Zinc(II)-catalyzed redox cross-dehydrogenative coupling of propargylic amines and terminal alkynes for synthesis of N-tethered 1,6-enynes

Article abstract of DOI:10.1021/ja211092q

The zinc(II)-catalyzed redox cross-dehydrogenative coupling (CDC) of propargylic amines and terminal alkynes proceeds to afford N-tethered 1,6-enynes. In the current CDC reaction, a C(sp)-C(sp³) bond is formed between the carbon adjacent to the nitrogen atom in the propargylic amine and the terminal carbon of the alkyne with reduction of the C-C triple bond of the propargylic amine, which acts as an internal oxidant.

Full text of DOI:10.1021/ja211092q

Communication
pubs.acs.org/JACS
Zinc(II)-Catalyzed Redox Cross-Dehydrogenative Coupling of
Propargylic Amines and Terminal Alkynes for Synthesis of N-
Tethered 1,6-Enynes
Tsuyuka Sugiishi and Hiroyuki Nakamura*
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
S
* Supporting Information
C1(sp3)−Ha bond adjacent to the nitrogen atom of tertiary
ABSTRACT: The zinc(II)-catalyzed redox cross-dehy-
drogenative coupling (CDC) of propargylic amines and
terminal alkynes proceeds to afford N-tethered 1,6-enynes.
In the current CDC reaction, a C(sp)−C(sp3) bond is
formed between the carbon adjacent to the nitrogen atom
in the propargylic amine and the terminal carbon of the
alkyne with reduction of the C−C triple bond of the
propargylic amine, which acts as an internal oxidant.
amine 1 could provide a reactive iminium intermediate that
might be alkynylized (TS) to afford propargylic amine 3
(Scheme 2). By treatment of tertiary amine 1 containing a C−
C triple bond, which plays the role of an oxidant, CDC would
proceed without the addition of an external oxidant and the C−
C triple bond would be reduced.7 Indeed, propargylic amines
acted as oxidative tertiary amines 1 in the presence of zinc(II)
salts to give N-tethered 1,6-enynes 3.
We recently reported the copper(I)-catalyzed alkyne
substitution reaction of propargylic amines with terminal
alkynes.8 Aside from our report, other transition-metal-
catalyzed cross-coupling reactions of propargylic amines with
terminal alkynes have been published.9 Herein we describe the
zinc(II)-catalyzed redox10 CDC of propargylic amines 1 and
terminal alkynes 2 to afford N-tethered 1,6-enynes 3.
The screening results for propargylic amines 1 are
summarized in Table 1. Treatment of propargylic amines 1
with 3 equiv of ethynyl benzene 2a under our optimized
he 1,6-enyne skeleton is highly versatile because it
T
undergoes transition-metal-catalyzed reactions, including
cycloaddition reactions,1 cycloisomerizations,2 and cascade
isomerizations.3 N-Tethered 1,6-enynes, in particular, are
important synthetic precursors for the construction of bioactive
ring systems.4 In general, N-tethered 1,6-enynes with
substituents at the propargylic position are synthesized by the
addition of alkynylides to N-allyliminium intermediates in situ.5
Li et al. developed a copper-catalyzed cross-dehydrogenative
coupling (CDC) method that uses terminal alkynes, tertiary
amines, and stoichiometric oxidants, such as tert-butyl hydro-
peroxide, for the synthesis of propargylic amines.6c CDC is one
of the most efficient atom-economic strategies for C−C bond
formation as it does not require a substrate prefunctionalization
step (Scheme 1).6
Table 1. ZnBr2-Catalyzed CDC of Various Propargylic
a
Amines and Ethynyl Benzene 2a
Scheme 1. CDC Methodology
We envisaged a novel synthetic approach toward N-tethered
1,6-enynes through the CDC pathway, which utilizes tertiary
amines 1 with an internal oxidant6o,p in their structures
(Scheme 2). After deprotonation of terminal alkyne 2 and
reduction of the internal oxidant, catalytic oxidation of the
a
Isolated yields. Propargyl amine 1 (0.3 mmol), ethynyl benzene 2a
(0.9 mmol), and ZnBr2 (0.06 mmol) were heated in toluene in a
closed vial tube under N2 at 100 °C for 24 h. 50 mol % of ZnBr2 were
loaded. Determined by H NMR spectroscopy of the E/Z mixture.
