Facile Synthesis and Isolation of Secondary Amines via a Sequential Titanium(IV)-Catalyzed Hydroamination and Palladium-Catalyzed Hydrogenation

Article abstract of DOI:10.1002/adsc.201500861

An atom economical and catalytic route for the synthesis of aryl- and alkyl-substituted secondary amines has been developed. Using a bis(amidate)bis(amido)titanium(IV) precatalyst, the hydroamination of terminal alkynes with a range of amines results in the selective formation of the anti-Markovnikov product. The crude enamine/imine mixtures are effectively hydrogenated using palladium on carbon (Pd/C) and H₂ to afford the corresponding secondary amine in excellent yields. Simple work-up procedures allow for the isolation of pure compounds while avoiding purification via column chromatography.

Full text of DOI:10.1002/adsc.201500861

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DOI: 10.1002/adsc.201500861
Facile Synthesis and Isolation of Secondary Amines via a
Sequential Titanium(IV)-Catalyzed Hydroamination and
Palladium-Catalyzed Hydrogenation
Erica K. J. Luia and Laurel L. Schafera,*
a
Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada
V6T 1Z1
E-mail: schafer@chem.ubc.ca
Received: September 16, 2015; Revised: December 8, 2015; Published online: February 11, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500861.
Abstract: An atom economical and catalytic route
for the synthesis of aryl- and alkyl-substituted sec-
ondary amines has been developed. Using a bis(ami-
date)bis(amido)titanium(IV) precatalyst, the hydro-
amination of terminal alkynes with a range of
amines results in the selective formation of the anti-
Markovnikov product. The crude enamine/imine
mixtures are effectively hydrogenated using palladi-
um on carbon (Pd/C) and H2 to afford the corre-
sponding secondary amine in excellent yields.
Simple work-up procedures allow for the isolation
of pure compounds while avoiding purification via
column chromatography.
highly selective catalysts deliver either the Markovni-
kov[4c,5] or the anti-Markovnikov[6] product from ter-
minal alkynes.
Similar to reductive amination, further reduction of
the intermediate imine/enamine hydroamination
products is required to access the targeted amine
products (Scheme 1). While some sequential hydro-
amination/reduction reactions still implement stoi-
chiometric amounts of reductant,[5a,f,6d,7] in the past
decade, groups have shifted their focus to the employ-
ment of catalytic reduction routes, such as metal-cata-
lyzed hydrogenation using H2,[8] frustrated Lewis pair
hydrogenation,[5d] hydrosilylation,[5e,9] and more re-
cently, transfer hydrogenation.[10] Although great
progress has been achieved in this field, reduction of
catalytic loadings and the prevention of by-product
formation remains an ongoing challenge, while the
substrate scope reported to date is very focused.[8d–g]
Previous work from our group disclosed a bis(ami-
date)bis(amido)titanium complex (1a, 1b) for inter-
molecular terminal alkyne hydroamination with excel-
Keywords: hydroamination; hydrogenation; palladi-
um on carbon; sequential reactions; titanium cata-
lysts
Amine-containing compounds play an important role lent regioselectivity for the anti-Markovnikov product
in many aspects of biological and industrial process-
es.[1] Not only are they found in all living organisms,
such as the building blocks of life (amino acids), but
they are also found in a wide variety of pharmaceuti-
cal and agrochemical agents.[1] It is therefore not sur-
prising that great effort has been devoted toward the
synthesis and derivatization of amine-containing mol-
ecules.[1]
In an effort to develop more efficient amine synthe-
À
ses, hydroamination, the direct addition of an N H
bond across an unsaturated C C bond, is an attrac-
[2]
À
tive synthetic approach. Hydroamination reactions
can be catalytic and are completely atom economical.
However, the intermolecular hydroamination of al-
kenes remains a significant challenge in catalysis re-
Scheme 1. Previously reported amine syntheses using se-
quential catalytic hydroamination and stoichiometric hy-
search.[2,3] Alternatively, the hydroamination of al-
kynes has been well developed.[2,4] To date, some dride reducing agents.
