Synthesis of novel furo-, thieno-, and pyrroloazepines

Article abstract of DOI:10.1055/s-0030-1257910

The synthesis of novel furo-, thieno-, and pyrroloazepine compounds, using the oxidative radical alkylation of three five-membered heterocyclic 3-acetic acid derivatives, is described. The bicyclic systems were obtained, via a small number of steps, directly from commercially available materials. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1257910

3346
PAPER
Synthesis of Novel Furo-, Thieno-, and Pyrroloazepines
Synthesis of
Nov
a
el Furo-,
T
h
ieno-,
a
l
nd Pyrr
o
oloazepine
s
s Villarreal, Roberto Martínez*
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S. N., Ciudad Universitaria, México D. F. 04510,
México
E-mail: robmar@servidor.unam.mx
Received 23 April 2010; revised 10 June 2010
ization of the amino acid 8, which could prepared by a C2
Abstract: The synthesis of novel furo-, thieno-, and pyrroloazepine
xanthate-based oxidative radical alkylation of pyrrole
compounds, using the oxidative radical alkylation of three five-
acetate 9. Compound 9 can be derived by Arndt–Eistert
homologation of 1H-pyrrole-3-carboxylic acid (10).
membered heterocyclic 3-acetic acid derivatives, is described. The
bicyclic systems were obtained, via a small number of steps, direct-
ly from commercially available materials.
O
Key words: oxidative radicals, carboxylic acid homologation,
furan, thiophene, pyrrole, azepinones
O
Ph
O
H
SMe
N
N
As part of our ongoing interest in the development of nov-
el heterocyclic compounds that inhibit the growth of can-
cer cells, we have employed a molecular mimicry
paradigm to generate new active leads from azetopyr-
roloazepines 1 (Scheme 1).1 The mechanism of action un-
derlying the antiproliferative activity of compound 1 is
still unknown, and further exploration of the pyrroloaze-
pinone pharmacophore is advisable. Our previous studies
suggested that a pyrroloazepine group and two aromatic
groups, such as those found in pyrroloazepines 2, are re-
quired for cytotoxic activity.2
N
N
R
R
1
O
H
N
N
NO2
R
2
Recently, we observed that bromine derivative 3, a con-
formationally constrained analogue of 2, was cytotoxic to
the U-251 central nervous system cancer cell line
(Figure 1). Indeed, these structures are closely related to
well-known pyrroloazepine moieties that are present in a
number of natural and synthetic products such as
paullones 4, which have been described as potent cyclin-
dependent kinase and glycogen synthase kinase-3
inhibitors3 (Figure 1).
Scheme 1
O
O
H
N
R
HN
N
N
H
Br
3
4a R = Br
4b R = NO2
Kenpaullone (4a) was found to be inactive against the U-
251 cancer cell line, but alsterpaullone (4b) showed a po-
tency that was 25 times the potency of 3 (IC50 = 0.68
0.02 mM vs IC50 = 18.14 1.02 mM). One plausible expla-
nation of the lower potency of 3, compared with 4b, is that
4b achieves a better fit at the target active site than does 3.
Therefore, we hypothesize that compounds such as 5
could provide an improved fit at the active site such that
they will be more cytotoxic than 3.
O
HN
X
5 X = NH
6 X = O
7 X = S
Figure 1
Here we report a novel straightforward synthetic route to
the pyrrolo[2,3-d]azepinone 5 and its bioisosteric furo and
thieno analogues. The retrosynthetic analysis and key
strategic bond breakages are shown in Scheme 2. Thus,
compound 5 can be synthesized by intramolecular lactam-
In accordance with the synthetic strategy shown in
Scheme 3, 1-benzyl-1H-pyrrole-3-carboxylic acid (12)
was prepared in good yield from ethyl 1H-pyrrole-3-car-
boxylate (11) by protection with benzyl bromide in the
presence of sodium hydride followed by alkaline hydrol-
ysis; 11 was synthesized from tosylmethyl isocyanide
(TosMIC) and ethyl acrylate by the van Leusen reaction.4
Arndt–Eistert homologation5 of 12 was accompanied by
SYNTHESIS 2010, No. 19, pp 3346–3352
x
x.
x
x
.
2
0
1
0
Advanced online publication: 30.07.2010
DOI: 10.1055/s-0030-1257910; Art ID: M02910SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Novel Furo-, Thieno-, and Pyrroloazepines
3347
homologation
lactamization
O
CO2H
CO2H
CO2H
NH2
NH
N
R
N
R
N
R
N
H
oxidative
radical
alkylation
5
8
9
10
Scheme 2 Retrosynthetic analysis of title compound 5
decomposition of the starting material. We assumed that vide an accessible sequence (Scheme 4). Thus, alkylation
acyl chloride formation with thionyl chloride was ineffi- of 13 with S-(cyanomethyl) O-ethyl carbonodithioate
cient. Therefore, we required a mild method for the acti- [CNCH2SC(S)OEt] in the presence of dilauroyl peroxide
vation of the carboxylic acid.
(DLP) afforded a mixture 3:1 of ethyl 1-benzyl-2-(cya-
nomethyl)-1H-pyrrole-3-acetate (16) and ethyl 1-benzyl-
2,5-bis(cyanomethyl)-1H-pyrrole-3-acetate, which could
be separated by column chromatography. Reduction of
the nitrile 16 with sodium borohydride/nickel(II) chloride
system,10 in the presence of di-tert-butyl dicarbonate, pro-
vided the N-Boc amine 17 in 79% yield; Boc protection
was required to prevent dimerization and decomposi-
tion.11 N-Benzylpyrroloazepinone 19 was prepared in
moderate yields by intramolecular lactamization (DMAP
and EDCI) of 18, which in turn was obtained from 17 by
alkaline hydrolysis and N-Boc deprotection with trifluo-
roacetic acid. Compound 19 can also be obtained, in 82%
overall yield, from 17 by N-Boc deprotection with trifluo-
roacetic acid, followed by ring closure of the resulting
amino ester with potassium carbonate in methanol
(Scheme 4).12 Finally, N-benzyl deprotection of 19 using
metallic sodium in liquid ammonia at –78 °C afforded
compound 5 in 55% yield.
