Gold- and silver-catalyzed reactions of propargylic alcohols in the presence of protic additives

Article abstract of DOI:10.1002/chem.201102830

A wide range of primary, secondary and tertiary propargylic alcohols undergo a Meyer-Schuster rearrangement to give enones at room temperature in the presence of a gold(I) catalyst and small quantities of MeOH or 4-methoxyphenylboronic acid. The syntheses of the enone natural products isoegomaketone and daphenone were achieved using this reaction as the key step. The rearrangement of primary propargylic alcohols can readily be combined in a one-pot procedure with the addition of a nucleophile to the resulting terminal enone, to give β-aryl, β-alkoxy, β-amino or β-sulfido ketones. Propargylic alcohols bearing an adjacent electron-rich aryl group can also undergo silver-catalyzed substitution of the alcohol with oxygen, nitrogen and carbon nucleophiles. This latter reaction was initially observed with a batch of gold catalyst that was probably contaminated with small quantities of silver salt.

Full text of DOI:10.1002/chem.201102830

DOI: 10.1002/chem.201102830
Gold- and Silver-Catalyzed Reactions of Propargylic Alcohols in the
Presence of Protic Additives
Matthew N. Pennell,[a] Peter G. Turner,[b] and Tom D. Sheppard*[a]
Abstract: A wide range of primary, sec-
ondary and tertiary propargylic alco-
hols undergo a Meyer–Schuster rear-
rangement to give enones at room tem-
perature in the presence of a gold(I)
catalyst and small quantities of MeOH
or 4-methoxyphenylboronic acid. The
syntheses of the enone natural products
isoegomaketone and daphenone were
achieved using this reaction as the key
step. The rearrangement of primary
propargylic alcohols can readily be
combined in a one-pot procedure with
the addition of a nucleophile to the re-
sulting terminal enone, to give b-aryl,
b-alkoxy, b-amino or b-sulfido ketones.
Propargylic alcohols bearing an adja-
cent electron-rich aryl group can also
undergo silver-catalyzed substitution of
the alcohol with oxygen, nitrogen and
carbon nucleophiles. This latter reac-
tion was initially observed with a batch
of gold catalyst that was probably con-
taminated with small quantities of
silver salt.
Keywords: gold
·
homogeneous
catalysis Meyer–Schuster rear-
·
rangement · propargylic alcohols ·
silver
Introduction
effective even with sterically hindered carbonyls. This two-
step process can therefore offer a highly attractive method
to synthesise a,b-unsaturated carbonyl compounds
(Scheme 1).
a,b-Unsaturated carbonyl compounds are important build-
ing blocks in organic synthesis and are commonly used as
substrates in a wide variety of transformations including Mi-
chael additions,[1] Diels–Alder reactions,[2] cyclopropana-
tions[3] and a wide variety of organocatalytic processes.[4]
This diversity in application makes them common inter-
mediates in the total synthesis of natural products and the
synthesis of drug molecules. Traditionally a,b-unsaturated
carbonyl compounds are synthesised by aldol condensation
reactions, or by a Wittig,[5] Horner–Wadsworth–Emmons[6]
or Petersen[7] olefination reaction. The Meyer–Schuster rear-
rangement[8,9] of a propargylic alcohol can provide a conven-
ient alternative to these processes, which avoids the produc-
tion of stoichiometric by-products such as phosphorous
oxides.
Scheme 1. Convenient access to a,b-unsaturated carbonyl compounds.
The classical Meyer–Schuster rearrangement involves
heating the alcohol with strong acid, and is hence incompati-
ble with many functional groups.[8] However, more recently
a number of highly effective metal-catalysed methods for
achieving this reaction have been reported.[10–14] The emer-
gence of AuI catalysis[15] in particular has revived this reac-
tion, and conditions have been developed that enable the re-
arrangement to take place under very mild conditions. The
first reports required the alcohol to be converted to the cor-
responding acetate derivative,[11] but more recently proce-
dures have been developed for the direct rearrangement of
the alcohols themselves.[12] We have previously reported that
carrying out the Au-catalyzed rearrangement in a non-coor-
dinating solvent, in the presence of one equivalent of metha-
nol, greatly accelerates the reaction.[14]
The required propargylic alcohol can readily be synthes-
ised through an alkynyl anion addition to an aldehyde or
ketone, typically a high yielding process that is also highly
[a] M. N. Pennell, Dr. T. D. Sheppard
Department of Chemistry, University College London
Christopher Ingold Laboratories
20 Gordon Street, London, WC1H 0AJ, (UK)
Fax : (+44)
E-mail: matthew.pennell.09@ucl.ac.uk
tom.sheppard@ucl.ac.uk
Herein, we report on the full scope of this room tempera-
ture Meyer–Schuster rearrangement with regard to the rear-
rangement of secondary and tertiary propargylic alcohols,
and its application to the synthesis of the natural products
isoegomaketone and daphenone. We also report convenient
one-pot procedures for the direct conversion of primary
propargylic alcohols into b-arylketones, b-alkoxyketones, b-
[b] Dr. P. G. Turner
GlaxoSmithKline R & D Limited,
Medicines Research Centre,
Gunnels Wood Road, Stevenage, Herts, SG1 2NY, (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102830.
4748
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FULL PAPER
aminoketones and b-sulfidoketones via intermediate termi-
nal enones. During the course of these studies it was ob-
served that propargylic substitution reactions of electron-
rich propargylic alcohols took place in some cases. This in-
teresting side reaction, which works with a wide range of
oxygen, carbon and nitrogen nucleophiles, was shown to be
mediated by silver salts, probably present as impurities in
some batches of the gold catalyst.
catalyzed Meyer–Schuster rearrangement was more efficient
using a cationic gold catalyst[16] in non-polar solvents in the
presence of a small quantity of a protic additive (either
a boronic acid or methanol).[14] A wide range of secondary
propargylic alcohols underwent a Meyer–Schuster rear-
rangement at room temperature upon treatment with AuI
catalyst (2 mol%) and MeOH (1 equiv) in PhMe as the sol-
vent (Table 1). In nearly all cases the enone was obtained as
the pure E isomer after purification (see the Supporting In-
formation).
Results and Discussion
A variety of alkyl, alkenyl and aryl substituents at R1 on
the alkyne were tolerated (Table 1, entries 1–7) and the re-
action could be run on a 1 g scale without difficulty with
only 1 mol% Au catalyst (entry 1). An alkoxy group could
Rearrangement of secondary propargylic alcohols: In our
preliminary experiments we quickly identified that the Au-
Table 1. Meyer–Schuster rearrangement of secondary propargylic alcohols.
Entry Propargylic
Alcohol
Enone
Yield [%] Entry Propargylic
(E/Z)[a]
Alcohol
Enone
Yield [%]
(E/Z)[a]
N
ACHTUNGTRENNUNG
91
83[b] (17:1)
1
2
1a
1b
2a
12
1l
2l
78 (18:1)
2b 80[c] (14:1) 13
1m
2m 96 (19:1)
2n 99 (12:1)
2o 15 (8:1)
3
4
1c
1d
2c 43 (7:1)
2d 99 (8:1)
14
15
1n
1o
5
1e
2e 97 (18:1)
16
1p
2p 84 (7:1)
2q 85 (5:1)
6
7
8
1 f
1g
1h
2 f 99 (6:1)
2g 88 (11:1)
17
18
1q
1r
1s
2r
2s
98 (13:1)
92 (5:1)
2h 91[d] (20:1) 19
9
1i
2i 96 (20:1)
20
1t
2t
93 (24:1)
10
11
1j
2j 98 (18:1)
2k 77 (15:1)
21
22
1u
1v
2u 87 (10:1)
2v 84 (3:2)[e]
1k
[a] E/Z ratio measured by crude 1H NMR spectroscopy. [b] 1 g scale with 1 mol% catalyst. [c] 16 h at room temperature. [d] EtOH was used instead of
MeOH. [e] Crude E,E/E,Z ratio, after chromatography the pure E/Z isomer was obtained. Bn=benzyl.
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T. D. Sheppard et al.
be incorporated to give access to an a,b-unsaturated ester
(Table 1; entry 8). Compounds containing both electron-rich
aromatic groups (Table 1, entry 6) and electron-deficient ar-
omatic groups (Table 1, entry 5) at R1 rearranged smoothly,
as did a substrate containing a thiophene ring (Table 1,
entry 7). The sterically congested substrate containing a terti-
ary butyl substituent (Table 1, entry 2) rearranged to the
corresponding enone in very good yield, but required a pro-
longed reaction time of 16 h. A substrate containing a conju-
gated alkene at R1 (Table 1, entry 3) gave a lower yield, but
this probably reflects the relative instability of the dienone
product 2c rather than the yield of the reaction itself. A va-
riety of substituents could also be incorporated at the R2 po-
sition (Table 1, entries 9–15). Benzylic alcohols rearrange ef-
ficiently (Table 1, entries 9–17) with substrates containing
electron-deficient (Table 1, entry 11–13) or moderately elec-
tron-donating (Table 1, entry 10) substituents giving excel-
lent yields. Although the electron-rich alcohol 1n gave the
corresponding enone 2n in excellent yield, dimethylaniline
1o gave only a 15% yield of the corresponding enone 2o.
