Palladium-catalyzed oxidative allylation of bis[(pinacolato)boryl]methane: synthesis of homoallylic boronic esters

Abstract

A palladium-catalyzed oxidative allylation of bis[(pinacolato)boryl]methane to afford the corresponding homoallylic organoboronic esters with moderate to excellent yields is reported. This novel transformation provides an efficient strategy for the construction of homoallylic organoboronic esters in one step with a broad substrate scope. It is proposed that the palladium-catalyzed oxidative allylic C–H bond activation process may be involved in the catalytic cycle.

---

1,1-Bisborylalkanes have emerged as a valuable synthon in contemporary organic synthesis due to their easy access to highly functionalized, complicated organoboron molecules.^1–3 Shibata and co-workers reported the pioneering work on the allylation of bis[(pinacolato)boryl]methane with allyl halides under mild conditions, giving highly valuable homoallylic boronic esters.⁴ Hoveyda et al. reported the Cu-catalyzed enantioselective allylic substitution (EAS) of allylic electrophiles with 1,1-bisborylalkanes.⁵ Niu's group developed the iridium-catalyzed asymmetric allylation strategy to prepare β-substituted chiral homoallyl boronic esters.⁶ Despite the significant progress that has been achieved along this line, all of these elegant developments employed the unique and high reactivity of 1,1-bisborylalkanes toward electrophiles. However, the application of 1,1-bisborylalkanes as soft nucleophiles in the allylic C–H activation process has not been investigated, and is still highly desirable.

The transition metal-catalyzed oxidative functionalization of allylic C–H bonds has been recognized as a powerful method toward the construction of carbon–carbon or carbon–heteroatom bonds in a concise manner.^7,8 Most notably, palladium-catalyzed oxidative allylic C–H bond activation has been defined as an expedient and atom-economic strategy for the synthesis of complex molecules.⁹ As a class of high-activity electrophiles, the key allylpalladium intermediate could undergo cross-coupling reactions with various nucleophiles.^10–13 Recently, our group has realized the palladium-catalyzed direct coupling of terminal alkenes with water,^11c amines^12h and alcohols.^10a,11g On the basis of the previous endeavours, we envision that the allyl-Pd intermediate could be captured by the 1,1-bisborylalkanes to afford the organoboron compounds by introducing an α-boroalkyl group. Herein, we disclose a strategically distinct approach to synthesize homoallylic boronic esters through palladium-catalyzed oxidative allylic C–H functionalization of terminal olefins (Scheme 1).

Scheme 1 Strategies for the synthesis of homoallylic boronic esters.

Inspired by these advances and our previous work,^6,11g,12h we investigated the oxidative α-boroalkylation reaction of allylbenzene (1a) and bisborylmethane (2a). At first, the reaction was initially carried out with the combination of Pd(OAc)₂, AgOTf and ^tBuOK in 1,4-dioxane at 50 °C for 24 h under 1 atm of oxygen. Unfortunately, no desired product 3a was detected (Table 1, entry 1). Subsequently, a series of silver salts were screened, such as AgTFA, AgOAc and AgBF₄ (Table 1, entries 2–4), among which AgBF₄ was the optimal one and afforded the desired product 3a in trace yield (entry 4). Next, various bases were surveyed, and KH₂PO₄ was found to be the most effective base for this reaction (Table 1, entry 8). Further examination of oxidants revealed that NQ (1,4-naphthoquinone) increased the yield of 3a distinctly (Table 1, entry 15). After screening of different ligands (Table 1, entries 16–20), 1,2-bis(phenylsulfinyl)ethane was identified as the optimal ligand for the present transformation (Table 1, entry 20). Screening of various solvents indicated that 1,4-dioxane gave the best result for this reaction (see the ESI† for details). Thus, the standard conditions were obtained as Pd(OAc)₂ (10 mol%), AgBF₄ (20 mol%), KH₂PO₄ (2.0 equiv.), NQ (2 equiv.) and 1,2-bis(phenylsulfinyl)ethane (15 mol%) in 1,4-dioxane (2.0 mL) at 50 °C with stirring for 24 h.

