Synthesis of propargylamines by a copper-catalyzed tandem anti-Markovnikov hydroamination and alkyne addition

Article abstract of DOI:10.1055/s-0028-1088194

A highly efficient tandem anti-Markovnikov hydroamination and alkyne addition reaction catalyzed by a Cu(I) or Cu(II) catalyst was developed. Various propargylamines were obtained in moderate to good yields. This tandem process provides a novel and simple approach to propargylamine derivatives from alkynes and amines.

Full text of DOI:10.1055/s-0028-1088194

LETTER
937
Synthesis of Propargylamines by a Copper-Catalyzed Tandem
Anti-Markovnikov Hydroamination and Alkyne Addition
S
ynthesis of Pro
e
pargylami
i
a
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax +1(514)3983797; E-mail: cj.li@mcgill.ca
b
College of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. of China
Received 20 November 2008
Cu-catalyzed tandem hydroamination and addition of
simple terminal alkynes to generate propargylamines
without any co-catalyst or additive.
Abstract: A highly efficient tandem anti-Markovnikov hydroami-
nation and alkyne addition reaction catalyzed by a Cu(I) or Cu(II)
catalyst was developed. Various propargylamines were obtained in
moderate to good yields. This tandem process provides a novel and
simple approach to propargylamine derivatives from alkynes and
amines.
At the beginning of this study, we found that the propar-
gylamine product can be formed in 25% yield by using
CuBr as a catalyst at 60 °C for 24 hours (Table 1, entry 1).
Subsequently, it was found that the reaction gives the best
yields at 100 °C (Table 1, entries 1–5). Among the various
copper catalysts examined, CuBr gave the best result (Ta-
Key words: copper, hydroamination, propargylamine, alkynes,
amines
Hydroamination of alkynes is a desirable transformation
leading to C–N bond formation. It offers a direct route to
the synthesis of nitrogen-containing organics such as
enamines or imines which can readily undergo further
transformations to generate valuable nitrogen-containing
compounds.1 The high atom economy makes hydroami-
nation highly attractive, because no intrinsic byproducts
are produced.2
Table 1 Copper-Catalyzed Reaction between Phenylacetylene and
Diallylaminea
catalyst
toluene
N
+
Ph
2
Ph
NHAll2
Catalysts derived from both early and late transition met-
als have been employed to overcome the high activation-
energy barrier for such a process. The ability of copper
complexes to catalyze intramolecular hydroaminations of
alkynes has been known for decades. As early as in the
1960s, Castro et al. described a high-yielding synthesis of
indoles by treating o-iodoanilines with cuprous acetylides
in refluxing pyridine.3 However, compared to intramolec-
ular hydroaminations,4 there are very few examples on the
copper-catalyzed intermolecular hydroamination,1j espe-
cially the anti-Markovnikov addition of secondary amines
to terminal alkynes.5
Ph
Entry
1
Catalyst
CuBr
Temp (°C)
Yield (%)b
60
80
25
55
79
77
0
2
CuBr
3
CuBr
100
120
r.t.
4
CuBr
5
CuBr
6
CuOTf
CuCN
CuI
100
100
100
100
100
100
100
100
100
100
15
33
62
41
70
73
10
0
7
On the other hand, great progress has been made by our
group6 and others7 on the Grignard-type reactions of
alkynes to aldehydes and imines to generate propargyl al-
cohols and propargylamines via catalytic C–H activation
in water (and in organic media). Because of our continued
interest in synthesizing propargylamine via activation of
alkynes, we discovered a new copper-catalyzed amine–
alkyne–alkyne addition via an enamine intermediate.8
However, our early success in such three-component ad-
ditions has been largely limited to the allyl- or benzyl-pro-
tected amine and requires alkyne-bearing electron-
withdrawing groups. Herein, we wish to report a novel
8
9
CuCl
10
11
12
13
14
15
CuBr2
CuCl2
AuI
AuCl3
AgCl
0
AgBF4/HBF4
trace
a Reaction conditions: diallylamine (0.5 mmol), phenylacetylene (2
mmol), catalyst (5 mol%), toluene (2 mL), N2 atmosphere, 24 h.
b Measured by 1H NMR.
SYNLETT 2009, No. 6, pp 0937–0940
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088194; Art ID: U12208ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

