Cascade Reductive Friedel-Crafts Alkylation Catalyzed by Robust Iridium(III) Hydride Complexes Containing a Protic Triazolylidene Ligand

Article abstract of DOI:10.1021/acscatal.1c00740

The synthesis of complex molecules like active pharmaceutical ingredients typically requires multiple single-step reactions, in series or in a modular fashion, with laborious purification and potentially unstable intermediates. Cascade processes offer attractive synthetic remediation as they reduce time, energy, and waste associated with multistep syntheses. For example, triarylmethanes are traditionally prepared via several synthetic steps, and only a handful of cascade routes are known with limitations due to high catalyst loadings. Here, we present an expedient catalytic cascade process to produce triarylmethanes. For this purpose, we have developed a bifunctional iridium system as the efficient catalyst to build heterotriaryl synthons via reductive Friedel-Crafts alkylation from ketones, arenes, and hydrogen. The catalytically active species were generated in situ from a robust triazolyl iridium(III) hydride complex and acid and is composed of a metal-bound hydride and a proximal ligand-bound proton for reversible dihydrogen release. These complexes catalyze the direct hydrogenation of ketones at slow rates followed by dehydration. Appropriate adjustment of the conditions successfully intercepts this dehydration and leads instead to efficient C-C coupling and Friedel-Crafts alkylation. The scope of this cascade process includes a variety of carbonyl substrates such as aldehydes, (alkyl)(aryl)ketones, and diaryl ketones as precursor electrophiles with arenes and heteroarenes for Friedel-Crafts coupling. The reported method has been validated in a swift one-step synthesis of the core structure of a potent antibacterial agent. Excellent yields and exquisite selectivities were achieved for this cascade process with unprecedentedly low iridium loadings (0.02 mol %). Moreover, the catalytic activity of the protic system is significantly higher than that of an N-methylated analogue, confirming the benefit of the Ir-H/N-H hydride-proton system for high catalytic performance.

Full text of DOI:10.1021/acscatal.1c00740

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Research Article
Cascade Reductive Friedel−Crafts Alkylation Catalyzed by Robust
Iridium(III) Hydride Complexes Containing a Protic Triazolylidene
Ligand
Iryna D. Alshakova and Martin Albrecht*
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ABSTRACT: The synthesis of complex molecules like active
pharmaceutical ingredients typically requires multiple single-step
reactions, in series or in a modular fashion, with laborious
purification and potentially unstable intermediates. Cascade
processes offer attractive synthetic remediation as they reduce
time, energy, and waste associated with multistep syntheses. For
example, triarylmethanes are traditionally prepared via several
synthetic steps, and only a handful of cascade routes are known
with limitations due to high catalyst loadings. Here, we present an
expedient catalytic cascade process to produce triarylmethanes. For
this purpose, we have developed a bifunctional iridium system as
the efficient catalyst to build heterotriaryl synthons via reductive
Friedel−Crafts alkylation from ketones, arenes, and hydrogen. The
catalytically active species were generated in situ from a robust triazolyl iridium(III) hydride complex and acid and is composed of a
metal-bound hydride and a proximal ligand-bound proton for reversible dihydrogen release. These complexes catalyze the direct
hydrogenation of ketones at slow rates followed by dehydration. Appropriate adjustment of the conditions successfully intercepts this
dehydration and leads instead to efficient C−C coupling and Friedel−Crafts alkylation. The scope of this cascade process includes a
variety of carbonyl substrates such as aldehydes, (alkyl)(aryl)ketones, and diaryl ketones as precursor electrophiles with arenes and
heteroarenes for Friedel−Crafts coupling. The reported method has been validated in a swift one-step synthesis of the core structure
of a potent antibacterial agent. Excellent yields and exquisite selectivities were achieved for this cascade process with
unprecedentedly low iridium loadings (0.02 mol %). Moreover, the catalytic activity of the protic system is significantly higher than
that of an N-methylated analogue, confirming the benefit of the Ir−H/N−H hydride-proton system for high catalytic performance.
