Single isomer trisubstituted olefins bearing alkyl groups

Article abstract of DOI:10.1016/j.tet.2010.09.002

E-β-Chloro-α-iodo-α,β-unsaturated esters were converted to single isomer trisubstituted olefins bearing alkyl substituents by using and alkyl-Suzuki cross coupling. The process was highly selective, and the products in all cases were isolated as single isomers. Mechanistic investigations indicated that this process transfers a hydrogen from water to the α-position of the substrate, and then an alkyl group is introduced to the β-position of the intermediate template while replacing a chloride.

Full text of DOI:10.1016/j.tet.2010.09.002

Tetrahedron 66 (2010) 8739e8744
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Single isomer trisubstituted olefins bearing alkyl groups
*
Thivisha Rajagopal, Alison B. Flynn, William W. Ogilvie
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON, Canada K1N6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 June 2010
Received in revised form 31 August 2010
Accepted 1 September 2010
Available online 8 September 2010
E-b-Chloro-a-iodo-a,b-unsaturated esters were converted to single isomer trisubstituted olefins bearing
alkyl substituents by using and alkyl-Suzuki cross coupling. The process was highly selective, and the
products in all cases were isolated as single isomers. Mechanistic investigations indicated that this
process transfers a hydrogen from water to the
introduced to the -position of the intermediate template while replacing a chloride.
Ó 2010 Elsevier Ltd. All rights reserved.
a-position of the substrate, and then an alkyl group is
b
Keywords:
Trisubstituted olefins
Alkyl-Suzuki
Stereoselective
Regiospecific
1. Introduction
2. Results and discussion
The stereocontrolled synthesis of trisibstituted olefins remains
a significant challenge in organic synthesis. Carbonecarbon coupling
strategies, such as the Wittig,1 HornereWadswortheEmmons,2 or
metathesis reactions3 often produce mixtures of isomers that can be
difficult to separate. Indirectmethods such as the carbometallation of
alkynes,4,5 or cross couplings with olefin templates6 can successfully
overcome the stereochemical problems, but may introduce issues of
a regiochemical nature. While these methods have been utilized to
achieve selectivity in the production of trisubstituted olefins,
methods that are able to introduce alkyl substituents onto the double
bond are relatively uncommon.
As shown in Table 1, treatment of template 1 with 9-octyl-BBN
28 at room temperature in the presence of PdCl2(dppf) using K3PO4
as a base gave no reaction. Heating the mixture to reflux again
returned the starting material, along with a small amount of 3. To
try to improve the cross coupling, a small amount of H2O was in-
troduced,9 however this modification was unfruitful. When the
hydrated form of K3PO4 was instead employed as the base, the
production of a small amount of the trisubstituted olefin 4 resulted.
Because of difficulties encountered during the separation of the
product from the non-polar substrate when 9-octyl-BBN was used
Table 1
We recently described an efficient synthesis of trisubstituted
olefins from E-b-chloro-a-iodo-a,b-unsaturated ester templates
Attempts to prepare
a
tetrasubstituted olefin from E-
b
-chloro-a-iodo-a,b-un-
saturated esters and alkyl boranes
and organoboronic acids.7 This method utilized very small ligands
in mild reaction conditions, and reliably produced the products as
single isomers. The boronic acids used in this study were invariably
aromatic or sp2 hybridized, and while useful, this technology would
benefit if alkyl substituted groups could also be employed. In this
paper we describe the development of a method for the prepara-
Cl
CO2Et
Cl
( )7
PdCl2(dppf)
base, THF
3
CO2Et
( )6
B
+
I
CO2Et
1
2
( )7
tion of trisubstututed olefins from E-b-chloro-a-iodo-a,b-un-
H
saturated ester templates that allows for the introduction of alkyl
substituents. This method is simple and, more importantly, pro-
vides the products as single isomers.
4
Entrya
Base
Temperature ꢀC
Product (yield)
1
2
3
4
K3PO4
K3PO4
25
66
66
66
NR
3: trace
3: trace
4: 27%
K3PO4þH2O
K3PO4$H2O
a
Conditions: 0.05 equiv of PdCl2(dppf), 3.0 equiv of base, 3.0 equiv of
1-(9-borabicyclo[3.3.1]nonana-9-yl)-hexane, THF (0.09 M), 18 h.
* Corresponding author. Tel.: þ1 613 562 5800; fax: þ1 613 562 5170; e-mail
address: wogilvie@uottawa.ca (W.W. Ogilvie).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.002

8740
T. Rajagopal et al. / Tetrahedron 66 (2010) 8739e8744
as the coupling partner, the reaction was optimized using a more
polar coupling partner 5. An initial experiment, run at room tem-
perature for 18 h produced only an 8% yield of the trisubstituted
olefin product 6 using dppf as a ligand. Although the yield was
disappointingly low, the reaction proceeded at room temperature
and gave the compound as a single isomer (Table 2, entry 1). Other
bridged diaryl phosphine ligands were tried, that resulted in im-
proved yields of the trisubstituted olefin 6 (entries 2e6).
