Transition Metal Catalyzed Alkylation at Sp3 , Sp2 , and Sp Carbons

Home , Carbometalation, Grignard reagent

Transition Metal Catalyzed Alkylation at sp 3─ , sp 2─ , and sp ─ Carbons Nobuaki Kambe, 1 Jun Terao, 2 and Takanori Iwasaki 1

1 Department of Applied Chemistry, Faculty of Engineering, Osaka University Suita, Osaka 565 0871, Japan 2 ─ Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University Nishikyo ─ ku, Kyoto 615 ─ 8510, Japan

(Received August 19, 2011; E ─ mail: [email protected])

Abstract: Transition metal catalyzed alkylation reactions resulting in cross ─ coupling and multicomponent ─ coupling are described. These reactions proceed efciently under mild conditions using a combination of transition metal catalysts and alkyl (pseudo)halides in the presence of Grignard reagents and represent the practi- 3 2 cal routes to the alkylation of sp ─ , sp ─ , and sp ─ carbons. Anionic transition metal complexes play important roles as active catalytic species for S N2 and electron transfer processes in reactions with alkyl halides. The carbometalation of C ─ C unsaturated bonds with alkylmetal species is also a promising tool for the introduction of alkyl groups.

alkyl halides containing a β ─ hydrogen resulted in homocou- 1． Introduction pling and/or disproportionation with the formation of only 4 Transition metal catalyzed cross ─ coupling and multicom- small amounts of cross ─ coupling products (Scheme 1). ponent ─ coupling reactions have evolved as powerful tools for carbon ─ carbon bond formation, and have routinely been Scheme 1. Metal ─ catalyzed reaction of ArMgX with organohalides. applied to the synthesis of functional materials and bioactive compounds as well as various synthetic intermadiates. 1 In these synthetic manipulations of organic compounds promoted by transition metals, bond disconnection and reconnec- tion usually takes place on unsaturated carbons such as those Even after the breakthrough development of novel cata- found on aryl, alkenyl, and alkynyl substrates. Alkyl halides lytic systems for the cross ─ coupling of organo(pseudo)halides 5 and pseudo halides (Alkyl ─ X) are readily available and versa- with organometallic reagents in the 1970s, alkyl halides were tile alkylating reagents but have not often been used in transi- not yet recognized as suitable reagents for cross ─ coupling, due tion metal catalyzed reactions, for the following major reasons. to the reasons mentioned above, except for the case of Cu. The oxidative addition of alkyl halides to transition metals is During the past decade, however, remarkable progresses have 2 slower and less efcient than the cases of aryl and vinyl halides been achieved in the eld of cross ─ coupling using alkyl halides and, probably more importantly, β ─ hydrogen (or a hetero- by developing efcient catalytic systems that employ new atom) elimination from the alkylmetal intermediates that are ligands. 6 formed in catalytic cycles readily takes place to give olens. 2.1 Ni and Pd Catalyzed Cross ─ coupling Reactions Electron transfer from a metal to alkyl halides and homolytic About a decade ago, we found that Ni catalyzes the cross ─ M ─ C bond cleavage of alkylmetal intermediates lead to dis- coupling of Grignrad reagents with alkyl halides in the pres- proportionation and homocoupling. Furthermore, the reduc- ence of 1,3 ─ butadiene as an additive without the need for tive elimination of alkyl groups on metals is slower than that phosphine ligands. For example, the reaction of n ─ decyl bro- 2 3 for (sp )C units. mide with n ─ butyl Grignard reagent proceeded efciently in

The present article summarizes our investigations into the presence of isoprene and a catalytic amount of NiCl 2 in 7 transition metal catalyzed carbon ─ carbon bond forming reac- THF at 25 ℃ to give tetradecane in high yield (eq. 1). In the tions involving an alkyl group(s) as the reacting partner(s), absence of isoprene, reduction and elimination predominated which include not only cross ─ coupling but also the alkylation and signicant amounts of decane and decenes were produced at unsaturated carbons of alkenes, dienes, allenes, alkynes etc. in the reactions. Unsubstituted 1,3 ─ butadiene showed a higher 3 activity for this cross ─ coupling reaction. 2． Alkylation at sp Carbons by Cross coupling Reactions Using Alkyl Hali─des ─ Alkyl halides and Grignard reagents have been widely employed in organic reactions as carbon electrophiles and nucleophiles, respectively. The chemical behaviors of transition metals in reactions between these two reagents have been extensively studied in the 1940s as the pioneering work by Kharasch and co ─ workers. They revealed that ArMgBr reagents could be cross ─ coupled with vinyl halides in the presence of Co, Cr, or Cu salts as the catalysts, however the use of

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有機合成化学69-11＿10論文_Kambe.indd 77 2011/10/20 16:40:48 This reaction exhibited an interesting chemoselectivity in an allyl moiety. Thus, this catalytic cycle proceeds via Ni(II) ─ 2 16 which the (sp )C ─ Br bond survived intact in the present system Ni(IV) complexes having 16 electrons. (eq. 2). Alkyl chlorides and tosylates also underwent this The cross ─ coupling of Grignard reagents with alkyl bro- 3 cross ─ coupling reaction, giving rise to the desired products in mides and tosylates was examined using various η ─ allylnickel 8 3 good yields (eq. 3). Even alkyl uorides could be cross ─ cou- and η ─ allylpalladium complexes as catalysts and the yields pled with alkyl Grignard reagents in the presence of bisdienes were shown in eq. 6. 17 When nickel and palladium complexes 9,10 1 which functioned more efciently than butadiene (eq. 4). containing one allyl ligand, such as (C 3H 5NiCl) 2 (6b) and

