Copper(I)-catalysed deacetylenative cross-coupling reaction of terminal alkynes with propargylic amines via C(sp)-C(sp3) bond cleavage

Article abstract of DOI:10.1055/s-0031-1290376

The catalytic deacetylenative coupling reaction of terminal alkynes with various N-substituted propargylic amines proceeded in the presence of CuCl (10 mol%) and NaPO(4 equiv) in THF at 130 °C to give the corresponding substituted propargylic amines in go

Full text of DOI:10.1055/s-0031-1290376

1686▌
LETTER
lCettoerpper(I)-Catalysed Deacetylenative Cross-Coupling Reaction of Terminal
Alkynes with Propargylic Amines via C(sp)–C(sp3) Bond Cleavage
Cross-Coupling Reaction of Terminal Alkynes with Propargylic Amines
Yongeun Kim, Hiroyuki Nakamura*
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax +81(3)59921029; E-mail: hiroyuki.nakamura@gakushuin.ac.jp
Received: 16.04.2012; Accepted after revision: 20.04.2012
catalyst to afford substituted propargylic amines.10 In this
Abstract: The catalytic deacetylenative coupling reaction of termi-
transformation, the C(sp)–C(sp3) bond cleavage of
nal alkynes with various N-substituted propargylic amines proceed-
propargylic amines 1 is the key step for the generation of
ed in the presence of CuCl (10 mol%) and Na2HPO4 (4 equiv) in
copper acetylides 2 and iminium intermediates 3. Iminium
intermediates 3 undergo fragment exchange with addi-
tional aldehydes, amines, and/or alkynes to yield substi-
tuted propargylic amines 1′–1′′′ (Scheme 1).
Furthermore, we found that the redox CDC reaction of
propargylic amines and terminal alkynes also proceeded
in the presence of zinc(II) catalysts, giving the N-tethered
1,6-enynes.11
THF at 130 °C to give the corresponding substituted propargylic
amines in good to high yields.
Key words: alkynes, amines, copper, cleavage, catalysis
Recently, much attention has been focused on transition-
metal-catalyzed C–H bond activation and subsequent C–
C bond-forming reactions in modern organic chemistry.1
In particular, the formation of C–C bonds via an iminium
intermediate generated by the activation of the α-sp3 C–H
bonds of nitrogen in amines is one of the attractive strate-
gies for selective cross-dehydrogenative coupling
(CDC).2 Murahashi et al. were the first to report an amine
substitution reaction through direct C–H activation to
generate iminium intermediates,3 and related transforma-
tions were subsequently developed based on this amine
exchange reaction.4 Li and co-workers developed the cop-
per-catalyzed CDC2 of tertiary amines with terminal al-
kynes,5 active methylenes, and nitromethane.6 Although
this coupling reaction required additive oxidants, such as
O2, H2O2, and some peroxides, this protocol has been uti-
lized not only for the activation of the α-sp3 C–H bonds of
nitrogen in amines but also for the activation of the α-sp3
C–H bonds of oxygen in ethers,7 benzylic sp3 C–H bonds,8
and even alkane C–H bonds.9
Although the transformation was able to be utilized for the
deacetylenative homocoupling reaction, which is one of
the convenient reactions for the synthesis of symmetric
1,4-diamino-2-butynes,12 the reaction conditions still
need improvement prior to application in the deacetylen-
ative coupling reaction of terminal alkynes with propar-
gylic amines.10 In the current study, we succeeded in the
deacetylenative cross-coupling reaction of alkynes with
various N-substituted propargylic amines under modified
reaction conditions.
