The application of vinylogous iminium salt derivatives to efficient formal syntheses of the marine alkaloids lamellarin G trimethyl ether and ningalin B

Article abstract of DOI:10.1016/j.tet.2009.03.085

Studies directed at the synthesis of lamellarin G trimethyl ether and ningalin B via vinylogous iminium salt derivatives are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 1,2,3,4-tetrasubstituted pyrrole fr

Full text of DOI:10.1016/j.tet.2009.03.085

Tetrahedron 65 (2009) 4283–4292
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The application of vinylogous iminium salt derivatives to efficient formal
syntheses of the marine alkaloids lamellarin G trimethyl ether and ningalin B
*
John T. Gupton , Benjamin C. Giglio, James E. Eaton, Elizabeth A. Rieck, Kristin L. Smith, Matthew J.
Keough, Peter J. Barelli, Lauren T. Firich, Jonathan E. Hempel, Timothy M. Smith, Rene P.F. Kanters
Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Studies directed at the synthesis of lamellarin G trimethyl ether and ningalin B via vinylogous iminium
salt derivatives are described. The successful strategy relies on the formation of a 2,4-disubstituted
pyrrole or a 1,2,3,4-tetrasubstituted pyrrole from a vinylogous iminium salt or vinylogous iminium salt
derivative. Subsequent transformations of these highly substituted pyrroles lead to efficient and re-
giocontrolled formal syntheses of the respective pyrrole containing natural products.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 January 2009
Received in revised form 11 March 2009
Accepted 26 March 2009
Available online 1 April 2009
Keywords:
Vinamidinium salt
Pyrrole
Marine natural product
Microwave acceleration
1. Introduction
The first synthesis of the lamellarins was accomplished by
Steglich4 and co-workers whereby lamellarin G trimethyl ether was
The first lamellarin alkaloids were initially isolated from marine
prosobranch mollusks and reported1 by Faulkner and Clardy in
1985 and, since that time, great interest has emerged2 as a conse-
quence of their very interesting biological activity.3 The lamellarins
can be viewed as having three types of structural motifs as repre-
sented in Figure 1, in which a carbonyl group at C-2 and oxygenated
aryl groups at C-3 and C-4 are always present. The more structurally
complex lamellarins 2 and 3 possess isoquinoline and lactone
functionality in addition to the basic pyrrole core. There are over 30
compounds to date that are considered to be members of this
family of marine alkaloids and Steglich4 has suggested that this
class of natural products arises from secondary metabolites of 3,4-
dihydroxyphenylalanine. Bailly5 has shown that a number of
lamellarins have a clear specificity for acting on DNA manipulating
enzymes such as topoisomerase I. Lamellarins that contain the
isoquinoline architecture show the most promising bioactivity as
inhibitors of HIV-1 integrase,6 as cytotoxic7 and multi-drug re-
sistance reversal agents8 for various cancer cell lines. A number of
important reviews9 have appeared, which discuss the specific
mode of actions of these alkaloids along with structure–activity
relationships.
prepared based on a biomimetic approach as presented in Scheme 1.
A key intermediate in Steglich’s route is a pentasubstituted
pyrrole 7, which is prepared from a symmetrical bis-ketoacid 5 via
condensation with arylethylamine 6 thereby generating the highly
functionalized pyrrole 7. This pentasubstituted pyrrole is then
lactonized with lead tetraacetate and this is followed by an intra-
molecular cross-coupling reaction, which incorporates
a de-
carboxylation step and results in the desired lamellarin G trimethyl
ether (8). A variety of different synthetic approaches to lamellarin G
trimethyl ether (8) have been reported by Opatz,10 Handy,11 Iwao,12
and Ruchirawat13 and a number of recent reviews14 describe al-
ternative approaches to various lamellarins by other workers in the
field. We have previously reported formal syntheses of related
pyrrole containing natural products (Fig. 2) such as polycitone A15
(14), ningalin B16 (16), lukianol A17 (17), and permethyl stornia-
mide18 (18). We have also completed a total synthesis of the pyr-
rolopyrimidine alkaloids rigidin19 (9) and rigidin E (13). In this
paper we now describe the evolution of our strategy as it relates to
the modular and the convergent syntheses of lamellarin G tri-
methyl ether (8).
2. Results and discussions
One of the synthetic strategies that we have employed15–19 in
the past utilizes a 2,4-disubstituted pyrrole, which can be prepared
* Corresponding author. Tel.: þ1 804 287 6498; fax: þ1 804 287 1897.
E-mail address: jgupton@richmond.edu (J.T. Gupton).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.085

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J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
RO
OR
RO
N
OR
RO
RO
RO
RO
RO
OH
HO
RO
O
O
RO
N
O
O
CO2Me
N
Z
RO
Y
X
X
3
2
1
Z = oxygenated phenyl group
connected by a one or two carbon
tether to nitrogen; a carbonyl group
may be present in the tether.
X = MeO or HO or H
Y = HO or H
X = MeO or HO or H
R = Me or H or SO3Na
R = Me or H
Figure 1. Lamellarin marine natural products.
from an appropriate vinamidinium salt, as a basic building block for
the construction of many of the natural products depicted in Fig-
ure 2. Such pyrroles have been formylated at C-5 by a microwave
accelerated version18 of the Vilsmeier–Haack–Arnold procedure
and further elaborated to yield storniamide type alkaloids. We have
already mentioned that pentasubstituted pyrrole 7 (Scheme 1) was
a key intermediate in Steglich’s synthesis of lamellarin G trimethyl
ether and we have opted to use our general strategy to prepare this
highly functionalized pyrrole 7. A formylated pyrrole 19, which has
already been described in our storniamide paper,18 was iodinated
with subsequent Suzuki cross-coupling to yield a tetrasubstituted
pyrrole 21 in 50% yield for two steps after purification. N-alkylation
of such tetrasubstituted pyrroles has been accomplished in the past
by our group and also Boger’s group20 by employing base mediated
reaction with arylethyl mesylates or arylethyl halides. The mesylate
required for the alkylation step was prepared by bromination of 2-
(3,4-dimethoxyphenyl)ethanol (22) with NBS to give 2-(2-bromo-
4,5-dimethoxyphenyl)ethanol11 (23), which was then reacted with
methanesulfonyl chloride in the presence of triethylamine yielding
2-(2-bromo-4,5-dimethoxyphenethyl) methanesulfonate (24). One
of the problems with such alkylations is the formation of styrenes
via an elimination pathway and careful temperature control for
these reactions becomes crucial. By running this alkylation with
microwave heating at 70 ꢀC we overcame this side reaction and
provided the desired pentasubstituted pyrrole 25 very cleanly in
67% yield. Subsequent oxidation of the formyl group was accom-
plished with sodium chlorite to yield the corresponding acid 26 in
84% yield and the final hydrolysis step to prepare the Steglich
synthon 7 (96% yield) was carried out in aqueous DMSO at 80 ꢀC.
