Gold(I)-catalyzed arylmethylation of terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2009.03.067

AuCl/AgOTf catalyzes the reaction of terminal alkynes with aryl trichloroacetimidate to afford arylmethylation products in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2009.03.067

Tetrahedron Letters 50 (2009) 2533–2535
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold(I)-catalyzed arylmethylation of terminal alkynes
*
Changkun Li, Weibin Li, Jianbo Wang
Beijing National Laboratory of Molecular Sciences (BNLMS), and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
a r t i c l e i n f o
a b s t r a c t
Article history:
AuCl/AgOTf catalyzes the reaction of terminal alkynes with aryl trichloroacetimidate to afford arylmethy-
lation products in moderate to good yields.
Received 31 January 2009
Revised 6 March 2009
Accepted 10 March 2009
Available online 16 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Au-catalyzed reaction
Terminal alkyne
Arylmethylation
Nucleophilic substitution
Gold-catalyzed reactions have attracted considerable attention
in recent years.1 The research activities in this field so far have
been mostly concentrated on the reaction of gold-activated alkynes
functioning as electron-deficient species to accept nucleophilic at-
tack (Fig. 1. path a). The alternative process, namely the gold-al-
kyne species functioning as nucleophile (path b), is much less
developed except simple protonation or elimination.
Recently, gold-catalyzed C–C bond formation via the reaction of
terminal alkyne C–H bonds has appeared in the literature and
opened up new possibilities.2 Li and co-workers have reported a
gold-catalyzed three-component reaction of aldehyde, alkyne,
and amine.3 In this reaction a gold acetylide species is proposed
as the reactive intermediate, which adds to C@N bond of iminium
ion. More recently, they further reported a Au-catalyzed cascade
addition/cyclization of terminal alkynes with ortho-alkynylaryl
aldehyde, in which gold (I)-acetylide addition to C@O bond is sug-
gested as the C–C bond forming step in the reaction mechanism.4
On the other hand, Wang and Zhang have reported a Au(III)-cata-
lyzed acyl migration of propargylic esters in which the intramolec-
ular attack of nucleophilic Au(III)–C(sp2) to C@O bond is supposed
as the key step in the reaction mechanism.5 These results indicate
that the nucleophilicity of Au–C bond can be exploited in the for-
mation of C–C bond.
[Au]
[
]
Au
Nu
Nu
Base
b
R
R
Au
a
R
Figure 1. Gold-catalyzed reaction of alkyne.
been rare.6 As far as our knowledge is concerned, the nucleophilic
substitution of Au-acetylide in catalytic process has not been doc-
umented in the literature.
To achieve this goal, an electrophilic reaction partner containing
a suitable leaving group is pivotal. After some initial examination
of the electrophiles, it turned out that trichloroacetimidoxyl group
was an excellent leaving group for this purpose.7 Herein we report
the AuOTf-catalyzed reaction of terminal alkyne with benzylic tri-
chloroacetimidate. The reaction, in which the nucleophilic substi-
tution of protonated trichloroacetimidoxyl group by gold-
acetylide species is supposed to be the key step, gave arylmethyla-
tion products in moderate to good yields (Scheme 1).
At the outset, the reaction of benzyl trichloroacetimidate 1a and
phenylacetylene 2a with 5 mol % AuCl and AgOTf as catalysts at
room temperature in DCE was examined (Table 1). After 48 h,
1,3-diphenylpropyne 3a was isolated in low yield (entry 1), and
Besides nucleophilic addition to C@N or C@O bonds, SN2-type
substitution can be reasonably considered as another possibility
for the reaction of the intermediate containing nucleophilic Au–C
bond. However, gold-catalyzed reaction based on this process has
NH
CCl3
O
cat.
Ph
+
+
Ph
Ph
O
Cl3C
NH2
Ph
3a
1a
4
2a
* Corresponding author.
E-mail address: wangjb@pku.edu.cn (J. Wang).
