寒食节风俗Highly Chemolective Metal-Free Reduction of Tertiary Amides
Guillaume Barbe and Andre ´B.Charette*
De ´partement de chimie,Uni V ersite ´de Montre ´al,P.O.Box 6128,Station Downtown,鼻骨歪了
Montre ´al,Quebec,Canada H3C 3J7
Received September 27,2007;E-mail:andre.charette@umontreal.ca
The reduction of amides to amines is a well-documented process
for which a large number of reaction conditions have been reported in the literature.They include the u of highly reactive reagents such as aluminum and boron hydrides as the most frequently encountered hydrogen sources.1The methods are usually high yielding and have been efficiently ap
橡胶沥青plied to the synthesis of a wide array of biologically active alkaloids.However,the low functional-group tolerance and tedious purification procedures often associated with such reaction conditions still reprent a major drawback.Over the past decade,silanes have emerged as an alternative hydrogen source in the transition-metal-catalyzed reduction of amides.For example,Rh,2a,b Ru,2c,d Pt,2e Mo,2f and Ti 2g complexes have been shown to exhibit catalytic activity in the hydrosilylation of carboxamides.Although improvements in terms of byproduct removal have been described,the high costs associated with catalysts and/or silane reagents along with the moderate chemo-lectivity obrved in most of the reduction reactions still impaired their generality.Herein,we describe a highly chemolective metal-free reduction process for the reduction of tertiary amides.
We previously reported that amides can be lectively trans-formed into a variety of carboxylic acid derivatives 3a and chiral piperidines 3b via an electrophilic activation with trifluoromethane-sulfonic anhydride (Tf 2O)in the prence of pyridine and a suitable nucleophile.More recently,Movassaghi reported the synthesis of polysubstituted pyridines and pyrimidines from amides using Tf 2O and 2-chloropyridine as activating agents and alkynes/alkenes or nitriles as respective nucleophiles.4In an effort to find mild and chemolective reaction conditions for the reduction of carboxa-mides,we hypothesized that treating an amide with Tf 2O would generate a highly electrophilic iminium derivati
ve that could subquently be reduced to the corresponding amine using a mild reducing agent.
Over the past century,1,4-dihydropyridines have been widely studied as hydrogen transfer agents for the reduction of unsaturated organic compounds.5More specifically,the Hantzsch ester (HEH)has been shown to reduce a wide variety of ketiminium and aldiminium species even at low temperature.This has recently found
赵二斗clever applications in organocatalytic enantiolective hydrogen transfer reactions.6
After surveying the reaction conditions,we were plead to find that submitting N ,N -dibenzylbenzamide to triflic anhydride 7and HEH 8,9in DCM 10at room temperature led to the formation of tribenzylamine in 70%isolated yield after 1h (Table 1,entries 1and 2).9We then investigated the electronic and steric effects of the reaction.By substituting the benzamide with electron-withdraw-ing (entry 3)and -donating (entry 4)groups at the para position of the benzoyl moiety,similar yields could be obtained.Moreover,N -aryl-(entries 5-8)and N -allylbenzamides (entry 9)were also found to be reduced under the conditions,albeit in slightly lower yields.Interestingly,the class of substrates are known to produce considerable amounts of the corresponding primary alco-hols and condary amines when reduced with LiAlH 4.11However,unde
r our reaction conditions,the questration of the oxygen atom by the electrophilic triflyl moiety completely prevented the forma-tion of such byproducts.
It is noteworthy that the reaction can also be performed on 1g scale without affecting the yield (entries 2and 6).As shown in entries 10and 11,amides bearing aliphatic substituents on either the nitrogen or the carbonyl unit were also found to be suitable substrates for the reaction.However,increasing the steric demand on either side of the amide moiety drastically impairs the reduction step (entries 13and 14).
We evaluated the chemolectivity of the reduction process by grafting different functionalities on N -benzoylpiperidine (Table 2).By positioning the functionalities at the 4-position of
the
Table 1.Metal-Free Reduction of Tertiary Amides
a
a
All reactions were performed on 1mmol of amide.b Reaction was performed on 1g scale.c No column chromatography
required.
Published on Web 12/13/2007
18
9
J.AM.CHEM.SOC.2008,130,18-19
10.1021/ja077463q CCC:$40.75©2008American Chemical Society
piperidine moiety,we minimized both the steric and electronic influence of the functional group on the reaction.We were delighted to find that,under our reaction conditions,a ketone (entry 1),esters (entries 2-4),an R , -unsaturated ester (entry 4),a nitrile (entry 5),an epoxide (entry 6),an alkyne (entry 7),and ethers (entries 5-7)were all tolerated,providing the corresponding amines in moderate to excellent yields.It should be noted that,in all of the cas,none of the reduced functionalities could be obrved,thereby demonstrating the high chemolectivity of the reduction process.A demonstration of the synthetic potential is shown in Scheme 1.Donepezil (5),an acetylcholine estera inhibitor ud for the management of Alzheimer’s dia,was marketed in the U.S.as Aricept (donepezil hydrochloride)in 1996.12It was originally synthesized from 4via a debenzoylation/benzylation quence.13This two-step process can now be reduced to a single step of amide reduction,providing donepezil (5)in 49%yield without the necessity of a flash chromatography.It is also noteworthy that the prence of the amide functionality results in crystalline material for all of the donepezil synthetic intermediates.