Interestingly, the relative rates of cross ─ coupling decreased in (C 3H 5PdCl) 2 (6e), were used, MeMgBr was coupled with decyl the order R ─ Br＞R ─ F＞R ─ Cl, demonstrating the potent syn- bromide to give the expected cross ─ coupling products in good thetic utility of alkyl uorides as alkylating reagents in transi- yields, whereas the use of n BuMgCl resulted in the reduction tion metal chemistry. The strong interaction between the leav- and elimination of decyl bromides, probably due to the β ─ ing F anion and the Mg cation at the transition state in elimination of the allyl(butyl)metal intermediates. Nickel and 3 comparison with heavier halides provides a reasonable expla- palladium complexes containing no η ─ allyl ligand (6c and 6f) 3 nation for the high reactivity of alkyl uorides (vide infra). were not effective. Bis(η ─ allyl)nickel and ─ palladium com- Palladium also catalyzes the cross ─ coupling reaction of alkyl plexes (6a and 6d) exhibited excellent catalytic activities for tosylates and bromides with Grignard reagents in the presence these alkyl ─ alkyl coupling reactions. These results support the 11 of 1,3 ─ butadiene. catalytic pathway depicted in Scheme 2 and indicate that both Bisdiene 2 was also effective for the Ni ─ catalyzed cross ─ allyl groups on the metal play important roles but the ethylene

coupling reaction of organozinc reagents with alkyl halides tether (CH 2CH 2) connecting two allyl ligands of 3 in Scheme 2 12 (eq. 5). This catalytic system tolerates a wide variety of func- is not essential. Ni complexes were found to catalyze cross ─ tional groups, including nitriles, ketones, amides, and esters. 13 coupling at lower temperatures and showed a higher perfor- mance than the corresponding Pd complexes. Theoretical calculations were performed based on the pathway shown in Scheme 2 using bis(allyl)Ni complexes (3, 6a, 6g), a Me anion instead of Grignard reagents (RMgX), and MeCl. 18 From the calculated free energy changes for each process along the reaction pathway it was proposed that the oxidative addition step (i.e., 4→5 in Scheme 2) was likely to be the rate determining step. It was suggested that allyl ligands inuence the reaction rates of this process. Actually the free energy changes for the oxidative addition of MeCl to nickelate

complexes 4a, 7a, 7g leading to the corresponding (allyl) 2NiMe 2 decrease in the order 4a＞7a＞7g, indicating that a strained

Scheme 2. Catalytic cycle for Ni ─ catalyzed cross ─ coupling reactions using alkyl halides via an η 1,η 3─ octadienediylnickel complex.

A plausible reaction pathway for this Ni catalyzed cross ─ coupling is depicted in Scheme 2. Ni(0), formed by the reduc-

tion of NiCl 2 with Grignard reagents, reacts with 2 moles of 14 1,3 ─ butadiene to afford the bis(π ─ allyl)nickel complex 3, 1 3 which reacts with Grignard reagents to form the anionic η ,η ─ octadienediylnickel complex 4. 15 This complexation might enhance the nucleophilicity of Ni toward alkyl halides. Cou- pling products are formed by the nucleophilic substitution of alkyl halides on the nickel of 4 yielding the dialkylnickel complex 5, followed by reductive elimination. 1,3 ─ Butadienes play an important role in the conversion of Ni(0) to Ni(II), which is inert toward oxidative addition with organic halides but reacts readily with R ─ MgX to form anionic complex 4, and sup- presses the β ─ hydrogen elimination process by occupying the 1 3 coordinating site on the nickel via the dynamic η ─ η shift of Figure 1. Theoretical calculations of bis(allyl)Ni intermadiates.

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有機合成化学69-11＿10論文_Kambe.indd 78 2011/10/20 16:40:56 form of 7g is the most reactive for this step. Interestingly, 4a LFNO showed a slightly higher reactivity than LFPO. The 1 3 3 3 and 7g possess η ─ ,η ─ coordination of allyl ligands but η ─ ,η ─ present coupling reaction was found to be catalyzed by trace coordination seems possible for 7a probably due to its high amounts of Ni or Pd that had been leached from perovskites exibility. The reductive elimination of ethane from with a very high TON (ca. 10 7).

(allyl) 2NiMe 2 is exergonic and should be a rapid process. In comparison to 5a (R=Alkyl=Me in Scheme 2) and

(C 3H 5) 2NiMe 2 (8a), the reductive elimination from 8g is relatively less exergonic with a higher barrier (ca. 20 kcal/mol). The alkyl ─ alkyl cross ─ coupling of alkyl halides with dial- kylzincs, prepared in situ by the reaction of ZnBr 2 with the Since Ni shows a high TON as a catalyst for alkyl ─ alkyl 22 corresponding RMgX, using bisdienes (1,3,8,10 ─ tetraenes) is cross ─ coupling, we performed kinetic studies. We rst exam- operationally simple and gives good yields of products carry- ined the time course for the reaction of nonyl bromide (9a) ing various functional groups including amides, esters, ketones with excess butyl Grignard reagent using various Ni salts and 12 and nitriles. However, one drawback to this procedure is that 1,3 ─ butadiene in THF at 0 ℃. As shown in Figure 2, all of the only one of the alkyl groups on Zn can be transferred ef- Ni salts afforded tridecane in quantitative yields within 15 ciently (Scheme 3). minutes, based on the bromide, but an induction period was In order to achieve highly atom economical cross ─ cou- observed for several salts probably due to their low solubilities pling, we optimized the reaction conditions for the Ni ─ cata- in THF. NiBr 2/dme and Ni(acac) 2 did not show any apparent lyzed cross ─ coupling of Grignard reagents with alkyl halides induction period. and a tosylate in the presence of a simple diene and found that When we examined the reaction of heptyl tosylate (9b) this catalytic system can tolerate amide, ester and ketone func- using different concentrations of n BuMgCl, an interesting tionalities as well as acetal and ether groups (eqs. 7, 8). 19 result was obtained (Figure 3). The reaction was accelerated Unfortunately, the acyl moiety in methyl ketones did not sur- with increasing concentrations of n BuMgCl up to ca. 0.4 M, vive under the present conditions. while the rate became constant in the higher concentration region. Scheme 3. Ni ─ catalyzed cross ─ coupling of alkyl halides having functional groups.

n Figure 2. Time course for the reaction of C 9H 19Br (9a, 0.2 M) with n BuMgCl (0.6 M) using 2.5 mol% of a Ni salt (0.005 M) and 1,3 ─ butadiene (0.2 M) in THF at 0 ℃.