Compound 12 was then converted into the corresponding
diazo ketone via the mixed anhydride generated in situ
with ethyl chloroformate, followed by the addition of ex-
cess ethereal diazomethane.6 Next, the crude diazo ketone
was treated with silver oxide in ethanol–1,4-dioxane at
100 °C to afford the homologated ethyl 1-benzyl-1H-pyr-
role-3-acetate (13) in 5% yield (Scheme 3). Compound 13
was also obtained, in better yields, by hydrogenolysis7 of
the pyrrole glyoxylate 15. Thus, pyrrole-3-glyoxylate 14
was prepared from pyrrole according to a procedure re-
ported by Bray and co-workers,8 followed by protection
with benzyl bromide in the presence of sodium hydride to
afford the N-benzyl derivative 15. Next, hydrogenolysis
of 15 with the Pd/C/NaH2PO2·H2O system afforded 13 in
77% yield (Scheme 3).
CO2H
CO2Et
CO2Et
c
a,b
N
N
H
N
CO2Et
NHBoc
CO2Et
CO2Et
CN
Bn
12
Bn
13
b
a
11
N
N
N
Bn
17
Bn
13
Bn
16
g
f,g
O
O
OEt
O
OEt
O
c,d
f
d,e
O
O
N
H
N
H
N
CO2H
NH2
NH
NH
Bn
15
h
e
14
N
H
N
N
Scheme 3 Synthesis of ethyl 1-benzyl-1H-pyrrole-3-acetate (13).
Reagents and conditions: (a) NaH, BnBr, DMF, r.t., 3 h, 70%; (b)
10% KOH, EtOH–H2O (1:1), reflux, 12 h, 47%; (c) 1. ClCO2Et, Et3N,
THF, 0 °C, 30 min, 2. excess CH2N2, Et2O, r.t., 16 h, 3. Ag2O (5
equiv), EtOH–1,4-dioxane (2:1), reflux, 2 h, 5% (overall from 12); (d)
NaH, TIPSCl, DMF, 0 to 25 °C, 2 h, 97%; (e) ethyl oxalyl chloride,
py, DCE, reflux, 16 h, 64%; (f) NaH, BnBr, DMF, r.t., 3 h, 91%; (g)
10% Pd/C, NaH2PO2·H2O (5 equiv), 1,4-dioxane, reflux, 8 h, 77%.
Bn
18
Bn
19
5
Scheme 4 Synthesis of pyrroloazepinone 5. Reagents and condi-
tions: (a) CNCH2SC(S)OEt, DLP (1.3 equiv), DCE, reflux, 44% (16),
14.5% [ethyl 1-benzyl-2,5-bis(cyanomethyl)-1H-pyrrole-3-acetate];
(b) NaBH4 (8 equiv), NiCl2·6 H2O, Boc2O (2 equiv), MeOH, 0 to 25
°C, 16 h, 79%; (c) 10% KOH, EtOH–H2O (1:1), reflux, 16 h; (d) TFA,
CH2Cl2, 25 °C, 2 h; (e) EDCI, DMAP, CH2Cl2, 25 °C, 12 h; (f) TFA,
CH2Cl2, 25 °C, 1 h; (g) K2CO3 (8 equiv), MeOH, 16 h, 82%; (h) Na,
liquid NH3, THF, –78 °C, 30 min, 55%.
Having prepared compound 13, the next step of the syn-
thesis of 5 involved the introduction of the C2 aminoethyl
side chain in 13, as shown in Scheme 2. We envisaged
that C2 alkylation of 13 with a cyanomethyl group by xan-
thate-based oxidative radical substitution,9 followed by
reduction of the resulting nitrile to an amine would pro-
These results led us to investigate the synthesis of pyr-
roloazepinone bioisosteres through substitution of the
pyrrole nucleus by a furan 6 or a thiophene ring 7.
Synthesis 2010, No. 19, 3346–3352 © Thieme Stuttgart · New York

3348
C. Villarreal, R. Martínez
PAPER
O
N2
CO2H
CO2Me
CO2Me
CN
a
c
b
X
X
X
X
20 X = O
21 X = S
22 X = O 70%
23 X = S 90%
24 X = O 85%
25 X = S 80%
26 X = O 60%
27 X = S 46%
d
O
CO2Me
CO2Me
NH2
NH
e
f
NHBoc
X
X
X
6 X = O 75%
7 X = S 70%
30 X = O
31 X = S
28 X = O 72%
29 X = S 78%
Scheme 5 Synthesis of furo- and thienoazepinones 6 and 7. Reagents and conditions: (a) 1. SOCl2 (5 equiv), r.t., 16 h, 2. excess CH2N2, Et2O–
THF, 0 °C, 2 h; (b) PhCO2Ag, Et3N, MeOH, reflux, 2 h; (c) CNCH2SC(S)OEt, DLP (1.3 equiv), DCE, reflux; (d) NaBH4 (8 equiv), NiCl2·6H2O,
Boc2O (2 equiv), MeOH, 0 to 25 °C, 16 h; (e) TFA, CH2Cl2, 25 °C, 1 h; (f) K2CO3 (8 equiv), MeOH, 16 h.
