Palladium-catalysed asymmetric arylation of tert-cyclobutanols via enantioselective C–C bond cleavage

Abstract

Palladium-catalysed arylation of tert-cyclobutanols with aryl bromide involving enantioselective C–C bond cleavage affords chiral ketones with moderate to good enantioselectivity.

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Transition metal-catalysed asymmetric reactions have been used as modern and powerful methods for the synthesis of optically active compounds, mainly by a carbon–hydrogen, a carbon–heteroatom, and a carbon–carbon bond formation to create a new chiral centre on carbon.¹ In sharp contrast, although a metal-catalysed selective C–C bond cleavage reaction has been found in recent years,² the example of the enantioselective C–C bond cleavage reaction has been scarcely reported to the best of our knowledge.³ We have recently disclosed a Pd(0)-catalysed arylation of tert-cyclobutanols involving β-carbon elimination from an intermediate arylpalladium(II)-alcoholate to afford arylated ketones [eqn. (1)].⁴ This ring cleavage reaction has a potential to produce chiral ketones if the enantioselective carbon–carbon bond cleavage via palladium(II)-alcoholate of 3-substituted-cyclobutanols A (bond a or b) would occur as shown in Scheme 1.

Scheme 1

In our preliminary communication of this novel reaction, the produced ketones were racemic in spite of the use of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) as a chiral phosphine ligand. In the search for a successful asymmetric arylation involving an enantioselective C–C bond cleavage using several chiral phosphine ligands, we found that some monophosphine ligands work effectively to give the chiral ketones in high yields with moderate to good enantiomeric excess. We wish to report here the effective asymmetric arylation of 3-substituted tert-cyclobutanols.

First, the arylation of tert-cyclobutanol 1a was carried out using some commercially available chiral bisphosphine ligands, such as (R)-Tol-BINAP, (R)-(S)-BPPFA, (+)-Me-DUPHOS and (+)-DIOP, in place of BINAP. Only slight stereoselectivity was observed (∼2% ee), but the product yields were quite low [eqn. (2)]. Interestingly, monophosphine ligands such

as (R)-MeO-MOP and (S)-H-MOP⁵ were found to give the product ketone 1b in good yields with up to ca. 30% ee (the results are not shown). However, the improvement of the optical yields could not be attained using such ligands during the optimisation of the reaction conditions. Next, we examined a commercially available ligand (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine [(R)-(S)-PPFA, I] and we found that it showed a better selectivity. Treatment of 1a (cis/trans = 98/2) with 1.2 equiv. of PhOTf (phenyl trifluoromethanesulfonate) in the presence of 5 mol% Pd(OAc)₂, 20 mol% ligand I and 1.2 equiv. of Cs₂CO₃ as a base in THF at 90 °C afforded 1b in 42% yield with 59% ee (Table 1, entry 1). In this reaction, the ratio of the isomeric alcohols greatly affected the ee value of the product ketone. For example, when the arylation of 1a (cis/trans = 80/20) with PhOTf was carried out under the same conditions as entry 1 in Table 1, the ee value of 1b decreased to 36%. Then, we attempted to optimise the reaction conditions by changing the solvent, the reaction temperature, the base and the arylating agent using 1a (cis/trans = 98/2). When the reaction was carried out in toluene, an improvement in product yield was observed, although the optical yield slightly decreased (entry 3). Bromobenzene as arylating agent gave 1b in both higher selectivity and yield (entries 4–6). The use of K₂CO₃ instead of Cs₂CO₃, on the other hand, seriously diminished the product yield (entry 7). Next, other chiral ligands II and III were synthesised⁶ and applied to this arylation. The use of III resulted in higher selectivity than the use of I or II, and thus, 1b was obtained in 93% yield with 74% ee (entry 9).