Nickel and palladium ─ containing perovskites (metal

oxides with the general formula ABO 3), LaFe 0.8Ni 0.2O 3

(LFNO) and LaFe 0.95Pd 0.05O 3 (LFPO), were found to function n n as effective catalyst sources for the cross ─ coupling of nonacti- Figure 3. C 7H 15OTs (9b, 0.2 M), BuMgCl (0.2 ─ 0.8 M), NiBr 2/dme vated alkyl halides and tosylates with Grignard reagents in the (0.005 M), 1,3 ─ butadiene (0.2 M), at 1 ℃ for 2.5 min. presence of conjugated dienes (eq. 9). 20,21 The reaction proceeded at room temperature or below in THF using only ca. The rate of Ni ─ catalyzed cross ─ coupling obeyed rst order 1 mol% of catalysts with respect to Ni or Pd and the kinetics with respect to the concentrations of the nickel salt perovskites could be reused without substantial loss of activity. and alkyl halides. Therefore, under conditions where an excess

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有機合成化学69-11＿10論文_Kambe.indd 79 2011/10/20 16:41:02 amount of Grignard reagent is used, the reaction rate can be orides and gave only 3% yields of the cross ─ coupling products expressed by from octyl chloride under the same conditions. Competitive reactions with PhMgBr revealed that the reactivities increase in the order R ─ Cl＜R ─ Br＜R ─ F indicating the high reactivity of alkyl uorides as in the case of Ni ─ catalyzed reaction (vide Figure 4 shows the Eyring plots and the activation param- supra). eters are shown in Table 1. The data indicate that the activation entropies are relatively small and that the reaction rates are mainly controlled by enthalpy factors (vide infra). The relative rates are calculated to be, n n n C 7H 15OTs： C 9H 19Br： C 6H 13I = 0.015：1：15 (at 25 ℃) = 0.018：1：19 (at 0 ℃) = 0.022：1：25 (at -25 ℃) We found that Cu effectively catalyzed cross ─ coupling indicating that alkyl bromides react 50 times faster than tosyl- reactions of alkyl chlorides with Grignard reagents when 1 ─ 24 ates and that iodides react 20 times faster than bromides. phenylpropyne was used as an additive. For example, n ─ nonyl chloride reacted with n ─ BuMgCl in the presence of a catalytic amount of CuCl 2 and 1 ─ phenylpropyne when reuxed in THF for 6 h to give tridecane in ＞98% yield (eq. 12). In the absence of 1 ─ phenylpropyne, tridecane was obtained in only 3% yield and 95% of the n ─ nonyl chloride was recovered. This reaction has wide generalities in terms of the scope of reagents and gives good yields of products from primary ─ , secondary ─ , and tertiary ─ alkyl and aryl Grignard reagents and primary ─ alkyl chlorides, uorides, and mesylates as well as bromides and tosylates. The present catalytic system has a major advantage for large scale production, since the reaction proceeds efciently using less expensive alkyl chlorides

as the reagent and CuCl 2 as the catalyst with the combined use of an easily available alkyne as the ligand. A highly siteselec- tive sequential cross ─ coupling reaction using two different alkyl Grignard reagents has been achieved by the use of bro- Figure 4. Eyring plots of Ni ─ catalyzed cross ─ coupling. mochloroalkane 10 (eq. 13).

Table 1. Activation free energies (0 ℃) and activation parameters of Ni ─ catalyzed cross ─ coupling.

If the reaction in scheme 2 proceeds via 5, the above activation parameters should correspond to this oxidative addition step. Fu and co ─ workers performed a kinetic study of the oxidative addition of alkyl halides to Pd(0) as a key step in Pd catalyzed cross ─ coupling and revealed that the activation parameters of the oxidative addition of nonyl bromide with t Pd(P Bu 2Me) 2 leading to the formation of n t ‡ ‡ C 9H 19PdBr(P Bu 2Me) 2 were ΔG =87.1 kJ/mol at 20 ℃, ΔH =10 kJ/mol, and ΔS ‡=-2.6×10 2 J/Kmol. 23 It is interesting to Lithium cuprates are known to react with alkyl halides by a note that the reaction of a Pd complex with alkyl halides has a single electron transfer (SET) mechanism in some cases, 25 small activation enthalpy and is controlled by an entropy fac- however, the following evidence may exclude the possibility of tor, while the reaction of the Ni complex 4 with alkyl halides is radical mechanism for our cross ─ coupling reactions. 6 ─ enthalpy ─ controlled. Chloro ─ 1 ─ hexene did not afford cyclized products, and the 2.2 Cu Catalyzed Cross coupling Reactions reaction of (chloromethyl)cyclopropane with PhMgBr gave In 2003, we revealed─ the rst example of Cu catalyzed only benzylcyclopropane (13) in 98% yield without any detect- cross ─ coupling reactions of non ─ activated alkyl uorides with able formation of 4 ─ phenyl ─ 1 ─ butene (14), which may arise 26 Grignard reagents, which proceeded under mild conditions in from the ring ─ opening of the cyclopropylmethyl radical if 9a the presence of 1,3 ─ butadienes as an additive (eq. 11). Intere- generated (eq. 14). An S N2 mechanism for the present reaction stingly, alkyl chlorides were found to be less reactive than u- is supported by the net inversion in stereochemistry, as evi-