Through application of the previously described method- sults do not allow it to give a reasonable explanation of cy-
ology, furo- and thienoazepinones were obtained from 3- totoxic behavior of 3.
furoic acid (20) and thiophene-3-carboxylic Acid (21), re-
spectively, as shown in Scheme 5.
In conclusion, we have developed a novel and straightfor-
ward methodology for the synthesis of heterocyclic ring-
In contrast with the pyrrole acetate 13, furan and fused pyrrolo-, furo-, and thienoazepinones via carboxylic
thiophene acetates 24 and 25 were prepared in good yields acid homologation, oxidative radical alkylation, and in-
by Arndt–Eistert homologation of carboxylic acids 20 and tramolecular lactamization.
21, respectively. In our case, carboxylic acids were pre-
pared by oxidation, with chromic acid solution, of furan-
The starting materials and reagents were obtained from commercial
3-carbaldehyde and thiophene-3-carbaldehyde, respec-
tively. The carboxylic acids 20 and 21 were then convert-
ed into the corresponding a-diazo ketones 22 and 23 via
acyl chlorides with thionyl chloride followed by the addi-
tion of excess ethereal diazomethane. To conclude the ho-
mologation, Wolff rearrangement13 of the diazo ketones,
with silver benzoate in methanol, afforded the desired me-
thyl esters 24 and 25. Rearrangement of 22 occurred under
gentle reflux, and rearrangement of 23 occurred at room
temperature, respectively. C2 Oxidative radical alkylation
of 24 and 25, with S-(cyanomethyl) O-ethyl carbono-
dithioate in the presence of dilauroyl peroxide, provided
nitriles 26 and 27 in moderate yields with recovery of a
significant quantity of starting material. In these cases, the
dialkylated products were not observed. Reduction of 26
and 27 with sodium borohydride and nickel(II) chloride in
the presence of di-tert-butyl dicarbonate afforded N-Boc
amines 28 and 29, respectively.
suppliers and were used without further purification. Solvents were
distilled before use: THF and Et2O were dried over Na/benzophe-
none; pyridine, DMF, CH2Cl2, and DCE were distilled from CaH2
prior to use. Ethereal solns of diazomethane (CH2N2) were prepared
from N-methyl-N-nitroso-p-toluenesulfonamide (Diazald) as de-
scribed in the literature.6 Melting points (uncorrected) were deter-
mined in open glass capillaries using a Mel-temp II melting point
apparatus. Products were purified by flash chromatography on Mer-
ck silica gel, 230–400 mesh.14 IR spectra were determined on a
1
Nicolet FT Magna-IR 750 spectrophotometer. H and 13C NMR
spectra were determined on a Varian Unity VXR 300 instrument
relative to TMS as internal standard. Mass spectra were recorded on
a Jeol JEM AX505HA EI spectrometer with a lower resolution of
70 eV. Elemental analysis (C, H, N) were performed on a CE-440
Exeter Analytical Inc.
Ethyl 1H-Pyrrole-3-carboxylate (11)
A soln of TosMIC (4.68 g, 24 mmol) and ethyl acrylate (1.9 g, 19
mmol) in Et2O–DMSO (1:1, 95 mL) was added dropwise at 0 °C to
a suspension of 60% NaH dispersion in mineral oil (0.96 g, 24
mmol) in Et2O (38 mL). The mixture was stirred for 6 h and then
reaction was quenched by addition of H2O (50 mL) and stirred for
15 min. The mixture was extracted with EtOAc (2 × 50 mL), and
washed with H2O (50 mL) and brine (50 mL). The combined organ-
ic extracts were dried (anhyd Na2SO4), and the solvents were evap-
orated in vacuo. The residue was purified by column
chromatography (hexane–EtOAc, 8:2) to afford 11 (2.0 g, 75%) as
a pale yellow oil. Spectroscopic data agreed well with results previ-
ously reported in the literature.15
Finally, N-Boc deprotection of 28 and 29 with trifluoro-
acetic acid in dichloromethane and subsequent intramo-
lecular lactamization of the resulting amino esters 30 and
31 with potassium carbonate in methanol afforded the
azepinone derivatives 6 and 7, respectively.
Pyrroloazepinone 5 and its bioisosteric derivatives 6 and
7 were evaluated in vitro for their ability to inhibit growth
of PC3 (prostate), U291 (central nervous system), K562
(leukemia), and MCF7 (breast adenocarcinoma) cancer
cell lines. Unfortunately, these compounds did not inhibit
the proliferation of the four cancer cell lines, and these re-
1-Benzyl-1H-pyrrole-3-carboxylic Acid (12)
To a soln of 11 (2.6 g, 19 mmol) in DMF (40 mL), 60% NaH dis-
persion in mineral oil (1.6 g, 38 mmol) was added portionwise at 0
°C. The mixture was stirred for 30 min and then BnBr (3.42 g, 20
mmol) was added dropwise. The mixture was allowed to reach r.t.
Synthesis 2010, No. 19, 3346–3352 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Furo-, Thieno-, and Pyrroloazepines
3349
and was stirred for 3 h. H2O (80 mL) was added and the mixture was
extracted with EtOAc (2 × 80 mL). The combined extracts were
washed with H2O (2 × 40 mL) and brine (1 × 40 mL) and dried (an-
hyd Na2SO4). The solvents were evaporated in vacuo to give a res-
idue that was purified by column chromatography (hexane–EtOAc,
8:2) to afford ethyl 1-benzyl-1H-pyrrole-3-carboxylate (3.0 g, 70%)
as a yellow oil. Spectroscopic data agreed well with results previ-
ously reported in the literature.16 To a soln of the N-benzyl deriva-
tive (1.7 g, 7.4 mmol) in EtOH–H2O (1:1, 148 mL), a soln of 10%
KOH (37 mL) was added and the mixture was stirred at reflux for
12 h. After removal of EtOH in vacuo, the mixture was acidified to
pH ~1 with 2 M HCl and extracted with Et2O (90 mL). The com-
bined organic extracts were dried (anhyd Na2SO4), and the solvents
were evaporated in vacuo to afford 12 (1.24 g, 47%) as a white sol-
id; mp 88–92 °C.
