One-Pot Two-Step Double Annulation of N-Methoxybenzamides with Alkynes and Alkenes: Regioselective Construction of Isoindolo[2,1-b]isoquinolin-5(7H)-ones

Article abstract of DOI:10.1002/adsc.202100414

A one-pot two-step double annulation strategy to produce isoindolo[2,1-b]isoquinolin-5(7H)-ones via the reaction of N-methoxybenzamides with symmetrical/unsymmetrical alkynes and alkenes has been developed, which proceeds through Ru-catalysed unsymmetrica

Full text of DOI:10.1002/adsc.202100414

Title: Ru(II)-Catalyzed Sequential One-Pot Double Annulation of N-
Methoxybenzamides with Symmetrical/Unsymmetrical Alkynes
and Alkenes: Regioselective Construction of Isoindolo[2,1-
b]isoquinolin-5(7H)-one Framework
Authors: Praveen Kumar Naikawadi, Lingaswamy Mucherla, Rambabu
Dandela, Madhavi Sambari, and Shiva Kumar Kota
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202100414
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10.1002/adsc.202100414
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
One-Pot
Two-Step
Double
Annulation
of
N-
Methoxybenzamides with Alkynes and Alkenes: Regioselective
Construction of Isoindolo[2,1-b]isoquinolin-5(7H)-ones
Praveen Kumar Naikawadi, a Lingaswamy Mucherla,a Rambabu Dandela,b Madhavi
Sambari,a K. Shiva Kumara*
aDepartment of Chemistry, Osmania University, Hyderabad-500 007, India
E-mail: shivakumarkota@yahoo.co.in; shivakumarkota@osmania.ac.in
bDepartment of Industrial and Engineering Chemistry, Institute of Chemical Technology, IOC-Odisha Campus,
Samantpuri, Bhubaneswar-751013, India
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
α-diazo-1,3-diketones,[8]
sulfoxonium ylides,[9]
Abstract. A one-pot two-step double annulation strategy to
produce isoindolo[2,1-b]isoquinolin-5(7H)-ones via the alkynes,[10] carbon monoxide,[5b] benzoquinone[11]
and carbon dioxide[12] in the second step has been
achieved.
reaction
of
N-methoxybenzamides
with
symmetrical/unsymmetrical alkynes and alkenes has been
developed, which proceeds through Ru-catalysed
unsymmetrical double annulations using a single DG under
single catalytic conditions. Furthermore, we have
developed amide-alkyne regioselective annulations using
unsymmetrical internal alkynes having oxygen/nitrogen
substituents leading to a single isomer. The developed
procedure offers broad substrate scope, tolerates a wide
range of functional groups and affords good product yields.
Keywords: isoindolo[2,1-b]isoquinolin-5(7H)-one;
regioselective; ruthenium; annulations; amides
Introduction
The one-pot annulation strategy has emerged as an
ideal one-step powerful platform to furnish various
structurally novel complex molecules, particularly
polycyclic heteroaromatic systems with extended
conjugation.[1] In this regard, tandem cyclization via
transition metal (TM)-catalysed and directing group
(DG)-supported activation/functionalization, and
annulation of inert C−H bonds with high regio- and
chemoselectivity are invaluable[2] and has found good
applications in the synthesis of complex natural
products with promising bioactivities.[3-7]
Generally, two synthetic steps are required to realize
a cascade 2-fold annulation of arenes/heteroarenes
with different coupling partners. Consequently,
reactions involving diverse functional groups require
different catalytic conditions (Scheme-1a).[5] In
Scheme 1. 2-Fold symmetrical/unsymmetrical annulations
of arenes/hetero arenes
Du and Li et al[4b]
reported Rh(III)-catalysed
particular,
construction
of
various
fused
synthesis of isoindolo[2,1-b]isoquinolines in two
steps involving oxidative coupling reaction between
