Parameters Influencing Reactivity and Regioselectivity in the Methoxycarbonylation of Arylalkenes

Article abstract of DOI:10.1055/s-0035-1560912

Previous research showed that the steric bulk, electronic character, and bite angle of the ligand have an influence on both the catalyst activity and regioselectivity of hydroformylation and hydroesterification reactions. However, little is known in this regard about the influence of the steric and electronic environment around the double bond of the substrate. A variety of arylalkenes were therefore subjected to methoxycarbonylation to investigate the steric and electronic effects of substituents on the aromatic ring of the substrate on the regioselectivity and reactivity in the methoxycarbonylation reaction of these substrates with a Pd(II)/Al(OTf)₃/Ph₃P catalyst system.

Full text of DOI:10.1055/s-0035-1560912

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 557–565
paper
557
M. du Plessis et al.
Paper
Synthesis
Parameters Influencing Reactivity and Regioselectivity in the
Methoxycarbonylation of Arylalkenes
Maretha du Plessis
R3
R1
Charlene Marais
R1
Pd(OAc)2, Al(OTf)3, Ph3P
R2
Barend C. B. Bezuidenhoudt*
R2
MeOH, CO
R4
Department of Chemistry, University of the Free State,
PO Box 339, Bloemfontein 9300, South Africa
bezuidbc@ufs.ac.za
16–96% conversion
R1
R3
17 examples
R1 = H, p-OMe, o-OMe, p-CF3, o-OTf
R1 = H, p-OMe, o-OMe, p-CF3, o-OTf
R
R
2 = H, Me, Ph
3 = H, Ph
R
R
R
2 = H, Me, Ph, Bn, CH2COOMe, COOMe
3 = H, COOMe, Me
4 = H, COOMe, Me
Received: 15.09.2015
Accepted after revision: 12.10.2015
Published online: 24.11.2015
mers of the ester products, the regioselectivity and enan-
tioselectivity of methoxycarbonylations have been studied
extensively and led to, amongst others, the effect of many
Brønsted [e.g., MsOH, TfOH, p-TsOH, borosalicylic acid
(BSA)]14,16,17 and Lewis acids [e.g., Al(OTf)3]18,19 as well as
combinations of the two types, being studied. The applica-
tion requirements of linear versus branched products (or
vice versa) as well as catalyst life-time also led to the evalu-
ation of a plethora of mono- and bidentate ligands to be
used in the catalyst system.20–26 During these studies the
substituents on the phosphorus atom were varied to evalu-
ate the effect of electron-donating or electron-withdrawing
groups attached to the ligand on catalyst activity and selec-
tivity towards the linear product,14,27,28 as well as towards
the preferential formation of the branched product.29,30
Other studies focused on the use of heterobidentate P,N-do-
nor ligands,31–33 and chelating nitrogen ligands31,34 as well
as the effect of the counterion14,16–19 in this regard. While
several reports covered the issue of regioselective control
induced by the ligands present in the catalyst system, only
two papers deal to some extent with the effect of the sub-
strate on the linear to branched ratio found in the products.
In this regard, Claver et al.35 varied the substituents in the
para-position of styrene and found the reactivity of the
substrate to decrease as the electron-donating nature of the
substituent decreases, while virtually no influence on the
linear/branched (l/b) ratio of the product was observed
when a PdCl2/Phosphetane/p-TsOH catalysts system was
employed. Similar results with regard to l/b ratio and reac-
tivity of styrenes were observed by Alper et al.14 when re-
acting substituted styrenes, and α-methylstyrenes with
palladium–borate complexes as catalysts. In this instance,
however, electron-donating substituents attached to allyl-
benzene gave lower yields and/or required longer reaction
times when compared to the unsubstituted analogue.
DOI: 10.1055/s-0035-1560912; Art ID: ss-2015-t0537-op
Abstract Previous research showed that the steric bulk, electronic
character, and bite angle of the ligand have an influence on both the
catalyst activity and regioselectivity of hydroformylation and hydroes-
terification reactions. However, little is known in this regard about the
influence of the steric and electronic environment around the double
bond of the substrate. A variety of arylalkenes were therefore subjected
to methoxycarbonylation to investigate the steric and electronic effects
of substituents on the aromatic ring of the substrate on the regioselec-
tivity and reactivity in the methoxycarbonylation reaction of these sub-
strates with a Pd(II)/Al(OTf)3/Ph3P catalyst system.
Key words hydroesterification, arylalkenes, palladium, aluminum tri-
flate, regioselectivity
The alkoxycarbonylation of alkenes (also known as hy-
droesterification or hydroalkoxycarbonylation), a specific
variation of carbonylation (the Reppe reaction, which might
involve various nucleophiles) was first reported by Reppe in
1953.1,2 While Reppe’s initial discovery triggered a vast
number of publications, patents and reviews covering many
aspects of the alkoxycarbonylation reaction, some topics,
like the exact catalytic cycle for all catalyst systems, are still
not fully understood.3–7 Although cobalt,3,8,9 nickel,1–3 and
other transition-metal catalysts3 have been reported for the
Reppe carbonylation reaction, palladium-based catalysts
are the catalysts of choice as palladium allows for milder re-
action conditions.3,10–13 In these reactions, the Pd-catalyst
accompanied by an acid promoter is used to transform a
mixture of olefin, alcohol, and carbon monoxide into linear
or branched esters, which may find applications in the
fields of fatty acid derived lubricants, surfactants, per-
fumes, flavorings, and anti-inflammatory agents.3,6,7,13–15
Since different applications require different structural iso-
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558
M. du Plessis et al.
Paper
Synthesis
Due to the fact that the solubility of some of the envis-
aged substrates (vide infra) were rather low in pure metha-
nol, the effect of less polar solvent mixtures on the meth-
oxycarbonylation of trans-β-methylstyrene (1) was subse-
quently investigated with PdCl2 as catalyst. As is evident
from the data in Table 1 and in agreement with literature
results,35 it was found that pure methanol outperforms all
other solvent systems, with a combination of methanol and
THF (1:1) or methanol and dimethoxyethane (1:1) being
the best solvent mixtures investigated for substrates not
soluble in methanol.
95%
94%
T = 95 °C
77%
T = 85 °C
stirring at
700 rpm
97%
92%
stirring at
300 rpm
T = 100 °C
1
T = 105 °C
Table 1 Solvent System Optimization for trans-β-Methylstyrene (1)
P = 45 bar
Carbonylationa
98%
97%
P = 25 bar
93%
Entry
Catalyst system
Solvent system (ratio)b
Conv. (%)c
1
2
3
4
5
6
PdCl2/Al(OTf)3/Ph3P
PdCl2/Al(OTf)3/Ph3P
PdCl2/Al(OTf)3/Ph3P
PdCl2/Al(OTf)3/Ph3P
PdCl2/Al(OTf)3/Ph3P
PdCl2/Al(OTf)3/Ph3P
MeOH
90
80
34
ndd
60
61
Figure 1 Optimization of reaction conditions for the methoxycarbon-
ylation of trans-β-methylstyrene (1). Reaction conditions: Pd(OAc)2 (5
mol%), Al(OTf)3 (10 mol%), Ph3P (20 mol%) in MeOH (8 mL) for 3 h at
95 °C, 35 bar CO pressure, and 500 rpm stirring speed, unless indicated
otherwise.
