Cobalt-Catalyzed Cross-Coupling Reactions

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reactions between organic halides and Grignard reagents.3 ... mechanism of cobalt-catalyzed cross-couplings of Grignard reagents with vinyl halides.6 ...

Cobalt-Catalyzed Cross-Coupling Reactions Nicole S. White Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697–2025 [email protected] Received Date

ABSTRACT

R1 X +

R2 M

cat. Co(II)

R1 R2

R1 = Vinyl, Aryl, Alkyl A review of cobalt-catalyzed cross-coupling reactions of vinyl, aryl, and alkyl halides with organometallic reagents is presented. These reactions are believed to proceed by an uncommon mechanism involving a carbon-centered radical species. Cobalt complexes can also be used to effect cascade transformations in which radical cyclization is followed by subsequent cross-coupling.

Transition metal-catalyzed cross-coupling reactions are among the most important carbon–carbon bond forming reactions in organic synthesis.1 Throughout the years, the most significant advances have been achieved employing transition metals such as Ni, Pd, and Fe. Recently, the use of cobalt complexes to catalyze cross-coupling reactions has grown tremendously and proven to be complementary to the more commonly used Pd and Ni catalysts.2 Described herein is the scope of cobalt-catalyzed crosscoupling reactions of vinyl, aryl, and alkyl halides with organometallic reagents. The low cost of cobalt complexes, coupled with their interesting mode of action, make cobalt complexes an attractive alternative for use in crosscoupling reactions and cascade transformations. In 1941, Kharasch and coworkers investigated the effect of transition metal salts such as FeCl2, NiCl2, and CoCl2 in reactions between organic halides and Grignard reagents.3 When phenylmagnesium bromide was treated with bromobenzene in the presence of catalytic CoCl2, the major product obtained was biphenyl (Scheme 1). The biphenyl product was derived exclusively from the Grignard reagent employed, since replacement of bromobenzene with p-tolyl bromide or ethyl bromide did not significantly decrease the yield of biphenyl. Interestingly, biphenyl was not formed without an aryl or alkyl bromide present, thus it was concluded that the aryl/alkyl bromide functioned as a re-

oxidant for the catalyst, facilitating catalyst turnover. The reaction mixture also contained traces of terphenyl, quadriphenyl and benzene suggesting the intermediacy of a carbon-centered radical intermediate. This information would eventually be used to design selective crosscoupling reactions.

Scheme 1. Cobalt-Catalyzed Dimerization of Grignard Reagents Ph MgBr + Ph Br

3 mol% CoCl2

Ph Ph

86%

Few advances in cobalt-catalyzed cross-couplings were made until the late 1990's when Cahiez and coworkers described the reaction of a vinyl halide with 1.1 equiv of an organomagnesium reagent in the presence of 3 mol% of Co(acac)2 to obtain di- and tri-substituted olefins (Table 1).4 An essential feature of the reaction conditions was the requirement of a 1:1 mixture of NMP:THF as the solvent. In addition to vinyl bromides, vinyl iodides and chlorides proved to be productive coupling partners (entry 2). The reaction was also stereo- and chemoselective (entries 2–4). A variety of organomagnesium reagents participated in the cross-coupling reaction. Of primary interest was use of methylmagnesium bromide to provide methylated product 2e in 82% yield (entry 4). In addition, Knochel and coworkers demonstrated that zinc organometallics (R2Zn or

1 Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd Ed.; Wiley-VCH: Weinheim, Germany, 2004. 2 Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081–2091. 3 (a) Kharasch, M.; Fields, E. J. Am. Chem. Soc. 1941, 63, 2316–2320. (b) Kharasch, M.; Hambling, J.; Rudy, T. J. Org. Chem. 1959, 24, 303– 305.

4

1

Cahiez, G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159–6162.

