The application of vinylogous iminium salt derivatives and microwave accelerated Vilsmeier-Haack reactions to efficient relay syntheses of the polycitone and storniamide natural products

Article abstract of DOI:10.1016/j.tet.2008.03.038

Studies directed at the synthesis of polycitone and storniamide natural products via vinylogous iminium salts and microwave accelerated Vilsmeier-Haack formylations are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 2,3,4-trisubstituted pyrrole from a vinamidinium salt or vinamidinium salt derivative followed by formylation at the 5-position of the pyrrole. Subsequent transformations of the selectively formylated pyrroles lead to efficient and regiocontrolled relay syntheses of the respective pyrrole containing natural products.

Full text of DOI:10.1016/j.tet.2008.03.038

Tetrahedron 64 (2008) 5246–5253
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The application of vinylogous iminium salt derivatives and microwave
accelerated Vilsmeier–Haack reactions to efficient relay syntheses
of the polycitone and storniamide natural products
,
a
a
a
a
John T. Gupton a , Edith J. Banner , Melissa D. Sartin , Matthew B. Coppock , Jonathan E. Hempel ,
Anastasia Kharlamova a, Daniel C. Fisher a, Ben C. Giglio a, Kristin L. Smith a, Matt J. Keough a,
Timothy M. Smith a, Rene P.F. Kanters a, Raymond N. Dominey a, James A. Sikorski b
*
a Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
b AtheroGenics Inc., 8995 Westside Parkway, Alpharetta, GA 30004, 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 polycitone and storniamide natural products via vinylogous iminium
salts and microwave accelerated Vilsmeier–Haack formylations are described. The successful strategy
relies on the formation of a 2,4-disubstituted pyrrole or a 2,3,4-trisubstituted pyrrole from a vinamidi-
nium salt or vinamidinium salt derivative followed by formylation at the 5-position of the pyrrole.
Subsequent transformations of the selectively formylated pyrroles lead to efficient and regiocontrolled
relay syntheses of the respective pyrrole containing natural products.
Received 4 February 2008
Received in revised form 11 March 2008
Accepted 12 March 2008
Available online 15 March 2008
Keywords:
Vinamidinium salt
Pyrrole
Ó 2008 Elsevier Ltd. All rights reserved.
Marine natural product
Microwave acceleration
1. Introduction
on the efficient and regiocontrolled preparation of 2-carboalkoxy-
3,4-diarylpyrroles (11) or 2,5-dicarboalkoxy-3,4-diarylpyrroles (12)
Pyrrole containing marine natural products and their derivatives
continue to be a source of compounds with very interesting bio-
logical properties.1 A number of recent reviews2 have appeared,
which describe synthetic efforts as well as structure–activity re-
lationships and mode of action studies for this large and diverse
class of substances.
Our own interest in this area of chemistry has allowed us to
develop relay and total syntheses of certain members of this class of
alkaloids (Fig. 1) such as rigidin,3 rigidin E,3 polycitones A and B,4
ningalin B,5 and lukianol A.6 Edstrom7 and Sakamoto8 have suc-
cessfully synthesized rigidin, while Steglich has synthesized poly-
citones A and B,9 ningalin10 type natural products, and various other
members of this class of substances. Boger has also made a major
synthetic effort in this area and has completed syntheses of ninga-
lins A and B, lukianol A, and permethylstorniamide A.11 The research
groups of Banwell,12 Furstner,13 Handy,14 Bullington,15 Iwao,16 Ishi-
bashi,17 and Ruchirawat18 havealso made majorcontributions tothis
area of chemistry. The majority of the synthetic methods to date rely
as key synthetic intermediates (Fig. 2), which are further elaborated
to the desired natural products. Interestingly, the conversion of the
2-carboalkoxy-3,4-diarylpyrroles (11) to the 2,5-dicarboalkoxy-3,4-
diarylpyrroles (12) has not been utilized presumably due to the
surprising lack of reactivity of these 2,3,4-trisubstituted pyrroles
(11) at the 5-position with carbon bearing electrophiles. Such
a transformation becomes quitesignificant for the preparationof the
2,3,4,5-tetrasubstituted pyrrole core, which is found in the majority
of the natural products that have been previously mentioned. Con-
sequently, any new synthetic methods or strategies, which provide
the efficient and regiocontrolled preparation of these two scaffolds
(11 and 12), are of importance.
2. Results and discussions
Our research efforts have demonstrated the ability to efficiently
prepare
4-aryl-2-carbethoxypyrroles,19
5-aryl-2-carbethoxy-
pyrroles,20 3-aryl-2-carbethoxypyrroles,21 and 3,4-diaryl-2-carb-
ethoxypyrroles22 from vinylogous iminium salts (14 and 18) and
their derivatives (19) with regiochemical control. Our general
strategy for the synthesis of 4-aryl-2-carbethoxypyrroles (15) and
3,4-diaryl-2-carbethoxypyrroles (20) is described in Scheme 1.
* 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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.038

J.T. Gupton et al. / Tetrahedron 64 (2008) 5246–5253
5247
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
1 X = Y = Z = H Rigidin
2 X = OCH3 Y = Z = H Rigidin B
3 Y = OCH3 X = Z = H Rigidin C
4 X = Y = OCH3 Z = H Rigidin D
5 X = Y = H Z = CH3 Rigidin E
6 Polycitone A X = 4-hydroxyphenethyl
7 Polycitone B X = H
HO
OMe
OMe
OH
HO
HO
OH
MeO
MeO
OMe
OMe
OH
H
N
H
N
O
O
N
N
N
O
O
O
O
MeO
OMe
OH
OMe
10 Permethyl Storniamide A
Figure 1. Pyrrole containing marine natural products.
