DOI:10.1002/anie.200905646
Asmbly of Substituted Phenothiazines by a Sequentially Controlled CuI/l -Proline-Catalyzed Cascade C ÀS and C ÀN Bond Formation**
Dawei Ma,*Qian Geng,Hui Zhang,and Yongwen Jiang
The phenothiazine structural motif has been successfully employed in the design of a variety of pharmaceuticals.Successful examples include promazine drugs (1a –c ),which are clinically ud for psychotropic medication;[1]quaternized trifluoropromazine derivative 2that has antitubercular activ-ity;[2]cholinestera inhibitor 3;[3]histamine H 1antagonist 4;[4]and MDR (multiple drug resistance)reverting agent 5.[5]Substituted phenothiazines have also attracted interest
becau of their optoelectrochemical and photophysical properties.Phenothiazines have been utilize
d as,for example,molecular wires,[6]electrogenerated chemiluminescene (ECL)emitters,[7]chemonsors for the lective fluorescence detection of flavins,[8]and intramolecular electron donors for the photoinduced reductive repair of thymine glycol.[9]As the substituents on the phenothiazine rings have a great influence on their properties,efficient methods for the preparation of a diver range of substituted phenothiazines are highly desirable.
am i right
Traditionally,phenothiazines are synthesized using the iodine-catalyzed reaction of diphenylamines with sulfur.[10]When meta -substituted diphenylamines are employed,the thionation reaction proceeds at high temperatures to afford two regioisomers in a near 1:1ratio.Becau of their high structural similarity,paration of the regioisomers is difficult,and fractional crystallization has been frequently ud to solve this problem.To overcome this drawback,a four-step procedure bad on the Smiles rearrangement was developed to asmble substituted phenothiazines from 2-aminobenzenethiol and substituted 2-chloro-nitrobenze-nes.[11a]However,the difficulty of this synthesis has limited the application of this protocol.[11b,c]Functionalization of unsubstituted phenothiazine is another commonly ud approach,[12,13]although this suffers from a lack of regio-lectivity in most cas.More recently,Jørgenn and co-workers reported an elegant method for preparing substituted phenothiazines that relied on the palladium-catalyzed three-component cou
pling reaction of substituted 1-bromo-2-iodo-benzenes,primary amines and 2-bromo-benzenethiol.[14]However,in most cas substituted 2-iodoanilines are more readily available than substituted 1-bromo-2-iodobenzenes;therefore,we investigated the u of the former as the coupling partner in the reactions with 2-bromobenzenethiols.To our delight,this coupling reaction was effectively catalyzed by CuI/l -proline to produce substituted phenothiazines in high yields,thereby offering a general and efficient approach to the heterocycles.[15]Herein,we wish to prent the results.
In our previous studies,we showed that CuI/l -proline can catalyze the N-arylation [16]of aryl amines,and the S-aryla-tion [17]of aryl thiols.As both 2-haloanilines and 2-halobenze-nethiols have two reaction centers that can undergo cross-coupling reactions,controlling the reaction quence is esntial for obtaining the desired products in good yields.Becau aryl thiols are more reactive than aryl amines in CuI/l -proline-catalyzed coupling reactions,[18]we decided to employ the less reactive 2-bromobenzenethiols as the sub-strates in our investigation.We expected that the reagents would couple exclusively with 2-iodoanilines,and not undergo lf-coupling to their corresponding dimerization products.Therefore,the reaction of 2-iodoaniline with 2-bromobenzenethiol in the prence of a CuI/l -proline catalyst (10mol %and 20mol %,respectively)in dimethoxyethane at 908C afforded only the simple S-arylation product 9a in 90%yield (Table 1,entry 1),which indicated that the
first coupling reaction proceeded smoothly and in accordance with our planned reaction quence.Next,we heated the reaction mixture at 1108C to attempt to facilitate the N-arylation cyclization step.However,in this ca we obrved
a
[*]Prof.Dr.D.Ma,Dr.Y.Jiang
State Key Laboratory of Bioorganic &Natural Products Chemistry,Shanghai Institute of Organic Chemistry,Chine Academy of Sciences
354Fenglin Lu,Shanghai 200032(China)Fax:(+86)21-6416-6128
E-mail:**************.ac Q.Geng,Prof.Dr.H.Zhang
Department of Chemistry,Shanghai University Shanghai 200444(China)
[**]The authors are grateful to the Chine Academy of Sciences and the
National Natural Science Foundation of China (grant 20621062and 20872156)for their financial
support.
Supporting information for this article is available on the WWW under dx.doi/10.1002/anie.200905646.