A survey of bases was then conducted to try to improve the yield
of the process. As shown in Table 3, the use of K3PO4 resulted in
a recovery of only 3% of the product. Adding H2O to the reaction
mixture restored some reactivity, but the reaction was not as effi-
cient as that using K3PO4$H2O as the base. Other bases were tried,
in each case a matching amount of water was included in the
medium.11
Table 3
Effect of the base used on the formation of trisubstituted olefins from E-
b-chloro-
Table 2
a
-iodo- -unsaturated esters and alkyl boranes
a,b
Effect of the ligand used on the formation of trisubstituted olefins from E-b-chloro-
a
-iodo-
a
,
b
-unsaturated esters and alkyl boranes
Cl
Pd(OAc)2, S-Phos
BzO
Cl
CO2Et
CO2Et
Pd(OAc)2, ligand
BzO
B
( )5
+
( )5
5
CO2Et
BzO
CO2Et
base, THF
BzO
B
( )5
I
+
H
6
( )5
5
K3PO4·H2O, THF
1
I
H
6
1
Entrya
Base
Yieldb (%)
Entrya
Ligand
Yieldb (%)
1
2
3
4
5
6
7
8
9
K3PO4$H2O
K3PO4
86
3
52
11
5
65
78
0
1
2
3
4
5
6
7
8
dppf
8
3
0
K3PO4þH2O
K2HPO4þH2O
KH2PO4þH2O
K2CO3þH2O
CsCO3þH2O
Et3NþH2O
dppm
dppp
dppb
Xantphos
Diphos
21
36
31
39
6
60
79
61
60
86
PPh3
EtiPr2NþH2O
DABCOþH2O
0
0
PMe3$HBF4
PEt3$HBF4
PtBu2Me$HBF4
PCy3
Davephos
S-phos
10
9
10
11
12
13
a
Conditions: 0.05 equiv of Pd(OAc)2, 0.10 equiv of S-phos, 3.0 equiv of Base,
3.0 equiv of 5-(9-borabicyclo[3.3.1]nonan-9-yl)pentyl benzoate, THF (0.09 M), 23 ꢀC,
18 h.
b
Isolated yield; Products were obtained as single isomers.
a
Conditions: 0.05 equiv of Pd(OAc)2, 0.10 equiv of ligand, 3.0 equiv of K3PO4$H2O,
3.0 equiv of 5-(9-borabicyclo[3.3.1]nonan-9-yl)pentyl benzoate, THF (0.09 M), 23 ꢀC,
18 h.
In almost all cases, the yield was significantly lowered com-
pared to the reaction using K3PO4$H2O. Two exceptions were
K2CO3 and CsCO3 (entries 6 and 7), however the hydrate of K3PO4
proved to be superior to either of these bases. Finally, the use of
amine bases was completely ineffective, as the presence of the
product could not be detected in any of these reaction mixtures
(entries 8e10).
b
Isolated yield; products were obtained as single isomers.
When PPh3 was used as a ligand, no improvement in yield was
noted. The use of trialkyl phosphine ligands produced significant
improvements in the yield of the process (entries 9e10). This study
suggested that employing hindered ligands could be an effective
Other boron-containing groups9 were investigated in the cou-
pling process. In all cases however, no product could be detected
when cross coupling was attempted using an alkyl catecholbor-
ane,12 alkyl-pinacol borane,13 alkyl boronic acid or alkyl BF3 salt.14
In each case only starting material was recovered.
Finally we investigated the effect of adding additional water.
When using K3PO4$H2O as the base, a yield of 86% of 6 was obtained
by cross coupling template 1 and borane 5. A reaction in which
3 equiv of water was introduced gave a slightly reduced yield of
product (73%). Using iPrOH as an additive15 was also explored, but
this modification did not produce an improvement in yield (48%
yield of 6 was observed).
way to effect the transformation of E-b-chloro-a-iodo-a,b-un-
saturated esters, such as 1, into the corresponding trisubstituted
olefins, such as 6. Toward this end, the use of the biaryl ligands
Davephos and S-phos was explored (entries 12 and 13). S-Phos
proved to be the best ligand for this transformation, giving tri-
substituted olefin 6 in 86% isolated yield from the reaction between
template 1 and borane 5.
The stereochemistry of each product was confirmed using NOE
interactions. As shown in Scheme 1, the key reaction product 6
displayed a strong NOE interaction between the g-methyl and the
CH2 group of the added alkyl substituent, as well as an enhance-
ment between the first alkyl methylene and the olefinic hydrogen.
The E-olefin product 6 was isomerized to the Z-product 7 using brief
photolysis. Product 7 displayed an NOE enhancement between the
methyl group and the olefin hydrogen, while no interaction was
seen between the alkyl methylene group and the olefin. These NOE
interactions were consistent with the assignment of an E-configu-
ration to the original cross coupled product 6. The regiochemistry of
product 6 was established by the magnitude of the coupling con-
stant between the olefinic hydrogen and the methyl group (1.2 Hz).
