(Scheme 16) [97]. These complexes have proven seminal within the ortho-HIE
domain and have among the highest activity [98], substrate/solvent scope
[99, 100], and tritiation reaction cleanliness of any such catalyst reported to date.
Additionally, ortho-HIE process with these complexes has been studied experimentally and computationally, strengthening the case for a Ir(III)-based reaction mechanism akin to that proposed by Heys [98]. More specifically, kinetic isotope effect
(KIE) measurements [101] revealed that C–H bond cleavage was the rate-limiting
step of the reaction (54 ! 55), and detailed NMR studies revealed (via
2 J P–C
coupling information) the trans-geometry of the ancillary ligands [98]. The same
study was also able to reveal the origins of the selective reactivity of such catalysts
for 5- over 6-mmi substrates, citing dual kinetic and thermodynamic favorability for
the 5-mmi. The calculated transition states 56 and 57 revealed, for the first time, the
sigma-bond-assisted metathesis (sigma-CAM) process at the heart of the all-Ir(III)
C–H activation step [98, 102].
While developing a rare method for labeling primary sulfonamides, Kerr and
co-workers considered directing group chemoselectivity in detail [102]. It was
observed that the sulfonamide vs. pyrazole selectivity in celecoxib 58 varied dramatically with catalyst choice (Scheme 17). Whereas encumbered and most-often
used NHC/phosphine catalysts facilitated labeling adjacent to the pyrazole moiety,
giving 58b, neutral NHC/Cl catalysts, such as 59, facilitated selective sulfonamide
labeling, delivering 58a, for the first time. Accompanying DFT studies revealed that
the substrate binding event was likely to be product-determining (60a vs. 60b), even
though C–H activation remained rate-limiting (Scheme 17). A similar rationale was
presented for multifunctional molecules containing esters as the targeted directing
group [103]. Following this, Derdau and co-workers significantly expanded on the
HIE studies of competing directing groups, showing once again that calculated
binding energies could serve as a semiquantitative and predictive tool for rationalizing directing group chemoselectivity in HIE [42].
Building on Kerr’s work, Ir(III)-catalyzed ortho-HIE has continued to flourish
[3, 11, 13, 15, 35, 41, 42]. From the same group, and others applying the developments therefrom, the application of bulky NHC–phosphine systems in HIE has
steadily advanced in terms of the applicable substrate and solvent scope [42, 102,
104–108]. With regard to solvent scope, Kerr and Tamm have reported complementary strategies toward modifying the solubility profile of existing iridium HIE
catalysts. On the one hand, Kerr explored the use of the bulky tetrakis[3,5-bis
(trifluoromethyl)phenyl]borate (BArF) counterion in place of the standard
hexafluorophosphate (PF 6 ) [104, 109], and on the other, Tamm integrated a related
borate anion into the backbone of an anionic carbene ligand (Scheme 18) [110]. The
wide range of solvents made applicable in extending the Kerr catalyst series through
61a–61d evidenced new opportunities to tune HIE regioselectivity through simple
solvent switching [104]. From Tamm’s most recent developments, catalysts 62a,
62b, and 62e have been identified as competent HIE catalysts in hexane and
cyclohexane for the first time [110].
A growing community of researchers have, in more recent times, contributed a
wider range of elaborated ligand spheres around tractable iridium(I) pre-catalysts. In
284
M. Reid
domain and have among the highest activity [98], substrate/solvent scope
[99, 100], and tritiation reaction cleanliness of any such catalyst reported to date.
Additionally, ortho-HIE process with these complexes has been studied experimentally and computationally, strengthening the case for a Ir(III)-based reaction mechanism akin to that proposed by Heys [98]. More specifically, kinetic isotope effect
(KIE) measurements [101] revealed that C–H bond cleavage was the rate-limiting
step of the reaction (54 ! 55), and detailed NMR studies revealed (via
2 J P–C
coupling information) the trans-geometry of the ancillary ligands [98]. The same
study was also able to reveal the origins of the selective reactivity of such catalysts
for 5- over 6-mmi substrates, citing dual kinetic and thermodynamic favorability for
the 5-mmi. The calculated transition states 56 and 57 revealed, for the first time, the
sigma-bond-assisted metathesis (sigma-CAM) process at the heart of the all-Ir(III)
C–H activation step [98, 102].
While developing a rare method for labeling primary sulfonamides, Kerr and
co-workers considered directing group chemoselectivity in detail [102]. It was
observed that the sulfonamide vs. pyrazole selectivity in celecoxib 58 varied dramatically with catalyst choice (Scheme 17). Whereas encumbered and most-often
used NHC/phosphine catalysts facilitated labeling adjacent to the pyrazole moiety,
giving 58b, neutral NHC/Cl catalysts, such as 59, facilitated selective sulfonamide
labeling, delivering 58a, for the first time. Accompanying DFT studies revealed that
the substrate binding event was likely to be product-determining (60a vs. 60b), even
though C–H activation remained rate-limiting (Scheme 17). A similar rationale was
presented for multifunctional molecules containing esters as the targeted directing
group [103]. Following this, Derdau and co-workers significantly expanded on the
HIE studies of competing directing groups, showing once again that calculated
binding energies could serve as a semiquantitative and predictive tool for rationalizing directing group chemoselectivity in HIE [42].
Building on Kerr’s work, Ir(III)-catalyzed ortho-HIE has continued to flourish
[3, 11, 13, 15, 35, 41, 42]. From the same group, and others applying the developments therefrom, the application of bulky NHC–phosphine systems in HIE has
steadily advanced in terms of the applicable substrate and solvent scope [42, 102,
104–108]. With regard to solvent scope, Kerr and Tamm have reported complementary strategies toward modifying the solubility profile of existing iridium HIE
catalysts. On the one hand, Kerr explored the use of the bulky tetrakis[3,5-bis
(trifluoromethyl)phenyl]borate (BArF) counterion in place of the standard
hexafluorophosphate (PF 6 ) [104, 109], and on the other, Tamm integrated a related
borate anion into the backbone of an anionic carbene ligand (Scheme 18) [110]. The
wide range of solvents made applicable in extending the Kerr catalyst series through
61a–61d evidenced new opportunities to tune HIE regioselectivity through simple
solvent switching [104]. From Tamm’s most recent developments, catalysts 62a,
62b, and 62e have been identified as competent HIE catalysts in hexane and
cyclohexane for the first time [110].
A growing community of researchers have, in more recent times, contributed a
wider range of elaborated ligand spheres around tractable iridium(I) pre-catalysts. In
284
M. Reid