methyl benzohydroxamate and alkyne to give
isoquinolone in the first step, followed by olefin
insertion in the second step (Scheme-1b). Only three
compounds were prepared using this one pot method
isoquinolones in the presence of transition metal
catalysts via the two steps synthetic process, in which
the first step involves construction of isoquinolone
ring followed by the oxidative annulation of NH-
isoquinolone with different coupling partners such as
1
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10.1002/adsc.202100414
Advanced Synthesis & Catalysis
without isolation of isoquinolone intermediate. Very
recently Reddy et al[13a] demonstrated Rh(III)-
catalysed synthesis of aromathecins via domino [4+2]
cymene)]2 in combination with Cu(OAc)2.H2O as the
catalyst (known for annulation reactions under mild
reaction condition)[15,19] provided the mono annulated
product 4aa in 85% yield. The reaction was
performed using o-xylene as a solvent at room
temperature for 8 h (entry 1). The second annulation
product (expected after participation of alkene) was
not obtained even with the increase in the reaction
time (16 h) (entry 2). To obtain the unsymmetrical
double annulation product 5aac, the annulation
between the 1a, 2a, and 3c was conducted at room
temperature for 8 h (where alkyne undergoes
cyclization) and followed by 110 °C (olefin insertion
via C-H activation) for 4 h to deliver the desired
product 5aac with complete regiocontrol in a single
pot under one catalytic condition (Table 1, entry 3).
When we used Cu(OAc)2 and Cu(OTf)2 as oxidants,
the product yield was decreased to 25% and 20%,
respectively (entries 4 and 5). During the screening of
various additives, NaOPiv KOAc and AgOAc gave
moderate yields compared to NaOAc (entries 6–8).
Changing the additive to CsOAc, affected the reaction
productivity and gave the product in 80% yield (entry
9). A lower yield of 5aac was achieved when the
reaction was performed at a lower temperature i.e 80
oC and or at a higher temperature i.e 130 oC (entries
10 and 11). Finally, the reaction of 1a and 2a under
the catalyst system [RuCl2(p-cymene)]2 (5 mol %),
NaOAc (40 mol%) in o-xylene at room temperature
for 8 h followed by the addition of 3c (1.5 equiv),
[RuCl2(p-cymene)]2 (5 mol %) and Cu(OAc)2·H2O
(2.0 equiv) at 110 oC for 4 h afforded 5aac (entry 3).
The reaction was further optimized for reaction
stoichiometry, solvent, and other reaction parameters
(for more details, please see Table S1 in the SI).[20]
annulation/aza-Michael
addition
of
N-
(pivaloyloxy)benzamides with 1,5-enynes involving a
C-H activation process(Scheme-1c). Volla et al[13b]
reported synthesis of isoindolo[2,1-b]isoquinolin-
5(7H)-ones via Rh(III)-catalysed redox-neutral
cascade annulation of benzamides with p-quinone.
The
isoindolo[2,1-b]isoquinolin-5(7H)-one
framework has been found to be an integral part of
several natural products, bioactive molecules and
drugs. Among them rosettacin, camptothecin and 22-
hydroxyacuminatine etc.[14] are notable examples.
However, limited efforts have been devoted towards
the development of one-pot two-fold C-H
functionalization method for the synthesis of this
class of fused heterocycles. While their synthesis
have attracted attention[15] in recent time but most of
the reported methods are limited to the use of i) two
step process, ii) 2-fold symmetrical C−H diannulation,
iii) symmetrical alkynes only and iv) expensive Rh
catalyst. Additionally, most of the reported
procedures involving metal catalysed amide-alkyne
annulations use symmetrical or unsymmetrical
internal
alkynes
having
carbon/nitrogen/oxygen/sulphur
substituents.