OH
OH
8 Ningalin B
9 Lukianol A
detection of an NOESY signal between the aldehyde hydrogen and
the pyrrole hydrogen (22b) or pyrrole methyl hydrogens (22h). The
equivalent NOESY signal could not be detected for compound 22a
due to the close proximity of the signals and broadness of the
pyrrole hydrogen signal. NOESY, HSQC, and HMBC spectra for these
compounds (22a, 22b, and 22h) allowed for the assignment of all
signals in the proton and carbon NMR spectra (Table 2).
O
O
O
N
H
11
N
H
RO
OR
OR
12
With the ability to achieve high yielding, regioselective, for-
mylations in place, we turned our attention to using this method-
ology to prepare polycitone- and storniamide-type natural
products. We have previously reported4 a relay synthesis of poly-
citones A and B based upon a key intermediate (25) prepared by the
Steglich group9 in their synthesis of the polycitones (Scheme 2).
The precursor to the symmetrical diacylpyrrole (25), as developed
by Steglich and co-workers, is a symmetrical pyrroledicarboxylic
acid (24), which also can be viewed as a relay intermediate for the
preparation of the polycitones. Consequently, using the appropriate
formylated pyrrole (22k), we were able to rapidly carry out a syn-
thesis (Scheme 3) of this tetrasubstituted pyrrole (24) in two steps
and in 62% yield from 22k and thereby accomplish a second relay
synthesis of the polycitones. Interestingly, we also applied micro-
wave acceleration reaction conditions for the preparation of pyrrole
21k (analogous to the conversion of 19 to 20 in Scheme 1) by
reacting the corresponding chloroenal with glycine ethyl ester in
which case a 91% yield of the 2,3,4-trisubstituted pyrrole (21k) was
obtained.
Figure 2. General pyrrole natural product motifs.
As mentioned previously, the ability to introduce carbon bearing
electrophiles at the 5-position (ortho to nitrogen) of highly
substituted pyrroles is quite significant. The Vilsmeier–Haack re-
agent23 has traditionally been a useful means to introduce a formyl
group at this position but, at least in the substrates that we have
examined (such as 21a–21k, Table 1), traditional heating of the
pyrrole with DMF and phosphorous oxychloride does not provide
a clean and high yielding method (typically in the 30% range) for
the preparation of the desired formylpyrroles. We have had some
success in the past in applying microwave acceleration conditions
to reactions that appeared sluggish for either electronic or steric
reasons. Consequently, we decided to subject some of our repre-
sentative pyrroles to a microwave accelerated version of the Vils-
meier–Haack reaction and the results are presented in Table 1. To
date the only example of microwave acceleration in the presence of
the Vilsmeier–Haack reagent is described by Perumal and Dina-
karan24 in their preparation of chloroenals (such as 19 in Scheme 1)
from aryl methyl ketones.
When comparing the spectral data of our material (24) with
those reported by Steglich, the symmetrical nature of the Steglich
intermediate (24) made the comparisons very straightforward and
we were able to observe an identical match by proton and carbon
NMR.
The microwave accelerated Vilsmeier–Haack reaction is typi-
cally carried out in a microwave reactor at 100 ꢀC for 14 min and
produces a near analytically pure product that requires minimal if
any purification. In fact, we have found that in most cases the re-
action is fully complete within 3–4 min. The regiochemistry of
compounds 22b and 22h was unambiguously established by the
Permethylstorniamide A (10) has been an attractive synthetic
target by a number of international research groups,13,16,25 and
Boger’s efforts11 in this regard also rely on
a symmetrical

5248
J.T. Gupton et al. / Tetrahedron 64 (2008) 5246–5253
POCl3, DMF
and heat followed by
NaPF6/H2O
Me
N
Me
N
H2N
CO2Et
COOH
DABCO, DMF
and heat
Me
Me
CO2Et
N
H
PF6
15
13
14
Cl
H
Me
N
Me
O
O
DMF acetal,
DMF and heat
POCl3 in CH2Cl2
and heat
Me
N
OPOCl2
Me
18
16
17
H2O and THF
Cl
H
O
H2N
CO2Et
NaH, DMF and heat
CO2Et
N
H
19
20
Scheme 1. Gupton group methodology for pyrrole synthesis.
tetrasubstituted pyrrole (27) as a key precursor to this natural
product (Scheme 4). This pyrrole (27) is prepared by Boger via his
Diels–Alder/retrograde Diels–Alder strategy coupled with re-
ductive hydrogenolysis chemistry.
synthesis involves a Suzuki cross-coupling reaction of the iodo-
pyrrole (31) with 3,4,5-trimethoxyphenylboronic acid resulting in
a 65% yield of the key synthon (27). As was the case for the Steglich
polycitone precursor (24), the Boger synthon (27) is highly sym-
metrical, which made the spectral comparisons of our material to
the data reported by Boger very straightforward, in which case
there was an identical match for the proton and carbon NMR.
Starting from the appropriate formylated pyrrole (22a, Table 1),
oxidation with sodium chlorite with subsequent basic hydrolysis
yields the pyrrole diacid (29) very cleanly and in an overall yield of
85% in two steps (Scheme 5). Methylation of both carboxylic acid
groups with N,N-dimethylformamide dimethylacetal followed by
iodination yields a tetrasubstituted pyrrole (31) in 50% yield in two
steps. The bisalkylation step has not been fully optimized (51%
yield) so there is substantial room for improvement in this regard.