EtOH
MeOH–toluene (3:2)
MeOH–DMA (3:2)
MeOH–DME (1:1)
MeOH–THF (1:1)
In this paper, we would like to report on the influence of
the electronic and steric environment present in the arylal-
kene on regioselectivity and reactivity in the methoxycar-
bonylation of these substrates when utilizing the
Pd(OAc)2/Al(OTf)3/Ph3P catalyst system.
a Reaction conditions: PdCl2 (1 mol%), Al(OTf)3 (2 mol%), Ph3P (4 mol%) in
for 24 h.
b DMA = N,N-dimethylacetamide; DME = 1,2-dimethoxyethane.
c Determined by GC with xylene as internal standard.
d Not detected.
The Pd(II)/Al(OTf)3/Ph3P catalyst system, developed by
Williams et al.,18 was chosen for optimization of the meth-
oxycarbonylation reaction conditions for the selected aryl-
alkene substrates and it was decided to use trans-β-methyl-
styrene (1) as substrate for the optimization process (Figure
1). Three variables – temperature, pressure, and the speed
of mechanical stirring – were considered during optimiza-
tion of the reaction conditions with methanol as solvent.
When trans-β-methylstyrene (1) was subjected to 35 bar
CO in MeOH with Pd(OAc)2, Al(OTf)3, and Ph3P, decreasing
the temperature from 95 to 85 °C caused a drastic decrease
in the conversion (determined by GC) from 95 to 77%. How-
ever, an increase in temperature to beyond 95 °C did not
have a significant effect on the conversion. Since an in-
crease or decrease in external CO pressure and CO concen-
tration in solution (stirring speed with a gas-entrainment
stirrer) seems to have very little effect on the conversion, it
was decided to perform all subsequent reactions at 95 °C,
35 bar of CO pressure, and 500 rpm.
To be able to compare the results from the current in-
vestigation with literature, oct-1-ene (2) and styrene (4),
both renowned for high reactivity and therefore widely
used during the development of methoxycarbonylation
methodologies and catalyst systems, were subjected to the
optimized reaction conditions first (Scheme 1). As is evi-
dent from Table 2, both these substrates gave high conver-
sions to mainly the linear products 5 and 7 (l/b ratio, both
3:1). Since it is known that palladium may cause double
bond isomerization36,37 and disubstituted alkenes are less
reactive than their monosubstituted counterparts,13 the
low yield despite high conversion observed for the oct-1-
ene reaction may be due to isomerization to internal
octenes, of which the 3- and 4-isomers did not give any ob-
servable hydroesterification products. The conversion ob-
served for styrene (4) (91%) was in good agreement with
what was reported by Williams et al.18 (81–98%).
R3
Pd(OAc)2 (5 mol%), Al(OTf)3 (10 mol%), Ph3P (20 mol%)
R1
R2
R2
R1
MeOH, CO (35 bar), 95 °C
68–87%
2 R1 = (CH2)5Me, R2 = H
3 R1 = (CH2)4Me, R2 = Me
4 R1 = Ph, R2 = H
5 R1 = (CH2)5Me, R2 = COOMe, R3 = H
6 R1 = (CH2)5Me, R2 = H, R3 = COOMe
7 R1 = Ph, R2 = COOMe, R3 = H
8 R1 = Ph, R2 = H, R3 = COOMe
Scheme 1 Methoxycarbonylation of oct-1-ene (2), oct-2-ene (3), and styrene (4)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 557–565

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M. du Plessis et al.
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Table 2 Methoxycarbonylation of Oct-1-ene (2), Oct-2-ene (3), and
Styrene (4)
isomerization
R
R
R = H or OMe
Entry Substrate Time
(min)
Conv.
(%)a
Yield
(%)a
Products
(l/b ratio)
TOF
b
(h–1
)
methoxycarbonylation
COOMe
1
2
3
2
3
4
25
100
25
100
83
76
68
87
5/6 (3:1)
5/6 (2:1)
7/8 (3:1)
104
15
91
113
R
R
R
COOMe
a Determined by GC with xylene as internal standard.
b Turnover frequency based on Pd(OAc)2.
linear
benzylic
branched
COOMe
Scheme 3 Formation of linear (l), branched (b), and benzylic (bn)
products via isomerization of the double bond
When trans-β-methylstyrene (1) was subjected to the
optimized conditions (Scheme 2), three products in a ratio
of 3:2:1 were obtained in a combined yield of 89% and a
conversion of 95% after three hours (Table 3, entry 1). The
first product (tR = 19.8 min.) was identified as the linear
product (l), 4-phenylbutanoic acid (16), while the second
and third products (tR = 17.3 and 16.7 min, respectively)
were recognized as the branched (b) and benzylic (bn)
products, 17 and 18, respectively, by GC, GC/MS, and 1H
NMR analyses. Due to palladium’s ability to catalyze double
bond isomerization,36,37 the formation of the linear product
16 is explicable in terms of palladium-catalyzed isomeriza-
tion of the double bond to the terminal position prior to
methoxycarbonylation (Scheme 3).
Extending the reaction to allylbenzene (11) resulted in
the same three products 16, 17, and 18 being formed in 88%
yield, albeit in a ratio of 8:2:1 and a conversion of 96% after
90 minutes. The formation of the third product 18, with the
ester moiety in the benzylic position, can again be ascribed
to palladium-catalyzed isomerization of the double bond
(Scheme 3). When the reaction was extended to trans-p-
methoxy-β-methylstyrene (anethole) (9) and p-methoxy-
substituted allylbenzene (4-allylanisole, 12), prolonged re-
action times (4 h) were required for the formation of the l
19, b 20, and bn 21 products with conversions of 49 and
66%, respectively (yields of 48 and 54% and l:b:bn ratios of
2:1:1 and 7:1:1, respectively) (Table 3, entries 2 and 5).
When the reaction of trans-β-methylstyrene (1) is com-
pared to that of its p-methoxy-substituted analogue 9, it is
clear that the addition of an electron-donating substituent
to the aromatic ring results in a decrease in overall reactivi-
ty towards methoxycarbonylation (TOF of 10 h–1 vs 7 h–1)
(Table 3, entries 1 and 2). Although this result contradicts
those reported by Alper et al.14 and Claver et al.35 for sty-
renes and their catalyst systems, it must be kept in mind
that trans-β-methylstyrenes 1 and 9 are prone to isomeri-
zation, which may alter the results completely.
