Site-Selective and Stereoselective trans-Hydroboration of 1,3-Enynes Catalyzed by 1,4-Azaborine-Based Phosphine–Pd Complex

Abstract

A concise synthesis of monobenzofused 1,4-azaborine phosphine ligands (Senphos) is described. These Senphos ligands uniquely support Pd-catalyzed trans-selective hydroboration of terminal and internal 1,3-enynes to furnish corresponding dienylboronates in high efficiency and diastereoselectivity. X-ray structural analysis of the Senphos–Pd(0) complex reveals a κ²-P-η²-BC coordination mode, and this isolated complex has been shown to serve as a competent catalyst for the trans-hydroboration reaction. This work demonstrates that the expanded chemical space provided by the BN/CC isosterism approach translates into the functional space in the context of stereoselective catalytic transformations.

BN/CC isosterism, i.e., the replacement of a CC bond unit with the isoelectronic and isosteric BN bond unit, has recently emerged as a viable strategy to increase the structural diversity of organic molecules.¹ While early applications have appeared in the area of materials science² and biomedical research,³ efforts taking advantage of expanded chemical space provided by BN/CC isosterism in ligand-supported catalysis for organic synthesis have lagged behind.^4–6 This is surprising in view of tremendous opportunities for achieving new reactivity and selectivity in catalytic transformations that the electronic tuning through BN/CC isosterism could potentially provide. In a recent example, we disclosed that the 1,4-azaborine-based pyridine ligand A (Scheme 1) exhibits a κ²N-η²-BC coordination with group 10 transition metals and that the phosphine derivative B in conjunction with Pd could uniquely catalyze the hydroboration of a terminal enyne in a trans-selective fashion.⁷ In contrast to B, the corresponding carbonaceous phosphine ligand isostere C behaves more similarly to a monodentate phosphine such as PPh₃ in terms of hydroboration selectivity and yield, producing preferentially allenes via 1,4-hydroboration; bisphosphine ligands such as 1,2-bis(diphenylphosphino)ethane (dppe) furnish syn-hydroboration products exclusively.⁸ Despite this promising preliminary result, our trans-hydroboration reaction still needed optimization with regard to yield and selectivity. More importantly, we wondered whether we could develop a trans-hydroboration protocol for internal enynes, a substrate class that is considered significantly more challenging (vide infra).

Scheme 1.

An Application of BN/CC Isosterism in Catalysis

To date, only a handful of metal-catalyzed systems have been demonstrated to achieve trans-hydroboration of alkynes.⁹ Miyaura reported the first example in 2000 using Ir or Rh catalysts (Scheme 2).¹⁰ In 2012, Leitner showed that a Ru/PNP pincer complex can produce Z-vinylboronates via trans-hydroboration of alkynes with H-Bpin,¹¹ and Chirik introduced a Co-based system in 2015.¹² What these systems have in common is that they require the presence of the terminal alkyne proton due to the operating reaction mechanisms. Metal vinylidene species have been proposed for the Miyaura¹⁰ and Leitner¹¹ catalysts whereas the Chirik system involves a Co-alkynyl¹² intermediate. Thus, internal enynes would not be suitable substrates for these systems. Lee and Yun reported very recently a copper(I)–thiophene-2-carboxylate/DPEphos catalyzed trans-hydroboration of terminal aryl-alkynes in which the terminal alkyne proton does not undergo a migration that is observed in the Miyaura, Leitner, and Chirik systems.¹³ To the best of our knowledge, the only metal-catalyzed system that can achieve the trans-hydroboration of internal alkynes is the [Cp*Ru(MeCN)₃]PF₆ system by Fürstner.¹⁴ This system works particularly well with symmetrical internal alkynes, and enynes have been pointed out as a problematic substrate for Fürstner’s Ru catalyst.

Scheme 2.

Transition-Metal-Catalyzed trans-Selective Hydroboration of Alkynes

In this communication, we disclose a Pd-catalyzed trans-selective hydroboration of both terminal and internal 1,3-enynes with high site selectivity and stereoselectivity that is supported by 1,4-azaborine-based phosphine ligands. Key to the successful development of this reaction is a new, concise synthesis of monobenzofused 1,4-azaborine phosphines (Senphos), which we report here as well.

