Synthesis of 2,2′-bipyrrole-5-carboxaldehydes and their application in the synthesis of B-ring functionalized prodiginines and tambjamines

Article abstract of DOI:10.1016/j.tet.2013.07.067

Facile, versatile, and cost-effective synthetic routes for the preparation of a range of new 3-alkyl-, 4-alkyl-, 3,4-dialkyl-, and 3-halo-4-alkyl-2, 2′-bipyrrole-5-carboxaldehydes have been developed. These 2,2′-bipyrrole-5-carboxaldehydes offer interesting potential as building blocks for making bioactive natural and unnatural products, as demonstrated by the synthesis of B-ring functionalized prodiginines (PGs) and tambjamines.

Full text of DOI:10.1016/j.tet.2013.07.067

Tetrahedron 69 (2013) 8375e8385
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Synthesis of 2,20-bipyrrole-5-carboxaldehydes and their application
in the synthesis of B-ring functionalized prodiginines and
tambjamines
,
y
*
Papireddy Kancharla, Kevin A. Reynolds
Department of Chemistry, Portland State University, Portland, OR 97207-0751, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 June 2013
Received in revised form 16 July 2013
Accepted 18 July 2013
Available online 26 July 2013
Facile, versatile, and cost-effective synthetic routes for the preparation of a range of new 3-alkyl-, 4-alkyl-,
3,4-dialkyl-, and 3-halo-4-alkyl-2,20-bipyrrole-5-carboxaldehydes have been developed. These 2,20-bi-
pyrrole-5-carboxaldehydes offer interesting potential as building blocks for making bioactive natural and
unnatural products, as demonstrated by the synthesis of B-ring functionalized prodiginines (PGs) and
tambjamines.
Ó 2013 Published by Elsevier Ltd.
Keywords:
2,20-Bipyrrole-5-carboxaldehydes
4-Methoxy-2,20-bipyrrole-5-
carboxaldehyde
MBC
Prodiginines
Tambjamines
Pyrrolylpyrromethene (PPM)
1. Introduction
of the currently available methods are efficient and scalable but are
limited in applicability to generation of A- and C-ring functional-
4-Methoxy-2,20-bipyrrole-5-carboxaldehyde (MBC,1) is a known
precursor in the biosynthesis of many pyrrolylpyrromethene (PPM)
natural products, such as prodigiosin (2), streptorubin B (3), and is
likely also used in the biosynthesis of marineosin (4), and tambj-
amines (5 and 6) (Fig.1).1,2 MBC and analogs thereof also can serve as
building blocks in the synthesis of analogs of these natural products,
which have been demonstrated to have a wide-range of biological
activities (including DNA interchelation,3 antimicrobial,4 immuno-
suppressive,5 antitumor,4a,b,6 anticancer,7 cell pH regulation by Hþ/
Clꢀ symport/antiport activity,8 phosphatase inhibition,9 and anti
malarial).10,11
Although MBC’s (1) chemical structure is relatively simple and
known for more than 50 years, only a few synthetic routes are
available in the literature.4b,12 Recently, Dairi et al. developed
a simple and practical method,13 and this MBC is useful to explore
the structureeactivity relationship (SAR) studies of C-ring func-
tionalized prodiginines (PGs) and tambjamines (Fig. 1). Indeed, all
ized PGs and often require the use of expensive catalysts. The
methods do not readily permit for providing the various sub-
stituents on ring-B, owing to limited number of commercial supply
of starting materials.
D’Alessio et al. demonstrated that elaborating the ring-B
methoxy group to provide other ethers has improved the thera-
peutic potential of certain PGs.5f The only other variation in ring B
of PGs is recent work by Lubell’s group who introduced alkylamine
groups by a diversity-oriented strategy.14 Our recent work on the
potent antimalarial activities of PGs,11 which to date have been
limited to SAR studies of A- and C-ring functionalized PGs. With
a few exceptions,5f,7,14 there have been no reports of a compre-
hensive series of B-ring functionalized PGs and tambjamines being
prepared and evaluated for biological activities. A methodology for
enhancing the diversity of 2,20-bipyrrole-5-carboxaldehyde moiety
is thus desirable to further advance SAR studies of interesting PPM
products (PGs, tambjamines and etc.).
In view of the potential importance of the ring-B of PPM de-
rivatives in medicinal chemistry as well as the general lack of syn-
thetic approaches in the literature, we have undertaken an
examination of several syntheses of 2,20-bipyrrole-5-carboxalde
hydes, which directly offer interesting potential as building blocks
for making B-ring functionalized PGs and tambjamines. Here we
* Corresponding author. Tel.: þ1 503 296 4829; fax: þ1 503 725 5262; e-mail
address: reynoldk@pdx.edu (K.A. Reynolds).
y
Office of Academic Affairs, Portland State University, P.O. Box 751, Portland, OR
97207-0751, USA.
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.07.067

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P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
Fig. 1. Structures of 4-methoxy-2,20-bipyrrole-5-carboxaldehyde (MBC, 1) and 4-methoxy-pyrrolic natural products (2e6).
report the first and straightforward synthetic routes for the syn-
thesis of 3-alkyl-2,20-bipyrrole-5-carboxaldehydes, 4-alkyl-2,20-bi
pyrrole-5-carboxaldehydes, 3,4-dialkyl-2,20-bipyrrole-5-carboxalde
hydes, and 3-chloro-4-ethyl-2,20-bipyrrole-5-carboxaldehyde from
simple starting materials in a cost-effective manner, and demon-
strated their application in the synthesis of B-ring functionalized
PGs and tambjamines for subsequent SAR studies.
ethylpyrrole (11) used pyrrole (7) as a starting material (Scheme
2), which treated with phenylsulfonyl chloride in the presence of
NaOH provided a N-phenylsulfonylpyrrole (8).17 Use of AlCl3 per-
mitted the regioselective acylation of 8 at the 3 position with the
acyl chloride to obtain the N-phenylsulfonyl-3-acylpyrrole (9),18
which was subsequently hydrolyzed under basic (5 N NaOH) con-
ditions to give 3-acylpyrrole (10).18 Compound 10 was then
smoothly converted to 11 using 2 equiv of LiAlH4 in THF under
reflux (Scheme 2).19 It was originally planned to take the advantage
of the efficient protocol of Bocchi20 for the oxidation of 11 to obtain
the desired 4-ethyl-3-pyrrolin-2-one (12a) using peroxide (H2O2)
under basic conditions (BaCO3). Further VilsmeiereHaack re-
action13 on 12a might then provide the bromopyrrole enamine
intermediate and subsequent Suzuki cross-coupling reaction with
N-Boc-2-pyrroleboronic acid13,21 would give the desired 4-ethyl-
2,20-bipyrrole-5-carboxaldehyde (13). However, the Bocchi’s oxi-
dation instead provided 3-ethyl-3-pyrrolin-2-one (12b) in 60%
isolated yield (Scheme 2), our desired synthon, 12a was identified
in small amount (5%).22 The structures of 12a, and 12b were con-
firmed by 2D-NMR analysis.23
2. Results and discussion
It is well established in the literature that PGs (2 and 3) and
tambjamines (5 and 6) can be conveniently formed by the con-
densation of an appropriate pyrrole and/or alkylamine segments
with MBC (1).12,16 Early studies have outlined productive routes to
the latter and have described numerous modifications of the parent
PPM core by replacing the pyrrole units with other heterocycles, or
by changing the substitution pattern on the individual aromatic
rings, especially A- and C-rings. In contrast, however, variations of
the ring-B core are scarce since a general entry into compounds of
this type is missing. Outlined in Scheme 1 is a flexible approach to
B-ring analogues of PGs (I) and tambjamines (II) from various 2,20-
bipyrrole-5-carboxaldehydes (III), which have a variety of sub-
stitution pattern at 3 and 4 positions. With the goal of synthesizing
a range of new 2,20-bipyrrole-5-carboxaldehydes (III), we have
designed various synthetic routes as shown in Schemes 2e6 and
executed these in a straightforward manner in good yields.
In continuation of our efforts toward the synthesis of 13,
an efficient synthetic route was investigated as outlined in
Scheme 3. Formylation of 11 under standard Vilsmeier conditions
(DMF/POCl3, 0 ꢁC) resulted in the mixture of two products, 3-
ethyl-pyrrole-2-carboxaldehyde (14a), and 4-ethyl-pyrrole-2-
carboxalde
Scheme 1. Retrosynthetic pathway of B-ring functionalized PGs (I), and tambjamines (II).
