On the Regioselectivity of the Nickel-Catalyzed Insertion of Alkynes into the Carbon-Carbon Bond of Oxetan-3-one

Article abstract of DOI:10.1055/s-0036-1589052

The study of the regioselectivity of insertion of unsymmetrical alkynes into the carbon-carbon bond of oxetan-3-one in the presence of a nickel catalyst has revealed a strong directing effect of a 2-thienyl substituent. This effect is larger than those of 2-vinylbenzene, trimethylsilyl, aryl, or 3-thienyl groups.

Full text of DOI:10.1055/s-0036-1589052

SYNTHESIS
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X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
special topic
A
en
M. Barday et al.
Special Topic
Synthesis
On the Regioselectivity of the Nickel-Catalyzed Insertion of
Alkynes into the Carbon–Carbon Bond of Oxetan-3-one
Manuel Barday
R1
O
O
NiBr2(PPh3)2 (10 mol%)
R2
Christopher Janot
O
Zn (50 mol%)
R1
R2
Daniel Clare
THF, 70 °C, 17 h
O
Caitlin Carr-Knox
Bradley Higginson
Kelvin Y. T. Ho
influence of alkyne substituents on regioselectivity
R
X
S
Ph
SiMe3
>
>
>>
~
Christophe Aïssa*
0
0
0
0
0-
0
0
3
0-
7
5
0
9-
4
3
5
X = S, O
Department of Chemistry, University of Liverpool,
Crown Street, Liverpool L69 7ZD, UK
aissa@liverpool.ac.uk
Published as part of the Special Topic Advanced
Strategies in Synthesis with Nickel
Received: 31.03.2017
OH
O
Accepted after revision: 17.05.2017
Published online: 27.06.2017
HO
HO
DOI: 10.1055/s-0036-1589052; Art ID: ss-2017-c0213-st
EtO2C
O
O
O
O
O
Abstract The study of the regioselectivity of insertion of unsymmetri-
cal alkynes into the carbon–carbon bond of oxetan-3-one in the pres-
ence of a nickel catalyst has revealed a strong directing effect of a 2-
thienyl substituent. This effect is larger than those of 2-vinylbenzene,
trimethylsilyl, aryl, or 3-thienyl groups.
HO
antibacterial
OH
immunosuppressant
OMe
O
OH
HO
HO
MeO
HO
Key words carbon–carbon bond activation, nickel, catalysis, oxeta-
none, alkynes, regioselectivity, insertion, pyrans
nPr
NF-ΚB inhibitor
O
O
O
nematocide
Pyrans are prominent heterocycles found in numerous
compounds of biological interest1 that display various prop-
erties such as antibacterial,2 immunosuppressant,3 nemato-
cidal,4 or other inhibitory activity5 (Figure 1). Recently, we
reported the synthesis of 2H-pyran-3(6H)-ones by insertion
of alkynes into the carbon–carbon bond of oxetan-3-one in
the presence of a nickel catalyst.6–8 This reaction is a rela-
tively rare example of metal-catalyzed cleavage of a C–C
bond9 in oxetane derivatives,10 as C–O bond cleavage is
much more frequent under a wide array of conditions.11,12
Significantly, oxetan-3-one is now an essential building
block in the synthesis of numerous oxetane derivatives that
have recently gained a great interest in medicinal chemistry
and pharmaceutical industry,13 and it is therefore import-
ant to understand its reactivity. Herein, we report on the
regioselectivity of the insertion of unsymmetrical alkynes
into the C–C bond of oxetan-3-one in the presence of a
nickel catalyst generated in situ from an air-stable Ni(II)
precursor.
Figure 1 Examples of biologically active compounds containing a
pyran motif
Louie et al. reported that NiCl2(PPh3)2 or NiBr2(PPh3)2 with
zinc powder in MeCN were also competent systems, but the
regioselectivity of the insertion of unsymmetrical alkynes
into the C–C bond of oxetan-3-one was not examined.14
Moreover, we observed that using NiBr2(PPh3)2 and Zn led
to inferior results in the regioselective cycloaddition of
azetidin-3-ones and 1,3-enynes when compared to the
combination of Ni(cod)2 and PPh3.15 Thus, the cycloaddition
of N-Ts-azetidin-3-one 1 (Ts = p-toluenesulfonyl) with 2-
methylhex-1-en-3-yne led to the isolation of 4 in only 14%
yield (Table 1, entry 1). However, the yield was greatly im-
proved by using THF instead of MeCN (entry 2). Moreover,
the cycloaddition of N-Boc-azetidin-3-one 2 (Boc = tert-but-
oxycarbonyl) with methylphenylacetylene led to a superior
yield of 5 in i-PrOH as compared to the reaction in THF (en-
tries 3 vs 4). Focusing our attention on oxetan-3-one 3 and
its cycloaddition with bis-phenylacetylene into 6 (entries
5–9), we found that using NiBr2(PPh3)2 and zinc powder in
THF gave the best yield (entry 7) when compared to other
combinations of pre-catalyst and solvent, and those condi-
In our initial study, we reported only three examples of
the nickel-catalyzed cycloaddition of alkynes with oxetan-
3-one using a combination of Ni(cod)2 (cod = cyclooctadi-
ene) and triphenylphosphine as pre-catalyst.6 Recently,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
M. Barday et al.
Special Topic
Synthesis
tions were therefore used in the study of the regioselectivi-
ty of the reaction with unsymmetrical alkynes 7a–o16
(Scheme 1, method A). It is noteworthy that the zinc pow-
der was used without activation.17
R1
R2
R2
O
O
R2
O
R1
method A, B, C or D
O
3
R1
7a–o
O
O
8a–m
9a–m
Table 1 Optimization of General Reaction Conditionsa
CF3
SiMe3
O
SiMe2Ph
Ph
SiMe3
R1
O
O
O
Ph
O
Ni(II) catalyst (5–10 mol%)
O
R2
Zn (50 mol%)
R1
R2
O
O
solvent, 40–80 °C, 17 h
X
(1.1 equiv)
X
4–6
8c, 73% (>19:1) [A]
8a, 85% (>19:1) [A]
8b, 57% (>19:1) [A]
99% (19:1) [D]
1–3
SiMe3
SiMe3 Ph
n-C8H17
Et
S
Ph
O
O
O
O
Ph
3
O
O
Ph
O
Ph
4
5
6
O
O
O
N
N
8d, 55% (>19:1) [A]
8e, 76% (6.6:1) [A]
8f, 59% (3:1) [A]
Ts
Boc
OMe
n-Bu
O
R
Entry Product Ni(II) catalystb
Solvent
Temp (°C) Yield (%)c r.r.d
O
O
1
2
3
4
5
6
7
8
9
4
4
5
5
6
6
6
6
6
NiBr2(PPh3)2
NiBr2(PPh3)2
NiBr2(PPh3)2
NiBr2(PPh3)2
NiBr2(PPh3)2
NiBr2(PPh3)2
NiBr2(PPh3)2
NiCl2(PPh3)2
NiCl2(PPh3)2
MeCN
THF
70
70
40
40
70
70
70
80
70
14
67
84
60
50
76
86
77
13
84:16
83:17
89:11
90:10
n.a.
O
O
8g, 96% (3.5:1) [A]
8h (R = n-Bu), 66% (4.5:1) [A]
8i (R = i-Bu), 66% (3.7:1) [B]
88% (2.8:1) [C]
92% (3.8:1) [D]
i-PrOH
THF
n-Bu
S
n-C8H17
n-Bu
S
O
O
Ph
O
i-PrOH
MeCN
THF
n.a.
O
O
O
8j, 71% (7.9:1) [A]
8k, 63% (9:1) [A]
n.a.
