Gold-catalyzed intermolecular carboalkoxylation of alkenes

Article abstract of DOI:10.1055/s-0032-1317492

A gold-catalyzed intermolecular carboalkoxylation of alkenes has been developed. Readily available and inexpensive dimethyl acetals have been employed as a facile reagent to achieve the carboalkoxylation of alkenes. Copyright

Full text of DOI:10.1055/s-0032-1317492

LETTER
▌2799
letter
Gold-Catalyzed Intermolecular Carboalkoxylation of Alkenes
Gold-Catalyzed Carboalkoxylation
Wenmin Dong,a Moran Zhang,a Fenfen Xiao,a Yunxia Wang,a Wu Liu,a Xiangdong Hu,*a,b Qiang Yuan,a
Shaofei Zhanga
a
Department of Chemistry & Material Science, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of
Education of China, Northwest University, Xi′an 710069, P. R. of China
Fax +86(29)88305919; E-mail: xiangdonghu@nwu.edu.cn
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Received: 29.08.2012; Accepted after revision: 26.09.2012
catalysis and has significantly enhanced the degree of
complexity of molecules that gold-catalyzed transforma-
tions can reach. However, stoichiometric or superstoi-
chiometric amounts of oxidants are always required in
these processes. Herein, we present a new gold-catalyzed
approach for the intermolecular carboalkoxylation of al-
kenes by employing readily available and inexpensive
dimethyl acetal derivatives without the need for oxidants.
Abstract: A gold-catalyzed intermolecular carboalkoxylation of
alkenes has been developed. Readily available and inexpensive
dimethyl acetals have been employed as a facile reagent to achieve
the carboalkoxylation of alkenes.
Key words: gold catalysis, carboalkoxylation, alkenes, acetal,
1,3-dimethoxyl compounds
Recently, we disclosed a gold-catalyzed intermolecular
methoxyl transfer process between alkynes and dimethyl
acetals, which is an interesting alternative to the direct
aldol reaction, and is applicable to acetals but not alde-
hydes (Scheme 1, Equation 1).8 Inspired by the study, we
anticipated that this intermolecular methoxyl transfer pro-
cess could also take place between alkenes and dimethyl
acetals. The generated gold intermediate A would attack
cationic intermediate B and furnished the 1,3-dimethoxyl
products (Scheme 1, Equation 2). The resulting transfor-
mation would constitute an important pathway to intermo-
lecular carboalkoxylation of alkenes.
Difunctionalization of alkenes, representing an intriguing
strategy to access a large number of versatile organic
building blocks, has attracted significant attention from
organic chemists. From the detailed investigation on
osmium-mediated
dihydroxylation
and
amino-
hydroxylation1 to metal-catalyzed diamination2 and vari-
ous oxidative difunctionalization of alkenes reported in
the past years,3 this important and challenging area of re-
search in organic synthesis has seen significant achieve-
ments.
In the last decade, electrophilic gold complexes were
shown to be superior activators for carbon–carbon multi-
ple bonds. So far, numerous gold-catalyzed trans-
formations4 had been developed. For instance, attack on
alkenes by various nucleophiles under the activation of
gold complexes, albeit with lower reactivity compared to
alkynes, has been reported.5 Recently, the advent of gold-
catalyzed cross-coupling reactions under the assistance of
oxidants6 has highlighted a new avenue for the difunction-
alization of alkenes.7 Clearly, this is an extremely valu-
able breakthrough in the field of homogeneous gold
In the beginning of our work, to verify our expectation,
the combination of benzaldehyde dimethyl acetal and
styrene was examined with different cationic gold
complexes (Table 1).9 Pleasingly, by employing
[PicAuCl2]/2AgNTf2 in toluene at 50 °C, the product 3a10
was afforded in 85% yield with a diastereoselective ratio
of 1.17:1 (entry 4); no reaction took place when the reac-
tion was run at room temperature (entry 5). Other gold
systems, such as AuCl3, [(Cy)2(o-biphenyl)PAuCl]/
Me
+O
Me
R2
R1
Me Me
O
R1
Me Me
Me
R2
O
O
Au
– Au
O
O
O
O
R1
(1)
(2)
Au
+
R1
R2
R2
Au
O
our previous work
Me
Au
Me
R2
Me Me
Me Me
R1
O
R1
Au
Me
Me
O
O
–
Au
Au
O
O
O
O
R1
+
R1
R2
R2
R2
proposal of this work
A
B
Scheme 1
SYNLETT 2012, 23, 2799–2802
Advanced online publication: 09.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317492; Art ID: ST-2012-W0725-L
© Georg Thieme Verlag Stuttgart · New York

