Tropos Ligands in Asymmetric Rhodium(I)-Catalyzed Addition of

4150

Organometallics 2009, 28, 4150–4158 DOI: 10.1021/om900306s

Tropos Ligands in Asymmetric Rhodium(I)-Catalyzed Addition of Arylboronic Acids to Enones: How a Tunable Coordination Gives Different Reaction Products Sarah Facchetti, Irene Cavallini, Tiziana Funaioli, Fabio Marchetti, and Anna Iuliano* Dipartimento di Chimica e Chimica Industriale, Universit a di Pisa, Via Risorgimento 35, 56126 Pisa, Italy Received April 22, 2009

Different tropos deoxycholic acid derived biphenylphosphites were used as Rh(I) chiral ligands, at P/Rh 1:1 and 2:1 molar ratios, to obtain mono- or disubstituted Rh(I) complexes, which act as catalytic precursors in the asymmetric conjugate addition of arylboronic acids to cyclic enones, giving the addition products in high to quantitative yields and ee’s up to 92%. In addition, using an excess of arylboronic acid only the disubstituted complexes gave diastereomerically pure 1,3-diarylcyclohexanols with ee’s up to 94%. The tropos nature of the complexes, as well as the coordination mode, was investigated by 31P NMR spectroscopy. A disubstituted rhodium complex was isolated, and its X-ray molecular structure was determined.

Introduction The asymmetric activation of tropos moieties, by means of incorporation of flexible biphenyl units into ligand frameworks containing fixed elements of chirality that allow a preferred conformation of a diastereomeric complex to be assumed,1 constitutes a rather new entry in the development of monodentate ligands for asymmetric catalysis. This approach is advantageous not only because of the easy preparation of monodentate ligands with respect to bidentate ones but also because time-consuming and expensive resolution procedures of racemic biaryl compounds are avoided. As a matter of fact, the flexible nature of the tropos moiety results in a shift of the equilibrium between the two diastereoisomeric forms toward the most stable one, so determining the presence of a highly prevalent species in solution and hence the achievement of high levels of asymmetric induction.1 In this context, a great deal of interest has been *Corresponding author. E-mail: [email protected]. (1) (a) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M. Synlett 2002, 1561. (b) Mikami, K.; Yamanaka, M. Chem. Rev. 2003, 103, 3369. (2) (a) Alexakis, A.; Polet, D.; Benhaim, C.; Rosset, S. Tetrahedron: Asymmetry 2004, 15, 2199. (b) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262. (c) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 9, 1375. (d) Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org. Chem. 2004, 69, 5660. (e) Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.; van den Heuvel, A.; Levque, J.; Maze, F.; Rosset, S. Eur. J. Org. Chem. 2000, 4011. (f ) Wakabayashi, K; Aikawa, K.; Kawauchi, S.; Mikami, K. J. Am. Chem. Soc. 2008, 130, 5012. (3) (a) Reetz, M. T.; Neugebeauer, T. Angew. Chem., Int. Ed. 1999, 38, 179. (b) Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 2897. (c) Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 8737. (4) (a) Buisman, G. J. H.; van der Veen, L. A.; Klotwijk, A.; de Lange, W. G. J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Vogt, D. Organometallics 1997, 16, 2929. (b) Dieguez, M.; Pamies, O.; Ruiz, A.; Castilln, S.; Claver, C. Chem. Commun. 2000, 1607. (c) Dieguez, M.; Pamies, O.; Ruiz, A.; Castilln, S.; Claver, C. Chem.;Eur. J. 2001, 7, 3086. (d) Pamies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2001, 12, 3441. pubs.acs.org/Organometallics

Published on Web 06/26/2009

addressed toward the design of tropos phosphorus ligands, which have been successfully used in the enantioselective copper-catalyzed conjugate addition of dialkylzincs to enones or nitroolefins,2 in asymmetric hydrogenation3 and hydroformylation,4 and in the titanium-catalyzed asymmetric Strecker reaction.5 Less attention has been paid to the use of these systems in the asymmetric rhodium-catalyzed conjugate addition of aryl and alkenyl boronic acids to electron-poor olefins,6 first introduced by Miyaura and Hayashi,7 in spite of the success related to the use of various chiral phosphorus ligands in this reaction.8 Our recent experience in the design of bile acid derived tropos biphenylphosphites demonstrated that the cholestanic backbone of cholic and deoxycholic acids is able to induce a prevalent sense of twist to the biphenylphosphite unit, depending on the position where it is linked on the steroidal skeleton,9 and efficient chiral ligands for asymmetric reactions were obtained by linking biphenylphosphite moieties to the 12-position of deoxycholic acid (Figure 1).10 The success of these phosphites as transition metal ligands and the attractiveness of the asymmetric conjugate addition (5) W€ unnemann, S.; Fr€ ohlich, R.; Hoppe, D. Eur. J. Org. Chem. 2008, 684. (6) (a) Monti, C.; Gennari, C.; Piarulli, U. Chem. Commun. 2005, 5281. (b) Monti, C.; Gennari, C.; Piarulli, U. Chem.;Eur. J. 2007, 13, 1547. (7) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. (8) (a) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 4, 646. (b) Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503. (c) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (d) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. Adv. Synth. Catal. 2007, 349, 2331. (e) Boiteau, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003, 68, 9481. (f ) Iguchi, Y.; Itooka, R.; Miyaura, N. Synlett 2003, 7, 1040. (9) Iuliano, A.; Facchetti, S.; Uccello-Barretta, G. J. Org. Chem. 2006, 71, 4943. (10) (a) Facchetti, S.; Losi, D.; Iuliano, A. Tetrahedron: Asymmetry 2006, 17, 2993. (b) Iuliano, A.; Losi, D.; Facchetti, S. J. Org. Chem. 2007, 72, 8472. r 2009 American Chemical Society

Article

Organometallics, Vol. 28, No. 14, 2009

4151

Table 1. Asymmetric Conjugate Addition of Arylboronic Acids to Cyclohexenone Promoted by Phosphites 1-5

entry L* (Rh:L* ratio)a ArB(OH)2 t (h) yield (%)b ee (%)c ACd

Figure 1. Structure of deoxycholic acid derived biphenylphosphites and binaphthylphosphites.

of arylboronic acids to enones prompted us to check the activity and enantioselectivity of these systems as Rh(I) ligands in this reaction. The preliminary use of 1 as a Rh(I) ligand in the conjugate addition of phenylboronic acid to cyclohexenone has revealed an unusual behavior of this phosphite. The spectroscopic investigation carried out on the mixtures between 1 and [{RhCl(C2H4)2}2] at 1/Rh molar ratios of 1 and 2 showed unequivocally that two different complexes can be obtained, acting in a different fashion as catalysts of the reaction.11 As a matter of fact the monosubstituted complex is able to catalyze the conjugate addition of phenylboronic acid to cyclohexenone in an enantioselective way, whereas in the presence of the disubstituted complex the usual conjugate addition or a double asymmetric addition leading to 1,3-diphenylcyclohexanol took place, depending on the reaction conditions.11 In this paper we report the asymmetric conjugate addition of arylboronic acids to cyclic enones, catalyzed by the monosubstituted and disubstituted Rh(I) complexes of 12deoxycholic acid derived tropos biphenylphosphites 1-5, as well as the asymmetric double-addition reaction promoted by the disubstituted complexes. A 31P NMR investigation on the Rh(I) complexes aimed at elucidating some aspects concerning the use of these precursors and a crystallographic characterization of one disubstituted complex, which catalyzes the asymmetric double addition, are also presented.