Ethyl 2-(1-Benzyl-1H-pyrrol-3-yl)-2-oxoacetate (15)
To a soln of 14 (2.8 g, 17 mmol) in DMF (35 mL), 60% NaH dis-
persion in mineral oil (0.816 g, 20.4 mmol) was added portionwise
at 0 °C. The mixture was stirred for 45 min and BnBr (3.77 g, 22.1
mmol) was added dropwise. The mixture was allowed to warm to
r.t. and was stirred for 3 h. After addition of H2O (50 mL), the mix-
ture was extracted with EtOAc (2 × 50 mL). The combined organic
extracts were washed with H2O (2 × 50 mL) and dried (anhyd
Na2SO4). The solvent was evaporated in vacuo, and the residue was
purified by column chromatography (hexane–EtOAc, 8:2) to afford
15 (4.0 g, 91%) as a solid.
IR (film): 3120, 2983, 1731, 1656, 1526, 1271, 1239, 1159, 1032,
713 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 (t, J = 7.2 Hz, 3 H), 4.35 (q,
J = 7.2 Hz, 2 H), 5.08 (s, 2 H), 6.65 (d, J = 3.0 Hz, 1 H), 6.80 (d,
J = 3.0 Hz, 1 H), 7.14–7.18 (m, 2 H), 7.31–7.39 (m, 3 H), 7.74 (t,
J = 1.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.0, 54.0, 61.9, 111.1, 121.6,
123.3, 127.3, 128.3, 129.0, 130.6, 135.9, 163.0, 178.3.
MS (EI, 70 eV): m/z (%) = 257 (2.5) [M+], 184 (100), 91 (77.9).
IR (KBr): 3031 (br), 1655, 1538, 1445, 1388, 1350, 1244, 958, 743,
726 cm–1.
1H NMR (300 MHz, CDCl3–DMSO-d6): d = 5.05 (s, 2 H), 6.57 (dd,
J = 2.7, 1.5 Hz, 1 H), 6.64 (t, J = 2.7 Hz, 1 H), 7.13–7.17 (m, 2 H),
7.28–7.36 (m, 4 H).
13C NMR (75 MHz, CDCl3–DMSO-d6): d = 53.1, 109.9, 116.0,
121.5, 124.1, 125.8, 126.7, 126.4, 128.2, 128.9, 136.2, 166.0.
Ethyl 1-Benzyl-1H-pyrrole-3-acetate (13)
MS (EI, 70 eV): m/z (%) = 201 (84) [M+], 91 (100).
A soln of NaH2PO2·H2O (8.4 g, 78 mmol) in H2O (7.5 mL) was add-
ed to a suspension of 15 (4.0 g, 15.5 mmol) in the presence of 10%
Pd/C (1.6 g, 10 wt %) in 1,4-dioxane (46 mL). The mixture was re-
fluxed for 4 h and then allowed to cool to r.t. Another portion of
Pd/C (1.6 g, 10 wt %) and a soln of NaH2PO2·H2O (8.4 g, 78 mmol)
in H2O (7.5 mL) were added, and refluxing was continued for an ad-
ditional 4 h. The mixture was allowed to reach r.t., was filtered
through Celite, and the precipitate was washed with several por-
tions of EtOAc. The combined organic extracts were evaporated in
vacuo. The residue was purified by column chromatography (hex-
ane–EtOAc, 9:1) to give 13 (2.92 g, 77%).
Ethyl 1-Benzyl-1H-pyrrole-3-acetate (13)
Et3N (3.3 mL) and ClCO2Et (2.6 g) were added at 0 °C to a soln of
12 (4 g, 20 mmol) in THF (100 mL). The mixture was stirred for 30
min and an excess of CH2N2 (3–5 equiv), as an ethereal soln, was
added at 0 °C. The mixture was allowed to reach r.t. and was stirred
for 16 h. The solvent and excess CH2N2 were evaporated in vacuo.
An excess of Ag2O (10 g, 50 mmol, 5 equiv) was added to a soln of
the crude residue in a mixture of EtOH–1,4-dioxane (2:1, 100 mL).
The mixture was refluxed for 2 h, it was allowed to reach r.t. and fil-
tered, and the solvents were evaporated in vacuo. The residue was
purified by column chromatography (hexane–EtOAc, 9:1) to afford
the desired product (0.26 g, 5%) as a colorless oil.
Ethyl 1-Benzyl-2-(cyanomethyl)-1H-pyrrole-3-acetate (16), 3:1
Mixture with Ethyl 1-Benzyl-2,5-bis(cyanomethyl)-1H-pyrrole-
3-acetate; Typical Procedure
To a soln of 13 (2.92 g, 12.0 mmol) and CNCH2SC(S)OEt (2.9 g,
18.0 mmol) in DCE (25 mL) under reflux was added DLP (5–10
mol%) every 90 min for 12 h. The mixture was allowed to reach r.t.,
and the solvent was evaporated in vacuo. The mixture was separated
by column chromatography (hexane–EtOAc, 9:1).
IR (film): 2981, 2932, 1733, 1499, 1451, 1346, 1302 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.2 Hz, 3 H), 3.46 (s,
2 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.99 (s, 2 H), 6.10–6.11 (m, 1 H),
6.58–6.61 (m, 2 H), 7.09–7.13 (m, 2 H), 7.23–7.34 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 33.1, 53.3, 60.4, 109.3,
115.9, 119.9, 121.1, 127.0, 127.6, 128.6, 137.9, 172.4.
