Synthesis of Unsymmetrical ortho-Biphenols and ortho-Binaphthols via Silicon-Tethered Pd-Catalyzed C–H Arylation

Abstract

A mild, practical, and efficient method for the synthesis of unsymmetrical ortho-biphenols (including ortho-phenol-naphthols and ortho-binaphthols) has been developed. Unsymmetrical bis-aryloxy silanes, which were readily prepared in a semi-one-pot fashion, underwent the Pd-catalyzed intramolecular arylation followed by a routine TBAF desilylation step to furnish valuable unsymmetrical biphenols without necessity of isolation of 7-membered intermediates. The excellent functional group tolerance allows for synthesis of a variety of functionalized ortho-biphenols and ortho-binaphthols from easily available staring materials.

The ortho-biphenol framework is a key unit found in natural and synthetic bioactive molecules,¹ and in various ligand families.² Due to the favorable single-electron phenolic oxidation,³ the strategies towards assembly of biphenols largely concentrate on the oxidative phenol coupling reactions. Nonetheless, the synthesis of biphenols via these approaches is limited to symmetrical and electron-rich systems, often employing toxic heavy metal oxidants.⁴ The synthesis of unsymmetrical biphenols via oxidative cross-coupling of phenols suffers from significant amounts of self-coupling byproducts and undesired oligomers.^3c,5 There are a few reports on synthesis of unsymmetrical biphenols employing a silicon tether concept.⁶ Yet, these reactions are limited to the electron-rich substrates. Recently, we⁷ reported the Pd-catalyzed arylation of phenols⁸ via an easy-on and -off silicon-tethered strategy,⁹ which allowed assembling of unsymmetrical biphenol C via further oxidation of a 6-membered oxasilacylce B (eq 1). However, oxidation of the C-Si bond required harsh conditions, and is limited to the particular substitution pattern. Herein, we wish to report a mild, general, and efficient method for the synthesis of unsymmetrical biphenols 3 via intramolecular Pd-catalyzed C-H arylation^7,10 of 1 to form 2, followed by a routine desilylation step (eq 2).

(1)

(2)

We hypothesized that if intramolecular C-H arylation10f–k of easily available bis-aryloxy silane 1 would be efficient to form 7-membered¹¹ silacycles 2, it would provide an easy route to biphenols 3 via a simple deprotection. To test this hypothesis, we subjected 1a to the previously reported arylation conditions.⁷ However, under these conditions only reductive debromination occurred, with trace amounts of 2a produced. Fagnou showed the possibility of 7-membered ring formation employing bulky electron-deficient bidentate ligands combined with palladium acetate.^10i,j Still, employment of these conditions did not give any arylation product in silicon-tethered case, as only reductive product 4 was obtained. After extensive screening of reaction parameters, including palladium sources, ligands, bases and solvents,¹² we found that bulky electron-deficient monodentate ligand P(C₆F₅)₃ in nonpolar solvents is capable for suppressing the C-Br reduction process. Employment of bases K₃PO₄ and Ag₂CO₃ resulted in higher efficiency of arylation (Table 1, entries 2, 3). Application of additives did not cause improvement (entries 4, 5). Gratifyingly, the combination of K₃PO₄ and Ag₂CO₃ dramatically improved the yield and the arylation/reduction ratio, resulting in 73% isolated yield of 2a and high arylation/reduction ratio (entry 9). Next, these conditions were tested on substrates 1b–d (entries 10 – 12). In all cases, the yields were high with negligible amounts of debromination byproducts 4 obtained. Naturally, the standard TBAF deprotection protocol afforded 3a quantitively.¹² Semi-one-pot procedure from 1a to 3a demonstrated the same efficiency (Table 2, entry 1). For easier separation, all other biphenols were isolated as acetates without loss of the yields.

Table 1.