KEYWORDS: cascade reaction, reductive Friedel−Crafts alkylation, protic carbene, iridium, proton hydride transfer
bifunctional catalysis, where ligands participate directly in the
bond activation step and undergo a reversible chemical
transformation.11,12 Such cooperation between the metal as
the hydride acceptor and the ligand as the internal Lewis base
proceeds synergistically13 and substantially lowers the other-
wise high H−H bond dissociation energy (435.8 kJ/mol)14
and the unattractively high pKa (∼35 in tetrahydrofuran
(THF)),15 even though the acidity changes drastically once
hydrides are formed.16,17
INTRODUCTION
■
Cascade reactions offer attractive synthetic opportunities by
improving resource efficiency on multiple levels.1−3 This
concept usually implies reducing the overall load of required
solvents and reagents, as well as decreasing the amount of
waste and byproducts. Moreover, it optimizes labor costs, as
usually only a single workup and purification step is required.
Many cascade reactions involve (reversible) hydrogen transfer
to produce reactive intermediates in situ via hydrogen
borrowing processes.4,5 Direct hydrogenation has been applied
in tandem with other reactions as an efficient and atom
economical method for advanced substrate functionaliza-
tion.6−9 The activation of the H−H bond by transition-metal
complexes has been dominated in the field for a long time. In
many classical examples in homogeneous catalysis, such
transformations occur at the metal center by oxidative
addition, homolytic or heterolytic cleavage, while the ligands
remain unchanged over the course of the reaction.10 More
recent discoveries introduced the concept of metal−ligand
This concept has led to a surge of ligands with reliable metal
coordination to accommodate metal hydrides and sterically
Received: February 18, 2021
Revised: June 23, 2021
Published: July 8, 2021
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constrained basic ligand sites for proton harboring.18−29
Despite the striking benefits of this concept, it has been only
rarely applied with N-heterocyclic carbenes (NHCs), though
the emergence of protic imidazole-derived NHCs has
resurrected interest.30,31 Remarkably, the synthetically much
more easily accessible and versatile triazolylidene subclasses of
NHC ligands32−34 have not been considered for such
applications until now. Here, we demonstrate that protic
triazolylidene iridium complexes are readily accessible and
provide attractive catalytic performance in the reductive
Friedel−Crafts alkylation using abundant ketones and
aldehydes as the alkylating agent, thus considerably expanding
the range of alkyl halide surrogates for aromatic substitution.
Previously, benzyl alcohols have been used as the main
substitutes of alkyl halides in Friedel−Crafts transformation for
the synthesis of diaryl- and triarylmethanes.28,35−41 Other
precursors, such as ethers,28,42,43 benzyl carboxylic esters,28
styrenes,42 and sulfones,44 have also been explored as alkylating
agents. Aldehydes, when involved in Friedel−Crafts alkylation,
undergo often undesired double benzylation with the
formation of triarylmethanes.45−48 Under reducing conditions,
ketones, as alkylating agents, can be attractive alternatives for
the production of unsymmetrical triarylmethanes, especially
when considering the synthetic accessibility of structurally
diverse carbonyl compounds.49,50
a bifunctional catalyst composed of a metal center for hydride
stabilization and a ligand site for transient proton binding.
Herein, we demonstrate that the iridium(III) hydride
complexes bearing a 1,2,3-triazolyl ligand with unsubstituted
nitrogen that is available for protonation provide access to Ir−
H/N−H complexes that are efficient catalysts in the reductive
Friedel−Crafts alkylation. These catalysts are remarkably
robust under acidic conditions and provide efficient and
atom-economic access to heterotriarylmethanes from aromatic
carbonyl compounds in the presence of atmospheric pressure
of H2.
