Ring-Opening of Vinylcyclopropane-1,1-dicarboxylates by Boronic Acids under Ligandless Palladium Catalysis in Neat Water

Article abstract of DOI:10.1021/acs.joc.5b00672

We report a highly efficient ring-opening reaction of vinylcyclopropanes by boronic acids in water, using palladium nanoparticles formed from Pd(OAc)₂ under ligandless conditions. Unsubstituted vinylcyclopropanes provide linear addition products with high selectivity, while a switch in regioselectivity to branched products is observed for aryl-substituted vinylcyclopropanes.

Full text of DOI:10.1021/acs.joc.5b00672

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Featured Article
Ring-Opening of Vinylcyclopropane -1,1-dicarboxylates by
Boronic acids under Ligandless Palladium Catalysis in Neat Water
JieXiang Yin, and Christopher J. T. Hyland
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00672 • Publication Date (Web): 23 Apr 2015
Downloaded from http://pubs.acs.org on May 3, 2015
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Ring-Opening of Vinylcyclopropane -1,1-dicarboxylates
by Boronic acids under Ligandless Palladium Catalysis
in Neat Water
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JieXiang Yin and Christopher J. T. Hyland*
School of Chemistry, University of Wollongong, Wollongong, NSW 2500, Australia
ABSTRACT: We report a highly efficient ring-opening reaction of vinylcyclopropanes by boronic
acids in water, using palladium nanoparticles formed from Pd(OAc)2 under ligandless conditions.
Unsubstituted vinylcyclopropanes provide linear addition products with high selectivity, while a switch
in regioselectivity to branched products is observed for aryl-substituted vinylcyclopropanes.
EWG
EWG
EWG
EWG
EWG EWG
Pd(OAc)2 (1 mol%)
H2O, r.t, 8h
R2-B(OH)2
+
R2
Ar
R2
R1
Linear If R1=H
13 examples 23-96% yield
linear selectivity up to 43:1 branched selectivity up to 60:1
Branched If R1 = Ar
Neat water
No ligand required
EWG = -CO2Et, -CN
R1 = H, Aryl
R2 = Aryl, Alkenyl
13 examples 38-96% yield
INTRODUCTION
Vinylcyclopropane-1,1-dicarboxylates are highly versatile synthetic building blocks that can undergo
ready C-C bond cleavage in the presence of an activating agent.1-4 In the presence of Lewis-acids they
undergo nucleophilic attack to form an acyclic product, or cycloaddition to give a cyclic structure. Due
to the presence of the double bond in these systems, additional reactivity is revealed through
ring-opening with low-valent transition-metals to give electrophilic π-allyl complexes (Scheme 1a).
These complexes can undergo cycloaddition with alkenes,5-8 aldehydes 9 or imines.10 Polarity inversion
of these systems to form nucleophilic allyl complexes has also recently been demonstrated with iridium
catalysts.11 Most investigations into the reactivity of electrophilic π-allyl complexes derived from
vinylcyclopropanes have centered on cycloaddition chemistry, while nucleophilic attack to give acyclic
products is less developed. Nucleophilic attack is of interest because of the possibility of obtaining
linear or branched ring-opened products from SN2 or SN2’ type ring-opening respectively. A rare
example of nucleophilic attack has recently been reported by Plietker and co-workers, where they show
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that nucleophilic ferrate Bu4N[Fe-(CO)3(NO)] (TBAFe) is a catalyst for the generation of an allyl-Fe
intermediate from vinylcyclopropanes, which is then subject to attack by soft carbonucleophiles, such
as malonates (Scheme 1b).12 Fürstner reported an Fe-catalyzed addition of Grignard reagents to
vinylcyclopropanes, to give the linear ring-opened products with moderate to good selectivity over the
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branched product.
a. Reactions of donor-acceptor vinylcyclopropanes via π-allyl complexes
IrLn
CO2R
CO2R
MLn
CO2R
CO2R
CO2R
CO2R
MLn
MLn
δ−
Nu
δ−
Nu
δ+
E
δ+
E
Nu
Nu
E
CO2R
CO2R
E
CO2R
RO2C
b. Reaction of donor-acceptor vinylcyclopropanes with nucleophiles under Fe-
catalysis
Fe(acac)3
R'MgX
R'
EWG
EWG
EWG
EWG
Fürstner
Plietker
Pd(0)-pincer
complex
TBAFe
Nu
EWG
EWG
soft NuH
[B(OH)2]2
R'
EWG
EWG
Pd(PPh3)4
R'I
(HO)2B
EWG
EWG
Szabó
EWG = electron-withdrawing group
c. Reaction of π-allyl complexes derived from donor-acceptor vinylcyclopropanes
with boronic acids -this work
R'
CO2R
R = H
Pd(OAc)2
CO2R
R
CO2R
CO2R
CO2R
R
R'-B(OH)2
water
CO2R
M
R'
R = Ar
Ar
R'
CO2R
CO2R
Scheme 1. Examples of reactions of donor-acceptor cyclopropanes and proposed reaction
(Scheme 1b)13 Both of these examples provide linear structures as the major product, however, Szabó
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and co-workers had reported an alternative, and elegant, strategy that involved palladium-catalyzed
ring-opening of vinylcyclopropane dicarboxylates to produce allylboronates which can subsequently
react with iodobenzenes to give branched products (Scheme 1b).14
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The synthetic versatility of vinylcyclopropane-1,1-dicarboxylate nucleophilic ring opening would be
significantly increased if the range of nucleophiles could be increased to include non-stabilised,
bench-stable nucleophiles, such as boronic acids – and if both branched and linear products could be
obtained in a single step. An attractive feature of vinylcyclopropane-1,1-dicarboxylate nucleophilic
ring-opening is the traceless nature of the process, which is highly atom-economical. To further
enhance the credentials of reactions involving vinylcyclopropanes we sought out a catalyst system that
was free of ligands and could operate in an aqueous system. This would allow potential application to
bioorthogonal reactivity for protein labeling.15 The use of an amphiphilic palladium(II) pincer complex
in water has been reported to form vesicles that catalyse the addition of boronic acids to vinyl epoxide
but displays poor regioselectivity and utilizes a complex catalyst.16 On the other hand, It has been
shown that palladium nanoparticles can form in neat water from Pd(OAc)2 under ligandless conditions
and catalyze allyl-aryl coupling.17
Herein, we report the efficient and regioselective addition of boronic acids to vinylcyclopropanes,
using a ligandless Pd(OAc)2 pre-catalyst system in neat water, giving a highly efficient and selective
arylation of vinylcyclopropanes to linear or branched systems depending upon the substitution pattern
on the alkene (Scheme 1c).
RESULTS AND DISCUSSION
Studies commenced with diethyl 2-vinylcyclopropane-1,1-dicarboxylate 1, which is easily prepared
from (E)-1,4-dibromobut-2-ene and diethyl malonate, as the starting vinylcyclopropane in conjunction
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with phenylboronic acid. Conditions that we had previously reported for the ring-opening of
vinyl-aziridines utilising a Pd(II)-catalyst system led to ring-opening (Table 1, entry 3), but the product
could only be isolated in 48% with low E:Z selectivity, and accompanied by a significant amount of an
inseparable impurity.18 We then turned our attention to a Pd(0)-catalyst system (entry 2) that had been
reported for the Suzuki-Miyaura coupling of allylic carbonates with arylboronic acids.19 These
conditions returned the desired product with a good linear:branched and trans:cis ratio but in moderate
conversion and yield. In an attempt to identify a simple catalyst system without ligands we turned
attention to the use of Pd(OAc)2 in water, a system which has been reported to produce Pd(0)
nanoparticles in the presence of boronic acids.17 Under these conditions vinylcyclopropane 1 reacted
smoothly with phenylboronic acid to provide the linear trans ring-opened product in high yield and
selectivity (entry 1). Importantly, these conditions negated the use of additional ligands or organic
solvents, rendering the process operationally simple; the reaction could also be carried out in the air.
The importance of the catalyst was highlighted by the observation that under aqueous conditions in the
absence of any catalyst a low conversion to a roughly equal amount of branched:linear product was
observed (entry 4). Low conversion was also observed when the reaction was carried out in wet THF
(entry 5) and only trace product was observed in the anhydrous THF (entry 6). Using Pd(PPh3)4 as an
alternative source of Pd(0) proved ineffective with no product being observed (entry 7).
