Synthesis of a novel series of tetra-substituted furan[3,2-b]pyrroles

Article abstract of DOI:10.1016/S0040-4039(03)00895-5

Furan[3,2-b]pyrroles are important isosteres for the indole scaffold in which the benzene ring is replaced by the furan ring. A series of novel tetra-substituted furan[3,2-b]pyrroles was synthesized from a simple furaldehyde. The divergent synthesis allows for substitution on multiple positions on the scaffold, creating the potential for the formation of large libraries.

Full text of DOI:10.1016/S0040-4039(03)00895-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4257–4260
Synthesis of a novel series of tetra-substituted
furan[3,2-b]pyrroles
Karen L. Milkiewicz,* Daniel J. Parks and Tianbao Lu
3-Dimensional Pharmaceuticals, 665 Stockton Drive, Exton, PA 19341, USA
Received 10 January 2003; revised 3 April 2003; accepted 4 April 2003
Abstract—Furan[3,2-b]pyrroles are important isosteres for the indole scaffold in which the benzene ring is replaced by the furan
ring. A series of novel tetra-substituted furan[3,2-b]pyrroles was synthesized from a simple furaldehyde. The divergent synthesis
allows for substitution on multiple positions on the scaffold, creating the potential for the formation of large libraries. © 2003
Elsevier Science Ltd. All rights reserved.
Furan[3,2-b]pyrroles are isosteres for the indole ring
system in which the benzene ring is replaced by the
furan ring. Efficient synthetic routes to these heterocy-
cles are of great interest,1 as the core scaffold has been
found in compounds with diverse biological activities,
including analgesic,2 anti-inflammatory,2 and anti-
allergy3 activities. The furan[3,2-b]ring system is elec-
tron-rich, and amenable to multiple chemical
reactions.4 These scaffolds are ideal for synthesis of a
large library of compounds, as they contain five poten-
tial diversity sites. Herein we describe a synthesis of the
core scaffold, along with the formation of a small series
of diverse compounds. One attractive feature of this
synthetic method is its use of simple commercially
available starting materials.
Scheme 1. Reagents and conditions: (a) Phenylboronic acid
(2.0 equiv.), Pd(PPh3)4 (0.02 equiv.), Na2CO3 (2.5 equiv.),
toluene/EtOH (6/1), 80°C, 2 h; (b) NBS (1.1 equiv.), acetoni-
trile, rt, 16 h; (c) ethyl azidoacetate (8.0 equiv.), Na (4.0
equiv.), EtOH, 0°C, 2 h; (d) toluene reflux, 16 h.
Our synthesis of the furo[3,2-b]pyrrole scaffold began
with commercially available 5-bromo-furan-2-carbalde-
hyde (1), which was converted into 5-phenyl-furan-2-
form 7. At this point, it was desired to incorporate
carbaldehyde
(2)
through
Suzuki
coupling.5
diversity at the pyrrole nitrogen. Compound 7 was
treated with a variety of alkylating agents to afford 8a–j
(Table 1). Finally, these esters were saponified to the
corresponding acids (9a–j) (Scheme 2).
Bromination with NBS in acetonitrile led exclusively to
the desired isomer6 (3) in good yield. The furo[3,2-
b]pyrrole ring system was formed through a modified
Hemetsberger indole synthesis,7 in which the furan ring
replaces the more typical phenyl ring. Condensation
with methyl or ethyl azidoacetate8 (4) in the presence of
sodium methoxide or ethoxide gave the azide (5), which
led to the desired furo [3,2-b]pyrrole (6) upon
thermolysis9,10 (Scheme 1).
Alternatively, it was found that the order of reactions
may be reversed, with the nitrogen alkylation per-
formed prior to the second Suzuki reaction. This allows
diversity in the 3 position while keeping the 4 position
constant. In this way, compounds 11a and 11b were
synthesized (Scheme 3). The esters were saponified in
the same manner as in the previous scheme.
To elaborate on this core scaffold, 6 was subjected to a
Suzuki coupling with 4-chlorophenylboronic acid to
Extension of the Suzuki couplings to heterocyclic rings
allowed for greater diversity in the 3-position. Com-
* Corresponding author. Tel.: 610-458-5624, ext. 6591; fax: 610-458-
8249; e-mail: karen.milkiewicz@3dp.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00895-5

