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Gold(III)- and Platinum(II)-Catalyzed Domino Reaction Consisting of Heterocyclization and 1 2-Migration Efficient Synthesis of Highly Substituted 3(2H)-Furanones.

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Communications
Scheme 1. Projected synthesis of 3(2H)-furanones 2 by a catalyzed
domino reaction consisting of heterocyclization and a-ketol rearrangement.
Cyclization
DOI: 10.1002/anie.200601836
Gold(III)- and Platinum(II)-Catalyzed Domino
Reaction Consisting of Heterocyclization and
1,2-Migration: Efficient Synthesis of Highly
Substituted 3(2H)-Furanones**
Stefan F. Kirsch,* Jrg T. Binder, Clmence Libert, and
Helge Menz
Transition-metal-catalyzed rearrangements of unsaturated
frameworks provide rapid access to complex structures.
Owing to their exceptional ability to activate alkynes
toward nucleophilic attack, gold[1, 2] and platinum[3] complexes
have found increased use as catalysts.[4] In the context of our
ongoing efforts to develop cascade reactions initiated by
transition-metal-catalyzed p-activation,[5] we now report a
novel approach to 3(2H)-furanones by a catalyzed heterocyclization/1,2-migration cascade.
Recently, a AuCl3-catalyzed cyclization of 2-(1-alkynyl)-2alken-1-ones was reported leading to substituted furans.[6, 7]
This reaction is believed to proceed via oxonium ions. Based
on this, we envisaged that alkynyl carbonyl compound 1
bearing a hydroxy group at the propargylic position might
undergo a previously unknown transformation (Scheme 1).
The intermediate oxonium ion is expected to trigger an
irreversible 1,2-shift analoguous to a formal a-ketol rearrangement.[8] In contrast to the related pinacol rearrangements,[9] oxonium ion rearrangements have not been used to
terminate cationic cyclizations. The overall sequence provides
an efficient and flexible access to 3(2H)-furanones 2, which
[*] Dr. S. F. Kirsch, J. T. Binder, C. Li?bert, H. Menz
Department Chemie
Technische UniversitAt MBnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (+ 49) 89-2891-3315
E-mail: stefan.kirsch@ch.tum.de
[**] This project was supported by the Deutsche Forschungsgemeinschaft (DFG) and the Fonds der Chemischen Industrie. We thank
Andrea Rothballer and Markus Scheerer for excellent technical
assistance.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5878
are structural elements in many natural products[10] and
pharmaceutically active substances.[11] Moreover, the reaction
represents a significant departure from the conventional
strategy for constructing 3(2H)-furanones, as bond formations between C5 and O1 typically are used in a cyclization
step, and the hydroxy function at C2 is usually installed at an
earlier stage.[12]
To probe the feasibility of this concept, we initially
focused on the conversion of the alkynyl carbonyl compound
1 a into the spirocyclic compound 2 a (Table 1). Whereas the
use of cationic gold(I) and silver(I) complexes was accomTable 1: Efficiency of transition-metal catalysts for the conversion of 1 a
into 2 a.[a]
Entry
Cat.
Conditions
Yield [%]
1 a[b,c]
2 a[b]
1
2
3
4
5
6[d]
7
8
AuCl3
AuCl3
(Ph3P)AuBF4
AgSbF6
Pd(OAc)2
CuI
PtCl2
PtCl2
23 8C, CH2Cl2, 90 min
38 8C, CH2Cl2, 90 min
23 8C, CH2Cl2, 90 min
23 8C, CH2Cl2, 90 min
23 8C, CH2Cl2, 90 min
80 8C, DMF, 120 min
23 8C, CH2Cl2, 240 min
80 8C, toluene, 90 min
83
95
0
50
0
22
15
93
0
0
10
12
98
67
81
0
[a] Conditions: 1 a (0.03 m), 5 mol % catalyst, solvent. [b] Yield of pure
product after column chromatography. [c] Recovered starting material
1 a. [d] 10 mol % CuI, 0.08 m.
