Microwave-assisted Paal-Knorr reaction - Three-step regiocontrolled synthesis of polysubstituted furans, pyrroles and thiophenes

Article abstract of DOI:10.1002/ejoc.200500387

An efficient and highly versatile synthesis of furans, pyrroles and thiophenes is described. Starting from commercially available or easily prepared β-keto esters, functional homologation provides differently substituted 1,4-diketones that can be transfor

Full text of DOI:10.1002/ejoc.200500387

FULL PAPER
DOI: 10.1002/ejoc.200500387
Microwave-Assisted Paal–Knorr Reaction – Three-Step Regiocontrolled
Synthesis of Polysubstituted Furans, Pyrroles and Thiophenes
Giacomo Minetto,[a] Luca F. Raveglia,[b] Alessandro Sega,[a] and Maurizio Taddei*[a]
Keywords: Pyrroles / Microwaves / Cyclocondensation / Peptidomimetics
An efficient and highly versatile synthesis of furans, pyrroles
and thiophenes is described. Starting from commercially
available or easily prepared β-keto esters, functional homolo-
gation provides differently substituted 1,4-diketones that can
be transformed, through a microwave-assisted Paal–Knorr
condensation, into the corresponding methoxycarbonyl het-
erocycles. The methoxycarbonyl moiety can be directly
transformed into an NH2 group by hydrolysis to carboxylic
acid and Curtius rearrangement or into an amide by reaction
with a primary amine in the presence of Me3Al. The method
is compatible with the presence of a CbzNH group so that
the final heterocycle can be inserted into a peptide sequence
as a turn inducer. By using this procedure, a collection of
more than 60 different tetrasubstitued pyrroles or trisubsti-
tuted thiophenes has been prepared.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Heterocyclic chemistry is currently experiencing a re-
With the aim of using this procedure for the preparation
naissance because of the interest in heterocyclic scaffolds as of different scaffolds for parallel synthesis of arrays of poly-
templates for combinatorial chemistry.[1] As heteroaromatic functionalised heterocycles, we began to investigate the po-
compounds are present in many natural products[2] and are tentials and the limitations of this synthetic procedure. We
the constituents of numerous therapeutic agents,[3] they rep- report now that, with this synthetic strategy, it is possible
resent ideal druglike structures for the elaboration of and to prepare template structures that contain furan, pyrrole
increase in molecular diversity. Thus, the availability of sim- and thiophene rings with a high level of diversity and with
ple synthetic procedures that enable the preparation of dif- different functional groups that can be used for further dec-
ferent heterocycles with functionalisable groups as substitu- oration of the scaffold.
ents is an important task for organic and medicinal chem-
Since the common intermediate for the synthesis of these
ists. The Paal–Knorr cyclocondensation of 1,4-diketones families of heterocycles is the keto ester with the general
with amines and other nitrogen derivatives is a well-estab- formula 2 (Scheme 1), we started to look for the best reac-
lished and valuable tool for the preparation of pyrroles and tion conditions that are compatible with the presence of
related heterocycles.[4] The 1,4-dicarbonyl compound pro- different functional groups for R1 and R2.
vides four atoms (with the substituents) and the amine
group provides the nitrogen atom with the substituent. The
drawbacks of this reaction are the harsh conditions re-
quired for the cyclisation and some synthetic problems re-
lated to the availability of differently substituted 1,4-dike-
tones.[5]
We recently communicated a possible solution to this
problem that is based on the functional homologation of
commercially available β-keto esters with Et2Zn/CH2I2 and
aldehydes followed by pyridinium chlorochromate (PCC)
Scheme 1. Retrosynthetic analysis of five-membered heterocycles.
oxidation, which provides polysubstituted 1,4-dicarbonyl
Compound 2 was obtained from the reaction of a β-keto
ester with Et2Zn/CH2I2. The cyclopropyl intermediate re-
compounds in two steps. Further microwave-assisted Paal–
Knorr cyclisation afforded pyrroles in good yields.[6]
arranges to the carbanion, which is quenched by an electro-
phile.[7] When an aldehyde is used, the alcohol 4 is obtained,
which requires an additional oxidative step to obtain the
diketone 2.
In order to avoid the last step, we tried different C=O
electrophiles to directly introduce the required functionality
into the molecule by using the β-keto ester with R1 = tBu
[a] Dipartimento Farmaco Chimico Tecnologico, Università degli
Studi di Siena,
Via A. Moro, 53100 Siena, Italy
E-mail: taddei.m@unisi.it
[b] Nikem Research srl,
Via Zambeletti 25, 20021 Baranzate, Milano, Italy
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as the model compound. Acyl chlorides, and other kinds of
activated carbonyl compounds such as RCOOCOEt,
RCOOBt (Bt = benzotriazol-1-yl), RCOOC6F5 or nitriles
RCN did not react. When thioesters RCOSEt were used,
the formation of the expected ketones in acceptable yields
was observed.[8] However, different amounts of the products
from the simple homologation were obtained (3; E = H in
Scheme 2), and thus required a chromatographic purifica-
tion step. The reported yields of the products obtained with
this procedure compared with those of the products ob-
tained by addition of the aldehyde and PCC oxidation of
the crude are reported in Table 1. When the R1 and R2
groups are structurally not complex, the use of thioester as
the electrophile may be more convenient, whereas with
Scheme 2. Mechanism for the transformation of a β-keto ester into
a 1,4-dicarbonyl ester.
more complex substrates, the two-step procedure with the creased the reactivity of the aldehyde and reduced the yields
aldehyde is recommended. With regard to the oxidation of in the further cyclisation reaction.
alcohol 4 to ketone 5, 1–2 equiv. of PCC is generally re-
It was more convenient to remove the proton from the
quired for a quantitative conversion. In this case the yields NHCbz group by using an additional equivalent of Et2Zn.
were unsatisfactory, and the reaction could be driven to Thus, when a solution of the α- or β-amino aldehydes 29–
completion by further addition of PCC until the starting 30 was treated with Et2Zn and then added to the reaction
material disappeared. It is worth mentioning that this result mixture containing the β-keto ester, Et2Zn and CH2I2, the
was not obtained when starting with a large excess of PCC. expected alcohols were obtained. Further oxidation with
Purification of products 6–25 (obtained from the last PCC gave compounds 21–27 in acceptable yields (see
method) was carried out by passing the crude through a Scheme 3 and Table 1).
plug of silica and eluting with Et2O. This process generally
gave a product that was sufficiently pure for further cy- construction of cyclic structures and has been widely ap-
clocondensation.
plied to the synthesis of heterocycles.[4d] Recently, micro-
The Paal–Knorr reaction is a powerful method for the
When an acid proton was present, as in the case of N- waves have been applied to increase the yields, reduce the
Cbz α- or β-amino aldehydes, the simple homologated γ- reaction time and provide milder reaction conditions.[10]
keto ester was exclusively generated by quenching of the Zn Previously prepared diketones were subjected to microwave-
intermediate (3; E = H in Scheme 2).[9] A possible solution assisted reactions in AcOH in the presence of different
to this problem is the use of aldehydes that carry a doubly amines to give the corresponding pyrroles. The best results
protected nitrogen atom such as NCBz2 or NBn2. However, were obtained in an open vessel at 120–150 °C for 2–
the increase in the hindrance around the nitrogen atom de- 10 min, depending on the nature of the substrates em-
Table 1. Preparation of 1,4-dicarbonyl compounds.
R1
R2
Meth-
od[a]
Compound: yield [%][b]
R1
R2
Method[a] Compound: yield [%]
[b]
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Et
C6H5
C6H5
A
B
A
B
A
B
A
B
B
B
B
C
B
6: 75
6: 90
C6H5
C6H5
C6H5
Me
Me
Et
tBu
tBu
C6H5
Me
Me
p-Cl–C6H4
C3H7
C6H5CH2
C6H5
C3H7
B
B
B
B
B
C
C
C
C
C
C
C
16: 70
17: 74
p-Cl–C6H4
p-Cl–C6H4
o-CF3C6H4
o-CF3C6H4
C6H5CH2
C6H5(CH2)2
C3H7
C6H5
p-Cl–C6H4
C6H5
7: 70
18: 76
7: 76
19: 68[c]
20: 83
8: 20
8: 70
CbzNHCH2CH2
CbzNHCH2CH2
PhCH2CH(NHCbz)CH2
CbzNHCH2CH2
PhCH2CH(NHCbz)CH2
CbzNHCH2CH2
PhCH2CH(NHCbz)
21: 76
9: 61
22: 54[c]
23: 51
10: 88
11: 76
12: 77
13: 88
14: 67[c]
15: 86
24: 70
25: 66[c]
26: 65[c]
27: 63[c]
Et
Et
Et
tBu
C3H7
[a] Method A: Et2Zn, CH2I2, CH2Cl2, R2COSEt. Method B: a) Et2Zn, CH2I2, CH2Cl2, R2CHO; b) PCC, CH2Cl2, SiO2. Method C
a) Et2Zn, CH2I2, CH2Cl2 followed by Et2Zn, R2CHO in CH2Cl2; b) PCC, CH2Cl2, SiO2. [b] Yields of crude products with purities higher
than 90% (1H NMR spectroscopic analysis). [c] Yields of isolated and fully characterised products.
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Microwave-Assisted Paal–Knorr Reaction
FULL PAPER
[12] cyclised to pyrroles 64–70 in good yields. This behaviour
suggests that the reaction may be successfully carried out
when at least two CH2 groups are close to the reactive
centres of the partner.
Scheme 3. Use of N-Cbz amino aldehydes in the functional homol-
ogation.
Scheme 4.
ployed.[11] Finally, an aqueous workup removed the AcOH,
and the pyrroles were isolated by column chromatography
Furans 71–73 were easily obtained by heating diketones
on silica gel. Starting from diketones 6–26 and by using 6, 10 and 19 under microwave irradiation (sealed vessel,
different amines, pyrroles 31–60 were obtained in good 100 °C, 13.6 atm max. internal pressure) in acid solution
yields (see Table 2). Remarkably, compound 27 did not (see Table 3).[13] Analogously, thiophenes 74–78 were ob-
cyclise, even with nonhindered amines. On the other hand, tained from diketones by a microwave-assisted reaction
it is worth noting that the presence of an NHCBz group is using Lawesson’s reagent for the introduction of the sulfur
compatible with the reaction conditions, since compounds atom.[14] The reaction was carried out in toluene at 110 °C,
20–26 gave good yields from the Paal–Knorr reaction. The and the presence of Lawesson’s reagent in solution allowed
same trend was also observed in the case of the amine em- this temperature to be reached even when using a solvent
ployed in the cyclisation. Esters derived from α-amino acids with a low value of tan δ (as is the case for toluene).[15]
did not cyclise properly, whereas 1,2-diamines 61–63 Thiophenes 74–78 were always obtained together with dif-
(Scheme 4) (obtained from the corresponding amino acids) ferent amounts (from 10 to 25%) of the corresponding fu-
Table 2. Preparation of pyrroles.
[a] Yields of isolated and fully characterised products.
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G. Minetto, L. F. Raveglia, A. Sega, M. Taddei
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Table 3. Preparation of furans and thiophenes.
R1
R2
Method[a]
Compound: yield [%][a]
R1
R2
Method[a]
Compound: yield [%][b]
tBu
tBu
Me
tBu
C6H5
C6H5(CH2)2
C3H7
A
A
A
B
X = O 71 76
X = O 72 80
X = O 73 84
X = S 74 70
tBu
tBu
Me
C6H5(CH2)2
C3H7
B
B
B
B
X = S 75 71
X = S 76 80
X = S 77 80
X = S 78 50
C3H7
C3H7
C6H5
C6H5
[a] Method A: EtOH/HCl, microwaves, 100 °C, 4 min. Method B: Lawesson’s reagent, toluene, microwaves, 120 °C, 6–8 min. [b] Yields of
isolated and fully characterised products.
rans and they had to be separated by column chromatog- H2O) to give acids 79–84 in almost quantitative yields. Acid
raphy on silica gel. When a large excess of Lawesson’s rea- 80 reacted further with DPPA/H2O to give amine 85
gent was employed in order to prevent the formation of the through a Curtius rearrangement. These acids or amines
furan, the corresponding methyl thiophene-3-thiocarboxyl- could be further functionalised by standard coupling tech-
ate was obtained.
niques. The COOMe group in the 3-position was also trans-
Thus, starting from a common β-keto ester structure, dif- formed into the corresponding amide by reaction with dif-
ferent heterocycles with a high level of diversity were ob- ferent amines and AlMe3 in CH2Cl2.[16] The reaction was
tained with a simple three-step (or in some cases two-step) carried out in a parallel mode, working up the crude with
procedure. In order to improve the molecular diversity of stoichiometric amounts of HCl (10% in H2O), passing the
our system, we investigated the possibility of additional mixture through a short pad of silica, washing with CH2Cl2
functionalisations of the heterocyclic substituents. The CO- and evaporating the solvent. Pyrrole and thiophene amides
OMe group in the 3-position of pyrroles 30, 35, 46 and 48 86–96 were obtained in very good yields (see Table 4). Com-
and thiophenes 74 and 76 was hydrolysed (NaOH, MeOH, pound 58 was finally employed to introduce the polysubsti-
tuted pyrrole moiety into a peptide frame as a possible turn
inducer.[17] Thus, hydrolysis of the methyl ester of 58 was
Table 4. Functionalisation at position 3 of pyrroles and thiophenes.
carried out as described previously, and the resulting acid
was coupled with H–Ala–OMe [DMTMM,[18] THF, N-
methylmorpholine (NMM), 80%] to give 97. The Cbz
group was removed by microwave-assisted transfer hydro-
genolysis,[19] and the amine was coupled with Boc–Phe–OH
in 88% yield. Hydrolysis of the methyl ester provided the
acid 98 that could be coupled with other amino acids or
peptides through a solution or solid-phase synthesis proto-
col. Products 97 and 98 (Scheme 5) were obtained as single
diastereoisomers (1HNMR, 600 MHz analysis), which
shows that racemisation did not occur during the synthetic
sequence.
