Gold(I)-catalyzed tandem alkoxylation/lactonization of γ-hydroxy- α,β-acetylenic esters

Article abstract of DOI:10.1002/adsc.201100115

The formation of 4-alkoxy-2(5H)-furanones was achieved via tandem alkoxylation/lactonization of γ-hydroxy-α,β-acetylenic esters catalyzed by 2 mol% of [2,6-bis(diisopropylphenyl)imidazol-2-ylidine]gold bis(trifluoromethanesulfonyl)imidate [Au(IPr)(NTf₂)]. The economic and simple procedure was applied to a series of various secondary propargylic alcohols allowing for yields of desired product of up to 95%. In addition, tertiary propargylic alcohols bearing mostly cyclic substituents were converted into the corresponding spiro derivatives. Both primary and secondary alcohols reacted with propargylic alcohols at moderate temperatures (65-80 °C) in either neat reactions or using 1,2-dichloroethane as a reaction medium allowing for yields of 23-95%. In contrast to [Au(IPr)(NTf₂)], reactions with cationic complexes such as [2,6-bis(diisopropylphenyl)imidazol-2-ylidine] (acetonitrile)gold tetrafluoroborate [Au(IPr)(CH₃CN)][BF₄] or (μ-hydroxy)bis{[2,6-bis(diisopropylphenyl)imidazol-2-ylidine]gold} tetrafluoroborate or bis(trifluoromethanesulfonyl)imidate - [{Au(IPr)} ₂(μ-OH)][X] (X=BF₄, NTf₂) - mostly stop after the alkoxylation. Analysis of the intermediate proved the exclusive formation of the E-isomer which allows for the subsequent lactonization. Copyright

Full text of DOI:10.1002/adsc.201100115

FULL PAPERS
DOI: 10.1002/adsc.201100115
Gold(I)-Catalyzed Tandem Alkoxylation/Lactonization of
g-Hydroxy-a,b-Acetylenic Esters
Rubꢀn S. Ramꢁn,a Christophe Pottier,a Adriꢂn Gꢁmez-Suꢂrez,a
and Steven P. Nolana,*
a
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST, U.K.
Fax : (+44)-(0)1334-463-808; e-mail: snolan@st-andrews.ac.uk
Received: February 15, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100115.
Abstract: The formation of 4-alkoxy-2(5H)-furan- 23–95%. In contrast to [AuACHTNUGTRENNUG(IPr)HCATUNGTREN(NGUN NTf2)], reactions
ACHTUNGTRENNUNGones was achieved via tandem alkoxylation/lactoniza- with cationic complexes such as [2,6-bis(diisopropyl-
tion of g-hydroxy-a,b-acetylenic esters catalyzed by phenyl)imidazol-2-ylidine](acetonitrile)gold
2 mol% of [2,6-bis(diisopropylphenyl)imidazol-2-yli- fluoroborate [Au(IPr)(CH3CN)][BF4]
dine]gold bis(trifluoromethanesulfonyl)imidate hydroxy)bis{[2,6-bis(diisopropylphenyl)imidazol-2-
[Au(IPr)(NTf2)]. The economic and simple proce- ylidine]gold} tetrafluoroborate or bis(trifluorometh-
dure was applied to a series of various secondary anesulfonyl)imidate – [{Au(IPr)}2A(m-OH)][X] (X=
tetra-
A
E
U
or
(m-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
CHTUNGTRENNUNG
propargylic alcohols allowing for yields of desired BF4, NTf2) – mostly stop after the alkoxylation.
product of up to 95%. In addition, tertiary propar- Analysis of the intermediate proved the exclusive
gylic alcohols bearing mostly cyclic substituents were formation of the E-isomer which allows for the sub-
converted into the corresponding spiro derivatives. sequent lactonization.
Both primary and secondary alcohols reacted with
propargylic alcohols at moderate temperatures (65–
808C) in either neat reactions or using 1,2-dichloro- Keywords: alkoxylation; catalysis; furanones; gold;
ethane as a reaction medium allowing for yields of N-heterocyclic carbenes
Introduction
amine,[5] alcohols remain unreactive upon alkyne ad-
dition without prior activation and, to the best of our
During the past decade the use of gold catalysis has knowledge, only a few reports of methoxylated
developed into a research area of enormous and con- 2(5H)-furanones are present in the literature. These
tinuing growth.[1] In the course of explorative studies, methods are in need of stoichiometric amounts of re-
Nolan et al. contributed, amongst others, with the agent or base.[3d,4e,i,6]
gold catalyzed Meyer–Schuster rearrangement of
Teles and co-workers reported, in seminal work,
propargylic alcohols.[2] In the context of scouting ef- the highly efficient gold-catalyzed alkoxylation of al-
forts in the course of this study, an unexpected reac- kynes. This study indicated the significant potential of
tivity for progargylic alcohols bearing ethyl esters in gold catalysis in this arena.[7] Here, we report the
the acetylenic position was observed and the novel base-free gold-catalyzed formation of 4-alkoxy-2(5H)-
products formed using this method were identified as furanones from a variety of propargylic alcohols using
4-alkoxy-2(5H)-furanones. Since furanones or tetronic a simple and straightforward procedure.
acids are common motifs in natural products and of
potential relevance in pharmaceutical applications,[3]
further investigations on this reaction were undertak- Results and Discussion
en (Scheme 1).
In the past, various approaches leading to fura- For the present studies, IPr [IPr=2,6-bis(disopropyl-
nones and tetronic acids have been devised.[3c,d,f,4] phenyl)imidazol-2-ylidene] is the preferred ligand on
While 4-amino-2(5H)-furanones can be synthesized gold for a number of reasons: [Au
ACHTUNGTREN(NUNG IPr)Cl] (C1)
without use of a catalyst due to the basicity of the proved an excellent choice for both the Meyer–Schus-
Adv. Synth. Catal. 2011, 353, 1575 – 1583
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1575

Rubꢀn S. Ramꢁn et al.
