 3 H trans),
2.40 (s, 3 H cis), 3.77 (s, 2 H cis), 3.82 (s, 2 H trans), 6.97 (s, 2 H),
7.12Ϫ7.38 (m, 20 H) ppm. 13C NMR (100.6 MHz, CDCl3) for the
mixture of diastereoisomers: δ ϭ Ϫ6.2 (cis), Ϫ4.2 (trans), Ϫ2.4
(cis), 20.7, 33.5 (trans), 34.5 (cis), 114.6, 119.5 (trans), 119.6 (cis),
124.0 (trans), 124.1 (cis), 126.5 (trans), 126.7 (cis), 128.1, 129.9,
130.3 (cis), 130.4 (trans), 134.5 (trans), 134.6 (cis), 138.7, 143.9 (cis),
144.4 (trans) ppm. LRMS (70 eV, EI) ϭ m/z (%) ϭ cis: 393 (57)
[Mϩ], 144 (100); trans: 393 (47) [Mϩ], 144 (100). C27H27NSi (393.6):
calcd. C 82.49, H 6.90, N 3.56; found C 82.61, H 6.84, N 3.60.
2,4,5,6-Tetrahydro-2-(4-methylphenyl)-4,5,5-triphenylsilolo[3,4-c]-
pyrrole (6a): Treatment of amine 1b (0.84 g, 2 mmol) with tBuLi
(5.33 mL, 8 mmol) and TMEDA (1.2 mL, 8 mmol) was followed
by addition of dichlorodiphenylsilane (0.50 g, 2 mmol). Treatment
with DDQ (0.46 g, 2 mmol) in CH2Cl2 (20 mL) at 20 °C, workup as
above and purification by column chromatography (hexane/EtOAc,
40:1) yielded 6a (0.71 g, 81%) as a white solid. M.p. 163Ϫ165 °C.
1H NMR (400 MHz, CDCl3): δ ϭ 2.31 (s, 3 H), 2.32 (d, J ϭ
17.4 Hz, 1 H), 2.55 (d, J ϭ 17.4 Hz, 1 H), 4.19 (s, 1 H), 6.79Ϫ6.81
(m, 1 H), 6.91Ϫ6.98 (m, 4 H), 7.00Ϫ7.06 (m, 2 H), 7.07Ϫ7.16 (m,
6 H), 7.18Ϫ7.24 (m, 3 H), 7.34Ϫ7.43 (m, 3 H), 7.64Ϫ7.69 (m, 2 H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 9.3, 20.7, 34.1, 114.1,
114.7, 119.6, 124.1, 126.4, 127.2, 127.3, 127.8, 127.9, 129.2, 129.6,
129.8, 130.9, 132.8, 134.5, 134.8, 135.2, 138.7, 143.8 ppm. LRMS
(70 eV, EI): m/z (%) ϭ 441 (55) [Mϩ], 105 (100). C31H27NSi (441.6):
calcd. C 84.31, H 6.16, N 3.17; found. C 84.50, H 6.08, N 3.21.
3-(1-Deuterioethyl)-4-(deuteriomethyl)-1-(4-methylphenyl)-1H-
pyrrole (5e): Treatment of amine 1d (0.72 g, 2 mmol) with tBuLi
(5.33 mL, 8 mmol) and TMEDA (1.2 mL, 8 mmol) was followed by
addition of deuterium oxide (excess). Treatment with DDQ (0.46 g,
2 mmol) in CH2Cl2 (20 mL) at 20 °C and workup as above, fol-
lowed by purification by column chromatography (hexane), yielded
5e (0.34 g, 85%) as a colorless oil. Rf ϭ 0.14 (hexane). 1H NMR
(400 MHz, CDCl3): δ ϭ 1.20Ϫ1.23 (m, 3 H), 2.05Ϫ2.07 (m, 2 H),
2.32 (s, 3 H), 2.42Ϫ2.51 (m, 1 H), 6.78Ϫ6.81 (m, 2 H), 7.13Ϫ7.23
(m, 4 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 9.8 (t, JC/D
ϭ
19.5 Hz), 14.3, 18.2 (t, JC/D ϭ 19.5 Hz), 20.7, 115.6, 116.9, 119.4,
127.3, 129.8, 134.1, 138.4 ppm. LRMS (70 eV, EI) ϭ m/z (%) ϭ
201 (49) [Mϩ], 186 (100). C14H15D2N (201.3): calcd. C 83.53, H/D
9.51, N 6.96; found C 83.29, H/D 9.60, N 7.01.
3,4-Bis(deuteriophenylmethyl)-1-(4-methylphenyl)-1H-pyrrole (5c):
Treatment of amine 1c (1.0 g, 2 mmol) with tBuLi (5.33 mL,
8 mmol) and TMEDA (1.2 mL, 8 mmol) was followed by addition
of deuterium oxide (excess). Treatment with DDQ (0.46 g, 2 mmol)
in CH2Cl2 (20 mL) at 20 °C, workup as above and purification by 3-(2-Hydroxy-1,2-dimethylpropyl)-4-(2-hydroxy-2-methylpropyl)-1-
column chromatography (hexane/EtOAc, 40:1) yielded 5c (0.62 g, (4-methylphenyl)-1H-pyrrole (5f): Treatment of amine 1d (0.72 g,
91%) as a white solid. M.p. 74Ϫ76 °C. 1H NMR (200 MHz,
2 mmol) with tBuLi (5.33 mL, 8 mmol) and TMEDA (1.2 mL,
CDCl3): δ ϭ 2.34 (s, 3 H), 3.74 (s, 2 H), 6.73 (s, 2 H), 7.10Ϫ7.36 8 mmol) was followed by addition of acetone (0.24 g, 4.2 mmol).
(m, 14 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.7, 31.5 (t, Treatment with DDQ (0.46 g, 2 mmol) in CH2Cl2 (20 mL) and
JC/D ϭ 19.5 Hz), 117.7, 119.4, 123.8, 125.7, 128.2, 128.6, 129.8,
workup as above, followed by purification by column chromato-
134.3, 138.1, 141.1 ppm. LRMS (70 eV, EI): m/z (%) ϭ 339 (78) graphy (hexane/EtOAc, 2:1), yielded 5f (0.45 g, 71%) as a reddish
1
[Mϩ], 262 (100). C25H21D2N (339.5): calcd. C 88.45, H/D 7.42, N oil. Rf ϭ 0.15 (hexane/EtOAc, 3:1). H NMR (400 MHz, CDCl3):
4.13; found C 88.28, H/D 7.33, N 4.14.
δ ϭ 1.19 (s, 3 H), 1.22Ϫ1.27 (m, 9 H), 1.30 (s, 3 H), 2.07 (br. s, 2
Eur. J. Org. Chem. 2003, 771Ϫ783
777

´
J. Barluenga, F. J. Fan˜anas, R. Sanz, J. M. Ignacio
FULL PAPER
H), 2.36 (s, 3 H), 2.64 (d, J ϭ 14.3 Hz, 1 H), 2.75 (d, J ϭ 14.3 Hz, (5.33 mL, 8 mmol) and the corresponding ester (2 mmol) was car-
1 H), 2.91 (q, J ϭ 7.2 Hz, 1 H), 6.91 (d, J ϭ 2.4 Hz, 1 H), 6.93 (d, ried out as described above. The crude product was dehydrogenated
J ϭ 2.4 Hz, 1 H), 7.18Ϫ7.28 (m, 4 H) ppm. 13C NMR (100.6 MHz, with an equimolar amount of DDQ (0.46 g, 2 mmol) in CH2Cl2
CDCl3): δ ϭ 17.7, 20.7, 25.5, 28.3, 28.5, 29.5, 38.8, 40.6, 70.1, 72.8, (20 mL). After the mixture had been stirred for 15 min at room
116.2, 117.8, 119.5, 120.9, 127.5, 129.9, 134.8, 137.9 ppm. LRMS temperature, aqueous NaOH (1 , 20 mL) was added (alternatively,
(70 eV, EI): m/z (%) ϭ 238 (100). C20H29NO2 (315.4): C 76.15, H
9.27, N 4.44; found C 76.28, H 9.30, N 4.37.
oxidation could be performed by stirring the solution exposed to
the air for 24 h). The mixture was extracted with CH2Cl2 (3 ϫ
20 mL), the combined organic layers were dried over anhydrous
Na2SO4, and the solvents were removed under vacuum. The re-
sulting residue was purified by flash column chromatography [silica
gel, hexane/EtOAc, 10:1 (for compounds 9 and 16) or 5:1 (for com-
pounds 10 and 18)] to afford compounds 9, 10, 16 and 18.
