Synthesis of masked 2-amino-3-furancarboxaldehydes

Article abstract of DOI:10.1055/s-0029-1218641

5-Substituted 2-(2-amino-3-furanyl)-1,3-dimethyl-1H-benzimidazolium bromides were obtained in excellent yields upon heating (1,3-dimethyl-1,3- dihydro-2H-benzimidazol-2-ylidene)ace-tonitrile with-bromo ketones in refluxing N,N-dimethylform-amide. Reductio

Full text of DOI:10.1055/s-0029-1218641

PAPER
1009
Synthesis of Masked 2-Amino-3-furancarboxaldehydes
S
ynthesis of Mask
l
ed2-A
e
x
a
hydes nder V. Denisenko,a Anton V. Tverdokhlebov,*b Andrey A. Tolmachev,a,b Yulian M. Volovenko,a
Svitlana V. Shishkina,c Oleg V. Shishkinc
a
Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
b
Fax +380(44)5373253; E-mail: atver@univ.kiev.ua
STC Institute for Single Crystals, NAS of Ukraine, 60 Lenina ave., 61001 Kharkiv, Ukraine
c
Received 13 October 2009; revised 23 November 2009
benzimidazolium salt precursors were obtained from the
readily accessible nitrile 3.8 Continuing the research,7 we
now describe the applicability of compound 3 to the syn-
thesis of vicinal amino aldehydes in the furan series.
Abstract: 5¢-Substituted 2-(2-amino-3-furanyl)-1,3-dimethyl-1H-
benzimidazolium bromides were obtained in excellent yields upon
heating (1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)ace-
tonitrile with a-bromo ketones in refluxing N,N-dimethylform-
amide. Reduction of the prepared quaternary salts with sodium
borohydride afforded 5-substituted 3-(1,3-dimethyl-2,3-dihydro-
1H-benzimidazol-2-yl)-2-furanamines. The latter were shown to be
masked amino aldehydes. Thus, the corresponding 2-amino-3-
furancarboxaldehyde phenylhydrazones and semicarbazones were
obtained upon treatment with phenylhydrazine and semicarbazide,
respectively, whereas condensation with malononitrile yielded 2-
substituted 6-aminofuro[2,3-b]pyridine-5-carbonitriles.
Me
Me
N
N
O
N
N
O
Me
Me
H2N
H2N
N
N
R
X
Key words: amino aldehydes, furans, hydrazones, nitriles, reduc-
tions
1
2
Figure 1 R = alkyl, substituted phenyl; X = CH2, S
Vicinal (hetero)aromatic amino aldehydes are powerful
synthons in heterocyclic chemistry;1 however, within the
furan series these derivatives are hitherto unknown. The
most common approach to 2-amino-3-carbonylfurans in-
cludes alkylation of suitably substituted acetonitriles with
a-halo ketones.2 Its application to the preparation of the
target amino aldehydes requires the use of scarcely avail-
able formylacetonitrile.3 Furthermore, even neglecting the
availability problems, the method appears to be inapplica-
ble because of the very high reactivity of the formylaceto-
nitrile, which results in both self-condensation reactions
under basic alkylation conditions4 and competitive hetero-
cyclizations with participation of the formyl group rather
than the nitrile. A few less general approaches5 to 2-ami-
no-3-carbonylfuran derivatives have also utilized substi-
tuted acetonitriles as the starting materials and, therefore,
can not provide the target compounds. Hence, the synthe-
sis of 2-amino-3-furancarboxaldehyde derivatives is a
challenge we decided to meet.
It was found that treatment of compound 3 with a-bromo
ketones in refluxing N,N-dimethylformamide afforded 5¢-
substituted 2-(2-amino-3-furanyl)-1,3-dimethyl-1H-benz-
imidazolium bromides 4a–d in excellent yields
(Scheme 1). Clearly, the derivatives 4 are formed through
initial C-alkylation of compound 3 with the a-bromo ke-
tones followed by hydrogen bromide assisted enolization
and intramolecular addition of the hydroxy group to the
nitrile. The latter step is accompanied by the positive
charge transfer to the benzimidazole moiety. Thus, an
equivalent amount of hydrogen bromide liberated in the
first step of the reaction is then utilized in the second step.
There is some resemblance between this reaction and the
above-mentioned typical synthesis2 of 2-amino-3-carbon-
ylfurans; however, the advantage of compound 3 com-
pared to other substituted acetonitriles is the absence of a
carbonyl group, providing complete selectivity in the
ring-closure step. Also, it is important to note that basic
conditions are not needed for the alkylation of the
enamine-type carbon atom of derivative 3, contrary to the
alkylation of substituted acetonitriles.