FULL PAPERS
Scheme 1. 2(5H)-Furanone formation as observed in an earlier contribution by Nolan et al.[2]
ter rearrangement[2] as well as for the related alkyne As illustrated in Table 2, the catalytic system tolerat-
hydration reaction[8] and it is commercially available ed a broad spectrum of substrates and good to excel-
and therefore easily accessible to synthetic chemists.[9] lent yields were obtained. Both mesityl and naphthyl
It was decided, however, to target the use of a well- substituents on the propargylic alcohol allowed for
defined catalyst and move from the two-component conversion into their corresponding furanones 3b and
catalytic system [Au
to be active in the present targeted transformation, to stituted phenyl groups bearing both electron-with-
single component species, such as [Au(IPr)(NTf2)] drawing as well as electron-donating functional
(C2),[10] [Au
(IPr)(CH3CN)][BF4] (C3), [{Au(IPr)}2A(m- groups in the para position (Table 2, entries 4–7). It
OH)][BF4] (C4) and [{Au(IPr)}2A(m-OH)]
ACHTUNGRTEN(NUNG IPr)Cl]/AgSbF6, already shown 3c (Table 2, entries 2 and 3) as well as a series of sub-
A
ACHTUNGTRENNUNG
A
E
E
N
CHTUNGTRENNUNG
A
E
G
ACHTUNGRTEN[NGNU NTf2] should be noted that in some cases the reaction time
(C5),[11] in order to avoid the use of sensitive silver(I) had to be prolonged to 12 h in order to provide com-
salts.[12] Interestingly, results of this narrow catalyst plete conversion of the methoxylated intermediates.
screening revealed superior conversions with While in the case of the electron-donating para-phen-
[AuACHTUNGTRENNUNG(IPr)ACHTUNGTRENNUNG(NTf2)]. The methoxylation of the propargyl- oxy-substituted propargylic alcohol a 57% yield of 3d
ic alcohol 1a occurred rapidly for all catalysts tested. could be obtained after 2 h reaction time, its electron-
However, the conversion of the intermediate 2a into withdrawing nitro-substituted congener showed only
the 2(5H)-furanone 3a was accelerated in the case of ~55% NMR conversion after 2 h and required 12 h
C2 allowing for full conversion to the corresponding heating to finally yield 68% of the furanone 3e. In the
furanone after 3 h at room temperature. This was a same manner, the halogenated substrates required
rather unexpected result considering the estimated prolonged reaction times (Table 2, entries 6 and 7).
(based on NMR data) lower Lewis acidity of C2 com- Encouraged by the initial results, both furan and thio-
pared to C3–C5 (Table 1). The increased conversion phene derivatives were prepared and tested in the
with C5 in comparison to C4 raises the possibility of a catalysis. The yields of their corresponding furanones
slight counteranion effect in the lactonization step.
Next, C2 was tested in a substrate screening in and 51%, respectively (Table 2, entries 8 and 9).
order to evaluate the scope of the catalytic system. In The scope was then expanded to a series of aliphat-
3h and 3i after the standard 2 h reaction time were 65
order to facilitate analysis and shorten reaction times, ic substituents. While isobutyl- and tert-butyl-substi-
the operational reaction temperature was raised to tuted propargylic alcohols converted in good yields
658C and a standard reaction time of 2 h was used. into their corresponding furanones 3k and 3l (Table 2,
Table 1. Catalyst screening.[a]
Entry
Catalyst
CCarbene [ppm]
HImidazole [ppm]
2[b]
3[b]
1
2
3
4
[Au
[Au
[{Au
N
G
168.9
166.3
162.6
162.9
7.33
7.38
7.26
7.25
45
90
95
83
55
10
5
ACHTUNGTRENNUNG
E
E
N
ACHTUNGTRENNUNG
A
17
[a]
Reaction time was 3 h.
Values are in %; conversions were determined by NMR.
[b]
1576
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1575 – 1583

Gold(I)-Catalyzed Tandem Alkoxylation/Lactonization of g-Hydroxy-a,b-Acetylenic Esters
Table 2. Scope of the Au(I)-catalyzed methoxylation/lactoni-
zation.
Table 2. (Continued)
Entry
2(5H)-Furanone
3
Yield [%][a]
76
12
3l
64[b]
Entry
1
2(5H)-Furanone
3
Yield [%][a]
71
13
3m
[a]
Isolated yields.
3a
[b]
Reaction time was prolonged to 12 h.
2
3
3b
3c
43
entries 11 and 12), surprisingly 4-cyclohexyl-4-hy-
AHCTUNGTREGdNNUN roxybut-2-ynoate remained idle at the intermediate
stage, even after heating for 12 h (Table 2, entry 13).
After evaluation of the scope for secondary alco-
hols, a series of tertiary alcohols was tested under
similar reaction conditions. The reaction times were
however increased to 12 h. In an initial attempt, the
acyclic tertiary propargylic alcohol did convert
(Table 3, entry 1) and delightfully, a 75% yield of the
expected furanone 3n was obtained.
95[b]
4
3d
57
Cyclic substrates were next considered, as they
would allow for rather interesting spiro compounds.
As shown in Table 3, good to excellent conversions
were observed for these tertiary alcohols. We began
5
6
3e
3f
68[b]
with
a cyclohexyl-substituted propargylic alcohol
(Table 3, entry 2), which resulted in a pleasing 82%
yield. This scope was extended to the bicyclic norbo-
nane derivative yielding an excellent 92% yield of 3p
followed by the adamantyl-substituted which afforded
61% of 3q (Table 3, entries 3 and 4).
