Introduction of Hindered Electrophiles via C-H Functionalization in a Palladium-Catalyzed Multicomponent Domino Reaction

Article abstract of DOI:10.1055/s-0034-1380198

A general method for the incorporation of secondary alkyl iodides in a palladium-catalyzed multicomponent domino reaction is reported. With the relatively inexpensive Pd(OAc)₂ as the catalyst and norbornene as a mediator, a variety of 1,2,3-trisubstituted aromatic compounds were synthesized. The reaction was shown to be scalable, producing excellent isolated yields on up to 5 mmol scale. Chiral alkyl iodides were also incorporated without any loss of stereochemical information. The developed method offers an expedient and mild C-H functionalization strategy for the synthesis of sterically congested aromatic compounds in a one-pot process.

Full text of DOI:10.1055/s-0034-1380198

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2446–2456
2446
special topic
Z. Qureshi et al.
Special Topic
Synthesis
Introduction of Hindered Electrophiles via C–H Functionalization
in a Palladium-Catalyzed Multicomponent Domino Reaction
Zafar Qureshi
R4
R2
R3
∗
Waldemar Schlundt
Mark Lautens*
complete transfer
of
R2
R3
∗
H
R4
stereochemical
information
I
I
Pd
Davenport Research Laboratories,
80 St. George St., Toronto, ON, M5S 3H6, Canada
mlautens@chem.utoronto.ca
R1
R1
27 examples
24–99% yield
Received: 23.02.2015
Accepted after revision: 14.03.2015
Published online: 13.04.2015
ortho functionalization
DOI: 10.1055/s-0034-1380198; Art ID: ss-2015-z0123-st
H
ipso functionalization
alkyl/aryl
Pd–norbornene
catalysis
R2
R1
I
Abstract A general method for the incorporation of secondary alkyl
iodides in a palladium-catalyzed multicomponent domino reaction is
reported. With the relatively inexpensive Pd(OAc)2 as the catalyst and
norbornene as a mediator, a variety of 1,2,3-trisubstituted aromatic
compounds were synthesized. The reaction was shown to be scalable,
producing excellent isolated yields on up to 5 mmol scale. Chiral alkyl
iodides were also incorporated without any loss of stereochemical in-
formation. The developed method offers an expedient and mild C–H
functionalization strategy for the synthesis of sterically congested aro-
matic compounds in a one-pot process.
R1
1,2,3-trisubstituted products
Scheme 1 General Catellani reaction scheme
During the course of our studies, we have published ac-
counts detailing the utility of this remarkable reaction,
most recently demonstrating its synthetic utility in the
complex natural product synthesis of (+)-linoxepin.3 Short-
ly after this publication, the group of Gu reported an ele-
gant synthesis of (±)-rhazinal by utilizing an ortho arylation
strategy of an iodinated pyrrole.4 These reports testify to
the reliability of the Catellani reaction to provide complex
molecular scaffolds in useful quantities while reducing the
number of synthetic steps, resulting in concise syntheses.
Despite these advances, technological limitations of the
method prevent further strategic applications. The vast ma-
jority of reports utilizing this type of reaction have been re-
stricted to simple primary alkyl halides. The few reports
that have utilized hindered alkyl halides suffer from low
conversions, harsh reaction conditions, and poor modulari-
ty. The first report of the incorporation of isopropyl iodide
in the Catellani reaction gave 31% conversion over three
days.5 In 2000, a more practical procedure was reported
that produced sterically hindered 2,6-diisopropyl biphenyl
in 71% yield after 144 hours.6 In 2007, our group utilized a
tethering strategy to improve the utilization of secondary
alkyl halides (Scheme 2). Good yields were obtained, but
the reaction required microwave irradiation with extreme
temperatures (150–180 °C).7,8 Moreover, the need for a
Key words multicomponent reaction, palladium, Catellani reaction,
domino reaction, C–H functionalization
In the recent past, there has been an ongoing drive to
develop directed C–H functionalization methods. Transition
metals such as palladium, rhodium, and ruthenium have
been shown to perform C–H functionalizations in a selec-
tive manner, provided that there is a suitable directing
group.1 However, these types of C–H activation strategies
are very sensitive to sterically congested systems. Few ex-
amples of 1,2,3-trisubstituted aromatic compounds have
been reported using these methods, the most common of
which has been the method developed by Catellani.2 Since
2000, our group has explored the power of this methodolo-
gy, which utilizes a palladium catalyst, to functionalize an
iodinated aromatic substrate at the ortho- and ipso-posi-
tions. The standard Catellani reaction involves an aryl io-
dide that is either alkylated or arylated ortho to the starting
iodide, and a catalytic cycle terminator, generally an olefin,
which undergoes a Mizoroki–Heck coupling (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

2447
Z. Qureshi et al.
Special Topic
Synthesis
tether limits the scope of the reaction because the starting
materials have to be prepared in a number of steps. Demon-
strations of a scalable intermolecular multicomponent re-
action with secondary halides remain scarce. To advance
this methodology, we looked for ways to improve the incor-
poration of hindered alkyl iodides. In an effort to maximize
modularity, our studies focused primarily on the reaction
conditions. In particular, we looked to decrease reaction
temperature. Lastly, we wanted to develop a method that
would be easily scalable.
Table 1 Reaction Optimizationa
CO2t-Bu
Pd source
ligand
2a
I
Cs2CO3
CO2t-Bu
I
OMe
3a
OMe
1a
4a
Entry
iPrI
(equiv)
Catalyst
(mol%)
Solvent
Time
(h)
Yield
(%)
first use of isopropyl iodide in the Catellani reaction:
1
2
3
4
5
6
7
8
9
10
10
10
10
5
10
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
4
6
92
72
52
–
I
I
CO2Me
2.5
1
16
24
6
Pd–norbornene
72 h
CO2Me
10
10
10
10
10
96
47
70
36
58
31% conv.
2.5
2.5
1
6
6
intramolecular variant:
I
MeCN
DMF
6
1
6
Z
a Reaction conditions: 2-iodoanisole (1 equiv), catalyst, PPh3 (22 mol%),
Cs2CO3 (5 equiv), tert-butyl acrylate (5 equiv), norbornene (5 equiv), sealed
tube, 90 °C, solvent (3 mL).
Pd–norbornene
160 °C (MW)
Y
Z
X
m
O
Y
m
n
O
n
up to 90%
Table 2 Heck Acceptor Screena
this work:
R2
R3
Pd(OAc)2 (10 mol%)
Ph3P (10 mol%)
Cs2CO3 (5 equiv)
R2
R3
I
I
I
R4
Pd–norbornene
i-PrI (10 equiv)
R
R4
R
OMe
R1
R1
OMe
(5 equiv)
1a
Entry
2
4
Scheme 2 Previous reported use of secondary alkyl halides
Compound
Heck acceptor
Olefin
(equiv)
Yield
(%)
We began our studies on the incorporation of secondary
alkyl halides with an excess (10 equiv) of isopropyl iodide.
Relatively inexpensive Pd(OAc)2 (10 mol%) with triphenyl
phosphine (22 mol%) as ligand/reducing agent9 was chosen
as the starting catalyst. The reaction has been well docu-
mented10 to require an excess of inorganic base and, as
such, anhydrous Cs2CO3 was selected and used in a 5-fold
excess to the starting ortho-substituted aryl iodide, 2-iodo-
anisole. Although norbornene is catalytic in the reaction,
five equivalents were used to ensure selectivity over tert-
butyl acrylate, which was used as the catalytic cycle termi-
nator in 5-fold excess. A polar aprotic solvent, anhydrous
and degassed acetonitrile, was used as solvent. The reaction
was set up in a sealed vial with a Teflon-coated cap in a pre-
heated (90 °C) oil bath. Gratifyingly, the reaction was com-
1
2
3
4
5
6
7
8
9
4a
4a
4a
4b
4c
4d
4e
4f
tert-butyl acrylate
tert-butyl acrylate
tert-butyl acrylate
methyl acrylate
ethyl acrylate
5
92
58
36
24
39
44
66
49
33
2.5
1
5
5
benzyl acrylate
hexyl acrylate
5
5
tert-butyl acrylamide
styrene
5
4g
5
a Reaction conditions: 2-iodoanisole (0.13 mL, 1 mmol), i-PrI (1ml, 10
mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), Ph3P (57.6 mg, 0.22 mmol),
Cs2CO3 (1.63 g, 5 mmol), norbornene (470 mg, 5 mmol), sealed tube,
90 °C, MeCN (3 mL).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

2448
Z. Qureshi et al.
Special Topic
Synthesis
plete within four hours and provided the 1,2,3-trisubstitut-
ed aromatic compound in an isolated yield of 92% (Table 1,
entry 1). Attempts to reduce the catalyst loading resulted in
a decrease in the yield, and the reaction required longer to
reach full conversion (entries 2–4). Reducing the number of
equivalents of isopropyl iodide to five equivalents gave a
similar yield (entry 5) but we observed a drop in yield
when less than five equivalents was used (entries 6–9). The
use of N,N-dimethylformamide (DMF) as solvent partially
offset this decrease (compare entries 6 and 7 to 8 and 9).