Table 1 Screening for optimal reaction conditions^a

Entry	Additive	Ligand	Base	Oxidant	Yield^b (%)
a A mixture of 1a (0.25 mmol, 2.5 equiv.), 2a (0.1 mmol), base (0.2 mmol, 2 equiv.), Pd(OAc)2 (10 mol%), additive (20 mol%), ligand (15 mol%), oxidant (2 equiv.) and anhydrous 1,4-dioxane (2 mL) was sealed in a 25 mL Schlenk tube at 50 °C for 24 h. N.D. = not detected. L1: PPh3. L2: dppf. L3: 4,4′-bipyridine. L4: 1,2-bis(phenylsulphonyl)ethane. L5: 1,2-bis(phenylsulfinyl)ethane. b Isolated yield based on 2a. c BQ : DDQ = 2 : 1. d BQ : DDQ = 4 : 1.
1	AgOTf	—	^tBuOK	O2	N.D.
2	AgTFA	—	^tBuOK	O2	N.D.
3	AgOAc	—	^tBuOK	O2	N.D.
4	AgBF4	—	^tBuOK	O2	Trace
5	AgBF4	—	Cs2CO3	O2	Trace
6	AgBF4	—	CF3COONa	O2	12
7	AgBF4	—	KPF6	O2	23
8	AgBF4	—	KH2PO4	O2	30
9	AgBF4	—	KH2PO4	PhI(OAc)2	N.D.
10	AgBF4	—	KH2PO4	BQ	Trace
11	AgBF4	—	KH2PO4	DDQ	Trace
12	AgBF4	—	KH2PO4	DMBQ	Trace
13^c	AgBF4	—	KH2PO4	BQ/DDQ	35
14^d	AgBF4	—	KH2PO4	BQ/DDQ	55
15	AgBF4	—	KH2PO4	NQ	60
16	AgBF4	L1	KH2PO4	NQ	N.D.
17	AgBF4	L2	KH2PO4	NQ	N.D.
18	AgBF4	L3	KH2PO4	NQ	N.D.
19	AgBF4	L4	KH2PO4	NQ	43
20	AgBF 4	L5	KH 2 PO 4	NQ	83

---

The generality of the new protocol was next tested as the optimized conditions established. Several structurally diverse allylbenzenes were initially explored, and the representative results are summarized in Table 2. Generally, both electron-donating (Me, Et, OMe) and electron-withdrawing groups (F, Cl, CF₃) were compatible with this method (3a–3k). In addition, when (2-methylallyl)benzene (1l) was treated with 2a under the optimized conditions, two regioisomeric products 3l and 3l′ were obtained (dr = 1.2 : 1, determined using the NMR spectrum). Disubstituted allylbenzenes could also undergo this transformation, furnishing the corresponding boronic ester derivatives in good yields (3m–3q). Notably, functionalized allylbenzene derivatives, such as 1-allyl-2,3,4,5,6-pentafluorobenzene (3r), were transformed to the desired products with excellent yields. Only a trace amount of the desired product was detected by GC-MS when but-3-en-1-ylbenzene (1u) was surveyed.

Table 2 Substrate scope of various allylbenzenes^a,b

a Reaction conditions: 1 (0.25 mmol, 2.5 equiv.), 2a (0.1 mmol), Pd(OAc)₂ (10 mol%), AgBF₄ (20 mol%), L5 (15 mol%), KH₂PO₄ (0.2 mmol, 2 equiv.), NQ (0.2 mmol, 2 equiv.) and anhydrous 1,4-dioxane (2 mL) were sealed in a 25 mL Schlenk tube at 50 °C for 24 h. b Isolated yields based on 2a.

---

In view of the further applications of this transformation, the substrate scope was expanded to different substituted α-methylstyrenes (Table 3). α-Methylstyrene was first surveyed, which delivered a good yield of product 5a under our optimized conditions. Moreover, α-methylstyrenes bearing different functional groups such as F, Cl and Br at the para- or ortho-positions of the phenyl ring could also react smoothly to give the corresponding products 5c–5e in good yields ranging from 62% to 83%. Pleasingly, the reactions of 1-(prop-1-en-2-yl)naphthalene and 2-(prop-1-en-2-yl)naphthalene proceeded efficiently to give the corresponding products 5g and 5h in 82% and 78% yields, respectively.

Table 3 Substrate scope of α-methylstyrenes^a,b

a Reaction conditions: 4 (0.25 mmol, 2.5 equiv.), 2a (0.1 mmol), Pd(OAc)₂ (10 mol%), AgBF₄ (20 mol%), L5 (15 mol%), KH₂PO₄ (0.2 mmol, 2 equiv.), NQ (0.2 mmol, 2 equiv.) and anhydrous 1,4-dioxane (2 mL) were sealed in a 25 mL Schlenk tube at 50 °C for 24 h. b Isolated yields based on 2a.

