An alternative approach to direct aldol reaction based on gold-catalyzed methoxyl transfer

Article abstract of DOI:10.1002/adsc.201100789

A mild and catalyzed alternative to the direct aldol reaction has been developed based on the gold-catalyzed methoxy group transfer from dimethyl acetals to terminal alkynes. Due to the simultaneous activation of the acetals, this aldol approach is only functional for acetals but not aldehydes. A ligand effect from the gold complex has also been observed. Copyright

Full text of DOI:10.1002/adsc.201100789

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DOI: 10.1002/adsc.201100789
An Alternative Approach to Direct Aldol Reaction Based on
Gold-Catalyzed Methoxyl Transfer
Moran Zhang,a Yunxia Wang,a Yang Yang,a and Xiangdong Hua,*
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, Peopleꢀs Republic of China
E-mail: xiangdonghu@nwu.edu.cn
Received: October 12, 2011; Revised: December 5, 2011; Published online: March 27, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100789.
Abstract: A mild and catalyzed alternative to the
direct aldol reaction has been developed based on
the gold-catalyzed methoxy group transfer from di-
methyl acetals to terminal alkynes. Due to the si-
multaneous activation of the acetals, this aldol ap-
proach is only functional for acetals but not alde-
hydes. A ligand effect from the gold complex has
also been observed.
other intramolecular or intermolecular nucleophiles,
can be efficiently avoided during the process or up-
stream of a multiple-step synthesis. However, only
few cases can be found so far in this field, such as
strategies based on the isomerization of allylic alco-
hol,[7] the addition of silanols to ynamide[8] and the re-
cently reported addition of boronic acid to alkynes.[9]
Meanwhile, all the processes have focused only on the
formation of the active enolates or the equivalents
through either in situ activation of carbonyl com-
pounds or certain transformations of the masked car-
bonyl compounds. And attention has been barely paid
to the activation of the electrophile side. Herein, we
present a new approach to the direct aldol reaction as
the first example involving not only the in-situ forma-
Keywords: acetals; alkynes; direct aldol reaction;
gold catalysis; ligand effect; methoxyl transfer
As one of the most practical ways to build up carbon- tion of the enol ether but also the simultaneous acti-
carbon bonds between organic molecules, the aldol vation of the electrophile through a gold-catalyzed in-
reaction commonly involves two carbonyl compounds termolecular methoxy group transfer.[10] Two masked
as the nucleophile and electrophile, respectively. To carbonyl compounds, dimethyl acetals and terminal
avoid unnecessary side products during the process, alkynes, were employed as the starting materials. It is
the formation of enolates or equivalents in good che- noteworthy that this transformation possesses two
moselectivity is usually pivotal. One popular method features: (i) this process can only work with acetals
is performing the enolization of the particular carbon- rather than aldehydes since alkynes and dimethyl ace-
yl compound in advance of the transformation.[1] As tals are both activated at the same time, (ii) an inter-
another important strategy, the direct aldol reaction, esting ligand effect had been observed. As terminal
featured with the selective formation of enolates or alkynes involved, an electrophilic gold complex had
equivalents in the presence of the electrophile, has been formed as the Buchwald-type ligand[11] featuring
appeared in recent decades. To date, this field mostly the gold complex, (t-Bu)2(o-biphenyl)PAuCl/AgNTf2,
