Organozinc-mediated direct cross-coupling under microwave irradiation

Abstract

We report a direct cross-coupling reaction between (het)aryl pivalates/tosylates and di(het)arylzinc species in 2-methyltetrahydrofuran/N-methyl pyrrolidone (1:1), which occurs via C–O bond cleavage under microwave irradiation. The reaction takes place smoothly in short reaction times without the addition of any catalyst or ligand. The reaction is suitable for a broad scope of substrates and exhibits good functional group compatibility, utilizes a simple work-up procedure, and gives the desired products in high purity.

Introduction

Biaryls have been widely applied in the syntheses of natural products, polyaromatic molecules, and pharmaceuticals.^1–3 Transition-metal (TM) catalyzed cross-coupling reactions are very powerful tools for constructing such structural units. However, various issues remain, including high costs and the poor stability of many TM catalysts and ligands, and the necessity of disposal of heavy-metal residues. Transition-metal-free (TM-free) cross-coupling methods have attracted significant attention in recent years.^4–12 Examples include the reactions of organohalides (R-Hal, including R-I, R-Br, and unreactive R-Cl) with aryl Grignard,^13,14 arylzinc,^15,16 organoaluminum ¹⁷ reagents, and among others.^5,18 Different from classical cross-coupling reactions, most TM-free couplings occur as single-electron transfer (SET) processes, and can be regarded as one-electron-catalyzed cross-coupling reactions. ¹⁹ The key process in the SET catalytic cycle is the formation of the radical anion R-Hal^•−, which undergoes further propagation (with R-M) and electron exchange (with another R-Hal) to form the product and to regenerate itself. ²⁰ The SET mechanisms have been clarified by means of both experimental ²¹ and theoretical ²² methods.

Phenol derivatives have some advantages: (1) phenol derivatives are easily available and are less expensive than the corresponding halides; (2) the use of halides, which pollute the environment is avoided; and (3) phenol derivatives can exhibit orthogonal reactivity to organohalides. ²³ There are many known methods for cross-coupling phenols derivatives. ²⁴ However, no examples utilize simple phenol derivatives (e.g. pivalate esters, sulfonates, carbamates, and sulfamates) for cross-coupling by SET processes. Organozinc reagents have emerged as attractive candidates due to their easy preparation and high functional group tolerance in cross-coupling reactions for the construction of biaryl and aryl–vinyl structural scaffolds.^25,26 To the best of our knowledge, phenol derivatives have never been used in couplings with organozinc reagents by SET-catalyzed cross-coupling. Herein, we report the first cross-coupling reactions of phenol derivatives with arylzinc reagents to construct C–C bonds under SET-catalyzed cross-coupling reaction conditions.

Results and discussion

We started our investigation by utilizing phenyl pivalate ester 1a as a model substrate. The desired biaryl 3a was not obtained using 1 equiv. of the 4-methoxyphenylzinc reagent prepared from the corresponding arylmagnesium bromide and zinc bromide (Table 1, entry 1). The method utilized to prepare the arylzinc reagent is crucial for smooth conversion.

Table 1.

