Microwave-promoted three-component coupling of aldehyde, alkyne, and amine via C-H activation catalyzed by copper in water

Article abstract of DOI:10.1021/ol049936t

(Equation presented) An efficient three-component coupling of aldehyde, alkyne, and amine to generate propargylamines has been effected under microwave irradiation in water using only Cul catalyst without the noble metal cocatalyst. This method has proved to be applicable to a wide range of substrates. In addition, the preliminary experiment using (S)-proline methyl ester as a chiral source demonstrated that it could be developed to be a direct and highly diastereoselective method for construction of chiral propargylamines.

Full text of DOI:10.1021/ol049936t

ORGANIC
LETTERS
2004
Vol. 6, No. 6
1001-1003
Microwave-Promoted Three-Component
Coupling of Aldehyde, Alkyne, and
Amine via C−H Activation Catalyzed by
Copper in Water
Lei Shi, Yong-Qiang Tu,* Min Wang, Fu-Min Zhang, and Chun-An Fan
Department of Chemistry and State Key Laboratory of Applied Organic Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received January 12, 2004
ABSTRACT
An efficient three-component coupling of aldehyde, alkyne, and amine to generate propargylamines has been effected under microwave irradiation
in water using only CuI catalyst without the noble metal cocatalyst. This method has proved to be applicable to a wide range of substrates.
In addition, the preliminary experiment using (S)-proline methyl ester as a chiral source demonstrated that it could be developed to be a direct
and highly diastereoselective method for construction of chiral propargylamines.
Microwave (MW)-promoted reactions, especially those run
in water, have been attracting increasing research interest
from chemists in recent years, not only because these
reactions exhibit some particular or unexpected reactivities
in some cases but also because they are significantly useful
for green chemistry.1 In our corresponding investigations,
we have reported a MW-promoted coupling reaction of two
components (aromatic halide and amine).2 As a continued
interest, we recently have developed another MW-promoted
procedure in a water system of three-component coupling
of aldehyde, alkyne, and amine (A3 coupling).3 We chose
this reaction because it produces important propargylamines,3-5
which are major skeletons6 or synthetically versatile and key
intermediates7 for preparation of many biologically active
nitrogen compounds such as conformationally restricted
peptide isosteres, oxotremorine analogues, and â-lactams.
Although several methods for construction of such units in
water were reported,3 some required expensive Au3c or Ag3d
as catalyst, while some were limited to only one kind of
aldehyde (the aromatic3c or aliphatic3d) or the aromatic
(4) For the preparation of propargylamines in other systems, see: (a)
Enders, D.; Schankat, J. HelV. Chim. Acta 1995, 78, 970. (b) Brasseur, D.;
Marek, I.; Normant, J.-F. Tetrahedron 1996, 52, 7235. (c) Aubrecht, K.
B.; Winemiller, M. D.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 11084.
(d) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319. (e) Akullian, L.
C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4244.
(f) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem. Eur. J.
2003, 9, 2797. (g) Jiang, Biao.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43,
216.
(1) (a) Villemin, D.; Caillot, F. Tetrahedron Lett. 2001, 42, 639. (b)
Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (c)
Organic Synthesis in Water; Grieco, P. A., Ed.; Blacky Academic and
Professional: London, 1998. (d) Li, C.-J. Chem. ReV. 1993, 93, 2023. (e)
Chan, T. H.; Isaac, M. B. Pure. Appl. Chem. 1996, 68, 919. (f) Li, C.-J.
Acc. Chem. Res. 2002, 35, 533.
(2) Shi, L.; Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett.
2003, 5, 3515.
(3) For the preparation of propargylamines in water, see: (a) Li, C.-J.;
Wei, C. M. Chem. Commun. 2002, 268. (b) Wei, C. M.; Li, C.-J. J. Am.
Chem. Soc. 2002, 124, 5638. (c) Wei, C. M.; Li, C.-J. J. Am. Chem. Soc.
2003, 125, 9584. (d) Wei, C. M.; Li, Z. G.; Li, C.-J. Org. Lett. 2003, 5,
4473.
(5) For Cu-mediated addition of terminal acetylenes to N-alkyl imines
at elevated temperatures, see: Rohm and Haas Co. U.S. Patent 2,665,311,
1950.
(6) (a) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G.
D.; Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715. (b) Huffman, M. A.;
Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60,
1590. (c) Boulton, A. A.; Davis, B. A.; Durden, D. A.; Dyck, L. E.; Juorio,
A. V.; Li, X.-M.; Paterson, I. A.; Yu, P. H. Drug DeV. Res. 1997, 42, 150.
(7) (a) Nilsson, B.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med.
Chem. 1992, 35, 285. (b) Hattori, K.; Miyata, M.; Yamamoto, H. J. Am.
Chem. Soc. 1993, 115, 1151. (c) Jenmalm, A.; Berts, W.; Li, Y. L.; Luthman,
K.; Csoregh, I.; Hacksell, U. J. Org. Chem. 1994, 59, 1139. (d) Miura, M.;
Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.
10.1021/ol049936t CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/24/2004