For our subsequent reactions, ten equivalents of iodide
were used, foreseeing difficulty with more hindered sub-
strates. With these results in hand, we screened a range of
olefins as the chain terminator.
that steric effects in the ester played a significant role in de-
termining the product yield. Our hypothesis is that, under
the reaction conditions, the less sterically hindered acry-
lates are hydrolyzed prior to the final Heck reaction, which
leads to lower overall yields (entries 4–7). Both tert-butyl
acrylamide and styrene were competent in the reaction, al-
though with decreased yield. To ensure we had developed a
reliable and scalable reaction, we repeated our conditions
on 5 mmol scale and were able to isolate the desired prod-
uct in 90% yield (Scheme 3). With the conditions optimized,
a range of alkyl halides were then tested.
Straight-chain alkyl iodides worked well in the reaction
(Scheme 3), with yields ranging from 42% for 3-octyl, to
near quantitative for 2-butyl. Cycloalkyl substituents could
also be incorporated (43%). Substrates with β-heteroatoms
were participants, giving good to excellent yields (48, 53,
and 99%). γ-Heteroatoms were also amenable in the reac-
Decreasing the number of equivalents of tert-butyl ac-
rylate resulted in a decrease in yield (Table 2, entries 1–3).
By varying the size of the ester it became readily apparent
Pd source
ligand
R1
R2
Cs2CO3
R1
R2
I
CO2t-Bu
CO2t-Bu
I
OMe
OMe
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
OMe
OMe
OMe
OMe
4a
92%a
4h
99%
4i
77%
4j
42%
OMe
PhO
TBSO
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
OMe
OMe
OMe
4n
OMe
4k
43%
4l
48%b
4m
53%
99%
TBSO
PhS
PhTsN
CO2t-Bu
CO2t-Bu
CO2t-Bu
OMe
OMe
OMe
4o
79%b
4p
80%b
4q
49%b
Scheme 3 Reagents and conditions: 2-iodoanisole (0.13 mL, 1 mmol), tert-butyl acrylate (0.72 mL, 5 mmol), alkyl iodide (10 mmol), Pd(OAc)2 (22.4
mg, 0.1 mmol), Ph3P (57.6 mg, 0.22 mmol), Cs2CO3 (1.63 g, 5 mmol), norbornene (470 mg, 5 mmol), sealed tube, 90 °C, MeCN (3mL). All alkyl iodides
used were either commercially available or prepared by reported methods. a Yield: 90% on 5 mmol scale. b Reaction carried out in DMF (3 mL).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

2449
Z. Qureshi et al.
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Synthesis
standard
conditions
in MeCN, 10 h
*
TBSO
O
TBSCl, imidazole
OH
I
OH
OTBS
then
O
Ph3P, I2 imidazole
OMe
95% ee
3m
48% (2 steps)
[α]D +9.5 (c 4.34, CHCl3)
4m
53%
20
standard conditions in DMF, 10 h
then TFA
TFA (10 equiv)
CH2Cl2, r.t. 1 h
*
*
HO
O
HO
O
OH
OH
OMe
OMe
5
5
99%
94% ee
65% (2 steps)
40% ee
Scheme 4 Catellani reaction with chiral alkyl iodide with β-heteroatom
tion, giving good yields for the oxygen-, sulfur-, and nitro-
gen-containing substrates. Although all of these reactions
required 10 equivalents of the alkyl iodide, the nonvolatile
iodides could be recovered through flash column chroma-
tography.
Our next goal was to probe the alkylation step. In a pre-
vious report, our group reported the use of chiral, tethered
alkyl iodides in which the alkylation step was shown to
proceed without loss of stereochemical information.7 To
build a synthetically useful methodology, we needed to de-
termine whether this was also the case in our intermolecu-
lar reaction. Enantioenriched propane diol, prepared in 95%
ee by using the method of Jacobsen, was silylated at the pri-
mary hydroxyl group (Scheme 4).11,12 The Appel reaction
was utilized to convert the secondary alcohol into iodide
3m.13 When this substrate was introduced into the reaction
with MeCN as solvent, the product was obtained in 53%
yield. Since 4m was inseparable by chiral HPLC, the TBS
group and the tert-butyl ester were cleaved by treatment
with trifluoroacetic acid (10 equiv). The resulting acid 5,
was found to have 94% ee. The excess iodide was recovered
with little erosion of the ee. In contrast, racemization was
1. LiAlH4
2. TBSCl
3. Ph3P, imidazole, I2
standard
conditions
in DMF, 5 h
*
TBSO
O
OH
I
CO2Me
O
OTBS
OMe
97% ee
3o
39% (3 steps)
[α]D +48.9 (c 1.70, CHCl3)
4o
79%
20
TBAF (1 equiv)
THF, 0 °C, 1 h
HO
O
O
OMe
6
82%
0% ee
Scheme 5 Catellani reaction with chiral alkyl iodide without β-heteroatom
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

2450
Z. Qureshi et al.
Special Topic
Synthesis
observed when the reaction was performed in DMF; the
product after deprotection had 40% ee. Moreover, the re-
covered iodide was almost completely racemized. Although
the alkyl iodide was shown to racemize in DMF, the product
was obtained in higher yield compared with that obtained
when the reaction was performed in MeCN (Scheme 4). To
determine the absolute stereochemistry of 5, both samples
(from MeCN and DMF) were subjected to crystallization
conditions. The sample with 94% ee failed to crystallize de-
spite numerous attempts. The sample with 40% ee pro-
duced crystals; however, the crystals obtained were race-
mic.14
We took a similar approach to obtain 4o (Scheme 5). En-
antioenriched iodide 3o, was synthesized starting from
commercial methyl (R)-3-hydroxybutyrate. Reduction with
LiAlH4,15 followed by protection of the primary hydroxyl
group under cryogenic conditions led to an intermediate al-
cohol, which was transformed into iodide 3o. Introducing
3o into the reaction mixture with MeCN as solvent pro-
duced trace amounts of 4o. In DMF, 4o was obtained in 79%
yield, but with 0% ee (ee determined for the free alcohol).
The excess starting material was also recovered as the race-
mate. Under these conditions, β-heteroatoms thus appear
to be essential for providing access to enriched products
(Scheme 5).
Finally, we looked at the influence of the aryl iodide.
Both electron-rich and electron-poor substrates gave good
yields (Scheme 6). Notably, when 2-iodophenyl acetate was
introduced into the reaction mixture, the product obtained
was not the acetylated phenol. Rather, the acetyl group was
cleaved in situ and the resultant phenoxide was converted
into the corresponding isopropyl ether, 4s. The incorpora-
tion of the chlorinated aromatic compound provides an ex-
tra handle for derivatization.16
In conclusion, we have developed a general procedure
with which to incorporate hindered secondary alkyl iodides
in the Catellani reaction in an intermolecular fashion. The
optimized procedure allows for the incorporation of various
Pd source
ligand
Cs2CO3
I
CO2t-Bu
R
CO2t-Bu
R
I
CO2t-Bu
CO2t-Bu
CO2t-Bu
O
OMOM
OiPr
X
4r
99%
4ta, X = H, 90%
4tb, X = OMe, 90%
4s
99%a
CO2t-Bu
CO2t-Bu
CO2t-Bu
MeO
OMe
4w
93%
4v
49%
4u
85%
CO2t-Bu
CO2t-Bu
CO2t-Bu
CF3
F
Cl
4x
62%
4y
62%
4z
44%
Scheme 6 Scope of the reaction with respect aryl iodide. Reagents and conditions: 2-iodoaromatic (1 mmol), tert-butyl acrylate (0.72 mL, 5 mmol), i-PrI
(1 mL, 10 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), Ph3P (57.6 mg, 0.22 mmol), Cs2CO3 (1.63 g, 5 mmol), norbornene (470 mg, 5 mmol), sealed tube,
90 °C, MeCN (3 mL). All aryl iodides used were either commercially available or prepared by reported methods. a 2-Iodophenyl acetate used as starting
material.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

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Z. Qureshi et al.
