Hydroacylation of 2-butyne from the alcohol or aldehyde oxidation level via ruthenium catalyzed C-C bond forming transfer hydrogenation

Article abstract of DOI:10.1016/j.tet.2009.03.068

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to alcohols 1a-1j to deliver α,β-unsaturated ketones 3a-3j in good to excellent isolated yields with complete E-stereoselectivity. Under identical conditions, aldehydes 2

Full text of DOI:10.1016/j.tet.2009.03.068

Tetrahedron 65 (2009) 5024–5029
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Tetrahedron
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Hydroacylation of 2-butyne from the alcohol or aldehyde oxidation level
via ruthenium catalyzed C–C bond forming transfer hydrogenation
*
Vanessa M. Williams, Joyce C. Leung, Ryan L. Patman, Michael J. Krische
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin, TX 78712, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to alcohols 1a–1j
Received 20 February 2009
Received in revised form 21 March 2009
Accepted 23 March 2009
Available online 1 April 2009
to deliver
selectivity. Under identical conditions, aldehydes 2a–2j couple to 2-butyne to provide an identical set of
-unsaturated ketones 3a–3j in good to excellent isolated yields with complete E-stereoselectivity.
Nonsymmetric alkyne 4a couples to alcohol 1d or aldehyde 2d in good yield to deliver enone 3k as a 5:1
mixture of regioisomers. Thus, intermolecular alkyne hydroacylation is achieved from the alcohol or
aldehyde oxidation level. In earlier studies employing the same ruthenium catalyst under slightly dif-
ferent conditions, alkynes were coupled to carbonyl partners from the alcohol or aldehyde oxidation
level to furnish allylic alcohols. Therefore, under the conditions of C–C bond forming transfer hydroge-
a,b-unsaturated ketones 3a–3j in good to excellent isolated yields with complete E-stereo-
a,b
nation, all oxidation levels of substrate (alcohol or aldehyde) and product (allylic alcohol or
saturated ketone) are accessible.
a,b-un-
Published by Elsevier Ltd.
1. Introduction
conceptually to hydrogen auto-transfer processes.12,13 Whereas
conventional hydrogen auto-transfer reactions provide products of
alcohol substitution by way of oxidation–condensation–reduction
mechanisms, alcohol–unsaturate couplings provide products of
carbonyl addition by way of hydrogen shuffling to generate nu-
cleophile–electrophile pairs. A unique feature of alcohol–un-
saturate C–C coupling resides in the ability to achieve formal C–H
functionalization at the carbinol carbon through introduction of
a nonstabilized carbanion equivalent (Scheme 1).
Whereas rhodium catalyzed intramolecular alkene hydro-
acylation using aldehydes as acyl donors is well developed,1 in-
termolecular variants typically suffer from competitive aldehyde
decarbonylation.2–7 Although exceptions exist for certain substrate
combinations,3,4 efficient intermolecular alkene hydroacylation
generally requires acyl donors that exploit
decarbonylation, such as
-unsaturated aldehydes,5a salicylalde-
hydes,5b–e -sulfido-aldehydes,5f,9c–e,g and (N-2-pyridyl)aldimines.5g
b-chelation to suppress
g,d
b
Remarkably, for the ruthenium catalyzed diene–alcohol and
diene–aldehyde transfer hydrogenative C–C couplings, conditions
were identified such that formation of either the homoallylic
While cobalt6 and ruthenium7 catalysts have been explored, rhodium
appears unique in its ability to promote intermolecular alkene
hydroacylation under mild conditions in a selective fashion, not-
withstanding the aforementioned limitations. Alkyne hydroacylation
is far less developed. To our knowledge, efficient and stereoselective
intermolecular alkyne hydroacylation is restricted to systems that
alcohol or b,g-unsaturated ketone is achieved from the alcohol or
aldehyde oxidation level, the latter process representing a formal
diene hydroacylation.11b The step-economy associated with the
ability to access alternate oxidation levels of starting material or
product compelled us to explore the generality of this concept in
the context of alkyne–carbonyl coupling.11e,14 Here, we report
that under the conditions of ruthenium catalyzed C–C bond
forming transfer hydrogenation,11,12 efficient intermolecular al-
kyne hydroacylation is achieved from either the alcohol or
aldehyde oxidation level with complete levels of E/Z-stereo-
exploit b
-chelation to suppress decarbonylation,9,10 and the first ef-
ficient intramolecular alkyne hydroacylations only recently were
disclosed by Fu and Tanaka.8
In prior work from our laboratory, ruthenium catalyzed diene–
alcohol and diene–aldehyde transfer hydrogenative C–C couplings
were developed.11a,b,12 The former process belongs to a broad new
subset of alcohol–unsaturate C–C couplings that are related
selectivity, and in the absence of
b-chelation assistance. As in
earlier studies conditions for ruthenium catalyzed alkyne–car-
bonyl coupling en route to products of carbonyl vinylation were
established,11e all oxidation levels of substrate (alcohol or alde-
hyde) and product (allylic alcohol or
accessible (Scheme 2).
a,b-unsaturated ketone) are
* Corresponding author. Tel.: þ1 512 232 5892; fax: þ1 512 471 8696.