General Procedure for the Preparation of Dihydropyrrole Derivatives
7: A solution of the starting amine 1a (0.69 g, 2 mmol) in diethyl
ether (15 mL) was treated at Ϫ78 °C with tBuLi (4 equiv., 5.33 mL
of a 1.5  solution in pentane, 8 mmol). The reaction mixture was
stirred for 30 min at this temperature and for 1 h at room temper-
ature. The ethereal suspension of dianion 3a was again cooled to
Ϫ78 °C, and 1.0 equiv. of one of the different neat carboxylic esters
was added. The mixture was then stirred for 1 h at this temperature,
quenched with methanol and extracted with EtOAc (3 ϫ 20 mL).
The combined organic layers were dried over anhydrous Na2SO4.
The solvent was removed under vacuum and the resulting residue
was purified by flash column chromatography (silica gel, hexane/
EtOAc, 10:1), yielding the dihydropyrrole derivatives 7.
3-(2-Cyclopropyl-2-oxoethyl)-4-methyl-1-(4-methylphenyl)-1H-
pyrrole (9a): Treatment of amine 1a (0.69 g, 2 mmol) with tBuLi
(5.33 mL, 8 mmol) and ethyl cyclopropanecarboxylate (0.23 g,
2 mmol) for 1 h at Ϫ78 °C, was followed by treatment with DDQ
(0.46 g, 2 mmol) in CH2Cl2 (20 mL) at 20 °C. Workup as above
yielded 9a (0.35 g, 69%) as a yellowish oil. Rf ϭ 0.23 (hexane/
1
EtOAc, 10:1). H NMR (200 MHz, CDCl3): δ ϭ 0.69Ϫ0.80 (m, 2
H), 0.89Ϫ1.00 (m, 2 H), 1.89Ϫ2.03 (m, 4 H), 2.24 (s, 3 H), 3.56 (s,
2 H), 6.72Ϫ6.76 (m, 1 H), 6.82Ϫ6.86 (m, 1 H), 7.00Ϫ7.16 (m, 4 H)
ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 10.1, 11.0, 19.3, 20.6,
40.7, 117.2, 117.4, 117.9, 119.4, 120.0, 129.8, 134.5, 138.1, 209.0
ppm. LRMS (70 eV, EI): m/z (%) ϭ 253 (13) [Mϩ], 184 (100).
C17H19NO (253.3): calcd. C 80.60, H 7.56, N 5.53; found C 80.49,
H 7.62, N 5.54.
3-(2-Cyclopropyl-2-oxoethyl)-2,5-dihydro-4-methyl-1-(4-methyl-
phenyl)-1H-pyrrole (7a): Amine 1a (0.69 g, 2 mmol) was treated
with tBuLi (5.33 mL of a 1.5  solution in pentane, 8 mmol). Addi-
tion of ethyl cyclopropanecarboxylate (0.23 g, 2 mmol) and workup
as above yielded 7a (0.42 g, 82%) as a colorless oil. Rf ϭ 0.25 (hex-
ane/EtOAc, 10:1). 1H NMR (200 MHz, CDCl3): δ ϭ 0.85Ϫ0.99
(m, 2 H), 1.02Ϫ1.12 (m, 2 H), 1.82 (s, 3 H), 1.93Ϫ2.07 (m, 1 H),
2.27 (s, 3 H), 3.39 (s, 2 H), 4.05 (s, 4 H), 6.40Ϫ6.50 (m, 2 H),
7.01Ϫ7.11 (m, 2 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 11.0,
11.5, 19.6, 20.0, 41.5, 57.5, 58.9, 110.7, 124.4, 129.5, 131.2, 144.7,
207.4 ppm. LRMS (70 eV, EI): m/z (%) ϭ 255 (33) [Mϩ], 184 (100).
C17H21NO (255.4): calcd. C 79.96, H 8.29, N 5.49; found C 80.11,
H 8.22, N 5.38.
3-Methyl-1-(4-methylphenyl)-4-(2-oxopropyl)-1H-pyrrole
(9b):
Treatment of amine 1a (0.69 g, 2 mmol) with tBuLi (5.33 mL,
8 mmol) and EtOAc (0.20 mL, 2 mmol) for 1 h at Ϫ78 °C was fol-
lowed by treatment with DDQ (0.46 g, 2 mmol) in CH2Cl2 (20 mL)
at 20 °C. Workup as above yielded 9b (0.31 g, 68%) as a yellowish
1
solid. M.p. 67Ϫ69 °C. H NMR (200 MHz, CDCl3): δ ϭ 2.06 (s,
3 H), 2.20 (s, 3 H), 2.36 (s, 3 H), 3.56 (s, 2 H), 6.83Ϫ6.87 (m, 1 H),
6.91Ϫ6.94 (m, 1 H), 7.15Ϫ7.25 (m, 4 H) ppm. 13C NMR
(50.3 MHz, CDCl3): δ ϭ 10.1, 20.7, 28.8, 41.0, 117.3, 117.4, 117.9,
119.6, 119.9, 129.9, 134.7, 138.1, 207.3 ppm. LRMS (70 eV, EI):
m/z (%) ϭ 227 (16) [Mϩ], 184 (100). C15H17NO (227.3): calcd. C
79.26, H 7.54, N 6.16; found C 79.41, H 7.49, N 6.17.
General Procedure for the Preparation of Hydroxy-dihydropyrrole
Derivatives 8: A solution of the starting amine 1a (0.69 g, 2 mmol)
in diethyl ether (15 mL) was treated at Ϫ78 °C with tBuLi (4 equiv.,
5.33 mL of a 1.5  solution in pentane, 8 mmol). The reaction mix-
ture was stirred for 30 min at this temperature and for 1 h at room
temperature. The ethereal suspension of dianion 3a was again co-
oled to Ϫ78 °C and 1.0 equiv. of one of the different neat esters
was added. The mixture was then allowed to come to room temper-
ature and was stirred overnight. The mixture was hydrolyzed with
water and extracted with EtOAc (3 ϫ 20 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4, the solvent was
removed under vacuum, and the resulting residue was purified by
flash column chromatography (silica gel, hexane/EtOAc, 5:1) to af-
ford the dihydropyrrole derivatives 8.
3-Methyl-1-(4-methylphenyl)-4-(2-oxobutyl)-1H-pyrrole (9c): Amine
1a was treated at Ϫ78 °C with tBuLi (5.33 mL of a 1.5  solution
in pentane, 8 mmol) and ethyl propionate (0.23 mL, 2 mmol) for
1 h. Exposure of a CH2Cl2 (20 mL) solution to the air and workup
as above yielded 9c (0.36 g, 75%) as a yellow solid. M.p. 40Ϫ42 °C.
1H NMR (200 MHz, CDCl3): δ ϭ 1.07 (t, J ϭ 7.3 Hz, 3 H), 2.07
(s, 3 H), 2.36 (s, 3 H), 2.53 (q, J ϭ 7.3 Hz, 3 H), 3.55 (s, 2 H),
6.82Ϫ6.86 (m, 1 H), 6.91Ϫ6.95 (m, 1 H), 7.14Ϫ7.27 (m, 4 H) ppm.
13C NMR (50.3 MHz, CDCl3): δ ϭ 7.8, 10.1, 20.6, 34.5, 39.7,
117.3, 117.5, 117.8, 119.5, 119.9, 129.8, 134.5, 138.0, 209.8 ppm.
LRMS (70 eV, EI): m/z (%) ϭ 241 (19) [Mϩ], 184 (100). C16H19NO
(241.3): calcd. C 79.63, H 7.94, N 5.80; found C 79.57, H 8.01,
N 5.69.
5-Cyclopropyl-2-(4-methylphenyl)-1,2,3,4,5,6-hexahydrocyclopenta-
[c]pyrrol-5-ol (8a): Amine 1a (0.69 g, 2 mmol) was treated with
tBuLi (5.33 mL of a 1.5  solution in pentane, 8 mmol). Addition
of ethyl cyclopropanecarboxylate (0.23 g, 2 mmol) and workup as
above yielded 8a (0.41 g, 80%) as a white solid. M.p. 133Ϫ135 °C.
1H NMR (200 MHz, CDCl3): δ ϭ 0.34Ϫ0.57 (m, 4 H), 1.17Ϫ1.32
(m, 1 H), 1.76 (br. s, 1 H), 2.25 (s, 3 H), 2.34 (d, J ϭ 15.9 Hz, 2
H), 2.54 (d, J ϭ 15.9 Hz, 2 H), 3.88 (s, 4 H), 6.38Ϫ6.48 (m, 2 H),
6.99Ϫ7.09 (m, 2 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 1.2,
20.1, 20.5, 42.8, 52.0, 86.4, 110.6, 124.1, 129.6, 138.3, 145.5 ppm.
