Highly efficient palladium-catalyzed Suzuki-Miyaura reactions of potassium aryltrifluoroborates with 5-iodo-1,3-dioxin-4-ones in water: an approach to α-aryl-β-ketoesters

Article abstract of DOI:10.1016/j.tet.2009.11.027

The high efficient palladium-catalyzed Suzuki-Miyaura reactions of potassium aryltrifluoroborates 3 with 5-iodo-1,3-dioxin-4-ones 2a-b in water as only solvent in the presence of n-Bu₄NOH as base is reported. The respective 5-aryl-1,3-dioxin-4-ones 4a-n were obtained in good to excellent yields. The catalyst system provides high efficiency at low load using electronically diverse coupling partners. The obtained 2,2,6-trimethyl-5-aryl-1,3-dioxin-4-ones were transformed into corresponding α-aryl-β-ketoesters 6 by reaction with an alcohol in the absence of solvent.

Full text of DOI:10.1016/j.tet.2009.11.027

Tetrahedron 66 (2010) 773–779
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient palladium-catalyzed Suzuki–Miyaura reactions of potassium
aryltrifluoroborates with 5-iodo-1,3-dioxin-4-ones in water: an approach
to
a-aryl-
b-ketoesters
a
b
c
d
´
Adriano S. Vieira , Rodrigo L.O.R. Cunha , Clecio F. Klitzke , Julio Zukerman-Schpector ,
a,
*
´
Helio A. Stefani
a
ˆ
ˆ
˜
˜
Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13 Sup. 05508-900 Sao Paulo, SP, Brazil
b Centro de Cieˆncias Naturais e Humanas, Universidade Federal do ABC, Av. dos Estados, 5001 Santo Andre´, SP, Brazil
c Laborato´rio de Espectrometria de Massas, Centro de Toxinologia AplicadadCAT/CEPID, Instituto Butantan, S˜ao Paulo, SP, Brazil
d Departamento de Qu´ımica, Universidade Federal de S˜ao Paulo, S˜ao Carlos, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The high efficient palladium-catalyzed Suzuki–Miyaura reactions of potassium aryltrifluoroborates 3
with 5-iodo-1,3-dioxin-4-ones 2a–b in water as only solvent in the presence of n-Bu4NOH as base is
reported. The respective 5-aryl-1,3-dioxin-4-ones 4a–n were obtained in good to excellent yields. The
catalyst system provides high efficiency at low load using electronically diverse coupling partners. The
Received 30 September 2009
Received in revised form 4 November 2009
Accepted 4 November 2009
Available online 10 November 2009
obtained 2,2,6-trimethyl-5-aryl-1,3-dioxin-4-ones were transformed into corresponding
a-aryl-b-
ketoesters 6 by reaction with an alcohol in the absence of solvent.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Suzuki–Miyaura
Potassium aryltrifluoroborates
Water
a
-Aryl-b-ketoesters
1. Introduction
Transition-metal-mediated cross-coupling reactions have rev-
olutionized organic synthesis, and their development transformed
the creation of carbon–carbon bonds.3,4 The palladium-catalyzed
coupling of organoboranes with organic halides or triflates under
basic conditions (Suzuki–Miyaura coupling) provides a highly ver-
satile and powerful method for the construction of new carbon–
carbon bonds.5,6 This reaction is one of the most frequently applied
transition-metal-catalyzed reactions both in academic institutions
and in the pharmaceutical industry, and these processes are rou-
tinely used in fields ranging from materials science7 to natural
product synthesis8 and medicinal chemistry.9 The Suzuki–Miyaura
cross-coupling is particularly valued because boron compounds
present many important advantages in relation to other organo-
metallic compounds, including ease of accessibility and ultimate
product isolation, minimal toxicity, and other important environ-
mental factors.
Diverse organoboronic components have been utilized effec-
tively for Suzuki–Miyaura coupling reactions. However, in recent
years, potassium organotrifluoroborate salts (RBF3K) have received
a great deal of attention with regard to their application in organic
synthesis10 and have emerged as some of the most important or-
ganometallic reagents for Suzuki–Miyaura cross-coupling reactions
due to its important features. These compounds are crystalline
solids that are very stable to air and moisture and are easily
Water is the most abundant molecule on Earth and the universal
solvent in which the chemistry of most life processes occurs. In-
terest in water as a solvent was invigorated in the 1990s with the
introduction of the concept of Green Chemistry.1 In this context,
water, being cheap, safe, non-toxic, and environmentally benign,
was soon recognized as perhaps the ultimate ‘green’ solvent.2 In
view of the potential rewards of replacing hazardous organic sol-
vents with water, researchers took up the academic challenge of
developing new synthetic methods that are compatible with the
aqueous medium. Another important aspect is the development of
chemical reactions in water that can achieve the desired chemical
transformations without the need for the protection–deprotection
of reactive functional groups or for generation of anhydrous con-
ditions. This fact is particularly important in industrial scale-up
processes to replace the use of hazardous and flammable organic
solvents. The combination of these aspects is highly challenging
and will provide even more benefits for chemical synthesis.
* Corresponding author. Tel.: þ55 11 3091 3654; fax: þ55 11 3815 4418.