Ethyl 1-Benzyl-2-(cyanomethyl)-1H-pyrrole-3-acetate (16)
Pale yellow semisolid; yield: 1.5 g (44%).
MS (EI, 70 eV): m/z (%) = 243 (53) [M+], 170 (100), 91 (63.9).
IR (KBr): 2923, 2852, 2249, 1730, 1495, 1446, 1302, 1269, 1210,
1113, 1034, 726 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3 H), 3.45 (s,
2 H), 3.55 (s, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 5.14 (s, 2 H), 6.12 (d,
J = 2.7 Hz, 1 H), 6.68 (d, J = 2.7 Hz, 1 H), 7.01–7.06 (m, 2 H),
7.28–7.36 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 13.7, 14.1, 32.6, 51.2, 60.9, 109.3,
115.9, 116.2, 117.5, 122.7, 126.4, 127.9, 129.0, 136.8, 171.5.
MS (EI, 70 eV): m/z (%) = 282 (40.8) [M+], 208 (57.8), 91 (100).
Ethyl 2-Oxo-2-(1H-pyrrol-3-yl)acetate (14)
To a soln of pyrrole (4.82 g, 72 mmol) in DMF (100 mL), 60% NaH
dispersion in mineral oil (3.17 g, 79 mmol) was added portionwise
at 0 °C. The mixture was stirred for 45 min and then TIPSCl (13.9
g, 72 mmol) was added dropwise. The mixture was allowed to reach
r.t. and stirred for 2 h. The mixture was diluted with H2O (100 mL)
and extracted with Et2O (2 × 100 mL). The combined organic ex-
tracts were dried (anhyd Na2SO4), and the solvent was evaporated
in vacuo. The residue was purified by column chromatography
(hexane–EtOAc, 98:2) to afford 1-(triisopropylsilyl)pyrrole (15.6 g,
97%) as a brown oil. A soln of the N-TIPS-pyrrole (13.0 g, 58
mmol), ethyl oxalyl chloride (23.9 g, 175 mmol), and pyridine (13.8
g, 175 mmol) in DCE (100 mL) was gently refluxed for 16 h. The
mixture was allowed to reach r.t. and the solvent was evaporated in
vacuo. The residue was purified by column chromatography (hex-
ane–EtOAc, 7:3) to afford 14 (6.0 g, 62%) as a brown solid. Spec-
troscopic data agreed well with the results previously reported in the
literature.7
Ethyl 1-Benzyl-2,5-bis(cyanomethyl)-1H-pyrrole-3-acetate
Pale yellow viscous oil; yield: 0.57 g (14.5%).
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 3 H), 3.46 (s,
2 H), 3.53 (s, 2 H), 3.60 (s, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 5.18 (s,
2 H), 6.21 (s, 1 H), 6.68–6.92 (m, 2 H), 7.26–7.35 (m, 3 H).
Synthesis 2010, No. 19, 3346–3352 © Thieme Stuttgart · New York

3350
C. Villarreal, R. Martínez
PAPER
Ethyl 1-Benzyl-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-
pyrrole-3-acetate (17); Typical Procedure
1H NMR (300 MHz, CDCl3): d = 2.76 (t, J = 5.4 Hz, 2 H), 3.46 (s,
2 H), 3.47–3.53 (m, 2 H), 5.81 (t, J = 2.4 Hz, 1 H), 6.54 (t, J = 2.4
Hz, 1 H), 7.17 (br s, 1 H), 10.01 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 27.3, 34.0, 38.8, 108.1, 109.1,
115.2, 124.6, 175.3.
To a mixture of 16 (0.14 g, 0.5 mmol), Boc2O (0.21 g, 1.0 mmol),
and NiCl2·6 H2O (0.117 g, 0.5 mmol) in MeOH (5 mL) was added
at 0 °C NaBH4 (0.132 g, 3.5 mmol) in small portions over 15 min;
the reaction was exothermic after each addition. The mixture was
allowed to reach r.t. and stirred overnight. The solvent was evapo-
rated in vacuo, and the residue was dissolved in EtOAc (30 mL) and
filtered through Celite and the precipitate was washed with several
portions of EtOAc. The combined organic extracts were evaporated
in vacuo. The residue was purified by flash chromatography (hex-
ane–EtOAc, 8:2) to afford 17 (0.154 g, 79%) as a colorless viscous
oil.
MS (EI, 70 eV): m/z (%) = 150 (76.8) [M+], 93 (100).
Anal. Calcd for C8H10N2O: C, 63.98; H, 6.71; N, 18.65. Found: C,
63.61; H, 6.47; N, 18.88.
3-Furoic Acid (20); Typical Procedure
Aq 1.32 M chromic acid soln17 (50 mL) was added dropwise at 0–5
°C to a soln of furan-3-carbaldehyde (5.0 g, 52 mmol) in Et2O (100
mL). The mixture was stirred for 3 h and then diluted with H2O (50
mL). The organic layer was separated, dried (anhyd Na2SO4), and
the solvent was evaporated in vacuo to give 20 (3.2 g, 55%) as a
white solid; mp 120 °C (Lit.18 120–122 °C).
IR (film): 3379, 2977, 2932, 1709, 1499, 1453, 1365, 1251, 1170,
1031 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.2 Hz, 3 H), 1.42 (s,
9 H), 2.69 (t, J = 6.9 Hz, 2 H), 3.13–3.11 (m, 2 H), 3.42 (s, 2 H),
4.15 (q, J = 7.2 Hz, 2 H), 4.82 (br s, 1 H), 5.05 (s, 2 H), 6.10 (d,
J = 2.4 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 6.98–7.00 (m, 2 H),
7.23–7.32 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 24.8, 28.3, 32.6, 40.3, 50.6,
60.6, 108.9, 114.0, 121.3, 126.4, 127.4, 128.7, 138.3, 155.9, 172.6.