Scheme 5. Preparation of pyrrole-containing peptidomimetics.
[a] Yields of crude products with purities higher than 90 % (1H
NMR spectroscopic analysis).
In summary, we have explored the possibility of using the
Paal–Knorr reaction to prepare differently functionalised
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Microwave-Assisted Paal–Knorr Reaction
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1-[o-(Trifluoromethyl)phenyl]-2-(methoxycarbonyl)-5,5-dimethyl-
1,4-hexanedione (8): 1H NMR δ = 1.14 (s, 9 H, tBu), 3.05 and 3.24
(AB part of an ABX system, 2 H, CH2), 3.60 (s, 3 H, COOMe),
4.70 (X part of an ABX system, 1 H, CH), 7.40 (m, 2 H, Ar), 7.88
(m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.4 32.8,
41.7, 50.6, 124.3, 125.5, 127.8, 135.3, 139.9, 171.8, 198.2,
212.6 ppm. C17H19F3O4: calcd. C 59.30Ј H 5.56; found C 59.55, H
5.60.
pyrroles, furans and thiophenes. These scaffolds can show
a high level of diversity with variations in positions 1, 2
and 5 around the pyrrole ring through the original synthetic
scheme, and one additional level of diversification at posi-
tions 1, 2 and 3 through traditional combinatorial peptide
chemistry. The synthesis of new cyclic peptides that incor-
porate these heterocyclic building blocks and the corre-
sponding structural studies are currently under investiga-
tion.
3-(Methoxycarbonyl)-6,6-dimethyl-1-phenyl-2,5-heptanedione (9):
1H NMR (200 MHz, CDCl3): δ = 1.12 (s, 9 H, tBu), 2.91 and 3.09
(AB part of an ABX system, 2 H, CH2), 3.52 (s, 3 H, COOMe),
3.86 (AB system, 2 H, CH2Ar), 4.10 (X part of an ABX system, 1
H, CH), 7.2 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
26.4, 31.4, 43.7, 48.6, 50.4, 51.4, 126.0, 126.9, 127.0, 134.3, 171.9,
201.2, 210.7 ppm. C17H22O4: calcd. C 70.32, H 7.64; found C 70.50,
H 7.59.
Experimental Section
General: All reagents were purchased from Sigma-Aldrich Italia
(Milan, Italy) in the highest available purity and were used as such.
All solvents were purchased from Riedel-de Haën and were used
without further purification except when differently stated. LC-MS
data were recorded with a Waters ZQ electronspray mass spectrom-
eter equipped with an Alliance HT Waters 2790 separation module
and a Waters 996 Photodiode array detector using a Luna C18
column (4.6×50 mm, 3 m), eluent: 95% water, 5% acetonitrile, 0.1%
formic acid. Proton NMR spectra were recorded with a Bruker
ARX 300 MHz instrument using TMS as internal standard. The
irradiation with microwaves was carried out in the cavity of a Dis-
cover system from CEM.
4-(Methoxycarbonyl)-7,7-dimethyl-1-phenyl-3,6-octanedione (10):
1H NMR (200 MHz, CDCl3): δ = 1.10 (s, 9 H, tBu), 2.96 and 3.19
(AB part of an ABX system, 2 H, CH2), 3.40 (t-like, 2 H, COCH2),
3.50 (s, 3 H, COOMe), 3.88 (AB system, 2 H, CH2Ar), 4.15 (X
part of an ABX system, 1 H, CH), 7.2 (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 26.0, 31.4, 33.6, 41.7, 48.8, 50.4, 52.7,
126.1, 126.9, 127.0, 134.8, 173.0, 201.9, 214.8 ppm. C18H24O4:
calcd. C 71.03, H 7.95; found C 70.99, H 7.99.
5-(Methoxycarbonyl)-2,2-dimethyl-3,6-nonanedione (11): Identified
by comparison with reported data.[21]
2-(Methoxycarbonyl)-5,5-dimethyl-1-phenyl-1,4-hexanedione
(6):
2-(Methoxycarbonyl)-1-phenyl-1,4-hexanedione (12): 1H NMR
(200 MHz, CDCl3): δ = 1.07 (t, J = 7 Hz, 3 H, Me), 3.10–3.30 (m,
4 H, CH2), 3.50 (s, 3 H, COOMe), 4.86 (m, 1 H, CH), 7.30–7.50
(m, 3 H, Ar), 7.91 (m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = 16.8, 31.4, 32.5, 49.7, 51.9, 128.3, 129.7, 133.3, 138.3, 171.2,
196.7, 210.7 ppm. C14H16O4: calcd. C 67.73, H 6.50; found C 67.59,
H 6.46.
Diethylzinc (30 mL of a 1.0  solution in hexane, 30 mmol) was
dissolved in dry dichloromethane (60 mL) under nitrogen, and the
mixture was cooled to 0 °C. Diiodomethane (2.4 mL, 30 mmol) was
slowly added, and the mixture was stirred for 10 min. After the
formation of a white precipitate, methyl 4,4-dimethyl-3-oxopen-
tanoate (1.2 mL, 7.3 mmol) was added, and the reaction mixture
was stirred for 30 min. Benzaldehyde (previously distilled under
vacuum and collected over molecular sieves) (0.78 mL, 7.68 mmol)
was added, and the mixture was stirred at 0 °C for 1 h. Silica gel
(20.0 g) was added, and the mixture was stirred at room tempera-
ture for an additional 30 min. The mixture was filtered under vac-
uum, and the solvent was evaporated. The crude (2.26 g) was dis-
solved in dry dichloromethane, PCC (3.3 g, 15.3 mmol) was added,
and the mixture was stirred at room temperature until TLC analysis
(eluent hexane/AcOEt, 5:1) showed the disappearance of the start-
ing material. Eventually, additional PCC (1.65 g, 7.51 mmol) was
added. The mixture was passed through a short path of silica gel
and eluted with dichloromethane. The eluent was collected, and the
solvent was evaporated under vacuum to give product 6 (1.9 g, 90%
yield), which was identified by comparison with reported data.[20]
An analytical sample was purified by column chromatography on
silica gel (eluent hexane/AcOEt, 3:1). 1H NMR (200 MHz, CDCl3):
δ = 1.10 (s, 9 H, tBu), 3.10 (m, 2 H, CH2), 3.51 (s, 3 H, COOMe),
4.86 (t, J = 7 Hz, 1 H, CH), 7.30–7.50 (m, 3 H, Ar), 7.91 (m, 2 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.9, 32.5, 44.7, 51.9,
128.3, 129.7 133.3, 138.3, 170.2, 194.7, 213.7 ppm. C16H20O4: calcd.
C 69.54, H 7.30; found C 69.10, H 7.20.
1
1-(p-Chlorophenyl)-2-(methoxycarbonyl)-1,4-hexanedione (13): H
NMR (200 MHz, CDCl3): δ = 1.09 (t, J = 7 Hz, 3 H, Me), 3.10–
3.30 (m, 4 H, CH2), 3.55 (s, 3 H, COOMe), 4.85 (m, 1 H, CH),
7.30–7.60 (m, 4 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
16.6, 32.4, 33.5, 49.7, 51.0, 126.3, 129.2, 134.3, 139.3, 171.2, 198.7,
211.7 ppm. C14H15ClO4: calcd. C 59.48, H 5.35; found C 59.58, H
5.30.
3-(Methoxycarbonyl)-1-phenyl-2,5-heptanedione (14): 1H NMR
(200 MHz, CDCl3): δ = 1.00 (t, J = 7 Hz, 3 H, Me), 3.00–3.25 (m,
4 H, CH2), 3.50 (s, 3 H, COOMe), 4.00 (m, 2 H, CH2Ar), 4.85 (m,
1 H, CH), 7.30 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ
= 16.8, 32.8, 34.5, 40.8, 49.0, 51.2, 126.0, 127.3, 128.2, 134.3, 171.2,
199.9, 212.7 ppm. C15H18O4: C 68.68, H 6.92; found C 68.55; H
6.89.
1
5-(Methoxycarbonyl)-3,6-nonanedione (15): H NMR (200 MHz,
CDCl3): δ = 1.00–1.11 (2 t, J = 7 Hz, 6 H, 2 Me), 1.89 (m, 2 H,
CH2), 3.10–3.30 (m, 6 H, 3 CH2CO), 3.50 (s, 3 H, COOMe), 4.85
(m, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.9, 14.8,
16.8, 32.8, 34.5, 33.7, 49.8, 51.7, 171.8, 201.6, 206.7 ppm.
C11H18O4: calcd. C 61.66, H 8.47; found C 61.40, H 8.40.
1-(p-Chlorophenyl)-2-(methoxycarbonyl)-5,5-dimethyl-1,4-hexane-
dione (7): 1H NMR (200 MHz, CDCl3): δ = 1.14 (s, 9 H, tBu), 3.15
and 3.34 (AB part of an ABX system, 2 H, CH2), 3.62 (s, 3 H,
COOMe), 4.83 (X part of an ABX system, 1 H, CH), 7.41 (m, 2
H, Ar), 7.93 (m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ
= 29.9, 32.0, 42.7, 50.1, 128.5, 129.8, 133.3, 138.6, 171.2, 196.0,
210.7 ppm. C16H19ClO4: calcd. C 61.84, H 6.16; found C 61.40, H
6.21.
1-(p-Chlorophenyl)-2-(methoxycarbonyl)-4-phenyl-1,4-butanedione
(16): Identified by comparison with reported data.[22]
3-(Methoxycarbonyl)-1-phenyl-1,4-heptanedione (17): 1H NMR
(200 MHz, CDCl3): δ = 1.00 (t, J = 7 Hz, 3 H, Me), 1.87 (m, 2 H),
3.10–3.35 (m, 4 H, CH2), 3.48 (s, 3 H, COOMe), 4.80 (m, 1 H,
CH), 7.30–7.50 (m, 3 H, Ar), 7.91 (m, 2 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 16.8, 17.7, 32.4, 33.5, 49.0, 51.0, 128.0,
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129.3, 133.3, 138.5, 174.2, 197.7, 210.7 ppm. C15H18O4: calcd. C
68.68, H 6.92; found C 68.59, H 6.96.
(s, 9 H, tBu), 3.10 (AB part of an ABX system, 2 H, CH2CO), 3.22
(m, 2 H, CH2Ph), 3.38 (m, 2 H, COCH2), 3.53 (s, 3 H, COOMe),
4.18 (m, 1 H, CH2N), 4.40 (m, 1 H, CH), 5.12 (s, 2 H, Cbz), 6.10
(s, 1 H, NH), 7.20–7.35 (m, 10 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 15.8 (3C), 32.4, 33.5, 38.5, 41.7, 47.9, 49.0, 51.0, 56.9,
126.5, 128.0, 129.3, 138.5, 164.8, 174.2, 203.5, 210.7 ppm.
C27H33NO6: calcd. C 69.36, H 7.11; found C 69.56, H 7.13.