Our original synthesis of Senphostype ligands via ring-closing metathesis⁷ was unfortunately not amenable to scale-up¹⁵ and ready modification of the C(3) position, which we believe could play an important role due to its proximity to the catalytically active Pd metal. This synthetic limitation significantly hampered our ability to develop a general and versatile trans-hydroboration protocol. Recognizing that N-vinyl-B-Cl intermediate D (Scheme 3, top) contains a nucleophilic enamine and an electrophilic boron atom, we envisioned that D could be poised to undergo intramolecular electrophilic cyclization¹⁶ to furnish C3-substituted monobenzofused 1,4-azaborine E after aromatization, thus circumventing the limiting ring-closing-metathesis approach. Intermediate D should be accessible from commercially available 2-bromoaniline, a variety of acyl chlorides, and (diisopropylamino)boron dichloride.

Scheme 3.

Retrosynthetic Analysis and Preparation of Senphos Ligands L2–L6

With a new synthetic strategy in hand, we began our synthesis of a library of ligands with the acylation and methylation of 2-bromoaniline to provide amides 1a–c. The critical enamine functionality was introduced using a protocol developed by Nagashima.¹⁷ Treatment of 1 with polymethylhydrosiloxane (PHMS) in the presence of 0.05 mol% of Vasaka’s complex (PPh₃)₂(CO)IrCl as a catalyst furnished the corresponding enamines 2a–c in 63–86% yield. Subsequent lithium–halogen exchange followed by addition of i-Pr₂NBCl₂ and distillation of the resulting reaction mixture under attenuated pressure afforded directly the versatile B-Cl-substituted monobenzofused 1,4-azaborines 3a–c.¹⁸ The structure of 3a is further unambiguously confirmed by single crystal X-ray diffraction analysis (see Supporting Information). Finally, the substitution reaction of 3a–c with phosphine-containing organolithium nucleophiles gave targeted Senphos ligands L2–6.

We chose terminal E-1,3-enyne 4a as our initial substrate to probe the effects of the ligand structure on the trans-hydroboration selectivity. In the presence of 4 mol % catalyst “L1 (= B)/Pd(0)”, reaction of 4a with 1 equiv of catecholborane (HBCat) in CH₂Cl₂ at room temperature and subsequent transesterification with pinacol¹⁹ afforded the corresponding trans-hydroboration product 5a with decent trans-hydroboration stereoselectivity (93:7) in 59% yield (Table 1, entry 1). No background reaction was observed in the absence of the catalyst under otherwise identical reaction conditions. The C3-substituent in L plays an important role in the optimization of stereoselectivity. For example, when L4, which bears the sterically more demanding i-Pr group at the C3 position, is used as the ligand, the reaction gave superior (>98:2) trans-hydroboration selectivity compared to those with the smaller substituents (Table 1, entry 4 vs entries 1–3). Switching the boron substituent from the o-diphenylphosphinophenyl to 2-diphenylphosphinonaphth-1-yl group did not result in obvious trends in terms of both reactivity and stereoselectivity (Table 1, entry 2 vs 5, entry 3 vs 6). The isolated yield of dienylboronate ester 5a could be elevated to 86% when 1.5 equiv of CatBH is used instead of 1.0 equiv (Table 1, entry 7).

Table 1.

Ligand Survey of trans-Hydroboration of Terminal 1,3-Enyne 4a Catalyzed by L/Pd(0)

entry	L	trans-hydroboration selectivitya	yield (%)b
1	L1	93:7	59
2	L2	92:8	60
3	L3	96:4	56
4	L4	>98:2	62
5	L5	96:4	59
6	L6	94:6	68
7c	L4	>98:2	86

^aThe diastereomeric ratio was determined by ¹H NMR of crude material before addition of pinacol.

^bYield of isolated product, based on 4a.

^c1.5 equiv of HBC was applied. dba: dibenzylidineacetone.

Under optimized reaction conditions, various terminal E-1,3-enynes 4 were subjected to the trans-selective hydroboration, and the results are summarized in Table 2. High yield and trans-selectivity were observed consistently with an array of electronically and sterically different substituents on the alkene. The stereochemistry of dienylboronate 5a was confirmed by single crystal X-ray diffraction analysis (Table 2).

