or how to convert RNHCOR′ into RNHCOR″ avoiding drastic hydrolyses

Tetrahedron Letters,Vol.28,No.3,pp Printed in Great Britain

0040-4039/87 $3.00 + .OO Pergamon Journals Ltd.

341-342,1987

NEW SYNTHETIC "TRICKS". FROM ALIPHATIC AMINES AND AMIDES TO AZIDES AND/OR HOW TO CONVERT RNHCOR' INTO RNHCOR" AVOIDING DRASTIC HYDROLYSES

Jordi Garcia and Jaume Vilarrasa Departanr+ntdeQuioricaOr@nica, FacultatdeQ&ica,DnivarsitatdeJkrcelona(III), 08028E!arcelona,C&alonia,Spein

Cxmrolladreduction of N-alky1-N-nitroscmide.s to hydraaides followed by nitrosation and fragmentation affords azidesin 80% overall yields, undermildconditions. Thissimpleideais thebasisof methods fortheconversion of alkylaedues andN-alkylanddea to alkylasides, of RNKIX' intoRNKIX"or RN(CIX')2, and of lactanes into+azido estersorw-azidoacids. Traaafonaation of RNH~intoRN~,thereverse process of thewidelyutilized reduction of azidasto amines, haa beencccasioaally investigated, withseveral purposes (although nainlyaimedat protecting i+.a k=ic/aucle@ilic/reduciagamiao group)anNtith variable success. l-5 Also, ++%.F=Y*o

in connection withotherstudies in tich we developed a one-pot reaction fortheconversion of azidestoarnides to recycle scm amides (e.g., L-+gt6 we hadthought toazidesforsavingstartingnaterial. We report herethat solvedby-

these

1

2

7--

tm synthetic problems(and tm othercmmnted below) may be closely related and

of thefollowing gmeralstrategy

introduces theadditional nitrogen atansstepby a&p but

which

moreconfidently, generally in betteroverall yields.

According

to thisszhem,RNKOR' (andobviouslyRNH2) couldbe converted intoI+,' RNHODR' couldbe changed to

RNU%?8 or RN(CD?)2avoiding previous drastic hydrolyses of RNKDR'to RNH2,andN-alkylhydrzides (andN-alkylhydrazines) couldbe prepared fromamides(oramimes).Furthermore, whenR andR' are linked(i.e.in Lactames) the acidsorw-azidoesters.Sincethenitroeationofmtxtanrides

cleavage of theN-CDR'bondcouldgiverisetow&do

(stepA) can be performed quantitatively in cold,underanhydrous conditions,g*10 and since

step

Db

beenalready

diaclo=k6 onlythereduction step(B)and thenitrosatior+f~tationstep(C)are enphasized here. Reduction of Nitroscanrides to Hydraaides We havesystematically investigated thereductionof

N-nitr

cecemides Z&to theirN-am6noderivativesunder the -following conditions: (a)SnCl2/KZl,Et~/r.t.; (b)Sn@Ac)2/AcOIt/r.t.; (c)Sn/aqHCl,EtCH/r.t.; (d)L&/AcCH/r.t.; (e) zn/~OH,~CLE~@X;

(f)H2/Pd-C/MsGL!r.t.; (g)H2/Pd-C/A&/r.t.; (h)Al-Hg/aq Et2Ur.t.;(i)A&H&q

Et2C/AcCIU

r.t.;(j)TiCl@IaAcCVH$,&@I/r.t.; and (k)TiCl@g/(X$l2,Et2C#JC. %+-$=

(?q2-?g(ar2)1f13

3

mT

(--J&

$I$

q*

4 !I

7

(N-L..

TnebestresultshavebeenobtainedwithZn/AcOH(8085%ofpurehydrazidesll_eisolatedafteraddingdropvise solutions of_38_into a suspension of Zn in AcCHnaintajmed at1C-15cc)andtithTX&& (ca.fX3% yields). Underthe renain& conditions, theyieldaofRN(NH2)cDR' havealways teenixlowlC& thecorrespondimgawides beingthepredominantproducts. 341

342 Nitrosationof N-AlkylhydrazidesandCleav~e Although thenitrceation of msubstituted hydrazides is kxwn to affordacyltides since1898,l* thereactivity ofRQ-NR~2a.ndRUMR~withnitrosating

agentshasnot been reported, to ourknowledge. LJsingRN(NMc)CLR',

perform@ thenitrosation in CH2Cl2withN$4 in cold,9*10 and treating thenitrcmtedprcducttithNk@ incoldor heating it i.nMIHor inH2O/'IBFfor a fewhours, azideswereobtained in 7C-75%yieldsin allcases.For instance: pncHTEIII_cc(H2pn- mq-2fi NHAc N(m)Ac

w

n'

Fw2-N3

(+ Acm t rm$mI)

lhe reaction canalsobe accmplished by nitrosation of thenon-ace tylated hydrazides, i.e.R-N(NH2)a', with NW/A&,

thoughin nrxevariable yields(4m

of azide).