RESULTS AND DISCUSSION
■
Synthesis of the Iridium(III) Complexes. The target
iridium complexes were prepared starting from the appropriate
aryl azide 1a−c through base-catalyzed click reaction with 2-
ethynylpyridine to give 1,5-substituted 1,2,3-triazoles 2a−c
followed by metalation with [IrCp*Cl2]2 in the presence of
NaOAc (Scheme 2).53 The iridium(III) complexes 3a−c
Scheme 2. Synthesis of Iridium(III) Complexes 3a−c
Bearing 1,2,3-Triazolyl Ligands and the ORTEP Plot of
Complex 3b (30% Probability)
Cascade direct hydrogenation/Friedel−Crafts alkylation
reaction as an efficient method for the functionalization of
arenes has not been explored yet, although reductive Friedel−
Crafts alkylation has a few precedents (Scheme 1).42,51,52
Scheme 1. Strategies for Reductive Friedel−Crafts
Alkylation
featured the iridium-bound triazolyl carbon nuclei at δC 161.5
1 in the 13C{1H} NMR spectrum and X-ray diffraction
analyses of complexes 3a and 3b confirmed the postulated
connectivity (Figure S79).
The corresponding iridium(III) hydride complexes 4a−c
were obtained by chloride abstraction using either HSiEt3 or
NaH (Scheme 3). Although the silane was utilized in large
excess, this reaction was highly selective and allowed the
product to be conveniently isolated by crystallization. Less
HSiEt3 was required when the reaction was performed in the
presence of a silyl scavenger such as NaOTf or AgOTf, but the
formed byproducts complicated product isolation and
purification. Formation of the hydride complexes was
Tsuchimoto et al. used benzaldehydes and 1,3-propanediol in
the presence of 10 mol % Sc(OTf)3 to form a reactive acetal as
the alkylating agent.51 Using an NHC−Ir complex and 2-
propanol as a reducing agent, Prades et al. expanded the
substrates to benzophenone.42 Finally, Savela et al. reported an
iron-catalyzed Friedel−Crafts alkylation with ketones and
aldehydes mediated by organosilanes.52 The process utilizes
Et3SiH for the hydrosilylation of the carbonyl compound and
Me3SiCl for the following nucleophilic substitution to form the
corresponding alkyl chloride involved in iron(III)-catalyzed
Friedel−Crafts alkylation.
1
confirmed by H NMR spectroscopy, revealing a diagnostic
hydride resonance at around −15.20 ppm for complexes 4a−c.
All hydride complexes 4a−c are moderately air and moisture
stable in crystalline form and can be stored without protection
for up to a week. Extended storage leads to gradual
decomposition, indicated by loss of the hydride signal and
1
concomitant appearance of a series of new signals in the H
NMR spectrum. However, these complexes rapidly decompose
in moist solutions. Suitable crystals for X-ray diffraction
analysis were obtained for complexes 4a and 4b from a
saturated dry THF solution by slow diffusion of ether and
hexane, respectively (Figure S80).
We reasoned that an atom-efficient procedure may be
accessible using hydrogen as the reducing agent combined with
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protonated THF (vs −15.20 ppm for 4a) and a diagnostic
sharp singlet at 15.89 ppm attributed to the N−H proton.54,55
Protonation may be imparted by the silver(I)-mediated
oxidation of hydrosilane to form trifluoromethanesulfonic
acid (HOTf) in situ.
