Electron transfer promoted photochemical reductive radical cyclization reactions of allyl 2-bromoaryl ethers

Article abstract of DOI:10.1016/j.tetlet.2013.02.103

Tin-free, photoinduced electron transfer promoted reductive radical cyclization reactions of allyl 2-bromoaryl ethers in the presence of NaOH in 2-PrOH were found to take place efficiently to give 3-methyl-2,3- dihydrobenzofurans. In contrast to conventio

Full text of DOI:10.1016/j.tetlet.2013.02.103

Tetrahedron Letters 54 (2013) 2419–2422
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Electron transfer promoted photochemical reductive radical cyclization
reactions of allyl 2-bromoaryl ethers
⇑
Yasuharu Yoshimi , Hirotomo Kanai, Keisuke Nishikawa, Yasushi Ohta, Yoshiki Okita, Kousuke Maeda,
Toshio Morita
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Tin-free, photoinduced electron transfer promoted reductive radical cyclization reactions of allyl 2-
bromoaryl ethers in the presence of NaOH in 2-PrOH were found to take place efficiently to give 3-
methyl-2,3-dihydrobenzofurans. In contrast to conventional radical cyclization reactions that employ
AIBN/Bu3SnH in benzene, the new method utilizes NaOH and 2-PrOH that are both readily available
and benign. Consequently, the newly developed photochemical process serves as a versatile and environ-
mentally friendly method for carrying out aryl radical cyclization reactions.
Received 1 February 2013
Revised 25 February 2013
Accepted 28 February 2013
Available online 7 March 2013
Keywords:
Electron transfer
Photoreaction
Ó 2013 Elsevier Ltd. All rights reserved.
Tin-free reductive radical cyclization
reaction
Allyl 2-bromoaryl ether
Radical cyclization reactions have become powerful methods
for the preparation of cyclic organic compounds.1 An example of
this process is found in the radical cyclization reaction of allyl 2-
bromophenyl ether that produces 3-methyl-2,3-dihydrobenzofu-
ran in high yield (Scheme 1).2 Transformations of this type are typ-
ically performed using AIBN as a radical initiator agent and Bu3SnH
as a halogen/hydrogen transfer reagent. However, the overall util-
ity of radical cyclization reactions is limited by the toxicity of these
reagents and difficulties associated with the removal of tin con-
taining byproducts. As a result, several recent efforts have focused
on developing tin-free radical cyclization processes. These efforts
have uncovered conditions that involve the use of LiAlH4,3
NaBH4/methyldihydroacridine and visible light irradiation,4 N-het-
erocyclic carbene boranes with thiols,5 and electrochemical reduc-
tion in the presence of phenanthrene.6 In addition, photoinduced
reductive methodologies, employing either the enolate anion of
acetone or the anion of ethyl benzoate with 2-propoxide ion (2-
PrOÀ),7 represent highly environmentally-friendly procedures for
promoting radical cyclization reaction of allyl 2-bromophenyl
ether. However, these processes require the use of both an excess
of t-BuOK or sodium metal for anion generation and liquid ammo-
nia as solvent. As a consequence of their synthetic power, simple
methods for promoting reductive radical cyclization reactions that
do not require toxic or expensive reagents and that can be con-
ducted under a mild condition are desired.
Recently, we reported that Birch-type reductions of arenes and
reductive dehalogenations of aryl halides take place under photo-
induced electron transfer (PET) conditions in the presence of NaOH
and 2-PrOH.8 In these processes, the excited triplet states of aro-
matic chromophores participate as acceptors in single electron
transfer (SET) processes in which hydroxide or 2-propoxide ions
serve as donors. This process generates arene radical anions, which
are either protonated to form cyclohexadienyl radicals in the
reduction pathway or undergo loss of halide to form aryl radicals
in the dehalogenation route. These earlier observations encouraged
us to carry out a study to determine whether this mechanistic sce-
nario would operate to promote photoinduced reductive aryl rad-
ical cyclization reactions of allyl 2-bromoaryl ethers. The results of
an investigation, described below, targeted at evaluating this pos-
sibility show that the photochemical method can be used to gener-
ate aryl radicals as part of cyclization reactions that take place
under mild conditions and employ less toxic and readily available
reagents.
In order to probe the feasibility of the photoinduced radical
cyclization methodology, 3 mM solutions of various allyl 2-bromo-
aryl ethers 1 (Table 1) in 2-PrOH containing NaOH (20 mM) under
an argon atmosphere at room temperature were irradiated using a
100 W high-pressure mercury lamp and a Pyrex filter (k >280 nm).
In each case, the photolysate was concentrated in vacuo to give a
residue that was subjected to column chromatography on silica
gel. These reactions generated the respective 3-methyl-2,3-dihy-
⇑
Corresponding author. Tel.: +81 776 27 8633; fax: +81 776 27 8747.
E-mail address: yyoshimi@u-fukui.ac.jp (Y. Yoshimi).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.103

