Development of a palladium catalyzed addition of boronic acids to alkynyl esters: synthesis of trisubstituted olefins as single isomers

Article abstract of DOI:10.1016/j.tet.2009.08.029

Very small phosphine ligands allow access to single isomer trisubstituted olefins from alkynyl esters with complete control of both stereochemistry and regiochemistry. This method provides a convenient synthesis of single isomer trisubstituted olefins wit

Full text of DOI:10.1016/j.tet.2009.08.029

Tetrahedron 65 (2009) 8502–8506
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of a palladium catalyzed addition of boronic acids to alkynyl
esters: synthesis of trisubstituted olefins as single isomers
*
Alexander Graham Bush, Jojo Liu Jiang, Philippa R. Payne, William W. Ogilvie
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON, K1N6N5, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2009
Received in revised form 10 August 2009
Accepted 11 August 2009
Available online 15 August 2009
Very small phosphine ligands allow access to single isomer trisubstituted olefins from alkynyl esters with
complete control of both stereochemistry and regiochemistry. This method provides a convenient syn-
thesis of single isomer trisubstituted olefins without requiring olefin templates.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
PhB(OH)2,
Pd(PPh3)4
AcOH
CO2Et
H
CO2Et
n-Bu
CO2Et
n-Bu
The synthesis of trisubstituted olefins in a stereocontrolled
manner is a challenging endeavor in organic chemistry. Direct
syntheses such as the Wittig,1 Horner–Wadsworth–Emmons,2 or
olefin metathesis reactions3 typically produce mixtures of isomers
that can be difficult to separate. To address this issue of stereo-
selectivity, indirect approaches have been explored.4,5 Metal-
catalyzed addition reactions of organometallic reagents to alkynes
provides a direct entry to trisubstituted olefins, provided that regio-
and stereochemistry can be tightly controlled.6
n-Bu
dioxane
80 °C
H
1
2
3
Scheme 1. Coupling of arylboronic acids and alkynyl esters.
acids.11 As part of this work, a mechanistic study was done that
involved submitting an alkynyl ester to the template cross-coupling
reaction conditions. This experiment produced trisubstituted ole-
fins such as 5 and regioisomeric products such as 612 in low yield
(10%). Although inefficient, the high stereoselectivity encouraged us
to develop this process to produce single isomer trisubstituted
olefins.
Recent work has shown that alkynes,7 alkenes,8 or organoboronic
acids9,10 can be added to alkynes using catalysts to generate
trisubstituted olefinproducts. The addition of avariety of arylboronic
acids to alkynyl esters was enabled by the use of copper acetate in
methanol, givingregioisomerssuch as2 excluseively.10 Whenalkynyl
esters were used as coupling partners in the presence of a palladium
catalyst and under mildly acidic conditions, the corresponding tri-
2. Results and discussion
substituted a,b-unsaturated esters were obtained inverygood yields,
but as mixtures of regioisomers 2 and 39a,b (Scheme 1). Further
research improved the regioselectivity using a pincer-type aryl
phosphine ligand,9c however small amounts of regioisomeric
products such as 3 were always present. In this paper we present
acatalystsystemthatproducessingleisomertrisubstitutedolefinsby
enabling the addition of boronic acids to alkynyl esters in very mild
conditions. The process utilizes neutral conditions and small phos-
phine ligands, and appears to function through a palladium-hydride
system.
Using our previous mechanistic observation as a starting point,
a 3:1 mixture of the desired product 5 and the regioisomer 6 was
isolated in a 10% combined yield (Table 1, entry 1). Adding water to
the reaction mixture13 increased the yield to 50%, however, no
improvement in regioselectivity was noted (entry 2). Employing
Pd(OAc)2 as a palladium source resulted in an increase in both yield
(89%) and regioselectivity in favor of 5 over 6 (entry 3). The use of
bulky ligands such as Cy3P gave high regioselectivity (19:1) to-
gether with good overall yields (entry 4). When PPh3 was used as
the ligand, the efficiency of the process suffered (entry 5). A re-
action performed with S-Phos (entry 6) gave very good regiose-
lectivity (97:3) but the overall yield was moderate. The use of
smaller alkyl-substituted ligands produced success. As shown in
entry 7, t-Bu2MeP worked quite well as a ligand, giving high yield
(95%) and excellent regioselectivity. By decreasing the size of the
ligand slightly to Et3P, we were able to suppress the formation of 6,
Previous work in our laboratory had shown that single isomer
trisubstituted olefins could be synthesized from (E)-
b-chloro-a-
iodo- -unsaturated esters by cross-coupling with organoboronic
a,b
* Corresponding author. Tel.: þ1 613 562 5800; fax: þ1 613 562 5170.
