Palladium-Catalyzed 1,2-Addition of Alkylborane Reagents to Aldehydes
Tetsuya YAMAMOTO,* Taro OKABE,** Michiko IIZUKA,** Yoshihiko ITO,** Yohei OE,* and Tetsuo OHTA*
(Received July 15, 2009)
Triethylborane reacts with aldehydes in the presence of a base and a catalytic amount of a palladium(0) complex with chloroform, affording the corresponding 1-phenyl-1-propanol derivatives in good yields. Of the catalysts surveyed, the combination of Pd(OAc)2 and tricyclohexylphosphine is the most effective catalyst for this reaction.
Key Words: palladium, organoborane, 1,2-addition, aldehydes, alcohol, alkylation
1. Introduction
Carbon–carbon bond formation reactions using transition metal catalyst are very important methods in organic synthesis. Organoboron reagents have low toxicity and are practically useful for carbon–carbon bond formations with various electrophiles in the presence of several kinds of transition metals.1 Recently, transition metal catalyzed 1,2-additions of organoboron compounds to aldehydes have been developed. Aryl- and alkenyl boron reagents react with aldehydes in the presence of various metal catalysts, such as rhodium,2 copper,3 palladium,4 nickel,5 platinum,6 and iron.7 However, to the best of our knowledge, there is only one report of the metal catalyzed alkylation of aldehydes with conventional alkylborane reagents.8
Previously, we have reported the palladium catalyzed 1,2-addition to aldehydes with arylboronic acids (Scheme 1).4b,l In this reaction, conventional palladium complex becomes catalytically active by the addition of a catalytic amount of chloroform. We thought that this catalyst system is applicable to the alkylation of aldehydes using alkylborane reagents.
Herein, we report the first example of a palladium catalyzed alkylation of aldehydes with alkylboranes.
Ar1 H O
Ar2B(OH)2
Ar1 Ar2 OH +
Phosphine
Base Pd catalyst
CHCl3 Previous work
This work
Ar1 H O
Alkyl-B Ar1 Alkyl
OH +
Phosphine
Base Pd catalyst
CHCl3
B = Alkyl2B, B(OH)2
1 2 3
Scheme 1. Palladium-catalyzed 1,2-addition to aldehydes with organoborane reagents
2. Experimental
2.1. Analytical instrument
Nuclear magnetic resonance spectra were measured on a Varian MERCURY plus300-4N spectrometer (1H NMR 300 MHz).
2.2. Reagents
All solvents were dried by standard methods and distilled under argon. Commercially available compounds were used without purification.
2.3. Palladium catalyzed alkylation of aldehydes with alkylboranes.
Pd complex (0.025 mmol or 0.05 mmol, 5 mol%),
* Department of Biomedical Information, Doshisha University, Kyotanabe, Kyoto 610-0394 Telephone: +81-774-65-6548, Fax: +81-774-65-6789, E-mail: [email protected]
phosphine (0.1 mmol, 10 mol%), alkylborane (2.0 mmol), aldehyde (1.0 mmol), and base (1.0 mmol) were dissolved in solvent (2.0 mL) and chloroform (0.01 mL).
After the mixture was stirred at 60 °C for 24 h, the product was extracted with CH2Cl2. The analytically pure alcohol was obtained by chromatography on silica gel.
2.4. 4-(1-Hydroxypropyl)benzonitrile (3a)
1H-NMR (CDCl3, 300 MHz) G 0.92 (t, J = 7 Hz, 3H), 1.71-1.81 (m, 2H), 2.00 (m, 1H), 4.69 (s, 1H), 7.42 (d, J
= 7 Hz, 2H), 7.50 (d, J = 7 Hz, 2H).
2.5. 1-(4-Methylphenyl)-1-propanol (3b)
1H-NMR (CDCl3, 300 MHz) G 0.88 (t, J = 7 Hz, 3H), 1.65-1.84 (m, 2H), 2.00 (m, 1H), 2.33 (s, 3H), 4.51 (s, 1H), 7.13 (d, J = 7 Hz, 2H), 7.19 (d, J = 7 Hz, 2H).
2.6. 1-Phenyl-1-propanol (3c)
1H-NMR (CDCl3, 300 MHz) G 0.92 (t, J = 7 Hz, 3H), 1.69-1.89 (m, 2H), 1.90 (m, 1H), 4.58 (s, 1H), 7.23-7.37 (m, 5H).
2.7. 1-(4-Trifluoromethylphenyl)-1-propanol (3d)
1H-NMR (CDCl3, 300 MHz) G 0.91 (t, J = 7 Hz, 3H), 1.70-1.82 (m, 2H), 2.20 (m, 1H), 4.65 (s, 1H), 7.42 (d, J
= 6 Hz, 2H), 7.58 (d, J = 6 Hz, 2H).