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有機合成化学69-11＿10論文_Kambe.indd 80 2011/10/20 16:41:07 denced by the reaction of diastereometrically pure α, β ─ d 2─ β ─ According to this reaction pathway, as shown in Scheme 4, 24 adamantylethyl chloride (15) with PhMgBr (eq. 15). when an alkylation reaction was conducted using a β ─ phenethyl Grignard reagent, styrene should be formed in situ and could act as the substrate. As expected, the same products were obtained from β ─ phenethyl Grignard reagents and alkyl halides without the use of styrene in the presence of zirconocene catalyst. 32 The present reaction proceeds more efciently when alkyl uorides are used as the alkylating reagents than with the corresponding chlorides, bromides, or tosylates (eq. 16).

Ni was found to catalyze the alkylation of allyl ethers with alkyl uorides and tosylates in a substitution manner by the use of vinyl Grignard reagents (eqs. 17, 18). 33 In this reaction, Ni(0) undergoes a selective oxidative addition with allyl ethers, and not with alkyl uoride or tosylates, to give allylnickelate

intermediates (allyl)Ni(vinyl) 2·MgX by the reaction with vinylmagnesium chloride, which acts as a nucleophile toward the Although the structure of the active catalytic species is not alkylating reagents. The key for the success of this reaction is presently known, 1 ─ phenylpropyne could coordinate to cop- the use of alkyl uorides and tosylates which are inert or less per 28a and prevent the decomposition of the thermally unstable reactive for the oxidative addition to low valent transition met- alkylcopper(I) intermediates. 28b als. Since allyl ethers are converted into allylic nucleophiles in

2 this reaction, unlike the case of Tsuji ─ Trost allylation, allylsi- 3． Alkylation at sp Carbons ─ lanes were obtained in good yields when the reaction was con- 3.1 Alkylation of Oleﬁns ducted in the presence of chlorosilanes. Olens coordinated on metals are usually activated as electrophiles, and this methodology has been widely applied to synthetic reactions as represented by the Wacker oxidation, an industrial process. We have reported a prototype of nucleophilic activation of olens by forming anionic zirconocene complexes which permits the alkylation and silylation of olens with alkyl halides 29a and chlorosilanes, 29b ─ d respectively (Scheme 4).

Scheme 4. Zr ─ catalyzed alkylation and silylation of styrenes.

The formation of carbon ─ carbon bonds using carbon radical intermediates promoted by transition metals promises to usher in a new era in synthetic organic chemistry. We found that anionic Ti and Ni complexes readily transfer electrons to alkyl halides, resulting in the formation of alkyl radical species and can participate in multi ─ component coupling reactions. As shown in Scheme 5, Ti catalyzes the double alkylation of styrenes by the combined use of two different alkyl halides in THF in the presence of butyl Grignard reagent. This reaction is regioselective and the more branched alkyl group is intro- In the present reaction, the anionic zirconocene complex duced at the terminal carbon and the less branched one at the 30 34a 16, formed by the reaction of zirconocene ─ olen complex benzylic carbon. When this reaction is performed in the with n BuMgCl, 31 reacts formally with alkyl halides at the ben- presence of an alkyl bromides and a chlorosilane, carbosi- zylic carbon and with chlorosilanes at the terminal carbon to lylation takes place. 34b The present reactions involve (i) a one form the Zr(IV) intermediates 17 and 18. A subsequent β ─ electron transfer from the anionic dibutyltitanocene(III) com- hydrogen elimination results in the production of the alkyla- plex 19 to the alkyl bromide, leading to cleavage of the C ─ Br tion and silylation products. 30 bond to give an alkyl radical, (ii) addition of alkyl radicals to

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有機合成化学69-11＿10論文_Kambe.indd 81 2011/10/20 16:41:14 styrene at the terminal carbon, (iii) recombination of the gnard reagent was transferred to the product.

resulting benzyl radical with Cp 2Ti, (iv) transmetalation with This reaction proceeds via electron transfer from a titanate the butyl Grignrad reagent, and (v) electrophilic trapping of complex 19 to a β ─ bromoalkyl ether, yielding an alkyl radical the formed benzyl Grignard reagents by alkyl halides (or chlo- 24. The key step in this reaction is the subsequent SET step rosilanes). between 24 and n BuMgCl to form a butyl radical and 25 (or directly giving ethylene and MgClOR). A kinetic study indi- Scheme 5. Reaction pathway for the Ti ─ catalyzed regioselective cated that Ti does not contribute to this process. Thus, the double alkylation and carbosilylation. formed butyl radical adds to styrene following the same path- ways of Scheme 5 and equation 19, giving rise to 21 ─ 23. 3.2 Alkylation of Dienes and Enynes A new method for the regioselective three ─ component cross ─ coupling reaction of alkyl halides, 1,3 ─ butadienes, and aryl Grignard or zinc reagents using a nickel catalyst was developed (eq. 20). 37 This reaction involves two different carbon ─ carbon bond forming steps, i.e., (i) the addition of alkyl radicals to 1,3 ─ butadienes and (ii) the reductive elimination of allyl(aryl)Ni(II) intermediates. In this reaction, alkyl radical species are generated from alkyl halides by a single electron transfer from anionic Ni complexes 26. Silver was found to catalyze the alkylation of an enyne with an alkyl iodide in the presence of i BuMgCl to give an It should be noted that course of the reaction can be allenyl Grignard reagent, which can be trapped with electro- switched by changing the solvent. Alkylation proceeds in the philes (eq. 21). 38 Alkylsilver would be expected to be formed as 39 substitution mode to furnish a Mizoroki ─ Heck type transfor- an active species and to add to the enyne. This catalytic sys- mation, when conducted in ether under similar conditions to tem can also be applied to the alkylation of alkynes (vide afford an alkylated styrene probably via the β ─ elimination infra). from a Ti(III) intermediate corresponding to 20 in Scheme 5 (eq. 19). 35

