Transition-Metal-Free Addition of Acetylenes to Ketimines: the First Base-Catalyzed Ethynylation of the C=N Bond

Article abstract of DOI:10.1002/ejoc.201800850

A one-pot transition metal-free synthesis of propargylamines in good to excellent yield from ketone-derived imines and aryl- and hetarylacetylenes in the presence of KOBu^t/DMSO superbase system (40 °C, 10 min) has been developed. The reaction i

Full text of DOI:10.1002/ejoc.201800850

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Accepted Article
Title: Superbase-Catalyzed Synthesis of Propargylamines from
Ketimines and Acetylenes
Authors: Boris A. Trofimov
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10.1002/ejoc.201800850
European Journal of Organic Chemistry
COMMUNICATION
Transition-Metal-Free Addition of Acetylenes to Ketimines: the
First Base-Catalyzed Ethynylation of the C=N Bond
Ivan A. Bidusenko, Elena Yu. Schmidt, Igor A. Ushakov, and Boris A. Trofimov*
Abstract:
A
one-pot transition metal-free synthesis of
(congeners of Favorsky propargylalcohols). Because of a lower
electrophilicity of the C=N bond compared to that of the C=O
bond, the acetylenic anions should be in a higher concentration
and of a stronger nucleophilicity to accomplish the target
addition.
propargylamines in good to excellent yield from ketone-derived
imines and aryl- and hetarylacetylenes in the presence of
KOBut/DMSO superbase system (40oC, 10 min) has been
developed. The reaction involves
a nucleophilic addition of
acetylenic carbanions to the C=N bond thus for the first time
featuring the aza-Favorsky reaction.
Indeed, earlier it was published a one-pot synthesis of 3-
arylamino-1-butynes in 25-30% yields from aniline[12] or N-
arylamides[12b,13] and acetylene in the superbase media like
potassium
phenylamide/dioxane
or
potassium
Currently, propargylamines are increasingly becoming the
privileged molecules owing to their synthetic[1] and
pharmaceutical[2] importance. Since the pioneering syntheses of
these compounds by aminoalkylation of acetylenes published by
Mannich[3] and Reppe,[4] the research in this field was not too
intensive until 2001, when iridium-catalyzed three-component
reaction between primary amines, aldehydes and acetylenes to
give propargylamines was reported.[5] Afterwards, the research
activity on this synthesis, which is now abbreviated as A3
condensation, has acquired an avalanche-like character.[1,6]
Originally performed as the catalyst-free[3] or copper-catalyzed[4]
process, now it is carried out in the presence of various
transition metal catalysts.[1c] Still, newer catalytic systems and
protocols keep being claimed.[7] However, such three-component
reactions involving ketones (especially aromatic ketones),
amines and alkynes (KA2 coupling) are far from being developed
enough because of a lower reactivity observed for ketones in
this process .[8, 9, 10]
acetyl(aryl)amide/THF. The reaction was assumed to proceed
via nucleophilic addition of acetylenic anion to the intermediate
arylimine (the initial product of aniline vinylation, Scheme 1).[12,13]
Scheme 1. Superbase-catalyzed one-pot synthesis of 3-arylamino-1-butyne
from aniline and acetylene.[12]
Since it has been shown[7g, 8] that the preformed aldimines
react with acetylenes slower to give propargylamines in poorer
yields, a most probable key step of A3 condensation is the
nucleophilic substitution of the hydroxyl group in intermediate α-
hydroxyalkylamines by π/σ-metal acetylene complexes. The
known limitation of A3 condensation is that it meets certain
difficulties when extended over the ketones, sometimes
requiring additional microvawe activation[9] or special transition-
metal-based catalytic systems.[10]
This work presents a successful attempt to overcome this
limitation by the development of superbase-catalyzed
ethynylation of ketone-derived imines, i.e. to extend the
Favorsky alkynylation of ketones[11] over their nitrogen
analogues (ketimines). Actually, from point of view of the basic
chemistry, the C=N bond, like C=O bond, can accept the
nucleophilic attack by acetylenic anions to give propargylamines
We have started the present study with the question whether the
base-catalyzed ethynylation of ketimines is possible and, if yes,
which base catalyst is most suitable for further development of
this reaction. We have chosen the interaction of ketimine 1a
(acetophenone/aniline Schiff adduct) with phenylacetylene 2a as
a reference reaction and as probable catalytic systems were
taken combination of alkali metal hydroxides or alkoxides with
different solvents, which can significantly change the total
basicity of the system, sometimes producing superbases like
KOBut/DMSO (pKa 30-32).[14]
The selected experimental results (Table 1) show that the
base-catalyzed ethynylation of the C=N bond is indeed possible.
