The sandmeyer reaction on some selected heterocyclic ring systems: Synthesis of useful 2-chloroheterocyclic-3-carbonitrile intermediates

Article abstract of DOI:10.1055/s-0030-1258149

The Sandmeyer reaction on some selected heterocycles bearing the 2-amino-3-carbonitrile structural moiety has been investigated in order to prepare the corresponding 2-chloro-3-carbonitrile derivatives as synthetic useful intermediates for further develop

Full text of DOI:10.1055/s-0030-1258149

PAPER
2725
The Sandmeyer Reaction on Some Selected Heterocyclic Ring Systems:
Synthesis of Useful 2-Chloroheterocyclic-3-carbonitrile Intermediates
2
-Chloroheterocyc
a
lic-3-carbo
n
nitriles by Sa
i
ndmey
e
er Reactionl da Silva,a,b Abdelouahid Samadi,*a Mourad Chioua,a Maria do Carmo Carreiras,b José Marco-Contelles*a
a
Laboratorio de Radicales Libres y Química Computacional (LRL/QC), IQOG (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain
Fax +33(91)5622900; fax +34(91)5644853; E-mail: samadi@iqog.csic.es; E-mail: iqoc21@iqog.csic.es
b
iMEd.UL, Research Institute for Medicines and Pharmaceutical Sciences, Fac. Pharmacy, Univ. Lisbon, Av. Forças Armadas,
1600-083 Lisbon, Portugal
Received 30 March 2010; revised 27 April 2010
CN
CN
Abstract: The Sandmeyer reaction on some selected heterocycles
bearing the 2-amino-3-carbonitrile structural moiety has been in-
vestigated in order to prepare the corresponding 2-chloro-3-carbo-
nitrile derivatives as synthetic useful intermediates for further
development.
R
N
Cl
Cl
HN
O
N
R
R
IV
V
Ar
Ar
Key words: Sandmeyer reaction, 2-amino(heterocyclic)-3-carbo-
nitriles, 2-aminopyrazoles, 2-aminooxazoles, 2-amino-4H-pyrans,
2-amino-1,4-dihydropyridines, 2-aminopyridines, 2-chloro(hetero-
cyclic)-3-carbonitriles
CN
Cl
CN
Cl
R
X
N
VI
(X = O, NH)
VII
In the context of a current project in progress in our labo-
ratory for the synthesis of pharmacological active com-
pounds,1 we have recently synthesized some differently
substituted 2-chloropyridine-3-carbonitrile intermediates
I by Sandmeyer reaction2 of easily available 2-aminopyri-
dine derivatives II (Scheme 1). Eventually, intermediates
I could also be prepared by reaction with sodium nitrite in
hydrochloric acid,3 or by reaction with phosphorus oxy-
chloride from 2-pyridones III.4
Figure 1 Heterocyclic ring systems 1V–VII studied in this work
this communication we describe the results we have ob-
tained in these transformations.
The Sandmeyer reaction2 is a well known protocol for the
preparation of aryl halides via the corresponding aryldia-
zonium halides, obtained from arylamines by diazotiza-
tion using sodium nitrite/hydrohalic acid in water, or alkyl
nitrites and anhydrous copper(II) halides under the condi-
tions reported by Doyle et al.7 The mechanism of the
Sandmeyer reaction seems to proceed by a radical mech-
anism, and catalytic for the copper(I) salt,8 where in a sin-
gle electron-transfer the diazonium salt is reduced to a
aryldiazenyl radical, which quickly loses nitrogen to give
an aryl radical, that reacts with the copper(II) salt com-
plexes and regenerates the copper(I) species.
R
R
R
CN
CN
O
CN
Cl
POCl3
Sandmeyer reaction
or
N
NH2
N
H
N
NaNO2, HCl
III
I
II
Scheme 1
Starting thus, with the readily available 3-amino-1-meth-
yl-1H-pyrazole-4,5-dicarbonitrile (1)9 (Figure 2), after
some experimentation, conditions (amine/isoamyl nitrite/
CuCl2, 1:1.51:1.46) were found in order to get the best re-
sults. Accordingly, the new 3-chloro-1-methyl-1H-pyra-
zole-4,5-dicarbonitrile (2) was obtained in 65% yield,
accompanied by minor amounts of 1-methyl-1H-pyra-
zole-4,5-dicarbonitrile (3) (Figure 2).
2-Chloro(heterocyclic)-3-carbonitriles are well known,
useful synthetic intermediates in heterocyclic chemistry
that have been transformed into complex and more ad-
vanced heterocyclic compounds.5 However, after check-
ing the current literature, we were much surprised to see
that compounds bearing the key 2-chloro-3-carbonitrile
structural moiety, installed in relevant heterocyclic ring
systems such as the pyrazolo, oxazolo, the highly poly-
functionalized 4H-pyran, 1,4-dihydropyridine, or pyridines,
have not been previously described.6 Consequently, we
decided to prepare compounds of type IV–VII (Figure 1),
that can be considered intermediates of high synthetic val-
ue, from the corresponding easily available 2-amino het-
erocyclic derivatives, using the Sandmeyer raction.2 In
Under the same experimental conditions, 5-amino-2-(4-
methoxyphenyl)oxazole-4-carbonitrile (4)10 gave the ex-
pected and new 5-chloro-2-(4-methoxyphenyl)oxazole-4-
carbonitrile (5) (Figure 2), albeit in low chemical yield
(13%) (Figure 2).