Results and Discussion At first we checked the activity and enantioselectivity of mono- and disubstituted complexes of ligands 1-5 in the conjugate addition of arylboronic acids 8a-e to cyclohexenone: the results obtained are reported in Table 1. Optimized reaction conditions affording only 3-arylcyclohexanones were chosen, i.e., room temperature and a nearly stoichiometric amount of arylboronic acid, and the reactions were stopped at complete substrate conversion or when it did not proceed further. It is worth noting that ligands 1-5 give rise to Rh(I) complexes displaying good catalytic activity (11) Iuliano, A.; Facchetti, S.; Funaioli, T. Chem. Commun. 2009, 457.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

1 (1:1) 1 (1:2) 2 (1:1) 3 (1:1) 3 (1:2) 4 (1:1) 5 (1:1) 6b (1:1) 6a (1:1) 1 (1:1) 1 (1:1) 1 (1:2) 1 (1:1) 1 (1:1) 1 (1:2)

8a 8a 8a 8a 8a 8a 8a 8a 8a 8b 8c 8c 8d 8e 8e

8 5 8 8 8 8 8 8 48 8 5.5 5 8 8 23

99 94 50 92 96 90 67 94

88 90 62 68 78 69 33 91

(R) (R) (R) (R) (R) (R) (S) (R)

99 99 99 99 40 50

92 86 92 87 82 88

(R) (R) (R) (R) (R) (R)

a Precatalysts were formed by stirring the dioxane mixture of [{RhCl (C2H4)2}2] and L* for 24 h in the case of Rh:L* 1:1 molar ratio, or for 0.5 h in the case of Rh:L* 1:2 molar ratio. b Isolated yield. c Determined by HPLC analysis; see Experimental Part for details. d Assigned on the basis of elution order by comparison with literature data where the sign of optical rotations was also reported.

even at room temperature, making the hydrolysis of phenylboronic acid slow inasmuch as it is not competitive with the conjugate addition, so that a large excess of arylboronic acid is not necessary12 to obtain satisfactory yields of products 9. Perusal of Table 1 shows that all the phosphites 1-5 were able to promote the conjugate addition of phenylboronic acid in an enantioselective way when used at P/Rh=1 molar ratio (entries 1, 3, 4, 6, 7), even if when used at P/Rh=2 molar ratio slightly higher asymmetric inductions (entries 2 and 5) in shorter reaction times (entry 2) were obtained. Very high to quantitative yields of 3-phenylcyclohexanone were obtained using 1 as Rh(I) ligand (entries 1 and 2). Substitution on the phosphite biphenyl moiety affects the catalytic activity of the Rh(I) complexes depending on structure and position of the substituents: as a matter of fact, substitution at the 5,50 positions of the biphenyl moiety with phenyl or benzoyl groups did not affect to a great extent the catalytic activity of the Rh(I) complexes (entries 4-6), whereas the presence of isopropyl groups at these positions decreased the catalytic activity, giving only a 50% yield of 9a (entry 3). Also the substitution at the 3,30 positions of the biphenyl moiety had a negative effect on the catalytic activity of the Rh(I) complex of phosphite 5, which afforded 9a in 67% yield (entry 7). High enantiomeric excesses were obtained using 1, whereas substitution at the 5,50 positions of the biphenyl moiety resulted in worsening of the asymmetric induction, using both the monosubstituted Rh(I) complexes of phosphites 2-4 (entries 3, 4, 6) and the disubstituted complex of 3 (entry 5) as catalytic precursors. The presence of phenyl groups at the 3,30 positions of the biphenyl moiety of (12) In another recent paper a low arylboronic acid:enone ratio has been employed: Morgan, B. P.; Smith, R. C. J. Organomet. Chem. 2008, 693, 11.

4152


phosphite 5 had a detrimental effect on the enantioselectivity of the reaction, and 9a was obtained in only 33% enantiomeric excess. The good asymmetric induction obtained with phosphites 1-4 points out the presence of a high prevalence of screw sense of the biphenylphosphite moieties in the catalytically active Rh(I) complexes, which led to the prevailing formation of the (R)-3-phenylcyclohexanone (entries 1-6). By contrast, the low enantiomeric excess obtained using 5 as Rh(I) ligand is accompanied by the inversion of the asymmetric induction sense, giving a low prevalence of the (S)3-phenylcyclohexanone. In order to check for a possible correlation between the sense of asymmetric induction and the prevailing sense of twist assumed by the biphenylphosphite moieties of ligands 1-5 in their Rh(I) complexes, the atropoisomeric analogues 6a and 6b, bearing (R)- and (S)binaphthylphosphite moieties, respectively, were used as Rh(I) ligands. Phosphite 6b behaved like 1, giving (R)-9a in 94% yield and 91% ee (entry 8), whereas 6a, surprisingly, did not afford the product even after prolonged reaction times of up to 48 h (entry 9). These results show that only the deoxycholic acid derived phosphite having an S-configured binaphthyl moiety guarantees the formation of a catalytically active Rh(I) complex, which, in turn, affords an R-configured addition product. This suggests also that the biphenyl moieties of the tropos phosphites 1-5 must have a prevailing P sense of twist, corresponding to an S absolute configuration, in the catalytically active Rh(I) complexes, which afford (R)-9a when phosphites 1-4 bearing a biphenyl group or a 5,50 -disubstituted biphenyl group are used. The achievement of the opposite enantiomer of the product using 5 as Rh(I) ligand suggests a change in the asymmetric induction mechanism, probably due to the presence of the phenyl substituents at the 3,30 positions of the biphenyl moiety. Phosphite 1 was the best Rh(I) ligand both in monosubstituted and in disubstituted Rh(I) complexes, affording 9a in highest yield and ee. Therefore, it was used as Rh(I) ligand in the conjugate addition of other arylboronic acids to cyclohexenone. The monosubstituted complex worked very well as catalyst precursor toward the conjugate addition of arylboronic acids bearing electron-donating substituents, such as 8b-d (entries 10, 11, 13), giving the corresponding (R)-3-arylcyclohexanones 9b-d in 99% yield and ee’s ranging from 86% to 92%. The disubstituted complex checked in the reaction of 8c afforded (R)-9c in 99% yield and, as usual, in a slightly higher ee (entry 12). Again, it is to be noted that the good catalytic performances of these Rh(I) complexes allow the use of only a slight excess of arylboronic acid also in the case of 8c, whose hydrolysis is fast. By contrast the reaction of 8e, bearing an electron-withdrawing group, was significantly slower, and (R)-9e was obtained in only 40% yield and 82% ee (entry 14). The use of the disubstituted complex did not significantly improve the yield, even prolonging the reaction time, although a slight increase in ee was observed (entry 15). The results concerning the screening of ligands 1-5 in the conjugate addition of arylboronic acids to cyclopentenone are reported in Table 2. The previous optimized reaction conditions were used for comparative purposes, and the reactions were stopped at complete substrate conversion or when it did not proceed further. Cyclopentenone reacted faster than cyclohexenone with phenylboronic acid using both monosubstituted and disubstituted Rh(I) complexes of 1-5, giving good yields of (R)-3-phenylcyclopentanone (entries 1-9).

