Rh(III)-Catalyzed Intramolecular Oxidative Annulation of Propargyl Amino Phenyl Benzamides to Access Pyrido/ Isoquinolino Quinoxalinones

Article abstract of DOI:10.1002/adsc.201900772

A rhodium catalyzed copper mediated double oxidative annulation of propargylamino phenyl benzamides is developed. A quick assembly of tri, tetra and penta cyclic pyrido/isoquinolo-quinoxilines are thus achieved from readily available linear substrates. The reaction is shown to be very general by accommodating a large variety of substrates in the transformation. A mechanism through an amide directed C?H bond activation followed by an intramolecular alkyne activation/annulation followed by an oxidation is postulated. (Figure presented.).

Full text of DOI:10.1002/adsc.201900772

UPDATES
DOI: 10.1002/adsc.201900772
Rh(III)-Catalyzed Intramolecular Oxidative Annulation of
Propargyl Amino Phenyl Benzamides to Access Pyrido/
Isoquinolino Quinoxalinones
Gurram Ravi Kumar,a, b Ravi Kumar,b, c Manda Rajesh,a, b B. Sridhar,d and
Maddi Sridhar Reddya, b,*
a
OSPC Division, CSIR-Indian Institute of Chemical Technology, Habsiguda, Hyderabad 500007, India
E-mail: msreddy@cdri.res.in; msreddy@csiriict.in
Academy of Scientific and Innovative Research, New Delhi 110001, India
MPC Division, CSIR-CDRI, Sitapur Road, Lucknow-226031, India
Analytical Division, CSIR-IICT, Habsiguda, Hyderabad-500007, India
b
c
d
Manuscript received: June 24, 2019; Revised manuscript received: August 28, 2019;
Version of record online: September 11, 2019
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900772
On the other hand, isoquinolones and their fused
Abstract: A rhodium catalyzed copper mediated
double oxidative annulation of propargylamino
analogues have gained substantial attention in both
drug discovery and material chemistry.[8,9] Although a
phenyl benzamides is developed. A quick assembly
number of approaches for their construction are
of tri, tetra and penta cyclic pyrido/isoquinolo-
known, oxidative addition of alkynes with benzamides
quinoxilines are thus achieved from readily avail-
have drawn great attention as it does not require much
able linear substrates. The reaction is shown to be
prefunctionalization of the substrates while affording
very general by accommodating a large variety of
the multisubstituted adducts. Various groups[2,3] re-
substrates in the transformation. A mechanism
ported the annulations of both terminal and internal
through an amide directed CÀ H bond activation
alkyens with benzamides with varied N-substitution
followed by an intramolecular alkyne activation/
(Scheme 1a).
annulation followed by an oxidation is postulated.
The group of Glorius[2b] successfully annulated
even the alkynyl boronic acids with similar benza-
Keywords: Annulation; Rhodium; Oxidation; Ben-
mides to get regioselectivly borylated isoquinolones.
zamides; Quinoxalinones
Park’s and Gulı'as groups independently reported the
intramolecular capture of the alkyne with the benza-
mide tether to synthesize isoquinolone fused tricyclic
Oxidative annulations of alkynes with unsaturated compounds (Scheme 1b).[5] Very recently, Eycken et al
systems have grabbed an enormous attention in the reported an elegant synthesis of indolizinone and
recent past. With an appropriate choice of starting quinolizinone based natural products rosettacin and
materials, it allowed synthesizing huge varieties of oxypalmatime
through
such
intramolecular
hetero and carbocycles.[1–7] Rhodium,[2] ruthenium,[3a–d] cyclizations.[6] A major advantage of intramolecular
nickel,[3e] cobalt,[3f,g] palladium[3h,i] and even copper[3j] cyclization is the defined regioselectivity and the
based catalysts which are capable of activating CÀ H ability to quickly construct multicyclic frameworks
bonds are found to execute such annulations. Having from linear compounds, which thus demands huge
an alkyne as a tether in the basic unsaturated substrate search for novel such transformations. In continuation
itself at appropriate position enables an intramolecular of our interest in discovery of novel reactions via
annulation towards a quick assembly of multicyclic activation of alkynes,[10] we herein report the synthesis
compounds.[4–7] In the light of difficulties associated of pyridoquinoxaline fused tri-, tetra-, and pentacyclic
with the systematic building of multicyclic compounds, compounds through intramolecular double oxidative
which especially becomes a tedious job when huge annulations of propargyl aminophenyl benzamides
libraries of such compounds are required to be built, (Scheme 1c).
these intramolecular annulations gain special attention.
We chose 1a to optimize the reaction conditions.
