Palladium-Catalyzed Reaction of Boronic Acids with Chiral and

Palladium-Catalyzed Reaction of Boronic Acids with Chiral and Racemic r-Bromo Sulfoxides Nuria Rodrı´guez, Ana Cuenca, Carmen Ramı´rez de Arellano, Mercedes Medio-Simo´n,* Denissa Peine, and Gregorio Asensio Departamento de Quı´mica Orga´ nica, Universidad de Valencia, Avda. Vicent Andres Estelles s/n, 46100 Burjassot, Spain [email protected] Received July 21, 2004

Palladium-catalyzed cross-coupling reactions of racemic R-bromo sulfoxides with boronic acids are carried out in either aqueous or nonaqueous medium with formation of a new C sp3-C sp2 bond. The arylation of chiral R-bromo sulfoxides occurs without racemization. The cross-coupling reaction is general and gives high yields with arylboronic acids substituted with either donor or acceptor groups but gives poor results with heteroarylboronic acids. The best yields are obtained using degassed solvents and CsF instead of aqueous base. The use of aqueous base and the presence of oxygen favor the homocoupling side reaction. Introduction Palladium-catalyzed Suzuki-Miyaura cross-coupling of organic electrophiles with organometallic compounds is a useful method for the formation of C-C bonds.1,2 Suzuki couplings offer the advantage of being largely unaffected by the presence of water, tolerate a wide range of functionalities, and yield nontoxic byproducts. This reaction has been widely applied to the formation of C sp2-C sp2 bonds through the reaction of an aryl halide or triflate (electrophile) with an arylboronic acid (nucleophile). This approach has become a general and convenient methodology in organic chemistry for the synthesis of biaryls and polyarylenes, and is used in many fields, including natural products, nucleoside analogues, and pharmaceuticals.3 Triarylphosphine/Pd complexes are commonly used as catalysts for this reaction, but because of the broad scope of this method, great advances have been made over the past few years in the development of active and efficient catalysts through the modification of the traditional ligands. Sterically demanding electronrich phosphines such as tri-tert-butylphosphine4 and its analogues di(tert-butyl)arylphosphine and dicyclohexylarylphosphine5 have been shown to exhibit high coupling activity for a variety of substrates. Trialkylphosphonium hydroboronofluorides have been proposed to overcome the air-sensitivity problem associated with phosphine-based catalysts.6 The use of phosphine oxides, phosphapalladacycles, water-soluble phosphines, chelating phosphine (1) Tsuji, J. Transition Metal Reagents and Catalysts; Wiley: Chichester, U.K., 2000. (2) Miyaura, N. Cross-Coupling Reactions; Springer-Verlag: Berlin, Heidelberg, 2002. (3) Sambasivarao, K.; Kakali, L.; Dhurke, K. Tetrahedron 2002, 58, 9633. (4) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (5) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. (6) Neverthon, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.

compounds, and non-phosphine ligands7 and the development of free ligand conditions8 have also contributed to broadening the scope of this reaction. The combination of aryl halides with an arylboronic acid to give a new C sp2-C sp2 bond has been thoroughly examined.9 In contrast, the reactions of aryl or alkyl halides with an alkylboronic acid, with the respective formation of a C sp2-C sp3 or C sp3-C sp3 bond, are rather uncommon.10 Two likely causes for this comparative lack of success are the slow oxidative addition of alkyl halide electrophiles to palladium and the facility for the β-hydride elimination. However, Fu11 recently described the formation of C sp3-C sp3 bonds through the crosscoupling of alkyl halides with alkylboronic acids. The problems associated with slow addition and the β-hydride elimination are overcome in this case through the use of bulky electron-rich phosphines. With these phosphine ligands oxidative addition occurs with alkyl halides at temperatures below 50 °C, which also minimizes the β-hydride elimination side reaction. The formation of C sp2-C sp3 bonds has been pursued using arylboronic acids as reactants and C sp3 centered electrophiles lacking β-hydrogen atoms, for example, R-halocarbonyl compounds.12-14 Nevertheless, the crosscoupling is still difficult due to the low rate of the oxidative addition of the C sp3-halide bond to the (7) Tao, B.; Boykin, D. W. Tetrahedron Lett. 2002, 43, 4955 and references therein. (8) Molander, G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867. (9) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (10) Cardenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018. (11) (a) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662. (b) Netherton, M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. (12) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405. (13) Goossen, L. J. Chem. Commun. 2001, 669. (14) (a) Duan, Y.-Z.; Deng, M.-Z. Tetrahedron Lett. 2003, 44, 3423. (b) Liu, X.-X.; Deng, M.-Z. Chem. Commun. 2002, 622. 10.1021/jo0487552 CCC: $27.50 © 2004 American Chemical Society

