CuBr2-promoted tetrahydrofuranylation of alcohols and 1,3-dione

Article abstract of DOI:10.1055/s-0032-1318347

A method for the CuBr₂-promoted tetrahydrofuranylation of alcohols and 1,3-dione has been developed. A variety of different alcohols were efficiently converted into the corresponding 2-tetrahydrofuran ethers in the presence of CuBr₂. It is noteworthy that this protocol also successfully converted 1,3-diphenyl-1,3-dione into the corresponding 2-tetrahydrofuran derivative in good yield. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318347

LETTER
▌737
lCettuer Br2-Promoted Tetrahydrofuranylation of Alcohols and 1,3-Dione
Tetrahydrofuranylation of Alcohols and 1,3-Diones
Meng-Ke Wang, Zeng-le Zhou, Ri-Yuan Tang, Xing-Guo Zhang, Chen-liang Deng*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(577)86689300; E-mail: dengchenliang78@tom.com
Received: 07.01.2013; Accepted after revision: 11.02.2013
per catalyst and did not provide any of the desired tetrahy-
drofuranylation product 3 (Table 1, entry 1). In contrast,
the yield of 3 increased significantly following the addi-
tion of 10 mol% CuBr2 to the reaction mixture (Table 1,
Abstract: A method for the CuBr2-promoted tetrahydrofuranyl-
ation of alcohols and 1,3-dione has been developed. A variety of
different alcohols were efficiently converted into the corresponding
2-tetrahydrofuran ethers in the presence of CuBr2. It is noteworthy
that this protocol also successfully converted 1,3-diphenyl-1,3-di- entry 2). Based on this result, a series of cuprous and cu-
one into the corresponding 2-tetrahydrofuran derivative in good
yield.
pric salts were then examined (Table 1, entries 3–9). The
Table 1 Optimization of the Reaction Conditionsa
Key words: copper, protecting groups, alcohols, diones, ethers
O
[Cu] (10 mol%)
OH
O
O
+
During the course of the past five decades, a multitude of
different strategies have been developed for the protection
of important functional groups in organic compounds.1
Tetrahydropyranylation2 and tetrahydrofuranylation3
have become widely used methods in organic synthesis
for the protection of hydroxyl groups. Tetrahydropyranyl
(THP) and tetrahydrofuranyl (THF) ethers make ideal
protecting groups because of their ease of preparation and
stability towards a broad range of reaction conditions,
such as strongly basic media, hydrides, and acylating and
alkylating agents. Although the former reaction has been
extensively researched, the latter has often been disre-
garded and consequently explored to a lesser extent.
There have been several reports describing methods for
the formation of 2-tetrahydrofuranyl ethers. For example,
the activation of tetrahydrofuran has recently been report-
ed with a variety of one-electron oxidants, including ceri-
um(IV) reagents,4 p-TsOH,5 CrCl2,6 alkylperoxy-λ3-
iodane,7 peroxodisulfates,8 Mn(0) powder,9 aluminum tri-
flate,10 and allyl chloride.11 Unfortunately, there are issues
associated with all of these methods, including the use of
1a
2a
3
Entry
Catalyst (10 mol%) Solvent
Temp (°C) Yield (%)b
1
2
–
THF
80
80
NR
76
CuBr2
CuCl2
CuF2
THF
3
THF
80
63
4
THF
80
56
5
CuO
THF
80
NR
NR
NR
NR
NR
trace
70
6
Cu(OAc)2
Cu(acac)2
CuI
THF
80
7
THF
80
8
THF
80
9
Cu (powder)
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
THF
80
10
11
THF (N2)
THF (O2)
THF
80
80
expensive reagents, elevated temperatures, strongly acidic 12
conditions, toxic reagents, and low levels of functional
group tolerance. The development of a mild, environmen-
tally benign and efficient alternative method capable of 14
60
44
13
THF
100
120
100
88
THF
89
overcoming these issues still represents a significant chal-
c
15
CuBr2
THF
47
lenge for chemists. Herein, we report the development of
a CuBr2-promoted tetrahydrofuranylation of alcohols un- a Reaction conditions: 1a (0.3 mmol), 2a (2 mL), [Cu] (10 mol%), un-
der air for 24 h.
der mild conditions (Scheme 1). Furthermore, the catalyt-
ic system can be used for the protection of 1,3-dione
compounds.
b Isolated yield.
c CuBr2 (5 mol%).
