Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights to Realize the Enantioselective Synthesis of Piperazines

Article abstract of DOI:10.1021/acs.joc.6b01884

An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η⁶-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated. Substrate scope investigations suggest that hydrogen-bonding interactions between the oxygen in the backbone of the ether-containing substrate and the [(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's. This insight led to a mechanistic proposal that predicts the observed absolute stereochemistry. Most importantly, this mechanistic insight allowed for the extension of this strategy to include N as an alternative hydrogen bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted piperazines is also demonstrated.

Full text of DOI:10.1021/acs.joc.6b01884

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pubs.acs.org/joc
Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic
Insights To Realize the Enantioselective Synthesis of Piperazines
Ying Yin Lau, Huimin Zhai, and Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
S
* Supporting Information
ABSTRACT: An efficient and practical catalytic approach for the enantioselective
synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction
employing both hydroamination and asymmetric transfer hydrogenation reactions is
described. Starting from ether-containing aminoalkyne substrates, a commercially
available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is
subsequently reduced using the Noyori−Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η6-p-
cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric
excesses of >95%. A wide range of functional groups is tolerated. Substrate scope
investigations suggest that hydrogen-bonding interactions between the oxygen in the
backbone of the ether-containing substrate and the [(S,S)-Ts-DPEN] ligand of the Ru
catalyst are crucial for obtaining high ee’s. This insight led to a mechanistic proposal that
predicts the observed absolute stereochemistry. Most importantly, this mechanistic
insight allowed for the extension of this strategy to include N as an alternative hydrogen
bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted
piperazines is also demonstrated.
Examples of other catalytic strategies from prochiral starting
materials include enantioselective α-chlorination of aldehydes
followed by reductive amination and base-induced cyclization,7
oxyamination,8 Pd-catalyzed carboamination,3c and hydro-
amination of functionalized aminoalkenes to arrive at
disubstituted morpholines diastereoselectively.9 The enantio-
selective preparation of N-heterocycles with substitutions α to
N is of interest due to the biological relevance of α-chiral
amines;10 however, none of these aforementioned approaches
can be used to synthesize such morpholine products in an
enantioselective manner.
Catalytic hydroamination, the direct addition of an N−H
bond across a C−C unsaturation, is an efficient and atom-
economical transformation to yield new C−N bonds.11 Our
research group has developed the bis(amidate)bis(amido)
titanium precatalyst 1 for the hydroamination of alkynes.12 We
previously reported a tandem sequential, one-pot catalytic
approach to 3-substituted morpholines by hydroamination of
functionalized aminoalkynes to yield cyclic imines, which can
then be reduced enantioselectively by Ru-catalyzed asymmet-
ric-transfer hydrogenation (ATH, Scheme 1).9b This route
effectively affords the first catalytic, enantioselective approach
for the synthesis of 3-substituted morpholine products in good
yields. Furthermore, our results show that the known
oxophilicity of Group 4 catalytic systems does not preclude
their application in the synthesis of biologically relevant
morpholines.
INTRODUCTION
■
The synthesis of enantiopure 3-substituted morpholines is of
interest in contemporary organic chemistry.1 These structural
motifs are prevalent in biologically relevant compounds, and
they present an important research challenge in the develop-
ment of new tools for the preparation of potential
pharmaceuticals. Traditional synthetic approaches to enantio-
pure, substituted morpholines generally employ a stepwise
synthetic strategy from enantioenriched starting materials that
are derived from naturally occurring chiral amino acids.2 These
syntheses are not catalytic, and they result in stoichiometric
amounts of byproducts and waste. In addition, the reliance on
enantiopure starting materials poses a limitation on the
morpholine products that can be accessed by these routes,
as most affordable commercial starting materials are derived
from naturally occurring amino acids.2a,3 Here, our strategy
instead focuses on the assembly of prochiral substrates, with
variable substituent patterns and functional group incorpo-
ration, to realize the selective synthesis of either enantiomer by
using tandem hydroamination, asymmetric-transfer hydro-
genation.
Prochiral substrates can be used to construct 3-substituted
morpholine products in both a diastereoselective and
enantioselective fashion. Bode and co-workers have recently
reported the preparation of racemic 3-substituted morpholines
and piperazines and the diastereoselective synthesis of
disubstituted 2,3-morpholines from commercially available
SnAP reagents and aldehydes.5 Enantioenriched 2-substituted
morpholines with moderate ee values (up to 60%) can be
realized through Pd-catalyzed allylic substitution reactions.6
Received: August 2, 2016
© XXXX American Chemical Society
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Scheme 1. Strategies for Synthesizing Enantioenriched 3-Morpholines2c,4
Asymmetric-transfer hydrogenation is an industrially im-
portant synthetic method for reliably reducing ketones to
chiral alcohols under mild conditions; however, the application
of this synthetic protocol to the reduction of imines to yield
amines is only consistently applicable for select aryl-substituted
substrates.13 Specifically, the Noyori−Ikariya catalyst (2)9b
yields outstanding enantioselectivities with isoquinolines or
cyclic imine substrates that bear adjacent steric bulk and
aromatic groups. Mechanistic proposals rationalizing the high
enantioselectivities have suggested that these aromatic
substituents participate in important stabilizing CH/π
interactions with the η6-cymene ring of the Ru catalyst as
well as CH/π interactions with the TSPEN ligand.14 This
proposal is consistent with the low ee’s previously reported in
the preparation of 2-substituted piperidines via asymmetric-
transfer hydrogenation of precursor cyclic imines.15 Interest-
ingly, in our case excellent enantioselectivities are observed for
a wide range of alkyl-substituted morpholine products.9b
Here, we explore the substrate scope of this one-pot
synthetic protocol in the synthesis of a wide range of 3-
substituted morpholines in good yields with excellent
enantioselectivities. Based upon substrate scope observations,
we put forward a mechanistic proposal that implicates
hydrogen-bonding interactions between the cyclic imine
substrates and the Ru catalyst 2 to afford morpholine products
with high ee’s. Furthermore, this mechanistic insight points
toward a new application of this synthetic strategy: the
catalytic preparation of selectively substituted piperazines with
good ee’s (Scheme 2).
Scheme 2. Asymmetric Synthesis of 3-Alkylated N-
Benzylpiperazine via Hydroamination and Asymmetric-
Transfer Hydrogenation
of aminoalkyne substrates required for tandem catalysis
investigations. By using a flexible approach, aminoalkyne
substrates could be prepared using a modular three step
synthetic route featuring modified literature procedures
(Scheme 3).
Boc-protected ethanolamine and a propargyl bromide
substrate were reacted under modified Williamson ether
synthesis conditions to yield the corresponding ether.16
When propargyl bromide is used as a reagent, the reaction
proceeds smoothly at room temperature to give protected
terminal aminoalkyne 3 in 79% yield. For alkyl-substituted
propargyl bromides, elevated temperatures are required for the
reaction to progress, affording 4i−l in 69−81% yield. The
preparation of aryl-substituted aminoalkyne substrates (4a−g,
yields = 37−91%) was easily achieved using Sonagashira cross-
coupling conditions starting from tert-butyl (2-(prop-2-yn-1-
yloxy)ethyl)carbamate (3).17 These protected aminoethers
undergo Boc deprotection using acidic conditions to give the
requisite primary aminoalkyne substrates (5a−l, yields = 51%-
quantitative; see the Experimental Section and Table 2).
Morpholine Synthesis. We initiated our investigations of
intramolecular hydroamination using aminoalkyne 5a with 5
mol % of precatalyst 1 at 110 °C in toluene (Table 1, entry 1),
in accordance with previously established catalytic condi-
tions.12b Even with increased reaction temperatures (entry 2)
and extended reaction times (entry 3), this reaction did not go
RESULTS AND DISCUSSION
■
Synthesis of Aminoalkyne Substrates. Our initial
efforts into this new synthetic methodology were preceded
by the search for a facile, modular preparation for the assembly
B
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Scheme 3. General Synthetic Route for the Preparation of Aminoalkyne Substrates
Table 1. Optimization of Hydroamination Reaction Conditions
a
b
entry
precatalyst loading (mol %)
temp (°C)
ratio
1
2
5
5
110
120
130
110
3:1: 0.1
3:1: 0.1
3:1: 0.1
0:1: 0.1
c
3
5
4
10
a
Precatalyst loading calculated with resepect to 0.2 mmol of 5a. Reactions conducted in a sealed J-Young NMR tube in 0.5 mL of d8-toluene.
b
c
Determined by 13C NMR spectroscopy (400 MHz, 298 K). Reaction time extended to 24 h.
to completion. We attribute this sluggish reactivity to the
presence of the potentially chelating oxygen heteroatom in this
class of aminoalkyne substrates. When 10 mol % of precatalyst
1 was used, the hydroamination reaction proceeded smoothly
to completion at 110 °C overnight to produce imine 6a, along
with the enamine isomer 6b. These reactions were monitored
using 13C NMR spectroscopy by observing the disappearance
of signals corresponding to the alkyne carbons (∼90−75 ppm)
and the formation of a diagnostic imine signal at ∼165 ppm.
Notably, hydroamination and asymmetric-transfer hydro-
genation can be performed in a facile one-pot tandem
sequential fashion without isolation and purification of the
imine intermediate. The crude mixture of imine and enamine
isomers was enantioselectively reduced using 1 mol % of
commercially available RuCl [(S,S)-Ts-DPEN] (η6-p-cymene)
(2) as a catalyst (eq 1).18 Notably, the presence of the Ti
extraction to afford 7a in 78% yield with 98% ee, as
determined by supercritical fluid chromatography (Table 2,
entry 1). Even while avoiding column chromatography, this
product was >95% pure, as determined by 1H NMR
spectroscopy (see the SI). The (R)-configuration of product
7a was determined by comparing the optical rotation of the
pure product with the literature value of the isolated (S)-
enantiomer, which was synthesized from enantiopure (S)-
phenylalanol.19 The absolute configurations for all other
examples here were assigned by analogy.
