Gold(I)-catalyzed 6-endo-dig hydrative cyclization of an alkyne-tethered ynamide: Access to 1,6-dihydropyridin-2(3H)ones

Article abstract of DOI:10.1002/chem.201301599

Hydrate your chemistry! Hydrative cyclization of 5-yne-ynamides in the presence of Echavarren's catalyst and p-toluenesulphonic acid (PTSA)×H₂O at room temperature affords an array of 1,6-dihydropyridin-2(3H)one derivatives. Isomerization, epoxidation, and hydrogenation of the double bond and insertion of an extended π-conjugate system into the pyridinone skeleton have been successfully accomplished (see scheme; Ts=tosyl). Copyright

Full text of DOI:10.1002/chem.201301599

DOI: 10.1002/chem.201301599
Gold(I)-Catalyzed 6-endo-Dig Hydrative Cyclization of an Alkyne-Tethered
Ynamide: Access to 1,6-Dihydropyridin-2(3H)ones
[
a]
Nayan Ghosh, Sanatan Nayak, and Akhila K. Sahoo*
9428
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 9428 – 9433

COMMUNICATION
Lewis acid promoted cyclization of p-tethered ynamide
ration and tautomerization to afford the pyridinone moiety
as depicted in Scheme 1. The pyridinone structural motif is
present in a wide array of naturally occurring alkaloids and
derivatives affords a diverse array of nitrogen-bearing het-
[1]
erocycles in a single-step. The inherent polarization of the
nitrogen lone-pair to the ynamide triple-bond under the in-
fluence of p-acids/Brønsted acids enhances the electrophilic-
ity at the a-carbon to the nitrogen atom, which in turn pro-
pels regioselective attack of the nucleophile to a ketinimini-
[3]
pharmaceutically important molecules. Herein, we report a
novel strategy for the synthesis of 1,6-dihydropyridin-
2(3H)ones from easily accessible 5-yne-ynamides in the
[12]
presence of Echavarrenꢁs catalyst and p-toluenesulphonic
[1]
[11a]
um intermediate I (Scheme 1). Thus, intramolecular cycli-
acid (PTSA)·H O.
2
To test the feasibility of the reaction, we investigated the
[13]
Au-catalyzed hydrative cyclization of 1a first.
Table 1
summarizes the details of the optimization studies. Reaction
of substrate 1a with Echavarrenꢁs catalyst (A; 5 mol%) and
H O (1.0 equiv) in 1,4-dioxane at room temperature led to a
2
[
a]
Table 1. Optimization of reaction parameters.
[
b]
Entry Catalyst [mol%] Additive [equiv] Solvent
Yields [%]
2
a
3a/4a
Scheme 1. Known mode of reactivity of ynamides and reverse mode of
reactivity of 5-yne-ynamides in this study. EWG=electron-withdrawing
group; TM=transition metal; Ts=tosyl.
[c]
1
2
3
4
5
6
7
8
9
A (5)
A (5)
A (5)
A (5)
A (3)
B (5)
C (5)
D (5)
E (5)
F (5)
A (5)
A (5)
A (5)
A (5)
H
2
O (1)
dioxane
dioxane
dioxane
–
PTSA·H
PTSA·H
PTSA·H
2
2
2
O (1)
O (2)
40 45 (3:1)
20 63 (3:1)
O (2.5) dioxane
6
4
91 (1:0)
89 (1:0)
PTSA·H
2
O (2.5) dioxane
O (2.5) dioxane
O (2.5) dioxane
O (2.5) dioxane
O (2.5) dioxane
O (2.5) dioxane
O (2.5) THF
[
2a–c]
[2d]
zations of ene-ynamides,
allene-ynamides,
enyne-
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H O (2.5) acetonitrile
PTSA·H
PTSA·H O (2.5) THF
2
22 71 (9:1)
19 70 (1:2)
18 68 (3:1)
43 31 (3:1)
22 65 (6:1)
15 73 (3:1)
28 60 (9:1)
[2e]
[2f]
ynamides, arene-ynamides, and various other p-nucleo-
phile-tethered ynamide derivatives
2
2
2
2
2
2
[2g,h]
have successfully
been carried out for the synthesis of novel biologically im-
[3]
10
portant nitrogen-containing molecules. Furthermore, the
1
1
1
2
[
4]
[5]
intermolecular oxidations, nucleophilic additions, and cy-
O (2.5) toluene
[
6]
[
d]
cloadditions of ynamides have been well explored. An ele-
gant approach for ynamide alkyne dimerization has also
13
14
15
–
2
[
[
[
e]
f]
f]
2
O
A
H
U
G
R
N
U
G
37 48 (1:0)
65 29 (1:0)
68 15 (1:0)
[7]
In
Cu
Pd(OAc)
ACHTUNGTRENNUNG( OTf)
2
2
been demonstrated recently.
