Scope and mechanistic studies of electrophilic alkoxyetherification

Article abstract of DOI:10.1021/ol202751s

A one-pot electrophilic alkoxyetherification using an olefin, a cyclic ether, a carboxylic acid, and N-bromosuccinimide has been developed. The oxygen nucleophiles, the olefinic substrates, and the cyclic ether partners can be varied to produce a wide range of alkoxyether derivatives.

Full text of DOI:10.1021/ol202751s

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6456–6459
Scope and Mechanistic Studies of
Electrophilic Alkoxyetherification
Jie Chen, Shuyun Chng, Ling Zhou, and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543
chmyyy@nus.edu.sg
Received October 13, 2011
ABSTRACT
A one-pot electrophilic alkoxyetherification using an olefin, a cyclic ether, a carboxylic acid, and N-bromosuccinimide has been developed. The
oxygen nucleophiles, the olefinic substrates, and the cyclic ether partners can be varied to produce a wide range of alkoxyether derivatives.
Multicomponent reactions (MCRs) are important and
useful synthetic methods that offer an opportunity for
building complex molecules in a convergent and atom-
Scheme 1. Bromonium Ion Promoted Electrophilic Cascades
economic manner.1 A major focus of MCR is on the
development of new reactions,2 and many endeavors to
develop green and sustainable processes have been carried
out.3 However, electrophilic MCRs have been less re-
ported, partly because of the common incompatibility of
electrophiles with the other components.4
Further investigation using acetic acid as the nucleo-
philic partner showed that the reaction was highly
dependent on the concentration, in which a higher
reaction yield (86%) of the desired product was obtained
under a diluted (0.04 M) condition (Table 1, entry 3).
The reaction was readily scalable without loss of effi-
ciency (Table 1, entry 4).6
In the course of our effort on the development of
electrophilic bromine initiated MCR, recently we reported
a novel electrophilic cascade using an olefin, a cyclic ether,
a sulfonamide, and NBS. During that study, we also
disclosed that instead of a sulfonamide, an oxygen nucleo-
phile, which contained an acidic proton, could also partici-
pate in this cascade (Scheme 1).5
(1) For selected reviews, see: (a) Ugi, I.; Domling, A.; Horl, W.
€
(4) For selected electrophilic MCRs, see: (a) Serguchev, Y. A.;
PonomarenkoM. V.; Lourie, L. F.; Chernega, A. N. J. Fluorine Chem.
2003, 123, 207–215. (b) Nair, V.; Menon, R. S.; Beneesh, P. B.; Sreekumar,
V.; Bindu, S. Org. Lett. 2004, 6, 767–769. (c) Nair, V.; Beneesh, P. B.;
Sreekumar, V.; Bindu, S.; Menon, R. S.; Deepthi, A. Tetrahedron Lett.
2005, 46, 201–203. (d) Yeung, Y. Y.; Gao, X. R.; Corey, E. J. J. Am.
Chem. Soc. 2006, 128, 9644–9645. (e) Church, T. L.; Byrne, C. M.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2007, 129, 8156–
8162. (f) Hajra, S.; Bar, S.; Sinha, D.; Maji, B. J. Org. Chem. 2008, 73,
4320–4322. (g) Abe, T.; Takeda, H.; Miwa, Y.; Yamada, K.; Yanada,
R.; Ishikura, M. Helv. Chim. Acta 2010, 93, 233–241. (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, 1835–1841.
(i) Bonney, K. J.; Braddock, D. C.; White, A. J. P.; Yaqoob, M. J. Org.
Chem. 2011, 76, 97–104. (j) Snyder, S. A.; Treitler, D. S.; Bruchks, A. P.;
Sattler, W. J. Am. Chem. Soc. 2011, 133, 15898–15901.
Endeavour 1994, 18, 115–122. (b) Domling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168–3210. (c) Multicomponent Reactions; Zhu, J.,
ꢀ
Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005. (d) Domling, A. Chem.
€
Rev. 2005, 106, 17–89. (e) Domling, A. Chem. Rev. 2005, 106, 17–89. (f)
Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486.
(g) Sunderhaus, J. D.; Martin, S. F. Chem.;Eur. J. 2009, 15, 1300–1308.
ꢀ
(2) (a) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472. (b) Ramon,
D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
(3) (a) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey,
G. R.; Leazer, J. J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.;
Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007,
9, 411–420. (b) Rosamilia, A. E.; Scott, J. L.; Strauss, C. R. Org. Lett.
2005, 7, 1525–1528. (c) Rosamilia, A. E.; Strauss, C. R.; Scott, J. L. Pure
Appl. Chem. 2007, 79, 1869–1877. (d) Shi, D. Q.; Ni, S. N.; Yang, F.; Ji,
S. J. J. Heterocycl. Chem. 2008, 45, 1275–1280. (e) Andriushchenko,
A. Y.; Desenko, S. M.; Chernenko, V. N.; Chebanov, V. A. J. Hetero-
cycl. Chem. 2011, 48, 365–367.
(5) Zhou, L.; Tan, C. K.; Zhou, J.; Yeung, Y.-Y. J. Am. Chem. Soc.
2010, 132, 10245–10247.
r
10.1021/ol202751s
Published on Web 11/16/2011
2011 American Chemical Society