In all reactions using the olens mentioned above, Gri- gnard reagents acted as reducing agents and the alkyl groups of alkyl halides were transferred to the products. We found that alkyl group of alkyl Grignard reagents could be transferred to olens when β ─ bromoalkyl ethers were used as the oxidizing agents (Scheme 6). When a THF solution containing styrene, butylmagnesium chloride, β ─ bromoethyl ether, and 5 mol% of titanocene dichloride was stirred at -20 ℃, regioselective dialkylation was achieved to give 21. 36 When the same reaction was conducted in the presence of chlorosilane, carbosilylation took place selectively to give 22. On the other

hand, the use of Et 2O instead of THF afforded the substitution product 23. In these reactions, the butyl group of the Gri- 3.3 Alkylation of in situ Generated Dienes We found that highly regioselective three ─ component coupling reactions of 2 molecules of vinyl Grignard reagents with Scheme 6. Alkylation with Grignrad reagent. alkyl uorides proceed, when a nickel catalyst is used (eq. 22). 40

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有機合成化学69-11＿10論文_Kambe.indd 82 2011/10/20 16:41:22 This reaction proceeds efciently using primary or secondary Scheme 8. Ti ─ catalyzed dimerization alkylation of vinyl Grignrad alkyl uorides and vinyl Grignard reagents under mild condi- reagent. tions affording a homoallyl Grignard reagent having an alkyl chain at the β ─ carbon. Alkyl uorides react with the anionic nickel complex 29 at the vinylic γ ─ carbon. The present study provided the rst example of a catalytic reaction that demon- strates the superiority of alkyl uorides as alkylating reagents over the corresponding chlorides, bromides and iodides. The latter class of halides may undergo oxidative addition to Ni(0) species such as 28 or an electron transfer from 29, leading to the formation of reduction or elimination byproducts. On the other hand, alkyl uorides are inert in such reactions and serve solely as electrophiles with the assistance of a Mg cation. Homoallylic Grignard reagents obtained in the present reaction can be subjected to cross ─ coupling by the simple addi- Scheme 9. Titanocene dichloride reacts with two equivalents tion of different alkyl halides and butadiene to the resulting of vinylmagnesium chloride to afford the divinyl titanocene 35, mixture. The present one ─ pot procedure would be a useful which undergoes reductive coupling to form the titanocene ─ method for the synthesis of terminal olens having alkyl chains butadiene complex 36. 43 Then, 36 reacts with vinylmagnesium at the α ─ and β ─ positions (eq. 23). chloride to give the titanate complex 37. A subsequent one electron transfer from 37 to an alkyl halide yields an alkyl radical along with a titanocene(III) complex 38. Finally the addition of the alkyl radical to a coordinated butadiene ligand of 1 38 leads to the formation of an η ─ allyltitanocene complex 39, 44 which undergoes transmetalation with vinyl magnesium chloride to afford the allyl Grignard reagent 31 and the regen- eration of 35.

Scheme 9. Ti ─ catalyzed alkylation dimerization of vinyl Grignard The present reaction can be performed using epoxides or reagent. oxetanes as electrophiles instead of alkyl uorides and could be applied to a medium scale production of 30 (eq. 24). 41

The above Ni ─ catalyzed reaction of vinyl Grignard reagents and alkyl uorides or cyclic ethers results in the formation of alkylated homoallyl Grignard reagents. When titanocene was used as the catalyst, allylic Grignard reagents carrying an alkyl chain at the terminal carbon can be gener- 3.4 Alkylation of Dienes, Enynes, and Allenes via ated (Scheme 7). 42 Carbometalation The direct addition of Grignard reagents to conjugated Scheme 7. Formation of homoallyl and allyl Grignard reagents. dienes and enynes can be achieved by the use of Cu salts as catalyst precursors (Scheme 10). 45

Scheme 10. Cu ─ catalyzed carbomagnesiation of dienes and enynes.

The reaction was carried out by stirring a THF solution of vinyl magnesium chloride, 2 ─ bromo ─ 2 ─ methyloctane and a

catalytic amount of Cp 2TiCl 2 at -20 ℃. The formed allyl Gri-

gnard reagent 31 was quenched with a ketone, CO 2, and chlo- The formed allyl and allenyl Grignard reagents can be rosilane to give olens 32 ─ 34, respectively (Scheme 8). Primary trapped by a variety of electrophiles. Selected examples of this and secondary alkyl bromides and iodides can be employed are shown in eqs. 25 ─ 29. Alky groups were introduced regiose- but the yields are decreased to 48 ─ 69%. lectively at a terminal olenic carbon, while trapping took A plausible reaction pathway for this reaction is shown in place either on the other terminal end or on an inner carbon,

