Design, scope and mechanism of highly active and selective chiral NHC-iridium catalysts for the intramolecular hydroamination of a variety of unactivated aminoalkenes

Article abstract of DOI:10.1039/d0sc05884j

Chiral, cationic NHC-iridium complexes are introduced as catalysts for the intramolecular hydroamination reaction of unactivated aminoalkenes. The catalysts show high activity in the construction of a range of 5- and 6-membered N-heterocycles, which are accessed in excellent optical purity, with various functional groups being tolerated with this system. A major deactivation pathway is presented and eliminated by using alternative reaction conditions. A detailed experimental and computational study on the reaction mechanism is performed providing valuable insights into the mode of action of the catalytic system and pointing to future modifications to be made for this catalytic platform.

Full text of DOI:10.1039/d0sc05884j

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Design, scope and mechanism of highly active and
selective chiral NHC–iridium catalysts for the
intramolecular hydroamination of a variety of
unactivated aminoalkenes†
Cite this: Chem. Sci., 2021, 12, 3751
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
Daven Foster,a Pengchao Gao,a Ziyun Zhang,b Gellert Sipos,
‡
´
Alexandre N. Sobolev,c Gareth Nealon,c Laura Falivene,§b Luigi Cavallo
b
a
*
and Reto Dorta
Chiral, cationic NHC–iridium complexes are introduced as catalysts for the intramolecular hydroamination
reaction of unactivated aminoalkenes. The catalysts show high activity in the construction of a range of 5-
and 6-membered N-heterocycles, which are accessed in excellent optical purity, with various functional
groups being tolerated with this system. A major deactivation pathway is presented and eliminated by
using alternative reaction conditions. A detailed experimental and computational study on the reaction
mechanism is performed providing valuable insights into the mode of action of the catalytic system and
pointing to future modifications to be made for this catalytic platform.
Received 26th October 2020
Accepted 4th January 2021
DOI: 10.1039/d0sc05884j
rsc.li/chemical-science
or synthetic drugs and are abundantly encountered in
commodity and specialty chemicals. Among these, optically
1. Introduction
active N-heterocyclic compounds are of particular importance
and are found in 59% of FDA approved drugs.2 Six-membered
rings, ve-membered rings and fused rings are the most prev-
alent classes of ring systems. Specically, both pyrrolidines and
indolines are in the top ve most common ve-membered
nonaromatic nitrogen heterocycles in FDA drugs (Fig. 1).2
Piperidines, piperazines and morpholines all feature in the top
5 most common 6-membered N-heterocycles, with tetrahy-
droisoquinolines also being present in the structure of many
natural products. Overall then, reactions targeting the forma-
tion and alteration of nitrogen heterocycles are of high interest
and value.
Chiral N-heterocyclic compounds incorporating stereo-
centers adjacent to the nitrogen atom could potentially be
accessed through the use of an enantioselective olen HA
reaction starting from the appropriate aminoolen precursor
molecules. Although great progress has been achieved over the
Over the last decades, intense research has been devoted to
developing catalytic alkene hydroamination (HA) protocols, as
such a transformation would represent a very attractive route to
valuable nitrogen-containing compounds starting from simple
olen and amine precursors.1 An especially appealing factor of
these classical HA reactions is the fact that they represent a rare
example of a chemical transformation with almost perfect atom
economy, with the only waste material generated being the
spent catalyst.
While many studies have been devoted to advance the HA
reaction with the ultimate goal of discovering catalytic systems
able to couple the most simple HA partners, namely ammonia
and ethylene, a possibly even more interesting application of
the HA reaction lies in the area of asymmetric catalysis. Here,
the same reaction is able to form chiral, amine-containing
compounds that are ubiquitous scaffolds of natural products
aDepartment of Chemistry, School of Molecular Sciences, University of Western
Australia, M310, 35 Stirling Highway, 6009 Perth, WA, Australia. E-mail: reto.
dorta@uwa.edu.au
bKing Abdullah University of Science and Technology (KAUST), Chemical and Life
Sciences and Engineering, Kaust Catalysis Center, Thuwal 23955-6900, Saudi Arabia
cCentre for Microscopy, Characterisation and Analysis, University of Western Australia,
35 Stirling Highway, 6009 Perth, WA, Australia
† Electronic supplementary information (ESI) available. CCDC 2022610. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0sc05884j
‡ Current address: ComInnex Inc., Zahony Utca 7, 1031 Budapest, Hungary.
`
§ Current address: Dipartimento di Chimica, Universita di Salerno, Via Giovanni
Paolo II, I-84084, Fisciano, Italy.
Fig. 1 Representative 5- and 6-membered N-heterocycles.
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last two decades in developing such asymmetric HA reactions,
they are still far from being well established. Furthermore, the
variety of target structures has remained very limited and
research has mostly focused on accessing methylated pyrroli-
dines in optically enriched form. Advances since Marks' and
coworkers rst reports of asymmetric intramolecular HA reac-
tions (Fig. 2),3 have concentrated on developing the original
rare-earth systems and have expanded to include alkali and
alkaline earth metal catalysts as well as early-transition metal
compounds.4 Indeed, results by the groups of Schafer,5 and
most recently Sadow,6 have shown that chiral zirconium cata-
lysts are able to provide pyrrolidine products with high enan-
tiopurity and represent the current state of the art for these
asymmetric transformations. The major drawback that remains
with these catalytic systems is their highly sensitive nature and
very limited functional group tolerance that impedes a broader
implementation of this elegant synthetic methodology within
the chemical community. Moreover and as discussed above,
these systems have not been applied successfully to substrate
classes other than pyrrolidines, e.g. to indolines, piperidines or
similar.
Substitution of these air and moisture sensitive compounds
with more tolerant late-transition metal (LTM) catalysts would
without a doubt alleviate the problem, but the asymmetric HA
reaction of electronically unbiased amines and simple olens
has not yet been developed to the same degree with these
metals. For example, a single report exists in the literature for
the asymmetric intramolecular HA to access pyrrolidines, in
which Buchwald et al. use a cationic rhodium system with chiral
MOP-type ligands.7 In terms of developing intermolecular
versions of the asymmetric hydroamination reaction with
LTMs, known examples that employ simple olens and amines
are normally restricted to very particular types of olens and
amines as exemplied in Fig. 3.8,9 Progress has been made in
this eld over the last few years through discoveries pioneered
by Miura and Buchwald,10,11 who were able to overcome some of
these limitations by introducing formal intermolecular HA
reactions that use electrophilic aminating reagents and rely on
the use of an exogenous hydrogen source. These advances
though come at a price, as these processes employ super-
stoichiometric amounts of additives and are thus moving away
from the concept of atom economy epitomized by the classical
Fig. 3 Asymmetric intermolecular HA with simple amines/olefins.
HA reaction. Furthermore, because these reactions are cata-
lyzed by Cu–H species, they again pose unfortunate limitations
in terms of functional groups being tolerated (i.e. reducible
functional groups such as carbonyl groups).
Our entry into the asymmetric HA reaction was inspired by
a report where Stradiotto et al. had shown that simple
[IrCl(COD)]2 can act as a precatalyst in the intramolecular HA
reaction (Fig. 4, top le).12 Attempts by the same group at
developing chiral versions failed.13 Because one of our main
research themes evaluates the use of chiral sulfoxides as ligand
entities in asymmetric metal catalysis,14 we began studying Ir-
disulfoxides of general formula [Ir(disulfoxide)Cl]2 for the
Fig. 2 Asymmetric intramolecular HA reaction with lanthanides and
early-transition metals based catalysts.
Fig. 4 Selected LTM systems for the intramolecular HA reaction.