Table 1. Alkoxyetherification of Cyclohexene Using Acetic
Acid
Table 2. Alkoxyetherification of Cyclohexene Using Various
Oxygen Nucleophilesa
entrya
concentration (M)
isolated yield (%)
1
0.13
0.06
0.04
0.04
48
58
86
85
2
3
4b
a Reactions were carried out with cyclohexene (0.6 mmol), NBS (0.6
mmol), and AcOH (0.5 mmol) in THF at 25 °C for 24 h. b Reaction was
conducted on a 1.0 g scale.
Other carboxylic acids were also subjected to investiga-
tion. In general, the reaction varied with the acidity of the
carboxylic acid partner (Table 2). Comparing to benzoic
acid (1b) (entry 1, pKa = 4.20), less acidic partners includ-
ing 3-methylbenzoic acid (1c) (entry 2, pKa = 4.24),
4-methylbenzoic acid (1d) (entry 3, pKa = 4.34), and
4-methoxybenzoic acid (1e) (entry 4, pKa = 4.47) gave
lower yields. Moderate yields were obtained when rela-
tively more acidic partners were used, such as 4-chloro-
benzoic acid (1f) (entry 5, pKa = 3.99) and 4-nitrobenzoic
acid (1g) (entry 6, pKa = 3.44).7 In particular, high yield
(78%) of the desired product was obtained using penta-
fluorobenzoic acid (1h) (Table 1, entry 7).
Interestingly, when using hydroxyl carboxylic acids in-
cluding glycolic acid (1k) (entry 10, pKa = 3.83), (R)-(À)-
mandelic acid (1l) (entry 11, pKa = 3.41), and salicyclic
acid (1n) (entry 13, pKa = 2.98),8 and 3,5-dibromosalicyc-
lic acid (1o) (entry 14), high reaction yields of the carbox-
ylate-adducts were obtained.7,9 It is noteworthy that in
these acids, although both the hydroxyl and the carboxylic
acid groups could potentially participate in the reaction,
the less nucleophilic carboxylic group preferred to attack
(vida infra). Masking the hydroxyl group of 1l as a methyl
ether (i.e., acid 1m), however, led to a lower reaction yield
a Reactions were carried out with cyclohexene (0.6 mmol), NBS (0.6
mmol), and oxygen nucleophile 1 (0.5 mmol) in THF (0.04 M) at 25 °C
for 24 h. The productyields are isolated yields. b 1.8 mmol NBS was used,
and the corresponding 3,5-dibromosalicyclic adduct was obtained.
(Table 2, entry 12).10,11 The products were confirmed not
only by NMR but also by the hydrolysis of 2l.12
Next, various olefinic substrates were examined using
(R)-(À)-mandelic acid (1l) and 3,5-dibromosalicyclic
acid (1o) as the nucleophilic partners. In many cases,
the desired alkoxyethers 3 were obtained with good
yields. In addition, excellent chemoselectivities and po-
sitional selectivities were observed, wherein the reac-
tion occurred on the more electron-rich olefin (Table 3,
entry 2), and the Markovnikov-type products were iso-
lated (Table 3, entries 1À8).10 Furthermore, high stereo-
selectivity was also obtained, where the cascade resulted
(6) We have briefly investigated using less THF, i.e., using THF as a
stoichiometric reagent instead of a solvent. However, the results were
not satisfactory. For details, see the Supporting Information.
(7) For references of the pKa values, see: (a) Brown, H. C. et al. In
Braude, E. A.; Nachod, F. C. Determination of Organic Structures by
Physical Methods; Academic Press: New York, 1955. (b) Dippy, J. F. J.;
Hughes, S. R. C.; Rozanski, A. J. Chem. Soc. 1959, 2492. (c) Bjerrum, J. et
al. Stability Constants; Chemical Society: London, 1958.
(8) When using salicyclic acid (1n), the corresponding 3,5-dibromo-
salicyclic adduct was obtained as the sole product. Identical result was
observed when using 3,5-diromosalicyclic acid (1o) as the nucleophlic
partner.
(9) Representative procedure: To a solution of olefin (0.6 mmol) and
oxygen nucleophile (0.5 mmol) in dry THF (6 mL) in the dark was added
N-bromosuccinimide (107 mg, 0.6 mmol) in four portions at 1-h inter-
vals at 25 °C. After stirring for 24 h at 25 °C, the reaction was quenched
with saturated Na2S2O3 (10 mL). The mixture was extracted with EtOAc
(3 Â 10 mL). The combined extracts were washed with brine (15 mL),
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography to yield the
corresponding product.
(10) For the reactions that used acids 1l and 1m (Table 2, entries 11
and 12; Table 3, entries 1 and 2; Table 4), the products existed as
diastereoisomeric mixtures.
(11) The carboxylic acids with neighboring hydroxyl groups (acids
1k, 1l, 1n, and 1o) returned high reaction yields; for acid 1l, removing
(Table 2, entry 11 vs 8) or masking (Table 2, entry 11 vs 12) the hydroxyl
group gave a lower yield. The hydroxyl group seemed could enhance the
acidity of the carboxylic acid, potentially through an intramolecular
hydrogen bonding (Table 2, entry 1 vs 13; 8 vs 11).
(12) The details appear in the Supporting Information.
Org. Lett., Vol. 13, No. 24, 2011
6457

