Formyl group activation of a bromopyrrole ester in Suzuki cross-coupling reactions: Application to a formal synthesis of Polycitone A and B and Polycitrin A

Article abstract of DOI:10.1016/j.tet.2014.02.091

A new pyrrole building block is described, which allows for the regiospecific synthesis of 2,3,5-trisubstituted pyrroles and 2,3,4,5-tetrasubstituted pyrroles. Optimization studies are presented for the preparation of the pyrrole building block along with the evaluation of various cross-coupling conditions and cross-coupling agents. A short, formal synthesis of the natural products Polycitone A, Polycitone B, and Polycitrin A from the pyrrole building block is also described.

Full text of DOI:10.1016/j.tet.2014.02.091

Tetrahedron 70 (2014) 2738e2745
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formyl group activation of a bromopyrrole ester in Suzuki cross-
coupling reactions: application to a formal synthesis of Polycitone
A and B and Polycitrin A
*
John T. Gupton , Nakul Telang, Michael Wormald, Kristin Lescalleet, Jon Patteson,
Will Curry, Andrew Harrison, Megan Hoerrner, John Sobieski, Michael Kimmel,
Emily Kluball, Thomas Perry
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:
A new pyrrole building block is described, which allows for the regiospecific synthesis of 2,3,5-
trisubstituted pyrroles and 2,3,4,5-tetrasubstituted pyrroles. Optimization studies are presented for the
preparation of the pyrrole building block along with the evaluation of various cross-coupling conditions
and cross-coupling agents. A short, formal synthesis of the natural products Polycitone A, Polycitone B,
and Polycitrin A from the pyrrole building block is also described.
Received 20 January 2014
Received in revised form 25 February 2014
Accepted 27 February 2014
Available online 6 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Suzuki cross-coupling
Pyrrole
Vilsmeier formylation
Marine natural products
1. Introduction
Br
Br
OH
Br
HO
Br
Br
Br
HO
Br
OH
Br
For some time now our research group has been interested in
using vinylogous iminium salt derivatives1 as key building blocks
for the construction of highly functionalized pyrroles. These sub-
stances have proven to be important precursors for the synthesis of
a variety of pyrrole-containing natural products such as the Poly-
citones2 (1a and 1b) as indicated in Fig.1. The interest by a variety of
international researchers to prepare such pyrrole-containing nat-
ural products is driven by their significant biological activities such
as their inhibition of HIV-1 integrase, their cytotoxic activity against
a variety of cancer cell lines, and their multi-drug resistance re-
versal activity. Consequently, a number of important reviews3 have
appeared, which discuss the synthesis and specific modes of action
of many of these alkaloids along with their structureeactivity
relationships.
Br
Br
Br
Br
O
O
N
HO
OH
N
X
O
O
1a, X = 4-Hydroxyphenyl: Polycitone A
1b, X = H: Polycitone B
OH
2, Polycitrin A
Fig. 1. Polycitone A (1a), Polycitone B (1b), and Polycitrin A (2).
A partial example of our previously published4 approach to the
synthesis of the Polycitones is presented in Scheme 1 and involves
the formation of a symmetrical vinamidinium salt (4), followed by
in good yield. This material (6) can be further functionalized to an
intermediate (7) reported by Steglich5 and co-workers in the first
reported synthesis of the Polycitones.
the reaction of this salt with the appropriate
a-aminocarbonyl
Although our approach to such natural products has provided
very effective transformations to the desired targets, the method-
ology is limited by not having a single key intermediate, which can
be rapidly transformed into any of the desired pyrrole-containing
natural products. Since the primary difference between many of
compound (5) such that a 2,4-disubstituted pyrrole (6) is generated
* Corresponding author. Tel.: þ1 804 287 6498; fax: þ1 804 287 1897; e-mail
address: jgupton@richmond.edu (J.T. Gupton).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.091

J.T. Gupton et al. / Tetrahedron 70 (2014) 2738e2745
2739
OMe
POCl3, DMF and Heat
followed by H2O and NaPF6
-
PF6
COOH
MeO
CH3
N+
CH3
N
H3C
CH3
3
4
O
NH2.PTSA
NaH, DMF
and Heat
MeO
5
MeO
OMe
MeO
MeO
OMe
Several Steps
OMe
N
H
O
O
N
H
O
7
6
Scheme 1. Gupton group synthesis of key Polycitone precursor.
these targets involves the variation of the aromatic or hetero-
aromatic groups attached to the pyrrole core, an ideal strategy
would involve a key pyrrole-containing compound, which could be
rapidly functionalized with a variety of aromatic and hetero-
aromatic groups. We have previously employed1 the Suzu-
kieMiyaura cross-coupling methodology in some of our steps to
prepare pyrrole-containing natural products but have not utilized
this reaction as the core strategy. Reports by Furstner,6 Alvarez,7
Banwell,8 Handy,9 Langer,10 and Iwao11 describe the use of such
methodology but usually the pyrrole nitrogen is substituted when
good yields are obtained. When the nitrogen has been unsub-
stituted, poor to modest yields are usually the result and the ob-
vious implication is that such pyrrole based cross-coupling
reactions work much better when nitrogen is substituted. In our
previously mentioned SuzukieMiyaura cross-coupling work, we
have noticed that good yields are also obtained for nitrogen
unsubstituted, brominated pyrroles, when the bromine is ortho to
an ester group. When a typical substrate contains bromine, which is
in two synthetic steps. Consequently, we have studied the for-
mylation of ethyl 4-bromopyrrole-2-carboxylate (8) using Vils-
meiereHaackeArnold conditions13 and our results are summarized
in Table 1 (Scheme 2). The results suggest that the reaction is
very solvent-dependent and very good yields of ethyl 3-bromo-2-
formylpyrrole-5-carboxylate (9) are obtained at room temperature,
when conducted in chlorinated solvents. Interestingly, we could not
detect any formylated product when the reaction was run in DMF.
This three-step synthetic process can be easily scaled up such that
multi-gram quantities of the ethyl 3-bromo-2-formylpyrrole-5-
carboxylate (9) are easily accessed. It should be noted that the
crude formylated product is usually very pure and can be employed
in subsequent steps without any detrimental effect.
