A facile synthesis of 5-alkoxypyrrol-2(5H)-ones using a modified aza-Achmatowicz oxidation

Article abstract of DOI:10.1016/j.tet.2009.03.011

An efficient approach to 2,4-disubstituted pyrroles has been uncovered and is based on an oxidative rearrangement of a furanyl carbamate followed by sequential reaction of the resulting 5-methoxypyrrol-2(5H)-one with various alkyl lithiates. The final ste

Full text of DOI:10.1016/j.tet.2009.03.011

Tetrahedron 65 (2009) 6720–6729
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A facile synthesis of 5-alkoxypyrrol-2(5H)-ones using a modified aza-
Achmatowicz oxidation
*
Sezgin Kiren, Xuechuan Hong, Carolyn A. Leverett, Albert Padwa
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach to 2,4-disubstituted pyrroles has been uncovered and is based on an oxidative
rearrangement of a furanyl carbamate followed by sequential reaction of the resulting 5-methoxypyrrol-
2(5H)-one with various alkyl lithiates. The final step of the procedure involves heating the ring opened
1-methoxy-5-oxopentylcarbamate with a primary amine. The overall process can be carried out under
mild conditions and complements existing methods to prepare 2,4-disubstituted pyrroles.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 January 2009
Received in revised form 26 February 2009
Accepted 2 March 2009
Available online 9 March 2009
Keywords:
Oxidative
Rearrangement
Furanyl carbamate
Lithiate
Addition
2,4-Disubstituted pyrrole
1. Introduction
H
O
R3
N
R3
steps
OR2
R1
5-Hydroxy and the related 5-alkoxypyrrol-2(5H)-one (1) sys-
tems exhibit a wide range of interesting pharmacological proper-
ties,1 and have been used on occasion as intermediates in the
synthesis of several alkaloids2 and are also suitable precursors for
O
OR2
R1
H
H
N
N
O
N
O
O
Me
O
1; R1 = alkyl or alkoxy,
2
3; (+)-gelsemine
R
2 = H or alkyl
R4
AgOTf
COR1
the preparation of unusual g-amino acids such as statine and its
analogues.3 The chemistry of this unique pyrrolidinone ring has
been explored by a number of research groups.4 Because of its
multifunctional core, this heterocyclic system can take part in
several stereoselective transformations such as conjugate addi-
tion,5 cycloadditions,6 acyliminium ion chemistry,7 and allylic
substitutions8 (Scheme 1). A noteworthy example from the Hiem-
stra/Speckamp laboratory involves the use of 5-iso-
propoxypyrrolinone 1 (R1¼Me; R2¼(CH3)2CH) as an effective
starting material for the synthesis of gelsemine (3).6
CO2Me
N
1. (PhCH2CH2)2CuLi
2. H+
N
H
O
OR2
O
H
HN
R4
CO2Me
N
H
5
4
5-Hydroxypyrrol-2(5H)-ones derivatives have been prepared
by the oxidative bromination reaction of nicotine,9 amination of
the corresponding lactones,10 metal-catalyzed condensation–cy-
clization reaction of acyl cyanides with 3-oxoamides,11 and the
Scheme 1.
Ni-catalyzed cyanation of a
-keto-alkynes in H2O.12 The majority
corresponding
g
-lactones,10,14 Grignard addition to maleimide
derivatives,15 and the photosensitized oxygenation of pyrroles,16
diazepines,17 and 2-furyl carbamates.18 In spite of the availability
of these methods, the development of a highly efficient protocol
for the synthesis of various 5-alkoxypyrrol-2(5H)-ones is still of
of synthetic approaches used for the preparation of the related
5-alkoxypyrrol-2(5H)-one system are based on the cyclization of
a,b
-unsaturated keto amides,13 amination reactions of the
high interest, especially since the known routes to these
a,b-
unsaturated lactams generally suffer from either low yields or
long reaction times.
* Corresponding author. Tel.: þ1 404 727 0283; fax: þ1 404 727 6629.
E-mail address: chemap@emory.edu (A. Padwa).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.011

S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
6721
Some years ago, we reported on a useful approach for the
preparation of hydroxylated piperidine alkaloids19 by making
use of the aza-Achmatowicz oxidation.20 This earlier work
prompted us to explore the related oxidative rearrangement of
furanyl amides and carbamates into 5-alkoxypyrrol-2(5H)-ones.
This paper describes in detail our studies dealing with the
iodine-promoted oxidation of 2-amidofurans and 2-furanyl
carbamates as well as a subsequent adaptation of the reaction,
I2
H
I
+
R1CONH
R1CONH
O
O
9a; R1 = CH3
9b; R1 = CH2Ph
10
9c; R1 = CH2OCH2Ph
9d; R1 = Ot-Bu
H2O
NaHCO3
O
9e; R1 = OC2H5
which allows for the synthesis of
disubstituted pyrroles.
a wide range of 2,4-
O
O
OR2
N
COR1
NH
COR1
H
2. Results and discussion
R2 = H or CH3
11
As part of an ongoing research program dealing with the syn-
thesis of novel azapolycyclic compounds, we have been in-
vestigating the intramolecular [4þ2]-cycloaddition/rearrangement
cascade of 2-amidofurans as a strategy for the preparation of hex-
ahydroindolinone alkaloids.21 During the course of this work we
developed an efficient, scalable method for the synthesis of various
2-furanyl amides of type 9 by an acyl azide formation/Curtius
rearrangement sequence (Scheme 2) starting from furoic acid 6.22
Treatment of the resulting carbamate 7 with n-BuLi provides the
corresponding anion, which undergoes ready acylation with
a number of acid chlorides or mixed anhydrides.23 The Boc pro-
tecting group of the acylated imidofuran 8 can be easily removed by
treatment with Mg(ClO4)2 in CH3CN to provide a variety of ami-
dofurans 9.24 The compounds synthesized include products which
contain alkyl, aryl, or heteroaryl R-substituents. The reaction of the
resulting furanyl amide 9 with 3.0 equiv of I2 and 6.0 equiv of
NaHCO3 in aqueous acetone at 25 ꢀC occurred smoothly and fur-
nished a variety of 5-hydroxypyrrol-2(5H)-ones (1). More than
likely the reaction proceeds via intermediates 10 and 11 as
indicated in Scheme 3. The initially formed 2-hydroxy-5-oxo-2,5-
dihydro-1H-pyrrole (1) could be readily converted into the corre-
sponding methoxy derivative by treatment with methyl iodide and
silver(I) oxide in CH2Cl2 at 25 ꢀC (vide infra). The yield of the
resulting 5-hydroxypyrrol-2(5H)-one from the amido furan is quite
good (ca. 85%) and the final product is easily isolated by column
chromatography on silica gel.
1a; R1 = CH3
1b; R1 = CH2Ph
1c; R1 = CH2OCH2Ph
1d; R1 = Ot-Bu
1e; R1 = OC2H5
Scheme 3.
into 13 using a wide variety of Lewis acids (i.e., SnCl4, TiCl4, MgI2,
BF3$OEt2, etc.) failed and only recovered starting material was
obtained, even under prolonged reaction conditions. We also
attempted to induce this cyclization using a variety of acids (i.e.,
p-TsOH, HCl, TFA, TfOH, PPA, etc.) at high temperatures but this
also resulted in complete failure. While the cyclization of N-
acylamines has been well explored,27 it would seem that the
cyclization behavior of a N-diacylamine such as 12 is dramatically
different. More than likely, the inability of this system to cyclize is
due to the lack of interaction of the nitrogen lone pair of elec-
trons of the diacylated amine with the adjacent hydroxyl group
thereby retarding formation of the required cationic intermediate.
steps
H
OH
N
O
OMe
OMe
O
N
CO2t-Bu
O
CH2
9d
12
Having ascertained the reaction conditions necessary for N-
hydroxypyrrolinone formation, we became interested in exploring
the use of these intermediates for alkaloid synthesis. Because of
our interest in using N-acyliminium ion chemistry for total syn-
thesis,25 we decided to explore the possibility of using a cycliza-
tion reaction of 5-hydroxypyrrolinone 12 to generate the core
structure 13 whose skeleton is found in a number of natural
products such as crispine A (14).26 This potential synthetic route
would allow us to readily convert furanyl carbamate 9d into
a crispine A precursor (i.e., 13) in only four steps (Scheme 4).
Unfortunately, all of our attempts to induce the cyclization of 12
Lewis or
protic acid
??
OMe
steps
O
N
N
O
OMe
14; ( )-crispine A
O
OMe
13
Scheme 4.
Realizing that simple iminium ion generation and cyclization
of 12 is unlikely to produce the desired product 13, we then
became interested in determining whether a
p-allyl palladium
1. NaN3
mediated cyclization might occur.28 With this in mind, we pre-
pared the necessary allylic acetate intermediate 15 in 73% yield
by treating 12 with acetic acid and pyridine. As before, all of our
attempts to induce the desired cyclization reaction failed. A va-
riety of palladium-catalyzed conditions were examined but all
failed to give any characterizable products. Only in the case when
Pd(Ph3)4 and i-propanol was used were we able to isolate
a product (97%) whose structure was subsequently identified as
5-isopropoxypyrrolin-2(5H)-one 16. It would appear that a large
excess of a nucleophilic solvent (i.e., i-PrOH) is necessary before
NHCO2t-Bu
CO2H
O
O
2. t-BuOH
heat
7
6
1. n-BuLi
2. RCOX
Mg(ClO4)2
CH3CN
NHCOR
NCO2t-Bu
O
O
O
R
9
addition to the
(Scheme 5).
p-allyl complexed pyrrolinone core can occur
8
Scheme 2.