The N,N¢-dimethylbenzimidazolium moiety is well
known as a synthetic equivalent of the aldehyde function-
ality.6 Its reduction into the 2,3-dihydro derivative yields
the masked formyl group, which can be liberated by hy-
drolytic cleavage, if necessary.6a Recently, we successful-
ly employed such an approach for the preparation of
masked amino aldehyde derivatives of pyrrole 17a and cer-
tain fused pyrrole 27b cores (Figure 1). The corresponding
The structure of the salts 4 was initially deduced from
their 1H and 13C NMR spectra and then confirmed unam-
biguously by an X-ray crystallographic study carried out
on derivative 4d (Figure 2). According to the crystal data,
the two heterocyclic moieties are turned relative to each
other; the torsion angle N(2)–C(7)–C(8)–C(9) is –50.7°.
The N(1)–C(7) and N(2)–C(7) bonds are almost equalized
(1.343 and 1.335 Å, respectively). Hence, conjugation be-
tween the two parts of the molecule is disrupted; the pos-
SYNTHESIS 2010, No. 6, pp 1009–1013
x
x
.
x
x
.2
0
1
0
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218641; Art ID: P14209SS
© Georg Thieme Verlag Stuttgart · New York

1010
A. V. Denisenko et al.
PAPER
O
Br
R1
DMF, reflux
Br–
Me
N+
N
N
N
Me
Me
Me
H2N
NC
3
O
R1
4a–d
R2
NaBH4
HN
N
NC
R2NHNH2⋅HCl
CH2(CN)2
cat. NH4Cl
H2N
R1
N
N
Me
H2N
Me
O
O
H2N
N
R1
6a–c
7a–c
8a,c
O
R1
5a–d
Scheme 1 For compounds 4–8: a R1 = Ph, b R1 = 4-EtC6H4, c R1 = 4-BrC6H4, d R1 = CF3; for compounds 6, R2 = Ph; for compounds 7,
R2 = CONH2
in the expected furo[2,3-b]pyridine-5-carbonitrile deriva-
tives 8a,c. All these reactions proceeded upon heating and
better yields (60–80%) were achieved by carrying them
out under an argon atmosphere. So, although the furans 5
are stable in air in the solid state, their solutions neverthe-
less undergo oxidation at elevated temperature. Also, it
should be noted that most of the reported annulations of
pyridines to the furan core were based on the condensa-
tion of 3-unsubstituted 2-furanamines with 1,3-dicarbonyl
compounds or their equivalents9 and were often compli-
cated by the unavailability or instability of the furan-
amines.9a The present Friedländer-type synthesis of
compounds 8 seems to offer a good alternative to this
Figure 2 X-ray molecular structure of compound 4d·0.5H2O with method9 and to a few other less common approaches that
are known.10
the atom numbering used in the crystallographic analysis
To summarize, the present investigation has resulted in
itive charge is really located at the benzimidazole moiety
the first synthesis of masked vicinal amino aldehyde de-
and is distributed between the nitrogen atoms N(1) and
N(2) in the usual manner.
rivatives of the furan core. The method consists of alkyla-
tion of the nitrile 3 with a-bromo ketones and further
Reduction of the benzimidazolium bromides 4 with ex-
cess sodium borohydride in methanol furnished the 2-
furanamine derivatives 5a–d in 90–95% yield. Despite the
fact that the 2-furanamines 5 are devoid of electron-with-
drawing substituents, they appear to be stable for several
days up to a week, even in the presence of air. The struc-
ture of compounds 5 was confirmed by 1H and 13C NMR
data. The signals of 2-H and 2-C of the dihydrobenzimi-
dazole moiety, observed at 4.85–4.95 and 84–86 ppm, re-
spectively, were especially remarkable attributes of the
reduction.
reduction of the obtained benzimidazolium salts 4. The
starting materials are readily available and the procedures
are very simple, thus making the method convenient and
tempting. Moreover, compound 3 has been shown to be a
suitable precursor to various heterocyclic vicinal amino
aldehydes, namely 1, 2 and 5.7 In fact, it was used as the
formal equivalent of formylacetonitrile, avoiding the un-
desired features of the latter. Thereby, further research on
the practical applications of compound 3 in the field is in
progress.
Nitrile 3 was prepared according to the described procedure.8 The
a-bromo ketones were either commercially available or prepared as
reported.11 Commercial DMF was kept over P2O5 overnight and
then distilled under reduced pressure. Other reagents and solvents
were commercially available and were used without additional pu-
rification. All melting points were determined in open capillary
tubes with a Thiele apparatus and are uncorrected. 1H and 13C NMR
spectra (400 and 100 MHz, respectively) were recorded on DMSO-
The amino aldehyde nature of compounds 5 was demon-
strated by several transformations. Thus, the correspond-
ing phenylhydrazones 6a–c and semicarbazones 7a–c
were obtained by the reaction of derivatives 5 with phe-
nylhydrazine and semicarbazide hydrochlorides, respec-
tively. Additionally, the ammonium chloride catalyzed
condensation of compounds 5 with malononitrile resulted
Synthesis 2010, No. 6, 1009–1013 © Thieme Stuttgart · New York

PAPER
Synthesis of Masked 2-Amino-3-furancarboxaldehydes
1011
d6 solutions on a Varian UNITY Plus 400 spectrometer. Chemical
shifts (d) are given in ppm downfield from internal TMS; J values
are in hertz. In the assignment of NMR data, f = furanyl and Bim =
benzimidazolyl. Elemental analyses were performed at the Mi-
croanalytical Department of the Institute of Organic Chemistry,
NAS, Kiev, Ukraine. The purity of all compounds obtained was
checked by 1H NMR spectroscopy and LC/MS on an Agilent 1100
instrument.
