Copper(II) triflate-catalyzed three-component coupling of aldehydes, alkynes and carbamates

Article abstract of DOI:10.1002/adsc.201000379

A simple and efficient synthesis of propargylcarbamates was developed through a copper(II) triflate-catalyzed coupling of aldehydes, alkynes and carbamates. No co-catalyst or ligand is required.

Full text of DOI:10.1002/adsc.201000379

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DOI: 10.1002/adsc.201000379
Copper(II) Triflate-Catalyzed Three-Component Coupling of
Aldehydes, Alkynes and Carbamates
Xiao-Yong Dou,a,b Qi Shuai,a Liang-Nian He,b,* and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Fax : (+1)-514-398-3797; e-mail: cj.li@mcgill.ca
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
b
of China
Fax : (+86)-22-2350-4216; e-mail: heln@nankai.edu.cn
Received: May 14, 2010; Revised: August 3, 2010; Published online: September 23, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000379.
Abstract: A simple and efficient synthesis of prop-
argylcarbamates was developed through a cop-
ACHTUNGTRENNUNGper(II) triflate-catalyzed coupling of aldehydes, al-
kynes and carbamates. No co-catalyst or ligand is
required.
Propargylcarbamates are important members of
propargylic amine family,[8] and the synthesis of these
compounds via the A3-coupling reaction has not been
accomplished. In the field of propargylcarbamate syn-
thesis, traditional methods often required demanding
reaction conditions and stepwise operations with poor
functional group compatibility, which limited their ap-
plication in organic synthesis.[9] In order to circumvent
these obstacles, we have developed the first copper-
mediated (and catalyzed) direct nucleophilic addition
of alkynes to reactive N-acylimines and N-acylimini-
um ions (generated in situ from a-amido sulfones or
Keywords: A3-coupling; aldehydes; alkynes; carba-
mates; copper(II) triflate
Propargylic amine is an important structural motif in methoxy groups as stable precursors) to generate
organic synthesis[1] and has been widely used in creat- propargylcarbamates in water.[10] Alternatively, we,
ing biomimetic polymers[2] and producing various bio- Arndtsen, and Carreira reported gold-, copper-, and
logically active compounds (e.g., natural products, ther- zinc-catalyzed couplings of imines, acid chlorides, and
apeutic drug molecules, herbicides, and fungicides).[3]
alkynes to provide rapid accesses to propargylcarba-
One of the most convenient methodologies for the mates and propargylic amides in excellent yields.[11] In
synthesis of these compounds is via the three-compo- addition, we also developed a general method for the
nent couplings of aldehydes, alkynes and amines (A3- site-specific functionalization of free-(NH) peptides
À
coupling) with water as the only theoretical by-prod- and glycine derivatives via C H bond activation,
uct, which has undergone great progress in recent through a copper-catalyzed addition of terminal al-
years. We and others have reported various highly ef- kynes and other nucleophiles to in situ generated acy-
ficient A3-couplings catalyzed by copper, silver, gold liminium intermediates.[12]
and other catalysts to afford various propargyl-
Based on our extensive interest in A3-coupling re-
amines.[4,5] Recently, we and Wangꢀs group also dem- actions, we envisioned that the simplest and most
onstrated that cheap, readily available iron complexes direct protocol for the synthesis of propargylic carba-
can serve as highly active catalysts for this transfor- mates is via the three-component coupling of alde-
mation.[6] By using a chiral copper catalyst, a highly hydes, alkynes, and carbamates (Scheme 1).[13] How-
enantioselective addition of alkynes to imines to ever, to the best of our knowledge, such a coupling re-
afford optically active propargylamines (AA3-cou- action has not been achieved. Herein, we report our
pling) in water or organic media has also been devel-
oped.[7] While a great deal of progress has been made
in the A3-coupling reaction, thus far the A3-coupling
reaction has been limited mostly to secondary and ar-
omatic amines, other aliphatic primary amines and
amine derivatives are challenging substrates that are
often not viable for this transformation.
Scheme 1. Synthesis of propargylcarbamates via the coupling
of aldehydes, alkynes and carbamates.
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Xiao-Yong Dou et al.
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research results on the direct coupling of aldehydes, catalysts under the identical reaction conditions (en-
