Enantioselective Gold(I)-Catalyzed Hydrative Cyclizations of N-Propargyl-ynamides into 3,6-Dihydropyridinones

Article abstract of DOI:10.1021/acs.orglett.9b02644

This study discloses the first enantioselective variant of the gold(I)-catalyzed hydrative cyclizations of ynamides, which have been implemented by using bis-gold(I) complexes of chiral diphosphines. Starting from N-propargyl-ynamides and water in the presence of p-toluenesulfonic acid, the cyclization reactions afford N-tosyl-3,6-dihydropyridin-2(1H)-ones in good isolated yields and with high levels of stereocontrol (20 examples, enantiomeric ratios up to 94:6).

Full text of DOI:10.1021/acs.orglett.9b02644

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Gold(I)-Catalyzed Hydrative Cyclizations of
N‑Propargyl-ynamides into 3,6-Dihydropyridinones
Julie Febvay,† Youssouf Sanogo,† Pascal Retailleau,† Manash Protim Gogoi,‡ Akhila K. Sahoo,‡
Angela Marinetti,*,† and Arnaud Voituriez*,†
†
́
́
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite Paris-Sud, Universite Paris-Saclay, 1 av. de la Terrasse,
91198 Gif-sur-Yvette, France
‡School of Chemistry, University of Hyderabad, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: This study discloses the first enantioselective
variant of the gold(I)-catalyzed hydrative cyclizations of
ynamides, which have been implemented by using bis-gold(I)
complexes of chiral diphosphines. Starting from N-propargyl-
ynamides and water in the presence of p-toluenesulfonic acid,
the cyclization reactions afford N-tosyl-3,6-dihydropyridin-
2(1H)-ones in good isolated yields and with high levels of
stereocontrol (20 examples, enantiomeric ratios up to 94:6).
intramolecular cyclopropanation to give the bicyclic product.
uring the past decade, the widespread use of gold(I) in
Dcatalytic organic synthesis has grown considerably due to Following these pioneering studies, ynamides proved to be
highly synthetically useful substrates for Au-catalyzed oxidative
cyclization processes.4 However, to the best of our knowledge,
none of these reactions have been carried out enantioselec-
tively using chiral gold(I) catalysts.5 Moreover, beyond
ynamide chemistry, the literature shows that very few gold-
promoted oxidative cyclization reactions could be made
enantioselective by means of chiral Au(I) complexes.6 In the
work reported here, we have targeted enantioselective variants
of the hydrative cyclizations of the N-propargyl-ynamides 1,
shown in Scheme 1b. This transformation, initially developed
by one of us by using achiral gold(I) catalysts,7 involves water
as the external nucleophile and p-toluenesulfonic acid (PTSA)
as the promoter.7a They are especially remarkable from a
mechanistic point of view, as far as they involve the unusual
activation of the propargylic CC bond by gold(I), and the
expected activation of the ynamide triple bond (Scheme 1b).
The postulated mechanism indeed involves the addition of
pTol-SO3H to the ynamide, leading to the intermediate enol
sulfonate (I). Then, the gold-activated CC bond of the N-
propargyl unit is engaged in a 6-endo-dig cyclization with the
olefin function, concomitant with the hydrolysis step.
