P-TsOH Promoted Au(I)-Catalyzed Consecutive Endo Cyclization of Yne-Tethered Ynamide: Access to Benzofused Dihydroisoquinolones

Article abstract of DOI:10.1021/acs.orglett.5b02946

A novel synthetic route to benzo[f]dihydroisoquinolone through a p-TsOH promoted cascade cyclization of easily accessible diyne-tethered ynamides in the presence of a Au(I)-catalyst is described. This reaction unveils a broad substrate scope, constructing a wide range of benzo[f]dihydroisoquinolones in good yields. The diyne-tethered ynamides are synthesized from inexpensive o-iodoaniline through Sonogashira couplings and the Cu-mediated C-N bond formation. The role of p-TsOH is examined, and the reaction pathway is also deduced. The benzo[f]isoquinoline scaffold is constructed from benzo[f]dihydroisoquinolones.

Full text of DOI:10.1021/acs.orglett.5b02946

Letter
pubs.acs.org/OrgLett
p‑TsOH Promoted Au(I)-Catalyzed Consecutive Endo Cyclization of
Yne-Tethered Ynamide: Access to Benzofused Dihydroisoquinolones
Sanatan Nayak, Nayan Ghosh, B. Prabagar, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad-500046, India
S
* Supporting Information
ABSTRACT: A novel synthetic route to benzo[f]dihydro-
isoquinolone through a p-TsOH promoted cascade cyclization
of easily accessible diyne-tethered ynamides in the presence of
a Au(I)-catalyst is described. This reaction unveils a broad
substrate scope, constructing a wide range of benzo[f]dihydro-
isoquinolones in good yields. The diyne-tethered ynamides are
synthesized from inexpensive o-iodoaniline through Sonoga-
shira couplings and the Cu-mediated C−N bond formation. The role of p-TsOH is examined, and the reaction pathway is also
deduced. The benzo[f ]isoquinoline scaffold is constructed from benzo[f ]dihydroisoquinolones.
soquinoline derivatives are potentially useful building blocks
widely found in natural products and pharmaceutically active
Scheme 1. Ynamide As Enol Equivalent for Cascade
Cyclization/1,5-Enyne Cycloisomerization Strategy
I
compounds (Figure 1).1 In general, the isoquinoline frameworks
Figure 1. Isoquinoline derivatives containing natural products.
are readily manufactured from the dihydroisoquinolone motifs.2
The benzo[f]isoquinolines, another class of fused N-hetero-
cycles, structurally resemble the isoquinoline derivatives. Thus,
the benzo[f ]isoquinolines analogues, which can be easily
accessed from benzo[f]dihydroisoquinolones, show interesting
biological properties as do isoquinoline derivatives. With our
current research interest in ynamides, we intend to investigate
Au(I)-catalyzed cascade cyclization of diyne-tethered ynamide,
which will eventually lead to the step-efficient synthesis of an
unprecedented benzo[f ]dihydroisoquinolone core (eq 2,
Scheme 1).3−5
In general, the preformed alkyne-bearing enol-ethers 1 [alkyl/
silyl enol ethers, and silyl ketene amides] are efficiently employed
in Au-catalyzed cyclizations (Scheme 1).6 In contrast, the
intramolecular cyclization of an in situ generated vinyl-Au-
species, formed through an exo/endo-cyclization of enol-ethers
and a pendant alkyne moiety in 1, with the tethered-yne motif, is
less explored.7 Likewise, cascade electrophile promoted nucleophilic
cyclization (EPNC) of diyne-bearing species 2 directly constructs
polyfused heterocycles in a single operation; these trans-
formations explicitly involve 5-endo-dig/6-endo-dig cyclizations.8
Despite this notable success, the cascade reaction of diyne-
tethered ynamide is so far unprecedented (Scheme 1). We thus
envisaged the formation of benzo[f ]dihydroisoquinolone 4
through the cascade EPNC reaction of transient enol-ether 3′
(ketene N,O-acetal), readily generated involving the facile attack
of p-TsOH to the ambivalent ynamide 3 in situ (eq 2, Scheme
1).9 We could foresee a 6-endo-dig cyclization of 3′ with the
suitably substituted yne motif in the presence of a Au(I)-catalyst
to form a six-membered vinyl-gold intermediate, a perfect 1,5-
enyne precursor, which subsequently undergoes cyclization
followed by aromatization to result 4 (eq 2, Scheme 1).10 We
herein show a convergent synthetic manifestation engendering
benzo[f ]dihydroisoquinolones from easily accessible diyne-
tethered ynamides through Au-catalysis in the presence of p-
TsOH.
