Hg(OTf)2-catalyzed arylene cyclization

Article abstract of DOI:10.1021/ol800450x

Novel Hg(OTf)₂-catalyzed arylene cyclization was achieved with highly efficient catalytic turnover (up to 200 times). The reaction takes place via protonation of allylic hydroxyl group by in situ formed TfOH of an organomercurlc intermediate to

Full text of DOI:10.1021/ol800450x

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1767-1770
Hg(OTf)2-Catalyzed Arylene Cyclization
Kosuke Namba, Hirofumi Yamamoto, Ikuo Sasaki, Kumiko Mori, Hiroshi Imagawa,
and Mugio Nishizawa*
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan
mugi@ph.bunri-u.ac.jp
Received February 28, 2008
ABSTRACT
Novel Hg(OTf)2-catalyzed arylene cyclization was achieved with highly efficient catalytic turnover (up to 200 times). The reaction takes place
via protonation of allylic hydroxyl group by in situ formed TfOH of an organomercuric intermediate to generate a cationic species. Subsequent
smooth demercuration regenerates the catalyst.
Transition metal-catalyzed arylyne cycloisomerizations have
been intensively studied and play an important role in modern
organic synthesis.1,2 In sharp contrast, catalytic arylene
cycloisomerization is almost unknown. We reported that
Hg(OTf)2-tristetramethylurea (TMU) complex catalyzes the
efficient cycloisomerization of arylalkyne 1 to give dihy-
dronaphthalene derivative 2 with a catalytic turnover up to
1000 times.3 The reaction involves protonation of the alkenyl
mercury intermediate 3 with in situ formed TfOH to generate
cation 4. Subsequent smooth demercuration leads to 2 and
the regenerated catalyst.4,5 Hg(OTf)2 was originally devel-
oped in 1983 as an efficient olefin cyclization agent,6 and
the reaction of farnesyl sulfone 5 with 1.2 equiv of
(1) (a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403. (b) Furstner,
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10.1021/ol800450x CCC: $40.75
Published on Web 04/09/2008
2008 American Chemical Society

