Synthesis of 4-amino-3,5-dicyano-arylpyrazoles, part 2: Isolation and characterization of by-products

Article abstract of DOI:10.1080/00397911.2010.543304

Reaction of (dicyanomethylidene-hydrazino)benzoic acids with chloroacetonitrile, under basic conditions, gave cyanomethyl-3-(7-amino-3,5- dicyano-1H-pyrazolo[4,3-d] pyrimidin-1-yl-benzoates and para-substituted cyanomethyl benzoates, in addition to the expected cyanomethyl 3-(4-amino-3,5-dicyano-1H-pyrazol-1-yl)-benzoates. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.543304

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Synthesis of 4-Amino-3,5-dicyano-
arylpyrazoles, Part 2: Isolation and
Characterization of By-Products
M. S. T. Gonçalves a , A. M. F. Oliveira-Campos a , L. M. Rodrigues a &
M. F. R. P. Proença a
a Chemistry Centre, University of Minho, Campus de Gualtar ,
Braga , Portugal
Accepted author version posted online: 17 Nov 2011.Published
online: 03 Feb 2012.
To cite this article: M. S. T. Gonçalves , A. M. F. Oliveira-Campos , L. M. Rodrigues & M. F. R. P.
Proença (2012) Synthesis of 4-Amino-3,5-dicyano-arylpyrazoles, Part 2: Isolation and Characterization
of By-Products, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:11, 1695-1703, DOI: 10.1080/00397911.2010.543304
To link to this article: http://dx.doi.org/10.1080/00397911.2010.543304
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Synthetic Communications1, 42: 1695–1703, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.543304
SYNTHESIS OF 4-AMINO-3,5-DICYANO-
ARYLPYRAZOLES, PART 2: ISOLATION AND
CHARACTERIZATION OF BY-PRODUCTS
M. S. T. Gonc¸alves, A. M. F. Oliveira-Campos,
L. M. Rodrigues, and M. F. R. P. Proenc¸a
Chemistry Centre, University of Minho, Campus de Gualtar, Braga, Portugal
GRAPHICAL ABSTRACT
Abstract Reaction of (dicyanomethylidene-hydrazino)benzoic acids with chloroacetonitrile,
under basic conditions, gave cyanomethyl-3-(7-amino-3,5-dicyano-1H-pyrazolo[4,3-d]
pyrimidin-1-yl-benzoates and para-substituted cyanomethyl benzoates, in addition to the
expected cyanomethyl 3-(4-amino-3,5-dicyano-1H-pyrazol-1-yl)-benzoates.
Keywords Aminocyanopyrazoles; aminopyrazoles; malononitrile; pyrazolo[4,3-d]-
pyrimidines
INTRODUCTION
Pyrazole derivatives are well recognized for their biological activities as
potential HIV-1 inhibitors, antiviral, anticancer agents, insecticides, and
fungicides.[1–4]
Pyrazole fused-heterocycles, namely pyrazolo[4,3-d]pyrimidine derivatives, are
also of great interest as potential biologically active molecules. Several members of
this class exhibit recognized pharmacological activities for treatment of thromboem-
bolic disorders, with affinity at adenosine receptors for the treatment of bronchocon-
striction and cardiac insufficiency, as well as Hsp90 inhibitory activity.[5–7]
A classical method of pyrazole synthesis involves the reaction between hydra-
zines and b-difunctional compounds, and it was applied to the preparation of 4-
amino-1-phenyl-1H-pyrazole-3,5-dicarbonitrile 1 (Fig. 1).[8] This methodology was
initially used by our research group to synthesize aminocyanopyrazoles containing
a carboxylic ester group, such as compounds 2 (Fig. 1).[9] Following this successful
Received October 27, 2010.
Address correspondence to M. S. T. Gonc¸alves, Chemistry Center, University of Minho, Campus
de Gualtar, 4710-057, Braga, Portugal. E-mail: msamciro@quimica.uminho.pt
1695

1696
M. S. T. GONC¸ ALVES ET AL.
Figure 1. Structure of pyrazoles 1 and 2.