1-Diazo-2-(3-furoyl)ethanone (22); Typical Procedure
SOCl2 (6 mL) was added to 3-furoic acid 20 (2.3 g, 20 mmol). The
mixture was stirred at r.t. overnight and the excess SOCl2 was evap-
orated in vacuo. The crude acyl chloride was used in the next step
without further purification. To the soln of acyl chloride and Et3N
(3.0 mL) in THF (100 mL), a freshly prepared ethereal soln of dia-
zomethane (60 mL) was added at 0 °C. The mixture was stirred for
2 h and the excess diazomethane, if present, was decomposed by the
addition of 1 M AcOH. The solvent was evaporated in vacuo, and
the residue was diluted with CH2Cl2 (100 mL). The mixture was se-
quentially washed with H2O (50 mL), sat. NaHCO3 soln (50 mL),
and brine (50 mL), then dried (anhyd Na2SO4). The solvent was
evaporated in vacuo and the residue was purified by flash chroma-
tography (EtOAc–hexane, 2:8) to afford 22 (1.9 g, 70%) as a yellow
solid; mp 37–38 °C.
IR (KBr): 3090, 3054, 2124, 1609, 1512, 1405, 1357, 1158, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.58 (s, 1 H), 6.67 (dd, J = 4.5, 0.9
Hz, 1 H), 7.44–7.45 (m, 1 H), 7.91 (dd, J = 1.5, 0.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 54.5, 108.2, 126.2, 144.1, 144.6,
180.2.
MS (EI, 70 eV): m/z (%) = 386 (9.5) [M+], 256 (44), 59 (96.5), 43
(100).
1-Benzyl-4,6,7,8-tetrahydropyrrolo[3,2-d]azepin-5(1H)-one
(19); Typical Procedure
To a soln of 17 (1.23 g, 3.18 mmol) in CH2Cl2 (32 mL) at 0 °C was
added TFA (9.5 mL). The mixture was allowed to reach r.t. and was
stirred for 1 h. The solvent and the excess TFA were evaporated in
vacuo. The residue was dissolved in anhyd MeOH (32 mL) and
K2CO3 (3.82 g) was added. The mixture was stirred for 16 h and
then the solvent was evaporated in vacuo. The residue was dis-
solved with EtOAc (100 mL), washed with H2O (60 mL), and dried
(anhyd Na2SO4). The solvent was evaporated in vacuo and the res-
idue was purified by column chromatography (hexane–EtOAc, 8:2)
to afford 19 (0.63 g, 82%) as a white solid; mp 199–200 °C.
IR (KBr): 3209, 3087, 2905, 1667, 1490, 1444, 1400, 1356, 799,
721 cm–1.
MS (EI, 70 eV): m/z (%) = 136 (100) [M+], 95 (81).
1H NMR (300 MHz, CDCl3): d = 2.61 (t, J = 5.7 Hz, 2 H), 3.51 (m,
2 H), 3.59 (s, 2 H), 4.95 (s, 2 H), 5.98 (d, J = 3.0 Hz, 1 H), 6.06 (s,
1 H), 6.60 (d, J = 3.0 Hz, 1 H), 6.95–6.98 (m, 2 H), 7.22–7.33 (m, 3
H).
13C NMR (75 MHz, CDCl3): d = 27.0, 34.7, 39.4, 50.5, 108.9,
111.5, 120.3, 125.8, 126.3, 127.4, 128.8, 137.8, 176.2.
Methyl Furan-3-acetate (24); Typical Procedure
A soln of silver benzoate (0.46 g, 2.6 mmol) in Et3N (4.2 mL) was
added to a soln of 22 (1.4 g, 10.2 mmol) in MeOH (50 mL). The
mixture was refluxed gently 2 h and then the solvent was evaporated
under reduced pressure. The residue was dissolved in Et2O (30 mL),
washed with sat. NaHCO3 soln (30 mL) and H2O (30 mL), dried
(anhyd Na2SO4), and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, EtOAc–hexane, 2:98)
to give 24 (1.2 g, 85%) as a colorless oil.
MS (EI, 70 eV): m/z (%) = 240 (78.2) [M+], 183 (61.2), 91 (100).
Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71; N, 11.66. Found: C,
73.79; H, 6.80; N, 10.92.
IR (film): 2955, 1741, 1437, 1276, 1245, 1166, 1021, 874 cm–1.
4,6,7,8-Tetrahydropyrrolo[3,2-d]azepin-5(1H)-one (5)
To a soln of 19 (0.20 g, 0.84 mmol) in THF (15 mL) at –78 °C was
added liquid NH3 (~15 mL) , followed by Na (100 mg, 4.1 mmol)
in small portions. The mixture was stirred at –78 °C for 30 min, then
quenched with solid NH4Cl (400 mg). The mixture was allowed to
reach r.t. and NH3 was evaporated. Brine (20 mL) was added, and
the mixture was extracted with CH2Cl2 (3 × 40 mL). The combined
organic extracts were dried (anhyd Na2SO4) and the solvent evapo-
rated in vacuo. The residue was purified by flash chromatography
(CH2Cl2–MeOH, 97:3) to afford 5 (70 mg, 55%) as a white solid;
mp >210 °C.
1H NMR (300 MHz, CDCl3): d = 3.46 (s, 2 H), 3.71 (s, 3 H), 6.37–
6.38 (m, 1 H), 7.37–7.38 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 30.1, 51.9, 111.2, 117.2, 140.3,
142.9, 171.5.
