Tandem Gold Self-Relay Catalysis for the Synthesis of 2,3-Dihydropyridin-4(1 H)-ones: Combination of σ and π Lewis Acid Properties of Gold Salts

Article abstract of DOI:10.1002/chem.201403340

The dual ability of gold salts to act as π- and σ Lewis acids has been exploited in a tandem self-relay catalysis. Thus, triphenylphosphanegold(I) triflate mediated the intramolecular carbonyl addition of the amide functionality of homoprogargyl amides to a triple bond. The formation of a σ complex of the gold salt with the intermediate oxazine promoted a nucleophilic addition followed by a Petasis-Ferrier rearrangement. This tandem protocol, catalyzed by the same gold salt under the same reaction conditions, gave rise to the efficient synthesis of 2,3-dihydropyridin-4-(1 H)-ones, which contain a cyclic quaternary α-amino acid unit. The asymmetric version was performed by generating the starting materials from the corresponding sulfinylimines.

Full text of DOI:10.1002/chem.201403340

DOI: 10.1002/chem.201403340
Full Paper
&
Autocatalysis
Tandem Gold Self-Relay Catalysis for the Synthesis of
2,3-Dihydropyridin-4(1H)-ones: Combination of s and p
Lewis Acid Properties of Gold Salts
Santos Fustero,*[a, b] Javier Mirꢀ,[a] Marꢁa Sꢂnchez-Rosellꢀ,[a, b] and Carlos del Pozo*[a]
Abstract: The dual ability of gold salts to act as p- and
s Lewis acids has been exploited in a tandem self-relay catal-
ysis. Thus, triphenylphosphanegold(I) triflate mediated the
intramolecular carbonyl addition of the amide functionality
of homoprogargyl amides to a triple bond. The formation of
a s complex of the gold salt with the intermediate oxazine
promoted a nucleophilic addition followed by a Petasis–Fer-
rier rearrangement. This tandem protocol, catalyzed by the
same gold salt under the same reaction conditions, gave rise
to the efficient synthesis of 2,3-dihydropyridin-4-(1H)-ones,
which contain a cyclic quaternary a-amino acid unit. The
asymmetric version was performed by generating the start-
ing materials from the corresponding sulfinylimines.
Introduction
ic species is possible in this case; therefore, the use of catalysts
is very efficient and favorable in terms of time and energy.
However, the difficulty in the optimization of the separated
processes independently has made these processes very
challenging.
Tandem catalysis can be defined as a set of reactions catalyzed
independently by one or more catalysts in a consecutive
manner. Because one of the main interests of academia and in-
dustry is the enhancement of synthetic efficiency, this method-
ology is becoming increasingly important in several areas of
organic chemistry, including natural-products synthesis, drug
discovery, and process chemistry.[1] Additionally, this process is
one of the strategies used by nature in the preparation of bio-
molecules.[2] In this manner, by using single starting materials,
molecular complexity can be increased in a single operation,
thus allowing the synthesis of complex molecules and avoiding
the loss of time and product associated with the isolation and
purification of intermediates in multistep sequences. This ap-
proach provides environmental and economic benefits and
also fulfills the principles of green chemistry.