68[b]
In a logical extension, heterocyclic substrates were
tested and revealed an interesting and surprising
anomaly. While the tetrahydropyran derivative con-
verted, as expected, into the cyclized spiro-derivative
in excellent 97% yield (Table 3, entry 5), the tetrahy-
drothiopyran derivative reacted following a complete-
ly different pathway. While the propargylic alcohol
did not react at all, a transesterification of the ester
moiety was observed and the methoxy ester was iso-
lated in a 69% yield (Table 3, entry 6). It remains un-
clear how sulfur, which is most likely responsible, is
interacting with the catalytic system to cause such a
radical change in reactivity compared to its cyclohexyl
and tetrahydropyran analogues.
Apart from the study of substrate scope of the pres-
ent catalytic system, the tolerance for different alco-
hols also appeared to be of major interest since earli-
er reports were limited to the addition of methanol to
the alkyne moiety. Therefore, a series of alcohols was
tested. Taking into account the higher steric demands
of most alcohols investigated, the standard reaction
temperature was increased to 808C. Moreover, in
7
8
3g
3h
87[b]
65
9
3i
51
82
71
10
11
3j
3k
Adv. Synth. Catal. 2011, 353, 1575 – 1583
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1577

Rubꢀn S. Ramꢁn et al.
FULL PAPERS
Table 3. Scope of the Au(I)-catalyzed methoxylation/lactoni-
Table 4. Reaction of 1a with various alcohols.
zation of tertiary propargylic alcohols.
Entry
1
2(5H)-Furanone
3
Yield [%][a]
67[b]
Entry
1
2(5H)-Furanone
3
Yield [%][a]
75
3u
3n
2
3
4
5
6
3o
3p
3q
3r
3s
3t
82
92
61
97
69
53
2
3
4
5
6
3v
3w
3x
3y
3z
54
48[b]
58
nr
nr
7
[a]
Isolated yields.
7
8
9
3aa
3ab
3ac
33
order to ensure an easy work-up, the reactions were
performed either in neat conditions for alcohols such
as ethanol and isopropyl alcohol or in 1,2-dichloro-
ethane for, for example, octanol, depending on the
actual boiling point, availability and toxicity of the al-
cohol selected.
In comparison to methanol, primary alkyl alcohols
like ethanol (Table 4, entry 1) as well as octanol
(Table 4, entry 2) allowed for slightly diminished but
still acceptable yields of 67% for 3u and 54% for 3v.
Moreover, a moderate yield of 48% for 3w was also
obtained using isopropyl alcohol (Table 4, entry 3)
representing an example of a secondary alcohol being
compatible with the methodology. Moving to benzyl
alcohol, 58% of 3x could be obtained (Table 4,
entry 4). As expected, reactions with tert-butyl alcohol
and phenol (Table 4, entries 5 and 6) failed due to
their steric and electronic properties.[7,13]
51[c]
23[c]
10
3ad
65[c]
[a]
Isolated yields.
[b]
[c]
Reaction performed at 658C using the alcohol as solvent.
12 h heating.
Next, a reaction with allyl alcohol was envisioned
(Table 4, entry 7). The reasoning for this test was to
1578
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1575 – 1583

Gold(I)-Catalyzed Tandem Alkoxylation/Lactonization of g-Hydroxy-a,b-Acetylenic Esters
Scheme 2. Proposed mechanism for the gold-catalyzed furanone formation.
allow for a Claisen rearrangement following the al- Conclusions
koxylation/lactonization step yielding the interesting
5-phenyl-3-vinylfuran-2,4
nately, under the given reaction conditions the Clais- koxylated furanones has been developed. With re-
en rearrangement proceeded prior to lactonization spect to the lactonization step, [Au(IPr)(NTf2)]
(3H,5H)-dione.[14] Unfortu- An efficient catalytic system for the synthesis of al-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
yielding 33% of 3aa (Table 4, entry 7). This reactivity proved more efficient than digold or gold-nitrile com-
pattern is attributed to a significant decrease of the plexes. The catalyst and method permit, in some in-
activation barrier for the Claisen rearrangement by stances, for the potentially useful exclusive alkoxyla-
gold. The reaction usually requires heating at over tion without following lactonization. The new catalyt-
1008C to proceed.
ic system tolerates numerous propargylic alcohols,
However, changing to homoallyl alcohol the regular both secondary and tertiary with various primary and
alkoxylated furanone 3ab was obtained in 51% yield secondary alcohols allowing for the assembly of a sig-
(Table 4, entry 8). Reaction of a functionalized secon- nificant variety of furanones.
dary alcohol was realized using 1,6-heptadien-4-ol.
The yield of 3ac was however notably diminished to
23% (Table 4, entry 9) in comparison to 3ab. To con- Experimental Section
clude, 1,3-propanediol was subjected to this catalysis
and 65% of the corresponding 3ad was isolated
(Table 4, entry 10).
Unless otherwise stated, manipulations were performed
under air. Solvents were of puriss grade and used as re-
ceived. NMR spectra were recorded on 400 MHz and
300 MHz spectrometers at ambient temperature in CDCl3.
Chemical shifts are given in parts per million (ppm) with re-
spect to TMS.
In terms of mechanism, the proposal is straightfor-
ward (Scheme 2). Due to the observation of the key
intermediate 2, evaluation of the E/Z configuration
was most important in order to distinguish between
an E/Z isomerization of 2 allowing for full conver-
sions or alternatively an initial E-selectivity of the
gold-catalyzed alkoxylation. Therefore, catalyst C4
was used to obtain 2 selectively followed by analysis
using an NOE (nuclear Overhauser effect) experi-
ment. The NOESY-NMR obtained exclusively
showed NOE contacts between the methyl vinyl ether
and the vinyl proton supporting a selective formation
of the E-isomer which directly allows lactonization.
As a consequence of these NOE experimental results,
the initially envisioned isomerization of (possibly
formed) Z-isomers does not need to be invoked.[2]
Moreover, this would represent a rare example of
syn-addition in gold catalysis.[15] which is however
strongly related to the unique substrate properties.