The iodination reaction consistently proceeds in very good yield
(97%). The final reaction to make the Boger intermediate (27) to
permethylstorniamide A11 (10) and thereby complete a relay
Table 2
NMR chemical shift assignments for compounds 22a, 22b, and 22h via NOESY, HSQC,
and HMBC studies
X"
X'
x4
x3
x2
x1
X"
p3
p4
p5
e3
p2
H
e1 O
O
k
e2
N
z
O
Table 1
Microwave accelerated Vilsmeier–Haack formylation of selected pyrroles
X
Y
Label 22a; X0¼X00¼OMe, Z¼H
22b; X0¼Br, X00¼Z¼H
22h; X0¼Z¼Me, X00¼H
X
Y
POCl3, DMF and
microwave heating
13C NMR
1H NMR
9.8a
13C NMR
1H NMR
13C NMR
1H NMR
H
CO2Et
CO2Et
N
Z
N
Z
Z
10.05
34.8
130.7
137.7
116.8
128.7
182.5
130.1
129.5
129.3
137.8
21.2
4.35
O
p2
p3
p4
p5
k
x1
x2
x3
x4
X0
X00
e1
e2
e3
130.2
136.1
115.2
127.6
180.6
128.2
106.5
153.6
138.5
61.0
130.1
134.6
115.2
127.8
180.3
131.6
130.5
132.1
122.5
21
22
7.03
9.83
6.69
7.02
9.75
6.99
9.79
Compound 21
X
Y
Z
% Yield for 22
a
b
c
d
e
f
g
h
i
3,4,5-Trimethoxyphenyl
4-Bromophenyl
3,4-Dimethoxyphenyl
Phenyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
76
70
63
91
84
67
81
7.37
7.60
7.31
7.25
4-Chlorophenyl
3.92
3.93
2.42
4-Methylphenyl
4-Methoxyphenyl
4-Methylphenyl
4-Methoxyphenyl
3,4-Dimethoxyphenyl
4-Methoxyphenyl
56.3
160.2
61.5
160.1
61.6
14.3
160.9
60.9
14.3
Me 81
Me 81
Me 62
4.43
1.43
4.42
1.42
4.38
1.41
14.3
j
k
a
Due to broadness of the NH resonance and overlap with the sharp aldehyde
4-Methoxyphenyl
H
74
signal, higher precision was not warranted.

J.T. Gupton et al. / Tetrahedron 64 (2008) 5246–5253
OMe
5249
MeO
OMe
MeO
Ammonia and
Molecular Sieves
HOOC
COOH
COOH
HOOC
N
H
O
O
23
24
Oxalyl Chloride and
DMF followed by AlCl3
and Anisole
Br
Br
HO
Br
OH
MeO
OMe
Aluminium Triiodide followed
by excess Br2 and HOAc
Br
Br
Br
Br
HO
MeO
OH
OMe
N
N
O
O
O
O
H
H
Br
25
Polycitone B
7
Scheme 2. Steglich synthesis of polycitone B.
MeO
OMe
MeO
OMe
MeO
OMe
NaClO2 in DMSO
and water with buffer
KOH, EtOH with
water and heat
H
HO
HOOC
COOH
CO2Et
CO2Et
N
H
N
N
H
O
O
H
22k
24
70% Yield
26
88% Yield
Scheme 3. Gupton group relay synthesis of polycitone A and B synthon.
OMe
OMe
MeO
MeO
OMe
OMe
OMe
OMe
MeO
OMe
OMe
H
N
H
N
Several Steps
N
O
O
MeO
MeO2C
MeO
CO2Me
N
H
OMe
OMe
10 Permethyl Storniamide A
27
Scheme 4. Boger approach to permethylstorniamide A.
3. Conclusions
4. Experimental
In summary, Vilsmeier–Haack formylations of pyrrole substrates
can be significantly improved by microwave accelerations. Such
formylated pyrroles are key precursors to the ever growing class of
pyrrole containing marine natural products such as polycitones A
and B as well as permethylstorniamide A. These formylation re-
actions in combination with our vinylogous iminium salt based
approach to highly functionalized pyrroles provide efficient, flexi-
ble, and regiocontrolled methodology for the preparation of this
important class of natural products and related derivatives. These
synthetic strategies and procedures should also provide rapid
access to a wide range of highly functionalized pyrroles for
subsequent biologically driven SAR studies.
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 GE Omega 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 by the Midwest Center for Mass Spectrom-
etry at the University of Nebraska at Lincoln or on a Biotof Q

5250
J.T. Gupton et al. / Tetrahedron 64 (2008) 5246–5253
OMe
O
OMe
O
MeO
MeO
MeO
NaClO2 in DMSO
and water with buffer
MeO
HO
H
CO2Et
CO2Et
N
H
N
H
28
22a
91% Yield
KOH, EtOH with
water and heat
OMe
MeO
OMe
DMF acetal,
CH2Cl2 at rt
MeO
MeO
MeO
MeO2C
CO2Me
N
HOOC
COOH
H
30
N
H
51% Yield
29
93% Yield
NaOH, I2 in DMF
OMe
OMe
MeO
MeO
MeO
MeO
OMe
OMe
Pd(PPh3)4, Toluene
K2CO3, EtOH and heat
I
MeO
MeO2C
CO2Me
MeO2C
OMe
CO2Me
N
H
N
H
MeO
OMe
27
65% Yield
31
97% Yield
B(OH)2
Scheme 5. Gupton group relay synthesis of permethylstorniamide A.