LRMS (70 eV, EI): m/z (%) ϭ 255 (100) [Mϩ]. C17H21NO (255.4):
calcd. C 79.96, H 8.29, N 5.49; found C 79.84, H 8.35, N 5.43.
3-Methyl-1-(4-methylphenyl)-4-(2-oxopentyl)-1H-pyrrole
(9d):
Treatment of amine 1a (0.69 g, 2 mmol) with tBuLi (5.33 mL,
8 mmol) and ethyl butyrate (0.27 mL, 2 mmol) for 1 h at Ϫ78 °C
was followed by treatment with DDQ (0.46 g, 2 mmol) in CH2Cl2
(20 mL) at 20 °C. Workup as above yielded 9d (0.35 g, 69%) as a
1
clear brown solid. M.p. 46Ϫ48 °C. H NMR (200 MHz, CDCl3):
δ ϭ 0.80 (t, J ϭ 7.4 Hz, 3 H), 1.42Ϫ1.61 (m, 2 H), 1.95 (s, 3 H),
2.24 (s, 3 H), 2.37 (t, J ϭ 7.4 Hz, 2 H), 3.42 (s, 2 H), 6.71Ϫ6.75
(m, 1 H), 6.80Ϫ6.84 (m, 1 H), 7.03Ϫ7.16 (m, 4 H) ppm. 13C NMR
General Procedure for the Preparation of Pyrrole Derivatives 9, 10,
16 and 18: Treatment of amine 1a (0.69 g, 2 mmol) with tBuLi (50.3 MHz, CDCl3): δ ϭ 10.1, 13.6, 17.2, 20.6, 40.0, 43.3, 117.3,
778 Eur. J. Org. Chem. 2003, 771Ϫ783

Synthesis of Pyrrole Derivatives
FULL PAPER
117.4, 117.8, 119.5, 119.9, 129.8, 134.5, 138.0, 209.2 ppm. LRMS tBuLi (5.33 mL, 8 mmol) and ethyl cyclopropanecarboxylate
(70 eV, EI): m/z (%) ϭ 255 (14) [Mϩ], 184 (100). C17H21NO (255.4): (0.23 g, 2 mmol) at 20 °C overnight was followed by treatment with
calcd. C 79.96, H 8.29, N 5.49; found C 80.10, H 8.19, N 5.42.
DDQ (0.46 g, 2 mmol) in CH2Cl2 (20 mL) at 20 °C. Workup as
above yielded 10a (0.33 g, 65%) as a white solid. M.p. 132Ϫ134 °C.
1H NMR (200 MHz, CDCl3): δ ϭ 0.33Ϫ0.43 (m, 4 H), 1.05Ϫ1.23
(m, 1 H), 1.94 (br. s, 1 H), 2.24 (s, 3 H), 2.53 (d, J ϭ 15.6 Hz, 2
H), 2.73 (d, J ϭ 15.6 Hz, 2 H), 6.62 (s, 2 H), 7.01Ϫ7.15 (m, 4 H)
ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 1.3, 19.5, 20.6, 39.1, 88.1,
111.8, 119.9, 128.5, 129.8, 134.4, 138.8 ppm. LRMS (70 eV, EI):
m/z (%) ϭ 253 (16) [Mϩ], 184 (100). C17H19NO (253.3): calcd. C
80.60, H 7.56, N 5.53; found C 80.48, H 7.47, N 5.50.
3-Methyl-4-(3-methyl-2-oxobutyl)-1-(4-methylphenyl)-1H-pyrrole
(9e): Amine 1a (0.69 g, 2 mmol) was treated at Ϫ78 °C with tBuLi
(5.33 mL of a 1.5  solution in pentane, 8 mmol) and ethyl isobu-
tyrate (0.27 mL, 2 mmol) for 1 h. Exposure of a CH2Cl2 (20 mL)
solution to the air and workup as above yielded 9e (0.40 g, 78%) as
a yellow oil. Rf ϭ 0.34 (hexane/EtOAc, 10:1). 1H NMR (200 MHz,
CDCl3): δ ϭ 1.02 (d, J ϭ 7.0 Hz, 6 H), 1.93 (s, 3 H), 2.22 (s, 3 H),
2.69 (hept, J ϭ 7.0 Hz, 1 H), 3.49 (s, 2 H), 6.70Ϫ6.74 (m, 1 H),
6.79Ϫ6.83 (m, 1 H), 7.02Ϫ7.15 (m, 4 H) ppm. 13C NMR
(50.3 MHz, CDCl3): δ ϭ 10.0, 18.3, 20.5, 37.7, 39.3, 117.2, 117.8,
119.4, 119.9, 129.8, 134.4, 138.2, 212.1 ppm. LRMS (70 eV, EI):
m/z (%) ϭ 255 (9) [Mϩ], 184 (100). C17H21NO (255.4): calcd. C
79.96, H 8.29, N 5.49; found C 79.80, H 8.39, N 5.46.
5-Methyl-2-(4-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-
5-ol (10b): Treatment of amine 1a (0.69 g, 2 mmol) with tBuLi
(5.33 mL, 8 mmol) and EtOAc (0.20 mL, 2 mmol) at 20 °C over-
night was followed by treatment with DDQ (0.46 g, 2 mmol) in
CH2Cl2 (20 mL) at 20 °C. Workup as above yielded 10b (0.29 g,
64%) as a white solid. M.p. 140Ϫ142 °C. 1H NMR (200 MHz,
CDCl3): δ ϭ 1.54 (s, 3 H), 2.13 (br. s, 1 H), 2.25 (s, 3 H), 2.75 (d,
J ϭ 15.4 Hz, 2 H), 2.87 (d, J ϭ 15.4 Hz, 2 H), 6.74 (s, 2 H),
7.14Ϫ7.24 (m, 4 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.7,
27.4, 41.6, 86.2, 112.0, 120.1, 128.9, 129.9, 134.6, 138.8 ppm.
LRMS (70 eV, EI): m/z (%) ϭ 227 (16) [Mϩ], 184 (100). C15H17NO
(227.3): calcd. C 79.26, H 7.54, N 6.16; found C 79.21, H 7.45,
N 6.20.
3-Deuteriomethyl-4-(3-methyl-2-oxobutyl)-1-(4-methylphenyl)-1H-
pyrrole [9e(D)]: Amine 1a (0.69 g, 2 mmol) was treated at Ϫ78 °C
with tBuLi (5.33 mL of a 1.5  solution in pentane, 8 mmol) and
ethyl isobutyrate (0.27 mL, 2 mmol) for 1 h. The mixture was
quenched with MeOD. Exposure of a CH2Cl2 (20 mL) solution to
the air and workup as above yielded 9e(D) (0.38 g, 74%) as a yellow
oil. Rf ϭ 0.34 (hexane/EtOAc, 10:1). 1H NMR (400 MHz, CDCl3):
δ ϭ 1.12 (d, J ϭ 6.9 Hz, 6 H), 2.01Ϫ2.05 (m, 2 H), 2.35 (s, 3 H),
2.80 (hept, J ϭ 6.9 Hz, 1 H), 3.60 (s, 2 H), 6.82Ϫ6.84 (m, 1 H),
6.90Ϫ6.92 (m, 1 H), 7.16Ϫ7.24 (m, 4 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ ϭ 9.9 (t, JC/D ϭ 19.6 Hz), 18.4, 20.7, 37.8,
39.4, 117.3, 117.4, 117.9, 119.5, 119.9, 129.8, 134.5, 138.1, 212.1
ppm. LRMS (70 eV, EI): m/z (%) ϭ 256 (18) [Mϩ], 185 (100).
C17H21NO (255.4): calcd. C 79.65, H/D 8.65, N 5.46; found C
79.76, H/D 8.59, N 5.44.
5-Ethyl-2-(4-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-5-
ol (10c): Amine 1a (0.69 g, 2 mmol) was treated at 20 °C with tBuLi
(5.33 mL of a 1.5  solution in pentane, 8 mmol) and ethyl propi-
onate (0.23 mL, 2 mmol) overnight. Exposure of a CH2Cl2 (20 mL)
solution to the air and workup as above yielded 10c (0.36 g, 75%)
as a clear brown solid. M.p. 126Ϫ128 °C. 1H NMR (200 MHz,
CDCl3): δ ϭ 1.04 (t, J ϭ 7.4 Hz, 3 H), 1.81 (q, J ϭ 7.4 Hz, 2 H),
2.06 (br. s, 1 H), 2.26 (s, 3 H), 2.67 (d, J ϭ 15.8 Hz, 2 H), 2.84 (d,
J ϭ 15.8 Hz, 2 H), 6.72 (s, 2 H), 7.11Ϫ7.25 (m, 4 H) ppm. 13C
NMR (50.3 MHz, CDCl3): δ ϭ 8.8, 20.7, 33.2, 39.5, 89.3, 112.0,
120.0, 128.8, 129.8, 134.5, 138.9 ppm. LRMS (70 eV, EI): m/z
(%) ϭ 241 (24) [Mϩ], 184 (100). C16H19NO (241.3): calcd. C 79.63,
H 7.94, N 5.80; found C 79.74, H 7.99, N 5.72.
