Photo-induced radical cyclization of aromatic halides with sodium borohydride

Article abstract of DOI:10.1055/s-2005-872243

Direct UV irradiation of ortho-allyloxy- and ortho-but-3-enyloxy-iodo- and bromo-benzenes in the presence of NaBH₄ or NaBH₃CN gave radical cyclization products in high yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872243

2248
LETTER
Photo-Induced Radical Cyclization of Aromatic Halides with Sodium
Borohydride
P
hoto-Induced Cyc
i
lizatio
a
n of
A
roma
n
tic Halide
s
g Liu, Bing Han, Wei Zhang, Li Yang, Zhong-Li Liu,* Wei Yu*
National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China
Fax +86(931)8625657; E-mail: yuwei@lzu.edu.cn
Received 12 May 2005
In a typical experiment, a solution of ortho-allyloxy-
iodobenzene (1a, 1 mmol) and excess of NaBH4 (5 mmol)
in 20 mL DMF was irradiated in a quartz tube with a high-
pressure mercury lamp (emission centered at l = 254 nm)
under argon atmosphere at ambient temperature for 4
hours to complete the reaction. Conventional work up fol-
lowed by flash chromatographic separation (silicon gel,
PE–EtOAc, 50:1) gave the pure radical cyclization prod-
uct 3-methyl-2,3-dihydrobenzofuran (2a) in high yield,
and no dehalogenation product allyloxybenzene was
Abstract: Direct UV irradiation of ortho-allyloxy- and ortho-but-
3-enyloxy-iodo- and bromo-benzenes in the presence of NaBH4 or
NaBH3CN gave radical cyclization products in high yield.
Key words: radical cyclization, photolysis, halobenzenes, sodium
borohydride
Intramolecular radical cyclization is an important method
for construction of five- and six-membered rings in or-
ganic synthesis, and organotin reagents are currently the
almost automatic choice for inducing such a trans-
formation.1 However, organotin residues are notoriously
difficult to remove from desired end products, and many
organotin compounds are neurotoxins, that makes organ-
otin reagents inappropriate for syntheses of medicines and
other formulations intended for human consumption.
Hence, a great deal of attention has been directed recently
to radical generation with tin-free reagents.2 In our ongo-
ing research program on synthetic potentials of photo-in-
duced electron transfer reactions3 we noticed a report on
photo-induced radical cyclization of ortho-allyloxy-ha-
lobenzenes sensitized by 10-methyl-9,10-dihydro-acri-
dine (AcrH2) in the presence of excessive NaBH4.4 This
reaction was suggested to be initiated by photo-induced
electron transfer between AcrH2 and the ortho-allyloxy-
halobenzene, and the function of NaBH4 was proposed as
to reduce AcrH+ and regenerate AcrH2. It was also report-
ed that reductive dehalogenation of aryl halides and radi-
cal cyclization of ortho-allyloxy-halobenzenes by NaBH4
could be initiated by photolysis of di-tert-butyl peroxide
(DTBP).5 However, we found that the cyclization could
also take place in the absence of AcrH2 or DTBP if ortho-
allyloxy- and ortho-but-3-enyloxy-halobenzenes were di-
rectly excited by UV irradiation in the presence of NaBH4
(Scheme 1),6 and the yield and selectivity are even better
than the previously reported methods.4,5
1
formed as evidenced by the H NMR spectrum of the
crude product, demonstrating the high efficiency of the
present approach for the radical cyclization reaction.
ortho-Allyloxy-bromobenzene (1b) gave the same prod-
uct under the same experimental conditions, except for
longer irradiation time for completing the reaction. Other
structurally similar halobenzenes 1c–j were subjected to
the same treatment, and the results are summarized in
Table 1.
As shown in Table 1, ortho-cyclohex-2-enyloxy-haloben-
zenes (1c and 1d) and ortho-prop-2-ynyloxy-halo-
benzenes (1e and 1f) also gave cyclization products 2b
and 2c, respectively, as the unique product. In the case of
ortho-but-3-enyloxy-halobenzenes (1g and 1h), however,
reductive dehalogenation product 3d was formed accom-
panied with the cyclization product 4-methyl-2,3-dihy-
drobenzopyran (2d). This is due to the fact that free
radical cyclization for six-membered rings is remarkably
less favorable than that for five-membered rings,7 hence
the reduction could compete with the cyclization. In the
case of ortho-3,3-dimethylallyoxy-halobenzenes (1i and
1j), two cyclization products 2e and 3e were obtained.
