Arylchlorogermanes/TBAF/“Moist” Toluene. A Promising Combination for Pd-Catalyzed Germyl-Stille Cross-Coupling

Abstract

The trichlorophenyl,- dichlorodiphenyl,- and chlorotriphenylgermanes undergo Pd-catalyzed cross-couplings with aryl bromides and iodides in the presence of TBAF in toluene with addition of the measured amount of water. One chloride ligand on the Ge center allows efficient activation by fluoride to promote transfer of one, two or three phenyl groups from the organogermane precursors.

The Pd-catalyzed cross-coupling of organogermanes has thus far received much less attention¹ than the couplings involving organostannanes and organosilanes.² This is due to the lower reactivity of tetracoordinated organogermanium species, the less developed syntheses of vinyl/aryl germanyl derivatives, and the higher cost of germanium relative to silicon.³ The carbagermatranes 1, with internal coordination of nitrogen to germanium, were the first examples of reactive tetracoordinated germanes applied to Pd-catalyzed cross-coupling reactions with aryl bromides⁴ (Figure 1). The oxagermatranes 2 were found to be more efficient than carbagermatranes and triethoxygermanes.^5,6 Fluoride-promoted couplings with aryltri(2-furyl)germanes⁷ and NaOH-activated couplings with arylgermanium trichlorides⁸ or their hydrolyzed and stable sesquioxide alternatives⁹ were also reported. The bis(2-naphthylmethyl)arylgermanes 3 were developed as photochemically activated arylgermanes for the synthesis of biaryls.^10,11 The vinyl tris(trimethylsilyl)germanes 4 were employed as transmetalation reagents in “ligand- and fluoride-free” coupling reactions with halides under oxidative conditions (H₂O₂).^12,13 The (α-fluoro)vinyl germanes 5 gave access to fluoroalkenes¹⁴ although application of (α-fluoro)vinyl stannanes and silanes to couplings has had limited success.^15,16 Recently, couplings of vinyltributylgermanes with aryl halides were found to occur more efficiently under Heck than Stille conditions to give preferentially Z-alkenes.¹⁷

Figure 1.

Organogermanes utilized in Pd-catalyzed couplings.

In general, couplings with organogermanes appear to be promoted by: (i) activation of germanium by internal coordination/chelation,^4,5,17 (ii) formation of the hypervalent species with germanium-oxygen bonds;^7-9,13 and (iii) the presence of two labile heteroatom ligands (e.g. Cl or F) on Ge atom.^10,11 Herein, we report that chlorophenylgermanes with at least one labile chloride ligand are activated by fluoride in “moist” toluene to allow efficient transfer of up to three phenyl groups from germane precursors during Pd-catalyzed coupling reactions with aryl halides.

Treatment of PhGeMe2Cl 6 with 1-iodonaphthalene in the presence of tetrabutylammonium fluoride (TBAF) and tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] in toluene gave cross-coupling product 7a in addition to the binaphthyl homocoupling byproduct 8a (Table 1). The amount of TBAF was found to be crucial for the successful coupling (entries 1-5). At least 4 equiv of TBAF were required to produce 7a in maximum yield. Other Pd catalysts afforded 7a in lower yields and a decreased ratio of 7a to 8a (entries 6-7). Replacing 1M TBAF/THF solution with neat TBAF•3H₂O also gave product 7a (entry 8). Coupling in the presence of Me4NF, CsF or NH₄F instead of TBAF failed to produce 7a. The reaction also proceeded successfully at 80 oC (80%; 10:1) and 110 °C (93%; 10:1) as well as at reflux in benzene (90%; 10:1), requiring 12 h for the best results (entry 4).

Table 1.

Effect of various reaction parameters on the efficiency of cross-coupling of chlorodimethylgermane 6 with 1-iodonaphthalene^a

entry	Pd	TBAFb	7a [yield(%)]c	ratio (7a:8a)
1	Pd2(dba)3	1.0	19	1:1
2	Pd2(dba)3	2.0	61	9:1
3	Pd2(dba)3	3.0	79	17:1
4	Pd2(dba)3	4.0	93d,e	20:1
5	Pd2(dba)3	5.0	94	12:1
6	Pd(OAc)2	4.0	58	5:2
7	Pd(PPh3)4	4.0	5	2:1
8	Pd2(dba)3	4.0f	70	6:1

^aCouplings were performed on 0.14 mmol scale of 6 (0.04 M) with 1.1 equiv of iodonaphthalene and 0.09 equiv of Pd catalyst.

^bCommercial 1M THF solution containing 5% of water, unless otherwise noted.

^cDetermined by GC-MS of the crude reaction mixture.

^dIsolated yield.

^eAfter 4 h, 49% (8:1); 8 h, 78% (15:1).

