Synthesis of an α-amino nitrile and a bis α-amino nitrile derivative of thiadiazole: Reaction mechanism

Article abstract of DOI:10.1002/poc.1257

The first nucleophilic addition of an inorganic nucleophile (cyanide) to the activated, rigid, α-diazomethine groups of a 1,2,5-thiadiazole 1,1-dioxide is reported here. An α-amino nitrile and a bis a-amino nitrile derivatives were obtained in good yields (62 and 98%, respectively) and characterized by spectroscopic, analytical, and single crystal X-ray diffraction techniques. The course of the reaction, followed by cyclic voltammetry (CV), showed that cyanide adds to only one of the two C=N double bonds of the thiadiazole, forming an anion from which an N-methyl derivative was obtained. Adequate concentrations of cyanide and methyl iodide (MeI) produced directly the bis a-amino nitrile derivative. Copyright

Full text of DOI:10.1002/poc.1257

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2007; 20: 1081–1087
Published online 25 September 2007 in Wiley InterScience
(
www.interscience.wiley.com) DOI: 10.1002/poc.1257
Synthesis of an a-amino nitrile and a bis
a-amino nitrile derivative of thiadiazole:
reaction mechanism
1,3
1
2
1
Mar ı´ a Virginia Mir ´ı fico, * Jos e´ Alberto Caram, Oscar Enrique Piro and Enrique Julio Vasini
1
Instituto de Investigaciones Fisicoqu ı´ micas Te o´ ricas y Aplicadas (INIFTA), Facultad de Ciencias Exactas, Departamento de Qu ı´ mica,
Universidad Nacional de La Plata, Casilla de Correo 16, Sucursal 4, (1900) La Plata, Argentina
2
Departamento de F ı´ sica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and IFLP (CONICET), C. C. 67, 1900 La Plata,
Argentina
3
Facultad de Ingenier ı´ a, Departamento de Ingenier ı´ a Qu ı´ mica, Universidad Nacional de La Plata, Calle 47 y 1, (1900) La Plata, Argentina
Received 23 May 2007; revised 23 July 2007; accepted 24 July 2007
ABSTRACT: The first nucleophilic addition of an inorganic nucleophile (cyanide) to the activated, rigid,
a-diazomethine groups of a 1,2,5-thiadiazole 1,1-dioxide is reported here. An a-amino nitrile and a bis a-amino
nitrile derivatives were obtained in good yields (62 and 98%, respectively) and characterized by spectroscopic,
analytical, and single crystal X-ray diffraction techniques. The course of the reaction, followed by cyclic voltammetry
—
(CV), showed that cyanide adds to only one of the two C—N double bonds of the thiadiazole, forming an anion from
which an N-methyl derivative was obtained. Adequate concentrations of cyanide and methyl iodide (MeI) produced
directly the bis a-amino nitrile derivative. Copyright # 2007 John Wiley & Sons, Ltd.
KEYWORDS: nucleophilic addition; thiadiazole heterocycles; sequential reaction; cyclic voltammetry; X-ray diffraction
INTRODUCTION
,2,5-Thiadiazoles, -thiadiazolines, and -thiadiazolidines
are broadly applied in the areas of pharmaceutical, agricul-
In connection with this work, it is convenient to recall
two aspects of our previous reports on nucleophilic
addition reaction to thiadiazoles.
In the first place, we have found that alcohols, thiols,
aromatic monoamines, and monocarboxamides in aprotic
1
1
tural, industrial, and polymer chemistry. In several of
these applications, 1,1-dioxide and 1-oxide derivatives
9
,10,12,15,19,20
solvent solution,
and ethoxide in absolute
2–6
9
—
are employed.
We have studied many aspects of the chemistry and
ethanol solution add to only one of the two C—N double
bonds of 1 and other related thiadiazoles in an equilibrium
reaction [Eqn (1)]. This decrease in reactivity after the
first addition was also observed in the reaction of 1 with
Grignard reagents. We have rationalized the difficulty
of diaddition reactions, based in the structural details
obtained through X-ray diffraction studies and theoretical
7
–20
physical-organic chemistry of 1,1-dioxides
21,22
oxides derivatives,
and 1-
particularly structure-reactivity
27
analysis, electrochemical properties, and addition reac-
tions of organic nucleophiles.