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Table 1. Selected optimisation conditions
EtO2C
CO2Et
EtO2C
EtO2C
EtO2C
EtO2C
conditions
PhB(OH)2
Ph
Ph
1
2
3
Selectivity
Entry
1
Conditions
Yield
84%
2:3 a
Pd(OAc)2 (1 mol%), H2O
11.5: 1
(E/Z= 98: 2)
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51%
Pd(OAc)2 (2 mol%)
8.7: 1
PPh3 (4 mol%), THF/H2O
(E/Z= 95: 5)
48%b
Pd(OAc)2 (10 mol%)
Phen (15 mol%),
Only 2
(E/Z= 67:33)
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AgSbF6 (10 mol%), DCE
No catalyst, H2O
4
29%c
1.2: 1
(only E observed)
5
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7
Pd(OAc)2, THF/H2Oe
Pd(OAc)2, THF
26%c
trace
NR
only linear E observed
only linear E observed
N/A
Pd(PPh3)4, H2Oe
a Ratios measured from the 1H NMR of the crude reaction mixture. b Inseparable impurity also formed. c Conversion, product not
isolated.d 5 equivalent distilled water used. e The reaction was carried out under nitrogen.
Using the optimized conditions, a range of boronic acids were added to vinylcyclopropane 1 in
generally high yield and linear selectivity (Table 2). A range of aryl and alkenyl boronic acids proved
effective giving generally excellent yields and linear trans selectivity. Electron-deficient arylboronic
acids generally gave the desired product in excellent yield (entries 2-5, 7, 9-10). Ortho substitution was
also tolerated (entry 5). The yield was lower for more electron-rich systems and naphtyl-derived
boronic acids (entry 6, 8 and 11). A cyano group could also be tolerated as the electron-withdrawing
group on the vinylcyclopropane (entry 13). Alkenyl boronic acids could also be coupled in moderate
yield and with complete linear selectivity. (entry 12).
Table 2. Reaction scope for linear product with respect to boronic acid
EWG EWG
EWG
Pd(OAc)2 (1 mol%)
R2 B(OH)2
+
H2O, r.t, 8h
EWG
R2
1
2
Entry
Producta
Entry
Producta
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EtO2C
EtO2C
EtO2C
EtO2C
6
7
1
8
8
9
84%, 2a/3a = 11.5: 1.0
E/Z= 98: 2
48%, 2h/3h = 20.4: 1.0
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E/Z= 96: 4
EtO2C
EtO2C
EtO2C
NO2
O
O
EtO2C
2
3
4
9
95%, 2b/3b = 45.9: 1.0
E/Z= 94: 6
90%, 2i/3i = 9.7: 1.0
E/Z= 96: 4
EtO2C
EtO2C
EtO2C
EtO2C
O
F
10
11
72%, 2j/3j = 9.7: 1.0
E/Z= 96:4
86%, 2c/3c = 25.0: 1.0
E/Z= 95:5
EtO2C
EtO2C
EtO2C
EtO2C
O
Cl
O
96%, 2d/3d = 14.9: 1.0
E/Z= 94:6
23%, 2k/3k = 8.3: 1.0
E/Z= 93:7
EtO2C
EtO2C
EtO2C
Cl
EtO2C
12
13
5
6
65%, 2e/3e = 7.6: 1.0
E/Z = 87:13
59%, 2lb
E/Z = 85:15
EtO2C
EtO2C
NC
NC
36%, 2f/3f = 5.3: 1.0
E/Z= 91:9
54%, 2m/3m = 14.8: 1.0
E/Z= 73:17
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EtO2C
EtO2C
O
7
6
7
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9
61%, 2g/3g = 18.7: 1.0
E/Z= 93:7
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a ratios measured from the crude 1H NMR b no branched isomer observed
In order to see if branched ring-opened products could be obtained, attention was turned to
vinycyclopropanes 4 that are substituted with an aryl group on the olefin unit (Table 3). These
vinylcyclopropanes can be simply prepared by cross-metathesis between 1 and the corresponding
commercially available styrene. Gratifyingly, using the previously optimized reaction conditions,
branched alkene 5 was obtained as the major product over the linear product 6. The branched products
5 were also obtained solely as E-isomers. The scope of this ring-opening was explored with a range of
arylboronic acids and proved to be general, providing high or exclusive selectivity for the branched
product in each case. A range of functional groups, including halides (entries 2, 4-5), esters (entry 6)
and ketones (entry 3), were tolerated. Both electron-rich (entry 8) and highly electron-deficient boronic
acids could be used (entry 7). Ortho-substituted boronic acids could also be used but a drop in yield
was observed (entry 5), also, pent-1-en-1-ylboronic acid, which gave a moderate yield in Table 2,
resulted in a complex mixture of products when reacted with substituted vinylcyclopropane 4a.
Reaction scope with respect to the Ar’ group on the vinylcyclopropane was also investigated (Table 3,
entries 10-13). The high selectivity for the branched products remained for these substrates and
aryl-bromides could be tolerated with no Suzuki-type products observed.
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Table 3. Reaction scope with respect to boronic acid for branched systems.
4
5
6
7
8
Ar CO2Et
CO2Et
Ar'
Ar'
EtO2C CO2Et
Pd(OAc)2 (1 mol%)
H2O, r.t.,8 h
5
ArB(OH)2
+
9
Ar'
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Ar
CO2Et
CO2Et
4
6
Entry
Producta
Entry
Producta
CO2Et
CO2Et
CO2Et
CO2Et
1
8
84%, 5a/6a = 25: 1
84%, 5g/6g = 19:1
F
CO2Et
CO2Et
2
9
CO2Et
CO2Et
82%, 5bb
72%, 5h/6h = 4: 1
O
CO2Et
CO2Et
CO2Et
3
4
10
11
CO2Et
64%, 5cb
77%, 5i/6i = 35: 1
Cl
Cl
CO2Et
CO2Et
CO2Et
CO2Et
80%, 5j/6j = 93: 1
61%, 5d/6d = 16: 1
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CO2Et
CO2Et
Cl
CO2Et
CO2Et
8
9
Br
43%, 5kb
38%, 5eb
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O
O
CO2Et
CO2Et
CO2Et
CO2Et
6
13
O
62%, 5f/6f = 21: 1
64%, 5l/6l = 59: 1
O2N
CO2Et
CO2Et
7
37%, 5mc
a ratios measured from the crude 1H NMR, only the E isomer of the major product was observed b no linear isomer observed
We also briefly investigated the decarboxylation of 2a and showed this to be a facile process under
Krapcho conditions to provide ester 7a (Scheme 2).
Scheme 2. Decarboxylation reaction
The proposed mechanism for reaction is shown in Scheme 3. As demonstrated by Zhang and
co-workers17, Pd(0) nanoparticles can be generated by the reaction of palladium acetate and two molar
equivalents of arylboronic acid. In their paper they used TEM analysis to show that Pd nanoparticules
1
are formed by mixing Pd(OAc)2 and phenylboronic acid. The H NMR of the crude reaction mixtures
in this present work also showed trace biphenyl, indicating that the Pd(OAc)2 may have been reduced
to Pd(0) nanoparticles. Following catalyst activation, oxidative addition to the vinylcyclopropane can
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occur to give the Pd-allyl complex A. Transmetallation likely occurs by assistance of water or
alternatively the ester enolate – in the later case the mechanism would be reminiscent of an
intramolecular base-assisted transmetallation (B).20 Furthermore, it has been postulated that facile
transmetallation in the coupling of 1,1-diboron compounds is probably assisted by internal coordination
between boron and an ester.21 It is also possible that water plays a role in accelerating transmetallation
by forming palladium hydroxide species that have been shown to undergo rapid transmetallation with
boronic acids.22 The resulting complex C can then undergo reductive elimination to provide the final
ring-opened product and it is this step that dictates the regiochemical outcome of the reaction.
Reductive elimination when R=H occurs at the least hindered carbon to provide linear products 2. On
the other hand, when R = Ar then the reductive elimination occurs to give the branched products 5.
The selective formation of linear product 2 when R = H can be explained by the reductive elimination
occurring to place the Ar group on the terminal carbon yielding the thermodynamically more stable
internal alkene rather than the terminal alkene 3. Furthermore, steric repulsion between Pd-Ar and the
vinylcyclopropane substrate is minimised by reductive elimination to the terminal carbon. Conversely,
the branched product formation when R = Ar can be explained as reductive elimination occurs to give
the more stable conjugated system 5 over the internal alkene 6; for this reason the transition state for
the formation of the conjugated product 5 is also likely to be lower in energy than that for the formation
of 5.