The hydrolysis step was surprisingly sluggish perhaps due to the
sterically hindered nature of the ester group. The overall yield of
the Steglich synthon was 27% from the formylpyrrole 19 and, al-
though our strategy has significantly more steps than Steglich’s
scheme, our route provides a very modular approach for the
HOOC
O
n-BuLi at -70 °C followed
by I2 followed by rt
O
HOOC
O
MeO
MeO
COOH
OMe
MeO
MeO
4
5
OMe
NH2
Br
Molecular sieves
and rt
OMe
OMe
6
MeO
MeO
OMe
OMe
MeO
MeO
MeO
MeO
MeO
OMe
1. Pb(OAc)4, EtOAc
and heat
HOOC
COOH
O
N
N
2. Pd(OAc)2, PPh3
Et3N and heat
in MeCN
O
Br
Lamellarin G trimethyl ether
8
OMe
OMe
7
Scheme 1. Steglich synthesis of lamellarin G trimethyl ether.

J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
4285
Y
HO
Br
Br
HO
OH
Br
O
Z
HO
X
N
Br
Br
HO
O
Br
OH
N
H
N
X
N
H
O
O
O
Br
Br
9 X = Y = Z = H Rigidin
10 X = OCH3 Y = Z = H Rigidin B
11 Y = OCH3 X = Z = H Rigidin C
12 X = Y = OCH3 Z = H Rigidin D
13 X = Y = H Z = CH3 RigidinE
14 Polycitone A X = 4-hydroxyphenethyl
15 Polycitone B X = H
HO
OMe
OMe
OH
N
HO
HO
OH
OH
MeO
MeO
OMe
OMe
H
N
H
N
O
O
N
N
O
O
O
O
MeO
OMe
OH
OMe
18 Permethyl Storniamide A
Figure 2. Pyrrole containing marine natural products.
OH
OH
16 Ninaglin B
17 Lukianol A
preparation of SAR guided analogs and subsequent biological
evaluation of these substances.
We have reported16 (Scheme 5) the preparation of 3-chloro-2,3-
bis(3,4-dimethoxyphenyl)chloroenal (33) and we have used this
material as a mixture of E and Z isomers and also as the pure E-
isomer in our synthesis of ningalin B hexamethyl ether (36). The E-
isomer, which is predominant when the chloroenal is formed,
normally precipitates during workup and can be easily isolated in
pure form. Alternatively, one can workup the product so as to iso-
late a 4:1 mixture of E:Z isomers.
During the course of our work on our initial route (Scheme 2) to
the Steglich synthon 7, we decided to look at a more convergent
manner for introducing N-substitution on possible pyrrole in-
termediates. We were intrigued by the report of Pfefferkorn21 and
co-workers at Pfizer in which case they were able to cleanly prepare
ethyl N-isopropyl glycinate by reaction of isopropyl amine with
ethyl
ucts. As a result, we reacted (Scheme 3) 2 equiv of 3,4-dimethoxy-
phenyethylamine (27) with ethyl -bromoacetate in THF at room
a
-bromoacetate without detecting any over alkylation prod-
With this material in hand, we reacted (Scheme 6) the pure
E-isomer with N-2-(2-bromo-4,5-dimethoxyphenylethyl)glycine
ethyl ester (29) with microwave heating in DMF at 150 ꢀC for
a three-hour period in which case we isolated an 83% yield of the
desired tetrasubstituted pyrrole 37. When the reaction was re-
peated with the mixture of E and Z isomers of chloroenal 33, an 88%
yield of tetrasubstituted pyrrole 37 was obtained. This reaction
proved to be very clean and efficient thereby generating a very
highly functionalized pyrrole. Formylation of pyrrole 37, using our
microwave accelerated version of the Vilsmeier–Haack–Arnold
reaction, produced a 92% yield of pentasubstituted pyrrole 25,
which was chromatographically and spectroscopically identical to
the material (Scheme 2) that we had generated by our initial route
thereby constituting an alternative formal synthesis of the Steglich
synthon (Scheme 1).
a
temperature. The second equivalent of the amine is used to neu-
tralize the hydrogen bromide that is generated and precipitates as
the salt, which is removed by filtration. The filtrate is concentrated
to give nearly analytical pure N-2-(3,4-dimethoxyphenyl-
ethyl)glycine ethyl ester (28) in 96% yield. This material was used
without further purification and was brominated with NBS to give
N-2-(2-bromo-4,5-dimethoxyphenylethyl)glycine ethyl ester (29)
in 78% yield. With appropriately N-substituted glycine esters 28
and 29 in hand, we wanted to test the ability of such compounds
to undergo successful condensation with vinylogous iminium salts
or their derivatives in generating N-substituted pyrroles in good
yield.
We have previously reported17,22 that N-methylglycinate esters
react (Scheme 4) cleanly with b-chloroenals such as 30, which are
derived from chloropropenimium salts, and produce 1,2,3,4-tetra-
substituted pyrroles in yields in the 90% range. When we reacted N-
2-(3,4-dimethoxyphenylethyl)glycine ethyl ester (28) with such
As a consequence of our earlier studies16 (Scheme 5) on ningalin
B hexamethyl ether, we realized that we should now be able to
extrapolate (Scheme 7) our new more convergent approach to
this alkaloid as well. Reaction of N-2-(3,4-dimethoxyphenyl-
ethyl)glycine ethyl ester (28) with 3-chloro-2,3-bis(3,4-dimeth-
oxyphenyl)chloroenal (33, as a mixture of E and Z isomers) with
microwave heating in DMF for 3 h produced (Scheme 7) the desired
tetrasubstituted pyrrole 38 in 98% yield. Base mediated hydrolysis
of this material resulted in a 68% yield of carboxylic acid 39, which
was spectroscopically and chromatographically identical to the
a b-chloroenal (as a mixture of E and Z isomers) with microwave
heating in DMF for 3 h, the desired pyrrole 32 was obtained in 54%
yield. No attempt was made to optimize this reaction and, given
that a proof of concept was established, we proceeded to apply such
conditions to our alternative synthesis of the Steglich synthon 7.