The reaction of benzyl alcohol (1a) with THF (2a) was se-
CuBr2
O
O
(10 mol%)
lected as a model reaction to optimize the reaction condi-
tions, and the results are summarized in Table 1. The
reaction was initially conducted in the absence of any cop-
R
OH
O
100 °C, 24 h, air
R
Scheme 1 CuBr2-promoted tetrahydrofuranylation of alcohols
SYNLETT 2013, 24, 0737–0740
Advanced online publication: 06.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318347; Art ID: ST-2013-W0019-L
© Georg Thieme Verlag Stuttgart · New York

738
M.-K. Wang et al.
LETTER
results revealed that several cupric halides could efficient- der an N2 atmosphere, none of the target product was
ly facilitate the reaction, whereas other cuprous and cupric observed by GC-MS (Table 1, entry 10), whereas the tet-
salts investigated provided no benefit to the reaction. For rahydrofuranylation product was formed in 70% yield
example, CuCl2 and CuF2 were found to be suitable cata- when the reaction was performed under an O2 atmosphere
lysts for the tetrahydrofuranylation, and afforded 3 in 63 (Table 1, entry 11). Based on these results, it was clear
and 56% yield, respectively (Table 1, entries 3 and 4). In that O2 played an important role in the tetrahydrofuranyl-
contrast, CuO, Cu(OAc)2, Cu(acac)2, CuI and Cu (pow- ation process. Evaluation of the reaction temperature also
der) did not have any discernible impact on the transfor- revealed that the reaction provided the best results when it
mation, with none of the desired product being isolated was conducted at 100 °C (Table 1, entry 13). A reduction
(Table 1, entries 5–9). We then proceeded to conduct the in the loading of CuBr2 to 5 mol% resulted in a lower
reaction under N2 and O2 to evaluate the effect of the re- yield (Table 1, entry 15).
action atmosphere. When the reaction was conducted un-
Table 2 CuBr2-Promoted Tetrahydrofuranylation of Alcoholsa
CuBr2
(10 mol%)
O
O
R
OH +
O
100 °C, 24 h, air
R
Entry
1
1
2
Time (h) Product
Yield (%)b
75
O
Cl
1b
2a
2a
26
26
4
5
O
OH
Cl
O
O2N
O
2
1c
78
OH
O2N
O
OH
O
3
4
1d
1e
2a
2a
32
36
6
7
79
82
O
MeO
O
OH
OH
MeO
O
MeO
MeO
MeO
MeO
O
O
5
6
7
1f
2a
2a
2a
38
40
46
8
9
95
51
64
OH
OH
O
1g
1h
OH
O
HO
I
O
10
I
Ph
OH
8
9
1i
1j
2a
2a
58
56
11
12
53
57
O
Ph
Ph
O
Ph
Ph
Ph
OH
O
O
OH
O
O
O
10c
1k
2a
46
13
53
O
Synlett 2013, 24, 737–740
© Georg Thieme Verlag Stuttgart · New York

LETTER
Tetrahydrofuranylation of Alcohols and 1,3-Diones
739
Table 2 CuBr2-Promoted Tetrahydrofuranylation of Alcoholsa (continued)
CuBr2
(10 mol%)
O
O
R
OH +
O
100 °C, 24 h, air
R
Entry
11c
1
2
Time (h) Product
Yield (%)b
OH
O
S
O
S
1l
2a
76
14
22
O
O
Ph
O
O
O
O
12
13
1m
1n
2a
2a
46
30
15
16
62
31
Ph
Ph
Ph
OH
O
H
H
N
N
Me
Me
O
O
14
1o
2a
24
17
67
OH
O
OH
15
16
1p
1a
2a
2b
44
28
18
3
29
25
O
O
O
OH
O
O
O
O
17
18
1a
1a
2c
34
24
19
37
–
N
2d
–
–
O
a Reaction conditions: 1a (0.3 mmol), 2a (2 mL), CuBr2 (10 mol%), 100 °C under air until complete consumption the starting material (reaction
monitored by TLC and GC-MS).
b Isolated yield.
c Reaction conducted at 80 °C.