Next, a series of known and easily available polyfunction-
alized 4H-pyran derivatives have been investigated in the
Sandmeyer type reaction. Thus, ethyl 6-amino-5-cyano-2-
methyl-4-pyridin-3-yl-4H-pyran-3-carboxylate (6)11 gave
the corresponding and new 2-chloro derivative 7 in 40%
SYNTHESIS 2010, No. 16, pp 2725–2730
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258149; Art ID: P05210SS
© Georg Thieme Verlag Stuttgart · New York

2726
D. da Silva et al.
PAPER
CN
CN
N
NC
Me
X
X
O
N
N
MeO
4 X = NH2
1 X = NH2
2 X = Cl (65%)
3 X = H (21%)
5 X = Cl (13%)
N
S
EtO2C
CN
EtO2C
CN
X
t-BuO2C
CN
X
O
X
O
O
6 X = NH2
7 X = Cl (40%)
8 X = NH2
9 X = Cl (34%)
10 X = NH2
11 X = Cl (23%)
Y
Y
S
EtO2C
CN
X
EtO2C
CN
X
EtO2C
CN
X
EtO2C
CN
X
N
H
N
N
N
12 X = NH2, Y = F
14 X = NH2, Y = NO2
13 X = NH2, Y = F (49%)
15 X = Cl, Y = NO2 (15%)
16 X = NH2
17 X = Cl (64%)
18 X = NH2
19 X = Cl (67%)
X
NC
CN
Cl
NC
X
CN
EtO2C
CN
H2N
N
N
N
N
NH2
N
H
20a
20b X = NH2
21 X = Cl (52%)
22 X = NH2
23 X = Cl (69%)
24 X = NH2
25 X = Cl (10%)
Figure 2 Precursors and products from the Sandmeyer reaction
yield (Figure 2). Similarly, the thiophene-substituted 4H- To sum up, the Sandmeyer reaction, under the usual alkyl
pyran 8,11and the tert-butyl ester 4H-pyran 1012 gave the nitrite mediated conditions,7 is an efficient method for the
expected 2-chloro-4H-pyrans 9 and 11, respectively, in synthesis of 2-chloro substituted heterocyclic ring sys-
moderate yields (Figure 2).
tems from the corresponding 2-amino precursors, giving
the expected products in moderate to good yields. Very in-
terestingly, under our experimental conditions, no chlori-
nation products were observed at the benzylic positions,
or at the phenyl ring (precursor 16), in the heterocyclic
ring (precursor 20, 22, and 25), or in the heterocycle locat-
ed at C4 in the 4H-pyrano or the pyridine rings (precursors
6, 8, and 18). Only in one case (precursor 1) we have de-
tected the reduced compound 3, although its presence as
well as other secondary not isolated and not characterized
products could not be excluded in the Sandmeyer reac-
tions of precursors 4, 10, 12, and 24.
Interestingly, related 1,4-dihydropyridines (DHP) 1213
and 1413 did not afford the desired 2-chloro-DHPs. Not
unexpectedly, thus, the DHP 1213 was aromatized giving
the corresponding 2-aminopyridine 1314 as major product
and a trace of the corresponding 2-chloropyridine, while
DHP 1413 aromatized giving the corresponding 2-ami-
nopyridine, which after the in situ Sandmeyer reaction af-
forded the final 2-chloropyridine 15. The analytical and
spectroscopic data of the resulting products are in good
agreement with the 2-aminopyridine 1314 and 2-chloropy-
ridine 15, respectively (Figure 2). In fact, 2-aminopyri-
dine 1614 gave compound 17,15 whereas pyridine 1816
provided the new 2-chlorpyridine 19, in good yield
(Figure 2). Pyridine 20b [prepared by reacting 2-amino-6-
chloropyridine-3,5-dicarbonitrile (20a)1 with allylamine]
and 22,17 without an aryl ring at C4 provided also the ex-
pected 2-chloro derivatives 21 and 2318 in satisfactory
yields (Figure 2). Finally, tacrine (12),19 a potent cholin-
ergic agent, which has been employed for the treatment of
Melting points were determined on a microscope type apparatus,
and are uncorrected. 1H NMR and 13C NMR spectra were recorded
at r.t. in CDCl3 or DMSO-d6 at 300, 400, or 500 MHz and at 75, 100,
or 125 MHz, respectively, using solvent peaks [CDCl3: 7.26, 77.2
ppm; and DMSO-d6: 2.49, 40 ppm] as internal reference. The as-
signment of chemical shifts is based on standard NMR experiments
(1H, 1H-COSY, gHSQC, gHMBC). Mass spectra were recorded on
a GC/MS spectrometer with an API-ES ionization source. Elemen-
Alzheimer’s disease, under the same experimental condi- tal analyses were performed at CQO (CSIC, Spain). TLC was per-
formed on silica gel F254 and detection by UV light at 254 nm or
by charring with either ninhydrin or phosphomolybdic/H2SO4 dye-
tions, afforded the known 9-chloro-1,2,3,4-tetrahydro-
acridine (25) in low yield (Figure 2).
