Ureate Titanium Catalysts for Hydroaminoalkylation: Using Ligand Design to Increase Reactivity and Utility

Article abstract of DOI:10.1021/acscatal.1c00014

Hydroaminoalkylation describes the atom-economical catalytic synthesis of amines by forming new Csp3-Csp3 bonds using readily available amine and alkene feedstocks. Herein, we describe an earth-abundant and cost-efficient titanium catalyst generated in si

Full text of DOI:10.1021/acscatal.1c00014

pubs.acs.org/acscatalysis
Research Article
Ureate Titanium Catalysts for Hydroaminoalkylation: Using Ligand
Design to Increase Reactivity and Utility
Manfred Manßen,§ Danfeng Deng,§ Cameron H. M. Zheng, Rebecca C. DiPucchio, Dafa Chen,
and Laurel L. Schafer*
Cite This: ACS Catal. 2021, 11, 4550−4560
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Hydroaminoalkylation describes the atom-econom-
3
3
ical catalytic synthesis of amines by forming new Csp −Csp bonds
using readily available amine and alkene feedstocks. Herein, we
describe an earth-abundant and cost-efficient titanium catalyst
generated in situ using commercially available Ti(NMe2)4 and a
simple to synthesize urea proligand. This system demonstrates high
TOFs for hydroaminoalkylation with unactivated substrates and
features easy to use commercially available titanium amido
precursors. Additionally, a high catalytic activity, scope of reactivity,
and regioselectivity are all demonstrated in the transformation of
unactivated terminal olefins with various alkyl and aryl secondary
amines. Finally, syntheses of useful amine-containing monomers
suitable for the generation of amine-containing materials, as well as
amine-containing building blocks for medicinal chemistry, are disclosed. These preparative methods avoid the necessity of glovebox
techniques and are modified to be useful to all synthetic chemists.
KEYWORDS: amines, titanium, ligands, catalysts, hydroaminoalkylation
aminoalkylation (Figure 1B) is an emerging reaction where
INTRODUCTION
■
3
3
the formation of a new Csp −Csp bond occurs by hydro-
functionalization of C−C multiple bonds with a C−H bond α
to the nitrogen of an amine. This strategy has proven to be an
efficient method in recent years.4 It is completely atom
economical, and the variant that avoids prefunctionalized
coupling partners and utilizes less toxic and less expensive
earth-abundant base metals features early transition metals
from groups 3−5. Since its first discovery by Clerici and
Maspero in 19809 and revival by Herzon and Hartwig in
2007,10 the scope of hydroaminoalkylation has been expanded
tremendously and several highly active catalytic systems, using
tantalum and titanium, have been developed.4,6,7,11,12 Titanium
is of particular interest for this application, as it is the second
most abundant transition metal,13,14 is inexpensive, is low in
toxicity, and is already used in many important industrial
processes.15 Titanium is also featured in well-established
catalytic transformations such as the Kulinkovic16 and
Atom-economical N-centered chemistry has been identified as
one of the “10 most sought after chemical transformations”,
sparking intense interest in developing new routes for catalytic
amination.1 The efficient synthesis of amine products is
important for generating small molecules relevant to the
pharmaceutical, agrochemical, and fine chemical industries.2 In
this regard, transition-metal-catalyzed hydroamination and
hydroaminoalkylation are powerful synthetic strategies for
the amination of alkenes to generate amine products with
100% atom efficiency from commercially available starting
materials.3−5 Specifically, titanium shows immense promise for
satisfying a longstanding industrial interest in being able to add
amines to alkenes.6,7 However, catalyst and reaction develop-
ment remain an area of ongoing investigation, due to the fact
that up to now there is no broadly useful catalyst system that
can use N-heterocycles and N-aryl- and N-alkylamines for
intermolecular reactions with both activated and unactivated
alkenes. Furthermore, the catalytic control of regio- and
stereoselective amination remains an unmet challenge.
Received: January 2, 2021
Revised: February 27, 2021
Published: March 30, 2021
Currently, the most commonly used concept for amine
synthesis in industry is the hydroformylation of alkenes, which
uses primarily cobalt- or rhodium-containing hydroformylation
catalysts and subsequent reductive amination (Figure 1A).8 In
general, this process favors the formation of linear amine
products. In contrast to this two-step approach, hydro-
https://doi.org/10.1021/acscatal.1c00014
© 2021 American Chemical Society
ACS Catal. 2021, 11, 4550−4560
4550

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Figure 1. Synthesis of amines using classic industrial hydroformylation and reductive amination (A) and alternative hydroaminoalkylation (B)
using early transition metals (left, titanium; right, tantalum) and (C) the titanium hydroaminoalkylation catalyst presented in this work.
Pauson−Khand reactions,17,18 Sharpless epoxidation,19 and
more recently in the catalytic synthesis of pyrroles.20−22,6,7
Starting from relatively inactive homoleptic systems (e.g.,
Ti(NMe2)4,23 TiBn4,24 Ta(NMe2)525)9 and highly electroni-
cally stabilizing indenyl ligands,26−28 the latest trends for
titanium as well as tantalum indicate that 1,3-N,X-chelated
catalyst systems (X = N, O) enhance the electrophilic
character of the early transition metals. This increased
electrophilicity coupled with the dynamic coordination
behavior of these ligands has afforded excellent reactivity
(Figure 1).6,29
For tantalum, 1,3-N,O-chelating ligands, including pyrido-
nate, amidate, and ureate ligands, were either used as
preisolated complexes or prepared in situ to realize improved
reactivities from the early catalyst systems reported.30−32
These same ligands have been featured in group 4 catalyzed
hydroamination.33−36 Whereas readily accessible acyclic ureate
tantalum catalysts delivered superior TOFs and TONs in the
reaction of N-methylaniline derivatives with either terminal or
challenging internal alkenes,37 cyclic ureate tantalum com-
plexes preferentially react with alkylamine substrates while they
retain good catalyst activity in the presence of N-methylaniline
(Figure 1B, right).38 However, in both cases organometallic
Ta(CH2SiMe3)3Cl2 was required as a catalyst precursor, which
can be handled reliably under an inert atmosphere but requires
an inconvenient multistep synthesis.
For titanium, 1,3-N,N-chelating ligands in the form of
primarily disubstituted aminopyridinate catalysts and mono-
coordinated formamidinate ligands (preisolated and in situ),
first reported by Eisen for the polymerization of propylene,39
were studied extensively in combination with the widely
commercially available and inexpensive titanium amido
precursor Ti(NMe2)4. Aminopyridinate complexes displayed
good activity for intramolecular hydroaminoalkylation40 to
form cyclopentyl-/cyclohexylamines and improved catalyst-
controlled selectivity for the intermolecular reaction of
styrenes/alkyl-substituted alkenes to generate linear prod-
ucts.41−44 Formamidinate complexes yield almost entirely the
branched hydroaminoalkylation products45 and can be used
with gaseous industrially relevant feedstocks such as dimethyl-
amine46 and ethylene.47 In general, these titanium amido
catalysts need harsh reaction conditions (up to 180 °C in n-
hexane) with reaction times of up to 96 h. However, the latest
results by the Doye group showed that the in situ preparation
of a monocoordinated formamidinate titanium complex using
TiBn4 as the organometallic starting material and solvent-free
conditions results in a catalyst system that gives reaction times
of minutes rather than days (Figure 1B, left).48 Unfortunately,
4551
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
the multistep synthesis of the ligand and the use of light- and
temperature-sensitive TiBn4 (storage at −30 °C in the
glovebox) make this catalyst inconvenient. This is especially
problematic to those without the necessary Schlenk and
glovebox equipment. These general limitations of early-
transition-metal catalysts are hindering the broad scale use of
such reactive metals as catalysts for hydroaminoalkylation in
synthesis.