Table 1
Formylation of ethyl 4-bromopyrrole-2-carboxylate
Entry Solvent
Ratio of POCl3 to DMF % Yield via HPLC % Yield isolated
1
2
3
4
5
6
CH2Cl2
CHCl3
CH3CCl3 2.0:2.5
DMF
THF
CH2Cl2
2.0:2.5
2.0:2.5
82
79
67
0
0
87
81
80
56
NI
NI
86
conjugated to
a b-electron withdrawing group, the Suzu-
kieMiyaura cross-coupling reaction is normally facilitated. Conse-
quently, it appears that the presence of an electron-withdrawing
group ortho to the halogen is a more significant factor in the success
of the cross-coupling reaction than having the pyrrole nitrogen
protected in some manner. This also suggests that a variety of other
electron-withdrawing groups attached to a pyrrole carbon and
ortho to a bromine bearing carbon would produce a similar acti-
vating effect. On this basis we now describe a general methodology
for rapid construction of a variety of nitrogen unsubstituted, aryl
pyrroles from a single pyrrole building block that contains bromine
at C-3 and a formyl group at C-2 of the pyrrole core. We also de-
scribe the application of this methodology to the formal synthesis
of Polycitone A and B and Polycitrin A (Fig. 1).
2.0:2.5
2.0:2.5
3.0:3.5
NIdnot isolated; HPLC analyses were carried out on a Waters Alliance 2695 in-
strument with an Inertsil ODS-2 column using a 1:1 methanol/acetonitrile eluant at
a flow rate of 0.25 mL per minute.
Br
Br
POCl3/DMF at rt
Solvent
O
H
O
N
H
N
H
9
O
O
O
8
2. Results and discussions
Scheme 2. Formylation of ethyl 4-bromopyrrole-2-carboxylate.
Since many of the pyrrole-containing natural products possess
carbonyl substitution at C-2 and/or C-5 of the pyrrole core, we de-
cided to examine ethyl 3-bromo-2-formylpyrrole-5-carboxylate (9)
as our ‘potential pyrrole core building block’. The regiospecific
preparation of ethyl 4-bromopyrrole-2-carboxylate (8) from 2-
trichloroacetylpyrrole has been reported12 in very good yield (90%)
With substantial amounts of ethyl 3-bromo-2-formylpyrrole-5-
carboxylate (9) in hand we next examined a variety of Suzu-
kieMiyaura cross-coupling reaction conditions. Potassium 4-
methylphenyltrifluoroborate was utilized as the cross-coupling

2740
J.T. Gupton et al. / Tetrahedron 70 (2014) 2738e2745
Table 3
partner in our initial studies and the results are reported in Table 2
(Scheme 3). Several different solvents were evaluated (entries 1e4,
Table 2) and very little difference in product yield and purity was
noted. As a result, we decided to stick with the toluene/ethanol mix,
which we have utilized previously in other SuzukieMiyaura cross-
Optimization of Suzuki cross-coupling reaction stoichiometry of ethyl 3-bromo-2-
formylpyrrole-5-carboxylate with potassium 4-methylphenyltrifluoroborate
Entry
Catalyst
equivalents
DABCO
equivalents
Trifluoroborate
equivalents
% Yield via HPLC
(isolated)
1
2
3
4
5
6
7
8
9
0.01
0.05
0.10
0.05
0.05
0.05
0.05
0.05
0.05
2.0
2.0
2.0
1.0
1.4
3.0
2.0
2.0
2.0
1.3
1.3
1.3
1.3
1.2
1.3
1.0
1.6
2.0
98
95 (99)
100
83
99 (99)
90
79
72
64
Table 2
Evaluation of solvent, base, and catalyst in the Suzuki cross-coupling reaction of
ethyl
3-bromo-2-formylpyrrole-5-carboxylate
with
potassium
4-
methylphenyltrifluoroborate
Entry
Solvent
Base
Catalyst
% Yield via HPLC
(isolated)
1
2
3
4
5
6
7
8
Toluene/EtOH
THF
CH3CN
DIPEA
DIPEA
DIPEA
DIPEA
Cs2CO3
K2CO3
Na2CO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
PdCl2
86
86
86
86
72
73
83
91
84
98
53 (42)
100 (89)
95 (99)
HPLC analyses were carried out on a Waters Alliance 2695 instrument with an
Inertsil ODS-2 column using a 1:1 methanol/acetonitrile eluant at a flow rate of
0.25 mL per minute.
EtOH
Toluene/EtOH
Toluene/EtOH
Toluene/EtOH
Toluene/EtOH
Toluene/EtOH
Toluene/EtOH
Toluene/EtOH
Toluene/EtOH
Toluene/EtOH
Me
Me
BF3K
9
Br
10
11
12
13
11
PdDBA
PdCl2(PPh3)2
PdDPPF(Cl)2
H
O
H
O
N
H
9
N
H
10
O
O
PdDPPF, DABCO
in Toluene/EtOH
O
O
HPLC analyses were carried out on a Waters Alliance 2695 instrument with an
Inertsil ODS-2 column using a 1:1 methanol/acetonitrile eluant at a flow rate of
0.25 mL per minute.
Microwave Heating for
2 hr at 110 0C
Scheme 4. Optimization of the stoichiometry for the Suzuki cross-coupling reaction of
ethyl 3-bromo-2-formylpyrrole-5-carboxylate with potassium 4-methylphenyl
trifluoroborate.
Me
Me
BF3K
Oxygenated phenyl groups were examined (entries 2, 4, 5, 9, 11, and
12 Table 4), since this functionality is most often present in the
various pyrrole-containing marine natural products.3 These cross-
coupling agents gave very good yields and product purities. In an
overall sense, the variously substituted aryl groups produced very
respectable yields and the lower yields in a couple of instances may
have been due to physical losses during the purification process.
Br
(11, 1.3 equivs)
H
O
H
O
N
H
N
H
Catalyst (0.05 equivs)
Base (2.0 equivs)
O
O
O
O
10
9
Solvent
Microwave Heating for
2 hr at 110 0C
Table 4
Reactions of various aryl and heteroaryl boronic acid derivatives with ethyl 3-
bromo-2-formylpyrrole-5-carboxylate under Suzuki cross-coupling conditions
Scheme 3. Suzuki cross-coupling studies of ethyl 3-bromo-2-formylpyrrole-5-
carboxylate with potassium 4-methylphenyltrifluoroborate.