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EWG
EWG
Pd(OAc)2
ArB(OH)2
R2
2
6
or
Ar CO2Et
CO2Et
7
8
9
+
2 AcOB(OH)2
Ar-Ar
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EtO2C CO2Et
Ar
PdNPs
5
reductive
elimination
oxidative
addition
R
B(OH)2
EtO
O
Pd(II)
Ar
EtO
O
Pd
EtO2C
R
EtO2C
R
A
C
(HO)2B
EtO
Ar
Pd(II)
O
EtO2C
R
B
transmetallation
Scheme 3. Proposed reaction mechanism
CONCLUSION
In summary, we have developed a new method for the ring-opening of activated vinylcyclopropanes
with boronic acids that proceeds under mild conditions using only water as a solvent. The
regioselectivity for the process is driven by the reductive elimination step in the catalytic cycle, with
branched ring-opened products being obtained for vinylcyclopropane dicarboxylates that have an aryl
substituent on the alkene and linear products being obtained for systems with a terminal alkene. The
use of a simple Pd(II) pre-catalyst without the need for ancilliary ligands renders the process practical
and economical. Investigation into enantioselective variants of this reaction will be the subject of future
work.
EXPERIMENTAL SESSION
General Information. All reactions were performed under atmosphere of nitrogen in oven-dried
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glassware. Anhydrous solvents were purified by passage through a solvent purification system
(purification over activated alumina, copper catalyst, and/or molecular sieves). Flash grade silica gel
was used for column chromatography and thin layer chromatography was performed on silica gel 60
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F254 aluminium backed sheets. H NMR and 13C{1H} NMR were recorded in deuterated chloroform
(CDCl3) and coupling constants are recorded in Hz and chemical shifts are recorded as δ values in ppm,
referenced against residual solvent peaks (1H NMR) or to the 13C{1H} resonances of the solvent. The
following abbreviations are used in the assignments of 1H NMR signals; s = singlet; d =doublet; td=
doublet of triplet; tdd = triplet of doublet of doublet; m= multiplet. Other reagents and starting
materials were commercially available and used without further purification.
GP1. The Preparation of Diethyl 2-vinylcyclopropane-1,1-dicarboxylate 1.23 To a solution of
(E)-1,4-dibromobut-2-ene (3.0 g, 14.0 mmol, 1.0 eq) in anhydrous tetrahydrofuran (70 mL) was added
diethyl malonate (2.14 mL, 14.0 mmol, 1.0 eq) and caesium carbonate (11.4 g, 35.1 mmol, 2.5 eq). The
mixture was refluxed at 60oC. After the reaction proceeds for 16h, the mixture was extracted with ethyl
acetate (50 mL×3) and the combined organic layer was washed with distilled water and dried over
MgSO4. After filtration, the solvent was removed in vacuo. The residue was purified by flash column
chromatography (Ethyl acetate: Hexane, 10:90) to furnish a clear oily liquid in the yield of 87%. Note
Data matched that reported previous.
The Preparation of 2-vinylcyclopropane-1,1-dicarbonitrile b.23 This compound was synthesized in
43% yield according to the GP1 using 1,4-dibromobutene (1.0 g, 4.67 mmol, 1.0 eq), malononitrile
(339.7 mg, 5.14 mmol, 1.1 eq), caesium carbonate (3.81 g, 11.2 mmol, 2.5 eq) and anhydrous
tetrahydrofuran (23.4 mL). Ethyl acetate cannot be completely removed due to volatility of this
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compound. Note Data matched that reported previous.
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GP2. The preparation of (E)-diethyl 2-styrylcyclopropane-1,1-dicarboxylate 4a.23-25 To a solution
of cinnamaldehyde (3.3 g, 25.0 mmol, 1.0 eq) in anhydrous dichloromethane (40 mL), which was
cooled with -5oC ice/salt water was added diethyl malonate (6.4 g, 39.9 mmol, 1.6 eq) dropwise over
10 mins. A few drops of piperidine and sodium sulphate (10 g) were then added at room temperature.
The reaction mixture was stirred for 24 hrs, diluted with ethyl acetate (50 mL), washed with distilled
water (3 × 50 mL), and organic layer was dried over MgSO4 and evaporated under reduced pressure.
The resulting crude product was purified with Kugelrohr distillation to give the intermediate as a dark
oil. Note Data matched that reported previous. To a mixture of sodium hydride (0.535 g, 22.3 mmol,
1.1 eq, 60 % dispersion in mineral oil) and trimethylsulfonium iodide (4.90 g, 22.3 mmol, 1.1 eq) in
anhydrous dimethylformamide (28.5 mL), which has been stirred at room temperature for 30 mins, was
added a solution of the intermediate in anhydrous dimethylformamide (12.1 ml). The reaction mixture
was stirred for overnight, diluted with ethyl acetate (50 ml), washed with distilled water (3 × 50 mL),
dried over MgSO4, evaporated under reduced pressure and purified with 15% ethyl acetate in hexane to
give yellow oil (1.00 g) as product in 14% overall yield. Note Data matched that reported previous.
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GP3. The preparation of substituted styrenyl cyclopropane.26
1. Preparation of (E)-diethyl 2-(4-methylstyryl)cyclopropane-1,1-dicarboxylate 4i. An oven-dried
10 ml flask was charged with Grubbs catalyst 2nd generation (34.5 mg, 0.041 mmol, 5 mol%) under
nitrogen atmosphere at room temperature. A solution of 1 (300 mg, 1.41 mmol, 1.0 eq) and
4-methylstyrene (0.21 mL, 1.63 mmol, 2.0 eq) in anhydrous dichloromethane (3.2 mL) was added to
o
the flask. Ethyl acetate (50 mL) was added after which the reaction mixture was refluxed at 65 C
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overnight, then it was washed with brine (3×30 mL) and the organic phase was dried over MgSO4.
After filtration, the solvent was removed in vacuo. The resulting crude product was then purified with
flash column chromatography (20% ethyl acetate in hexane). The product was isolated as a light green
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oil (134.1 mg) in 55% yield. H NMR (CDCl3, 300MHz) δ 7.19 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.8
Hz, 2H), 6.60 (d, J = 15.6 Hz, 1H), 5.76 (dd, J = 15.9, 8.7 Hz, 1H), 4.27-4.14 (m, 4H), 2.72 (q, J = 8.7
Hz, 1H), 2.31 (s, 3H), 1.81 (dd, J = 7.2, 5.1 Hz, 1H), 1.64 (dd, J = 7.2, 5.1 Hz, 1H), 1.28 (t, J = 7.2 Hz,
3H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (75Mz, CDCl3) δ 169.9, 167.9, 137.7, 134.2, 133.8, 129.5,
126.3, 123.9, 61.9, 61.8, 36.6, 31.6, 21.5, 21.3, 14.5, 14.4. HRMS (ESI-TOF): m/z 325.1403 [C18H22O4
+ Na]+, calcd. 325.1416. IR ν(cm-1): 2926, 2360, 2333, 1734, 1718, 1559, 1502, 1457, 1374, 1319,
1280, 1250, 1201, 1135, 1026, 964.
2. Preparation of (E)-diethyl 2-(2-chlorostyryl)cyclopropane-1,1-dicarboxylate 4j. This compound
was synthesized in 96% yield according to the GP3 using 1 (150 mg, 0.707 mmol, 1.0 eq),
2-chlorostyrene (0.18 mL, 1.41 mmol, 2.0 eq) and Grubbs catalyst 2nd generation (30.0 mg, 0.0350
mmol, 5 mol%) in anhydrous dichloromethane (2.7 mL). 1H NMR (CDCl3, 300 MHz) δ 7.41-7.38 (m,
1H), 7.34-7.31(m, 1H), 7.20-7.12 (m, 2H), 7.03 (d, J = 15.6 Hz, 1H), 5.82 (dd, J = 15.6, 9.0 Hz, 1H),
4.29-4.16 (m, 4H), 2.79 (q, J = 7.5 Hz, 1H), 1.83 (dd, J = 7.2, 4.8 Hz, 1H), 1.69 (dd, J = J = 7.2, 4.8
Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (75Mz, CDCl3) δ 169.4,
167.5, 134.8, 132.7, 129.7, 129.7, 128.5, 127.8, 126.8, 126.5, 61.7, 61.6, 36.4, 31.1, 21.1, 14.2, 14.1.
HRMS (ESI-TOF): m/z 345.0886 [C17H19ClO4 + Na]+, calcd. 345.0870. IR ν(cm-1): 1730, 1718, 1653,
1559, 1317, 1274, 1199, 1126, 963, 749.