Table 1. Benchmark Hydroaminoalkylation Reaction of
Norbornene and 4-Methoxy-N-methylaniline for In Situ
a
ligand Screening for Ti1 and Ti2
Challenged by this perceived limitation, we were highly
interested in developing a titanium catalyst for hydro-
aminoalkylation, which not only shows excellent reactivity
and substrate scope but also is an easy to use catalyst that is
generated in situ with easily synthesized ligands and
commercially available titanium sources. Therefore, we
investigated a broad range of 1,3-N,X-chelated (X = N, O)
catalysts to identify the optimal ligand class to provide the
most active system. Moreover, we demonstrate the difference
in reactivity of isolated versus in situ prepared catalysts with
this set of hemilabile ligands. We demonstrate the high
reactivity and selectivity for the branched hydroaminoalkyla-
tion product through various transformations of unactivated
and activated terminal alkenes with alkyl- and arylamines as
well as an N-heterocycle. Finally, we feature a reaction
procedure that avoids glovebox techniques and we demon-
strate its utility in the synthesis of monomers suitable for
making N-containing polymers49,50 and the synthesis of
building blocks for medicinally relevant amine small molecules.
LIGAND DESIGN AND SCREENING
■
For the identification of the most active catalytic system, we
established a rapid ligand screening procedure for probing a
diverse set of 1,3-N,X-chelating (X = N, O) ligand effects in
hydroaminoalkylation catalysis. The reactive catalyst system
was generated in situ (Table 1) through a protonolysis reaction
of 2 equiv of the ligand to 1 equiv of the metal precursor (10
mol %) to study their activity in the NMR tube scale
hydroaminoalkylation reaction between norbornene and 4-
methoxy-N-methylaniline in toluene-d8 at 160 °C for 24 h.
These conditions were used as a starting point for our
investigations due to the fact that titanium hydroaminoalky-
lation catalysts are known to have high temperature require-
ments,6 whereas the substrates were chosen because of their
established excellent reactivity in hydroaminoalkylation due to
favorable amine electronic effects and alkene ring strain.6,7 The
conversions to the hydroaminoalkylation products were
1
determined by H NMR spectroscopy via integration of the
a
Reaction conditions: 4-methoxy-N-methylaniline (0.5 mmol),
signals of the ortho protons of the aromatic amines of the
starting material and product at 6.3 and 6.4 ppm, respectively.
For the titanium source we decided to use the widely
commercially available and inexpensive titanium amido
precursor Ti(NMe2)4 (Ti1) and organometallic
Ti(CH2SiMe3)4 (Ti2), inspired by the work of the Doye
group on organometallic TiBn4 and our work on Ta-
(CH2SiMe3)3Cl2.37,38,48 In general, such organometallic
catalyst precursors are inconvenient to use in comparison to
titanium amido precursors such as Ti(NMe2)4 (Ti1), due to
their laborious syntheses and specialized storage requirements.
First, we tested the homoleptic titanium sources without any
addition of supporting ligands. Ti(NMe2)4 (Ti1) is one of the
first ever tested catalysts for hydroaminoalkylation, and it is
known for its low reactivity even with activated substrates
(20% after 24 h, 78% after 96 h).24 In comparison,
Ti(CH2SiMe3)4 (Ti2) shows similarly low activity under our
norbornene (0.5 mmol), Ti1/Ti2 (0.05 mmol), ligand (0.10
mmol), toluene-d8 (0.7 mL). The conversion was determined by H
NMR spectroscopy (integration of ortho proton signals of the product
vs the starting material).
1
conditions (16% after 24 h). Unfortunately, further inves-
tigations with the use of supporting ligands did not justify the
use of Ti2 as the titanium source, because in all cases the
conversions were comparable to or lower than those of Ti1
(>10% difference). Additionally, we observed the formation of
polynorbornene in several cases, which is likely attributed to
the ring-opening metathesis polymerization (ROMP) of
norbornene51 catalyzed by the in situ formation of titanium
carbene complexes, via α-H abstraction of the CH2SiMe3
ligand.
4552
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
1
Next we decided to focus our studies on the commercially
available Ti(NMe2)4 (Ti1). Our group in the past has
demonstrated the use of tantalum pyridonate catalysts for
intermolecular hydroaminoalkylation32 and titanium pyrido-
nate complexes for accessing intramolecular hydroaminoalky-
lation over hydroamination.31 In both cases, 2-substituted
pyridonate ligands showed good activity for these trans-
formations and 3-methylpyridin-2-ol (L1) was an especially
excellent candidate for intermolecular catalysis.52 However, the
reaction of norbornene with 4-methoxy-N-methylaniline and
Ti1 as the titanium source and pyridone L1 as the proligand
produced only small amounts of product (23%).
scale. The yields were determined by H NMR spectroscopy
using 1,3,5-trimethoxybenzene as an internal standard by
integrating the signal of the ortho protons of N-methylaniline
vs the signal of the internal standard at the start of the reaction
and comparing this value with the signal of the ortho protons of
the amine product vs the internal standard at various points as
the reaction progressed.
For our first investigation we chose ureate ligand L7 with 1,
2, and 3 equiv relative to 5 mol % of Ti(NMe2)4 (Ti1) catalyst
loading and stopped the reaction after 3 h. In general, for
titanium catalysts in hydroaminoalkylation mono- and bis-
ligated complexes with 1,3-N,X ligands have been extensively
investigated, while tris-ligated complexes are unfavorable due
to the steric congestion about the metal center.6,7 Here, we
observed for the 1/1 metal/ligand system quantitative yields
after 3 h, while 2 and 3 equiv achieved significantly lower but
comparable yields to each other of 70% and 67%, respectively.
This indicates that the monoligated ureate ligand L7/
Ti(NMe2)4 (Ti1) in situ system is preferred. However, to get
a better understanding, we determined turnover frequencies
(TOFs) for the reaction for the mono- and bis-ligated catalyst
systems using the same conditions (Figure 2). Due to the
difficulty in accurately determining the reaction yields at early
stages of the reaction, time points for the first 30 min of the
reaction were not considered.
We further explored the use of carbamates L2 and
sulfinamides L3. Even though the latter are known to be
versatile ligands in other enantioselective catalytic trans-
formations,53 they have not been used in early-transition-
metal-catalyzed hydrofunctionalizations. Unfortunately, both
ligand classes are very susceptible to nucleophilic attack, as
evidenced by the identification of ligand byproducts via GC-
MS, and no hydroaminoalkylation products were observed.
Additionally, it was not possible to identify or isolate L2 and
L3 after the reaction, which further confirms the reaction
between the ligands and the hydroaminoalkylation substrates.
Encouraged by our work on titanium catalyzed hydro-
amination,54−57 we investigated the reactivity of amidate
ligands. Ligands L4 and L5 showed excellent activity with
90% and 97% yields, which is particularly interesting, as both
these ligands are known to have excellent activity for titanium-
catalyzed hydroamination as well. Furthermore, we tested
ureate ligands, which have been used to great advantage in
tantalum catalyzed intermolecular hydroaminoalkylation.37,38
Here one of the most active ureates for tantalum-catalyzed
hydroaminoalkylation, L6,58 showed good results with 92%
yield; this ligand can be further sterically enhanced to achieve
the best observed yield for this reactivity screening
(quantitative for L7). These findings indicate that both
amidate and ureate ligands are particularly suitable for
enhancing the reactivity of the early-transition-metal center.
