Intramolecular hydroamination of trisubstituted aminoallenes catalyzed by titanium complexes of diaryl substituted tridentate imine-diols

Article abstract of DOI:10.1016/j.poly.2021.115070

Our laboratory has developed catalysts based on earth abundant titanium for asymmetric reactions including intramolecular hydroamination. Previously, we showed that titanium complexes of imine diol ligands showed improved enantioselectivity relative to complexes with bidentate amino alcohol ligands. As the catalyst with the highest selectivity had di-tert-butyl substitution, we sought to increase the steric protection by preparing three new ligands with diaryl substitution. These ligands were readily prepared in two steps: first, synthesis of diaryl substituted salicylaldehydes by a Suzuki coupling and second, a Schiff base condensation with a chiral amino alcohol. After characterizing the ligands, in situ hydroamination/cyclization with 6-methyl-hepta-4,5-dienylamine was carried out at temperatures ranging from 105 °C to 135 °C to give exclusively 2-(2-methyl-propenyl)-pyrrolidine with enantioselectivity up to 22 %ee. Unexpected dimerization of the catalyst resulted in reduced activity, so the reaction required a catalyst loading of 10–20%.

Full text of DOI:10.1016/j.poly.2021.115070

Polyhedron 198 (2021) 115070
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Polyhedron
journal homepage: www.elsevier.com/locate/poly
Intramolecular hydroamination of trisubstituted aminoallenes catalyzed
by titanium complexes of diaryl substituted tridentate imine-diols
⇑
Emily Y. Fok, Veronica L. Show, Adam R. Johnson
Department of Chemistry, Harvey Mudd College, 301 Platt Blvd., Claremont, CA 91711, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Our laboratory has developed catalysts based on earth abundant titanium for asymmetric reactions
including intramolecular hydroamination. Previously, we showed that titanium complexes of imine diol
ligands showed improved enantioselectivity relative to complexes with bidentate amino alcohol ligands.
As the catalyst with the highest selectivity had di-tert-butyl substitution, we sought to increase the steric
protection by preparing three new ligands with diaryl substitution. These ligands were readily prepared
in two steps: first, synthesis of diaryl substituted salicylaldehydes by a Suzuki coupling and second, a
Schiff base condensation with a chiral amino alcohol. After characterizing the ligands, in situ hydroami-
nation/cyclization with 6-methyl-hepta-4,5-dienylamine was carried out at temperatures ranging from
Received 30 November 2020
Accepted 26 January 2021
Available online 9 February 2021
Keywords:
Asymmetric hydroamination
Titanium complex
Amino alcohol
105 °C to 135 °C to give exclusively 2-(2-methyl-propenyl)-pyrrolidine with enantioselectivity up to
Schiff base
22 %ee. Unexpected dimerization of the catalyst resulted in reduced activity, so the reaction required a
catalyst loading of 10–20%.
Ó 2021 Elsevier Ltd. All rights reserved.
1
. Introduction
Hydroamination is the addition of an NAH bond across an
[2 + 2] cycloaddition to form the metallaazacyclobutane. Protonol-
ysis by another incoming substrate molecule regenerates the cata-
lyst. Metal catalysts from across the periodic table have been
studied [3,16–20]. In 2007, the Toste group reported enantiomeric
excesses above 99% for gold(I) catalyzed intramolecular hydroam-
ination of allenes [21]. However, there are aspects of this work that
could be improved upon. First, as is typical for late metal catalyzed
hydroamination reactions, the gold reaction requires the use of
protected amine substrates, leading to additional steps in protect-
ing the substrates and deprotecting the products [5,15,22]. Second,
the preparation of ligands such as (R)-3,5-xylyl-BINAP requires
multistep synthesis as well as expensive chiral resolving agents
making the process time consuming and costly [23,24].
unsaturated CAC bond of an alkene, allene, or alkyne to synthesize
amine or imine derivatives [1–5]. This reaction has garnered much
interest as it is 100% atom economical and the nitrogen-containing
products can be further used in organic synthesis, pharmaceuticals,
and other industrial applications [2,6–8]. However, practical appli-
cation of hydroamination still has many challenges including a
high reaction barrier, and difficulty controlling the regio- or stere-
oselectivity of the resulting products. The reaction barrier can be
overcome through use of a catalyst, while a well-designed catalyst
is needed to control the regio- and/or stereoselectivity.