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3. Preparation of (E)-diethyl 2-(4-methoxystyryl)cyclopropane-1,1-dicarboxylate 4l. This
compound was synthesized in 66% yield according to the GP3 using 1 (120 mg, 0.565 mmol, 1.0 eq),
4-methoxystyrene (0.15 mL, 1.13 mmol, 2.0 eq) and Grubbs catalyst 2nd generation (24.0 mg, 0.028
mmol, 5 mol%) in anhydrous dichloromethane (2.1 mL). Note compound contained 10% of
homo-coupled styrene which could not be completely removed following multiple attempts at
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chromatography. H NMR (CDCl3, 500 MHz) δ 7.23 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H),
6.58 (d, J = 15.5 Hz, 1H), 5.68 (dd, J = 16.0, 8.5 Hz, 1H), 4.26-4.15 (m, 4H), 3.79 (s, 3H), 2.71 (q, J =
8.0 Hz, 1H), 1.80 (dd, J = 7.5, 4.5 Hz, 1H), 1.64 (dd, J = 7.5, 4.5 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H),
1.22 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.7, 167.6, 159.2, 133.1, 129.6, 127.3,
122.4, 114.0, 61.6, 61.5, 55.3, 36.3, 31.4, 21.0, 14.3, 14.1. HRMS (ESI-TOF): m/z 341.1378 [C18H22O5
+ Na]+, calcd. 341.1365. IR ν(cm-1): 2166, 2022, 1734, 1719, 1654, 1636, 1578, 1512, 1254, 1201,
1176, 1132, 1032, 964.
4. Preparation of (E)-diethyl 2-(4-bromostyryl)cyclopropane-1,1-dicarboxylate 4k. This compound
was synthesized in 13% yield according to the GP3 using 1 (111.5 mg, 0.5250 mmol, 1.0 eq),
4-bromostyrene (0.14 mL, 1.1 mmol, 2.0 eq) and Grubbs catalyst 2nd generation (22.3 mg, 0.0260
1
mmol, 5 mol%) in anhydrous dichloromethane (2.1 mL). H NMR (CDCl3, 500 MHz) δ 7.40 (d, J =
8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 15.5 Hz, 1H), 5.82 (dd, J = 16.0, 9.0 Hz, 1H),
4.26-4.15 (m, 4H), 2.71 (q, J = 8.5 Hz, 1H), 1.81 (dd, J = 6.5, 4.5 Hz, 1H), 1.66 (dd, J = 6.5, 4.5 Hz,
1H), 1.29 (t, J = 7.5 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.5,
167.5, 135.7, 132.4, 131.7, 127.6, 125.8, 121.3, 61.7, 61.6, 36.3, 31.0, 21.0, 14.2, 14.1. HRMS
(ESI-TOF): m/z 389.0381 [C17H19BrO4 + Na]+, calcd. 389.0364. IR ν(cm-1): 2983, 1721, 1489, 1370,
1318, 1274, 1200, 1131, 1073, 1024, 1009, 964, 813.
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GP4: Palladium-Catalyzed Coupling of Vinylcyclopropanes a-h with Boronic Acids in Water. To
a 10 mL Schlenck flask equipped with a stir bar, was added Pd(OAc)2 (1 mol%), the vinylcyclopropane
(1.0 eq), arylboronic acid (1.5 eq) and H2O (0.25 M wrt to the vinylcyclopropane). The mixture was
stirred at room temperature and after 8h, it was extracted with ethyl acetate (3 x 10 mL). The combined
organic layers were dried over MgSO4, filtered, and evaporated to dryness under reduced pressure. The
residue was purified by flash column chromatography (typically ethyl acetate: Hexane, 20:80) or
straight dichloromethane to furnish the corresponding coupling products. Data for major isomer only
reported.
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(E)-diethyl 2-(4-phenylbut-2-en-1-yl)malonate 2a. 147.0 mg 2a was prepared in 84% yield via the
GP4 from 1 (127.7 mg, 0.2230 mmol, 1.0 eq), phenylboronic acid (110.2 mg, 0.3350 mmol, 1.5 eq)
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and palladium acetate (1.35 mg, 0.00223 mmol, 1 mol%)26; H NMR (300 MHz, CDCl3) δ 7.30-7.25
(m, 2H), 7.20-7.13 (m, 3H), 5.74-5.65 (m, 1H), 5.53-5.43 (m, 1H), 4.19-4.13 (m, 4H), 3.40 (t, J = 7.5
Hz, 1H), 3.32 (d, J = 6.9 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 6H). 13C{1H} NMR (75
MHz, CDCl3) δ 169.0, 140.3, 132.4, 128.5, 128.4, 127.0, 126.0, 61.4, 52.2, 39.0, 31.8, 14.1. HRMS
(ESI-TOF): m/z 313.1428 [C17H22O4 + Na]+, calcd. 313.1416. IR ν(cm-1): 1729, 1516, 1262, 1233,
1152, 1140, 1026.
(E)-diethyl 2-(4-(3-nitrophenyl)but-2-en-1-yl)malonate 2b. 120 mg 2b was prepared in 95% yield
via the GP4 from 1 (80.0 mg, 0.377 mmol, 1.0 eq), 3-nitrophenylboronic acid (94.5 mg, 0.566 mmol,
1.5 eq) and palladium acetate (0.85 mg, 0.0038 mmol, 1 mol%); 1H NMR (500 MHz, CDCl3) δ 8.06 (d,
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J = 7.5 Hz, 1H), 8.01 (s, 1H), 7.50-7.44 (m, 2H), 5.72-5.66 (m, 1H), 5.59-5.53 (m, 1H), 4.23-4.14 (m,
4H), 3.43 (d, J = 6.5 Hz, 2H), 3.42 (t, J = 8.0 Hz, 1H), 2.65 (t, J = 6.5 Hz, 2H), 1.25 (t, J = 7.5 Hz,
6H). 13C{1H} NMR (125 MHz, CDCl3) δ 168.8, 148.3, 142.3, 134.8, 130.6, 129.2, 128.6, 123.3, 121.3,
61.4, 51.9, 38.4, 31.6, 14.0. HRMS (ESI-TOF): m/z 358.1271 [C17H21NO6 + Na]+, calcd. 358.1267. IR
ν(cm-1): 1734, 1730, 1528, 1351, 1153, 1031, 971, 733.
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(E)-diethyl 2-(4-(4-fluorophenyl)but-2-en-1-yl)malonate 2c. 100 mg of 2c was prepared in 86%
yield via the GP4 from 1 (80.0 mg, 0.377 mmol, 1.0 eq), 4-fluorophenylboronic acid (79.2 mg, 0.566
mmol, 1.5 eq) and palladium acetate (0.85 mg, 0.0038 mmol, 1 mol%); 1H NMR (300 MHz, CDCl3) δ
7.11-7.07 (m, 2H), 6.95 (t, J = 8.7 Hz, 2H), 5.71-5.61 (m, 1H), 5.51-5.42 (m, 1H), 4.17 (q, J = 7.2 Hz,
4H), 3.40 (t, J = 7.2 Hz, 1H), 3.28 (d. J = 6.0 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 1.24 (t, J = 6.9 Hz,
6H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.0, 161.4 (d, J = 242.2 Hz), 135.9 (d, J = 2.9 Hz), 132.2,
129.8 (d, J = 7.6 Hz), 127.1, 115.1 (d, J = 21 Hz), 61.4, 52.1, 38.1, 31.7, 14.1. HRMS (ESI-TOF): m/z
331.1315 [C17H21FO4 + Na]+, calcd. 331.1322. IR ν(cm-1): 1749, 1734, 1507, 1369, 1221, 1156, 1032,
971, 734.