The deacetylenative coupling reaction of phenylacetylene
with N,N-dihexylnon-1-yn-3-amine (1a) was initially ex-
amined under various conditions, and the results are
shown in Table 1. Previously, we reported that the reac-
tion proceeded in the presence of CuCl catalyst (20 mol%)
and n-Oct3N (0.5 equiv) at 100 °C in THF for 24 hours,
giving N,N-dihexyl-1-phenylnon-1-yn-3-amine (2a) in
33% yield (Table 1, entry 1).10 We found that elevating
the temperature to 130 °C affected the reaction yield:
We have recently reported that propargylic amines under-
go a substitution reaction in the presence of a copper(I)
R2
R2
HNR1'
+
2
NHR1
cat. Cu(I)
Cu
2
NR1'
NR1
+
2
2
R2
H
Csp–Csp3
amine
exchange
H
H
2
3
1'
1
cleavage
HNR1'2, R2'CHO
iminium exchange
alkyne
exchange
R3
H
R2'
R2
NR1'
NR1
2
2
R3
H
1'''
1"
Scheme 1 Copper-catalyzed alkyne substitution reactions of propargylic amines
SYNLETT 2012, 23, 1686–1690
Advanced online publication: 13.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290376; Art ID: ST-2012-U0331-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reaction of Terminal Alkynes with Propargylic Amines
1687
Compound 2a was obtained in 66% yield (Table 1, entry amines 1. The results are shown in Table 2. The reaction
2) when the reaction was carried out at 130 °C. Decreas- was performed in the presence of CuCl catalyst (10
ing the amount of CuCl catalyst to 10 mol% and 5 mol% mol%) and Na2HPO4 (4 equiv) at 130 °C in THF. Under
resulted in a slight increase of the yields (Table 1, entries these reaction conditions, isobutyl (1b), dihexyl (1c),13 di-
3 and 4). However, deacetylenative homocoupling prod- allyl (1d), morpholyl (1e), dicyclohexyl (1f), and N-ethyl-
uct 3a12 was generated in 4% yield under the 5 mol% cat- benzyl (1g) propargylic amines underwent the
alyst condition (Table 1, entry 4). Then, the effect of bases deacetylenative coupling reaction to give corresponding
on the deacetylenative coupling reaction was examined. 5-methyl-1-phenylhex-1-yn-3-amines 2b–g in 72–98%
Na2HPO4 was found to be an effective base for the reac- yields (Table 2, entries 1–6).14 It should be noted that a
tion: the yield of 2a was increased to 81% (10 mol% CuCl propargylic moiety selectively undergoes the deacetylen-
in Table 1, entry 5) and 83% (5 mol% CuCl in Table 1, en- ative coupling in the presence of allylic moieties (Table 2,
try 6), and this was accompanied by an increase in the entry 3).
amount of generated 3a. N,N-Dimethylaminopyridine
(DMAP) or Cs2CO3 was not an efficient base for the cur-
rent transformation (Table 1, entries 7 and 8). The effect
of solvents was also examined. Although the reaction pro-
The reaction did not proceed with N,N-bis(pyridine-2-yl-
methyl)prop-2-yn-1-amine. In addition, N,N-dibenzyl-
prop-2-yn-1-amine (1h), which has no substituent at the
propargylic position, gave corresponding product 2h in
ceeded in various solvents, such as EtOAc, ethylene di-
30% yield (Table 2, entry 7). These results indicate that
chloride (EDC), and cyclopentyl methyl ether (CPME), at
the substituents at the propargylic position markedly af-
fect the current transformation. A variety of substituted
propargylic N,N-dibenzylamines, such as n-pentyl (1i),
isopropyl (1j), cyclohexyl (1k), benzyl (1l), and phenethyl
(1m), were employed for the deacetylenative coupling re-
action to afford corresponding substituted N,N-dibenzyl-
3-phenylprop-2-yn-1-amines 2i–m in 58–81% yields (Ta-
ble 2, entries 8–12). The reaction was also applied to het-
130 °C, the yields of 2a were reduced to 44–65% after 24
hours (Table 1, entries 9–11). It should be noted that both
n-Oct3N and Na2HPO4 were effective for the deacetylen-
ative coupling reaction. Since Na2HPO4 is an inorganic
base and readily removed from the reaction mixture, the
purification process of the products using Na2HPO4 was
much simpler than that using n-Oct3N. Therefore,
Na2HPO4 was employed for further experiments.
eroaromatic substituted propargylic N,N-dibenzylamines,
After a suitable set of conditions for the deacetylenative such as 2-furanyl (1n) and 3-furanyl (1o) substituted
coupling reaction were established, we investigated the propargylic amines, and corresponding 3-phenylprop-2-
reaction of phenylacetylene with various propargylic yn-1-amines 2n and 2o were obtained in 61% and 51%
Table 1 Optimization of Reaction Conditionsa
N(Hex)2
N(Hex)2
N(Hex)2
Cu cat.