8l, 64% (5:1) [A]
MeCN
THF
n.a.
R
n-Bu
O
N
n.a.
O
n-Bu
a Reaction conditions: 1–3 (0.22 mmol), alkyne (0.24 mmol), Ni(II) catalyst
(0.022 mmol), Zn powder (0.11 mmol), solvent (0.2 M), 17 h, except other-
wise noted.
N
O
R
8n (R = H)
8o (R = Me)
8m, 28% (9:1) [A]
32% (9:1) [B]
b Five mol% of Ni(II) catalyst was used in entries 3 and 4.
c Yield of combined regioisomers after isolation.
d Regioisomers ratio determined by 1H NMR analysis of the crude mixture.
n.a.: Not applicable.
12% (9:1) [C]
Scheme 1 Regioselective insertion of unsymmetrical alkynes into the
C–C bond of oxetan-3-one. Reagents and conditions: [A]: as in Table 1,
entry 7; [B]: as A but 10 mol% PPh3 was added whilst oxetan-3-one and
the alkyne were added as a THF solution to a solution of the nickel cata-
lyst; [C]: as in Table 1, entry 8; [D]: 10 mol% Ni(cod)2, 30 mol% PPh3,
1,4-dioxane, 90 °C.6 Yields are given for the combined regioisomers af-
ter isolation. The ratio of regioisomers 8/9 is given in parentheses and
was determined from purified material, except for 8g (ratio from crude
material).
All the cycloadditions of alkynes substituted with a silyl
group at one terminus and an aryl or thienyl group at the
other gave only one regioisomer, as determined by NMR
spectroscopy. Thus, 2H-pyran-3(6H)-ones 8a–d were isolat-
ed in 55–85% yield according to our optimized method A
(Scheme 1). Alkyne 7e with a trimethylsilyl substituent at
one terminus and a linear alkyl chain at the other gave a
mixture 8e and 9e. It is noteworthy that silylated alkynes
do not undergo the same reaction with cyclobutanones,18
although the strain energies of oxetane, azetidine, and
cyclobutane are very similar.19 Alkynes substituted with an
alkyl group at one terminus and an aryl group at the other
gave superior yields in the case of an electron-poor aryl
group (8g vs 8f and 8h). However, the regioselectivity was
minimally better in the case of an electron-rich aryl group.
Substitution of the alkyl chain, even in the homopropargyl-
ic position, led to a slight erosion of the regioselectivity (8i).
Although the origin of this effect is not clear, it is notewor-
thy that the conditions had to be modified by adding 10
mol% of PPh3 and by adding a solution of oxetan-3-one 3
and alkyne 7i to a solution of the nickel catalyst in order to
obtain 8i in good yield (Scheme 1, method B). The same
mode of addition was also necessary for this alkyne in our
previous protocol based on Ni(cod)2.6 As was the case with
azetidin-3-ones,15 the reaction of a 1,3-enyne with oxetan-
3-one gave 8j with good regioselectivity. Strikingly, a much
better regioselectivity was observed when the alkyne was
substituted with a 2-thienyl group than with the 3-thienyl
isomer (8k vs 8l) whereas and the regioselectivity was the
same when the 2-thienyl group was replaced with a 2-furyl
group, although 8m was only isolated in low to moderate
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
M. Barday et al.
Special Topic
Synthesis
yields. However, 2-pyridylalkynes 8n and 8o did not under-
go the desired reaction, the former being recovered intact
whereas the latter underwent decomposition.
ordination of the sulfur atom of the thienyl group. Accord-
ingly, the difference of regioselectivity observed during the
formation of 8k and 8l would not be easily explained by in-
voking a η2-coordination of the thienyl group in either of
the pathways, as both 2-thienyl and 3-thienyl isomers
would be equally capable of such coordination in both
pathways. Similarly, neither η1-coordination nor η2-coordi-
nation of the thienyl group are possible if we postulate an
insertion of alkyne 7k into the C(sp3)–Ni bond of III in the
pathway leading to the major regioisomer of 8k. It would
follow that only the cleavage of C(sp2)–Ni bond in III occurs
in pathway b, as we would otherwise obtain the same level
of regioselectivity for 8k and 8l.
Moreover, it is noteworthy that using a combination of
NiCl2(PPh3)2 and Zn in MeCN (Scheme 1, method C) led to a
markedly decreased yield in the case of 8m, when com-
pared with the other methods, whereas regioselectivity in
the of case 8g was slightly inferior when we used this
method. On the other hand, the previously reported meth-
od relying on Ni(cod)2 and PPh3 in 1,4-dioxane (Scheme 1,
method D)6 and the method relying on NiBr2(PPh3)2 and Zn
in THF (Scheme 1, method A) gave very good results both
with challenging substrates (e.g., 7c into 8c) and with more
reactive substrates (e.g., 7g into 8g).
The markedly enhanced regioselectivity observed in the
conversion of 2-(hex-1-yn-1-yl)thiophene (7k) into 8k
when compared to the conversion of 3-(hex-1-yn-1-yl)thio-
phene (7l) into 8l could be explained by ηl-coordination of
the sulfur atom (Scheme 2),20 either in oxidative cyclization
transition state I towards intermediate II (pathway a) or in
transition state IV from intermediates III to V (pathway b).
Both pathways would converge towards intermediate V
that would then liberate the catalyst and the major regio-
isomer of 8k.
Moreover, as discussed previously,6 and on the basis of
the NMR data of isolated nickel-alkyne complexes,26 the
electronic density at the alkyne terminus attached to the
silyl group is greater than at the other terminus, and inser-
tion of the alkyne into the polarized C(sp3)(δ–)–Ni(δ+) bond
of the metallacycle that results from the oxidative addition
of the catalyst into the C–C bond of oxetan-3-one 3 would
then match the polarization of the alkyne in the reactions
leading to 8a–e.24,26 This electronic effect can overcome ste-
ric hindrance, as illustrated with the formation of 8e as ma-
jor regioisomer. Overall, by comparing the ratios of regio-
isomers for 8e–h and 8j–m, the influence of substituents
on the regioselectivity of the alkyne insertion in this reac-
tion decreases in the order 2-thienyl, 2-furyl > 2-vinylben-
zene > trimethylsilyl > aryl ~ 3-thienyl.
We also examined the regioselectivity of the ring open-
ing with substituted oxetan-3-one 10 that was prepared by
the method reported by Zhang.27 In stark contrast to the
nickel-catalyzed insertion of alkynes in substituted azeti-
din-3-ones that leads exclusively to the cleavage of the least
sterically hindered C–C bond,6,7b,14,15 we observed that the
reaction of 10 with oct-4-yne led to a mixture of regioiso-
mers 11 and 12, independently of the pre-catalyst, although
combining Ni(cod)2 and PPh3 in 1,4-dioxane gave a much
superior yield and better regioselectivity (Scheme 3). This
result also contrasts with the closely related nickel-cata-
lyzed cycloadditions of 1,6-diynes with cyclobutanones,28
of alkynes and 1,3-dienes with benzocyclobutanones,29 and
of 1,3-dienes with azetidin-3-ones.10b In all cases, only
cleavage of the least sterically hindered C–C bond of the 4-
membered ring was observed. The decrease of regioselec-
tivity in the ring cleavage of 10, as compared to the selectiv-
ity observed for similarly substituted azetidin-3-ones with
various protective groups on the nitrogen atom,6,7b,14,15 is
likely a result of the decreased steric bulk around the oxy-
gen atom of the oxetane.