Our initial efforts focused on the synthesis of 4-ethyl- and/or 4-
methyl-2,20-bipyrrole-5-carboxaldehydes (13 and 24, Schemes 2
and 3), which are relatively similar to the MBC (1, Fig. 1) with re-
placement of OMe by ethyl or methyl substituent. Synthesis of 3-
hyde (14b) in 2.5:1 ratio (by crude 1H NMR) respectively, in good
yield (Scheme 3).22 The individual compounds, 14a and 14b were
isolated by column chromatography and characterized by NMR
analysis.23 At this juncture, we believed that compound 14a would

P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
8377
Scheme 2. Synthesis of 3-ethylpyrrole (11), and 3/4-ethyl-3-pyrrolin-2-ones (12a, and 12b).
Scheme 3. Synthesis of 4-alkyl-2,20-bipyrrole-5-carboxaldehydes (13 and 24).
Scheme 4. Synthesis of 3-alkyl-2,20-bipyrrole-5-carboxaldehydes (30e33).
be the preferred synthon to achieve 13. By using reported pro-
cedures, N-Boc-protected pyrrole 15 was prepared in 95% yield
using di-tert-butyl dicarbonate (Boc2O) in the presence of 4-(di-
methyl amino)pyridine (DMAP),15 and subsequently the aldehyde
group was protected by trimethyl orthoformate under acidic
conditions (PTSA) in methanol to obtain the desired N-Boc-2-
dimethoxymethyl-3-ethyl-pyrrole (16).24 Compound 16 was fur-
ther reacted with triisopropyl borate/LDA in THF at 0e5 ꢁC and
aqueous solution of KHSO4/NH4Cl at room temperature and pro-
vided the desired boronic acid 17 in excellent yield.24,25 The crude
product, 17, was carried forward into the next reaction with 18
without further purification. The N-Boc-2-bromopyrrole (18) was

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P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
Scheme 5. Synthesis of 3,4-dialkyl-2,20-bipyrrole-5-carboxaldehydes (44e47).
Scheme 6. Synthesis of 3-chloro-4-ethyl-2,20-bipyrrole-5-carboxaldehyde (50) and 30.
prepared by employing the reported procedure.26 Since the
compound 18 is highly unstable under solvent free conditions, we
stored as a 25% solution in hexane at ꢀ20 ꢁC, and used it as such
for further reactions. Finally, the Suzuki cross-coupling reaction
between 18 and the boronic acid 17,13,21 and subsequent depro-
tection of Boc group with LiOH in THFeMeOH27 led to the desired
bipyrrole-5-carboxaldehyde 13 in 76% isolated yield (Scheme 3)
and fully characterized by spectroscopic analysis.23
Having demonstrated the feasibility of this new synthetic ap-
proach (Scheme 3) for 13, we have successfully synthesized the
4-methyl-2,20-bipyrrole-5-carboxaldehyde (24) via the appropriate
intermediates 20a, 21, 22, 23, and 18 from the commercially

P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
8379
available 3-methylpyrrole (19) (Scheme 3) in good yield. It is
noteworthy to mention here that this is a unique synthetic strategy
to generate various alkyl substitutions at the 4 position of 2,20-
bipyrrole-5-carboxaldehydes.
carboxaldehydes 40a,b, which when further treated with 27 in THF
at ꢀ78 ꢁC to room temperature provided the 5-bromo-3,4-dialkyl-
pyrrole-2-carboxaldehydes 41a,b.22
At the same time, we employed the similar reaction sequence on
38c,d to furnish the 43a,b, unfortunately we ended up with mixture
of isomeric products, owing to the different alkyl groups (R1sR2,
Scheme 5) at 3 and 4 positions. Therefore, we envisaged an alter-
native route that exclusively leads to the formation of 43a,b. For
this, same 3,4-dialkyl-pyrrole-2-carboxylic acid ethyl esters, 38c,d
were further functionalized by Vilsmeier formylation at the 5-
position and subsequent hydrolysis to obtain 5-formyl-3,4-
dialkyl-pyrrole-2-carboxylic acids, 42a,b. As expected, 43a,b were
successfully obtained by decarboxylative bromination of 42a,b
using pyridinium tribromide/pyridine in 51% yield.33 Subsequently,
Suzuki cross-coupling reaction between 41a,b, 43a,b and the bo-
ronic acid 29 and further deprotection of the Boc group led to the
dialkyl-bipyrrole-5-carboxaldehyde, 44e47 (Scheme 5).
Subsequent investigation of this chemistry was focused on
introducing a chloro substituent at 3-position of 2,20-bipyrrole-5-
carboxaldehydes. To this end, a one-pot synthetic strategy, which
involves the consecutive chlorination by N-chlorosuccinimide
(NCS) and Vilsmeier formylation of 11 outlined in Scheme 6,
was employed.22,34 Interestingly, this one-pot method supplied a
mixture of two chlorinated pyrroles, including 4-chloro-3-ethyl-
pyrrole-2-carboxaldehyde (48a, 55%), and 5-chloro-3-ethyl-pyr-
role-2-carboxaldehyde (48b, 7%), which were characterized by
2D-NMR analysis.23 The chloro derivative 48a was converted to 5-
bromo-4-chloro-3-ethyl-pyrrole-2-carboxaldehyde (49) by bro-
mination reaction using 27.22 Selective Suzuki cross-coupling of
compound 49 with 29 followed by deprotection of N-Boc
group gave desired 3-chloro-4-ethyl-2,20-bipyrrole-5-carboxalde
hyde (50) in good yield. On the other hand, bipyrrole 30 was
also successfully accomplished by using Suzuki-coupling re
action starting from chlorinated pyrrole 48b in moderate yield
(Scheme 6).
Next, we turned our attention to the synthesis of the 3-alkyl-
2,20-bipyrrole-5-carboxaldehydes 30e33 (Scheme 4). Synthesis of
30, and 31 commenced from 4-ethyl-pyrrole-2-carboxaldehyde
(14b) and 4-methyl-pyrrole-2-carboxaldehyde (20b), which were
the side products in Vilsmeier reaction of 11 and 19, respectively
(Scheme 3). The intermediates, 14b and 20b were then smoothly
converted to 5-bromo-4-ethyl-pyrrole-2-carboxaldehyde (28a)
and 5-bromo-4-methyl-pyrrole-2-carboxaldehyde (28b),28 re-
spectively, via regioselective bromination at 5 position using 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH, 27) in THF (initially at
ꢀ78 ꢁC and warming to room temperature) in excellent yields
(Scheme 4).22 This kind of bromination has been previously re-
ported by using Br2/pyridine,28 but to our knowledge, 27 has never
been exploited to the synthesis of 5-bromo-4-alkyl-pyrrole-2-
carboxaldehydes. To demonstrate the generality, the reaction was
carried out under the same reaction conditions (27, THF, ꢀ78 ꢁC to
room temperature) on 4-isopropylpyrrole-2-carboxaldehyde (25)29
and 4-tert-butylpyrrole-2-carboxaldehyde (26)30 and obtained the
respective regioselective brominated products 28c and 28d, which
are key synthons to 32 and 33 in excellent yields. With the key
intermediates 28aed in hand, we then sought and successfully
synthesized the 3-alkyl-2,20-bipyrrole-5-carboxaldehydes 30e33
using Suzuki-coupling reaction with commercially available N-Boc-
2-pyrroleboronic acid (29),13,21 and subsequent treatment with
LiOH in THF/MeOH (1:1),27 as outlined in Scheme 4.