In conclusion,a highly chemolective metal-free reduction of tertiary amides has been developed.As was demonstrated in the chemolective synthesis of donepezil,we believe this could find great interest in the synthesis of highly functionalized molecules and especially in the synthesis
of natural products.Efforts are actually directed toward the extension of this methodology to condary amides,and the results will be reported in due cour.Acknowledgment.This work was supported by NSERC (Canada),the Canada Rearch Chairs Program,the Canadian Foundation for Innovation,and the Universite ´de Montre ´al.G.B.thanks NSERC (ES D)and Boehringer Ingelheim (Canada)Ltd.for postgraduate fellowships.
Supporting Information Available:Experimental details and spectroscopic data (PDF).This material is available free of charge via the internet at pubs.acs.References
(1)Seyden-Penne,J.Reductions by the Alumino and Borohydrides in Organic
Synthesis ,2nd ed.;Wiley:New York,1997.
(2)(a)Ohta,T.;Kamiya,M.;Nobutomo,M.;Kusui,K.;Furukawa,I.Bull.
Chem.Soc.Jpn 2005,78,1856-1861.(b)Kuwano,R.;Takahashi,M.;Ito,Y.Tetrahedron Lett.1998,39,1017-1020.(c)Motoyama,Y.;Mitsui,K.;Ishida,T.;Nagashima,H.J.Am.Chem.Soc.2005,127,13150-13151.(d)Igarashi,M.;Fuchikami,T.Tetrahedron Lett.2001,42,1945-1947.(e)Hanada,S.;Motoyama,Y.;Nagashi
ma,H.Tetrahedron Lett.2006,47,6173-6177.(f)Fernandes,A.C.;Romao,C.C.J.Mol.Catal.A 2007,272,60-63.(g)Selvakumar,K.;Rangareddy,K.;Harrod,J.F.Can.J.Chem.2004,82,1244-1248.
(3)(a)Charette,A.B.;Grenon,M.Can.J.Chem.2001,79,1694-1703and
references therein.(b)Charette,A.B.;Grenon,M.;Lemire,A.;Pourashraf,M.;Martel,J.J.Am.Chem.Soc.2001,123,11829-11830.
(4)(a)Movassaghi,M.;Hill,M.D.;Ahmad,O.K.J.Am.Chem.Soc.2007,
129,10096-10097.(b)Movassaghi,M.;Hill,M.D.J.Am.Chem.Soc.2006,128,14254.(c)Movassaghi,M.;Hill,M.D.J.Am.Chem.Soc.2006,128,4592.
(5)(a)Lavilla,R.J.Chem.Soc.,Perkin Trans.12002,1141-1156.(b)Stout,
D.M.Chem.Re V .1982,82,223-243.(c)Eisner,U.;Kuthan,J.Chem.Re V .1972,72,1-42.
(6)(a)Yang,J.W.;Hechavarria Fonca,M.T.;Vignola,N.;List,B.Angew.
Chem.,Int.Ed.2005,44,108-110.(b)Ouellet,S.G.;Tuttle,J.B.;MacMillan,D.W.C.J.Am.Chem.Soc.2005,127,32-33.(c)Mayer,S.;List,B.Angew.Chem.,Int.Ed.2006,45,4193-4195.(d)Tuttle,J.B.;Ouellet,S.G.;MacMillan,D.W.C.J.Am.Chem.Soc.2006,128,12662-12663.(e)Martin,N.J.A.;List,B.J.Am.Chem.Soc.2006,128,13368-13369.(f)Rueping,M.;Sugiono,E.;Azap,C.;Theissmann,T.;Bolte,M.Org.Lett.2005,7,3781-3783.(g)Hoffmann,S.;Seayad,A.M.;List,B.Angew.Chem.,Int.Ed.2005,44,7424-7427.(h)Storer,R.I.;Carrera,D.E.;Ni,Y.;MacMillan,D.W.C.J.Am.Chem.Soc.2006,128,84-86.(i)Hoffmann,S.;Nicoletti,N.;List,B.J.Am.Chem.Soc.2006,128,13074-13075.(j)Rueping,M.;Antonchick,A.P.;Theissmann,T.Angew.Chem.,Int.Ed.2006,45,3683-3686.(k)Rueping,M.;Antonchick,A.P.;Theissmann,T.Angew.Chem.,Int.Ed.2006,45,6751-6755.
(7)Unlike other reagents that were screened (e.g.,POCl 3,(COCl)2,Et 3+OBF 4-),
歌唱祖国完整歌曲原唱Tf 2O reacts rapidly (<5min)and is not substrate-dependent.
(8)A small excess is necessary due to some HEH decomposition in the
reaction conditions:(a)van Bergen,T.J.;Mulder,T.;Kellogg,R.M.J.Am.Chem.Soc.1976,98,1960-1962.(b)
van Bergen,T.J.;Kellogg,R.M.J.Am.Chem.Soc.1976,98,1962-1964.(9)See Supporting Information for more details.
(10)Other solvents such as MTBE,Et 2O,THF,or toluene led to low conversion
due to low solubility of the iminium triflate and HEH.
(11)Akamatsu,H.;Kusumoto,S.;Fuka,K.Tetrahedron Lett.2002,43,
8867-8869and references therein.
(12)(a)Roberson,E.D.;Mucke,L.Science 2006,781-784.(b)Melnikova,
朝花惜拾
I.Nat.Re V .Drug Disco V ery 2007,6,341-342.
(13)Sugimoto,H.;Iimura,Y.;Yamanishi,Y.;Yamatsu,K.J.Med.Chem.
1995,38,4821-4829.
JA077463Q
Table 2.Reduction of Functionalized Amides
a显示器闪烁
a
All reactions were performed on 1mmol of amide.b No column chromatography required.
Scheme 1.Chemolective Synthesis of
Donepezil
C O M M U N I C A T I O N S
J.AM.CHEM.SOC.
药圣李时珍
9
VOL.130,NO.1,200819