S
Ph3P
Ph3P
O
S
Ni
Ni
O
n-Bu
n-Bu
O
O
n-Bu
I
II
O
S
a
b
3
8k
Ni
O
PPh3
n-Bu
n-Bu
V
O
S
Ni
Ni
O
PPh3
PPh3
S
O
O
III
IV
Scheme 2 Possible rationale explaining the enhanced regioselectivity
of the insertion of 2-(hex-1-yn-1-yl)thiophene (7k) during the forma-
tion of 8k
Pathway a would be in agreement with recent theoreti-
cal studies of the nickel-catalyzed reductive coupling of
alkynes and aldehydes,21 whereby the η1-coordination of
the sulfur atom in I and II would replace the η3-coordina-
tion proposed to explain the regioselectivity observed for
1,3-enynes.22 It would also be in agreement with several
isolated nickel-dihydrofuran complexes.23 However, recent
theoretical studies by Lin and Li suggest that the rearrange-
ment of II into V is not kinetically viable under the reaction
conditions, and the direct C–C oxidative addition of 3 to the
active nickel catalyst would instead be much more feasible
and lead to III.24 Nevertheless, the regioselectivity of the in-
sertion of alkyne 7k into the C(sp2)–Ni bond of III to V via
transition state IV25 would also be controlled by the η1-co-
In conclusion, we have examined the regioselectivity of
the insertion of unsymmetrical alkynes in oxetan-3-one in
the presence of a nickel catalyst generated in situ from an
air-stable precursor and we have observed that the 2-thienyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
M. Barday et al.
Special Topic
Synthesis
MS (CI): m/z (%) = 189 (10) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C12H17N2: 189.1386; found:
n-Pr
n-Pr
oct-4-yne
(1.1 equiv)
method A or D
O
O
n-Pr
O
n-Pr
Ph
Ph
189.1393.
Ph
2
O
O
2
2
O
17 h
10
11
12
Nickel-Catalyzed Cycloadditions of Alkynes with Oxetan-3-one;
General Procedures
[A]: 29% conversion, 14% yield (11/12 = 2.5:1)
[D]: 68% conversion, 55% yield (11/12 = 3.7:1)
Method A: A J-Young Teflon-screw flame-dried Schlenk tube equipped
with a small stirrer bar was charged with NiBr2(PPh3)2 (16 mg, 0.022
mmol, 0.1 equiv), Zn (7 mg, 0.111 mmol, 0.5 equiv), and degassed THF
(0.4 mL) under N2. Then, 3 (14 μL, 0.22 mmol, 1.0 equiv) and the
alkyne (0.244 mmol, 1.1 equiv) were added, followed by THF (0.6 mL).
The tube was sealed and the mixture was stirred at 70 °C (oil bath
temperature) for 17 h before being filtered through a small plug of sil-
ica gel. After evaporation of all volatiles under reduced pressure, the
relevant 2H-pyran-3(6H)-one was obtained after purification by flash
chromatography as specified.
Scheme 3 Regioselective C–C cleavage of substituted oxetan-3-one
10. Reagents and conditions: [A]: as in Table 1, entry 7; [D]: 10 mol%
Ni(cod)2, 30 mol% PPh3, 1,4-dioxane, 90 °C.
group exerts a stronger directing effect than 2-vinylben-
zene or trimethylsilyl substituents and approximately
twice as strong as the 3-thienyl group or other aryl groups.
Method B: This method was identical to method A except that the
alkyne (0.244 mmol, 1.1 equiv) was dissolved in THF (0.6 mL) and that
this solution was added to a mixture made of NiBr2(PPh3)2, Zn, and
PPh3 (5.8 mg, 0.022 mmol, 0.1 equiv) in THF (0.4 mL), before sealing
the Schlenk tube.
Unless otherwise noted, all reactions were carried out in flame-dried
glassware under dry N2 atmosphere. THF was purified with the sol-
vent purification system Pure Solv MD-6 from innovative Technology.
MeCN and 1,4-dioxane were purchased as anhydrous solvent on MS
4Å. Merck silica gel 60 (230–00 mesh) was used for chromatography.
NMR: Spectra were recorded on a Bruker DRX 500 in CDCl3; chemical
shifts (δ) are given in ppm. The solvent signals were used as referenc-
Method C: This method was identical to method A except that the re-
action temperature of the oil bath was set at 80 °C and that
NiCl2(PPh3)2 (14 mg, 0.022 mmol, 0.1 equiv) and MeCN (1 mL) were
used instead of NiBr2(PPh3)2 and THF, respectively.
es and the chemical shifts converted to the TMS scale (CDCl3: δC
=
77.0; residual CHCl3 in CDCl3: δH = 7.26); apparent splitting patterns
are designated using the standard abbreviations. In 13C NMR, an APT
sequence was used to separate methylene groups and quaternary car-
bons (e, even) from methine and methyl groups (o, odd). The re-
giochemistry of 8a–m, 11, and 12 was established by either HMBC or
NOE experiments. IR: PerkinElmer Spectrum 100 FT-IR spectropho-
tometer. The intensity of the peaks is indicated by w (weak), m (me-
dium), and s (strong). High-resolution mass spectra (HRMS) were de-
termined at the University of Liverpool on micromass LCT mass spec-
trometer (ESI) and Trio-1000 or Agilent QTOF 7200 mass
spectrometers (CI). Melting points: Griffin melting point apparatus
(not corrected). Elemental analyses: University of Liverpool. Com-
pounds 1,6 2,6 4–6,6 7a,30 7b,31 7e,32 7f,33 7g,6 7h,34 7i,6 7j,15 7k,19 7l,19
7m,35 7n,36 8c,6 8g,6 and 1027 were described previously. Compounds
3, 7c, and 7d are commercially available. All commercially available
reagents were used as received.
5-[4-(Trifluoromethyl)phenyl]-4-(trimethylsilyl)-2H-pyran-
3(6H)-one (8a)
This compound was obtained from 7a (59 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 9:1) afford-
ed 8a as a white amorphous solid; yield: 59 mg (85%); Rf = 0.3.
FT-IR (neat): 2962 (w), 1662 (s), 1570 (m), 1435 (m), 1407 (w), 1323
(vs), 1242 (s), 1164 (s), 1128 (vs), 1109 (vs), 1069 (vs), 1028 (m), 1014
(m), 977 (w), 934 (m), 828 (vs), 759 (m), 688 cm–1 (w).
1H NMR (CDCl3, 500 MHz): δ = 7.68 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.2
Hz, 2 H), 4.41 (s, 2 H), 4.18 (s, 2 H), –0.10 (s, 9 H).
13C NMR (CDCl3, 125 MHz): δ = 197.7 (e), 166.9 (e), 141.4 (e), 137.4
(e), 131.5 (e, q, J = 33.1 Hz), 128.3 (o, 2 C), 125.5 (o, q, J = 4.0 Hz, 2 C),
123.7 (e, q, J = 272.6 Hz), 71.5 (e), 70.1 (e), 0.2 (o, 3 C).
Anal. Calcd for C15H17F3O2Si: C, 57.31; H, 5.45. Found: C, 57.11; H,
5.44.
2-(Hex-1-yn-1-yl)-4,6-dimethylpyrimidine (7o)
CuI (12 mg, 0.06 mmol, 0.02 equiv), PdCl2(PPh3)2 (42 mg, 0.06 mmol,
0.02 equiv), PPh3 (30 mg, 0.12 mmol, 0.04 equiv), anhyd i-Pr2NEt (12
mL), anhyd Et3N (3 mL), 2-chloro-4,6-dimethylpyrimidine (426 mg, 3
mmol, 1 equiv), and hex-1-yne (0.52 mL, 4.5 mmol, 1.5 equiv) were
added under N2 to a flame-dried two neck round bottom flask. The
mixture was stirred at 100 °C for 68 h. The crystalline precipitate was
filtered off and all volatiles were removed under vacuum. Purification
of the oily residue by flash chromatography (PE/EtOAc, 85:15) gave 7o
as a yellow oil; yield: 171 mg (30%); Rf = 0.3.