3-Methyl-1-(4-methylphenyl)-4-(2-oxo-2-phenylethyl)-1H-pyrrole
(9f): Treatment of amine 1a (0.69 g, 2 mmol) at Ϫ78 °C with tBuLi
(5.33 mL, 8 mmol) and ethyl benzoate (0.30 g, 2 mmol) for 1 h was
followed by treatment with DDQ (0.46 g, 2 mmol) in CH2Cl2
(20 mL) at 20 °C. Workup as above yielded 9f (0.40 g, 69%) as a
1
reddish solid. M.p. 82Ϫ84 °C. H NMR (200 MHz, CDCl3): δ ϭ
2.00 (s, 3 H), 2.23 (s, 3 H), 4.04 (s, 2 H), 6.73Ϫ6.77 (m, 1 H),
6.79Ϫ6.83 (m, 1 H), 7.00Ϫ7.15 (m, 4 H), 7.30Ϫ7.51 (m, 3 H),
7.92Ϫ7.99 (m, 2 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 10.3,
20.7, 35.7, 117.3, 117.4, 118.0, 119.5, 120.0, 128.4, 128.5, 129.8,
132.8, 134.5, 136.7, 138.1, 197.9 ppm. LRMS (70 eV, EI): m/z
(%) ϭ 289 (14) [Mϩ], 184 (100). C20H19NO (289.4): calcd. C 83.01,
H 6.62, N 4.84; found C 82.87, H 6.55, N 4.88.
2-(4-Methylphenyl)-5-propyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-
5-ol (10d): Treatment of amine 1a (0.69 g, 2 mmol) at 20 °C with
tBuLi (5.33 mL, 8 mmol) and ethyl butyrate (0.27 mL, 2 mmol)
overnight, was followed by treatment with DDQ (0.46 g, 2 mmol)
in CH2Cl2 (20 mL) at 20 °C. Workup as above yielded 10d (0.35 g,
68%) as a pale yellow solid. M.p. 98Ϫ100 °C. 1H NMR (200 MHz,
CDCl3): δ ϭ 0.88 (t, J ϭ 7.1 Hz, 3 H), 1.32Ϫ1.55 (m, 2 H),
1.60Ϫ1.73 (m, 2 H), 2.03 (br. s, 1 H), 2.24 (s, 3 H), 2.59 (d, J ϭ
15.5 Hz, 2 H), 2.75 (d, J ϭ 15.5 Hz, 2 H), 6.63 (s, 2 H), 7.02Ϫ7.16
(m, 4 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 14.6, 17.8, 20.6,
40.0, 43.0, 88.9, 111.9, 120.0, 128.8, 129.8, 134.4, 138.8 ppm.
LRMS (70 eV, EI): m/z (%) ϭ 255 (13) [Mϩ], 184 (100). C17H21NO
(255.4): calcd. C 79.96, H 8.29, N 5.49; found C 80.10, H 8.33,
N 5.42.
3-(6-Bromo-2-oxohexyl)-4-methyl-1-(4-methylphenyl)-1H-pyrrole
(16): Treatment of amine 1a (0.69 g, 2 mmol) at Ϫ78 °C with tBuLi
(5.33 mL, 8 mmol) and ethyl 5-bromovalerate (0.42 g, 2 mmol) for
1 h, was followed by exposure of a CH2Cl2 (20 mL) solution to the
air at 20 °C. Workup as above yielded 16 (0.48 g, 69%) as a color-
less oil. Rf ϭ 0.20 (hexane/EtOAc, 10:1). 1H NMR (400 MHz,
CDCl3): δ ϭ 1.59Ϫ1.68 (m, 2 H), 1.69Ϫ1.78 (m, 2 H), 1.95 (s, 3
H), 2.26 (s, 3 H), 2.43 (t, J ϭ 7.2 Hz, 2 H), 3.27 (t, J ϭ 6.6 Hz, 2
H), 3.44 (s, 2 H), 6.74Ϫ6.76 (m, 1 H), 6.81Ϫ6.83 (m, 1 H),
7.06Ϫ7.16 (m, 4 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ
10.1, 20.7, 22.2, 31.9, 32.2, 40.0, 40.1, 117.1, 117.4, 117.8, 119.5,
119.9, 129.9, 134.7, 138.0, 208.5 ppm. LRMS (70 eV, EI): m/z
(%) ϭ 349 (4) [Mϩ ϩ 2], 347 (4) [Mϩ], 184 (100). C18H22BrNO
(348.3): calcd. C 62.07, H 6.37, N 4.02; found C 62.15, H 6.28,
N 3.99.
5-Isopropyl-2-(4-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]-
pyrrol-5-ol (10e): Amine 1a (0.69 g, 2 mmol) was treated at 20 °C
with tBuLi (5.33 mL of a 1.5  solution in pentane, 8 mmol) and
ethyl isobutyrate (0.27 mL, 2 mmol) overnight. Exposure of a
CH2Cl2 solution (20 mL) to the air and workup as above yielded
10e (0.39 g, 77%) as a yellowish solid. M.p. 115Ϫ117 °C. 1H NMR
(200 MHz, CDCl3): δ ϭ 0.97 (d, J ϭ 6.9 Hz, 6 H), 1.72 (br. s, 1
H), 1.89 (hept, J ϭ 6.9 Hz, 1 H), 2.27 (s, 3 H), 2.58 (d, J ϭ 15.6 Hz,
5-Cyclopropyl-2-(4-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]- 2 H), 2.81 (d, J ϭ 15.6 Hz, 2 H), 6.68 (s, 2 H), 7.06Ϫ7.20 (m, 4 H)
pyrrol-5-ol (10a): Treatment of amine 1a (0.69 g, 2 mmol) with ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 17.6, 20.6, 36.7, 38.6,
Eur. J. Org. Chem. 2003, 771Ϫ783
779

´
J. Barluenga, F. J. Fan˜anas, R. Sanz, J. M. Ignacio
FULL PAPER
91.6, 111.8, 119.9, 128.0, 129.7, 134.3, 138.8 ppm. LRMS (70 eV,
with tBuLi (5.33 mL of a 1.5  solution in pentane, 8 mmol) and
EI): m/z (%) ϭ 255 (11) [Mϩ], 184 (100). C17H21NO (255.4): calcd. ethyl isobutyrate (0.27 mL, 2 mmol) for 1 h. THF (20 mL) and allyl
C 79.96, H 8.29, N 5.49; found C 79.88, H 8.28, N 5.47.
bromide (0.174 mL, 2 mmol) were added, and the mixture was
heated to reflux. Exposure of a CH2Cl2 (20 mL) solution to the air
and workup as above yielded 14b (0.32 g, 55%) as a yellowish oil.
2-(4-Methylphenyl)-5-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-
5-ol (10f): Treatment of amine 1a (0.69 g, 2 mmol) at 20 °C with
tBuLi (5.33 mL, 8 mmol) and ethyl benzoate (0.30 g, 2 mmol) over-
night was followed by treatment at 20 °C with DDQ (0.46 g,
2 mmol) in CH2Cl2 (20 mL). Workup as above yielded 10f (0.38 g,
1
Rf ϭ 0.30 (15:1). H NMR (400 MHz, CDCl3): δ ϭ 1.01 (d, J ϭ
6.4 Hz, 3 H), 1.09 (d, J ϭ 7.2 Hz, 3 H), 2.12 (s, 3 H), 2.35 (s, 3 H),
2.37Ϫ2.45 (m, 1 H), 2.69Ϫ2.80 (m, 2 H), 3.81 (dd, J ϭ 8.2, 6.6 Hz,
1 H), 4.97Ϫ5.01 (m, 1 H), 5.05Ϫ5.11 (m, 1 H), 5.73Ϫ5.84 (m, 1
H), 6.79Ϫ6.84 (m, 2 H), 7.16Ϫ7.23 (m, 4 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ ϭ 10.3, 18.3, 18.9, 20.7, 36.9, 39.1, 47.9,
116.0, 117.0, 117.3, 119.3, 121.8, 129.8, 134.6, 136.6, 138.0, 213.8
ppm. LRMS (70 eV, EI): m/z (%) ϭ 295 (7) [Mϩ], 224 (100).
C20H25NO (295.4): calcd. C 81.31, H 8.53, N 4.74; found C 81.43,
H 8.61, N 4.69.