With optimized reaction conditions in hand, we proceeded containing two methoxy groups on its aromatic ring, gave
to explore the scope of substrates 1 and 2; the results are an excellent yield of the corresponding product under the
summarized in Table 2. In the presence of CuBr2, alcohols optimized conditions (Table 2, entry 5). Alcohols bearing
1a–o reacted smoothly under the reaction conditions to af- bulky functional groups were also tolerated. For example,
ford moderate to excellent yields of the target products alcohols 1g–i reacted smoothly with THF under the opti-
(Table 2, entries 1–14). The results demonstrated that a mized conditions to give the corresponding products in
variety of different functional groups could be tolerated in moderate yields (Table 2, entries 6–8). Substrate 1g, a
the alcohols under the optimized conditions (Table 2, en- bulky diol with two methyl groups on its aromatic ring,
tries 1–9). For example, substrates 1b and 1c, bearing gave 51% yield of the corresponding singularly tetrafura-
electron-withdrawing groups on their aromatic rings, re- nylated product (Table 2, entry 6). (2-Iodophenyl)metha-
acted successfully under the optimized conditions to give nol (1h), bearing an iodine atom at the 2-position of its
the corresponding products 4 and 5 in 75 and 78% yield, aromatic ring, afford 64% yield of the desired product
respectively (Table 2, entries 1 and 2). Substrates 1d–f, (Table 2, entry 7). Substrate 1i, containing two bulky phe-
containing electron-donating groups, were also compati- nyl groups, also provided 53% yield of the desired product
ble with the optimized conditions. For example, substrates under the optimized conditions (Table 2, entry 8). The al-
1d and 1e, bearing a methyl and a methoxy group on their lylic substrate 1j also successfully underwent the tetrahy-
aromatic rings, respectively, gave the desired products in drofuranylation process to give 57% yield of the desired
79 and 82% yield (Table 2, entries 3 and 4). Substrate 1f, product 12 (Table 2, entry 9). Interestingly, two heterocy-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 737–740

740
M.-K. Wang et al.
LETTER
Province Fund (Nos. 201120337), and Wenzhou University for
their financial support.
clic alcohols, 1k and 1l, were suitable substrates for the re-
action, and gave the target products in 53 and 22% yield,
respectively, following an extended reaction time (Table
2, entries 10 and 11). It is noteworthy that dione com-
pound 1,3-diphenyl-1,3-dione (1m) also smoothly under-
went the reaction to give 62% yield of the desired product
(Table 2, entry 12). Treatment of an aliphatic alcohol with
tetrahydrofuran under the optimized conditions afforded
the corresponding coupling product in 31% yield (Table
2, entry 13). Substrate 1o, bearing an alkyne group, was
also suitable, providing the desired product in 67% yield
(Table 2, entry 14). Pleasingly, p-methylphenol (1p) also
reacted smoothly under the optimized conditions (Table 2,
entry 15).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Chemistry; Wiley: New York, 1999, Chap. 2, 57–58.
(2) For recent tetrahydropyranylations, see: (a) Miyashita, M.;
Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977, 42, 3772.
(b) Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. Synthesis
1979, 618. (c) Morizawa, Y.; Mori, I.; Hiyama, T.; Nozaki,
H. Synthesis 1981, 899. (d) Olah, G. A.; Husain, A.; Singh,
B. P. Synthesis 1985, 703. (e) Bolitt, V.; Mioskowski, C.;
Shin, D. S.; Falck, J. R. Tetrahedron Lett. 1988, 29, 4583.
(f) Ranu, B. C.; Saha, M. J. Org. Chem. 1994, 59, 8269.
(g) Bhalerao, U. T.; Davis, K. J.; Rao, B. V. Synth. Commun.
1996, 26, 3081. (h) Habibi, M. H.; Tangestaninejad, S.;
Mohammadpoor-Baltork, I.; Mirkhani, V.; Yadollahi, B.
Tetrahedron Lett. 2001, 42, 2851. (i) Stephens, J. R.; Butler,
P. L.; Clow, C. H.; Oswald, M. C.; Smith, R. C.; Mohan, R.
Eur. J. Org. Chem. 2003, 3827.
A variety of substrates 2 were also investigated in the
presence of 1a. 2,3-Dihydrofuran (2b) and tetrahydro-2H-
pyran (2c) successfully reacted with 1a, albeit in slightly
lower yields than 2a (Table 2, entries 16 and 17). Unfor-
tunately, the reaction of substrate 2d under the optimized
conditions failed to afford any of the desired product (Ta-
ble 2, entry 18).