Optimization of Reaction Conditions.^a

no.	R	base (equiv)	additive (equiv)	yield, [%]b	2:4c
1	H (1a)	K2CO3d (2)	none	25	5:1
2	1a	K3PO4 (2)	none	31	14:1
3	1a	Ag2CO3 (2)	none	49	15:1
4	1a	K3PO4 (2)	PivOH (0.3)	42	15:1
5	1a	K3PO4 (2)	3-NO2-Py (0.3)	43	17:1
6	1a	K3PO4 (2) Ag2CO3 (0.5)	none	66	26:1
7	1a	K3PO4 (2) Ag2CO3 (1.5)	none	73	41:1
8	1a	K3PO4 (1) Ag2CO3 (1)	none	78	32:1
9	1a	K3PO4 (2) Ag2CO3 (1)	none	85 (73)	34:1
10	p-OMe (1b)	”	none	(70)	> 99:1
11	p-CF3 (1c)	”	none	(90)	> 99:1
12	o-Me (1d)	”	none	(80)	100:0

^aSee the Supporting Information for details.

^bGC yields of 2, isolated yields are in parentheses.

^cGC ratio.

^dp-Xylene was used as a solvent.

Table 2.

Synthesis of Unsymmetrical ortho-Biphenols, ortho-Phenol-naphthols and ortho-Binaphthols via Silicon-tethered C-H Arylation (3-step, semi-one-pot).^a,^b

no.	substrates (1)	products (3)	yield, [%]
1		a	72 (100)c
2		b	81
3		e	82
4		f	86
5		c	83
6		g	74
7		h	51
8		d	68
9		i	56d
10		j	72e (2.6:1)
11		k	80e (7:1)
12		l	79e (1:1.2)
13		m	67e,f (5:1)
14		n	66e,f(9:1)
15		o	72
16		p	61
17		q	89
18		r	86
19		s	96
20		t	83
21		u	89
22		v	80
23		w	90
24		x	77
25

^aIsolated yields.

^bTo simplify isolation, the biphenols were further converted to their corresponding acetates.

^cTwo-step semi-one-pot procedure gave unprotected 2,2′-biphenol in 72% yield; yield in the parenthesis is desilylation from 2a to 3a.

^d1H NMR yield (against CH₂Br₂ as an internal standard).

^eMajor regioisomer shown.

^f4 equiv of TBAF, 15 equiv of Ac₂O and 15 equiv of pyridine were used; 3m = 3n.

Next, the scope of this protocol toward synthesis of unsymmetrical biphenols, phenol-naphthols, and binaphthols was examined (Table 2). Gratifyingly, it was found that this method is general and efficient, regardless on the electronic properties of substituents on either phenol ring. Thus, a variety of functional groups, such as MeO, F, Cl, CF₃, CHO, NO₂, and even Br, can be perfectly tolerated under these reaction conditions producing the unsymmetrical biphenol acetates in 3-step semi-one-pot in high to excellent overall yields. As expected, meta-substituted phenols gave mixtures of regio-isomers. The regioselectivity was affected by both electronics and sterics. For example, although CF₃ and Me groups are comparable in size, the substrate 1k, possessing an electron-withdrawing group (R=CF₃), reacted more regioselectively compared to Me-substituted 1j. Expectedly, the steric effect on the regioselectivity of arylation has also been observed. Thus, differently O-protected resorcinol provided varied regioselectivity increasing with bulkier protecting groups (1l < 1m < 1n). 1-Naphthols and 2-naphthols could efficiently be employed in this arylation reaction, as well (entries 15–25). Thus, differently substituted 2-bromophenols underwent smooth arylation with 1-naphthol producing unsymmetrical phenol-naphthols in 61 – 96% yields. The unsymmetrical mixed 1- and 2-naphthol products (3v, 3w) were also obtained highly efficiently. It deserves mentioning that 3w represents the core structure of a series of small molecule inhibitors of Stat3 oncogene.^1c Arylation of 1y afforded a 1.7:1 mixture of unsymmetrical 2,2′-BINOL¹³ derivative (3y) and 1,2′-binaphthyl-2,3′-diol derivative (3y′) in excellent overall yield (entry 25).

In summary, a mild, practical, and efficient method for the synthesis of symmetrical and unsymmetrical ortho-biphenols, ortho-phenol-naphthols, and ortho-binaphthols has been developed. The method involves a Pd-catalyzed intramolecular C-H arylation of unsymmetrical bis-aryloxy silanes to give the 7-membered oxasilacycles, which via a consecutive routine TBAF deprotection furnishes valuable unsymmetrical ortho-biphenols and ortho-binaphthols. The method allows for easy synthesis of a wide variety of functionalized symmetrical and unsymmetrical ortho-biphenols and ortho-binaphthols from easily available staring materials.