E-mail address: mkrische@mail.utexas.edu (M.J. Krische).
0040-4020/$ – see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.03.068

V.M. Williams et al. / Tetrahedron 65 (2009) 5024–5029
Hydrogen Auto-Transfer Process
5025
Alcohol-Unsaturate C-C Coupling Process
OH
OH
R2
OH
R1
R1
EWG
R2
MLn
MLn
R1
EWG
EWG
R1
R2
R1
R2
Base, LnM
Base-H
LnM, Base
Base-H
Base, LnM
LnM
Base-H, LnM(H)2
LnM(H)2
LnM
EWG
R2
O
O
O
R1
MLn
R1
R2
R1
R2
R2
- H2O
Carbonyl Addition from the Alcohol Oxidation Level Employing
Unsaturates as Non-Stabilized Carbanion Equivalents
Carbonyl Condensation from the Alcohol Oxidation Level Employing
Conventional Stabilized Carbanionic Olefinating Agents
Scheme 1. Simplified schematic depictions of the catalytic mechanism of an alcohol–unsaturate C–C coupling reaction and a related hydrogen auto-transfer process.
O
O
RuHCl(CO)(PPh3)3 (5 mol %)
(p-MeOPh)3P (15 mol %)
or rac-BINAP (5 mol %)
OH
R1 OH
R2
Ru(O2CCF3 )2(CO)(PPh3)2
(5 mol%)
R1
Me
R2
or
R
Me
R
or
Me
THF (0.2 M), 95 °C, 13 Hr
m-NO2BzOH (2.5 mol %)
Acetone (2.5 mol %)
THF, 95 °C
Me
Me
OH
OH
R2
For Aldehydes
HCO2H (100 mol%)
Allylic Alcohols
Branched Alcohols
R
(JACS 2009, 131, 2006)
(JACS 2008, 6338)
For Aldehydes
HCO2H (200 mol%)
All Oxidation Levels of Substrate
and Product are Accessible
O
O
RuH2(CO)(PPh3)3 (5 mol %)
CF3CO2H (5 mol %)
R1
O
O
Ru(O2CCF3 )2(CO)(PPh3)2
(5 mol%)
R1
Me
R
R2
or
R2
Me
R
or
Me
THF (2 M), 110 °C, 30 Hr
PhMe (2-4 M)
110 °C
Me
Me
β,γ-Enones
OH
OH
R2
For Aldehydes
i-PrOH (100 mol%)
α,β-Enones
R
(This Work)
(JACS 2008, 14120)
Scheme 2. Transcending the boundaries of oxidation level through C–C bond forming transfer hydrogenation.
2. Results and discussion
conjugated enones could be achieved simply by conducting the
reaction at higher temperature and longer reaction times. Higher
reaction concentration also should promote oxidation of the ini-
tially formed allylic alcohol by facilitating formation of the allylic
In previously disclosed alkyne–carbonyl couplings employing
Ru(O2CCF3)2(CO)(PPh3)2 as precatalyst,11e small quantities of
a,b-
unsaturated ketone accompanied formation of the desired allylic
alcohols. Hence, it was postulated that efficient formation of
Table 2
Hydroacylation of 2-butyne from the aldehyde oxidation levela
Table 1
O
O
Ru(O2CCF3 )2(CO)(PPh3)2
(5 mol%)
Hydroacylation of 2-butyne from the alcohol oxidation levela
Me
Me
R
R
O
HO
Me
(150 mol %)
Entry
Ru(O2CCF3 )2(CO)(PPh3)2
(5 mol%)
Me
i-PrOH (100 mol%)
THF (2 M), 110 °C
30 Hr
Me
3a-3j
2a-2j
Me
R
R
Me
(150 mol %)
Entry
(100 mol %)
THF (2 M), 110 °C
30 Hr
Me
3a-3j
1a-1j
(100 mol %)
Alcohol
Product
R group
Yield
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-NO2Ph
Ph
m-MeOPh
p-BrPh
p-(MeO2C)Ph
3,5-Me2Ph
p-CF3Ph
CH2Ph
85%
Alcohol
Product
R group
Yield
85%d
74%d
84%
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-NO2Ph
Ph
m-MeOPh
p-BrPh
p-(MeO2C)Ph
3,5-Me2Ph
p-CF3Ph
88%
79%
71%b
90%
91%
80%
82%
81%
70%
99%c
76%c
80%d
80%b
81%d,e
69%
n-C6H17
CH2Ph
n-C6H17
2j
3j
(CH2)2NPhtl
66%b
a
In all cases, cited yields are of isolated material. See Supplementary data for
1j
3j
(CH2)2NPhtl
detailed experimental procedures.