E-mail address: wogilvie@uottawa.ca (W.W. Ogilvie).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.029

A.G. Bush et al. / Tetrahedron 65 (2009) 8502–8506
8503
isolating only product 5 in 85% yield (entry 8).14 The smaller ligand,
Me3P (entry 9) gave exclusive regioselectivity, however, the yield
decreased to 59%.
component had minimal impact on the reactivity, regardless of
whether the substituent was in the ortho-, meta-, or para-positions
(entries 2–7). Electron-withdrawing groups were compatible with
the process, giving the trisubstituted products in moderate yields
(entries 8 and 9). Coupling with sp2 hybridized partners such as
vinyl or styrenyl boronic acids gave moderate to good yields as
shown in entries 10 and 11. No loss of olefin stereochemical in-
formation in the coupling partner was noted and these products
were isolated as single isomers. The steric bulk of the boronic acid
did not affect the yield of the process, as shown in entries 12 and 13
in which the use of either 1- or 2-naphthylboronic acids afforded
the respective addition products in good yields. Heterocyclic bo-
ronic acids were also tolerated, as shown by the results of entry 14
employing a 3-thiophenylboronic acid.
Table 1
Optimization of the formation of trisubstituted olefins from alkynyl esters and
boronic acids
CO2Et
H
4-MeC6H4B(OH)2
Pd(OAc)2
ligand, Cs2CO3
CO2Et
CO2Et
toluene, 23 °C
H
4
5
6
Entrya
Ligand
Yield (%)
Ratio (5:6)
1b,c
2b
3
4
5
6
7
8
9
t-Bu3P$HBF4
t-Bu3P$HBF4
t-Bu3P$HBF4
Cy3P$HBF4
Ph3P
10
50
89
86
53
69
95
85
59
75:25
75:25
85:15
95:5
93:7
97:3
96:4
Only 5
Only 5
The presence of branched substituents on the alkynyl starting
material resulted in an efficient coupling as shown in entry 15 in
which a cyclohexyl substituent was used. It was possible to sub-
stitute the alkyne component with a phenyl group, a modification
that produced the desired trisubstituted olefin as a single isomer
(entry 16). In both of these cases the newly introduced hydrogen
and aryl ring were syn to each other, indicating that product ste-
reochemistry was a consequence of mechanism and not of ther-
modynamics. The presence of substituted alkyl chains was
compatible with the reaction conditions as shown in entries 18 and
19, although using methyl propyolate as a substrate did not provide
useful amounts of product (entry 17). Finally, the reaction pro-
ceeded with complete selectivity when the carboxylate moiety on
the alkyne was replaced with a Weinreb amide (entries 20 and 21).
In all cases, the products were isolated as single isomers.16
In order to identify the hydrogen source, a series of isotope la-
beling experiments were done. Only product 7 was obtained when
4 was coupled with PhB(OH)2 in C6D6 indicating that the solvent
was not the hydrogen source (Table 3, entry 2). Performing a re-
action between alkyne 4 and phenylboronic acid in the presence of
D2O gave the alkene products 7 and 34 with 70% deuterium in-
corporation (entry 3). Using an excess of D2O did not significantly
increase the proportion of the deuterated product 34, as shown in
entry 4. Performing a reaction with a deuterated boronic acid (40%
D) resulted in almost no deuterium incorporation (entry 5). These
results suggested that H2O or boronic acid was the hydrogen
source. A significant deuterium isotope effect was operative. Evi-
dence supporting this is shown in entry 6, in which a reaction was
S-Phos
t-Bu2MeP$HBF4
Et3P$HBF4
Me3P$HBF4
a
0.06 equiv of Pd(OAc)2, 0.18 equiv of ligand, 2.0 equiv of 4-MeC6H4B(OH)2,
2.1 equiv of Cs2CO3, 10 equiv of H2O, toluene, 23 ꢀC, 18 h.
b
Pd2(dba)3 was used in place of Pd(OAc)2.
No H2O was added.