Scheme 3. Synthesis of Triazolyl Iridium(III) Hydride
Complexes 4a−c, Formation of N-Protonated Carbene
Iridium(III) Hydride Complexes 5a−c and Subsequent
Dehydrogenation to 6a−c, and ORTEP Plots of 4a and 4b
Indeed, when THF solutions of iridium(III) hydride
complexes 4a−c were treated with anhydrous HOTf under
an inert atmosphere, carbene complexes 5a−c formed
instantaneously via protonation of the triazole N3 position
(Scheme 3). The formation of the protic carbene complexes
1
5a−c was supported by a sharp H NMR signal around 15.85
( 0.08) ppm, while the hydride signal shifted downfield and
appeared at δ = −14.45 ( 0.02) ppm (Table S1). Although
these NH−carbene iridium hydride complexes 5a−c dehydro-
genated within minutes, they were sufficiently stable to record
1H NMR spectra, yet more time-consuming NMR spectro-
scopic experiments were not possible.56 Using more con-
centrated samples or working at lower temperatures resulted in
even faster degradation. Attempts to run this reaction in
CD3NO2 or MeCN did not prevent rapid precipitation while
using CD2Cl2 instead of THF altered the reactivity and led to
ligand protonation as well as hydride abstraction. Weaker acids
such as NH4PF6, trifluoroacetic acid, formic acid, or anhydrous
ethereal HCl did not induce protonation of 4a, indicating a
remarkably low basicity of the triazolyl nitrogen site.
All three protic carbene complexes 5a−c were unstable and
released H2, identified by an NMR signal at δH = 4.55 ppm in
the reaction mixtures (THF-d8). Concomitantly, a red
precipitate assigned to 6a−c formed (Figure S31),57 which
was insoluble in most common polar or nonpolar solvents
except CD3NO2.58 While standard 1H and 13C NMR
spectroscopy did not allow us to distinguish complexes 6a−c
from a dimeric form with noncoordinating OTf− counter-
ions,59−61 the diffusion ordered spectroscopy (DOSY) analysis
of the mixture of 6b and 3b revealed highly similar diffusion
During optimization of the procedure for the synthesis of
hydride complex 4a, we noted that using 2 equiv of AgOTf
with 3 equiv of HSiEt3 yielded a new compound, which was
assigned to the protonated iridium hydride 5a based on the
downfield-shifted hydride resonance at δH = −14.5 ppm in
a
Table 1. Hydrogenation of Acetophenone
yield
entry
precatalyst
acid loading (mol %)
conversion (%)
8
9
10
11
1
2
3
4
5
6
7
8
3a
4a
3a
3b
3c
4a
4b
4c
6a
6b
6c
3a
3a
3a
<2
<2
67
68
48
70
69
49
68
67
48
10
22
<2
1
1
1
1
1
1
29%
29%
22%
30%
29%
24%
30%
28%
23%
8%
18%
19%
10%
23%
21%
9%
12%
15%
8%
<3%
<3%
5%
<3%
<3%
5%
<3%
<3%
<3%
<3%
<3%
17%
17%
10%
15%
17%
10%
22%
22%
12%
<3%
13%
9
10
11
12
13
14
0.5
3
1
1
3
b
6%
c
d
15
16
27
e
d
3a
52
a
b
Reaction conditions: acetophenone (2.1 mmol), iridium complex (21 μmol), toluene (10 mL), H2 (1 bar), HOTf. AgOTf instead of HOTf.
c
d
e
HBF4·OEt2 or CF3COOH instead of HOTf. 1,3,5-triphenylbenzene was formed. In the absence of H2.
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a
Table 2. Reductive Friedel−Crafts Alkylation of Toluene
yield
entry
precatalyst
3a
4a
3a
3a
4a
3a
3a
3b
3c
4a
4b
4c
6a
6b
6c
precatalyst loading (mol %)
acid loading (mol %)
conversion (%)
10
12 (para/ortho)
13
1
2
3
4
5
6
7
8
1
1
0.1
3
3
3
1
1
3
5
3
3
3
3
3
3
3
3
3
3
3
1
1
100
100
100
34
63% (4.7/1)
60% (5.7/1)
99% (4.5/1)
10% (1.0/0)
11% (1.0/0)
96% (5.0/1)
95% (5.3/1)
94% (5.3/1)
42% (4.3/1)
95% (4.8/1)
96% (5.0/1)
45% (4.0/1)
97% (5.1/1)
95% (5.3/1)
38% (5.3/1)
37%
39%
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.1
12%
12%
10%
10%
<3%
<3%
<3%
17%
<3%
<3%
15%
<3%
<3%
18%
35
100
100
100
63
100
100
64
100
100
63
9
<3%
<3%
5%
10
11
12
13
14
15
16
17
18
b
[IrCp*Cl2]2
2a
21
b
0.1
32
b
52
c
19
d
3a
3a
1
1
57
100
40%
10%
<3%
29% (1.0/0)
13%
57%
20
a
b
Reaction conditions: acetophenone (2.1 mmol) and iridium complex in toluene (10 mL), H2 (1 bar), HOTf. Formation of 1,3,5-triphenyl-
c
d
benzene. Plus 2 mol % KOTf. Plus 2 mol % AgOTf.