Expectedly, the best catalytic systems proved to be superbasic
pairs KOBut/DMSO and KOBut/DMF securing 46 and 48% yields
of the target propargylamine 3a at 20oC for 2 h (entries 5,6),
whereas other base/solvent combinations were inactive. When
the reactants (ketimine 1a + acetylene 2a) were allowed to
contact without a base (entry 1), no reaction was observed.
[*]
Dr. I. A. Bidusenko, Dr. E. Yu. Schmidt, Dr. I. A. Ushakov, Prof. B.
A. Trofimov
9, 10]
Indeed, according to the literature data,[8,
KA2
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of
Russian Academy of Sciences
1 Favorsky Str., 664033 Irkutsk (Russia)
E-mail: boris_trofimov@irioch.irk.ru
condensations are catalyzed by transition metals used in
amounts of not less than 5 mol%, usually 20 mol%. Therefore, if
even trace amounts of transition metals are present in the
reaction mixture, they cannot catalyze these processes.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800850
European Journal of Organic Chemistry
COMMUNICATION
1
2
1:1:1
1:1:1
15
20
40
50
60
40
40
40
40
40
40
120
120
120
120
120
120
5
36
45
59
56
49
62
63
70
68
64
28
Table 1. Effect of base/solvent combination on the reaction of ketimine 1a
with acetylene 2a.[a]
3
1:1:1
4
1:1:1
5
1:1:1
6
1:1.5:1
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:1.5:0.2
Entry
Base
_
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)[b]
0
7
1
2
8
10
NaOH
KOH
traces
28
9
30
3
10
11
120
120
4
NaOBut
KOBut
KOBut
KOBut
KOBut
KOBut
KOBut
37
5
48 (45)[c]
46 (41)[c]
n.d.
[a] Reaction conditions: 1a (1 mmol, 195 mg), 2a (1 or 1.5 mmol), KOBut (0.2-
1 mmol), DMSO (3 mL); [b] Molar ratio; [c] Isolated yield after column
chromatography (SiO2, n-hexane/ethyl acetate, 50:1).
6
7
NMP
Thus, with these provisionally optimum conditions for
implementation of the synthesis, we have investigated the
substrate scope of the reaction, first changing ketimine 1
structure and retaining phenylacetylene 2a as a reference (Table
3).[15]
8
THF
traces
n.d.
9
1,4-dioxane
toluene
10
n.d.
Table 3. The effect of ketimine structure on the yield of propargylamine 3b-o
in the reaction of ketimines 1b-o with acetylene 2a.[a]
[a] Reaction conditions: 1a (1 mmol, 195 mg), 2a (1 mmol, 102 mg), base (1
mmol), solvent (3 mL), 20oC, 2 h; [b] According to 1H NMR data of the crude
product (CDCl3, n-dodecane was used as an internal standard); [c] Isolated
yield after column chromatography (SiO2, n-hexane/ethyl acetate, 50:1). n.d.
= not detected.
Next, using the KOBut/DMSO superbase catalyst we have
examined the influence of its concentration, the reactants ratio,
reaction temperature and time on the process efficiency aiming
to improve it (to increase yield of the target product 3a and to
shorten the reaction time).
