First direct synthesis of 3-hydroxy-pent-4-ynoic acids. Application to the synthesis of pyran-2-ones

Article abstract of DOI:10.1016/j.tet.2013.06.069

We describe a direct method for the synthesis of 3-hydroxy-pent-4-ynoic acids by the nucleophilic addition of bis-(TMS) ketene acetals to alkynones promoted by BF₃·Et₂O. A systematic study involving electron withdrawing and electron donor groups (R¹=NO₂, CF₃, Br, Cl, H, Me, OMe) in the propargyl ketone reveals a strong dependence of electronic effects on the regiochemistry of the nucleophilic addition. Using a halolactonization protocol, we demonstrated the synthetic potential of these acids by their efficient transformation into new 5-bromo-3,4-dihydro-2H-pyran-2-ones.

Full text of DOI:10.1016/j.tet.2013.06.069

Tetrahedron xxx (2013) 1e8
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First direct synthesis of 3-hydroxy-pent-4-ynoic acids. Application
to the synthesis of pyran-2-ones
a
,
a
b
*
ꢀ
ꢀ
ꢀ
ꢀ
Morelia E. Lopez-Reyes , Jose G. Lopez-Cortes , M. Carmen Ortega-Alfaro ,
R. Alfredo Toscano a, Cecilio Alvarez-Toledano a
Instituto de Química UNAM, Circuito Exterior, Ciudad Universitaria, Mexico 04510, D.F., Mexico
,
*
a
ꢀ
b
ꢀ
Instituto de Ciencias Nucleares, UNAM, Circuito Exterior, Cd. Universitaria, Mexico 04510, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a direct method for the synthesis of 3-hydroxy-pent-4-ynoic acids by the nucleophilic
addition of bis-(TMS) ketene acetals to alkynones promoted by BF3$Et2O. A systematic study involving
electron withdrawing and electron donor groups (R1¼NO2, CF3, Br, Cl, H, Me, OMe) in the propargyl
ketone reveals a strong dependence of electronic effects on the regiochemistry of the nucleophilic ad-
dition. Using a halolactonization protocol, we demonstrated the synthetic potential of these acids by
their efficient transformation into new 5-bromo-3,4-dihydro-2H-pyran-2-ones.
Received 30 April 2013
Received in revised form 17 June 2013
Accepted 19 June 2013
Available online xxx
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Ketene acetal
Halolactonization
Pyran-2-ones
1. Introduction
3-Hydroxy-pent-4-ynoic acids are interesting synthetic targets
due to the presence of different functional groups on their struc-
ture, which could result in a huge range of compounds; by slightly
changing the reaction conditions or the reagents used. Their use as
synthetic intermediates has been sparsely reported and only some
examples related to the synthesis of biologically active compounds,
such as: ustiloxin D,1 cyanobacterin,2 (þ)-phorboxazole,3 and
mevalonate derivatives4 are reported, probably because a general
method for the synthesis of these compounds is not available.
The 3-hydroxy-pent-4-ynoic acids can be prepared using a-hal-
oesters and propargyl ketones or aldehydes via the Reformatsky re-
action.5 Another two complementary strategies are the nucleophilic
addition of acetylide ions to 1,3-dicarbonyl esters,6 or the addition of
ester enolates to propargyl ketones or aldehydes7 (Scheme 1).
However in these complementary strategies, the hydrolysis of the
ester formed is a required critical stage, and this reaction often pro-
ceeds with low yields due to undesirable side reactions, such as de-
hydration, decarboxylation or polymerization of the carboxylic acid.
On the other hand, the use of ketene acetals as potential 1,3-
dinucleophiles,8,9 in combination with different substrates,10 has
been an interesting strategy used in the synthesis of diverse
Scheme 1.
compounds. In this context, we have envisaged a direct method for
the synthesis of 3-hydroxy-pent-4-ynoic acids by the nucleophilic
addition of bis-(trimethylsilyl) ketene acetals to acetylenic ketones
in the presence of an appropriated Lewis acid (Scheme 2). The 3-
hydroxy-pent-4-ynoic acids thus obtained can be used in the syn-
thesis of new highly functional lactones.
* Corresponding authors. Tel.: þ52 555 622 4464; fax: þ52 555 616 2203; e-mail
ꢀ
addresses: moreunice@comunidad.unam.mx (M.E. Lopez-Reyes), cecilio@unam.mx
(C. Alvarez-Toledano).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.069
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M.E. Lopez-Reyes et al. / Tetrahedron xxx (2013) 1e8
2
Scheme 2.
2. Results and discussion
We started the study with the reaction of 4-phenyl-3-butyn-2-
one 1a and the ketene acetal 2a in CH2Cl2 (Table 1, entry 1).
However after 24 h no product was observed; we therefore used an
t
activating agent. We first tried with BuOK and TBAF (Table 1, en-
Scheme 3. Proposed pathway for the formation of 3-hydroxy-pent-4-ynoic acid 3 and
enyne 4.
tries 2 and 3) to promote the cleavage of the siliconeoxygen bond
in the ketene acetal releasing the corresponding anion, but this
reaction did not afford good results.
In view of these results, we then tested several Lewis acids
(entries 5e7) to enhance the selectivity of the reaction; however, in
all cases, a low yield of 3a was obtained. The reaction was finally
improved using diethyl ether as solvent. Under these conditions
and by using BF3$Et2O as activating agent (entry 8, Table 1) the
reaction provided a 10:1 mixture of 3a and 4a in 96% yield.
Having established the best reaction conditions, we decided to
test the reactivity of the acetylenic ketone 1a, against different bis-
(trimethylsilyl) ketene acetals (Table 2).
Table 1
Conditions for the reaction between acetylenic ketone and bis-(trimethylsilyl) ke-
tene acetal
Table 2
Reaction between acetylenic ketone and different bis-(trimethylsilyl) ketene acetals
Entry Activating agent t (h) Solvent Molar ratio 3a/4a Global yield (%)
1a
2a
3a
4b
5a
6a
7b
8c
9c
Non
TBAF
24
24
24
4
24
24
2
CH2Cl2
CH2Cl2 1:0
CH2Cl2
CH2Cl2 3:2
CH2Cl2 1:0
CH2Cl2 1:1
CH2Cl2 1:0
d
n.r
10
n.r
80
31
10
62
96
49
tBuOK
BF3$Et2O
InCl3
d
Cu(OTf)2
TiCl4
BF3$Et2O
TiCl4
4
2
Et2O
Et2O
10:1
1:0
a
The reactions were carried out with 1a (1.4 mmol), 2a (1.2 equiv), and the ac-
tivating agent (1.0 equiv) in 15 mL of dichloromethane, at room temperature.
b
Same reaction condition, but the addition of Lewis acid took place at 0 ꢀC.
The reaction was carried out in diethyl ether 15 mL and the addition of Lewis
Entry
R2
R3
Molar ratio 3/4/5
Global yield (%)
c
1
2
3
4
5
2a
2b
2c
2d
2e
Me
e(CH2)4e
Ph
Me
H
Me
10:1:0
5:2:0
9:0:1
9:1:2
4:0:2
96
92
93
94
72
acid took place at 0 ꢀC.
H
H
H
Next, we used BF3$Et2O as Lewis acid to promote the addition of
1a to the carbonyl group of 2a (Table 1, entry 4), the reaction oc-
curred with high conversion and we obtained a mixture of two
products, 3a and 4a in a 3:2 ratio, respectively. The proposed
pathway of this Mukaiyama-type aldol reaction conduces in a first
step to the formation of intermediate A by the nucleophilic addition
of ketene acetal 2 to the activated alkynone; the hydrolysis of in-
termediate A gives to the corresponding carboxylic acid 3. Alter-
All the reactions were carried out with 1a (3.5 mmol), 2 (1.2 equiv), and BF3$Et2O
(1.0 equiv) in 25 mL of diethyl ether, at 0 ꢀC, while stirring for 4 h.
In all cases examined the reaction provided good yields, but
when the unsubstituted ketene acetal 2e was used the yield de-
creased and the relative amount of the corresponding dehydration
product 5e increased.
With the aim of knowing the substrate scope, we first tested the
reaction of ketene acetal 2a toward phenylpropargyl aldehyde (1b)
natively, A can cyclize to give
b-lactone B. In according with
literature,11 the intermediate B can also undergo a decarboxylation
leading the enyne 4 (Scheme 3).