coefficients for both compounds, indicating similar molecular
volumes of both species (Figure S44) and hence a monomeric
structure of 6b. Mass spectra of 6a−c showed the pertinent [M
+ H]+ signals, in agreement with a coordinated triflate anion in
a monomeric complex (e.g., m/z 669.1207 for 6a). No signal
for a dimeric species was detected. Remarkably, addition of
HSiEt3 to a suspension of 6a−c in THF regenerated the
iridium hydride complexes 4a−c, thus identifying the triazolyl
iridium scaffold as a competent system for shuttling H2.
Moreover, these reactivities indicate high robustness of the
triazolylidene iridium scaffold toward acidolysis even in the
presence of strong acids such as HOTf or HCl.62
Direct Hydrogenation Catalysis. The facile dehydrogen-
ation of complexes 5a−c suggests these species as well as
complexes 6a−c as potential hydrogen-transfer catalysts.
Neither iridium(III) chloride complex 3a nor iridium(III)
hydride complex 4a catalyzes the hydrogenation of acetophe-
none under atmospheric pressure of H2 (Table 1, entries 1 and
2). However, addition of 1 equiv HOTf per iridium center, i.e.,
conditions that form complexes 5a−c, activates catalytic
turnover (entries 3−8). The selectivity was modest, affording
phenethyl alcohol 8 from hydrogenation together with the
corresponding ether 9 from subsequent dehydration, traces of
styrene 10 as the other product of dehydration, and
ethylbenzene 11 due to styrene hydrogenation. The fact that
only traces of styrene are observed suggests that hydrogenation
of olefins is faster than that of ketones. In contrast to
complexes 3 and 4, iridium species 6a−c catalyze hydro-
genation without the addition of TfOH (entries 9−11) and
with activities and selectivities that are essentially identical to
iridium complexes 3a−c and 4a−c upon HOTf activation,
indicating the same catalytically active species and revealing
full stability of the Ir−C bond under acidic conditions, as
demonstrated previously for related Ir carbene complexes.62,63
When AgOTf was used as an additive instead of the acid, a
much lower conversion of acetophenone was observed under
otherwise identical conditions (entry 13). Likewise, HBF4 or
CF3COOH failed to induce catalytic activity (entry 14).
The aryl substituent on the triazole had only a mediocre
influence on the catalytic activity, which is in agreement with
the only minor chemical shift differences of the hydride NMR
frequencies of complexes 5a−c (Table S1). Notably, bromide
substituents led to the lower catalytic performance of complex
6c and likewise 3c and 4c, which may be attributed to their
electron-withdrawing nature and the ensuing lower proton
affinity of the triazole.64 However, the electron-donating
methoxy group in complex 6b did not lead to enhanced
catalytic activity, even though the stability of the hydrogenated
complex 5b was higher compared to 5a and 5c (see above).
