A robust first-pass protocol for the heck-mizoroki reaction

Article abstract of DOI:10.1021/op300364p

The Heck-Mizoroki (HM) reaction is one of the most widely used C-C bond-forming methods of contemporary synthesis. Notwithstanding this, these reactions frequently require significant optimization before efficient transformations can be obtained. We describe here the results of a study that aimed to establish a generic experimental protocol for HM reactions which enables acceptable yields from first-pass experiments. The methodology utilizes readily available stable catalysts and can be applied to a broad range of coupling partners.

Full text of DOI:10.1021/op300364p

Article
pubs.acs.org/OPRD
A Robust First-Pass Protocol for the Heck−Mizoroki Reaction
Paul M. Murray,*,†,§ John F. Bower,† David K. Cox,† Ewan K. Galbraith,† Jeremy S. Parker,†,∥
and Joseph B. Sweeney*,‡
†AstraZeneca Process R&D, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, U.K.
‡Department of Chemical and Biological Sciences, University of Huddersfield, Huddersfield HD1 3DH, U.K.
S
* Supporting Information
ABSTRACT: The Heck−Mizoroki (HM) reaction is one of the most widely used C−C bond-forming methods of
contemporary synthesis. Notwithstanding this, these reactions frequently require significant optimization before efficient
transformations can be obtained. We describe here the results of a study that aimed to establish a generic experimental protocol
for HM reactions which enables acceptable yields from first-pass experiments. The methodology utilizes readily available stable
catalysts and can be applied to a broad range of coupling partners.
ineffective; a time-consuming lengthy optimization process was
required to provide acceptable yields in the key cross-coupling.
Given the extensive literature reports and commercial use of HM
reactions, a reliable and robust procedure for Heck reactions
would be of considerable value. Challenged by the limitations
imposed upon our chemistry by probably the best-known and
most widely used Pd-catalyzed cross-coupling method, we
sought to design a set of generic conditions6 for HM reactions,
and we report here the results of our studies in the area.
INTRODUCTION
■
The use of transition metal-catalyzed coupling reactions has
revolutionized organic synthesis, and the goal of achieving a fuller
understanding of these processes means the area continues to
provide a fertile ground for researchers. Although ground-
breaking advances in metal-catalysed amination, amidation,
etherification, alcohol activation, hydroamination, and hydro-
acylation reactions have been reported in the past two decades,
even “mature” metal-catalyzed C−C bond-forming reactions,
such as alkene-aryl halide/pseudohalide cross-couplings [the
Heck−Mizoroki (HM) reaction],1 continue to provide chal-
lenges. This is particularly true from the perspective of predictive
catalysis, which aims to establish a reliable methodology for a
broad range of metal-catalyzed bond-forming processes. In the
latter arena, the continuing disclosure of modifications to HM
reactions2,3 is a telling comment upon the unmet need for
optimization and genericization. Thus, despite the enormous
effort expended in the area, and the ubiquity of HM reactions in
academic and industrial4 contexts, many class-leading studies
have been tightly focused, for instance, on the use of particular
substrates (such as aryl chlorides) or catalyst/ligand permuta-
tions, rather than aimed at delivering general, robust, and
efficient protocols. The pursuit of a ubiquitous HM protocol
which consistently delivers good yields of coupled product is,
therefore, a challenging target; this is due to the complexity
typical of metal-catalyzed reactions, where a remarkable diversity
of ingredients (ligand, cocatalyst, solvent, base, additives, etc.)
can be (and often are) needed for satisfactory performance. It
remains the case that there is no single experimental protocol for
HM reactions which has been clearly demonstrated to give
acceptable first-pass yields when reacting a broad range of
coupling partners. Indeed, to the nonexpert practitioner there is a
daunting diversity of reported procedures for every type of
transition metal-catalyzed reaction, often resulting in the need for
significant optimization. This became clear to us when, as part of
a program of research directed toward the production of Crestor
(rosuvastatin calcium),5 we anticipated that an HM process
would facilitate a key C−C bond-forming event but were
disappointed to find that a range of “standard” conditions were
RESULTS AND DISCUSSION
■
As mentioned, a great deal of effort has been expended in
designing ligands which tune the key steps of HM reactions;
however, there is still no single protocol which is reported to
work “off the shelf”, and delivering such a flexible method was our
primary goal. For the purposes of our study, we defined a
“successful reaction” as one which delivered an at least 70% yield
of cross-coupled product in a first-pass reaction. To tailor a
generic method for HM reaction, one must take account of the
eclectic cocktail of catalyst, cocatalyst(s), reagents, base, solvent,
and additive(s) which are often required, so we planned our
study to proceed in several phases. In the first phase, we analyzed
catalyst variation,7 using a representative set of aryl bromides
(still the most widely used oxidative addition substrates), with
the members of the bromide set chosen to map the spectrum of
electronic (bromides 3−6 and 8−10) and steric factors
(bromides 6−10); the initial alkene coupling partner sets were
Received: December 20, 2012
© XXXX American Chemical Society
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Table 1. A Generic Heck−Mizoroki Protocol for Styrene
a
conversion (%)
entry
catalyst
1
2
3
4
5
6
7
8
9
10
11
50
12
95
13
b
b
b
b
A
B
C
D
E
F
G
H
I
X1
X2
X3
NE
60
0
14
NE
15
15
0
100
11
100
34
NE
0
0
0
0
0
0
NE
0
0
80
75
4
26
NE
NE
67
88
0
0
99
0
6
99
0
99
b
b
99
99
3
99
0
99
0
99
15
0
c
X4
0
30
0
3
15
30
X5
0
0
100
100
0
100
100
0
0
12
13
0
0
100
0
100
66
100
14
4
X6
0
0
0
0
0
0
X7
0
30
0
3
0
0
0
72
0
0
b
X8
30
99
99
99
NE
0
99
3
0
0
0
0
30
15
0
X9
100
100
90
99
99
99
100
100
100
100
90
99
99
15
63
81
100
73
80
100
100
76
99
99
30
100
100
70
100
100
79
100
100
99
J
X10
X11
K
80
a
b
c
Assessed using GC/GCMS, using internal standards to ensure reproducibility. Reaction not examined. “Homeopathic” palladium.