With the success in synthesizing 4-alkyl- and 3-alkyl-2,20-
bipyrrole-5-carboxaldehydes (13, 24, and 30e33) by straightforward
routes, we thus focused on synthesizing the 3,4-dialkyl-2,20-bipyr-
role-5-carboxaldehydes 44e47 (Scheme 5). The key intermediates
3,4-dialkyl-pyrrole-2-carboxylic acid ethyl esters, 38aed were pre-
pared via BartoneZard’s method,31 using 2-acetoxy-3-nitroalkanes
(37aed), which were obtained in high yield by condensation of
nitroalkanes, 35a,b with aliphatic aldehydes, 34a,b in two steps
(Scheme 5).32 Upon treating with NaOH in ethylene glycol under
reflux,32 38a,b were smoothly converted to 3,4-dialkylpyrroles 39a,b
in excellent yields by successive hydrolysis and decarboxylation of
the ester group. Using the standard Vilsmeier formylation method,
39a,b were then smoothly transformed to 3,4-dimethyl-pyrrole-2-
Finally, we demonstrated the utility of the bipyrrole-carboxal
dehydes, 13, 24, 32, 33, 44, 46, and 50 in the synthesis of B-ring
functionalized PGs and tambjamines. Acid-catalyzed condensation
of either alkylpyrroles (51),11 or commercially available alkylamines
with 13, 24, 32, 33, 44, 46, and 50 provided the desired B-ring
functionalized PGs, 52aed and tambjamines, 53aed, respectively,
in good to excellent isolated yields (Scheme 7).
Scheme 7. Synthesis of B-ring functionalized prodiginines (52aed) and tambjamines (53aed).

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P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
3. Conclusion
J¼1.6 Hz, 1H), 3.90 (d, J¼1.4 Hz, 2H), 2.29e2.23 (m, 2H), 1.13 (t,
J¼7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 175.7, 141.3, 136.6, 46.7,
In summary, we have developed various straightforward syn-
thetic routes to the synthesis of 3-alkyl-, 4-alkyl-, 3,4-dialkyl-, and 3-
halo-4-alkyl-2,20-bipyrrole-5-carboxaldehydes and demonstrated
their application in the synthesis of B-ring functionalized PGs and
tambjamines for the first time. These feasible synthetic routes can be
carried out in large scale and are suited for the generation of a library
of B-ring functionalized PGs and tambjamines for their advanced
biological activities and SAR studies. Our methodologies also provide
an efficient way for the synthesis of various substituted 2,20-bipyr-
roles and oligopyrroles. In the course of this work, we also have de-
veloped a simple and convenient method for the bromination of 4-
alkyl-pyrrole-2-carboxaldehydes by using DBDMH and it has sev-
eral advantages over existing methods. The preparation of a library
containing structurally diversified analogues of PGs and tambjamines
is currently underway in our laboratory. The biological activities of
these compounds and the comparison with natural products (PGs
and tambjamines) will be reported elsewhere in due course.
18.6, 11.9; HRMS (ESI) calcd for C6H10NO (MþH)þ 112.0757, found
112.0761 (see Supplementary data for the complete spectra in-
cluding 1D and 2D NMR).
4.3. Formylation of 11 by standard Vilsmeier conditions
Phosphorus oxychloride (POCl3) (16.10 g, 105.26 mmol) was
added dropwise to dimethylformamide (DMF) (8.45 g, 115.79
mmol) at 0 ꢁC. The resulting solution was stirred at 0 ꢁC until the
formation of Vilsmeier complex as a solid material. After the solid
was dried in vacuo for 20 min, dichloromethane (DCM) (50 mL) was
added to the solid and the mixture was cooled to 0 ꢁC. A solution of
11 (5.0 g, 52.63 mmol) in DCM (50 mL) was added dropwise, and
the mixture was warmed to room temperature and then stirred for
10 h. After removing all solvent under vacuo, the residue was mixed
with water (100 mL). To the stirred mixture, sodium hydroxide
(16.84 g, 421.05 mmol) was added slowly and the mixture was
allowed to stir for 1 h at room temperature. Ethyl acetate (EtOAc)
(200 mL) was added to the resulting precipitate, the two layers
were separated, and the aqueous layer was further extracted with
EtOAc (2ꢂ50 mL). The organic layers were combined, washed with
brine, dried over anhydrous Na2SO4, filtered, and the solvent was
removed by rotary evaporation to furnish the crude mixture of 14a
and 14b in 2.5:1 ratio, respectively, which was confirmed by NMR
analysis. Then the mixture of products was chromatographed on
silica gel using hexane/ethyl acetate as mobile phase to afford 14a
(3.82 g, 59%), and 14b (1.36 g, 21%).
4. Experimental section
4.1. General
Melting points were recorded on Electrothermal MET-TEMP
capillary melting point apparatus and are uncorrected. NMR spec-
tra were recorded on Bruker AMX-400, and AMX-600, spectrome-
ters at 400, 600 MHz (1H), and 100, 150 MHz (13C). Experiments
were recorded in CDCl3, CD3OD, Acetone-d6, and DMSO-d6 at 25 ꢁC.
Chemical shifts were given in parts per million (ppm) downfield
from internal standard Me4Si (TMS). HRMS (ESI) were recorded on
high-resolution (30,000) thermo LTQ-Orbitrap Discovery hybrid
mass spectrometry (San Jose, CA). Reagents were from Aldrich and
used as supplied, unless otherwise noted. Reactions which required
the use of anhydrous, inert atmosphere techniques were carried
out under an atmosphere of Argon/Nitrogen. Chromatography was
executed on CombiFlash Rf 200 instrument, using silica gel
(230e400 mesh) and/or neutral-alumina as stationary phase and
mixtures of ethyl acetate and hexane as eluents.
4.3.1. 3-Ethyl-pyrrole-2-carboxaldehyde (14a). Syrup, Rf¼0.35 (15%
EtOAc/hexanes); 1H NMR (CDCl3, 600 MHz) 10.34 (br s, 1H), 9.64 (d,
J¼0.8 Hz, 1H), 7.08 (t, J¼2.2 Hz, 1H), 6.19 (t, J¼2.3 Hz, 1H), 2.82 (q,
J¼7.6 Hz, 2H), 1.30 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz)
d
177.6, 140.2, 128.7, 126.6, 111.0, 18.6, 16.1; HRMS (ESI) calcd for
C7H10NO (MþH)þ 124.0757, found 124.0755.
4.3.2. 4-Ethyl-pyrrole-2-carboxaldehyde (14b).35 Syrup, Rf¼0.40
(15% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz) 10.05 (br s, 1H),
9.45 (d, J¼0.9 Hz, 1H), 6.98 (d, J¼0.8 Hz, 1H), 6.85 (t, J¼1.9 Hz, 1H),
2.54 (q, J¼7.5 Hz, 2H), 1.23 (t, J¼7.5 Hz, 3H); HRMS (ESI) calcd for
C7H10NO (MþH)þ 124.0757, found 124.0755.
4.2. Oxidation of 3-ethylpyrrole (11)
A solution of 11 (2.0 g, 21.05 mmol), BaCO3 (410 mg, 2.08 mmol),
and H2O2 (5 mL of a 36% v/v aqueous solution) in H2O (200 mL) was
refluxed for 5 h, after which time PbO2 was carefully added until
complete disappearance of effervescence. The mixture was filtered
through filter paper and the water removed under reduced pressure
to give a crude residue. The residue was picked up with 1,4-dioxane
(20 mL) and vigorously stirred for 10 min. The mixture was filtered
through filter paper and the residue was subjected to the same
operation two times again. The orange filtrates were combined and
concentrated under reduced pressure, which was further chroma-
tographed on silica gel, eluting with ethyl acetate/hexanes to afford
the pure products, 4-ethyl-3-pyrrolin-2-one (12a) (120 mg, 5%), and
3-ethyl-3-pyrrolin-2-one (12b) (1.40 g, 60%).