Use of CuCl[7a] following Han’s work did not produce
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Table 1. Optimization studies.[a]
S.No. catalyst
Additive
Solvent Yield[b]
1
2
3
4
5
6
7
8
CuCl
Pd(OAc)2
Ni(acac)2
Co(acac)2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
–
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
n.r
n.r
n.r
n.r
69
55
50
trace
n.r
52
CsOAc
CsOAc
CsOAc
CsOAc
KOAc
NaOAc
AcOH
NaOTf
O2 (balloon)
9
10
11
12
13
14
15
16
Cu(OAc)2 ·H2O DCE
88
76
[Ru(p-cymene)Cl2] Cu(OAc)2 ·H2O DCE
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Cu(OAc)2 ·H2O tAmOH 79
Cu(OAc)2 ·H2O Dioxane 56
Cu(OAc)2 ·H2O Toluene 65
Cu(OAc)2 ·H2O THF
40
[a] Reaction conditions: 2.5 mol% catalyst, 2.2 equiv. additive at
Scheme 1. Oxidative annulation of alkynes with benzamides.
°
90 C for 16 h under air.
[b] Isolated yield.
any desired product 2a in our case (Table 1, entry 1).
Pd(OAc)2, well known for CÀ H activation, also totally tbutyl benzamides 1b–c reacted as good as 1a to
failed to deliver even a trace amount of the expected produce the expected products 2b–c in 79–81% yields.
product (entry 2). Similarly, no product was observed We were next curious about dimethyl amide 1d which
when Ni(acac)2 or Co(acac)2 were employed as has two different sites to react and may produce two
catalysts in presence of CsOAc as additive (entry 3,4). regioisomers. Surprisingly, only 2d was obtained as
Pleasingly, employing [Cp*RhCl2]2 as catalyst along single regioisomer in 76% yield. We reason that the
°
with CsOAc in DCE at 90 C (under air) produced the rhodium complexation, after CÀ H activation, adjacent
desired product 2a in 69% yield (entry 5). Employing to methyl group suffers some steric discomfort and
other additives like KOAc, NaOAc, AcOH or NaOTf hence it only occurred at less hindered other position.
was found to be less effective or totally ineffective Alkyl substation even on 1,2-diaminobenzene core
(entry 6–9). A control experiment without any (1e) was also equally tolerated (2e). Next, Trimethoxy
additive, but in presence of O2, indeed gave the product amides 1f could be smoothly transformed to the
but in 52% yield (entry 10). Use of Cu(OAc)2.H2O as corresponding adduct 2f in similar high yield. Dime-
an additive/oxidant (along with air) cleanly produced thoxy amide 1g also gave a single regioisomer (2g in
the annulated adduct in 88% yield (entry 11). Use of 75% yield), despite having the second but sterically
less expensive [Ru(p-cymene)Cl2] in similar conditions congested site, as in case of 1d. But similar substrate
indeed produced 2a cleanly, but in relatively lower 2h with methylene dioxy substitution (than dimethoxy)
yield (entry 12). The other solvents like t-AmOH, gave a mixture of isomers. Compared to 1d and 1g, it
dioxane, toluene or THF with Rh-catalyst were not as obviously exerts less steric hindrance difference
good as DCE (entry 12–16). The structure of 2a was between the available two sites and thus it led to form
determined by its X-ray diffraction.[11]
a mixture of two regioisomers. Halogenated substrates
With the optimal reaction conditions in hand, 1i–k also consistently showed normal reactivity to
diversified alkyne-amides were investigated to exam- deliver the desired products (2i–k) in excellent yields
ine the scope of this double oxidative annulation (70–76%). Electron deficient cyano and nitro substi-
(Table 2). The influence of substituents on amide unit tuted substrates 1l–m were found to be less productive
was initially studied. Substrates with p-methyl or p-
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Table 2. Scope of benzamides.[a]
Table 3. Scope of alkynes.
compared to their electron rich and neutral substrates
and thus produced 2l–m in 62–66% yields.
We next moved to evaluate the scope of varied aryl
substitution on alkyne terminus (Table 3). Methyl and
methoxy phenyl substrates 1n–o reacted generally and
gave the corresponding products 2n–o in 71–77%
yields. Bromo and trifluoromethyl phenyl substrate
gave slightly lower yields of the corresponding adducts
2q–r. Like in earlier set of examples 1l–m, electron
deficient materials 1s–t with nitro and cyano groups
led to a fair reduction in the product yields (2s, t in
48–59%). Expanding the scope this oxidative annula-
tion, the aliphatic substitution on alkyne terminus (1u)
cleanly fit in the reaction to afford the adduct 2u in
66% yield.
[a] Reaction conditions: 2.5 mol% catalyst, 2.2 equiv. additive,
°
DCE (2 mL) at 90 C for 16 h under air.
