Asymmetric boron conjugate addition to α,β-unsaturated carbonyl compounds catalyzed by CuOTf/Josiphos under non-alkaline conditions

Abstract

The asymmetric boron conjugate addition onto α,β-unsaturated ketones and esters has been developed by using the CuOTf/Josiphos complex as the catalyst under non-alkaline conditions. It was found that the addition of MeOH into the reaction system is crucial to the catalytic reactivity. Good to excellent enantioselectivity (up to 96% ee) and yields (up to 98%) have been achieved for 15 examples.

---

In the past few decades, the synthesis of α-chiral boron compounds has attracted much attention in chemical synthesis since they serve as precursors to many chiral products containing C–O, C–N and C–C bonds;¹ they are also important bioactive building blocks for drug design and synthesis.² Among the efforts to obtain α-chiral boron compounds, the copper catalyzed asymmetric boron conjugate addition to α,β-unsaturated carbonyl compounds has undoubtedly achieved great success.³ However, to the best of our knowledge, all the existing asymmetric catalytic systems with copper salts require the use of strong inorganic bases, such as NaO^tBu, Cs₂CO₃, etc., as additives, or copper precursors (e.g. Cu(OH)₂,^4a CuCO₃,^4betc.^4c,d) should be used with water as the solvent. The strong base additives were believed to play important roles in achieving high catalytic reactivity,⁵ and they can also act as catalysts in the boron additions at high temperatures.⁶ It is necessary to develop a catalytic system in the absence of base additives to avoid potential problems like elimination or racemization in complex compounds.^3q,7

Several examples of non-alkaline catalytic systems for the boron conjugate addition reaction have been reported, which include the use of platinum catalysts,⁸ CuOTf/monophosphine catalysts⁹ and organo catalysts (phosphines,^10a NHC,^10betc.). Meanwhile, a mixed sp²–sp³ hybridized diboron reagent¹¹ can enable this reaction to be performed under non-alkaline conditions. However, there is no successful enantioselective boron addition example based on these catalytic systems reported so far. Herein, we would like to report a new Cu(I)-catalyzed asymmetric boron conjugate addition reaction under non-alkaline conditions.

We initiated this work with 5 mol% CuOTf and 6 mol% monodentate ligands as it was described that no desired product was formed with the bidentate phosphine ligand at room temperature in Hosomi's work.⁹ The commercially available bis(pinacolato)diboron (B₂Pin₂) and chalcone were chosen as the boron reagent and the standard substrate, respectively. We first employed the C2 symmetric chiral NHC ligand (L1).¹² However, only poor or moderate enantioselectivity was obtained (Table 1, entries 1–3). When methanol was added as an additive, the enantioselectivity and reactivity were significantly enhanced (Table 1, entry 2).¹³ The reactivity can be further increased albeit it caused slight harm to the enantioselectivity when methanol was used as the solvent (entry 3). The spiro monophosphoramidite ligand [(S,R,R)-L2] was then applied for this boron addition reaction. The enantioselectivity was close to the result obtained by the NHC ligand L1 while the reactivity was much higher (entry 4). When its diastereoisomer, (R,R,R)-L3, was applied, we observed the inversed configuration in the product which means that the chirality on the spiro backbone is more important than the chirality on the amine part of the ligand (entry 5). We also increased the loading of the ligand to 12 mol% for comparison and almost the same result was obtained (entry 6) which could indicate that only one molecule of phosphoramidite was coordinated to the Cu(I) catalyst species.