4.4. Synthesis of N-Boc-3-ethyl-pyrrole-2-carboxaldehyde (15)
4-(Dimethyl-amino)pyridine (DMAP) (200 mg, 1.64 mmol) was
added to a stirred solution of 3-ethyl-pyrrole-2-carboxaldehyde
(14a) (2.0 g, 16.26 mmol), and di-tert-butyl dicarbonate (Boc2O)
(4.25 g, 19.51 mmol) in acetonitrile (ACN) (30 mL) and the reaction
left to stir for 1 h at room temperature. Dichloromethane (DCM)
(150 mL) was added and the solution was washed with water
(2ꢂ50 mL), brine, dried over anhydrous Na2SO4, filtered, and the
solvent was removed by rotary evaporation to furnish the crude
product. The crude compound was chromatographed on silica gel
using hexane/ethyl acetate as mobile phase to afford 15 (3.44 g,
95%). Syrup, Rf¼0.80 (15% EtOAc/hexanes); 1H NMR (CDCl3,
4.2.1. 4-Ethyl-3-pyrrolin-2-one (12a). Semisolid, Rf¼0.15 (70%
400 MHz)
J¼3.2 Hz, 1H), 2.84 (q, J¼7.5 Hz, 2H), 1.62 (s, 9H), 1.19 (t, J¼7.5 Hz,
3H); 13C NMR (CDCl3, 100 MHz)
183.8, 148.8, 142.7, 129.8, 126.5,
d
10.40 (d, J¼0.5 Hz, 1H), 7.34 (d, J¼3.2 Hz, 1H), 6.19 (t,
EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 7.72 (br s, 1H), 5.78 (d,
J¼1.4 Hz, 1H), 3.90 (s, 2H), 2.38e2.32 (m, 2H), 1.14 (t, J¼7.5 Hz, 3H);
d
13C NMR (CDCl3, 100 MHz)
d
176.4, 165.1, 120.9, 50.7, 23.2, 12.2;
112.9, 85.5, 28.2 (3C), 21.1, 14.2; HRMS (ESI) calcd for C12H18NO3
HRMS (ESI) calcd for C6H10NO (MþH)þ 112.0757, found 112.0761
(see Supplementary data for the complete spectra including 1D and
2D NMR).
(MþH)þ 224.1281, found 224.1280.
4.5. Synthesis of N-Boc-2-dimethoxymethyl-3-ethyl-pyrrole (16)
4.2.2. 3-Ethyl-3-pyrrolin-2-one (12b). Mp 72e74 ꢁC, Rf¼0.25 (70%
A solution of aldehyde 15 (3.0 g, 13.45 mmol), trimethyl ortho-
formate (2.85 g, 26.90 mmol) and a catalytic amount (50 mg) of p-
EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 8.28 (br s,1H), 6.69 (q,

P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
8381
toluenesulfonic acid (PTSA) in MeOH (20 mL) was stirred at room
temperature for 1 h. The reaction mixture was diluted with Et2O
(200 mL) and washed with a solution of NaHCO3. The combined
organic layer was dried over anhydrous Na2SO4, filtered, and the
solvent was removed by rotary evaporation to furnish the crude
product. The crude compound was chromatographed on silica gel
using hexane/ethyl acetate as mobile phase to afford 16 (3.33 g,
92%). Syrup, Rf¼0.75 (10% EtOAc/hexanes); 1H NMR (CD3OD,
4.8.1. 3-Methyl-pyrrole-2-carboxaldehyde (20a).36a Mp 91e93 ꢁC,
Rf¼0.35 (15% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 10.43 (br
s, 1H), 9.63 (d, J¼0.6 Hz, 1H), 7.07 (t, J¼2.4 Hz, 1H), 6.14 (dd, J¼2.1,
2.4 Hz, 1H), 2.40 (s, 3H); 13C NMR (CDCl3, 100 MHz)
129.5, 126.7, 112.7, 10.6.
d 177.7, 133.4,
4.8.2. 4-Methyl-pyrrole-2-carboxaldehyde (20b).36b Mp 47e49 ꢁC,
Rf¼0.40 (15% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 10.54 (br
400 MHz)
3.33 (s, 6H), 2.65 (q, J¼7.5 Hz, 2H), 1.58 (s, 9H), 1.12 (t, J¼7.5 Hz, 3H);
13C NMR (CD3OD, 100 MHz)
150.6, 132.6, 128.0, 122.9, 112.7, 101.9,
d
7.16 (d, J¼3.4 Hz, 1H), 6.07 (s, 1H), 6.03 (d, J¼3.4 Hz, 1H),
s, 1H), 9.42 (d, J¼1.1 Hz, 1H), 6.97 (d, J¼0.8 Hz, 1H), 6.81 (t, J¼1.6 Hz,
1H), 2.14 (s, 3H); 13C NMR (CDCl3, 100 MHz)
122.6, 121.9, 11.5.
d 179.2, 132.6, 126.2,
d
84.8, 54.6 (2C), 28.2 (3C), 20.8,15.6; HRMS (ESI) calcd for C14H24NO4
(MþH)þ 270.1700, found 270.1703.
4.9. Synthesis of N-Boc-3-methyl-pyrrole-2-carboxaldehyde
(21)37
4.6. Synthesis of 4-ethyl-5-formyl-pyrrole-2-boronic acid (17)
Compound, 21 (3.6 g, 94%) was synthesized by the same pro-
cedure as described for 15. Syrup, Rf¼0.80 (15% EtOAc/hexanes); 1H
To a stirred solution of 16 (2.0 g, 7.43 mmol) in THF (10 mL) was
added triisopropyl borate (2.10 g, 11.15 mmol). The solution was
cooled to 0e5 ꢁC in an ice bath, and lithium diisopropylamide
(LDA, 2 M) (7.5 mL, 14.87 mmol) was added over 20 min and
stirring was continued for an additional hour. The saturated am-
monium chloride (5 mL) and 10% aqueous potassium bisulfate
solution (50 mL) to adjust the pH to 2, followed by stirring at room
temperature for 2 h. The reaction mixture was diluted with
EtOAc (200 mL), washed with brine solution, and dried over an-
hydrous Na2SO4. The solvent was removed by rotary evaporation
to furnish the desired product 17 (1.18 g, 95%) as a brown solid. The
crude product 17 was carried forward into the next reaction
without further purification. Rf¼0.30 (60% EtOAc/hexanes); 1H
NMR (CDCl3, 400 MHz)
d
10.40 (s, 1H), 7.31 (d, J¼3.2 Hz, 1H), 6.11 (d,
J¼3.2 Hz, 1H), 2.38 (s, 3H), 1.61 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d
183.7, 148.4, 135.9, 130.2, 125.9, 114.6, 85.2, 27.9 (3C), 13.8.
4.10. Synthesis of N-Boc-2-dimethoxymethyl-3-methyl-pyr-
role (22)
Compound, 22 (3.21 g, 88%) was synthesized by the same pro-
cedure as described for 16. Syrup, Rf¼0.75 (10% EtOAc/hexanes); 1H
NMR (CDCl3, 400 MHz)
d
7.13 (d, J¼3.3 Hz, 1H), 6.11 (s, 1H), 5.94 (d,
J¼3.3 Hz, 1H), 3.38 (s, 6H), 2.22 (s, 3H), 1.59 (s, 9H); 13C NMR (CDCl3,
100 MHz)
d 149.0, 126.0, 124.5, 121.3, 113.7, 100.2, 83.4, 53.9 (2C),
28.0 (3C), 12.7; HRMS (ESI) calcd for C13H22NO4 (MþH)þ 256.1543,
NMR (CD3OD, 400 MHz)
d 9.58 (s, 1H), 6.57 (s, 1H), 2.80 (q,
found 256.1540.
J¼7.4 Hz, 2H), 1.28 (t, J¼7.4 Hz, 3H); HRMS (ESI) calcd for
C7H11BNO3 (MþH)þ 168.0828, found 168.0831.
4.11. Synthesis of 4-methyl-5-formyl-pyrrole-2-boronic acid
(23)
4.7. Synthesis of 4-ethyl-2,20-bipyrrole-5-carboxaldehyde (13)
Compound 23 (1.73 g, 94%) was synthesized by the same pro-
cedure as described for 17. Rf¼0.30 (60% EtOAc/hexanes); 1H NMR
To a degassed solution of 18 (1.0 g, 4.08 mmol) and 17 (1.02 g,
6.12 mmol) in 10% water/dioxane (50 mL) was added Pd(PPh3)4
(235 mg, 0.20 mmol) and Na2CO3 (865 mg, 8.16 mmol). The mixture
was stirred for 3 h at 100 ꢁC and poured onto water (100 mL). The
pH of the solution was lowered to pH 7 with 2 N HCl and extracted
with ethyl acetate (3ꢂ75 mL). The combined organic layer was
washed with water, brine, dried over anhydrous Na2SO4, and
evaporated under reduced pressure to provide the crude product.
This was then dissolved in THF (10 mL) and LiOH (1.0 g, 41.66 mmol)
in methanol (10 mL) was added dropwise under Argon atmosphere.
The resulting mixture was stirred at room temperature for 30 min.