1
66%) as a yellowish solid. M.p. 133Ϫ135 °C. H NMR (200 MHz,
CDCl3): δ ϭ 2.26 (s, 3 H), 2.40 (br. s, 1 H), 2.94 (d, J ϭ 15.6 Hz,
2 H), 3.21 (d, J ϭ 15.6 Hz, 2 H), 6.70 (s, 2 H), 7.02Ϫ7.56 (m, 9 H)
ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 21.1, 43.2, 89.6, 112.5,
120.5, 125.4, 127.3, 128.8, 128.9, 130.3, 135.0, 139.3, 146.1 ppm.
LRMS (70 eV, EI): m/z (%) ϭ 289 (12) [Mϩ], 184 (100). C20H19NO
(289.4): calcd. C 83.01, H 6.62, N 4.84; found C 83.06, H 6.65,
N 4.81.
3-(1-Benzyl-3-methyl-2-oxobutyl)-4-methyl-1-(4-methylphenyl)-1H-
pyrrole (14c): Amine 1a (0.69 g, 2 mmol) was treated at Ϫ78 °C
with tBuLi (5.33 mL of a 1.5  solution in pentane, 8 mmol) and
ethyl isobutyrate (0.27 mL, 2 mmol) for 1 h. THF (20 mL) and
benzyl chloride (0.23 mL, 2 mmol) were added, and the mixture
was heated to reflux. Exposure of a CH2Cl2 (20 mL) solution to
the air and workup as above yielded 14c (0.36 g, 52%) as a yellow-
ish oil. Rf ϭ 0.23 (25:1). 1H NMR (400 MHz, CDCl3): δ ϭ 0.76
(d, J ϭ 6.9 Hz, 3 H), 0.86 (d, J ϭ 6.9 Hz, 3 H), 1.92 (s, 3 H), 2.26
(s, 3 H), 2.50 (hept, J ϭ 6.9 Hz, 1 H), 2.78 (dd, J ϭ 13.4, 5.9 Hz,
1 H), 3.23 (dd, J ϭ 13.4, 8.8 Hz, 1 H), 3.91 (dd, J ϭ 8.8, 5.9 Hz, 1
H), 6.71 (s, 2 H), 7.03Ϫ7.18 (m, 9 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ ϭ 10.1, 18.0, 18.4, 20.7, 39.4, 39.9, 50.0, 117.0, 117.3,
119.3, 119.4, 122.0, 125.9, 128.1, 129.0, 129.9, 134.7, 138.0, 140.5,
213.8 ppm. LRMS (70 eV, EI): m/z (%) ϭ 345 (4) [Mϩ], 274 (100).
C20H25NO (345.5): calcd. C 83.44, H 7.88, N 4.05; found C 83.31,
H 8.00, N 4.03.
5-(4-Bromobutyl)-2-(4-methylphenyl)-2,4,5,6-tetrahydrocyclo-
penta[c]pyrrol-5-ol (18): Treatment of amine 1a (0.69 g, 2 mmol) at
20 °C with tBuLi (5.33 mL, 8 mmol) and ethyl 5-bromovalerate
(0.42 g, 2 mmol) overnight was followed by exposure of a CH2Cl2
(20 mL) solution to the air. Workup as above yielded 18 (0.31 g,
45%) as a white solid. M.p. 100Ϫ102 °C. 1H NMR (400 MHz,
CDCl3): δ ϭ 1.63Ϫ1.73 (m, 2 H), 1.79Ϫ1.85 (m, 2 H), 1.90Ϫ1.98
(m, 2 H), 2.10 (br. s, 1 H), 2.36 (m, 3 H), 2.73 (d, J ϭ 15.5 Hz, 2
H), 2.87 (d, J ϭ 15.5 Hz, 2 H), 3.46 (t, J ϭ 6.8 Hz, 2 H), 6.76 (s,
2 H), 7.17Ϫ7.25 (m, 4 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ
20.7, 23.3, 33.1, 33.7, 39.6, 40.1, 88.7, 112.1, 120.1, 128.5, 129.9,
134.7, 138.8 ppm. LRMS (70 eV, EI): m/z (%) ϭ 349 (2) [Mϩ ϩ 2],
347 (4) [Mϩ], 184 (100). C18H22BrNO (348.3): calcd. C 62.07, H
6.37, N 4.02; found C 61.97, H 6.28, N 4.07.
Preparation of 3-(1-Deuterio-3-methyl-2-oxobutyl)-4-methyl-1-(4-
methylphenyl)-1H-pyrrole (14a): Amine 1a (0.69 g, 2 mmol) was
treated at Ϫ78 °C with tBuLi (5.33 mL of a 1.5  solution in pent-
ane, 8 mmol) and ethyl isobutyrate (0.27 mL, 2 mmol). After the
solution had been stirred for 1 h at this temperature, THF (20 mL)
was added. The cooling bath was removed and the mixture was
allowed to come to room temperature and was quenched with D2O.
Extraction with EtOAc (3 ϫ 20 mL) and workup as described
above, followed by exposure to the air and purification by silica gel
column chromatography (hexane/EtOAc, 30:1) afforded compound
14a (0.32 g, 63%) as a yellow oil. Rf ϭ 0.34 (hexane/EtOAc, 10:1).
1H NMR (400 MHz, CDCl3): δ ϭ 1.13 (d, J ϭ 7.0 Hz, 6 H), 2.05
(s, 3 H), 2.36 (s, 3 H), 2.81 (hept, J ϭ 7.0 Hz, Ͻ1 H), 3.57Ϫ3.61
(m, 1 H), 6.83Ϫ6.85 (m, 1 H), 6.91Ϫ6.93 (m, 1 H), 7.16Ϫ7.24 (m,
4 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 10.2, 18.3, 18.4,
20.7, 37.5 (t, JC/D ϭ 19.2 Hz), 39.5, 117.3, 117.9, 119.6, 120.0,
129.8, 134.6, 138.2, 212.8 ppm. LRMS (70 eV, EI): m/z (%) ϭ 256
(6) [Mϩ], 186 (100).
Synthesis of 3-Methyl-1-(4-methylphenyl)-4-(2-oxocyclohexyl)-1H-
pyrrole (17): Dianion 3a, formed by treatment of amine 1a (0.69 g,
2 mmol) with tBuLi (5.33 mL, 8 mmol) as described above, was
treated at Ϫ78 °C with ethyl 5-bromovalerate (0.42 g, 2 mmol).
After the solution had been stirred for 1 h at this temperature, THF
(40 mL) was added. The mixture was allowed to come to room
temperature and stirring was continued for 3 h. The mixture was
quenched with water and extracted with EtOAc (3 ϫ 20 mL). The
combined organic layers were dried over Na2SO4 and solvents were
removed under vacuum. The residue was exposed to the air as de-
scribed above. Purification by column chromatography (hexane/
EtOAc, 10:1) yielded 17 (0.33 g, 61%) as a yellowish solid. M.p.
1
92Ϫ94 °C. H NMR (400 MHz, CDCl3): δ ϭ 1.66Ϫ1.80 (m, 2 H),
1.84Ϫ1.98 (m, 5 H), 2.00Ϫ2.12 (m, 1 H), 2.23Ϫ2.32 (m, 4 H),
2.34Ϫ2.51 (m, 2 H), 3.48 (dd, J ϭ 12.0, 5.4 Hz, 1 H), 6.76Ϫ6.81
(m, 2 H), 7.06Ϫ7.17 (m, 4 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ ϭ 10.5, 20.6, 25.4, 27.9, 34.3, 41.9, 48.8, 116.5, 117.2,
119.5, 119.8, 122.4, 129.7, 134.3, 138.2, 210.5 ppm. LRMS (70 eV,
EI): m/z (%) ϭ 267 (100) [Mϩ]. C18H21NO (267.4): calcd. C 80.86,
H 7.92, N 5.24; found C 81.02, H 7.98, N 5.22.
Preparation of Substituted Pyrrole Derivatives 14b and 14c: Amine
1a (0.69 g, 2 mmol) was treated at Ϫ78 °C with tBuLi (5.33 mL of a
1.5  solution in pentane, 8 mmol) and ethyl isobutyrate (0.27 mL,
2 mmol). After the solution had been stirred for 1 h at this temper-
ature, THF (20 mL) and alkyl halide (2 mmol) were added. The
cooling bath was removed, and the mixture was allowed to come
to room temperature and was then heated at reflux until reaction
was complete. Extraction with EtOAc (3 ϫ 20 mL) and workup as
described above, followed by exposure to the air, afforded com-
pounds 14b and 14c, which were purified by silica gel column chro-
matography (hexane/EtOAc, 30:1).