RZnX) could be used in the place of organomagnesium reagents (entry 6).5

reductive elimination would afford cross-coupled product 5 in diminished enantiopurity. Alternatively, it was suggested that transmetallation could occur with retention of configuration providing 8, followed by subsequent bond homolysis to radical intermediates 6 and 7 (Scheme 2). This later possibility seemed less likely because the reaction was conducted at –78 ºC. Importantly, no racemization of the cross-coupled product was observed when Pd(II) or Ni(II) complexes were employed, suggesting that Co(II) operates by a novel mechanistic pathway. Further insight into the mechanism of cobalt-catalyzed cross-coupling reactions was obtained when Oshima and coworkers carried out cross-coupling reactions in the presence of a stoichiometric amount of CoCl2(dppe) (dppe = Ph2P(CH2)2PPh2).8 The yield of cross-coupled product was dependent on the equivalents of Grignard reagent employed. When less than four equivalents of Grignard reagent were employed, cross-coupled product 13 was isolated in lower yield, along with biphenyl. Therefore, they proposed an alternative mechanism wherein CoCl2(dppe) reacts with four equivalents of the Grignard reagent to yield the 17 e- cobalt species 9 (Scheme 3). A SET from 9 to the halide coupling partner generates a radical anion that decomposes to radical 10 after loss of the halide. Radical 10 can then recombine with cobalt species 11 to give alkyl cobalt species 12, which after reductive elimination yields cross-coupled product 13.

Table 1. Scope of Vinyl Halides and Organometallic Reagents 3 mol% Co(acac)2

R1 X1 + R2 MX2

R1 R2

–5 to 0 ºC, THF/NMP

1

entr y

1

1a

2

Yield (%)

nOctylMgBr

2 a

88

nButylMgBr

2 b

nButylMgBr

2 c

nButylMgBr

2 d

65

MeMgBr

2 e

82

NC(CH2)2Zn I

2f

50

2

Br

nHex

2b

X

3 Cl Cl

O

4 AcO(CH2)6 Ph

5c Br Ph

6d Br

a

2a-2f

R –MX

2

X= Br 80 X= I 80 X= Cl 73 63

Without NMP as a co-solvent, 2a was obtained in 45% yield. b 2b was obtained as > 99.5% E configuration; when the Z isomer was reacted the product was obtained in >99.5% Z configuration. c Reaction carried out at 15–20 ºC. d Reaction carried out at 55 ºC with 25 mol% Co(acac)2.

Scheme 3. Oshima's Proposed Mechanism

Scheme 2. Hoffman's Proposed Mechanism MgCl Ph

+

X

3 Oxidative Addition

4

cat. Co(II) THF/NMP, –78 ºC 30%, 55% ee

–MgX2

Ph 5

CoIICl2(dppe)

R + –MgX+ 10

+ Co 6

2 PhMgBr

CoIIPh2(dppe)

Co0(dppe) Ph Ph

R X

8 Ph

Ph R 13

THF, 0 ºC

2 PhMgBr

Reductive Elimination

Ph

SET

1 equiv Co(II)

R = alkyl

Co

transmetallation –MgX2

XCo

PhMgBr + R X

[CoIPh2(dppe)]MgBr 11

R

[Co0Ph2(dppe)](MgBr)2 9

[CoIIPh2(dppe)]MgBr 12

Ph R 13

7

Both mechanisms involve carbon-centered radical intermediates. Radical intermediate 6 proposed in Scheme 2 is derived from the Grignard reagent, whereas radical intermediate 10 proposed in Scheme 3 is derived from the alkyl halide. Mechanistic studies in which radical intermediate 10 is trapped by a 5-hexenyl radical cyclization provide further support for the mechanism proposed in Scheme 3. While the mechanistic investigation accomplished by Oshima and coworkers employed alkyl halides, the work of Hoffman and coworkers utilized vinyl halides. Therefore, it is possible that the mechanism of cobalt-catalyzed cross-coupling reactions is dependent on the nature of the coupling partner employed.

