A silica-supported titanium catalyst for heterogeneous hydroamination and multicomponent coupling reactions

Article abstract of DOI:10.1039/c9dt01835b

Highly dehydrated silica gel, SiO₂⁷⁰⁰, gave a material with a total surface hydroxyl density of 0.31 ± 0.05 mmol g^-1, 0.9 ± 0.1 Si-OH sites per nm². Treatment of this material with Ti(NMe₂)₄

Full text of DOI:10.1039/c9dt01835b

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A silica-supported titanium catalyst for
heterogeneous hydroamination and
Cite this: DOI: 10.1039/c9dt01835b
multicomponent coupling reactions†
Kelly E. Aldrich
and Aaron L. Odom
*
Highly dehydrated silica gel, SiO2700, gave a material with a total surface hydroxyl density of 0.31
0.05 mmol g−1, 0.9 0.1 Si–OH sites per nm2. Treatment of this material with Ti(NMe2)4 gave Ti(NMe2)3/
SiO2700, which is 1.50% 0.07 Ti, where the titanium is bound to the surface, on average, through a single
O–Si–Ti linkage. This material was tested for its properties as a catalyst for C–N bond forming reactions
and was found to be a competent alkyne hydroamination and iminoamination catalyst. For iminoamina-
tion, which is the 3-component coupling of an alkyne, primary amine, and isonitrile, this heterogeneous
catalyst was able to carry out some catalyses faster than previously reported homogeneous catalysts with
lower catalyst loadings. The material is also a catalyst for the addition of aniline to dicyclohexyl-
carbodiimide to form a substituted guanidine. In addition, a known quinoline with biological activity was
prepared using the heterogeneous catalyst in a one-pot procedure using half the catalyst loading of the
previously reported synthesis.
Received 1st May 2019,
Accepted 30th June 2019
DOI: 10.1039/c9dt01835b
rsc.li/dalton
organic
transformations
involving
C–N
bond
Introduction
formation.1,5,6,12,13,17,18,20–32 These transformations lead to
Homogeneous transition metal complexes that catalyze C–N heterocycles and other organic building blocks that are more
bond forming reactions are abundant and varied, and high difficult to access via other synthetic methodologies.5,7,33
oxidation state Group-4 transition metals have been extensively Recent efforts employing these catalysts often focus on
studied for this purpose.1–3 In addition to simple C–N bond improvements in rate, substrate scope, selectivity, or new reac-
forming reactions like hydroamination, some of the same cata- tion pathways, requiring new ancillary ligand designs.34,35
lysts enable multicomponent coupling reactions.4–13 For Despite these advancements, recent work in the field also
example, titanium complexes can catalyze the 3-component demonstrates some of the fundamental limits of homo-
coupling (3CC) of an amine, alkyne, and isonitrile to yield tau- geneous catalysts. For example, often with these catalysts, the
tomers of 1,3-diimines (Fig. 1); the reaction is the formal active species can dimerize or undergo other equilibrium pro-
addition of an iminyl group and an amine to an alkyne, cesses that reduce the catalyst’s activity or deactivate it
iminoamination.14,15 A small selection of relevant Group-4 altogether; noninnocence with ancillary ligands is also
transition metal catalysts and precatalysts competent for C–N reported.34,36
bond forming reactions is shown in Fig. 1. Catalysts such as
While a tremendous amount of work has gone into
these have been thoroughly studied over the past few decades. different ancillary ligands for hydroamination, there are rela-
These studies have provided a well-developed mechanistic tively few studies on heterogeneous catalysts for the reaction.
understanding, illustrating the details of these C–N bond For hydroamination chemistry, and the related iminoamina-
forming reactions.16–19 This, in turn, supports targeted design tion reaction (Fig. 1), this approach seemed promising and
of improved catalysts.
