TETRAHEDRON
LETTERS
Tetrahedron Letters43(2002)4127–4129
Pergamon
A new synthetic approach for novel
4-substituted-5-nitroimidazoles†
reus
Maxime D.Crozet,a,b Patricia Perfetti,a Mustapha Kaafarani,a Patrice Vanelle a,b,*and
Michel P.Crozet a
a LCMO,UMR6517,Avenue Escadrille Normandie-Niemen,BP562,13997Marille Cedex20,France
b Laboratoire de Chimie Organique,Faculte´de Pharmacie,27Bd J.Moulin,13385Marille Cedex05,France
Received17April2002;accepted19April2002
Abstract—A new synthetic approach,involving an S RN1reaction of the anion of1-methyl-4-phenylsulfonyl-methyl-5-nitro-1H-imidazole with2,2-dinitropropane and a radical anion or a concerted radical reductive elimination of sulfonyl and nitro groups affords an original5-nitroimidazole bearing a trisubstituted ethylenic double bond at4-position.©2002Elvier Science Ltd.All rights rerved.
The S RN1reaction of1-methyl-2-chloromethyl-5-nitro-1H-imidazole with the lithium salt of a condary nitroalkane followed by nitrous acid elimination has been shown to be a good method for t
he preparation of various1-methyl-5-nitro-1H-imidazoles bearing a trisubstituted double bond in the2position.1By this method,very active compounds against anaerobic bac-teria have been prepared.2Becau,1-methyl-4-chloromethyl-5-nitro-1H-imidazole is unknown and its precursor,1-methyl-4-hydroxymethyl-5-nitro-1H-imi-dazole,is relatively difficult to synthesize,3another approach was necessary to prepare various1-methyl-5-nitro-1H-imidazoles bearing a trisubstituted double bond in4-position in order to compare their biological activities with the2-substituted isomers.The vicarious nucleophilic substitution of hydrogen(VNS)in nitroarenes with carbanions bearing leaving groups X at the anion center is a process of general character and significant practical value for organic synthesis.In1-methyl-5-nitro-1H-imidazole ries,Makosza et al. have been prepared by VNS reaction,1-methyl-4-phenylsulfonylmethyl-5-nitro-1H-imidazole2in63% yield from chloromethyl phenyl sulfone and the easily available1-methyl-5-nitro-1H-imidazole1.4Then,the VNS reaction is a powerful method to pre-pare a phenylsulfone bearing1-methyl-4-substituted-5-nitro-1H-imidazole,which after removal of a proton by a strong ba to give the stabilized carbanion2−could be ud as nucleophile for S RN1reactions with various nitro electrophiles.Indeed,Ono et al.have shown that carbanions bearing a sulfonyl group and an electron-withdrawing group(cyano,ethyl ester)are able to react by S RN1reaction with gem-dinitroalkanes.5
On the other hand,a-nitrosulfones are uful synthetic intermediates.For example,the lithium or sodium salts of(phenylsulfonyl)nitromethane gave predominant C-alkylation when treated with methyl iodide,primary alkyl iodides,and benzylic bromides or iodides.6This is in sharp contrast to typical nitronates which give pre-dominant O-alkylation under the conditions.So,the study of the reactivity in S RN1reaction of a carbanion bearing a phenylsulfonyl group and a nitroheterocyclic group with a gem-dinitroalkane to give3became an interesting problem concerning scope and limitations of S RN1reaction.Finally,to complete the synthesis of 1-methyl-5-nitro-1H-imidazoles bearing a trisubstituted double bond,it was of interest to examine the ea with which the condary sulfonyl group and the tertiary nitro group could be eliminated in a radical anion7or a concerted radical reductive elimination8from the b-nitrosulfone3.In this paper,we would like to report that the stabilized carbanion2−is able to react by the S RN1mechanism with different nitro electrophiles9and that1-methyl-5-nitro-1H-imidazole bearing a trisubsti-tuted double bond in4position as4can be prepared according to the following scheme:
Keywords:S RN1reaction;sulfonyl carbanion;C-alkylation;desul-fonylation;5-nitroimidazole.