16
17
18
A
H
U
G
R
N
U
G
2
PTSA·H
PTSA·H
PTSA·H
2
2
2
O (2.5) THF
(2.5) dioxane
O (2.5) dioxane
A detailed literature survey revealed that cyclization of
unactivated-yne-tethered ynamides in the presence of transi-
[f]
[d]
A
T
N
R
N
N
2
O
A
H
U
G
E
N
N
–
98
[g]
–
[8]
tion-metal-p-acid is rare. Despite the ambivalent nature of
ynamides, regioselective attack of the nucleophile followed
by cyclization to the tethered-alkyne moiety has not yet
been explored. Our inherent interest in developing novel
[
a] Catalyst A: [Au
AgSbF ; C: [Au(JohnPhos)
(Ph P)]/AgSbF F: [AuCl
A
H
U
G
R
N
U
G
A
H
U
G
E
N
N
6
;
B: [AuCl
(IPr)]/AgSbF
Reaction conditions: 1a
0.2 mmol), solvent (3.0 mL). [b] Isolated yields. [c] Complex reaction
profile. [d] Decomposition of 1a occurred. [e] Reaction was heated at
08C for 2 h. [f] Catalyst (5 mol%). [g] Monohydration of 1a. Tf=triflur-
ACHTUNGTRENNUNG
6
A
H
U
T
E
N
G
A
H
N
R
N
U
2
A
H
U
G
E
U
6
A
H
U
G
R
N
U
3
6
;
A
H
U
G
R
N
N
3
2
.
(
[9,10]
Au-catalyzed transformations
inspired us to apply the
6
concept of hydrative cyclization of 1,n-diynes to 5-yne-
omethanesulfonyl. PTSA=p-toluenesulfonic acid.
[11]
ynamides in the presence of an Au catalyst in this study.
We envisioned that preferential attack of a foreign nucleo-
phile, such as H O, to the a-carbon atom of the ketenimini-
complex reaction mixture with the complete consumption of
the precursor (Table 1, entry 1). To our delight, use of
PTSA·H O (1.0 equiv) instead of H O produced a mixture
2
um intermediate, would trigger 6-endo-dig cyclization of the
b-carbon atom of the keteniminium-p-bond with the TsN-
propargyl-alkyne-activated species, followed by protodeau-
2
2
of inseparable cyclized product 3a and dihydration product
a in a 3:1 ratio in 45% yield; the monohydration product
4
[
a] N. Ghosh, S. Nayak, Prof. Dr. A. K. Sahoo
School of Chemistry, University of Hyderabad
Hyderabad-500046 (India)
Fax : (+91)40-23134822
E-mail: akhilchemistry12@gmail.com
Homepage: http://chemistry.uohyd.ernet.in/~aks/
2a was also obtained in 40% yield (entry 2). The combined
yield of 3a and 4a was increased to 63% when PTSA·H O
2
(
2.0 equiv) was employed in the reaction (entry 3). Surpris-
ingly, the hydrative cyclization of 1a in the presence of
PTSA·H O (2.5 equiv) proceeded well, forming 3a in 91%
2
yield; although a trace amount of 2a was detected by
H NMR spectroscopy of the crude reaction mixture
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301599.
1
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www.chemeurj.org
9429

A. K. Sahoo et al.
[
a]
(
entry 4). The structure of 3a was confirmed by detailed
Table 2. Substrate scope of 1.
[14]
spectroscopic analysis and X-ray crystallographic studies.