b
c
1
Scheme 2. Plausible CDC Pathway with Oxidative Amine 1
conditions,11 namely, in the presence of 20 mol % of zinc(II)
bromide in toluene at 100 °C for 24 h, provided corresponding
N-tethered 1,6-enynes 3a−3i. Tertiary or secondary C(sp3)−H
Received: November 26, 2011
Published: January 26, 2012
© 2012 American Chemical Society
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Communication
bonds adjacent to nitrogens were activated (3a−3d). The N,N-
dibenzyl amino group in propargylic amines 1 required the
loading of 50 mol % of zinc bromide to furnish corresponding
1,6-enyne 3e in 50% yield, undergoing zinc-mediated redox
CDC. In order to investigate regioselectivity in the current
CDC reaction, we employed a 1,2,3,4-tetrahydroisoquinoline
derivative and N-methylbutylamine derivative as propargylic
amines 1 and obtained major products 3f and 3g, respectively.
With respect to the generation of 1,6-enyne 3f, the alkynylation
took place at the C1 position preferentially and no isomer of
1,6-enyne 3f was observed. The formation of 3g indicates that
the secondary C−H bond preferentially undergoes the
alkynylation rather than the primary C−H bond. Moreover,
even in the case in which an alkyl group was introduced to the
terminal position of propargylic amine 1 (R4 = Me or Bu), the
corresponding 1,6-enyne 3h or 3i was obtained in moderate
yield (1.7:1 d.r. and 1.4:1 d.r., respectively).12
(3o−3t) or an electron-withdrawing group (3u and 3v), and
whether the aromatic group is substituted at the para (3o, 3r,
3s, and 3u), meta (3p), or ortho (3q and 3v) position. Diynes
were employed in particular, and 3w and 3x were synthesized.13
To gain further insight into the reaction mechanism, the
reaction of deuterated substrates d1-1a, d-1a, or d-2a was
carried out, as shown in eqs 1 −5. The deuterium at the carbon
adjacent to the nitrogen atom shifted to the position cis to the
Table 2 depicts the scope of terminal alkyne 2 in the reaction
with N,N-diisobutyl amine derivative 1d. The generation of
desired compounds 3 dramatically increased in some cases by
Table 2. ZnBr2-Catalyzed CDC of N,N-Diisobutyl Propargyl
Amine 1d and Various Terminal Alkynes 2
amino methyl group in 1,6-enyne d-3a (eq 1). The kinetic
isotope effect (kH/kD) was 3.0, suggesting that the activation of
the C−H bond adjacent to the nitrogen atom is a kinetically
relevant process in this reaction (eq 1). H/D scrambling
between d1-1a and 1h did not occur. The results indicate that
the current CDC proceeds with the intramolecular hydride shift
of propargylic amine 1 (eq 2). The deuterium of d-2a was
incorporated at the position geminal to the amino methyl
group of d-3 h (eq 3). Similarly, the deuterium of d-2a was
added to the multiple bond of 1a (eq 4). In eq 4, the deuterium
atoms incorporated in the alkene positions of d-3a were
situated cis and located on the terminal carbon of the alkene
position preferentially rather than on the substituted carbon.
The deuterium at the terminal alkyne position of d-1a might
have been eliminated and exchanged with a proton (eq 5).
Finally, we propose the reaction mechanism on the basis of
the isotopic labeling experiments, as shown in Scheme 3.
