Intermolecular gold(I)-catalyzed alkyne carboalkoxylation reactions for the multicomponent assembly of β-alkoxy ketones

Article abstract of DOI:10.1002/adsc.201200825

A new gold(I)-catalyzed multicomponent synthesis of β-alkoxy ketones from aldehydes, alcohols, and alkynes is described. This atom economical synthesis was achieved through the use of the gold complex (SPhos)AuNTf ₂ as a catalyst, and allows for the preparation of a diverse array of β-alkoxy ketone products. Mechanistic studies illustrate that these reactions proceed via gold(I)-catalyzed hydrolysis of the alkyne to an aryl ketone, which then undergoes an aldol reaction with an oxocarbenium ion generated in situ from the aldehyde and alcohol components.

Full text of DOI:10.1002/adsc.201200825

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DOI: 10.1002/adsc.201200825
Intermolecular Gold(I)-Catalyzed Alkyne Carboalkoxylation
Reactions for the Multicomponent Assembly of b-Alkoxy
Ketones
Danielle M. Schultz,a,* Nicholas R. Babij,a and John P. Wolfea,*
a
Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, MI 48109-1055, USA
E-mail: danims@umich.edu or jpwolfe@umich.edu
Received: September 12, 2012; Published online: December 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200825.
Abstract: A new gold(I)-catalyzed multicomponent
synthesis of b-alkoxy ketones from aldehydes, alco-
hols, and alkynes is described. This atom economi-
cal synthesis was achieved through the use of the
gold complex (SPhos)AuNTf2 as a catalyst, and
allows for the preparation of a diverse array of b-
alkoxy ketone products. Mechanistic studies illus-
trate that these reactions proceed via gold(I)-cata-
lyzed hydrolysis of the alkyne to an aryl ketone,
which then undergoes an aldol reaction with an
intramolecular oxyauration reactions with alkynes to
generate oxocarbenium or iminium ions and gold(I)
enols or enol ethers.[5] These reactive species can then
undergo further transformation via capture of the cat-
ionic electrophile with the gold(I) enol intermediate
to generate heterocyclic products. Given this prece-
dent, we reasoned that an intermolecular oxyauration
reaction of an alkyne with hemiacetal 3 could provide
4, which may fragment to gold(I) enol 6 and oxocar-
benium ion 5 (Scheme 1). The oxocarbenium ion and
the gold(I) enol intermediate could then undergo in-
termolecular addition to furnish b-alkoxy ketone
product 7.[6] In principle, we felt that the requisite
hemiacetal could be generated in situ by the reaction
of the aldehyde with one equivalent of the alcohol.
oxoACHTUNGTRENNUNGcarbenium ion generated in situ from the alde-
hyde and alcohol components.
Keywords: aldehydes; alkynes; carbocations; gold;
multicomponent reactions
b-Alkoxy ketones are valuable building blocks in or-
ganic synthesis, and are also displayed in biologically
active compounds and natural products such as dihy-
dromilletonone methyl ether (1) and ovalitnin B
(2).[1,2] We sought to develop a convenient new ap-
proach to the generation of these compounds via an
Au(I)-catalyzed multicomponent coupling of readily
available aldehydes, alcohols, and alkynes.[3,4] In this
communication we describe our preliminary results in
this area, and our initial investigations into the mech-
anism of this transformation.
Scheme 1. Postulated mechanism for Au(I)-catalyzed synthe-
sis of b-alkoxy ketones via oxyauration of hemiacetals.
In our preliminary experiments we elected to exam-
Recently several groups have illustrated that ace- ine the coupling of 4-bromobenzaldehyde (8) and
tals, hemiacetals, and hemiaminals can participate in methanol with phenylacetylene (9). We reasoned that
the aromatic aldehyde should stabilize the requisite
oxocarbenium ion 5, and thereby facilitate fragmenta-
tion of 4. Moreover, phenylacetylene has proven to
be a viable substrate in several Au-catalyzed reactions
that involve oxyauration.[7] To optimize catalyst struc-
ture, a range of air-stable phosphine and NHC Au(I)
bis(trifluoromethanesulfonyl)imidate catalysts[8,9] that
have been shown to promote other oxyauration pro-
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Table 1. Optimization of reaction conditions.[a]
Entry
LAuNTf2
Equiv. MeOH
Conv. [%][b]
Yield 10 [%][c]
1
2
3
4
5
6
7
8
IPrAuNTf2 (11)
Ph3PAuNTf2
t-BuXPhosAuNTf2 (12)
10
10
10
10
10
3
3
3
3
3
0
26
0
0
18
0
0
11
53
54
56
A
0
SPhosAuNTf2 (14)
11
Ph3PAuNTf2
12
13
14
AgNTf2
HNTf2
16
74
63
78
88
90
0
9
63
10
11
12
66 (59)[d]
3
3
0
0
0
[a]
Reaction conditions: all reactions were run in vials for 12 h using 1.0 equiv. of 4-bromobenzaldehyde, 1.5 equiv. phenylace-
tylene, 3–10 equiv. MeOH, 5 mol% catalyst, CH2Cl2 (0.1M).