Scheme 1. Synthesis of pyrazoles 4 and their secondary products.
work, similar heterocyclic compounds 4 containing a cyano group in the pyrazole ring
replacing the ethyl ester were obtained by the same route[10] (Scheme 1). The synthesis
started by diazotisation of m-aminobenzoic acids and further reaction of the resulting
diazonium salts with malononitrile giving (dicyanomethylidene-hydrazino)benzoic
acids 3, which cyclized by treatment with chloroacetonitrile in dimethylformamide
(DMF), triethylamine being used as the base.[8] When the results obtained by heating
the reaction mixtures at reflux for short periods (5–15 min) were compared to those of
heating at 80–90 ꢀC for longer times (1–4 h), it was found that in some cases, the last
procedure led to lower yields, and this was attributed to possible decomposition (as
monitored by thin-layer chromatography TLC) and=or formation of by-products,
which was not investigated at that point.
As part of our research interest in the synthesis and study of pyrazoles and their
related fused heterocycles,[9–14] it was decided to reconsider the previously reported
synthesis and use other bases, namely 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
and sodium hydride. The products were identified as the pyrazolo[4,3-d]pyrimidines
5, the para-substituted cyanomethyl benzoates 6, and the expected pyrazoles 4.[10]
RESULTS AND DISCUSSION
3-[2-(Dicyanomethylene)hydrazinyl]-(5-(un)substituted)-benzoic
acids
3,
obtained by diazotization of the corresponding aminobenzoic acids followed by
reaction with malononitrile,[10] were reacted with chloroacetonitrile in DMF using
a non-nucleophilic organic base or an inorganic base, namely DBU or sodium
hydride, respectively (Scheme 1). After purification by column chromatography in
silica gel, pyrazolo[4,3-d]pyrimidines 5 and para-substituted cyanomethyl benzoates
6 were isolated simultaneously with the expected pyrazoles 4, in variable yields, as

4-AMINO-3,5-DICYANO-ARYLPYRAZOLES
1697
shown in Table 1. The open chain ester, such as compound 7, was observed in all the
experiments on TLC, but only 7a was quantitatively determined for the reaction
from 3-[2-(dicyanomethylene)hydrazinyl]benzoic acid 3a.
Cyclization of 3-[2-(dicyanomethylene)hydrazinyl]benzoic acid 3a using sodium
hydride added stepwise gave the best yields for the pyrazoles 4a and pyrazolo[4,3-
d]pyrimidine 5a, and the cyanomethylester 7a was also isolated (Table 1, entry 1).
Starting from precursor 3b and using the same base, pyrazolo[4,3-d]pyrimidine 5b
was obtained in addition to the pyrazole 4b and the cyanomethyl ester 6b (Table 1,
entry 3).
When these reactions were repeated under the same conditions, they were
not reproducible. Thus, it was decided to use DBU as the base when the yields of
pyrazoles 4a and 4b were 17% and 21%, respectively (Table 1, entries 2 and 4).
The cyclization of 3c with DBU gave a poor yield of the pyrazole 4c, and this
preparation was repeated for a shorter period with a minute improvement (Table 1,
entries 5 and 6). Reaction under the same conditions with the methoxylated
compound 3d gave the lowest yield and it was decided to repeat the reaction using
a larger excess of base and no solvent. However, this gave a slight improvement only
(Table 1, entries 7 and 8).
Compounds 5 and 6 were fully characterized by high-resolution mass spec-
trometry (HRMS) or elemental analysis, IR, and NMR (1H and 13C) spectroscopy.
Compounds 4 [10] and 7a[9] were described previously.
The main feature on the 1H NMR spectra for pyrazolo[4,3-d]pyrimidines 5a–d
is the position of the NH2 that moves to 7.41–7.45 (acetone-d6) or to 8.16–8.20
(DMSO-d6) ppm, as compared with 6.50–6.68 (DMSO-d6) (for 4a–d),[10] while the
remaining signals do not change significantly. Their EI mass spectra showed always
a molecular ion that was 52 units higher than that of the corresponding aminopyra-
zoles 4a–d.[10] In their EI mass spectra, losses due to the ester side chain were
observed together with ions due to loss of 52 (C2N2) or 53 (C2N2þH), which might
result from cleavage on the pyrazole or pyrimidine moieties.