This may be due to the presence of the coordinating nitro-
gen atom, which can potentially interfere with the gold cata-
lyst (see below). Propargylic alcohols containing electron-
rich heterocycles gave the corresponding enones in good
yield (Table 1, entries 16 and 17), and there was no evidence
for the Au-catalyzed reaction of the electron-rich heterocy-
cle with the pendant enone in the product.[17] Further combi-
nations of substituents could also be incorporated (Table 1,
entries 18–22) including cyclopropanes (1r and 1v), which
did not undergo ring-opening during the rearrangement re-
action. The dienone 2v (Table 1, entry 22) can be generated
in excellent yield from the corresponding propargylic alco-
hol 1v. Interestingly the initial major product observed from
the rearrangement was the E,E isomer. However after pu-
rification the pure E,Z isomer 1v was obtained cleanly in
good yield. Presumably this latter isomer is actually thermo-
dynamically more stable in this case.
Scheme 3. Synthesis of daphenone by a Meyer–Schuster rearrangement.
We also carried out a short synthesis of daphenone 13
(Scheme 3), a natural product isolated from daphne odora
which showed cytotoxicity against five human tumour cell
lines.[21] Sonogashira coupling of 4-iodophenol (8) with tri-
methylsilyl (TMS)-acetylene (7) gave phenol 9[22] after desi-
lylation. After protection of the phenol as a silyl ether, the
alkyne 10 was lithiated and treated with dihydrocinnamalde-
hyde 11 to give propargylic alcohol 12. Meyer–Schuster rear-
rangement of 12 proceeded cleanly without deprotection of
the silyl ether, which was cleaved with fluoride to give the
natural product 13 (58% yield over 6 steps from 8).
Problematic substrates for the Meyer–Schuster rearrange-
ment: As mentioned above, propargylic alcohols containing
nitrogen functionality did not undergo efficient Meyer–
Schuster rearrangement (Table 1, entry 15 and Scheme 4).
Application to natural product synthesis: Isoegomaketone 6
is an essential oil component of perilla frutescens britt and
has been shown to exhibit anti-inflammatory properties.[18–19]
The natural product 6 was synthesised in two steps by fluo-
ride-mediated addition[20] of commercially available silylace-
tylene 3 to aldehyde 4, followed by Meyer–Schuster rear-
rangement of the resulting mixture of alcohol 5a and its cor-
responding TMS ether 5b, with concomitant silyl deprotec-
tion. (Scheme 2). The natural product 6 was obtained in
86% overall yield with high E/Z selectivity from the two-
step sequence.
Scheme 4. Attempted Meyer–Schuster rearrangement of nitrogen-con-
taining compounds.
Tertiary amine 14 was completely unreactive, whereas pyri-
dine 15 gave the abnormal rearrangement product 16 in
10% yield. The low reactivity of these substrates is presum-
ably a consequence of the ability of the basic nitrogen atom
to coordinate to the Au-catalyst and deactivate it. Addition
of one equivalent of pyridine to alcohol 1 f completely in-
hibited the Meyer–Schuster rearrangement of this otherwise
reactive substrate. It should be noted that there are virtually
no reports of the Au-catalyzed Meyer–Schuster rearrange-
ment of nitrogen-containing compounds in the literature.[23]
Propargylic substitution reactions: During the course of our
Scheme 2. Two-step synthesis of E-isoegomaketone.
evaluation of the substrate scope of the reaction (Table 1),
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Gold- and Silver-Catalyzed Reactions of Propargylic Alcohols
FULL PAPER
we initially observed the formation of propargylic substitu-
tion product 17a in 54% yield when rearrangement of elec-
tron-rich alcohol 1n was attempted, with 2n being produced
as a minor product (Scheme 5). It subsequently transpired
that the formation of such products was not reproducible,
and appeared to be dependent on the batch of gold catalyst
used in the reaction—with a new batch of catalyst the
Meyer–Schuster rearrangement proceeded cleanly
Scheme 5. Substitution of the propargylic alcohol with “contaminated”
Au catalyst.
Table 2. Ag-catalyzed substitution reactions of propargylic alcohols.
in good yield (Table 1, entry 14).
We hypothesised that the propargylic substitution
reaction was probably mediated by an impurity
present in the original batch of gold catalyst.[24] The
most likely candidate seemed to be AgNTf2,[25] used Entry
during the preparation of the catalyst,[16] and pleas-
ingly treatment of propargylic alcohol 1n with
Propargylic
Alcohol
NuH
Product
Yield
[%]
AgNTf2/MeOH in PhMe led to the formation of
substitution product 17a in good yield (Table 2,
1
1n
MeOH
76
17a
entry 1). Reaction of alcohol 1n with HNTf2/
MeOH in PhMe led to a complex mixture of prod-
ucts suggesting that this is not simply an acid-cata-
2
MeOH
BnOH
77
82
77
lyzed process.[26,27]
These reaction conditions were applied to
a range of different nucleophiles to illustrate the
scope of the reaction (Table 2). Substitution reac-
tions with oxygen (Table 2, entries 1–3), carbon
(Table 2, entries 4–7) and nitrogen nucleophiles
(Table 2, entries 8 and 9) were all possible. In the
1w
1n
17b
17c
3
absence of an external nucleophile, dimerisation of
the propargylic alcohol took place to form the sym-
metrical ether as a mixture of diastereoisomers
(Table 2, entry 10). The presence of both an alkyne
and an electron-rich aromatic ring at R1 seem to be
necessary for the substitution reaction to take
place. Propargylic alcohols 1a, 1 f and 1l did not
react in the presence of AgNTf2 and MeOH even
at 608C; similarly, benzhydrol (Ph2CHOH) and 1-
phenylethanol were also unreactive. Note that nei-
ther HNTf2 nor AgNTf2 were able to mediate the
Meyer–Schuster rearrangement of the propargylic
alcohols 1a, 1 f and 1l, which suggests that an Au
catalyst is essential for this reaction.[27]
It is notable that the Ag-catalyzed substitution
reaction must be highly efficient, since it was the
dominant reaction pathway in our original experi-
ments, even though the quantity of Ag present as
an impurity in the 2 mol% Au-catalyst used must
have been very small. We carried out an NMR ex-
periment to determine the relative rates of the
silver- and gold-catalyzed reactions (Scheme 6).
Treatment of alcohol 1n with 1 mol% of each of
the catalysts in the presence of MeOH (2 equiv) in
C6D6 gave a 20:1 ratio of substitution product 17a
to Meyer–Schuster rearrangement product 2n after
10 min at room temperature, illustrating that the
substitution reaction is considerably faster than the
Meyer–Schuster rearrangement. There are several
4
5
1n
1n
17d
17e
96
6
7
8
1n
1n
1n
83
17 f
17g
98
H2NBoc
59[a]
17h
9
1n
1n
H2NTs
none
74[a]
17i
17j
10
80[b]
reports in the literature of metal-catalyzed substitu- [a] 608C overnight. [b] 1.3:1 mixture of diastereoisomers. PMP=4-methoxyphenyl.
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T. D. Sheppard et al.
Table 3. Meyer–Schuster rearrangement of tertiary propargylic alcohols.
Scheme 6. Competition between the Au and Ag-catalyzed reactions of al-
cohol 1n.
Entry
Propargylic
Alcohol
Enone
Yield [%]
(E/Z)[a]
AHCTUNGTRENNUNG
tion reactions of alcohols[25,28] and in light of these results, it
is possible that some of these processes may actually be
mediated or assisted by trace quantities of Ag-salts that are
present, particularly the reactions for which Ag salts have
been added as a co-catalyst.[29] However, it should be noted
that AuIII-catalyzed substitution reactions have been report-
ed to work with propargylic alcohols that do not contain an
electron-rich aromatic substituent.[28d]
1
2
3
4
23a
23b
23c
23d
24a
24b
24c
24d
75[c]
67 (3.5:1)[c]
78 (2:1)[c]
83 (2.3:1)[b]
74 (3:1)[c]
77 (>30:1)[b]
During the course of these investigations, we also ex-
plored the rearrangement of terminal propargylic alcohols
to see whether it was possible to obtain a,b-unsaturated al-
dehydes through a Meyer–Schuster rearrangement.[30] The
initial reactions were carried out by treatment of alcohol 18
with the contaminated Au catalyst and gave a mixture of
the desired aldehyde 19 and a-methoxyketone 20
(Scheme 7). The latter product is presumably formed by Ag-
72 (1.3:1)[c]
83 (2.3:1)[b]
5
23e
24e
79 (1.5:1)[c]
82 (4.7:1)[b]
6
7
23 f
23g
24 f
24g
82[c]
[a] Crude ratio determined by 1H NMR spectroscopy. [b] With 0.2 equiv
boronic acid 25, 16 h at RT. [c] With 1 equiv MeOH, 6 h at RT.
selectivity is observed (Table 3, entry 4), and even when the
groups are of similar size moderate selectivity is still ob-
tained (Table 3, entry 2). In general, reactions of tertiary
propargylic alcohols were found to be slower than those of
secondary propargylic alcohols.