Facchetti et al. Table 2. Asymmetric Conjugate Addition of Arylboronic Acids to Cyclopentenone Promoted by Phosphites 1-5

entry L* (Rh:L* ratio)a ArB(OH)2 t (h) yield (%)b ee (%)c ACd 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

1 (1:1) 1 (1:2) 2 (1:1) 2 (1:2) 3 (1:1) 3 (1:2) 4 (1:1) 4 (1:2) 5 (1:1) 3 (1:1) 3 (1:1) 3 (1:1) 3 (1:1) 4 (1:2) 4 (1:2)

8a 8a 8a 8a 8a 8a 8a 8a 8a 8b 8c 8d 8e 8d 8b

2 2 5 5 5 5 8 3 8 3 3 5 10 7 3

100 100 70 70 100 100 92 98 92 98 98 70 50 80 100

56 59 45 50 72 56 59 80 35 68 40 90 77 83 67

(R) (R) (R) (R) (R) (R) (R) (R) (R) (R) (R) (R) (R)

a Precatalysts were formed by stirring the dioxane mixture of [{RhCl (C2H4)2}2] and L* for 24 h in the case of Rh:L* 1:1 molar ratio, or for 0.5 h in the case of Rh:L* 1:2 molar ratio. b Isolated yield. c Determined by HPLC analysis; see Experimental Part for details d Assigned on the basis of the elution order or the sign of optical rotation, by comparison with literature data.

It is notable that all the phosphites showed the same sense of asymmetric induction, suggesting that, with this substrate, the asymmetric induction mechanism is similar also in the case of phosphite 5, which is still the least enantioselective. The ee’s were lower than those of 9a, ranging from 35% to 80% and slightly higher (entries 2 and 4) when disubstituted complexes of 1 and 2 were used. Interestingly, the disubstituted Rh(I) complex of 4 gave (R)-11a with a remarkable higher ee than the corresponding monosubstituted complex (entries 8 and 7), whereas the disubstituted complex of 3 gave (R)-11a with a remarkable lower ee than the corresponding monosubstituted complex (entries 6 and 5). Therefore, the monosubstituted complex of 3 and the disubstituted complex of 4, which gave the best results, were used as catalytic precursors in the conjugate addition of different arylboronic acids to cyclopentenone. Using the monosubstituted complex of 3 a quick addition of 8b and 8c was observed, giving (R)-11b and (R)-11c with 68% and 40% ee, respectively (entries 10 and 11). The addition of 8d was slower (entry 12), and 8e reacted much more slowly (entry 13), as already observed for the addition to cyclohexenone. However, both these reactions were more enantioselective, and (R)-11d was obtained in 90% ee. The same trend is observed with the reaction promoted by the disubstituted Rh(I) complex of 4: 8d reacted more slowly and more enantioselectively than 8b (entries 14 and 15). It is to be noted that, using cyclopentenone as reaction substrate, the best performing disubstituted complex gave lower ee’s than the best performing monosubstituted complex (entries 10, 12, 15, 14). Given that the disubstituted complex of 1 had shown the interesting property of catalyzing the double addition (1,4 plus 1,2) to cyclohexenone when an excess of phenylboronic acid and moderately high reaction temperature were used,11 we checked the general applicability of this new reaction by reacting different boronic acids with

Article


Table 3. Asymmetric 1,2 þ 1,4 Addition of Arylboronic Acids to Cyclohexenone Promoted by Phosphites 1-5

entry L* 1 2 3 4 5 6 7 8 9 10 11 12

1 1 1 1 1 1 3 3 4 4 5 6b

ArB(OH)2 8a (3 equiv) 8a (5 equiv) 8b (3 equiv) 8c (3 equiv) 8d (3 equiv) 8e (3 equiv) 8b (3 equiv) 8b (2.3 equiv) 8b (2.3 equiv) 8d (2.3 equiv) 8a (3 equiv) 8a (3 equiv)

t (h) T (°C) yield (%)a de (%)b ee (%)c 6 3 5 22 22 24 6 8 8 24 24 72

60 60 60 60 60 60 60 rt rt rt 60 rt

83 86 85 50 55

>99 >99 >99 >99 >99

80 80 83 82 94

70 71 90 75 -d Tracese

>99 >99 >99 >99

78 78 91 88

n.d.

n.d.

a Isolated yield. b Determined by 1H NMR. c Determined by HPLC analysis; see Experimental Part for details. d (S)-9a was obtained in 99% yield and 73% ee. e Very low conversion of cyclohexenone was observed.

cyclohexenone and using as catalytic precursors the disubstituted complexes of other phosphites besides 1: the results are reported in Table 3. The addition of phenylboronic acid to cyclohexenone catalyzed by the disubstituted Rh(I) complex of 1 gave (1R,3R)-1,3-diphenylcyclohexanol in 83% yield, with complete diastereoselectivity and 80% ee after 6 h reaction (entry 1). Increasing the amount of phenylboronic acid up to 5 equiv only shortened the reaction time and slightly increased the yield (entry 2). Very similar results were obtained by reacting 8b, which afforded diastereoisomerically pure 12b in 85% yield and 83% ee (entry 3). The diastereomeric composition was evaluated on the basis of the 1H NMR signals relative to the resonances of H3: only the triplet of triplets at 3.16 ppm, attributable to the H3 of the syn diastereoisomer, was detectable.13 On the basis of the NMR results and the reaction trend the (R,R) absolute configuration was attributed to this product.14 In fact, the reaction proceeds through the formation of the (R)-3-arylcyclohexanone, which further reacts, giving the final syn-1,3-diarylcyclohexanol, having as a result an (R,R) absolute configuration. It is to be noted that 12a was obtained in lower ee with respect to 9a, prepared using the same disubstituted complex (see Table 1 for comparison), which is the intermediate product of this reaction. Given that the reaction is completely diastereoselective, this result can be tentatively explained considering a slower reactivity of the prevailing enantiomer of the intermediate 9a, which indeed is not completely converted to 12a: however, this point deserves further investigations. The reaction of the two methoxyphenylboronic acids 8c and 8d was slower and afforded moderate yields of the products (entries 4 and 5). The lower yields are attributable not only to the hydrolysis of the methoxyphenylboronic acids, faster than the hydrolysis of the other arylboronic acids, but also to the incomplete conversion of the conjugate addition product. This last step seems particularly slow in the case of the (13) Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.; Van Meervelt, L.; Van der Eycken, J. Org. Lett. 2006, 8, 363. (14) The (R,R) absolute configuration was attributed to 12a by comparison with literature data.13