Table 1. Coupling of Aldehyde, Alkyne, and Amine Catalyzed by CuI in Watera
entry
R1
amine (R2, R3)
morpholine
R4
product
time (min)
yield (%)b
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
20
20
20
20
20
20
30
30
5
90
89
88
90
91
90
82
85
41
86
88
90
78
93
91
90
83
75
0c
2-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
2-furyl
1-naphthyl
cyclohexyl
n-C3H7
Ph
morpholine
3
morpholine
4
morpholine
5
morpholine
6
morpholine
7
morpholine
1g
1h
1i
8
morpholine
9
morpholine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
morpholine
1j
20
20
20
20
10
20
20
20
20
10
20
10
10
20
20
20
morpholine
1k
1l
morpholine
morpholine
1m
2a
2b
2c
2d
2e
2f
pyrrolidine
Ph
piperidine
Ph
R2 ) R3 ) Et
R2 ) R3 ) (Me)2CH
R2 ) R3 ) c-C6H11
R2 ) R3 ) Ph
R2 ) Bn, R3 ) Me
R2 ) Ph, R3 ) H
R2 ) (Me)3C, R3 ) H
morpholine
Ph
Ph
Ph
Ph
2g
2h
2i
83
85
76
83
80d
86
Ph
Ph
Ph
n-C5H11
TMS
3a
3b
3c
Ph
morpholine
Ph
morpholine
CH2OTBS
a For a detailed experimental operation, see Supporting Information. All reactions were carried out on a 1 mmol scale with aldehyde/amine/alkyne )
1:1.3:1.6, 15 mol % CuI, and 1.5 mL of water. b Isolated yields based on the aldehyde. c No desired product was obtained. d Under solvent-free conditions.
aldehyde and primary amine in the presence of RuCl3
cocatalyst;8 all of these reactions often proceeded slowly in
water. In comparison to the methods above, our recently
developed method showed particular advantages: (i) it
required only the cheaper CuI as catalyst without Au, Ag,
or other additives; (ii) it was applicable to a broader substrate
scope (both aromatic and aliphatic aldehydes and secondary
amines); and (iii) it proceeded faster and gave good to high
yield, and its experimental process was simple and easy. In
this paper, we present our experimental results.
The MW-promoted A3 coupling experiment was per-
formed (for the general procedure, see Supporting Informa-
tion) by irradiation of the three-component/H2O system in
the presence of 15 mol % CuI (it is necessary to freshly
prepare CuI rather than using commercial CuI) in a sealed
tube to afford the desired propargylamines within 30 min in
good to excellent yields. The results are listed in Table 1. In
each example we isolated mostly the propargylamine prod-
ucts, together with a small amount of oligomerization of the
excessive alkynes in some cases (entries 1-8, 10-18, and
20-22). Additionally, a sealed tube was necessary for this
reaction; otherwise, a low conversion and more byproducts
were obtained.
At the beginning of the search for the aldehyde substrate
scope, morpholine and phenylacetylene were used as model
substrates (entries 1-13), and the results indicated that
aromatic aldehydes bearing such functional groups as fluoro,
chloro, bromo, methyl, or methoxy were able to effect the
A3 coupling. We have also observed delicate electronic
effects:3 that is, aryl aldehydes with electron-withdrawing
groups (entries 2-6) reacted rapidly, while substitution of
electron-rich groups (entries 7 and 8) on the benzene ring
decreased the reactivity, requiring longer reaction times.
Moreover, a very low yield for 4-nitrobenzaldehyde (entry
9), the substrate with a strong electron-withdrawing group,
was observed because of the low conversion. When the
reaction time was prolonged, a complicated mixture (not
identified) was obtained. In addition, the 2-furaldehyde (entry
10) and 1-naphthaldehyde (entry 11) also gave good yields
(86 and 88%, respectively) of products. On the other hand,
the aliphatic aldehydes (entries 12 and 13) still displayed
high reactivity and clean reactions under this standard
condition. While unwanted trimerization of aliphatic alde-
(8) Some cocatalysts such as RuCl3 or activations such as TMSOTf, BF3‚
Et2O have been used; see: (a) Ref 4a. (b) Bloch, R. Chem. ReV. 1998, 98,
1407. (c)Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
1002
Org. Lett., Vol. 6, No. 6, 2004