a
b
In all cases, cited yields are of isolated material. See Supplementary data for
The reaction was conducted at 130 ꢀC.
c
detailed experimental procedures.
The reaction was conducted for 40 h.
The reaction was conducted using 2-MeTHF as solvent.
The reaction was conducted using 10 mol % Ru(O2CCF3)2(CO)(PPh3)2.
b
d
The reaction was conducted at 130 ꢀC.
The reaction was conducted for 40 h.
c
e

5026
V.M. Williams et al. / Tetrahedron 65 (2009) 5024–5029
Ru(O2CCF3 )2(CO)(PPh3)2
(5 mol%)
OH
O
Me
Me
Me
Me
OBn
OBn
THF (2 M), 110 °C
30 Hr
Br
Br
Br
OBn
4a
1d
(100 mol%)
(150 mol%)
3k, 70% Yield
5:1 rr
Ru(O2CCF3 )2(CO)(PPh3)2
(5 mol%)
O
O
i-PrOH (100 mol%)
THF (2 M), 110 °C
30 Hr
Br
OBn
4a
2d
(150 mol%)
(100 mol%)
3k, 65% Yield
5:1 rr
Scheme 3. Regioselective hydroacylation of nonsymmetric alkyne 4a from the alcohol or aldehyde oxidation level.
ruthenium alkoxide, which upon
b
-hydride elimination generates
hydroaminoalkylation),15 may be viewed as carbonyl or imine ad-
ditions from the alcohol or amine oxidation levels, respectively.
These transformations, in which a redistribution of hydrogen
accompanies covalent bond formation, may be viewed as hydro-
gen-auto-transfer processes.13 The ability to circumvent reductive
preactivation of nucleophiles (discrete carbanion generation) and
oxidative preactivation of electrophiles (discrete alcohol oxidation)
is inherently step-economic, redox-economic and defines a de-
parture from the use of preformed organometallic reagents in
carbonyl and imine addition chemistry.
the enone. This hypothesis was borne out experimentally in the
coupling of 2-butyne to p-nitrobenzyl alcohol 1a. By extending
reaction time from 13 h to 30 h, modestly raising the temperature
from 95 ꢀC to 110 ꢀC and increasing concentration from 0.2 M to
2.0 M, the a,b-unsaturated ketone 3a was formed in 88% isolated
yield to the exclusion of the allylic alcohol (Table 1, entry 1).
To explore the scope of this process, 2-butyne was coupled to
benzylic alcohols 1a–1g. In each case, good to excellent isolated
yields of enones 3a–3g were obtained. As demonstrated by the
formation of 3h–3j, aliphatic alcohols also participate in the cou-
pling. For all coupling products 3a–3j, the enone moiety appears as
a single geometrical isomer (>95:5, E/Z selectivity). For the corre-
sponding aldehyde couplings, isopropanol, a hydride donor, is re-
quired to initiate the purported hydrometallative mechanism.
Although, in principle, only substoichiometric quantities of iso-
propanol are required to initiate the catalytic cycle, slightly better
isolated yields were obtained using 1 equiv of isopropanol. Notably,
an identical set of enone products 3a–3j were formed as single
geometrical isomers (>95:5, E/Z selectivity) from the aldehydes
2a–2j (Table 2). Thus, ruthenium catalyzed hydroacylation of 2-
butyne is achieved with equal facility from the alcohol or aldehyde
oxidation level.
Preliminary studies on the hydroacylation of nonsymmetric al-
kynes reveal promising levels of regioselectivity in certain cases.
For example, the coupling of nonsymmetric alkyne 4a to alcohol 1d
occurs in good isolated yield to deliver enone 3k as a 5:1 mixture of
regioisomers and as a single geometrical isomer (>95:5, E/Z se-
lectivity). Similarly, the coupling of nonsymmetric alkyne 4a to
aldehyde 2d provides enone 3k in comparable isolated yield and as
a single geometrical isomer (>95:5, E/Z selectivity) (Scheme 3).
