Photo-mediated synthesis of halogenated spiro[4,5]trienones of: N-aryl alkynamides with PhI(OCOCF3)2 and KBr/KCl

Article abstract of DOI:10.1039/d0ob00057d

A novel and convenient photo-mediated halogenated spirocyclization of N-(p-methoxyaryl)propiolamides has been developed. The photolysis of phenyliodine bis(trifluoroacetate) (PIFA) as an iodination reagent led to iodinated ipso-cyclization under the irrad

Full text of DOI:10.1039/d0ob00057d

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Photo-Mediated Synthesis of Halogenated Spiro[4,5]trienones of
N-Aryl Alkynamides with PhI(OCOCF3)2 and KBr/KCl
Received 00th January 20xx,
Accepted 00th January 20xx
Tong Liu, Yaming Li , Linlin Jiang, Jiaao Wang, Kun Jin, Rong Zhang and Chunying Duan 
DOI: 10.1039/x0xx00000x
A novel and convenient photo-mediated halogenated spirocyclization of N-(p-methoxyaryl)propiolamides has been
developed. The photolysis of phenyliodine bis(trifluoroacetate) (PIFA) as an iodination reagent led to iodinated
ipsocyclization under the irradiation of a xenon lamp, while the brominated ipsocyclization or chlorinated ipsocyclization
were achieved by irradiating the mixture of PIFA with KBr/KCl under a blue LED. The present protocol simply utilizes light
as the safe and clean energy source, and without the aid of external photocatalyst providing various 3-
halospiro[4,5]trienones in good to excellent yields (up to 93%).
and BF3•Et2O (Scheme 1, eq 4). However, there are few
reports on the application of hypervalent iodine(III) for
construction of iodinated heterocycles, in which the iodo
Introduction
Spirocycles, including spiro[4,5]decatrienones, are essential
kind of skeletons in many natural products and
pharmaceuticals (Figure 1).1 Among the various spirocycles,
the azaspiro[4,5]trienones are crucial and interesting because
of their remarkable biological activities2 and diverse synthetic
applications.3 The considerable efforts have been devoted to
develop novel and efficient synthesis of the core spirocyclic
structure.4
moiety originated from the hypervalent iodine reagent.14
Furthermore, a kind of iodine(III)-based halogenating reagent
generated in situ by hypervalent iodine(III) with inorganic
halides, has attracted wide attention.15 Therefore, the
development of simple, mild, environmentally friendly method
to access halogenated spiro[4,5]trienones is still highly
desirable.
In recent years, organic transformations under visible light
irradiation with photocatalyst-free have captured much
attention.16 In 2017, Mahiuddin17 reported a visible light-
induced selenylative spirocyclization of N-arylpropiolamides at
room temperature in oxygen atmosphere without external
photocatalyst (Scheme 1, eq 5). Herein we report an efficient
and clean synthesis of halogenated spiro[4,5]trienones based
on photo-induced photocatalyst-free radical-cyclization-
dearomatization process of N-(p-methoxyaryl) propiolamides
at room temperature (Scheme 1, eq 6). This strategy involves a
connection of the halogen radical with the electron-deficient
carbon-carbon triple bond to generate the halogenated
spiro[4,5]trienones skeletons.
Generally, the spiro[4,5]trienone structures can be
constructed via the oxidative spiro-cyclization of phenol
derivatives,5 electrophilic ipso-cyclization,6 transition-metal-
mediated intramolecular nucleophilic ipso-cyclization,7 and the
radical coupling ipso-cyclization.8
It is worth noting that halogen functionalities are good
synthetic intermediates for further transformation to
functional materials. In 2005, Larock9 firstly reported a method
that N-(p-methoxyphenyl)-3-phenylpropiolamide converted to
spiro[4,5]trienone with 2 equiv of I2. In 2008, Li10 reported a
method for the synthesis of halogenated spiro[4,5]trienones
from N-(p-methoxyaryl)propiolamides with CuX (X= I, Br, SCN)
and electrophilic fluoride reagents (Scheme 1, eq 1). In 2012,
the same group11 disclosed halogenated spiro[4,5]trienones by
the electrophilic spirocyclization of N-arylpropiolamides with
NXS (Scheme 1, eq 2). Recently, Qiu12 reported the synthesis of
brominated spiro[4,5]trienones from N-arylpropiolamides
using ZnBr2 as bromine source and oxone as oxidant at room
temperature (Scheme 1, eq 3). Meanwhile, Du13 developed a
metal-free oxidative protocol for iodinated spiro[4,5]trienone
skeletons from N-(p-fluoroaryl)propiolamides by using PIFA
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian
University of Technology, Dalian 116024, Liaoning, P.R. China
†Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
x0xx00000x
Fig. 1 Structure of representative spirocyclic bio-active
compounds.