Reductive Friedel−Crafts Alkylation. The slow con-
version of acetophenone under atmospheric H2 pressure paired
with the high stability of the complexes toward Brønsted acids
was exploited in reductive Friedel−Crafts alkylation by slightly
increasing the amount of HOTf with respect to the iridium
precatalyst. This modification radically switched the chemo-
selectivity of the reaction toward electrophilic alkylation of the
aromatic solvent. Thus, toluene is alkylated in the presence of
either 3a or 4a when acetophenone was reacted in the
presence of 3 mol % acid and 1 mol % iridium complex to yield
the cross-coupled diaryl-ethane as a mixture of ortho and para
substitution (Table 2, entries 1 and 2), in line with general
selectivity principles.65 In addition, minor quantities of
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compound 13 were formed due to homocoupling of the
intermediate from acetophenone hydrogenation and dehy-
dration. Reducing the loading of the iridium precatalyst to 0.1
mol % significantly improved selectivity and yielded exclusively
the cross-coupled product 12 (entry 3). Further lowering of
the iridium loading to 0.02 mol % is tolerated, yet the HOTf
portion is critical as selectivity and activity erode when HOTf
is reduced from 3 to 1 mol % (entries 4−6). Increasing the
acid concentration did not lead to any improvement (entry 7).
Iridium complex 3b was as efficient as 3a, while the bromide-
functionalized complex 3c was again less active (entries 8 and
9), in agreement with the activity observed for hydrogenation
(cf. Table 1). Iridium complexes 4a and 6a showed identical
selectivity and activity patterns as 3a, suggesting the formation
of a common active species (entries 6,10,13). The same
conclusion emerges when comparing 3b, 4b, and 6b and 3c,
4c, and 6c, respectively. The availability of a protic N−H and a
hydridic Ir−H unit appeared to be essential for imparting
reductive Friedel−Crafts alkylation. [IrCp*Cl2]2, free ligand
2a, or blank reactions did not show catalytic activity toward
reductive Friedel−Crafts alkylation and only formed minor
quantities of 1,3,5-triphenylbenzene from trimerization of the
styrene intermediate (entries 16−18). Likewise, chloride
abstraction with other reagents (e.g., 2 mol % KOTf or
AgOTf) did not lead to significant cross-coupling (entries 19
and 20).
Scheme 4. Proposed Transformation Pathways for
Acetophenone in the Presence of Catalyst 5a under Acidic
Conditions; with Diaryl Ketones and Aldehydes,
Dehydration Leads to Ether Rather Than Olefin Formation
and yields 13 as the major product (Scheme 5). Hence, key to
the cascade process presented here is the slow formation of
Scheme 5. Conversion of 1-Phenylethanol 8 in the Presence
of HOTf
The relevance of the protic triazolylidene unit was further
demonstrated by comparison with the analogous iridium
complex 15a containing an N-methylated ligand, which was
obtained by post-modification of 3a with MeOTf. Complex
15a also required HOTf to become catalytically active, though
conversions were slower than with the protic analogue 3a
(entries 19 and 20; Figure 1).
alcohol, which keeps its concentration constantly low. In the
presence of a sufficiently large excess of arene, this alcohol in
acidic media leads to selective Friedel−Crafts alkylation rather
than elimination, viz. formation of styrene and homocoupling
products. In support of this model, the chemoselectivity of the
process strongly depends on the relative amounts of toluene
and ketone in the reaction mixture (Table S2). At low toluene/
ketone ratios (up to 5:1), dehydration of the alcohol leads to
significant amounts of the homocoupled product 13 and the
trimerization product 14. Higher toluene ratios increase the
selectivity toward reductive Friedel−Crafts alkylation, and with
40 equiv toluene, up to 96% conversion to 12 was achieved
with exquisite selectivity and efficient suppression of 13 or 14.
This high toluene/ketone ratio can also be achieved with lower
toluene quantities and by addition of the ketone in small
portions, which allows to use the aryl component only in small
excess.
Substrate Scope. Expansion of the substrate scope
included variation of both the ketone and the aryl components
and generally gave excellent conversions and yields (Table 3).