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Published on Web 10/20/2004

Suzuki-Type Arylation of R-Bromo Sulfoxides

palladium catalyst. Consequently, special conditions are still required to perform palladium-catalyzed reactions with C sp3 electrophiles. For example, the cross-coupling reaction of ethyl bromoacetate with phenylboronates requires a special base, Tl2CO3.12 On the other hand, the cross-coupling of bromoacetic acid derivatives with arylboronic acids takes place only with bulky ligands such as P(1-Nap)313 in the catalyst, and the reaction of bromoacetamides with arylboronic acids requires the presence of P(Cy)3 or additives such as Cu2O.14 Buchwald and Hartwig15 have described an alternative approach to the Suzuki-Miyaura reaction for the arylation of carbonyl compounds at the R-position. This procedure consists of the cross-coupling of an aryl halide (electrophile) and a palladium enolate (nucleophile) generated in situ with base. Following a similar approach, Belestkaya et al.16 recently described the R-arylation of sulfones, but the reaction only takes place when the R-position is activated by the presence of an additional electron-withdrawing substituent and cannot be extended to the arylation of simple sulfones. In contrast, we recently reported C sp3-C sp2 bond formation by the arylation of simple R-bromo sulfoxides with aryl boronic acids in a Suzukitype cross-coupling reaction.17 Remarkably, this reaction proceeds under standard Suzuki conditions, and the expected β-hydride elimination reaction only occurs to a very low extent during the arylation of the secondary bromo sulfoxide 1b.17 We report here our findings on the arylation of bromo sulfoxides 1 and the extension of our method to the synthesis of chiral aryl benzyl sulfoxides.18 Results and Discussion We have found that Pd(PPh3)4 catalyzes the crosscoupling reaction of R-bromo sulfoxides 119 with boronic acids 2 under mild conditions in the presence of aqueous Na2CO3 to give the corresponding R-monoarylated sulfoxides 3 in high to moderate yields (Scheme 1, Table 1, entries 1-17). The generality of the C sp2-C sp3 crosscoupling reaction was investigated using several arylboronic acids, 2a-j, and bromo sulfoxides 1, including the secondary bromo sulfoxide 1b. The reaction of 1a with electron-rich substituted boronic acids 2b and 2c using the same conditions as in the case of the parent acid 2a gave 3b and 3c, respectively, with similar chemoselectivity and conversion. In contrast, with the nitrosubstituted acid 2h, the homocoupling was the main reaction and gave rise to the formation of biaryl 4h and the cross-coupling product 3h in only 11% yield (see Table 1, entry 11). With thienylboronic acids 2f and 2g, the homocoupling reaction predominates, with only partial conversion of the starting bromo sulfoxide 1a under our standard conditions (Table 1, entries 10-12). (15) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 122, 1360. (b) Kawatsura, M.; Jorgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557 and references therein. (16) Kashin, A. N.; Mitin, A. V.; Belestkaya, I. P.; Wife, R. Tetrahedron Lett. 2002, 43, 2539. (17) Rodrı´guez, N.; Cuenca, A.; Ramı´rez de Arellano, C.; MedioSimo´n, M.; Asensio, G. Org. Lett. 2003, 5, 1705. (18) For use of chiral sulfoxides in asymmetric synthesis see: (a) Garcı´a-Ruano, J. L. Top. Curr. Chem. 1999, 204, 1. (b) Carren˜o, M. C. Chem. Rev. 1995, 95, 1717. (19) Cinquini, M.; Colonna, S. J. Chem. Soc., Perkin Trans. 1 1972, 1883.

SCHEME 1. Palladium-Catalyzed Reaction of r-Bromo Sulfoxides 1 with Arylboronic Acids 2

Optimization of the Reaction Conditions. Reactions in Degasified Solvents under Anhydrous Conditions. The poor results obtained in terms of crosscoupling products with some of the boronic acids used in this initial survey prompted us to modify the standard reaction conditions. First, we performed the reactions of 1 with 2 under a complete absence of oxygen using degassed solvents17 (Table 1, runs 18-23). The yield of 3 increased significantly under these conditions. For instance, with the o-methoxy boronic acid 2d, the yield increased from 56% to 81% (Table 1, runs 5 and 18), and p-nitro boronic acid 2h gave cross-coupled sulfoxide 3h in 70% yield (Table 1, runs 11 and 19). In some cases, if the reactants contain hydrolyzable groups, Suzuki reactions cannot be performed satisfactorily under the usual conditions. Thus, the use of CsF in an anhydrous solvent instead of a water-soluble base such as Na2CO3 is a useful alternative to promote the cross-coupling reaction and improves the scope of the methodology. With this precedent, we tested the crosscoupling of R-bromo sulfoxides 1 with arylboronic acids 2 in dry THF containing CsF. An atmosphere free of O2 was used in these runs, considering the improved results observed in our previous experiments when air was carefully excluded. Under these alternative conditions, the cross-coupling reaction took place as expected, and more interestingly, the yield of the cross-coupling product 3 increased in all the cases, while the formation of the undesired byproducts 4 and 5a was minimized (Table 1, entries 24-30). The effect of the amount of palladium catalyst used on the yield was also examined in the reaction between 1a and 2b. Similar results were obtained with 10% or 5% Pd(PPh3)4 (Table 1, entry 31), but a further reduction in the amount of the catalyst to 2% resulted in a lower yield of 3b (Table 1, entry 32). Arylation. Experiments with Other Phosphine Ligands. The arylation of 1 catalyzed by Pd(Ph3)4 required relatively long reaction times. Therefore, we examined other phosphine ligands to accelerate the J. Org. Chem, Vol. 69, No. 23, 2004 8071