Finally, inspired by the work of the Doye group on
aminopyridinate and formamidinate ligands,40−47 we tested
the guanidines L8 and L9 to expand knowledge of the
reactivity of 1,3-N,N-chelating ligands for hydroaminoalkyla-
tion. However, even though the Doye group could
demonstrate highly active systems formed with the 1,3-N,N-
chelating ligand class, these two candidates underperformed
significantly (0−33% yield). In the case of L8, this is
specifically attributed to the reaction of the ligand with excess
4-methoxy-N-methylaniline under Lewis acidic conditions to
form the corresponding guanidine, which could be isolated
after the screening. This process inhibits hydroaminoalkylation,
and L8 and L9 were deemed unsuitable.
Figure 2. Yield vs time plot observed for the reaction of N-
methylaniline and 1-octene for L5 (diamonds), 1 equiv of L7
(squares), and 2 equiv of L7 (triangles).
For both in situ catalyst systems, with 1 and 2 equiv of ureate
ligand L7, linear behavior was observed for the reaction
progression over time from 30 to 70 min (Figure 2), giving
TOF’s for both systems. Here, the monoligated ureate ligand
L7/Ti(NMe2)4 (Ti1) in situ system shows slightly higher
initial TOFs for the reaction of N-methylaniline and 1-octene
(Figure 2, 11 h−1) in comparison to the catalyst system with 2
equiv of ureate ligand L7 (9 h−1). What is most notable is that
the catalyst generated with 2 equiv of the ligand starts with a
significantly lower yield at 30 min, consistent with a more
significant induction period. This indicates not only that the
additional ligand slightly interferes with the hydroaminoalky-
lation mechanism by blocking one of the coordination sites for
incoming substrates47,59,60 but also that the additional ligand
perhaps has to be exchanged by amine substrates at higher
temperatures during the induction period to achieve reactivity
With the identification of the amidate ligand L5 and ureate
ligand L7 in combination with the commercially available
titanium amido precursor Ti(NMe2)4 (Ti1) as the preferred
candidates, we explored further reactivity studies to optimize
concentrations and ligand equivalents and we compared in situ
catalyst preparations with preisolated catalyst behavior.
REACTIVITY STUDIES
■
For our reactivity studies with amidate ligand L5 and ureate
ligand L7 in combination with Ti(NMe2)4 (Ti1) we used
0.5 mmol of N-methylaniline and 0.5 mmol of unactivated 1-
octene with a catalyst loading of 5 mol % on an NMR tube
4553
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
similar to that of the monoligated system. With a TOF of 11
h−1, our monoligated ureate ligand L7/Ti(NMe2)4 (Ti1)
system demonstrates excellent activity for this specific reaction
with unactivated substrates and compares favorably to other
titanium catalysts based on commercially available Ti(NMe2)4
(Ti1). Furthermore, there is no indication of interference of
the liberated dimethylamine in the hydroaminoalkylation
process, which has been observed in other systems (vide
infra).41,42,45,61
We were interested in a direct comparison of the L7/Ti1 in
situ system to the preisolated titanium catalyst. However, even
when the temperature was lowered to −30 °C and addition of
the ligand to a very dilute solution of Ti(NMe2)4 (Ti1) was
slow, only a mixture of mono- and bis-ligated titanium ureate
complexes could be isolated. This has been reported with other
1,3-N,X-chelating ligands (X = N, O) on titanium.62,63 With
further reaction monitoring, the mixture was observed to
further disproportionate to Ti(NMe2)4 (Ti1) and bis-ligated
titanium ureate complex Ti3 at room temperature overnight,
suggesting that the bis-ligated titanium ureate complex Ti3 is
the thermodynamic product. This is consistent with the
observation that Ti3 can be rapidly and selectively synthesized
by addition of 2 equiv of ureate ligand L7 to Ti(NMe2)4 (Ti1).
The resulting product was characterized by single-crystal X-ray
diffraction (Figure 3).64 Interestingly, isolated Ti3 shows initial
with a TOF of only 3 h−1. This is consistent with the finding
that ureate ligands afford more reactive tantalum hydro-
aminoalkylation catalysts in comparison to amidate com-
plexes.37,38 This enhanced reactivity of ureate ligands can be
attributed to the enhanced electrophilic character of the metal
center.
This work resulted in the identification of the optimized
method for carrying out these reactions; an in situ catalyst
synthesis using a 1/1 ratio of ureate ligand L7 and Ti(NMe2)4
(Ti1). The confirmed favorable reactivity with both activated
(norbornene) and unactivated (1-octene) hydroaminoalkyla-
tion substrates demanded further investigation of the amine
and alkene scope of this system.
SCOPE OF ALKENES AND AMINES
■
First, we sought to explore the alkene substrate scope of the
catalyst system prepared with Ti1 and L7 for N-methylaniline
and terminal alkenes (Table 2) using similar NMR tube scale
reactions (160 °C, 0.5 mmol of hydroaminoalkylation
substrates, 1,3,5-trimethoxybenzene as internal standard).
Reaction times were adapted to favor maximized yields while
a minimal catalyst loading was maintained.
For the reaction of 1-octene (Table 2, entry 1) quantitative
yields with excellent regioselectivities for the branched product
Table 2. Substrate Scope of Ti1 and L7 for
Hydroaminoalkylation of Various Alkenes with N-
a
Methylaniline
Figure 3. ORTEP representation of the molecular structure of Ti3
(50% probability; hydrogen atoms are omitted for clarity). Selected
bond distances (Å) and angles (deg): Ti1−O1 2.1014(11), Ti1−O2
2.1632(11), Ti1−N1 2.0852(12), Ti1−N2 2.1387(12), Ti1−N4
1.9245(13), Ti1−N5 1.9108(13), O1−C1 1.2992(17), O2− C2
1.2868(17), N1−C2 1.3422(18), N2−C1 1.3259(17), N3−C1
1.3558(17), N6−C2 1.3628(18); N1−Ti1−O2 62.08(4), N2−Ti1−
O1 62.19(4), N4−Ti1−N5 97.27(6).
rates and an induction period to the reaction similar to those
observed for the in situ experiment with 2 equiv of ureate
ligand L7 (identical TOF of 9 h−1, see the Supporting
Information). This indicates that Ti3 was rapidly formed in the
in situ investigations.
Finally, we investigated the TOFs for the in situ use of 1
equiv of amidate L5 with Ti(NMe2)4 (Ti1) for the reaction of
N-methylaniline and 1-octene (Figure 2). Whereas for the
reaction of norbornene with 4-methoxy-N-methylaniline over
24 h the amidate L5 and ureate L7 seemed to be
interchangeable, here L5 gave a catalyst that was less reactive
a
Reaction conditions: N-methylaniline (0.5 mmol), alkene (0.5
mmol), toluene-d8 (0.7 mL), 1,3,5-trimethoxybenzene (0.17 mmol),
catalyst loadings as shown. Yields were determined by 1H NMR
spectroscopy (integration of product signals vs internal standard).
Selectivity was determined by GC analysis.
4554
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
are achieved within 2 h, which is considerably faster than those
of other reported easily assembled titanium catalysts based on
Ti(NMe2)4 (Ti1),41,42,45,61 and approaches the reactivity of
the corresponding acyclic ureate tantalum catalysts.37,58
Interestingly, for the in situ system of Ti1 and L7, catalyst
loadings can be reduced to 1% for this specific reaction with 1-
octene; however, the reaction times increase to 72 h to obtain
a quantitative yield.