alkynes, and carbamates which afforded propargylcar- tries 4–7). To our delight, when the CuOTf·toluene
bamates efficiently.
complex and CuACHTNGUTERNNU(G OTf)2 were used as catalysts, desired
Due to the high catalytic activity of copper catalysts product 4a was obtained in high yields (entries 8 and
in the A3-coupling reactions in our previous work, 9, Table 1). This reaction can also be catalyzed by
several copper salts were examined in a model reac- HOTf or CuCl2/HOTf; however, low yields were ob-
tion employing n-butyl carbamate (1a), benzaldehyde tained (entries 10 and 11). Lowering the loading of
(2a), and phenylacetylene (3a) as substrates in our ini- the catalyst decreased the yield (entry 12). The reac-
tial studies, and the results are summarized in Table 1. tion temperature was also found to be important in
The copper salts (10 mol%) CuBr, CuBr2 and CuCl this transformation and a lower yield was obtained
can all catalyze the reaction to give a trace amount of when the reaction was conducted at 708C (entry 13).
the corresponding propargylcarbamate (entries 1–3, Other solvents such as THF, DCE, and CH3CN af-
Table 1). However, no product was detected when forded the coupling products in low yields (en-
employing CuCl2, CuACHTNUGTRNNEUG(OAc)2, CuACHTUNGTREN(NNGU acac)2 and CuI as tries 14–16). No desired product was obtained in
polar solvents (entries 17–20). It is worth mentioning
that a moderate yield of the desired product was ob-
tained under neat conditions (entry 21). The addition
of TMEDA impeded the coupling reaction complete-
ly (entry 22). The use of some nitrogen-based ligands
such as 2,2’-bipyridine and 1,10-phenanthroline de-
creased the yield significantly (entries 23 and 24). Fi-
nally, the optimized reaction conditions were deter-
mined to be 1.0 equivalent of aldehyde, 1.2 equiva-
lents of carbamate, 1.5 equivalents of alkyne and
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuBr
CuBr2
CuCl
CuCl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
DCE
CH3CN
EtOH
DMF
DMSO
H2O
trace
trace
trace
0
0
0
10 mol% of CuACTHNUGTRNEG(UN OTf)2 in toluene at 1008C under N2.
With the optimized reaction conditions in hand, we
began to examine the scope of this coupling reaction
with various aldehydes, alkynes and carbamates
(Table 2). Firstly, we examined the effect of varying
the carbamate component on the reaction. When it
was changed from the n-butyl carbamate to a benzyl
carbamate, the yields of the desired products were
slightly decreased (4a, 4b, 4c, and 4d). Next, we exam-
ined the effect of different aldehydes on this transfor-
mation. Both electron-withdrawing and electron-do-
nating substituted aromatic aldehydes gave similar
yields (4e, 4f, 4g and 4h), while a lower yield was ob-
tained when 4-(trifluoromethyl)benzaldehyde was the
substrate (4i). Aliphatic aldehydes, such as hydrocin-
namaldehyde, hexanal and cyclohexylcarboxaldehyde,
were also investigated under the optimized reaction
conditions. It was found that only cyclohexylcarboxal-
dehyde gave a low yield of the desired product (4k)
and the corresponding propargylcarbamates were not
detected using either hydrocinnamaldehyde or hexa-
nal as a substrate. Finally, the alkyne component of
the three-component coupling reaction was examined,
which showed that electron-poor aromatic alkynes
gave better yields than the electron-rich ones (4l, 4m,
4n, 4o, and 4p). Aliphatic alkynes examined (e.g., 1-
tetradecyne and 1-decyne) gave much lower yields,
possibly due to their decreasing acidity.
Cu
Cu
U
CuI
0
CuOTf·toluene
CuACHTUNGTRENNUNG(OTf)2
HOTf
CuCl2/HOTf
77
87
28
28
61
37
39
44
32
0
0
0
0
53
0
9
10[c]
11[d]
12[e]
13[f]
14
15
16
17
18
19
20
21
22[g]
23[h]
24[i]
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
T
N
ACHTUNGTRENNUNG
C
E
E
E
G
G
neat
toluene
toluene
toluene
18
20
ACHTUNGTRENNUNG
[a]
Benzaldehyde (0.2 mmol), phenylacetylene (0.3 mmol),
carbamate (0.24 mmol), copper catalyst (10 mol%), and
solvent (0.4 mL).
NMR yield using an internal standard.
HOTf (20 mol%).
[b]
[c]
[d]
[e]
[f]
CuCl2 (10 mol%) and HOTf (20 mol%).
Cu
ACHTUNGTRENNUNG(OTf)2 (5 mol%).
A tentative mechanism for the copper-catalyzed al-
Tetramethylethylenediamine (TMEDA, 10 mol%) was dehyde–alkyne–carbamate coupling is proposed in
At 708C.
[g]
added.
Scheme 2. Firstly, Cu(II) coordinates to a terminal
alkyne and generates a terminal copper-acetylide in-
termediate. Meanwhile, the carbamate reacts with an
[h]
[i]
2,2’-BipyridineACHTUNGTRENNUNG(10 mol%) was added.
1,10-PhenanthrolineACTHNUGRTNEUNG(10 mol%) was added.
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Adv. Synth. Catal. 2010, 352, 2437 – 2440