^fWith TBAF•3H₂O.

Toluene was the obvious solvent choice since attempts in DMSO (5%, 110 °C) or THF at reflux (0%) or dioxane at reflux (59%; 3:1) failed or afforded 7a in lower yields. Higher yield for the coupling in dioxane than in THF may be attributable to the increased temperature of the reaction as well the difference in dielectric constant [7.58 for THF as compared to dioxane (2.21) and toluene (2.15)].¹⁸ Bases such as NaOH [Pd(OAc)₂; dioxane/H₂O, 2:1] or KOSiMe₃ [Pd₂(dba)₃, toluene)], instead of TBAF, failed or were less efficient in promoting couplings.

We next examined couplings of Ph₂GeCl₂ 9 or Ph₃GeCl 10 with iodonaphthalene. Treatment of 9 with 1.1 equiv of iodide and 7 equiv of TBAF gave 7a (Table 2, entry 1). Coupling of 9 with 2.2 equiv of iodonaphthalene also resulted in total consumption of iodide to afford 7a and 8a (entry 2). Interestingly, couplings in toluene with addition of the measured amount of water (1 M TBAF/THF//H₂O; ∼1:5 M/M) gave a higher yield of 7a with a superior ratio of 7a:8a (entries 3 vs 1 and 4 vs 2). An investigation of the coupling reactions with different amounts of water, revealed that addition of 100 μL of H₂O (∼40 equiv) gave optimal yields (entry 10). Two phenyl groups were efficiently transferred in the presence of excess iodide (e.g., 89%, entry 4; yield is based upon two phenyl groups transferring from the chlorogermane reagent 9). It is worth noting that halides are often used in couplings as limiting reagents to reduce formation of homocoupling byproducts and the yields are based on the halide components unlike herein.

Table 2.

Cross-coupling of chlorophenylgermanes 9 and 10 with 1-iodonaphthalene promoted by TBAF and TBAF/H₂O

entry	germane	RX (equiv)	methoda	7a [yield(%)]b	ratio (7a:8a)
1	9	1.1	A	32c (30)	2.7:1
2	9	2.2	A	58 (55)	2.2:1
3	9	1.1	B	45 (42)	23:1
4	9	2.2	B	91 (89)	10:1
5	10	1.1	A	13d (12)	1:1.4
6	10	2.2	A	37 (35)	2:1
7	10	3.3	A	40 (39)	1.2:1
8	10	1.1	B	18 (17)	2.5:1
9	10	2.2	B	60 (60)	9:1
10	10	3.3	B	95e (88)	13:1

^aMethod A: Couplings were performed on 0.14 mmol scale of germane (0.04 M) with Pd₂(dba)₃ (0.09 equiv) and 7 equiv of TBAF (1M/THF). Method B: as in Method A with addition of H₂O (100 μL).

^bBased upon transferring two phenyl groups from 9 or three phenyl groups from 10. Determined by GC-MS of the crude reaction mixture (isolated yields in parenthesis).

^c26% and 31% with 6 and 8 equiv. of TBAF.

^d11% and 14% with 6 and 8 equiv of TBAF.

^e57% (3.8:1) with 50 μL H₂O; 82% (7:1) with 150 μL H₂O.

Couplings of 10 with 1.1, 2.2 or 3.3 equiv of iodonaphthalene proceeded with efficient transfer of up to three phenyl groups to give 7a (entries 5-10). [See supporting information for the GC/MS of the crude reaction mixture between 9 or 10 with iodonaphthalene (entries 4 and 10).] Again, yields and 7a:8a ratios increased when wet toluene was used. Atom-efficient Stille cross-couplings of Ar₄Sn with aryl halides, where all four substituents on tin participate in the carbon-carbon bond formation, are known.^19,20 Also, vinylpolysiloxanes were showed to transfer each of their vinyl groups during Pd-catalyzed couplings with aryl and alkenyl iodides in the presence of TBAF.²¹ However, attempts to induce multiple transfer of the phenyl group during fluoride-promoted couplings of (allyl)_XPh_4-XSi (x = 1 or 2) with aryl halides failed.²²

Couplings of 9 or 10 with other aryl, alkenyl, and heterocyclic iodides and bromides (using 2.2 or 3.3 equiv of halides, respectively) promoted by TBAF/H₂O are presented in Table 3 (entries 1-14). Reactions of germanes 9 or 10 with reactive 4-iodoacetophenone produced 7d in low yields in addition to large quantities of the reductive homocoupling byproduct 8d. However, coupling of the less reactive 4-bromoacetophenone at higher temperature (115 °C) resulted in better yields and improved 7d:8d ratios (entries 5 vs 4 and 12 vs 11). Treatment of PhGeCl₃ 11 with halides and TBAF/toluene or wet toluene also afforded coupling products 7 (entry 15-22), although it has been reported that fluoride ion did not promote the couplings of PhGeCl₃ with aryl halides.⁸ It appears that reactivity of the chlorogermanes increases with the number of halogen ligands on the Ge center (10 < 9 < 11). As expected,⁷ coupling attempts with Ph₄Ge failed reinforcing the needs for at least one labile heteroatom ligand at the Ge center. The necessity of two halogen ligands had been proposed for nucleophilic activation by F^- or OH^- ions.¹¹

Table 3.