With optimized reaction conditions in hand, we explored the
substrate scope for this method using 10 mol % of precatalyst
1, followed by 1 mol % of 2 as catalyst (Table 2). Good yields
and excellent enantioselectivities were obtained with morpho-
line products containing variously substituted aromatic ring
systems (Table 2, entries 1−7). Both Ti and Ru catalysts
display tolerance to electron-donating substituents (Table 2,
entry 5) and electron-withdrawing substituents (Table 2,
entries 3 and 4) on the aromatic ring. Aryl bromide
functionalities are permitted (7b), and the product retains an
important functional group amenable to further synthetic
manipulations such as cross coupling.20 Nitrogen-containing
heteroaromatic systems, such as pyridine (Table 2, entry 6),
are also tolerated.
To our delight, good yields and high enantioselectivities
were also obtained with aminoalkyne substrates containing
alkyl groups (Table 2, entries 8−12). Imines with minimal
steric bulk such as those substituted with simple methyl and n-
propyl substituents yielding products 7h and 7i are reduced
with good enantioselectivities. Notably, substrate 5k bearing a
hydroamination catalyst in the enamine/imine mixture does
not hinder subsequent transfer hydrogenation reactivity. The
crude morpholine product was purified by acid−base
C
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Table 2. Synthesis of 3-Substituted Morpholines by Tandem Hydroamination and Asymmetric Transfer Hydrogenation
a
b
c
Crude yield (>95% pure). Determined by supercritical fluid chromatography. Determined by supercritical fluid chromatography after
d
e
derivatization with tosyl chloride. Isolated yield after flash chromatography. Isolated by derivatization into oxalate salt (vide infra).
tert-butyl group afforded 7k in 74% yield with only 74% ee.
This lowered enantioselectivity is attributed to the increased
steric bulk of the tert-butyl group interfering with the transfer
hydrogenation step of the synthetic sequence (vide infra).
While the crude 3-substituted morpholines described in
Table 2 are synthesized in more than 95% purity in most cases,
further purification of the resulting products can be readily
achieved through isolation of the oxalate salt of the amine.
D
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Recrystallization of the oxalate salt of 7b from diethyl ether
resulted in a further increase in enantioselectivity resulting in
>99% ee (Scheme 4).
functionalities that can undergo a variety of further synthetic
transformations.21 There are many examples of late-transition-
metal hydroamination catalysts which display functional group
tolerance toward nitrile groups, but examples of such
functional group tolerance with early-transition-metal catalysts
are noticeably lacking in the literature.22
Scheme 4. Derivatization of Morpholine 7b into Oxalate
Salt 8
Hydroamination of 10 occurred successfully to yield the
corresponding cyclic imine, which was subsequently reduced
with sodium borohydride to afford racemic morpholine
product 11 in good yield (78%) and purity. While the racemic
morpholine was successfully isolated, reduction of the cyclic
imine with RuCl [(S,S)-Ts-DPEN] (η6-p-cymene) failed to
yield the analogous enantiomerically enriched morpholine
product. This demonstrates that the titanium hydroamination
catalyst is tolerant to the nitrile functionality and C−N
unsaturations; however, the nitrile group interferes with the
asymmetric transfer hydrogenation, as an intractable mixture of
products is obtained after this step of the reaction.
Probing Mechanism. A wide range of substrates are
compatible with our tandem sequential catalysis method to
form 3-substituted morpholines with excellent enantioselecti-
vies (Table 2). Most importantly, this protocol does not
demand aromatic substituents or sterically demanding
substrates to realize excellent ee’s. These results are particularly
intriguing considering all previous reports require aromatic
substituents to access excellent enantioselectivities.13a,b,14b One
hypothesis for the excellent enantioselectivies in our case could
be that the residual Lewis acidic titanium species remaining
after the hydroamination step has an advantageous effect on
the ATH reaction. As a control experiment, the volatile
aminoalkyne 5h was selected to probe the role of the titanium
residue on the ATH reaction (Scheme 8). The toluene solvent
and the intermediate imine formed upon hydroamination
could be vacuum transferred away from the titanium catalyst
and into a clean reaction vessel. Complex 2 and all other
reagents for ATH were then added, and upon reaction
completion 7h was obtained in 90% ee (average ee after the
experiment was performed in triplicate) in contrast to the one-
pot procedure where 7h was yielded with >99% ee (Table 2,
entry 8), indicating that indeed the presence of the titanium
catalyst has a notable impact.23
As illustrated in Table 2, the use of commercially available
RuCl [(S,S)-Ts-DPEN] (η6-p-cymene) for asymmetric transfer
hydrogenation with the cyclic imines generated by hydro-
amination affords enantioenriched 3-substituted morpholine
products. For product 7a, the corresponding (S)-enantiomer
can be synthesized through the use of commercially available
RuCl [(R,R)-Ts-DPEN] (η6-p-cymene) (2a) with comparable
yields and enantioselectivies as the (S,S)-Ru catalyst (Scheme
5). The optical rotation of the resulting product matches the
(S)-enantiomer, which was previously reported in the
literature.19
Scheme 5. Synthesis of (S)-3-Benzylmorpholine (9)
Furthermore, this synthetic protocol for the enantioselective
synthesis of morpholines is also amenable to gram-scale
synthesis (Scheme 6). Starting from 1 g of aminoalkyne 5a,
Scheme 6. Gram-Scale Synthesis of (R)-3-Benzylmorpholine
Next, we examined the use of additives in the second step of
the reaction in Scheme 7 in an effort to restore the
enantioselectivity to the >99% ee observed in the one-pot
process (Table 3). First, we carried out the sequence shown in
Scheme 8 and then added titanium complex 1 into the ATH
reaction (a stepwise reaction rather than a one-pot reaction),
and interestingly, the observed ee was raised from 90% ee to
94% ee, but was less than the one-pot reaction (entry 1).24 To
test if this effect was due to the Lewis acidic character of
residual [Ti] species, Ti(NMe2)4 was used as an additive, and a
similar ee value was achieved (entry 2). However, this effect
was not limited to titanium, as the addition of Zr(NMe2)4 also
increased the enantiomeric excess to 94% (entry 3). However,
when the late transition metal Lewis acid AgOTf was used, a
dramatic decline in ee to 71% was observed (entry 4),
suggesting that perhaps the slight restoration in ee is not a
Lewis acid effect, but rather an amine or amide ligand effect
arising from the use of precatalyst 1. Interestingly, the addition
of 20 mol % of just proligand resulted in an increase in ee to
93% (entry 5), while the addition of a simple amine additive
also raised the ee’s to 95% (entry 6). The compilation of these
data highlight that hydrogen bonding interactions alone affect
(R)-3-benzylmorpholine (7a) can be synthesized. Purification
through simple acid−base extraction yields the desired product
in 72% yield with 95% ee, which is comparable to the results
obtained on smaller scale as presented in Table 2. No further
purification by column chromatography or recrystallization was
required.
During the exploration of the substrate scope of this
method, an aminoalkyne substrate containing a nitrile group
was synthesized (10, Scheme 7). Nitrile groups are versatile
Scheme 7. Synthesis of Nitrile-Containing Morpholine
Product 11
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Scheme 8. Asymmetric Transfer Hydrogenation of 5h in the Absence of [Ti]
Table 3. Asymmetric Transfer Hydrogenation of 5h in the
Absence of [Ti]
the ee’s of ATH, and the presence of added metal is not
required. However, the combination of the residual Ti catalyst
mixture that remains in the reaction mixture during the one-
pot protocol cannot be duplicated through the use of
precatalyst, proligand, or other Lewis acidic additives alone.
Efforts to characterize the residual Ti catalyst mixture have not
been successful.
Proposal. The proposed mechanism of ATH of carbonyl
substrates postulates a concerted cyclic six-membered tran-
sition state, where hydride and proton transfer from the
catalyst to the substrate occurs without coordination of the
substrate to the metal center.13g,14b,c,25 A more recent DFT
investigation concludes that this proposed transition state is
only applicable to gas-phase calculations and in solution, the
reaction is a two-step process where transfer of the hydride
from the Ru catalyst occurs, followed by a proton transfer from
either the solvent or the TsDPEN ligand.26
Experimental and computational investigations into the
mechanism of ATH for imines suggest that these substrates
undergo reduction via a different reaction pathway. First, acidic
activation of the imine by either a Brønsted or a Lewis acid is
required for these reactions to proceed.18,27 Gas phase
̌
calculations by Kacer and co-workers show that the imine
a
Determined by supercritical fluid chromatography after derivitization
substrates are protonated by formic acid that is present under
catalytic reaction conditions, and the substrate can interact
with the oxygen atoms of the sulfonyl group through hydrogen
bonding to stabilize the transition state.14a,b Other significant
b
with tosyl chloride. Experiments performed in duplicate, and ee value
presented is the average of the two runs.
Figure 1. Proposed mechanistic rationale for asymmetric transfer hydrogenation invoking key role of heteroatom in favorable H-bonding
interactions.
F
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effects include CH/π interactions between the substrate and
the η6-arene ring of the Ru catalyst, which can lower the
overall energy of the transition state up to 12.3 kJ/mol.14c This
rationalizes how substrates with aromatic rings adjacent to the
CN bond are known to give high ee’s with the Noyori−
Ikariya catalyst.14a,b,15,18 However, in our studies, excellent
enantioselectivities are achieved even with nonsterically
demanding alkyl-substituted imines that cannot access the
crucial CH/π interactions discussed above. In the case of
morpholine, we have the O in the ring which could engage in
further hydrogen-bonding interactions. Computational work
substituted morpholines without the need for CH/π
interactions with the substrate.