However, the possible addition reactions of inorganic
nucleophiles have not been explored so far, despite the
chemical functionalization and synthetic possibilities that
they might offer. This work reports the first study of this
kind. We have selected 3,4-diphenyl-1,2,5-thiadiazole
19
calculations.
1
,1-dioxide (1) as the substrate and the cyanide anion
ꢀ
ð1Þ
23–25
(NC )
nitriles as organic synthesis intermediates.
as the nucleophile, due to the importance of
26
*
Correspondence to: M. V. Mir ´ı fico, Instituto de Investigaciones Fisi-
The monoaddition products are stable in solution, but
non-isolable, reverting to the reactants on solvent
coqu ´ı micas Te o´ ricas y Aplicadas (INIFTA), Facultad de Ciencias
Exactas, Departamento de Qu ´ı mica, Universidad Nacional de La Plata,
Casilla de Correo 16, Sucursal 4, (1900) La Plata, Argentina.
E-mail: mirifi@inifta.unlp.edu.ar
9
evaporation. However, we have found for the addition
ꢀ
reaction of EtO to 1 that a stable and isolable N-methyl
Copyright # 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2007; 20: 1081–1087

´
M. V. MIRIFICO ET AL.
1
082
substituted thiadiazoline can be obtained if methyl iodide
glove-box. Their water content (<30 ppm) was measured
by Karl–Fischer coulometric titration.
(
(
MeI) is incorporated to the reaction before work-up [Eqn
2)].
Commercial potassium cyanide (KCN) was dried
over P O at reduced pressure and room temperature.
2
5
1
13
H and C NMR spectra were measured with a
Brucker 200 MHz instrument and IR spectra with a
Shimadzu IR-435 spectrophotometer (KBr disc).
ð2Þ
Solution preparation, synthesis reactions, and other
manipulations were made in a glove-box under a dry
nitrogen atmosphere at room temperature (ca 25 8C).
Single crystals of the compounds were obtained from
MeCN solutions by slow evaporation of the solvent.
Single crystal X-ray data for 3 were obtained with a
KappaCCD diffractometer, using w and v scans and
Secondly, we have also reported that primary aliphatic
—
amines and phenylhydrazine add to both C—N double
bonds, but the products are unstable and, loosing
sulfamide, give a-bis-imines or a-bis-hydrazone, respect-
ively.
Stable diaddition products are obtained with bifunc-
tional nitrogen nucleophiles such as mono- and symme-
trically disubstituted ureas and thioureas, which add to
17
˚
graphite monocromated MoKa radiation (l ¼ 0.71073 A)
in the W range from 3.33 to 25.008. Compound 2 was
measured with an Enraf-Nonius CAD-4 diffractometer,
using the v ꢀ 2W scan technique and graphite mono-
˚
cromated CuKa radiation (l ¼ 1.54184 A) in the W range
from 3.60 to 68.018.
The structures were solved by direct and Fourier
methods and the final molecular model obtained by
—
both C—N double bonds of 1 yielding bicyclic
compounds (Fig. 1).
We report in this work that, depending on the reaction
16
2
full-matrix least-squares refinement on F , employing the
conditions, both monoaddition and diaddition to 1 took
ꢀ
SHELXS-97 and SHELXL-97 programs. The hydrogen
atoms of both compounds were positioned stereochemi-
cally and refined with the riding model. The methyl
hydrogen atoms locations were optimized during the
refinement by treating them as rigid bodies which were
allowed to rotate around the corresponding N—C bond.
place in the case of the CN nucleophile. The addition
reaction products were isolated as a N-methyl substituted
0
thiadiazoline (2, for monoaddition) or a N,N -dimethyl
disubstituted thiadiazolidine (3, for diaddition).
The course of the reactions was followed by cyclic
voltammetry (CV), used as an electrochemical spectro-
28
scopic technique : the peak potential (E ) was used to
p
characterize a chemical species (reagent, intermediate, or
product) and the current intensity of the peak (I ) was
employed as a concentration measure.