Hoffman and coworkers have investigated the mechanism of cobalt-catalyzed cross-couplings of Grignard reagents with vinyl halides.6 Treatment of enantionenriched Grignard reagent 3 with vinyl halide 4 provided 5 in reduced enantiopurity (Scheme 2).7 A single-electron transfer (SET) mechanism was suggested to occur after oxidative addition of the vinyl halide species with the cobalt complex to give the configurationally unstable radical intermediate 6 and cobalt centered radical 7 (Scheme 2). Recombination of radical intermediates 6 and 7 would provide alkyl cobalt complex 8, which after 5 Avedissian, H.; Berillon, L.; Cahiez, C.; Knochel, C. Tetrahedron Lett. 1998, 39, 6163–6166. 6 Holzer, B.; Hoffman, R. Chem. Commun. 2003, 732–733. 7 Enantioenriched Grignard reagent 3 was obtained in 90% ee.

8 Ohmiya, H.; Wakabayashi, H.; Oshima, K. Tetrahedron 2006, 62, 2207–2213.

2

Recently, cobalt mediated cross-coupling reactions have been extended to aryl halides. Knochel and coworkers have described the cobalt-catalyzed cross-coupling of aryl halides or tosylates with aryl cuprates to yield mixed biaryl products (Table 2).9,10 Aryl bromides, fluorides and tosylates were all competent coupling partners (entry 2). Tosylates are of special interest because they are readily accessed from the corresponding phenols. A variety of aryl or heteroaryl cuprates were tolerated (entries 1–4). Furthermore, cuprates bearing halide substitution also proved to be productive coupling partners (entry 3). Additionally, Gosmini and coworkers have reported the use of aryl halides and vinyl acetates in a cobalt-catalyzed vinylation reaction to yield styrene derivatives.11 Several other groups have also described the cross-coupling reaction of heterocyclic chlorides with alkyl, aryl or heteroaryl Grignard reagents in the presence of a cobalt complex.12

halides possessing β-hydrogens; however, several groups have recently overcome this difficulty.13 Oshima and coworkers have obtained excellent results in the crosscoupling of alkyl halides with allylic Grignard reagents in the presence of CoCl2(dppp) (dppp = Ph2P(CH2)3PPh2).14 Tertiary, secondary and primary alkyl halides all proved to be productive coupling partners upon reaction with allylmagnesium chloride (Table 3, entries 1–4). Additionally, alkyl halides bearing an alkoxy group β to the halide were competent substrates (entry 4). A salient feature of this reaction is its ability to couple two sp3 hybridized carbon centers, allowing for the formation of a new quaternary carbon center.

Table 3. Scope of Alkyl Halides in Cobalt-Catalyzed CrossCoupling Reaction

X + Ar2 Cu(CN)MgBr

7.5 mol% Co(acac)2 DME:THF:DMPU Bu4NI, rt, 20% F

Ar1–X

entry

Ar2

Ar1

1

Ar2

14a-14d

14

Yield (%)

14a

77

14b

X = Br 79 b X = F 98 X = OTs 82

nOct

THF, temp

Yield (%)

T (ºC)/ La,b,c

MgCl

15a

90

–20ºC/ dppp

MgCl

15b

73

–20 ºC/ dppe

I

MgCl

15c

82

–40ºC/ dppp

I

MgCl

15d

82

–40 ºC/ dppp

15e

90

25 ºC/ tmeda

15f

99

25 ºC/ i

15g

86

25 ºC/ i

15h

74

25 ºC tmeda

15i

88

0 ºC/ dppp

15j

82

25 ºC/ i

R 2–MgX2

Br

2d

tBu PMP Me Br

3

Ph

R1 R2 15a-15j

15

R1–X1

entry

Table 2. Scope of Aryl Halides in Cobalt-Catalyzed CrossCoupling Reactiona Ar1

5 mol% [CoCl2(L)]

R1 X1 + R2 MgX2

Br CO2Et

b

1

X

Ph

OnBu

O

2

MeO

Ph Br

3b

O

4 nBuO

MgBr

Br

14c

Ph

5e

I

nOct

6

I

nOct

7

I

nOct

8e

I

nOct

Me3Si

62

N

PhMgBr

OTs O b

4 a

14d

Ph EtO

74

S

All cuprates were generated by treating the corresponding Grignard reagent with CuCN•2LiCl at –20 ºC for 10-15 min, the subsequent crosscoupling was run in the same reaction vessel. b Reaction was run at 80 ºC.