E-mail address: hstefani@usp.br (H.A. Stefani).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.027

774
A.S. Vieira et al. / Tetrahedron 66 (2010) 773–779
Table 1
prepared by the addition of inexpensive KHF2 to a variety of
organoboronic intermediates or starting from the easily accessible
organolithium10 or Grignard reagents.10,11 In addition, the organo-
trifluoroborate salts are more reactive in Suzuki–Miyaura reactions
compared with their boronic acid or boronate ester analogs, and
have high compatibility with aqueous media.6c Leadbeater and co-
workers studied the Suzuki reaction extensively and found that it is
possible to perform couplings of aryl halides in neat water using
microwave heating at low concentration of palladium as catalyst.12
Optimization of conditions for the cross-coupling reaction
O
O
PhBF3K (1.1 equiv)
I
O
O
H3C
H3C
[Pd], base,
solvent,
80 °C, 2 h
H3C
H3C
O
CH3
O
CH3
2a
4a
Entry
Catalysta
Baseb
Solvent
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
n-Bu4NOH
n-Bu4NOH
Et3N
i-Pr2NH
i-Pr2NH
1,4-Dioxane–H2Od
1,4-Dioxane–H2Od
1,4-Dioxane–H2Od
1,4-Dioxane–H2Od
1,4-Dioxane–H2Od
1,4-Dioxane–H2Od
H2O
57
59
65
80
59
72
89
43
47
53
Pd(AcO)2
Pd(Ph3P)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
2. Results and discussion
As part of our ongoing research interest in the chemistry of
potassium organotrifluoroborate salts,13 5-halo-1,3-dioxin-4-ones,
and their potential use as intermediates in organic synthesis, we
report herein a new and highly efficient method for the synthesis of
5-aryl-1,3-dioxin-4-ones by the Suzuki–Miyaura palladium-cata-
lyzed cross-coupling reaction of 5-iodo-1,3-dioxin-4-ones and po-
tassium aryltrifluoroborate salts in water as solvent.
1,3-Dioxin-4-ones are important building blocks in organic
synthesis as direct precursors of 1,3-dicarbonilic compounds.14 The
functionalization of position 5 of the 1,3-dioxin-4-ones with an
electrophile leads to products with a potential use as pharmaceu-
ticals and agrochemical intermediates.15 Thus, the iodination of the
readily available 1,3-dioxin-4-ones 1a–b with N-iodosuccinimide
(NIS) in acetic acid furnishes 5-iodo-1,3-dioxin-4-ones 2a–b in 68–
85% isolated yield15b as depicted in Scheme 1.
CH3OH
CH3OH
CH3OH
a
1.0 mol % of palladium catalyst.
1.5 equiv of base.
Isolated yield of pure product.
1,4-Dioxane–H2O, ratio: 2:1.
b
c
d
O
O
BF3K
I
Pd2(dba)3, K2CO3
O
+
O
H3C
H3C
H3C
H3C
1,4-dioxane/H2O,
80 °C, 2 h
O
CH3
O
CH3
3a
2a
4a
O
O
Scheme 2. Synthesis of 2,2,6-trimethyl-5-phenyl-1,3-dioxin-4-one (4a).
I
H
NIS, CH3CO2H
O
O
H3C
H3C
H3C
H3C
R1
25 °C, 15 h, dark
O
R1
The reaction demonstrated sensitivity to oxygen and because of
this it was necessary to degas the solvent and the base prior to per-
forming the reaction; otherwise, the isolated yield decreased. This
cross-couplingreactiontakesplacewith1,4-dioxane–H2O(2:1)asthe
solvent, unlike the commonly used palladium-mediated processes,
which employ alcoholic aqueous solvents. Curiously, alcohol–H2O
mixtures did not provide the desired product in satisfactory yields.
TheuseofCs2CO3 and n-Bu4NOHasbasealsoprovidedgoodresults
(Table 1, entries 5–7). In light of these results, we decided to evaluate
the behavior of the reaction in the presence of 1.5 equiv of base by
using only water as the solvent due to the fact that the use of water as
solvent is environmentally sound. The effect of base and solvent
system onyield was noteworthy. Much to our surprise, when the cross-
coupling reaction was performed in water as the solvent in the pres-
ence of 1.5 equiv of n-Bu4NOH, an appreciable improvement in the
yield was observed, and the desired product (4a) was obtained in 89%.
Larger excesses of base (3.0 equiv) gave no improvement in the yield.
We evaluated the influence of the organotrifluoroborates
counter ion by starting from the tetra-n-butylammonium phenyl-
trifluoroborate salt and found no significant influence on the
reaction behavior with respect to yield. Considering that the tetra-
n-butylammonium aryltrifluoroborate salt must be further
prepared and isolated, its use is not experimentally advantageous.
O
1a, R1 = CH3
1b, R1 = C6H5
2a, R1 = CH3
2b, R1 = C6H5
Scheme 1. Synthesis of 5-iodo-1,3-dioxin-4-ones 2a–b.
The preparation of the potassium aryltrifluoroborates 3 was
achieved starting from Grignard reagents.10,11 The addition of tri-
methylborate to the organomagnesium bromide at ꢀ30 ꢁC and
treatment with aqueous KHF2, followed by recrystallization from
acetone–Et2O, was used to prepare the requisite potassium aryl-
trifluoroborates 3. Salts of type 3 are air- and water-stable solids
that can be stored for extended periods of time at room tempera-
ture with no further precautions.10
Our initial studies were focused on the development of an
optimum set of reaction conditions for the palladium-catalyzed
cross-coupling reaction of potassium aryltrifluoroborates with
5-iodo-1,3-dioxin-4-one 2. For this purpose, several reaction
conditions were evaluated, as depicted in Table 1.
The cross-coupling of 2a was optimized by using potassium
phenyltrifluoroborate (3a) as the nucleophile, using several palla-
dium catalysts (Pd(PPh3)4, Pd(AcO)2, Pd2(dba)3, and PdCl2), a vari-
ety of different bases (e.g., Et3N, Hunig’s base, i-Pr2NH, Li2CO3,
Na2CO3, K2CO3, Cs2CO3, n-Bu4NOH, and K3PO4), and different sol-
vent systems (MeOH, EtOH, i-PrOH, THF, DME, and 1,4-dioxane)
under both anhydrous and aqueous conditions. Among the exam-
ined solvents, the mixture of 1,4-dioxane–H2O (2:1) (3 mL) and
Pd2(dba)3 (1 mol %) as catalyst provided the best results. In this
mixture, not all potassium aryltrifluoroborates and bases were
completely soluble, but over time and with applied heat (80 ꢁC) the
reaction mixtures homogenized. In the presence of 1 mol % of
Pd2(dba)3 and 1.5 equiv of K2CO3 at 80 ꢁC for 2 h, this solvent sys-
tem furnished the 2,2,6-trimethyl-5-phenyl-1,3-dioxin-4-one 4a in
80% isolated yield (Scheme 2).