Table 3. Substrate Scope of Ti1 and L7 for
Hydroaminoalkylation of Various Amines with 1-Octene
a
With an increase of steric bulk on the alkene, including
benzyl, cyclohexyl, and phenyl (Table 2, entries 2−4), the
reaction times increase slightly, but all reactions are still
completed within one workday (<8 h). Interestingly, there is
no notable alkene electronic effect upon reactivity, as
cyclohexyl- and phenyl-substituted alkenes require comparable
times to reach quantitative yields. However, the changing
electronic environment does affect the regioselectivity, such
that the selectivity for the branched product decreases with the
use of styrene substrates. This is attributed to the inverted
electronic characteristics of styrenes, which can afford the
formation of the linear hydroaminoalkylation product, in
comparison to alkyl-substituted alkenes.6,41,42,65 A similar shift
from the preferential formation of the branched product (entry
5, b/l = 61/39) could be observed with trimethylvinylsilane,
another electronically varied alkene.
Furthermore, we tested alkenes with silyl-protected alcohols,
which are interesting substrates for post-hydroaminoalkylation
functionalizations to generate N-containing fine chemicals
(vide infra). Here, the allyl substitution pattern (Table 2, entry
6) requires a dramatically increased reaction time and catalyst
loading (48 h, 20%) and, even under these forcing conditions,
complete conversion cannot be achieved (71%). Similar
behavior has been observed for the few hydroaminoalkylation
catalysts reported for use with protected allylic alcohol
substrates,11,66 while many other catalysts are incompatible
with this starting material.6 This is likely due to steric crowding
and a reduction of electrophilic character at the reactive metal
center due to coordination of the silyl ether functionality
during the alkene insertion step (see B, Figure 4). Accordingly,
by addition of one more carbon atom to the alkyl chain of the
silyl-protected alcohol (entry 7), excellent reactivity is restored.
We next focused our attention on exploring the amine
substrate scope (Table 3). Consistent with previous work,
para-substituted N-methylaniline derivatives (entries 1 and 2)
are well tolerated, including halide substituents, which are
a
Reaction conditions: amine (0.5 mmol), 1-octene (0.5 mmol),
toluene-d8 (0.7 mL), 1,3,5-trimethoxybenzene (0.17 mmol), catalyst
loadings as shown. Yields were determined by 1H NMR spectroscopy
(integration of product signals vs internal standard). Selectivity was
determined by GC analysis.
compatible with d0 titanium that does not undergo oxidative
addition to aryl halides. Such aryl halides can then be used in
further cross-coupling reactions with late-transition-metal
cross-coupling catalysts.67−69 Furthermore, for a test of the
more sterically demanding N-benzylaniline and 1,2,3,4-
tetrahydroquinoline (entries 3 and 4) the reaction times had
to be increased to 16 h and for 1,2,3,4-tetrahydroquinoline the
catalyst loading had to be doubled, but in both cases good
yields and only slightly lower regioselectivities were observed.
Finally, we investigated the reactivity of dialkyl-substituted
amines. To our delight, very challenging substrates such as N-
methylcyclohexylamine and N-butylmethylamine (entries 5
and 6) provided great yields and regioselectivities after 24 h.
This is interesting, as the corresponding acyclic ureate
tantalum complexes were not reactive for dialkylamines.37
Furthermore, this is a rare example of a titanium catalyst that
achieves excellent yields for hydroaminoalkylation with both
aryl- and alkylamines.
EASY TO USE CATALYST SYSTEM
■
Titanium and tantalum catalysts based on commercially
available M(NMe2)n (such as Ti1) are known to be susceptible
to side reactions and inhibition of catalytic turnover due to the
release of dimethylamine during the induction period.48
Dimethylamine can inhibit the formation of titanaaziridines
A with the amine substrate, the catalytically active species for
the hydroaminoalkylation59,60 and consequently reduce the
catalytic activity (Figure 4). For example, this “unwanted” side
Figure 4. General mechanism for the titanium-catalyzed intermo-
lecular hydroaminoalkylation of alkenes that gives the branched
product using terminal alkenes.
4555
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
reaction has been used to advantage in a recent report where
dimethylamine was a useful substrate for hydroaminoalkyla-
tion.46 Typically, to avoid unwanted reactions with the
dimethylamine released upon catalyst activation, and to
achieve high reactivities using Ti1 for the generation of
catalysts, the released, gaseous dimethylamine must be released
from the reaction system.
Recently, we reported the synthesis of secondary amine
containing polymers using the tantalum-catalyzed hydro-
aminoalkylation of dienes and subsequent ring-opening
metathesis polymerization (ROMP).49,50 This strategy has
opened a new avenue to synthesize amine-functionalized
materials with tunable rheological and mechanical properties,
and improved methods featuring green, easy to use, and
inexpensive titanium catalysts would make these materials
more accessible. With our new catalyst we reacted N-
methylaniline with norbornadiene (NBD) and 1,5-cyclo-
octadiene (COD) neat to generate amine-containing mono-
mers 1 (98 mg) and 2 (107 mg), respectively, suitable for
subsequent ROMP (Figure 5a). Both reactions are completed
Interestingly, our reactivity studies using Ti1 and L7 did not
show any indication of unproductive reactions with dimethyl-
amine, even though the reactions were carried out in small J.
Young NMR tubes with little headspace. Consequently, we
tested a variety of reaction vessels with different volumes of
headspace to confirm the negligible relevance of dimethyl-
amine on catalytic activity. For this study, we used the same
benchmark reaction of N-methylaniline and 1-octene with 5%
catalyst loading and scaled the reactions to 1.0 mmol of amine.
Additionally, we avoided the use of solvent and instead
proceeded with neat reaction conditions using 2.5 equiv of the
alkene. Neat reaction conditions have been used to improve
the catalyst activity in some reported cases48 and are especially
interesting in the field of green chemistry (vide infra). The
conversion to the hydroaminoalkylation product and possible
byproduct formation from dimethylamine hydroaminoalkyla-
tion were determined using NMR spectroscopy and GC-MS.
First, we tested commercially available high-pressure glass
vials equipped with a stir bar and heated in an aluminum block.
This configuration is often used by chemists using microwave
reactors. Under these conditions (with several milliliters of
headspace) a drop in the rate of the reaction was observed
(64% after 2 h) in comparison to the NMR screening
technique (95%), although full conversion without any
byproducts from alkene addition to dimethylamine was
achieved after 4 h. Interestingly, by a switch to significantly
larger reaction vessels (100 mL Schlenk flask and consequently
approximately 100 mL of headspace), while the same reaction
scale was maintained, no significant increase in reactivity was
observed (70% after 2 h, full conversion after 4 h). When the
headspace was expanded dramatically by using a balloon, the
reaction time required to reach quantitative product formation
was reduced slightly to 3 h. These results show that the
interference of gaseous dimethylamine released upon catalyst
activation is negligible in our hydroaminoalkylation catalytic
system and any standard-sized reaction vessels with or without
additional headspace can be used.
Figure 5. Synthetic applications using Ti1 + L7 for hydro-
aminoalkylation to form (a) amine-containing monomers 1 and 2
and (b) β-substituted γ-amino acid 5 and 3-methylpyrrolidine
hydrochloride 7.
quantitatively within 8 h for NBD and 72 h for COD. The
relatively long reaction time for the COD reaction is attributed
to the reduced ring strain, which makes this a more challenging
alkene substrate. Due to the neat reaction conditions and the
quantitative yields, both monomers can be isolated in high
purity, as confirmed by GC-MS and NMR spectroscopy,
simply by filtration through Celite and removal of the
unreacted excess diene in vacuo.64 No further purification
steps were needed, and the unreacted diene removed under
vacuum can be reused. Consequently, this synthetic concept
for N-containing monomers 1 and 2 is very efficient and
especially “green” due to the use of earth-abundant titanium
catalysts and no requirement for additional solvents.