Rodrı´guez et al. TABLE 1. Palladium-Catalyzed r-Arylation of r-Bromo Sulfoxides with Arylboronic Acids run

1

2

methoda

convnb (%)

yield of 3 (%)

yield of 5 (%)

ratio 3:4

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

a a a a a a a a a a a a b b b a a a a a a a a a a a a a a a a a a a a a a c c c

a b c d d e f f f g h h a e e i j d h f g i j a b c d e i j b b b d b b b a b i

A A A A B A Ac Ad B Ac,d A B A A B A A C C C Cc C C D D D D D D D De Df E E F G H D D D

100 100 89 74 89 100 26 62 13 22 38 22 85e 72 60f 82 72 90 100 76 25 100 92 100 90 77 88 100 100 72 89 61 100 73 91 11 79 100 100 100

a (80) b (87) c (76) d (53) d (56) e (60) f (7) f (25) f (0) g (0) h (11) h (0) i (43) j (43) j (0) k (74) l (65) d (81) h (70) f (39) g (0) k (75) l (90) a (96) b (85) c (75) d (65) e (96) k (94) l (66) b (84) b (55) b (78) d (55) b (85) b (11) b (70) m (98) n (94) o (97)

a (20) a (13) a (13) a (21) a (34) a (40) a (19) a (37) a (13) a (22) a (27) a (22) b (23) b (29) b (19) a (8) a (7) a (9) a (30) a (37) a (25) a (25) a (2) a (4) a (5) a (2) a (22) a (4) a (6) a (6) a (6) a (6) a (22) a (18) a (6) a (0) a (9) c (2) c (2) c (2)

2:1 2.5:1 1.7:1 1:1 1.1 2.3:1

1:3 2.6:1 3.0:1 2.5:1 3.8:1 2.8:1 2:1 3.2:1 5:1 2:1 2:1 6:1 1.3:1 2.5:1 6.5:1 6:1 3:1 3:1 3.5:1 1:1 2.5:1 2.5:1 2:1 1.5:1 6:1

a Method A: MeOH, Na CO 2 M, 10% Pd(PPh ) , 16 h. Method 2 3 3 4 B: DME, Na2CO3 2 M, 10% Pd(PPh3)4, 16 h. Method C: method A using degassed solvents. Method D: THF, CsF, 10% Pd(PPh3)4. Method E: THF, CsF, 10% Pd(OAc)2/20% P(C6H11)3. Method F: THF, CsF, 10% Pd(OAc)2/20% P(o-tolyl)3. Method G: THF, CsF, rt, 10% Pd(OAc)2/20% P(1-Np)3. Method H: THF, CsF, 10% Pd(OAc)2/10% BINAP. b Conversion of 1 determined by NMR. c 32 h. d 20% Pd(PPh3)4. e 5% Pd(PPh3)4. f 2% Pd(PPh3)4.

process. The oxidative addition step was thought to be the rate-limiting step due to the slow addition of palladium to C sp3-Br bonds. Thus, we tested the effectiveness of palladium complexes with bulky, electron-rich monodentate phosphine ligands such as P(o-tol)3, P(1Np)3, and P(Cy)3. Due to the high catalytic activity of these complexes in other C-C bond forming reactions, we considered that electron-richness might facilitate the oxidative addition and steric demands might favor ligand dissociation.4 However, in our case, no significant rate enhancement was observed when these phosphine ligands were used instead of triphenylphosphine (Table 1, entries 33-36). The activity of bidentate phosphine ligands such as BINAP was also tested (Table 1, entry 37). A longer reaction time was required with this ligand probably due to the lower stability of the oxidative addition complex when the phosphine ligands are forced to be coordinated 8072 J. Org. Chem., Vol. 69, No. 23, 2004