Over the past 30 years, many research groups have studied this
reaction. Catalysts from across the periodic table have been
developed including those based on transition metals, main group
metals, lanthanides, actinides, and Brønsted acids [7,9,10].
Intramolecular hydroamination of aminoallenes has been studied
extensively since the early mechanistic work of Bergman [11,12]
and Marks [13,14] as these reactions can lead to chiral heterocycles
with an alkene retained in the product (Scheme 1) [5,15]. The
Group IV complexes show great potential for hydroamination
and other reactions [1,25–33]. These metals are an especially
attractive choice due to their low cost and toxicity, and while gen-
erally considered to be not functional group compatible, appropri-
ate catalyst design can lead to tolerance of oxygen- and nitrogen-
containing functional groups [34]. Titanium, in particular, is attrac-
tive because of its high earth abundance. Catalytic alkene
hydroamination with other first row transition metals has been
recently reviewed [35], and the development of earth-abundant
catalysts has become an important goal for the organometallic
community [36,37]. While these high oxidation state early metal
complexes have been studied immensely over the years due to
their practicality and usefulness, challenges come from the
reaction proceeds first by protonolysis of NMe
2
groups by the
incoming substrate to form the active catalyst followed by a
⇑
Corresponding author.
E-mail address: adam_johnson@hmc.edu (A.R. Johnson).
https://doi.org/10.1016/j.poly.2021.115070
277-5387/Ó 2021 Elsevier Ltd. All rights reserved.
0

E.Y. Fok, V.L. Show and A.R. Johnson
Polyhedron 198 (2021) 115070
2 2 2 2
Scheme 1. The generally accepted mechanism for the titanium catalyzed hydroamination of aminoallenes (R = CH CH CH CH = C = CMe ).
propensity of these species to dimerize, undergo ligand exchange,
or experience other processes that reduce catalytic reactivity [38].
Titanium catalyzed hydroamination has been studied by groups
such as Schafer [9,39–41], Odom [38,42], and Doye [43–46]. Our
group has carried out extensive research on titanium catalysts with
bidentate nitrogen–oxygen chelating ligands [47,48]. Our early
work suggested that the titanium complexes were dimeric com-
plexes with bridging alkoxide oxygens in the solid state [49]. Our
corresponding Tantalum complexes, however, appear to be mono-
meric and also tend to give higher enantioselectivities [50]. We
hypothesized that the reduction in enantioselectivity for our Tita-
nium complexes may be due to their dimeric nature relative to the
corresponding Tantalum complexes. To address this hypothesis,
we prepared ligands that contain an additional neutral donor atom
to form a tridentate ligand in order to prevent dimerization of the
titanium complex [51]. In this prior work, the di-tert-butyl substi-
tuted ligand (Fig. 1a) gave the highest stereoselectivity then
reported for a titanium catalyzed hydroamination reaction at 17
and stored under nitrogen (diethyl ether and toluene). Column
chromatography was carried out using a CombiFlash NextGen
300 + system (Teledyne ISCO). Solutions of ligands (ca. 0.05 M in
6 6 6 6
C D ) and substrates (ca. 1.5 M in C D ) for catalysis were dried
over molecular sieves overnight and stored at ꢀ35 °C. All air and/
or moisture sensitive compounds were manipulated under an
atmosphere of nitrogen using standard Schlenk techniques, or in
1
13
a glovebox (MBraun Unilab). H and
C NMR spectra were
recorded at ambient temperature on a Brüker Avance NEO 400
spectrometer and referenced to internal tetramethylsilane or
residual solvent peaks. Carbon assignments were made using DEPT
experiments. Coupling constants (J values) are given in Hz.
Polarimetry was carried out using a JASCO P1010 instrument. IR
spectroscopy was carried out using a Thermo-Nicolet iS5 FTIR
using a diamond anvil ATR accessory. GC-MS analysis was carried
out using a Hewlett Packard 5890 Series II Gas Chromatograph.
