铜催化苯酚与重氮盐的O-芳基化反应方法学

正文

二芳基酸骨架广泛存在于各类天然产物、农用化学品、药物分子以及聚合物

中。并且，在过去的几十年里，已经成功设计出多种构建二芳基酸分子的合成转

化策略(Scheme1-1)。然而，上述的策略存在使用贵金属催化剂或空气敏感的瞬

配体、反应条件苛刻、形成有毒副产物等弊端。受到近年来对于苯酚与重氮盐参

与相关反应方法学(Scheme1-11)以及铜催化Sandmeyer-与Meerwein-型芳基化反

应方法学⑷相关研究报道的启发，这里，报道一种全新的铜催化苯酚与重氮盐的

。•芳基化反应方法学，进而成功完成一系列二芳基醍分子的构建(Scheme1c)。

Previousworks:

(I)Synthesisofdiarylethers

—ulM.④。逊

X=Cl.Br,I,B.Si,Sn.Bi

(II)Reactivityofphenolswithdiazoniumsalts

(a)TraditionalMeerweinreactivitywithphenols

(b)RadicalC(sp2)-Harylationofphenolswithdiazoniumsalts

5-10equiv.

Thiswork:

(c)Cu-catalyzedO-arylationofphenolswithdiazoniumsalts

/^NBF4心fOH[Cu].rt.6h

@2+igr-------④麴

•Mildconditions44examples

•Broadsubstratescopeupto93%yield

•Latestagemodification

Scheme1Synthesisofdiarylethersandreactionsof

electrophilicdiazoniumsalts.

1彳先，作者米用4-methoxybenzenediazoniumsaltAl与4■羟基文月青B1作为

模型底物，进行相关反应条件的优化筛选(Table1)。进而确定最佳的反应条件为:

采用［卬1\/160\1)4厮4作为催化剂，2,4,6-三甲基毗咤作为配体，Na2c。3作为碱，在

MeCN反应溶剂中，反应温度为室温，最终获得91%收率的产物C1。

Table1OpeimUMtecftfwr«ectioncortdktom*

N声.fCu|(2Omol%)

^md(40momi

bMe(20eo«vX<1

soMrtQ5dRN;

A1Bl

C4UlyttligindSotv♦nfYieldo<Cl<%>YiHdofDI<%>

MCO,045

阳.

KMMe<NLNa1coi6610

(CMMKNMBF.ZAJoMrwrum910

KMMKNM24,J*dineM.KO>890

Cu(OTf)O.SC4K23.6<o«idme900

CuCI24.JOMMyo.S30

CuBr2,4,6-coMineyo,810

CuiJoflidineyo.830

7OT0,”.JoMine1511

CgOAcbHjO24.Jo«i(MeM12CO»033

CuCI,23.6-coftdineHI,COB730

ZMeCNkM2<6《oNidixN'CO.5621

K3MMLM2>lutidineN^CO,80trace

(Cu(MKNk)BF.pyridineXOj860

(Cu(MKNh]BF.N.N<Wnefhy1pyndin-4*mineNaXOl5312

(Cu(Me<Nh)BF.2,2*-bi|>yridineN^O,22trace

“MMkM1.1(^phenanthrolineN.g10trace

(Cu(MKNhJBF.2.4,a《ottid2MO>66tr«ce

18K3MKNLM2.4>coNidine"O.6313

19(Cu(Me<NU)BF«2.4,6-coNidineN1HCO>70trace

2O

S2.4,6coNidineN.Po.trace

:|Cu(Me<NkM1n

22(CuIMKNhlBF.2,4,JoiidZtrace

2J«MMKNkM2,4>co«idineNa^O,810

”

:(CuiMKN^jBF.2.4>coNidineMeCN409

5

KSMMNkM“QcoNidigNa^OiMethanol24trace

2"6KuiMKNMBF.2.4,JoNidixXOi5536y

[CMMKNLM2,4,6-coNidineNa>CO,dichloroethAne18trace

28

”KuIMKNkjBF.2,4,6collidif”XO>ACOUf109

M>2,4,6coNidigNaXOiDMSO0tr*c«

”