Scheme 1. Catalytic reaction of terminal alkyne with benzylic trichloroacetimidate.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.067

2534
C. Li et al. / Tetrahedron Letters 50 (2009) 2533–2535
Table 1
Table 2
Reaction of 1a with 2a under various catalytic conditions
Gold(I)-catalyzed arylmethylation of terminal alkynes
5 mol% AuCl
5 mol% AgOTf
R1
Entry
Cat. (5 mol %)
Solvent
T (°C)
t (h)
Yielda (%)
R1 NH
+
R2
2a-c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
AuCl + AgOTf
AuCl + AgOTf
AuCl + AgOTf + Et3N
Ph3PAuCl + AgOTf
AuCl
AgOTf
AgBF4
AuCl3
CuI
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Dioxane
CHCl3
MeCN
C6H6
DCE
25
80
80
80
80
80
80
25
80
80
80
100
61
25
80
80
48
3
5
5
5
12
5
5
5
5
5
5
5
5
0.5
5
13
Ar
65
ClCH2CH2Cl
reflux
Ar
O
CCl3
R2
N.R.b
53
1a-n
3a-p
Yielda (%)
N.R.b
Trace
15
Entry
Trichloroacetimidate (1, Ar, R1)
Alkyne (2, R2)
t (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1a, C6H5, H
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2b, p-BrC6H4
2c, n-C4H9
2a, C6H5
2a, C6H5
3
4
4
3.5
10
10
4
4
4
3
4
5
3
4
4
4
5
5
65
54
62
63
79
85
55
69
63
84
66
48
66
55
57
30
0b
1b, o-ClC6H4, H
1c, o-BrC6H4, H
1d, o-IC6H4, H
1e, m-ClC6H4, H
1f, m-BrC6H4, H
1g, p-FC6H4, H
1h, p-ClC6H4, H
1i, p-BrC6H4, H
1j, m-Me-p-BrC6H3, H
1k, o-MeC6H4, H
1l, p-PhC6H4, H
1m, p-tBuC6H4, H
1n, C6H5, C6H5
1a, C6H5, H
c
—
N.R.
Trace
Trace
15
PtCl2
Pd(PPh3)4 + CuI
AuCl + AgOTf
AuCl + AgOTf
AuCl + AgOTf
AuCl + AgOTf
TfOH
32
Trace
60d
17
a
Isolated yields.
No reaction.
Reaction gave complex mixture.
b
c
d
Diphenylmethane was the isolated product.
1a, C6H5, H
1o, p-NO2C6H4, H
1p, 6-MePy, H
0
a
most of 1a was recovered. Trichloroacetamide 4 was also identified
in GC–MS. When the reaction was conducted in refluxing DCE, 1a
was all consumed to afford 3a in moderate yield (entry 2). When
triethylamine was added in the reaction as base, no reaction oc-
curred (entry 3). Replacing the AuCl with AuPPh3Cl gave similar re-
sult (entry 4), but no reaction was observed when AuCl alone was
used as the catalyst in the absence of AgOTf (entry 5). With Ag(I)
salt as the only catalyst, trace amount or low yield of 3a could be
obtained (entries 6 and 7). Reaction with AuCl3 alone resulted in
a complex mixture (entry 8). Some other catalysts were also exam-
ined. CuI and PtCl2 were found to be not effective in the reaction
(entries 9 and 10), neither did the Sonogashira coupling catalyst
system[Pd(PPh3)4+CuI] (entry 11).
With AuCl/AgOTf catalytic system, the solvent effects were
examined and DCE was found to be the most suitable solvent (en-
tries 12–14). It was interesting to note that when the reaction was
carried out in benzene, the expected 3a was not formed, instead,
diphenylmethane was isolated in 60% yield (entry 15). The forma-
tion of diphenylmethane is likely due to Friedel–Crafts reaction of
Au(I)-activated 1a and benzene. It was worth noting that in all
experiments described above the formation of metallic gold or sil-
ver was not observed and the reaction remained homogenous. Fi-
nally, it was also noted that protic acid TfOH could catalyze the
same reaction, but affording 3a in much lower yield (entry 16).
Under the optimized condition, the scope of the reaction was
examined with a variety of substrates (Table 2).8 The trichloroace-
timidate substrates 1b–n with alkyl and halide substitution in the
phenyl ring could all react smoothly to give moderate yields, as
shown in Table 2. Under the same condition, 1,3,3-triphenyl-1-pro-
pyne9 could be prepared by using diphenylmethanol-derived
trichloroacetimidate 1n (entry 14). However, the trichloroacetimi-
date substrates with p-nitrophenyl and pyridine substituents failed
to react under the same condition (entries 17 and 18). The scope of
alkyne substrate was also examined. Substitution on the phenyl
ring of phenylacetylene seems to not effect the reaction (entry
15). Aliphatic alkynes could react similarly, but the yield was low
(entry 16).
Isolated yields after column chromatography.
Starting materials were recovered.
b
bility is limited. The gold-catalyzed arylmethylation reaction of
terminal alkynes described above is under mild and almost neutral
conditions.
A mechanistic proposal for this reaction is shown in Scheme 2.
The coordination of the gold catalyst with alkynes raises the acid-
ity of the terminal proton of A. The basicity of the nitrogen in the
benzyl trichloroacetimidate is strong enough to remove the termi-
nal proton from Au-activated alkyne A, presumably with the for-
mation of gold acetylide intermediate B.2,3 On the other hand,
the trichloroacetimidoxyl group of 1a turns to be a better leaving
group after being protonated.12 The nucleophilic gold acetylide at-
tacks the benzyl position to form a new carbon–carbon bond. Tri-
chloroacetamide is released as a leaving group, which is neutral
and does not interfere with the activity of gold catalyst. In this
mechanism, the trichloroacetimidoxyl group in the substrate plays
two pivotal roles: the nitrogen atom can function as a base to gen-
erate gold acetylide through deprotonation of gold-activated ter-
minal alkyne, the protonated trichloroacetimidoxyl group then
becomes a very good leaving group, which accepts the attack of
gold acetylide.