The necessity for secondary hydrogen-bonding interactions
between the oxygen in the backbone of the cyclic imine and
the TsDPEN ligand for high enantioselectivities is further
corroborated by experimental results when this synthetic
strategy is applied to the synthesis of other N-heterocycles
(Table 4). For example, as was reported previously,15
Table 4. Synthesis of Substituted N-Heterocycles by
Tandem Hydroamination and Asymmetric Transfer
Hydrogenation
̌
presented by Kacer and co-workers inspired us to propose the
mechanistic rationale shown in (Figure 1). We propose that a
highly ordered transition state for the hydrogen transfer
process can be accessed in which two key hydrogen-bonding
interactions between the substrate and the chiral ligand are
imperative for enantioselectivity: one between the proton of
the iminium moiety and the oxygen atoms of the TsDPEN
ligand the second between the oxygen heteroatom of the imine
substrate and the hydrogen atoms of the neutrally bound
ethylenediamine ligand. Note that this simplified proposed
mechanism focuses on the profound effect of the Noyori−
Ikariya catalyst and does not consider the more subtle effect of
residual Ti catalyst.14a,b
The substrate enters the catalytic cycle as an iminium ion
due to protonation by the formic acid that is present in the
reaction medium. The protonated substrate approaches the
catalytically active Ru hydride complex from the side away
from the chiral ligand, facilitating hydride transfer to the
electrophilic imine C. The orientation of the imine substrate
for reduction is proposed to occur as depicted in Figure 1 to
facilitate two key hydrogen-bonding interactions. The
predicted stereochemical outcome resulting from this proposed
mechanism is in agreement with observed experimental results.
In particular, the (S,S)-Ru catalyst affords the R-enantiomeric
product and the (R,R)-Ru catalyst yields the corresponding S-
enantiomer product. An alternative approach of the substrate
promoting hydride delivery to the Re face of the imine would
have the R-substituent oriented down toward the TsDPEN
ligand of 2; however, this creates major steric congestion
between the substrate and the cymene ligand (Figure 2). Also,
a
b
Crude yield. Determined by supercritical fluid chromatography.
c
Determined by supercritical fluid chromatography after derivitization
d
with tosyl chloride. Determined by 19F NMR spectroscopy after
derivitization with (R)-(−)-α-methoxy-α-(trifluoromethyl)-
phenylacetyl chloride.
piperidines, with no potential for hydrogen bonding in the
4-position, see dramatic reductions in ee’s (24%, entry 2).
However, when hydrogen bonding slightly larger thiomorpho-
lines (with longer C−S bonds (1.82 Å) vs (C−O) (1.46 Å),28
the ee’s are somewhat restored (66%, entry 3). Using the tosyl-
protected piperazines, the observed ee is only 70% (entry 4).
We suggest that the impeding steric bulk and variable
hydrogen-bonding character of the tosyl group reduces the
potential for favorable interactions with the N of the ring.
However, this result suggests that the incorporation of a
substituent on N that is neither capable of hydrogen bonding
nor sterically demanding should favor the desirable hydrogen-
bonding interactions with the ethylene diamine ligand.
To test this hypothesis, the non-hydrogen-bonding benzyl-
protected diaminoalkyne was prepared (Scheme 6) and used
in our one-pot enantioselective protocol (Table 4, entry 5).
Aminoalkyne 12d was synthesized by starting from reductive
amination of BOC-protected ethylene diamine and benzalde-
hyde to yield 14,29 followed by the installation of the
Figure 2. Alternative transition state for asymmetric transfer
hydrogenation.
favorable hydrogen bonding interactions with the oxygen
cannot be accommodated in this alternative transition state
model. Therefore, Figure 1 suggests the relatively less sterically
demanding substrate trajectory and gives rise to the possibility
of effective hydrogen bonding between the O atom and the
ethylene diamine ligand. The experimental observation that
sterically demanding R groups yield products with reduced ee’s
(7k, ee = 74%) is consistent with this proposal, as the
additional steric bulk on the imine substrate perturbs this
approach into the catalyst active site. Therefore, high ee’s can
be achieved for the synthesis of a range of alkyl- and aryl-CH2
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Scheme 9. Synthetic Route to 12d
propargylic functional group through base mediated alkylation
conditions (Scheme 9). Removal of the BOC protecting group
using 4 M HCl in dioxane yields the substrate 12d, which was
subjected to the general reaction conditions for hydro-
amination, but complete conversion to the cyclic imine was
not observed, suggesting catalyst deactivation by this
potentially chelating substrate. Catalyst deactivation was
observed to be slow, as partial conversion to the imine was
observed after 14 h by NMR spectroscopy; however, no
further conversion was observed with prolonged reaction times
and increased reaction temperatures. Conversion to the desired
cyclic imine can be improved through a second addition of 10
mol % of 1 and increased reaction time. The introduction of a
second portion of Ti catalyst reacts with uncyclized amino-
alkyne substrates after the first portion of Ti is no longer
catalytically active. Finally, the cyclic imine was reduced using
standard ATH reaction conditions to yield (R)-1-benzyl-3-
methylpiperazine. Derivatization with (R)-(−)-α-methoxy-α-
(trifluoromethyl)phenylacetyl chloride allowed for ee determi-
nation by in situ 19F NMR spectroscopy.30 Gratifyingly, only
one enantiomer was observed (Table 4, entry 5).
This synthetic strategy may be extended for the preparation
of other piperazine compounds with high enantioselectivities.
The synthesis of (R)-3-benzyl-1-(3-phenylprop-2-yn-1-yl)-
piperazine (17) from aminoalkyne (16) successfully yielded
the desired product with a high ee of 96% (Scheme 10). This
target compound is amenable to further synthetic manipu-
lations through the pendent alkyne functionality; however, the
yield for 17 is low (14%), and the desired product was
inseparable from the starting material as the product was
isolated as a mixture containing the aminoalkyne starting
material. Similar to the preparation of 13d, incomplete
conversion in the hydroamination step was observed by
NMR spectroscopy, due to possible catalyst deactivation of 1
by the potentially chelating aminoalkyne substrate. Never-
theless, these data demonstrate that the scope for ATH of
cyclic imines is no longer limited to substrates containing
aromatic groups, but cyclic imines with hydrogen-bond
acceptors incorporated into the substrate can be reduced
with good enantioselectivities, providing that other destabiliz-
ing interactions can be avoided. This achievement is a powerful
extension of ATH to access more chiral heterocycles using this
catalytic strategy and provides new insights for the develop-
ment of alternative approaches for enantioselective morpholine
and piperazine synthesis.
Further extension of the substrate scope of N-benzyl 2-
substituted piperazines was explored. Good ee’s were obtained
for piperazine products 19 (87%) and 21 (81%, Scheme 11);
however, complete conversion to the desired product was not
achieved. Even with sequential loading of the catalyst, yields
ranging from 8−10% after tosylation were achieved and further
investigations to improve the conversion of the hydro-
amination step are currently underway. Interestingly, unlike
the morpholine case, the asymmetric reduction to yield the
desired piperazine products showed greater variation in
enantioselectivies with changes to the R group of the cyclic
imine. Even with the minor increase in steric bulk moving
from methyl to ethyl, a significant impact on the selectivity is
observed (13d vs 21). While the ee’s of the benzyl-protected
piperazine products are lower than those achieved with the
oxygen containing substrates, they are improved from the
tosyl-protected piperazine (Table 4, entry 2 vs entry 5),
highlighting the importance of carefully considering the
accessibility of the hydrogen-bond accepting site in the
substrate for effective ATH.
Scheme 10. Synthesis of (R)-3-Benzyl-1-(3-phenylprop-2-
yn-1-yl)piperazine
CONCLUSIONS
■
An efficient and practical one-pot tandem sequential approach
to enantioenriched 3-substituted morpholines through the use
of Ti-catalyzed hydroamination and Ru-catalyzed asymmetric
transfer hydrogenation was presented. Precatalysts 1 and 2 are
tolerant to a wide range of functional groups and give
morpholine products with good yields and excellent ee’s of
>95% in most cases. From experimental observations, a
mechanistic proposal was derived in which key hydrogen-
bonding interactions between cyclic imine substrates and Ru
H
DOI: 10.1021/acs.joc.6b01884
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Scheme 11. Synthesis of Piperazines 19 and 21
are referenced to the center line of deuterochloroform (7.27 ppm for
1H NMR spectra and 77.0 ppm 13C NMR spectra). Assignment of
13C{1H} NMR shifts have been made by DEPT-135 experiments.
catalytically active species give rise to the resulting high
enantioselectivities. This proposal led to a substrate scope
extension of this method to include benzyl-protected 3-
substituted piperazines. Good ee’s were achieved with the
piperazine products (>81%), highlighting that good to
excellent enantioselectivities can be achieved with asymmetric
transfer hydrogenation of imine substrates to access
enantioenriched piperazine products. Other methods for the
generation of imine substrates that can exploit such hydrogen
bonding capabilities are currently being designed and
investigated for the synthesis of α-chiral substituted amines.
High-resolution mass spectra (HRMS) were obtained by time-of-
flight (TOF) electrospray ionization (ESI). Optical rotations were
recorded with a polarimeter using a sample cell with a path length of
1 dm. The enantiomeric excess values were measured by supercritical
fluid chromatography (SFC), 19F NMR after in situ derivatization with
(R)-α-methoxy-α-trifluoromethylphenylacetic acid chloride, or chiral
HPLC. Fourier transform infrared (FTIR) spectra were collected neat
on NaCl disks and are reported in cm−1.
General Procedure A for Sonagashira Cross Coupling. CuI
(5 mol %), tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (5−10
mmol, 1 equiv), and triethylamine (12.0 mL) were added into a
Schlenk flask under N2. ArX (1.1 equiv) and Pd(PPh3)2Cl2 (2 mol %)
were added, and the mixture was heated at 60 °C (X = I) or 100 °C
(X = Br) for 16 h. The solvent was diluted with CH2Cl2 (40 mL),
washed with aqueous HCl (1 M, 2 × 20 mL) and brine, dried over
Na2SO4, filtered, and concentrated under vacuum. The dark residue
was purified by flash chromatography (15% ethyl acetate in hexanes).