L
Mass spectra were obtained using an Advion expression APCI
Mass Spectrometer with quadrupole mass analyzer. Specific rota-
ꢀ1
2
ꢀ1
%
ee. Since the 3,5 di-tert-butyl substituted ligand was the best per-
tion values [
D
a] , are given in 10 deg cm g . Elemental analyses
forming ligand, we sought to prepare other ligands with differing
steric bulk on the phenol ring (Fig. 1b–d). Substituted aryl rings
could be readily attached to these positions by a Suzuki coupling
on the starting halogenated salicylaldehyde. Substitution of tert-
butyl by phenyl would also result in a different electronic environ-
ment, albeit modest. We anticipated that phenyl rather than tert-
butyl substitution in these new ligands would enhance the enan-
tioselectivity of the reaction.
were performed by Midwest Microlab, Indianapolis, IN.
2.2. Synthesis of aldehydes by Suzuki coupling
2
-Hydroxy-3,5-di-4-(trifluoromethyl)phenylbenzaldehyde
A2).
,5-dibromosalicylaldehyde (1.1757 g, 4.20 mmol), 4-(trifluo-
romethyl)phenylboronic acid (2.00 g, 10.5 mmol, 2.5 equiv.), [Pd
dba) ] (0.1657 g, 0.263 mmol, 6.2 mol%), and PPh (0.1314 g,
0.501 mmol, 11.9 mol%) were combined with toluene (100 mL),
ethanol (25 mL), and aqueous Na CO (2 M, 50 mL) under an atmo-
sphere of N . The reaction mixture was stirred overnight in an oil
(
3
(
2
3
2
. Experimental section
2
3
2.1. General
2
bath at 90 °C. The reaction was cooled to room temperature under
air for 30 min. The aqueous phase was extracted with ether
(2 ꢁ 25 mL). The combined organic phase was washed twice with
All reagents were obtained from commercial suppliers and puri-
fied by standard methods [52] or used as received. Ligand precur-
sor (S)-2-amino-1,1,3-triphenylpropanol was prepared by
literature procedures [53,54]. Aldehydes (A1) and (A3) have been
reported previously [55,56], and were prepared analogously to
aldehyde (A2); our spectra are consistent with the literature. The
purity of compounds was established by 1H NMR spectroscopy
and elemental analysis. Solvents were dried by vacuum transfer
4
brine, dried (MgSO ), and filtered to remove palladium black.
Crude products were purified by flash column chromatography to
yield a white solid (1.2854 g, 3.13 mmol, 75%). The product could
also be purified by recrystallization from ethanol. Mp:143.0–
144.6 °C. Anal. Calc. for C21
H
12
F
6
O
2
: C, 61.47; H, 2.95. Found: C,
61.38; H, 3.04. H NMR (400 MHz, CDCl ): d 11.65 (s, 1H, ArOH),
10.07 (s, 1H, HC = O), 7.85–7.72 (m, 10H, ArH).
(100 MHz, CDCl ): d 196.82 (HC = O), 158.94 (4°), 142.64 (4°),
1
3
13
from sodium/benzophenone (C
6
D
6
) or by passage through a col-
C NMR
umn of activated alumina (Innovative Technology PS-400–5-MD)
3
Fig. 1. a) 3,5-di-tert-butyl substituted ligand [51], b–d) the ligands used in this study.
2

E.Y. Fok, V.L. Show and A.R. Johnson
Polyhedron 198 (2021) 115070
1
1
39.70 (4°), 136.42 (CH), 132.31 (CH), 132.20 (4°), 130.21 (q, 2-
3.51; N, 1.68. Found: C, 63.44; H, 3.73; N, 1.76. H NMR (400 MHz,
2
J
CF = 33 Hz), 130.10 (4°), 129.98 (q,
J
CF = 32 Hz), 129.82 (CH),
CDCl
(apparent d, 1H, J = 9.8 Hz, CHCH
J = 13.5 Hz, CHCH Ph), 2.80 (m, 2H, OH, CHCH
(100 MHz, CDCl ): d 165.88 (HC = N), 159.66 (4°), 145.03 (4°),
143.90 (4°), 141.98 (4°), 139.08 (4°), 138.69 (4°), 132.46 (4°, q,
3
): d 13.97 (s, 1H, ArOH), 8.02–6.92 (m, 24H, ArH, HC = N), 4.37
3
3
1
27.10 (CH), 126.22 (q,
J
CF = 3.7 Hz), 125.50 (q,
JCF = 3.7 Hz),
a b
H
Ph), 3.04 (apparent d, 1H,
1
1
13
1
24.26 (q,
J
CF = 271 Hz), 124.14 (q,
J
CF = 271 Hz), 121.33 (4°).
a
H
b
a b
H Ph). C NMR
1
9
F NMR (376 MHz, CDCl
3
): d ꢀ 62.46 (CF
3
), ꢀ 62.58 (CF
3
). MS
3
+
ꢀ1
(
APCI): m/z 411[M + H] . IR (ATR, diamond): (HC = O) = 1660 cm
.