This salt is generated in situ by
a mixture of potassium
aryltrifluoroborate with n-Bu4NOH in aqueous medium.16 Among
the several reaction conditions tested, one in particular is
notable (Table 1, entry 7): The treatment of the potassium
O
O
I
BF3K
Pd2(dba)3, n-Bu4NOH
O
O
+
H3C
H3C
H3C
H3C
H2O, 80 °C, 50 min
O
CH3
O
CH3
3a
2a
4a
Scheme 3. Optimized conditions for the cross-coupling reaction.

A.S. Vieira et al. / Tetrahedron 66 (2010) 773–779
775
Table 2
Table 2 (continued)
Cross-coupling reactions of 5-iodo-1,3-dioxin-4-ones 2a–b with potassium aryltri-
fluoroborates 3a–n
Reaction
time (min)
Yieldb
(%)
Entry Ar1–BF3K (3)a
Product (4)
O
O
Pd2(dba)3 (1.0 mol%)
Ar1
R1
I
Ar1-BF3K
O
+
O
13
C6H5BF3K (3a)
60
62
H3C
H3C
H3C
H3C
n-Bu4NOH (1.5 equiv)
3a-l
O
R1
O
H2O, 80 °C
2a-b
4a-n
Entry Ar1–BF3K (3)a
Reaction
Product (4)
Yieldb
time (min)
(%)
14
4-CH3OC6H4BF3K (3d)
50
75
O
a
1.1 equiv of the Ar1–BF3K.
Isolated yield of pure product.
O
1
2
C6H5BF3K (3a)
50
55
89
H3C
H3C
b
O
CH3
4a
phenyltrifluoroborate 3a (1.1 equiv) with n-Bu4NOH (1.5 equiv) in
degassed water (3 mL) under inert atmosphere for 2 min, followed
by the addition of Pd2(dba)3 (1.0 mol %) and 2,2,6-trimethyl-5-iodo-
1,3-dioxin-2-one 2 (1.0 equiv) and vigorous stirring for 50 min at
80 ꢁC, afforded the 2,2,6-trimethyl-5-phenyl-1,3-dioxin-2-one (4a)
in 89% yield after column chromatography (Scheme 3).
F
O
4-FC6H4BF3K (3b)
77
O
H3C
O
CH3
4b
H3C
3
4
5
4-ClC6H4BF3K (3c)
4-CH3OC6H4BF3K (3d)
4-EtSC6H4BF3K (3e)
55
40
40
79
94
91
These optimal conditions were subsequently applied to the
cross-coupling reaction of 2a–b with different potassium aryltri-
fluoroborates 3b–l. As outlined in Table 2, the reaction proceeded
with satisfactory yields in all cases. All reactions were monitored by
TLC until consumption of 2a or 2b was complete. In this method-
ology, the reaction was tolerant of a variety of functional groups,
including ethers, thioethers, aldehyde, and carbamate groups,
despite the aqueous and basic conditions. Moreover, potassium
aryltrifluoroborates bearing both electron-withdrawing and elec-
tron-donating groups react with 2a–b, affording the desired
products in good yields.
ortho-Substituted substrates (Table 2, entry 8) react to provide
the coupling products in satisfactory yields. Even in the case of the
hindered potassium 2-methyl-phenyltrifluroborate (3h), good
yield of the desired product 4h was obtained. The reaction could be
scaled up to 1 g of the 5-iodo-1,3-dioxin-4-ones without alteration
of the reaction time and yield. Furthermore, analysis of the 1H NMR
and 13C NMR spectra showed that all 5-aryl-1,3-dioxin-4-ones 4a–n
presented data in full agreement with their assigned structures.
We studied the cross-coupling reaction of 5-bromo-1,3-dioxin-
4-one 2c with potassium aryltrifluoroborate. For this purpose the
2,2,6-trimethyl-5-bromo-1,3-dioxin-4-one was prepared from the
1,3-dioxin-4-one 1a according to the literature procedures15 and
was submitted to the cross-coupling reaction with potassium
phenyltrifluoroborate 3a. By using the reactions conditions found
for the iodide 2a, the 5-aryl-1,3-dioxin-4-one 4a was obtained in
only 35% isolated yield (Scheme 4). This result is due to the fact the
C–Br bond is stronger than the C–I bond and in this way vinyl io-
dides are more reactive as electrophile compared to vinyl bromides.
CHO
O
6
7
4-CHOC6H4BF3K (3f)
70
50
73
82
O
H3C
H3C
O
CH3
4f
4-CBzNHC6H4BF3K (3g)
8
9
2-CH3C6H4BF3K (3h)
60
78
67
3,4-(CF3)2C6H3BF3K (3i) 80
O
O
Pd2(dba)3 (1.0 mol%)
BF3K
Br
O
10
11
2-C10H7BF3K (3j)
50
75
83
76
O
+
n-Bu4NOH (1.5 equiv)
H3C
H3C
H3C
H3C
O
2c
CH3
O
4a
CH3
H2O, 80 °C, 35%
3a
Scheme 4. Cross-coupling reaction of the 5-bromo-1,3-dioxin-4-one 2c.
1,4-(BF3K)2C6H4 (3k)
b-Ketoesters are important building blocks in synthetic organic
chemistry, especially in the preparation of heterocyclic com-
pounds.17 However, classical methodologies for the preparation of
12
3-C4H3S-BF3K (3l)
55
73
b-ketoesters may require harsh reaction conditions and the use of
strong bases.

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A.S. Vieira et al. / Tetrahedron 66 (2010) 773–779
In order to test the potential use of the 5-aryl-1,3-dioxin-4-ones
4 as direct precursors of -ketoesters, we were interested in the
b
ring opening of the 5-aryl-1,3-dioxin-4-ones in the presence of an
alcohol.15b For this purpose, the 2,2,6-trimethyl-5-phenyl-1,3-di-
oxin-4-one 4a was heated with benzylic alcohol (5a) (1.5 equiv) in
toluene at 110 ꢁC for 2 h (Scheme 5). The reaction proceeds only
with moderate yield (64%). In light of this result, we tested different
solvents, reaction times, and elevated temperatures in this re-
action; however, in all cases, the yield was never above to 70%.