On completion of the reaction, the solvent was removed under
reduced pressure. The resulting solid was picked up with ethyl
acetate (200 mL), washed with water, brine, and dried over anhy-
drous Na2SO4. Then the organic solution was concentrated under
reduced pressure to give the crude product, which was further
chromatographed on silica gel, eluting with ethyl acetate/hexanes
to afford the title compound 13 (770 mg, 76%). Mp 186e188 ꢁC,
(CD3OD, 400 MHz) d 9.61 (s, 1H), 6.56 (br s, 1H), 2.35 (s, 3H); HRMS
(ESI) calcd for C6H9BNO3 (MþH)þ 154.0671, found 154.0668.
4.12. Synthesis of 4-methyl-2,20-bipyrrole-5-carboxaldehyde
(24)
Compound, 24 (520 mg, 73%) was synthesized by the same
procedure as described for 13. Mp 234e236 ꢁC, Rf¼0.40 (30% EtOAc/
hexanes); 1H NMR (CDCl3þDMSO-d6, 400 MHz)
d 11.19 (br s, 1H),
10.77 (br s, 1H), 9.30 (s, 1H), 6.67 (t, J¼1.2 Hz, 1H), 6.39 (t, J¼2.1 Hz,
1H), 6.10 (s, 1H), 6.05 (dd, J¼2.5, 5.2 Hz, 1H), 2.20 (s, 3H); 13C NMR
(CDCl3þDMSO-d6, 100 MHz)
d 174.9, 134.9, 134.4, 128.5, 123.7,
119.7, 109.5, 108.4 (2C), 10.6; HRMS (ESI) calcd for C10H11N2O
(MþH)þ 175.0866, found 175.0863.
4.13. Representative procedure for the synthesis of 5-bromo-
4-ethyl-pyrrole-2-carboxaldehyde (28a)
Rf¼0.40 (30% EtOAc/hexanes); 1H NMR (CDCl3, 600 MHz)
d 11.94 (br
s,1H), 11.63 (br s,1H), 9.36 (s,1H), 6.98 (d, J¼1.2 Hz,1H), 6.71 (s,1H),
6.43 (d, J¼2.3 Hz, 1H), 6.31 (dd, J¼2.5, 5.8 Hz, 1H), 2.82 (q, J¼7.6 Hz,
2H), 1.36 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3þDMSO-d6, 100 MHz)
To a stirred solution of 14b (1.0 g, 8.13 mmol) in THF (50 mL) was
added portion wise DBDMH (27) (1.15 g, 4.06 mmol) in a period of
10 min at ꢀ78 ꢁC. Then the reaction mixture was stirred for 5 h
while it was allowed to warm to room temperature. The reaction
was quenched with 5% aqueous KHSO4 solution, and extracted with
ethyl acetate (3ꢂ50 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and evaporated under
reduced pressure. The crude product was further chromatographed
on silica gel, eluting with ethyl acetate/hexanes to afford the pure
compound, 28a (1.30 g, 80%). Mp 130e132 ꢁC, Rf¼0.55 (15% EtOAc/
d
174.8, 142.2, 134.8, 127.7, 123.8, 119.8, 109.6, 108.6, 106.9, 18.5, 15.9;
HRMS (ESI) calcd for C11H13N2O (MþH)þ 189.1022, found 189.1026.
4.8. Synthesis of 3-methyl-pyrrole-2-carboxaldehyde (20a)
and 4-methyl-pyrrole-2-carboxaldehyde (20b)
Compounds, 20a (2.42 g, 60%) and 20b (770 mg, 19%) were
synthesized by the same procedure as described for 14a and 14b.
hexanes); 1H NMR (CDCl3, 400 MHz)
d 10.28 (br s, 1H), 9.61 (d,

8382
P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
J¼0.9 Hz, 1H), 7.11 (dd, J¼0.9, 3.2 Hz, 1H), 2.79 (q, J¼7.6 Hz, 2H), 1.26
4.15. Synthesis of 3,4-dimethyl-pyrrole-2-carboxaldehyde
(40a), and 3,4-diethyl-pyrrole-2-carboxaldehyde (40b)
(t, J¼7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 177.6, 137.7, 128.4,
126.2, 100.4, 17.8, 16.1; HRMS (ESI) calcd for C7H9BrNO
(MþH)þ 201.9862, found 201.9853.
Compounds, 40a (1.53 g, 79%), and 40b (1.51 g, 82%) were syn-
thesized by the same procedure as described for 14a, and 14b.
4.13.1. 5-Bromo-4-methyl-pyrrole-2-carboxaldehyde (28b).28a,b Yield
(1.46 g, 85%), Rf¼0.55 (15% EtOAc/hexanes); 1H NMR (CDCl3,
4.15.1. 3,4-Dimethyl-pyrrole-2-carboxaldehyde (40a).38 Mp 125e
127 ꢁC, Rf¼0.35 (30% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
400 MHz)
d
10.55 (br s,1H), 9.31 (s,1H), 6.80 (d, J¼2.4 Hz,1H), 2.08 (s,
3H); HRMS (ESI) calcd for C6H7BrNO (MþH)þ 187.9706, found
d
9.60 (s, 1H), 9.48 (br s, 1H), 6.87 (d, J¼2.4 Hz, 1H), 2.29 (s, 3H), 2.03
187.9710.
(s, 3H).
4.13.2. 5-Bromo-4-isopropyl-pyrrole-2-carboxaldehyde (28c). Yield
(1.24 g, 79%), mp 68e70 ꢁC, Rf¼0.60 (20% EtOAc/hexanes); 1H
4.15.2. 3,4-Diethyl-pyrrole-2-carboxaldehyde (40b).39 Mp 40e42 ꢁC,
Rf¼0.40 (30% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 9.98 (br
NMR (CDCl3, 400 MHz)
d
10.33 (br s, 1H), 9.32 (s, 1H), 6.82 (d,
s, 1H), 9.60 (s, 1H), 6.93 (d, J¼2.7 Hz, 1H), 2.76 (q, J¼7.6 Hz, 2H), 2.48
J¼2.6 Hz, 1H), 2.89e2.82 (m, 1H), 1.20 (d, J¼7.0 Hz, 6H); 13C NMR
(q, J¼7.5 Hz, 2H), 1.20e1.19 (m, 6H).
(CDCl3, 100 MHz)
d 177.6, 133.3, 132.6, 119.4, 110.7, 25.9, 23.1 (2C);
HRMS (ESI) calcd for C8H11BrNO (MþH)þ 216.0019, found
4.16. Synthesis of 5-bromo-3,4-dimethyl-pyrrole-2-carboxal
dehyde (41a), and 5-bromo-3,4-diethyl-pyrrole-2-carboxalde
hyde (41b)
216.0015.
4.13.3. 5-Bromo-4-tert-butyl-pyrrole-2-carboxaldehyde (28d). Yield
(1.21 g, 80%), Rf¼0.65 (20% EtOAc/hexanes); 1H NMR (CDCl3,
Compounds, 41a (1.31 g, 80%), and 41b (1.26 g, 83%) were syn-
thesized by the same procedure as described for 28a.
400 MHz)
d
10.31 (br s, 1H), 9.33 (s, 1H), 6.86 (d, J¼3.0 Hz, 1H), 1.38
(s, 9H); 13C NMR (CDCl3, 100 MHz)
d 177.8, 134.6, 131.6, 120.1, 108.6,
31.1, 29.9 (3C); HRMS (ESI) calcd for C9H13BrNO (MþH)þ 230.0175,
4.16.1. 5-Bromo-3,4-dimethyl-pyrrole-2-carboxaldehyde (41a).28c Mp
148e150 ꢁC, Rf¼0.50 (30% EtOAc/hexanes); 1H NMR (CDCl3, 400
found 230.0171.
MHz)
d 9.88 (br s, 1H), 9.49 (s, 1H), 2.30 (s, 3H), 1.98 (s, 3H).
4.14. Synthesis of 3-alkyl-2,20-bipyrrole-5-carboxaldehydes
(30e33)
4.16.2. 5-Bromo-3,4-diethyl-pyrrole-2-carboxaldehyde
(41b). Mp
102e104 ꢁC, Rf¼0.55 (30% EtOAc/hexanes); 1H NMR (CDCl3,
Compounds, 30 (600 mg, 71%), 31 (700 mg, 75%), 32 (710 mg,
76%), and 33 (745 mg, 79%) were synthesized by the same pro-
cedure as described for 13.