c
Variations in the ligand to palladium ratio were explored and it
was found that a 3:1 ratio of ligand to metal was optimal. Using
a 2:1 or 4:1 ratio of ligand to metal resulted in lower yields of 5 (45
and 61%, respectively).15
Simple boronic acids worked well under the reaction conditions,
giving trisubstituted olefins in good yield (Table 2, entry 1). The
presence of an electron-donating group on the boronic acid
Table 2
Formation of trisubstituted olefins from alkynyl esters and boronic acids
R2B(OH)2, Pd(OAc)2
CO2Et
H
Et3P·HBF4, Cs2CO3
CO2Et
R1
R1
R2
H2O, toluene, 23 °C, 18 h
Entrya
Substrate
Productb
Yield (%)
1
2
3
4
4: R1¼Me
7: R2¼C6H5
77
85
75
80
67
67
58
58
49
51
86
77
78
56
77
66
10
71
68
60
56
Table 3
4: R1¼Me
5: R2¼4-MeC6H4
Source of hydrogen during trisubstituted olefin formation from alkynes
4: R1¼Me
8: R2¼3-MeC6H4
9: R2¼2-MeC6H4
10: R2¼4-MeOC6H4
11: R2¼3-MeOC6H4
12: R2¼2-MeOC6H4
13: R2¼4-FC6H4
CO2Et
H
CO2Et
D
4: R1¼Me
PhB(OH)2, Pd(OAc)2
Et3P·HBF4, Cs2CO3
5
4: R1¼Me
CO2Et
6
4: R1¼Me
7c
8
4: R1¼Me
toluene, 23 °C, 18 h
4: R1¼Me
4
7
34
9c
10
11c
12
13
14
15
16
17d
18
19
20e
21e
4: R1¼Me
14: R2¼4-MeCOC6H4
15: R2¼C6H4CHCH
16: R2¼C6H13CHCH
17: R2¼1-naphthyl
18: R2¼2-naphthyl
19: R2¼3-thiophene
21: R2¼4-MeC6H4
23: R2¼4-MeC6H4
25: R2¼4-MeC6H4
27: R2¼4-MeC6H4
29: R2¼4-MeC6H4
31: R2¼4-MeC6H4
33: R2¼C6H5
4: R1¼Me
Entrya
Boronic acid
Additive
Yield (%)
Ratio (7:34)b
4: R1¼Me
4: R1¼Me
1
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
H2O
H2O
D2O
D2O
H2O
D2O
None
H2O
D2O
H2O
77
64
66
72
63
68
100:0
100:0
30:70
27:73
97:3
4: R1¼Me
2c
3
4: R1¼Me
20: R1¼Cy
22: R1¼Ph
24: R1¼H
4d
5
e
PhB(OD)2
PhB(OD)2
e
6
7
8
9
30:70
26: R1¼BnO(CH2)2
28: R1¼TIPSO(CH2)4
30: R1¼Me(CH2)5
32: R1¼C6H12
PhB(pin)2
PhB(pin)2
PhB(pin)2
C6D5B(OH)2
Trace
36
100:0
40:60
100:0
30
78
10
a
a
0.06 equiv of Pd(OAc)2, 0.18 equiv of Et3P$HBF4, 2.0 equiv of R2B(OH)2, 2.1 equiv
0.06 equiv of Pd(OAc)2, 0.18 equiv of Et3P$HBF4, 2.0 equiv of PhB(OH)2, 2.1 equiv
of Cs2CO3, 10 equiv of H2O, toluene, 23 ꢀC, 18 h.
of Cs2CO3, 10 equiv of additive, toluene, 23 ꢀC, 18 h.
b
b
Products were obtained as single isomers.
t-Bu2MeP$HBF4 was used in place of Et3P$HBF4.
Methyl ester was used.
Weinreb amide was used in place of the ester.
Products were obtained as single isomers.
Reaction performed in C6D6.
30 equiv of D2O were used.
40% D.
c
c
d
d
e
e

8504
A.G. Bush et al. / Tetrahedron 65 (2009) 8502–8506
done using both deuterated boronic acid (40% D) and D2O that gave
only 70% deuterium incorporation.17
without further purification unless otherwise indicated. Reactions
were monitored by TLC analysis using aluminum plates precoated
with silica gel 60 F254. The plates were visualized using ultraviolet
light, potassium permanganate, ceric ammonium molybdate, and/
or p-anisaldehyde stains. Flash chromatography was carried out on
230–400 mesh silica gel 60. 1H and 13C NMR spectra were acquired
on a Bruker Advance 400 MHz instrument in the specified solvent,
reporting chemical shifts downfield from tetramethylsilane. In-
frared spectra were acquired from neat films on a sodium chloride
cell using a Bomen Michaelson 100 FTIR spectrometer. High reso-
lution mass spectra were obtained using an Analytical Concept
spectrometer using either electron impact (EI) or chemical ioniza-
tion (CI). High resolution mass spectroscopy (HRMS) was performed
with an electron beam of 70 eV, or using a double focusing magnetic
sector mass spectrometer. Melting points were determined using an
Electrothermal Meltemp apparatus and are uncorrected.
Using the pinacol ester of phenylboronic acid, the reaction did
not proceed. However when water was added to the mixture
a moderate yield of product 7 was noted (entries 7 and 8). Per-
forming a coupling with the pinacol ester and D2O, we observed 60%
deuterium incorporation in the product. The remaining 40%
(product 7) could possibly have arisen from the Et3P$HBF4 salt. As
a
final control experiment, we performed a reaction with
C6D5B(OH)2 and H2O in order to see if the hydrogen could have been
derived from a 1,4-Pd shift on the aryl group of the product.18 No
deuterium incorporation was observed under these conditions
(entry 10).
Based on these experiments and on previous proposals,8,9,19 the
following mechanism is proposed (Scheme 2). Palladium un-
dergoes oxidative insertion into an OH bond to form an initial H–
Pd–OX species. This step is suggested by the observation of an
isotope effect for hydrogen transfer and by the fact that pinacol
boronic esters do not undergo the process in the absence of water.