These two products were also observed previously in the
samarium-mediated cyclization of 1i.10
It has been reported previously that reductive dehalogena-
tion of aromatic halides could be achieved by direct UV
irradiation in the presence of sodium borohydride via a
radical chain mechanism and/or electron transfer mecha-
nism.11 Similar mechanism might be applicable to the
present photo-induced cyclization as depicted in
Scheme 2. In the scheme direct photo-homolysis of the
halobenzene (1) generates the initiating radical 4 and the
halogen radical X•. The halogen atom abstracts one hydro-
gen from borohydride to form the propagating borane rad-
ical anion, which reacts with 1 to propagate the chain
reaction. The intermediate phenyl radical 4 can rapidly
subject to radical cyclization to form radical 5, and the
X
hν
X = I, Br n = 1, 2
n
n
NaBH4
O
O
1
2
Scheme 1
SYNLETT 2005, No. 14, pp 2248–2250
0
2
.0
9
.2
0
0
5
Advanced online publication: 26.07.2005
DOI: 10.1055/s-2005-872243; Art ID: U14505ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Photo-Induced Cyclization of Aromatic Halides
2249
Table 1 Photo-Induced Radical Cyclization of 2-Allyloxy-halobenzenes in the Presence of NaBH4
Substrate
Time (h) Productsa
Yield (%)b
X
X
I
Br
1a
1b
4
10
2a
2b
2c
88
76
O
X
O
I
Br
1c
1d
6
12
90
74
O
O
X
I
Br
1e
1f
6
13
90c
87d
O
O
I
Br
1g
1h
4.5
12
2d
2e
3d
3e
62:24e
57:23e
X
O
O
O
I
Br
1i
1j
6
13
45:41e
43:34e
X
O
O
O
a The products were characterized by comparing their 1H NMR and EI-MS spectral data with those reported in the literature.4,7–9
b Isolated yields unless otherwise specified.
c Based on 67% conversion of 1e.
d Based on 33% conversion of 1f and determined by 1H NMR integration.
e Yields of compounds 2, 3 were determined by 1H NMR integration.
latter abstracts one hydrogen from borohydride to form
the cyclization product 2 and generates the borane radical
X
+
anion. The phenyl radical 4 could also directly abstract
O
O
O
3e
one hydrogen from borohydride to form the reduction
product 3, as in the case of substrates 1g and 1h, when the
cyclization is not fast enough to completely inhibit the di-
rect reduction. In the case of ortho-3,3-dimethylallyoxy-
halobenzenes (1i and 1j), since the intermediate radical 5e
is a relatively stable secondary radical, disproportionation
can take place to give the oxidized cyclization product 3e
(Scheme 3).10
1i, j
2e
hν
disp.
–
BH4
O
O
4e
5e
Scheme 3
hν
X
BH4
BH3
BH4
HX
X
B2H7
BH3
BH3
O
1
4
– X
O
BH4
O
BH4
3
CH2
CH3
BH3
O
O
5
2
Scheme 2
Synlett 2005, No. 14, 2248–2250 © Thieme Stuttgart · New York

2250
Q. Liu et al.
LETTER
While this reaction worked well with compounds 1a–j,
NaBH4 was found to be a too strong reducing agent for
tolerance of electron-deficient double bonds. For in-
stance, b-(2-halophenoxy)methyl acrylates (1k and 1l)
and b-(2-halophenoxy)methyl acrylonitrile (1m and 1n)
produced double bond reduction products 3f and 3g, re-
spectively, as the major products along with the expected
cyclization products 2f and 2g (Scheme 4, Table 2) by us-
ing the procedure mentioned above. To overcome this
drawback on functional group tolerance, a milder reduc-
ing agent, NaBH3CN, was used in lieu of NaBH4. It was
found that NaBH3CN worked very well for the cyclization
of 1k and 1m, giving excellent yields of 2f and 2g, respec-
tively. For ortho-bromo-substituted substrates 1l and 1n,
the cyclization also proceeded well, although with a little
bit lower yield and prolonged reaction time (Table 2).
Acknowledgment
We thank the National Natural Science Foundation of China (grant
No. 20372030) for financial support.
References
(1) (a) Davies, A. G. Organotin Chemistry; Wiley-VCH:
Weinheim, 1997. (b) Motherwell, W. B.; Crich, D. Free
Radical Chain Reactions in Organic Synthesis; Academic
Press: London, 1992, Chapt. 3. (c) Dowd, P.; Zhang, W.
Chem. Rev. 1993, 93, 2091. (d) Sibi, M. P.; Ji, J. Prog.
Heterocycl. Chem. 1996, 8, 14. (e) Curran, D. P. Synthesis
1988, 417. (f) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.
Chem. Rev. 1991, 91, 1237.
(2) (a) Baguley, P. A.; Walton, J. C. Angew. Chem. Int. Ed.
1998, 37, 3072. (b) Studer, A.; Amrein, S. Synthesis 2002,
835. (c) Mikami, S.; Fujita, K.; Nakamura, T.; Yorimitsu,
H.; Shinokubo, H.; Matsubara, S.; Oshima, K. Org. Lett.
