α,β-Functionalization of saturated ketones with anthranils: Via Cu-catalyzed sequential dehydrogenation/aza-Michael addition/annulation cascade reactions in one-pot

Article abstract of DOI:10.1039/c7cc01195d

An efficient method to access functionalized quinolines from the readily available saturated ketones and anthranils has been explored. This one-pot cascade reaction involves the in situ generation of α,β-unsaturated ketones by the copper catalysed dehydro

Full text of DOI:10.1039/c7cc01195d

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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α,β-Functionalization of Saturated Ketones with Anthranils via Cu-
Catalyzed Sequential Dehydrogenation/Aza-Michael
Addition/Annulation Cascade Reactions in One-Pot
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
Dipak Kumar Tiwari,
Mandalaparthi Phanindrudu,a,b Sandip Balasaheb Wakade,a,b Jagadeesh
DOI: 10.1039/x0xx00000x
Babu Nanubolu,c and Dharmendra Kumar Tiwari*,a,b
www.rsc.org/
An efficient method to access functionalized quinolines from the intermediates, readily engaging in various transition metals
readily available saturated ketones and anthranils have been catalyzed C-C and C-N bond forming reactions to get value
explored. This one-pot cascade reaction involves the in situ added products. The direct C─H amination10 and annulations11
generation of α,β-unsaturated ketones by the copper catalysed reactions by anthranil have drawn considerable attention in
dehydrogenation of saturated ketones followed by the aza- organic transformations (Fig-1, eq-1). We envisioned that the
Michael addition of anthranils and subsequent annulation.
coupling of in situ generated α,β-unsaturated ketones with
anthranils might produce quinolines via amination followed by
annulation (Fig-1, eq.-2).
The direct functionalizations of saturated ketones via in situ
generation of α,β-Unsaturated ketones by catalytic
dehydrogenation, have received much attention in the recent
past.1-3 The aforementioned protocol overcomes the problem
of troublesome preparation and isolation of α,β-unsaturated
ketones due to their poor stability and high reactivity.3
Generally, the synthesis of α,β-unsaturated ketones required
multiple steps4,5 and equimolar amount of reagents such as 2-
iodoxybenzoic acid (IBX) and 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ). 6,7 However, in recent past the transition
metals such as palladium, ruthenium, iridium, copper and
nickel catalyzed oxidation of saturated carbonyl compounds
to the corresponding α-β unsaturated carbonyl compounds
has become an attractive and atom economical alternative to
these methods.[2] Subsequently, the α,β unsaturated carbonyl
compounds that are produced in situ, undergoes various
organic transformations such as arylation, amination and
conjugate addition to produce β-functionalized ketones.1e-1f, 8
Considering the synthetic potential of α,β-unsaturated ketones
and in frame of our own research interest in copper catalyzed
heterocycle synthesis,9 we became interested in exploring the
annulation of α,β-unsaturated carbonyl compounds with
anthranils. In general, anthranils serves as versatile synthetic
Previous reports:
O
DG
H
O
DG
TBSO
Me
H
N
N
H
Me
Ts
(1)
O
N
[Rh]
[Au]
N
N
Ts
.....................................................................................................................................
Current report:
O
O
R1
Cu(OAc)2/TEMPO
R3
4Å MS; 1,2 DCB
R3
O
+
R1
R2
(2)
R2
N
N
2a
1a
3aa
Electrophlic center
Base and external ligand free conditons
√
√
Nucleophliccenter
,
-carbon functionalization
α β
One pot tandem dehydrogenation, amination
√
and annulation reaction
Figure 1. Use of anthranil in amination and annulation reactions (eq-1) along
with present study (eq.2).
Wide abundance of quinoline framework in pharmaceuticals
and natural products make it privileged scaffold, and therefore
considerable efforts have been made to develop efficient and
operationally simple methods for their synthesis.[12-14] The
classical methods for quinoline synthesis involve the Skraup,
Combes, Conrad–Limpach and Friedlander reactions.[15] Lately,
metal catalyzed tandem cyclization and multi-component
coupling reactions have been developed for the synthesis of
functionalized quinolines.[16] Although these protocols are
effective, most of them suffer from several shortcomings, such
as elaborately designed starting materials and copious waste
generation. Therefore, a direct access to quinolines from
simpler starting materials remains an important research
objective. In turn to test our hypothesis, we chose the readily
available propiophenone (1a) and anthranil (2a) as model
substrates for the proposed reaction cascade. Our initial
efforts in reacting propiophenone (1a, 1.0 mmol), anthranil
a.Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500607(India).
