Facile ring-closure cyclization of arenes by nucleophilic C-alkylation reaction in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2009.10.065

A novel synthetic method using an ionic liquid (IL) for a six-membered ring-closure cyclization is described. The ring-closure cyclization by nucleophilic C-alkylation was achieved with various halo- and alkanesulfonyloxyalkyl aromatic compounds in high yields with minimal byproducts using ILs as the reaction media in the absence of any catalyst. For example, the cyclization of 2-(3-methanesulfonyloxy-propoxy)naphthalene (1a) to 2,3-dihydro-1H-naphtho[2,1-b]pyran (2) in IL [bmim][PF₆] proceeded selectively at 150 °C for 24 h in 85% yield.

Full text of DOI:10.1016/j.tetlet.2009.10.065

Tetrahedron Letters 51 (2010) 54–56
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile ring-closure cyclization of arenes by nucleophilic C-alkylation reaction
in ionic liquid
a,
Dong Jin Hong a, Dong Wook Kim b, , Dae Yoon Chi
*
*
a Department of Chemistry, Sogang University, 1 Shinsudong Mapogu, Seoul 121-742, Republic of Korea
b Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk
561-712, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthetic method using an ionic liquid (IL) for a six-membered ring-closure cyclization is
described. The ring-closure cyclization by nucleophilic C-alkylation was achieved with various halo-
and alkanesulfonyloxyalkyl aromatic compounds in high yields with minimal byproducts using ILs as
the reaction media in the absence of any catalyst. For example, the cyclization of 2-(3-methanesulfonyl-
oxy-propoxy)naphthalene (1a) to 2,3-dihydro-1H-naphtho[2,1-b]pyran (2) in IL [bmim][PF6] proceeded
selectively at 150 °C for 24 h in 85% yield.
Received 19 August 2009
Revised 14 October 2009
Accepted 15 October 2009
Available online 20 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Compounds bearing the chromane moiety are widespread in
nature and have received much interest given their physiological
properties.1 As shown in Figure 1, ring-closure cyclizations by
C-alkylation of phenyl ethers (Path A)2 or O-alkylation of alkyl phe-
nols (Path B)3 are the typical synthetic strategies for the prepara-
tion of chromanes.4 Although O-alkylation is much more adept
than C-alkylation, this strategy is less attractive given the difficulty
in preparation of the alkyl phenol substrates.3 Thus, much atten-
tion has been focused on facile ring-closure cyclization via C–C
bond formation of phenyl ethers to chromanes on account of the
ease of preparation of the phenyl ether substrates.2 Ring-closure
cyclization by Friedel–Crafts approach is the most common meth-
od for these purposes. However, these reactions generally require
vigorous reaction conditions in the presence of a strong Lewis acid
catalyst.2,5
Over the past decade, room temperature ILs have been exten-
sively investigated as eco-friendly alternative reaction media to re-
place volatile organic solvents in various chemical processes on
account of their intrinsic physical and chemical properties.6 In par-
ticular, it has been reported that ILs containing imidazolium cat-
ions and their counteranions (Fig. 2) can act as powerful reaction
media in nucleophilic substitution-type reactions for acceleration
of the reaction rate, as well as for improvement of selectivity. Such
examples of nucleophilic substitutions include: Friedel–Crafts
reaction;7 fluorination with alkali metal salts;8 hydroxylation
using water;9 dealkylation of ethers to phenols;10 and C-alkylation
of pyrrole.11 Herein the successful use of ILs such as [bmim][X]12 as
a solvent for the significant rate enhancement of ring-closure cycli-
zations of halo- or alkanesulfonyloxyalkyl benzenes into cyclic
compounds via an intra C–C bond formation in the absence of
any kind of Lewis acid or other catalyst is reported.
As shown in Scheme 1, the intracyclization of 2-(3-bromoprop-
oxy)naphthalene (1d) in the IL [bmim][BF4] at 150 °C proceeded in
the absence of any kind of catalyst, affording 2,3-dihydro-1H-
naphtho[2,1-b]pyran (2) in 54% yield. However, a naphthol byprod-
uct 3 was formed in 29% yield because of the generation of HBr
from cleavage of the ether to phenol, due to dealkylation in the
IL9 during the cyclization reaction process. The HBr acts as an effec-
tive nucleophile and acid catalyst. To remove this in situ generated
HBr and maintain neutral or basic reaction conditions, NaHCO3 was
used as a scavenger to provide chromane product 2 in a yield (52%)
similar to the reaction in the absence of NaHCO3, along with 27% of
alcohol byproduct 4 on account of hydroxylation by the water gen-
erated from the reaction process. These results show that the IL
Figure 1. Two different synthetic paths to benzopyrans.
* Corresponding authors. Tel.: +82 63 250 2396; fax: +82 63 255 1172 (D.W.K.);
tel.: +82 2 705 8442; fax: +82 2 702 0967 (D.Y.C.).
E-mail addresses: kimdw@chonbuk.ac.kr (D.W. Kim), dychi@sogang.ac.kr (D.Y.
Chi).
Figure 2. Structure of ILs.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.065

