Straightforward synthesis of functionalized chroman-4-ones through cascade radical cyclization-coupling of 2-(allyloxy)arylaldehydes

Article abstract of DOI:10.1039/c5cc09730d

A novel and direct approach to synthesize a series of phosphonate, azide and hydroxy functionalized chroman-4-ones has been developed. The cascade transformation appears to proceed through an intramolecular addition of an in situ generated acyl radical onto the alkene, followed by a selective nucleophilic radical-electrophilic radical cross coupling.

Full text of DOI:10.1039/c5cc09730d

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Straightforward synthesis of functionalized
chroman-4-ones through cascade radical
Cite this:DOI: 10.1039/c5cc09730d
cyclization-coupling of 2-(allyloxy)arylaldehydes†
Received 25th November 2015,
Accepted 1st February 2016
ab
ab
a
a
a
Jingjing Zhao,‡ Pan Li,‡ Xinjian Li, Chungu Xia and Fuwei Li*
DOI: 10.1039/c5cc09730d
www.rsc.org/chemcomm
A novel and direct approach to synthesize a series of phosphonate,
azide and hydroxy functionalized chroman-4-ones has been developed.
The cascade transformation appears to proceed through an intra-
molecular addition of an in situ generated acyl radical onto the
alkene, followed by a selective nucleophilic radical–electrophilic
radical cross coupling.
The chroman-4-one scaffold with functional groups widely
exists in natural products, and has found abundant applications
1
in biological and medicinal compounds. Consequently, the
development of atom-economical and efficient approaches to
synthesize these functionalized chroman-4-ones has attracted
2
much attention. The internal hydroacylation between an
Scheme 1 N-heterocyclic carbene and radical approaches to 3-(phos-
aldehyde and alkene provides an elegant route to produce the phonomethyl)chroman-4-ones.
3
chroman-4-one skeleton. Beyond that, sequentially coupling
4
5
hydroacylation with another functionalization of unactivated
alkenes may represent one of the most direct routes to func- another functional radical, such as a phosphonyl-, azide-, or
tionalized chroman-4-ones.
hydroxyl-radical.
As a representative example, phosphonate chroman-4-ones
could be synthesized via a polarity reversal strategy enabled by mation via direct oxidative coupling between the Csp –H of
In 2012, we reported the first Pd-catalyzed C–P bond for-
2
the N-heterocyclic carbene (NHC) catalyzed Stetter reaction of azole and the P–H of dialkyl phosphite. This transformation
7
(
vinylphosphonate)arylaldehyde, which was obtained by the was determined to be a non-radical process. It has been
2 2 8
Rh-catalyzed hydrophosphinylation of a protected functional demonstrated that silver salts/K S O are efficient catalyst
6
8
alkyne (Scheme 1). Inverse synthetic analysis indicated that these systems for phosphonyl radicals initiating. Therefore, we started
compounds could possibly be prepared through a more straight- our conditions screening from a model reaction of 2-(allyloxy)-
forward hydroacylation–phosphorylation of 2-(allyloxy)arylalde- benzaldehyde 1a and diethyl phosphite 2a, and the desired
hydes, and it could be assumed to proceed in the following way: product 3aa was obtained in 16% yield using AgNO
3
as the metal
the in situ generated acyl radical species would react with the catalyst and K as the oxidant in DMSO at room temperature
2 2 8
S O
neighbouring alkene (similar to the hydroacylation reaction in (Table 1, entry 1). The yield of 3aa rose up to 48% when running
form) to generate an active cyclic alkyl radical intermediate, which the reaction at a slightly higher temperature (35 1C) (Table 1,
could undergo a second functionalization by cross coupling with entry 2). Further raising the temperature instead decreased the
2 2 8
reactivity (Table 1, entry 3). When replacing the oxidant K S O
with Na S O , (NH ) S O , Mg(NO ) Á6H O or Cu(NO ) Á6H O,
2
2
8
4 2
2
8
3 2
2
3 2
2
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
E-mail: fuweili@licp.cas.cn; Fax: +86-931-4968129
lower or even no yields were obtained (Table 1, entries 4–7).
Compared with DMSO, a wide range of other solvents, such as
toluene, dioxane, MeCN, THF, DCE, DCM, DMF, EtOAc, and
MeOH, all gave much lower 3aa yields (see Table S1 in the ESI†).
b
Graduate University of Chinese Academy of Sciences, Beijing, 100049, China
Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc09730d
These authors contributed equally.
†
‡
Because of the important role of K
2
S O
2 8
in generating the
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a
Table 1 Optimization of the reaction conditions
Entry
Catalyst
Oxidant (equiv.)