1H NMR: d = 3.92 (s, 6 H, 2 × CH3), 7.59 (s, 1 H, Hf), 7.70 (m, 2 H,
Bim), 7.82 (s, 2 H, NH2), 8.06 (m, 2 H, HBim).
13C NMR: d = 33.0 (2 × CH3), 76.8 (3-Cf), 113.4 (4,7-CBim), 116.9
(4-Cf), 119.6 (q, JCF = 211.0 Hz, CF3), 126.7 (5,6-CBim), 132.4
(3a,7a-CBim), 145.9 (2-Cf), 150.9 (q, JCF = 33.0 Hz, 5-Cf), 161.0 (2-
H
CBim).
Anal. Calcd for C14H13F3N3OBr: C, 44.70; H, 3.48; N, 11.17; Br,
21.24. Found: C, 44.71; H, 3.33; N, 11.20; Br, 21.46.
Benzimidazolium Bromides 4a–d; General Procedure
A soln of nitrile 3 (1.85 g, 0.01 mol) and an a-bromo ketone (0.01
mol) in DMF (20 mL) was refluxed for 15 min. The solvent was re-
moved under reduced pressure, and the residue was triturated with
anhyd acetone (20 mL), collected by filtration and washed with an-
hyd acetone (10 mL) to give compound 4a–d. Usually, the products
were sufficiently pure for further use. The analytical samples were
additionally recrystallized from acetone.
2-Furanamines 5a–d; General Procedure
NaBH4 (1.9 g, 0.05 mol) was added in portions to a stirred and ice-
cooled soln of the appropriate salt 4a–d (5 mmol) in MeOH (15
mL). After the addition was complete, stirring was continued for 10
min and then the mixture was poured into H2O (50 mL). The precip-
itate that formed was collected by filtration and recrystallized from
an appropriate solvent to give derivative 5a–d.
3-(1,3-Dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)-5-phenyl-
2-furanamine (5a)
Yield: 1.43 g (94%); mp 91 °C (i-PrOH).
2-(2-Amino-5-phenyl-3-furanyl)-1,3-dimethyl-1H-benzimida-
zolium Bromide (4a)
Yield: 3.53 g (92%); mp 259 °C (acetone).
1H NMR: d = 2.54 (s, 6 H, 2 × CH3), 4.92 (s, 1 H, NCHN), 5.87 (s,
2 H, NH2), 6.41 (m, 2 H, HBim), 6.59 (m, 2 H, HBim), 6.86 (s, 1 H, 4-
H), 7.12 (t, J = 7.5 Hz, 1 H, 4-HR1), 7.32 (t, J = 7.5 Hz, 2 H, 3,5-
HR1), 7.50 (d, J = 7.5 Hz, 2 H, 2,6-HR1).
1H NMR: d = 3.96 (s, 6 H, 2 × CH3), 7.26 (t, J = 7.5 Hz, 1 H, 4-HR1),
7.37 (s, 1 H, Hf), 7.44 (t, J = 7.5 Hz, 2 H, 3,5-HR1), 7.62 (d, J = 7.5
Hz, 2 H, 2,6-HR1), 7.65 (m, 2 H, HBim), 7.69 (s, 2 H, NH2), 8.02 (m,
2 H, HBim).
13C NMR: d = 33.4 (2 × CH3), 85.3 (NCHN), 94.5 (3-C), 106.2
(4,7-CBim), 108.2 (4-C), 119.2 (5,6-CBim), 121.9 (2,6-CR1), 125.7 (4-
CR1), 129.2 (3,5-CR1), 131.4 (1-CR1), 142.6 (5-C), 142.7 (3a,7a-
13C NMR: d = 33.1 (2 × CH3), 78.4 (3-Cf), 108.0 (4-Cf), 113.1 (4,7-
C
Bim), 122.7 (2,6-CR1), 126.2 (5,6-CBim), 127.2 (4-CR1), 129.4 (3,5-
CR1), 130.0 (1-CR1), 132.5 (3a,7a-CBim), 144.3 (5-Cf), 147.3 (2-Cf),
159.9 (2-CBim).
CBim), 157.5 (2-C).
Anal. Calcd for C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C,
74.53; H, 6.44; N, 13.70.
