Copper(II) catalysis provides cyclohexanone-derived propargylamines free of solvent or excess starting materials: Sole by-product is water

Article abstract of DOI:10.1039/c2gc35713e

A high-yielding three-component reaction proceeds under mild, solvent-free conditions for access to a wide variety of fully-substituted propargylamines. Inexpensive copper(ii) chloride catalyzes the coupling of equimolar amounts of amines, alkynes, and cyclohexanone such that the only by-product is one equivalent of water.

Full text of DOI:10.1039/c2gc35713e

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COMMUNICATION
Copper(II) catalysis provides cyclohexanone-derived propargylamines free of
solvent or excess starting materials: sole by-product is water†
Conor J. Pierce and Catharine H. Larsen*
Received 10th May 2012, Accepted 26th June 2012
DOI: 10.1039/c2gc35713e
aldehydes, piperidine, and phenylacetylene in greater than 92%
yield in 3 h at 120 °C with an impressive 0.1 mol% of a
Cu(OH)x–Fe3O4 catalyst.16 In contrast, their best of two ketone
substrates requires 7 days for a maximum 38% yield under iden-
tical conditions, and only secondary amines react. Van der
Eycken and co-workers describe what they term a KA2 reaction
of benzylamines and phenylacetylene with cyclohexanones
using 20 mol% CuI, microwave conditions, and varying excesses
of alkyne and ketone for yields of 31–82%.17 Chan et al.
efficiently couple secondary amines, ketones, and phenylacety-
lene with 4 mol% AuBr3.18 However, an excess 0.5 equivalent
each of ketone and of alkyne was required, and the gold catalyst
is expensive.19 Though the low reactivity of ketones other than
cyclohexanone is expected,13–15 reduced yields from alkyl
alkynes and when switching from secondary to primary amines
is not adequately addressed. Accordingly, these KA2 couplings
remain a green synthetic challenge for a variety of reasons: waste
in the form of excess substrate, high loading or expensive cata-
lyst, long reaction times, and low yielding alkynes and
amines.16–18
A high-yielding three-component reaction proceeds under
mild, solvent-free conditions for access to a wide variety of
fully-substituted propargylamines. Inexpensive copper(II)
chloride catalyzes the coupling of equimolar amounts of
amines, alkynes, and cyclohexanone such that the only by-
product is one equivalent of water.
Introduction
Propargylamines are valuable intermediates in organic synthesis,
providing access to nitrogen-containing biologically active com-
pounds and natural products.1 The most direct approach to acces-
sing propargylamines is the three-component coupling of an
aldehyde, alkyne, and amine. Referred to as A3 coupling, this
method has been widely investigated2,3 as it circumvents syn-
thesis and isolation of imine or enamine intermediate.4 These
multicomponent5 couplings are greener6 processes as they elimi-
nate reagents and materials7 that would have been used in the
course of generating and purifying imine or enamine.
The vast majority of methods are optimized towards the reac-
tion of aldehydes with electron-rich primary anilines or secon-
dary amines.2,3 Our group recently published an alternative
method catalyzed by copper(II) triflate, Cu(OTf)2, that provides
propargylamines from both electron-rich and electron poor
primary and secondary amines.8 Under the same reaction
conditions applied to aldehydes,9,10 this copper-catalyzed route
surprisingly allows for the incorporation of a less-reactive cyclo-
hexanone to produce a propargylamine bearing a fully-substi-
tuted, or quaternary, adjacent carbon center. Formation of this
propargylamine proceeds via a ketimine-type intermediate,
formed in situ from the condensation of amine and ketone.
Ketimines are less reactive than their aldimine counterparts
towards nucleophilic addition,11 but cyclohexanone-derived
ketimines12–14 react more readily due to the release of torsional
strain.15
To achieve the primary goal of an eco-friendly6 KA2 reaction
of cyclohexanones,12 the following criteria were set: (1) solvent-
free conditions, (2) an economical, more benign catalyst, (3) no
co-catalysts or additives, (4) high yields of product for both
primary and secondary amines, (5) efficient reaction of aryl- and
non-aryl alkynes, and (6) complete atom economy7 with one
equivalent each of three starting materials.
Herein, we report a highly-efficient CuCl2-catalyzed one-pot
coupling of cyclohexanone with either primary or secondary
amines and a range of alkynes (Scheme 1). This direct formation
of fully-substituted propargylamines satisfies all six goals and is
a true example of atom economy7 as the sole additive is catalyst
and the only by-product is water.
