Reaction of Lithiated Propargyl Ethers with Carbonyl Compounds-A Regioselective Route to Furan Derivatives

Article abstract of DOI:10.1055/s-0040-1705958

The deprotonation of 3-Aryl-substituted alkyl propargyl ethers with n-butyllithium provides an ambident anion that reacts with carbonyl compounds to provide mixtures of γ-substituted products with alkoxyallene substructure and of α-substituted propargyl ethers. The ratio of the two product types strongly depends on the solvent: in diethyl ether the γ-substituted products predominate whereas the more polar tetrahydrofuran favors the α-Adducts. The primary addition products undergo 5-endo-trig or 5-endo-dig cyclizations under various reaction conditions to afford isomeric furan derivatives. The highest selectivity in favor of α-substituted products was achieved by employing a MOM-protected propargyl ether. During the protonation step no evidence for a proton shift leading to an isomeric allenyl anion was found. A brief mechanistic discussion tries to rationalize the observed regio? selectivities.

Full text of DOI:10.1055/s-0040-1705958

SYNTHESIS
0
0
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9
-
7
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8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–J
paper
A
en
I. Linder et al.
Paper
Synthesis
Reaction of Lithiated Propargyl Ethers with Carbonyl Compounds
– A Regioselective Route to Furan Derivatives
Ar
Ar
OMe
Igor Linder
1. nBuLi, Et2O
•
R
Robby Klemme
Hans-Ulrich Reissig*
2.
R
R
R
H
OMe
O
R
O
0
0
0
0
-
0
0
0
2
-
1
9
1
2
-
9
6
3
5
R
OH
OMe
major product
Institut für Chemie und Biochemie,
Freie Universität Berlin, Takustr. 3, 14195 Berlin,
Germany
Ar
major product
hans.reissig@chemie.fu-berlin.de
OMe
OMe
1. nBuLi, THF
Ar
R
R
R
2.
R
Ar
O
R
O
HO
R
HIe
n
M
asntaisitCl-uoUhtralfrrüneicsrsh.pCreoRhinesdimssiisgniie@ggucAhn
u
edtmh
B
oiieor.cfuh-ebmeireli,nF.rd
e
eie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
(Scheme 1, equation a). A second deprotonation occurs at
the more acidic -carbon of B and electrophiles add to this
position to give 1,1,3-trisubstituted alkoxyallenes C. This
multi-step protocol was employed by our group to prepare
a series of dihydrofuran and dihydropyrrole derivatives, in-
cluding the natural product codonopsinine.5
Received: 20.08.2020
Accepted after revision: 26.09.2020
Published online: 28.10.2020
DOI: 10.1055/s-0040-1705958; Art ID: ss-2020-c0440-op
Abstract The deprotonation of 3-aryl-substituted alkyl propargyl
ethers with n-butyllithium provides an ambident anion that reacts with
carbonyl compounds to provide mixtures of -substituted products
with alkoxyallene substructure and of -substituted propargyl ethers.
The ratio of the two product types strongly depends on the solvent: in
diethyl ether the -substituted products predominate whereas the
more polar tetrahydrofuran favors the -adducts. The primary addition
products undergo 5-endo-trig or 5-endo-dig cyclizations under various
reaction conditions to afford isomeric furan derivatives. The highest se-
lectivity in favor of -substituted products was achieved by employing a
MOM-protected propargyl ether. During the protonation step no evi-
dence for a proton shift leading to an isomeric allenyl anion was found.
A brief mechanistic discussion tries to rationalize the observed regio-
selectivities.
1. nBuLi
Et2O or THF
1. nBuLi
Et2O or THF
R2
H
R2
H
OR1
OR1
El
OR1
H
a)
R2
•
•
γ
α
–78 or –40 °C
2. ROH
2. El-X
A
B
C
R2 = Alkyl, Aryl
O
R3
1. nBuLi
Et2O, –40 °C
2. R2-CN
3. R3-CO2H
Ar
R3
N
OR1
O
HN
"– H2O"
b)
Ar
Ar
R2
HO
R2
γ
α
OR1
OR1
D
E
F
Scheme 1 a) Lithiation of propargyl ethers A, regioselective protona-
tion to alkoxyallenes B, and transformation into 1,1,3-trisubstituted al-
lenes C; b) lithiation of aryl-substituted propargyl ethers D and three-
component reaction with nitriles and carboxylic acids to -alkoxy--ke-
toenamides E, versatile precursors of functionalized heterocycles such
as F (all compounds of this report are racemic; nevertheless, we prefer
to present geometrically correct allene moieties)
Key words alkoxyallene, alkyne, cyclization, furan, gold catalysis,
lithiation, regioselectivity, silver catalysis
Alkoxyallenes and derivatives thereof are versatile
building blocks for the synthesis of carbocycles and hetero-
cycles.1 Of particular value are lithiated alkoxyallenes that
react with a large variety of electrophiles and hence lead to
many useful product types. The reactivity of simple com-
pounds such as methoxyallene (1-methoxypropa-1,2-di-
ene) and its lithiated intermediates is reasonably well un-
derstood and was exploited in many applications,2 but the
corresponding 3-substituted 1-alkoxy-1,2-dienes are not as
easily available and as a consequence they are less ex-
plored.3 During our studies on 3-aryl-substituted alkoxyal-
lenes we explored the known route4 via propargylic ethers
A which can be deprotonated at the -position to the
alkoxy group with n-butyllithium and regioselectively pro-
tonated in -position to furnish the expected allenes B
In a three-component reaction, lithiation of aryl-substi-
tuted propargylic ethers D and treatment with nitriles as
electrophiles and subsequently with carboxylic acids unex-
pectedly provided -alkoxy--ketoenamides E as products
(Scheme 1, equation b).6 In this case, the electrophile was
connected to the -position of lithiated D. The general
mechanism of the formation of -alkoxy--ketoenamides E
was discussed in earlier publications7 and as very first step
we proposed the addition of a lithiated alkoxyallene to the
nitrile. Compounds E are excellent precursors for the syn-
thesis of functionalized pyridine, pyrimidine, and oxazole
derivatives.8 In order to understand the mechanisms
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
I. Linder et al.
Paper
Synthesis
involved in lithiations of aryl-substituted propargylic ethers
D and their reactions with electrophiles we undertook the
investigations described in this report.
highly substituted allenes have rarely been employed for
further synthetic applications.
The required starting aryl-substituted methyl propargyl
ethers are easily available by Sonogashira–Hagihara cou-
pling of 3-methoxy-1-propyne. We started with phenyl-
substituted compound 1 and first studied its deprotonation
and deuteration at low temperatures. Compound 1 was
lithiated at –78 °C in diethyl ether with a slight excess of n-
butyllithium and samples were quenched with perdeuter-
ated methanol after certain periods (Scheme 3).12 Even after
120 minutes at –78 °C only the -deuterated allene 2 was
detected by 1H NMR analysis. The isomeric compounds
with deuterium incorporation in -position, 1-D1 with a
propargyl ether structure, and 3 with an allenic structure
were not found within the limits of NMR analyses. Similar
experiments at –40 °C did not provide clear evidence of an
isomerization and formation of compound 3.13 At higher
temperatures lithiated 1 started to decompose.
In an accepted scenario, lithiation of D with n-butyllith-
ium provides the ambident carbanion which is represented
by the two mesomeric formulas G′ and G′′ showing the nuc-
leophilicity of this species in its - and in -position
(Scheme 2).9 Reaction of this carbanion with electrophiles
can therefore afford the two isomeric products I and J. As
mentioned above, protonation occurs selectively in -posi-
tion to provide allenes J. In literature, the reaction of other
electrophiles such as alkyl halides were also reported to
give the allenes J whereas with carbonyl compounds mix-
tures of compounds were obtained.10 For the observed for-
mation of products E from D (Scheme 1) we proposed an
isomerization by a proton shift leading from G′/G′′ to the al-
lenyl anion H. This proton shift may occur as direct 1,3-shift
or more likely by protonation of G′/G′′ to J (El = H) and
deprotonation to H which can also be presented in a second
mesomeric formula; because of the known predominating
reaction to products such as K only structure H is depicted.
