Boron/zinc exchange for the conjugate arylation of unsaturated Meldrum's acid derivatives

Article abstract of DOI:10.1016/j.tet.2020.130967

An approach for the conjugate arylation reaction of unsaturated Meldrum's acid derivatives is reported. The reaction takes place through a Boron-Zinc exchange reaction between arylboronic acids and diethylzinc and the subsequent transfer of thus generated reactive aryl groups to the β-position of the double bond of the Meldrum's derivatives. The compounds obtained are valuable synthetic intermediates and can give rise to bioactive molecules such as β,β-disubstituted carboxylic acids and amides.

Full text of DOI:10.1016/j.tet.2020.130967

Journal Pre-proof
Boron/zinc exchange for the conjugate arylation of unsaturated Meldrum's acid
derivatives
Micaela Jardim, Lucas L. Baldassari, Maria Eduarda Contreira, Angélica V. Moro,
Diogo S. Lüdtke
PII:
S0040-4020(20)30059-4
https://doi.org/10.1016/j.tet.2020.130967
TET 130967
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 November 2019
Revised Date: 16 January 2020
Accepted Date: 18 January 2020
Please cite this article as: Jardim M, Baldassari LL, Contreira ME, Moro AngéV, Lüdtke DS, Boron/zinc
exchange for the conjugate arylation of unsaturated Meldrum's acid derivatives, Tetrahedron (2020), doi:
https://doi.org/10.1016/j.tet.2020.130967.
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Boron/Zinc Exchange for the Conjugate Arylation of Unsaturated
Meldrum’s Acid Derivatives
Micaela Jardim, Lucas L. Baldassari, Maria Eduarda Contreira, Angélica V.
Moro*, Diogo S. Lüdtke*
Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av. Bento
Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil. Phone: +55 51 3308 9637
E-mail: angelica.venturini@ufrgs.br; dsludtke@iq.ufrgs.br
Dedicated to Professor Nuno Maulide on his receipt of the Tetrahedron
Young Investigator Award
Abstract: An approach for the conjugate arylation reaction of unsaturated
Meldrum’s acid derivatives is reported. The reaction takes place through a
Boron-Zinc exchange reaction between arylboronic acids and diethylzinc and
the subsequent transfer of thus generated reactive aryl groups to the β-position
of the double bond of the Meldrum´s derivatives. The compounds obtained are
valuable synthetic intermediates and can give rise to bioactive molecules such
as β,β-disubstituted carboxylic acids and amides.
Keywords: Meldrum’s acid • organozinc reagents • arylation • boronic acids
Graphical Abstract:
1

Introduction
Meldrum’s acid and its unsaturated derivatives are important building blocks,
widely employed in organic synthesis.1 Several reports can be found in the
literature in which Meldrum´s acid alkyl(aryl)idenes have served as substrates
for a wide range of reactions with subsequent applications in the total synthesis
of natural products and biologically relevant molecules.2-8 For example, the
synthesis of taiwanaquinol B,9 ar-turmerone and α-curcumene,10 and coumarin
derivatives11,12 have all been accomplished through the use of Meldrum´s acid
alkylidenes as a key intermediate in the synthesis endeavor. The interest in
using unsaturated Meldrum’s acid derivatives arises due to their excellent ability
to act as electrophiles for conjugate addition reactions with a range of
nucleophiles. Conjugate additions of organometallic species to Meldrum´s
alkyl(aryl)idenes stand out as a valuable tool to forge carbon-carbon bonds in
these systems. Among them, the most studied reaction is the conjugate addition
of alkynes, that can be catalyzed by copper,13 zinc,14 and rhodium,15 or the
direct alkynylation using zinc-,16 aluminum-, and Grignard-alkynilides.17 Copper-
catalyzed conjugate alkylations using dialkylzinc reagents18 as well as the Rh-
catalyzed addition of vinylstannanes19 have also been reported. On the other
hand, the conjugate addition of aryl nucleophiles to Meldrum´s derivatives have
been less studied. Reported examples include the Rh-catalyzed addition of
dioxaborinanes,20 and copper-catalyzed Grignard addition.21 These methods,
however, present some limitations; the former demands the use of an alkylidene
with of an aryl group bearing a coordinating oxygen atom at the ortho position,
while the latter is limited to only a few variations of substituents at both
reactants (Scheme 1A).
2

As part of the research interests of our group, over the past few years we have
studied the boron-zinc exchange reaction between arylboronic acids and
diethylzinc for the generation of transferable aryl groups. The thus generated
mixed arylzinc reagents have been used for the mild and selective addition to a
variety of carbonyl eletrophiles.22,23 With this in mind, we wondered if this
strategy might be examined towards a Michael-type acceptor. Herein we report
our results of a mild, transition-metal-free conjugate arylation of unsaturated
Meldrum´s acid derivatives enabled by the a B/Zn exchange reaction (Scheme
1B). The ensuing products are versatile compounds that can be readily
converted to β,β-disubstituted carboxylic acids and amides, which are structural
units present in a number of biologically relevant molecules.
Scheme 1. Precedents and this work
3