Scheme 7. Ag/Au-catalyzed reactions of terminal alkynes in the presence
of MeOH.
mediated substitution of the alcohol, followed by Au-cata-
lyzed hydration of the terminal alkyne.[31] Reaction of 18
with a new batch of catalyst gave a-hydroxyketone 21 as the
major product, together with traces of aldehyde 19. As
above (Table 2), treatment of alcohol 18 with catalytic
AgNTf2 in the presence of MeOH gave the substitution
product 22 cleanly in good yield. Treatment of 22 with cata-
lytic Au gave ketone 20, providing evidence that product 20
was formed in our original experiment by two separate steps
catalyzed by the two different metals.[29]
Scheme 8. Enhancement of the E/Z ratio by addition of boronic acid 25.
The use of p-methoxyphenyl boronic acid[13,14,32] 25 rather
than MeOH as the reaction additive was found to give
higher yields and higher E/Z selectivity in many cases,
though longer reaction times were necessary. Extending the
reaction time with MeOH as the additive did not increase
the E/Z selectivity however. Interestingly, addition of boron-
ic acid 25 to the 3:1 ratio of enone 24d obtained from Au/
MeOH catalyzed rearrangement, led to further isomerisa-
tion of the product to give an enhanced E/Z ratio
(Scheme 8). This indicates that the boronic acid is involved
in the isomerisation of the alkene, possibly through an addi-
tion process to give cyclic boronate 26.
Tertiary propargylic alcohols: Tertiary propargylic alcohols
23 can be easily prepared by addition of alkynyl anions to
ketones, and provide access to sterically congested trisubsti-
tuted enones 24 upon Meyer–Schuster rearrangement. We
were able to demonstrate the formation of a range of sym-
metrically and unsymmetrically substituted enones 24 in
good to excellent yield and with high levels of geometric
control in some cases (Table 3). Where there is a large dif-
ference in the size of the propargylic substituents, impressive
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Gold- and Silver-Catalyzed Reactions of Propargylic Alcohols
FULL PAPER
Table 4. Rearrangement of primary propargylic alcohols and addition of
nucleophiles to the resulting terminal enones.
Primary propargylic alcohols: The rearrangement of primary
propargylic alcohols should provide a highly effective and
mild method for accessing terminal enones. However,
during the rearrangement of 27 in the presence of methanol
as the additive, some addition of MeOH to enone 28a was
observed to give 29 (Scheme 9).[12a]
Entry[a]
“Nucleophile”
Product[c]
Yield
[%]
1
2
3
4
25/cat. Pd
30a
30b
30c
30d
81
58
45
39
25/cat. Pd
Scheme 9. Meyer–Schuster rearrangement of a primary propargylic alco-
hols with MeOH as the additive.
PhB(OH)2/cat. Pd
o-tolylB(OH)2/cat. Pd
Pleasingly, in the presence of boronic acid 25 as an addi-
tive, clean rearrangement to the unsubstituted enone 28a
was observed. The reaction provides a mild method for gen-
erating highly reactive terminal enones, and the crude prod-
uct is clean enough to be used directly in further transfor-
mations. We therefore developed reaction conditions for the
synthesis of a range of functionalised products by addition
of nucleophiles to the crude enone, generated in situ from
the propargylic alcohol (Table 4). In our preliminary report
we outlined how Pd-catalyzed addition of boronic acids[33]
could be used to access b-aryl ketones 30 in moderate to
good yield (Table 4, entries 1–4).[14] b-Alkoxyketones 31
(Table 4, entries 5 and 6), b-aminoketones 32 (Table 4, en-
tries 7–12) and b-sulfidoketones 33 (Table 4, entries 13 and
14) can also be readily prepared by simple one-pot proce-
dures, by addition of the appropriate nucleophile directly to
the reaction mixture after the Meyer–Schuster rearrange-
ment reaction is complete.
5
6
7
BnOH[a]
iPrOH
HNEt2
31a
31b
32a
63
76
70
8
9
Bn2NH
32b
32c
65
83
10
11
12
32d
32e
32 f
79
84
52
PhNHMe
Conclusion
13
14
n-hexylSH
33a
33b
41
46
PhSH
In the presence of catalytic PPh3AuNTf2 and a protic addi-
tive such as MeOH or 4-methoxyphenylboronic acid, the
Meyer–Schuster rearrangement of a wide range of propar-
gylic alcohols occurs in generally good to excellent yield.
Secondary alcohols rearrange with high selectivity for the E
isomer of the enone product and tertiary alcohols with mod-
erate to high selectivity. This reaction was employed as
a key step in the synthesis of the enone natural products iso-
egomaketone and daphenone. The rearrangement of pri-
mary propargylic alcohols can be combined with the addi-
tion of carbon, oxygen or nitrogen nucleophiles to the re-
sulting terminal enone to give access to b-substituted ke-
tones in a one-pot procedure. During the course of this
work, we also observed that propargylic alcohols bearing an
electron-rich aryl group readily undergo substitution of the
alcohol, with a variety of oxygen, carbon and nitrogen nu-
cleophiles in the presence of a silver catalyst. This latter re-
action was the dominant pathway over the desired Meyer–
Schuster rearrangement with a batch of AuI catalyst that
was probably contaminated with AgI salts.
Experimental Section
All reactions were carried out under an atmosphere of air unless other-
wise indicated. Tetrahydrofuran was used following purification from
a zeolite drying apparatus. All other chemicals were used as supplied
unless otherwise indicated. Column chromatography was carried out
using silica gel (40–60 mm) and analytical thin layer chromatography was
carried out using aluminium-backed plates coated with silica gel. Compo-
nents were visualised using combinations of UV light, iodine, ceric am-
monium molybdate, phosphomolybdic acid and potassium permanganate.
1H NMR spectra were recorded at 500 or at 600 MHz in CDCl3 using re-
sidual protic solvent CHCl3 (d=7.26 ppm, s) as the internal standard.
Chemical shifts are quoted in ppm using the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; qn, quintet; m, multiplet; br,
broad or a combination of these. The coupling constants (J) are mea-
sured in Hertz. 13C NMR spectra were recorded at 125 or 150 MHz in
CDCl3 using the central reference of CHCl3 (d=77.0 ppm, t) as the inter-
nal standard.
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T. D. Sheppard et al.
Meyer–Schuster Rearrangements to give enones 2, 16, and 24
HRMS (CI): m/z: calcd for C14H16OF3: 257.11532 [M+H]; found:
257.11501.
Compounds 2a, 2b, 2d, 2 f, 2r, 2u, and 24a–24 f have previously been re-
ported.[14]
(E)-1-(4-Bromophenyl)hept-1-en-3-one
(2m):
1H NMR
(CDCl3,
500 MHz): d=7.52 (d, J=8.5 Hz, 2H), 7.50 (d, J=16.1 Hz, 1H), 7.40 (d,
J=8.5 Hz, 2H), 6.72 (d, J=16.1 Hz, 1H), 2.65 (t, J=7.4 Hz, 2H), 1.65
(appqn, J=7.4 Hz, 2H), 1.38 (appsx, J=7.4 Hz, 2H), 0.94 ppm (t, J=
7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=200.4, 140.9, 133.6, 132.2,
129.7, 126.8, 124.7, 41.0, 26.5, 22.5, 14.0 ppm; IR (film) n˜ =2964, 2951,
2930, 2868, 1685 cmÀ1; HRMS (CI): m/z: calcd for C13H16OBr: 267.03845
[M+H]; found: 267.03824.
General procedure
A (preparation of compounds 2, 6 and 13):
[Ph3PAuNTf2]2PhMe (1 mol%) and methanol (1 equiv) or 4-methoxyphe-
nylboronic acid (0.2 equiv) were added to a solution of propargylic alco-
hol in toluene (10 mLgÀ1) and the solution stirred magnetically at room
temperature until starting material had disappeared (TLC). The solvent
was removed in vacuo and the crude product purified by column chroma-
tography.