Compound E could be derived from an in situ formed inter-
mediate K (El = R2–C=NH), which subsequently reacts in a
multi-step process with the carboxylic acid.6,7
1. 1.1 equiv nBuLi
Et2O, –78 °C
OMe
Ph
D
OMe
H
Ph
•
5, 15, 30, 60, 120 min
2. CD3OD
1
2
Ph
H
OMe
D
OMe
Ph
•
D
1-D1
3
OR1
H
Li
OR1
nBuLi
Ar
Ar
Scheme 3 Conversion of phenyl-substituted propargyl ether 1 into 3-
deuterated methoxyallene derivative 2
D
G´
Li
•
Ar
OR1
Li
OR1
H
With benzaldehyde as electrophile we investigated the
influence of reaction conditions on the regioselectivity of
the additions of lithiated 1 in detail (Scheme 4 and Table 1).
In most cases the yields were only determined after cycliza-
tion of the fairly sensitive primary alkoxyallene 4 to the fu-
ran derivative 6. Conditions similar to the deuteration ex-
periment above were applied in entry 1, which gave a crude
product mixture of unconsumed precursor 1, the expected
-addition product 4 (diastereomers are very likely formed,
but could not be identified in the crude product mixture)
and the -addition product 5 (ca. 2:1 mixture of syn/anti-
diastereomers). After application of catalytic amounts of
silver nitrate in the presence of potassium carbonate,14 2,3-
diphenylfuran (6) was isolated in 50% overall yield, whereas
substituted propargylic ether 5 was re-isolated unchanged
in 5% yield. During these experiments we learned that the
analysis and purification of the resulting mixtures is less te-
dious, when only 0.9 equivalent of n-butyllithium were em-
ployed as base which led to a higher amount of uncon-
sumed 1. Entry 2 essentially confirmed the first experiment
furnishing a slightly more -addition product 5. We repeat-
ed the conditions of entry 2, but performed the cyclization
under strongly basic conditions with potassium tert-butox-
ide15 that provided furan derivative 6 in 50% yield (entry 3).
Interestingly, these conditions also led to a large extent to a
~ H
•
Ar
H
H
G´´
El
El
OR1
El
Ar
El
OR1
H
OR1
H
Ar
•
•
Ar
H
El
K
J
I
2 Li
Ar
El
OR1
El
2 El
nBuLi
OR1
•
G´/G´´
Ar
•
L
M
Scheme 2 Lithiation of aryl-substituted propargyl ether D to interme-
diate G′/G′′ and its possible reactions to allene J and propargyl ether I;
formation of allene K by isomerization to allenyl anion H; formation of
dilithiated species L and reaction to allene M
The situation is even more complex since it is also
known that the carbanion G′/G′′ can be lithiated by an ex-
cess of n-butyllithium to provide the dianion L, which sub-
sequently reacts with electrophiles to give tetrasubstituted
alkoxyallenes of type M.11 Despite the demonstrated high
synthetic usefulness of alkoxyallenes these easily accessible
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

C
I. Linder et al.
Paper
Synthesis
cyclization of 5 to 2,5-diphenylfuran (7) in 10% yield. A
complete cyclization of 5 was observed when gold catalysis
was applied for the cyclization step (entry 4).16,17 Now the
two furan derivatives 6 and 7 were isolated in 39% and 19%
yield, respectively. The deviation of the ratio of -product
(compound 6) and -products (compounds 5 and 7) are
very likely not due to the changed cyclization conditions
but to the differing mass balances of the two experiments.
The addition of lithiated 1 to benzaldehyde is less selective
at –40 °C and it showed a lower mass balance indicating
starting decomposition of the carbanion (entry 5).
Ph
Ph
Ph
Ph
H
Ph
OMe
H
– MeOH
5-endo-trig
5-endo-dig
•
Ph
OMe
O
O
OH
4
8
6
H
OMe
Ph
OMe
Ph
– MeOH
Ph
Ph
Ph
Ph
O
O
HO
5
9
7
Scheme 5 Cyclization of allene 4 to 2,5-dihydrofuran 8 followed by
formation of 6 and cyclization of alkyne 5 to 2,3-dihydrofuran 9 and
formation of 7
1. equiv nBuLi
Et2O or THF
–78 °C or –40 °C
Ph
γ
OMe
H
OMe
2,3-dihydrofuran intermediate 9 under silver(I) catalysis
and only slowly under basic conditions. The soft Lewis acid
gold(I) smoothly promotes this process generating 9 and af-
ter a 1,2-elimination of methanol furan derivative 7.17 We
could demonstrate the efficiency of this reaction by con-
verting pure compound 5 into 7 in 73% yield.
OMe
•
α
Ph
Ph
+
2.
Ph
γ
α
Ph
Ph
O
OH
HO
1
H
4
5
cyclization
method
A, B, C
–78 °C, 1 h
3. H2O
Ph
Ph
Next, the influence of the solvent was examined and a
4:1 mixture of diethyl ether and hexanes was employed to
decrease the polarity (Table 1, entry 6). After cyclization,
15% of 1 and 40% of 2,3-diphenylfuran (6) were isolated.
The product of an -addition 5 was not observed. This re-
sult indicates that the polarity of the solvent has a consider-
able influence on the regioselectivity; since the applied
base n-butyllithium is delivered in hexanes as solvent the
concentration (amount of diethyl ether) certainly has a con-
siderable impact on the outcome of these reactions.18 This
effect was not further studied, but instead we increased the
polarity of the applied solvent by using tetrahydrofuran
(entries 7–9). In all experiments, the amount of the -addi-
tion product 4 (respective its subsequent product 6) was
decreased to 15–33%, whereas the -addition product 5
and/or its cyclization product increased to 50–60%. The best
+
5
+
Ph
Ph
O
O
7
6
Scheme 4 Reaction of lithiated propargyl ether 1 with benzaldehyde
under different conditions followed by cyclization (for details, see Table
1, Method A: 0.2 equiv AgNO3, 3–5 equiv K2CO3, CH3CN, r.t., 19 h;
Method B: 0.3 equiv KOtBu, DMSO, r.t., 19 h; Method C: 0.05 equiv
AuCl, 0.15 equiv pyridine, CH2Cl2, r.t., 19 h)
The cyclization scenarios are illustrated without mecha-
nistic details in Scheme 5. A 5-endo-trig cyclization con-
verts allenyl alcohol 4 into the 2,5-dihydrofuran derivative
8 which undergoes fast 1,4-elimination of methanol to the
aromatized heterocycle 6. This cyclization proceeds with
the three methods applied. On the other hand, the isomeric
alkynyl alcohol 5 does undergo a 5-endo-dig cyclization to
Table 1 Reaction of Lithiated Methyl Propargyl Ether 1 with Benzaldehyde under Different Conditions Followed by Cyclization
Entry
Equiv nBuLi
Temperature
Solvent
Cyclization
methoda
Recovered 1
-Product 6
-Product 5
Furan 7
1
2
3
4
5
6
1.2
0.9
0.9
0.9
0.9
0.9
–78 °C
–78 °C
–78 °C
–78 °C
–40 °C
–78 °C
Et2O
Et2O
Et2O
Et2O
Et2O
A
A
B
C
B
A
7%
22%
27%
10%
12%
15%
50%
48%
50%
39%
23%
40%
5%
15%
5%
–
–
–
10%
19%
–
20%
–
Et2O/
hexanes (4:1)
–
7
8
9
0.9
0.9
0.9
–78 °C
–78 °C
–40 °C
THF
THF
THF
A
–
33%
24%
15%
54%
7%b
–
–
C
2%
2%
51%
60%
Cc
a Method A: 0.2 equiv AgNO3, 3–5 equiv K2CO3, CH3CN, r.t., 19 h; Method B: 0.3 equiv KOtBu, DMSO, r.t., 19 h; Method C: 0.05 equiv AuCl, 0.15 equiv pyridine,
CH2Cl2, r.t., 19 h.
b Only anti-5 was re-isolated.
c Due to the slow reaction of anti-5 the cyclization protocol was applied twice.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

D
I. Linder et al.
Paper
Synthesis
result with respect to the yield of 2,5-diphenylfuran (7) is
recorded in entry 9 where a reaction temperature of –40 °C
was applied. In this experiment, we also observed that the
syn-diastereomer of 5 isomerized faster and some anti-5
remained unchanged after the first cyclization reaction.