Entry
Compound
Ar
% Yield isolated
1
2
3
4
5
6
7
8
10
12
13
14
15
16
17
18
19
20
21
22
23
4-MePh
4-MeOPh
4-ClPh
3,4-(MeO)2Ph
3,4,5-(MeO)3Ph
Ph
4-MeSPh
4-FPh
Benzo(3,4)dioxolyl
3,4-(Cl)2Ph
4-HOPh
4-CF3OPh
N-Phenylsulfonyl-3-indolyl
99
86
69
70
64
78
63
coupling reactions. We next examined the use of several different
bases (entries 1 and 5e8, Table 2) and all the examples worked
reasonably well but DABCO consistently gave better yields and
cleaner cross-coupled products. Subsequently, a variety of palla-
dium catalysts were evaluated (entries 8e13, Table 2) with dichloro
51 (69)a
99
[1,10-bis-(diphenylphosphino)-ferrocene]palladium(II)
dichloro-
9
methane adduct [PdDPPF(Cl)2] giving the cleanest reaction prod-
ucts in very high yield. The dichloro-(bistriphenylphosphine)
palladium(II) catalyst also proved quite effective. The rationale for
the success of these particular catalysts is not obvious at this point.
The last optimization parameter that we decided to look at was
stoichiometry (Table 3 and Scheme 4). Various concentrations of
catalysts were evaluated and no discernable differences in product
yield or purity were observed. It was decided to utilize a 5 mol %
concentration of the PdDPPFCl2 for standard reaction conditions.
When the quantities of base and boronic acid derivative were
evaluated, the best yields and product purity were realized (entry 5,
Table 3) when a slight excess of each reagent was used.
10
11
12
13
90a
66a
96a
55
a
These reactions utilized the corresponding boronic acids. All other reactions
utilized the corresponding trifluoroborate.
The N-phenylsulfonyl-3-indolyl group (entry 13, Table 4) was
chosen to study as a consequence of its presence14 in several im-
portant, pyrrole-containing natural products (Scheme 5).
In addition to the studies that we have described, it was de-
cided to demonstrate the flexibility of the methodology by pre-
paring isomeric 3,4-diarylpyrroles. Since the actual pyrrole
starting materials (10 and 12, Scheme 6) were derived from ethyl
3-bromo-2-formylpyrrole-5-carboxylate (9), the utility of the
pyrrole building block is thereby extended. Bromination of both
Following the completion of our optimization studies, we next
turned our attention to examine the scope and limitation of our
‘formyl group activation methodology’ and several boronic acid
derivatives were studied and the results are presented in Table 4.

J.T. Gupton et al. / Tetrahedron 70 (2014) 2738e2745
2741
Br
R
MeO
MeO
H
MeO
BF3K
R BF3K
OMe
26
H
O
H
O
Br
N
H
N
H
O
O
Pd(PPh3)4 or PdDPPF, DABCO
in Toluene/EtOH
O
O
PdDPPF, DABCO
in Toluene/EtOH
H
O
O
N
H
N
H
9
10
O
O
O
O
Microwave Heating for
Microwave Heating for
2 hr at 110 0C
2 hr at 110 0C
27
29, 72% yield
Scheme 5. Suzuki cross-coupling reactions of ethyl 3-bromo-2-formylpyrrole-5-
carboxylate with various aryl and heteroaryl boronic acid derivatives.
NaClO2, Buffer
in DMSO/Water
pyrroles (10 and 12, Scheme 6) generated the corresponding 3-
bromopyrroles (24 and 27, Scheme 6) in very good yields (97%
and 83%). Subsequently, applying our optimized cross-coupling
conditions to these brominated pyrroles produced the corre-
sponding 3-aryl cross-coupled analogs (25 and 28, Scheme 6) in
good yields (68% and 77%) as well.
The ultimate application of the ‘formyl group activation’ is to
utilize the methodology for the construction of one of the pyrrole-
containing marine natural products as suggested earlier. Polycitone
A, Polycitone B, and Polycitrin A (Fig. 1) were chosen as the initial
targets. Steglich5,15 and co-workers have utilized a tetrasubstituted
symmetrical pyrrole (31) as a key precursor to all three natural
products (1a, 1b, and 2, Fig. 1) and therefore a synthesis (Scheme 7)
of this material (31) would constitute a formal synthesis of Poly-
citone A, Polycitone B, and Polycitrin A.
MeO
HO
MeO
OMe
OMe
KOH, EtOH/Water and Reflux
OH
HO
O
N
H
N
H
O
O
O
O
31, 75% yield
Key Steglich Precursor
30, 90% yield
Scheme 7. Formal synthesis of Polycitone A, Polycitone B, and Polycitrin A.
Me
Me
Me
MeO
BF3K
OMe
KOH, NBS
DMF, rt
26
Br
PdDPPF, DABCO
in Toluene/EtOH
H
O
H
O
H
O
N
H
N
H
N
H
O
O
O
O
O
O
Microwave Heating for
2 hr at 110 0
C
25, 68% Yield
24, 97% yield
10
MeO
H
MeO
H
MeO
H
Me
Me
BF3K
KOH, NBS
DMF, rt
11
Br
O
O
O
PdDPPF, DABCO
in Toluene/EtOH
N
H
N
H
N
H
O
O
O
O
O
O
Microwave Heating for
2 hr at 110 0
28, 77% yield
12
27, 83% yield
C
Scheme 6. Selective preparation of isomeric 3,4-diarylpyrroles via formyl group activation.
Cross-coupling of pyrrole 27 with potassium 4-methoxy
trifluoroborate (26) under optimized conditions produced a tetra-
substituted pyrrole (29) in 72% yield. Oxidation of the cross-
coupled product (29) with sodium chlorite in aqueous DMSO pro-
duced the pyrrole monoacid (30) in 90% yield and subsequent hy-
drolysis of this material under basic conditions gave the Steglich
synthon5,15 (31) in 75% yield. This sequence represents a five-step
process from ethyl 3-bromo-2-formylpyrrole-5-carboxylate (9) in
an overall yield of 42%.
a variety of boronic acid derivatives in good yield. This methodology
allows for the convenient and efficient construction of various types
of tetrasubstituted-3,4-diarylpyrroles including regioisomers. The
completion of a short, formal synthesis of Polycitone A, Polycitone B,
and Polycitrin A is also described. This methodology should prove
very useful for the synthesis of libraries of highly functionalized
pyrroles as a part of detailed SAR studies.