(E)-1-(4-Methoxyphenyl)hept-1-en-3-one (2n):[10c] 1H NMR (CDCl3,
600 MHz): d=7.51 (d, J=16.0 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 6.91 (d,
J=8.6 Hz, 2H), 6.63 (d, J=16.0 Hz, 1H), 3.84 (s, 3H), 2.64 (t, J=7.5 Hz,
2H), 1.67 (appqn, J=7.5 Hz, 2H), 1.38 (appsx, J=7.5 Hz, 2H), 0.94 ppm
(t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=200.9, 161.6, 142.2,
130.1, 127.3, 124.2, 114.5, 55.5, 40.7, 26.8, 22.6, 14.1 ppm; IR (film) n˜ =
(E)-1-(Cyclohex-1-en-1-yl)hex-2-en-1-one (2c):[10c] 1H NMR (CDCl3,
600 MHz): d=6.91–6.88 (m, 1H), 6.84 (dt, J=15.4, 7.4 Hz, 1H), 6.63
(brd, J=15.4 Hz, 1H), 2.30–2.24 (m, 4H), 2.20 (appq, J=7.4 Hz, 2H),
1.68–1.56 (m 4H), 1.50 (appsx, J=7.4 Hz, 2H), 0.94 ppm (t, J=7.4 Hz,
3H); 13C NMR (CDCl3, 150 MHz): d=191.6, 147.0, 140.00, 139.96, 125.0,
34.8, 26.3, 23.5, 22.1, 21.7, 21.6, 13.9 ppm; IR (film) n˜ =2962, 2936, 2875,
1711 cmÀ1; HRMS (EI): m/z: calcd for C12H18O: 178.13522 [M]; found:
178.13492.
(E)-1-(4-(Trifluoromethyl)phenyl)hex-2-en-1-one (2e): 1H NMR (CDCl3,
600 MHz): d=8.00 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.12–7.07
(dt, J=15.4, 7.2 Hz, 1H), 6.86–6.83 (brdt, J=15.4, 1.4 Hz, 1H), 2.33
(brqd, J=7.2, 1.5 Hz, 2H), 1.60–1.53 (appsx, J=7.4 Hz, 2H), 0.98 ppm
(t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=190.2, 151.6, 141.0,
134.0 (q, J=32.5 Hz), 128.9, 125.9, 125.7 (q, J=3.7 Hz), 123.9 (q, J=
274 Hz), 35.1, 21.5, 13.9 ppm; HRMS (EI): m/z: calcd for C13H13OF3:
242.09130 [M]; found: 242.09084.
(E)-1-(Thiophen-3-yl)hex-2-en-1-one (2g): 1H NMR (CDCl3, 600 MHz):
d=8.05 (m, 1H), 7.59 (brd, J=4.9 Hz, 1H), 7.33–7.31 (m, 1H), 7.08 (dt,
J=15.5, 7.1 Hz, 1H), 6.77 (brd, J=15.5 Hz, 1H), 2.30–2.25 (m, 2H), 1.54
(appsx, J=7.4 Hz, 2H), 0.96 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3,
150 MHz): d=184.4, 149.1, 142.9, 132.1, 127.6, 126.7, 125.4, 34.9, 21.6,
13.9 ppm; IR (film) n˜ =2963, 2933, 2874, 1665 cmÀ1; HRMS (EI): m/z:
calcd for C10H12OS: 180.06034 [M]; found: 180.06071.
2958, 2934, 2872, 1685 cmÀ1
.
1
(E)-1-(4-(Dimethylamino)phenyl)hept-1-en-3-one (2o): H NMR (CDCl3,
600 MHz): d=7.50 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 6.68 (d,
J=8.8 Hz, 2H), 6.56 (d, J=16.0 Hz, 1H), 3.03 (s, 6H), 2.62 (t, J=7.5 Hz,
2H), 1.65 (appqn, J=7.5 Hz, 2H), 1.38 (appsx, J=7.5 Hz, 2H), 0.94 ppm
(t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=201.1, 152.0, 143.3,
130.1, 122.3, 121.7, 112.0, 40.4, 40.3, 27.1, 22.7, 14.1 ppm; IR (film) n˜ =
2956, 2931, 2871, 1646 cmÀ1; HRMS (EI): m/z: calcd for C15H21ON:
231.16176 [M]; found: 231.16240.
(E)-1-(5-Methylthiophen-2-yl)hept-1-en-3-one (2p): 1H NMR (CDCl3,
600 MHz): d=7.58 (d, J=15.8 Hz, 1H), 7.08 (brd, J=3.6 Hz, 1H), 6.72
(brd, J=3.6 Hz, 1H), 6.41 (dd, J=15.8 Hz, 1H), 2.59 (t, J=7.4 Hz, 2H),
2.50 (s, 3H), 1.63 (appqn, J=7.4 Hz, 2H), 1.38 (appsx, J=7.4 Hz, 2H),
0.93 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=200.4,
144.4, 138.1, 135.4, 132.5, 126.8, 123.9, 40.9, 26.7, 22.6, 16.0, 14.1 ppm; IR
(film) n˜ =2960, 2932, 2873, 1651 cmÀ1
C12H16OS: 208.09164 [M]; found: 208.09115.
; HRMS (EI): m/z: calcd for
(E)-Ethyl 5-phenylpent-2-enoate (2h):[34] 1H NMR (CDCl3, 600 MHz):
d=7.29 (t, J=7.5 Hz, 2H), 7.20 (t, J=7.5 Hz, 1H), 7.18 (d, J=7.5 Hz,
2H), 7.00 (dt, J=15.7, 6.9 Hz, 1H), 5.84 (dt, J=15.7, 1.6 Hz, 1H), 4.18
(q. J=7.2 Hz, 2H), 2.77 (t, J=7.6 Hz, 2H), 2.55–2.50 (m, 2H), 1.28 ppm
(t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=166.7, 148.2, 140.9,
128.6, 128.4, 126.3, 121.9, 60.3, 34.4, 34.1, 14.4 ppm; HRMS (EI): m/z:
calcd for C11H11O: 159.08044 [MÀOEt]; found: 159.08089.
(E)-1-(Furan-2-yl)hept-1-en-3-one (2q): 1H NMR (CDCl3, 600 MHz): d=
7.49 (brd, J=1.5 Hz, 1H), 7.32 (d, J=15.8 Hz, 1H), 6.65 (d, J=3.4 Hz,
1H), 6.64 (d, J=15.8 Hz, 1H), 6.47 (brdd, J=3.4, 1.5 Hz, 1H), 2.60 (t,
J=7.4 Hz, 2H), 1.67–1.61 (m, 2H), 1.36 (appsx, J=7.4 Hz, 2H),
0.93 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=200.4,
151.3, 144.9, 128.6, 123.5, 115.7, 112.6, 41.3, 26.6, 22.6, 14.0 ppm; IR
(film) n˜ =2961, 2934, 2875, 1611 cmÀ1
C11H14O2: 178.09883 [M]; found: 178.09903.
; HRMS (EI): m/z: calcd for
(E)-1-Phenylhept-1-en-3-one (2i):[35] 1H NMR (CDCl3, 600 MHz): d=
7.55 (d, J=16.3 Hz, 1H), 7.56–7.53 (m, 2H), 7.41–7.38 (m, 3H), 6.75 (d,
J=16.3 Hz, 1H), 2.64 (t, J=7.5 Hz, 2H), 1.69–1.64 (m, 2H), 1.39 (appsx,
J=7.5 Hz, 2H), 0.94 ppm (t, J=7.5 Hz, 3H); 13C NMR (CDCl3,
150 MHz): d=200.9, 142.4, 134.7, 130.5, 129.1, 128.4, 126.4, 40.8, 26.6,
1-(4-Methoxyphenyl)hept-2-en-1-one (2s): Z enone: 1H NMR (CDCl3,
600 MHz): d=7.94 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.6 Hz, 2H), 6.75 (dt,
J=11.6, 1.5 Hz, 1H), 6.26 (dt, J=11.6, 7.5 Hz, 1H), 3.87 (s, 3H), 2.60
(qd, J=7.5, 1.5 Hz, 2H), 1.45 (appqn, J=7.5 Hz, 2H), 1.35 (appsx, J=
7.5 Hz, 2H), 0.90 ppm (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d=191.1, 163.3, 148.7, 131.7, 130.8, 124.5, 113.8, 55.6, 31.6, 29.7, 22.6,
14.1 ppm; E enone: 1H NMR (CDCl3, 600 MHz): d=7.95 (d, J=8.8 Hz,
2H), 6.75 (dt, J=15.5, 7.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 6.89 (dt, J=
15.5, 1.5 Hz, 1H), 3.87 (s, 3H), 2.31 (qd, J=7.5, 1.5 Hz, 2H), 1.50
(appqn, J=7.5 Hz, 2H), 1.38 (appsx, J=7.5 Hz, 2H), 0.93 ppm (t, J=
7.5 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=189.3, 163.3, 149.2, 131.0,
130.9, 125.6, 113.8, 55.6, 32.7, 30.5, 22.5, 14.0 ppm; IR (film) n˜ =2962,
22.6, 14.1 ppm; IR (film) n˜ =2955, 2942, 2926, 2866, 1649 cmÀ1
.