(3) For recent tetrahydrofuranylations, see: (a) Kruse, C. G.;
Broekhof, N. L. J. M.; van der Gen, A. Tetrahedron Lett.
1976, 1725. (b) Kruse, C. G.; Poels, E. K.; Jonkers, F. L.;
van der Gen, A. J. Org. Chem. 1978, 43, 3548. (c) Yu, B.;
Hui, Y. Synth. Commun. 1995, 25, 2037. (d) Hon, Y. S.; Lee,
C. F. Tetrahedron Lett. 1999, 40, 2389. (e) Barks, J. M.;
Gilbert, B. C.; Parsons, A. F.; Upeandran, B. Tetrahedron
Lett. 2000, 41, 6249. (f) French, A. N.; Cole, J.; Wirth, T.
Synlett 2004, 2291.
O
OR
HBr
O2
CuBr
CuBr2
R-OH
(4) Maione, A. M.; Romeo, A. Synthesis 1987, 250.
(5) Van Boom, J. H.; Herschied, J. D. M.; Reese, C. B. Synthesis
1973, 169.
O
O
O2
O
Br
(6) Baati, R.; Valleix, A.; Mioskowski, C.; Barma, D. K.; Falk,
J. R. Org. Lett. 2000, 2, 485.
A
B
C
(7) Masahito, O.; Takuya, S. Tetrahedron Lett. 2004, 45, 3557.
(8) Jung, J. C.; Choi, H. C.; Kim, Y. H. Tetrahedron Lett. 1993,
34, 3581.
Scheme 2 Proposed mechanism
(9) Falck, J. R.; Li, D. R.; Bejot, R.; Mioskowski, C.
Tetrahedron Lett. 2006, 47, 5111.
(10) Williams, D. B. G.; Simelane, S. B.; Lawton, M.; Kinfe, H.
H. Tetrahedron 2010, 66, 4573.
(11) Troisi, L.; Granito, C.; Ronzini, L.; Rosato, F.; Videtta, V.
Tetrahedron Lett. 2010, 51, 5980.
(12) Typical Procedure: To a Schlenk tube were added
phenylmethanol 1 (0.3 mmol), CuCl2 (10 mol%), and THF
(2 mL). The tube was stirred at 100 °C (oil bath temperature)
under an air atmosphere for the indicated time until complete
consumption of starting material was monitored by TLC and
GC-MS analyses. When the reaction was finished, the
mixture was cooled to room temperature, diluted in diethyl
ether, and washed with brine. The aqueous phase was re-
extracted with diethyl ether and the combined organic
extracts were dried over Na2SO4 and concentrated in
vacuum, and the resulting residue was purified by silica gel
column chromatography (hexane–EtOAc) to afford the
target product 3.
Based on our current results and on information reported
in the literature,6,9,10 we have proposed a mechanism for
the current transformation, as outlined in Scheme 2. Ini-
tially, oxygen abstracts a hydrogen atom from the methy-
lene group of the tetrahydrofuran adjacent to the oxygen
atom to generate intermediate B. Intermediate B would
then become brominated by CuBr2 to generate C. Finally,
intermediate C would condense with the alcohol to give
the target product.
In summary, we have developed a CuBr2-promoted tetra-
hydrofuranylation for the protection of hydroxyl groups.12
It is noteworthy that the protocol can be used not only for
the protection of alcohols and phenols, but also for the
protection of 1,3-diones under mild conditions. Further
studies aimed at expanding the scope of this reaction are
underway in our laboratory.
2-(Benzyloxy)tetrahydrofuran (3): Colorless liquid. 1H
NMR (300 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H), 5.25–5.23
(m, 1 H), 4.73 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 12.0 Hz,
1 H), 4.01–3.88 (m, 2 H), 2.10–1.84 (m, 4 H). 13C NMR
(125 MHz, CDCl3): δ = 138.4, 128.4, 127.85 (s), 127.5,
103.1, 68.8, 67.0, 32.4, 23.5. MS (EI, 70 eV): m/z (%) = 178
(2) [M]+, 91 (100), 71 (48), 108 (28), 92 (25).
Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
21102104, 21002070), the Department of Education of the Zhejiang
Synlett 2013, 24, 737–740
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