Synthesis of Spiro Compound 19: NaH (18 mg, 0.75 mmol) was ad-
ded to a solution of 18 (175 mg, 0.5 mmol) in THF (10 mL). The
resulting mixture was heated at reflux for 24 h. Water was added
and the mixture was extracted with EtOAc (3 ϫ 10 mL). The com-
bined organic layers were dried over Na2SO4 and the solvent was
removed under vacuum. Purification of the residue by column
chromatography (hexane/EtOAc, 10:1) afforded compound 19
(75 mg, 56%) as a white solid. M.p. 98Ϫ100 °C. 1H NMR
3-(1-Allyl-3-methyl-2-oxobutyl)-4-methyl-1-(4-methylphenyl)-1H- (400 MHz, CDCl3): δ ϭ 1.54Ϫ1.65 (m, 2 H), 1.69Ϫ1.81 (m, 4 H),
pyrrole (14b): Amine 1a (0.69 g, 2 mmol) was treated at Ϫ78 °C 2.36 (s, 3 H), 2.79 (d, J ϭ 15.2 Hz, 2 H), 2.98 (d, J ϭ 15.2 Hz, 2
780
Eur. J. Org. Chem. 2003, 771Ϫ783

Synthesis of Pyrrole Derivatives
FULL PAPER
H), 3.78 (t, J ϭ 5.4 Hz, 2 H), 6.72 (s, 2 H), 7.15Ϫ7.25 (m, 4 H) with MeOH or allowed to reach 20 °C and stirred overnight at this
ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 20.6, 20.7, 25.9, 35.4,
temperature before the quenching with water. In both cases, after
37.0, 63.4, 90.0, 111.6, 120.1, 128.5, 129.8, 134.4, 139.0 ppm. the usual workup, these compounds were separated and purified
LRMS (70 eV, EI): m/z (%) ϭ 267 (100) [Mϩ]. C18H21NO (267.4): by silica gel column chromatography (hexane/EtOAc, 20:1 to 5:1).
calcd. C 80.86, H 7.92, N 5.24; found C 81.00, H 7.87, N 5.25.
(4R,5S,6S)-5-Isopropyl-2-(4-methylphenyl)-4,6-diphenyl-1,2,3,4,5,6-
Treatment of Dianion 3b with Ethyl Isobutyrate: Ethyl isobutyrate
(0.27 mL, 2 mmol) was added at Ϫ78 °C to a solution of dianion
3b, prepared by treatment of amine 1b (0.84 g, 2 mmol) with tBuLi
hexahydrocyclopenta[c]pyrrol-5-ol (24): White solid. M.p. 76Ϫ78
°C. H NMR (400 MHz, [D6]acetone): δ ϭ 1.14 (d, J ϭ 6.8 Hz, 6
H), 1.55 (s, 1 H), 2.15 (hept, J ϭ 6.8 Hz, 1 H), 2.19 (s, 3 H),
1
(5.33 mL, 8 mmol) and TMEDA (1.2 mL, 8 mmol) as described 3.86Ϫ3.95 (m, 2 H), 3.99Ϫ4.07 (m, 2 H), 4.13 (s, 2 H), 6.39Ϫ6.43
above. If the reaction mixture was stirred for 1 h at Ϫ78 °C and (m, 2 H), 6.96Ϫ7.01 (m, 2 H), 7.19Ϫ7.24 (m, 2 H), 7.29Ϫ7.37 (m,
then hydrolyzed with MeOH, a 56:18:17:9 mixture of 20, 21, 22 8 H) ppm. 13C NMR (100.6 MHz, [D6]acetone): δ ϭ 18.9, 21.4,
and 23 was obtained after the usual workup. On the other hand, if
the reaction mixture was stirred overnight at 20 °C after the addi- 144.5, 147.7 ppm. LRMS (70 eV, EI): m/z (%) ϭ 409 (30) [Mϩ],
tion of the ester and was then hydrolyzed with water, a 31:12:43:13 338 (100). C29H31NO (409.6): calcd. C 85.04, H 7.63, N 3.42; found
41.1, 53.2, 55.9, 92.1, 112.8, 125.7, 128.4, 129.8, 131.5, 131.9, 140.6,
mixture of 20, 21, 22 and 23 was obtained after the usual workup. C 84.96, H 7.55, N 3.38.
These compounds were separated and purified by silica gel column
chromatography (hexane/EtOAc, 40:1 to 10:1). Alcohol 23 could
not be characterized.
(4R*,6R*)-5-Isopropyl-2-(4-methylphenyl)-4,6-diphenyl-1,2,3,4,5,6-
hexahydrocyclopenta[c]pyrrol-5-ol (25): White solid. 1H NMR
(400 MHz, C6D6): δ ϭ 0.62 (d, J ϭ 6.8 Hz, 3 H), 0.74 (d, J ϭ
6.8 Hz, 3 H), 1.36 (br. s, 1 H), 1.78 (hept, J ϭ 6.8 Hz, 1 H), 2.20
(s, 3 H), 3.60Ϫ3.87 (m, 4 H), 3.91Ϫ3.97 (m, 2 H), 6.20Ϫ6.24 (m,
3-Benzyl-2,5-dihydro-4-(3-methyl-2-oxobutyl)-1-(4-methylphenyl)-
1H-pyrrole (20): White solid. M.p. 89Ϫ91 °C. 1H NMR (400 MHz,
[D6]acetone): δ ϭ 1.11 (d, J ϭ 6.8 Hz, 6 H), 2.17 (s, 3 H), 2.79 2 H), 6.99Ϫ7.15 (m, 12 H) ppm. 13C NMR (100.6 MHz, [D6]ace-
(hept, J ϭ 6.8 Hz, 1 H), 3.56 (s, 2 H), 3.60 (s, 2 H), 3.88Ϫ3.92 (m, tone): δ ϭ 19.1, 19.2, 21.3, 36.3, 52.9, 53.3, 56.4, 62.8, 94.3, 112.7,
2 H), 4.04Ϫ4.08 (m, 2 H), 6.33Ϫ6.37 (m, 2 H), 6.94Ϫ6.98 (m, 2
125.7, 128.3, 128.5, 129.6, 130.0, 131.1, 131.4, 132.5, 140.3, 141.3,
144.8, 145.5, 147.7 ppm. LRMS (70 eV, EI): m/z (%) ϭ 409 (35)
H), 7.18Ϫ7.32 (m, 5 H) ppm. 13C NMR (100.6 MHz, [D6]acetone):
δ ϭ 19.6, 21.3, 34.3, 39.7, 42.1, 58.7, 59.6, 112.7, 125.6, 128.0, [Mϩ], 338 (100). C29H31NO (409.6): calcd. C 85.04, H 7.63, N 3.42;
130.3, 130.4, 131.4, 135.4, 140.9, 147.0, 207.1 ppm. LRMS (70 eV,
EI): m/z (%) ϭ 333 (8) [Mϩ], 260 (100). C23H27NO (333.5): calcd.
C 82.84, H 8.16, N 4.20; found C 83.01, H 8.11, N 4.14.
found C 85.11, H 7.55, N 3.45.
(4R,5R,6S)-5-Isopropyl-2-(4-methylphenyl)-4,6-diphenyl-1,2,3,4,5,6-
hexahydrocyclopenta[c]pyrrol-5-ol (26): White solid. M.p. 190Ϫ192
°C. 1H NMR (400 MHz, C6D6): δ ϭ 0.75 (d, J ϭ 6.7 Hz, 6 H),
1.80 (hept, J ϭ 6.7 Hz, 1 H), 1.89 (br. s, 1 H), 2.21 (s, 3 H),
3.61Ϫ3.75 (m, 6 H), 6.20Ϫ6.25 (m, 2 H), 6.99Ϫ7.21 (m, 12 H)
2,5-Dihydro-3-methyl-1-(4-methylphenyl)-4-(3-methyl-2-oxo-1-
phenylbutyl)-1H-pyrrole (21): White solid. M.p. 93Ϫ95 °C. 1H
NMR (400 MHz, [D6]acetone): δ ϭ 1.05 (d, J ϭ 6.9 Hz, 3 H), 1.12
(d, J ϭ 6.9 Hz, 3 H), 1.89Ϫ1.92 (m, 3 H), 2.17 (s, 3 H), 2.84 (hept, ppm. 13C NMR (100.6 MHz, [D6]acetone): δ ϭ 19.5, 21.3, 33.2,
J ϭ 6.9 Hz, 1 H), 3.81Ϫ3.89 (m, 1 H), 3.92Ϫ4.05 (m, 2 H),
4.18Ϫ4.26 (m, 1 H), 5.31 (s, 1 H), 6.35Ϫ6.40 (m, 2 H), 6.94Ϫ7.00 143.9, 147.7 ppm. LRMS (70 eV, EI): m/z (%) ϭ 409 (40) [Mϩ],
(m, 2 H), 7.25Ϫ7.39 (m, 5 H) ppm. 13C NMR (100.6 MHz, [D6]ace-
338 (100). C29H31NO (409.6): calcd. C 85.04, H 7.63, N 3.42; found
53.2, 64.3, 97.6, 112.7, 125.7, 128.5, 130.0, 131.4, 131.7, 141.8,
tone): δ ϭ 12.9, 19.7, 20.0, 21.4, 41.8, 56.0, 57.8, 60.9, 112.7, 125.7, C 85.14, H 7.70, N 3.40.
