Synthesis of 6-Amino-2-bromo-4-hydroxynicotinaldehyde derivatives

Article abstract of DOI:10.1055/s-0030-1258371

Acylation of (1,3-dimethylbenzimidazol-2-ylidene)-, (3-methylbenzothiazol- 2-ylidene)-, and (3,4-dimethylthiazol-2-ylidene)-acetonitriles with 1-(cyanoacetyl)-3,5-dimethylpyrazole was found to proceed at the exocyclic carbon atom, yielding the appropriate 2-heterylidene-3-oxopentanedinitriles. Treatment of the prepared dinitriles with hydrobromic acid in refluxing acetic acid afforded 2-(6-amino-2-bromo-4-hydroxypyridin-3-yl)-substituted quaternary salts of benzimidazolium, benzothiazolium, and thiazolium. Their structures were confirmed unambiguously by X-ray crystallographic studies. Reduction of these quaternary salts with excess sodium borohydride yielded the corresponding dihydro (in the case of benzoazoles) or tetrahydro (in the case of thiazole) derivatives, which were shown to be synthetic equivalents of the title nicotinaldehyde. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258371

PAPER
251
Synthesis of 6-Amino-2-bromo-4-hydroxynicotinaldehyde Derivatives
6
-Amino-2-bromo
l
-4-hydr
e
oxynicotin
x
aldehyde ander 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 +380445373253; E-mail: atver@univ.kiev.ua
STC Institute for Single Crystals, NAS of Ukraine, 60 Lenina ave., 61001 Kharkiv, Ukraine
c
Received 26 October 2010
the reduction of 2-bromonicotinonitriles with diisobutyl-
aluminum hydride.1a,2b,d,3c This is a mild and convenient
procedure that is only limited by the availability of the
corresponding bromonitriles. The third approach is based
Abstract: Acylation of (1,3-dimethylbenzimidazol-2-ylidene)-,
(3-methylbenzothiazol-2-ylidene)-, and (3,4-dimethylthiazol-2-
ylidene)-acetonitriles with 1-(cyanoacetyl)-3,5-dimethylpyrazole
was found to proceed at the exocyclic carbon atom, yielding the ap-
propriate 2-heterylidene-3-oxopentanedinitriles. Treatment of the on aldehyde group formation from a methyl group
prepared dinitriles with hydrobromic acid in refluxing acetic acid
through radical bromination or chlorination and further
transformation of the halomethyl moiety.5 However, this
afforded 2-(6-amino-2-bromo-4-hydroxypyridin-3-yl)-substituted
quaternary salts of benzimidazolium, benzothiazolium, and thiazo-
method is not practical because of the long stepwise se-
lium. Their structures were confirmed unambiguously by X-ray
quences and harsh conditions.5b,c Finally, Vilsmeyer
crystallographic studies. Reduction of these quaternary salts with
formylation of certain 2-bromo-6-dialkylamino-pyridines
was reported.3d,e This approach seems to be promising but,
thus far, the amount of published data does not allow its
scope and limitations to be accurately assessed.
excess sodium borohydride yielded the corresponding dihydro (in
the case of benzoazoles) or tetrahydro (in the case of thiazole) de-
rivatives, which were shown to be synthetic equivalents of the title
nicotinaldehyde.
The N,N¢-dimethylbenzimidazolium6 and N-methyl-
benzothiazolium7 moieties are well known as synthetic
equivalents of aldehyde functionality. Their reduction
into 2,3-dihydro derivatives yields the masked formyl
group,6,7 which can, if necessary, be liberated by hydrolyt-
ic cleavage.6a,7 Recently, we successfully employed such
an approach for the preparation of masked aldehydes of
pyrrole 1,8a furan 2,8b and certain fused pyrrole 38c cores
(Figure 1). The corresponding quaternary salt precursors
of compounds 1–3 were obtained from the readily avail-
able nitriles 4a and 4b.9 Continuing our research in the
field, we examined the application of compounds 4 to the
synthesis of aldehydes of pyridine series and report the re-
sults herein.