4-[Dimethyl(phenyl)silyl]-5-phenyl-2H-pyran-3(6H)-one (8b)
This compound was obtained from 7b (58 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 9:1) afford-
ed 8b as a white amorphous solid; yield: 39 mg (57%); Rf = 0.3.
FT-IR (neat): 3050 (w), 2951 (w), 1656 (vs), 1600 (w), 1560 (s), 1488
(m), 1424 (m), 1376 (m), 1291 (s), 1277 (s), 1254 (s), 1138 (s), 1114
(s), 1079 (w), 1052 (w), 969 (m), 938 (s), 837 (vs), 809 (vs), 775 (m),
760 (s), 698 cm–1 (vs).
1H NMR (CDCl3, 500 MHz): δ = 7.52–7.45 (m, 2 H), 7.36 (tt, J = 6.4, 1.3
Hz, 1 H), 7.32–7.25 (m, 6 H), 7.15–7.10 (m, 2 H), 4.45 (s, 2 H), 4.18 (s, 2
H), 0.09 (s, 6 H).
FT-IR (neat): 2959 (w), 2933 (w), 2242 (m), 1583 (s), 1536 (m), 1459
(w), 1440 (m), 1369 (s), 1343 (w), 957 (s), 908 (w), 856 (m), 725 cm–1
(vs).
13C NMR (CDCl3, 125 MHz): δ = 197.9 (e), 170.2 (e), 138.7 (e), 137.5
(e), 135.0 (e), 133.9 (o, 2 C), 129.6 (o), 128.7 (o), 128.4 (o, 2 C), 128.0
(o, 2 C), 127.5 (o, 2 C), 71.5 (e), 70.3 (e), –1.2 (o, 2 C).
1H NMR (CDCl3, 500 MHz): δ = 6.89 (s, 1 H), 2.48–2.37 (m, 8 H), 1.59
(quint, J = 7.3 Hz, 2 H), 1.43 (sext, J = 7.4 Hz, 2 H), 0.88 (t, J = 7.5 Hz, 3
H).
MS (ESI): m/z (%) = 331 (100) [M + Na]+.
13C NMR (CDCl3, 125 MHz): δ = 166.9 (e, 2 C), 152.5 (e), 118.6 (o), 89.5
(e), 79.9 (e), 30.0 (e), 23.8 (o, 2 C), 22.0 (e), 18.9 (e), 13.5 (o).
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M. Barday et al.
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Synthesis
HRMS (ESI): m/z [M + Na]+ calcd for C19H20O2SiNa: 331.1130; found:
331.1125.
13C NMR (CDCl3, 125 MHz): δ = 193.6 (e), 156.7 (e), 144.6 (e), 142.0
(e), 128.5 (o, 2 C), 128.3 (o, 2C), 125.8 (o), 72.1 (e), 68.8 (e), 36.2 (e),
31.6 (e), 29.1 (e), –0.84 (o, 3 C).
5-Phenyl-4-(trimethylsilyl)-2H-pyran-3(6H)-one (8c)
4-Octyl-5-phenyl-2H-pyran-3(6H)-one (8f)
This compound was obtained from 7c (43 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 9:1) afford-
ed 8c as a colorless oil; yield: 40 mg (73%); Rf = 0.3. The analytical data
obtained were in agreement with that previously published.6
This compound was obtained from 7f (52 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 9:1) afford-
ed the major regioisomer 8f [yellow oil; yield: 28 mg (45%); Rf = 0.3]
besides the minor regioisomer 9f [yellow oil; yield: 9 mg (14%); Rf =
0.25].
5-(Thiophen-3-yl)-4-(trimethylsilyl)-2H-pyran-3(6H)-one (8d)
This compound was obtained from 7d (44 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 95:5) af-
forded 8d as a pale pink amorphous solid; yield: 31 mg (55%); Rf =
0.25.
Major Regioisomer 8f
FT-IR (neat): 2955 (m), 2924 (s), 2854 (m), 2815 (w), 1680 (vs), 1625
(w), 1491 (w), 1442 (m), 1379 (m), 1335 (m), 1245 (m), 1146 (s),
1119 (s), 1074 (w), 964 (m), 758 (s), 700 cm–1 (vs).
1H NMR (CDCl3, 500 MHz): δ = 7.46–7.36 (m, 3 H), 7.24–7.20 (m, 2 H),
4.52 (s, 2 H), 4.23 (s, 2 H), 2.24–2.18 (m, 2 H), 1.37–1.09 (m, 12 H),
0.85 (t, J = 7.1 Hz, 3 H).
FT-IR (neat): 3106 (w), 2964 (w), 2898 (w), 2866 (w), 2820 (w), 1753
(m), 1654 (vs), 1567 (s), 1431 (m), 1420 (w), 1409 (w), 1359 (w),
1273 (s), 1240 (s), 1182 (m), 1130 (s), 1065 (w), 1051 (w), 1032 (w),
966 (m), 940 (m), 926 (m), 834 (vs), 784 (s), 697 cm–1 (m).
1H NMR (CDCl3, 500 MHz): δ = 7.39 (dd, J = 3.0, 2.1 Hz, 1 H), 7.27 (d, J =
1.3 Hz, 1 H), 7.05 (dd, J = 3.6, 1.3 Hz, 1 H), 4.42 (s, 2 H), 4.14 (s, 2 H), –
0.02 (s, 9 H).
13C NMR (CDCl3, 125 MHz): δ = 194.8 (e), 154.7 (e), 135.9 (e), 134.6
(e), 128.73 (o), 128.67 (o, 2 C), 127.3 (o, 2 C), 72.0 (e), 69.7 (e), 31.8 (e),
29.5 (e), 29.13 (e), 29.10 (e, 2 C), 25.1 (e) 22.6 (e), 14.1 (o).
13C NMR (CDCl3, 125 MHz): δ = 198.3 (e), 163.6 (e), 138.4 (e), 136.7
MS (CI): m/z (%) = 287 (100) [M + H]+.
(e), 127.5 (o), 126.6 (o), 125.5 (o), 71.6 (e), 70.0 (e), 0.1 (o, 3 C).
MS (CI): m/z (%) = 253 (8) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C19H27O2: 287.2006; found:
287.2016.
HRMS (CI): m/z [M + H]+ calcd for C12H17O2SSi: 253.0640; found:
253.0722.
Minor Regioisomer 9f
1H NMR (CDCl3, 500 MHz): δ = 7.42–7.36 (m, 2 H), 7.36–7.31 (m, 1 H),
7.14–7.07 (m, 2 H), 4.48 (s, 2 H), 4.26 (s, 2 H), 2.17–2.09 (m, 2 H),
1.44–1.35 (m, 2 H), 1.30–1.09 (m, 10 H), 0.86 (t, J = 7.0 Hz, 3 H).
Anal. Calcd for C12H16O2SSi: C, 57.10; H, 6.39; S, 12.70. Found: C,
56.39; H, 6.29; S, 12.59.
13C NMR (CDCl3, 125 MHz): δ = 193.2 (e), 159.0 (e), 135.3 (e), 133.0
(e), 129.8 (o, 2 C), 128.2 (o, 2 C), 127.7 (o), 72.2 (o), 68.2 (o), 31.73 (e),
31.65 (e), 29.5 (e), 29.03 (e), 28.97 (e), 27.9 (e), 22.6 (e), 14.1 (o).