3-(Methoxycarbonyl)-1,5-diphenyl-1,4-pentanedione (18): 1H NMR
(200 MHz, CDCl3): δ = 3.35 (m, 2 H, CH2), 3.55 (s, 3 H, COOMe),
4.02 (AB system, 2 H, CH2Ar), 4.66 (m, 1 H, CH), 7.23–7.60 (m,
10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 33.5, 41.4, 49.0,
52.0, 126.0, 126.3, 126.9, 127, 8, 129.2, 134.3, 170.5, 199.0,
199.9 ppm. C19H18O4: calcd. C 73.53, H 5.85; found C 73.42, H
5.88.
6-[(Benzyloxycarbonyl)amino]-3-(methoxycarbonyl)-1-phenyl-1,4-
1
hexanedione (24): H NMR (200 MHz, CDCl3): δ = 3.10 (m, 2 H,
2-(Methoxycarbonyl)-1-phenyl-1,4-pentanedione (19): 1H NMR
(200 MHz, CDCl3): δ = 2.78 (s, 3 H, Me), 3.05 (m, 2 H, CH2), 3.56
(s, 3 H, COOMe), 4.60 (m, 1 H, CH), 7.30 (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 30.5, 40.4, 52.0, 60.3, 126.0, 126.3,
126.9, 134.3, 170.5, 199.0, 199.9 ppm. C13H14O4: calcd. C 66.66, H
6.02; found C 66.48, H 6.00.
CH2CO), 3.38 (t-like, 2 H, COCH2), 3.59 (s, 3 H, COOMe), 4.01
(t-like, 2 H, CH2N), 4.48 (m, 1 H, CH), 5.16(s, 2 H, Cbz), 6.20 (s,
1 H, NH), 7.20–7.40 (m, 8 H, Ar), 7.89 (m, 2 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 32.4, 33.5, 40.9, 49.0, 51.0, 56.8,
126.5, 126.9, 128.0, 128.8, 129.3, 134.8, 138.5, 169.8, 173.2, 198.5,
210.7 ppm. C22H23NO6: calcd. C 66.49, H 5.83; found C 66.59, H
5.86.
1
4-(Methoxycarbonyl)-2,5-octanedione (20): H NMR (200 MHz,
2-[(Benzyloxycarbonyl)amino]-5-(methoxycarbonyl)-1-phenyl-4,7-oc-
tanedione (25): 1H NMR (200 MHz, CDCl3): δ = 2.98 (s, 3 H, Me),
3.11 (AB part of an ABX system, 2 H, CH2CO), 3.22 (m, 2 H,
CH2Ph), 3.50 (s, 3 H, COOMe), 3.59 (m, 2 H, CH2CO), 4.35 (m,
1 H, CH), 4.45 (m, 1 H, CHN), 5.12 (s, 2 H, Cbz), 6.15 (s, 1 H,
NH), 7.30 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
30.8, 36.4, 39.5, 42.7, 48.9, 50.0, 57.0, 59.9, 126.5, 128.0 129.3,
138.5, 164.8, 174.2, 203.5, 210.7 ppm. C24H27NO6: C 67.75, H 6.40,
N 3.29; found C 67.60, H 6.41, N 3.31.
CDCl3): δ = 1.11 (t, J = 7 Hz, 3 H, Me), 1.46 (s, 3 H, Me), 2.01
(m, 2 H), 3.00–3.30 (m, 4 H, 2 CH2CO), 3.55 (s, 3 H, COOMe),
4.65 (m, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.9,
16.8, 22.7, 24.9, 32.8, 34.5, 49.8, 51.7, 172.8, 201.6, 208.7.
C10H16O4: calcd. C 59.98, H 8.05; found C 59.88, H 8.00.
1-[(Benzyloxycarbonyl)amino]-4-(methoxycarbonyl)-3,6-octanedione
(21): Diethylzinc (30 mL of a 1.0  solution in hexane, 30 mmol)
was dissolved in dry dichloromethane (60 mL) under nitrogen, and
the mixture was cooled to 0 °C. Diiodomethane (2,4 mL, 30 mmol)
was slowly added, and the mixture was stirred for 10 min. After the
formation of a white precipitate, methyl 3-oxopentanoate (1.3 mL,
7.3 mmol) was added, and the reaction mixture was stirred for
30 min. A solution of 3-Cbz-aminopropanal (1.51 g, 7.3 mmol) in
dichloromethane (8 mL) containing diethylzinc (8 mL of a 1.0 
solution in hexane, 8 mmol) was slowly added, and the mixture
stirred at 0 °C for 1 h. Silica gel (20.0 g) was added, and the mixture
was stirred at room temperature for an additional 30 min. The mix-
ture was filtered under vacuum, and the solvent was evaporated.
The crude (2.16 g) was dissolved in dry dichloromethane, PCC
(3.3 g, 15.3 mmol) was added, and the mixture was stirred at room
temperature until TLC analysis (eluent hexane/AcOEt, 1:1) showed
the disappearance of the starting material. Eventually, additional
PCC (1.65 g, 7.51 mmol) was added. The mixture was passed
through a short path of silica gel and eluted with dichloromethane.
The eluent was collected, and the solvent was evaporated under
vacuum to give product 21 (1.9 g, 76% yield). An analytical sample
was purified by column chromatography on silica gel (eluent hex-
ane/AcOEt, 1:1). 1H NMR (200 MHz, CDCl3): δ = 1.11 (t, J =
7 Hz, 3 H, Me), 3.00–3.10 (m, 4 H, 2CH2CO), 3.36 (t-like, 2 H,
COCH2), 3.55 (s, 3 H, COOMe), 3.99 (t-like, 2 H, CH2N), 4.44 (m,
1 H, CH), 5.10 (s, 2 H, Cbz), 6.00 (s, 1 H, NH), 7.28 (m, 5 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3): δ = 10.8, 32.4, 33.5, 38.5, 44.9,
49.0, 51.0, 56.8, 126.5, 128.0, 129.3, 138.5, 165.8, 171.2, 202.5,
211.7 ppm. C18H23NO6: calcd. C 61.88, H 6.64; found C 61.59, H
6.66.
1-[(Benzyloxycarbonyl)amino]-4-(methoxycarbonyl)-3,6-heptane
1
dione (26): H NMR (200 MHz, CDCl3): δ = 1.18 (t, J = 7 Hz, 3
H, Me), 3.16 (m, 2 H, CH2CO), 3.38 (t-like, 2 H, COCH2), 3.54 (s,
3 H, COOMe), 3.90 (t-like, 2 H, CH2N), 4.46 (m, 1 H, CH), 5.12
(s, 2 H, Cbz), 5.98 (s, 1 H, NH), 7.28 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 16.8, 32.4, 33.5, 44.9, 49.0, 51.0, 56.8, 126.5,
128.0, 129.3, 138.5, 166.8, 170.2, 203.5, 210.7 ppm. C17H21NO6:
calcd. C 60.89, H 6.31; found C 60.67, H 6.33.
2-[(Benzyloxycarbonyl)amino]-4-(methoxycarbonyl)-7,7-dimethyl-1-
phenyl-3,6-octanedione (27): 1H NMR (200 MHz, CDCl3): δ = 1.15
(s, 9 H, tBu), 3.11 (AB part of an ABX system, 2 H, CH2CO), 3.22
(m, 2 H, CH2Ph), 3.50 (s, 3 H, COOMe), 4.19 (m, 1 H, CH2N),
4.45 (m, 1 H, CH), 5.12 (s, 2 H, Cbz), 6.15 (s, 1 H, NH), 7.20–7.35
(m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.8, 32.4,
33.5, 41.7, 47.9, 49.0, 51.0, 56.9, 126.5, 128.0, 129.3, 138.5, 164.8,
174.2, 203.5, 210.7 ppm. C26H31NO6: C 68.86, H 6.89; found C
68.66, H 6.91.
1-Benzyl-5-tert-butyl-3-(methoxycarbonyl)-2-phenylpyrrole (31):
Product 6 (1.0 g, 3,44 mmol) was dissolved in acetic acid (3 mL) in
a 50-mL round-bottomed flask, equipped with a stirrer bar and a
reflux condenser. Benzylamine (1.84 g, 17.2 mmol) was added, and
the flask was inserted into the cavity of a Discovery Microwave
System apparatus (from CEM) and heated at 150 W for 12 min
(internal temperature 170 °C). The mixture was diluted with Ac-
OEt, and the solution was washed several times with a saturated
solution of NaHCO3. The organic layer was dried with anhydrous
1-[(Benzyloxycarbonyl)amino]-4-(methoxycarbonyl)-7,7-dimethyl-
1
Na2SO4, and the solvent was evaporated. The H NMR spectrum
1
3,6-octanedione (22): H NMR (200 MHz, CDCl3): δ = 1.15 (s, 9
of the crude showed the presence of compound 31 together with
benzylammonium acetate. The required pyrrole was purified by
flash chromatography (eluent hexane/AcOEt, 8:1; Rf = 0.37) to give
product 31 as a solid (0.87 g, 70% yield). M.p. 87–89 °C. 1H NMR
(200 MHz, CDCl3): δ = 1.14 (s, 9 H, tBu), 3.59 (s, 3 H, COOMe),
5.16 (s, 2 H, CH2), 6.56 (s, 1 H, 4-H), 7.10–7.30 (m, 10 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 28.7, 32.2, 49.3, 50.6, 107.1,
112.4, 125.4, 126.8, 127.5, 127.9, 128.2, 130.5, 132.1, 138.9, 140.6,
H, tBu), 3.10 (AB part of an ABX system, 2 H, CH2CO), 3.38 (t-
like, 2 H, COCH2), 3.53 (s, 3 H, COOMe), 3.89 (t-like, 2 H, CH2N),
4.40 (X part of an ABX system, 1 H, CH), 5.10 (s, 2 H, Cbz), 6.11
(s, 1 H, NH), 7.28 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = 15.8, 32.4, 33.5, 38.5, 41.7, 44.9, 49.0, 51.3, 56.9, 126.5, 128.0,
129.3, 138.5, 165.8, 171.2, 201.5, 215.7 ppm. C20H27NO6: calcd. C
63.64, H 7.21; found C 63.76, H 7.23.
2-[(Benzyloxycarbonyl)amino]-5-(methoxycarbonyl)-8,8-dimethyl-1- 142.3, 166.7 ppm. ES/MS: m/z = 348 [M + 1]+. C23H25NO2: calcd.
phenyl-4,7-nonanedione (23): 1H NMR (200 MHz, CDCl3): δ = 1.15 C 79.51, H 7.25, N 4.03; found C 68.66, H 6.91, N 4.00.
5282
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5277–5288

Microwave-Assisted Paal–Knorr Reaction
FULL PAPER
1-Butyl-5-tert-butyl-2-(p-chlorophenyl)-3-(methoxycarbonyl)pyrrole 2-Benzyl-5-tert-butyl-3-(methoxycarbonyl)-1-(2-picolyl)pyrrole (39):
(32): 1H NMR (200 MHz, CDCl3): δ = 0.67 (t, J = 7 Hz, 3 H, Me),
0.96–1.17 (m, 2 H, CH2), 1.30–1.35 (m, 2 H, CH2), 1.38 (s, 9 H,
tBu), 3.57 (s, 3 H, COOMe), 3.89 (t, 2 H, J = 8 Hz, N–CH2), 6.42
1H NMR (200 MHz, CDCl3): δ = 1.07 (s, 9 H, tBu), 3.62 (s, 3 H,
COOMe), 4.08 (s, 2 H, CH2Ar), 5.15 (s, 2 H, CH2N), 6.12 (d, 1 H,
4-H), 6.90–7.20 (m, 8 H, Ar), 8.34 (d-like, 1 H, CH-pyridine) ppm.
13C NMR (75 MHz, CDCl3): δ = 23.8, 31.0, 50.9, 51.0, 107.1,
(s, 1 H, 4-H), 7.27 (d-like, 2 H, Ar), 7.36 (d-like, 2 H, Ar) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 12.7, 19.2, 29.5, 30.2, 31.7, 32.5, 45.0, 112.2, 120.2, 122.3, 126.3, 128.3, 137.2, 138.6, 139.1, 141.9, 149.3,
49.7, 106.4, 110.8, 127.6, 128.7, 131.6, 133.6, 137.4, 140.9,
162.4 ppm. ES/MS: m/z = 348–350 [M + 1]+. C20H26ClNO2: calcd.
C 69.05, H 7.53, N 4.03; found C 68.97, H 7.60, N 4.01.
158.3, 166.1 ppm. C23H26N2O3: calcd. C 76.21, H 7.23, N 8.83;
found C 76.41, H 7.22, N 8.90.