On the other hand, the p Lewis acidity of gold(I) salts has
been extensively explored. The ability of these salts to activate
alkynes under mild conditions toward the addition of a wide
variety of nucleophiles has converted gold complexes into ap-
preciated catalysts to promote tandem reactions.[4] Although
explored to a lesser extent, gold salts also exhibit interesting
behavior as s Lewis acids. This type of Lewis acidity of gold
salts has been shown in the activation of several oxygen-[5] and
nitrogen-containing compounds.[6] However, examples in
which gold salts play a dual role, that is, by taking advantage
of both hard (s Lewis acid) and soft (p Lewis acid) Lewis acidi-
ty, are scarce even though they constitute a new paradigm in
the reactivity of gold complexes.[7]
Among the different types of tandem catalysis, auto-catalysis
(also named self-relay catalysis) is probably the most efficient.[3]
This technique involves the combination of two or more dis-
tinct reactions promoted by the same catalyst, all of which
occur under the same reaction conditions in a concurrent
manner. In comparison with other types of tandem catalysis
(assisted and orthogonal), no interference between the catalyt-
Homopropargyl amines are usual partners in gold-catalyzed
reactions. Depending on the substituent attached to the nitro-
gen atom, these compounds undergo cyclization to render
a great variety of pyrrolidine and piperidine scaffolds.[8] In this
context, Rhee and co-workers reported that tert-butoxycarbon-
yl (Boc)- or carbobenzyloxy (Cbz)-protected amines bearing
a methoxymethyl moiety in the presence of gold salts evolve
in a formal aza-Prins cyclization, thus giving rise to piperidine
enol ethers that were subsequently hydrolyzed to the corre-
sponding piperidones (Scheme 1).[8h] On the other hand, Zhang
and co-workers reported that the alkyne moiety of homopro-
pargyl amides can be activated by gold, thus promoting addi-
[a] Prof. S. Fustero, J. Mirꢀ, Dr. M. Sꢁnchez-Rosellꢀ, Dr. C. del Pozo
Departamento de Quꢂmica Orgꢁnica
Universidad de Valencia
46100-Burjassot (Spain)
E-mail: santos.fustero@uv.es
carlos.pozo@uv.es
[b] Prof. S. Fustero, Dr. M. Sꢁnchez-Rosellꢀ
Laboratorio de Molꢃculas Orgꢁnicas
Centro de Investigaciꢀn Principe Felipe
46012-Valencia (Spain)
tion of
a carbonyl group to furnish the corresponding
oxazines; furthermore, due to their high lability, these com-
pounds were reduced in situ with a borane to the hemiaminal,
which in turn underwent a spontaneous aza-Petasis–Ferrier re-
arrangement and final reduction of the carbonyl moiety
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403340.
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tion/formal aza-Diels–Alder reaction sequence to generate
tetracyclic frameworks (Scheme 1).[9]
Herein, we describe the reactivity of these amines after their
conversion into the corresponding amides toward gold(I) salts.
Homopropargyl amides 1 underwent a new tandem reaction
in the presence of gold(I) salts to give access to a new family
of 2,3-dihydropyridin-4(1H)-ones, skeletons that have been
used as versatile intermediates in the synthesis of several pi-
peridine, indolizidine, and quinolizidine alkaloids[10] (Scheme 1).
The overall process, which could be considered to be a gold
self-relay catalysis, takes advantage of the dual behavior of
gold salts as hard and soft Lewis acids. It is important to men-
tion that, in comparison with previous reports, the entire pro-
cess is promoted by gold in this case, thus displaying a new re-
activity pattern. The presence of the quaternary center was
crucial in this observed divergent reactivity. The scope of this
process and a plausible mechanistic proposal are disclosed
herein. Additionally, the use of chiral sulfinylimines allowed us
to develop an asymmetric version of this protocol.
Results and Discussion
Compound 1a was used as a model substrate to evaluate the
reactivity toward gold salts. Initially, we treated substrate 1a
with AuCl3 in dichloromethane at room temperature. Oxazine
2a, which arises from the addition of the carbonyl group to
the triple bond, was obtained after 24hours in 40% yield with
40% of 5a, which comes from the hydration of the alkyne
toward the methyl ketone (Table 1, entry 1). Similar results
were obtained with AuCl (Table 1, entry 2). However, the use of
[AuClPPh3] in combination with AgOTf led to a drastic decrease
Scheme 1. Reactivity of homopropargyl amines versus gold salts. TsOH=to-
luenesulfonic acid.
(Scheme 1). The overall process constitutes a modular ap-
proach to the preparation of 4-piperidinols.[8g]
In the context of an ongoing project in our laboratory, we
evaluated the reactivity of protected homopropargylic amines
bearing a quaternary center, which have not been studied to
date. We hypothesized that depending on the nature of the
protecting group, we could expect a differential reactivity;
thus, when these amines contain an aryl substituent, they
evolve in the presence of gold salts in a tandem hydroamina-
Table 1. Reactivity toward gold(I) salts.
Abstract in Spanish: La doble capacidad de las sales de oro
para actuar como ꢂcidos de Lewis p y s ha sido utilizada en
un proceso tꢂndem catalꢁtico de tipo self-relay. De esta forma,
el triflato de trifenilfosfina oro(I) promueve la adiciꢀn intramo-
lecular del grupo carbonilo de la funciꢀn amida de amidas ho-
mopropargꢁlicas sobre el triple enlace. Posteriormente, la for-
maciꢀn de un complejo s de la sal de oro con la oxazina inter-
media induce un ataque nucleofꢁlico seguido de un reagrupa-
miento tipo Petasis-Ferrier. El proceso tꢂndem, que estꢂ catali-
zado por la misma sal de oro en las mismas condiciones de
reacciꢀn, conduce de forma eficaz a 2,3-dihidropiridin-4-(1H)-
onas, compuestos que adicionalmente contienen una unidad
a-amino ꢂcido en su estructura. La versiꢀn asimꢄtrica se llevꢀ
a cabo generando los sustratos de partida a partir de las corre-
spondientes sulfinil iminas.
