A remarkable reductive dearomatization of thiophene and furan rings

Article abstract of DOI:10.1055/s-0033-1338416

Reduction of a 2-nitrothiophene 4 and the corresponding 2-nitrofuran 20 with zinc and acetic acid produced a remarkable dearomatization and fragmentation reaction to give acyclic nitriles 6 and 22, respectively. The intermediate 2-aminothiophene 5 was trapped by acylation with acetic anhydride to give acetamide 7. An additional acrylonitrile intermediate 17 was also trapped by Michael addition with benzyl mercaptan to give adduct 18. An alternate synthesis of nitrile 22 produced in the reduction of nitrofuran 20 provided an authentic sample of the product. The conversion of nitroaromatic heterocycles 4 and 20 into aliphatic nitriles 6 and 22 are remarkable and unprecedented reactions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338416

1904▌
PAPER
paper
A Remarkable Reductive Dearomatization of Thiophene and Furan Rings
Fragmentation of Thiophene and Furan Rings
Son T. Nguyen, Xiaoyuan Ding, Norton P. Peet*
Department of Chemistry, Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605-4332, USA
Fax +1(508)7571999; E-mail: npeet@microbiotix.com
Received: 20.12.2012; Accepted: 17.03.2013
The authors would like to dedicate this work to Professor Scott Denmark on the occasion of his 60th birthday, in appreciation of his enthu-
siastic mentorship to young scientists, including Son Nguyen, over the years.
rantoin is used to treat urinary tract infections. These
Abstract: Reduction of a 2-nitrothiophene 4 and the corresponding
drugs might have multiple mechanisms of action, which
2-nitrofuran 20 with zinc and acetic acid produced a remarkable
include the production of reactive intermediates formed
by bioreduction of these nitrofurans that are thought to
dearomatization and fragmentation reaction to give acyclic nitriles
6 and 22, respectively. The intermediate 2-aminothiophene 5 was
trapped by acylation with acetic anhydride to give acetamide 7. An cause damage to bacterial DNA.
additional acrylonitrile intermediate 17 was also trapped by
Michael addition with benzyl mercaptan to give adduct 18. An al-
ternate synthesis of nitrile 22 produced in the reduction of nitrofu-
ran 20 provided an authentic sample of the product. The conversion
of nitroaromatic heterocycles 4 and 20 into aliphatic nitriles 6 and
22 are remarkable and unprecedented reactions.
O
O
O
NH
N
N
N N
O
O
O
O2N
O2N
Key words: thiophene, furan, zinc, furazolidone, nitrofurantoin, re-
ductive dearomatization
nitrofurantoin
furazolidone
Figure 1 Structures of nitrofuran-containing drugs
Nitrofurans and nitrothiophenes, as well as aminofurans
and aminothiophenes, are important building blocks for
the construction of biologically active compounds. Dis-
placement of a nitro group on a furan or thiophene ring has
afforded aminofurans, aminothiophenes, and other syn-
thetically useful furans and thiophenes.1–4 2-Aminofurans
have been used as dienophiles for Diels–Alder reactions
in the preparation of anilines.5
We became interested in preparing 2-nitrofurans, 2-nitro-
thiophenes, and their corresponding 2-amino compounds,
bearing dialkylamino functionalities at the 5-positions, of
the general structures shown in Figure 2. We envisioned
using these compounds as building blocks for new com-
pound construction and also proposed to produce the ami-
no compounds directly from the nitro compounds by
reduction.
3-Aminofurans are present in the proximicin series of nat-
ural products, which display both antibacterial and anti-
cancer activities.6 Highly-substituted 3-aminofurans can
be prepared from thiazolium salts and dimethylacetylene
dicarboxylate;7 2-nitrofurans and 2-nitrothiophenes have
also been prepared using cycloaddition reactions, from 2-
(chlorocarbonyl)-2-phenyl ketene.8 Several 2-nitrothio-
phenes have been synthesized and shown to have antimi-
crobial properties,8,10,11 and a review on the importance of
2-aminothiophenes in drug design has appeared.12 Finally,
it is known that bioreduction of the nitro group to reactive
intermediates or an amino group in the nitrofurans and ni-
trothiophenes is generally responsible for the biological
activity produced by these compounds,13 and this biore-
ductive process has been used as a designed delivery sys-
tem for drug targeting.14
R2N
X
R2N
X
O
S
1a, X = NO2
1b, X = NH2
2a, X = NO2
2b, X = NH2
Figure 2 Proposed furan and thiophene building blocks
To this end, the synthesis of 5-(4-morpholinyl)-2-nitro-
thiophene (4) and its reduction to the corresponding 2-
aminothiophene 5 were undertaken (Scheme 1). Starting
from commercially available 2-bromo-5-nitrothiophene
(3), nitrothiophene 4 was prepared by treatment with mor-
pholine. Subsequent treatment of nitrothiophene 4 with
zinc in acetic acid completely consumed the nitrothio-
phene, but to our surprise, aminothiophene 5 was not pro-
duced. After chromatographic purification, it was clear
that our major product was no longer a thiophene deriva-
tive. On the basis of spectral data the product was identi-
fied as the nitrile 6, which was obtained in 61% yield.