To directly access the benzo[f ]dihydroisoquinolone skeleton,
investigation was initiated to examining Brønsted acid promoted
Au(I)-catalyzed consecutive endo-cyclizations of diyne-tethered
ynamide 3a. Accordingly, compound 3a was synthesized from
the inexpensive 2-iodoaniline involving consecutive Sonogashira
reactions followed by C−N bond formation in four steps with
overall appreciable yield.11 The ynamide unit is usually
Received: October 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02946
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Letter
a
surprisingly occurred, when 3a and p-TsOH were stirred in
dioxane at rt for 10 min; subsequently, catalyst A in DCE was
introduced and the reaction was continued at rt until the
disappearance of the intermediate species; finally, heating the
resulting mixture at 80 °C for 20 h led to 4a in 83% yield (entry
11). Under the identical conditions in entry 11, other catalysts
turned moderate (entries 12 and 13). Regrettably, reaction under
Ag-catalysis exclusively provided 3a″ (entries 14 and 15).
We next set out to examine the scope of Au-catalyzed cascade
cyclization of diyne-tethered ynamides 3 for the construction of
benzo[f ]dihydroisoquinolone skeletons 4 and 5 (Figures 2 and
Table 1. Optimization of the Reaction Conditions
c
yield (%)
b
entry
catalyst (mol %)
solvent
CH3CN
3a″
−
4a′
4a
1
2
3
4
5
6
7
8
9
10
A (5)
A (5)
A (5)
B (5)
C (5)
D (5)
E (5)
F (5)
A (5)
A (5)
A (5)
B (5)
D (5)
G (5)
H (5)
dioxane
6
35
−
20
35
40
5
50
−
20
40
48
−
dioxane
80
45
10
−
79
82
trace
0
dioxane
dioxane
dioxane
dioxane
dioxane
−
−
25
−
−
DCE
dioxane/DCE
dioxane/DCE
dioxane/DCE
dioxane/DCE
dioxane/DCE
dioxane/DCE
62
83
60
50
−
d
11
0
5
d
12
−
−
85
30
30
−
d
13
14
15
82
−
−
a
Reactions were carried out using 3a (0.2 mmol), p-TsOH (0.3
Figure 2. Substrate Scope I. Reactions were carried out using 3 (0.2
mmol), p-TsOH (0.3 mmol), catalyst A (5.0 mol %) in dioxane/DCE
(1:2, 3.0 mL) at rt−80 °C for 24 h. Isolated yields.
mmol), and catalyst (5.0 mol %) in solvent (3.0 mL) at rt−80 °C for
b
−
24 h. Catalyst A: JohnphosAu(I) (NCMe)]+SbF6 ; B: Johnpho-
sAuNTf2; C: JohnphosAuCl + AgSbF6; D: IPrAuCl + AgSbF6; E:
Ph3PAuCl + AgSbF6; F: Ph3PAuCl + AgNTf2; G: AgSbF6; H: AgNTf2.
c
d
Isolated yields. Reaction was conducted by stirring 3a and p-TsOH
3). First, ynamide 3 having a variation of substitutions on the aryl
moiety on the alkyne terminus was surveyed under the catalytic
conditions shown in entry 11, Table 1 (Figure 2). The ynamide
3a produced 4a in 83% yield. Interestingly, cascade cyclization of
ynamides 3b and 3c (o-substitution on the aryl group) provided a
1:1 mixture of two atropisomers of the corresponding 4b and 4c
in dioxane for 10 min followed by addition of catalyst in DCE and
continued for 4 h at rt, and finally heating the resulting mixture for 20
h at 80 °C.
responsive to acid catalysts and H2O; we could thus anticipate
the formation of amide 3a″, dihydropyridinone 4a′, and the
desired 4a from 3a (Table 1).
