Nucleophile-assisted Pt-catalyzed cyclization of enynones: an access to synthesis of highly substituted furans

Article abstract of DOI:10.1016/j.tetlet.2006.05.119

A new and efficient Pt-catalyzed hydroxy- or alkoxy cyclization of 2-(1-alkynyl)-2-alkene-1-ones offers a general synthetic pathway to a wide range of highly substituted furans in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.05.119

Tetrahedron Letters 47 (2006) 5307–5310
Nucleophile-assisted Pt-catalyzed cyclization of enynones:
an access to synthesis of highly substituted furans
Chang Ho Oh,* V. Raghava Reddy, Ahyun Kim and Chul Yun Rhim
Department of Chemistry, Hanyang University, Sungdong-Gu, Seoul 133-791, Republic of Korea
Received 22 April 2006; revised 18 May 2006; accepted 19 May 2006
Available online 12 June 2006
Abstract—A new and efficient Pt-catalyzed hydroxy- or alkoxy cyclization of 2-(1-alkynyl)-2-alkene-1-ones offers a general synthetic
pathway to a wide range of highly substituted furans in good to excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Substituted furan derivatives are important synthetic
intermediates1 and are found as structural units in many
natural products such as pheromones2 or polyether anti-
biotics.3 Because of their many applications in pharma-
ceutical fields, synthetic investigations to furan
derivatives have continuously attracted attentions to
many organic chemists.4 Among various strategies, cat-
alytic transformation by means of transition metal cata-
lysts such as essential palladium-catalyzed processes is
one of the modern approaches for the syntheses of
substituted furan derivatives from cyclization of alkyne-
or allene-containing substrates.5
phile-trapped cyclization reactions. Larock and his
coworkers reported a novel method of highly substi-
tuted furans by AuCl3-catalyzed nucleophilic addition
followed by cyclization reaction, although it was limited
to specific substrate classes.9 To circumvent such sub-
strate limitation and enhance the scope of the reaction,
we have elected to investigate Pt(II) complexes for our
preliminary studies. Herein we wish to report that cer-
tain Pt complexes are highly effective catalysts for the
hydroxyl- or alkoxy cyclization of 2-(1-alkynyl)-2-
alkene-1-ones.
In our initial study, we examined the reaction of eny-
none 1a with several Pt catalysts in various reaction sol-
vents as summarized in Table 1. The use of Pt(0)
complexes like Pt(PPh3)4 and Pt(CH2@CH2)(PPh3)2
did not show the reactivity for this transformation (en-
tries 1–2). Gratifyingly, treatment of 1a with 5 mol %
of Pt(II) catalyst in MeOH solvent afforded the corre-
sponding methoxy-incorporated furan derivative 2aa
in high yields. Utilization of nonpolar solvents such as
toluene was to be unsuccessful for this transformation
(entry 6). More conveniently, however, the same proto-
col could be performed in the presence of a nucleophile
(MeOH, 2 equiv) in toluene resulting in formation of
2aa with only marginal yield erosion (entry 7). Under
these reaction conditions various alcoholic solvents such
as methanol, n-butanol, i-propanol, allyl alcohol, and
propargyl alcohol were incorporated well affording the
corresponding alkoxy substituted furan derivatives in
91, 74, 78, 67, and 76% yields, respectively (entries 8–
12).10 Additionally, this method could provide a variety
of amine derivatives by utilizing amine nucleophiles.
Thus, we applied this reaction with aniline to afford
Activating alkynes by coordination to electrophilic tran-
sition-metal complexes has a lead to the development of
a variety of catalytic cyclization reactions involving a
carbon–carbon or carbon–heteroatom bond formation.6
The potential of late-transition metal-based Lewis acid
has recently been witnessed for synthetic versatility
including total synthesis of natural products.7 Recently,
Echavarren and his coworkers extended the scope of this
reaction in detail for hydroxyl- or alkoxy cyclization of
enynes, which was particularly attractive because it
allowed the sequential formation of a C–C and a C–O
bond from enynes.8 Nevertheless, there is room for the
implementation of new partners in this process.
It is particularly important to find highly effective reac-
tivity profile of metal catalysts for these tandem nucleo-
Keywords: Platinum; Nucleophile; Cyclization; Furan.