938
L. Zhou et al.
LETTER
Table 2 Copper-Catalyzed Tandem Hydroamination and Addition
ble 1, entries 3–11). CuCl2 and CuBr2 are also effective,
albeit generating the product with a slightly decreased
yield (Table 1, entries 10 and 11). Other catalysts such as
AuI, AuCl3, AgCl, and AgBF4/HBF4 were found to be es-
sentially ineffective in this reaction (Table 1, entries 12–
15). Different solvents were also tested, and the best result
was obtained by using toluene as the solvent.
of Alkynesa (continued)
R1
CuBr (5 mol%)
R1
+
NHR2R3
R1
toluene, 100 °C
NR2R3
1
2
3
Entry Alkyne
Amine
Product Yield (%)b
Having optimized the reaction conditions, we explored
the scope of the reaction and the results are summarized in
Table 2. Treatment of diallylamine with different terminal
alkynes 1a–h furnished the corresponding propargyl-
amines 3a–h in moderate to good yields (Table 2, entries
1–8). The reaction can tolerate a halogen group in sub-
strate 1e (Table 2, entry 5). Substrate 1f, bearing two tri-
fluoromethyl groups, also reacted with diallylamine 1a
smoothly at 100 °C to give the product in 84% yield
(Table 2, entry 6). In the reaction of diallylamine and 1,4-
diethynylbenzene, a monoaddition adduct was obtained as
the sole product (Table 2, entry 7) in 55% yield.
F3C
6
2a
2a
3f
84
55
F3C
1f
7
3g
1g
Aliphatic alkyne appeared less reactive. Treatment of 1-
octyne with diallyamine afforded the desired product in
40% yield (Table 2, entry 9). Subsequently, several sec-
ondary amines 2b–e were evaluated, and all were suitable
substrates for the reaction with terminal alkynes under the
standard conditions (entries 10–16). 4-Phenylpiperidine
(2d), for example, reacted with phenylacetylene and 4-
ethynyltoluene to afford the corresponding products 3l
and 3p in 75% and 77% yields, respectively (Table 2, en-
tries 12 and 16). The molecular structure of 3o was further
confirmed by its X-ray crystal diffraction (Figure 1).
8
2a
3h
55
MeO
1h
H13C6
9
2a
3i
3j
40
68
1i
NH
10
11
12
13
1a
1a
1a
1a
2b
NH
2c
3k
3l
49
75
52
Table 2 Copper-Catalyzed Tandem Hydroamination and Addition
of Alkynesa
R1
Ph
NH
CuBr (5 mol%)
R1
+
NHR2R3
R1
toluene, 100 °C
NR2R3
2d
1
2
3
O
NH
Product Yield (%)b
3m
Entry Alkyne
Amine
2e
2b
Ph
1
All2NH 2a
3a
3b
74
81
14
15
16
1b
1d
1b
3n
3o
3p
73
69
77
1a
2b
2d
2
2a
2a
1b
a Reaction conditions: amine (0.5 mmol), terminal alkyne (2 mmol),
CuBr (5 mol%), toluene (2 mL), N2 atmosphere, 24 h.
b Isolated yield.
3
3c
58
OMe
1c
To understand the mechanism of the reaction, we per-
formed two ‘control experiments’. No enyne product was
observed after phenylacetylene and CuBr were stirred at
100 °C in toluene for 24 hours under nitrogen, and 80% of
phenylacetylene remained unreacted. However, the reac-
tion of phenylacetaldehyde, piperidine, and phenylacetyl-
ene gave the compound 3j in 27% yield after stirring at
100 °C in toluene for 24 hours (Scheme 1). This result
suggests that the first step of this reaction is the hydroami-
nation of alkynes followed by the addition of alkyne to the
Ph
4
5
2a
2a
3d
3e
68
72
1d
Br
1e
Synlett 2009, No. 6, 937–940 © Thieme Stuttgart · New York