4153

addition of methoxyphenylboronic acids. The overall finding was that the products were obtained as pure diastereoisomers and with high ee’s. The double-addition reaction did not take place with 8e at all (entry 6). Also the disubstituted complex of 3 was able to catalyze the double addition, affording after 6 h at 60 °C diastereomerically pure (R,R)12b in 70% yield and 78% ee (entry 7). The same reaction performed at room temperature with just a slight excess of 8b gave the same results only with a longer reaction time (entry 8). Again, working at rt makes possible the use of a minor amount of arylboronic acid, since, under these reaction conditions, its hydrolysis was not competitive with the addition reaction. Phosphite 4 gave the best performing disubstituted complex, able to catalyze the formation of diastereomerically pure (R,R)-12b in 90% yield and 91% ee (entry 9). It was best performing also toward the reaction of 8d, which despite that it required 24 h to give a good conversion of the in situ formed conjugate product, afforded diastereomerically pure 12d in 75% yield although in lower ee (entry 10). It is to be noted that under these reaction conditions also the hydrolysis of 8d was slowed, so that the same slight excess of boronic acid was sufficient for carrying out the reaction. Surprisingly, the reaction was not promoted by phosphite 5: even prolonging the reaction time only the conjugate addition product was obtained. The atropoisomeric phosphite 6b poorly reacted when used at P:Rh 2:1 molar ratio (entry 12), probably because of the greater steric hindrance of the binapthyl moiety, which results in crowding of the Rh center, making very hard the coordination of the substrate and hence its reaction. On the basis of the results obtained some questions can be addressed about the behavior of phosphites 1-5 as Rh(I) ligands in the addition of arylboronic acids to cyclic enones: the tropos nature of both mono- and disubstituted complexes and the prevailing sense of twist of the biphenyl moiety of the phosphites in the complexes, the anomalous behavior of 5, which affords low asymmetric induction in the conjugate addition and does not promote the double addition, and why the disubstituted complexes of these phosphites are able to catalyze the double-addition reaction. To find answers, some spectroscopic investigations on the mono- and disubstituted complexes of the phosphites were performed. The tropos nature of the Rh(I) complexes was ascertained by means of variable-temperature 31P NMR measurements. The variable-temperature profile of the 31P NMR spectra of the monosubstituted complex of 1, chosen as representative of the monosubstituted complexes of phosphites 1-4, is shown in Figure 2. The 31P NMR spectrum recorded at 25 °C shows the presence of a doublet, at δ=137.0 ppm (J = 292.3 Hz), which undergoes a slight downfield shift and broadens until coalescence, observed at -60 °C. Further lowering of the temperature to -80 °C causes complete decoalescence of the signal, which splits in two doublets at δ = 137.4 ppm (J = 294.3 Hz) and δ = 140.4 ppm (J = 289.1 Hz), attributable to the two M-P diastereoisomers, fast interconverting at room temperature (Figure 3A). The integrated areas of the two signals give a 50:50 ratio between the two diastereoisomeric complexes. A more complex situation is found in the case of the disubstituted complex of 1. Its 31P NMR spectrum recorded at 25 °C (Figure 4) shows the presence of two doublets at δ = 144.3 ppm (J=297.0 Hz) and at δ=147.9 ppm (J=295.6 Hz), assigned to the monomeric and dimeric forms of the disubstituted complex in slow equilibrium at 25 °C.11 These signals

4154


Figure 2. VT 31P NMR spectra (121.4 MHz, [D8]toluene) of the monosubstituted complex [{RhCl(C2H4)(1)}2].

Figure 3. M-P equilibrium in mono- and disubstituted complexes (the monomeric species are represented for clarity).

coalesce at 80 °C, and only one doublet at δ = 145.2 ppm (J = 295.6 Hz) is present at 100 °C, where the equilibrium between monomeric and dimeric forms becomes fast. The behavior at low temperature shows complete decoalescence of the two doublets at -60 °C, where a lot of signals, attributable to the presence of several species, arising from the M-P equilibrium of the biphenyl moieties of ligands 1 are present. Attribution of these signals is very difficult, because several of them are superimposed. The complexity of the spectrum points out a similar behavior for the disubstituted complex to that of the monosubstituted one, i.e., the lack of preference for a sense of twist of the biphenyl moiety when ligands 1 coordinate to the Rh center (Figure 3B). As a matter of fact, this situation would engender in the NMR spectrum, for each form, besides two doublets, as observed in the spectrum of the monosubstituted complex, two doublets of doublets due to the inequivalence of the two phosphorus nuclei when the biphenyl moieties of the two ligands on the same Rh(I) center have an opposite sense of twist. The lack of prevalence of one sense of twist suggests a nonselective

Facchetti et al.

Figure 4. VT 31P NMR spectra (121.4 MHz, [D8]toluene) of the disubstituted complex 1/[{RhCl(C2H4)2}2] (2:1 P/Rh).

complexation of 1 in the formation of the monosubstituted complex as well as of the disubstituted one. Nevertheless, a high level of asymmetric induction can be reached because only one of the interconverting diastereoisomers affords a catalytically active species, and the tropos nature of the complexes allows shift of the equilibrium toward the catalytically active one. Phosphite 5 showed quite a different behavior with respect the other ligands: when used at P/Rh = 1 molar ratio, it afforded products 9a and 11a in surprisingly low ee’s, and when used at P/Rh 2:1 molar ratio, it did not promote the double-addition reaction. Given that the double addition is catalyzed only by disubstituted complexes, the different reactivity would suggest a different behavior of 5 in the Rh(I) coordination, which was investigated by 31P NMR spectroscopy. The 31P NMR spectrum recorded on a mixture of [{RhCl(C2H4)2}2] and 5 at P/Rh = 1 molar ratio in [D8]toluene as solvent (Figure 5) at 25 °C shows a large signal between 140 and 150 ppm that, on lowering the temperature to -20 °C, decoalesces, giving two doublets at 144.7 ppm (J=302.1 Hz) and 148.0 ppm (J=295.3 Hz): the signal of the free ligand is not detectable, suggesting complete coordination of 5 to Rh. The spectrum recorded on the same mixture at -20 °C after 24 h appears unchanged (Figure 5d), suggesting that the complex present in the just prepared solution does not undergo any change with time.11 Addition of further 5 to this solution to increase the P/Rh molar ratio to 1.5 caused the appearance of the free 5 signal at 161.6 ppm, whose intensity increased after further addition of 5 to P/Rh = 2 molar ratio. At the same time the doublet signal at 148.0 ppm disappeared. This trend suggests that, unlike the other phosphites, ligand 5 can give rise only to a monosubstituted Rh(I) complex. The two doublet signals, visible in the spectrum recorded at -20 °C, are attributable to the two diastereoisomeric M and P forms of the monosubstituted complex (Figure 3A). Disappearance of the doublet signal at 148.0 ppm when free ligand is present in solution suggests that an