Table 3. Alkoxyetherification of Various Olefins
Table 4. Alkoxyetherification of Cyclohexene Using Various
Cyclic Ethersa
a Reactions were carried out with cyclohexene (0.6 mmol), NBS (0.6
mmol), and (R)-mandelic acid (1l) (0.5 mmol) in cyclic ether (0.04 M) at
25 °C for 24 h. The product yields are isolated yields.
Scheme 2. Probing the Reaction Mechanism
yield was highly dependent on the acidity of the nucleo-
philic partner.13
In fact, we have carried out two experiments in order to
further illuminate the mechanistic picture. First, 10 mol %
of radical scavenger 2,6-di-tert-butyl-4-methylphenol
(BHT) was added to the cascade reaction involving cyclo-
hexene, NBS, acetic acid, and THF (Scheme 2, eq 1). After
24 h, 48% of the desired product was obtained, which was
identical to the reaction without the addition of BHT.
Second, a competition experiment, which involved equal
molar amounts of methanol and acetic acid as the nucleo-
philes in the cyclohexeneÀTHFÀNBS cascade, was also
performed (Scheme 2, eq 2). After 24 h, a 48% of the acetic
acid-adduct was obtained, while no methanol-associated
product was detected.
a Reactions were carried out with olefin (0.6 mmol), NBS (0.6 mmol),
and oxygen nucleophiles (0.5 mmol) in THF (0.04 M) at 25 °C for 24 h.
b 1.0 mmol of olefin was used. c Isolated yield.
in the formation of only trans-addition products (Table 3,
entries 5 and 9À11).
Other than examining the olefinic substrates, a variety of
cyclic ethers, including oxetane, 3,3-dimethyloxetane, tet-
rahydropyran, and 1,4-dioxane, were also subjected to
investigation. Cyclohexene, NBS, and (R)-mandelic acid
(1l) were used as the counter partners, and moderate to
good reaction yields of the corresponding alkoxyethers
were observed (Table 4).10
(13) Similar observation appeared in related studies; for reference,
see: (a) Zhou, L.; Zhou, J.; Tan, C. K.; Chen, J.; Yeung, Y.-Y. Org. Lett.
2011, 13, 2448–2451. (b) Zhou, L.; Chen, J.; Zhou, J.; Yeung, Y.-Y. Org.
Lett. 2011, 13, 5804–5807.
(14) (a) DeLaMare, P. B. D.; Bolton, R. Electrophilic Additions to
Unsaturated Systems, 2nd ed.; Elsevier: New York, 1982; pp 136À197.
(b) Ruasse, M.-F. Adv. Phys. Org. Chem. 1993, 28, 207. (c) Schmid,
G. H.; Garrat, D. G. In The Chemistry of Double Bonded Functional
Groups; Patai, S., Ed.; Wiley: New York, 1977; Suppl. A, Part 2, p 725.
Toward the understanding of the mechanism, we be-
lieved that the carboxylic acid partner played a crucial role
in activating NBS; an additional NBS activator was not
necessary in this alkoxyetherification, and the reaction
6458
Org. Lett., Vol. 13, No. 24, 2011

