Synthesis of tetrasubstituted propargylamines from cyclohexanone by solvent-free copper(ii) catalysis

Article abstract of DOI:10.1039/c4gc02318h

Copper(ii) chloride catalyzes the three-component coupling of cyclohexanone, amines, and alkynes to produce tetrasubstituted propargylamines. As a wide range of substrates react without solvent, excess starting material, or other additives, water is the sole by-product. Studies demonstrate that this reaction is first order in copper, cyclohexanone, amine, and alkyne. These mild conditions allow for the first direct, catalytic synthesis of silyl-protected tetrasubstituted propargylamines. This journal is

Full text of DOI:10.1039/c4gc02318h

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DOI: 10.1039/C4GC02318H
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The synthesis of tetrasubstituted propargylamines
from cyclohexanone by solvent-free copper(II)
catalysis
Cite this: DOI: 10.1039/x0xx00000x
Zachary L. Palchak,a Daniel J. Lussier,a Conor J. Pierce,a Catharine H. Larsena
Received 00th January 2012,
Accepted 00th January 2012
Copper(II) chloride catalyzes the three-component coupling of cyclohexanone, amines, and alkynes to
produce tetrasubstituted propargylamines. As a wide range of substrates react without solvent, excess
starting material, or other additives, water is the sole by-product. Studies demonstrate that this
reaction is first order in copper, cyclohexanone, amine, and alkyne. These mild conditions allow for the
first direct, catalytic synthesis of silyl-protected tetrasubstituted propargylamines.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Scheme 1b demonstrates that by heating an additional 30 °C,
the aldehyde can be replaced with cyclohexanone (1), and
the same Cu(OTf)2 catalyst, solvent, amine (2a), and
terminal alkyne (3a) provides an 80% yield of
Introduction
Background
Three-component couplings of aldehydes, alkynes, and
amines are the most efficient method of forming
trisubstituted propargylamine building blocks for rapid
access to biologically active targets.1-4 By circumventing the
synthesis and isolation of imine intermediates for subsequent
alkynylation,3 these multicomponent5 reactions reduce
waste.6 Most of these methods are optimized for the
conversion of aldehydes to trisubstituted propargylamines
and fail to convert ketones to tetrasubstituted
propargylamines.1 The ketimine formed in situ from the
condensation of an amine and a ketone is a less reactive
electrophile for nucleophilic attack than its aldimine
counterpart.7,8 Cyclohexanones represent an especially
reactive class of ketones due to strain release upon attack.9-11
In fact, cyclohexanones have been known to react under
catalytic conditions developed for aldehydes.12
tetrasubstituted propargylamine 4a.12
The first catalytic propargylamine synthesis developed
specifically to incorporate cyclohexanones was reported by
Van der Eycken (Scheme 2a).13 In analogy to ubiquitous A3
(Aldehyde-Amine-Alkyne) couplings, they abbreviate this
Ketone-Amine-Alkyne coupling as a KA2 reaction. The
microwave activated KA2 coupling of primary benzylamines
and phenylacetylene with cyclohexanones utilizes 20 mol%
CuI at 100 °C.13 The following year Ji reported that a lower
4 mol% loading of AuBr3 catalyzes a similar three-
component coupling of cyclic secondary amines at 60 °C
(Scheme 2b).14
By operating solvent-free, both the methods of Van der
Eycken and Ji (Scheme 2) produce significantly less waste
than reactions carried out in toluene (Scheme 1b).12-14 As
solvents represent the largest amount of “auxiliary waste,”
discussions on atom economy15 often highlight classes of
greener solvents.16 However, solvent-free reactions leave a
smaller environmental footprint17 and should be pursued and
appear more frequently in publications on green chemistry.16
a)
O
HN
Me
10 mol %
Cu(OTf)2
Me
H2N
Me
H
n-Hex
Me
1'
1.1 equiv.
n-Hex
toluene
80 °C, 72 h
2a
1.0 equiv.
3a
1.5 equiv.
4'
94% yield
a) Van der Eycken
HN
20 mol %
CuI
O
b)
OMe
O
HN
H2N
10 mol %
Cu(OTf)2
R
H2N
MW
100 °C
R
OMe
O
n-Hex
R = Ph, 76%
n-Hex, 31%
n-Hex
1.0 equiv
1.2 equiv 1.2 equiv
toluene
110 °C, 22 h
1
2a
3a
1.5 equiv.
4a
80% yield
O
1.1 equiv.
1.0 equiv.
b) Ji
Bn
Bn
4 mol %
AuBr3
N
Scheme 1. Similar conditions allow for the three-component coupling of an
aldehyde to 4’ or of cyclohexanone to 4a.
N
R'
R'
N
60 °C
R
H
R
R
1.0 equiv 1.5 equiv 1.5 equiv
For example, copper(II) triflate catalyzes the three-
component coupling of 2-methyl-propanal (1'), benzylamine
(2a), and 1-octyne (3a) in toluene (1.0 M) at 80 °C for a
94% yield of trisubstituted propargylamine 4' (Scheme 1a).
