Acylation of 3，4－Diaminofurazan

WU Min－jie（吴敏杰）， CHEN Shu－sen（陈树森）， XIONG Shu－ling（熊书玲），JIN Shao－hua（金韶华）， LI Li－jie（李丽洁）

（School of Material Science and Engineering，Beijing Institute of Technology，Beijing 100081，China）

3－amino－4－acylaminofurazan and 3，4－diacylamino－furazan are useful compounds.It has been identified that they have the functions of histamine H2－antagonistic activity［1－3］，bradykinin B1receptor antagonists［4］and anti－cancer activity［5］.They are also used as initial material to synthesize other compounds with the structure of furazan.3－amino－4－acylaminofurazan can be used to synthesize some metal complexes［6］， 3，4－dibromo acetylaminofurazan can be used to synthesize high nitrogen compound［7－8］.At present，nearly all the synthesis methods of these compounds starts from acyl halogen under the catalysis of alkali［2－10］，except for the formyl substituted compounds that are synthesized from formic acid under catalysis of hydrochloric acid［6］.G.Sorba［1－3］et al.synthesized a serials of these kinds compounds using acetyl chloride as a reagent，and the acyl was converted into alkyl in follow.Li Zhanxiong［7－8］used bromoacetyl bromide to synthsize 3，4－dibromoacetylaminofurazan that is then converted into 3，4－diazidoacetylaminofurazan.A newly acylation of 3，4－diaminofurazan method were proposed in this paper.

1 Experiment

1.1 Materials and instrument

All chemicals are commercial and without further purification.3，4－diaminofurazan were synthesized following the procedures described in Ref.［9］.Melting points are uncorrected.The NMR spectra were obtained with a 400MHz NMR spectrameter at room temperature.

1.2 Synthesis

1.2.1 Synthesis of 3－amino－4－formylamino furazan 1a

1.2.1.1 Method A

3，4－diaminofurazan 2.0 g（20 mmol），p－Toluenesulfonic acid1.72g（10 mmol）and formic acid 3 mL（88%，60 mmol）were added to a 25 mL flask with a condenser and a thermometer.The mixture was heated under reflux with stirring for 2 h.After cooled to ambient temperature，the mixture was neutralized with concentrated ammonia so－lution to pH＝7－8.After cooled，the precipitated was filtered off.After washing with water and dried，the pale yellow product was obtained with weighed of 2.43 g and yield of 95%.The reaction scheme is shown in Fig.1.

Fig.1 Reaction of acylation to 3，4－diaminofurazan

1.2.1.2 Method B

Following the same procedure in method A，3，4－diaminofurazan 2.0 g（20 mmol）and formic acid 3 mL（88%，60 mmol）were stirred under reflux for 9 h to get 1.24 g pale yellow product with yield of 48%and mp of 170－171℃ （mp 169－170 ℃in Ref.［7］）.Product with higher purity can be obtained through recrystallization with tetrahydrogenfuran and water mixture.The characteristics of the products were as follows：1H NMR（DMSO－d6，20℃）δ6.06 ＆ 6.13 （NH2），8.35 ＆ 8.76（O ==CH），10.42 ＆10.88（NH）；13C NMR（DMSO－d6）δ143.3＆143.9（C—NH2），150.3 ＆151.8（C—NH），160.3 ＆162.5（C ==O）；IR（KBr）3 411，3 218，3 074，1 704，1 650，1 566，1 531，1 432，1 164，612 cm－1；EI m／z 128［M］＋；Anal.Calcd.for C3H4N4O2：C，28.13；H，3.15；N，43.74.Found：C，28.17；H，3.19；N，43.68.

1.2.2 Synthesis of 3－amino－4－acetylamino furazan 1b

Following the same procedure in method A，2.0 g （20 mmol）3，4－diaminofurazan，1.7 g（10 mmol）p－Toluene sulfonic acid and 3.5 mL（99.5%，60 mmol）acetic acid were mixed and stirred for 3 h.Finally，2.2 g product was obtained with the yield of 78%.The characteristics of the products were as follows：mp 197－198℃ （mp 191－192℃ in Ref.［2］）；1H NMR（DMSO－d6）δ2.11（s，3H，CH3），5.98（s，2H，NH2），10.57（s，1H，NH）；13C NMR（DMSO－d6）δ24.7（CH3），146.0 （C—NH2）， 153.9 （C—NH），171.3（C ==O）；IR（KBr）3 472，3 325，3 066，3 013，2 993，1 710，1 639，1 588，1 537，1 416，1 373，1 332，1 260，1 037，590cm－1；EI m／z 142［M］＋；Anal.Calcd.for C4H6N4O2：C，33.81；H，4.26；N，39.42.Found：C，33.92；H，4.24；N，39.31.