Key words: aldehydes, heterocycles, hydrazones, nitriles, py-
ridines
2-Bromopyridine-3-carbaldehydes are known as versatile
building blocks in modern chemistry.1–3 Multifarious re-
activity of the aldehyde group1 combined with the possi-
bility of various cross-coupling reactions of the bromine2
offers great opportunities for chemical modifications in-
cluding different rings annulations.1a,d,2c–e,3 A number of
efforts in this field have provided particularly useful re-
sults. Thus, potent melanocortin1a and endothelin
receptor2d,3d,e antagonists have been obtained starting
from suitable 2-bromonicotinaldehyde derivatives. More-
over, some of these substances were prepared in multi-ki-
logram scales for clinical studies2d,3d and, for this purpose,
large-scale syntheses (tens of kilograms) of the appropri-
ate bromonicotinaldehyde precursors were elaborated.2d,3d
Thus, the search for new approaches to the 2-bromopyri-
dine-3-carbaldehyde core that allows the introduction of
additional functionalities seems to be an important task.
Me
O
Me
R2
N
N
N
O
X
R1
O
N
Me
H2N
Me H2N
2
N
1
Z
N
N
To date, four general methods for achieving the target nic-
otinaldehyde derivatives are known. The first and most
popular approach includes lithiation of 2-bromopyridines,
followed by the trapping of the metalated species with
N,N-dimethylformamide.1b–e,2c,e,3b,4 However, despite
wide use, the lithiation conditions do not tolerate many
functional groups, thus the reaction requires multiple pro-
tection, which reduces its value. The second approach is
Me H2N
3
Figure 1 Previously prepared masked aldehydes. X = NMe or S;
R1 = alkyl or Ar; R2 = CF3 or Ar; Z = CH2 or S.
The reaction of 1,5-dinitriles with HBr is known to give 2-
bromopyridine derivatives,10–12 and it has been well docu-
mented for aliphatic,10 aromatic,11 and heterocyclic11c,12
dinitriles. Treatment of compounds 4a and 4b with cy-
anoacetic acid pyrazolide 513 was found to yield 1,5-dini-
triles 6a and 6b, respectively (Scheme 1). It should be
noted that the pyrazolide 5 was widely used for the acyl-
SYNTHESIS 2011, No. 2, pp 0251–0256
x
x
.
x
x
.2
0
1
1
Advanced online publication: 20.12.2010
DOI: 10.1055/s-0030-1258371; Art ID: P16110SS
© Georg Thieme Verlag Stuttgart · New York

252
A. V. Denisenko et al.
PAPER
Br
N
X
NH2
HO
Me
Br–
CN
N+
CN
X
CN
CN
O
N
Me
Me
N
O
N
N
X
7
5
HBr, AcOH
NH2
N
4a,b
6a,b
NH2
Br
HO
Me
Br–
CN
N+
X
N • HBr
CN
S
CN
O
Br
HO
5
HBr, AcOH
Me
Me
Me
Br–
N+
S
N
N
S
8a,b
4c
6c
8c
Scheme 1 Synthesis and reaction of 1,5-dinitriles with HBr. a: X = NMe, b: X = S.
ation of various amines and for the preparation of a range selectively, leading to the formation of a single com-
of cyanoacetamide derivatives.14 To the best of our pound. Since the spectral data did not allow the isomers 7
knowledge, the present synthesis of derivatives 6 is the and 8 to be distinguished, an X-ray crystallographic study
first example of a C-acylation reaction with compound 5. was carried out to assign the structure unambiguously
However, it was the predictable result, since nitriles 4a (Figure 2). This study clearly revealed the products to be
and 4b were previously shown to react with certain elec- the 2-bromo-6-aminopyridine derivatives 8a and 8b.
trophiles at the exocyclic carbon atom.8,9a,15
It was apparent that the reaction occurred through initial
With the dinitriles 6a and 6b in hand, their cyclization selective HBr addition to the appropriate nitrile (1-CN)
with hydrobromic acid was studied. Formally, it could af- and further ring closure at the expense of intramolecular
ford two isomeric pyridines, 7 and 8. In the literature, for addition of the formed imidoyl bromide salt moiety to the
unsymmetrical 1,5-dinitriles, both selective10b,11,12d,f and second nitrile group (5-CN). The latter was accompanied
unselective12a,b,e cyclizations have been described. Never- with a positive charge transfer to the benzoazole moiety.
theless, in the present case, the reaction appeared to occur A higher reactivity towards HBr of 1-CN versus 5-CN is
explained by the conjugation of 1-CN with the electron
pair of the benzoazole nitrogen, which facilitates protona-
tion of the nitrile, the primary act of HBr addition.