Imine 1
Product, yield[b]
1b
3b, 96%
As seen from the selected results (Table 2), the yield of
propargylamine 3a can reach 70%, when the reactants were
allowed to contact at 40oC during just 10 min. The further
increase of the reaction time 10 → 30 →120 min did not lead to
a higher yield. On the contrary, it slightly dropped from 70 → 68
1c
3c, 80%
→
64%, thus implying
a
slow transformation of the
propargylamine formed. Indeed, when pure propargylamine 3a
was kept for 120 min at 40oC in the same system after the
workup of the reaction mixture, 5% loss of the propargylamine
was observed. Probably, in this case, a slow superbase-
catalyzed head-to-tail polycondensation of the final product
and/or anionic polymerization across the acetylenic moiety occur.
1d
1e
3d, 73%
3e, 76%
Table 2. Effects of the reactant/KOBut ratio, temperature and time on the yield
of 3a.[a]
1f
3f, 73%
3g, 78%
Entry
1a:2a:KOBut[b]
T (oC)
t (min)
Yield (%)[c]
1g
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10.1002/ejoc.201800850
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COMMUNICATION
in the former case, the starting ketimine was completely
recovered, in the two latter cases, mixtures of products,
containing no the expected propargylamines, were formed.
Obviously, the donor effect of the methyl substituent depolarizes
the C=N bond, thereby decreasing its electrophilicity and, hence,
retarding nucleophilic addition of acetylenic carbanion. As to the
allyl and benzyl substituents, their active methylene groups likely
participate in the adverse proton transfers.
1h
3h, 77%
3i, 66%
The scope of acetylene substrates 2 has been examined for
the reference ketimine 1a (Table 4).
1i
Table 4. The effect of acetylene structure on the yield of propargylamine 3p-v
in the reaction of ketimine 1a with acetylenes 2b-n.[a]
1j
3j, 38%
Acetylene 2
Product, yield[b]
1k
1l
3k, 85%
3l, 84%
2b
2c
3p, 79%
3q, 52%
1m
3m, 66%
2d
2e
3r, 83%
3s, 62%
1n
1o
3n, 53%
3o, 64%
2f
3t, 81%
[a] Reaction conditions: 1 (1 mmol), 2a (1.5 mmol, 153 mg),
KOBut (0.5 mmol, 56 mg), DMSO (3 mL), 40oC, 10 min; [b]
Isolated yield (column chromatography, SiO2, n-hexane/ethyl
acetate, 50:1).
2g
2h
3u, 76%
3v, 84%
As follows from Table 3, the synthesis is efficiently extendable
over a great diversity of ketimines derived from aliphatic,
cycloaliphatic, aromatic and heteroaromatic ketones. The yields
range 64-96% with no evident regularities of the substituents
effect. Apparently, the latter is a combination of mutually
dependent factors: steric, inductive, conjugative and propensity
for auto-condensation. The decreased yield (38 and 53%) for
bromosubstituted ketimines 1j,n is likely due to solvolysis of
bromine atom under the action of the KOBut/DMSO system,
which, besides, results in quenching of its catalytic activity.
Certainly, to reach a higher yield for each ketimine, an additional
tuning of the reaction conditions is required.
[a] Reaction conditions: 1a (1 mmol, 195 mg), 2 (1.5 mmol), KOBut (0.5 mmol,
56 mg), DMSO (3 mL), 40oC, 10 min; [b] Isolated yield (column
chromatography, SiO2, n-hexane/ethyl acetate, 50:1).
The experiments have shown that the reaction tolerates a
large series of aryl- and hetarylacetylenes with donor and
acceptor substituents, the yields of propargylamines 3p-v being
52-84%. In this case, the steric effect seems to be more
pronounced and is likely the major cause of a lower yield in case
of acetylene 2c (R4 = 4-PhC6H4).
The experiments with ketimines having methyl, allyl and
benzyl substituents at the nitrogen atom have shown that while
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European Journal of Organic Chemistry
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P. Riederer, L. Vécsei, K. Magyar, J. Neural Transm. 2018, DOI:
10.1007/s00702-018-1853-9.
From the reaction of ketimine 1a with tert-butylacetylene and
cyclohexylacetylene under the same conditions, only the latter
was almost completely recovered (93-95%), whereas no the
starting acetylenes were detected in the crude product.
Generally, for the whole reaction the integral substituent
effect is in keeping with the mechanism of the process as a
nucleophilic addition to the polarized C=N bond (Scheme 2).