2-[2-(Benzyloxycarbonylamino)ethyl]-5-tert-butyl-3-(methoxycar-
bonyl)-1-(2-methylpropyl)pyrrole (40): 1H NMR (200 MHz,
CDCl3): δ = 0.60 and 0.65 (2 s, 6 H, Me2), 1.10 (s, 9 H, tBu), 1.70
(m, 1 H, CH), 3.03 (t, J = 8 Hz, 2 H, CH2-pyrrole), 3.60 (s, 3 H,
COOMe), 4.06 (d, J = 8 Hz, 2 H, CH2–N), 4.30 (t, J = 8 Hz, 2 H,
CH2NHCbz), 5.16 (s, 2 H, OCH2Ph), 6.10 (br. s, 1 H, NH), 6.22
(d, 1 H, 4-H), 7.30 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.0, 15.3, 29.5, 31.2 (3 C), 31.9, 33.4, 44.6, 49.6, 51.7, 70.3,
103.4, 111.8, 127.6, 128.7, 131.6, 133.6, 137.4, 138.7, 156.7,
164.4 ppm. ES/MS: m/z = 415 [M + 1]+. C24H34N2O4: calcd. C
69.54, H 8.27, N 6.76; found C 69.47, H 8.30, N 6.73.
5-tert-Butyl-2-[o-(trifluoromethyl)phenyl]-3-(methoxycarbonyl)-1-(2-
methylpropyl)pyrrole (33): 1H NMR (200 MHz, CDCl3): δ = 0.51
and 0.57 (2 d, J = 7 Hz, 6 H, Me), 1.35 (s, 9 H, tBu), 1.65 (m, 1
H, CH), 3.55 (s, 3 H, COOMe), 3.75 (d, J = 8 Hz, 2 H, N–CH2),
6.42 (s, 1 H, 4-H), 7.27–7.56 (m, 4 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 11.7, 16.2, 28.5, 30.0, 32.7, 32.4, 45.6, 48.7,
103.4, 111.8, 127.6, 128.7, 131.6, 133.6, 137.4, 139.7, 140.9,
162.4 ppm. ES/MS: m/z = 382 [M + 1]+. C21H26F3NO2: calcd. C
66.13, H 6.87, N 3.67; found C 66.07, H 6.80, N 3.71.
1-Benzyl-5-tert-butyl-2-(p-chlorophenyl)-3-(methoxycarbonyl)pyr-
role (34): 1H NMR (200 MHz, CDCl3): δ = 1.29 (s, 9 H, tBu), 3.35
(s, 3 H, COOMe), 5.19 (s, 2 H, CH2), 6.53 (s, 1 H, 4-H), 7.06–7.30
(m, 9 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.5, 31.7,
45.9, 49.9, 104.4, 112.8, 126.5, 126.6, 128.6, 128.7, 129.3, 131.6,
133.6, 137.4, 139.7, 165.4 ppm. ES/MS: m/z = 383–385 [M + 1]+.
C23H24ClNO2: calcd. C 72.34, H 6.33, N 3.67; found C 72.17, H
6.30, N 3.65.
1-Benzyl-2-[2-(benzyloxycarbonylamino)ethyl]-5-tert-butyl-3-(meth-
oxycarbonyl)pyrrole (41): 1H NMR (200 MHz, CDCl3): δ = 1.10 (s,
9 H, tBu), 3.13 (t, J = 7 Hz, 2 H, CH2-pyrrole), 3.60 (s, 3 H, CO-
OMe), 4.30 (t, J = 8 Hz, 2 H, CH2NHCbz) 4.86 (s, 2 H, CH2–N),
5.16 (s, 2 H, OCH2Ph), 6.11 (br. s, 1 H, NH), 6.32 (d, 1 H, 4-H),
7.30 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.2,
15.3, 29.5, 31.2, 31.9, 33.4, 40.7, 44.6, 52.7, 70.9, 103.4, 111.8,
126.3, 127.4, 127.6, 128.6, 128.7, 131.6, 133.6, 134.6, 137.4, 138.7,
155.7, 165.4 ppm. ES/MS: m/z = 449 [M + 1]+. C27H32N2O4: calcd.
C 72.30, H 7.19, N 6.25; found C 72.20, H 7.12, N 6.29.
1-Benzyl-5-tert-butyl-3-(methoxycarbonyl)-2-(2-phenylethyl)pyrrole
1
(35): H NMR (200 MHz, CDCl3): δ = 1.24 (s, 9 H, tBu), 2.69 (t,
2 H, J = 8 Hz, CH2), 3.24 (t, 2 H, J = 8 Hz, CH2), 3.73 (s, 3 H,
COOMe), 4.89 (s, 2 H, CH2N), 6.45 (s, 1 H, 4-H), 7.25–7.45 (m,
10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.5, 31.7, 37.8,
41.6, 45.9, 49.9, 104.4, 112.8, 126.9, 126.6, 128.6, 128.7, 129.3,
131.6, 133.6, 137.4, 165.4 ppm. ES/MS: m/z = 376 [M + 1]+.
C25H29NO2: calcd. C 79.96, H 7.78, N 3.73; found C 79.84, H 7.74,
N 3.69.
2-[2-(Benzyloxycarbonylamino)-3-phenylpropyl]-5-tert-butyl-3-
(methoxycarbonyl)-1-(2-methylpropyl)pyrrole (42): 1H NMR
(200 MHz, CDCl3): δ = 0.61 and 0.63 (2 s, 6 H, Me2), 1.10 (s, 9 H,
tBu), 1.70 (m, 1 H, CH), 3.00 (AB part of an ABX system, 2 H,
CH2-Ar), 3.40 (AB part of an ABX system, 2 H, CH2-pyrrole),
3.60 (s, 3 H, COOMe), 4.16 (d, J = 8 Hz, 2 H, CH2–N), 4.50 (m,
1 H, CHNHCbz), 5.16 (s, 2 H, OCH2Ph), 6.11 (br. s, 1 H, NH),
6.54 (s, 1 H, 4-H), 7.30 (m, 10 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 11.2, 15.3, 29.5, 31.2, 31.9, 33.4, 40.7, 44.6, 49.6, 52.7,
70.9, 103.4, 111.8, 126.3, 127.4, 127.6, 128.6, 128.7, 131.6, 133.6,
134.6, 137.4, 138.7, 155.7, 165.4 ppm. ES/MS: m/z = 506
[M + 1]+. C31H40N2O4: calcd. C 73.78, H 7.99, N 5.55; found C
73.20, H 8.01, N 5.60.
5-tert-Butyl-3-(methoxycarbonyl)-1-(2-methylpropyl)-2-phenylpyr-
1
role (36): H NMR (200 MHz, CDCl3): δ = 0.50 and 0.59 (2 d, J
= 7 Hz, 6 H, Me), 1.35 (s, 9 H, tBu), 1.66 (m, 1 H, CH), 3.58 (s, 3
H, COOMe), 3.75 (d, J = 8 Hz, 2H N–CH2), 6.45 (s, 1 H, 4-H),
7.30 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.9,
16.0, 29.5, 31.0, 31.7, 32.4, 44.6, 49.7, 103.4, 111.8, 127.6, 128.7,
131.6, 133.6, 137.4, 138.7, 164.4 ppm. ES/MS: m/z = 314
[M + 1]+. C20H27NO2: calcd. C 76.64, H 8.68, N 4.47; found C
76.47, H 8.70, N 4.43.
1-Benzyl-2-[2-(benzyloxycarbonylamino)-3-phenylpropyl]-5-tert-bu-
1
tyl-3-(methoxycarbonyl)pyrrole (43): H NMR (200 MHz, CDCl3):
5-tert-Butyl-3-(methoxycarbonyl)-1-(2-morpholinoethyl)-2-phenyl-
δ = 1.12 (s, 9 H, tBu), 3.02 (AB part of an ABX system, 2 H, CH2-
Ar), 3.43 (AB part of an ABX system, 2 H, CH2-pyrrole), 3.60 (s,
3 H, COOMe), 4.50 (m, 1 H, CHNHCbz), 4,87 (s, 2 H, CH2–N),
5.10 (s, 2 H, OCH2Ph), 6.11 (br. s, 1 H, NH), 6.45 (s, 1 H, 4-H),
7.30 (m, 15 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.7,
15.2, 28.5, 31.2, 32.0, 33.4, 41.7, 44.6, 49.6, 52.7, 70.9, 103.4, 111.8,
126.3, 127.4, 127.6, 128.6, 128.7, 128.9, 131.6, 133.6, 135.7, 134.6,
137.4, 138.7, 155.7, 165.4 ppm. ES/MS: m/z = 506 [M + 1]+.
C34H38N2O4: calcd. C 75.81, H 7.11, N 5.20; found C 75.60, H
7.10, N 5.10.
1
pyrrole (37): H NMR (200 MHz, CDCl3): δ = 1.39 (s, 9 H, tBu),
2.03 (t-like, 4 H, CH2N), 2.26 (t, J = 7 Hz, 2 H, CH2N), 3.48 (t-
like, 4 H, CH2O), 3.68 (s, 3 H, COOMe), 4.06 (t, J = 7 Hz, 2 H,
CH2N-pyrrole), 6.40 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 31.2, 32.0, 32.4, 49.7, 51,4, 55.4, 66.8,
103.4, 111.8, 126.6, 127.7, 128.0, 130.6, 134.4, 136.7, 165.4 ppm.
ES/MS: m/z = 314 [M + 1]+. C22H30N2O3: C 71.32, H 8.16, N 7.56;
found C 71.44, H 8.12 N 7.53.
5-tert-Butyl-3-(methoxycarbonyl)-1-(2-picolyl)-2-propylpyrrole (38):
1H NMR (200 MHz, CDCl3): δ = 0.74 (t, J = 7 Hz, 3 H, Me), 1.11
(s, 9 H, tBu), 1.30 (m, 2 H, CH2), 2.57 (t, J = 7 Hz, 2 H, CH2),
3.65 (s, 3 H, COOMe), 5.28 (s, 2 H, CH2), 6.18 (s, 1 H, 4-H), 7.01
(m, 1 H, Ar), 7.41 (m, 2 H, Ar), 8.42 (m, 1 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.2, 23.4, 27.4, 30.8, 32.1, 50.8, 71.2, 106.9,
110.8, 120.3, 122.4, 137.3, 141.1, 142.3, 149.4, 158.2, 165.9 ppm.
1-Benzyl-5-ethyl-3-(methoxycarbonyl)-2-phenylpyrrole (44): Iden-
tified by comparison with reported data.[20]
5-Ethyl-3-(methoxycarbonyl)-1-(2-methylpropyl)-2-propylpyrrole
(45): Identified by comparison with reported data.[20]
2-Benzyl-5-ethyl-3-(methoxycarbonyl)-1-[2-(p-methoxyphenyl)ethyl]-
C19H26N2O3: calcd. C 72.58, H 8.33, N 8.91; found C 72.40, H pyrrole (46): 1H NMR (200 MHz, CDCl3): δ = 1.30 (t, J = 7 Hz, 3
8.32, N 8.93.
H, Me), 2.42–2.61 (m, 6 H, CH2), 3.66 (s, 3 H, COOMe), 3.86 (s,
Eur. J. Org. Chem. 2005, 5277–5288
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Minetto, L. F. Raveglia, A. Sega, M. Taddei
3 H, OMe), 4.38 (s, 2 H, CH2Ar), 6.44 (s, 1 H, 4-H), 6.81 (d-like, = 0.61 and 0.66 (2 s, 6 H, 2 Me), 1.73 (m, 1 H, CH), 3.06 (t, J =
FULL PAPER
2 H, Ar), 6.88 (d-like, 2 H, Ar), 7.20 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.2, 19.3, 30.8, 36.0, 45.5, 50.6, 55.2, 106.2,
11.18, 114.0, 126.5, 128.1, 128.5, 129.6, 129.8, 134.5, 136.6, 139.2,
158.5, 166.9 ppm. ES/MS: m/z = 378 [M + 1]+. C24H27NO3: calcd.
C 76.36, H 7.21, N 3.71; found C 76.21, H 7.18, N 3.72.
8 Hz, 2 H, CH2-pyrrole), 3.63 (s, 3 H, COOMe), 4.00 (d, J = 8 Hz,
2 H, CH2–N), 4.35 (t, J = 8 Hz, 2 H, CH2NHCbz), 5.16 (s, 2 H,
OCH2Ph), 6.10 (br. s, 1 H, NH), 7.20–7.40 (m, 10 H, Ar) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 11.0, 15.3, 31.9, 33.7, 45.6, 48.6, 51.9,
71.3, 103.6, 111.9, 126.7, 127.0, 127.5, 127.6, 128.0, 128.7, 131.5,
131.6, 133.6, 137.4, 138.7, 156.7, 164.4 ppm. ES/MS: m/z = 415 [M
+ 1]+. C26H30N2O4: calcd. C 71.87, H 6.96, N 6.45; found C 71.69,
H 6.93, N 6.43.