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K. L. Milkiewicz et al. / Tetrahedron Letters 44 (2003) 4257–4260
Table 1. Reaction of furo[3,2-b]pyrrole scaffold with alkylating agents
Scheme 3. Reagents and conditions: (a) Alkyl bromide or
chloride (2.0 equiv.), NaH (2.0 equiv.), NaI (2.0 equiv.), 60°C,
16 h; (b) phenylboronic acid (2.0 equiv.), Pd(PPh3)4 (0.02
equiv.), Na2CO3 (2.5 equiv.), toluene/EtOH (6/1). 10a, 11a:
R1=Cl, R2=Cl, 10b, 11b: R1=H, R2=H. Yields: 10a=44%,
10b=77%, 11a=79%, 11b=78%.
Scheme 2. Reagents and conditions: (a) 4-Chlorophenyl
boronic acid (2.0 equiv.), Pd(PPh3)4 (0.02 equiv.), Na2CO3
(2.5 equiv.), toluene/EtOH (6/1); (b) alkyl bromide or chlo-
ride, (2.0 equiv.), NaH, (2.0 equiv.), NaI (2.0 equiv.), 60°C, 16
h; (c) NaOH, EtOH, 50°C, 4 h.
manner similar to 8a–j. First, 6 was subjected to a
Suzuki coupling with N-(BOC)indole-2-boronic acid,
followed by alkylation of the furan pyrrole nitrogen
with benzyl bromide. The BOC protecting group was
removed through treatment with 10% TFA/CH2Cl2 at
rt for 2 h. This product was saponified as above to
form the desired acid 14.
pounds 12–14 are examples of heterocycles at the 3-
position (Fig. 1).
Compounds 12 and 13 were synthesized by the alkyla-
tion of 6 with 4-chlorobenzyl chloride and 3-tri-
fluoromethylbenzyl bromide, respectively. They were
both coupled to pyridine-3-boronic acid 1,3-propane-
diol ester in a Suzuki coupling. Saponification with
aqueous sodium hydroxide and heat led to the desired
acids 12 and 13. Compound 14 was synthesized in a
Finally, compound 9a was converted to the acid chlo-
ride with thionyl chloride, followed by coupling to
N1,N1-dimethyl-ethane-1,2-diamine to form compound
15, thus illustrating another position for diversity
(Scheme 4).