Furthermore, we were interested in the synthesis of building
blocks for medicinally relevant small molecules (Figure 5b). β-
Substituted γ-amino acids are relevant GABA derivatives, such
as the pharmaceuticals pregabalin and gabapentin, and are used
as anticonvulsants and for treating nerve pain.70 Here, the
GABA derivative 5 was prepared using a stepwise approach by
Motivated by these findings, we explored experimental
procedures that eliminated the need for a glovebox. For this,
we prepared the aforementioned reaction with dry reagents
and under exclusion of oxygen and moisture outside of the
glovebox using Teflon-capped vials with septa, standard syringe
techniques, and balloons filled with inert gas (for detailed
pictures see the Supporting Information).64 Not only does this
procedure afford the same quantitative product yields after 4 h
but also, due to the ease of handling of L7, Ti1 and all
substrates, this method is broadly accessible to all synthetic
chemists.
SYNTHETIC APPLICATION
■
With this new catalyst system (Ti1 + L7) and the easy to
handle synthetic procedures in hand, we were motivated to
feature our catalyst in the synthesis of small molecules that can
be used in functional materials synthesis or as building blocks
for preparing compounds with biological activity.
4556
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
reacting 4-methoxy-N-methylaniline with a homoallylic silyl-
protected alcohol to give the protected amino alcohol product
3 in excellent yield (94%). Upon alcohol deprotection with
TBAF amino alcohol 4 could be isolated.64 Boc protection of
the amine and direct oxidation of the alcohol to amino acid 5
proceeded with a good yield of 77% over all three steps.64
Alternatively, intermediate 3 could be used to access a β-
methylated pyrrolidine derivative. 3-Methylpyrrolidines are
important building blocks in medicinal chemistry and are used
in kinase inhibitors and other small-molecule chemical probes
for proteins.71,72 Such β-methylated amine/N-heterocyclic
products are often targeted because of their “magic methyl”
effects in medicinal chemistry.73 This specific product of the 3-
methylpyrrolidine class, which is normally synthesized via
reduction of the corresponding lactams,74,75 can be prepared
by cyclizing the precursor silyl-protected amino alcohol 3 using
p-toluenesulfonyl fluoride (for the isolated PMP-protected
pyrrolidine 6 see the Supporting Information)66 and
subsequent deprotection of the PMP group. Here, trichlor-
oisocyanuric acid (TCCA) generated the amine hydrochloride
7 with a yield of 62% over the two steps.
This alternative disconnection for the synthesis of such β-
methylated N-heterocycle products offers a cost-effective and
complementary preparative route. For 3-methylpyrrolidine this
synthetic route costs 1 order of magnitude less than that from
commercial sources. This can be attributed to the use of low-
cost titanium-catalyzed hydroaminoalkylation. Additionally,
this illustrates the usefulness of using PMP-protected amines
in hydroaminoalkylation in order to access free amine products
upon oxidative deprotection. PMP-protected amines exhibit
high reactivity for this transformation and offer access to useful
building blocks ready for N-coupling.
synthesis description here were purchased from commercial
sources and used without further purification, unless otherwise
noted. All amines and alkenes were dried over CaH2 and
distilled and degassed prior to use in catalytic experiments.
Solvents were dried according to standard procedures and
stored over activated molecular sieves (4 Å). Toluene-d8 was
dried over sodium/ketyl and distilled prior to use. Experiments
conducted with an NMR tube scale were performed in J.
Young NMR tubes (8 in. × 5 mm) sealed with screw-type
Teflon caps. All glassware was dried in a 180 °C oven
overnight before use. See the Supporting Information for a
detailed description of the synthesis and characterization of
ligands and titanium complexes.
Ligand Screening. The ligand (0.10 mmol) was weighed
into a vial and dissolved in toluene-d8 (0.3 mL). Ti(NMe2)4/
Ti(CH2SiMe3)4 (0.05 mmol) was added with a micropipet. 4-
Methoxy-N-methylaniline (0.5 mmol) and norbornene (0.5
mmol) were weighed into a different vial, dissolved in toluene-
d8 (0.2 mL), and added to the catalyst system with a
micropipet. The resultant reaction mixture was transferred into
a J. Young NMR tube, and the vials were rinsed with an
1
additional 0.2 mL of toluene-d8. An initial H NMR spectrum
was recorded, and the sample was placed in a preheated oil
1
bath. All conversion values were determined by H NMR
spectroscopy (integration of ortho proton signals of the
product vs the starting material).
Reactivity Studies. The ligand (0.15 mmol/0.30 mmol)
was weighed into a vial and dissolved in toluene-d8 (1.8 mL).
Ti(NMe2)4 (0.15 mmol) was added with a micropipet. N-
Methylaniline (3.0 mmol), 1-octene (3.0 mmol), and 1,3,5-
trimethoxybenzene (168 mg, 1.0 mmol) were weighed into a
different vial, dissolved in toluene-d8 (2.4 mL), and added to
the catalyst system with a micropipet. The resultant reaction
mixture was distributed into six identical volumes, and these
were again transferred into six J. Young NMR tubes. For the
catalyst system Ti3 the first two steps were combined. The
CONCLUSIONS
■
In summary, we have identified a highly active titanium ureate
catalyst for atom- and step-economical hydroaminoalkylation
by screening a wide variety of 1,3-N,X-chelated titanium
systems. This earth-abundant titanium catalyst can be easily
synthesized in situ by using commercially available and
inexpensive Ti(NMe2)4 (Ti1) and the sterically demanding
asymmetric urea ligand L7, which can be prepared in one step.
This system exhibits excellent TOFs for titanium catalysts, and
most importantly, this easy to use catalyst is compatible with a
wide range of alkene substrates such as alkyl, aryl, and
functionalized terminal alkenes in combination with a variety
of amines. Even challenging substrates, such as dialkylamines,
were transformed within 1 day. Easy to use experimental
protocols have been developed and exploited in the synthesis
of monomers for amine-functionalized materials and amino
acid and N-heterocyclic building blocks for medicinal
chemistry. These achievements confirm that ligand design
can be used to promote enhanced electrophilic character at the
metal center for improved reactivity and increased steric access
to the reactive metal center for catalysis. These results illustrate
the promise of easy to use titanium hydroaminoalkylation
catalysts for organic synthesis, while avoiding directing groups
or activated alkenes.
1
initial H NMR spectra were recorded, and the samples were
placed in a preheated oil bath and individually collected after
1
the corresponding times. All yields were determined by H
NMR spectroscopy using 1,3,5-trimethoxybenzene as an
internal standard by integrating the signal of the ortho protons
of N-methylaniline vs the signal of the internal standard at the
start of the reaction and comparing this value with the signal of
the ortho protons of the amine product vs the internal standard
at various points as the reaction progressed.
Amine and Alkene Scope. L7 (8.5 mg, 0.025 mmol) was
weighed into a vial and dissolved in toluene-d8 (0.3 mL).
Ti(NMe2)4 (5.6 mg, 0.025 mmol) was added with a
micropipet. The selected amine (0.5 mmol), alkene (0.5
mmol), and 1,5,5-trimethoxybenzene (28.0 mg, 0.166 mmol)
were weighed into a different vial, dissolved in toluene-d8 (0.2
mL), and added to the catalyst system with a micropipet. The
resultant reaction mixture was transferred into a J. Young
NMR tube, and the vials were rinsed with an additional 0.2 mL
of toluene-d8. An initial 1H NMR spectrum was recorded, and
the sample was placed in a preheated oil bath. All yields were
1
determined by H NMR spectroscopy using 1,3,5-trimethox-
ybenzene as an internal standard by integrating the character-
istic signals of the starting amine vs the signal of the internal
standard at the start of the reaction and comparing this value
with the signal of the amine product vs the internal standard at
the selected time. The selectivity was determined by GC-MS
analysis.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were performed
under a N2 atmosphere using Schlenk or glovebox techniques,
unless otherwise stated. All chemicals without a detailed
4557
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
(2) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274.