Article

Figure 5. VT 31P NMR spectra (121.4 MHz, [D8]toluene) of a 2:1 mixture of 5/[{RhCl(C2H4)2}2] (1:1 P/Rh): (a) t=0.5 h, 25 °C; (b) t=0.5 h, 0 °C; (c) t = 0.5 h, -20 °C; (d) t=24 h, -20 °C; (e) t = 24 h, -20 °C after addition of a further 1 equiv of 5 (1.5:1 P/ Rh); (f) t=24 h, -20 °C after addition of a further 2 equiv of 5 (2:1 P/Rh).

equilibrium between free and coordinate phosphite takes place, leading to the formation of only one diastereomeric form of the complex. Its formation is favored by the tropos nature of the phosphite,10a which allows the M-P equilibrium in the free ligand to be shifted toward the diastereoisomer that affords the thermodynamically favored complex. The exclusive formation of a monosubstituted complex starting from 5 likely happens because of the greater steric hindrance around its phosphorus atom due to the presence of the two phenyl groups present at the 3,30 positions of the biphenyl group, which prevents the coordination of two ligands at the same rhodium center.15 Failure to form a disubstituted complex at P/Rh=2 molar ratio is the reason that phosphite 5 did not promote the double-addition reaction. The low ee obtained when 5 was used at P/Rh=1 molar ratio can be explained on the basis of the presence of the M and P diastereoisomers of the complex at 25 °C, which, in this case, can give rise to catalytically active species affording enatiomeric products, as also suggested by the inversion of the sense of asymmetric induction (see Table 1, entry 7). The slow equilibrium between the two diastereoisomeric forms prevents a shift toward the thermodynamically favored species, and the presence of both diastereoisomeric complexes gives rise to lower ee. On the contrary, the equilibrium between free and coordinated phosphite, when an excess of 5 is present in solution, leading to the preferential formation of (15) Niyomura, O.; Iwasawa, T.; Sawada, N.; Tokunaga, M.; Obora, Y.; Tsuji, Y. Organometallics 2005, 24, 3468.


4155

only one diastereomeric form of the complex, explains the higher yield and ee of 9a, obtained when 5 is used as Rh(I) ligand at P/Rh=2 molar ratio (see Table 3, entry 11, footnote d). The results obtained demonstrate that the monosubstituted Rh(I) complexes of phosphites 1-5 allow the achievement of the conjugate addition products, thus behaving as the disubstituted Rh(I) complexes of monodentate and bidentate phosphorus ligands reported in the literature.8 By contrast, the disubstituted complexes show an unusual behavior, being able to catalyze the double-addition reaction. Therefore, as a first step to shed light on this point, we became interested in acquiring further information about the structural features of these unique catalytic precursors, and hence the crystal structure of the disubstituted complex of phosphite 1 was analyzed. Single crystals of the disubstituted complex [RhCl(1)2]2 suitable for X-ray analysis were obtained by diffusion of hexane into a toluene solution of the complex at room temperature.16 The molecular structure of [RhCl(1)2]2 is shown in Figure 6. Two rhodium atoms exhibit pseudo-square-planar coordination geometry with two bridging chlorides and four phosphite ligands. The coordination squares are not perfectly planar, but show small tetrahedral distorsions. If we refer to the square Rh(1), Cl(1), Rh(2), Cl(2), which is almost perfectly planar, the largest deviation from the mean plane being shorter than 0.03 A˚, the planes P(1), Rh(1), P(2) and P(3), Rh(2), P(4) make dihedral angles of 6.5° and 8.1°, respectively, from opposite sides of this square plane. As reported in the caption of Figure 6, the Rh-Cl bond distances show a significant dispersion with respect to the estimated standard deviations; their mean value, 2.426 A˚, however, is in keeping with the values found for chlorines bridging between Rh(I) species.17 The Rh-P bond lengths are less dispersed, and their mean value, 2.149 A˚, is the shortest Rh-P distance found in tetracoordinated Rh(I) phosphite complexes, which range between 2.22 and 2.27 A˚.18 It compares well, however, with Rh-P bond distances found in dinuclear dichloro phosphoramidites of Rh(I).19 The absolute configuration of the chiral phosphite groups could not be directly established by this structural study, because the estimated standard deviation of the Flack absolute structure parameter20 at the end of refinement makes it unreliable. The correct configuration could be obtained by fixing the known configuration of the cholestanic moiety.21 As shown in Figure 7, the configuration of the biphenyl moieties is M22 (A) in three of the four phosphite ligands and (16) The solution of the crystals in [D8]toluene afforded the same 31P NMR spectrum as the solution of the powder. (17) (a) Yuan-Wen, Ge; Sharp, P. R. Inorg. Chem. 1991, 30, 1671. (b) Liedtke, J.; Ruegger, H.; Loss, S.; Grutzmacher, H. Angew. Chem., Int. Ed. 2000, 39, 2478. (c) Yamamotoa, Y.; Suzuki, H.; Tajima, N.; Tatsumi, K. Chem.-Eur. J. 2002, 8, 372. (18) (a) Magistrato, A.; Merlin, M.; Pregosin, P. S.; Rothlisberger, U.; Albinati, A. Organometallics 2000, 19, 3591. (b) Rubio, M.; Vargas, S.; Suarez, A.; Alvarez, E.; Pizzano, A. Chem.-Eur. J. 2007, 13, 1821. (c) Bachmann, C.; Gutmann, R.; Czermak, G.; Dumfort, A.; Eller, S.; Fessler, M.; Kopacka, H.; Ongania, K.-H.; Bruggeller, P. Eur. J. Inorg. Chem. 2007, 3227. (19) (a) Kunze, C.; Neda, I.; Freytag, M.; Jones, P. G.; Schmutzler, R. Z. Anorg. Allg. Chem. 2002, 628, 545. (b) Mariz, R.; Brice~no, A.; Dorta, R.; Dorta, R. Organometallics 2008, 27, 6605. (20) Flack, H. D. Acta Crystallogr. 1983, A39, 876. (21) Stankovic, S.; Argay, G.; Kalman, A.; Miljkovic, D. A.; Kuhajda, K.; Hranisavljevic, J. T. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1988, 44, 531. (22) Helmchen, G. Houben-Weyl: Methods of Organic Chemistry; Georg Thieme Verlag: New York, 1995; Vol. E 21a, pp 10-13.