focuses on direct aldol reactions of two carbonyl com- we applied, however, a nucleophilic gold complex
pounds, especially their catalyzed versions using cata- that had been mainly generated when Ph3PAuNTf2
lysts, for instance, magnesium halide,[2] chiral primary- was employed.
tertiary diamine,[3] heterobimetallic complex,[4] l-pro-
Our work started from the notion that the gold
complex activated-alkynes could be attacked by one
line[5] and its derivatives.[6]
In recent years, the direct aldol reaction involving methoxy group from the dimethyl acetals, since gold
masked carbonyl compounds has appeared as another complexes have been proven as excellent activators of
important alternative. As a result, carbonyl com- carbon-carbon multiple bonds.[12] The formed inter-
pounds are no longer the exclusive starting materials. mediates B and C will serve as active nucleophiles
Many undesired reactions of carbonyl compounds, and electrophiles of the aldol reaction, and then fur-
such as the reduction to alcohols or the attack from nish the protected aldol product 5 or the hydrolyzed
Adv. Synth. Catal. 2012, 354, 981 – 985
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Moran Zhang et al.
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product 3 [Eq. (1)]. Therefore, benzaldehyde dimeth- result to produce 3a came from the adoption of (t-
yl acetal and phenylacetylene were selected as model Bu)2(o-biphenyl)PAuCl/AgNTf2 in toluene (entry 4).
substrates and examined under different conditions The
comparable
Cy2(o-biphenyl)PAuCl/AgNTf2
(Table 1). To our delight, there are several conditions system provided a similar result (entry 7). Some con-
that can make the reaction happen. And another trol experiments have been conducted and (t-Bu)2(o-
product observed is not the expected product 5 but biphenyl)PAuCl or AgNTf2 alone cannot make the
the propargyl product 4a, especially when process work (entries 11 and 12). Additionally, the re-
Ph3PAuNTf2 was applied (entry 1). This should be due action in tetrahydrofuran afforded products in yields
to the known process to form the gold acetylide com- very close to those in toluene (entry 8). 1,2-Dichloro-
plex D from terminal alkynes and a gold complex[13] ethane and acetonitrile had been demonstrated as un-
[Eq. (2)]. Also, the propargylic product will be suitable solvents for this transformation (entries 9 and
formed through the attack of complex D to the active 10).
intermediate C. However, there is also a high possibil-
With these optimized conditions in hand, various
ity that 3a could be formed from the hydration of 4a. dimethyl acetals and terminal alkynes have been ap-
In this regard, 4a was then subjected to (t-Bu)2(o-bi- plied to check the scope of the transformation
phenyl)PAuCl/AgNTf2 under the same conditions. (Table 2). Most of the cases were carried out at room
But no reaction happened even after 20 h. The best temperature for 6–8 h, and the b-methoxy ketones
Table 1. Optimization iof the reaction conditions.
Entry
Catalyst
Conditions[a]
Yield [%] of 3a[b]
Yield [%] of 4a[b]
1
2
3
4
5
6
7
8
Ph3PAuNTf2
PicAuCl2/2AgNTf2
Ph3PAuCl/AgOTf
ACHTUNGTRENNUNG
toluene, r.t.
toluene, r.t.
toluene, r.t.
toluene, r.t.
toluene, r.t.
toluene, r.t.
toluene, r.t.
THF, r.t.
50
5
40
5
15
5
0
33
6
4
19
60
12
25
58
58
5
T
ImesAuCl/AgNTf2
(Cy)2(o-biphenyl)PAuCl/AgNTf2
N
A
9
DCE, r.t.
0
10
11
12
N
CH3CN, r.t.
toluene, r.t.–708C
toluene, r.t.–708C
0
0
0
0
0
0
[a]
Conducted with phenylacetylene (0.2 mmol), benzaldehyde dimethyl acetal (0.26 mmol) and catalyst (0.01 mmol) in 4 mL
solvent.
Estimated by H NMR using dioxane as internal reference.
[b]
1
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Adv. Synth. Catal. 2012, 354, 981 – 985