+
+
base
solvent, 24 h
N(Hex)2
(1.5 equiv)
2a
3a
1a
Entry
Catalyst (mol%)
Solvent
Base
Temp (°C)
Yield of 2a (%)b
Yield of 3a (%)c
1
2
CuCl (20)
CuCl (20)
CuCl (10)
CuCl (5)
THF
THF
THF
THF
THF
THF
THF
THF
EtOAc
EDC
CPME
n-Oct3N (0.5)
n-Oct3N (0.5)
n-Oct3N (0.5)
n-Oct3N (0.5)
Na2HPO4 (4.0)
Na2HPO4 (4.0)
DMAP (2.0)
100
130
130
130
130
130
130
130
130
130
130
33
–
–
66
3
77
–
4
81
4
5
CuCl (10)
CuCl (5)
81
3
6
83
7
7
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
9 (68)
4 (95)
65 (16)
44 (9)
44 (38)
–
8
Cs2CO3 (2.0)
Na2HPO4 (4.0)
Na2HPO4 (4.0)
Na2HPO4 (4.0)
–
9
10
–
10
11
–
a Unless otherwise specified, the reactions were carried out with propargylic amines 1 (0.3 mmol) and phenylacetylene (0.45 mmol) in the pres-
ence of CuCl (5–20 mol%) and a base in THF (1.2 mL) under N2 atmosphere using a sealed vial tube.
b Yield of product isolated after silica gel chromatography. Percentage of recovered 1a is indicated in parenthesis.
c ‘–’ indicates ‘not observed’.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1686–1690

1688
Y. Kim, H. Nakamura
LETTER
yields, respectively (Table 2, entries 13 and 14). However, 5-(dibenzylamino)-7-methyloct-3-yn-1-ol (2t) were ob-
phenyl and 3-pyridinyl group (R2) substituted propargylic tained in moderate yields with the recovery of 1b. These
N,N-dibenzylamines did not undergo the deacetylenative products shown in Table 3 were not able to be obtained
coupling reaction.
under the previously reported conditions.10
We next examined the alkyne substitution reaction with In conclusion, we have developed an efficient method for
various terminal alkynes. The results are shown in Table the synthesis of 3-substituted propargylic amines 2 from
3. The reaction of 1b with 4-ethynylanisole, 1-hexyne corresponding propargylic amines 1, which employs the
gave corresponding 3-substituted 1-isobutyl-propargylic copper-catalyzed deacetylenative coupling reaction. A
amines 2p and 2q in 73% and 64% yields, respectively. propargylic moiety selectively underwent the deacetylen-
Ethyl propiolate, propargyl alcohol, and 3-butyn-1-ol ative coupling in the presence of allylic moieties. Elevat-
were also employed for the deacetylenative coupling reac- ing the temperature to 130 °C is essential not only for
tion and ethyl 4-(dibenzylamino)-6-methylhept-2-ynoate improvement of the reaction yields but also for applica-
(2r), 4-(dibenzylamino)-6-methylhept-2-yn-1-ol (2s), and tion to alkynes with various functionalities. Under the cur-
Table 2 Copper-Catalyzed Alkyne Substitution Reaction of 1 with Various Propargylic Amines 2a
.
R2
R2
NR1
CuCl (10 mol%)
2
+
Ph
NR1 Na2HPO4 (4 equiv)
2
Ph
THF, 130 °C, 1 d
1
2
Entry
1
2
Yield (%)b
i-Bu
NR1
2
H
1
2
3
4
5
6
R1 = Bn
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
98
94
80
89
72
84
R1 = n-Hex
R1 = allyl
NR12 = morpholyl
R1 = Cy
R1 = (Et)(Bn)
1g
2g
R2
NBn2
H
7
8
R2 = H
1h
1i
2h
2i
30d
79
R2 = n-Pent
R2 = i-Pr
R2 = Cy
9
1j
2j
81
10
11
12
1k
1l
2k
2l
58e
59
R2 = Bn
R2 = BnCH2
1m
2m
80
R2
=
13
14
1n
1o
2n
61
51
O
R2
=
2oc
O
a Unless otherwise specified, the reactions were carried out with propargylic amines 1 (0.3 mmol) and phenylacetylene (0.45 mmol) in the pres-
ence of CuCl (0.03 mmol) and Na2HPO4 (1.20 mmol) in THF (1.2 mL) at 130 °C under N2 atmosphere using a sealed vial tube.
b Yield of product isolated after silica gel chromatography.
c CuCl (0.06 mmol) and phenylacetylene (3.0 equiv) were used.
d Compound 1h was recovered in 36% yield.
e Compound 1k was recovered in 15% yield.