Entry Catalyst
Additive
Solvent
t
Yield
Yield Yield
4a [%] 5a [%]
[h] 2a [%]
1
2
AuCl3
AuCl
–
–
CH2Cl2 24 40
CH2Cl2 24 37
CH2Cl2
CH2Cl2
–
–
–
–
40
35
30
30
–
3
4
[AuClPPh3] AgOTf
[AuClPPh3] AgNTf2
3
6
3
57
50
72 (83)[a]
–
–
5
[AuClPPh3] AgOTf/MS (3 ꢅ) CH2Cl2
–
6
7
AgOTf
TfOH
–
–
CH2Cl2 24
CH2Cl2 24
toluene 24 25[b]
CH3CN 22 35[b]
MeOH
MeOH
MeOH 24
–
–
–
–
8
9
10
11
12
[AuClPPh3] AgOTf
[AuClPPh3] AgOTf
[AuClPPh3] AgOTf
[AuClPPh3] AgNTf2
–
–
93
87
47
35
34
–
–
33
3
5
–
–
–
AuCl
–
[a] The yield determined by GC-MS is given in brackets..[b] The conver-
sion was not complete and some starting material was recovered. MS=
molecular sieves, NTf2 =bis(trifluoromethylsulfonyl)imide, Tf=trifluorome-
thanesulfonyl.
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in reaction time. Total consumption of the starting material
was observed after 3hours, and oxazine 2a was isolated in
57% yield, again with the acetyl derivative 5a (Table 1,
entry 3). The use of a different silver salt (i.e., silver triflimide)
led to comparable results (Table 1, entry 4). At this point, it is
important to mention that TLC analysis revealed that product
5a was derived from oxazine 2a and can be assumed to form
from traces of water present in the reaction medium. To avoid
this hydrolysis, the reaction was performed in the presence of
molecular sieves (3 ꢅ), which led to a significant improvement
in the yield (Table 1, entry 5). Although the yield determined
by GC-MS was 83%, the yield of the isolated oxazine 2a was
72%, thus indicating that this compound is labile and decom-
poses during purification. Substrate 1a was inert either in the
presence of the silver salt or triflic acid, thus indicating the role
of gold in catalyzing the reaction (Table 1, entries 6 and 7). The
next step of our study was the evaluation of the solvent in the
process. The use of toluene or acetonitrile as solvents led to
a decrease in efficiency (Table 1, entries 8 and 9). However, the
use of methanol gave a surprising result, in which the exclu-
sive formation of dihydropyridone 4a was observed in excel-
lent yield after 3 hours (Table 1, entry 10). The use of silver tri-
flimide gave comparable results, although with longer reaction
times (Table 1, entry 11). On the other hand, it took 24 hours to
complete the process and a mixture of 4a and 5a was ob-
tained when AuCl was used as catalyst (Table 1, entry 12).
With these results, we proceeded to study the behavior of
other homopropargylic amides under the optimized condi-
tions. Thus, when homopropargyl amides 1 were treated with
[AuClPPh3] in combination with AgOTf in dichloromethane in
the presence of molecular sieves, a clean formation of oxazines
2 was observed (Table 2, entries 1–7). As mentioned before,
these compounds partially decompose during purification, but
obtaining good yields of the isolated products was possible.
Hydrolysis of oxazines 2 took place in almost quantitative
yields in all cases to render the alkyne hydrolysis products 5
(Table 2, entries 1–7). It seems that the hydration of the triple
bond under gold catalysis is assisted by the carbonyl group.
The solvent played a crucial role in the process, and the exclu-
sive formation of dihydropyridones 4 in methanol was ob-
served in good-to-excellent yields (Table 2, entries 1–7).
Table 2. Preparation of oxazines 2, dihydropyridones 4, and acetyl deriva-
tives 5.