O
O
O
PhCH2OH (5a)
O
CH3
O
PhCH3,
H3C
H3C
O
4a
CH3
110 °C, 2 h
Figure 1. Crystal structure of 5-(4-fluorophenyl)-2,2,6-trimethyl-1,3-dioxin-4-one (4b).
6a
3. Conclusion
Scheme 5. Synthesis of b-ketoester 6a.
In summary, we have shown that a range of functionalized
potassium aryltrifluoroborates can readily react with 5-iodo-1,3-
dioxin-4-ones in water as solvent in the presence of n-Bu4NOH as
base. Remarkable functional group compatibility was observed in
the starting potassium aryltrifluoroborate, including the presence
of a Cl, CF3, CHO, N(H)CO2Bn, and SC2H5. The cross-coupling
products were obtained in very good yields and were trans-
Next we performed the reaction by simple mixture of the 2,2,6-
trimethyl-5-phenyl-1,3-dioxin-4-one 4a and benzylic alcohol
(1.5 equiv)and stirring for 2 h at 100 ꢁC without solvent. Much toour
surprise, the respective b-ketoester 6a was obtained in 93% isolated
yield via column chromatography. This very simple condition was
extended to a series of different alcohols as depicted in Table 3. The
b-ketoesters 6 were obtained in 1:1 ratio of stereoisomers (Table 3).
formed into corresponding b-ketoesters by reaction with an al-
cohol in the absence of solvent. This methodology is
advantageous relative to many other organometallic-compound-
based cross-coupling reactions because of the ready availability,
high stability, very low toxicity, mildly nucleophilic character,
and unique compatibility with aqueous media of the potassium
organotrifluoroborate salts.
Table 3
Reaction of the 5-aryl-1,3-dioxin-4-one 4a with alcohol
O
O
R1-OH (1.5 equiv)
100 oC, 2 h
O
R1O
CH3
O
H3C
H3C
O
CH3
4a
6
4. Experimental
4.1. General
Entry
1
Product (6)
Yielda (%)
O
O
BnO
CH3
All air-sensitive and/or water-sensitive reactions were carried
out under nitrogen atmosphere with dry solvents under anhy-
drous conditions. Standard syringe techniques were applied for
transfer of dry solvents and some air-sensitive reagents. The re-
actions were monitored by TLC carried out on Merk silica gel (60
F254) by using UV light as visualizant agent and 5% vanillin in 10%
H2SO4 and heat as developing agents. Baker silica gel (particle
size 0.040–0.063 mm) was used for flash chromatography. Tolu-
ene was distilled from CaH2 and stored over sodium-wire. Dry
THF was distilled from sodium benzophenone ketyl prior to use.
EtOH was dried, distilled from CaH2, and stored over MS 4 Å. Et3N
was distilled from KOH pellets. NMR spectra were recorded with
Bruker DPX 300 (300 MHz) instrument using CDCl3 as solvent
and calibrated using tetramethylsilane as internal standard.
93
82
6a
2
3
4
84
88
CH3
O
O
O
H3
C
CH3
Chemical shifts are reported in
d parts per million relative to
5
(CH3)4Si for 1H and CDCl3 for 13C NMR. Coupling constants (J) are
reported in hertz. Infrared (IR) spectra were obtained from CHCl3
solutions, using a Varian 3100 FT-IR spectrophotometer and
wavelengths are reported in cmꢀ1. Mass spectra (MS) were
measured on a Shimadzu GC-MS-QP5050A mass spectrometer.
The HRMS spectra were measured on a Bruker Daltonics Micro
TOF (direct inlet probe).
6d
O
O
O
CH3
5
85
6e
a
Isolated yield of pure product.
4.2. Typical procedure for the synthesis of 5-iodo-
1,3-dioxin-4-ones (2)15b
The crystal structure of 5-(4-fluorophenyl)-2,2,6-trimethyl-1,3-
dioxin-4-one (4b) is representative of the class of 4a–n compounds
(Fig. 1). Compound 4b was carefully crystallized from dry methanol
to afford the desired crystal. The compound crystallizes as a dis-
crete monoclinic system.18
The preparation of the 2,2,6-trimethyl-5-iodo-1,3-dioxin-4-one
(2a) is representative. A solution of 2,2,6-trimethyl-1,3-dioxin-4-
one 1a (1.42 g; 10 mmol) and N-iodosuccinimide (NIS or NBS for 2c)
(2.92 g; 13 mmol) in acetic acid (25 mL) was stirred for 15 h at room

A.S. Vieira et al. / Tetrahedron 66 (2010) 773–779
777
temperature in the dark. The reaction mixture was diluted with
water (30 mL) and extracted with ethyl acetate (3ꢂ30 mL). The
organic layer was washed with water (20 mL) and dried over
MgSO4. The residue obtained after evaporation of the solvent was
chromatographed on silica gel (hexane–AcOEt 10:1) to give the
2,2,6-trimethyl-5-iodo-1,3-dioxin-4-one 2a as pale yellow prisms
(1.77 g; 6.8 mmol; 68%); mp 62–63 ꢁC (from Et2O–hexane).
237.0927 (MþH)þ; found: 237.0923 (MþH)þ. IR (CHCl3 solution,
cmꢀ1): 3025, 2940, 1717, 1683, 1512, 1395, 1275, 1203, 1011, 774.
4.3.3. 5-(4-Chlorophenyl)-2,2,6-trimethyl-4H-1,3-dioxin-4-one
(4c). Yellow solid, mp 69–70 ꢁC. 1H NMR (300 MHz, CDCl3)
d 1.73 (s,
6H), 1.93 (s, 3H), 7.19 (d, J¼8.4 Hz, 2H), 7.31 (d, J¼8.4 Hz, 2H). 13C
NMR (75 MHz, CDCl3)
d 18.6, 25.2, 105.5, 107.1, 128.5, 130.9, 132.0,
133.7, 161.0, 165.4. GC–MS: m/z (relative intensity): 252 (6) [Mþ],
184 (51), 152 (62), 124 (10), 43 (100). HRMS (ESI, positive) m/z calcd
for C13H13ClO3: 253.0632 (MþH)þ; found: 253.0659 (MþH)þ. IR
(CHCl3 solution, cmꢀ1): 3015, 2941, 1718, 1632, 1513, 1391, 1275,
1009, 773.