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M.E. Lopez-Reyes et al. / Tetrahedron xxx (2013) 1e8
3
and 2-octynal (1c), we found that carboxylic acids 3f and 3g were
produced with excellent yields (Table 3, entries 1 and 2). Next, we
examined the reaction with alkynones bearing a trimethylsilyl, al-
kyl or phenyl group on the alkyne moiety. We found that the re-
action proceeded without decarboxylation (entries 3e5), getting
the carboxylic acids 3h, 3i, and 3j in 98%, 91%, and 70% yield, re-
spectively. Then, our attention was turned to the evaluation of the
electronic influence of the substituent attached to the carbonyl
group, we thus replaced the substituent R1 with different phenyl
groups p-substituted (Table 3, entries 6e12). The reaction pro-
ceeded with both excellent yield and selectivity, when R1 is a phe-
nyl group p-substituted with a withdrawing group gave the
compound 3 almost exclusively (Table 3, entries 6e8). Neverthe-
less, we found that when R1 is a p-ClPh, the starting material is
completely consumed, but in addition to 3, we obtained allene 6,
which is formed by addition of two units of bis-(trimethylsilyl)
ketene acetal to acetylenic ketone (Table 3, entry 9). With the
purpose of improving the yield of allene 6, we performed another
reaction by adding 2 equiv of bis-(trimethylsilyl) ketene acetal, and
after purification we mostly isolated allene 6 (Table 3, entry 10). On
the other hand, when R1 is a phenyl group p-substituted with an
electron releasing group (Table 3, entries 11 and 12), the main
product is allene 6. The structure of 6p was fully established by
means of X-ray diffraction analysis (Fig. 1). Data on the crystals and
the refining of this compound are summarized in Table 4.
Fig. 1. ORTEP representation of allene 6p. ꢀThermal ellipsoids at 30% probability level.
ꢁ
Selected bond length (A) and bond angles ( ): O(1)eC(1), 1.276(4); O(2)eC(1), 1.238(4);
O(3)eC(7), 1.221(4); O(4)eC(7), 1.297(4); C(1)eC(2), 1.519(5); C(2)eC(3), 1.537(4);
C(3)eC(4), 1.314(5); C(3)eC(19), 1.507(4); C(4)eC(5), 1.300(5); C(5)eC(12) 1.490(5);
C(5)eC(6), 1.546(4); C(6)eC(7), 1.513(5); C(3)eC(19), 1.507(4); C(5)eC(12), 1.490(5);
O(2)eC(1)eO(1), 123.3(3); O(2)eC(1)eC(2), 121.3(3); O(1)eC(1)eC(2), 115.3(3); C(1)e
C(2)eC(3), 109.2(3); C(4)eC(3)eC(19), 119.0(3); C(4)eC(3)eC(2), 118.9(3); C(19)eC(3)e
C(2), 122.0(3); C(5)eC(4)eC(3), 172.8(3); C(4)eC(5)eC(12), 119.0(3); C(4)eC(5)eC(6),
119.5(3); C(12)eC(5)eC(6), 121.5(3); C(7)eC(6)eC(11), 106.7(3); C(7)eC(6)eC(5),
109.6(3); O(3)eC(7)eO(4), 123.0(3); O(3)eC(7)eC(6), 123.3(3); O(4)eC(7)eC(6),
113.7(3), C(4)eC(3)eC(19), 119.0(3); C(19)eC(3)eC(2), 122.0(3); C(4)eC(5)eC(12),
119.0(3); C(12)eC(5)eC(6), 121.5(3).
Table 3
Synthesis of 3-hydroxy-pent-4-ynoic acids
Table 4
X-ray data collection and structure refinement details for compounds 6p, 7d, and 7k
Compound
6l
7d
7k
Formula
C
24H26O4
C19H16BrNO5
418.24
C13H13BrO3
297.14
MW gꢁ1 molꢁ1
378.45
Crystal size (mm3) 0.464ꢂ0.104ꢂ
0.396ꢂ0.168ꢂ
0.418ꢂ0.138ꢂ
Entry R1
R4
t (h) Product Molar ratio 3/4/6 Global yield (%)
0.068
0.118
0.126
1a
H
H
Me
Ph
Ph
Ph
2
1
2
4
4
1
1
1
4
f
1:0:0
1:0:0
1:0:0
1:0:0
1:0:0
1:0.2:0
1:0.3:0
1:0:0
11:3:6
9:1:13
0:2:9
98
99
98
91
70
91
99
90
95
99
49
30
Crystal system
Space group
Monoclinic
P21/c
13.562(2)
11.964(2)
13.353(2)
90
92.779(2)
90
2164.0(5)
4
Monoclinic
P21/c
10.330(2)
6.3346(9)
26.551(4)
90
96.037(2)
90
1727.7(4)
4
Orthorhombic
P212121
6.285(1)
11.520(2)
17.479(2)
90
90
90
1265.5(3)
4
1.560
2.12e25.32
ꢁ7ꢃhꢃ7
ꢁ13ꢃkꢃ8
ꢁ20ꢃlꢃ17
4040
2a
CH3(CH2)4
SiMe3
CH3(CH2)3
Ph
g
h
i
j
k
l
m
n
n
o
p
3a
ꢁ
a/A
4a
ꢁ
b/A
5a
ꢁ
c/A
6a
p-NO2 Ph Ph
p-BrPh Ph
p-CF3Ph Ph
p-ClPh
p-ClPh
a
/(ꢀ)
7a
b
/(ꢀ)
8a
g
/(ꢀ)
9a
Ph
Ph
3
ꢁ
Volume/A
10b
11b
12b
4
5
16
Z
p-OMePh Ph
p-MePh Ph
dc/Mg mꢁ3
1.162
1.608
0:0:1
ꢀ
Q
/
2.27e25.40
ꢁ16ꢃhꢃ16
ꢁ14ꢃkꢃ14
ꢁ16ꢃlꢃ16
22,698
1.98e25.38
ꢁ10ꢃhꢃ12
ꢁ7ꢃkꢃ7
ꢁ31ꢃlꢃ32
9853
a
Index ranges
The reactions were carried out with 1 (3.5 mmol), 2 (1.2 equiv), and BF3$Et2O
(1.0 equiv) in 25 mL of diethyl ether, at 0 ꢀC.
b
The reactions were carried out with 2 equiv of the ketene acetal 2a.
Reflections
collected
Independent
reflections
Data/parameters
Final R indices
[I>2s(I)]
To explain the formation of allene 6, we propose the following
pathway. This compound could come from the previously de-
scribed b-lactone intermediate (B), which can be opened generat-
ing the transient propargylic carbocation C stabilized by resonance,
then the nucleophilic attack of a second molecule of ketene acetal
takes place giving E, which hydrolyzes leading the corresponding
allene 6 (Scheme 4). This explains why electron donating sub-
stituents that will stabilize a cation increase the amount of com-
pound 6.
3967
3170
2310
[R(int)¼0.0792]
[R(int)¼0.0353]
[R(int)¼0.0244]
3967/264
3170/240
2310/160
R1¼0.0760
wR2¼0.1601
R1¼0.0304
wR2¼0.0709
R1¼0.0392
wR2¼0.0750
1.022
R1¼0.0368
wR2¼0.0712
R1¼0.0475
wR2¼0.0751
0.994
R indices (all data) R1¼0.1395
wR2¼0.1834
GoF(F2)
1.077
Semi-empirical
from equivalents from equivalents from equivalents
Absorptions
corrections
Semi-empirical
Semi-empirical
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M.E. Lopez-Reyes et al. / Tetrahedron xxx (2013) 1e8
4
Fig. 2. ORTEP representation of 7f.ꢀThermal ellipsoids at 30% probability level. Selected
ꢁ
bond length (A) and bond angles ( ) : Br(1)eC(4), 1.894(2); O(1)eC(1), 1.200(3); O(2)e
C(1), 1.365(3); O(2)eC(5), 1.409(3); O(3)eC(3), 1.417(3); C(1)eC(2), 1.514(4); C(2)eC(3),
1.567(3); C(3)eC(4), 1.513(3); C(4)eC(5), 1.327(3); C(1)eO(2)eC(5), 120.1(2); O(1)e
C(1)eO(2), 116.8(2); O(1)eC(1)eC(2), 125.6(2); O(2)eC(1)eC(2), 117.4(2); C(1)eC(2)e
C(3), 110.5(2); O(3)eC(3)eC(4), 111.7(2); O(3)eC(3)eC(2), 109.3(2); C(4)eC(3)eC(2),
107.8(2); C(5)eC(4)eC(3), 124.1(2); C(5)eC(4)eBr(1), 119.2(2); C(3)eC(4)eBr(1),
116.7(2); C(4)eC(5)eO(2), 121.0(2).
Scheme 4. Proposed pathway for allene formation (R¼p-OMePh, p-MePh, p-ClPh).
