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Synlett 2009(6): 994-998  
DOI: 10.1055/s-0028-1088198
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Rhodium-Catalyzed Asymmetric 1,4-Addition of Heteroaryl Cyclic Triolborate to α,β-Unsaturated Carbonyl Compounds

Xiao-Qiang Yu, Yasunori Yamamoto*, Norio Miyaura*
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax: +81(11)7066561; e-Mail: yasuyama@eng.hokudai.ac.jp; e-Mail: miyaura@eng.hokudai.ac.jp;

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Publication History

Received 16 December 2008
Publication Date:
16 March 2009 (online)

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Abstract

Rhodium-catalyzed asymmetric 1,4-additions of electron-deficient heteroaryl groups to α,β-unsaturated carbonyl compounds were established. The reaction resulted in very low yields due to competitive C-B bond cleavage when arylboronic acids, their pinacol esters, or potassium trifluoroborates were used. However, the corresponding lithium heteroaryl(triol)borates afforded 1,4-adducts with high enantioselectivities up to 97% in the presence of a rhodium(I) catalyst chelated with a chiral BINAP or BIPAM ligand.

Key words

heteroaryl cyclic triolborate - rhodium catalyst - asymmetric reaction - conjugate addition

The transition-metal-catalyzed asymmetric 1,4-addition to α,β-unsaturated carbonyl compounds is a powerful method for producing stereodefined C-C bonds, particularly in the enantioselective synthesis of biologically important molecules in natural products and drug candidates. [¹] Copper complexes have been successfully used for organolithium, -magnesium, or -zinc reagents, [²] [³] rhodium complexes have been successfully used for organoboranes, -silicones, or -stannanes, [4] and palladium(II) complexes have been successfully used for arylboron, -silicone, and -bismuth compounds. [4c] [5] Among these extensive studies on asymmetric C-C bond formation, 1,4-addition of arylboronic acids has attracted much attention due to their low toxicity, compatibility to a broad range of functional groups, and high stability in water and air. Although excellent yields and selectivities have been achieved by using typical arylboronic acids possessing no heteroatoms, there has been little use of pyridine and thiophene analogues [6-8] due to the high coordination ability of heteroatoms to catalysts and slow transmetalation and insertion of electron-deficient heteroaryl rings, thus facilitating C-B bond cleavage with water relative to 1,4-addition to unsaturated carbonyl compounds. Recognition of the importance of heteroaryl groups in biologically active compounds recently prompted us to develop novel cyclic triolborates for C-C and C-N bond formation via coupling reactions catalyzed by palladium or copper complexes. [9] [¹0] We herein report asymmetric 1,4-additions of pyridyl- and thienyl(triol)borates (2) catalyzed by rhodium(I) complexes ligated by a (S)- BINAP, [¹¹] (S,S)-CHIRAPHOS, [¹²] or (R)-Me-BIPAM [¹³] ligand (Scheme  [¹] and Figure  [¹] ). Addition of triolborates possessing a donating substituent such as a methoxy group gave 1,4-addition products with high enantioselectivities at 95 ˚C in nonaqueous 1,4-dioxane.

Scheme 1 1,4-Addition of heteroaryl(triol)borates

Lithium triolborates 2 were synthesized by alkylation of B(Oi-Pr)3 with RLi, followed by ester exchange with triol by evaporating 2-propanol in vacuo (Scheme  [²] ).

By this protocol, heteroarylborates sensitive to hydrolytic B-C bond cleavage were synthesized in high yields. The ¹H NMR analysis in DMSO-d 6 showed the presence of some water of crystallization (ca. 2 molar amounts) which was not removable in vacuo (1.33˙10-5 bar) at room temperature. They are white solids stable in air and moisture.

1,4-Addition of lithium p-tolyl(triol)borate (2g, 1.5 equiv) to 2-cyclohexenone smoothly proceeded at 50 ˚C in dioxane or in aqueous dioxane in the presence of a Rh(I)/(S)-BINAP catalyst (3 mol%, Table  [¹] ). The reaction was faster in aqueous dioxane than in dry dioxane and was further accelerated in the presence of 1 equivalent of triethyl­amine. [¹4] The enantioselectivities (higher than 97% ee) were comparable to those achieved by a rhodium/BINAP catalyst and p-tolylboronic acid or potassium p-tolyl(tri­fluoro)borate. [¹¹] [¹5]