Protodeauration is the final step that delivers the 3,6-
dihydropyridin-2(1H)-ones 2. Thus according to the postu-
lated mechanism, the stereochemistry of the final product
should be determined at the 6-endo-dig cyclization step and
might be controlled by suitable chiral gold(I) complexes. This
working hypothesis founds our work toward asymmetric
variants of these reactions. Also, this asymmetric process
allows us to expand the range of metal-catalyzed hydrative
the design of new catalysts and the development of innovative
methodologies.1 Among others, notable advancements in gold
catalysis relate to the Au-catalyzed oxidative cyclizations
involving the in situ formation of α-oxo gold carbenes from
alkynes and an external oxidant.2,3 The formation of these
highly reactive species from simple C−C triple bonds and
easily accessible gold(I) complexes avoids the hazardous
handling of diazo compounds. Numerous substrates were
used in these oxidative processes, such as enynes, propargylic
alcohols and esters, alkynylcyclopropanes, and others. Notably,
in 2013, Li developed the cyclopropanation of N-allyl-
ynamides, with pyridine N-oxide as the external oxidant
(Scheme 1a).4g According to the postulated mechanism, the
reaction involves an α-oxo gold carbenoid, which undergoes an
Scheme 1. Representative Gold(I)-Catalyzed Oxidative and
Hydrative Cyclizations
Received: July 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02644
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclizations8 and also to give a straightforward synthesis of this
skeleton of interest. Indeed, the 2(1H)-pyridone backbone and
the related dihydropyridinone rings are present in a wide
variety of naturally occurring alkaloids or biologically active
molecules. They are also very useful synthetic intermediates for
the preparation of other chiral nitrogen-containing molecules,
such as piperidin-2-one and piperidine derivatives.9
Table 1. Optimization of the Enantioselective Gold(I)-
Catalyzed Hydrative Cyclization of 1a
At the outset of this study, the N-tosyl-N-propargyl-ynamide
1a was selected as the model substrate to optimize the
conditions of the hydrative cyclization in the presence of chiral
gold complexes (Table 1). The reaction produces the desired
3,6-dihydropyridinone 2a together with variable amounts of
the phenylacetamides 3 and 4 in different ratios depending on
the catalysts and the solvents used. Compounds 3 and 4 result
from the hydration of either one or both of the alkyne units of
1a. The literature conditions, using the achiral [Au(JohnPhos)-
(CH3CN)]SbF6 catalyst and stoichiometric amounts of PTSA·
H2O in dioxane at room temperature, afford 2a as the major
product (95% yield), with <5% of the side product 3 (Table 1,
entry 1).7a A systematic screening of chiral gold(I) precatalysts
revealed that a gold(I) complex of the spiranic phosphor-
amidite (I) gives a 6:3:1 mixture of products and an almost
racemic dihydropyridinone 2a (Table 1, entry 2). The minor
products 3 and 4 are separable from the desired compound 2a
by column chromatography on silica gel. The bimetallic gold
chlorides of BINAP-type ligands (II) and (III), combined with
AgNTf2 as the silver salt in dioxane, led to an encouraging
80:20 enantiomeric ratio (er) as well as to a good
chemoselectivity, with a 2a/4 ratio of 8:2 (entries 3 and 4).
The gold(I) complexes of atropochiral diphosphines of the
MeO−BIPHEP series (IV−VII) did not significantly improve
the chemo- or the enantioselectivity levels (entries 5−8). The
best ligand of this series, V (entry 6), displays 2-furyl
substituents on phosphorus. It furnished the desired
dihydropyridinone 2a in ∼75% yield and with an 80:20 er.
Finally, the SEGPHOS−diphosphine IX (Ar = 3,5-Me2C6H3)
afforded the best results: a 80:20 ratio 2a/4 and a slightly
higher enantioselectivity with respect to BINAPs (er = 83:17,
entry 10). It is noteworthy that the (R)-(3,5-Me2C6H3−
SEGPHOS)(AuCl)2 precatalyst IX gives much higher stereo-
control than the more hindered (DTBM−SEGPHOS)(AuCl)2
catalyst VIII (entry 9, 61:39 er), showing the huge impact of
the phosphorus substituents of the diphosphine on the
reaction outcome. Starting from these satisfying preliminary
results, we continued the optimization studies on precatalyst
IX. We screened different silver salts as the chloride removal
agents under the same reaction conditions (in dioxane, at
room temperature) (entries 10−14). Among all of the AgX
salts tested (X = NTf2, OTf, SbF6, PF6, TFA, and BF4), silver
tetrafluoroborate (AgBF4) was identified as giving the best
results (87% NMR yield, 88:12 er, entry 14). Finally, a solvent
screening (entries 14−19) revealed that xylene is the best
solvent for this reaction, giving the chiral N-tosyl-3,6-
dihydropyridin-2(1H)-one 2a in 79% isolated yield and with
93:7 er (entry 19).10 A decrease in the reaction temperature to
0 °C did not improve this result (entry 20).