4. Experimental section
4.1. General
All reactions were run under an atmosphere of argon, unless
otherwise indicated. Anhydrous solvents were transferred via oven-
dried syringe. Reaction tubes were oven-dried and cooled under
a stream of argon. Reaction tubes were purchased from Fisher Sci-
entific (catalog number 14-959-35C). Tetrahydrofuran was purified
using the Pure-Solv MD-5 Solvent Purification System (Innovative
Technology, inc). 2-Methyl tetrahydrofuran was purified by distilla-
tion from calcium hydride and was stored over molecular sieves.
Ru(O2CCF3)2(CO)(PPh3)2 was prepared in accordance with lit-
erature procedure.16 Anhydrous isopropanol (99.5% over molecular
sieves) was purchased from Acros and used as received. Commer-
cially available alcohols and alkynes were used as received. Alkyne
4a was prepared according to literature procedure.17 Commercially
available aldehydes were purified via distillation or re-
crystallization prior to use.
Analytical thin-layer chromatography (TLC) was carried out
using 0.2-mm commercial silica gel plates (DC-Fertigplatten Kie-
selgel 60 F254) and products were visualized by UV, KMnO4, vanillin
and/or anisaldehyde stain. Preparative column chromatography
employing silica gel was performed according to the method of
Still.18 Solvents for chromatographic separation are listed as vol-
ume/volume ratios. Infrared spectra were recorded on a Perkin–
Elmer 1600 spectrometer. High-resolution mass spectra (HRMS)
were obtained on a Karatos MS9 and are reported as m/z (relative
intensity). Accurate masses are reported for the molecular ion
[MþH]þ or a suitable fragment ion. Proton nuclear magnetic reso-
nance (1H NMR) spectra were recorded with a Varian Gemini
(400 MHz or 300 MHz) spectrometer. Chemical shifts are reported
3. Conclusion
In summary, we report a protocol for alkyne hydroacylation
under the conditions of ruthenium catalyzed transfer hydrogena-
tion.11,12 Unlike the prototypical rhodium catalyzed alkyne hydro-
acylations,9 efficient intermolecular coupling is observed in the
absence chelation assistance. Furthermore, through C–C bond
forming transfer hydrogenation, enone formation is achieved from
the alcohol or aldehyde oxidation level. In earlier studies employing
the same ruthenium catalyst under less forcing conditions, alkynes
were coupled to carbonyl partners from the alcohol or aldehyde
oxidation level to furnish allylic alcohols. Thus, all oxidation levels
of substrate (alcohol or aldehyde) and product (allylic alcohol or
in delta (d) units, parts per million (ppm) downfield from trime-
thylsilane. Coupling constants are reported in hertz (Hz). Carbon-13
nuclear magnetic resonance (13C NMR) spectra were recorded with
a Varian Gemini 300 (75 MHz) or 400 (100 MHz) spectrometer.
a
,b
-unsaturated ketone) are accessible.
The alcohol–unsaturate C–C couplings developed in our labo-
ratory, as well as related amine–unsaturate C–C couplings (termed
Chemical shifts are reported in delta (d) units, parts per million

V.M. Williams et al. / Tetrahedron 65 (2009) 5024–5029
5027
relative to the center of the triplet at 77.0 ppm for deuterio-
chloroform. 13C NMR spectra were routinely run with broadband
decoupling.
(d, J¼8.3 Hz, 2H), 7.49 (dt, J¼8.3, 1.2 Hz, 1H), 7.40 (dt, J¼8.3, 1.2 Hz,
2H), 6.40 (q, J¼6.8 Hz, 1H), 1.97 (s, 3H), 1.88 (d, J¼6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3):
d 198.9, 141.5, 138.8, 137.6, 131.2, 129.1,
127.9, 14.7, 12.1. FTIR (neat): 3057, 2919, 2847, 1628, 1268, 1023, 970,
698 cmꢁ1. HRMS (CI): calcd for C11H13O [MþH]þ: 161.0965, found:
161.0966.
4.1.1. General procedure A for the coupling of 2-butyne to alcohols
To a pressure tube equipped with magnetic stir bar was added
Ru(O2CCF3)2(CO)(PPh3)2 (13.2 mg, 0.015 mmol, 5 mol %). At this
stage, solid alcohol substrates (0.300 mmol,100 mol %) were added.