An Alternative Approach to Direct Aldol Reaction Based on Gold-Catalyzed Methoxyl Transfer
Table 2. Study of the scope of the reaction.[a]
Entry
R1
R2
Yield [%] of 3[b]
Yield [%] of 4[b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
60 (53)
86 (77)
63 (55)
73 (66)
70 (45)[c]
55 (43)
80 (72)
56 (49)
40 (35)
69 (65)
82 (76)
79 (71)
81 (75)
44 (35)
48 (39)
N.R.[d]
5
0
13
16
10
30 (24)
6
9
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-MeO-C6H4
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
a-naphthyl
Ph
9
Ph
0
10
11
12
13
14
15
16
3-Me-C6H4
3-Me-4-F-C6H3
4-F-C6H4
4-Br-C6H4
15
12
13
10
0
Ph
Ph
Ph
R
4-MeO-C6H4
T
C
0
–
T
[a]
Conducted with (t-Bu)2(o-biphenyl)PAuCl (0.01 mmol), AgNTf2 (0.01 mmol), alkyne (0.2 mmol) and dimethyl acetal
(0.26 mmol) in 4 mL toluene at room temperature for 6–8 h.
Estimated by H NMR of crude products using dioxane as internal reference (isolated yield).
Conducted in an ice-water bath for 2 h.
No reaction occurred.
[b]
[c]
[d]
1
were obtained constantly as major products in moder- active in this transformation since the catalyzed me-
ate to good yields. An ice/water bath was employed thoxy transfer activated not only the alkynes through
for the para-methoxybenzaldehyde dimethyl acetal the in-situ formation of an enol ether but also the ace-
since it reacted very rapidly at room temperature. tals by the generation of the oxonium ion intermedi-
Also the product did not show good stability during ates C at the same time. To prove this, experiments
the isolation (entry 5). The bulky vicinal group in ace- with the corresponding aldehydes and alkynes have
tals exerted an effect on the distribution of products. been conducted using (t-Bu)2(o-biphenyl)PAuCl/
The propargylic product was formed in higher yield AgNTf2. As expected, no products of 3 and/or 4 could
than the others (entry 6). With aliphatic substrates, be observed even with elongated reaction times in all
the reaction is functional in those cases where one of cases. The only reaction that occurred is the hydration
the reactants is aliphatic (entries 14 and 15). How- of the alkynes. As a result, this alternative process to
ACHTUNGTRENNUNGever, when both reactants were aliphatic it did not the direct aldol reaction presents an extraordinary re-
work (entry 16).
activity to dimethyl acetals[14] rather than aldehydes.
Additionally, another phenomenon during our
As an example of non-terminal alkynes, methyl
phenylpropiolate was submitted to the reaction and study triggered our further interest, which is that the
the product 3n was isolated as a 1:1 mixture of epi- propargylic product 4a had been formed in 40% yield
mers in 40% yield [Eq. (3)].
when Ph3PAuNTf2 was used. To figure out whether
Acetals, as is well known, are widely applied in or- this is an accident or a ligand effect, an expanded re-
ganic synthesis as the protected form of aldehydes. search was executed. As the results shown in Table 3
However, we anticipated that aldehydes could be less indicate, the propargylic products have been obtained
in yields very close to those of the aldol products in
some cases (entries 1, 5, 7 and 8) and even as the
major products in more cases (entries 2, 3, 4, 6, 9 and
10). So it is evident that the employment of
Ph3PAuNTf2 prefers the formation of gold acetylide
complex D and the following propargylation reactions
when terminal alkynes are used. On the contrary, the
Buchwald-type ligand bearing gold complex, (t-
Adv. Synth. Catal. 2012, 354, 981 – 985
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Table 3. Reaction promoted by Ph3PAuNTf2.[a]
Entry
R1
R2
Yield [%] of 3[b]
Yield [%] of 4[b]
1
2
3
4
5
6
7
8
9
10
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-F-C6H4
50 (43)
13
40 (34)
61 (58)
46 (28)
45 (38)
32 (28)
51 (43)
40 (36)
37 (32)
53 (41)
58 (55)
[c]
[d]
4-MeO-C6H4
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
a-naphthyl
Ph
33 (16)
28 (24)
42 (32)
37 (31)
39 (32)
37 (29)
32 (23)
30 (21)
3-Me-C6H4
3-Me-4-F-C6H3
4-F-C6H4
Ph
Ph[c]
[a]
Conducted with Ph3PAuNTf2 (0.01 mmol), alkyne (0.2 mmol) and dimethyl acetal (0.26 mmol) in 4 mL toluene at room
temperature for 6–8 h.
Estimated by H NMR of crude products using dioxane as internal reference (isolated yield).
Conducted at 608C for 5–6 h.
Conducted in an ice/water bath for 3 h.
[b]
[c]
[d]
1
Bu)2(o-biphenyl)PAuCl/AgNTf2, displays a distinct Acknowledgements
suppression of the formation of propargylic products.
We are grateful to financial support from the National Natu-
Although the ligand effect has been discovered in
a number of gold-catalyzed transformations,[15] our
report discloses for the first time that an electrophilic
gold complex A can be switched to a nucleophilic
gold complex D through a change of the ligand of the
catalyst.
In summary, the discovered gold-catalyzed methoxy
group transfer from dimethyl acetals to terminal alk-
ACHTUNGTRENNUNGynes has been established as a mild and catalyzed al-
ternative process to the direct aldol reaction. To the
best of our knowledge, this is the first example of an
aldol approach only that is functional to acetals
rather than aldehydes. Beside, an interesting ligand
effect on the way of combination of gold complex
with terminal alkynes has been observed.
ral Science Foundation of China (NSF-21002078), Ph.D. Pro-
grams Foundation for young teachers of Ministry of Educa-
tion of China (20106101120004), Science and Technology
Department of Shaanxi Province (2010JQ2006), Education
Department of Shaanxi Province (2010JK873), Northwest
University (PR11025, NF0910) and the Open foundation
from Key Laboratory of Synthetic and Natural Functional
Molecule Chemistry of Ministry of Education. Y. Yang was
funded by fostering talents in basic science of the National
Natural Science Foundation of China (J0830417).
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