128.9, 130.4, 130.5, 130.8, 131.4, 132.7, 139.4, 146.9, 207.1 ppm.
Treatment of Dianion 3a with Iodine or 1,2-Dibromoethane. Pre-
LRMS (70 eV, EI): m/z (%) ϭ 333 (8) [Mϩ], 262 (100). C23H27NO
(333.5): calcd. C 82.84, H 8.16, N 4.20; found C 82.95, H 8.09,
N 4.23.
paration of 3,4-Bismethylene-N-(4-methylphenyl)pyrrolidine (28):
Either iodine (1.07 g, 4.2 mmol) or 1,2-dibromoethane (0.36 mL,
4.2 mmol) was added at Ϫ78 °C to a suspension of 3a in diethyl
2,5-Dihydro-3-(3-methyl-2-oxobutyl)-1-(4-methylphenyl)-4-(3- ether, prepared by treatment of amine 1a at Ϫ78 °C with tBuLi
methyl-2-oxo-1-phenylbutyl)-1H-pyrrole (22): White solid. M.p. (5.33 mL of a 1.5  solution in pentane, 8 mmol), followed by
109Ϫ111 °C. H NMR (400 MHz, [D6]acetone): δ ϭ 1.04 (d, J ϭ warming up to 20 °C. The mixture was stirred and allowed to come
6.9 Hz, 3 H), 1.09 (d, J ϭ 6.9 Hz, 3 H), 1.11 (d, J ϭ 6.9 Hz, 6 H), to room temperature, and was then hydrolyzed with water. After
2.17 (s, 3 H), 2.77 (hept, J ϭ 6.9 Hz, 1 H), 2.84 (hept, J ϭ 6.9 Hz, the usual workup, the crude 28 obtained could not be purified. H
1 H), 3.62 (d, J ϭ 17.0 Hz, 1 H), 3.70 (d, J ϭ 17.0 Hz, 1 H), NMR (200 MHz, CDCl3) for crude 28: δ ϭ 2.19 (s, 3 H), 3.99 (s,
1
1
3.85Ϫ3.93 (m, 1 H), 3.99Ϫ4.11 (m, 2 H), 4.24Ϫ4.32 (m, 1 H), 5.34 4 H), 4.99 (m, 2 H), 5.47 (m, 2 H), 6.39Ϫ6.46 (m, 2 H), 6.86Ϫ7.04
(s, 1 H), 6.35Ϫ6.39 (m, 2 H), 6.94Ϫ7.00 (m, 2 H), 7.20Ϫ7.40 (m, (m, 2 H) ppm. 13C NMR (50.3 MHz, CDCl3) for crude 28: δ ϭ
5 H) ppm. 13C NMR (100.6 MHz, [D6]acetone): δ ϭ 19.5, 19.6, 20.1, 53.7, 104.1, 112.1, 125.6, 129.5, 143.0, 145.1 ppm. LRMS
19.7, 19.9, 21.4, 39.9, 41.9, 42.2, 56.0, 57.8, 59.7, 112.7, 125.8,
129.0, 130.5, 130.6, 130.9, 131.4, 134.3, 139.2, 146.9, 207.1, 211.7
ppm. LRMS (70 eV, EI): m/z (%) ϭ 403 (3) [Mϩ], 330 (100).
C23H27NO (403.6): calcd. C 80.36, H 8.24, N 3.47; found C 80.22,
H 8.17, N 3.50.
(70 eV, EI): m/z (%) ϭ 185 (77) [Mϩ], 184 (100).
Preparation of 2,5-Dihydro-3,4-bis(hydroxymethyl)-1-(4-methyl-
phenyl)-1H-pyrrole (30): A solution of dianion 3a, generated by
treatment of amine 1a (0.69 g, 2 mmol) with tBuLi (5.33 mL,
8 mmol) as described above, was treated at Ϫ78 °C with trimethyl
borate (2 equiv., 0.47 mL, 4 mmol). The resulting mixture was
stirred at this temperature for 30 min, the cooling bath was re-
Treatment of Dianion 3c with Ethyl Isobutyrate: Ethyl isobutyrate
(0.27 mL, 2 mmol) was added at Ϫ78 °C to a solution of dianion
3c, formed by treatment of amine 1c (1.0 g, 2 mmol) with tBuLi moved, and the stirring was continued for 1 h at room temperature
(5.33 mL of a 1.5  solution in pentane, 8 mmol) and TMEDA
(1.2 mL, 8 mmol) as described above. A 71:9:20 mixture of com-
pounds 24, 25 and 26 was obtained irrespective of whether the
reaction mixture was stirred for 1 h at Ϫ78 °C and then hydrolyzed
(addition of 5 mL of THF was necessary because of the low solu-
bility of the reaction mixture in diethyl ether). The reaction mixture
was cooled to 0 °C and a solution made up of hydrogen peroxide
(4 equiv., 0.8 mL of a 10  solution in water, 8 mmol) and sodium
Eur. J. Org. Chem. 2003, 771Ϫ783
781

´
J. Barluenga, F. J. Fan˜anas, R. Sanz, J. M. Ignacio
FULL PAPER
hydroxide (4 equiv., 2.7 mL of a 3  solution in water, 8 mmol) was δ ϭ 20.2, 51.2, 55.8, 59.0, 110.7, 116.8, 124.4, 129.7, 135.8, 138.8,
added dropwise. After addition was complete, the reaction mixture
was heated at reflux for 30 min. Boron salts were separated by fil-
145.4 ppm. LRMS (70 eV, EI): m/z (%) ϭ 240 (90) [Mϩ], 170 (100).
C16H20N2 (240.3): calcd. C 79.96, H 8.39, N 11.66; found C 80.01,
tration, the filtrate was extracted with EtOAc (3 ϫ 20 mL), and the H 8.40, N 11.57.
combined organic layers were dried over anhydrous Na2SO4. The
2-Butyl-1,2,3,4,5,6-hexahydro-5-(4-methylphenyl)pyrrolo[3,4-c]-
solvents were removed under vacuum and the resulting yellowish
solid was purified by column chromatography (EtOAc), yielding
pyrrole (32c): Dibromide 31 (0.69 g, 2 mmol) was treated with bu-
tylamine (0.20 mL, 2 mmol) and K2CO3 (0.55 g, 4 mmol) in
CH3CN (20 mL). Workup as above, followed by purification by
column chromatography (EtOAc/Et3N, 50:1), yielded 32c (0.38 g,
75%) as a white solid. M.p. 159Ϫ161 °C. 1H NMR (200 MHz,
CDCl3): δ ϭ 0.95 (t, J ϭ 7.2 Hz, 3 H), 1.26Ϫ1.61 (m, 4 H), 2.26
(s, 3 H), 2.73 (t, J ϭ 7.3 Hz, 2 H), 3.57 (s, 4 H), 4.02 (s, 4 H),
6.39Ϫ6.48 (m, 2 H), 7.01Ϫ7.10 (m, 2 H) ppm. 13C NMR
(50.3 MHz, CDCl3): δ ϭ 14.0, 20.1, 20.4, 31.3, 51.2, 56.2, 110.7,
116.8, 124.4, 129.8, 138.9, 145.5 ppm. LRMS (70 eV, EI): m/z
1
diol 30 (0.33 g, 75%) as a white solid. M.p. 154Ϫ156 °C. H NMR
(200 MHz, [D6]DMSO): δ ϭ 2.15, (s, 3 H), 4.04 (s, 4 H), 4.12 (d,
J ϭ 5.2 Hz, 4 H), 4.79 (t, J ϭ 5.2 Hz, 2 H), 6.32Ϫ6.41 (m, 2 H),
6.92Ϫ7.01 (m, 2 H) ppm. 13C NMR (50.3 MHz, [D6]DMSO): δ ϭ
19.9, 55.4, 56.4, 110.8, 123.4, 129.6, 133.2, 144.9 ppm. C13H17NO2
(219.3): calcd. C 71.21, H 7.81, N 6.39; found C 71.07, H 7.76,
N 6.35.