In product 4 the coupling constant associated with the olefinic
hydrogen and the methyl group was also small (0.8 Hz).10
The scope of the process was explored using a variety of cou-
pling partners (Table 4). A simple methyl substitution at the
sition of the E- -chloro- -iodo- -unsaturated ester template 1
b po-
b
a
a,b
provided an excellent yield when 5 was used as the coupling
partner (entry 1). Switching the methyl group on the chloroeiodo
template to a hydrogen (entry 2) decreased the yield of the cross
coupled product significantly (30%). Interestingly, this compound
proved to be the Z-isomer, and was the only compound in this study
in which the introduced alkyl group and the ester of the original
substrate were syn to each other. Branched substituents, such as
a cyclohexyl group (entry 3) were tolerated in the process and
produced a moderate yield of the trisubstituted olefin product
11 (46%).
O
O
H
H
hv
BzO
O
BzO
Substituted alkyl chains were compatible with the reaction
conditions as shown in entry 4, in which a TIPS ether was present
on the substrate side chain. Treating a variety of terminal alkenes
with 9-BBN produced 9-alkyl-9-BBN boranes that were used to
( )4
( )4
O
6
7
Scheme 1. Determination of the stereochemistry of product 6.

T. Rajagopal et al. / Tetrahedron 66 (2010) 8739e8744
8741
Table 4
was confirmed by subjecting iodide 21 to the reaction conditions. In
this experiment, the trisubstituted product 16 was not detected,
instead only the tetrasubstituted product 22 was obtained.
If the hydrogen introduction was indeed the initial step in the
process, then cross coupling with chlorides, such as 23 or 24 should
lead cleanly to trisubstituted products, such as 6. When the trans
chloride 2317 was used in a coupling with borane 5, the tri-
substituted product 6 was produced. The use of the corresponding
cis chloride 2417 in a similar reaction led to the formation of iso-
meric olefin 7. The results of these experiments were consistent
with a sequence in which the hydrogen was introduced onto the
template before the alkyl group was transferred. These observa-
tions also suggested that the stereochemistry of the final tri-
substituted olefins was established during the introduction of the
hydrogen onto the chloroeiodo template.
Formation of trisubstituted olefins from E-
and alkyl boranes
b
-chloro-
a
-iodo-
a
,
b
-unsaturated esters
R1
Cl
Pd(OAc)2, S-Phos
K3PO4·H2O, THF
CO2Et
CO2Et
R1
R2
B
+
R2
I
H
Entrya
Substrate
Productb
Yieldc (%)
1
1: R1¼CH3
6: R2¼BzO(CH2)5
86
30
46
74
66
82
73
60
76
0
2d
3
8: R1¼H
9: R2¼BzO(CH2)5
e
10: R1¼C6H12
11: R2¼BzO(CH2)5
13: R2¼BzO(CH2)5
15: R2¼BzO(CH2)5
3: R2¼CH3(CH2)7
16: R2¼BnO(CH2)5
4d
5
12: R1¼CH3(CH2)4
14: R1¼TIPSO(CH2)4
1: R1¼CH3
6
7
8
9
1: R1¼CH3
1: R1¼CH3
17: R2¼TIPSO(CH2)5
1: R1¼CH3
18: R2¼BzO(CH2)3CHCH3
10
1: R1¼CH3
19: R2¼c-C6H11
3. Conclusion
a
Conditions: 0.05 equiv of Pd(OAc)2, 0.10 equiv of S-phos, 3.0 equiv of
K3PO4$H2O, 3.0 equiv of borane, THF (0.09 M), 23 ꢀC, 18 h.
A stereoselective and regiospecific cross coupling of alkyl bo-
ranes and E-b-chloro-a-iodo-a,b-unsaturated ester templates that
b
Products were obtained as single isomers.
Isolated yield.
The methyl ester was used in place of the ethyl ester.
The Z-isomer was produced exclusively in this reaction.
c
d
produces single isomer trisubstituted olefins was developed. This
method is convenient, and is a reliable way to selectively prepare
stereodefined trisubstituted olefins. The reaction is compatible
with a variety of functional groups and proceeds under very mild
reaction conditions. Mechanistic experiments are consistent with
a process in which the stereochemistry of the product is established
during an initial proton transfer. The details of this process are still
unclear and will require further investigation to elucidate.
e
cross couple to the E-b-chloro-a-iodo-a,b-unsaturated ester tem-
plate 1 under our optimized conditions. Using a straight alkyl chain
such as an octyl group (entry 6) produced the desired product with
an excellent yield (82%). Starting with a benzyloxy substituted al-
kene (entry 7), resulted in a very good yield (73%), similar to that
obtained when a benzoyloxy protected alkene was employed as the
starting material (entry 2). Using a more bulky triisopropylsilyloxy
protected alkene resulted in a slight decrease in the yield of the
transformation to 60% (entry 8). Finally, a benzoyloxy protected
branched alkene (entry 9) worked beautifully in the process to
provide a good yield of the cross coupled material (76%). Un-
fortunately, the presence of branching at the boronic acid was not
tolerated in the reaction, as exemplified by the results of entry 10 in
which no product could be constructed.
4. Experimental section
4.1. General
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 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 mo-
lybdate, and/or p-anisaldehyde stains. Flash chromatography was
carried out on 230e400 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 tetra-
methylsilane. Infrared spectra were acquired from neat films on
a sodium chloride cell using a Bomen Michaelson 100 FTIR spec-
trometer. High resolution mass spectra were obtained using an
Analytical Concept spectrometer using either electron impact (EI)
or chemical ionization (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 appa-
ratus and are uncorrected.