[b] Isolated yield.
[c] Ratio of 3,4-Methylene dioxy- and 4,5-Methylene dioxy is
8.2:1.8.
We next became curious to see the fate of substrates
with amide tethers other than benzamides under the
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optimized conditions. Pleasingly, methacrylamide 1v
and phenyl acrylamide 1w cleanly reacted in the
standard conditions and afforded the corresponding
tricyclic adduct 2v–w in 81% and 78% yields
respectively (Table 4). But in case of β-alkyl substi-
Table 4. Scope of acrylic/hetrocyclic amides.
Scheme 2. proposed mechanisum.
could also coordinate to alkyne moiety (b). Cyclization
with the NÀ Rh bond intact formed c and subsequent
reductive elimination gave the semi-saturated tetracyclic
intermediate d. Oxidation of d afforded the desired adduct
2. Reoxidation of reduced Rh or the oxidation of d or part
of both were done with the assistance of aireal oxygen as
the demand of Cu(OAc) 2.H2O was only in two
equivalents.
In conclusion, we have developed an expeditious
synthesis of quinoxaline fused tri, tetra and penta
cyclic compounds through a double oxidative annula-
tion of propargylamino phenyl benzamides. The reac-
tion, catalyzed by Rh(III) and directed by stoichiomet-
ric copper(II) acetate, is assumed to go through an
amide directed CÀ H bond activation followed by an
intramolecular alkyne activation/annulation prior to the
oxidation. A detailed investigation is done on the scope
of the reaction to show the generality, and a variety of
tuted acrylamides 1x and 1y, the cyclization occurred fused hetero pyrido quinoxalinones are thus achieved.
on aniline aryl itself to give amidated quinolines
apparently through a competitive electrophilic cycliza-
tion. Gratifyingly, thiophenamide 1z and furanamide
Experimental Section
General procedure for synthesis starting material 1from N-
propargyl 1,2-diaimo benzene (II) taking Synthesis of 1a as an
Example: In a 50 ml round bottom flask N-propargyl 1,2-diaimo
benzene[12] (222 mg, 1 mmol, 1 equiv.) in DMF (6 mL) was
added HATU (384 mg, 1 mmol, 1 equiv.), DIPEA (0.69 ml,
4 mmol, 4 equiv.) and Benzoic acid (122 mg, 1 mmol, 1 equiv.),
1aa participated well in the reaction and produced the
desired tetracyclic products 2z–aa in 68% and 70%
yields respectively. Expanding the scope further, 2-
chromonamide 1ab also could be transformed to the
expected pentacyclic product 2ab albeit in 56% yield.
With the assistance of some literature precedence[5a,b,6c]
we propose a plausible reaction mechanism as depicted in
Scheme 2. An active Cp*Rh(OAc)2 was generated by a
ligand exchange with Cu(OAc)2.H2O. Amide directed
CÀ H bond activation led to the intermediate a where Rh
°
at 0 C under N2 atmosphere and the reaction mixture was
stirred at RT for 30 min. upon completion, reaction mixture was
diluted with ice water and extracted with ethyl acetate. The
combined extracts were dried over Na2SO4 concentrated under
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reduced pressure. The crude material was purified on silica gel
using 20% EtOAc/hexane to get 1 (293 mg 90%) as white solid.
Ni catalysed: e) H. Shiota, Y. Ano, Y. Aihara, Y.
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[4] a) J.-P. Krieger, D. Lesuisse, G. Ricci, M.-A. Perrin, C.
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General procedure for synthesis compound 2from 1taking
Synthesis of 2a as an Example: In a 50 ml round bottom flask
1a (65 mg, 0.2 mmol, 1 eq), [Cp*RhCl2]2 (3 mg, 0.005 mmol,
2.5 mol%) and Cu(OAc)2.H2O (87 mg, 0.4 mmol, 2.2 equiv.) in
°
DCE (2 mL). the reaction mixture was stirred at 90 C under air
until complete conversion of starting materials (16 h). upon
completion, the reaction continents were concentrated under
reduced pressure. The reaction mixture was diluted with water
and extracted with EtOAc (2×10 mL). Combined extracts were
washed with brine (10 mL) and dried over Na2SO4 and
concentrated under reduced pressure. The crude material was
purified on silica gel using 30% EtOAc/hexane to get 2a
(56 mg, 88%) light yellow color solid.
Acknowledgements
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GRK, RK and MR thank CSIR for the fellowships. We thank
analytical division CSIR-IICT for the analytical support. We
gratefully acknowledge the financial support by DST (EMR/
2017/0002413). Manuscript Communication Number: (IICT/
Pubs./2019/299).
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