We recently reported that the same conditions applied for A3
coupling of aldehydes successfully couple less-reactive cyclo-
hexanone (1) with benzylamine (2a) and 1-octyne (3a) in 80%
yield (Scheme 2, 10 mol% copper(II) triflate, Cu(OTf)2).8 This
Highlighting the difficulty of incorporating ketones versus
aldehydes,9–15 Yus et al. report propargylamine formation from
Department of Chemistry, University of California Riverside, 501 W Big
Springs Rd, Riverside, CA 92521, USA. E-mail: catharine.larsen@ucr.edu;
Tel: (+1)-951-827-4964
†Electronic supplementary information (ESI) available: Spectroscopic
data and detailed procedures for all compounds are available online free
of charge. See DOI: 10.1039/c2gc35713e
Scheme 1 Versatile KA2 of cyclohexanone, amines, and alkynes.
2672 | Green Chem., 2012, 14, 2672–2676
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unusual result served as the starting point for an improved green,
versatile method for synthesis of propargylamines from
cyclohexanone.
presence of halide ligands consistently provides >70% GC yield
of product 4a under solvent-free conditions (entries 3, 4, 12, 13,
14, and 16). CuCl2 and CuBr·Me2S afford the highest overall
GC yields, 99% and 94%, respectively, but CuCl2 is more
reliable across the range of substrates. Entries 1 and 4 in Table 1
clearly show that Cu(II) chloride is superior to the original Cu(II)
triflate catalyst; CuCl2 provides near quantitative GC yield and
faster reaction rate than Cu(OTf)2.
If not for the goal of an eco-friendly solvent-free process,
CuCl2 may not have been identified as a superior catalyst as it is
nearly inactive in solution. No conversion is observed in
acetone, acetonitrile, 1,4-dioxane, THF, chloroform, ethyl
acetate, DMF, DMSO, methanol, water, or dichloroethane.
Toluene and hexanes yield 5–10% product. No difference in
reactivity is observed under an atmosphere of nitrogen versus
argon. In air the reaction of 1a, 2a, and 3a proceeds as cleanly
but conversion to 4a is 18% less than in N2 or Ar.
From this initial reaction (shown in Scheme 2 below), a more
atom economical method was sought to reduce catalyst loading,
eliminate solvent, and avoid excess substrates while maintaining
a high yield of N-benzylpropargylamine 4a. The first two modes
of rendering synthetic methods greener are a major focus, but
reducing waste from excess starting material, a serious detractor
from the advantages of multicomponent reactions, receives less
attention.6 In solution, the high reactivity of Cu(OTf)2 results in
excellent conversion to product, but side products appear with
this catalyst in the absence of solvent. Therefore, the develop-
ment of a greener method began by testing a wide array of
copper catalysts at half the catalyst loading under solvent-free
conditions, and with equimolar amounts of ketone 1, amine 2,
and alkyne 3.
Table 1 summarizes the copper(I) and copper(II) catalysts
tested at 5 mol% loading. While every copper source tested exhi-
bits reasonable activity, no product is detected over three days in
the absence of a copper catalyst. No apparent correlation exists
between metal oxidation state and catalytic activity: Cu(I) and
Cu(II) bromide produce identical GC yields (entry 12 vs. 3), and
Cu(I) acetate is superior to Cu(II) acetate (entry 11 vs. 2), but
Cu(II) chloride outperforms Cu(I) chloride (entry 4 vs. 13). The
Scheme 3 below shows that this greener process, using
5 mol% CuCl2 in a neat 1 : 1 : 1 ratio of starting materials results
in a higher 91% yield of product 4a (80% yield in Scheme 2).
As previous cyclohexanone KA2 reactions were limited to
either primary17 or secondary18 amines coupled mostly with
phenylacetylene, investigations began by surveying the amine
substrates operable with 1-octyne in this solvent-free catalytic
Scheme 3 Green method provides higher yield and shorter reaction
Scheme 2 Starting point for a greener propargylamine synthesis.
time.
Table 1 Copper(II) chloride found to be optimal catalyst under solvent-free conditions and with equimolar amounts of starting materialsa
Entry
Cu source
GC yield (%) at l h
GC yield (%) at 18 h
1
2
3
4
5
6
7
8
Cu(II) triflate
Cu(II) acetate
Cu(II) bromide
Cu(II) chloride
Cu(II) perchlorate hexahydrate
Cu(II) sulfate
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
11
18
15
42
8
2
4
8
2
11
7
39
19
33
22
15
12
59
72
72
99
50
38
52
27
32
45
56
72
89
94
70
81
46
9
10
11
12
13
14
15
16
17
Cu(I) hexafluorophoshate tetrakisacetonitrile
a All reactions were carried out with cyclohexanone (0.5 mmol), N-benzylamine (0.5 mmol), 1-octyne (0.5 mmol), and copper (0.025 mmol).