trans to the organic group.20 Thus, the rate-determining oxidative addition step is expected to be decelerated in this case. Bromination and Arylation of Chiral Sulfoxides. At this point we thought it would be interesting to investigate the synthesis of optically pure benzyl sulfoxides. Optically pure alkyl aryl sulfoxides are readily available using well-known procedures in which the key step is displacement of a chiral auxiliary from the sulfur atom by reaction with an alkyllithium or alkylmagnesium derivative.21 Optically pure benzyl p-tolyl sulfoxide was prepared by Evans et al.22 using the N-sulfinyloxazolidinone methodology, but the behavior of benzyl sulfoxides in displacement reactions can often be considered a special case since the benzyl group itself undergoes nucleophilic displacement reactions.23 This type of reactivity represents a serious drawback since it allows the racemization of chiral benzyl sulfoxides. On the other hand, the lability of the benzylic C-S bond in these compounds has been used in carbon-for-carbon substitution reactions on the sulfinyl group to obtain chiral dialkyl sulfoxides.24 Chiral alkyl aryl sulfoxides have also been synthesized by the asymmetric oxidation of sulfides.25 With this approach, the optimum ee is obtained for aryl methyl sulfides, while aryl benzyl sulfides are usually poor substrates for catalytic oxidations.26a The process was optimized by using titanium catalysts.26 The first step in extending our methodology to the preparation of chiral aryl benzyl sulfoxides was the synthesis of chiral R-bromo sulfoxides. Bromination of racemic sulfoxides can be performed efficiently, with moderate to good yields, using Br2 in pyridine as described in the literature procedure.19 However, when the substrate in this reaction is a chiral sulfoxide, partial racemization of the sulfinyl center occurs during bromination. It has been reported27 that bromination of (R)methyl p-tolyl sulfoxide with Br2 in pyridine gives the corresponding bromomethyl sulfoxide derivative with a retention of the configuration at the sulfur and an optical purity of 76% (Scheme 2). On the other hand, when the same reaction is carried out in the presence of AgNO3, the reaction is much more stereoselective and the bromo derivative is obtained with an optical purity of 98%, but inversion of the configuration at the sulfur occurs in this case. Unfortunately, in our hands the reaction of (R)methyl p-tolyl sulfoxide with Br2 in pyridine gave the corresponding bromomethyl sulfoxide with only 40% ee. In fact, the R-halogenation of neutral sulfoxides occurs by electrophilic attack of the sulfinyl group by halogen,28 (20) Vicente, J.; Arcas, A.; Bautista, D. Organometallics 1997, 16, 2127. (21) (a) Andersen, K. K. J. Org. Chem. 1964, 29, 1953. (b) Mioskoski, C.; Solladie´, G. Tetrahedron 1980, 36, 227. (c) Whitesell, J. K.; Wong, M. S. J. Org. Chem. 1991, 56, 4552. (d) Llera, J. M.; Ferna´ndez, I.; Alcudia, F. Tetrahedron Lett. 1991, 32, 7299. (22) Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. J. Am. Chem. Soc. 1992, 114, 5977. (23) Durst, T.; LeBelle, M. J.; Van Der Elzen, R.; Tin, K.-C. Can. J. Chem. 1974, 52, 761. (24) Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Rosito, V. J. Org. Chem. 2002, 67, 7289 and references therein. (25) For reviews, see Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651. (b) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961. (26) (a) Pinchen, P.; Dun˜ach, E.; Deshmukh, M. N.; Kagan, H. B. J. Am. Chem. Soc. 1984, 106, 8188. (b) Donnoli, M. I.; Superchi, S.; Rosini, C. J. Org. Chem. 1998, 63, 9392. (27) Cinquini, M.; Colonna, S.; Montanari, F. J. Chem. Soc., Perkin Trans. 1 1974, 1719.

Suzuki-Type Arylation of R-Bromo Sulfoxides SCHEME 2.

Bromination of Chiral Sulfoxides

and consequently, the reaction is expected to occur with partial racemization as observed. Therefore, we decided to examine a different bromination approach to preserve the configuration of the sulfur atom in the starting sulfoxide. Accordingly, we attempted the bromination of the sulfoxide anion, considering that R-sulfinyl carbanions are configurationally stable and therefore widely used in asymmetric synthesis to introduce a sulfinyl group as a chiral auxiliary.29 We found that the chiral sulfoxide anion 6a reacted with bromine to give the expected R-bromo sulfoxide 1c in moderate yield and with a complete retention of configuration. Different reaction conditions were explored to optimize the reaction. The main difficulty was avoiding the reaction of 1c with a second equivalent of bromine to give the corresponding dibrominated sulfoxide. This process is favored in basic medium by the greater acidity of the S(O)CH2Br group relative to that of the methyl sulfoxide precursor. The optimal reaction conditions found for the monobromination reaction are detailed in the Experimental Section. Floriani and co-workers reported racemization of the chiral sulfur center in chiral R-sulfinyl-palladium(II) complexes.30 Despite this precedent, when we explored the asymmetric version of our cross-coupling method between chiral R-bromo sulfoxide 1c and boronic acids 2a, 2b, and 2i under palladium catalysis, we found that it proceeds very satisfactorily and leads to the corresponding chiral aryl benzyl sulfoxides 3m, 3o, and 3n, respectively, in high yields (Table 1, entries 38-40). The absolute configuration at the sulfur atom is fully preserved throughout the process under our reaction conditions. Mechanism of the Palladium-Catalyzed Reaction between r-Bromo Sulfoxides and Arylboronic Acids. (1) Cross-Coupling Cycle. We were able to prove that the arylation (cross-coupling process) occurs through the usual catalytic cycle (oxidative addition, transmetalation, and reductive elimination) (cycle a, Scheme 3). The racemic R-sulfinyl-palladium(II) complex Ia (R1 ) H; Hal ) Br) (Figure 1) derived from the oxidative addition of 1a to Pd(PPh3)4 was stable enough to be isolated and characterized by X-ray single-crystal diffraction17 of the deuterated dichloromethane solvate. The structure of Ia shows a slightly distorted square planar palladium complex with the bromine atom trans to the sulfinyl ligand. This geometry is similar to that found for the analogous chlorine complex30 Ib (R1 ) H; Hal ) Cl). The stability of Ia allows for its isolation, and can be explained on the basis of its geometry and the transpho(28) Cinquini, M.; Colonna, S.; Fornasier, R.; Montanari, F. J. Chem. Soc., Perkin Trans. 1 1972, 1886. (29) Solladie´, G. Synthesis 1981, 185. (30) Veya, P.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Organometallics 1994, 13, 441.