Initially, the zinc alkynylide species would be generated from
terminal alkyne 2.14 There might be equilibrium between 5 and
6 in the case in which propargylic amine 1 bears a terminal
alkyne (R4 = H). Next, the multiple bond of propargylic amine
1 would be coordinated by zinc(II) to give complex 7,15 which,
in turn, would afford iminium intermediate 8 via a 1,5-hydride
shift.16 There would be the avoidance of the methylene group
and the zinc atom in the case in which propargylic amine 1 is an
a
Isolated yields. N,N-Diisobutyl propargyl amine 1d (0.45 mmol),
alkyne 2 (0.3 mmol), and ZnBr2 (0.06 mmol) were heated in toluene
in a closed vial tube under N2 at 100 °C for 24 h. N,N-Diisobutyl
b
propargyl amine 1d (0.3 mmol) and alkyne 2 (0.9 mmol) were used.
c
N,N-Diisobutyl propargyl amine 1d (0.3 mmol) and alkyne 2 (0.3
d
mmol) were used. N,N-Diisobutyl propargyl amine 1d (0.9 mmol)
and diyne 2 (0.3 mmol) were used.
changing the ratios of propargyl amine 1d to terminal alkynes 2
from the optimized reaction conditions for the synthesis of 1,6-
enyne 3a. The ratio of the substrates was optimized for each
synthesis due to the higher yield of the corresponding 1,6-
enyne 3. Decyne (R = Oct), 4-methyl-1-pentyne (R = iBu), and
ethynyl(trimethyl)silane (R = TMS) were applied to the
current CDC (3j−3l); however more bulky alkyl-substituted
terminal alkynes 2 did not work. Treatment of ethyl propionate
(R = CO2Et) with propargyl amine 1d afforded the
corresponding 1,6-enyne 3m in 44% yield. Aryl-substituted
terminal alkynes 2 were tolerated for this reaction, and
corresponding 1,6-enynes 3d and 3n−3v were obtained in
moderate to high yields. The reaction proceeded regardless of
whether the aromatic group has an electron-donating group
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Journal of the American Chemical Society
Communication
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Scheme 3. Proposed Mechanism for ZnBr2-Catalyzed CDC
of Propargylic Amines 1 and Terminal Alkynes 2
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Soc. 2011, 133, 13864. For CDC with internal oxidant: (o) Condie, A.
internal alkyne (R4 = Me or Bu). The attack of the zinc
alkynylide to the iminium ion followed by the protonation of σ-
vinylzinc complex 9 furnishes 1,6-enyne 3. Thus, alkynes 2 are
substituted at the carbon adjacent to the nitrogen atom of
propargylic amine 1, with the generation of an allyl group.
In conclusion, we have demonstrated the synthesis of N-
tethered 1,6-enynes from propargylic amines 1 and terminal
alkynes 2 by the zinc(II)-catalyzed redox cross-dehydrogenative
coupling reaction. This cross-coupling reaction should attract
attention from an atom economic point of view. The current
CDC offers a novel approach to the synthesis of useful
structures with an internal oxidant in the molecule of the
starting materials and without generation of waste.
ASSOCIATED CONTENT
■
S
* Supporting Information
́ ́
G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2010, 132, 1464. (p) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F.
J. Am. Chem. Soc. 2011, 133, 2350.
Details of synthesis and characterization. This information is
available free of charge via the Internet at http://pubs.acs.org/.
(7) Lumbroso, A.; Koschker, P.; Vautravers, N. R.; Breit, B. J. Am.
Chem. Soc. 2011, 133, 2386.
(8) Sugiishi, T.; Kimura, A.; Nakamura, H. J. Am. Chem. Soc. 2010,
132, 5332.
AUTHOR INFORMATION
Corresponding Author
hiroyuki.nakamura@gakushuin.ac.jp
■
(9) (a) ForCu-catalyzed dimerization of terminal propargyl amines:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Keiji Mori (Gakushuin Univ.) for kind and
helpful suggestion about analysis of E/Z mixtures.
■
REFERENCES
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