(E)-diethyl 2-(4-(4-chlorophenyl)but-2-en-1-yl)malonate 2d. 118 mg of 2d was prepared in 96%
yield via the GP4 from 1 (80.0 mg, 0.377 mmol, 1.0 eq), 4-chlorophenylboronic acid (88.5 mg, 0.566
mmol, 1.5 eq) and palladium acetate (0.85 mg, 0.0038 mmol, 1 mol%); 1H NMR (500 MHz, CDCl3) δ
7.23 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.5 Hz, 2H), 5.67-5.60 (m, 1H), 5.52-5.45 (m, 1H), 4.17 (q, J =
7.2 Hz, 4H), 3.40 (t, J = 7.5 Hz, 1H), 3.27 (d, J = 6.3 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 1.24 (t, J = 6.9
Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 168.9, 138.7, 131.8, 129.8, 128.8, 128.4,127.4, 61.4, 52.0,
38.2, 31.7, 14.1. HRMS (ESI-TOF): m/z 347.1017 [C17H21ClO4 + Na]+, calcd. 347.1026. IR ν(cm-1):
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(E)-diethyl 2-(4-(2-chlorophenyl)but-2-en-1-yl)malonate 2e. 79.8 mg of 2e was prepared in 65%
yield (some starting material was inseparable) via the GP4 from 1 (80.0 mg, 0.377 mmol, 1.0 eq),
2-chlorophenylboronic acid (88.5 mg, 0.566 mmol, 1.5 eq) and palladium acetate (0.85 mg, 0.0038
mmol, 1 mol%); 1H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 9.0 Hz, 1H), 7.26-7.10 (m, 3H), 5.73-5.63
(m, 1H), 5.51-5.42 (m, 1H), 4.15 (q, J = 6.9 Hz, 4H), 3.42 (d, J = 6.6 Hz, 2H), 3.39 (t, J = 7.8 Hz, 2H),
2.61 (t, J = 7.8 Hz, 2H), 1.23 (t, J = 6.9 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.0, 138.0,
130.4, 130.3, 129.4, 127.7, 127.5, 126.8, 61.4, 52.1, 36.4, 31.8, 14.1. HRMS (ESI-TOF): m/z 347.1031
[C17H21ClO4 + Na]+, calcd. 347.1026. IR ν(cm-1): 1749, 1734, 1369, 1266, 1151, 1034, 736.
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(E)-diethyl 2-(4-(naphthalen-1-yl)but-2-en-1-yl)malonate 2f. 79.8 mg of 2f was prepared in 36%
yield via the GP4 from 1 (80.0 mg, 0.377 mmol, 1.0 eq), 1-naphthalenephenylboronic acid (97.4 mg,
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0.566 mmol, 1.5 eq) and palladium acetate (0.85 mg, 0.0038 mmol, 1 mol%); H NMR (500 MHz,
CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.51-7.45 (m,
2H), 7.41 (t, J = 7.0 Hz, 1H), 7.29 (d, J = 7.0 Hz, 1H), 5.85-5.81 (m, 1H), 5.54-5.49 (m, 1H), 4.18-4.07
(m, 4H), 3.77 (d, J = 6.0 Hz, 2H), 3.37 (t, J = 7.0 Hz, 1H), 2.61 (t, J = 7.0 Hz, 2H), 1.19 (t, J = 6.5 Hz,
6H). 13C{1H} NMR (125 MHz, CDCl3) δ 168.9, 136.4, 133.9, 131.9, 131.9, 128.7, 127.3, 126.9, 126.1,
125.8, 125.6, 125.5, 124.0, 61.3, 52.1, 36.0, 31.8, 14.1. HRMS (ESI-TOF): m/z 363.1576 [C21H24O4 +
Na]+, calcd. 363.1572. IR ν(cm-1): 1744, 1734, 1506, 1369, 1150, 1030, 970, 859, 777.
(E)-diethyl 2-(4-(3-acetylphenyl)but-2-en-1-yl)malonate 2g. 78.7 mg of 2g was prepared in 61%
yield via the GP4 from 1 (80.0 mg, 0.377 mmol, 1.0 eq), 3-acetylphenylboronic acid (92.8 mg, 0.566
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mmol, 1.5 eq) and palladium acetate (0.85 mg, 0.0038 mmol, 1 mol%); 1H NMR (500 MHz, CDCl3) δ
7.77 (d, J = 7.0 Hz, 1H), 7.73 (s, 1H), 7.38-7.33 (m, 2H), 5.70-5.65 (m, 1H), 5.53-5.49 (m, 1H),
4.20-4.12 (m, 4H), 3.39 (d, J = 7.5 Hz, 1H), 3.37 (d, J = 7.0 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 2.59 (s,
3H), 1.22 (t, J = 7.5 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 198.3, 168.9, 140.8, 137.3, 133.3,
131.6, 128.6, 128.3, 127.6, 126.2, 61.4, 52.0, 38.7, 31.7, 26.7, 14.1. HRMS (ESI-TOF): m/z 355.1518
[C19H24O5 + Na]+, calcd. 355.1521. IR ν(cm-1): 1734, 1727, 1684, 1269, 1175, 1155, 969, 859, 797.
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(E)-diethyl 2-(4-(p-tolyl)but-2-en-1-yl)malonate 2h. 54.6 mg of 2h was prepared in 48% yield via the
GP4 from 1 (80.0 mg, 0.377 mmol, 1.0 eq), 4-methylphenylboronic acid (76.9 mg, 0.566 mmol, 1.5 eq)
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and palladium acetate (0.85 mg, 0.0038 mmol, 1 mol%); H NMR (500 MHz, CDCl3) δ 7.08 (d, J =
8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 5.69-5.66 (m, 1H), 5.49-5.43 (m, 1H), 4.21-4.12 (m, 4H), 3.39 (t,
J = 7.5 Hz, 1H), 3.28 (d, J = 7.5 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.24 (t, J = 7.5 Hz,
6H). 13C{1H} NMR (125 MHz, CDCl3) δ 168.9, 137.2, 135.5, 132.6, 129.1, 128.4, 126.7, 61.4, 52.2,
38.5, 31.8, 21.0, 14.1. HRMS (ESI-TOF): m/z 327.1577 [C18H24O4 + Na]+, calcd. 327.1572. IR ν(cm-1):
1743, 1734, 1559, 1507, 1369, 1153, 1030, 970, 805.
(E)-diethyl 2-(4-(4-(ethoxycarbonyl)phenyl)but-2-en-1-yl)malonate 2i. 90.1 mg of 2i was prepared
in 90% yield via the GP4 from 1 (58.4 mg, 0.275 mmol, 1.0 eq), 4-ethoxycarbonylphenylboronic acid
(80.1 mg, 0.413 mmol, 1.5 eq) and palladium acetate (0.62 mg, 0.0028 mmol, 1 mol%); 1H NMR (500
MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 5.71-5.65 (m, 1H), 5.53-5.48 (m,
1H), 4.36 (q, J = 7.5 Hz, 2H), 4.22-4.12 (m, 4H), 3.40 (t, J = 8.0 Hz, 1H), 3.37 (d, J = 6.5 Hz, 2H),
2.63 (t, J = 7.0 Hz, 2H), 1.39 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (125 MHz,
CDCl3) δ 168.9, 166.6, 145.7, 131.4, 130.0, 129.7, 128.5, 127.8, 61.4, 60.8, 52.1, 38.9, 31.7, 14.4, 14.1.
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HRMS (ESI-TOF): m/z 385.1622 [C20H26O6 + Na]+, calcd. 385.1627. IR ν(cm-1): 1749, 1723, 1715,
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(E)-diethyl 2-(4-(3-methoxyphenyl)but-2-en-1-yl)malonate 2j. 51.0 mg of 2j was prepared in 72%
yield via the GP4 from 1 (49.4 mg, 0.220 mmol, 1.0 eq), 3-methoxyphenylboronic acid (50.1 mg, 0.330
mmol, 1.5 eq) and palladium acetate (0.50 mg, 0.0022 mmol, 1 mol%); 1H NMR (500 MHz, CDCl3) δ
7.19 (t, J = 8.0 Hz, 1H), 6.74-6.73 (m, 2H), 6.69 (s, 1H), 5.71-5.65 (m, 1H), 5.51-5.46 (m, 1H),
4.22-4.14 (m, 4H), 3.79 (s, 3H), 3.40 (t, J = 7.5 Hz, 1H), 3.29 (d, J = 6.5 Hz, 2H), 2.62 (t, J = 7.5 Hz,
2H), 1.24 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.0, 159.7, 141.9, 132.1, 129.3,
127.0, 120.8, 114.1, 111.3, 61.3, 55.1, 52.1, 38.9, 31.7, 14.0. HRMS (ESI-TOF): m/z 343.1519
[C18H24O5 + Na]+, calcd. 343.1521. IR ν(cm-1): 1734, 1730, 1260, 1151, 1034, 970, 858, 779.