2
,5-Dimethyl-3,4-diphenyl-1,2,5-
p
thiadiazolidine-3,4-dicarbonitrile
1,1-dioxide (3)
1 (224.1 mg, 0.83 mmol) and KCN (159 mg, 2.4 mmol)
were added to the DMF solvent (10 ml). The mixture was
EXPERIMENTAL
29
stirred for 1.5 h at r.t. (ca 25 8C). The colorless solution
Compound 1 was synthesized according to Wright.
Standard methods were used for purification of MeCN
gradually developed
a
yellow–green color. MeI
30–32
(496.5 mg, 3.5 mmol) was added to the reaction mixture
and the solution was left to stand overnight until the color
vanished. Evaporation of the solvent at 35 8C and reduced
pressure yielded a solid residue which was washed with
and DMF commercial solvents.
Purified solvents
were further dried with freshly activated 4A molecular
sieves and stored under a dry nitrogen atmosphere in a
copious H O and dried at reduced pressure at 40 8C
2
(crude: 290.0 mg). The crude product was recrystallized
(
Cl CH -n-Hex) at r.t. to give 284.4 mg (0.81 mmol) of a
2
2
chromatographically (TLC) pure white solid 3 in 98%
yield; mp 260.0–261.0 8C. An identical procedure, except
that MeCN was the solvent employed, produced a lower
yield (55%) of the same solid.
IR(KBr): 3050 (vw, C —H), 2995, and 2910 (w,
Ar
—
—
CAliph—H), 2480 (vw, C—N), 2310 (vw, C—N), 1600
vw, Ph), 1490 (m), 1335 and 1320 (shoulder) (s, SO2),
(
1225 (s), 1165 (s, SO ), 1140 (s), 1110 (s), 1085 (m).
2
Anal. Calcd for C H N O S: C: 61.35; H: 4.58; N:
15.90; O: 9.08; S: 9.10. Found: C: 60.47; H: 4.46; N:
15.89; S: 9.54.
18 16 4 2
Figure 1. Stable products obtained by the addition of
mono- and symmetrically disubstituted ureas and thioureas
to both C—N double bonds of 1
—
Copyright # 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2007; 20: 1081–1087
DOI: 10.1002/poc

AMINO NITRILE DERIVATIVES OF THIADIAZOLE
1083
IR(KBr): 3050 and 3030 (w, doublet, C —H), 2930,
Ar
—
900, and 2850 (w, CAliph—H), 2310 (vw, C—N), 1590
2
(
(
s), 1540 (s), 1490 (m), 1470 (m), 1450 (s), 1340 and 1320
shoulder) (s, SO ), 1165 (s, SO ).
Anal. Calcd for C H N O S: C: 61.72; H: 4.21; N:
2
2
16 13 3 2
1
1
3.50; O: 10.28; S: 10.30. Found: C: 61.59; H: 4.30; N:
3.46; S: 10.58.
1
H NMR (DMF-d7): d: 8.04–7.58 (m, 10H, H—CAr),
.85 (s, 3H, N-CH ).
2
3
13
2
heteroc
C NMR (DMF-d7): d: 171.1 (Csp
), 136.4,
1
1
31.8, 131.2, 131.0, 130.9, 130.3, 127.4, 126.8 (C ),
Ar
—
13.6 (C—N), 72.4 (Csp
3
heteroc
), 26.7 (N-CH3).
C H N O S, M ¼ 311.35, crystal dimensions 0.20 ꢁ
1
6 13 3 2
0
.16 ꢁ 0.16 mm, crystal system, space group: mono-
˚
˚
clinic, P2 /a, a ¼ 11.028(2) A, b ¼ 11.243(2) A, c ¼
1
˚
3
˚
1
r
2.441(2) A, b ¼ 99.49(2)8, V ¼ 1521.4(5) A , Z ¼ 4,
ꢀ
3
¼ 1.359 g cm , R1 ¼ 0.0394 [2202 reflections with
ꢀ
˚
calcd
3
Figure 2. Molecular plot of 3 showing the labeling of the
non-H atoms and their displacement ellipsoids at the 50%
probability level
I>2s(I)], residual electron density 0.269–0.291 eA . An
33
ORTEP diagram of 2 is shown in Fig. 3.