a
b
entry
[LAuCl]
X
solvent
2a/3/4
er 2a (%)
c
1
R2R′PAuCl
(I)
(II)
(III)
(IV)
(V)
(VI)
(VII)
(VIII)
(IX)
(IX)
(IX)
(IX)
(IX)
(IX)
(IX)
(IX)
(IX)
(IX)
(IX)
SbF6
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
OTf
SbF6
TFA
BF4
BF4
BF4
BF4
BF4
BF4
BF4
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
95/5/0
d
2
60/30/10
80/0/20
80/0/20
60/30/10
75/0/25
90/0/10
80/0/20
50/0/50
80/0/20
60/40/0
70/0/30
88/12/0
87/13/0
80/10/10
70/30/0
30/50/20
80/3/17
54:46
80:20
79:21
3
4
5
6
7
8
9
64.5:35.5
80:20
61:39
68:32
61:39
83:17
10
11
12
13
14
15
16
17
18
19
80.5:19.5
88:12
87.5:12.5
88:12
88.5:11.5
86:14
CH2Cl2
toluene
mesitylene
xylene
91:9
92:8
93:7
96:4
e
80 /3/17
60/10/30
f
20
xylene
a
Determined by 1H NMR using trimethoxybenzene as internal
standard. Determined by supercritical fluid chromatography (SFC)
on a chiral stationary phase. From ref 7a: [Au(JohnPhos)(CH3CN)]-
SbF6 catalyst (3 mol %), PTSA·H2O (2.5 equiv). 5 mol % of
AgNTf2. 79% isolated yield of 2a on a 0.05 mmol scale. At 0 °C.
b
c
d
e
f
First, the reaction tolerates the presence of substituted aryl
groups Ar1 on the propargylic unit (Scheme 2a). Substrates
with electron-donating methyl and methoxy substituents on
the aromatic groups furnished the corresponding dihydropyr-
idinones 2b−d in moderate to good yield and with
enantiomeric ratios ranging from 81:19 to 92:8. Some
electron-withdrawing groups such as chlorine and fluorine
are also well tolerated on the same aryl-propargyl moiety Ar1.
Compounds 2e−g have been obtained in 65−80% yield and
with up to 93:7 er. When comparing substrates 1d (Ar1 =
pMeOC6H4) and 1f (Ar1 = pFC6H4), it can be noticed that the
It must be noticed that this reaction has been scaled up to a
0.5 mmol scale while retaining the same enantioselectivity,
however, with a yield reduced to 43%. The scope of these
enantioselective gold-catalyzed hydrative cyclization reactions
was then investigated under the optimized conditions of entry
19 in Table 1. The results are displayed in Scheme 2.
B
DOI: 10.1021/acs.orglett.9b02644
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Enantioselective Gold(I)-Catalyzed Hydrative Cyclizations of Ynamides 1a−p
electron-withdrawing fluoride substituent in 1f increases the
reaction yield while keeping the same high enantioselectivity
level. We then investigated substrates with substituted aryl
groups Ar2 on the ynamide unit (Scheme 2b). Substrates
bearing electron-donating groups such as dimethyl, tert-butyl,
and methoxy groups proved to be well suited, affording the
corresponding dihydropyridinones 2h−j in up to 78% yield
with 73.5:26.5 to 83:17 er. Substrate 1k, displaying the
strongly electron-withdrawing trifluoromethyl substituent at
the para position of the aromatic group Ar2, gave the desired
product 2k in 40% yield, with a good 81:19 er. Finally,
substituted aryl groups have been used for both Ar1 and Ar2,
giving compounds 2l,m for Ar1 ≠ Ar2 and 2n−p, for Ar1 = Ar2
(Scheme 2c). Once again, yields are dependent on the
substitution of aromatic rings, and the enantiomeric ratios
range from 78:22 to 94:6. The electronic effect of the
substituents of either the ynamide or the propargylic moieties
could have an impact on the activation selectivity by gold of
these functions and therefore on the isolated yields.