Procedure A
In a vial, [AuACHTUNTRGENNUG(IPr)ACHUTGNTREN(NUGN NTf2)] (2 mol%) was added to a solution
of the corresponding propargylic alcohol (100 mg, 1 equiv.)
in MeOH (2 mL). The solution was stirred for 2 h at 658C
and the resulting mixture was concentrated under reduced
pressure. The crude product was purified by flash column
chromatography using a gradient of pentane/ethyl acetate.
Procedure B
Analogous to procedure A, but with 12 h heating.
Procedure C
In a vial, [AuACHTUNGRTNENUG(IPr)ACHTUTGNREN(NUGN NTf2)] (8.5 mg, 2 mol%) was added to a
solution of 1a (100 mg, 0.5 mmol) and the corresponding al-
cohol (1.1 equiv.) in DCE (2 mL). The solution was stirred
for 6 h at 808C and the resulting mixture was concentrated
under reduced pressure. The crude product was purified by
Adv. Synth. Catal. 2011, 353, 1575 – 1583
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1579

Rubꢀn S. Ramꢁn et al.
FULL PAPERS
flash column chromatography using a gradient of pentane/
ethyl acetate.
Synthesis of 5-(4-Chlorophenyl)-4-methoxyfuran-
2(5H)-one (3g)
Following procedure B, a white solid was obtained; yield:
87%. 1H NMR (300 MHz, CDCl3): d=7.44–7.31 (m, 2H),
7.33–7.30 (m, 2H), 5.72 (s, 1H), 5.22 (d, J=1.0 Hz, 1H),
3.91 (s, 1H); 13C NMR (75 MHz, CDCl3): d=181.3, 172.3,
135.3, 132.6, 129.1, 128.0, 88.2, 79.4, 59.9; HR-MS: m/z=
247.0136, calcd. for C11H9O3NaCl: 247.0138.
Synthesis of 4-Methoxy-5-phenylfuran-2(5H)-one (3a)
Following procedure A, a white solid was obtained, yield:
71%. 1H NMR (400 MHz, CDCl3): d=7.41–7.38 (m, 3H),
7.34–7.27 (m, 2H), 5.69 (s, 1H), 5.16 (s, 1H), 3.85 (s, 1H);
13C NMR (75 MHz, CDCl3): d=181.7, 172.6, 134.1, 129.5,
129.0, 126.8, 88.3, 80.4, 59.8; HR-MS: m/z=191.0702, calcd.
for C11H11O3: 191.0703.
Synthesis of 4-Methoxy-5-(furan-3-yl)furan-2(5H)-one
(3h)
Synthesis of 5-Mesityl-4-methoxyfuran-2(5H)-one
Following procedure A, a yellow oil was obtained; yield:
65%. 1H NMR (400 MHz, CDCl3): d=7.53–7.49 (m, 1H),
7.41 (t, J=1.7 Hz, 1H), 6.34 (dd, J=1.7, 0.6 Hz, 1H), 5.69
(s, 1H), 5.15 (d, J=1.0 Hz, 1H), 3.89 (s, 3H); 13C NMR
(101 MHz, CDCl3): d=181.0, 172.2, 144.0, 141.2, 119.6,
108.2, 88.6, 73.6, 59.8; HR-MS: m/z=203.0317, calcd. for
C9H8O4Na: 203.0320.
(3b)
Following procedure A, an off-white was obtained; yield:
43%. H NMR (300 MHz, CDCl3): d=6.85 (br. s., 2H), 6.20
(d, J=1.2 Hz, 1H), 5.25 (d, J=1.2 Hz, 1H), 3.86 (s, 3H),
2.50–2.10 (m, 9H); 13C NMR (75 MHz, CDCl3): d=181.7,
172.9, 139.2, 138.2, 131.2, 129.7, 125.8, 89.7, 77.8, 59.8, 21.0;
HR-MS: m/z=233.1164, calcd. for C14H17O3: 233.1172.
1
Synthesis of 4-Methoxy-5-(thiophen-3-yl)furan-2(5H)-
one (3i)
Synthesis of 4-Methoxy-5-(naphthalen-1-yl)furan-
2(5H)-one (3c)
Following the procedure A, an orange solid was obtained;
Following procedure B, a pale yellow oil was obtained;
yield: 95%. 1H NMR (300 MHz, CDCl3): d=8.11 (d, J=
7.7 Hz, 1H), 8.01–7.89 (m, 2H), 7.70–7.45 (m, 4H), 6.57 (s,
1H), 5.33 (d, J=1.0 Hz, 1H), 3.87 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=182.3, 172.8, 133.8, 131.4, 130.0, 129.8,
128.9, 126.8, 126.1, 125.3, 124.4, 123.0, 88.9, 77.2, 59.8; HR-
MS: m/z=263.0682, calcd. for C15H12O3Na: 263.0684.
1
yield: 51%. H NMR (CDCl3, 300 MHz,): d=7.36–7.31 (m,
2H), 7.02 (dd, J=5.0, 1.4 Hz, 1H), 5.78 (s, 1H), 5.14 (d, J=
1.0 Hz, 1H), 3.87 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=
181.2, 172.3, 134.8, 126.9, 125.3, 124.1, 88.4, 76.6, 59.8; HR-
MS: m/z=219.0086, calcd. for C9H8O3NaS: 219.0092.
Synthesis of 5-Butyl-4-methoxyfuran-2(5H)-one (3j)
Synthesis of 4-Methoxy-5-(3-phenoxyphenyl)furan-
2(5H)-one (3d)
Following procedure A, a white solid was obtained; yield:
82%. 1H NMR (300 MHz, CDCl3): d=5.10 (d, J=0.8 Hz,
1H), 4.79 (qd, J=3.7, 0.4 Hz, 1H), 3.93 (s, 3H), 1.96–1.89
(m, 1H), 1.67–1.60 (m, 1H), 1.44–1.29 (m, 4H), 0.94 (t, J=
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=182.6, 172.8,
88.6, 78.9, 59.4, 31.4, 26.3, 22.3, 13.8; HR-MS: m/z=
193.0845, calcd. for C9H14O3Na: 193.0841.