Table 1 Asymmetric catalytic boron conjugate addition to chalcone under various conditions^a

Entry	Ligand	Solvent	Additive (equiv.)	Time (h)	Conv.^b (%)	ee^c (%)
a Reactions were run under argon protection and mostly repeated twice. Reaction conditions: 0.1 mmol scale, [substrate] = 0.04 M, 2.5 mol% (CuOTf)2. Benzene, 6 mol% ligand, solvent volume = 2.5 mL, room temperature (23–26 °C). b Determined by crude ^1H NMR analysis. c Determined by chiral HPLC analysis. d The (NHC)CuOTf catalyst was prepared by anion exchange with (NHC)CuCl and AgOTf. e 12 mol% ligand.
1^d	L1	Toluene	—	16	7	8(S)
2^d	L1	Toluene	MeOH (1)	16	17	47
3^d	L1	MeOH	—	16	46	41
4	L2	Toluene	MeOH (1.5)	30	97	42
5	L3	Toluene	MeOH (1.5)	46	35	−50(R)
6^e	L2	Toluene	MeOH (1.5)	30	95	43
7	L4	Toluene	MeOH (1.5)	30	2	ND
8	L5	Toluene	MeOH (1.5)	30	74	−92
9	L13	Toluene	MeOH (1.5)	30	100	−45
10	L5	Toluene	—	30	0	—
11	L5	Toluene	MeOH (12)	30	80	−93
12	L5	Toluene	MeOH (25)	18	93	−91
13	L5	MeOH	—	30	100	−33
14	L5	DCM	MeOH (25)	30	0	—
15	L5	THF	MeOH (25)	30	62	−6
16	L5	CH3CN	MeOH (25)	30	5	ND
17	L5	DMF	MeOH (25)	30	94	−51
18	L5	Toluene	EtOH (25)	46	64	−92
19	L5	Toluene	^iPrOH (25)	46	24	−93
20	L5	Toluene	^tBuOH (25)	46	<2	ND
21	L5	Toluene	AcOH (25)	46	14	0
22	L5	Toluene	PhOH (2.5)	46	23	−4
23	L6	Toluene	MeOH (25)	46	44	−70
24	L7	Toluene	MeOH (25)	20	95	−13
25	L8	Toluene	MeOH (25)	20	90	7
26	L9	Toluene	MeOH (25)	46	<2	ND
27	L10	Toluene	MeOH (25)	20	100	−4
28	L11	Toluene	MeOH (25)	20	94	−13
29	L12	Toluene	MeOH (25)	20	51	−39

---

As the enantioselectivity has been proven to be low to moderate when using a monodentate ligand, we next attempted to utilize bidentate diphosphine ligands (L4 and L5) and aminophos ligand (L12). Although the bidentate ligands were proved to show no catalytic activity at all in the boron addition reaction (Table 1, entry 10) in Hosomi's work, the reactivity was dramatically changed by adding MeOH as an additive into the reaction system, and the enantioselectivity reached 92% ee by the use of Josiphos (L5) (entry 8). Nevertheless, another diphosphine ligand, Binap, showed very poor catalytic activity even by addition of MeOH (entry 7). The aminophos ligand (L12) achieved a higher reactivity though only 43% ee was obtained (entry 9). Then we continued catalytic condition optimization by using Josiphos L5. Increasing the loading of methanol could enhance the reactivity further while a slight decrease of enantioselectivity was also observed with 25 equiv. of MeOH (entry 12). If methanol was used as the solvent, the enantioselectivity dropped to 33% (entry 13). We screened several other common solvents, but only DMF could give moderate enantioselectivity and good reactivity (entries 14–17). We then compared other protonic additives in toluene. When various alcohols were used (Table 1), the reactivity decreased while the bulk of the alcohol increased. But the enantioselectivity can be maintained well with the two alcohol additives (entries 18–20). The acidic additives, such as acetic acid and phenol, would lead to dramatically decreases of the reactivity and enantioselectivity (entries 21 and 22). Other Josiphos type ligands were also checked for this reaction with results shown in Table 1. However, changing the substituent groups on the P atoms cannot lead to higher enantioselectivity (entries 23–29).