6722
S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
an appropriate amine in the presence of a trace amount of p-TsOH
in a microwave reactor at 150 ꢀC (Scheme 6). In all cases, the de-
sired 2,4-disubstituted pyrrole was obtained in good yield with no
evidence of any products arising from simple hydrolysis or alter-
natively by furan formation. On the other hand, heating an aqueous
DMF solution of 19a (R1¼Ph; R2¼n-C4H9) in a microwave reactor
afforded an almost quantitative yield of the NH-pyrrole 20j. How-
ever, when 19a is heated in toluene in the presence of a CSA/
quinoline catalyst, only the Boc-pyrrole 20k was formed in 76%
yield.
Oi-Pr
OAc
O
OMe
OMe
O
Pd(PPh3)4
OMe
OMe
N
N
i-PrOH
O
CH2
16
O
CH2
15
97%
Scheme 5.
Even though our attempted iminium ion cyclization studies did
not proceed as we had hoped, we did see some other synthetic
utility for these substituted hydroxypyrrolinones. In particular, we
became interested in using these compounds for the synthesis of
various 2,4-disubstituted pyrroles. The biological activity of
substituted pyrroles has made them a focus of medicinal chemistry
over the years.29 Pyrroles occur in numerous pharmacologically
active natural and unnatural products.30 Additionally, functional-
ized pyrroles represent building blocks of natural tetrapyrrole
pigments, such as porphyrobilinogen or bilirubin, and of various
other natural products and their analogues.31 For more than
a century, many diverse methods have been developed to prepare
pyrroles with various ring substitution patterns,32 including the
classical Hantzsch, Knorr, and Paal–Knorr procedures.33 With this
in mind, we have developed a four-step approach to a variety of 2,4-
disubstituted pyrroles using 5-methoxypyrrol-2(5H)-one (17). This
compound was readily obtained from the corresponding hydroxy
derivative 1d by treatment with methyl iodide and silver(I) oxide in
CH2Cl2 at 25 ꢀC. The yield of the resulting 5-methoxypyrrol-
2(5H)one 17 from the starting furanyl carbamate 9d is quite good
(ca. 85%) and the final product is easily isolated by column chro-
matography on silica gel.
R1
R1
R3NH2
O
OCH3
CO2t-Bu
19
HN
p-TsOH
R2
N
R3
20
R2
150 °C
microwave
20a; R1 = n-C4H9; R2 = Ph; R3 = CH2Ph (90%)
20b; R1 = n-C4H9; R2 = R3 = Ph (97%)
R
1 = n-C4H9
R2 = Ph
19a
20c; R1 = n-C4H9; R2 = Ph; R3 = 2-CH2(furanyl) (65%)
20d; R1 = n-C4H9; R2 = Ph; R3 = cyclohexyl (90%)
20e; R1 = Ph; R2 = CH3; R3 = CH2Ph (70%)
20f; R1 = n-C4H9; R2 = CH3; R3 = CH2Ph (81%)
20g; R1 = CH3; R2 = 2-thienyl; R3 = CH2Ph (86%)
20h; R1 = n-C6H13; R2 = C2H5; R3 = CH2Ph (42%)
20i; R1 = CH3; R2 = n-C4H9; R3 = CH2Ph (54%)
n-C4H9
Ph
N
R4
20j; R4 = H (98%)
20k; R4 = CO2t-Bu (76%)
Scheme 6.
We have also examined the Diels–Alder cycloaddition reaction of 5-
methoxypyrrol-2(5H)-one (17) with cyclopentadiene (Scheme 7).
The reaction works well and the expected cycloadduct 21 was
obtained in almost quantitative yield. Further treatment of adduct
21 with phenyllithium followed by heating with benzylamine
afforded the novel bridged pyrrole 22 in 43% yield.
The conjugate addition of various cuprates to the
a,b-un-
saturated lactam system of 17 proceeded in 60–92% yield with
high stereoselectivity. The 1H NMR spectra of the crude product
only showed the presence of a single trans-addition product in all
cases. The assignment was based on the 1H NMR vicinal coupling
constant of H5. In a trans-lactam this coupling is 0–1 Hz, whereas
a cis-lactam has a coupling of 5–6 Hz.34 The products obtained
from the cuprate additions were then used in the next step,
which consisted of treating the 2-methoxy-3-alkyl substituted
oxypyrrolidinone 18 with an alkyl lithium reagent to give the ring
opened 1-methoxy-5-oxopentylcarbamate 19. The results for the
conjugate addition–alkyl lithiation reaction of differently
substituted systems in THF at ꢁ78 ꢀC are summarized in Table 1.
From the table it can be seen that the reaction is quite general:
R2¼various alkyl, phenyl or 2-thienyl groups with yields ranging
from 65% to 94%.
+
O
OCH3
CO2t-Bu
N
110 °C
17
1. PhLi
2. PhCH2NH2
150 °C
OCH3
The 2,4-disubstituted pyrrole (20) system was then prepared by
heating a mixture of the 1-methoxy-5-oxopentylcarbamate 19 and
O
N
Ph
N
CO2t-Bu
21
CH2Ph
22
Table 1
Scheme 7.
Conjugate addition–alkyl lithiation reaction of 5-methoxypyrrol-2(5H)-one (17)
R1
R1
R2Li
R1Li
CuI
O
OCH3
O
O
HN
OCH3
OCH3
N
N
Interestingly, when the reaction sequence was carried out in a one-
pot fashion using 5-oxopyrrolidinone 18c and vinyl lithium fol-
lowed by heating with benzylamine, the only product that could be
isolated corresponded to N-benzyl-4-n-butyl-2-methyl-1H-pyrrole
(20f). This somewhat surprising result can be explained by the
series of reactions outlined in Scheme 8. More than likely, the
transient vinyl oxypentylcarbamate 23 that is first formed reacts
with excess benzylamine to eventually give enamine 24. Pro-
tonation of 24 to iminium ion 25 followed by loss of PhCH2N]CH2
under the reaction conditions furnishes 26, which is readily iso-
merized to pyrrole 20f.
R2
CO2t-Bu
CO2t-Bu
17
CO2t-Bu
18
19
Entry
R1
Yield of 18
R2
Yield of 19
a
b
c
d
e
f
t-Bu
Ph
n-C4H9
n-C4H9
CH3
80%
75%
92%
d
Allyl
CH3
Ph
72%
70%
94%
85%
86%
80%
65%
CH3
80%
d
2-Thienyl
n-C4H9
C2H5
CH3
n-C6H13
g
60%

S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
6723
4.1.2. 5-Hydroxy-1-(2-phenylacetyl)-1H-pyrrol-2(5H)-one (1b)
n-C4H9
n-C4H9
To a stirred solution of tert-butyl furan-2-ylcarbamate (9d)
(0.2 g, 1.1 mmol) in THF (8 mL) at 0 ꢀC was added n-BuLi (0.5 mL,
1.3 mmol, 2.5 M in hexane) dropwise and the mixture was stirred
at 0 ꢀC for 30 min. In a separate flask, phenylacetic acid (0.15 g,
1.1 mmol) was dissolved in THF (8 mL) and the mixture was cooled
to 0 ꢀC. 4-Methylmorpholine (0.12 mL, 1.1 mmol) and isobutyl
chloroformate (0.14 mL, 1.1 mmol) were added dropwise and the
solution was stirred for 5 min. The mixture was filtered over Celite
with THF (4 mL) and the filtrate was cooled to 0 ꢀC. The preformed
furanyl lithiate from above was added dropwise by cannula. The
resulting reaction mixture was stirred for 2 h at 0 ꢀC and was then
quenched with H2O and extracted with EtOAc. The organic layers
were washed with a saturated aqueous NaHCO3 solution, dried
over MgSO4, filtered over a pad of silica gel, and concentrated
under reduced pressure. The residue was dissolved in CH3CN
(10 mL) and was added to a stirred solution of Mg(ClO4)2 (0.23 g,
1.0 mmol) in CH3CN (5 mL) at 40 ꢀC and the mixture was heated at
40 ꢀC for 25 min. The solution was cooled to 0 ꢀC and quenched
with H2O and extracted with Et2O. The organic layer was dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography to give
0.03 g (12%) of N-(furan-2-yl)-2-phenylacetamide (9b) as pale
yellow oil. IR (thin film) 3242, 3064, 2918, 1666, 1562, 1379, 1248,
Li
H+
O
OCH3
O
OCH3
HN
N
CO2t-Bu
CO2t-Bu
H2C
18c
23
PhCH2NH2, H+
steps
n-C4H9
H+
n-C4H9
+
PhCH2NH
PhCH2NH
N
N
CH2Ph
CH2Ph
24
25
-PhCH2N=CH2
n-C4H9
n-C4H9
H+
CH3
H2C
N
N
CH2Ph
CH2Ph
26
20f
Scheme 8.
1196, 1147, 791, and 703 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
2H), 6.31–6.35 (m, 2H), 7.00 (dd, 1H, J¼2.0 and 0.8 Hz), 7.30–7.41
(m, 5H), and 7.65 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
44.0, 95.6,
111.7, 128.0, 129.5, 129.7, 134.1, 135.6, 145.2, and 167.6.
d 3.73 (s,
3. Conclusion
d
In summary, the new oxidative rearrangement chemistry of
furanyl carbamates described herein gives rapid access to a variety
of 5-alkoxypyrrol-2(5H)-ones. Treatment of these heterocycles
with various cuprate reagents followed by a subsequent reaction
with an alkyl lithiate and then a primary amine furnishes 2,4-di-
substituted pyrroles in good yield.