(E)-1-(4-Tolyl)hept-1-en-3-one (2j):[35] 1H NMR (CDCl3, 500 MHz): d=
7.53 (d, J=16.3 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz,
2H), 6.70 (d, J=16.3 Hz, 1H), 2.65 (t, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.65
(qn, J=7.5 Hz, 2H), 1.39 (sx, J=7.5 Hz, 2H), 0.94 ppm (t, J=7.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz): d=201.0, 142.5, 141.0, 131.9, 129.8,
128.4, 125.5, 40.7, 26.7, 22.6, 21.6, 14.1 ppm; IR (film) n˜ =2955, 2930,
2862, 1648 cmÀ1
.
2935, 1600 cmÀ1
; HRMS (CI): m/z: calcd for C14H19O2: 219.13850
(E)-1-(4-Fluorophenyl)hept-1-en-3-one (2k):[10c] 1H NMR (CDCl3,
500 MHz): d=7.53 (brdd, J=8.6, 5.4 Hz, 2H), 7.50 (d, J=16.2 Hz, 1H),
7.08 (t, J=8.6 Hz, 2H), 6.67 (d, J=16.2 Hz, 1H), 2.65 (t, J=7.4 Hz, 2H),
1.65 (qn, J=7.4 Hz, 2H), 1.38 (appsx, J=7.4 Hz, 2H), 0.94 ppm (t, J=
7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=200.5, 162.2 (d, J=
250.7 Hz), 141.0, 130.9 (d, J=3.8 Hz), 130.2 (d, J=8.6 Hz), 126.0 (d, J=
1.9 Hz), 116.1 (d, J=22.0 Hz), 40.9, 26.5, 22.5, 14.0 ppm; HRMS (CI): m/
z: calcd for C13H16OF: 207.11806 [M+H]; found: 207.11852.
[M+H]; found: 219.13812.
(E)-1-(4-Methoxyphenyl)-5-phenylpent-2-en-1-one
(2t):
1H NMR
(CDCl3, 600 MHz): d=7.91 (d, J=8.9 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H),
7.22 (m, 3H), 7.07 (dt, J=15.4, 6.9 Hz, 1H), 6.94 (d, J=8.9 Hz, 2H), 6.88
(dt, J=15.4, 1.3 Hz, 1H), 3.05 (s, 3H), 2.85 (t, J=7.5 Hz, 2H), 2.64 ppm
(m, 2H); 13C NMR (CDCl3, 150 MHz): d=189.2, 163.4, 147.5, 141.1,
131.0, 130.8, 128.63, 128.55, 126.3, 113.9, 55.6, 34.69, 34.66 ppm; IR (film)
n˜ =2965, 2938, 1618 cmÀ1
266.13013 [M]; found 266.13090.
AHCTUNGTRENNUNG
(2E,4Z)-1-Cyclopropylocta-2,4-dien-1-one (2v): 1H NMR (CDCl3,
; HRMS (EI): m/z: calcd for C18H18O2:
(E)-1-(4-(Trifluoromethyl)phenyl)hept-1-en-3-one
(2l):[10c]
1H NMR
(CDCl3, 500 MHz): d=7.63 (s, 4H), 7.56 (d, J=16.3 Hz, 1H), 6.80 (d, J=
16.3 Hz, 1H), 2.68 (t, J=7.4 Hz, 2H), 1.67 (qn, J=7.4 Hz, 2H), 1.38
(appsx, J=7.4 Hz, 2H), 0.95 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3,
125 MHz): d=200.2, 141.3, 138.1, 131.9 (q, J=32.7 Hz), 128.4, 128.3,
125.6 (q, J=3.8 Hz), 123.9 (q, J=271.6 Hz), 41.1, 26.3, 22.5, 14.0 ppm;
600 MHz): d=7.23–7.18 (dd, J=15.4, 9.6 Hz, 1H), 6.21 (d, J=15.4 Hz,
1H), 6.21–6.15 (m, 2H), 2.18–2.14 (m, 2H), 2.14–2.10 (m, 1H), 1.50–1.42
(appsx, J=7.4 Hz, 2H), 1.10–1.06 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), 0.91–
4754
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4748 – 4758

Gold- and Silver-Catalyzed Reactions of Propargylic Alcohols
FULL PAPER
0.87 ppm (m, 2H); 13C NMR (CDCl3, 150 MHz): d=200.6, 145.6, 142.8,
129.2, 128.1, 35.3, 22.0, 19.3, 13.8, 11.1 ppm; IR (film) n˜ =2965, 2936,
2876, 1704 cmÀ1; HRMS (EI): m/z: calcd for C11H16O: 164.11957 [M];
found 164.11993.
(E)-1-(Pyridin-2-yl)hept-2-en-1-one (16): 1H NMR (CDCl3, 600 MHz):
d=8.71 (m, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.85 (td, J=7.9, 1.5 Hz, 1H),
7.58 (dt, J=15.6, 1.2 Hz, 1H), 7.49–7.45 (m, 1H), 7.24 (dt, J=15.6,
7.0 Hz, 1H), 2.35 (brqd, J=7.0, 1.2 Hz, 2H), 1.55–1.48 (m, 2H), 1.41–
1.35 (m, 2H), 0.93 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d=189.7, 154.3, 150.8, 148.9, 137.1, 126.9, 124.5, 123.0, 32.8, 30.4, 22.5,
14.0 ppm; IR (film) n˜ =2960, 2933, 2831, 1621 cmÀ1; HRMS (CI): m/z:
calcd for C12H16ON: 190.12319 [M+H]; found 190.12364.
1,3,3-Triphenylprop-2-en-1-one (24g):[36] 1H NMR (CDCl3, 600 MHz): d=
7.91 (brd, J=7.3 Hz, 2H), 7.49 (brt, J=7.3 Hz, 1H), 7.41–7.36 (m, 7H),
7.29–7.25 (m, 3H), 7.20–7.17 (m, 2H), 7.12 ppm (s, 1H); 13C NMR
(CDCl3, 150 MHz): d=192.8, 154.9, 141.5, 139.1, 138.3, 132.8, 129.9,
129.5, 128.9, 128.7, 128.58, 128.51, 128.49, 128.2, 124.1 ppm; HRMS (CI):
m/z: calcd for C21H16O: 283.1174 [M+H]; found 283.11288.
Silver-catalyzed substitution of propargylic alcohols
General procedure B (preparation of compounds 17 and 22): AgNTf2
(1 mol%) and nucleophile (2 equiv) were added to a solution of propar-
gylic alcohol in toluene (10 mLgÀ1) and the solution stirred magnetically
at room temperature until the starting material had disappeared (TLC)
or at 608C overnight. The reaction was quenched with aq. NaHCO3 and
the organic phase extracted with diethyl ether. The combined organic
phases were washed with brine, dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash column chromatography to give
17.
1-Methoxy-4-(1-methoxyhept-2-yn-1-yl)benzene
(17a):[38]
1H NMR
(CDCl3, 600 MHz): d=7.42 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),
5.02 (brt, J=1.9 Hz, 1H), 3.81 (s, 3H), 3.37 (s, 3H), 2.29 (td, J=7.2,
1.9 Hz, 2H), 1.56–1.51 (m, 2H), 1.47–1.40 (m, 2H), 0.92 ppm (t, J=
7.3 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=159.7, 131.5, 128.9, 113.8,
88.5, 77.8, 72.9, 55.5, 55.4, 30.9, 22.1, 18.7, 13.7 ppm; HRMS (EI): m/z:
calcd for C15H20O2: 232.14578 [M]; 232.14620.
2-(3-(Cyclohex-1-en-1-yl)-1-methoxyprop-2-yn-1-yl)-5-methylthiophene
(17b): 1H NMR (CDCl3, 600 MHz): d=6.94 (d, J=3.4 Hz, 1H), 6.60 (m,
1H), 6.19 (m, 1H), 5.37 (s, 1H), 3.39 (s, 3H), 2.46 (s, 3H), 2.19–2.14 (m,
2H), 2.12–2.08 (m, 2H), 1.66–1.61 (m, 2H), 1.61–1.55 ppm (m, 2H);
13C NMR (CDCl3, 150 MHz): d=141.1, 139.9, 136.0, 126.5, 124.6, 120.1,
89.0, 83.3, 68.8, 55.0, 29.2, 25.7, 22.3, 21.5, 15.6 ppm; IR (film) n˜ =3007,
2958, 2238 cmÀ1; HRMS (EI): m/z: calcd for C15H18OS: 246.10729 [M];
found: 246.10810.