FIGURE 1. Oxidative addition (I) and transmetalation (II)

palladium intermediates in the arylation of R-bromo sulfoxides 1 and thermal ellipsoid plot (50% probability level) of compound Ia (R1 ) H; Hal ) Br).

SCHEME 3. Cross-Coupling and Homocoupling Catalytic Cycle

bia theory.31 This theory accounts for the lack of stability of palladium(II) complexes when a C-donor ligand is placed trans to P-donor or C-donor ligands. In fact, it has been shown that palladium compounds with a pair of ligands with high transphobia in trans positions, one of which is generally a C-donor, undergo a further reaction such as coupling, insertion of atmospheric O2 into the C-Pd bond, or an intramolecular redox reaction.32 In contrast, if the trans ligands have low transphobia, the reaction product tends to be stable. This trend in the geometry and stability of palladium(II) complexes is supported by the number of structures recovered from the Cambridge Structural Database (CSD). Only 155 structures (20%) of the 747 square planar palladium(II) compounds containing both C-donor and P-donor ligands have a P atom trans to a C atom (see the Supporting Information). Among these 155 structures, we found no geometrical requirement for the P-donor to be trans to a C-donor in only three compounds, [Pd(N,N-Me2benzo[b]furan-2-carboselenoamid-3-yl)Cl(P(nBu)3],33 [Pd(SeC6H4(31) Vicente, J.; Abad, J. A.; Martı´nez-Viviente, E.; Jones, P. G. Organometallics 2002, 21, 4454. (32) Vicente, J.; Abad, J. A.; Herna´ndez-Mata, F. S. and Jones, P. G. J. Am. Chem. Soc. 2002, 124, 3848. (33) Nonoyama, M.; Nakajima, N.; Mizuno, H.; Hayashi, S. Inorg. Chim. Acta 1994, 215, 91.

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Me-4)2(CNC6H4Me-4)(PPh3)],34 and [Pd(1,3-di-tBu-imidazolin-2-ylidene)I2(PPh3)].35 The distances found for C-Pd bonds trans to a P-donor are in the upper range (C-Pd > 2.00 Å) observed for C-Pd distances in square planar compounds (1.84-2.21 Å). The C-Pd distance observed in compound Ia, 2.053(4) Å, is in the upper limit of the range found for a Pd-C bond trans to bromine (1.85-2.13). This is also observed for other monocoordinated CH2R ligands trans to bromine found in the CSD (see the Supporting Information). The R-sulfinyl group in compound Ia shows a configurational disorder. This type of disorder has been observed in the crystal structures of the R-sulfinyl complexes trans[Pd(CH2SOPh)Cl(PPh3)2]‚THF (Ib) and [Pd(CH2SOPh)(NCMe)(PPh3)2](CF3SO3)‚NCMe.30 To ascertain whether Ia was an intermediate in the arylation of 1a, the complex was allowed to react with 2a, and led, as expected, to the formation of the crosscoupling product 3a. The intermediacy of Ia in the formation of the cross-coupling products was clearly established in this way. (2) Formation of Side Products. Regarding the formation of the side products, the proposed catalytic cycle must explain three main observations in the palladium-catalyzed reaction between R-bromo sulfoxides and arylboronic acids: (i) the side products 4 and 5 are not produced in equal amounts, (ii) the selectivity of the cross-coupling toward homocoupling is increased in the absence of oxygen, and (iii) the use of fluoride ion instead of hydroxide ion to promote cross-coupling gives 3 in much better yield, especially with substituted arylboronic acid containing electron-withdrawing groups such as -CF3 or -NO2. Previously reported mechanisms suggest two alternative reaction paths for the formation of biaryls 4 and sulfoxide 5a resulting from the homocoupling of 3 and debromination of 1, respectively. The first (cycle b) is based on the mechanism proposed by Zhang36 to explain the formation of homocoupling products in the reaction of R-halocarbonyl compounds and boronic acids, and involves the participation of the bromo derivative. According to this mechanism, the R-bromo sulfoxide reacts with Pd(0) to give the R-sulfinyl-Pd(II) complex Ia, with which a double transmetalation followed by reductive elimination would account for the symmetrical biaryls 4 (homocoupling products). This mechanism accounts for compounds 4 and 5a, the latter of which is generated after the second transmetalation reaction, but has the drawback that both side products should be obtained in equimolecular amounts. An alternative path (cycle c) accounts for the homocoupling products 4 through direct Pd(0) catalysis. Different mechanisms have been proposed by Moreno-Man˜as37 and Yoshida38 to explain the formation of symmetrical biaryls from boronic acids. Cycle c accounts for the formation of biaryls 4, but does (34) Kuniyasu, H.; Maruyama, A.; Kurosawa, H. Organometallics 1998, 17, 908. (35) Herrmann, W. A.; Bohm, V. P. W.; Gstottmayr, C. W. K.; Grosche, M.; Reisinger, C.-P.; Weskamp, T. J. Organomet. Chem. 2001, 617, 616. (36) Lei, A.; Zhang, X. Tetrahedron Lett. 2002, 43, 2525. (37) Moreno-Man˜as, M.; Pe´rez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346. (38) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2003, 44, 1541.