Synlett 2012, 23, 1686–1690
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reaction of Terminal Alkynes with Propargylic Amines
1689
having labile functional groups, such as ester and alcohol,
and propargylic amines without generating the deacety-
lenative homocoupling products. The current study offers
an important protocol for C(sp)–C(sp3) bond cleavage in
organic synthesis.
Table 3 Copper-Catalyzed Alkyne Substitution Reaction of Propar-
gylamine 1b with Various Alkynes 4a,b,e
CuCl (10 mol%)
R3
+
Na2HPO4 (4 equiv)
NBn2
1b
NBn2
THF, 130 °C, 1 d
4
R3
2
Typical Procedure for the Synthesis of N,N-Dihexyl-1-phenyl-
oct-1-yn-3-amine (2a)
Entry
Product
Yield (%)
To a mixture of 1a (88 mg, 0.3 mmol), CuCl(I) (3 mg, 0.03 mmol),
and Na2HPO4 (170 mg, 1.2 mmol) in THF (1.2 mL) was added ethy-
nylbenzene (50 μL, 0.45 mmol) in a sealed vial tube under N2, and
the mixture was stirred at 130 °C for 1 d. After insoluble materials
were removed by Celite filtration, the filtrate was concentrated un-
der vacuo. The residue was purified by column chromatography on
silica gel with hexane–EtOAc as eluent to give 2a10 (90 mg, 81%
yield) as colorless oil. In a similar manner, 2b–t were obtained from
the corresponding 1b–o in 30–98% yields.
MeO
N
1
73
2p
Acknowledgment
We thank ZEON Co. Japan for kindly donating CPME. Y. Kim
thanks the Japan Society for the Promotion of Science (JSPS, ID
No. P09240) for the financial support.
N
2
3
4
5
64 (35)
56 (31)
48 (37)
60 (34)
2qc
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
EtO
O
N
(1) (a) Dyker, G. Angew. Chem. Int. Ed. 1999, 38, 1698.
(b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102,
1731. (c) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(d) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087.
(e) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev.
2009, 38, 2447. (f) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 5094.
(g) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.
Int. Ed. 2009, 48, 9792.
(2) (a) Li, C. J. Acc. Chem. Res. 2009, 42, 335.
(b) Scheuermann, C. J. Chem. Asian. J. 2010, 5, 436.
(3) Murahashi, S.; Hirano, T.; Yano, T. J. Am. Chem. Soc. 1978,
100, 348.
(4) (a) Murahashi, S. I.; Komiya, N.; Terai, H.; Nakae, T. J. Am.
Chem. Soc. 2003, 125, 15312. (b) Murahashi, S. I.; Komiya,
N.; Terai, H. Angew. Chem. Int. Ed. 2005, 44, 6931.
(5) Li, Z.; Li, C. J. J. Am. Chem. Soc. 2004, 126, 11810.
(6) Li, Z.; Bohle, D. S.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 8928.
(7) (a) Zhang, Y.; Li, C. J. Angew. Chem. Int. Ed. 2006, 45,
1949. (b) Zhang, Y.; Li, C. J. J. Am. Chem. Soc. 2006, 128,
4242.
2r
2sd
2t
N
OH
N
OH
a Unless otherwise specified, the reactions were carried out with
propargylic amine 1b (0.3 mmol) and terminal alkynes 4 (0.45 mmol)
in the presence of CuCl (0.03 mmol) and Na2HPO4 (1.20 mmol) in
THF (1.2 mL) at 130 °C under N2 atmosphere using a sealed vial tube.
b Yield of product isolated by silica gel chromatography.
c 1-Hexyne (3.0 equiv) was used.