Having established a method for synthesizing 3-hydroxy-pent-
4-ynoic acids, we tested the synthetic efficacy of these compounds
in the preparation of lactones via an intramolecular electrophilic
annulation12 using N-bromosuccinimide as halogenating agent13
(Table 5). This reaction leads to the regioselective formation of 7
in good yields. Nevertheless, when R3¼H (Table 5: entries 4 and 6),
formation of the 2H-pyran-2-ones 7d0 and 7e0 is observed, which
could be due to the dehydration of the tertiary alcohol 7, promoted
by a slight increase in temperature. The structure of lactones 7d and
7f was fully established by means of X-ray diffraction analysis (Figs.
2 and 3.). Data on the crystals and the refining of these compounds
are summarized in Table 4.
Table 5
Synthesis of 5-bromo-3,4-dihydro-2H-pyran-2-ones
Fig. 3. ORTEP representation of 7d. Thermal ellipsoids at 30% probability level. Se-
ꢀ
ꢁ
lected bond length (A) and bond angles ( ) : Br(1)eC(4), 1.899(4); O(1)eC(1), 1.201(4);
O(2)eC(1), 1.362(5); O(2)eC(5), 1.397(4); C(1)eC(2), 1.505(5); C(2)eC(3), 1.533(5),
C(3)eC(4), 1.519(5); C(4)eC(5), 1.319, C(1)eO(2)eC(5), 121.4(3); O(1)eC(1)eO(2),
116.7(3); O(1)eC(1)eC(2), 126.2(4); O(2)eC(1)eC(2), 117.0(3); C(1)eC(2)eC(3),
111.3(3); O(3)eC(3)eC(2), 105.1(3); C(4)eC(3)eC(2), 106.9(3); C(5)eC(4)eC(3), 122.9
(3); C(5)eC(4)eBr(1), 119.1(3); C(3)eC(4)eBr(1), 117.6; C(4)eC(5)eO(2), 120.3(3).
Entry
3
R1
R2
R3
T (ꢀC)
t (h)
Product
Yield (%)
5-bromo-3,4-dihydro-2H-pyran-2-ones using a halolactonization
protocol. Finally, we are still working on the development of the
stereoselective synthesis of 3-hydroxy-pent-4-ynoic acids and their
annulation using different electrophiles.
1
2
3
4
5
6
7
8
9
3a
3b
3d
3d
3e
3e
3j
3k
3l
3n
Me
Me
Me
Me
Me
Me
Ph
p-NO2Ph
p-BrPh
p-ClPh
Me
e(CH2)4e
Me
Me
H
Me
0
0
0
25
0
25
0
0
0
0
2
2
2
4
2
4
2
2
4
3
7a
7b
7d
7d0
7e
7e0
7j
7k
7l
7n
75
94
76
73
58
54
66
74
77
71
H
H
H
H
Me
Me
Me
Me
H
4. Experimental section
Me
Me
Me
Me
4.1. General considerations
10
All reagents and solvents were obtained from commercial
sources and used without further purification. All compounds were
characterized by IR spectra, recorded on a Bruker Tensor 27 spec-
trophotometer, by KBr or film techniques, and all data are
expressed in wave numbers (cmꢁ1). Melting points were obtained
on a Melt-Temp II apparatus and are uncorrected. NMR spectra
were measured with a Bruker Advance III, 300 MHz using CDCl3
and DMSO-d6 as solvents. Chemical shifts are in parts per million
All reactions were carried out with 3 (0.3 g), NBS (1.2 equiv), in 10 mL of CH3CN.
3. Conclusions
In conclusion, we have developed a direct method for the syn-
thesis of good yields of 3-hydroxy-pent-4-ynoic acids, by the nu-
cleophilic addition of bis-(trimethylsilyl) ketene acetals to
acetylenic ketones and aldehydes. The formation of allene 6 as side-
product is observed, when the carbonyl group has as substituent an
electron donating group. The 3-hydroxy-pent-4-ynoic acids ob-
tained by this new method were efficiently transformed into new
(d), relative toTMS. The following abbreviations are used: s¼singlet,
d¼doublet, t¼triplet, dd¼double doublet, m¼multiplet. The MS-EI
spectra were obtained with a JEOL JMSAX505 HA using 70 eV as
ionization energy and for MS-FAB a JEOL JMS-SX102A using
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M.E. Lopez-Reyes et al. / Tetrahedron xxx (2013) 1e8
5
nitrobenzyl alcohol and ethylene glycol as a matrix. Elemental
analysis was measured with an Elemental analyzer External Ana-
lytical Inc. CE 440. Starting materials: bis-(trimethylsilyl) ketene
acetals 2aee were prepared according to published method9 and
alkynones (1bem) were prepared following the literature reported
method.14
acetate). Mp 155e157 ꢀC. Anal. Calcd for C18H16O3: C, 77.12; H, 5.75.
Found: C, 77.13, H, 5.60. IR (KBr, cmꢁ1
nmax: 3596, 3055, 2990, 2234,
1682, 1222. 1H NMR (300 MHz, CDCl3):
(ppm)¼7.33e7.29 (m, CH),
7.24e7.18 (m, CH), 7.14e7.07 (m, CH), 3.82 (m, CH), 1.24 (m, CH3). 13
NMR (75 MHz, CDCl3):
130.0 (CH), 128.59 (CH), 128.54 (CH), 128.4 (CH), 128.2 (CH), 122.2
(C) 91.5 (C), 84.1 (C), 68.5 (C), 60.6 (CH), 26.7 (CH3). MS (FABþ) m/z
(%): 281 (3) [Mþþ1].
)
d
C
d
(ppm)¼178.1 (C), 132.7 (C), 131.7 (CH),
4.2. Structure determination by X-ray crystallography
Suitable X-ray quality crystals of 7d were grown through slow
evaporation of a dichloromethane/n-hexane solvent mixture at
ꢁ5 ꢀC, and crystals of 6p and 7k were grown through slow evapo-
ration of an ethyl acetate/n-hexane solvent mixture at room tem-
perature. Single white crystals of compounds 6p, 7d, and 7k were
mounted on a glass fiber at room temperature. The crystals were
then placed on a Bruker SMART APEX CCD diffractometer, equipped
4.3.4. 3-Hydroxy-2,3-dimethyl-5-phenylpent-4-ynoic acid (3d).
Obtained as pale yellow oil, chromatography column (hexane/ethyl
acetate). IR (Film, cmꢁ1 nmax: 3408, 3082, 2987, 2235,1709. 1H NMR
)
(300 MHz, CDCl3):
2.79 (q, J¼9 Hz, CH), 2.17 (s, OH), 1.65 (s, CH3), 1.43 (d, J¼9 Hz, CH3),
1.45 (s, CH3), 1.37 (s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼7.41e7.39 (m, CH), 7.29e7.26 (m, CH),
d
(ppm)¼179.9
(C), 131.7 (2CH), 128.5 (CH), 128.2 (CH), 122.3 (C), 89.5 (C), 84.6 (C),
69.7 (C), 50.0 (CH), 28.4 (CH3), 13.3 (CH3). MS (EI) m/z (%): 218 (10)
[Mþ], 201 (20) [MþꢁOH], 171 (19) [MþꢁCOOH]. HRMS: calcd for
with Mo Ka radiation; decay was negligible in both cases. Details of
crystallographic data collected on compounds 6p, 7d, and 7k are
provided in Table 4. Systematic absences and intensity statistics
were used in space group determinations. The structures were de-
termined using direct methods.15 Anisotropic structure refinements
were achieved using full-matrix, least-squares techniques on all
non-hydrogen atoms. All hydrogen atoms were placed in idealized
positions, based on hybridization, with isotropic thermal parame-
ters fixed at 1.2 times the value of the attached atom. Structure
solutions and refinements were performed using SHELXTL v 6.10.16
C13H14O3: calculated 218.0943, found 218.0950.
4.3.5. 3-Hydroxy-3-methyl-5-phenylpent-4-ynoic acid (3e). Obtained
as red oil, chromatography column (hexane/ethyl acetate). IR (Film,
cmꢁ1
CDCl3):
7.01 (s, COOH), 2.88 (d, J¼15 Hz, CH2), 2.75 (d, J¼15 Hz, CH2), 2.65 (s,
OH),1.64 (s, CH3).13C NMR (75 MHz, CDCl3):
)
nmax: 3260, 3060, 2986, 2232, 1713. 1H NMR (300 MHz,
d
(ppm)¼7.39 (d, CH), 7.37 (s, CH), 7.27 (d, CH), 7.25 (d, CH),
d
(ppm)¼175.6 (C), 131.7
(CH), 128.4 (CH), 128.2 (CH), 122.3 (C), 91.0 (C), 83.2 (C), 65.6 (C), 46.6
(CH2), 29.5 (CH3). MS (EI) m/z (%): 204 (10) [Mþ], 187 (70) [MþꢁOH].