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not explain the formation of 5a. The simultaneous operation of the mechanisms represented in cycles b and c would explain the formation of compounds 4 and 5a in different proportions. A third mechanism (cycle d) that has not been previously proposed to explain the homocoupling of boronic acids involves both Pd(II) and Pd(0) species and hence combines the two paths described above. This path supposes the formation of the oxidative addition R-sulfinyl-Pd(II) complex, which, instead of a double transmetalation, would undergo hydroxide ion-mediated disproportionation to afford Pd(0), which could catalyze the homocoupling of boronic acids. The disproportionation of Pd(II) species has been previously examined for (Ph3P)2PdCl2.39 By analogy with Alper’s mechanism, the disproportionation process could in our case yield, along with Pd(0) and triphenylphosphine oxide, the sulfoxide 5a. In fact, we did observe the formation of black palladium when the R-sulfinyl-palladium(II) complex Ia was refluxed with aqueous Na2CO3 in methanol for 16 h. In addition, 1H NMR and 31P NMR of the crude reaction mixture revealed the presence of sulfoxide 5a and Ph3Pd O, respectively. The disproportionation of complex Ia mediated by hydroxide ion is also supported by the fact that the formation of homocoupling products 4 and debrominated sulfoxide 5a diminishes sharply when the reactions are promoted with CsF instead of hydroxide ion in aqueous medium. The formation of 5a is not completely avoided probably because of the lack of absolute dryness due to moisture introduced with CsF and/or boronic acids. These trace amounts of water could explain the small amounts of side products 4 and 5a obtained under these conditions. The proposed disproportionation mechanism (cycle d) is consistent with the different results obtained when complex Ia was allowed to react with boronic acids 2a and 2h. Under aqueous conditions, the reaction with 2a gave the expected cross-coupled product 3a, but in the reaction with 2h only the homocoupling product 4h and debrominated sulfoxide 5a were obtained independent of whether O2 was present in the reaction medium. In contrast, when the same reaction was performed under anhydrous THF/CsF conditions, the cross-coupling product 3h was obtained along with 4h and sulfoxide 5a. According to the mechanism depicted in cycle d, the significance of the disproportionation process promoted by hydroxide ion would increase when the transmetalation step is slow. Accordingly, in the case of boronic acids 2a and 2h, the latter would give rise to the transmetalation step at a lower rate than the parent compound 2a according to the electron-withdrawing character of the -NO2 substituent. The disproportionation of complex Ia in the presence of hydroxide ion should compete efficiently with the cross-coupling reaction. Conversely, when an aqueous base is substituted for CsF in anhydrous THF, the cross-coupling reaction takes place even with the deactivated boronic acid 2h. It could be argued that the results obtained in the reaction of complex Ia with acids 2a and 2h in aqueous medium can also be explained by the mechanism proposed by Zhang36 because of the different stabilities of (39) Grushin, V. V.; Alper, H. Organometallics 1993, 12, 1890.

Suzuki-Type Arylation of R-Bromo Sulfoxides

the intermediates IIa and IIh. Since IIh should be more stable than IIa due to the presence of electron-withdrawing substituents, reductive elimination should be slower40 in the case of IIh, and thus, the second transmetalation reaction would be more likely to take place. However, the results obtained with CsF are more difficult to explain by this mechanism. Although the mechanism proposed by Zhang36 cannot be excluded, we do not believe that it represents the major reaction path in our case because (i) the side products 4 and 5a are obtained in different yields and (ii) the formation of compounds 4 and 5a decreases very significantly when a nonaqueous base is used to promote the coupling reaction. Conclusions The described palladium-catalyzed Suzuki-Miyaura reaction of R-bromo sulfoxides with boronic acids enables the R-arylation of sulfoxides with very good yields under mild conditions. The reaction is general for arylboronic acids substituted with either donor or acceptor groups, and the best results are obtained when the reactions are conducted in O2-free anhydrous THF and promoted with CsF. Chiral R-bromo sulfoxides are also adequate substrates, and the arylation proceeds in this case with a complete retention of configuration at the chiral sulfur atom. The chiral version of the arylation of R-bromo sulfoxides reveals a new and general insight into the synthesis of chiral benzyl sulfoxides which are not always readily available. The isolation and characterization of the oxidative addition R-sulfinyl-Pd(II) complex intermediate as well as the formation of cross-coupling products when it is allowed to react with boronic acids indicate the formation of this complex in the coupling reaction. The difference in the course of the reaction in aqueous or anhydrous medium, especially in the case of deactivated boronic acids, strongly suggests that the side products observed arise through disproportionation of the oxidative addition intermediate complex.