1291
Angew.Chem.Int.Ed.2010,49,1291–1294
2010Wiley-VCH Verlag GmbH &Co.KGaA,
Weinheim
complicated mixture containing the desired product 8a .Changing the solvent to DMSO and increasing the catalytic loading afforded the isolated product 8a in 66%yield,although some unidentified side products were also formed (Table 1,entry 2).The results demonstrated that the so
lvent plays a key role in this cascade reaction process;therefore,other polar solvents were then examined.The reaction in N -methylpyrrolidone gave 8a in moderate yield (Table 1,entry 3),whereas dioxane and 1,3-dimethoxypropane both gave phenothiazine 8a in low yields (Table 1,entries 4and 5);the best result was obtained using 2-methoxyethanol (Table 1,entry 6).Reducing the loading of the CuI catalyst to 10mol %caud the reaction yield to drop to 62%(Table 1,entry 7).Under the reaction conditions,three other ligands gave 8a in relatively low yields (Table 1,entries 8–10).Thus,we established our optimized reaction conditions to be using l -proline as a ligand and 2-methoxyethanol as the solvent.
After the optimized reaction conditions were established,we examined the scope and the limitations of our cascade process for the asmbly of substituted phenothiazines (Table 2).Using 2-bromobenzenethiol 7a as a coupling partner,we tested a number of substituted 2-iodoanilines.It was found that 5-substituted 2-iodoanilines containing both electron-rich and electron-deficient substituents worked well,giving their corresponding 2-substituted 10H -phenothiazines in good yields (Table 2,entries 1–7).However,the electronic influence of the substituent has a marked effect on the reaction rate of both the S-arylation and the N-arylation steps.In the S-arylation step,2-iodoanilines bearing an electron-withdrawing group generally reacted faster than tho with an electron-donating
group (Table 2,compare entries 1and 2with 3–7).However,this trend was inverted in the N-arylation step,made evident by the longer reaction times required by
the more electron-deficient anilines to complete the cycliza-tion.This phenomenon is consistent with previous studies on CuI/l -proline-catalyzed reactions,[16,17]and can be rational-ized by comparing the different nucleophilicities caud by their substituents.A similar reactivity trend was also noted when 4-substituted 2-iodoanilines were utilized as substrates.
Table 1:CuI-catalyzed coupling of 2-iodoaniline and 2-bromobenzene-thiol under different reaction conditions.
[a]
Entry Ligand [b]
Solventthe shadow
Product Yield [%][c]1A dimethoxyethane 9a 90[d,e]2A DMSO
8a 663A N -methylpyrrolidone 8a 484A dioxane
8a 225A 1,3-dimethoxypropane 8a 186A 2-methoxyethanol 8a 777A 2-methoxyethanol 8a 62[d]8B 2-methoxyethanol 8a 369C 2-methoxyethanol 8a 5210
D
2-methoxyethanol
8a
32
[a]Reaction conditions:6a (0.5mmol),7a (0.55mmol),CuI (0.1mmol),ligand (0.2mmol),K 2CO 3(2.5mmol),solvent (2mL),908C,48h;then 1108C,72h.[b]Ligand:A =l -proline,B =trans -4-hydroxy-l -proline,C =N ,N -dimethylglycine,D =1,10-phenanthronine.[c]Yield of isolated product.[d]0.05mmol of CuI and 0.1mmol of l -proline were added.[e]The reaction was carried out at 908C for 48h.
Table 2:CuI/l -proline-catalyzed coupling of 2-iodoanilines and 2-bro-mobenzenethiols for the asmbly of substituted phenothiazines.[a]Entry
Product
t 1[h]
t 2[h]
Yield [%][b]
140507128c :X =Me 40607538d :X =F 24728548e :X =Cl 28728558f :X =CF 32872836489670[c]78g :X =COMe
307079
840487398i :X =CF 3267286108j :X =COMe 306777118k :X =CN 307282128l :X =CO 2Me 356885138m :X =NO 2307284
14
48
60
64
15287088[d]圣诞节快乐英语怎么说
16267285[d]
17406077[e]
1848[f]80
暂时的英文1970[f]46[g]
2048[f]81[g]
[a]Reaction conditions:2-iodoaniline (0.50mmol),7a (0.55mmol),CuI (0.10mmol),l -proline (0.20mmol),K 2CO 3(2.5mmol),2mL of 2-methoxyethanol,908C,t 1;then 1108C,t 2.[b]Yield of isolated product.[c]The reaction was carried out in DMSO with 4mmol of 2-iodo-4-trifluoromethylaniline.[d]2-Bromo-4-methylbenzenethiol was ud as the coupling partner.[e]2-Bromo-5-fluorobenzenethiol was ud as the coupling partner.[f]DMSO,908C,for the indicated time.[g]2-Bromo-4,6-dimethylbenzenethiol was ud as the coupling partner.