[b]
[c]
The reaction conversion is based on the amount of aldehyde consumed in the transformation.
1
Yields were determined by H NMR analysis of crude reaction mixtures that contained phenanthrene as an internal stan-
dard.
[d]
Isolated yield of product judged to be ꢀ95% pure by 1H NMR analysis.
cesses were examined.[10] In our initial experiments ketones 15–18 and 20–23 were formed in moderate to
we elected to use a ten-fold excess of methanol to fa- good yield (Table 2). The main side products observed
cilitate hemiacetal formation. Under these conditions in these reactions were aryl ketones resulting from
the NHC-ligated catalyst IPrAuNTf2 (11) (Table 1, hydration of the alkyne and acetals derived from the
entry 1) showed no reactivity and use of the starting aldehyde and alcohol. In some instances the
phosphine-derived catalysts PPh3AuNTf2 (entry 2) formation of 3-aryl-1,5-diketone side products was
and SPhosAuNTf2 (14) (entry 5) led to low conversion also observed. These presumably result from ioniza-
and formation of b-alkoxy ketone product 10 in only tion of the b-alkoxy ketone products followed by cap-
modest yield. However, when the amount of metha- ture of the resulting carbocation with a second equiv-
nol present in the reaction mixture was decreased alent of the enol nucleophile. In addition to aromatic
from ten equivalents to three equivalents the reactivi- aldehydes, trans-cinnamaldehyde also proved to be
ty improved significantly. Nearly complete conversion a viable substrate, affording 19 and 24 in 56% and
was observed in 12 h with catalyst 14, and the desired 42% yield, respectively. In contrast, when aliphatic al-
product was obtained in 59% isolated yield dehydes were employed only the corresponding ace-
(entry 10). Control experiments using AgNTf2 or tals were formed.
HNTf2 as catalysts did not afford the b-alkoxy ketone
A wide variety of alcohol reaction partners can be
10 (entries 11 and 12), which indicates the observed successfully employed in these reactions including
reactivity is due to the Au(I) catalyst rather than ad- (S)-2-methylbutan-1-ol (21), cyclobutanemethanol
ventitious protic acid or silver triflimide (used for cat- (24), and allyl alcohol (20). The secondary alcohol cy-
alyst preparation).
clohexanol was also a viable reaction partner, leading
With optimized conditions in hand we explored the to the formation of 23 in 57% yield. However, at-
scope of this transformation by varying the aldehyde, tempts to employ tertiary alcohols or phenols led to
alkyne, and alcohol reaction partners. Both electron- no conversion of the starting materials.
withdrawing and electron-donating substituents on
The transformations were effective with several dif-
the aryl aldehyde were well tolerated, and b-alkoxy ferent arylalkynes as coupling partners including 3-
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Intermolecular Gold(I)-Catalyzed Alkyne Carboalkoxylation Reactions
Table 2. Scope of the Au(I)-catalyzed carboalkoxylation re-
As described above in Scheme 1, we had initially
envisioned a mechanism for b-alkoxy ketone forma-
tion that proceeds via intermolecular oxyauration of
the alkyne with a hemiacetal followed by generation
and intermolecular trapping of an oxocarbenium ion.
However, the products formed in reactions of 25 led
us to question this mechanism. In addition, since for-
mation of acetals and aryl ketones was observed, we
wondered if these species may in fact be the reactive
participants that lead to the b-alkoxy ketone products.
As such, we conducted a series of control experi-
ments to probe the possibility of product formation
via Au(I)-catalyzed hydration of the alkyne followed
by Au(I)-catalyzed reaction of the resulting aryl
ketone with either the aldehyde or the corresponding
acetal. As shown in Eq. (2), treatment of 8 and 28
with SPhosAuNTf2 led to no reaction.[11] In contrast,
a competition experiment in which 1.5 equiv. of 29
were added to a “standard” reaction of 8 and 9 led to
the formation of a 1:1 mixture of 30 and 10 in 65%
NMR yield [Eq. (3)]. In a similar manner, use of di-
methyl acetal 31 in place of 8 also provided a 1:1 mix-
ture of 32 and 33 in high yield [Eq. (4)]. Finally, the
actions.[a]
[a]
Reaction conditions: all reactions were run in vials using
1.0 equiv. of aldehyde, 1.5 equiv. alkyne, 3 equiv. MeOH,
5 mol%SPhosAuNTf2, CH2Cl2 (0.1M). Reaction times
were not minimized, but complete consumption of start-
ing material was typically observed in <24 h. All yields
are isolated yields of products judged to be ꢀ95% pure
by 1H NMR analysis.