However, the use of unsymmetrical internal alkynes
with uncontrollable regioselectivity afforded
a
mixture of products in several cases.[16] Yao et al[17]
demonstrated that the annulation of unsymmetrical
internal alkynes having sulphur based substituted
phenyl(phenylethynyl)sulfane
methoxybenzamides through
C−H/N−O activation resulted in a mixture of
regioisomers.
and
Ru-
N-
catalysed
Thus, the sequential one-pot, 2-fold unsymmetrical
C−H di annulation of arenes/heteroarenes with
Table 1. Optimization of reaction conditions for the
synthesis of 5aac [a]
different
coupling
partners
having
(symmetrical/unsymmetrical
alkyne
oxygen/nitrogen substituents and alkene) in the
presence of a single directing group under single
catalytic conditions is attractive for the construction
of isoindolo[2,1-b]isoquinolin-5(7H)-one ring. In
continuation of our study on the development of
Yield (%)[b]
Entry
Additive
Temperature
(oC)
RT
construction of
various heterocycles via C-H
activation/functionalizations,[18] we disclose herein a
Ru-catalysed regioselective controlled annulation of
4aa
5aac
-
-
1
2
3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOPiv
KOAc
AgOAc
CsOAc
NaOAc
NaOAc
85[c]
110
73[c]
N-methoxybenzamide
with
RT/110
RT/110
RT/110
RT/110
RT/110
RT/110
RT/110
RT/80
-
-
-
-
-
-
-
20
-
84
25
20
32
22
18
80
52
80
symmetrical/unsymmetrical alkyne followed by
olefin insertion via C-H activation. This process
afforded isoindolo[2,1-b]isoquinolin-5(7H)-ones via
the formation of four (two C-C and two C-N) bonds
(Scheme-1d).
4[d]
5[e]
6
7
8
9
10
11
Results and Discussion
RT/130
Our initial attempts to achieve the one-pot two-step
sequential double annulation process focused on the
reaction between N-methoxybenzamides (1a) with
alkyne (2a) and alkene (3c) (Table 1). [RuCl2(p-
[a]Conditions: 1a (0.331 mmol, 1.0 equiv), 2a (0.331 mmol,
1.0 equiv), [RuCl2(p-cymene)]2 (5 mol %), additive (40
mol%), o-xylene (1.5 mL) at rt for 8 h; then [RuCl2(p-
cymene)]2 (5 mol %), Cu(OAc)2.H2O (0.662 mmol, 2.0
2
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10.1002/adsc.202100414
Advanced Synthesis & Catalysis
Table 2. Substrate scope of hetero(arene) amides, N-
equiv), alkene (0.496 mmol, 1.5 equiv) at 110 °C for 4 h.
[b]Isolated yields. [c]All of the reactants and catalyst added
in one time. [d]Cu(OAc)2 was used instead of
Cu(OAc)2.H2O. [e]Cu(OTf)2 was used instead of
Cu(OAc)2.H2O
propargylindoles and acrylate[a][b]
With the optimal reaction conditions in hand, the
cascade cyclization scope of various N-methoxy
amides (1) with unsymmetrical alkyne (2) and alkene
(3) were investigated. As shown in Table 2, a variety
of N-propargylindoles (2a−h), which had different
substituted indole moieties, were investigated. The
indoles containing electron donating substitute such
as methoxy reacted smoothly to give the
corresponding double annulated product 5bgc in
82% yield. The presence of halogens on indole ring
did not change the reaction pathway and afforded the
desired products in good yields (entry 5aca and
5bcb). Different substituents on phenyl groups at the
terminal position of the triple bonds, were
investigated. The reaction was compatible with
substituents present at the para-position of the
benzene rings of internal alkynes, such as Me−
(entries 5aab, 5aac, 5aad and 5bgc), MeO− (entries
5abb, 5abc, 5abd, 5aca, 5bba, 5bbc, 5bbd, 5bbf,
5bcb, 5cba, 5cbb, 5cbc and 5eba) and Cl− group
(entry 5bfb), providing the corresponding
isoindolo[2,1-b]isoquinolin-5(7H)-one products in
good yields (72%−84%). Furthermore, a heterocyclic
thiophene motif could also give the corresponding
product in 72-75% yield (entries 5adb and 5bdc).