Entry
R1
R2
R3
Yield 2
Yield 4
Yield 5
[%]
[%]
[%]
1
2
3
4
5
6
7
8
CF3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Ph
Me
Me
Me
Me
Et
Me
Me
Me
2a 72 (83)[a]
2b 70 (86)[a]
2c 80 (94)[a]
2d 88 (98)[a]
2e 61 (95)[a]
2 f 76
4a 93
4b 93
4c 80
4d 94
4e 70[b]
4 f 75
4g 76
–
5a 99
5b 99
5c 99
5d 99
5e 99
5 f 84
5g 99[c]
–
CF2Ph
CF2Bn
CF2allyl
CF3
Ph
CF3
2g 74
[d]
Ph
H
–
[a] The yield determined by GC-MS is given in brackets. [b] The formation
of 28% of 5e was also observed. [c] To carry out the hydrolysis in this
case, it was necessary to add 5 mol% of the gold(I) salt to activate the ox-
azine for the nucleophilic attack. [d] The substrate remained unaltered in
methanol.[8]
aza-Wittig reaction with chiral phosphazene 7 and the corre-
sponding iminoester 8 was treated in situ with propargyl bro-
mide and activated zinc in DMF under Barbier-type conditions.
The addition of propargylzinc was completely selective, thus
affording homopropargylic sulfinylamine 9 as a single diaste-
reoisomer. Protecting-group removal and acetylation led to the
starting amide 1a in enantiomerically pure form.[11] Reaction of
1a with [AuOTfPPh3] gave oxazine 2a in dichloromethane,
acetyl derivative 5a upon hydrolysis, and dihydropyridone 4a
in methanol (Scheme 2). Compound 4a contains a cyclic qua-
ternary a-amino acid unit, which infers more relevance to the
asymmetric process.
In all cases, a quaternary center is present in the starting
amides 1. The reactivity of substrates that arise from non-fluo-
rinated aldimines (Table 1, entry 8) has been described
before;[8g] although the formation of the corresponding oxa-
zine has been reported, these compounds were unstable and
were subjected to further transformations without isolation.
Additionally, this substrate was inert in the presence of the
gold salt in methanol, even in the presence of acidic additives,
thus preventing the complexation of gold and the basic nitro-
gen atom (Table 2, entry 8). It is clear that the presence of the
quaternary center plays a significant role in the process, but
we do not have an explanation so far for this different
behavior.
As mentioned before, hydration products 5 come from oxa-
zines 2. In the same way, we observed by TLC analysis that the
first step in the reaction performed in methanol was once
again the formation of oxazines 2, thus indicating that these
compounds are also intermediates in the formation of dihydro-
pyridones 4. To prove this observation and the role of the gold
salt in the process, several experiments were performed. First,
when oxazine 2a was dissolved in dry methanol, it remained
unaltered after 24 hours at room temperature (Table 3,
entry 1). When a catalytic amount of triflic acid was added to
the reaction mixture, total consumption of the starting materi-
al was observed after 6 hours, thus giving rise to 4a in 61%
yield (Table 3, entry 2). On the other hand, the reaction in the
presence of AgOTf did not proceed, thus recovering the start-
ing material untouched after 24 hours at room temperature
The next step of our study was an asymmetric version of the
sequence. To this end, sulfinylimines were used as chiral auxil-
iaries. Thus, ethyl trifluoropyruvate (6) was subjected to an
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purpose, we planned an isolation of the intermediate complex
of [AuOTfPPh3] with oxazine 2a to prove the identity of the in-
volved species. To this end, 2a was treated with one equiva-
lent of the gold salt (previous filtration of the AgCl formed
during the preparation of the catalytic species) in CDCl3, and
the clean formation of a new species was observed after 10 mi-
nutes. 31P NMR spectroscopic analysis showed a singlet at d=
29.6 ppm (shifted downfield in comparison with the signal for
free [AuOTfPPh3], which appears at d=27.5 ppm, according to
its less cationic character after forming the s complex with the
oxazine), whereas 19F NMR spectroscopic analysis revealed two
signals that correspond to the CF3 groups of the oxazine
moiety and the counterion. Low-resolution mass-spectrometric
analysis spectra indicated the existence of complex 10 (m/
1
z 710.27); in addition, H and 13C NMR spectroscopic data were
also in agreement with the presence of this complex (see the
Supporting Information).[12] As expected, complex 10 turned
into dihydropyridone 4a after removal of the solvent and the
addition of methanol (Scheme 3).
Scheme 2. Asymmetric version of the tandem process. DMF=N,N-dimethyl-
formamide, Tol=toluene.
Table 3. Transformation of oxazine 2a into dihyropyridone 4a.