Synthesis 2010, No. 16, 2725–2730 © Thieme Stuttgart · New York

PAPER
2-Chloroheterocyclic-3-carbonitriles by Sandmeyer Reaction
2727
ing reagents. Anhyd solvents were used in all experiments. Column
chromatography was performed on silica gel 60 (230 mesh).
MS (EI): m/z = 234 (M)+, 206, 191, 171, 154, 133, 119, 111, 103,
90, 76, 63, 50.
MS (ESI): m/z = 235 (M + H)+, 201.
Sandmeyer Reaction; General Procedure
Anal. Calcd for C11H7ClN2O2: C, 56.31; H, 3.01; N, 11.94; Cl,
15.11. Found: C, 56.50; H, 3.22; N, 11.75; Cl, 14.98.
The corresponding 2-amino substituted heterocyclic precursor (1
equiv) and CuCl2 (1.5 equiv) were suspended in anhyd MeCN under
argon. Isoamyl nitrite (1.5 equiv) was added and the mixture heated
at 65 °C until TLC analysis showed complete reaction. The solution
was acidified with aq 2 N HCl to pH 3 and extracted with CH2Cl2
(3 × 75 mL). After drying the combined organic layers (Na2SO4),
the solvent was removed in vacuo, and the crude product purified
by flash column chromatography (for eluents of individual prod-
ucts, see below).
Ethyl 6-Chloro-5-cyano-2-methyl-4-pyridin-3-yl-4H-pyran-3-
carboxylate (7)
Following the General Procedure, ethyl 6-amino-5-cyano-2-meth-
yl-4-pyridin-3-yl-4H-pyran-3-carboxylate (6;11 155.2 mg, 0.54
mmol), CuCl2 (96.4 mg, 0.72 mmol), and isoamyl nitrite (0.110 mL,
0.79 mmol) were reacted in anhyd MeCN (10 mL) for 1 h. Flash
chromatography of the crude product using CH2Cl2–MeOH (0–1%)
as eluent afforded compound 7 (65.8 mg, 40%) as an oil.
Sandmeyer Reaction of 3-Amino-1-methyl-1H-pyrazole-4,5-di-
carbonitrile (1)
IR (KBr): 3445, 2988, 2221, 1729, 1678, 1626, 1488, 1479, 1426,
1380, 1322 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.5 (m, 2 H, H-2¢, H-6¢ py), 7.57
(dt, J = 1.6, 8.0 Hz, 1 H, H-4¢ py), 7.30 (m, 1 H, H-5¢ py), 4.61 (s, 1
H, H-4 pyran), 4.06 (q, J = 3.6 Hz, 2 H, OCH2CH3), 2.44 (s, 3 H,
CH3 pyran), 1.11 (t, J = 3.2 Hz, 3 H, OCH2CH3).
Following the General Procedure, 19 (104.0 mg, 0.71 mmol), CuCl2
(143.5 mg, 1.04 mmol), and isoamyl nitrite (0.15 mL, 1.07 mmol)
were reacted in anhyd MeCN (10 mL) for 13 min. Flash chromatog-
raphy of the crude product using hexane–EtOAc (9:1) as eluent
gave compounds 2 (75.9 mg, 65%) and 3 (19.5 mg, 21%).
13C NMR (CDCl3, 100 MHz): d = 164.4 (C=O), 159.5 (C-6 pyran),
149.4 (C-2 pyran), 149.2 (C-2¢ py), 149.1 (C-6¢ py), 136.8 (C-3¢ py),
135.5 (C-4¢ py), 123.9 (C-5¢ py), 114.7 (CN), 106.1 (C-3 pyran),
91.8 (C-5 pyran), 61.3 (OCH2CH3), 39.4 (C-4 pyran), 18.5 (CH3 py-
ran), 13.9 (OCH2CH3).
3-Chloro-1-methyl-1H-pyrazole-4,5-dicarbonitrile (2)
Mp 103–105 °C.
IR (KBr): 2226, 2244, 1533, 1423, 1410, 1289, 1107, 1038 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 4.08 (s, 3 H, NCH3).
13C NMR (100 MHz, DMSO-d6): d = 143.0 (C-3), 120.8 (C-5),
108.3 (CN C-4), 106.6 (CN C-5), 99.3 (C-4), 40.1 (NCH3).
MS (EI): m/z = 304 (M)+, 275 (M – CH2CH3)+, 259 (M –
OCH2CH3)+, 241, 226, 198.
MS (EI): m/z = 166 (M)+, 131 (M – Cl)+.
MS (ESI): m/z = 167 (M + H)+.
MS (ESI): m/z = 327 (M + Na)+, 305 (M + H)+.
Anal. Calcd for C15H13ClN2O3: C, 59.12; H, 4.30; N, 9.19; Cl,
11.63. Found: C, 58.94; H, 4.25; N, 9.01; Cl, 11.45.
Anal. Calcd for C6H3ClN4: C, 43.26; H, 1.82; N, 33.64; Cl, 21.28.
Found: C, 43.30; H, 2.11; N, 33.75; Cl, 21.07.
