Direct introduction of cyano group on furoxan ring.
Lorenzo Annaratone, Stefano Guglielmo and Konstantin Yu. Chegaev*
Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy. Fax +39 011 670 7687; e-mail. konstantin.chegaev@unito.it
Potassium cyanide reacts with 3-aryl-4-phenylsulfonyl furoxan / furazan under mild conditions in DMF at rt, in the presence of 18-crown-6 ether to afford 3-aryl-4-cyano furoxan / furazan in 45-50% yield.
N+ N O (O-)n O S
O Ar
N+ NO N
(O-)n Ar KCN, DMF,
18-crown-6 n = 0, 1
Since the discovery of the biological function of nitric oxide (NO) by Ignarro et. al in early 90
ththis small gaseous molecule was recognized as a ubiquitous regulator species involved in nearly every aspect of human biological processes. Produced from L-arginine by the NO-synthases enzyme family NO mainly acts via the soluble guanylate cyclase (sGC) pathway activation.
1Gaseous NO is poorly soluble in water and quite difficult to handle because of its reactivity versus oxygen with consequent nitrogen dioxide formation.
That is why the use of molecules capable to release NO under physiological conditions
(NO-donors) is required. Different classes of NO-donors were developed for biological
application in the past three decades.
2-4Among them 1,2,5-oxadiazoles (furoxans) (Figure
1), compounds able to release NO under biological thiols action, were extensively
N N+ O
R"
R'
O-
1 2
3 4
5 N N+
O O- N
N N+ O O- N
1 2
Figure 1
The ability to release NO strongly depends on the nature of substituents on carbon atoms of the furoxan ring. The presence of electron withdrawing groups (e.g. cyano, nitro or sulfonyl) favours the nucleophilic attack of thiols and results in increased quantity and velocity of NO release.
9-11In particular the two isomers of cyanophenylfuroxan (1 and 2, Figure 2) were found to be the most effective NO donors in different biological experiments.
12,13In our work, we have met the necessity to synthesise a significant amount of 4- cyano-3-phenyl furoxan 2. The known procedures for the synthesis of cyano furoxans pass via dehydration of corresponding amide or oxyme.
14-16The synthesis of 2 is a multistep process that requires a difficult chromatographic separation of isomeric phenyl- hydroxymethylfuroxans (3 and 4) after thermal isomerisation (Scheme 1).
17,18OH
N N+ O
OH
O- 3
N+ N O O H
O- N N+
O N
O- 2 4
Scheme 1
Therefore, we decided to study the possibility of direct introduction of cyano group by the nucleophilic substitution of phenylsulfonyl moiety with cyanide anion starting from readily available 4-phenyl-3-phenylsulfonyl furoxan (5) (Scheme 2).
N+ N O O- O S
O
N+ NO N
O- 2 5
CN-
Scheme 2
The substitution of phenylsulfonyl group is well studied for the O- and S- nucleophiles,
19while only few papers describe the use of nitrogen based nucleophiles, C- nucleophiles or halogen anions.
20-22Here we described the study of the reaction between cyanide anion and phenylsulfonyl substituted furoxans and related furazans.
Discussion
First reaction of 5 with KCN was performed in acetonitrile at RT for 24h. Only partial
conversion of starting compound into desired cyano derivative (2) was observed. All
attempts to push the reaction further by increasing reaction time, temperature or KCN:5
molar ratio were unsuccessful. Therefore, we have studied the use of phase transfer
catalysts. Using 2 eq. of KCN in CH
2Cl
2/H
2O mixture in the presence of n-Bu
4N
+HSO
4-the
starting compound 5 was completely consumed in 72 h, but the yield of 2 was quite low
(27%). Extensive decomposition of 5 was observe probably due to hydrolysis of KCN and
the reaction of 5 with hydroxyl anion. The use of n-Bu
4N
+CN
-in dry CH
2Cl
2helped to
overcome this problem and permitted to obtain 2 with 42% yield in 24 h. Using the excess
of KCN gave 2 in 45% of yield after 1 h. The yield was further improved by the use of 18- crown-6 ether as a catalyst (Table 1).
Table 1 Influence of reaction conditions on the yield of 2.
Cyanide source Solvent 5:CN- molar ratio t (h) Catalyst Yield Comments
KCN CH3CN up to 1:10 72 25% Low conversion
KCN CH2Cl2 / H2O 1:2 72 nBu4N+HSO4- 27% Decomposition
nBu4N+CN- CH2Cl2 1:1 24 42%
nBu4N+CN- CH2Cl2 1:2 1.5 32%
KCN DMF 1:1 1 45%
KCN DMF 1:1 1 18-crown-6 58%
Once the optimal reaction conditions were found, we explored the possibility to apply this reaction to other furoxans and furazans bearing good leaving groups. The use of 3-phenyl-4-nitro furoxan (6) in the same conditions permitted to obtain 2 in nearly the same yield, but in a shorter time. Corresponding 3-phenyl-4-phenylsulfonyl furazan (7) was transformed into 3-cyano-4-phenyl furazan (8) in 18 h with a good yield. While we were unable to isolate any product from the reaction of 4-phenyl-3-phenylsulfonyl furoxan (9) with KCN (Scheme 3). It seems that nucleophilic attack of CN
-on 3-carbon atom of 9 results in furoxan ring opening with consequent formation of highly hydrophilic compounds.
