Hg(OAc)2·0.1Sc(OTf)3-catalyzed cycloisomerization of 2-(4-pentynyl)furan

Article abstract of DOI:10.1021/ol070335m

Figure presented Although the Hg(OTf)₂·3TMU-catalyzed Friedel-Crafts-type reaction of 3-(4-pentynyl)furan afforded the exo cyclization product, the reaction of 2-(4-pentynyl)furan furnished a very low yield. We found a 10:1 mixed reagent of Hg(

Full text of DOI:10.1021/ol070335m

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1399-1402
Hg(OAc)2‚0.1Sc(OTf)3-Catalyzed
Cycloisomerization of
2-(4-Pentynyl)furan
Hirofumi Yamamoto, Ikuo Sasaki, 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 9, 2007
ABSTRACT
Although the Hg(OTf)2‚3TMU-catalyzed Friedel−Crafts-type reaction of 3-(4-pentynyl)furan afforded the exo cyclization product, the reaction of
2-(4-pentynyl)furan furnished a very low yield. We found a 10:1 mixed reagent of Hg(OAc)2 and Sc(OTf)3 showed remarkable catalytic activity
for the latter transformation. The actual reacting species is presumed to be Hg(OAc)(OTf), which is efficiently generated in situ by mixing the
two reagents.
Transition-metal-catalyzed cycloisomerization of arylalkynes
has been intensively studied and has played an important
role in modern organic synthesis.1 Electron-rich arenes react
with alkynes in the presence of electrophilic metal halides
or Brønsted acids.2 We have also reported six-endo cyclo-
isomerization of arylalkynes to give dihydronaphthalene
derivatives.3 Intramolecular reaction of furan with alkynes,
however, mostly affords phenolic products via Diels-Alder
reaction followed by a fragmentation.4 Although an endo
mode Friedel-Crafts-type cyclization of furanoalkynes af-
fording benzofurans has been reported,5 exo mode cyclization
of alkynyl furans has not been recorded except for one
example using PtCl2 as catalyst, affording a benzofuran
derivative.4e Therefore, the Friedel-Crafts-type cycloisomer-
ization of alkynyl furans is an almost unknown area of
research, and thus we have investigated the cycloisomeriza-
tions of 3-(4-pentynyl)furan (1) and 2-(4-pentynyl)furan (3)
by using the reagent that we originated, mercuric triflate [Hg-
(OSO2CF3)2, hereafter Hg(OTf)2].6-13 The latter type of
cycloisomerization (3 to 4) is entirely unknown. The reaction
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Echavarren, A. M. Angew. Chem., Int. Ed. 2001, 40, 4754-4757. (e) Martin-
Matute, B.; Nevado, C.; Cardenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2003, 125, 5757-5766.
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hedron Lett. 1983, 24, 2581-2584. (b) Nishizawa, M.; Morikuni, E.; Asoh,
K.; Kan, Y.; Uenoyama, K.; Imagawa, H. Synlett 1995, 169-170. (c)
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Org. Lett. 2003, 5, 4563-4565.
10.1021/ol070335m CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/28/2007