4. Experimental
4.1. General
3. Conclusions
In this article we have described the preparation of a very flexible
pyrrole synthon [ethyl 3-bromo-2-formylpyrrole-5-carboxylate
(9)], which can undergo SuzukieMiyaura cross-coupling with
All chemicals were used as received from the manufacturer
(Aldrich Chemicals and Fisher Scientific). All solvents were dried
ꢀ
over 4 A molecular sieves prior to their use. NMR spectra were

2742
J.T. Gupton et al. / Tetrahedron 70 (2014) 2738e2745
obtained on either a Bruker 300 MHz spectrometer, or a Bruker
500 MHz spectrometer in either CDCl3, DMSO-d6, or acetone-d6
solutions. IR spectra were recorded on a Nicolet Avatar 320 FT-IR
spectrometer with an HATR attachment. High-resolution mass
spectra were obtained on a Shimadzu IT-TOF mass spectrometer at
the University of Richmond. Low-resolution GCeMS spectra were
obtained on a Shimadzu QP 5050 instrument. Melting points and
boiling points are uncorrected. Chromatographic purifications were
carried out on a Biotage SP-1 instrument or a Biotage Isolera in-
strument (both equipped with a silica cartridge). Gradient elution
with ethyl acetate/hexane was accomplished in both instances. The
reaction products were normally eluted within the range of 4e8
column volumes of eluant with a gradient mixture of 60:40 ethyl
acetate/hexane. TLC analyses were conducted on silica plates with
hexane/ethyl acetate as the eluant. All purified reaction products
gave TLC results, flash chromatograms, and 13C NMR spectra con-
sistent with a sample purity of >95%.
J¼7.2 Hz, 3H). It should be noted that a control experiment was run
on 4-bromo-2-carbethoxypyrrole (the compound minus the 2-
formyl group) under conditions as described above in which case
a gross mixture of products was obtained.
4.1.3. Ethyl 2-formyl-3-(4-methoxyphenylpyrrole)-5-carboxylate
(12). This material was prepared in a manner identical to the
previous example with the exceptions that diisopropylethylamine
(DIPEA) was used as the base instead of DABCO and tetrakis(-
triphenylphosphine)palladium (0) was used as the catalyst and
potassium 4-methoxyphenyltrifluoroborate was used as the cou-
pling agent. Work up of the reaction mixture produced a dark solid,
which was purified by flash chromatography on a Biotage Isolera
system in which case a light colored solid was obtained (0.280 g,
72% yield). We have previously described13 the synthesis of this
substance by a different synthetic route and the spectral properties
exhibited by this reaction product were identical to those reported
earlier: 1H NMR (CDCl3)
7.00e7.02 (m, 3H), 4.41 (q, J¼6.9 Hz, 2H), 3.88 (s, 3H), and 1.42 (t,
J¼6.9 Hz, 3H).
d
9.76 (s, 1H), 7.43 (d, J¼9.0 Hz, 2H),
4.1.1. Ethyl
3-bromo-2-formylpyrrole-5-carboxylate
(9). Into
a 100 mL round bottom flask equipped with magnetic stirring and
a rubber septum cap was placed 10 mL of anhydrous dichloro-
methane, 4.83 g (0.0661 mol) of dry DMF, 8.69 g (0.0566 mol) of
phosphorus oxychloride, and the resulting mixture was stirred for
10 min. To this flask was then added 4.12 g (0.0189 mol) of ethyl 4-
bromopyrrole-2-carboxylate in 15 mL of anhydrous dichloro-
methane and the resulting mixture was stirred overnight at room
temperature. The reaction was worked up by the addition of 80 mL
of water and separation of the two phases. The aqueous phase was
extracted with additional dichloromethane (3ꢀ20 mL) and the
combined dichloromethane phases were washed with brine
(1ꢀ15 mL), dried over anhydrous sodium sulfate, and concentrated
in vacuo to yield 4.01 g (86% yield) of a brown solid. This material
was of sufficient purity to be used in subsequent experiments but
an analytical sample was prepared by purification via flash chro-
matography on a Biotage Isolera system in which case a light col-
ored solid was obtained, which exhibited the following physical
4.1.4. Ethyl 2-formyl-3-(4-chlorophenylpyrrole)-5-carboxylate
(13). This material was prepared in a manner identical to the
previous example with the exception that potassium 4-
chlorophenyltrifluoroborate was used as the coupling agent.
Work up of the reaction mixture produced a dark solid, which was
purified by flash chromatography on a Biotage Isolera system in
which case a light colored solid was obtained (0.116 g, 69% yield).
We have previously described13 the synthesis of this substance by
a different synthetic route and the spectral properties exhibited by
this reaction product were identical to those reported earlier: 1H
NMR (CDCl3)
d
9.76 (s, 1H), 7.45 (d, J¼8.5 Hz, 2H), 7.44 (d, J¼8.5 Hz,
2H), 7.02 (d, J¼2.9 Hz, 1H), 4.42 (q, J¼7.2 Hz, 2H), and 1.42 (t,
J¼7.2 Hz, 3H).
4.1.5. Ethyl 2-formyl-3-(3,4-dimethoxyphenylpyrrole)-5-carboxylate
(14). This material was prepared in a manner identical to the pre-
vious example with the exception that potassium 3,4-
dimethoxyphenyltrifluoroborate was used as the coupling agent.
Work up of the reaction mixture produced a dark solid, which was
purified by flash chromatography on a Biotage Isolera system in
which case a light colored solid was obtained (0.300 g, 70% yield).
We have previously described13 the synthesis of this substance by
a different synthetic route and the spectral properties exhibited by
this reaction product were identical to those reported earlier: 1H
properties: mp 91e92 ꢁC; 1H NMR (CDCl3)
d 9.74 (s, 1H), 6.96 (d,
J¼1.2 Hz, 1H), 4.40 (q, J¼7.2 Hz, 2H), and 1.39 (t, J¼7.2 Hz, 3H); 13
C
NMR (acetone-d6)
d 179.0, 159.1, 131.0, 128.4, 117.5, 106.0, 61.1, and
13.6; IR (neat) 1711 and 1671 cmꢂ1; HRMS (ES, Mþ) m/z calcd for
C8H8BrNO3 244.9688, found 244.9057.