Results and Discussion
At the outset, we selected the alkylidene 1a and phenylboronic acid as model
substrates for the optimization of the reaction conditions. The reactive arylating
agent was generated in situ by the reaction of diethylzinc and phenylboronic
acid. Initial screenings have been focused on the optimization of the reaction
solvent and stoichiometry (Table 1). In our first attempt, using 1.2 equiv. of
phenylboronic acid and 3.6 equiv. of diethylzinc in toluene as the solvent, the
desired product was not formed (entry 1), mainly due to the low solubility of the
4

Meldrum´s arylidene in the reaction mixture. When THF was used to solubilize
the arylidene 1a, the desired arylated product 2a was isolated in 78% yield
(entry 2). Increasing of the amount of Et2Zn led to a decreased yield of product
2a (entry 3). Since we have observed that the arylidene was not completely
consumed in the initial experiments, we decided to increase the amount of the
arylating agent. Thus, when the reaction was performed in the presence of 1.6
equiv. of the mixed arylzinc reagent, the desired product was obtained in an
increased 86% yield (entry 4). Increasing the amount of the arylating agent
even further did not provide better yields (entry 5). Additional solvent screening
was carried out and revealed that THF outperforms all other solvents
investigated (entries 6−9). To further optimize the yield of the reaction, we
studied the reaction time combined with different amounts of nucleophile
(entries 10-12). In this study, we have found that the best yields have been
achieved when 1.6 equiv. of the mixed arylzinc reagent (generated from 1.6
equiv. phenylboronic acid and 4.8 equiv. of Et2Zn) was used (entry 11).
Table 1. Optimization of the reaction conditionsa
Et2Zn
(equiv.)
Yield
(%)b
PhB(OH)2
(equiv.)
Entry
Time (h)
Solvent
5

1
2
1.2
1.2
1.2
1.6
2.4
1.2
1.2
1.2
1.2
1.2
1.6
2.4
3.6
3.6
4.0
4.8
7.2
3.6
3.6
3.6
3.6
3.6
4.8
7.2
4
2
2
2
2
4
2
2
2
4
4
4
toluene
NR
78
60
86
82
58
14
49
46
86
94
95
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/DCM
toluene/DMF
toluene/CPME
toluene/MTBE
toluene/THF
toluene/THF
toluene/THF
3
4
5
6
7
8
9
10
11
12
a The reaction was performed on the 0.3 mmol scale. Diethylzinc was used as a 1.5 M
solution in toluene. b Yield determined by NMR spectroscopy using mesitylene as the
internal standard.
With suitable reaction conditions in hands, we investigated the scope of
the reaction using a broader range of Michael acceptors and phenylboronic acid
as the aryl source (Scheme 2). The reaction proceeded efficiently for a number
of substrates bearing different groups with electron-donating and electron-
withdrawing effects, at ortho, meta or para positions. For example, the arylation
of substrates bearing p-Cl, p-OMe, p-CF3, o-Me and m-Br were successfully
used and the corresponding β,β´-arylated derivatives 2a, 2b, 2d, 2j, and 2h
were obtained in very good yields (80-91%). Steric effects have also been
examined and the reaction is equally efficient when ortho substituents are
present at the starting material. Hence, the transfer of a phenyl group to the
alkylidenes with ortho-methoxy and ortho-trifluoromethyl groups provided the
desired products 2i and 2k in 60% yield and 90% yield, respectively. The bulkier
1-naphthyl substituent at the β-position is also well tolerated and the product 2m
6

was obtained in 42% yield. Conversely, the presence of two ortho-methoxy
groups causes a more severe steric hindrance and a decrease in the yield of
product 2l. Nevertheless, despite the more congested environment, the arylated
product 2l was still formed in 29% yield. The arylation of arylidenes substituted
with heterocyclic side chains 2-furyl and 2-thienyl was also performed and the
compounds 2n and 2o were obtained in 70% and 87% yield, respectively.
Finally, the arylation of alkylidenes was also possible and product 2p and 2q
bearing aliphatic side chains was also achieved in good yields.
We next turned our attention to the scope of the boronic acid reaction
partner (Scheme 2). The conjugate arylation reaction was performed with the
arylidene 1b and both boronic acids bearing electron-withdrawing and electron-
donating groups were successfully used (2r-w). The presence of substituents
with different electronic effects at the aryl group, such as p-Cl (2r), m-OMe (2s),
o-Me (2t), p-OMe (2u), o-OMe (2v), and p-Me (2w), was well tolerated, and the
products have been obtained in good yields.
Scheme 2. Scope of the aryl transfer reaction to unsaturated Meldrum´s
acid derivatives
7