5-(3-Phenylpropyl)-4-(trimethylsilyl)-2H-pyran-3(6H)-one (8e)
This compound was obtained from 7e (106 mg, 0.448 mmol, 1.1
equiv) according to method A. Flash chromatography (PE/EtOAc, 95:5)
afforded the major regioisomer 8e [pale yellow oil; yield: 84 mg
(66%); Rf = 0.25] besides the minor regioisomer 9e [pale yellow oil;
yield: 13 mg (10%); Rf = 0.3].
5-(4-Acetylphenyl)-4-butyl-2H-pyran-3(6H)-one (8g)
This compound was obtained from 7g (98 mg, 0.488 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 9:1) afford-
ed the major regioisomer 8g [colorless oil; yield: 79 mg (65%); Rf =
0.3] as well as a mixture of 8g and 9g (1:3.9) [colorless oil; yield: 41
mg (31%)]. The analytical data obtained were in agreement with that
previously published.6
Major Regioisomer 8e
FT-IR (neat): 3062 (w), 3026 (w), 2945 (w), 2857 (w), 2812 (w), 1663
(s), 1583 (m), 1496 (w), 1453 (w), 1436 (w), 1378 (w), 1279 (m), 1246
(m), 1187 (w), 1139 (w), 1115 (m), 1082 (w), 1055 (w), 1029 (w), 964
(w), 936 (w), 841 (s), 765 (m), 750 (m), 699 (m), 641 (w), 624 cm–1
(w).
4-Butyl-5-(4-methoxyphenyl)-2H-pyran-3(6H)-one (8h)
1H NMR (CDCl3, 500 MHz): δ = 7.35–7.29 (m, 2 H), 7.23–7.19 (m, 1 H),
7.18–7.15 (m, 2 H), 4.18 (s, 2 H), 4.01 (s, 2 H), 2.70–2.62 (m, 2 H),
2.35–2.28 (m, 2 H), 1.85–1.75 (m, 2 H), 0.2 (s, 9 H).
13C NMR (CDCl3, 125 MHz): δ = 197.9 (e), 171.0 (e), 141.0 (e), 134.4
(e), 128.6 (o, 2 C), 128.4 (o, 2 C), 126.2 (o), 71.5 (e), 68.6 (e), 36.0 (e),
33.7 (e), 31.0 (e), 1.1 (o, 3 C).
This compound was obtained from 7h (46 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 9:1) afford-
ed the major regioisomer 8h [yellow oil; yield: 31 mg (54%); Rf = 0.3]
besides 9h [yellow oil; yield: 7 mg (12%); Rf = 0.2].
Major Regioisomer 8h
FT-IR (neat): 2957 (m), 2930 (m), 2859 (m), 1675 (vs), 1606 (s), 1573
(w), 1510 (s), 1462 (m), 1441 (m), 1379 (m), 1336 (m), 1289 (s), 1250
(vs), 1177 (s), 1150 (vs), 1116 (s), 1075 (w), 1039 (m), 1026 (s), 966
(m), 921 (m), 831 (s), 723 cm–1 (m).
MS (ESI): m/z (%) = 311 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H24O2SiNa: 311.1443; found:
311.1437.
Anal. Calcd for C17H24O2Si: C, 70.78; H, 8.39. Found: C, 70.59; H, 8.49.
1H NMR (CDCl3, 500 MHz): δ = 7.20–7.15 (m, 2 H), 6.97–6.93 (m, 2 H),
4.50 (s, 2 H), 4.21 (s, 2 H), 3.84 (s, 3 H), 2.26 (dd, J = 9.2, 7.3 Hz, 2 H),
1.36–1.29 (m, 2 H), 1.23–1.16 (m, 2 H), 0.78 (t, J = 7.3 Hz, 3 H).
Minor Regioisomer 9e
1H NMR (CDCl3, 500 MHz): δ = 7.30–7.25 (m, 2 H), 7.20–7.15 (m, 3 H),
4.35 (s, 2 H), 4.10 (s, 2 H), 2.66 (t, J = 7.7 Hz, 2 H), 2.40–2.33 (m, 2 H),
1.75–1.70 (m, 2 H), 0.15 (s, 9 H).
13C NMR (CDCl3, 125 MHz): δ = 194.9 (e), 160.0 (e), 154.5 (e), 134.3
(e), 129.0 (o, 2 C), 128.1 (e), 114.1 (o, 2 C), 72.0 (e), 69.8 (e), 55.3 (o),
31.4 (e), 25.0 (e), 22.6 (e), 13.8 (o).
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Synthesis
MS (CI): m/z (%) = 261 (100) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C16H21O3: 261.1485; found:
13C NMR (CDCl3, 125 MHz): δ = 194.4 (e), 147.4 (e), 136.1 (e), 134.9
(e), 134.8 (o), 129.3 (o), 128.9 (o, 2 C), 127.2 (o, 2 C), 122.5 (o), 72.0
(e), 65.4 (e), 31.9 (e), 29.8 (e), 29.6 (e), 29.4 (e), 29.2 (e), 23.5 (e), 22.6
(e), 14.1 (o).
261.1489.
MS (CI): m/z (%) = 313 (100) [M + H]+.
Minor Regioisomer 9h
HRMS (CI): m/z [M + H]+ calcd for C21H29O2: 313.2162; found:
313.2174.
1H NMR (CDCl3, 500 MHz): δ = 7.03 (d, J = 8.7 Hz, 2 H), 6.92 (d, J = 8.6
Hz, 2 H), 4.46 (s, 2 H), 4.25 (s, 2 H), 3.82 (s, 3 H), 2.18–2.13 (m, 2 H),
1.43–1.35 (m, 2 H), 1.27–1.19 (m, 2 H), 0.81 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 193.5 (e), 159.1 (e), 158.9 (e), 134.8
(e), 130.9 (o, 2 C), 125.1 (e), 113.7 (o, 2 C), 72.2 (e), 68.3 (e), 55.2 (o),
31.5 (e), 30.1 (e), 22.7 (e), 13.7 (o).
4-Butyl-5-(thiophen-2-yl)-2H-pyran-3(6H)-one (8k)
This compound was obtained from 7k (80 mg, 0.488 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 95:5) af-
forded the major regioisomer 8k [amorphous brown solid; yield: 65
mg (63%); Rf = 0.3] as well as a mixture of 8k and 9k (1:6.5) [amor-
phous brown solid; yield: 10 mg (9%)].
4-Isobutyl-5-(4-methoxyphenyl)-2H-pyran-3(6H)-one (8i)
This compound was obtained from 7i (46 mg, 0.244 mmol, 1.1 equiv)
according to method B. Flash chromatography (PE/EtOAc, 9:1) afford-
ed the major regioisomer 8i [yellow oil; yield: 30 mg (52%); Rf = 0.4]
besides 9i [yellow oil; yield: 8 mg (14%); Rf = 0.2].
Major Regioisomer 8k
FT-IR (neat): 3120 (w), 3075 (w), 2958 (w), 2922 (w), 2858 (w), 1661
(s), 1590 (s), 1511 (w), 1467 (w), 1454 (w), 1435 (m), 1416 (m), 1387
(w), 1337 (m), 1319 (s), 1280 (s), 1227 (m), 1184 (m), 964 (s), 860
(m), 730 (s), 714 cm–1 (s).