In addition to the lower reactivity, a relative decrease in
the formation of the linear 19 and branched 20 products
and thus an increase in the benzylic product 21 were also
observed for the methoxy-substituted analogue 9 (3:2:1 vs
2:1:1, for 1 and 9, respectively). Since the branched product
can be formed from the prop-1-ene isomer 11 as well as the
internal alkene 1, the fact that a 1:1 ratio for the b/bn prod-
R2
R1
R1
R3
R4
1 R1 = H
9 R1 = p-OMe
10 R1 = o-OMe
16 R1 = H, R2 = CH2COOMe, R3 = R4 = H
17 R1 = H, R2 = Me, R3 = COOMe, R4 = H
18 R1 = H, R2 = Me, R3 = H, R4 = COOMe
Pd(OAc)2 (5 mol%), Al(OTf)3 (10 mol%), Ph3P (20 mol%)
19 R1 = p-OMe, R2 = CH2COOMe, R3 = R4 = H
20 R1 = p-OMe, R2 = Me, R3 = COOMe, R4 = H
21 R1 = p-OMe, R2 = Me, R3 = H, R4 = COOMe
22 R1 = o-OMe, R2 = Me, R3 = COOMe, R4 = H
23 R1 = o-OMe, R2 = Me, R3 = H, R4 = COOMe
24 R1 = o-OMe, R2 = CH2COOMe, R3 = R4 = H
25 R1 = p-CF3, R2 = Me, R3 = COOMe, R4 = H
26 R1 = p-CF3, R2 = Me, R3 = H, R4 = COOMe
27 R1 = p-CF3, R2 = CH2COOMe, R3 = R4 = H
28 R1 = o-OTf, R2 = Me, R3 = COOMe, R4 = H
29 R1 = o-OTf, R2 = Me, R3 = H, R4 = COOMe
MeOH, CO (35 bar), 95 °C
48–89%
R1
11 R1 = H
12 R1 = p-OMe
13 R1 = o-OMe
14 R1 = p-CF3
15 R1 = o-OTf
Scheme 2 Methoxycarbonylation of substituted arylalkenes 1 and 9–15
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 557–565

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M. du Plessis et al.
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Table 3 Methoxycarbonylation of Arylalkenes 1, 9–15, and 34–36
c
Entry
Substrate
Time (min)
Conv. (%)a
Yield (%)a
Product(s) (l/b/bn ratio)b
TOF (h–1
)
1
2
1
9
180
240
120
90
95
49
95
96
66
95
88
93
64
85
38
89
48
85
88
54
80
66
86
66
63
26
16/17/18 (3:2:1)
19/20/21 (2:1:1)
22/23/24 (10:4:1)
16/17/18 (8:2:1)
19/20/21 (7:2:1)
22/23/24 (15:5:1)
25/26/27 (9:2:1)
28/29 (5:1:nd)
40/41 (na:1:21)
42
10
7
3
10
11
12
13
14
15
34
35
36
11
30
20
25
32
31
4
4
5
240
90
6
7
360
40
8
9
420
240
360
10
11
6
43
2
a Determined by GC with xylene as internal standard.
b Not detected (nd); not applicable (na).
c Turnover frequency based on Pd(OAc)2.
ucts in the latter case (Table 3, entry 2) was found, indi-
cates that the hydropalladation step in the widely pub-
lished catalytic cycle (Scheme 4)14,24,38,39 shows a preference
towards attaching the palladium to the benzylic carbon of
the substrate.
tion is, however, taken into account, some (diminished) ef-
fect should be observed and was indeed found as again a
relative increase in the formation of the benzylic product 21
compared to the branched 20 and linear products 19 (8:2:1
vs 7:2:1) was observed (Table 3, entry 4 vs 5).
The tendency for carbonylation to preferentially take
place at the benzylic rather than the branched position was
confirmed by subjecting 1,3-diphenylpropene (34) to the
optimized reaction conditions (Scheme 6, vide infra). In this
instance, isomerization of the double bond would not lead
to a more reactive monosubstituted α-olefin and the for-
mation of the linear product could therefore be excluded.
Even if the statistical effect of two benzylic positions versus
one branched position is taken into account, entry 9 in Ta-
ble 3 illustrates a 10:1 preference for carbonylation at the
benzylic center.
The fact that a methoxy substituent in the para-position
of the aromatic ring in both β-methylstyrene 9 and allyl-
benzene 12 leads to a reduction in reaction rate (Table 3,
entries 1 vs 2 and 4 vs 5) may serve as an indication that
isomerization of the double bond to the 1-position of the
propene moiety and thus the more reactive isomer is sup-
pressed by the presence of the electron-donating substitu-
ent. It may, however, also be an indication that the rate of
alkene insertion into the Pd–H bond or another step in the
catalytic cycle is slowed down by the more electron-rich
double bond or benzylic position. The improved reaction
rate (TOF 32 vs 20 h–1) observed for the substrate with an
electron-withdrawing CF3 group attached to the para-posi-
tion of the allylbenzene substrate 14, when compared to
the methoxy-substituted analogue 12 (Table 3, entries 5
and 7), may serve as confirmation for this observation.
The results obtained from the reaction of allylbenzenes
with ortho-subtituents 13 and 15 as well as the o-substitut-
ed β-methylstyrene 10 warrants some comment: In both
O
Ph
OMe
O
+
OMe
Ph
H
Pd
Ph
MeOH
O
PdLn
PdLn
Ph
Ph
+
PdLn
+
O
Ph
PdLn
Ph
CO
Scheme 4 Postulated catalytic cycle for the methoxycarbonylation of
trans-β-methylstyrene (1)
In comparison, the reactivity of 4-allylanisole (12) also
proved to be lower than that of its deoxy analogue 11 (TOF
20 h–1 vs 30 h–1, respectively), even though the methoxy
substituent attached to the aromatic ring, in principle,
should not have any influence on the isolated double bond
in 12 (Table 3, entries 4 and 5). If double bond isomeriza-
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M. du Plessis et al.