remains relatively unexplored, particularly with Group-
Many groups (Bergman, Doye, Mountford, Odom, Schafer, 4 metals. Hydroamination has been examined with a few
Tonks, and others) have demonstrated the versatility and prac- different types of heterogeneous catalysts,37–41 including a
ticality of such high oxidation state catalysts for complex recent example by Copéret, which used a silica-supported Zn
catalyst to produce indoles via an intramolecular hydroamina-
tion.42 These examples primarily utilize late transition metals
Department of Chemistry, Michigan State University, 578 S Shaw Ln, East Lansing,
in low oxidation states. Additionally, multicomponent coup-
MI, 48824 USA. E-mail: odoma@msu.edu
ling of the sort shown in Fig. 1 with heterogeneous catalysts is
†Electronic supplementary information (ESI) available: Details for all experi-
not common.32
ments. See DOI: 10.1039/c9dt01835b
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To alter the reactivity of our surface-supported Ti(NMe2)2/
SiO2
catalyst,32 we turned to the well-explored silica gel
preparation of Copéret and coworkers,37 which often gives
species bound to the surface by a single oxygen. A titanium
species bound to a SiO2 surface via a single Si–O–Ti linkage
provides a few substantial differences, and possible advan-
200
200
tages, compared to the previously studied Ti(NMe2)2/SiO2
catalyst. First, reducing the number of bonds to the surface
should provide a dramatically different steric profile around
the active metal center. Second, one of the Ti–O bonds, effec-
tively a siloxide ligand, is replaced by an additional dimethyl-
amide, which will participate in protolytic substitution in the
reaction mixture. This provides an electronic modification to
the active Ti metal.34 With the objective of producing a catalyst
material with titanium bound through a single site to SiO2,
700
SiO2
was prepared using a slightly modified version of the
Copéret procedure.37 Onto the SiO2700, Ti(NMe2)4 was grafted,
to provide the target material.
In this study, the preparation and characterization of the
700
new Ti(NMe2)3/SiO2
is presented, including NMR titration
and ICP-OES analysis of titanium content in the as-prepared
material. Reactivity of the material in both hydroamination and
iminoamination reactions was explored. Activity for hydroami-
nation was comparable to that of Ti(NMe2)2/SiO2200, while dra-
matic improvement in iminoamination catalysis was observed.
Fig. 1 (Top) A selection of Group-4 transition metal catalysts compe-
tent for C–C and C–N bond formation reactions. (Middle) The addition
of a primary amine to an alkyne is catalyzed by all of the example
catalysts shown, which provides imines as products. (Bottom)
Iminoamination effectively adds an iminyl group and an amine across
the triple bond of the alkyne, which is catalyzed by Ti(dpm)(NMe2)2 and
Ti(dpma)(NMe2)2. The products of the reaction are unsymmetrical tauto-
mers of 1,3-diimines.
Results and discussion
Ti(NMe2)3/SiO2700 characterization and properties
A
highly dehydroxylated, high-surface area SiO2 support
material was prepared from slight modification of the litera-
ture reported method.37 The production of SiO2
involves
700
Of course, there are disadvantages to this strategy, perhaps heating commercially available, high surface area, fumed silica
most significant of which is a loss of the detailed understand- for extended periods of time at several different temperatures.
ing associated with molecular catalysis. Thus, in targeting a A detailed procedure is given in the ESI,† but, since the pro-
heterogeneous system, we sought to retain a similar coordi- cedure includes heating up to 700 °C, we are using the
nation environment at the metal to the homogeneous systems. moniker SiO2700. Upon dehydroxylation, the surface density of
With this goal in mind, the use of silica-supported titanium hydroxyl sites was determined by NMR titration with Ti(NEt2)4.
catalysts with 2 or more protolytically active sites on the metal The release of NHEt2 was monitored relative to the number of
(Fig. 1) became an attractive option.37,43
equivalents of Ti(NEt2)4 consumed vs. hexamethyldisiloxane as
In a recently published study,32 we examined the catalytic an internal standard. This gave a total surface hydroxyl density
activity of a silica-bound titanium species similar to one of 0.31 0.05 mmol g−1, or 0.9 0.1 Si–OH sites per nm2;
reported by Beaudoin and Scott.44 In this study, the activity of additionally, this correlates with 0.98 0.04 moles of NHEt2
the heterogeneous titanium precatalyst, Ti(NMe2)2/SiO2200, was released per 1.0 mole of Ti(NEt2)4 consumed to saturate the
explored for hydroamination and iminoamination activity. acidic SiOH sites.