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Journal Name
NaOAc (2 equiv) in MeCN at room temperature in oxygen
View Article Online
DOI: 10.1039/D0OB00057D
atmosphere under the irradiation of a Xenon lamp for 18 h.
With the optimized reaction conditions in hand, the scope of
this iodinated spirocyclization method was investigated (Table
2). Firstly, a series of aryl substituents at the terminal alkynes
were examined. Bearing both electron-donating (2b-2d) and
electron-withdrawing (2e-2m) groups at the para-position of
the phenyl ring gave the corresponding products in good yields.
Additionally, steric factors also influenced on the iodinated
spirocyclization process (2j-2l), and the spirocyclization
reaction could not occur in the case of ortho-bromo
substitution of the phenyl connected with the alkyne.
Gratifyingly, the method was extended to heteroaromatic
alkyne leading to 2n in 56% yield. Unfortunately, treatment of
terminal alkyne (R1=H) with PIFA failed to construct product 2o.
Besides, the substrate with free N-H (R2=H) of
arylpropiolamide only gave a trace amount of the desired
product 2p. It was unfortunately that only trace target product
2q was obtained when a methyl was substituted on the alkyne.
Table 1. Optimization of the Iodinated Spirocyclization Reaction
Conditionsa
Scheme 1 The Intramolecular Spiro-cyclization of Alkynes.
Additive
(equiv.)
Base
Time
(h)
yieldb
(%)
Entry
1c
Solvent
Results and discussion
(equiv.)
In 2018, Qing18 developed the visible light-induced
decarboxylative trifluoromethylation of (hetero)arenes using
C6F5I(OCOCF3)2 as the trifluoromethylating reagent. Inspired by
this work, we initially postulated an intramolecular cyclization
reaction of N-(p-methoxyaryl)propiolamide (1a) in the
MeCN
Na2HPO4 (4.0)
Na2HPO4 (4.0)
Na2HPO4 (4.0)
Na2HPO4 (4.0)
Na2HPO4 (3.0)
Na2HPO4 (2.0)
-
12
33
2
3
MeCN
CH2Cl2
PhMe
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
12
12
12
12
12
12
12
12
12
12
12
12
12
18
18
18
51
49
4
45
presence
of
PIFA
to
afford
3-trifluoromethyl
5
64
spiro[4,5]trienones. The reaction was carried out with 1a and
PIFA in the presence of Na2HPO4 in MeCN at room
temperature under the irradiation of a Xenon lamp for 12 h.
However, iodinated spiro[4,5]trienone was detected in 33%
yield without expected 3-trifluoromethyl spiro[4,5]trienone
(Table 1,entry 1). Encouraged by this result, increasing the
amount of PIFA to 2 equiv gave 2a in overall 51% yield (Table 1,
entry 2). In an attempt to improve the reaction efficiency, a
variety of solvents were tested, and MeCN gave the best yield
(Table 1, entries 3-4). Varying the amount of Na2HPO4 revealed
that 2.0 equiv Na2HPO4 was preferable (Table 1, entries 5-7).
With the addition of TBHP or BPO, the yields decreased
obviously (Table 1, entries 8-9). Notably, without irradiation of
a Xenon lamp the spirocyclization reaction did not occur (Table
1, entry10). Screening of other bases, such as K2CO3, NaOAc,
NaHCO3 and Cs2CO3, the NaOAc gave the highest yield of 80%
(Table 1, entries 11-14). Prolonged irradiation time to 18 h
ledto higher yield (Table 1, entry 15). Notably, the use of
oxygen atmosphere in lieu of air improved the reaction
efficacy and the product 2a was isolated in 93% yield (Table 1,
entry 16). Therefore, the optimized conditions for this process
were defined as the use of 1a (1 equiv) with PIFA (2 equiv), and
6
72
7
32
8
TBHP
BPO
Na2HPO4 (2.0)
Na2HPO4 (2.0)
Na2HPO4 (2.0)
K2CO3 (2.0)
21
9
54
10d
11
12
13
14
15
16e
17f
N.D.
65
NaOAc (2.0)
NaHCO3 (2.0)
Cs2CO3 (2.0)
NaOAc (2.0)
NaOAc(2.0)
NaOAc(2.0)
80
69
17
84
93
N.D.
aAll reactions were performed in a Schlenk tube around condensate water with
1a (1.0 equiv, 0.2 mmol), PIFA (2.0 equiv), base in solvent (2 mL) at room
temperature under the irradiation of a Xenon lamp. bIsolated yields. c1 equiv of
PIFA. dWithout irradiation. eIn oxygen atmosphere. f With the irradiation of blue
LED.