The CVexperiments were performed in a conventional
undivided gas-tight glass cell with dry nitrogen gas inlet
and outlet. The working electrode was a 3 mm diameter
vitreous carbon disk encapsulated in Teflon, the counter-
1
H NMR (Cl CD): d: 7.60–7.34 (m, 10H, H—C ),
3
Ar
2
1
0
.90 (s, 6H, N-CH ).
3
C NMR (Cl CD): d: 131.7, 129.1, 128.4, 127.1 (C ),
3
—
12.6 (C—N), 74.2 (Csp
13
2
þ
electrode was a 2 cm Pt foil, and a Ag (0.1 M, MeCN)/
Ag reference electrode (to which all potentials reported
are referred) was used. The supporting electrolyte was
Ar
3
heteroc
), 30.2 (N-CH3).
C H N O S, M ¼ 352.41, crystal dimensions 0.20 ꢁ
18 16 4 2
ꢀ
1
.20 ꢁ 0.16 mm, crystal system, space group: orthor-
0.2–0.3 M NaClO . The sweep rate (v) was 0.2 V s . A
4
˚
˚
hombic, P2 2 2 , a ¼ 10.077(1) A, b ¼ 12.324(1) A, c ¼
LYP-M2 potentiostat, a three-module LYP sweep gen-
erator, and a Houston Omnigraphic 2000 pen recorder
were used.
As above mentioned, CV was used as an electro-
chemical spectroscopic technique to follow the course of
the reactions: in a typical experiment, a solution of the
reactants at selected initial concentrations and 1/KCN
1
1 1
3
ꢀ3
˚
˚
1
4.084(1) A, V¼ 1749.1(3) A , Z¼ 4, r
¼ 1.338 g cm ,
33
calcd
R1 ¼ 0.0381 [2591 reflections with I>2s(I)], residual
ꢀ
3
electron density 0.149–0.237 eA . An ORTEP dia-
˚
gram of 3 is shown in Fig. 2.
5
-Methyl-3,4-diphenyl-1,2,5-
thiadiazoline-4-carbonitrile 1,1-dioxide (2)
1
(141.3 mg, 0.52 mmol) and KCN (45.5 mg, 0.7 mmol)
were added to DMF (50 ml) under agitation and the
mixture was stirred for 1.5 h at r.t. A yellow–green color
developed after 10 min. The reaction mixture was left to
stand overnight. Upon MeI addition (227.0 mg, 1.6 mmol),
the green–yellow color decreased very slowly. After 48 h,
the solvent was evaporated at 40 8C and reduced pressure
from the almost colorless solution. The light-yellow pasty
residue obtained was dried at 40 8C and reduced pressure
for 5 days, producing a viscous, caramel colored, oil
containing a white powder suspension. Extraction with
copious CH Cl (10 ꢁ 1 ml) left a white solid residue,
2
2
identified as KI, and a caramel colored solution that was
treated with activated charcoal and concentrated at r.t.
under reduced pressure until a light opalescence was
observed. Upon refrigeration (4 8C), large slightly
off-white crystals formed. The filtered crystals were
washed with n-hexane and dried under reduced pressure
at 40 8C. The chromatographically (TLC) pure solid
obtained was identified as 2 (99.7 mg, 0.32 mmol, 62%),
mp 135.0–135.5 8C.
Figure 3. Molecular plot of 2 showing the labeling of the
non-H atoms and their displacement ellipsoids at the 50%
probability level
Copyright # 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2007; 20: 1081–1087
DOI: 10.1002/poc

´
M. V. MIRIFICO ET AL.
1
084
molar ratio was prepared and its CVs scanned at
convenient reaction times until a time-independent CV
was obtained. MeI, in a large stoichiometric excess, was
then added to the solution, and new CV scans were run.
When no further changes were observed in the CV, the
MeI excess was eliminated by dry N bubbling and a final
2
CV was scanned.
RESULTS AND DISCUSSION
It was found that when an excess of MeI was added to a
solution of 1 and KCN in a molar concentration ratio
R ¼ [KCN] /[1] ca 3 the 3 thiadiazolidine was obtained,
o
o
Figure 4. (——) CV of 1 (12.6 mM) and KCN (12.6 mM); (- -
-) after addition of MeI (0.072 M); (ꢀ ꢄ ꢀ) after dry nitrogen
bubbling to eliminate MeI excess. DMF solvent, sweep rate:
whereas the thiadiazoline 2 was the product if an excess
of MeI was added to a solution with R slightly larger than
-
ꢀ
1
1
(see Section ‘Experimental’). ORTEP diagrams of
0
.200 V s , supporting electrolyte: NaClO (0.25 M)
4
these reaction products are shown in Figs 2 and 3,
respectively.