---

trans-β-Methylstyrene derivatives could be recognized as a precursor of allylic electrophiles. Thus, 6a and 6b were applied in this process and converted into the organoboronic esters in moderate yields (Scheme 2).

Scheme 2 Substrate scope of trans-β-methylstyrenes. Reaction conditions: 6 (0.25 mmol, 2.5 equiv.), 2a (0.1 mmol), Pd(OAc)₂ (10 mol%), AgBF₄ (20 mol%), L5 (15 mol%), KH₂PO₄ (0.2 mmol, 2 equiv.), NQ (0.2 mmol, 2 equiv.) and 1,4-dioxane (2 mL) were sealed in a 25 mL Schlenk tube at 50 °C for 24 h. Isolated yields based on 2a.

To demonstrate the synthetic utility of this protocol further, the homoallylic boronic esters were transferred into other desired synthons using the established chemistry (Scheme 3). For example, compound 3a could be oxidized by NaBO₃·4H₂O to homoallylic alcohol 8, which has been engaged in a wide range of chemical reactions to synthesize structurally complex products. Moreover, 3a could undergo amination to form homoallylic amine 9 in 78% yield.

Scheme 3 Elaboration of homoallyl boronates. Conditions: (a) 3a (0.2 mmol), NaBO₃·4H₂O (6.0 equiv.) in THF/H₂O (2 mL/2 mL) at room temperature for 12 h. (b) 3a (0.2 mmol), N-ethylaniline (0.1 mL), Cu(OAc)₂ (10 mol%), and Ag₂CO₃ (2.0 equiv.) in toluene at 100 °C with stirring for 20 h.

In light of the previous literature, a plausible mechanism is outlined in Scheme 4. Initially, the catalytic cycle would begin with the coordination of palladium with olefins to generate the intermediate I. Next, the corresponding π-allylpalladium species II is formed by the electrophilic allylic C–H cleavage in the presence of ligand L5.^10b,11a,14 With the addition of silver salt, 1,1-bis[(pinacolato)boryl]methane undergoes a deborylative transmetallation process to form an alkyl silver species III.^6,15 Then, the π-allylpalladium intermediate II reacts with intermediate III by transmetallation to give a Pd-(α-boroalkyl) complex IV. The product homoallylic organoboronic ester would be obtained through the reductive elimination process. Finally, the reactive Pd(II) species is regenerated by the oxidation of NQ¹⁶ (see the ESI† for details).

Scheme 4 Possible reaction mechanism.

In summary, a practical Pd-catalyzed oxidative α-boroalkylation reaction of simple olefins with 1,1-bis[(pinacolato)boryl]methane is presented. This novel procedure provides an efficient and attractive protocol for the construction of functionalized homoallylic boronic esters in good to excellent yields from readily available olefins with a broad substrate scope and excellent functional group compatibility. Remarkably, an efficient construction of the Csp³–Csp³ bond has been realized via the Pd-catalyzed oxidative functionalization of the allylic C–H bond.

We are grateful to the National Key Research and Development Program of China (2016YFA0602900), the National Natural Science Foundation of China (21672072, 21420102003 and 21502055), and the Fundamental Research Funds for the Central Universities (2015ZY001 and 2017ZD062).