comprised of styrene (14) and acrylates 15 and 16 (these two
alkene classes significantly outnumber every other HM substrate
class reported in the contemporary literature). With regard to
catalysts, given the plethora of reported complex−ligand
combinations, the selection process was more daunting; to
simplify the primary analysis, we chose to analyze palladium
catalysts X1−X11 based primarily on the criteria of ready
availability, stability, and cost. The reactions were conducted
using a hindered amine base (methyldicyclohexylamine) to
accelerate reductive elimination, in a polar solvent [dimethyla-
cetamide (DMAC)] in the presence of substoichiometric
subset indicated that electronics were now a significant factor
(entries R4/5 and T4/5).
Somewhat less explicably, reactions of both electron-rich and
electron-deficient meta-substituted bromides were often in-
efficient with the first-generation privileged catalyst set (entries
Q11−Q13 to V11−V13), with the full data set indicating that
only catalysts X10 [Pd(tBu3P)2] and X11 [PdCl2(DBPF)2] were
consistently successful in providing acceptable conversions to the
cross-coupled product. It should be pointed out here that in these
screening processes (Tables 1 and 2), no trace of biaryl side
products was observed and GC analysis indicated high yields of
cross-coupled products.
To assess the impact of intimate substitution in the alkene
coupling partner, we next examined methyl crotonate as a
substrate (Table 3). With a subset of the aryl bromide pool, yields
were generally acceptable with the exception of that of 2-
bromobenzoate (Table 3, entry E).
In the next phase of our study, we validated the yields of the
HM reactions of styrene and acrylates and examined the scope of
cross-coupling reactions using privileged catalyst X11 (the most
stable and easiest- handled of the triad of privileged catalysts
identified); Scheme 1 summarizes the results obtained from
single, unoptimized reactions, the majority of which proceeded in
high yield. In addition to the good yields for first-time reactions,
of particular note were the generally efficient reactions with
notoriously hindered substrates, such as 2,6-diethylbromoben-
zene, which delivered coupled product 17k in 77% yield (at 90%
conversion). It is also reassuring that variations in the electron
density of the oxidative addition substrates seem to have little
effect, with both electron-deficient and electron-rich aryl
bromides reacting efficiently. As mentioned above, it was
especially satisfying to witness the successful and generally
a
tetrabutylammonium chloride (TBAC). Thus, we commenced
with a study of HM reactions of styrene (Table 1).8 This process
quickly identified catalysts X9−X11 as privileged mediators of
the HM reaction, with electronic factors seemingly non-
significant, and only the sterically encumbered 2-ethyl
bromobenzene 7 proving to be a demanding coupling partner
(entries I7−K7). Because transition metal-catalyzed couplings of
ortho-substituted partners are usually sensitive to steric effects,
this was not surprising. Another noteworthy observation was the
efficient cross-coupling of 3-hydroxybromobenzene (entries B13
and C13 and I13−K13), because the literature is sparsely
populated by reports of successful HM reactions of unprotected
phenols.9
When the screening process was extrapolated to acrylates
(Table 2), catalysts X9−X11 again proved to be the most
effective mediators, but with less efficient conversions;
encouragingly, the cross-coupling of demanding substrate 7
proceeded with acceptable conversions (entries Q7, S7, and U7),
with methacrylate proving to be a more challenging substrate
partner (entries R7, T7, and V7). The reactions of the acrylate
B
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Table 2. A Generic Heck−Mizoroki Protocol for Acrylates
a
conversion (%)
entry
catalyst
1
2
3
4
5
6
7
8
9
10
11
76
12
92
13
acrylate
b
b
b
b
b
b
b
A
B
C
D
E
X1
NE
NE
99
30
0
42
NE
NE
45
0
81
26
0
99
62
0
NE
NE
0
24
0
0
30
0
NE
NE
0
0
0
15
16
15
16
15
16
15
16
15
16
15
16
15
16
15
16
15
16
15
16
15
16
b
8
0
0
17
32
0
29
0
X2
X3
X4
X5
X6
X7
X8
X9
X10
X11
67
0
0
0
52
64
75
75
0
0
0
0
0
0
0
0
0
b
b
b
b
NE
NE
NE
NE
60
15
15
0
99
75
99
15
100
48
67
29
0
99
99
30
0
3
0
15
0
99
0
99
99
60
15
0
99
30
45
0
99
99
99
15
100
25
60
6
F
0
0
0
G
H
I
0
3
0
15
0
0
0
0
0
0
0
0
100
24
100
28
0
0
100
53
100
37
44
10
99
60
77
55
90
46
93
100
0
57
57
93
77
0
0
100
0
100
34
100
25
100
18
45
0
9
J
0
0
0
0
0
0
K
L
15
0
30
0
3
0
0
0
0
0
0
0
0
0
M
N
O
P
30
0
99
0
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
b
99
15
99
99
99
99
99
99
NE
NE
15
0
30
0
3
0
15
0
15
0
0
45
0
15
0
b
0
0
0
Q
R
S
100
41
99
99
99
99
99
99
78
35
80
39
94
99
99
99
99
62
0
96
45
80
45
88
70
92
59
14
12
82
70
76
53
57
83
94
80
99
99
99
99
99
15
88
48
53
0
78
40
77
35
90
80
47
57
60
56
92
60
96
T
U
V
51
88
85
70
100
a
b
Assessed using GC/GCMS, using internal standards to ensure reproducibility. Reaction not examined.