panied by a significant amount of decomposition, treatment
of the starting alkyne 1 a with PtCl2 or AuCl3 resulted in the
clean formation of 3(2H)-furanone 2 a. Depending on the
reaction temperature, AuCl3 provided the desired compound
2 a after 90 min in CH2Cl2 in yields of 83 % or 95 % (Table 1,
entries 1 and 2). In the presence of catalytic amounts of PtCl2,
isomerization was observed at an impractical rate at 23 8C in
CH2Cl2. Nevertheless, increasing the reaction temperature to
80 8C (in toluene) led to the anticipated increase in reaction
rate (Table 1, entry 8).
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 5878 –5880
Angewandte
Chemie
The scope of this transition-metal-catalyzed domino
approach to substituted 3(2H)-furanones is summarized in
Table 2. When AuCl3 was used as the catalyst, spirocyclic
Table 3: Transition-metal-catalyzed synthesis of 3(2H)-furanones 2 l–o
by cycloisomerization of 1 l–o.[a]
Table 2: Transition-metal-catalyzed synthesis of 3(2H)-furanones 2 b–k
by cycloisomerization of 1 b–k.[a]
1
1l
2l
85[c] (4 h)
2
1m
2m
50 (24 h)
3
1n
2n
51 (48 h)
4
1o
2o
56 (18 h)
Substr.
R3
Product
Yield [%][b]
1
1b
2-MeO-C6H4
2b
2
1c
4-F-C6H4
2c
3
4
5
6
1d
1e
1f
1g
4-tBu-C6H4
3-thienyl
nPent
(CH2)3OTHP
2d
2e
2f
2g
7
8
9
10[d]
1h
1i
1j
1k
CH2(c-C6H11)
c-C6H11
1-cyclohexenyl
TMS
2h
2i
2j
2k
91 (18 h)
81 (5 h)[c]
90 (15 h)
70 (4 h)[c]
87 (18 h)
65 (18 h)
65 (2 h)
82 (4 h)
11 (6 h)[c]
75 (12 h)
78 (3 h)
68 (3 h)
57 (19 h)
Entry
Entry
Substrate
Yield [%][b]
Product
[a] Conditions: 1 (0.03 m), 5 mol % PtCl2, 80 8C, toluene. [b] Yield of pure
product after column chromatography. [c] Determined by 1H NMR
spectroscopy.
[a] Conditions: 1 (0.03 m), 5 mol % PtCl2, 80 8C, toluene. [b] Yield of pure
product after column chromatography. [c] Conditions: 1 (0.03 m),
5 mol % AuCl3, 23 8C, CH2Cl2. [d] 10 mol % PtCl2, 90 8C.
compounds 2 were formed in high yields and R3 was restricted
to aryl substituents (Table 2, entries 1 and 2). Furanones
having an alkyl substituent as R3 were obtained in low yields
with concomitant decomposition of the starting material
(Table 2, entry 6). Gratifyingly, the PtCl2-catalyzed reaction
proceeds without this limitation, thus expanding the scope of
the method markedly [5 mol % PtCl2, 80 8C, toluene (0.03 m)].
In the presence of PtCl2, a broad variety of alkynes 1 with
different R3 groups were effectively converted into the
corresponding furanones (Table 2). Notably, the reaction of
aromatic and heteroaromatic substrates was as clean as the
reaction of substrates containing silyl, alkyl, and alkenyl
substituents.
This approach to spirocyclic compounds is of particular
synthetic value since alkyl migration is not limited to forming
five-membered ring systems. For example, substrates 1 l and
1 m derived from cycloheptanone and cyclooctanone, respectively, undergo ring contraction to give the corresponding
spirocycles (Table 3, entries 1 and 2). Furthermore, acyclic
systems also reacted by migration of alkyl and aryl groups,
although the yields were modest (Table 3, entries 3 and 4).