Anal. Calcd for C19H18N3OBr: C, 59.39; H, 4.72; N, 10.93; Br,
20.79. Found: C, 59.40; H, 4.53; N, 11.11; Br, 20.70.
3-(1,3-Dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)-5-(4-eth-
ylphenyl)-2-furanamine (5b)
Yield: 1.57 g (94%); mp 86 °C (i-PrOH).
2-[2-Amino-5-(4-ethylphenyl)-3-furanyl]-1,3-dimethyl-1H-
benzimidazolium Bromide (4b)
Yield: 3.91 g (95%); mp 268 °C (acetone).
1H NMR: d = 1.18 (t, J = 8.0 Hz, 3 H, CH3), 2.53 (s, 6 H, 2 × CH3),
2.58 (q, J = 8.0 Hz, 2 H, CH2), 4.90 (s, 1 H, NCHN), 5.79 (s, 2 H,
NH2), 6.41 (m, 2 H, HBim), 6.59 (m, 2 H, HBim), 6.74 (s, 1 H, 4-H),
7.17 (d, J = 8.0 Hz, 2 H, HR1), 7.41 (d, J = 8.0 Hz, 2 H, HR1).
1H NMR: d = 1.21 (t, J = 7.5 Hz, 3 H, CH3), 2.63 (q, J = 7.5 Hz, 2
H, CH2), 3.95 (s, 6 H, 2 × CH3), 7.26 (s, 1 H, Hf), 7.28 (d, J = 8.0
Hz, 2 H, HR1), 7.53 (d, J = 8.0 Hz, 2 H, HR1), 7.56 (s, 2 H, NH2), 7.66
(m, 2 H, HBim), 8.02 (m, 2 H, HBim).
13C NMR: d = 16.0 (CH3), 28.3 (CH2), 33.4 (2 × CH3), 85.3
(NCHN), 94.4 (3-C), 106.1 (4,7-CBim), 107.2 (4-C), 119.2 (5,6-
CBim), 122.0 (2,6-CR1), 128.5 (3,5-CR1), 129.0 (4-CR1), 141.3 (1-
CR1), 142.7 (3a,7a-CBim), 142.9 (5-C), 157.2 (2-C).
13C NMR: d = 15.9 (CH3), 28.4 (CH2), 33.1 (2 × CH3), 78.3 (3-Cf),
107.0 (4-Cf), 113.1 (4,7-CBim), 122.8 (2,6-CR1), 126.3 (5,6-CBim),
127.6 (4-CR1), 128.8 (3,5-CR1), 132.5 (3a,7a-CBim), 143.0 (1-CR1),
144.6 (5-Cf), 147.4 (2-Cf), 159.7 (2-CBim).
Anal. Calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C,
75.81; H, 6.75; N, 12.43.
Anal. Calcd for C21H22N3OBr: C, 61.17; H, 5.38; N, 10.19; Br,
19.38. Found: C, 61.16; H, 5.08; N, 10.18; Br, 19.51.
5-(4-Bromophenyl)-3-(1,3-dimethyl-2,3-dihydro-1H-benz-
imidazol-2-yl)-2-furanamine (5c)
Yield: 1.79 g (93%); mp 165 °C (EtOH).
2-[2-Amino-5-(4-bromophenyl)-3-furanyl]-1,3-dimethyl-1H-
benzimidazolium Bromide (4c)
Yield: 4.35 g (94%); mp 275 °C (acetone).
1H NMR: d = 2.53 (s, 6 H, 2 × CH3), 4.90 (s, 1 H, NCHN), 5.97 (s,
2 H, NH2), 6.41 (m, 2 H, HBim), 6.59 (m, 2 H, HBim), 6.92 (s, 1 H, 4-
H), 7.46 (d, J = 9.0 Hz, 2 H, HR1), 7.49 (d, J = 9.0 Hz, 2 H, HR1).
1H NMR: d = 3.95 (s, 6 H, 2 × CH3), 7.46 (s, 1 H, Hf), 7.55 (d,
J = 8.0 Hz, 2 H, HR1), 7.64 (m, 4 H, 2 × HR1, 2 × HBim), 7.75 (s, 2 H,
NH2), 8.02 (m, 2 H, HBim).
13C NMR: d = 33.4 (2 × CH3), 85.2 (NCHN), 94.6 (3-C), 106.2
(4,7-CBim), 109.4 (4-C), 118.0 (4-CR1), 119.3 (5,6-CBim), 123.7 (2,6-
CR1), 130.5 (1-CR1), 132.0 (3,5-CR1), 141.4 (5-C), 142.7 (3a,7a-
CBim), 157.9 (2-C).
13C NMR: d = 33.1 (2 × CH3), 78.6 (3-Cf), 109.1 (4-Cf), 113.1 (4,7-
C
Bim), 119.7 (4-CR1), 124.5 (2,6-CR1), 126.3 (5,6-CBim), 129.3 (1-
CR1), 132.3 (3,5-CR1), 132.5 (3a,7a-CBim), 143.2 (5-Cf), 147.1 (2-
Cf), 160.1 (2-CBim).