Fax: (+)91-040-27161637
E-mail: dktiwari@iictres.in & dkt80.org@gmail.com
b.Academy of Scientific & Innovative Research (AcSIR), New Delhi 110001, India
X-Ray crystallography Center CSIR-Indian Institute of Chemical Technology
c.
Uppal road, Tarnaka, Hyderabad 500607(INDIA)
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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(
2a, 1.1 mmol) in the presence of CuI (10 mol%), bipyridyl (10 under these catalytic conditions. Role of oxidant was also
mol%) and TEMPO (1.0 mmol) in DME (4.0 mL) at 110 °C for 12 investigated by performing the reaction in absence of TEMPO
hrs, under argon atmosphere did not yield any desired product but, the desired quinoline 3aa was not obtained (entry-14).
(Table 1, entry-1). Use of different copper catalysts such as Further, several oxidants such as tert-butyl hydroperoxide
Cu(OTf)2 and CuSO4 also failed to induce the reaction (entries (TBHP), tert-butyl perbenzoate (TBPB) and K2S2O8, were also
2-3). However, when CuBr (10 mol%) was employed as a tested for this transformation but none of them could
catalyst, 3-keto quinoline was obtained, albeit in a poor yield promote the reaction (entries 15-17). Attempts to use lower
(14%) (entry-4). Further, the isolated yield of 3aa was amount of TEMPO resulted significant decrease in the yield of
improved to 65% when Cu(OAc)2 was used as catalyst
Table 1. Optimization studies.a
corresponding 3aa (entry-18). Switching the metal catalyst
from Cu(II) to Pd (II), Ni (II) and Co (II) did not produce the
desired product 3aa (entries19-21). Increasing the reaction
temperature from 110 to 130 °C furnished low yield of the
desired 3aa (entry-22). A dramatic fall in the yield (55%) of 3aa
was observed when reaction was performed at 90 °C instead
of 110 °C (entry-23).
O
O
Cat./oxidant
O
+
N
solvent, Temp
N
3aa
2a
1a
Entry
Catalyst
(10 mol%)
Oxidant
(1.0 equiv)
Solvent
Temp/
[°C]
Yield
(%)b
After having optimized reaction conditions in hand (Table-1
entry 13), the substrate scope of this one pot tandem reaction
with respect to various propiophenones (1a-1u) and anthranils
1
CuI
TEMPO
DME
110
tracea
2
3
4
5
Cu(OTf)2
CuSO4
CuBr
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
--
DME
DME
DME
DME
DME
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
130
90
n.o a
n.o a
14%a
65%a
86%c
69%a
49%a
31%a
52%a
24%a
92%a
92%d
0%e
Table-2 Substrate scope of the present studya
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Pd(OAc)2
NiBr2
O
O
O
O
6
7
8
9
Toluene
Dioxane
DMSO
DMF
N
N
F
N
Cl
N
3aa
3ea
3ba
3ca
3da
Br
; Yield: 92%
; Yield: 88%
, Yield: 93%
; Yield: 92%
O
O
O
O
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NMP
N
F3C
N
Br
N
N
F
1,2 DCB
1,2 DCB
1,2 DCB
1,2 DCB
1,2 DCB
1,2 DCB
1,2 DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
3fa
3ga
3ha
; Yield: 90%
; Yield: 94%
; Yield: 93%
; Yield: 94%
O
O
O
O
O2N
TBHP
TBPB
n.od
n.od
N
O
N
BnO
N
HO
N
3ia; Yield: 95%
3ja; Yield: 85%
3ka; Yield: 87%
3la; Yield: 81%
K2S2O8
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
n.od
O
O
O
O
40%f
n.o
S
O
O
O
N
N
N
N
n.o
3oa; Yield: 86%
3pa; Yield: 87%
3ma; Yield: 83%
3na; Yield: 87%
CoCl2
Cu(OAc)2
Cu(OAc)2
n.o
Ph
Ph
O
Ph
80%g
55%h
O
O
S
O
O2N
N
Yield: 84%
N
N
N
N
aReaction was performed using 1a (1.0 mmol), 2a (1.1 mmol), Cu catalyst (0.10 mmol),
bpy (0.10 mmol), TEMPO (1.0 mmol) solvent (4 mL) 110 °C, N2 atmosphere 12h.
bisolated yields. c4 Å MS was added, dNo bipyridyl (bpy) added. eno oxidant. f(0.5 mmol)
of TEMPO was used., gRun at 130 °C, hRun at 90 °C. n.o = not obtained.