(8) Li, Z.; Cao, L.; Li, C. J. Angew. Chem. Int. Ed. 2007, 46,
6505.
(9) Zhang, Y.; Feng, J.; Li, C. J. J. Am. Chem. Soc. 2008, 130,
2900.
(10) Sugiishi, T.; Kimura, A.; Nakamura, H. J. Am. Chem. Soc.
2010, 132, 5332.
(11) Sugiishi, T.; Nakamura, H. J. Am. Chem. Soc. 2012, 134,
2504.
d Propargyl alcohol (3.0 equiv) was used.
e Percentage of recovered 1b is indicated in parenthesis.
(12) Kim, Y.; Nakamura, H. Chem. Eur. J. 2011, 17, 12561.
(13) Typical Procedure for the Preparation of N,N-Dihexyl-5-
methylhex-1-yn-3-amine (1c, Table 2, Entry 2)
To a solution of CuBr(I) (0.036 g, 0.25 mmol) in toluene
(100 mL) were added ethynyltrimethylsilane (0.69 mL, 5
rent reaction conditions, the amounts of acetylenes and
copper catalysts were able to be reduced. Furthermore, the
copper-catalyzed deacetylenative cross-coupling reaction
was shown to be applicable to various terminal alkynes
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1686–1690

1690
Y. Kim, H. Nakamura
LETTER
mmol), isobutylaldehyde (0.54 mL, 5 mmol), and
IR (neat): 3309, 2929, 2858, 1467, 1379, 1166, 1093 cm–1.
ESI-HRMS: m/z calcd for C19H38N [M + H]+: 280.3004;
found: 280.3002.
N,N-dihexylamine (1.17 mL, 5 mmol) under nitrogen
atmosphere, and the mixture was stirred for 2 d at r.t. The
mixture was filtered on a Celite bed and concentrated. The
residue was dissolved in THF (10 mL) and TBAF (1 M in
THF, 1.6 mL) was added at 0 °C. The mixture was stirred at
0 °C for 30min, diluted with H2O, and extracted with Et2O.
The organic layer was washed with brine, dried over anhyd
MgSO4, and concentrated. Purification by column
chromatography on silica gel with hexane as eluent gave the
amine 1c (1.15 g, 82% yield) as a colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 3.53 (td, J = 7.6, 2.4 Hz, 1 H), 2.51–
2.44 (m, 2 H), 2.33–2.26 (m, 2 H), 2.15 (d, J = 2.4 Hz, 1 H),
1.88 (nonet, J = 6.8 Hz, 1 H), 1.48–1.23 (m, 18 H), 0.92–
0.86 (m, 12 H). 13C NMR (100 MHz, CDCl3): δ = 83.5, 71.7,
51.7, 51.5, 43.3, 32.0, 28.8, 27.4, 25.0, 22.9, 22.8, 22.6, 14.3.
(14) N,N-Dihexyl-5-methyl-1-phenylhex-1-yn-3-amine (2c,
Table 2, Entry 2)
Yield 101 mg (94%); colorless liquid. 1H NMR (400 MHz,
CDCl3): δ = 7.41–7.37 (m, 2 H), 7.30–7.23 (m, 3 H), 3.74 (t,
J = 7.6 Hz, 1 H), 2.59–2.52 (m, 2 H), 2.44–2.37 (m, 2 H),
1.95 (sept, J = 6.8 Hz, 1 H), 1.57 (t, J = 7.2 Hz, 2 H), 1.52–
1.22 (m, 16 H), 0.96 (t, J = 6.4 Hz, 6 H), 0.90–0.87 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 131.8, 128.3, 127.7, 123.9,
89.5, 84.4, 52.2, 51.8, 43.3, 32.0, 28.7, 27.4, 25.1, 22.8, 22.7,
14.2. IR (neat): 2955, 2928, 2857, 1597, 1488, 1466, 1378,
1366, 1312, 1166, 1092, 1026, 911, 754, 690, 584, 527 cm–1.
ESI-HRMS: m/z calcd for C25H42N [M + H]+: 356.3317;
found: 356.3312.
Synlett 2012, 23, 1686–1690
© Georg Thieme Verlag Stuttgart · New York

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