Following procedure A, a colourless oil was obtained; yield:
57%. 1H NMR (300 MHz, CDCl3): d=7.35–7.30 (m, 3H),
7.13–6.95 (m, 6H), 5.63 (s, 1H), 5.13 (d, J=0.8 Hz, 1H),
3.83 (s, 3H); 13C NMR (75 MHz, CDCl3): d=181.4, 172.4,
157.8, 156.8, 136.0, 130.3, 130.0, 123.8, 121.3, 119.5, 119.2,
117.2, 88.4, 79.9, 59.8; HR-MS: m/z=283.0958, calcd. for
C17H15O4: 283.0965.
Synthesis of 5-Isobutyl-4-methoxyfuran-2(5H)-one
(3k)
Synthesis of 5-(4-Nitrophenyl)-4-methoxyfuran-
2(5H)-one (3e)
Following procedure A, a colourless oil was obtained; yield:
71%. 1H NMR (300 MHz, CDCl3): d=5.00 (d, J=0.9 Hz,
1H), 4.73 (ddd, J=9.8, 3.1, 0.7 Hz, 1H), 3.84 (s, 3H), 1.91–
1.84 (m, 1H), 1.67–1.58 (m, 1H), 1.48–1.38 (m, 1H), 0.93 (d,
J=3.1 Hz, 3H), 0.91 (d, J=3.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=183.2, 172.8, 88.2, 77.7, 59.4, 41.2, 24.9, 23.2,
21.8; HR-MS: m/z=193.0841, calcd. for C9H14O3Na:
193.0841.
Following procedure B, a pale orange solid was obtained;
1
yield: 68%. H NMR (300 MHz, CDCl3): d=8.34–8.12 (m,
2H), 7.64–7.43 (m, 2H), 5.78 (s, 1H), 5.18 (d, J=1.2 Hz,
1H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3): d=180.7,
171.8, 148.5, 141.2, 127.4, 124.0, 88.3, 78.7, 60.1; HR-MS:
m/z=236.0546, calcd. for C11H10O5N: 236.0553.
Synthesis of 5-(4-Bromophenyl)-4-methoxyfuran-
2(5H)-one (3f)
Synthesis of 5-(tert-Butyl)-4-methoxyfuran-2(5H)-one
(3l)
Following procedure B, a white solid was obtained; yield:
68%. 1H NMR (400 MHz, CDCl3): d=7.52–7.49 (m, 2H),
7.20–7.17 (m, 2H), 5.63 (s, 1H), 5.15 (d, J=1.0 Hz, 1H),
3.84 (s, 1H); 13C NMR (101 MHz, CDCl3): d=181.3, 172.3,
133.2, 132.1, 128.3, 123.6, 88.3, 79.5, 59.9; HR-MS: m/z=
290.9632, calcd. for C11H9O3Na79Br: 290.9633.
Following procedure A, a white solid was obtained; yield:
76%. 1H NMR (CDCl3, 300 MHz): d=5.08 (d, J=0.9 Hz,
1H), 4.42 (d, J=0.9 Hz, 1H), 3.85 (s, 3H), 0.99 (s, 9H);
13C NMR (CDCl3, 101 MHz): d=182.3, 172.8, 90.0, 86.1,
59.4, 34.9, 25.4; HR-MS: m/z=193.0847, calcd. for
C9H14O3Na: 193.0841.
1580
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1575 – 1583

Gold(I)-Catalyzed Tandem Alkoxylation/Lactonization of g-Hydroxy-a,b-Acetylenic Esters
Synthesis of 5-(E)-Ethyl 4-Cyclohexyl-4-hydroxy-3-
methoxybut-2-enoate (3m)
Synthesis of Methyl 3-(4-Hydroxytetrahydro-2H-
thiopyran-4-yl)propiolate (3s)
Following procedure B, a colourless oil was obtained; yield:
64%. H NMR (400 MHz, CDCl3): d=5.24 (s, 1H), 4.14 (q,
Following procedure B, an off-white solid was obtained;
yield: 69%. 1H NMR (400 MHz, CDCl3): d=3.77 (s, 3H),
2.90 (s, 1H), 2.81–2.68 (m, 4H), 2.27–2.17 (m, 2H), 2.03–
1.92 (m, 2H); 13C NMR (101 MHz, CDCl3): d=153.9, 89.2,
77.0, 67.5, 53.1, 39.7, 25.4; HR-MS: m/z=201.0581, calcd.
for C9H13O3S: 201.0580.
1
J=7.1 Hz, 2H), 3.99 (s, 3H), 3.75 (t, J=6.2 Hz, 1H), 1.88–
1.50 (m, 7H), 1.27 (t, J=7.1 Hz, 3H), 0.96–1.24 (m, 4H);
13C NMR (101 MHz, CDCl3): d=171.3, 165.5, 96.0, 78.3,
61.7, 60.0, 42.1, 29.8, 27.9, 26.4, 26.3, 26.1, 14.4; HR-MS:
m/z=265.1423, calcd. for C13H24O4Na: 265.1416.
Synthesis of 3-Methoxy-2’,3’-dihydro-5H-spiro[furan-
2,1’-inden]-5-one (3t)
Synthesis of 5-Isopropyl-4-methoxy-5-phenylfuran-
2(5H)-one (3n)
Following procedure B, a pale orange solid was obtained;
yield: 53%. H NMR (400 MHz, CDCl3): d=7.48–7.35 (m,
1
Following procedure B, an off-white solid was obtained;
2H), 7.35–7.28 (m, 1H), 7.24–7.10 (m, 1H), 5.27 (s, 1H),
3.93 (s, 3H), 3.35–3.20 (m, 1H), 3.18–3.04 (m, 1H), 2.77–
2.61 (m, 1H), 2.59–2.47 (m, 1H); 13C NMR (101 MHz,
CDCl3): d=182.9, 171.8, 145.1, 138.6, 130.1, 127.2, 125.2,
123.2, 92.9, 88.3, 59.7, 35.2, 30.2; HR-MS: m/z=217.0861,
calcd. for C13H13O3: 217.0859.