Special Topic
Synthesis
alkyl iodide electrophiles starting from a range of aryl io-
dides. The termination step was shown to be flexible, and a
range of olefins could be used. The multicomponent reac-
tion offers a highly modular approach for the synthesis of
sterically congested 1,2,3-trisubstituted aromatic com-
pounds. Excellent isolated yields were obtained on reaction
scales up to 5 mmol. Chiral products could also be pro-
duced from readily available starting materials, with com-
plete transfer of stereochemical information.
approximately 10 min. 2-Iodoanisole (0.65 mL, 5 mmol, 1 equiv), 2-
iodopropane (5 mL, 50 mmol, 10 equiv), and tert-butyl acrylate (3.6
mL, 25 mmol, 5 equiv) were added successively to the reaction mix-
ture by using a syringe. The mixture was stirred for 10 min, then solid
norbornene (2.35 g, 25 mmol, 5 equiv) was added. After a final argon
purge, the flask was capped and placed in an oil bath that had been
preheated to 90 °C. After 4 h, the mixture was cooled to r.t., filtered
over a pad of Celite (eluting with CH2Cl2), and concentrated in vacuo.
The crude oil was purified by flash column chromatography (CH2Cl2–
hexanes, 1:5, then again with Et2O–hexanes, 1:100→1:25) to obtain
the desired product (1.24 g, 4.5 mmol, 90%) as a clear oil.
tert-Butyl (E)-3-(2-Isopropyl-6-methoxyphenyl)acrylate (4a)
Yield: 254 mg (92%); clear oil.
TLC was performed with EMD TLC silica gel 60 F254 aluminum
sheets. Visualization was accomplished with 254 nm UV light fol-
lowed by staining with potassium permanganate or vanillin solution.
Flash and gradient column chromatography were carried out using
Silicycle Ultra-Pure 230–400 mesh silica gel. Melting points were
measured with a Fisher–Johns melting-point apparatus and are un-
corrected. IR spectra were obtained with a Perkin–Elmer Spectrum
1000 FTIR spectrophotometer as neat films or as solutions (CHCl3) on
a NaCl plate. Data are presented as frequency of absorption (cm–1). 1H
and 13C NMR spectra were recorded at 23 °C in CDCl3 with a Bruker
Avance 400 spectrometer, Varian Mercury 400 spectrometer, Varian
Unity 500 spectrometer, or Agilent DD2-600 spectrometer. Shifts for
protons are reported in parts per million (δ scale) and are referenced
to residual proton signals in the NMR solvent (CDCl3: δ = 7.26 ppm).
Chemical shifts for carbon resonances are reported in parts per mil-
lion (δ scale) and are referenced to the carbon resonances of the sol-
vent (CDCl3: δ = 77.16 ppm). Data are represented as follows: chemi-
IR (neat): 2965, 1722, 1623, 1595, 1572, 1470, 1456, 1447, 1436,
1391, 1367, 1311, 1263, 1061, 753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 16.15 Hz, 1 H), 7.27 (t,
J = 8.06 Hz, 1 H), 6.96 (d, J = 7.97 Hz, 1 H), 6.77 (d, J = 8.30 Hz, 1 H),
6.49 (d, J = 16.12 Hz, 1 H), 3.85 (s, 3 H), 3.37 (hept, J = 6.82 Hz, 1 H),
1.56 (s, 9 H), 1.25 (d, J = 6.85 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 167.30, 158.53, 149.86, 137.53,
129.93, 124.94, 121.78, 117.90, 108.31, 80.19, 55.54, 29.44, 28.36,
23.91.
HRMS (DART): m/z [M + H] calcd for C17H25O3: 277.18037; found:
277.18024.
Methyl (E)-3-(2-Isopropyl-6-methoxyphenyl)acrylate (4b)
Yield: 56 mg (24%); clear oil.
cal
shift,
multiplicity
(s = singlet,
d = doublet,
t = triplet,
IR (neat): 2960, 2927, 2869, 2358, 1733, 1717, 1595, 1572, 1471,
pent = pentet, m = multiplet), coupling constant (J, Hz) and integra-
tion. HPLC chromatograms were recorded with an Agilent 1100 series
instrument, controlled by ChemStation LC 3D software, v. 10.02.
High-resolution mass spectra were obtained with a SI2 Micromass
70S-250 mass spectrometer (EI) or an ABI/Sciex Qstar mass spec-
trometer (ESI).
1460, 1456, 1436, 1309, 1263, 1219, 1194, 1166, 1061, 1047, 772 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 16.2 Hz, 1 H), 7.29 (t,
J = 8.1 Hz, 1 H), 6.96 (dd, J = 7.8, 1.1 Hz, 1 H), 6.77 (d, J = 8.3 Hz, 1 H),
6.56 (d, J = 16.2 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 3.35 (hept,
J = 6.8 Hz, 1 H), 1.24 (d, J = 6.8 Hz, 7 H).
13C NMR (101 MHz, CDCl3): δ = 168.36, 158.62, 150.04, 138.97,
General Procedure
130.26, 122.91, 121.69, 118.01, 108.44, 55.64, 51.72, 29.55, 23.97.
Pd(OAc)2 (22.4 mg, 0.10 mmol, 0.1 equiv), Ph3P (57.6 mg, 0.22, 0.22
equiv), and Cs2CO3 (1.63 g, 5 mmol, 5 equiv) were added to a flame-
dried, sealable vial under argon. Dry, degassed MeCN or DMF (3 mL)
was added and the yellow mixture was stirred under argon for ap-
proximately 5 min. Aryl iodide (1.00 mmol, 1 equiv), alkyl iodide
(10.00 mmol, 10 equiv), and olefin (5.00 mmol, 5 equiv) were added
successively to the reaction mixture under argon. The mixture was
stirred for 5 min, then solid norbornene (470 mg, 5.00 mmol, 5 equiv)
was added. After a final argon purge, the vial was capped and placed
in an oil bath that had been preheated to 90 °C. After 4–10 h, the mix-
ture was cooled to r.t. Reactions performed in MeCN were filtered
over a short pad of Celite (eluting with CH2Cl2) and concentrated in
vacuo. Reactions performed in DMF were diluted with EtOAc–
hexanes (1:1) and washed with brine twice. After drying with MgSO4,
the organic layer was filtered and concentrated. The crude products
were purified by flash column chromatography (CH2Cl2–hexanes, 1:5,
then Et2O–hexanes, 1:100→1:25).
HRMS (DART): m/z [M + H] calcd for C14H19O3: 235.13342; found:
235.13352.
Ethyl (E)-3-(2-Isopropyl-6-methoxyphenyl)acrylate (4c)
Yield: 97 mg (39%); clear oil.
IR (neat): 2963, 2938, 2871, 2838, 2358, 25331, 2323, 1699, 1668,
1623, 1595, 1572, 1471, 1462, 1456, 1436, 1365, 1201, 1109, 1095,
1060, 407, 986, 791, 754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 16.1 Hz, 1 H), 7.28 (t,
J = 8.1 Hz, 1 H), 6.96 (dd, J = 7.9, 1.0 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H),
6.55 (d, J = 16.2 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.85 (s, 3 H), 3.35
(hept, J = 6.8 Hz, 1 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.24 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 167.97, 158.60, 150.02, 138.70,
138.69, 130.18, 123.31, 123.30, 121.75, 117.99, 108.40, 60.47, 55.64,
29.53, 23.97, 14.52.
HRMS (DART): m/z [M + H] calcd for C15H21O3: 249.14907; found:
249.14853.
Large-Scale Reaction
Pd(OAc)2 (112 mg, 0.5 mmol, 0.1 equiv), Ph3P (288 mg, 1.1 mmol, 0.22
equiv), and Cs2CO3 (8.15 g, 25 mmol, 5 equiv) were added to a flame-
dried 150 mL pressure flask under argon. Dry, degassed MeCN (15
mL) was added and the yellow mixture was stirred under argon for
Benzyl (E)-3-(2-Isopropyl-6-methoxyphenyl)acrylate (4d)
Yield: 136 mg (44%); clear oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

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Special Topic
Synthesis
IR (neat): 2958, 2930, 2871, 2859, 2358, 2331, 2323, 2312, 1711,
1627, 1595, 1572, 1471, 1460, 1437, 1035, 1263, 1231, 1183, 166,
13C NMR (126 MHz, CDCl3): δ = 157.59, 148.58, 138.32, 134.06,
128.71, 128.04, 127.45, 126.54, 125.17, 123.09, 118.03, 108.21, 55.74,
29.53, 24.08.