Synthesis of the natural products isoegomaktone (6) and daphenone (13)
(E)-Isoegomaketone (6):[18,19] Isobutraldehyde (110 mg, 1.52 mmol),
(furan-3-ylethynyl)trimethylsilane (500 mg, 3.65 mmol), and tetrabuty-
lammonium triphenyldifluorosilicate (8 mg, 0.15 mmol) were dissolved in
dry THF (5 mL). The resultant solution was stirred for 20 min at 08C.
The reaction was quenched with aq. NaHCO3 and the organic phase ex-
tracted with diethyl ether. The combined organic phases were washed
with brine, dried (MgSO4) and concentrated in vacuo to give 5a and 5b
as a mixture. Compound 5 was submitted without further purification to
the Meyer–Schuster rearrangement reaction conditions (general proce-
dure C) to give E-isoegomaketone in 86% yield over the two steps.
1H NMR (CDCl3, 600 MHz): d=8.04 (m, 1H), 7.45 (app br t, J=1.7 Hz,
1H), 7.02 (dd, J=15.4, 6.8 Hz, 1H), 6.83 (br dd, J=1.7, 0.8 Hz, 1H), 6.49
(dd, J=15.4, 1.5 Hz, 1H), 2.53 (app sxd, J=6.8, 1.3 Hz, 1H), 1.11 ppm
(d, J=6.8 Hz, 6H); 13C NMR (CDCl3, 150 MHz): d=185.0, 154.7, 147.2,
144.3, 128.2, 124.1, 109.3, 31.4, 21.5 ppm; IR (film) n˜ =2966, 2934, 2873,
1667 cmÀ1; HRMS (EI): m/z: calcd for C10H12O2: 164.08318 [M]; found:
164.08354.
tert-Butyl(4-ethynylphenoxy)dimethylsilane (10):[37] (4-Hydroxyphenyl)a-
cetylene 9[20] (400 mg, 3.43 mmol) and imidazole (230 mg, 3.43 mmol)
were dissolved in DMF (10 mL) and tert-butyldimethylsilyl chloride
(TBSCl) (510 mg, 3.43 mmol) was added. The reactants were stirred at
room temperature overnight and then quenched with the addition of
water. The resultant slurry was extracted with diethyl ether, the com-
bined organic phases were washed with brine, dried (MgSO4) and con-
centrated in vacuo. The residue was purified by flash column chromatog-
raphy to give the protected acetylene 10. 1H NMR (CDCl3, 600 MHz):
d=7.38 (d, J=8.6 Hz, 2H), 6.78 (d, J=8.6 Hz, 2H), 2.99 (s, 1H), 0.98 (s,
9H), 0.20 ppm (s, 6H); 13C NMR (CDCl3, 150 MHz): d=156.4, 133.7,
120.3, 114.9, 83.8, 76.0, 25.7, 0.17, À4.3 ppm; IR (film) n˜ =2957, 2930,
2896, 2860, 2157 cmÀ1; HRMS (EI): m/z: calcd for C14H20OSi: 232.12779
[M]; found: 233.12850.
1-(1-(Benzyloxy)hept-2-yn-1-yl)-4-methoxybenzene
(17c):
1H NMR
(CDCl3, 600 MHz): d=7.45 (d, J=8.6 Hz, 2H), 7.39–7.33 (m, 4H), 7.28
(m, 1H), 6.89 (d, J=8.6 Hz, 2H), 5.16 (brt, J=1.9 Hz, 1H), 4.65 (d, J=
11.7 Hz, 1H), 4.62 (d, J=11.7 Hz, 1H), 3.81 (s, 3H), 2.31 (td, J=7.1,
1.9 Hz, 2H), 1.55 (appqn, J=7.4 Hz, 2H), 1.45 (appsx, J=7.4 Hz, 2H),
0.93 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=159.6,
138.2, 131.6, 129.0, 128.5, 128.2, 127.7, 113.8, 88.6, 78.0, 70.4, 69.6, 55.4,
30.9, 22.1, 18.7, 13.8 ppm; IR (film) n˜ =2958, 2933, 2872, 2230 cmÀ1
HRMS (EI): m/z: calcd for C21H24O2: 308.17708 [M]; found: 308.17794.
;
2-(1-(4-Methoxyphenyl)hept-2-yn-1-yl)furan (17d): 1H NMR (CDCl3,
600 MHz): d=7.32 (d, J=8.7, 2H), 7.30 (m, 1H), 6.86 (d, J=8.7 Hz,
2H), 6.28 (brdd, J=3.2, 1.9 Hz, 1H), 6.16 (brdt, J=3.2, 0.9 Hz, 1H), 4.96
(brt, J=2.2 Hz, 1H), 3.79 (s, 3H), 2.26 (td, J=7.1, 2.2 Hz, 2H), 1.52
(appqn, J=7.4 Hz, 2H), 1.43 (appsx, J=7.4 Hz, 2H), 0.91 ppm (t, J=
7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=158.8, 155.1, 142.1, 131.8,
128.9, 114.0, 110.3, 106.1, 84.2, 78.2, 55.4, 36.6, 31.1, 22.1, 18.7, 13.8 ppm;
IR (film) n˜ =2957, 2930, 2871, 2265, 1607 cmÀ1; HRMS (EI): m/z: calcd
for C18H20O2: 268.14577 [M]; found: 268.14630.
2-(1-(4-Methoxyphenyl)hept-2-yn-1-yl)-5-methylfuran (17e): 1H NMR
(CDCl3, 600 MHz): d=7.32 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H),
6.02 (brd, J=2.9 Hz, 1H), 5.86 (brdd, J=2.9, 1.1 Hz, 1H), 4.91 (brs,
1H), 3.79 (s, 3H), 2.26 (td, J=7.1, 2.2 Hz, 2H), 2.23 (s, 3H), 1.53 (appqn,
J=7.4 Hz, 2H), 1.43 (appsx, J=7.4 Hz, 2H), 0.92 ppm (t, J=7.4 Hz,
3H); 13C NMR (CDCl3, 150 MHz): d=158.7, 153.2, 151.7, 132.1, 128.9,
113.9, 106.8, 106.2, 84.0, 78.5, 55.4, 36.6, 31.1, 22.1, 18.7, 13.77, 13.76 ppm;
IR (film) n˜ =2956, 2932, 2871, 2837, 2249, 1609 cmÀ1; HRMS (EI): m/z:
calcd for C19H22O2: 282.16142 [M]; found: 282.16170.
3-(1-(4-Methoxyphenyl)hept-2-yn-1-yl)pentane-2,4-dione (17 f): 1H NMR
(CDCl3, 600 MHz): d=7.23 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H),
4.36 (dt, J=10.8, 2.3 Hz, 1H), 4.05 (d, J=10.8 Hz, 1H), 3.78 (s, 3H), 2.30
(s, 3H), 2.16 (td, J=7.1, 2.3 Hz, 2H), 1.89 (s, 3H), 1.47–1.41 (m, 2H),
1.35 (appsx, J=7.4 Hz, 2H), 0.88 ppm (t, J=7.4 Hz, 3H); 13C NMR
(CDCl3, 150 MHz): d=202.31, 202.29, 158.9, 130.9, 129.1, 114.2, 85.3,
79.0, 76.4, 55.4, 37.1, 31.4, 30.9, 28.6, 22.0, 18.5, 13.7 ppm; IR (film) n˜ =
2957, 2928, 2871, 2160, 1700 cmÀ1; HRMS (EI): m/z: calcd for C19H24O3:
300.17200 [M]; found: 300.17241.
1-(Dec-1-en-5-yn-4-yl)-4-methoxybenzene (17g):[28c] 1H NMR (CDCl3,
600 MHz): d=7.27 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.86 (m,
1H), 5.07 (m, 2H), 3.79 (s, 3H), 3.68 (m, 1H), 2.45 (appt, J=7.0 Hz,
2H), 2.25 (td, J=7.0, 2.3 Hz, 2H), 1.51 (m, 2H), 1.42 (appsx, J=7.4 Hz,
2H), 0.92 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=
158.4, 136.0, 134.2, 128.5, 116.3, 113.9, 84.0, 81.5, 55.4, 43.3, 37.6, 31.3,
1-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-5-phenylpent-1-yn-3-ol
(12):
Prepared according to general procedure SA (see the Supporting Infor-
mation). 1H NMR (CDCl3, 600 MHz): d=7.32 (d, J=8.6 Hz, 2H), 7.31–
7.28 (m, 2H), 7.26–7.24 (m, 2H), 7.22–7.19 (m, 1H), 6.79 (d, J=8.6 Hz,
2H), 4.59 (brt, J=5.5 Hz, 1H), 2.86 (t, J=7.5 Hz, 2H), 2.14–2.08 (m,
2H), 1.96 (brs, 1H), 0.98 (s, 9H), 0.20 ppm (s, 6H); 13C NMR (CDCl3,
150 MHz): d=156.2, 141.5, 133.3, 128.7, 128.6, 126.1, 120.3, 115.4, 88.6,
85.4, 62.5, 39.5, 31.6, 25.8, 18.3, À4.3 ppm; IR (film) n˜ =3650, 3007, 2944,
2293 cmÀ1; HRMS (EI): m/z: calcd for C23H30O2Si: 366.20096 [M]; found:
366.20131.