The mechanism of the reaction is presumed to occur through an initial
coordination of the electron deficient zinc atom from the ArZnEt (which was
generated in situ by the reaction of the arylboronic acid with diethylzinc24) to the
8

carbonyl group, followed by an intramolecular delivery of the aryl group25 by a
conjugate addition22c,d,f (Scheme 3).
Scheme 3. Mechanistic hypothesis
To highlight the utility of the reaction developed, derivatization reactions of the
β,β-diarylated products have been performed (Scheme 4). Initially, we have
carried out the hydrolysis reaction of the compounds 2a and 2b, and the β-
disubstituted carboxylic acids 3b-c were obtained in excellent yields.
Additionally, we have reacted 2c with benzylamine and the corresponding
amide 3a was isolated in 81% yield.
Scheme 4. Derivatization of the arylated products
9

Conclusion
In summary, we have developed an efficient approach for the conjugate
arylation reaction of unsaturated Meldrum’s acid derivatives. The reaction
showed good functional group tolerance and the arylated products were
obtained in good yields, without the need of using additional transition metal
catalysts. The compounds obtained are valuable synthetic intermediates and
can give rise to bioactive molecules such as β-disubstituted carboxylic acids
and amides. This methodology is operationally simple a and should be useful
for the synthesis of a variety of compounds thus opening a perspective for the
use of the mixed zinc species in conjugate addition reactions. Importantly, the
use of mildly nucleophilic organozinc reagents opens up the possibility of the
development of an enantioselective version of the reaction which is otherwise
more difficult to achieve by using more nucleophilic Grignard reagents.
Experimental Section
General Information. NMR spectra were recorded in CDCl3 solution either on a
400 or 500 MHz spectrometer at room temperature. Chemical shifts (δ) are
given in parts per million from the peak of tetramethylsilane (δ = 0.00 ppm) as
1
internal standard in H NMR or from the solvent peak of CDCl3 (δ = 77.0 ppm)
13
in C NMR. ESI-QTOF-MS measurements were performed in the positive ion
mode (m/z 50-2000 range). IR spectra were obtained on a FTIR-ATR
instrument. Flash chromatography was performed using silica gel (230-400
mesh). Thin layer chromatography (TLC) was performed using supported silica
gel GF254, 0.25 mm thickness. For visualization, TLC plates were either placed
under UV light 254 nm, stained with iodine vapor or treated with vanillin solution
10

followed by heating. Air‐ and moisture‐sensitive reactions were conducted in dry
glassware system equipped with tightly fitted rubber septa and under a positive
pressure of dry argon. Meldrum’s acid and unsaturated derivatives were
synthesized according to literature procedures.26,27
General Procedure for the Aryl Transfer Reaction. A 1.5 M solution of Et2Zn
in toluene (4.8 equiv., 1.44 mmol, 0.96 mL) was slowly added to a solution of
arylboronic acid (1.6 equiv., 0.48 mmol) in dry toluene (1 mL) under argon. The
mixture was stirred at 60 °C for 1 h and then coole d to 0 °C. Subsequently, a
solution of the unsaturated Meldrum´s acid derivative (0.3 mmol) in dry THF (2
mL) was added at 0 °C and the reaction mixture kept stirring at room
temperature for 4 h. After this, saturated aqueous of NH4Cl (5 mL) was carefully
added at 0 °C. The product was extracted with ethyl acetate (3ꢀ× 10 mL). The
combined organic layers were dried with MgSO4, filtered, the mixture was
concentrated under reduced pressure and the crude was purified by flash
chromatography on silica gel with hexane/ethyl acetate.
5-((4-chlorophenyl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2a).28 White solid. Yield: 94.1 mg, 91%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
80:20). H NMR (400 MHz, CDCl3) δ 7.34 – 7.22 (m, 9H), 5.37 (d, J = 2.7 Hz,
13
1H), 4.27 (d, J = 2.7 Hz, 1H), 1.76 (s, 3H), 1.57 (s, 3H). C NMR (100 MHz,
CDCl3) δ 164.5, 164.4, 139.6, 138.6, 133.0, 130.7, 129.1, 128.6, 128.5, 127.3,
105.2, 51.1, 48.3, 28.2, 27.5.
11

