JACS-THayashi-炔,格式试剂,ArI三组分偶联得到四取代烯烃

Nickel-Catalyzed Three-Component Domino Reactions of Aryl Grignard Reagents,Alkynes,and Aryl Halides Producing

Tetrasubstituted Alkenes Fei Xue,?Jin Zhao,*,?T.S.Andy Hor,*,?,?and Tamio Hayashi *,?,?

?Department of Chemistry,National University of Singapore,Singapore 117543,Singapore

?Institute of Materials Research and Engineering,Agency for Science,Technology and Research,Singapore 117602,Singapore *Supporting Information

ransition-metal-catalyzed multicomponent domino and

tandem reactions have been powerful tools for constructing complex molecules in a single ?ask.1One representative reaction is the Pd-catalyzed three-component reaction,reported by

Larock,of internal alkynes,aryl iodides,and arylboronic acids producing tetrasubstituted alkenes.2,3The reaction proceeds through an alkenylpalladium species as a key intermediate,which

is formed by oxidative addition of aryl iodide to Pd(0)followed by arylpalladation of alkyne.It reacts with arylboronic acid to give the tetrasubstituted alkene through reductive elimination (Scheme 1a).4,5Another synthesis scheme to produce tetrasubstituted alkenes from alkynes,aryl halides,and arylmetal reagents can be via alkenyl metals generated by carbometalation

of alkynes.There have been several reports on the addition of organomagnesium 6or -zinc 7reagents to unfunctionalized alkynes forming the corresponding alkenyl metals,catalyzed by

transition metal salts or complexes,and these have been subjected to further reactions to produce tetrasubstituted alkenes

by taking advantage of their high reactivity.8Scheme 1b illustrates some reactions where the alkenyl metal reagents were used for the next step.Alkenyl Grignard reagents generated

by Fe-or Cr-catalyzed carbomagnesiation of alkynes are mixed with organic halides in the presence of a Ni or Pd complex that catalyzes the cross-coupling to give tetrasubstituted alkenes.6e,g

Alternatively,the alkenyl metal reagents are converted ?rst into alkenyl iodides and then they are subjected to Ni-or Pd-catalyzed cross-coupling with organometallic reagents.7a,f,9To our knowl-

edge,there have been no reports on the reactions where a mixture of alkyne,organometallic reagent,and organic halide produces a tetrasubstituted alkene by the carbometalation/cross-

coupling sequence 8(Scheme 1c).The three-component reaction should consist of two sequential reactions:carbometalation generating alkenyl metal species (cm1)and its cross-coupling with organic halide (cc1).One serious problem in a three-component reaction would be a possible side reaction where R 1?MX reacts with organic halide X ?R 2(cc2)before the reaction with alkyne.Another problem is the carbometalation of alkyne with the alkenyl metal generating dienyl metal species (cm2).To realize the three-component reaction,cm1must be much faster Received:December 26,2014

Published:February 25,2015

Scheme 1.Three-Component Reactions of Organometallics,Alkynes,and Aryl Halides Producing Tetrasubstituted

Alkenes

?2015American Chemical Society 3189DOI:10.1021/ja513166w J.Am.Chem.Soc.2015,137,3189?3192

than the unfavorable competing cross-coupling (cc2),and cc1must be much faster than cm2.During our studies on the NiCl 2-catalyzed arylmagnesiation of arylalkynes generating alkenylmagnesium reagents,6b we found that the three-component domino reaction of aryl Grignard reagents,alkynes,and aryl halides is also e ?ciently catalyzed by NiCl 2.Table 1summarizes the results obtained for the reaction of diphenylacetylene (1a )with phenylmagnesium bromide (2a )and 4-iodoanisole (3a )in the presence of transition metal salts and complexes that have been reported to catalyze the carbomagnesiation and/or cross-coupling reactions.The highest selectivity in forming the tetrasubstituted alkene was obtained with NiCl 2as a catalyst in a THF/toluene mixed solvent.Thus,to a mixture of 1a (0.50mmol),3a (0.60mmol),and NiCl 2(0.005

mmol,1mol %)in toluene (2.0mL),was added PhMgBr/THF (2a ,0.60mL of 1.0M THF solution,0.60mmol),and the mixture was stirred at 30°C for 2h (entry 1).Aqueous workup gave 82%yield of the three-component coupling product 4a .Formation of a minor amount of triphenylethene (5a ,5%)and tetraphenylethene (7a ,5%),together with biaryl 6a (11%),was also observed.It is likely that 5a is formed by hydrolysis of 8a and that 7a is formed by cross-coupling of 8a with phenyl iodide that is generated by the Mg/I exchange reaction.10No 1,3-dienes,which would be formed by the addition of 8a to 1a ,were detected.11