To a stirred solution of the above furanyl amide 9b (0.02 g,
0.12 mmol) in acetone/H2O (18:1, 9.5 mL) at 0 ꢀC was added
NaHCO3 (0.06 g, 0.7 mmol). The solution was then stirred at this
temperature for 10 min. A sample of iodine (0.09 g, 0.36 mmol) was
added in 3 portions and the mixture was stirred at 0 ꢀC for 40 min,
then quenched with a saturated aqueous sodium thiosulfate solu-
tion and extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
give 0.02 mg (67%) of the titled compound 1b as a white solid, mp
109–110 ꢀC. IR (thin film) 3450, 3102, 2924, 1738, 1686, 1348, 1242,
4. Experimental
4.1. General
Melting points are uncorrected. Mass spectra were determined
at an ionizing voltage of 70 eV. Unless otherwise noted, all reactions
were performed in flame-dried glassware under an atmosphere of
dry nitrogen. A representative procedure for the oxidative rear-
rangement of the furanyl carbamate involved stirring a sample of
the furan in acetone/H2O at 0 ꢀC. Sodium bicarbonate was added
followed by iodine crystals in 3 portions. After stirring for 3 h at
0 ꢀC, the mixture was quenched with sodium thiosulfate and
extracted with ethyl acetate. Solutions were evaporated under
reduced pressure with a rotary evaporator and the residue was
chromatographed on a silica gel column using an ethyl acetate/
hexane mixture as the eluent unless specified otherwise.
1197, and 1089 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 4.28 (s, 1H), 4.29
(s, 2H), 6.15–6.16 (m, 1H), 6.22 (d, 1H, J¼6.0 Hz), 7.17 (dd, 1H, J¼6.0
and 1.6 Hz) and 7.28–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
42.7, 82.4, 127.5, 128.8, 130.0, 133.5, 147.7, 167.8, and 172.6.
4.1.3. 1-(2-(Benzyloxy)acetyl)-5-hydroxy-1H-pyrrol-2-(5H)-
one (1c)
To
a stirred solution of 2-(benzyloxy)acetic acid (1.0 g,
6.0 mmol) in CH2Cl2 (15 mL) was added oxalyl chloride (1.6 mL,
18.0 mmol) followed by 2 drops of DMF. The reaction mixture was
stirred at rt for 1 h and was then concentrated under reduced
pressure, taken up in THF (15 mL), and cooled to ꢁ78 ꢀC. In a sep-
arate flask, tert-butyl furan-2-ylcarbamate (9d) (1.3 g, 7.2 mmol)
was dissolved in THF (10 mL) at 0 ꢀC. To this mixture was added n-
BuLi (2.6 mL, 6.6 mmol, 2.5 M in hexane) dropwise and the mixture
was stirred at 0 ꢀC for 0.5 h. The resulting solution was transferred
dropwise by cannula into a solution of the above acid chloride at
ꢁ78 ꢀC. The solution was stirred for 1 h while slowly warming from
ꢁ78 ꢀC to 0 ꢀC. The mixture was then quenched with H2O, extracted
with EtOAc, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel chroma-
tography to give 1.5 g (77%) of tert-butyl-2-(benzyloxy)-
acetyl(furan-2-yl)carbamate as a white solid, mp 64–66 ꢀC. IR (thin
film) 3127, 2981, 2934, 1790, 1745, 1611, 1500, 1371, 1306, 1271, 1153,
4.1.1. 1-Acetyl-5-hydroxy-1H-pyrrol-2(5H)-one (1a)
To a stirred solution of N-(furan-2-yl)acetamide (9a) (0.08 g,
0.65 mmol) in acetone/H2O (20:1, 50 mL) at 0 ꢀC was added
NaHCO3 (0.33 g, 3.9 mmol) and the reaction mixture was stirred for
10 min. A sample of iodine (0.49 g, 1.9 mmol) was added in 3 por-
tions and the mixture was stirred at 0 ꢀC for 3 h, then quenched
with a saturated aqueous sodium thiosulfate solution and extracted
with EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to provide 0.05 g
(57%) of 1-acetyl-5-hydroxy-1H-pyrrol-2(5H)-one (1a) as a white
solid, mp 86–87 ꢀC.35 1H NMR (CDCl3, 400 MHz)
d
2.54 (s, 3H), 4.38
1092, 1013, 955, 847, 772, 738, and 698 cmꢁ1 1H NMR (400 MHz,
;
(d, 1H, J¼4.0 Hz), 6.14–6.15 (m, 1H), 6.21 (dd, 1H, J¼6.0 and 1.2 Hz),
CDCl3) d 1.41 (s, 9H), 4.65 (s, 2H), 4.66 (s, 2H), 6.17–6.18 (m,1H), 6.43
and 7.16 (dd, 1H, J¼6.0 and 1.6 Hz).
(dd, 1H, J¼3.6 and 2.0 Hz), and 7.27–7.41 (m, 6H); 13C NMR

6724
S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
(100 MHz, CDCl3)
d
27.9, 71.2, 73.5, 84.6, 106.4, 111.5, 128.1, 128.3,
silica gel chromatography to provide 0.2 g (93%) of 2-(3,4-dime-
thoxyphenyl)-N-(furan-2-yl)acetamide as a yellow oil. IR (thin film)
3268, 3151, 3061, 2943, 2836, 1666, 1608, 1552, 1515, 1464, 1263,
128.6, 137.7, 140.9, 142.8, 151.6, and 172.8; HRMS calcd for
[(C13H13NO4)þKþ]: 286.0482, found: 286.0459.
The above Boc furanyl carbamate (1.1 g, 3.0 mmol) was dis-
solved in CH3CN (5 mL) and was added to a stirred solution of
Mg(ClO4)2 (0.84 g, 3.8 mmol) in CH3CN (50 mL) at 40 ꢀC. The re-
action mixture was heated at 40 ꢀC for 10 min, cooled to rt, and
diluted with H2O. The aqueous layer was extracted with EtOAc,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
afford 0.63 g (90%) of 2-(benzyloxy)-N-(furan-2-yl)acetamide (9c)
as a pale yellow oil. IR (neat) 3375, 3281, 3155, 3064, 2914, 2867,
1694, 1608, 1531, 1455, 1376, 1344, 1239, 1208, 1108, and
1235, 1143, and 1027 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 3.67 (s,
2H), 3.88 (s, 3H), 3.89 (s, 3H), 6.33–6.35 (m, 1H), 6.31–6.32 (m, 1H),
6.80–6.89 (m, 3H), 6.99 (dd, 1H, J¼2.0 and 0.8 Hz), and 7.59 (br s,
1H); 13C NMR (CDCl3, 100 MHz)
d 43.6, 56.1, 95.5, 111.7, 111.9, 112.6,
122.0, 126.4, 135.6, 145.2, 148.9, 150.7, and 167.8.
To a stirred solution of the above furanyl amide (1.66 g,
6.4 mmol) in acetone/H2O (20:1, 50 mL) at 0 ꢀC was added NaHCO3
(3.2 g, 38.1 mmol) and the mixture was stirred at 0 ꢀC for 5 min. A
sample of iodine (4.8 g, 19.1 mmol) was added in 3 portions and
the mixture was stirred at 0 ꢀC for 3 h, then quenched with a sat-
urated aqueous sodium thiosulfate solution and extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to provide 1.76 g
(77%) of 12 as a white solid, mp 109–110 ꢀC. IR (thin film) 3454,
3101, 3002, 2938, 2837, 1736, 1686, 1517, 1349, 1264, 1228, and
1011 cmꢁ1
6.35–6.39 (m, 2H), 7.07 (dd, 1H, J¼2.0 and 0.8 Hz), 7.32–7.42 (m,
5H), and 8.65 (br s, 1H); 13C NMR (100 MHz, CDCl3)
69.3, 74.0,
; d 4.11 (s, 2H), 4.64 (s, 2H),
1H NMR (400 MHz, CDCl3)
d
95.6, 111.8, 128.3, 128.7, 129.0, 135.8, 136.5, 144.7, and 166.1.
To a stirred solution of the above furanyl amide 9c (0.35 g,
1.5 mmol) in acetone/H2O (18:1, 51 mL) at 0 ꢀC was added NaHCO3
(0.77 g, 9.1 mmol) and the mixture was stirred for 10 min. A sample
of iodine (1.2 g, 4.6 mmol) was added in 3 portions. The reaction
mixture was stirred at 0 ꢀC for 40 min, then quenched with a sat-
urated aqueous sodium thiosulfate solution and extracted with
EtOAc. The organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to provide 0.26 g (70%) of the
titled compound 1c as a white solid, mp 105–106 ꢀC. IR (thin film)
1141 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 3.86 (s, 3H), 3.87 (s, 3H),
4.23 (s, 2H), 4.30 (d, 1H, J¼3.6 Hz), 6.15–6.16 (m, 1H), 6.22 (dd, 1H,
J¼6.0 and 0.4 Hz), 6.82–6.88 (m, 3H), and 7.17 (dd, 1H, J¼6.4 and
2.0 Hz); 13C NMR (100 MHz, CDCl3)
d 42.1, 56.0, 56.1, 82.4, 111.3,
113.0, 122.1, 125.8, 128.7, 147.7, 148.4, 149.0, 167.8, and 172.8. Anal.
Calcd for C14H15NO5: C, 60.65, H, 5.45; N, 5.05. Found: C, 60.43; H,
5.41; N, 5.14.