S BrMg MgBr Me3Si

Br

9

A principle limitation of Pd- and Ni-catalyzed crosscoupling reactions has been the inability to couple alkyl

Ph

MgCl

OMe

10f 9 (a) Korn, T.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 2947– 2951. (b) Korn, T.; Schade, M.; Schade, S.; Knochel, P. Org. Lett. 2006, 8, 725–728. 10 In the absence of the cobalt catalyst no formation of the product was observed. 11 (a) Gomes, P.; Gosmini, C.; Perichon, J. J. Org. Chem. 2003, 68, 1142–1145. (b) Gomes, P.; Gosmini, C.; Perichon, J. Org. Lett. 2003, 5, 1043–1045. (c) Amatore, M.; Gosmini, C.; Perichon, J. Eur. J. Org. Chem. 2005, 989–992. 12 For use of heterocyclic chlorides and aryl or heteroaryl Grignard reagents, see: (a) Korn, T.; Cahiez, G.; Knochel, P. Synlett 2003, 12, 1892–1894. (b) Korn, T.; Schade, M.; Cheemala, M.; Wirth, S.; Guevara, S.; Cahiez, G.; Knochel, P. Synthesis 2006, 21, 3547–3574. For use of chloropyridines and aryl or alkyl Grignard reagents, see: (c) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2004, 33, 1240–1241.

I

O

PhMgBr

a Ph2 P(CH2 )nPPh2 n =2 dppe, n =3 dppp. b Tmeda = tetramethylethylenediamine. c i = (1R, 2R)-tetramethycyclohexane-1,2-diamine. d PMP = paramethoxyphenyl. e 20 mol% CoIII(acac)3 used as catalyst. f trans/cis ratio of the product was 95:5.

13 (a) Frisch, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–688. (b) Zhou, J; Fu, G. J. Am. Chem. Soc. 2003, 125, 12527–12530. (c) Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186–11187. 14 (a) Tsuji, T.; Yorimitsu, H,; Oshima, K. Angew. Chem., Int. Ed. 2002, 41, 4137–4139. (b) Ohmiya, H; Tsuji, T.; Yorimitsu, H.; Oshima, K. Chem. Eur. J. 2004, 10, 5640–5648.

3

The allylation reaction reported in Table 3 (entries 1–4) is thought to proceed by transmetallation of the allyl Grignard reagent to cobalt, followed by oxidative addition of the alkyl halide through a SET from the allyl-cobalt species to the alkyl halide, as previously discussed in Scheme 3. It is proposed that the π-allyl ligands may prevent the formation of a vacant coordination site necessary for β-H elimination, in turn facilitating reductive elimination of the allylated product. The intermediacy of a carbon centered radical offers the potential for asymmetric cross-coupling of racemic alkyl halides. An encouraging result was obtained when the tertiary bromide depicted in entry 2 (Table 3) was reacted with allylmagnesium chloride in the presence of a cobalt complex containing a chiral phosphine ligand to provide the cross-coupled product in 22% ee.15 It has also been reported that alkyl halides can undergo cross-coupling with vinyl, aryl, heteroaryl, propargyl, or benzyl Grignard reagents in the presence of a cobalt(II) complex (Table 3, entries 5–9).14,16 A Ueno-Stork halo acetal bearing a stereogenic center next to the halogenated carbon proved to be a productive coupling partner and did not suffer β-alkoxy elimination (Table 3, entry 10).

