Metal-free radical 5-exo-dig cyclizations of phenol-linked 1,6-enynes for the synthesis of carbonylated benzofurans

Article abstract of DOI:10.1002/anie.201408978

A new metal-free radical 5-exo-dig cyclization of phenol-linked 1,6-enynes with O₂, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and tBuONO is described. With this general method, carbonylated benzofurans can be accessed through incorporation

Full text of DOI:10.1002/anie.201408978

Angewandte
Chemie
DOI: 10.1002/anie.201408978
Heterocycle Synthesis
Metal-Free Radical 5-exo-dig Cyclizations of Phenol-Linked
1,6-Enynes for the Synthesis of Carbonylated Benzofurans**
Ming Hu, Ren-Jie Song, and Jin-Heng Li*
Abstract: A new metal-free radical 5-exo-dig cyclization of
phenol-linked 1,6-enynes with O2, 2,2,6,6-tetramethyl-1-piper-
idinyloxy (TEMPO), and tBuONO is described. With this
general method, carbonylated benzofurans can be accessed
through incorporation of two oxygen atoms into the product
from O2 and TEMPO through dioxygen activation and
conditions, limited functional group tolerability, and/or the
cost of the catalytic system.[3–6] Furthermore, the assembly of
carbonylated benzofuran scaffolds remains a great chal-
lenge.[3,4] Therefore, the development of mild and efficient
routes and especially metal-free strategies towards carbony-
lated benzofurans is desirable.[6]
À
oxidative cleavage of the N O bond, respectively.
The cyclization of 1,n-enynes has emerged as a powerful
transformation that allows the rapid assembly of various
complex ring systems in an atom- and step-economic
manner.[7] Within the last years, many applications of the
1,n-enyne cyclization for the construction of various hetero-
cycles, such as furans, pyrans, pyrroles, indoles, pyridines,
quinolines, and other fused polyheterocycles, have been
reported.[7,8] However, approaches using the real 1,n-enyne
cyclization strategy to access benzofurans are lacking.[5] This
is due to the fact that the intramolecular cyclization of phenol-
linked 1,6-enynes in the presence of a rhodium catalyst leads
Benzofurans,
including
carbonylated
benzofurans
(Figure 1), are pervasive structural motifs found in natural
products and pharmaceutical compounds with powerful
biological properties.[1–2] For example, brazanquinones show
selective inhibitory activity against a series of cancer cell
to b-oxygen elimination/cyclization through cleavage and
2
À
formation of the C(sp ) O bonds rather than direct enyne
cyclization (Scheme 1a).[5] We reasoned that direct cycliza-
tion reactions of phenol-linked 1,6-enynes might be realized
Figure 1. Examples of important carbonylated benzofurans.
Scheme 1. Cyclization of phenol-linked 1,6-enynes into benzofurans.
binap=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl, cod=cycloocta-
1,5-diene.
lines.[2a–c] Balsaminones, which were isolated from the peri-
carp of the fruit Impatiens balsamina L., have significant
antipruritic activity.[2d–f] Considerable efforts have thus been
directed towards the discovery of efficient methods for their
synthesis.[3–6] Despite remarkable advances in benzofuran
synthesis, most of the traditional methods suffer from harsh
under metal-free conditions. In the field of 1,n-enyne
cyclization, radical strategies have played great roles and
are now also shown to be useful for 1,n-enyne cyclizations.[7,8]
However, the majority of radical cyclization reactions suffer
from a requirement for precious and/or toxic metal complexes
(often tin hydride reagents) and the difficult purification of
the desired products from a large amount of unwanted side
products and waste; therefore, they have received less
attention over the past decade.[7,8] Herein, we report a novel
metal-free radical 5-exo-dig cyclization of phenol-linked
1,6-enynes with air, 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), and tBuONO[9] for the formation of carbonylated
benzofuran scaffolds (Scheme 1b). In this transformation, the
[*] M. Hu, Dr. R.-J. Song, Prof. Dr. J.-H. Li
State Key Laboratory of Chemo/Biosensing and Chemometrics
College of Chemistry and Chemical Engineering, Hunan University
Changsha 410082 (China)
E-mail: jhli@hnu.edu.cn
Prof. Dr. J.-H. Li
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (China)
[**] We thank the NSFC (21172060), the Specialized Research Fund for
the Doctoral Program of Higher Education (20120161110041), and
the Hunan Provincial Natural Science Foundation of China
(13JJ2018) for financial support.