Entry
Catalyst
t
[h]
Yield 4a
Scheme 3. Preparation of s gold complex 10. LRMS=low-resolution mass
spectrometry, MALDI-TOF=matrix-assisted laser desorption ionization/time
of flight,
[%][a]
1
2
3
4
5
–
24
6
24
–
61
–
71
84
TfOH
AgOTf
[AuClPPh3]/AgOTf
BF3·OEt2
0.5
4
A plausible explanation of the reaction outcome is depicted
in Scheme 4. Initially, when amide 1a was treated with
[AuOTfPPh3] in dichloromethane, coordination with the triple
bond occurred (A), thus activating the bond to the addition of
the carbonyl group. Proto-deauration of intermediate B ren-
dered oxazine 2a. The next step was the coordination of the
gold salt with the oxygen atom of the imidate functionality,
which activates it to the addition of an external nucleophile.
When the nucleophile was water (R=H), the addition to com-
plex 10 gave rise to hemiacetal C, which is in equilibrium with
the opened intermediate D, thus rendering hydration product
5a after tautomerization. A completely different situation ap-
peared when the nucleophile was methanol (R=Me); namely,
the mixed acetal F formed, which is susceptible to undergoing
a gold-catalyzed Petasis–Ferrier rearrangement.[13] Thus, the
acetal moiety undergoes ring opening to form the oxonium
ion G, which cyclized again into pyridine H. Methanol elimina-
tion and further isomerization of the double bond of I gave
rise to dihydropyridone 4a (Scheme 4).
[a] Yield of the isolated product after flash chromatography.
(Table 3, entry 3). A completely different situation emerged
with the addition of [AuClPPh3] in combination with AgOTf.
The reaction was complete after 30 minutes, thus affording 4a
in 71% yield (Table 3, entry 4). Finally, the use of a Lewis acid
(e.g., BF3·OEt2) gave rise to the final product 4a in 4 hours
(Table 3, entry 5). Additional evidence of this dual role played
by gold salts can be inferred from the reaction performed with
AuCl (Table 1, entry 11). This neutral gold species (softer than
the cationic [AuOTfPPh3]) is less effective in the s activation of
the imidate, which led to longer reaction times and the ap-
pearance of an increased amount of hydration product 5a.
These observations clearly indicate that the gold salt acts as
a s Lewis acid and promotes the transformation of oxazine 2a
into dihydropyridone 4a more efficiently than a strong Brønst-
ed or Lewis acid (i.e., triflic acid or BF3·OEt2, respectively).
Therefore, the formation of 4a involved a tandem reaction
catalyzed by the same gold salt (self-relay catalysis). The overall
process took advantage of the dual role of the gold catalyst,
With these results achieved, we decided to firmly establish
the ability of this gold salt to perform the s activation. For this
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Acknowledgements
We thank the Spanish Ministerio de Economꢁa y Competitivi-
dad (CTQ-2010-19774-C02-01) and Generalitat Valenciana (GV/
Prometeo/2010/061) for their financial support. J.M. thanks the
University of Valencia for a predoctoral fellowship. Technical
and human support provided by SGIker (UPV/EHU, MINECO,
GV/DJ, ERDF, and ESF) is gratefully acknowledged.
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[11] The absolute configuration of acetylamide 1a was determined by
means of an X-ray studies. CCDC-984448 (1a) contains the supplemen-
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Chem. Eur. J. 2014, 20, 1 – 7
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Received: April 30, 2014
Published online on && &&, 0000
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FULL PAPER
Working together: The bifunctional
Lewis acid properties of gold(I) salts
were exploited to implement a tandem
process. Homopropargylic amides 1 re-
acted with triphenylphosphanegold(I)
triflate in a triple self-relay catalytic pro-
cess to render 2,3-dihydropyridin-4-
(1H)-ones 4 (see picture; MS=molecu-
lar sieves, Tf=trifluoromethanesulfonyl).
This protocol takes advantage of the
dual behavior of gold salts as s- and p
Lewis acids; this ability of gold salts to
act as s Lewis acids was demonstrated
by the isolation and characterization of
the s complex.
&
Autocatalysis
S. Fustero,* J. Mirꢀ, M. Sꢁnchez-Rosellꢀ,
C. del Pozo*
&& – &&
Tandem Gold Self-Relay Catalysis for
the Synthesis of 2,3-Dihydropyridin-
4(1H)-ones: Combination of s and p
Lewis Acid Properties of Gold Salts
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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These are not the final page numbers! ÞÞ