A series of mechanistic experiments were performed to try to
identify the source of hydrogen and stereoselectivity in this pro-
cess. As shown in Scheme 2, the use of K3PO4$D2O as the base
resulted in the observation of deuterated product 20. This sug-
gested that the olefinic hydrogen in the product was most likely
derived from the water present in the reaction medium. Previous
experience with E-b-chloro-a-iodo-a,b
-unsaturated esters7,16 had
shown that initial cross couplings invariably occurred at the iodide
position. That this selectivity was operative in the present process
BzO
CO2Et
CO2Et
( )5
Cl
Pd(OAc)2, S-Phos
K3PO4·D2O, THF
CO2Et
H
D
BzO
BzO
B
B
6
+
+
( )5
5
+
I
1
BzO
BnO
( )5
20
Pd(OAc)2, S-Phos
BnO
I
( )5
( )4
21
( )5
22
OBz
( )5
5
K3PO4·D2O, THF
35 %
CO2Et
CO2Et
4.2. General procedure for the preparation of trisubstituted
alkenes from (2E)-3-chloro-2-iodo-2-alkenoates. (6E)-8-
Ethoxy-6-methyl-8-oxoocto-6-enyl benzoate (6)
Pd(OAc)2, S-Phos
CO2Et
H
BzO
BzO
CO2Et
BzO
BzO
B
B
( )5
Cl
+
+
( )5
5
K3PO4·D2O, THF
59 %
H
H
To an oven dried flask equipped with a Teflon-coated stir bar
was added Pd(OAc)2 (6.1 mg, 0.0091 mmol), S-phos (7.5 mg,
0.0182 mmol), and K3PO4$H2O (125 mg, 0.546 mmol) under a ni-
trogen atmosphere. Freshly distilled THF was added (1.0 mL) fol-
lowed by a solution of (2E)-ethyl 3-chloro-2-iodobut-2-enoate 118
(50 mg, 0.182 mmol) in THF (1 mL). To a second oven dried flask
6
23
Pd(OAc)2, S-Phos
H
( )5
Cl
( )5
5
K3PO4·D2O, THF
51 %
CO2Et
CO2Et
7
24
Scheme 2. Mechanistic experiments.

8742
T. Rajagopal et al. / Tetrahedron 66 (2010) 8739e8744
equipped with a Teflon-coated stir bar were added pent-4-enyl
benzoate (104 mg, 0.546 mmol) and 9-borabicyclo[3.3.1]nonane
(0.5 M solution in THF, 1.10 mL, 0.546 mmol). The resulting mixture
was stirred at room temperature for 2 h. This alkyl-9-BBN solution
was transferred to the first flask via cannula, and the resulting
mixture was stirred for 18 h at room temperature. The solution was
then diluted with Et2O and washed three times with H2O. The or-
ganic phase was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The pure product (48 mg, 86%) was obtained as
a yellow oil by flash chromatography (2% EtOAc in hexane): 1H NMR
chromatography (2% EtOAc in hexane) as a colorless oil (43 mg,
74%). 1H NMR (400 MHz, CDCl3)
8.05e8.02 (m, 2H), 7.58e7.53 (m,
d
1H), 7.46e7.42 (m, 2H), 5.63 (s, 1H), 4.32 (t, J¼6.8 Hz, 2H), 3.67
(s, 3H), 2.59 (td, J¼7.6, 2.0 Hz, 2H), 2.17 (td, J¼7.6, 0.8 Hz, 2H), 1.79
(m, 2H), 1.59e1.41 (m, 8H), 1.35e1.30 (m, 2H), 0.89 (t, J¼7.2 Hz, 3H);
13C NMR (400 MHz, CDCl3)
d 166.9 (C), 166.6 (C), 164.8 (C), 132.8
(CH), 130.4 (C), 129.5 (CH), 128.3 (CH), 114.8 (CH), 64.8 (CH2), 50.8
(CH3), 38.2 (CH2), 32.1 (CH2), 32.0 (CH2), 28.6 (CH2), 28.4 (CH2),
27.3 (CH2), 25.8 (CH2), 22.5 (CH2), 14.0 (CH3); IR (neat) 1712,
1701 cmꢁ1; MS 315.2 (MþꢁOCH3); HRMS calcd for C20H27O3
(MþꢁOCH3) 315.1955, found 315.1953.