D. J. Hong et al. / Tetrahedron Letters 51 (2010) 54–56
55
Table 1
Cyclization under various reaction conditionsa
Entry
IL or solvent
X
Time (h)
Yield of productb (%)
1
2
3
Scheme 1. Intramolecular cycloalkylation via C–C bond formation using IL
[bmim][BF4] as a solvent. Reagents and conditions: (a) [bmim][BF4], 150 °C, 12 h;
(b) [bmim][BF4], NaHCO3 as a HBr scavenger, 150 °C, 24 h.
1
2
3
4
[bmim][BF4]
[bmim][OTf]
[bmim][PF6]
[bmim][SbF6]
[bmim][NTf2]
DMF
1,4-Dioxane/ZnCl2
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OTs
I
48
24
24
36
36
48
24
24
20
48
48
48
Trace
Trace
Trace
—
Trace
90
Trace
—
—
75
71
85
59
75
—
27
71
79
75
Trace
—
—
—
—
—
5
—
6
—
media system could allow intracyclization by nucleophilic C-alkyl-
ation to proceed in the absence of any kind of catalyst.
7c
8
56d
—
Table 1 concerns the cyclization reactions of various halo- and
alkanesulfonyloxypropoxynaphthalenes to chromane product 2
under various reaction conditions. As entries 1–5 demonstrate, in
order to determine the optimal IL, cyclization of model compound
2-(3-methanesulfonyloxypropoxy)naphthalene (1a), of which
mesylate is a good leaving group but not become a nucleophile
caused the dealkylation as a side reaction, was carried out in vari-
ous imidazolium-based ILs, such as [bmim][X] (X = BF4, OTf, PF6,
SbF6, and NTf2). Among the various ILs, [bmim][PF6] showed the
best performance (entry 3). In particular, a comparison of entries
3 and 6 showed that [bmim][PF6] enhanced the reaction rate sig-
nificantly compared with organic solvents. Where the cyclization
of mesylate 1a in organic solvents such as DMF at 150 °C (in a pres-
sure vial) hardly occurred, even after 48 h (entry 6), the same reac-
tion in [bmim][PF6] was complete within 24 h, affording cyclic-
product 2 in 85% yield (entry 3). Entry 7 shows that a Friedel–
Crafts-type alkylation using ZnCl2 as a Lewis acid catalyst for the
cyclization, which afforded the desired product 2 in only 27% yield
together with chlorocompound 1e as a byproduct, was inefficient
compared to the nucleophilic C-alkylation using the IL. The desired
cyclic-product 2 was also produced in good yield by the cyclization
of tosylate 1b with [bmim][PF6] (entry 8). Next, the cyclization of
9
Trace
Trace
—
10
11
12
Br
Cl
F
—
99
100
—
a
All reactions were carried out on a 1.0 mmol reaction scale of starting material
using 3.0 mL of IL at 150 °C.
b
Isolated yield.
c
3.0 equiv of ZnCl2 as a Lewis acid was used in 1,4-dioxane (4.5 mL) at reflux
condition.
d
2-(3-Chloropropoxy)naphthalene (1e) was formed in 56% yield as a byproduct.
fluoro-, chloro-, bromo-, and iodo-substrate in the optimal IL
[bmim][PF6] was carried out. Interestingly, nucleophilic cyclization
of iodo- and bromo-substrates (1c and 1d) using [bmim][PF6] pro-
ceeded selectively to afford cyclic-product 2 in high yield (79% and
75%, entries 9 and 10, respectively), almost without any ether
cleavage side reaction to naphthol 3; compare this with the same
reaction using [bmim][BF4] in Scheme 1. However, chloro- and
fluoro-substrates (1e and 1f) were hardly converted to the desired
cyclic-product under the same reaction conditions, even after 48 h
(entries 11 and 12). The halide reaction order is the obvious one
expected; the reaction rates follow the order: I > Br ꢀ Cl > F.
Table 2
Cyclization of Various Substrates in [bmim][PF6]a
Entry
1
Compound
Time (h)
18
Yieldb (%)
70
Product
2
3
4
7 days
48
71
9
7-Methoxychromane (50%)
5-Methoxychromane (15%)
48
65
5
6
48
48
—
—
No reaction
No reaction
a
Unless otherwise noted, all reactions were carried out under the same condition as entry 3 in Table 1.
Isolated yield.
b

56
D. J. Hong et al. / Tetrahedron Letters 51 (2010) 54–56
Table 2 illustrates further characteristics of this ring-closure
References and notes
cyclization reaction with various substrates in [bmim][PF6], in
the absence of any kind of catalyst and under the reaction condi-
tions described previously (Table 1, entry 3). The cyclization of a
secondary iodoalkane (entry 1) proceeded smoothly within 18 h,
affording the corresponding chromane in 70% yield, with 1,2,3,4-
tetrahydrophenanthrene produced in high yield by cyclization of
2-(4-mesyloxybutyl)naphthalene (entry 2). However, thiochro-
mane was obtained in poor yield (9%) with the corresponding sul-
fane under the same reaction conditions. A comparison of entries 4
and 5 shows that cyclization of the methoxybenzene substrate
containing the electron-donating group proceeded smoothly, pro-
viding methoxychromane in 65% yield, whereas the same reaction
of the bromobenzene substrate containing electron-withdrawing
groups did not proceed at all. The dihydrobenzofuran compound
also could not be obtained through a five-membered ring-closure
cyclization by nucleophilic C-alkylation.
In summary, a novel method for the ring-closure cyclization of
select primary and secondary halo- and alkanesulfonyloxyalkyl
aromatic systems to the corresponding cyclic compounds in ILs
such as [bmim][PF6] has been described. The ILs act as an impor-
tant driving force and reaction medium in the intramolecular
cycloalkylation via C–C bond formation without any kind of cata-
lyst. Further studies on more efficient green protocols (shorter
reaction times, lower reaction temperatures) for these cyclizations
using ILs, as well as polymer-supported ionic liquids (PSIL),13 are in
progress in our laboratories.
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Acknowledgments
This work was supported by research funds of Chonbuk Na-
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grant funded by the Korean government (MEST) (Grant code:
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gram through the National Research Foundation of Korea (NRF)
funded by MEST (Grant code: 2009-0081956).
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Supplementary data
Supplementary data (experimental section, characterization,
and 1H and 13C NMR spectra of all compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.10.065.