Table 2. Diastereoselective A3 Coupling Induced with Chiral
Amine Substratea
Scheme 1
amine
(G, R3)
yield
R4 product drb (%)c
entry R1
1
2
3
Ph (S)-proline methyl ester
Ph
4a
4b
4c
95:5
88
Ph G ) (S)-Ph(CH3)CH, R3 ) H Ph
Ph G ) (S)-Ph(CH3)CH, R3 ) Bn Ph
67:33 83
67:33 81
To examine the reaction process of the MW-promoted A3
coupling, further investigations were performed. Without
MW irradiation, the A3 coupling under heating required more
than 5 days. In a stepwise experiment, the two-component
coupling of phenylacetylene and the pre-made imine in the
presence of 15 mol % CuI took one more day under
conventional heating condition. These reactions proceeded
very slowly, and only low conversions and yields were
achieved. These facts indicated that MW irradiation was very
necessary for speeding up both the A3 coupling and the
separate formation of alkynylcopper10 and imine.11 On the
basis of the above experimental results, together with some
literature reports,3 a tentative mechanism was proposed as
shown in Scheme 1. The MW irradiation first promoted CuI-
catalyzed activation of the C-H bond of alkyne to give the
copper acetylide as well as the formation of iminium ion.
Then, the copper acetylide intermediate added to iminium
ion to give the final propargylamine, with the Cu(I) catalyst
being released for further cycle of reactions.
In summary, we have successfully developed a facile,
economic, and green method for construction of propargy-
lamines. In particular, the information that (S)-proline methyl
ester could induce the high diastereoselectivity suggested that
a general and useful method to the optically active propar-
gylamines could be established. Investigations of the scope,
absolute stereochemistry, and synthetic applications of this
chiral reaction are now in progress in our laboratories.
a For a detailed experimental operation, see Supporting Information. All
reactions were carried out on a 1 mmol scale with aldehyde/amine/alkyne
) 1:1.3:1.6, 15 mol % CuI, and 1.5 mL of water. b Diastereomeric ratio
1
(dr) was determined by H NMR; the absolute configuration has been not
determined. c Isolated yields based on the aldehyde.
hydes was a major limitation of the A3 coupling catalyzed
by Au and Cu in water,3 no trimer could be isolated in our
experiments of entries 12 and 13.
To expand the scope of amine substrates, we used
benzaldehyde and phenylacetylene as model substrates and
examined various amines, including primary or secondary
amines (entries 14-22). The coupling (except for entry 19)
proceeded smoothly to afford the corresponding propargy-
lamines in good yields under standard conditions. It was
important to notice that N-substitution on amines could affect
this reaction. Whereas dialkylamines reacted smoothly under
these conditions, the bulky amines (entries 16-19) would
lead to the lower yields of products. Particularly, when the
two substituents were phenyls (entry 19), no expected product
was observed.
Subsequently, a variety of other alkynes were also
examined for the coupling using benzaldehyde and morpho-
line as model substrates (entries 23-25). In these cases, the
reactions proceeded smoothly to give the corresponding
propargylamines in a yield of 80-86%. It is worthwhile
noting that this reaction under solvent-free conditions af-
forded a higher yield than that in water in entry 24, which
may be due to the destabilization of TMS in microwave-
assisted water.
Acknowledgment. We are grateful for the financial
support of the NSFC (No. 29925205, 30271488, 20021001,
and 203900501).
Considering that chiral propargylamines are widely present
in many important bioactive compounds, we subsequently
tried to investigate a novel substrate-controlled asymmetric
MW-promoted A3 coupling in water using the same method
as above. Therefore, three chiral amines sources, (S)-proline
methyl ester, (S)-R-methylbenzylamine, and (S)-N-benzyl-
1-phenylethylamine, were selected for examination using
benzaldehyde and phenylacetylene as model substrates, and
the results are summarized in Table 2. It was interesting to
note that (S)-proline methyl ester exhibited high diastereo-
selectivity (95:5). This preliminary result implied that it was
possible for the highly diastereoselective A3 coupling to be
achieved for additional substrates. It is also useful that the
chiral imines in our experiment were not necessarily pre-
made9 but simply derived in situ from aldehydes and amines.
Supporting Information Available: Experimental details
and data on the A3 coupling reaction. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049936T
(9) For diastereoselective additions to chiral CdN compounds, see: (a)
Chang, Z. Y.; Coates, R. M. J. Org. Chem. 1990, 55, 3464. (b) Chang, Z.
Y.; Coates, R. M. J. Org. Chem. 1990, 55, 3475. (c) Basha, A.; Henry, R.;
McLaughlin, M. A.; Ratajczyk, J. D.; Wittenberger, S. J. J. Org. Chem.
1994, 59, 6103. (d) Ref 8b. (e) Fa¨ssler, R.; Frantz, D. E.; Oetiker, J.; Carreira,
E. M. Angew. Chem., Int. Ed. 2002, 41, 3054. (f) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42,
5763.
(10) Alkynylcopper(I) is known to be stable in water and require a long
time to be prepared; see: Olbrich, F.; Kopf, J.; Weiss, E. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1077.
(11) For MW-promoted synthesis of imines, see: Varma, R. S.; Dahiya,
R.; Kumar, S. Tetrahedron Lett. 1997, 38, 2039.
Org. Lett., Vol. 6, No. 6, 2004
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