Trialkylsilyl ethers such as 3 (V = SiMe3) and 4 (V = SiEt3)
also underwent PtCl2-initiated ring-contracting cyclization
providing 3(2H)-furanone 2 a in good yields (Scheme 2).
Although we have not yet conducted detailed mechanistic
studies, the results listed in Table 4 indicate that the rearrangement is stereospecific. In each case, product formation is
consistent with the rearrangement proceeding via the cyclic
oxonium ion intermediate A. Accordingly, the alkynyl
carbonyl compound 5 a provided 3(2H)-furanone 7 a exclusively, whereas formation of diastereomer 7 b was not
Angew. Chem. Int. Ed. 2006, 45, 5878 –5880
Scheme 2. PtCl2-catalyzed reaction of silyl ethers 3 and 4.
observed. In the case of 5 b, the spirocyclic compound 7 b
was obtained as the sole product. When the alkynyl carbonyl
compound 6 was employed as a mixture of diastereomers, the
diastereomeric products 7 a (from 6 a) and 7 b (from 6 b) were
obtained in ratios identical to those of the starting material.
In summary, a novel approach to 3(2H)-furanones is
described that combines a transition-metal-catalyzed activation of alkynes with a heterocyclization and subsequent 1,2-
Table 4: Stereospecific course of the domino reactions of 5 and 6.
Substr.
W
X
Y
Z
a/b[a]
5a
5b
6a
6b
H
Me
H
H
Me
H
H
H
H
H
H
Me
H
H
Me
H
> 95:5
< 5:95
80:20
25:75
Yield [%]
7 a/7 b
74
76
88
85
> 95:5
< 5:95
80:20
25:75
[a] Ratio of starting compounds 5 a/5 b or 6 a/6 b.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5879
Communications
alkyl shift. The use of 2-hydroxy-2-alkynylcarbonyl compounds as starting materials is particularly convenient as
these substrates can be prepared by simple oxygenation of aalkynyl carbonyl compounds using 2-iodoxybenzoic acid
(IBX).[13] We are currently working to expand this concept
for the synthesis of related heterocycles.
[8]
[9]
[10]
Experimental Section
General procedure: Synthesis of 2 a: PtCl2 (5 mol %, 6.3 mg) was
added to a solution of 1 a (100 mg, 0.46 mmol) in toluene (16 mL), and
the reaction vial was sealed. The resulting pale yellow solution was
stirred at 80 8C for 90 min (until TLC analysis indicated complete
conversion). The mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica
(pentanes/EtOAc 85:15) gave furanone 2 a as a colorless solid
(93 mg, 0.43 mmol, 93 %). Rf = 0.42 (pentanes/EtOAc 80:20);
1
H NMR (360 MHz, CDCl3): d = 1.95–2.10 (m, 8 H), 6.01 (s, 1 H),
7.50 (tt, J = 7.0, 1.5 Hz, 2 H), 7.57 (tt, J = 7.0, 1.5 Hz, 1 H), 7.84 ppm
(dt, J = 7.0, 1.5 Hz, 2 H); 13C NMR (90.6 MHz, CDCl3): d = 25.7 (t),
37.2 (t), 98.9 (s), 99.9 (d), 127.1 (d), 128.8 (d), 129.4 (s), 132.5 (d), 183.7
(s), 206.1 ppm (s); MS (70 eV): m/z (%): 214 (42) [M+], 173 (90), 102
(100), 77 (12). HRMS calcd for C14H14O2 : 214.0994, found: 214.0991.
[11]
[12]
[13]
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Received: May 10, 2006
Published online: July 26, 2006
.
Keywords: cyclization · domino reactions · heterocycles ·
platinum · rearrangement
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5880
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platinum, consisting, reaction, heterocyclizations, iii, catalyzed, efficiency, synthesis, domino, migration, gold, substituted, furanones, highly
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