The tube was then sealed with a rubber septum, purged with argon
and THF (1.5 mL, 0.2 M concentration with respect to the alcohol)
was added. At this stage, liquid alcohol coupling partners
(0.300 mmol, 100 mol %) were added. The reaction vessel was
4.1.5. Synthesis of (E)-2-methyl-1-(3-methoxyphenyl)but-2-en-1-
one (3c)
Procedure A was employed using alcohol 1c. After heating the
reaction at 130 ꢀC for 30 h the mixture was concentrated in vacuo
and purified by flash column chromatography (SiO2, 5:95 ethyl
acetate/hexanes) to furnish the title compound (55 mg) as a clear
oil in 71% yield. Procedure B was employed using aldehyde 2c. In
a modification to procedure B, 2-methyltetrahydrofuran was used
as solvent. After heating the reaction at 110 ꢀC for 30 h the mixture
was concentrated in vacuo and purified by flash column chroma-
tography (SiO2, 5:95 ethyl acetate/hexanes) to furnish the title
compound (55 mg) as a clear oil in 74% yield. 1H NMR (400 MHz,
cooled to ꢁ78 ꢀC. 2-Butyne (35
mL, 0.450 mmol, 150 mol %) was
added and the rubber septum was quickly replaced with a screw
cap. The reaction vessel was allowed to reach room temperature
and the reaction mixture was heated to the specified temperature
and for the indicated time. The reaction mixture was concentrated
in vacuo and purified by flash column chromatography (SiO2) under
the conditions noted to furnish the a,b-unsaturated ketone.
CDCl3):
d
7.33–7.27 (m, 1H), 7.18–7.14 (m, 2H), 7.03 (ddd, J¼8.4, 2.6,
4.1.2. General procedure B for the coupling of 2-butyne to aldehydes
To a pressure tube equipped with magnetic stir bar was added
Ru(O2CCF3)2(CO)(PPh3)2 (13.2 mg, 0.015 mmol, 5 mol %). At this
stage, solid aldehyde substrates (0.300 mmol, 100 mol %) were
added. The tube was then sealed with a rubber septum, purged
with argon and THF (1.5 mL, 0.2 M concentration with respect to
0.8 Hz, 1H), 6.43 (q, J¼6.8 Hz, 1H), 3.83 (s, 3H), 1.96 (s, 3H), 1.87 (d,
J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 198.6, 159.2, 141.5,
140.1, 137.5, 128.9, 121.7, 117.3, 113.9, 55.3, 14.7, 12.1. FTIR (neat):
3003, 2941, 2839, 1642, 1584, 1272, 1241, 1027, 724 cmꢁ1. HRMS
(CI): calcd for C12H15O2 [MþH]þ: 191.1072, found: 191.1074.
the aldehyde) and 2-propanol (36
added. At this stage, liquid aldehyde coupling partners
(0.300 mmol, 100 mol %) were added. The reaction vessel was
m
L, 0.300, 100 mol %) were
4.1.6. Synthesis of (E)-2-Methyl-1-(4-bromophenyl)but-2-en-
1-one (3d)
Procedure A was employed using alcohol 1d. After heating the
reaction at 110 ꢀC for 30 h the mixture was concentrated in vacuo
and purified by flash column chromatography (SiO2, 5:95 ethyl
acetate/hexanes) to furnish the title compound (64 mg) as a pale
yellow oil in 90% yield. Procedure B was employed using aldehyde
2d. After heating the reaction at 110 ꢀC for 30 h the mixture was
concentrated in vacuo and purified by flash column chromatogra-
phy (SiO2, 5:95 ethyl acetate/hexanes) to furnish the title com-
pound (60 mg) as a pale yellow oil in 84% yield. 1H NMR (400 MHz,
cooled to ꢁ78 ꢀC. 2-Butyne (35
mL, 0.450 mmol, 150 mol %) was
added and the rubber septum was quickly replaced with a screw
cap. The reaction vessel was allowed to reach room temperature
and the reaction mixture was heated to the specified temperature
and for the indicated time. The reaction mixture was concentrated
in vacuo and purified by flash column chromatography (SiO2) under
the conditions noted to furnish the a,b-unsaturated ketone.