(E)-diethyl 2-(4-(3,4-dimethoxyphenyl)but-2-en-1-yl)malonate 2k. 18.5 mg of 2k was prepared in
23% yield via the GP4 from 1 (48.1 mg, 0.227 mmol, 1.0 eq), 3,4-dimethoxyphenylboronic acid (62.3
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mg, 0.341 mmol, 1.5 eq) and palladium acetate (0.510 mg, 0.00227 mmol, 1 mol%); H NMR (500
MHz, CDCl3) δ 6.81-6.78 (m, 1H), 6.70-6.67 (m, 2H), 5.70-5.63 (m, 1H), 5.51-5.45 (m, 1H), 4.21-4.14
(m, 4H), 3.87 (s, 3H), 3.85 (s, 3H), 3.40 (t, J = 7.5 Hz, 1H), 3.26 (d, J = 6.5 Hz, 2H), 2.62 (t, J = 7.0
Hz, 2H), 1.24 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.0, 148.9, 147.4, 133.0,
132.6, 126.7, 120.3, 111.9, 111.3, 61.4, 56.0, 55.9, 52.2, 38.5, 31.7, 14.1. HRMS (ESI-TOF): m/z
373.1618 [C19H26O6 + Na]+, calcd. 373.1627. IR ν(cm-1): 1729, 1727, 1515, 1262, 1233, 1153, 1140,
1025.
Diethyl 2-((2E,5E)-nona-2,5-dien-1-yl)malonate 2l. 64.1 mg of 2l was prepared in 59% yield via the
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GP4 from 1 (82.4 mg, 0.388 mmol, 1.0 eq), 1-pentenylphenylboronic acid (66.4 mg, 0.582 mmol, 1.5
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eq) and palladium acetate (0.870 mg, 0.00388 mmol, 1 mol%); H NMR (300 MHz, CDCl3) δ
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5.75-5.63 (m, 1H, Branched), 5.58-5.45 (m, 1H, Linear trans), 5.38-5.21 (m, 3H, Linear trans),
5.05-4.99 (m, 2H, Branched), 4.19 (q, J = 6.9 Hz, 4H, Branched+Linear trans), 3.38 (t, J = 7.5 Hz, 1H,
Branched+Linear trans), 2.68-2.65 (m, 2H, Branched+Linear trans), 2.59 (t, J = 6.9 Hz, 2H,
Branched+Linear trans), 2.02-1.93 (m, 2H, Branched+Linear trans), 1.39 (m, 2H, Branched+Linear
trans), 1.26 (t, J = 7.2 Hz, 6H, Branched+Linear trans), 0.88 (t, J = 7.2 Hz, 3H, Branched+Linear
trans). 13C{1H} NMR (125 MHz, CDCl3) δ 169.0, 132.3, 131.3, 128.0, 125.8, 61.3, 52.2, 35.5, 34.7,
31.8, 22.6, 14.1, 13.7. HRMS (ESI-TOF): m/z 305.1716 [C16H26O4 + Na]+, calcd. 305.1729. IR ν(cm-1):
1751, 1734, 1559, 1457, 1228, 1151, 1096, 1033, 968, 858. Note Proton signals for branched isomer
reported where clearly distinguished, this was not the case for the 13C{1H} hence only the major linear
trans product is reported.
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(E)-2-(4-phenylbut-2-en-1-yl)malononitrile 2m. 210 mg of 2m was prepared in a yield of 54% via
the GP4 from b (237 mg, 2.01 mmol, 1.0 eq), phenylboronic acid (368 mg, 3.01 mmol, 1.5 eq) and
palladium acetate (4.50 mg, 0.0201 mmol, 1 mol%); 1H NMR (500 MHz, CDCl3) δ 7.30 (t, J = 7.0 Hz,
2H, cis+trans), 7.24-7.16 (m, 3H, cis+trans), 6.00-5.94 (m, 1H, cis+trans), 5.58-5.49 (m, 1H,
cis+trans), 3.69 (t, J = 6.0 Hz, 1H, cis+trans), 3.48 (d, J = 7.0 Hz, 2H, cis), 3.38 (d, J = 6.5 Hz, 2H,
trans), 2.86 (t, J = 7.5 Hz, 2H, cis), 2.70 (t, J = 7.0 Hz, 2H, trans). 13C{1H} NMR (125 MHz, CDCl3) δ
139.1, 137.7, 136.0 (cis), 128.8 (cis), 128.7, 128.6, 128.4 (cis), 126.6 (cis), 126.5, 122.1, 121.1 (cis),
112.3, 38.8, 33.8, 33.7 (cis), 28.7 (cis), 23.4, 22.9 (cis). HRMS (ESI-TOF): m/z 195.0914 [C13H12N2 -
H]-, calcd. 195.0922. IR ν(cm-1): 2258, 1768, 1653, 1559, 1266, 1174, 1037, 971, 735, 699. N.B. only
visible cis signals highlighted in 13C{1H} NMR.
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(E)-diethyl 2-(2,4-diphenylbut-3-en-1-yl)malonate 5a. 64.8 mg of 5a was prepared in 82% yield via
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palladium(II) acetate (0.500 mg, 0.002 mmol, 1 mol%). H NMR (CDCl3, 300 MHz) δ 7.36-7.20 (m,
10H), 6.44 (d, J = 15.9 Hz, 1H), 6.29 (dd, J = 15.9, 8.1 Hz, 1H), 4.17 (q, J = 7.2 Hz, 4H), 3.48 (app q,
J = 8.1 Hz, 1H), 3.36 (t, J = 7.5 Hz, 1H), 2.46-2.37 (m, 2H), 1.25 (app q, J = 6.9 Hz, 6H). 13C{1H}
NMR (CDCl3, 75 MHz) δ 169.5, 169.4, 142.8, 137.1, 132.2, 130.6, 128.7, 128.5, 127.6, 127.4, 126.8,
126.2, 61.4, 50.2, 47.0, 34.6, 14.1, 14.0. HRMS (ESI-TOF ): m/z 389.1745 [C23H26O4 + Na]+, calcd.
389.1729. IR ν(cm-1): 1744, 1734, 1369, 1150, 1028, 966, 859, 746, 693.
(E)-diethyl 2-(2-(3-nitrophenyl)-4-phenylbut-3-en-1-yl)malonate 5m. 30.1 mg of 5m was prepared
in 23% yield via the GP4 from 4a (94.0 mg, 0.326 mmol, 1.0 eq), 3-nitrophenylboronic acid (81.7 mg,
0.488 mmol, 1.5 eq) and palladium acetate (0.730 mg, 0.00326 mmol, 1 mol%). 1H NMR (CDCl3, 500
MHz) δ 8.14 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.35
(d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.26-7.22 (m, 1H), 6.48 (d, J = 16.0 Hz, 1H), 6.23 (dd, J
= 15.5, 8.5 Hz, 1H), 4.21-4.11 (m, 4H), 3.62 (app q J = 8.0 Hz, 1H), 3.35 (t, J = 7.5 Hz, 1H),
2.47-2.42(m, 2H), 1.28-1.22 (m, 6H). 13C{1H} NMR (CDCl3, 75 MHz) δ 169.1, 169.0, 148.5, 145.2,
136.4, 133.8, 132.0, 130.3, 129.7, 128.6, 127.8, 126.3, 122.5, 122.0, 61.7, 61.6, 50.0, 46.8, 34.3, 14.0,
14.0. HRMS (ESI): m/z 434.1601 [C23H25NO6 + Na]+, calcd. 434.1580. IR ν(cm-1): 1744, 1734, 1719,
1528, 1349, 1152, 1027, 968, 736, 694, 690.
(E)-diethyl 2-(2-(4-fluorophenyl)-4-phenylbut-3-en-1-yl)malonate 5b. 69.7 mg of 5b was prepared
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in 82% yield via the GP4 from 4a (64.2 mg, 0.223 mmol, 1.0 eq), 4-fluorophenylboronic acid (46.8 mg,
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0.334 mmol, 1.5 eq) and palladium acetate (0.50 mg, 0.00223 mmol, 1 mol%). H NMR (CDCl3, 500
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(d, J = 16.0 Hz, 1H), 6.24 (dd, J = 15.5, 7.5 Hz, 1H), 4.19-4.11 (m, 4H), 3.47 (app q, J = 7.5 Hz, 1H),
3.33 (t, J = 7.0 Hz, 1H), 2.43-2.34 (m, 2H), 1.25-1.21 (m, 6H). 13C{1H} NMR (CDCl3, 125 MHz) δ
169.4, 169.3, 161.7 (d, J = 244 Hz), 138.6, 137.0, 132.0, 130.8, 129.1 (d J = 8 Hz), 128.6, 127.5,
126.3, 115.5 (d, J = 30 Hz), 61.5, 50.2, 46.3, 34.7, 14.1, 14.1. HRMS (ESI-TOF): m/z 407.1642
[C23H25FO4 + Na]+, calcd. 407.1635. IR ν(cm-1): 1750, 1729, 1507, 1221, 1158, 1027, 967, 832, 744,
693.