2
2
J = 33 Hz), 131.76 (4°, q, J = 33 Hz), 131.81 (CH), 130.86 (CH),
1
1
29.82 (CH), 129.75 (CH), 129.12 (4°), 128.76 (CH), 128.71 (CH),
28.61 (CH), 128.05 (4°), 127.56 (CH), 127.40 (CH), 126.78 (CH,
2.3. Synthesis of ligands by Schiff base condensation
shoulder), 126.76 (CH), 126.40 (CH), 126.23 (CH), 123.59 (CF
3
, q,
1
3
1
2
-Hydroxy-3,5-diphenyl-benzaldehyde
propanol)imine (L1).
Diphenyl substituted aldehyde A1 (0.8132 g, 2.96 mmol) and
S)-2-amino-1,1,3-triphenylpropanol (0.8994 g, 2.96 mmol,
2-S-(1,1,3-triphenyl-
J = 273 Hz), 123.43 ((CF
J = 3 Hz, para), 120.91 (CH, septet, J = 3 Hz), 119.17 (4°), 79.92
3
, q, J = 273 Hz), 121.45 (CH, septet,
3
1
9
(
(
4°), 78.61(CH), 37.50 (CH
2
). F NMR (376 MHz, CDCl
3
): ꢀ 62.66
+
(
1
CF ). MS (APCI): m/z 831 [M + H] . IR (ATR, dia-
3
), ꢀ 62.80 (CF
3
ꢀ
1
equiv.) were each dissolved in ethanol (25 mL) in a flask with a
reflux condenser open to air. The aldehyde solution was added to
the amine solution and the reaction mixture was heated at reflux
overnight. The solvent was removed in vacuo. The crude product
was purified by flash column chromatography to give a bright yel-
low solid (2.51 mmol, 1.4030 g, 85%). The product could also be
mond): (C@N) = 1633 cm
.
2.4. In situ catalysis
Hydroamination was carried out using a slight modification to
our previous in situ catalysis procedures [47,51,57]. Inside the
glovebox, deuterated benzene (212.5 L), Ti(NMe (100 L of a
mmol), and ligand (75 L of a
purified by recrystallization from hexane. Mp: 97.6–99.0 °C. [
158° (c = 0.006 g/mL, EtOAc). Anal. Calcd for C40
5.84; H, 5.94; N, 2.50. Calcd for C40 33NO O: C, 84.48; H,
ꢂ1/2 H
.03; N, 2.46. Found: C, 84.49; H, 6.22; N, 2.47. H NMR
): d 13.4 (s, 1H, ArOH), 7.74–7.01 (m, 28H, ArH,
HC = N) , 4.45 (dd, 1H, J = 10.0, 1.6 Hz, CHCH Ph), 3.22 (br s,
Ph), 2.95 (dd,
D
a] :
l
2
)
4
l
l
ꢀ
2
H33NO : C,
ꢀ3
0
.0375 M solution, 3.75ꢂ10
8
6
H
2
2
ꢀ
3
1
0.05 M solution, 3.75ꢂ10 mmol) were combined in a medium-
walled J. Young NMR tube. The solution was heated at 100 °C for
(
400 MHz, CDCl
3
2
h. Then, 6-methyl-hepta-4,5-dienylamine (12.5 lL of a 1.5 M
a
H
b
solution, 0.019 mmol 5 equiv.) was added and the J. Young NMR
1
1
1
1
1
1
1
a b
H, OH), 3.04 (apparent d, 1H, J = 12.6, CHCH H
Ph). 1 C NMR (100 MHz, CDCl
3
tube was heated at 105–135 °C. Reactions were monitored period-
H, J = 13.8, 10.1, CHCH
a
H
b
3
): d
1
ically by H NMR spectroscopy until completed or when conver-
67.01 (HC = N), 157.68 (4°), 145.63 (4°), 144.19 (4°), 140.24 (4°),
39.04 (4°), 137.63 (4°), 132.42 (CH), 132.01 (4°), 130.15 (4°),
29.88 (CH), 129.50 (CH), 128.95 (CH), 128.66 (CH), 128.58 (CH),
28.53 (CH), 128.39 (CH), 127.52 (CH), 127.22 (CH), 127.10 (CH),
27.05 (CH), 126.70 (CH), 126.56 (CH), 126.23 (CH), 126.00 (CH),
sion stalled. Percent conversion of products were determined by
1
H NMR spectroscopy (allene hydrogen is a pseudo-nonet at
5
.02 ppm, while the pyrrolidine hydrogen is a doublet of septets
at 5.19 ppm).