The HOX species may be water as a fast exchange between boronic
acid and water would account for the observed isotope effect.20
Following the oxidative insertion, there occurs a syn carbopalla-
dation into the triple bond of the alkynyl ester, forming a palladium
intermediate with the observed regio- and stereochemistry.
Transmetallation of the arylboronic acid is followed by reductive
elimination to regenerate the palladium catalyst and produce the
final product.
4.2. General procedure for the preparation of trisubstituted
alkenes. (E)-Ethyl-3-p-tolylbut-2-enoate (5)11
To a flame-dried vial equipped with a Teflon-coated stir bar
were added Pd(OAc)2 (4.8 mg, 0.007 mmol), Et3P$HBF4 (4.1 mg,
0.02 mmol), 4-tolylboronic acid (29.9 mg, 0.22 mmol), and Cs2CO3
(74.9 mg, 0.23 mmol). Freshly distilled toluene was introduced
(2.0 mL) followed by H2O (20.0 mL, 1.1 mmol) and ethyl 2-butynoate
4 (12.5 mg, 0.112 mmol). The solution was stirred for 18 h at room
temperature, then diluted with Et2O, and washed three times with
H2O. The organic phase was dried over anhydrous MgSO4, filtered,
and concentrated. The pure product 511 (20.1 mg, 88%) was
obtained as a clear oil by flash chromatography (100% petroleum
ether followed by 5% Et2O in petroleum ether). 1H NMR (400 MHz,
CO2Et
H
H-OX
R
[Pd]
Ar
acetone-d6)
d
7.46 (d, J¼8.0 Hz, 2H), 7.23 (d, J¼7.8 Hz, 2H), 6.12 (q,
J¼1.2 Hz, 1H), 4.16 (q, J¼7.2 Hz, 2H), 2.55 (d, J¼1.2 Hz, 3H), 2.35 (s,
CO2Et
H
3H), 1.27 (t, J¼7.2 Hz, 3H).
R
H
[Pd] OX
[Pd] Ar
4.3. (E)-Ethyl 3-(3-methylphenyl)-but-2-enoate (8)
XOB(OH)2
Prepared from ethyl 2-butynoate (12.5 mg, 0.112 mmol) and 3-
tolylboronic acid (29.9 mg, 0.22 mmol) using a procedure similar to
that described for (E)-ethyl 3-(4-methylphenyl)-but-2-enoate 5
that provided the title compound after purification by flash column
chromatography (100% petroleum ether followed by 5% Et2O in
petroleum ether) as a colorless oil (17.2 mg, 75%). 1H NMR
CO2Et
CO2Et
R
R
H
[Pd] OX
ArB(OH)2
Scheme 2. Proposed mechanism.
(400 MHz, CDCl3)
d 7.29–7.24 (m, 3H), 7.19–7.16 (m, 1H), 6.13 (q,
3. Conclusion
J¼1.2 Hz, 1H), 4.22 (q, J¼7.2 Hz, 2H), 2.57 (d, J¼1.2 Hz, 3H), 2.38 (s,
3H), 1.32 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.9 (C),
By using the sterically unencumbered phosphine ligand, Et3P,
single isomer trisubstituted olefins have been generated from
alkynyl esters by coupling with either aryl or alkenyl boronic acids.
The reactions proceeded easily at room temperature under very
mild conditions and in all cases produced the products as single
isomers. Ligand size proved to be critical in this process as only
small ligands such as Me3P or Et3P resulted in the production of
single isomers. This new methodology provides a convenient syn-
thesis of trisubstituted olefins without the need to generate olefin
templates.
155.7 (C), 142.2 (C), 138.1 (C), 129.7 (CH), 128.4 (CH), 127.0 (CH),
123.4 (CH), 116.9 (CH), 59.8 (CH2), 21.4 (CH3), 18.0 (CH3), 14.3 (CH3);
IR (neat) 1713, 1631 cmꢁ1; MS 175.1 (MþꢁC2H5); HRMS calcd for
C11H11O2 (MþꢁC2H5) 175.0759, found 175.0754.
4.4. (E)-Ethyl 3-(2-methylphenyl)-but-2-enoate (9)
Prepared from ethyl 2-butynoate (12.5 mg, 0.112 mmol) and 2-
tolylboronic acid (29.9 mg, 0.22 mmol) using a procedure similar to
that described for (E)-ethyl 3-(4-methylphenyl)-but-2-enoate 5
that provided the title compound as a colorless oil (18.3 mg, 80%)
after purification by flash column chromatography (100% petro-
leum ether followed by 5% Et2O in petroleum ether). 1H NMR
4. Experimental
4.1. General
(400 MHz, CDCl3)
d 7.21–7.13 (m, 3H), 7.06–7.04 (m, 1H), 5.74 (q,
J¼1.6 Hz, 1H), 4.20 (q, J¼7.2 Hz, 2H), 2.43 (d, J¼1.6 Hz, 3H), 2.72 (s,
Reactions were performed under nitrogen in flame-dried
glassware equipped with a magnetic stir bar and a rubber septum.