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asymmetric intramolecular HA (Fig. 4, bottom le).15 While NHC ligand using two identical 2,7-dicyclohexyl-1-naphthyl
these initial trials reached appreciable reactivity when applied units as side chains, giving NHC salts (DiPh-2,7-
to the generic intramolecular HA reaction of N-benzyl-2,2- SICyNap$HBF4) (1) and neutral iridium complex [(Ra,Ra,S,S)]-
diphenylpent-4-en-1-amine, they also showed rather low enan- 2Cl, as well as (2,7-FuCySICyNap$HBF4) (3) and diastereomers
tioselectivity (a maximum of 40% ee).
In the last few years, our group surmised that a potentially cationic iridium complexes whose structure is shown in Fig. 5.
more successful approach for increasing reactivity (and with it While synthetic details, a discussion as well as full charac-
of complex 4Cl. Ultimately, this led to the synthesis of six
the enantioselectivity) would be to use harder, cationic and terization can be found in the ESI,†21 we may point out the fact
monomeric [(L)3Ir]+ systems. To keep the overall electronic that these cationic, formally 14-electron complexes all show
situation in these complexes similar to the neutral, catalytically uxional behavior. The apparent uxionality that we see in
1
active IrCl(COD) fragment developed by Stradiotto, we specu- solution on the H NMR time scale may originate from either
lated that substitution of the anionic halide with an electron- a windshield-wiper mechanism as depicted on the top of Fig. 6
rich, chiral N-heterocyclic carbene (NHC) ligand might or from rotation around the NHC–[Ir] axis in a helicopter-type
provide a direct entry to catalytically active, monomeric movement (bottom of Fig. 6), with the latter being more likely.22
complexes of formula [Ir(NHC*)(COD)]+. Given the high
propensity of iridium compounds to undergo cyclometallation
events, we were well aware of the fact that such formally 14-
electron complexes might not be isolable, especially in light of
literature precedents with classical aryl-substituted NHCs that
undergo such decomposition events.16
Gratifyingly though, rst attempts indicated that the special
naphthyl-substituted side chain groups that characterize our
family of NHCs,17 is able to prevent decomposition of these
[Ir(NHC)(COD)]+ compounds by creating a stabilizing interac-
tion between the empty coordination site on the metal and one
of these naphthyl side chains.18 Even more rewarding was the
fact that this rst system showed markedly enhanced reactivity
compared to the simple system developed by Stradiotto and
allowed us to access optically highly enriched pyrrolidines when
introducing enantiopure [Ir(NHC*)(COD)]+ catalysts.19
2.2 Comparison of catalyst performance
We started our catalytic investigation by taking complexes 2[X]
and 4[PF6] and applying them to the model substrate N-benzyl-
2,2-diphenylpent-4-en-1 amine (5a) to access the corresponding
methylated pyrrolidine product 5b. Reactions were conducted
in NMR tubes using CD2Cl2 in order to be able to follow
conversions in real time, at relatively high concentrations
(0.6 M, 0.5 mL solvent volume), and xing the catalyst loadings
at 2 mol%. This rst set of experiments (Fig. 7) was performed
ꢀ
using the four catalysts with the identical PF6 counteranion.
[(Ra,Ra,R,R)]-4[PF6] (in red) outperformed [(Ra,Ra,S,S)]-2[PF6] (in
blue) and especially its diastereomeric sibling [(Ra,Sa,R,R)]-4
[PF6] (grey) and [(Sa,Sa,R,R)]-4[PF6] (green). Indeed, this latter
catalyst was not able to fully convert the substrate.
Herein, we provide a complete account of our studies using
[Ir(NHC*)(COD)]+ catalysts for the asymmetric intramolecular
hydroamination (HA). The rst aim of the study was to under-
stand whether incorporation of a more electron-rich backbone
onto our chiral NHC ligand would generate a more active
catalyst while maintaining the high selectivity seen in our
preliminary report with (Ra,Ra,S,S)-[(DiPh-2,7-SICyNap)Ir(COD)]
[X]. This was realized by substituting the chiral diphenyl back-
bone with a chiral, fused cyclohexyl unit, an approach that has
so far not been successful in chiral NHC ligand design.20
Secondly, we sought to expand the substrate scope of the
asymmetric intramolecular hydroamination of unactivated
aminoolens, focusing in particular on testing substrates that
contain functional groups that clearly sets this system apart
from known catalysts and on ring systems that have not been
investigated previously. Furthermore and most relevant to
future developments of this catalyst platform, we present
a detailed mechanistic investigation that employs a combina-
tion of experimental and computational techniques revealing
the likely processes at play for the enantioselective formation of
the products.
Fig. 5 Chiral cationic NHC–iridium complexes for catalytic testing.
2. Results and discussion
2.1 Cationic [(NHC*)Ir(COD)][X] precatalysts
Optically
pure
(S,S)-diphenyldiamine
or
(R,R)-dia-
Fig. 6 Possible ligand movements explaining fluxionality in 2[X]. Top:
minocyclohexane were incorporated into the backbone of the COD flip. Bottom: rotation around the NHC–Ir bond.
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Fig. 7 (a) Catalyst structures tested in the intramolecular HA reaction of 5a. (b) Catalytic HA reaction of model substrate 5a. (c) Plot of conversion
(%) of substrate 5a to pyrrolidine 5b vs. time (min) (left) for four different NHC*–[Ir] complexes at 2 mol%. DCM-d2 (0.5 mL), [5a] ¼ 0.6 M, [Ir] ¼
0.012 M. Plot of conversion (%) of substrate 5a to pyrrolidine 5b vs. time (min) (right) for (Ra,Ra,S,S)-2[X] at 1 mol% where X is PF6, BArF24 or NTf2.
1
DCM-d2 (0.5 mL), [5a] ¼ 0.6 M, [Ir] ¼ 0.006 M. Monitored using H NMR.
Enantioselectivity though followed the opposite trend for the data, as enantiomeric ratios of 5b varied from ca. 66 : 1 er (with
two top-performing catalysts, where [(Ra,Ra,S,S)]-2[PF6] was 2[BArF24]) to ca. 200 : 1 er (with 2[NTf2]).
more selective (98.5% ee) than [(Ra,Ra,R,R)]-4[PF6] (94% ee).
Here again, [(Ra,Sa,R,R)]-4[PF6] and [(Sa,Sa,R,R)]-4[PF6] were not
2.3 Catalytic results for pyrrolidine-type products
competitive and showed vastly diminished (and reversed)
selectivity (57% ee and ꢀ20% ee respectively). In this context,
two comments are warranted here. First, the enantioselectivity
for 5b recorded with [(Ra,Ra,S,S)]-2[PF6] sets a new benchmark
for systems that use substrate 5a (or its primary amine
analogue) and underline the validity of the catalyst design.
Second, [(Ra,Ra,R,R)]-4[PF6] is the rst catalyst to feature a fused
cyclohexyl backbone in its NHC ligand design which shows high
levels of enantiodiscrimination.20
With these results in hand, we moved ahead and started
a broader investigation into the substrate scope to access opti-
cally enriched, methylated pyrrolidine products using 2[NTf2] as
the catalyst of choice and the results are tabulated below (Table
1). In the rst row of reported products (5b–12b), we systemat-
ically varied the nitrogen substituent of the starting material.