Subjecting the crude product again to the cyclization condi-
tions led to complete conversion and isolation of 7 in 60%
yield.
The solvent dependence of the /-regioselectivity was
confirmed by experiments employing the ,-unsaturated
cinnamic aldehyde (Scheme 6). Lithiated propargyl ether 1
in diethyl ether and this electrophile furnished -adduct 10
which after cyclization/elimination afforded the 2-stryl-
substituted furan derivative 11 in moderate yield. On the
other hand, the reaction in tetrahydrofuran mainly provid-
ed -addition product 12 which finally provided the 2,5-
disubstituted furan derivative in 13 in 25% yield and com-
pound 11 in 5% yield. Although the overall yields are only
moderate to low the examples reveal that isomeric furan
derivatives are easily available by changing the reaction
conditions. Further optimization may increase the efficien-
cy of these simple transformations.
1. 1.2 equiv nBuLi
Et2O
–78 °C, 15 min
OMe
R
OMe
Ph
OMe
H
Ph
Ph
•
+
R
2.
R
O
5 : 1
HO
OH
14
1
H
15
–78 °C, 2 h
3. H2O
1. 0.2 equiv AgNO3
7 equiv K2CO3
CH3CN/THF, r. t., 19 h
2. SiO2, CHCl3
R = C11H23
Ph
R
+
15 13%
O
16 61% overall yield
Scheme 7 Reaction of lithiated propargyl ether 1 with dodecanal fol-
lowed by silver-promoted cyclization to furan derivative 16
5:1 mixture of the primary - and -addition products 17
and 18 (Scheme 8). Silver-catalyzed isomerization of allene
17 gave 2,5-dihydrofuran derivative 19 in 54% overall yield
and unchanged 18 was isolated in 11% yield. The aromatiza-
tion to furan derivatives is not possible in this case due to
the dimethyl substitution at C-2 of 19. Application of the
standard reaction conditions but addition of HMPA as high-
ly polar co-solvent inverted the ratio of 17:18 to ca. 1:9. Un-
fortunately the crude product was not sufficiently pure to
allow full purification and isolation of defined compounds,
but this experiment confirms that higher polarity of the
solvent shifts the regioselectivity to -addition.
1. 0.9 equiv nBuLi
Et2O
–78 °C, 15 min
2.
Ph
Ph
OMe
H
1. Method A
2. SiO2
•
1
Ph
Ph
O
Ph
OH
O
10
30% overall yield
11
H
–78 °C, 1 h
3. H2O
1. 1.2 equiv nBuLi
Et2O
–78 °C, 15 min
OMe
Ph
OMe
H
1. 0.9 equiv nBuLi
THF
–78 °C, 15 min
•
+
Ph
1
OMe
2.
O
Method C
Ph
OH
5 : 1
HO
Ph
1
Ph
2.
17
18
Ph
O
HO
12 ( + 10 + 1)
Ph
0.2 equiv AgNO3
3 equiv K2CO3
CH3CN
–78 °C, 2 h
3. H2O
O
25% overall yield
(+ 5% 11)
13
H
–78 °C, 1 h
3. H2O
r. t., 19 h
Ph
Scheme 6 Reaction of lithiated propargyl ether 1 with cinnamic alde-
hyde in diethyl ether or in tetrahydrofuran leading after cyclization to
2,3- and 2,5-disubstituted furan derivatives 11 and 13, respectively
(Method A: 0.2 equiv AgNO3, 3–5 equiv K2CO3, CH3CN, r.t., 19 h; Meth-
od C: 0.05 equiv AuCl, 0.15 equiv pyridine, CH2Cl2, r.t., 19 h).
+
18 11%
OMe
O
19 54% overall yield
Scheme 8 Reaction of lithiated propargyl ether 1 with acetone fol-
lowed by silver-catalyzed cyclization to dihydrofuran derivative 19 as
major product
As representative of an aliphatic aldehyde dodecanal
was examined as electrophile and after its reaction with
lithiated 1 under standard conditions in diethyl ether, a
mixture of the primary products 14 and 15 (ratio ca. 5:1)
was obtained (Scheme 7). The crude product mixture was
subjected to the silver nitrate cyclization method and the
oxygen sensitive 2-alkyl-3-aryl-substituted furan deriva-
tive 16 was isolated in 61% overall yield; a second fraction
provided 13% of pure 15.
Comparable results were obtained by combining lithia-
tated propargyl ether 1 with cyclohexanone (Scheme 9).
The crude product mixture of 20 and 21 (ratio ca. 4:1) was
treated under basic conditions to give the 2,2-dialkyl-sub-
stituted dihydrofuran derivative 22 in 52% overall yield. Un-
changed alkynyl alcohol 21 was isolated in 13% yield.
The results obtained with phenyl-substituted methyl
propargyl ether 1 were confirmed with precursors bearing
an electron-donating methoxy or a fluorine substituent in
para-position of the aryl group (Scheme 10). In both cases,
The reaction of lithiated 1 with aliphatic or cyclic ke-
tones provided similar results. Under the standard reaction
conditions in diethyl ether as solvent, acetone furnished a
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

E
I. Linder et al.
Paper
Synthesis
1. 0.9 equiv nBuLi
THF
–78 °C, 15 min
1. 1.2 equiv nBuLi
Et2O
–78 °C, 15 min
Ph
OMOM
OMOM
Ph
OMOM
Ph
OMe
H
OMe
•
Ph
Ph
+
•
1
Ph
+
2.
Ph
Ph
H
2.
O
O
OH
HO
29
OH
4 : 1
HO
H
30
31
20
21
–78 °C, 1 h
3. H2O
0.2 equiv AgNO3
3 equiv K2CO3
CH3CN, r. t., 19 h
–78 °C, 2 h
3. H2O
0.3 equiv KOtBu
DMSO
r. t., 19 h
OMOM
Ph
Ph
Ph
Ph
+
Ph
O
HO
+
21 13%
OMe
O
6
14%
31
80%
22 52% overall yield
Scheme 11 Reaction of lithiated propargyl ether 29 with benzalde-
hyde leading to alkynyl alcohol 31 as major product
Scheme 9 Reaction of lithiated propargyl ether 1 with cyclohexanone
followed by base-promoted cyclization to spiro compound 22 as major
product
the carbonyl compounds. The simplified interpretation
(Scheme 12) regards the ambident anions as ion pairs with
relatively weak interaction with the lithium cation (see ref.