Ethyl 6-Chloro-5-cyano-2-methyl-4-(2-thienyl)-4H-pyran-3-
carboxylate (9)
1-Methyl-1H-pyrazole-4,5-dicarbonitrile (3)
Following the General Procedure, ethyl 6-amino-5-cyano-2-meth-
yl-4-(2-thienyl)-4H-pyran-3-carboxylate (8;11 150.7 mg, 0.52
mmol), CuCl2 (89.1 mg, 0.64 mmol), and isoamyl nitrite (0.110 mL,
0.79 mmol) were reacted in anhyd MeCN (8 mL) for 30 min. Flash
chromatography of the crude product using hexane–EtOAc (95:5)
as eluent gave compound 9 (54.5 mg, 34%) as an oil.
Mp 69–71 °C.
IR (KBr): 3124, 2242, 1798, 1532, 1488, 1448, 1398, 1285, 1188
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.36 (s, 1 H, H pyrazole), 4.07
(s, 3 H, NCH3).
13C NMR (100 MHz, DMSO-d6): d = 142.6 (C-3), 19.9 (C-5), 111.1
(CN C-4), 108.2 (CN C-5), 98.2 (C-4), 39.7 (NCH3).
IR (KBr): 3431, 2985, 2929, 2225, 1716, 1673, 1629, 1379, 1322,
1273 cm–1.
MS (EI): m/z = 132 (M)+, 131 (M – H)+,105 (M – CN) +.
MS (ESI): m/z = 133 (M + H)+.
1H NMR (400 MHz, CDCl3): d = 7.2 (m, 1 H, H-5 thienyl), 6.9 (m,
2 H, H-3, H-4 thienyl), 4.95 (s, 1 H, H-4¢ pyran), 4.1 (m, 2 H,
OCH2CH3), 2.41 (s, 3 H, CH3 pyran), 1.20 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
13C NMR (100 MHz, CDCl3): d = 164.8 (C=O), 158.7 (C-6 pyran),
148.9 (C-2 pyran), 144.8 (C-2¢ thienyl), 127.2 (C-4¢ thienyl), 125.8
(C-3¢, C-5¢ thienyl), 115.0 (CN), 107.1 (C-3 pyran), 92.3 (C-5 pyr-
an), 61.3 (OCH2CH3), 36.4 (C-4 pyran), 18.4 (CH3 pyran), 13.9
(OCH2CH3).
Anal. Calcd for C6H4N4: C, 54.54; H, 3.05; N, 42.41. Found: C,
54.36; H, 3.15; N, 42.35.
5-Chloro-2-(4-methoxyphenyl)oxazole-4-carbonitrile (5)
Following the General Procedure, 5-amino-2-(4-methoxyphe-
nyl)oxazole-4-carbonitrile (4;10 108.0 mg, 0.50 mmol), CuCl2 (79.9
mg, 0.58 mmol), and isoamyl nitrite (0.100 mL, 0.71 mmol) were
reacted in anhyd MeCN (10 mL) for 5 min. Flash chromatography
of the crude product using hexane–EtOAc (95:5) as eluent gave 5
(15.3 mg, 13%) as a white-yellowish solid; mp 119–121 °C.
MS (EI): m/z = 209 (M)+, 280 (M – CH2CH3)+, 263 (M –
OCH2CH3)+, 235 (M – CO2CH2CH3)+, 226 (M – thienyl)+, 200 (M
– Cl – OCH2CH3)+.
IR (KBr): 3436, 2918, 2847, 2237, 1612, 1586, 1557, 1500, 1442,
1426, 1310 cm–1.
1H NMR (400 MHz CDCl3): d = 7.92 (d, J = 8.8 Hz, 2 H, H-3, H-5
arom), 6.99 (d, J = 8.8 Hz, 2 H, H-2, H-6 arom), 3.92 (s, 3 H,
OCH3).
13C NMR (100 MHz CDCl3): d = 162.7 (C-4 arom), 161.7 (C-2 ox-
azole), 143.7 (C-5 oxazole), 128.5 (C-2¢, C-6¢ arom), 117.5 (C-1¢
arom), 114.6 (C-3¢, C-5¢ arom), 112.1 (CN), 110.8 (C-4 oxazole),
55.5 (OCH3).
MS (ESI): m/z = 310 (M + H)+.
Anal. Calcd for C14H12ClNO3S: C, 54.28; H, 3.90; N, 4.52; S, 10.35;
Cl, 11.45. Found: C, 54.00; H, 4.17; N, 4.58; S, 10.54; Cl, 11.24.
tert-Butyl 6-Chloro-5-cyano-2-methyl-4-phenyl-4H-pyran-3-
carboxylate (11)
Following the General Procedure, tert-butyl 6-amino-5-cyano-2-
methyl-4-phenyl-4H-pyran-3-carboxylate (10;12 150.4 mg, 0.48
mmol), CuCl2 (80.9 mg, 0.60 mmol), and isoamyl nitrite (0.110 mL,
Synthesis 2010, No. 16, 2725–2730 © Thieme Stuttgart · New York

2728
D. da Silva et al.
PAPER
Ethyl 6-Chloro-5-cyano-2-methyl-4-phenylnicotinate (17)
Following the General Procedure, ethyl 6-amino-5-cyano-2-meth-
yl-4-phenylnicotinate (16;14 198.9 mg, 0.71 mmol), CuCl2 (122.9
mg, 0.89 mmol), and isoamyl nitrite (0.15 mL, 1.08 mmol) were re-
acted in anhyd MeCN (16 mL) for 2 h. Flash chromatography of the
crude product using hexane–EtOH (10%) as eluent afforded 1715
(135.6 mg, 64%); mp 112–113 °C.