Table 2.

trans-Hydroboration of Terminal 1,3-Enynes 4 Catalyzed by L4/Pd(0)^a

^aYield of isolated product (average of 2 runs), based on 4. The diastereomeric ratio in parentheses was determined by ¹H NMR of crude material before addition of pinacol.

The metal-catalyzed trans-hydroboration of internal 1,3-enynes is a significantly more demanding problem and has currently no precedent in the literature. Internal 1,3-enynes are generally less reactive toward hydroboration, and the control of both site selectivity and stereoselectivity is more challenging.²⁰ Gratifyingly, when the concentration of the reaction is increased from 0.25 to 1.25 M,²¹ the reaction of internal E-1,3-enyne 6a with CatBH (see eq 1) in the presence of 4 mol % L1/Pd was complete

(1)

within 90 min at room temperature, affording 7a in 89% yield with 90:10 trans-hydroboration selectivity after treatment with pinacol. Other regioisomers were not observed. Further optimization with regard to the ligand structure revealed that the C3-ethyl substituted L3 was the best performing ligand producing 7a in 92% yield and 96:4 trans-hydroboration selectivity.²²

The substrate scope for the trans-hydroboration of internal 1,3-enynes is summarized in Table 3. In general, 1,4-disubstituted 1,3-eynes 6 bearing an aryl group at the R¹ position gave superior trans-hydroboration selectivity compared to alkyl groups (Table 3, entries 7h–7l vs 7a–7g). Increasing the substituent size of the R³ substituent in 6 reduces trans-hydroboration selectivity (Table 3, entries 7l–7p, in particular 7l vs 7p). The bond connectivity of dienylboronate 7a and the hydroboration stereoselectivity were unambiguously confirmed by the solid-state structure of 7a (Table 3).

Table 3.

trans-Hydroboration of Internal 1,3-Enynes 6 Catalyzed by L3/Pd(0)^a

^aYield of isolated product (average of 2 runs), based on 6. The diastereomeric ratio in parentheses was determined by ¹H NMR of crude material before addition of pinacol.

Our method is amendable to scale up. Trans-hydroboration of 1,3-enyne 6l (1.138 g, 8.0 mmol) with a reduced catalyst loading (1 mol % Pd) furnished the desired product 7l in 89% yield (1.819 g) without erosion of stereoselectivity (see Supporting Information).

Dienylboronate esters such as 7l are versatile intermediates in organic synthesis,²³ and Scheme 4 illustrates that 7l is capable in engaging in subsequent C–C bond forming transformations stereospecifically. For example, 7l undergoes Pd catalyzed Suzuki–Miyaura²⁴ coupling with bromobenzene to furnish 1,3-diene 8 in 83% yield with complete retention of the olefin stereochemistry (Scheme 4, eq 2). Furthermore, Diels–Alder reaction of 7l with N-methylmaleimide afforded bicyclic 9 containing four stereogenic centers with high diastereoselectivity (endo/exo >98:2) in 67% yield (Scheme 4, eq 3).²⁵ Finally, homologation of 7l with deprotonated carbamate 10 followed by oxidation furnished corresponding dienol 11 in 62% yield (Scheme 4, eq 4).²⁶

Scheme 4.

Functionalization of Hydroboration Product 7l

We were able to obtain the single crystal X-ray structure of Senphos L4 bound to Pd(0)dba. Scheme 5 shows that the κ²-P-η²-BC coordination mode to Pd(0) in complex 12 is preserved even with the sterically demanding i-Pr group at the C(3) position.²⁷ Complex 12 is a chemically and kinetically competent catalyst. trans-Hydroboration of substrate 4a with the isolated Pd(0) complex 12 as the catalyst furnished the desired product 5a in the same amount of yield and diastereoselectivity within 30 min as described in Table 1.

Scheme 5.

Isolated Pd(0) Complex 12 Is a Competent Catalyst for trans-Hydroboration

In summary, we have developed a modular and concise synthesis of monobenzofused 1,4-azaborine-based phosphine ligands. Their Pd(0) complexes have been found to catalyze trans-hydroboration of both terminal and internal E-1,3-enynes with high site selectivity and stereoselectivity under mild conditions. The method is also amendable to gram-scale synthesis without erosion of selectivity. Mechanistic studies including the origin of trans-hydroboration selectivity and further application of Senphos ligands in catalytic transformations are currently underway in our laboratory.