*
Corresponding author. Tel.: +82 2 2220 0932; fax: +82 2 2299
0762; e-mail: changho@hanyang.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.119

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C. H. Oh et al. / Tetrahedron Letters 47 (2006) 5307–5310
Table 1. Pt-catalyzed cyclization of enynone 1a under various reaction conditions
Ph
Nu
O
O
Ph
[Pt] conditions
Solvent (Nu-)
(1)
1a
2
Pt catalysts (mol %)
Solvents (nucleophile)
Temperature (°C)/time (h)
Products
Isolated yielda (%)
1
2
3
4
5
6
7
8
Pt(PPh3)4 (5)
Pt(CH2@CH2)(PPh3)2 (5)
Pt(Phen)Cl2 (5)
Pt(MeCN)2Cl2 (5)
PtCl2(5)/AgSbF6 (10)
PtCl2 (5)
MeOH (A)
MeOH
MeOH
MeOH
MeOH
Toluene
Toluene/MeOH (2 equiv)
MeOH (A)
Reflux/14
Reflux/14
rt/10
rt/8
rt/3
40/24
40/8
40/8
—
—
2aa
2aa
2aa
—
2aa
2aa
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
No reaction
No reaction
73
68
74
No reaction
PtCl2 (5)
PtCl2 (5)
85
91
74
78
67
76
65
71
71
68
9
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)/AgSbF6 (10)
n-BuOH (B)
i-PrOH (C)
Allyl alcohol (D)
Propargyl alcohol (E)
Aniline (F)
Acetic acid (G)
Water/acetone (H)
1,3-Diphenyl acetone (I)
rt/5
rt/6
40/8
40/10
40/10
40/10
40/8
10
11
12a
13
14
15b
16c
Reflux/12
a Propargyl alcohol (2 equiv) was used as a nucleophile in toluene solvent.
b Water/acetone (v/v = 10:1).
c 1,3-Diphenylacetone (1.2 equiv) was used as a nucleophile in CH2Cl2 solvent.
Table 2. Pt-catalyzed tandem nucleophile assisted cyclization of
2-(alkylethynyl)-2-cyclohexenones in MeOH
the corresponding furan 2af in 65% yield. And the
acetate functionality could be readily incorporated to give
the resulting furan derivative 2ag in 71% yield. The use
of water as solvent has many advantages in organic
synthesis from both economical and environmental
points of view;11 thus the reaction in aqueous medium
of water/acetone (10:1) provided the alcoholic furan
derivative 2ah in 71% yield.
R1
O
O
R1
PtCl2 (5 mol%)
MeOH
(2)
OMe
1
2
Substrates (R1)
Temperature (°C)/ Products Isolated
Ph
Ph
time (h)
yield (%)
O
O
1
2
3
4
5
6
Cyclohexenyl 1b rt/7
2ba
2ca
2da
2ea
2fa
2ga
83
67a
30
82
78
72
TMS
1c 40/8
O
H
1d 40/10
1e 40/10
1f 40/10
1g 40/10
Ph
NHPh
n-Propyl
t-Butyl
NC(CH2)3
2af
2ai
Ph
a Yield of TMS-deprotected product 2 (R1 = H).
Furthermore, the beneficial effect of this new reaction
condition of 1a with carbon nucleophile should allow
for the simultaneous formation of C–C and C–O bond
from the corresponding enynone (entry 16). Thus, these
new conditions appeared to be far more efficient than
those previously used Au procedures. And in the pres-
ence of cationic Pt complexes (PtCl2 plus AgSbF6) we
were also pleased to observe that the enynone 1a gave
the corresponding products (entries 5 and 16).
deprotected furan derivative in 67% yield and the termi-
nal free alkyne was rather sluggish under the above reac-
tion conditions to give the corresponding furan
derivative in only 30% yield (entries 2 and 3). Despite
these draw backs, we were excited to observe the forma-
tion of furan derivatives in high yields when the internal
alkynes 1e, 1f, and 1g were subjected to these reaction
conditions (entries 4–6). However, in contrast with the
broad scope and excellent reproducibility of Pt(II)-cata-
lyzed cyclizations, AuCl3 failed in the cyclization of
these enynones such as 1e, 1f, and 1g probably because
of the hygroscopic nature of this metal chloride. Indeed,
Pd catalysts also failed to exhibit useful catalytic activity
presumably due to competing reduction of Pd(II) to
Pd(0).