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cases, it was found that the effect of a methoxy substituent
in this position exceeds that of the same substituent in the
para-position. The reactivity (TOF) of the compounds with an
o-methoxy group increased from 7 h–1 to 11 h–1 and 20 h–1
to 25 h–1 for the β-methylstyrene and allylbenzene ana-
logues, respectively (Table 3, entries 3 vs 2 and 6 vs 5); the
conversion and yield following a similar trend. This might
be attributable to steric interaction between the o-methoxy
group and the incoming palladium catalyst resulting in less
isomerization to the less reactive internal olefin 10 in the
case of the allylbenzene analogue 13 and more facile re-
verse isomerization to the α-olefin for the β-methylstyrene
compound 10. The fact that a slight increase in the forma-
tion of the linear products and a drastic decrease in the for-
mation of the benzylic products (15:5:1 vs 7:2:1 and 10:4:1
vs 7:2:1 for the ortho- and para-substituted analogues, re-
spectively) was also found for both ortho-substrates 13 and
10 compared to the electronically similar para-substrates
seem to support this hypothesis. Agostic interaction be-
tween the methoxy hydrogens and the palladium could,
however, also have a stabilizing effect on one of the transi-
tion states and cannot be ignored as probable cause of the
higher reactivity observed for the o-methoxy-substituted
compounds. Support for the postulation of steric interac-
tion between the ortho-substituent and the palladium cata-
lyst leading to reduced isomerization to the internal olefin
as cause of this increase in reactivity, stems from the fact
that an o-triflate group [as in allylbenzene (15)] has an even
more profound effect on reactivity (TOF of 31 h–1 vs 25 h–1)
and selectivity (5:1:0 vs 15:5:1) towards the linear product
(Table 3, entry 8 vs 6). In this instance, the formation of the
benzylic product is completely suppressed, whereas it is
significantly reduced in the former cases (l/b/bn 15:5:1 vs
7:2:1 for 13 and 12 and 10:4:1 vs 2:1:1 for 10 and 9).
In order to reduce the steric bulk of the ortho electron-
donating substituent, 2-hydroxyallylbenzene (30) was sub-
sequently subjected to the alkoxycarbonylation reaction.
Although three products, namely 31, 32, and 33, could in
principle be formed through intramolecular cyclization
during the carbonylation process, only the five- and six-
membered-ring products, 32 and 33, were detected and
isolated in 55% combined yield (60% conversion, 10 h–1)
(Scheme 5).
O
O
X
Pd(OAc)2 (5 mol%)
Al(OTf)3 (10 mol%)
Ph3P (20 mol%)
31
OH
O
O
O
THF
CO (35 bar)
95 °C
32
33
30
O
Scheme 5 Intramolecular methoxycarbonylation of 30
as seen before (vide supra). If this had not been the case,
the six-membered product 32 should have been the major
product as it may originate from the more reactive mono-
substituted α-olefin as well as the ‘branched’ position of the
internal alkene.
When α-methylstyrene (35), a 1,1-disubstituted olefin
for which the isomerization is not a factor, was subjected to
the methoxycarbonylation reaction with the current
Al(OTf)3 catalyst system, only the linear product 42 was
formed in 63% yield with 85% conversion after an extended
reaction period of four hours (Scheme 6).
The trisubstituted double bond analogue 36 showed ex-
tremely low reactivity (TOF of 2 h–1) with the linear product
43 being obtained as sole product in 26% yield (Table 3, en-
try 11), implicating first a double bond isomerization to the
terminal position prior to methoxycarbonylation (Scheme
6) and secondly, the isomerization to be more facile than
methoxycarbonylation in higher substituted alkenes.
Finally, the investigation was extended to β-phenyl-sub-
stituted arylalkenes, namely stilbenes 37–39 (Scheme 6). In
this instance, the solubility of the substrates in pure metha-
nol and ethanol was so low that a mixture of MeOH and
THF (1:1) had to be used as solvent system. The reduced
methanol concentration (vide supra) and conjugated nature
of the double bond led to a severe reduction in reactivity
(TOF 0.08–0.39 h–1) and conversion (16–19%) and pro-
longed reaction times (24 h) were required to achieve some
product formation (Table 4). Although conversion and yield
values are so low that drawing conclusions from these
would be risky, it seems as if the introduction of a p-meth-
oxy group to one of the aromatic rings again led to a reduc-
tion in reactivity, while the o-methoxy analogue 39 once
again proved to be slightly more reactive than its p-meth-
oxy counterpart 38. Since isomerization in this instance
could be ruled out as the cause of this phenomenon, it must
be concluded that agostic interaction is responsible for this
phenomenon. As expected, introduction of a methoxy
group into the ortho-position of one aromatic ring resulted
in an increase in methoxycarbonylation at the ‘other’ ben-
zylic position (product ratio: 1.3:1 for the p-methoxy ana-
logue vs 4:1 for the o-methoxy analogue).
Since the linear isomers 16, 19, 22, 25, and 28 were
formed as major products during all of the preceding reac-
tions (vide supra), the absence of compound 31 could only
be explained by its unfavorable seven-membered-ring
structure. It was, furthermore, observed that the five- and
six-membered-ring products, 33 and 32, were formed in
equal quantities, i.e. a 1:1 ratio. The fact that 32 and 33
were formed in equal quantities suggests that the o-OH
group enhances isomerization of the double bond to the in-
ternal position, while it also directs the carbonylation to-
wards the more stable incipient carbocation intermediate,
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M. du Plessis et al.
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Ph
34
35
R2
R1
R3
Pd(OAc)2 (5 mol%), Al(OTf)3 (10 mol%), Ph3P (20 mol%)
R4
40 R1 = H, R2 = Bn, R3 = COOMe, R4 = H
41 R1 = H, R2 = Bn, R3 = H, R4 = COOMe
42 R1 = H, R2 = COOMe, R3 = H, R4 = Me
43 R1 = H, R2 = CH2COOMe, R3 = Me, R4 = H
44 R1 = H, R2 = Ph, R3 = COOMe, R4 =H
45 R1 = p-OMe, R2 = Ph, R3 = COOMe, R4 = H
46 R1 = p-OMe, R2 = Ph, R3 = H, R4 = COOMe
47 R1 = o-OMe, R2 = Ph, R3 = COOMe, R4 = H
48 R1 = o-OMe, R2 = Ph, R3 = H, R4 = COOMe
MeOH or MeOH–THF (1:1), CO (35 bar), 95 °C
2–66%
R2
R1
R3
36 R1 = H, R2 = R3 = Me
37 R1 = H, R2 = Ph, R3 = H, trans-isomer
38 R1 = p-OMe, R2 = Ph, R3 = H, cis- and trans-isomer
39 R1 = o-OMe, R2 = Ph, R3 = H, cis- and trans-isomer
Scheme 6 Methoxycarbonylation of arylalkenes 34–39
Table 4 Methoxycarbonylation of Stilbenes 37–39
nomenon is probably attributable to steric hindrance lead-
ing to less double bond isomerization to internal olefins
and thus less reactive disubstituted substrates.
Probably due to the conjugated double bond present in
the molecule, stilbene substrates are much lower in reactiv-
ity than their alkyl-substituted counterparts. It was fur-
thermore observed that electronic as well as steric effects
result in methoxycarbonylation taking place at the benzylic
position furthest away from the electron-rich aromatic
ring.
Entry Substrate Time
(min)
Conv.
(%)a
Yield
(%)b
Product(s)
(ratio)
TOF
a
(h–1
)
1
2
3
37
38
39
24
24
24
17
16
19
6
2
4
44
0.14
0.08
0.39
45/46 (1.3:1)
47/48 (4:1)
a Due to the insolubility of the stilbene substrates in the cold solvent system,
the large difference in conversion and yield might be ascribed to some start-
ing material precipitating inside the internals of the reactor, thus leading to
inflated conversion values.
b Isolated yield.