S
To obtain information on the course of the reaction, the
CV experiments detailed below were performed.
The CV scans of DMF solutions of 1 and KCN in
equimolar concentrations (R ¼ 1) showed, immediately
after their preparation, a gradual decrease to an almost
complete disappearance of the two reversibly couples of 1
sponding to the 4 anionic species, unchanged, and did
not produce any other changes in the CVs. Thus, it was
ꢀ
concluded that the CN monoaddition reaction [Eqn (3)]
was the only reaction taking place in the 1/KCN solution.
13
This was further supported by the C NMR spectrum of
the 1/KCN system, which showed, besides the eight
.
.
S
S
2S
16
2
signals of the phenyl C-atoms, one sp and one sp
3
(
1/1 at ca ꢀ0.8 V and 1 /1 at ca ꢀ1.4 V), along
with the appearance and development of a new cathodic
peak at ca ꢀ2.2 V. A final CV was reached in which a
weak signal corresponding to the electroreduction of 1
remained while the current intensity of the peak at ꢀ2.2 V
reached a maximum constant value (Fig. 4, solid line).
Two anodic peaks were also observed, labeled in Fig. 4 as
heterocyclic C-atom signals (170.6 and 75.5 ppm,
respectively) and one sp C-atom signal (120.4 ppm).
These chemical shifts were similar to those of the
corresponding C-atoms of the synthesized 2 (see Section
‘Experimental’). Since CV peak intensities, in the same
experimental conditions, are proportional to concen-
trations, the current intensity of the 1 peak in the presence
of an equimolar amount of KCN, I ([1] ¼ [KCN] ), in
1
successive electrooxidation of 1 to 1 (peak 1a, Fig. 4)
a and 2a, their peak potentials correspond to the
S
.
2ꢀ
p
o
o
.
and of 1 to 1 (peak 2a, Fig. 4).
S
DMF solvent was compared with the current intensity of a
Experiments described below allowed the assignment
S
DMF solution of 1 at the same concentration, I ([1] ), to
p
o
of the ꢀ2.2 V peak to the anion 4 , formed by the addi-
obtain a measure of the extent of reaction Rex ¼
{I (1) ꢀ I ([1] ¼ [KCN] )}/I (1) . Figure 5 (circles)
ꢀ
tion of CN to 1 [Eqn (3)].
p
o
p
o
o
p
o
shows that Rex increased with an increase in the
concentration of reactants. An equilibrium constant for
3
ꢀ1
Eqn (3) [K ¼ (9.3 ꢂ 1) ꢁ 10 M ] was estimated by a
1=2
nonlinear fit of the Rex experimental values to the
ð3Þ
equation Rex¼½ꢀð4K½1ꢃ þ 1Þ þ2K½1ꢃ þ1ꢃ=ð2K½1ꢃ Þ
o
o
0
(
solid line, Fig. 5).
The initial reactant concentrations and the experimen-
ꢀ
ꢀ
tal current intensity of the 4 CV peak (Ip4 ) are listed in
.ꢀ
ꢀ
ꢀ
The weak CV signal corresponding to the 1/1 couple
remained after the addition of MeI. The reversibility of
Table 1. The equilibrium concentration of 4 ([4 ]),
calculated using the estimated K and the initial con-
centrations of the reactants, is also included. A least-
ꢀ
ꢀ
the CN addition reaction [Eqn (3)] and the consumption
of CN through its reaction with MeI, which are further
discussed below, account for these observations.
ꢀ
squares linear regression gave Ip4 /mA ¼ 60 mA þ
4
ꢀ1
ꢀ
(4.0 ꢂ 2) ꢁ 10 mA M ꢁ [4 ] (r ¼ 0.96).