Solvents were freshly distilled prior to use as follows: THF and
toluene over sodium/benzophenone; dioxane over calcium hydride.
All other reagents were obtained from commercial sources and used
3H), 1.29 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.6 (C),
158.2 (C), 143.9 (C), 133.9 (C), 130.4 (CH), 127.6 (CH), 127.1 (CH),
125.7 (CH), 119.4 (CH), 59.8 (CH2), 20.8 (CH3), 19.7 (CH3), 14.3 (CH3);
IR (neat) 1716, 1635 cmꢁ1; MS 189.1 (MþꢁCH3); HRMS calcd for
C12H13O2 (MþꢁCH3) 189.0910, found 189.0902.

A.G. Bush et al. / Tetrahedron 65 (2009) 8502–8506
8505
4.5. (2E,4E)-Ethyl 3-methylundeca-2,4-dienoate (16)
4.9. Ethyl 7-(triisopropylsilyloxy)-hept-2-ynoate (28)
Prepared from ethyl 2-butynoate (12.5 mg, 0.112 mmol) and 1-
octenylboronic acid (34.3 mg, 0.22 mmol) using a procedure similar
to that described for (E)-ethyl 3-(4-methylphenyl)-but-2-enoate 5
that provided the title compound after purification by flash column
chromatography (100% petroleum ether followed by 5% Et2O in
petroleum ether) as a colorless oil (21.1 mg, 86%). 1H NMR
To an oven-dried round bottom flask equipped with a Teflon-
coated stir bar was added freshly distilled THF (50 mL) and (hex-5-
ynyloxy)-triisopropylsilane (4.9 g,19.3 mmol). The resulting solution
was cooled to ꢁ78 ꢀC and butyllithium (9.2 mL, 23.1 mmol) was
added by syringe pump over 10 min. After all the butyllithium had
been added, a solution of ethyl chloroformate (3.7 mL, 38.5 mmol) in
THF (15 mL) was added by syringe pump over 45 min. After the
addition of the ethyl chloroformate was complete, the reaction
mixture was warmed to room temperature and stirred overnight.
The reaction was quenched with saturated NH4Cl solution and
extracted thrice with EtOAc. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The crude oil was purified by
flash chromatography (1% ether in petroleum ether) to afford the
title compound as a clear oil (4.53 g, 72%). 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
6.10 (m, 2H), 5.69 (d, J¼1.2 Hz, 1H), 4.16 (q,
J¼7.2 Hz, 2H), 2.26 (d, J¼1.2 Hz, 3H), 2.18–2.13 (m, 2H), 1.45–1.38
(m, 2H), 1.34–1.25 (m, 9H), 0.89 (t, J¼7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 167.3 (C), 152.7 (C), 137.5 (CH), 133.6 (CH), 117.5
(CH), 59.6 (CH2), 33.0 (CH2), 31.7 (CH2), 29.0 (CH2), 28.9 (CH2), 22.6
(CH2), 14.3 (CH3), 14.1 (CH3), 13.8 (CH3); IR (neat) 1714, 1638 cmꢁ1
;
MS 224.2 (Mþ); HRMS calcd for C12H19O (MþꢁC2H5O) 179.1436,
found 179.1438.
d
4.21 (q, J¼6.9 Hz, 2H), 3.71 (t, J¼6.0 Hz, 2H), 2.78 (t, J¼6.9 Hz, 2H),
1.62–1.73 (m, 4H), 1.30 (t, J¼7.2 Hz, 3H), 1.02–1.11 (m, 21H); 13C NMR
4.6. (E)-Ethyl 3-(thiophen-3-yl)-but-2-enoate (19)
(100 MHz, CDCl3) d 153.9 (C), 89.3 (C), 73.3 (C), 62.6 (CH2), 61.7 (CH2),
31.9 (CH2), 24.2 (CH2), 18.5 (CH2), 18.0 (CH3), 14.0 (CH), 11.9 (CH3); IR
(neat) 2240, 1714 cmꢁ1; MS 283.2 (MþꢁC3H7); HRMS calcd for
C15H27O3Si (MþꢁC3H7) 283.1729, found 283.1739.