1H NMR (CDCl3, 500 MHz): δ = 7.53 (dd, J = 5.0, 1.0 Hz, 1 H), 7.22 (dd,
J = 3.8, 1.0 Hz, 1 H), 7.14 (dd, J = 5.0, 3.8 Hz, 1 H), 4.68 (s, 2 H), 4.21 (s,
2 H), 2.59 (m, 2 H), 1.48–1.34 (m, 4 H), 0.91 (t, J = 7.2 Hz, 3 H).
Major Regioisomer 8i
FT-IR (neat): 2956 (m), 2868 (w), 1727 (w), 1675 (s), 1605 (s), 1510
(s), 1463 (m), 1440 (w), 1382 (m), 1326 (m), 1291 (m), 1247 (vs),
1177 (m), 1153 (s), 1116 (m), 1025 (m), 1007 (m), 968 (m), 896 (w),
833 cm–1 (s).
13C NMR (CDCl3, 125 MHz): δ = 194.3 (e), 145.1 (e), 136.8 (e), 133.9
(e), 128.7 (o), 128.4 (o), 127.7 (o), 71.9 (e), 69.2 (e), 30.9 (e), 25.4 (e),
22.9 (e), 13.9 (o).
1H NMR (CDCl3, 500 MHz): δ = 7.16 (d, J = 8.9 Hz, 2 H), 6.94 (d, J = 8.8
Hz, 2 H), 4.50 (s, 2 H), 4.22 (s, 2 H), 3.84 (s, 3 H), 2.21 (d, J = 7.2 Hz, 2
H), 1.68 (sept, J = 6.9 Hz, 1 H), 0.71 (d, J = 6.5 Hz, 6 H).
MS (CI): m/z (%) = 237 (100) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C13H17O2S: 237.0944; found:
13C NMR (CDCl3, 125 MHz): δ = 195.1 (e), 159.9 (e), 155.7 (e), 133.5
(e), 129.3 (o, 2C), 128.1 (e), 114.1 (o, 2C), 72.0 (e), 70.1 (e), 55.3 (o),
33.4 (e), 27.8 (o), 22.4 (o).
MS (CI): m/z (%) = 261 (100) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C16H21O3: 261.1485; found:
237.0950.
Anal. Calcd for C13H16O2S: C, 66.07; H, 6.82; S, 13.57. Found: C, 66.90;
H, 7.17; S, 13.25.
261.1494.
Minor Regioisomer 9k
1H NMR (CDCl3, 500 MHz): δ = 7.40 (dd, J = 5.0, 1.2 Hz, 1 H), 7.07 (dd,
J = 5.00, 3.5 Hz, 1 H), 6.94 (dd, J = 3.5, 1.2 Hz, 1 H), 4.48 (s, 2 H), 4.27 (s,
2 H), 2.35–2.29 (m, 2 H), 1.52–1.43 (m, 2 H), 1.35–1.22 (m, 2 H), 0.87
(t, J = 7.3 Hz, 3 H).
Minor Regioisomer 9i
1H NMR (CDCl3, 500 MHz): δ = 7.01 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.7
Hz, 2 H), 4.44 (s, 2 H), 4.26 (s, 2 H), 3.83 (s, 3 H), 2.10 (d, J = 7.6 Hz, 2
H), 1.72 (sept, J = 6.9 Hz, 1 H), 0.82 (d, J = 6.6 Hz, 6 H).
13C NMR (CDCl3, 125 MHz): δ = 192.5 (e), 161.3 (e), 132.3 (e), 128.5
(e), 128.3 (o), 126.7 (o), 126.6 (o), 72.2 (e), 68.6 (e), 31.8 (e), 30.4 (e),
22.8 (e), 13.7 (o).
13C NMR (CDCl3, 125 MHz): δ = 193.6 (e), 159.0 (e), 157.9 (e), 135.8 (e)
131.1 (o, 2 C), 125.2 (e), 113.7 (o, 2 C), 72.3 (e), 68.6 (e), 55.2 (o), 40.8
(e), 27.1 (o), 22.6 (o).
4-Butyl-5-(thiophen-3-yl)-2H-pyran-3(6H)-one (8l)
(E)-4-Octyl-5-styryl-2H-pyran-3(6H)-one (8j)
This compound was obtained from 7l (40 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 95:5) af-
forded the major regioisomer 8l [pale yellow oil; yield: 28 mg (53%);
Rf = 0.3] besides 9l [colorless oil; yield: 6 mg (11%); Rf = 0.2].
This compound was obtained from 7j (59 mg, 0.244 mmol, 1.1 equiv)
according to method A. Flash chromatography (PE/EtOAc, 9:1) afford-
ed 8j as a yellow amorphous solid; yield: 98 mg (71%); and a mixture
of regioisomers 8j/9j (7.9:1); Rf = 0.3; only the major regioisomer is
described below.
Major Regioisomer 8l
FT-IR (neat): 3061 (w), 2917 (m), 2850 (m), 1665 (s), 1614 (m), 1585
(w), 1494 (w), 1466 (w), 1444 (w), 1419 (w), 1343 (m), 1325 (m),
1306 (w), 1288 (w), 1244 (m), 1131 (m), 1121 (m), 956 (s), 723(s),
689 (m), 668 cm–1 (s).
1H NMR (CDCl3, 500 MHz): δ = 7.52–7.47 (m, 2 H), 7.42–7.37 (m, 3 H),
7.18 (d, J = 16.5 Hz, 1 H), 6.80 (d, J = 16.5 Hz, 1 H), 4.69 (s, 2 H, major),
4.19 (s, 2 H), 2.57–2.50 (m, 2 H), 1.47–1.22 (m, 12 H), 0.91–0.83 (m, 3
H).
FT-IR (neat): 3102 (w), 2956 (m), 2928 (m), 2858 (w), 2814 (w), 1670
(s), 1612 (m), 1439 (w), 1409 (w), 1378 (w), 1360 (w), 1329 (m), 1283
(m), 1227 (w), 1191 (w), 1145 (s), 1118 (m), 945 (w), 900 (m), 869
(w), 839 (m), 783 (s), 720 (m), 701 cm–1 (m).
1H NMR (CDCl3, 500 MHz): δ = 7.42 (dd, J = 5.0, 2.9 Hz, 1 H), 7.33 (dd,
J = 2.9, 1.4 Hz, 1 H), 7.09 (dd, J = 5.0, 1.4 Hz, 1 H), 4.56 (s, 2 H), 4.21 (s,
2 H), 2.37 (m, 2 H), 1.42–1.36 (m, 2 H), 1.28 (m, 2 H), 0.84 (t, J = 7.3 Hz,
3 H).
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M. Barday et al.
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Synthesis
13C NMR (CDCl3, 125 MHz): δ = 194.7 (e), 148.7 (e), 136.1 (e), 134.6
(e), 127.1 (o), 126.5 (o), 124.8 (o), 72.0 (e), 69.3 (e), 31.4 (e), 25.2 (e),
22.8 (e), 13.8 (o).
MS (CI): m/z (%) = 237 (100) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C13H17O2S: 237.0944; found:
1H NMR (CDCl3, 500 MHz): δ = 7.32–7.26 (m, 2 H), 7.25–7.14 (m, 3 H),
4.36 (d, J = 17.0 Hz, 1 H), 4.28 (d, J = 17.0 Hz, 1 H), 3.88–3.80 (m, 1 H),
2.85–2.67 (m, 2 H), 2.33–2.11 (m, 5 H), 2.05–1.92 (m, 1 H), 1.50 (sext,
J = 7.7 Hz, 2 H), 1.36 (sext, J = 7.8 Hz, 2 H), 0.99 (t, J = 7.3 Hz, 3 H), 0.91
(t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 196.0 (e), 155.8 (e), 141.6 (e), 133.3
(e), 128.6 (o, 2 C), 128.3 (o, 2 C), 125.8 (o), 79.0 (o), 66.9 (e), 32.6 (e),
31.7 (e), 31.3 (e), 26.3 (e), 22.5 (e), 21.4 (e), 14.3 (o), 14.2 (o).