3qa;
3ra;
3sa
3ta
; Yield: 70%
Yield: 84%
; Yield: 79%
Substitiuted Anthranils
O
O
X
O
O
O
O
O
O
N
3ad; Yield: 85%
N
N
R
Where R = H; X = Cl;
N
(entry-5). At this stage, the structure of 3aa was well
characterized using different spectroscopic techniques and the
spectral data of 3aa was exactly matching with previously
reported compound.[17] The ultimate proof was obtained by
single-crystal X-ray diffraction of one of the derivative 3af (vide
infra). Since this reaction represents an efficient and mild
route to pharmaceutically valuable quinoline derivative, we
systematically carried out extensive optimization of the
reaction conditions (Table 1).
3ua;b
; Yield: 88%
3ab
3ae; Yield: 84%
Yield: 68%
= CF3;X = Cl 3gb; Yield: 87%;
3ac
= H; X= F;
; Yield: 89%
3gc
= CF3; X = F;
; Yield: 86%
aReaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), Cu(OAc)2 (0.1 mmol), TEMPO (1.0
mmol), 4 Å MS, 1,2-dichlorobenzene (4 mL), 110 °C, N2 atmosphere, 12 h. bReaction
was run for 24 h, Yield indicates the yields of the isolated product.
(
2a-2g) were investigated. The reaction was found to be
compatible with various ketones bearing aromatic,
heteroaromatic and aliphatic groups (1a-1u). As shown in table
2, the propiophenones containing electron withdrawing
(EWGs) or electron donating groups (EDGs) at different
position of phenyl ring readily delivered the desired quinolines
in good yields (3b-3m) whereas it is worth mentioning that
propiophenones bearing EWGs provided better yields
comparatively. Various functional group such as fluoro (1c),
As water is expected as the byproduct, the use of 4 Å
molecular sieves improved the yield to a greater extent (86%)
(entry-6). Among the various solvents screened, 1,2-
dichlorobenzene (DCB) was found to be the best for the overall
formation of 3aa (92%) (entry 12), whereas toluene, 1,4-
dioxane, DMSO, DMF and NMP furnished the desired 3-keto
quinoline (3aa) in low yields (entries 7-11). Interestingly, the
absence of ligand 2,2’-bipyridyl did not affect the reaction as
the product 3aa was obtained in excellent yield (entry-13). This
can be reasoned that anthranil itself might be acting as ligand
chloro (1d), bromo (1e
& 1h), trifluoromethyl (1g), nitro (1i),
alkoxy (1j), aryloxy (1k) and hydroxyl (1l) were well tolerated
under these catalyitc conditions and furnished corresponding
3-keto quinolines in excellent yields. The method was further
2 | J. Name., 2012, 00, 1-3
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proposed. First Cu(OAc)2 enolizes saturated ketone (1a) to give
complex which undergoes homolytic bond cleavage to
generate Cu(I) species and intermediate which on reaction
with TEMPO produced α-TEMPO-substituted ketone C.
Another molecule of TEMPO then abstracted β-hydrogen of
intermediate C, resulting in elimination of TEMPOH from C to
form desired α,β-unsaturated ketone D. Cu(I) species gets
oxidized by TEMPO or TEMPOH to regenerate Cu(II) species.