efficient cross-couplings of 3-bromophenol (to give products
17o−r). Hetarene cross-coupling reactions using bromides
containing σ-donors (such as pyridines), known to be sluggish
substrates10 in HM reactions, proceed smoothly (to give
compounds 17s−aa). It is important to reiterate that these
data were obtained from first-pass, single reactions; to the best of
our knowledge, this is the first general HM protocol to be
identified as such a robust method.
To complete the study, having demonstrated the broad
applicability of our method in electron-neutral and electron-
deficient alkenes, we conducted a scoping analysis for electron-
rich and unpolarized alkene coupling partners. Thus, butyl vinyl
ether 18 reacted in good yield, but with variable regiocontrol
(Table 4).
Dimethylpentene 21 reacted in good yield with a subset of the
bromide coupling pool (Table 5), but with variable regiose-
lectivity (here the use of Cy2NMe as a base is crucial, because it
minimises the lifetime of transient Pd-H species, ensuring
selectivity likely results from β-hydride elimination rather than
isomerisation of the initial product7). In most cases, the major
product was styrene 22, which was always accompanied by
substantial (in the case of 3-bromopyridine, dominating)
amounts of isomerised linear product 23.
successfully identified the first general “first-pass” protocol which
provides good yields in cross-coupling, giving a broad range of
molecules of interest and utility to a diverse range of chemists.
The protocol has been used by a large number of industry
chemists and shown to be reliable and efficient, and also
applicable to compounds for which rigorous purification is not
possible. We are currently engaged in a more complete analysis of
Heck−Mizoroki reactions (especially with a view of reducing
catalyst loading) and the details of the mechanism in play (we
currently favor a process involving ligated mononuclear Pd
complexes as the catalytically competent species) and will
disclose our results in due course.
EXPERIMENTAL SECTION
■
Chemicals and Methods. All palladium catalysts were
purchased from Johnson Matthey. Dimethylacetamide (DMAC)
was purchased (>99% pure) from Acros as spectrophotometric
grade with <0.05% water and used without further purification or
drying. Dicyclohexylamaine (Cy2NMe) and tetrabutylammo-
nium chloride (TBAC) were purchased (>97% pure) from Fluka
and used as received. All alkenes and aryl bromides were
purchased from Aldrich and used as received. Catalysts were
b
stored and used in an MBraun glovebox. Solid reagents were
dispensed using a Mettler Toledo Flexiweigh. Liquid reagents,
base, and solvents were dispensed using a Mettler Toledo
MiniMapper. The removal of solvents in vacuo was achieved
CONCLUSION
■
This project was established to define an experimental protocol
for Heck−Mizoroki reactions which would be predictable and
robust using a range of substrates, in an industrial environment.
Our studies have probed the catalyst map for HM reactions and
using a Buchi rotary evaporator. Commercially available Merck
̈
Kieselgel 60F254 aluminium-backed plates were used for TLC
analysis. Visualisation was achieved by either UV fluorescence or
C
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Table 3. A Generic Heck−Mizoroki Protocol for Crotonate
a
1
Determined by H NMR.
a basic KMnO4 solution and heat. Flash column chromatography
(FCC) was performed using Radley’s prepacked Silica SPE
cartridges (10.0 g); the crude material was applied to the column
by preadsorption onto silica. Melting points were determined
using a Stuart Scientific melting point apparatus (aluminium
block) and are uncorrected. NMR spectra were recorded on a
Varian Inova 400 MHz spectrometer. Chemical shifts are quoted
MgSO4), and concentrated in vacuo to afford the crude product,
which was purified by FCC.
(E)-3-p-Tolylacrylic Acid Methyl Ester 17a.11 FCC (9:1 to
4:1 i-hexane/EtOAc) afforded the title compound (256 mg,
88%) as a colourless, crystalline solid: mp 51−52.5 °C (CH2Cl2/
i-hexane); δH (400 MHz, CDCl3) 2.36 (s, 3H), 3.79 (s, 3H), 6.39
(d, J = 16.0, 1H), 7.18 (d, J = 8.0, 2H), 7.41 (d, J = 8.0, 2H), 7.67
(d, J = 16.0, 1H); δC (100 MHz, CDCl3) 21.4, 51.6, 116.7, 128.0,
129.6, 131.6, 140.7, 144.8, 167.6. The spectroscopic properties of
this compound were consistent with reported data.