Figure 1 Chiral ligands

Scheme 2 Synthesis of cyclic triolborates

Table 1 1,4-Addition of p-Tolyl(triol)borate

Solvent/base Yield (%) ee (%)
dioxane 68 97
dioxane-H2O (10:1) 87 98
dioxane-H2O (10:1), Et3N 96 98

Although typical aryl(triol)borates possessing no hetero­atom smoothly undergo 1,4-addition under mild conditions, heteroarylborates suffered from low yields due to competitive hydrolytic B-C bond cleavage. Thus, boron reagents, catalysts, and solvents were re-optimized by using 6-methoxy-3-pyridylboron derivatives (1.5 equiv of 4-6 or 2c) for 2-cyclohexenone (Table  [²] , entries 1-9). The reactions were carried out at 95 ˚C in dioxane-H2O (10:1) or dried dioxane in the presence of [Rh(nbd)2]BF4 (3 mol%), (S)-BINAP (3.3 mol%), and triethylamine (1 equiv). 2-Methoxypyridine resulting from hydrolytic B-C bond cleavage was a major product for all boron derivatives when aqueous dioxane was used as the solvent (entries 1, 3, 5, and 7). No desired product was obtained by boronic acid (4) and pinacol ester derivative (5) even in nonaqueous solvent (entries 2 and 4), but quaternary potassium trifluoroborate (6) gave 3a in 13% yield (entry 6). The yield was further increased to 83% with 97% ee when triolborate 2c was used (entry 8). Although a preliminary experiment at 50 ˚C shown in Table  [¹] revealed an accelerating effect of triethylamine, it was not significant at 95 ˚C (entry 9). Finally, an almost quantitative yield was obtained by increasing the catalyst loading to 5 mol% in dioxane (entry 10).

A combination of [Rh(nbd)2]BF4 and BINAP was found to be the best catalyst for 2-cyclohexenone among the representative chiral rhodium(I) complexes (entries 11-15). Rhodium-cod complexes such as [Rh(cod)2]BF4 and [Rh(OH)(cod)]2 (entry 11 and 13) resulted in lower enantio­selectivities than those of coe and nbd complexes due to slow exchange of the cod ligand with chiral BINAP. CHIRAPHOS and Me-BIPAM were less efficient than BINAP (entries 14 and 15).

Lithium 6-methoxy-3-pyridylborate (2c) underwent 1,4-addition to five-, six-, and seven-membered enones in good yields and with high enantiomeric excess under optimized conditions shown in Table  [²] (Table  [³] , entries 1-3). The conditions also worked well for acyclic ketone and ester substrates (3d and 3e, entries 4 and 5), whereas all attempts at increasing the yield of unsaturated amide (3f) were unsuccessful (entry 6).

Table 2 Reaction Conditionsa

Entry ArBX Catalyst Solvent additive Yield (%)b ee (%)c
 1 4 [Rh(nbd)2]BF4/BINAP dioxane-H2O, Et3N  0 -
 2 4 [Rh(nbd)2]BF4/BINAP dioxane, Et3N trace -
 3 5 [Rh(nbd)2]BF4/BINAP dioxane-H2O, Et3N  0 -
 4 5 [Rh(nbd)2]BF4/BINAP dioxane, Et3N trace -
 5 6 [Rh(nbd)2]BF4/BINAP dioxane-H2O, Et3N  5 -
 6 6 [Rh(nbd)2]BF4/BINAP dioxane, Et3N 13 91
 7 2c [Rh(nbd)2]BF4/BINAP dioxane-H2O, Et3N 10 -
 8 2c [Rh(nbd)2]BF4/BINAP dioxane, Et3N 83 97
 9 2c [Rh(nbd)2]BF4/BINAP dioxane 80 97
10 2c [Rh(nbd)2]BF4/BINAPd dioxane 94 97
11 2c [Rh(cod)2]BF4/BINAP dioxane 46 55
12 2c [RhCl(coe)2]2/BINAP dioxane 33 73
13 2c [Rh(OH)(cod)]2/BINAP dioxane 95 91
14 2c [Rh(nbd)2]BF4/CHIRAPHOS dioxane 91 94
15 2c [Rh(nbd)2]BF4/Me-BIPAM dioxane 63 67
a A mixture of 2-cyclohexenone (0.5 mmol), boron compound 4-6, 2c (1 mmol), and Et3N (if used, 0.5 mmol) in dioxane or dioxane-H2O (10:1) was stirred in the presence of rhodium(I) complex (3 mol%) and chiral ligand (3.3 mol%).
b Isolated yields by chromatography.
c The ee was determined by chiral stationary columns.
d Rh catalyst (5 mol%) was used.