400 MHz)
d
10.25 (br s, 1H), 9.50 (s, 1H), 2.75 (q, J¼7.6 Hz, 2H), 2.45
(q, J¼7.6 Hz, 2H), 1.25 (t, J¼7.6 Hz, 3H), 1.13 (t, J¼7.6 Hz, 3H).
4.17. Synthesis of 3-ethyl-5-formyl-4-methyl-pyrrole-2-carbo
xylic acid (42a), and 4-ethyl-5-formyl-3-methyl-pyrrole-2-
carboxylic acid (42b)
4.14.1. 3-Ethyl-2,20-bipyrrole-5-carboxaldehyde (30). Mp 174e176 ꢁC,
Rf¼0.40 (40% EtOAc/hexanes); 1H NMR (CDCl3þDMSO-d6, 400 MHz)
d
11.31 (br s,1H),10.76 (br s,1H), 9.15 (s,1H), 6.70 (br s, 2H), 6.39 (br s,
1H), 6.10 (s, 1H), 2.53 (q, J¼7.5 Hz, 2H),1.14 (t, J¼7.5 Hz, 2H); 13C NMR
Compounds, 42a (1.21 g, 81%), and 42b (1.18 g, 79%) were syn-
thesized by the same procedure as described for 14a, and 14b.
(CDCl3þDMSO-d6, 100 MHz)
d 176.8, 131.3, 130.2, 124.7, 123.7, 122.4,
119.2, 109.5, 108.9, 20.3, 13.6; HRMS (ESI) calcd for C11H13N2O
(MþH)þ 189.1022, found 189.1027.
4.17.1. 3-Ethyl-5-formyl-4-methyl-pyrrole-2-carboxylic acid (42a). Mp
173e175 ꢁC, Rf¼0.30 (60% EtOAc/hexanes); 1H NMR (Acetone-d6,
4.14.2. 3-Methyl-2,20-bipyrrole-5-carboxaldehyde (31). Mp 182e
184 ꢁC, Rf¼0.35 (30% EtOAc/hexanes); 1H NMR (CDCl3þDMSO-d6,
400 MHz)
3H), 1.13 (t, J¼7.6 Hz, 3H).
d
9.75 (s, 1H), 9.52 (br s, 1H), 2.77 (q, J¼7.6 Hz, 2H), 2.32 (s,
400 MHz)
d 11.30 (br s, 1H), 10.76 (br s, 1H), 9.13 (s, 1H), 6.71 (dd,
J¼1.4, 3.8 Hz, 1H), 6.62 (s, 1H), 6.40 (dd, J¼1.4, 3.5 Hz, 1H), 6.10 (dd,
J¼3.4, 5.9 Hz, 1H), 2.11 (s, 3H); 13C NMR (CDCl3þDMSO-d6,
4.17.2. 4-Ethyl-5-formyl-3-methyl-pyrrole-2-carboxylic
acid
(42b).40 Mp 199e201 ꢁC, Rf¼0.30 (60% EtOAc/hexanes); 1H NMR
100 MHz) d 176.8, 132.1, 130.1, 124.6, 124.0, 119.3, 117.8, 109.6, 109.0,
13.3; HRMS (ESI) calcd for C10H11N2O (MþH)þ 175.0866, found
(CDCl3, 400 MHz)
d
10.98 (br s, 1H), 9.89 (s, 1H), 2.80 (q, J¼7.6 Hz,
2H), 2.31 (s, 3H), 1.16 (t, J¼7.6 Hz, 3H).
175.0857.
4.14.3. 3-Isopropyl-2,20-bipyrrole-5-carboxaldehyde (32). Mp 142e
144 ꢁC, Rf¼0.35 (30% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
4.18. Representative procedure for the synthesis of 5-bromo-
4-ethyl-3-methyl-pyrrole-2-carboxaldehyde (43a)38,39a
d
11.79 (br s, 1H), 11.45 (br s, 1H), 9.22 (s, 1H), 7.05e7.01 (m, 2H),
6.76e6.74 (m, 1H), 6.38e6.36 (m, 1H), 3.31e3.26 (m, 1H), 1.34 (d,
To a stirred solution of pyridinium perbromide (5.29 g,
J¼6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz)
d
176.4, 133.7, 132.1, 130.0,
16.57 mmol) in anhydrous DCM (50 mL) and dry pyridine (4.36 g,
55.24 mmol) was added dropwise 42a (2.0 g, 11.04 mmol) in dry
DCM (50 mL). The reaction mixture was stirred overnight at room
temperature, and mixture was then washed with 1 N HCl. The or-
ganic layer was washed with saturated NaHCO3 solution and brine,
dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The crude product was chromatographed on silica gel,
eluting with ethyl acetate/hexanes to afford the pure product, 43a
(1.13 g, 51%). Mp 128e130 ꢁC, Rf¼0.55 (30% EtOAc/hexanes); 1H
123.7, 123.2, 120.4, 110.6, 110.1, 25.6, 23.3 (2C); HRMS (ESI) calcd for
C
12H15N2O (MþH)þ 203.1179, found 203.1174.
4.14.4. 3-tert-Butyl-2,20-bipyrrole-5-carboxaldehyde
(33). Mp
113e115 ꢁC, Rf¼0.45 (50% EtOAc/hexanes); 1H NMR (CDCl3,
400 MHz)
d 10.55 (br s, 1H), 9.99 (br s, 1H), 9.30 (s, 1H), 7.01 (d,
J¼2.7 Hz, 1H), 6.95e6.93 (m, 1H), 6.65e6.64 (m, 1H), 6.33 (dd,
J¼2.6, 6.1 Hz, 1H), 1.39 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d
177.8, 135.2, 131.7, 129.6, 123.1, 122.6, 119.6, 112.6, 109.5, 31.3,
NMR (CDCl3, 400 MHz) d 9.61 (br s, 1H), 9.50 (s, 1H), 2.44 (q,
30.9 (3C); HRMS (ESI) calcd for C13H17N2O (MþH)þ 217.1335,
J¼7.5 Hz, 2H), 2.33 (s, 3H), 1.10 (t, J¼7.5 Hz, 3H); HRMS (ESI) calcd
found 217.1331.
for C8H11BrNO (MþH)þ 216.0019, found 216.0024.

P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
8383
4.18.1. 5-Bromo-3-ethyl-4-methyl-pyrrole-2-carboxaldehyde
on silica gel using hexane/ethyl acetate as mobile phase to afford
48a (2.72 g, 55%), and 48b (350 mg, 7%).
(43b). Yield 837 mg (47%), mp 109e111 ꢁC, Rf¼0.70 (40% EtOAc/
hexanes); 1H NMR (CDCl3, 400 MHz)
d 10.07 (br s, 1H), 9.49 (s, 1H),
2.74 (q, J¼7.6 Hz, 2H), 2.01 (s, 3H), 1.22 (t, J¼7.6 Hz, 3H); 13C NMR
4.20.1. 4-Chloro-3-ethyl-pyrrole-2-carboxaldehyde (48a). Mp 120e
122 ꢁC, Rf¼0.35 (10% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
(CDCl3, 100 MHz)
d 176.1, 138.5, 129.4, 120.1, 112.0, 17.6, 16.4, 9.3;
HRMS (ESI) calcd for C8H11BrNO (MþH)þ 216.0019, found 216.0024.
d
10.52 (br s, 1H), 9.59 (d, J¼0.9 Hz, 1H), 7.06 (q, J¼1.0 Hz, 1H), 2.80
(q, J¼7.6 Hz, 2H), 1.27 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
4.19. Synthesis of 3,4-dialkyl-2,20-bipyrrole-5-carboxaldehydes
(44e47)
d 177.6, 135.9, 127.8, 123.8, 114.4, 17.0, 15.6; HRMS (ESI) calcd for
C7H9ClNO (MþH)þ 158.0367, found 158.0371.
Compounds, 44 (720 mg, 77%), 45 (700 mg, 74%), 46 (714 mg,
76%), and 47 (750 mg, 80%) were synthesized by the same pro-
cedure as described for 13.