The sequence was extended to the new derivative 4c,
which was successfully converted into the corresponding
dinitrile 6c in the same manner (Scheme 1). Treatment of
6c with hydrobromic acid furnished a product with 1H and
13C NMR spectra that were similar to those of derivatives
8a and 8b, and were consistent with the structure 8c.
However, elemental analysis indicated a significant ex-
cess of bromine, which approximately corresponded to
the presence of an additional bromine atom. To clarify this
point, an X-ray crystallographic study was performed
(Figure 3), which revealed that the product did indeed
have the quaternary salt structure 8c, but that it was ob-
tained with an additional hydrobromide salt at the pyri-
dine moiety. Perhaps the better solubility in the reaction
mixture of compound 8c compared to its analogues 8a and
8b caused its precipitation as the hydrobromide salt dur-
ing isolation.
Figure 2 X-ray molecular structure of compound 8a·H2O with the
atom numbering used in the crystallographic analysis. The asymme-
tric part of the crystal unit cell contains one organic cation and two
bromide anions located in special positions on the symmetry elements
(two-fold axis). The population of each bromide anion is 0.5, there-
fore the total charge is –1. The organic salt exists as the monohydrate
in the crystal phase. The water molecule is disordered over two posi-
tions with equal populations and its one position coincides with the
symmetry element (two-fold axis).
Synthesis 2011, No. 2, 251–256 © Thieme Stuttgart · New York

PAPER
6-Amino-2-bromo-4-hydroxynicotinaldehyde
253
To summarize, the present study has resulted in the syn-
thesis of new polyfunctional nicotinaldehyde derivatives,
namely the masked 2-bromo-6-amino-4-hydroxynicoti-
naldehydes 9a–c. For the first time, aldehyde functional-
ity has been brought into the pyridine core in the form of
a quaternary benzoazolium salt. Furthermore, the thiazo-
lium salt 8c has been shown to be also applicable for this
purpose. Generally, nitriles 4 were established to be suit-
able precursors for the synthesis of unique heterocyclic al-
dehydes 1–3 and 9.8 Their synthetic potential is believed
not to be exhausted and, therefore, further investigations
in the field are in progress.
Nitriles 4a, 4b,9 and pyrazolide 513 were prepared according to the
described procedures. Other reagents were commercially available.
All melting points were determined in open capillary tubes with a
Thiele apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded with a Bruker Avance 500 (500 MHz for 1H and 125 MHz
for 13C) spectrometer in DMSO-d6 solutions. Chemical shifts (d) are
given in ppm downfield from internal TMS; J values are in Hz. To
obtain clear spectra, in the case of compounds 9a–c, samples should
be analyzed as soon as possible after sample preparation. In the
spectral assignments, hydrogen and carbon atoms of the pyridine
core are marked with subscript Py, while the atoms of other (hete-
ro)aromatic moities are referred with subscript Ar. Elemental anal-
yses were performed at the Microanalytical Department of the
Figure 3 X-ray molecular structure of compound 8c·HBr·2H2O
with the atom numbering used in the crystallographic analysis.
Reduction of the quaternary salts 8a and 8b with excess
sodium borohydride afforded the target masked nicotin-
aldehyde derivatives 9a and 9b, respectively in 30–55%
overall yield calculated from the nitriles 4 (Scheme 2). In
the case of compound 8c, the same reaction resulted in
complete reduction of the thiazolium ring and formation
of the thiazolidine analogue 9c. It is noteworthy that sim-
ilar reductions of other thiazolium salts were observed
previously.16 The structures of the prepared compounds
Institute of Organic Chemistry, NAS, Kiev, Ukraine. The purities of
9a–c were confirmed by H and 13C NMR spectroscopic all compounds were checked by H NMR spectroscopic analysis
1
1
and by LC/MS analysis on an Agilent 1100 instrument.