2001, 3, 1853. (d) Inoue, K.; Sawada, A.; Shibata, I.; Baba,
A. J. Am. Chem. Soc. 2002, 124, 906. (e) Vaillard, S. E.;
Postigo, A.; Rossi, R. A. J. Org. Chem. 2004, 69, 2037.
(3) (a) Jin, M.-Z.; Yang, L.; Wu, L.-M.; Liu, Y.-C.; Liu, Z.-L.
Chem. Commun. 1998, 2451. (b) Jin, M.-Z.; Zhang, D.;
Yang, L.; Liu, Y.-C.; Liu, Z.-L. Tetrahedron Lett. 2000, 41,
7357. (c) Zhang, W.; Shao, X.; Yang, L.; Liu, Z.-L.; Chow,
Y.-L. J. Chem. Soc., Perkin Trans. 2 2002, 1029.
(d) Zhang, J.; Jin, M.-Z.; Zhang, W.; Yang, L.; Liu, Z.-L.
Tetrahedron Lett. 2002, 43, 9687. (e) Zhang, W.; Jia, X.;
Yang, L.; Liu, Z.-L. Tetrahedron Lett. 2002, 43, 9433.
(f) Zhang, W.; Guo, Y.; Yang, L.; Liu, Z.-L. J. Chem. Res.
2004, 418.
Y
Y
CH2Y
hν
+
reductant
O
O
O
X
1k: X = I, Y = CN
1l: X = Br Y = CN
1m: X = I, Y = CO2C2H5
1n: X = Br, Y = CO2C2H5
2f: Y = CN
2g:Y = CO2C2H5
3f: Y = CN
3g:Y = CO2C2H5
Scheme 4
Table 2 Photo-Induced Reductive Cyclization of b-(2-Halophen-
oxy)methyl Acrylate and b-(2-Halophenoxy)methyl Acrylonitrilea
(4) Boisvert, G.; Giasson, R. Tetrahedron Lett. 1992, 33, 6587.
(5) Abeywickrema, A. N.; Beckwith, A. L. J. Tetrahedron Lett.
1986, 27, 109.
(6) A similar photo-stimulated method using the combination of
irradiation and metal hydrides was reported for the
construction of macrocyclic lactones from w-iodoalkyl-
acrylates. See: Abe, M.; Hayashikoshi, T.; Kurata, T. Chem.
Lett. 1994, 1789.
Substrate
Reductant Time (h)
NaBH4
Productsb
Yields (%)c
1k
5
2f, 3f
2f
35:50d
95
NaBH3CN 4.5
1l
NaBH3CN
8
2f
73
(7) (a) Johnson, L. J.; Lusztyk, J.; Wayner, D. M.;
Abeywickrema, A. N.; Beckwith, A. L. J.; Scaiano, J. C.;
Ingold, K. U. J. Am. Chem. Soc. 1985, 107, 4594.
(b) Beckwith, A. L. J.; Gara, W. B. J. Chem. Soc., Perkin
Trans. 2 1975, 795.
(8) Kurono, N.; Honda, E.; Komatsu, F.; Orito, K.; Tokuda, M.
Tetrahedron 2004, 60, 1791.
(9) Bhandal, H.; Patel, V. F.; Pattenden, G.; Russell, J. J. J.
Chem. Soc., Perkin Trans. 1 1990, 2691.
1m
NaBH4
NaBH3CN
5
5
2g, 3g
2g
31:52d
93
1n
NaBH3CN
9
2g
82
a The reactions were performed by UV irradiation of a mixture of 1
mmol substrate and 5 mmol of reductant in 20 mL DMF solution.
b The products were characterized by comparing their 1H NMR and
EI-MS spectral data with those reported in the literature.12,13
c Isolated yields unless otherwise specified.
(10) Curran, D. P.; Totleben, M. J. J. Am. Chem. Soc. 1992, 114,
6050.
d Yields of compounds 2, 3 were determined by 1H NMR integral.
(11) (a) Barltrop, J. A.; Bradbury, D. J. Am. Chem. Soc. 1973, 95,
5085. (b) Kropp, M.; Schuster, G. B. Tetrahedron Lett.
1987, 28, 5295.
(12) Burns, P. A.; Taylor, N. J.; Rodrigo, R. Can. J. Chem. 1994,
72, 42.
In conclusion, this work provides a simple photochemical
approach for reductive radical cyclization by sodium
borohydride. The reaction is conducted at ambient tem-
perature and there is no need of any sensitizers or initia-
tors. The yield and selectivity are better than the methods
using photo-sensitizer or photo-initiator reported previ-
ously.4,5 This method can be applied to substrates with
electron deficient double bonds by using NaBH3CN in
lieu of NaBH4. Extension of this work to other substrates
is underway in this laboratory.
(13) Bhandal, H.; Howeli, A. R.; Patel, V. F.; Pattenden, G. J.
Chem. Soc., Perkin Trans. 1 1990, 2709.
Synlett 2005, No. 14, 2248–2250 © Thieme Stuttgart · New York