4.1.3. Synthesis of (E)-2-methyl-1-(4-nitrophenyl)but-2-en-
1-one (3a)
CDCl3):
d
7.55 (dd, J¼8.5, 2.1 Hz, 2H), 7.49 (dd, J¼8.5, 2.1 Hz, 2H),
6.38 (q, J¼6.8 Hz, 1H), 1.96 (s, 3H), 1.88 (d, J¼6.8 Hz, 3H). 13C NMR
Procedure A was employed using alcohol 1a. After heating the
reaction at 110 ꢀC for 30 h the mixture was concentrated in vacuo
and purified by flash column chromatography (SiO2, 1:9 ethyl
acetate/hexanes) to furnish the title compound (54 mg) as a light
brown oil in 88% yield. Procedure B was employed using aldehyde
2a. After heating the reaction at 110 ꢀC for 30 h the mixture was
concentrated in vacuo and purified by flash column chromatogra-
phy (SiO2, 1:9 ethyl acetate/hexanes) to furnish the title compound
(52.5 mg) as a light brown oil in 85% yield. 1H NMR (400 MHz,
(100 MHz, CDCl3): d 197.5, 141.6, 137.4 (two carbons), 131.2, 130.7,
125.9, 14.7, 12.0. FTIR (neat): 3057, 2919, 2847, 1628, 1575, 1392,
1067, 1005, 1277, 832, 738 cmꢁ1. HRMS (CI): calcd for C11H12BrO
[MþH]þ: 239.0066, found: 239.0066.
4.1.7. Synthesis of (E)-methyl 4-(2-methylbut-2-enoyl)-
benzoate (3e)
Procedure A was employed using alcohol 1e. After heating the
reaction at 110 ꢀC for 30 h the mixture was concentrated in vacuo and
purified by flash column chromatography (SiO2, 0:100 to 5:95 ethyl
acetate/hexanes) to furnish the title compound (59.4 mg) as a color-
less crystalline solid in 91% yield. Procedure B was employed using
aldehyde 2e. After heating the reaction at 110 ꢀC for 40 h the mixture
was concentrated in vacuo and purified by flash column chroma-
tography (SiO2, 0:100 to 5:95 ethyl acetate/hexanes) to furnish the
title compound (49.5 mg) as a colorless crystalline solid in 76% yield.
CDCl3):
d
8.27 (d, J¼8.7 Hz, 2H), 7.72 (d, J¼8.7 Hz, 2H), 6.41 (q,
J¼6.8 Hz,1H),1.99 (s, 3H), 1.93 (d, J¼6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 196.7, 149.0, 144.6, 144.2, 137.7, 129.7, 123.2, 15.0, 11.7. FTIR
(neat): 3022, 1709, 1650, 1524, 1347, 1278, 1104, 748, 715, 667 cmꢁ1
.
HRMS (CI): calcd for C11H12NO3 [MþH]þ: 208.0809, found:
208.0811.
4.1.4. Synthesis of (E)-2-methyl-1-phenylbut-2-en-1-one (3b)
Procedure A was employed using alcohol 1b. After heating the
reaction at 110 ꢀC for 30 h the mixture was concentrated in vacuo
and purified by flash column chromatography (SiO2, 5:95 ether/
pentane) to furnish the title compound (39 mg) as a clear oil in 79%
yield. Procedure B was employed using aldehyde 2b. In a modifi-
cation to procedure B, 2-methyltetrahydrofuran was used as sol-
vent. After heating the reaction at 110 ꢀC for 30 h the mixture was
concentrated in vacuo and purified by flash column chromatogra-
phy (SiO2, 5:95 ether/pentane) to furnish the title compound
1H NMR (400 MHz, CDCl3):
2H), 6.41 (q, J¼7.3 Hz, 1H), 3.95 (s, 3H), 1.97 (s, 3H), 1.90 (d, J¼7.3 Hz,
3H). 13C NMR (100 MHz, CDCl3):
198.0, 166.3, 143.0, 142.8, 137.6,
132.0,129.2,128.8, 52.3,14.9,11.8. FTIR (neat): 2952,1722,1647,1435,
1404, 1271, 1178, 1106, 720 cmꢁ1. HRMS (CI): calcd for C13H15O3
[MþH]þ: 219.1021, found: 219.1024.