Nitrofuran-containing drugs are used to treat bacterial in-
fections. Both furazolidone15 and nitrofurantoin,16 shown
in Figure 1, are sold under a variety of brand names. Fu-
razolidone is used to treat diarrhea and enteritis; nitrofu-
We next attempted to determine whether aminothiophene
5 might be produced as an intermediate in the zinc reduc-
tion of nitrothiophene 4. Thus, as shown in Scheme 2, the
zinc reduction was performed in the presence of acetic an-
hydride. Interestingly, acetamide 7 was isolated in 41%
yield, which verified the intermediacy of aminothiophene
SYNTHESIS 2013, 45, 1904–1908
Advanced online publication: 08.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338416; Art ID: SS-2012-C0967-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fragmentation of Thiophene and Furan Rings
1905
Zn, Ac2O
AcOH
morpholine
N
NO2
THF
80 °C
86%
Br
S
NO2
S
N
NO2
N
N
NHAc
S
S
O
THF, toluene
41%
O
O
O
3
4
7
4
Zn
Pd/C, HCO2NH4
MeOH, THF
AcOH
H
or Pd/C, H2, EtOH
61%
H
N
N
H
N
H
S
S
S
O
N
CN
5
8
intermediate
N
NH2
O
S
O
6
5
S
N
CN
Scheme 1 Synthesis of 4-(3-cyanopropionyl)morpholine (6)
CN
N
SH
O
O
6
9
5 in the reduction of nitrothiophene 4. Based on this result,
the mechanism for the conversion of aminothiophene 5 to
nitrile 6 is proposed as shown in Scheme 2, in which tau-
tomerism of 5 to 8 occurs, followed by fragmentation as
shown to give 9, which is the tautomer of thioamide 6. It
is noteworthy that this process involves the conversion of
an amino group to a nitrile and the dearomatization of the
thiophene ring to produce an acyclic thioamide.
Scheme 2 Trapping of 2-amino-5-(4-morpholinyl)thiophene (5)
Based on the furazolidone metabolic pathway, another
trapping experiment with benzyl mercaptan was attempt-
ed next as shown in Scheme 4. Interestingly, when the re-
duction of thiophene 4 was performed with zinc and acetic
acid in the presence of benzyl mercaptan, Michael adduct
18 was obtained, albeit in low (5%) yield, in addition to
nitrile 6 in 44% yield. Comprehensive NMR analysis of
compound 18, including a two dimensional Heteronuclear
Interestingly, a metabolic route for the veterinary medi-
cine furazolidone has been proposed on the basis of sev-
eral in vitro and in vivo studies.17–22 This route is
summarized in Scheme 3, where reduction of furazoli-
done to the hydroxylamino intermediate 10 is proposed;
tautomerism to 11 is followed by fragmentation, as
shown, to produce acrylonitrile 12. Reduction of 12 was
then proposed to account for the formation of nitrile 13.
Glutathione conjugate 14 was characterized by exchange
with mercaptoethanol. The position of the thiol addition to
acrylonitrile 14 was not rigorously determined in these
studies.
Multiple Bond Correlation (HMBC) H, 13C experiment,
1
convinced us that the position of the benzylmercapto
group was adjacent to the nitrile, as shown in structure 18.
Our overall understanding of the reductive conversion of
nitrothiophene 4, based on the production and isolation of
compounds 6, 7, and 18, is summarized and displayed in
Scheme 4.
