NBS-initiated electrophilic phenoxyetherification of olefins

Article abstract of DOI:10.1021/ol4005646

A one-pot electrophilic phenoxyetherification using an olefin, a cyclic ether, a phenol, and N-bromosuccinimide has been developed. This type of multicomponent reaction (MCR) is useful in the synthesis of building blocks that are potentially applicable to

Full text of DOI:10.1021/ol4005646

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
NBS-Initiated Electrophilic
Phenoxyetherification of Olefins
Zhihai Ke and Ying-Yeung Yeung*
3 Science Drive 3, Department of Chemistry, National University of Singapore,
Singapore 117543
chmyyy@nus.edu.sg
Received February 28, 2013
ABSTRACT
A one-pot electrophilic phenoxyetherification using an olefin, a cyclic ether, a phenol, and N-bromosuccinimide has been developed. This type of
multicomponent reaction (MCR) is useful in the synthesis of building blocks that are potentially applicable to self-assembly complex construction.
To synthesize target compounds with great efficiency
and atom economy, many highly effective and powerful
synthetic tools have been developed in modern green
chemistry.1 Among these, multicomponent reactions
(MCRs) have been considered as the “cream of the crop”,
by generating structural complexity in a single step from
three or more reactants generally and reliably.2 Although
successes had been reported on MCRs, developing new
reactions is still of significant importance.3 Partly due to
the common incompatibility of electrophiles with the other
components, electrophilic MCRs have been relatively less
reported.4
In the course of our endeavor to develop electrophilic
MCR utilizing N-bromosuccinimide (NBS) as the bromi-
nating initiator, we have disclosed a number of electro-
philic cascades using various nucleophilic partners.5 In
these studies, it was found that a nucleophile that contains
an acidic proton is necessary to achieve high reaction yield.
The acidic proton may be used to activate the halogen
source NBS. Herein, we report the use of electron-deficient
phenol as the nucleophilic partner in this type of MCR.
The resulting products B, which contain a ether linkage
and a functionalized phenoxy unit, can be further manipu-
lated to give building blocks (e.g., C) that are potentially
useful for self-assembly complex construction (vida infra)
(Scheme 1).
(1) (a) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey,
G. R.; Leazer, J. L.; Linderman, R. J., Jr.; Lorenz, K.; Manley, J.;
Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9,
411. (b) Rosamilia, A. E.; Scott, J. L.; Strauss, C. R. Org. Lett. 2005, 7,
1525. (c) Rosamilia, A. E.; Strauss, C. R.; Scott, J. L. Pure Appl. Chem.