ꢀ
Similar experiments performed with different reactant
concentration ratios showed that, for a given initial
concentration of 1, the increase of R up to ca 1.3 caused a
proportional peak current intensity increase of the ꢀ2.2 V
peak, but experiments up to R ¼ 9, the highest ratio
experimentally measured, left the ꢀ2.2 V peak, corre-
The functional relation between 4 concentration and
ꢀ
the current intensity of its electroreduction peak (Ip4 )
was indicated by the fact that 1 was its electroreduction
product (Fig. 4, peaks 1a and 2a). Thus, the first charge
2ꢀ
ꢀ
transfer to 4 should produce the corresponding radical
.
2
.
dianion 4 , which decomposes rapidly to 1 and CN .
ꢀ
S
ꢀ
Copyright # 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2007; 20: 1081–1087
DOI: 10.1002/poc

AMINO NITRILE DERIVATIVES OF THIADIAZOLE
1085
Scheme 1.
2
electrode area, A ¼ 0.071 cm , diffusion coefficient, D of
ꢀ
5
2 ꢀ1
S
the substrate ¼ 1 ꢁ 10 cm s ), give Ip4 ¼ 5.9 ꢁ
4
ꢀ
1
0 ꢁ [4 ] mA. This was considered an acceptable
agreement, given the approximate nature of the calcu-
lations involved.
When an excess of MeI was added to an equimolar or
nearly equimolar solution (R ffi 1) of 1 and KCN that had
undergone the changes described above, the CV scanned
after the MeI addition showed a gradual intensity
decrease of the cathodic peak at ꢀ2.2 V (although
somewhat obscured by the MeI peak at ꢀ2.5 V), along
with the development of a new cathodic peak at ca ꢀ1.4 V
(Fig. 4, broken line). When the MeI excess was
Figure 5. Extent of reaction [Rex, Eqn (3)] as a function of
reactant concentration at equal initial concentrations of 1
and KCN. The extent of reaction was measured voltame-
trically as Rex ¼ ½Ipð1Þ ꢀ Ipð½1ꢃ ¼ ½KCNꢃ Þ=Ipð1Þ , where,
o
o
o
o
for a given concentration of 1, I (1) is the current intensity
p
o
of the first CV peak of 1, and I ([1] ¼ [KCN] ) is the current
p
o
o
intensity of the same peak in the presence of KCN. Circles
indicate experimental measurements. The solid line is a
nonlinear regression adjustment of the points to the
eliminated from the solution by dry N bubbling, only
2
the peak at ca ꢀ1.4 (Fig. 4, dash-dot-dash line) remained.
The peak at ꢀ1.4 V was assigned to the electroreduction
of 2, formed in the reaction of Eqn (4), by comparison
with an authentic sample (a CV scan of a DMF solution of
2 is shown in Fig. 6, solid line).
1
=2
equation Rex ¼ ½ ꢀ ð4K½1ꢃ þ1Þ þ 2K½1ꢃ þ 1ꢃ=ð2K½1ꢃ Þ,
o
o
o
3
ꢀ1
which gave K ¼ (9.3 ꢂ 1) ꢁ 10 M
.S
Since the electroreduction potential of 1 is ca ꢀ1.4 V, it
2
ꢀ
would be immediately electroreduced at ꢀ2.2 V to 1 . The
electrode process would be an E CE process (Scheme 1).
1
2
The dependence of the CV peak current intensity with
the experimental parameters for an E CE process, with
1
2
E ꢅ E , and assuming that the chemical step C is very
ð4Þ
2
1
34
ꢀ
1=2
fast, is very well known: Ip4 ¼ ðn1 þ n2ÞFAD
1
=2 1=2
ꢀ
1=2
ðn1F=RTÞ
v
If these conditions are met, the peak value for the
½4 ꢃp xðatÞ.