This catalyst was easily prepared and performed well as a high-
The amount of physisorbed or coordinated (Fig. 2c) amine
yielding, highly regioselective catalyst for intermolecular in the isolated catalyst was investigated by treatment with
hydroamination of a variety of anilines and alkynes. However, excess pyridine in the presence of an internal standard. This
the catalyst was intolerant of alkylamines and performed resulted in liberation of 9% HNMe2 relative to the number of
poorly as a catalyst for iminoamination. Steric protection of moles of titanium sites. This observation suggests that during
the aniline substrate at the 2 and/or 6 position was necessary the titration experiments described above, up to 1.07
to outcompete hydroamination, and the off-cycle formation of 0.4 moles of amine may be released per titanium complex
formamidine, in the multicomponent coupling.14 While initial added to the silica surface. The stoichiometry determined by
results were promising, we sought more active and selective titration alone may then provide a slight underestimate of the
heterogeneous catalysts.
amount of amine released due to amine interaction with the
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bound via one Si–O–Ti linkage (Fig. 2a). It is worth mentioning
that the bulk properties reported here leave some room for
variation at individual Ti sites. For example, there could be
small numbers of titanium atoms bound by more than one Ti–
O bond, as depicted in Fig. 2b. There could also be small
numbers of Ti species where HNR2 remains datively bound to
the Ti after protonation (Fig. 2c). Our bulk characterization in
no way rules out some statistical mixture of these site vari-
ations, but these potential site variations also don’t preclude
the material’s use in the targeted catalysis. Naturally, this
difficulty in determination of the true active species is not
unique to heterogeneous catalysis and is a problem shared by
those studying homogeneous catalysis as well.
Fig. 2 A selection of potential surface site variations in the Ti(NMe2)3/
700
SiO2
bulk material: (a) the stoichiometry calculated from NMR titra-
700
tions and ICP-OES determination of Ti content; (b) Ti bound to SiO2
through two Ti–O bonds, similar to Ti(NMe2)2/SiO2
200 32
;
(c) Ti bound
Catalytic activity of Ti(NMe2)3/SiO2700 for hydroamination
through one Ti–O bond, which retains an equivalent of datively bound
amine.
700
The application of Ti(NMe2)3/SiO2
as a catalyst for hydro-
amination (HA) was examined with a variety of substrates
(Table 1), including aniline; substituted anilines; and a variety
of alkynes, including terminal alkyl, terminal aromatic,
internal aromatic, and diphenylacetylene.
silica support itself. However, both measurements indicate
values very close to 1 amine per titanium site and nearly
within experimental error from triplicate measurement using
Yields of hydroamination product are relatively high,
overall, for hydroamination, however, there are a few substrates
with which this catalyst does not perform well. These include
HA with aniline and phenylacetylene (entry 3), as well as reac-
tions with alkylamines (entries 5, 6, and 9), and an electron-
withdrawing aniline derivative, 3,5-bis(trifluoromethyl)aniline
(entry 10). While this catalyst material is slightly more tolerant
of different amines than the previously studied Ti(NMe2)2/
SiO2200, the yields obtained with some amines are still quite
low.
the two techniques. The predicted weight percentage of the
700
SiO2
upon saturation with Ti(NMe2)4 was calculated to be
1.46% 0.12. This value closely matches the experimentally
determined wt% of 1.50%
measurements.
0.07, established by ICP-OES
700
The Ti(NMe2)3/SiO2
catalyst was examined by IR spec-
troscopy as well, which shows new resonances consistent with
C–H bonds, which is expected with the proposed dimethyl-
amide structure. No N–H resonance was observed, but, as indi-
cated by the pyridine experiment above to release coordinated
and physisorbed amine, the amine present is quite small in
the catalyst material, even relative to the 1.5 wt% titanium.
Consistent with the above, solid-state 13C NMR resonances at
43 and 36 ppm are observed and tentatively assigned to the di-
methylamide and dimethylamine in the sample, respectively
(Scheme 1).
The regioselectivities of substrates that this catalyst toler-
ates are high (entries 1, 2, 7, 8, and 11–14), giving results com-
parable to those obtained with homogeneous catalysts.1,5 This
700
heterogeneous Ti(NMe2)3/SiO2
offers some additional
benefits over other available catalysts, including the ease with
which the catalyst material can be separated from the organic
reaction mixture, an advantage when organic compounds pro-
duced via this route are carried on in organic synthesis.45,46
The catalyst material does not perform hydroamination of
N-methylaniline. This is preliminary support that the catalyst
may favor the Bergman-mechanism for hydroamination, where
the active species is a titanium-imide that undergoes cyclo-
addition with the alkyne, as opposed to a Marks-mechanism
These bulk material characterizations suggest that the
700
average titanium species in the Ti(NMe2)3/SiO2
material is
where olefin insertion into
a
metal–amide bond is
observed.17,18,47 Additionally, it is worth noting that upon
addition of a primary amine or aniline, the catalyst material
goes from pale yellow to an intense red color, reminiscent of
200
similar homogeneous titanium catalysts and Ti(NMe2)2/SiO2
.