5-Ethyl-3-(methoxycarbonyl)-1-(2-morpholinoethyl)-2-propylpyrrole
(47): 1H NMR (200 MHz, CDCl3): δ = 0.93 (t, J = 7 Hz, 3 H, Me),
1.21–1.58 (m, 5 H, CH2), 2.41–2.64 (m, 8 H, CH2), 2.85 (t, J =
7 Hz, 2 H, CH2), 3.65 (s, 3 H, COOMe), 3.87 (t, J = 7 Hz, 6 H,
CH2), 6.21 (s, 1 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
12.2, 19.3, 30.8, 36.0, 45.5, 51,4, 55.4, 66.8, 103.4, 111.8, 126.6
136.7, 166.4 ppm. ES/MS: m/z = 309 [M + 1]+. C17H28N2O3: calcd.
C 66.20, H 9.15, N 9.08; found C 66.44, H 9.12, N 9.04.
3-(Methoxycarbonyl)-5-methyl-1-(2-picolyl)-2-propylpyrrole (54): 1H
NMR (200 MHz, CDCl3): δ = 0.92 (t, J = 7 Hz, 3 H, Me), 1.70
(m, 2 H, CH2), 2.11 (s, 3 H, Me), 2.76 (t, J = 7 Hz, 2 H, CH2),
3.66 (s, 3 H, COOMe), 5.10 (s, 2 H, CH2N), 6.45 (d, 1 H, 4-H),
7.40 (m, 2 H, Ar), 7.86 (m, 1 H, Ar), 8.34 (d-like, 1 H, CH-pyridine)
ppm. 13C NMR (75 MHz, CDCl3): δ = 12.4, 22.5, 34.6, 37.8, 45.6,
56.7, 106.6, 112.3, 120.5, 126.5, 127.9, 129.8, 135.6, 148.6,
151.2 ppm. C16H20N2O2: calcd. C 70.56, H 7.40, N 10.29; found C
70.48, H 7.37, N 10.25.
3-(Methoxycarbonyl)-5-phenyl-1-(2-phenylpropyl)-2-propylpyrrole
(48): 1H NMR (200 MHz, CDCl3): δ = 1.04 (t, J = 7 Hz, 3 H, Me),
1.59 (m, 2 H, CH2), 2.69 (t, J = 7 Hz, 2 H, CH2), 2.97 (t, J = 7 Hz,
2 H, CH2), 3.65 (s, 3 H, COOMe), 4.19 (t, J = 7 Hz, 2 H, CH2N),
6.61 (s, 1 H, 4-H), 6–80–7.50 (m, 10 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.7, 19.6, 30.8, 36.8, 41.2, 46.9, 106.8,
116.3, 125.6, 126.2, 126.8, 128.7, 128.9, 128.9, 129.9, 134.4, 134.8,
137.3, 167.2 ppm. ES/MS: m/z = 347 [M + 1]+. C23H25NO2: calcd.
C 79.51, H 7.25, N 4.03; found C 79.67, H 7.21, N 4.04.
3-(Methoxycarbonyl)-5-methyl-1-(2-methylpropyl)-2-propylpyrrole
(55): 1H NMR (200 MHz, CDCl3): δ = 0.60 and 0.64 (d, J = 7 Hz,
6 H, 2 Me), 0.89 (t, J = 7 Hz, 3 H, Me), 1.68 (m, 3 H, CH and
CH2), 2.02 (s, 3 H, Me), 3.01, (t, J = 7 Hz, 2 H, CH2), 3.65 (s, 3
H, COOMe), 4.01 (d, J = 8 Hz, 2 H, CH2N), 6.65 (s, 1 H, 4-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 11.4, 11.4, 12.8, 22.5, 26.4,
33.6, 37.8, 46.7, 50.7, 106.6, 112.3, 120.5, 126.5, 166.2 ppm. ES/
MS: m/z = 238 [M + 1]+. C14H23NO2: calcd. C 70.85, H 9.77, N
5.90; found C 70.88, H 9.76, N 5.90.
1
2-Benzyl-3-(methoxycarbonyl)-1,5-diphenylpyrrole (49): H NMR
(200 MHz, CDCl3): δ = 3.60 (s, 3 H, COOMe), 3.99 (s, 2 H, CH2),
6.62 (s, 1 H, 4-H), 7.00–7.40 (m, 15 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 36.0, 46.9, 107.8, 112.3, 124.6, 126.2, 126.4,
126.8 (4 C), 127.3, 127.8, 128.0, 128.7, 128.9, 128.9, 129.9, 134.4,
134.8, 137.3, 166.2 ppm. ES/MS: m/z = 368 [M + 1]+. C25H21NO2:
calcd. C 81.72, H 5.76, N 3.81; found C 81.75, H 5.79, N 3.79.
1
2-Benzyl-3-(methoxycarbonyl)-5-methyl-1-phenylpyrrole (56): H
NMR (200 MHz, CDCl3) 2.02 (s, 3 H, Me), 3.67 (s, 3 H, COOMe),
6.35 (s, 1 H, 4-H), 7.20–7.40 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.4, 46.7, 106.6, 112.3, 120.5, 126.5, 126.4, 127.0,
127.8, 128.3, 128.6, 128.9, 134.4, 135.6, 166.2 ppm. ES/MS: m/z =
292 [M + 1]+. C19H17NO2: calcd. C 78.33, H 5.88, N 4.81; found
C 78.40, H 5.90, N 4.79.
3-(Methoxycarbonyl)-1-(2-morpholinoethyl)-5-phenyl-2-propylpyr-
1
role (50): H NMR (200 MHz, CDCl3): δ = 0.95 (t, J = 7 Hz, 3 H,
Me), 1.69 (m, 2 H, CH2), 2.13 (t-like, 4 H, CH2N), 2.28 (t, J =
7 Hz, 2 H, CH2N), 2.93 (t, J = 7 Hz, 2 H, CH2-pyrrole), 3.48 (t-
like, 4 H, CH2O), 3.67 (s, 3 H, COOMe), 3.95 (t, J = 7 Hz, 2 H,
NCH2), 6.48 (s, 1 H, 4-H), 7.25 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.4, 23.8, 27.8, 41.7, 53.9, 56.1, 59.5, 66.0,
110.5, 112.1, 127.8, 128.7, 129.7, 133.4, 133.6, 141.3, 165.4 ppm.
ES/MS: m/z = 357 [M + 1]+. C21H28N2O3: calcd. C 70.76, H 7.92,
N 7.86; found C 70.85, H 7.90, N 7.82.
3-(Methoxycarbonyl)-5-methyl-1-(2-phenylethyl)-2-propylpyrrole
(57): 1H NMR (200 MHz, CDCl3): δ = 0.80 (t, J = 7 Hz, 3 H, Me),
1.67 (m, 2 H, CH2), 2.10 (s, 3 H, Me), 2.90 (t, J = 8 Hz, 2 H, CH2-
Ar), 3.01 (t, J = 7 Hz, 2 H, CH2), 3.65 (s, 3 H, COOMe), 3.97 (t,
J = 8 Hz, 2 H, CH2N), 6.46 (s, 1 H, 4-H), 7.25 (m, 5 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.4, 20.7, 26.4, 46.7, 50.4, 56.9,
106.6, 112.3, 120.5, 126.5, 127.0, 128.3, 128.9, 134.4, 166.2 ppm.
ES/MS: m/z = 286 [M + 1]+. C18H23NO2: calcd. C 75.76, H 8.12,
N 4.91; found C 75.60, H 8.11, N 4.89.
1-Benzyl-2-(p-chlorophenyl)-3-(methoxycarbonyl)-5-phenylpyrrole
(51): 1H NMR (200 MHz, CDCl3): δ = 3.61 (s, 3 H, COOMe), 3.90
(s, 2 H, CH2), 6.64 (s, 1 H, 4-H), 7.00–7.50 (m, 14 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 35.7, 48.2, 107.8, 112.0, 124.7,
126.6, 126.5, 126.7, 126.8, 127.0, 127.3, 127.8, 128.4, 128.6, 128.7,
129.0, 129.5, 134.7, 135.2, 138.3, 166.2 ppm. ES/MS: m/z = 402
and 404 [M + 1]+. C25H20ClNO2: calcd. C 74.71, H 5.02, N 3.49;
found C 74.65, H 5.09 N 3.51.
1-Benzyl-2-[2-(benzyloxycarbonylamino)-3-phenylpropyl]-3-(meth-
1
oxycarbonyl)-5-methylpyrrole (58): H NMR (200 MHz, CDCl3): δ
= 2.05 (s, 3 H, Me), 3.04 (AB part of an ABX system, 2 H, CH2-
Ar), 3.33 (AB part of an ABX system, 2 H, CH2-pyrrole), 3.65 (s,
3 H, COOMe), 4.51 (m, 1 H, CHNHCbz), 4,88 (s, 2 H, CH2–N),
5.12 (s, 2 H, OCH2Ph), 6.21 (br. s, 1 H, NH), 6.45 (s, 1 H, 4-H),
7.30 (m, 15 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.7,
15.2, 24.3, 28.5, 33.4, 41.7, 44.6, 49.6, 52.7, 70.9, 103.4, 111.8,
126.3, 127.4 (2 C), 127.6 (2 C), 128.6, 128.7, 128.9, 131.6, 133.6,
135.7, 134.6, 137.4, 138.7, 155.7, 165.4 ppm. ES/MS: m/z = 497 [M
+ 1]+. C31H32N2O4: calcd. C 74.98, H 6.50, N 5.64; found C 74.89,
H 6.47, N 5.60.
2-Benzyl-1-[2-(3,4-dimethoxyphenyl)ethyl]-3-(methoxycarbonyl)-5-
1
phenylpyrrole (52): H NMR (200 MHz, CDCl3): δ = 2.48 (t, J =
8 Hz, 2 H, CH2-Ar), 2.55 (t, J = 8 Hz, 2 H, CH2-Ar), 3.01 (t, J =
8 Hz, 2 H, CH2-pyrrole), 3.66 (s, 3 H, COOMe), 3.70 (s, 3 H,
OMe), 3.72 (s, 3 H, OMe), 4.02 (t, J = 8 Hz, 2 H, CH2–N), 6.59
(s, 1 H, 4-H), 6.80 (m, 3 H, Ar), 7.10–7.30 (m, 10 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 26.4, 38.9, 41.5, 45.6, 50.3, 56.9, 58.7,
106.7, 112.0, 112.6, 113.6, 121.0, 124.6, 126.0, 126.5, 127.3, 127.6,
128.3, 128.9, 134.6, 134.6, 135.0, 145.6, 147.6, 166.7 ppm. ES/MS:
m/z = 470 [M + 1]+. C30H31NO4: calcd. C 76.73, H 6.65, N 2.98,
found C 76.66, H 6.63, N 2.97.
1-Benzyl-2-[2-(benzyloxycarbonylamino)ethyl]-3-(methoxycarbonyl)-
5-methylpyrrole (59): 1H NMR (200 MHz, CDCl3): δ = 2.10 (s, 3
H, Me), 3.13 (t, J = 7 Hz, 2 H, CH2-pyrrole), 3.65 (s, 3 H, CO-
OMe), 4.33 (t, J = 8 Hz, 2 H, CH2NHCbz), 4.71 (s, 2 H, CH2–N),
2-[2-(Benzyloxycarbonylamino)ethyl]-3-(methoxycarbonyl)-1-(2- 5.11 (s, 2 H, OCH2Ph), 6.11 (br. s, 1 H, NH), 6.60 (s, 1 H, 4-H),
methylpropyl)-5-phenylpyrrole (53): 1H NMR (200 MHz, CDCl3): δ 7.30 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.2,
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Microwave-Assisted Paal–Knorr Reaction
FULL PAPER
15.3, 26.5, 30.9, 33.4, 40.7, 44.6, 52.7, 70.9, 103.4, 111.8, 126.3,
127.4, 127.6, 128.6, 128.7, 131.6, 133.6, 134.6, 137.4, 138.7, 155.7,
165.4 ppm. ES/MS: m/z = 407 [M + 1]+. C24H26N2O4: calcd. C
70.92, H 6.45, N 6.89; found C 70.80, H 6.41, N 6.88.
111.0, 126.4, 126.8, 126.9, 127.4, 127.6, 128.3, 128.4, 134.2, 134.8,
136.0, 158.4, 167.2 ppm. ES/MS: m/z = 490 [M + 1]+. C30H38N2O4:
calcd. C 73.44, H 7.81, N 5.71; found C 73.51, H 7.84, N 5.73.