9). The result with the MOM-protected compound 29 sug-
gests that a larger distance between the anion N′/N′′ and
the counter ion preferentially leads to -substitution prod-
uct O. A similar effect is operating when THF is employed as
solvent which is a better ligand for the lithium cation and
may lead to a solvent separated ion pair. On the other hand,
a shorter distance and stronger interaction of the lithium
cation as depicted in P′/P′′ in the less polar solvent diethyl
ether (possibly a contact ion pair) leads to the favored for-
mation of the -addition product Q. The -position of P′/P′′
is also the preferred position of attack of other electrophiles
(proton, deuteron and alkyl halides4).20 In none of our ex-
periments we gained evidence that a proton shift of the
lithiated propargyl ethers P′/P′′ to an isomeric allenyl spe-
cies such as R occurs. For a sound mechanistic explanation
of the formation of products such as E (Scheme 1) addition-
al experiments are required.
lithiation under standard conditions, reaction with acetone
and silver-catalyzed isomerization provided mixtures of
the dihydrofuran derivatives 24 or 27 with the alkynyl alco-
hols 25 or 28, respectively. The ratio of - and -products is
slightly lower (ca. 2.5:1 or 3:1) compared with the parent
compound 1. It is pure speculation to attribute this lower
selectivity to the electron-donating effect of the aryl group
and a higher electron density in -position of the ambident
anion (see intermediate G′ in Scheme 2 and discussion be-
low).
1. 1.2 equiv nBuLi
Ar
Et2O
OMe
OMe
Ar
–78 °C, 15 min
Ar
+
OMe
O
2.
HO
O
23 Ar = 4-MeO-C6H4-
26 Ar = 4-F-C6H4-
50% 24 Ar = 4-MeO-C6H4-
52% 27 Ar = 4-F-C6H4-
21% 25
16% 28
–78 °C, 2 h
3. H2O
4. 0.2 equiv AgNO3
3 equiv K2CO3
CH3CN, r. t., 19 h
Scheme 10 Reaction of lithiated propargyl ethers 23 and 26 with ace-
tone followed by silver-catalyzed cyclization to dihydrofuran derivatives
24 and 27 and alkynyl ethers 25 and 28
R
Li
Li
O
OMe
OMe
O
O
OMOM
R
Ph
Ph
Ph
Ph
•
Ph
H
OH
H
H
in THF
major pathway
R
•
R
N´
Li
N´´
O
Finally, the influence of the alkoxy group was briefly in-
vestigated. MOM-Protected propargyl ether 2919 bearing
the methoxymethly instead of a methyl substituent was
lithiated in tetrahydrofuran as solvent and after addition of
benzaldehyde the two primary products 30 and 31 were
formed with the latter clearly being the dominating compo-
nent (Scheme 11). Silver-promoted cyclization of the crude
product gave 2,3-diphenylfuran (6) in 14% yield and un-
changed alkynyl alcohol 31 was isolated in 80% yield. By us-
ing the more polar solvent tetrahydrofuran and the stron-
ger complexing alkoxy substituent a reasonably and high
yielding access to -addition products of type 31 could be
achieved.
R
O
R
Li
Ph
R
OMe
H
OMe
H
OMe
H
•
R
in Et2O
major pathway
OH
Q
P´
P´´
~ H
Ph
H
OMe
Li
•
R
Scheme 12 Mechanistic interpretation of the observed regioselectivi-
ties of ambident anion N′/N′′ (solvent separated ion pair) and P′/P′′
(contact ion pair)
Our mechanistic explanation is based on the plausible
assumption that the regioselectivity of the overall process is
decided by the addition of the lithiated propargyl ethers to
In summary, this study shows that the deprotonation of
alkyl propargyl ethers with n-butyllithium provides an am-
bident anion which reacts with carbonyl compounds to give
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

F
I. Linder et al.
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Synthesis
mixtures of the expected -addition and -addition prod-
ucts. The observed regioselectivity depends on the solvent
employed: in diethyl ether the -adducts are favored and in
THF the -adducts predominate. After cyclization either un-
der silver or gold catalysis, -adducts such as benzaldehyde-
derived allenyl alcohol 4 provided 2,3-disubstituted furans
like 6. On the other hand, the regioisomeric 2,5-disubstitut-
ed furan 7 was smoothly obtained by the gold-catalyzed
isomerization of -addition product 5. The regioselective
reactions of lithiated propargyl ethers with ketones as elec-
trophile provide the corresponding 2,5-dihydrofuran deriv-
atives, for instance spiro-compound 22. These products
contain a ketal moiety at C-5 of the 2,5-dihydrofuran ring
which should allow subsequent Lewis acid-promoted sub-
stitution reactions. Although the methods reported here
were not optimized they show an interesting regiodiver-
gent approach to specifically substituted furan and dihy-
drofuran derivatives.21
General Procedure for Silver(I)-Catalyzed Cyclizations (GP2)
Under exclusion of light, the crude addition product, silver nitrate (0.2
equiv) and potassium carbonate (5 equiv) were put into a flask which
was evacuated and flushed with argon. The mixture was dissolved in
acetonitrile (5 or 10 mL), stirred for 19 h at room temperature and fil-
tered through a pad of Celite. After washing with ethyl acetate and
evaporation of the filtrate, the crude product was purified by column
chromatography.
General Procedure for Gold(I)-Catalyzed Cyclizations (GP3)
In a flame-dried flask under argon, to a solution of the crude addition
product in dichloromethane (10 mL) were added pyridine (0.15
equiv) and gold(I) chloride (0.05 equiv) and the mixture was stirred
for 19 h at room temperature. Dichloromethane (5 mL), saturated
aqueous sodium NaHCO3 solution (5 mL) and water (5 mL) were add-
ed and the aqueous phase was extracted with dichloromethane (3 ×
10 mL/mmol). The combined organic phases were dried with MgSO4,
concentrated in vacuo and purified by column chromatography.
Deuteration Experiments
According to GP1, propargyl ether 1 (100 mg, 0.68 mmol) in diethyl
ether (3 mL) was treated with nBuLi (0.3 mL, 0.75 mmol, 1.2 equiv) at
–78 °C. Small samples of the mixture were taken via syringe and
quenched with methanol-D4 within the syringe (slight warming be-
fore deuteration cannot be excluded). Samples were taken after 5, 15,
30, 45, 60 und 120 min. Without purification, the resulting product
mixture was analyzed by 1H NMR spectroscopy.
Reactions were generally performed under argon in flame-dried
flasks, and the components were added by syringe. Unless otherwise
stated, yields refer to analytically pure samples.
The solvents (THF, CH2Cl2, CH3CN, and Et2O) were dried with the sol-
vent system SPS-800 (M. Braun GmbH). Hexanes (mixture of isomers)
and EtOAc were dried with CaH2 or K2CO3, respectively, and distilled
of before use. Et3N and pyridine were distilled from CaH2 and stored
under an argon atmosphere. The concentration of nBuLi (ca. 2.4 M in
hexanes, Acros) was determined by the diphenylacetic acid method.
Reagents were purchased and used without further purification. KOtBu
was freshly sublimed in vacuo before use. TLC was performed with
silica gel 60 F254 plates (Merck), column chromatography was per-
formed with silica gel 60 (230–400 mesh, 40–63 m, Merck or Fluka).
1H NMR [CHCl3 ( = 7.26 ppm), TMS ( = 0.00 ppm) as internal stan-
dard] and 13C NMR spectra [CDCl3 ( = 77.0 ppm) as internal standard]
were recorded in CDCl3 solutions with Bruker AC 250, EXC 400 instru-
ments or a Joel Eclipse 500 instrument. Integrals are in accordance
with assignments; coupling constants are given in Hz. Multiplicities
refer to: Cquart. (s), CH (d), CH2 (t), CH3 (q). 1H/13C-correlated spectra
(HSQC, HMBC) and 1H/1H-correlated spectra (COSY, NOESY) were re-
corded for assignments. IR spectra were measured with Nicolet 5 SXC
FTIR or Nicolet 205 FTIR spectrometers. MS analyses were performed
with Aligent 6210 (ESI-TOF, 4 kV), Ionspec QFT-7 (ESI-FT-ICR), CH-5
(FAB), Varian, and with MAT 711 (EI, 80 eV, 8 kV), Finigan. The ele-
mental analyses were recorded with Vario El, III (Elementar).