Hg(OTf)2•PhNMe2 afforded bicyclic product 6 in 74%
yield.6a Because the latter reaction produces stable organo-
mercuric product 6, it is essentially a stoichiometric reaction.7
To achieve catalytic arylene cyclization, we tried to introduce
an oxygen-based functional group into the allylic position
for the protonation site, thereby triggering smooth demer-
curation. We found that the reaction of the (E)-6-(3,5-
dimethoxyphenyl)-2-hexen-1-ol (7) with 0.5 mol % of
Hg(OTf)2 in toluene at reflux temperature for 5 min was
sufficient to afford cyclization product 8 in 96% yield. The
alkenyl functional group maintained in the product 8 should
be useful for further molecular modification such as hy-
droboration, ozonolysis, and metathesis. Friedel-Crafts type
aryl allyl alcohol cyclization was reported using triflic acid
as solvent.8 Although related Pd-catalyzed aryl halide allyl
acetate cyclization9 and InCl3-catalyzed aryl allyl bromide
cyclization10 have been recorded, catalytic turnovers are not
very high. Recently Pt-catalyzed arylene cyclization was
reported by Widenhoefer and co-workers.11
Table 1. Catalytic Cyclization of 7
yield (%)a
catalyst
(mol %)
time
solvent temperature (h)
entry
8
7
1
2
3
4
5
6
7
8
9
Hg(OTf)2 (1)
Hg(OTf)2 (1)
Hg(OTf)2 (1)
Hg(OTf)2 (1)
Hg(OTf)2 (1)
Hg(OTf)2 (1)
Hg(OTf)2 (1)
CH3CN
CH3CN
rt
24
24
-
95
reflux
reflux
reflux
reflux
reflux
rt
reflux
reflux
reflux
reflux
43
1.5 82
17
-
CH3NO2
CH2Cl2
(CH2Cl)2
C6H5CH3
C6H5CH3
24
30
0.5 82
0.08 84
38
-
-
24
-
74
-
Hg(OTf)2 (0.5) C6H5CH3
Hg(OTf)2 (0.1) C6H5CH3
0.08 96
24
24
-
-
90
98
12
10 Hg(OTFA)2 (1) C6H5CH3
11 TfOH (0.5)
C6H5CH3
0.08 60
a Isolated yield.
afforded 8 in 96% yield when 0.5 mol % of Hg(OTf)2 was
used under reflux conditions for 5 min (entry 8). Reaction
using 1 mol % catalyst gave 84% yield, probably due to
partial decomposition of the product (entry 6). When the
reaction in toluene was performed at room temperature no
products were formed (entry 7). The yield using 0.1 mol %
catalyst was too low to justify further investigation (entry
9). Reactions with Hg(OTFA)2 as well as triflic acid were
also examined under the same conditions. Although 1 mol
% of Hg(OTFA)2 was entirely inert for the reaction (entry
10), 0.5 mol % of TfOH also afforded 8 in 60% yield (entry
11), indicating that the Hg(OTf)2 is the real catalytic species
of our reaction (Scheme 1).
Scheme 1. Hg(OTf)2-Induced and Catalyzed Cyclizations
We propose that the reaction is likely to be initiated from
a π-complex 9.4,5 Friedel-Crafts type cyclization leads to
carbocation 10, and the organomercuric intermediate 11 is
produced by deprotonation. Protonation of the hydroxyl
moiety of 11 by in situ generated TfOH leads to oxonium
cation 12. Demercuration regenerates the catalyst Hg(OTf)2
and affords the product 8 (Scheme 2).
Scheme 2. Possible Reaction Mechanism
Initially, we examined the reaction of 7 with 1 mol % of
Hg(OTf)2 in acetonitrile at room temperature. However, no
reaction products could be detected (Table 1, entry 1). When
the mixture was heated to reflux, a slow reaction took place
and afforded desired product 8 in 43% yield along with 17%
of starting material after 24 h (entry 2). Among the solvents
investigated, toluene was found to be the best. Toluene
(5) (a) Menard, D.; Vidal, A.; Barthomeuf, C.; Lebreton, J.; Gosselin,
P. Synlett 2006, 57–60. (b) Sim, S. H.; Lee, S. I.; Seo, J.; Chung, Y. K. J.
Org. Chem. 2007, 72, 9818–9821.
(6) (a) Nishizawa, M.; Takenaka, H.; Nishide, H.; Hayashi, Y. Tetra-
hedron Lett. 1983, 24, 2581–2584. (b) Nishizawa, M.; Morikuni, A.; Asoh,
K.; Kan, Y.; Uenoyama, K.; Imagawa, H. Synlett 1995, 169–170. (c)
Nishizawa, M. Studies in Natural Product Chemistry. StereoselectiVe
Synthesis, Part A. Rahman, A. U., Ed.; Elsevier: Amsterdam, 1988; Vol.
1, pp 655-676. (d) Nishizawa, M. J. Syn. Org. Chem. Jpn. 1999, 57, 677–
688. (e) Nishizawa, M.; Imagawa, H. J. Syn. Org. Chem. Jpn. 2006, 64,
744–751.
We subsequently examined the reaction of Z-allyl alcohol
13 with 0.5 mol % of Hg(OTf)2 in toluene. The same
cyclization product 8 was obtained in 95% yield after reflux
for 10 min (Table 2). Thus, the geometry of the double bond
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Org. Lett., Vol. 10, No. 9, 2008