34
1
/2
function p x(at), is 0.487. These, together with our
The MeI incorporated to the 1/KCN reaction mixture
ꢀ
ꢀ1
experimental values (sweep rate, v ¼ 0.2 V s , working
also reacted with CN to give MeCN and iodide ion (see
ꢀ
Table 1. Experimental initial concentrations of reactants and measured peak current for the 4 peak at ꢀ2.2 V
ꢀ
[
1] (mM)
o
[KCN] (mM)
o
Ip (mA)
[4 ] calc. (mM)
Ip (calc.) (mA)
2
2
7
8
.13
.31
.74
.16
4.30
2.33
3.68
23.0
6.44
20.0
6.30
28.0
28.0
25.0
67.6
25.5
24.0
12.6
16.7
56.5
25.0
34.5
100
108
138
272
275
300
305
335
345
354
382
500
560
609
629
660
950
1140
2.03
1.87
1.71
8.10
3.24
7.78
5.53
7.74
7.66
7.40
7.44
12.5
12.3
11.5
12.3
12.6
23.4
32.6
141
135
128
384
189
371
281
370
366
356
357
560
552
520
552
563
997
1365
1
2.6
7
6
7
7
7
7
2.6
2.4
2.6
2.6
2.6
5.0
4.5
.85
.3
.78
.70
.44
.45
1
1
1
1
1
2
3
ꢀ
3
ꢀ1
The calculated 4 concentration, based on Keq ¼ 9.3 ꢁ 10 M for the reaction of Eqn (3), and the calculated peak currents, based on a linear least-squares
regression (see text) are also listed.
Copyright # 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2007; 20: 1081–1087
DOI: 10.1002/poc

´
M. V. MIRIFICO ET AL.
1
086
Figure 6. (——) CV of 2 (13.2 mM); (- - - -) after addition of
Figure 7. (——) CV of 1 (12.6 mM) and KCN (56.6 mM); (- -
-) after addition of MeI (0.13 M); (ꢀ ꢄ ꢀ) after dry nitrogen
bubbling to eliminate MeI excess. DMF solvent, sweep rate:
ꢀ1
KCN (8.22 mM). DMF solvent, sweep rate: 0.200 V s
supporting electrolyte: NaClO (0.25 M)
,
-
4
ꢀ
.200 V s , supporting electrolyte: NaClO (0.25 M)
4
1
0
the synthesis of 2, Section ‘Experimental’), it must be
concluded that, in our reaction conditions, the N-
much weaker for the anion. PM3 calculations gave
2
fractional electron charges on the heterocyclic sp C-atom
ꢀ
ꢀ
methylation of 4 [Eqn (4)] was favored over the loss
ꢀ
of 0.15 for 2 and ꢀ0.16 for 4 .
ꢀ
of CN [back reaction of Eqn (3)] followed by the
ꢀ
The assignment of the ꢀ1.99 V CV peak to 5 was
reaction of CN with MeI. However the balance left some
further supported when, upon addition of MeI, the peak at
ꢀ1.99 V disappeared and was replaced by a peak of
similar current intensity at ꢀ2.7 V (not shown in Fig. 6).
As it is discussed immediately below, the peak at ꢀ2.7 V
corresponds to the thiadiazolidine 3 [Eqn (6)].
unreacted substrate 1, as observed (Fig. 4, dash-dot-dash
line). The ideal experimental conditions for the highest
possible yield of 2 were not further investigated.
ꢀ
—
It was found that addition of CN to the remaining C—
N double bond of 2 also took place. In a CVexperiment in
which KCN was added to a DMF solution of 2 to a
[
KCN] /[2] molar ratio of 0.62 (initial concentrations:
o o
1
3.2 mM 2; 8.22 mM KCN), it was observed that the CV
peak of 2 (Fig. 6, solid line) decreased with time while a
new cathodic peak at ꢀ1.99 V developed. When all
changes ceased (Fig. 6, broken line), the CV showed that
the current intensity of the peak of 2 had decreased to ca
ð6Þ
3
7% of its original current intensity of 378 mA, while the
current intensity of the new peak at ꢀ1.99 V was 200 mA,
Thiadiazolidine 3 was also observed in CVexperiments
performed at a larger [KCN] /[1] relation (e.g., Fig. 7;
that is, 53% of the original intensity of the 2 peak.