237.0947.
Anal. Calcd for C13H16O2S: C, 66.07; H, 6.82; S, 13.57. Found: C, 65.59;
H, 6.95; S, 12.90.
MS (ESI): m/z (%) = 309 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H26O2Na: 309.1831; found:
309.1837.
Minor Regioisomer 9l
1H NMR (CDCl3, 500 MHz): δ = 7.35 (dd, J = 5.0, 3.0 Hz, 1 H), 7.15 (dd,
J = 3.0, 1.3 Hz, 1 H), 6.95 (dd, J = 5.0, 1.3 Hz, 1 H), 4.46 (s, 2 H), 4.25 (s,
2 H), 2.24 (m, 2 H), 1.43 (m, 2 H), 1.28 (m, 2 H), 0.84 (t, J = 7.4 Hz, 3 H).
6-Phenethyl-4,5-dipropyl-2H-pyran-3(6H)-one (12)
1H NMR (CDCl3, 500 MHz): δ = 7.33–7.28 (m, 2 H), 7.24–7.18 (m, 3 H),
4.27 (d, J = 16.8 Hz, 1 H), 4.23 (dd, J = 10.1, 2.7 Hz, 1 H), 4.07 (d, J = 16.9
Hz, 1 H), 2.92–2.83 (m, 1 H), 2.79–2.70 (m, 1 H), 2.37–2.29 (m, 1 H),
2.28–2.20 (m, 2 H), 2.11–1.88 (m, 3 H), 1.53–1.45 (m, 1 H), 1.42–1.32
(m, 3 H), 0.95 (t, J = 7.4 Hz, 3 H), 0.92 (t, J = 7.4 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 194.5 (e), 159.6 (e), 141.4 (e), 133.6
(e), 128.50 (o, 2 C), 128.46 (o, 2 C), 126.1 (o), 74.6 (o), 67.8 (e), 32.7
(e), 32.5 (e), 32.3 (e), 26.4 (e), 22.6 (e), 21.8 (e), 14.4 (o), 14.2 (o).
13C NMR (CDCl3, 125 MHz): δ = 193.0 (e), 159.7 (e), 132.4 (e), 130.3
(e), 129.0 (o), 124.9 (o), 124.7 (o), 72.2 (e), 68.4 (e), 31.6 (e), 30.3 (e),
22.8 (e), 13.7 (o).
4-Butyl-5-(furan-2-yl)-2H-pyran-3(6H)-one (8m)
This compound was obtained from 7m (36 mg, 0.244 mmol, 1.1
equiv) according to method A. Flash chromatography (PE/EtOAc, 95:5)
afforded 8m as a brown oil; yield: 14 mg (28% yield); and a mixture of
regioisomers 8m/9m (9:1); Rf = 0.4; only the major regioisomer is de-
scribed below.
Funding Information
FT-IR (neat): 2957 (m), 2930 (m), 2860 (m), 2821 (m), 1667 (vs), 1601
(m), 1468 (m), 1443, (w) 1401 (w), 1378 (w), 1336 (s), 1287 (m), 1260
(m), 1228 (m), 1203 (m), 1148 (s), 1121 (w), 1089 (vw), 1045 (m),
1018 (m), 967 (m), 940 (m), 905 (m), 885 (m), 816 (m), 746 cm–1 (s).
1H NMR (CDCl3, 500 MHz): δ = 7.60 (dd, J = 1.8, 0.6 Hz, 1 H), 6.73 (dd,
J = 3.6, 0.5 Hz, 1 H), 6.56 (dd, J = 3.6, 1.8 Hz, 1 H, major), 4.72 (s, 2 H),
4.20 (s, 2 H), 2.70–2.60 (m, 2 H), 1.46–1.38 (m, 4 H), 0.94 (t, J = 7.3 Hz.
3 H).
We thank the EPSRC (EP/P505615/1 studentship to K.Y.T.H. and
EP/N509267/1 studentship to D.C.), the University of Liverpool (stu-
dentships to M.B. and C.J.), and AstraZeneca for financial support.
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5
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Acknowledgment
We are grateful to Prof. Dr. Matthias Brust and Dr. Casper Kunstmann
for their assistance with the scanning electron microscopy analysis of
the zinc powder.
13C NMR (CDCl3, 125 MHz): δ = 194.5 (e), 149.3 (e), 144.7 (o), 139.6
(e), 131.8 (e), 114.4 (o), 112.3 (o), 72.1 (e), 66.0 (e), 30.6 (e), 25.1 (e),
23.1 (e), 13.9 (o).
MS (CI): m/z (%) = 221 (100) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C13H17O3: 221.1099; found:
Supporting Information
221.1181.
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589052.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Nickel-Catalyzed Cycloaddition of Oct-4-yne with Oxetanone 10
Inside a glovebox, J-Young Teflon-screw flame-dried Schlenk tube
equipped with a small stirrer bar was charged with Ni(cod)2 (6 mg,
0.022 mmol, 0.1 equiv) and taken out of the glovebox. Under N2, PPh3
(18 mg, 0.066 mmol, 0.3 equiv) and 1,4-dioxane (1.3 mL) were added.
The suspension was stirred for 5 min and then oxetanone 10 (39 mg,
0.22 mmol, 1 equiv) was added as solid in one portion. After stirring
for 5 more min, oct-4-yne (36 μL, 0.224 mmol, 1.1 equiv) was added
and the flask was sealed and immersed into an oil bath pre-heated at
90 °C. After stirring for 17 h at that temperature, the mixture was al-
lowed to cool and filtered through a silica plug before evaporation of
all volatiles. Purification by flash chromatography (PE/EtOAc, 95:5) af-
forded 11 as a colorless oil; yield: 24 mg (38%) and 1:5 mixture of 11
and 12 as a colorless oil; yield: 8 mg (13%).
References
(1) For selected recent reviews, see: (a) Ghosh, A. K.; Brindisi, M.
RSC Adv. 2016, 6, 111564. (b) Varela, J. A.; Saa, C. Synthesis 2016,
48, 3470. (c) Jacques, R.; Pal, R.; Parker, N. A.; Sear, C. E.; Smith,
P. W.; Ribaucourt, A.; Hodgson, D. M. Org. Biomol. Chem. 2016,
14, 5875. (d) Naysmith, B. J.; Hume, P. A.; Sperry, J.; Brimble, M.
A. Nat. Prod. Rep. 2017, 34, 25.
(2) Clayton, J. P.; O’Hanlon, P. J.; Rogers, N. H.; King, T. J. J. Chem.
Soc., Perkin Trans. 1 1982, 2827.
(3) Ali, A.; Khajuria, A.; Sidiq, T.; Kumar, A.; Thakur, N. L.; Naik, D.;
Vishwakarma, R. A. Immunol. Lett. 2013, 150, 79.
(4) Takayuki, S. German Patent DE 4207301 C1, 1993.
(5) Gehrt, A.; Erkel, G.; Anke, T.; Sterner, O. J. Antibiot. 1998, 51, 455.
(6) Ho, K. Y. T.; Aïssa, C. Chem. Eur. J. 2012, 18. 3486.
(7) Azetidin-3-ones also undergo the same reaction smoothly. See
ref. 6 and: (a) Kumar, P.; Louie, J. Org. Lett. 2012, 14, 2026.
(b) Ishida, N.; Yuhki, T.; Murakami, M. Org. Lett. 2012, 14, 3898.