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J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
OMe
OMe
O
MeO
MeO
I
NaOH, I2 in DMF
H
H
CO2Et
CO2Et
N
H
N
H
O
19
20 (82% yield)
OMe
OMe
Pd(PPh3)4, Toluene
K2CO3, EtOH and heat
OMe
O
OMe
MeO
OMe
B(OH)2
H
OMe
MeO
OMe
CO2Et
N
OMe
K2CO3 in DMF
with microwave heating
Br
OMs
H
CO2Et
N
H
OMe
O
OMe
Br
25 (67% yield)
21 (61% yield)
OMe
OMe
24
NaClO2 in DMSO/H2O
with buffer
OMe
OMe
OH
OMe
OMe
OMe
MeO
OMe
MeO
KOH/H2O/DMSO
and heat
HO
HO
Br
N
CO2Et
N
O
O
O
Br
OMe
OMe
OMe
OMe
7 Steglich Synthon (96% yield)
26 (84% yield)
Scheme 2. Gupton group route 1 to Steglich synthon.
material previously reported by the Steglich group4 and our
research group16 as a precursor to ningalin B hexamethyl ether.
for this biologically important class of marine alkaloids. Such
methodology relies on the use of readily available vinylogous imi-
nium salt derivatives along with microwave accelerated reaction
conditions. In addition, the convergent approach (Scheme 6) was
also successfully applied to an improved formal synthesis (Scheme
7) of the marine alkaloid ningalin B. This methodology should fa-
cilitate further studies directed at probing the structure–activity
relationships for the lamellarins, the ningalins and other related
3. Conclusions
In this paper we have reported two new methods for the formal
synthesis of lamellarin G trimethyl ether (8) thereby establishing
both a modular (Scheme 2) and a convergent (Scheme 6) synthesis
OMe
OMe
OMe
NBS, chloroform
and heat
OMe
OMe
OMe
THF at rt
O
Br
Br
OEt
N
NH2
27
N
H
H
EtO
O
EtO
O
28 (96% yield)
29 (78% yield)
Scheme 3. Preparation of N-substituted glycines.

J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
4287
MeO
OMe
OMe
Cl
H
DMF and heat
OEt
MeO
O
N
R
R
OEt
N
O
H
O
30
R = Me
R =
31 (90% yield) R = Me
32 (54% yield) R =
OMe
OMe
Scheme 4. Convergent synthesis of N-substituted pyrroles.
OMe
OMe
classes of important marine natural products and their
derivatives.23
spectrometer at the University of Richmond. Low resolution GC–MS
spectra were obtained on a Shimadzu QP 5050 instrument. Melting
points and boiling points are uncorrected. Flash chromatographic
separations were carried out on a Biotage SP-1 instrument, which
had been equipped with a silica cartridge, and ethyl acetate/hexane
was used as the eluant. The desired, pyrrole containing products
were eluted within the range of 6–8 column volumes of eluant with
a mix of 60–80% ethyl acetate/20–40% hexane. Microwave accel-
erated reactions were carried out in a Biotage Liberator system.
Microwave reactions were controlled at a constant temperature
whereby the microwave power was allowed to fluctuate so as to
maintain a constant temperature and safe pressure limits. TLC
analyses were conducted on silica plates with hexane/ethyl acetate
as the eluant. Vinamidinium salts utilized for pyrrole formation
were prepared according to standard procedures.24 All purified
reaction products gave TLC results, GC–MS spectra, flash
4. Experimental
4.1. General
All chemicals were used as received from the manufacturer
(Aldrich Chemicals and Fisher Scientific) and all reactions were
carried out under a nitrogen or argon atmosphere. All solvents were
dried over 4 Å molecular sieves prior to their use. NMR spectra
were obtained on either a Bruker 300 MHz spectrometer or
a Bruker 500 MHz spectrometer in either CDCl3, DMSO-d6 or ace-
tone-d6 solutions. IR spectra were recorded on a Nicolet Avatar 320
FT-IR spectrometer with an HATR attachment. High resolution mass
spectra were provided on
a
Biotof Q electrospray mass
MeO
OMe
MeO
MeO
OMe
OMe
Cl
OMe
H2N
O
O
MeO
MeO
H
CO2Me
DMF and heat
N
H
33
34 (92% yield)
MeO
MeO
OMs
NaH, DMF
and heat
MeO
MeO
MeO
OMe
MeO
MeO
OMe
OMe
O
N
CO2Me
N
O
1. NaOH, water/EtOH and heat
2. LTA, Ethyl Acetate and heat
OMe
OMe
OMe
OMe
36 (47% yield of Ningalin B
Hexamethyl Ether for two steps)
35 (71% yield)
Scheme 5. Gupton group initial route to ningalin B hexamethyl ether.

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J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
MeO
MeO
OMe
OMe
Br
MeO
H
OMe
MeO
MeO
CO2Et
N
Cl
NH
CO2Et
29
O
MeO
MeO
Br
DMF with microwave
heating at 150 °C for 3 hrs.
OMe
OMe
33
37 (88% yield from a mix of E and Z
isomeric chloroenals and an 83% yield
from the pure E -chloroenal isomer)
MeO
MeO
OMe
OMe
H
CO2Et
N
O
Br
POCl3 in DMF and
microwave heating
at 100 °C for 7 mins.
OMe
OMe
25 (92% yield)
Scheme 6. Gupton group route 2 to Steglich synthon.
chromatograms and 13C NMR spectra consistent with a sample
purity of >95%. When the preparation of an analytical sample is
reported, the crude reaction product was of sufficient purity to be
used in subsequent steps without further purification.
4.1.1. Ethyl 2-formyl-3-(3,4-dimethoxyphenyl)-4-iodopyrrole-5-
carboxylate (20)
Into a three-necked, round bottom flask, equipped with a stir
bar was charged 0.500 g (16.5 mmol) of ethyl 2-formyl-3-(3,4-
MeO
MeO
OMe
OMe
MeO
OMe
MeO
CO2Et
N
Cl
NH
MeO
28
CO2Et
O
MeO
MeO
H
DMF with microwave
heating at 150 °C for 3 hrs.
OMe
OMe
33
38 (98% yield from a mix of E and Z
isomeric chloroenals and an 97% yield
from the pure E -chloroenal isomer)
MeO
MeO
OMe
OMe
KOH, Ethano/Water
and heat
CO2H
N
OMe
OMe
39 (68% yield)
Scheme 7. Gupton group route 2 to ningalin B synthon.