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(E)-diethyl 2-(2-(4-chlorophenyl)-4-phenylbut-3-en-1-yl)malonate 5d. 65.2 mg of 5d was prepared
in 61 % yield via the GP4 from 4a (63.9 mg, 0.222 mmol, 1.0 eq), 4-chlorophenylboronic acid (52.1
mg, 0.333 mmol, 1.5 eq) and palladium acetate (0.500 mg, 0.00222 mmol, 1 mol%). 1H NMR (CDCl3,
300 MHz) δ 7.36-7.29 (m, 5H), 7.23-7.18 (m, 4H), 6.42 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.6, 7.8
Hz, 1H), 4.21-4.10 (m, 4H), 3.47 (app q, J = 7.8 Hz, 1H), 3.33 (t, J = 7.2 Hz, 1H), 2.45-2.33 (m, 2H),
1.24 (app q, J = 7.5 Hz, 6H). 13C{1H} NMR (CDCl3, 125 MHz) δ 169.3, 169.2, 141.4, 136.9, 132.5,
131.6, 131.0, 129.0, 128.9, 128.6, 127.5, 126.3, 61.5, 50.2, 46.4, 34.5, 14.1, 14.0. HRMS (ESI-TOF):
m/z 423.1347 [C23H25ClO4 + Na]+, calcd. 423.1339. IR ν(cm-1): 1750, 1729, 1490, 1369, 695.
(E)-diethyl 2-(2-(2-chlorophenyl)-4-phenylbut-3-en-1-yl)malonate 5e. 25.3 mg of 5e was prepared
in 38% yield via the GP4 from 4a (47.8 mg, 0.166 mmol, 1.0 eq), 2-chlorophenylboronic acid (38.9 mg,
0.249 mmol, 1.5 eq) and palladium acetate (0.370 mg, 0.00166 mmol, 1 mol%). 1H NMR (CDCl3, 500
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MHz) δ 7.37-7.33 (m, 3H), 7.29-7.26 (m, 4H), 7.22-7.15 (m, 2H), 6.47 (d, J = 15.5 Hz, 1H), 6.23 (dd,
J = 15.5, 8.0 Hz, 1H), 4.17 (app q, J = 7.0 Hz, 4H), 4.11-4.06 (m, 1H), 3.37 (t, J = 7.0 Hz, 1H),
2.49-2.38 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (CDCl3, 125 MHz)
δ 169.3, 169.3, 140.2, 137.0, 134.0, 131.5, 130.6, 130.0, 128.5, 128.2, 127.8, 127.5, 127.3, 126.3, 61.5,
50.2, 42.7, 33.8, 14.1, 14.0. HRMS (ESI-TOF): m/z 423.1357 [C23H25ClO4 + Na]+, calcd. 423.1339. IR
ν(cm-1): 1750, 1734, 1369, 1153, 1034, 966, 749, 697.
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(E)-diethyl 2-(2-(naphthalen-1-yl)-4-phenylbut-3-en-1-yl)malonate 5h. 94.4mg of 5h was prepared
in 72% yield via the GP4 from 4a (97.8 mg, 0.340 mmol, 1.0 eq), 1-naphthalenephenylboronic acid
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(87.6 mg, 0.509 mmol, 1.5 eq) and palladium acetate (0.760 mg, 0.00340 mmol, 1 mol%). H NMR
(CDCl3, 300 MHz) δ 8.20 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H),
7.55-7.14 (m, 9H), 6.53 (d, J = 15.9 Hz, 1H), 6.46 (dd, J = 15.9, 7.2 Hz, 1H), 4.36 (app q, J = 6.9 Hz,
1H), 4.20 (q, J = 6.9 Hz, 2H), 4.17-4.07 (m, 2H), 3.49 (t, J = 7.2 Hz, 1H), 2.61-2.54 (m, 2H), 1.26 (t, J
= 7.2 Hz, 3H), 1.16 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ 169.5, 169.5, 139.1, 137.0,
134.1, 131.8, 131.5, 131.3, 129.0, 128.5, 128.4, 127.4, 127.4, 126.3, 126.1, 125.6, 124.1, 123.2, 61.5,
50.3, 41.6, 34.5, 14.1, 14.0. HRMS (ESI-TOF): m/z 439.1882 [C27H28O4 + Na]+, calcd. 439.1885. IR
ν(cm-1): 1749, 1729, 1369, 1151, 1027, 969, 778, 697.
(E)-diethyl 2-(2-(3-acetylphenyl)-4-phenylbut-3-en-1-yl)malonate 5c. 46.1 mg of 5c was prepared in
60% yield via the GP4 from 4a (54.9 mg, 0.191 mmol, 1.0 eq), 3-acetylphenylboronic acid (46.9 mg,
0.286 mmol, 1.5 eq) and palladium acetate (0.430 mg, 0.00191 mmol, 1 mol%). 1H NMR (CDCl3, 500
MHz) δ 7.85 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.33
(d, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.22-7.19 (m, 1H), 6.45 (d, J = 16.0 Hz, 1H), 6.26 (dd, J
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= 16.0, 8.5 Hz, 1H), 4.19-4.12 (m, 4H), 3.56 (app q, J = 8.0 Hz, 1H), 3.34 (t, J = 7.0 Hz, 1H), 2.60 (s,
3H), 2.47-2.39 (m, 2H), 1.26-1.21 (m, 6H). 13C{1H} NMR (CDCl3, 125 MHz) δ 198.3, 169.5, 169.4,
143.9, 137.8, 137.0, 132.3, 131.7, 131.5, 129.2, 128.8, 127.8, 127.5, 127.2, 126.5, 61.8, 61.7, 50.4, 47.3,
34.7, 27.0, 14.3, 14.2. HRMS (ESI-MS): m/z 431.1834 [C25H28O5 + Na]+, calcd. 431.1834. IR ν(cm-1):
1749, 1734, 1727, 1684, 1559, 1507, 1369, 1267, 1151, 1027, 967, 693.
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(E)-diethyl 2-(4-phenyl-2-(p-tolyl)but-3-en-1-yl)malonate 5g. 61.1 mg of 5g was prepared in 84%
yield via the GP4 from 4a (55.3 mg, 0.192 mmol, 1.0 eq), 4-methylphenylboronic acid (39.2 mg, 0.288
mmol, 1.5 eq) and palladium acetate (0.440 mg, 0.00192 mmol, 1 mol%). 1H NMR (CDCl3, 500 MHz)
δ 7.31 (d, J = 8.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (s, 4H), 6.42 (d, J =
16.0 Hz, 1H), 6.27 (dd, J = 16.0, 8.5 Hz, 1H), 4.22-4.10 (m, 4H), 3.44 (app q, J = 8.0 Hz, 1H), 3.34 (t,
J = 8.0 Hz, 1H), 2.45-2.34 (m, 2H), 2.32 (s, 3H), 1.28-1.20 (m, 6H). 13C{1H} NMR (CDCl3, 125 MHz)
δ 169.5, 169.4, 139.8, 137.2, 136.3, 132.6, 130.4, 129.4, 128.5, 127.5, 127.3, 126.3, 61.4, 50.3, 46.6,
34.7, 21.1, 14.1. HRMS (ESI-TOF): m/z 403.1871 [C24H28O4 + Na]+, calcd. 403.1885. IR ν(cm-1): 1749,
1734, 1265, 1152, 1028, 967, 734, 703.
(E)-diethyl 2-(2-(4-(ethoxycarbonyl)phenyl)-4-phenylbut-3-en-1-yl)malonate 5f. 84.2 mg of 5f was
prepared in 62% yield via the GP4 from 4a (89.3 mg, 0.310 mmol, 1.0 eq),
4-ethoxycarbonylphenylboronic acid (90.2 mg, 0.465 mmol, 1.5 eq) and palladium acetate (0.790 mg,
0.00310 mmol, 1 mol%). 1H NMR (CDCl3, 500 MHz) δ 8.00 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.0 Hz,
4H), 7.29-7.25 (m, 2H), 7.22-7.19 (m, 1H), 6.43 (d, J = 15.5 Hz, 1H), 6.25 (dd, J = 15.5, 8.5 Hz, 1H),
4.36 (q, J = 7.5 Hz, 2H), 4.19-4.10 (m, 4H), 3.55 (app q, J = 7.5 Hz, 1H), 3.31 (t, J = 7.5 Hz, 1H),
2.46-2.38 (m, 2H), 1.38 (t, J = 7.5 Hz, 3H), 1.26-1.20 (m, 6H). 13C{1H} NMR (CDCl3, 125 MHz)
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δ169.5, 169.4, 166.6, 148.3, 137.0, 131.5, 131.5, 130.2, 129.3, 128.8, 127.8, 127.8, 126.5, 61.7, 61.1,
50.3, 47.3, 34.6, 14.6, 14.3, 14.2. HRMS (ESI-MS): m/z 461.1942 [C26H30O6 + Na]+, calcd. 461.1940.