5-((4-methoxyphenyl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2b).28 White solid. Yield: 90.8 mg, 89%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
75:25). H NMR (400 MHz, CDCl3) δ 7.32 – 7.28 (m, 4H), 7.27 – 7.21 (m, 3H),
6.86 – 6.80 (m, 2H), 5.34 (d, J = 2.7 Hz, 1H), 4.28 (d, J = 2.7 Hz, 1H), 3.78 (s,
13
3H), 1.74 (s, 3H), 1.52 (s, 3H). C NMR (100 MHz, CDCl3) δ 164.9, 164.7,
158.6, 140.4, 132.0, 130.5, 128.9, 128.4, 127.0, 113.7, 105.1, 55.2, 51.2, 48.5,
28.2, 27.6.
2,2-dimethyl-5-(phenyl(p-tolyl)methyl)-1,3-dioxane-4,6-dione (2c). White
solid (mp: 120 °C). Yield: 67.07 mg, 69%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
80:20). H NMR (400 MHz, CDCl3) δ 7.32 – 7.28 (m, 4H), 7.27 – 7.22 (m, 1H),
7.21 – 7.16 (m, 2H), 7.14 – 7.08 (m, 2H), 5.35 (d, J = 2.8 Hz, 1H), 4.29 (d, J =
2.8 Hz, 1H), 2.32 (s, 3H), 1.73 (s, 3H), 1.51 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 164.8, 164.7, 140.2, 136.9, 136.7, 129.1, 129.08, 129.07, 128.4, 127.0, 105.1,
51.2, 48.8, 28.2, 27.6, 21.0. IR (νmax, cm-1): 2918, 1789, 1743, 1386, 1362,
1304, 1008, 723, 700. HRMS (ESI+): exact mass calculated for [M+H]+
(C20H21O4) requires m/z 325.1440, found: m/z 325.1439.
2,2-dimethyl-5-(phenyl(4-(trifluoromethyl)phenyl)methyl)-1,3-dioxane-4,6-
dione (2d).28 White solid. Yield: 90.7 mg, 80%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 80:20). 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.53 (m, 2H), 7.46
– 7.40 (m, 2H), 7.37 – 7.27 (m, 5H), 5.45 (d, J = 2.7 Hz, 1H), 4.31 (d, J = 2.7
Hz, 1H), 1.78 (s, 3H), 1.59 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.4, 164.3,
12

144.2 (q, J = 1.2 Hz), 139.2, 129.6, 129.3 (q, J = 32.6 Hz), 129.2, 128.7, 127.5,
125.3 (q, J = 3.8 Hz), 124.1 (q, J = 272.0 Hz), 105.3, 51.0, 48.5, 28.2, 27.5.
5-((4-(tert-butyl)phenyl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2e).29 White solid. Yield: 88.9 mg, 81%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
80:20). H NMR (400 MHz, CDCl3) δ 7.34 – 7.20 (m, 9H), 5.35 (d, J = 2.7 Hz,
1H), 4.30 (d, J = 2.7 Hz, 1H), 1.73 (s, 3H), 1.48 (s, 3H), 1.30 (s, 9H). 13C NMR
(100 MHz, CDCl3) 164.8, 164.78, 149.9, 140.2, 136.9, 129.2, 128.8, 128.3,
127.0, 125.3, 105.1, 51.2, 48.8, 34.4, 31.3, 28.2, 27.7.
5-((4-bromophenyl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2f).28 White solid. Yield: 102.4 mg, 84%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
80:20). H NMR (400 MHz, CDCl3) δ 7.44 – 7.40 (m, 2H), 7.35 – 7.24 (m, 5H),
7.21 – 7.17 (m, 2H), 5.35 (d, J = 2.7 Hz, 1H), 4.28 (d, J = 2.7 Hz, 1H), 1.76 (s,
3H), 1.57 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.5, 164.4, 139.5, 139.1,
131.4, 131.0, 129.1, 128.6, 127.3, 121.2, 105.2, 50.9, 48.3, 28.2, 27.5.
5-((4-fluorophenyl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2g).28 White solid. Yield: 80.7 mg, 82%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
80:20). H NMR (400 MHz, CDCl3) δ 7.35 – 7.24 (m, 7H), 7.02 – 6.95 (m, 2H),
5.38 (d, J = 2.7 Hz, 1H), 4.28 (d, J = 2.7 Hz, 1H), 1.76 (s, 3H), 1.55 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 164.7, 164.5, 163.8 (d, J = 246.2 Hz), 139.9, 135.7
13