Among them, 3e and 3f resulted in ca. 10% lower selectivities than those reported in 1,4-addition of arylboronic acids to these substrates with a Rh(I)/(S)-BINAP catalyst. [¹6] Addition of unsubstituted 2-pyridylborate 2a failed (entry 7), but an electron-rich 6-methoxy derivative 2b gave a 1,4-addition product 3h in 56% yield and 55% ee (entry 8). Thus, the presence of a donating methoxy group was effective for increasing the reaction rate by accelerating the insertion of the enone into the C-Rh bond. The presence of a substituent at the position adjacent to the nitrogen will also work to block coordination to the catalyst. The enantioselectivity was very low when a BINAP or CHIRAPHOS catalyst was used (ca. 60% ee), but 93% ee was finally achieved when (R)-Me-BIPAM [¹³] was used as the chiral auxiliary in the presence of 20 mol% of powdered KOH (entry 9). Me-BIPAM was also good for an acyclic substrate, 63% yield and 81% ee being achieved (entry 10).

Thienylation of cyclic and acyclic enones with 3-thienyl­borate 2f proceeded without any difficulties in the presence of a rhodium/(S)-BINAP catalyst (Table  [4] , entries 1-3). The enantioselectivities were in the range of 84-95% ee. However, the corresponding reaction of a 2-thienyl analogue failed to give a 1,4-addition product (entry 4). This effect of heteroatoms might be due to the higher sensitivity of 2-thienylborate 2f with water than 3-thienyl derivative 2d and lower nucleophilicity of the 2-position in the thienyl ring rather than that of the 3-position.

Indeed, the reaction proceeded smoothly when electron-rich 5-methoxy-2-thienylborate 2e was used for cyclic and acyclic substrates (entries 5 and 6).

Table 3 1,4-Addition of Cyclic Pyridylboratesa
Entry 1 2 Product 3
Yield (%)b ee (%)c
 1 1a 2c 3a

96 97
 2 1b 2c 3b

92 92
 3 1c 2c 3c

9, 93
 4 1d 2c 3d

97 91
 5 1e 2c 3e

83 82
 6 1f 2c 3f

23 76
 7 1b 2a 3g

0 -
 8d 1b 2b 3h

56 55
 9e 1b 2b 3h

67 93
10e 1d 2b 3i

63 81
a A mixture of carbonyl compound 1 (0.5 mmol) and boron compound 2 (1 mmol) in dioxane was stirred in the presence of [Rh(nbd)2]BF4 (3.0 mol%) and (S)-BINAP (3.3 mol%).
b Isolated yields by chromatography. c The ee was determined by chiral stationary columns.
d KOH (powder, 0.1 mmol) was used.
e (R)-Me-BIPAM was used in the presence of KOH (powder, 0.1 mmol).
Table 4 1,4-Addition of Cyclic Thienylboratesa
Entry 1 2 Product 3
Yield (%)b ee (%)c
1 1a 2f 3j

90 88
2 1b 2f 3k

90 90
3 1d 2f 3l

93 84
4 1b 2d 3m

trace -
5 1b 2e 3n

63 90
6 1d 2e 3o

63 88
a A mixture of carbonyl compound 1 (0.5 mmol) and boron compound 2 (1 mmol) in dioxane was stirred in the presence of [Rh(nbd)2]BF4 (3.0 mol%) and (S)-BINAP (3.3 mol%).
b Isolated yields by chromatography.
c The ee values were determined on chiral stationary columns.

In conclusion, we have demonstrated the efficiency of lithium triolborates for the first 1,4-addition of 2-pyridyl and 2-thienyl groups to α,β-unsaturated carbonyl compounds. Triolborates showed several advantages over their boronic acids or related quaternary metal trifluoro­borates: 1) high nucleophilicity of aryl rings attached to the boron atom for smooth transmetalation to metal catalysts and 2) high solubility in organic solvents, allowing the use of water-free solvents for preventing hydrolytic B-C bond cleavage. Since enantiomerically enriched compounds substituted with a heteroaryl ring at the stereogenic carbon center are expected to be versatile synthetic intermediates of biologically active compounds, further investigations into the applications of these cyclic triolborates are under way.

Acknowledgment

This work was supported by a Grand-in-Aid for Science Research on Priority Areas (No. 18064001, Synergy of Elements), and the global COE program (No. B01, Catalysis as the Basis for the Innovation in Materials Science) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Scheme 1 1,4-Addition of heteroaryl(triol)borates

Figure 1 Chiral ligands

Scheme 2 Synthesis of cyclic triolborates