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有機合成化学69-11＿10論文_Kambe.indd 83 2011/10/20 16:41:30 depending on the trapping agent used. Tertiary and secondary catalysts. If a similar addition to alkynes were to proceed, vinyl alkyl Grignard reagents afforded good yields of products, but Grignard reagents would be expected to be formed. Silver was primary alkyl Grignard reagents reacted sluggishly. found to be an effective catalyst for the regioselective carbomagnesiation of terminal alkynes with alkyl Grignard reagents 46 in the presence of 1,2 ─ dibromoethane (eq. 32). This reaction proceeds with either primary, secondary, or tertiary alkyl Grignard reagents to form vinyl Grignard reagents 47 in high yields, which can be trapped with various

electrophiles including aldehydes, chlorosilanes, and CO 2. Ter- minal acetylenes containing 3 ─ thienyl and dimethyl(phenyl)- silyl groups can also undergo carbomagnesiation with t BuMgCl to give the corresponding Grignard reagents in good yield (65%, E/Z=3/97 and 66%, E/Z=8/92, respectively, after ＋ H quenching). The combined use of AgOTs and Ar 3P was also effective for this transformation albeit it was slightly less efcient. A plausible catalytic cycle is depicted in Scheme 11. The t s fact that the competitive reaction of Bu ─ MgCl, Bu ─ MgCl, n and Bu ─ MgCl with phenylacetylene afforded the corresponding addition products in 59%, 8%, and ＜1% yields, respectively, suggests that radical intermediates are involved in this reaction. 1,2 ─ Dibromoethane would oxidize Ag(0), formed by side reactions such as homocoupling, homolytic bond cleavage, β ─ hydrogen elimination of R ─ Ag etc., to regenerate Ag(I). The reaction proceeded in the absence of 1,2 ─ dibromoethane but the yields were decreased. Silver salts also catalyze the carbomagnesiation of enynes, as well as alkynes (vide infra), with secondary and tertiary Scheme 11. Silver catalyzed addition of RMgX to alkynes. alkyl Grignard reagents under mild conditions (eq. 30). 46

Allenes react with alkyl Grignard reagents and chlorosilanes in the presence of a Pd catalyst to give carbosilylation products 45 (eq. 31). 47 This reaction proceeds efciently when primary alkyl, methyl, and aryl Grignard reagents are The addition of Grignard reagents to alkynes described employed, but the use of secondary or tertiary alkyl Grignard above results in the formation of alkylated vinyl Grignard reagents resulted in hydrosilylation to form 46, probably due to reagents 52 (Scheme 12, route A), 46 which react with electro- the β ─ elimination of an alkylpalladium intermediate. philes, thus providing a useful and practical method for the synthesis of multisubstituted alkenes 53. As a more practical and convenient route to 52, we developed the three component coupling reaction of alkynes, alkyl iodides and i BuMgCl catalyzed by AgOTs without necessity of preparing a Grignard

Scheme 12. Ag ─ catalyzed fornation of vinyl Grignard reagents.

4． Alkylation at sp ─ Carbons As shown in the previous section, alkyl Grignard reagents add to C ─ C double bonds in the presence of Cu, Ag, or Pd

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有機合成化学69-11＿10論文_Kambe.indd 84 2011/10/26 14:23:33 reagent prior to the reaction (Scheme 12, route B). 38 lar to Scheme 11 but includes an additional step from 59 to 60. As shown in eq. 33, this reaction was complete in 1 h at This process was conrmed by a stoichiometric reaction of 59, i t -10 ℃. A higher alkyl group affords better yields and the use generated in situ from AgOTs, PPh 3, and BuMgCl, with BuI i of an ortho ─ tolyl substituent improved the stereoselectivity. to give a 73% yield of BuI. Silylacetylene also worked well to give a vinyl silane in good 5． Conclusion yield. As a synthetic application of this reaction, 55, formed in We developed some unique alkylation methods via the use solution, was subjected to Pd ─ catalyzed cross ─ coupling with of ate complexes (Scheme 15). Anionic nickelate and palladate PhI and the desired arylated product 56 was obtained in good complexes stabilized by π ─ carbon ligands play important roles yield (Scheme 13). The simple trapping of 55 with various as nucleophiles that attack alkyl (pseudo)halides resulting in electrophiles was also successful. Cycloalkane rings can be efcient alkyl ─ alkyl cross ─ coupling reactions when the reac- constructed by this reaction, when δ ─ iodoalkynes are tion is performed in the presence of butadiene. This methodol- employed (eq. 34). ogy was extended to copper chemistry and versatile alkyl ─ alkyl The present reaction proceeds via Scheme 14 which is simi- cross ─ coupling reactions were developed by the combined use of copper and 1,3 ─ diene or alkynes as its ligands. Scheme 13. Trapping and synthetic manipulation of vinyl Grignard Scheme 15. Alkylation via ate complexes. reagent.

Anionic complexes react with electrophiles directly at their carbon ligands, or via the elimination of thermodynamically stable allylic and benzylic anions. When alkyl halides are used as the electrophile, the alkylation of olens, allyl ethers, and dienes with unactivated alkyl halides can be achieved. Anionic Ti and Ni complexes serve as single electron transfer reagents toward alkyl halides to form alkyl radicals which add to unsaturated carbon ─ carbon bonds. This reaction allows Scheme 14. Ag ─ catalyzed three component coupling. the alkylation of olens and dienes by alkyl halides without the need to activate the unsaturated substrates. 3 2 Metal ─ (sp )C bonds are weaker than metal ─ (sp )C and metal ─ (sp)C bonds and alkylsilver and ─ copper species

Scheme 16. Carbometalation across unsaturated bonds.