J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
4289
dimethoxyphenyl)pyrrole-5-carboxylate18 (19), 15 mL of DMF, and
0.369 g (65.9 mmol) of powdered KOH. The resulting mixture was
stirred for 30 min and 0.836 g (32.9 mmol) of iodine was added in
one portion. The reaction vessel was capped and wrapped with
aluminum foil and the resulting mixture was stirred for 48 h at
room temperature. The reaction mixture was subsequently diluted
with 45 mL of 20% aqueous sodium thiosulfate and extracted with
3ꢁ30 mL of ethyl acetate. The combined organic phases were
washed with 30 mL of brine and dried over anhydrous magnesium
sulfate. The drying agent was then removed by filtration and the
filtrate was concentrated in vacuo to give 0.580 g (82% yield) of
a light brown solid. This material was of sufficient purity for use in
subsequent reactions. However, an analytical sample was prepared
by flash chromatography using an ethyl acetate/hexane gradient.
The purified product exhibited the following physical properties:
d 148.5, 148.4, 129.8, 115.8, 114.4, 113.9, 62.4, 56.2, 56.1, and 39.0; IR
(neat) broad absorption 3413 cmꢂ1; HRMS (ES) m/z calcd for
C10H13BrO3Na 282.9940, found 282.9941.
4.1.4. 2-Bromo-4,5-dimethoxyphenethyl methanesulfonate (24)
A
2.69 g (0.0103 mol) sample of 2-bromo-4,5-dimethoxy-
phenethyl alcohol (23) was dissolved in 60 mL of methylene chlo-
ride and placed into a 100 mL round bottom flask, which had been
equipped with a stir bar. To this mixture was added 2.16 mL
(0.0154 mol) of triethylamine and the resulting mixture was stirred
for 5 min, cooled in an ice-water bath, and methanesulfonyl chlo-
ride (1.00 mL, 0.0123 mol) was added dropwise. After the resulting
solution had stirred for 1 h, the reaction mixture was extracted
with 2ꢁ20 mL of 10% hydrochloric acid and 20 mL of brine solution.
The organic phase was dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to yield 3.33 g (95% yield) of an
red solid, which could be used without further purification and
exhibited the following physical properties: mp 97–100 ꢀC; 1H
mp 175–177 ꢀC; 1H NMR (DMSO-d6)
d 13.19 (br s, 1H), 9.49 (s, 1H),
7.04 (d, J¼8.0 Hz, 1H), 7.00 (d, J¼2.0 Hz, 1H), 6.93 (d of d, J¼2.0 Hz,
J¼8.0 Hz, 1H), 4.33 (q, J¼7.0 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), and
1.36 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
d
180.8, 159.3, 149.6, 148.8,
NMR (CDCl3)
d
7.04 (s,1H), 6.80 (s,1H), 4.43 (t, J¼7.0 Hz, 2H), 3.88 (s,
139.7, 130.9, 127.4, 124.1, 123.5, 113.9, 111.0, 61.9, 56.1, 55.0, and 14.3;
IR (neat) 3383, 1713, and 1658 cmꢂ1; HRMS (ES) m/z calcd for
C16H16NO5INa 451.9965, found 451.9972.
3H), 3.87 (s, 3H), 3.15 (t, J¼7.0 Hz, 2H), and 2.93 (s, 3H); 13C NMR
(CDCl3) d 148.9, 148.6, 127.4, 115.7, 114.3, 114.0, 68.7, 56.2, 56.1, 37.4,
and 35.7; IR (neat) 1336 and 1161 cmꢂ1; HRMS (ES) m/z calcd for
C11H15BrO5Na 360.9716, found 360.9708.
4.1.2. Ethyl 5-formyl-3,4-bis-(3,4-dimethoxyphenyl)pyrrole-2-
carboxylate (21)
4.1.5. Ethyl N-2-(2-Bromo-4,5-dimethoxyphenethyl)-3,4-bis-(3,4-
Into a dry, 7 mL microwave reaction vessel were placed 0.200 g
(0.466 mmol) of ethyl 2-formyl-3-(3,4-dimethoxyphenyl)-4-iodo-
pyrrole-5-carboxylate (20), 6 mL of a 3:1 mixture of toluene/etha-
nol, 0.254 g (1.39 mmol) of 3,4-dimethoxyphenylboronic acid,
potassium carbonate (0.219 g, 1.58 mmol), 0.107 g (0.093 mmol) of
palladium tetrakistriphenylphosphine, and 2 drops of water. The
reaction vessel was sealed (Crymper seal) and heated by micro-
waves at 110 ꢀC for 1 h in a Liberator Microwave Reactor. This
process was repeated for two additional runs and the three crude
reaction mixtures were combined and passed through a short plug
of silica. The silica plug was washed with 50 mL of ethyl acetate and
the combined filtrate was washed with 2ꢁ50 mL of 10% NaOH so-
lution and 50 mL of brine. After drying the organic phase over an-
hydrous magnesium sulfate and filtering off the drying agent, the
reaction mixture was concentrated in vacuo and the resulting crude
product was purified by flash chromatography with a hexane/ethyl
acetate gradient, which resulted in 0.376 g (61% yield) of a solid that
exhibited the following properties: mp 161–163 ꢀC; 1H NMR
dimethoxyphenyl)-5-formylpyrrole-2-carboxylate (25)
4.1.5.1. Method A. A 0.300 g (0.682 mmol) sample of ethyl 5-for-
myl-3,4-bis(3,4-dimethoxyphenyl)pyrrole-2-carboxylate (21) was
placed into a 20 mL microwave reactor vessel along with potassium
carbonate (0.283 g, 2.04 mmol), 12 mL of dry DMF, and a stir bar.