2.8. 1-(2-Naphthyl)-1-propanol (3e)
1H-NMR (CDCl3, 300 MHz) G 0.95 (t, J = 7 Hz, 3H), 1.82-1.95 (m, 2H), 1.92 (m, 1H), 4.78 (s, 1H), 7.43-7.49 (m, 3H), 7.77-7.85 (m, 4H).
3. Results and Discussion
3.1. Survey of the combination of palladium source and phosphine
Palladium-catalyzed addition of triethylborane to 4-cyanobenzaldehyde was examined and summarized in Table 1, which shows effects of palladium precursors
together with phosphine ligands. As a result, the combination of Pd(OAc)2 and Cy3P catalyzed ethylation of 4-cyanobenzaldehyde in good yield (67 %, Table 1, entry 1). In the presence of Cy3P ligand, other palladium precursors, such as Pd2(dba)3, PdCl2(CH3CN)2, [PdCl(S-C3H5)]2 and Pd(acac)2, had low or no effect for this reaction (Table 1, entries 2-5).
Also PdCl2(Cy3P)2 has not promoted the addition reaction (Table 1, entry 6). Additionally, in the presence of Pd(OAc)2, several other phosphine ligands have been employed, and most of them showed no effect for this reaction (Table 1, entries 7-15).
Table 1. Survey of the Combination of Palladium Source and Phosphine a
NC
H O
Et3B
NC
Et OH +
Phosphine Cs2CO3 1,4-dioxane
24 h, 60 oC CHCl3 Pd source
1a 2a 3a
Entry Palladium
source Phosphine Yield (%)b
1 Pd(OAc)2 Cy3P 67c
2 Pd2(dba)3 Cy3P 38
3 PdCl2(CH3CN)2 Cy3P 4
4 [PdCl(S-C3H5)]2 Cy3P 7
5 Pd(acac)2 Cy3P 0
6 Pd Cl2(Cy3P)2 - 0
7 Pd(OAc)2 PhPCy2 13
8 Pd(OAc)2 Ph2PCy 3
9 Pd(OAc)2 PPh3 0
10 Pd(OAc)2 (C4H3O)3P 0 11 Pd(OAc)2 (4-F-C6H4)3P 0 12 Pd(OAc)2 (2-Me-C6H4)3P 6
13 Pd(OAc)2 DPPE 0
14 Pd(OAc)2 DPPP 0
15 Pd(OAc)2 DPPF 13
a Reaction conditions: 4-cyanobenzaldehyde 1.0 mmol, triethylborane 2.0 mmol, palladium precursour 5 mol%, phosphine 10 mol%, Cs2CO3 1.0 mmol, 1,4-dioxane 2.0 mL, CHCl3 0.01 mL, 24 h, 60 ͠. b Determined by 1H-NMR.
c Isolated yield.
3.2. Effect of solvent
Pd(OAc)2-Cy3P-catalyzed alkylation of 4-cyano- benzaldehyde with triethylborane was summarized in Table 2, which shows effects of solvents. The use of non-polar solvents, such as benzene, toluene and 1,2-dichloroethane, gave the products in low yields (Table 2, entries 1-4). Etheral solvents, 1,4-dioxane and DME, were the solvent of choice for this reaction (Table 2, entries 5-8). However, we observed low yield in THF (Table 2, entries 9 and 10). Also polar solvents, such as ethanol and acetonitrile, were poor solvent (Table 2, entries 11 and 12).
Table 2. Effect of Solventa
NC
H O
Et3B
NC
Et OH +
PCy3 Cs2CO3
solvent 24 h CHCl3 Pd(OAc)2
1a 2a 3a
Entry Solvent Temp
(͠)
Yield (%)b
1 Benzene 80 26
2 Toluene 80 23
3 Toluene 60 14
4 1,2-Dichloroethane 80 17
5 1,4-Dioxane 80 51c
6 1,4-Dioxane 60 67c
7 1,4-Dioxane 40 66c
8 DME 80 59c
9 THF 80 22
10 THF 60 13
11 EtOH 70 10
12 CH3CN 60 2
a Reaction conditions: p-cyanobenzaldehyde 1.0 mmol, triethylborane 2.0 mmol, Pd(OAc)2 5 mol%, PCy3 10 mol%, Cs2CO3 1.0 mmol, solvent 2.0 mL, CHCl3 0.01 mL, 24 h.
b Determined by 1H-NMR. c Isolated yield.
3.3. Effect of Base
Pd(OAc)2-Cy3P catalyzed alkylation of 4-cyanobenzaldehyde with triethylborane was summarized in Table 3, which shows effects of bases.