2007, 79, 1869. (d) Shi, D. Q.; Ni, S. N.; Yang, F.; Ji, S. J. J. Heterocycl.
Chem. 2008, 45, 1275. (e) Andriushchenko, A. Y.; Desenko, S. M.;
Chernenko, V. N.; Chebanov, V. A. J. Heterocycl. Chem. 2011, 48, 365.
€
(2) For selected reviews on MCRs, see: (a) Ugi, I.; Domling, A.; Horl,
€
W. Endeavour 1994, 18, 115. (b) Domling, A.; Ugi, I. Angew. Chem., Int.
ꢀ
Ed. 2000, 39, 3168. (c) Multicomponent Reactions; Zhu, J., Bienayme,
€
H., Eds.; Wiley-VCH: Weinheim, 2005. (d) Domling, A. Chem. Rev. 2005,
ꢀ
106, 17. (e) Ganem, B. Acc. Chem. Res. 2009, 42, 463. (f) Toure, B. B.;
Hall, D. G. Chem. Rev. 2009, 109, 4439. (g) Sunderhaus, J. D.; Martin,
S. F. Chem.;Eur. J. 2009, 15, 1300.
ꢀ
(3) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(4) For selected electrophilic MCRs, see: (a) Serguchev, Y. A.;
Ponomarenko, M. V.; Lourie, L. F.; Chernega, A. N. J. Fluorine Chem.
2003, 123, 207. (b) Nair, V.; Menon, R. S.; Beneesh, P. B.; Sreekumar, V.;
Bindu, S. Org. Lett. 2004, 6, 767. (c) Nair, V.; Beneesh, P. B.; Sreekumar,
V.; Bindu, S.; Menon, R. S.; Deepthi, A. Tetrahedron Lett. 2005, 46, 201.
(d) Yeung, Y. Y.; Gao, X. R.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
9644. (e) Church, T. L.; Byrne, C. M.; Lobkovsky, E. B.; Coates, G. W.
J. Am. Chem. Soc. 2007, 129, 8156. (f) Hajra, S.; Bar, S.; Sinha, D.; Maji,
B. J. Org. Chem. 2008, 73, 4320. (g) Abe, T.; Takeda, H.; Miwa, Y.;
Yamada, K.; Yanada, R.; Ishikura, M. Helv. Chim. Acta 2010, 93, 233.
(h) Braddock, D. C.; Millan, D. S.; Perez-Fuertes, Y.; Pouwer, R. H.;
Sheppard, R. N.; Solanki, S.; White, A. J. P. J. Org. Chem. 2009, 74,
1835. (i) Bonney, K. J.; Braddock, D. C.; White, A. J. P.; Yaqoob, M.
J. Org. Chem. 2011, 76, 97. (j) Snyder, S. A.; Treitler, D. S.; Bruchks,
A. P.; Sattler, W. J. Am. Chem. Soc. 2011, 133, 15898.
(5) (a) Zhou, L.; Tan, C. K.; Zhou, J.; Yeung, Y.-Y. J. Am. Chem.
Soc. 2010, 132, 10245. For other examples of electrophilic Br initiated
cascades, see: (b) Zhou, L.; Zhou, J.; Tan, C. K.; Chen, J.; Yeung, Y.-Y.
Org. Lett. 2011, 13, 2448. (c) Zhou, L.; Chen, J.; Zhou, J.; Yeung, Y.-Y.
Org. Lett. 2011, 13, 5804. (d) Chen, J.; Chng, S.; Zhou, L.; Yeung, Y.-Y.
Org. Lett. 2011, 13, 6456. (e) Zhou, J.; Zhou, L.; Yeung, Y.-Y. Org. Lett.
2012, 14, 5250. For some selected recent examples of cohalogenation
reactions, see: (f) Cai, Y.; Liu, X.; Hui, Y.; Jiang, J.; Wang, W.; Chen,
W.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2010, 49, 6160. (g) Cai, Y.;
Liu, X.; Jiang, J.; Chen, W.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2011,
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L.; Feng, X. Chem.;Eur. J. 2011, 17, 14916.
r
10.1021/ol4005646
XXXX American Chemical Society