3403, 3056, 2925, 2855, 1742, 1707, 1265, 1132, 1092, and 738 cmꢁ1
1H NMR (400 MHz, CDCl3)
4.61 (s, 2H), 4.64 (s, 2H), 4.99 (s, 1H),
6.04 (d, 1H, J¼6.4 Hz), 6.09 (s, 1H), 7.01 (dd, 1H, J¼6.4 and 2.0 Hz),
and 7.25–7.36 (s, 5H); 13C NMR (100 MHz, CDCl3)
69.9, 73.1, 81.1,
127.2, 127.7, 127.8, 128.2, 136.9, 148.6, 168.0, and 170.8. Anal. Calcd
for C13H13NO4: C, 63.15; H, 5.30; N, 5.66. Found: C, 63.08; H, 5.21; N,
5.73.
;
4.1.5. Acetic acid 1-[2-(3,4-dimethoxyphenyl)acetyl]-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl ester (15)
d
To a stirred solution of 5-hydroxypyrrol-2(5H)-one 12 (0.5 g,
2.0 mmol) in pyridine (10 mL) was added acetic anhydride (0.2 mL,
2.4 mmol). The reaction mixture was stirred at rt for 16 h, quenched
with H2O, and extracted with EtOAc. The organic layer was washed
with 1 N HCl followed by H2O, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to provide 0.6 g (95%) of 15 as a colorless
oil. IR (thin film) 3098, 2938, 2837, 1742, 1704, 1516, 1351, 1265,
d
4.1.4. 1-(2-(3,4-Dimethoxyphenyl)acetyl)-5-hydroxy-1H-pyrrol-
2(5H)-one (12)
To a stirred solution of tert-butyl furan-2-ylcarbamate (9d)
(2.1 g, 11.7 mmol) in THF (20 mL) at 0 ꢀC was added n-BuLi (4.9 mL,
12.3 mmol, 2.5 M in hexane) dropwise and the reaction mixture
was stirred at 0 ꢀC for 30 min. In a separate flask, 3,4-dimethoxy-
benzoic acid (2.75 g, 14.0 mmol) was dissolved in THF (20 mL) and
the mixture was cooled to 0 ꢀC. 4-Methylmorpholine (1.5 mL,
14.0 mmol) was first added and then isobutyl chloroformate
(1.8 mL, 14.0 mmol) was subsequently added dropwise and the
solution was stirred for 5 min. The mixture was filtered over Celite
with THF and the filtrate was cooled to 0 ꢀC and the preformed
furanyl lithiate was added dropwise by cannula. The resulting
mixture was stirred for 30 min, quenched with H2O, and extracted
with EtOAc. The organic layer was washed with a saturated aque-
ous NaHCO3 solution, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography to give 3.1 g (76%) of tert-butyl 2-(3,4-dimethoxy-
phenyl)acetyl(furan-2-yl)carbamate as a yellow oil. IR (thin film)
2980, 2936, 2836, 1783, 1746, 1609, 1516, 1265, 1154, 1093, and
1237, and 1027 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 2.07 (s, 3H), 3.84
(s, 3H), 3.85 (s, 3H), 4.17 (d, 1H, J¼16.0 Hz), 4.23 (d, 1H, J¼16.0 Hz),
6.23 (d, 1H, J¼6.0 Hz), 6.79–6.86 (m, 3H), and 7.12–7.16 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d 20.6, 42.1, 55.8, 80.4, 111.0, 112.7, 121.9,
125.5, 128.7, 145.1, 148.1, 148.7, 167.9, 169.3, and 169.9.
4.1.6. 1-[2-(3,4-Dimethoxyphenyl)acetyl]-5-isopropoxy-1,5-
dihydropyrrol-2-one (16)
To a stirred solution of 5-acetoxypyrrol-2(5H)-one 15 (0.42 g,
1.45 mmol) in i-PrOH (20 mL) was added Pd(PPh3)4 (0.08 g,
0.073 mmol) and the reaction mixture was stirred at rt for 5 h. The
mixture was then concentrated under reduced pressure and puri-
fied by silica gel chromatography to give 0.41 g (97%) of 16 as
a colorless oil. IR (thin film) 2971, 2934, 2836,1737,1699,1516,1465,
1342, 1263, 1222, and 1028 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.15
(d, 3H, J¼6.4 Hz), 1.19 (d, 3H, J¼6.0 Hz), 3.86 (s, 3H), 3.87 (s, 3H),
4.22 (s, 2H), 4.27 (p, 1H, J¼12.4, 6.4, and 6.0 Hz), 5.98 (d, 1H,
J¼2.0 Hz), 6.10 (d, 1H, J¼6.0 Hz), 6.81–6.87 (m, 3H), and 7.01 (dd,
1029 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
1.40 (s, 9H), 3.85 (s, 6H),
1H, J¼6.0 and 2.0 Hz); 13C NMR (100 MHz, CDCl3)
d 23.3, 42.7, 55.99,
56.0, 73.6, 87.0, 111.3, 112.9, 122.1, 126.5, 127.1, 148.1, 148.2, 149.0,
168.7, and 171.4.
4.04 (s, 2H), 6.11–6.12 (m,1H), 6.39–6.41 (m,1H), 6.77–6.81 (m, 3H),
and 7.32 (dd, 1H, J¼2.0 and 0.8 Hz); 13C NMR (CDCl3, 100 MHz)
d
27.9, 43.3, 56.00, 56.03, 84.1, 106.2, 111.2, 111.4, 112.9, 121.9, 126.5,
140.7, 144.0, 148.2, 148.9, 151.5, and 173.3.
4.1.7. 2-Methoxy-5-oxo-2,5-dihydropyrrole-1-carboxylic acid tert-
butyl ester (17)
To a stirred solution of Mg(ClO4)2 (0.24 g, 1.1 mmol) in CH3CN
(9 mL) at 45 ꢀC was added a solution of the above Boc carbamate
(0.3 g, 0.84 mmol) in CH3CN (2 mL). The mixture was stirred at
45 ꢀC for 15 min and was then diluted with H2O and extracted with
EtOAc. The organic layer was dried over MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified by
To a stirred solution of tert-butyl furan-2-ylcarbamate (9d)
(0.37 g, 2.0 mmol) in 35 mL of an 18:1-mixture of acetone/H2O at
0 ꢀC was added NaHCO3 (1.0 g, 12.0 mmol) and the solution was
stirred at 0 ꢀC for 10 min. A sample of iodine (1.5 g, 6.0 mmol) was
added in 3 portions and the mixture was stirred at 0 ꢀC for 3 h, then

S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
6725
quenched with a saturated aqueous sodium thiosulfate solution
and extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography to provide 0.35 g (87%) of tert-butyl 2-hydroxy-5-oxo-2,5-
dihydro-1H-pyrrole-1-carboxylate (1d) as a pale yellow solid, mp
80–81 ꢀC. IR (thin film) 1766, 1368, 1314, 1258, 1160, 1106, and
ether. The organic layer was washed with a saturated aqueous
NaHCO3 solution, dried over MgSO4, filtered and concentrated
under reduced pressure. The resulting residue was purified by silica
gel chromatography to afford 0.06 g (80%) of compound 18a as
a colorless oil. IR (thin film) 1792, 1760, 1476, 1370, 1304, 1158, and
1088 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 0.90 (s, 9H), 1.54 (s, 9H),
1.92 (dd, 1H, J¼9.2 and 1.2 Hz), 2.33 (d, 1H, J¼18.4 and 1.6 Hz), 2.76
1047 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.51 (s, 9H), 4.26–4.27 (m,
(dd, 1H, J¼18.4 and 9.2 Hz), 3.39 (s, 3H), and 5.20 (s, 1H); 13C NMR
1H), 5.93 (d, 1H, J¼2.4 Hz), 6.09 (d, 1H, J¼4.4 Hz), and 7.00 (dd, 1H,
(CDCl3, 100 MHz) d 27.0, 28.2, 31.9, 33.4, 47.6, 56.1, 83.5, 91.3, 150.1,
J¼4.4 and 1.2 Hz); 13C NMR (100 MHz, CDCl3)
d
28.0, 82.1, 83.9,
and 174.2; HRMS calcd for [(C14H25NO4)þH]þ: 271.1783, found:
128.4, 146.3, 149.9, and 166.4. Anal. Calcd for C9H13NO4: C, 54.26; H,
6.58; N, 7.03. Found: C, 54.13; H, 6.41; N, 7.28.
271.1781.
To a stirred solution containing the above 5-hydroxypyrrol-
2(5H)-one 1d (0.24 g, 1.2 mmol) in CH2Cl2 (10 mL) were added
silver(I) oxide (1.4 g, 6.0 mmol) and iodomethane (3 mL, 48 mmol).
The resulting solution was stirred for 14 h at rt and then filtered
over Celite. The filtrate was concentrated under reduced pressure
and purified by silica gel chromatography to yield 0.25 g (99%) of
the titled compound 17 as a colorless oil. IR (thin film) 1783, 1723,
4.1.10. tert-Butyl 2-methoxy-5-oxo-3-phenylpyrrolidine-1-
carboxylate (18b)
To a 0 ꢀC stirred suspension of CuBr$Me2S (1.0 g, 4.9 mmol) in
THF (10 mL) was added phenyllithium (6.2 mL, 11.0 mmol, 1.8 M in
cyclohexane) dropwise. The resulting mixture was stirred at 0 ꢀC
for 1.5 h, cooled to ꢁ78 ꢀC, and TMSCl (3.6 mL) was added. The
mixture was stirred for an additional 10 min and then a solution of
compound 17 (0.3 g, 1.4 mmol) in THF (3 mL) was slowly added. The
mixture was stirred at ꢁ78 ꢀC for 5 min, warmed to rt, and stirred
for an additional 3 h. The reaction mixture was quenched by the
slow addition of a saturated aqueous NH4Cl solution and then
extracted with ether. The organic layer was washed with a satu-
rated aqueous NaHCO3 solution and dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography to give 0.41 g (75%) of 18b as
a colorless oil. IR (thin film) 1792, 1723, 1455, 1369, 1154, 1085, and
1612, 1356, 1285, 1163, and 1046 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
1.56 (s, 9H), 3.33 (s, 3H), 5.86–5.87 (m, 1H), 6.18–6.20 (m, 1H), and
6.96 (dd, 1H, J¼6.4 and 0.8 Hz); 13C NMR (100 MHz, CDCl3)
d 27.7,
53.1, 82.9, 87.8, 128.4, 145.3, 148.7, 167.1; HRMS calcd for
[(C10H15NO4)þH]þ: 214.1079, found: 214.1074.