Table 1. Experimental conditions, and yields for the synthesis of pyrazoles 4
(chloroacetonitrile 2.2 mequiv., was used in all reactions)
Product yield (%)
Starting
material
Time (h)=
temp. (ꢀC)a
Base
(mequiv.)
Entry
4
5
6
7
1
2
3
4
5
6
7
8
3a
3ab
3b
3b
3c
5=80 þ 10=100
NaH (4.2)c
DBU (2.2)
NaH (4.2)c
DBU (2.2)
DBU (2.2)
DBU (2.2)
DBU (2.2)
DBU (6.0)
54
17
16
21
6
21
—
32
—
10
4
—
—
6
3
10
3
5=80 þ 10=100
—
—
—
—
—
—
10
10
2
—
18
—
—
3
3c
11
2
3d
3dd
2
10
2
5
14
aThe reaction temperature was 100–120 ꢀC except when otherwise stated.
bSimilar result was obtained when the reaction was carried out under N2.
cStepwise addition of base.
dReaction carried out without solvent.

1698
M. S. T. GONC¸ ALVES ET AL.
A detailed analysis of the 13C NMR data showed a set of signals that was very
similar in both the corresponding aminopyrazole 4a–d[10] and the new compound
5a–d, and this was assigned to the benzene nucleus. Three signals for cyano groups
could be observed for all the compounds; for example, for compound 5d they appear
at 116.2, 115.1, and 116.0 ppm.
The full assignment of 13C signals for compound 5d was carried out by
bidimensional heteronuclear multiple bond correlation (HMBC) and heteronuclear
multiple quantum correlation (HMQC) techniques, and this allowed us to conclude
that they would fit the proposed structure.
The infrared (IR) spectra of these fused heterocycles 5a–d, as in the case of
pyrazoles 4a–d,[10] showed the expected bands, due to stretching vibrations of the
cyano groups (2220–2250 cmꢁ1), the amine (3225–3500 cmꢁ1) and ester functions
(1707–1735 cmꢁ1), as well as a strong band of the C N bond (1588–1643 cmꢁ1) as
=
result of the heterocyclic ring.
In most preparations, a by-product identified as the para-substituted cyano-
1
methyl benzoate 6 was also isolated, and its H NMR spectrum conclusively showed
signals due to an aromatic ring containing two substituents in para position and a
methylenic signal at about 5 ppm. Although the cyano absorption band was not
present in the IR spectrum, it is known that the intensity of such a band may be very
low.[15] Therefore, because the amounts obtained were minute, it was decided to pre-
pare the esters 6c and 6d by an independent method, from the corresponding benzoic
1
acids and chloroacetonitrile. The H NMR showed two doublets in the aromatic
region and the methylenic group at d 4.89 (6c) or 4.93 (6d) ppm, but no cyano group
was detected on their IR spectra. When EI mass spectra were obtained, however, they
showed the expected Mþ ion and also the base peak corresponding to loss of the frag-
ment OCH2CN. For both compounds, 13C NMR spectra also showed a signal at d
115.9 (6c) or 116.2 (6d) ppm, which was attributed to the cyano carbon. It is thought
that these compounds are very prone to hydrolysis and this might explain why, to the
knowledge of the authors, they were not reported in the literature before.