MS (EI, 70 eV): m/z (%) = 140 (46.2) [M+], 112 (27.8), 81 (100).
Methyl 2-(Cyanomethyl)furan-3-acetate (26)
Following the typical procedure for 16 using 24 (1.0 g, 7.1 mmol)
gave 26 (0.76 g, 60%) as the sole product as a yellow pale semisolid.
IR (film): 2955, 2922, 2257, 1738, 1437, 1275, 1202, 1171 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.45 (s, 2 H), 3.71 (s, 3 H), 3.77
(s, 2 H), 6.35 (d, J = 2.1 Hz, 1 H), 7.35 (d, J = 1.8 Hz, 1 H).
IR (KBr): 3241, 2886, 1669, 1479, 1428, 1353, 1139, 721 cm–1.
Synthesis 2010, No. 19, 3346–3352 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Furo-, Thieno-, and Pyrroloazepines
3351
13C NMR (75 MHz, CDCl3): d = 15.8, 30.4, 52.2, 110.3, 112.9,
Methyl 2-(Cyanomethyl)thiophene-3-acetate (27)
Following the typical procedure for 16 using 25 (0.78 g, 5 mmol)
gave 27 (0.44 g, 46%) as the sole product as a yellow pale semisolid.
IR (film): 2926, 2254, 1736, 1436, 1266, 1174 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.63 (s, 2 H), 3.71 (s, 3 H), 3.90
(s, 2 H), 6.94 (d, J = 5.4 Hz, 1 H), 7.21 (d, J = 5.1 Hz, 1 H).
115.0, 139.7, 142.3, 170.7.
MS (EI, 70 eV): m/z (%) = 179 (35) [M+], 120 (95), 119 (100).
Anal. Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.83; H, 5.01; N, 7.25.
Methyl {2-[(tert-Butoxycarbonyl)amino]ethyl}furan-3-acetate
(28)
Following the typical procedure for 17 using 26 (0.5 g, 2.8 mmol)
13C NMR (75 MHz, CDCl3): d = 16.6, 29.5, 52.2, 123.3, 124.4,
127.1, 129.9, 132.0, 170.4.
MS (EI, 70 eV): m/z (%) = 195 (39) [M+], 136 (100).
gave 28 (0.57 g, 72%) as a colorless viscous oil.
IR (film): 3372, 2975, 1738, 1713, 1517, 1252, 1170 cm–1.
Anal. Calcd for C9H9NO2S: C, 55.37; H, 4.65; N, 7.17. Found: C,
55.14; H, 4.11; N, 7.45.
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9 H), 2.79 (t, J = 6.6 Hz,
2 H), 3.38 (s, 2 H), 3.34–3.42 (m, 2 H), 3.70 (s, 3 H), 4.85 (s wide,
1 H), 6.30 (d, J = 2.1 Hz, 1 H), 7.29 (d, J = 1.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 26.5, 28.3, 30.2, 38.0, 52.0, 79.2,
111.9, 113.3, 141.0, 150.0, 155.8, 171.7.
Methyl 2-{2-[(tert-Butoxycarbonyl)amino]ethyl}thiophene-3-
acetate (29)
Following the typical procedure for 17 using 27 (0.44 g, 2.25 mmol)
gave 29 (0.52 g, 78%) as a colorless viscous oil.
MS (EI, 70 eV): m/z (%) = 283 (2) [M+], 166 (100), 57 (98.7).
IR (film): 3374, 2975, 1738, 1713, 1517, 1252, 1170 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.44 (s, 9 H), 2.97 (t, J = 6.6 Hz,
2 H), 3.33–3.40 (m, 2 H), 3.57 (s, 2 H), 3.69 (s, 3 H), 4.84 (br s, 1
H), 6.90 (d, J = 5.1 Hz, 1 H), 7.12 (d, J = 5.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 28.3, 30.4, 33.7, 41.5, 52.0, 79.3,
122.8, 126.7, 129.1, 130.1, 155.8, 171.5.
MS (EI, 70 eV): m/z (%) = 299 (82) [M+], 243 (11.2), 182 (66.8), 57
(100).
4,6,7,8-Tetrahydro-5H-furo[3,2-d]azepin-5-one (6)
Following the typical procedure for 19 using 28 (0.53 g, 1.9 mmol)
gave 6 (0.21 g, 75%) as a white solid; mp 113–114 °C.
IR (KBr): 3221, 3089, 2953, 1662, 1478, 1425, 1409, 1179, 1126
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.83–2.85 (m, 2 H), 3.48 (s, 2 H),
3.54–3.57 (m, 2 H), 6.17 (d, J = 1.5 Hz, 1 H), 6.70 (br s, 1 H), 7.26
(d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 28.5, 32.5, 38.8, 111.1, 112.1,
140.6, 148.6, 175.5.
4,6,7,8-Tetrahydro-5H-thieno[3,2-d]azepin-5-one (7)
Following the typical procedure for 19 using 27 (0.5 g, 1.7 mmol)
gave 7 (0.2 g, 70%) as a solid; mp 149–150 °C.
MS (EI, 70 eV): m/z (%) = 151 (100) [M+], 94 (78).
IR (KBr): 3190, 3095, 2916, 1692, 1630, 1478, 1431, 1403 cm–1.
Anal. Calcd for C8H9NO2: C, 63.56; H, 6.00; N, 9.27. Found: C,
63.66; H, 6.42; N, 9.78.
1H NMR (500 MHz, CDCl3): d = 3.05 (t, J = 5.5 Hz, 2 H), 3.63–
3.66 (m, 2 H), 3.74 (s, 2 H), 6.54 (br s, 1 H), 6.72 (d, J = 5.5 Hz, 1
H), 7.09 (d, J = 5.0 Hz, 1 H).