Cross-coupling of chlorogermanes 9-11 with halides^a

entry	germane	halide	product	yield (%)b	ratio(7:8)
1	9	1-Bromonaphthalenec	7a	54 (48)	7.2:1
2	9	(4)CH3OPhI	7b	86d (85)	9.8:1
3	9	(3)CF3PhI	7c	70 (68)	3.4:1
4	9	(4)CH3COPhI	7d	12 (10)	3:2
5	9	(4)CH3COPhBr	7d	26d (21)	99:1
6	9	PhCH=CHBr	7e	8e,g (5)	1:3
7	9	2-Iodo-5-Me-thiophene	7f	13e (6)	2:3
8	10	1-Bromonaphthalene	7a	24	1.4:1
9	10	(4)CH3OPhI	7b	48f (40)	4:1
10	10	(3)CF3PhI	7c	48	3:2
11	10	(4)CH3COPhI	7d	3	1:20
12	10	(4)CH3COPhBr	7d	24d	1:1
13	10	PhCH=CHBr	7e	3g	1:8
14	10	2-Iodo-5-Me-thiophene	7f	3g	2:3
15	11	1-Iodonaphthalene	7a	99h (96)	35:1
16	11	1-Bromonaphthalene	7a	90g (82)	99:1
17	11	(4)CH3OPhI	7b	88g (80)	10:1
18	11	(3)CF3PhI	7c	93 (87)	9:1
19	11	(4)CH3COPhI	7d	99 (88)	99:1
20	11	(4)CH3COPhBr	7d	91	99:1
21	11	PhCH=CHBr	7e	30e,g (28)	3:1
22	11	2-Iodo-5-Me-thiophene	7f	48e,g (35)	3:2

^aCouplings were performed on 0.14 mmol scale of germanes (0.04 M) with 0.09 equiv of Pd catalyst, 1.1 (11), 2.2 (9) or 3.3 (10) equiv of halides and TBAF/(1 M/THF, 7 equiv)/water (100 μL).

^bBased upon transferring of one, two or three phenyl groups from 11, 9 or 10, respectively. Determined by GC-MS of the crude reaction mixture (isolated yields in parenthesis).

^cCoupling with 1-chloronaphthalene failed.

^d115 °C.

^eBiphenyl was also produced (∼25-50%).

^f28 h.

^gWithout H₂O.

^h88% (81%, 19:1) without H₂O.

TBAF most likely facilitates the coupling by generating the more reactive hypervalent fluorogermanium species. It is viable that the germanium species with extra halogen ligands formed after each transmetalation cycle is rendered more reactive to efficiently transfer a second or third phenyl group from the Ge atom. Reactivity of these hypervalent Ge species could be superior in toluene solvent due to the weak solvation. Water might play multiple roles in enhancing the efficiency of the couplings as was found with organosilanes, including the formation of the reactive hydroxypalladium intermediates.^1,23,24 For example, the hydration level of Cs₂CO₃ and CsOH were found to be a decisive factor during the coupling of the aryl(dimethyl)silanols with aryl halides.²⁵ Also, Denmark and Sweis showed that water was a critical additive in the fluoride promoted reaction of alkenylsilanols with phenyl nonaflate.^1,26 In addition, the fluorination of the bulky chlorogermanes may be accelerated by the addition of water as was reported for hindered chlorosilanes.²⁷

Mixing of 6 with TBAF in benzene-d₆ at ambient temperature showed the formation of a distinctive septet at δ -194.3 (³J_F-H ∼ 6.0 Hz) for PhGeMe₂F in agreement with the literature report for similar compounds.¹¹ Prolonged time and/or heating promoted equilibration with perfluorinated species [δ -150.8 (br s), -126.4 (br s)] analogous to the reported hypervalent tin^28-30 and silicon^31-33 species, which were successfully utilized in cross-coupling reactions.

We have demonstrated that arylchlorogermanes undergo Pd-catalyzed cross-couplings with aryl halides in the presence of TBAF in wet toluene. One chloride ligand on Ge center allows efficient activation by fluoride to promote transfer of up to three aryl groups from germane. The methodology shows that organogermanes can render a coupling efficiency comparable to the more established stannane and silane counterparts.