700
Iminoamination catalysis with Ti(NMe2)3/SiO2
700
Ti(NMe2)3/SiO2
demonstrates marked improvement over
200
previously-studied Ti(NMe2)2/SiO2
both in terms of yield
and substrate tolerance for iminoamination reactions.32 First,
considering the same substrate scope as was studied with Ti
200
700
(NMe2)2/SiO2
(entries 1–5, Table 2), the yields are higher
Scheme 1 Synthesis of Ti(NMe2)3/SiO2
from commercially available
SiO2 and Ti(NMe2)4.
and the amounts of formamidine and hydroamination side
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Table 1 Substrate scope for intermolecular hydroamination using Ti
(NMe2)3/SiO2
Table 2 Iminoamination substrate scope examined with Ti(NMe2)3/
SiO2700 as catalyst
700 a
Yieldb (%)
(isomer ratio)
NH2R
Alkyne
Product (major)
Product
(major)
Yieldb (%)
(isomer ratio)
Entry NH2R
1
Alkyne
1
2
H2NPh
92 (>100 : 1)
94 (6.6 : 1) 6%
HAc,d
92 (15 : 1)
71 (>100 : 1)d
33 (1.5 : 1)d
3
4
33 (28 : 1)
92
2
3
5
H2NCyc
11d (1 : 1)
4
5
8e(>100 : 1) 16%
HAc
6
7
34d (2.1 : 1)
85 (43 : 1)
61 (3.0 : 1) 5%
HAc
8
9
91 (>100 : 1)
0
6
7
H2NPh
H2NPh
88a (10.3 : 1)
52a (6.3 : 1)
10
28d (>100 : 1)
11
12
69 (60 : 1)
a Yields given are after 18 h. b Yields are calculated from GC/FID stan-
dardized with internal dodecane, utilizing the authentic isolated pro-
ducts or a close derivative to calibrate the FID responses (see ESI†).
c HA = hydroamination product. d A trace of formamidine due to coup-
ling of the amine and isonitrile was detected. e The yield of the com-
pound made isolation very difficult, and the calibration curve for a
derivative with a similar formula was used to estimate the GC yield.
59 (>100 : 1)
13
14
86 (>100 : 1)
80 (>100 : 1)
hydroamination (HA) and formamidine (FA) are noted by GC
analysis. The only substrate combination not significantly
improved is that in entry 4, which is still quite low; the combi-
nation of coupling a terminal alkyne with the small but very
electron rich aniline is not productive.
In addition, we noted one other vast improvement with Ti
(NMe2)3/SiO2700—it can couple unsubstituted aniline with
internal and terminal aromatic alkynes in iminoamination
reactions (entries 6 and 7). These substrate combinations did
a Entries 1 and 2 were run for less than 1 h. Yields for all other entries
were determined at 12 h. b Calibrated GC/FID yields with dodecane as
the internal standard. The GC response was found by reducing the
imine to the amine, isolating the amine, and calibrating amine deriva-
tive response versus dodecane. That calibration curve was used to get
the GC yield for each related imine. c Cy = cyclohexyl. d Because of the
low yield, the compound couldn’t be isolated for GC calibration, and
the calibration curve for a derivative with a close molecular formula
was used. The correct regioisomer is unestablished in these cases and
the isomer shown is simply one possibility.
not result in observable quantities of iminoamination product
200 32
with Ti(NMe2)2/SiO2
.