4.1.8. 2-Methoxy-5-oxo-2,5-dihydropyrrole-1-carboxylic acid
ethyl ester
To a stirred solution of ethyl furan-2-ylcarbamate (9e) (6.1 g,
39 mmol) in 667 mL of an 18:1-mixture of acetone/H2O at 0 ꢀC was
added NaHCO3 (19.8 g, 236 mmol) and the resulting mixture
was stirred for 5 min at 0 ꢀC. A sample of iodine (30 g, 118 mmol)
was added in 3 portions and the mixture was stirred at 0 ꢀC for 3 h,
then quenched with a saturated aqueous sodium thiosulfate solu-
tion and extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography to provide 5.2 g (83%) of ethyl 2-hydroxy-5-oxo-2,5-
dihydro-1H-pyrrole-1-carboxylate (1e) as a pale yellow oil. IR (thin
943 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 1.51 (s, 9H), 2.54 (dd, 1H,
J¼17.6 and 0.8 Hz), 3.17 (dd, 1H, J¼17.6 and 8.8 Hz), 3.38 (d, 1H,
J¼8.8 Hz), 3.47 (s, 3H), 5.17 (s, 1H), 7.14–7.16 (m, 2H), and 7.24–7.36
(m, 3H); 13C NMR (CDCl3, 100 MHz)
d 27.9, 37.7, 42.9, 56.6, 83.5,
95.2, 126.6, 127.5, 129.1, 140.6, 149.7, and 173.5; HRMS calcd for
[(C16H21NO4)þKþ]: 330.1108, found: 330.1101.
4.1.11. tert-Butyl 3-butyl-2-methoxy-5-oxopyrrolidine-1-
carboxylate (18c)
To a stirred suspension of CuI (4.9 g, 26 mmol) in THF (80 mL)
0 ꢀC was added n-BuLi (14.7 mL, 37 mmol, 2.5 M in hexane)
dropwise. The mixture was stirred at 0 ꢀC for 1.5 h, cooled to
ꢁ78 ꢀC, and TMSCl (12 mL) was added. The mixture was stirred for
an additional 5 min and compound 17 (1.0 g, 4.7 mmol) in THF
(3 mL) was slowly added. The solution was stirred at ꢁ78 ꢀC for
10 min, then warmed to rt and stirred for an additional 1 h. The
mixture was quenched by the slow addition of a saturated aque-
ous NH4Cl solution and extracted with ether. The organic layer
was washed with a saturated aqueous NaHCO3 solution, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography to give
1.17 g (92%) of 18c as a colorless oil. IR (thin film) 1793, 1760, 1458,
film) 1775, 1726, 1532, 1374, 1207, 1098, and 1052 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
1.40 (t, 3H, J¼7.2 Hz), 4.11 (br s, 1H), 4.40 (q, 2H,
J¼14.0 and 7.2 Hz), 6.05 (s, 1H), 6.19–6.21 (m, 1H), and 7.10 (dd, 1H,
J¼6.0 and 2.0 Hz); 13C NMR (100 MHz, CDCl3)
d 14.6, 63.5, 82.4,
128.9, 146.7, 151.9, and 166.3.
To a stirred solution of the above compound (4.2 g, 25 mmol) in
CH2Cl2 (200 mL) were added silver(I) oxide (28.7 g, 124 mmol) and
iodomethane (62 mL, 992 mmol). The mixture was stirred for 14 h
at rt and then filtered over Celite. The filtrate was concentrated
under reduced pressure and purified by silica gel chromatography
to furnish 4.48 g (98%) of the titled compound as a colorless oil. IR
(thin film) 1788, 1753, 1466, 1373, 1299, 1272, and 1100 cmꢁ1
NMR (400 MHz, CDCl3)
;
1H
d
1.35 (d, 3H, J¼7.2 Hz), 3.34 (s, 3H), 4.34 (q,
1368, 1305, 1158, and 843 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 0.87
2H, J¼7.2 Hz), 5.90 (dd, 1H, J¼2.0 and 0.8 Hz), 6.18 (dd, 1H, J¼6.4
(t, 3H, J¼7.2 Hz), 1.21–1.43 (m, 6H), 1.52 (s, 9H), 2.08–2.12 (m, 2H),
and 0.8 Hz), and 7.00 (d, 1H, J¼6.4 and 2.0 Hz); 13C NMR (100 MHz,
2.82 (dd, 1H, J¼17.6 and 7.6 Hz), 3.37 (s, 3H), and 5.01 (s, 1H); 13C
CDCl3)
d
14.3, 53.6, 62.9, 88.1, 128.6, 145.9, 150.6, and 166.9.
NMR (CDCl3, 100 MHz) d 13.9, 22.5, 27.9, 29.0, 32.2, 36.9, 37.4, 56.2,
83.2, 93.8, 150.2, and 173.7; HRMS calcd for [(C14H25NO4)þH]þ:
4.1.9. tert-Butyl 3-tert-butyl-2-methoxy-5-oxopyrrolidine-1-
carboxylate (18a)
272.1862, found: 272.1864.
To a stirred suspension of CuI (0.3 g, 1.6 mmol) in THF (5 mL) at
0 ꢀC was added t-BuLi (1.4 mL, 2.2 mmol, 1.6 M in pentane) drop-
wise. The mixture was stirred at 0 ꢀC for 1.5 h, then cooled to
ꢁ78 ꢀC and TMSCl (5.8 mL) was added. The mixture was stirred for
an additional 5 min and then a solution of compound 17 (0.06 g,
0.28 mmol) in THF (1 mL) was slowly added. The solution was
stirred at ꢁ78 ꢀC for 5 min and then warmed to rt and stirred for an
additional 2 h. The mixture was quenched by the slow addition of
a saturated aqueous NH4Cl solution and was then extracted with
4.1.12. tert-Butyl 2-methoxy-3-methyl-5-oxopyrrolidine-1-
carboxylate (18e)
To a 0 ꢀC stirred suspension of CuI (0.98 g, 5.1 mmol) in THF
(20 mL) was added MeLi (4.6 mL, 7.2 mmol, 1.6 M in ether) drop-
wise. The resulting solution was stirred at 0 ꢀC for 1.5 h, cooled to
ꢁ78 ꢀC, and TMSCl (2.4 mL) was added. The mixture was stirred for
5 min and a solution of compound 17 (0.2 g, 0.94 mmol) in THF
(3 mL) was slowly added. The mixture was stirred at ꢁ78 ꢀC for
5 min, warmed to rt, and stirred for an additional 45 min. The

6726
S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
mixture was quenched by the slow addition of an aqueous NH4Cl
solution and then extracted with ether. The organic layer was
washed with a saturated aqueous NaHCO3 solution, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography to give
0.06 g (80%) of 18e as a colorless oil. IR (thin film) 1790, 1760, 1721,
J¼7.6 Hz), 5.03 (s, 2H), 6.08 (d, 1H, J¼1.6 Hz), 6.45 (d, 1H, J¼1.6 Hz),
6.96–6.98 (m, 2H), and 7.16–7.26 (m, 8H); 13C NMR (100 MHz,
CDCl3) d 14.2, 22.8, 26.9, 33.4, 50.6, 109.3, 120.5, 125.2, 126.6, 126.9,
127.4, 128.5, 128.8, 133.6, 134.9, and 139.3; HRMS calcd for
[(C21H23N)þH]þ: 290.1909, found: 290.1907.