4156


Facchetti et al.

Figure 6. Pespective view of the molecular structure of [RhCl(1)2]2. A simplified representation has been adopted for clarity. Only the most populated positions of disordered groups have been drawn. Thermal ellipsoids of Rh, Cl, P, and O atoms have been represented at 30% probability. Bond lengths (A˚) and angles (deg) around the rhodium atoms: Rh(1)-Cl(1), 2.4250(7); Rh(1)-Cl(2), 2.4329(7); Rh(2)-Cl(1), 2.4512(7); Rh(2)-Cl(2), 2.3930(7); Rh(1)-P(1), 2.1515(8); Rh(1)-P(2), 2.1344(8); Rh(2)-P(3), 2.1529(7); Rh(2)-P(4), 2.1573(7); P(2)-Rh(1)-P(1), 91.27(3); P(2)-Rh(1)-Cl(1), 170.15(3); P(1)-Rh(1)-Cl(1), 98.39(3); P(2)-Rh(1)-Cl(2), 88.43(3); P(1)-Rh(1)-Cl(2), 175.00(3); Cl(1)-Rh(1)-Cl(2), 82.10(2); P(3)-Rh(2)-P(4), 93.36(3); P(3)-Rh(2)-Cl(2), 169.93(3); P(4)-Rh(2)-Cl(2), 92.20(3); P(3)-Rh(2)-Cl(1), 92.37(3); P(4)-Rh(2)-Cl(1), 174.04(3); Cl(2)-Rh(2)-Cl(1), 82.37(2); Rh(1)-Cl(1)-Rh(2), 97.02(2): Rh(2)-Cl(2)-Rh(1), 98.38(2).

Conclusions

Figure 7. Different configurations of the biphenyl moieties. The A configuration is adopted by the units bonded to P(1), P(2), and P(3); the B one, by the unit bonded to the P(4) atom.

P22 (B) in the fourth one. Although we cannot find an easy explanation, it may be pointed out that the phosphite ligand carrying the P twisted biphenyl group binds the Rh(2) atom, the rhodium showing a “short” bond distance from the Cl(2) atom. The nonsymmetrical arrangement of the phosphites coordinated to Rh, which shows three biphenyl moieties having a M sense of twist and only one having an P sense of twist, appears unusual and can be attributed to a poor preference for one sense of twist not only in solution but also in the crystal. The molecules of the dinuclear complex are not closely packed in the crystal, and the cavities present among them can accommodate one toluene molecule for each molecule of the complex. Moreover, they allow the presence of a conformational disorder in several external moieties of the molecule of the complex. Other large cavities with a volume of up to 215 A˚3 remain in the crystal, however, probably due to the highly asymmetric structure of the cholestanic backbone, which prevents close packing.

The use of phosphites 1-5 as Rh(I) ligands in the asymmetric conjugate addition of arylboronic acids to cyclic enones has shown their effectiveness in promoting the 1,4addition, when used at P/Rh 1:1 molar ratio, which gives rise to the formation of monosubstituted Rh(I) complexes. In addition, these phosphites used at the most commonly employed P/Rh 2:1 molar ratio give rise to the formation of disubstituted Rh(I) complexes, acting as catalytic precursors not only toward the conjugate addition but also, depending on the equivalents of boronic acid, toward a double 1,2 plus 1,4 addition, leading to diastereomerically pure syn1,3-diarylcyclohexanols with ee’s up to 94%. Monosubstituted complexes of phosphites 1-4 are obtained by virtue of their size, which allows the formation of a kinetically favored disubstituted complex, equilibrating in 24 h to a thermodynamically stable monosubstituted complex: as a matter of fact, when the most sterically hindered phosphite 5 is used, only the monosubstituted complex is obtained, even in the presence of an excess of ligand. The comparison of activity and enantioselectivity of the Rh(I) complexes of phosphites 1-5 with those of the Rh(I) complexes of the analogous atropoisomeric binaphthylphosphites allowed to establish that not only the sense of asymmetric induction but also the activity of the complexes depend on the configuration of the biaryl moiety of the phosphite. As a matter of fact, only the phosphite bearing an (S)-binaphthyl moiety gives rise to a catalytically active complex, affording an R-configured product. The tropos nature of both mono- and disubstituted Rh(I) complexes plays a fundamental role in determining the stereochemical outcome of the addition reactions. In fact, although a nonselective complexation of the phosphites, leading to the formation of a statistical mixture of M and P diastereoisomeric complexes, is observed, high levels of

Article


asymmetric induction are reached, given that only one of the diastereomeric complexes is catalytically active and their tropos nature allows a shift of the equilibrium toward the achievement of only one species in solution. The biphenyl moieties of this species assume a P sense of twist, corresponding to the S absolute configuration, as deduced on the basis of the comparison with the binaphthylphosphites. The X-ray analysis on [RhCl(1)2]2 shows that the unusual behavior of the disubstituted complexes, affording the double addition, is flanked by a very unique crystal structure devoid of a symmetrical arrangement of the ligands. A direct correlation between the structure of the complex and its reactivity is not evident at present, and further studies are in progress on the mechanism of the double addition.