1060, 1050, 957, 868, 791, 753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 16.1 Hz, 1 H), 7.49–7.26 (m,
6 H), 6.96 (dd, J = 7.9, 1.0 Hz, 1 H), 6.77 (dd, J = 8.3, 1.3 Hz, 1 H), 6.64
(d, J = 16.2 Hz, 1 H), 5.27 (s, 2 H), 3.85 (s, 3 H), 3.36 (hept, J = 6.8 Hz,
1 H), 1.24 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 167.85, 158.73, 150.15, 139.26,
139.25, 136.45, 130.35, 128.68, 128.41, 128.40, 128.28, 122.77,
122.77, 121.56, 117.99, 108.43, 66.34, 55.62, 29.54, 23.97.
HRMS (ESI): m/z [M + H] calcd for C18H21O2: 253.1587; found:
253.1591.
tert-Butyl (E)-3-[2-(sec-butyl)-6-methoxyphenyl]acrylate (4h)
Yield: 288 mg (99%); clear oil.
IR (neat): 2964, 2933, 1705, 1627, 1595, 1572, 1471, 1465, 1367,
1311, 1261, 1149, 1062, 983, 875, 752 cm–1
.
HRMS (DART): m/z [M + H] calcd for C20H23O3: 311.16472; found:
311.16499.
1H NMR (600 MHz, CDCl3): δ = 7.84 (d, J = 16.11 Hz, 1 H), 7.26 (m,
1 H), 6.90 (dd, J = 1.02, 7.92 Hz, 1 H), 6.76 (dd, J = 1.28, 8.2 Hz, 1 H),
6.45 (d, J = 16.13 Hz, 1 H), 3.85 (s, 3 H), 3.31 (hept, J = 6.97 Hz, 1 H),
1.61 (m, 2 H), 1.55 (s, 9 H), 1.21 (d, J = 6.85 Hz, 6 H).
Hexyl (E)-3-(2-Isopropyl-6-methoxyphenyl)acrylate (4e)
Yield: 201 mg (66%); clear oil.
13C NMR (151 MHz, CDCl3): δ = 167.32, 158.51, 149.95, 137.77,
129.83, 125.04, 122.52, 118.45, 108.19, 80.22, 55.57, 36.38, 31.00,
28.40, 21.85, 12.26.
IR (neat): δ = 2963, 2940, 2871, 2837, 2358, 2331, 2323, 2312, 1697,
1683, 1622, 1595, 1572, 1497, 1472, 1456, 1437, 1373, 1364, 1389,
1321, 1184, 1109, 1059, 1050, 957, 868, 753 cm–1
.
HRMS (DART): m/z [M + H] calcd for C18H27O3: 291.19602; found:
1H NMR (500 MHz, CDCl3): δ = 7.93 (d, J = 16.2 Hz, 1 H), 7.28 (dd,
J = 8.3, 7.8 Hz, 1 H), 6.96 (dd, J = 7.9, 1.0 Hz, 1 H), 6.77 (dd, J = 8.3,
1.3 Hz, 1 H), 6.56 (d, J = 16.1 Hz, 1 H), 4.20 (t, J = 6.8 Hz, 2 H), 3.85 (s,
3 H), 3.35 (hept, J = 6.8 Hz, 1 H), 1.71 (ddt, J = 8.9, 7.9, 6.7 Hz, 2 H),
1.45–1.37 (m, 2 H), 1.37–1.29 (m, 4 H), 1.24 (s, 3 H), 1.23 (s, 3 H),
0.94–0.88 (m, 3 H).
13C NMR (126 MHz, CDCl3): δ = 168.06, 158.62, 150.01, 138.63,
130.18, 123.30, 123.29, 121.72, 117.98, 108.41, 64.73, 55.64, 31.64,
29.55, 28.87, 25.83, 23.96, 22.71, 14.16.
291.19637.
tert-Butyl (E)-3-[2-(Hexan-2-yl)-6-methoxyphenyl]acrylate (4i)
Yield: 245 mg (77%); clear oil.
IR (neat): 2961, 2928, 2865, 1708, 1632, 1599, 1573, 1473, 1436,
1390, 1369, 1315, 1265, 1152, 1068, 985, 881, 793, 768, 756 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.83 (d, J = 16.1 Hz, 1 H), 7.30–7.19 (m,
1 H), 6.90 (dd, J = 7.9, 1.0 Hz, 1 H), 6.75 (dd, J = 8.2, 1.1 Hz, 1 H), 6.43
(d, J = 16.1 Hz, 1 H), 3.84 (s, 3 H), 3.16 (hept, J = 6.9 Hz, 1 H), 1.63–1.57
(m, 2 H), 1.54 (s, 9 H), 1.31–1.24 (m, 3 H), 1.21 (d, J = 6.8 Hz, 3 H),
1.18–1.11 (m, 1 H), 0.84 (t, J = 7.1 Hz, 3 H).
HRMS (DART): m/z [M + H] calcd for C19H29O3: 305.21167; found:
305.21134.
13C NMR (126 MHz, CDCl3): δ = 167.27, 158.45, 149.23, 137.77,
129.83, 125.15, 125.14, 122.46, 118.48, 108.14, 80.24, 55.60, 38.06,
34.71, 29.95, 28.42, 22.96, 22.28, 14.16.
N-(tert-Butyl) (E)-3-(2-Isopropyl-6-methoxyphenyl)acrylamide
(4f)
Yield: 135 mg (49%); white solid; mp 156–157 °C.
HRMS (DART): m/z [M + H] calcd for C20H31O3: 319.22732; found:
319.23010.
IR (neat): 3267, 2964, 2929, 2869, 1651, 1619, 1614, 1595, 1572,
1547, 15374, 1532, 1470, 1453, 1437, 1390, 1363, 1359, 1334, 1265,
1256, 1223, 1204, 1811, 1062, 1048, 987, 791, 771, 751 cm–1
.
tert-Butyl (E)-3-[2-Methoxy-6-(octan-3-yl)phenyl]acrylate (4j)
Yield: 145 mg (42%); clear oil.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 15.6 Hz, 1 H), 7.25 (t,
J = 8.0 Hz, 1 H), 6.95 (dd, J = 7.9, 1.0 Hz, 1 H), 6.76 (dd, J = 8.1, 1.2 Hz,
1 H), 6.44 (d, J = 15.6 Hz, 1 H), 5.40 (s, 1 H), 3.84 (s, 3 H), 3.39 (hept,
J = 6.8 Hz, 1 H), 1.44 (s, 10 H), 1.22 (d, J = 6.8 Hz, 6 H).
IR (neat): 2958, 2929, 2857, 1706, 1700, 1628, 1595, 1577, 1468,
1464, 1456, 1367, 1310, 1259, 1149, 1063, 981, 878, 847, 770 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.83 (dd, J = 16.1, 0.5 Hz, 1 H), 7.29–
7.17 (m, 1 H), 6.85 (dd, J = 7.9, 1.0 Hz, 1 H), 6.74 (ddt, J = 8.2, 1.0,
0.4 Hz, 1 H), 6.43 (d, J = 16.1 Hz, 1 H), 3.85 (s, 3 H), 2.98 (tt, J = 8.7,
5.6 Hz, 1 H), 1.76–1.62 (m, 2 H), 1.54 (s, 9 H), 1.37–1.05 (m, 7 H),
0.92–0.85 (m, 1 H), 0.82 (t, J = 6.9 Hz, 3 H), 0.76 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 167.30, 158.36, 147.68, 138.16,
138.16, 129.69, 125.16, 123.62, 108.00, 80.20, 55.56, 36.66, 32.20,
29.79, 28.43, 27.20, 22.67, 14.20, 12.12.
13C NMR (101 MHz, CDCl3): δ = 166.11, 158.37, 150.02, 134.11,
129.49, 126.82, 122.19, 118.05, 108.41, 55.68, 51.55, 29.42, 29.12,
24.01.
HRMS (ESI): m/z [M + H] calcd for C17H26NO2: 276.1958; found:
276.1971.
(E)-1-Isopropyl-3-methoxy-2-styrylbenzene (4g)
Yield: 83 mg (33%); clear oil.
HRMS (DART): m/z [M + H] calcd for C22H35O3: 347.25862; found:
347.25808.
IR (neat): 2963, 2936, 2880, 2869, 2834, 2358, 2331, 2323, 2312,
1595, 1570, 1493, 1469, 1459, 1436, 1253, 1062, 1045, 1028, 980,
786, 751, 691 cm–1
.
tert-Butyl (E)-3-(2-Cyclohexyl-6-methoxyphenyl)acrylate (4k)
Yield: 136 mg (43%); clear oil.