This was done in order to gain insights into functional group
tolerance and also because the only other LTM system reported
thus far is extremely sensitive to slight changes of this benzyl
group.7a With catalyst 2[NTf2], products 5b to 12b are uniformly
accessed in high yield and with excellent optical purity, in some
cases approaching complete selectivity. Functional group
tolerance was just as satisfying, with the different benzyl
substitutions leading to excellent reaction outcomes. When
analyzing possible electronic effects of these substitutions by
looking at the kobs or TOF50 value, we do not see any apparent
trend that relates reactivity to the electronic nature of the benzyl
substitution. Replacing these benzyl groups with purely
aliphatic substituents is equally successful (11b, 12b), although
a slight erosion in enantioselectivity can be seen for the methyl
substituted substrate 12a (incidentally, 12a also shows the
fastest reaction rate). This probably indicates that a more
sterically encumbered N-substituent (5a to 11a) is benecial for
selectivity and is recognized by the catalyst structure. When
switching to the similarly sized, but electronically distinct N-
phenyl substituent, reactivity decreased dramatically and the
Overall though, we selected catalyst [(Ra,Ra,S,S)]-2[PF6] based
on its combination of high activity and excellent selectivity.
Before moving to test its applicability to a diverse range of
substrates, we nevertheless decided to perform a small study on
the effect of the gegenion on the reaction outcome (Fig. 7). For
ꢀ
this, we introduced BArF24 as a well-known and successful
ꢀ
alternative to PF6 in iridium catalysis,23 and also tested the
NTf2ꢀ counteranion, a moiety that to the best of our knowledge
has never been investigated in iridium (or rhodium) chem-
istry.24 The outcome of this study, where the catalyst loading
was lowered to 1 mol%, was rather unexpected as it showed that
2[NTf2] outperformed not only 2[PF6], but was also slightly more
active than 2[BArF24]. Overall reaction rates are impressively
high with corresponding TOF50 values increasing from 377 hꢀ1
(for 2[PF6]), to 1071 hꢀ1 (for (2[BArF24]), all the way to 1500 hꢀ1
for 2[NTf2], placing these catalysts on par or above the most
active HA catalysts reported (rare-earth systems). Analysing the
optical purity of product 5b also produced rather unexpected
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Table 1 Cyclization of aminoalkenes to pyrrolidines using catalyst 2[NTf2]a
Product
ee (%)
>99
95
98
92
20
437
97
91
92
1969
98
95
49
1312
>99
89
54
>99
91
25
99
92
9.4
211
90
89
Yieldb (%)
kobs (10ꢀ2 minꢀ1
)
31c
>71d
>1500d
TOF50 (hꢀ1
)
1357c
1148
520
Product
ee (%)
97
96
2.3
49.4
99
93
17
265
96
96
1.7
37.5
98
81
>99
95
12
98
95
1.9
42.0
96
88
1.5
>99e
75
41
Yield (%)
kobs (10ꢀ2 minꢀ1
)
>52d
>1125d
TOF50 (hꢀ1
)
258
32.6
1312
Product
ee (%)
97/99f,g
93
68
99/99f,g
92
75
94/77f,g
90
18
96/76f,g
93
7
86/63f,g
94
3.4
20f,h
69
—
—
88e,f (87)f,i
85 (93)
—
n/a
Yield (%)
91e,f
0.73j
6.4j
kobs (10ꢀ2 minꢀ1
)
TOF50 (hꢀ1
)
1467
1479
156
62.8
74.4
—
a
Conditions: [substrate] ¼ 0.6 M, 2 mol% Ir cat., solvent ¼ CD2Cl2 unless otherwise stated. Yields and ee values reported as an average of duplicate
runs. b Isolated yield. c 1 mol% Ir. d kobs and TOF50 values extrapolated from data as reaction nished upon rst 1H NMR scan (see ESI for details).
e
f
g
r.t. in TFT. 5 mol% Ir. Diastereomeric ratios: 1.1 : 1 (21b, 22b), 3 : 4 (23b), 1 : 1 (24b), 3 : 2 (25b). Isolated yields are for the mixture of
h
i
t
j
diastereomers. 80 ꢁC in 1,2-C6H4F2. 60 ꢁC in BuOH. Product precipitates out of solution in NMR tube, so observed kobs and TOF50 are only
a (conservative) estimate.
corresponding product is no longer obtained in optically derived 2,20-substituted backbone again gave essentially opti-
enriched form (92% yield, 9% ee, see ESI†).25
cally pure product 20b. While conversion to product was
Various 3,30-substituted spirocyclic pyrrolidine products quantitative, subsequent purication steps resulted in slightly
13b–17b were accessed next as shown in the second row of lower isolated yields. The yield of 16b with an N-methyl
Table 1. Here again, excellent reactivity produced methylated substituted piperidine spirocycle suffered from what appears to
pyrrolidines with very high optical purity. Hydrocarbon-based be catalyst inhibition and/or rapid catalyst decomposition as
spirocycles 13a–15a as well as dimethyl-substituted substrates observed in the corresponding time/conversion graph (see
18a and 19a provided high yields and enantioselectivities of the ESI†).
products. A spirocyclic, N-tosyl protected piperidine substrate
The next class of compounds tested featured unsymmetri-
(17a) was perfectly amenable to undergo cyclization, high- cally 2,20-disubstituted substrates (21a–25a). All of these
lighting the functional group tolerance of the present LTM compounds underwent cyclization to give diastereomer
system. Substrate 20a featuring an electron-poor, malonate- mixtures. Within this category, 2,20-disubstituted 21a and 22a
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gave rise to two diastereomers in roughly equal amount, with 8.79 ppm, and most diagnostically, the carbene signal appears
both resulting products showing excellent optical purity. at ca. 209 ppm (see ESI† for details).28 There is no evidence for
Kinetic resolution was also not observed in the case of racemic (Ra,Ra,S,S)-2[NTf2] in the spectrum (carbene peak ca. 188
N-benzyl-2-phenylpent-4-en-1-amine,
bromophenyl)pent-4-en-1-amine or N-benzyl-2-isopropylpent- solvent as the only plausible source of chloride.
N-benzyl-2-(4- ppm).29 Formation of (Ra,Ra,S,S)-2Cl must involve the DCM
4-en-1-amine (23a–25a), again giving rise to diastereomer
Unfortunately, a literature search on relevant decomposition
mixtures in approximately equal amounts. Not surprisingly, the of cationic [Ir]+ species, used extensively as catalysts to promote
single backbone substitution in the substrates resulted in lower (asymmetric) hydrogenation reactions in DCM, did not yield
overall reactivity, but reactions could still be run at room any pertinent information. (Ra,Ra,S,S)-2Cl seems to be produced
temperature giving high yields of isolated product. The enan- from the reaction of the pyrrolidine product 24b (a tertiary
tioselectivity of one of the diastereomers was consistently amine) with the methylene chloride solvent through a nucleo-
higher than that of the other. A straightforward explanation for philic substitution reaction (Menshutkin reaction). Generally,
these results would see a scenario where the backbone substrate these types of reactions are very slow with a half-life for trime-
substitution is recognized by the catalyst structure, and where thylamine and CH2Cl2 of a month,30 although well-dened and
omitting it (H instead of R) would lead to a certain loss of conned macrocycles are known to greatly accelerate the reac-
enantioselection due to a less ordered transition state (see also tion.31 In our case, it is reasonable to assume that the highly
2.9 for in silico discussions).
electrophilic nature of our catalyst is able to intermittently bind
Gratifyingly, a 2,20-diuoro substituted aminoalkene (27a) DCM and thus signicantly activate the carbon atom towards
was also amenable to cyclization to give the corresponding nucleophilic attack of our pyrolidine product as shown in Fig. 8
uorinated pyrrolidine product in high yield and optical purity (bottom center).32 The resulting, partially deuterated ammo-
(93% yield, 88% ee). Such partially uorinated pyrrolidines are nium salt 24c was indeed identied via high-resolution mass
of central importance in drug development,26 and our results spectrometry aer the catalytic reaction run.
