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Synlett 2010(19): 2883-2886  
DOI: 10.1055/s-0030-1259040
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Cross-Coupling Reactions between C(sp²)-H and C(sp³)-H Bonds via Sequential Dehydrogenation and C-H Insertion

Yoichiro Kuninobu*, Daisuke Asanoma, Kazuhiko Takai*
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima, Kita-ku, Okayama 700-8530, Japan
Fax: +81(86)2518094; e-Mail: kuninobu@cc.okayama-u.ac.jp; e-Mail: ktakai@cc.okayama-u.ac.jp;

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Publication History

Received 8 September 2010
Publication Date:
10 November 2010 (online)

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Abstract

Formal C(sp²)-H and C(sp³)-H cross-coupling reactions were carried out by iridium-catalyzed transfer dehydrogenation of primary alcohols and sequential manganese-catalyzed insertion of the formed aldehydes into a carbon-hydrogen bond of aromatic or olefinic compounds.

Key words

manganese - iridium - C-H activation - dehydrogenation - cross-coupling

Cross-coupling reactions are powerful tools to synthesize complex organic molecules. [¹] In these transformations, organometallic reagents and organic halides or triflates are usually employed as substrates, and efficient and regio­selective couplings can be achieved. Unfortunately, metal salts are formed as undesired side products. Recently, to improve the efficiency, cross-coupling reactions between carbon-metal and carbon-hydrogen bonds [²] or carbon-­hydrogen and carbon-halogen bonds [³] have been reported. The most ideal method, however, is dehydrogenative coupling reactions between carbon-hydrogen bonds of two substrates. [4] However, it is usually difficult to control the regioselectivity in such transformations. Although there have been several reports on coupling reactions between two aromatic compounds, those based on C(sp³)-H bonds are still rare. [5] Among the methods to synthesize benzylic (or allylic) alcohols, dehydrogenative coupling between aromatic (or olefinic) compounds and primary alcohols is one of the most direct approaches (Scheme  [¹] , step a). However, the transformation is still difficult. Therefore, we devised a new sequential strategy: (1) dehydrogenation of a primary alcohol (the first C-H bond activation, Scheme  [¹] , step b-1), and (2) insertion of the formed aldehyde into the carbon-hydrogen bond of aromatic or olefinic compounds (the second C-H bond activation; Scheme  [¹] , step b-2). We report herein formal coupling ­reactions between aryl-alkyl and alkenyl-alkyl groups to give benzylic and allylic alcohols.

In the first step of our strategy (Scheme  [¹] , step b-1), iridium-catalyzed transfer dehydrogenation of alcohols was selected to prepare aldehydes. [6] To achieve the insertion of the formed aldehydes into the carbon-hydrogen bond of aromatic or olefinic compounds (Scheme  [¹] , step b-2), we chose a manganese complex, which has already been employed as a catalyst to promote the insertion of aldehydes into a carbon-hydrogen bond of aromatic or olefinic compounds. [7]

Scheme 1 Strategy for C(sp²)-C(sp³) cross-coupling reactions

In previous iridium-catalyzed transfer dehydrogenations of alcohols, acetone was used as both solvent and hydrogen acceptor. [6] However, manganese-catalyzed insertion of an aldehyde into an aromatic or olefinic C-H bond is inhibited by acetone and isopropanol which is generated by the hydrogenation of acetone. As another example of dehydrogenation of alcohols under iridium catalysis, toluene was used as a solvent without a hydrogen acceptor. Unfortunately, in the case of dehydrogenation of primary alcohols, the yields of the formed aldehydes were low. [8] Therefore, we investigated several unsaturated molecules to find a suitable hydrogen acceptor, that is, one that will receive hydrogen well without inhibiting the subsequent manganese-catalyzed transformation in toluene. As a result, (E)-3-methyl-3-penten-2-one (2) was found to be the most effective hydrogen acceptor. [9] [¹0] The reaction of benzyl alcohol (1a) and 2 with catalytic amounts of an iridium complex, [Cp*IrCl2]2, and K2CO3 in toluene, followed by treatment with 1-methyl-2-phenyl-1H-imidazole (3a), HSiEt3, and a catalytic amount of a manganese complex, MnBr(CO)5, afforded benzyl ether 4a in 78% yield (Scheme  [²] ). [¹¹] In this reaction sequence, a new carbon-carbon bond was constructed between the sp³-carbon of alcohol 1a and the sp²-carbon of aromatic compound 3a.