The lower loading of catalyst A (3 instead of 5 mol%) did
not show pronounced effect in the product yield, delivering
8
9% of 3a (entry 5). Screening of other Au catalysts (en-
tries 6–10) revealed that catalyst A was uniquely effective
entries 4 and 5). Solvent effect was next examined, for ex-
(
ample, THF and toluene were found to produce moderate
results (entries 11 and 12). Unfortunately, the reaction in
acetonitrile led to the decomposition of the precursor 1a
(
entry 13). The products 3a (48%) and 2a (37%) were
cleanly isolated when the reaction was conducted at 608C
for 2 h (entry 14). Attempts to cyclize 1a in the presence of
In
fording 2a as the major product (entries 15 and 16). Decom-
position of precursor 1a was observed when Pd(OAc) was
ACHTUNGTRENNUNG( OTf) or Cu ACHTUNGTRENNUNG( OTf) also produced moderate results af-
2
2
AHCTUNGTRENNUNG
2
used as the catalyst (entry 17). Surprisingly, 1a underwent
monohydration with PTSA·H O (2.5 equiv) in dioxane at
2
RT in 30 min (entry 18), justifying the participation of the
reactive ketiniminium intermediate. Thus, the occurrence of
highly selective 6-endo-dig hydrative cyclization of 1a under
the influence of the mixture of Au catalyst and PTSA·H O
2
in the formation of pyridinone 3a appears to be interesting
and noteworthy.
The substrate generality of this reaction is investigated
under the optimized catalytic conditions shown in entry 5 in
Table 1. The results are summarized in Table 2. As observed
in the optimization studies, the electron-neutral phenyl ring
bearing substrate 1a gave the cyclization product 3a in 89%
yield. The electron-donating groups, such as p-Me and p-
OMe on arene did not affect the reaction efficiency and fur-
nished the desired 1,6-dihydropyridin-2(3H)one derivatives
3
b and 3c in good yields. The N-heterocyclic dihydropyridi-
none products 3d–g were isolated in lucrative yields from
the corresponding electron-withdrawing halo group contain-
ing precursors 1d–g. The Au-catalyzed hydrative cyclization
of meta-substituted arene in 5-yne-ynamide 1h resulted in
the desired product 3h in 83% yield. The electron-donating
methyl- or the methoxy-groups and the electron-withdraw-
ing bromo- or iodo-groups at the ortho-position on the
arene rings did not affect the reaction efficiency and the de-
sired products 3i–l were isolated in good yields. X-ray dif-
[
(
[
2
a] Reaction conditions: 1 (0.25 mmol), catalyst A (3 mol%), PTSA·H O
0.63 mmol), 1,4-dioxane (3.0 mL), RT, 4 h. Isolated yields are given.
b] Reaction completed in 2 h. [c] A minor amount of the inseparable di-
hydration product was detected along with the cyclization product.
drative cyclization, as a result 3t was obtained in low yield.
Examination of the alkyl substituents at the N-propargyl
alkyne terminus was next studied. Gratifyingly, various 4-
alkyl-3-phenyl-substituted
1,6-dihydro-pyridin-2(3H)ones
[14]
fraction data elucidates the structure of 3k. Similarly, the
naphthyl-bearing product 3m was isolated in 76% yield.
Gratifyingly, this reaction delivered the 2-thienyl and N-pro-
tected 3-indolyl-substituted 1,6-dihydropyridin-2(3H)one
products 3n and 3o, respectively, with ease. Similarly, sub-
strate 1p produced 3p in moderate yield. The precursors
3u–w were synthesized in excellent yields. The pyridinones
3x and 3y were successfully isolated in 74 and 81% yield,
respectively, from the substrates bearing an alkyl group at
the alkyne terminus of the ynamide side. Interestingly, the
presence of the alkyl-group at both sides of the alkyne ter-
minus did not affect the hydrative cyclization, producing the
desired 3z in 83% yield.