See the Supporting Information for a detailed reaction vessel
comparison and application examples.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c00014.
■
(3) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
̈
sı
Hydroamination: Direct Addition of Amines to Alkenes and Alkynes.
Chem. Rev. 2008, 108, 3795−3892.
(4) Edwards, P. M.; Schafer, L. L. Early transition metal-catalyzed
C−H alkylation: hydroaminoalkylation for Csp3−Csp3 bond
formation in the synthesis of selectively substituted amines. Chem.
Commun. 2018, 54, 12543−12560.
(5) Roesky, P. W. Catalytic Hydroaminoalkylation. Angew. Chem.,
Int. Ed. 2009, 48, 4892−4894.
(6) Manßen, M.; Schafer, L. L. Titanium catalysis for the synthesis of
fine chemicals - development and trends. Chem. Soc. Rev. 2020, 49,
6947−6994.
(7) Schafer, L. L.; Manßen, M.; Edwards, P. M.; Lui, E. K. J.; Griffin,
S. E.; Dunbar, C. R.; Pérez, P. J. Chapter Seven - Titanium catalyzed
synthesis of amines and N-heterocycles. Adv. Organomet. Chem. 2020,
74, 405−468.
(8) Franke, R.; Selent, D.; Börner, A. Applied Hydroformylation.
Chem. Rev. 2012, 112, 5675−5732.
(9) Clerici, M. G.; Maspero, F. Catalytic C-Alkylation of Secondary
Amines with Alkenes. Synthesis 1980, 1980, 305−306.
(10) Herzon, S. B.; Hartwig, J. F. Direct, Catalytic Hydro-
aminoalkylation of Unactivated Olefins with N-Alkyl Arylamines. J.
Am. Chem. Soc. 2007, 129, 6690−6691.
(11) Garcia, P.; Lau, Y. Y.; Perry, M. R.; Schafer, L. L.
Phosphoramidate Tantalum Complexes for Room-Temperature C-
H Functionalization: Hydroaminoalkylation Catalysis. Angew. Chem.,
Int. Ed. 2013, 52, 9144−9148.
(12) Chong, E.; Brandt, J. W.; Schafer, L. L. 2-Pyridonate Tantalum
Complexes for the Intermolecular Hydroaminoalkylation of Sterically
Demanding Alkenes. J. Am. Chem. Soc. 2014, 136, 10898−10901.
(13) Hunt, A. J.; Farmer, T. J.; Clark, J. H., Elemental Sustainability
and the Importance of Scarce Element Recovery. In Element Recovery
and Sustainability; The Royal Society of Chemistry: 2013; pp 1−28.
(14) Haynes, W. M.; Lide, D. R.; Bruno, T. J. CRC handbook of
chemistry and physics; CRC Press: 2017.
Full experimental details, crystallographic parameters,
and NMR spectra (PDF)
A crystallographic information file for Ti3 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Laurel L. Schafer − Department of Chemistry, University of
British Columbia, Vancouver, British Columbia V6T 1Z4,
Canada; orcid.org/0000-0003-0354-2377;
Email: schafer@chem.ubc.ca
Authors
Manfred Manßen − Department of Chemistry, University of
British Columbia, Vancouver, British Columbia V6T 1Z4,
Canada; orcid.org/0000-0002-7619-269X
Danfeng Deng − Department of Chemistry, University of
British Columbia, Vancouver, British Columbia V6T 1Z4,
Canada
Cameron H. M. Zheng − Department of Chemistry,
University of British Columbia, Vancouver, British Columbia
V6T 1Z4, Canada
Rebecca C. DiPucchio − Department of Chemistry, University
of British Columbia, Vancouver, British Columbia V6T 1Z4,
Canada
Dafa Chen − Shenzhen Grubbs Institute, Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, People’s Republic of China; orcid.org/
0000-0002-7650-4024
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c00014
(15) Collins, R. A.; Russell, A. F.; Mountford, P. Group 4 metal
complexes for homogeneous olefin polymerisation: a short tutorial
review. Appl. Petrochem. Res. 2015, 5, 153−171.
Author Contributions
(16) Okamoto, S. Synthetic Reactions Using Low-valent Titanium
Reagents Derived from Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) in the
Presence of Me3SiCl and Mg. Chem. Rec. 2016, 16, 857−872.
(17) Geis, O.; Schmalz, H.-G. New Developments in the Pauson−
Khand Reaction. Angew. Chem., Int. Ed. 1998, 37, 911−914.
§M.M. and D.D. contributed equally.
Funding
Feodor Lynen Research Fellowship by the Alexander von
Humboldt Foundation, National Natural Science Foundation
of China (Grant Nos. 21673064 and 51902072), and NSERC.
(18) Blanco-Urgoiti, J.; Anorbe, L.; Pérez-Serrano, L.; Domínguez,
̃
G.; Pérez-Castells, J. The Pauson−Khand reaction, a powerful
synthetic tool for the synthesis of complex molecules. Chem. Soc.
Rev. 2004, 33, 32−42.
Notes
The authors declare the following competing financial
interest(s): A provisional patent has been submitted which
includes elements of the work disclosed.
(19) Li, J. J., Sharpless asymmetric epoxidation. In Name Reactions:
A Collection of Detailed Mechanisms and Synthetic Applications, 5th ed.;
Li, J. J., Ed.; Springer International Publishing: Cham, Switzerland,
2014; pp 552−554.
ACKNOWLEDGMENTS
■
(20) Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Catalytic formal [2 +
2+1] synthesis of pyrroles from alkynes and diazenes via TiII/TiIV
redox catalysis. Nat. Chem. 2016, 8, 63−68.
NSERC is thanked for financial support of this work. MM
thanks the Alexander von Humboldt Foundation for their
support. DD and DC thank the National Natural Science
Foundation of China for support. LLS thanks the Canada
Research Chair program for partial support of this work.
(21) Chiu, H.-C.; Tonks, I. A. Trimethylsilyl-Protected Alkynes as
Selective Cross-Coupling Partners in Titanium-Catalyzed [2 + 2+1]
Pyrrole Synthesis. Angew. Chem., Int. Ed. 2018, 57, 6090−6094.
(22) Chiu, H.-C.; See, X. Y.; Tonks, I. A. Dative Directing Group
Effects in Ti-Catalyzed [2 + 2+1] Pyrrole Synthesis: Chemo- and
Regioselective Alkyne Heterocoupling. ACS Catal. 2019, 9, 216−223.
(23) Kubiak, R.; Prochnow, I.; Doye, S. Titanium-Catalyzed
Hydroaminoalkylation of Alkenes by C−H Bond Activation at sp3
Centers in the α-Position to a Nitrogen Atom. Angew. Chem., Int. Ed.
2009, 48, 1153−1156.
REFERENCES
■
(1) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.
A.; Wells, A.; Zaks, A.; Zhang, T. Y. Key green chemistry research
areasa perspective from pharmaceutical manufacturers. Green Chem.
2007, 9, 411−420.
4558
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
(24) Prochnow, I.; Kubiak, R.; Frey, O. N.; Beckhaus, R.; Doye, S.
Tetrabenzyltitanium: An Improved Catalyst for the Activation of sp3
C−H Bonds Adjacent to Nitrogen Atoms. ChemCatChem 2009, 1,
162−172.