Temp. (1C)
Yield (%)
1
2
3
4
5
6
7
8
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
3
3
3
3
3
3
3
3
3
3
3
K
K
K
2
2
2
S
S
S
2
2
2
O
O
O
8
8
(4)
(4)
(4)
25
35
50
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
16
48
36
30
27
0
8
Na
(NH
Mg(NO
Cu(NO
2
S
4
2
O
8
(4)
)
2
S
3
2
)
O
8
(4)
Á6H O (2)
Á6H O (2)
2
2
3
)
2
2
0
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
8
8
8
8
8
8
(3)
(2)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
50
33
35
45
51
49
58
49
45
49
63
70
47
Trace
0
9
b
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
c
AgOTf
Ag
2
Ag
2
Ag
2
Ag
2
CO
3
SO
SO
O
4
3
Scheme 2 Scope of the phosphonyl compounds and 2-(allyloxy)arylal-
AgOAc
AgSbF
AgSbF
AgSbF
6
dehydes. Reaction conditions:
1 (0.3 mmol), 2 (1.2 mmol), AgSbF
6
d
6
(0.06 mmol) and K (0.9 mmol) in DMSO (3 mL) at 35 1C for 5 h
2 2 8
S O
d,e
6
6
under Ar. Reported yields are isolated yields.
f
AgSbF
a
To study the proposed mechanism, a series of radical
h. Reported yields are the isolated yields. 3 equiv. of diethyl trapping experiments was carried out. The common radical
All reactions were carried out on a 0.3 mmol scale in DMSO (3 mL) for
b
5
c
d
e
phosphite. 5 equiv. of diethyl phosphite. Under Ar. 10 mol% of
AgSbF for 12 h. 200 mol% of AgSbF .
6 6
scavengers TEMPO (2,2,6,6-tetramethylpiperidinooxy) and BHT
butylated hydroxytoluene) could prevent the reaction comple-
tely (Scheme 3a). This reaction could also be suppressed by
,1-diphenylethylene. Besides, a little of the coupling product of
f
(
1
phosphonyl radical, the ratio of 2a and K S O significantly
2
2 8
the phosphonyl radical with 1,1-diphenylethylene was detected
by GC-MS (Scheme 3b). These results not only suggest that the
reaction experiences a radical process, but also indicate that a
phosphonyl radical could be involved in this transformation.
Such a transformation involving C–C and C–P bond forma-
tions is proposed to proceed via either an acyl radical addition
affects the reactivity, and a 50% yield of 3aa was realized using
equiv. of 2a and 3 equiv. of K S O (Table 1, entries 8–11). Upon
4
2
2 8
6
using various silver salts as the catalyst, AgSbF displayed the best
catalytic activity, giving the desired 3aa in 63% yield (Table 1,
entries 12–18), and the yield of 3aa could be improved to 70%
under an argon atmosphere (Table 1, entry 19). However, only
9,10
to the alkene or a phosphate radical addition to the alkene.
4
7% yield of 3aa was obtained when reducing the amount of
To gain more insights into the reaction pathway, the following
control experiments were conducted. The reaction of 1-(allyl-
oxy)-4-methoxybenzene 1y and 2a did not afford the desired
phosphate derivatives and 90% of 1y was recovered
silver catalyst (Table 1, entry 20). It is worth noting that both
the silver catalyst and oxidant are indispensable in this transfor-
mation (Table 1, entries 21 and 22).
With the optimized conditions in hand (Table 1, entry 19),
we then turned our attention to examining the scope and
limitations of this method (Scheme 2). First, we evaluated a
series of phosphonyl compounds. Dialkyl phosphites afforded
the corresponding products in moderate to good yields (3aa–3af).
Unfortunately, diphenylphosphine oxide and diphenyl arylalde-
hydesnate were not suitable for this transformation. Subsequently,
a series of 2-(allyloxy)arylaldehydes were investigated. The benzene
rings with electron-donating (Me, OMe and tert-butyl) and
(
Scheme 4a). Surprisingly, the product 3aa was not detected
when 1y was added to the model reaction, 88% of 1a and 92%
of 1y were recovered (Scheme 4b). These two results appear to
indicate that the addition of a phosphonyl radical onto the
alkene was not involved in the transformation, although the
presence of a phosphonyl radical was indicated by the reaction
-
withdrawing (Br and Cl) groups all worked smoothly with
dialkyl phosphites, affording the desired phosphonate
chroman-4-ones in 32% to 70% yields (3ba–3ga, 3bd–3gd).