N+ N O N
O- 2 6
N+ NO O- N+
O-
O KCN, DMF, 18-crown-6, 0.5h, 48%
N N O N
8 7
N NO O S
O
KCN, DMF, 18-crown-6, 18h, 50%
N N+
O N
O- 1 9
N N+
O O S
O
O-
Scheme 3
Finally, the possibility to extend this reaction for differently substituted 4- phenylsulfonyl furoxans and furazans was studied (Table 2).
Table 2 Attempts to apply the reaction for differently substituted 4-phenylsulfonyl furoxans / furazans.
N+ NO
R"
N
(O-)n N+
NO R"
(O-)n R'
CN-
R’ = R” = n = Conditions Results
SO2Ph SO2Ph 1 KCN/DMF/18-crown-6/rt decomposition SO2Ph SO2Ph 1 nBu4N+CN-/CH2Cl2/rt decomposition SO2Ph SO2Ph 1 nBu4N+CN-/CH2Cl2/-15 °C decomposition SO2Ph SO2Ph 1 nBu4N+CN-/CH2Cl2/-78 °C no reaction observed SO2Ph OEt 1 KCN/DMF/18-crown-6/rt decomposition SO2Ph CH3 1 KCN/DMF/18-crown-6/rt decomposition NO2 CH3 1 KCN/DMF/18-crown-6/rt decomposition SO2Ph SO2Ph 0 KCN/DMF/18-crown-6/rt decomposition SO2Ph SO2Ph 0 nBu4N+CN-/CH2Cl2/rt decomposition SO2Ph SO2Ph 0 nBu4N+CN-/CH2Cl2/-15 °C decomposition SO2Ph SCH2Ph 0 KCN/DMF/18-crown-6/rt decomposition SO2Ph OEt 0 KCN/DMF/18-crown-6/rt decomposition SO2Ph CH3 0 KCN/DMF/18-crown-6/rt decomposition
However, it seems that none of the substituents except aryl group are allowed in the 3-position of furoxan or furazan ring.
In summary, the results obtained allow one to synthesize 3-aryl-4-cyano furoxans and furazans via direct nucleophilic substitution of phenylsulfonyl or nitro leaving group under the action of cyanide anion.
Chemistry
Anhydrous sodium sulfate (Na
2SO
4) was used as drying agent for the organic
phases. Organic solvents were removed under reduced pressure at 30 °C. Synthetic-purity
solvents dichloromethane, dimethylformamide (DMF) and 40–60 petroleum ether (PE)
were used. Dry DMF was obtained through storage on 4Å molecular sieves. The progress
4-Cyano-3-phenyl furoxan (2). To the solution of 3-phenyl-4-phenylsulfonyl
furoxan (300 mg, 1.00 mmol) in dry DMF (10 mL) KCN (65 mg, 1.00 mmol) was added in one portion followed by 18-crown-6 ether (260 mg, 1.00 mmol). Reaction was stirred at room temperature for 1 h, than poured into cold water (30 mL) and extracted with CH
2Cl
2(2×25 mL). Organic solvent was washed with water (20 mL), brine (20 mL), dried and evaporated. Obtained yellow oil was purified by flash chromatography (eluent PE:CH
2Cl
2= 8:2) to give a desired cyano derivative as a white solid. Yield 98 mg (58%). Analytically pure sample was obtained by crystallization from hexane. Mp 84-85 °C (C
6H
14), lit.
15mp 81
°C.
1H NMR (300 MHz, CDCl
3) (ppm): 7.99 – 8.02 (m, 2H), 7.60 – 7.62 (m, 3H).
13C NMR (75 MHz, CDCl
3) : 133.0 (
4C, Fx), 132.1 (CH of C
6H
5), 129.7 (2CH of C
6H
5), 126.4 (2CH of C
6H
5), 119.6 (C of C
6H
5), 112.6 (
3C, Fx), 108.4 (CN).
3-Cyano-4-phenyl furazan (8). To the solution of 3-phenyl-4-phenylsulfonyl
furazan (290 mg, 1.00 mmol) in dry DMF (10 mL) KCN (65 mg, 1.00 mmol) was added in one portion followed by 18-crown-6 ether (260 mg, 1.00 mmol). Reaction was stirred at room temperature for 18 h, than poured into cold water (30 mL) and extracted with CH
2Cl
2(2×25 mL). Organic solvent was washed with water (20 mL), brine (20 mL), dried and evaporated. Obtained yellow oil was purified by flash chromatography (eluent PE:CH
2Cl
2= 9:1) to give a desired cyano derivative as a white solid. Yield 86 mg (50%). Analytically pure sample was obtained by crystallization from hexane. Mp 45-46 °C (C
6H
14), lit.
23mp 40-41 °C.
1H NMR (300 MHz, CDCl
3) (ppm): 8.00 – 8.04 (m, 2H), 7.57 – 7.68 (m, 3H).
13