*Corresponding author.Fax:33491794677;e-mail:
patrice.vanelle@pharmacie.univ-mrs.fr
†This paper is dedicated to the late Professor Jean-Marie Surzur.
Decead on January24,2002.
偏心的意思0040-4039/02/$-e front matter©2002Elvier Science Ltd.All rights rerved. PII:S0040-4039(02)00767-0
M .D .Crozet et al ./Tetrahedron Letters 43(2002)4127–4129
4128First and foremost,it has been shown that the sodium salt of 2reacted with p -nitrobenzyl chloride,the classical nitro electrophile to study a substitution reaction which proceeds via radical anion intermediates,10and that the stabilized carbanion 2−reacted with p -nitrobenzyl chlo-ride either by the S N 2mechanism,the S RN 1mechanism or by the two mechanisms.
The sodium salt of 2has been prepared from 2in DMSO under argon at room temperature by reaction of sodium hydride (60%dispersion in mineral oil)and reacted with p -nitrobenzyl chloride during 24h under photostimula-tion.After work-up and puri fication,the product 3a has been obtained in 70%yield.The same reaction in prence of p -dinitrobenzene 11(5%molar)gave 3a in 75%yield showing no inhibition.To con firm that 2−is able to react by S N 2mechanism with different primary alkyl halides,the C -alkylation of 2−has been studied under the same experimental conditions with benzyl bromide and methyl iodide.The corresponding condary sulfones 3b and 3c have been obtained in,respectively,81%and 84%yields.The same yields of 3a –c are approximately obtained under spontaneous initiation.
Under photostimulation,a ,p -dinitrocumene gave traces of 3d and p ,p %-dinitrobicumyl 12in 22%yield.By addition of p -dinitrobenzene (5%molar),the formation of 3d signi ficantly incread (12%yield)showing that the S RN 1C -alkylation of 2−by a nitro electrophile at a tertiary carbon atom
is possible and p -dinitrobenzene with a relatively slow electron-transfer chain reaction speeds up the reaction.12
Under the experimental conditions (sodium salt,DMSO,photostimulation,RT,argon,24h),2,2-dinitropropane (1equiv.)gave after column chromatography (silica gel,ethyl acetate)the desired compound 3in 27%yield and a mixture of 2and 3%resulting from nitrous acid elimination from 3.With a small excess (1.1equiv.)of 2,2-dinitropropane or 2-bromo-2-nitropropane and entrainment 10by the lithium salt of 2-nitropropane,3was obtained in 38%yield with a mixture of 40%of 2and 15%of 3%as calculated from 1H NMR spectra.To prepare the alkene 4,first the experimental conditions for reduc-tive elimination reaction induced by a reducing agent such as Na 2S were ud.The b -nitrosulfone 3was treated with
Na 2S,9H 2O (1.5equiv.)in DMF at room temperature under argon with photostimulation to give after puri fica-tion by column chromatography (silica gel,ethyl acetate)4in 28%yield and 3%in 16%yield.A higher yield in 4(55%)after column chromatography (silica gel,CHCl 3/Et 2O:6/4)was obtained with modi fication of the exper-imental conditions described 8for reductive elimination induced by tin radical (Bu 3SnH,2.5equiv.,AIBN,0.9equiv.,22h).
In conclusion,a new synthetic approach,involving an S RN 1reaction of the stabilized anion formed from 1-methyl-4-phenylsulfonyl-methyl-5-nitro-1H -imidazole with 2,2-dinitropropane and a radical anion or a con-certed radical reductive elimination of sulfonyl and nitro groups affords an original 5-nitroimidazole bearing a trisubstituted ethylenic double bond at 4-position.The extension of this direct and rapid radical approach to new 4-substituted-5-nitroimidazoles to more complex nitro electrophiles and other nitroheterocyclic sulfones is in progress in our laboratories.