HRMS C12H12O3 [Mþ]: calculated 204.0786, found 204.0791.
4.3. General procedure for the synthesis of the 3-hydroxy-
pent-4-ynoic acids 3(aen)
At 0 ꢀC under argon atmosphere we added BF3$Et2O (0.44 mL,
3.47 mmol) to a solution of 4-phenyl-3-butyn-2-one (1a) (0.5 g,
3.47 mmol) in anhydrous diethyl ether (20 mL), and stirred this for
3 min. Then we slowly added bis-(trimethylsilyl) ketene acetal 2a
(0.96 mL, 4.1 mmol) at 0 ꢀC. The reaction was stirred for 4 h at room
temperature. The reaction mixture was washed with water (15 mL)
and extracted with dichloromethane (2ꢂ15 mL). The organic layer
was dried over anhydrous Na2SO4 and the solvent was evaporated
in vacuum. The crude was purified by column chromatography on
silica gel using a mixture of hexane and ethyl acetate as eluent.
4.3.6. 3-Hydroxy-2,2-dimethyl-5-phenylpent-4-ynoic acid (3f).
Obtained as pale yellow solid, chromatꢁo1graphy column (hexane/
ethyl acetate), mp 72e74 ꢀC. IR (KBr, cm
) nmax: 3431, 2977, 2221,
1690. 1H NMR (300 MHz, CDCl3):
CH), 7.04 (s, COOH), 4.77 (s, CH), 1.39 (s, CH3), 1.36 (s, CH3). 13C NMR
(75 MHz, CDCl3):
d
(ppm)¼7.42 (m, CH), 7.30 (m,
d
(ppm)¼182.3 (C), 131.7 (CH), 128.5 (CH), 128.2
(CH), 122.3 (C), 86.5 (C), 86.4 (C), 68.5 (C), 47.7 (C), 22.7 (CH3), 19.4
(CH3). MS (I.E) m/z (%): 218 (5) [Mþ], 201 (6) [MþꢁOH], 131 (100)
[MþꢁC4H7O2]. HRMS: calcd for C13H14O3: calculated 218.0943,
found 218.0944.
4.3.1. 3-Hydroxy-2,2,3-trimethyl-5-phenylpent-4-ynoic acid (3a).
4.3.7. 3-Hydroxy-2,2-dimethyldec-4-ynoic acid (3g). Obtained as
orange oil, filtration over silica gel with a mixture of hexane/ethyl
Obtained as white solid, chromatꢁo1graphy column (hexane/ethyl
acetate), mp 60e62 ꢀC. IR (Film, cm
)
nmax: 3081, 2987, 2234, 1700.
acetate. IR (Film, cmꢁ1
(300 MHz, CDCl3):
1.50 (t, CH2),1.30 (s, CH3),1.28 (s, CH3), 0.89 (t, CH2).13C NMR (75 MHz,
CDCl3):
)
nmax: 3490, 2934, 2229, 1708 cmꢁ1. 1H NMR
1H NMR (300 MHz, CDCl3):
7.37 (d, CH), 7.27 (d, CH), 7.25 (s, CH), 1.58 (s, CH3), 1.45 (s, CH3), 1.37
(s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼7.52 (s, COOH), 7.39 (d, CH),
d
(ppm)¼7.87 (s, COOH), 4.52 (s, CH), 2.32 (t, CH2),
d
(ppm)¼182.8 (C]O), 131.7
d
(ppm)¼182.6 (C), 87.3 (C), 77.6 (C), 68.2 (CH), 47.6 (C), 30.9
(CH), 128.4 (CH), 128.2 (CH), 122.4 (C), 90.5 (C), 84.4 (C), 72.6 (C),
50.4 (C), 24.7 (CH3), 22.1 (CH3), 20.8 (CH3). MS (FABþ) m/z (%): 233
(10) [Mþþ1], 215 (20) [MþꢁOH], 187 (40) [MþꢁCOOH]. MS calcd for
(CH2), 28.1 (CH2), 22.6 (CH3), 22.1 (CH2), 19.2 (CH3), 18.5 (CH2), 13.9
(CH3). MS (I.E) m/z (%): 213 (5) [Mþþ1], 195 (18) [MþꢁOH]. HRMS:
calcd for C12H21O3: calculated 213.1491, found 213.1495.
C
14H16O3: calculated 232.1099, found 232.1097.
4.3.8. 3-Hydroxy-2,2,3-trimethyl-5-(trimethylsilyl)pent-4-ynoic acid
4.3.2. 1-(2-Hydroxy-4-phenylbut-3-yn-2-yl)cyclohexanecarboxylic
(3h). Obtained as white solid, filtration over silica gel witꢁh1a mix-
3344, 2964, 2790, 2171, 1716. 1H NMR (300 MHz, CDCl3):
d
acid (3b). Obtained as white solid, chromatograꢁp1hy column (hex-
ture of hexane/ethyl acetate, mp 57e59 ꢀC. IR (KBr, cm
)
nmax
(ppm)¼
1.44 (s, CH3), 1.34 (s, CH3), 1.44 (s, CH3), 0.105 (s, CH3). 13C NMR
(75 MHz, CDCl3):
:
ane/ethyl acetate), mp 130e131 ꢀC. IR (KBr, cm
)
nmax
:
1H NMR
(300 MHz, CDCl3):
d
(ppm)¼7.43e7.40 (m, CH), 7.30e7.25 (m, CH),
2.37 (d, J¼12 Hz, CH2), 2.23 (d, J¼12 Hz, CH2), 1.75e1.65 (m, CH2),
d
(ppm)¼182.9 (C), 106.8 (C), 88.7 (CH), 72.1 (C),
1.59 (s, CH3), 1.46e1.34 (m, CH2), 1.21e1.13 (m, CH2). 13C NMR
50.1 (C), 24.3 (CH3), 21.8 (CH3), 20.5 (CH3), ꢁ0.29 (CH3). MS (I.E) m/z
(%): 228 (2) [Mþ], 311 (30) [MþꢁOH], 141 (100) [MþꢁC4H7O2].
HRMS: calcd for C11H19O2Si: calculated 211.1154, found 211.1161.
(75 MHz, CDCl3):
d
(ppm)¼181.0 (C), 131.7 (CH), 128.5 (CH), 128.3
(CH), 122.3 (C), 90.4 (C), 85 (C), 73.3 (C), 55.8 (C), 29.7 (CH2), 29.5
(CH2), 25.48 (CH2), 25.42 (CH3), 23.5 (CH2), 23.4 (CH2). MS (FABþ)
m/z (%): 273 (2) [Mþþ1], 255 (40) [MþꢁOH], 227 (20) [MþꢁCOOH].
HRMS: calcd for C17H19O2: calculated 255.1385, found 255.1390.
4.3.9. 3-Hydroxy-2,2-dimethyl-3-phenylnon-4-ynoic acid (3i).
Obtained as pale yellow solid, chromatography column (hexane/
ethyl acetate), mp 65e67 ꢀC. IR (KBr, cmꢁ1
)
nmax: 3489, 2929, 2234,
(ppm)¼7.67 (m, CH), 7.36
(m, CH), 2.32 (t, CH2), 1.55 (m, CH2), 1.49 (m, CH2), 1.30 (s, CH3), 1.25
4.3.3. 3-Hydroxy-3-methyl-2,5-diphenylpent-4-ynoic acid (3c).
Obtained as brown solid, chromatography column (hexane/ethyl
1706, 1664. 1H NMR (300 MHz, CDCl3):
d
ꢀ
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M.E. Lopez-Reyes et al. / Tetrahedron xxx (2013) 1e8
6
(s, CH3), 0.96 (s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼183.1 (C),
C
16H18: C, 91.37; H, 8.63. Found: C, 91.62, H, 8.55. IR (Film, cmꢁ1
nmax: 2933, 2857, 2202. 1H NMR (300 MHz, CDCl3):
(ppm)¼
7.38e7.28 (m, CH), 7.27e7.11 (m, CH), 2.41 (t, CH2), 2.12 (t, CH2), 1.78
(s, CH3), 1.52e1.42 (m-CH2). 13C NMR (75 MHz, CDCl3):
)
139.1 (C), 127.8 (CH), 127.2 (CH), 87.2 (C), 81.1 (C), 76.4 (C), 51.5 (C),
30.4 (CH2), 22.0 (CH3), 21.8 (CH2), 22.4 (CH3), 18.2 (CH2), 13.4 (CH3).
MS (I.E) m/z (%): 273 (3) [Mþꢁ1], 257 (68) [MþꢁOH], 187 (100)
[MþꢁC4H7O2]. HRMS: calcd for C17H21O3: calculated 273.1491,
found 273.1490.
d
d
(ppm)¼
148.12 (C), 131.2 (CH), 128.2 (CH), 127.4 (CH), 124.3 (C), 108.4 (C),
91.3 (C), 90.8 (C), 33.8 (CH2), 30.1 (CH2), 27.9 (CH2), 27.6 (CH2), 26.5
(CH2), 18.0 (CH3). MS (I.E) m/z: 210 (10) [Mþ].
4.3.10. 3-Hydroxy-2,2-dimethyl-3,5-diphenylpent-4-ynoic acid (3j).
Obtained as white solid, chromatography column (hexane/ethyl
4.3.16. 1-(4-Methyl-1-phenylpent-3-en-1-yn-3-yl)-4-nitrobenzene
acetate), mp 108e110 ꢀC. IR (KBr, cmꢁ1
)
nmax: 3060, 2226, 1696. 1H
(4k). Obtained as orange oil, chromatography column (hexane). IR
NMR (300 MHz, CDCl3):
7.35e7.28 (m, CH), 1.29 (s, CH3), 1.26 (s, CH3). 13C NMR (75 MHz,
CDCl3):
d
(ppm)¼7.70 (d, CH), 7.45 (d, CH),
(Film, cmꢁ1 nmax: 2952, 2853, 2199, 1596, 1518, 1345. 1H NMR
)
(300 MHz, CDCl3):
d
(ppm)¼8.21 (d, J¼9 Hz, CH), 7.53 (d, J¼9 Hz,
d
(ppm)¼183.1 (C), 138.7 (C), 131.8 (CH), 128.7 (CH), 128.5
CH), 7.43e7.42 (m, CH), 7.40 (d, J¼3 Hz, CH), 7.31e7.30 (m, CH), 7.29
(CH), 128.2 (CH), 127.9 (CH), 127.5 (CH), 122.2 (C), 90.1 (C), 86.5 (C),
76.9 (C), 51.8 (C), 22.1 (CH3), 20.5 (CH3). MS (I.E) m/z (%): 293 (5)
[Mþꢁ1], 277 (18) [MþꢁOH], 207 (100) [MþꢁC4H7O2]. HRMS:
calcd for C19H18O3: calculated 294.1252, found 294.1256.
(d, J¼3 Hz, CH), 2.24 (s, CH3),1.88 (s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼146.5 (C), 146.2 (C), 145.8 (C), 131.3 (CH), 130.1 (CH), 128.3
(CH), 128.1 (CH), 123.4 (2CH), 117.6 (C), 93.2 (C), 88.9 (C), 24.4 (CH2),
21.7 (CH3). MS (I.E) m/z (%): 277 (100) [Mþ]. HRMS: calcd for
C18H15O2N: calculated 277.1103, found 277.1105.
4.3.11. 3-Hydroxy-2,2-dimethyl-3,5-diphenylpent-4-ynoic acid (3k).
Obtained as orange solid, chromatography column (hexane/ethyl
4.3.17. 1-Bromo-4-(4-methyl-1-phenylpent-3-en-1-yn-3-yl)benzene
acetate), mp 112e114 ꢀC. IR (KBr, cmꢁ1
)
nmax: 3411, 3080, 2227,
(ppm)¼8.20 (d, CH), 7.89 (d,
CH), 7.46e7.43 (m, CH), 7.35e7.30 (m, CH) 1.31 (s, CH3), 1.26 (s, CH3).
13CNMR(75MHz,CDCl3):
(4l). Obtained as pale yellow oil, chromatography column (hex-
1700 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
ane). IR (Film, cmꢁ1 nmax: 2926, 2198, 1485, 755. 1H NMR
)
(300 MHz, CDCl3):
7.29e7.25 (m, CH), 7.23 (d, J¼9 Hz, CH), 2.19 (s, CH3), 1.83 (s, CH3).
13C NMR (75 MHz, CDCl3):
d
(ppm)¼7.47 (d, J¼9 Hz, CH), 7.42e7.39 (m, CH),
d
(ppm)¼182.9(C),147.7(C),146.0(C),131.8
(CH), 129.1 (CH), 128.4 (CH), 122.6 (CH), 121.6 (C), 88.9 (C), 87.3 (C),
76.5 (C), 51.7 (C), 21.9 (CH3), 20.5 (CH3). MS (I.E) m/z (%): 339 (2) [Mþ],
339 (20) [MþꢁOH], 294 (15) [MþꢁCOOH], 252 (100) [MþꢁC4H7O2].
HRMS: calcd for C19H17O4N: calculated 323.1158, found 323.1157.
d
(ppm)¼143.8 (C), 138.3 (C), 131.3 (CH),
131.2 (CH), 130.9 (CH), 128.2 (CH), 127.8 (CH), 123.8 (C), 120.8 (C),
118.1 92.5 (C), 89.7 (C), 24.1 (CH3), 21.6 (CH3). MS (I.E) m/z (%): 310
(85) [Mþ], 268 (100) [MþꢁC3H6]. HRMS: calcd for C18H15Br: cal-
culated 310.0357, found 310.0354.
4.3.12. 3-(4-Bromophenyl)-3-hydroxy-2,2-dimethyl-5-phenylpent-4-
ynoic acid (3l). Obtained as white solid, chromatography column
4.3.18. 1-Chloro-4-(4-methyl-1-phenylpent-3-en-1-yn-3-yl)benzene
(hexane/ethyl acetate), mp 116e118 ꢀC. IR (KBr, cmꢁ1
)
nmax: 3059,
(ppm)¼7.56 (d, J¼9 Hz,
CH), 7.46 (d, J¼9 Hz, CH), 7.44e7.41 (m, CH), 7.31e7.25 (m, CH) 1.27
(s, CH3), 1.23 (s, CH3). 13C NMR (75 MHz, CDCl3):
(4n). Obtained as yellow oil, chromatography column (hexane). IR
2227, 1697. 1H NMR (300 MHz, CDCl3):
d
(Film, cmꢁ1 nmax: 2908, 2726, 2198, 1594, 1486, 1092. 1H NMR
)
(300 MHz, CDCl3):
d
(ppm)¼7.42e7.39 (m, CH), 7.31e7.25 (m, CH),
d
(ppm)¼183.2 (C),
2.19 (s, CH3), 1.83 (s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼143.8
137.9 (C),131.8.0 (CH),130.6 (CH), 129.7 (CH), 128.9 (CH), 128.4 (CH),
122.5 (C), 121.9 (C), 89.6 (C), 86.7 (C), 76.5 (C), 51.6 (C), 22.0 (CH3),
20.4 (CH3). MS (FABþ) m/z (%): 373 (2) [Mþ], 355 (30) [MþꢁOH], 287
(50) [MþꢁC4H7O2]. HRMS: calcd for C19H16O2Br: calculated
355.0334, found 355.0342.
(C),137.9 (C), 132.6 (C), 131.3 (CH),130.6 (CH), 128.3 (CH),127.8 (CH),
123.8 (C), 118.0 (C), 92.5 (C), 89.8 (C), 24.1 (CH3), 21.6 (CH3). MS (I.E)
m/z (%): 266 (100) [Mþ]. HRMS: calcd for C18H15Cl: calculated
266.0862, found 266.0864.
4.3.19. 1-Methoxy-4-(4-methyl-1-phenylpent-3-en-1-yn-3-yl)ben-
4.3.13. Hydroxy-2,2-dimethyl-5-phenyl-3-(4-trifluoromethyl)phenyl
pent-4-ynoic acid (3m). Obtained as white solid, chromatography
zene (4o). Obtained as orange oil, chromatography column (hex-
ane). IR (Film, cmꢁ1 nmax: 2907, 2838, 2196, 1605, 1509, 1247. 1H
)
column (hexane/ethyl acetate), mp 94e96 ꢀC. IR (Film, cmꢁ1
)
nmax
(ppm)¼7.83 (d,
J¼9 Hz, CH), 7.61 (d, J¼9 Hz, CH), 7.44 (dd, CH), 7.33e7.28 (m, CH),
1.30 (s, CH3), 1.25 (s, CH3). 13C NMR (75 MHz, CDCl3):
:
NMR (300 MHz, CDCl3):
7.26e7.24 (m, CH), 6.87 (d, J¼9 Hz, CH), 3.78 (s, CH3), 2.18 (s, CH3),
1.84 (s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼7.41 (dd, CH), 7.28 (d, J¼9 Hz, CH),
3060, 2227, 1698. 1H NMR (300 MHz, CDCl3):
d
d
(ppm)¼158.3 (C), 142.5
d
(ppm)¼183.2
(C), 131.7 (C), 131.1 (CH), 130.2 (CH), 128.1 (CH), 127.5 (CH), 124.0
(CH), 118.4 (C), 113.3 (C), 91.9 (C), 90.4 (C), 55.1 (CH3), 24.0 (CH3),
21.5 (CH3). MS (I.E) m/z: 262 (100) [Mþ]. HRMS: calcd for C19H18O:
calculated 262.1358, found 262.1361.
(C),142.8 (C),131.8 (CH),130.6 (C),130.2 (C),128.9 (CH),128.4 (2CH),
125.8 (C), 124.4 (C), 122.2 (C), 121.8 (C), 89.5 (C), 86.9 (C), 76.6 (C),
51.7 (C), 22.0 (CH3), 20.4 (CH3). MS (IEþ) m/z (%): 362 (1) [Mþ], 345
(50) [MþꢁOH], 275 (100) [MþꢁC4H7O2]. HRMS: calcd for
C
20H16O2F3: calculated 345.1102, found 345.1100.
4.3.20. 3-(4-Chlorophenyl)-2,2,6,6-tetramethyl-5-phenylhepta-3,4-
dienedioic acid (6n). Obtained as white solid, chromatꢁo1graphy
4.3.14. 3-(4-Chlorophenyl)-3-hydroxy-2,2-dimethyl-5-phenylpent-4-
ynoic acid (3n). Obtained as pale yellow oil, chromatography col-
column (hexane/ethyl acetate), mp 161e163 ꢀC. IR (KBr, cm
) nmax:
3056, 2984, 1739, 1695. 1H NMR (300 MHz, CDCl3):
(s, COOH), 7.38e7.25 (m, CH), 1.53 (d, 2CH3), 1.48 (s, 2CH3). 13C NMR
(75 MHz, CDCl3):
d
(ppm)¼10.61
umn (hexane/ethyl acetate). IR (Film, cmꢁ1
)
nmax: 3081, 2227, 1698.
(ppm)¼7.62 (d, CH), 7.43 (dd, CH),
7.32e7.27 (m, CH), 1.27 (s, CH3), 1.23 (s, CH3). 13C NMR (75 MHz,
CDCl3):
1H NMR (300 MHz, CDCl3):
d
d
(ppm)¼204.4 (C), 183.88 (C), 183.82 (C), 134.53
(C), 133.42 (C), 133.13 (C), 128.73 (CH), 128.62 (CH) 127.46 (CH),
115.22 (C), 113.99 (C), 45.52 (C), 45.39 (C), 26.25 (CH3), 26.08 (CH3),
25.91 (CH3), 25.77 (CH3). MS (FABþ) m/z (%): 398 (3) [Mþ], 353 (15)
[MþꢁCOOH], 311 (100) [MþꢁC4H7O2]. HRMS: calcd for C22H22O2Cl:
calculated 353.1308, found 353.1314.
d
(ppm)¼183.0 (C), 137.54 (C), 134.3 (C), 131.9 (CH), 129.4
(CH), 128.9 (CH), 128.4 (CH), 127.7 (CH), 122.0 (C), 89.8 (C), 86.7 (C),
76.6 (C), 51.8 (C), 22.12 (CH3), 20.5 (CH3). MS (FABþ) m/z (%): 328 (2)
[Mþ], 311 (20) [MþꢁOH], 241 (40) [MþꢁC4H7O2]. HRMS: calcd for
C
19H16O2Cl: calculated 311.0839, found 311.0836.
4.3.21. 1-(4-Methoxyphenyl)-2,2,6,6-tetramethyl-5-phenylhepta-
4.3.15. (3-Cyclohexylidenebut-1-yn-1-yl)benzene (4b). Obtained as
orange oil, chromatography column (hexane). Anal. Calcd for
3,4-dienedioic acid (6o). Obtained as white solid (recrystallized
from hexane/ethyl acetate), mp 200e202 ꢀC. IR (KBr, cmꢁ1
) nmax:
ꢀ
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M.E. Lopez-Reyes et al. / Tetrahedron xxx (2013) 1e8
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3062, 2980, 1699, 1603. 1H NMR (300 MHz, DMSO):
7.36e7.26 (m, CH), 7.19 (t, CH), 6.86 (d, CH), 3.69 (s, CH3), 1.36 (s,
4CH3). 13C NMR (75 MHz, DMSO):
177.98 (C), 158.2 (C), 135.2 (C), 128.3 (CH), 128.0 (CH), 127.0 (C),
126.8 (CH), 114.5 (C), 114.4 (C), 113.8 (CH), 55.0 (CH3), 44.46 (C),
44.40 (C), 26.18 (CH3), 26.13 (CH3), 25.6 (CH3), 25.5 (CH3). MS
(FABþ) m/z (%): 394 (3) [Mþ], 350 (10) [MþꢁCOO], 307 (65)
[MþꢁC4H7O2]. HRMS: calcd for C23H27O3: calculated 351.1960,
found 351.1967.
d
(ppm)¼
(CH3), 20.2 (CH), 9.8 (CH3). MS (EI) m/z (%): 296 (15) [Mþꢁ1].
HRMS: calcd for
297.0126.
C13H14O3Br: calculated 297.0125, found
d
(ppm)¼203.3 (C), 178.0 (C),
4.4.4. 5-Bromo-3,4-dimethyl-6-phenyl-2H-pyran-2-one
(7d0). Obtained as white solid (0.18 g, 73%), chromatography col-
umn (hexane/ethyl acetate), mp 104e106 ꢀC. IR (KBr, cmꢁ1
)
nmax
(ppm)¼7.73e7.70
(m, CH), 7.45e7.43 (m, CH), 2.36 (s, CH3), 2.20 (s, CH3). 13C NMR
(75 MHz, CDCl3):
:
2993, 1744, 1669. 1H NMR (300 MHz, CDCl3):
d
d
(ppm)¼162.1 (C), 154.4 (C), 150.0 (C), 132.6 (C),
4.3.22. 2,2,6,6-Tetramethyl-3-phenyl-5-(p-tolyl)hepta-3,4-dienedioic
acid (6p). Obtained as white solid (recrystallized from hexane/
130.2 (CH), 129.3 (CH), 128.1 (CH), 121.2 (C), 104.4 (C), 20.7 (CH3),
14.1 (CH3). MS (EI) m/z (%): 278 (48) [Mþꢁ1]. HRMS: calcd for
ethyl acetate), mp 162 ꢀC. IR (KBr, cmꢁ1
)
nmax: 3060, 2987,
(ppm)¼12.54 (s, COOH),
7.38e7.16 (m, CH), 7.10 (d, CH), 2.23 (s, CH3), 1.39e1.37 (m, 4CH3).
13C NMR (75 MHz, DMSO):
C13H12O2Br: calculated 279.0013, found 279.0021.
1699 cmꢁ1. 1H NMR (300 MHz, DMSO):
d
4.4.5. 5-Bromo-4-hydroxy-4-methyl-6-phenyl-3,4-dihydro-2H-py-
d
(ppm)¼203.5 (C), 177.8 (C), 177.7 (C),
ran-2-one (7e). Obtained as white solid (0.16 g, 58%), chromatog-
136.2 (C), 135.2 (C), 132.1 (C), 128.9 (CH), 128.3 (CH), 126.8 (2CH),
114.8 (C), 114.7 (C), 44.44 (C), 44.41 (C), 26.2 (CH3), 26.1 (CH3), 25.7
(CH3), 25.6 (CH3), 20.5 (CH3). MS (I.E) m/z (%): 377 (12) [Mþ], 332
(25) [MþꢁCOOH], 291 (100) [MþꢁC4H7O2]. HRMS: calcd for
raphy column (hexane/ethyl acetate), mp 124 ꢀC. IR (KBr, cmꢁ1
)
nmax: 3444, 1737, 1660. 1H NMR (300 MHz, CDCl3):
d
(ppm)¼
7.63e7.59 (m, CH), 7.39 (d, CH), 7.37 (d, CH), 3.11 (d, J¼15 Hz, CH2),
2.99 (d, J¼15 Hz, CH2), 2.31 (s, OH), 1.54 (s, CH3). 13C NMR (75 MHz,
C
24H25O4: calculated 377.1753, found 377.1753.