analysis. Their aldehyde nature was demonstrated by for-
mation of the appropriate phenylhydrazone 10 and semi-
(3,4-Dimethylthiazol-2-ylidene)acetonitrile (4c)
carbazone 11 upon treatment of derivatives 9a–c with
(4-Methylthiazol-2-yl)acetonitrile17 (13.8 g, 0.10 mol) and dimethyl
sulfate (16.4 g, 0.13 mol) were mixed without a solvent and heated
phenylhydrazine and semicarbazide, respectively. Prepa-
ration of the same compounds 10 and 11 starting from all
the derivatives 9a–c is good additional evidence for their
structural assignments. It should be emphasized that better
yields of compounds 10 and 11 were achieved by carrying
out the reactions under an argon atmosphere because of a
tendency of derivatives 9a–c to oxidize. Indeed, benzimi-
dazoline 9a was found to be sensitive towards air, and ox-
idized significantly within several hours. Fortunately, the
thiazole analogues 9b and 9c were found to be more stable
and could be stored in air for several weeks without sig-
nificant changes. Hence, since the yields of compounds
9a–c were comparable, the thiazole derivatives 9b and 9c
seem to be more convenient nicotinaldehyde equivalents
for practical use.
on a water bath at 70–75 °C for 1.5–2 h, until the initially formed
melt had solidified. Upon cooling, the solid was dissolved in H2O
(100 mL) and aq NaOH (10%, 50 mL) was added; this resulted in
the separation of an oil, which quickly solidified. The solid was fil-
tered and recrystallized from i-PrOH to give compound 4c.
Yield: 10.8 g (71%); mp 116 °C.
1H NMR: d = 2.10 (s, 3 H, CH3), 3.12 (s, 3 H, NCH3), 4.22 (s, 1 H,
CHCN), 6.19 (s, 1 H, 5-H).
13C NMR: d = 14.3 (CH3), 32.6 (NCH3), 50.7 (CHCN), 97.0 (5-C),
122.7 (CN), 139.0 (4-C), 165.5 (2-C).
Anal. Calcd for C7H8N2S: C, 55.23; H, 5.30; N, 18.40; S, 21.06.
Found: C, 55.25; H, 5.18; N, 18.36; S, 21.10.
2-Heterylidene-3-oxopentanedinitriles 6a–c; General Proce-
dure
A solution of compound 4a–c (30 mmol) and the pyrazolide 5 (6.36
Me
N
HO
R
for 8a,b
HN
NH2
OH
N
X
N
Br
9a,b
R-NH-NH2
NaBH4
8a–c
NH2
N
10,11
Br
Me
N
HO
for 8c
NH2
S
N
Br
9c
Scheme 2 Reduction of the quaternary salts. a: X = NMe, b: X = S. 10: R = Ph, 11: R = CONH2.
Synthesis 2011, No. 2, 251–256 © Thieme Stuttgart · New York

254
A. V. Denisenko et al.
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2-(6-Amino-2-bromo-4-hydroxypyridin-3-yl)-3-methylben-
zothiazolium Bromide (8b)
Yield: 5.94 g (95%); mp 260 °C (DMF).
1H NMR: d = 4.22 (s, 3 H, CH3), 4.58 (br s, 2 H, NH2, exch. D2O),
6.19 (s, 1 H, 5-HPy), 7.30 (br s., 1 H, OH, exch. D2O), 7.94 (m, 1 H,
ArH), 8.01 (m, 1 H, ArH), 8.45 (d, J = 8.5 Hz, 1 H, ArH), 8.64 (d,
J = 8.0 Hz, 1 H, ArH).
13C NMR: d = 38.0 (CH3), 90.1 (5-CPy), 101.3 (3-CPy), 118.6 (4-
CAr), 125.5 (6-CAr), 129.6 (5-CAr), 130.5 (7-CAr), 131.9 (7a-CAr),
139.4 (2-CPy), 141.6 (4a-CAr), 159.9 (4-CPy), 161.4 (6-CPy), 169.7
(2-CAr).
g, 39 mmol) in anhydrous dioxane (40 mL) was heated at reflux for
3 h. After cooling, the solution was diluted with i-PrOH (80 mL)
and the precipitate formed was filtered, washed with i-PrOH (15
mL) and recrystallized from an appropriate solvent yielding deriva-
tives 6a–c.