4.20.2. 5-Chloro-3-ethyl-pyrrole-2-carboxaldehyde (48b). Mp 96e
98 ꢁC, Rf¼0.40 (10% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d
10.20 (br s, 1H), 9.26 (s, 1H), 6.75 (d, J¼2.7 Hz, 1H), 2.39 (q,
J¼7.6 Hz, 2H), 1.12 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
4.19.1. 3,4-Dimethyl-2,20-bipyrrole-5-carboxaldehyde (44). Mp 224e
226 ꢁC, Rf¼0.35 (40% EtOAc/hexanes); 1H NMR (DMSO-d6, 400 MHz)
d 177.8, 130.5, 124.7, 123.0, 121.5, 18.4, 13.9; HRMS (ESI) calcd for
C7H9ClNO (MþH)þ 158.0367, found 158.0371.
d
11.20 (br s, 2H), 9.50 (s, 1H), 6.94 (dd, J¼1.4, 3.7 Hz, 1H), 6.48 (d,
J¼2.4 Hz,1H), 6.18 (dd, J¼2.7, 5.9 Hz,1H), 2.24 (s, 3H), 2.09 (s, 3H); 13
C
4.21. Synthesis of 5-bromo-4-chloro-3-ethyl-pyrrole-2-carbo
xaldehyde (49)
NMR (CDCl3þDMSO-d6, 100 MHz)
d 174.7, 132.9, 131.7, 127.6, 123.8,
119.2, 116.6, 109.3, 109.0, 10.1, 8.5; HRMS (ESI) calcd for C11H13N2O
(MþH)þ 189.1022, found 189.1017.
Compound, 49 (1.39 g, 62%) was synthesized by the same pro-
cedure as described for 28a. Mp 95e97 ꢁC, Rf¼0.45 (10% EtOAc/
4.19.2. 3,4-Diethyl-2,20-bipyrrole-5-carboxaldehyde (45). Mp 185e
187 ꢁC, Rf¼0.45 (50% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
hexanes); 1H NMR (CDCl3, 400 MHz)
d 10.46 (br s, 1H), 9.52 (s, 1H),
2.81 (q, J¼7.6 Hz, 2H), 1.27 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3,
d
11.79 (br s, 1H), 11.75 (br s, 1H), 9.38 (s, 1H), 7.03 (d, J¼0.9 Hz, 1H),
100 MHz) d 176.4, 136.6, 128.6, 115.7, 110.6, 17.4, 15.7; HRMS (ESI)
6.76 (s, 1H), 6.37 (dd, J¼2.4, 5.6 Hz, 1H), 2.82e2.71 (m, 4H),
calcd for C7H8BrClNO (MþH)þ 235.9472, found 235.9480.
1.33e1.25 (m, 6H); 13C NMR (CDCl3, 100 MHz)
d
173.9, 142.7, 134.3,
127.0, 124.3,123.4,120.4,110.4, 110.1, 17.8, 17.7, 17.1, 14.5; HRMS (ESI)
4.22. Synthesis of 3-chloro-4-ethyl-2,20-bipyrrole-5-carboxal
dehyde (50) and 30
calcd for C13H17N2O (MþH)þ 217.1335, found 217.1329.
4.19.3. 3-Ethyl-4-methyl-2,20-bipyrrolyl-5-carboxaldehyde (46). Mp
174e176 ꢁC, Rf¼0.35 (40% EtOAc/hexanes); 1H NMR (CDCl3,
Compounds, 50 (306 mg, 64%), and 30 (180 mg, 50%) were
synthesized by the same procedure with some modifications as
described for 13. Compound 50: mp 194e196 ꢁC, Rf¼0.45 (40%
400 MHz)
d 11.69 (br s, 2H), 9.36 (s, 1H), 7.01e7.00 (m, 1H),
6.75e6.74 (m, 1H), 6.37e6.35 (m, 1H), 2.73 (q, J¼7.4 Hz, 2H), 2.34 (s,
EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 11.64 (br s, 1H), 11.36
3H), 1.23 (t, J¼7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d
174.0, 135.9,
(br s, 1H), 9.37 (s, 1H), 7.25 (s, 1H), 7.02 (d, J¼1.0, 1H), 6.37 (d, J¼2.4,
134.1, 127.9, 124.9, 123.4, 120.4, 110.2, 110.0, 17.9, 13.9, 8.6; HRMS
1H), 2.83 (q, J¼7.6 Hz, 2H), 1.31 (t, J¼7.6 Hz, 3H); 13C NMR
(ESI) calcd for C12H15N2O (MþH)þ 203.1179, found 203.1181.
(CDCl3þDMSO-d6, 100 MHz)
d 175.6, 137.3, 129.7, 125.9, 121.8, 119.8,
110.3, 109.6, 109.3, 16.7, 15.8; HRMS (ESI) calcd for C11H12ClN2O
4.19.4. 4-Ethyl-3-methyl-2,20-bipyrrolyl-5-carboxaldehyde (47). Mp
206e208 ꢁC, Rf¼0.35 (40% EtOAc/hexanes); 1H NMR (CDCl3,
(MþH)þ 223.0623, found 223.0617.
400 MHz)
d
11.78 (br s, 2H), 9.34 (s, 1H), 7.02 (d, J¼1.2 Hz, 1H), 6.74
4.23. Representative procedure for the synthesis of 40-ethyl-
50-((5-undecyl-pyrrol-2-yl)methylene)-2,20-bipyrrole hydro-
chloride (52a)
(br s, 1H), 6.36 (dd, J¼2.5, 5.9 Hz, 1H), 2.79 (q, J¼7.6 Hz, 2H), 2.25 (s,
3H), 1.26 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 173.8, 143.1,
134.9, 126.9, 123.9, 120.5, 117.5, 110.8, 109.9, 17.1, 16.8, 10.5; HRMS
(ESI) calcd for C12H15N2O (MþH)þ 203.1179, found 203.1180.
To a stirred solution of 13 (50 mg, 0.26 mmol), and 2-undecyl-
pyrrole (51) (117 mg, 0.53 mmol) in anhydrous methanol (5 mL)
was added methanolic 2 N HCl (catalytic amount). The resulting
bright red colored solution was stirred for 2 h at room tempera-
ture. The methanol was removed under reduced pressure, and the
crude product was chromatographed on silica gel, eluting with
ethyl acetate/hexanes to afford the desired prodiginine analogue
52a. HCl (82 mg, 72%) as a bright red colored compound. Mp
86e88 ꢁC, Rf¼0.30 (50% EtOAc/hexanes); 1H NMR (CDCl3,
4.20. Synthesis of chlorinated pyrrole-carboxaldehyes (48a and
48b)
To a stirred solution of 11 (3.0 g, 31.57 mmol) in 120 mL of dry
THF was added N-chlorosuccinimide (NCS) (4.20 g, 31.57 mmol) at
ꢀ78 ꢁC. The reaction mixture was stirred for an additional 4 h at the
same temperature. To the reaction mixture was added dropwise
Vilsmeier reagent (63.15 mmol, in-situ generation from POCl3/DMF,
400 MHz) d 13.05 (br s, 2H), 12.73 (br s, 1H), 7.25 (br s, 1H), 6.99 (br
0
ꢁC, 1 h) in 50 mL of DCM at ꢀ78 ꢁC. The mixture was stirred for
s, 1H), 6.90 (br s, 2H), 6.68 (s, 1H), 6.37 (br s, 1H), 6.26 (br s, 1H),
2.99 (br s, 2H), 2.72 (q, J¼7.6 Hz, 2H), 1.79 (br s, 2H), 1.37 (q,
J¼7.6 Hz, 3H), 1.27 (br s, 16H), 0.89 (t, J¼6.8 Hz, 3H); 13C NMR
10 h while it was allowed to warm to room temperature. The sol-
vent was removed under reduced pressure at room temperature
and added 100 mL of water. To the stirred mixture, sodium hy-
droxide (2 N, 100 mL) was added slowly and the mixture was
allowed to stir for 1 h at room temperature. Ethyl acetate (200 mL)
was added to the resulting precipitate, the two layers were sepa-
rated, and the aqueous layer was further extracted with ethyl ac-
etate (2ꢂ50 mL). The organic layers were combined, washed with
brine, dried over anhydrous Na2SO4, filtered, and the solvent was
removed by rotary evaporation to furnish the crude mixture of
48a and 48b. Then the mixture of products was chromatographed
(CDCl3, 100 MHz)
d 155.1, 153.8, 148.3, 130.8, 129.2, 127.6, 127.0,
122.1, 118.9, 117.9, 114.5, 113.4, 112.0, 31.9, 29.6 (3C), 29.4 (2C), 29.3,
29.2, 22.7 (2C), 19.7, 14.1 (2C); HRMS (ESI) calcd for C26H38N3
(MþH)þ 392.3060, found 392.3056.