IR ν(cm-1): 1750, 1729, 1718. 1273, 1104, 1020, 968, 855, 694.
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(E)-diethyl 2-(2-phenyl-4-(p-tolyl)but-3-en-1-yl)malonate 5i. 128.7 mg of 5i was prepared in 77%
yield via the GP4 from 4i (134.1 mg, 0.4440 mmol, 1.0 eq), phenylboronic acid (81.2 mg, 0.666 mmol,
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1.5 eq) and palladium acetate (0.994 mg, 0.000444 mmol, 1 mol%). H NMR (CDCl3, 500 MHz) δ
7.31 (t, J = 7.0 Hz, 2H), 7.27-7.14 (m, 5H), 7.08 (d, J = 8.0 Hz, 2H), 6.40 (d, J = 16.0 Hz, 1H), 6.22
(dd, J = 15.5, 8.5 Hz, 1H), 4.18-4.11 (m, 4H), 3.46 (app q, J = 8.5 Hz, 1H), 3.35 (t, J = 7.5 Hz, 1H),
2.44-2.35 (m, 2H), 2.31 (s, 3H), 1.23 (app q, J = 9.0 Hz, 6H). 13C{1H} NMR (CDCl3, 125 MHz) δ
169.5, 169.4, 143.1, 137.1, 134.3, 131.2, 130.5, 129.2, 128.7, 127.6, 126.7, 126.1, 61.4, 50.3, 47.0, 34.7,
21.1, 14.1, 14.0. HRMS (ESI-TOF): m/z 403.1903 [C24H28O4 + Na]+, calcd. 403.1885. IR ν(cm-1): 1749,
1730, 1653, 1507, 1457, 1369, 1150, 1097, 1030, 969, 853, 807, 761, 700.
(E)-diethyl 2-(4-(2-chlorophenyl)-2-phenylbut-3-en-1-yl)malonate 5j. 177.1 mg of 5j was prepared
in 80% yield via the GP4 from 4j (218.1 mg, 0.6760 mmol, 1.0 eq), phenylboronic acid (123.6 mg,
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1.014 mmol, 1.5 eq) and palladium acetate (1.501 mg, 0.006760 mmol, 1 mol%). H NMR (CDCl3,
500 MHz) δ 7.48 (d, J = 5.5 Hz, 1H), 7.35-7.32 (m, 2H), 7.27-7.22 (m, 3H), 7.19-7.13 (m, 3H), 6.83 (d,
J = 16.0 Hz, 1H), 6.26 (dd, J = 15.5, 8.5 Hz, 1H), 4.20-4.12 (m, 4H), 3.54 (app q, J = 8.5 Hz, 1H),
3.37 (t, J = 8.0 Hz, 1H), 2.47-2.40 (m, 2H), 1.23 (app q, J = 6.5 Hz, 6H). 13C{1H} NMR (CDCl3, 125
MHz) δ 169.4, 169.3, 142.6, 135.2, 135.1, 132.9, 129.6, 128.8, 128.4, 127.6, 126.9, 126.9, 126.8, 126.8,
61.5, 50.2, 47.3, 34.5, 14.1, 14.1. HRMS (ESI-MS): m/z 423.1348 [C23H25ClO4 + Na]+, calcd. 423.1339.
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IR ν(cm-1): 1748, 1727, 1472, 1437, 1369, 1264, 1150, 1031, 966, 856, 750, 699.
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(E)-diethyl 2-(4-(4-methoxyphenyl)-2-phenylbut-3-en-1-yl)malonate 5l. 78.8 mg of 5l was prepared
in 64% yield via the GP4 from 4l (99.6 mg, 0.313 mmol, 1.0 eq), phenylboronic acid (57.2 mg, 0.470
mmol, 1.5 eq) and palladium acetate (0.700 mg, 0.000313 mmol, 1 mol%). 1H NMR (CDCl3, 500 MHz)
δ 7.31 (t, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 4H), 7.21 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H),
6.37 (d, J = 16.0 Hz, 1H), 6.13 (dd, J = 16.0, 8.0 Hz, 1H), 4.18-4.10 (m, 4H), 3.77 (s, 3H), 3.45 (app q,
J = 8.0 Hz, 1H), 3.35 (t, J = 7.5 Hz, 1H), 2.42-2.37 (m, 2H), 1.28-1.21 (m, 6H). 13C{1H} NMR (CDCl3,
125 MHz) δ 169.5, 169.4, 159.0, 143.1, 130.1, 130.0, 129.9, 128.7, 127.6, 127.4, 126.7, 113.9, 61.4,
55.3, 50.3, 47.1, 34.7, 14.1. HRMS (ESI-MS): m/z 419.1832 [C24H28O5 + Na]+, calcd. 419.1834. IR
ν(cm-1): 1748, 1727, 1608, 1511, 1457, 1369, 1248, 1150, 1030, 967, 760, 700.
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(E)-diethyl 2-(4-(4-bromophenyl)-2-phenylbut-3-en-1-yl)malonate 5k. 13.5 mg of 5k was prepared
in 43% yield via the GP4 from 4k (25.6 mg, 0.0715 mmol, 1.0 eq), phenylboronic acid (13.1 mg, 0.107
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mmol, 1.5 eq) and palladium acetate (0.160 mg, 0.0000715 mmol, 1 mol%). H NMR (CDCl3, 500
MHz) δ 7.40 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.26-7.22 (m, 3H), 7.19 (d, J = 8.5 Hz, 2H),
6.36 (d, J = 16.0 Hz, 1H), 6.27 (dd, J = 16.0, 7.5 Hz, 1H), 4.19-4.11 (m, 4H), 3.47 (app q, J = 8.0 Hz,
1H), 3.31 (t, J = 7.0 Hz, 1H), 2.45-2.36 (m, 2H), 1.22 (app q, J = 6.5 Hz, 6H). 13C{1H} NMR (CDCl3,
125 MHz) δ 169.4, 169.3, 142.5, 136.0, 133.2, 131.6, 129.4, 128.8, 127.8, 127.6, 126.9, 121.1, 61.5,
50.2, 47.1, 34.5, 14.1. HRMS (ESI-MS): m/z 467.0856 [C23H25BrO4 + Na]+, calcd. 467.0834. IR
ν(cm-1): 1734, 1694, 1646, 1551, 1515, 1462, 1370, 1223, 1154, 1034, 972, 858, 804, 695.
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Procedure for Decarboxylation of Targeted product 2a.28 A solution of 2a (108.6 mg, 0.374 mmol,
1.0 eq) and NaCl (30.0 mg, 0.512 mmol, 1.37 eq) in DMSO (0.62 mL) and distilled water (25.4 µL)
was heated at 170°C for 1 hr in a microwave. Distilled water (20 mL) was added and the mixture was
extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over Na2SO4 and
concentrated in vacuo. The crude product was purified with column chromatography (15% ethyl
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acetate in hexane) to afford 7a (49 mg, 60%) as a brown oily liquid. H NMR (CDCl3, 500 MHz) δ
7.30-7.26 (m, 2H), 7.20-7.16 (m, 3H), 5.66-5.57 (m, 1H), 5.55-5.46 (m, 1H), 4.12 (t, J = 6.5 Hz, 2H),
3.33 (d, J = 6.5 Hz, 2H), 2.40-2.36 (m, 4H), 1.25 (q, J = 6.5 Hz, 3H). 13C{1H} NMR (CDCl3, 125 MHz)
δ 173.2, 140.7, 130.2, 129.7, 128.5, 128.4, 126.0, 60.3, 49.2, 39.0, 34.3, 27.8, 14.3. HRMS (ESI-TOF):
m/z 241.1208 [C14H18O2 + Na]+, calcd. 241.1204. IR ν(cm-1): 1734, 1495, 1452, 1373, 1248, 1178,
1156, 1030, 968, 745, 698.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
chris_hyland@uow.edu.au
Notes
The author declares no competing financial interest.
ACKNOWLEDGMENTS
The University of Wollongong is acknowledged for generous support of this research. J. X. thanks the
University of Wollongong for IPTA and UPA scholarships.
Supporting Information
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1H NMR and 13C{1H} NMR spectra of compound 4. This material is available free of charge via the
Internet at http:// pubs.acs.org.
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