General Procedure B for BOC Deprotection. To a solution of
the N-Boc-protected amine (1−8 mmol, 1 equiv) in methanol (15
mL) was added HCl in dioxane (4 M, 2−4.0 mL) at 0 °C. The
reaction mixture was stirred at 0 °C for 1 h and then 14 h at room
temperature. The solvent was evaporated, diethyl ether (30 mL) was
added, and the solid was filtered and washed with diethyl ether (15
mL). The free base was obtained by neutralization of the HCl salt
with saturated aqueous NaHCO3, and the aqueous layer was extracted
with CH2Cl2 (2 × 15 mL). The organic layers were combined,
washed with brine, dried over Na2SO4, filtered, and concentrated to
about 6 mL. The CH2Cl2 solution was further dried with CaH2,
filtered, and concentrated to afford the anhydrous primary amine,
which was vacuum-dried at 65 °C overnight before being transferred
to the glovebox.
General Procedure C for the Tandem Intramolecular
Hydroamination followed by NaBH4 Reduction. A J. Young
NMR tube was charged with a solution precatalyst (10 mol %) and
the aminoalkyne (0.25−0.5 mmol,1 equiv) dissolved in anhydrous d8-
toluene (0.5 mL). The tube was sealed and maintained at 110 °C for
14 h. After the reaction mixture was allowed to cool to room
temperature, the resulting mixture from the hydroamination reaction
was diluted with MeOH (7 mL). NaBH4 (4.0 equiv) was added, and
the reaction mixture was stirred for 2 h at room temperature. After
removal of the solvent in vacuo, the residue was diluted with EtOAc
(8 mL) and washed with aqueous HCl (1 M, 3 × 5 mL). The
combined aqueous layers were basified with saturated aqueous
NaHCO3 (20 mL) and extracted with EtOAc (3 × 8 mL). The
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated by rotary evaporation to provide light
yellow oil as the corresponding racemic 3-substituted morpholine
with >95% purity in most cases. The racemic 3-morpholine products
were used for development of SFC methods for ee determination.
EXPERIMENTAL SECTION
■
General Methods. Synthesis of metal complexes and subsequent
reactions involving these precatalysts were performed under an inert
atmosphere of nitrogen using standard Schlenk line or glovebox
techniques. Tetrahydrofuran, diethyl ether, and toluene were purified
by passage over activated alumina. Dichloromethane was dried over
CaH2 and distilled. Toluene-d8 was degassed via three cycles of
freeze−pump−thaw and stored over 4 Å molecular sieves in the
glovebox. Thin-layer chromatography (TLC) was performed on
fluorescence UV silica plates (60 Å thick). All chemicals were
purchased from commercial sources and used as received. Hydro-
amination precatalyst 1 was prepared using the literature procedur-
e.12a,31 The following compounds were synthesized using known
literature procedures, and the spectral data were in accordance with
those previously published: tert-butyl (2-hydroxyethyl)carbamate,16
tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (3),16 tert-butyl (2-
aminoethyl)carbamate,32 tert-butyl (2-(benzylamino)ethyl)carbamate
(14),33 3-phenylprop-2-yn-1-ol,34 and (3-bromoprop-1-yn-1-yl)-
benzene.34,35 The following compounds were synthesized as described
in our previously published report: tert-butyl (2-((3-phenylprop-2-yn-
1-yl)oxy)ethyl)carbamate (4a), tert-butyl (2-((3-(4-bromophenyl)-
prop-2-yn-1-yl)oxy)ethyl)carbamate (4b), tert-butyl (2-((3-
(perfluorophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (4d), tert-butyl
(2-((3-(pyridin-2-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate (4f), tert-
butyl (2-(pent-2-yn-1-yloxy)ethyl)carbamate (4i), tert-butyl (2-((5-
(benzyloxy)pent-2-yn-1-yl)oxy)ethyl)carbamate (4j), tert-butyl (2-
((4,4-dimethylpent-2-yn-1-yl)oxy)ethyl)carbamate (4k), (R)-3-ben-
zylmorpholine (7a), (R)-3-(4-bromobenzyl)morpholine (7b), (R)-3-
((perfluorophenyl)methyl)morpholine (7d), (R)-3-(pyridin-2-
ylmethyl)morpholine (7f), (R)-3-methylmorpholine (7h), (R)-3-
propylmorpholine (7i), (R)-3-(3-(benzyloxy)propyl)morpholine
(7j), (R)-3-neopentylmorpholine (7k), and (R)-3-(4-bromobenzyl)-
morpholine oxalate salt (8), (S)-2-benzylpiperidine (13a), (R)-3-
methylthiomorpholine (13b), and (R)-3-methyl-1-tosylpiperazine
(13c).9b
Instrumentation. Proton (1H NMR) and carbon (13C{1H}
NMR) spectra were recorded in deuterochloroform at 300 or 400
1
MHz for H NMR spectra and 75 or 100 MHz for 13C{1H} NMR
spectra. Chemical shifts are reported in parts per million (ppm) and
I
DOI: 10.1021/acs.joc.6b01884
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General Procedure D for the Tandem Intramolecular
Hydroamination followed by Catalytic Asymmetric Transfer
Hydrogenation. All hydroamination reactions were prepared in a
N2-filled glovebox. A 10 mL Schlenk tube equipped with a magnetic
stir bar was charged with a solution of precatalyst (10 mol %) and the
aminoalkyne (0.25−0.4 mmol), dissolved in anhydrous toluene (0.5
mL). The Schlenk tube was sealed and maintained at 110 °C for 14 h.
After the reaction mixture was allowed to cool to room temperature,
RuCl[(S,S)-TsDPEN(p-cymene)] (1 mol %) in dry DMF (0.1 mL)
was added followed by a 5:2 mixture of formic acid/triethylamine (0.1
mL), and the reaction mixture was stirred at room temperature for 14
h under nitrogen. The solution was diluted with 8 mL of EtOAc and
washed with water (5 mL) and aqueous HCl (1 M, 2 × 5 mL). The
combined aqueous layers were washed with EtOAc (5 mL), basified
with saturated aqueous NaHCO3 (15 mL), and extracted with EtOAc
(3 × 8 mL). The combined organic layers were washed with water (2
× 5 mL) and brine, dried over Na2SO4, filtered, and concentrated by
rotary evaporation to provide a brownish yellow oil as the
corresponding 3-substituted morpholine with above 95% purity in
most cases.
General Procedure E for the Synthesis of N-Tosylated
Morpholines. Tosyl chloride (1.1 equiv) was added to a solution of
crude 3-substituted morpholine (1.0 equiv) and triethylamine (2.0
equiv) in CH2Cl2 (10 mL) at 0 °C, and the resulting solution was
stirred at 0 °C for 1 h and then overnight at room temperature. The
reaction mixture was washed with aqueous HCl (1 M, 3 mL),
saturated aqueous NaHCO3 (3 mL), and brine before being dried
over Na2SO4 and filtered. The solvent was removed by rotary
evaporation, and the residue was purified by flash chromatography
(15% EtOAc/hexanes).
28.4 (CH3); IR (NaCl, cm−1) 3359, 3059, 2932, 2248, 1714; HRMS-
ESI (m/z) [M + Na]+ calcd for C20H23NO3Na 348.1576, found
348.1591.
tert-Butyl (2-((3-Cyclohexylprop-2-yn-1-yl)oxy)ethyl)carbamate
(4l). 4-Cyclohexylbut-2-yn-1-ol (0.500 g, 3.6 mmol, synthesized
using known literature procedure)36 and triphenylphosphine (1.415
g, 5.4 mmol) were dissolved in CH2Cl2 (50 mL), and the solution
was cooled to 0 °C. Carbon tetrabromide (1.890 g, 5.7 mmol) in
CH2Cl2 (10 mL) was added dropwise. After 15 min of stirring at 0
°C, the cold solution was diluted with hexanes (30 mL) and filtered
through a plug of silica gel. The solvent was removed by rotary
evaporation, followed by a second filtration through a short pad of
silica gel with 5% of EtOAc in hexanes to provide (3-bromoprop-1-
yn-1-yl)cyclohexane as a pale yellow oil (0.667 g, 92%). (3-
Bromoprop-1-yn-1-yl)cyclohexane is a known compound and spectral
1
data are in agreement with those previously reported: H NMR (300
MHz, CDCl3) δ 3.85 (d, J = 2.4 Hz, 2H), 2.46−2.40 (m, 1H), 1.83−
1.64 (m, 4H), 1.55−1.26 (m, 6H).37 tert-Butyl (2-hydroxyethyl)-
carbamate (0.458 g, 2.8 mmol)16 and (3-bromoprop-1-yn-1-yl)-
cyclohexane (0.630 g, 3.1 mmol) were stirred in THF (10 mL).
Tetrabutylammonium iodide (0.103 g, 0.28 mmol) and sodium iodide
(0.042 g, 0.28 mmol) were added, followed by portionwise addition
of KOH (0.930 g, 5.6 mmol). The reaction mixture was stirred at
room temperature for 72 h. The solvent was removed in vacuo, and
the residue was dissolved in H2O (30 mL) and extracted with EtOAc
(3 × 30 mL). The organic extracts were combined, washed with 10%
metabisulfite solution (30 mL) and brine, dried over NaSO4, filtered,
and concentrated. Purification by column chromatography (10%
1
EtOAc in hexanes) yielded 4l as pale yellow oil (0.573 g, 73%): H
NMR (300 MHz, CDCl3) δ 4.93 (br s, 1 H), 4.15 (d, J = 3 Hz, 2 H),
3.56 (t, J = 4.8 Hz, 2 H), 3.33 (q, J = 5.4 Hz, 2 H), 2.43−2.37 (m,
1H), 1.84−1.65 (m, 4H), 1.52−1.18 (m, 6H), 1.44 (s, 9H); 13C{1H}
NMR (75 MHz, CDCl3) δ 156.0 (C), 91.6 (C), 79.3 (C), 75.6 (C),
68.8 (CH2), 58.9 (CH2), 40.5 (CH2), 32.7 (CH2), 29.2 (CH), 28.5
(CH3), 25.9 (CH2), 25.0 (CH2); IR (NaCl, cm−1) 3382, 2992, 2856,
1692, 1519; HRMS-ESI (m/z) [M + Na]+ calcd for C16H27NO3Na
304.1889, found 304.1892.