(Cu(Me<Nk)BF.2.4,JoNidixXO.DMF00

;J

(Cu(Me<Nh)BF.2.4>co«idineMS,1.44MAne0tr*ce

|Cu(MKNU)BF.2,4,JoiidixN七gMKN6610

•ReMtioncontfillon:Al(1mmol2.0eqeiv).Bl(0.5mmol.1.0equ*v).(20mol%),Ii<jnd(40moM),Zte(1nwnol.L0wlvent(2.5ml),N加6h.HHC

0HdvUngbiphenylMtheIrMefnaltUndird.P—g10mofK(Cu(MeCN)4)BF«and20mot%2,4.6coli<ftne.IXing0.SmmolNa^CO).，nair.

在上述的最佳反应条件下，作者分别对一系列茶酚以及重氮盐底物(Table2)

的应用范围进行深入研究。

Table2Substratescope0

[Cu(MeCN)JBF4(20mol%)

246<ollidine(40mol%)

Na2cO3(2.0equiv),rtGT°逾

MeCN(2.5mL).6h.N2

R

6°n

C1:R=OMe,88%CN

C16:R=CH.65%

C2:R=H.88%3

C3:R=Me.84%C17:R«OMe,93%

C18:R=SCH,59%

C4:R=Et.80%3

C19:R=O.51%

C5:R='Pr,86%6：n

C6:R«92%C21:Ri=H：R21PhC,N55%

C7:R-OEt91%w°uC22:Ri=R?=Me.70%

C8:R=COMe,71%

C23:55%CN

C9:R=F.44%

C10:R=CI,69%°tn°u

C11:R=Br,45%廿dCN

c

C12:R=CF.75%C25:50%.62%

3C24:45%,50%c

C13:R-CN.61%

C14:R«CO2Et,65%MeQU

C15:R=CO2Me,59%

CNC1:R=CN.88%

MQQC37:92%

C26:R»COMe.80%

C27:R=COEt,82%

6$

C36:88%C28:R=CO；Me,86%

C29:R=CO：Et.84%

C30:R=COPh,84%

C39:40%C31:R=Ph.6O%

C32:R=CFj62%

C33:R=Cl.40%,51%6

C34:R=Bu33%,42%6

C35:R=OMe,31%.41%°

C40：45%

C42:41%

RXO

C45:40%

•Reactionconditions:A(1mmol2.0equiv),B(0.5mmol,l.Oequh/),[Cu(MeCN)4lBF4(20mol%)f

#

2,4,6-collidine(40mol%),Na:CO>(1mmol,2.0equiv),MeCN(2.5ml),N2,6%isolatedyield.

Reactiontime=12h.cReactiontime=24h.

(I)

stardard

conditions

TEMPOCNMeO

(2.0equiv)

C1detectedbyLCMS

trace

1mmol0.5mmolm/z(M♦H]*2641958

fourd:2641962

standardPh

conditions

1,1-diphenylethylene

-HX咦

N(2.0equiv)

OMe530%40%bMe

A1B1

1mmol0.5mmol

(III)

N2BF4

[Cu(MeCN)4]EF4(20mol%)

2463lltdine(40mol%)

Na2co3(20equiv),rt

OMeMeCN(2.5mL),6h,N2

A1TEMPO(2.0equiv)

1mmol

Scheme3Preliminarymechanisticcontrolexperiments.

Note*ofSctvcme3

1)IM*edontheseredoxpotcntMls,wepropoMthattheCu(l)speciescanreadilyreducethedi«i/oniufr

cations.

2}When2equivalentsoffreeradicalsc^vengei2.2.6.6tetramethylpipcridm<1oxyl(TEMPO)wasadded

intotheetherificationreactionofA1andB1unlertheoptHnizedconditions,onlyatraceamountofC1

wasobtained(SchemeThisresultsuggestsafreeradicalcoupling.

3)Theseresultsareconsistentwiththefoon・tbnofaryl-Isintheethenfic4tk>nreaction.

a.Thehighresolutionmassspectrometry(HRMS)spectrum(Fig.