Photo-induced Carboiodination: A Simple Way to Synthesize Functionalized Dihydrobenzofurans and Indolines

Article abstract of DOI:10.1002/chem.201603608

Herein, we report a simple, redox-neutral and pH-neutral photo-induced carboiodination reaction under very mild conditions. This protocol employs readily available and cheap aryl bromides and sodium iodide as the starting materials to synthesize valuable functionalized dihydrobenzofurans and indolines in good to excellent yields with broad functional-group compatibility. As examples to demonstrate the utility of this protocol, gram-scale reactions and further transformations of the products were accomplished towards the synthesis of bioactive drug candidates. Most significantly, to the best of our knowledge, this reaction represents the first example of a cascade atom-radical-transfer addition involving the cleavage of aromatic C?Br bond.

Full text of DOI:10.1002/chem.201603608

A Journal of
Accepted Article
Title: Photo-induced Carboiodination: A Simple Way to Synthesize Functionalized
Dihydrobenzofurans and Indolines
Authors: Xiaobo Yang; Wenbo Liu; Lu Li; Wei Wei; Chao-Jun Li
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Chemistry - A European Journal
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COMMUNICATION
Photo-induced Carboiodination: A Simple Way to Synthesize
Functionalized Dihydrobenzofurans and Indolines
Xiaobo Yang, Wenbo Liu, Lu Li, Wei Wei and Chao-Jun Li*
indolines structural motifs.
Abstract: Herein, we report a simple, redox-neutral and pH neutral
photo-induced carboiodination reaction under very mild conditions.
This protocol employs readily available and cheap aryl bromides and
motifs in natural products, bioactive molecules and
pharmaceuticals. For example, compounds I, II and III (Figure 1)
possess cytotoxicity and anti-inflammatory activity and are
sodium iodide as the starting materials to synthesize valuable
functionalized dihydrobenzofurans and indolines in good to excellent
yields with broad functional group compatibility. As examples to
demonstrate the utility of this protocol, gram scale reaction and
further transformation of the products were accomplished towards
the synthesis of bioactive drug candidates. Most significantly, to our
best of knowledge, this reaction represents the first cascade atom-
radical-transfer addition example involving the cleavage of aromatic
C-Br bond.
[
3-5]
promising drug candidates.
From the retrosynthesis
perspective, compounds I, II and III can all be synthesized from
one type of versatile intermediate IV. Thus, methods that can
readily create the general structure IV would be highly desirable.
To our knowledge, there are two well established methods
[
6]
(
Scheme 1) to synthesize these intermediates in the literature.
In 2011, Lautens and co-workers established a palladium-
catalyzed carboiodination protocol by using o-alkoxyaryliodide
as the starting material. Following this, they further extended
[
1]
[2]
Dihydrobenzofurans
structural
and indolines
are two common
[7]
this strategy to aryl bromides as the starting material by adding
[8]
KI into the reaction system. These reports represent significant
advancement in the metal-catalyzed carbohalogenation
research field. Nonetheless, there are still some restrictions
including 1) relatively high reaction temperature, 2) special and
expensive ligand, and 3) the required absence of -H next to the
iodine. In 2014, Studer and co-workers reported another elegant
[
9]
Sandmeyer-type protocol to synthesize intermediate IV. In their
report, they employed in situ generated diazonium salt as the
key reactant species, which could be reduced by the iodide to
form the phenyl radical. Due to the favorable intramolecular ring
closure, the phenyl radical can be trapped by the double bonds
to form the desired rings. This protocol proceeds at room
temperature with broad functional group tolerance. However, the
requirement of stoichiometric amount of a special nitrite and
strong acid as well as the need to selectively synthesize allyl
ether in presence of a highly reactive amine would offset its
synthetic application especially at the larger scale. Therefore,
the development of a simple, efficient, and greener synthetic
approach to intermediate IV remains very useful.
Figure 1. Representative bioactive compounds with dihydrobenzofurans and
[
+]
[+]
[*]
Dr. X. B. Yang, W. B. Liu, Dr. L. Li, Dr. W. Wei, Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Centre for Green Chemistry
and Catalysis, McGill University
801 Sherbrooke St. W., Montreal, Quebec H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
[
+]
Dr. X. B. Yang
Institute of Catalysis for Energy and Environment, College of
Chemistry & Chemical Engineering
Shenyang Normal University, Shenyang, 110034 (PR China).
These authors contributed equally to this work.
+
[
]
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Scheme 1. Studies of carbohalogenations
mmol), additive (0.02 mmol), 18 h, solvent (1 mL), at room temperature (ca
2
5°C) under Ar atmosphere. [b] Yields were determined by NMR, with 1,3,5-
trimethoxybenzene as the internal standard. [c] reaction time: 24 h. [d] No NaI.
e] In the darkness. [f] Under air atmosphere. [g] Under O atmosphere.