Scheme 2

Next, we investigated the scope and limitations of alcohols 1 and aromatic or olefinic compounds 3 (Table  [¹] ). Benzylic alcohols with an electron-donating or -withdrawing group at the para-position, 1b-e, gave benzylic ethers 4b-e in good to excellent yields (entries 1-4). The corresponding benzylic ester 4f was produced in 71% yield without losing the bromine atom (entry 5). A methyl group at the ortho-position of benzylic alcohol 1g inhibited the reaction slightly, and benzylic ether 4g was formed in 56% yield (entry 6). (1-Naphthalenyl)methanol (1h) and (2-furanyl)methanol (1i) provided the corresponding benzylic ethers 4h and 4i in moderate yields, respectively (entries 7 and 8). Benzylic ether 4j was generated with aliphatic alcohol 1j (entry 9). The reaction also proceeded using an olefinic substrate 3b, and the corresponding allylic ether 4k was afforded in 38% yield (entry 10). In the above reactions, unreacted aromatic and olefinic compounds 3a and 3b were recovered. The total percentages of the recovery of 3a and the yields of products 4 were nearly 100%; however, ca. 20% of olefinic compound 3b was decomposed. On the other hand, aldehydes were consumed mainly by hydrosilylation of the aldehydes with hydrosilane 2. The yields of 4 were not improved by increasing the amounts of 1 and/or 2.

Table 1 Cross-Coupling Reactions between Alcohols 1 with Aromatic or Olefinic Compounds 3 a

Entry R Alcohols 3 Products Yield (%)b
 1c 4-MeOC6H4 1b

3a 		4b 63 (73)
 2 4-MeC6H4 1c 3a 4c [¹4] 77 (86)
 3 4-PhC6H4 1d 3a 4d 78 (84)
 4d 4-F3CC6H4 1e 3a 4e 87 (90)
 5 4-BrC6H4 1f 3a 4f 71 (73)
 6c 2-MeC6H4 1g 3a 4g 56 (59)
 7c 1-naphthyl 1h 3a 4h 62 (64)
 8e 2-furyl 1i 3a 4i 45 (46)
 9 n-C8H17 1j 3a 4j 43 (46)
10f Ph 1a

3b 		4k 38 (50)
a 1 (2.0 equiv).
b Isolated yield. Yield determined by ¹H NMR is reported in parentheses.
c HSiEt3 (3.0 equiv).
d Step 1: 2 h; step 2: HSiEt3 (4.0 equiv).
e Step 1: 2 h; step 2: HSiEt3 (3.0 equiv).
f Step 2: [ReBr(CO)3(thf)]2 (2.5 mol%) and 4 Å MS were used instead of MnBr(CO)5.

The proposed mechanism is as follows (Scheme  [³] ): (1) iridium-catalyzed dehydrogenation of an alcohol; [6] [¹²] (2) manganese-catalyzed carbon-hydrogen bond activation at the ortho position of an aromatic or alkenyl imidazole; [7] (3) insertion of the formed aldehyde into the manganese-carbon bond; (4) transmetalation with hydrosilane via dehydrogenation.

Scheme 3 Proposed mechanism for formal cross-coupling reactions between sp³- and sp²-carbons

When an aromatic ketimine was employed instead of 1-methyl-2-phenyl-1H-imidazole (3a), successive intramolecular cyclization took place, and an isobenzofuran derivative was obtained (Scheme  [4] ). Thus, treatment of benzyl alcohol (1a) with aromatic ketimine 5 in the presence of catalytic amounts of an iridium complex, [Cp*IrCl2]2, a rhenium complex, [ReBr(CO)3(thf)]2, and 4 Å molecular sieves in toluene at 115 ˚C for 24 hours, gave 1,3-diphenylisobenzofuran (6) in 91% yield (Scheme  [4] ). Both iridium-catalyzed dehydrogenation of 1a and manganese-catalyzed C-H bond activation followed by the insertion of an aldehyde proceeded in toluene. Therefore, this reaction could be performed in one operation.