2-(1,3-Dimethyl-2,3-dihydrobenzimidazol-2-ylidene)-3-oxopen-
tanedinitrile (6a)
Yield: 5.90 g (78%); mp 196 °C (EtOH).
1H NMR: d = 3.78 (s, 6 H, 2 × CH3), 4.03 (s, 2 H, CH2), 7.52 (m,
2 H, ArH), 7.80 (m, 2 H, ArH).
13C NMR: d = 29.3 (CH2), 33.3 (2 × NCH3), 59.0 (2-C), 112.4 (4,7-
CAr), 117.2 (CN), 121.5 (CN), 125.5 (5,6-CAr), 132.2 (3a,7a-CAr),
151.4 (2-CAr), 177.7 (3-CO).
Anal. Calcd for C13H11Br2N3OS: C, 37.43; H, 2.66; N, 10.07; Br,
38.31; S, 7.69. Found: C, 37.32; H, 2.54; N, 10.10; Br, 38.40; S,
7.91.
Anal. Cacld for C14H12N4O: C, 66.66; H, 4.79; N, 22.21. Found: C,
66.60; H, 4.99; N, 22.34.
2-(6-Amino-2-bromo-4-hydroxypyridin-3-yl)-3,4-dimethylthia-
zolium Bromide Hydrobromide (8c)
2-(3-Methylbenzothiazol-2(3H)-ylidene)-3-oxopentanedinitrile
Yield: 5.75 g (83%); mp 232 °C (DMF–i-PrOH, 1:1).
(6b)
1H NMR: d = 2.64 (s, 3 H, CH3), 3.83 (s, 3 H, NCH3), 4.62 (br s,
2 H, NH2, exch. D2O), 6.16 (s, 1 H, 5-HPy), 7.27 (br s., 1 H, OH,
exch. D2O), 8.29 (s, 1 H, ArH), 10.47 (br s, detected by integration
only, 1 H, N·HBr).
13C NMR: d = 14.5 (CH3), 38.1 (NCH3), 89.9 (5-CPy), 101.7 (3-CPy),
123.4 (5-CAr), 140.0 (2-CPy), 147.2 (4-CAr), 159.5 (4-CPy), 161.6 (6-
CPy), 164.7 (2-CAr).
Yield: 3.60 g (47%); mp 262 °C (EtOH).
1H NMR: d = 4.19 (s, 3 H, CH3), 4.21 (s, 2 H, CH2), 7.47 (t,
J = 8.0 Hz, 1 H, ArH), 7.63 (t, J = 8.0 Hz, 1 H, ArH), 7.78 (d,
J = 8.0 Hz, 1 H, ArH), 8.03 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR: d = 30.3 (CH2), 36.4 (CH3), 75.9 (2-C), 113.8 (4-CAr),
116.3 (CN), 119.5 (CN), 123.2 (6-CAr), 125.5 (7-CAr), 126.6 (7a-
CAr), 128.2 (5-CAr), 140.3 (3a-CAr), 165.8 (2-CAr), 182.0 (3-CO).
Anal Calcd for C10H11Br2N3OS·HBr: C, 26.00; H, 2.62; N, 9.10; Br,
51.89; S, 6.94. Found: C, 26.14; H, 2.60; N, 9.11; Br, 51.64; S, 7.12.
Anal. Calcd for C13H9N3OS: C, 61.16; H, 3.55; N, 16.46; S, 12.56.
Found: C, 61.21; H, 3.38; N, 16.31; S, 12.50.
Masked 6-Amino-2-bromo-4-hydroxynicotinaldehydes 9a–c;
General Procedure
2-(3,4-Dimethylthiazol-2(3H)-ylidene)-3-oxopentanedinitrile
(6c)
Yield: 5.46 g (83%); mp 208 °C (MeOH).
1H NMR: d = 2.34 (s, 3 H, CH3), 3.91 (s, 3 H, NCH3), 4.16 (s, 2 H,
CH2), 7.10 (s, 1 H, ArH).
