Compatibility Assessment of Unactivated Internal Alkynes in Rhodium-Catalyzed [2+2+2] Cycloadditions

Functionalized 1,2,4,5-tetrasubstituted benzenes are synthetically difficult or laborious to access. The Rh-catalyzed [2+2+2] cyc-loaddition of a diyne and internal alkyne offers a seemingly straightforward route to these scaffolds; however, this has been largely restricted to alkynes bearing activating (coordinating) functional groups, with very few examples of unactivated alkynes. In this work, we disclose an assessment of Rh-catalyzed [2+2+2] cycloadditions employing unacti-vated internal alkynes, focusing on the structural diversity and compatibility of both alkyne and diyne components. The limitations of this method are disclosed, with exceptionally bulky alkynes and specific functional groups undergoing side reactions. Furthermore, the practi-calities of gram-scale reactions and catalyst recovery/reuse are demonstrated.

][3][4][5][6][7][8][9][10][11] First disclosed by Berthelot in 1890, 12 the process involves the confluence of three alkynes to generate (hetero)arenes.Reppe improved on Berthelot's discovery by utilizing nickel catalysis, greatly reducing the thermal requirements, and initiating the development of transition-metal-catalyzed [2+2+2] cycloaddition. 13he Rh-catalyzed [2+2+2] reaction has become broadly useful and inspired a range of practical methodologies. 7,8hese reactions are classified in three main ways: intramolecular, semi-intramolecular, and intermolecular (often termed mono-, bi-, and trimolecular reactions).Each offer distinct benefits and drawbacks: for instance, the intramolecular variant offers complete chemoselectivity and regiochemical control; however, the starting materials are complex.The fully intermolecular reaction, whilst the most modular, has issues with regioselectivity and chemoselectivity. 11In contrast, the semi-intramolecular reaction of an alkyne and diyne (Scheme 1a) strikes the balance of being modular and using starting materials that are generally accessible both commercially and synthetically.Mechanistic analysis in this area has been dominated by electronic arguments based on empirically observed enhanced reactivity of electron-deficient alkynes.5][16] Our

Letter Synlett
group recently disclosed evidence that the apparent electronic influence was misattributed and, instead, coordination of the electron-withdrawing groups to the Rh(III) intermediate was responsible for improved reactivity. 17uring this analysis, we noted an absence of skeletal diversity in this chemical space, which was presumably due to limitations in reaction efficiency using unactivated internal alkynes.
Our previous work has shown that the reaction requires high Rh loadings to generate the desired products in acceptable yields when unactivated alkynes are used. 17This is due to steric parameters dominating reaction kinetics, limiting productive catalytic turnover. 17We recently demonstrated that this can be overcome in boron-based systems to generate borylated arenes and benzoxaboroles (Scheme 1b). 18To better explore the chemical space available and provide greater insight into reaction tolerance, we assessed the scope and limitations of this Rh-catalyzed [2+2+2] cycloaddition using unactivated alkynes (Scheme 1c).
We selected general conditions based on a survey of the literature and an initial variable screen (see the Supporting Information).We avoided bespoke ligands, preferring commercial Rh sources and ligands, and selecting those with increased tolerance to air and moisture.The conditions shown in Scheme 2 were found to be widely applicable and offered improved tolerance to air and bench solvents when compared to alternative catalyst systems based on Co or Ir.
Regarding limitations, the reaction was not tolerant of nitriles (36) due to competing nitrile [2+2+2] cycloaddition. 19Whilst an enyne was tolerated to give 14, the allyl derivative (37) gave a range of unidentifiable side products.It is possible that the desired product was formed and subsequently underwent further cyclization reactions, such as those disclosed by Evans and coworkers. 20Secondary amines (38) were also not applicable.Aldehydes (39, 40) were unsuitable due to Rh-catalyzed decarbonylation reactions, which are well documented. 21Alkynyl bromide (41) lead to a complete shutdown of [2+2+2] reactivity, with full recovery of the diyne noted.Finally, exceptionally bulky alkynes (42, 43) yielded no desired product due to the poor catalytic turnover resulting from steric congestion. 17o assess the scalability of the methodology, a gramscale reaction (with respect to alkyne, ca.7.0 mmol) was performed (Scheme 3a), giving 32 in comparable yield.In addition to demonstrating scalability, catalyst recovery was found to be feasible.Trituration of the crude reaction mixture allowed isolation of the [Rh(BINAP) 2 ]BF 4 complex 46, with 89% recovery.

Letter Synlett
This conveniently allows for the simultaneous recovery of both the metal catalyst and ligand in a single step.Singlecrystal X-ray diffraction confirmed the structure of 46, which was isolated as a mixture of the heterochiral complex 46a ((R),(R) and (S),(S)) and homochiral complex 46b ((R),(S)) (Scheme 3b).Compound 46a could be isolated on reasonable scale, allowing assessment for catalytic competency in the [2+2+2] reaction under the same conditions as Scheme 2 (Scheme 3c). 22While 46a displays some catalytic activity, this was displayed significantly poorer [2+2+2] ac-tivity than the precatalyst-ligand mixture.This is likely due to a comparatively unfavorable dissociation of BINAP to allow rhodacycle formation with the diyne component.To facilitate BINAP dissociation, an additive screen was performed (Scheme 3c -see the Supporting Information, Table S1).Attempts to encourage BINAP dissociation via coordination to boron (BH 3 ) or Ag(I) were unsuccessful at restoring catalytic competency.Similarly, addition of 1,5-cyclooctadiene (COD) as a competing ligand to displace BINAP was unsuccessful.However, it was found that the addition of 10 Scheme 2 Scope and limitations of Rh-catalyzed semi-intermolecular [2+2+2] cycloadditions using unactivated internal alkynes.Alkyne (0.1 mmol, 1.0 equiv), diyne (6.0 equiv added over 15 h in acetone), [Rh(COD)(MeCN) 2 ]BF 4 (20 mol%), rac-BINAP (40 mol%), acetone, 60 °C, 16 h.Yields determined by 1 H NMR spectroscopy using an internal standard (trichloroethylene), isolated yields in parentheses.a 1 H NMR yield with no slow addition.b Isolated as aldehyde after acid workup.This observation offers insight into catalyst speciation, off-cycle processes, and resting states during these Rh/BINAP-catalyzed [2+2+2] reactions.The general requirement for 1:2 Rh:BINAP stoichiometry is well-established; 7- 10 however, the 1:2 complex 46 has low catalytic activity.This suggests that 46 may act as a resting state during [2+2+2] reactions, with BINAP dissociation required for Rh(I) to re-enter productive catalysis (i.e., cyclometalation with the diyne).A figurative description is shown in Scheme 4. This observation is consistent with previous reports demonstrating enhanced catalytic activity of Rh(I)/BINAP complexes following COD removal via hydrogenation. 23

Scheme 4 Figurative description of catalyst-ligand speciation
In summary, we have disclosed an assessment of the scope and limitations of unactivated internal alkynes in Rhcatalyzed semi-intermolecular [2+2+2] cycloadditions.A range of useful functional groups and substitution patterns can be tolerated, yielding complex arene derivatives.The limitations of the reaction have been explored and documented, with insight on competing reactions, poor reactivity, and catalyst deactivation.The scalability of the reaction has been assessed, which offers comparable yield on submmol and gram scale.][26]
Gram-scale reaction and catalyst recovery (b) X-ray structures of complexes 46a and 46b (c) Re-use and catalytic competency of recovered complex 46 C Synlett 2024, 35, A-E J. M. Halford-McGuff et al.