Optimization of the reaction conditions. ^a

Entry	Organic zinc reagent	Solvent	Time (h)	Temperature (°C)	Mode of heating b	Yield c
1	1ArMgBr + 1ZnCl2	THF	8	80	∆	–
2	1ArMgBr + 1ZnBr2	THF	8	80	∆	<5%
3	2ArMgBr + 1ZnBr2	THF	8	80	∆	10%
4	1ArMgBr + 1ZnBr2 + 1LiCl	THF	8	80	∆	18%
5	2ArMgBr + 1ZnBr2 + 1LiCl	THF	8	80	∆	39%
6	2ArMgBr + 1ZnBr2 + 1LiBr	THF	8	80	∆	<5%
7	2ArMgBr + 1ZnBr2 + 1MgBr2	THF	8	80	∆	–
8	2ArMgBr + 1ZnBr2 + 2LiCl	THF	8	80	∆	46%
9	2ArMgBr + 1ZnBr2 + 3LiCl	THF	8	80	∆	47%
10	2ArMgBr + 1ZnBr2 + 2LiCl	THF	8	80	MW	68%
11 d	2ArZnI LiCl	THF	8	80	MW	23%
12 d	2ArZnI LiCl + 2MgBr2	THF	8	80	MW	24%
13	2ArMgBr + 1ZnBr2 + 2LiCl	DMA	8	80	MW	–
14	2ArMgBr + 1ZnBr2 + 2LiCl	NMP	8	80	MW	35%
15	2ArMgBr + 1ZnBr2 + 2LiCl	iPr2O	8	80	MW	–
16	2ArMgBr + 1ZnBr2 + 2LiCl	1,4-dioxane	8	80	MW	–
17	2ArMgBr + 1ZnBr2 + 2LiCl	DMF	8	80	MW	5%
18	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF	8	80	MW	75%
19	2ArMgBr + 1ZnBr2 + 2LiCl	Diglyme	8	80	MW	32%
20	2ArMgBr + 1ZnBr2 + 2LiCl	Toluene	8	80	MW	37%
21	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/toluene (1:1)	8	80	MW	56%
22	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/NMP (1:1)	8	80	MW	87%
23	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/diglyme (1:1)	8	80	MW	61%
24	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/NMP (1:1)	1	80	MW	92%
25	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/NMP (1:1)	0.5	80	MW	93% (91%)
26	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/NMP (1:1)	10 min	80	MW	88%
27	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/NMP (1:1)	0.5	50	MW	45%
28	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/NMP (1:1)	0.5	100	MW	92%
29	2ArMgBr + 1ZnBr2 + 2LiCl	2-Me-THF/NMP (1:1)	0.5	80	∆	25%

MW: microwave.

a

Conditions: 1a (0.2 mmol) was treated with 2a (0.3 mmol, 1.5 equiv.) in solvent (3 mL) by heating under argon.

b

∆ conventional heating.

c

GC yield using tridecane as an internal standard; isolated yield is given in parentheses.

d

See Chen et al. ¹³

No matter if 1 or 2 equiv. of the arylmagnesium bromide is mixed with 1 equiv. of zinc bromide (Table 1, entries 2 and 3), the response was very poor. The reaction yield was improved slightly by adding 1 equiv. of lithium chloride (Table 1, entries 4 and 5); however, the reaction proceeded sparingly or not at all when lithium bromide or magnesium bromide were added (Table 1, entries 6 and 7). The yield reached 46% using 2 equiv. of lithium chloride (Table 1, entry 8), but the yield did not increase significantly when 3 equiv. of lithium chloride were added (Table 1, entry 9).

Under the same conditions as those in entry 9, microwave (MW) heating led to a yield of 68% (Table 1, entry 10). Actually, the arylzinc iodide/lithium chloride complex reported by Knochel ²⁷ gave lower yields of the product, even in the presence of an external magnesium salt (Table 1, entries 11 and 12). The use of N,N-dimethylacetamide (DMA), ⁱPr₂O, and 1,4-dioxane as solvents were demonstrated to be of no effect (Table 1, entries 13, 15, and 16). When N,N-dimethylformamide (DMF) was used, a yield of 5% was obtained (Table 1, entry 17). The use of 1-methylpyrrolidin-2-one (NMP), 2-Me-Tetrahydrofuran (THF), diglyme, and toluene led to the desired product, and 2-Me-THF gave the highest yield (Table 1, entries 14 and 18–20). Mixtures (1:1) of 2-Me-THF/toluene, 2-Me-THF/NMP, or 2-Me-THF/diglyme behaved better than a single solvent, with 2-Me-THF/NMP (1:1) leading to the highest yield (Table 1, entries 21–23). The reaction yield did not increase on extending the reaction time, with only 0.5 h being required to obtain the highest yield (Table 1, entries 24–26). When the reaction was run at 80 °C, a 93% yield was achieved. A reaction temperature higher than 80 °C did not further improve the yield, while a temperature lower than 80 °C led to a decrease in the yield (Table 1, entries 25, 27, and 28). However, conventional heating led, under the same conditions, to a yield of only 25% (Table 1, entry 29).