4.1.2. Ethyl 2-formyl-3-(4-methylphenylpyrrole)-5-carboxylate
(10). Into a 20 mL microwave reaction tube was placed a mag-
netic stir bar, ethyl 3-bromo-2-formylpyrrole-5-carboxylate
(0.250 g, 1.02 mmol), potassium 4-methylphenyltrifluoroborate
(0.255 g, 1.32 mmol), and DABCO (0.229 g, 2.04 mmol). A mixture
of 3:1 toluene/ethanol (12 mL) was added to the microwave re-
action tube along with 20 drops of water. After stirring for several
minutes, dichloro[1,10-bis-(diphenylphosphino)ferrocene]palladiu-
m(II) dichloromethane adduct (0.037 g, 0.051 mmol) was added to
the reaction mixture and the tube was capped and sealed with
a crimping tool. The reaction mixture was heated in a Biotage Ini-
tiator microwave system for 2 h at 110 ꢁC. After cooling to room
temperature, the reaction mixture was filtered through a short plug
of silica gel and the silica was subsequently washed with 2ꢀ30 mL
of ethyl acetate and the combined organic materials were con-
centrated in vacuo to give a dark solid (0.260 g, 99% yield). This
material was quite pure by TLC and HPLC analysis but an analytical
sample was prepared by flash chromatography on a Biotage Isolera
system in which case a light colored solid was obtained. We have
previously described13 the synthesis of this substance by a different
synthetic route and the spectral properties exhibited by this re-
action product were identical to those reported earlier: 1H NMR
NMR (CDCl3)
d
9.79 (s,1H), 7.04 (dd, J¼2.0, 8.5 Hz,1H). 7.00e7.02 (m,
3H), 4.42 (q, J¼7.2 Hz, 2H), 3.95 (s, 6H), and 1.42 (t, J¼7.2 Hz, 3H).
4.1.6. Ethyl 2-formyl-3-(3,4,5-trimethoxyphenylpyrrole)-5-
carboxylate (15). This material was prepared in a manner identi-
cal to the previous example with the exception that potassium
3,4,5-trimethoxyphenyltrifluoroborate was used as the coupling
agent. Work up of the reaction mixture produced a dark solid,
which was purified by flash chromatography on a Biotage Isolera
system in which case a light colored solid was obtained (0.110 g,
64% yield). We have previously described13 the synthesis of this
substance by a different synthetic route and the spectral properties
exhibited by this reaction product were identical to those reported
earlier: 1H NMR (CDCl3)
d
9.82 (s, 1H), 7.28 (d, J¼2.4 Hz, 1H), 6.68 (s,
2H), 4.40 (q, J¼6.9 Hz, 2H), 3.91 (s, 6H), 3.90 (s, 3H), and 1.41 (t,
J¼6.9 Hz, 3H).
4.1.7. Ethyl 2-formyl-3-phenylpyrrole-5-carboxylate (16). This ma-
terial was prepared in a manner identical to the previous example
with the exception that potassium phenyltrifluoroborate was used
as the coupling agent. Work up of the reaction mixture produced
(CDCl3)
d
9.78 (s, 1H), 7.40 (d, J¼8.1 Hz, 2H), 7.29 (d, J¼8.1 Hz, 2H),
7.02 (d, J¼2.4 Hz, 1H), 4.41 (q, J¼7.2 Hz, 2H), 2.43 (s, 3H), and 1.42 (t,

J.T. Gupton et al. / Tetrahedron 70 (2014) 2738e2745
2743
a dark solid, which was purified by flash chromatography on
a Biotage Isolera system in which case a light colored solid was
obtained (0.256 g, 78% yield). We have previously described13 the
synthesis of this substance by a different synthetic route and the
spectral properties exhibited by this reaction product were iden-
1H), 4.42 (q, J¼7.2 Hz, 2H), and 1.42 (t, J¼7.2 Hz, 3H); 13C NMR
(CDCl3)
d 179.9, 159.9, 133.2, 133.0, 132.7, 132.6, 130.9, 130.7, 130.1,
128.2, 127.9, 115.2, 61.6, and 14.3; IR (neat) 1717 and 1668 cmꢂ1
;
HRMS (ES, MþH) m/z calcd for C14H12Cl2NO3 312.0194, found
312.0182.
tical to those reported earlier: 1H NMR (acetone-d6)
d 9.83 (s, 1H),
7.63 (d, J¼7.5 Hz, 2H), 7.49 (t, J¼7.5 Hz, 2H), 7.42 (t, J¼7.5 Hz, 1H),
4.1.12. Ethyl 2-formyl-3-(4-hydroxyphenylpyrrole)-5-carboxylate
(21). This material was prepared in a manner identical to the
previous example with the exception that potassium 4-
hydroxyphenylboronic acid was used as the coupling agent. Work
up of the reaction mixture produced a dark solid, which was pu-
rified by flash chromatography on a Biotage Isolera system in which
case a light colored solid was obtained (0.173 g, 66% yield) and this
material exhibited the following physical properties: mp
7.07 (s, 1H), 4.38 (q, J¼7.5 Hz, 2H), and 1.38 (t, J¼7.5 Hz, 3H).
4.1.8. Ethyl 2-formyl-3-(4-methylthiophenylpyrrole)-5-carboxylate
(17). This material was prepared in a manner identical to the
previous example with the exception that DABCO was used as the
base,
dichloro[1,10-bis-(diphenylphosphino)ferrocene]palladiu-
m(II) dichloromethane adduct was used as the catalyst, and po-
tassium 4-methylthiophenyltrifluoroborate was used as the
coupling agent. Work up of the reaction mixture produced a dark
solid, which was purified by flash chromatography on a Biotage
Isolera system in which case a light colored solid was obtained
(0.184 g, 63% yield), which exhibited the following physical prop-
158e159 ꢁC; 1H NMR (CDCl3)
d
9.76 (s, 1H), 7.38 (d, J¼8.7 Hz, 2H),
6.99 (d, J¼2.7 Hz, 1H), 6.94 (d, J¼8.7 Hz, 2H), 4.41 (q, J¼7.2 Hz, 2H),
and 1.42 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d 180.7, 160.3, 155.9,
135.8, 130.5, 130.1, 127.7, 125.3, 115.9, 115.1, 61.5, and 14.3; IR (neat)
3254, 1701, and 1634 cmꢂ1; HRMS (ES, MþH) m/z calcd for
erties: mp 123e124 ꢁC; 1H NMR (CDCl3)
d
9.78 (s, 1H), 7.42 (d,
C14H14NO4 260.0923, found 260.0908.
J¼8.4 Hz, 2H), 7.35 (d, J¼8.4 Hz, 2H), 7.02 (d, J¼2.7 Hz, 1H), 4.42 (q,
J¼7.2 Hz, 2H), 2.55 (s, 3H), and 1.42 (t, J¼7.2 Hz, 3H); 13C NMR
4.1.13. Ethyl 2-formyl-3-(4-trifluoromethoxyphenylpyrrole)-5-
carboxylate (22). This material was prepared in a manner identi-
cal to the previous example with the exception that potassium 4-
trifluoromethoxyphenylboronic acid was used as the coupling
agent. Work up of the reaction mixture produced a dark solid
(0.320 g, 96% yield), which did not require additional purification.