show how the asymmetric HA reaction might be used for
The generation of neutral chloro-complex (Ra,Ra,S,S)-2Cl
accessing this family of compounds. Unfortunately, replacing during catalysis unfortunately also leads to product contami-
the uorine atoms by hydrogens and trying to ring-close the nation as 2Cl cannot be separated and removed efficiently
parent N-benzyl-pent-4-en-1-amine (26a) was not successful. during workup and column chromatographic purication of
While the intramolecular HA reaction did occur under forcing the organic products. Such behavior has been problematic in
conditions (80 ꢁC, 5 mol% cat.) to give acceptable yields of 26b other catalytic transformations, most notably with spent
(69%), the enantioselectivity of the transformation was negli- ruthenium-catalysts used in metathesis reactions.33 Aer
gible (20% ee). The last entry of Table 1 shows the unexpected unsuccessfully applying a literature procedure for removal of
outcome when subjecting N-benzyl-4-uoro-2,2-diphenylpent-4- Grubbs-type ruthenium catalyst contaminants,32a we developed
en-1-amine (28a) to the intramolecular HA reaction. This a protocol where the cationic iridium complex is reformed as its
substrate was chosen as a representative to possibly access 2[PF6] salt. The salt can then be separated aer the reaction run
a chiral quaternary carbon atom featuring a C–F bond. While by extracting the organic product into a nonpolar solvent at the
the ring-closing itself proceeded unexpectedly smoothly and beginning of the chromatographic purication procedure (see
rapidly, we were not able to isolate the desired product as it the ESI† for details). Nevertheless and before moving forward
rapidly formed iminium uoride 28b in close to quantitative and expanding the substrate scope for catalyst 2[NTf2], we
yield. Whereas the outcome was unfortunate, it should be wanted to identify a more suitable solvent where decomposition
pointed out that product 28b represents what appears to be the of the catalyst as described here can be excluded.
rst example of a naked uoride containing the 3,4-dihydro-2H-
2.4.2 Alternative reaction solvents. Initially, tBuOH was
chosen as a potential substitute for DCM. While we were
delighted to see that a protic solvent such as tBuOH represents
a suitable reaction medium (a run with model substrate 5a
giving high yield and similar enantioselectivity to DCM), solu-
pyrrolium cation motif.27
2.4 Catalyst decomposition and further optimisation
2.4.1 Menshutkin reaction/product contamination. For bility issues arose which prevented reactions to be performed at
some of the more challenging reaction runs shown in Table 2 room temperature. We then identied triuorotoluene (TFT) as
(e.g. single backbone substitution in the starting material, 23a– another potential alternative, as it has been used as a DCM
25a), NMR analysis of the mixture at the end of the catalytic run substitute in both organic reactions and more recently in metal-
revealed that a substantial part of the catalyst had transformed catalyzed transformations.34 Besides having the added benet
back to the neutral, catalytically inactive (Ra,Ra,S,S)-2Cl of a higher boiling point than DCM, applying a simple pre-
precursor as evidenced by the appearance of diagnostic signals saturation solvent suppression sequence also made it amenable
1
in their 1H and 13C NMR spectra. Specically and taking the to monitoring catalytic conversions via H NMR spectroscopy.
transformation of 24a to 24b as an example, the upeld protons To understand and compare the solvents' behavior under
involved in the C–H/p interaction between the backbone phenyl catalytic conditions, we rst monitored the conversion of model
and the 2-cyclohexyl group of the NHC ligand split into two pyrrolidine precursor 5a at 1 mol% 2[NTf2] (see ESI†), resulting
signals at ca. ꢀ0.16 and ꢀ0.54 ppm, the H8 proton of the in similar reaction speeds for DCM-d2 (kobs ¼ 27.0 ꢂ 10ꢀ2) and
naphthyl side chain experiences a downeld shi to ca. TFT (kobs ¼ 34.2 ꢂ 10ꢀ2).
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Gratifyingly, the superior performance of TFT became
apparent under more challenging reaction conditions
(0.5 mol% 2[NTf2]). At this very low loading where catalyst
decomposition is becoming problematic, full conversion of 5a
is no longer observed in DCM-d2 (ca. 70% maximum conver-
sion, kobs value of 3.1 ꢂ 10ꢀ2, Fig. 9). On the other hand, when
the same reaction is performed in TFT at room temperature, full
conversion of 5a to 5b was observed together with a substantial
increase in reaction rate (kobs ¼ 14.3 ꢂ 10ꢀ2).
Fig. 9 Plot of Ln([5a]/[5a]0) vs. time of model substrate 5a to pyrroli-
dine 5b vs. time (min) using (Ra,Ra,S,S)-2[NTf2] at 0.5 mol%. Reactions
conducted in DCM-d2 or TFT (0.5 mL), [5a] ¼ 0.6 M, [Ir] ¼ 0.003 M.
Conversion monitored using 1H NMR.
2.5 Catalytic results for indoline-type products
With this overall improved catalyst/solvent system, we turned
our attention to a challenging substrate of particular interest
(29a), which would furnish the model 2-methylated indoline
product 29b upon successful hydroamination. Such substituted
indoline motifs are found in many pharmaceutical
compounds,2 with the 2-methyl derivative featuring promi-
nently in the anti-hypertensive/diuretic drug indapamide (as
racemate) and in various potential anti-cancer drugs, among
them the selective PI3Kb inhibitor SAR-260301.35 Not surpris-
ingly then, a wide range of synthetic strategies have been
developed for the asymmetric synthesis of these structures.
Methods include the asymmetric hydrogenation of indole
precursors,36 or directly using indoline starting materials and
accessing optically pure compounds via kinetic resolution
strategies.37 Constructing the indoline unit via ring-closing of
appropriate precursors has also been explored, and formal
hydroaminations with chiral copper catalysts have been
described by both Chemler and Buchwald.11b,38
Fig. 10 shows hydroamination results as applied to model
substrate 29a, again recorded both in DCM-d2 and TFT. When
raising the catalyst loading to 5 mol% 2[NTf2], full conversion of
29a to the indoline product 29b was observed in both solvents at
room temperature. Comparing the two solvents led to a similar
increase in reaction rate as observed for pyrrolidine-type
substrates when switching from DCM to TFT (kobs ¼ 0.83 ꢂ
10ꢀ2 to kobs ¼ 3.4 ꢂ 10ꢀ2, i.e. a 4-fold increase). More impor-
tantly, the already high enantioselectivity recorded in DCM-d2
(90% ee) was substantially improved in TFT (95% ee), equating to
more than doubling the ratio of the preferred enantiomer of 29b.
Table 2 gives an overview of results for 2-methylated indoline
synthesis via our asymmetric HA protocol catalyzed by 2[NTF2].
The para-position of the starting aniline substrate was system-
atically varied with both electron-rich and electron-poor
substituents. Data indicate that there is a clear electronic
trend favoring cyclization of electron-rich aniline substrates.
TOF50 values reect this, ranging from 6.3 hꢀ1 (for 33a) to
55.1 hꢀ1 (31a) and 62.7 hꢀ1 (30a). Electron-poor substituents
such as 34a and 35a did not react at room temperature. Under
slight heating (60 ꢁC), cyclization did occur but a competing
side reaction involving isomerization of the double bond yiel-
ded lower than expected amounts of product (34b and 35b).
Trends in enantioselectivity were similar, with excellent
results obtained for 29b to 33b (95–97% ee), while an erosion of
optical purity was observed for 34b and 35b. A brief survey on
the substitution pattern of the aniline core showed mixed
outcomes with no apparent trends. Methyl substitution in both
ortho and meta positions forms products 36b and 38b in excel-
lent isolated yields and enantioselectivities, while a uoro-
substitution in the same positions proceeded smoothly, but
led to drastically lower optical purity of the products (37b, 39b).