With promising results in hand, we next tested the analogous cross-coupling of several other electrophilic partners (Table 2). In addition to the aryl pivalate ester (Table 2, entry 1), the corresponding carbamate and sulfamate were deemed competent substrates (Table 2, entries 2 and 3). Furthermore, sulfonate derivatives of phenol also gave high yields of the coupled product (Table 2, entries 4–6), and aryl sulfonates (in particular, tosylates) were relatively unreactive compared to triflates; however, tosylates were more easily handled, stable and considerably less expensive than aryl triflates. Moreover, the use of a phenyl methyl ether did not lead to the desired product under our optimized conditions (Table 2, entry 7).

Table 2.

Survey of cross-coupling partners. ^a

Entry	X	Yield (%) b
1	OPiv	93
2	OSO2NMe2	75
3	OCONEt2	56
4	OTs	88
5	OMs	85
6	OTf	96
7	OMe	–

a

Conditions: 1a (0.2 mmol), 2a (0.3 mmol, 1.5 equiv.), in 2-Me-THF/NMP (1:1) (3 mL), MW irradiation, 80 °C, 0.5 h.

b

GC yield using tridecane as an internal standard.

Having identified optimized reaction conditions (Table 1, entry 25), we next investigated the scope of the substrates (Table 3). Aryl pivalates/tosylates containing electron-donating groups were efficiently coupled to provide the corresponding biaryl products in good to excellent yields (Table 3, entries 3b, 3c, 3d, and 3e), with the ortho methyl-substituted aryl pivalates/tosylates giving lower yields compared to their meta- and para-substituted analogues. More sterically hindered 2,6-xylyl pivalate underwent the reaction with 2a to afford 3g in 49% yield (Table 3, entry 3g); however, 2,6-xylyl triflate gave a more satisfactory yield under the same conditions. Aryl pivalates/tosylates containing electron-withdrawing groups (Table 3, entries 3i, 3j, and 3k) and naphthyl pivalates/tosylates (Table 3, entry 3f) were efficiently coupled to provide the corresponding biaryl products in excellent isolated yields. It is worth mentioning that an aryl triflate containing chloride reacted with 2a occurred efficiently, with the potentially reactive C−Cl bond untouched (Table 3, entry 3k), p-Bromophenyl pivalate reacted with 2a to give product 3l in 35% yield (Table 3, entry 3l) along with 1,4-bis(4-methoxyphenyl)benzene (16%) as a by-product. Various sensitive functional groups, including unprotected phenol (Table 3, entry 3h), ester (Table 3, entries 3n and 3o), and amide (Table 3, entry 3m) groups were well tolerated. N-Methylindolyl and pyridyl pivalates/tosylates also gave good yields of the expected products (Table 3, entries 3p and 3q).

Table 3.

Cross-couplings of aryl pivalate esters and sulfonates with the 4-methoxyphenylzinc reagent.^a,b

a

Conditions: 1 (0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), 2-Me-THF/NMP (1:1) (3 mL), MW irradiation, 80 °C, 0.5 h.

b

Isolated yields.

We further inspected the reactivity of different zinc reagents (Table 4). Both electron-rich and electron-deficient (het)aryl zinc reagents (Table 4, entries 3r, 3s, 3t, 3u, 3v, 3w, 3ae, and 3ag) were smoothly participated in the cross-coupling. Compared with 3w, the reaction of 3v was not sensitive to the steric hindrance of (het)aryl zinc reagents. Heteroaryl zinc reagents were efficiently coupled with aryl pivalates/tosylates in excellent yields (Table 4, entries 3w, 3x, 3y, 3z, 3af, 3ah, 3aj, and 3ak). A variety of functional groups was also compatible under these reaction conditions, including nitrile, ketone, amide, and ester (Table 4, entries 3aa, 3ab, 3ac, 3ad, and 3ai). It is worth noting that an easily enolizable ketone (Table 4, entry 3ah) was well tolerated, and no notable byproducts resulting from the addition of Grignard reagents to these groups were found.