13C NMR: d = 14.4 (CH3), 29.5 (CH2), 36.9 (NCH3), 74.2 (2-C),
109.3 (5-CAr), 116.6 (CN), 120.3 (CN), 140.7 (4-CAr), 164.7 (2-
CAr), 180.0 (3-CO).
NaBH4 (3.04 g, 70 mmol) was added cautiously in portions to an
ice-cooled and stirred solution of the salt 8a–c (7 mmol) in aqueous
MeOH (20 mL; MeOH–H2O, 7:3). After the addition was complete,
the mixture was stirred at 0–5 °C for 1 h. The precipitate formed
was filtered, washed with H2O (10 mL) and recrystallized from an
appropriate solvent to give derivatives 9a–c.
6-Amino-2-bromo-3-(1,3-dimethyl-2,3-dihydrobenzimidazol-2-
yl)pyridin-4-ol (9a)
Yield: 1.03 g (44%); mp 230 °C (i-PrOH).
Anal. Calcd for C10H9N3OS: C, 54.78; H, 4.14; N, 19.16; S, 14.62.
Found: C, 54.85; H, 4.09; N, 19.20; S, 14.82.
1H NMR: d = 2.62 (s, 6 H, 2 × CH3), 5.34 (s, 1 H, NCHN), 5.85 (s,
1 H, 5-HPy), 6.40 (s, 2 H, NH2), 6.59 (m, 2 H, ArH), 6.71 (m, 2 H,
ArH), 10.49 (s, 1 H, OH).
13C NMR: d = 33.3 (2 × CH3), 90.1 (NCHN), 93.1 (5-CPy), 104.2
(4,7-CAr), 108.4 (3-CPy), 117.2 (5,6-CAr), 141.6 (3a,7a-CAr), 141.7
(2-CPy), 159.9 (4-CPy), 164.8 (6-CPy).
Quaternary Salts 8a–c; General Procedure
Compounds 6a–c (15 mmol) were dissolved in 40% HBr in acetic
acid (30 mL, obtained by saturation of acetic acid with gaseous
HBr) and the resulting solution was heated at reflux for 10 min.
Upon cooling, the mixture was diluted with acetone (50 mL) and the
solid precipitated was filtered, washed with cold acetone (10 mL)
and recrystallized from a suitable solvent, affording derivatives
8a–c.
Anal. Calcd for C14H15BrN4O: C, 50.17; H, 4.51; N, 16.71; Br,
23.84. Found: C, 50.24; H, 4.60; N, 16.54; Br, 23.76.
2-(6-Amino-2-bromo-4-hydroxypyridin-3-yl)-1,3-dimethyl-
benzimidazolium Bromide (8a)
Yield: 6.03 g (97%); mp 300 °C (DMF).
6-Amino-2-bromo-3-(3-methyl-2,3-dihydrobenzothiazol-2-
yl)pyridin-4-ol (9b)
Yield: 2.04 g (86%); mp 218 °C (i-PrOH).
1H NMR: d = 3.95 (s, 6 H, 2 × CH3), 4.93 (br s, 2 H, NH2, exch.
D2O), 6.23 (s, 1 H, 5-HPy), 7.37 (br s, 1 H, OH, exch. D2O), 7.79 (m,
2 H, ArH), 8.16 (m, 2 H, ArH).
1H NMR: d = 2.62 (s, 3 H, CH3), 5.85 (s, 1 H, SCHN), 6.31 (s, 2 H,
NH2), 6.39 (s, 1 H, 5-HPy), 6.58 (m, 2 H, ArH), 6.92 (t, J = 6.5 Hz,
1 H, ArH), 6.97 (d, J = 6.5 Hz, 1 H, ArH, 10.60 (s, 1 H, OH).
13C NMR: d = 33.0 (2 × CH3), 90.0 (5-CPy), 97.0 (3-CPy), 114.3 (4,7-
CAr), 127.6 (5,6-CAr), 132.2 (3a,7a-CAr), 140.4 (2-CPy), 146.5 (4-
CPy), 160.3 (6-CPy), 162.0 (2-CAr).