LETTER
Synthesis of Propargylamines
939
In conclusion, we have developed a highly efficient tan-
dem hydroamination and addition of terminal alkynes cat-
alyzed by Cu catalysts. This tandem process provides a
novel and simple approach to propargylamine derivatives
from alkynes and amines. The detailed mechanism, the
reason for the regioselelctive anti-Markovnikov addition
of amines to alkynes, and the scope of the reaction are cur-
rently under investigation.
Acknowledgment
We are grateful to the Canada Research Chair (Tier I) foundation (to
D.S.B. and C.J.L.), the CFI, NSERC, and McGill ACS-GCI Phar-
maceutical Roundtable for support of our research. L.Z. thanks the
China Scholarship Council for a Visiting Scholarship.
References and Notes
Figure 1 X-ray crystal diffraction of 3o as a racemic mixture of R,S-
isomers
(1) For recent reviews on catalytic hydroamination, see:
(a) Odom, A. L. Dalton Trans. 2005, 225. (b) Hultzsch,
K. C. Adv. Synth. Catal. 2005, 347, 367. (c) Hong, S.;
Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (d) Doye, S.
Synlett 2004, 1653. (e) Roesky, P. W.; Müller, T. E. Angew.
Chem. Int. Ed. 2003, 42, 2708. (f) Bytschkov, I.; Doye, S.
Eur. J. Org. Chem. 2003, 935. (g) Pohlki, F.; Doye, S.
Chem. Soc. Rev. 2003, 32, 104. (h) Alonso, F.; Beletskaya,
I. P.; Yus, M. Chem. Rev. 2004, 104, 3079. (i) Severin, R.;
Doye, S. Chem. Soc. Rev. 2007, 36, 1407. (j) Müller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev.
2008, 108, 3795.
Ph
CuBr (5 mol%), Et3N
toluene, 100 °C
Ph
Ph
80% (1H NMR) of phenylacetylene remained
CuBr (30 mol%)
CHO
3j
+
+
Ph
toluene, 100 °C
27% (1H NMR)
N
H
(2) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(b) Trost, B. M. Science 1991, 254, 1471.
Scheme 1 Copper(I)-catalyzed alkyne dimerization and aldehyde–
amine–alkyne coupling
(3) (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28,
2163. (b) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963,
28, 3313.
enamine intermediate, rather than the addition of amine to
enyne9 after the dimerization of alkynes.10 Therefore, a
tentative mechanism for this reaction is proposed in
Scheme 2. Terminal alkyne 1 is activated by CuBr to gen-
erate intermediate A. Intermediate A further reacts with a
secondary amine to give the hydroamination product B,
which is protonated to give an iminium intermediate
C.6d,7e,h,11 Subsequently, an intramolecular transfer of the
alkyne moiety to the iminium ion produces propargyl-
amine 3 and regenerates the copper catalyst. Alternative-
ly, the hydroamination may proceed through an acetylide
intermediate.
(4) (a) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B.
Tetrahedron Lett. 1998, 39, 5159. (b) Müller, T. E.;
Grosche, M.; Herdtweck, E.; Pleier, A. K.; Walter, E.; Yan,
Y. K. Organometallics 2000, 19, 170. (c) Peng, C.; Cheng,
J.; Wang, J. Adv. Synth. Catal. 2008, 350, 2359. (d) Müller,
T. E.; Pleier, A.-K. J. Chem. Soc., Dalton Trans. 1999, 583.
(e) Kamijo, S.; Jin, T.; Yamamoto, Y. Angew. Chem. Int. Ed.
2002, 41, 1780. (f) Xu, L.; Lewis, I. R.; Davidsen, S. K.;
Summers, J. B. Tetrahedron Lett. 1998, 39, 5159.
(5) (a) Fukumoto, Y.; Asai, H.; Shimizu, M.; Chatani, N. J. Am.
Chem. Soc. 2007, 129, 13792. (b) Tzalis, D.; Koradin, C.;
Knochel, P. Tetrahedron Lett. 1999, 40, 6193. (c) Park,
R2
R3
+
N
R1
R1
R2
R3
[CuX]
••
N
[CuX]
H
R1
HX
A
2
C
R2
R3
+
N
[Cu]
R1
R1
D
R1
R1
NR2R3
HX
[CuX]
[CuX]
H+
R1
R1
1
3
B
NR2R3
Scheme 2 Tentative mechanism for the copper-catalyzed hydroamination and addition of alkynes
Synlett 2009, No. 6, 937–940 © Thieme Stuttgart · New York