2800
W. Dong et al.
LETTER
Table 1 Optimization of Gold-Catalyzed Intermolecular Carboalkoxylation of Alkenesa
Me
O
Me
Me
Ph
O
O
O
+
Ph
1a
Me
Ph
Ph
2a
3a
Entry
Catalyst
AuCl3
Temp (°C)
Time (h)
Yield (%)b
anti/cisc
1
2
3
4
5
6
7
8
9
80
50
8
3
3
3
3
5
5
5
9
39
35
18
85
0
1.1:1
[(Cy)2(o-biphenyl)PAuCl]/AgNTf2
[IMesAuCl]/AgNTf2
[PicAuCl2]/2AgNTf2
[PicAuCl2]/2AgNTf2
[Ph3PAuNTf2]
1.41:1
50
1.37:1
50
1.17:1
r.t.
80
–
–
–
–
–
0
[PicAuCl2]
50
0
d
AgNTf2
50
0
PtCl2
110
0
a Reaction conditions: styrene (1.0 mmol), benzaldehyde dimethyl acetal (1.5 mmol), catalyst (0.05 mmol), solvent (4 mL).
b Estimated on the basis of 1H NMR spectroscopic analysis using dioxane as internal reference.
c Diastereomeric ratio of product 3a.
d 0.1 mmol.
AgNTf2, and [IMesAuCl]/AgNTf2 were also suitable, but With the optimized conditions in hand, various dimethyl
the yields were inferior (entries 1–3). The widely applied acetals were then examined; it was established that heat-
complex [Ph3PAuNTf2] was ineffective in this process ing to 50 °C was essential in all cases (Table 2). Aryl ac-
(entry 6). Control experiments clearly demonstrated that etals functioned very well in this process, and no
[PicAuCl2] or AgNTf2 alone were ineffective (entries 7 significant difference was found between those bearing
and 8). The use of PtCl2 was also checked, but no reaction electron-withdrawing groups and those with electron-do-
was observed even when performed under heating to re- nating groups (entries 3–8). However, the reaction
flux in toluene (entry 9).
showed sensitivity towards the steric bulk of the sub-
strates. Thus, o-tolualdehyde dimethyl acetal afforded the
product 3b in only 31% yield (entry 2), and n-pentyl di-
methyl acetal, as an example of alkyl acetals (entry 9),
also formed the product in poor yield.
Table 2 Scope of the Reaction with Acetalsa
Entry Acetal
Product
Yield (%)b anti/cisc
Me
Me
R
Me
O
O
O
The scope of the reaction with respect to alkenes was also
checked (Table 3). Mono-aryl-substituted substrates were
functionalized (entries 1–4), even at room temperature, al-
though no product was obtained from the mono-alkyl-
substituted alkene (entry 5). Electron-withdrawing sub-
stituents on the aromatic ring led to a slight decrease in the
yield (entry 2). Interestingly, when the substrate contained
both a carbon–carbon double bond and a triple bond, only
the product from the carboalkoxylation of the alkene was
observed (entry 7). As another example of alkyl-substitut-
ed alkene, methylenecyclohexane could also undergo the
reaction and the elimination product 3n was formed in
good yield (entry 8).
Me
Ph
3a
3b
3c
3d
3e
3f
R
O
1
2
3
4
5
6
7
8
9
R = Ph
85
31
89
72
83
78
76
66
20
1.17:1
1.40:1
1.21:1
1:1
R = o-MeC6H4
R = m-MeC6H4
R = p-MeC6H4
R = p-BrC6H4
R = p-FC6H4
1.33:1
1.37:1
1.34:1
1.27:1
1.14:1
R = p-MeOC6H4
R = p-O2NC6H4
R = n-pentyl
3g
3h
3i
The combination of benzaldehyde dimethyl acetal and
styrene was then examined with 0.05 equivalent of either
triflic acid or trimethylsilyl triflate at room temperature
for one hour. Under these conditions, product 3a was ob-
tained with a diastereomeric ratio of 1.52:1 and 1.48:1, re-
spectively, in yields of 49 and 41%; benzaldehyde was
a Reaction conditions: styrene (1.0 mmol), acetal (1.5 mmol),
[PicAuCl2] (0.05 mmol), AgNTf2 (0.1 mmol), toluene (4 mL), 50 °C.
b Isolated yield.
c Diastereomeric ratio of product 3.
Synlett 2012, 23, 2799–2802
© Georg Thieme Verlag Stuttgart · New York