Adv. Synth. Catal. 2016, 358, 713 – 718
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Erica K. J. Lui and Laurel L. Schafer
(Scheme 1).[11,12] These initial reports featured stoi-
chiometric amounts of lithium aluminum hydride as
the reducing agent to access amines.[11,12]
Table 1. Optimization of the sequential reaction conditions.
Due to the high regioselectivity, excellent substrate
scope and clean reaction profile delivered by our tita-
nium catalyst, we envisioned an atom economical and
catalytic route for the synthesis of secondary amines
by coupling hydroamination with catalytic hydrogena-
tion. This sequential approach has been useful in pre-
paring racemic mixtures of a-branched secondary
amines resulting from Markovnikov hydroamination
of terminal alkynes[5d] or regioselective hydroamina-
tion of internal alkynes.[8c] Thus, we targeted a modi-
fied synthetic approach that minimizes waste genera-
tion and reduces the amount of solvent required to
access a broad range of electronically and sterically
modified unbranched secondary amine products in
high yield.
Herein we disclose an optimized hydroamination
methodology with a reduced catalyst loading of only
1 mol%. Subsequent hydrogenation of the enamine/
imine mixture is achieved using easily removed Pd/C
catalyst. Finally, a streamlined work-up procedure has
been established which features filtration protocols,
and avoids purification by column chromatography in
most cases. Notably, yields of 81% or higher are ob-
Entry
Solvent
Time [h]
Yield [%][a]
1[b]
2
3
4
5
MeOH
MeOH
THF
i-PrOH
Benzene
72
3
3
3
3
65
98
96
96
92
[a]
Reported yield percentages refer to obtained yield after
work-up conditions.
Hydrogenation reaction was performed at 1 bar.
[b]
tained in most cases. As a demonstration of utility, solvent of choice due to its favorable environmental
secondary amines have been prepared and isolated on and health hazard profile.[13]
a multigram scale in 5–10 h from commercially avail-
able terminal alkyne and primary amine starting ma- conditions, an easy work-up procedure was estab-
terials. lished to afford the desired amine (Figure 1). Due to
In addition to developing optimized hydrogenation
To optimize reaction conditions, the hydroamina- the lack of by-products formed in this reaction se-
1
tion reaction was monitored by H NMR spectroscopy quence and the low solubility of the ligand in hexanes,
to determine substrate-dependent reaction times simple filtration of the crude reaction mixture
(30 min to 6 h) giving TOFs of 1.3 to 200 hÀ1 at 708C through Celiteꢁ removed the titanium and palladium
with a minimal catalyst loading of 1 mol% of 1b (Sup-
porting Information, Table S1). A variety of alkyl-
and arylamines and alkynes of different electronic
and steric natures were successfully employed in the
hydroamination step.
Initial studies on the feasibility of performing a se-
quential hydroamination/hydrogenation reaction were
performed using ethynylbenzene and tert-butylamine
as model substrates (Table 1). The hydroamination re-
action was set-up in a scintillation vial in an inert at-
mosphere glove-box using dried and distilled starting
materials. The reaction mixture was removed from
the glove-box and was stirred at 708C for 1 h before
transferring the reaction mixture by syringe to the
Fischer-Porterꢁ tube used for hydrogenation. Reduc-
tion of the hydroamination product was first per-
formed at 1 bar of H2 over 3 days, yielding 65% of
the desired product (entry 1). In an attempt to short-
en the reaction time, the pressure of H2 was increased
Figure 1. Crude 1H NMR spectrum (CDCl3, 400 MHz,
298 K) for the sequential hydroamination/hydrogenation re-
to 3 bar resulting in a reaction time of only 3 h and an
improved yield (entry 2). Although different solvents
delivered similar yields, methanol was selected as the action of ethynylbenzene and tert-butylamine.