(Table 1, entries 10À12). This result is consistent with our
previous observation in which the acidic proton plays a
crucial role in the MCR, potentially acting as the NBS
activator.5,7 Finally, the reaction was readily scalable with
equal reaction efficiency (Table 1, entry 13).
Scheme 1. NBS-Promoted Electrophilic Cascades
Table 2. Electrophilic Phenoxyetherification Using Various
Olefins
In our preliminary study on the MCR using cyclohex-
ene, tetrahydrofuran (THF), and NBS as the components,
it was found that phenol and nitrophenols were bromi-
nated and the desired adducts were achieved in moderate
Table 1. Electrophilic Phenoxyetherification of Cyclohexene
entrya
phenol
C6H5OH
product, R
yielde (%)
1b
2
3c
4c
5
1a, 2,4,6-Br3C6H2
42
42
85
45
96
18
50
44
42
2,4,6-Br3C6H2OH
4-NO2C6H4OH
2-NO2C6H4OH
1a, 2,4,6-Br3C6H2
1b, 2,6-Br2-4-NO2C6H2
1c, 4,6-Br2-2-NO2C6H2
2,6-Br2-4-NO2C6H2OH 1b, 2,6-Br2-4-NO2C6H2
6
C6F6OH
1d, C6F6
7
3,5-(CF3)2C6H3OH
4-CF3C6H4OH
4-CF3OC6H4OH
1e, 3,5-(CF3)2C6H3
1f, 2,6-Br2-4-CF3C6H2
1g, 2,6-Br2-4-CF3OC6H2
no reaction
8c
9c
10c 4-tBuC6H4OH
11c 4-CH3C6H4OH
no reaction
12
2,6-Br2-4-CH3C6H2OH no reaction
13d 2,6-Br2-4-NO2C6H2OH 1b, 2,6-Br2-4-NO2C6H2
95
a Reactions were carried out with cyclohexene (0.6 mmol), phenol
(0.5 mmol), and NBS (0.6 mmol) in THF (4.0 mL) at 25 °C for 16 h.
b Using 4.5 equiv of NBS. c Using 3.5 equiv of NBS. d The reaction was
conducted on a 5 mmol scale. e Isolated yields.
a Reactions were carried out with cyclohexene (0.6 mmol), phenol
(0.5 mmol), and NBS (0.6 mmol) in THF (4.0 mL) at 25 °C for 16 h.
b Isolated yields.
to good yields (Table 1, entries 1À4). Other electron-
deficient phenols were also examined, and moderate to
good yields were obtained in general (Table 1, entries
5À9).6 However, for the highly electron-deficient penta-
fluorophenol (Table 1, entry 6), low yield was observed
which may be partly attributed to the low nucleophilicity
of the counter phenoxy anion that results in the low A f B
conversion efficiency (Scheme 1).
Having proven the feasibility of this multicomponent
reaction, various olefinic substrates were then subjected to
investigation (Table 2).8 In general, the reactions pro-
ceeded smoothly with good to excellent yields. Further-
more, high chemoselectivities were observed, as the more
electron-rich olefinic position react more readily (Table 2,
Some relatively electron-rich phenols, including 4-methyl-,
4-tert-butyl-, and 2,6-dibromo-4-methylphenols, weresub-
jected to the reaction, and no desired product was detected
(7) We had also suspected that the cyclic ether might be preopened by
the phenols before the bromoetherification of olefin. Nonetheless, we
attempted to mix 2,6-dibromo-4-nitrophenol and NBS in THF for 16 h
at 25 °C in which no THF ring-opening product was observed.
(6) The pKa values of the phenols are summarized in the Supporting
Information (Table S1).
B
Org. Lett., Vol. XX, No. XX, XXXX