This marks a dramatic improvement
700
products noted in these reactions are much lower. In fact, with in the substrate tolerance of the Ti(NMe2)3/SiO2
relative to
the most sterically protected aniline, 2,6-dimethylaniline Ti(NMe2)2/SiO2200. For those substrates in entries 1, 2, and
700
(entry 1), the yield of the iminoamination product is 94% 5–7, the simple Ti(NMe2)3/SiO2
catalyst provides yields that
under the standard reaction conditions. Only trace amounts of could be isolated or easily carried on in additional reactions
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(vide infra).4,14 While these results indicate enhancement of Recyclability of the Ti(NMe2)3/SiO2700 material
catalytic activity over the previous effort, we are currently inves-
Following a single use of the catalyst for either hydroamination
or 3CC, subsequent reuse of the same catalyst material
resulted in dramatically reduced activity. After hydroamination
or iminoamination following the general procedure, the cata-
lyst material was removed from the reaction mixture by fil-
tration in the glovebox. The catalyst was then rinsed with
toluene, followed by pentanes, and was then dried in vacuo.
The dried material was added, as recovered, to a second reac-
tion, for which the general procedure was followed for either
HA or 3CC. After the second run of each batch of catalyst, with
a variety of substrates in both HA and 3CC, only trace amounts
of product (<5% yield) were observed, even after extended reac-
tion times.
tigating ways to further improve the scope of the catalyst, such
as iminoamination involving unsubstituted aniline and term-
inal alkynes with CyNC.
Application of Ti(NMe2)3/SiO2700 to quinoline synthesis
The one-pot, two-step synthesis of substituted quinoline
derivatives has been previously reported by our group.45
Utilizing homogeneous titanium catalysts to perform imino-
amination reactions, followed by acid-catalyzed heterocycle
formation with glacial acetic acid, quinolines can be produced
from simple starting materials. Further, these quinoline pro-
ducts are of interest in biological applications, as they have
been shown to exhibit µM inhibition of the human protea-
some, which bears relevance to several human diseases.45
With previously reported Ti(NMe2)2/SiO2200, small amounts
of titanium leaching were detected during catalysis.32 To verify
whether the same phenomenon was affecting Ti(NMe2)3/
SiO2700, batches of the used catalyst from both HA and 3CC
were examined by ICP-OES. The results of these analyses show
very similar amounts of titanium before and after Ti(NMe2)3/
As mentioned above, for several substrate combinations,
700
Ti(NMe2)3/SiO2
provides clean reactions with high enough
yields to pursue functionalization of the 3CC product. We
sought a direct comparison with the homogeneous titanium-
catalyzed pathway to these substituted quinolines in order to
assess the practicality of the heterogeneous catalyst.
700
SiO2 use in catalysis (Table 3); consequently, it appears that
the metal is not leaching from the surface during catalysis to
any measurable extent.
The reaction shown in Scheme 2 was carried out to produce
No experimental evidence has been found to date to
(N,N,2)-trimethyl-3-phenylquinolin-6-amine, which has
a
700
∼10 µM LC50 value for proteasome inhibition.45 With 5 mol%
Ti(NMe2)3/SiO2700, the iminoamination step was run for 16 h,
followed by heating with glacial acetic acid for 20 h. A final iso-
lated yield of 43% was obtained after column chromatography.
The original report used 10 mol% Ti(dpm)(NMe2)2 for 24 h,
and glacial acetic acid for 24 h, to achieve a final yield of
50%. The overall yield between the homogeneous and
heterogeneous catalyzed reactions are very similar. With
respect to both reaction time and amount of catalyst used,
however, the heterogeneous catalyst outperforms the homo-
geneous catalyst, i.e., 36 h compared to 48 h with half the cata-
lyst loading.
suggest why HA catalysis deactivates Ti(NMe2)3/SiO2
.
However, we have observed, via a post-reaction acid wash of
the catalyst used in iminoamination, several organic residues
not observed in the crude reaction solution. Several of these
species show m/z ratios and fragmentation patterns that don’t
match any of the previously encountered products or side pro-
ducts in these catalysed reactions. Among these new organic
residues are two interesting sets of m/z peaks that correspond
to 1,3-dicyclohexylurea and 1-cyclohexyl-3-phenylurea.
These same organic residues are noted when the alkyne in
the iminoamination reaction is changed, suggesting that the
alkyne does not affect the formation of these organic residues
(Scheme 3). These observations suggest that, in the case of the
3CC reactions, side reactions between the silica-bound tita-
nium sites, aniline, and excess isonitrile in the reaction solu-
tions may contribute to the deactivation of the material.