All the chemicals used were purchased from Sigma-Aldrich and used
as received. Reactions were performed in a 4590 Parr reactor (25 mL
vessel), with the use of a gas entrainment stirrer. The CO used in all
methoxycarbonylation reactions were passed through a CrO3 silica
bed for purification purposes. 1H and 13C NMR as well as 2D experi-
ments were done on a 600 MHz Bruker AM FT spectrometer at 20 °C
at 600 MHz for 1H NMR and 151 MHz for 13C in CDCl3 or acetone-d6 as
solvent. 1H NMR chemical shifts are given relative to the TMS signal at
0 ppm and 13C NMR shifts are given relative to the CDCl3 peak at 77.16
ppm, coupling constants are measured in Hz and chemical shifts in
ppm. Mass spectrometry was performed on a Shimadzu GCMS QP-
2010 instrument using electrospray ionization, DB-5 MS column (30
m, 0.32 mm i.d., 0.25 μm film thickness).
In conclusion, a comparison of the reactivity of the 1,2-
disubstituted 34 and 1,1-disubstituted alkenes 35, for
which the effect of isomerization is excluded, indicates that
1,1-disubstitution is less detrimental to the alkoxycarbon-
ylation of arylalkenes with the Pd(II)/Al(OTf)3/Ph3P catalyst
system.
It has also been shown that the position as well as type
of substituent attached to the aromatic ring of the alkene
substrate has a significant effect on both the reactivity of
the substrate as well as the isomer distribution observed in
the product mixture.
In this regard, electron-donating substituents in the
para-position of the aryl ring seem to reduce the reaction
rate, while enhancing the formation of benzylic, and to a
lesser extent, the branched products, which is the opposite
of what is observed for electron-withdrawing groups.
Substituents in the ortho-position of the aromatic ring
have a much larger effect and leads to significantly en-
hanced reaction rates, while also producing considerably
more of the linear product and less benzylic product when
compared to their para-substituted counterparts. This phe-
Methoxycarbonylation of Alkenes 1–4, 9–15, 30 and 34–39; Gener-
al Procedure
Al(OTf)3 (10 mol%), Ph3P (20 mol%), xylene (0.5 g), and the appropri-
ate alkene (4 mmol) were added together in the Parr reactor and dis-
solved in MeOH (6 mL). The reactor was degassed and allowed to heat
up to 95 °C. Pd(OAc)2 (5 mol%) dissolved in MeOH (2 mL) was injected,
whereafter the pressure was set to 35 bar of CO. Conversions, yields,
and product ratios were determined utilizing a Shimadzu 2010 GC in-
strument with xylene as the internal standard (Tables 2–4). Where
applicable, the products were directly purified by flash column chro-
matography [100 g Merck Kieselgel 60 (230–400 mesh) per gram of
crude mixture] with the eluent as indicated.
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M. du Plessis et al.
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Methyl Nonanoate (5)40 and Methyl 2-Methyloctanoate (6)40
2 H, H-2, (19)], 2.11–2.07 [m, 0.1 H, H-3a/b, (21)], 1.94 [pent, J = 7.54
Hz, 2 H, H-3, (19)], 1.81–1.76 [m, 0.1 H, H-3a/b, (21)], 1.16 [d, J = 6.92
Hz, 0.6 H, 2-CH3, (20)], 0.90 [t, J = 7.34 Hz, 0.3 H, H-4, (21)].
Light yellow oil; tR = 27.0 (5) and 24.0 min (6).
1H NMR (600 MHz, CDCl3/TMS): δ = 3.67 [s, 0.7 H, OCH3, (6)], 3.66 [s, 3
H, OCH3, (5)], 2.44–2.41 [m, 0.2 H, H-2, (6)], 2.29 [t, J = 7.57 Hz, 2 H, H-
2, (5)], 1.64–1.59 [m, 2 H, H-3, (5)], 1.32–1.22 [m, 10 H, H-4 to H-8
(5)], 1.32–1.22 [m, 2.2 H, H-3 to H-7, (6)], 1.13 [d, J = 7.02 Hz, 0.7 H, 2-
CH3, (6)], 0.87 [t, J = 7.02 Hz, 0.7 H, H-8, (6)], 0.87 [t, J = 7.02 Hz, 3 H,
H-9, (5)].
MS (EI): m/z (%) = 208 [39, (19)], 208 [13, (20)], 208 [21, (21)].
Methyl 4-(2′-Methoxyphenyl)butanoate (22),46 Methyl 3-(2′-
Methoxyphenyl)-2-methylpropanoate (23),43 and Methyl 2-(2′-
Methoxyphenyl)butanoate (24)
13C NMR (151 MHz, CDCl3/TMS): δ = 177.51 [C-1, (6)], 174.42 [C-1,
(5)], 51.50 [OCH3, (5)], 51.34 [OCH3, (6)], 39.55 [C-2, (6)], 34.19 [C-2,
(5)], 33.93 (6), 31.9 (5), 31.79, (6), 29.32 (5), 29.27 (6), 29.26 (5), 29.22
(5), 27.3 (6), 25.06 [C-3, (5)], 22.74 (5), 22.69 (6), 17.15 [2-CH3, (6)],
14.17 [C-9, (5)], 14.14 [C-8, (6)].
Light yellow oil; tR = 24.6 (22), 22.8 (23), and 22.3 min (24).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.25–7.23 [m, 0.04 H, H-4′, (24)],
7.2–7.15 [m, 1.2 H, H-4′, (22) and (23)], 7.11–7.07 [m, 1.25 H, H-6′,
(22), (23), and (24)], 6.94–6.91 [m, 0.04 H, H-5′, (24)], 6.88–6.84 [m,
1.2 H, H-5′, (22) and (23)], 6.83–6.81 [m, 1.25 H, H-3′, (22), (23), and
(24)], 3.8 [s, 0.12 H, 4′-OCH3, (24)], 3.79 [s, 0.6 H, 4′-OCH3, (23)], 3.78
[s, 3 H, 4′-OCH3, (22)], 3.76–3.75 [m, 0.04 H, H-2, (24)], 3.64 [s, 3 H,
CO2CH3, (22)], 3.63 [s, 0.12 H, CO2CH3, (24)], 3.61 [s, 0.6 H, CO2CH3
(23)], 2.98 [dd, J = 7.1, 13.22 Hz, 0.2 H, H-3a/b, (23)], 2.86–2.8 [m, 0.2
H, H-2, (23)], 2.7 [dd, J = 7.59, 13.22 Hz, 0.2 H, H-3a/b, (23)], 2.65 [t, J =
7.56 Hz, 2 H, H-4, (22)], 2.32 [t, J = 7.56 Hz, 2 H, H-2, (22)], 2.08–2.03
[m, 0.04 H, H-3a/b, (24)], 1.92 [pent, J = 7.56 Hz, 2 H, H-3, (22)], 1.78–
1.73 [m, 0.04 H, H-3a/b, (24)], 1.13 [d, J = 7 Hz, 0.6 H, 2-CH3, (23)],
0.89 [t, J = 7.39 Hz, 0.12 H, H-4, (24)].