The nitrogen atom of anthranil then attacks at β-position of
extended to the heteroaromatic ketones such as 2-
A
propionylthiophene
(1o), 2-propionylfuran (1p) and 2-
B
propionyl thiazole (1q) and excellent yields of the desired
products (3oa-3qa) were obtained. Furthermore, β-substituted
ketones (1r-1t), also participated in this reaction and gave
slightly lower yields of corresponding 2-substiituted-3-
ketoquinolines (3ra-3ta). The aliphatic carbonyl compound
such as 1-cyclohexylpropan-1-one (1u) took longer time (24 h)
to complete the reaction and gave inferior yield (68%) of the
desired product (3ua). The various substituted anthranils (2b-
enone (
intermediate
D
) to give intermediate E. The polarized N-O bond of
gets cleaved to produce intermediate , which
E
F
eventually undergoes intramolecular cyclization followed by
TMP mediated dehydration to produce the dihydroquinolene
2e
) worked well and furnished the corresponding 3-
ketoquinolines (3ab-3ae) in excellent yields.
H
. Finally, the intermediate
H undergoes to copper catalyzed
.
3-substitiuted anthranils (2f and 2g) expectedly took longer
time (24 h) for the completion of the reaction and furnished
the desired products 3af and 3ag in 75% and 67% yields along
with uncyclized 3af’ and 3ag’ in 9% and 20% yields respectively
(scheme-1). This discrimination in the yields of desired 3af and
3ag can be explained by electron withdrawing and electron
donating nature of phenyl and methyl groups respectively. The
structure of 3af was unambiguously confirmed by single crystal
X-ray diffraction data analysis.
aerobic oxidation20 to give the desired 3aa
O
Ph
H2O
+
N
1a
H
LnCuIIX2
TMP
-HX
O
Ph
Ln
Cu[II]
Cu
N
O
+
N
OH
X
A
O
O
N
Ph
2a
D
O
N
O
N
Ph
O
H
Ph
B
O
O
Scheme-1. Quinoline synthesis with 3-substitiuted anthranils (2f-2g)a
Ph
O
E
Ph
O
N
O
N
O
O
N
O
Ph
C
Ref 1e
O
N
H
F
OH O
H
O
Ph
Ph Cu/[O]
solvent
Ph
TMP -H
O
N
2
N
N
3aa
H
H
G
H
Scheme-4. Plausible reaction mechanism
X-ray-3afb
Conclusions
aReaction conditions: 1a (1.0 mmol), 2f (1.1 mmol), Cu(OAc)2 (0.1 mmol), TEMPO (1.0
mmol), 4Å MS, 1,2-dichlorobenzene (4 mL), 110 °C, N2 atmosphere, 24 h; bORTEP In conclusion, we have developed a ligand and base free,
diagram of 3af [18]
catalytic procedure for 3-keto quinolines from readily available
This initial success propelled us to investigate the synthetic utility of
saturated ketones and anthranils using Cu(OAc)2 via one pot
current methodology in the synthesis of biologically valuable
tandem sequential dehydrogenation, aza-Michael addition and
targets (scheme-2). The (2-bromophenyl)(quinolin-3-yl)methanone
annulation reactions. The reaction is compatible with various
Scheme-2- Efficient synthesis of biologically important substituted benzodiazepine.19
ketones and substituted anthranils. As a result, a series of
quinolines were prepared in excellent yields. Considering the
wide availability of starting materials, broad substrate scopes
and operational simplicity, the present method provides an
_______________________________________________________
attractive and novel protocol for the synthesis of the 3-
(3ha) produced from the reaction of 2’-bromopropiophenone (2h)
substitiuted quinolines.
and anthranil (2a) under optimized standard condition, enabled to
Acknowledgements
prepare 2,3-dihydro-5-(3-quinolinyl)-1H-1,4-benzodiazepine (5), an
important fungicide,19 efficiently executed by heating 3ha with
The authors thank the Department of Science and Technology
(DST), New Delhi, India, for financial support in the form of an
INSPIRE-Faculty grant and a Startup Research Grant for young
researchers (GAP 0414 and GAP 0512). D. K. T., M. P., and S. B.
Wakade gratefully acknowledge the Academy of Scientific and
Innovative Research (AcSIR) for PhD registration.
ethylenediamine (4) in 85% yield.
To probe the reaction mechanism some controlled experiments
were conducted (for more details please see the SI). When anthranil
(2a) was treated with chalcones (1a’ & 1s’) under optimized
reaction conditions, furnished the desired 3aa and 3sa but in low
yields (scheme 3). This result demonstrates that the reaction is
going through enone intermediate.
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Çꢀꢁꢂꢃ ꢄꢅ /ꢄꢆꢇꢃꢆꢇ
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