4.2.1. 2,2,6-Trimethyl-5-iodo-1,3-dioxin-4-one (2a)15b. Mp 62–
63 ꢁC. 1H NMR (300 MHz, CDCl3) 1.70 (s, 6H), 2.31 (s, 3H). 13C NMR
d
(75 MHz, CDCl3)
d 24.1, 25.0, 62.4, 106.6, 158.1, 169.5. GC–MS: m/z
(relative intensity): 268 (10) [Mþ], 210 (62), 167 (58), 142 (75), 127
(15), 43 (100).
4.3.4. 5-(4-Methoxyphenyl)-2,2,6-trimethyl-4H-1,3-dioxin-4-one
4.2.2. 2,2-Dimethyl-5-iodo-6-phenyl-1,3-dioxin-4-one (2b)15b. Yellow
(4d). White solid, mp 83–84 ꢁC. 1H NMR (300 MHz, CDCl3)
d 1.78 (s,
prisms. Mp 72–73 ꢁC. 1H NMR (300 MHz, CDCl3)
d
1.67 (s, 6H), 7.30–
6H), 1.95 (s, 3H), 3.83 (s, 3H), 6.93 (d, J¼8.6 Hz, 2H), 7.19 (d,
7.47 (m, 3H), 7.8 (d, J¼8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d
25.5,
J¼8.6 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 18.3, 24.9, 55.0, 104.9,
70.1,106.8,126.3,128.8,131.0,132.1,161.7,165.0. GC–MS: m/z (relative
107.5, 113.5, 124.3, 131.4, 158.8, 161.3, 164.5. GC–MS: m/z (relative
intensity): 248 (2) [Mþ], 190 (100), 148 (77), 134 (20), 120 (24), 91
(12), 43 (60). HRMS (ESI, positive) m/z calcd for C14H16O4: 249.1127
(MþH)þ; found: 249.1124 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3015,
2939, 1712, 1633, 1609, 1514, 1247, 1219, 1020, 771.
intensity): 330 (13) [Mþ], 272 (74), 229 (53), 127 (19), 43 (100).
4.2.3. 2,2,6-Trimethyl-5-bromo-1,3-dioxin-4-one (2c)15b. Pale yel-
low oil (1.83 g; 8.3 mmol; 83%). 1H NMR (300 MHz, CDCl3)
d 1.64 (s,
6H), 2.16 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 20.3, 25.0, 90.0, 106.5,
157.2, 166.5. GC–MS: m/z (relative intensity): 220 (10) [Mþ], 162
4.3.5. 5-[4-(Ethylthio)phenyl]-2,2,6-trimethyl-4H-1,3-dioxin-4-one
(75), 119 (44), 43 (100).
(4e). Yellow solid, mp 55–56 ꢁC. 1H NMR (300 MHz, CDCl3)
d 1.32 (t,
J¼7.3 Hz, 3H), 1.77 (s, 6H), 1.94 (s, 3H), 2.96 (q, J¼7.3 Hz, 2H), 7.17 (d,
4.3. General procedure for the cross-coupling reaction
of potassium aryltrifluoroborates with 5-iodo-1,3-dioxin-
4-ones (2a–b)
J¼8.4 Hz, 2H), 7.31 (d, J¼8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d
14.3, 18.6, 25.1, 27.3, 105.3, 107.6, 128.4, 129.7, 131.0, 136.4, 161.2,
165.1. GC–MS: m/z (relative intensity): 278 (4) [Mþ], 194 (30), 151
(100), 123 (46), 43 (25). HRMS (ESI, positive) m/z calcd for
C15H18SO3, 279.1055 (MþH)þ; found: 279.1067 (MþH)þ. IR (CHCl3
solution, cmꢀ1): 3016, 2942, 1717, 1632, 1597, 1390, 1250, 1202,
1008, 772.
The synthesis of 2,2,6-trimethyl-5-phenyl-1,3-dioxin-4-one
(4a) is representative. To
a solution of potassium phenyl-
trifluoroborate (3a) (202 mg, 1.1 mmol; 1.1 equiv) in degassed
water (3 mL) was added 50% aqueous solution of n-Bu4NOH
(0.8 mL; 394 mg, 1.5 mmol; 1.5 equiv). The mixture was vigorously
stirred for 2 min under a nitrogen atmosphere. Next, Pd2(dba)3
(9.1 mg; 1.0 mol %) was added, followed by 2,2,6-trimethyl-5-
iodo-1,3-dioxin-2-one (2a) (268 mg; 1.0 mmol; 1.0 equiv). The
reaction was heated at 80 ꢁC and vigorously stirred for 50 min.
After TLC analysis the reaction mixture was cooled to room tem-
perature and was then transferred to an extraction funnel with
ethyl acetate (30 mL), and the organic phase was removed. The
aqueous phase was extracted with ethyl acetate (3ꢂ15 mL), and
the combined organic phases were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude 2,2,6-trimethyl-
5-phenyl-1,3-dioxin-4-one was purified by flash chromatography
(hexanes–EtOAc, 10:1) to afford the product 4a in 89% yield
(193 mg) as a white solid. Mp 51–52 ꢁC.
4.3.6. 4-(2,2,6-Trimethyl-4-oxo-4H-1,3-dioxin-5-yl)benzaldehyde
(4f). White solid, mp 107–108 ꢁC. 1H NMR (300 MHz, CDCl3)
d
1.79
(s, 6H), 2.00 (s, 3H), 7.47 (d, J¼7.8 Hz, 2H), 7.90 (d, J¼7.8 Hz, 2H),10.0
(s, 1H). 13C NMR (75 MHz, CDCl3)
18.8, 25.2, 105.7, 107.4, 129.5,
d
131.3, 135.4, 139.0, 160.6, 165.9, 191.8. GC–MS: m/z (relative in-
tensity): 246 (2) [Mþ], 120 (100), 91 (45), 43 (97). HRMS (ESI,
positive) m/z calcd for C14H14O4: 247.0971 (MþH)þ; found:
247.0983 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3026, 2951, 1715,
1703, 1627, 1606, 1397, 1276, 1204, 1011, 779.