1
q–s containing two electron-donating methyl or methoxy
groups on arenes in m-/m-, m-/p-, or o-/p- positions success-
fully underwent hydrative cyclization yielding the 3q–s in
good yields. However, the di-ortho-methoxy-substituted 1t
resulted in moderate amounts of 3t; even though the reac-
tion continued for prolonged time, incomplete conversion of
the starting material was observed along with the isolation
We next examined the effect of the substituents on the
aryl-group at the TsN-alkyne terminus keeping the phenyl
group at the TsN-propargyl-alkyne terminus fixed. The re-
sults are described in Table 3. Thus, substrates 5a–e bearing
electron-withdrawing groups on the aryl ring underwent cyc-
lization efficiently and the desired products 6a–e were pro-
duced in moderate to good yields. Ester, carbonyl, and
nitro-functional groups did not affect the reaction efficiency
[15]
of the monohydration product 2t. The steric effect of two
ortho-OMe groups on the aryl ring hinders the effective hy-
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Access to 1,6-Dihydropyridin-2(3H)ones
COMMUNICATION
[a]
Table 3. Substrate scope of 2.
the pyridinone derivatives could be useful for the prepara-
tion of optically active analogues by asymmetric hydrogena-
tion, complex structural entities by the Diels–Alder reac-
tion, and extended p-conjugated systems through oxidative
dehydrogenative coupling of the aryl moieties.
We next turned our attention to explore the CÀO bond-
forming reactions on 3a. Epoxidation on 3a with m-chloro-
perbenzoic acid (m-CPBA) gave the desired product 8 in
9
2% yield (Scheme 2). Furthermore, hydrogenation of 3a
[
a] Reaction conditions:
5
(0.25 mmol), catalyst
A
(3.0 mol%),
PTSA·H
2
O (0.63 mmol), 1,4-dioxane (3.0 mL), RT. Isolated yields are
given. [b] A minor amount of the inseparable dihydration product was
detected along with the cyclization product.
Scheme 2. Epoxidation and hydrogenation of 3a.
and the product yields. Similarly, hydrative cyclization of 5 f,
containing
electron-rich
3,5-dimethylphenyl-substituted
TsN-ynamide gave 6 f in good yield. The presence of elec-
tron-withdrawing and/or -donating groups on the aryl rings
at both the alkyne terminus of 5 did not affect the reaction
outcome, delivering the desired cyclization products 6g and
was smoothly carried out with H /Pd/C in EtOAc and the
2
product cis-9 was exclusively obtained in excellent yield.
Similarly, the isomerized compound 7a under identical hy-
drogenation conditions gave cis-9. The cis-stereochemistry
of compound 9 was confirmed by X-ray crystallographic
6
h in 69 and 81% yields, respectively. The yield of the cy-
[14]
clized product 6i, obtained from the substrate bearing the
thienyl and p-ClC H groups at both the alkyne terminuses,
analysis (Scheme 2).
The iodo-group in the molecular template 1,6-dihydropyr-
idin-2(3H)ones was successfully employed to introduce ex-
tended p-conjugated systems by Suzuki and Sonogashira re-
actions (Scheme 3). For instance, Suzuki reaction of 7g with
6
4
was excellent.
This methodology demonstrates the synthesis of 1,6-dihy-
dropyridin-2(3H)ones with broad substrate scope and with
the toleration of various functionalities and protecting
groups. Next, we envisioned isomerization of the nonconju-
gated double bond to a conjugated double bond considering
the advantage of the acidic proton at the 3-position. Pleas-
ingly, compound 3a was converted to 7a (92% yield) upon
PhB(OH) under Pd ACHTUNGTRENNUN(G OAc) and Na CO in DMF/H O deliv-
2 2 3 2
2
[16]
ered 10 in 91% yield. An excellent yield of the Sonoga-
shira product 11 was obtained from 7g and phenyl acetyl-
[17]
AHCTUNGTERNNUNGe ne.
refluxing with Et N in EtOAc (Table 4). Under identical
3
conditions, 3g, 3l, and 3o were smoothly isomerized to the
corresponding products 7g, 7l, and 7o, respectively. The re-
sults are shown in Table 4. The conjugated double bond in
Table 4. Isomerization of the nonconjugated double bond.
Scheme 3. Synthesis of extended p-conjugated systems.