the halide from radical anion 17 affords 5-hexenyl radical intermediate 18, which cyclizes to give cyclopentylmethyl radical 19. The cobalt species 11 can then recombine with the carbon-centered radical to form divalent cobalt species 20, which undergoes reductive elimination to provide the cross-coupled product 21 and cobalt complex 22. Reaction of complex 22 with excess Grignard reagent regenerates the active catalyst. Tandem radical cyclization/cross-coupling can be carried out with allyl, aryl, vinyl, propargyl, or alkyl Grignard reagents (Table 4). Additionally, substitution at the allylic position, as well as the olefin terminus, is tolerated. By far, the most general catalyst to effectively promote sequential cyclization/cross-coupling reactions is a cobalt Nheterocyclic carbene complex (entry 6).17

Table 4. Scope of Tandem Cyclization/Cross–Coupling R3 I

en try 1a,

R1

X

R2

+

16

3c Ph 21 b,

[Co0Ph2(dppe)](MgBr)2 9

4

BuO

MgBr+

PhMgBr

5b, X [Co0Ph(dppe)](MgBr)

[CoIPh2(dppe)](MgBr)

22

11

Ph

[CoIIPh2(dppe)](MgBr) 20

19

Yield (%)

O

77

O

Ts N

I BuO

Ph

PhMgBr

81

TsN

O

O

Me3Si MgBr

I

BuO

SiMe3

78

O

MgBr

O

SiMe3

66

O

I

X–

18

R4

O

BuO

Me3Si

Ts N

6e 21

R1 R2

24

d

17

X 24

R4-MgX

AllylMgCl

16

R3

THF, –40 ºC

23

d

X

MgX

I

Scheme 4. Proposed Mechanism of Cobalt-Catalyzed Radical Cyclization/Cross-Coupling Reaction

X

5 mol% CoCl2(L)

23

b

CoCl2(dppe) PhMgBr

R4

O

SiMe2Ph MgCl

TsN

SiHMe2Ph

78

I

a The ligand used was dppp. b Products isolated as lactones after Jones oxidation. c Ligand used was dppe, reaction conducted at 0 ºC. d 20 mol% CoIII(acac)3 used as catalyst and tmeda as ligand, reaction conducted at 25 IMes•HCl = ºC. e Reaction conducted at 25 ºC, used IMes•HCl ligand.

Cobalt complexes have also been utilized to facilitate cascade transformations. The treatment of 6-halo-1-hexene (16) with a Grignard reagent yielded 21 by a sequential radical cyclization/cross-coupling reaction. This result further supports the mechanism suggested by Oshima and coworkers (Schemes 3 and 4).17 Reaction of CoIICl2(dppe) with excess Grignard reagent generates a 17 e- cobalt species 9, which undergoes a SET to 6-halo-1-hexene (16), generating radical anion 17 (Scheme 4). Immediate loss of

N Cl

N

In summary, cobalt-catalyzed cross-coupling reactions of vinyl, aryl, or alkyl halides and an organometallic reagent have broad scope and numerous applications in organic synthesis. These reactions proceed by a novel mechanism in which oxidative addition is accomplished through a single-electron transfer. The radical intermediate can also be utilized to facilitate tandem radical cyclization/cross-coupling reactions, allowing for the formation of highly functionalized systems in one reaction vessel. The mild reaction conditions, high chemoselectivity and low cost of cobalt salts make cobalt-catalyzed crosscoupling reactions a powerful method for carbon–carbon bond construction and a promising area for future development.

15 Enantioenriched phosphine ligand employed was (–)-Chiraphos [CH3CH 2(PPh2)CH 2(PPh2)CH 3], which gave 22% ee. 16 Cross-coupling of alkyl halides with: For aryl Grignard reagents, see: (a) Ohmiya, H.; Wakabayashi, H.; Oshima, K. Tetrahedron 2006, 62, 2207–2213. (b) Ohmiya, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886–1889. For vinyl or propargyl Grignard reagents, see: (c) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2006, 8, 3093–3096. 17 (a) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374–5375. (b) Someya, H.; Ohmiya, H.; Yorrimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1565–1567.

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