Preparation
of
3,4-Bis(bromomethyl)-2,5-dihydro-1-(4-methyl-
phenyl)-1H-pyrrole (31): A solution of diol 30 (0.44 g, 2 mmol) in (%) ϭ 256 (52) [Mϩ], 253 (100). C17H24N2 (256.4): calcd. C 79.64,
hydrobromic acid (48%, 4 mL) was heated for 2 h under reflux. The
resulting mixture was cooled to 0 °C and neutralized with aqueous
sodium hydroxide (3 ⁾. The mixture was extracted with CH2Cl2 (3
ϫ 20 mL) and the combined organic layers were dried over
Na2SO4. The solvent was removed under vacuum, and the resulting
residue was purified by column chromatography (hexane/EtOAc,
25:1), affording dibromide 31 (0.58 g, 84%) as a white solid. M.p.
H 9.44, N 10.93; found C 79.49, H 9.51, N 10.87.
Treatment of Dibromide 31 with 1,2-Dihydroxybenzene. Preparation
of 2,3,4,11-tetrahydro-2-(4-methylphenyl)-1H-[1,6]benzodioxocino-
[3,4-c]pyrrole (33): A solution of dibromide 31 (0.69 g, 2 mmol),
1,2-dihydroxybenzene (0.22 g, 2 mmol) and K2CO3 (0.55 g,
4 mmol) in acetone (20 mL) was stirred overnight under reflux.
Water was added and the organic product was extracted with
EtOAc (3 ϫ 20 mL). The organic layers were dried over Na2SO4
and the solvent was removed under vacuum. The resulting product
was purified by column chromatography (hexane/EtOAc, 15:1) to
afford 33 (0.45 g, 77%) as a white solid. M.p. 151Ϫ153 °C. 1H
NMR (200 MHz, CDCl3): δ ϭ 2.28 (s, 3 H), 4.08 (s, 4 H), 4.98 (s,
4 H), 6.35Ϫ6.44 (m, 2 H), 6.99Ϫ7.02 (m, 4 H), 7.03Ϫ7.11 (m, 2 H)
ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.2, 56.4, 68.4, 110.8,
122.7, 123.9, 124.9, 129.7, 133.2, 144.5, 147.8 ppm. LRMS (70 eV,
EI): m/z (%) ϭ 293 (96) [Mϩ], 184 (100). C19H19NO2 (293.4): calcd.
C 77.79, H 6.53, N 4.77; found C 77.90, H 6.54, N 4.72.
1
203Ϫ205 °C (decomp). H NMR (200 MHz, CDCl3): δ ϭ 2.27 (s,
3 H), 4.12 (s, 4 H), 4.26 (s, 4 H), 6.42Ϫ6.48 (m, 2 H), 7.02Ϫ7.07
(m, 2 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.2, 22.8, 57.1,
111.4, 125.8, 129.8, 133.5, 144.1 ppm. LRMS (70 eV, EI): m/z
(%) ϭ 184 (100). C13H15Br2N (345.1): calcd. C 45.25, H 4.38, N
4.06; found C 45.41, H 4.29, N 4.03.
Treatment of Dibromide 31 with Primary Amines. Preparation of
Diazabicyclic Compound 32. A solution of dibromide 31 (0.69 g,
2 mmol) and the corresponding primary amine (benzylamine, al-
lylamine or butylamine, 2 mmol) in CH3CN (20 mL) was treated
with K2CO3 (0.55 g, 4 mmol). The resulting mixture was stirred
under reflux for 3 h. Water was added and the organic product was
extracted with EtOAc (3 ϫ 20 mL). The combined organic layers
were dried over Na2SO4 and the solvent was removed under va-
cuum. The resulting residues were purified by column chromato-
graphy, affording compounds 32.
Preparation of 2,5-dihydro-1-(4-methylphenyl)-3,4-bis(phenylthiome-
thyl)-1H-pyrrole (34). Thiophenol (0.41 mL, 4 mmol) was added to
aqueous sodium hydroxide (0.7 , 0.16 g in 5.7 mL H2O, 4 mmol).
Dibromide 31 (0.69 g, 2 mmol), dissolved in 15 mL of THF, was
added to the resulting solution. The mixture was stirred for 48 h at
room temperature. Water was added and the organic product was
extracted with EtOAc (3 ϫ 20 mL). The combined organic layers
were dried over Na2SO4 and the solvent was removed under va-
cuum. The resulting residue was purified by column chromato-
graphy (hexane/EtOAc, 20:1), yielding 34 (0.52 g, 65%) as a white
solid. M.p. 107Ϫ109 °C. 1H NMR (200 MHz, CDCl3): δ ϭ 2.25
(s, 3 H), 3.29 (s, 4 H), 4.12 (s, 4 H), 6.37Ϫ6.45 (m, 2 H), 7.00Ϫ7.09
(m, 2 H), 7.11Ϫ7.39 (m, 10 H) ppm. 13C NMR (50.5 MHz,
CDCl3): δ ϭ 20.2, 30.8, 56.8, 111.0, 124.7, 127.1, 128.8, 129.7,
131.3, 131.5, 135.1, 144.7. C25H25NS2 (403.6): calcd. C 74.40, H
6.24, N 3.47; found C 74.56, H 6.31, N 3.52.
2-Benzyl-1,2,3,4,5,6-hexahydro-5-(4-methylphenyl)pyrrolo[3,4-c]-
pyrrole (32a): Dibromide 31 (0.69 g, 2 mmol) was treated with
benzylamine (0.19 mL, 2 mmol) and K2CO3 (0.55 g, 4 mmol) in
CH3CN (20 mL). Workup as above, followed by purification by
column chromatography (hexane/EtOAc, 1:1), yielded 32a (0.42 g,
1
72%) as a yellowish solid. M.p. 136Ϫ138 °C. H NMR (200 MHz,
CDCl3): δ ϭ 2.17 (s, 3 H), 3.49 (s, 4 H), 3.84 (s, 2 H), 3.91 (s, 4
H), 6.29Ϫ6.38 (m, 2 H), 6.91Ϫ7.00 (m, 2 H), 7.09Ϫ7.34 (m, 5 H)
ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 20.2, 51.1, 56.1, 60.5,
110.7, 124.4, 127.0, 128.3, 128.5, 129.7, 138.9, 139.3, 145.4 ppm.
LRMS (70 eV, EI): m/z (%) ϭ 290 (88) [Mϩ], 170 (100). C20H22N2
(290.4): calcd. C 82.72, H 7.64, N 9.65; found C 82.79, H 7.61,
N 9.59.
Acknowledgments
´
Financial support from the Ministerio de Ciencia y Tecnologıa
2-Allyl-1,2,3,4,5,6-hexahydro-5-(4-methylphenyl)pyrrolo[3,4-c]-
pyrrole (32b): Dibromide 31 (0.69 g, 2 mmol) was treated with al-
lylamine (0.15 mL, 2 mmol) and K2CO3 (0.55 g, 4 mmol) in
CH3CN (20 mL). Workup as above, followed by purification by
column chromatography (EtOAc/Et3N, 50:1), yielded 32b (0.37 g,
(grant PB97Ϫ1271) and FEDER (project BQU2001Ϫ1079) and the
Junta de Castilla y Leon (BU-24/02) is gratefully acknowledged.
SCAI (Universidad de Burgos) is also acknowledged. J. M. I.
´
´
thanks the Junta de Castilla y Leon for a fellowship.
1
77%) as a yellowish solid. M.p. 156Ϫ158 °C. H NMR (200 MHz,
[1]
CDCl3): δ ϭ 2.26 (s, 3 H), 3.40 (d, J ϭ 6.4 Hz, 2 H), 3.59 (s, 4 H),
4.02 (s, 4 H), 5.11Ϫ5.32 (m, 2 H), 5.83Ϫ6.05 (m, 1 H), 6.39Ϫ6.49
(m, 2 H), 7.01Ϫ7.11 (m, 2 H) ppm. 13C NMR (50.3 MHz, CDCl3):
W. F. Bailey, T. V. Ovaska, in Advanced in Detailed Reaction
Mechanisms (Ed.: J. M. Coxon); JAI Press: Greenwich, CT,
1994; Vol. 3, pp 251Ϫ273.
782
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´
J. Barluenga, R. Sanz, A. Granados, F. J. Fan˜anas, J. Am.
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[7]
´
´
R. Pedrosa, C. Andres, J. M. Iglesias, A. Perez-Encabo, J. Am.
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´
Fan˜anas, R. Sanz, C. Marcos, Org. Lett. 2002, 4, 1587Ϫ1590
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1
2001,
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Received July 22, 2002
[O02411]
Eur. J. Org. Chem. 2003, 771Ϫ783
783