The mixture was placed under a nitrogen blanket and stirred for 1 h
after which 1.158 g (3.41 mmol) of 2-bromo-4,5-dimethoxy-
phenethyl methanesulfonate (24) was added in one portion. The
reaction vessel was sealed and heated by microwaves at 70 ꢀC for
3 h. After cooling to room temperature, the reaction mixture was
diluted with 20 mL of ethyl acetate and 30 mL of water. After sep-
arating the phases, the aqueous phase was extracted with 3ꢁ20 mL
of ethyl acetate and the combined organic phases were dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The resulting crude material was purified by flash chromatography
with a Biotage 25S silica column using an ethyl acetate/hexane
gradient. The purified product (0.314 g, 67% yield) exhibited the
following physical properties: mp 50–53 ꢀC; 1H NMR (acetone-d6)
(DMSO-d6)
d
9.61 (br s, 1H), 6.88 (d, J¼8.4 Hz, 1H), 6.83 (d, J¼8.4 Hz,
1H), 6.76 (d of d, J¼2.1 Hz, J¼8.4 Hz, 1H), 6.74 (d, J¼2.1 Hz, 1H), 6.70
(d, J¼2.1 Hz, 1H), 6.64 (d of d, J¼2.1 Hz, J¼8.4 Hz, 1H), 4.15 (q,
J¼7.2 Hz, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 3.58 (s, 3H), 3.52 (s, 3H), and
d
9.64 (s, 1H), 7.08 (s, 1H), 6.91 (d, J¼7.0 Hz, 1H), 6.81–6.84 (m, 2H),
6.75 (d, J¼2.0 Hz, 1H), 6.63 (d, J¼2.0 Hz, 1H), 6.62 (s, 1H), 6.59 (d of
d, J¼2.0 Hz, J¼8.5 Hz, 1H), 5.11 (t, J¼6.5 Hz, 2H), 3.92 (q, J¼7.0 Hz,
2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.66 (s, 3H),
3.62 (s, 3H), 3.12 (t, J¼6.5 Hz, 2H), and 0.91 (t, J¼7.0 Hz, 3H); 13C
1.13 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d 181.3, 160.3, 148.8, 148.6,
148.4, 148.1, 134.9, 130.3, 129.8, 124.0, 123.9, 123.8, 123.4, 123.3,
114.3, 113.8, 111.0, 110.5, 61.2, 55.9, 55.8, 55.7, 55.6, and 14.2; IR
(neat) 1685 and 1658 cmꢂ1; HRMS (ES) m/z calcd for C24H25NO7INa
462.1523, found 462.1525.
NMR (CDCl3)
d 182.3, 161.3, 148.5, 148.3, 148.2, 148.1, 148.0, 147.9,
137.5, 129.4, 129.1, 129.0, 128.1, 126.1, 124.2, 123.7, 122.8, 115.1, 114.7,
113.9, 113.8, 113.4, 110.6, 110.3, 61.1, 56.1, 55.9, 55.8, 55.7, 55.6, 46.3,
37.5, and 13.7; IR (neat) 1709 and 1654 cmꢂ1; HRMS (ES) m/z calcd
for C34H37NO9Br 682.1652, found 682.1666.
4.1.3. 2-Bromo-4,5-dimethoxyphenethyl alcohol (23)
3,4-Dimethoxyphenethyl alcohol (22, 3.00 g, 0.0164 mol) was
dissolved in 100 mL of chloroform and placed in a round bottom
flask, which had been equipped with a stir bar and reflux con-
denser. To the reaction mixture was added 3.22 g (0.0181 mol) of N-
bromosuccinimide and the resulting mixture was heated at reflux
for 6 h. After cooling to room temperature, the reaction mixture
was washed with 20% aqueous sodium thiosulfate, dried over an-
hydrous magnesium sulfate, filtered, and concentrated in vacuo to
yield 4.26 g (100% yield) of an oil. The resulting material could be
used without further purification and exhibited11 the following
4.1.6. Ethyl N-2-(2-bromo-4,5-dimethoxyphenethyl)-3,4-bis-(3,4-
dimethoxyphenyl)-2-carbethoxypyrrole-5-carboxylic acid (26)
Ethyl N-[2-(2-bromo-4,5-dimethoxyphenethyl)]-3,4-bis-(3,4-
dimethoxyphenyl)-5-formylpyrrole-2-carboxylate (25, 0.220 g,
0.322 mmol) was dissolved in 40 mL of DMSO and placed in
a 100 mL round bottom flask, which had been equipped with
a stir bar. Sodium hydrogen phosphate monohydrate (0.044 g,
0.322 mmol) was dissolved in 10 mL of water and added to the
reaction mixture. The resulting solution was cooled in an ice/
water bath and a solution of 0.087 g (0.967 mmol) sodium chlorite
in 10 mL of water was added to the reaction mixture, dropwise
properties: bp 138–139 ꢀC; 1H NMR (CDCl3)
d 7.05 (s, 1H), 6.81 (s,
1H), 3.87–3.90 (m, 8H), and 2.98 (t, J¼6.5 Hz, 2H); 13C NMR (CDCl3)

4290
J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
with stirring. The resulting mixture was stirred for 20 h at room
temperature, made acidic with 6 M hydrochloric acid, and
extracted with 3ꢁ30 mL of ethyl acetate. The combined organic
phases were washed with 1ꢁ50 mL of brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to leave
a dark brown solid (0.260 g, 84% yield). An analytical sample was
prepared by radial chromatography on a 2 mm thick plate of silica
with a hexane/ethyl acetate gradient and the resulting purified
material exhibited the following physical properties: mp 135–
4.1.9. N-2-(2-Bromo-4,5-dimethoxyphenylethyl)glycine
ethyl ester (29)
N-2-(3,4-Dimethoxyphenylethyl)glycine ethyl ester (28, 2.000 g,
0.00748 mol) was placed in a 100 mL round bottom flask, which had
been equipped with a stir bar. To the flask were added 50 mL of
chloroform and N-bromosuccinimide (1.465 g, 0.00823 mol) and
the resulting mixture was refluxed for 6 h. After cooling the reaction
mixture to room temperature, the chloroform solution was extrac-
ted with 3ꢁ30 mL of 20% sodium thiosulfate solution, 3ꢁ30 mL of
saturated sodium bicarbonate solution, and 1ꢁ30 mL of brine. The
organic phase then was dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to leave a dark oil (2.022 g, 78%
yield). An analytical sample was prepared by Kugelrohr bulb to bulb
distillation and the resulting distillate exhibited the following
137 ꢀC; 1H NMR (acetone-d6)
d 7.07 (s, 1H), 6.75–6.77 (m, 2H),
6.66–6.70 (m, 2H), 6.63 (s, 1H), 6.59 (d, J¼2.0 Hz, 1H), 6.55 (d of d,
J¼2.0 Hz, J¼8.0 Hz, 1H), 5.09 (t, J¼6.5 Hz, 2H), 3.94 (q, J¼7.0 Hz,
2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.75 (s, 3H), 3.64 (s,
3H), 3.62 (s, 3H), 3.15 (t, J¼6.5 Hz, 2H), and 0.92 (t, J¼7.0 Hz, 3H);
13C NMR (acetone-d6)
d
162.2, 161.2, 149.1, 148.9, 148.4, 148.3,
properties: bp 154–155 ꢀC at 1.6 Torr; 1H NMR (CDCl3)
d 6.98 (s, 1H),
148.2, 148.1, 130.9, 130.0, 129.4, 127.4, 125.5, 123.1, 122.9, 115.9,
115.7, 115.2, 115.1, 114.1, 114.0, 110.9, 110.8, 110.7, 60.1, 55.6, 55.3,
6.76 (s,1H), 4.16 (q, J¼7.5 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.42 (br s,
2H), 2.85 (br s, 4H), and 1.25 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3)
55.2, 55.1, 55.0, 45.7, 37.5, and 13.1; IR (neat) 1705 and 1666 cmꢂ1
;
d 172.3, 148.4, 148.2, 131.0, 115.7, 114.2, 113.4, 60.7, 56.1, 56.0, 50.9,
HRMS (ES) m/z calcd for C34H36NO10BrNa 720.1415, found 720.