O
O
O
O
O
metabolism
N
N
N
O
N
N
N
+
NO2
CN
CN
O
O
O
S
Glu
13
furazolidone
14
glutathione
conjugate
reduction
O
H
N
reduction
O
N
N
O
glutathione
OH
10
H
O
O
N
N
N
CN
O
N
O
N
O
O
– H2O
OH
12
11
Scheme 3 Proposed metabolic route for furazolidone
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1904–1908

1906
S. T. Nguyen et al.
PAPER
H
Ac2O
H
CN
N
NHAc
N
N
H
N
N
H
N
S
S
S
SH
O
O
O
O
7
5
8
9
intermediate
[H2]
H
H
Zn
AcOH
H
N
NO2
N
N
N
N
S
S
S
O
O
O
OH
OH
4
15
16
S
S
SBn
CN
CN
[H2]
BnSH
N
CN
N
N
S
O
O
O
6
17
18
intermediate
Scheme 4 Trapping of acrylonitrile 17; overall mechanism of thiophene dearomatization reaction
The furan analogue of nitrothiophene 4 was prepared However, we were unable to isolate the acetylaminofuran
next, as shown in Scheme 5. Treatment of 2-bromo-5-ni- corresponding to compound 7 (i.e., compound 21) when
trofuran (19) with morpholine under mild conditions gave nitrofuran 20 was treated with zinc, acetic acid, and acetic
a 44% yield of 5-(4-morpholinyl)-2-nitrofuran (20). anhydride. This result may indicate that the aminofuran
When nitrofuran 20 was treated with zinc and acetic acid corresponding to aminothiophene 5 is not as stable as 5
under the same conditions that produced nitrile 6 from ni- and is not long-lived enough to be trapped, which is con-
trothiophene 4, the corresponding nitrile 22 was isolated sistent with thiophenes having more aromatic stabiliza-
in 30% yield. An authentic sample of nitrile 22 was also tion energy than furans.23
prepared, as shown in Scheme 5, by basic hydrolysis of
In conclusion, attempted reductions of nitrothiophene 4
commercially available methyl 3-cyanopropionate (23)
and nitrofuran 20 to aminothiophene 5 and the corre-
followed by coupling of the resulting acid 24 with mor-
sponding aminofuran produce, instead, nitriles 6 and 22,
pholine. The nitrile 22 synthesized in this manner was
respectively. Proposed mechanistic pathways for these re-
ductions are presented, and elucidated by the identifica-
identical in all respects with the sample of 22 produced in
the chemical reduction of 20 with zinc and acetic acid.
tion of trapped intermediates
7 and 18. These
unprecedented reductive processes may prove to be syn-
thetically useful.
morpholine
N
NO2
Et2O
38 °C
44%
Br
NO2
O
O
19
O
All commercially obtained solvents and reagents were used as re-
ceived. H and 13C NMR spectra were recorded on a Bruker 300
1
20
MHz instrument. Chemical shifts are given in δ values referenced
to the internal standard TMS. MS spectra were recorded on a Ther-
mo LCQ Fleet instrument. High-resolution mass spectra were re-
corded on a Bruker Daltonic High Resolution Q-FTMS instrument.
FTIR spectra were recorded on a Perkin Elmer Spectrum 400 instru-
ment.
Zn
AcOH
Zn, Ac2O
AcOH
30%
O
N
CN
N
NHAc
5-(4-Morpholinyl)-2-nitrothiophene (4)24
O
O
O
To a stirred solution of 5-bromo-2-nitrothiophene (3; 3.0 g, 14.4
mmol) in THF (50 mL) was added morpholine (6.3 mL, 71.8
mmol). The mixture was heated to 80 °C for 2 h, allowed to cool to
r.t., and filtered. The solid was crystallized from EtOH (100 mL) to
provide the product as orange-colored needles (1.9 g). To the fil-
trate, H2O (15 mL) was added. Slow evaporation at r.t. provided an-
other crop of pure product (0.75 g); total yield: 2.65 g (86%); mp
167–169 °C; Rf = 0.42 (hexanes–EtOAc, 1:1, UV).
21
22
morpholine
EDC·HCl
O
O
NaOH
22
THF–MeOH
3.5 h
HO
CN
MeO
CN
DMAP
CH2Cl2, 23 h
23
24
50%
30%
Scheme 5 Reduction of 5-(4-morpholinyl)-2-nitrofuran (20)
Synthesis 2013, 45, 1904–1908
1H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 6.3 Hz, 1 H), 5.99 (d,
J = 6.3 Hz, 1 H), 3.86 (t, J = 4.8 Hz, 4 H), 3.35 (t, J = 4.8 Hz, 4 H).
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fragmentation of Thiophene and Furan Rings
1907
13C NMR (75 MHz, CDCl3): δ = 165.9, 135.3, 132.6, 103.0, 65.7,
5-(4-Morpholinyl)2-nitrofuran (20)5
49.1.