electrospray mass spectrometerat 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 Horizon
HFC or SP-1 instrument, which had been equipped with a silica
cartridge, and ethyl acetate/hexane was used as the eluant. Micro-
wave accelerated reactions were carried out in a Biotage Liberator
system. Microwave reactions were controlled at a constant tem-
perature 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
asthe eluant. Vinamidiniumsaltsutilized for pyrrole formationwere
prepared according to standard procedures.19 All purified reaction
products gaveTLC results, GC–MS spectra, flashchromatograms, and
13C NMR spectra consistent with a sample purity of >95%.
sulfate. The resulting solution was filtered, concentrated in vacuo,
which resulted in a tan solid (0.553 g, 80% yield), which exhibited
the following properties: mp 140–141 ꢀC; 1H NMR (CDCl3) d 9.14 (br
s, 1H), 7.28 (s, 2H), 7.20 (dd, J¼5.0 Hz and J¼2.5 Hz, 1H), 7.16 (d of d,
J¼5.0 Hz and J¼2.5 Hz, 1H), 4.38 (q, J¼12 Hz, 2 H), 3.93 (s, 6H) and
3.88 (s, 3H); 13C NMR (CDCl3) d 161.1, 153.6,136.9,130.5,127.0, 123.7,
119.3, 112.4, 102.8, 61.0, 60.6, 56.2 and 14.5; IR (neat) 3270 and
1670 cmꢂ1; HRMS (ES MþH) m/z calcd for C16H20NO5 306.1336,
found 306.1342.
4.1.2. Ethyl 2-formyl-3-(3,4,5-trimethoxyphenyl)pyrrole-5-
carboxylate (22a)
Method A: a 7-mL microwave reaction vessel was equipped with
a stir bar and was charged with 5 mL of DMF and 0.302 g
(1.96 mmol) of phosphorous oxychloride and the resulting mixture
was allowed to stir in an ice bath for 45 min. To this mixture was
then added 0.200 g (0.655 mmol) of ethyl 4-(3,4,5-trimethoxy-
phenyl)pyrrole-5-carboxylate in 1 mL of DMF. The reaction vessel
was sealed (Crymper-seal) and heated by microwaves at 100 ꢀC for
14 min in a Liberator Microwave Reactor. After cooling to room
temperature, the reaction mixture was diluted with 20 mL of water
and extracted with 3ꢁ20 mL of ethyl acetate. The combined organic
layers were washed with 3ꢁ20 mL of brine and dried over anhy-
drous magnesium sulfate. The resulting solution was filtered,
concentrated in vacuo, which resulted in a tan solid (0.166 g, 76%
4.1.1. Ethyl 4-(3,4,5-trimethoxyphenyl)pyrrole-2-carboxylate (21a)
Into a 250-mL flask equipped with a magnetic stirring bar was
placed 1.00 g (2.27 mmol) of 3,4,5-trimethoxyphenylvinamidinium
hexafluorophosphate along with 0.921 g (6.60 mmol) of ethyl gly-
cinate, 0.740 g (6.58 mmol) of DABCO, and 100 mL of DMF. The
resulting mixture was heated at reflux for 3 h, cooled to room
temperature, and concentrated in vacuo. The residue was taken up
in 100 mL of ethyl acetate and extracted with 3ꢁ50 mL of water and
one 50 mL portion of brine, and dried over anhydrous magnesium

J.T. Gupton et al. / Tetrahedron 64 (2008) 5246–5253
5251
yield). 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: mp
110–111 ꢀC; 1H NMR (CDCl3) d 9.88 (br s, 1H), 9.83 (s, 1H), 7.03 (d,
J¼2.7 Hz, 1H), 6.69 (s, 2H), 4.43 (q, J¼7.1 Hz, 2H), 3.93 (s, 6H), 3.92
(s, 3H) and 1.43 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3) d 180.6, 160.2,
153.6, 138.5, 136.1, 130.2, 128.2, 127.6, 115.2, 106.5, 61.5, 61.0, 56.3
and 14.3; IR (neat) 3256, 1715 and 1642 cmꢂ1; HRMS (EI) m/z calcd
for C17H19NO6 333.1212, found 333.1215.
Method B: into a 50-mL flask, which had been equipped with
a condenser and magnetic stirring bar, was placed 10 mL of DMF
followed by the addition of 0.901 g (5.89 mmol) of phosphorous
oxychloride. The resulting mixture was stirred in an ice bath for
45 min and ethyl 4-(3,4,5-trimethoxyphenyl)pyrrole-5-carboxylate
(0.500 g, 1.96 mmol) was added. The resulting mixture was heated
at reflux for 2 h. After cooling to room temperature, the reaction
mixture was diluted with 30 mL of water and extracted with
3ꢁ30 mL of ethyl acetate. The combined organic layers were
washed with 3ꢁ30 mL of brine and dried over anhydrous magne-
sium sulfate. The resulting solution was filtered, concentrated in
vacuo, which resulted in a tan solid (0.225 g, 34% yield). This
material was identical to the product obtained by method A as
determined by 1H NMR and TLC comparison.
was obtained: mp 96–98 ꢀC; 1H NMR (CDCl3) d 9.97 (br s,1H), 9.76 (s,
1H), 7.45 (d, J¼8.5 Hz, 2H), 7.43 (d, J¼8.5 Hz, 2H), 7.02 (d, J¼3.0 Hz,
1H), 4.42 (q, J¼7.5 Hz, 2H) and 1.42 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3)
d 180.3, 160.1, 134.5, 132.1, 131.6, 130.5, 130.1, 127.8, 122.6, 115.2, 61.6
and 14.3; IR (neat) 3256, 1719 and 1666 cmꢂ1; HRMS (EI) m/z calcd
for C14H12NO3Cl 277.0506, found 277.0504.