This material exhibited the following physical properties: mp
(CDCl3)
d 180.7, 160.3, 139.1, 135.5, 130.2, 129.4, 129.2, 127.8, 126.6,
115.2, 61.5, 15.6, and 14.3; IR (neat) 1701 and 1685 cmꢂ1; HRMS (ES,
MþH) m/z calcd for C15H16NO3S 290.0851, found 290.0837.
4.1.9. Ethyl 2-formyl-3-(4-fluorophenylpyrrole)-5-carboxylate
(18). This material was prepared in a manner identical to the
previous example with the exception that 4-fluorophenylboronic
acid was used as the coupling agent. Work up of the reaction
mixture produced a dark solid, which was purified by flash chro-
matography on a Biotage Isolera system in which case a light col-
ored solid was obtained (0.219 g, 69% yield), which exhibited the
52e54 ꢁC; 1H NMR (CDCl3)
d
9.77 (s, 1H), 7.53 (d, J¼8.0 Hz, 2H), 7.33
(d, J¼8.0 Hz, 2H), 7.03 (d, J¼2.5 Hz, 1H), 4.42 (q, J¼7.0 Hz, 2H), and
1.43 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
d 180.3, 160.2, 149.3, 134.3,
131.4, 130.4, 130.2, 127.8, 121.4, 120.5 (q, J¼251.6 Hz), 115.3, 61.9, and
14.3; IR (neat) 1718 and 1661 cmꢂ1; HRMS (ES, MþH) m/z calcd for
following physical properties: mp 95e96 ꢁC; 1H NMR (CDCl3)
d
9.75
C15H13F3NO4 328.0797, found 328.0796.
(s, 1H), 7.47 (dd, J¼5.4, 8.7 Hz, 2H), 7.17 (t, J¼8.7 Hz, 2H), 7.01 (d,
J¼2.4 Hz, 1H), 4.42 (q, J¼7.2 Hz, 2H), and 1.42 (t, J¼7.2 Hz, 3H); 13
C
4.1.14. Ethyl 3-(1-benzenesulfonyl-1H-indol-3-yl)-2-formylpyrrole-
5-carboxylate (23). This material was prepared in a manner iden-
tical to the previous example with the exceptions that diisopro-
pylethylamine (DIPEA) was used as the base instead of DABCO and
potassium 1-benzenesulfonyl-1H-indol-3-trifluoroborate was used
as the coupling agent. Work up of the reaction mixture produced
a dark orange solid, which was purified by flash chromatography on
a Biotage Isolera system in which case a bright orange solid was
obtained (0.470 g, 55% yield) and this material exhibited the fol-
NMR (CDCl3)
d
180.4, 162.9 (d, J¼248.4 Hz), 160.2, 134.9, 130.7 (d,
J¼8.0 Hz), 103.2, 128.7 (d, J¼3.5 Hz), 127.7, 115.9 (d, J¼82.3 Hz),
115.3, 61.5, and 14.3; IR (neat) 1686 and 1655 cmꢂ1; HRMS (ES,
MþH) m/z calcd for C14H13FNO3 262.0879, found 262.0868.
4.1.10. Ethyl 2-formyl-3-[benzo(3,4)dioxolylpyrrole]-5-carboxylate
(19). This material was prepared in a manner identical to the
previous example with the exception that potassium benzo[1,3]
dioxolyltrifluorofluoroborate was used as the coupling agent. Work
up of the reaction mixture produced a dark solid (0.300 g, 99%
yield). This material was quite pure by TLC and HPLC and was not
purified further. This material exhibited the following physical
lowing physical properties: mp 164e166 ꢁC; 1H NMR (CDCl3)
d 9.94
(s, 1H), 8.10 (d, J¼8.0 Hz, 1H), 7.97 (d, J¼8.5 Hz, 2H), 7.70 (s, 1H), 7.65
(d, J¼8.0 Hz, 1H), 7.60 (t, J¼8.5 Hz, 1H), 7.51 (t, J¼8.5 Hz, 2H), 7.44 (t,
J¼8.5 Hz, 1H), 7.36 (t, J¼8.5 Hz, 1H), 7.13 (d, J¼3.0 Hz, 1H), 4.43 (q,
J¼7.0 Hz, 2H), and 1.43 (t, J¼7.0 Hz, 3H); 13C NMR (acetone-d6)
properties: mp 140e141 ꢁC; 1H NMR (acetone-d6)
d 9.81 (s, 1H), 7.15
(d, J¼1.5 Hz, 1H), 7.10 (dd, J¼1.5, 8.0 Hz, 1H), 7.01 (s, 1H), 6.95 (d,
d 179.8, 159.8, 137.9, 135.1, 134.5, 131.7, 130.0, 129.7, 128.3, 127.0,
J¼8.0 Hz, 1H), 6.08 (s, 2H), 4.36 (q, J¼7.0 Hz, 2H), and 1.37 (t,
125.6, 125.3, 124.2, 124.0, 120.3, 115.6, 115.0, 113.7, 60.8, and 13.7; IR
J¼7.0 Hz, 3H); 13C NMR (acetone-d6)
d
180.1, 159.9, 148.2, 147.7,
(neat) 1714 and 1659 cmꢂ1; HRMS (ES, MþH) m/z calcd for
134.6, 130.6, 127.7, 127.0, 123.0, 115.0, 109.3, 108.4, 101.4, 60.7, and
C22H18N2O5S 423.1009, found 423.1003.
13.6; IR (neat) 1704 and 1644 cmꢂ1; HRMS (ES, MþH) m/z calcd for
C
15H14NO5 288.0872, found 288.0873.
4.1.15. Ethyl 4-bromo-2-formyl-3-(4-methoxyphenylpyrrole)-5-
carboxylate (27). Into a 100 mL round bottom flask equipped
with magnetic stirring was placed ethyl 2-formyl-3-(4-
methoxyphenylpyrrole)-5-carboxylate (0.140 g, 0.513 mmol), po-
tassium hydroxide (0.0575 g, 1.03 mmol) and 15 mL of DMF. The
mixture was stirred for 15 min and N-bromosuccinimide (0.0913 g,
0.513 mmol) was added to the reaction flask and the resulting re-
action mixture was allowed to stir overnight at room temperature.