1
in parts per million; H NMR and 13C NMR spectra are
referenced to TMS as an internal standard. Coupling constants
(J) are quoted to the nearest 0.5 Hz. Other abbreviations used are
as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad. Assignments of 1H NMR and 13C NMR signals were
made, where possible, using COSY, HMQC, and HMBC
experiments. Mass spectra were determined by either electron
impact (EI) or chemical ionisation (CI) using a Varian Saturn
2000 msms instrument. Reactions were monitored by GC using a
Varian CP 3800 GC system. Analytical conditions: injector, 300
°C; column, 10 m × 0.53 mm fused silica coating UF 5 ms MS
DF 0.25 mm; GC, 1.5 mL/min constant flow, 100 °C, 0.5 min
hold, 60 °C/min to 300 °C, hold 2.17 min (total run time of 6
min); MS, 0 to 0.4 min; filament delay, 0.4 to 6 min, 50 to 450 m/
z EI auto.
General Experimental Procedure for the Heck Reac-
tion. In a glovebox (vide supra), PdCl2(DBPF) or Pd(tBu3P)2 (2
mol % relative to aryl bromide), TBAC (45.8 mg, 0.17 mmol),
4,4′-di-tert-butylbiphenyl (44 mg, 0.17 mmol, internal standard),
Cy2NMe (530 μL, 2.47 mmol), aryl bromide (1.65 mmol), and
alkene (1.2 or 2 equiv relative to aryl bromide) were dissolved in
N,N-dimethylacetamide (3.00 mL), and the resulting mixture
was heated to 80 °C for 24 h unless otherwise stated. The mixture
was then cooled to rt, diluted with methyl tert-butyl ether (25
mL), washed with water (2 × 25 mL), dried (Na2SO4 or
(E)-3-(4-Cyanophenyl)acrylic Acid Methyl Ester 17b.12
FCC (9:1 to 4:1 i-hexane/EtOAc) afforded the title compound
(290 mg, 94%) as a cream-coloured, crystalline solid: mp 110−
112 °C (CH2Cl2/i-hexane); δH (400 MHz, CDCl3) 3.83 (s, 3H),
6.52 (d, J = 16.0, 1H), 7.59−7.71 (m, 5H); δC (100 MHz,
CDCl3) 52.0, 113.4, 118.3, 121.3, 128.4, 132.6, 138.6, 142.4,
166.5. The spectroscopic properties of this compound were
consistent with reported data.
(E)-3-(4-Acetylphenyl)acrylic Acid Methyl Ester 17c.13
FCC (9:1 to 4:1 i-hexane/EtOAc) afforded the title compound
(316 mg, 94%) as a cream-coloured, crystalline solid: mp 95−97
°C (CH2Cl2/i-hexane); δH (400 MHz, CDCl3) 2.62 (s, 3H), 3.83
(s, 3H), 6.53 (d, J = 16.0, 1H), 7.58−7.63 (m, 2H), 7.71 (d, J =
16.0, 1H), 7.95−8.00 (m, 2H); δC (100 MHz, CDCl3) 26.6, 51.9,
120.3, 128.1, 128.8, 138.0, 138.7, 143.3, 166.9, 197.2. The
spectroscopic properties of this compound were consistent with
reported data.
(E)-3-(2-Ethyl)phenylacrylic Acid Methyl Ester 17d.14
FCC (9:1 to 4:1 i-hexane/EtOAc) afforded the title compound
(276 mg, 88%) as a colourless oil: δH (400 MHz, CDCl3) 1.21 (t,
J = 7.5, 3H), 2.78 (q, J = 7.5, 2H), 3.81 (s, 3H), 6.37 (d, J = 16.0,
1H), 7.18−7.24 (m, 2H), 7.28−7.33 (m, 1H), 7.52−7.57 (m,
D
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Scheme 1. A Generic Heck−Mizorocki Protocol for Validation
a
A 50:50 ratio of alkenes.
b
Yield based on recovered SM.
c
A 80:20 ratio of alkenes.
d
A 1,2:1,1-prodict = 92:8.
e
A 92:8 ratio of alkenes.
1H), 8.02 (d, J = 16.0, 1H); δC (100 MHz, CDCl3) 15.8, 26.3,
51.6, 119.0, 126.3, 126.5, 129.2, 130.2, 132.7, 142.3, 143.8, 167.4.
The spectroscopic properties of this compound were consistent
with reported data.
m/z (EI+) 210 ([M]+, 100%). The spectroscopic properties of
this compound were consistent with reported data.
(E)-3-(2-Methoxyphenyl)acrylic Acid Methyl Ester
17f.16 FCC (1:0 to 19:1 i-hexane/EtOAc) afforded the title
compound (196 mg, 62%) as a colourless oil: δH (400 MHz,
CDCl3) 3.79 (s, 3H), 3.87 (s, 3H), 6.53 (d, J = 16.0, 1H), 6.90 (d,
J = 8.0, 1H), 6.95 (t, J = 7.5, 1H), 7.31−7.36 (m, 1H), 7.50 (dd, J
= 7.5, 1.5, 1H), 8.00 (d, J = 16.0, 1H); δC (100 MHz, CDCl3)
51.6, 55.4, 111.1, 118.2, 118.2, 123.3, 128.9, 131.5, 140.2, 158.3,
167.9. The spectroscopic properties of this compound were
consistent with reported data.
1-Methoxy-2-[(E)-styryl]benzene 17e.15 FCC (1:0 to
19:1 i-hexane/EtOAc) afforded the title compound (196 mg,
56%) as a colourless oil: δH (400 MHz, CDCl3) 3.86 (s, 3H), 6.81
(td, J = 7.5, 1.5, 1H), 6.85−6.90 (m, 2H), 6.96 (t, J = 7.5, 1H),
7.10 (d, J = 16.5, 1H), 7.20−7.27 (m, 2H), 7.30−7.36 (m, 1H),
7.49 (d, J = 16.5, 1H), 7.51−7.54 (m, 1H), 7.57−7.60 (m, 1H);
E
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Table 4. A Generic Heck−Mizoroki Protocol for Vinyl Ethers
a
b
c
1
Estimated from H NMR spectra of crude products. Yield based on recovered SM. Yield of the corresponding carbonyl compound.
