Synthesis of 5-alkynyl-2,2,6-trimethyl-1,3-dioxin-4-ones and 1,4-disubstituted-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2011.04.072

Herein we report an approach to the formation of 5-alkynyl-1,3-dioxin-4- ones using Suzuki-Miyaura cross-coupling reaction of potassium alkynyltrifluoroborate salts with 2,2,6-trimethyl-5-iodo-1,3-dioxin-4-one. The resulting 5-ethynyltrimethylsilyl-1,3-dioxin-4-ones obtained through the Sonogashira reaction were further reacted in a Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition to form functionalized 1,4-disubstituted-1,2,3-triazoles in good yields, using mild conditions and ultrasonic radiation to expedite the reaction.

Full text of DOI:10.1016/j.tetlet.2011.04.072

Tetrahedron Letters 52 (2011) 4256–4261
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Tetrahedron Letters
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Synthesis of 5-alkynyl-2,2,6-trimethyl-1,3-dioxin-4-ones and
1,4-disubstituted-1,2,3-triazoles
Hélio A. Stefani a, , Adriano S. Vieira a, Mônica F. Z. J. Amaral a, Leora Cooper b
⇑
a Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil
b Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report an approach to the formation of 5-alkynyl-1,3-dioxin-4-ones using Suzuki–Miyaura
cross-coupling reaction of potassium alkynyltrifluoroborate salts with 2,2,6-trimethyl-5-iodo-1,3-
dioxin-4-one. The resulting 5-ethynyltrimethylsilyl-1,3-dioxin-4-ones obtained through the Sonogashira
reaction were further reacted in a Cu(I)-catalyzed Huisgen azide–alkyne 1,3-dipolar cycloaddition to
form functionalized 1,4-disubstituted-1,2,3-triazoles in good yields, using mild conditions and ultrasonic
radiation to expedite the reaction.
Received 15 March 2011
Accepted 18 April 2011
Available online 24 April 2011
Keywords:
Suzuki–Miyaura
2,2,6-Trimethyl-5-iodo-1,3-dioxin-4-one
Alkynyltrifluoroborates
Cross-coupling reaction
1,4-Disubstituted-1,2,3-triazoles
Ó 2011 Elsevier Ltd. All rights reserved.
CuSO4
N
1. Introduction
N
sodium ascorbate
R1
R2
R1-N3
N
+
H
R2
Transition metal-catalyzed cross-coupling reactions have be-
come ubiquitous in modern organic synthesis.1 Carbon–carbon
bond-formation processes, which are typically mediated by nickel,
palladium, iron, or copper catalysts, have become commonplace
both in academic research and in the pharmaceutical industry. Of
these carbon–carbon bond-forming reactions, the Suzuki–Miyaura
cross-coupling reaction2 is distinguished because the boron com-
pounds have many significant advantages over the other organome-
tallic reagents used in these types of reactions. The high versatility
and high functional-group tolerance of the Suzuki–Miyaura reac-
tion, as well as the recent advances in the coupling of sterically hin-
dered substrates, have increased the utility of the reaction in the
syntheses of complicated and sensitive molecules, including phar-
maceutical compounds such as Diovan and Cozaar.3
t
-BuOH, H2O
Scheme 1. The Huisgen [3+2] cycloaddition.
yields without forming offensive byproducts.5 These reactions
have already been used to efficiently access useful new com-
pounds. Among these ‘click chemistry’ reactions, the Huisgen
[3+2] cycloaddition has enabled the reliable synthesis of a plethora
of new compounds, which has been very useful in drug discovery.
This Cu(I) catalyzed reaction has been largely successful because it
provides virtually quantitative yields and because the robust reac-
tion is not sensitive to solvents and functional groups. The use of
Cu(I) is superior to that of other metal catalysts in this reaction be-
cause it is significantly less expensive and easier to handle than
other catalysts described to accomplish the same transformation.
Most of the other metal catalyzed reactions involve the reduction
of stable Cu(II) sources, such as CuSO4, and use sodium salts or
the comproportionation of Cu(II)/Cu(0) species (Scheme 1).
The availability of a reliable reaction to form azoles has lead to
advances in the applications of azoles in medicinal chemistry,
chemical biology, and materials science.7
Originally discovered by Huisgen in the 1960’s,4 the 1,3-dipolar
cycloaddition reaction between acetylenes and azides was revis-
ited and expanded by Sharpless and others during the develop-
ment of ‘click chemistry’.5
Recently Fokin and co-workers reported the synthesis of 1,5-
diarylsubstituted 1,2,3-triazoles from aryl azides and terminal al-
kynes in DMSO using a catalytic amount of tetraalkylammonium
hydroxide.6
The concept of ‘click chemistry’ takes advantage of a wide range
of modular, stereospecific reactions and gives products in high
The regioselectivity of the reaction coupled with its modularity,
high yields and simple conditions and purification techniques have
lead to the use of 1,3-dipolar cycloaddition reactions between al-
kynes and azides in numerous syntheses of modified nucleosides
and oligonucleotides that have
a broad range of important
⇑
Corresponding author.
E-mail address: hstefani@usp.br (H.A. Stefani).
applications.8
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.072