2 | J. Name., 2012, 00, 1-3
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Table 2. Substrate Scope of Iodinated Spiro[4,5]trienonesa
irradiation, the yield of 3a was drastically reduced to 46%
(Table 3, entry 2). Subsequently, screening the amount of PIFA,
View Article Online
DOI: 10.1039/D0OB00057D
KBr, solvent and irradiation time, the optimized conditions of
brominated spirocyclization were achieved as using 1a (1 equiv)
with PIFA (1.5 equiv), KBr (2.0 equiv) and NaOAc (2 equiv) in
MeCN at room temperature under irradiation of a 15W blue
LED for 2h. Gratifyingly, the reaction of substrate 1a with PIFA
and KCl processed smoothly under irradiation of a blue LED,
affording the corresponding chlorinated spiro[4,5]trienone 3b
in 76% yield.
With the optimized reaction conditions in hand, the scopes
of the brominated spiro[4,5]trienones and chlorinated
spiro[4,5]trienones were investigated as shown in Table 4. It
showed good tolerance for a series of aryl substituents at the
alkynes. When R1 was 4-methoxyphenyl, the reaction gave the
corresponding chlorinated spiro[4,5]trienones (3c) in good
yield. Extensive screening revealed that electron-deficient
groups at the para-position of the phenyl ring were well-
tolerated, affording the desired products in moderate yields
(3d-3j). Furthermore, the heteroaromatic alkyne gave the
desired products 3k and 3l in
62% and 54% yields, respectively. Particularly, with phenyl 3-
phenylpropiolate, the reaction proceeded smoothly as well, to
afford 3m in good yields. Notably, the substrate with free N-H
(R2=H) of arylpropiolamide, which was not easy to
20
halogenation spirocyclization under metal catalyst8g,
or
visible-light-catalyzed conditions,8o served well for the
synthesis of free N-H brominated spiro[4,5]trienone (3n) under
the optimal conditions. Unfortunately, none of cyclization
products 3o and 3p was observed when terminal alkyne (R1=H)
was utilized in this process.
Table 3. Optimization of the Brominated Spirocyclization Reaction
Conditionsa
aAll reactions were performed in a Schlenk tube around condensate water with 1
(1.0 equiv, 0.2 mmol), PIFA (2 equiv), NaOAc (2 equiv) in CH3CN (2 mL) at room
temperature in oxygen atmosphere under the irradiation of a Xenon lamp for 18
h.
PIFA
KBr
Time
(h)
Entry
Solvent
Yieldb(%)
(equiv)
(equiv)
Encouraged by the good results of iodination
spirocyclization, we turned our attention to the reaction of
brominated and chlorinated spirocyclization of N-(p-
methoxyaryl)propiolamides. In 2017, Hu19 reported RuIII
photoredox catalyzed oxidative C–H chlorination of aromatic
compounds using NaCl as the chlorine source and Na2S2O8 as
the oxidant. In 2019, Nagib and Fuchs15e developed site-
selective hetero(aryl) C–H functionalization strategy by in situ
generation of non-symmetric iodanes from PhI(OAc)2 and the
anions of acids, salts, and acyl halides. Herein we investigated
a photo-induced brominated spirocyclization and chlorinated
spirocyclization with PIFA and KBr/KCl as sources of halogen
radical. Initially, we used N-(p-methoxyaryl)propiolamide 1a,
as a model, 1.0 equiv of PIFA and 2.0 equiv of KBr in CH2Cl2
under irradiation of a 15W blue LED, and the desired
brominated spiro[4,5]trienone was obtained in 88% yield
(Table 3, entry 1). For the control experiment, without
1
2
1.0
1.0
1.5
2.0
-
2.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
DMF
18
18
18
18
18
18
18
18
12
6
88
65
90
92
N.D.
94
64
57
94
92
90
90
45
92
3
4
5
6
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
7
8
THF
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10
11
12
13c
14d
3
2
2
2
aAll reactions were performed in a Schlenk tube with 1a (1.0 equiv, 0.2 mmol),
PIFA, KBr, NaOAc (2,0 equiv) in solvent (2 mL) at room temperature under the
irradiation of a 15 W blue LED. bIsolated yields. cWithout irradiation. dUnder the
irradiation of a Xenon lamp.