Anal. Calcd for C19H18N3OBr: C, 59.39; H, 4.72; N, 10.93; Br,
20.79. Found: C, 59.61; H, 4.53; N, 10.94; Br, 20.84.
Anal. Calcd for C19H17N3OBr2: C, 49.27; H, 3.70; N, 9.07; Br,
34.50. Found: C, 49.47; H, 3.70; N, 9.09; Br, 34.66.
3-(1,3-Dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)-5-(trifluo-
romethyl)-2-furanamine (5d)
Yield: 1.37 g (92%); mp 116 °C (MeCN).
2-[2-Amino-5-(trifluoromethyl)-3-furanyl]-1,3-dimethyl-1H-
benzimidazolium Bromide (4d)
Yield: 3.61 g (96%); mp 228 °C (acetone).
1H NMR: d = 2.52 (s, 6 H, 2 × CH3), 4.88 (s, 1 H, NCHN), 6.42 (m,
4 H, NH2, 2 × HBim), 6.60 (m, 2 H, HBim), 7.00 (s, 1 H, 4-H).
Synthesis 2010, No. 6, 1009–1013 © Thieme Stuttgart · New York

1012
A. V. Denisenko et al.
PAPER
13C NMR: d = 33.5 (2 × CH3), 84.8 (NCHN), 92.4 (3-C), 106.4
(4,7-CBim), 116.0 (4-C), 119.4 (5,6-CBim), 120.3 (q, JCF = 210.0 Hz,
CF3), 128.4 (q, JCF = 34.0 Hz, 5-C), 142.6 (3a,7a-CBim), 159.7 (2-C).
H, 3,5-HR1), 7.47 (d, J = 7.0 Hz, 2 H, 2,6-HR1), 7.70 (s, 1 H, CH=N),
9.64 (s, 1 H, CONH).
13C NMR: d = 94.1 (3-C), 107.4 (4-C), 121.9 (2,6-CR1), 125.9 (4-
CR1), 129.2 (3,5-CR1), 131.0 (1-CR1), 136.4 (CH=N), 142.2 (5-C),
156.7 (2-C), 157.4 (CONH2).
Anal. Calcd for C14H14F3N3O: C, 56.56; H, 4.75; N, 14.13. Found:
C, 56.72; H, 4.73; N, 14.16.
Anal. Calcd for C12H12N4O2: C, 59.01; H, 4.95; N, 22.94. Found: C,
59.03; H, 5.00; N, 22.89.
2-Amino-3-furancarboxaldehyde Phenylhydrazones 6a–c and
Semicarbazones 7a–c; General Procedure
A soln of a 2-furanamine 5a–c (4 mmol) and phenylhydrazine hy-
drochloride (0.87 g, 6 mmol) or semicarbazide hydrochloride (0.67
g, 6 mmol) in i-PrOH (10 mL) was refluxed for 2 h under argon at-
mosphere. Upon cooling, the mixture was diluted with H2O (30
mL); the solid that formed was collected by filtration and recrystal-
lized from a suitable solvent to give compound 6a–c or 7a–c.
2-Amino-5-(4-ethylphenyl)-3-furancarboxaldehyde Semicarba-
zone (7b)
Yield: 0.87 g (80%); mp 210 °C (EtOH).
1H NMR: d = 1.17 (t, J = 7.0 Hz, 3 H, CH3), 2.57 (q, J = 7.0 Hz, 2
H, CH2), 6.35 (br s, 2 H, CONH2), 6.73 (s, 2 H, 2-NH2), 6.85 (s, 1
H, 4-H), 7.18 (d, J = 7.0 Hz, 2 H, HR1), 7.39 (d, J = 7.0 Hz, 2 H,
HR1), 7.69 (s, 1 H, CH=N), 9.63 (s, 1 H, CONH).
2-Amino-5-phenyl-3-furancarboxaldehyde Phenylhydrazone
13C NMR: d = 16.0 (CH3), 28.3 (CH2), 94.0 (3-C), 106.4 (4-C),
122.1 (2,6-CR1), 128.5 (3,5-CR1), 128.6 (4-CR1), 136.5 (CH=N),
141.5 (1-CR1), 142.5 (5-C), 156.5 (2-C), 157.4 (CONH2).
(6a)
Yield: 0.65 g (59%); mp 190 °C (EtOH).
1H NMR: d = 6.57 (s, 2 H, NH2), 6.66 (t, J = 7.0 Hz, 1 H, 4-HR2),
6.97 (m, 3 H, 4-H, 2,6-HR2), 7.16 (m, 3 H, 4-HR1, 3,5-HR2), 7.35 (t,
J = 7.5 Hz, 2 H, 3,5-HR1), 7.52 (d, J = 7.5 Hz, 2 H, 2,6-HR1), 7.80 (s,
1 H, CH=N), 9.70 (s, 1 H, NH).
Anal. Calcd for C14H16N4O2: C, 61.75; H, 5.92; N, 20.57. Found: C,
61.70; H, 5.77; N, 20.60.