2
-(Allyloxy)-1-naphthaldehyde also worked using this transfor-
mation, affording 3ha in 30% yield. Furthermore, phosphonate
,3-dihydroquinolin-4-one 3ia with a nitrogen atom in the
2
skeleton could also be synthesized by this procedure.
Scheme 3 Radical trapping experiments.
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Scheme 4 Control experiments.
Scheme 6 Plausible reaction mechanisms.
in Scheme 3b. In addition, 1y could prevent the reaction from
occurring. The addition products of the phosphonyl radical and
styrene were also not observed, and the styrene was found to be
polymerized (Scheme 4c). Similar to 1y, styrene could also
inhibit the reaction (Scheme 4d). These results further excluded
the possibility that the reaction underwent a phosphonyl
radical addition to the alkene. Based on the above investiga-
tions, it could be tentatively assumed that this cascade reaction
preferred to undergo an acyl radical addition onto the alkene.
In order to further verify and extend the application of the
above strategy involving acyl radical cascade cyclization with an
alkene and subsequent coupling with another electrophilic
radical, we tested the reaction of 1a with other radicals. It has
OMe and naphthalene) were obtained in 28% to 40% yields
5b–5d). In addition, the desired hydroxyl chroman-4-one 6a
(
was isolated from the reaction of 1a with a hydroxyl radical
produced by KI/TBHP in 43% yield, and 4 was also detected by
GC-MS (Scheme 5b). Similarly, other hydroxyl chroman-4-one
derivatives (Me, OMe and naphthalene) were synthesized in
25% to 38% yields via the same strategy (6b–6d). These results
further indicate that these reactions underwent an intra-
molecular addition of the acyl radical to the alkene, followed
by a selective coupling between the nucleophilic alkyl radical
1
3
14
1
1
12
and electrophilic azide radical or hydroxyl radical.
Based on the above experiments, a proposed mechanism is
been reported that the azide radical or peroxide could
initiate aldehydes to generate acyl radicals. To our delight, 1a
1
5
drawn in Scheme 6. Initially, acyl radical A and a phosphonyl
radical were initiated from 1 and 2 under the catalysis of a silver
catalyst and K S O . Then A undergoes an intramolecular
could transform into the desired N
one 5a in 51% yield under an azide radical generating reaction
system, and by-product was obtained in 20% yield
Scheme 5a). Other azide chroman-4-one derivatives (Me,
3
functionalized chroman-4-
2
2 8
4
1
0
cyclization to generate a new alkyl radical B. Finally, the
desired product 3 is obtained via the coupling of nucleophilic
alkyl radical B and an electrophilic phosphonyl radical
(
1
6
(
Scheme 6, Path A). Inevitably, radical B might transform into
the by-product 4 via hydrogen abstraction from 1 along with the
regeneration of A. Alternatively, the formation of 3 could
possibly be due to the addition of a phosphorus radical to the
9
alkene, followed by the addition of alkyl radical C to the CQO
bond generating oxygen radical D. Eventually, D could convert
1
7
to 3 via a single electron oxidation process (Scheme 6, Path B).
Based on the control experiments (Scheme 4) and the formation
of by-product 4, we are inclined to favour the formation of 3 via
Path A. Likewise, the formation of the azido and hydroxyl
chroman-4-ones may follow Path A.
In summary, we have developed a novel and straightforward
approach to synthesize phosphonate chroman-4-ones. The reaction
employs a simple silver salt as the catalyst and K S O as an oxidant
2
2 8
under mild conditions. It was found to involve an alkyl radical
intermediate B generated by acyl radical addition to the alkene,
followed by its selectively coupling with a phosphonyl radical.
Interestingly, such an acyl radical addition onto a neighbouring
Scheme 5 Synthesis of 3-(azidomethyl) and 3-(hydroxymethyl)
chroman-4-ones.
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alkene and a subsequent radical/radical cross coupling strategy
could also extend to azido and hydroxyl radicals, and the synthesis
of the corresponding functionalized chroman-4-ones was achieved
smoothly. The successful application of the present strategy for the
diverse and green synthesis of functional compounds will stimulate
more interest on the development of radical-involving cascade
reactions.
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9
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and the National Natural Science Foundation of China (21133011,
21373246, and 21522309) for generous financial support.
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0 For selected examples on the acyl radical cascade reactions, see:
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(
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2
For selected examples on the synthesis of functionalized chroman-4- 11 For an example on the generation of acyl radical in the presence of
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2
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À
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(
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4
5
1
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2 2 8
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(
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7
2
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8
CQX bonds, see: D. Liu, C. Liu and A. Lei, Chem. – Asian J., 2015,
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2 2 8
S O
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