[
2
Recently, we have reported photo-induced metal-free
[
10]
[11]
aromatic
trifluoromethylation
Finkelstein,
Sonogashira
reactions at
and
aromatic
in 67% yield (entry 5). Then, the yield was further improved
significantly by prolonging the reaction time to 24h (entry 6)
(99%, the apparent quantum efficiency is 0.2). No target product
[
12]
room
temperature.
[
13]
Considering the advantages of photochemical reaction
and in
continuation of our interest in photo-induced halogen exchange
reactions, herein, we wish to report a new protocol to synthesize
intermediate IV (Scheme 1). This protocol operates at room
temperature, without adding external acid or base, high yielding
and with broad functional group compatibility. Notably, our
method can tolerate substrates with-H, in comparison to the
metal-catalyzed protocol.
was obtained in the absence of NaI and I (entry 7), and the
2
yield declined to 71% in the absence of I (entry 9). It was
2
noticed that the addition of I could raise the yield of the desired
2
product due to the inhibition of reduced product (ArH) formation.
No reaction occurred when it was run in the dark (entry 8). A
control experiment showed that the yields decreased when the
reaction was carried out under the air or O atmosphere (entries
2
At the outset of this study, the reaction of 1-(allyloxy)-2-
bromobenzene (1a) and NaI was selected as the model reaction
to optimize the conditions. The initial experiments were
performed with 1a (0.2 mmol) and NaI (0.4 mmol) in presence of
10, 11). The desired product 2a was also obtained in high yield
when 10% water was added in the solvent (entries 12), which
suggests that this reaction is not sensitive to water.
With the optimized conditions in hand, the substrate scope
of the photo-induced carboiodinations was investigated as
shown in Table 2. Bromoarenes with either electron-donating
I
2
(0.1 equiv) at room temperature (ca 25 °C) under UV
irradiation (UVC, 254 nm) in PhCF (1 mL) for 18 h. The airtight
3
quartz tube containing reactants and solvent was evacuated by
four freeze−pump−thaw cycles and back-filled with ultra-purified
argon (>99.999%) prior to use. As shown in Table 1, to our
delight, the desired product 2a was obtained in 42 % yield under
these conditions (entry 1). Encouraged by this result, several
other solvents were examined (compare entries 1-5), among
which acetonitrile was the best choice affording the expected
product 2a
(e.g., Me, OMe) or electron-withdrawing (e.g., CF ) groups were
3
all efficiently converted to the corresponding cyclized
dihydrobenzofurans 2a-d in good to excellent yields. Notably,
the chloro-substituted bromoarene performed well to afford the
corresponding product (2e) in 85% yield, which provides the
opportunity to selectively functionalize Br in the presence of Cl.
Cyano and ester group substituted bromoarenes also
demonstrated excellent reactivity, affording products 2f and 2g
in good yields. Moreover, bromonaphthalene could also deliver
the desired product (2h) in 93% yield. In addition, 3-
Table 1.
Optimiz
ation of
the
(
iodomethyl)-3-methyl-2,3-dihydrobenzofuran (2i) was obtained
in satisfactory yield (82%). Besides the 5-member ring closure,
6-member ring closure product 2j can also be isolated in 73%
yield. As the twin of allyl phenyl ether, two propargylic phenyl
ethers were also compatible with our protocol, affording products
reaction
conditio
[
a]
ns.
2k and 2l with good yields (Both compounds were obtained as
[
b]
E/Z mixtures). This cyclization will provide a potential useful
method to synthesize vinyl iodides, highly useful starting
materials for various cross couplings. However, 7-exo cyclization
products were not observed under the standard conditions
possibly due to the unfavorable geometry for the radical
cyclization. Instead, only I-Br exchange products (2m and 2n)
were obtained, which was consistent with our previous
entry
additive (mmol)
solvent (mL)
yield (%)
1
2
3
4
5
I
2
(0.1 eq.)
(0.1 eq.)
(0.1 eq.)
(0.1 eq.)
(0.1 eq.)
PhCF
THF
3
42
I
2
60
I
2
acetone
MeOH
24
I
2
12
[10]
discovery.
Besides O-heterocycles, synthesis of other heterocycles via
I
2
CH
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
67
[
c]
d]
e]
6
2
I (0.1 eq.)
99
[
7
8
9
0
none
0
[
2
I (0.1 eq.)
0
[
[
c]
none
71
c, f]
1
I
2
(0.1 eq.)
(0.1 eq.)
(0.1 eq.)
56
[
c, g]
11
I
2
34
[
c]
12
I
2
CH
3
CN/H
2
O (10:1)
89
[
a] Reaction conditions: 1-(allyloxy)-2-bromobenzene (1a) (0.2 mmol), NaI (0.4
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COMMUNICATION
Figure 2. Derivatizations of iodides
[
a]
Table 2. Photo-induced Carboiodinations.
[
a] Reaction conditions: 1a (0.2 mmol), NaI (0.4 mmol), iodine (0.02 mmol),
24 h, CH
3
CN (1 mL), at room temperature (ca 25°C) under Ar atmosphere.