13C NMR: d = 95.8 (3-C), 106.4 (4-C), 111.9 (2,6-CR2), 117.9 (4-
CR2), 122.0 (2,6-CR1), 125.9 (4-CR1), 129.2 (3,5-CR1), 129.4 (3,5-
CR2), 131.1 (1-CR1), 133.8 (CH=N), 142.8 (1-CR2), 146.6 (5-C),
156.3 (2-C).
2-Amino-5-(4-bromophenyl)-3-furancarboxaldehyde Semicar-
bazone (7c)
Yield: 0.88 g (68%); mp 245 °C (DMF–H2O).
1H NMR: d = 6.35 (br s, 2 H, CONH2), 6.86 (s, 2 H, 2-NH2), 7.01
(s, 1 H, 4-H), 7.39 (d, J = 8.5 Hz, 2 H, HR1), 7.51 (d, J = 8.5 Hz, 2
H, HR1), 7.68 (s, 1 H, CH=N), 9.64 (s, 1 H, CONH).
Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.53; H, 5.49; N, 15.17.
13C NMR: d = 94.2 (3-C), 108.6 (4-C), 118.1 (4-CR1), 123.7 (2,6-
CR1), 130.2 (1-CR1), 132.1 (3,5-CR1), 136.2 (CH=N), 141.0 (5-C),
157.0 (2-C), 157.4 (CONH2).
2-Amino-5-(4-ethylphenyl)-3-furancarboxaldehyde Phenylhy-
drazone (6b)
Yield: 0.92 g (75%); mp 194 °C (EtOH).
Anal. Calcd for C12H11N4O2Br: C, 44.60; H, 3.43; N, 17.34; Br,
24.73. Found: C, 44.80; H, 3.55; N, 17.19; Br, 24.75.
1H NMR: d = 1.19 (t, J = 7.5 Hz, 3 H, CH3), 2.59 (q, J = 7.5 Hz, 2
H, CH2), 6.51 (s, 2 H, NH2), 6.65 (t, J = 7.5 Hz, 1 H, 4-HR2), 6.88
(s, 1 H, 4-H), 6.95 (d, J = 7.5 Hz, 2 H, 2,6-HR2), 7.18 (m, 4 H,
2 × HR1, 3,5-HR2), 7.44 (d, J = 7.5 Hz, 2 H, HR1), 7.78 (s, 1 H,
CH=N), 9.68 (s, 1 H, NH).
13C NMR: d = 16.0 (CH3), 28.3 (CH2), 95.7 (3-C), 105.5 (4-C),
111.9 (2,6-CR2), 117.9 (4-CR2), 122.2 (2,6-CR1), 128.6 (3,5-CR1),
128.7 (4-CR1), 129.4 (3,5-CR2), 133.8 (CH=N), 141.6 (1-CR1), 143.1
(1-CR2), 146.6 (5-C), 156.0 (2-C).
Furo[2,3-b]pyridine-5-carbonitriles 8a,c; General Procedure
A soln of 2-furanamine 5a or 5c (4 mmol), NH4Cl (0.03 g, 0.5
mmol) and malononitrile (0.4 g, 6 mmol) in i-PrOH (10 mL) was re-
fluxed for 2 h under argon atmosphere. After cooling, the mixture
was diluted with H2O (30 mL); the solid that precipitated was col-
lected by filtration and recrystallized from a suitable solvent to give
derivative 8a or 8c.
Anal. Calcd for C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C,
74.53; H, 6.30; N, 13.89.
6-Amino-2-phenylfuro[2,3-b]pyridine-5-carbonitrile (8a)
Yield: 0.65 g (69%); mp 203 °C (EtOH).
1H NMR: d = 7.15 (s, 1 H, 3-H), 7.31 (t, J = 7.0 Hz, 1 H, 4-HR1),
7.43 (t, J = 7.0 Hz, 2 H, 3,5-HR1), 7.53 (d, J = 7.0 Hz, 2 H, 2,6-HR1),
7.94 (s, 1 H, 4-H), 8.96 (s, 2 H, NH2).
2-Amino-5-(4-bromophenyl)-3-furancarboxaldehyde Phenyl-
hydrazone (6c)
Yield: 1.01 g (71%); mp 224 °C (AcOH).
13C NMR: d = 60.2 (5-C), 99.5 (3a-C), 101.3 (3-C), 117.3 (CN),
118.1 (4-CR1), 123.4 (2,6-CR1), 128.4 (4-C), 128.7 (1-CR1), 129.5
(3,5-CR1), 146.1 (2-C), 147.0 (6-C), 166.6 (7a-C).