The preliminary data prompted to us to investigate
different substituents with respect to the R1 at alkyne
terminus aimed at favoring tandem nucleophile-
assisted cyclized products as shown in Table 2.
At first, the cyclohexenyl group at alkyne terminus
reacted well under above reaction conditions and the
TMS substituent produced the corresponding TMS

C. H. Oh et al. / Tetrahedron Letters 47 (2006) 5307–5310
5309
Table 3. Pt-catalyzed tandem nucleophile assisted cyclization of various enynones in MeOH
Ph
O
O
Ph
PtCl2 (5 mol%)
MeOH
(3)
OMe
Entry
1
Enynones
Temperature (°C)/time (h)
Products
Isolated yield (%)
O
Ph
Ph
3
5
40/10
4a
85
73
O
2
40/5
6a
O
3
4
5
7
Reflux/24
40/10
—
No reaction
Ph
O
O
8
9a
72
78
Ph
Ph
10
40/10
11a
O
O
Ph
Ph
6
7
12
14
40/12
40/12
13a
15a
88
76
Ph
O
Me
Given the success of this new observation, we further
investigated the scope of this reaction with a wide range
of substrates as summarized in Table 3. Cyclic enynones
(3–8) were readily prepared from the known literature
procedures.12 Varying the steric demand on cyclohexene
ring did not diminish the efficiency of this present proto-
col (entries 1 and 2). Disappointingly, the reaction of
five-membered enynone 7 has failed to afford the
expected cyclized product even after a longer reaction
time. In contrast, the seven-membered enynone 8 re-
acted well under our catalytic condition to furnish the
furan 9a in 71% yield. A similar outcome was observed
in the cyclization trapping reaction of benzopyran de-
rived enynone 10. To our delight, subjection of acyclic
enynones such as 12 and 14 into these cyclization condi-
tions afforded to the corresponding products 13a and
15a in 88% and 76% yields, respectively.
tuents at alkyne terminus than related Au-catalyzed
cyclization.
In conclusion, a new approach to the synthesis of fused
bicyclic furan derivatives has been developed under
Pt(II)-catalysis. Extension to asymmetric variants13
and one pot arylative cyclizations14 of the present meth-
od is currently under active investigation.
Acknowledgements
This work was supported by research fund (HY-2004-i)
of Hanyang University, Korea. A.K. thanks BK21
(KRF) for the graduate scholarship of this research.
References and notes
These cyclization reactions proceeded in maximum
atom economics under neutral and relatively mild condi-
tions and were environmentally benign. These hydroxy-
or alkoxy cyclizations of enynones catalyzed by Pt(II)
were of particular interest, because these transforma-
tions allowed for the simultaneous formation of the
two C–O bonds from the enynones. Additionally, it
1. (a) Guindon, Y.; Therien, M.; Girard, Y.; Yoakim, G.
J. Org. Chem. 1982, 52, 1680; (b) Goldschmith, D. J.;
Kennadey, E.; Cambell, R. J. J. Org. Chem. 1975, 40,
3571; (c) Lisphutz, B. H. Chem. Rev. 1986, 86, 795.
2. (a) Mori, K. Tetrahedron 1989, 45, 3233; (b) Wright, D. L.
Chem. Innov. 2001, 31, 17; (c) Keay, B. A.; Dibble, P. W..
In Comprehensive Heterocyclic Chemistry II; Elsevier:
Oxford, 1997; Vol. 2, pp 395.
showed
a greater tolerance for alkylated substi-

5310
C. H. Oh et al. / Tetrahedron Letters 47 (2006) 5307–5310
´
3. Westley, J. W. Polyether Antibiotics: Naturally Occurring
Chem. Soc. 2003, 125, 5757; (d) Mendez, M.; Munoz, M.
˜
Acid Ionophores; Marcel Dekker: New York, 1982.
4. (a) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990,
55, 3450; (b) Marshall, J. A.; Wang, X. J. J. Org. Chem.
1992, 57, 3387; (c) Hashimi, A. S. K.; Ruppero, T. L.;
Knoefl, T.; Bats, J. W. J. Org. Chem. 1997, 62, 7295; (d)
Sperry, J. B.; Whitehead, C. R.; Ghiviriga, I.; Walczack,
R. M.; Wright, D. L. J. Org. Chem. 2004, 69, 3726; (e)
Hashimi, A. S. K.; Schwartz, K.; Choi, J. H.; Frost, T. M.