13C NMR: d = 33.1 (CH3), 73.3 (NCHS), 93.6 (5-CPy), 108.8 (3-
CPy), 116.5 (4-CAr), 118.3 (7-CAr), 120.9 (5-CAr), 125.7 (6-CAr),
126.4 (7a-CAr), 141.8 (2-CPy), 148.5 (3a-CAr), 160.5 (4-CPy), 166.0
(6-CPy).
Anal. Calcd for C14H14Br2N4O: C, 40.61; H, 3.41; N, 13.53; Br,
38.59. Found: C, 40.60; H, 3.42; N, 13.30; Br, 38.52.
Anal. Calcd for C13H12BrN3OS: C, 46.17; H, 3.58; N, 12.42; Br,
23.62; S, 9.48. Found: C, 46.23; H, 3.60; N, 12.50; Br, 23.82; S,
9.41.
Synthesis 2011, No. 2, 251–256 © Thieme Stuttgart · New York

PAPER
6-Amino-2-bromo-4-hydroxynicotinaldehyde
255
6-Amino-2-bromo-3-(3,4-dimethylthiazolidin-2-yl)pyridin-4-ol
(9c)
Yield: 1.90 g (89%); mp 138 °C (MeCN).
1H NMR: d = 1.25 (d, J = 4.0 Hz, 3 H, CH3), 2.30 (s, 3 H, NCH3),
2.81 (m, 2 H, SCH2), 3.15 (m, 1 H, NCH), 5.14 (s, 1 H, SCHN),
5.73 (s, 1 H, 5-HPy), 6.20 (s, 2 H, NH2), 12.80 (s, 1 H, OH).
is 1.38 Å. Full-matrix least-squares refinement against F2 in aniso-
tropic approximation for non-hydrogen atoms using 2826 reflec-
tions converged to R1 = 0.054, wR2 = 0.134 [for 2141 reflections
with F >4s(F)], S = 0.974. Full crystallographic parameters have
been deposited with the Cambridge Crystallographic Data Centre
under reference number CCDC 796000.
13C NMR: d = 18.8 (CH3), 36.8 (SCH2), 37.2 (NCH3), 64.0 (NCH),
73.9 (SCHN), 93.5 (5-CPy), 107.7 (3-CPy), 141.1 (2-CPy), 160.6 (4-
CPy), 166.3 (6-CPy).
X-ray Crystal Structure Determination of Compound 8c
Intensities of 18303 reflections (4963 independent, Rint = 0.047)
were measured with an Xcalibur-3 diffractometer in the w-2Q scan
mode, 2Qmax = 60°, using graphite monochromated Mo-Ka radia-
tion (l = 0.71073 Å). The absorption correction was performed
using the multiscan method (Tmin = 0.260, Tmax = 0.699). Crystal
data: [C10H12N3OBrS]2+·2Br–·2H2O; Mr = 498.05; monoclinic;
a = 7.5513(3) Å, b = 11.0491(3) Å, c = 20.7868(7) Å,
b = 97.941(3)°; V = 1717.7(1) Å3; T = 293 K; space group P21/c;
Z = 4; m (Mo-Ka) = 7.175 mm–1. The structure was solved by direct
method using the SHELXTL program package.18 Positions of hy-
drogen atoms were located from electron density difference maps
and refined by the riding model with Uiso = nUeq of the carrier atom
(n = 1.5 for the methyl groups and water, n = 1.2 for the rest of hy-
drogens). Full-matrix least-squares refinement against F2 in aniso-
tropic approximation for non-hydrogen atoms using 4938
reflections converged to R1 = 0.036, wR2 = 0.061 [for 2784 reflec-
tions with F >4s(F)], S = 0.857. Full crystallographic parameters
have been deposited with the Cambridge Crystallographic Data
Centre under reference number CCDC 796001.
Anal. Calcd for C10H14BrN3OS: C, 39.48; H, 4.64; N, 13.81; Br,
26.27; S, 10.54. Found: C, 39.33; H, 4.57; N, 13.80; Br, 26.39; S,
10.52.
Phenylhydrazone 10 and Semicarbazone 11; General Proce-
dure
A solution of compound 9a–c (3.0 mmol) and phenylhydrazine hy-
drochloride (0.48 g, 3.3 mmol) or semicarbazide hydrochloride
(0.37 g, 3.3 mmol) in i-PrOH (10 mL) was heated at reflux under
argon atmosphere for 2 h. After cooling, the mixture was poured
into H2O (30 mL) and the solid that separated was filtered, washed
with H2O (5 mL) and recrystallized from a suitable solvent to yield
derivatives 10 and 11.