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4256–4261
4257
Table 1
Optimization of the conditions for the Suzuki–Miyaura cross-coupling reaction between 1 and 2a
O
O
[Pd], base,
solvent
I
O
O
BF3K
+
H3C
H3C
H3C
H3C
O
CH3
80 oC, 2 h
O
CH3
2a
(1.1 eq)
1
3a
Entry
Catalysta
Baseb
Solvent
Yieldc (%)
1
2
3
4
5
6
7
8
9
Pd(AcO)2
Pd2(dba)3
Pd(Ph3P)4
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Et3N
i-Pr2NEt
K3PO4
K2CO3
K2CO3
1,4-Dioxane/H2Od
1,4-Dioxane/H2Od
1,4-Dioxane/H2Od
1,4-Dioxane/H2Od
1,4-Dioxane/H2Od
1,4-Dioxane/H2Od
1,4-Dioxane/H2Od
1,4-Dioxane/H2Od
THF/H2O (3:1)
42
51
64
72
51
47
32
43
78
31
10
CH3OH
a
b
c
1.0 mol % of palladium catalyst.
1.5 equiv of base.
Isolated yield of pure product.
1,4-Dioxane/H2O ratio: 2:1.
d
sium hydrogen difluoride (KHF2). After the solvents were removed,
the crude salt was recrystallized in an acetone/diethyl ether mix-
ture to form the corresponding potassium alkynyl trifluoroborate
2a–h. These reactions gave good yields and were relatively easy
to perform.
These potassium alkynyltrifluoroborates were then used in the
development of a Suzuki–Miyaura reaction. Our initial studies
were focused on the optimization of the reaction conditions for
the palladium-catalyzed cross-coupling of potassium alkynyl tri-
fluoroborates 2 with 5-iodo-1,3-dioxin-4-one 1. The optimization
was done by screening the reaction conditions, the results of which
are summarized in Table 1. During the screening process, several
palladium catalysts including Pd(PPh3)4, Pd(AcO)2, Pd2(dba)3 and
PdCl2 were tested, and a variety of different bases (Et3N, i-Pr2NEt,
K2CO3, Cs2CO3 and K3PO4) and different solvent systems (MeOH,
EtOH, i-PrOH, THF, DME, and 1,4-dioxane) under both anhydrous
and aqueous conditions were evaluated.
The use of alcohol as solvent decreased the yield of the coupling
product (Table 1, entry 10). This is probably because the presence
of the alcohol at the required temperature for the reaction can pro-
mote the ring-opening reaction of the 1,3-dioxin-4-one, which can
compete with the Suzuki–Miyaura cross-coupling reaction.
The optimal conditions for the cross-coupling reaction found
were treating 1.1 equiv of potassium phenylethynyl trifluoroborate
2a (1.1 mmol) with 1.5 equiv of K2CO3 in 3 mL of degassed THF/
H2O (3:1). To this solution, 2.0 mol % of PdCl2 and 1.0 equiv of 5-
iodo-1,3-dioxin-4-one 1 were added and the reaction mixture
was stirred vigorously for 3 h at 80 °C (Table 2).
As is shown in Table 2, the coupling reactions of potassium
alkynyl trifloroborates 2 gave only moderate to low yields, with a
few exceptions.11 Aromatic substrates (2a–c,f,g) (Table 2, entries
1–3) formed their corresponding products in relatively good yields,
while aliphatic substrates (2d,e) (Table 2, entries 4 and 5) gave the
2. Results and discussion
As part of our ongoing research in the chemistry of potassium
organotrifluoroborate salts,9 Cu(I) alkyne–azide Huisgen [3+2]
cycloaddition, 5-halo-1,3-dioxin-4-ones, and the potential use of
these compounds as intermediates in organic synthesis, we report
an efficient method for the synthesis of 5-alkynyl-1,3-dioxin-4-one
compounds by the Suzuki–Miyaura palladium-catalyzed cross-
coupling reaction of 5-iodo-1,3-dioxin-4-one and potassium aryl-
trifluoroborate salts. The product of the coupling of potassium
ethynyltrimethylsilyltrifluoroborate and 5-iodo-1,3-dioxin-4-one,
obtained using the Sonogashira coupling reaction, was then used
in a series of Huisgen [3+2] cycloaddition reactions, mediated by
ultrasound, to form the respective 1,2,3-triazole substituted 1,3-di-
oxin-4-ones very quickly. The Letter ends with two ring-opening
deprotection reactions9f of the 1,2,3-triazole substituted dioxin-
4-ones to demonstrate the versatility of the substrate and the reac-
tions summarized herein.
The functionalization of position 5 of 1,3-dioxin-4-ones with an
electrophile forms compounds that are potentially useful as pharma-
ceuticals and agrochemical intermediates.10 The starting material for
these reactions was formed by the iodination of commercially avail-
able 2,2,6-trimethyl-1,3-dioxin-4-one with N-iodosuccinimide (NIS)
in acetic acid and protected from light to form 5-iodo-1,3-dioxin-4-
one 1 in 68% isolated yield.
The potassium alkynyltrifluoroborate salts (2a–h) were pre-
pared from organolithium reagents as described in the literature2
(Scheme 2). The lithium acetylides were formed by adding a
1.6 M solution of n-BuLi in hexanes to a solution of the acetylene
in THF at À40 °C and allowing the mixture to react for 1 h. The lith-
ium acetylides were then treated with B(OCH3)3 for 2 h at À30 °C
to generate lithium acetylide trimethylborates, after which the
products were treated with a saturated aqueous solution of potas-
n
-BuLi, THF, -40 oC, 1 h
R1
KHF2, H2O
B(OMe)3
1)
2) B(OCH3)3, -30 oC, 2 h
R1
R1
BF3K
H
25 oC, 2 h
Li
2
Scheme 2. Synthesis of potassium alkynyl trifluoroborates 2.