1-[2-(Benzyloxycarbonylamino)propyl]-5-tert-butyl-3-(methoxycar-
1
2-[2-(Benzyloxycarbonylamino)ethyl]-3-(methoxycarbonyl)-
5-methyl-1-(2-methylpropyl)pyrrole (60): 1H NMR (200 MHz,
CDCl3): δ = 0.60 and 0.71 (d, J = 7 Hz, 6 H, Me2), 1.78 (m, 1 H,
CHMe2), 2.10 (s, 3 H, Me), 3.18 (t, J = 7 Hz, 2 H, CH2-pyrrole),
3.65 (s, 3 H, COOMe), 4.33 (d, J = 7 Hz, 2 H, CH2NHCbz) 4.51
(d, J = 7 Hz, 2 H, CH2–N), 5.11 (s, 2 H, OCH2Ph), 6.11 (br. s, 1
bonyl)-2-propylpyrrole (69): H NMR (200 MHz, CDCl3): δ = 0.87
(t, J = 7 Hz, 3 H, Me), 0.91 (d, J = 7 Hz, 3 H, Me), 1.30 (s, 9 H,
tBu), 1.87 (m, 2 H, CH2), 3.06 (t, J 0 = 7 Hz, 2 H, CH2-pyrrole),
3.58 (s, 3 H, COOMe), 4.11 (m, 2 H, CH2N), 4.37 (m, 1 H, CHN),
5.20 (s, 2 H, OCH2), 6.18 (br. s, 1 H, NH), 6.43 (s, 1 H, 4-H), 7.25
(m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.4, 13.6,
H, NH), 6.60 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar) ppm. 13C NMR 21.6, 29.5, 30.9, 31.6, 34.7, 55.6, 58.7, 70.3, 103.5, 111.9, 126.4,
(75 MHz, CDCl3): δ = 11.2, 15.3, 26.5, 30.9, 33.4, 40.7, 44.6, 52.7,
70.9, 103.4, 111.8, 126.3, 127.6, 128.6, 131.6, 133.6, 134.5,
165.4 ppm. ES/MS: m/z = 373 [M + 1]+. C21H28N2O4: calcd. C
67.72, H 7.58, N 7.52; found C 67.79, H 7.54, N 7.56.
126.8, 127.6, 128.3, 134.2, 135.0, 158.4, 165.2 ppm. ES/MS: m/z =
415 [M + 1]+. C24H34N2O4: calcd. C 69.54, H 8.27, N 6.76; found
C 69.59, H 8.28, N 6.77.
1-[2-(Benzyloxycarbonylamino)ethyl]-5-ethyl-3-(methoxycarbonyl)-
1-[2-(Benzyloxycarbonylamino)ethyl]-5-tert-butyl-3-(methoxycar-
2-propylpyrrole (70): 1H NMR (200 MHz, CDCl3): δ = 0.88 (t, J =
bonyl)-2-phenylpyrrole (64): 1H NMR (200 MHz, CDCl3): δ = 1.36 8 Hz, 3 H, Me), 0.91 (t, J = 8 Hz, 3 H, Me), 1.65 (m, 2 H, CH2),
(s, 9 H, tBu), 3.65 (s, 3 H, COOMe), 4.01 (t, J = 8 Hz, 2 H, CH2N),
4.37 (t, J = 8 Hz, 2 H, CH2N), 5.12 (s, 2 H, OCH2), 6.10 (br. s, 1
2.78 (q, J = 8 Hz, 2 H, CH2-pyrrole), 3.07 (t, J = 7 Hz, 2 H, CH2-
pyrrole), 3.60 (s, 3 H, COOMe), 4.18 (t, J = 8 Hz, 2 H, CH2N),
H, NH), 6.48 (s, 1 H, 4-H), 7.20–7.35 (m, 10 H, Ar) ppm. 13C 4.30 (t, J = 8 Hz, 2 H, CH2N), 5.19 (s, 2 H, OCH2), 6.00 (br. s, 1
NMR (75 MHz, CDCl3): δ = 29.5, 30.9, 46.7, 54.6, 58.7, 70.9, H, NH), 6.27 (s, 1 H, 4-H), 7.32 (m, 5 H, Ar) ppm. 13C NMR
103.4, 111.8, 126.3, 126.8, 127.4, 128.3, 134.2, 136.3, 158.7, (75 MHz, CDCl3): δ = 11.1, 14.5, 28.4, 30.4, 43.6, 44.7, 54.6, 58.9,
165.8 ppm. ES/MS: m/z = 435 [M + 1]+. C26H30N2O4: calcd. C
71.87, H 6.96, N 6.45; found C 71.49, H 6.99, N 6.46.
70.4, 104.4, 110.6, 126.3, 126.8, 127.4, 128.3, 134.2, 136.3, 155.8,
167.8 ppm. ES/MS: m/z = 372 [M + 1]+. C21H28N2O4: calcd. C
67.72, H 7.58, N 7.52; found C 67.66, H 7.56, N 7.51.
1-[2-(Benzyloxycarbonylamino)-3-phenylpropyl]-5-tert-butyl-3-
(methoxycarbonyl)-2-phenylpyrrole (65): 1H NMR (200 MHz,
CDCl3): δ = 1.30 (s, 9 H, tBu), 2.96 (m, 2 H, ArCH2), 3.66 (s, 3 H,
COOMe), 4.11 (m, 2 H, CH2N), 4.47 (m, 1 H, CHN), 5.11 (s, 2 H,
5-tert-Butyl-3-(methoxycarbonyl)-2-phenylfuran (71): Product 6
(0.5 g, 1,64 mmol) was dissolved in EtOH (2 mL) in a 50-mL
round-bottomed flask, equipped with a stirrer bar and a reflux
OCH2), 6.11 (br. s, 1 H, NH), 6.55 (s, 1 H, 4-H), 7.20–7.50 (m, 15 condenser. HCl (0.1 mL of a 37% solution) was added, and the
H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.5, 30.9, 32.6,
46.0, 54.6, 59.7, 70.9, 103.5, 111.0, 126.4, 126.8, 126.9, 127.4, 127.6,
128.3, 128.4, 134.2, 134.8, 136.0, 158.4, 167.2 ppm. ES/MS: m/z =
525 [M + 1]+. C33H36N2O4: calcd. C 75.55, H 6.92, N 5.34; found
C 75.59, H 6.99, N 5.37.
flask was inserted into the cavity of a Discovery Microwave System
apparatus (from CEM) and heated at 150 W for 4 min (internal
temperature 100 °C). The mixture was diluted with AcOEt, and
the solution was washed several times with a saturated solution of
NaHCO3. The organic layer was dried with anhydrous Na2SO4,
and the solvent was evaporated. The 1H NMR spectrum of the
crude showed the presence of pure furan 71 that could eventually
be further purified by flash chromatography (eluent hexane/AcOEt,
8:1; Rf = 0.75) to give the product (0.49 g, 95% yield). It was iden-
tified by comparison with reported data.[23]
1-[2-(Benzyloxycarbonylamino)propyl]-5-tert-butyl-3-(methoxycar-
bonyl)-2-phenylpyrrole (66): 1H NMR (200 MHz, CDCl3): δ = 0.93
(d, J = 7 Hz, 3 H, Me), 1.30 (s, 9 H, tBu), 3.56 (s, 3 H, COOMe),
4.01 (m, 2 H, CH2N), 4.33 (m, 1 H, CHN), 5.15 (s, 2 H, OCH2),
6.11 (br. s, 1 H, NH), 6.50 (s, 1 H, 4-H), 7.20 (m, 10 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.6, 29.5, 30.9, 31.6, 55.6, 58.7,
70.3, 103.5, 111.9, 126.4, 126.8, 127.6, 128.3, 134.2, 135.0, 158.4,
165.2 ppm. ES/MS: m/z = 449 [M + 1]+. C27H32N2O4: calcd. C
72.30, H 7.19, N 6.25; found C 72.59, H 7.18, N 6.27.
1
5-tert-Butyl-3-(methoxycarbonyl)-2-(2-phenylethyl)furan (72): H
NMR (200 MHz, CDCl3): δ = 1.10 (s, 9 H, tBu), 2.8 (t, J = 7 Hz,
2 H, CH2Ar), 3.18 (t, J = 7 Hz, 2 H, CH2-furan), 3.60 (s, 3 H,
COOMe), 6.98 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 29.6, 30.3, 34.5, 38.4, 57.8, 106.8, 118.2,
120.5, 126.6, 127.6, 127.8, 130.8, 134.7, 166.6 ppm. ES/MS: m/z =
287 [M + 1]+. C18H22O3: C 75.50, H 7.74; found C 75.30, H 7.74.
1-[2-(Benzyloxycarbonylamino)ethyl]-5-tert-butyl-3-(methoxycar-
1
bonyl)-2-propylpyrrole (67): H NMR (200 MHz, CDCl3): δ = 0.86
(t, J = 8 Hz, 3 H, Me), 1.36 (s, 9 H, tBu), 1.79 (m, 2 H, CH2), 3.07
(t, J = 7 Hz, 2 H, CH2-pyrrole), 3.60 (s, 3 H, COOMe), 4.08 (t, J 3-(Methoxycarbonyl)-5-methyl-2-propylfuran (73): 1H NMR
= 8 Hz, 2 H, CH2N), 4.37 (t, J = 8 Hz, 2 H, CH2N), 5.10 (s, 2 H,
(200 MHz, CDCl3): δ = 0.87 (t, J = 7 Hz, 3 H, Me), 1.19 (m, 2 H,
OCH2), 6.19 (br. s, 1 H, NH), 6.58 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar) CH2), 2.67 (s, 3 H, Me), 3.00 (t, J = 7 Hz, 2 H, CH2-furan), 3.56
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.5, 28.4, 29.5, 31.4, 43.6,
44.7, 54.6, 58.9, 70.4, 104.4, 110.6, 126.3, 126.8, 127.4, 128.3, 134.2,
136.3, 155.8, 167.8 ppm. ES/MS: m/z = 401 [M + 1]+. C23H32N2O4:
calcd. C 68.97, H 8.05, N 6.99; found C 70.04, H 8.09, N 7.00.
(s, 3 H, COOMe), 7.00 (s, 1 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.3, 28.9, 30.7, 39.7, 108.8, 119.2, 121.5, 135.7,
165.6 ppm. ES/MS: m/z = 183 [M + 1]+. C10H14O3: calcd. C 65.91,
H 7.74; found C 65.80, H 7.73.
1-[2-(Benzyloxycarbonylamino)-3-phenylpropyl]-5-tert-butyl-3- 5-tert-Butyl-3-(methoxycarbonyl)-2-phenylthiophene (74): Lawes-
(methoxycarbonyl)-2-propylpyrrole (68): 1H NMR (200 MHz,
CDCl3): δ = 0.90 (t, J = 7 Hz, 3 H, Me), 1.30 (s, 9 H, tBu), 1.80
son’s reagent (4.0 g) was added to a solution of compound 6 (1.0 g,
3.62 mmol) in toluene (10 mL), and the mixture was heated under
(m, 2 H, CH2), 2.90 (m, 2 H, ArCH2), 3.03 (t, J = 8 Hz, 2 H, CH2- microwave irradiation at 150 W (open vessel in the cavity of a Dis-
pyrrole), 3.65 (s, 3 H, COOMe), 4.11 (m, 2 H, CH2N), 4.47 (m, 1 cover apparatus) for 6 min. After cooling, the mixture was filtered
H, CHN), 5.11 (s, 2 H, OCH2), 6.11 (br. s, 1 H, NH), 6.55 (s, 1 H, through Celite, the solvent was evaporated, and the product was
4-H), 7.20–7.50 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.4, 17.9, 29.5, 30.9, 32.6, 36.4, 46.0, 54.6, 59.7, 70.9, 103.5,
isolated by column chromatography on silica gel (eluent hexane/
AcOEt, 3:1) to give the product (0.82 g, 70 % yield). 1H NMR
Eur. J. Org. Chem. 2005, 5277–5288
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5285

G. Minetto, L. F. Raveglia, A. Sega, M. Taddei
FULL PAPER
(200 MHz, CDCl3): δ = 1.13 (s, 9 H, tBu), 3.52 (s, 3 H, COOMe),
7 Hz, 6 H, Me), 1.25 (s, 9 H, tBu), 1.72 (m, 1 H, CH), 3.75 (d, J
7.30 (m, 6 H, Ar + 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = = 8 Hz, 2 H, N–CH2), 6.51 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar), 10.4
29.4, 31.3, 53.8, 108.8, 120.2, 123.3, 126.6, 127.6, 127.8, 130.8,
135.7, 167.5 ppm. ES/MS: m/z = 275 [M + 1]+. C16H18O2S: calcd.