4.1.7. Ethyl 2-formyl-3-(4-methylphenylpyrrole)-5-
carboxylate (22f)
Using a procedure analogous to method A as described in
Section 4.1.2, a 67% yield of a solid with the following physical
properties was obtained: mp 104–106 ꢀC; 1H NMR (CDCl3) d 9.78 (br
s, 2H), 7.40 (d, J¼8.1 Hz, 2H), 7.29 (d, J¼8.1 Hz, 2H), 7.02 (d, J¼3.0 Hz,
1H), 4.41 (q, J¼6.9 Hz, 2H) and 1.42 (t, J¼6.9 Hz, 3H); 13C NMR
(CDCl3) d 180.8, 160.3, 138.2, 136.1, 130.2, 129.7, 129.6, 128.9, 127.6,
115.2, 61.4, 21.2 and 14.3; IR (neat) 3258, 1697 and 1658 cmꢂ1
;
HRMS (EI) m/z calcd for C15H15NO3 257.1052, found 257.1049.
4.1.8. Ethyl 2-formyl-3-(4-methoxyphenylpyrrole)-5-
carboxylate (22g)
Using a procedure analogous to method A as described in
Section 4.1.2, a 81% yield of a solid with the following physical
properties was obtained: mp 103–105 ꢀC; 1H NMR (CDCl3) d 9.84 (br
s, H), 9.77 (s, 1H), 7.43 (d, J¼9.0 Hz, 2H), 7.00–7.02 (m, 3H), 4.42 (q,
J¼7.0 Hz, 2H), 3.88 (s, 3H) and 1.42 (t, J¼7.0 Hz, 3H); 13C NMR
(CDCl3) d 180.7, 160.3, 159.8, 135.9, 130.2, 130.1, 127.7, 125.1, 115.1,
4.1.3. Ethyl 2-formyl-3-(4-bromophenyl)pyrrole-5-
carboxylate (22b)
114.4, 61.4, 55.4 and 14.1; IR (neat) 3273, 1703 and 1662 cmꢂ1
;
Using a procedure analogous to method A as described in Sec-
tion 4.1.2, a 70% yield of a solid with the following physical prop-
erties was obtained: mp 108–110 ꢀC; 1H NMR (CDCl3) d 10.05 (br s,
1H), 9.75 (s, 1H), 7.60 (d, J¼8.4 Hz, 2H), 7.37 (d, J¼8.4 Hz, 2H), 7.02
HRMS (EI) m/z calcd for C15H15NO4 273.1001, found 273.0994.
4.1.9. Ethyl N-methyl-2-formyl-3-(4-methylphenylpyrrole)-5-
carboxylate (22h)
(d, J¼2.7 Hz,1H), 4.42 (q, J¼7.1 Hz, 2H) and 1.42 (t, J¼7.1 Hz, 3H); 13
C
Using a procedure analogous to method A as described in
Section 4.1.2, a 81% yield of a solid with the following physical
properties was obtained: mp 75–76 ꢀC; 1H NMR (CDCl3) d 9.79 (s,
1H), 7.31 (d, J¼8.0 Hz, 2H), 7.25 (d, J¼8.0 Hz, 2H), 6.99 (s, 1H), 4.38
(q, J¼7.1 Hz, 2H), 4.35 (s, 3H), 2.42 (s, 3H) and 1.41 (t, J¼7.1 Hz, 3H);
13C NMR (CDCl3) d 182.5,160.9,137.8, 137.7, 130.7, 130.1, 129.5, 129.3,
128.7,116.8, 60.9, 34.8, 21.2 and 14.3; in addition, NOESY (3 s mixing
time) cross-peaks were observed between the resonances at 4.35
(pyrrole N-CH3) and 9.78 ppm (aldehyde hydrogen) establishing
the location of the formyl group as being ortho to the pyrrole ni-
trogen; IR (neat) 1712 and 1662 cmꢂ1; HRMS (EI) m/z calcd for
NMR (CDCl3) d 180.3, 160.1, 134.6, 132.1, 131.6, 130.5, 130.1, 127.8,
122.5, 115.2, 61.6 and 14.3; in addition, NOESY (1 s mixing time)
cross-peaks were observed between the resonances at 10.05 (pyr-
role NH) and 9.75 ppm (aldehyde hydrogen) establishing the
location of the formyl group as being ortho to the pyrrole nitrogen;
IR (neat) 3282, 1712 and 1663 cmꢂ1; HRMS (EI) m/z calcd for
C
14H12NO3Br 321.0001, found 320.9995.
4.1.4. Ethyl 2-formyl-3-(3,4-dimethoxyphenyl)pyrrole-5-
carboxylate (22c)
Using a procedure analogous to method A as described in
Section 4.1.2, a 63% yield of a solid with the following physical
properties was obtained: mp 107–109 ꢀC; 1H NMR (CDCl3) d 9.80
(br s, 2H), 7.05 (dd, J¼2.0 Hz, J¼8.5 Hz, 1H), 7.00–7.02 (m, 2H), 6.97
(d, J¼8.5 Hz, 1H), 4.42 (q, J¼7.0 Hz, 2H), 3.95 (s, 6H) and 1.42 (t,
J¼7.0 Hz, 3H); 13C NMR (CDCl3) d 180.7, 160.2, 149.4, 149.3, 136.0,
130.1, 127.6, 125.4, 121.7, 115.1, 112.2, 111.5, 61.5, 56.1, 56.0 and 14.3;
IR (neat) 3277, 1711 and 1655 cmꢂ1; HRMS (EI) m/z calcd for
C16H17NO3 271.1208, found 271.1209.