1
yield: 75%. H NMR (300 MHz, CDCl3): d=7.54–7.45 (m,
2H), 7.40–7.27 (m, 3H), 4.97 (s, 1H), 3.86 (s, 3H), 2.49 (spt,
J=6.8 Hz, 1H), 0.92 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz,
3H); 13C NMR (101 MHz, CDCl3): d=183.8, 172.4, 138.5,
128.5, 128.1, 125.2, 89.6, 87.8, 59.7, 34.5, 16.7, 16.2; HR-MS:
m/z=233.1172, calcd. for C14H17O3: 233.1172.
Synthesis of 4-Ethoxy-5-phenylfuran-2(5H)-one (3u)
Synthesis of 5-(4-Methoxy)-1-oxaspiroACHTUNGTREN[NGNU 4.5]dec-3-en-2-
Following procedure A but with 6 h heating in ethanol, a
pale yellow solid was obtained; yield: 67%. 1H NMR
(300 MHz, CDCl3): d=7.46–7.28 (m, 5H), 5.67 (s, 1H), 5.12
(d, J=1.0 Hz, 1H), 4.27–3.86 (m, 2H), 1.35 (t, J=7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=180.7, 173.0, 134.3,
129.4, 128.9, 126.7, 88.2, 80.5, 69.0, 14.0; HR-MS: m/z=
204.0783, calcd. for C12H12O3: 204.0781.
one (3o)
Following procedure B, a pale orange solid was obtained;
yield: 82%. 1H NMR (400 MHz, CDCl3): d=4.95 (s, 1H),
3.86 (s, 3H), 1.54–1.83 (m, 10H); 13C NMR (75 MHz,
CDCl3): d=186.4, 172.2, 87.1, 83.9, 59.4, 33.1, 24.5, 21.8;
HR-MS: m/z=205.0835, calcd. for C10H14O3Na: 205.0841.
Synthesis of 4-(Octyloxy)-5-phenylfuran-2(5H)-one
(3v)
Synthesis of 3’-Methoxy-5’H-spiro
heptane-2,2’-furan]-5’-one (3p)
ACHUTGTNRENN[GU bicycloCAHTUNGTRENN[UGN 2.2.1]-
Following procedure C, a colourless oil was obtained; yield:
54%. 1H NMR (400 MHz, CDCl3): d=7.43–7.35 (m, 3H),
7.35–7.28 (m, 2H), 5.67 (s, 1H), 5.10 (d, J=1.0 Hz, 1H),
4.03 (td, J=6.5, 9.8 Hz, 1H), 3.92 (td, J=6.5, 9.8 Hz, 1H),
1.78–1.62 (m, 2H), 1.40–1.12 (m, 10H), 0.87 (t, J=6.9 Hz,
3H); 13C NMR (101 MHz, CDCl3): d=180.9, 173.0, 134.4,
129.3, 128.8, 126.6, 88.1, 80.4, 73.3, 31.8, 29.1, 29.1, 28.3, 25.6,
22.7, 14.2; HR-MS: m/z=288.1718, calcd. for C18H24O3:
288.1720.
Following procedure B, an off-white solid was obtained;
yield: 92%. 1H NMR (300 MHz, CDCl3): d=4.89 (s, 1H),
3.85 (s, 3H), 2.35–2.28 (m, 2H), 2.16–1.81 (m, 3H), 1.70–
1.28 (m, 5H); 13C NMR (101 MHz, CDCl3): d=185.5, 172.4,
89.4, 86.5, 59.6, 46.1, 40.8, 38.5, 36.5, 27.4, 23.8; HR-MS:
m/z=195.1015, calcd. for C11H15O3: 195.1016.
Synthesis of 3-Methoxy-5H-spiro[furan-2,2’-tricyclo-
[3.3.1.13,7]decan]-5-one (3q)
Synthesis of 4-Isopropoxy-5-phenylfuran-2(5H)-one
(3w)
Following procedure B, a colourless solid was obtained;
yield: 61%. 1H NMR (400 MHz, CDCl3): d=4.99 (s, 1H),
3.87 (s, 3H), 2.41–2.21 (m, 4H), 2.02–1.82 (m, 4H), 1.79–
1.70 (m, 4H), 1.69–1.56 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=187.3, 171.6, 88.2, 88.0, 59.5, 37.9, 36.4, 34.6,
33.3, 26.7, 26.3; HR-MS: m/z=257.1155, calcd. for
C14H18O3Na: 257.1154.
Following procedure A but with 6 h heating in isopropyl al-
cohol, a pale yellow solid was obtained; yield: 48%.
1H NMR (300 MHz, CDCl3): d=7.44–7.26 (m, 5H), 5.63 (s,
1H), 5.08 (d, J=0.9 Hz, 1H), 4.39 (spt, J=6.1 Hz, 1H), 1.35
(d, J=6.1 Hz, 3H), 1.21 (d, J=6.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=179.7, 173.3, 134.4, 129.3, 128.8, 126.8,
88.1, 80.7, 76.9, 21.4, 21.0; HR-MS: m/z=218.0939, calcd.
for C13H14O3: 218.0937.
Synthesis of 3’-Methoxy-5’H-spiro
heptane-2,2’-furan]-5’-one (3r)
ACHUTGTNRENN[GU bicycloCAHTUNGTRENN[UGN 2.2.1]-
Following procedure B, a white solid was obtained; yield:
97%. 1H NMR (300 MHz, CDCl3): d=5.02 (s, 1H), 3.99–
3.86 (m, 5H), 3.79 (d, J=2.1 Hz, 2H), 2.16–2.05 (m, 2H),
1.56–1.45 (m, 2H); 13C NMR (101 MHz, CDCl3): d=184.7,
171.5, 87.8, 81.1, 63.7, 59.7, 33.1; HR-MS: m/z=185.0803,
calcd. for C9H13O4: 185.0808.