Results for 38b are noteworthy for the fact that the speed of
reaction is dramatically increased, a result also reected by the
ortho-substituted naphthyl-type substrate 40a. How and why
catalytic turnover is facilitated for these substrates is currently
unknown, as is the reason for the drop in enantioselectivity
when going from 38b to 40b.
2.6 Catalytic results for six-membered N-heterocyclic
products
Results on classical asymmetric hydroamination protocols so
far show that catalysts that produce 5-membered rings with
high enantioselectivity ($90% ee) fail to deliver 6-membered N-
heterocycles with acceptable optical purity (or vice versa). Given
our excellent results on cyclizing both pyrrolidine- and indoline-
type substrates with 2[NTf2], we examined its performance with
a small range of substrates that would deliver important 6-
Fig. 8 Proposed deactivation pathway for 2[NTf2], forming 24c and
2Cl via the intermediate shown.
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Table 2 Cyclization of aminoolefins to give indolines using catalyst 2[NTf2]a
Product
2mol%/5mol%
95/95
97/99
ee (%)
96
83
97
87
97
99
96c
58
90c,d,e
68
Yieldb (%)
kobs (10ꢀ2 minꢀ1
)
1.7/3.3
36.7/29.3
6.2
62.7
7.1
55.1
1.9
16.5
0.5
6.3
—
—
TOF50 (hꢀ1
Product
)
ee (%)
72c,d
45
—
—
91
83
1.9
15.2
77
89
0.1
0.9
96
96
59
524
44
87
0.6
5.0
79
99
27
180
Yield (%)
kobs (10ꢀ2 minꢀ1
)
TOF50 (hꢀ1
)
a
Conditions: [anilino olen] ¼ 0.6 M, 5 mol% Ir cat., solvent ¼ TFT and conducted at r.t. unless otherwise stated. All yields and ee values reported
b
c
d
e
as an average of duplicate runs. Isolated yield. Only one run performed. Reaction conducted at 60 ꢁC. ee determined via Mosher amide
derivatization; single determination.
membered nitrogen-containing structures (Table 3). To do so, pyrrolidine (5b). Ring-expansion in the case of indoline-type
we evaluated substrates 41a to 45a, which upon cyclization substrates leads to tetrahydroquinoline 43b, which in fact
would furnish the parent methylated piperidine (41b), tetrahy- outperforms its ve-membered sibling in terms of optical purity
droisoquinoline (42b), tetrahydroquinoline (43b), tetrahy- of the product (97% ee), although longer reaction times were
droquinoxaline (44b) or the corresponding methylated dihydro- required to obtain full conversion. In contrast, tetrahy-
1,4-benzoxazine (45b).
droisoquinoline (42b) is formed almost instantaneously even at
The three entries on the top row (41b–43b) showed high low temperature (<3 min), but does not show the same high
reactivity with full conversion to their products. Unfortunately, selectivity observed for 43b (74% ee).
enantioselectivity for the formation of methylated piperidine
The last two entries (44b, 45b) underline the versatility of 2
41b was lower than for the analogous ve-membered [NTf2] further as the catalyst is also able to perform the HA
reaction to access heterocyclic rings with more than one
heteroatom. Here, catalyst recognition appears to be crucial
though, as we observe negligible enantioselectivity for 45b (22%
ee), whereas tetrahydroquinoxaline 44b is produced with very
high optical purity (90% ee).
2.7 Application of the HA reaction to access
a pharmaceutically important molecule
The intramolecular hydroamination reaction has been modi-
ed and improved over the past 30 years in order to delimit the
range of substrates available for such reactions with the ulti-
mate aim being its incorporation into reaction schemes that
access N-heterocycles of biological importance. To the best of
our knowledge, not a single such application has been per-
formed involving such a (asymmetric) hydroamination reaction.
Fig. 10 Plot of Ln([29a]/[29a]0) vs. time of substrate 29a to indoline
29b using (Ra,Ra,S,S)-2[NTf2] at 5 mol%. Reactions conducted in DCM-
The anti-tumor agent SAR-260301 (48), a pyrimidine indoline
amide PI3Kb inhibitor, was our synthetic target for investiga-
d2 or TFT (0.5 mL), [29a] ¼ 0.6 M, [Ir] ¼ 0.03 M. Conversion monitored
using 1H NMR.
tion (Fig. 11). Prior research had shown that the (S)-congured
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Table 3 HA of aminoolefins with 2[NTf2] to give 6-membered ringsa
With the above synthetic application, it becomes clear that
the asymmetric hydroamination has potential as a synthetic
methodology and with catalyst 2[NTf2], we would now also be
able to incorporate various functional groups into our indoline
core and study the effect of these on the modied pharmaco-
phores of 48 or related structures.
2.8 Experimental mechanistic investigations
Product
A number of mechanistic pathways have been investigated for
the hydroamination of alkenes. In terms of data available for
group 9 metal catalysts, one of the two predominant catalytic
cycles features an N–H oxidative addition, followed by insertion
into the bound olen and reductive elimination.8b–d,39 This
mechanism was uncovered for the intermolecular hydro-
amination reaction between norbornene or its derivatives and
anilines. Mechanistic evidence for both rhodium and iridium
catalyzed intramolecular hydroaminations point towards
a distinct mechanism where initial olen binding is followed by
external attack of the amine onto the olen to establish the C–N
bond, with subsequent hydrogen transfer to the terminal
alkene/alkyl position.7d,e,12b,40,41
Given that the present catalyst 2[NTf2] is rather distinct from
previously reported neutral iridium systems and given the fact
that detailed mechanistic investigations of chiral HA catalysts
are overall very rare,3b,4a,6,42 we decided to gain insight into the
mechanism at play with our catalyst system.
In addition, because the two major classes of starting
materials and products shown above (Tables 1 and 2) feature
electronically rather distinct amines (aliphatic for pyrrolidines,
aromatic for indolines), we also believed that mechanistic data
for both these substrate/product classes were required in order
to guide the development of future classes of chiral HA
catalysts.
Kinetic parameters were gathered for the HA of representa-
tive pyrrolidine educt 5a and indoline precursor 29a catalyzed
by 2[NTf2], with the reaction medium for all mechanistic
investigations set to TFT as the solvent for the reasons cited
above. Monitoring the disappearance and appearance of 5a/
b and 29a/b resulted in pseudo-rst order rate constants over
the course of (typically) 2–3 half-lives (1H NMR).
2.8.1 Kinetic order for pyrrolidine formation. Starting with
the order for pyrrolidine formation (5b), various concentrations
of [Ir] [3 to 9 mM (0.5–2.0 mol%)] were added to 5a (0.6 M) in
TFT at room temperature. Fig. 12a displays that a plot of reac-
tion rate (kobs) versus [Ir] was linear, indicating rst-order
kinetic dependence on catalyst. However, a non-linear least-
squares t to f(x) ¼ a[Ir]n resulted in an order (n) of 1.8, which
seems to t more with a second-order dependence of [Ir] than
a rst-order one (Fig. S4b, ESI†). However, it should be noted
that a relatively high degree of error is associated with each of
these pyrrolidine experiments as the reaction rates are unusu-
ally high under the conditions tested (2–10 minutes for 3 half-
lives).
ee (%)
Yield (%)
63
86
74b
98
97
99
Product
ee (%)
Yield (%)
a
90c
27
22
56
Conditions: [amine] ¼ 0.6 M, 5 mol% Ir cat., solvent ¼ TFT at 60 ꢁC
unless otherwise stated. All isolated yields and ee values reported are
b
c
averages of at least two runs. Reaction run at ꢀ9 ꢁC. Only one run
performed.
indoline core is signicantly more active than the (R)-enan-
tiomer. The enantiomers were accessed in optically pure form
aer a classical preparative HPLC separation step using chiral
stationary phases.34c
Direct access to SAR-260301 (48) was straightforward starting
with the asymmetric hydroamination of 29a using 2[NTf2] to
obtain the indoline core structure 29b, followed by deprotection
that furnished intermediate 46. The last step involved amide
bond formation by reacting 46 with sodium carboxylate 47
(synthesized from commercially available starting materials
over 2 steps in 32% yield) according to the published protocol to
directly furnish target compound (S)-SAR-260301 (48).