Data of deuterated compound 2
1H NMR (400 MHz, CDCl3):  = 3.45 (s, 3 H, OMe), 7.08 (s, 1 H, =CH),
7.30–7.35, 7.38–7.43 (2 m, 3 H, 2 H, Ph).
2,3-Diphenylfuran (6)
According to GP1 (Table 1, entry 1), propargyl ether 1 (205 mg, 1.40
mmol) in Et2O (10 mL) was treated with nBuLi (0.71 mL, 1.68 mmol)
for 15 min at –78 °C. Benzaldehyde (164 mg, 1.54 mmol) was added
and the mixture was quenched after 1 h with water. Work-up provid-
ed the crude product (595 mg) as a mixture of compounds 4 and 5.
According to GP2, the crude product mixture was stirred with AgNO3
(48 mg, 0.28 mmol), K2CO3 (966 mg, 7.00 mmol) in acetonitrile (10
mL) for 19 h at room temperature. Purification by chromatography
(silica gel, hexanes/EtOAc 50:1 to 20:1) furnished 1 (14 mg, 7%), 6
(138 mg, 50%) and 5 (18 mg, 5%, ratio of diastereomers: syn/anti ≈
2:1) as yellow oils.
2,3-Diphenylfuran (6)
1H NMR (400 MHz, CDCl3):  = 6.55 (d, J = 1.8 Hz, 1 H, 4-H), 7.26–7.43
(m, 8 H, Ph), 7.49 (d, J = 1.8 Hz, 1 H, 5-H), 7.50–7.54 (m, 2 H, Ph).
The data agree with those of the literature.17c
General Procedure for Lithiation of the Propargylic Ethers (GP1)
Under an atmosphere of dry argon, the corresponding propargylic
ether (1.0 equiv) was dissolved in Et2O (4 mL/mmol), cooled to –40 °C
or –78 °C and a solution of nBuLi (0.9–1.2 equiv) was added. After
stirring for the indicated time and temperature, the corresponding
electrophile was added. After the indicated time, the mixture was
quenched with saturated aqueous NaHCO3 solution (10 mL/mmol).
The phases were separated and the aqueous phase was extracted
with Et2O (2 × 10 mL/mmol). The combined organic phases were
dried (Na2SO4), filtered and evaporated in vacuo to provide the crude
product.
syn-2-Methoxy-1,4-diphenylbut-3-yn-1-ol (5)
1H NMR (400 MHz, CDCl3):  = 3.50 (s, 3 H, OMe), 4.37 (d, J = 4.3 Hz, 1
H, 2-H), 4.96 (d, J = 4.2 Hz, 1 H, 1-H), 7.26–7.41, 7.46–7.52 (2 m, 8 H, 2
H, Ph); the signal of OH could not be detected.
13C NMR (101 MHz, CDCl3):  = 57.3 (q, OMe), 75.4, 77.2 (2 d, C-1,
C-2), 84.4, 88.7 (2 s, C-3, C-4), 122.5, 127.0, 128.2, 128.4, 128.4, 128.7,
131.9, 139.5 (s, 6 d, s, Ph).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

G
I. Linder et al.
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Synthesis
anti-2-Methoxy-1,4-diphenylbut-3-yn-1-ol (5)
13C NMR (101 MHz, CDCl3):  = 112.8, 115.4 (2 d, Furan-CH, C=CH),
124.7, 126.5, 127.2, 127.7, 128.2, 128.5, 128.8, 128.9 (3 d, s, 4 d, Fu-
ran-C, Ph, C=CH), 133.7, 137.3 (2 s, Ph), 142.0 (d, Furan-CH), 148.6 (s,
Furan-C).
1H NMR (400 MHz, CDCl3):  = 3.58 (s, 3 H, OMe), 4.16 (d, J = 8.0 Hz,
1 H, 2-H), 4.80 (d, J = 8.0 Hz, 1 H, 1-H), 7.26–7.40, 7.46–7.52 (2 m, 8 H,
2 H, Ph); the signal of OH could not be detected.
13C NMR (101 MHz, CDCl3):  = 57.1 (q, OMe), 76.5, 77.2 (2 d, C-1,
C-2), 84.7, 88.5 (2 s, C-3, C-4), 122.4, 127.5, 128.1, 128.2, 128.4, 128.7,
131.8, 139.2 (s, 6 d, s, Ph).
The data agree with those of the literature.23
(E)-2-Phenyl-5-styrylfuran (13)
According to GP1 but using THF, propargyl ether 1 (200 mg, 1.37
mmol) in THF (10 mL) was treated with nBuLi (0.55 mL, 1.23 mmol)
for 1 h at –78 °C. Cinnamic aldehyde (189 mg, 1.50 mmol) was added
and the mixture was quenched after 1 h with water. Work-up provid-
ed the crude product (330 mg) as a mixture of compounds 10, 12 and
1.
Data of both isomers
IR (ATR): 3450 (O-H), 3060–2820 (=C-H, C-H), 2225 (C≡C), 1605 (C=C)
cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H16O2Na: 275.1043;
found: 275.1045.
According to GP3, the crude product mixture was stirred with AuCl
(14 mg, 0.06 mmol), pyridine (15 L, 0.18 mmol) in CH2Cl2 (10 mL) for
19 h at room temperature. Purification by chromatography (silica gel,
hexanes/EtOAc 50:1 to 20:1) furnished 13 (75 mg, 25%), 11 (15 mg,
5%) and precursor 1 (45 mg, 25%).
1H NMR (400 MHz, CDCl3):  = 6.44, 6.70 (2 d, J = 3.4 Hz, 1 H each, 3-H,
4-H), 6.92, 7.14 (2 d, J = 16.2 Hz, 1 H each, HC=CH), 7.19–7.53, 7.74 (m,
mc, 9 H, 1 H, Ph).
2,5-Diphenylfuran (7)
According to GP1 but using THF (Table 1, entry 9), propargyl ether 1
(197 mg, 1.35 mmol) in THF (10 mL) was treated with nBuLi (0.54 mL,
1.21 mmol) for 1 h at –40 °C. Benzaldehyde (158 mg, 1.48 mmol) was
added and the mixture was quenched after 1.5 h with water. Work-up
provided the crude product (546 mg) as a mixture of compounds.
According to GP3, the crude product mixture was stirred with AuCl
(14 mg, 0.06 mmol), pyridine (15 L, 0.18 mmol) in CH2Cl2 (10 mL) for
19 h at room temperature. The received crude product still contained
compound anti-5 and therefore the procedure was repeated. Purifica-
tion by chromatography (silica gel, hexanes/EtOAc 50:1 to 20:1) fur-
nished 1 (4 mg, 2%) and a 20:80 mixture of 6 and 7 (200 mg, 75%); the
calculated yields of 6 and 7 are 15% and 60%.
1H NMR (400 MHz, CDCl3):  = 6.74 (s, 2 H, 3-H, 4-H), 7.28, 7.37–7.44,
7.72–7.77 (mc, 2 m, 2 H, 4 H, 4 H, Ph).
The data agree with those of the literature.22
13C NMR (101 MHz, CDCl3):  = 107.5, 111.2, 116.5 (3 d, Furan-CH,
C=CH), 124.0, 126.5, 127.1, 127.6, 127.7, 128.9 (6 d, Ph, Furan-CH),
130.8, 137.2, 153.0, 153.6 (4 s, Ph, Furan-C).