MS (EI): m/z (%) = 172 [2, (5)], 172 [1, (6)].
Methyl 3-Phenylpropanoate (7)41 and Methyl 2-Phenylpropanoate
(8)42
Colorless oil; tR = 17.6 (7) and 15.7 min (8).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.34–7.26 [m, 2.7 H, H-Ar, (7) and
(8)], 7.22–7.19 [m, 2.9 H, H-Ar, (7) and (8)], 3.72 [q, J = 7.17 Hz, 0.2 H,
H-2, (8)], 3.67 [s, 3 H, OCH3, (7)], 3.65 [s, 0.5 H, OCH3, (8)], 2.95 [t, J =
7.89 Hz, 2 H, H-3, (7)] 2.63 [t, J = 7.89 Hz, 2 H, H-2, (7)], 1.5 [d, J = 7.17
Hz, 0.5 H, H-3, (8)].
MS (EI): m/z (%) = 208 [40, (22)], 208 [22, (23)], 208 [34, (24)].
13C NMR (151 MHz, CDCl3/TMS): δ = 175.12 [C-1, (8)], 173.47 [C-1,
(7)], 140.67 [C-1′, (8)], 140.63 [C-1′, (7)], 128.76 [C-4′, (8)], 128.63 [C-
Ar, (7)], 128.4 [C-Ar, (7)], 127.58 [C-Ar, (8)], 127.26 [C-Ar, (8)], 126.39
[C-4′, (7)], 52.15 [OCH3, (8)], 51.74 [OCH3 (7)], 45.56 [C-2, (8)], 35.82
[C-2, (7)], 31.05 [C-3, (7)], 18.72 [C-3, (8)].
Methyl 4-(4′-Trifluoromethylphenyl)butanoate (25),47 Methyl 2-
Methyl-3-(4′-trifluoromethylphenyl)propanoate (26), and Methyl
2-(4′-Trifluoromethylphenyl)butanoate (27)
Light yellow oil; tR = 20.9 (25), 18.3 (26), and 17.5 min (27).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.54–7.53 [m, 2.2 H, H-3′, H-5′,
(25) and (26)], 7.3–7.27 [m, 2.3 H, H-2′, H-6′, (25) and (26)], 3.67 [s, 3
H, OCH3, (25)], 3.64 [s, 0.5 H, OCH3, (26)], 3.09–3.06 [m, 0.15 H, H-2,
(26)], 2.78–2.73 [m, 0.3 H, H-3a, H-3b, (26)], 2.71 [t, J = 7.55 Hz, 2 H,
H-4, (25)], 2.34 [t, J = 7.55 Hz, 2 H, H-2, (25)], 1.97 [pent, J = 7.55 Hz, 2
H, H-3, (25)] and 1.18 [d, J = 6.82 Hz, 0.5 H, 2-CH3, (26)].
MS (EI): m/z (%) = 164 [35, (7)], 164 [23, (8)].
Methyl 4-Phenylbutanoate (16),14 Methyl 2-Methyl-3-phenylpro-
panoate (17),43 and Methyl 2-Phenylbutanoate (18)44
Light yellow oil; tR = 19.8 (16), 17.3 (17), and 16.7 min (18).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.33–7.24 [m, 4.8 H, H-Ar, (16),
(17), and (18)], 7.22–7.15 [m, 4.5 H, H-Ar, (16), (17), and (18)], 3.66 [s,
3 H, OCH3 (16)], 3.65 [s, 1 H, OCH3 (18)], 3.64 [s, 1.7 H, OCH3 (17)],
3.46 [t, J = 7.71 Hz, 0.3 H, H-2, (18)], 3.03 [dd, J = 6.83, 13.37 Hz, 0.6 H,
H-3a/b, (17)], 2.77–2.71 [m, 0.6 H, H-2, (17)], 2.66 [dd, J = 7.83, 13.37
Hz, 0.6 H, H-3a/b, (17)], 2.65 [t, J = 7.56 Hz, 2 H, H-4, (16)], 2.33 [t, J =
7.56 Hz, 2 H, H-2, (16)], 2.14–2.06 [m, 0.3 H, H-3a/b, (18)], 1.96 [pent,
J = 7.56 Hz, 2 H, H-3, (16)], 1.83–1.76 [m, 0.3 H, H-3a/b, (18)], 1.15 [d,
J = 6.92 Hz, 1.7 H, 2-CH3, (17)], 0.94 [t, J = 7.37 Hz, 1 H, H-4, (18)].
MS (EI): m/z (%) = 246 [10, (25)], 246 [18, (26)], 246 [8, (27)].
Methyl 4-(2′-Trifluoromethanesulfonyloxyphenyl)butanoate (28)
and Methyl 2-Methyl-3-(2′-trifluoromethanesulfonyloxyphe-
nyl)propanoate (29)
Colorless oil; tR = 24.6 (28) and 22.4 min (29).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.35–7.24 [m, 6.2 H, H-Ar, (28)
and (29)], 3.68 [s, 3 H, OCH3, (28)], 3.63 [s, 1.6 H, OCH3, (29)], 3.11–
3.07 [m, 0.5 H, H-2, (29)], 2.85–2.81 [m, 1 H, H-3, (29)], 2.76 [t, J = 7.63
Hz, 2 H, H-4, (28)], 2.37 [t, J = 7.63 Hz, 2 H, H-2, (28)], 1.98 [pent, J =
7.63 Hz, 2 H, H-3, (28)], 1.2 [d, J = 6.71 Hz, 1.6 H, CH3, (29)].
MS (EI): m/z (%) = 178 [37, (16)], 178 [18, (17)], 178 [18, (18)].
Methyl 4-(4′-Methoxyphenyl)butanoate (19),14 Methyl 3-(4′-
Methoxyphenyl)-2-methylpropanoate (20),43 and Methyl 2-(4′-
Methoxyphenyl)butanoate (21)45
3-Methylchroman-2-one (32)48
White solid; mp 50 °C; tR = 20.7 min.
Light yellow oil; tR = 25.5 (19), 23.8 (20), and 23.4 min (21).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.27–7.24 (m, 1 H, H-5′), 7.18 (br
dd, J = 7.46 Hz, 1 H, H-3′), 7.09 (br td, J = 7.46, 1.10 Hz, 1 H, H-4′), 7.04
(br dd, J = 1.10 Hz, 1 H, H-6′), 2.98 (dd, J = 14.85, 5.37 Hz, 1 H, H-4a/b),
2.86–2.76 (m, 2 H, H-3, H-4a/b), 1.38 (d, J = 6.54 Hz, 3 H, CH3).