1H NMR (500 MHz, CDCl3): δ = 7.54 (ddd, J = 7.8, 1.3, 0.6 Hz, 2 H),
7.42–7.35 (m, 2 H), 7.31–7.23 (m, 1 H), 7.24–7.19 (m, 2 H), 6.99 (dd,
J = 7.9, 1.0 Hz, 1 H), 6.95 (d, J = 16.5 Hz, 1 H), 6.81–6.77 (m, 1 H), 3.85
(s, 3 H), 3.44 (hept, J = 6.8 Hz, 1 H), 1.27 (d, J = 6.9 Hz, 6 H).
IR (neat): 2949, 2934, 1706, 1595, 1583, 1472, 1367, 1307, 1267,
1237, 1219, 1066, 1052, 982, 776, 753 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

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Special Topic
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.84 (d, J = 16.10 Hz, 1 H), 7.26 (m,
1 H), 6.93 (dd, J = 1.03, 7.91 Hz, 1 H), 6.76 (dd, J = 1.25, 8.30 Hz, 1 H),
6.48 (d, J = 16.12 Hz, 1 H), 3.85 (s, 3 H), 2.91 (m, 1 H), 1.80 (m, 5 H),
1.55 (s, 9 H), 1.43 (m, 4 H), 1.27 (m, 1 H).
tert-Butyl (S,E)-3-(2-{1-[(tert-Butyldimethylsilyl)oxy]propan-2-
yl}-6-methoxyphenyl)acrylate (4m)
Yield: 215 mg (53%); clear oil; [α]D20 +11.9 (c = 2.28, CHCl3). Enantio-
mers could not be separated on HPLC.
13C NMR (126 MHz, CDCl3): δ = 167.36, 158.71, 149.05, 137.49,
129.88, 124.95, 121.83, 118.65, 108.40, 80.21, 55.62, 40.34, 34.41,
28.44, 27.03, 26.39.
IR (neat): 2956, 2928, 2875, 1724, 1653, 1456, 1437, 1390, 1367,
1309, 1257, 1149, 1091, 1057, 837, 752 cm–1
.
1H NMR (399 MHz, CDCl3): δ = 7.82 (d, J = 16.2 Hz, 1 H), 7.25 (t,
J = 8.0 Hz, 1 H), 6.90 (dd, J = 8.0, 1.0 Hz, 1 H), 6.81–6.75 (m, 1 H), 6.42
(d, J = 16.2 Hz, 1 H), 3.84 (s, 3 H), 3.68 (dd, J = 9.8, 6.1 Hz, 1 H), 3.60
(dd, J = 9.7, 7.3 Hz, 1 H), 3.43–3.33 (m, 1 H), 1.54 (s, 9 H), 1.24 (d,
J = 6.9 Hz, 3 H), 0.84 (s, 9 H), –0.03 (s, 3 H), –0.05 (s, 3 H).
HRMS (DART): m/z [M + H] calcd for C20H29O3: 317.21167; found:
317.21227.
tert-Butyl (E)-3-[2-Methoxy-6-(1-phenoxypropan-2-yl)phenyl]ac-
rylate (4l)
13C NMR (100 MHz, CDCl3): δ = 166.85, 158.17, 145.47, 137.71,
129.38, 125.49, 123.20, 118.91, 108.46, 80.07, 68.71, 55.51, 37.32,
28.24, 25.86, 18.01, –5.48.
Yield: 177 mg (48%); clear oil.
IR (neat): 2976, 2933, 1724, 1705, 1626, 1599, 1496, 1469, 1456,
1367, 1311, 1244, 1149, 1039, 754, 692 cm–1
.
HRMS (DART) m/z [M + H] calcd for C22H39O4Si: 407.26176; found:
1H NMR (500 MHz, CDCl3): δ (mixture of rotomers) = 7.88 (d,
J = 16.1 Hz, 0.64 H), 7.87 (d, J = 16.2 Hz, 0.22 H), 7.31–7.18 (m, 3 H),
6.98 (dd, J = 7.9, 1.0 Hz, 0.26 H), 6.95–6.85 (m, 3.59 H), 6.84–6.78 (m,
1 H), 6.63 (d, J = 16.1 Hz, 0.64 H), 6.46 (d, J = 16.1 Hz, 0.23 H), 4.59
(hept, J = 6.2 Hz, 0.71 H), 4.09 (dd, J = 9.1, 6.1 Hz, 0.24 H), 3.98 (dd,
J = 9.1, 7.4 Hz, 0.24 H), 3.87 (s, 1.82 H), 3.86 (s, 0.81 H), 3.73 (hept,
J = 7.0 Hz, 0.27 H), 3.29 (dd, J = 14.0, 6.7 Hz, 0.70 H), 2.97 (dd, J = 14.0,
6.4 Hz, 0.70 H), 1.54 (s, 2.50 H), 1.54 (s, 5.79 H), 1.38 (d, J = 6.9 Hz,
0.70 H), 1.29 (d, J = 6.1 Hz, 2.05 H).
13C NMR (126 MHz, CDCl3): δ (mixture of rotomers) = 167.31, 166.98,
159.16, 159.01, 158.48, 157.92, 144.71, 140.06, 137.54, 137.53,
129.88, 129.78, 129.58, 129.51, 125.85, 125.00, 123.74, 123.19,
122.87, 120.84, 120.79, 118.82, 116.21, 114.74, 109.47, 108.99, 80.39,
80.26, 74.47, 72.91, 55.68, 55.60, 40.66, 34.88, 28.39, 19.77, 18.85.
407.26260.
(E)-3-[2-(1-Hydroxypropan-2-yl)-6-methoxyphenyl]acrylic Acid
(5)
The starting tert-butyl ester 4m (51 mg, 0.13 mmol) was dissolved in
CH2Cl2 (5 mL) and TFA (96 μL, 130 μmol). The mixture was stirred for
1 h at r.t., then concentrated. The resulting acid was purified by col-
umn chromatography (EtOAc–hexanes, 1:1) to give the acid 5 (29 mg,
99%) as a clear oil, which was crystallized by slow evaporation from
hexanes as white crystals.
IR (neat): 2968, 2875, 2841, 2359, 1786, 1689, 1681, 1622, 1595,
1573, 1471, 1456, 1438, 1369, 1346, 1307, 1261, 1219, 1165, 1057,
983, 873, 775, 754 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 16.1 Hz, 1 H), 7.34 (t,
J = 8.1 Hz, 1 H), 6.91 (dd, J = 7.9, 1.0 Hz, 1 H), 6.86 (dd, J = 8.4, 1.2 Hz,
1 H), 6.58 (d, J = 16.1 Hz, 1 H), 4.45 (dd, J = 10.8, 6.6 Hz, 1 H), 4.40 (dd,
J = 10.8, 7.3 Hz, 1 H), 3.88 (s, 3 H), 3.78–3.63 (m, 1 H), 1.35 (d,
J = 6.9 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C23H28O4Na: 391.1880; found:
391.1894.
tert-Butyl (S)-(2-Iodopropoxy)dimethylsilane (3m)
13C NMR (126 MHz, CDCl3): δ = 158.73, 157.48, 142.54, 139.99,
130.67, 123.12, 122.34, 118.38, 109.60, 71.83, 55.61, 33.76, 18.08.
To a solution of propandiol (4 g, 52.6 mmol) in CH2Cl2 (50 mL) at 0 °C
was added imidazole (3.58 g, 52.6 mmol) followed by tert-butyldi-
methylsilyl chloride (7.89 g, 52.6 mmol). The reaction was stirred at
0 °C for 30 min, then the imidazole·HCl salt was filtered. In a separate
flask, triphenylphosphine (13.79 g, 52.6 mmol) and imidazole (3.58 g,
52.6 mmol) are dissolved in CH2Cl2 (100 mL) at 0 °C. Molecular iodine
(13.37 g, 52.6 mmol) was added and the reaction was stirred at 0 °C
for 15 min. The solution of the monosilylated diol was added drop-
wise over 5 min and the mixture was stirred for 30 min at 0 °C. The
mixture was washed with an aqueous solution of Na2SO3, and the or-
ganic layer was separated and concentrated. The residue was purified
by column chromatography (hexanes) to give the (S)-iodide 3m.
HRMS (DART): m/z [M + H] calcd for C13H17O4: 237.11268; found:
237.11279.