While we were not able to reproduce the reported yield for
this last step (44% yield, reported yield for racemic 48: 59%), we
were nevertheless able to access (S)-48 in 28% over only 3 linear
steps from 29a, with the high optical purity of 29b being
retained over the last two steps (see ESI† for details).34d
The kinetic order of pyrrolidine precursor 5a was investi-
gated subsequently by using a constant [Ir] (0.003 M) and
various concentrations of 5a (0.225–0.9 M). A decrease in
Fig. 11 Enantioselective synthesis of SAR-260301 (48).
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Fig. 12 (a) Relationship between kobs and [5a] (TFT, 25 ꢁC). Concentrations: [5a] ¼ 0.6 M and [Ir] ¼ 3 mM to 12 mM. (b) Relationship between kobs
and [5a] (TFT, 25 ꢁC). Concentrations: [5a] ¼ 0.225–0.9 M and [Ir] ¼ 6 mM. (c) Eyring plot for the hydroamination of 5a with 2[NTf2] (TFT, 0–60
ꢁC). Concentrations: [5a] ¼ 0.3 mM, [Ir] ¼ 0.03 mM with ee values 98.2–99.4% over this temperature range. Rate constants kR and kS determined
according to kR ¼ kobs(1 ꢀ ee)/2 and kS ¼ kobs(1 + ee)/2. (d) Arrhenius plot for HA of 5a with 2[NTf2] [for conditions, see (c)]. (e) Relationship
between kobs and [Ir] for 29a (TFT, 25 ꢁC). Concentrations: [29a] ¼ 0.6 M and [Ir] ¼ 6 mM to 30 mM (f) relationship between kobs and [29a] (TFT, 25
ꢁC). Concentrations: [29a] ¼ 0.15–0.45 M and [Ir] ¼ 15 mM. (g) Eyring plot for HA of 29a with 2[NTf2] (TFT, 0–60 ꢁC). Concentrations: [29a] ¼
0.3 mM, [Ir] ¼ 15 mM with ee values of 93.0–95.3% over this temperature range. Rate constants kR and kS were determined according to kR
¼
k
obs(1 ꢀ ee)/2 and kS ¼ kobs(1 + ee)/2. (h) Arrhenius plot for HA of 29a with 2[NTf2] [for conditions, see (g)].
reaction rate as initial substrate concentration increases was in order to obtain activation parameters for the hydroamination
observed, which is consistent with an inverse order dependence of 5a with 2[NTf2]; pseudo-rst order rate constants were
of the rate of reaction on substrate concentration. Similar to our extracted from linear plots of [5a]t versus time for each
kinetic order dependence on catalyst, the data are not clear-cut, temperature value. Activation parameters for the lower transi-
as substrate concentrations between 0.45-0.9 M all gave very tion state to pyrrolidine (S)-5b (DH‡ ¼ 6.2 kcal molꢀ1, DS‡ ¼
similar kobs values (Fig. 12b).
ꢀ39.4 cal Kꢀ1 molꢀ1) and for the higher transition state (R)-5b
2.8.2 Activation parameters for pyrrolidines. A series of (DH‡ ¼ 9.5 kcal molꢀ1, DS‡ ¼ ꢀ38.9 cal Kꢀ1 molꢀ1) were
reactions were employed over a range of temperatures (0–60 ꢁC) extracted from the Eyring plot (Fig. 12c). The diastereomeric
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transition states have a difference of DDH‡ ¼ 3.3 kcal molꢀ1
while the difference in order is DDS‡ ¼ 0.5 cal Kꢀ1 molꢀ1
,
,
olen. This would then mean that such an olen activation
mechanism is rather more likely than the amine-OA pathway,
indicating very similarly ordered transition states for the where work by Brookhart has seen the opposite electronic
formation of (S)-5b and (R)-5b.
trend.43
2.8.6 Kinetic isotope studies. Model pyrrolidine substrate
The Arrhenius plot (Fig. 12d) generates activation energy
values for the formation of the major enantiomer (S)-5b (Ea ¼ 5a and indoline substrate 29a were monodeuterated at the
6.8 kcal molꢀ1
10.1 kcal molꢀ1). The difference in activation energy DEa
)
and minor enantiomer (R)-5b (Ea
¼
¼
nitrogen in order to gain an understanding of the turnover-
limiting step of the mechanism through evaluation of the H/D
3.3 kcal molꢀ1 would correspond to product formation with an kinetic isotope effect (KIE, Fig. 14). The pseudo-rst order
approximately 200 : 1 ratio of (S)-5b versus (R)-5b, which is fully plots (see ESI Fig. S7†) of the cyclization of 5a and 5a-d1 in TFT
consistent with our experimentally obtained results.
at room temperature provided kobs values of 0.31 and 0.092
2.8.3 Kinetic order for indolines. Kinetic studies were respectively, resulting in a primary KIE (3.37). For the indoline
repeated for the indoline precursor 29a, with parameters as substrate, pseudo-rst order plots of 29a and 29a-d1 (see ESI
follows; [Ir] [6 to 30 mM (1.0–5.0 mol%)], and [29a] (0.6 M) in Fig. S8†) resulted in kobs values of 0.033 and 0.0195 respectively
TFT at room temperature. Fig. 12e shows that a plot of reaction and a smaller primary KIE (1.69). For both of these substrate
rate (kobs) versus [Ir] was linear, again suggesting rst-order classes, these results imply that breaking of the N–H bond or
kinetic dependence on the catalyst. In this case, a non-linear subsequent breaking of the Ir–H bond are part of the rate-
least-squares t to f(x) ¼ a[Ir]n provided (n) of 1.0, clearly con- determining step. Taken together with results from our Ham-
rming rst-order kinetics (Fig. S5b, ESI†).
mett study, the classical hydroamination pathway with initial
Studies on the kinetic order of indoline precursor 29a were oxidative addition of the amine (and subsequent insertion +
performed next by using a constant [Ir] concentration (0.015 M) reductive elimination) can be ruled out for indoline type
and systematically varying the concentration of 29a from 0.15 to substrates and appears highly unlikely for pyrrolidines as well.
0.45 M. Again, we notice a decreasing reaction rate as initial The difference in KIE values between 5a and 29a indicates that
substrate concentration increases, as expected for an inverse these two substrate classes go via transition states with differing
order dependence reaction rate from the substrate concentra- degrees of linearity.44
tion (Fig. 12f).