(400 MHz, acetone-d6)
d 8.03e8.01 (m, 2H), 7.66e7.61 (m, 1H),
7.54e7.49 (m, 2H), 5.68 (q, J¼1.2 Hz, 1H), 4.32 (t, J¼6.4 Hz, 2H), 4.08
(q, J¼7.2 Hz, 2H), 2.22 (td, J¼7.6, 1.2 Hz, 2H), 2.15 (d, J¼1.2 Hz, 3H),
1.82 (p, J¼6.4 Hz, 2H), 1.64e1.47 (m, 4H), 1.21 (t, J¼7.2 Hz, 3H); 13C
4.2.5. (6E)-6-(2-Ethoxy-2-oxoethylidene)-10-(triisopropylsilyloxy)
decyl benzoate (15). Prepared from ethyl (2E)-3-chloro-2-iodo-
7-(triisipropylsilyloxy)hept-2-enoate 14 (50 mg, 0.103 mmol) using
a procedure similar to that described above that provided the title
compound after purification by flash chromatography (2% EtOAc in
hexane) as a colorless oil (35 mg, 66%). 1H NMR (300 MHz, CDCl3)
NMR (400 MHz, acetone-d6)
d 167.8 (C), 167.7 (C), 134.8 (CH),
132.4 (C), 131.1 (CH), 130.4 (CH), 130.1 (C), 117.4 (CH), 66.4 (CH2),
60.7 (CH2), 42.1 (CH2), 30.2 (CH2), 28.7 (CH2), 27.3 (CH2), 19.6
(CH3), 15.6 (CH3); IR (neat) 1718, 1648 cmꢁ1; MS 304.2 (Mþ); HRMS
calcd for C18H24O4 304.1675, found 304.1659.
d
8.05e8.02 (m, 2H), 7.59e7.53 (m, 1H), 7.47e7.41 (m, 2H), 5.64
(s, 1H), 4.32 (t, J¼6.6 Hz, 2H), 4.13 (q, J¼7.2 Hz, 2H), 3.69 (t, J¼6.0 Hz,
2H), 2.63 (t, J¼7.5 Hz, 2H), 2.18 (t, J¼6.9 Hz, 2H), 1.79 (m, 2H),
1.58e1.43 (m, 8H), 1.27 (t, J¼7.2 Hz, 3H), 1.04 (s, 21H); 13C NMR
4.2.1. (2E)-Ethyl 3-methylundec-2-enoate (3). Prepared from ethyl
(2E)-3-chloro-2-iodobut-2-enoate 118 (50 mg, 0.182 mmol) using
a procedure similar to that described that provided the title com-
pound after purification by flash chromatography (1% EtOAc in
hexane) as a colorless oil (34 mg, 82%). 1H NMR (400 MHz, acetone-
(300 MHz, CDCl3)
d 166.6 (C), 166.5 (C), 163.9 (C), 132.8 (CH), 130.4
(C), 129.5 (CH), 128.3 (CH), 115.6 (CH), 64.9 (CH2), 63.1 (CH2),
59.5 (CH2), 38.1 (CH2), 33.1 (CH2), 31.7 (CH2), 28.6 (CH2), 27.3 (CH2),
25.8 (CH2), 24.9 (CH2), 18.0 (CH3), 14.3 (CH3), 11.9 (CH); IR (neat)
1716, 1720 cmꢁ1; MS 475.3 (MþꢁCH(CH3)2); HRMS calcd for
C27H43O5Si (MþꢁCH(CH3)2) 475.2874, found 475.2909.
d6)
d
5.65 (q, J¼1.2 Hz, 1H), 4.09 (q, J¼7.2 Hz, 2H), 2.17 (td, J¼7.2,
1.2 Hz, 2H), 2.14 (d, J¼1.2 Hz, 3H), 1.53e1.26 (m, 12H), 1.22
(t, J¼7.2 Hz, 3H), 0.88 (t, J¼6.8 Hz, 3H); 13C NMR (400 MHz, acetone-
d6)
d 167.8 (C), 161.7 (C), 117.2 (CH), 60.7 (CH2), 42.3 (CH2), 33.6
(CH2), 31.1 (CH2), 30.9 (CH2), 30.9 (CH2), 29.2 (CH2), 24.3 (CH2), 19.6
(CH3), 15.6 (CH3), 15.3 (CH3); IR (neat) 1637 cmꢁ1; MS 226.2 (Mþ);
HRMS calcd for C14H26O2 (Mþ) 226.1933, found 226.1904.
4.2.6. (2E)-Ethyl 8-(benzyloxy)-3-methyloct-2-enoate (16). Prepared
from ethyl (2E)-3-chloro-2-iodobut-2-enoate 118 (50 mg, 0.182mmol)
using a procedure similar to that described above that provided the
title compound after purification by flash chromatography (2% EtOAc
in hexane) as a colorless oil (39 mg, 73%).1H NMR (400 MHz, acetone-
4.2.2. (6Z)-8-Methoxy-8-oxooct-6-enyl benzoate (9). Prepared from
ethyl (2E)-3-chloro-2-iodoacrylate 818 (57 mg, 0.230 mmol) using
a procedure similar to that described above that provided the title
compound after purification by flash chromatography (2% EtOAc in
hexane) as a colorless oil (19.1 mg, 30%).1H NMR (400 MHz, acetone-
d6)
d
7.34e7.24 (m, 5H), 5.66 (q, J¼1.2 Hz, 1H), 4.48 (s, 2H), 4.09
(q, J¼7.2 Hz, 2H), 3.47 (t, J¼6.4 Hz, 2H), 2.18 (td, J¼7.6, 0.9 Hz, 2H), 2.14
(d, J¼1.2 Hz, 3H), 1.66e1.59 (m, 2H), 1.55e1.48 (m, 2H), 1.43e1.36 (m,
2H),1.22 (t, J¼7.2 Hz, 3H); 13C NMR (400 MHz, acetone-d6)
d 167.8 (C),
d6)
d
8.04e8.01 (m, 2H), 7.66e7.61 (m, 1H), 7.53e7.49 (m, 2H),
161.6 (C), 141.1 (C), 130.0 (CH), 129.2 (CH), 129.1 (CH), 117.3 (CH), 74.2
(CH2), 71.7 (CH2), 60.7 (CH2), 42.3 (CH2), 31.3 (CH2), 28.9 (CH2).