R = Ph, 89% R = Ph, 29%
n-Bu, 45%
Scheme 2. The first three-component couplings designed for cyclohexanones
J. Name., 2013, 00, 1-3 | 1
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ARTICLE
DOI: 10.1039/C4GC02318H
Ideally, the substrate scope in both of the methods dedicated
to cyclohexanones (Scheme 2) would be expanded to
include primary and secondary amines and non-aryl terminal
alkynes. Both methods exhibit a precipitous drop in yield
when alkyl alkynes are used in place of aryl alkynes. In the
reaction of p-methoxybenzylamine with cyclohexanone
catalyzed by 20 mol % CuI with microwave (MW) heating,
phenylacetylene provides a 76% yield while 1-octyne
provides a 31% yield (Scheme 2a).13 Scheme 2b shows that
the yield drops from 89% with phenylacetylene to 45% with
1-hexyne in the gold-catalyzed KA2 reaction of morpholine
and cyclohexanone.14 In neither case is the lower yield with
alkyl alkynes explained. When phenylacetylene is
maintained in the reaction with cyclohexanone, the yield
drops three-fold when acyclic N,N-dibenzylamine is utilized
instead of cyclic morpholine (Scheme 2b).14 In addition,
although AuBr3 is utilized at one-fifth the loading of CuI, it
is over 100-times more expensive.18
Results and discussion
Optimization of synthetic procedure
While copper(II) triflate catalyzes the reaction of a primary
benzylamine, cyclohexanone, and an alkyl alkyne in high
yield (Scheme 1b), removing the toluene solvent was the
first condition for the development of a greener KA2 reaction
(Scheme 2). In a solution of toluene, the high reactivity of
Cu(OTf)2 results in excellent conversion to product 4a, but
side products appear under the same 10 mol % loading of
catalyst in the absence of solvent. Thus, the development of
a greener method began by testing a wide array of copper
catalysts at half the catalyst loading (5 mol%) under solvent-
free conditions, and with equimolar amounts of
cyclohexanone 1, benzylamine 2a, and 1-octyne 3a.
Table 1.19 Cu halides are superior to triflates under solvent-free
conditions
Goal of green catalysis with expanded substrate scope
5 mol %
CuCl2
O
HN
Lower catalyst loadings are a major focus in green
chemistry,6 but reducing waste from excess starting material
receives little attention.16 Starting material waste must be
considered more seriously when a method is to be applied in
total synthesis. When one or more of the coupling partners is
a result of multiple synthetic steps, wasting any of this
precious material due to a procedure that requires an excess
of two of the three starting materials should be avoided. All
three methods waste between 0.4–1.0 equivalents of starting
materials (Schemes 1 and 2).12-14 Therefore, in addition to
removing solvent, another condition imposed upon the
H2N
n-Hex
n-Hex
110 °C
18 h
1
2a
3a
4a
Entry
GC yield (%)
Copper Source
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
59
72
72
99
50
38
52
27
32
45
56
72
89
94
70
81
46
Cu(II) triflate
Cu(II) acetate
Cu(II) bromide
Cu(II) chloride
Cu(II) perchlorate hexahydrate
Cu(II) sulfate
discovery of
a more environmentally friendly three-
component coupling was to use one equivalent of each
reactant to avoid starting material waste. The formation of
water as a by-product would then be the sole by-product of
this KA2 reaction of cyclohexanone.
Melding the different advantages of each of these three
methods12-14 into one synthetic protocol requires: 1) no
solvent, 2) lower loadings of an inexpensive catalyst, 3) no
other additives, 4) efficient reaction of primary and
secondary amines, 5) high yields for aryl- and non-aryl
alkynes, and 6) equimolar amounts of all three starting
materials (Scheme 3).
Cu(II) ethoxide
Cu(II) bis(hexafluoroacetoacetonato) hydrate
Cu(II) hydroxide
Cu(I) triflate tetrakisacetonitrile
Cu(I) acetate
Cu(I) bromide
Cu(I) chloride
Cu(I) bromide dimethylsulfide
Cu(I) thiophene-2-carboxylate
Cu(I) iodide
Cu(I) hexafluorophosphate tetrakisacetonitrile
O
copper
catalyst?
temperature?
HN
[a] Reactions were carried out with cyclohexanone (1.0 mmol), amine
(1.0 mmol), 1-octyne (1.0 mmol), and copper source (0.05 mmol).
H2N
n-Hex
n-Hex
1
2a
1.0 equiv.
3a
no solvent
or additives?
4a
Copper(I) and copper(II) catalysts were tested at 5 mol%
loading rather than the 10% or 20% previously reported in
these KA2 reactions (Table 1).19 A control reaction carried
out with no catalyst over 3 days confirms that a copper
source is necessary for formation of propargylamine 4a.
Under solvent-free conditions, the catalytic activity does not
appear to be correlated to the oxidation state of the copper
source. Cu(II) bromide and Cu(I) bromide have identical GC
yields (72% and 72%, entries 3 and 12), but Cu(II) chloride
is superior to Cu(I) chloride (99% and 89%, entries 4 and
13). The sole pattern apparent is that both copper (I) and
copper(II) halides consistently provide greater than 70% GC
yield of propargylamine 4a (Table 1, entries 3, 4, 12, 13, 14,
and 16). Although CuCl2 and CuBr•Me2S afford the highest
overall GC yields at 18h, CuCl2 provides a faster initial
rate.19 Entry 1 versus entry 4 allows for a direct comparison
1.0 equiv.