The toluene/THF mixed-solvent system is important for high selectivity of 4a .Using all THF gave 4a in only 51%yield,with a greater amount of the side products (entry 2).The yield of 4a was 77%using diethyl ether in place of toluene as a diluting solvent (entry 3).Interestingly,arylmagnesiation or cross-coupling did not take place with 2a in diethyl ether,with starting 1a being recovered intact (entry 4).Addition of a small amount of THF to the toluene/diethyl ether mixed-solvent system gave essentially the same result as that of toluene/THF (entry 5).NiCl 2·6H 2O catalyzed the three-component reaction as well as NiCl 2to give 4a in a comparable yield (81%,entry 6).Because of its easy handling,NiCl 2·6H 2O was used as one of the standard conditions for the present study (vide infra).Other Ni salts,Ni(acac)2and Ni(OAc)2·4H 2O,also catalyzed the reaction,but the yield of 4a was a little lower (entries 7and 8).NiCl 2(PPh 3)2,

known to catalyze both cross-coupling of Grignard reagents 12and arylmagnesiation of alkynes,6a gave 6a as a main product

together with a minor amount of three-component coupling product 4a in both THF/toluene and Et 2O/toluene (entries 9and 10).PdCl 2(PPh 3)

2did not catalyze the formation of 3-component coupling product 4a at all,whereas 6a was formed at a high yield (70%,entry 12).Reactions in the presence of Fe(acac)3/IPr (entry 13)and MnCl

2(entry 14),both of which have been reported to catalyze arylmagnesiation,6c,e either did not produce 4a at all or gave 4a in a very low yield,respectively,although phenylmagnesiation proceeded to some extent.The present system can be scaled up 10-fold without di ?culty (entry 15,4a in 81%yield).

By monitoring the reaction progress of 1a ,2a ,and 3a in the presence of 1mol %NiCl 2(Table 1,entry 1),we gained substantial information on the reaction mechanism (Figure 1).The most signi ?cant feature is that phenylmagnesiation of 1a to form 8a is very fast.Within 10min,more than 70%of 1a is converted into 8a ,and in 20min all 1a is consumed.Second,the cross-coupling of 8a with 3a ,giving ?nal product 4a ,is slow Table 1.Three-Component Reaction of Diphenylacetylene (1a),Phenylmagnesium Bromide (2a),and 4-Iodoanisole (3a)

a entry catalyst yield 4a recovd 1a yield 5a yield 6a

b yield 7a 1NiCl 282051152

c NiCl 2510121793

d NiCl 277081374

e NiCl 2098<1005

f NiCl 282061236NiCl 2·6H 2O 81071157Ni(acac)275081538Ni(OAc)2·4H 2O 620152739NiCl 2(PPh 3)233251853910c NiCl 2(PPh 3)23255255011NiCl 2(dppe)30105515312PdCl 2(PPh 3)2088970013

g Fe(acac)3/IPr

h 040383214

i MnCl 2552335215

j NiCl 28105156a To a mixture of

1a (0.50mmol),

3a

(0.60

mmol),

and catalyst

(0.005

mmol,1mol %)in toluene (2.0mL)was added PhMgBr (2a :1.0M in

THF,0.60mL,0.60mmol),and the mixture was stirred under N 2at 30°C for 2h.Values given are percent isolated yield.b

Based on the

amount of 3a used.c PhMgBr (2a :1.0M in THF,0.60mL)+THF (2.0mL).d

PhMgBr (2a :1.0M in THF,0.60mL)+Et 2O (2.0mL).

e PhMgBr (2a :1.0M in Et 2O,0.60mL)+toluene (2.0mL).

f PhMgBr (2a :1.5M in Et 2O,0.40mL)+toluene (2.0mL)+THF (0.20mL).

g Fe(acac)3(5mol %)and IPr (20mol %)at 60°C for 16h.h

IPr =

1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.i MnCl 2(10mol

%)at 100°C for 16h.j The reaction was scaled up

10-fold.Figure

1.Time-dependent percentage of 1a ,4a ,5a ,6a ,and 7a in the reaction of 1a (0.50mmol),2a (0.60mmol),and 3a (0.60mmol)in the presence

of NiCl 2

(1mol %)in toluene

(2.0

mL)

at 30°C (Table 1,

entry

1).Reaction was quenched by addition of H 2O,and organic layer was analyzed by GC-MS using hexadecane as an internal standard.The amount of 5a should correspond to that of alkenylmagnesium 8a .