References
1.Crozet,M.P.;Surzur,J.-M.;Vanelle,P.;Ghiglione,C.;Maldonado,J.Tetrahedron Lett .1985,26,1023–1026.sofnon
2.(a)Vanelle,P.;Crozet,M.P.;Maldonado,J.;Barreau,M.Eur .J .Med .Chem .1991,26,167–178;(b)Jentzer,O.;Vanelle,P.;Crozet,M.P.;Maldonado,J.;Barreau,M.Eur .J .Med .Chem .1991,26,687–697;(c)Vanelle,P.;Crozet,M.P.Recent Res .Dev .Org .Chem .1998,2,547–566.
3.(a)Bochwic,B.;Frankowski,A.;Kuswik,G.;Seliga,C.Pol .J .Chem .1985,55,1055–1061;(b)Baker,D.C.;Putt,S.R.;Showalter,H.D.H.J .Heterocycl .Chem .1983,20,629–63
4.
阅读网4.Makosza,M.;Kwast,E.Bull .Pol .Acc .:Chem .1987,35,287–292.
5.Ono,N.;Tamura,R.;Nakatsuka,T.;Hayami,J.;Kaji,A.Bull .Chem .Soc .Jpn .1980,53,3295–3300.
6.Wade,P.A.;Hinney,H.R.;Amin,N.V.;Vail,P.D.;Morrow,S.D.;Hardinger,S.A.;Saft,M.S.J .Org .Chem .1981,46,765–770.
7.Kornblum,N.;Boyd,S.D.;Pinnick,H.W.;Smith,R.G.J .Am .Chem .Soc .1971,93,4316–4318.
8.Ono,N.;Kamimura,A.;Kaji,A.J .Org .Chem .1987,52,5111–5116.
M.D.Crozet et al./Tetrahedron Letters43(2002)4127–41294129
9.4-[1-Benzenesulfonyl-2-(4-nitrophenyl)-ethyl]-1-methyl-5-
nitro-1H-imidazole3a:Yellow solid,mp175°C(ethanol),
1H NMR300MHz(CDCl
becau of you mp33
)
l 3.63(dd,J=3.6Hz, J=13.8Hz,1H);3.80–4.00(m,4H);5.60(dd,J=3.8Hz, J=11.7Hz,1H);7.24–8.04(m,10H).13C NMR75MHz (CDCl3)l32.4(CH2);36.1(CH3);63.9(CH);123.8 (CH);128.9(CH);129.1(CH);129.9(CH);134.3(CH);
135.8(C);137.1(C);139.9(CH);144.1(C);146.9(C).
Anal.Calcd for C18H16N4O6S(416.41):C,51.92;H,3.87;
N,13.45.Found:C,52.12;H,3.88;N,13.50.4-[1-Ben-zenesulfonyl-2-phenyl-ethyl]-1-methyl-5-nitro-1H-imida-zole3b:White solid,mp163°C(ethanol).1H NMR300 MHz(CDCl3)l3.52(dd,J=3.6Hz,J=13.6Hz,1H);
3.66–3.76(m,1H); 3.82(s,3H); 5.62(dd,J=3.6Hz,
战胜自我J=11.7Hz,1H);7.02–7.83(m,11H).13C NMR75MHz (CDCl3)l33.14(CH2);36.4(CH3);64.9(CH);127.2 (CH);128.9(CH);129.3(CH);129.4(CH);134.5(CH);
136.7(C);137.1(C);138.0(C);138.2(C);140.4(CH).
Anal.Calcd for C18H17N3O4S(371.41):C,58.21;H,4.61;
N,11.31.Found:C,57.91;H,4.59;N,11.35.4-[1-Ben-zenesulfonyl-ethyl]-1-methyl-5-nitro-1H-imidazole3c: White solid,mp156°C(ethanol).1H NMR300MHz (CDCl3)l1.72(d,J=7.0Hz,3H);3.91(s,3H);5.34(q, J=7.0Hz,1H);7.46–7.80(m,6H).13C NMR75MHz (CDCl3)l12.8(CH3);36.0(CH3);58.4(CH);128.9 (CH);133.9(CH);137.3(C);138.1(C);140.0(CH).Anal.