Thiophene-3-carboxylic Acid (21)
13C NMR (125 MHz, CDCl3): d = 29.7, 36.5, 122.5, 127.6, 129.9,
Following the typical procedure for 20 using thiophene-3-carbalde-
hyde (4.0 g, 33 mmol) gave 21 (3.34 g, 80%) as a pale yellow solid;
mp 139–140 °C (Lit.19 136–141 °C).
135.1, 174.8.
MS (EI, 70 eV): m/z (%) = 167 (64.3) [M+], 110 (100).
Anal. Calcd for C8H9NOS: C, 57.46; H, 5.42; N, 8.38. Found: C,
57.83; H, 5.74; N, 8.67.
1-Diazo-2-(thiophen-3-yl)ethanone (23)
Following the typical procedure for 22 using 21 (2.5 g, 20 mmol)
gave 23 (2.7 g, 90%) as a yellow solid; mp 57–58 °C.
Acknowledgment
IR (KBr): 3081, 3051, 2108, 1597, 1427, 1356, 1236, 829 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.74 (s, 1 H), 7.33 (dd, J = 5.1, 3.0
Hz, 1 H), 7.41 (dd, J = 5.1, 1.2 Hz, 1 H), 7.88 (dd, J = 3.1, 1.2 Hz,
1 H).
13C NMR (75 MHZ, CDCl3): d = 54.4, 125.8, 126.6, 129.0, 140.7,
180.5.
We wish to thank DGAPA, UNAM (Proyect PAPIIT 1N-204910)
for financial support. We also thank R. Patiño, J. Perez, L. Velazco,
H. Rios, N. Zavala, E. Huerta, and A. Peña for technical support.
We also thank M.Sc. Vilchis, M. and M.Sc. Solano, J. for cytotoxi-
city tests. Carlos Villarreal is CONACyT Graduate Scholarship hol-
der.
MS (EI, 70 eV): m/z (%) = 152 (100) [M+], 111 (64.3), 96 (88.7).
References
Methyl Thiophene-3-acetate (25)
Following the typical procedure for 24 using 23 (1.2 g, 7.6 mmol),
with the reaction carried out at r.t., gave 25 (0.94 g, 80%) as a col-
orless oil.
IR (film): 2954, 1741, 1438, 1337, 1268, 1155, 1014 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.66 (s, 2 H), 3.70 (s, 3 H), 7.04
(dd, J = 5.1, 1.2 Hz, 1 H), 7.13–7.15 (m, 1 H), 7.29 (dd, J = 5.1, 3.3
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 35.6, 51.9, 122.8, 125.7, 128.4,
133.5, 171.5.
MS (EI, 70 eV): m/z (%) = 156 (28.7) [M+], 97 (100).
(1) Martínez, R.; Clara-Sosa, A.; Ramírez Apan Ma, T. Bioorg.
Med. Chem. 2007, 15, 3912.
(2) Martínez, R.; Ávila, J. G.; Ramírez, Ma. T.; Pérez, A.;
Martínez, A. Bioorg. Med. Chem. 2006, 14, 4007.
(3) (a) Lahusen, T.; De Siervi, A.; Kunick, C.; Senderowicz, A.
Mol. Carcinog. 2003, 36, 183. (b) Kunick, C.; Zeng, Z.;
Gussio, R.; Zaharevitz, D.; Leost, M.; Totzke, F.;
Schaechtele, C.; Kubbutat, M. H. G.; Meijer, L.; Lemcke, T.
ChemBioChem 2005, 6, 541.
(4) van Leusen, A. M.; Siderius, H.; Hoogenboom, H.;
Van Leusen, D. Tetrahedron Lett. 1972, 13, 5337.
(5) Bachman, W. E.; Stuve, W. S. Org. React. 1942, 1, 38.
Synthesis 2010, No. 19, 3346–3352 © Thieme Stuttgart · New York

3352
C. Villarreal, R. Martínez
PAPER
(13) Newman, M. S.; Beal, P. F. J. Am. Chem. Soc. 1950, 72,
(6) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell,
A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th
ed.; Longman: Essex, 1989, 430.
(7) Demopoulos, V. J. Synth. Commun. 1989, 19, 2585.
(8) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell,
T. T.; Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990,
55, 637.
(9) Osornio, Y. M.; Cruz-Almanza, R.; Jiménez-Montaño, V.;
Miranda, L. D. Chem. Commun. 2003, 2316.
(10) Caddick, S.; Judd, D. B.; Lewis, A. K.de K..; Reich, M. T.;
Williams, M. R. V. Tetrahedron 2003, 59, 5417.
(11) Caddick, S.; Haynes, A. K.de K.; Judd, D. B.; Williams, M.
R. V. Tetrahedron Lett. 2000, 41, 3513.
5163.
(14) Still, W. C.; Khan, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
(15) Flitsch, W.; Pandl, K.; Rubkamp, P. Liebigs Ann. Chem.
1983, 529.
(16) Shim, Y. K.; Youn, J. I.; Chun, J. S.; Park, T. H.; Kim, M.
H.; Kim, W. J. Synthesis 1990, 753.
(17) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell,
A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th
ed.; Longman: Essex, 1989, 609.
(18) Ghosh, A.; Raha, C. R. Indian Chem. Soc. 1954, 31, 461.
(19) Friedmanh, L.; Fishel, D. L.; Shechter, H. J. Org. Chem.
1965, 30, 1457.
(12) Reyes-Gutierrez, P. E.; Torres-Ochoa, R. O.; Martínez, R.;
Miranda, L. D. Org. Biomol. Chem. 2009, 7, 1388.
Synthesis 2010, No. 19, 3346–3352 © Thieme Stuttgart · New York