=
addition of TEMPO across the C C bond, oxidative elimi-
À
nation through cleavage of the N O bond with tBuONO,
cyclization with an alkyne, and radical dioxygen activation are
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408978.
achieved.[10] It should be noted that the two oxygen atoms that
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constitute the newly formed carbonyl groups of the benzo-
furan system originate from O2 and TEMPO, respectively.
Our initial investigations began with the reaction of 1-
(phenylethynyl)-2-(vinyloxy)benzene (1a) with air, TEMPO,
and tBuONO for reaction optimization (Table 1). Treatment
reaction with respect to a range of 1-ethynyl-2-(vinyloxy)-
benzenes 1 (Table 2). Gratifyingly, both electron-donating
(2b–g and 2o) and electron-withdrawing (2h–n) aromatic
substituents were tolerated at the terminal alkyne. Moreover,
even with bulky ortho-substituted aryl groups, the carbony-
lated benzofurans were furnished in good yields (2c, 2 f, 2g,
and 2k), although these substrates were less reactive than
their para- or meta-substituted counterparts. For example,
whereas para-methyl-substituted 1,6-enyne 1b afforded 2b in
76% yield, ortho-methyl-substituted 1,6-enyne 1c was con-
verted into 2c in 71% yield. For methoxy-substituted 1,6-
enynes 1d–f, the reactivity decreased from para to meta to
ortho substitution (2d–f). Notably, substrates with strongly
electron-withdrawing cyano and acetyl groups also delivered
the carbonylated benzofurans 2m and 2n in good yields.
Halide substituents (I, Br, Cl, and F) were well tolerated
under these oxidative conditions (2h–l), and may serve as
handles for further synthetic manipulations. 1,6-Enyne 1o,
which bears two methyl groups, and 1,6-enyne 1p, which
features a naphthalen-1-yl group, afforded benzofurans 2o
and 2p in 75% and 59% yield, respectively. We were pleased
to find that heteroaryl-substituted alkynes 1q–s were also
suitable substrates and allowed the formation of 2q–s in
moderate to high yields. Furthermore, the optimized reaction
conditions were applicable to 1,6-enyne 1t, which bears an
alkyl group at the terminal alkyne (2t). Subsequently,
representative 1,6-enynes were selected to illustrate the
tolerance for substituents on the aryl ring of the 1-(vinyl-
oxy)benzene moiety (2u–w). The substrate with an electron-
donating methyl group afforded benzofuran 2u in 57% yield,
whereas with an electron-withdrawing CN substituent, ben-
zofuran 2v was obtained in 80% yield at 808C. We were
pleased to find that 2w, with a polycyclic ring system, was
furnished in 75% yield.[2d,e] However, internal alkenes 1x and
1y did not react under the current cyclization conditions
[Eq. (1)].
Table 1: Optimization of the reaction conditions.[a]
Entry
tBuONO
[equiv]
TEMPO
[equiv]
Solvent
T [8C]
Yield[b] [%]
1
2
3
0
3
3
3
3
3
3
3
3
3
3
3
0
3
3
3
3
3
3
3
3
DMF
DMF
DMF
MeCN
EtOAc
toluene
DMF
DMF
DMF
DMF
DMF
RT
RT
RT
RT
RT
RT
40
60
40
40
40
65
0
0
3[c]
4
48
38
18
73
71
73
trace
71
5
6
7[d]
8
9[e]
10[f]
11[g]
[a] Reaction conditions: 1a (0.3 mmol), tBuONO, TEMPO, air (1 atm),
solvent (2 mL), 8 h. [b] Yield of isolated product. [c] Another product, (2-
(nitromethyl)benzofuran-3-yl)(phenyl)methanone (4a), was isolated in
23% yield together with >50% yield of 1a. [d] Product 3 was isolated in
70% yield based on the amount of TEMPO used. [e] Under O2
atmosphere (1 atm). [f] Under argon atmosphere (1 atm) and in
degassed solvent. [g] 1a (1 g, 4.5 mmol), 24 h.