1.0 equiv.
Scheme 3. Basis for developing a green KA2 with broader substrate scope.
Herein, we report rate studies to elucidate the role of
each constituent in our CuCl2-catalyzed KA2 reaction.19 This
direct formation of tetrasubstituted propargylic amines
appears to be first order in each reaction component: copper,
cyclohexanone, amine, and alkyne. Moreover, this efficient
three-component coupling of cyclohexanone with either
primary or secondary amines now produces an expanded
range of silyl-protected propargylamines. The six goals set
for atom economy15 are achieved as the sole additive is the
copper catalyst and the only by-product is one equivalent of
water. Beginning the development of this reaction from a
platform of green chemistry was the key to its discovery.
2 | Green Chem., 2012, 00, 1-3
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Table 2.19 Range of amines for KA2 with cyclohexanone and 1-octyne
of the catalytic activity of 5 mol % Cu(OTf)2 versus 5 mol
CuCl2 for the three-component coupling of
%
cyclohexanone 1, benzylamine 2a, and 1-octyne 3a under
solvent-free conditions. Whereas CuCl2 provides 99% GC
yield of fully-substituted propargylamine 4a, Cu(OTf)2
provides a significantly lower 59% GC yield in the same
time frame of 18 h (Table 1, entries 4 and 1). When the
standard reaction of cyclohexanone, benzylamine, and 1-
octyne is carried out with 5 mol % CuCl2 neat at 110 °C,
tetrasubstituted propargylamine 4a is isolated in 91% yield
after 6 h (Scheme 4).
R1 R2
O
N
R1
R2
5 mol % CuCl2
110 °C
N
H
n-Hex
n-Hex
1
2
3a
4
Entry
Amine
time (h)
Product
Yield (%)
HN
HN
HN
HN
H2N
n-Hex
O
5 mol %
CuCl2
HN
2a
4a
4b
4c
4d
4e
1
2
3
6
5
5
91
87
74
H2N
n-Hex
n-Hex
110 °C
6 h
1
2a
1.0 equiv.
3a
H2N
H2N
4a
OMe
n-Hex
91% yield
1.0 equiv.
1.0 equiv.
OMe
Scheme 4. No solvent and less catalyst for a faster reaction and higher yield
The goal of a greener method without solvent was critical to
the identification of copper(II) chloride as the superior
catalyst for this KA2 reaction. When cyclohexanone,
benzylamine, and 1-octyne are heated with catalyst at 110
°C for 18 hours, no conversion was observed in a range of
solvents at 0.1 M concentration: acetone, acetonitrile,
chloroform, dichloroethane, dioxane, dimethylformamide,
dimethyl sulfoxide, ethyl acetate, hexanes, methanol,
tetrahydrofuran, toluene, and water. No difference in
reactivity is observed under an atmosphere of nitrogen
versus argon. In air, the reaction proceeds cleanly but
conversion is 18% less than under inert atmosphere.
CF3
n-Hex
CF3
H2N
Me
n-Hex
4
5
6
4
82
88
Me
N
N
N
H
As previous cyclohexanone KA2 reactions were limited
to either primary13 or secondary14 amines coupled mostly
with phenylacetylene, investigations began by surveying the
amine substrates operable with 1-octyne in this solvent-free
catalytic method (Table 2).19 Entries 2-4 show that
additional primary amines produce N-4-methoxybenzyl
(4b), N-4-(trifluoromethyl)benzyl (4c) and N-propylphenyl
(4d) propargylamines in good yield. The 87% yield of 4b is
almost triple the previous report of 31% yield that required a
four-fold higher catalyst loading.13 In contrast to Scheme 2b
where an acyclic secondary amine provides a yield three-
times lower than cyclic,14 an 88% yield of 4e from N-
methylbenzylamine is nearly identical to the 88-92% yields
of 4f-4h from cyclic piperidine, morpholine, and pyrrolidine
(Table 2, entries 5-8). Under the same conditions, 2
equivalents of 1-octyne and 2 equivalents of cyclohexanone
react with cyclic diamine piperazine to produce tricyclic bis-
propargylamine 4i (Table 2, entry 9).
A broad scope in the alkyne component is exhibited in
Table 3.19 In contrast to Scheme 2 where application of 1-
octyne instead of phenylacetylene resulted in half the yield,
under the new conditions reported herein, 1-octyne and
phenylacetylene (4f and 4j, 90% and 89%, entries 1 and 2)
react with nearly identical yields. Products bearing
propylphenyl (4k), 3-methylbutyl (4l), and tert-butyl (4m)
substituents also form in good yield from piperidine and
cyclohexanone (entries 3-5). Finally, propargylic
n-Hex
n-Hex
N
H
6
3
90
4f
O
N
O
N
H
n-Hex
n-Hex
7
8
3
2
92
88
4g
4h
N
N
H
n-Hex
H
N
N
N
N
H
n-Hex
morpholines bearing
a tert-butyldimethylsilyl-protected
9
16
4i
68b
alkyne (4n) or alcohol (4o) are produced in 91% and 84%
yield, respectively. To the best of our knowledge,16-18 these
represent the first silyl and silyloxy tetrasubstituted
propargylamines obtained from a direct, catalytic reaction of
cyclohexanone.3a
[a] All reactions were carried out with cyclohexanone (1.0 mmol), amine
(1.0 mmol), 1-octyne (1.0 mmol), and CuCl2 (0.05 mmol).