27.6 (CH2), 19.6 (CH3), 15.6 (CH3); IR (neat) 1634 cmꢁ1; MS 245.2
(MþꢁOCH2CH3); HRMS calcd for C16H21O2 (MþꢁOCH2CH3) 245.1536,
found 245.1574.
6.36e6.29 (dt, J¼11.2, 7.2 Hz, 1H), 5.79 (dt, J¼11.2, 1.6 Hz, 1H), 4.32
(t, J¼6.4 Hz, 2H), 3.65 (s, 3H), 2.70 (dq, J¼7.2, 2.0 Hz, 2H), 1.84e1.77
(m, 2H), 1.56e1.48 (m, 4H); 13C NMR (400 MHz, acetone-d6)
d
167.9 (C),167.8 (C),151.9 (CH),134.8 (CH),132.5 (C),131.1 (CH),130.4
(CH), 121.2 (CH), 66.4 (CH2), 52.1 (CH3), 30.3 (CH2), 30.0 (CH2), 29.9
(CH2), 27.2 (CH2); IR (neat) 1713, 1637 cmꢁ1; MS 245.1 (MþꢁOCH3);
HRMS calcd for C15H17O3 (MþꢁOCH3) 245.1178, found 245.1154.
4.2.7. (2E)-Ethyl 3-methyl-8-(triisopropylsilyloxy)oct-2-enoate (17).
Prepared from ethyl (2E)-3-chloro-2-iodobut-2-enoate 118 (50 mg,
0.182 mmol) using a procedure similar to that described above that
provided the title compound after purification by flash chroma-
tography (2% EtOAc in hexane) as a colorless oil (34 mg, 60% from
4.2.3. (6Z)-6-Cyclohexyl-8-ethoxy-8-oxoocto-6-enyl benzoate (11).
Prepared from ethyl (2E)-3-chloro-3-cyclohexyl-2-iodoacrylate
1018 (50 mg, 0.146 mmol) using a procedure similar tothat described
above that provided the title compound after purification by flash
chromatography (2% EtOAc in hexane) as a colorless oil (25 mg, 46%).
ethyl but-2-ynoate). 1H NMR (300 MHz, acetone-d6)
d 5.66
(s, 1H), 4.08 (q, J¼7.2 Hz, 2H), 3.74 (t, J¼6.0 Hz, 2H), 2.19 (t, J¼7.2 Hz,
2H), 2.14 (d, J¼1.2 Hz, 3H), 1.62e1.38 (m, 6H), 1.22 (t, J¼7.2 Hz, 3H),
1H NMR (400 MHz, acetone-d6)
d
8.04e8.02 (m, 2H), 7.66e7.61 (m,
1.09e1.06 (m, 21H); 13C NMR (400 MHz, acetone-d6)
d 167.8
1H), 7.53e7.49 (m, 2H), 5.59 (br, 1H), 4.33 (t, J¼6.4 Hz, 2H), 4.08
(C), 161.5 (C), 117.3 (CH), 64.9 (CH2), 60.7 (CH2), 42.3 (CH2), 34.5
(CH2), 28.9 (CH2), 27.2 (CH2), 19.6 (CH3), 19.4 (CH), 15.7 (CH3),
13.7 (CH3); IR (neat) 1645 cmꢁ1; MS 313.2 (MþꢁCH(CH3)2); HRMS
calcd for C17H33O3Si (Mþ) 313.2193, found 313.2181.
(q, J¼7.2 Hz, 2H), 3.68 (m, 1H), 2.22 (t, J¼6.4 Hz, 2H), 1.87e1.26 (m,
16H), 1.22 (t, J¼6.8 Hz, 3H); 13C NMR (400 MHz, acetone-d6)
d 169.7
(C), 167.7 (C), 167.6 (C), 134.8 (CH), 132.5 (C), 131.1 (CH), 130.4 (CH),
116.2 (CH), 66.4 (CH2), 60.8 (CH2), 42.3 (CH), 34.7 (CH2), 32.7 (CH2),
30.3 (CH2), 29.9 (CH2), 28.2 (CH2), 27.7 (CH2), 15.6 (CH3); IR (neat)
1717, 1633 cmꢁ1; MS 327.2 (MþꢁOCH2CH3); HRMS calcd for
C21H27O3 (MþꢁOCH2CH3) 327.1955, found 327.1933.
4.2.8. (5E)-7-Ethoxy-3,5-dimethyl-7-oxohept-5-enyl benzoate (18).