0.79 mmol) were reacted in anhyd MeCN (10 mL) for 15 min. Flash
chromatography using hexane–EtOAc (95:5) as eluent gave com-
pound 11 (36.3 mg, 23%); mp 101–103 °C.
IR (KBr): 3436, 2979, 2226, 1709, 1676, 1631, 1319, 1199, 1164,
1077 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.4–7.2 (m, 5 H, C6H5), 4.51 (s, 1
H, H-4 pyran), 2.39 (s, 3 H, CH3 pyran), 1.24 [s, 9 H, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 164.1 (C=O), 157.6 (C-6 pyran),
148.2 (C-2 pyran), 141.2 (C-1¢ Ph), 128.9 (C-3¢, C-5¢ Ph), 128.0 (C-
2¢, C-6¢ Ph), 127.9 (C-4¢ Ph), 115.3 (CN), 108.0 (C-3 pyran), 92.5
(C-5 pyran), 82.0 [C(CH3)3], 42.0 (C-4 pyran), 27.8 [C(CH3)3], 18.0
(CH3 pyran).
MS (EI): m/z = 331 (M)+, 304 (M – HNC)+, 277, 258, 240, 226, 198.
MS (ESI): m/z = 354 (M + Na)+, 332 (M + H)+.
IR (KBr): 2986, 2233, 1727, 1557, 1535, 1493, 1445, 1409, 1377,
1360, 1305 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.5–7.3 (m, 5 H, C6H5), 4.04 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 2.65 (s, 3 H, CH3 pyran), 0.91 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): d = 165.9 (C=O), 160.0 (C-2 py),
154.3 (C-4 py), 152.8 (C-6 py), 133.9 (C-1¢ Ph), 130.2 (C-4¢ Ph),
128.8 (C-3¢, C-5¢ Ph), 128.7 (C-3 py), 128.0 (C-2¢, C-6¢ Ph), 113.9
(CN), 108.3 (C-5 py), 62.2 (OCH2CH3), 23.2 (CH3), 13.4
(OCH2CH3).
Anal. Calcd for C18H18ClNO3: C, 65.16; H, 5.47; N, 4.22; Cl, 10.69.
Found: C, 65.02; H, 5.49; N, 4.50; Cl, 10.59.
MS (EI): m/z = 300 (M)+, 272 (M – CH2CH3)+, 255 (M –
OCH2CH3)+, 228 (M – CO2CH2CH3)+, 219, 191, 164.
Ethyl 6-Amino-5-cyano-2-methyl-4-(4-fluorophenyl)nicotinate
(13)
MS (ESI): m/z = 323 (M + Na)+, 301 (M + H)+.
Following the General Procedure, 1,4-dihydropyridine 1213 (159.2
mg, 0.53 mmol), CuCl2 (81.7 mg, 0.59 mmol), and isoamyl nitrite
(0.11 mL, 0.79 mmol) were reacted in anhyd MeCN (10 mL) for 5
min. Flash chromatography of the crude product using CH2Cl2–
MeOH (0–1%) afforded 1314 (71.4 mg, 49%); mp 216–218 °C.
Anal. Calcd for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31; Cl,
11.79. Found: 64.05; H, 4.27; N, 9.45; Cl, 11.68.
Ethyl 6-Chloro-5-cyano-2-methyl-2¢-thienylnicotinate (19)
Following the General Procedure, ethyl 6-amino-5-cyano-2-meth-
yl-4-(thiophen-2¢-yl)nicotinate (18;16 103.4 mg, 0.36 mmol), CuCl2
(59.1 mg, 0.43 mmol), and isoamyl nitrite (0.07 mL, 0.50 mmol)
were reacted in anhyd MeCN (10 mL) for 40 min. Flash chromatog-
raphy of the crude product using hexane–EtOAc (10%) as eluent af-
forded 19 (73.6 mg, 67%); mp 127–129 °C.
IR (KBr): 3398, 330, 3189, 2984, 2852, 2222, 1713, 1667, 1607,
1568, 1607 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.3 (m, 2 H, H¢-2, H¢-6 C6H4F),
7.25–7.11 (m, 2 H, H¢-3, H¢-5 C6H4F), 5.38 (s, 2 H, NH2), 3.99 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 2.52 (s, 3 H, CH3), 0.93 (t, J = 7.1 Hz,
3 H, OCH2CH3).
MS (EI): m/z = 299 (M)+, 284, 254, 227.
MS (ESI): m/z = 322 (M + Na)+, 300 (M + H).