K. L. Milkiewicz et al. / Tetrahedron Letters 44 (2003) 4257–4260
4259
1
9f: H NMR (400 MHz, CDCl3/CD3OD l): 7.51–7.46
(m, 2H), 7.45–7.36 (m, 5H), 7.24–7.22 (m, 2H), 6.90
(s, 1H), 4.57–4.50 (m, 2H), 2.86–2.81 (m, 2H), 2.77
(q, J=7.2 Hz, 4H), 1.07 (t, J=7.2 Hz, 6H). MS
(ESI): m/z 437.16 (MH+).
9g: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.54–
7.45 (m, 5H), 7.43–7.40 (m, 2H), 7.28–7.25 (m, 2H),
6.93 (s, 1H), 4.47–4.41 (m, 2H), 3.73 (t, J=4.8 Hz,
4H), 2.75–2.69 (m, 2H), 2.50–2.45 (m, 4H). MS (ESI):
m/z 451.07 (MH+).
Figure 1. 12: R1=4-Cl, 13: R1=3-CF3.
9h: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.62–
7.34 (m, 9H), 6.93 (s, 1H), 4.75–4.56 (m, 2H), 3.19–
3.06 (m, 2H), 2.04–1.88 (m, 4H), 1.00–0.78 (m, 4H).
MS (ESI): m/z 435.12 (MH+).
1
9i: H NMR (400 MHz, CDCl3/CD3OD l): 8.50–8.46
Scheme 4. Reagents and conditions: (a) Thionyl chloride (5
equiv.), CH2Cl2, 5 min; (b) N,N-DMEDA (2.5 equiv.),
TEA (2.5 equiv.), −20°C, 20 h.
(m, 1H), 7.63–7.57 (m, 1H), 7.42–7.39 (m, 2H), 7.31–
7.29 (m, 1H), 7.28–7.11 (m, 7H), 7.08 (s, 1H), 6.56
(d, J=8.0 Hz, 1H), 5.53 (s, 2H). MS (ESI): m/z
428.89 (MH+).
1
9j: H NMR (400 MHz, CDCl3/CD3OD l): 8.46 (d,
J=4.4 Hz, 1H), 8.25 (s, 1H), 7.44–7.36 (m, 4H),
7.28–7.18 (m, 4H), 7.09 (d. J=8.0 Hz, 1H), 7.07 (s,
1H), 5.51 (s, 2H). MS (ESI): m/z 429.27 (MH+).
In conclusion, we have synthesized a diverse series of
novel furan[3,2-b]pyrroles, exploiting four different
diversity sites, including aromatic rings, heteroaro-
matic rings, and aminoalkyl substituents. This chem-
istry can be further extended to synthesize large
libraries of furan[3,2-b]pyrroles.
11a: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.41–
7.37 (m, 2H), 7.25–7.22 (m, 3H), 7.15–7.10 (m, 4H),
7.00 (s, 1H), 6.61 (d, J=8.4 Hz, 2H), 5.42 (s, 2H).
MS (ESI): m/z 462.21 (MH+).
Data for selected compounds:
11b: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.44–
7.29 (m, 5H), 7.17–7.13 (m, 3H), 7.06 (s, 1H), 6.70–
6.66 (m, 2H), 5.44 (s, 2H). MS (ESI): m/z 394.27
(MH+).
9a: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.34–
7.30 (m, 2H), 7.22–7.13 (m, 5H), 7.13–7.08 (m, 3H),
7.05–7.01 (m, 2H), 6.95 (s, 1H), 6.63–6.60 (m, 2H),
5.40 (s, 2H). MS (ESI): m/z 428.35 (MH+).
12: 1H NMR (400 MHz, CDCl3/CD3OD l): 8.69–
8.37 (m, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.39 (s, 1H),
7.35–7.31 (m, 2H), 7.27–7.22 (m, 3H), 7.12 (d, J=8.8
Hz, 2H), 7.05 (s, 1H), 6.58 (d, J=8.4 Hz, 2H), 5.49
(s, 2H). MS (ESI): m/z 429.25 (MH+).
1
9b: H NMR (400 MHz, CDCl3/CD3OD l): 8.06 (d,
J=8.8 Hz, 2H), 7.45–7.38 (m, 2H), 7.31 (d, J=8.4
Hz, 2H), 7.28–7.25 (m, 3H), 7.12 (d, J=7.6 Hz, 2H),
7.11 (s, 1H), 6.83 (d, J=8.4 Hz, 2H), 5.54 (s, 2H).
MS (ESI): m/z 473.41 (MH+)
13: 1H NMR (400 MHz, CDCl3/CD3OD l): 8.82–
8.76 (m, 1H), 8.72–8.65 (m, 1H), 7.91 (d, J=7.6 Hz,
1H), 7.77–7.69 (m, 1H), 7.43 (d, J=7.6 Hz, 1H),
7.37–7.25 (m, 6H), 7.10 (s, 1H), 6.93–6.87 (m, 2H),
5.72 (s, 2H). MS (ESI): m/z 463.13 (MH+).
9c: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.37–
7.29 (m, 6H), 7.22–7.14 (m, 3H), 6.96–6.89 (m, 2H),
5.90–5.85 (m, 1H), 5.34 (s, 2H). MS (ESI): m/z
462.10 (MH+).
9d: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.40–
7.36 (m, 4H), 7.36–7.31 (m, 2H), 7.20–7.12 (m, 3H),
6.85 (s, 1H), 4.21–4.14 (m, 1H), 4.07–3.97 (m, 1H),
3.74–3.68 (m, 1H), 3.35–3.27 (m, 1H), 3.11–3.02 (m,
1H), 1.67–1.59 (m, 1H), 1.35–1.16 (m, 5H). MS (ESI):
m/z 436.29 (MH+).
1
14: H NMR (400 MHz, CDCl3/CD3OD l): 8.64 (s,
1H), 7.55 (d, J=8.8 Hz, 1H), 7.47–7.42 (m, 2H),
7.23–7.05 (m, 9H), 6.97 (s, 1H), 6.71–6.63 (m, 2H),
6.43 (d, J=1.2 Hz, 1H), 5.52 (s, 1H). MS (ESI): m/z
433.30 (MH+).
15: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.38–
7.33 (m, 2H), 7.25–7.11 (m, 8H), 7.08 (d, J=8.4 Hz,
2H), 6.81–6.75 (bt, 1H), 6.70–6.65 (m, 2H), 6.64 (s,
1H), 5.47 (s, 2H). MS (ESI): m/z: 498.23 (MH+).
9e: 1H NMR (400 MHz, CDCl3/CD3OD l): 7.42–
7.39 (m, 2H), 7.32–7.28 (m, 2H), 7.26–7.22 (m, 3H),
7.18–7.15 (m, 2H), 7.00 (s, 1H), 6.27 (s, 1H), 5.53 (s,
2H), 2.62 (s, 3H). MS (ESI): m/z 448.77 (MH+).

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istry II; Ramsden, C. A., Pergamon: Oxford, 1996; Vol.
Acknowledgements
2, 1, p. 1.
The authors thank Mike Kolpak and Karen DiLoreto
for their assistance in running NMR and MS experi-
ments.
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