Prepared from ethyl 2-butynoate (12.5 mg, 0.112 mmol) and 3-
thiofuranylboronic acid (28.2 mg, 0.22 mmol) using a procedure
similar to that described for (E)-ethyl 3-(4-methylphenyl)-but-2-
enoate 5 that provided the title compound after purification by
flash column chromatography (100% petroleum ether followed by
5% Et2O in petroleum ether) as a colorless oil (12.3 mg, 56%). 1H
4.10. (E)-Ethyl 3-p-tolyl-5-(triisopropylsilyloxy)-
pent-2-enoate (29)
NMR (400 MHz, CDCl3) d 7.49–7.48 (m, 1H), 7.32–7.31 (m, 2H), 6.23
Prepared from ethyl 7-(triisopropylsilyloxy)pent-2-ynoate 28
(72.3 mg, 0.221 mmol) using a procedure similar to that described
for (E)-ethyl 3-(4-methylphenyl)-but-2-enoate 5 that provided the
title compound after purification by flash column chromatography
(100% petroleum ether followed by 5% Et2O in petroleum ether) as
(q, J¼1.6 Hz,1H), 4.21 (q, J¼7.2 Hz, 2H), 2.57 (d, J¼1.6 Hz, 3H),1.32 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 167.1 (C),148.9 (C), 143.4
(C), 126.1 (CH), 125.2 (CH), 124.1 (CH), 115.3 (CH), 59.8 (CH2), 17.2
(CH3), 14.3 (CH3); IR (neat) 1709, 1621 cmꢁ1; MS 196.1 (Mþ); HRMS
calcd for C10H12O2S (Mþ) 196.0558, found 196.0558.
a colorless oil (62.9 mg, 68%). 1H NMR (400 MHz, acetone-d6)
d 7.43
(d, J¼8.4 Hz, 2H), 7.22 (d, J¼8.4 Hz, 2H), 6.03 (s, 1H), 4.16 (q,
J¼7.2 Hz, 2H), 3.70 (t, J¼6.0 Hz, 2H), 3.18 (t, J¼7.6 Hz, 2H), 2.35 (s,
3H), 1.62–1.51 (m, 4H), 1.27 (t, J¼7.2 Hz, 3H), 1.08–1.02 (m, 21H); 13C
4.7. (E)-Ethyl 3-cyclohexyl-3-p-tolylacrylate (21)
Prepared from ethyl 3-cyclohexylpropiolate21 (40.2 mg,
0.223 mmol) using a procedure similar to that described for (E)-
ethyl 3-(4-methylphenyl)-but-2-enoate 5 that provided the title
compound after purification by flash column chromatography
(100% petroleum ether followed by 5% Et2O in petroleum ether) as
a colorless oil (46.7 mg, 77%). 1H NMR (400 MHz, acetone-d6)
NMR (100 MHz, acetone-d6)
d 167.7 (C), 162.1 (C), 140.8 (C), 140.0
(C), 131.1 (CH), 128.4 (CH), 118.2 (CH), 64.7 (CH2), 61.1 (CH2), 34.6
(CH2), 31.6 (CH2), 27.1 (CH2), 22.2 (CH3), 19.4 (CH3), 15.7 (CH3), 13.7
(CH3); IR (neat) 1715, 1623 cmꢁ1; MS 375.2 (MþꢁC3H7); HRMS
calcd for C22H35O3Si (MþꢁC3H7) 375.2355, found 375.2346.
d
7.19–7.17 (m, 2H), 7.12–7.10 (m, 2H), 5.60 (s, 1H), 4.15 (q, J¼7.2 Hz,
2H), 3.81–3.74 (m, 1H), 2.33 (s, 3H), 1.75–1.62 (m, 5H), 1.41–1.23 (m,
8H); 13C NMR (100 MHz, acetone-d6)
168.3 (C), 167.3 (C), 140.3 (C),
4.11. (E)-N-Methoxy-N-methyl-3-p-tolylnon-2-enamide (31)
Prepared from N-methoxy-N-methylnon-2-ynamide 3023
(20.6 mg, 0.104 mmol) using a procedure similar to that described
for (E)-ethyl 3-(4-methylphenyl)-but-2-enoate 5 that provided the
title compound after purification by flash column chromatography
(3% EtOAc in petroleum ether followed by 5% EtOAc in petroleum
ether) as a colorless oil (18.0 mg, 60%). 1H NMR (400 MHz, acetone-
d
139.0 (C), 130.3 (CH), 129.3 (CH), 120.1 (CH), 61.2 (CH2), 42.3 (CH),
33.3 (CH2), 28.2 (CH2), 27.6 (CH2), 22.1 (CH3), 15.6 (CH3); IR (neat)
1715, 1626 cmꢁ1; MS 272.2 (Mþ); HRMS calcd for C17H21O2
(MþꢁCH3) 257.1542, found 257.1535.
4.8. (E)-Ethyl 5-(benzyloxy)-3-p-tolylpent-2-enoate (27)
d6)
d
7.40 (d, J¼8.4 Hz, 2H), 7.21 (d, J¼8.4 Hz, 2H), 6.49 (s, 1H), 3.72
(s, 3H), 3.18 (s, 3H), 3.06 (t, J¼7.2 Hz, 2H), 2.34 (s, 3H), 1.42–1.23 (m,
Prepared from ethyl 5-(benzyloxy)-pent-2-ynoate22 (26.4 mg,
0.112 mmol) using a procedure similar to that described for (E)-
ethyl 3-(4-methylphenyl)-but-2-enoate 5 that provided the title
compound after purification by flash column chromatography
(100% petroleum ether followed by 5% Et2O in petroleum ether)
8H), 0.85 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, acetone-d6)
d 169.2
(C), 158.2 (C), 141.0 (C), 140.1 (C), 131.0 (CH), 128.4 (CH), 117.6 (CH),
62.8 (CH2), 33.3 (CH2), 32.0 (CH2), 31.0 (CH2), 30.7 (CH2), 24.2 (CH2),
22.1 (CH3), 15.3 (CH3); IR (neat) 1650; MS 229.2 (MþꢁC2H6NO);
HRMS calcd for C16H21O (MþꢁC2H6NO) 229.1592, found 229.1586.