(25) Dörfler, J.; Doye, S. A Commercially Available Tantalum
Catalyst for the Highly Regioselective Intermolecular Hydro-
aminoalkylation of Styrenes. Eur. J. Org. Chem. 2014, 2014, 2790−
2797.
Highly Regioselective Hydroaminoalkylation of Styrenes and 1,3-
Butadienes. Angew. Chem., Int. Ed. 2014, 53, 7918−7922.
(43) Warsitz, M.; Doye, S. Two-Step Procedure for the Synthesis of
1,2,3,4-Tetrahydroquinolines. Eur. J. Org. Chem. 2020, 2020, 6997−
7014.
(44) Warsitz, M.; Doye, S. Linear Hydroaminoalkylation Products
from Alkyl-Substituted Alkenes. Chem. - Eur. J. 2020, 26, 15121−
15125.
(26) Kubiak, R.; Prochnow, I.; Doye, S. [Ind2TiMe2]: A Catalyst for
the Hydroaminomethylation of Alkenes and Styrenes. Angew. Chem.,
Int. Ed. 2010, 49, 2626−2629.
(45) Dörfler, J.; Preuß, T.; Brahms, C.; Scheuer, D.; Doye, S.
Intermolecular hydroaminoalkylation of alkenes and dienes using a
titanium mono(formamidinate) catalyst. Dalton Trans. 2015, 44,
12149−12168.
(27) Rohjans, S. H.; Ross, J. H.; Luhning, L. H.; Sklorz, L.;
̈
Schmidtmann, M.; Doye, S. Titanium Catalysts with Linked Indenyl−
Amido Ligands for Hydroamination and Hydroaminoalkylation
Reactions. Organometallics 2018, 37 (23), 4350−4357.
(28) Preuß, T.; Saak, W.; Doye, S. Titanium-Catalyzed Intermo-
lecular Hydroaminoalkylation of Conjugated Dienes. Chem. - Eur. J.
2013, 19, 3833−3837.
(29) Clarkson, J. M.; Schafer, L. L. Bis(tert-butylimido)bis(N,O-
chelate)tungsten(VI) Complexes: Probing Amidate and Pyridonate
Hemilability. Inorg. Chem. 2017, 56 (10), 5553−5566.
(30) Braun, C.; Nieger, M.; Bräse, S.; Schafer, L. L. Planar-Chiral
[2.2]Paracyclophane-Based Pyridonates as Ligands for Tantalum-
Catalyzed Hydroaminoalkylation. ChemCatChem 2019, 11 (21),
5264−5268.
(31) Chong, E.; Schafer, L. L. 2-Pyridonate Titanium Complexes for
Chemoselectivity. Accessing Intramolecular Hydroaminoalkylation
over Hydroamination. Org. Lett. 2013, 15 (23), 6002−6005.
(32) Brandt, J. W.; Chong, E.; Schafer, L. L. Ligand Effects and
Kinetic Investigations of Sterically Accessible 2-Pyridonate Tantalum
Complexes for Hydroaminoalkylation. ACS Catal. 2017, 7, 6323−
6330.
(33) Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L.
Broadening the Scope of Group 4 Hydroamination Catalysis Using a
Tethered Ureate Ligand. J. Am. Chem. Soc. 2009, 131, 18246−18247.
(34) Leitch, D. C.; Platel, R. H.; Schafer, L. L. Mechanistic
Elucidation of Intramolecular Aminoalkene Hydroamination Cata-
lyzed by a Tethered Bis(ureate) Complex: Evidence for Proton-
Assisted C−N Bond Formation at Zirconium. J. Am. Chem. Soc. 2011,
133, 15453−15463.
(46) Bielefeld, J.; Doye, S. Dimethylamine as a Substrate in
Hydroaminoalkylation Reactions. Angew. Chem., Int. Ed. 2017, 56,
15155−15158.
(47) Rosien, M.; Toben, I.; Schmidtmann, M.; Beckhaus, R.; Doye,
S. Titanium-Catalyzed Hydroaminoalkylation of Ethylene. Chem. -
Eur. J. 2020, 26, 2138−2142.
(48) Bielefeld, J.; Doye, S. Fast Titanium-Catalyzed Hydro-
aminomethylation of Alkenes and the Formal Conversion of
Methylamine. Angew. Chem., Int. Ed. 2020, 59, 6138−6143.
(49) Kuanr, N.; Tomkovic, T.; Gilmour, D. J.; Perry, M. R.; Hsiang,
S.-J.; van Ruymbeke, E.; Hatzikiriakos, S. G.; Schafer, L. L. Dynamic
Cross-Linking of Catalytically Synthesized Poly(Aminonorbornenes).
Macromolecules 2020, 53, 2649−2661.
(50) Perry, M. R.; Ebrahimi, T.; Morgan, E.; Edwards, P. M.;
Hatzikiriakos, S. G.; Schafer, L. L. Catalytic Synthesis of Secondary
Amine-Containing Polymers: Variable Hydrogen Bonding for
Tunable Rheological Properties. Macromolecules 2016, 49, 4423−
4430.
(51) Eisch, J. J.; Adeosun, A. A.; Dutta, S.; Fregene, P. O. The
Decomposition of Transition Metal Alkyls Revisited: Surprising
Wellspring of Novel Reagents for Organic Synthesis. Eur. J. Org.
Chem. 2005, 2005, 2657−2670.
(52) Edwards, P. M.; Schafer, L. L. In Situ Generation of a Regio-
and Diastereoselective Hydroaminoalkylation Catalyst Using Com-
mercially Available Starting Materials. Org. Lett. 2017, 19, 5720−
5723.
(53) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and
Applications of tert-Butanesulfinamide. Chem. Rev. 2010, 110, 3600−
3740.
(54) Lui, E. K. J.; Hergesell, D.; Schafer, L. L. N-Silylenamines as
Reactive Intermediates: Hydroamination for the Modular Synthesis of
Selectively Substituted Pyridines. Org. Lett. 2018, 20, 6663−6667.
(55) Lui, E. K. J.; Brandt, J. W.; Schafer, L. L. Regio- and
Stereoselective Hydroamination of Alkynes Using an Ammonia
Surrogate: Synthesis of N-Silylenamines as Reactive Synthons. J.
Am. Chem. Soc. 2018, 140, 4973−4976.
(56) Hao, H.; Thompson, K. A.; Hudson, Z. M.; Schafer, L. L. Ti-
Catalyzed Hydroamination for the Synthesis of Amine-Containing π-
Conjugated Materials. Chem. - Eur. J. 2018, 24, 5562−5568.
(57) Lui, E. K. J.; Schafer, L. L. Facile Synthesis and Isolation of
Secondary Amines via a Sequential Titanium(IV)-Catalyzed Hydro-
amination and Palladium-Catalyzed Hydrogenation. Adv. Synth. Catal.
2016, 358, 713−718.
(35) Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer,
L. L. Chiral Neutral Zirconium Amidate Complexes for the
Asymmetric Hydroamination of Alkenes. Angew. Chem., Int. Ed.
2007, 46, 354−358.
(36) Bexrud, J. A.; Schafer, L. L. Zirconium bis(pyridonate): a
modified amidate complex for enhanced substrate scope in amino-
alkene cyclohydroamination. Dalton Transactions 2010, 39 (2), 361−
363.
(37) DiPucchio, R. C.; Rosç a, S.-C.; Schafer, L. L. Catalytic and
Atom-Economic C − C Bond Formation: Alkyl Tantalum Ureates for
Hydroaminoalkylation. Angew. Chem., Int. Ed. 2018, 57, 3469−3472.