Prepared from ethyl (2E)-3-chloro-2-iodobut-2-enoate 118 (50 mg,
0.182 mmol) using a procedure similar to that described above that
provided the title compound after purification by flash chromatog-
raphy (2% EtOAc in hexane) as a colorless oil (42 mg, 76%). 1H NMR
4.2.4. (6E)-6-(2-Methoxy-2-oxoethylidene)undecyl benzoate (13).
Prepared from methyl (2E)-3-chloro-2-iodooct-2-enoate 1218
(53 mg, 0.168 mmol) using a procedure similar to that described
that provided the title compound after purification by flash
(400 MHz, acetone-d6)
d 8.05e8.02 (m, 2H), 7.66e7.61 (m, 1H),
7.54e7.49 (m, 2H), 5.70 (q, J¼1.2 Hz, 1H), 4.44e4.34 (m, 2H), 4.09 (q,
J¼7.2 Hz, 2H), 2.32e2.28 (m, 1H), 2.15 (d, J¼1.2 Hz, 3H), 2.09 (dd,

T. Rajagopal et al. / Tetrahedron 66 (2010) 8739e8744
8743
J¼1.2, 8.0 Hz, 1H), 1.87e1.79 (m, 1H), 1.65e1.57 (m, 2H), 1.22 (t,
J¼7.2 Hz, 3H), 0.97 (d, J¼6.4 Hz, 3H); 13C NMR (400 MHz, acetone-d6)
a Teflon-coated stir bar was added ethyl 7-(triisopropylsilyloxy)
hept-2-ynoate (1.05 g, 3.22 mmol) in 32 mL ClCH2CH2Cl followed by
BU4NI (3.6 g, 9.67 mmol). The solution was refluxed for 72 h.
When the reaction was judged to be complete by TLC, the solution
was cooled and washed twice with 10% aqueous NaHSO3, saturated
sodium bicarbonate, and brine. The organic phase was then dried
over MgSO4 and concentrated in vacuo. The crude oil was purified
by flash chromatography (1% Et2O in hexanes) to afford the title
compound as a clear oil (0.7 g, 43%). 1H NMR (300 MHz, CDCl3)
d
167.7 (C), 167.6 (C), 160.0 (C), 134.8 (CH), 132.4 (C), 131.1 (CH), 130.4
(CH), 118.9 (CH), 64.6 (CH2), 60.8 (CH2), 49.9 (CH2), 37.1 (CH2), 29.8
(CH), 20.7 (CH3), 19.5 (CH3), 15.6 (CH3); IR (neat) 1645 cmꢁ1; MS
259.1 (MþꢁOCH2CH3); HRMS calcd for C16H19O3 (MþꢁOCH2CH3)
259.1329, found 259.1359.
4.2.9. (6E)-7-Deutero-8-ethoxy-6-methyl-8-oxoocto-6-enyl benzoate
(20). Prepared from ethyl (2E)-3-chloro-2-iodobut-2-enoate 118
d
4.28 (q, J¼6.9 Hz, 2H), 3.72 (t, J¼6.3 Hz, 2H), 2.72 (t, J¼7.2 Hz,
2H), 1.76e1.57 (m, 4H), 1.33 (t, J¼7.2 Hz, 2H), 1.07e1.03 (m, 21H);
13C NMR (400 MHz, CDCl3)
165.0 (C), 138.9 (C), 80.3 (C), 62.8
(50 mg, 0.182 mmol) and D2O (10 mL, 0.546 mmol) using a pro-
cedure similar to that described above that provided the title com-
pound after purification by flash chromatography (2% EtOAc in
hexane)asacolorlessoil.1HNMR(400MHz,acetone-d6)(H/D:1:0.67)
d
(CH2), 62.4 (CH2), 41.4 (CH2), 31.8 (CH2), 23.3 (CH2), 18.1 (CH3), 13.9
(CH3), 12.0 (CH3); IR (neat) 1732 cmꢁ1; MS 445.0 (MþꢁCH(CH3)2);
HRMS calcd for C15H27ClIO3Si (MþꢁCH(CH3)2) 445.0457, found
445.0483.
d
8.03e8.01 (m, 2H), 7.66e7.61 (m, 1H), 7.54e7.49 (m, 2H), 5.68 (q,
J¼1.2 Hz, 0.33H), 4.32 (t, J¼6.4 Hz, 2H), 4.08 (q, J¼7.2 Hz, 2H), 2.22 (td,
J¼1.2, 7.6 Hz, 2H), 2.15 (d, J¼1.2 Hz, 3H), 1.82 (p, J¼6.4 Hz, 2H),
1.64e1.47 (m, 4H),1.21 (t, J¼7.2 Hz, 3H); 13C NMR (400 MHz, acetone-
Acknowledgements
d6) d167.8(C),167.7(C),161.3(C),134.7(CH),132.4(C),131.1(CH),130.3
(CH), 117.3 (CH), 66.4 (CH2), 60.7 (CH2), 42.1 (CH2), 30.2 (CH2), 28.7
(CH2), 27.3 (CH2),19.5 (CH3),15.6 (CH3); IR (neat) 1713,1648 cmꢁ1; MS
305.2 (MþꢁOCH2CH3); HRMS calcd for C16H18DO3 (MþꢁOCH2CH3)
260.1391, found 260.1374.