Optimized procedure lhe bestwaywehavefound to shortenorsimplify.the experimental procedure is to performthefirstnitrosation (A)and thereduction (B)as a onepotreaction and to carryoutthesecondnitrosation and thecleavage at thesaw tin& as follows: CXle~loftheanrideandca.403~ofNaAd)in3mlofPc20and3mlofAc(%Iweretr~t~at~100Cwith250mg of li3+HSO4-; whenthenitrosation vascanplete (TLC), urea and thena coldsuspension of Zn pn&r in AcCII wre added; almxtimnzdiately themixturewsfiltered, thesolutionwsconcentrated undervacunn, and theresiduewas purified by chramtography to affordthediacylhydrazine. lhiscaqxnmd(0.8mls), iqentyl nitrite (ca.8 mls), and Z-10 ml of OL'l4 wereheatedat refluxovernight; elimination of thesolvent andexcessof isqentylnitrite and purifie tionof theresidue on silicagelgavetheazide.'lkus, 2v+astransformed to 1 in goodyield(8%&): hwz04-, then2n -2

-1 AC$, A&, NaAcQ‘l@C (=%)

In similar overall

yields(ca.8o%)M2m2Ph

+as converted intom2N3,

caprolactaw afforded

N3(a2)5ccoc5Hll, anddc&xanolactaw gaveN3(cH2)11CIXC5B11. For theconversion of RNH2to RN3,theacetylation of thetie in situ,by the"solvent" itself(A@, Ad& NaAcO), is obviously rexnnended.

1) Yieldsbetxen 23%and 47%areobtained frcmRM&X andTsN3,according to RNH@+T.sN+~TsNH@(W.Fischer,J.P. Ansel11e,JACS-89,5284,1967; J.B.Hendrickzxx1,W.A.Wolf,JCC33,3610,19@; J.P.Anselw,W.Fischer,T-25,855,1%9). 2) Ar&ogousdiaz-transfer reactions, usingRNH2and triflyl azide,proceed in 19-78% yields(C.J.Ck~vender,V.J. &iner,~37,3567,1972; J.&kan,D.C.Roberts,JCC46,5173,1~1). 3)'Ihereactionof cyclohexylamjne plusrrethyllithiuntithN~under pressure onlygivesal%yield of cyclohexyl azide(G.Koga,J.P.Anselmz,J~,446,1%8). 4) Treabwntof RNH1with organic hyponitrites didnotgiveRN3at all (F.Urp~,Grad.Thesis,Lkv.Barcelona,1~1). 5) Forotherapproaches to alkylazidesfranalkylamines see:(a)A.R.Katritzky et al.,~PTI,849,1980; (b)P.J. k&ristopheret al.,JACS-91,2384,1969; J.B.kndricksm et al.,JACS-95,3412,1973. Banaszek,Iz27,639,1986; J.Garcia, 6) J.Garti,F.Urp~,J.Vilarrasa,TL-25,4841,1984; J.Garcia,J.VLlarrasa,X.Bordas,A. tkct.Thesis,univ.E!arceloI?a,l~. 7)Albeitlonger, it couldbe an alternative route to theabov-tioned d&x-transfer reactions forrrolecuks including fun&i& groupsor unsaturations incanpstiblewithTfN3orTf@ orwithTsN3orbasicwdia. 8) Thisis thecanplmentof sn earl&rprccess9 in tich theaminenrketyof amideswith"valuable" acylgroupsis ("Valuable" nmns herewithsaw functions, chiral replaced by another amine:R$ccNHR' -R$CON(NO)R'-RF'. centers, or protecting groupssensitive to acids,bases,or heating.) In thepresent paperthealternative poasibilityis devel&ed:R'~~-tN3R$ -+R"CLNHR$. 9) J.c&-cia,~.Vilarrasa 23,1127, 932;J.Garcla,.J.Gonz&z,R.Segura,F.Urp~,J.V~a=,~9,3322~~~. 1OjE.H.Whit&J&77,ti,'195~. at ll)Either hydrazid~RN(NH2)CUR' or RN(NHAc)m'rrey beobtainedatwill: if theexcessof ACOHis *ted r.t.(va~um~punp), thefreeN canbe isolated; on the otherhsnd,ifAd3Hiseliminatedat@m of if thereduction is performzd in thepresence of Ac$ (i.e.with&/~A$), thediacylhydrazine is directly obtainad. 12)cf. ‘Methoden derOrgan&&n Me (Bouba+&yl)",Band 8,p.681,G.Thieme Verlag,Stuttgart,l952. (Received

in UK 11 November

1986)