experiment (Scheme 2, eq 2), and alcohol-adducts 5 and
6 should be obtained as the major products, respectively.
However, since only the carboxylic acid-associated
products were obtained (Tables 2À4), this type of reac-
tion may not follow the proposal presented in Scheme 3.
A possible explanation is that instead of a carboxylic
acid group, a carboxylate anion, which is more nucleo-
philic than a hydroxyl group, may be involved in captur-
ing intermediate B.15
Scheme 3. A Plausible Mechanistic Pathway
In accordance to our previous mechanistic proposal,13b
the carboxylic acid nucleophile might act as a Brønsted
acid to activate NBS (Scheme 4, species D). After the
formation of bromonium intermediate with an olefin
(e.g., cyclohexene) (D f E) and the cyclic ether nucleo-
philic attack (E f F), the counter succinimide anion might
deprotonate the acid and give the carboxylate-oxonium
pair F. Subsequent capturing of the oxonium ion by the
acetate could furnish the desired product 2a (Scheme 4, eq
1). On the other hand, a Br exchange between the acid and
NBS might exist, which would result in the active electro-
philic brominating source AcOBr (Scheme 4, species
G).16,17 Through a G f H f I sequence, the target
molecule 2a could also be obtained (Scheme 4, eq 2).
In summary, we have developed a general and efficient
electrophilic alkoxyetherification that uses an olefin, NBS, a
carboxylic acid, and a cyclic ether. This MCR is catalyst-
free, readily scalable, and highly practical using inexpensive
and commercially available reagents. Furthermore, good
regio- and steroselectivity are also observed in this MCR.
Scheme 4. Proposed Mechanism of the Electrophilic Bro-
moalkoxyetherification Reaction
Acknowledgment. We are thankful for financial sup-
port from National University of Singapore (Grant No.
143-000-428-112). We also thank Prof. Scott E. Denmark
(University of Illinois) for his valuable advice on this
project.
Since thisMCR seemednottobea radical-typereaction,
based on the cationic proposal,14 the mechanistic pathway
should ensue: (1) nucleophilic attack of bromonium inter-
mediate A by a cyclic ether (e.g., THF) to form B; (2)
oxonium intermediate B is captured by an oxygen nucleo-
phile to give C; (3) deprotonation of C yields the desired
product (Scheme 3). This proposal should follow the
nucleophilicity, in which comparing to a carboxylic acid
group, the more nucleophilic hydroxyl group should be
more reactive and should attack B to form C, i.e., in the
cascade (e.g., Table 2, entry 11) and the competition
Supporting Information Available. Experimental pro-
cedures and additional information. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(17) For studies of bromonium and related electrophiles activation
by Lewis basic sulfur and selenium, see: (a) Synder, S. A.; Treitler, D. S.;
Brucks, A. P.; Sattler, W. J. Am. Chem. Soc. 2011, 133, 15898–15901.
(b) Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. J. Am. Chem. Soc. 2011,
133, 15308–15311. (c) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Org. Lett.
2011, 13, 2738–2741. (d) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y.
J. Am. Chem. Soc. 2011, 133, 9164–9167. (e) Tan, C. K.; Chen, F.;
Yeung, Y.-Y. Tetrahedron Lett. 2011, 52, 4892–4895. (f) Denmark, S. E.;
Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20655–20660.
(g) Synder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010,
132, 14303–14314. (h) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung,
Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474–15476.
(15) (a) Li, Z.; Nakashige, M.; Chain, W. J. J. Am. Chem. Soc. 2011,
133, 6553–6556. (b) Zhou, Q.; Chen, X.; Ma, D. Angew. Chem., Int. Ed.
2010, 49, 3515–3516.
(16) (a) Chen, K.; Baran, P. S. Nature 2009, 459, 824–828. (b) Chen,
K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247–7249.
(c) Levine, S. G.; Wall, M. E. J. Am. Chem. Soc. 1959, 81, 2826–2829.
(d) Lauer, G.; Oberdorfer, F. Angew. Chem., Int. Ed. 1993, 32, 272–273.
Org. Lett., Vol. 13, No. 24, 2011
6459