of 1,6-enyne 1a with air, TEMP,O and tBuONO in DMF at
room temperature for eight hours afforded the desired 3-
benzoylbenzofuran-2-carbaldehyde (2a) in 65% yield
(entry 1). However, in the absence of either TEMPO or
tBuONO, the reaction did not result in the formation of
detectable amounts of 2a (entries 2 and 3). Without TEMPO,
the nitration/cyclization product (2-(nitromethyl)benzofuran-
3-yl)(phenyl)methanone (4a) was isolated in 23% yield
(entry 3). Three other solvents, namely MeCN, EtOAc, and
toluene, effected the reaction but were inferior to DMF
(entries 4–6). Screening the effect of the reaction temperature
revealed that higher temperatures were favorable, and 408C
was found to be the preferred temperature (entries 1, 7, and
8). Notably, the reaction at 408C gave 2a in 73% yield, while
TEMPO was converted into 2,2,6,6-tetramethyl-1-nitrosopi-
peridine (3) in 70% yield (entry 7). When varying the
amounts of TEMPO and tBuONO, we found that the reaction
with three equivalents of TEMPO and tBuONO gave the best
results (entry 7; see also the Supporting information,
Table S1).[11] The yield under O2 atmosphere was identical
to that under air (entry 9), but the reaction was completely
suppressed by using argon and degassed solvent (entry 10).
The reaction with one gram of substrate 1a gave the desired
product in good yield (entry 11).
To elucidate the mechanism, some control experiments,
including 18O-labeling experiments, were conducted.[11] As
expected, an 18O atom was introduced into the ketonic
carbonyl group under 18O2 atmosphere (1 atm) as determined
by GC-MS and 13C NMR analysis (Scheme 2a). However,
according to GC-MS and 13C NMR analysis, 18O atoms were
not incorporated into the carbonyl groups in the presence of
H218O (5 equiv) and anhydrous DMF (Scheme 2a). Notably,
the results in Table 1 show that during the reaction, TEMPO
is converted into 2,2,6,6-tetramethyl-1-nitrosopiperidine (3).
These results imply that the oxygen atom of the aldehydic
carbonyl group originates from TEMPO. Substrate 5 was
subjected to the reaction with air, TEMPO, and tBuONO, but
the desired product 2a was not observed (Scheme 2b).
With the optimized reaction conditions in hand, we next
investigated the generality of this metal-free cyclization
2
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Table 2: Substrate scope.[a]
Scheme 3. Possible mechanism.
NO2, NO, and H2O.[9,12] Initially, addition of TEMPO across
=
the C C bond of 1,6-enyne 1a takes place to produce alkyl
radical intermediate A, followed by a cyclization that affords
vinyl radical intermediate B. Intermediate B is trapped by O2
to afford superoxide radical C. Oxidative cleavage of the
À
N O bond in intermediate C with the aid of NO and single-
electron transfer (SET)[10] occurs to form peroxyl intermedi-
ate D and 2,2,6,6-tetramethyl-1-nitrosopiperidine (3). Finally,
À
O O bond cleavage/isomerization of intermediate D delivers
product 2a.
In summary, we have developed the first metal-free 5-exo-
dig cyclization of phenol-linked 1,6-enynes with O2, TEMPO,
and tBuONO through a radical process for the synthesis of
carbonylated benzofurans. Importantly, this transformation
incorporates two oxygen atoms from O2 and TEMPO,
respectively into the benzofuran system. Owing to its metal-
free nature, this reaction satisfies the particular purity
requirements of biological and medicinal chemistry. This
simple radical strategy will renew our interest into applica-
tions of 1,n-enyne radical cyclizations, and related studies are
currently underway in our laboratory.
[a] Reaction conditions: 1 (0.3 mmol), tBuONO (3 equiv), TEMPO
(3 equiv), air (1 atm), DMF (2 mL), 408C, 8 h. [b] At 808C.
Received: September 10, 2014
Revised: October 19, 2014
Published online: && &&, &&&&
Keywords: benzofurans · cyclization · dioxygen activation ·
.
enynes · radical reactions
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=
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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.
Angewandte
Communications
Communications
Heterocycle Synthesis
M. Hu, R.-J. Song,
J.-H. Li*
&&&& — &&&&
Metal-Free Radical 5-exo-dig Cyclizations
of Phenol-Linked 1,6-Enynes for the
Synthesis of Carbonylated Benzofurans
Benzofurans are obtained by the
that constitute the newly formed carbonyl
groups of the benzofuran system origi-
nate from O2 and 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO), respectively.
tBuONO-initiated radical 5-exo-dig cycli-
zation of enynes under mild and metal-
free conditions. The two oxygen atoms
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!