自学韩语
Calcd for C12H13N3O4S(295.32):C,48.80;H,4.44;N,
14.23.Found:C,48.88;H,4.44;N,14.14.4-[1-Benzene-
sulfonyl-2-methyl-2-(4-nitro-phenyl)-propyl]-1-methyl-5-nitro-1H-imidazole3d:Yellow solid,mp225°C(ethanol),
1H NMR300MHz(CDCl
3
)l1.67(s,3H);2.07(s,3H);
悉尼大学排名3.77(s,3H);5.95(s,1H);7.30–8.04(m,10H).13C NMR
75MHz(CDCl3)l26.3(CH3);27.6(CH3);36.1(CH3);
43.7(C);69.7(CH);123.2(CH);127.2(CH);127.8(CH);
128.7(CH);133.5(CH);137.6(C);139.8(CH);140.0(C);
146.4(C);154.2(C).Anal.Calcd for C20H20N4O6S (444.46):C,54.05;H,4.54;N,12.61.Found:C,54.03;H,
maincour4.58;N,12.43.4-(1-Benzenesulfonyl-2-methyl-2-nitro-
propyl)-1-methyl-5-nitro-1H-imidazole3:White solid,
mp189–191°C(acetone/petroleum spirit60–80:3/5).1H NMR300MHz(CDCl3)l1.67(s,3H);2.34(s,3H);
3.88(s,3H);6.56(s,1H);7.42–7.66(m,6H).13C NMR
75MHz(CDCl3)l23.9(CH3);27.1(CH3);36.2(NCH3);
65.9(CH);89.5(C);128.3(2CH);129.2(2CH);133.8(C);
134.5(CH);138.3(C);140.1(CH);(C-NO2not obrved under the conditions of this experiment).Anal.Calcd for C14H16N4O6S(368.37):C,45.65;H, 4.38;N,15.21.
铃儿响叮当 英文Found:C,45.38;H,4.38;N,15.38.The structure of3 was further confirmed by single crystal X-ray diffraction.
Crozet,M. D.Thesis,University of Aix-Marille,in preparation.4-(1-Benzenesulfonyl-2-methyl-propenyl)-1-methyl-5-nitro-1H-imidazole3%:Pale yellow solid,mp 135–136°C(ethanol).1H NMR300MHz(CDCl3)l1.74 (s,3H);2.21(s,3H);4.00(s,3H);7.44–7.60(m,4H);
7.88–8.00(m,2H).13C NMR75MHz(CDCl3)l21.6
(CH3);25.2(CH3);35.9(NCH3);127.5(CH);128.8(CH);
131.0(C);132.9(CH);137.0(C);137.8(C);139.9(CH);
142.4(C);155.7(CH).Anal.Calcd for C14H15N3O4S (321.35):C,52.33;H,4.70;N,13.08.Found:C,52.27;H,
4.71;N,13.08.4-(2-Methylpropenyl)-1-methyl-5-nitro-
1H-imidazole4:Yellow solid,mp106–107°C(hexane).
1H NMR300MHz(CDCl
3
)l2.00(s,3H);2.19(s,3H);
3.96(s,3H);6.77(s,1H);7.46(s,1H).13C NMR75MHz
(CDCl3)l20.7(CH3);27.9(CH3);35.9(NCH3);115.0 (CH);139.9(CH);144.3(C);146.9(C);(C-NO2not obrved under the conditions of this experiment).Anal.
Calcd for C8H11N3O2(181.19):C,53.03;H, 6.12;N,
23.19.Found:C,53.07;H,6.06;N,22.84.
10.Kornblum,N.Angew.Chem.,Int.Ed.Engl.1975,14,
734–745.
11.Chanon,M.;Tobe,M.L.Angew.Chem.,Int.Ed.Engl.
1982,21,1–23.
12.Kornblum,N.;Cheng,L.;Davies,T.M.;Earl,G.W.;
Holy,N.L.;Kerber,R.C.;Kester,M.M.;Manthey,J.
W.;Musr,M.T.;Pinnick,H.W.;Snow, D.H.;
Stuchal,F.W.;Swiger,R.T.J.Org.Chem.1987,52, 196–204.