6-Amino-2-bromo-4-hydroxynicotinaldehyde Phenylhydra-
zone (10)
Yield: 0.67 g (73%); mp 231 °C (i-PrOH–H2O, 2:1).
1H NMR: d = 5.92 (s, 1 H, 5-HPy), 6.60 (s, 2 H, NH2), 6.80 (t,
J = 8.0 Hz, 1 H, ArH), 6.84 (d, J = 8.0 Hz, 2 H, ArH), 7.26 (t,
J = 8.0 Hz, 2 H, ArH), 8.26 (s, 1 H, N=CH), 10.54 (s, 1 H, OH),
12.32 (s, 1 H, NH).
13C NMR: d = 92.7 (5-CPy), 106.5 (3-CPy), 111.9 (2,6-CAr), 119.8 (4-
CAr), 129.9 (3,5-CAr), 140.4 (1-CAr), 141.7 (CH=N), 144.5 (2-CPy),
159.9 (4-CPy), 165.2 (6-CPy).
References
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(d) Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen,
D. M.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer,
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9658. (e) Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis
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Anal. Calcd for C12H11BrN4O: C, 46.93; H, 3.61; N, 18.24; Br,
26.01. Found: C, 46.84; H, 3.63; N, 18.12; Br, 26.24.
6-Amino-2-bromo-4-hydroxynicotinaldehyde Semicarbazone
(11)
Yield: 0.54 g (66%); mp 251 °C (MeOH).
1H NMR: d = 5.86 (s, 1 H, 5-HPy), 6.30 (s, 2 H, NH2), 6.62 (s, 2 H,
CONH2), 8.21 (s, 1 H, CH=N), 10.34 (s, 1 H, OH), 11.73 (br s, 1 H,
CONH).
13C NMR: d = 93.3 (5-CPy), 109.1 (3-CPy), 140.2 (CH=N), 143.5 (2-
CPy), 158.2 (CO), 159.4 (4-CPy), 165.6 (6-CPy).
Anal. Calcd for C7H8BrN5O2: C, 30.68; H, 2.94; N, 25.55; Br,
29.15. Found: C, 30.65; H, 3.13; N, 25.54; Br, 29.05.
(3) (a) de la Fuente, M. C.; Dominguez, D. Tetrahedron 2009,
65, 3653. (b) Srinivasan, J. M.; Bruks, H. E.; Smith, C. R.;
Viswanatan, R.; Johnston, J. N. Synthesis 2005, 330.
(c) Chelucci, G.; Addis, D.; Baldino, S. Tetrahedron Lett.
2007, 48, 3359. (d) Kato, Y.; Niiyama, K.; Nemoto, T.;
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X-ray Crystal Structure Determination of Compound 8a
Intensities of 9696 reflections (2913 independent, Rint = 0.040)
were measured with an Xcalibur-3 diffractometer in the w-2Q scan
mode, 2Qmax = 50°, using graphite monochromated Mo-Ka radia-
tion (l = 0.71073 Å). The absorption correction was performed
using the multiscan method (Tmin = 0.564, Tmax = 0.615). Crystal
data: [C14H14N4OBr]+Br–·H2O; Mr = 1708.4; orthorhombic;
a = 7.1595(4) Å, b = 20.634(1) Å, c = 22.631(1) Å; V = 3343.3(3)
Å3; T = 293 K; space group C2221; Z = 2; m(Mo-Ka) = 4.859 mm–1.
The structure was solved by direct method using the SHELXTL
program package.18 Positions of hydrogen atoms were located from
electron density difference maps and refined by the riding model
with Uiso = nUeq of the carrier atom (n = 1.5 for the methyl groups
and water, n = 1.2 for the rest of hydrogens). The disordered water
molecule was refined isotropically. During the refinement, a re-
straint was placed on the bond lengths in the benzene ring, CAr–CAr
Synthesis 2011, No. 2, 251–256 © Thieme Stuttgart · New York

256
A. V. Denisenko et al.
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