The reaction mixture was subsequently quenched with 45 mL of
water and extracted with ethyl acetate (3ꢀ20 mL). The combined
organic phases were washed with a saturated, aqueous solution of
lithium chloride and this was followed by drying the organic phase
4.1.11. Ethyl 2-formyl-3-(3,4-dichlorophenylpyrrole)-5-carboxylate
(20). This material was prepared in a manner identical to the
previous
example
with
the
exception
that
3,4-
dichlorophenylboronic acid was used as the coupling agent. Work
up of the reaction mixture produced a dark solid, which was pu-
rified by flash chromatography on a Biotage Isolera system in which
case a light colored solid was obtained (0.340 g, 90% yield) and this
material exhibited the following physical properties: mp
160e161 ꢁC; 1H NMR (CDCl3)
7.55 (d, J¼8.1 Hz, 1H), 7.33 (dd, J¼2.1, 8.1 Hz, 1H), 7.02 (d, J¼2.4 Hz,
d
9.77 (s, 1H), 7.60 (d, J¼2.1 Hz, 1H),

2744
J.T. Gupton et al. / Tetrahedron 70 (2014) 2738e2745
over anhydrous sodium sulfate. The drying agent was removed by
filtration and the filtrate was concentrated in vacuo to give a solid
product. This material was subjected to flash chromatography on
a Biotage Isolera system with a hexane/ethyl acetate gradient in
which case a tan solid (0.150 g, 83% yield) was obtained, which
exhibited the following physical properties: mp 132e134 ꢁC; 1H
(s, 3H), and 1.25 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d 181.3, 160.2,
159.3, 136.9, 134.8, 131.8, 130.6, 129.8, 129.3, 128.3, 123.9, 123.6,
113.8, 61.1, 56.2, 21.6, and 14.0; IR (neat) 1704 and 1659 cmꢂ1
;
HRMS (ES, MþNa) m/z calcd for C22H21NNaO4 386.1368, found
386.1382.
NMR (CDCl3)
2H), 4.45 (q, J¼7.0 Hz, 2H), 3.89 (s, 3H), and 1.45 (t, J¼7.0 Hz, 3H);
13C NMR (CDCl3)
180.6, 160.1, 159.3, 135.5, 131.8, 129.8, 124.7,
122.2, 114.1, 104.3, 61.8, 55.3, and 14.3; IR (neat) 1690 and
1664 cmꢂ1; HRMS (ES, MþH) m/z calcd for C15H15BrNO4 352.0184,
found 352.0195.
d
9.55 (s, 1H), 7.41 (d, J¼6.9 Hz, 2H), 7.03 (d, J¼6.9 Hz,
4.1.19. Ethyl 2-formyl-3,4-bis-(4-methoxyphenyl)pyrrole-5-
carboxylate (29). This material was prepared in a manner identi-
cal to the previous example with the exception that potassium 4-
methoxyphenyltrifluoroborate was employed as the cross-
coupling agent. After the standard work up and purification a tan
solid (0.232 g, 72% yield) was obtained, which exhibited the fol-
d
lowing physical properties: mp 130e132 ꢁC; 1H NMR (CDCl3)
d 9.62
4.1.16. Ethyl 4-bromo-2-formyl-3-(4-methylphenylpyrrole)-5-
carboxylate (24). This material was prepared in a manner identi-
cal to the previous example with the exception that 2-formyl-3-(4-
methylphenylpyrrole)-5-carboxylate was used as the starting ma-
terial for the reaction. The solid product (0.441 g, 97% yield) was
sufficiently pure to be used in a subsequent reaction but an ana-
lytical sample was prepared by flash chromatography on a Biotage
Isolera system with a hexane/ethyl acetate gradient. The resulting
purified solid exhibited the following physical properties: mp
(s, 1H), 7.08e7.14 (m, 4H), 6.84 (d, J¼5.7 Hz, 2H), 6.82 (d, J¼5.7 Hz,
2H), 4.28 (q, J¼7.2 Hz, 2H), 3.82 (s, 6H), and 1.26 (t, J¼7.2 Hz, 3H);
13C NMR (CDCl3)
d 181.5, 160.3, 159.3, 158.8, 134.8, 131.9, 131.8,
130.4,129.9,124.6,123.8,123.6,113.9,113.1, 61.1, 55.2, 55.1, and 14.1;
IR (neat) 1704 and 1655 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C22H21NNaO5 402.1317, found 402.1320.
4.1.20. 3,4-Bis-(4-methoxyphenyl)pyrrole-2,5-dicarboxylic acid mon-
oethyl ester (30). Into a 20 mL microwave reaction tube equipped
with a magnetic stir bar was placed ethyl 2-formyl-3,4-bis-(4-
methoxyphenyl)pyrrole-5-carboxylate (0.100 g, 0.264 mmol),
DMSO (10 mL), 0.050 M aqueous sodium dihydrogen phosphate
(3 mL), and sodium chlorite monohydrate (0.143 g, 1.58 mmol). The
reaction tube was capped and sealed with a crimping tool and the
reaction mixture was heated in a Biotage Initiator microwave system
for 2 h at 60 ꢁC. The reaction mixture was cooled to room temper-
ature, acidified with 6 M hydrochloric acid, diluted with 300 mL of
water, and extracted with ethyl acetate (3ꢀ30 mL). The combined
organic layers were washed with water, dried over anhydrous so-
dium sulfate, filtered, and concentrated in vacuo to leave a tan solid
(0.0940 g, 90% yield). This material was sufficiently pure to be used
in the next step and exhibited the following physical properties: mp
125e127 ꢁC; 1H NMR (CDCl3)
d
9.55 (s, 1H), 7.37 (d, J¼8.1 Hz, 2H),
7.31 (d, J¼8.1 Hz, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.45 (s, 3H), and 1.45 (t,
J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d 180.7, 162.6, 159.4, 135.7, 130.5,
129.8, 129.3, 127.1, 124.8, 104.2, 61.8, 21.3, and 14.3: IR (neat) 1690
and 1659 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C15H14BrNNaO3
358.0055, found 358.0057.