d
8.08 (d, J¼8.5 Hz, 2H), 7.63 (d, J¼8.5 Hz,
d
4.1.8. Synthesis of (E)-2-methyl-1-(3,5-dimethylphenyl)but-2-en-1-
one (3f)
Procedure A was employed using alcohol 1f. After heating the
reaction at 110 ꢀC for 30 h the mixture was concentrated in vacuo
(41 mg) as a clear oil in 85% yield. 1H NMR (400 MHz, CDCl3):
d 7.60

5028
V.M. Williams et al. / Tetrahedron 65 (2009) 5024–5029
and purified by flash column chromatography (SiO2, 5:95 ether/
pentane) to furnish the title compound (57 mg) as a pale yellow oil
in 80% yield. Procedure B was employed using aldehyde 2f. In
a modification to procedure B, 2-methyltetrahydrofuran was used
as solvent. After heating the reaction at 110 ꢀC for 30 h the mixture
was concentrated in vacuo and purified by flash column chroma-
tography (SiO2, 5:95 ether/pentane) to furnish the title compound
(57 mg) as a pale yellow oil in 80% yield. 1H NMR (400 MHz, CDCl3):
4.1.12. Synthesis of (E)-2-(4-methyl-3-oxohex-4-enyl)-isoindole-
1,3-dione (3j)
Procedure A was employed using alcohol 1j. After heating the
reaction at 110 ꢀC for 40 h the mixture was concentrated in vacuo
and purified by flash column chromatography (SiO2, 1:9 ethyl ac-
etate/hexanes) to furnish the title compound (76.8 mg) as a color-
less crystalline solid in 99% yield. Procedure B was employed using
aldehyde 2j. After heating the reaction at 130 ꢀC for 30 h the mix-
ture was concentrated in vacuo and purified by flash column
chromatography (SiO2, 1:9 ethyl acetate/hexanes) to furnish the
title compound (51.2 mg) as a colorless crystalline solid in 66%
d
7.20 (s, 2H), 7.12 (s, 1H), 6.39 (q, J¼6.8 Hz, 1H), 3.41 (s, 6H), 1.95 (s,
3H),1.87 (d, J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 199.2,141.1,
138.9, 137.7, 137.5, 132.7, 126.9, 21.2, 14.7, 12.1. FTIR (neat): 3043,
2914, 2856, 1646, 1596, 1303, 1232, 1152, 738 cmꢁ1. HRMS (CI):
calcd for C13H17O [MþH]þ: 188.1279, found: 188.1281.
yield. 1H NMR (400 MHz, CDCl3):
d
7.84 (dd, J¼5.5, 3.1 Hz, 2H), 7.72
(dd, J¼5.5, 3.1 Hz, 2H), 6.74 (q, J¼6.8 Hz, 1H), 4.00 (t, J¼7.5 Hz, 2H),
3.10 (t, J¼7.5 Hz, 2H), 1.84 (d, J¼6.8 Hz, 3H), 1.77 (s, 3H). 13C NMR
4.1.9. Synthesis of (E)-2-methyl-1-(4-trifluoromethyl)phenyl)but-2-
en-1-one (3g)
(100 MHz, CDCl3): d 198.6,168.1,138.1,133.9,132.0,123.2, 35.4, 34.0,
14.8, 10.8 (only 10 signals were observed). FTIR (neat): 2927, 1772,
1709, 1663, 1439, 1392, 1365, 998, 910, 717 cmꢁ1. HRMS (CI): calcd
for C15H16NO3 [MþH]þ: 258.1130, found: 258.1130.
Procedure A was employed using alcohol 1g. After heating the
reaction at 110 ꢀC for 30 h the mixture was concentrated in vacuo
and purified by flash column chromatography (SiO2, 5:95 ethyl
acetate/hexanes) to furnish the title compound (69 mg) as a color-
less oil in 82% yield. Procedure B was employed using aldehyde 2g.
After heating the reaction at 130 ꢀC for 30 h the mixture was con-
centrated in vacuo and purified by flash column chromatography
(SiO2, 5:95 ethyl acetate/hexanes) to furnish the title compound
(55 mg) as a colorless oil in 80% yield. 1H NMR (400 MHz, CDCl3):
4.1.13. Synthesis of (E)-2-(2-benzyloxy)ethyl-1-(4-bromophenyl)-
but-2-en-1-one (3k)
In a modification to procedures A and B, alkyne 4a was used in
place of 2-butyne. Procedure A was employed using alcohol 1d.
After heating the reaction at 110 ꢀC for 30 h the mixture was con-
centrated in vacuo and purified by flash column chromatography
(SiO2, 1:9 ethyl acetate/hexanes) to furnish the title compound
(76 mg) as a colorless oil in 70% yield as a 5:1 mixture of
regioisomers. Procedure B was employed using aldehyde 2d. After
heating the reaction at 110 ꢀC for 30 h the mixture was concen-
trated in vacuo and purified by flash column chromatography (SiO2,
1:9 ethyl acetate/hexanes) to furnish the title compound (70 mg) as
a colorless oil in 65% yield as a 5:1 mixture of regioisomers. 1H NMR
d
7.68 (s, 4H), 6.40 (q, J¼7.2 Hz, 1H), 1.98 (s, 3H), 1.91 (d, J¼7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3):
d
197.5, 143.2, 142.2, 137.7, 132.5,
129.2, 125.0, 122.3, 14.9, 11.8. FTIR (neat): 3057, 2932, 2852, 1646,
1321, 1277, 1140, 1125, 1063, 845, 694 cmꢁ1. HRMS (CI): calcd for
C12H11F3O [MþH]þ: 229.0840, found: 229.0838.