Table 1 Palladium-catalysed asymmetric arylation of 1,3-diphenyl-1-cyclobutanol 1a^a

Entry	Ligand	PhX	Solvent (mL)	Temp. (°C)	Time (h)	GLC yield (%)^b	ee (%)
a Reaction conditions: 1a (0.10 mmol), Pd(OAc)2 (0.005 mmol), ligand (0.02 mmol), PhX (0.12 mmol), Cs2CO3 (0.12 mmol), under N2. 1a was completely consumed in entries 8 and 9. b Based on 1a employed. c Isolated yield. d K2CO3 was used as a base.
1	I	PhOTf	THF (1.0)	90	24	42	59
2	I	PhOTf	1,4-dioxane (1.0)	90	24	12	52
3	I	PhOTf	toluene (1.0)	90	24	70	48
4	I	PhOTf	toluene (0.5)	70	72	24	57
5	I	PhBr	toluene (0.5)	70	72	71^c	59
6	I	PhBr	toluene (0.5)	80	48	70^c	58
7^d	I	PhBr	toluene (0.5)	80	48	11	57
8	II	PhBr	toluene (0.5)	80	48	98^c	49
9	III	PhBr	toluene (0.5)	80	48	93^c	74

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The results of the asymmetric arylation of several monocyclic tert-cyclobutanols leading to chiral γ-arylated ketones under the optimised conditions described above are listed in Table 2.† Using bromobenzene as arylating agent under the conditions composed of Pd(OAc)₂, ligand III,‡ and Cs₂CO₃ in toluene, the substrate alcohols were completely consumed within 24 h, and 3-substituted cyclobutanols 1a, 2a, and 3a gave the corresponding γ-arylated ketones 1b, 2b, and 3b in high yields with moderate to good enantioselectivity, respectively (entries 1, 5 and 6). The lower reaction temperature (60 °C) did not affect the ee value (entry 2). The arylation of 1a with p-bromochlorobenzene or p-bromotoluene also occurred smoothly to give 1c and 1d in high yields with good ee value (entries 3 and 4). Similarly, the reaction of 3a with 2-bromonaphthalene afforded 3c in high yield (entry 7). It should be noted that this arylation could also be applied to the 1-alkyl-substituted cyclobutanol 4a, and the corresponding dialkylketone 4b was obtained in high yield with moderate enantioselectivity (entry 8). 3-Disubstituted cyclobutanols gave the corresponding ketones having quaternary carbon centres.⁷ Treatment of cyclobutanol 5a⁸ under the same conditions for 47 h afforded (−)-6⁹ with 61% ee, while the isomer 5b⁸ gave (+)-6⁹ with 43% ee when reacted for 37 h [eqns. (3) and (4)]. These results suggest

that the enantioselective C–C bond cleavage preferentially occurs at the C–C bond in the same direction in ligand III-ligated palladium(II)-alcoholates, irrespective of the substituents at the 3-position on the cyclobutane ring, although details are not yet known.

Table 2 Palladium-catalysed asymmetric arylation of tert-cyclobutanols^a

Entry	Substrate (cis/trans)	Ar	Product and isolated yield (%)		ee (%)^b
a Reaction conditions: alcohol (0.2 mmol), Pd(OAc)2 (0.01 mmol), (R)-(S)-III (0.04 mmol), aryl bromide (0.24 mmol), Cs2CO3 (0.24 mmol), toluene (1 mL), 80 °C, 24 h under N2. b Determined by HPLC. c 60 °C, 48 h. d 42 h.
1		Ph		99	77
2^c	1a (98/2)	Ph	1b	83	78
3		p-ClC6H4	1c	90	73
4		p-MeC6H4	1d	91	75
5	2a (96/4)	Ph	2b	99	64
6	3a (97/3)	Ph	3b	99	53
7		2-naphthyl	3c	92	60
8^d	4a (99/1)	Ph	4b	86	60

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In summary, we have described the novel asymmetric arylation of tert-cyclobutanols involving C–C bond cleavage, in which the possibility of enantioselective C–C bond cleavage was demonstrated using some chiral ligands. Our study for finding a more efficient stereocontrolled catalytic system for this reaction is now in progress.