Synthesis and Characterization of Compounds. tert-Butyl (2-
((3-(4-(Trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate
(4c). Following the general procedure A, the reaction of tert-butyl (2-
(prop-2-yn-1-yloxy)ethyl)carbamate (3, 0.500 g, 2.5 mmol)16 and 4-
iodobenzotrifluoride (0.748 g, 2.8 mmol) afforded the title compound
1
4c (0.723 g, 91%) as a brown oil: H NMR (300 MHz, CDCl3) δ
7.58−7.51 (m, 4H), 4.94 (br s, 1H), 4.38 (s, 2H), 3.64 (t, J = 5.1 Hz,
2H), 3.37 (q, J = 5.1 Hz, 2H), 1.43 (s, 9H); 13C{1H} NMR (75 MHz,
CDCl3) δ 155.8 (C), 131.8 (CH), 130.0 (q, J = 32.4 Hz, C), 126.2
(C), 123.7 (q, J = 270 Hz, C), 125.0 (q, J = 3.3 Hz, CH), 87.4 (C),
84.7 (C), 78.9 (C), 69.0 (CH2), 58.5 (CH2), 40.2 (CH2), 28.1
(CH3); 19F NMR (282 MHz, CDCl3) δ −63.2; IR (NaCl, cm−1)
3357, 2975, 29718, 1713, 1169; HRMS-ESI (m/z) [M + Na]+ calcd
for C17H20NO3F3Na 366.1293 found 366.1288.
2-((3-(4-(Trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)ethanamine
(5c). Following general procedure B, 4c (0.476 g, 1.6 mmol) was
1
deprotected to yield 5c as a yellow oil (0.497 g, quantitative): H
NMR (300 MHz, CDCl3) δ 7.43−7.37 (m, 4H), 4.26 (s, 2H), 3.74 (t,
J = 5.4 Hz, 2H), 2.77 (t, J = 5.1 Hz, 2H), 1.61 (br s, 2H); 13C{1H}
NMR (75 MHz, CDCl3) δ 131.8 (CH), 129.8 (q, J = 32 Hz, C),
126.3 (C), 124.7 (q, J = 271 Hz, C), 125.0 (q, J = 3.3 Hz, C), 87.6
(C), 84.6 (C), 72.3 (CH2), 58.6 (CH2), 41.5 (CH2); 19F NMR (282
MHz, CDCl3) δ −63.4; IR (NaCl, cm−1) 3299, 2923, 2854, 1324;
HRMS-ESI (m/z) [M + H]+ calcd for C12H13NOF3 244.0949, found
244.0950.
tert-Butyl (2-((3-(3-Methoxyphenyl)prop-2-yn-1-yl)oxy)ethyl)-
carbamate (4e). Following the general procedure A, the reaction
of tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (3, 1.000 g, 5.0
mmol)16 and 3-bromoanisole (1.028 g, 5.5 mmol) afforded the title
1
compound 4e (0.560 g, 37%) as a brown oil: H NMR (300 MHz,
2-((3-(3-Methoxyphenyl)prop-2-yn-1-yl)oxy)ethanamine (5e).
Following general procedure B, 4e (0.476 g, 1.6 mmol) was
CDCl3) δ 7.21 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.97 (t, J
= 1.2 Hz, 1H), 6.87 (dd, J = 7.8, 2.1 Hz, 1H), 4.95 (br s, 1 H), 4.37
(s, 2 H), 3.79 (s, 3H), 3.64 (t, J = 5.1 Hz, 2 H), 3.37 (q, J = 5.4 Hz, 2
H), 1.43 (s, 9 H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.4 (C),
156.1 (C), 129.5(CH), 124.4 (CH), 123.5 (C), 116.7 (CH), 115.3
(CH), 86.5 (C), 84.7 (C), 79.4 (CH2), 69.3 (CH2), 59.1 (CH2), 55.4
(CH3), 40.5 (CH2), 28.5 (CH3); IR (NaCl, cm−1) 3364, 2975, 2931,
1713; HRMS-ESI (m/z) [M + Na]+ calcd for C17H23NO4Na
328.1525, found 328.1523.
1
deprotected to yield 5e as a yellow oil (0.304 g, 95%): H NMR
(300 MHz, CDCl3) δ 7.21 (t, J = 8.1 Hz, 1H), 7.03 (d, J = 7.8 Hz,
1H), 6.97 (t, J = 1.2 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 4.39 (s,
2 H), 3.79 (s, 3H), 3.62 (t, J = 5.1 Hz, 2 H), 2.93 (br s, 2 H), 1.8 (br
s, 2 H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.1 (C), 129.2 (CH),
124.1 (CH), 123.4 (C), 116.5 (CH), 114.9 (CH), 86.1 (C), 84.8 (C),
70.5 (CH2), 69.3 (CH2), 58.8 (CH2), 55.1 (CH3), 40.9 (CH2); IR
(NaCl, cm−1) 3369, 2937, 2858, 1158; HRMS-ESI (m/z) [M + H]+
calcd for C12H16NO2 206.1181, found 206.1179.
tert-Butyl (2-((3-(Naphthalen-1-yl)prop-2-yn-1-yl)oxy)ethyl)-
carbamate (4g). Following the general procedure A, the reaction
of tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (3, 1.000 g, 5.0
mmol)16 and 4-iodonapthalene (0.699 g, 2.8 mmol) afforded the title
2-((3-(Naphthalen-1-yl)prop-2-yn-1-yl)oxy)ethanamine (5g). Fol-
lowing general procedure B, 4g (0.439 g, 1.4 mmol) was deprotected
1
1
to yield 5g as a yellow oil (0.287 g, 94%): H NMR (300 MHz,
compound 4g (0.439 g, 54%) as a light brown oil: H NMR (300
CDCl3) δ 8.32 (d, J = 8.7 Hz, 1H), 7.76 (t, J = 7.2 Hz, 2H), 7.66 (d, J
= 7.2 Hz, 1H), 7.56−7.42 (m, 2H), 7.35 (dd, J = 8.4, 7.5 Hz, 1H),
4.48 (s, 2H), 3.62 (t, J = 5.1 Hz, 2H), 2.87 (t, J = 5.1 Hz, 2H), 1.38
(br s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 133.1 (C), 132.9 (C),
130.5 (CH), 128.8 (CH), 128.1 (CH), 126.6 (CH), 126.2 (CH),
125.9 (CH), 125.0 (CH), 120.1 (C), 90.0 (C), 84.1 (C), 72.3 (CH2),
59.0 (CH2), 41.7 (CH2); IR (NaCl, cm−1) 3370, 3057, 2925, 2858,
MHz, CDCl3) δ 8.32 (d, J = 4.2 Hz, 1H), 7.84−7.80 (m, 2H), 7.69
(dd, J = 7.2, 1.2 Hz, 1H), 7.54 (m, 2H), 7.40 (dd, J = 8.1, 6.9 Hz,
1H), 5.09 (br s, 1H), 4.52 (s, 2H), 3.73 (t, J = 5.1 Hz, 2H), 3.42 (q, J
= 5.1 Hz, 2H), 1.44 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ
156.0 (C), 133.3 (C), 133.1 (C), 130.8 (CH), 129.0 (CH), 128.3
(CH), 126.8 (CH), 126.4 (CH), 126.0 (CH), 125.1 (CH), 120.1 (C),
89.7 (C), 84.6 (C), 79.3 (C), 69.2 (CH2), 59.2 (CH2), 40.5 (CH2),
J
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1
1586; HRMS-ESI (m/z) [M + H]+ calcd for C15H16NO 226.1232,
found 226.1228.
2-((3-Cyclohexylprop-2-yn-1-yl)oxy)ethanamine (5l). Following
4H), 0.92−0.72 (m, 2H); 13C{ H} NMR (75 MHz, CDCl3) δ 143.4
(C), 138.2 (C), 129.8 (CH), 127.2 (CH), 69.0 (CH2), 66.2 (CH2),
51.1 (CH), 40.7 (CH2), 35.5 (CH2), 34.3 (CH), 33.4 (CH2), 33.2
(CH2), 26.2 (CH2), 26.2 (CH2), 21.6 (CH3); IR (NaCl, cm−1) 2923,
2852, 1449,1347; HRMS-ESI (m/z) [M + Na]+ calcd for
C18H27NO3SNa 360.1609, found 360.1616.
general procedure B, 4l (0.560 g, 2.0 mmol) was deprotected to
1
yield 5l as a yellow oil (0.270 g, 79%): H NMR (300 MHz, CDCl3)
δ 4.16 (d, J = 2.1 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 2.87 (t, J = 5.1
Hz, 2H), 2.42−2.35 (m, 1H), 1.82−1.24 (m, 10H); 13C{1H} NMR
(75 MHz, CDCl3) δ 91.2 (C), 75.7 (C), 71.9 (CH2), 58.9 (CH2),
41.8 (CH2), 32.6 (CH2), 29.1 (CH), 25.8 (CH2), 25.0 (CH2); IR
(NaCl, cm−1) 3370, 2929, 2853, 1449; HRMS-ESI (m/z) [M + H]+
calcd for C11H20NO 182.1545, found 182.1542.
(3R)-3-(4-(Trifluoromethyl)benzyl)morpholine (7c). Following
general procedure D, the reaction of 5c (0.055 g, 0.23 mmol)
afforded the title compound 7c as a light brown oil (0.029 g, 52%, ee
= 98%): [α]D = +4 (c = 8.8, chloroform); 1H NMR (300 MHz,
CDCl3) δ 7.56 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 3.82−
3.75 (m, 2H), 3.57−3.49 (m, 1H), 3.27 (dd, J = 11, 9.6 Hz, 1H),
3.07−2.98 (m, 1H), 2.92−2.82 (m, 2H), 2.71 (dd, J = 14, 5.1 Hz,
1H), 2.55 (dd, J = 14, 8.7 Hz, 1H), 1.89 (br s, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 142.2 (C), 129.6 (CH), 129.1 (q, J = 19.8 Hz,
C), 127.9 (q, J = 270 Hz, CF3), 125.7 (q, J = 3.3 Hz, CH), 72.4
(CH2), 67.6 (CH2), 56.0 (CH), 46.2 (CH2), 38.8 (CH2); 19F NMR
(282 MHz, CDCl3) δ −63.8; IR (NaCl, cm−1) 3426, 2922, 2851,
1164; HRMS-ESI (m/z) [M + H]+ calcd for C12H15NOF3 246.1106,
found 246.1104.