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Y. Yoshimi et al. / Tetrahedron Letters 54 (2013) 2419–2422
Table 2
AIBN,
O
O
O
Bu3SnH
Base effect on the photocyclization reactions of allyl 2-bromoaryl ether 1ea
80 °C
Benzene
Br
ν
h
Base
1e
3 mM
Scheme 1. Conventional radical cyclization reaction of allyl 2-bromophenyl ether
using AIBN/Bu3SnH in benzene.
2e
2-PrOH
Table 1
Photocyclization reactions of allyl 2-bromoaryl ethers 1a–ea
Entry
Base
Yield of 2eb (%)
1
2
3
4
5
6
7
8
9
NaOH (1 mM)
NaOH (3 mM)
NaOH (10 mM)
NaOH (20 mM)
NaOH (50 mM)
NaOH (100 mM)
KOH (10 mM)
LiOH (10 mM)
n-BuLi (20 mM)
14
61
78
82
73
70
57
85
80
hν
O
O
NaOH (20 mM)
2-PrOH
R
Br
R
1a; R = H
2
1b
1c
1d
1e
; R = C(CH3)3
; R = OCH3
; R = F
; R = CN
a
Photoreactions of 2-PrOH solutions of 1e (3 mM) containing bases under an Ar
atmosphere were carried out for 1 h.
b
Isolated yields.
Entry
1
Irrad. time (h)
Yield of 2b (%)
1
2
3
4
5
1a (3 mM)
1b (3 mM)
1c (3 mM)
1d (3 mM)
1e (3 mM)
1e (3 mM)
1e (3 mM)
1e (5 mM)
1e (10 mM)
5
3
3
1
1
3
1
1
8 (80)c
71
60
5 (85)
hν (1h)
NaOH (20 mM)
O
O
c
82
68
10
81
78
2-PrOH
NC
Br
NC
6
7d
8
3
4
76 %
3 mM
9
1.5
hν (1h)
NaOH (20 mM)
O
O
a
Photoreactions of 1 were carried out in 2-PrOH solutions containing 20 mM
NaOH under an Ar atmosphere.
2-PrOH
NC
b
NC
Br
Isolated yields.
E/Z=5:1
c
5
6
Yields determined by using GC–MS analysis of the crude photolysates are in
77 %
3 mM
parentheses.
d
Photoreaction was carried out under an air atmosphere.
Scheme 2. Photoreactions of 3 and 5 with NaOH in 2-PrOH.
drobenzofuran derivatives 2 in modestly high isolated yields (en-
tries 1–5), except in the cases of benzofurans 2a and 2d, which
were produced in low isolated yields. GC–MS analysis of the crude
photolysates revealed that 2a and 2d are indeed formed in high
yields prior to isolation (entries 1 and 4), indicating that their high
volatility is responsible for losses incurred in workup and purifica-
tion steps.
the molecular oxygen quenchable triplet state of 1e is
involved in the process. Furthermore, the yields of 2e were ob-
served to slightly decrease when higher concentrations of 1e
(5 or 10 mM) were employed in the photoreaction (entries 8
and 9).
The effects of base and solvent on the photoreaction of 1e were
examined. The results show that the use of higher concentrations
of NaOH caused an increase in the yield of 2e (Table 2, entries 1–
4) but that when the concentration of NaOH was greater than
20 mM the yield of 2e decreases, presumably a consequence of
the occurrence of secondary photoreaction(s) (entries 5 and 6). In
addition, KOH and LiOH9 can be utilized in place of NaOH in the
photoreactions of 1e and the yields of 2e were found to increase
in the order KOH < NaOH < LiOH (entries 3, 7, and 8). Moreover,
when n-BuLi is employed instead of NaOH to generate the 2-prop-
oxide ion (2-PrOÀ) the photocyclization reaction of 1e takes place
in a high yield (entry 9). This observation demonstrates that 2-
propoxide ion can serve as electron donors in these SET promoted
photoreactions. Primary alcohols (e.g., CH3OH and CH3CH2OH) are
not effective solvents for the photoreaction of 1e (1 h) in the pres-
ence of NaOH (20 mM), as indicated by the low yields of 2e (13%
and 45%, respectively) produced and the significant amounts of
starting 1e recovered (65% and 15%, respectively). Also, 2e was
not generated in the photoreaction of 1e carried out in the tertiary
alcohol (CH3)3COH10 or aq CH3CN. These findings show that the
photocyclization reaction requires the use of an alcohol that has
Further studies provided mechanistically and synthetically
important information about the new cyclization strategy. Even
though the efficiencies of the excitation of the allyl 2-bromoaryl
ethers 1 are low in this light source (see Supplementary data for
absorption spectra of 1a–e), irradiation is required to promote
these reactions. In addition, the irradiation times needed to drive
these reactions to completion were found to be dependent on
the aryl ring substituent R. Moreover, high yields of 2 were ob-
tained in photoreactions of substrates possessing both electron-
donating and withdrawing substituents. For example, irradiation
of a 3 mM solution of 1e (R = CN) for 1 h led to formation of 2e
in a high isolated yield (entry 5). However, the use of a longer irra-
diation time (3 h) caused the yield of 2e to decrease owing to the
existence of secondary photoreactions of 2e (entry 6). In fact, irra-
diation of 2e (3 mM) for 3 h in a NaOH (20 mM) containing 2-PrOH
solution followed by workup led to only a 47% yield of recovered
2e due to the photochemical Birch-type reduction of the aromatic
ring of 2e reported by us.8
The results of further investigations showed that the effi-
ciency of the photoreaction of 1e was significantly suppressed
when an air atmosphere was utilized (entry 7), suggesting that
a readily donatable hydrogen atom at the
a-position to the hydro-
xy group. Finally, when NaOH was not present in the reaction mix-