Experimental Section Materials. Bromo sulfoxides 1a and 1b were prepared according to described procedures.19 Sulfoxides 5a and 5c were obtained commercially. Sulfoxide 5b was prepared by oxidation of the corresponding commercially available sulfide with MCPBA. Sulfoxide 3a was obtained commercially. Sulfoxides 3b, 3d, 3h, 3i, 3j, 3k, 3m, and 3o were identified by comparison with authentic pure samples prepared as described in the literature.41-44 Biaryls 4a-j were identified by comparison with samples obtained by Suzuki cross-coupling of the corresponding aryl halides with boronic acids45 except when the product was commercially available. The absolute configuration of sulfoxides 3m and 3o was established by comparison with data in the literature.22,46 (40) Drago, D.; Pregosin, P. S.; Tschoerner, M.; Albinati, A. J. Chem. Soc., Dalton Trans. 1999, 2270. (41) Katritzky, A. R.; Yang, B.; Qian, Y. Synlett 1996, 701. (42) Kersten, M.; Wenschuh, E. Phosphorus, Sulfur Silicon Relat. Elem. 1993, 80 (1-4), 81. (43) Yoshimura, T.; Tsukurimichi, E.; Iizuka, Y.; Mizuno, H.; Isasi, H.; Shimasaki, C. Bull. Chem. Soc. Jpn. 1989, 62, 1891. (44) Renaud, P.; Bourquard, T.; Carrupt, P. A.; Gerater, M. Helv. Chim. Acta 1998, 81, 1048. (45) Cossi, J.; Belotti, D. J. Org. Chem. 1997, 62, 7900. (46) Donnoti, M. I.; Superchi, S.; Rosini, C. J. J. Org. Chem. 1998, 63, 9392.

Synthesis of (S)-Bromomethyl p-Tolyl Sulfoxide [(S)1c].27 Procedure A. To a solution of LDA (5.75 mmol) in THF (12 mL) at -78 °C under an argon atmosphere was added dropwise (+)-(R)-methyl p-tolyl sulfoxide (5c) (5 mmol) in THF (20 mL), and the solution was stirred for 1 h at the same temperature. The mixture was then allowed to gradually warm to 0 °C. The solution was recooled to -78 °C and added dropwise to precooled neat Br2 (3 mmol) at the same temperature. The resulting solution was stirred at -78 °C for 5 min. The resulting mixture was treated with a solution of Na2S2O3 (2 N, 10 mL), extracted with dichloromethane, dried over anhydrous Na2SO4, and concentrated to dryness. The crude material was purified by flash column chromatography (hexane/ethyl acetate, 5:1) to yield sulfoxide 1c (46%). The ee value measured by HPLC (Chiracel OD, hexane/2-propanol, 90:10, flow 0.8) was g99%. Procedure B. To a solution of 5c (10 mmol) and anhydrous pyridine (22 mmol) in dry acetonitrile (40 mL) cooled at -40 °C under an argon atmosphere was added dropwise a solution of bromine (20 mmol) in dry acetonitrile (20 mL) at -20 °C. The mixture was stirred first at -40 °C for 1 h and then overnight at room temperature. The solvent was evacuated in a vacuum, and the residue was redissolved in dichloromethane. The organic layer was washed with Na2S2O3 (0.02 N, 30 mL), dried over anhydrous Na2SO4, and concentrated to dryness. The crude material was purified by flash column chromatography (hexane/ethyl acetate, 5:1) to yield sulfoxide 1c (80%). The ee value measured by HPLC (Chiracel OD, hexane/2-propanol, 90:10, flow 0.8) was 34%. Data for 2-Methylbenzyl Phenyl Sulfoxide (3c). 1H NMR (CDCl3): δ 3.85-4.10 (AB, 2H, J ) 12.5 Hz), 6.75 (d, 1H, J ) 8.0 Hz), 6.90 (t, 1H, J ) 8.0 Hz), 7.00-7.40 (m, 7H). 13 C NMR (CDCl3): δ 19.2 (q), 61.8 (t), 124.3 (d), 126.0 (d), 127.7 (s), 128.4 (d), 128.7 (d), 129.1 (d), 131.1 (d), 131.3 (d), 137.5 (s), 142.9 (s). HRMS: m/z calcd for C14H14OS 230.0765, found 230.0766. Data for 4-Bromobenzyl Phenyl Sulfoxide (3e). 1H NMR (CDCl3): δ 3.80-4.00 (AB, 2H, J ) 12.1 Hz), 6.70 (d, 2H, J ) 8.5 Hz), 7.20-7.50 (m, 7H). 13C NMR (CDCl3): δ 62.8 (t), 123.0 (s), 124.7 (d), 129.0 (s), 129.4 (d), 131.3 (d), 131.6 (d), 131.9 (d), 142.7 (s). HRMS: m/z calcd for C13H11BrOS 293.9714, found 293.9714. Data for 3-Thienylbenzyl Phenyl Sulfoxide (3f). 1H NMR (CDCl3): δ 3.85-4.10 (AB, 2H, J ) 12.5 Hz), 6.65 (dd 1H, J ) 5 and 3 Hz), 6.90 (dd, 1H, J ) 3 and 1 Hz), 7.15 (dd 1H J ) 5 and 1 Hz) 7.40-7.60 (m, 5H). 13C NMR (CDCl3): δ 58.6 (t), 124.2 (d), 125.5 (d), 125.7 (d), 128.7 (d), 128.8 (d), 131.1 (d), 133.4 (s), 142.8 (s). HRMS: m/z calcd for C11H10OS2 222.0173, found 222.0181. Data for 2-(Trifluoromethyl)benzyl Phenyl Sulfoxide (3l). 1H NMR (CDCl3): δ 3.90-4.15 (AB, 2H, J ) 12.5 Hz), 7.15-7.70 (m, 9H). 13C NMR (CDCl3): δ 62.7 (t), 123.5 (q, J ) 289 Hz), 124.4 (d), 126.8 (d), 126.9 (d), 128.9 (d), 129.2 (d), 129.6 (d), 131.8 (d), 132.4 (s), 133.8 (s), 144.1 (s). 19F NMR: δ -59.03 (s). Data for (R)-4-(Trifluoromethyl)benzyl p-Tolyl Sulfoxide (3n). 1H NMR (CDCl3): δ 2.20 (s, 3H), 3.85-4.15 (AB, 2H, J ) 12.5 Hz), 7.35 (d, 2H, J ) 7.5 Hz), 7.50-7.60 (m, 4H), 7.65 (d, 2H, J ) 7.5 Hz). 13C NMR (CDCl3): δ 21.8 (q), 63.0 (t), 125.1 (q, J ) 287 Hz), 125.7 (d), 126.2 (d), 103.1 (d), 130.5 (s), 130.9 (d), 133.1 (s), 139.4 (s), 142.4 (s). 19F NMR: δ -63.03 (s). HRMS: m/z calcd for C15H13F3OS 298.3223, found 298.3224. The ee value measured by HPLC (Chiracel OD, hexane/2propanol, 90:10, flow 0.8) was g99%. (R)-4-Methoxybenzyl p-Tolyl Sulfoxide (3o). The ee value measured by HPLC (Chiracel OD, hexane/2-propanol, 90:10, flow 0.8) was g99%. Preparation of trans-[Pd(CH2SOPh)Br(PPh3)2] (Ia). To Pd(PPh3)4 (1.16 g, 1 mmol) was added at room temperature a solution of 1a (0.28 g, 1.80 mmol) in dry toluene (15 mL) under a nitrogen atmosphere, and the mixture was stirred until the solid was dissolved. The reaction mixture was kept at room