49.3, 36.3, and 14.2; IR (neat) 1728 cmꢂ1; HRMS (ES) m/z calcd for
1405.
C14H21NO4Br 346.0649, found 346.0658.
4.1.7. N-2-(2-Bromo-4,5-dimethoxyphenethyl)-3,4-bis-(3,4-
dimethoxyphenyl)pyrrole-2,5-dicarboxylic acid (7)
4.1.10. Ethyl N-2-(3,4-dimethoxyphenethyl)-3,4-bis-(4-
methoxyphenyl)pyrrole-2-carboxylate (32)
A 250 mL three-necked, round bottom flask was equipped
with a condenser, thermometer, and stir bar. Into the flask was
N-2-(3,4-Dimethoxyphenylethyl)glycine ethyl ester (28, 0.172 g,
0.644 mmol) was placed into a 10 mL microwave reactor vessel
along with 3-chloro-2,3-bis(4-methoxyphenyl)propenal (30,
0.150 g, 0.495 mmol, a mixture of E and Z isomers) and 5 mL of DMF.
The reaction vessel was sealed and heated by microwaves at 150 ꢀC
for 3 h. After cooling to room temperature, the reaction mixture was
concentrated in vacuo and the residue was taken up in ethyl acetate
(50 mL) and washed with 3ꢁ15 mL of 5% hydrochloric acid and
1ꢁ50 mL of brine. The organic phase was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to leave
a dark brown solid (0.172 g, 54% yield). An analytical sample was
prepared by flash chromatography with a Biotage 25S silica column
using an ethyl acetate/hexane gradient and the resulting material
exhibited the following properties: mp 34–37 ꢀC; 1H NMR (acetone-
placed 30 mL of
a 50:50 DMSO/water mixture along with
powdered potassium hydroxide (0.225 g, 4.01 mmol) and ethyl N-
2-(2-bromo-4,5-dimethoxyphenethyl)-3,4-bis-(3,4-dimethoxyph-
enyl)-2-carbethoxypyrrole-5-carboxylic
acid
(26,
0.200 g,
0.286 mmol). The reaction mixture was heated at 80 ꢀC for 72 h,
cooled to room temperature, adjusted to pH 2 with 6 M hydro-
chloric acid, and diluted with 40 mL of water. The resulting mix-
ture was extracted with 3ꢁ30 mL of ethyl acetate and the
combined organic phases were washed with 30 mL of brine. After
drying over anhydrous magnesium sulfate and filtering off the
drying agent the organic phase was concentrated in vacuo to leave
an orange solid (0.192 g, 96% yield). An analytical sample was
prepared by trituration of the crude solid with a small amount of
ethyl acetate and the resulting material exhibited the following
physical properties: mp 182–185 ꢀC (lit. 201 ꢀC); 1H NMR (DMSO-
d6)
d
7.10 (d, J¼8.5 Hz, 2H), 7.00 (s,1H), 6.96 (d, J¼8.5 Hz, 2H), 6.88 (d,
J¼8.5 Hz, 2H), 6.87 (d, J¼8.5 Hz, 2H), 6.77 (d of d, J¼2.0 Hz, J¼8.0 Hz,
1H), 6.73 (d, J¼2.0 Hz, 1H), 6.72 (d, J¼8.0 Hz, 1H), 4.60 (t, J¼7.0 Hz,
2H), 4.02 (q, J¼7.0 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.73
(s, 3H), 3.05 (t, J¼7.0 Hz, 2H), and 0.98 (t, J¼7.0 Hz, 3H); 13C NMR
d6)
d
7.08 (s, 1H), 6.75 (d, J¼8.0 Hz, 2H), 6.63 (s, 1H), 6.53–6.55 (m,
4H), 4.90 (t, J¼7.0 Hz, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 3.69 (s, 6H),
3.52 (s, 6H), and 3.02 (t, J¼7.0 Hz, 2H); 13C NMR (DMSO-d6)
(CDCl3)
d 161.8, 158.4, 157.8, 148.9, 147.8, 131.8, 131.2, 131.0, 129.1,
d
163.0, 148.9, 148.7, 147.8, 147.7, 129.8, 129.6, 127.5, 125.1, 123.1,
128.5, 127.2, 126.1, 123.7, 120.9, 119.6, 113.6, 112.9, 112.3, 111.4, 59.6,
56.0, 55.8, 55.2, 55.1, 51.7, 37.9, and 13.8; IR (neat) 1685 cmꢂ1; HRMS
(ES) m/z calcd for C31H33NO6Na 538.2200, found 538.2190.
116.1, 115.2, 114.2, 114.1, 111.2, 56.4, 55.9, 55.8, 55.7, 46.2, and 37.8;
IR (neat) 1712 cmꢂ1; HRMS (ES) m/z calcd for C32H32NO10BrNa
692.1102, found 692.1091.