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Facile Synthesis and Isolation of Secondary Amines
metal residues, while the addition of cold hexanes fol- imine intermediates in an hour or less. More sterical-
lowed by a second filtration allowed for full recovery ly-demanding substituents require longer reaction
of the amide proligand. Using this protocol, no times (2c–f). Arylamines (2g–j), including arylamines
column chromatography was required to obtain clean with both electron-withdrawing (e.g., 2h) and elec-
1
products (>95% purity as established by H NMR tron-donating substituents (e.g., 2j) are also compati-
spectroscopy) and thus, all reported yields are crude, ble with these low catalyst loadings. Although the
unless stated otherwise.
aforementioned work-up procedure was transferrable
In order to investigate the scope and limitations of towards all alkylamines screened (2a–f), arylamines
the sequential procedure, we first examined the reac- (2g–j) required further purification to remove minor,
tion of ethynylbenzene with a wide variety of amines unidentified impurities. Although the chloro- (2k) and
(Scheme 2). Alkylamines, both acyclic (2a–c) and cyano- (2l) substituted aniline substrates could yield
cyclic (2d–f), deliver excellent yields of enamine/ enamine/imine intermediates via Ti-catalyzed hydro-
amination (Supporting Information, Table S1), these
compounds were incompatible with the Pd-catalyzed
hydrogenation step and no secondary amine products
could be obtained. In the case of diphenethylamine
derivatives (2m, 2n), this protocol affords the desired
products quantitatively; however, the insolubility of
these amines in hexanes complicates isolation. In
these cases column chromatography could not be
used effectively to separate impurities from the de-
sired secondary amine products. Thus, to obtain the
amine in pure form, the optimized work-up procedure
required isolation of the amine-HCl salt product de-
rivative followed by re-basification and extraction.
The reaction of sec-butylamine with a variety of ter-
minal alkynes was also examined (Scheme 3). Both
electron-withdrawing and electron-donating para-sub-
stituted ethynylbenzenes (3a–d) were successfully syn-
thesized in excellent yields. The meta- (3e) and ortho-
substituted (3f) ethynylbenzenes were also tolerated,
though the latter was obtained in lower yield, presum-
ably due to steric bulk. Such steric hinderance has not
been observed to dramatically impact hydroamina-
tion, but could hinder palladium-catalyzed hydrogena-
tion. More importantly, less electronically and steri-
cally biased alkylalkynes also smoothly reacted in a re-
gioselective manner with the amine in the hydroami-
nation step (3g, 3h). To the best of our knowledge,
catalyst 1b is the only highly regioselective catalyst
using such alkylalkynes and alkylamines as substrates.
In the hydrogenation step of alkyl-substituted imines
(3g–k) a higher catalyst loading of between 1 and
5 mol% of Pd/C and slightly prolonged reaction times
were necessary to realize full hydrogenation of these
unactivated species. In all instances presented in
Scheme 3, no further purification was required
beyond the established filtration protocol to afford
pure products.
We have previously shown[6d,11,14] that the hydroami-
nation of alkynes containing protected alcohols,
esters, or amides can be tolerated by complexes 1a or
1b, notably these substrates are not compatible with
the low catalyst loading and short reaction times tar-
geted here. However, by increasing the loading of 1b,
the streamlined one-day process could also be ach-
Scheme 2. Effect of amine modification on reaction with
ethynylbenzene.
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Erica K. J. Lui and Laurel L. Schafer
Scheme 4. One-pot approach.
transformation that is mediated by titanium and a con-
trol experiment confirmed that Pd/C does not cata-
lyze the hydroamination reaction itself.
A varied selection of substrates was synthesized
using the one-pot approach (Scheme 4). In this case,
both Ti catalyst 1b and Pd/C were loaded into a scin-
tillation vial in the glove-box. Benzene, amine and
alkyne were added before removing the reaction
vessel from the glove-box. After stirring and heating
the hydroamination reaction mixture for the previous-
ly determined optimized reaction times, a hydrogen-
filled balloon was attached to the reaction vial. Upon
reaction completion our optimized reaction protocol
was used to obtain yields comparable to those of the
sequential approach. Only minor impurities can be
Scheme 3. Effect of alkyne modification on reaction with
sec-butylamine.
1
observed in the baseline of the H NMR spectra (see
the Supporting Information).