Angew. Chem. 2000, 112, 2382; Angew. Chem., Int. Ed.
2000, 39, 2285; (f) Hashimi, A. S. K.; Sinha, P. Adv. Synth.
Catal. 2004, 346, 432.
5. (a) Trost, B. M.; Macintosh, M. C. J. Am. Chem. Soc.
1995, 117, 7255; (b) Hou, X. L.; Cheng, H. Y.; Hon, T. Y.;
Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955; (c) Aso, M.; Ojida, A.; Yang,
G.; Cha, O.-J.; Osawa, E.; Kanematsu, K. J. Org. Chem.
1993, 58, 3960.
P.; Echavarren, A. M. J. Am. Chem. Soc. 2000, 122, 11549;
(e) Galland, J.-C.; Saviganc, M.; Geˆnet, J.-P. Tetrahedron
Lett. 1997, 38, 8695.
9. (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc.
2004, 126, 11164; (b) Yao, T.; Zhang, X.; Larock, R. C.
J. Org. Chem. 2005, 70, 7679; (c) Patil, N. T.; Wu, H.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 4531.
10. A typical procedure for the Pt-catalyzed cyclization of 2-
(phenylethynyl)-2-cyclohexenone 1a in MeOH is shown.
To a mixture of 2-(phenylethynyl)-2-cyclohexenone 1a
(0.4 mmol) and 5 mol % of PtCl2, MeOH (1.2 mL) was
added as both a nucleophile and a reaction medium. The
resulting suspension was stirred at ambient temperature
for 10 min. After heating for the time specified, the
reaction mixture was allowed to cool to room tempera-
ture. The excess solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography. All the product (2aa–15a) have been
´
6. (a) Mendez, M.; Echavarren, A. M. Eur. J. Org. Chem.
1
2002, 15; (b) Aubert, C.; Busine, O.; Malacria, M. Chem.
Rev. 2002, 102, 813; (c) McDonald, F. E. Chem. Eur. J.
1999, 5, 3103.
characterized by H, 13C NMR, IR and HRMS.
11. For the use of water in organic synthesis, see: (a) Grecio,
P. A. Organic Synthesis in Water; Blackie Academic &
Professional: London, 1998; (b) Li, C.-J.; Chen, T.-H.
Organic Reactions in Aqueous Media; Kluwer Academic:
Dordrecht, 1997; (c) Cornils, B.; Hermann, W. A. Aque-
ous-Phase Organometallic Catalysis, Concepts and Appli-
cations; Wiley-VCH: Weinheim, 1998.
7. For recent contributions, see: (a) Chatani, N.; Kataoka,
K.; Murai, S.; Furukawa, N.; Seki, Y. J. Am. Chem. Soc.
1998, 120, 9104; (b) Trost, B. M.; Doherty, G. A. J. Am.
´
Chem. Soc. 2000, 122, 3801; (c) Mendez, M.; Munoz, M.
˜
´
P.; Navado, C.; Cardenas, D. J.; Echavarren, A. M. J. Am.
Chem. Soc. 2001, 123, 10511; (d) Furstner, A.; Stelzer, F.;
Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863; (e) Lloyd-
Jones, G. C. Org. Biomol. Chem. 2003, 1, 215.
12. (a) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senana-
yake, C. B.; Wovkulich, P. M.; Uskokovic, M. R.
Tetrahedron Lett. 1992, 33, 917; (b) Miller, M. W.;
Johnson, C. R. J. Org. Chem. 1997, 62, 1582; (c) Yao,
T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
11164.
¨
8. (a) Navedo, C.; Charruault, L.; Michelet, V.; Nieto-
´
Oberhuber, C.; Munoz, M. P.; Mendez, M.; Rager, M.-N.;
˜
Geˆnet, J.-P.; Echavarren, A. M. Eur. J. Org. Chem. 2003,
´
706; (b) Nevado, C.; Cardenas, D. J.; Echavarren, A. M.
13. Charruault, L.; Michelet, V.; Taras, R.; Gladiali, S.;
Geˆnet, J.-P. Chem. Commun. 2004, 850.
Chem. Eur. J. 2003, 9, 2627; (c) Martin-Matute, B.;
´
Navedo, C.; Cardenas, D. K.; Echavarren, A. M. J. Am.
14. Denmark, S. E.; Wang, Z. Org. Lett. 2001, 3, 1073.