Y. Yoshimi et al. / Tetrahedron Letters 54 (2013) 2419–2422
2421
3
hν (1h)
NaOH (20 mM)
*
O
OH- or 2-PrO-
PET
O
1
hν
*
1e
5 mM
1
1
NC
OH
R
Br
D
2e-d
d-content 70%
D
2-propanol-2d1
O
O
OH
H
Scheme 3. Deuterium labeling experiment of 1e in 2-propanol-2d1.
or
H
O
O
H-atom abstraction
tures, photoreactions of 1 (3 mM) in 2-PrOH (1 h) resulted in sig-
nificantly lower yields of 2 (2a; 1%, 2b; 7%, 2c; 17%, 2d; 9%, 2e;
7%)11 and in each case by-products, such as 2-bromophenol deriv-
atives produced via photo-Claisen type rearrangements, were
generated.12
+
OH or 2-PrO
R
Br
9
- Br-
Dehalogenation
In a brief effort aimed at elucidating the substrate scope of the
process, PET promoted photocyclization reactions of allyl 2-bromo-
aryl ethers 3 and 5, which contain methyl substituted alkene moi-
eties, were carried out using the optimal conditions (NaOH
(20 mM) in 2-PrOH for 1 h) (Scheme 2). Each of these processes
was found to generate the corresponding 2,3-dihydrobenzofuran
derivatives 4 and 6 in modestly high yields.
O
O
Cyclization
R
R
7
8
To gain further insight into the mechanism of this photocycliza-
tion reaction, we carried out a deuterium labeling experiment
employing 1e and the mono-deuterated solvent 2-propanol-2d1
(Scheme 3). The results of a 1 h irradiation induced reaction
showed that the efficiency of the photoreaction is significantly
diminished (2e 31% and recovered of 1e 31%), presumably a result
of the operation of a deuterium kinetic isotope effect. In addition,
the methyl group of 2e was found to be mono-deuterated to the
extent of 70%. These findings indicate that hydrogen atom transfer
O
O
OH
H(D)
H-atom
abstraction
or
SET
9
H(D)
O
O
R
R
CH3(D)
from the a-position of 2-PrOH to a key radical intermediate in the
10
Protonation
2
reaction pathway is involved in the mechanistic route and that this
step determines the quantum efficiency of the overall process.
A plausible mechanism for the PET-promoted reductive radical
cyclization reactions of allyl 2-bromoaryl ethers 1, which is consis-
tent with the observations described above, is displayed in
Scheme 4. From the quenching for the formation of 2e by molecu-
lar oxygen and the heavy atom effect of 1, the excited triplet state
of 1 could be the reactive species in this photoreaction. As de-
scribed earlier by us,8 PET from hydroxide or 2-propoxide ions,
generated by the acid base reaction of NaOH with 2-PrOH, to the
excited triplet state of 1 leads to the formation of the radical anion
of 1 and hydroxyl or 2-propoxyl radicals. Loss of halide ion from
the radical anion of 1 produces the aryl radical 7, which then
undergoes cyclization to generate the primary radical 8 that is
transformed to the 3-methyl-2,3-dihydrobenzofuran 2 mainly
through hydrogen atom abstraction (H-atom abstraction) from 2-
PrOH or 2-propoxide ion (Scheme 4). Another possible pathway
for termination of the cyclization process involves SET to radical
8 from the acetone anion radical 9, formed by H-atom abstraction
of radicals (hydroxyl or 2-propoxyl or primary radicals 8) from the
2-propoxide ion or by hydroxide ion promoted deprotonation of
the 2-hyroxypropyl radical.13 This process generates anion 10,
which then is protonated by 2-PrOH to give 2. However, the results
of the deuterium labeling study suggest that the pathway involving
product formation through H-atom abstraction from 2-PrOH
predominates.
OH
H(D)
+
O
OH
or
O
9
OH-
R
CH3
2
9
SET
O
Br
1
7
2
R
Scheme 4. Plausible mechanism for PET-promoted reductive radical cyclization
reactions of 1.
tion product. Unfortunately, attempts to detect acetone in the
product mixture were unsuccessful.15
In the study described above, we uncovered a novel and effi-
cient photoinduced reductive radical cyclization reaction of allyl
2-bromoaryl ethers 1 that generates 3-methyl-2,3-dihydrobenzo-
furans 2. The process is promoted by irradiation of the substrates
in 2-PrOH solutions containing NaOH. In contrast to conventional
radical cyclization methods that employ AIBN/Bu3SnH in benzene,
the newly developed photocyclization process is more economical
and environmentally friendly. Although a similar procedure for
generating aryl radicals that uses t-butoxide ion without irradia-
tion has been developed for inducing cross-coupling reactions of
aryl halides with arenes,16 it requires the use of high temperatures
and diamines such as 1,10-phenanthroline. We envisage that the
new photochemical method will be generally applicable to the for-
mation of aryl radicals from corresponding bromoarenes under
An alternative mechanistic route for the PET promoted radical
cyclization reaction, differing in the method for generation of the
allyl 2-bromoaryl ether radical anion, involves SET from the radical
anion of acetone 9 (Scheme 4, bottom), which is a very strong elec-
tron donor implicated earlier in radical forming dehalogenation
reactions of aryl halides.14 Independent of the pathway followed,
the PET promoted reductive radical cyclization reaction utilizes
2-PrOH as the reducing agent and produces acetone as the oxida-