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. For pioneering work in this area, see: (a) K. Endo, T. Ohkubo, M. Hirokami and T. Shibata, J. Am. Chem. Soc., 2010, 132, 11033; (b) K. Endo, T. Ohkubo and T. Shibata, Org. Lett., 2011, 13, 3368; (c) J. C. H. Lee, R. McDonald and D. G. Hall, Nat. Chem., 2011, 3, 894; (d) K. Endo, T. Ohkubo, T. Ishioka and T. J. Shibata, Org. Chem., 2012, 77, 4826; (e) X. Feng, H. Jeon and J. Yun, Angew. Chem., Int. Ed., 2013, 52, 3989; (f) M. V. Joannou, B. S. Moyer, M. J. Goldfogel and S. J. Meek, Angew. Chem., Int. Ed., 2015, 54, 14141; (g) J. Kim, S. Park, J. Park and S. H. Cho, Angew. Chem., Int. Ed., 2016, 55, 1498.
2. (a) K. Hong, X. Liu and J. P. Morken, J. Am. Chem. Soc., 2014, 136, 10581; (b) S. Xu, X. Shangguan, H. Li, Y. Zhang and J. Wang, J. Org. Chem., 2015, 80, 7779; (c) Z.-Q. Zhang, C.-T. Yang, L.-J. Liang, B. Xiao, X. Lu, J.-H. Liu, Y.-Y. Sun, T. B. Marder and Y. Fu, Org. Lett., 2014, 16, 6342; (d) Z.-Q. Zhang, B. Zhang, X. Lu, J.-H. Liu, X.-Y. Lu, B. Xiao and Y. Fu, Org. Lett., 2016, 18, 952; (e) J. Park, Y. Lee, J. Kim and S. H. Cho, Org. Lett., 2016, 18, 1210; (f) A. Ebrahim-Alkhalil, Z.-Q. Zhang, T.-J. Gong, W. Su, X.-Y. Lu, B. Xiao and Y. Fu, Chem. Commun., 2016, 52, 4891.
3. (a) C. Sun, B. Potter and J. P. Morken, J. Am. Chem. Soc., 2014, 136, 6534; (b) B. Potter, A. A. Szymaniak, E. K. Edelstein and J. P. Morken, J. Am. Chem. Soc., 2014, 136, 17918.
4. K. Endo, T. Ohkubo, T. Ishioka and T. J. Shibata, Org. Chem., 2012, 77, 4826.
5. Y. Shi and A. H. Hoveyda, Angew. Chem., Int. Ed., 2016, 55, 3455.
6. M. Zhan, R.-Z. Li, Z.-D. Mou, C.-G. Cao, J. Liu, Y.-W. Chen and D. Niu, ACS Catal., 2016, 6, 3381.
7. For selected reviews, see: (a) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921; (b) J. Thomas and F. Peter, Chem. – Eur. J., 2009, 15, 9632; (c) C. J. Engelin and P. Fristrup, Molecules, 2011, 16, 951; (d) H. Li, B.-J. Li and Z.-J. Shi, Catal. Sci. Technol., 2011, 1, 191; (e) F. Liron, J. Oble, M. M. Lorion and G. Poli, Eur. J. Org. Chem., 2014, 5863.
8. For selected examples, see: (a) H. M. L. Davies, P. Ren and Q. H. Jin, Org. Lett., 2001, 3, 3587; (b) B. X. Yu, T. Jiang, J. P. Li, Y. P. Su, X. F. Pan and X. G. She, Org. Lett., 2009, 11, 3442; (c) D. Huang, H. Wang, H. Guan, H. Huang and Y. Shi, Org. Lett., 2009, 13, 1548; (d) A. T. Parsons and S. L. Buchwald, Angew. Chem., Int. Ed., 2011, 50, 9120; (e) M. E. Harvey, D. G. Musaev and J. DuBois, J. Am. Chem. Soc., 2011, 133, 17207; (f) M. Sekine, L. Ilies and E. Nakamura, Org. Lett., 2013, 15, 714; (g) Y. Shibata, E. Kudo, H. Sugiyama, H. Uekusa and K. Tanaka, Organometallics, 2016, 35, 1547.
9. For selected examples, see: (a) B. M. Trost, S. Mahapatra and M. Hansen, Angew. Chem., Int. Ed., 2015, 54, 6032; (b) G. Hu, J. Xu and P. Li, Org. Lett., 2014, 16, 6036; (c) Q. Yang, Y. Zhou, J. Chen, X. He, J. Xu, F. Kwong and B. Fan, Eur. J. Org. Chem., 2015, 5330; (d) H.-P. Deng, L. Erikssonb and K. J. Szabó, Chem. Commun., 2014, 50, 9207; (e) B. M. Trost and M. Osipov, Angew. Chem., Int. Ed., 2013, 52, 9176; (f) K. Liu, M. T. Hovey and K. A. Scheidt, Chem. Sci., 2014, 5, 4026.