To understand the pathway leading to compounds 4, 5, and 6, an NMR study
was carried out on the evolution of compound 3 in dimethylformamide and in the
presence of 1,8-diazabicyclo[5.4.]undec-7-ene and chloroacetonitrile. The starting
material 3 (15 mg) was dissolved in DMF-d6 (0.5 mL) in an NMR tube, 2 equivalents
of both chloroacetonitrile and DBU were added, and the NMR spectra were regis-
tered after 30, 60, 90, and 120 min. The signals at d 8.0–8.20, 7.53, 6.97, 6.70, and
6.53 ppm from compounds 6, 3, 5, hydrocyanic acid, and 4, respectively, were fol-
lowed to quantify the relative ratio of these materials in solution. The results obtained
from this study are shown in Fig. 2 and Table 2. They indicate that the disappearance
of the starting material originated mainly at compound 4 and that compounds 5 and 6
were always present in a 1:1 molar ratio. After 30 min at room temperature, 9.6% of 4,
2.4% of hydrocyanic acid, and 0.6% of both 5 and 6 were identified in solution. After a
period of 2 h the reaction mixture still contained approximately 50% of the starting
material 3, together with 22% of 4, 4.6% of hydrocyanic acid, 10% of 6, and 10%
of 5. This suggests that the major pathway leads to the formation of compound 4
from the reaction of 3 with chloroacetonitrile. The formation of 5 possibly results
from the reaction between two molecules of 4, eliminating hydrocyanic acid and
the aromatic moiety 6. The compound mixture generated in the NMR study was

4-AMINO-3,5-DICYANO-ARYLPYRAZOLES
1699
Figure 2. NMR study of the evolution of 3d in DMF with DBU and chloroacetonitrile. (Figure is
provided in color online.)
Table 2. Data obtained by NMR study of the reaction of compound 3d
Concentration (%) of compounds
Time (min)
3d
HCN
6d
5d
4d
0
100
87
0
0
0
0
30
60
90
120
2.4
4.3
4.1
4.6
0.6
5.6
8.2
10
0.6
5.6
8.2
10
9.6
12.5
18.5
22
72
63
53
separated by preparative layer chromatography (PLC), confirming the structure
assignment to all the heterocyclic=aromatic products.
EXPERIMENTAL
Melting points were measured on a Gallenkamp melting-point apparatus and
are uncorrected. IR spectra were registered on a Perkin-Elmer FTIR-1600.
Ultraviolet (UV) spectra were determined on a Hitachi U-2000. NMR spectra were
obtained on a Varian Unity Plus spectrometer at an operating frequency of
1
300 MHz for H NMR and 75.4 MHz for 13C NMR or a Bruker Avance III 400 at
an operating frequency of 400 MHz for 1H NMR and 100.6 MHz for 13C NMR using
the solvent peak as internal reference at 25 ꢀC. All chemical shifts are given in parts
per million (ppm) using dH Me4Si ¼ 0 ppm as reference and J values are given in hertz
(Hz). Assignments were made by comparison of chemical shifts, peak multiplicities,
and J values and were supported by spin decoupling–double resonance and bidimen-
sional heteronuclear HMBC and HMQC correlation techniques.
Low-resolution EI mass spectra were determined on a Unicam GC-MS 120.
High-resolution mass spectra were obtained on a VG Ultima or AutoSpec E spectro-
meters. Elemental analyses were obtained on a Leco CHNS-932. TLC and PLC were
carried out on plates coated with silica gel 60 F . Column chromatography was
254

1700
M. S. T. GONC¸ ALVES ET AL.
performed on silica gel (<230 mesh) with mixtures of light petroleum and diethyl
ether of increasing polarity, unless other conditions are described. Light petroleum
refers to the fraction boiling in the range 40–60 ꢀC.
General Procedures for the Cyclization of Compounds 3a–d
Method 1. To a solution of the intermediate (3, 1 mequiv.) in dry DMF
(1.6 mL), DBU (2.2 mequiv., except for 3d, Table 1), and chloroacetonitrile (2.2
mequiv.) were added, and the mixture was kept stirring at the temperature and time
indicated in Table 1. After cooling, the solvent was removed under reduced pressure
and the dark oily mixture obtained was purified by column chromatography or PLC.
Method 2. NaH (2.2 or 4.2 mequiv.) was suspended in DMF (2 mL), and a
solution of the intermediate (1 mequiv.) in DMF (3 mL) was added slowly with
stirring. Chloroacetonitrile (2.2 mequiv.) was added, and the mixture was heated
at the temperature and time mentioned in Table 1.