Experimental Part Materials. TLC analyses were performed on silica gel 60 sheets; chromatography separations were carried out on adequate dimension columns using silica gel 60 (70-230 mesh). Toluene and dioxane were refluxed over sodium and distilled before use. Water and the solution of 2 M KOH were degassed before use. Unless otherwise specified, the reagents were used without any purification. [{RhCl(C2H4)2}2] was prepared according to literature procedures.23 Phosphites 1-6 were synthesized as described elsewhere9,10 and matched the reported characteristics. Preparation and characterization of monoand disubstituted complexes of phosphite 1 were previously described.11 Single crystals of the disubstituted complex of 1 were obtained by diffusion of hexane into a toluene solution and showed the same characteristics of the powder. NMR Spectroscopy. 1H (300 MHz), 13C (75 MHz), and 31P (121.5 MHz) NMR spectra were recorded in CDCl3, [D8]toluene, or [D6]benzene on a Varian INOVA-300 spectrometer. The following abbreviations are used: s = singlet, d = doublet, dd = double doublet, t = triplet, m = multiplet, br = broad. 1H and 13C NMR chemical shifts are referred to TMS as external standard. 31P NMR chemical shifts are referred to H3PO4 as external standard. The temperature was controlled to (0.1 °C by means of the Varian unity control. Analyses. Elemental analyses were performed at Laboratorio di Microanalisi Faculty of Pharmacy University of Pisa. HPLC analyses were performed on a JASCO PU-980 intelligent HPLC pump equipped with a JASCO UV-975 detector. GC analyses were performed on a Perkin-Elmer Autosystem XL chromatograph equipped with a BP-1 dimethyl polysiloxane column (25 m 0.25 mm 0.25 μm), using nitrogen as transport gas. Peak identification was performed using independently synthesized samples. General Procedure for the Asymmetric Rh(I)-Catalyzed Conjugate Addition of Arylboronic Acid to Cyclic Enones. Under a nitrogen atmosphere 1,4-dioxane (1 mL) was added to [{RhCl(C2H4)2}2] (1.5 mol %) and the phosphite (3 or 6 mol %). The mixture was stirred for 24 h (P/Rh = 1 molar ratio) or 30 min (P/Rh=2 molar ratio), and then water (0.1 mL), 2 M KOH (0.5 mL), phenylboronic acid (1.2 equiv), and the enone (1 mmol) were added. The mixture was stirred at 25 °C, and the reaction was monitored by GC. After complete conversion, the mixture was poured into 1 M NaHCO3 and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to yield the crude product. Chromatography on silica gel (hexane/EtOAc, 70:30) gave 3-aryl-substituted cyclic ketones as a colorless oil. The spectroscopic characteristics of the products were in agreement with literature data. The ee was determined by HPLC

(23) Cramer, R.; McCleverty, J. A.; Bray, J. Inorg. Synth. 1990, 28, 86.

4157

analyses on chiral stationary phases. The absolute configuration of the prevailing enantiomer was assigned on the basis of the chromatographic elution order or on the basis of the sign of the optical rotatory power, by comparison with literature data as specified for each compound. 3-Phenylcyclohexanone (9a):. Chiralcel OD-H, 220 nm, 1.0 mL/ min, hexane/2-propanol, 99:1, tR = 15.43 min (S), 16.97 min (R).24 3-(4-Methylphenyl)cyclohexanone (9b):. Chiralpak AD, 220 nm, 0.7 mL/min, heptane/2-propanol, 95:5, t = 7.3 min (S), t=7.9 min (R).25 3-(4-Methoxyphenyl)cyclohexanone (9c):. Chiralcel OJ, 220 nm, 1 mL/min, hexane/2-propanol, 90:10, t = 11.8 min (R), t=14.3 min (S).25 3-(3-Methoxyphenyl)cyclohexanone (9d):. Chiralcel OD-H, 220 nm, 1 mL/min, hexane/2-propanol, 99:1, t=40.9 min (S), t=47.3 min (R).26 3-(4-Trifluoromethylphenyl)cyclohexanone (9e):. Chiralcel OD-H, 220 nm, 0.5 mL/min, hexane/2-propanol, 90:10, t=15.4 min (R), t=16.3 min (S).26 3-Phenylcyclopentanone (11a):. Chiralcel OB, 220 nm, 1.0 mL/min, hexane/2-propanol, 99.75:0.25, tR =44.5 min (S), 48.6 min (R).27 3-(4-Methylphenyl)cyclopentanone (11b):. Chiralcel OB, 220 nm, 1.0 mL/min, hexane/2-propanol, 99.5:0.5, tR = 25.9 min (maj.), 31.0 min (min.); [R]18 D = þ63.7 (c 1.3, CHCl3) for a sample having 67% ee, corresponding to an R absolute configuration.28 3-(4-Methoxyphenyl)cyclopentanone (11c):. Chiralcel OD-H, 220 nm, 1.0 mL/min, hexane/2-propanol, 95:5, tR = 11.5 min (maj.), 12.3 min (min.); [R]18 D = þ28.8 (c 1.1, CHCl3) for a sample having 40% ee, corresponding to an R absolute configuration.28 3-(3-Methoxyphenyl)cyclopentanone (11d):. Chiralcel OB, 220 nm, 1.0 mL/min, hexane/2-propanol, 95:5, tR = 35.3 min (maj.), 43.4 min (min.); [R]18 D = þ46.7 (c 0.42, CHCl3) for a sample having 83% ee, lit.29 [R]23 D = -70 (c 0.42 in CHCl3) (92% ee). 3-(4-Trifluoromethylphenyl)cyclopentanone (11e):. Chiralcel OJ, 220 nm, 1.0 mL/min, hexane/2-propanol, 98:2, tR = 17.9 min (min.), 20.3 min (maj.); [R]18 D = þ47.2 (c 0.98, CHCl3) for a sample having 77% ee, corresponding to an R absolute configuration.28 General Optimized Procedure for the Asymmetric Rh(I)-Catalyzed 1,2 þ 1,4 Addition of Arylboronic Acid to 2-Cyclohexen-1one. Under a nitrogen atmosphere 1,4-dioxane (1 mL) was added to [{RhCl(C2H4)2}2] (1.5 mol %) and the phosphite (6 mol %). The mixture was stirred for 30 min; then water (0.1 mL), 2 M KOH (0.5 mL), phenylboronic acid (2.3 equiv), and 2-cyclohexen-1-one (1 mmol) were added. The mixture was stirred at 25 °C, and the reaction was monitored by GC. After complete conversion, the mixture was poured into a 1 M NaHCO3 solution and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Chromatography on silica gel (hexane/EtOAc, 70:30) gave 1,3-diarylcyclohexanols. The diastereoisomeric composition was evaluated by 1H NMR spectroscopy; the enantiomeric excess, by HPLC analysis on chiral stationary phase. (1R,3R)-1,3-Diphenylcyclohexanol (12a):. Chiralcel OD-H, 220 nm, 1.0 mL/min, hexane/2-propanol, 95:5, T=25 °C, tR = 10.87 min (1S,3S), 19.54 min (1R,3R).13 1H NMR (300 MHz, CDCl3, δ): 1.45-1.62 (m, 1H); 1.80-2.15 (m, 7H); 3.11-3.23 (m, 1H); 7.18-7.39 (m, 8H); 7.54-7.60 (m, 2H). 13C NMR (24) Kasak, P.; Arionb, V. B.; Widhalma, M. Tetrahedron: Asymmetry 2006, 17, 3084. (25) Gini, F.; Hessen, B.; Feringa, B. L.; Minnaard, A. J. Chem. Commun. 2006, 710. (26) Chen, Q.; Kuriyama, M.; Soeta, T.; Hao, X.; Yamada, K.; Tomioka, K. Org. Lett. 2005, 7, 4439. (27) Feng, C.-H; Wang, Z.-Q.; Shao, C.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 4101. (28) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1999, 40, 6957. (29) Ye, Q.; Grunewald, G. L. J. Med. Chem. 1989, 32, 478.