Next, we surveyed the scope of the reaction with
various substituted benzamides 1. Pleasingly, N-
methoxybenzamides having para-substituents on the
arene moiety, electron-donating −CH3 (entries 5bba,
5bbc, 5bbd, 5bbf, 5beb, 5bfb, 5bdc, 5bgc, 5bcb and
5bhb), −tBu (5cba, 5cbb and 5cbc) and strong
electron-withdrawing groups –NO2 (5deb) smoothly
reacted with 2 and 3 under the optimized procedure to
afford corresponding double annulated isoindolo[2,1-
b]isoquinolin-5(7H)-one. Moreover, methyl acrylate
(5aca, 5bba, 5cba and 5eba), ethyl acrylate (5aab,
5abb, 5adb, 5beb, 5bfb, 5bcb, 5cbb, 5deb and
5bhb), butyl acrylate (5aac, 5abc, 5bbc, 5bdc, 5bgc
and 5cbc) tert-butyl acrylate (5aad, 5abd and 5bbd)
and acrylonitrile (5bbf) found to be effective for the
synthesis of isoindolo[2,1-b]isoquinolin-5(7H)-one.
Unfortunately, styrene failed to provide the desired
product (5aae). In addition, the product 5bhb is
formed in good yields (80%) when symmetrical
alkyne [diphenylacetylene (2h)] is used in the place
of unsymmetrical alkyne.
We further extended the scope of unsymmetrical
alkyne N-propargyl-7-azaindoles for the synthesis of
important
isoindolo[2,1-b]isoquinolin-5(7H)-one
class
of
azaindoles
substituted
derivatives
(Table-3). The reaction worked well in the presence
of different functional groups [(neutral (H), rich
3
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10.1002/adsc.202100414
Advanced Synthesis & Catalysis
The versatility of the optimised Ru-catalysed
regioselective double annulation strategy for
isoindolo[2,1-b]isoquinolin-5(7H)-one analogues was
not limited to N-propargyl indoles/azaindoles. Indeed,
this protocol could be successfully extended to
[a]Reaction conditions: 1 (0.331 mmol), 2 (0.331 mmol),
[RuCl2(p-cymene)]2 (5 mol %), NaOAc (40 mol %), o-
xylene (2.0 mL) at rt for 8 h; then [RuCl2(p-cymene)]2 (5
mol %), acrylates 3 ( 0.496 mmol), Cu(OAc)2.H2O (0.662
mmol) at 110 oC for 4 h, [b]isolated yield.
unsymmetrical
internal
alkynes
having
oxygen/nitrogen substituents like propargyl aryl
ethers (8a-d) and propargyl aryl amines (8e-f). These
moieties were well tolerated under the standard
reaction conditions to afford corresponding double
annulated products. Propargyl aryl ethers (8) having
the substituents at the para-position on the benzene
rings of alkynes, such as electron donating -OMe (8b)
and strong electron withdrawing group -NO2 (8c)
(methyl) and poor (nitro)] at the C4 position of the
amide
ring,furnishing
azaindoles
substituted
isoindolo[2,1-b]isoquinolin-5(7H)-one (7) in good
yields. Similarly, N-propargyl-7-azaindoles 6 with
methyl (3a), ethyl (3b), n-butyl (3c), tert-butyl (3d)
acrylates and acrylamide (3g) were compatible and
afforded the corresponding products (7bab, 7abd,
7acb, 7bbc, 7dca, 7bdb and 7bag). Likewise, the use
of a N-propargyl pyrrole substrate turned out to be
viable that gave the desired product in good yields
(7bdb, 71%). The regioselectivity of annulation was
further confirmed by the X-ray crystallographic
analysis of product 7acb (Please see SI).[21]
provided
the
corresponding
regioselective
isoindolo[2,1-b]isoquinolin-5(7H)-one products 9bbc
and 9bca in 82% and 75% yields, respectively. The
structure of 9aab was unambiguously confirmed by
X-ray single crystal analysis. (Please see SI).[21] The
propargyl aryl amines having N-benzylaniline (8e)
and N-phenylbenzene sulfonamide (8f) were well
tolerated under the standard conditions, and furnished
the corresponding products (9beb, 9fec and 9dfb) in
good yields (70-82%). Additionally, the reaction
employing the non-functionalized internal alkynes
(8g) also proceeded smoothly to furnish the
corresponding isoquinolones 9bgb in good yields.