(R)-3-(3-Methoxybenzyl)morpholine (7e). Following general
procedure D, the reaction of 5e (0.050 g, 0.24 mmol) afforded the
title compound 7e as a light brown oil (0.043 g, 85%, ee = 94%):
[α]D = +80 (c = 0.9, methanol); 1H NMR (300 MHz, CDCl3) δ 7.27
(dd, J = 15, 7.8 Hz, 1H), 6.84−6.78 (m, 3H), 3.88−3.80 (m, 2H),
3.83 (s, 3H), 3.62−3.54 (m, 1H), 3.31 (t, J = 9.6 Hz, 1H), 3.08−3.00
(m, 1H), 2.95−2.84 (m, 2H), 2.68 (dd, J = 13, 4.8 Hz, 1H), 2.49 (dd,
J = 13, 9.3 Hz, 1H), 1.97 (br s, 1H); 13C{1H} NMR (75 MHz,
CDCl3) δ 159.1 (C), 139.2 (C), 129.7 (CH), 121.6 (CH), 114.9
(CH), 112.0 (CH), 72.5 (CH2), 67.5 (CH2), 56.2 (CH), 55.3 (CH3),
46.3 (CH2), 39.0 (CH2); IR (NaCl, cm−1) 3321, 2952, 2849, 1599,
1583, 1488; HRMS-ESI (m/z) [M + H]+ calcd for C12H18NO2
208.1339, found 208.1338.
(S)-3-Benzylmorpholine (9). Known compound19 synthesized from
2-((3-phenylprop-2-yn-1-yl)oxy)ethan-1-amine9b (0.047 g, 0.27
mmol) using general procedure D, except 1 mol % RuCl[(R,R)-
TsDPEN(p-cymene)] catalyst was used. The title compound was
isolated as a light brown oil (0.038 mmol, 80%, 95% ee): [α]D = −39
(c = 1.6, methanol; lit. [α]D = −38.2, c = 0.056, methanol);19 1H
NMR (300 MHz, CDCl3) δ 7.34−7.18 (m, 5 H), 3.81 (dt, J = 10, 3
Hz, 2H), 3.61−3.52 (m, 1H), 3.30 (t, J = 10 Hz, 1H), 3.07−2.96 (m,
1H), 2.93−2.83 (m, 2H), 2.65 (dd, J = 13, 4.8 Hz, 1H), 2.49 (dd, J =
13, 9 Hz, 1H), 2.29 (br s, 1H); HRMS-ESI (m/z) [M + H]+ calcd for
C11H16NO 178.1232, found 178.1228.
4-(3-(2-Aminoethoxy)prop-1-yn-1-yl)benzonitrile (10). Following
general procedure A, the reaction of tert-butyl (2-(prop-2-yn-1-
yloxy)ethyl)carbamate1 (0.500 g, 2.5 mmol) and 4-iodobenzonitrile
(0.630 g, 2.8 mmol) afforded tert-butyl (2-((3-(4-cyanophenyl)prop-
2-yn-1-yl)oxy)ethyl)carbamate (0.776 g, 52%) as a light brown oil
1
(10a): H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 2H), 7.41
(d, J = 8.4 Hz, 2H), 5.04 (br s, 1H), 4.30 (s, 2H), 3.55 (t, J = 5.1 Hz,
2H), 3.27 (q, J = 5.1 Hz, 2H), 1.33 (s, 9H); 13C{1H} NMR (75 MHz,
CDCl3) δ 155.8 (C), 132.0 (CH), 131.8 (CH), 127.2 (C), 118.1 (C),
111.7 (C), 89.4 (C), 84.6 (C), 69.2 (CH2), 58.6 (CH2), 40.1 (CH2),
28.2 (CH3); IR (NaCl, cm−1) 3365, 2977, 2933, 2229, 1713; HRMS-
ESI (m/z) [M + Na]+ calcd for C17H20N2O3Na 323.1372, found
323.1372. Following general procedure B, tert-butyl (2-((3-(4-
cyanophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (0.776 g, 2.6
mmol) was deprotected to yield 10 as a light brown oil (0.452 g,
1
87%): H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.7 Hz, 2H), 7.50
(d, J = 8.4 Hz, 2H), 4.40 (s, 2H), 3.60 (t, J = 5.1 Hz, 2H), 2.91 (t, J =
5.4 Hz, 2H), 1.42 (br s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ
132.4 (CH), 132.1 (CH), 127.6 (C), 118.4 (C), 112.0 (C), 89.9 (C),
84.7 (C), 72.8 (CH2), 59.0 (CH2), 41.9 (CH2); IR (NaCl, cm−1)
3340, 2924, 2856, 2228, 1604; HRMS-ESI (m/z) [M + H]+ calcd for
C12H13N2O 201.1028, found 201.1029.
(R)-3-(Naphthalen-1-ylmethyl)morpholine (7g). Following gen-
eral procedure D, the reaction of 5g (0.050 g, 0.24 mmol) afforded
the title compound 7g as a light brown oil (0.036 g, 72%, ee = 93%):
4-(Morpholin-3-ylmethyl)benzonitrile (11). Following general
procedure C, 10 (50 mg, 0.25 mmol) was reacted to yield 11 as a
1
1
light brown oil (39 mg, 78%): H NMR (300 MHz, CDCl3) δ 7.58
[α]D = +40 (c = 0.2, methanol); H NMR (300 MHz, CDCl3) δ
(d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 3.76 (dd, J = 11, 2.7 Hz,
2H), 3.53−3.45 (m, 1H), 3.23 (t, J = 9.6 Hz, 1H), 3.05−2.96 (m,
1H), 2.90−2.80 (m, 2H), 2.69 (dd, J = 13, 5.1 Hz, 1H), 2.55 (dd, J =
13, 8.7 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 143.8 (C),
132.5 (CH), 130.0 (CH), 118.8 (C), 110.7 (C), 72.2 (CH2), 67.5
(C), 55.8 (CH2), 46.1 (CH2), 39.1 (CH2); IR (NaCl, cm−1) 3309,
2954, 2852, 2227, 1607; HRMS-ESI (m/z) [M + H]+ calcd for
C12H15N2O 203.1184, found 203.1178.
8.08−8.01 (m, 1H), 7.90−7.84 (m, 1H), 7.76 (d, 1H), 7.57−7.47 (m,
2H), 7.43−7.34 (m, 2H), 3.90 (dd, J = 11, 2.7 Hz, 1H), 3.78 (dt, J =
11, 2.7 Hz, 1H), 3.65−3.52 (m, 1H), 3.40 (dd, J = 11, 9 Hz, 1H),
3.24−3.16 (m, 2H), 2.95−2.76 (m, 3H), 1.95 (br s, 1H); 13C{1H}
NMR (75 MHz, CDCl3) δ 134.2 (C), 133.9 (C), 132.1 (C), 129.0
(CH), 127.6 (CH), 126.2 (CH), 125.9 (CH), 125.5 (CH), 123.8
(CH), 72.7 (CH2), 67.5 (CH2), 55.36 (CH2), 46.3 (CH2), 36.0
(CH); IR (NaCl, cm−1) 2922, 2850, 1453, 1105; HRMS-ESI (m/z)
[M + H]+ calcd for C15H18NO 228.1388, found 228.1384.
N1-Benzyl-N1-(prop-2-yn-1-yl)ethane-1,2-diamine (12d). Follow-
ing general procedure B, tert-butyl (2-(benzyl(prop-2-yn-1-yl)amino)-
ethyl)carbamate (15, 1.77 g, 4.8 mmol) was deprotected to yield N1-
benzyl-N1-(prop-2-yn-1-yl)ethane-1,2-diamine (12d) as a light brown
(R)-3-(Cyclohexylmethyl)morpholine (7l). Following general pro-
cedure D, the reaction of 5l (0.104 g, 0.24 mmol) afforded the title
compound 7l as a light brown oil (0.053 g, 85%): [α]D = +92 (c =
1
1
oil (1.27 g, quantitative): H NMR (400 MHz, CDCl3) δ 7.35−7.23
1.0, dichloromethane); H NMR (300 MHz, CDCl3) δ 3.74 (dt, J =
(m, 5H), 3.64 (s, 2H), 3.31 (d, J = 1.6 Hz, 2H), 2.77 (t, J = 5.6 Hz,
2H), 2.64 (t, J = 6.0 Hz, 2H), 2.23 (t, 2.4 H, 1H), 1.66 (br s, 2H);
13C{1H} NMR (75 MHz, CDCl3) δ 138.3 (C), 128.7 (CH), 127.9
11, 3.0 Hz, 2H), 3.46 (dt, J = 11, 3.0 Hz, 1H), 3.09 (t, J = 9.9 Hz,
1H), 2.97−2.80 (m, 1H), 2.35 (br s, 1H), 1.68−1.59 (m, 4H), 1.33−
0.76 (m, 7H); 13C{1H} NMR (75 MHz, CDCl3) δ 73.2 (CH2), 67.6
(CH2), 52.2 (CH), 46.3 (CH2), 40.2 (CH2), 34.1 (CH), 33.7 (CH2),
33.3 (CH2), 26.6 (CH2), 26.3 (CH2), 26.2 (CH2); IR (NaCl, cm−1)
3320, 2921, 2850, 1448, 1107; HRMS-ESI (m/z) [M + H]+ calcd for
C11H22NO 184.1701, found 184.1704.
(CH), 126.8 (C), 78.2 (C), 72.9 (C), 57.5 (CH ), 55.7 (CH2), 41.2
2
(CH2), 39.0 (CH2); IR (NaCl, cm−1) 30556, 2926, 2822, 1489;
HRMS-ESI (m/z) [M + H]+ calcd for C12H17N2 189.1392, found
189.1396.