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有機合成化学69-11＿10論文_Kambe.indd 85 2011/10/20 16:41:46 undergo addition to unsaturated C ─ C bonds, probably via Chem. Int. Ed. 2007, 46, 2086. homolytic metal carbon bond cleavage. Therefore a trans- 25） The reaction of lithium diorganocuprates with secondary alkyl iodides ─ may generate a radical intermediate. (a) Ashby, E. C.; Coleman, D. J. metalation ─ addition ─ transmetalation sequence represents a Org. Chem. 1987, 52, 4554. (b) Ashby, E. C.; Depriest, R. N.; Tuncay, new carbomagnesiation method to form vinyl and allyl Gri- A.; Srivastava, S. Tetrahedron Lett. 1982, 23, 5251. gnard reagents by the aid of Ag or Cu catalysts (Scheme 16). 26） Maillard, B.; Forrest, D.; Ingold, K. U. J. Am. Chem. Soc. 1976, 98, 7024. 27） Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122, References 7294. 1） For recent reviews of synthetic applications of cross ─ coupling reac- 28） (a) Schulte, P.; Behrens, U. J. Organomet. Chem. 1998, 563, 235. (b) tions, see for example; (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, Miyashita, A.; Yamamoto, T.; Yamamoto, A. Bull. Chem. Soc. Jpn. 111, 2177. (b) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 1977, 50, 1109. 3027. 29） (a) Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663. (b) Terao, 2） Ariafard, A.; Lin, Z. Organometallics 2006, 25, 4030. J.; Kambe, N. Chem. Record. 2007, 7, 57. (c) Terao, J.; Torii, K.; Saito, 3） Abis, L.; Sen, A.; Halpern, J. J. Am. Chem. Soc. 1978, 100, 2915. K.; Kambe, N.; Baba, A.; Sonoda, N. Angew. Chem. Int. Ed. 1998, 37, 4） Kharasch, M. S.; Fuchs, C. F. J. Am. Chem. Soc. 1943, 65, 504. 2653. (d) Terao, J.; Jin, Y.; Torii, K.; Kambe, N. Tetrahedron 2004, 60, 5） (a) Tamura, M.; Kochi, J. J. Am. Chem. Soc. 1971, 93, 1487. (b) 1301. Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun. 1972, 144. 30） Negishi, E.; Nguyen, T.; Maye, J. P.; Choueiri, D.; Suzuki, N.; Taka- (c) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, hashi, T. Chem Lett. 1992, 2367. 94, 4374. (d) Yamamura, M.; Moritani, I.; Murahashi, S. ─ I. J. 31） (a) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. Organomet. Chem. 1975, 91, C39. 1986, 27, 2829. (b) Negishi, E.; Swanson, D. R.; Takahashi, T. J. 6） Kambe, N.; Iwasaki, T.; Terao, J. Chem. Soc. Rev. 2011, 40, 4937 and Chem. Soc., Chem Commun. 1990, 1254. references cited therein. 32） Terao, J.; Begum, S. A.; Oda, A.; Kambe, N. Synlett 2005, 1783. 7） Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. 33） Terao, J.; Watabe, H.; Watanabe, H.; Kambe, N. Adv. Synth. Catal. Chem. Soc. 2002, 124, 4222. 2004, 346, 1674. 8） For seminal papers on cross ─ coupling reaction using alkyl chlorides, 34） (a) Terao, J.; Saito, K.; Nii, S.; Kambe, N.; Sonoda, N. J. Am. Chem. see: (a) Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem. Int. Ed. Soc. 1998, 120, 11822. (b) Nii, S.; Terao, J.; Kambe, N. J. Org. Chem. 2002, 41, 1945. (b) Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. 2000, 65, 5291. Angew. Chem. Int. Ed. 2002, 41, 4056. (c) Nakamura, M.; Matsuo, K.; 35） Terao, J.; Watabe, H.; Miyamoto, M.; Kambe, N. Bull. Chem. Soc. Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. Jpn. 2003, 76, 2209. 9） (a) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 36） Terao, J.; Kato, Y.; Kambe, N. Chem. Asian J. 2008, 3, 1472. 2003, 125, 5646. (b) Terao, J.; Todo, H.; Watabe, H.; Ikumi, A.; 37） Terao, J.; Nii, S.; Chowdhury, F. A.; Nakamura, A.; Kambe, N. Adv. Shinohara, Y.; Kambe, N. Pure Appl. Chem. 2008, 80, 941. Synth. Catal. 2004, 346, 905. 10） Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119. 38） Kambe, N.; Moriwaki, Y.; Fujii, Y.; Iwasaki, T.; Terao, J. Org. Lett. 11） Terao, J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Lett. 2003, 32, 2011, 13, 4656. 890. 39） Alkylsilver (RAg) and its ate complex (R 2Ag・MgX) are known to 12） Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe, N. Angew. add to enynes: Westmijze, H.; Kleijn, H.; Vermeer, P. J. Organomet. Chem. Int. Ed. 2004, 43, 6180. Chem. 1982, 234, 117. 13） For transition metal catalyzed Negishi coupling using alkyl halides, 40） Terao, J.; Watabe, H.; Kambe, N. J. Am. Chem. Soc. 2005, 127, 3656. see for example: (a) Devasagayaraj, A.; Stüdemann, T.; Knochel, P. 41） Fujii, Y.; Terao, J.; Watabe, H.; Watanabe, H.; Kambe, N. Tetrahedron Angew. Chem., Int. Ed. Engl. 1995, 34, 2723. (b) Zhou, J.; Fu, G. C. J. 2007, 63, 6635. Am. Chem. Soc. 2003, 125, 12527. (c) Nakamura, M.; Ito, S.; Matsuo, 42） Fujii, Y.; Terao, J.; Kato, Y.; Kambe, N. Chem. Commun. 2008, 5836. K.; Nakamura, E. Synlett 2005, 1794. (d) Takahashi, H.; Inagaki, S.; 43） It is known that Cp 2TiCl 2 reacts with vinyl lithium in the presence of Nishihara, Y.; Shibata, T.; Takagi, K. Org. Lett. 2006, 8, 3037. (e) TMEDA to yield butadiene. (a) Beckhaus, R.; Thiele, K. ─ H.; J. Gong, H.; Sinisi, R.; Gagne, M. R. J. Am. Chem. Soc. 2007, 129, 1908. Organomet. Chem. 1986, 317, 23. (b) Beckhaus, R.; Flatau, S.; 14） Benn, R.; Büssemeier, B.; Holle, S.; Jolly, P. W.; Mynott, R.; Trojanov, S.; Hofmann, P. Chem. Ber. 1992, 125, 291. (c) Beckhaus, R. Tkatchenko, I.; Wilke, G. J. Organomet. Chem. 1985, 279, 63. Angew. Chem., Int. Ed. Engl. 1997, 36, 686. 1 15） (a) Kaschube, W.; Pörschke, K. R.; Angermund, K.; Krüer, C.; Wilke, 44） Cp 2Ti(η ─ allyl)X complex has been reported. (a) Sato, F.; Iida, K.; G. Chem. Ber. 1988, 121, 1921. (b) Holle, S.; Jolly, P. W.; Mynott, R.; Iijima, S.; Morita, H.; Sato, M. J. Chem. Soc., Chem. Commun. 1981, Salz, R. Z. Naturforsch., B: Anorg. Chem. Org. Chem. 1982, 37, 675. 1140. (b) Hanzawa, Y.; Kowase, N.; Taguchi, T. Tetrahedron Lett.