Daphenone (13):[21] Prepared according to general procedure A;
1H NMR (CDCl3, 600 MHz): d=7.85 (d, J=8.8 Hz, 2H), 7.29 (m, 2H),
7.21 (m, 3H), 7.07 (dt, J=15.3, 6.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.88
(dt, J=15.3, 1.3 Hz, 1H), 6.44 (brs, 1H), 2.84 (t, J=7.5 Hz, 2H),
2.64 ppm (m, 2H); 13C NMR (CDCl3, 150 MHz): d=189.7, 160.4, 148.1,
141.0, 131.4, 130.6, 128.6, 128.5, 126.30, 126.26, 115.5, 34.69, 34.63 ppm;
IR (film) n˜ =2954, 2926, 2856, 1737 cmÀ1; HRMS (EI): m/z: calcd for
C17H16O2: 252.11448 [M]; found: 252.11537.
Chem. Eur. J. 2012, 18, 4748 – 4758
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4755

T. D. Sheppard et al.
22.1, 18.7, 13.8 ppm; IR (film) n˜ =2958, 2933, 2873, 2250, 1641 cmÀ1
;
General
procedure
C
(preparation
of
compounds
31–33):
HRMS (CI): m/z: calcd for C17H22O: 243.17489 [M+H]; found:
243.17533.
[Ph3PAuNTf2]2PhMe (1 mol%) and alcohol (2 equiv) or 4-methoxyphe-
nylboronic acid (0.2 equiv) were added to a solution of propargylic alco-
hol in toluene (10 mLgÀ1) and the solution stirred magnetically at room
temperature until starting material had disappeared (TLC). After this
time nucleophile (2 equiv) was added to the solution and it was stirred
overnight at room temperature. The solvent was removed in vacuo and
the crude product purified by column chromatography to give the b-sub-
stituted ketone.
1-(Benzyloxy)hexan-3-one (31a): 1H NMR (CDCl3, 600 MHz): d=7.36–
7.25 (m, 5H), 4.51 (s, 2H), 3.74 (t, J=6.3 Hz, 2H), 2.69 (t, J=6.3 Hz,
2H), 2.43 (t, J=7.3 Hz, 2H), 1.59 (appsx, J=7.4 Hz, 2H), 0.91 ppm (t,
J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=209.6, 138.2, 128.5,
127.81, 127.77, 73.4, 65.5, 45.5, 43.0, 17.1, 13.8 ppm; IR (film) n˜ =2963,
2935, 2875, 1712 cmÀ1; HRMS (EI): m/z: calcd for C13H19O2: 207.13850
[M+H]; found: 207.13812.
1-Isopropoxyhexan-3-one (31b): 1H NMR (CDCl3, 600 MHz): d=3.62 (t,
J=6.5 Hz, 2H), 3.51 (septet, J=6.1 Hz, 2H), 2.58 (t, J=6.5 Hz, 2H),
2.37 (t, J=7.4 Hz, 2H), 1.60 (appsx, J=7.4 Hz, 2H), 1.08 (d, J=6.1 Hz,
6H), 0.86 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=
209.9, 71.8, 63.2, 45.4, 43.2, 22.1, 17.1, 13.8 ppm; IR (film) n˜ =2966, 2935,
2875, 1710 cmÀ1; HRMS (EI): m/z: calcd for C9H19O2: 159.13850 [M+H];
found: 159.13881.
1-(Diethylamino)hexan-3-one (32a): 1H NMR (CDCl3, 600 MHz): d=
2.74 (t, J=7.5 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.50 (q, J=7.3 Hz, 4H),
2.40 (t, J=7.3 Hz, 2H), 1.59 (appsx, J=7.4 Hz, 2H), 1.01 (t, J=7.3 Hz,
6H), 0.91 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=
210.9, 47.4, 47.0, 45.3, 40.5, 17.3, 13.9, 11.8 ppm; IR (film) n˜ =2968, 2928,
2856, 1709 cmÀ1; HRMS (EI): m/z: calcd for C10H21ON: 171.16177 [M];
found: 171.16234.
1-(Dibenzylamino)hexan-3-one (32b): 1H NMR (CDCl3, 600 MHz): d=
7.33–7.22 (m, 10H), 3.55 (s, 4H), 2.76 (t, J=7.2 Hz, 2H), 2.56 (t, J=
7.2 Hz, 2H), 2.23 (t, J=7.4 Hz, 2H), 1.53 (appsx, J=7.4 Hz, 2H),
0.85 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=210.6,
139.5, 129.0, 128.3, 127.1, 58.4, 48.7, 44.6, 41.0, 17.2, 13.8 ppm; IR (film)
n˜ =2961, 2932, 2874, 1708 cmÀ1; HRMS (EI): m/z: calcd for C20H25NO:
295.19307 [M]; found: 295.19352.
1-Morpholinohexan-3-one (32c): 1H NMR (CDCl3, 600 MHz): d=3.68
(brt, J=4.6 Hz, 4H), 2.67–2.55 (m, 4H), 2.42 (brs, 4H), 2.40 (t, J=
7.4 Hz, 2H), 1.60 (appsx, J=7.4 Hz, 2H), 0.90 ppm (t, J=7.4 Hz, 3H);
13C NMR (CDCl3, 150 MHz): d=209.9, 67.0, 53.7, 53.2, 45.1, 40.1, 17.2,
13.8 ppm; IR (film) n˜ =2960, 2855, 2809, 1709 cmÀ1; HRMS (EI): m/z:
calcd for C10H20O2N: 186.14940 [M]; found: 186.15011.
t-Butyl (1-(4-methoxyphenyl)hept-2-yn-1-yl)carbamate (17h): 1H NMR
(CDCl3, 600 MHz): d=7.41 (brd, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,
2H), 5.57 (brs, 1H), 4.96 (brs, 1H), 3.80 (s, 3H), 2.24 (td, J=7.1, 2.1 Hz,
2H), 1.50 (appqn, J=7.4 Hz, 2H), 1.44 (s, 9H), 1.40 (appsx, J=7.4 Hz,
2H), 0.91 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=
159.2, 154.9, 132.6, 128.2, 113.9, 85.3, 80.0, 78.6, 55.4, 46.0, 30.8, 28.5, 22.1,
18.6, 13.7 ppm; IR (film) n˜ =3351, 2959, 2933, 2870, 2250, 1699 cmÀ1
;
HRMS (EI): m/z: calcd for C19H27O3NNa: 340.1889 [M+Na]; found:
340.1881.
N-(1-(4-Methoxyphenyl)hept-2-yn-1-yl)-4-methylbenzenesulfonamide
1
(17i): H NMR (CDCl3, 600 MHz): d=7.76 (brd, J=8.1 Hz, 2H), 7.37 (d,
J=8.8 Hz, 2H), 7.28 (brd, J=8.1 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 5.24
(brdt, J=8.8, 2.1 Hz, 1H), 4.79 (brd, J=8.8 Hz, 1H), 3.78 (s, 3H), 2.42
(s, 3H), 1.96 (td, J=7.0, 2.1 Hz, 2H), 1.30–1.22 (m, 4H), 0.85 ppm (t, J=
7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=159.6, 143.3, 137.7, 130.4,
129.5, 128.7, 127.6, 114.0, 87.4, 76.9, 55.4, 49.1, 30.5, 22.0, 21.7, 18.3,
13.7 ppm; IR (film) n˜ =3270, 2958, 2933, 2872, 2251 cmÀ1; HRMS (ES):
m/z: calcd for C21H25NO3SNa: 394.1453 [M+Na]; found: 394.1446.