as a colorless oil (26.2 mg, 71%). 1H NMR (400 MHz, CDCl3)
d 7.40
(d, J¼8.5 Hz, 2H), 7.35–7.25 (m, 5H), 7.17 (d, J¼8.0 Hz, 2H), 6.12 (s,
1H), 4.49 (s, 2H), 4.20 (q, J¼7.0 Hz, 2H), 3.64 (t, J¼7.0 Hz, 2H), 3.45
(t, J¼7.0 Hz, 2H), 2.37 (s, 3H), 1.31 (t, J¼7.0 Hz, 3H); 13C NMR
4.12. 3-Cyclohexyl-N-methoxy-N-methylpropiolamide (32)
To an oven-dried round bottom flask equipped with a Teflon-
coated stir bar was added ethynylcyclohexane (0.35 mL, 2.7 mmol)
in freshly distilled THF (25 mL). The solution was cooled to ꢁ78 ꢀC
and butyllithium (1.2 mL, 3.0 mmol) was added via syringe pump
over 30 min. After stirring for 30 min, methoxy(methyl)carbamic
chloride24 (0.52 mL, 5.4 mmol) was added via cannula, rinsing the
flask once with THF (10 mL), and the resulting solution was stirred
(100 MHz, CDCl3)
d 166.4 (C), 156.8 (C), 139.1 (C), 138.5 (C), 138.2
(C), 129.2 (CH), 128.2 (CH), 127.5 (CH), 127.3 (CH), 126.7 (CH),
117.9 (CH), 72.6 (CH2), 69.3 (CH2), 59.9 (CH2), 31.6 (CH2), 21.2
(CH3), 14.3 (CH3); IR (neat) 1705, 1618 cmꢁ1
; MS 279.1
(MþꢁC2H5O); HRMS calcd for C19H19O2 (MþꢁC2H5O) 279.1385,
found 279.1389.

8506
A.G. Bush et al. / Tetrahedron 65 (2009) 8502–8506
for 60 min at ꢁ78 ꢀC. After warming the reaction to room tem-
perature and stirring overnight, the reaction was quenched with
10% HCl solution (50 mL) then extracted three times with EtOAc.
The combined organic extracts were then washed with saturated
NaHCO3 followed by brine and then dried over MgSO4. The solvent
was removed in vacuo and the crude product was purified by flash
column chromatography (1% Et2O in hexanes followed by 4% Et2O
in hexanes) to afford the title compound as a clear oil (458.2 mg,
2. (a) Iorga, B.; Eymery, F.; Mourie`s, V.; Savignac, P. Tetrahedron 1998, 54, 14637;
(b) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73.
3. (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490;
(b) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
4. (a) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91, 1851; (b) Siddall,
J. B.; Biskup, M.; Fried, J. H. J. Am. Chem. Soc. 1969, 91, 1853; (c) Mueller, A. J.;
Jennings, M. P. Org. Lett. 2007, 9, 5327; (d) Walker, J. R.; Rothman, S. C.; Poulter, C.
D. J. Org. Chem. 2008, 73, 726.
5. (a) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651; (b) Kinney, W. A.;
Teleha, C. A.; Thompson, A. S.; Newport, M.; Hansen, R.; Ballentine, S.; Ghosh,
S.; Mahan, A.; Grasa, G.; Zanotti-Gerosa, A.; Dingenen, J.; Schubert, C.; Zhou, Y.;
Leo, G. C.; McComsey, D. F.; Santulli, R. J.; Maryanoff, B. E. J. Org. Chem. 2008, 73,
2302; (c) Molander, G. A.; Yokoyama, Y. J. Org. Chem. 2006, 71, 2493; (d) Liron,
F.; Fosse, C.; Pernolet, A.; Roulland, E. J. Org. Chem. 2007, 72, 2220; (e) Tan, Z.;
Negishi, E.-I. Angew. Chem., Int. Ed. 2006, 45, 762.
94%). 1H NMR (300 MHz, CDCl3)
2.59 (m, 1H), 1.81–1.85 (m, 2H), 1.67–1.74 (m, 2H), 1.48–1.56 (m,
3H), 1.30–1.38 (m, 3H); 13C NMR (100 MHz, CDCl3)
97.1 (C), 77.2
d 3.77 (s, 3H), 3.24 (s, 3H), 2.54–
d
(CH3), 73.1 (C), 61.8 (CH3), 31.5 (CH2), 29.0 (CH), 25.6 (CH2), 24.5
(CH2); IR (neat) 2232, 1643 cmꢁ1; MS 195.1 (Mþ); HRMS calcd for
C11H17NO2 (Mþ) 195.1259, found 195.1259.