Table 5. A Generic Heck−Mizoroki Protocol for Dimethylpentene
a
b
1
Yield based on recovered SM. Estimated from H NMR spectra of crude products.
2-[(E)-2-Methoxycarbonyl]phenyl Acrylic Acid Methyl
MHz, CDCl3) 51.7, 52.3, 120.6, 127.9, 129.3, 129.7, 130.7, 132.3,
136.3, 143.9, 166.9, 167.1. The spectroscopic properties of this
compound were consistent with reported data.
Ester 17g3. FCC (9:1 to 7:3 i-hexane/EtOAc) afforded the title
compound (338 mg, 93%) as a pale yellow oil: δH (400 MHz,
CDCl3) 3.81 (s, 3H), 3.93 (s, 3H), 6.31 (d, J = 16.0, 1H), 7.43
(td, J = 7.5, 1.5, 1H), 7.51−7.55 (m, 1H), 7.59 (dd, J = 7.5, 1.0,
1H), 7.96 (dd, J = 7.0, 1.0, 1H), 8.45 (d, J = 16.0, 1H); δC (100
2-[(E)-Styryl]benzoic Acid Methyl Ester 17h.17 FCC (1:0
to 19:1 i-hexane/EtOAc) afforded the title compound (300 mg,
76%) as a colourless oil: δH (400 MHz, CDCl3) 3.91−3.92 (m,
F
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3H), 7.00 (d, J = 15.5, 1H), 7.21−7.39 (m, 4H), 7.49 (td, J = 7.5,
1.5, 1H), 7.52−7.56 (m, 2H), 7.71 (d, J = 7.5, 1H), 7.92 (dd, J =
8.0, 1.5, 1H), 7.99 (d, J = 16.0, 1H); m/z (EI+) 238 ([M]+,
100%). The spectroscopic properties of this compound were
consistent with reported data.
(characteristic signals only) 3.66 (d, J = 1.5, 2H), 3.74 (s, 3H),
5.57 (dt, J = 1.5, 1.0, 1H), 6.29−6.30 (m, 1H); δC (100 MHz,
CDCl3) (signals for exo only) 14.0, 52.3, 112.8, 118.4, 129.3,
130.9, 131.5, 132.7, 133.6, 136.2, 137.1, 168.3; m/z (EI+) 201
([M]+, 40%), 141 (100); HRMS-GCT m/z [M+] calcd for
C12H11NO2 201.0790, found 201.0786.
2-[(E)-2-Methoxycarbonylpropenyl]benzoic Acid
Methyl Ester and 2-(2-Methoxycarbonylallyl)benzoic
Acid Methyl Ester 17i. FCC (1:0 to 4:1 i-hexane/EtOAc)
afforded the title compound (302 mg, 78%, 1:1 endo:exo) as a
pale yellow oil and as an inseparable mixture of isomers: δH (400
MHz, CDCl3) 1.90 (d, J = 1.5, 3H, endo), 3.76 (s, 3H), 3.83 (s,
3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.02−4.03 (m, 2H, exo), 5.21 (dt,
J = 1.5, 1.0, 1H, exo), 6.18−6.20 (m, 1H, exo), 7.15−7.56 (m,
6H), 7.89−8.06 (m, 2H), 8.10 (s, 1H, endo); δC (400 MHz,
CDCl3) 13.8, 35.9, 51.9, 51.9, 52.0, 52.1, 125.6, 126.5, 127.8,
127.9, 130.0, 130.2, 130.7, 130.8, 131.5, 131.9, 132.0, 137.8,
139.7, 140.0, 140.1, 142.4, 166.9, 167.4, 167.7, 168.8. The
s p e c t r o s c o p i c p r o p e r t i e s o f 2 - [ ( E ) - 2 -
methoxycarbonylpropenyl)benzoic acid methyl ester18 were
consistent with the data available in the literature.
3-[(E)-Styryl]phenol 17o.22 FCC (1:0 to 4:1 i-hexane/
EtOAc) afforded the title compound (320 mg, 99%, ∼12:1 β:α)
as a cream-coloured solid: mp 109−109 °C (CH2Cl2/i-hexane);
δH (400 MHz, CDCl3) (data for β-17o only) 6.73 (ddd, J = 8.0,
2.0, 0.5, 1H), 7.05 (d, J = 4.5, 1H), 7.06−7.10 (m, 2H), 7.19−
7.28 (m, 2H), 7.32−7.37 (m, 2H), 7.47−7.51 (m, 2H); δC (100
MHz, CDCl3) (data for β-17o only) 113.0, 114.7, 119.5, 126.6,
127.7, 128.2, 128.7, 129.2, 129.9, 137.1, 139.1, 155.7. The
spectroscopic properties of this compound were consistent with
reported data.