Table 2. Hg(OTf)2-Catalyzed Arylene Cyclization
Table 3. Hg(OTf)2-Catalyzed Arylene Cyclization
a Isolated yield.
Hg(OTf)2 in toluene at reflux for 10 min afforded p-
cyclization product 17 in 71% yield12 along with o-
cyclization product 18 in 23% yield. Although o-methoxy
substituted hexenol derivative 19 afforded cyclization product
20 in very low yield (30%) along with unidentified complex
products, p-substituted 21 gave 22 in 90% yield. Nonacti-
vated phenyl-substituted 23 could also be used giving rise
to 24 in 65% yield after reflux for 5 min.13 Reaction of
biphenyl derivative 25 with 1 mol % of Hg(OTf)2 produced
alkenyl substituted dihydrophenanthrene derivatives 26 and
27 in 67 and 25% yield, respectively. Reaction of indole
derivative 28 with 1 mol % of Hg(OTf)2 generated tricyclic
indole 29 in 90% yield. Reaction of alternative allylic alcohol
(7) (a) Nishizawa, M.; Takenaka, H.; Hirotsu, K.; Higuchi, T.; Hayashi,
Y. J. Am. Chem. Soc. 1984, 106, 4290–4291. (b) Nishizawa, M.; Takenaka,
H.; Hayashi, Y. J. Am. Chem. Soc. 1985, 107, 522–523. (c) Nishizawa,
M.; Takenaka, H.; Hayashi, Y. J. Org. Chem. 1986, 51, 806–813. (d)
Nishizawa, M.; Yamada, H.; Hayashi, Y. J. Org. Chem. 1987, 52, 4878–
4884. (e) Nishizawa, M.; Morikuni, E.; Takeji, M.; Asoh, K.; Hyodo, I.;
Imagawa, H.; Yamada, H. Synlett 1996, 927–928. (f) Nishizawa, M.;
Iyenaga, T.; Kurisaki, T.; Yamamoto, H.; Sharfuddin, M.; Namba, K.;
Imagawa, H.; Shizuri, Y.; Matsuo, Y. Tetrahedron Lett. 2007, 48, 4229–
4233.
a Isolated yield. b NMR yield using CH2Br2 as the internal standard.
(8) Ma, S.; Zhang, J. Tetrahedron 2003, 59, 6273–6283.
(9) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. H. Chem.-Eur. J. 2007,
13, 5197–5206.
does not contribute to the reactivity. Reaction of allylic
acetate 14 afforded 8 in 63% yield after 1 h reflux in toluene,
which is slower than the reaction with alcohol 7 or 13. The
corresponding methoxy derivative 15 also afforded 8 in 76%
yield after 1 h reflux in toluene. Reaction of (E)-6-(3-
methoxyphenyl)-2-hexen-1-ol (16) with 1 mol % of
(10) Cook, G. R.; Hayashi, R. Org. Lett. 2006, 8, 1045–1048.
(11) Liu, C.; Bender, C. F.; Han, X.; Widenfoefer, R. A. Chem. Commun.
2007, 3607–3618.
(12) Tietze, L. F.; Schimpf, R. Angew. Chem., Int. Ed. Engl. 1994, 33,
1089–1091.
(13) Hocke, H.; Uozumi, Y. Tetrahedron 2004, 60, 9297–9306.
Org. Lett., Vol. 10, No. 9, 2008
1769

30 also provided 31 in 99% yield by the reaction with 1
mol % of Hg(OTf)2 in toluene at reflux temperature for 10 h.
The methoxy group of vinyl methyl ether also could act
as a protonation site. Thus, compound 32 (E/Z 6:4 mixture)
was treated with 1 mol % of Hg(OTf)2 in toluene. The
reaction was completed within 5 min at room temperature,
giving rise to dihydronaphthalene 33 in 67% yield along with
dimeric product 34 in 24% yield (Table 3).3 p-Substituted
35, however, did not afford any cyclization product at room
temperature but afforded hydrolyzed aldehyde at elevated
temperature. Reaction of a biphenyl derivative 37 with 1 mol
% of Hg(OTf)2 in toluene at room temperature for 10 min
afforded phenanthrene derivative 38 in 84% yield along with
9% of 39.2j Indole derivative 40 was converted to tricyclic
product 41 in 67% yield along with dimeric byproducts by
the reaction in toluene at room temperature for 5 min.
In conclusion, we achieved novel Hg(OTf)2-catalyzed
arylene cyclization by introducing a protonation site at the
appropriate position to obtain high catalytic turnover. The
results described in this paper should enable the creation of
new quaternary carbon centers and facilitate the development
of catalytic asymmetric cyclization which have been very
difficult to accomplish the cyclization initiated from alkyne.14
Acknowledgment. This study was financially supported
by a Grant-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology of the Japanese Govern-
ment, and a MEXT.HAITEKU, 2003-2007.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800450X
(14) Although a variety of chiral auxiliaries were examined for the
Hg(OTf)2-catalyzed enyne cyclization, no trace of chiral induction was
detected.
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Org. Lett., Vol. 10, No. 9, 2008