700
Table 3 Ti content in the as-prepared Ti(NMe2)3/SiO2
and used
catalyst from both hydroamination and 3 component coupling reactions
determined by ICP-OES
Sample species
Ti(NMe2)3/SiO2
ICP-OES wt%
Predicted wt%a
700
1.50 (0.07)
1.44 (0.03)
1.48 (0.04)
1.46 (0.12)
Ti(NMe2)3/SiO2700 (used for HA)
Ti(NMe2)3/SiO2700 (used for 3CC)
1.35–1.46 (0.10)b
a Calculated from the surface density of Si–O–H sites determined by
700
.
b Variable weight% from Ti predicted
NMR titrations of SiO2
Scheme 2 One-pot, two-step quinoline synthesis utilizing Ti(NMe2)3/
because of differences that could occur in speciation of ligands on Ti
after reactions are complete (e.g., dimethylamide ligands will be
replaced by anilides or other protonated species in the catalytic
mixture).
700
SiO2
catalyst. The overall reaction yield is comparable to that
achieved with homogeneous Ti catalysts, with half of the catalyst
loading.
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additional catalytic C–N bond forming reaction for which Ti
700
(NMe2)3/SiO2
is competent is exciting and suggests further
exploratory reactivity studies with the catalyst material may be
fruitful. Additionally, this reaction in particular highlights one
700
of the Ti(NMe2)3/SiO2
catalyst’s inherent advantages over a
homogeneous system. The heterogeneous catalyst can success-
fully catalyse the formation of products which would exchange
with ancillary ligands in homogeneous systems, irreversibly
altering the homogeneous catalyst’s reactivity.
Conclusions
700
The Ti(NMe2)3/SiO2
material presented here has low tita-
nium content by mass (1.50 wt%), yet demonstrates good cata-
lytic activity for both hydroamination and multicomponent
coupling chemistry. The catalyst performs the intermolecular
hydroamination of anilines and alkynes in moderate to high
yields (∼30–90%) with high regioselectivities. The catalyst also
demonstrates moderate to high yields of 1,3-diimine tauto-
mers from the 3-component coupling of anilines, alkynes, and
isonitriles, provided either the alkyne or the aniline derivative
are sterically hindered (52–94%). Despite substrate scope limit-
Scheme 3 Products observed by GCMS after mild acid treatment of
the catalyst material post-iminoamination reaction. The two urea
species shown were observed, in addition to several other masses.
However, no specific products or reaction routes have been
clearly identified.
ations relative to some homogeneous catalysts active for the
700
same reactions, the Ti(NMe2)3/SiO2
material shows marked
Surface-bound species with sufficient thermodynamic stabi-
lity could certainly prevent re-entry into the active catalytic
cycle. An example of this type of deactivation has been pre-
viously presented by Mountford in homogeneous systems.48 In
this instance, homogeneous titanium catalysts for hydroami-
nation could undergo addition of 2 equivalents of alkyne to
the active titanium-imide. This extra insertion forms an isol-
able complex with a 6-membered ring that includes the tita-
nium and may inhibit this catalysis, even though double
alkyne insertion is useful for other transformations.24,49,50
Efforts to circumvent or reverse catalyst poisoning with the
material are ongoing.
improvement over closely-related Ti(NMe2)2/SiO2200. In fact, Ti
700
(NMe2)3/SiO2
only falls short when trying to use small
aniline derivatives in conjunction with terminal alkyl-substi-
tuted alkynes.
700
The usefulness of Ti(NMe2)3/SiO2
was tested directly by
functionalizing a 3CC product to form a quinoline. In this
700
one-pot, two-step transformation Ti(NMe2)3/SiO2
provides
43% isolated yield of N,N,2-trimethyl-3-phenylquinolin-6-
amine in 36 h with 5 mol% catalyst. This result is competitive
with homogeneous titanium-catalyzed reactions of this type,
while using half the catalyst loading.
Additionally, other benefits noted with this catalyst over the
typical homogeneous catalyst primarily include: (1) the ease
with which it is separated from the complex organic reaction
mixture (2) ease of preparation, and (3) the lower catalyst load-
Catalytic guanidine formation from 1,3-dicyclo-
hexylcarbodiimide
ings relative to homogeneous systems.45,46 With some sub-
Richeson and coworkers have previously demonstrated that a
terminal titanium imide can react directly with carbodiimide,
resulting in the formation of a guanidine.51,52 In these guani-
dine-forming reactions, the ancillary ligands are themselves
often guanidines.