4.1.10. Ethyl N-methyl-2-formyl-3-(4-methoxyphenylpyrrole)-5-
carboxylate (22i)
Using a procedure analogous to method A as described in
Section 4.1.2, a 81% yield of a solid with the following physical
properties was obtained: mp 73–75 ꢀC; 1H NMR (CDCl3) d 9.77 (s,
1H), 7.34 (d, J¼9.0 Hz, 2H), 6.97–6.99 (m, 3H), 4.36 (q, J¼7.0 Hz, 2H),
4.34 (s, 3H), 3.87 (s, 3H) and 1.40 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
d 182.4, 160.9, 159.6, 137.5, 130.7, 130.6, 128.7, 125.5, 116.7, 114.4,
60.9, 55.4, 34.8 and 14.3; IR (neat) 1706 and 1650 cmꢂ1; HRMS (ES
MþH) m/z calcd for C16H18NO4 288.1230, found 288.1235.
C
16H17NO5 303.1107, found 303.1113.
4.1.5. Ethyl 2-formyl-3-phenylpyrrole-5-carboxylate (22d)
Using a procedure analogous to method A as described in Sec-
tion 4.1.2, a 91% yield of a solid with the following physical prop-
erties was obtained: mp 110–112 ꢀC; 1H NMR (CDCl3) d 9.87 (br s,
1H), 9.79 (s, 1H), 7.43–7.52 (m, 5H), 7.05 (d, J¼3.0 Hz, 1H), 4.42 (q,
J¼7.0 Hz, 2H) and 1.43 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3) d 180.8,
160.3, 136.0, 132.7, 130.3, 129.1, 128.9, 128.2, 127.7, 115.3, 61.5 and
14.3; IR (neat) 3269, 1716 and 1663 cmꢂ1; HRMS (EI) m/z calcd for
4.1.11. Ethyl N-methyl-2-formyl-3-(3,4-dimethoxyphenylpyrrole)-
5-carboxylate (22j)
Using a procedure analogous to method A as described in Sec-
tion 4.1.2, a 62% yield of a solid with the following physical prop-
erties was obtained: mp 107–109 ꢀC; 1H NMR (CDCl3) d 9.80 (s, 1H),
6.98 (s, 1H), 6.93–6.95 (m, 3H), 4.37 (q, J¼7.5 Hz, 2H), 4.35 (s, 3H),
3.95 (s, 3H), 3.93 (s, 3H) and 1.41 (q, J¼7.5 Hz, 3H); 13C NMR (CDCl3)
d 182.5, 160.9, 149.1, 149.0, 137.6, 130.8, 128.7, 125.8, 122.3, 116.7,
112.7, 111.2, 61.0, 56.1, 56.0, 34.8 and 14.3; IR (neat) 1711 and
1655 cmꢂ1; HRMS (ES MþH) m/z calcd for C17H20NO5 318.1336,
found 318.1346.
C
14H13NO3 243.0895, found 243.0894.
4.1.6. Ethyl 2-formyl-3-(4-chlorophenylpyrrole)-5-
carboxylate (22e)
Using a procedure analogous to method A as described in Section
4.1.2, a 84% yield of a solid with the following physical properties

5252
J.T. Gupton et al. / Tetrahedron 64 (2008) 5246–5253
4.1.12. Ethyl 3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylate (21k)
A 7-mL microwave reaction vessel was equipped with a stir bar
and was charged with 6 mL of DMF and 0.200 g (0.660 mmol) of
a mixture of E- and Z-3-chloro-2,3-bis(4-methoxyphenyl)-prope-
nal, 0.277 g (1.98 mmol) of glycine ethyl ester, and 0.222 g
(1.98 mmol) of DABCO, and the resulting mixture was allowed to stir
for 30 min. The reaction vessel was sealed (Crymper-seal) and
heated by microwaves at 150 ꢀC for 14 min in a Liberator Microwave
Reactor. After cooling to room temperature, the reaction mixture
was diluted with 20 mL of water and extracted with 3ꢁ20 mL of
ethyl acetate. The combined organic layers were washed with
3ꢁ20 mL of brine and dried over anhydrous magnesium sulfate. The
resulting solution was filtered and concentrated in vacuo, which
resulted in a solid (0.210 g, 91% yield) that was identical by TLC and
proton NMR to a sample previously reported by our research group.
This material was of sufficient purity to be used in subsequent
transformations without additional purification.
properties to those reported by Steglich and co-workers: mp 200–
202 ꢀC (lit.9 268–270 ꢀC); 1H NMR (DMSO-d6) d 12.58 (br s, 2H),
11.58 (br s, 1H), 6.96 (d, J¼8.5 Hz, 4H), 6.73 (d, J¼8.5 Hz, 4H) and
3.70 (s, 6H); 13C NMR (DMSO-d6) d 161.9, 158.2, 132.2, 130.2, 126.5,
122.6, 113.1 and 55.3; IR (neat) 3240 and 1683 cmꢂ1; HRMS (EI) m/z
calcd for C20H17NO6 367.1056, found 367.1052.
