Metal-Free Oxidative Annulation/Cyclization of 1,6-Enynes for the Synthesis of 4-Carbonylquinolines

Article abstract of DOI:10.1002/adsc.201900013

Herein we report on the development of a metal-free oxidative annulation reaction of 1,6-enynes, leading to 4-carbonylquinolines by using dioxygen as a green sustainable oxidant. Key advances include the use of readily available tert-butyl nitrite (TBN) to promote radical annulation of 1,6-enynes and easy-to-handle reaction conditions. Preliminary mechanistic studies including radical capture reactions and isotope labelling experiments are also conducted. (Figure presented.).

Full text of DOI:10.1002/adsc.201900013

Title: Metal-Free Oxidative Annulation/Cyclization of 1,6-Enynes for the
Synthesis of 4-Carbonylquinolines
Authors: Xiao-Feng Xia, Wei He, and Dawei Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900013
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10.1002/adsc.201900013
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free Oxidative Annulation/Cyclization of 1,6-Enynes for
the Synthesis of 4-Carbonylquinolines
Xiao-Feng Xia,a* Wei He, a and Dawei Wang a
a
Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering,
Jiangnan University, Wuxi, Jiangsu, 214122, People’s Republic of China. E-mail: xiaxf@jiangnan.edu.cn.
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))
Abstract. Herein we report on the development of a metal-
free oxidative annulation reaction of 1,6-enynes, leading to
4-carbonylquinolines by using dioxygen as green
Keywords: cascade annulation; 1,6-enynes; metal-free;
tert-butyl nitrite; 4-carbonylquinolines
a
sustainable oxidant. Key advances include the use of readily
available tert-butyl nitrite (TBN) to promote radical
annulation of 1,6-enynes and easy-to-handle reaction
conditions. Preliminary mechanistic studies including radical
capture reactions and isotope labelling experiments are also
conducted.
Among these processes, 1,n-enynes have attracted
considerable attention as highly efficient radical
acceptors in cascade annulation reactions for the
synthesis of complex ring systems employing
different carbon- and heteroatom-based radical
precursors under metal-catalyzed or visible light-
induced conditions.[5] On the other hand, tert-butyl
nitrite (TBN) as an efficient radical initiator for the
construction of C-N bonds has been recently studied
by Jiao, Li and other groups (Scheme 1).[6] For
instance, in 2014, an efficient dehydrogenative N-
incorporation reaction of simple imines for the
synthesis of quinoxaline N-oxides using tert-butyl
nitrite (TBN) as the NO source was realized by Jiao
group.[6b] At the same time, Li group reported an
radical cascade nitration/annulation reaction of 1,7-
enynes for the construction of the pyrrolo[4,3,2-
de]quinolinone scaffold using TBN as NO2 source.[6c]
Inspired by Jiao’s recently work using TBN as single-
electron oxidant to afford the amino radical[6a]
through N-H bond cleavage and continuing our
interest in radical annulation of 1,6-enynes,[7] we
hypothesized that if alkynyl groups were introduced
into the ortho-position of enamine, a single-electron
oxidation, intramolecular radical cyclization/oxygen
atom insertion[8] sequence can be realized to produce
4-carbonylquinoline derivatives under metal-free
conditions (Scheme 2).
Introduction
The acylated quinoline unit is an important structural
motif that widely existed in many bioactive and
nature compounds. In particular, the 4-
carbonylquinoline moiety represents a relevant class
of derivatives which own the antiplasmodial activity,
cytotoxic activity, antibacterial and antifungal
activities.[1] Since the properties of these compounds
are in connection with 4-substituents on the quinoline
rings, the development of effective and
straightforward methods for the synthesis of
substituted 4-carbonylquinolines is highly desirable.
The traditional synthetic route to 4-carbonylquinoline
skeleton often occurred under strongly acidic
conditions with multisteps involved, which limited its
wide utilization in large scale synthesis of drugs and
organic compounds.[2] Although metal-catalyzed
approaches have made reaction conditions milder but
there is still a scope of improvement in terms of
generality of reaction and functional-group
tolerance.[3] Consequently, the development of green
and straightforward synthetic strategies to construct
multi-substituted quinoline derivatives with selective
control of substitution patterns is of urgent desire and
a challenging task.
