Copper(I)-catalyzed substitution reactions of propargylic amines: Importance of C(sp)-C(sp3) bond cleavage in generation of iminium intermediates

Article abstract of DOI:10.1021/ja9109055

Substitution reactions of propargylic amines proceed in the presence of copper(I) catalysts. Mechanistic studies showed that C(sp)?C(sp³) bond cleavage assisted by nitrogen lone-pair electrons is essential for the reaction, and the resulting iminium intermediates undergo amine exchange, aldehyde exchange, and alkyne addition reactions. Because iminium intermediates are key to aldehyde?alkyne?amine (A³) coupling reactions, this transformation is effective not only for reconstruction of propargylic amines but also for chiral induction of racemic compounds in the presence of chiral catalysts.

Full text of DOI:10.1021/ja9109055

Published on Web 03/30/2010
Copper(I)-Catalyzed Substitution Reactions of Propargylic Amines:
Importance of C(sp)-C(sp3) Bond Cleavage in Generation of Iminium
Intermediates
Tsuyuka Sugiishi, Akifumi Kimura, and Hiroyuki Nakamura*
Department of Chemistry, Faculty of Science, Gakushuin UniVersity, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Received December 27, 2009; E-mail: hiroyuki.nakamura@gakushuin.ac.jp
Amines are not suitable leaving groups for organic synthesis. In
general, C-N bond activation is carried out by converting amines
into ammonium and iminium ions.1 A few examples using amines
as leaving groups include nucleophilic substitution reactions of
highly electron-deficient aromatic compounds,2 palladium-catalyzed
carbonylation,3,4 deprotection of N-allylamines,5 and palladium- and
ruthenium-catalyzed amine exchange reactions.6,7 In particular,
direct C-H activation to generate iminium intermediates in amine
exchange reactions was first reported by Murahashi and co-workers6
and has become one of the most important strategies for related
transformations.8 Li and co-workers developed the copper-catalyzed
cross-dehydrogenative coupling (CDC)9 of tertiary amines with
terminal alkynes,10 active methylenes, and nitromethane (eq 1).11
We have developed a palladium-catalyzed hydride transfer reaction
for the synthesis of allenes 3 via iminium complex 2 (eq 2, path
a).12,13 In this paper, we report the copper-catalyzed substitution
reaction of propargylic amines. In this transformation, the
C(sp)-C(sp3) bond cleavage step is essential for generating copper
acetylides and iminium intermediates 4, which undergo fragment
exchange with additional aldehydes, amines, and alkynes to give 5
(eq 2, path b).
zylamine but also with various secondary amines (entries 7-15)
to give the corresponding amine-exchanged products (5g-o) in
good to high yields. The use of toluene (entries 8-11 and 15) or
dioxane (entry 12) instead of THF as the solvent was more effective
in certain cases. The substitution reaction using N-methylaniline
resulted in a relatively low yield (30%) (entry 15). The reactions
of 1g and 1h with dibenzylamine gave 5f in 61 and 68% yield,
respectively (entries 16 and 17).
Table 1. CuBr-Catalyzed Substitution Reactions of Propargylic
Amines 1 with Secondary Amines (HNR4R5)a
The results are shown in Table 1. When N,N-dicyclohexylpro-
pargylamine (1a) was treated with 3 equiv of dibenzylamine in the
presence of CuBr catalyst (20 mol %) in THF at 100 °C in a sealed
vial tube, the substitution reaction proceeded, generating the
corresponding amine-exchanged product 5a in 73% yield (entry
1). Propargylic amines 1b and 1c, which have a substituent at R2,
also underwent the substitution reaction with dibenzylamine to give
propargylic dibenzylamines 5b and 5c in 55 and 64% yields,
respectively (entries 2 and 3). The reaction was also applied to
a The reactions of propargylic amines 1 (0.5 mmol) with disubstituted
amines (HNR4R5) were carried out in the presence of CuBr (0.1 mmol)
in THF (1.5 mL) at 100 °C under an Ar atmosphere using a vial tube.
b Isolated yields based on 1. c Toluene was used as the solvent.
d Dioxane was used as the solvent.
To clarify the mechanism, we examined the substitution reactions
of dibenzylamine with 1f in the presence of 4-tolaldehyde and 1e
in the presence of benzaldehyde [Scheme S1 in the Supporting
Information (SI)]. Interestingly, N,N-dibenzyl-1-phenylpropargy-
lamine (5f) was obtained as the major product in both cases. These
results suggest that the substitution reaction involves C(sp)-C(sp3)
1-substituted propargylic amines 1d (R3 ) 4-FC6H4), 1e (R3
)
4-CH3C6H4), and 1f (R3 ) Ph), and the corresponding propargylic
dibenzylamines (5d-f) were obtained in 52-74% yield (entries
4-6). The substitution reactions proceeded not only with diben-
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5332 J. AM. CHEM. SOC. 2010, 132, 5332–5333
10.1021/ja9109055  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. CuCl-Catalyzed Alkyne Substitution Reactions of
33-73% yield (entries 14-16). However, the propargylic amines
having a substituent at the terminal position, such as 1b and N,N-
dicyclohexyl-2-butyn-1-ylamine, did not undergo the alkyne sub-
stitution reaction.
Propargylic Amines with Various Alkynesa
In conclusion, we have found that the substitution reactions of
propargylic amines proceed in the presence of copper(I) catalysts.
As described in the detailed mechanistic discussion in Scheme S2,
C(sp)-C(sp3) bond cleavage assisted by the nitrogen lone-pair
electrons is essential for the reaction, and the resulting iminium
intermediates undergo amine exchange, aldehyde exchange, and
alkyne addition reactions, although the possibility that the mech-
anism proceeds through copper allenylidene complexes14 or pro-
pargylic cation intermediates15,16 generated by C-N bond cleavage
to give the amine-exchanged products cannot be excluded. Because
iminium intermediates are key to aldehyde-alkyne-amine (A3)
coupling reactions,17-19 this transformation is effective not only
for reconstruction of propargylic amines but also for chiral induction
of racemic compounds in the presence of chiral catalysts.
entry
R6
baseb
1
1 or 6
yield (%)c
1d
2d
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
nBu3N
1a
1i
1j
1a
1a
1i
1a
1i
1a
1a
1a
1a
1a
1k
1l
1b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
74
83
47
44
48
61
58
53
58
44
63
40
42
73
33
39
Na2HPO4
nBu3N
4-biphenyl
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
2-(6-CH3O)Naph
4-(CH3)2NC6H4
4-CF3C6H4
Ph(CH3)C(OH)
EtO2C
nOct3N
Na2HPO4
Na2HPO4
nBu3N
Na2HPO4
nOct3N
nOct3N
Na2HPO4
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformations of Carbon Resources” from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
nBu3N
Na2HPO4
Na2HPO4
nOct3N
Ph
Ph
4-CH3OC6H4
Na2HPO4
1k
Supporting Information Available: Experimental data. This ma-
a The reaction of propargylic amines 1 (0.3 mmol) with alkynes 7
(0.9 mmol) was carried out in the presence of CuCl (0.06 mmol) in
THF (1.2 mL) at 100 °C under an Ar atmosphere using a vial tube.
b The amount of each base used in the reaction was as follows:
Na2HPO4 (1.2 mmol); nBu3N (0.3 mmol); nOct3N (0.15 mmol).
c Isolated yields based on 1. d Using 5 equiv of phenylacetylene.
terial is available free of charge via the Internet at http://pubs.acs.org.
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