In summary, this protocol offers an alternative to
ieved with alkynes containing silyl ether (3j) and reductive amination for the synthesis of secondary
amide (3k) functionalities. amines, using terminal alkynes and amines as starting
With the potential synthetic relevance of our meth- materials. Titanium-catalyzed regioselective, intermo-
odology in mind, larger-scale reactions of 25 mmol lecular alkyne hydroamination can be performed
were performed in a 100-mL round-bottomed flask. quantitatively at low catalyst loading (1 mol%) in
Following the general procedure for the sequential short reaction times. The resultant intermediate en-
approach and simplified filtration work-up protocol, amine/imine mixtures can then undergo quantitative
4.3 g (97% yield) of 2-methyl-N-phenethylpropan-2- hydrogenation with a commonly available Pd/C cata-
amine and 3.3 g (83% yield) of N-(sec-butyl)hexan-1- lyst to give secondary amine products. These products
amine were obtained with the same degree of purity can typically be isolated cleanly using a simple filtra-
as that obtained for the smaller scale reactions.
tion protocol to give a variety of alkyl- and aryl-sub-
With this facile procedure in hand, we next devel- stituted secondary amine products. Within 5–10 h, this
oped a one-pot approach. Experiments confirmed sequential reaction affords a clean product that typi-
that Pd/C does not affect the desired hydroamination cally avoids the need for column chromatography.
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Facile Synthesis and Isolation of Secondary Amines
using filter paper and a funnel. Unless otherwise stated, con-
centration of filtrate under reduced pressure afforded the
desired secondary amine in high purity.
Most importantly, we have demonstrated that this
protocol can be carried out on a multigram scale, and
is suitable for general laboratory use.
General Procedure for the Large-Scale Sequential
Hydroamination/Hydrogenation Synthesis of
Secondary Amines
Experimental Section
General Procedure for the Time Optimization of the
Hydroamination Reaction
Inside an inert atmosphere box, benzene (20 mL) was added
to the titanium complex (0.25 mmol, 1 mol% Ti) in a 5-dram
vial. The solution was then transferred to a 100-mL round-
bottom flask. The amine (25 mmol, 1 equiv.) and alkyne
(25 mmol, 1 equiv.) were pre-weighed to separate 5-dram
vials and transferred to the reaction vessel. The remaining
benzene (5 mL) was used to rinse the vials containing amine
and alkyne, these rinses were also transferred to the reaction
vessel. The mixture was sealed, taken out of the inert atmos-
phere box and stirred at 708C for 1 to 2 h, depending on the
substrate. Half an hour prior to the completion of the hydro-
amination step, an oven-dried Fischer-Porter tube was
cooled under N2. Under a N2 flow, palladium on carbon
(0.125 mmol, 0.5 mol% Pd or 0.25 mmol, 1 mol% Pd) and
methanol (10 mL) were added to the vessel, which was then
pressurized and vented with H2 five times. After allowing
the hydroamination reaction mixture to cool down, the solu-
tion was added to the Fischer-Porter tube using a 10-mL sy-
ringe. Additional 15 mL of methanol were used to rinse the
vial containing the first step, and this liquid was also added
to the Fischer-Porter tube. The tube was then sealed and
pressurized to 3 bar. The reaction was allowed to proceed at
room temperature for 3 to 5 h depending on the substrate.
The crude was concentrated under reduced pressure and fil-
tered through a short plug of Celite using hexanes. The fil-
trate was concentrated under reduced pressure, affording
a mixture of ligand and product. The mixture was chilled in
the fridge for a few hours. Cold hexanes were added to the
concentrated oil and the suspension formed was filtered
using filter paper and a funnel. Unless otherwise stated, con-
centration of filtrate under reduced pressure afforded the
desired secondary amine in high purity.