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Y. Yoshimi et al. / Tetrahedron Letters 54 (2013) 2419–2422
6. Kurono, N.; Honda, E.; Komatsu, F.; Orito, K.; Tokuda, M. Tetrahedron 2004, 60,
1791–1801.
mild conditions, a proposal that is being addressed in our current
studies of intramolecular and intermolecular cross coupling
processes.
7. Vaillard, S. E.; Postigo, A.; Rossi, R. A. J. Org. Chem. 2004, 69, 2037–2041.
8. (a) Yoshimi, Y.; Ishise, A.; Oda, H.; Moriguchi, Y.; Kanezaki, H.; Nakaya, Y.;
Katsuno, K.; Itou, T.; Inagaki, S.; Morita, T.; Hatanaka, M. Tetrahedron Lett. 2008,
49, 3400–3404; (b) Yoshimi, Y.; Wada, N.; Sasamoto, K.; Itou, T.; Hatanaka, M.
Chem. Lett. 2008, 37, 782–783.
9. An attempt to prepare 10 mM of LiOH was difficult because this base is not
completely soluble in 2-PrOH.
10. An attempt to prepare 20 mM of NaOH was difficult because this base is not
completely soluble in (CH3)3COH.
11. The yields of 2a and 2d were determined by using GC–MS analysis.
12. (a) Yoshimi, Y.; Sugimoto, A.; Maeda, H.; Mizuno, K. Tetrahedron Lett. 1998, 39,
4683–4686; (b) Galindo, F. J. Photochem. Photobiol., C 2005, 6, 123–138.
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Phys. Chem. 1973, 77, 1283–1288.
Supplementary data
Supplementary data (experimental details, 1H and 13C NMR
spectra, UV absorption of 1a–e) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.02.103.
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