[b] Cyclohexanone (2.0 mmol) and 1-octyne (2.0 mmol) were used.
This journal is © The Royal Society of Chemistry 2012
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ARTICLE
DOI: 10.1039/C4GC02318H
Table 3.19 Mild copper catalysis for alkyl, aryl, siloxy, and silyl alkynes
base (B) forms the copper acetylide nucleophile (5). The
ketimine electrophile (6) is formed from the condensation of
a primary amine and cyclohexanone. Imine coordination to
the copper acetylide is believed to precede attack of the
imine formed from the condensation of a primary amine and
cyclohexanone.1c,3 1,2-Addition to the ketimine forms the
tetrasubstituted propargylamine product (4), and liberates
the copper to re-enter the catalytic cycle (Scheme 5).
X
X
O
5 mol % CuCl2
N
R3
N
H
110 °C
R3
Yield (%)
1
2
3
4
Entry
Alkyne
time (h)
Product
H
R
Alkyne Activation
N
R'
3
B
N
[Cu]
n-Hex
R'
R'
4
[Cu]
BH
Copper Acetylide
R'
n-Hex
BH
N
3
1
90
3a
4f
[Cu]
R
[Cu]
5
N
Condensation to Imine
R'
[Cu]
R
R
R
NH2
2
O
N
N
R'
1,2-Addition
to Imine
2
3
2
4
89
78
4j
4k
4l
H2O
6
1
Imine Coordination
N
Scheme 5. Catalytic cycle for cyclohexanone-amine-alkyne coupling.
Condensation to ketimine is reversible (Scheme 5), and a
steady-state concentration of ketimine is observed in KA2
reactions of benzylamine. This is not surprising as imines
derived from cyclohexanone and primary amines have been
well-studied for over half a century.21 The ketimine formed
from primary benzylamine is detectible by GC analysis of
reaction aliquots and correlated to samples of ketimine
synthesized separately and confirmed by proton NMR.22
Interestingly, the addition of one to three equivalents of
water has little effect on the reaction. At five to ten added
equivalents of water, product formation is reduced. The
additional water should shift the equilibrium to disfavor
ketimine formation, favoring ketimine hydrolysis to starting
materials. As a secondary amine forms a ketiminium upon
condensation with cyclohexanone, this cationic intermediate
is not expected to be observable by GC. Attempts to detect
positively-charged ketiminia in the crude reaction mixture
by NMR (without flushing though silica) are hampered by
the paramagnetic nature of the copper(II) catalyst.
Cyclohexanone (1) and amine (2) are incorporated into
the ketimine (6) that is attacked by the copper acetylide (5)
formed from the copper catalyst and terminal alkyne (3).
Thus, if acetylide addition to ketimine is the rate-
determining step for the formation of product (4), then the
overall reaction should be first order in copper catalyst, in
cyclohexanone, in amine, and in alkyne.
To determine the order in each component, the rate of
product formation (4a) is measured while varying the
concentration of each constituent in the reaction of
cyclohexanone (1), benzylamine (2a), and 1-octyne (3a).
Though it is an optimal catalyst under solvent-free
conditions, CuCl2 is rendered inactive upon significant
dilution in solvent. However, as the total reaction time is a
2-6 h, a slower reaction rate is required for reasonable
sampling intervals during the first 10% of product
formation. Diluting to 1.0 M instead of 0.1 M does not
maintain reactivity in coordinating solvents like acetonitrile.
Toluene is ideal in that it cuts the rate of reaction in half.20
N
Me
Me
Me
Me
4
3
92
N
Me
Me
Me
Me
Me
Me
4m
5
6
2
5
81
91
O
N
Me
Si
t-Bu
Me
TBS
4n
O
N
Me
t-Bu
O Si
Me
OTBS
84
7
6
4o
[a] All reactions were carried out with cyclohexanone (1.0 mmol), amine
(1.0 mmol), 1-octyne (1.0 mmol), and CuCl2 (0.05 mmol).
Reaction mechanism and rates
A mechanism by which copper(II) chloride can catalyze the
three-component coupling of cyclohexanone (1), an amine
(2), and a terminal alkyne (3) is shown in Scheme 5.
Beginning with alkyne activation in which the alkyne
terminus is acidified by binding to copper, deprotonation by
4 | Green Chem., 2012, 00, 1-3
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of product formation over time for cyclohexanone,
benzylamine, and 1-octyne are provided in the
Supplementary Information.20 Figure 3 graphs the initial rate
of product formation (V0) at each concentration of
cyclohexanone for a linear plot with R2 = 0.991, indicating
that the reaction is first order in ketone starting material.
O
HN
1-10 mol %
CuCl2
H2N
n-Hex
n-Hex
1
2a
3a
toluene (1 M)
110 °C, 1.5 h
4a
1 equiv.
1 equiv.
1 equiv.