(38) Daneshmand, P.; Rosç a, S.-C.; Dalhoff, R.; Yin, K.; DiPucchio,
R. C.; Ivanovich, R. A.; Polat, D. E.; Beauchemin, A. M.; Schafer, L. L.
Cyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkyla-
tion with Aliphatic Amines: Mechanistic Insights into Substrate
Controlled Reactivity. J. Am. Chem. Soc. 2020, 142, 15740−15750.
(39) Elkin, T.; Kulkarni, N. V.; Tumanskii, B.; Botoshansky, M.;
Shimon, L. J. W.; Eisen, M. S. Synthesis and Structure of Group 4
Symmetric Amidinate Complexes and Their Reactivity in the
Polymerization of α-Olefins. Organometallics 2013, 32, 6337−6352.
(58) DiPucchio, R. C.; Rosca, S.-C.; Athavan, G.; Schafer, L. L.
Exploiting Natural Complexity: Synthetic Terpenoid-Alkaloids by
Regioselective and Diastereoselective Hydroaminoalkylation Catal-
ysis. ChemCatChem 2019, 11, 3871−3876.
(59) Manßen, M.; Lauterbach, N.; Dörfler, J.; Schmidtmann, M.;
Saak, W.; Doye, S.; Beckhaus, R. Efficient Access to Titanaaziridines
by C-H Activation of N-Methylanilines at Ambient Temperature.
Angew. Chem., Int. Ed. 2015, 54, 4383−4387.
(40) Dörfler, J.; Bytyqi, B.; Huller, S.; Mann, N. M.; Brahms, C.;
̈
Schmidtmann, M.; Doye, S. An Aminopyridinato Titanium Catalyst
for the Intramolecular Hydroaminoalkylation of Secondary Amino-
alkenes. Adv. Synth. Catal. 2015, 357, 2265−2276.
(60) Prochnow, I.; Zark, P.; Muller, T.; Doye, S. The Mechanism of
̈
(41) Dörfler, J.; Doye, S. Aminopyridinato Titanium Catalysts for
the Hydroaminoalkylation of Alkenes and Styrenes. Angew. Chem., Int.
Ed. 2013, 52, 1806−1809.
the Titanium-Catalyzed Hydroaminoalkylation of Alkenes. Angew.
Chem., Int. Ed. 2011, 50, 6401−6405.
(61) Bielefeld, J.; Kurochkina, E.; Schmidtmann, M.; Doye, S. New
Titanium Complexes and Their Use in Hydroamination and
(42) Dörfler, J.; Preuß, T.; Schischko, A.; Schmidtmann, M.; Doye,
S. A 2,6-Bis(phenylamino)pyridinato Titanium Catalyst for the
4559
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Hydroaminoalkylation Reactions. Eur. J. Inorg. Chem. 2019, 2019,
3713−3718.
(62) Payne, P. R.; Bexrud, J. A.; Leitch, D. C.; Schafer, L. L.
Asymmetric hydroamination catalyzed by in situ generated chiral
amidate and ureate complexes of zirconium  Probing the role of the
tether in ligand design. Can. J. Chem. 2011, 89, 1222−1229.
(63) Perry, M. R.; Gilmour, D. J.; Schafer, L. L. Mono, bis, and
tris(phosphoramidate) titanium complexes: synthesis, structure, and
reactivity investigations. Dalton Trans. 2019, 48, 9782−9790.
(64) For further information see the Supporting Information.
(65) Liu, F.; Luo, G.; Hou, Z.; Luo, Y. Mechanistic Insights into
Scandium-Catalyzed Hydroaminoalkylation of Olefins with Amines:
Origin of Regioselectivity and Charge-Based Prediction Model.
Organometallics 2017, 36, 1557−1565.
(66) Payne, P. R.; Garcia, P.; Eisenberger, P.; Yim, J. C. H.; Schafer,
L. L. Tantalum Catalyzed Hydroaminoalkylation for the Synthesis of
α- and β-Substituted N-Heterocycles. Org. Lett. 2013, 15, 2182−2185.
(67) Zhang, Z.; Hamel, J.-D.; Schafer, L. L. TaMe3Cl2-Catalyzed
Intermolecular Hydroaminoalkylation: A Simple Complex for
Enhanced Reactivity and Expanded Substrate Scope. Chem. - Eur. J.
2013, 19, 8751−8754.
̈ ̈
(68) Weers, M.; Luhning, L. H.; Luhrs, V.; Brahms, C.; Doye, S.
One-Pot Procedure for the Synthesis of 1,5-Benzodiazepines from N-
Allyl-2-bromoanilines. Chem. - Eur. J. 2017, 23, 1237−1240.
̈
(69) Luhning, L. H.; Strehl, J.; Schmidtmann, M.; Doye, S.
Hydroaminoalkylation of Allylsilanes and a One-Pot Procedure for
the Synthesis of 1,5-Benzoazasilepines. Chem. - Eur. J. 2017, 23,
4197−4202.
(70) Belliotti, T. R.; Capiris, T.; Ekhato, I. V.; Kinsora, J. J.; Field, M.
J.; Heffner, T. G.; Meltzer, L. T.; Schwarz, J. B.; Taylor, C. P.; Thorpe,
A. J.; Vartanian, M. G.; Wise, L. D.; Zhi-Su, T.; Weber, M. L.;
Wustrow, D. J. Structure−Activity Relationships of Pregabalin and
Analogues That Target the α2-δ Protein. J. Med. Chem. 2005, 48,
2294−2307.
(71) Noji, S.; Hara, Y.; Miura, T.; Yamanaka, H.; Maeda, K.; Hori,
A.; Yamamoto, H.; Obika, S.; Inoue, M.; Hase, Y.; Orita, T.; Doi, S.;
Adachi, T.; Tanimoto, A.; Oki, C.; Kimoto, Y.; Ogawa, Y.; Negoro,
T.; Hashimoto, H.; Shiozaki, M. Discovery of a Janus Kinase Inhibitor
Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052
(Delgocitinib) as a New Dermatological Agent to Treat Inflammatory
Skin Disorders. J. Med. Chem. 2020, 63, 7163−7185.
(72) Moustakim, M.; Christott, T.; Monteiro, O. P.; Bennett, J.;
Giroud, C.; Ward, J.; Rogers, C. M.; Smith, P.; Panagakou, I.; Díaz-
Sáez, L.; Felce, S. L.; Gamble, V.; Gileadi, C.; Halidi, N.; Heidenreich,
D.; Chaikuad, A.; Knapp, S.; Huber, K. V. M.; Farnie, G.; Heer, J.;
Manevski, N.; Poda, G.; Al-awar, R.; Dixon, D. J.; Brennan, P. E.;
Fedorov, O. Discovery of an MLLT1/3 YEATS Domain Chemical
Probe. Angew. Chem., Int. Ed. 2018, 57, 16302−16307.
(73) Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. The
̈
Methylation Effect in Medicinal Chemistry. Chem. Rev. 2011, 111,
5215−5246.
(74) Budhram, R. S.; Pourahmady, N.; Syed, A. S.; Eisenbraun, E. J.
3-Methylsuccinimide and 3-Methylpyrrolidine. Org. Prep. Proced. Int.
1986, 18, 295−297.
(75) Kondo, K.; Ogawa, H.; Shinohara, T.; Kurimura, M.; Tanada,
Y.; Kan, K.; Yamashita, H.; Nakamura, S.; Hirano, T.; Yamamura, Y.;
Mori, T.; Tominaga, M.; Itai, A. Novel Design of Nonpeptide AVP V2
Receptor Agonists: Structural Requirements for an Agonist Having 1-
(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine as a Tem-
plate. J. Med. Chem. 2000, 43, 4388−4397.
4560
https://doi.org/10.1021/acscatal.1c00014
ACS Catal. 2021, 11, 4550−4560