Table 4.

Cross-coupling of aryl pivalate esters and sulfonates with different zinc reagents.^a,b

a

Conditions: 1 (0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), 2-Me-THF/NMP (1:1) (3 mL), MW irradiation, 80 °C, 0.5 h.

b

Isolated yields.

The SET-catalyzed cross-coupling reactions are more sensitive to steric hindrance. However, the promising results obtained for para- and meta-substituted aryl pivalates/tosylates render this system a new and useful tool in SET-catalyzed cross-coupling reactions. For instance, under these conditions, the selective one-pot synthesis of disubstituted phenol sulfonates gave unsymmetrically substituted terphenyl compounds in satisfactory yields (Scheme 1).

Scheme 1.

One-pot synthesis of an unsymmetric terphenyl compound.

In Hayashi’s report, ²⁸ the occurrence of SET initiation in the coupling of aryl Grignard reagents with aryl halides was confirmed by the observation that the addition of lithium 4,4-di-tert-butylbiphenylide (LDBB) drastically accelerated the coupling. This result may be rationally understood by inferring that LDBB works as a much more efficient single-electron donor than Grignard reagents in the slow initiation step, and thus, the overall reaction rate is increased. We conducted similar experiments on the arylzinc coupling using LDBB as a single-electron donor. The reactivity of PhOPiv (1a) toward (4-MeOC₆H₄)₂Zn 2a was quite low at 50 °C over 30 min, when giving only a 45% yield of the coupling product 3a (Scheme 2). By contrast, treatment of 1a with LDBB (0.2 equiv.) ²⁹ gave 3a in 54% yield. The observed acceleration is compatible with SET initiation, and it is likely that [PhOPiv]•−, generated by SET, has a lifetime long enough to react with 1a before undergoing decomposition to Ph^•.^30,31

Scheme 2.

Effect of the addition of single-electron donors.

Considering the above result in conjunction with similarities in the intrinsic character between arylzinc and arylmagnesium reagents, the present coupling reaction likely follows a Grignard cross-coupling mechanism^2,4,32–34 as shown in Scheme 3, and exemplified by the reaction of PhOPiv 1a with (4-MeOC₆H₄)₂Zn 2a. The reaction is initiated by SET from (4-MeOC₆H₄)₂Zn to PhOPiv to give the anion radical [PhOPiv]•−, which reacts with (4-MeOC₆H₄)₂Zn. SET from the resulting anion radical, [4-MeOC₆H₄-Ph]•−, to PhOPiv gives the coupling product 4-MeOC₆H₄-Ph and regenerates [PhOPiv]•−, thereby beginning another propagation cycle.

Scheme 3.

A plausible mechanism.

Conclusion

The reactions of (het)aryl pivalates/tosylates with di(het)arylzincs gave biaryl compounds in short reaction times under microwave irradiation. The reaction is suitable for a broad scope of substrates and exhibits good functional group compatibility. This reaction is applicable to simple hydroxybenzenes that are widely distributed in nature. No catalyst or ligand is required, and a simple work-up procedure is employed. The reaction is believed to occur via a SET mechanism for activation of the aryl pivalates.