O
HN
5 mol %
CuCl2
H2N
n-Hex
n-Hex
1
2a
3a
toluene (1 M)
110 °C, 1.5 h
4a
0.5-2.5 equiv. 1 equiv.
1 equiv.
Figure 1. The formation of product over time at catalyst loadings from 1-10
mol% CuCl2 each provide a linear plot with R2 > 0.99.
The initial rate of product formation, measured during
the first 10% of product formation, is determined by GC
sampling under each set of reaction parameters. Comparison
to a dodecane internal standard provides the concentration of
propargylamine 4a over time at 1, 2.5, 5, 7.5, and 10 mol%
CuCl2 and is plotted in Figure 1. For each set of conditions,
a batch of identical reactions is started at the same time such
that every data point represents the sole sample taken from
one reaction. The linear plot with R2 > 0.99 at each catalyst
loading indicates that the data is reliable and that reactions
run in parallel are uniform and reproducible. When each of
these initial rates (V0) is plotted against the concentration of
CuCl2, the resulting straight line (R2 = 0.998) demonstrates
that the KA2 reaction is first order in copper catalyst.20
Figure 3. Linear plot indicates first order dependence on cyclohexanone.
When the initial rate of product formation (V0) at each
concentration of benzylamine is graphed in Figure 4,20
a
linear plot with R2 = 0.996 indicates that the KA2 reaction is
first order in this primary amine starting material.
O
HN
5 mol %
CuCl2
H2N
n-Hex
n-Hex
1
2a
3a
toluene (1 M)
110 °C, 1.5 h
4a
O
HN
1-10 mol %
H2N
1 equiv. 0.25-1.0 equiv.
1 equiv.
CuCl2
n-Hex
n-Hex
1
2a
3a
toluene (1 M)
110 °C, 1.5 h
4a
1 equiv.
1 equiv.
1 equiv.
Figure 4. Linear plot indicates first order dependence on amine.
When the initial rate of product formation (V0) at each
concentration of 1-octyne is graphed,20 a linear plot with R2
= 0.994 indicates that the three-component coupling is first
order in the terminal alkyne starting material (Figure 5).
Figure 2. Linear plot indicates first order dependence on copper(II) chloride.
A similar process was followed to determine the order in
each of the three reaction components. The individual plots
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more stable, electron-rich ketimine (6, X = OMe) forms in a
higher concentration but is less susceptible to copper
acetylide attack. The less stable, electron-poor ketimine (6,
X = CF3) forms in a lower concentration but is more
susceptible to copper acetylide attack.
O
HN
5 mol %
CuCl2
H2N
n-Hex
n-Hex
toluene (1 M)
110 °C, 1.5 h
1
2a
1 equiv.
3a
4a
1 equiv.
0.5-2.5 equiv.
5 mol %
CuCl2
O
HN
H2N
n-Hex
X
X
toluene
(1 M)
110 °C
1.5 h
n-Hex
X =
1
3a
4
OMe, Me, Cl, CF3
1 equiv.
1 equiv.
1 equiv.
H2O
N
[Cu]
X
R
6
5
Figure 5. Linear plot indicates first order dependence on alkyne.
The rate-determining step of three-component couplings of
amine and alkynes with carbonyl compounds is generally
believed to be the addition of the metal acetylide nucleophile
to the imine electrophile (Figure 6, intermediates 5 and 6).3,4
If the formation and subsequent nucleophilicity of this
acetylide is most critical, some difference in rate would be
expected between an alkyl acetylide and an aryl acetylide.
For a terminal alkyne, a stronger base should accelerate the
formation of copper acetylide. In this case, electron-donating
substituents on benzylamine would be expected to increase
the rate of reaction and electron-withdrawing substituents on
benzylamine would be expected to decrease the rate of
reaction.
Figure 6 plots the formation of propargylamine over time
in the KA2 reaction of cyclohexanone (1) and 1-octyne (3a)
catalyzed by 5 mol % CuCl2 at 110 °C with para-substituted
benzylamines. GC analysis of reaction aliquots taken over
the first 90 minutes of the reaction in toluene provides the
data on the relative rates of product formation for 4-
methoxybenzylamine, 4-methylbenzylamine, 4-chloro-
benzylamine, and 4-(trifluoromethyl)benzylamine. Contrary
to what might be expected, the most electron-poor 4-CF3-
benzylamine reacts an order of magnitude faster than the
most electron-rich 4-MeO-benzylamine. 4-Cl-benzylamine
reacts almost four-times faster and 4-Me-benzylamine reacts
over twice as fast as 4-MeO-benzylamine.
Figure 6. Electron-poor 4-(trifluoromethyl)benzylamine reacts 10.5-times
faster in a KA2 reaction than electron-rich 4-methoxybenzylamine.