1.2.3 Synthesis of 3－amino－4－propionylamino furazan 1c

Following the same procedure in method A，1.0 g （10 mmol）3，4－diaminofurazan，0.8 g（5 mmol）p－Toluene sulfonic acid and 3 mL（99%，40 mmol）propionic acid were mixed，under reflux for 5 h.Finally，1.42 g yellow product was obtained with the yield of 91%.The characteristics of the products were as follows：mp 160－162℃；1H NMR（DMSO－d6）δ1.07（t，3H，CH3），2.41（5，2H，CH2），5.99（s，2H，NH2），10.53（s，1H，NH）；13C NMR（DMSO－d6）δ9.1（CH3），28.6（CH2），144.2（C—NH2），152.1（C—NH），173.1（C ==O）；IR（KBr）3 429，3 343，3 261，3 187，3 075，2 983，2 943，1 677，1 552，1 434，1 356，1 275，1 219，1 081，1 012，827，673，575cm－1；EI m／z 156［M］＋；Anal.Calcd.for C5H8N4O2：C，38.46；H，5.16；N，35.88.Found：C，38.53；H，5.21；N，35.78.

1.2.4 Synthesis of 3－amino－4－butylramino furazan 1d

Following the same procedure above，1.0 g（10 mmol）3，4－diaminofurazan，0.8 g（5 mmol）p－Toluenesulfonic acid and 4 mL （99%，40 mmol）butyric acid were heated to 120℃ with stirring.After reaction for 5 h，the mixture was cooled to room temperature，and neutralized to pH＝7－8.The solution was then put in refrigerator overnight.The precipitate was filtered out to get pale yellow product.The product was recrystallized to get 0.83 g white power product with yield of 48%.The characteristics of the products were as follows：mp 135－137℃；1H NMR（DMSO－d6）δ0.90（t，3H，CH3），1.59（m，2H，CH2），2.37（t，2H，CH2），5.98（s，2H，NH2），10.58（s，1H，NH）；13C NMR（DMSO－d6）δ13.5（CH3），18.1（CH2），37.2（CH2），144.3（C—NH2），152.1（C—NH），172.3（C== O）；IR（KBr）3 437，3 354，3 275，3 079，2 973，1 679，1 552，1 433，1 273，1 199，1 088，1 019，786，630cm－1；EI m／z 170［M］＋；A－nal.Calcd.for C6H10N4O2：C，42.35；H，5.92；N，32.92.Found：C，42.38；H，5.96；N，32.83.

1.2.5 Synthesis of 3－amino－4－benzoylamino furazan 1e

Following the same procedure above，1.0 g（10 mmol）3，4－diaminofurazan，0.8 g（5 mmol）p－Toluene sulfonic acid，3.66 g（30 mmol）benzoic acid and 2 mL dioxane were added to a 25 mL flask.The mixture was heated to 120℃with stirring for 6 h，and brown solid was obtained.After recrystallization，1.96 g pale yellow product was obtained with the yield of 96%.White crystal was obtained after being recrystallized with ethyl acetate／hexane.The characteristics of the final product were：mp 134－136℃ （mp 147－148℃）［2］；1H NMR（DMSO－d6）δ6.12（s，2H，NH2），7.54－8.02（m，5H，5ArH），10.93（s，1H，NH）；13C NMR（DMSO－d6）δ128.3（2o－CH），128.6（2m－CH），132.6（p－CH），132.7（Ar－C），144.5（C—NH2），153.0（C—NH），166.1（C== O）；IR（KBr）3 395，3 365，3 288，3 172，3 064，1 693，1 679，1 578，1 419，1 329，1 268，898，704，648cm－1；EI m／z 204［M］＋；Anal.Calcd.for C9H8N4O2：C，52.94；H，3.95；N，27.44.Found：C，53.02；H，3.98；N，27.35.