C 70.04, H 6.61; found C 70.08, H 6.63.
(br. s, 1 H, COOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.9,
16.0, 29.5, 31.0, 31.7, 32.4, 44.6, 103.4, 111.8, 127.6, 128.7, 131.6,
133.6, 137.4, 138.7, 164.4 ppm. ES/MS: m/z = 298 [M – 1]+.
C19H25NO2: C 76.22, H 8.42, N 4.68; found C 76.37, H 8.40, N
4.63.
5-tert-Butyl-3-(methoxycarbonyl)-2-(2-phenylethyl)thiophene (75):
1H NMR (200 MHz, CDCl3): δ = 1.11 (s, 9 H, tBu), 2.87 (t, J =
7 Hz, 2 H, CH2Ar), 3.22 (t, J = 7 Hz, 2 H, CH2-furan), 3.65 (s, 3
H, COOMe), 7.13 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.6, 31.3, 36.5, 39.4, 57.8, 116.8, 120.2,
121.5, 126.6, 127.6, 127.8, 130.8, 135.7, 164.9 ppm. ES/MS: m/z =
287 [M + 1]+. C18H22O2S: calcd. C 71.48, H 7.33; found C 71.29,
H 7.34.
5-tert-Butyl-3-(methoxycarbonyl)-2-propylthiophene (76): 1H NMR
(200 MHz, CDCl3): δ = 0.76 (t, J = 7 Hz, 3 H, Me), 1.10 (s, 9 H,
tBu), 1.67 (t, J = 7 Hz, 2 H, CH2), 3.32 (t, J = 7 Hz, 2 H, CH2),
3.55 (s, 3 H, COOMe), 7.10 (s, 1 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.5, 28.6, 29.9, 31.3, 37.5, 57.8, 107,3, 120.2, 121.5,
135.7, 164.9 ppm. ES/MS: m/z = 241 [M + 1]+. C13H20O2S: C
64.96, H 8.39, found C 64.88, H 8.34.
1-(2-Methylpropyl)-5-phenyl-2-propylpyrrole-3-carboxylic Acid (82):
1H NMR (200 MHz, CDCl3): δ = 0.98 and 1.04 (2 d, J = 6 Hz, 6
H, 2 Me), 1.11 (t, J = 7 Hz, 3 H, Me), 1.59 (m, 2 H, CH2), 2.69 (t,
J = 7 Hz, 2 H, CH2), 2.97 (t J = 7 Hz, 2 H, CH2), 4.19 (t, J =
7 Hz, 2 H, CH2N), 6.61 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar), 10.3 (br.
s, 1 H, COOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.7, 19.6,
30.8, 36.8, 41.2, 106.8, 116.3, 125.6, 126.2, 126.8, 128.7, 128.9,
128.9, 129.9, 134.4, 134.8, 137.3, 167.2 ppm. ES/MS: m/z = 284
[M – 1]+. C18H23NO2: calcd. C 79.76, H 8.12, N 4.91; found C
79.69, H 8.11, N 4.94.
1
5-tert-Butyl-2-phenylthiophene-3-carboxylic Acid (83): H NMR
(200 MHz, CDCl3): δ = 1.13 (s, 9 H, tBu), 7.30 (m, 6 H, Ar + 4-
H) 11.0 (br. s, 1 H, COOH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 29.4, 31.3, 108.8, 120.2, 123.3, 126.6, 127.6, 127.8, 130.8, 135.7,
167.5 ppm. ES/MS: m/z = 259 [M – 1]+. C15H16O2S: calcd. C 69.20,
H 6.19; found C 69.18, H 6.16.
5-Methyl-2-propylthiophene-3-carboxylic Acid (84): 1H NMR
(200 MHz, CDCl3): δ = 0.90 (t, J = 7 Hz, 3 H, Me), 1.28 (m, 2 H,
CH2), 2.33 (s, 3 H, Me), 3.09 (t, J = 7 Hz, 2 H, CH2-furan), 7.23
(s, 1 H, 4-H), 9.98 (br. s, 1 H, COOH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.3, 29.6, 30.7, 38.1, 109.8, 120.2, 121.9, 135.7,
165.6 ppm. ES/MS: m/z = 183 [M – 1]+. C9H12O2S: calcd. C 58.67,
H 6.56; found C 58.50, H 6.53.
3-Amino-1-butyl-5-tert-butyl-2-(p-chlorophenyl)pyrrole (85): 1H
NMR (200 MHz, CDCl3): δ = 0.67 (t, J = 7 Hz, 3 H, Me), 0.96–
1.19 (m, 2 H, CH2), 1.25–1.33 (m, 2 H, CH2), 1.36 (s, 9 H, tBu),
3.80 (t, J = 8 Hz, 2 H, N–CH2),3.77 (br. s, 2 H, NH2) 6.22 (s, 1 H,
4-H), 7.20 (d-like, 2 H, Ar), 7.36 (d-like, 2 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.7, 19.2, 29.5, 30.2, 31.7, 32.5, 45.0, 106.4,
110.8, 127.6, 128.7, 131.6, 133.6, 137.4, 140.9, 162.4 ppm. ES/MS:
m/z = 305–307 [M + 1]+. C18H25ClN2: calcd. C 70.92, H 8.27, N
9.19; found C 70.83, H 8.21, N 9.21.
1
3-(Methoxycarbonyl)-5-methyl-2-propylthiophene (77): H NMR
(200 MHz, CDCl3): δ = 0.89 (t, J = 7 Hz, 3 H, Me), 1.25 (m, 2 H,
CH2), 2.33 (s, 3 H, Me), 3.09 (t, J = 7 Hz, 2 H, CH2-furan), 3.50
(s, 3 H, COOMe), 7.23 (s, 1 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.3, 29.6, 30.7, 38.1, 56.7, 109.8, 120.2, 121.9, 135.7,
165.6 ppm. ES/MS: m/z = 199 [M + 1]+. C10H14O2S: calcd. C 60.57,
H 7.12;, found C 60.39, H 7.13.
1
3-(Methoxycarbonyl)-5-phenyl-2-propylthiophene (78): H NMR
(200 MHz, CDCl3): δ = 0.80 (t, J = 7 Hz, 3 H, Me), 1.22 (m, 2 H,
CH2), 3.00 (t, J = 7 Hz, 2 H, CH2-furan), 3.50 (s, 3 H, COOMe),
7.30 (s, 6 H, Ar, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.3,
28.6, 34.1, 56.7, 109.8, 120.2, 121.9, 126.2, 127.7, 128.9, 134.3,
135.7, 165.6 ppm. ES/MS: m/z = 261 [M + 1]+. C15H16O2S: calcd.
C 69.20, H 6.19, found C 69.10, H 6.13.
1-Butyl-5-tert-butyl-2-(p-chlorophenyl)pyrrole-3-carboxylic Acid
(79). General Procedure for Acids: Pyrrole 32 (0.1 g, 0.28 mmol)
was dissolved in a solution of EtOH (5 mL) that contained NaOH
(50 mg, 1.25 mmol). The mixture was stirred at room temperature
for 12 h. The solvent was evaporated, and HCl (5% in H2O, 2 mL)
was added. The aqueous layer was extracted three times with
EtOAc, the fractions were collected, and the solvent was evapo-
rated to give product 79, which was practically pure (89 mg, 96%
yield). An analytical sample was isolated by column chromatog-
raphy on silica gel (eluent EtOAc/hexane, 3:1). 1H NMR
(200 MHz, CDCl3): δ = 0.67 (t, J = 7 Hz, 3 H, Me), 0.96–1.17 (m,
2 H, CH2), 1.25–1.30 (m, 2 H, CH2), 1.36 (s, 9 H, tBu), 3.89 (t, J
= 8 Hz, 2 H, N–CH2), 6.42 (s, 1 H, 4-H), 7.20 (d-like, 2 H, Ar),
7.36 (d-like, 2 H, Ar), 10.2 (br. s, 1 H, COOH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.7, 19.2, 29.5, 30.2, 31.7, 32.5, 45.0, 106.4,
110.8, 127.6, 128.7, 131.6, 133.6, 137.4, 140.9, 162.4 ppm. ES/MS:
m/z = 333–335 [M + 1]+. C19H24ClNO2: calcd. C 68.35, H 7.25, N
4.20; found C 68.27, H 7.21, N 4.21.
N,1-Dibenzyl-5-tert-butyl-2-phenylpyrrole-3-carboxamide (86):
Compound 79 (0.15 g, 0.45 mmol) was dissolved in dry toluene
(2 mL) under nitrogen, and DPPA (0.34 g, 1.24 mmol) was added
to this solution followed by Et3N (0.26 mL). The mixture was
heated to reflux for 2 h, then cooled, and H2O (1.3 mL) was added.
The mixture was heated further to reflux for 2 h, and the solvent
was evaporated under vacuum. Column chromatography on silica
gel (eluent EtOAc/hexane, 3:1) gave product 86 (0.91 g, 67% yield).
1H NMR (200 MHz, CDCl3): δ = 1.14 (s, 9 H, tBu), 4.56 (s, 2 H,
CH2), 5.16 (s, 2 H, CH2), 6.56 (s, 1 H, 4-H), 7.10–7.50 (m, 16 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 28.7, 32.2, 49.3, 55.6, 107.1,
112.4, 125.4, 126.8, 127.5, 127.9, 128.2, 130.5, 132.1, 138.9, 140.6,
142.3, 166.7 ppm. ES/MS: m/z = 423 [M + 1]+. C29H30N2O: calcd.
C 82.43, H 7.16, N 6.63; found C 82.46, H 7.12, N 6.60.
1-Benzyl-5-tert-butyl-2-(2-phenylethyl)pyrrole-3-carboxylic Acid
1
(80): H NMR (200 MHz, CDCl3): δ = 1.23 (s, 9 H, tBu), 2.71 (t,
1-Benzyl-5-tert-butyl-N-[2-(p-methoxyphenyl)ethyl]-2-phenylpyrrole-
3-carboxamide (87): 1H NMR (200 MHz, CDCl3): δ = 1.16 (s, 9 H,
tBu), 2,09 (t, J = 7 Hz, 2 H, CH2Ar), 3.66 (s, 3 H, OMe), 4.06 (t,
J = 7 Hz, 2 H), 5.16 (s, 2 H, CH2), 6.56 (s, 1 H, 4-H), 7.10–7.50
(m, 15 H, Ar and NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
28.7, 32.2, 49.3, 51.4, 56.6, 60.6, 107.1, 112.4, 125.4, 126.8, 127.5,
127.9, 128.2, 130.5, 132.1, 138.9, 140.6, 142.3, 166.7 ppm. ES/MS:
m/z = 467 [M + 1]+. C31H34N2O: calcd. C 79.79, H 7.34, N 6.00;
found C 79.69, H 7.32, N 6.58.
J = 8 Hz, 2 H, CH2), 3.20 (t, J = 8 Hz, 2 H,CH2), 4.90 (s, 2 H,
CH2N), 6.41 (s, 1 H, 4-H), 7.20–7.35 (m, 10 H, Ar), 10.3 (br. s, 1
H, COOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.5, 31.7, 37.8,
41.6, 45.9, 104.4, 112.8, 126.9, 126.6, 128.6, 128.7, 129.3, 131.6,
133.6, 137.4, 165.4 ppm. ES/MS: m/z = 366 [M – 1]+. C24H27NO2:
calcd. C 79.74, H 7.53, N 3.87; found C 79.80, H 7.54, N 3.89.
5-tert-Butyl-1-(2-methylpropyl)-2-phenylpyrrole-3-carboxylic Acid
(81): 1H NMR (200 MHz, CDCl3): δ = 0.60 and 0.69 (2 d, J =
5286
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Eur. J. Org. Chem. 2005, 5277–5288

Microwave-Assisted Paal–Knorr Reaction
FULL PAPER
1-Benzyl-5-tert-butyl-N-(2-morpholinoethyl)-2-phenylpyrrole-3-car-
5-Methyl-N-(2-morpholinoethyl)-2-propylthiophene-3-carboxamide
boxamide (88): 1H NMR (200 MHz, CDCl3): δ = 1.16 (s, 9 H, tBu), (95): 1H NMR (200 MHz, CDCl3): δ = 0.89 (t, J = 7 Hz, 3 H, Me),
2,29 (t, J = 7 Hz, 2 H, CH2N), 2.67 (m, 4 H, CH2N), 3.60 (m, 4 1.25 (m, 2 H, CH2), 2.33 (s, 3 H, Me), 2.86 (m, 2 H, CH2N), 3.02
H, CH2O), 4.00 (t, J = 7 Hz, 2 H, CH2), 5.16 (s, 2 H, CH2), 6.56
(s, 1 H, 4-H), 7.10–7.50 (m, 11 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.7, 32.2, 36.8, 44.8, 49.3, 51.4, 60.6, 107.1, 112.4,
125.4, 126.8, 127.5, 127.9, 128.2, 130.5, 132.1, 138.9, 140.6, 142.3,
(m, 4 H, CH2N), 3.09 (t, J = 7 Hz, 2 H, CH2-thiophene), 3.80 (m,
4 H, CH2O), 4.01 (m, 2 H, CH2N), 7.19 (br. s, 1 H, NH), 7.23 (s,
1 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3, 29.6, 30.7,
38.1, 40.5, 46.9, 55.9, 58.7, 109.8, 120.2, 121.9, 135.7, 165.6 ppm.