1H NMR: d = 6.65 (m, 3 H, NH2, 4-HR2), 6.96 (d, J = 8.5 Hz, 2 H,
2,6-HR2), 7.04 (s, 1 H, 4-H), 7.17 (t, J = 8.5 Hz, 2 H, 3,5-HR2), 7.44
(d, J = 8.0 Hz, 2 H, HR1), 7.52 (d, J = 8.0 Hz, 2 H, HR1), 7.78 (s, 1
H, CH=N), 9.71 (s, 1 H, NH).
13C NMR: d = 96.0 (3-C), 107.6 (4-C), 111.9 (2,6-CR2), 117.9 (4-
CR2), 118.2 (4-CR1), 123.9 (2,6-CR1), 129.4 (3,5-CR2), 130.2 (1-CR1),
132.1 (3,5-CR1), 133.5 (CH=N), 141.6 (1-CR2), 146.5 (5-C), 156.6
(2-C).
Anal. Calcd for C14H9N3O: C, 71.48; H, 3.86; N, 17.86. Found: C,
71.47; H, 3.80; N, 17.63.
6-Amino-2-(4-bromophenyl)furo[2,3-b]pyridine-5-carbonitrile
(8c)
Yield: 0.77 g (61%); mp 210 °C (dioxane).
1H NMR: d = 7.19 (s, 1 H, 3-H), 7.47 (d, J = 8.5 Hz, 2 H, HR1), 7.61
(d, J = 8.5 Hz, 2 H, HR1), 7.96 (s, 1 H, 4-H), 9.00 (s, 2 H, NH2).
Anal. Calcd for C17H14N3OBr: C, 57.32; H, 3.96; N, 11.80; Br,
22.43. Found: C, 57.39; H, 3.72; N, 12.04; Br, 22.31.
13C NMR: d = 60.7 (5-C), 99.4 (3a-C), 102.3 (3-C), 117.1 (CN),
118.0 (4-CR1), 121.2 (1-CR1), 125.3 (2,6-CR1), 128.0 (4-C), 132.5
(3,5-CR1), 145.9 (2-C), 146.3 (6-C), 166.6 (7a-C).
2-Amino-5-phenyl-3-furancarboxaldehyde Semicarbazone (7a)
Yield: 0.73 g (75%); mp 180 °C (EtOH).
1H NMR: d = 6.37 (br s, 2 H, CONH2), 6.79 (s, 2 H, 2-NH2), 6.93
(s, 1 H, 4-H), 7.13 (t, J = 7.0 Hz, 1 H, 4-HR1), 7.34 (t, J = 7.0 Hz, 2
Anal. Calcd for C14H8N3OBr: C, 53.53; H, 2.57; N, 13.38; Br,
25.44. Found: C, 53.53; H, 2.45; N, 13.51; Br, 25.50.
Synthesis 2010, No. 6, 1009–1013 © Thieme Stuttgart · New York

PAPER
Synthesis of Masked 2-Amino-3-furancarboxaldehydes
1013
X-ray Crystal Structure Determination of Compound 4d
Suitable crystals of hemihydrate of 4d were grown from aq MeOH.
Intensities of 6371 reflections (2831 independent, Rint = 0.022)
were measured with an Xcalibur-3 diffractometer operating in the
w-2q scan mode, 2qmax = 50°, and using graphite monochromated
Mo Ka radiation (l = 0.71073 Å). The absorption correction was
performed using the multiscan method (Tmin = 0.425, Tmax = 0.882).
Crystal data: C14H13BrF3N3O·0.5H2O, Mr = 770.38, triclinic,
a = 8.2771(5) Å, b = 8.5196(3) Å, c = 12.9101(6) Å, a = 74.765°,
b = 97.480(5)°, g = 67.376°, V = 808.83(7) Å3, T = 293 K, space
group P1, Z = 2, m(Mo Ka) = 2.579 mm–1. The structure was solved
by direct methods using the SHELXTL program package.12 Posi-
tions of hydrogen atoms were located from electron-density differ-
ence maps and refined by riding model with Uiso = nUeq of the
carrier atom (n = 1.5 for the methyl groups, n = 1.2 for the rest of
the hydrogens). Full-matrix least-squares refinement against F2 in
anisotropic approximation for non-hydrogen atoms using 2796 re-
flections was converged to R1 = 0.038, wR2 = 0.093 [for 2102 re-
flections with F > 4s(F)], S = 0.951. Full crystallographic
parameters have been deposited with the Cambridge Crystallo-
graphic Data Centre under reference no. CCDC 748905. These data
can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
(4) (a) Raulin, F.; Toupance, G. Bull. Soc. Chim. Fr. 1975, 188.
(b) Jachak, M.; Kriessmann, U.; Mittelbach, M.; Junek, H.
Monatsh. Chem. 1993, 124, 199.
(5) (a) Safar, P.; Cepec, P.; Povazonek, F.; Korenova, A.;
Pronayova, N. Collect. Czech. Chem. Commun. 1994, 59,
2481. (b) Yasuda, H.; Hagashi, T.; Midorikawa, H. J. Org.