[α]D20 +28.8 (c = 0.18 CHCl3)
HPLC (Chiralpak AD-H column; flow: 0.5 mL/min; hexane–2-propa-
nol, 98:2): tR = 35.6 (major), 40.1 (minor) min; 94% ee from reaction
20
in MeCN. tR = 35.2 (major), 39.5 (minor) min; [α]D +5.4 (c = 0.22,
CHCl3), 40% ee from reaction in DMF.
Compound crystallizes as a racemate; mp 127–128 °C (crystals ob-
tained from reaction in DMF).
20
Yield: 7.28 g (46%, 2 steps); clear oil; [α]D +9.5 (c = 4.34, CHCl3).
Enantiomers could not be separated on HPLC.
tert-Butyl (E)-3-[2-Methoxy-6-(1-methoxypentyl)phenyl]acrylate
(4n)
IR (neat): 2955, 2928, 2885, 2856, 1464, 1450, 1386, 1379, 1253,
1170, 1139, 1111, 1078, 1045, 1004, 989, 837, 777, 669 cm–1
.
Yield: 345 mg (99%); clear oil.
1H NMR (500 MHz, CDCl3): δ = 4.15–4.03 (m, 1 H), 3.81 (dd, J = 10.5,
5.5 Hz, 1 H), 3.61 (dd, J = 10.5, 7.8 Hz, 1 H), 1.86 (d, J = 6.8 Hz, 3 H),
0.90 (s, 9 H), 0.07 (s, 6 H).
13C NMR (126 MHz, CDCl3): δ = 70.59, 28.28, 26.00, 24.46, 18.43,
–5.03, –5.13.
IR (neat): 2956, 2931, 2872, 2860, 1705, 1626, 1595, 1573, 1469,
1456, 1367, 1311, 1265, 1151, 1093, 983, 875, 754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 16.1 Hz, 1 H), 7.20 (t,
J = 8.1 Hz, 1 H), 6.85 (dd, J = 7.5, 1.0 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H),
6.61 (dd, J = 16.1, 0.6 Hz, 1 H), 3.86 (s, 3 H), 3.30 (m, 4 H), 3.06 (dd,
J = 13.8, 6.3 Hz, 1 H), 2.78 (dd, J = 13.8, 6.5 Hz, 1 H), 1.53 (s, 9 H), 1.49–
1.37 (m, 2 H), 1.31–1.20 (m, 2 H), 0.90–0.82 (m, 3 H).
HRMS (DART): m/z [M + H] calcd for C19H22IOSi: 301.0486; found:
301.04820.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456

2454
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Synthesis
13C NMR (101 MHz, CDCl3): δ = 167.29, 159.14, 140.93, 137.51,
129.66, 124.91, 123.96, 122.64, 109.22, 82.07, 80.21, 57.52, 55.59,
38.61, 33.82, 28.42, 27.66, 22.96, 14.20.
J = 7.9, 1.0 Hz, 0.8 H), 6.82 (dd, J = 7.6, 1.1 Hz, 0.2 H), 6.81–6.74 (m,
1 H), 6.60 (d, J = 16.1 Hz, 0.2 H), 6.42 (d, J = 16.1 Hz, 0.8 H), 3.86 (s,
0.6 H), 3.85 (s, 2.4 H), 3.42–3.29 (m, 0.8 H), 3.30–3.18 (m, 0.2 H), 2.92
(t, J = 7.9 Hz, 0.4 H), 2.76 (t, J = 7.8 Hz, 1.6 H), 2.00–1.84 (m, 2 H), 1.55
(s, 7 H), 1.53 (s, 2 H), 1.33 (d, J = 6.7 Hz, 0.6 H), 1.23 (d, J = 6.8 Hz,
2.4 H).
HRMS (DART): m/z [M + H] calcd for C20H31O4: 349.23788; found:
349.23724.
13C NMR (126 MHz, CDCl3): δ (mixture of rotomers) = 167.34, 167.11,
159.30, 158.48, 147.30, 143.50, 137.51, 137.11, 136.58, 135.23,
132.01, 130.00, 129.96, 129.05, 128.93, 126.81, 125.84, 125.57,
124.82, 122.81, 122.52, 118.31, 109.08, 108.55, 80.40, 80.25, 55.64,
42.87, 38.29, 37.44, 34.16, 31.48, 28.43, 22.39, 21.27.
tert-Butyl (E)-3-(2-{4-[(tert-Butyldimethylsilyl)oxy]butan-2-yl}-6-
methoxyphenyl)acrylate (4o)
Yield: 332 mg (79%); clear oil. Enantiomers could not be separated on
HPLC.
IR (neat): 2956, 2929, 2856, 1708, 1624, 1595, 1572, 1471, 1437,
HRMS (DART): m/z [M + H] calcd for C24H31O3S: 399.19939; found:
399.19876.
1390, 1367, 1311, 1149, 1099, 1060, 983, 835, 775 cm–1
.
1H NMR (399 MHz, CDCl3): δ = 7.82 (d, J = 16.2 Hz, 1 H), 7.25 (t,
J = 7.5 Hz, 1 H), 6.89 (d, J = 7.9 Hz, 1 H), 6.74 (d, J = 8.2 Hz, 1 H), 6.40
(dd, J = 16.1, 0.8 Hz, 1 H), 3.83 (s, 3 H), 3.61–3.44 (m, 2 H), 3.33 (hept,
J = 7.0 Hz, 1 H), 1.98–1.72 (m, 2 H), 1.53 (d, J = 0.9 Hz, 9 H), 1.22 (d,
J = 6.8 Hz, 3 H), 0.85 (d, J = 0.9 Hz, 9 H), –0.02 (d, J = 0.9 Hz, 6 H).
tert-Butyl (E)-3-(2-Methoxy-6-{4-(N-phenyl 4-methylphenylsul-
fonamido)butan-2-yl}phenyl)acrylate (4q)
Yield: 262 mg (49%); clear oil.
IR (neat): 2966, 2928, 2870, 1705, 1699, 1629, 1595, 1573, 1494,
1471, 1456, 1367, 1350, 1311, 1261, 1165, 1151, 1082, 1070, 1606,
13C NMR (100 MHz, CDCl3): δ = 167.00, 158.41, 148.28, 137.67,
129.79, 125.24, 122.61, 118.53, 108.24, 80.14, 61.41, 55.57, 40.68,
31.28, 28.37, 26.08, 22.65, 18.38, –5.23, –5.28.
979, 815, 754, 698, 655, 574, 545 cm–1
.
1H NMR (399 MHz, CDCl3): δ = 7.73 (d, J = 16.2 Hz, 1 H), 7.40 (d,
J = 8.1 Hz, 2 H), 7.32–7.15 (m, 6 H), 7.06–6.92 (m, 2 H), 6.82–6.72 (m,
2 H), 6.35 (d, J = 16.1 Hz, 1 H), 3.83 (s, 3 H), 3.48 (ddd, J = 13.1, 9.0,
6.3 Hz, 1 H), 3.37 (ddd, J = 13.0, 8.9, 6.4 Hz, 1 H), 3.16 (hept, J = 6.9 Hz,
1 H), 2.40 (s, 3 H), 1.75 (dtd, J = 8.8, 6.6, 3.9 Hz, 2 H), 1.57 (d, J = 0.8 Hz,
9 H), 1.17 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.04, 158.41, 147.23, 143.33,
139.20, 137.47, 135.23, 130.00, 129.45, 129.16, 129.04, 128.79,
128.35, 127.87, 127.85, 125.50, 122.51, 118.23, 108.54, 80.44, 55.64,
48.87, 36.13, 32.24, 30.10, 29.84, 28.42, 22.44, 21.65.
HRMS (DART): m/z [M + H] calcd for C24H41O4Si: 421.27741; found:
421.27942.
tert-Butyl (E)-3-(2-{4-Hydroxybutan-2-yl}-6-methoxyphenyl)ac-
rylate (6)
To a solution of 4o (33 mg, 79 μmol) in anhydrous THF (3 mL) at 0 °C
was added TBAF (1 M in THF, 79 μL, 79 μmol). The mixture was
stirred at 0 °C for 1 h under Ar, then aqueous NH4Cl was added. The
aqueous phase was extracted with EtOAc (3×) and dried with Mg2SO4.
After filtration, the organic layer was concentrated and the residue
was purified by column chromatography (EtOAc–hexanes, 1:20) to
give 6.
HRMS (DART): m/z [M + H] calcd for C31H38NO5S: 536.24707; found:
536.24831.
Yield: 14.7 mg (61%); clear oil.
tert-Butyl (E)-3-[2-Isopropyl-6-(methoxymethoxy)phenyl]acry-
late (4r)
IR (neat): 2958, 2926, 2872, 1734, 1716, 1653, 1558, 1435, 1394,
1367, 1261, 1219, 1062, 1049, 773 cm–1
.
