串联自由基环化分子间偶联高效构建官能团化吡咯并吲哚啉反应方法学

C3a-取代毗咯并吧喙咻骨架广泛存在于各类天然产物以及生物活性分子中

(Fig.l)o并且，在过去的几十年里，已经成功设计出多种构建C3a-取代毗咯并呵

晚琳分子的合成转化策略(Schemesla和lb)。然而，上述的方法涉及过渡金属

催化剂或光氧化还原催化剂的使用。受到近年来2-azaallylanions参与串联环化

反应方法学以及酰胺基自由基参与相关反应方法学⑷研究报道的启发，这里，首

次报道一种全新的2-azaallylanions与叫噪乙酰胺衍生物参与的串联自由基环化/

分子间偶联反应方法学，进而成功完成官能团化毗咯井口引口朵咻分子的构建

(Schemelc)o

Fig.1RepresentativeC3a-substitutedpyrroloindolinenatural

products.

a.Transition*metal-catalyzedcyclizationtoC3a-substitutedpyrroloindoline

MacMillan.2012

Wang.2018

c.Thiswork

Scheme1(a)Transition-metal-catalyzedcyclizationtoC3a-

substitutedpyrroloindoline.(b)Visible-light-inducedradical

cyclizationtoC3a-OHpyrroloindoline.(c)SED2-azaallylanions

enablesynthesisofC3a-substitutedpyrroloindolines(this

work).

首先，作者采用Af-benzylketiminela与口引跺N-芳氧基乙酰胺衍生物

(indoleN-aryloxyacetamide)2a作为模型底物，进夕亍相关反应条件的优化筛选

进而确定最佳的反应条件为：采用作为碱，在反应溶

(Tablel)oNaHMDSDMSO

剂中，反应温度为室温，最终获得89%收率的产物3aa(dr=1.2:l)。

Table1Optimizationofcouplingofketiminelaandamide2aab

o

1a(1.0equiv.)2a(2.0equiv.)3aa

Cone.

EntryBase(equiv.)SolventYield(%产

(M)

1LiOrBu(1.5)DMSO0.256(dr=1:1)

2NaCHBu(1.5)DMSO0.261(dr=1:1)

3KO?Bu(1.5)DMSO0.265(dr=1.3:1)

4□HMDS(1.5)DMSO0.259(dr=1:1)

5NaHMDS(15)DMSO0.289(86下(dr=1.2:1)

6KHMDS(l.S)DMSO0.265(dr=1:1)

7NaHMDS(1.5)THF0.20

8NaHMDS(1.5)DMF0.20

9NaHMDS(1.5)CPME0.20

10NaHMDS(1.5)MTBE0.20

11NaHMDS(1.5)MeCN0.20

12NaHMDS(1.5)DMSO0.178(dr=1:1)

13NaHMDS(1.5)DMSO0.0568(dr=1:1)

14NaHMDS(2.0)DMSO0.272(dr=1:1)

15dNaHMDS(1.5)DMSO0.122(dr=1:1)

16*NaHMDS(lS)DMSO/THF=1:10.18(dr=1:1)

°Reactionconditions:la(0.1mmol,1.0equiv),2a(0.2mmol,2.0equiv),

base,rt.,3h.tAssayyield(AY)determinedbyNMRspectroscopyof

thecrudereactionmixtureusingC2H2cLasaninternalstandard.e

Isolatedyieldafterchromatographicpurification.a60℃.e0*C.

在上述的最佳反应条件下，作者分别对一系列N-benzylketimines底物（Table

2）以及口引噪乙酰胺底物（Table3）的应用范围进行深入研究。

Table2ScopeofKetimineslab

3qa86%,dr■14:13rW82%.dr■15:13sa88%.1.5:1

•Reactionsconductedon0.4mf»olsoleusing1equivofla-loand2equrv

of2«.*Isolatedyieldafterchromatographicpurification.Flu■9-fuorenyl.PG

=protectgroup.^-(SH-Fluoren-S-yl)«lkylanimineasthe2-azaallylprecursor.

Table3Scopeofindoleacetamides2ab

3ab63%,dr«2.1:13ac65%.dr■1.1:13ad60%.de■1.2:1

NCPh2

*

Me

7S%,dr-1.1:1

3ah72%,dr«1:13ai52%,dr»1.2:13aj46%,df«1.1:1

3ak56%,dr=1:13sm67%,drs1.2:1

°Reactionsconductedon0.4mmolKaleusing2equivof2b*2l,and1equw

ofla.aIsolatedyieldafterchromatographicpurification.Flu:9-fuorenyl.PG

aprotectgroup.rN-(9H-Fluoren-9-yl)«lkylammineasthe2-azaally1precur$or.

NotesofTabto3

a.Arangeofindot^A/-oryioxy18tamx>+b«aringvariousgroup*wereall

compatiblewithourmtthod.generatingthepynoloindolineproductsinmoderaU

togoody&ds(46-78%>.

b.Forinstance,tndolederivativeswithelectrorwlonatingsubstituents,suchas7-

Me(2t>).$<OMe(2c)andS-O6n|2d),affordedcyclizationpcoducti3ab,3acand

3ad

in63%.65%and60%yields,respectively.

c.MoteacatamWMwMhelKtaMgMivefuMlMMl^MChas5-F(2e)and5*8r

(2f).providedthecorrespondingproducts3Mand3afIn58%and60%yW4dt.

d.Itifnoteworthythatindoledtdv.Hv”wrttiatwterocycbcpiperonylgroup<2g)

andstericaltyhinderedruphltiylgroup(2h)3tocouplingproduct*ggand3ah

S78%and72%yields,respecUvely.

e.Inaddition,weexploredarangeofindole^arytoxyac»Um«desubstrates.

Gratifyingty.whenweextendedc'wiro：匚f-jcr」，》曲•卜tc

thwn•[厂m,thecorrespondingsix*andwv，rwn«nb»rringproducts3ai

and3ajwereobtainedin)7，、««idyick：i.respectively.

f.Furtheffncxe.weintroducedMerichinderancealtheC2posttionofiMole

substrates(2-m«thy1(2k)andZVyl(20],lead*ngtocyclizaticmproducts3«kMMS

3alin对;.andS5%ytkl».

gNext,wauseindolederivativesbearingbenzyl(2m),altyl(2n)andBoc(2o)

substituents,whichaffordedcyclttabonproducts3sm.”nand3som67.70and

M%yltldi,wipecliyly._____________________________________

之后，该小组通过如下的一系列研究进一步表明，这一全新的串联SET/自由

基环化/分子间偶联策略具有潜在的合成应用价值（Scheme2）。

aGram-scalereaction

Ph-NH

22a,8.0mmolNCPh?

4c,1)THF,50℃

4.0mmol…NaN(SiMe3)2

12h(1.5equiv.)

2)Remove

DMSO,rt,3h

solvent

Me

4.0mmol1a.4.0mmol3aa,74%

1.40g,dr=1.2:1

bProducthydrolysis

3aa4aa.92%

Scheme2(a)Gram-scalesequentialone-potsynthesis,(b)

Hydrolysisoftheproductimine.

接下来，作者对上述串联SET/自由基环化/分子间偶联过程的反应机理进行

进一步研究（Scheme3）。

2a(2.0equlv)(2.0equlv)5aa.trace

Scheme3Controlexperiments.(a)Radicaltrapping

experiment.(b)Reactionintheabsenceofketimine.

NotesofScheme3

1)Together,theseresultssuggestthatthereactionproceedsviaaradical

pathway,supportingthekeySET/radicalcychzatkxi/couplingpathway.

a.First,theexperimentwiththeadditionof2.0equiv