4.1.17. Ethyl 2-formyl-4-(4-methoxyphenyl)-3-(4-methylphenyl)pyr-
role-5-carboxylate (25). Into a 20 mL microwave reaction tube
equipped with a magnetic stir bar was placed ethyl 4-bromo-2-
formyl-3-(4-methylphenylpyrrole)-5-carboxylate
(0.150
g,
0.446 mmol), potassium 4-methoxyphenyltrifluoroborate (0.124 g,
0.580 mmol), and DABCO (0.100 g, 0.892 mmol). A mixture (12 mL)
of 3:1 of toluene/ethanol was added to the reaction tube along with
20 drops of water followed by dichloro[1,10-bis-(diphenylphos-
phino)ferrocene]palladium(II) dichloromethane adduct (0.016 g,
0.022 mmol). The reaction tube was capped and sealed with
a crimping tool and the reaction mixture was heated in a Biotage
Initiator microwave system for 2 h at 110 ꢁC. After cooling to room
temperature, the reaction mixture was filtered through a short plug
of silica gel and the silica was subsequently washed with 2ꢀ30 mL
of ethyl acetate and the combined organic materials were con-
centrated in vacuo to give a dark solid. This material was subjected
to flash chromatography on a Biotage Isolera system with a hexane/
ethyl acetate gradient in which case a tan solid (0.162 g, 68% yield)
was obtained and exhibited the following physical properties: mp
259e260 ꢁC; 1H NMR (DMSO-d6)
d
6.97 (d, J¼8.5 Hz, 2H), 6.95 (d,
J¼8.5 Hz, 2H), 6.74 (d, J¼8.5 Hz, 4H), 4.10 (q, J¼7.2 Hz, 2H), 3.71 (s,
6H), and 1.13 (t, J¼7.2 Hz, 3H); 13C NMR (DMSO-d6)
d 162.0, 160.4,
158.3, 158.2, 132.3, 132.2, 130.6, 130.1, 126.4, 126.3, 123.1, 121.9, 113.1,
60.4, 55.4, 55.3, and 14.3; IR (neat) 1699 and 1659 cmꢂ1; HRMS (ES,
MþNa) m/z calcd for C22H21NNaO6 418.1267, found 418.1252.
4.1.21. 3,4-Bis-(4-methoxyphenyl)pyrrole-2,5-dicarboxylic
acid
(31). Into a 100 mL round bottom flask equipped with magnetic
stirring and a reflux condenser was placed 3,4-bis-(4-methoxy
phenyl)-pyrrole-2,5-dicarboxylic acid monoethyl ester (0.100 g,
0.253 mmol), potassium hydroxide (0.142 g, 2.53 mmol), and 30 mL
of a 1:1 mixture of ethanol/water. The reaction mixture was
refluxed overnight, cooled to room temperature, and acidified to
pH 2 with 6 M hydrochloric acid. The mixture was diluted with
100 mL of water, extracted with ethyl acetate (3ꢀ30 mL), and the
combined organic phases were washed with brine and dried over
anhydrous sodium sulfate. The drying agent was removed by fil-
tration and the filtrate was concentrated in vacuo to yield a solid
(0.070 g, 75% yield). This material exhibited spectral properties
identical to those reported by Steglich15 and co-workers: mp
116e118 ꢁC; 1H NMR (CDCl3)
d
9.62 (s, 1H), 7.12 (br d, J¼8.7 Hz, 4H),
7.05 (d, J¼8.4 Hz, 2H), 6.82 (d, J¼9.0 Hz, 2H), 4.28 (q, J¼7.2 Hz, 2H),
3.81 (s, 3H), 2.35 (s, 3H), and 1.26 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d
181.4, 160.3, 158.8, 137.5, 135.1, 131.9, 130.5, 130.4, 129.9, 129.1,
128.4, 124.6. 123.8, 113.1, 61.2, 55.1, 21.1, and 14.1: IR (neat) 1690 and
1664 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C22H21NNaO4 386.1368,
found 386.1372.
4.1.18. Ethyl 2-formyl-3-(4-methoxyphenyl)-4-(4-methylphenyl)pyr-
role-5-carboxylate (28). This material was prepared in a manner
identical to the previous example with the exception that ethyl 4-
bromo-2-formyl-3-(4-methoxyphenylpyrrole)-5-carboxylate was
used as the starting material and potassium 4-methyl
phenyltrifluoroborate was employed as the cross-coupling agent.
After the standard work up and purification a tan solid (0.150 g, 77%
yield) was obtained, which exhibited the following physical prop-
254e256 ꢁC (lit. 268e270 ꢁC); 1H NMR (DMSO-d6)
d 6.96 (d,
J¼8.5 Hz, 4H), 6.73 (d, J¼8.5 Hz, 4H), and 3.71 (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) 1659 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C20H17NNaO6
390.0954, found 390.0947.
Acknowledgements
erties: mp 130e131 ꢁC; 1H NMR (CDCl3)
6H), 6.83 (d, J¼9.0 Hz, 2H), 4.27 (q, J¼7.2 Hz, 2H), 3.81 (s, 3H), 2.35
d
9.62 (s, 1H), 7.09e7.11 (m,
We gratefully thank the National Institutes of Health (grant no.
R15-CA67236) for support of this research. Thanks also to the Floyd

J.T. Gupton et al. / Tetrahedron 70 (2014) 2738e2745
2745
(c) Bailly, C. Curr. Med. Chem. Anti-Cancer Agents 2004, 363; (d) Gupton, J.
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Antitumor Antibiotics: Topics in Heterocyclic Chemistry; Springer: Berlin/Hei-
delberg, Germany, 2006; Vol. 2, p 53.
4. Gupton, J.; Miller, R.; Clough, S.; Krumpe, K.; Banner, E.; Kanters, R.; Du, K.;
Keertikar, K.; Lauerman, N.; Solano, J.; Adams, B.; Callahan, D.; Little, B.; Scharf,
A.; Sikorski, J. Tetrahedron 2005, 61, 1845.
5. Kreipl, A.; Reid, C.; Steglich, W. Org. Lett. 2002, 4, 3287.
6. Furstner, A.; Krause, H.; Thiel, O. Tetrahedron 2002, 58, 6373.
7. Pla, D.; Marchal, A.; Olsen, C.; Albericio, F.; Alavarez, M. J. Org. Chem. 2005, 70,
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8. (a) Banwell, M.; Bray, A.; Edwards, A.; Wong, D. J. Chem. Soc., Perkin Trans. 1
2002, 1340; (b) Banwell, M.; Goodwin, T.; Ng, S.; Smith, J.; Wong, D. Eur. J. Org.
Chem. 2006, 14, 3043.
D. and Elisabeth S. Gottwald Endowment and to the University of
Richmond Faculty Research Grant program for support to J.T.G. We
are exceedingly grateful to Mr. Dave Patteson formerly of Biotage
Inc. for the generous donation of an SP-1 flash chromatography
system, which was used in the majority of sample purifications. We
are also very appreciative of Advion Inc. for the generous donation
of a CMS electrospray mass spectrometer. Previous grants from the
MRI program of the National Science Foundation for the purchase
of a 500 MHz NMR spectrometer (CHE-0116492) and a high-reso-
lution electrospray mass spectrometer (CHE-0320669) are also
gratefully acknowledged.
9. Handy, S.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004, 69, 2362.
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References and notes
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