The data agree with those of the literature.22
3-Phenyl-2-undecylfuran (16)
According to GP1, propargyl ether 1 (200 mg, 1.37 mmol) in Et2O (10
mL) was treated with nBuLi (0.66 mL, 1.64 mmol) for 15 min at –78
°C. Dodecanal (252 mg, 1.37 mmol) was added and the mixture was
quenched after 2 h with water. Work-up provided a mixture of crude
product 14 and 15 (ratio ca. 5:1, 815 mg).
Synthesis of 7 Starting with Pure Compound 5
According to GP2, the crude product mixture was stirred with AgNO3
(46 mg, 0.27 mmol), K2CO3 (945 mg, 9.84 mmol) in acetonitrile (10
mL) and THF (10 mL) for 19 h at room temperature. To complete the
elimination, the crude product was dissolved in CHCl3 (10 mL) and
stirred under argon with silica gel for 10 h at room temperature. Puri-
fication by chromatography (silica gel, alumina, hexanes/EtOAc 20:1
to 4:1) furnished 16 (376 mg, 61%) as yellow oil, a 4:1 mixture of 15
and 16 (20 mg, 4%) and pure compound 15 (65 mg, 13%, ratio of dia-
stereomers syn/anti ≈ 2.1).
1H NMR (400 MHz, CDCl3):  = 0.90 (t, J = 6.8 Hz, 3 H, Me), 1.22–1.37,
1.71 (m, mc, 16 H, 2 H, CH2), 2.79 (t, J = 7.5 Hz, 2 H, 2-CH2), 6.51 (d, J =
1.6 Hz, 1 H, 4-H), 7.25–7.31 (m, 1 H, Ph), 7.36 (dd, J = 0.5, 1.6 Hz, 1 H,
5-H), 7.38–7.43 (m, 4 H, Ph).
According to GP3, alkynyl alcohol 5 (140 mg, 0.56 mmol) was stirred
with AuCl (6.5 mg, 0.03 mmol) and pyridine (6.7 L, 0.08 mmol) in
CH2Cl2 (9 mL) for 19 h at room temperature. The received crude prod-
uct was dissolved in CHCl3 and stirred with silica gel to complete the
elimination of methanol. Purification by chromatography (silica gel,
hexanes/EtOAc 20:1) furnished 7 (90 mg, 73%) as solid.
(E)-3-Phenyl-2-styrylfuran (11)
According to GP1, propargyl ether 1 (200 mg, 1.37 mmol) in Et2O (10
mL) was treated with nBuLi (0.53 mL, 1.23 mmol) for 15 min at –78
°C. Cinnamic aldehyde (181 mg, 1.37 mmol) was added and the mix-
ture was quenched after 1 h with water. Work-up provided the crude
product (600 mg) as a mixture of compounds 10 and 1.
13C NMR (101 MHz, CDCl3):  = 14.2 (q, Me), 22.8, 27.0, 28.6, 29.45,
29.46*, 29.67, 29.74, 29.75, 32.0 (9 t, CH2), 111.3 (d, C-4), 120.8 (s,
C-3), 126.4, 127.9, 128.6, 134.5 (3 d, s, Ph), 140.4 (d, C-5), 152.2 (s,
C-2); * signal with higher intensity.
According to GP2, the crude product mixture was stirred with AgNO3
(42 mg, 0.25 mmol), K2CO3 (846 mg, 6.15 mmol) in acetonitrile (10
mL) for 19 h at room temperature. To complete the elimination, the
crude product was dissolved in CHCl3 (10 mL) and stirred under argon
with silica gel for 10 h at room temperature. Purification by chroma-
tography (silica gel, hexanes/EtOAc 50:1 to 20:1) furnished 11 (90 mg,
30%) as yellow oil.
1H NMR (400 MHz, CDCl3):  = 6.62 (d, J = 1.9 Hz, 1 H, 4-H), 7.12, 7.22
(2 d, J = 16.1 Hz, 1 H each, HC=CH), 7.24–7.29, 7.33–7.39 (2 m, 2 H, 3
H, Ph), 7.46 (d, J = 1.9 Hz, 1 H, 5-H), 7.47–7.52 (m, 5 H, Ph).
syn-3-Methoxy-1-phenylpentadec-1-yn-4-ol (15)
1H NMR (400 MHz, CDCl3):  = 0.87 (t, J = 6.9 Hz, 3 H, Me), 1.13–1.38,
2.12–2.19 (2 m, 18 H, 2 H, CH2), 2.60 (br s, 1 H, OH), 3.52 (s, 3 H, OMe),
3.77–3.84 (m, 1 H, 4-H), 4.17 (d, J = 3.9 Hz, 1 H, 3-H), 7.28–7.36, 7.40–
7.49 (2 m, 2 H, 3 H, Ph).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

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I. Linder et al.
Paper
Synthesis
anti-3-Methoxy-1-phenylpentadec-1-yn-4-ol (15)
1H NMR (500 MHz, CDCl3):  = 1.13 (qt, J = 12.9, 3.4 Hz, 1 H, CH2),
1.59–1.84 (m, 9 H, CH2), 3.47 (s, 3 H, OMe), 5.70 (d, J = 1.2 Hz, 1 H, 2-
H), 5.78 (d, J = 1.2 Hz, 1 H, 3-H), 7.30–7.35 (m, 5 H, Ph).
13C NMR (126 MHz, CDCl3):  = 22.4, 22.7, 25.2, 35.8, 36.8 (5 t, CH2),
54.2 (q, OMe), 89.9 (s, C-5), 106.5 (d, C-2), 122.53 (d, C-3), 127.9,
128.3, 128.5, 134.4 (3 d, s, Ph), 153.7 (s, C-4).
1H NMR (400 MHz, CDCl3):  = 0.87 (t, J = 6.9 Hz, 3 H, Me), 1.13–1.38,
1.83–1.89 (2 m, 18 H, 2 H, CH2), 2.60 (br s, 1 H, OH), 3.52 (s, 3 H, OMe),
3.69–3.74 (m, 1 H, 4-H), 3.97 (d, J = 7.7 Hz, 1 H, 3-H), 7.28–7.36, 7.41–
7.51 (2 m, 2 H, 3 H, Ph).
The sensitive compounds 16 and 15 decomposed by oxidation before
further characterization.
HRMS (pos. ESI): m/z [M + Na]+ calcd for C16H20O2Na: 267.1356;
found: 267.1362.
5-Methoxy-2,2-dimethyl-3-phenyl-2,5-dihydrofuran (19)
Anal. Calcd for C16H20O2 (244.3): C, 78.65; H, 8.25. Found: C, 78.58; H,
8.14.
According to GP1, propargyl ether 1 (200 mg, 1.37 mmol) in Et2O (5
mL) was treated with nBuLi (0.66 mL, 1.64 mmol) for 15 min at –78
°C. Acetone (0.30 mL, 235 mg, 4.10 mmol) was added and the mixture
was quenched after 2 h with water. Work-up provided the crude
product (280 mg) as a 5:1 mixture of compounds 17 and 18.
1-(1′-Methoxy-3′-phenylprop-2′-ynyl)cyclohexanol (21)
IR (ATR): 3455 (O-H), 3080–2820 (=C-H, C-H), 2220 (C≡C), 1595 (C=C)
cm–1
.
According to GP2, the crude product mixture was stirred with AgNO3
(47 mg, 0.27 mmol), K2CO3 (568 mg, 4.11 mmol) in acetonitrile (5 mL)
for 19 h at room temperature. Purification by chromatography (alu-
mina, hexanes/EtOAc 20:1 to 4:1) furnished 19 (152 mg, 54%) and 18
(31 mg, 11%) as yellow oils.
