**1. Introduction**

Boronic acids and esters serve as precursors for a variety of functional groups and as synthetic handles for C–C bond formation [1,2]. Over the past two decades, iridium-catalyzed C–H borylation (CHB) of arenes have emerged as useful additions to the synthetic chemist's toolbox [3–7]. The regiochemistry of iridium-catalyzed CHB of arenes is traditionally governed by sterics [3,7,8]; often complementing regiochemical outcomes of electrophilic aromatic substitution and directed *ortho* metalation. Since its discovery [9], methods to expand regiocontrol (*ortho*, *meta,* and *para*) [10–12], sp<sup>3</sup> borylation protocols [13–21] and one-pot reactions [22–27] have been developed.

In contrast, few tactical advances have expanded the chemoselectivity of iridium-catalyzed CHBs. This is not to say that CHBs have poor functional group tolerance. Ester, amide, ether, carbamate, and nitrile functionalities are all well tolerated. Satisfactorily, CHB of halogenated arenes leaves the carbon-halogen bonds intact, which differs from other protocols involving palladium or nickel. In contrast, substrates bearing alkenes or unhindered alkynes have been considered problematic owing to the propensity of these groups to react under the borylation conditions. In fact, addition of hydroborane or diboron reagents across triple bonds can occur with catalytic systems similar to the traditional conditions used for CHB (Scheme 1a) [28–32]. However, there are reports in which CHB of arenes or heteroarenes bearing an alkyne functionality have been successful (Scheme 1b) [33–36]. It is likely that in these examples the presence of two bulky substituents on the alkyne hinder its reactivity, allowing for chemoselective borylation of the porphyrin moiety (**1**, **2**) or the polyarene skeleton (**3**, **4**). The dichotomy of these results was the first subject of our study.

**Scheme 1.** (**a**) Reactivity and (**b**) tolerance of alkynes in iridium C–H borylations [28–36}.

Unwanted alkyne reactivity can be viewed as a CHB limitation, since borylated aromatic alkynes have found use in the synthesis of extensively conjugated polymeric materials [37] and in crystal engineering, biological inhibition, molecular sensing, chirality, and structural assignment, etc., [38–41]. The preparation of borylated aromatic alkynes usually involves introduction of the boronic ester/acid functionality on an aromatic alkyne by metalation/borylation [42,43] or Pd-catalyzed borylation of aromatic halides [44]. We hypothesized that by courtesy of CHB halogen tolerance it would be possible to make such intermediates in the opposite order, namely, to synthesize borylated aromatic alkynes by a CHB/Sonogashira coupling sequence. If such a sequence could also be accomplished in a one-pot fashion, it would streamline the synthesis of borylated aromatic alkynes while allowing access to target molecules bearing the contra-electronic substitution patterns often associated with CHB reactions.

#### **2. Results and Discussion**

The prior art was inconclusive as to the compatibility between alkynes and CHB conditions. Therefore, we began by subjecting alkynyl arenes to CHB conditions (Scheme 2, Equation (1)). Attempted borylation of phenyl acetylene (**5**) using the [Ir(cod)OMe]2/dtbpy catalyst system was unsuccessful. Considering that the terminal C–H bond in acetylene may be too acidic, we examined the borylation of 1-phenyl-1-propylene (**6**) and diphenyl acetylene (**7**). Neither of these alkynes underwent aromatic borylation. It was also found that the addition of 10 mol % of diphenylacetylene (**7**) halts the ongoing borylation of an otherwise suitable CHB substrate as shown in Scheme 2, Equation (2). Furthermore, attempted borylation of diphenyl acetylene with an (Ind)Ir(cod)/ dmpe catalyst system at 150 ◦C gave a mixture of products arising from hydrogenation, hydroboration, and catalytic borylation. These results suggest that the alkynyl group binds tightly to the active borylation catalyst at 25 ◦C, but at elevated temperatures the alkynyl group becomes a reactive partner.

**Scheme 2.** Attempted CHB in the presence of alkynes.

These results drove our decision to develop a CHB/Sonogashira protocol. Others had demonstrated the tolerance of boronic esters under Sonogashira cross-coupling reaction conditions [39,40,45–47]. While our group previously showed that despite the propensity for self-Suzuki reactions, one-pot reactions involving CHB of aryl halides followed by C–N cross-coupling of the C–halogen bond [27] or dehalogenation [23], that keep the C–B bond intact are possible (Scheme 3). These studies provided the foundation from which we would seek to establish a one-pot CHB/Sonogashira cross-coupling of aryl halides to access borylated aryl alkynes.

**Scheme 3.** One-pot CHB of aryl halides followed by selective reaction of the C–Halogen bond [23,27].

3-Bromobenzotrifluoride was chosen as our test substrate. First, borylated 3-bromobenzotrifluoride (**9**) was subjected to Sonogashira cross-coupling under Fu's conditions using phenyl acetylene (**5**) and CuI cocatalyst [48]. We were pleased to observe the formation of the desired borylated aromatic alkyne without any significant deborylation or polyphenylene formation. However, the reaction had stopped at about 90% conversion after 18 h and homocoupling of the alkyne was observed by GC-MS. As Buchwald had shown that a copper co-catalyst may inhibit Sonogashira coupling [49] and given that CuI can promote oxidative homocoupling of alkynes, we shifted to copper-free conditions reported by Soheili [50]. This resulted in full conversion of substrate in 10 h and the resulting borylated aromatic alkyne was isolated in 75% yield (Scheme 4). We used this protocol with a couple of other aryl borylated bromides (**10**, **11**) and the Sonogashira products were obtained in good yields (**13**, **14**). Synthesis of **14** was run in a bigger scale (10 g, 31.5 mmol) which shows the robustness of this reaction.