It next appeared interesting to engage alkyl-substituted
substrates 1q−t in this catalytic transformation to establish the
full scope of our methodology (Scheme 3). The applicability
and scope of this transformation were examined with
functionalized and unfunctionalized alkyl chains at the
propargylic position (R1 = CH2OBn, nBu, nPent). The
corresponding compounds 2q−s were isolated in good yield
and with enantiomeric ratios ranging from 78:22 to 82:18. The
use of a 4-phenylbutynamine derivative (substrate 1t, R2 =
CH2CH2Ph) afforded the product 2t in 55% yield and with
low enantioselectivity (60/40 er). Overall, various substrates
are tolerated in this reaction, giving simple and efficient access
to highly functionalized dihydropyridinones.
Scheme 3. Extension of the Methodology to the Substrates
1q−t
the only expected product, whereas compound 7 represents an
unprecedented outcome of this class of reactions.
The mechanistic proposal in Scheme 4b accounts for the
production of both 6 and 7 through divergent reaction
pathways. The intermediate (II) is postulated to be formed
though the gold-promoted hydrative cyclization of substrate 5.
In this stage, the two possible pathways are the 6-endo-dig and
the 5-exo-dig cyclizations of the ene function with the pendant
alkyne unit to form products 6 and 7, respectively, after
aromatization and protodeauration steps. Both products have
been isolated and characterized by NMR analysis, and the
structures have been ascertained by X-ray diffraction studies.
This new synthetic method paves the way to the synthesis of
original 3,4-dihydronaphtho[1,2-f ]isoquinolinone and
tetrahydrobenzo[6,7]indeno[2,1-c]pyridinone derivatives. It
allows an efficient access to unprecedented polycyclic
compounds using a simple one-step procedure.11 Unfortu-
nately, using the optimized reaction conditions in Table 1, the
development of the asymmetric version of this transformation
has proved to be unsuccessful up to now.
To further expand the scope of this reaction, we synthesized
the naphthalene-tethered substrate 5 (Scheme 4a). With the
use of 3 mol % of the [Au(JohnPhos)(CH3CN)]SbF6 catalyst,
products 6 and 7 were formed in a 1:1 ratio and in 71% overall
yield. On the basis of previous literature,7b compound 6 was
In conclusion, we have demonstrated that the use of (3,5-
Me2C6H3−SEGPHOS)(AuCl)2 chiral catalyst IX, in combina-
C
DOI: 10.1021/acs.orglett.9b02644
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Organic Letters
Letter
Scheme 4. Synthesis of Tetracyclic Heterocycles 6 and 7
Angela Marinetti: 0000-0002-4414-073X
Arnaud Voituriez: 0000-0002-7330-0819
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The “Indo-French Center for the Promotion of Advanced
Research” (IFCPAR/CEFIPRA, project no. 5505-2, 2016) is
acknowledged for a post-doctoral grant to Y.S. We acknowl-
edge financial support from the “Agence Nationale de la
Recherche” (ANR) (Helphos project: ANR-15-CE29-0012-
01) for a Ph.D. grant to J.F. and from the “Centre National de
la Recherche Scientifique” (CNRS).
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02644.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
Accession Codes
CCDC 1935637−1935638 and 1957862 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: arnaud.voituriez@cnrs.fr.
*E-mail: angela.marinetti@cnrs.fr.
ORCID
Akhila K. Sahoo: 0000-0001-5570-4759
D
DOI: 10.1021/acs.orglett.9b02644
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Letter
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DOI: 10.1021/acs.orglett.9b02644
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