940
L. Zhou et al.
LETTER
(10) For recent examples, see: (a) Katagiri, T.; Tsurugi, H.;
Y. J.; Kwon, B.-I.; Ahn, J.-A.; Jun, C.-H. J. Am. Chem. Soc.
2004, 126, 13892.
Satoh, T.; Miura, M. Chem. Commun. 2008, 3405.
(b) Nishimura, T.; Guo, X.-X.; Ohnishi, K.; Hayashi, T. Adv.
Synth. Catal. 2007, 349, 2669. (c) Tsukada, N.; Ninomiya,
S.; Aoyama, Y.; Inoue, Y. Org. Lett. 2007, 9, 2919.
(d) Weng, W.; Guo, C.; Celenligil-Cetin, R.; Foxman, B. M.;
Ozerov, O. V. Chem. Commun. 2006, 197. (e) Munro-
Leighton, C.; Delp, S. A.; Alsop, N. M.; Blue, E. D.;
Gunnoe, T. B. Chem. Commun. 2008, 111.
(6) (a) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395. (b) Wei, C.;
Mague, J. T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5749. (c) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003,
125, 9584. (d) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5,
4473. (e) Wei, C.; Li, C.-J. Green Chem. 2002, 4, 39.
(f) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638.
(g) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268.
(h) Zhang, J.; Wei, C.; Li, C.-J. Tetrahedron Lett. 2002, 43,
5731. (i) Huang, B.; Yao, X.; Li, C.-J. Adv. Synth. Catal.
2006, 348, 1528. (j) Yao, X.; Li, C.-J. Org. Lett. 2006, 8,
1953. (k) Deng, G.; Li, C.-J. Synlett 2008, 10, 1571.
(l) Viswanathan, G.; Li, C.-J. Tetrahedron Lett. 2002, 43,
1613.
(7) For recent examples, see: (a) Asano, Y.; Hara, K.; Ito, H.;
Sawamura, M. Org. Lett. 2007, 9, 3901. (b) Colombo, F.;
Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano, G. J. Org.
Chem. 2006, 71, 2064. (c) Arimitsu, S.; Hammond, G. B.
J. Org. Chem. 2006, 71, 8665. (d) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed.
2003, 42, 5763. (e) Koradin, C.; Gommermann, N.; Polborn,
K.; Knochel, P. Chem. Eur. J. 2003, 9, 2797. (f) Lu, G.; Li,
X.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172.
(g) Chen, Z. L.; Xiong, W. N.; Jiang, B. Chem. Commun.
2002, 2098. (h) Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem. Int. Ed. 2002, 41, 2535. (i) Carreira, E. M.
Acc. Chem. Res. 2000, 33, 373; and references therein.
(8) (a) Zhou, L.; Jiang, H.-F.; Li, C.-J. Adv. Synth. Catal. 2008,
350, 2226. For our works on silver- and gold-catalyzed
hydroamination of alkynes, see: (b) Luo, Y.; Li, Z.; Li, C.-J.
Org. Lett. 2005, 7, 2675. (c) Zhang, Y.; Donahue, J. P.; Li,
C.-J. Org. Lett. 2007, 9, 627.
(11) (a) Zani, L.; Eichhorn, T.; Bolm, C. Chem. Eur. J. 2007, 13,
2587. (b) Aschwanden, P.; Stephenson, C. R. J.; Carreira,
E. M. Org. Lett. 2006, 8, 2437.
(12) Representative Experimental Procedure
Copper(I) bromide (3.6 mg, 0.025 mmol, 5 mol%) was
suspended in toluene (2 mL) in a 10 mL Schlenk tube under
nitrogen. Then, diallylamine (49 mg, 0.5 mmol) and
phenylacetylene (204 mg, 2 mmol) were added. The
resulting solution was stirred at 100 °C for 24 h. After
cooling to r.t., the resulting mixture was filtered through a
short path of SiO2 in a pipette eluting with EtOAc. The
volatiles were removed in vacuo, and the residue was
purified by column chromatography (SiO2, hexane–EtOAc,
10:1) to give 3a (111.3 mg, 74%) as a pale yellow oil. 1H
NMR (400 MHz, CDCl3): d = 7.42–7.39 (m, 2 H), 7.31–7.23
(m, 8 H), 5.88–5.79 (m, 2 H), 5.23 (d, J = 17.2 Hz, 2 H), 5.13
(d, J = 10.0 Hz, 2 H), 3.97 (t, J = 7.6 Hz, 1 H), 3.41(dt,
J = 14.0, 2.4 Hz, 2 H), 3.11–2.97 (m, 4 H). 13C NMR (75
MHz, CDCl3): d = 139.0, 136.6, 131.8, 129.7, 128.4, 128.3,
128.1, 126.5, 123.6, 117.5, 87.7, 86.2, 55.4, 54.3, 40.6. MS
(70 eV): m/z (%) = 301 [M+], 274, 242, 215, 210(100), 191,
168, 154, 128, 115, 91. HRMS (EI): m/z calcd for C22H23N
[M+]: 301.1831; found: 301.1814.
The experiments in Table 2 were carried out analogously.
All products were purified by column chromatography and
characterized by NMR spectroscopy and standard/high-
resolution mass spectrometry.
(9) For references on copper-catalyzed intermolecular
hydroamination of olefins, see: (a) Munro-Leighton, C.;
Blue, E. D.; Gunnoe, T. B. J. Am. Chem. Soc. 2006, 128,
1446. (b) Taylor, J.; Whittall, N.; Hii, K.-K. Org. Lett. 2006,
8, 3561.
Synlett 2009, No. 6, 937–940 © Thieme Stuttgart · New York