2-Phenethyl-4,5-dipropyl-2H-pyran-3(6H)-one (11)
FT-IR (neat): 2956 (m), 2930 (m), 1671 (vs), 1634 (m), 1603 (w), 1496
(w), 1454 (m), 1383 (w), 1175 (m), 1126 (s), 1084 (w), 1031 (w), 745
(s), 699 cm–1 (s).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
M. Barday et al.
Special Topic
Synthesis
(8) Recent reviews on nickel-catalyzed reactions: (a) Modern Orga-
nonickel Chemistry; Tamaru, Y., Ed.; Wiley-VCH: Weinheim,
2005. (b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
1346. (c) Tasker, S. Z.; Stanley, E. A.; Jamison, T. F. Nature 2014,
509, 299. (d) Ananikov, V. P. ACS Catal. 2015, 5, 1964.
(9) Selected reviews on metal-catalyzed C–C bond activation and
cleavage: (a) Aïssa, C. Synthesis 2011, 3389. (b) Chen, P.-h.;
Billett, B. A.; Tsukamoto, T.; Dong, G. ACS Catal. 2017, 7, 1340.
(c) Dong, G. Top. Curr. Chem. 2014, 346, 1. (d) Souillart, L.;
Cramer, N. Chem. Rev. 2015, 115, 9410. (e) Cleavage of Carbon-
Carbon Single Bonds by Transition Metals; Murakami, M.;
Chatani, N., Eds.; Wiley-VCH: Weinheim, 2016. (f) Murakami,
M.; Ishida, N. J. Am. Chem. Soc. 2016, 138, 13759. (g) Fumagalli,
G.; Stanton, S.; Bower, J. F. Chem. Rev. 2017, 117, in press;
DOI: 10.1021/acs.chemrev.6b00599.
(10) (a) Kumar, P.; Zhang, K.; Louie, J. Angew. Chem. Int. Ed. 2012, 51,
8602. (b) Thakur, A.; Facer, M. E.; Louie, J. Angew. Chem. Int. Ed.
2013, 52, 12161. (c) Ishida, N.; Nakanishi, Y.; Murakami, M.
Angew. Chem. Int. Ed. 2013, 52, 11875. (d) An, J.-H.; Yun, H.;
Shin, S.; Shin, S. Adv. Synth. Catal. 2014, 356, 3749. (e) Guo, R.;
Zheng, X.; Zhang, D.; Zhang, G. Chem. Sci. 2017, 8, 3002.
(11) (a) Bull, J. A.; Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K. F.
Chem. Rev. 2016, 116, 12150. (b) Dejaegher, Y.; Kuz’menok, N.
M.; Zvonok, A. M.; De Kimpe, N. Chem. Rev. 2002, 102, 29.
(12) For selected recent examples, see: (a) Burkhard, J. A.;
Tchichanov, B. H.; Carreira, E. M. Angew. Chem. Int. Ed. 2011, 50,
5379. (b) Guo, B.; Schwarzwalder, G.; Njardarson, J. T. Angew.
Chem. Int. Ed. 2012, 51, 5675. (c) Orr, D.; Tolfrey, A.; Percy, J. M.;
Frieman, J.; Harrison, Z. A.; Campbell-Crawford, M.; Patel, V. K.
Chem. Eur. J. 2013, 19, 9655. (d) Pawar, S. K.; Vasu, D.; Liu, R.-S.
Adv. Synth. Catal. 2014, 356, 2411.
(13) (a) Wuitschick, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.;
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew.
Chem. Int. Ed. 2006, 45, 7736. (b) Wuitschick, G.; Rogers-Evans,
M.; Buckl, A.; Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.;
Wagner, B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.;
Schweizer, W. B.; Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed.
2008, 47, 4512. (c) Wuitschick, G.; Carreira, E. M.; Wagner, B.;
Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K.
J. Med. Chem. 2010, 53, 3227.
MeOC6H4); 7j (R1 = n-octyl, R2 = 2-vinylbenzene); 7k (R1 = n-Bu,
R2 = 2-thienyl); 7m (R1 = n-Bu, R2 = 3-thienyl); 7n (R1 = n-Bu, R2
= 2-furyl).
(17) Zinc powder AnalaR® from BDH was used in these experiments.
The specifications of the powder were not provided by the sup-
plier. However, scanning electron microscopy showed flakes
and scales of 1–2 μm in length on the surface of the irregularly
shaped zinc particles of various sizes. Images of the SEM analy-
sis are included in the Supporting Information.
(18) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005,
127, 6932.
(19) (a) Bach, R. D.; Dmitrenko, O. J. Org. Chem. 2002, 67, 3884.
(b) Wiberg, K. B. In The Chemistry of Cyclobutanes; Rappoport,
Z.; Liebman, J. F., Eds.; Wiley: New York, 2005, Chap. 1, 4–5.
(20) Van den Hoven, B. G.; Alper, H. J. Org. Chem. 1999, 64, 9640.
(21) McCarren, P. R.; Liu, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K.
N. J. Am. Chem. Soc. 2009, 131, 6654.
(22) (a) Liu, P.; McCarren, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K.
N. J. Am. Chem. Soc. 2010, 132, 2050. (b) Mahandru, G. M.; Liu,
G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (c) Miller,
K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am.
Chem. Soc. 2004, 126, 4130. (d) Miller, K. M.; Jamison, T. F. Org.
Lett. 2005, 7, 3077.
(23) (a) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc.
2005, 127, 12810. (b) Ogoshi, S.; Arai, T.; Ohashi, M.; Kurusawa,
H. Chem. Commun. 2008, 1347.
(24) Li, Y.; Lin, Z. Organometallics 2013, 32, 3003.
(25) Transition state IV is drawn in accordance with the transition
state found for the nickel-catalyzed insertion of alkynes into
N-Boc-azetidin-3-one 2 in reference 23.
(26) (a) Bartik, T.; Happ, B.; Iglewsky, M.; Bandmann, H.; Boese, R.;
Heimbach, P.; Hoffmann, T.; Wenschuh, E. Organometallics
1992, 11, 1235. (b) Rosenthal, U.; Nauck, C.; Arndt, P.; Pulst, S.;
Baumann, W.; Burlakov, V. V.; Görls, H. J. Organomet. Chem.
1994, 484, 81.
(27) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550.
(28) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2006,
128, 2166.
(29) Juliá-Hernández, F.; Ziadi, A.; Nishimura, A.; Martin, R. Angew.
Chem. Int. Ed. 2015, 54, 9537.
(30) Torborg, C.; Zapf, A.; Beller, M. ChemSusChem 2008, 1, 91.
(31) Fleming, I.; Mwaniki, J. M. J. Chem. Soc., Perkin Trans. 1 1998,
1237.
(14) Thakur, A.; Evangelista, J. L.; Kumar, P.; Louie, J. J. Org. Chem.
2015, 80, 9951.
(15) Barday, M.; Ho, K. Y. T.; Halsall, C. T.; Aïssa, C. Org. Lett. 2016, 18,
1759.
(32) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005,
1794.
(16) 7a (R1 = SiMe3, R2 = 4-CF3C6H4); 7b (R1 = SiMe2Ph, R2 = Ph); 7c (R1
= SiMe3, R2 = Ph); 7d (R1 = SiMe3, R2 = 3-thienyl); 7e (R1 = SiMe3,
R2 = (CH2)3Ph); 7f (R1 = n-octyl, R2 = Ph); 7g (R1 = n-Bu, R2 = 4-
AcC6H4); 7h (R1 = n-Bu, R2 = 4-MeOC6H4); 7i (R1 = i-Bu, R2 = 4-
(33) Li, P.; Wang, L.; Li, H. Tetrahedron 2005, 61, 8633.
(34) Melzig, L.; Stemper, J.; Knochel, P. Synthesis 2010, 2085.
(35) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412.
(36) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001,
123, 2074.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H