Yield: 320 mg (99%); clear oil.
1H NMR (500 MHz, CDCl3): δ = 7.84 (d, J = 16.1 Hz, 1 H), 7.27 (t,
J = 8.0 Hz, 1 H), 6.92 (dd, J = 7.9, 1.0 Hz, 1 H), 6.76 (dd, J = 8.2, 1.2 Hz,
1 H), 6.46 (d, J = 16.1 Hz, 1 H), 3.85 (s, 3 H), 3.55 (td, J = 6.6, 3.4 Hz,
2 H), 3.38 (hept, J = 7.0 Hz, 1 H), 1.93–1.78 (m, 2 H), 1.53 (s, 9 H), 1.26
(d, J = 6.9 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 167.39, 158.55, 148.18, 137.55,
130.04, 125.25, 122.40, 118.48, 108.46, 80.46, 61.09, 55.61, 41.10,
31.24, 28.39, 22.19.
IR (neat): 2976, 2933, 2872, 2369, 1708, 1627, 1592, 1573, 1472,
1459, 1388, 1368, 1310, 1255, 1200, 1152, 1102, 1009, 983, 867,
754 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.83 (d, J = 16.2 Hz, 1 H), 7.25–7.21 (m,
1 H), 7.01–6.97 (m, 2 H), 6.40 (d, J = 16.2 Hz, 1 H), 5.21 (s, 2 H), 3.48 (s,
3 H), 3.38–3.26 (m, 1 H), 1.55 (s, 9 H), 1.23 (d, J = 6.8 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 167.10, 155.92, 149.72, 137.77,
137.77, 129.85, 125.34, 125.33, 122.90, 119.10, 112.11, 94.72, 80.35,
56.31, 29.57, 28.38, 23.93.
HRMS (DART): m/z [M + H] calcd for C18H27O4: 307.19093; found:
307.18999.
HRMS (DART): m/z [M + NH4] calcd for C18H30NO4: 324.21748; found:
324.21795.
HPLC (Chiralpak AD-H column; flow: 1.0 mL/min; hexane–2-pro-
panol, 90:10): tR (racemic sample) = 6.1, 7.7 min; tR (chiral
sample) = 6.1, 7.6 min; 0% ee.
tert-Butyl (E)-3-(2-Isopropoxy-6-isopropylphenyl)acrylate (4s)
Yield: 302 mg (99%); clear oil.
tert-Butyl (E)-3-{2-Methoxy-6-[4-(phenylthio)butan-2-yl]phe-
nyl}acrylate (4p)
IR (neat): 2965, 2928, 2870, 1708, 1626, 1594, 1572, 1472, 1453,
Yield: 318 mg (80%); clear oil.
1437, 1394, 1362, 1315, 1260, 1201, 1154, 1068, 985, 875, 754 cm–1
.
IR (neat): 2966, 2926, 1683, 1653, 1581, 1570, 1475, 1437, 1292,
1H NMR (500 MHz, CDCl3): δ = 7.84 (d, J = 16.2 Hz, 1 H), 7.22 (t,
J = 8.0 Hz, 1 H), 6.91 (dd, J = 7.9, 1.0 Hz, 1 H), 6.76 (dd, J = 8.1, 1.4 Hz,
1 H), 6.49 (d, J = 16.1 Hz, 1 H), 4.61–4.50 (m, 1 H), 3.34 (hept,
J = 6.7 Hz, 1 H), 1.54 (s, 9 H), 1.36 (d, J = 6.0 Hz, 6 H), 1.23 (d,
J = 6.8 Hz, 6 H).
1274, 1247, 1053, 1024, 1016, 914, 742, 688, 648 cm–1
.
1H NMR (500 MHz, CDCl3): δ (mixture of rotomers) = 7.82 (d,
J = 16.1 Hz, 0.8 H), 7.77 (d, J = 16.1 Hz, 0.2 H), 7.39–7.34 (m, 0.3 H),
7.30–7.24 (m, 1 H), 7.25–7.23 (m, 4 H), 7.17–7.11 (m, 0.7 H), 6.86 (dd,
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13C NMR (126 MHz, CDCl3): δ = 167.33, 156.82, 149.91, 137.71,
137.71, 129.59, 124.71, 124.70, 122.68, 117.56, 110.94, 79.96, 70.80,
29.38, 28.26, 23.82, 22.14.
1H NMR (400 MHz, CDCl3): δ = 7.84 (dd, J = 16.0, 0.6 Hz, 1 H), 6.59–
6.39 (m, 2 H), 6.34 (d, J = 2.4 Hz, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.40
(hept, J = 6.8 Hz, 1 H), 1.53 (s, 9 H), 1.23 (d, J = 6.8 Hz, 6 H).
HRMS (DART): m/z [M + H] calcd for C19H29O3: 305.21167; found:
305.21205.
13C NMR (100 MHz, CDCl3): δ = 168.04, 161.41, 160.62, 151.79,
137.12, 122.31, 114.64, 102.92, 95.81, 80.01, 55.63, 55.36, 29.68,
28.47, 23.89.
tert-Butyl (E)-3-[2-(Benzyloxy)-6-isopropylphenyl]acrylate (4ta)
HRMS (DART): m/z [M + H] calcd for C18H27O4: 307.19093; found:
307.19028.
Yield: 317 mg (90%); clear oil.
IR (neat): 2963, 2936, 2871, 1722, 1695, 1636, 1623, 1596, 1569,
1470, 1447, 1367, 1311, 1148, 1044, 1028, 984, 878, 845, 751,
tert-Butyl (E)-3-(2-Isopropyl-6-methylphenyl)acrylate (4w)
Yield: 242 mg (93%); clear oil.
735 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.90 (d, J = 16.2 Hz, 1 H), 7.47–7.43 (m,
2 H), 7.42–7.36 (m, 2 H), 7.35–7.29 (m, 1 H), 7.27–7.21 (m, 1 H), 6.98
(dd, J = 7.9, 1.0 Hz, 1 H), 6.82 (ddd, J = 8.3, 1.0, 0.5 Hz, 1 H), 6.54 (d,
J = 16.2 Hz, 1 H), 5.14 (s, 2 H), 3.38 (hept, J = 6.8 Hz, 1 H), 1.55 (s, 9 H),
1.26 (d, J = 6.8 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 167.20, 157.39, 149.92, 137.49,
137.09, 129.83, 128.60, 127.87, 127.09, 125.61, 125.60, 122.48,
118.28, 110.05, 80.16, 70.54, 29.58, 28.38, 23.94.
IR (neat): 2961, 2871, 1713, 1639, 1470, 1456, 1383, 1367, 1311,
1287, 1254, 1150, 980, 846, 771, 753 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.78 (dd, J = 16.4, 0.7 Hz, 1 H), 7.22–
7.11 (m, 2 H), 7.09–6.96 (m, 1 H), 5.91 (d, J = 16.3 Hz, 1 H), 3.16 (hept,
J = 6.8 Hz, 1 H), 2.30 (s, 3 H), 1.55 (s, 9 H), 1.20 (d, J = 6.8 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 166.05, 147.15, 142.76, 135.93,
133.73, 128.28, 127.86, 126.35, 122.98, 80.72, 29.98, 28.37, 23.98,
21.41.
HRMS (ESI): m/z [M + Na] calcd for C23H28O3Na: 375.1930; found:
375.1928.
HRMS (DART): m/z [M + H] calcd for C17H25O2: 261.18545; found:
261.18561.
tert-Butyl (E)-3-{2-Isopropyl-6-[(4-methoxybenzyl)oxy]phe-
nyl}acrylate (4tb)
tert-Butyl (E)-3-[2-Isopropyl-6-(trifluoromethyl)phenyl]acrylate
(4x)
Yield: 344 mg (90%); clear oil.
Yield: 195 mg (62%); clear oil.
IR (neat): 2963, 2928, 2870, 2358, 2329, 2323, 1706, 1698, 1515,
IR (neat): 2965, 2933, 2873, 1713, 1700, 1647, 1456, 1393, 1367,
1316, 1289, 1257, 1150, 1129, 1098, 978, 910, 875, 843, 807, 773,
1456, 1367, 1310, 1304, 1247, 1219, 1173, 1148, 034, 770 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 16.2 Hz, 1 H), 7.35 (dt,
J = 8.8, 0.6 Hz, 2 H), 7.23 (t, J = 8.1 Hz, 1 H), 6.95 (dd, J = 7.9, 1.0 Hz,
1 H), 6.93–6.87 (m, 2 H), 6.84–6.79 (m, 1 H), 6.47 (s, 1 H), 5.06 (s, 2 H),
3.81 (s, 3 H), 3.35 (hept, J = 6.4 Hz, 1 H), 1.52 (s, 9 H), 1.24 (d,
J = 6.8 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 167.29, 159.43, 157.57, 149.98,
137.52, 129.84, 129.18, 128.81, 125.53, 122.53, 118.27, 114.06,
110.24, 80.16, 70.46, 55.43, 29.60, 28.42, 23.97.