1368, 1310, 1093, and 1023 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
1.07
4.1.16. 4-Butyl-1,2-diphenyl-1H-pyrrole (20b)
(d, 3H, J¼7.2 Hz), 1.55 (s, 9H), 2.03 (d, 1H, J¼17.2 Hz), 2.30 (p, 1H,
A sample of 19c (0.03 g, 0.79 mmol) was mixed with aniline
(0.5 mL) and a catalytic amount of p-TsOH in a sealed tube. The
mixture was subjected to microwave irradiation at 150 ꢀC (200 W)
and a maximum internal pressure of 120 psi for 30 min. After
cooling to rt, the mixture was diluted with EtOAc and washed
with 1 N HCl. The organic layer was dried over Na2SO4 and the
solvent was removed under reduced pressure. The resulting res-
idue was purified by silica gel chromatography to furnish 0.02 g
(97%) of pyrrole 20b as a yellow oil. IR (thin film) 3064, 2955,
2926, 1599, 1500, 1407, and 1072 cmꢁ1; 1H NMR (400 MHz, CDCl3)
J¼14.8 and 7.6 Hz), 2.90 (dd, 1H, J¼25.2 and 8.0 Hz), 3.42 (s, 3H),
and 4.98 (s, 1H); 13C NMR (CDCl3, 100 MHz)
56.7, 83.5, 95.3, 150.5, and 173.9.
d 18.6, 28.2, 32.4, 38.8,
4.1.13. tert-Butyl 3-hexyl-2-methoxy-5-oxopyrrolidine-1-
carboxylate (18g)
To a stirred suspension of CuI (0.98 g, 5.1 mmol) in THF (20 mL)
at 0 ꢀC was added hexyllithium (3.2 mL, 7.2 mmol, 2.3 M in hexane)
dropwise. The mixture was stirred at 0 ꢀC for 1.5 h, cooled to
ꢁ78 ꢀC, and TMSCl (2.4 mL) was added. The solution was stirred for
5 min and compound 17 (0.2 g, 0.94 mmol) in THF (3 mL) was
slowly added. The mixture was stirred at ꢁ78 ꢀC for 5 min, warmed
to rt, and stirred for an additional 2 h. The reaction mixture was
quenched by the slow addition of a saturated aqueous NH4Cl
solution and extracted with ether. The organic layer was washed
with aqueous NaHCO3 solution, dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography to give 0.17 g (60%) of 18g as
a colorless oil. IR (thin film) 1794, 1760, 1459, 1368, 1304, 1157, and
d
0.97 (t, 3H, J¼7.6 Hz), 1.40–1.50 (m, 2H), 1.61–1.69 (m, 2H), 2.55
(t, 2H, J¼7.6 Hz), 6.33 (d, 1H, J¼2.0 Hz), 6.75 (d, 1H, J¼2.0 Hz), and
7.12–7.33 (m, 10H); 13C NMR (100 MHz, CDCl3)
14.2, 22.8, 26.8,
d
33.3, 111.6, 121.9, 125.7, 125.8, 126.2, 126.4, 128.2, 128.3, 129.1,
133.3, 133.5, and 140.8; HRMS calcd for [(C20H21N)þHþ]: 276.1747,
found: 276.1749.
4.1.17. 4-Butyl-1-(furan-2-ylmethyl)-2-phenyl-1H-pyrrole (20c)
A sample of 19c (0.03 g, 0.8 mmol) was mixed with furfuryl-
amine (0.5 mL) and a catalytic amount of p-TsOH in a sealed tube.
The mixture was subjected to microwave irradiation at 150 ꢀC
(200 W) and a maximum internal pressure of 120 psi for 30 min.
After cooling to rt, the mixture was diluted with EtOAc and washed
with 1 N HCl. The organic layer was dried over Na2SO4 and the
solvent was removed under reduced pressure. The resulting residue
was purified by silica gel chromatography to furnish 0.015 g (65%)
1093 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
0.88 (t, 3H, J¼6.8 Hz), 1.25–
1.55 (m, 10H), 1.55 (s, 9H), 2.10–2.15 (m, 2H), 2.85 (dd, 1H, J¼17.6
and 7.6 Hz), 3.40 (s, 3H), and 5.04 (s,1H); 13C NMR (CDCl3,100 MHz)
d
14.3, 22.8, 27.0, 28.2, 29.3, 31.8, 32.7, 37.1, 37.7, 56.5, 83.5, 94.1,
150.5, and 174.0; HRMS calcd for [(C16H29NO4)þKþ]: 338.1734,
found: 338.1728.
of pyrrole 20c as a yellow oil. 1H NMR (400 MHz, CDCl3)
d 0.93 (t,
4.1.14. tert-Butyl 1-methoxy-2-(2-oxo-2-phenylethyl)-
hexylcarbamate (19c)
3H, J¼7.6 Hz), 1.38–1.44 (m, 2H), 1.54–1.62 (m, 2H), 2.47 (t, 2H,
J¼7.6 Hz), 6.08 (d,1H, J¼2.0 Hz), 6.13 (dd,1H, J¼3.2 and 2.0 Hz), 6.31
(dd,1H, J¼3.2 and 2.0 Hz), 7.27–7.31 (m, 1H), and 7.36–7.43 (m, 5H);
To a stirred solution containing 0.21 g (0.76 mmol) of 18c in
4 mL of THF at ꢁ78 ꢀC was added phenyllithium (0.84 mL,
1.5 mmol, 1.8 M in di-n-butylether) slowly. After stirring for 1 h at
ꢁ78 ꢀC, the reaction mixture was quenched by the slow addition
of a saturated aqueous NaHCO3 solution and was then extracted
with CH2Cl2. The organic layer was dried over Na2SO4 and con-
centrated under reduced pressure. The residue was purified by
silica gel column chromatography to provide 0.25 g (94%) of 19c as
a colorless oil. IR (thin film) 3351, 3360, 2957, 2931, 1716, 1689,
13C NMR (100 MHz, CDCl3)
d 14.2, 22.8, 26.9, 33.3, 43.8, 108.0, 109.3,
110.5, 119.9, 125.2, 127.0, 128.5, 129.1, 133.4, 134.6, 142.6, and 151.7.
4.1.18. 4-Butyl-1-cyclohexyl-2-phenyl-1H-pyrrole (20d)
A sample of 19c (0.02 g, 0.63 mmol) was mixed with cyclohexyl-
amine (0.5 mL) and a catalytic amount of p-TsOH in a sealed tube.
The mixture was subjected to microwave irradiation at 150 ꢀC
(200 W) and a maximum internal pressure of 120 psi for 30 min.
After cooling to rt, the mixture was diluted with EtOAc and washed
with 1 N HCl. The organic layer was dried over Na2SO4 and removed
under reduced pressure. The resulting residue was purified by silica
gel chromatography to furnish 0.013 g (90%) of pyrrole 20d as
a colorless oil. IR (thin film) 3064, 2928, 2855, 1603, 1510, 1466,
1596, 1503, and 1366 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 0.87 (t,
3H, J¼7.2 Hz), 1.25–1.53 (m, 15H), 245–2.51 (m, 1H), 2.82 (dd, 1H,
J¼16.8 and 5.6 Hz), 3.09 (dd, 1H, J¼16.8 and 6.8 Hz), 3.30 (s, 3H),
4.77 (dd, 1H, J¼10.8 and 6.4 Hz), 5.02 (d, 1H, J¼10.8 Hz), 7.45–7.47
(m, 2H), 7.53–7.57 (m, 1H), and 7.94 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d
14.2, 23.1, 28.3, 29.2, 30.7, 39.0, 39.1, 55.5, 79.8, 85.3,
1450, and 1183 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 0.94 (t, 3H,
128.3, 128.7, 133.2, 137.3, 156.0, and 200.4; HRMS calcd for
[(C20H31NO4)þK]: 388.1890, found: 388.1886.
J¼7.6 Hz), 1.15–1.30 (m, 3H), 1.36–1.45 (m, 2H), 1.57–1.68 (m, 5H),
1.77–1.90 (m, 2H), 1.95–2.01 (m, 2H), 3.97 (1H, dt, J¼12.0 and
4.0 Hz), 5.99 (d, 1H, J¼2.0 Hz), 6.64 (d, 1H, J¼2.0 Hz), and 7.25–7.40
4.1.15. 1-Benzyl-4-butyl-2-phenyl-1H-pyrrole (20a)
(m, 5H); 13C NMR (100 MHz, CDCl3)
d 14.2, 22.9, 25.6, 26.1, 27.1, 33.3,
To a sample containing 0.07 g (0.2 mmol) of 19c in benzylamine
(0.5 mL) was added a catalytic amount of p-TsOH in a sealed tube.
The mixture was subjected to microwave irradiation at 150 ꢀC
(200 W) and a maximum internal pressure of 120 psi for 10 min.
After cooling to rt, the mixture was diluted with EtOAc and washed
with 1 N HCl. The organic layer was dried over Na2SO4 and the
solvent was removed under reduced pressure. The resulting residue
was purified by silica gel chromatography to furnish 0.05 g (90%) of
pyrrole 20a as a colorless oil. IR (thin film) 3064, 3029, 2955, 2925,
35.1, 55.2, 108.6, 115.7, 124.4, 126.7, 128.5, 129.1, 133.7, and 134.2.
4.1.19. 1-Benzyl-2-methyl-4-phenyl-1H-pyrrole (20e)
To a stirred solution containing 0.09 g (0.3 mmol) of 18b in
1.5 mL of THF at ꢁ78 ꢀC was added MeLi (0.25 mL, 0.39 mmol, 1.6 M
in diethyl ether) slowly. After stirring for 30 min at ꢁ78 ꢀC, the
reaction mixture was quenched by the slow addition of a saturated
aqueous NaHCO3 solution and then extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The residue was filtered through a pad of silica
gel. The residue was then mixed with benzylamine (0.5 mL) and
1603, 1453, and 1353 cmꢁ1; 1H NMR (400 MHz, CDCl3)
J¼7.6 Hz), 1.31–1.37 (m, 2H), 1.51–1.57 (m, 2H), 2.43 (t, 2H,
d 0.87 (t, 3H,

S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
6727
catalytic amount of p-TsOH in a sealed tube and subjected to mi-
crowave irradiation at 150 ꢀC (200 W) with a maximum internal
pressure of 120 psi for 10 min. After cooling to rt, the mixture was
diluted with EtOAc and washed with 1 N HCl. The organic layer was
dried over Na2SO4 and removed under reduced pressure. The
resulting residue was purified by silica gel chromatography to
furnish 0.06 g (70%, over 2 steps) of pyrrole 20e as a colorless oil. IR
The organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The residue was filtered through a pad of silica
gel and was then mixed with benzylamine (0.5 mL) and catalytic
amount of p-TsOH in a sealed tube and subjected to microwave
irradiation at 150 ꢀC (200 W) with a maximum internal pressure
of 120 psi for 10 min. After cooling to rt, the mixture was diluted
with EtOAc and washed with 1 N HCl. The organic layer was dried
over Na2SO4 and removed under reduced pressure. The resulting
residue was purified by silica gel chromatography to furnish
0.023 g (86%, over 2 steps) of pyrrole 20g as a colorless oil. IR (thin
film) 3029, 2923, 2854, 1539, 1495, 1453, 1422, and 1352 cmꢁ1; 1H
(thin film) 3060, 3031, 2922, 1603, 1528, 1452, and 1213 cmꢁ1
NMR (400 MHz, CDCl3) 2.19 (s, 3H), 5.05 (s, 2H), 6.30 (s, 1H), 6.96
(d, 1H, J¼2.4 Hz), 7.07–7.09 (m, 2H), 7.13–7.17 (m, 1H), 7.30–7.36 (m,
5H), and 7.49–7.52 (m, 2H); 13C NMR (100 MHz, CDCl3)
12.3, 50.7,
;
1H
d
d
105.6, 117.8, 123.8, 125.0, 125.3, 126.6, 127.6, 128.7, 129.0, 130.2,
136.1, and 138.3; HRMS calcd for [(C18H17N)þHþ]: 248.1434, found:
248.1435.