Recently, radical cascade reactions have proven to
be a powerful shortcut for the assembly of complex
carbo- and heterocycles in organic synthesis.[4]
1
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10.1002/adsc.201900013
Advanced Synthesis & Catalysis
crucial role in governing overall activity of reaction,
as entries 10 and 11 showed that changing
temperature from optimized condition (entry 13)
resulted in diminished yield of desired product. In
addition, the concentration of the reaction was also
screened, when the concentration of the system was
decreased to 0.05M, the desired product 2a was
achieved in 67% yield (entry 13). Interestingly, we
found that a comparable result could be obtained in a
shorter reaction time (only 15 min, entry 14).
Subsequently, the amount of the additive TBAB and
the effects of other additives were also probed, when
the additive TBAB was omitted, a slightly lower
yield was obtained (entry 15), and a similar result
was observed using 20 mol% of TBAB (entry 16),
whereas the addition of TBAI (tetrabutylammonium
iodide), TBAC (tetrabutylammonium chloride), and
TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy)
resulted in lower yields (entries 17-19). According to
the results shown in Table 1 (entries 13 and 15),
TBAB was not a catalyst of the reaction, but acted as
an additive, which can accelerate this transformation.
Scheme 1. TBN-induced radical cascade reactions.
[6b]
It was worth noting that when other oxidants like
t
tBuOOtBu, BuOOH and PhI(OAc)2 were tested in
present reaction condition, it was found that TBN
outperformed these oxidants depicting crucial role of
TBN in this transformation (entries 20-22).
Table 1. Screening of the reaction conditions[a]
Scheme 2. Hypothesis of TBN-induced radical
cyclization/oxygen atom insertion.
Entry
1[c]
2
Oxidant
(equiv.)
tBuONO
(2.0)
Solvent (mL)
CH3CN (2.0)
CH3CN (2.0)
CH3CN (2.0)
DCE (2.0)
Yield(%)[b]
Results and Discussion
40
45
30
0
To realize the conceptually simple metal-free
oxidative cyclization, optimization studies using
active 1,6-enyne 1a as the model substrate, TBN as
the oxidant, tetrabutylammonium bromide (TBAB)
as the additive are summarized in Table 1. Initially,
the oxidative annulation reaction was conducted
under air condition, and a 40% yield of target product
2a was isolated (Table 1, entry 1). A slightly higher
yield was obtained when the reaction was carried out
under dioxygen atmosphere (entry 2). The amount of
the oxidant was crucial for the transformation, and a
diminished yield was observed when 1.2 equiv. of
TBN was used (entry 3). In order to improve the
efficiency of the transformation, other solvents were
screened, and trifluoroethanol emerged as being
optimal (entries 4-8). The reactivity dramatically
decreased when the reaction was carried out under
argon atmosphere, and only 16% yield was obtained,
indicating that dioxygen was essential for this
transformation (entry 9). Temperature played a
tBuONO
(2.0)
3
tBuONO
(1.2)
4
tBuONO
(2.0)
5
tBuONO
(2.0)
THF (2.0)
0
6
tBuONO
(2.0)
DMF (2.0)
0
7[c]
8
tBuONO
(2.0)
CF3CH2OH
(2.0)
CF3CH2OH
(2.0)
CF3CH2OH
(2.0)
CF3CH2OH
(2.0)
41
60
16
55
50
52
tBuONO
(2.0)
9[d]
10[e]
11[f]
12
tBuONO
(2.0)
tBuONO
(2.0)
tBuONO
(2.0)
CF3CH2OH
(2.0)
CF3CH2OH
tBuONO
2
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10.1002/adsc.201900013
Advanced Synthesis & Catalysis
(2.0)
(1.0)
CF3CH2OH
(4.0)
CF3CH2OH
(4.0)
CF3CH2OH
(4.0)
CF3CH2OH
(4.0)
CF3CH2OH
(4.0)
CF3CH2OH
(4.0)
CF3CH2OH
(4.0)
CF3CH2OH
(4.0)
13
14[g]
15[h]
16[i]
17[j]
18[k]
19[l]
20
tBuONO
(2.0)
67
65
57
59
32
45
40
0
tBuONO
(2.0)
tBuONO
(2.0)
tBuONO
(2.0)
tBuONO
(2.0)
tBuONO
(2.0)
tBuONO
(2.0)
tBuOOtBu
(2.0)
21
tBuOOH
(2.0)
CF3CH2OH
(4.0)
0
22
PhI(OAc)2
(2.0)
CF3CH2OH
(4.0)
29
[a]
Reaction conditions: 1a (0.2 mmol), TBAB (10 mol%),
Oxidant (tBuONO), Time (30 min) at 60 C, under 1 atm
o
O2. [b] Isolated yield.