The substrate scope was examined by using CuOTf (5 mol%) and Josiphos ligand L5 (6 mol%) in toluene and MeOH (25.0 eq.) as the additive for 48 h (Table 2). The reactions were very clean with no side product observed by crude ¹H-NMR analysis. For the chalcone substrates, the substituents on the phenyl rings had a small influence on the enantioselectivity (entries 2–11), but the substituents on the ortho position of the phenyl ring which is adjacent to the newly formed chiral center led to a significant decrease in the reactivity (entries 2 and 11). It should be noted that the NO₂ substituent can tolerate the catalytic conditions and give the desired product with 95% yield and 95% ee (entry 3). As far as we know, it is the first example of using a substrate with the NO₂ group in such a catalytic boron addition reaction. When the phenyl group on the C=C bond in chalcone was replaced by the methyl group, the highest ee value (96%) was obtained (entry 13), but its isomer, (E)-4-phenylbut-3-en-2-one, only gave 72% ee and lower conversion (entry 12). The α,β-unsaturated esters were also analysed in this reaction. Good enantioselectivity was obtained for both of the tested ester substrates (entries 14 and 15). As we have developed a non-alkaline catalytic system, cinnamic acid was also studied as the substrate. Unfortunately, no reaction was observed in this case.

Table 2 Asymmetric boron conjugate addition to α,β-unsaturated compounds^a

Entry	R^1	R^2	Prod.	Yield^b (%)	ee^c (%)
a Reaction conditions are the same as those listed in Table 1, entry 12. b Yields of the isolated products. c % ee was determined by chiral HPLC analysis; the absolute configuration was determined by comparison of optical rotation with literature data.
1	C6H5	C6H5	2a	90	91(R)
2	2-ClC6H4	C6H5	2b	24	93(R)
3	3-NO2C6H4	C6H5	2c	95	95(+)
4	4-MeOC6H4	C6H5	2d	89	93(R)
5	4-FC6H4	C6H5	2e	96	95(−)
6	4-ClC6H4	C6H5	2f	98	95(R)
7	C6H5	4-MeOC6H4	2g	98	90(R)
8	C6H5	4-FC6H4	2h	96	95(R)
9	C6H5	4-ClC6H4	2i	86	92(−)
10	4-FC6H4	4-FC6H4	2j	95	94(−)
11	2,4-(MeO)2C6H3	4-FC6H4	2k	50	82(−)
12	C6H5	Me	2l	76	72(R)
13	Me	C6H5	2m	95	96(S)
14	C6H5	OBn	2n	62	84(R)
15	Me	OBn	2o	96	88(S)
16			2p	NR	—

---

The catalytic mechanism and the role of MeOH in this reaction are proposed in Scheme 1 based on the previous catalytic boron conjugate addition work involving copper¹⁴ and the coordination chemistry between Cu(I)X and Josiphos in various solvents reported by Feringa and co-workers.¹⁵ The Cu(I)X and Josiphos form different complexes in different solvents, which could be a mononuclear or a binuclear complex. Furthermore, the rapid equilibration to form either a mononuclear or a binuclear complex depending on the solvent employed was also observed by Feringa's group and indeed a mononuclear complex would form in methanol. We assume that CuOTf and Josiphos firstly formed a binuclear complex in toluene, in which the copper has already four coordination numbers and cannot react with B₂Pin₂ as the copper was saturated with 18e. By adding MeOH, a mononuclear copper complex is formed and reacted with B₂Pin₂ to produce (L*)Cu–BPin species (TS 1). The (L*)Cu–BPin species has been known as an efficient catalyst in the boron addition reaction, and reacts with chalcone followed by protonation to release the chiral product and (L*)CuX species. The species of (L*)CuX then reacts with B₂Pin₂ to produce (L*)Cu–BPin species (TS 1) again and finally to complete the catalytic cycle.

Scheme 1 Proposed mechanism for the non-alkaline catalytic system.

In conclusion, we have developed a novel non-alkaline catalytic system for asymmetric boron conjugate addition reaction with α,β-unsaturated ketones and esters, which involved the Cu(I) triflate and Josiphos ligand as the catalyst and chiral ligand, respectively. Methanol was proved to be a crucial additive for high reactivity while there would be no reaction in the absence of the additive in toluene. Further studies on the mechanism and applications of the non-alkaline catalytic system to other base sensitive chiral products are ongoing in our laboratory.