Enantiomeric excesses of the products were determined of their
1
2 2
18.81 (4°) , 79.87 (4°, C18), 78.96 (CHCH Ph), 37.55 (CH , C16).
One aromatic CH was not observed. MS (APCI): m/z 559 [M + H] .
IR (ATR, diamond): (C@N) = 1624 cm
benzyl derivatives. Benzyl bromide (2.25
lL, 0.02 mmol) and tri-
+
ethylamine (5.25 L, 0.04 mmol) were added to the J. Young
l
ꢀ1
.
NMR tube of a completed hydroamination reaction. The tube was
left to sit overnight and a crystalline solid precipitated out of solu-
2
-Hydroxy-3,5-di-4-(trifluoromethyl)phenylbenzaldehyde 2S-
(
1,1,3- triphenylpropanol)imine (L2).
L2 was prepared analogously to L1 starting from the mono-CF
tion. Isopropanol (100
then filtered through glass fibers in a pipette filter to remove any
residual TiO . The clear solution was diluted to a total volume of
mL with ether. The crude solution (0.2–0.5 L) was injected onto
lL) was added to the solution which was
3
substituted aldehyde A2 (2.0595 g, 5.02 mmol) and (S)-2-amino-
,1,3-triphenylpropanol (1.5228 g, 5.02 mmol, 1 equiv.) to yield a
cream solid that is bright yellow in solution (2.3568 g, 3.39 mmol,
8%). Mp: 84.4–84.5 °C. [ : ꢀ143° (0.006 g / mL, EtOAc). Anal.
Calcd for C42 NO : C, 72.51; H, 4.49; N, 2.01. Found: C,
2
1
4
l
the chiral GC capillary column (Chiraldex B-DM, 30 m ꢁ 0.25 mm,
6
a]
D
ꢀ1
split ratio 400, flow rate 41 cm s-1, 100 °C, 8 min, 1 °C min to
H
31
F
6
2
ꢀ1
1
36 °C, 10 °C min to 180 °C, hold 20 min). The two enantiomers
1
7
2.14; H, 4.71; N, 1.95. H NMR (400 MHz, CDCl
H, ArOH), 7.68–6.91 (m, 26H, ArH, HC = N), 4.36 (dd, 1H,
Ph), 2.98 (apparent d, 1H, J = 12.7 Hz,
Ph), 2.87 (s, 1H, OH), 2.82 (dd, 1H, J = 13.8, 10.3 Hz,
3
): d 13.67 (br s,
of 2-(2-methyl- propenyl)-pyrrolidine (2a) were separated with
retention time at approximately 41.5 min and 42.2 min.
1
J = 10.2, 1.6 Hz, CHCH
CHCH
CHCH
a b
H
a
H
b
1
3
a
H
b
Ph). C NMR (100 MHz, CDCl
58.90 (4°), 145.36 (4°), 144.03 (4°), 143.45 (4°), 141.01 (4°),
38.85 (4°), 132.24 (CH), 130.48 (4°), 130.28 (CH), 129.85 (CH),
3
): d 166.45 (HC = N),
3. Results & discussion
1
1
3.1. Design and synthesis of ligands
2
1
3 3
29.81 (CH), 129.32 (4°, CCF , q, JCF = 33 Hz), 129.27 (4°, CCF , q,
CF = 32 Hz), 129.15 (4°), 128.72 (CH). 128.64 (CH), 128.57 (CH),
27.40 (CH), 127.23 (CH), 126.88 (CH), 126.66 (CH), 126.25 (CH),
26.06 (CH), 125.96 (CH, q, JCF = 3.7 Hz), 125.35 (CH, q, JCF = 3.8-
Hz), 124.40 (CF
18.96 (4°), 79.88 (4°), 78.71 (CH). 37.53 (CH
376 MHz, CDCl
96 [M + H] . IR (ATR, diamond): (C@N) = 1616 cm
2
J
In our prior study we found that bulky ligands with 3,5-di-tert-
butyl substitution gave the highest enantioselectivity for the
intramolecular hydroamination of aminoallenes [51]. A similar zir-
conium catalyzed intramolecular hydroamination of aminoalkenes
has been reported [32]. We designed new ligands that could be
readily prepared that had differing steric protection at the 3,5-
positions (Fig. 1). The three aldehydes differ in the substitution
of the 3,5-diaryl rings, being phenyl (unsubstituted), or containing
1
1
3
3
3 3
, q, JCF = 270 Hz), 124.37 (CF JCF = 270 Hz),
, q, 1
1
1
9
1
2
).