4.1.16. 5-Carbethoxy-3-(3,4,5-trimethoxyphenyl)pyrrole-2-
carboxylic acid (28)
Ethyl 2-formyl-3-(3,4,5-trimethoxyphenyl)pyrrole-5-carboxyl-
ate (0.400 g, 1.20 mmol) was placed in flask equipped with a mag-
netic stirring bar and to this was added 40 mL of DMSO followed by
a solution containing 0.172 g (1.20 mmol) of sodium dihydrogen
phosphate in 10 mL of water. The mixture was cooled in an ice-
water bath and a solution of sodium chlorite (0.332 g, 3.61 mmol)
in 10 mL of water was added in a dropwise fashion to the reaction
mixture. After stirring for 24 h at room temperature, the reaction
mixture was adjusted to a pH of 2 with 6 M hydrochloric acid while
being cooled in an ice-water bath. The resulting mixture was
extracted with 3ꢁ30 mL of ethyl acetate and the combined organic
phases were washed with 30 mL of brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo to give 0.381 g (91%
yield) of a solid, which exhibited the following physical properties:
mp 118–120 ꢀC; 1H NMR (CDCl3) d 10.04 (br s, 1H), 6.98 (d, J¼2.5 Hz,
1H), 6.84 (s, 2H), 4.01 (q, J¼7.0 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 6H) and
1.41 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3) d 163.8, 160.3, 152.7, 137.7,
133.4, 129.1, 125.6, 120.7, 116.7, 106.9, 61.3, 60.9, 56.2 and 14.3; IR
(neat) 3283, 1706 and 1660 cmꢂ1; HRMS (EI) m/z calcd for
4.1.13. Ethyl 5-formyl-3,4-bis(4-methoxyphenyl)pyrrole-2-
carboxylate (22k)
Using a procedure analogous to method A as described in
Section 4.1.2, a 74% yield of a solid with the following physical
properties was obtained: mp 122–124 ꢀC; 1H NMR (CDCl3) d 9.88
(br s, 1H), 9.62 (s, 1H), 7.08–7.14 (m, 4 H), 6.84 (d, J¼6.0 Hz, 2H), 6.82
(d, J¼6.0 Hz, 2H), 4.28 (q, J¼6.9 Hz, 2H), 3.82 (s, 6H) and 1.26 (t,
J¼6.9 Hz, 3H); 13C NMR (CDCl3) d 181.4, 160.3, 159.3, 158.8, 134.8,
131.9, 131.8, 130.3, 129.8, 124.6, 123.8, 123.6, 113.8, 113.1, 61.1, 55.2,
55.1 and 14.1; IR (neat) 1675 and 1630 cmꢂ1; HRMS (EI) m/z calcd
for C22H21NO5 379.1420, found 379.1421.
C17H19NO7 349.1161, found 349.1160.
4.1.14. 5-Carbethoxy-3,4-bis(4-methoxyphenyl)pyrrole-2-
4.1.17. 3-(3,4,5-Trimethoxyphenyl)pyrrole-2,5-dicarboxylic
carboxylic acid (26)
acid (29)
Ethyl 5-formyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylate
(0.200 g, 0.530 mmol) and 50 mL of DMSO were place in a flask
equipped with a stirring bar and cooled in an ice-water bath. A
solution of sodium dihydrogen phosphate (0.023 g, 0.160 mmol in
10 mL of water) was added to the flask and the reaction mixture
was stirred for 15 min. Subsequently, a solution of sodium chlorite
(0.146 g, 1.59 mmol in 10 mL of water) was added to the flask
dropwise with cooling and the resulting reaction mixture was
stirred for 24 h at room temperature. The reaction mixture was
then cooled in an ice-water bath and concentrated hydrochloric
acid was added dropwise until the mixture reached a pH of ap-
proximately 2. The resulting mixture was vacuum filtered and the
resulting solid was dried under vacuum thereby producing 0.190 g
(88% yield) of material, which exhibited the following physical
properties: mp 120–272 ꢀC; 1H NMR (CDCl3) d 12.62 (s, 1H), 11.95 (s,
1H), 7.00–7.03 (m, 4H), 6.79 (d, J¼8.5 Hz, 4H), 4.10 (q, J¼7.0 Hz, 2H),
3.71 (s, 6H) and 1.13 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3) d 162.0,
160.4, 158.3, 158.3, 132.3, 132.2, 130.6, 130.1, 126.4, 126.3, 123.0,
121.9, 113.1, 113.0, 60.4, 55.4, 55.3 and 14.4; IR (neat) 3265, 1695 and
1663 cmꢂ1; HRMS (EI) m/z calcd for C22H21NO6 395.1369, found
395.1367.
Into a flask equipped with a stirring bar and reflux condenser
were placed 0.337 g (6.01 mmol) of potassium hydroxide and
60 mL of a 50:50 mixture of ethanol/water. The mixture was stirred
until all solid material dissolved and 5-carbethoxy-3-(3,4,5-trimeth-
oxyphenyl)pyrrole-2-carboxylic acid (0.700 g, 2.04 mmol) was
added to the flask and the resulting reaction mixture was refluxed
for 24 h. The reaction mixture was then cooled in an ice-water bath,
adjusted to a pH of 2 by the slow addition of 6 M hydrochloric acid,
and extracted with 3ꢁ30 mL of ethyl acetate. The combined organic
phases were washed with 1ꢁ30 mL of brine and dried over anhy-
drous magnesium sulfate. After removal of the drying agent, the
solution was concentrated in vacuo to give 0.600 g (93% yield) of
a solid, which exhibited the following physical properties: mp 178–
179 ꢀC (dec); 1H NMR (DMSO-d6) d 12.82 (br s, 2H), 11.90 (br s, 1H),
6.91 (d, J¼2.5 Hz, 1H), 6.85 (s, 2H), 3.77 (s, 6H) and 3.69 (s, 6H); 13
C
NMR (DMSO-d6) d 162.0,161.6,152.6,137.1,131.0,130.3,126.0,122.8,
116.7, 107.3, 60.5 and 56.3; IR (neat) 2925, 1690 and 1660 cmꢂ1
;
HRMS (EI) m/z calcd for C15H15NO7 321.0848, found 321.0851.