Synthesis of 4-(Benzyloxy)-5-phenylfuran-2(5H)-one
(3x)
Following procedure C, a pale yellow solid was obtained;
1
yield: 58%. H NMR (400 MHz, CDCl3): d=7.47–7.28 (m,
8H), 7.25–7.13 (m, 2H), 5.73 (s, 1H), 5.20 (d, J=0.9 Hz,
Adv. Synth. Catal. 2011, 353, 1575 – 1583
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1581

Rubꢀn S. Ramꢁn et al.
FULL PAPERS
1H), 5.08 (d, J=11.8 Hz, 1H), 5.01 (d, J=11.8 Hz, 1H);
13C NMR (101 MHz, CDCl3): d=180.2, 172.7, 134.1, 133.9,
129.4, 129.1, 128.9, 127.7, 126.7, 89.4, 80.5, 74.5; HR-MS:
m/z=266.0938, calcd. for C17H14O3: 266.0937.
(Swansea) and the Mass Spectrometry Services at St. An-
drews are gratefully acknowledged for conducting HR-MS
analyses. SPN is a Royal Society Wolfson Research Merit
Award holder.
Synthesis of Ethyl 2-(2-Hydroxy-2-phenylacetyl)pent-
4-enoate (3aa)
References
Following procedure C, a pale orange oil was obtained as a
mixture of isomers; yield: 33%. 1H NMR (300 MHz,
CDCl3): d=7.45–7.12 (m), 5.65–5.50 (m), 5.30–5.20 (m),
5.10–4.89 (m), 4.82–4.64 (m), 4.27–3.92 (m), 3.78 (q, J=
7.1 Hz), 3.71–3.50 (m), 2.63–2.20 (m), 1.27–1.09 (m), 0.97 (t,
J=7.1 Hz); 13C NMR (75 MHz, CDCl3): d=204.4, 203.8,
168.2, 168.1, 136.7, 136.4, 133.6, 133.5, 129.1, 129.1, 129.0,
128.1, 127.9, 118.3, 117.7, 80.6, 79.8, 62.0, 61.5, 53.7, 53.3,
33.5, 31.9, 14.2, 13.9; HR-MS: m/z=285.1096, calcd. for
C15H18O4: 285.1103.
[1] For selected reviews, see: a) N. D. Shapiro, F. D. Toste,
Synlett 2010, 675–691; b) R. Skouta, C.-J. Li, Tetrahe-
dron 2008, 64, 4917–4938; c) Z. Li, C. Brouwer, C. He,
Chem. Rev. 2008, 108, 3239–3265; d) A. S. K. Hashmi,
M. Rudolph, Chem. Soc. Rev. 2008, 37, 1766–1775;
e) N. Marion, S. P. Nolan, Chem. Soc. Rev. 2008, 37,
1776–1782; f) E. Jimꢀnez-NfflÇez, A. M. Echavarren,
Chem. Commun. 2007, 333–346; g) A. S. K. Hashmi,
Chem. Rev. 2007, 107, 3180–3211; h) A. Fürstner, P.
Davies, Angew. Chem. 2007, 119, 3478–3519; Angew.
Chem. Int. Ed. 2007, 46, 3410–3449; i) A. S. K. Hashmi,
G. J. Hutchings, Angew. Chem. 2006, 118, 8064–8105;
Angew. Chem. Int. Ed. 2006, 45, 7896–7936.
Synthesis of 4-(But-3-enyloxy)-5-phenylfuran-2(5H)-
one (3ab)
[2] R. S. Ramꢁn, N. Marion, S. P. Nolan, Tetrahedron 2009,
65, 1767–1773.
Following procedure C but with 12 h heating, a pale yellow
solid was obtained; yield: 51%. 1H NMR (300 MHz,
CDCl3): d=7.46–7.27 (m, 5H), 5.77–5.58 (m, 2H), 5.12 (d,
J=1.3 Hz, 1H), 5.10–5.05 (m, 1H), 5.05–5.00 (m, 1H), 4.15–
4.03 (m, 1H), 4.03–3.93 (m, 1H), 2.45 (tq, J=1.3, 6.7 Hz,
2H); 13C NMR (75 MHz, CDCl3): d=180.7, 172.8, 134.3,
132.6, 129.4, 128.9, 126.6, 118.3, 88.4, 80.4, 72.1, 32.7; HR-
MS: m/z=230.0936, calcd. for C14H14O3: 230.0937.
[3] For selected examples, see: a) R. Schobert, A. Schlenk,
Bioorg. Med. Chem. 2008, 16, 4203–4221; b) R. Scho-
bert, R. Stehle, H. Walter, Tetrahedron 2008, 64, 9401–
9407; c) A. L. Zografos, D. Georgiadis, Synthesis 2006,
19, 3157–3188; d) N. G. Clemo, G. Pattenden, J. Chem.
Soc. Perkin Trans. 1 1985, 2407–2411; e) A. T. Hopper,
D. T. Witiak, J. Ziemniak, J. Med. Chem. 1998, 41, 420–
427; f) T. Hiyama, H. Oishi, Y. Suetsugu, K. Nishide,
H. Saimoto, Bull. Chem. Soc. Jpn. 1987, 60, 2139–2150.
[4] For a small selection, see: a a) M. Poonoth, N. Krause,
J. Org. Chem. 2011, 76, 1934–1936; b) Y. Lei, Z.-Q.
Wang, Y.-X. Xie, S.-C. Yu, B.-X. Tang, J.-H. Li, Adv.
Synth. Catal. 2011, 353, 31–35; c) A. Alizadeh, H. Sa-
bahnoo, Z. Noaparast, N. Zohreh, A. Mikaeili, Synlett
2010, 1854–1858; d) A. L. Mallinger, T. Le Gall, C.