Chem. 1970, 35, 1234. (c) Offermann, W.; Eger, K.; Roth,
H. J. Arch. Pharm. (Weinheim, Ger.) 1981, 314, 168.
(d) Metwally, N. H. Synth. Commun. 2007, 37, 4227.
(6) (a) Craig, J. C.; Ekwuribe, N. N.; Fu, C. C.; Walker, K. A.
M. Synthesis 1981, 303. (b) Ramos, J. M.; Tarazi, M.;
Wuest, J. D. J. Org. Chem. 1987, 52, 5437. (c) Katritzky,
A. R.; Aslan, D. C.; Oniciu, D. C. Tetrahedron: Asymmetry
1998, 9, 2245. (d) Lee, I.-S. H.; Jeoung, E. H.; Kreevoy, M.
M. J. Am. Chem. Soc. 1997, 119, 2722. (e) Lee, I.-S. H.;
Jeoung, E. H. J. Org. Chem. 1998, 63, 7275.
(7) (a) Tverdokhlebov, A. V.; Denisenko, A. V.; Tolmachev, A.
A.; Volovenko, Yu. M. Synthesis 2007, 1811.
(b) Tverdokhlebov, A. V.; Denisenko, A. V.; Tolmachev, A.
A.; Volovenko, Yu. M.; Shishkina, S. V.; Shishkin, O. V.
Synthesis 2009, 1265.
(8) Rudnev, M. I.; Kurbatov, V. P.; Chub, N. K.; Osipov, O. A.
J. Gen. Chem. USSR (Engl. Transl.) 1988, 58, 2077; Zh.
Obshch. Khim. 1988, 58, 2334.
(9) (a) Lythgoe, D. L.; McClenaghan, I.; Ramsden, C. A.
J. Heterocycl. Chem. 1993, 30, 113. (b) Volochnyuk, D.
M.; Pushechnikov, A. O.; Krotko, D. G.; Sibgatulin, D. A.;
Kovalyova, S. A.; Tolmachev, A. A. Synthesis 2003, 1531.
(c) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Tolmachev, A. A. Synthesis 2007, 1861. (d) Bhupathy, M.;
Conlon, D. A.; Wells, K. M.; Nelson, J. R.; Reider, P. J.;
Rossen, K.; Sager, J. W.; Volante, R. P.; Dorsey, B. D.
J. Heterocycl. Chem. 1995, 32, 1283.
(10) (a) Makosza, M.; Tyrala, A. Acta Chem. Scand. 1992, 46,
689. (b) Snyder, H. R.; Ebenito, F. F. J. Heterocycl. Chem.
1966, 3, 202. (c) Charvat, T.; Potacek, M.; Marek, J.
Monatsh. Chem. 1995, 126, 333.
(11) (a) Ganesh, T.; Kumar, C. H.; Krupadanam, G. L. D. Synth.
Commun. 1999, 29, 2069. (b) Liberatore, A.-M.; Schulz, J.;
Favre-Guilmard, C.; Pommier, J.; Lannoy, J.; Pawlowski,
E.; Barthelemy, M.-A.; Huchet, M.; Auguet, M.; Chabrier,
P.-E.; Bigg, D. Bioorg. Med. Chem. Lett. 2007, 17, 1746.
(12) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
References
(1) For a review, see: Caluwe, P. Tetrahedron 1980, 36, 2359.
(2) (a) Mansour, T. S. Tetrahedron Lett. 1988, 29, 3437.
(b) Abdelrazek, F. M. J. Prakt. Chem. 1990, 332, 479.
(c) Antonov, D. M.; Belen’kiy, L. I.; Dudinov, A. A.;
Krayushkin, M. M. Chem. Heterocycl. Compd. (Engl.
Transl.) 1994, 30, 393; Khim. Geterotsikl. Soedin. 1994,
450. (d) Bakavoli, M.; Feizyzadeh, B.; Rahimizadeh, M.
Tetrahedron Lett. 2006, 47, 8965. (e) Korte, F.;Trautner, K.
Chem. Ber. 1962, 95, 307. (f) Temnikova, T. I.;
Kovalevskaya, R. N. Zh. Org. Khim. 1965, 1, 612.
(g) Blount, J. F.; Coffen, D. L.; Katonak, D. A. J. Org. Chem.
1978, 43, 3821.
(3) (a) Jachak, M.; Mittelbach, M.; Kriessmann, U.; Junek, H.
Synthesis 1992, 275. (b) Chu, C. K.; Watanabe, K. A.; Fox,
J. J. J. Heterocycl. Chem. 1980, 17, 1435. (c) Wermeckes,
B.; Beck, F. Chem. Ber. 1985, 118, 3771.
Synthesis 2010, No. 6, 1009–1013 © Thieme Stuttgart · New York