4.23.1. 30-Isopropyl-50-((5-undecyl-pyrrol-2-yl)methylene)-2,20-bi-
pyrrole hydrochloride (52b). Yield 82 mg (75%), mp 83e85 ꢁC,
Rf¼0.35 (50% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 13.35 (br
s, 1H), 12.93 (br s, 2H), 7.29e7.27 (m, 1H), 7.09e7.07 (m, 1H), 6.98 (d,

8384
P. Kancharla, K.A. Reynolds / Tetrahedron 69 (2013) 8375e8385
J¼1.9 Hz,1H), 6.93 (dd, J¼2.3, 4.0 Hz,1H), 6.86 (s,1H), 6.42e6.40 (m,
1H), 6.28 (dd, J¼1.6, 4.0 Hz,1H), 3.26e3.23 (m, 1H), 2.99 (t, J¼7.8 Hz,
2H), 1.81e1.77 (m, 2H), 1.43e1.23 (m, 22H), 0.88 (t, J¼6.8 Hz, 3H);
11.3; HRMS (ESI) calcd for C21H34N3 (MþH)þ 328.2747, found
328.2745.
13C NMR (CDCl3, 100 MHz)
d
158.4, 146.6, 139.5, 133.2, 131.7, 129.2,
4.24.2. N-((30-Chloro-40-ethyl-[2,20-bipyrrol]-50-ylidene)methyl)-2-
127.8, 126.7, 122.7, 121.7, 117.7, 114.1, 112.2, 31.9, 29.6 (2C), 29.6, 29.4,
29.3, 29.1, 28.6, 26.1, 22.7 (4C), 14.1; HRMS (ESI) calcd for C27H40N3
(MþH)þ 406.3217, found 406.3212.
methylpropan-1-amine (53c). Yield 58 mg (92%), mp 74e76 ꢁC,
Rf¼0.30 (70% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 7.40 (s,
1H), 7.30 (dd, J¼1.3, 3.8 Hz,1H), 7.09 (dd, J¼1.3, 2.6 Hz,1H), 6.33 (dd,
J¼2.6, 3.8 Hz, 1H), 3.40 (d, J¼6.9 Hz, 2H), 2.46 (q, J¼7.6 Hz, 2H),
4.23.2. 30-Ethyl-50-((3-(4-fluorobenzyl)-5-heptyl-pyrrol-2-yl)methy-
lene)-40-methyl-2,20-bipyrrole (52c)*. Yield 73 mg (65%), mp
102e104 ꢁC, Rf¼0.40 (40% EtOAc/hexanes); 1H NMR (CDCl3,
2.09e2.06 (m, 1H), 1.21 (t, J¼7.0 Hz, 3H), 1.04 (d, J¼6.7 Hz, 6H); 13
C
NMR (CDCl3, 100 MHz) d 144.8, 144.1, 137.7, 123.9, 121.1, 117.7, 114.5,
112.8, 110.8, 59.4, 29.4, 19.8 (2C), 17.7, 15.3; HRMS (ESI) calcd for
400 MHz)
d
7.13e7.10 (m, 2H), 6.96e6,91 (m, 2H), 6.78 (d, J¼3.2 Hz,
C
15H21ClN3 (MþH)þ 278.1419, found 278.1412.
1H), 6.71 (br s, 1H), 6.65 (br s, 1H), 6.61 (br s, 1H), 5.65 (s, 1H), 3.91
(s, 2H), 2.72 (q, J¼7.5 Hz, 2H), 2.26 (s, 3H), 2.21e2.19 (m, 2H),
1.35e1.12 (m, 13H), 0.86 (t, J¼6.7 Hz, 3H); 13C NMR (CDCl3,
4.24.3. N-((30-(tert-Butyl)-[2,20-bipyrrol]-50-ylidene)methyl)un-
decan-1-amine hydrochloride (53d). Yield 89 mg (95%), semisolid,
100 MHz)
d
162.5, 160.1, 159.7, 146.0, 143.7, 142.1, 136.9, 135.9,
Rf¼0.30 (60% EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 13.52
133.5, 129.9, 129.8, 127.9, 126.7, 121.6, 115.2, 115.0, 114.9, 112.0,
110.3, 109.8, 31.8, 29.5, 29.1, 28.8, 27.4, 22.7, 18.9, 14.4, 14.1, 9.6;
HRMS (ESI) calcd forC30H37FN3 (MþH)þ 458.2966, found 458.2954.
*More carbon signals than predicted are in the aromatic region due to
the long range coupling with the fluorine (F) substitution on the
phenyl ring.
(br s, 1H), 10.82 (two br s, 2H), 7.25 (d, J¼15.2 Hz, 1H), 7.01 (s, 1H),
6.87 (t, J¼2.8 Hz, 2H), 6.25e6.23 (m, 1H), 3.51e3.46 (m, 2H),
1.76e1.73 (m, 2H), 1.36 (s, 9H), 1.32e1.27 (m, 16H), 0.86 (t, J¼6.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz)
d 146.0, 140.1, 137.4, 128.1, 123.2,
122.6, 119.4, 116.1, 110.4, 51.5, 31.9, 31.4, 30.0, 29.9 (3C), 29.5, 29.4
(2C), 29.3, 29.1, 26.5, 22.7, 14.1; HRMS (ESI) calcd for C24H40N3
(MþH)þ 370.3217, found 370.3221.
4.23.3. 30-Ethyl-50-((4-ethyl-3,5-dimethyl-pyrrol-2-yl)methylene)-
40-methyl-2,20-bipyrrole hydrochloride (52d). Yield 61 mg (72%), mp
181e183 ꢁC, Rf¼0.45 (40% EtOAc/hexanes); 1H NMR (CDCl3,
Acknowledgements
400 MHz)
d 13.02 (br s, 1H), 12.76 (br s, 1H), 12.21 (br s, 1H),
This work was supported by a grant from the National Institutes
for Health (GM077147).
7.21e7.20 (m, 1H), 6.96e6.94 (m, 1H), 6.89 (d, J¼3.4 Hz, 1H),
6.37e6.35 (m, 1H), 2.96 (q, J¼7.5 Hz, 2H), 2.56 (s, 3H), 2.41 (q,
J¼7.6 Hz, 2H), 2.26 (s, 3H), 2.23 (s, 3H), 1.18 (t, J¼7.5 Hz, 3H), 1.06 (t,
J¼7.6 Hz, 3H); 13C NMR (CDCl3,100 MHz)
d 149.7, 144.2,142.6,138.8,
129.7, 129.2, 127.5, 125.7, 125.3, 121.9, 115.7, 115.5, 111.5, 18.6, 17.3,
Supplementary data
Spectra of all new compounds associated with this article
are available as supplementary data. Supplementary data related
to this article can be found at http://dx.doi.org/10.1016/j.tet.2013.
07.067.
14.6, 13.4, 12.5, 9.9 (2C); HRMS (ESI) calcd for
C20H26N3
(MþH)þ 308.2121, found 308.2114.
4.24. Representative procedure for the synthesis of N-((30,40-
dimethyl-[2,20-bipyrrol]-50-ylidene)methyl)-2-methylpropan-
1-amine (53a)
References and notes
To a stirred solution of 44 (50 mg, 0.26 mmol) and isobutyl-
amine (39 mg, 0.53 mmol) in anhydrous methanol (5 mL) was
added methanolic 2 N HCl (catalytic amount). The resulting pale
yellow colored solution was stirred at refluxing temperature for
3 h, and the solvent was removed under reduced pressure. The
crude solid was dissolved in EtOAc (50 mL), and washed with 2 N
HCl (2ꢂ10 mL). The organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure, and the
crude product was chromatographed on silica gel, eluting with
ethyl acetate/hexanes to afford the desired tambjamine 53a
(61 mg, 95%) a yellow colored solid. Mp 164e166 ꢁC, Rf¼0.25 (70%
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EtOAc/hexanes); 1H NMR (CDCl3, 400 MHz)
d 7.32 (s, 1H), 7.07 (dd,
J¼1.3, 2.5 Hz, 1H), 6.76 (dd, J¼1.8, 3.7 Hz, 1H), 6.30 (dd, J¼2.7,
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d 143.4, 140.6,
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