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Table 2 High yields with primary or secondary amines and 1-octynea
yield bearing fully-substituted carbon centers (entries 5–7).
Impressively, cyclic diamine piperazine forms bis-propargyl-
amine product 4h under identical conditions by adding 2 equiva-
lents of cyclohexanone and alkyne (entry 8).
Table 3 showcases the broad scope of the alkyne partner made
possible by this greener method. Note that in contrast to previous
reports where application of 1-octyne instead of phenylacetylene
caused a 45% drop in yield,17 under the green conditions
reported herein, nearly identical yields are obtained for 1-octyne
(90%, entry 1) and phenylacetylene (89% entry 2). Alkyl
alkynes bearing propylphenyl (4j), 3-methylbutyl (4k), and tert-
butyl (4l) also react efficiently with piperidine and cyclohexa-
none (entries 3–5). As a testament to the mildness of these neat
CuCl2 conditions compared to Cu(OTf)2 in toluene,8 no base is
needed to buffer couplings of morpholine with acid-sensitive
silyl alkynes (Table 3, 4m and 4n). Finally, morpholine propar-
gylamine 4o bearing a silyl-protected alcohol is produced in
84% yield. To the best of our knowledge,16–18 these represent
the first silyl and silyloxy alkynes incorporated under conditions
sufficiently activating for the KA2 reaction of cyclohexanone.
Entry Amine
1
Time (h) Product
6
Yield (%)
91
2
3
5
6
87
82
4
5
4
3
88
90
Conclusions
In the development of the greener method reported herein,
solvent is removed, catalyst loading is halved, and the largest
reduction in waste arises from the elimination of the excess start-
ing materials generally utilized. It is important to note that if
solvent-free green chemistry had not been targeted, the high
reactivity of this inexpensive copper(II) chloride catalyst may
have escaped discovery as it is nearly inactive in solution.
Primary and secondary amines rapidly react with cyclohexanone
and aryl, alkyl, silyl, and silyloxy alkynes to produce secondary
and tertiary N-propargylamines at fully-substituted carbon
centers. This efficient three-component coupling proceeds by
adding the copper(II) chloride catalyst to a 1 : 1 : 1 ratio of
amines, cyclohexanone, and alkynes, and the sole by-product is
water.
6
3
92
7
8
2
88
Experimental section
16
68b
General information
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 nitrogen. Flash column chromatography was per-
formed using silica purchased from Silicycle. All reagents were
obtained through commercial suppliers and purified by distilla-
tion before use as in W. L. F. Amerengo and D. D. Perrin,
Purification of Laboratory Chemicals, 4th ed., Butterworth-
Heineman,: Oxford, U.K., 1996.
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 (2.0 mmol)
cyclohexanone and (2.0 mmol) 1-octyne were used.
method (Table 2). Other primary amines provide good yields of
N-para-methoxybenzyl (4b) and N-propylphenyl (4c) propargyl-
amines. The 87% yield of 4b is almost triple the previous report
of 31% yield that required a four times higher catalyst loading.17
Secondary N-methylbenzylamine provides tertiary amine 4d in
88% yield (similar dibenzyl or di-n-butyl amines proceed in
29% or 52% yield with highly reactive AuBr3).18
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 singu-
larly 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
Heterocyclic secondary amines piperidine, morpholine, and
pyrrolidine convert in 2–3 h into products 4e–4g in and 88–92%
2674 | Green Chem., 2012, 14, 2672–2676
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Table 3 Alkyl, aryl, and silyl alkynes couple under mild conditionsa
reflection at the interface between the crystal and the solid
material. 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
either positive or negative ionization.
Entry Alkyne
1
Time (h) Product
3
Yield (%)
90
General procedure
To an oven-dried test tube equipped with magnetic stir bar and
Teflon-seal screw cap was added 5 mol% CuCl2. The flask was
purged with nitrogen for 5 min. Ketone (1.0 equiv), alkyne
(1.0 equiv), and amine (1.0 equiv) were added, and the reaction
was stirred at 110 °C for the indicated time. Upon completion as
judged by GC analysis, the mixture was cooled to room tempera-
ture and directly loaded atop a silica gel column. Chromato-
graphy with ethyl acetate in hexanes as eluent afforded the
desired product. The products were further identified by FT-IR,
1H NMR, 13C NMR and HRMS, which were all in good agree-
ment with the assigned structures.
2
2
89
3
4
4
3
78
92
Acknowledgements
Financial support was provided by the University of California
(UC), a UC Regents Faculty Fellowship, and a Cancer Research
Coordinating Committee Grant. We thank Mr Daniel Reza,
U undergraduate, for his assistance.
5
2
81
Notes and references
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