4.1.10. Synthesis of (E)-3-methyl-1-phenylpent-3-en-2-one (3h)
Procedure A was employed using alcohol 1h. After heating
the reaction at 110 ꢀC for 30 h the mixture was concentrated in
vacuo and purified by flash column chromatography (SiO2, 5:95
ether/pentane) to furnish the title compound (39 mg) as a pale
yellow oil in 81% yield. Procedure B was employed using alde-
hyde 2h. In a modification to procedure B, the reaction was
conducted in 2-methyltetrahydrofuran, with 10 mol % catalyst
loading. After heating the reaction at 110 ꢀC for 24 h the mixture
was concentrated in vacuo and purified by flash column chro-
matography (SiO2, 5:95 ether/pentane) to furnish the title
compound (39 mg) as a pale yellow oil in 81% yield. 1H NMR
(400 MHz, CDCl3):
d
7.54–7.25 (m, 9H), 6.37 (q, J¼6.9 Hz, 1H), 6.48
(s, 2H), 3.60 (t, J¼6.5 Hz, 2H), 2.82 (t, J¼6.5 Hz,1H),1.91 (d, J¼6.9 Hz,
3H). Characteristic signals for regioisomer: 7.81–7.60 (m, 2H), 5.9 (q,
J¼6.5 Hz, 2H), 4.37 (s, 2H), 3.5 (t, J¼6.5 Hz, 2H), 2.93 (t, J¼6.5 Hz,
2H), 1.48 (d, J¼6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 197.5,
138.9, 131.8, 131.2, 130.9, 129.5, 128.2, 127.5, 127.4, 72.8, 68.7, 38.4,
29.5, 27.0, 14.7. Characteristic signals for regioisomer: 198.4, 138.3,
137.5, 131.9, 131.5, 130.7, 128.3, 127.6, 126.2, 72.9, 70.1, 36.0, 29.6,
25.7, 15.8. FTIR (neat): 3020, 2857, 1647, 1585, 1482, 1294, 1285,
1098, 1070, 729, 697 cmꢁ1. HRMS (CI): calcd for C19H20OBr [MþH]þ:
359.0645, found: 359.0642.
(400 MHz, CDCl3):
d
7.36–7.18 (m, 5H), 6.87 (q, J¼6.8 Hz, 1H),
3.97 (s, 2H), 1.86 (d, J¼6.8 Hz, 3H), 1.78 (s, 3H). 13C NMR
Acknowledgements
(100 MHz, CDCl3):
d 199.1, 138.7, 137.9, 135.5, 129.2, 128.5, 126.5,
44.1, 14.9, 11.1. FTIR (neat): 3030, 2919, 2852, 1655, 1490, 1277,
Acknowledgement is made to the Robert A. Welch Foundation,
the ACS-GCI Pharmaceutical Roundtable, the NIH-NIGMS (RO1-
GM069445) for partial support of this research, and the C. M. Share
graduate fellows program (R.L.P.).
1023, 1063, 720, 694 cmꢁ1
. HRMS (CI): calcd for C12H15O
[MþH]þ: 175.1123, found: 175.1124.
4.1.11. Synthesis of (E)-3-methyldodec-2-en-4-one (3i)
Procedure A was employed using alcohol 1i. After heating the
reaction at 110 ꢀC for 30 h the mixture was concentrated in vacuo
and purified by flash column chromatography (SiO2, 5:95 ether/
pentane) to furnish the title compound (44 mg) as a clear oil in 70%
yield. Procedure B was employed using aldehyde 2i. After heating
the reaction at 110 ꢀC for 30 h the mixture was concentrated in
vacuo and purified by flash column chromatography (SiO2, 5:95
ether/pentane) to furnish the title compound (43 mg) as a clear oil
Supplementary data
Supplementary data in association with this article can be found
in the online version at doi:10.1016/j.tet.2009.03.068.
References and notes
in 69% yield. 1H NMR (400 MHz, CDCl3):
d
6.73 (q, J¼6.8 Hz, 1H),
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197.1905, found: 197.1904.

V.M. Williams et al. / Tetrahedron 65 (2009) 5024–5029
5029
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