To validate workable conditions for the construction of 4a, an
investigation was initiated exposing 3a to p-TsOH (1.5 equiv) in
the presence of Echavarren’s catalyst A (5.0 mol %) in CH3CN at
room temperature (rt); to our dismay, 3a did not survive,
providing a complex mixture (entry 1). Gratifyingly, 4a (50%)
was isolated along with 3a″ (6%) and 4a′ (35%), when the
reaction was performed in dioxane at rt (entry 2); in contrast,
reaction at 80 °C exclusively delivered 3a″ (entry 3). The use of
JohnphosAuNTf2 led to a poor amount of 4a (entry 4). The use
of a combination of catalysts (JohnphosAuCl/IPrAuCl with
AgSbF6 and Ph3PAuCl and AgSbF6/AgNTf2) was inferior
(entries 5−8). Catalyst A thus appeared to be the best (entry
2). The effect of solvents was next surveyed. The reaction of 3a
with catalyst A and p-TsOH in ClCH2CH2Cl (DCE) provided a
trace amount of 3a″ with incomplete consumption of 3a at 80 °C
(entry 9); the inadequate solubility of p-TsOH in DCE is
presumably responsible for the poor outcome. Results from
entries 2 and 9 thus inspired us to scrutinize the mixture of
solvents for this study. Interestingly, the reaction in dioxane and
DCE (1:2) resulted in a 62% yield of 4a, 4a′ (25%), and 3a″
(0%) at rt (entry 10). Due to this observation, the reaction was
pursued by performing it at various temperatures through
sequential addition of reagents.11 Complete consumption of 3a
Figure 3. Substrate Scope II. Reactions were carried out using 3 (0.2
mmol), p-TsOH (0.3 mmol), catalyst A (5.0 mol %) in dioxane/DCE
(1:2, 3.0 mL) at rt−80 οC for 24 h. Isolated yields.
B
DOI: 10.1021/acs.orglett.5b02946
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Letter
in good yields. The m- and p-substitution on the aryl moiety in
the alkyne terminus did not affect the reaction outcome affording
4d−f (76−80%), 4g (82%), 4h (85%), and 4i (69%). Ynamide 3j
[different aryl moiety on alkyne and ynamide terminus]
smoothly underwent cascade cyclization to yield 82% of 4j.
The N-Ms/-Ns protecting groups were tolerated providing the
desired 4k and 4l in good yields. Similarly, 4m was constructed in
60% yield.
Scheme 3. Control Experiment
Next, the effect of substitutions on the ynamide terminus in 3
was examined for the Au-catalyzed cascade cyclization (Figure
3). The substitutions at the o-, m-, or p- position on the aryl
moiety at the ynamide terminus in 3 did not show a pronounced
effect, constructing the respective 4n−v in good yields. The
structure of 4o was further confirmed by X-ray crystallographic
analysis (Figure 3).11 The modifiable functional groups −NO2
and −COCH3 were inert under the optimized conditions; the
−CF3, Cl, and I moieties did not show an adverse effect and were
tolerated. Likewise, the benzo[f ]dihydroisoquinolones 4w
(80%) and 4x (84%) were readily accessed from 3w and 3x
holding two-methyl or OMe and COMe substituents on the aryl
moiety at the ynamide terminus. Gatifyingly, the thiophenyl
bearing ynamide 3y effectively underwent cyclization to provide
4y in 75% yield. The effect of the aliphatic substituent at the
ynamide terminus in 3 was next surveyed (Figure 3). Pleasingly,
the alkyl moiety containing ynamides under the optimized
conditions delivered the nonseparable mixture of rotamer of the
designed products 5a/5a′ = 5:1 and 5b/5b′ = 7:1 in 69% and
72% yield, respectively.11 The cyclopropyl group on the ynamide
survived in the reaction, generating the mixture of rotamers 5c
and 5c′ = 4:1 in 73% yield.11 Thus, the current method
developed for benzo[f ]dihydroisoquinolones synthesis from
diyne-tethered ynamides proved to be general and broad
(Figures 2 and 3).
4a′ confirms the participation of the Au-vinyl complex (Scheme
3), when the reaction was performed with the Au-catalyst and p-
TsOH (3.0 equiv) in dioxane for 4 h at rt. Subsequently, heating
4a′ with a Au-catalyst in DCE at 80 °C delivered 4a (Scheme
3).9a,b
To further support the involvement of 3a′ and the source of
oxygen in this transformation, the reaction of 3a with a Au-
catalyst in H218O (in the absence of p-TsOH) was conducted.