2.8.7 Summary of kinetic experiments. Kinetic analysis of
2.8.4 Activation parameters for indolines. Subsequently, the 2[NTf2] catalyzed asymmetric intramolecular hydro-
the activation parameters for the hydroamination of 29a with 2 amination to produce methylated pyrrolidine 5b and methyl-
[NTf2] were obtained over an extended temperature range (0–60 ated indoline 29b has revealed rst order dependance on [Ir]
ꢁC); pseudo-rst order rate constants were again derived from and inverse order dependance with respect to both substrate
linear plots of [29a]t versus time for each temperature value. The [5a] and [29a]. The difference in activation energies leading to
activation parameters for the lower transition state to indoline (R) or (S) product (DEa ¼ 3.3 kcal molꢀ1 for 5b, DEa
¼
(S)-29b (DH‡ ¼ 9.7 kcal molꢀ1, DS‡ ¼ ꢀ33.2 cal Kꢀ1 molꢀ1) and 1.3 kcal molꢀ1 for 29b) generated from Arrhenius plots is
for the higher transition state (R)-29b (DH‡ ¼ 11.2 kcal molꢀ1
,
reasonably consistent with experimental ee values (>99% ee for
DS‡ ¼ ꢀ36 cal Kꢀ1 molꢀ1) were once more extracted from the 5b, 95% ee for 29b). The Hammett study on appropriately para-
Eyring plot (Fig. 12g). In the case of these indolines, the dia- substituted derivatives of 29a gave a large negative r value,
stereomeric cyclization transition states have a difference of indicating that electron donating groups speed up the reaction,
DDH‡ ¼ 1.5 kcal molꢀ1, while the difference in order is DDS‡ ¼ a result in line with a mechanism involving external attack of
2.8 cal Kꢀ1 molꢀ1, indicating a slightly more ordered transition the amine onto the coordinated olen with concomitant charge
state for formation of (S)-29b.
build-up and subsequent formation of an ammonium cation.
Activation energy values were generated from the Arrhenius Finally, values recorded from the kinetic isotope effect analysis
plot (Fig. 12h) for the formation of the major enantiomer (S)- (kH/kD ¼ 3.37 for 5b, kH/kD ¼ 1.69 for 29b) suggest that a primary
29b (Ea ¼ 10.5 kcal molꢀ1) and minor enantiomer (R)-29b (Ea ¼ KIE is involved for both substrate classes. This means that
11.8 kcal molꢀ1). The difference in activation energy DEa
¼
1.3 kcal molꢀ1 equates to an approximately 10 : 1 (S) versus (R)
ratio of the respective enantiomers, therefore slightly under-
valuing the recorded enantioselectivity for 29b (95% ee).
2.8.5 Hammett study (indoline-type). The rate of the 2
[NTf2]-catalyzed asymmetric hydroamination reaction of 29a–
33a (see Table 2), i.e. the substrates that undergo HA at room
temperature, was plotted as a function of the para-substituent
on the 2-allyl aniline starting materials (Fig. 13). The conversion
of 29a–33a to 29b–33b in the presence of 5 mol% 2[NTf2] was
followed by 1H NMR to obtain reaction rates. The Hammett plot
gave a very large, negative r value of ꢀ4.5.
It is tempting to assume that this arises from the build-up of
Fig. 13 Hammett plot for HA of anilines 29a–33a with 2[NTf2] (TFT, 25
a positive charge on the nitrogen following its attack onto the ꢁC). Concentrations: [29a–33a] ¼ 0.6 M and [Ir] ¼ 0.03 M.
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breaking of the N–H (or Ir–H) bond is part of the turnover- intermediates bear only one chiral center on the carbon atom,
limiting step (TLS). with R and S conguration, respectively. The energy barriers for
While Hammett studies as well as KIEs clearly point towards the favored C–D transition states leading to the D1 and D2
a mechanism of nucleophilic amine attack followed by proton intermediates are 14.3 and 19.4 kcal molꢀ1 from the (Sc, RN) C1
migration and product liberation, the lack of spectroscopic and (Rc, SN) C2 diastereoisomers, respectively.
evidence of any catalytic intermediates and our inability to
The alternative routes (light blue and dark red proles in
clearly differentiate the TLS led us to examine the mechanism of Scheme 1) starting from the other two diastereomers (with
the reaction further via DFT calculations.
opposite absolute stereochemistry on nitrogen) were ruled out,
since they require much higher energy barriers, i.e. 32.2 and
27.8 kcal molꢀ1 from the (Sc, SN) C3 and (Rc, RN) C4 diastereo-
isomers, respectively. Formation of the resulting intermediates
D1 and D2 is calculated to be endothermic with respect to the
most stable IrI cycloammonio-alkyl intermediates C1 and C2.
The reaction is completed by reductive elimination corre-
sponding to the H transfer from the Ir center to the Ir-bound
terminal CH2 group of the substrate, with formation of the
desired product and regeneration of the catalyst. Overall, the D
/ E step is straightforward as it requires overcoming a relative
small energy barrier, lower than 10 kcal molꢀ1 for both the Sc
and Rc isomers. Formation of product E is thermodynamically
favored by almost 10.0 kcal molꢀ1 over starting material A. It is
worth noting that the H transfer step (C / D) is required to
facilitate the subsequent reductive elimination step. In fact, all
of our attempts to localize a direct hydrogen transfer C / E
failed.
On the basis of these mechanistic results, the rate-
determining step involves an H transfer reaction, which is in
agreement with the experimentally determined KIE results.
Nevertheless, the rate-determining step involves a different
transition state along the two pathways that lead to the forma-
tion of the respective enantiomers. For the formation of the R-
congured product, the initial ammonium to metal hydrogen
transfer (C2–D2) at 12.6 kcal molꢀ1 represents the RDS, while
for formation of the preferred S product, it is the subsequent
reductive elimination step (D1–E1) at 8.3 kcal molꢀ1 that is
minimally higher than transformation C1–D1.
2.9 Computational mechanistic investigations
The reaction mechanism catalyzed by 2[NTf2] has been theo-
retically investigated for 18a and 29a as representative classes of
pyrrolidine and indoline precursors.
2.9.1 Reactivity of the pyrrolidine-type substrate. As re-
ported above, the catalytic cycle occurring under the reaction
conditions can involve either the initial activation of the olen
functionality (C]C bond activation pathway) or of the amine
functionality (N–H bond activation pathway, see Scheme S1†).
At rst, we explored the different ways of substrate coordi-
nation to the catalytically active species A (14-electron complex
without naphthyl-Ir stabilization), and we localized the three
structures B1 (alkene coordination), B2 (nitrogen coordination)
and B3 (aminoolen coordination) reported in Fig. 15. Both
olen coordination and nitrogen lone pair coordination to the
metal, B1 and B2, are energetically favored, with the nitrogen
adduct (B2) being 5.2 kcal molꢀ1 more stable than A and the
alternative alkene adduct B1 being 1 kcal molꢀ1 higher in
energy with respect to B2. Finally, the chelating aminoalkene B3
coordination is disfavored by 13.4 kcal molꢀ1 due to the crow-
ded coordination environment at the metal center.
2.9.2 Olen activation pathway. Starting from intermediate
B1, the amine can approach the olen functionality in the C–N
bond formation step through different trajectories, leading to
the simultaneous formation of two chiral centers (one on the
expected carbon atom of the substrate, and the other one on the
nascent ammonium ion). The resulting four diastereomeric IrI
cycloammonio-alkyl intermediates C1–C4 are in dynamic
equilibrium, as depicted in Scheme 1. These ring closure steps
are reversible, as all routes are calculated to be energetically
viable (starting from B1 the barriers leading to C1–C4 are all
around 7–9 kcal molꢀ1). Consequently, transient diastereomers
will nally accumulate into the most favored (SC, RN) C1
conguration, lying at ꢀ6.8 kcal molꢀ1
.
The following step, corresponding to the hydrogen transfer
from the ammonium ion to the iridium, leads to formation of
the transient IrIII-hydride intermediates D1–D2. These
Fig. 14 Determination of KIE values for 5a and 29a.
3762 | Chem. Sci., 2021, 12, 3751–3767
Fig. 15 Coordination modes of the substrate to Ir (kcal molꢀ1).