This result indicates that practically all CN has
o
o
ꢀ
R ¼ 4.5). As above mentioned, the initial changes were
almost identical to those observed for R ca 1 (Fig. 7, solid
line). After an excess of MeI was added, the resulting CV
peak of 2 at ca ꢀ1.4 V was much smaller than for R ¼ 1,
and a large, broad peak was observed at ca ꢀ2.7 V (Fig. 7,
broken line). Upon elimination of the MeI excess it was
observed (Fig. 7, dash-dot-dash line) that the broad peak
was a superimposition of the MeI peak at ꢀ2.5 V and a
new cathodic peak at ca ꢀ2.7 V. The peak at ꢀ2.7 V was
assigned to the electroreduction of 3 by comparison with
an authentic sample.
reacted to give a new species that is reduced at ꢀ1.99 V. It
seemed reasonable to assign the peak at ꢀ1.99 V to a
ꢀ
thiadiazolidine anion produced by the CN addition to
the remaining C¼N double bond of 2 anion [5 , Eqn (5)].
ꢀ
ð5Þ
ꢀ
ꢀ
Thus, the neutral molecule 2 added CN , but the 4
anion did not. This is of course reasonable, because the
CONCLUSIONS
ꢀ
effect of electron-withdrawing properties of the >SO2
group on the remaining sp heterocyclic C-atom must be
The CN nucleophile adds to one or to both azomethine
groups of 1. The corresponding thiadiazoline or
2
Copyright # 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2007; 20: 1081–1087
DOI: 10.1002/poc

AMINO NITRILE DERIVATIVES OF THIADIAZOLE
1087
thiadiazolidine are obtained in good yields and can be
isolated by standard procedures. This contrasts with
previously studied nucleophilic addition reaction of
monodentate nucleophiles which produced only mono-
addition to give thiadiazolines, most of which were only
stable in solution, reverting to the reactants on work-up,
or unstable diaddition thiadiazolidines which decom-
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. Wong T, Groutas CS, Mohan S, Lai Z, Alliston KR, Vu N,
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7
To the best of our knowledge, only two methods have
been reported for the formation of a carbon–carbon bond
between the heterocyclic C-atoms of 1 and a substituent,
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1
9. Mirı
993; 6: 341–346.
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39–945.
´
27
the first uses Grignard reagents and the second employs
1
15
a very strong acid catalyst (AlCl3). The synthesis
reported here takes place under mild conditions and can
be easily adjusted to produce mononitrile or dinitrile
derivatives, which are well known for their usefulness in
synthetic routes.
9
1
1
1. Mir ´ı fico MV, Vasini EJ. An. Quim. 1995; 91: 557–560.
2. Caram JA, Mir ´ı fico MV, Aimone SL, Vasini EJ. Can. J. Chem.
1996; 74: 1564–1571.
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Vasini EJ, Glossman MD. J. Phys. Org. Chem. 1998; 11: 91–100.
4. Svartman EL, Caram JA, Mir ´ı fico MV, Vasini EJ. Can. J. Chem.
1999; 77: 511–517.
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Synthesis 2002; 2399–2403.
6. Caram JA, Aimone SL, Mir ´ı fico MV, Vasini EJ. J. Phys. Org.
Chem. 2003; 16: 220–225.
7. Caram JA, Mir ´ı fico MV, Aimone SL, Piro OE, Castellano EE,
Vasini EJ. J. Phys. Org. Chem. 2004; 17: 1091–1098.
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J. Phys. Org. Chem. 2006; 19: 229–237.
9. Svartman EL, Rozas MF, Piro OE, Castellano EE, Mir ´ı fico MV.
Synthesis 2006; 2313–2318.
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1. Aimone SL, Mir ´ı fico MV, Caram JA, Glossman DM, Piro OE,
Castellano EE, Vasini EJ. Tetrah. Lett. 2000; 41: 3531–3535.
2. Castellano EE, Piro OE, Caram JA, Mir ´ı fico MV, Aimone SL,
Vasini EJ, M a´ rquez-Lucero A, Glossman-Mitnik D. J. Mol. Struct.
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2
The reactions steps were unambiguosly clarified by the
use of CV. This demonstrates once again the merits of this
electrochemical technique for the elucidation or organic
reactions mechanisms and the detection of intermediates.
In particular, it was shown that mono and diaddition did
not take place consecutively on the same substrate.
Instead, it was necessary to N-methylate the monoaddi-
ꢀ
tion nitrile before a second CN anion could be added.
Acknowledgements
This work was financially supported by the Consejo
Nacional de Investigaciones Cient ´ı ficas y T e´ cnicas
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Copyright # 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2007; 20: 1081–1087
DOI: 10.1002/poc