IR (KBr): 3090, 2981, 2934, 2235, 1729, 1557, 1541, 1447, 1403,
1381, 1365 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59 (dd, J = 5.0, 1.0 Hz, 1 H, H-
5¢ thienyl), 7.35 (dd, J = 3.7, 1.0 Hz, 1 H, H-3¢ thienyl), 7.18 (dd,
J = 5.0, 3.8 Hz, 1 H, H-4¢ thienyl), 4.19 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 2.64 (s, 3 H, CH3 pyran), 1.11 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
13C NMR (CDCl3, 75 MHz): d = 166.3 (C=O), 160.4 (C-2 py),
153.7 (C-6 py), 147.3 (C-4 py), 133.4 (C-2¢ thienyl), 131.1 (C-3¢
thienyl), 130.4 (C-5¢ thienyl), 129.5 (C-3 py), 128.4 (C-4¢ thienyl),
114.5 (CN), 108.7 (C-5 py), 62.9 (OCH2CH3), 23.7 (CH3), 14.1
(OCH2CH3).
Anal. Calcd for C16H14N3O2F: C, 64.21; H, 4.71; N, 14.04. Found:
C, 64.02; H, 4.83; N, 14.10.
Ethyl 6-Chloro-5-cyano-2-methyl-4-(4-nitrophenyl)nicotinate
(15)
Following the General Procedure, 1,4-dihydropyridine 1413 (109.4
mg, 0.33 mmol), CuCl2 (58.1 mg, 0.42 mmol), and isoamyl nitrite
(0.07 mL, 0.50 mmol) were reacted in anhyd MeCN (10 mL) for 5
min. Flash chromatography of the crude product using CH2Cl2–
MeOH (0–0.4%) afforded 15 (16.9 mg, 15%) as an oil.
MS (EI): m/z = 306 (M)+, 291 (M – CH3)+, 277 (M – CH2CH3)+, 260
(M – OCH2CH3)+, 234 (M – CO2CH2CH3)+, 225 (M – thienyl)+,
197, 163.
IR (KBr): 3112, 2926, 2855, 2238, 1723, 1604, 1561, 1527, 1497,
1471, 1446 cm–1.
1H NMR (CDCl3, 500 MHz): d = 8.37 (d, J = 8.8 Hz, 2 H, H-3¢, H-
5¢ arom), 7.57 (d, J = 8.8 Hz, 2 H, H-2¢, H-6¢ arom), 4.09 (q, J = 7.1
Hz, 2 H, OCH2CH3), 2.70 (s, 3 H, CH3), 1.00 (t, J = 7.1 Hz, 3 H, 3
H, OCH2CH3).
13C NMR (CDCl3, 125 MHz): d = 165.3 (C=O), 161.1 (C-2 py),
153.4 (C-4 py), 151.9 (C-6 py), 149.0 (C-4¢ arom), 140.2 (C-1¢
arom), 129.6 (C-2¢, C-6¢ arom), 128.3, 124.2 (C-3¢, C-5¢ arom),
113.5 (CN), 108.1 (C-5 py), 62.7 (OCH2CH3), 23.6 (CH3), 13.8
(OCH2CH3).
MS (ESI): m/z = 329 (M + Na)+, 307 (M + H)+.
Anal. Calcd for C14H11ClN2O2S: C, 54.81; H, 3.61; N, 9.13; S,
10.45; Cl, 11.56. Found: C, 55.02; H, 3.90; N, 9.26; S, 10.39; Cl,
11.68.
2-(Allylamino)-6-chloropyridine-3,5-dicarbonitrile (21)
Allylamination of 20a to 20b: 2-Amino-6-chloropyridine-3,5-dicar-
bonitrile (20a;1 0.54 g, 3 mmol) was suspended in a mixture of
THF–EtOH (30 mL, 3:1). Prop-2-en-1-amine (0.27 mL, 3.6 mmol)
was then added, followed by Et3N (0.916 mL, 6 mmol). The mixture
was then heated under reflux for 1 h, then at r.t. overnight. The sol-
vent was removed in vacuo and the resulting crude submitted to
flash column chromatography (10% of EtOAc in CH2Cl2), to give
20b (0.60, 99%) as a white solid; mp 135–137 °C.
MS (EI): m/z = 345 (M)+, 328, 317 (M – CH2CH3)+, 300 (M –
OCH2CH3)+, 272 (M – CO2CH2CH3)+, 254, 191, 164.
MS (ESI): m/z = 346 (M + H)+.
Anal. Calcd for C16H12ClN3O4: C, 55.58; H, 3.50; N, 12.15; Cl,
10.25. Found: C, 55.49; H, 3.61; N, 12.08; Cl, 10.30.
IR (KBr): 3341, 3226, 2208, 1631, 1602, 1578, 1509, 1478, 1305,
1269 cm–1.
Synthesis 2010, No. 16, 2725–2730 © Thieme Stuttgart · New York

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2-Chloroheterocyclic-3-carbonitriles by Sandmeyer Reaction
2729
1H NMR (400 MHz, CDCl3): d = 7.65 (s, 1 H, 4-H), 5.92–5.83 (m,
1 H, =CH), 5.71 (br s, 1 H, NH), 5.50 (br s, 2 H, NH2), 5.25–5.15
(m, 2 H, =CH2), 4.09–4.05 (m, 2 H, NCH2).