[
b] Isolated yields. [c] These two compounds are too unstable to be
2 2
isolated. Yields were determined by NMR, with CH Br as the internal
standard. [d] reaction time: 36 h.
our method was also explored. As shown in Table 2,
dihydrobenzothiophene 2o could be generated with a yield 56%
when the reaction time was extended to 36h. Sulfones 2p was
also compatible with the optimized conditions. Two indolines (2q,
2r), with -H and without -H respectively, were obtained in
moderate to excellent yields when the N was protected with an
electron-withdrawing group. As a precursor of the compound III
in Figure 1, 2s was also obtained in 87% yield. Subsequently,
gramscale reactions were conducted in a 100 mL of quartz flask
and gratifyingly, 2a and 2s were both obtained in good yields
(
86% and 81% respectively).
One major synthetic utility of carboiodination product was
based on the reactivity of C-I bonds. Further derivatizations were
performed and various new compounds were rapidly prepared
through forming C−C, C−O, C−N, and C−S bonds (Figure 2)
(
3a-3f). The newly introduced functional groups on these
derivatives will provide tremendous opportunity to construct
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COMMUNICATION
diverse libraries in medicinal chemistry for the further screening.
In particular, derivative 3e can be further converted to the core
structure of compound III, a prodrug which has been tested in
clinical trial (Figure 1). Compared to the previous methods, this
protocol is efficient and environmentally friendly, without using
any transition-metal or specialized reagents.
In order to explore the reaction mechanism, the following
control experiments were performed under the standard
conditions as shown in Scheme 2. When TEMPO was added,
the desired product 2a and TEMPO adduct 4a were obtained in
fragmentation formed phenyl radical II. Then 5-exo cyclization of
phenyl radical II generated the alkyl radical III which coupled
with iodine radical or elementary iodine to give the desired
product 2. Importantly, Curran has conducted serial
investigations on the atom-transfer-radical addition (ATRA)
3
[14d, 14e]
involving breaking sp C-I bonds.
breaking sp C-Br bond to achieve the ATRA, we believe that
this work represents the first example.
However, concerning
2
In summary, we have developed a simple and practical
photo-induced carboiodination reaction to synthesize valuable
functionalized dihydrobenzofurans and indolines under very mild
conditions using readily available and cheap aryl bromides and
sodium iodide as the starting materials. The substrates undergo
pseudo halogen transfer via 5-exo and 6-exo cyclization
reactions under the irradiation. The corresponding products, as
important intermediates for the construction of medicinal
molecules, were obtained in good to excellent yields. The scope,
mechanism and synthetic applications of this protocol is under
further investigation.
8% and 84% yields, respectively (Scheme 2a). However, a trace
amount of self-carbohalogenation product 5a and 27% of
TEMPO adduct 4a were obtained in the absence of NaI
(
Scheme 2b). The results indicated that NaI played the key role
in the generation of the phenyl radical to afford the desired
product in high yield. Additionally, 1-(allyloxy)-2-chlorobenzene
and 1-(allyloxy)-2-iodobenzene were also used as the substrates
under our standard conditions, and the desired product 2a was
†
obtained in 62% and 95% yields, respectively (see the ESI ).
The high yield
Experimental Section
The aryl bromide (0.2 mmol), NaI (0.4 mmol) and iodine (0.02 mmol)
were added into 1.0 mL acetonitrile in an airtight quartz tube (10 mL),
which was then evacuated by four freeze-pump-thaw cycles and back-
filled with ultra-purified argon (> 99.999%) prior to use. The reaction was
stirred at room temperature (ca 25 °C) under UV irradiation (254 nm) at
-
2
an intensity of 4.0 mWcm by using a standard LZC-4V photoreactor
from Luzchem Company for 24 h. After cooled to room temperature, the
resulting solution was concentrated via rotary evaporation, and the
residue was purified by column chromatography on silica gel to provide
the desired products (2a-s).
Scheme 2. Control experiments
Acknowledgements
We are grateful to the Canada Research Chair Foundation (to
C.-J. Li), the CFI, FQRNT Center for Green Chemistry and
Catalysis, NSERC, and McGill University for support of our
research. Dr. Xiaobo Yang is grateful for the support from China
Scholarship Council (CSC).
Keywords: photo-induced • carboiodination • radical •
dihydrobenzofurans • indolines
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COMMUNICATION
COMMUNICATION
A simple and practical photo-
induced carboiodination reaction
is reported. This protocol
employs readily available
starting materials to synthesize
valuable functionalized
dihydrobenzofurans and
indolines in good to excellent
yields with broad functional
group compatibility.
Xiaobo Yang, Wenbo Liu, Lu Li,
Wei Wei and Chao-Jun Li*
Page No. – Page No.
Photo-induced Carboiodination:
A Simple Way to Synthesize
Functionalized
Dihydrobenzofurans and
Indolines
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