After cooling, water and then 6 N HCl were added until a dark solid precipi-
tated. This was filtered, dried in the oven (45 ꢀC), and purified by chromatography.
In some of the attempts, only water was added and a brown oil separated, which was
extracted with acetone. The solvent was removed and the resulting oil was purified
by column chromatography or PLC.
Cyanomethyl 3-(7-Amino-3,5-dicyano-1H-pyrazolo[4,3-d]pyrimidin-
1-yl)benzoate 5a
After column chromatography, the pyrazolopyrimidine 5a was obtained as a
yellow solid (21%), mp 225.9–228.6ꢀC, IR (KBr, cmꢁ1): 3500, 3317, 3225, 2960,
2920, 2232, 2220, 1732, 1633, 1571; UV (EtOH): 230 nm (log e 4.48), 260 nm (log e
1
4.27), 375 nm (log e 3.91); H NMR (300 MHz, DMSO-d6): 5.29 (2H, s, CH2), 7.84
(1H, t J 8.0 Hz, 5-H), 8.08 (1H, dt J 8.0 and 1.0 Hz, 4-H), 8.25 (2H, br s, NH2),
8.42–8.48 (1H, m, 6-H), 8.61 (1H, t J 1.0 Hz, 2-H); 13C NMR (75.4 MHz, DMSO-d6):
50.12 (CH2), 111.5, 115.0 (CN), 115.8 (CN), 116.3 (CH2CN), 119.9, 122.2, 126.8,
128.9, 129.3, 130.4, 130.6, 137.7, 143.8, 155.6 (C-70), 163.9 (CO); m=z (%) (EI) 345
(Mþ þ 1, 24), 344 (Mþ, 100), 292 (Mþ ꢁ C2N2, 12), 288 (Mþ ꢁ OCH2CN, 87), 287
(21), 261 (11), 260 (Mþ ꢁ CO2CH2CN, 27), 208 (41), 207 (21), 206 (32), 181 (34),
144 (54), 129 (23), 119 (18), 116 (21), 103 (23), 102 (52), 92 (30), 90 (22), 83 (16), 77
(22), 76 (31), 66 (24), 65 (33), 64 (99), 63 (49), 61 (52). Anal. calcd. for C16H8N8O2:
C, 55.82; H, 2.33; N, 32.56%. Found: C, 55.62; H, 2.5; N, 32.30%.
Cyanomethyl-3 (7-Amino-3,5-dicyano-1H-pyrazolo[4,3-d]pyrimidin-
1-yl)-4-methylbenzoate 5b
After column chromatography followed by washing with diethyl ether, the
pyrazolopyrimidine 5b was obtained as a yellow solid (32%), mp 253.8–255.2 ꢀC;
IR (KBr, cmꢁ1): 3340, 3332, 3236, 2250, 2240, 1735, 1645, 1630, 1571; UV (EtOH):
1
230 nm (log e 4.32), 315 nm (log e 3.70), 375 nm (log e 4.04); H MNR (300 MHz,
acetone-d6): 2.34 (3H, s, Me), 5.26 (2H, s, CH2), 7.45 (2H, br s, NH2), 7.76 (1H, d
J 7.6 Hz, 5-H), 8.18–8.20 (1H, br s, 2-H), 8.22 (1H, dd J 7.6 and 1.9 Hz, 6-H);

4-AMINO-3,5-DICYANO-ARYLPYRAZOLES
1701
13C NMR (75.4 MHz, DMSO-d6): 17.7 (CH3), 49.9 (CH2), 115.0 (CN), 115.8 (CN),
115.9 (CH2CN), 116.6, 119.6, 125.8, 126.7, 128.9, 130.9, 132.1, 142.2, 144.4, 155.8
(C-70), 163.5 (CO); m=z (EI) (%) 359 (Mþ þ 1, 22), 358 (Mþ, 91), 357 (24), 318
(Mþꢁ CH2CN, 47), 306 (Mþꢁ C2N2, 48), 305 (79), 302 (Mþꢁ OCH2CN, 17), 274
(Mþꢁ CO2CH2CN, 16), 273 (14), 239 (18), 222 (40), 221 (19), 214 (38), 104 (21),
103 (53), 102 (24), 92 (35), 91 (33), 90 (45), 89 (100), 78 (45), 77 (78), 76 (46). HRMS
(EI): calcd. for C17H10N8O2 [Mþ]: 358.0929; found: 358.0916.