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Rodrı´guez et al. temperature, and Ia precipitated as a crystalline yellow solid. 1 H NMR (CD2Cl2): δ 2.30 (td, 1H, J ) 9 and 6 Hz), 2.70 (q, 1H, J ) 9 Hz), 6.65-6.80 (m, 2H), 7.10-7.75 (m, 33H). 13C NMR (CD2Cl2): δ 62.8 (t), 123.0 (s), 124.7 (d), 129.0 (s), 129.4 (d), 131.3 (d), 131.6 (d), 131.9 (d), 142.7 (s). 31P NMR (CD2Cl2): δ 28.8 (s). Cross-Coupling in Nonaqueous Medium. General Procedure. To a solution of the appropriate R-bromo sulfoxide 1 (0.4 mmol) in degassed THF (8 mL) were added boronic acid 2 (0.8 mmol), Pd(PPh3)4 (0.04 mmol), and CsF (1.6 mmol). After being refluxed for an appropriate duration (see Table 1), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with diethyl ether (2 × 15 mL) and dichloromethane (2 × 15 mL). The combined organic extracts were dried with Na2SO4 and evaporated under reduced pressure. Cross-Coupling in Aqueous Medium. General Procedure. To a solution of the appropriate R-bromo sulfoxide 1 (0.4 mmol) in methanol (8 mL) were added boronic acid 2 (0.8 mmol), Pd(PPh3)4 (0.04 mmol), and an aqueous solution of Na2CO3 (2 M, 0.8 mL, 1.6 mmol). After being refluxed for an appropriate duration (see Table 1), the reaction mixture was cooled to room temperature, quenched with water (10 mL), and

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extracted with diethyl ether (2 × 15 mL) and dichloromethane (2 × 15 mL). The combined organic extracts were dried with Na2SO4 and evaporated under reduced pressure. Cross-Coupling in Degassed Solvents. Reactions were carried out as above, but three freeze-pump-thaw cycles were performed before the reagents were mixed to exclude atmospheric oxygen from the reaction media.

Acknowledgment. Financial support from the Spanish Direccio´n General de Investigacio´n Cientı´fica y Te´cnica (Grant BQU2003-00315) and the Generalitat Valenciana (Grant GV CTIDIB 2002/239) is gratefully acknowledged. N.R. thanks the Spanish Ministerio de Educacion for a fellowship. We gratefully acknowledge the SCSIE (Universidad de Valencia) for access to their instrumental facilities. Supporting Information Available: Comparative structural data recovered from the CSD (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. JO0487552