(E)-3-(3-Hydroxyphenyl)-2-methylacrylic Acid Methyl
Ester 17p. FCC (1:0 to 4:1 i-hexane/EtOAc) afforded the title
compound (220 mg, 70%) as a pale yellow solid: mp 58−60 °C
(CH2Cl2/i-hexane); νmax (film) 3372 (br m), 1682 (s), 1579
(m), 1435 (s), 1241 (s), 1115 (s) cm−1; δH (400 MHz, CDCl3)
2.11 (d, J = 1.5, 3H), 3.83 (s, 3H), 6.14 (br s, 1H) 6.84 (dd, J =
8.0, 2.0, 1H), 6.89−6.92 (m, 1H), 6.94 (dd, J = 7.5, 0.5, 1H), 7.25
(t, J = 8.0, 1H), 7.65 (s, 1H); δC (100 MHz, CDCl3) 14.1, 52.3,
115.6, 116.4, 122.0, 128.3, 129.6, 137.2, 139.2, 155.8, 169.7; m/z
(CI+) 193 ([M + H]+, 100%); HRMS-GCT m/z [M+] calcd for
C11H12O3 192.0786, found 192.0745.
(E)-3-(3-Hydroxyphenyl)acrylic Acid Methyl Ester
17q.23 FCC (9:1 to 3:2 i-hexane/EtOAc) afforded the title
compound (270 mg, 92%) as a a pale yellow, crystalline solid: mp
78−79 °C (CH2Cl2/i-hexane); δH (400 MHz, CDCl3) 3.82 (s,
3H), 6.40 (d, J = 16.0, 1H), 6.91 (ddd, J = 8.0, 2.5, 1.0, 1H),
7.02−7.09 (m, 2H), 7.21−7.27 (m, 1H), 7.65 (d, J = 16.0, 1H);
δC (100 MHz, CDCl3) 52.0, 114.6, 117.7, 117.8, 120.7, 130.1,
135.7, 145.2, 156.3, 168.1. The spectroscopic properties of this
compound were consistent with reported data.
(E)-3-(3-Hydroxyphenyl)but-2-enoic Acid Methyl Ester
17r. FCC (1:0 to 9:1 i-hexane/EtOAc) afforded the title
compound (188 mg, 59%) as a pale yellow solid: mp 50−51 °C
(CH2Cl2/i-hexane); νmax (film) 3381 (br m), 1687 (s), 1622 (s),
1579 (m), 1435 (s), 1351 (m), 1294 (m), 1171 (s) cm−1; δH (400
MHz, CDCl3) 2.55 (s, 3H), 3.76 (s, 3H), 6.13 (s, 1H), 6.85 (dd, J
= 8.0, 2.5, 1H), 6.93−6.96 (m, 1H), 7.03 (d, J = 7.5, 1H), 7.20−
7.27 (m, 1H); δC (100 MHz, CDCl3) 18.0, 51.2, 113.3, 116.0,
116.8, 118.7, 129.7, 143.8, 155.7, 155.7, 167.5; m/z (EI+) 192
([M]+, 10%), 160 (100); HRMS-GCT m/z [M+] calcd for
C11H12O3 192.0786, found 192.0780.
(E)-3-(2-Formylphenyl)acrylic Acid Methyl Ester 17j.19
FCC (9:1 to 7:3 i-hexane/EtOAc) afforded the title compound
(257 mg, 82%) as a yellow, crystalline solid: mp 48−49 °C
(CH2Cl2/i-hexane); δH (400 MHz, CDCl3) 3.84 (s, 3H), 6.38 (d,
J = 16.0, 1H), 7.53−7.66 (m, 3H), 7.86−7.90 (m, 1H), 8.54 (d, J
= 16.0, 1H), 10.29 (s, 1H); δC (100 MHz, CDCl3) 51.9, 122.7,
127.9, 129.9, 132.4, 133.8, 133.9, 136.5, 141.2, 166.6, 191.8. The
spectroscopic properties of this compound were consistent with
reported data.
(E)-3-(2,6-Diethylphenyl)acrylic Acid Methyl Ester 17k.
FCC (1:0 to 19:1 i-hexane/EtOAc) afforded the title compound
(260 mg, 72%) as a yellow oil: νmax (film) 1721 (s), 1639 (m),
1454 (m), 1307 (m), 1269 (m), 1192 (m) cm−1; δH (400 MHz,
CDCl3) 1.18 (t, J = 7.5, 6H), 2.65 (q, J = 7.5, 4H), 3.82 (s, 3H),
6.04 (d, J = 16.5, 1H), 7.09 (d, J = 7.5, 2H), 7.21 (t, J = 7.5, 1H),
7.90 (d, J = 16.0, 1H); δC (100 MHz, CDCl3) 15.4, 26.8, 51.7,
123.8, 126.2, 128.5, 133.4, 142.3, 143.9, 166.9; m/z (CI+) 219
([M + H]+, 100%); HRMS-GCT m/z [M+] calcd for C14H18O2
218.1307, found 218.1297.
3-[(E)-Styryl]benzonitrile 17l.20 FCC (1:0 to 4:1 i-hexane/
EtOAc) afforded the title compound (302 mg, 89%) as a
colourless solid: mp 61−62 °C (CH2Cl2/i-hexane); δH (400
MHz, CDCl3) 7.03 (d, J = 16.5, 1H), 7.13 (d, J = 16.5, 1H),
7.26−7.46 (m, 6H), 7.47−7.54 (m, 2H), 7.66−7.72 (m, 1H),
7.72−7.77 (m, 1H); δC (100 MHz, CDCl3) 112.9, 118.8, 126.2,
126.8, 128.4, 128.8, 129.5, 129.8, 130.5, 130.7, 131.3, 136.3,
138.6. The spectroscopic properties of this compound were
consistent with reported data.