To a solution of 2-bromo-5-nitrofuran (19; 851 mg, 4.43 mmol) in
Et2O (40 mL) was added morpholine (0.77 mL, 8.87 mmol) drop-
wise at r.t. The solution was heated to 38 °C and stirred for 40 h. The
yellow reaction mixture was cooled to r.t. and concentrated by rota-
ry evaporation. The residue was purified by column chromatogra-
phy on silica gel (hexanes–EtOAc, 1:0 to 0:1) to provide furan 20
(390 mg, 44%) as a white solid; mp 118–122 °C; Rf = 0.26
(hexanes–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 4.2 Hz, 1 H), 5.38 (d,
J = 4.2 Hz, 1 H), 3.84–3.81 (t, J = 4.8 Hz, 4 H), 3.48–3.45 (t, J = 4.9
Hz, 4 H).
ESI-MS: m/z calcd for C8H10N2O3S: 214.0412; found: 215.1 [M + 1].
4-Morpholino-4-thioxobutanenitrile (6)
To a stirred solution of nitrile 4 (0.31 g, 1.45 mmol) in AcOH (30
mL) was added Zn dust (2.5 g, 38.2 mmol) in three portions. After
30 min, the suspension was filtered, and the solid was rinsed with
EtOAc (3 mL) and EtOH (3 mL). The filtrate was concentrated by
rotary evaporation at 40 °C. The residue was purified by silica gel
column chromatography (hexanes–EtOAc, 1:0 to 0:1, 20 min). Ni-
trile 6 was obtained as a brown viscous oil (0.16 g, 61%); Rf = 0.27
(hexanes–EtOAc, 1:1, UV).
13C NMR (75 MHz, CDCl3): δ = 159.8, 145.1, 120.3, 88.1, 66.3,
45.8.
IR (film): 2980, 2924, 2907, 2860, 2248, 1480, 1448, 1435, 1224
cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.35 (t, J = 5.1 Hz, 1 H), 3.82–3.76
(m, 6 H), 3.01–2.98 (m, 4 H). No deuterium exchange was observed
when treated with D2O.
13C NMR (75 MHz, CDCl3): δ = 198.1, 119.0, 66.5, 66.2, 50.3, 49.9,
36.1, 17.2.
ESI-MS: m/z calcd for C8H10N2O4: 198.0641; found: 198.9 [M + 1].
4-Morpholino-4-oxobutanenitrile (22)
To a solution of furan 20 (100 mg, 0.50 mmol) in AcOH (5.0 mL)
was added Zn dust (1 g). After 30 min, the orange-colored suspen-
sion became yellow. The mixture was filtered and the grey solid was
washed with EtOAc (20 mL). The filtrate was concentrated by rota-
ry evaporation and purified by preparative reversed-phase HPLC
(solvent A: H2O–0.2% TFA; solvent B: MeCN–0.2% TFA, gradient
10% B/A to 70% B/A in 10 min) to provide nitrile 22 (26 mg, 30%)
as a light yellow oil; Rf = 0.4 (EtOAc–MeOH, 1:1, UV).
1H NMR (300 MHz, CDCl3): δ = 3.70–3.64 (m, 4 H), 3.65–3.64 (m,
2 H), 3.46 (t, J = 4.7 Hz, 2 H), 2.73–2.66 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 167.5, 119.3, 66.7, 66.4, 45.6,
ESI-HRMS: m/z calcd for C8H10N2O3S: 184.0670; found: 185.0747
[M + 1].
N-(5-Morpholinothiophen-2-yl)acetamide (7)
To a stirred solution of nitrile 4 (65 mg, 0.30 mmol) in a mixture of
Ac2O (0.3 mL, 3.18 mmol), AcOH (1.1 mL), THF (0.7 mL), and tol-
uene (1.4 mL) was added Zn dust (0.5 g, 7.65 mmol) in three por-
tions. After 20 min, the suspension was filtered, and the solid was
rinsed with toluene (1 mL) and EtOAc (1 mL). The filtrate was con-
centrated by rotary evaporation. The residue was purified by silica
gel column chromatography (hexanes–EtOAc, 1:0 to 0:1, 16 min).
Acetamide 7 was obtained as a brown solid (28 mg, 41%); mp 152–
154 °C; Rf = 0.14 (hexanes–EtOAc, 1:1, UV).
42.2, 29.0, 13.0.
ESI-MS: m/z calcd for C8H12N2O2: 168.0899; found: 168.6 [M + 1].