(d, J = 3.2 Hz), 131.0 (d, J = 7.9 Hz), 129.0, 128.5, 127.2, 115.2, (d, J = 21.3
Hz), 105.2, 51.2, 48.3, 28.2, 27.6.
5-((3-bromophenyl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2h). White Solid (mp: 119 °C). Yield: 95.2 mg, 82%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
1
hexane/AcOEt = 80:20). H NMR (400 MHz, CDCl3, δ ppm): δ 7.47 (t, J = 1.8
Hz, 1H), 7.40 – 7.36 (m, 1H), 7.35 – 7.22 (m, 6H), 7.17 (t, J = 7.8 Hz, 1H), 5.35
(d, J = 2.6 Hz, 1H), 4.28 (d, J = 2.6 Hz, 1H), 1.76 (s, 3H), 1.57 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 164.4, 164.3, 142.5, 139.2, 132.2, 130.2, 129.8, 129.1,
128.6, 127.9, 127.4, 122.4, 105.2, 51.0, 48.4, 28.2, 27.5. IR (νmax, cm-1): 1785,
1748, 1309, 1292, 1187, 1053, 1013, 920, 786, 720, 697. HRMS (ESI+): exact
mass calculated for [M+H]+ (C19H18BrO4) requires m/z 389.0388, found: m/z
389.0387.
5-((2-methoxyphenyl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2i).28 White solid. Yield: 61.2 mg, 60%. Purified by flash chromatography using
hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt = 80:20).
1H NMR (400 MHz, CDCl3, δ ppm): δ 7.40 – 7.26 (m, 5H), 7.23 – 7.17 (m, 1H),
6.89 – 6.81 (m, 3H), 5.45 (d, J = 2.8 Hz, 1H), 4.28 (d, J = 2.8 Hz, 1H), 3.83 (s,
3H), 1.72 (s, 3H), 1.70 (s, 3H). 13C NMR (100 MHz, CDCl3, δ ppm): 165.5,
164.7, 156.0, 140.7, 130.7, 129.4, 128.9, 128.6, 127.9, 127.1, 120.5, 109.8,
104.5, 54.8, 50.4, 44.8, 28.2, 27.5.
2,2-dimethyl-5-(phenyl(o-tolyl)methyl)-1,3-dioxane-4,6-dione (2j). White
solid (mp: 121 °C). Yield: 79.7 mg, 82%. Purified by flash chromatography
14

using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
80:20). H NMR (400 MHz, CDCl3) δ 7.53 – 7.49 (m, 1H), 7.27 – 7.13 (m, 8H),
5.56 (d, J = 2.8 Hz, 1H), 4.26 (d, J = 2.8 Hz, 1H), 2.19 (s, 3H), 1.77 (s, 3H), 1.64
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.6, 164.1, 139.3, 138.6, 136.8, 130.8,
129.0, 128.2, 128.19, 127.3, 126.9, 126.3, 105.0, 51.3, 45.5, 28.3, 27.5, 20.0.
IR (νmax, cm-1): 2919, 1787, 1746, 1316, 1293, 1194, 1175, 1055, 1010, 897,
743. HRMS (ESI+): exact mass calculated for [M+H]+ (C20H21O4) requires m/z
325.1440, found: m/z 325.1449.
2,2-dimethyl-5-(phenyl(2-(trifluoromethyl)phenyl)methyl)-1,3-dioxane-4,6-
dione (2k). White solid (mp: 128 °C). Yield: 102.1 mg, 90%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 80:20). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H),
7.70 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.31 –
7.21 (m, 2H), 7.07 (d, J = 7.6 Hz, 2H), 5.80 (d, J = 3.5 Hz, 1H), 4.18 (d, J = 3.5
13
Hz, 1H), 1.76 (s, 6H). C NMR (100 MHz, CDCl3, δ ppm): 164.3, 163.7, 139.6
(q, J = 1.2 Hz), 138.7, 135.6, 133.5, 131.8 (q, J = 1.0 Hz), 128.4, 128.2, 127.4,
127.0, 126.0 (q, J = 6.1), 124.6 (q, J = 272.3 Hz), 105.1, 51.0 (q, J = 0.7 Hz),
43.8 (q, J = 1.9 Hz), 28.4, 27.0. IR (νmax, cm-1): 2926, 1716, 1309, 1154, 1116,
1062, 1036, 768, 697, 598. HRMS (ESI+): exact mass calculated for [M+H]+
(C20H18F3O4) requires m/z 379.1157, found: m/z 379.1155.
2,2-dimethyl-5-(phenyl(2,4,6-trimethoxyphenyl)methyl)-1,3-dioxane-4,6-
dione (2l). Orange solid (mp: 121 °C). Yield: 34.8mg, 29%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 70:30). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.32 (m, 2H), 7.25
15