LETTER
Gold-Catalyzed Carboalkoxylation
2801
Table 3 Scope of the Reaction with Alkenesa
erated alkylgold intermediate A will then attack the
carbon cation B formed in situ, and furnish the product.
Acetal activation is the primary feature of the second
pathway. It is also highly possible that the cationic gold
complex could act as Lewis acids to activate acetals di-
rectly, forming gold(III)-alkoxide C and carbon cation ion
B. Subsequent electrophilic addition of B to the alkenes
will generate intermediate D. Attack of C to D will furnish
the same product. Notably, this pathway matches very
well with the Prins reaction.11
Entry Alkene
Product
Yield anti/cisc
(%)b
Me
Me
Ph
O
O
R
R
1
2
3
4
5
R = o-MeC6H4
3bd
3fd
3jd
3kd
88
73
93
82
1.45:1
1.36:1
1.3:1
R = p-FC6H4
To further investigate the pathway followed in the trans-
formation, a number of experiments, including in situ
ESI-MS and NMR, were carried out, however, no clear
data were collected, and the mechanism still remains un-
clear.
R = p-(t-Bu)C6H4
R =2,4-Me2C6H3
R = c-Hex
1.44:1
n.r.e
Me
Me
Ph
R2
O
O
Acknowledgment
R1
R2
R1
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (NSF-21002078), PhD Programs Foun-
dation for young teachers of Ministry of Education of China
(20106101120004), Science and Technology Department of Shaan-
xi Province (2010JQ2006), Education Department of Shaanxi Pro-
vince (2010JK873), Northwest University (PR11025, NF0910),
and the Open Foundation from the Key Laboratory of Synthetic and
Natural Functional Molecule Chemistry of Ministry of Education.
6
7
R1 = Me, R2 = Ph
3ld
82
65
1.23:1
1:1
R1 = Me, R2 =1-butynyl 3mf
Me
O
8
R1–R2 = (CH2)4
71
–
Ph
3n
a Reaction conditions: alkene (1.0 mmol), benzaldehyde dimethyl ac-
etal (1.5 mmol), [PicAuCl2] (0.05 mmol), AgNTf2 (0.1 mmol), tolu-
ene (4 mL).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
b Isolated yield.
c Diastereomeric ratio of product 3.
d Reaction was performed at r.t.
e No reaction.
References and Notes
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f Reaction performed at 50 °C.
formed in approximately 35% yield in both reactions. In
comparison, hydration of acetals was much slower under
the gold catalysis conditions, and the product was gener-
ated in higher yield.
Although our work started with the anticipation that the
first step in the process should be the activation of alkenes
by the gold catalyst, plausible reaction mechanisms in-
clude two possible pathways, as illustrated in Scheme 2.
The first is through an alkene activation process, in which
alkenes activated by the cationic gold complex will under-
go attack from the methoxyl group of the acetal. The gen-
Me
Me
R2
O
O
R1
Au
Me
O
Me
O
alkene activation
– Au
R1
Au
Me
R2
Au
Me
O
A
B
Me
Me
R2
R1
O
O
O
+
R1
R2
C
C
Au OMe
Au OMe
R1
3
1
2
Me
Me
Au
O
O
– Au
R1
R2
R2
acetal activation
B
D
Scheme 2 Possible pathways to products 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2799–2802

2802
W. Dong et al.
LETTER
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Alkenes; General Procedure: A mixture of [PicAuCl2]
(0.05 mmol, 5 mol%) and AgNTf2 (0.10 mmol, 10 mol%)
was stirred in toluene (2.0 mL) for 2 min, and then a solution
of alkene (1.0 mmol) and acetal (1.5 mmol) in toluene (2.0
mL) was added. The system was heated to 50 °C until the
starting material was completed consumed. The system was
filtered through a short column of silica gel and eluted with
diethyl ether. The concentrated crude product was purified
by flash silica gel column chromatography using petroleum
ether and diethyl ether as eluent.
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(10) Compound 3a (as a typical product): 1H NMR (400 MHz,
CDCl3): δ (cis/anti) = 7.37–7.25 (m, 10 H), 4.06–4.03 (t, J =
7.2 Hz, 2 H), 3.14 (s, 6 H), 2.47–2.40 (m, J = 6.0 Hz, 1 H),
1.86–1.80 (m, J = 6.8 Hz, 1 H), 7.36–7.22 (m, 20 H); δ (anti)
= 4.45–4.40 (m, J = 2.4 Hz, 2 H), 3.25 (s, 6 H), 2.00–1.97 (q,
J = 2.4, 1.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ
(cis/anti) = 142.3, 141.6, 128.3, 127.6, 127.4, 126.8, 126.5,
80.8, 80.0, 56.7, 56.3, 47.6, 46.1; HRMS (ESI): m/z [M +
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Synlett 2012, 23, 2799–2802
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