DOI:10.1021/ja513166w J.Am.Chem.Soc.2015,137,3189?31923190

compared with phenylmagnesiation of 1a .We observed that 8a was gradually converted into cross-coupling product 4a over 90min.Third,the cross-coupling of 2a with 3a giving 6a took place in an initial stage.The yield of 6a was 16%at 20min and remained thus until the end of the reaction.This is ascribed to the fast consumption (<20min)of all of 2a ,mainly by the phenylmagnesiation of 1a and partly by the cross-coupling with 3a .Furthermore,7a formed between 8a and phenyl iodide (vide supra)can be detected after 20min,and the yield of 7a remained 5%over the course of the reaction.A competition reaction (Scheme 2)demonstrates that 2a is more reactive than 8a toward the Ni-catalyzed cross-coupling with 3a under the present conditions.Thus,to the solution of 8a generated by the NiCl 2-catalyzed phenylmagnesiation of 1a ,an equivalent amount of PhMgBr/THF 2a was added,and the resulting mixture of 8a and 2a ,containing the Ni catalyst,was allowed to react with 3a .Aqueous workup gave 78%yield of 5a and 63%of 6a with a minor amount (5%)of 4a and 7a .The high selectivity in giving the three-component arylmag-nesiation/cross-coupling product is mainly ascribed to the very fast arylmagnesiation of 1a with 2a in the presence of NiCl 2catalyst (Scheme 1,cm1).Although the cross-coupling of the resulting alkenylmagnesium reagent 8a with 3a to form 4a (cc1)is slower than the cross-coupling of 2a with aryl iodide (cc2),most of 2a is ?rst consumed by the phenylmagnesiation of 1a ;as a result,only a small amount of the unreacted 2a participates in the cross-coupling with 3a .Under the present conditions,the carbomagnesiation of 1a with 8a which would generate dienylmagnesium species (cm2)is not observed.The scope of the diarylacetylenes 1,arylmagnesium bromides 2,and aryl halides 3in the three-component domino reaction is summarized in Table 2.This method applies well to 2and 3with an electron-donating or -withdrawing group on the phenyl ring at di ?erent positions.The aryl iodides with a substituent in the para position gave higher yields than those in the ortho or meta position (entries 1?5).The electron-donating substituent on the aryl iodides gave a higher yield of 4than an electron-withdrawing substituent (entries 3and 4).Similar electronic and steric e ?ects were also observed for aryl Grignards.Aryl Grignard with a methyl group in the para position gave as high as 83%yield (entry 8),but the ortho -methyl gave 4in 60%yield at higher temperature (entry 10).Diarylacetylenes with an electron-rich substituent in the meta or para position position produced tetrasubstituted ole ?n only after longer reaction time (16h,entries 11?12).The reaction also works well with aryl bromides at an elevated temperature and after a longer reaction time (entries 13?14).High Z selectivity was observed in entries 15and 16,which demonstrates that the cross-coupling of alkenylmagnesium with aryl iodides proceeds with retention of ole ?n geometry.In the reaction of unsymmetrically substituted diarylacetylene (entry 17),the arylmagnesiation step is not highly regioselective to give a mixture of isomers.The domino reaction of alkyl(aryl)acetylenes also proceeded successfully (Scheme 3).The regiochemistry is consistent with Scheme 978b59f94793daef5ef7ba0d4a7302768e996f7apetition between Alkenylmagnesium 8a and PhMgBr (2a)in NiCl 2-Catalyzed

Cross-Coupling Table 2.Reaction of Diarylacetylenes with Aryl Iodides and the Grignard Reagents

a entry Ar 1Ar 2Ar 3-X yield (%)

b 1Ph Ph Ph-I 77(4b )2Ph Ph 3-MeC 6H 4-I 71(4

c )3Ph Ph 4-MeC 6H 4-I 78(4

d )4Ph Ph 4-FC 6H 4-I 64(4

e )