4.3.7. Benzyl 4-(2,2,6-trimethyl-4-oxo-4H-1,3-dioxin-5-yl)phenylcarba-
mate (4g). White solid, mp 136–137 ꢁC. 1H NMR (300 MHz, CDCl3)
d
1.75 (s, 6H),1.93 (s, 3H), 5.20 (s, 2H), 6.87 (s,1H), 7.18 (d, J¼8.4 Hz, 2H),
7.31–7.40 (m, 7H). 13C NMR (75 MHz, CDCl3)
d
18.6, 25.1, 66.9, 105.3
107.6, 118.5, 127.3, 128.2, 128.3, 128.6, 131.2, 136.1, 137.4, 153.4, 161.4,
165.1. GC–MS: m/z (relative intensity): 367 (2) [Mþ], 283 (5), 196 (13),
132 (31), 91 (100), 43 (57). HRMS (ESI, positive) m/zcalcd for C21H21NO5:
368.1498 (MþH)þ; found:368.1504 (MþH)þ. IR (CHCl3 solution, cmꢀ1):
3431, 3015, 2947, 1718, 1701, 1613, 1523, 1275, 1204, 1054, 774.
4.3.1. 5-Phenyl-2,2,6-trimethyl-4H-1,3-dioxin-4-one (4a). Following
the general procedure. 89% yield. White solid, mp 51–52 ꢁC. 1H
NMR (300 MHz, CDCl3)
d
1.79 (s, 6H), 1.96 (s, 3H), 7.27–7.33 (m, 2H),
18.4, 24.9, 105.1,
7.35–7.42 (m, 3H). 13C NMR (75 MHz, CDCl3)
d
108.0, 127.4, 128.0, 130.3, 132.2, 161.0, 164.8. GC–MS: m/z (relative
intensity): 218 (4) [Mþ], 160 (68), 118 (100), 90 (24), 43 (78). HRMS
(ESI, positive) m/z calcd for C13H14O3: 219.1021 (MþH)þ; found:
219.1008 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3015, 2937, 1717, 1632,
1397, 1275, 1219, 1012, 772.
4.3.8. 5-o-Tolyl-2,2,6-trimethyl-4H-1,3-dioxin-4-one
(4h). White
solid, mp 75–76 ꢁC. 1H NMR (300 MHz, CDCl3)
d 1.79 (s, 6H), 1.81 (s,
3H), 2.23 (s, 3H), 7.10 (d, J¼8.1 Hz, 1H), 7.17–7.25 (m, 3H). 13C NMR
(75 MHz, CDCl3)
d 18.2, 19.9, 25.1, 25.5, 105.4, 107.3, 125.9, 128.3,
130.2, 130.9, 131.9, 137.8, 160.8, 165.2. GC–MS: m/z (relative in-
tensity): 232 (2) [Mþ], 174 (86), 156 (46), 128 (43), 104 (30), 77 (15),
43 (100). HRMS (ESI, positive) m/z calcd for C14H16O3: 233.1178
(MþH)þ; found: 233.1197 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3015,
2939, 1716, 1633, 1396, 1272, 1219, 1011, 771.
4.3.2. 5-(4-Fluorophenyl)-2,2,6-trimethyl-4H-1,3-dioxin-4-one
(4b). Yellow solid, mp 81–82 ꢁC. 1H NMR (300 MHz, CDCl3)
d 1.75 (s,
6H),1.92 (s, 3H), 7.05 (t, J¼8.7 Hz, 2H), 7.23 (d, J¼8.7 Hz, 2H).13C NMR
(75 MHz, CDCl3)
d 18.5, 25.1, 105.4, 107.2, 115.3, 128.3, 132.3, 161.2,
162.3 (d, J¼240.1 Hz), 165.3. 19F NMR (282 MHz, CDCl3)
d
ꢀ37.5 (s)
(Ar-F). GC–MS: m/z (relative intensity): 236 (5) [Mþ], 178 (61), 136
(87), 108 (21), 43 (100). HRMS (ESI, positive) m/z calcd for C13H13O3F:
4.3.9. 5-[3,5-Bis-(trifluoromethyl)phenyl]-2,2,6-trimethyl-4H-1,3-di-
oxin-4-one (4i). White solid, mp 97–98 ꢁC. 1H NMR (300 MHz,

778
A.S. Vieira et al. / Tetrahedron 66 (2010) 773–779
CDCl3)
(75 MHz, CDCl3)
d
1.76 (s, 6H), 1.96 (s, 3H), 7.74 (s, 2H), 7.83 (s, 1H). 13C NMR
alcohol (81 mg; 0.75 mmol; 1.5 equiv) under a nitrogen atmo-
d
18.7, 25.2, 105.8, 106.2, 121.5, 125.0, 128.5, 131.6
sphere was stirred at 100 ꢁC for 2 h. The reaction was monitored
by TLC until consumption of 4a was complete. The crude product
6a was purified by column chromatography in hexanes–ethyl
acetate (98:2), affording 6a as a colorless oil in 93% yield
(124 mg).
(q, J¼37.5 Hz), 134.7, 160.2, 166.5. 19F NMR (282 MHz, CDCl3)
d 13.8
(s, CF3). GC–MS: m/z (relative intensity): 354 (3) [Mþ], 296 (37), 254
(46), 43 (100). HRMS (ESI, positive) m/z calcd for C15H12O3F6:
355.0769 (MþH)þ; found: 355.0775 (MþH)þ. IR (CHCl3 solution,
cmꢀ1): 3026, 2936, 1719, 1632, 1405, 1280, 1141, 777.