– 7.20 (m, 2H), 7.17 – 7.11 (m, 1H), 6.10 (s, 2H), 5.31 (d, J = 8.9 Hz, 1H), 4.82
13
(d, J = 8.9 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 6H), 1.81 (s, 3H), 1.77 (s, 3H). C
NMR (100 MHz, CDCl3) δ 164.7, 163.6, 160.0, 158.3, 142.1, 128.0, 127.7,
126.1, 109.3, 104.4, 91.3, 55.5, 55.2, 49.7, 39.8, 28.7, 27.2. IR (νmax, cm-1):
2941, 2836, 1745, 1593, 1291, 1203, 1126, 827, 697, 542. HRMS (ESI+): exact
mass calculated for [M+H]+ (C22H25O7) requires m/z 401.1600, found: m/z
401.1598.
2,2-dimethyl-5-(naphthalen-1-yl(phenyl)methyl)-1,3-dioxane-4,6-dione
(2m). Light brown solid (mp: 132 °C). Yield: 45.4 mg, 42%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
1
hexane/AcOEt = 80:20). H NMR (400 MHz, CDCl3, δ ppm): δ 7.98 – 7.86 (m,
2H), 7.82 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.51 – 7.42 (m, 3H), 7.25
– 7.18 (m, 5H), 6.20 (d, J = 2.6 Hz, 1H), 4.40 (d, J = 2.6 Hz, 1H), 1.76 (s, 3H),
13
1.65 (s, 3H). C NMR (100 MHz, CDCl3, δ ppm): 165.7, 164.0, 139.5, 136.0,
133.9, 131.3, 129.1 (2C), 128.4, 128.2, 127.13, 127.11, 126.6, 125.6, 125.2,
123.2, 105.1, 51.1, 45.2, 28.2, 27.6. IR (νmax, cm-1): 2923, 1705, 1494, 1306,
1198, 926, 779, 731, 601. HRMS (ESI+): exact mass calculated for [M+Na]+
(C23H20O4Na) requires m/z 383.1259, found: m/z 383.1243.
5-(furan-2-yl(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2n). Light
brown solid (mp: 119 °C). Yield: 63.0 mg, 70%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 80:20). 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.40 (m, 2H), 7.35
– 7.26 (m, 3H), 7.22 (dd, J = 5.1, 1.1 Hz, 1H), 7.01 (dt, J = 3.5, 1.1 Hz, 1H),
6.97 – 6.94 (m, 1H), 5.59 (d, J = 2.5 Hz, 1H), 4.24 (d, J = 2.5 Hz, 1H), 1.74 (s,
16

3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.2, 164.1, 142.7, 139.4,
129.0, 128.5, 127.6, 127.3, 126.7, 125.0, 105.2, 52.5, 44.8, 28.2, 27.5. IR (νmax
,
cm-1): 3002, 1781, 1743, 1602, 1441, 1383, 1205, 1078, 1011, 896. HRMS
(ESI+): exact mass calculated for [M+Na]+ (C17H16O5Na) requires m/z 323.0895,
found: m/z 323.0892.
2,2-dimethyl-5-(phenyl(thiophen-2-yl)methyl)-1,3-dioxane-4,6-dione
(2o).
Dark orange solid (mp: 111 °C). Yield: 82.5 mg, 87%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 80:20). 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.45 (m, 2H), 7.37
– 7.35 (m, 1H), 7.35 – 7.33 (m, 1H), 7.33 – 7.31 (m, 2H), 6.34 – 6.32 (m, 1H),
6.06 – 6.05 (m, 1H), 5.28 (d, J = 3.0 Hz, 1H), 4.26 (d, J = 3.0 Hz, 1H), 1.73 (s,
3H), 1.51 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.2, 164.1, 153.1, 141.4,
137.3, 129.7, 128.6, 128.0, 110.6, 108.0, 105.1, 50.4, 44.0, 28.2, 27.6. IR (νmax
,
cm-1): 2923, 2841, 1751, 1415, 1215, 1007, 696. HRMS (ESI+): exact mass
calculated for [M+H]+ (C17H17O4S) requires m/z 317.0848, found: m/z 317.0845.
2,2-dimethyl-5-(3-methyl-1-phenylbutyl)-1,3-dioxane-4,6-dione (2p). White
solid (mp: 121 °C). Yield: 68.8 mg, 79%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
90:10). H NMR (400 MHz, CDCl3) δ 7.36 – 7.18 (m, 5H), 3.87 (ddd, J = 10.1,
5.8, 3.1 Hz, 1H), 3.64 (d, J = 3.1 Hz, 1H), 2.30 (ddd, J = 13.9, 10.2, 5.5 Hz, 1H),
1.81 – 1.72 (m, 2H), 1.62 (s, 3H), 1.11 (s, 3H), 0.92 (dd, J = 6.6, 2.5 Hz, 6H).
13C NMR (100 MHz, CDCl3) δ 165.8, 164.7, 139.4, 129.1, 128.7, 127.6, 105.4,
51.5, 44.1, 41.2, 28.4, 28.0, 25.6, 23.1, 21.7. IR (νmax, cm-1): 2971, 1772, 1278,
17