entry 4). In the cases of trisubstituted cyclic (2c and 2d),
acyclic (2e and 2f), and benzylic (2g and 2h) olefins,
excellent regioselectivities were achieved wherein only the
Markovnikov-type products were found.
The scope of this phenoxyetherification disclosed herein
appears to be quite broad in regard to not only the olefinic
component but also the cyclic ether partner. We carried
out the reaction using cyclohexene, 2,6-dibromo-4-nitro-
phenol, and NBS in a variety of cyclic ethers (Table 3).
4 simply by double-Sonogashira coupling reactions
(Table 4). In particular, Fujita9 reported the application
of this type of compounds to the synthesis of self-assembly
spherical complexes potentially applicable to the construc-
tion of high-density data-storage materials. Those com-
plexes consist of metals and multistep-synthesized ligands
obtained from coupling between 2,6-dibromophenoxy
motif and 4-ethynylpyridine.
In our previous related studies, it is believed that the
counter nucleophiles, sulfonamides5b,c and carboxylic
acids,5d are responsible for the activation of NBS. In the
Table 3. Electrophilic Phenoxyetherification Using Various
Cyclic Ethers
Table 4. Sonogashira Coupling of 3d with Arylacetylene
a Reactions were carried out with 3d (0.2 mmol), arylacetylene
(0.6 mmol), Pd(OAc)2 (0.02 mmol), and Cs2CO3 (0.3 mmol) in DMF
(2.5 mL) at 80 °C for 12 h.
present study, we had also suspected that the same activa-
tion mode appeared in this phenoxyetherification reaction
which is the sole origin of reactivity. However, pentafluoro-
phenol that is more acidic than 2,6-dibromo-4-nitrophenol
did not return with higher reaction yield (Table 1, entry 6).
A NMR study on the mixture of NBS and 2,6-dibromo-
4-nitrophenol was performed in order to get further in-
sight. A new proton signal (8.47 ppm), which is more down-
field than that of the aromatic proton of 2,6-dibromo-4-
nitrophenol (8.45 ppm), appeared when mixing NBS
and 2,6-dibromo-4-nitrophenol. The NBS proton signal
(2.81 ppm) diminished accompanied by the generation of
succinimide (2.61 ppm). These chemical shifts resemble the
species 2,4,6-tribromophenol and 2,4,4,6-tetrabromo-2,5-
cyclohexadienone.10 In addition, upon mixing NBS with
2,6-dibromo-4-nitrophenol, the solution changed from
colorless to bright orange, which is identical to the color
of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (Figure 1).
Based on these results, we believe that 2,4,6-tribromo-4-
nitro-2,5-cyclohexadienone (5) might be generated in situ
a Reactions were carried out with cyclohexene (0.6 mmol), phenol
(0.5 mmol), and NBS (0.6 mmol) in THF (4.0 mL) at 25 °C for 16 h. b The
reaction was conducted on a 5 mmol scale. c Isolated yields.
Treatment of the substrates in oxetane gave the desired
product 3a in 78% yield, whereas adduct 3b was isolated in
87% yield when 3,3-dimethyloxetane was used (Table 3,
entries 1 and 2). Besides four- and five-membered-ring
cyclic ethers, a six-membered-ring tetrahydropyran was
also found to be effective in the reaction, giving 3c in 88%
yield (Table 3, entry 3). Interestingly, polyether adduct 3d
was isolated (95%) when 1,4-dioxane was used in the
reaction (Table 3, entries 4 and 5).
It is noteworthy that the resulting compounds could
serve as the fundamental units of metal complexation
ligands. For instance, compound 3d can be converted to
(8) Representative procedure: to a solution of olefin (0.6 mmol) in
cyclic ether (1 mL) were added phenol (0.5 mmol) and N-bromosucci-
nimide (107 mg, 0.6 mmol) at 0 °C. The reaction was shielded from light
and then stirred at 25 °C for 16 h. The solvent was then removed under
reduced pressure, and the residue was purified by flash column chro-
matography (n-hexane/EtOAc 20:1) to yield the corresponding product.
(9) Murase, T.; Sato, S.; Fujita, M. Angew. Chem., Int. Ed. 2007, 46,
1083.
(10) (a)Jana, N. K.;Verkade, J. G. Org. Lett. 2003, 5, 3787. (b) Bedekar,
A. V.; Gadde, R.; Ghosh, P. K. US Pat. Appl. Publ. 20040127750, 2004.
Org. Lett., Vol. XX, No. XX, XXXX
C

and acts as the active halogenating source. On the other
hand, no sharp color change upon mixing pentafluorophe-
nol with NBS.11 This can also explain why the more
electron-deficient aromatic systems, which should be less
reactive toward the generation of the para-brominated
species, gave lower reaction efficiency.
In summary, we have developed a general and efficient
electrophilic phenoxyetherification using an olefin, a cyclic
ether, a phenol, and NBS. The olefin and cyclic ether partners
can be flexibly varied to produce different kinds of phenoxy
ether derivatives. Furthermore, the coupling protocol allows
the facile ligand preparations. Hence, the resulting products
are potentially useful structural motifs in material chemistry.
Acknowledgment. We acknowledge financial support
from the Agency for Science, Technology and Research
Public Sector Funding (A*STAR-PSF) (Grant No. 143-
000-536-305) and the National University of Singapore
Cross Faculty Grant (Grant No. 143-000-528-133).
Supporting Information Available. Experimental de-
1
tails and H and 13C NMR spectral data for reaction
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. Color change when NBS is mixed with 2,6-dibromo-4-
nitrophenol.
(11) The details appear in the Supporting Information (Figure S1).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX