The Development of a Stereoselective Method for the Synthesis of Tetrasubstituted Derivatives of α,β-Unsaturated Carboxylic Acids

Article abstract of DOI:10.1002/hlca.201600079

Alkenes possessing four different carbon-linked substituents are the main structural motif of many biologically active compounds. The derivatives of (2E)-3-(3-methoxyphenyl)-2-methylpent-2-enoic acid ((E)-2c) are suitable precursors for the synthesis of Tapentadol, a novel centrally acting analgesic. It was found that the Ni-carbometallation reaction of disubstituted alkyne 8 with CO₂and an Et₂Zn allows for efficient and practical preparation of (E)-2c as a single (E)-regioisomer in 89% of isolated yield. The influence of the size of the aliphatic substituent of alkyne and the steric hindrance of the organozinc reagent on stereochemical course of the carbometallation reaction was evaluated. Finally, air-stable Ni(dme)Cl₂was proposed as an alternative to widely used Ni(cod)₂catalyst.

Full text of DOI:10.1002/hlca.201600079

Helv. Chim. Acta 2016, 99, 665 – 673
665
FULL PAPER
The Development of a Stereoselective Method for the Synthesis of Tetrasubstituted
Derivatives of a,b-Unsaturated Carboxylic Acids
by Jan Rzymkowski, and Anna Piatek*
z
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland (phone: +48225526246;
e-mail: apiatek@chem.uw.edu.pl)
Dedicated to Prof. Dr. hab. Janusz Jurczak on the occasion of his 75th birthday
Alkenes possessing four different carbon-linked substituents are the main structural motif of many biologically active
compounds. The derivatives of (2E)-3-(3-methoxyphenyl)-2-methylpent-2-enoic acid ((E)-2c) are suitable precursors for the
synthesis of Tapentadol, a novel centrally acting analgesic. It was found that the Ni-carbometallation reaction of disubstituted
alkyne 8 with CO2 and an Et2Zn allows for efficient and practical preparation of (E)-2c as a single (E)-regioisomer in 89% of
isolated yield. The influence of the size of the aliphatic substituent of alkyne and the steric hindrance of the organozinc
reagent on stereochemical course of the carbometallation reaction was evaluated. Finally, air-stable Ni(dme)Cl2 was proposed
as an alternative to widely used Ni(cod)2 catalyst.
Keywords: Tetrasubstituted alkenes, Ni-catalyzed carboxylation, Reductive elimination, Ketone olefination, Carbometallation
reaction.
as key precursors for Tapentadol preparation. The rare
enantioselective hydrogenation of these highly substituted
olefins would lead to 1 [12].
Introduction
The main structural motif of many biologically active
ingredients such as Tamoxifen [1], Vioxx [2], or Nileprost
[3], is the double-bond bearing four different aryl or alkyl
substituents. Moreover, the tetrasubstituted double bond
is a common feature of many more complicated com-
pounds possessing other functionalities [4]. Furthermore,
tetrasubstituted olefins are often key synthetic intermedi-
ates en route to target compounds [5]. Unlike for double-
substituted olefins, the stereoselective synthesis of
tetrasubstituted alkenes (especially acyclic) still poses a
significant synthetic challenge. The effectiveness and
stereoselectivity of traditional double-bond formation
methods such as Wittig or Horner–Wadsworth–Emmons
reactions are usually unsatisfactory for the preparation of
tetrasubstituted olefins [6]. Other synthetic methods are
therefore more applicable for the preparation of multisub-
stituted alkenes. These include the coupling of substituted
vinyl halides or pseudo-halides with organometallic com-
pounds [7], elimination reaction [8], carbometallation of
alkynes [9], and carbonyl olefination [10].
Results and Discussion
We tested several recently described approaches to the
synthesis of tetrasubstituted a,b-unsaturated carboxylic
acid derivatives as possible methods for the preparation
of 2a – c [13]. Our first attempt involved the stereoselec-
tive synthesis of tetrasubstituted a,b-unsaturated amides
ꢀ
2a using the Concellon et al. procedure [14]. This method
is based on reductive elimination of a,b-epoxyamides or
2-chloro-3-hydroxyamides using SmI2. In our tests, the
original conditions applied to the amide 3a led mainly to
trisubstituted alkene 4, a product of epoxide elimina-
tive opening (Scheme 2). Various conditions were
tested (with variations in SmI2 loading, reaction time,
additives) and it was found that the addition of 8 equiv.
of HMPA is required to provide the desired product
with 55% yield. Unfortunately, no (E)/(Z) selectivity was
observed.
On the other hand, only SmI2 is needed for the con-
version of ester derivative 3b to olefin 2b with 60% yield
and 2.8:1 (E)/(Z) selectivity in favor of the required iso-
mer. The assignment of configuration of major (E)-2b is
based on ROESY analysis, (Fig. 1), as a result of corre-
lations between ortho aromatic H-atoms with H-atoms
from Me group. This SmI2-promoted stereoselective b-
elimination methodology can also be used for the
Recently, our research interest has focused on the
search for a more effective and practical synthetic route
to Tapentadol (1), a novel centrally acting analgesic
(Scheme 1) [11].
This analgesic agent exists in four stereoisomeric
forms, among which the (R,R)-enantiomer is approved for
clinical use. We envisioned tetrasubstituted derivatives of
(2E)-3-(3-methoxyphenyl)-2-methylpent-2-enoic acid (2)
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Scheme 1
Scheme 2
Fig. 1. Configuration assignment of (E)-2b regioisomer based on analysis of the ROESY spectrum.
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667
Scheme 3
Fig. 2. Configuration assignment of (E)-2c regioisomer based on analysis of the ROESY spectrum.
Scheme 4
the undesired isomer, whereas using ester 5b provided
product 2b with 40% yield and near 2.7:1 (E)/(Z) selec-
tivity.
Since SmI2 reductive elimination of epoxides as well
as halohydrin derivatives proved to give products with
moderate yields and stereoselectivities, we shifted our
attention to ketone olefination by ynolates described by
Shindo et al. (Scheme 3) [15].
Treatment of ethyl 2-bromopropanoate (6) with LDA
generates the corresponding ynolate which reacts with
ketone 7 [16], leading to acid 2c. The assignment of config-
uration of major (E)-2c product was also based on ROESY
analysis (Fig. 2) as a result of correlations between ortho
aromatic H-atoms with H-atoms from the Me group.
Unfortunately, the effectiveness of this procedure applied
to our substrate was unreliable (the best result obtained
elimination of a,b-halohydrin esters or amides. Interest-
ingly, we observed a large difference between the stereo-
chemical course of the b-elimination of the amide and
ester derivatives of a-halohydrins. Specifically, for amide being 50% yield and 6.7:1 (E)/(Z) selectivity). Thus, all the
5a, SmI2-promoted elimination gave alkene 2a with ca. methods described above were found to suffer from low to
50% yield and near 0.2:1 (E)/(Z) selectivity in favor of
medium yields and/or low (E)/(Z) selectivity.
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Helv. Chim. Acta 2016, 99, 665 – 673
Scheme 5
mediated carbometallation reaction. For example, the use
Table 1. Carbometallation reaction of alkynes 10a, 10b, and 10c
with various zinc reagents catalyzed by Ni(cod)2
of Et2Zn in the preparation of a trisubstitiuted a,b-unsatu-
rated carboxylic acid gave the desired product with only
9% of yield, whereas application of Me2Zn (9a) gave the
corresponding product with 81% yield [17].
Therefore, we were pleased to find that treatment of
a freshly prepared suspension of Ni(cod)2 (0.8 equiv.),
DBU (10 equiv.) in CO2 atmosphere (1 atm) by alkyne 8
and subsequent Et2Zn (3 equiv.) addition led to the
desired product (E)-2c with 89% isolated yield
(Scheme 4).
We found that pure carboxylic acid could be isolated
from the reaction mixture without the need to convert it
to an ester derivative, as is described in the literature.
More importantly, this can be achieved via acid/base
extraction, then bulb to bulb distillation without needing
chromatographic purification.
Alkyne Me2Zna) Et2Zna) iPr2Zna)
10a
10b
10c
10a/11aa/12aa/13a 10a/11ab/12ab/13a 10a/11ac/12ac/13a
41:59:0:0 15:61:12:12 10:25:5:60
10b/11ba/12ba/13b 10b/11bb/12bb/13b 10b/11bc/12bc/13b
20:66:7:7
10c/11ca/12ca/13c
38:62:0:0
17:55:11:17
10c/11cb/12cb/13c
21:54:14:10
40:20:0:40
10c/11cc/12cc/13c
34:15:0:51
a) 0.4 mmol of alkyne in 0.5 ml of THF, 1.2 mmol of organozinc
reagent, 4 mmol DBU, 0.08 mmol Ni(cod)2 in 1 ml of THF, 1 atm
CO2, 0 °C, 20 h. The ratio of products was determined based on 1H-
NMR analysis.
Table 2. Carbometallation reaction of alkynes 10a and 10b with var-
ious zinc reagents catalyzed by Ni(dme)Cl2
We evaluated the effect of catalyst loading on reaction
efficiency. While 0.1 equiv. of Ni(cod)2 was employed,
only 40% of product was isolated. The crude reaction
mixture also contains a large amount of unreacted alkyne
8 and ca. 10% of trisubstituted acid of type 13. Increasing
the catalyst loading to 0.4 equiv. gave 69% yield.
To explore the scope of the carbometallation of alky-
nes of type 10, various commercially available alkynes
and organozinc reagents were examined (Scheme 5).
Many trends can be seen from the data collected in
Table 1.
Alkyne
Me2Zna)
Et2Zna)
10a
10a/11aa/12aa/13a
31:66:0:3
10a/11ab/12ab/13a
24:47:13:16
10b
10b/11ba/12ba/13b
64:36:0:0
10b/11bb/12bb/13b
32:49:5:14
a) 0.4 mmol of alkyne in 0.5 ml of THF, 1.2 mmol of organozinc
reagent, 4 mmol DBU, 0.08 mmol Ni(dme)Cl2 in 1 ml of THF,
1 atm CO2, 0 °C, 20 h. The ratio of products was determined based
on 1H-NMR analysis.
In a first rough estimate, the size of the alkyne linear
aliphatic substituent appears to exert little influence on
the conversion. In contrast, the steric hindrance of the
organozinc reagent has a major effect on the product dis-
tribution. However, while Me2Zn (9a) and Et2Zn (9b)
gave similar yields of major product 11,1) the use of
iPr2Zn (9c) dramatically lowered the reaction effective-
ness (15 – 25% yield). In Me2Zn (9a), a large amount of
unreacted substrate was present without formation of side
products, whereas for Et2Zn, a higher conversion of the
substrate was present in favor of the unwanted
Continuing our search for a more effective and stere-
oselective synthetic method for tetrasubstituted deriva-
tives of a,b-unsaturated carboxylic acids, we considered
the promising approach to such compounds developed by
Mori et al. [17]. This method is based on Ni-catalyzed
addition of CO2 and organozinc reagent to disubstituted
alkynes. The proposed mechanism of this reaction
excludes the formation of unwanted (Z) stereoisomer.
However, to synthesize the desired derivatives of
pent-2-enoic acid (E)-2c, alkyne 8 is needed [18]. This
type of alkyne had never been applied to Ni-catalyzed
carboxylation. The other necessary reagent is Et2Zn (9b).
Interestingly, its use was rarely explored in the Ni-
1) For 11aa and 11ac see [19a][19b]; for 11ba, see [19c]; for
11ca, see [19d]; for 11ab, see [19e]; for 11bb, see [19f]; for
11cb, see [19g].
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Helv. Chim. Acta 2016, 99, 665 – 673
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Scheme 6
regioisomer 122) and trisubstituted alkene 13 [21]. These
results highlighted the differences between reactivity of
double-substituted alkynes provided derivatives of (2E)-
3-(3-methoxyphenyl)-2-methylpent-2-enoic acid (2) with
Me2Zn and Et2Zn. Due to the significant steric hindrance high yields. This method circumvents the problem of
i
of Pr2Zn, the Ni-promoted catalyzed carboxylation reac-
tion led mainly to alkene 13, a product of only CO2 addi- of view, we found that acid/base extraction, followed by
tion without subsequent organozinc transmetallation. bulb-to-bulb distillation is suitable for isolation and
Although Ni(cod)2 is an efficient catalyst for car- purification of acid (E)-2c. We have shown that the ali-
unwanted (Z)-isomer formation. From a practical point
bometallation reaction, it is very air and water sensitive
and its application requires the use of a glovebox. There-
fore, air-stable catalyst would greatly simplify the syn-
thetic procedure. Toward this end, we tested application
of other NiII complexes (0.2 equiv.) in reaction of alkyne
8 with Et2Zn, in the presence of 3 equiv. of DBU under
an atmosphere of CO2 (Scheme 6).
phatic unbranched substituents in the tested alkynes
have a modest influence on yield. However, the steric
bulkiness of substituents in organozinc reagent has a
major effect on conversion and product distribution.
Finally, we showed that, an air stable Ni(dme)Cl2 com-
plex could be used as catalyst for carbometallation reac-
tion with only slight loss of efficiency for the desired
Simple NiCl2 is almost inactive under those conditions target (E)-2c.
(8% of product (E)-2c) and 87% of unreacted alkyne 8
was recovered. However, commercially available nickel This work has been financially supported by the Small
(II) acetylacetonate (Ni(acac)2) gave 45% of desired pro- Grant Scheme Project (No. 206060) from the National
duct (E)-2c along with 12% of regioisomer 14 and 7% of
15 [22]. Next, we turned our attention toward Ni(dme)
Cl2, a complex readily prepared in a single step from
NiCl2 and 1,2-dimethoxyethane [23]. This complex is air
stable and can be stored in a desiccator without decompo-
sition. Application of this catalyst (0.2 mol.-equiv.) led to
alkene (E)-2c in 61% yield. To evaluate the effectiveness
of Ni(dme)Cl2 in broader scope of substrates, the reaction
of Me2Zn and Et2Zn reagents with alkynes 10a and 10b
were examined (Table 2, Scheme 5).
Centre for Research and Development (NCBiR).
Experimental Part
General
All commercially available compounds were purchased
and used as received. THF, toluene, CH2Cl2, and Et2O
were purchased from Sigma–Aldrich and used as
received. Thin-layer chromatography was performed
using Merck TLC SiO2 60 F254 aluminum sheets. Flash
chromatography separations were performed on Merck
SiO2 60M (230 – 400 mesh). 1H- (300 or 200 MHz) and
13C-NMR (75 or 50 MHz) spectra were recorded with a
Bruker AVANCE spectrometer (300 MHz) or Varian
UNITYplus (200 MHz). The NMR analyses were per-
formed in CDCl3 at 298 K. H-atom chemical shifts are
reported relative to residual solvent peak of CDCl3 at
d = 7.26. C-atom chemical shifts are reported relative to
CDCl3 at d = 77.0. High-resolution mass spectra (HR-
MS) were measured with a Quattro LC Micromass unit
using ESI technique.
The comparison of Tables 1, 2 revealed similar pro-
duct distribution. However, the yield of major products
11 is slightly lower for the Ni(dme)Cl2 complex as com-
pared to Ni(cod)2, with one noticeable example for the
preparation of 11ba (36% conversion).
Conclusions
In summary, we tested several methods suitable for the
synthesis of tetrasubstituted alkenes. Reductive elimina-
tion of amide or ester derivatives of a,b-epoxycarboxylic
acid or 2-chloro-3-hydroxy carboxylic acids using SmI2,
as well as ketone olefination by ynolates proved to be
ineffective methods in terms of yield and selectivity. In
contrast, the application of Ni-catalyzed carboxylation of
Typical Procedure for Reductive Elimination of a,b-
Epoxy-2-chloro-3-hydroxy-amides or Esters. A soln. of
SmI2 (0.1M in THF, 7.57 ml, 0.757 mmol) was slowly
added to a soln. of either 3a, or 3b, or 5a, or 5b
2) For 12aa, see [20a][20b][20c]; for 12ba, see [20d][20e]; for
12ab and 12bb, see [20f].
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(0.189 mmol, 1 equiv.) in THF (2 ml) under Ar. The mixture was stirred at ꢀ78 °C for 90 min, after which it
mixture was then stirred at 20 °C for 30 min – 1.5 h was allowed to warm to 0 °C. After 30 min, the mixture
(depending on the substrate used). Then, the mixture was
quenched with 0.1M aq. HCl (9.5 ml) followed by addition
of AcOEt (10 ml) and finally addition of sat. aq. soln. of
was allowed to warm to r.t. and a soln. of 1-(3-methoxy-
phenyl)propan-1-one (181 mg, 1 mmol) in THF (2 ml)
was added dropwise. The mixture was stirred overnight
potassium sodium tartrate and NaHCO3 (10 ml, 1:1 under Ar. Then, sat. aq. NH4Cl was added (5 ml), and
mixture). The resulting mixture was extracted with
AcOEt (2 9 20 ml). The combined org. layers were dried
(MgSO4) and concentrated. The residue was purified by
column chromatography (SiO2, hexane/AcOEt 10:1) to
afford compound (E)-2a or (E)-2b as colorless viscous oil.
(2E)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-2-enamide
((E)-2a). Obtained in 3% yield according to the general
1
above procedure. H-NMR: 0.86 (t, J = 7.5, 3 H); 1.70 (s, chromatography (SiO2, CH2Cl2) to give (E)-2c as yellow
3 H); 2.29 (q, J = 7.5, 2 H); 3.05 (d, J = 12, 6 H); 3.80 (s, oil (103 mg, 47%). 1H-NMR: 0.89 (t, J = 7.5, 3 H); 1.68
the mixture was acidified with 10% HCl soln. (5 ml) and
was extracted with CH2Cl2 (2 9 20 ml). The org. phase
was then extracted with 5% NaOH soln. (2 9 30 ml).
The alkaline aq. phase was then acidified with HCl and
the product was extracted with CH2Cl2 (2 9 50 ml). The
org. phase was washed with brine, dried (MgSO4) and
concentrated. The residue was then purified by column
3
H); 6.68 – 6.72 (m, 2 H); 6.75 – 6.82 (m, 1 H); (s, 3 H); 2.67 (q, J = 7.5, 2 H); 3.75 (s, 3 H); 6.58 – 6.64
7.23 – 7.27 (m, 1 H). 13C-NMR: 12.4 (q); 16.9 (q); 28.5 (t); (m, 2 H); 6.75 – 6.78 (m, 1 H); 7.28 – 7.33 (m, 1 H). 13C-
34.1 (q); 37.6 (q); 55.2 (q); 112.1 (d); 114.2 (d); 120.9 (d); NMR: 12.8 (q); 17.5 (q); 29.7 (t); 55.2 (q); 112.4 (d); 113.3
127.8 (s); 129.2 (d); 139.8 (s); 141.4 (s); 159.4 (s); 172.9 (d); 120.0 (d); 123.3 (s); 129.4 (d); 143.4 (s); 155.2 (s);
(s). HR-ESI-MS: 270.1470 ([M + Na]+, C15H21NNaOþ2 ; 159.5 (s); 175.0 (s). LR-ESI-MS: 219.08 ([M ꢀ H]ꢀ).
calc. 270.1461).
3-Ethyl-3-(3-methoxyphenyl)-N,N,2-trimethyloxirane-2-
carboxamide (3a). A soln. of LDA (1M in THF, 1.1 ml,
((Z)-2a). Obtained in 45% yield according to the general 2.2 mmol) was slowly added to a soln. of 2-chloro-N,N-
(2Z)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-2-enamide
1
above procedure. H-NMR: 0.93 (t, J = 7.5, 3 H); 2.01 (s, dimethylpropanamide (0.13 ml, 1 mmol) in THF (1 ml) at
3 H); 2.40 (br. s, 1 H); 2.55 (br. s, 1 H); 2.60 (s, 3 H); 2.63 ꢀ78 °C under Ar. After 10 min, a soln. of ketone 7
(s, 3 H); 3.79 (s. 3 H); 6.73 – 6.81 (m, 3 H); 7.20 (ddd, (144 mg, 0.875 mmol) in THF (1 ml) was slowly added.
J = 8.1, 7.3, 0.8, 1 H). 13C-NMR: 12.4 (q); 16.1 (q); 26.1 The mixture was then stirred for 1 h at ꢀ78 °C. Then, the
(t); 34.1 (q); 37.7 (q); 55.2 (q); 112.9 (d); 113.2 (d); 120.2 mixture was warmed, and the reaction was quenched with
(d); 127.3 (s); 128.8 (d); 140.5 (s); 142.5 (s); 159.1 (s); a sat. aq. soln. of NH4Claq (5 ml). The mixture was
173.6
C15H21NNaOþ2 ; calc. 270.1461).
Ethyl
((E)-2b). Obtained in 25% yield according to the general (SiO2, hexane/AcOEt 95:5) to afford compound 3a (color-
(s).
HR-ESI-MS:
270.1470
([M + Na]+, extracted with CH2Cl2 (2 9 10 ml). The combined org.
layers were dried (MgSO4) and concentrated in vacuo.
(2E)-3-(3-Methoxyphenyl)-2-methylpent-2-enoate The residue was purified by column chromatography
1
1
above procedure. H-NMR: 0.98 (t, J = 7.5, 3 H); 1.36 (t, less viscous oil, 144 mg, 63%). H-NMR: 0.77 (t, J = 7.2,
J = 7.2, 3 H); 1.74 (s, 3 H); 2.59 – 2.64 (m, 2 H); 3.83 (s, 3 3 H); 1.11 (s, 3 H); 1.27 – 1.31 (m, 1 H); 2.08 – 2.12 (m, 1
H); 4.28 (q, J = 7.2, H); 6.66 – 6.72 (m, H); H); 2.91 (s, 3 H); 3.12 (br. s, 3 H); 3.74 (s, 3 H); 6.81 (m,
2
2
6.80 – 6.83 (m, 1 H); 7.24 – 7.28 (m, 1 H). 13C-NMR: 12.8 3 H); 7.18 – 7.22 (m, 1 H). 13C-NMR: 9.0 (q); 17.5 (q);
(q); 14.3 (q); 17.4 (q); 29.4 (t); 55.2 (q); 60.4 (t); 112.3 (d); 29.2 (t); 35.2 (q); 36.8 (q); 55.3 (q); 67.2 (s); 70.5 (s); 112.4
113.6 (d); 120.3 (d); 124.9 (s); 129.3 (d); 143.1 (s); 150.3 (d); 113.1 (d); 119.4 (d); 129.2 (d); 138.9 (s); 159.5 (s);
(s); 159.7 (s); 170.0 (s). HR-ESI-MS: 271.1310 170.1
([M + Na]+, C15H20NaO3þ; calc. 271.1310). C15H21NNaOþ3 ; calc. 286.1419).
Ethyl (2Z)-3-(3-Methoxyphenyl)-2-methylpent-2-enoate Ethyl 3-Ethyl-3-(3-methoxyphenyl)-2-methyloxirane-2-car-
(s).
HR-ESI-MS:
286.1418
([M + Na]+,
((Z)-2b). Obtained in 11% yield according to the general boxylate (3b). A soln. of potassium bis(trimethylsilyl)
1
above procedure. H-NMR: 0.86 (t, J = 7.2, 3 H); 0.96 (t, amide (HMDSK; 0.38 g, 1.91 mmol) in toluene (4 ml)
J = 7.5, 3 H); 2.05 (s, 3 H); 2.48 (q, J = 7.2, 2 H); 3.81 (s, was slowly added to a soln. of ethyl 2-chloropropanoate
3 H); 3.86 (q, J = 7.2, 2 H); 6.70 – 6.72 (m, 2 H); (0.2 g, 1.47 mmol) in THF (2.5 ml) at ꢀ78 °C under Ar.
6.78 – 6.81 (m, 1 H); 7.22 – 7.25 (m, 1 H). 13C-NMR: 11.9 After 10 min, a soln. of ketone 7 (0.24 g, 1.47 mmol) in
(q); 13.5 (q); 15.6 (q); 28.0 (t); 55.2 (q); 60.1 (t); 111.8 (d); THF (2.5 ml) was slowly added. Then, the mixture was
113.0 (d); 120.1 (d); 125.7 (s); 128.9 (d); 144.2 (s); 148.3 warmed, and the reaction was quenched with a sat. aq.
(s); 159.2 (s); 170.8 (s). HR-ESI-MS: 271.1302 soln. of NH4Cl (12 ml). The mixture was extracted with
([M + Na]+, C15H20NaOþ3 ; calc. 271.1310).
CH2Cl2 (2 9 20 ml). The combined org. layers were dried
Synthesis of (E)-2c via Ketone Olefination by Ynolates. (MgSO4) and concentrated in vacuo. The residue was
A soln. of ethyl 2-bromopropanoate (6; 164 mg, 1 mmol) purified by column chromatography (SiO2, hexane/AcOEt
in THF (2 ml) was added dropwise to a soln. of lithium
diisopropylamide (1M in THF/hexane, 1.05 ml,
14:1) to afford compound 3b (colorless viscous oil,
1
250 mg, 65%). H-NMR: 0.88 (t, J = 7.5, 3 H); 1.21 (s, 3
t
1.05 mmol) at ꢀ78 °C. After 20 min, a BuLi soln. (1.7M
H); 1.35 (t, J = 7.2, 3 H); 1.60 – 1.64 (m, 1 H); 2.05 – 2.09
(m, 1 H); 3.82 (s, 3 H); 4.30 (q, J = 7.2, 2 H); 6.85 – 6.89
in pentane, 1.88 ml, 3.2 mmol) was added dropwise. The
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1
(m, 3 H); 7.23 – 7.27 (m, 1 H). 13C-NMR: 9.2 (q); 14.3 5b (colorless viscous oil, 37 mg, 25%). H-NMR: 0.79 (td,
(q); 16.8 (q); 26.9 (t); 55.2 (q); 61.4 (t); 65.6 (s); 70.3 (s); J = 7.3, 0.8, 3 H); 0.91 – 0.96 (m, 1 H); 1.20 – 1.24 (m, 3
112.7 (d); 113.0 (d); 119.3 (d); 129.3 (d); 138.5 (s); 159.5 H); 1.60 – 1.64 (m, 1 H); 3.83 (s, 3 H); 4.16 – 4.20 (m, 2
(s); 170.7 (s). HR-ESI-MS: 287.1260 ([M + Na]+, H); 6.89 – 6.93 (m, 2 H); 7.25 – 7.29 (m, 2 H). 13C-NMR:
C15H20NaOþ4 ; calc. 287.1259).
7.8 (q); 13.8 (q); 24.8 (q); 28.9 (t); 55.3 (q); 62.6 (t); 80.4
(s); 87.1 (s); 112.4 (d); 112.6 (d); 120.1 (d); 128.3 (d);
140.6 (s); 159.6 (s); 170.7 (s). LR-ESI-MS 323.1
(3E)-2-Hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpent-
3-enamide ((E)-4). Isolated in 85% yield during the CC/
SiO2 purification of (E)-2a (hexane/AcOEt 6:4) H-NMR: ([M + Na]+).
1
1.59 (d, J = 6.6, 3 H); 1.60 (s, 3 H); 2.92 (br. s, 3 H); 3.15
1-Methoxy-3-(prop-1-yn-1-yl)benzene (8). To a suspen-
(br. s, 3 H); 3.81 (s, 3 H); 5.97 (q, J = 6.6, 1 H); sion of CuI (360 mg, 1.88 mmol) and (Ph3P)4Pd (360 mg,
6.78 – 6.82 (m, 3 H); 7.21 (ddd, J = 8.2, 7.5, 0.6, 1 H). 0.31 mmol) in dry toluene (10 ml) was added 1-iodo-3-
13C-NMR: 14.9 (q); 23.9 (q); 37.4 (q); 38.5 (q); 55.2 (q); methoxybenzene (0.76 ml, 6.3 mmol), trimethyl(prop-1-
75.8 (s); 112.5 (d); 115.0 (d); 121.6 (d); 123.8 (d); 128.8 ynyl)silane (0.94 ml, 6.3 mmol), Et3N (3 ml, 21 mmol),
(d); 138.8 (s); 142.8 (s); 159.1 (s); 174.6 (s). LR-ESI-MS.
286.1 ([M + Na]+, 549.5 ([2M + Na]+).
2-Chloro-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethyl-
pentanamide (5a). A soln. of LDA (1M in THF, 1.1 ml,
and Bu4NF (1M in THF, 6.3 ml, 6.3 mmol). The mixture
was stirred under Ar overnight at 20 °C. Then, H2O was
added (5 ml), and the resulting mixture was extracted with
Et2O (2 9 10 ml). The org. phase was dried (MgSO4) and
2.2 mmol) was slowly added to a soln. of 2-chloro-N,N- concentrated. The residue was purified by column chro-
dimethylpropanamide (0.13 ml, 1 mmol) in THF (0.5 ml)
at ꢀ85 °C under Ar. After 10 min, a soln. of ketone 7
(82 mg, 0.5 mmol) in THF (0.5 ml) was slowly added.
matography (SiO2, hexane/AcOEt 10:1) to give 8 (717 mg,
78%). 1H-NMR: 7.17 – 7.19 (m, 1 H); 6.94 – 6.98 (m, 2 H);
6.81 – 6.85 (m, 1 H); 3.77 (s, 3 H); 2.04 (s, 3 H). 13C-NMR:
The mixture was then stirred for 1 h at ꢀ78 °C. Then, the 4.5 (q); 55.4 (q); 79.9 (s); 85.9 (s); 114.3 (d); 116.6 (d); 124.2
reaction was quenched with a sat. aq. soln. of NH4Cl (d); 125.2 (s); 129.5 (d); 159.5 (s). During the LR-ESI-MS
(0.54 ml), and the mixture was warmed and extracted analysis, 8 was not ionizable.
with CH2Cl2 (2 9 5 ml). The combined org. layers were
dried (Na2SO4) and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/ pension of Ni(cod)2 (19 mg, 0.07 mmol) in dry, degassed
Typical Procedure for Nickel-Catalyzed Carboxylation
of 8. DBU (0.51 ml, 3.4 mmol) was added to a stirred sus-
AcOEt 10:0.5) to afford compound 5a (colorless viscous THF (2 ml) under Ar at 0 °C. A balloon filled with CO2
oil, 30 mg, 20%) as a mixture of two diastereoisomers A
and (relative configuration was not determined).
was connected to the reaction vessel. After 15 min, a soln.
of 1-methoxy-3-(prop-1-ynyl)benzene (50 mg, 0.34
B
8
1
Diastereoisomer A: H-NMR: 0.75 (t, J = 7.2, 3 H); 1.65 mmol) in dry, degassed THF (2 ml) was added dropwise
(s, 3 H); 2.26 – 2.30 (m, 1 H); 2.54 – 2.58 (m, 1 H); 3.09 to the resulting pale green mixture. After that, a soln. of
(br. s, 3 H); 3.27 (br. s, 3 H); 3.85 (s, 3 H); 5.97 (s, 1 H);
6.84 – 6.88 (m, 1 H); 7.27 – 7.31 (m, 3 H). 13C-NMR: 8.2
Et2Zn (1M in hexane, 1.02 ml, 1.02 mmol) was added
dropwise. The mixture was allowed to warm to r.t. and
(q); 23.9 (q); 28.2 (t); 39.6 (q); 40.2 (q); 55.2 (q); 72.4 (s); stirred overnight, after which it was acidified at 0 °C with
82.9 (s); 112.1 (d); 115.5 (d); 121.5 (d); 127.9 (d); 141.2 10% HCl. The mixture was then extracted with AcOEt
1
(s); 158.8 (s); 173.0 (s). Diastereoisomer B: H-NMR: 0.78 (2 9 10 ml), washed with brine (10 ml), dried (Na2SO4)
(t, J = 7.2, 3 H); 1.98 (s, 3 H); 2.04 – 2.08 (m, 1 H); and concentrated. The residue was further purified by
2.35 – 2.39 (m, 1 H); 2.82 (s, 6 H); 3.83 (s, 3 H); 5.38 (s, 1
distillation giving (E)-2c (89% isolated yield) or
H); 6.78 – 6.83 (m, 1 H); 7.11 – 7.14 (m, 2 H); 7.21 – 7.27 11aa – 11cc.
(m, 1 H). 13C-NMR: 7.9 (q); 27.2 (q); 27.3 (t); 39.6 (q);
(2E)-2-Methyl-3-phenylbut-2-enoic Acid (11aa). Obtained
55.2 (q); 75.4 (s); 81.3 (s); 112.4 (d); 114.6 (d); 120.9 (d); in 54% yield (38 mg). 1H-NMR: 1.83 (d, J = 1.5, 3 H);
128.1 (d); 142.8 (s); 158.9 (s); 172.1 (s). HR-ESI-MS: 2.13 (d, J = 1.8, 3 H); 2.05 (s, 3 H); 7.16 – 7.21 (m, 2 H);
322.1172 ([M + Na]+, C15H22ClNNaOþ3 ; calc. 322.1186).
Ethyl 2-Chloro-3-hydroxy-3-(3-methoxyphenyl)-2-methyl-
pentanoate (5b). A soln. of potassium bis(trimethylsilyl)
amide (HMDSK; 0.22 g, 1.1 mmol) in toluene (0.5 ml)
was slowly added to a soln. of ethyl 2-chloropropanoate
7.29 – 7.31 (m, 1 H); 7.38 – 7.41 (m, 2 H); 11.8 (br. s, 1
H). 13C-NMR: 17.4 (q); 23.7 (q); 123.8 (s); 126.9 (d); 127.2
(d); 128.4 (d); 143.8 (s); 150.3 (s); 175.3 (s). LR-ESI-MS:
175.2 ([M ꢀ H]ꢀ).
(2E)-2-Ethyl-3-phenylbut-2-enoic Acid (11ba). Obtained
(0.14 g, 1.1 mmol) in THF (0.5 ml) at ꢀ85 °C under Ar. in 59% yield (45 mg). 1H-NMR: 1.00 (t, J = 7.5, 3 H);
After 10 min, a soln. of ketone 7 (82 mg, 0.5 mmol) in 2.22 (q, J = 7.5, 2 H); 2.35 (s, 3 H); 7.16 – 7.19 (m, 2 H);
THF (0.5 ml) was slowly added. The mixture was stirred
for 1 h at ꢀ78 °C. Then, the reaction was quenched with
a sat. aq. soln. of NH4Cl (0.54 ml), and the mixture was
warmed and extracted with CH2Cl2 (2 9 5 ml). The com-
bined org. layers were dried (Na2SO4) and concentrated
in vacuo. The residue was purified by column chromatog-
raphy (SiO2, hexane/AcOEt 10:0.5) to afford compound
7.29 – 7.33 (m, 1 H); 7.37 – 7.41 (m, 2 H); 11.7 (br. s, 1
H). 13C-NMR: 13.9 (q); 23.9 (q); 24.3 (t); 126.9 (d); 127.1
(d); 128.4 (d); 130.6 (s); 143.5 (s); 148.4 (s); 175.1 (s). LR-
ESI-MS: 189.3 ([M ꢀ H]ꢀ).
(2E)-2-(1-Phenylethylidene)hexanoic Acid (11ca). Obtained
in 59% yield (52 mg). 1H-NMR: 0.80 (t, J = 7.2, 3 H);
1.19 – 1.22 (m, 2 H); 1.37 – 1.40 (m, 2 H); 2.19 (t, J = 7.5,
€
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www.helv.wiley.com

672
Helv. Chim. Acta 2016, 99, 665 – 673
Cancer 1999, 35, 1628; N. F. McKinley, D. F. O’Shea, J. Org.
Chem. 2006, 71, 9552; K. Shimizu, M. Takimoto, M. Mori, Y.
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2 H); 2.35 (s, 3 H); 7.15 – 7.17 (m, 2 H); 7.27 – 7.30 (m, 1
H); 7.36 – 7.40 (m, 2 H); 11.7 (br. s, 1 H). 13C-NMR: 13.8
(q); 22.5 (t); 23.9 (q); 30.7 (t); 31.5 (t); 126.8 (d); 127.1 (d);
128.4 (d); 129.6 (s); 143.5 (s); 148.2 (s); 175.6 (s). LR-ESI-
MS: 217.3 ([M ꢀ H]ꢀ).
[2] F. Caturla, M. Amat, R. F. Reinoso, M. Cordoba, G. Warrel-
low, Bioorg. Med. Chem. Lett. 2006, 16, 3209; M. Wadman, Nat-
ure 2006, 440, 277; P. Prasit, Z. Wang, C. Brideau, C. C. Chan,
S. Charleson, W. Cromlish, D. Ethier, J. F. Evans, A. W. Ford-
Hutchinson, J. Y. Gauthier, R. Gordon, J. Guay, M. Gresser, S.
(2E)-2-Methyl-3-phenylpent-2-enoic Acid (11ab). Obtained in
1
57% yield (44 mg). H-NMR: 1.01 (t, J = 7.5, 3 H); 1.78 (s,
ꢀ
Kargman, B. Kennedy, Y. Leblanc, S. Leger, J. Mancini, G. P.
3 H); 2.80 (q, J = 7.5, 2 H); 7.28 – 7.32 (m, 2 H);
7.36 – 7.41 (m, 3 H); 11.7 (br. s, 1 H). 13C-NMR: 12.8 (q);
17.5 (q); 29.7 (t); 123.4 (s); 127.2 (d); 127.6 (d); 128.3 (d);
141.9 (s); 155.5 (s); 175.6 (s). LR-ESI-MS: 189.2
([M ꢀ H]ꢀ).
O’Neill, M. Ouellet, M. D. Percival, H. Perrier, D. Riendeau, I.
ꢀ
Rodger, P. Tagari, M. Therien, P. Vickers, E. Wong, L.-J. Xu,
R. N. Young, R. Zamboni, S. Boyce, N. Rupniak, Bioorg. Med.
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Am. Chem. Soc. 1989, 111, 643.
(2E)-2-Ethyl-3-phenylpent-2-enoic Acid (11bb). Obtained in
1
[4] J. Taipale, J. K. Chen, M. K. Cooper, B. Wang, R. K. Mann, L.
Milenkovic, M. P. Scott, P. A. Beachy, Nature 2000, 406, 1005.
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51% yield (41 mg). H-NMR: 1.01 (t, J = 7.5, 3 H); 1.02
(t, J = 7.5, 3 H); 2.16 (q, J = 7.5, 2 H); 2.71 (q, J = 7.5, 2
H); 7.13 – 7.17 (m, 2 H); 7.28 – 7.40 (m, 3 H); 11.6 (br. s,
1 H). 13C-NMR: 12.7 (q); 13.9 (q); 24.5 (t); 29.9 (t); 127.4
(d); 128.2 (d); 130.3 (d); 133.9 (s); 141.6 (s); 153.3 (s);
175.6 (s). LR-ESI-MS: 203.2 ([M ꢀ H]ꢀ).
[6] T. Takeda, in ‘Modern Carbonyl Olefination’, Wiley-VCH,
Weinheim, Germany, 2004.
[7] R. Rossi, F. Bellina, A. Carpita, F. Mazzarella, Tetrahedron
1996, 52, 4095; A. G. Myers, M. M. Alauddin, M. A. M. Fuhry,
P. S. Dragovich, N. S. Finney, P. M. Harrington, Tetrahedron
Lett. 1989, 30, 6997; H. Nakatsuji, Y. Ashida, H. Hori, Y. Sato,
A. Honda, M. Taira, Y. Tanabe, Org. Biomol. Chem. 2015, 13,
8205; M. Shimizu, C. Nakamaki, K. Shimono, M. Schelper, T.
Kurahashi, T. Hiyama, J. Am. Chem. Soc. 2005, 127, 12506; T.
Hata, H. Kitagawa, H. Masai, T. Kurahashi, M. Shimizu, T.
Hiyama, Angew. Chem., Int. Ed. 2001, 40, 790.
(2E)-2-(1-Phenylpropylidene)hexanoic Acid (11cb). Obtained
in 50% yield (46 mg). 1H-NMR: 0.80 (t, J = 7.3, 3 H);
1.01 (t, J = 7.2, 3 H); 1.20 (q, J = 7.2, 2 H); 1.34 – 1.44
(m, 2 H); 2.14 (t, J = 7.8, 2 H); 2.71 (q, J = 7.5, 2 H);
7.11 – 7.15 (m, 2 H); 7.28 – 7.44 (m, 3 H); 11.7 (br. s, 1
H). 13C-NMR: 12.8 (q); 13.8 (q); 22.5 (t); 29.9 (t); 30.8 (t);
31.4 (t); 127.6 (d); 128.2 (d); 129.3 (d); 132.9 (s); 141.6 (s);
153.1 (s); 175.8 (s). LR-ESI-MS: 231.3 ([M ꢀ H]ꢀ).
(2E)-2,4-Dimethyl-3-phenylpent-2-enoic Acid (11ac). Obtained
in 19% yield (16 mg). 1H-NMR: 0.98 (d, J = 6.9, 6 H); 1.63
(s, 3 H); 3.64 – 3.66 (m, 1 H); 7.01 – 7.04 (m, 2 H);
7.33 – 7.42 (m, 3 H); 12.0 (br. s, 1 H). 13C-NMR: 13.7 (q);
17.5 (q); 21.4 (q); 31.6 (d); 126.8 (s); 127.9 (d); 128.5 (d);
129.8 (d); 135.6 (s); 141.2 (d); 156.6 (s); 174.4 (s). LR-ESI-
MS: 203.2 ([M ꢀ H]ꢀ).
[8] M. B. Smith, J. March, in ‘March’s Advanced Organic Chem-
istry’, 5th edn., John Wiley & Sons, Inc., New York, 2001.
[9] J. F. Normant, A. Alexakis, Synthesis 1981, 841; M. P. Doyle, in
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Abel, F. G. A. Stone, G. Wilkinson, L. Hegedus, Pergamon
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[10] S. Chandrasekhar, J. Yu, J. R. Falck, C. Mioskowski, Tetrahe-
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[12] J. A. Wiles, S. H. Bergens, K. P. M. Vanhesche, D. A. Dobbs,
V. Rautenstrauch, Angew. Chem., Int. Ed. 2001, 40, 914; M.
Christensen, A. Nolting, M. Shevlin, M. Weisel, P. E. Maligres,
J. Lee, R. K. Orr, C. W. Plummer, M. T. Tudge, L.-C. Cam-
peau, R. T. Ruck, J. Org. Chem. 2016, 81, 824.
(2E)-2-Ethyl-4-methyl-3-phenylpent-2-enoic Acid (11bc).
1
Obtained in 15% yield (13 mg). H-NMR: 0.93 (t, J = 7.4,
3 H); 0.98 (d, J = 6.9, 6 H); 2.01 (q, J = 7.5, 2 H);
3.46 – 3.49 (m, 1 H); 7.04 – 7.07 (m, 2 H); 7.32 – 7.39 (m,
3 H); 11.5 (br. s, 1 H). 13C-NMR: 13.6 (q); 13.8 (q); 20.6
(t); 21.4 (q); 32.0 (d); 128.6 (d); 130.6 (d); 133.9 (s); 135.5
(s); 140.9 (d); 153.9 (s); 174.2 (s). LR-ESI-MS: 217.3
([M ꢀ H]ꢀ).
[13] E. Marom, M. Mizhiritskii, MAPI Pharma, WO 2011/80736; M.
Vajda, Acta Chim. Acad. Sci. Hung. 1964, 40, 295.
ꢀ
ꢀ
ꢀ
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68, 9492.
(2E)-2-(2-Methyl-1-phenylpropylidene)hexanoic Acid (11c
c). Obtained in 12% yield (12 mg). 1H-NMR: 0.73 (t,
J = 7.2, 3 H); 0.97 (d, J = 9, 6 H); 1.22 – 1.25 (m, 2 H);
1.31 – 1.34 (m, 2 H); 1.96 – 199 (m, 2 H); 3.42 – 3.46 (m,
1 H); 7.03 – 7.05 (m, 2 H); 7.35 – 7.44 (m, 3 H); 12.1 (br.
s, 1 H). 13C-NMR: 13.8 (q); 13.9 (q); 21.4 (q); 22.8 (t);
27.1 (t); 31.0 (t); 31.4 (d); 128.5 (d); 129.4 (d); 132.8 (s);
135.6 (s); 140.9 (d); 154.5 (s); 174.2 (s). LR-ESI-MS: 245.3
([M ꢀ H]ꢀ).
[15] M. Shindo, K. Matsumoto, Top. Curr. Chem. 2012, 327, 1.
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