Copper(II) Triflate-Catalyzed Three-Component Coupling of Aldehydes, Alkynes and Carbamates
Table 2. Copper(II) triflate-catalyzed three-component cou-
product and regenerates the Cu(II). Based on the re-
sults obtained, the formation of the imino amide in-
termediate is likely the rate-determining step. Com-
pared to aliphatic aldehydes, aromatic ones favor the
formation of conjugated imino amide intermediates,
which can explain the different reactivities between
aromatic and aliphatic aldehydes.
In conclusion, we have developed a simple, direct,
and effective three-component coupling of aldehydes,
alkynes, and carbamates with copper(II) triflate as
catalyst. The method allows us to prepare a diverse
range of propargylcarbamates in moderate to high
yields. In addition, no other co-catalyst or ligand was
required in this transformation with water as the only
thereotical by-product. Further investigation into the
enantioselective version of this process and its exten-
sion to other amino derivatives are underway.
pling of aldehydes, alkynes, and carbamates.[a]
Entry R1
R2
R3
Prod- Yield
uct
[%][b]
1
2
3
4
5
6
7
8
n-Bu Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
71
70
65
64
68
71
73
67
35
51
8
53
43
62
71
74
45
Et
Me
Bn
Ph
Ph
Ph
n-Bu 4-CH3-C6H4
n-Bu 4-Cl-C6H4
n-Bu 4-Br-C6H4
n-Bu 2-Br-5-F-C6H3 Ph
9
n-Bu 4-CF3-C6H4
n-Bu 1-naphthyl
n-Bu Cy
n-Bu Ph
n-Bu Ph
n-Bu Ph
n-Bu Ph
n-Bu Ph
n-Bu Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
4j
4k
4-CH3-C6H4 4l
4-n-Bu-C6H4 4m
4-t-Bu-C6H4 4n
4-CF3-C6H4
2-F-C6H4
Experimental Section
4o
4p
Typical Procedure for the Coupling of n-Butyl
Carbamate, Benzaldehyde, and Phenylacetylene
4-C6H5-C6H4 4q
[a]
Aldehyde (0.5 mmol), alkyne (0.75 mmol), carbamate
(0.6 mmol), and copper (II) triflate (10 mol%) in toluene
(1.0 mL) under N2.
An oven-dried reaction vessel was charged with n-butyl car-
bamate (70.3 mg, 0.6 mmol), benzaldehyde (51 mL,
0.5 mmol), and toluene (0.3 mL) under N2 (1 atm). The re-
sulting mixture was stirred at room temperature for 20 min.
[b]
Isolated yield based on benzaldehyde.
Then CuACTHNURTGENNG(U OTf)2 (18.1 mg, 0.05 mmol), phenylacetylene
(83 mL, 0.75 mmol) and toluene (0.7 mL) were added to the
reaction vessel, which was then sealed and the resulting so-
lution was stirred at 1008C for 24 h. The resulting mixture
was cooled to room temperature and the residue was puri-
fied by column chromatography (silica gel, hexane/diethyl
aldehyde to generate an imino amide intermediate,
which is protonated by the HOTf generated in situ to
form the acyl immonium intermediate. Then, a nucle-
ophilic addition of the terminal copper-acetylide to
the immonium salt gives the propargylic carbamate ether) to give 4a as a white solid.
Scheme 2. Tentative mechanism.
Adv. Synth. Catal. 2010, 352, 2437 – 2440
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Xiao-Yong Dou et al.
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Adv. Synth. Catal. 2010, 352, 2437 – 2440