4,4’-(Oxybis(hept-2-yne-1,1-diyl))bis(methoxybenzene) (17j): Mixture of
diastereoisomers A and B, crude ratio of A/B was 1.3:1. A: 1H NMR
(CDCl3, 600 MHz): d=7.47 (d, J=8.7 Hz, 4H), 6.86 (d, J=8.7 Hz, 4H),
5.53 (brt, J=1.9 Hz, 2H), 3.79 (s, 6H), 2.32 (td, J=7.2, 1.9 Hz, 4H), 1.55
(m, 4H), 1.45 (appsx, J=7.4 Hz, 4H), 0.93 (t, J=7.4 Hz, 6H); 13C NMR
(CDCl3, 150 MHz): d=159.5, 131.8, 129.2, 113.7, 88.5, 78.1, 69.2, 57.4,
1
30.9, 22.1, 18.7, 13.8 ppm; B: H NMR (CDCl3, 600 MHz): d=7.41 (d, J=
8.7 Hz, 4H), 6.88 (d, J=8.7 Hz, 4H), 5.14 (brt, J=1.9 Hz, 2H), 3.8 (s,
6H), 2.26 (td, J=7.2, 1.9 Hz, 4H), 1.54–1.49 (m, 4H), 1.41 (appsx, J=
7.4 Hz, 4H), 0.91 ppm (t, J=7.4 Hz, 6H); 13C NMR (CDCl3, 150 MHz):
d=159.7, 131.5, 129.4, 113.9, 88.3, 78.4, 68.5, 55.4, 30.8, 22.2, 18.8,
13.8 ppm; IR (film) n˜ =2956, 2932, 2871, 2238 cmÀ1; HRMS (ES): m/z:
calcd for C28H35O3: 419.2586 [M+H]; 419.2600.
Attempted Meyer–Schuster rearrangement of terminal alkynes
Reaction of 18 using contaminated gold catalyst[24] according to general
procedure A gave a 1:5 mixture of 19 and 20, respectively. Reaction of
18 using a different batch of gold catalyst gave a mixture of compounds
19 and 21.
(E)-3-(4-Methoxyphenyl)acrylaldehyde
(19):
1H NMR
(CDCl3,
600 MHz): d=9.65 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.43 (d,
J=15.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 6.62 (dd, J=15.8, 7.6 Hz, 1H),
3.86 ppm (s, 3H); 13C NMR (CDCl3, 150 MHz): d=193.9, 162.3, 152.9,
127.9, 126.9, 126.7, 114.7, 55.64 ppm.
1-(4-Methylpiperazin-1-yl)hexan-3-one
(32d):
1H NMR
(CDCl3,
1-Methoxy-1-(4-methoxyphenyl)propan-2-one (20):[39] Reaction of 22 ac-
600 MHz): d=2.65 (t, J=7.1 Hz, 2H), 2.58 (t, J=7.1, 2H), 2.39 (t, J=
7.4 Hz, 2H), 2.26 (s, 3H), 2.71–2.20 (m, 8H), 1.58 (appsx, J=7.4 Hz,
2H), 0.89 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=
210.2, 55.2, 53.1, 52.8, 46.1, 45.1, 40.4, 17.3, 13.9 ppm; IR (film) n˜ =2961,
2936, 2876, 2794, 1711 cmÀ1; HRMS (EI): m/z: calcd for C11H22ON2:
198.17266 [M]; found: 198.17302.
cording to general procedure A with an uncontaminated batch of gold
1
catalyst gave 20 as the sole product. H NMR (CDCl3, 600 MHz): d=7.29
(d, J=8.5 Hz, 2H), 6.91 (d, J=8.5 Hz, 2H), 4.61 (s, 1H), 3.81 (s, 3H),
3.35 (s, 3H), 2.10 ppm (s, 3H); 13C NMR (CDCl3, 150 MHz): d=206.8,
160.1, 130.5, 128.5, 114.4, 89.0, 57.1, 55.4, 25.4 ppm; IR (film) n˜ =3002,
2937, 2909, 1716 cmÀ1
.
1-(1,2,3,4-Tetrahydroisoquinolin-2-yl)hexan-3-one
(32e):
1H NMR
1-Hydroxy-1-(4-methoxyphenyl)propan-2-one (21): General procedure
A: 1H NMR (CDCl3, 600 MHz): d=7.23 (d, J=8.9 Hz, 2H), 6.91 (d, J=
8.9 Hz, 2H), 5.05 (brd, J=3.5 Hz, 1H), 4.24 (brd, J=3.5 Hz, 1H), 3.81
(s, 3H), 2.07 ppm (s, 3H); 13C NMR (CDCl3, 150 MHz): d=207.5, 160.0,
130.1, 128.8, 114.5, 79.7, 55.4, 25.4 ppm; IR (film) n˜ =3465, 3055, 2988,
1712 cmÀ1; HRMS (EI): m/z: calcd for C10H12O3: 180.07810 [M]; found:
180.07883.
(CDCl3, 600 MHz): d=7.13–7.07 (m, 3H), 7.01 (m, 1H), 3.63 (brs, 2H),
2.89 (brt, J=6.0 Hz, 2H), 2.84 (t, J=7.3 Hz, 2H), 2.74 (t, J=6.0 Hz,
2H), 2.71 (t, J=7.3 Hz, 2H), 2.44 (t, J=7.4 Hz, 2H), 1.61 (appsx, J=
7.4 Hz, 2H), 0.91 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d=210.2, 134.5, 134.2, 128.7, 126.7, 126.3, 125.8, 56.2, 52.7, 51.1, 45.2,
40.8, 29.2, 17.3, 13.9 ppm; IR (film) n˜ =2960, 2931, 2874, 1709 cmÀ1
;
HRMS (EI): m/z: calcd for C15H22ON: 232.1701 [M]; found: 232.1707.
1
1-Methoxy-4-(1-methoxyprop-2-yn-1-yl)benzene (22): Prepared according
to general procedure B. 1H NMR (CDCl3, 600 MHz): d=7.44 (d, J=
8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 5.04 (brd, J=2.1 Hz, 1H), 3.81 (s,
3H), 3.42 (s, 3H), 2.65 ppm (brd, J=2.1 Hz, 1H); 13C NMR (CDCl3,
150 MHz): d=159.9, 130.3, 128.9, 114.0, 81.6, 75.7, 72.5, 55.8, 55.4 ppm;
IR (film) n˜ =2995, 2936, 2904, 2174 cmÀ1; HRMS (EI): m/z: calcd for
C11H12O2: 176.08318 [M]; found: 176.08350.
1-(Methyl
G
d=7.24 (m, 2H), 6.71 (m, 3H), 3.64 (t, J=6.9 Hz, 2H), 2.92 (brs, 3H),
2.67 (t, J=6.9 Hz, 2H), 2.38 (t, J=7.4 Hz, 2H), 1.63–1.54 (2H, m, CH2),
0.89 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=210.5,
129.4, 128.7, 116.7, 112.5, 47.5, 45.6, 39.4, 38.6, 17.2, 13.8 ppm; IR (film)
n˜ =2963, 2951, 2810, 1710 cmÀ1; HRMS (EI): m/z: calcd for C13H19ON:
205.14612 [M]; found: 205.14639.
1-Hexylsulfanyl-hexan-3-one (33a):[40] 1H NMR (CDCl3, 600 MHz): d=
2.73 (m, 2H), 2.68 (m, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.40 (t, J=7.5 Hz,
One-pot syntheses of b-substituted ketones 30–33
Compounds 30a–d have previously been reported.[14]
4756
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4748 – 4758

Gold- and Silver-Catalyzed Reactions of Propargylic Alcohols
FULL PAPER
2H), 1.65–1.53 (m, 4H), 1.39–1.22 (m, 6H), 0.91 (t, J=7.2 Hz, 3H),
0.88 ppm (t, J=7.0 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=209.5,
45.1, 42.9, 32.6, 31.5, 29.7, 28.7, 25.9, 22.7, 17.3, 14.2, 13.8 ppm; IR (film)
[15] a) A. Corma, A. Leyva-Pꢂrez, M. J. Sabater, Chem. Rev. 2011, 111,
1657–1712; b) A. Pradal, P. Y. Toullec, V. Michelet, Synthesis 2011,
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[16] N. Mꢂzailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133–4136.
[17] For AuIII-catalyzed additions of electron-rich heterocycles to enones,
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[18] a) C. H. Jin, Y. D. Park, D. S. Choi, D. S. Kim, S.-J. Kang, I. Y.
Jeong, H. J. Lee, K.-I. Seo, J. Agric. Food Chem. 2010, 58, 860–867;
b) H. Ito, Chem. Abstr. 1965, 62, 6336.
n˜ =2958, 2926, 2857, 1710 cmÀ1
.
1-(Phenylthio)hexan-3-one (33b):[41] 1H NMR (CDCl3, 600 MHz): d=
7.35–7.32 (m, 2H), 7.31–7.27 (m, 2H), 7.21–7.18 (m, 1H), 3.14 (t, J=
7.4 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 2.37 (t, J=7.4 Hz, 2H), 1.55 (m,
2H), 0.90 ppm (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=
209.2, 135.9, 129.5, 129.1, 126.4, 45.1, 42.2, 27.6, 17.3, 13.8 ppm; IR (film)
n˜ =2961, 2933, 2875, 1710 cmÀ1
.
Acknowledgements
This work was supported by the Engineering and Physical Sciences Re-
search Council (EP/E052789/1, EP/G040680/1) and GlaxoSmithKline.
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