Experimental

General information

The reactions were carried out at 50–80 W in a CEM Discover (0–600 W, 2450M) focused microwave reactor equipped with a pressure controller under isothermal conditions. Standard 5 mL glass reaction vessels were used as supplied with the CEM reactor. The reaction mixtures were stirred magnetically. LiCl, ZnBr₂, ZnCl₂, and LiBr were purchased from Aldrich. MgBr₂ was purchased from Alfa Aesar. Other reagents are available commercially and were used without further purification, unless otherwise indicated. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. THF was dried over alumina under N₂ using a Grubbs-type solvent purification system. All arylzinc reagents were prepared from the corresponding arylmagnesium bromides, LiCl and ZnBr₂. All aromatic phenols were purchased from Alfa Aesar. Spectroscopic data for known compounds match with the data reported in the corresponding references. Reactions were monitored with Agilent GC Series 6890N and instruments GCMS 7890A. All compounds were characterized by ¹H NMR spectroscopy using a Bruker 400 M spectrometer (Bruker Avance III 400 MHz NMR). New compounds are characterized by HRMS (TripleTOF™ 5600+). ¹H NMR was recorded in CDCl₃ using tetramethylsilane (TMS) and deuterium oxide as the internal standard. Chemical shifts were reported in parts per million. The signal patterns are indicated as follows: s, singlet; d, doublet; t, triplet; dd, doublet of doublets; dt, doublet of triplets; and m, multiplet. Coupling constants, J, are reported in Hertz (Hz). The products were purified by column chromatography on Aladdin silica gel 300–400 mesh under an argon atmosphere.

Experimental procedures

General procedure for the reaction between (het)aryl pivalates 1 and diarylzinc reagents 2. In a glovebox, (het)aryl pivalate 1 (0.2 mmol) and NMP (1.5 mL) were added to the diarylzinc 2 (0.3 mmol, prepared by mixing zinc bromide, lithium chloride, and the corresponding aryl magnesium bromide in 1.5 mL of THF) in a reaction tube. The reaction mixture was then heated at 80 °C for 0.5 h under MW irradiation. After completion of the reaction, the mixture was concentrated under vacuum, and saturated NH₄Cl added. The mixture was extracted with CH₂Cl₂ several times. The combined organic layers were dried over anhydrous MgSO₄, concentrated in vacuo, and the residue was purified by column chromatography on silica gel to give the coupling product 3.

(2,6-Dimethylphenyl)-5-methoxypyridine (3w)

Product 3w was obtained following the general procedure. Purification via silica gel column chromatography (petroleum ether/EtOAc = 10:1, v/v) afforded the desired product. ¹H NMR (400 MHz, CDCl₃): δ 7.99 (dd, J = 2.4, 0.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.4 Hz, 1H), 7.21-7.12 (m, 3H), 6.84 (dd, J = 8.4, 0.7 Hz, 1H), 4.01 (s, 3H), 2.07 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 163.1, 146.6, 139.7, 137.9, 136.9, 129.4, 127.5, 110.7, 53.4, 21.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅NO: 214.1154; found: 214.1229.

4’-Benzoyl-[1,1’-biphenyl]-2-carbonitrile (3ai)

Product 3ai was obtained following the general procedure. Purification via silica gel column chromatography (petroleum ether/EtOAc = 10/1, v/v) afforded the desired product. ¹H NMR (400 MHz, CDCl₃): δ 7.93 (dt, J = 8.2, 1.7 Hz, 2H), 7.87~7.85 (m, 2H), 7.82~7.81 (m, 1H), 7.70~7.67 (m, 3H), 7.62~7.56 (m, 2H), 7.54~7.49 (m, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 196.2, 144.4, 142.1, 137.7, 137.4, 134.0, 133.1, 132.8, 130.6, 130.2, 128.9, 128.5, 128.4, 118.5, 111.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₃NO: 284.0997; found: 284.1075.

Supplemental Material

sj-doc-1-chl-10.1177_17475198211026479 – Supplemental material for Organozinc-mediated direct cross-coupling under microwave irradiation

Supplemental material, sj-doc-1-chl-10.1177_17475198211026479 for Organozinc-mediated direct cross-coupling under microwave irradiation by Chun-Jing Li in Journal of Chemical Research