四级英语分值分配细则
1292www.angewandte
birth是什么意思2010Wiley-VCH Verlag GmbH &Co.KGaA,Weinheim
Angew.Chem.Int.Ed.2010,49,1291–1294
Their reaction with7a afforded3-substituted phenothiazines 8h–m in yields ranging from73%to86%(Table2,entries8–13).Furthermore,the reaction could be scaled up to the gram-scale without any problems(Table2,entry6).
2,3-Dimethyl-10H-phenothiazine8n was obtained from 4,5-dimethyl-2-iodoaniline in64%yield(Table2,
entry14). To further demonstrate the capability of this process for the elaboration of polysubstituted phenothiazines,we attempted the coupling reactions between substituted2-bromobenzene-thiols and substituted2-iodoanilines,and were plead to isolate2,8-disubstituted phenothiazines8o and8p,the3,7-disubstituted phenothiazines8q,the1,3-disubstituted pheno-thiazine8r,the6,8-disubstituted phenothiazine8s,and the 1,3,6,8-tetrisubstituted phenothiazine8t in satisfactory yields (Table2,entries15–20).The results demonstrated that we would be able to introduce functional groups at the1,2,3,6,7, and/or8-positions of the phenothiazine ring by employing suitable coupling partners.A wide range of functional groups, such as fluoro,nitro,keto,methoxy,ester,and cyano groups were well-tolerated under the reaction conditions,which, along with the ability to decorate the phenothiazine ring at a variety of positions,makes this process very promising for synthesizing phenothiazines of great diversity.Importantly,2-bromobenzenethiols were esntial for this reaction as low yields were obrved when2-chlorobenzenethiol was ud as the coupling partner.
Next,we moved our attention to employing N-substituted 2-iodoanilines to synthesize N-substituted phenothiazines. The coupling reactions of diamines10a–10c with7a worked well,providing chlorpromazine11a,triflupromazine11b,and acepromazine11c in75–81%yields(Scheme1).The three compounds are clinically ud psychotropic drugs,whilst chlorpromazine11a has shown potential for the treatment of tuberculosis.
In conclusion,we have developed a new approach to construct functionalized phenothiazines,starting from sub-stituted2-iodoanilines and2-bromobenzenethiols,bad on a quentially controlled CuI/l-proline-catalyzed cascade pro-cess.The efficiency and substituent tolerance of this proce-dure have been fully demonstrated by synthesizing a number of functionalized phenothiazines.Some of the products are known psychotropic drugs or intermediates for preparing bioactive compounds.Considering the inexpensive catalytic system,and the convenient availability of the starting materials,this method can find numerous applications in organic synthesis.
Experimental Section
Typical procedure:An oven-dried Schlenk tube was charged with2-iodoaniline6a(0.5mmol),CuI(19mg,0.1mmol),l-proline (11.5mg,0.2mmol),and K2CO3(2.5mmol).The tube was evacuated and backfilled with argon,and then2-bromobenzenethiol7a (0.55mmol)and2-methoxyethanol(2.0mL)were added.The reaction mixture was stirred at908C for24–48h and then heated to 1108C for48–72h.After removal of the solvent in vacuo,the residue was partitioned between ethyl acetate and water.Extraction work-up followed by silica gel chromatography gave the desired phenothia-zine.
Received:October8,2009
Revid:December4,2009
Published online:January7,2010
.Keywords:copper·cross-coupling·heterocycles·homogeneous catalysis·phenothiazines
[1]A.Basta-Kaim,B.Budziszewska,L.Jaworska-Feil,M.Tetich,
M.Kubera,M.Les´kiewicz,M.Otczyk,W.Lason´,Neuropsycho-pharmacology2006,31,853.
[2]A.B.Bate,J.H.Kalin,E.M.Fooksman,E.L.Amoro,C.M.
Price,H.M.Williams,M.J.Rodig,M.O.Mitchell,S.H.Cho,Y.
Wang,S.G.Franzblau,Bioorg.Med.Chem.Lett.2007,17,1346.
[3]S.Darvesh,K.V.Darvesh,R.S.McDonald,D.Mataija,R.
Walsh,S.Mothana,O.Lockridge,E.Martin,J.Med.Chem.2008, 51,4200.normalization
[4]K.Kubota,H.Kurebayashi,H.Miyachi,M.Tobe,M.Onishi,Y.
e book
Isobe,Bioorg.Med.Chem.Lett.2009,19,2766.
[5]A.Bisi,M.Meli,S.Gobbi, A.Rampa,M.Tolomeo,L.
Dusonchet,Bioorg.Med.Chem.2008,16,6474.