[b]
Table 3. Substrate scope of N-propargyl-7-azaindoles[a]
Table 4. Substrate scope of propargyl aryl ethers/
propargyl aryl amines[a][b]
[a]Reaction conditions: 1 (0.331 mmol), 6 (0.331 mmol),
[RuCl2(p-cymene)]2 (5 mol %), NaOAc (40 mol %), o-
xylene (2.0 mL) at rt for 8 h; then [RuCl2(p-cymene)]2 (5
mol %), acrylates 3 (0.496 mmol), Cu(OAc)2.H2O (0.662
mmol) at 110 oC for 4 h, [b]isolated yield.
[a]Reaction conditions: 1 (0.331 mmol), 8 (0.331 mmol),
[RuCl2(p-cymene)]2 (5 mol %), NaOAc (40 mol %), o-
4
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10.1002/adsc.202100414
Advanced Synthesis & Catalysis
xylene (2.0 mL) at rt for 8 h; then [RuCl2(p-cymene)]2 (5
mol %), acrylates 3 (0.496 mmol), Cu(OAc)2.H2O (0.662
mmol) at 110 oC for 4 h, [b]isolated yield.
propargyl aryl ether 8d (0.5 equiv) and propargyl
aryl amine 8e (0.5 equiv) with ethyl acrylate (3b)
(1.0 equiv) was performed under the optimized
conditions (Scheme 2d) when 9bdb was obtained
in 42% yield and 9beb in 32% yield. This result
indicated that the propargyl aryl ether is more
reactive then propargyl aryl amines for the
synthesis of isoindolo[2,1-b]isoquinolin-5(7H)-
one under present experimental conditions.
Encouraged by the above results, we explored the
one-pot two-step sequential double annulation of N-
methoxy-4-methylbenzamide (1b) with N-propargyl-
substituted indole (2g) and diphenylacetylene (2h)
using Ru(II) catalyst and produced the corresponding
isoquinolino[3,2-a]isoquinolineone derivative 10
(75%) as shown in Scheme-2a. In order to
demonstrate the utility of this chemistry, the Ru-
catalysed regioselective double annulation strategy
Based on the previous reports, a proposed mechanism
for the one-pot two-step sequential double
annulation of N-methoxybenzamides with N-
propargyl-substituted indoles and activated olefins is
shown in Scheme-3. First, the active complex Ru
catalyst coordinates with the N-moiety of N-
methoxybenzamides (1a), affording a five-membered
ruthenacyclic intermediate (E-1) via o-C(sp2)-H
activation of arene/heteroarene. Then, regioselective
coordination and insertion of alkyne into the
compound (E-1) occurs to generated the seven-
membered ruthenacycle intermediate (E-2). Then on
reductive elimination and N−O cleavage E-2 affords
the mono annulations intermediate isoquinolone (E-
4) via E-3. Subsequently, E-4 undergoes proximal
C−H metalation to deliver 5-membered Ru
metallacycle (E-5). The alkene 3b on coordination
with the Ru species in E-5 affords E-6, in which it is
inserted in to the Ru−C bond to give a seven-
membered ruthenacycle intermediate (E-7). The β-H
elimination[22] of E-7 affords the acrylic ester
intermediate (E-8) and a ruthenium complex that
regenerates the active Ru(II)-catalyst in the presence
of Cu(OAc)2.H2O.[15b,23] Finally, an intramolecular
aza-Michael addition would give the double
annulated product 5aab.[22,24]
for
isoindolo[2,1-b]isoquinolin-5(7H)-one
were
conducted on a gram scale. The reaction of 1a, 2a
and 3c was completed within 12 h under standard
conditions, generating the desired product (5aac) in
78% (2.53 g) yield (Scheme 2b). As discussed above,
the formation of isoindolo[2,1-b]isoquinoline was
assumed to take place via the generation of
isoquinolin-1(2H)-one (4aa) in situ. To confirm this,
we performed a reaction using isoquinolin-1(2H)-one
intermediate (4aa) (0.331 mmol) [RuCl2(p-cymene)]2
(5 mol %), 3c (0.496 mmol) and Cu(OAc)2.H2O
o
(0.662 mmol) in o-xylene (2 mL) at 110 C for 4 h.