1204, 1085, 1006, 726, 707, 545. HRMS (ESI+): exact mass calculated for
[M+H]+ (C17H23O4) requires m/z 291.1596, found: m/z 291.1591.
2,2-dimethyl-5-(2-methyl-1-phenylpropyl)-1,3-dioxane-4,6-dione (2q). White
solid (mp: 117 °C). Yield: 61.3 mg, 74%. Purified by flash chromatography
using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt =
1
90:10). H NMR (400 MHz, CDCl3) δ 7.38 – 7.12 (m, 5H), 3.89 (d, J = 3.2 Hz,
1H), 3.29 (dd, J = 11.4, 3.2 Hz, 1H), 2.86 – 2.70 (m, 1H), 1.60 (s, 3H), 1.21 (d, J
= 6.5 Hz, 3H), 0.99 (s, 3H), 0.76 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 166.5, 164.8, 139.8, 129.1, 128.7, 127.6, 105.5, 54.6, 48.7, 29.1, 28.6,
27.9, 21.6, 21.2. IR (νmax, cm-1): 2966, 1771, 1732, 1287, 1204, 1085, 1002,
726, 705, 541. HRMS (ESI+): exact mass calculated for [M+H]+ (C16H21O4)
requires m/z 277.1440, found: m/z 277.1434.
5-((4-chlorophenyl)(4-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-
4,6-dione (2r).30 Light brown solid. Yield: 76.5 mg, 68%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 80:20). 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.18 (m, 6H), 6.88
– 6.81 (m, 2H), 5.31 (d, J = 2.6 Hz, 1H), 4.25 (d, J = 2.6 Hz, 1H), 3.79 (s, 3H),
1.75 (s, 3H), 1.56 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.59, 164.56, 158.7,
138.9, 132.8, 131.4, 130.4, 130.38, 128.4, 113.9, 105.2, 55.2, 51.1, 47.7, 28.2,
27.5.
5-((3-methoxyphenyl)(4-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-
4,6-dione (2s). Yellow solid (mp: 146 °C). Yield: 74.4 mg, 67%. Purified by
flash chromatography using hexane:AcOEt (gradient from hexane/AcOEt =
18

90:10 to hexane/AcOEt = 75:25). 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.20 (m,
3H), 6.91 – 6.77 (m, 5H), 5.31 (d, J = 2.6 Hz, 1H), 4.26 (d, J = 2.6 Hz, 1H), 3.79
(s, 3H), 3.76 (s, 3H), 1.75 (s, 3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
164.9, 164.6, 159.5, 158.5, 142.0, 131.8, 130.4, 129.3, 121.2, 115.1, 113.7,
112.1, 105.0, 55.14, 55.11, 51.2, 48.4, 28.2, 27.5. IR (νmax, cm-1): 2929, 1735,
1609, 1585, 1512, 1489, 1454, 1180, 791. HRMS (ESI+): exact mass calculated
for [M+Na]+ (C21H22O6Na) requires m/z 393.1314, found: m/z 393.1305.
5-((4-methoxyphenyl)(o-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2t). Light brown solid (mp: 120 °C). Yield: 69.0 mg, 65%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 80:20). 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.50 (m, 1H), 7.25
– 7.13 (m, 3H), 7.11 – 7.05 (m, 2H), 6.80 – 6.74 (m, 2H), 5.50 (d, J = 2.7 Hz,
1H), 4.24 (d, J = 2.7 Hz, 1H), 3.75 (s, 3H), 2.17 (s, 3H), 1.76 (s, 3H), 1.63 (s,
13
3H). C NMR (100 MHz, CDCl3) δ 165.7, 164.1, 158.4, 139.0, 136.7, 131.1,
130.8, 130.3, 127.9, 127.1, 126.2, 113.5, 104.9, 55.1, 51.3, 45.0, 28.2, 27.5,
20.0. IR (νmax, cm-1): 2931, 1743, 1610, 1511, 1461, 1383, 1178, 1033, 1011.
HRMS (ESI+): exact mass calculated for [M+H]+ (C21H22O5Na) requires m/z
377.1365, found: m/z 377.1363.
5-(bis(4-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2u).31
White solid. Yield: 85.6 mg, 77%. Purified by flash chromatography using
hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to hexane/AcOEt = 75:25).
1H NMR (400 MHz, CDCl3) δ 7.25 – 7.19 (m, 4H), 6.85 – 6.80 (m, 4H), 5.28 (d,
J = 2.7 Hz, 1H), 4.25 (d, J = 2.7 Hz, 1H), 3.77 (s, 6H), 1.72 (s, 3H), 1.51 (s, 3H).
19