700
strates, Ti(NMe2)3/SiO2
(entries 1, 5, and 6 in Table 2) even
outperforms the homogeneous systems by increasing yield,
reducing side reactions, and approaching completion in
shorter reaction times. These results demonstrate the promise
of further investigation into silica-supported titanium catalysts
as C–N bond formation catalysts.
Unfortunately, the material is not recyclable for either of
the catalytic reactions investigated here. However, this lack of
reusability is not due to loss of titanium from the silica.
Alternative reaction conditions or post-reaction surface treat-
ments may allow for catalyst reactivation in future studies,
ð1Þ
In the catalytic reaction examined here with Ti(NMe2)3/ since the titanium remains on the surface.
700
700
SiO2
,
5
mol% Ti(NMe2)3/SiO2
,
1,3-dicyclohexyl-
For the iminoamination reaction in particular, this new tita-
carbodiimide, and aniline produce N,N′-dicyclohexyl-N″- nium-supported silica gel is a superior catalyst to previous
phenylguanidine in 79% isolated yield. The discovery of an homogeneous catalysts for some substrate combinations, e.g.,
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bulky anilines such as 2,6-dimethylaniline. Additionally, the powdery, pale yellow material. ICP-OES: 1.50% Ti ( 0.07) (see
supported catalyst can be further modified to tune reactivity, the ESI† for details of error analysis).
which is being explored for later reports.
700
General hydroamination procedure with Ti(NMe2)3/SiO2
700
A 15 mL pressure tube was charged with Ti(NMe2)3/SiO2
(163 mg, 5 mol%), a stir bar, and p-cymene (1.0 mL).
Separately, a volumetrically prepared 1.0 mL solution of NH2R
Experimental
General considerations
(1 mmol) and alkyne (2 mmol) in p-cymene was prepared. This
solution was added to the catalyst mixture in the pressure
tube, with stirring. The pressure tube was sealed and trans-
ferred from the glovebox to a preheated 180 °C aluminum well
plate. The reaction was heated with magnetic stirring for
40 min to 12 h depending on the substrates. The pressure tube
All syntheses and handling of materials were carried out under
an inert N2 atmosphere, either in an MBraun glovebox or by
standard Schlenck techniques. Any handling of materials in
air is specified. Generally, this was limited to column chrom-
atography and preparation of ICP or iminoamination GC
samples.
was ambiently cooled to room temperature and centrifuged to
700
compact the Ti(NMe2)3/SiO2
into an orange pellet at the
Fumed SiO2 was purchased from Sigma Aldrich and used
as received (200 25 m2 g−1, Lot # SLBT0198). The following
solvents were purchased commercially and dried prior to use:
para-cymene was dried over CaH2 and distilled in vacuo; pen-
tanes and toluene were dried by passage over activated
alumina and sparged with N2; and tetrahydrofuran was dried
over sodium and distilled under N2. C6D6 was purchased from
Sigma Aldrich, dried over CaH2, and distilled under N2. All
dried solvents were stored in an N2 glovebox after purification.
Additionally, CDCl3 used for routine organic product NMR
samples was purchased from Cambridge Isotopes and used as
received. On Ti(NMe2)3/SiO2700, solid-state CP-MAS 13C NMR
was carried out with a spin rate = 6 kHz, frequency = 100 MHz,
mixing time = 1.8 ms, a recycle delay = 2 s, and an acquisition
time = 5.12 ms. The spectra are in the ESI.†
bottom of the tube. The pressure tube was transferred back to
the glovebox, and the liquids decanted. The crude solution
was utilized for GC analysis.
700
General 3CC procedure with Ti(NMe2)3/SiO2
700
A 15 mL pressure tube was charged with Ti(NMe2)3/SiO2
(163 mg, 5 mol%), a stir bar, and p-cymene (1.0 mL).