1H NMR (400 MHz, CDCl3):  = 0.83–0.92 (m, 1 H, CH2), 1.52–1.77 (m,
9 H, CH2), 3.52 (s, 3 H, OMe), 3.95 (s, 1 H, 1′-H), 7.28–7.35, 7.45–7.49
(2 m, 3 H, 2 H, Ph); the signal of OH could not be detected.
13C NMR (101 MHz, CDCl3):  = 21.5, 21.6, 26.0, 32.5, 33.4 (5 t, CH2),
57.7 (q, OMe), 73.6 (s, C-1), 80.1 (d, C-1′), 85.5, 87.8 (2 s, C-2′, C-3′),
122.6, 128.4, 128.6, 131.9 (s, 3 d, Ph).
IR (ATR): 3060–2870 (=C-H, C-H), 1600 (C=C) cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.48, 1.57 (2 s, 3 H each, Me), 3.45 (s, 3
H, OMe), 5.69 (d, J = 1.2 Hz, 1 H, 5-H), 5.86 (d, J = 1.2 Hz, 1 H, 4-H),
7.30–7.36, 7.38–7.41 (2 m, 3 H, 2 H, Ph).
13C NMR (126 MHz, CDCl3):  = 28.0, 29.0 (2 q, Me), 54.4 (q, OMe),
88.4 (s, C-2), 106.6 (d, C-5), 121.8 (d, C-4), 127.4, 128.3, 128.5, 133.5
(3 d, s, Ph), 152.8 (s, C-3).
HRMS (pos. ESI): m/z [M + Na]+ calcd for C16H20O2Na: 267.1356;
found: 267.1368.
Anal. Calcd for C16H20O2 (244.3): C, 78.65; H, 8.25. Found: C, 78.54; H,
8.33.
5-Methoxy-3-(4-methoxyphenyl)-2,2-dimethyl-2,5-dihydrofuran
(24)
HRMS (pos. ESI): m/z [M + Na]+ calcd for C13H16O2Na: 227.1043;
found: 227.1043.
According to GP1, propargyl ether 23 (200 mg, 1.14 mmol) in Et2O (7
mL) was treated with nBuLi (0.55 mL, 1.36 mmol) for 15 min at –78
°C. Acetone (329 mg, 5.67 mmol) was added and the mixture was
quenched after 2 h with water to give after work-up the crude prod-
uct (384 mg).
Anal. Calcd for C13H16O2 (204.3): C, 76.44; H, 7.90. Found: C, 76.40; H,
7.07.
3-Methoxy-2-methyl-5-phenylpent-4-yn-2-ol (18)
IR (ATR): 3455 (O-H), 2990–2835 (=C-H, C-H), 2225 (C≡C), 1605 (C=C)
According to GP2, the crude product mixture was stirred with AgNO3
(39 mg, 0.23 mmol), K2CO3 (788 mg, 5.70 mmol) in acetonitrile (10
mL) for 19 h at room temperature. Purification by chromatography
(alumina, hexanes/EtOAc 20:1 to 4:1) furnished 24 (132 mg, 50%) and
25 (55 mg, 21%) as yellow oils.
cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.350, 1.354 (2 s, 3 H each, Me), 3.53 (s,
3 H, OMe), 3.97 (s, 1 H, 3-H), 7.30–7.34, 7.44–7.48 (2 m, 3 H, 2 H, Ph);
the signal of OH could not be detected.
13C NMR (101 MHz, CDCl3):  = 24.5, 25.6 (2 q, Me), 57.6 (q, OMe),
73.0 (s, C-2), 79.9 (d, C-3), 85.6, 87.4 (2 s, C-4, C-5), 122.5, 128.4,
128.7, 131.9 (s, 3 d, Ph).
IR (ATR): 3075–2835 (=C-H, C-H), 1610 (C=C) cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.47, 1.55 (2 s, 3 H each, Me), 3.42 (s, 3
H, OMe), 3.79 (s, 3 H, OMe), 5.66 (d, J = 1.3 Hz, 1 H, 5-H), 5.79 (d, J =
1.3 Hz, 1 H, 4-H), 6.84–6.88, 7.32–7.36 (2 m, 2 H each, Ar).
HRMS (pos. ESI): m/z for [M +Na]+ calcd for C13H16O2Na: 227.1043;
13C NMR (101 MHz, CDCl3):  = 28.1, 29.1 (2 q, Me), 54.3 (q, OMe),
55.3 (q, OMe), 88.3 (s, C-2), 106.6 (d, C-5), 113.9 (d, Ar), 120.2 (d, C-4),
125.6 (s, Ar), 128.6 (d, Ar), 152.28 (s, C-3), 159.6 (s, Ar).
found: 227.1049.
2-Methoxy-4-phenyl-1-oxaspiro[4.5]dec-3-ene (22)
According to GP1, propargyl ether 1 (230 mg, 1.57 mmol) in Et2O (5
mL) was treated with nBuLi (0.76 mL, 1.89 mmol) for 15 min at –78
°C. Cyclohexanone (462 mg, 4.71 mmol) was added and the mixture
was quenched after 2 h with water. Work-up provided the crude
product (603 mg, ratio of 20/21 ≈ 4:1).
HRMS (pos. ESI): m/z [M + Na]+ calcd for C14H18O3Na: 257.1148;
found: 257.1163.
3-Methoxy-5-(4-methoxyphenyl)-2-methylpent-4-yn-2-ol (25)
IR (ATR): 3470 (O-H), 2975–2825 (=C-H, C-H), 2220 (C≡C), 1605 (C=C)
cm–1
.
The crude product was stirred with KOtBu (53 mg, 0.47 mmol) in
DMSO (5 mL) for 19 h at room temperature. After quenching with sat-
urated aqueous NaHCO3 solution (4 mL) the aqueous phase was ex-
tracted with EtOAc (3 × 5 mL) and the combined organic phases were
dried with Na2SO4. After evaporation the crude product (395 mg) was
purified by chromatography (alumina, hexanes/EtOAc 20:1 to 10:1) to
provide 22 (201 mg, 52%) and 21 (49 mg, 13%) as yellow oils.
1H NMR (400 MHz, CDCl3):  = 1.32, 1.33 (2 s, 3 H each, Me), 3.51 (s, 3
H, OMe), 3.79 (s, 3 H, OMe), 3.93 (s, 1 H, 3-H), 6.79–6.86, 7.34–7.41 (2
m, 2 H each, Ar); the signal of OH could not be detected.
13C NMR (101 MHz, CDCl3):  = 24.5, 25.6 (2 q, Me), 55.4 (q, OMe),
57.6 (q, OMe), 73.0 (s, C-2), 80.0 (d, C-3), 84.1, 87.3 (2 s, C-4, C-5),
114.0 (d, Ar), 114.6 (s, Ar), 133.3 (d, Ar), 159.9 (s, Ar).
IR (ATR): 3080–2820 (=C-H, C-H), 1595 (C=C) cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

I
I. Linder et al.
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Synthesis
HRMS (pos. ESI): m/z [M + Na]+ calcd for C14H18O3Na: 257.1148;
found: 257.1149.
13C NMR (126 MHz, CDCl3):  = 24.1, 25.1 (2 q, Me), 57.2 (q, OMe),
72.5 (s, C-2), 79.4 (d, C-3), 84.9 (d, JCF = 1.5 Hz, C-5), 85.8 (s, C-4), 115.2
(dd, JCF = 22.1 Hz, Ar), 118.1 (d, JCF = 3.7 Hz, Ar), 133.3 (dd, JCF = 8.4 Hz,
Ar), 162.3 (d, JCF = 250.1 Hz, Ar).
Anal. Calcd for C14H18O3 (234.3): C, 71.77; H, 7.74; found: C, 71.53; H,
7.59.