753, 739, 715 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.92–7.67 (m, 1 H), 7.62–7.45 (m, 2 H),
7.44–7.32 (m, 1 H), 5.91 (dq, J = 16.3, 0.5 Hz, 1 H), 3.17 (dq, J = 13.6,
6.8 Hz, 1 H), 1.54 (s, 9 H), 1.20 (d, J = 6.8 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 165.26, 148.38, 139.88, 133.29 (q, J =
1.67 Hz), 129.13 (q, J = 1.1 Hz), 128.54 (q, J = 29.4 Hz), 128.17,
128.14–128.10 (m), 124.17 (q, J = 273.9 Hz), 123.56 (q, J = 5.6 Hz),
81.07, 29.85, 28.33, 23.84.
HRMS (ESI): m/z [M + Na] calcd for C24H30O4Na: 405.2050; found:
405.2056.
19F NMR (564 MHz, CDCl3): δ = –58.11.
HRMS (DART): m/z [M + NH4] calcd for C17H25F3NO2: 332.18374;
found: 332.18393.
tert-Butyl (E)-3-(2-Isopropylnaphthalen-1-yl)acrylate (4u)
Yield: 237 mg (85%); clear oil.
tert-Butyl (E)-3-(2-Fluoro-6-isopropylphenyl)acrylate (4y)
Yield: 164 mg (62%); clear oil.
IR (neat): 2961, 2932, 2871, 1725, 1713, 1700, 1697, 1468, 1456,
1391, 1367, 1331, 1301, 1281, 1257, 1149, 846, 818, 770, 748 cm–1
.
IR (neat): 2966, 2931, 1708, 1631, 1610, 1471, 1456, 1367, 1317,
1H NMR (500 MHz, CDCl3): δ = 8.11 (d, J = 16.3 Hz, 1 H), 8.02–7.97 (m,
1 H), 7.84–7.70 (m, 2 H), 7.56–7.40 (m, 3 H), 6.09 (d, J = 16.3 Hz, 1 H),
3.39 (hept, J = 6.8 Hz, 1 H), 1.59 (s, 9 H), 1.28 (d, J = 6.9 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 165.95, 144.11, 141.91, 132.10,
131.50, 130.11, 128.85, 128.25, 127.91, 127.90, 126.42, 125.52,
125.39, 123.69, 80.96, 30.40, 28.43, 23.84.
1244, 1151, 983, 945, 794, 752 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.76–7.71 (m, 1 H), 7.25 (td, J = 8.0,
5.6 Hz, 1 H), 7.09 (dd, J = 7.9, 1.2 Hz, 1 H), 6.92 (dddd, J = 11.1, 8.2, 1.2,
0.6 Hz, 1 H), 6.44 (dd, J = 16.2, 1.8 Hz, 1 H), 3.36–3.23 (m, 1 H), 1.53 (s,
9 H), 1.24 (d, J = 6.9 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.69 (d, J = 1.0 Hz), 162.68, 160.18,
150.56, 134.77 (d, J = 0.9 Hz), 130.30 (d, J = 9.7 Hz), 126.43 (d,
J = 12.4 Hz), 121.17 (d, J = 3.2 Hz), 121.00 (d, J = 11.1 Hz), 113.44 (d,
J = 23.4 Hz), 80.74, 29.65 (d, J = 2.4 Hz), 28.48–28.15 (m), 23.71.
HRMS (DART): m/z [M + H] calcd for C20H25O2: 297.18545; found:
297.18584.
tert-Butyl (E)-3-(2-Isopropyl-4,6-dimethoxyphenyl)acrylate (4v)
Yield: 150 mg (49%); clear oil.
19F NMR (376 MHz, CDCl3): δ = –111.52.
HRMS (DART): m/z [M + H] calcd for C16H22FO2: 265.16038; found:
265.16106.
IR (neat): 2966, 2933, 1701, 1600, 1456, 1365, 1313, 1271, 1203,
1147, 1062, 983, 835 cm–1
.
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Synthesis
tert-Butyl (E)-3-(2-Chloro-6-isopropylphenyl)acrylate (4z)
(2) For reviews of the Catellani reaction, see: (a) Sui, X.; Zhu, R.; Gu,
Z. Synlett 2013, 24, 2023. (b) Ferraccioli, R. Synthesis 2013, 45,
581. (c) Martins, A.; Mariampillai, B.; Lautens, M. Top. Curr.
Chem. 2010, 292, 1. (d) Lautens, M.; Alberico, D.; Bressy, C.;
Fang, Y.-Q.; Mariampillai, B.; Wilhelm, T. Pure Appl. Chem. 2006,
78, 351.
(3) (a) Weinstabl, H.; Suhartono, M.; Qureshi, Z.; Lautens, M.
Angew. Chem. Int. Ed. 2013, 52, 5305. (b) Qureshi, Z.; Weinstabl,
H.; Suhartono, M.; Lui, H.; Thesmar, P.; Lautens, M. Eur. J. Org.
Chem. 2014, 4053.
(4) Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu, Z. J. Am. Chem. Soc. 2013, 135,
9318.
(5) Catellani, M.; Cugini, F. Tetrahedron 1999, 55, 6595.
(6) Catellani, M.; Motti, E.; Minari, M. Chem. Commun. 2000, 157.
(7) Rudolph, A.; Rackelmann, N.; Lautens, M. Angew. Chem. Int. Ed.
2007, 46, 1485.
(8) Rudolph, A.; Rackelmann, N.; Turcotte-Savard, M.-O.; Lautens,
M. J. Org. Chem. 2009, 74, 289.
(9) (a) Jutand, A.; Mosleh, A. Organometallics 1994, 14, 1810.
(b) Amatore, C.; Carré, E.; Jutand, A.; M’Barki, M. A. Organome-
tallics 1995, 14, 1818.
(10) Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994, 33,
2421.
(11) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307.
Yield: 123 mg (44%); clear oil.
IR (neat): 2966, 2930, 1713, 1700, 1643, 1367, 1312, 1292, 1257,
1150, 977, 739 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 16.3 Hz, 1 H), 7.30–7.13 (m,
3 H), 6.08 (d, J = 16.3 Hz, 1 H), 3.20 (hept, J = 6.8 Hz, 1 H), 1.55 (s, 9 H),
1.21 (d, J = 7.0 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ (mixture of rotomers) = 165.61, 149.26,
139.70, 133.09, 132.61, 129.20, 127.61, 127.10, 123.99, 122.67, 80.84,
30.18, 28.27, 28.23, 23.90, 23.84.
HRMS (DART): m/z [M + NH4] calcd for C16H25ClNO2: 298.15738;
found: 298.15752.
Acknowledgment
The authors thank the Natural Sciences and Engineering Research
Council (NSERC), the University of Toronto, and Alphora Research Inc
for financial support. We thank NSERC/Merck for an Industrial Re-
search Chair and the Canada Council for the Arts for a Killam fellow-
ship. Z.Q. thanks Ontario Graduate Scholarship for funding. We also
thank S. Kim for helpful discussions.
Supporting Information
(12) Santaniello, E.; Casati, S.; Ciuffreda, P.; Gamberoni, L. Tetrahe-
dron: Asymmetry 2005, 16, 1705.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380198. Included are 1H and 13C
(13) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
(14) We attempted to determine the absolute stereochemistry of the
alkylated product but all efforts gave crystals that were not
suitable for X-ray crystal analysis. Use of the Mosher esters con-
firmed the ee but assigning the stereochemistry was not defini-
tive. We anticipate overall inversion of 3m occurred, in analogy
to our previous work, however we do not have definitive proof
in this case. See the Supporting Information for analysis of the
Mosher method.
NMR spectra of the coupling products.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
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References
(1) For recent reviews, see: (a) For palladium: Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (b) For rhodium: Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) For
ruthenium: Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem.
Rev. 2012, 112, 5879.
(15) Larchevêque, M.; Mambu, L.; Petit, Y. Synth. Commun. 1991, 21,
2295.
(16) For a recent review of C–N coupling, see: Surry, D. S.; Buchwald,
S. L. Chem. Sci. 2011, 2, 27.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2446–2456