Expanded scope of KA2 reaction of TIPS-acetylene
The synthetic utility of the alkyne portion of these
tetrasubstituted products (4) can be expanded by utilizing
silyl alkynes to form readily deprotectable propargylic
amines. A new, more complex terminal alkyne can be
unmasked by treatment with a fluoride source.23 This opens
a wide range of reactions beyond the fact that terminal
alkynes can be added to imines and other electrophiles.3a
One of the most ubiquitous reactions of terminal alkynes is
the Huisgen 1,3-dipolar cycloaddition reaction with azides
for the formation of triazoles via “click” chemistry.24
When Cu(OTf)2 was used as the catalyst in toluene for
A3 reactions involving trialkylsilyl alkynes, base was
required in equimolar amounts to triflate in order to avoid
protodesilylation.12 Table 4 is a testament to the mildness of
these neat CuCl2 conditions for KA2 reactions19 compared to
those developed with Cu(OTf)2. Demonstrating the scope of
these neat CuCl2 conditions, a variety of TIPS-protected
propargylamines were prepared from cyclohexanone (1),
(triisopropylsilyl)acetylene (3b), and an amine (2). Primary
and secondary benzylamines form tetrasubstituted products
4p–4r in 75-80% yield (Table 4, entries 1-3). New amine
starting materials also efficiently convert to silyl-protected
products. N-methylpiperazine forms diamine 4u, and a near
Intriguingly, closer examination of the GC data reveals
that a greater steady-state concentration of the cyclohexyl
ketimine formed from 4-methoxybenzylamine is observed
compared to 4-(trifluoromethyl)benzylamine. During the
course of the KA2 reaction with cyclohexanone (1) and 1-
octyne (3a), the ketimine stabilized by the electron-donating
methoxy group forms to a 30% greater extent than the
ketimine destabilized by the electron-withdrawing
trifluoromethyl group during the course of the reaction. The
6 | Green Chem., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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Journal Name
Green Chemistry
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ARTICLE
DOI: 10.1039/C4GC02318H
quantitative yield of TIPS-propargylamine 4t forms from 4-
methylpiperidine. In addition to synthetic manipulation of
the amine portion and alkyne pi-system,2,3 the new silyl-
protected alkynes in Table 4 provide a new dimension for
functionalization of tetrasubstituted propargylamines.3a
largest reduction in E factor. As this three-component
coupling proceeds by heating the copper(II) chloride catalyst
with a 1:1:1 ratio of cyclohexanone, amine, and alkyne, the
sole by-product is water. Thus, in addition to a wide
substrate scope, none of the aryl, alkyl, silyl, and silyloxy
alkynes nor primary and secondary amines are wasted in
order to achieve high yields in KA2 reactions with
cyclohexanone. A table of deprotectable triisopropylsilyl
propargylamines provides hindered substrates for conversion
into the corresponding complex terminal alkyne for triazole
formation via click chemistry. The cyclohexanone-amine-
alkyne coupling catalyzed by copper(II) chloride is found to
be first order in copper source, in cyclohexanone, in amine,
and in alkyne.
Table 4. Silyl alkynes react readily with cyclohexanone and a range of
amines.
R1 R2
O
N
R1
5 mol % CuCl2
110 °C, 18 h
R2
N
H
TIPS
TIPS
1
2
3b
4
Entry
Amine
Product
Yield (%)
HN
Experimental
H2N
CF3
CF3
General information
TIPS
1
2
80
75
76
4p
All reactions were set up on the benchtop in oven-dried
screw-cap test tubes with Teflon seal inserts and carried out
under an atmosphere of N2 or Ar. Column chromatography
was performed using silica purchased from Silicycle. All
reagents were obtained through commercial suppliers and
purified by distillation before use as in W. L. F. Amerengo
and D. D. Perrin, Purification of Laboratory Chemicals, 4th
ed., Butterworth-Heineman,: Oxford, U.K., 1996.
HN
H2N
TIPS
2a
4q
Me
N
Me
N
H
TIPS
3
4r
1H and 13C NMR spectra were measured on a Varian
Inova 400 (400 MHz) spectrometer using CDCl3 as a solvent
at room temperature. Some spectra include tetramethylsilane
as an internal standard. The following abbreviations are used
singularly or in combination to indicate the multiplicity of
signals: s - singlet, d - doublet, t - triplet, q - quartet, m -
multiplet and br - broad. Gas chromatography spectra were
obtained on an Agilent Technologies 6850 GC System using
dodecane as an internal standard. IR spectra were recorded
on Perkin Elmer Spectrum One FT-IR Spectrometer.
Attenuated total reflection infrared (ATR-IR) was used for
analysis with selected absorption maxima reported in cm-1.
Mass spectrometric data was collected on a HP 5989A
GC/MS quadrupole instrument. Exact masses were recorded
on a Waters GCT Premier ToF instrument using direct
injection of samples in acetonitrile into the electrospray
source (ESI) and positive ionization.
O
N
O
N
H
TIPS
73b
4s
4
Me
Me
N
N
H
TIPS
5
98
4t
Me
N
Me
N
N
N
H
TIPS
6
70
4u
General procedure
[a] All reactions were carried out with cyclohexanone (1.0 mmol), amine
(1.0 mmol), 1-octyne (1.0 mmol), and CuCl2 (0.05 mmol). [b] 6 hours.
To an oven-dried test tube equipped with magnetic stir bar
and Teflon-seal screw cap was added 5 mol % CuCl . The
2
flask was purged with nitrogen for 5 minutes. Ketone (1.0
equiv), alkyne (1.0 equiv), and amine (1.0 equiv) were
added, and the reaction was stirred at 110 °C for 18h. Upon
reaction completion as confirmed by GC analysis, the
mixture was cooled to room temperature and loaded directly
atop a silica gel column. Chromatography with the solvent
system indicated afforded the desired product.