1.4 Hz, 1 H, H-6 arom), 7.54 (ddd, J = 8.2, 6.9, 1.2 Hz, 1 H, H-7
arom), 3.13 (t, J = 5.5 Hz, 2 H, H-4 cyclohexyl), 3.02 (t, J = 5.7 Hz,
2 H, H-1 cyclohexyl), 1.9 (s, 4 H, H-2, H-3 cyclohexyl).
13C NMR (100 MHz, CDCl3): d = 160.7 (C-6), 159.1 (C-2), 146.1
(C-4), 133.4 (=CH), 117.2 (=CH2), 116.4 (CN), 116.2 (CN), 82.0,
79.6 (C-3, C-5), 43.0 (NCH2).
MS (EI): m/z = 217 (M)+, 182 (M – Cl)+.
MS (ESI): m/z = 218 (M + H)+.
Anal. Calcd for C13H12ClN: C, 71.72; H, 5.56; N, 6.43; Cl, 16.29.
Found: 71.57; H, 5.47; N, 6.41; Cl, 16.04.
MS (ES): m/z (%) = 200.2 (100, [M + H]+), 222.2 (31, [M + Na]+).
Anal. Calcd for C10H7N5: C, 60.29; H, 4.55; N, 35.16. Found: C,
60.19; H, 4.61; N, 34.99.
Acknowledgment
Sandmeyer Reaction of 20b: Following the General Procedure, 20b
(150.6 mg, 0.76 mmol), CuCl2 (88.5 mg, 0.64 mmol), and isoamyl
nitrite (0.12 mL, 0.86 mmol) were reacted in anhyd MeCN (10 mL)
for 25 min. Flash chromatography of the crude product using hex-
ane–EtOAc (5–30%) as eluent afforded 21 (71.7 mg, 52%); mp
168–170 °C.
Daniel da Silva thanks Fundação para a Ciência e Tecnologia do
Ministério da Ciência, Tecnologia e Ensino Superior of Portugal for
the grant belonging to project PTDC/SAU-NEU/64151/2006 M.
Chioua thanks ISCIII (MICINN) for a post-doctoral fellowship. A.
Samadi thanks CSIC for a I3P post-doctoral contract. JMC thanks
MICINN (SAF2006-08764-C02-01; SAF2009-07271), Comunidad
de Madrid (S/SAL-0275-2006), and ISCIII [Retic RENEVAS
(RD06/0026/1002)] for support.
IR (KBr): 3325, 2227, 1601, 1582, 1498, 1397, 1341, 1323, 1272
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.87 (s, 1 H, H-4 py), 6.03 (s, 1 H,
NH), 5.9 (m, 1 H, =CH), 5.3–5.2 (m, 2 H, =CH2), 4.19 (t, J = 5.8
Hz, 2 H, NCH2).
13C NMR (100 MHz, CDCl3): d = 157.9 (C-2 py), 156.8 (C-6 py),
146.1 (C-4 py), 132.1 (=CH), 118.4 (=CH2), 114.4 (CN C-5 py),
114.0 (CN C-3 py), 97.5 (C-3 py), 90.6 (C-5 py), 44.3 (NCH2).
References
(1) Chioua, M.; Samadi, A.; Soriano, E.; Lozach, O.; Meijer, L.;
Marco-Contelles, J. Bioorg. Med. Chem. Lett. 2009, 19,
4566.
(2) (a) Hodgson, H. H. Chem. Rev. 1947, 40, 251.
(b) Merkushev, E. B. Synthesis 1988, 923.
MS (EI): m/z = 218 (M)+, 203 (M – CH3), 191 (M – HCN), 164, 143,
128.
(3) Troschütz, R.; Karger, A. J. Heterocyl. Chem. 1996, 33,
1815.
(4) Elkasaby, M. A.; Elshahed, F. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1981, 20, 428.
MS (ESI): m/z = 219 (M + H)+.
Anal. Calcd for C10H7ClN4: C, 54.93; H, 3.23; N, 25.62; Cl, 16.22.
Found: C, 54.71; H, 3.40; N, 25.91; Cl, 15.95.
(5) (a) 3-Chloroquinoxaline-2-carbonitrile: Ortega, M. A.;
Montoya, M. E.; Zarranz, B.; Jaso, A.; Aldana, I.; Leclerc,
S.; Meijer, L.; Monge, A. Bioorg. Med. Chem. Lett. 2002,
10, 2177. (b) 2,6-Dichloro-5-fluoronicotinonitrile: Repine,
J. T.; Johnson, D. S.; Stuk, T.; White, A. D.; Stier, M. A.; Li,
T.; Yang, Z.; Maiti, S. N. Tetrahedron Lett. 2007, 48, 8189.
(c) 2-Chloro-6-methoxy-4-phenylpyridine-3,5-dicarbo-
nitrile: Quintela, J. M.; Soto, J. L. An. Quim. 1984, 80, 268.
(6) For the synthesis and reactivity of related ethyl 4-aryl-6-
chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carbox-
ylates, see: (a) Verdecia, Y.; Suárez, M.; Morales, A.;
Rodríguez, E.; Ochoa, E.; González, L.; Martín, N.;
Quinteiro, M.; Seoane, C.; Soto, J. L. J. Chem. Soc., Perkin
Trans. 1 1996, 947. (b) See also: Ojea, V.; Peinador, C.;
Quintela, J. M. Synthesis 1992, 798.