3-[(E)-Styryl]pyridine 17s.24 FCC (1:0 to 2:1 i-hexane/
EtOAc) afforded the title compound (165 mg, 55%) as a pale
yellow, crystalline solid: mp 68−70 °C (CH2Cl2/i-hexane); δH
(400 MHz, CDCl3) 7.06 (d, J = 16.5, 1H), 7.16 (d, J = 16.5, 1H),
7.24−7.32 (m, 2H), 7.34−7.40 (m, 2H), 7.50−7.54 (m, 2H),
7.81 (ddd, J = 8.0, 2.0, 2.0, 1H), 8.48 (dd, J = 5.0, 1.5, 1H), 8.72
(d, J = 2.0, 1H); δC (100 MHz, CDCl3) 123.5, 124.9, 126.6,
128.2, 128.8, 130.8, 132.6, 133.0, 136.6, 148.5 (only 10 signals
observed). The spectroscopic properties of this compound were
consistent with reported data.
(E)-3-(3-Cyanophenyl)acrylic Acid Methyl Ester 17m.21
FCC (9:1 to 4:1 i-hexane/EtOAc) afforded the title compound
(290 mg, 94%) as a cream-coloured, crystalline solid: mp 120−
121 °C (CH2Cl2/i-hexane); δH (400 MHz, CDCl3) 3.83 (s, 3H),
6.49 (d, J = 16.0, 1H), 7.52 (t, J = 8.0, 1H), 7.63−7.69 (m, 2H),
7.72−7.76 (m, 1H), 7.78−7.80 (m, 1H); δC (100 MHz, CDCl3)
51.9, 113.4, 118.1, 120.5, 129.8, 131.3, 131.9, 133.2, 135.6, 142.0,
166.6. The spectroscopic properties of this compound were
consistent with reported data.
(E)-3-(3-Cyanophenyl)-2-methylacrylic Acid Methyl
Ester 17n. FCC (1:0 to 7:3 i-hexane/EtOAc) afforded the
title compound (264 mg, 80%, 4:1 endo:exo) as a pale pink oil:
νmax (film) 2230 (m), 1710 (s), 1482 (m), 1435 (s), 1263 (s),
1179 (m) cm−1; δH (400 MHz, CDCl3) endo 2.10 (d, J = 1.5, 3H),
3.84 (s, 3H), 7.52 (dd, J = 7.50, 7.5, 1H), 7.62 (m, 4H), exo
(E)-3-Pyridin-3-ylacrylic Acid Methyl Ester 17t.25 FCC
(1:0 to 2:1 i-hexane/EtOAc) afforded the title compound (195
mg, 72%) as a yellow, crystalline solid: mp 38−40 °C (CH2Cl2/i-
hexane); δH (400 MHz, CDCl3) 3.83 (s, 3H), 6.52 (d, J = 16.0,
1H), 7.33 (dd, J = 8.0, 5.0, 1H), 7.69 (d, J = 16.0, 1H), 7.84 (ddd,
J = 8.0, 2.0, 1.5, 1H), 8.61 (dd, J = 5.0, 1.5, 1H), 8.75 (d, J = 2.0,
G
dx.doi.org/10.1021/op300364p | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
1H); δC (100 MHz, CDCl3) 51.8, 120.0, 123.7, 130.1, 134.1,
141.1, 149.7, 151.0, 166.7. The spectroscopic properties of this
compound were consistent with reported data.
MHz, CDCl3) 2.35 (s, 3H), 2.58 (d, J = 1.0, 3H), 3.74 (s, 3H),
5.98−6.00 (m, 1H), 6.86 (d, J = 5.0, 1H), 7.22 (d, J = 5.0, 1H); δC
(100 MHz, CDCl3) 16.2, 20.5, 51.1, 117.4, 124.6, 131.8, 135.5,
139.7, 149.7, 167.0; m/z (EI+) 196 ([M]+, 40%), 137 (100);
HRMS-GCT m/z [M+] calcd for C10H12O2S 196.0558, found
196.0543.
(E)-3-Quinolin-7-ylacrylic Acid Methyl Ester 17u. FCC
(1:0 to 2:1 i-hexane/EtOAc) afforded the title compound (293
mg, 83%) as a yellow solid: mp 86−87 °C (CH2Cl2/i-hexane);
νmax (film) 1704 (s), 1635 (s), 1500 (m), 1432 (m), 1280 (s)
cm−1; δH (400 MHz, CDCl3) 3.84 (s, 3H), 6.57 (d, J = 16.0, 1H),
7.42 (dd, J = 8.0, 4.5, 1H), 7.85 (d, J = 16.0, 1H), 7.87−7.91 (m,
2H), 8.08−8.12 (m, 1H), 8.16 (dd, J = 8.5, 1.0, 1H), 8.92 (dd, J =
4.0, 2.0, 1H); δC (100 MHz, CDCl3) 51.8, 119.1, 121.8, 127.2,
128.2, 129.2, 130.3, 132.6, 136.4, 143.8, 149.0, 151.3, 167.1; m/z
(CI+) 214 ([M + H]+, 100%); HRMS-GCT m/z [M+] calcd for
C13H11NO2 213.0790, found 213.0778.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data for products 17a−aa. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
j.b.sweeney@hud.ac.uk (J.B.S.) or paul.murray@catsci.com
(P.M.M.)