13C NMR (100 MHz, CDCl3) δ 164.8, 158.4, 132.3, 130.2, 113.6, 105.0, 55.1,
51.3, 47.9, 28.2, 27.6.
5-((2-methoxyphenyl)(4-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-
4,6-dione (2v). Brown solid (mp: 149 °C). Yield: 78.8 mg, 71%. Purified by
flash chromatography using hexane:AcOEt (gradient from hexane/AcOEt =
90:10 to hexane/AcOEt = 75:25). 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.29 (m,
2H), 7.22 – 7.16 (m, 1H), 6.94 – 6.81 (m, 5H), 5.38 (d, J = 2.6 Hz, 1H), 4.28 (d,
13
J = 2.6 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 1.71 (s, 3H), 1.69 (s, 3H). C NMR
(100 MHz, CDCl3) δ 165.5, 164.8, 158.5, 156.0, 132.6, 130.6, 130.5, 129.1,
127.8, 120.5, 113.9, 109.8, 104.4, 55.1, 54.8, 50.6, 44.1, 28.1, 27.5. IR (νmax
,
cm-1): 2870, 1735, 1512, 1492, 1181, 1119, 1028, 754. HRMS (ESI+): exact
mass calculated for [M+Na]+ (C21H22O6Na) requires m/z 393.1314, found: m/z
393.1306.
5-((4-methoxyphenyl)(p-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(2w). Yellow solid (mp: 170 °C). Yield: 86.12 mg, 81%. Purified by flash
chromatography using hexane:AcOEt (gradient from hexane/AcOEt = 90:10 to
hexane/AcOEt = 80:20). 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.21 (m, 2H), 7.21
– 7.16 (m, 2H), 7.13 – 7.08 (m, 2H), 6.85 – 6.80 (m, 2H), 5.29 (d, J = 2.7 Hz,
1H), 4.26 (d, J = 2.7 Hz, 1H), 3.78 (s, 3H), 2.31 (s, 3H), 1.73 (s, 3H), 1.52 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 164.9, 164.7, 158.5, 137.3, 136.6, 132.1,
130.4, 129.0, 128.8, 113.7, 105.0, 55.2, 51.3, 48.2, 28.2, 27.6, 21.0. IR (νmax
,
cm-1): 2994, 1742, 1610, 1541, 1295, 1011. HRMS (ESI+): exact mass
calculated for [M+H]+ (C21H22O5Na) requires m/z 377.1365, found: m/z
377.1354.
20

Procedure for the Decarboxylation Reaction. Following the method
developed by Frost,32 in a 25 mL flask coupled with reflux condenser were
added 0.125 mL of concentrated HCl, 5 mL of a 10:1 mixture of DMF/H2O and
the arylated product 2 (0.3 mmol). The reaction mixture was heated to 100 °C
and stirred for 1 h. After that, the system was cooled to room temperature and
the organic phase was extracted with ethyl acetate (3 x 10 mL). The organic
phase was dried with Na2SO4 and the product was concentrated under reduced
pressure. The product is obtained pure and does not require further purification
steps.
3-(4-chlorophenyl)-3-phenylpropanoic acid (3a).33 White solid. Yield: 74.3
mg, 95%. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.08 (m, 9H), 4.49 (t, J = 7.9 Hz,
1H), 3.05 (d, J = 7.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 177.0, 142.7, 141.7,
132.4, 129.0, 128.7, 128.73, 127.5, 126.8, 46.0, 40.2.
3-(4-methoxyphenyl)-3-phenylpropanoic acid (3b).32 White solid. Yield: 73.8
1
mg, 96%. H NMR (400 MHz, CDCl3) δ 7.24 – 7.01 (m, 7H), 6.78 – 6.68 (m,
13
2H), 4.39 (t, J = 7.9 Hz, 1H), 3.67 (s, 3H), 2.96 (d, J = 7.9 Hz, 2H). C NMR
(100 MHz, CDCl3) δ 177.6, 158.1, 143.6, 135.4, 128.55, 128.54, 127.5, 126.5,
114.0, 55.2, 45.8, 40.6.
Procedure for the Synthesis of Amide 3c. A solution of 2c (64.9 mg, 0.2
mmol) and benzylamine (22 µL, 0.2 mmol) in CH3CN (2 mL) was stirred at 90°C
for 16 h. The solvent was removed under reduced pressure. The remaining
21

crude was purified by column chromatography (in DCM) on silica flash to afford
the N-benzyl-3-phenyl-3-(p-tolyl)propenamide 3c (53.4 mg, 81%) as a yellow
solid.
N-benzyl-3-phenyl-3-(p-tolyl)propanamide (3c).34 White solid. Yield: 73.8 mg,
1
96%. H NMR (400 MHz, CDCl3) δ 7.34 – 7.05 (m, 12H), 6.92 – 6.85 (m, 2H),
5.53 (s, 1H), 4.56 (t, J = 7.9 Hz, 1H), 4.30 (d, J = 5.6 Hz, 2H), 2.92 (d, J = 7.9
Hz, 2H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 171.0, 143.8, 140.5, 137.9,
136.0, 129.3, 128.6, 128.4, 127.7, 127.6, 127.4, 127.2, 126.4, 47.1, 43.5, 43.4,
21.0.
Acknowledgements
This work was supported by CNPq, CAPES (Finance code 001), and INCT-
Catálise. We thank Mr André P. M. Roos for carrying out preliminary
experiments.
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25

Declaration of interests
The authors declare that they have no known competing finan interests or personal
relationships that could have appeared to influence the work reported in this paper.