F NMR
(
6
3
): d ꢀ 62.39 (CF
3
), ꢀ 62.51 (CF
3
). MS (APCI): m/z
+
ꢀ1
.
2
-Hydroxy-3,5-di-(3,5-di(trifluoromethyl))phenylbenzalde-
hyde 2S-(1,1,3- triphenylpropanol)imine (L3).
L3 was prepared analogously to L1 starting from di-CF
CF
ring.
The three aldehydes used in this study were prepared via a
Suzuki coupling using two different procedures. Procedure 1 used
Pd(dba) , 2.5 equiv. of boronic acid, 3,5-dibromosalicylaldehyde
and PPh [56]. Procedure 2 used Pd(PPh , 3,5-diiodosalicylalde-
3
groups, attached at either the 4- or 3,5-positions of the phenyl
3
substi-
tuted aldehyde A3 (0.8368 g, 1.53 mmol) and (S)-2-amino-1,1,3-
triphenylpropanol (0.4644 g, 1.53 mmol, 1 equiv.) to yield a yellow
solid (1.531 g, 1.84 mmol, 91%). Mp: 99.6–102.8 °C. [
c = 0.006 g / mL, EtOAc). Anal. Calcd for C44
a
]
D
: ꢀ69.08°
2
(
H
29
F12NO
2
: C, 63.54; H,
3
3 4
)
3

E.Y. Fok, V.L. Show and A.R. Johnson
Polyhedron 198 (2021) 115070
hyde, and 3 equiv. of boronic acid [58]. Either haloaldehyde could
be used in either synthesis, but procedure 1 gave higher yields and
was therefore adopted for the synthesis of all three aldehydes.
The resulting aldehydes were purified by recrystallization or
chromatography, and were isolated as white or yellow solids. A2
of 1-, 2-, and 4-hours; 1 h of preheating resulted in no eventual
conversion to product, but the 2- and 4-hour preheating times gave
similar results so we adopted the 2-hour procedure for all subse-
quent studies.
The hydroamination reactions were monitored by 1H NMR
spectroscopy and quenched when complete or when no additional
reaction progress was observed after a 16–24 h period. The reac-
tions proceeded to give only the desired pyrrolidine product, as
we have previously observed with this substrate [47,50,51]. The
time to reach conversion was usually around 18 h, though some
reactions continued to progress for several days. The reaction
reached 100% conversion at 20% catalyst loading for all ligands
and temperatures. Lower conversion was observed at 10% catalyst
loading, though some samples achieved 100% conversion. Essen-
tially no conversion was observed at our typical catalyst loading
of 5%. Enantioselectivities were determined by converting the
pyrrolidine product to its benzyl derivative using benzyl bromide.
Samples were injected onto the GC-MS instrument and enantiose-
lectivities were determined using our established procedure [51].
The results of our study of temperature and catalyst loading on
selectivity are found in Table 1.
was fully characterized by melting point, 1H, C, and F NMR
13
19
spectroscopy, mass spectrometry, and infrared spectroscopy. All
1
three aldehydes exhibited an OH and a C(O)H peak in the
H
NMR spectra near 12 and 10 ppm respectively, and A2 exhibited
1
9
CF
3
peaks in the F NMR spectra near ꢀ 62 ppm. All aldehydes
ꢀ1
exhibited a C@O stretch in the IR spectrum at near 1650 cm
.
The synthesis of the ligands L1, L2 and L3 was carried out by
combining the salicylaldehyde derivatives with the chiral amino
alcohol derived from phenylalanine (S)-2-amino-1,1,3-triphenyl-
propanol (Scheme 2). After an overnight reflux in ethanol, the
crude material was obtained simply by removing solvent. Ligands
could be purified either by recrystallization or by chromatography.