HRMS (pos. ESI): m/z [M + Na]+ calcd for C13H15FO2Na: 245.0948;
found: 245.0942.
1-Fluoro-4-(3-methoxy-1-propynyl)benzene (26)
Analogously to a literature procedure,24 to a flame-dried flask under
an atmosphere of argon were added methyl propargyl ether (1.40 g,
20.0 mmol), 1-fluoro-4-iodobenzene (5.62 g, 24.0 mmol),
Pd(PPh3)2Cl2 (421 mg, 0.60 mmol) and NEt3 (30 mL). After stirring for
5 min at room temperature, CuI (114 mg, 0.60 mmol) was added and
the mixture was stirred until the starting materials were fully con-
verted (TLC control). The mixture was filtered through a pad of Celite
which was washed with EtOAc and the filtrate was concentrated in
vacuo. The crude product was purified by chromatography (silica gel,
hexanes/EtOAc 20:1 to 10:1) to afford compound 26 (2.53 g, 94%) as
colorless oil.
2-(Methoxymethoxy)-1,4-diphenylbut-3-yn-1-ol (31)
According to GP1 but using THF, propargyl ether 29 (205 mg, 1.16
mmol) in THF (10 mL) was treated with nBuLi (0.46 mL, 1.05 mmol)
for 15 min at –78 °C. Benzaldehyde (136 mg, 1.28 mmol) was added
and the mixture was quenched after 1 h with water. Work-up provid-
ed the crude product (350 mg) as a mixture of compounds 30 and 31.
According to GP2, the crude product mixture was stirred with AgNO3
(36 mg, 0.21 mmol), K2CO3 (723 mg, 5.24 mmol) in acetonitrile (10
mL) for 19 h at room temperature. Purification by chromatography
(silica gel, hexanes/EtOAc 50:1 to 20:1) furnished 6 (32 mg, 14%) and
31 (236 mg, 80%, ratio of diastereomers syn/anti ≈ 4:1).
IR (ATR): 3075–2825 (=C-H, C-H), 2240, 2210 (C≡C), 1605 (C=C) cm–1
.
1H NMR (400 MHz, CDCl3):  = 3.44 (s, 3 H, OMe), 4.30 (s, 2 H, 3′-H),
6.97–7.03, 7.40–7.45 (2 m, 2 H each, Ar).
Data of syn-31
1H NMR (400 MHz, CDCl3):  = 3.00 (br s, 1 H, OH), 3.23 (s, 3 H, OMe),
4.68 (d, J = 6.7 Hz, 1 H, OCH2O), 4.73, 4.95 (2 d, J = 4.9 Hz, 1 H each,
2-H, 1-H), 4.98 (d, J = 6.7 Hz, 1 H, OCH2O), 7.27–7.41, 7.48–7.52 (2 m,
8 H, 2 H, Ph).
13C NMR (101 MHz, CDCl3):  = 55.8 (q, OMe), 72.0, 75.6 (2 d, C-1,
C-2), 84.1, 88.4 (2 s, C-3, C-4), 94.4 (t, OCH2O), 122.5, 127.0, 128.1,
128.2, 128.4, 128.8, 131.9, 139.5 (s, 6 d, s, Ph).
13C NMR (101 MHz, CDCl3):  = 57.8 (q, OMe), 60.4 (t, C-3′), 84.7 (d, JCF
= 1.6 Hz, C-1′), 85.4 (s, C-2′), 115.7 (dd, JCF = 22.1 Hz, Ar), 118.8 (d, JCF
3.5 Hz, Ar), 133.8 (dd, JCF = 8.4 Hz, Ar), 162.7 (d, JCF = 249.6 Hz, Ar).
=
HRMS (EI, 80 eV, 70 °C): m/z [M]+ calcd for C10H9FO: 164.06375;
found: 164.06386.
3-(4-Fluorophenyl)-5-methoxy-2,2-dimethyl-2,5-dihydrofuran
(27)
Data of anti-31
According to GP1, propargyl ether 26 (200 mg, 1.22 mmol) in diethyl
ether (10 mL) was treated with nBuLi (0.45 mL, 1.46 mmol) for 15 min
at –78 °C. Acetone (353 mg, 6.09 mmol) was added and the mixture
was quenched after 2 h with water to give after work-up the crude
product (364 mg).
1H NMR (400 MHz, CDCl3):  = 3.00 (br s, 1 H, OH), 3.28 (s, 3 H, OMe),
4.59 (d, J = 7.4 Hz, 1 H, 2-H), 4.74 (d, J = 6.7 Hz, 1 H, OCH2O), 4.88 (d,
J = 7.4 Hz, 1 H, 1-H), 5.05 (d, J = 6.7 Hz, 1 H, OCH2O), 7.27–7.41, 7.48–
7.52 (2 m, 8 H, 2 H, Ph).
13C NMR (101 MHz, CDCl3):  = 56.1 (q, OMe), 72.1, 76.5 (2 d, C-1,
C-2), 84.7, 88.0 (2 s, C-3, C-4), 94.7 (t, OCH2O), 122.5, 127.4, 128.7,
131.7, 139.2 (s, 3 d, s, Ph); several Ph signals of the minor isomer are
covered by those of the major isomer.
According to GP2, the crude product mixture was stirred with AgNO3
(41 mg, 0.24 mmol), K2CO3 (842 mg, 6.09 mmol) in acetonitrile (10
mL) for 19 h at room temperature. Purification by chromatography
(alumina, hexanes/EtOAc 20/1 to 10/1) furnished 27 (140 mg, 52%)
and 28 (42 mg, 16%) as yellow oils.
The data agree with those of the literature.19
IR (ATR): 3080–2825 (=C-H, C-H), 1605 (C=C) cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.44, 1.53 (2 s, 3 H each, Me), 3.43 (s, 3
H, OMe), 5.65 (s, 1 H, 5-H), 5.81 (s, 1 H, 4-H), 7.02 (t, JHH = JHF = 8.6 Hz,
2 H, Ar), 7.35 (dd, JHH = 8.6 Hz, JHF = 5.5 Hz, 2 H, Ar).
Funding Information
This work was supported by the Deutsche Forschungsgemeinschaft.
D
eutscheForsch
u
n
gsge
m
einschaft()
13C NMR (101 MHz, CDCl3):  = 27.9, 28.9 (2 q, Me), 54.5 (q, OMe),
88.3 (s, C-2), 106.5 (d, C-5), 115.5 (dd, JCF = 21.5 Hz, Ar), 121.9 (dd, JCF
=
1.3 Hz, C-4), 129.1 (dd, JCF = 8.1 Hz, Ar), 129.5 (d, JCF = 3.5 Hz, Ar), 151.9
(s, C-3), 162.7 (d, JCF = 248.1 Hz, Ar).
Acknowledgment
We thank Bayer Healthcare for support and Dr. Reinhold Zimmer for
discussions and help during preparation of the manuscript.
HRMS (pos. ESI): m/z [M + Na]+ calcd for C14H18O3Na: 245.0948;
found: 245.0930.
5-(4-Fluorophenyl)-3-methoxy-2-methylpent-4-yn-2-ol (28)
Supporting Information
IR (ATR): 3450 (O-H), 3070–2825 (=C-H, C-H), 2225 (C≡C), 1660 (C=C)
cm–1
.
Supporting information for this article is available online at
1H NMR (500 MHz, CDCl3):  = 1.325, 1.333 (2 s, 3 H each, Me), 3.51 (s,
3 H, OMe), 3.93 (s, 1 H, 3-H), 6.97–7.03, 7.40–7.44 (2 m, 2 H each, Ar);
the signal of OH could not be detected.
https://doi.org/10.1055/s-0040-1705958. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
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I. Linder et al.
Paper
Synthesis
1
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J