4.4.1. Benzyl 3-oxo-2-phenylbutanoate (6a). Colorless oil. 1H NMR
4.3.10. 5-(Naphthalen-2-yl)-2,2,6-trimethyl-4H-1,3-dioxin-4-one
(300 MHz, CDCl3)
J¼15.0 Hz, 1H), 5.40 (d, J¼15.0 Hz, 1H), 7.14–7.39 (m, 10H), 12.9 (s,
1H). 13C NMR (75 MHz, CDCl3)
27.2, 62.4, 71.2, 127.4, 128.0, 128.2,
128.4, 128.5, 129.1, 130.3, 132.2, 164.8, 206.2. GC–MS: m/z (relative
intensity): 268 (4) [Mþ], 208 (16), 160 (30), 118 (82), 91 (100), 43
(78). HRMS (ESI, positive) m/z calcd for C13H14O3: 219.1021
(MþH)þ; found: 219.1008 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3015,
2937, 1717, 1632, 1397, 1275.
d 1.85 (s, 3H), 2.15 (s, 3H), 4.72 (s, 1H), 5.11 (d,
(4j). White solid, mp 119–120 ꢁC. 1H NMR (300 MHz, CDCl3)
d
1.79
(s, 6H), 2.04 (s, 3H), 7.38 (dd, J¼8.4, 1.8 Hz, 1H), 7.44–7.49 (m, 2H),
7.72 (s, 1H), 7.79–7.85 (m, 3H). 13C NMR (75 MHz, CDCl3)
18.6, 25.1,
d
d
105.3, 108.1, 126.0, 126.1, 127.5, 127.8, 127.9, 128.2, 129.6, 129.8,
132.6, 133.0, 161.2, 165.3. GC–MS: m/z (relative intensity): 268 (2)
[Mþ], 184 (27), 141 (100), 115 (23), 43 (27). HRMS (ESI, positive) m/z
calcd for C17H16O3, 269.1178 (MþH)þ; found: 269.1186 (MþH)þ. IR
(CHCl3 solution, cmꢀ1): 3015, 2938, 1716, 1628, 1398, 1277, 1203,
1026, 772.
4.4.2. (RþS)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl
3-oxo-2-
phenylbutanoate (6b). Colorless oil. 1H NMR (300 MHz, CDCl3)
4.3.11. 5,50-(1,4-Phenylene)-bis-(2,2,6-trimethyl-4H-1,3-dioxin-4-
(ketoþenol)
d
0.73 (d, J¼7.2 Hz, 3H), 0.86 (d, J¼7.1 Hz, 3H), 0.95 (d,
one) (4k). White solid, mp 171–172 ꢁC. 1H NMR (300 MHz, CDCl3)
J¼7.1 Hz, 3H), 1.52–1.76 (m, 6H), 1.84 (s, 3H), 1.88–2.09 (m, 3H),
2.18 (s, 3H), 4.66 (s, 1H), 4.73–4.89 (m, 1H), 7.11 (d, J¼8.5 Hz, 2H),
7.26–7.37 (m, 3H), 13.1 (s, 1H). 13C NMR (75 MHz, CDCl3) (keto-
d
1.77 (s, 12H), 2.14 (6H), 7.34 (s, 4H). 13C NMR (75 MHz, CDCl3)
d
18.9, 25.8, 101.2, 107.8, 130.1, 158.7, 167.2. GC–MS: m/z (relative
intensity): 358 (1) [Mþ], 217 (32), 141 (21), 43 (100). HRMS (ESI,
positive) m/z calcd for C20H22O6: 359.1495 (MþH)þ; found:
359.1499 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3016, 2948, 1718,
1630, 1391, 1275, 1208, 1010, 772.
þenol)
d 15.9, 16.1, 20.6, 20.7, 21.9, 23.2, 23.3, 25.9, 26.0, 31.3, 31.4,
34.1, 40.5, 46.6, 46.9, 65.9, 75.8, 104.7, 126.7, 127.8, 128.1, 128.7,
129.3, 131.1, 132.8, 132.9, 135.3, 168.1, 172.2, 173.5, 201.5. GC–MS:
m/z (relative intensity): 316 (4) [Mþ], 178 (20), 160 (23), 136 (28),
118 (100), 83 (56), 69 (34), 55 (24), 43 (64). HRMS (ESI, positive)
m/z calcd for C20H28O3: 317.2117 (MþH)þ; found: 317.2108
(MþH)þ. IR (CHCl3 solution, cmꢀ1): 3009, 2941, 1757, 1729, 1638,
1510, 1285.
4.3.12. 2,2,6-Trimethyl-5-(thiophen-3-yl)-4H-1,3-dioxin-4-one
(4l). Yellow oil. 1H NMR (300 MHz, CDCl3)
d 1.71 (s, 6H), 2.01 (s,
3H), 7.05 (dd, J¼4.9, 1.2 Hz, 1H), 7.21 (dd, J¼3.0, 1.2 Hz, 1H), 7.28
(dd, J¼4.9, 3.0 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d 18.8, 25.1,
103.5, 105.2, 124.8, 124.9, 129.3, 132.0, 160.8, 165.2. GC–MS: m/z
(relative intensity): 224 (10) [Mþ], 166 (100), 124 (91), 96 (42), 70
(33), 57 (25), 43 (28). HRMS (ESI, positive) m/z calcd for
C11H12SO3: 225.0506 (MþH)þ; found: 225.0519 (MþH)þ. IR
(CHCl3 solution, cmꢀ1): 3010, 2941, 1719, 1630, 1270, 1209, 1012,
778.
4.4.3. (RþS)-(R)-(3,7-Dimethyl-oct-6-enyl)-3-oxo-2-phenyl-
butanoate (6c). Colorless oil. 1H NMR (300 MHz, CDCl3) (keto-
þenol)
d
0.88 (d, J¼7.2 Hz, 3H), 1.23–1.50 (m, 4H), 1.61 (s, 3H),
1.70 (s, 3H), 1.82–1.96 (m, 2H), 2.14 (s, 3H), 2.23 (s, 3H), 4.12 (t,
J¼7.3 Hz, 2H), 4.62 (s, 1H), 5.09 (t, J¼6.0 Hz, 1H), 7.23–7.51 (m,
5H). 13C NMR (75 MHz, CDCl3) (ketoþenol)
d 18.9, 19.1, 20.8, 23.1,
24.4, 27.8, 35.5, 37.6, 62.4, 70.3, 124.5, 127.5, 128.4, 129.1, 131.8,
138.5, 169.8, 174.3, 105.7, 203.7. GC–MS: m/z (relative intensity):
316 (2) [Mþ], 274 (33), 179 (48), 160 (100), 138 (44), 118 (77), 95
(52), 81 (62), 69 (70), 55 (47), 43 (66), 41 (89). HRMS (ESI, pos-
itive) m/z calcd for C20H28O3: 317.2117 (MþH)þ; found: 317.2123
(MþH)þ. IR (CHCl3 solution, cmꢀ1): 3010, 2945, 1753, 1728, 1630,
1513, 1275.