NMR (400 MHz, CDCl3) d 2.11 (s, 3H), 5.15 (s, 2H), 6.21 (d, 1H,
J¼1.6 Hz), 6.50 (s, 1H), 6.81 (dd, 1H, J¼3.2 and 1.2 Hz), 6.94–6.97
(m, 1H), 7.02–7.05 (m, 2H), 7.19 (dd, 1H, J¼5.2 and 1.2 Hz), and
7.20–7.33 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 12.0, 50.7, 111.8,
4.1.20. 1-Benzyl-4-butyl-2-methyl-1H-pyrrole (20f)
119.3, 121.7, 124.8, 125.2, 126.6, 127.0, 127.4, 127.5, 128.9, 135.0, and
139.0.
To a stirred solution containing 0.02 g (0.074 mmol) of 18c in
0.8 mL of THF at ꢁ78 ꢀC was added methyllithium (0.09 mL,
0.15 mmol, 1.6 M in diethyl ether) slowly. After stirring for 1 h at
ꢁ78 ꢀC, the reaction mixture was quenched by the slow addition
of a saturated aqueous NaHCO3 solution and then extracted with
CH2Cl2. The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The residue was filtered through a pad of
silica gel and was then mixed with benzylamine (0.5 mL) and
catalytic amount of p-TsOH in a sealed tube and subjected to
microwave irradiation at 150 ꢀC (200 W) with a maximum in-
ternal pressure of 120 psi for 10 min. After cooling to rt, the
mixture was diluted with EtOAc and washed with 1 N HCl. The
organic layer was dried over Na2SO4 and removed under reduced
pressure. The resulting residue was purified by silica gel chro-
matography to furnish 0.014 g (81%, over 2 steps) of pyrrole 20f as
a colorless oil. IR (thin film) 3064, 3030, 2955, 2925, 2855, 1606,
4.1.23. 1-Benzyl-2-ethyl-4-hexyl-1H-pyrrole (20h)
To a stirred solution containing 0.08 g (0.38 mmol) of 18g in
2.0 mL of THF at ꢁ78 ꢀC was added ethyllithium (0.9 mL, 0.46 mmol
0.5 M in benzene/cyclohexane) slowly. After stirring for 1 h at
ꢁ78 ꢀC, the reaction mixture was quenched by the slow addition of
a saturated aqueous NaHCO3 solution and then extracted with
CH2Cl2. The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The residue was filtered through a pad of
silica gel and was then mixed with benzylamine (0.5 mL) and cat-
alytic amount of p-TsOH in a sealed tube and subjected to micro-
wave irradiation at 150 ꢀC (200 W) with a maximum internal
pressure of 120 psi for 10 min. After cooling to rt, the mixture was
diluted with EtOAc and washed with 1 N HCl. The organic layer was
dried over Na2SO4 and removed under reduced pressure. The
resulting residue was purified by silica gel chromatography to
furnish 0.044 g (42%, over 2 steps) of pyrrole 20h as a colorless oil.
IR (thin film) 3064, 2958, 2925, 1496, 1454, 1426, 1376, and
1514, 1454, 1416, 1353, and 1143 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
0.91 (t, 3H, J¼3.6 Hz), 1.32–1.41 (m, 2H), 1.50–1.53 (m, 2H), 2.10
(s, 3H), 2.42 (t, 2H, J¼3.6 Hz), 4.95 (s, 2H), 5.79 (s, 1H), 6.39 (s, 1H),
7.00 (m, 2H), and 7.22–7.32 (m, 5H); 13C NMR (100 MHz, CDCl3)
1029 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 0.86–0.91 (m, 3H), 1.18 (d,
d
12.2, 14.2, 22.8, 26.9, 33.6, 50.3, 107.6, 118.0, 123.8, 126.5, 127.3,
3H, J¼7.2 Hz), 1.30–1.40 (m, 6H), 1.53–1.59 (m, 2H), 2.42–2.46 (m,
128.7, 128.8, and 138.9; HRMS calcd for [(C16H21N)þH]þ: 228.1752,
4H), 4.97 (s, 2H), 5.83 (s, 1H), 6.40 (s, 1H), 6.71–6.99 (m, 2H), and
found: 228.1746.
7.22–7.32 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 13.0,14.3, 19.6, 22.9,
27.3, 29.5, 31.4, 32.0, 50.1, 105.5, 118.1, 123.8, 126.5, 127.3, 128.8,
135.0, and 139.0; HRMS calcd for [(C14H17N)þHþ]: 200.1434, found:
200.1433.
4.1.21. One-pot reaction of tert-butyl 3-butyl-2-methoxy-5-
oxopyrrolidine-1-carboxylate (18c) with vinyl lithium followed
by benzylamine
To a stirred solution containing 0.05 g (0.17 mmol) of 18c in
1.0 mL of THF at ꢁ78 ꢀC was added a freshly prepared vinyl lithium
solution (0.84 mL, 0.25 mmol, 0.3 M in THF) slowly. After stirring
for 1 h at ꢁ78 ꢀC, the reaction mixture was quenched by the slow
4.1.24. 1-Benzyl-2-butyl-4-methyl-1H-pyrrole (20i)
To a stirred solution containing 0.08 g (0.34 mmol) of 18e in
2.0 mL of THF at ꢁ78 ꢀC was added n-butyllithium (0.26 mL,
0.41 mmol, 1.6 M in hexane) slowly. After stirring for 1 h at ꢁ78 ꢀC,
the reaction mixture was quenched by the slow addition of a satu-
rated aqueous NaHCO3 solution and then extracted with CH2Cl2.
The organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The residue was filtered through a pad of silica
gel and was then mixed with benzylamine (0.5 mL) and catalytic
amount of p-TsOH in a sealed tube and subjected to microwave
irradiation at 150 ꢀC (200 W) with a maximum internal pressure of
120 psi for 10 min. After cooling to rt, the mixture was diluted with
EtOAc and washed with 1 N HCl. The organic layer was dried over
Na2SO4 and removed under reduced pressure. The resulting residue
was purified by silica gel chromatography to furnish 0.04 g (54%,
over 2 steps) of pyrrole 20i as a colorless oil. IR (thin film) 3064,
3029, 2956, 2928, 1605, 1496, 1454, 1420, 1384, and 1183 cmꢁ1; 1H
addition of
a saturated aqueous NaHCO3 solution and then
extracted with CH2Cl2. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The residue was filtered
through a pad of silica gel and was then mixed with benzylamine
(0.5 mL) and catalytic amount of p-TsOH in a sealed tube and
subjected to microwave irradiation at 150 ꢀC (200 W) with a max-
imum internal pressure of 120 psi for 10 min. After cooling to rt, the
mixture was diluted with EtOAc and washed with 1 N HCl. The
organic layer was dried over Na2SO4 and removed under reduced
pressure. The resulting residue was purified by silica gel chroma-
tography to furnish 0.03 g (42%, over 2 steps) of pyrrole 20f as
a colorless oil.
4.1.22. 1-Benzyl-4-methyl-2-(thiophenyl-2-yl)-1H-pyrrole (20g)
To a stirred solution containing 0.02 g (0.1 mmol) of 18e in
0.8 mL of THF at ꢁ78 ꢀC was added 0.2 mL (0.21 mmol, 1.0 M in
THF) of 2-thienyllithium slowly. After stirring for 1 h at ꢁ78 ꢀC,
the reaction mixture was quenched by the slow addition of a sat-
urated aqueous NaHCO3 solution and then extracted with CH2Cl2.
NMR (400 MHz, CDCl3)
d
0.88 (t, 3H, J¼3.2 Hz), 1.35 (m, 1H,
J¼3.2 Hz), 1.50–1.57 (m, 2H), 2.07 (s, 3H), 2.42 (t, 2H, J¼3.2 Hz), 4.96
(s, 2H), 5.80 (d, 1H, J¼1.2 Hz), 6.37 (d, 1H, J¼1.2 Hz), 7.00–7.02 (m,
2H), and 7.25–7.31 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 12.1, 14.1,
22.7, 26.1, 31.2, 50.1, 107.4, 117.8, 118.7, 126.6, 127.4, 128.8, 133.8, and
139.0.