Conclusions
The decision to target solvent-free green chemistry was
crucial to the discovery of this mild catalytic procedure.
Although the inexpensive copper(II) chloride catalyst is
highly reactive in the absence of solvent, dilution in most
solvents renders the complex inactive. Next to the removal
of solvent, eliminating excess starting materials provides the
New compound characterization data
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 00, 1-3 | 7

Green Chemistry
Page 8 of 10
GrVeieewnArCtihcleeOmnliisnetry
ARTICLE
DOI: 10.1039/C4GC02318H
1-(oct-1-yn-1-yl)-N-(4-(trifluoromethyl)benzyl)
yield (0.291 g, 0.76 mmol) after chromatography on silica
gel (10% EtOAc in hexanes). IR (film) 2932, 2863, 2153,
1462, 1058 cm-1. 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.24
(d, J= 8 Hz, 2H), 7.20 (t, J = 8 Hz, 2H), 7.11 (t, J= 8 Hz,
1H), 3.53 (s, 2H), 2.06 (s, 3H), 1.96 (d, J = 12 Hz, 3H), 1.64
(m, 2H), 1.54 (t, J= 9.6 Hz, 2H), 1.45 (t, J= 12 Hz, 2H), 1.18
(m, 4H) 1.03 (d, J= 4 Hz, 18H). 13C NMR (100 MHz,
CDCl3, 25 °C) δ 141.2, 128.9, 128.2, 126.6, 109.0, 84.7,
59.6, 56.0, 36.98, 35.3, 25.9, 23.1, 18.9, 11.4. HRMS (ESI)
m/z calcd for [M+H]+ requires 384.3081, found 384.3089.
cyclohexanamine (4c): Prepared according to the general
procedure: 4-(trifluoromethyl)benzylamine (142 µL, 1.0
mmol), cyclohexanone (103 µL, 1.0 mmol), octyne (147 µL,
1.2 mmol), and CuCl2 (6.7 mg, 0.05 mmol) afford the title
compound as a yellow oil in 74% yield (0.270 g, 0.74 mmol)
after chromatography on silica gel (20% EtOAc in hexanes).
IR (film) 2946, 2853, 2155, 1460, 1325, 1174 cm-1. 1H
NMR (400 MHz, CDCl3, 25 °C) δ 7.47 (d, J= 8 Hz, 2H),
7.40 (d, J = 8 Hz, 2H), 3.86 (s, 2H), 2.17 (t, J = 6.8 Hz, 2H),
1.75 (d, J = 12 Hz, 2H), 1.60-1.12 (m, 17H), 0.81 (t, J= 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C) δ 145.8,
128.8, 128.7 (2 overlapping carbons), 125.3 (J= 4.0 Hz),
123.15, 84.9, 83.81, 55.0, 47.6, 38.7, 31.5, 29.3, 28.7, 26.1,
23.1, 22.8, 18.9, 14.2. HRMS (ESI) m/z calcd for [M+H]+
requires 366.2403, found 366.2420.
4-methyl-1-(1-((triisopropylsilyl)ethynyl)cyclohexyl)
piperidine (4t): Prepared according to the general procedure:
4-methyl-piperidine (117 µL, 1.0 mmol), cyclohexanone
(103 µL, 1.0 mmol), (triisopropylsilyl) acetylene (269 µL,
1.2 mmol), and CuCl2 (6.7 mg, 0.05 mmol) afford the title
compound as a yellow oil in 98% yield (0.354 g, 0.98 mmol)
after chromatography on silica gel (20% EtOAc in hexanes).
IR (film) 2926, 2863, 2154, 1462, 1258 cm-1. 1H NMR (400
MHz, CDCl3, 25 °C) δ 2.96 (d, J= 16 Hz, 2H), 2.14 (t, J =
12 Hz, 2H), 1.96 (d, J= 16 Hz, 3H), 1.58 (m, 7H), 1.30 (t, J
= 12.4 Hz, 3H), 1.13 (m, 5H), 1.01 (d, J= 4 Hz,18H). 13C
NMR (100 MHz, CDCl3, 25 °C) δ 108.9, 85.19, 59.4, 46.4,
36.3, 35.0, 31.1, 25.8, 23.2, 21.8, 18.8, 11.4. HRMS (ESI)
m/z calcd for [M+H]+ requires 362.3238, found 362.3226.
N-(4-(trifluoromethyl)benzyl)-1-((triisopropylsilyl)ethynyl)
cyclohexanamine (4p): Prepared according to the general
procedure: 4-(trifluoromethyl)-benzylamine (142 µL, 1.0
mmol),
cyclohexanone
(103
µL,
1.0
mmol),
(triisopropylsilyl) acetylene (269 µL, 1.2 mmol), and CuCl2
(6.7 mg, 0.05 mmol) afford the title compound as a yellow
oil in 80% yield (0.350 g, 0.80 mmol) after chromatography
on silica gel (20% EtOAc in hexanes). IR (film) 2936, 2863,
1
2155, 1462, 1323, 1163 cm-1. H NMR (400 MHz, CDCl3,
25 °C) δ 7.46 (d, J= 8 Hz, 2H), 7.39 (d, J = 8 Hz, 2H), 3.90
(s, 2H), 1.78 (d, J = 12 Hz, 3H), 1.58 (m, 6H), 1.33 (m, 2H),
1.13 (m, 2H) 1.02 (d, J= 4 Hz, 18H). 13C NMR (100 MHz,
CDCl3, 25 °C) δ 145.5, 128.8 (2 overlapping carbons), 125.3
(J= 4.0 Hz) (2 carbons overlapped), 112.1, 84.4, 55.8, 47.8,
38.4, 26.0, 23.1, 18.8, 11.4. HRMS (ESI) m/z calcd for
[M+H]+ requires 438.2798, found 438.2775.