■
(E)-3-(1H-Indol-6-yl)acrylic Acid Methyl Ester 17v.26
FCC (1:0 to 2:1 i-hexane/EtOAc) afforded the title compound
(304 mg, 91%) as a yellow solid: mp 91−92 °C (CH2Cl2/i-
hexane); δH (400 MHz, CDCl3) 3.81 (s, 3H), 6.45 (d, J = 16.0,
1H), 6.50−6.53 (m, 1H), 7.26 (t, J = 3.0, 1H), 7.33 (dd, J = 8.5,
1.5, 1H), 7.50 (s, 1H), 7.61 (d, J = 8.5, 1H), 7.82 (d, J = 16.0, 1H),
8.56 (br s, 1H); δC (100 MHz, CDCl3) 51.6, 103.0, 112.3, 115.2,
119.4, 121.1, 126.6, 128.3, 129.9, 135.9, 146.6, 168.2. The
spectroscopic properties of this compound were consistent with
reported data.
Present Addresses
§CatScI Ltd., CBCT2, Capital Business Park, Cardiff CF3 2PX,
U.K.
∥AstraZeneca, Charter Way, Silk Road Business Park, Maccles-
field, Cheshire SK10 2NA, U.K.
Notes
The authors declare no competing financial interest.
3-Methyl-2-[(E)-styryl]thiophene 17w.27 FCC (i-hexane)
afforded the title compound (211 mg, 64%) as a colourless solid:
mp 48−49 °C (CH2Cl2/i-hexane); δH (400 MHz, CDCl3) 2.31
(s, 3H), 6.82 (d, J = 5.0, 1H), 6.86 (d, J = 16.0, 1H), 7.08 (d, J =
5.0, 1H), 7.20−7.26 (m, 2H), 7.31−7.36 (m, 2H), 7.45−7.49 (m,
2H); δC (100 MHz, CDCl3) 14.0, 120.3, 122.8, 126.2, 127.4,
127.7, 128.7, 130.8, 135.6, 136.4, 137.3. The spectroscopic
properties of this compound were consistent with reported data.
(E)-3-Thiophen-3-ylacrylic Acid Methyl Ester 17x.28
FCC (1:0 to 19:1 i-hexane/EtOAc) afforded the title compound
(223 mg, 80%) as a colourless, crystalline solid: mp 44−46 °C
(CH2Cl2/i-hexane); δH (400 MHz, CDCl3) 3.79 (s, 3H), 6.26 (d,
J = 16.0, 1H), 7.29 (dd, J = 5.0, 1.0, 1H), 7.33 (ddd, J = 5.0, 3.0,
0.5, 1H), 7.49 (dd, J = 3.0, 1.0, 1H), 7.68 (d, J = 16.0, 1H); δC
(100 MHz, CDCl3) 51.6, 117.4, 125.1, 126.9, 128.1, 137.5, 138.3,
167.6. The spectroscopic properties of this compound were
consistent with reported data.
(E)-3-(3-Methylthiophen-2-yl)acrylic Acid Methyl Ester
17y.29 FCC (1:0 to 19:1 i-hexane/EtOAc) afforded the title
compound (232 mg, 77%) as a colourless oil: δH (400 MHz,
CDCl3) 2.33 (s, 3H), 3.78 (s, 3H), 6.17 (d, J = 15.5, 1H), 6.86 (d,
J = 5.0, 1H), 7.24 (d, J = 5.0, 1H), 7.85 (dd, J = 15.5, 1.0, 1H); δC
(100 MHz, CDCl3) 14.1, 51.6, 115.5, 126.9, 131.1, 133.5, 135.6,
141.3, 167.5. The spectroscopic properties of this compound
were consistent with reported data.
(E)-2-Methyl-3-(3-methylthiophen-2-yl)acrylic Acid
Methyl Ester 17z. FCC (1:0 to 19:1 i-hexane/EtOAc) afforded
the title compound (257 mg, 80%, 12:1 endo:exo) as a pale yellow
oil: νmax (film) 1699 (s), 1613 (m), 1433 (m), 1259 (s), 1120 (s)
cm−1; δH (400 MHz, CDCl3) (for 30 only) 2.21 (d, J = 1.5, 3H),
2.36 (s, 3H), 3.81 (s, 3H), 6.93 (q, J = 5.5, 1H), 7.39 (d, J = 5.0,
1H), 7.90−7.92 (m, 1H); δC (100 MHz, CDCl3) (data for 30
only) 14.2, 14.5, 52.2, 123.5, 127.6, 130.0, 130.2, 132.8, 140.7,
169.2; m/z (EI+) 196 ([M]+, 12%), 165 (100); HRMS-GCT m/z
[M+] calcd for C10H12O2S 196.0558, found 196.0529.
(E)-3-(3-Methylthiophen-2-yl)but-2-enoic Acid Methyl
Ester 17aa. FCC (1:0 to 9:1 i-hexane/EtOAc) afforded the title
compound (173 mg, 53%) as a yellow oil: νmax (film) 1710 (s),
1612 (s), 1433 (m), 1339 (m), 1258 (m), 1170 (s) cm−1; δH (400
ACKNOWLEDGMENTS
J.B.S. acknowledges the financial support of EPSRC and the
Royal Society (for provision of an Industry Fellowship).
■
ADDITIONAL NOTES
The addition of TBAC increases catalyst activity and
conversions. We thank Prof. G. C. Fu (Massachusetts Institute
of Technology, Cambridge, MA) for this recommendation.
The glovebox was used only to facilitate the automated
dispensing of reagents. The protocol is perfectly applicable under
“normal” (i.e., without O2 exclusion) laboratory conditions;
indeed, this was a key criterion of the project.
■
a
b
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