Inside an inert atmosphere box, benzene (0.3 mL) was
added to the titanium complex (0.01 mmol, 1 mol% Ti) in
a 5-dram vial. The solution was then transferred to a J-
Young tube. The amine (1 mmol, 1 equiv.) and alkyne
(1 mmol, 1 equiv.) were pre-weighed to separate 5-dram
vials and transferred to the J-Young tube. The remaining
benzene (0.7 mL) was used to rinse the vials containing
amine and alkyne, these rinses were also transferred to the
reaction tube. The J-Young tube was sealed, taken out of
the inert atmosphere box and a time zero 1H NMR spec-
trum was obtained. The reaction solution was heated at
1
708C and after every hour of heating, a H NMR spectrum
was obtained until full consumption of starting materials
was observed. For reactions that required more than 1 hour
of heating, a second reaction was set-up, in which no hourly
stoppages occurred. Other than the time zero 1H NMR spec-
1
trum, only the H NMR spectrum at the expected comple-
tion time was obtained.
General Procedure for the Sequential
Hydroamination/
Hydrogenation Synthesis of Secondary Amines
Inside an inert atmosphere box, benzene (3 mL) was added
to the titanium complex (0.05 mmol, 1 mol% Ti) in a 5-dram
vial. The solution was then transferred to a scintillation vial.
The amine (5 mmol, 1 equiv.) and alkyne (5 mmol, 1 equiv.)
were pre-weighed to separate 5-dram vials and transferred
to the reaction vessel. The remaining benzene (2 mL) was
used to rinse the vials containing amine and alkyne, these
rinses were also transferred to the reaction vessel. The mix-
ture was sealed, taken out of the inert atmosphere box and
stirred at 708C for 0.5 to 6 h, depending on the substrate.
Half an hour prior to the completion of the hydroamination
step, an oven-dried Fischer-Porter tube was cooled under
N2. Under an N2 flow, palladium on carbon (0.25 mmol,
0.5 mol% Pd or 0.5 mmol, 1 mol% Pd) and methanol
(2 mL) were added to the vessel, which was then pressurized
and vented with H2 five times. After allowing the hydroami-
nation reaction mixture to cool down, the solution was
added to the Fischer-Porter tube using a 5-mL syringe. Ad-
ditional 3 mL of methanol were used to rinse the vial con-
taining the first step, and this liquid was also added to the
Fischer-Porter tube. The tube was then sealed and pressur-
ized to 3 bar. The reaction was allowed to proceed at room
temperature for 3 to 5 h depending on the substrate. The
crude was concentrated under reduced pressure and filtered
through a short plug of Celite using hexanes. The filtrate
was concentrated under reduced pressure, affording a mix-
ture of ligand and product. The mixture was chilled in the
fridge for at least 30 min. Cold hexanes were added to the
concentrated oil and the suspension formed was filtered
General Procedure for the One-Pot Hydroamination/
Hydrogenation Synthesis of Secondary Amines
Inside an inert atmosphere box, benzene (3 mL) was added
to the titanium complex (0.05 mmol, 1 mol% Ti) in a 5-dram
vial. The solution was transferred to a scintillation vial con-
taining pre-weighed palladium on carbon (0.25 mmol,
0.5 mol% or 0.5 mmol, 1 mol% Pd). The amine (5 mmol,
1 equiv.) and alkyne (5 mmol, 1 equiv.) were pre-weighed to
separate 5-dram vials and transferred to the reaction vessel.
The remaining benzene (2 mL) was used to rinse the vials
containing amine and alkyne, and these rinses were also
transferred to the reaction vessel. The mixture was sealed,
taken out of the inert atmosphere box and stirred at 708C
for 0.5 to 3 h, depending on the substrate. Upon completion
of the hydroamination reaction, the mixture was allowed to
cool down and a balloon filled with hydrogen gas was at-
tached to the reaction vessel. The reaction was allowed to
proceed at room temperature for 40 h. The crude was con-
centrated under reduced pressure and filtered through
a short plug of Celite using hexanes. The filtrate was con-
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COMMUNICATIONS
Erica K. J. Lui and Laurel L. Schafer
centrated under reduced pressure, affording a mixture of
ligand and product. The mixture was chilled in the fridge for
at least 30 min. Cold hexanes were added to the concentrat-
ed oil and the suspension formed was filtered using filter
paper and a funnel. Unless otherwise stated, concentration
of filtrate under reduced pressure afforded the desired sec-
ondary amine in high purity.
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