[3]
[4]
C. Mannich, F. T. Chang, Ber. Dtsch. Chem. Ges. 1933, 66b, 418–420.
a) W. Reppe, O. Hecht, US2273141A, 1942; b) W. Reppe, Neue
Entwicklungen auf dem Gebiete der Chemie des Acetylens und
Kohlenoxyds, Springer, Berlin-Göttingen-Heidelberg, 1949, pp. 23-66.
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2534–2536; b) C. Fischer, E. M. Carreira, Org. Lett. 2001, 3, 4319-4321.
For selected examples, see: a) V. A. Peshkov, O. P. Pereshivko, E. V.
Van der Eycken, Chem. Soc. Rev. 2012, 41, 3790-3807; b) Y. Liu,
ARKIVOC 2014, i, 1-20; c) D. Seidel, Org. Chem. Front. 2014, 1, 426–
429.
[5]
[6]
[7]
For selected examples, see: a) A. Grirrane, E. Alvarez, H. García, A.
Corma, Angew. Chem. Int. Ed. 2014, 53, 7253–7258; b) H.-B. Chen, Y.
Zhao, Y. Liao, RSC Adv. 2015, 5, 37737–37741; c) A. M. Munshi, M.
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Rivera, F. Fuentes, Y. Otero, E. Ocando-Mavárez, A. Arce, J. M. Garcia,
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Balakrishna, Catal. Comm. 2018, 103, 78-82; f) J.-Y. Zhang, X. Huang,
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Scheme 2. Tentative mechanism.
[8]
[9]
C. E. Meyet, C. J. Pierce, C. H. Larsen, Org. Lett. 2012, 14, 964–967.
O. P. Pereshivko, V. A. Peshkov, E. V. Van der Eycken, Org. Lett. 2010,
12, 2638−2641.
Indeed, formation of the tetrasubstituted carbon centre
(intermediate A), resulted from the initial nucleophilic attack of
the acetylenic carbanion at C(sp2) atom, should be sterically
hindered, while the acceptor substituents, both in ketimine and
acetylene, should facilitate the process, particularly by
distribution of negative charge at the nitrogen atom in the
intermediate A and by increasing concentration of the acetylide
anions.
[10] For selected examples, see: a) C. J. Pierce, M. Nguyen, C. H. Larsen,
Angew. Chem. Int. Ed. 2012, 51, 12289−12292; b) M. J. Albaladejo, F.
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[11] a) A. E. Favorsky, Zh. Ross. Khim. Obshchestva 1906, 37, 643; b) M.
Smith, J. March, March,s Advanced Organic Chemistry, 6th ed., Wiley,
New York, 2007, p. 1360.
To conclude, the transition metal-free facile (40oC, 10 min)
synthesis of secondary propargylamines in good to excellent
yields by KOBut/DMSO-catalyzed addition of acetylenes to
ketone-derived imines has been developed. The synthesis
provides a short-cut to a series of propargylamines, hardly
accessible via transition metal-catalyzed A3 condensation.
[12] a) B. A. Trofimov, S. F. Malysheva, E. P. Vyalykh, Zh. Org. Khim. 1979,
15, 880; b) B. A. Trofimov, N. K. Gusarova, Russ. Chem. Rev. 2007, 76,
p. 507-527.
[13] B. A. Trofimov, S. F. Malysheva, E. P. Vyalykh, Zh. Org. Khim. 1981,
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[14] W. N. Olmstead, Z. Margolin, F. G. Bordwell, J. Org. Chem. 1980, 45,
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Acknowledgement
[15] See the Supporting Information for full experimental details, compounds
characterization data, and copies of NMR spectra.
We thank the Baikal Analytical Centre for collective use of the
Siberian Branch of the Russian Academy of Sciences for the
equipment.
Keywords: ketimines • acetylenes • propargylamines •
superbases • ethynylation
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I. A. Bidusenko, E. Yu. Schmidt, I. A.
Ushakov, and B. A. Trofimov*
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Superbase-Catalyzed Synthesis of
Propargylamines from Ketimines and
Acetylenes
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