3-Cyanopropanoic Acid (24)
1H NMR (300 MHz, CDCl3): δ = 7.65 (br s, 1 H), 6.34 (br s, 1 H),
5.88 (br d, J = 4.2 Hz, 1 H), 3.82 (t, J = 4.8 Hz, 4 H), 3.11–3.05 (br
m, 4 H), 2.15 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 167.1, 152.9, 127.9, 112.0, 102.9,
66.4, 52.0, 23.1.
To a solution of methyl 3-cyanopropionate (23; 717 mg, 6.34
mmol) in MeOH (20 mL) and THF (40 mL) was added 1 N aq
NaOH (16 mL) at r.t. The resulting colorless solution was stirred for
3.5 h and the solvents were removed by rotary evaporation. The res-
idue was diluted with CH2Cl2 (50 mL) and adjusted to pH 2 (aq 2 N
HCl). The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (10 mL). The combined organic extracts
were dried (Na2SO4), filtered, concentrated, and placed under vacu-
um (4 h) to provide acid 24 as a light yellow oil (300 mg, 50%); Rf =
0.5 (6% MeOH in CH2Cl2, UV).
ESI-MS: m/z calcd for C10H14N2O2S: 226.0776; found: 227.08 [M
+ 1].
2-(Benzylthio)-4-morpholino-4-thioxobutanenitrile (18)
To a stirred solution of 4 (0.2 g, 0.93 mmol) and benzyl mecaptan
(1 mL, 8.52 mmol) in a mixture of AcOH (3 mL) and toluene (5 mL)
was added zinc dust (0.5 g, 7.65 mmol) in two portions over 10 min.
After 1 h, the dark brown suspension was filtered through Celite and
the solid residue was rinsed with toluene (3 mL). The filtrate was
concentrated by rotary evaporation at 40 °C. The residue was puri-
fied by silica gel (40 g) column chromatography (hexanes–EtOAc,
1:0 to 0:1, 22 min). Two products were obtained: 18 as a light green
oil (9 mg, 5%) and 4 as a brown viscous oil (76 mg, 44%); Rf = 0.38
(hexanes–EtOAc, 1:1, UV/anisaldehyde).
1H NMR (500 MHz, CDCl3): δ = 7.41–7.25 (m, 5 H), 4.46 (dd, J =
6.1, 9 Hz, 1 H), 4.35 (dt, J = 13.7, 4.9 Hz, 1 H), 4.23 (dt, J = 13.7,
5.1 Hz, 1 H), 4.05 (d, J = 13.7 Hz, 1 H), 4.01 (d, J = 13.7 Hz, 1 H),
3.76 (t, J = 4.64 Hz, 2 H), 3.66–3.65 (m, 2 H), 3.62–3.57 (m, 1 H),
3.55–3.51 (m, 1 H), 3.04 (dd, J = 15.6, 9.0 Hz, 1 H), 2.82 (dd, J =
15.6, 6.1 Hz, 1 H).
1H NMR (300 MHz, CDCl3): δ = 2.80–2.64 (m, 2 H), 2.61–2.57 (m,
2 H).
ESI-MS: m/z calcd for C4H5NO2: 99.0320; found: 99.86 [M + 1].
Nitrile 22 from 3-Cyanopropanoic Acid (24)
To a solution of 24 (30 mg, 0.30 mmol), 4-(dimethylamino)pyridine
(4 mg, 0.02 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcar-
bodiimide hydrochloride (64 mg, 0.33 mmol) in CH2Cl2 (3.0 mL)
was added morpholine (0.03 mL, 0.30 mmol). The colorless solu-
tion was stirred at r.t. for 23 h and diluted with CH2Cl2 (10 mL). The
heterogeneous mixture was washed with H2O (3 × 2 mL), brine (2
mL), 2 N aq HCl (3 mL), dried (Na2SO4), filtered, concentrated, and
placed under vacuum (4 h) to provide the product (15 mg, 30%) as
a light yellow oil. The 1H NMR spectrum of the product was iden-
tical to that of 22, which was obtained from the reduction of 20.
13C NMR (125 MHz, CDCl3): δ = 196.0, 136.6, 129.2, 128.9, 127.8,
118.5, 66.4, 66.2, 50.2, 50.0, 43.2, 36.7, 32.4.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
ESI-MS: m/z calcd for C15H18N2OS2: 306.0861; found: 307.07 [M
+ 1].
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1904–1908

1908
S. T. Nguyen et al.
PAPER
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