5Ph Ph 1-naphthyl-I 65(4f )

6Ph 4-MeOC 6H 4Ph-I 64(4a )7Ph 3-MeC 6H 4Ph-I 64(4c )

8Ph 4-MeC 6H 4Ph-I 83(4d )

9c Ph 4-FC 6H 4Ph-I 62(4e )10d Ph 2-MeC 6H 4Ph-I 60(4g )11e 3-MeC 6H 4Ph 3-MeC 6H 4-I 70(4h )12e 4-MeC 6H 4Ph 4-MeC 6H 4-I 64(4i )13d ,e Ph Ph Ph-Br 62(4b )14d ,e Ph Ph 4-MeC 6H 4-Br 61(4d )15f Ph 4-MeOC 6H 44-MeOC 6H 4-I 73g (4j )16Ph 4-FC 6H 44-MeOC 6H 4-I 66h (4k )17c ,d 2-MeC 6H 4,Ph 2-MeC 6H 4Ph-I 51i (4l )a All reactions were carried out with diarylacetylene (0.50mmol),Ar 2MgBr/THF

(0.60mmol),Ar 3

X (0.60mmol),and NiCl 2·6H 2O (0.005

mmol)in toluene (2.0mL)under N 2at 30°C for 2h.b

Isolated yield.

c

For 6h.d At 60°C.e For 16h.f At 40°C.g Z /E =93:7.h Z /Ε=88:12.i Mixture of three isomers in a ratio of 70:25:5;2-MeC 6H 4MgBr (2.0

M in Et 2O,0.30

mL)+toluene (2.0mL)+THF (0.30mL).Scheme 3.Reaction of Alkyl(aryl)acetylenes with Aryl Iodides and the Grignard Reagents

a a Alkyl(aryl)acetylene 1(0.50mmol),Ar 2MgBr/THF 2(0.60mmol),

Ar 3I 3(0.60mmol),and NiCl 2·6H 2O (0.005mmol)in toluene (2.0mL).b Ratio of

4/4′

DOI:10.1021/ja513166w J.Am.Chem.Soc.2015,137,3189?31923191

our previous work on the arylmangesiation where magnesium attaches the aryl-substituted carbon.6b An array of arylmagne-sium bromides with electron-rich or-poor substituents reacted with1-phenyl-1-hexyne and iodobenzene to give tetrasubstituted alkenes4m,n,o with exclusive regioselectivity.The aryl iodides with electron-rich and-de?cient groups at para or meta position gave corresponding ole?ns4r,s,t with highly stereo-and regioselectivity.The ole?n products bearing a chloroalkyl(4p) or-aryl(4u),methyl ether(4q),and an amino group(4w, Tamoxifen)13were prepared by the present domino reaction. The molecular structures of4m,r,t,v were determined by X-ray single crystal di?raction.

We have studied a three-component domino coupling of internal alkynes with aryl Grignard reagents and aryl iodides, which is catalyzed by a simple Ni salt,NiCl2.Monitoring the reaction progress revealed that the arylmagnesiation of alkyne generating alkenylmagnesium species is extremely fast,which realizes the selective three-component coupling with a minimal amount of side products.This Ni-catalyzed reaction provides us with a new operationally simple method of synthesizing

tetrasubstituted alkenes with high stereo-and regioselectivity.■ASSOCIATED CONTENT

*Supporting Information

Experimental procedures,spectra,and crystallographic data.This material is available free of charge via the Internet at http://pubs.

978b59f94793daef5ef7ba0d4a7302768e996f7a.

■AUTHOR INFORMATION

Corresponding Authors

*chmzhaoj@978b59f94793daef5ef7ba0d4a7302768e996f7a.sg

*andyhor@978b59f94793daef5ef7ba0d4a7302768e996f7a.sg

*chmtamh@978b59f94793daef5ef7ba0d4a7302768e996f7a.sg

Notes

The authors declare no competing?nancial interests.■ACKNOWLEDGMENTS

We thank the Agency for Science,Technology,and Research (A*Star)of Singapore(R-143-000-566-305)and GlaxoSmithK-

line(R-143-000-492-592)for?nancial support.

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J.Am.Chem.Soc.2015,137,3189?3192 3192

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