**Scheme 4.** Sonogashira cross-coupling of an aryl bromide boronic ester.

With this success, we moved on to developing the one-pot borylation/Sonogashira sequence. In addition to polyphenylene formation and deborylation, we envisioned other potential issues negatively impacting this approach, such as residual iridium catalyst/ligand affecting the subsequent Sonogashira coupling. Iridium is also known to catalyze the polymerization of aromatic alkynes [51]. In practice, 3-bromobenzotrifluoride was borylated using a (Ind)Ir(cod)/dmpe catalyst system and the intermediate boronate ester was then subjected to Sonogashira coupling without isolation. The coupling went smoothly without any interference from residual iridium catalyst, ligand, or borylation by-products and the desired product was isolated in 64% yield (Table 1, entry 1). Other substrates reacted similarly with phenyl acetylene or TMS acetylene as the alkyne partner. The general one-pot borylation/Sonogashira coupling sequence and the product yields over two-steps are presented in Table 1.


**Table 1.** Scope of one-pot CHB/Sonagashira cross-coupling reactiona.

<sup>a</sup> See Materials and Methods (Section 3) for experimental details and Supplementary Materials for spectral data. <sup>b</sup> 3 mol % [Ir(cod)OMe]2/dtbpy was used for borylation. <sup>c</sup> Borylation was carried out with 0.6 equiv of B2pin2.

Both electron rich as well as electron deficient aryl bromides proved to be efficient substrates. Entries 10 and 11 show that a hindered C–Br bond in a bromoaryl boronate ester can undergo selective Sonogashira coupling without any deborylation of the more sterically accessible C–B bond. Double Sonogashira coupling can be carried out starting from 1,3-dibromobenzene (entry 12). Attempted mono-Sonogashira coupling on the intermediate boronic ester of 1,2-di-bromobenzene using 0.9 equiv of TMS-acetylene resulted in a 1:3 mixture of two regioisomers, however the di-Sonogashira product was the major species observed by GC-FID. The resulting borylated aromatic enediynes were isolated in good yields by using 2.2 equiv of alkyne (entries 13 and 14). To expand the scope of this methodology to heteroaromatics, we examined the one-pot borylation/Sonogashira coupling of 3-bromothiophene. Diborylation was complete in 1 h, however upon exposure to the Sonogashira conditions, extensive deborylation was observed (Scheme 5).

**Scheme 5.** Attempted di-borylation Sonogashira cross-coupling of 3-bromothiophene.

Considering that the presence of iridium may have caused deborylation [52,53], we ran the Sonogashira coupling on isolated 2-bromo-5-Bpin-thiophene. Although the Sonogashira coupling was complete in 2 h, about 80% of the coupled product was deborylated. These results suggest that the presence of Bpin functionality on the 2-position of thiophene is inherently unstable to the Sonogashira conditions. Indeed, Zheng also reported deborylation during microwave-assisted Sonogashira coupling of 2-borylated heteroaromatics [46].

## **3. Materials and Methods**

#### *3.1. Materials*

All commercially available chemicals were used as received or purified as described. Bis(η4-1,5-cyclooctadiene)-di-μ-methoxy-diiridium(I) [Ir(cod)OMe]2 [54], (η5-Indenyl)(cyclooctadiene) iridium (Ind)Ir(cod)} [55], and pinacolborane (HBpin) [56] were prepared as per the literature procedures. 4 -Di-t-butyl-2,2 -bipyridine (dtbpy), bis(pinacolato)diboron (B2pin2), and 3-bromobenzonitrile were sublimed before use. Liquid aryl bromides were refluxed over CaH2, distilled, and degassed. Phenyl acetylene was distilled before use. Acetonitrile was distilled over activated molecular sieves. n-Hexane was refluxed over sodium, distilled, and degassed. Silica gel (230–400 Mesh) was purchased from EMD™.

#### *3.2. General Procedure A: Sonogashira Cross-Coupling of Borylated Aryl Bromides*

In a glove box, borylated aryl bromide (1.0 mmol, 1 equiv), 1,4-diazabicyclo[2.2.2]octane [DABCO] (225 mg, 2.0 mmol, 2 equiv), allylpalladium chloride dimer (9 mg, 0.025 mmol, 2.5 mol %), P*t-*Bu3 (20 mg, 0.1 mmol, 10 mol %), alkyne (1.1 mmol, 1.1 equiv), and acetonitrile (3 mL) were transferred into a Schlenk flask equipped with a magnetic stirring bar [50]. The flask was then stoppered and stirred at room temperature until the Sonogashira coupling was judged complete by GC-FID. After completion, 5 mL of water were added to the reaction mixture. The reaction mixture was extracted with ether (10 mL × 3). The combined ether extractions were washed with brine (10 mL), followed by water (10 mL), dried over MgSO4 before being concentrated under reduced pressure on a rotary evaporator. The crude material was then subjected to column chromatography.