Without base, no reaction occurred at all. The use of Cs2CO3 showed the best yield of the product (Table 3, entry 1), while other bases used had little effect for this reaction (Table 3, entries 2-5).
Table 3. Effect of Basea
NC
H O
Et3B
NC
Et OH +
PCy3 base CHCl3 Pd(OAc)2
1a 2a 3a
1,4-dioxane 24 h, 60 oC
Entry Base Yield (%)b
1 Cs2CO3 67 c
2 Na2CO3 0
3 K2CO3 14
4 K3PO4 13
5 KOH 14
a Reaction conditions: p-cyanobenzaldehyde 1.0 mmol, triethylborane 2.0 mmol, Pd(OAc)2 5 mol%, PCy3 10 mol%, base 1.0 mmol, 1,4-dioxane 2.0 mL, CHCl3 0.01 mL, 24 h, 60 ͠. b Determined by 1H-NMR. c Isolated yield.
3.4. Scope of aldehydes on the ethylation Table 4. Scope of Aldehydes on the Ethylationa
R H
O
Et3B
R Et OH +
PCy3 Cs2CO3 1,4-dioxane
24 h, 60 oC CHCl3 Pd(OAc)2
1 2a 3
Entry R = Product Yield (%)b
1 NC 3a 67
2 Me 3b 34
3 3c 44
4 F3C 3d 43
5 3e 23
a Reaction conditions: aldehyde 1.0 mmol, triethylborane 2.0 mmol, Pd(OAc)2 5 mol%, PCy3 10 mol%, Cs2CO3 1.0 mmol, 1,4-dioxane 2.0 mL, CHCl3 0.01 mL, 24 h, 60 ͠. b Isolated yield.
Results of the reaction of aldehydes with
triethylborane are summarized in Table 4. Aldehydes with electron-withdrawing substituent, p-cyanobenz- aldehyde, and triethylborane reacted smoothly (Table 4, entry 1), while other aldehydes tried reacted slower (Table 4, entries 2-5).
3.5. Scope of conventional alkylboranes on the alkylation
Results of the reaction of 4-cyanobenzaldehyde with conventional alkylboranes are summarized in Table 5.
Only triethylborane reacted smoothly (Table 5, entry 1).
However other alkylboranes, such as tributylborane, methylboronic acid, and hexylboronic acid, did not react at all (Table 5, entries 2-4).
Table 5. Scope of Conventional Alkylboranes on the Alkylation a
PCy3 Cs2CO3 24 h, 60 oC 1,4-dioxane NC
H O
R3B
NC
R OH CHCl3
+
Pd(OAc)2
RB(OH)2 or
1a 2 3
Entry Alkylborane compounds Yield (%) b
1 Et3B 67
2 (n-Bu)3B 0
3 MeB(OH)2 0
4 (n-Hexyl)B(OH)2 0
a Reaction conditions: p-cyanobenzaldehyde 1.0 mmol, alkylborane compounds 2.0 mmol, Pd(OAc)2 5 mol%, PCy3 10 mol%, Cs2CO3 1.0 mmol, 1,4-dioxane 2.0 mL, CHCl3 0.01 mL, 24 h, 60 ͠. b Determined by 1H-NMR.
3.6. Reaction mechanism on the palladium catalyzed alkylation of aldehydes
We wish to propose the catalytic cycle of this reaction in Scheme 2. At first, dichloromethyl coordinating palladium(II)–phosphine intermediate 4 is generated by oxidative addition of chloroform to palladium(0)–phosphine complex, and then dichloromethylpalladium(II) intermediate 4 converts to a hydroxypalladium(II) species 5 by counter anion
exchange. The transmetalation between triethylborane and the hydroxyl palladium(II) species 5 occurs to generate an ethylpalladium(II) intermediate 6. The insertion of aldehyde into the carbon–palladium bond affords a corresponding alkoxypalladium 7. Hydrolysis of the intermediate 7 gives the corresponding alcohol and the hydroxypalladium(II) species 5.
CHCl2 CHCl3
Pd0
P P Pd2+
Cl
OH- Cl- OH
Ar Et CHCl2 Et-BEt2
Pd2+
P H2O OH
CHCl2 P
Pd2+
Pd2+ P Cl2HC Et
O Et
Ar
O H Ar 4
5
6 7
Scheme 2. Plausible reaction mechanism on the palladium catalyzed alkylation of aldehydes
4. Summary
In conclusion, we have disclosed the use of the carbon-bound palladium(II)-Cy3P catalyst, such as dichloromethylpalladium(II)-Cy3P intermediate that was generated from palladium(0)-Cy3P complex with chloroform, for the addition reactions to aldehydes using triethylborane. This result is the first example of a palladium catalyzed alkylation of aldehydes with alkylboranes.
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