Under air conditions.[d] Under Ar
[c]
atmosphere. [e] At 50 C. [f] At 70 C. [g] Time (15 min). [h]
o
o
Without TBAB. 20 mol% TBAB was used. [j] 10 mol%
[i]
TBAI was used. [k] 10 mol% TBAC was used. 10 mol%
[l]
TEMPO was used.
With the optimized conditions in hand (Table 1,
entry 13), the metal-free intramolecular oxidative
annulation scope of the transformation was
investigated. As shown in Scheme 3, a variety of 4-
carbonylquinolines with different functional groups
were synthesized in moderate yields (30-70%). It was
obvious that electron-withdrawing substituents, such
as F, Cl, Br, and CF3 at different positions, could be
well tolerated, showing the similar activities
compared with methyl group. The effect of steric
hindrance was not obvious, as ortho-substituted
substrates gave comparable results (2i and 2j).
Heterocycle-substituent, such as thiophene, also
appeared to be excellent in this transformation, and a
51% yield was obtained (2l). Except for 3-substituted
ethyl esters, benzoyl group was also tolerated, and a
lower yield of product 2m was separated. It was
noteworthy that alkyl alkyne substrate was likewise
suitable for this transformation, and an acceptable
yield was obtained (2n).
Scheme 3. The scope of intramolecular radical
cyclization/oxygen atom insertion. Reaction conditions:
1,6-enynes 1 (0.2 mmol), TBN (0.4 mmol), TBAB (0.02
mmol), CF3CH2OH (4 mL), 60 oC, O2, 30 min.
substituents, and the electronic property of
substitutent alkynes did not show great influences on
the reaction efficiency. Substrate containing naphthyl
could be tolerated, giving a lower yield due to the
steric hindrance (5m). Notably, heteroaromatic group
such as indolyl was also compatible with the reaction
conditions, and a 41% yield of product was obtained
(5n). In addition, the reaction of substrate with alkyl
alkyne with dimethyl but-2-ynedioate could also take
place, and the target product was isolated in 45%
yield (5o). To our disappointment, methyl propiolate
and methyl 3-phenylpropiolate were not suitable in
the standard conditions, no target products were
observed and substrate 3 can be recovered (not shown
in Scheme 4).
In view of these results, we turned our attention to
investigate
the
intermolecular
Michael
addition/oxidative annulation and oxygen atom
insertion. As described in Scheme 4, a great variety
of aminoalkynes could be easily transformed into the
corresponding 4-carbonylquinolines in moderate
yields (36-60%). A series of useful functional groups
were well tolerated, including methyl, tertiary butyl,
trifluoromethyl, ester, acetyl, nitrile, nitro, and ether
3
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10.1002/adsc.201900013
Advanced Synthesis & Catalysis
well tolerated, and moderate yield of products were
separated (52-60%). It is noteworthy that a scale-up
synthesis could be easily realized using this strategy
(Scheme 6).
Scheme 6. Scale-up reaction.