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J. Name., 2013, 00, 1-3 | 3
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Table 4. Substrate Scope of Brominated Spiro[4,5]trienones and
Chlorinated Spiro[4,5]trienonesa
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DOI: 10.1039/D0OB00057D
Scheme 2. Control Experiments
to form iodanyl radical A and trifluoroacetoxy radical B under
the irradiation of a Xenon lamp.22c Subsequently, the addition
of iodanyl radical A to the triple bond of arylpropiolamide 1a
gave vinyl radical C. Next, the intermediate D was produced by
spirocyclization and dearomatization of intermediate C. Then,
the trifluoroacetoxy radical B, released in the previous step,
attacked sp2 carbon to form E. Meanwhile, under the oxygen
atmosphere, the intermediate D could also converted to
intermediate F. E and F were converted to G with leaving of
the methoxy group23. An SNAr reaction occurred to form H,
which further afforded final product 2a.24 The oxygen atom of
the newly formed carbonyl group is mainly from PIFA.
The mechanism for brominated spirocyclization and
chlorinated spirocyclization reactions are illustrated in Scheme
3 path B and C. Initially, upon reaction with KX, intermediate
species PhI(OCOCF3)X was formed in situ from PIFA.15
Subsequently, two possible pathways could explain the
formation of product 3a/3b. As the major path, in path B,
halogen radical was produced from PhI(OCOCF3)X25 under the
irradiation of a blue LED. Next, the addition of halogen radical
to the triple bond of arylpropiolamide 1a gave vinyl radical I.15e
The intermediate I underwent spirocyclization and oxidation to
form intermediate L. Then, the trifluoroacetate anion attacked
the electron-positive aromatic C(sp2) to form M. Finally, the
intermediate M was converted to the target products 3a/3b.
Additionally, in path C, a halide cation is generated by
oxidation of halide ions with PIFA.19,26 Electrophilic
spirocyclization could be attributed to the synthesis of 3a/3b.
aAll reactions were performed in a Schlenk tube with
1 (1.0 equiv, 0.2
mmol), PIFA (1.5 equiv), KX (2.0 equiv), NaOAc (2 equiv) in CH3CN (2 mL) at
room temperature with the irradiation of a 15W blue LED for 2 h.
In order to understand the possible reaction mechanism, the
following control experiments were carried out (Scheme 2).
The reactions of N-(p-fluoroaryl)propiolamide provided the
corresponding halogenated spiro[4,5]trienones 2a/3a/3b in
good yields by delivering fluorine group, suggesting that the
carbonyl oxygen atom is not derived from the methoxy group
(Scheme 2, eq 1). When the reaction of 1a was performed
without PIFA, the spirocyclization product 2aa was not
detected, indicating that the free radical species formed by
PIFA attacked triple bond before forming the spirocyclization
intermediate 2aa (Scheme 2, eq 2). Furthermore, a radical
trapping experiment was conducted. When 3.0 equiv of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added into
reaction system, only trace amounts of the products 2a/3a/3b
were detected. However, mixing PIFA and TEMPO could lead
to the total reduction of PIFA to iodobenzene. 15a, The 1,1-
21
diphenylacetylene as the free radical scavenger suppressed
the spirocyclization, and the yields of 3a and 3b were only 42%
and 13%, respectively, indicated that the reaction of
halogenated spirocyclization mainly proceeds via a radical
pathway (Scheme 2, eqs 3 and 4).
According to the previous reports22 and our experimental
results, a plausible mechanism for iodinated spirocyclization
reaction is outlined in Scheme 3 path A. PIFA is photoexcited
4 | J. Name., 2012, 00, 1-3
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ARTICLE
Scheme 3. Proposed Mechanistic
process feature is a radical reaction, PIFA as iodination reagent
in iodination spirocyclization reaction or a reagent for initiating
bromine or chlorine radicals with KBr/KCl in brominated
spirocyclization and chlorinated spirocyclization. With
advantages such as mild conditions, environmental-friendly
and non-toxic photocatalysts, this new synthetic method is
expected to further applications of synthetic biologically active
compounds.
Conflicts of interest
There are no conflicts to declare.
Scheme 4. The Utilization of Product 2a
Finally, the functionalization
of
the
iodinated
spirocyclization has been performed to explore the utility of
this iodocyclization product. As shown in Scheme 4, the
substrate 2a underwent the Suzuki coupling and the
Sonogashira coupling to afford products 4a and 5a in 90% and
83% yields, respectively (Scheme 4).
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NSFC) (Project Nos. 21890318 and
21176039).
Conclusions
Notes and references
In conclusion, we have developed a metal photocatalyst-
free photo-mediated halogenated spirocyclization of N-(p-
methoxyaryl)propiolamides for the synthesis of halogenated
spiro[4,5]trienones skeletons at room temperature. This
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