Separately, a volumetrically prepared 1.0 mL solution of NH2R
(1 mmol), CyNC (1.5 mmol), and alkyne (2 mmol) in p-cymene
was prepared. This solution was added to the catalyst mixture
in the pressure tube, with stirring. The pressure tube was
sealed and transferred from the glovebox to a preheated
180 °C aluminum well plate. The reaction was heated with
magnetic stirring for 18–48 h. The pressure tube was ambiently
cooled to room temperature and centrifuged to compact the Ti
Ti(NMe2)4 and Ti(NEt2)4 were purchased from Gelest and
used as received. Aniline, 2,6-dimethylaniline, 2,5-dimethyl-
aniline, and 3,5-bis(trifluoromethyl)aniline were dried over an
appropriate drying agent and distilled under vacuum. The 4-N,
N-dimethylaniline was dried by azeotroping with benzene
using a Dean–Stark trap for 48 h under N2 prior to use. NH2Cy
was purchased from Strem and was dried over CaH2 and dis-
tilled under N2 before use; 1-NH2Ad was dried under reduced
pressure and recrystallized from dry solvents before use. The
alkynes phenylacetylene, 1-phenylpropyne, 1-octyne, and
4-octyne were purchased from Alfa and dried over Na2SO4,
then distilled under N2 before use. Cyclohexylisonitrile was
prepared according to literature procedures.53
700
(NMe2)3/SiO2
into an orange pellet at the bottom of the
tube. The pressure tube was transferred back to the glovebox,
and the liquids decanted. The crude solution was utilized for
GC analysis.
Synthesis of N,N,2-trimethyl-3-phenylquinolin-6-amine using
1-pot-2-step procedure
In the glovebox, a 15 mL pressure tube was loaded with
700
Ti(NMe2)3/SiO2
(320 mg, 5 mol%), a stir bar, and p-cymene
(1.0 mL). Separately, 2 mmol of each of the following reagents
was massed: 1-phenypropyne (232 mg, equiv.), CyNC
1
(218 mg, 1 equiv.), and 4-N,N-dimethylaniline (272 mg, 1
equiv.). These reagents were added to the stirred contents of
the pressure tube with additional p-cymene (1.0 mL). The
pressure tube was sealed and transferred from the glovebox to
a 180 °C aluminum well plate and was heated with stirring for
16 h. The tube was removed from heat and allowed to cool to
room temperature. Once cooled, the tube was opened in air,
700
SiO2 was prepared following slight modification of litera-
ture procedures,37 to accommodate differences in equipment,
etc. For a detailed procedure, see the ESI.†
700
Preparation of Ti(NMe2)3/SiO2
From Ti(NEt2)4 titrations, the surface abundance of Si–OH and 2 mL of glacial acetic acid was added. The tube was sealed
sites was estimated (0.00031 mol g−1). Based on this measure- and heated with stirring for an additional 20 h at 120 °C. The
700
ment, 1.2 equiv. of Ti(NMe2)4 was added to 1 equiv. of SiO2
stirred as a slurry in n-hexane. The SiO2
contents of the tube were transferred to a 100 mL beaker and
700
rapidly went from neutralized to a pH of 7–8 with sodium bicarbonate solution.
colorless to orangish-yellow. The mixture was stirred for 2 h at The neutralized mixture was extracted with Et2O (3 × 50 mL)
700
room temperature. The Ti(NMe2)3/SiO2
was then collected and concentrated by rotary evaporation to give a viscous
by filtration, rinsed with 20 mL of hexane, and 20 mL of reddish-brown solution. Note, the silica material becomes
700
benzene. The Ti(NMe2)3/SiO2
was dried in vacuo, yielding a suspended in the aqueous layer, and is separated from the
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organics during extraction. The crude product was purified by
column chromatography using neutral alumina and hexane
with 1% triethylamine (v : v) with a gradient to 20% EtOAc as
eluent. This provided the quinoline product as a red oil (43%,
224 mg). The properties of the isolated complex match those
previously reported by 1H and 13C NMR, and GCMS fragmenta-
tion pattern and retention time.46
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The general procedure for HA or iminoamination was followed.
Upon completion of the initial reaction (run 1), the pressure tube
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The catalyst material was collected by filtration and thoroughly
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700
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(163 mg,
5 mol%), a stir bar, and p-cymene (1.0 mL). To this solution
was added H2NPh (112 mg, 1.2 equivalents) and 1,3-dicyclo-
hexylcarbodiimide (208 mg, 1 equivalents). The tube was sealed
and transferred to a 180 °C aluminum block. The reaction was
heated with stirring for 2 h. The reaction was cooled to room
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