6728
S. Kiren et al. / Tetrahedron 65 (2009) 6720–6729
4.1.25. 4-Butyl-2-phenyl-1H-pyrrole (20j)
under reduced pressure. The resulting residue was purified by silica
gel chromatography to furnish 0.03 g (43%, over 2 steps) of pyrrole
22 as a colorless oil. IR (thin film) 3060, 1604, 1561, 1531, 1494, 1452,
To a 0.03 g (0.084 mmol) sample of 19c dissolved in 0.5 mL of
DMF and H2O (1:1) was added a small amount of p-TsOH. The
mixture was subjected to microwave irradiation at 150 ꢀC (200 W)
with a maximum internal pressure of 120 psi for 10 min. After
cooling to rt, the mixture was diluted with EtOAc and washed with
1 N HCl. The organic layer was dried over Na2SO4 and removed
under reduced pressure. The resulting residue was purified by silica
gel chromatography to furnish 0.016 g (98%) of pyrrole 20j as
1400, 1301, and 1171 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.36–2.45
(m, 2H), 3.80 (s, 1H), 3.84 (s, 1H), 4.96 (d, 1H, J¼16.4 Hz), 5.04 (d, 1H,
J¼16.4 Hz), 6.40 (s,1H), 6.75 (s, 2H), 7.02–7.04 (m, 2H), and 7.22–7.36
(m, 8H); 13C NMR (100 MHz, CDCl3)
d 44.8, 44.9, 50.6, 69.5, 114.3,
126.5,126.6,126.9,127.2,128.6,128.7,129.1,133.2,136.3,136.4,140.0,
142.8, and 142.9; HRMS calcd for [(C22H19N)þHþ]: 298.1590, found:
298.1591.
a yellow solid. 1H NMR (400 MHz, CDCl3)
d
0.94 (t, 3H, J¼7.2 Hz),
1.43 (m, 2H), 1.60 (m, 2H), 2.51 (t, 2H, J¼3.6 Hz), 6.38–6.40 (m, 1H),
6.64 (m, 1H), 7.16–7.20 (m, 1H), 7.32–7.36 (m, 2H), 7.46 (m, 2H), and
Acknowledgements
8.15 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 14.2, 22.7, 26.9, 33.4,
106.6, 116.2, 123.8, 126.1, 126.7, 129.0, 132.0, and 133.1.
The financial support provided by the National Science Foun-
dation (CHE-0742663) is greatly appreciated.
4.1.26. tert-Butyl 4-butyl-2-phenyl-1H-pyrrole-1-carboxylate
(20k)
References and notes
To a 0.03 g (0.077 mmol) sample of 19c dissolved in 0.5 mL of
toluene and was added a small amount of CSA/quinoline catalyst.
The mixture was subjected to microwave irradiation at 100 ꢀC
(150 W) with a maximum internal pressure of 100 psi for 10 min.
After cooling to rt, the mixture was diluted with EtOAc and
washed with 1 N HCl. The organic layer was dried over Na2SO4
and removed under reduced pressure. The resulting residue was
purified by silica gel chromatography to furnish 0.018 g (76%) of
pyrrole 20k as a yellow oil. IR (thin film) 3062, 3026, 2957, 2929,
1. (a) Wooldridge, T. A.; Lightner, D. A. J. Heterocycl. Chem. 1977, 14, 1283; (b)
Vitillo, B.; Buniva, G.; Bernareggi, A.; Assandri, A.; Perazzi, A.; Fuccella, L. M.;
´
Palumbo, R. Int. J. Clin. Parmacol. Ther. Toxicol. 1984, 22, 273; (c) Semonsky, M.;
ˇ
Cerny´, A.; Kotva, R.; Zika´n, V.; Kaka´c, B. Collect. Czech. Chem. Commun. 1968, 33,
2698; (d) Wiedhopf, R. M.; Trumbull, E. R.; Cole, J. R. J. Pharm. Sci. 1973, 62, 1206;
(e) Yakushijin, K.; Kozuka, M.; Ito, Y.; Suzuki, R.; Furukawa, H. Heterocycles 1980,
14, 1073.
2. (a) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989, 111, 2588;
(b) Newcombe, N. J.; Ya, F.; Vijin, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem.
Soc., Chem. Commun. 1994, 767; (c) Speckamp, W. N.; Newcombe, N. J.; Hiem-
stra, H.; Ya, F.; Vijin, R. J.; Koot, W. J. Pure Appl. Chem. 1994, 66, 2163; (d)
Casiraghi, G.; Spanu, P.; Rassu, G.; Pinna, L.; Ulgheri, F. J. Org. Chem. 1994, 59,
2906; (e) Griffart-Brunet, D.; Langois, N. Tetrahedron Lett. 1994, 35, 119.
3. (a) Jouin, P.; Castro, B. J. Chem. Soc., Perkin Trans. 1 1987, 1177; (b) Ma, D.; Ma, J.;
Ding, W.; Dai, L. Tetrahedron: Asymmetry 1996, 7, 2365.
2857, 1734, 1600, 1524, 1476, 1343, and 1158 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
0.86 (t, 3H, J¼7.2 Hz), 1.26–1.39 (m, 11H),
1.45–1.53 (m, 2H), 2.35 (t, 3H, J¼7.2 Hz), 5.99 (d, 1H, J¼2.0 Hz),
7.02 (m, 1H), and 7.20–7.26 (m, 5H); 13C NMR (100 MHz, CDCl3)
4. (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503; (b) Meyers, A. I.; Snyder,
L. J. Org. Chem. 1992, 57, 3814; (c) Farina, F.; Martin, M. V.; Paredes, M. C. Syn-
thesis 1973, 167; (d) Ma, S.; Xie, H. Org. Lett. 2000, 2, 3801.
d
14.1, 22.6, 26.6, 27.8, 32.5, 83.3, 115.9, 119.2, 126.7, 127.2, 127.7,
129.2, 134.8, 135.1, and 149.6.
5. (a) Jimenez, M. D.; Ortega, R.; Tito, A.; Farina, F. Heterocycles 1988, 27, 173; (b)
Koot, W. J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron: Asymmetry 1993, 4,
1941.
6. (a) Koot, W. J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1992, 57, 1059; (b)
Cooper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P.; Redpath, J. Tetrahedron
1995, 51, 7791.
7. Koot, W. J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1992, 33, 7969.
8. Cuiper, A. D.; Kellogg, R. M.; Feringa, B. L. Chem. Commun. 1998, 655.
9. McKennis, H.; Bowman, E. R.; Quin, L. D.; Denney, R. C. J. Chem. Soc., Perkin Trans.
1 1973, 2046.
4.1.27. 3-Methoxy-5-oxo-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-4-
carboxylic acid tert-butyl ester (21)
To a solution of 0.45 g (2.1 mmol) of 2-methoxy-5-oxo-2,5-
dihydro-pyrrole-1-carboxylic acid tert-butyl ester (9d) in 5 mL of
toluene was added 1 mL of fresh distilled cyclopentadiene and the
mixture was heated at 110 ꢀC in a sealed pressure tube for 6 h. The
solution was cooled to rt, the solvent was removed under reduced
pressure, and the residue was subjected to flash silica gel chro-
matography to give 0.57 g (97%) of the titled compound 21 as
a colorless oil. IR (neat) 3061, 2979, 2937, 2874, 2833, 1784, 1747,
10. (a) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. J. Org. Chem. 1996, 61, 2845; (b)
ˇ
´
´
Ziha´n, V.; Kaka´c, B.; Holubek, J.; Vesela, H.; Semonsky, M. Collect. Czech. Chem.
Commun. 1976, 41, 3113; (c) Farin˜a, F.; Martin, M. V.; Paredes, M. C. Heterocycles
1984, 22, 1733; (d) Gill, G. B.; James, G. D.; Oates, K. V.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1993, 2567.
1458, 1354, 1301, and 1159 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.36
11. Veronese, A. C.; Callegari, R.; Basato, M.; Valle, G. J. Chem. Soc., Perkin Trans. 1
1994, 1779.
12. Arzoumanian, H.; Jean, M.; Nuel, D.; Garcia, J. L.; Rosas, N. Organometallics 1997,
16, 2726.
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(d, 1H, J¼6.0 Hz), 1.48 (s, 9H), 1.54 (d, 1H, J¼6.0 Hz), 2.60 (dd, 1H,
J¼5.6 and 3.0 Hz), 3.13 (s, 1H), 3.22 (dd, 1H, J¼5.6 and 3.2 Hz), 3.30
(s, 1H), 3.34 (s, 3H), 4.76 (s, 1H), 6.08 (dd, 1H, J¼4.0 and 2.0 Hz),
6.14 (dd, 1H, J¼4.0 and 2.0 Hz); 13C NMR (100 MHz, CDCl3)
d 27.6,
41.9, 45.2, 46.0, 49.5, 50.8, 54.6, 82.6, 90.2, 132.7, 135.7, 149.2, and
174.6; HRMS calcd for [(C15H21NO4)þH]þ: 280.1549, found:
280.1543.
4.1.28. Formation of pyrrole 22
To a stirred solution containing 0.05 g (0.17 mmol) of 21 in 1.0 mL
of THF at ꢁ78 ꢀC was slowly added phenyllithium (0.2 mL,
0.34 mmol,1.8 M in di-n-butylether). After stirring for 1 h at ꢁ78 ꢀC,
the reaction mixture was quenched by the slow addition of a satu-
rated aqueous NaHCO3 solution and the mixture was extracted with
CH2Cl2. The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The residue was filtered through a pad of
silica gel and mixed with benzylamine (0.5 mL) together with
a catalytic amount of p-TsOH in a sealed tube. The mixture was
subjected to microwave irradiation at 150 ꢀC (200 W) with a maxi-
mum internal pressure of 120 psi for 10 min. After cooling to rt, the
mixture was diluted with EtOAc and washed with 1 N HCl. The
organic layer was dried over Na2SO4 and the solvent was removed
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