Cyanomethyl 3-(7-Amino-3,5-dicyano-1H-pyrazolo[4,3-d]pyrimidin-
1-yl)-4-chlorobenzoate 5c
After colunm chromatography followed by PLC, the pyrazolopyrimidine 5c
was obtained as a yellow solid (4 or 10%), mp 233.7–235.7 ꢀC; IR (KBr, cmꢁ1):
3454, 3343, 3250, 2241, 1733, 1622, 1585, 1571, 1541; UV (EtOH): 230 nm (log e
1
3.48), 300 nm (log e 3.45) nm, 375 (log e 3.78); H NMR (300 MHz, DMSO-d6):
5.22 (2H, s, CH2), 7.98 (1H, d J 8 Hz, 5-H), 8.16 (2H, br s, NH2), 8.20 (1H, dd J 8
and 2 Hz, 6-H), 8.31 (1H, d J 2 Hz, 2-H); 13C NMR (75.4 MHz, DMSO-d6): 49.9
(CH2), 115.0 (CN), 115.5, 115.8 (CN), 116.5 (CH2CN), 120.3, 125.5, 131.3, 131.6,
133.0, 134.0, 128.3, 137.1, 144.9, 156.0 (C-70), 163.0 (CO); HRMS (EI): calcd. for
C16H7N8O235Cl [Mþ]: 378.0383; found: 378.0366.
Cyanomethyl 3-(7-Amino-3,5-dicyano-1H-pyrazolo[4,3-d]pyrimidin-
1-yl)-4-methoxybenzoate 5d
After column chromatography followed by PLC, the pyrazolopyrimidine 5d
was obtained as a yellow solid (2 or 10%), that decomposes at 200 ꢀC without melting;
IR (KBr, cmꢁ1): 3473, 3366, 2242, 2228, 1707; UV (EtOH): 234 nm (log e 4.41),
1
308 nm (log e 3.70) nm, 374 nm (log e 3.98); H NMR (400 MHz, DMSO-d6): 3.87
(3H, s, OCH3), 5.21 (2H, s, CH2), 7.49 (1H, d J 8.8 Hz, 5-H), 8.06 (2H, br s, NH2),
8.13 (1H, d J 2 Hz, 2-H), 8.23 (1H, dd J 8.8 and 2.4 Hz, 6-H); 13C NMR
(100.6 MHz, DMSO-d6): 49.9 (CH2), 56.8 (OCH3), 113.5 (C-5), 115.1 (CN), 116.0
(CN), 116.2 (CH2CN), 119.6 (C-30 or C-70a), 120.3 (C-1), 124.7 (C-3), 125.5 (C-30
or C-70a), 130.8 (C-2), 133.9 (C-6), 144.8 (C-50), 155.9 (C-70), 159.3 (C-4), 163.4
(CO); HRMS (EI): calcd. for C17H10N8O3 [Mþ]: 374.087586; found: 374.086754.
Esters 6 Obtained During the Preparation of Pyrazoles 4
Cyanomethyl 4-methylbenzoate 6b. After PLC the ester 6b was obtained
as an oil (6%); IR (neat) (cmꢁ1): 2921, 2838, 1729, 1612; 1H NMR (300 MHz,
CDCl3): 2.45 (3H, s, CH3), 4.97 (2H, s, CH2), 7.30 (2H, d J 8.2 Hz, 3-H and 5-H),
7.96 (2H, d J 8.2 Hz, 2-H and 6-H); m=z (%) (EI) 175 (Mþ, 14), 120 (9), 119
(Mþꢁ OCH2CN, 100), 91 (39), 89 (10), 65 (4).
Cyanomethyl 4-chlorobenzoate 6c. After column chromatography
followed by PLC, ester 6c was obtained as a white oil that later solidified (18%);
the experimental data confirmed its structure and were in accordance with those
obtained in an independent synthesis.