of 3-(4-pentynyl)furan (1) and 1 mol % of mercuric triflate‚
3tetramethylurea (hereafter TMU) complex afforded exo
cyclization product 2 in 81% yield. However, the reaction
of 2-(4-pentynyl)furan (3) with a variety of modified Hg-
(OTf)2 reagents gave a very low yield of 4. We found that
a 10:1 mixed reagent of Hg(OAc)2 and Sc(OTf)3 showed
remarkable catalytic activity for the latter transformation
leading to 4. The actual reacting species is presumed to be
Hg(OAc)(OTf) efficiently generated in situ by mixing the
two reagents. First, we examined the reaction of 3-(4-
with Hg(OTf)2‚2TMU (1 mol %) afforded 2 in 50% yield
(NMR yield using naphthalene as the internal standard) along
with 20% of starting material; however, prolonged reaction
for 3 h resulted in decomposition to give 2 in only 7% yield
(entries 4 and 5). The best result was obtained by using Hg-
(OTf)2‚3TMU (1 mol %) in CH3CN at -20 °C for 20 min,
affording 2 in 81% yield (entry 6). However, prolonged
reaction for 3 h again decreased the yield significantly as
the result of some decomposition (entry 7). Neither 0.5 mol
% catalyst nor 0.1 mol % catalyst afforded good results
(entries 8 and 9). Reaction using AuCl3 (1 mol %) resulted
in complete decomposition of material (entry 10). In contrast,
the reaction with PtCl2 (1 mol %) at -25 °C for 1 h resulted
in recovery of starting material (entry 11). Thus, not only
the starting material 1 but also the product 2 were very
sensitive to even mildly acidic conditions.
Scheme 1
Next we examined the cycloisomerization of 2-(4-penty-
nyl)furan (3) by expecting a Friedel-Crafts type product
such as 4. As shown in Table 2, transformation of 3 to 4 is
pentynyl)furan (1) with 1 mol % of Hg(OTf)2 in CH3CN at
-20 °C for 3 h, and only a trace amount of 2 was detected
along with 25% of starting material and some polymeric
materials (Table 1, entry 1). This result suggested the
Table 2. Cycloisomerization of 3 in CH3CN for 20 min
yield (%)a
additive
(mol %)
temp
(°C)
entry
Hg salt (mol %)
4
3
1
2
3
4
5
6
7
8
Hg(OTf)2 (1)
0
0
25
0
8
40
55
18
b
Table 1. Cycloisomerization of 1 in CH3CN at -20 °C.
Hg(OTf)2‚3TMU (1)
Hg(OTf)2‚3TMU (1)
Hg(OTf)2‚3TMU (5)
Hg(OTf)2‚3TMU (5) AgSbF6 (0.5)
Hg(OTf)2 (5) Sc(OTf)3 (0.5)
Hg(OTf)2‚3TMU (5) Sc(OTf)3 (0.5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
17
36
30
38
yield (%)a
entry
catalyst
Hg(OTf)2
mol %
time
2
1
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
0.5
0.1
1
3 h
20 min
3 h
20 min
3 h
20 min
3 h
3 h
tr
5
tr
50
7
81
5
8
25
57
52
20
16
tr
Hg(OTf)2‚TMU
Hg(OTf)2‚TMU
Hg(OTf)2‚2TMU
Hg(OTf)2‚2TMU
Hg(OTf)2‚3TMU
Hg(OTf)2‚3TMU
Hg(OTf)2‚3TMU
Hg(OTf)2‚3TMU
AuCl3
4
61
90
86
60
60
37
AgSbF6 (0.5)
AgOTf (0.5)
9
10
11
12
13
14
15
16
17
18
19
La(OTf)3 (0.5)
Eu(OTf)3 (0.5)
Yb(OTf)3 (0.5)
Sc(OTf)3 (0.5)
Sc(OTf)3 (5)
19
26
39
80
3
36
78
9
10
11
3 h
5 min
1 h
10
b
90c
94
PtCl2
1
96b
Sc(OTf)3 (0.5)
TfOH (0.5)
TfOH (5)
Hg(OAc)2 (5)
Hg(OAc)2 (5)
PtCl2 (5)
66
a NMR yield using naphthalene as the internal standard. b Reactions in
acetone at -20 °C for 1 h afforded 2 in 2% yield along with 77% of 1.
b
d
a NMR yield using naphthalene as the internal standard. b Complex
mixture was formed. c Small amount of 5 was detected. d A 10:1 mixture
of phenol 6 and an unidentified product was obtained in 72% yield after
10 h at reflux in acetone.
existence of some catalyst suicide mechanism, probably by
the reaction of Hg(OTf)2 and the product 2. Reaction with
Hg(OTf)2‚TMU (1 mol %) for 20 min or 3 h also furnished
disappointing results (entries 2 and 3). A 20 min reaction
Nishizawa, M.; Imagawa, H. J. Syn. Org. Chem. Jpn. 2006, 64, 744-751.
(7) Nishizawa, M.; Skwarczynski, M.; Imagawa, H.; Sugihara, T. Chem.
Lett. 2002, 12-13.
(8) Nishizawa, M.; Yadav, V. K.; Skwarczynski, M.; Takao, H.;
Imagawa, H.; Sugihara, T. Org. Lett. 2003, 5, 1609-1611.
(9) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004, 6, 3679-
3681.
(10) (a) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Org. Lett. 2005, 7,
451. (b) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Synlett 2005, 703-705.
(11) Imagawa, H.; Asai, Y.; Takano, H.; Hamagaki, H.; Nishizawa, M.
Org. Lett. 2006, 8, 447-450.
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izawa, M. Tetrahedron Lett. 2006, 47, 4729-4731.
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Tetrahedron Lett. 2006, 47, 8369-8373.
very difficult even by using Hg(OTf)2‚3TMU complex. A
better result was obtained by the reaction of 3 with 1 mol %
catalyst in CH3CN at 25 °C for 20 min, but the yield was
still 36% (Table 2, entry 3). Thus, we decided to examine
other possibilities. Upon learning of the enyne cycloisomer-
ization catalyzed by a mixed reagent of Au complex and
AgSbF6,14 we tried the reaction of 3 with a 10:1 mixed
reagent of Hg(OTf)2‚3TMU and AgSbF6 in CH3CN at 25
1400
Org. Lett., Vol. 9, No. 7, 2007