10. For some examples of Pd-catalyzed allylic C–H alkylation: (a) H. Chen, C. Cai, X. Liu, X. Li and H. Jiang, Chem. Commun., 2011, 47, 12224; (b) L. Li, Q.-Y. Chen and Y. Guo, Chem. Commun., 2013, 49, 8764; (c) H. Jiang, W. Yang, H. Chen, J. Li, W. Wu and H. Jiang, Chem. Commun., 2014, 50, 7202; (d) S. Tang, X. Wu, W. Liao, K. Liu, C. Liu, S. Luo and A. Lei, Org. Lett., 2014, 16, 3584; (e) Y. Nishikawa, S. Kimura, Y. Kato, N. Yamazaki and O. Hara, Org. Lett., 2015, 17, 888; (f) C. C. Pattillo, I. I. Strambeanu, P. Calleja, N. A. Vermeulen, T. Mizuno and M. C. White, J. Am. Chem. Soc., 2016, 138, 1265; (g) H.-C. Lin, P.-S. Wang, Z.-L. Tao, Y.-G. Chen, Z.-Y. Han and L.-Z. Gong, J. Am. Chem. Soc., 2016, 138, 14354; (h) L.-L. Li, Z.-L. Tao, Z.-Y. Han and L.-Z. Gong, Org. Lett., 2017, 19, 102.
11. For some examples of Pd-catalyzed allylic C–H oxygenation: (a) K. J. Fraunhoffer, N. Prabagaran, L. E. Sirois and M. C. White, J. Am. Chem. Soc., 2006, 128, 9032; (b) A. N. Campbell, P. B. White, L. A. Guzei and S. S. Stahl, J. Am. Chem. Soc., 2010, 132, 15116; (c) H. Chen, H. Jiang, C. Cai, J. Dong and W. Fu, Org. Lett., 2011, 13, 992; (d) C. Le, K. Kunchithapatham, W. H. Henderson, C. T. Check and J. P. Stambuli, Chem. – Eur. J., 2013, 19, 11153; (e) R. Tomita, K. Mantani, A. Hamasaki, T. Ishida and M. Tokunaga, Chem. – Eur. J., 2014, 20, 9914; (f) S. E. Ammann, G. T. Rice and M. C. White, J. Am. Chem. Soc., 2014, 136, 10834; (g) W. Yang, H. Chen, J. Li, C. Li, W. Wu and H. Jiang, Chem. Commun., 2015, 51, 9575; (h) P.-S. Wang, P. Liu, Y.-J. Zhai, H.-C. Lin, Z.-Y. Han and L.-Z. Gong, J. Am. Chem. Soc., 2015, 137, 12732; (i) S. E. Ammann, W. Liu and M. C. White, Angew. Chem., Int. Ed., 2016, 55, 9571.
12. For some examples of Pd-catalyzed allylic C–H amination: (a) F. Nahra, F. Liron, G. Prestat, C. Mealli, A. Messaoudi and G. Poli, Chem. – Eur. J., 2009, 15, 11078; (b) G. Yin, Y. Wu and G. Liu, J. Am. Chem. Soc., 2010, 132, 11978; (c) Y. Shimizu, Y. Obora and Y. Ishii, Org. Lett., 2010, 12, 1372; (d) C. Jiang, D. J. Covell, A. F. Stepan, M. S. Plummer and M. C. White, Org. Lett., 2012, 14, 1386; (e) H. Chen, W. Yang, W. Wu and H. Jiang, Org. Biomol. Chem., 2014, 12, 3340; (f) Y. Nishikawa, S. Kimura, Y. Kato, N. Yamazaki and O. Hara, Org. Lett., 2015, 17, 888; (g) C. C. Pattillo, I. I. Strambeanu, P. Calleja, N. A. Vermeulen, T. Mizuno and M. C. White, J. Am. Chem. Soc., 2016, 138, 1265; (h) C. Li, J. Li, Y. An, J. Peng, W. Wu and H. Jiang, J. Org. Chem., 2016, 81, 12189.
13. For some examples of Pd-catalyzed allylic C–H silylation: J. M. Larsson, T. S. N. Zhao and K. J. Szabó, Org. Lett., 2011, 13, 1888.
14. For selected examples, see: (a) C. Engelin, T. Jensen, S. Rodriguez and P. Fristrup, ACS Catal., 2013, 3, 294; (b) F. J. S. Duarte, G. Poli and M. J. Calhorda, ACS Catal., 2016, 6, 1772.
15. K. Endo, F. Kurosawa and Y. Ukaji, Chem. Lett., 2013, 42, 1363.
16. G. Yin, Y. Wu and G. Liu, J. Am. Chem. Soc., 2010, 132, 11978.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental section, characterization of all compounds, copies of ¹H and ¹³C NMR spectra for selected compounds. See DOI: 10.1039/c7cc07788b

---