The key issue of the reaction mechanism of this investigation
is the generation of Au-acetylide as reactive intermediate. If Au-
H
AuOTf
2a
3a
+
O
H
AuOTf
A
CCl3CNH2
4
Au
B
Benzylacetylene and its derivatives are versatile synthetic inter-
mediates, and they are usually prepared by nucleophilic attack of
phenylacetylenyl anion to benzyl halide or p-toluenesulfonate,10
or by transition metal-catalyzed cross-coupling reactions with
organometallic reagents.11 These reactions are generally conducted
in strong basic conditions and thus the functional group compati-
NH
NH2
CCl3
O
CCl3
O
1a
C
Scheme 2. A plausible mechanism.

C. Li et al. / Tetrahedron Letters 50 (2009) 2533–2535
2535
Ph
D (98 atom % D)
(1.2 eq)
Supplementary data
O
CCl3
+
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.067.
Ph
+
NH
(1.0 eq)
p-Br-
C6H4
H
5
(1.2 eq)
References and notes
AuClPPh3 (5 mol%)
AgOTf (5 mol% )
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346; (d) Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449;
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3350; (i) Gorin, D. J.; Sherry, B. B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351–
3378.
p-Br-C6H4
H(D)
DCE, reflux, 24 h
Observed: 27% D
Scheme 3. Deuterium exchange experiment.
2. Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917–4938.
3. (a) Wei, L.; Li, C. J. J. Am. Chem. Soc. 2003, 125, 9584–9585; (b) Luo, Y.; Li, C.-J.
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acetylide is indeed involved, there will be exchange of protons
from different terminal alkynes. Previous study indicated that
b-phenylethyl trichloroacetimidate 5 did not react with terminal
alkynes under the identical reaction conditions. Thus, 5 was uti-
lized as a base in a H/D exchange experiment as shown in Scheme
3. If Au-acetylides are generated, the theoretical ratio of deute-
rium to hydrogen in p-bromophenylacetylene will be around
33.33% when complete equilibrium is reached. The observed deu-
terium content of the recovered p-bromophenylacetylene is
around 27%. For comparison, the H/D exchange experiment was
also carried out with TfOH as catalyst under otherwise identical
conditions. In such case, no H/D exchange was observed. The re-
sults of the H/D exchange experiment are consistent with pro-
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as reactive intermediate.13
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7. For recent reports on gold-catalyzed intramolecular reaction of alkyne with
trichloroacetimidate, see: (a) Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus,
J.; Frey, W. Eur. J. Org. Chem. 2006, 4905–4909; (b) Kang, J.; Kim, H.; Lee, J.; Shin,
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8. Typical procedure for the Au(I)-catalyzed arylmethylation of terminal alkynes. To
3 mL of 1,2-dichloroethane (DCE) were added AuCl (4.6 mg, 0.05 equiv) and
AgOTf (5.0 mg, 0.05 equiv). The solution was stirred for 5 min at room
temperature. Phenylacetylene (48 mg, 1.2 equiv) and benzyl trichloroacetimidate
(100 mg, 1.0 equiv) were added to the stirred solution of catalyst and then the
reaction mixture was heated to reflux. The reaction was monitored by TLC and FT–
IR. When the peak at 1665 cmÀ1 was converted to 1695 cmÀ1 completely, the
solvent was removed in vacuo and the crude product was purified by column
chromatography on silica gel with petroleum to give 1,3-diphenylprop-1-yne 3a
(49 mg, 65% yield) as a light yellow oil.
In conclusion, arylmethylation of terminal alkynes has been
realized by the catalysis of Au(I) complex. The process is simple
and mild and generates benzylacetylene and its derivatives in
good yields. Moreover, the study demonstrates the possibility of
Au–C bonds being exploited as nucleophiles in substitution
reactions.
9. Kabalka, G. W.; Yao, M.; Borella, S. Org. Lett. 2006, 8, 879–881. and references
cited therein.
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(e) Qian, M.; Negishi, E. Tetrahedron. Lett. 2005, 46, 2927–2930.
12. For a recent example of substitution reaction with trichloroacetimidates, see:
Li, C.; Wang, J. J. Org. Chem. 2007, 72, 7431–7434.
Acknowledgments
The project is generously supported by NSFC (Grant Nos.
20832002, 20772003, and 20821062), the Ministry of Education
of China, and National Basic Research Program of China (973 Pro-
gram, No. 2009CB825300).
13. In stoichiometric reaction, Au-acetylide has been prepared. See: Vicente, J.;
Chicote, M.-T.; Abrisqueta, M.-D. J. Chem. Soc., Dalton Trans. 1995, 497–498.