°C for 20 min and obtained 4 in 38% yield (entry 5). Then
we screened a variety of combinations of mercuric salts and
additives in a 10:1 ratio. Because no promising results were
obtained by using Hg(OTf)2 or its TMU complex (entries 6
and 7), we switched to Hg(OAc)2. Then, we found the
combination of Hg(OAc)2 and La(OTf)3 (10:1) affords 4 in
19% yield along with 60% of starting material (entry 10). A
10:1 combination of Hg(OAc)2 with Eu(OTf)3 also afforded
4 in 26% yield, and with Yb(OTf)3 gave a 39% yield of 4
together with significant quantities of starting material 3
(entries 11 and 12). Finally we found that the combination
of Hg(OAc)2 and Sc(OTf)3 (10:1) gave rise to 4 in 80% yield
(entry 13). However, the reaction using a 1:1 mixture of Hg-
(OAc)2 and Sc(OTf)3 afforded 4 only in 3% yield along with
complex polymeric products (entry 14). The reaction with
only Hg(OAc)2 (5 mol %) did not afford 4 at all, and most
of the starting material was recovered along with trace
amounts of unstable byproduct that is dimeric mercury
acetylide 5 (entry 15). Acetylide formation is a catalyst
suicide mechanism. Reaction with 0.5 mol % of Sc(OTf)3
resulted in complete recovery of starting material (entry 16).
However, a 10:1 combination of Hg(OAc)2 and TfOH
afforded 4 in 66% yield (entry 17), and a 1:1 reagent did
not afford 4, instead producing complex mixtures (entry 18).
When the reaction of 3 with PtCl2 (5 mol %) in acetone was
examined at reflux for 10 h, Diels-Alder and following
fragmentation took place to give a 10:1 mixture of phenol 6
and an unidentified product in 72% yield.4e,15
Scheme 2
to 16 in 91% yield. The reaction of 2-methyl-5-(4-nonynyl)-
furan (17) with 5 mol % of Hg(OAc)2‚0.1Sc(OTf)3 in CH3-
CN required 60 °C and afforded endo cyclized seven-
membered ring product 18 in 75% yield after 17 h. Although
the reaction of 2-(4-nonynoyl)furan (19) afforded seven-
membered ring product 20 in low yield (44%) even after 24
h reaction at 60 °C, the phenyl-substituted analogues 21 and
23 afforded endo cyclization products 22 (90% yield) and
24 (93% yield), respectively. Reaction of 2-(3-butynyl)-5-
methyfuran (25) with Hg(OAc)2‚0.1Sc(OTf)3 at 25 °C for
The results suggested the actual reacting species to be Hg-
(OAc)(OTf) generated by the reaction of Hg(OAc)2 and small
amounts of Sc(OTf)3 or TfOH (entries 13 and 17). When
Hg(OAc)2 and an equal amount of either Sc(OTf)3 or TfOH
were mixed, decomposition took place because of the
partially formed Hg(OTf)2 (entries 14 and 18). However, we
failed to detect any occurrence of Hg(OAc)(OTf) or Hg-
(OTf)2 by NMR experiment, probably due to too low
concentration.
Table 3. Reaction of Alkynyfurans with 5 mol % of
Hg(OAc)2‚0.1Sc(OTf)3 in CH3CN.
Therefore, we propose that the reaction is likely to be
initiated from π-complex 7, cyclized oxonium cation 9 is
generated probably via the spirocyclic cation 8, and the cation
9 produces the vinylmercury intermediate 10 by deprotona-
tion. Then, the protonation of 10 by in situ generated TfOH
leads to alternative oxonium cation 11 and upon demercu-
ration regenerates the catalyst Hg(OAc)(OTf) and affords
the product 4. Probably Hg(OAc)(OTf) is inert against 4.
However, as shown in Table 2, Hg(OTf)2 also reacts with
the product 4, generating cation 12. Further reaction of 12
with 4 should lead to complex polymerization products.
Occurrence of an sp3-C-Hg bond formed by the deproto-
nation of polymeric products should be the alternative
catalyst suicide mechanism.The procedure was applied to
the reaction of 2-methyl-5-(4-pentynyl)furan (13). A reaction
with 5 mol % of Hg(OAc)2‚0.1Sc(OTf)3 in CH3CN at room
temperature for 20 min afforded exo cyclization product 14
in 75% yield (Table 3). Malonate derivative 15 was converted
(14) Reetz, M. T.; Mommer, K. Eur. J. Org. Chem. 2003, 3485-3496.
(15) Barum, O.; Nandi, S.; Panda, K.; Ila, H.; Junjappa, H. J. Org. Chem.
2002, 67, 5398-5401.
a Starting material was recovered in 88% yield.
Org. Lett., Vol. 9, No. 7, 2007
1401

tively. The results reflect the stability of 28 over 27, and the
rearrangement to 29 was the only possible path (Scheme 3).
Scheme 3
Thus, we have developed a new, mild catalytic system,
Hg(OAc)2‚0.1Sc(OTf)3, and achieved novel cycloisomeriza-
tion of very sensitive substrates such as 2-(4-pentynyl)furan
and analogues.
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.
24 h resulted in 88% recovery of starting material without
forming 26. Elevating the reaction temperature to 60 °C for
24 h led to decomposition. These results suggest that the
rearrangement mechanism is from spirocyclic intermediate
8 to 9, since the case of 25 has to generate a spirocyclic
four-membered ring intermediate. It must be pointed out that
internal alkynyl furans 17, 19, 21, and 23 selectively afforded
seven-membered ring products 18, 20, 22, and 24, respec-
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL070335M
1402
Org. Lett., Vol. 9, No. 7, 2007