13C NMR (151 MHz, CDCl3/TMS): δ = 171.76 (C=O), 151.9 (C-1′),
128.33 (C-5′), 128.07 (C-3′), 124.36 (C-4′), 122.99 (C-2′), 116.73 (C-6′),
34.34 (C-3), 31.77 (C-4), 15.52 (CH3).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.25 [d, J = 8.7 Hz, 0.2 H, H-3′, H-
5′, (21)], 7.11 [d, J = 8.66 Hz, 2 H, H-3′, H-5′, (19)], 7.10 [d, J = 8.64 Hz,
0.4 H, H-3′, H-5′, (20)], 6.88–6.87 [d, J = 8.7 Hz, 0.2 H, H-2′, H-6′, (21)],
6.86–6.83 [m, 0.4 H, H-2′, H-6′, (20)], 6.85 [d, J = 8.66 Hz, 2 H, H-2′, H-
6′, (19)], 3.81–3.80 [s, 3.9 H, 4′-OCH3, (19), (20), and (21)], 3.68 [s, 3 H,
CO2CH3, (19)], 3.67 [s, 0.3 H, CO2CH3, (21)], 3.66 [s, 0.6 H, CO2CH3,
(20)], 3.43 [t, J = 7.73 Hz, 0.1 H, H-2, (21)], 2.98 [dd, J = 6.94, 13.53 Hz,
0.2 H, H-3a/b, (20)], 2.75–2.69 [m, 0.2 H, H-2, (20)], 2.65–2.63 [m, 0.2
H, H-3a/b, (20)], 2.61 [t, J = 7.54 Hz, 2 H, H-4, (19)], 2.34 [t, J = 7.54 Hz,
MS (EI): m/z = 162 (100%).
3-Ethylbenzofuran-2(3H)-one (33)49
White solid; tR = 18.6 min.
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1H NMR (600 MHz, CDCl3/TMS): δ = 7.32–7.29 (m, 1 H, H-5′), 7.27 (br
dd, J = 7.59 Hz, 1 H, H-3′), 7.15 (br td, J = 7.59, 0.97 Hz, 1 H, H-4′), 7.11
(br dd, J = 8.03, 0.97 Hz, 1 H, H-6′), 3.71 (t, J = 5.94 Hz, 1 H, H-3), 2.09–
2.04 (m, 2 H, CH2), 0.97 (t, J = 7.45 Hz, 3 H, CH3).
13C NMR (151 MHz, CDCl3/TMS): δ = 174.19 (C-1), 140.23 (C-1′ or C-
1′′), 140.00 (C-1′ or C-1′′), 129.89 (C-Ar), 129.46 (C-Ar), 129.12 (C-Ar),
128.88 (C-Ar), 128.15 (C-Ar), 127.17 (C-Ar), 54.16 (C-2), 52.11 (OCH3),
40.48 (C-3).
13C NMR (151 MHz, CDCl3/TMS): δ = 177.36 (C=O), 154.06 (C-1′),
128.87 (C-5′), 127.29 (C-2′), 124.29 (C-3′/C-4′), 124.19 (C-3′/C-4′),
110.8 (C-6′), 44.7 (C-3), 24.43 (CH2), 10.3 (CH3).
MS (EI): m/z = 240 (15%).
Methyl 3-(4′-Methoxyphenyl)-2-phenylpropanoate (45)54,55 and
Methyl 2-(4′-Methoxyphenyl)-3-phenylpropanoate (46)55
MS (EI): m/z = 162 (100%).
Light yellow oil; tR = 33.8 min (45 and 46); Rf = 0.24 (hexanes–CHCl3–
MeOH, 7:2:1 v/v).
Methyl 2,4-Diphenylbutanoate (40)50
Colorless oil; tR = 29.6 (40) and 29.0 min (41).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.31–7.29 [m, 2.8 H, H-2′′, H-3′′,
H-5′′, H-6′′, (45)], 7.27–7.21 [m, 4.7 H, H-4′′, (45) and H-2′, H-3′′, H-5′′,
H-6′, (46)], 7.18–7.16 [m, 1 H, H-4′′, (46)], 7.11–7.10 [m, 2 H, H-2′′, H-
6′′, (46)], 7.04–7.02 [m, 1.4 H, H-2′, H-6′, (45)], 6.85–6.83 [m, 2 H, H-
3′, H-5′, (46)], 6.78–6.76 [m, 1.4 H, H-3′, H-5′, (45)], 3.81–3.79 [m, 1.7
H, H-2, (45) and (46)], 3.79 [s, 3 H, 4′-OCH3, (46)], 3.76 [s, 2.1 H, 4′-
OCH3, (45)], 3.60 [s, 2.1 H, CO2CH3, (45)], 3.60 [s, 3 H, CO2CH3, (46)],
3.38 [dd, J = 13.75, 8.67 Hz, 1 H, H-3a/b, (46)], 3.35 [dd, J = 13.87, 8.88
Hz, 0.7 H, H-3a/b, (45)], 2.99 [dd, J = 13.75, 6.88 Hz, 1 H, H-3a/b, (46)]
and 2.96 [dd, J = 13.87, 6.69 Hz, 0.7 H, H-3a/b, (45)].
1H NMR (600 MHz, CDCl3/TMS): δ = 7.33–7.24 (m, 7 H, H-Ar), 7.19–
7.16 (m, 1 H, H-Ar), 7.15–7.13 (m, 2 H, H-Ar), 3.63 (s, 3 H, OCH3), 3.56
(t, J = 7.65 Hz, 1 H, H-2), 2.56 (t, J = 7.76 Hz, 2 H, H-4), 2.44–2.38 (m, 1
H, H-3a/b), 2.13–2.07 (m, 1 H, H-3a/b).
13C NMR (151 MHz, CDCl3/TMS): δ = 174.4 (C-1), 141.35 (C-1′′),
138.93 (C-1′), 128.79 (C-Ar), 128.57 (C-Ar), 128.5 (C-Ar), 128.11 (C-
Ar), 127.44 (C-Ar), 126.11 (C-Ar), 52.09 (OCH3), 50.89 (C-2), 35.01 (C-
3), 33.64 (C-4).
MS (EI): m/z = 254 (2%).
13C NMR (151 MHz, CDCl3/TMS): δ = 174.13 [C-1, (46)], 173.92 [C-1,
(45)], 158.85 [C-4′, (46)], 158.11 [C-4′, (45)], 139.12 [C-1′′, (46)],
138.69 [C-1′′, (45)], 131.11 [C-1′, (45)], 130.70 [C-1′, (46)], 129.90 [C-
2′ and C-6′, (45)], 128.98, 128.94, 128.63, 128.32, 127.97, 127.35 [C-
4′′, (45)], 126.33 [C-4′′, (46)], 114.01 [C-3′ and C-5′, (46)], 113.72 [C-3′
and C-5′, (45)], 55.24 [4′-OCH3, (46)], 55.19 [4′-OCH3, (45)], 53.88 [C-2
(45)], 52.72 [C-2 (46)], 51.96 [CO2CH3, (45) and (46)], 39.87 [C-3, (46)]
and 38.99 [C-3, (45)].