16） As a similar mechanism, lithium cuprates (R 2CuLi) react with R’X to 1998, 39, 583. (c) Hanzawa, Y.; Kowase, N.; Momose, S.; Taguchi, T. give R ─ R’ via Cu(III) intermediates. (a) Bertz, S. H.; Cope, S.; Dorton, Tetrahedron 1998, 54, 11387. D.; Murphy, M.; Ogle, C. A. Angew. Chem. Int. Ed. 2007, 46, 7082. (b) 45） Todo, H.; Terao, J.; Watanabe, H.; Kuniyasu, H.; Kambe, N. Chem. Gärtner, T.; Yoshikai, N.; Neumeier, M.; Nakamura, E.; Gschwind, Commun. 2008, 1332. R. M. Chem. Commun. 2010, 46, 4625. According to ref. 7, a radical 46） Fujii, Y.; Terao, J.; Kambe, N. Chem. Commun. 2009, 1115. mechanism via an electron transfer from the ate complex 4 to alkyl 47） Fujii, Y.; Terao, J.; Kuniyasu, H.; Kambe, N. J. Organomet. Chem. halides would not be likely. 2007, 692, 375. 17） Terao, J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Commun. 2007, 825. 18） Pratt, L. M.; Voit, S.; Okeke, F. N.; Kambe, N. J. Phys. Chem. A 2011, 115, 2281. 19） Singh, S. P.; Terao, J.; Kambe, N. Tetrahedron Lett. 2009, 50, 5644. 20） Singh, S. P.; Iwasaki, T.; Terao, J.; Kambe, N. Tetrahedron Lett. 2011, 52, 774. 21） Ley and co ─ workers demonstrated that Pd ─ containing perovskites exhibit high catalytic activities on heating and can be recovered and reused as catalysts for the Suzuki ─ Miyaura cross ─ coupling of aryl halides with aryl ─ or vinylboronic acids in alcohol solvents in the presence of a base. (a) Smith, M. D.; Stepan, A. F.; Ramarao, C.; Brennan, P. E.; Ley, S. V. Chem. Commun. 2003, 2652. (b) Andrews, S. P.; Stepan, A. F.; Tanaka, H.; Ley, S. V.; Smith, M. D. Adv. Synth. Catal. 2005, 347, 647. 22） Iwasaki, T.; Tsumura, A.; Omori, T.; Kuniyasu, H.; Terao, J.; Kambe, N. Chem. Lett., 2011, 40, 1024. 23） Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 5749. 24） Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew.

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有機合成化学69-11＿10論文_Kambe.indd 86 2011/10/20 16:41:47 PROFILE

Nobuaki Kambe is Professor of organic chemistry at Osaka University. He studied chemistry and received his Ph.D. degree (1981) from Osaka University. He joined the Department of Applied Chemistry, Faculty of Engineering, Osaka University in 1981 as an Assistant Professor. From 1982 to 1984, he was involved in research at Colorado State University with Professor L. S. Hegedus as a postdoctoral fellow. He was promoted to As- sociate Professor in 1989 and to Professor in 1999. He received the Chemical Society of Japan Award for Young Chemists in 1988 and the Japan Petroleum Institute Award for Encouragement of Research and Develop- ment in 1993. His research interests are in the areas of synthetic organic chemistry, organometallic chemistry, and physical organic chemistry.

Jun Terao is an Associate Professor of Kyoto University. He received his B.Sc (1994) and Ph.D. degree (1999) from Osaka University. After working as a postdoctoral fellow at Hokkaido University under Professor Tamotsu Takahashi, he joined the Graduate School of Engineering, the Department of Applied Chemistry, Osaka University, as an Assistant Professor. From 2002 to 2003, he worked at the University of Oxford with Professor H. L. Anderson as a postdoctoral fellow. He was promoted to Associate Profes- sor in 2008 in the Graduate School of Engi- neering, the Department of Energy and Hy- drocarbon Chemistry, Kyoto University. In 2006, he received Merck Banyu Lectureship Award. His research interests are in the areas of supramolecular chemistry and molecular electronics.

Takanori Iwasaki was born in Osaka, Japan, in 1981. He completed his B.Sc. in 2004 and M.Sc. in 2006 at the Graduate School of Engi- neering Science, Osaka University and received his Ph.D. in 2009 from Osaka Univer- sity under the supervision of Professors K. Mashima and T. Ohshima. He became an assistant professor in the Graduate School of Engineering, Osaka University in 2009, working with Professor N. Kambe. He also did research with Professor K. Kirchner, Vienna University Technology, Austria in 2005. His current research interests include the development of transition metal ─ catalyzed C ─ C bond formations applied to organic synthesis.

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