Scheme 4

Using an alcohol with an olefin moiety, 1k, oxidation of 1k, insertion of the formed aldehyde into a C-H bond of aromatic ketimine 5, intramolecular nucleophilic cyclization, elimination of aniline (formation of isobenzofuran derivative), and intramolecular cyclization by Diels-Alder reaction occurred. After dehydration under acidic conditions, naphthalene derivative 7 was obtained in 45% yield (Scheme  [5] ).

Scheme 5

In summary, we have succeeded in cross-coupling reactions between sp²- and sp³-carbon bonds by iridium-catalyzed dehydrogenation of primary alcohols and sequential manganese-catalyzed insertion of the formed aldehydes into a C-H bond of aromatic or olefinic compounds. [¹³] We hope that this sequential methodology will provide useful insight to realize cross-coupling reactions between substrates of difficulty.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

This work was partially supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

9

When (E)-3-methyl-3-penten-2-one (2) was used as a hydrogen acceptor, 3-methylpentan-2-one was formed. This result shows that the olefinic moiety of 2 was reduced.

10

Investigation of hydrogen acceptors in dehydrogenation of alcohol 1a {hydrogen acceptor: 1.5 equiv; [Cp*IrCl2]2: 0.50 mol%; K2CO3: 5.0 mol%; toluene, 150 ˚C; 18 h}: (E)-3-methyl-3-penten-2-one >99%; (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one >99%; 3-methyl-2-cyclohexenone 92%; (E)-4-phenyl-3-buten-2-one 92%; 1-penten-3-one 82%; p-benzoquinone 78%; 2-cyclohexenone 57%; 2-cyclo-pentenone 52%; 3-ethoxy-2-cyclohexenone 8%.

11

First, we conducted the reactions between benzyl alcohol (1a), (E)-3-methyl-3-penten-2-one (2), 1-methyl-2-phenyl-1H-imidazole (3a), and HSiEt3 in the presence of catalytic amounts of an iridium complex, [Cp*IrCl2]2, K2CO3, and a manganese complex, MnBr(CO)5, in toluene. However, the desired reaction did not proceed at all. Therefore, we carried out the coupling reactions in two steps.

12

3-Methyl-2-pentanone, which is formed by hydrogenation of (E)-3-methyl-3-penten-2-one (2), was observed by ¹H NMR and GCMS.

13

General Procedure of Formal Cross-Coupling Reaction
A mixture of alcohol (1, 0.500 mmol), (E)-3-methyl-3-penten-2-one (2, 73.6 mg 0.750 mmol), [Cp*IrCl2]2 (2.0 mg, 0.0025 mmol), K2CO3 (3.5 mg, 0.025 mmol), and toluene (1.0 mL) was heated at 150 ˚C for 18 h. Then, imidazole
(3, 0.250 mmol), HSiEt3 (58.1 mg, 0.500 mmol), and MnBr(CO)5 (3.4 mg, 0.013 mmol) were added, and the mixture was stirred at 115 ˚C for 24 h. The product was isolated by column chromatography on silica gel [hexane-EtOAc = 5:1. Before column chromatography, the silica
gel was treated with Et3N {5% solution in hexane-EtOAc
(5/1)}.] to give 4.

14

1-Methyl-2-[2-( p -tolyltriethylsilanyloxymethyl)phenyl]-1 H -imidazole (4c)
¹H NMR (400 MHz, CDCl3): δ = 0.54 (q, J = 8.0 Hz, 6 H), 0.86 (t, J = 8.0 Hz, 9 H), 2.23 (s, 3 H), 2.69 (s, 3 H), 6.15 (s, 1 H), 6.74 (d, J = 8.8 Hz, 2 H), 6.81 (s, 1 H), 6.93 (d, J = 6.8 Hz, 2 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.18 (s, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1 H), 8.03 (d, J = 7.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 4.7, 6.7, 32.4, 72.5, 120.2, 125.7, 126.1, 126.8, 127.8, 128.1, 128.3, 129.3, 129.8, 136.2, 141.7, 146.4, 146.6; IR (nujol): ν = 1178 (m), 1117 (m), 1072 (m), 1011 (m), 851 (m) cm-¹. HRMS (EI+): m/z calcd for C23H34N2OSi [M+]: 392.2284; found: 392.2291.

