Gold(III)- and platinum(II)-catalyzed domino reaction consisting of heterocyclization and 1,2-migration: Efficient synthesis of highly substituted 3(2H)-furanones

Article abstract of DOI:10.1002/anie.200601836

(Chemical Equation Presented) PtCl₂-catalyzed alkyne activation initiates a domino reaction, in which a heterocyclization is followed by a 1,2-alkyl migration, for the construction of a variety of substituted 3(2H)-furanones. This stereospecifi

Full text of DOI:10.1002/anie.200601836

Communications
Scheme 1. Projected synthesis of 3(2H)-furanones 2 by a catalyzed
domino reaction consisting of heterocyclization and a-ketol rearrange-
ment.
Cyclization
DOI: 10.1002/anie.200601836
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 forma-
tions between C5 and O1 typically are used in a cyclization
step, and the hydroxy function at C2is 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
1a into the spirocyclic compound 2a (Table 1). Whereas the
use of cationic gold(I) and silver(I) complexes was accom-
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,* Jörg T. Binder, ClØmence LiØbert, 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 hetero-
cyclization/1,2-migration cascade.
Recently, a AuCl3-catalyzed cyclization of 2-(1-alkynyl)-2-
alken-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 rear-
rangement.[8] In contrast to the related pinacol rearrange-
ments,[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
Table 1: Efficiency of transition-metal catalysts for the conversion of 1a
into 2a.[a]
Entry
Cat.
Conditions
Yield [%]
2a[b] 1a[b,c]
1
2
3
4
AuCl3
AuCl3
(Ph3P)AuBF4
AgSbF6
Pd(OAc)2
CuI
238C, CH2Cl2, 90 min
388C, CH2Cl2, 90 min
238C, CH2Cl2, 90 min
238C, CH2Cl2, 90 min
238C, CH2Cl2, 90 min
808C, DMF, 120 min
238C, CH2Cl2, 240 min
808C, toluene, 90 min
83
95
0
50
0
22
15
93
0
0
10
12
98
67
81
0
5
6[d]
7
PtCl2
PtCl2
8
[a] Conditions: 1a (0.03m), 5 mol% catalyst, solvent. [b] Yield of pure
product after column chromatography. [c] Recovered starting material
1a. [d] 10 mol% CuI, 0.08m.
[*] Dr. S. F. Kirsch, J. T. Binder, C. LiØbert, H. Menz
Department Chemie
panied by a significant amount of decomposition, treatment
of the starting alkyne 1a with PtCl2 or AuCl3 resulted in the
clean formation of 3(2H)-furanone 2a. Depending on the
reaction temperature, AuCl3 provided the desired compound
2a 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 238C in
CH2Cl2. Nevertheless, increasing the reaction temperature to
808C (in toluene) led to the anticipated increase in reaction
rate (Table 1, entry 8).
Technische Universität München
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (+49)89-2891-3315
E-mail: stefan.kirsch@ch.tum.de
[**] This project was supported by the Deutsche Forschungsgemein-
schaft (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.
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Angewandte
Chemie
Table 3: Transition-metal-catalyzed synthesis of 3(2H)-furanones 2l–o
by cycloisomerization of 1l–o.[a]
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
Entry
Substrate
Product
Yield [%][b]
1
1l
2l
85[c] (4 h)
Table 2: Transition-metal-catalyzed synthesis of 3(2H)-furanones 2b–k
by cycloisomerization of 1b–k.[a]
2
3
4
1m
1n
1o
2m
2n
2o
50 (24 h)
51 (48 h)
56 (18 h)
Entry
1
Substr.
R3
Product
Yield [%][b]
1b
2-MeO-C6H4
2b
91 (18 h)
81 (5 h)[c]
90 (15 h)
70 (4 h)[c]
87 (18 h)
65 (18 h)
65 (2 h)
2
1c
4-F-C6H4
2c
3
4
5
6
1d
1e
1 f
1g
4-tBu-C6H4
3-thienyl
nPent
2d
2e
2 f
2g
[a] Conditions: 1 (0.03m), 5 mol% PtCl2, 808C, toluene. [b] Yield of pure
product after column chromatography. [c] Determined by 1H NMR
spectroscopy.
(CH2)3OTHP
82 (4 h)
11 (6 h)[c]
75 (12 h)
78 (3 h)
7
8
1h
1i
CH2(c-C6H11)
c-C6H11
2h
2i
9
1j
1k
1-cyclohexenyl
TMS
2j
2k
68 (3 h)
57 (19 h)
10[d]
[a] Conditions: 1 (0.03m), 5 mol% PtCl2, 808C, toluene. [b] Yield of pure
product after column chromatography. [c] Conditions:
1 (0.03m),
5 mol% AuCl3, 238C, CH2Cl2. [d] 10 mol% PtCl2, 908C.
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, 808C, toluene (0.03m)].
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.
Scheme 2. PtCl2-catalyzed reaction of silyl ethers 3 and 4.
observed. In the case of 5b, the spirocyclic compound 7b
was obtained as the sole product. When the alkynyl carbonyl
compound 6 was employed as a mixture of diastereomers, the
diastereomeric products 7a (from 6a) and 7b (from 6b) 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 activa-
tion of alkynes with a heterocyclization and subsequent 1,2-
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 1l and
1m derived from cycloheptanone and cyclooctanone, respec-
tively, 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 2a in good yields (Scheme 2).
Although we have not yet conducted detailed mechanistic
studies, the results listed in Table 4 indicate that the rear-
rangement 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 5a provided 3(2H)-furanone 7a exclu-
sively, whereas formation of diastereomer 7b was not
Table 4: Stereospecific course of the domino reactions of 5 and 6.
Substr.
W
X
Y
Z
a/b[a]
Yield [%]
7a/7b
5a
5b
6a
6b
H
Me
H
Me
H
H
H
H
H
Me
H
H
Me
H
>95:5
<5:95
80:20
25:75
74
76
88
85
>95:5
<5:95
80:20
25:75
H
H
[a] Ratio of starting compounds 5a/5b or 6a/6b.
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Communications
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Experimental Section
General procedure: Synthesis of 2a: PtCl2 (5 mol%, 6.3 mg) was
added to a solution of 1a (100 mg, 0.46 mmol) in toluene (16 mL), and
the reaction vial was sealed. The resulting pale yellow solution was
stirred at 808C 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 2a as a colorless solid
(93 mg, 0.43 mmol, 93%). Rf = 0.42(pentanes/EtOAc 800:2);
1H NMR (360 MHz, CDCl3): d = 1.95–2.10 (m, 8H), 6.01 (s, 1H),
7.50 (tt, J = 7.0, 1.5 Hz, 2H), 7.57 (tt, J = 7.0, 1.5 Hz, 1H), 7.84 ppm
(dt, J = 7.0, 1.5 Hz, 2H); 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.
Received: May 10, 2006
Published online: July 26, 2006
Keywords: cyclization · domino reactions · heterocycles ·
.
platinum · rearrangement
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