4.1.11. Ethyl N-2-(2-bromo-4,5-dimethoxyphenethyl)-3,4-bis-(3,4-
4.1.8. N-2-(3,4-Dimethoxyphenylethyl)glycine ethyl ester (28)
Into a 100 mL round bottom flask, which had been equipped
with a stir bar, was placed ethyl bromoacetate (1.800 g, 0.0108 mol)
along with 10 mL of dry THF. To this reaction vessel was added 3,4-
dimethoxyphenethylamine (27, 3.907 g, 0.0216 mol) and the
resulting reaction mixture was stirred for 24 h. The solid by-prod-
uct (3,4-dimethoxyphenethylammonium bromide) was removed
by filtration and the filtrate was concentrated in vacuo to produce
2.755 g (96% yield) of an oil, which was sufficient for use in sub-
sequent reactions. An analytical sample was obtained by Kugelrohr
bulb to bulb distillation and the resulting distillate exhibited the
following properties: bp 160–161 ꢀC at 1.6 Torr; 1H NMR (CDCl3)
dimethoxyphenyl)pyrrole-2-carboxylate (37)
4.1.11.1. Method A. E-3-Chloro-2,3-bis(3,4-dimethoxyphenyl)-
chloroenal (33, 1.241 g, 3.60 mmol) was placed into a 20 mL mi-
crowave reactor vessel, which had been equipped with a stir bar,
along with 15 mL of dry DMF and N-2-(2-bromo-4,5-dimethoxy-
phenylethyl)glycine ethyl ester (29, 1.000 g, 2.80 mmol). The re-
action vessel was sealed and heated by microwaves at 150 ꢀC for
3 h. After cooling to room temperature, the reaction mixture was
concentrated in vacuo and the residue was taken up in ethyl acetate
(50 mL) and washed with 6ꢁ20 mL of 5% hydrochloric acid and
1ꢁ50 mL of brine. The organic phase was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to leave
a dark brown solid (1.199 g, 83% yield). An analytical sample was
prepared by flash chromatography on a Biotage 25S column using
a hexane/ethyl acetate gradient and the resulting material exhibi-
ted the following physical properties: mp 47–48 ꢀC; 1H NMR (ac-
d
6.56–6.62 (m, 3H), 3.97 (q, J¼7.5 Hz, 2H), 3.67 (s, 3H), 3.64 (s, 3H),
3.21 (br s, 2H), 2.68 (t, J¼7.0 Hz, 2H), 2.57 (t, J¼7.0 Hz, 2H), and 1.06
(t, J¼7.5 Hz, 3H); 13C NMR (CDCl3)
d 172.1, 148.9, 147.4, 132.2, 120.5,
112.0, 111.4, 60.4, 55.7, 55.6, 50.6, 50.5, 35.7, and 14.0; IR (neat)
1735 cmꢂ1; HRMS (ES) m/z calcd for C14H22NO4 268.1543, found
268.1572.
etone-d6)
d
7.12 (s, 1H), 6.94 (s, 1H), 6.89 (d, J¼8.0 Hz, 1H), 6.81 (d,

J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
4291
J¼2.0 Hz, 1H), 6.75 (d, J¼8.5 Hz, 1H), 6.69 (d of d, J¼2.0 Hz, J¼8.0 Hz,
1H), 6.64 (d of d, J¼2.0 Hz, J¼8.5 Hz, 1H), 6.61 (s, 1H), 6.54 (d,
J¼2.0 Hz, 1H), 4.66 (t, J¼7.0 Hz, 2H), 4.01 (q, J¼7.0 Hz, 2H), 3.83 (s,
3H), 3.82 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.50 (s, 3H),
3.19 (t, J¼7.0 Hz, 2H), and 0.98 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
J¼2.0 Hz, 1H), 6.78 (d of d, J¼2.0 Hz, J¼8.0 Hz, 1H), 6.76 (d, J¼8.0 Hz,
1H), 6.70–6.72 (m, 3H), 6.67 (d of d, J¼2.0 Hz, J¼8.0 Hz, 1H), 6.57 (d,
J¼2.0 Hz, 1H), 4.61 (t, J¼7.0 Hz, 2H), 4.04 (q, J¼7.0 Hz, 2H), 3.82 (s,
3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.51(s, 3H),
3.06 (t, J¼7.0 Hz, 2H), and 0.98 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
d
161.7, 148.4, 148.2, 148.0, 147.7, 147.1, 130.9, 129.6, 128.8, 127.2,
d 161.7, 148.9, 148.4, 148.2, 147.9, 147.8, 147.2, 131.1, 130.9, 129.0,
126.0, 123.8, 123.0, 119.9, 119.6, 115.3, 114.3, 114.2, 113.6, 111.4, 110.9,
110.4, 59.7, 56.1, 55.9, 55.8, 55.7, 55.3, 49.5, 38.0, and 13.9; IR (neat)
1685 cmꢂ1; HRMS (ES) m/z calcd for C33H37NO8Br 654.1697, found
654.1673.
127.4, 125.8, 123.7, 123.1, 120.9, 119.8, 119.7, 114.4, 112.3, 111.6, 111.4,
111.1,110.6, 59.7, 56.0, 55.9, 55.7, 55.5, 55.4, 55.3, 51.6, 37.9, and 13.9;
IR (neat) 1676 cmꢂ1; HRMS (ES) m/z calcd for C33H37NO8Na 598
2411, found 598.2410.
4.1.11.2. Method B. A mixture of E and Z isomers of 3-chloro-2,3-
bis(3,4-dimethoxyphenyl)chloroenal (33, 0.070 g, 0.190 mmol) was
placed into a 10 mL microwave reactor vessel, which had been
equipped with a stir bar, along with 5 mL of dry DMF and N-2-(2-
bromo-4,5-dimethoxyphenylethyl)glycine ethyl ester (29, 0.087 g,
0.25 mmol). The reaction vessel was sealed and heated by micro-
waves at 150 ꢀC for 3 h. After cooling to room temperature, the
reaction mixture was concentrated in vacuo and the residue was
taken up in ethyl acetate (50 mL) and washed with 6ꢁ15 mL of 5%
hydrochloric acid and 1ꢁ50 mL of brine. The organic phase was
dried over anhydrous magnesium sulfate, filtered, and concen-
trated in vacuo to leave a dark brown solid (0.111 g, 88% yield). This
material had identical physical properties (1H NMR and TLC be-
havior) to the material prepared by Method A.
4.1.13.2. Method B. A 10 mL microwave reaction vessel was
equipped with a stir bar and placed under a nitrogen atmosphere.
Into the reaction vessel was placed a mixture of E and Z isomers of
3-chloro-2,3-bis(3,4-dimethoxyphenyl)chloroenal (33, 0.200 g,
0.551 mmol), N-2-(4,5-dimethoxyphenylethyl)-glycine ethyl ester
(28, 0.192 g, 0.717 mmol), and 6 mL of dry DMF. The reaction vessel
was sealed and heated by microwaves at 150 ꢀC for 3 h. After
cooling to room temperature, the reaction mixture was diluted
with 50 mL of ethyl acetate and extracted with 3ꢁ20 mL of 5%
hydrochloric acid and once with 20 mL of brine. After drying over
anhydrous magnesium sulfate and filtering off the drying agent the
organic phase was concentrated in vacuo to leave a yellow solid
(0.311 g, 98% yield). The crude product was purified by flash chro-
matography on a Biotage 25S column using an ethyl acetate/hexane
gradient in which case 0.189 g (60% yield) of a yellow solid was
obtained. This material had identical physical properties (1H NMR
and TLC behavior) to the material prepared by Method A.