1.2.6 Hydrolysis of 3－amino－4－formylamino furazan

In 10 mL ethanol，0.568 g（4 mmol）3－amino－4－formylaminofurazan and 1 mL formic acid was added and refluxed for 2h with stirring.3，4－diamino furazan was obtained when the liquid was elimination by distill under vacuum.The acid could also be replaced by acetic acid or concentrated hydrochloric.

With similar method，the 3－amino－4－acetylaminofurazan was also be hydrolyzed to 3，4－diaminofurazan.

1.2.7 Synthesis of 3，4－diformylaminofurazan 2a

In a 25 mL flask，3－amino－4－formylamino furazan（1a）0.256 g （2 mmol）was added to the mixture of 2 mL dioxane and 1 mL formic acid（88%）.The reaction mixture was heated under reflux with stirring for 12 h.After elimination of the liquid in vacuo，ethyl acetate was added to the oil residue，eliminate the solvent again，added ethyl acetate，repeated 2－3times to afford the solid product，recrystallized from ethyl acetate／hexane，gave 0.21 g buff product，yield 67%：mp 139－140℃（mp 140 ℃）［7］；1H NMR（DMSO－d6，20 ℃）δ8.40＆8.77（s，COH），10.71（s，NH）；13C NMR（DMSO－d6）δ143.8，144.9＆146.2（C－N），160.2＆162.0（C== O）；IR（KBr）3 210，3 171，3 105，1 696，1 596，1 558，1 541，1 410，1 376，1 165，592 cm－1；EI m／z 156［M］＋，128［M－COH＋H］＋；A－nal.Calcd.for C4H4N4O3：C，30.78；H，2.58；N，35.89.Found：C，30.82；H，2.61；N，35.84.

1.2.8 Synthesis of 3，4－diacetylaminofurazan 2b

In a 25 mL three neck flask with thermometer acetic anhydride 8 mL（99.5%，85 mmol）was added to the mixture of 3，4－diaminofurazan 2.0 g（20 mmol） and p－Toluenesulfonic acid 1.72 g（10 mmol）with vigorously stirring.The temperature rose promptly.Keep the temperature in 120℃for 10 min，after cooled to room temperature，concentrated ammonia solution was added by drop，until the mixture pH＝7－8，stirred for 30 min after cooled，the solid precipitated was collected by filtration，by recrystallized the white product 3.31 g was obtained，yield 89%：mp 161－162℃；1H NMR（DMSO－d6）δ2.10（s，6H，2CH3），10.53（s，2H，2NH）；13C NMR（DMSO－d6）δ23.1（2CH3），146.9（2C ==N），171.8（2C ==O）；IR（KBr）3 232，3 095，3 006，2 939，1 717，1 568，1 518，1 384，1 242，1 044，588 cm－1；EI m／z 184［M］＋，142［M－COCH3＋H］＋；Anal.Calcd.for C6H8N4O3：C，39.13；H，4.38；N，30.42.Found：C，39.10；H，4.34；N，30.38.

1.2.9 Synthesis of 3，4－dipropionylaminofurazan2c

3，4－diaminofurazan 1.0 g （10 mmol）and p－Toluene sulfonic acid 0.8 g（5 mmol）was added in propionic anhydride 3 mL（98%，23 mmol），when heated to 130℃stirred for 2 h，the mixture was neutralized by concentrated ammonia solution to pH＝7－8，the solution was stayed in refrigerator for one night，the precipitated was filtration，the white product 1.41 g was collected，yield 67%.After recrystallized by ethyl acetate／hexane，got pale yellow solid：mp 129－131℃；1H NMR（DMSO－d6）δ1.06（t，6H，2CH3），2.04（4，4H，2CH2），10.44（s，2H，2NH）；13C NMR（DMSO－d6）δ9.0（2CH3），28.6（2CH2），146.3（2C－NH），172.4（2C==O）；IR（KBr）3 253，3 057，2 989，2 943，1 693，1 603，1 557，1 456，1 396，1 211，1 186，1 015，743 cm－1；EI m／z 212［M］＋，156［M－COC2H5＋H］＋；Anal.Calcd.for C8H12N4O3：C，45.28；H，5.70；N，26.40.Found：C，45.32；H，5.72；N，26.33.