Acknowledgements

We gratefully acknowledge the financial support from the Robert A. Welch Foundation (D-1361), NSFC (no. 21332005) and the Jiangsu Innovation Programs (P. R. China). We also thank NSF Grant CHE-1048553 and the CRIF program for supporting our NMR facility.

Notes and references

1. (a) T. Awano, T. Ohmura and M. Suginome, J. Am. Chem. Soc., 2011, 133, 20738; (b) S. L. Poe and J. P. Morken, Angew. Chem., Int. Ed., 2011, 50, 4189; (c) M. Tortosa, Angew. Chem., Int. Ed., 2011, 50, 3950; (d) R. P. Sonawane, V. Jheengut, C. Rabalakos, R. Larouche-Gauthier, H. K. Scott and V. K. Aggarwal, Angew. Chem., Int. Ed., 2011, 50, 3760; (e) J. K. Park, H. H. Lackey, B. A. Ondrusek and D. T. McQuade, J. Am. Chem. Soc., 2011, 133, 2410; (f) S. Nave, R. P. Sonawane, T. G. Elford and V. K. Aggarwal, J. Am. Chem. Soc., 2010, 132, 17096; (g) T. Ohmura, T. Awano and M. Suginome, J. Am. Chem. Soc., 2010, 132, 13191; (h) J. Chang, H. Lee and D. G. Hall, J. Am. Chem. Soc., 2010, 132, 5544; (i) D. Imao, B. W. Glasspoole, V. S. Laberge and C. M. Crudden, J. Am. Chem. Soc., 2009, 131, 5024; (j) E. Hupe, P. Marek and I. Knochel, Org. Lett., 2002, 4, 2861; (k) Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207.
2. (a) J.-B. Xie, J. Luo, T. R. Winn, D. B. Cordes and G. Li, Beilstein J. Org. Chem., 2014, 10, 746; (b) K. Hong and J. P. Morken, J. Am. Chem. Soc., 2013, 135, 9252; (c) M. A. Beenen, C. An and J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 6910.
3. (a) L. Zhao, Y. Ma, F. He, W. Duan, J. Chen and C. Song, J. Org. Chem., 2013, 78, 1677; (b) T. Iwai, Y. Akiyama and M. Sawamura, Tetrahedron: Asymmetry, 2013, 24, 729; (c) J.-L. Zhang, L.-A. Chen, R.-B. Xu, C.-F. Wang, Y.-P. Ruan, A.-E. Wang and P.-Q. Huang, Tetrahedron: Asymmetry, 2013, 24, 492; (d) C. Sole, A. Bonet, A. H. M. de Vries, J. G. de Vries, L. Lefort, H. Gulyás and E. Fernández, Organometallics, 2012, 31, 7855; (e) C. Solé, A. Tatla, J. A. Mata, A. Whiting, H. Gulyás and E. Fernández, Chem. – Eur. J., 2011, 17, 14248; (f) I. Ibrahem, P. Breistein and A. Córdova, Angew. Chem., Int. Ed., 2011, 50, 12036; (g) A. Bonet, C. Sole, H. Gulyás and E. Fernández, Chem. – Asian J., 2011, 6, 1011; (h) C. Solé, A. Whiting, H. Gulyás and E. Fernández, Adv. Synth. Catal., 2011, 353, 376; (i) B. Hong, Y. Ma, L. Zhao, W. Duan, F. He and C. Song, Tetrahedron: Asymmetry, 2011, 22, 1055; (j) X. Feng and J. Yun, Chem. – Eur. J., 2010, 16, 13609; (k) J. M. O'Brien, K.-S. Lee and A. H. Hoveyda, J. Am. Chem. Soc., 2010, 132, 10630; (l) J. K. Park, H. H. Lackey, M. D. Rexford, K. Kovnir, M. Shatruk and D. T. McQuade, Org. Lett., 2010, 12, 5008; (m) W. J. Fleming, H. Müller-Bunz, V. Lillo, E. Fernández and P. J. Guiry, Org. Biomol. Chem., 2009, 7, 2520; (n) H.-S. Sim, X. Feng and J. Yun, Chem. – Eur. J., 2009, 15, 1939; (o) C. Solé and E. Fernández, Chem. – Asian J., 2009, 4, 1790; (p) V. Lillo, A. Prieto, A. Bonet, M. M. Díaz-Requejo, J. Ramírez, P. J. Pérez and E. Fernández, Organometallics, 2009, 28, 659; (q) J.-E. Lee and J. Yun, Angew. Chem., Int. Ed., 2008, 47, 145.