166.7 ppm. ES/MS: m/z = 446 [M + 1]+. C28H35N2O3: C 75.47, H ES/MS: m/z = 297 [M + 1]+. C15H24N2O2S: calcd. C 60.78, H 8.16,
7.92, N 9.43; found C 75.39, H 7.90, N 9.40.
N 9.45; found C 60.69, H 8.13, N 9.41.
5-tert-Butyl-1-(2-methylpropyl)-3-(morpholinocarbonyl)-2-phenyl-
pyrrole (89): H NMR (200 MHz, CDCl3): δ = 0.60 and 0.69 (2 d,
N-(p-Methoxyphenyl)-5-methyl-2-propylthiophene-3-carboxamide
(96): 1H NMR (200 MHz, CDCl3): δ = 0.89 (t, J = 7 Hz, 3 H, Me),
1.25 (m, 2 H, CH2), 2.33 (s, 3 H, Me), 3.09 (t, J = 7 Hz, 2 H, CH2-
thiophene), 3.68 (s, 3 H, MeO), 6.87 (m, 2 H, Ar), 7.30 (m, 4 H,
Ar, 4-H and NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3,
30.7, 38.1, 55.9, 58.7, 109.8, 120.2, 121.9, 126.7, 128.3, 128.9, 133.2,
135.7, 165.6 ppm. ES/MS: m/z = 288 [M + 1]+. C16H19NO2S: calcd.
C 66.41, H 6.22, N 4.84; found C 66.35, H 6.26, N 4.80.
1
J = 7 Hz, 6 H, Me), 1.25 (s, 9 H, tBu), 1.72 (m, 1 H, CH), 3.60
(m, 4 H, CH2O), 3.75 (d, J = 8 Hz, 2 H, N–CH2), 4.01 (m, 4 H,
CH2N), 6.59 (s, 1 H, 4-H), 7.30 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 11.9, 16.0, 29.5, 31.0, 31.7, 32.4, 40.6, 44.6,
55.4, 103.4, 111.8, 127.6, 128.7, 131.6, 133.6, 137.4, 138.7,
164.4 ppm. ES/MS: m/z = 369 [M + 1]+. C23H32N2O2: C 74.96, H
8.75, N 7.60; found C 74.88, H 8.70, N 7.63.
Compound 97: Pyrrole 58 (0.1 g, 0.2 mmol) was dissolved in a solu-
tion of EtOH (5 mL) that contained NaOH (50 mg). The mixture
was stirred at room temperature for 12 h. The solvent was evapo-
rated, and HCl (5% in H2O, 2 mL) was added. The aqueous layer
was extracted three times with EtOAc, the extracts were combined,
and the solvent was evaporated. The crude was dissolved in THF
(5 mL), and HValOMe·HCl (35 mg, 0.2 mmol) was added to this
solution followed by DMTMM (82 mg, 0.3 mmol) and NMM
(60 mg, 0.6 mmol). The mixture was stirred at room temperature
for 12 h. The solid was filtered off, and the THF solution was di-
luted with EtOAc (5 mL) and washed with HCl (5 %, 10 mL),
Na2CO3 (10%, 10 mL) and brine. The organic layer was separated
and dried, and the solvent was evaporated. The product 97 was
isolated by column chromatography on silica gel (eluting with
EtOAc/hexane, 1:1) to yield 0.103 g, 89%. 1H NMR (600 MHz,
CDCl3): δ = 1.086 (d, J = 7 Hz, 3 H, MeAla), 2.086 (s, 3 H, Me),
3.144 (AB part of an ABX system, 2 H, CH2-Ar), 3.390 (AB part
of an ABX system, 2 H, CH2-pyrrole), 3.555 (s, 3 H, COOMe),
4.061 (AB system, 2 H, CH2N), 4.389 (qd, J = 7 and 12 Hz, 1 H,
CHN-Ala), 4.510 (m, 1 H, CHNHCbz), 4,885 (s, CH2–N), 5.122
(s, 2 H, OCH2Ph), 6.210 (br. s, 1 H, NH), 6.550 (s, 1 H, 4-H), 7.304
(m, 16 H, Ar and NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
15.2, 24.3, 33.4, 41.7, 44.6, 49.6, 52.7, 61.4, 103.4, 111.8, 126.3,
127.4, 127.6, 128.6, 128.7, 128.9, 131.6, 133.6, 135.7, 134.6, 138.7,
155.7, 165.4, 167.9 ppm. ES/MS: m/z = 568 [M + 1]+.
N,1-Dibenzyl-5-ethyl-2-phenylpyrrole-3-carboxamide (90): 1H NMR
(200 MHz, CDCl3): δ = 1.25 (t, J = 7 Hz, 3 H, Me), 2.45 (q, J =
7 Hz, 2 H, CH2-pyrrole), 3.98 (s, 2 H, CH2N), 4.97 (s, 2 H, CH2N),
6.60 (s, 1 H, 4-H), 6.84–7.43 (m, 16 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 11.9, 19.4, 47.3, 60.4, 106.8, 112.3, 125.3,
127.0, 127.6, 128.0, 128.5, 130.4, 131.8, 135.3, 137.7, 138.6,
165.3 ppm. ES/MS: m/z = 395 [M + 1]+. C27H26N2O: calcd. C
82.20, H 6.64, N 7.10; found C 82.11, H 6.59, N 7.13.
5-tert-Butyl-N-(3-methylpropyl)-2-phenylthiophene-3-carboxamide
(91): 1H NMR (200 MHz, CDCl3): δ = 0.89 and 0.92 (d, J = 8 Hz,
6 H, Me2), 1.13 (s, 9 H, tBu), 1.98 (m, 1 H, CH), 3,77 (m, 2 H,
CH2), 7.30 (m, 7 H, Ar + 4-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.9, 15.7, 29.4, 31.3, 36.8, 44.9, 108.8, 120.2, 123.3, 126.6,
127.6, 127.8, 130.8, 135.7, 167.5 ppm. ES/MS: m/z = 316
[M + 1]+. C19H25NOS: calcd. C 72.34, H 7.99, N 4.44; found C
72.28, H 7.95, N 4.42.
5-tert-Butyl-N-(2-morpholinoethyl)-2-phenylthiophene-3-carbox-
amide (92): 1H NMR (200 MHz, CDCl3): δ = 1.13 (s, 9 H, tBu),
2.88 (t, J = 8 Hz, 2 H, CH2N), 3.00 (m, 4 H, CH2N), 3,77 (m, 4
H, CH2O), 4.01 (t, J = 8 Hz, 2 H, CH2N), 7.30 (m, 6 H, Ar + 4-
H), 7.71 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
29.4, 31.3, 44.9, 48.9, 51.8, 55.9, 107.8, 120.2, 123.3, 126.6, 127.6,
127.8, 130.8, 135.7, 167.5 ppm. ES/MS: m/z = 373 [M + 1]+.
C21H28N2O2S: calcd. C 67.71, H 7.58, N 7.52; found C 67.66, H
7.55, N 7.50.
Compound 98: Product 97 (0.10 g, 0.18 mmol) was dissolved in iPr-
OH (3 mL), and HCOONH4 (20 mg) was added followed by Pd/C
(10%, 10 mg). The mixture was heated inside a microwave cavity
at 140 °C for 4 min. After cooling, EtOAc (10 mL) was added, and
the residue was filtered. The solvent was evaporated, and the crude
was dissolved in THF followed by addition of DMTMM (110 mg,
0.4 mmol), BocPheOH (53 mg, 0.2 mmol) and NMM (30 mg). The
mixture was stirred at room temperature for 12 h. The solid was
filtered off, and the THF solution was diluted with EtOAc (5 mL)
and washed with HCl (5%, 10 mL), Na2CO3 (10%, 10 mL) and
brine. The organic layer was separated and dried, and the solvent
was evaporated. The crude was dissolved in THF/H2O, 1:1 (5 mL,
5-Methyl-N-(3-methylpropyl)-2-propylthiophene-3-carboxamide
(93): 1H NMR (200 MHz, CDCl3): δ = 0.84 (t, J = 7 Hz, 3 H, Me),
1.01 (d-like, 6 H, Me2), 1.24 (m, 2 H, CH2), 1.98 (m, 1 H, CH),
2.33 (s, 3 H, Me), 3.09 (t, J = 7 Hz, 2 H, CH2-furan), 3.90 (d, J =
7 Hz, 2 H, CH2N) 7.03 (br. s, 1 H, NH), 7.23 (s, 1 H, 4-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 18.3, 20.2, 21.3, 29.6, 29.9, 30.7,
38.1, 56.7, 60.1, 109.8, 120.2, 121.9, 135.7, 165.6 ppm. ES/MS:
m/z = 240 [M + 1]+. C13H21NOS: calcd. C 65.23, H 8.84, N 5.85;
found C 65.26, H 8.80, N 5.88.
5-Methyl-N-(2-phenylethyl)-2-propylthiophene-3-carboxamide (94):
1H NMR (200 MHz, CDCl3): δ = 0.84 (t, J = 7 Hz, 3 H, Me), 1.24 containing LiOH, 810 mg), and the mixture was stirred at room
(m, 2 H, CH2), 2.33 (s, 3 H, Me), 2.67 (t, J = 7 Hz, 2 H, CH2Ar), temperature for 2 h. HCl (5% in H2O, 1 mL) was added, the sol-
3.09 (t, J = 7 Hz, 2 H, CH2-furan), 3.99 (d, J = 7 Hz, 2 H, CH2N), vent was evaporated under vacuum, and the product 98 was iso-
7.20–7.40 (s, 7 H, Ar, 4-H and NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.3, 29.6, 30.7, 38.1, 39.9, 47.8, 56.7, 60.1, 109.8,
120.2, 121.9, 135.7, 165.6 ppm. ES/MS: m/z = 285 [M + 1]+.
C17H21NOS: calcd. C 71.04, H 7.36, N 4.87; found C 71.09, H
7.33, N 4.83.
lated by column chromatography on silica gel (eluting with EtOAc/
hexane, 4:1) to yield 94 mg, 79%. An analytical sample was isolated
by preparative HPLC. H NMR (600 MHz, CDCl3): δ = 1.054 (d,
J = 7 Hz, 3 H, MeAla), 1.45 (s, 9 H, tBu), 2.091 (s, 3 H, Me), 2.986
(AB part of an ABX system, 2 H, CH2-Ar, Phe), 3.155 (AB part
1
Eur. J. Org. Chem. 2005, 5277–5288
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5287

G. Minetto, L. F. Raveglia, A. Sega, M. Taddei
FULL PAPER
A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press,
Oxford 1996, vol. 2, p. 119.
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of an ABX system, 2 H, CH2-Ar), 3.408 (AB part of an ABX
system, 2 H, CH2-pyrrole), 4.123 (AB system, 2 H, CH2N), 4.389
(qd, J = 7 and 12 Hz, 1 H, CHNH), 4.511 (m, 1 H, CHNH), 4.567
(m, 1 H, CHNH), 4,779 (s, 2 H, CH2–N), 6.331 (br. s, 1 H, NH),
6.554 (s, 1 H, 4-H), 7.20–7.50 (m, 15 H, Ar), 10.8 (s, 1 H, COOH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 11.7, 15.2, 24.3, 33.4, 41.7,
44.6, 49.6, 50.8, 52.7, 61.3, 70.9, 103.4, 111.8, 126.3, 127.4, 127.6
(2 C), 128.6, 128.7, 128.9, 131.6, 133.6, 135.7, 134.6, 138.7, 155.7,
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Acknowledgments
The work was financially supported by MIUR (Rome) as a project
within the project PRIN 2003. NikemResearch srl (Milan) is also
acknowledged for financial support.
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Received: May 31, 2005
Published Online: November 2, 2005
5288
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