4158


(75 MHz, CDCl3, δ): 22.5; 33.4; 38.5; 39.8; 46.8; 74.1; 124.6; 126.3; 127.1; 127.2; 128.5; 128.6; 146.9; 149.5. (1R,3R)-1,3-Di(4-methylphenyl)cyclohexanol (12b):. Chiralcel OD-H, 220 nm, 1.0 mL/min, hexane/2-propanol, 97:3, T = 20 °C, tR =8.85 min (1S,3S), 13.04 min (1R,3R). [R]18 D =þ22.8 (c 0.98, CHCl3) for a sample having 91% ee. 1H NMR (300 MHz, CDCl3, δ): 1.47-1.60 (m, 1H); 1.71 (s, 1H);1.80-2.10 (m, 7H); 2.36 (s, 3H); 2.38 (s, 3H); 3.16 (tt, 1H, J1 = 12 Hz, J2=3.6 Hz); 7.13-7.20 (m, 6H); 7.46 (d, 2H, J = 8.1 Hz). 13C NMR (75 MHz, CDCl3, δ): 21.2; 22.6; 33.7; 38.6; 39.4; 46.8; 73.9; 124.6; 127.1; 129.2; 129.3; 135.7; 136.6; 144.1; 146.8. Anal. Found: C 86.02, H 8.98. Calcd for C20H24O: C 85.67, H 8.63. (1R,3R)-1,3-Di(4-Methoxyphenyl)cyclohexanol (12c):. Chiralcel OD-H, 220 nm, 1.0 mL/min, hexane/2-propanol, 93:7, T = 25 °C, tR = 23.42 min (1S,3S), 25.58 min (1R,3R). [R]23 D = þ20.2 (c 0.46, CHCl3) for a sample having 82% ee. 1H NMR (300 MHz, CDCl3, δ): 1.38-1.52 (m, 1H); 1.61 (s, 1H);1.72-2.04 (m, 7H); 3.09 (tt, 1H, J1 = 12 Hz, J2 = 3.9 Hz); 3.78 (s, 3H); 3.80 (s, 3H); 6.88 (m, 4H); 7.18 (d, 2H, J=15 Hz); 7.45 (d, 2H, J = 15 Hz). 13C NMR (75 MHz, CDCl3, δ): 22.6; 33.7; 38.5; 39.0; 47.1; 55.4; 55.5; 73.7; 113.8; 114.0; 125.8; 128.0; 139.2; 141.9; 158.1; 158.6. Anal. Found: C 77.54, H 7.88. Calcd for C20H24O3: C 76.89, H 7.74; (1R,3R)-1,3-Di(3-Methoxyphenyl)cyclohexanol (12d):. Chiralpack AS, 220 nm, 1.0 mL/min, hexane/2-propanol, 95:5, T = 25 °C, tR = 13.94 min (1S,3S), 16.46 min (1R,3R). [R]23 D = þ19.7 (c 1.65, CHCl3) for a sample having 88% ee. 1H NMR (300 MHz, CDCl3, δ): 1.43-1.59 (m, 1H);1.80-2.10 (m, 8H); 3.14 (tt, 1H, J1 = 12 Hz, J2 = 4.2 Hz); 3.80 (s, 3H); 3.82 (s, 3H); 6.72-6.88 (m, 4H); 7.1 (m, 2H); 7.25 (m, 2H). 13C NMR (75 MHz, CDCl3, δ): 22.5; 33.4; 38.5; 39.9; 46.7; 55.4; 55.5; 74.1; 110.9; 111.4; 112.2; 113.2; 117.1; 119.6; 129.5; 129.6; 148.7; 151.4. Anal. Found: C 77.34, H 7.92. Calcd for C20H24O3: C 76.89, H 7.74. X-ray Crystallographic Study. X-ray crystallographic analysis of 1, empirical formula C163H212Cl2O28P4Rh2, fw 3019.93 g 3 mol-1, was performed using synchrotron radiation data, collected at ELETTRA (XRD-1 beamline), Trieste, Italy, λ=0.70001 A˚. A marCCD detector (marUSA Inc.) and focusing optics were employed for the measurements. A total of 360 diffraction images of the crystal of 1 were collected at T = 100 K with a 1° oscillation range. The degree of linear polarization was assumed to be 0.95, and the mosaic spread of the crystal was estimated to be 0.42°. Raw data were indexed, integrated, scaled, and reduced using the HKL package.30 The specimen used (0.40 0.32 0.21 mm3) (30) Otwinowski, Z.; Minor, W. In Methods in Enzymology, Volume 276: Macromolecular Crystallography, part A; Carter, C. W., Jr., Sweet, R. M., Eds.; Academic Press: New York, 1997; pp 307-326.

Facchetti et al. belongs to the orthorhombic system, space group P212121, a = 17.987(1) A˚, b = 27.320(2) A˚, c=31.536(2) A˚, V=15496.9(17) A˚3. The intensity data were merged to give 31 169 unique reflections, of which 30 311 had I g 2σ(I). The structure was solved by SHELXS-9731 and contained one solvent molecule (toluene) for each molecule of C156H204Cl2O28P4Rh2. The model containing all the non-hydrogen atoms was at first refined with isotropic thermal parameters. The presence of residual electron intensity near the atomic positions both in the solvent molecule and in some external moieties of the rhodium derivative suggested those parts were disordered. The moieties of the model where the electron density spread was more evident were refined as distributed in two limit positions, fixing to one the total occupancy for each atom. Hydrogen atoms were introduced in calculated positions and allowed to move following the convention of the “riding motion”. The final refinement cycles with anisotropic thermal parameters for all non-hydrogen atoms (1883 parameters) was performed by full-matrix least-squares methods. The final reliability factors, R1, calculated on the F values of the 30 311 observed reflections, was 0.0528 and wR2, calculated on the F2 of the 31 169 unique reflections, was 0.1506. The goodness of fit calculated on F2 was 1.021. All calculations were performed on a microcomputer using the SHELXL-97 and WINGX programs.17,32

Acknowledgment. This work was supported by University of Pisa and by MIUR-PRIN 2006-2007 (T.F. and F.M.). Dr. Elena Bonaccorsi, Universita di Pisa, is gratefully acknowledged for help in using the HKL software. Supporting Information Available: NMR spectra and HPLC analyses of new compounds (PDF file) and crystallographic data and experimental details for X-ray structure determination of 1 (CIF file) are available free of charge via the Internet at http://pubs.acs.org. These last were, moreover, deposited with the Cambridge Crystallographic Data Centre, dep. no. CCDC 728239. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (þ44)-1223-336-033; e-mail: [email protected]. ac.uk). (31) Sheldrick, G. M. SHELXS-97 and SHELXL-97, Programs for Solution and Refinement of Crystal Structures; University of G€ottingen: Germany, 1997. (32) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.

Tropos Ligands in Asymmetric Rhodium(I)-Catalyzed Addition of

Recommend Documents