CDCl3):
d
(ppm)¼166.1 (C), 147.1 (C), 132.2 (C), 130.0 (CH), 129.1
(CH), 128.1 (CH), 110.5 (C), 70.6 (C), 43.4 (CH2), 28.4 (CH3). MS (EI)
m/z (%): 283 (30) [Mþ]. HRMS: calcd for C12H11O3Br: calculated
281.9891, found 281.9889.
4.4. General procedure for the synthesis of the 5-bromo-3,4-
dihydro-2H-pyran-2-ones 7(aen)
At 0 ꢀC we added N-bromosuccinimide (0.15 g, 8.6 mmol) to
a solution of the 3-hydroxy-2,2,3-trimethyl-5-phenylpent-4-ynoic
acid (2a) (0.2 g, 8.6 mmol) in 5 mL of acetonitrile, the reaction
was stirred for 2 h at 0 ꢀC, after that the solvent was evaporated and
the residue was dissolved in CH2Cl2 and then washed with distilled
water (10 mL). The organic layer was dried over anhydrous Na2SO4
and the solvent was evaporated in vacuum. The crude was purified
by column chromatography on silica gel with a mixture of hexane
and ethyl acetate as eluent.
4.4.6. 5-Bromo-4-methyl-6-phenyl-2H-pyran-2-one (7e0). Obtained
as white solid (0.14 g, 54%), chromatoꢁg1raphy column (hexane/ethyl
acetate), mp 99e100 ꢀC. IR (KBr, cm
)
nmax: 1719, 1611. 1H NMR
(300 MHz, CDCl3):
d
(ppm)¼7.78e7.74 (m, CH), 7.50e7.45 (m, CH),
6.25 (q, J¼3 Hz, CH), 2.35 (d, J¼3 Hz, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼160.6 (C), 157.5 (C), 156.4 (C), 132.0 (C), 130.5 (CH), 129.2
(CH), 128.0 (CH), 112.8 (CH), 103.3 (C), 23.8 (CH3). MS (EI) m/z (%):
264 (50) [Mþ]. HRMS: calcd for C12H10O2Br: calculated 264.9864,
found 264.9870.
4.4.1. 5-Bromo-4-hydroxy-3,3,4-trimethyl-6-phenyl-3,4-dihydro-2H-
pyran-2-one (7a). Obtained as white solid (0.2 g, 75%) chroma-
tography column (hexane/ethyl acetate), mp 110e112 ꢀC. IR (KBr,
4.4.7. 5-Bromo-4-hydroxy-3,3-dimethyl-4,6-diphenyl-3,4-dihydro-
2H-pyran-2-one (7j). Obtained as white solid (0.17 g, 66%), chro-
matography column (hexane/ethyl acetate), mp 168e170 ꢀC. IR
cmꢁ1
)
nmax: 3476, 2989, 1753. 1H NMR (300 MHz, CDCl3):
d
(ppm)¼
7.63e7.62 (m, CH), 7.40e7.39 (m, CH), 2.33 (s, OH), 1.43 (s, CH3), 1.40
(s, CH3). 13C NMR (75 MHz, CDCl3):
(KBr, cmꢁ1 nmax: 3481, 2989, 1751, 1670. 1H NMR (300 MHz, CDCl3):
)
d
(ppm)¼7.74 (d, CH), 7.44e7.32 (m, CH), 2.78 (s, OH), 1.59 (s, CH3),
d
(ppm)¼172.7 (C), 145.3 (C),
1.06 (s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼172.0 (C), 146.5
134.3 (C), 132.2 (CH), 129.9 (CH), 128.9 (CH), 128.1 (CH), 111.3 (C),
74.6 (C), 46.7 (C), 23.9 (CH3), 20.2 (CH3), 19.5 (CH3). MS (EI) m/z (%):
310 (10) [Mþ]. HRMS: calcd for C14H15O3Br : calculated 310.0213,
found 310.0205.
(C), 139.8 (C), 132.0 (C), 130.2 (CH), 129.0 (CH), 128.7 (CH), 128.6
(CH), 128.2 (CH), 125.6 (CH), 110.9 (C), 79.3 (C), 47.9 (C), 22.5 (CH3),
19.5 (CH3). MS (EI) m/z (%): 374 (10) [Mþ]. HRMS: calcd for
C19H17O3Br: calculated 374.0339, found 374.0341.
4.4.2. 4-Bromo-5-hydroxy-5-methyl-3-phenyl-2-oxaspiro[5.5]un-
dec-3-en-1-one (7b). Obtained as white solid (0.24 g, 94%) (recrys-
tallized from hexane/dichlorometane), mp 98e100 ꢀC. IR (KBr,
4.4.8. 5-Bromo-4-hydroxy-3,3-dimethyl-4-(4-nitrophenyl)-6-
phenyl-3,4-dihydro-2H-pyran-2-one (7k). Obtained as white solid
(0.18 g, 74%), chromatoꢁgr1aphy column (hexane/ethyl acetate), mp
cmꢁ1
)
nmax: 3494, 2941, 1738. 1H NMR (300 MHz, CDCl3):
d
(ppm)¼
190e191 ꢀC. IR (KBr, cm
) nmax: 3488, 2985, 1752, 1655, 1518, 1348.
7.69e7.66 (m, CH), 7.45e7.41 (m, CH), 2.33 (s, OH), 2.13 (d, J¼12 Hz,
1H NMR (300 MHz, CDCl3):
CH), 7.64 (d, J¼9 Hz, CH), 7.49e7.46 (m, CH), 2.95 (s, OH), 1.60 (s,
CH3), 1.07 (s, CH3). 13C NMR (75 MHz, CDCl3):
d
(ppm)¼8.24 (d, J¼9 Hz, CH), 7.73 (dd,
CH2), 1.74 (d, J¼12 Hz, CH2), 1.42 (s, CH3), 1.24e1.15 (m, CH2). 13C
NMR (75 MHz, CDCl3):
d
(ppm)¼171.1 (C), 132.0 (C), 129.7 (CH),
d
(ppm)¼171.2 (C),
128.8 (CH), 128.0 (CH), 49.9 (C), 27.5 (C), 25.2 (CH2), 23.5 (CH2), 22.7
(CH2), 22.6 (CH3). MS (EI) m/z (%): 350 (10) [Mþꢁ1], 333 (30)
[MþꢁOH], 307 (15) [MþꢁCOO]. HRMS: calcd for C17H19O3Br: cal-
culated 351.0596, found 351.0606.
148.0 (C), 147.5 (C), 147.4 (C), 131.5 (C), 130.2 (CH), 128.9 (CH), 128.4
(CH), 127.03 (CH), 123.8 (CH), 109.0 (C), 79.2 (C), 47.7 (C), 22.3 (CH3),
19.9 (CH3). MS (EI) m/z (%): 417 (10) [Mþ]. HRMS: calcd for
C19H16BrO5N: calculated 417.0212, found 417.0209.
4.4.3. 5-Bromo-4-hydroxy-3,4-dimethyl-6-phenyl-3,4-dihydro-2H-
pyran-2-one (7d). Obtained as white solid (0.2 g 76%), chroma-
tography column (hexane/ethyl acetate), mp: 84e86 ꢀC. IR (KBr)
4.4.9. 5-Bromo-4-(4-bromophenyl)-4-hydroxy-3,3-dimethyl-6-
phenyl-3,4-dihydro-2H-pyran-2-one (7l). Obtained as white solid
(0.18 g, 77%), chromatography column (hexane/ethyl acetate), mp:
nmax
:
3471, 2992, 1744, 1666. 1H NMR (300 MHz, CDCl3):
180e182 ꢀC. IR (KBr, cmꢁ1
(300 MHz, CDCl3):
7.49e7.32 (m, CH), 7.30 (d, J¼6 Hz, CH), 2.81 (s, OH), 1.57 (s, CH3),
1.06 (s, CH3). 13C NMR (75 MHz, CDCl3):
(ppm)¼171.6 (C), 146.8
(C), 139.0 (C), 130.2 (CH), 128.9 (CH), 128.2 (CH), 127.4 (CH), 122.7
)
nmax: 3493, 2986, 1750, 1656. 1H NMR
d
(ppm)¼7.64e7.62 (m, CH), 7.4 (s, CH), 3.11 (q, J¼6 Hz, CH), 2.42
d
(ppm)¼7.73e7.72 (m, CH), 7.50 (d, J¼6 Hz, CH),
(s, OH), 1.42 (d, J¼6 Hz, CH3), 1.36 (s, CH3). 13C NMR (75 MHz,
CDCl3):
d
(ppm)¼169.5 (C), 145.5 (C), 132.1 (C), 129.9 (CH), 129.1
d
(CH), 129.0 (CH), 128.1 (CH), 112.5 (C), 72.8 (C), 45.7 (C), 22.2
ꢀ
Please cite this article in press as: Lopez-Reyes, M. E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.06.069

ꢀ
M.E. Lopez-Reyes et al. / Tetrahedron xxx (2013) 1e8
8
7. (a) Hatano, M.; Takagi, E.; Ishihara, K. Org. Lett. 2007, 9, 4527; (b) Hatano, M.;
Suzuki, S.; Takagi, E.; Ishihara, K. Tetrahedron Lett. 2009, 50, 3171.