Aryl substrates with substituents that uniquely define the
direction of the electrophilic attack such as m-xylene and
mesitylene were alkylated with acetophenone in excellent
yields and complete chemoselectivity, providing single
products 19 and 20, respectively (entries 1 and 2). Anisole
was alkylated in the para- and ortho-positions, in analogy to
the general selectivity of the Friedel−Crafts alkylation of
monosubstituted arenes (entry 3).65 Modification of the
ketone substrate from acetophenone to benzophenone 16
Figure 1. Time-conversion profiles for the consumption of
acetophenone in the reductive Friedel−Crafts alkylation of
acetophenone with toluene in the presence of 0.02 mol % 5a,
generated in situ from 3a (blue) and 15a (orange; conversion of
acetophenone monitored by H NMR spectroscopy, dioxane as the
internal standard).
1
This reductive Friedel−Crafts alkylation is presumed to be
the product of a cascade reaction starting from the iridium-
catalyzed hydrogenation of the ketone to the corresponding
alcohol (vide supra), followed by acid-mediated dehydrox-
ylation and formation of a carbocation for Friedel−Crafts
alkylation (Scheme 4). In agreement with the proposed
mechanism, HOTf on its own catalyzes Friedel−Crafts
alkylation of toluene with 1-phenylethanol, although the
reaction is dominated by the formal homocoupling of alcohol
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a
Table 3. Substrate Scope for Reductive Friedel−Crafts Alkylation
a
Reaction conditions: carbonyl compound (1.00 mmol), aryl compound (10 mmol), 3a (0.001 mmol), TfOH (0.03 mmol), H2 (1 atm), 80 °C, 5−
b
8 h. 19% of diphenylmethane as the side product.
resulted in quantitative conversion to triarylmethanes 22−24
(entries 4−6). Monitoring of the reaction of reductive
Friedel−Crafts alkylation of mesitylene with benzophenone
by 1H NMR spectroscopy indicated a transient resonance at δH
= 5.80 assigned to carbinol proton Ph2CH-OH (Figures S76
and S78), in agreement with the higher resistance of this
intermediate toward dehydration than 1-phenylethanol formed
from acetophenone. Time-dependent analysis of the reaction
composition provides excellent fit with a consecutive reaction
triarylmethanes due to double alkylation.47 Selective formation
of (phenyl)(aryl)methane products strongly supports the
proposed cascade mechanism with initial hydrogenation of
the aldehyde followed by Friedel−Crafts alkylation of the aryl
substrate. Moreover, substrates with more acidic α-hydrogen
protons such as 2-phenylacetophenone 18 led preferentially to
formal elimination from the carbocation intermediate and (E)-
stilbene 28 is produced predominantly, although Friedel−
Crafts alkylation of mesitylene also occurred, providing 27 as a
minor product (24%, entry 9).
This novel approach to triarylmethanes such as 22−24 is
attractive as such systems have been widely applied as core
structures for dyes,66 pH indicators,67 fluorescent probes,68,69
and as a valuable synthon in antitumor70 and antibacterial71
agents. For instance, triarylmethane 31 composed of three
different aryl groups displays attractive antibacterial activity in
vitro and in vivo against Mycobacterium fortuitum, Mycobacte-
rium tuberculosis, and other nontubercular mycobacteria.72
Here, we have applied the iridium-catalyzed reductive Friedel−
Crafts cascade to generate the heterotriaryl core of this potent
pharmaceutical from the commercially available precursor 29
in a single step and with high yield and selectivity (Scheme 6).
Further conversion of the triaryl product 30 into the final
and a markedly lower rate constant for hydrogenation, khydrog
=
=
0.35 h−1, than the subsequent Friedel−Crafts coupling, kFC
4.3 h−1 (Figure S77) This order of magnitude difference is in
agreement with the proposed mechanism and provides a
quantitative measure for the slow nature of the hydrogenation
vs Friedel−Crafts alkylation step.
Furthermore, high selectivity was achieved also with a
smaller amount of toluene (10 vs 40 equiv for acetophenone).