Mioskowski, J. Org. Chem. 2009, 74, 1124–1129;
e) A. R. Rajaram, L. Pu, Org. Lett. 2006, 8, 2019–2021;
f) D. Tejedor, A. Santos-Expꢁsito, F. García-Tellado,
Synlett 2006, 1607–1609; g) D. Tejedor, F. García-Tella-
do, Org. Prep. Proced. Int. 2004, 36, 33–59; h) D. Teje-
dor Aragꢁn, G. V. Lꢁpez, F. García-Tellado, J. J. Mar-
rero-Tellado, P. de Armas, D. Terrero, J. Org. Chem.
2003, 68, 3363–3365; i) D. T. Witiak, A. K. Tehim, J.
Org. Chem. 1987, 52, 2324–2327; j) H. Saimoto, M. Shi-
noda, S. Matsubara, K. Oshima, T. Hiyama, H. Nozaki,
Bull. Chem. Soc. Jpn. 1983, 56, 3088–3092.
[5] a) L.-H. Zhou, X.-Q. Yu, L. Pu, J. Org. Chem. 2009, 74,
2013–2017; b) M. V. Mavrov, L. D. Konyushkin, N. I.
Simirskaya, S. G. Zlotin, Russ. Chem. Bull. Int. Ed.
2005, 54, 2857–2866.
[6] a) T. Taniguchi, H. Ishibashi, Tetrahedron 2008, 64,
8773–8779; b) T. Taniguchi, G. Tanabe, O. Muraoka,
H. Ishibashi, Org. Lett. 2008, 10, 197–199; c) E. R. H.
Jones, M. C. Whiting, J. Chem. Soc. 1949, 1423–1430.
[7] a) J. H. Teles, S. Brode, M. Chabanas, Angew. Chem.
1998, 110, 1475–1478; Angew. Chem. Int. Ed. 1998, 37,
1415–1418; see also: b) A. Corma, V. R. Ruiz, A.
Leyva-Pꢀrez, M. J. Sabater, Adv. Synth. Catal. 2010,
352, 1701–1710.
Synthesis of 4-(Hepta-1,6-dien-4-yloxy)-5-
phenylfuran-2(5H)-one (3ac)
Following procedure C but with 12 h heating, a pale yellow
1
oil was obtained; yield: 23%. H NMR (400 MHz, CDCl3):
d=7.59–7.28 (m, 5H), 5.96–5.77 (m, 1H), 5.73 (s, 1H), 5.61–
5.36 (m, 1H), 5.32–5.11 (m, 3H), 5.06–4.83 (m, 2H), 4.44–
4.03 (m, 1H), 2.60–2.47 (m, 2H), 2.46–2.24 (m, 2H);
13C NMR (101 MHz, CDCl3): d=180.0, 173.1, 134.3, 132.3,
131.8, 129.4, 128.8, 126.8, 119.1, 119.0, 88.3, 82.8, 80.6, 37.5,
37.2; HR-MS: m/z=293.1164, calcd. for C17H18O3Na:
293.1154.
Synthesis of 4-(3-Hydroxypropoxy)-5-phenylfuran-
2(5H)-one (3ad)
Following procedure C but with 12 h heating, a pale yellow
solid was obtained; yield: 65%. 1H NMR (300 MHz,
CDCl3): d=7.51–7.15 (m, 5H), 5.66 (s, 1H), 5.14 (d, J=
1.0 Hz, 1H), 4.30–3.97 (m, 2H), 3.76–3.43 (m, 2H), 2.17 (br.
s., 1H), 1.90 (quin, J=6.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=180.9, 173.2, 134.1, 129.4, 128.9, 126.6, 88.4, 80.5,
70.2, 58.5, 31.1; HR-MS: m/z=234.0884, calcd. for C13H14O4:
234.0887.
Acknowledgements
The ERC (Advanced Investigator Award-FUNCAT) and the
EPSRC are gratefully acknowledged for support of this
work. The National Mass Spectrometry Service Centre
1582
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1575 – 1583

Gold(I)-Catalyzed Tandem Alkoxylation/Lactonization of g-Hydroxy-a,b-Acetylenic Esters
[8] N. Marion, R. S. Ramꢁn, S. P. Nolan, J. Am. Chem. Soc.
2009, 131, 448–449.
[12] Catalysts C2–C4 can be easily obtained starting from
C1. See ref.[11]
[9] The Supporting Information includes a screening of
[13] For successful gold-catalyzed phenol addition to al-
kynes, see: M. R. Kuram, M. Bhanuchandra, A. K.
Sahoo, J. Org. Chem. 2010, 75, 2247–2258.
[14] For examples of heat-catalyzed Claisen rearrangements
on furanones, see: a) R. Schobert, G. Gordon, A.
Bieser, W. Milius, Eur. J. Org. Chem. 2003, 18, 3637–
3647; b) J. Lçffler, R. Schobert, J. Chem. Soc. Perkin
Trans. 1 1996, 2799–2802.
[AuACHTUNGTRENNUNG(NHC)ACHTUNGTRENNUNG(NTf2)] catalysts revealing superior results
with bulky ligands such as IAd and ItBu. For the role
of NHCs in late transition metal catalysis, see: S. Díez-
Gonzꢂlez, N. Marion, S. P. Nolan, Chem. Rev. 2009,
109, 3612–3676.
[10] L. Ricard, F. Gagosz, Organometallics 2007, 26, 4704–
4707.
[11] R. S. Ramꢁn, S. Gaillard, A. Poater, L. Cavallo,
A. M. Z. Slawin, S. P. Nolan, Chem. Eur. J. 2011, 17,
1238–1246.
[15] A. S. K. Hashmi, Angew. Chem. 2010, 122, 5360–5369;
Angew. Chem. Int. Ed. 2010, 31, 5232–5241.
Adv. Synth. Catal. 2011, 353, 1575 – 1583
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1583