Methyl 3-Phenylbutanoate (42)51
Colorless oil; tR = 20.6 min.
1H NMR (600 MHz, CDCl3/TMS): δ = 7.30–7.27 (m, 2 H, H-3, H-5),
7.23–7.17 (m, 3 H, H-2, H-4, H-6), 3.60 (s, 3 H, OCH3), 3.31–3.25 (m, 1
H, H-3), 2.62 (dd, J = 6.90, 15.20 Hz, 1 H, H-2a or H-2b), 2.54 (dd, J =
8.25, 15.20 Hz, 1 H, H-2a or H-2b) and 1.29 (d, J = 7.00 Hz, 3 H, H-4).
MS (EI): m/z (%) = 270 [9, (47)], 270 [35, (48)].
13C NMR (151 MHz, CDCl3/TMS): δ = 172.86 (C-1), 145.75 (C-1′),
128.57 (C-3′ and C-5′), 126.76 (C-2′ and C-6′), 126.47 (C-4′), 51.51
(OCH3), 42.76 (C-2), 36.48 (C-3), 21.83 (C-4).
Methyl 3-(2′-Methoxyphenyl)-2-phenylpropanoate (47)56 and
Methyl 2-(2′-Methoxyphenyl)-3-phenylpropanoate (48)
MS (EI): m/z = 178 (22%).
Light yellow oil; tR = 33.26 (47) and 33.13 min (48); Rf = 0.64 (hex-
anes–CHCl3–MeOH, 80:14:6 v/v).
Methyl 3-Methyl-4-phenylbutanoate (43)52
1H NMR (600 MHz, CDCl3/TMS): δ = 7.30–7.28 [m, 4 H, H-2′′, H-3′′, H-
5′′, H-6′′, (47)], 7.24–7.20 [m, 3.5 H, H-Ar (47) and/or (48)], 7.18–7.15
[m, 1.6 H, H-Ar (47) and/or (48)], 7.12–7.11 [m, 1.2 H, H-Ar (47) and
(48)], 7.00 [br dd, J = 7.37 Hz, 1 H, H-6′, (47)], 6.92–6.89 [m, 0.6 H, H-
5′, (48)], 6.85 [br dd, J = 8.06 Hz, 0.6 H, H-3′, (48)], 6.82 [br dd, J = 8.14
Hz, 1 H, H-3′, (47)], 6.79–6.77 [m, 1 H, H-5′, (47)], 4.30 [m, 0.6 H, H-2,
(48)], 3.99 [m, 1 H, H-2, (47)], 3.82 [s, 3 H, 2′-OCH3, (47)], 3.76 [s, 1.8
H, 2′-OCH3, (48)], 3.60 [s, 1.8 H, CO2CH3, (48)], 3.59 [s, 3 H, CO2CH3,
(47)], 3.36–3.33 [m, 1.6 H, H-3a/b, (47) and (48)], 3.07 [dd, J = 13.46,
6.46 Hz, 1 H, (47)], 2.97 [dd, J = 13.68, 6.81 Hz, 0.6 H, (48)].
13C NMR (151 MHz, CDCl3/TMS): δ = 174.29 [C-1, (48)], 174.22 [C-1,
(47)], 157.57 [C-2′, (47)], 156.69 [C-2'′, (48)], 139.68 [C-1′′, (47) or
(48)], 139.30 [C-1′′, (47) or (48)], 130.82 [C-6′, (47)], 129.04, 128.49,
128.41, 128.32, 128.11, 127.91, 127.71, 127.26, 127.13, 126.11,
120.70 [C-5′, (48)], 120.22 [C-5′, (47)], 110.84 [C-3′, (48)], 110.09 [C-
3′, (47)], 55.56 [2′-OCH3, (48)], 55.22 [2′-OCH3, (47)], 51.88 [CO2CH3,
(47) and (48)], 51.21 [C-2, (47)], 46.36 [C-2, (48)], 38.74 [C-3, (48)],
34.92 [C-3, (47)].
Yellow oil; tR = 20.6 min.
1H NMR (600 MHz, CDCl3/TMS): δ = 7.29–7.27 (m, 2 H, H-3′, H-5′),
7.21–7.18 (m, 1 H, H-4′), 7.16–7.15 (m, 2 H, H-2′, H-6′), 3.64 (s, 3 H,
OCH3), 2.62 (dd, J = 13.45, 6.73 Hz, 1 H, H-4a/b), 2.50 (dd, J = 13.45,
7.44 Hz, 1 H, H-4a/b), 2.33 (dd, J = 14.64, 5.75 Hz, 1 H, H-2a/b), 2.31–
2.25 (m, 1 H, H-3), 2.14 (dd, J = 14.64, 7.84 Hz, 1 H, H-2a/b), 0.94 (d, J =
6.58 Hz, 3 H, 3-CH3).
13C NMR (151 MHz, CDCl3/TMS): δ = 173.64 (C-1), 140.34 (C-1′),
129.33 (C-2′, C-6′), 128.38 (C-3′, C-5′), 126.15 (C-4′), 51.53 (OCH3),
43.14 (C-4), 40.99 (C-2), 32.4 (C-3), 19.77 (3-CH3).
MS (EI): m/z = 192 (22%).
Methyl 2,3-Diphenylpropanoate (44)53
Yellow oil; tR = 30.8 min; Rf = 0.61 (hexanes–CH2Cl2–acetone, 6:2:2
v/v).
1H NMR (600 MHz, CDCl3/TMS): δ = 7.36–7.34 (m, 2 H, H-2′, H-6′ or
H-2′′, H-6′′), 7.33–7.30 (m, 2 H, H-3′, H-5′ or H-3′′, H-5′′), 7.27–7.24
(m, 1 H, H-4′ or H-4′′), 7.24–7.22 (m, 2 H, H-3′, H-5′ or H-3′′, H-5′′),
7.20–7.18 (m, 2 H, H-2′, H-6′ or H-2′′, H-6′′), 7.17–7.14 (m, 1 H, H-4′ or
H-4′′), 3.95 (dd, J = 8.90, 6.79 Hz, 1 H, H-2), 3.55 (s, 3 H, OCH3), 3.37
(dd, J = 13.70, 8.90 Hz, 1 H, H-3a/b), 3.02 (dd, J = 13.70, 6.79 Hz, 1 H,
H-3a/b).
MS (EI): m/z = 270 (10%).
Acknowledgment
Financial support by the University of the Free State and Sasol Tech-
nology Ltd. is greatly appreciated and acknowledged.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 557–565

565
M. du Plessis et al.
Paper
Synthesis
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560912.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 557–565