1-methyl-4-(1-((triisopropylsilyl)ethynyl)cyclohexyl)
piperazine (4u): Prepared according to the general
procedure: N-methyl-piperazine (110 µL, 1.0 mmol),
cyclohexanone (103 µL, 1.0 mmol), (triisopropylsilyl)
acetylene (269 µL, 1.2 mmol), and CuCl2 (6.7 mg, 0.05
mmol) afford the title compound as a yellow oil in 70%
yield (0.253 g, 0.70 mmol) after column chromatography on
silica gel (25% methanol in CH3Cl3). IR (film) 2932, 2863,
1
N-benzyl-1-((triisopropylsilyl)ethynyl)cyclohexanamine
(4q): Prepared according to the general procedure:
benzylamine (109 µL, 1.0 mmol), cyclohexanone (103 µL,
1.0 mmol), (triisopropylsilyl) acetylene (269 µL, 1.2 mmol),
and CuCl2 (6.7 mg, 0.05 mmol) afford the title compound as
a yellow oil in 75% yield (0.277 g, 0.75 mmol) after
chromatography on silica gel (10% EtOAc in hexanes). IR
2155, 1456, 1283 cm-1. H NMR (400 MHz, CDCl3, 25 °C)
δ 2.65 (bs, 4H), 2.46 (bs, 4H), 2.22 (s, 3H), 1.91 (d, J= 16
Hz, 3H), 1.56 (m, 6H), 1.32 (t, J= 12 Hz, 2H), 1.12 (m, 2H),
1.00 (d, J= 4 Hz,18H). 13C NMR (100 MHz, CDCl3, 25 °C)
δ 108.0, 86.2, 58.9, 55.6, 45.8, 45.7, 35.9, 25.6, 22.9, 18.7,
11.3. HRMS (ESI) m/z calcd for [M+H]+ requires 363.3190,
found 363.3203.
1
(film) 2931, 2862, 2154, 1461, 1279 cm-1. H NMR (400
MHz, CDCl3, 25 °C) δ 7.27 (d, J= 7.2 Hz, 2H), 7.21 (t, J =
7.2 Hz, 2H), 7.13 (t, J= 7.2 Hz, 1H), 3.84 (s, 2H), 1.80 (d, J
= 16 Hz, 3H), 1.59 (m, 6H), 1.34 (m, 2H), 1.17 (m, 2H) 1.03
(d, J= 4 Hz, 18H). 13C NMR (100 MHz, CDCl3, 25 °C) δ
141.2, 128.8, 128.6, 127.0, 112.5, 84.2, 55.9, 48.4, 38.4,
26.1, 23.3, 18.9, 11.5. HRMS (ESI) m/z calcd for [M+H]+
requires 370.2925, found 370.2936.
Acknowledgements
This material is based upon work supported by the National
Science Foundation under Grant No. (NSF CAREER award
CHE-1352665).
Notes and references
a
Department of Chemistry, University of California, Riverside, CA
92521. E-mail: catharine.larsen@ucr.edu; Tel: (+1)-951-827-4964.
N-benzyl-N-methyl-1-((triisopropylsilyl)ethynyl)
cyclohexanamine (4r): Prepared according to the general
procedure: N-methyl-benzylamine (129 µL, 1.0 mmol),
cyclohexanone (103 µL, 1.0 mmol), (triisopropylsilyl)
acetylene (269 µL, 1.2 mmol), and CuCl2 (6.7 mg, 0.05
mmol) afford the title compound as a yellow oil in 76%
†
Electronic Supplementary Information (ESI) available:
experimental details on rate studies and the synthesis of new products
as well as copies of the H and 13C NMR spectra for new products.
1
See DOI: 10.1039/b000000x/
8 | Green Chem., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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DOI: 10.1039/C4GC02318H
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This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 00, 1-3 | 9

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ARTICLE
DOI: 10.10G39r/eCe4nGCC0h2e3m18Histry
Table of contents entry:
By heating copper(II) chloride with cyclohexanone, an amine,
and a terminal alkyne, this multicomponent coupling proceeds
in high yield with no waste from excess starting materials,
solvents, ligands, or other additives. The reaction is found to
be first order in catalyst and in each starting material.
No ligand, additive, solvent, or excess starting material:
O
R1
R2
R1
R2
N
N
5 mol % CuCl2
110 °C
H
1 equiv. 1 equiv.
R3
R3
20 products
1 equiv.
70-98% yield
1°/2°/cyclic amine + alkyl, aryl, silyloxy, or silyl acetylene