Formation of new CÀC bonds at the periphery of the 1,6-
dihydropyridin-2(3H)one derivative would generate highly
substituted six-membered pyridinone derivatives. We there-
fore envisioned the reaction of 3k with an electrophile in
the presence of a strong base. Abstraction of the acidic 3H
proton by lithium diisopropylamide (LDA) generated the
corresponding allylic anion and subsequent isomerization
Chem. Eur. J. 2013, 19, 9428 – 9433
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9431

A. K. Sahoo et al.
and attack of the allylic anion to p-bromobenzaldehyde af-
forded 12 in 62% yield [Eq. (1)].
Scheme 5. Mechanistic study.
the cyclized product 3a even in trace amounts, ruling out
the possible involvement of 2a as an intermediate in the
synthesis of 3a (Scheme 5).
We next investigated the incorporation of a modifiable
functional group, for example, an ester moiety, into the 1,6-
dihydropyridin-2(3H)one skeleton. The precursor 13 re-
quired for this study was readily prepared from 1’’a and
The plausible reaction pathway for this cyclization reac-
tion is outlined in Scheme 6. Although the actual role of
PTSA·H O is yet to be established, on the basis of the ob-
2
[13]
ethyl 3-bromopropiolate. Hydrative cyclization of 13 with
catalyst A (3 mol%) and PTSA·H O (2.5 equiv) in acetoni-
2
trile at RT afforded the isomerized product 14, albeit in
moderate yield (Scheme 4). Hydrogenation of 14 with H2/
Scheme 6. Proposed catalytic cycle.
servations in the optimization studies (Table 1, entry 18), it
appears the catalyst A and PTSA·H O react with compound
2
[1,7]
À
1
a and generate the intermediate II.
Attack of ArSO3
to II and subsequent 6-endo-dig cyclization of the enolate
I
III to the Au -activated TsN-propargyl triple bond affords
the cyclic vinyl–Au species IV, which undergoes tautomeri-
zation, hydrolysis, and protodeauration to yield the desired
product 3a. Finally, the cationic Au complex is regenerated
for use in the next catalytic cycle. The mono- and dihydra-
tion side products 2a and 4a are presumably obtained from
intermediate III.
Scheme 4. Synthesis of ester-substituted dihydropyridinone derivative 14:
a) 13 (0.25 mmol), PTSA·H
2
O (0.63 mmol), catalyst A (3 mol%) in
CH CN (3.0 mL), RT, 4 h, 58%; b) silica gel.
3
Pd/C in EtOAc provided a quantitative amount of cis-15; X-
In summary, we have shown a novel synthetic route to
1,6-dihydropyridin-2(3H)ones through hydrative cyclization
of the easily accessible 5-yne-ynamides in the presence of
[14]
ray crystallographic analysis confirms its structure. Com-
pound 15 can be further used for the synthesis of various an-
alogues of cis-paroxetine and cis-femoxetine drugs, which in-
dicates the broad scope of application of this synthetic strat-
egy.
Echavarrenꢁs catalyst and PTSA·H O at room temperature.
2
The proposed reaction proceeds easily to afford the product
in good to excellent yields and exhibits broad substrate
scope; moreover, various functional groups are tolerated.
Isomerization, epoxidation, and hydrogenation of the
double bond are successfully demonstrated. Sonogashira
and Suzuki reactions at the iodo group help in the introduc-
tion of an extended p-conjugated system into the pyridinone
skeleton. Investigations aimed at applying this methodology
for the synthesis of complex molecular frameworks and in
The formation of 2a as the side product in the hydrative
cyclization of 1a indicated the participation of this active in-
termediate in this reaction. To validate this presumption,
substrate 2a was prepared from 1’’a and phenylacetic acid
through N’-(3-dimethylaminopropyl)-N-ethylcarbodiimide
[18]
(
EDC) coupling. Unfortunately, the reaction of 2a under
the optimized conditions (Table 1, entry 5) did not afford
9432
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Access to 1,6-Dihydropyridin-2(3H)ones
COMMUNICATION
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India for a fellowship.
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Keywords: gold catalysis
·
heterocycles
·
hydrative
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1
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Received: April 25, 2013
Published online: June 20, 2013
Chem. Eur. J. 2013, 19, 9428 – 9433
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9433