Ethyl 6-Chloro-5-cyano-2-methylnicotinate (23)
Following the General Procedure, ethyl 6-amino-5-cyano-2-meth-
ylnicotinate (22;17 153.8 mg, 0.75 mmol), isoamyl nitrite (0.15 mL,
1.07 mmol), and CuCl2 (133.4 mg, 0.99 mmol) were reacted in an-
hyd MeCN (10 mL) for 25 min. Flash chromatography of the crude
product using hexane–EtOAc (5%) as eluent gave 2318 (116.1 mg,
69%) as a yellowish-white solid; mp 62–64 °C.
IR (KBr): 3060, 2983, 2929, 2239, 1723, 1585, 1533, 1415, 1275,
1242, 1110 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.48 (s, 1 H, H-4 py), 4.40 (q,
J = 7.1 Hz, 1 H, OCH2CH3), 2.88 (s, 3 H, CH3 pyran), 1.41 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): d = 165.2 (C-2 py), 163.7 (C=O),
153.7 (C-6 py), 144.6 (C-4 py), 124.6 (C-3 py), 114.1 (CN), 108.1
(C-5 py), 62.3 (OCH2CH3), 25.1 (CH3), 14.1 (OCH2CH3).
(7) Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem.
1977, 42, 2426.
(8) Kochi, J. K. J. Am. Chem. Soc. 1957, 79, 2942.
(9) Dickenson, C. L.; Williams, J. K.; McKusick, B. C. J. Org.
Chem. 1964, 29, 1915.
MS (EI): m/z = 224 (M)+, 209 (M – CH3), 196 (M – CH2CH3), 179
(M – OCH2CH3), 152 (M – CO2CH2CH3), 124, 116.
MS (ESI): m/z = 225 (M + H)+.
(10) Freeman, F.; Kim Darrick, S. H. L. Tetrahedron Lett. 1989,
30, 2631.
Anal. Calcd for C10H9ClN2O2: C, 53.47; H, 4.04; N, 12.47; Cl,
15.78. Found: 53.47; H, 4.29; N, 12.43; Cl, 15.74.
(11) León, R.; Marco-Contelles, J.; García, A. G.; Villarroya, M.
Bioorg. Med. Chem. 2005, 13, 1167.
(12) Srivastava, S.; Batra, S.; Bhaduri, A. P. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1996, 35, 602.
(13) Marco-Contelles, J.; Leon, R.; de los Ríos, C.; Samadi, A.;
Bartolini, M.; Andrisano, V.; Huertas, O.; Barril, X.; Luque,
F. J.; Rodríguez-Franco, M. I.; Lopez, B.; López, M. G.;
García, A. G.; Carreiras, M. C.; Villarroya, M. J. Med.
Chem. 2009, 52, 2724.
9-Chloro-1,2,3,4-tetrahydroacridine (25)
Following the General Procedure, 1,2,3,4-tetrahydroacridin-9-
amine (24;19 140.1 mg, 0.71 mmol), CuCl2 (119.7 mg, 0.86 mmol),
and isoamyl nitrite (0.15 mL, 1.06 mmol) were reacted in anhyd
MeCN (10 mL) for 2 h. Flash chromatography of the crude product
using hexane–EtOAc (20%) as eluent afforded 2520 (14.6 mg,
10%); mp 65–67 °C.
(14) Marco, J. L.; de los Ríos, C.; García, A. G.; Villarroya, M.;
Carreiras, M. C.; Martins, C.; Eleuterio, A.; Morreale, A.;
Orozco, M.; Luque, F. J. Bioorg. Med. Chem. 2004, 12,
2199.
IR (KBr): 2929, 2866, 1578, 1554, 1481, 1394 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.17 (dd, J = 8.4, 1.1 Hz, 1 H, H-
8 arom), 7.98 (d, J = 8.3 Hz, 1 H, H-5 arom), 7.66 (ddd, J = 8.4, 6.9,
Synthesis 2010, No. 16, 2725–2730 © Thieme Stuttgart · New York

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D. da Silva et al.
PAPER
(18) Zhao, C.; Tovar, C.; Yin, X.; Xu, Q.; Todorov, I. T.;
Vassilev, L. T.; Chen, L. Bioorg. Med. Chem. Lett. 2009, 19,
319.
(19) Girgis, N. S.; Pedersen, E. B. Synthesis 1985, 547.
(20) Elsinghorst, P. W.; Haertig, W.; Goldhammer, S.; Grosche,
J.; Gütschow, M. Org. Biomol. Chem. 2009, 7, 3940.
(15) Elkasaby, M. A.; Elshahed, F. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1981, 20, 428.
(16) León, R.; Marco-Contelles, J.; García, A. G.; Villarroya, M.
Bioorg. Med. Chem. 2005, 13, 1167.
(17) Goldfarb, D. S. US Patent 2009163545, 2009; Chem. Abstr.
2009, 151, 92842.
Synthesis 2010, No. 16, 2725–2730 © Thieme Stuttgart · New York