[b]
The reaction was conducted with 5 mol% JohnPho-
sAuNTf2 in place of SPhosAuNTf2.
The product was generated as a 1:1 mixture of diastereo-
[c]
mers.
chlorophenylacetylene (15, 22) and 1-ethynyl-4-fluo-
robenzene (17, 19). Unfortunately, efforts to employ
internal alkynes have thus far been unsuccessful. In-
terestingly, use of the alkyl-substituted alkyne 3-
phenyl-1-propyne (25) as a coupling partner failed to
generate the expected b-alkoxy ketone products. In-
stead, the reactions between 4-bromobenzaldehyde
(8), 25, and either methanol or (S)-2-methylbutan-1-ol
led to the formation of a-phenyl-b-alkoxy ketones 26
and 27, respectively [Eq. (1)].
1
reaction of 8 and 9 was monitored by H NMR spec-
troscopy. During the first hour of this experiment no
formation of product 10 was observed. Instead, 8 was
transformed to the corresponding dimethyl acetal and
9 was hydrolyzed to acetophenone (28), and after ad-
ditional reaction time the formation of product 10
was then observed.[12]
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Danielle M. Schultz et al.
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To examine the possible intermediacy of b-hydroxy dehyde, and an alcohol to generate a b-alkoxy ketone
ketone 34, which could be generated by Au(I)-cata- product. These Au(I)-catalyzed transformations pro-
lyzed aldol reaction between 8 and 28,[13] 34 was pre- vide a new method for the construction of b-alkoxy
pared by independent synthesis and added to the ketones, from readily available precursors. In addi-
Au(I)-catalyzed reaction of 8 and 9. This experiment tion, this approach alleviates the need to use pre-
provided predominantly 33, with only a small amount formed acetals as the electrophilic component in
of 10 observed [Eq. (5)]. Thus, the conversion of 34 Au(I)-catalyzed aldol-type reactions of alkynes. Fur-
ther studies on expanding the scope of this method
are currently underway.
Experimental Section
General Procedure for the Au(I)-Catalyzed Coupling
of Alkynes, Aldehydes, and Alcohols
An oven-dried test tube was equipped with a magnetic stir
bar and cooled under a stream of N2 before being charged
with SPhosAuNTf2 (5 mol%). The tube was then charged
with a 0.1M CH2Cl2 solution of aldehyde (1 equiv.), alkyne
(1.5 equiv.) and alcohol (3 equiv.) before being sealed with
a septum. The resulting mixture was stirred at room temper-
ature and monitored by TLC analysis. After the starting ma-
terial had been consumed, the mixture was concentrated
under vacuum and purified by flash chromatography on
silica gel using hexanes/ethyl acetate as the eluent.
to 10 appears to be slow relative to the formation of
33 from the reaction between 8 and 9 (presumably by
way of ketone 28). This observation indicates that an
Au(I)-catalyzed aldol reaction followed by substitu-
tion of methoxide for hydroxide is not the predomi-
nant pathway for product formation.[14]
Taken together, these experiments suggest the most
plausible mechanism for our multicomponent cou-
pling of alcohols, alkynes, and aldehydes involves rel-
atively rapid Au(I)-catalyzed hydration[15,16] of the
alkyne to 36 and conversion of aldehyde to acetal 35
(Scheme 2). The Au(I)-catalyzed ionization of acetal
Acknowledgements
The authors thank the NSF (CHE-1111218) for financial
support of this work. Additional support was provided by
Amgen and GlaxoSmithKline.
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[16] We cannot rule out the possibility that the nucleophilic
species in these reactions are enol ethers (derived from
hydroalkoxylation of the alkyne) rather than enols.
However, we have not directly observed the formation
of these species.
[17] The lack of reactivity in the absence of the alkyne [Eq
(2)] suggests that the alkyne may serve as a ligand for
Au during one or more of the steps in this process. It is
unclear why addition of 10 mol% alkyne failed to facil-
itate the Au-catalyzed reaction of 8 with 28. However,
it is possible that at this low alkyne concentration the
binding of alcohol or aldehyde to the Au-complex out-
competes alkyne coordination (which is consistent with
the observed poor reactivity when 10 equiv. of alcohol
were employed in catalytic reactions). Under condi-
tions of the catalytic reaction between 8 and 9 both the
aldehyde and alcohol are consumed as the acetal inter-
mediate is generated, which may minimize catalyst in-
hibition through this pathway.
[11] Addition of 10 mol% 9 to this reaction mixture also led
to no observed reactivity.
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