4.3.13. 2,2-Dimethyl-5,6-diphenyl-1,3-dioxin-4-one (4m). White solid.
Mp 151–152 ꢁC. 1H NMR (300 MHz, CDCl3)
d 1.78 (s, 6H), 7.29 (d,
J¼8.2 Hz, 2H), 7.38–7.56 (m, 6H), 7.88 (d, J¼8.0 Hz, 2H). 13C NMR
(75 MHz, CDCl3)
d 26.1, 102.5, 104.8, 127.1, 127.8, 128.2, 128.5, 128.7,
128.8, 130.1, 132.3, 161.7, 168.2. GC–MS: m/z (relative intensity): 280
(3) [Mþ], 225 (56), 175 (35), 120 (27), 105 (100), 91 (45), 77 (20).
HRMS (ESI, positive) m/z calcd for C18H16O3: 281.1178 (MþH)þ;
found: 281.1190 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3011, 2940,
1718, 1632, 1273, 1207, 1010, 779.
4.4.4. (SþR)-(R)-(Octan-2-yl)-3-oxo-2-phenylbutanoate
(6d). Colorless oil. 1H NMR (300 MHz, CDCl3) (ketoþenol)
d 0.88
(t, J¼7.3 Hz, 3H), 1.25–1.31 (m, 8H), 1.37 (d, J¼7.2 Hz, 3H), 1.53 (q,
J¼7.3H, 2H), 2.13 (s, 3H), 2.24 (s, 3H), 4.07 (sext, J¼7.3 Hz, 1H),
4.40 (s, 1H), 7.20–7.35 (m, 5H). 13C NMR (75 MHz, CDCl3) (keto-
4.3.14. 5-(4-Methoxyphenyl)-2,2-dimethyl-6-phenyl-1,3-dioxin-4-
one (4n). White solid. Mp 175–173 ꢁC. 1H NMR (300 MHz, CDCl3)
d
1.81 (s, 6H), 3.85 (s, 3H), 6.93 (d, J¼8.1 Hz, 2H), 7.31 (d, J¼8.1 Hz,
þenol)
d 14.1, 20.2, 22.7, 23.1, 27.8, 29.0, 29.3, 31.8, 36.7, 62.7,
2H), 7.38–7.50 (m, 3H), 7.95 (d, J¼8.2 Hz, 2H). 13C NMR (75 MHz,
72.3, 103.4, 128.1, 128.3, 129.7, 134.5, 168.0, 169.8, 174.3, 203.6.
GC–MS: m/z (relative intensity): 290 (2) [Mþ], 247 (23), 177 (32),
133 (25), 113 (35), 77 (12), 57 (13), 43 (100). HRMS (ESI, positive)
m/z calcd for C18H26O3: 291.1960 (MþH)þ; found: 291.1978
(MþH)þ. IR (CHCl3 solution, cmꢀ1): 3012, 2947, 1754, 1729, 1631,
1510, 1279.
CDCl3)
d 25.8, 56.4, 101.6, 103.5, 113.8, 125.9, 126.6, 127.8, 128.3,
128.8, 139.4, 146.3, 160.9, 168.5. GC–MS: m/z (relative intensity):
310 (16) [Mþ], 282 (45), 252 (76), 233 (25), 207 (10), 152 (21), 103
(42), 77 (13). HRMS (ESI, positive) m/z calcd for C19H18O4: 311.1284
(MþH)þ; found: 311.1290 (MþH)þ. IR (CHCl3 solution, cmꢀ1): 3010,
2942, 1718, 1635, 1279, 1207, 779.
4.4.5. Allyl 3-oxo-2-phenylbutanoate (6e). Colorless oil. 1H NMR
4.4. General procedure for reaction of 5-phenyl-2,2,6-
trimethyl-1,3-dioxin-4-one with benzylic alcohol
(300 MHz, CDCl3) (ketoþenol)
d 2.13 (s, 3H), 2.25 (s, 3H), 4.49 (s,
1H), 4.75 (d, J¼6.1 Hz, 2H), 5.28 (dd, J¼16.3, 3.2 Hz, 1H), 5.42 (dd,
J¼10.1, 3.2 Hz, 1H), 6.06 (dd, J¼16.3, 10.1 Hz, 1H), 12.7 (s, 1H). 13C
The preparation of benzyl 3-oxo-2-phenylbutanoate (6a) is
NMR (75 MHz, CDCl3) (ketoþenol)
d 23.5, 27.8, 62.6, 78.6, 101.2,
representative.
A
mixture of 5-phenyl-2,2,6-trimethyl-1,3-di-
118.1, 128.3, 128.7, 129.0, 132.5, 133.9, 168.3, 169.1, 172.8, 202.8. GC–
oxin-4-one 4a (109 mg; 0.50 mmol; 1.0 equiv) and benzylic
MS: m/z (relative intensity): 218 (2) [Mþ], 177 (23), 175 (32), 43

A.S. Vieira et al. / Tetrahedron 66 (2010) 773–779
779
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R.; Vieira, A. S. Tetrahedron 2007, 63, 3623–3658; (c) Molander, G. A.; Figueroa,
R. Aldrichimica Acta 2005, 38, 49–56; (d) Molander, G. A.; Rivero, M. R. Org. Lett.
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127–135.
(100), 41 (79). HRMS (ESI, positive) m/z calcd for C13H14O3: 219.1021
(MþH)þ; found: 219.1030 (MþH)þ.
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The authors would like to acknowledge Conselho Nacional de
´
´
Desenvolvimento Cientıfico e Tecnologico (CNPq 300.613/2007-5)
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˜
and Fundaça˜o de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP
06/50190-7, 07/02382-7 and 07/59404-2) for financial support.
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