4.1.18. Dimethyl 3-(3,4,5-trimethoxyphenyl)pyrrole-2,5-
dicarboxylate (30)
A flask was equipped with a magnetic stir bar and to it were
added 3-(3,4,5-trimethoxyphenyl)pyrrole-2,5-dicarboxylic acid
(0.600 g, 1.87 mmol), 60 mL of dry chloroform, and 1.345 g
(11.3 mmol) of N,N-dimethylformamide dimethylacetal. The
resulting mixture was stirred at room temperature for 36 h and
diluted with 30 mL of water. After separating the two phases, the
aqueous phase was extracted with 3ꢁ30 mL of ethyl acetate and
the combined organic phases were washed with 30 mL of brine and
dried over anhydrous magnesium sulfate. After removal of the
drying agent, the solution was concentrated in vacuo to give 0.330 g
(51% yield) of a solid, which exhibited the following physical
properties: mp 118–118 ꢀC; 1H NMR (CDCl3) d 9.80 (s, 1H), 6.98 (d,
J¼3.5 Hz, 1H), 6.83 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.91 (s, 6H) and
4.1.15. 3,4-Bis(4-methoxyphenyl)pyrrole-2,5-dicarboxylic acid (24)
Into a flask equipped with a stirring bar and reflux condenser
were placed 0.064 g (1.10 mmol) of potassium hydroxide and 30 mL
of a 50:50 mixture of ethanol/water. The mixture was stirred until
all solid materials dissolved and ethyl 5-formyl-3,4-bis(4-methox-
yphenyl)pyrrole-2-carboxylate (0.150 g, 0.380 mmol) was added to
the flask, and the resulting reaction mixture was refluxed for 20 h.
The reaction mixture was then cooled in an ice-water bath and the
mixture was adjusted to a pH of 2 by the slow addition of 6 M
hydrochloric acid, which resulted in the formation of a white solid.
The solid was filtered and dried under vacuum yielding 0.097 g
(70% yield) of a solid product, which exhibited identical spectral

J.T. Gupton et al. / Tetrahedron 64 (2008) 5246–5253
5253
3.87 (s, 3H); 13C NMR (CDCl3) d 160.6, 160.5, 152.7, 137.7, 132.4,
129.2, 124.7, 121.1, 116.6, 106.8, 60.9, 56.2, 52.1 and 51.9; IR (neat)
3278, 1721 and 1706 cmꢂ1; HRMS (EI) m/z calcd for C17H19NO7
349.1161, found 349.1163.
to Mr. Dave Patteson of Biotage Inc. for the generous donation 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 all microwave
accelerated reactions. In addition, we would like to thank the
Midwest Center for Mass Spectrometry at the University of
Nebraska-Lincoln for providing some of the high-resolution mass
spectral analysis on the compounds reported in this paper. 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 spectrometer (CHE-0320669) are also
gratefully acknowledged. We also thank Dr. Jeff Seeman and Dr.
Wade Downey for helpful discussions during the preparation of this
manuscript.
4.1.19. Dimethyl 3-iodo-4-(3,4,5-trimethoxyphenyl)pyrrole-2,5-
dicarboxylate (31)
A flask was equipped with a magnetic stir bar and to it were
added dimethyl 3-(3,4,5-trimethoxyphenyl)pyrrole-2,5-dicarboxy-
late (0.150 g, 0.429 mmol), 15 mL of DMF, and 0.072 g (1.29 mmol)
of potassium hydroxide. The resulting mixture was stirred for 1 h,
iodine (0.142 g, 0.558 mmol) was added to the flask and the
resulting reaction mixture was stirred at room temperature for 20 h
while being protected from any light. The reaction mixture was
then cooled in an ice-water bath and quenched with 20 mL of a 10%
by weight aqueous solution of sodium thiosulfate. The reaction
mixture was diluted with additional water and extracted with
3ꢁ30 mL of ethyl acetate, and the combined organic phases were
washed with 30 mL of brine and dried over anhydrous magnesium
sulfate. After removal of the drying agent, the solution was con-
centrated in vacuo to give 0.198 g (97% yield) of a solid, which
exhibited the following physical properties: mp 213–216 ꢀC; 1H
NMR (CDCl3) d 10.02 (s, 1H), 6.55 (s, 2H), 3.99 (s, 3H), 3.94 (s, 3H),
3.89 (s, 6H) and 3.79 (s, 3H); 13C NMR (CDCl3) d 159.8, 159.7, 152.5,
137.8, 136.1, 129.1, 125.3, 122.3, 110.5, 108.1, 60.9, 56.2, 52.2 and 52.1:
IR (neat) 3257, 1726 and 1706 cmꢂ1; HRMS (ES MþH) m/z calcd for
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A 7-mL microwave reaction vessel was equipped with a stir bar
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Acknowledgements
We thank the National Institutes of Health (grant no. R15-
CA67236) for support of this research. We are exceedingly grateful