9

When (E)-3-methyl-3-penten-2-one (2) was used as a hydrogen acceptor, 3-methylpentan-2-one was formed. This result shows that the olefinic moiety of 2 was reduced.

10

Investigation of hydrogen acceptors in dehydrogenation of alcohol 1a {hydrogen acceptor: 1.5 equiv; [Cp*IrCl2]2: 0.50 mol%; K2CO3: 5.0 mol%; toluene, 150 ˚C; 18 h}: (E)-3-methyl-3-penten-2-one >99%; (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one >99%; 3-methyl-2-cyclohexenone 92%; (E)-4-phenyl-3-buten-2-one 92%; 1-penten-3-one 82%; p-benzoquinone 78%; 2-cyclohexenone 57%; 2-cyclo-pentenone 52%; 3-ethoxy-2-cyclohexenone 8%.

11

First, we conducted the reactions between benzyl alcohol (1a), (E)-3-methyl-3-penten-2-one (2), 1-methyl-2-phenyl-1H-imidazole (3a), and HSiEt3 in the presence of catalytic amounts of an iridium complex, [Cp*IrCl2]2, K2CO3, and a manganese complex, MnBr(CO)5, in toluene. However, the desired reaction did not proceed at all. Therefore, we carried out the coupling reactions in two steps.

12

3-Methyl-2-pentanone, which is formed by hydrogenation of (E)-3-methyl-3-penten-2-one (2), was observed by ¹H NMR and GCMS.

13

General Procedure of Formal Cross-Coupling Reaction
A mixture of alcohol (1, 0.500 mmol), (E)-3-methyl-3-penten-2-one (2, 73.6 mg 0.750 mmol), [Cp*IrCl2]2 (2.0 mg, 0.0025 mmol), K2CO3 (3.5 mg, 0.025 mmol), and toluene (1.0 mL) was heated at 150 ˚C for 18 h. Then, imidazole
(3, 0.250 mmol), HSiEt3 (58.1 mg, 0.500 mmol), and MnBr(CO)5 (3.4 mg, 0.013 mmol) were added, and the mixture was stirred at 115 ˚C for 24 h. The product was isolated by column chromatography on silica gel [hexane-EtOAc = 5:1. Before column chromatography, the silica
gel was treated with Et3N {5% solution in hexane-EtOAc
(5/1)}.] to give 4.

14

1-Methyl-2-[2-( p -tolyltriethylsilanyloxymethyl)phenyl]-1 H -imidazole (4c)
¹H NMR (400 MHz, CDCl3): δ = 0.54 (q, J = 8.0 Hz, 6 H), 0.86 (t, J = 8.0 Hz, 9 H), 2.23 (s, 3 H), 2.69 (s, 3 H), 6.15 (s, 1 H), 6.74 (d, J = 8.8 Hz, 2 H), 6.81 (s, 1 H), 6.93 (d, J = 6.8 Hz, 2 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.18 (s, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1 H), 8.03 (d, J = 7.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 4.7, 6.7, 32.4, 72.5, 120.2, 125.7, 126.1, 126.8, 127.8, 128.1, 128.3, 129.3, 129.8, 136.2, 141.7, 146.4, 146.6; IR (nujol): ν = 1178 (m), 1117 (m), 1072 (m), 1011 (m), 851 (m) cm-¹. HRMS (EI+): m/z calcd for C23H34N2OSi [M+]: 392.2284; found: 392.2291.

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Scheme 1 Strategy for C(sp²)-C(sp³) cross-coupling reactions

Scheme 2

Scheme 3 Proposed mechanism for formal cross-coupling reactions between sp³- and sp²-carbons

Scheme 4

Scheme 5