The amide product 3a″-18O with the insertion of 18O has
exclusively been obtained (HRMS, Scheme 4).11 While the
Scheme 4. Isotopic Labeling Experiment
reaction of 3a with p-TsOH in H218O under Au-catalysis
delivered 4a (80%); the incorporation of 18O is not observed
(HRMS, Scheme 4).11 It appears that the attack of p-TsOH to 3a
is facile over H2O, resulting in the rapid formation of enol-ether
3a′ (Scheme 3).
We next explored the makeover of benzo[f ]dihydro-
isoquinolone to benzo[f ]isoquinoline. The B2H6 mediated
amide reduction of 4k followed by N-Ms deprotection of 6
with Red-Al furnished 1,5-diphenyl-1,2,3,4-tetrahydrobenzo[f]-
isoquinoline 8 (Scheme 2). The reductive cleavage of the N-Ns
On the basis of the studies shown in Schemes 3 and 4, the
probable mechanistic path for the synthesis of 4 from 3 is
deduced (Scheme 5).5e The reaction initiates with the formation
Scheme 5. Plausible Mechanistic Cycle
Scheme 2. Synthesis of Benzo[f]isoquinoline Derivative
moiety of 4l provided 7; subsequently LiAlH4 reduction of the
amide moiety of 7 directly led to 8 (Scheme 2). Finally, oxidative
dehydrogenation of 8 with Pd/C delivered 1,5-diphenylbenzo-
[f ]isoquinoline 9 in 68% yield (Scheme 2).11
The participation of transient ketene N,O-acetal 3a′ (outlined
in eq 2, Scheme 1) for the synthesis of 4 from 3 under the Au(I)-
catalyzed cascade cyclization is established with the character-
ization of 3a′ (NMR and HRMS study), which is rapidly
obtained in situ from 3a and p-TsOH in dioxane at rt in 10 min
(Scheme 3). Furthermore, the isolation of monocyclic species
of ketene N,O-acetal 3a′, which is realized through the attack of
p-TsOH to the keteniminium intermediate of ynamide 3a.
Although both alkyne motifs undergo activation by a Au-catalyst,
the stereoelectronic effect on ketene N,O-acetal I favors 6-endo-
dig cyclization with the proximal Au(I) activated alkyne unit to
afford monocyclic vinyl−Au species II.7 The intermediate II
undergoes hydrolysis to result III and simultaneously proceeds in
the intramolecular cyclization of the ene moiety with the Au-
activated alkyne species to attain IV. Finally, aromatization and
C
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Weingand, V.; Rominger, F.; Hashmi, A. S. K. Chem. - Eur. J. 2013, 19,
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4a releasing the Au-complex for the next cycle. On the other
hand, the formation of 4a′, a 1,5-enyne surrogate, is possible with
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temperature, 4a′ undergoes 6-endo cyclization to generate IV
under Au-catalysis.10
In summary, a novel synthetic route to benzo[f ]dihydro-
isoquinolone through the p-TsOH promoted cascade cyclization
of the easily accessible diyne-tethered ynamides in the presence
of a Au(I) catalyst was demonstrated. The reaction exhibited
broad scope and tolerated common functional groups. Benzo-
[f ]isoquinoline was realized through the peripheral modifica-
tions of benzo[f ]dihydroisoquinolone. The reaction pathway
was deduced based on the detailed studies of intermediates.
Application of this method for the construction of a structurally
complex framework is currently being pursued.
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02946.
Experimental procedures (PDF)
Compound characterization data (PDF)
Crystallographic data for 4o (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: akhilchemistry12@gmail.com; akssc@uohyd.ac.in.
Notes
The authors declare no competing financial interest.
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2008, 130, 17642. (h) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.;
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ACKNOWLEDGMENTS
■
This manuscript is dedicated to Prof. D. Basavaiah, School of
Chemistry, University of Hyderabad for the development of the
Baylis−Hillman−Basavaiah (BHB) reaction and for his 65th
birthday. S.N, N.G., and P.B. thank CSIR, India for a fellowship.
Mr. Krishna Chari, UoH is thanked for the X-ray crystallographic
analysis.
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NOTE ADDED AFTER ASAP PUBLICATION
Scheme 4 was corrected on November 3, 2015.
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DOI: 10.1021/acs.orglett.5b02946
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