We thank the Natural Science and Engineering Research
Council of Canada (NSERC), the Canadian Foundation for Innovation,
the Ontario Innovation Trust and the University of Ottawa for
generous funding.
4.2.10. (2E)-Ethyl 7-(benzyloxy)-2-iodo-3-methylhept-2-enoate (21).
Toanoven dried roundbottomflask (100 mL)equippedwitha Teflon-
coatedstirbarwere added CuI(0.37 g,1.93 mmol) and freshlydistilled
THF (15.0 mL), followed by freshly titrated MeLi (1.0 M solution in
Et2O; 3.84 mL, 3.84 mmol) under a nitrogen atmosphere. The reaction
mixture was cooled to ꢁ78 ꢀC. A solution of ethyl 7-(benzyloxy)hep-
2-ynoate (0.5 g, 1.92 mmol) in THF (5.0 mL) was introduced via can-
nula and the resulting mixture was stirred at the same temperature
for 1 h. Following the addition of I2 (1.46 g, 5.76 mmol), the reaction
mixture was cooled to 0 ꢀC and stirred for an additional 2 h. The re-
action was quenched with saturated NH4Cl, the mixture was extrac-
ted twice with Et2O, then dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The pure product (0.52 g, 68%) was obtained
after flash chromatography (2% Et2O in hexane). 1H NMR (300 MHz,
Supplementary data
Experimental procedures and product characterization data for
the E isomers. 1H and 13C spectra for all new compounds. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2010.09.002. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
References and notes
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CDCl3)
d
7.35e7.27 (m, 5H), 4.49 (s, 2H), 4.22 (q, J¼7.2 Hz, 2H), 3.47 (t,
2. (a) Iorga, B.; Eymery, F.; Mouriès, V.; Savignac, P. Tetrahedron 1998, 54,
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J¼6.0 Hz, 2H), 2.46 (t, J¼7.2 Hz, 2H), 2.04 (s, 3H), 1.64e1.57 (m, 4H),
1.30 (t, J¼7.2 Hz, 3H); 13C NMR (400 MHz, CDCl3)
d 165.7 (C),153.9 (C),
138.5(C),128.4(CH),127.6(CH),127.5(CH), 72.9 (CH2), 69.9(CH2), 61.8
(CH2), 36.3 (CH2), 29.4 (CH2), 29.1 (CH3), 24.9 (CH2), 14.0 (CH3); IR
(neat) 1709 cmꢁ1; MS 402.1 (Mþ); HRMS calcd for C17H23O3I (Mþ)
402.0692, found 402.0701.
4.2.11. (6E)-11-(Benzyloxy)-6-(ethoxycarbonyl)-7-methylundec-
6-enyl benzoate (22). Prepared from (2E)-ethyl 7-(benzyloxy)-
2-iodo-3-methylhept-2-enoate 21 (50 mg, 0.124 mmol) using
a procedure similar to that described above that provided the title
compound after purification by flash chromatography (2% EtOAc in
hexane) as a colorless oil (18.4 mg, 35%). 1H NMR (300 MHz, CDCl3)
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d
8.06e8.02 (m, 2H), 7.58e7.52 (m, 1H), 7.46e7.41 (m, 2H),
7.34e7.27 (m, 5H), 4.49 (s, 2H), 4.31 (t, J¼6.6 Hz, 2H), 4.16 (q,
J¼7.2 Hz, 2H), 3.47 (t, J¼6.3 Hz, 2H), 2.27 (t, J¼7.8 Hz, 4H), 1.77
(s, 3H),1.67e1.39 (m,10H),1.27 (t, J¼7.2 Hz, 3H); 13C NMR (400 MHz,
CDCl3) d 169.9 (C),166.6 (C),144.2 (C),138.6 (C),132.8 (CH),130.5 (C),
129.5 (CH), 128.4 (C), 128.3 (CH), 128.2 (CH), 127.6 (CH), 127.4 (CH),
72.9 (CH2), 70.3 (CH2), 64.9 (CH2), 59.9 (CH2), 36.2 (CH2), 29.9
(CH2), 29.7 (CH2), 28.6 (CH2), 28.5 (CH2), 25.9 (CH2), 25.0 (CH2), 19.2
(CH3), 14.3 (CH3); IR (neat) 1717, 1698 cmꢁ1
; MS 421.2
7. Simard-Mercier, J.; Jiang, J. L.; Ho, M. L.; Flynn, A. B.; Ogilvie, W. W. J. Org. Chem.
2008, 73, 5899e5906.
(MþꢁOCH2CH3); HRMS calcd for C27H33O4 (MþꢁOCH2CH3)
8. (a) Knights, E. F.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 5280e5281; (b) Brown,
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421.2373, found 421.2369.
4.2.12. (E)-Ethyl 3-chloro-2-iodo-7-(triisopropylsilyloxy)hept-2-enoate
(14). To an oven dried round bottom flask (100 mL) equipped with
10. Similar analyses were carried out for the other products described in this work.

8744
T. Rajagopal et al. / Tetrahedron 66 (2010) 8739e8744
11. Reactions using the bases listed in entries 4e10 in which no water was added
resulted in no reaction
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