Similar imine-diol ligands we have prepared have been bright can-
ary yellow in the solid state, and all three were this color in solu-
tion. However, L2 was a cream color in the solid state following
chromatography. Multiple attempts were made to obtain X-ray
quality crystals of the three ligands but they have thus far been
unsuccessful. The X-ray crystal structure of a related ligand (4-
At 135 °C, the observed enantioselectivities ranged from 6 to 8%
at 20 mol% loading (entries 1, 6 and 11); the selectivity rose to 12–
15 %ee for TiL1 and TiL3 at 10 mol% loading, though the conver-
sions were low for both of these trials (entries 2 and 12). At
125 °C, the observed enantioselectivities were 21% for TiL1 (entry
3) 6% for TiL2 (entry 8) and 5% for TiL3 (entry 13) rising to 18% for
TiL3 at 10 mol% loading (entry 14). At 115 °C, the observed enan-
tioselectivities were 19% for TiL1, and 7% for both TiL2 and TiL3
(entries 4, 9 and 15). At 10 mol% loading, TiL3 gave a 21 %ee (entry
16). Finally, at 105 °C, the observed enantioselectivities were 22%
for TiL1, 8% for TiL2, and 6% for TiL3 (entries 5, 10 and 17).
Although there was a slight increase in enantioselectivity as
temperature dropped, the effect was not as substantial as observed
in a similar study carried out with sulfonamide ligands on titanium
and tantalum [48]. In addition, TiL1 gave the best selectivity, which
was unexpected as it was the least sterically crowded. Admittedly,
3
CH substituted) was obtained and published recently [59].
Ligands L1, L2, and L3 were completely characterized by melt-
ing point, optical rotation, 1H, and C NMR spectroscopy, mass
13
spectrometry, and infrared spectroscopy. Ligands L2 and L3 were
1
9
also characterized by F NMR spectroscopy. Each ligand exhibited
three doublets of doublets corresponding to the ligand backbone in
1
their H NMR spectra between 2 and 5 ppm, and L2 and L3 also
exhibited CF
All ligands contained a C@N stretch in the IR spectrum near
peaks at around -62 ppm in their 19F NMR spectra.
3
ꢀ
19
1
1
620–1630 cm . Although one aromatic CH was not observed
1
13
for L1, the H, F and C NMR spectra otherwise were consistent
1
2
with the proposed structures. Long range CF coupling ( JCF, JCF and
CF) was observed in both L2 and L3, although the quartet due to
3
J
the 2,6-carbons was not definitively located in L3.
3
the CF substitution on ligands L2 and L3 are not much larger than
a phenyl group, but we expected that the larger ligands would give
higher selectivity. We cannot rule out a small inductive electronic
effect on the selectivity of the reaction.
These results are a slight improvement on the imine-diol
derived catalysts we have reported previously [51]. In that work,
the highest enantioselectivity of 17 %ee was observed for the 3,5-
di-tert-butyl substituted ligand (Fig. 1a). The L1 ligand is more
selective by about 5%. The highest enantioselectivity for the tita-
nium catalyzed hydroamination of this dimethylaminoallene sub-
strate was recently reported at 27 %ee [47].
3
.2. Intramolecular hydroamination of aminoallenes
Hydroamination of aminoallene substrates was carried out
in situ. Titanium precatalyst complexes were prepared by mixing
a solution of the desired ligand with Ti(NMe in benzened in a
J. Young NMR tube and heated at 100 °C for 2 h. Catalysis was ini-
tiated by the addition of a solution of 6-methyl-hepta-4,5-dieny-
lamine in benzened
2
)
4
6
6
followed by heating to 135 °C, 125 °C,
15 °C, or 105 °C overnight (Scheme 3). Our established procedures
1
for hydroamination using this ligand type do not include any pre-
heating [51]. However, if we did not pre-form the complexes, no
conversion was observed. We studied different pre-heating times
The decrease in reactivity requiring increased catalyst loading is
perhaps explained by the unexpected formation of 2:1 complexes.
Scheme 2. Synthesis of ligands by Schiff base condensation.
4

E.Y. Fok, V.L. Show and A.R. Johnson
Polyhedron 198 (2021) 115070
Scheme 3. Hydroamination of trisubstituted aminoallenes.