(R)-3-(Cyclohexylmethyl)-4-tosylmorpholine (7l-Ts). Following
general procedure E, the reaction of 7l (0.048 g, 0.26 mmol)
afforded the title compound 7l-Ts as a clear, colorless oil (0.057 g,
(R)-1-Benzyl-3-methylpiperazine (13d). Known compound38
synthesized from N1-benzyl-N1-(prop-2-yn-1-yl)ethane-1,2-diamine
(12d, 0.100 g, 0.53 mmol) using general procedure D, except after
reaction with 1 at 110 °C for 14 h, an additional 10 mol % of 1 was
added, and the reaction mixture was heated to 110 °C for an
additional 14 h. Compound 13d was isolated as a brown oil (0.058 g,
58%). [α]D = +7.1 (c = 0.65, chloroform; lit. [α]D = +7.3, c = 0.68,
chloroform).38 >98% ee as determined by derivatization with (R)-α-
1
85%, ee = 95%): [α]D = −14 (c = 0.4, chloroform); H NMR (300
MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H),
3.85 (dt, J = 7.8, 2.4 Hz, 1H), 3.69 (dd, J = 12, 3.3 Hz, 1H), 3.60 (d, J
= 11 Hz, 1H), 3.53 (d, J = 13 Hz, 1H), 3.43 (dd, J = 12, 3 Hz, 1H),
3.38−3.18 (m, 2H), 2.41 (s, 3H), 1.73−1.36 (m, 7H), 1.21−1.11 (m,
K
DOI: 10.1021/acs.joc.6b01884
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The Journal of Organic Chemistry
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1
methoxy-α-(trifluoromethyl)phenylacetic acid chloride in situ using
the previously described experimental procedure,39 19F NMR (292
MHz, CDCl3) δ −72.1. Derivatization of the opposite enantiomer
synthesized using RuCl[(R,R)-TsDPEN(p-cymene) with (R)-α-
methoxy-α-(trifluoromethyl)phenylacetic acid chloride in situ using
previously described experimental procedure,39 19F NMR (292 MHz,
CDCl3) δ −73.4. Following general procedure E, 13d was isolated as
the tosylated piperazine compound as a colorless oil (0.062 g, 60%):
1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.30 (m,
7H), 4.06−4.04 (m, 1H), 3.58 (d, J =13 Hz, 1H), 3.47 (d, J = 13 Hz,
1H), 3.37 (d, J = 13 Hz, 1H), 3.23 (dt, J = 12, 2.8 Hz, 1H), 2.71 (d, J
= 10 Hz, 1H), 2.52 (d, J = 11 Hz, 1H), 2.43 (s, 3H), 2.16 (dd, J = 11,
3.6 Hz, 1H), 2.05 (dt, J = 12, 3.6 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H);
14%, 96% ee): H NMR (300 MHz, CDCl3) δ 7.23−7.20 (m, Ar−
H), 4.11 (apparent quartet, 1H), 3.51(s, 2H), 3.08−2.92 (m, 2H),
2.61 (dd, J = 14, 9 Hz, 1H), 2.39 (dt, J = 11, 3 Hz, 1H), 2.13 (t, J =
10 Hz, 1H); HRMS-ESI (m/z) [M + H]+ calcd for C20H23N2
291.1861, found 291.1858.
N1-Benzyl-N1-(3-phenylprop-2-yn-1-yl)ethane-1,2-diamine (18).
Following general procedure A, the reaction of tert-butyl (2-
(benzyl(prop-2-yn-1-yl)amino)ethyl)carbamate (1.000 g, 3.5 mmol)
and iodobenzene (0.785 g, 3.9 mmol, 0.43 mL) afforded tert-butyl (2-
(benzyl(3-phenylprop-2-yn-1-yl)amino)ethyl)carbamate (18a, 1.155
1
g, 91% yield) as a brown oil: H NMR (400 MHz, CDCl3) δ 7.47−
7.45 (m, 2H), 7.38−7.28 (m, 8H), 4.99 (br s, 1H), 3.72 (s, 2H), 3.53
(s, 2H), 3.32−3.27 (m, 2H), 2.77 (t, J = 5.6 Hz, 2H), 1.46 (2, 9H);
13C NMR (100 MHz, CDCl3) δ 156.1 (C), 138.5 (C), 131.9 (CH),
129.3 (CH), 128.5 (CH), 128.4 (CH), 128.2 (CH), 127.4 (CH),
123.2 (C), 85.9 (C), 84.1 (C), 79.2 (C), 58.0 (CH2), 52.7 (CH3),
42.3 (CH2), 38.0 (CH2), 28.6 (CH3); IR (NaCl, cm−1) 3426, 3299,
2976, 2835, 1712, 1485; HRMS-ESI (m/z) [M + H]+ calcd for
C23H29N2O2 365.2229, found 365.2232. Following general procedure
B, tert-butyl (2-(benzyl(3-phenylprop-2-yn-1-yl)amino)ethyl)-
carbamate (18a, 1.01 g, 2.8 mmol) was deprotected to yield 18 as
1
13C{ H} NMR (100 MHz, CDCl3) δ 143.0 (C), 138.1 (C), 137.9
(C), 129.6 (CH), 128.7 (CH), 128.2 (CH), 127.1 (CH), 62.5 (CH2),
57.8 (CH2), 52.7 (CH), 49.6 (CH2), 40.9 (CH2), 21.5 (CH3), 15.4
(CH3); IR (NaCl, cm−1) 2920, 2849, 1663; HRMS-ESI (m/z) [M +
H]+ calcd for C19H25N2O2S 345.1637, found 345.1633.
tert-Butyl (2-(Benzyl(prop-2-yn-1-yl)amino)ethyl)carbamate (15).
tert-Butyl (2-(benzylamino)ethyl)carbamate (3.26 g, 13 mmol) was
dissolved in EtOAc (100 mL). NaI (0.300 g, 2 mmol), Et4NI (0.300
g, 1 mmol), and K2CO3 (3.59 g, 26 mmol) were added, and the
suspension was heated to 70 °C for 20 h. The reaction mixture was
cooled to room temperature, and H2O was added (50 mL). The
resulting layers were separated, and the aqueous layer was extracted
with EtOAc (3 × 50 mL). The organic layers were combined and
washed with 10% metabisulfite solution (50 mL) and brine (50 mL)
before drying over Na2SO4. The crude reaction mixture was purified
by flash chromatography (15% EtOAc in hexanes) to yield the title
1
a brown oil (0.789 g, quantitative): H NMR (400 MHz, CDCl3) δ
7.48−7.45 (m, 2H), 7.40−7.25 (m, 8H), 3.73 (s, 2H), 3.54 (s, 2H),
2.83 (t, J = 6 HZ, 2H), 2.72 (t, J = 6.4 Hz, 2H), 1.61 (br s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 138.9 (C), 131.8 (CH), 129.2
(CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.2 (CH), 123.3 (C),
85.6 (C), 84.4 (C), 58.2 (CH2), 56.4 (CH2), 42.5 (CH2), 39.5
(CH2); IR (NaCl, cm−1) HRMS-ESI (m/z) [M + H]+ calcd for
C18H21N2 265.1705, found 265.1704.
1
compound as a pale yellow oil (15, 3.47 g, 93%): H NMR (300
(R)-1,3-Dibenzylpiperazine (19). Following general procedure D,
amino alkyne 18 (0.050 g, 0.38 mmol) was reacted; after reaction
with 1 at 110 °C for 14 h, an additional 10 mol % of 1 was added,
and the reaction mixture was heated to 110 °C for an additional 14 h.
Subsequent reduction with 2 yielded crude 19 as a brown oil (0.042
g, 84%). Following general procedure E, 19 was isolated as the
tosylated piperazine compound (0.005 g, 8%, 87% ee): 1H NMR (400
MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 2H), 7.34−7.24 (m, 7H), 7.15−
7.13 (m, 3H), 6.98−6.96 (m, 2H), 4.07−4.04 (m, 1H), 3.70 (d, J =
14 Hz, 1H), 3.45 (d, J = 13 Hz, 1H), 3.35−3.28 (m, 2H), 3.17 (dd, J
= 13, 11 Hz, 1H), 2.78 (d, J = 12 Hz, 1H), 2.65 (dd, J = 12, 4 Hz,
1H), 2.62 (d, J = 12 Hz, 1H), 2.41 (s, 3H), 2.05 (dt, J = 12, 3.2 Hz,
MHz, CDCl3) δ 7.38−7.23 (m, 5H), 3.64 (s, 2H), 3.31 (d, J = 2.4
Hz, 2H), 3.24 (q, J = 5.1 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.24 (t, J
= 2.4 Hz, 1H), 1.62 (br s, 1H), 1.45 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 156.0 (C), 138.3 (CH), 129.1 (CH), 128.5 (CH),
127.4 (C), 79.2 (C), 78.2 (C), 73.5 (CH2), 57.6 (CH2), 52.4 (CH2),
41.4 (CH2), 37.9 (C), 28.5 (CH3), IR (NaCl, cm−1) 3426, 3298,
2976, 2834, 1712, 1495; HRMS-ESI (m/z) [M + H]+ calcd for
C17H25N2O2 289.1916, found 289.1917.
N1,N1-Bis(3-phenylprop-2-yn-1-yl)ethane-1,2-diamine (16). DBU
(1.06 g, 7.0 mmol, 1.04 mL) was added to (3-bromoprop-1-yn-1-
yl)benzene (1.34 g, 7.0 mmol) dissolved in toluene (10 mL),
resulting in a dark brown reaction mixture. A solution of tert-butyl (2-
aminoethyl)carbamate (1.12 g, 7.0 mmol) in toluene (10 mL) was
added, and the reaction mixture was stirred at room temperature for
48 h. The solvent was removed in vacuo, and the residue was
dissolved in DCM (50 mL) and washed with 10% metabisulfite
solution (30 mL) and brine before drying over Na2SO4, filtering, and
concentrating into a brown oil. The crude material was purified by
flash chromatography (15% EtOAc in hexanes) to afford (2-(bis(3-
phenylprop-2-yn-1-yl)amino)ethyl)carbamate as a yellow oil (16a,
1H), 1.90 (dd, J = 11, 3.2 Hz, 1H); 13C{ H} NMR (100 MHz,
1
CDCl3) δ 143.2 (C), 138.8 (C), 138.2 (C), 138.7 (C), 129.8 (CH),
129.5 (CH), 129.4 (CH), 128.5 (CH), 128.4 (CH), 127.4 (CH),
127.2 (CH), 126.4 (CH), 62.9 (CH2), 55.8 (CH2), 53.3 (CH), 52.9
(CH2), 41.5 (CH2), 35.4 (CH2), 29.9 (CH2), 21.7 (CH2); IR (NaCl,
cm−1) 2923, 2853, 1351, 1161; HRMS-ESI (m/z) [M + H]+ calcd for
C25H29N2O2S 421.1950, found 421.1957.