4. (a) S. Kobayashi, P. Xu, T. Endo, M. Ueno and T. Kitanosono, Angew. Chem., Int. Ed., 2012, 51, 12763; (b) G. Stavbera and Z. Časar, Appl. Organomet. Chem., 2013, 27, 159; (c) T. Kitanosono, P. Xu and S. Kobayashi, Chem. – Asian J., 2014, 9, 179; (d) T. Kitanosono and S. Kobayashi, Asian J. Org. Chem., 2013, 2, 961.
5. J. A. Schiffner, K. Müther and M. Oestreich, Angew. Chem., Int. Ed., 2010, 49, 1194.
6. A. Bonet, C. Pubill-Ulldemolins, C. Bo, H. Gulyás and E. Fernández, Angew. Chem., Int. Ed., 2011, 50, 7158.
7. Z.-T. He, Y.-S. Zhao, P. Tian, C.-C. Wang, H.-Q. Dong and G.-Q. Lin, Org. Lett., 2014, 16, 1426.
8. Y. G. Lawson, M. J. G. Lesley, T. B. Marder, N. C. Norman and C. R. Rice, Chem. Commun., 1997, 2051.
9. H. Ito, H. Yamanaka, J.-I. Tateiwab and A. Hosomi, Tetrahedron Lett., 2000, 41, 6821.
10. (a) C. Pubill-Ulldemolins, A. Bonet, H. Gulyás, C. Bo and E. Fernández, Org. Biomol. Chem., 2012, 10, 9677; (b) K.-S. Lee, A. R. Zhugralin and A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131, 7253. Hoveyda and co-workers also reported highly stereoselective boron conjugate addition with the chiral NHC catalyst but with an excess of base: (c) H. Wu, S. Radomkit, J. M. O'Brien and A. H. Hoveyda, J. Am. Chem. Soc., 2012, 134, 8277.
11. M. Gao, S. B. Thorpe and W. L. Santos, Org. Lett., 2009, 11, 3478.
12. For more details about the NHC ligand L1, see: L. Wu, L. Falivene, E. Drinkel, S. Grant, A. Linden, L. Cavallo and R. Dorta, Angew. Chem., Int. Ed., 2012, 51, 2870.
13. For the alcohol acceleration effect, see: S. Mun, J.-E. Lee and J. Yun, Org. Lett., 2006, 8, 4887.
14. (a) L. Dang and Z. Lin, Organometallics, 2008, 27, 4443; (b) D. S. Laitar, E. Y. Tsui and J. P. Sadighi, J. Am. Chem. Soc., 2006, 128, 11036; (c) K. Takahashi, T. Ishiyama and N. Miyaura, Chem. Lett., 2000, 982.
15. (a) S. R. Harutyunyan, F. López, W. R. Browne, A. Correa, D. Peña, R. Badorrey, A. Meetsma, A. J. Minnaard and B. L. Feringa, J. Am. Chem. Soc., 2006, 128, 9103; (b) F. López, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard and B. L. Feringa, Angew. Chem., Int. Ed., 2005, 44, 2752.

---

Footnote

† Electronic supplementary information (ESI) available: ¹H-, ¹³C-NMR data and spectra, HRMS for the new compounds; ¹H NMR data, HPLC spectra and optical rotation for all products; experimental procedures and details. See DOI: 10.1039/c4qo00271g

---