(C), 110.0 (C), 78.9 (C), 47.7 (C), 22.3 (CH3), 19.9 (CH3). MS (EI) m/z
(%): 452 (10) [Mþ]. HRMS: calcd for C19H16O3Br2: calculated
451.9446, found 451.9460.
8. (a) Rudler, H.; Parlier, A.; Hamon, L.; Herson, P.; Daran, J. C. Chem. Commun.
2008, 4150; (b) Rudler, H.; Parlier, A.; Hamon, L.; Herson, P.; Daran, J. C.
Tetrahedron 2009, 65, 5552; (c) Schmidt, A.; Michalik, D.; Rotzoll, S.; Ullah, E.;
Fischer, C.; Reinke, H.; Gorls, H.; Langer, P. Org. Biomol. Chem. 2008, 6, 2804.
9. The bis-(trimethylsilyl) ketene acetals were prepared by Ainsworth method:
Ainsworth, C.; Kuo, Y. J. Organomet. Chem. 1972, 46, 73.
4.4.10. 5-Bromo-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethyl-6-
phenyl-3,4-dihydro-2H-pyran-2-one (7n). Obtained as white solid
(0.18 g, 71%), chromatography column (hexane/ethyl acetate), mp:
10. For examples see: (a) Xu, Y.; Aldeco-Perez, E.; Rudler, H.; Parlier, A.; Alvarez,
178 ꢀC. IR (KBr, cmꢁ1
(300 MHz, CDCl3):
7.39e7.32 (m, CH), 2.81 (s, OH), 1.57 (s, CH3), 1.07 (s, CH3). 13C NMR
(75 MHz, CDCl3):
)
nmax: 3493, 2967, 1750, 1654. 1H NMR
ꢀ
C. Tetrahedron Lett. 2006, 47, 4553; (b) Rudler, H.; Aldeco-Perez, E.; Parlier,
A.; Alvarez, C. J. Mex. Chem. Soc. 2008, 52, 145; (c) Gualo-Soberanes, N.;
d
(ppm)¼7.75e7.72 (m, CH), 7.46e7.43 (m, CH),
ꢀ
ꢀ
Ortega-Alfaro, M. C.; Lopez-Cortes, J. G.; Toscano, R. A.; Rudler, H.;
ꢀ
~
Alvarez-Toledano, C. Tetrahedron Lett. 2010, 51, 3186; (d) Garduno-Alva, A.;
Xu, Y.; Gualo-Soberanes, N.; Lopez-Cortes, J. G.; Rudler, H.; Parlier, A.; Or-
ꢀ
ꢀ
d
(ppm)¼171.7 (C), 146.8 (C), 138.5 (C), 134.6 (C),
tega-Alfaro, M. C.; Alvarez-Toledano, C.; Toscano, R. A. Eur. J. Org. Chem.
131.8 (C), 130.3 (CH), 129.0 (CH), 128.9 (CH), 128.3 (CH), 127.2 (CH),
110.2 (C), 79.0 (C), 47.8 (C), 22.3 (CH3), 19.9 (CH3). MS (IE) m/z (%):
406 (10) [Mþꢁ1]. HRMS: calcd for C19H16BrClO3: calculated
407.0050, found 407.0042.
~
ꢀ
ꢀ
2008, 21, 3714; (e) Garduno-Alva, A.; Ortega-Alfaro, M. C.; Lopez-Cortes, J.
ꢀ
ꢀ
G.; Chavez, I.; Barroso-Flores, J.; Toscano, R. A.; Rudler, H.; Alvarez-Toledano,
C. Can. J. Chem. 2012, 90, 469.
11. (a) Schaumann, E.; Ketcham, R. Angew. Chem., Int. Ed. Engl. 1982, 21, 225; (b)
Brady, W. T.; Gu, Y.-Q. J. Org. Chem. 1988, 53, 1353; (c) Nava Salgado, V. O.; Peters,
E.-M.; Peters, K.; von Schnering, H. G.; Adam, W. J. Org. Chem. 1995, 60, 3879; (d)
Sehnapp, K. A.; Motz, P. L.; Stoeckel, S. M.; Wilson, R. M.; Krause, J. A.; Bohne, C.
Tetrahedron Lett. 1996, 37, 2317; (e) Morao, I.; Lecea, B.; Arrieta, A.; Cossío, F. P. J.
Am. Chem. Soc. 1997, 119, 816; (f) Ocampo, R.; Dolbier, W. R., Jr.; Michael, D.;
Bartberger, M. D.; Paredes, R. J. Org. Chem. 1997, 62, 109; (g) Merlic, C. A.; Doroh,
B. C. J. Org. Chem. 2003, 68, 6056; (h) Shindo, M.; Yoshimura, Y.; Hayashi, M.;
Soejima, H.; Yoshikawa, T.; Matsumoto, K.; Shishido, K. Org. Lett. 2007, 9, 1963;
(i) Bejot, R.; Anjaiah, S.; Falck, J. R.; Mioskowski, C. Eur. J. Org. Chem. 2007, 101;
(j) Wang, X.-N.; Zhang, Y.-Y.; Ye, S. Adv. Synth. Catal. 2010, 352, 1892; (k) Cohen,
D. T.; Eichman, C. C.; Phillips, E. M.; Zarefsky, E. R.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2012, 51, 7309.
Acknowledgements
~
We thank Rocio Patino, Luis Velasco, Javier Perez, and María de
ꢀ
la Paz Orta Perez for their technical assistance. We would also like
to thank the DGAPA PAPIIT IN201211 and CONACYT 127796 projects
and CONACYT for the Ph.D. grant extended to M.E.L.R.
Supplementary data
12. (a) Godoi, B.; Shumacher, R. F.; Zeni, G. J. Chem. Rev. 2011, 111, 2937; (b) Mehta,
S.; Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141; (c) Alvarez-Corral, M.;
~
Munoz-Dorado, M.; Rodriguez-Garcia, I. Chem. Rev. 2008, 108, 3174; (d) Harkat,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.06.069.
ꢀ
ꢀ
ꢀ
ꢀ
Y.; Yenimegue-Dembele, A.; Weibel, J. M.; Blanc, A.; Pale, P. Tetrahedron 2009, 9,
1871; (e) Marchal, E.; Uriac, P.; Legoun, B.; Toupet, L.; Weghe, P. Tetrahedron
2007, 63, 9979.
13. (a) Krafft, G. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1981, 103, 5459; (b)
Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857; (c)
Palisse, A.; Kirsch, S. F. Org. Biomol. Chem. 2012, 10, 8041; (d) Denmark, S. E.;
Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20655; (e) Chen, F.; Jiang, X.; Er,
J. C.; Yeung, Y.-Y. Tetrahedron Lett. 2010, 51, 3433; (f) Zhou, L.; Tan, C. K.; Jiang,
X.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474; (g) Chen, J.; Zhou, L.;
Tan, C. K.; Yeing, Y.-Y. J. Org. Chem. 2012, 77, 999; (h) Snyder, S. A.; Treitler, D. S.;
Brucks, A. P. Aldrichimica Acta 2011, 44, 27.
14. Zhao, T.; Xu, B. Org. Lett. 2010, 12, 212.
15. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori,
G.; Canalli, M. J. Appl. Crystallogr. 1994, 27, 435.
16. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, A64, 112.
References and notes
ꢀ
1. Pixu, L.; Evans, C. D.; Wu, Y.; Cao, B.; Hamel, E.; Joullie, M. M. J. Am. Chem. Soc.
2008, 130, 2351.
2. Haga, Y.; Okazaki, M.; Shuto, Y. Biosci. Biotechnol. Biochem. 2003, 67, 2183.
3. Smith, A. B.; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001,
123, 10942.
4. Kudoh, T.; Park, C. S.; Lefurgy, S. T.; Sun, M.; Michels, T.; Leyh, T. S.; Silverman,
R. B. Bioorg. Med. Chem. 2010, 18, 1124.
5. Wiley, R. H.; Staples, C. E. J. Org. Chem. 1963, 28, 3408.
6. Ghosh, A. K.; Kim, J. Tetrahedron Lett. 2002, 43, 5621.
ꢀ
Please cite this article in press as: Lopez-Reyes, M. E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.06.069