Table 1
Hydroamination of 6-methyl-hetpa-4,5-dienylamine at various loadings and temperatures with in situ catalysts.
Entry
Catalyst
Catalyst Loading (%)
Temperature (°C)
Time (h)
NMR Yield (%)
% eea
1
2
3
4
5
6
7
8
9
TiL1
TiL1
TiL1
TiL1
TiL1
TiL2
TiL2
TiL2
TiL2
TiL2
TiL3
TiL3
TiL3
TiL3
TiL3
TiL3
TiL3
20
10
20
20
20
20
10
20
20
20
20
10
20
10
20
10
20
135
135
125
115
105
135
135
125
115
105
135
135
125
125
115
115
105
18
66
18
66
18
13
13
21
19
19
18
18
18
18
18
66
18
100
25
8
15
21
19
22
8
6
6
7
8
6
12
5
18
7
21
6
100
100
100
100
100
100
100
100
100
40
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
100
25
100
63
100
aOf the benzyl derivative, determined by GC, ±2%. All reactions favored the formation of the S-(-) enantiomer as determined by comparison to literature values [50,60–62].
Data reported as the average of at least two individual runs.
During the preparation of the hydroamination solutions, we occa-
sionally observed the formation of a yellow precipitate in the NMR
tubes. This precipitate was not observed with the prior imine-diol
ligands we have studied, though we did accidentally obtain a crys-
tal structure of a pseudooctahedral 2:1 complex of a similar ligand
on titanium [63], and structures of this type have been reported
previously [64]. Other groups have reported the observation of iso-
mers of complexes with imine-diol ligands on both copper [65] and
molybdenum [66], and it is possible that these isomers may in fact
be 2:1 complexes. The formation of this 2:1 complex would
remove the reactive dimethylamide groups, preventing it from
being a suitable precatalyst for the hydroamination reaction which
requires the formation of the titanium imido complex (Scheme 1).
Increasing the catalyst loading to 10–20 mol% allowed these com-
plexes to serve as effective catalysts for the hydroamination,
though the active catalyst concentration is surely lower.
aminoallenes was studied using their titanium complexes. The S-
(-)-enantiomer of the pyrrolidine product was favored in enan-
tiomeric excesses of up to 22%. This selectivity is the second high-
est observed, and is an improvement by about 5% from our
previous ligands of similar design. There is not a substantial differ-
ence in stereoselectivity at different temperatures, and the least
sterically encumbered ligand was found to give the highest selec-
tivity. Catalysis was carried out at 10–20 mol% loading due to the
formation of an unreactive 2:1 complex. Further investigation in
this area should focus on looking at steric width at the 3,5 positions
on the phenol ring to prevent the formation of the undesired com-
plex. It may be worthwhile to incorporate substitutions with a
more three-dimensional shape rather than planar rings.
CRediT authorship contribution statement
The formation of the 2:1 structure could also account for the
decrease in enantioselectivity. If the complex forms in situ by a dis-
proportionation reaction, an equal amount of Ti(NMe ) would
2 4
form according to Eq. (1). This titanium complex is competent for
the catalytic hydroamination reaction, albeit at a lower rate
Emily Y. Fok: Investigation, Writing - original draft, Writing -
review & editing. Veronica L. Show: Investigation, Writing -
review & editing. Adam R. Johnson: Conceptualization, Methodol-
ogy, Writing - review & editing, Data curation, Resources, Supervi-
sion, Project administration, Funding acquisition.
(
100% conversion at 135 °C in 67 h) and with no selectivity [57].
Although drawn as an equilibrium, precipitation of the Ti(X L)
2
2
complex would drive the reaction to the right, reducing the con-
centration of the active, chiral, catalyst. It is unclear why these
ligands favored the formation of the 2:1 complex so strongly but
clearly the steric protection afforded by the 3,5-diaryl substitution
does not prevent the formation of this complex.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
ð1Þ
Acknowledgements
4
. Conclusion
Financial support for this project was provided by the John
Stauffer Fund for Summer Research in Chemistry and Harvey Mudd
College. The authors thank Ty G. Waggener for providing artwork.
This paper is dedicated to the memory of RJC.
A series of imine-diol ligands with differently substituted aryl
groups was prepared, and intramolecular hydroamination of
5

E.Y. Fok, V.L. Show and A.R. Johnson
Polyhedron 198 (2021) 115070
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6