Notes and references

1. I. Ojima, Catalytic Asymmetric Synthesis, 2nd ed., Wiley-VCH, New York, 2000.
2. M. Murakami and Y. Ito, in Activation of Unreactive Bonds and Organic Synthesis, ed. S. Murai, Springer, New York, 1999, pp. 97–129.
3. Rhodium-catalysed asymmetric hydrogenolysis of the α-carbon–carbon bond of cyclobutanone involving an enantioselective C–C bond cleavage was presented by M. Murakami, H. Amii, and Y. Ito, at the 69th Annual Meeting of the Chemical Society of Japan, March 1995, Kyoto, Abstract II p.1127.
4. T. Nishimura and S. Uemura, J. Am. Chem. Soc., 1999, 121, 11010.
5. (a) Y. Uozumi and T. Hayashi, J. Am. Chem. Soc., 1991, 113, 9887; (b) Y. Uozumi, N. Suzuki, A. Ogiwara and T. Hayashi, Tetrahedron, 1994, 50, 4293.
6. T. Hayashi, T. Mise, M. Fukushima, M. Kagotani, N. Nagashima, Y. Hamada, A. Matsumoto, S. Kawakami, M. Konishi, K. Yamamoto and M. Kumada, Bull. Chem. Soc. Jpn., 1980, 53, 1138.
7. E. J. Corey and A. Guzman-Perez, Angew. Chem., Int. Ed., 1998, 37, 388.
8. Alcohols 5a and 5b were separated by high performance preparative liquid chromatography. However, the exact stereochemistry (cis or trans) is not yet clear. The stereochemistry presented here was presumed from the ¹H-NMR of an analogous alcohol.
9. Specific rotation of 6; (−)-6: [α]²⁵_D = −10.2 (c = 0.5, in CHCl₃); (+)-6; [α]²⁵_D = +4.2 (c = 0.5, in CHCl₃).

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Footnotes

† Experimental: A mixture of Pd(OAc)₂ (0.01 mmol), (R)-(S)-III (0.04 mmol), Cs₂CO₃ (0.24 mmol) and toluene (0.5 mL) in a 10 mL two-necked flask was stirred at rt under N₂. After 0.5 h, aryl bromide (0.24 mmol) and alcohol (0.20 mmol) in toluene (0.5 mL) were added and the mixture was stirred at 80 °C until the reaction had reached completion by monitoring with TLC analysis. The reaction mixture was cooled to rt and then filtered through a pad of Florisil. The filtrate was concentrated under vacuum to give an oil, which was subjected to column chromatography on SiO₂ with EtOAc–hexane (2 ∶ 98) as eluent. The enantiomeric excess was determined by HPLC using Daicel Chiralcel^® AD and OD columns (4.6 × 250 mm, 3% propan-2-ol–hexane) at 25 °C.

‡ Analytical data for ligand III: Ligand III is a new compound synthesised from (R)-(S)-PPFOAc and N-methylcyclohexylamine according to the reported procedure, ref 6. Yellow solid; mp 159.2–160.0 °C; [α]²⁵_D = −286.9 (c = 0.5, CHCl₃); IR (KBr) 2956, 2939, 2774, 1446, 1433, 818, 749, 739, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.49–1.58 (m, 10H), 1.29 (d, J = 6.3 Hz, 3H), 1.65 (s, 3H), 2.15–2.30 (m, 1H), 3.70 (s, 1H), 3.73–4.26 (m, 4H), 3.94 (s, 5H), 7.01–7.70 (m, 10H). ³¹P NMR (161.9 MHz, CDCl₃) δ 31.3. Anal. Calcd. for C₃₁H₃₆FeNP: C, 73.09; H, 7.12; N, 2.75; Found: C, 73.02; H, 7.07; N, 2.82%.

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