6. (a) Lin, P.-S.; Jeganmohan, M.; Cheng, C.-H. Chem.dEur. J. 2008, 14, 11296;
¨
(b) Kus¸, M.; ArtokO, A.; Ziyanak, F.; Artok, L. Synlett 2008, 2587; (c) Yamamoto,
Y.; Kirai, N. Org. Lett. 2008, 10, 5513.
7. (a) Trost, B. M.; Matsubara, S.; Caringi, J. J. J. Am. Chem. Soc. 1989, 111, 8745; (b)
Trost, B. M.; McIntosh, M. C. J. Am. Chem. Soc. 1995, 117, 7255; (c) Trost, B. M.;
Frontier, A. J. J. Am. Chem. Soc. 2000, 122, 11727.
4.13. (E)-3-Cyclohexyl-N-methoxy-N-methyl-3-
8. Lindhardt, A. T.; Mantel, M. L. H.; Skrydstrup, T. Angew. Chem., Int. Ed. 2008, 47,
2668.
phenylacrylamide (33)
9. (a) Oh, C. H.; Jung, H. H.; Kim, K. S.; Kim, N. Angew. Chem., Int. Ed. 2003, 42, 805;
(b) Oh, C. H.; Ryu, J. H. Bull. Korean Chem. Soc. 2003, 24, 1563; (c) Gupta, A. K.;
Kim, K. S.; Oh, C. H. Synlett 2005, 457.
10. Yamamoto, Y.; Kirai, N.; Harada, Y. Chem. Commun. 2008, 2010.
11. Simard-Mercier, J.; Jiang, J. L.; Ho, M. L.; Flynn, A. B.; Ogilvie, W. W. J. Org. Chem.
2008, 73, 5899.
Prepared from 3-cyclohexyl-N-methoxy-N-methylpropiolamide
32 (22.5 mg, 0.115 mmol) using a procedure similar to that de-
scribed for (E)-ethyl 3-(4-methylphenyl)-but-2-enoate 5 that pro-
vided the title compound as a colorless oil (17.2 mg, 55%). 1H NMR
12. Isomers such as 6 have been prepared by a variety of methods. For examples see:
(a) Navarre, L.; Darses, S.; Genet, J.-P. Adv. Synth. Catal. 2006, 348, 317; (b) Navarre,
L.; Darses, S.; Genet, J.-P. Chem. Commun. 2004, 1108; (c) Kabalka, G. W.; Ven-
kataiah, B.; Dong, G. J. Org. Chem. 2004, 69, 5807; (d) Kabalka, G. W.; Venkataiah,
B.; Dong, G. Org. Lett. 2003, 5, 3803; (e) Leung, L. T.; Leung, S. K.; Chiu, P. Org. Lett.
2005, 7, 5249.
(400 MHz, CDCl3)
d 7.30–7.35 (m, 3H), 7.18–7.21 (m, 2H), 6.07 (s,
1H), 3.67 (s, 3H), 3.25 (s, 3H), 1.61–1.77 (m, 5H), 1.33–1.43 (m, 2H),
1.19–1.29 (m, 3H), 1.02–1.10 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
142.1 (C), 127.8 (CH), 127.6 (CH), 127.1 (CH), 117.4 (CH), 61.4 (CH3),
40.8 (CH3), 32.6 (CH2), 31.7 (CH2), 26.4 (CH2), 26.0 (CH2); IR (neat)
1645 cmꢁ1; MS 273.2 (Mþ); HRMS calcd for C15H17O (MþꢁC2H6NO)
213.1279, found 213.1285.
13. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
14. Compound 5 was isolated as the single isomer shown. The regiochemistry of
this product was established by the small long-range coupling observed be-
tween the olefinic hydrogen and the methyl group. The stereochemistry of this
product was established by NOE analysis of the product and the corresponding
stereoisomer that was obtained by photolysis of the reaction product 5. See
Ref. 11
Acknowledgements
15. A small amount (5–7%) of the homo-coupled product 4,40-dimethyl-biphenyl
was detected in these reactions.
16. The relative stereochemistry of new products was assigned using NOE net-
works. See the Supplementary data and Ref. 11.
We thank the NSERC Canada for generous funding. J.L.J. and
P.R.P. thank NSERC for undergraduate research awards.
17. The initial ratio of available H:D was 10:90.
18. Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem. Soc. 2001, 123,
9918.
19. Ma, S.; Jiao, N.; Ye, L. Chem.dEur. J. 2003, 9, 6049.
20. The formation of the Pd-H intermediate may also be a consequence of the
presence of the Et3P$HBF4 salt as indicated in Ref. 8.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.08.029.
21. Liu, P.; Jordan, R. W.; Kibbee, S. P.; Goddard, J. D.; Tam, W. J. Org. Chem. 2006, 71,
3793.
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