[6]E.A.Weiss,M.J.Tauber,R.F.Kelley,M.J.Ahrens,M.A.
Ratner,M.R.Wasielewski,J.Am.Chem.Soc.2005,127,11842.
[7]R.Y.Lai,X.Kong,S.A.Jenekhe,A.J.Bard,J.Am.Chem.Soc.
2003,125,12631.
[8]H.-W.Rhee,S.J.Choi,S.H.Yoo,Y.O.Jang,H.H.Park,R.M.
Pinto,J.C.Camelle,F.J.Sandoval,S.Roje,K.Han,D.S.
Chung,J.Suh,J.-I.Hong,J.Am.Chem.Soc.2009,131,10107.
[9]T.Ito,A.Kondo,S.Terada,S.Nishmoto,J.Am.Chem.Soc.2006,
128,10934.
[10]a)N.L.Smith,J.Org.Chem.1950,15,1125;b)M.Mayer,P.T.
Lang,S.Gerber,P.B.Madrid,I.G.Pinto,R.K.Guy,T.L.James, Chem.Biol.2006,13,993;c)P.B.Madrid,W.E.Polgar,L.Toll, M.J.Tanga,Bioorg.Med.Chem.Lett.2007,17,3014.
[11]a)H.Yale,J.Am.Chem.Soc.1955,77,2270;b)C.Corral,J.
Lissavetzky,G.Quintanilla,J.Heterocycl.Chem.1978,15,1137;
c)R.Dixit,Y.Dixit,D.C.Gautam,N.Gautam,Phosphorus
Sulfur Silicon Relat.Elem.2008,183,1.
[12]For a review,e:H.W.Gschwend,H.R.Rodriguez,Org.React.
1979,26,47.
[13]For recent examples,e:a)M.Sailer, A.W.Franz,T.J.J.
Müller,Chem.Eur.J.2008,14,2602;b)M.Hauck,J.Schön-haber,A.J.Zucchero,K.I.Hardcastle,T.J.J.Müller,U.H.F.
Bunz,J.Org.Chem.2007,72,6714,and reference[7].
[14]T.Dahl, C.W.Tornøe, B.Bang-Anderson,P.Nieln,M.
Jørgenn,Angew.Chem.2008,120,1750;Angew.Chem.Int.
Ed.2008,47,1726.
[15]For lected examples of copper-catalyzed coupling reactions for
the preparation of heterocycles,e:a)R.Martín,R.Rodríguez, S.L.Buchwald,Angew.Chem.2006,118,7237;Angew.Chem.
Int.Ed.2006,45,7079;b)H.Miyamoto,Y.Okawa,A.Nakazaki, S.Kobayashi,Angew.Chem.2006,118,2332;Angew.Chem.Int.
Ed.2006,45,2274;c)B.Zou,Q.Yuan,D.Ma,Angew.Chem.
2007,119,2652;Angew.Chem.Int.Ed.2007,46,2598;d)X.
Liu, Scheme1.Synthesis of three psychotropic promazine drugs.
1293 Angew.Chem.Int.Ed.2010,49,1291–1294 2010Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim www.angewandte
H.Fu,Y.Jiang,Y.Zhao,Angew.Chem.2009,121,354;Angew.
英语四级考试流程
Chem.Int.Ed.2009,48,348;e)D.Ma,S.Xie,P.Xue,X.Zhang, J.Dong,Y.Jiang,Angew.Chem.2009,121,4286;Angew.Chem.
Int.Ed.2009,48,4222.
[16]a)H.Zhang,Q.Cai,D.Ma,J.Org.Chem.2005,70,5164;b)D.
世界上最远的距离 泰戈尔Ma,Q.Cai,Acc.Chem.Res.2008,41,1450.For recent reviews on copper-catalyzed carbon–heteroatom bond formation,e:
c)G.Evano,M.Toumi,A.Coste,Chem.Commun.2009,4166;
d)G.Evano,N.Blanchard,M.Toumi,Chem.Rev.2008,108,
3054;e)F.Monnier,M.Taillefer,Angew.Chem.2009,121,7088;
Angew.Chem.Int.Ed.2009,48,6954.
[17]a)H.Zhang,W.Cao,D.Ma,Synth.Commun.2007,37,25;b)W.
Deng,Y.Zou,Y.-F.Wang,L.Liu,Q.-X.Guo,Synlett2004,1254.
[18]Under CuI/l-proline catalysis,S-arylation of aryl iodides and
aryl thiols occurred at708C,whilst N-arylation of aryl iodides and anilines took place at908C;e references[16a]and[17a].
1294www.angewandte 2010Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim Angew.Chem.Int.Ed.2010,49,1291–1294