4.1.12. Ethyl N-2-(2-bromo-4,5-dimethoxyphenethyl)-3,4-bis-(3,4-
dimethoxyphenyl)-5-formylpyrrole-2-carboxylate (25)
4.1.12.1. Method B. Phosphorousoxychloride(0.392 mL, 4.29 mmol)
was added to DMF (15 mL) with cooling in a 20 mL microwave
reactor vessel, which had been equipped with a stir bar. After
stirring for 45 min, ethyl N-[2-(2-bromo-4,5-dimethoxyphen-
ethyl)]-3,4-bis-(3,4-dimethoxyphenyl)pyrrole-2-carboxylate (37,
0.935 g, 1.43 mmol) was added to the reaction vessel and the vessel
was sealed and heated by microwaves at 100 ꢀC for 7 min. After
cooling to room temperature, the reaction mixture was diluted with
60 mL of water and extracted with 3ꢁ50 mL of ethyl acetate and the
combined organic phases were washed with 50 mL of brine and
dried over anhydrous magnesium sulfate. The organic phase was
filtered and concentrated in vacuo to leave a dark brown solid
(0.910 g, 92% yield). An analytical sample was prepared by flash
chromatography on a Biotage 25M column using a hexane/ethyl
acetate gradient and the resulting material exhibited spectral and
physical properties identical to the material prepared by Method A.
4.1.14. N-2-(4,5-Dimethoxyphenethyl)-3,4-bis-(3,4-
dimethoxyphenyl)pyrrole-2-carboxylic acid (39)
A 250 mL three-necked, round bottom flask was equipped with
a condenser, thermometer, and stir bar. Into the flask was placed
20 mL of a 50:50 ethanol/water mixture along with powdered
potassium hydroxide (0.110 g, 1.96 mmol) and ethyl N-2-(4,5-
dimethoxyphenethyl)-3,4-bis-(3,4-dimethoxyphenyl)pyrrole-2-
carboxylate (38, 0.189 g, 0.328 mmol). The reaction mixture was
heated at reflux for 24 h, cooled to room temperature, adjusted to
pH 2 with 6 M hydrochloric acid, and diluted with 30 mL of water.
The resulting mixture was extracted with 3ꢁ30 mL of ethyl acetate
and the combined organic phases were washed with 30 mL of
brine. After drying over anhydrous magnesium sulfate and filtering
off the drying agent the organic phase was concentrated in vacuo to
leave a yellow solid (0.180 g, 68% yield). An analytical sample was
prepared by passing the yellow solid through a short plug of silica
gel with a hexane:ethyl acetate gradient whereby the resulting
yellow solid exhibited proton and carbon NMR spectra identical to
those previously reported16 by our research group.
4.1.13. Ethyl N-2-(4,5-dimethoxyphenethyl)-3,4-bis-(3,4-
dimethoxyphenyl)pyrrole-2-carboxylate (38)
4.1.13.1. Method A. A 10 mL microwave reaction vessel was equip-
ped with a stir bar and placed under a nitrogen atmosphere. Into
the reaction vessel were placed E-3-chloro-2,3-bis(3,4-dimethoxy-
phenyl)chloroenal (33, 0.150 g, 0.413 mmol), N-2-(4,5-dimethoxy-
phenylethyl)glycine ethyl ester (28, 0.144 g, 0.537 mmol), and 6 mL
of dry DMF. The reaction vessel was sealed and heated by micro-
waves at 150 ꢀC for 3 h. After cooling to room temperature, the
reaction mixture was diluted with 50 mL of ethyl acetate and
extracted with 3ꢁ20 mL of 5% hydrochloric acid and once with
20 mL of brine. After drying over anhydrous magnesium sulfate and
filtering off the drying agent the organic phase was concentrated in
vacuo to leave a yellow solid (0.230 g, 97% yield). The crude product
was purified by flash chromatography on a Biotage 25S column
using an ethyl acetate/hexane gradient in which case 0.204 g (86%
yield) of a yellow solid was obtained and this compound exhibited
the following physical properties: mp 128–131 ꢀC; 1H NMR (ace-
Acknowledgements
We thank the National Institutes of Health (grant no. R15-
CA67236) for support of this research. We are exceedingly grateful
to Mr. Dave Patteson formerly of Biotage Inc. for the generous do-
nation of a Horizon HFC and SP-1 flash chromatography systems,
which were used in the majority of sample purifications, and also
for the generous donation of a Personal Chemistry Emrys Liberator
US microwave reaction system, which was utilized for microwave
accelerated reactions. Recent grants from the MRI program of the
National Science Foundation for the purchase of a 500 MHz NMR
spectrometer (CHE-0116492) and an electrospray mass spectrom-
eter (CHE-0320669) are also gratefully acknowledged. We would
also like to thank the Arnold and Mabel Beckman Foundation for
fellowship support to Benjamin C. Giglio. I would also like to thank
Dr. Jeff Seeman and Dr. Wade Downey for reading this manuscript
and providing helpful comments.
tone-d6)
d
7.05 (s, 1H), 6.91 (d of d, J¼2.0 Hz, J¼8.0 Hz, 1H), 6.82 (d

4292
J.T. Gupton et al. / Tetrahedron 65 (2009) 4283–4292
2004; Vol. 16, pp 1–26; (e) Banwell, M.; Goodwin, T.; Ng, S.; Smith, J.; Wong, D.
References and notes
Eur. J. Org. Chem. 2006, 14, 3043.
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Keertikar, K.; Lauerman, N.; Solano, J.; Adams, B.; Callahan, D.; Little, B.; Scharf,
A.; Sikorski, J. Tetrahedron 2005, 61, 1845.
16. Gupton, J.; Clough, S.; Miller, R.; Lukens, J.; Henry, C.; Kanters, R.; Sikorski, J.
Tetrahedron 2003, 59, 207.
17. Gupton, J.; Krumpe, K.; Burnham, B.; Webb, T.; Shuford, J.; Sikorski, J. Tetrahe-
dron 1999, 55, 14515.
18. Gupton, J.; Banner, E.; Sartin, M.; Coppock, M.; Hempel, J.; Kharlamova, A.;
Fisher, D.; Giglio, B.; Smith, K.; Keough, M.; Smith, T.; Kanters, R.; Dominey, R.;
Sikorski, J. Tetrahedron 2008, 64, 5246.
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