Interestingly, also aldehydes serve as substrates. Thus, heating
benzaldehyde (17) with mesitylene and toluene under the
optimized conditions produces (phenyl)(aryl)methane prod-
ucts 25 and 26, respectively, in excellent yields (entries 7 and
8). Previous attempts to use benzaldehydes for reductive
Friedel−Crafts alkylation under acidic conditions resulted in
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Research Article
Scheme 6. One-Step Synthesis of Precursor 30 of the
Antimycobacterial Agent 31
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c00740.
■
sı
Experimental procedures for the synthesis of iridium
complexes, spectroscopic data for all complexes and
products, general catalytic procedures and optimization
details, kinetic analysis, and crystallographic data. CCDC
1997999, 1998000, 1998001, 1998003, and 2004712
(PDF)
3b (CIF)
3c (CIF)
4a (CIF)
4b (CIF)
6bb’ (CIF)
AUTHOR INFORMATION
Corresponding Author
■
antibiotic has been previously described and is unproble-
matic.44 In comparison, such compounds were previously
prepared in a three-step procedure starting from phenyl
sulfone, which was coupled with 1-bromo-3-fluorophenyl and
subsequently with 4-iodoanisole in the presence of 10%
Pd(OAc)2, followed by desulfonation in the presence of 10%
Sc(OTf)3 in an overall 39% yield.44 While the procedure
presented here affords the triarylmethane 30 as a racemic
mixture, our work suggests that enantioselective product
formation may emerge upon replacing HOTf with a chiral
Brønsted acid rather than from an enantiopure iridium
complex.
Martin Albrecht − Department of Chemistry, Biochemistry &
Pharmaceutical Sciences, University of Bern, 3012 Bern,
Switzerland; orcid.org/0000-0001-7403-2329;
Email: martin.albrecht@dcb.unibe.ch
Author
Iryna D. Alshakova − Department of Chemistry, Biochemistry
& Pharmaceutical Sciences, University of Bern, 3012 Bern,
Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c00740
Author Contributions
CONCLUSIONS
■
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Here, we provide a synthetic access to iridium complexes 5a−c
containing both a metal-bound hydride and a triazolylidene-
bound proton, which can be considered as dihydrogen adducts
of complex 6 and consequently serve as a hydrogenation
catalyst in the presence of ketones. While these complexes
spontaneously lose H2, their hydride precursors 4a−c are
stable and can be activated with HOTf without compromising
the Ir−C bond and the catalyst’s integrity. Ketone hydro-
genation is not particularly fast, which has been exploited in a
cascade process involving subsequent acid-mediated Friedel−
Crafts alkylation via alcohol dehydroxylation. Tailoring of the
relative concentrations of ketone and the corresponding
alcohol intermediate as well as the arene substrate provides
excellent conversions and exquisite selectivities with low
catalyst loadings (down to 0.02 mol % iridium complex) and
with various different carbonyl substrates including aldehydes
and diaryl ketones. The latter systems offer a new approach to
pharmacologically interesting triarylmethane, though the
excess of arene currently required poses limitations if the
arene is precious. Key for this cascade process is the constantly
low concentration of in situ generated alcohol (to avoid
homocoupling and ensure high selectivity) as well as the
robustness of the Ir−C bond under the highly acidic Friedel−
Crafts conditions (to avoid catalyst degradation), revealing
unique benefits of such Ir−H/N−H systems. Based on these
conclusions, lower reaction temperatures may be accessible by
developing more active ketone hydrogenation catalysts that
preserve the inertness toward Brønsted acids.
Funding
The authors acknowledge generous financial support from the
European Research Council (CoG 615653) and from the
Swiss National Science Foundation (200021_162868 and
20021_182663, R’equip projects 206021_128724 and
206021_170755).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Aino Visuri and Fabio Notter for technical
assistance and the group of Chemical Crystallography of the
University of Bern for the X-ray analysis of all reported
structures. They acknowledge generous financial support from
the Swiss National Science Foundation (20020_182663).
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