2 Result and discussion

2.1 Chemicals

3－amino－4－acylaminofurazan（1）were obtained from3，4－diaminofurazan in carboxyl acid，with p－Toluenesulfonic acid as catalysts under reflux.No disubstituted compound was found in the products，even the reaction time was extended until the compound was decompounded partly.3－amino－4－fomylamino furazan（1a）could also be obtained without catalysts，but the reaction time was longer and the yield was reduced.Instead of formic acid，when acetic acid reacted with 3，4－diaminofurazan following the same procedure，the yield and purity of 3－amino－4－acelyaminofurazan（1b）were low.So the formic acid could be used as the catalyst because of its character of strong acid.

The 3－amino－4－acylaminofurazan（1）was hydrolyzed to 3，4－diaminofurazan under reflux when ethanol was used as solvent and acid was used as catalyst.The catalyst could also be formic acid，acetyl acid or condense hydrochloric acid，with high yield.

Disubstituted acyl compounds of 3，4－diamino furazan were obtained when acid anhydride was used instead of carboxyl acid.It was easy to get target products with p－Toluenesulfonic acid as catalyst，and monosubstitution wasn’t found in products.The reaction was fast，especially when acetic anhydride was used as reagent.The reaction released lots of heat in a few minutes after the reactants were mixed.But it was still kept at about 120℃for ten more minutes to ensure all the reactants were consumed.

3，4－diformylaminofurazan（2a）was obtained when 3－amino－4－formylaminofurazan（1a）reacted with formic acids in dioxane under reflux for 12 h.Formic acid also acted as a catalyst in reaction.If p－Toluenesulfonic acid was added to reactant mixture，the compound 1a was decomposed quickly.It didn’t succeed if acetic acid was used to repeat the reaction，probably because of the character of formic acid’s strong acidity.

3－amino－4－acylaminofurazan（1b）reacted with formic acid in dioxane to afford the mixture of mono－and di－formylaminofurazan. The mixture product of mono－and di－formylaminfurazan was also obtained when formic acid and 3，4－diaminofurazan mixture was refluxed for 3 h with condense hydrochloric acid as catalyst（Fig.2）.

Fig.2 Other reaction to get 3－amino－4－formylaminofurazan and 3，4－diformylaminofurazan

The reaction didn’t happen when acetic acid reacted with 3，4－diaminofurazan under catalyzing of condense hydrochloric acid.

The yield and melting point of the compounds were listed in Tab.1.

Tab.1 Compound of acyl substituted 3，4－diaminofurazan

2.2 NMR analysis

The spacial isomers exist in formyl substituted compounds.As the p－πconjugate which formed by isolated double－electron of nitrogen atom with carbonyl of formyl group，the C—N bond possesses partial property of double bond，so the bond can’t round freely at low temperature.

It was confirmed that two spacial isomers of molecule 1aand three spacial isomers of molecule 2a exist at lower temperature，and the phenomena of special isomers disappeared at higher temperature（Fig.3and Fig.4）according to NMR spectra.

Because carbonyl had different magnetic shield effects on different isomers，every hydrogen atom and carbon atom of molecule 1adisplayed double peaks（Fig.5）in1H NMR and13C NMR spectra（20℃）.

In order to confirm the spacial isomers，the temperature－dependent1H NMR spectra were shown in Fig 6.From Fig.6，the1H NMR spectra show three double peaks at 30℃.As temperature increased，the round velocity of C—N bond became faster.The chemical shift of hydrogen atom in corresponding position of spacial isomers became identical.At the same time，all the peaks shifted upfield slightly.At 90℃，three double peaks are all turn to three single peaks.The same phenomena could be seen in temperature－dependent13C NMR spectra too.

The similar phenomena could also be seen in1H NMR and13C NMR spectra of 3，4－difomylamin－ofurazan.Because of the effect of two formyl，the spectra is more intricate.

3 Conclusion

A convenient and simple acylation method of 3，4－diaminofurazan was developed.The monoacylaminfurazan （3－amino－4－formylaminofurazan，3－amino－4－acetylaminofurazan， 3－amino－4－propionylaminofurazan，3－amino－4－butylramino furazan and 3－amino－4－benzoylaminofurazan）and di－acylaminfurazan （3，4－diacetylaminofurazan and 3，4－dipropionylaminofurazan）were synthesized using carboxyl acid（formic acid，acetic acid，propionic acid，butyric acid and benzoic acid）and acid anhydride（acetic anhydride and propionic anhydride）respectively under the catalyzing of p－Toluenesulfonic acid.The products were purified and the yields were high.

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