N1-Benzyl-N1-(but-2-yn-1-yl)ethane-1,2-diamine (20). 2-Butyn-1-
ol was stirred in THF, and the solution was cooled to 0 °C.
Triethylamine was added, followed by methanesulfonyl chloride
dropwise. The resulting reaction mixture was an orange solution with
a white precipitate. The reaction mixture was stirred for 15 min
before the precipitate was filtered off, and the filtrate was
concentrated into clear orange oil. The oil was dissolved in
acetonitrile (10 mL) and added to tert-butyl (2-(benzylamino)ethyl)-
carbamate (1.401 g, 5.5 mmol) and potassium carbonate (2.509 g, 18
mmol) in acetonitrile (20 mL). The reaction mixture was heated to a
reflux for 64 h. The reaction mixture was cooled to room
temperature, and the solvent was removed in vacuo. The residue
was dissolved in water (50 mL), and the aqueous solution was
extracted with ethyl acetate (3 × 50 mL). The organic fractions were
combined, washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated into brown oil. The crude material was
purified by column chromatography (5−15% ethyl acetate in
hexanes) to yield tert-butyl (2-(benzyl(but-2-yn-1-yl)amino)ethyl)-
carbamate as a clear, colorless oil (20a, 0.514 g, 31%): 1H NMR (400
MHz, CDCl3) δ 7.34−7.23 (m, 5H), 5.02 (br s, 1H), 3.62 (s, 2H),
3.26−3.20 (m, 4H), 2.65 (t, J = 6.0 Hz, 2H), 1.86 (s, 3H), 1.45 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.0 (C), 138.6 (C),
1
0.235 g, 9%): H NMR (300 MHz, CDCl3) δ 7.44−7.41 (m, 4H),
7.29−7.23 (m, 6H), 5.14 (br s, 1H), 3.70 (s, 4H), 3.30 (q, J = 4.8 Hz,
2H), 2.81 (t, J = 6.0 Hz, 2H), 1.43 (s, 9H); 13C{1H} NMR (75 MHz,
CDCl3) δ 156.0 (C), 131.8 (CH), 128.3 (CH), 128.2 (CH), 122.9
(C), 85.4 (C), 84.4 (C), 79.1 (C), 52.1 (CH2), 43.3 (CH2), 37.9 (C),
28.4 (CH3); IR (NaCl, cm−1) 3427, 3056, 2976, 2930, 1711, 1490;
HRMS-ESI (m/z) [M + H]+ calcd for C25H29N2O2 389.2222, found
389.2229. (2-(Bis(3-phenylprop-2-yn-1-yl)amino)ethyl)carbamate
(0.230 g, 0.59 mmol) was deprotected using general procedure B
to yield N1,N1-bis(3-phenylprop-2-yn-1-yl)ethane-1,2-diamine as a
1
yellow oil (16, 0.168 g, quantitative): H NMR (300 MHz, CDCl3) δ
7.46−7.40 (m, 4H), 7.30−7.27 (m, 6H), 3.72 (s, 2H), 2.86 (t, J = 5.7
1
Hz, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.12 (br s, 2H); 13C{ H} NMR
(75 MHz, CDCl3) δ 131.8 (CH), 128.3 (CH), 128.1 (CH), 123.0
(C), 85.2 (C), 84.7 (C), 55.8 (CH2), 43.5 (CH2), 39.4 (CH2); IR
(NaCl, cm−1) 3363, 2923, 2850, 1597, 1573. HRMS-ESI (m/z) [M +
H]+ calcd for C20H21N2 289.1705, found 289.1699.
(R)-3-Benzyl-1-(3-phenylprop-2-yn-1-yl)piperazine (17). Follow-
ing general procedure D, 16 (0.073 g, 0.25 mmol) was reacted to
yield 17 in a mixture with unreacted 16 as brown oil (NMR yield:
L
DOI: 10.1021/acs.joc.6b01884
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The Journal of Organic Chemistry
Featured Article
129.0 (CH), 128.3 (CH), 127.1 (CH), 80.9 (C), 78.9 (C), 73.4 (C),
57.7 (CH2), 52.3 (CH2), 41.7 (CH2), 37.9 (CH2), 28.4 (CH3), 3.43
(CH3). IR (NaCl, cm−1) 3359, 2913, 2849, 1712, 1494; HRMS-ESI
(m/z) [M + H]+ calcd for C18H27N2O2 303.2073, found 303.2066.
Following general procedure B, tert-butyl (2-(benzyl(but-2-yn-1-
yl)amino)ethyl)carbamate was deprotected to yield N1-benzyl-N1-
(but-2-yn-1-yl)ethane-1,2-diamine (20) as a clear, colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.33−7.19 (m, 5H), 3.60 (s, 2H), 3.24
(s, 2H), 2.74 (t, J = 5.6 Hz, 2H), 2.58 (t, J = 4.8 Hz, 2H), 1.83 (s,
3H), 1.34 (br s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.6
(C), 129.0 (CH), 128.1 (CH), 126.9 (CH), 80.6 (C), 73.7 (C), 57.9
(CH2), 56.1 (CH2), 41.9 (CH2), 39.5 (CH2), 3.40 (CH3); IR (NaCl,
cm−1) 3356, 2913, 2849, 1577, 1452; HRMS-ESI (m/z) [M + H]+
calcd for C13H19N2 203.1548, found 203.1545.
(4) Dugar, S.; Sharma, A.; Kuila, B.; Mahajan, D.; Dwivedi, S.;
Tripathi, V. Synthesis 2015, 47, 712−720.
(5) Luescher, M. U.; Bode, J. W. Angew. Chem., Int. Ed. 2015, 54,
10884−10888.
(6) Uozumi, Y.; Tanahashi, A.; Hayashi, T. J. Org. Chem. 1993, 58,
6826−2832.
(7) O’Reilly, M. C.; Lindsley, C. W. Org. Lett. 2012, 14, 2910−2913.
(8) Lu, Z.; Stahl, S. S. Org. Lett. 2012, 14, 1234−1237.
(9) (a) McGhee, A.; Cochran, B. M.; Stenmark, T. A.; Michael, F. E.
Chem. Commun. 2013, 49, 6800−6802. (b) Zhai, H.; Borzenko, A.;
Lau, Y. Y.; Ahn, S. H.; Schafer, L. L. Angew. Chem., Int. Ed. 2012, 51,
12219−12223.
(10) Chiral Amine Synthesis; Nugent, T. C., Ed.; Wiley-VCH:
Weinheim, 2010.
(R)-1-Benzyl-3-ethylpiperazine (21). Following general procedure
D, amino alkyne 20 (0.100 g, 0.49 mmol) was reacted; however, after
reaction with 1 at 110 °C for 14 h, an additional 10 mol % of 1 was
added and the reaction mixture was heated to 110 °C for an
additional 14 h. Subsequent reduction with 2 yielded crude 21 as a
brown oil (0.025 g, 24%). Following general procedure E, 21 was
isolated as the tosylated piperazine compound (0.004 g, 10%, 81%
(11) (a) Yim, J. C. H.; Schafer, L. L. Eur. J. Org. Chem. 2014, 2014,
6825−6840. (b) Hannedouche, J.; Schulz, E. Chem. - Eur. J. 2013, 19,
4972−4985. (c) Reznichenko, A.; Hultzsch, K., Early Transition
Metal (Group 3−5, Lanthanides and Actinides) and Main Group
Metal (Group 1, 2, and 13) Catalyzed Hydroamination. In
Hydrofunctionalization; Ananikov, V. P., Tanaka, M., Eds.; Springer:
Berlin, 2013; Vol. 43, pp 51−114. (d) Dion, I.; Beauchemin, A. M.
1
ee): H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 11 Hz, 2H), 7.29−
Angew. Chem., Int. Ed. 2011, 50, 8233−8235. (e) Muller, T. E.;
̈
7.20 (m, 7H), 3.80−3.75 (m, 1H), 3.66 (d, J = 19 Hz, 1H), 3.43 (d, J
= 18 Hz, 1H), 3.30−3.18 (m, 2H), 2.61 (d, J = 15 Hz, 2H), 2.43 (s,
3H), 1.90 (dt, J = 16, 4.4 Hz, 2H), 1.70 (sextet, J = 10 Hz, 2H), 0.78
(t, J =10 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.1 (C),
138.9 (C), 138.2 (C), 129.8 (CH), 128.8 (CH), 128.4 (CH), 127.3
(CH), 127.2 (CH), 62.8 (CH2), 55.7 (CH2), 52.5 (CH), 52.9 (CH2),
41.3 (CH2), 29.9 (CH3), 22.5 (CH2), 11.0 (CH3). IR (NaCl, cm−1)
2923, 2850, 1460, 1163; HRMS-ESI (m/z) [M + H]+ calcd for
C20H27N2O2S 359.1793, found 359.1786.
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ASSOCIATED CONTENT
* Supporting Information
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(b) Vac
́
́
́ ̌
e
́
S
Kace
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01884.
̌
́
́ ́
Bregeot, N.; de la Fuente, V.; Castillon, S.; Claver, C. ChemCatChem
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AUTHOR INFORMATION
Corresponding Author
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Janusc , J.; Kacer, P. Organometallics 2012, 31, 6496−6499.
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We thank UBC, Zalicus, Ms. Jennifer Moon, Ms. Anisa
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