As expected, this reaction resulted in the formation of
desired isoindolo[2,1-b]isoquinoline 5aac with 85%
yield (Scheme 2c). Moreover, we conducted an
experiment to assess the intermolecular competition
between propargyl aryl ether (8d) and propargyl aryl
amine (8e). The reaction of substrate 1b (1.0 equiv),
Scheme 2. Synthetic elaboration, gram-scale and control
experiments
5
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10.1002/adsc.202100414
Advanced Synthesis & Catalysis
Scheme 3. The proposed reaction pathway
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Conclusion
In summary, we have successfully developed
sequential one-pot two-step method for the
synthesis of isoindolo[2,1-b]isoquinolin-5(7H)-ones
via the 2-fold unsymmetrical double annulation of N-
methoxybenzamide
derivatives
with
symmetrical/unsymmetrical alkynes and activated
olefins via Ru-catalysed C-H activation. The different
unsymmetrical alkynes (N-propargyl-substituted
indole/azaindoles/pyrrole, propargyl aryl ether and
propargyl aryl amines) were successfully coupled
with N-methoxybenzamide and acrylate in
a
regioselective manner to afford the isoindolo[2,1-
b]isoquinolin-5(7H)-one derivatives in good yields.
Overall, this transformation involved the formation of
four (two C-C and two C-N) bonds.
Experimental Section
General Procedure for the Preparation of
Isoindolo[2,1-b]isoquinolin-5(7H)-ones (5/7/9/10)
To an oven-dried 50 mL Schlenk tube under an nitrogen
atmosphere were added N-methoxybenzamide (1) (0.331
mmol), alkyne (2/6/8) (0.331 mmol), [e.g. Ru(p-
cymene)Cl2]2 (5 mol%), NaOAc (40 mol %). The solvent
o-xylene (2.0 mL) was added to the reaction mixture and
the resulting mixture was stirred at room temperature for 8
h. Then to this reaction mixture was added Ru(p-
cymene)Cl2]2 (5 mol%), Cu(OAc)2.H2O (0.662 mmol) and
acrylate (3)/diphenyl acetylene (2h) (0.496 mmol) were
added. The resulting mixture was stirred at 110 C for 4 h.
The reaction mixture was cooled to ambient temperature,
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Chem. Soc. Rev. 2018, 47, 8925-8967; For a book,
see: (d) Wu, X.-F., Ed. Transition Metal-
Catalyzed Heterocycle Synthesis via C−H
Activation, Wiley, 2016.
filtered through
a
celite and then washed with
[4] a) L. Song, G. Tian, Y. He, E. V. Van der Eycken,
Chem. Commun. 2017, 53, 12394-12397; b) F.
Wang, G. Song, Z. Du, X. Li, J. Org. Chem. 2011,
76, 2926-2932.
dichloromethane (3×15 mL). The solvents were evaporated
under reduced pressure. The residue was purified by
column chromatography on silica gel using ethyl acetate-
hexane to give the desired product 5/7/9/10.
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KSK thanks the University Grants Commission (UGC), New
Delhi, for faculty position under FRP. We also thank CSIR
[02(0378)/19-EMR-II], OU-DST-PURSE-II and UGC-UPE-FAR
for funding this project. NPK thanks CSIR, New Delhi, for a
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FULL PAPER
One-Pot Two-Step Double Annulation of N-
Methoxybenzamides with Alkynes and Alkenes:
Regioselective Construction of Isoindolo[2,1-
b]isoquinolin-5(7H)-ones
Adv. Synth. Catal. Year, Volume, Page – Page
Praveen
Kumar
Naikawadi,
Lingaswamy
Mucherla, Rambabu Dandela, Madhavi Sambari,
K. Shiva Kumar*
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