1702
M. S. T. GONC¸ ALVES ET AL.
Cyanomethyl 4-methoxybenzoate 6d. After column chromatography and
PLC, the ester 6d was obtained as a colorless oil that later solidified (3%), mp
58.9–59.7ꢀC; the experimental data confirmed its structure and were in accordance
with those obtained in an independent synthesis.
Synthesis of the Esters 6c and 6d
Cyanomethyl 4-chlorobenzoate 6c. Potassium carbonate (0.44 g, 3.2
mequiv.) and chloroacetonitrile (0.2 mL, 3.2 mequiv.) were added to a solution of
p-chlorobenzoic acid (0.5 g, 3.2 mequiv.) in dry DMF (3 mL), and the mixture was
kept stirring overnight. Water was added, and the mixture was extracted with ether.
The organic extracts were dried (MgSO4), and the solvent removed to give ester 6c as
an oil, which later solidified (0.41 g, 65%), mp 48.5–50.3ꢀC; IR (neat, cmꢁ1): 3455,
1
2943, 1736, 1670, 1589; H NMR (300 MHz, CDCl3): 4.89 (2H, s, CH2), 7.27 (2H,
d J 9 Hz, 3 and 5-H) 7.80 (2H, d J 9 Hz, 2 and 6-H). 13C NMR (75.4 MHz, DMSO-d6):
50.0 (CH2), 115.9 (CN), 126.8 (C-1), 129.2 (C-3 and C-5), 131.3 (C-2 and C-6), 139.2
(C-4), 163.9 (C O); m=z (%) (EI) 197 (Mþ, 37Cl, 30), 195 (Mþ, 35Cl, 84), 141 (34), 139
=
(100), 113 (24), 111 (72), 76 (19), 75 (57), 74 (26). Anal. calcd. for C9H6NO2Cl: C,
55.26; H, 3.09; N, 7.16%. Found: C, 55.50; H, 3.05; N, 7.15.
Cyanomethyl 4-methoxybenzoate 6d. Following the method just described
for 6c and using p-methoxybenzoic acid, the ester 6d was obtained as a reddish brown
solid (79%), mp 60.2–62.0ꢀC; IR (KBr, cmꢁ1): 3426, 3014, 2972, 2939, 2844, 1916,
1
1724, 1608, 1580, 1513; H NMR (300 MHz, DMSO-d6): 3.84 (3H, s, OCH3), 5.17
(2H, s, CH2), 7.09 (2H, dd J 6.1 and 2.1 Hz, 3-H and 5-H), 7.95 (2H, dd J 6.9 and
2.1 Hz, 2-H and 6-H); 13C NMR (75.4 MHz, DMSO-d6): 49.5 (CH2), 55.7 (OCH3),
114.4 (C-3 and C-5), 116.2 (CN), 120.0 (C-1), 131.8 (C-2 and C-6), 163.9 (C-4),
164.3 (CO); m=z (EI) (%) 192 (Mþ þ 1, 8), 191 (Mþ, 57), 136 (10), 135 (Mþꢁ
OCH2CN, 100), 107 (14), 92 (29), 77 (13), 64 (6). HRMS (EI): calcd for
C10H19NO3 [Mþ]: 191.058243; found: 191.058294.
ACKNOWLEDGMENTS
´
´
We thank Junta Nacional de Investigac¸a˜o Cientıfica e Tecnologica (Portugal)
for financial support through (IBQF-UM) and PRAXIS XXI for support under
project PRAXIS=2=2.1=QUI=44=94 and for a scholarship to M. S. T. Gonc¸alves
(BD-2566-93-RM). The NMR spectrometer Bruker Avance III 400 is part of the
National NMR Network and was purchased in the framework of the National
Program for Scientific Re-equipment, Contract REDE=1517=RMN=2005, with
funds from POCI 2010 (FEDER) and FCT. We thank Miss Elisa Pinto for obtaining
the NMR, low-resolution mass, and elemental analyses data.
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