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Scheme 1 Energy profile for C]C bond activation pathway for HA of pyrrolidine precursor 18a with catalyst 2. Free energies in kcal molꢀ1
.
Overall, DDGsS–R is calculated to be 4.3 kcal molꢀ1 in favor of competing C–D transition states since we retain that the steric
the formation of the Sc enantiomer, in agreement with the high scenario is rather similar in C–D and subsequent D–E steps.
enantioselectivity emerging from the experiments. For an easier
The geometries reported in Fig. 16 highlight that the steric
analysis, in the following we compare the geometries of the two hindrance of the catalyst seems to play a key role in the enan-
tioselection of the product formed due to repulsive interactions
between the substrate and the naphthyl rings as well as the
cyclohexyl groups on the ligand. The geminal methyls and the
phenyl group on aminoalkene 18 are placed away from the
NHC-ligand in the favored pathway, leading to the Sc product
(Fig. 16, top), while several unfavorable short distances between
the NHC-ligand and the aminoalkene are found in structures
along the Rc pathway (Fig. 16, bottom).
2.9.3 N–H bond activation pathway. The alternative N–H
bond activation pathway, starting from the coordination inter-
mediate B2, has also been explored (see Scheme S2†) for the
formation of the experimentally favored S product.
The unfavored thermodynamic of the intermediates
involved, together with unaffordable energy barriers for the
initial N–H bond activation step (50.5 kcal molꢀ1) and the
following olen insertion into the Ir–N bond (61.5 kcal molꢀ1),
mean that this pathway can be ruled out.
2.9.4 Reactivity of the indoline-type substrate. The favored
olen activation pathway for substrate 29a is reported in
Scheme 2. As already discussed, the catalytic cycle begins with
the nucleophilic attack of the nitrogen on the olen function-
ality in species B1, lying 1.6 kcal molꢀ1 below A. Differently from
substrate 18b, and the results reported in Scheme 1, the C–N
Fig. 16 Optimized geometries of the C–D (Sc, RN) and C–D (Rc, SN)
bond formation step is endothermic for all four diastereomers,
transition states.
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Scheme 2 Energy profile for C]C activation pathway for HA reaction of indoline 29a in the presence of 2. Free energies in kcal molꢀ1
.
and requires overcoming an energy barrier ranging from 10 to asymmetric hydroamination between norbornene and aniline,
16 kcal molꢀ1 for the different pathways.
we report the development of cationic iridium systems of
The Ir–C bond cleavage proceeds again via a stepwise general formula [(NHC*)Ir(COD)][X] that are able to cyclize
mechanism including the proton transfer to the Ir center (C / unactivated aminoalkenes with unprecedented ease. Particu-
D) followed by a C–H reductive elimination step (D / E). As larly noteworthy features of these new catalysts are the incor-
observed for 18a, only two pathways are energetically affordable, poration of a chiral, (monodentate) NHC steering ligand (a rst
which are those passing through transition states C1–D1 and in this chemistry) as well as the use of the NTf2 anion, again
C2–D2 (see Scheme 2). The high energy barrier of 34.2 and a moiety that despite the popularity of cationic iridium catalysts
30.6 kcal molꢀ1 required to reach transition states C3–D1 and in catalysis has no precedence in the iridium literature.
C4–D2, respectively, allows us to rule out these two alternative
pathways.
Hydroamination products that can be obtained include
a range of highly enantioenriched methylated pyrrolidines and
Formation of the two enantiomeric products is determined indolines as representatives of ve-membered N-heterocycles
by different steps: the ring closure step via transition state B1– ($95% ee). The same catalyst system 2[NTf2] can also be used
C1, requiring a barrier of 15.9 kcal molꢀ1 for the formation of for the construction of tetrahydroquinolines and tetrahy-
a SC center, with the following proton transfer being easy; on the droquinoxaline, where we again see formation of products in
contrary, the rst proton transfer step, via transition state C2– high optical purity ($90% ee). Other 6-membered heterocycles
D2, is rate determining for the formation of the RC center, such as tetrahydroisoquinolines or dihydro-1,4-benzoxazine are
requiring a barrier of 17.9 kcal molꢀ1. The calculated DDGs of produced just as easily, but are not obtained with the same level
2.0 kcal molꢀ1 indicates a clear preference for the formation of of enantioselectivity.
the SC isomer, in agreement with experiments. The different
The present catalytic system not only shows a rather broad
nature of the determining transition states along the two range of applicability, but also stands out as it is the rst late-
pathways for 29a nicely matches with the different entropic transition metal system that easily matches and exceeds intra-
contributions measured by kinetic experiments for the forma- molecular HA results obtained in the past with chiral early-
tion of the two enantiomers (see above).
transition or lanthanide based systems. It therefore means
that it is now possible to incorporate important functional
groups (e.g. carbonyl-containing FG) into substrates, rendering
the present protocol more amenable to its incorporation into
synthetic strategies of more complex organic molecules. To
underline the validity of 2[NTf2] as a catalyst in this context, we
3. Conclusions
Two decades aer Togni et al. had shown that neutral iridium
catalysts containing chelating diphosphines can effect the
3764 | Chem. Sci., 2021, 12, 3751–3767
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employed it to access a pharmaceutical compounds in optically Australian Research Council for generous funding
enriched form, namely SAR-260301, an anti-tumor agent that (FT130101713).
acts as a PI3Kb inhibitor. As far as we are aware, it is the rst
asymmetric synthesis of SAR-260301 and the rst example
where the classical hydroamination reaction is employed to
access a pharmaceutically relevant molecule or natural product.
Notes and references
¨
In the quest to understand the exact role of the catalyst and
in view of future developments of the platform, we conducted
a comprehensive experimental and computational investigation
on the system. These studies have furnished important results
with regards to both individual reaction steps of the catalytic
cycle as well as mode of enantioselection with the 2[NTf2]
catalyst.
Collectively, the results of the investigations indicate that these
asymmetric intramolecular hydroamination reactions commence
with coordination of the olen functionality to the catalytically
active 14-electron iridium species. The catalytic mechanism
proceeds via the following fundamental steps: (1) smooth and
reversible ring-closure through external amine attack, resulting in
formation of the C–N bond; (2) proton migration from the
ammonium unit of the formed zwitterionic intermediate to the
metal center, followed by (3) C–H reductive elimination affording
the desired N-heterocyclic product. The nature of the rate-
determining transition state (H migration to iridium) is in
agreement with the experimentally measured KIE parameters for
both pyrrolidine-type and indoline-type substrates.
On the other hand, the high enantioselectivities, as
measured experimentally from the difference in activation
energies generated from Arrhenius plots, was further validated
and explained by our in silico studies. These ascribed such
energetic differences to repulsive interactions between the
substrate and the naphthyl rings on the ligand in the unfavored
reaction pathways leading to the (R)-congured product, indeed
a result that is again in line with the experimental outcome for
substrates 23–25, where the erosion of enantioselectivity must
come from similar repulsion when accessing the respective
diastereomers. Such repulsive steric interactions also seem
responsible for the pronounced effects that the various
substituents have when performing the asymmetric intra-
molecular hydroamination on indoline-type substrates.
We are therefore condent that heterocycles that at present
(with 2[NTf2]) cannot be produced in high optical purity will be
accessible. With the in depth study provided here, we are now in
a position where computational modeling can be performed
before modifying and ne-tuning the steric bulk of our chiral
NHC ligand. These studies and related investigations are
ongoing.
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Acknowledgements
D. F. and P. G. thank UWA for a Research Training Postgraduate
(RTP) Scholarship. G. S. thanks UWA for an International
Postgraduate Research Scholarship (IPRS). R. D. thanks the
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