To gain more insights into the mechanism, some
control
experiments
and
isotope
labelling
experiments were carried out (Scheme 7). First, the
radical quenching experiments were conducted. The
oxidative annulation reaction was found to be
completely inhibited using 2.0 equiv. of TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (2,6-
di-tert-butyl-4-methylphenol)
as
the
radical
scavengers, implying that some radical species are
involved in this transformation. Then, in order to
examine the origin of the oxygen atom of ketone
18
products, isotopic labelling experiments with H2 O
and 18O2 were studied. When 10 equiv. of 18O-
18
labelled H2 O was added into the standard conditions,
the labelled product 2j was obtained as the major
product. Finally, when the reaction was carried out
under 18O-labelled dioxygen atmosphere, a mixed
18O-labelled product 2j was observed by HRMS.
These phenomenons clearly showed that the oxygen
atom of ketone can be from water and molecule
oxygen in this transformation.
Scheme 4. The scope of intermolecular Michael
addition/radical annulation/oxygen atom insertion.
Scheme 5. The scope of intermolecular radical annulation
of o-alkenylanilines.
Finally,
the
intermolecular
Michael
addition/oxidative annulation of o-alkenylanilines
with dimethyl but-2-ynedioate for the synthesis of
2,3-disubstituted quinolines has been also
investigated in Scheme 5. Mechanistically, this
transformation underwent an intermolecular Michael
addition of amino group with but-2-ynedioate
followed by intramolecular insertion of the olefin,
and oxidative cleavage of C-C bond sequence.
Compared with previous reports,[3c,7b] this strategy
can give better yields in a shorter reaction time.
Substrates containing Me, F, Cl, and Br, could be
Scheme 7. Mechanism studies.
4
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10.1002/adsc.201900013
Advanced Synthesis & Catalysis
According to previous reports[3a,3b,6,7b] and control
experiments, a tentative mechanism was depicted in
Scheme 8. The first step of this transformation is the
formation of the tert-butoxy radical and NO radical
generated by homolysis of TBN.[6] Then, H
abstraction of the N–H bond by tert-butoxy radical
occurs to generate radical intermediate A,[6a] which is
in resonance with intermediate B stabilized by
electron withdrawing group (COOEt). The resulting
B then goes through an intramolecular radical
addition to give radical intermediate C, which can be
easily oxidized to vinyl cation D. The intermediate D
reacts with H2O to form the enolate adduct E,[8c]
which finally goes through further isomerization and
aromatization under the oxidation of dioxygen to give
the product 2a and H2O. However, the detailed
process of the mechanism is still challenging until
now.
Acknowledgements
We thank the National Science Foundation of China NSF
21402066 and the Natural Science Foundation of Jiangsu
Province (BK20140139) for financial support. Financial
support from MOE&SAFEA for the 111 project (B13025)
is also gratefully acknowledged.
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Scheme 8. Proposed mechanism.
Conclusion
In conclusion, we have developed a metal-free TBN
induced radical oxidative annulation of 1,6-enynes or
in-situ formed 1,6-enynes for the efficient
construction
of
multi-substituted
quinoline
derivatives. This protocol allows the formation of
C−C and C−O bonds simultaneously through an
intramolecular radical cyclization/oxygen atom
insertion. This strategy using molecular oxygen as the
oxidant and H2O as the oxygen source under mild
reaction conditions makes this protocol particularly
sustainable and practical.
Experimental Section
General Procedure
The mixture of 1,6-enynes 1 (0.20 mmol) and TBN (0.40
mmol), TBAB (0.020 mmol, 10 mol%) were combined in
CF3CH2OH (4.0 mL) at 60°C for 30 min under 1 atm
dioxygen atmosphere. After the reaction, 6 mL water was
added to quench the reaction, and the resulting mixture
was extracted twice with DCM (2×10 mL). The combined
organic extracts were washed with brine, dried over
Na2SO4 and concentrated. Purification of the crude product
by flash column chromatography afforded the desired
product (petroleum ether/ethyl acetate as eluent (10:1-8:1)).
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6
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FULL PAPER
Metal-Free Oxidative Annulation/Cyclization of 1,6-
Enynes for the Synthesis of 4-Carbonylquinolines
Adv. Synth. Catal. Year, Volume, Page – Page
Xiao-Feng Xia,* Wei He, and Dawei Wang
7
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