4258
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4256–4261
Table 2
Cross-coupling reactions of 5-iodo-1,3-dioxin-4-one 1 with potassium alkynyltrifluoroborates 3a–l
O
O
R
I
PdCl2, K2CO3
THF/H2O (3:1)
O
O
+
R
BF3K
2a-h
H3C
H3C
H3C
H3C
O
CH3
O
3a-h
CH3
80 o
C
1
Entry
R1a
Reaction time (h)
Product (3)
Yieldb (%)
O
O
1
Ph (2a)
3
78
H3C
O
CH3
H3C
3a
Cl
O
O
2
3
4-ClC6H4 (2b)
4
3
65
72
H3C
O
CH3
H3C
3b
CH3
O
4-MeC6H4 (2c)
O
O
O
H3C
H3C
O
CH3
CH3
3c
O
n
-C4H9
H3C
H3C
4
5
n-C4H9 (2d)
6
6
47
53
O
3d
O
CH2OCH3
H3C
H3C
MeOCH2 (2e)
O
CH3
H3C
3e
OCH3
O
O
6
2-Me4MeOC6H4 (2f)
4
63
H3C
H3C
O
CH3
3f
N
O
O
O
O
7
8
3-C5H5N (2g)
6
6
61
H3C
H3C
CH3
CH3
3g
O
SiMe3
H3C
H3C
Me3Si (2h)
—
O
3h
a
1.1 equiv of R1–C„C–BF3K.
Isolated yield of pure product.
b
products in more moderate yields, with longer reaction times. The
yields of all of these reactions could likely be improved by a more
detailed study of this reaction, including further optimization of
the reaction medium, the catalyst and the substrates.

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4256–4261
4259
Products 3a–h were analyzed by 1H and 13C NMR, and their
physical data are in full agreement with their assigned structures.
Crystallographic analysis of product 3c was also performed, and its
thermal ellipsoid plot is show in Figure 1. Compound 3c was
recrystallized in anhydrous methanol prior to its crystallographic
analysis (Fig. 1).12
Anomalous to the reasonably successful results found for both
aliphatic and aromatic trifluoroborate salts (Table 2, entries 1–7),
the Suzuki–Miyaura cross-coupling reaction of the trimethylsilyl
alkynyltrifluoroborate salt (2h) with the 5-iodo-1,3-dioxin-4-one
(1) was completely unsuccessful. The formation of this product re-
Figure 1. Thermal ellipsoid plot of 5-(p-tolyl-ethynyl)-2,2,6-trimethyl-4H-1,3-
dioxin-4-one 3c.
O
O
SiMe3
I
CH3
PdCl2, CuI, PPh3, Et3N
CH3CN, 50 oC, 2 h
O
Me3Si
O
H3C
H3C
+
H
H3C
H3C
O
4
O
CH3
1
3h
Scheme 3. Sonogashira coupling reaction of 5-iodo-1,3-dioxin-4-one.
Table 3
Huisgen 1,3-dipolar cycloaddition of 5-alkynyl-1,3-dioxin-4-one 3h with azides 5a–j
N
N
O
SiMe3
O
O
R1
N
CuI, TBAF
O
O
R1 N3
H3C
H3C
H3C
H3C
THF, sonication
25 oC, 5 min
O
CH3
CH3
5
3h
6
R1–N3 (5)
Reaction time (min)
Product (6)
Yieldb (%)
a
Entry
1
N
N
O
N
Ph
O
H3C
C6H5N3
5
80
O
CH3
H3C
6a
N
O
N
N
O
H3C
H3C
2
3
3-ClC6H4N3 (5b)
5
5
73
85
O
O
CH3
Cl
6b
N
N
N
O
I
H3C
H3C
4-IC6H4N3 (5c)
O
CH3
6c
N
N
O
O
N
O
NO2
H3C
H3C
4
5
4-O2NC6H4N3 (5d)
4
4
70
CH3
6d
H3C
N
N
O
O
N
O
NO
4-O2N,2-Me-C6H4N3 (5e)
81
H3C
H3C
CH3
6e
(continued on next page)

4260
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4256–4261
Table 3 (continued)
a
Entry
R1–N3 (5)
Reaction time (min)
Product (6)
Yieldb (%)
N
O
N
N
n
-C12H25
O
H3C
H3C
6
7
8
n-C12H25N3 (5f)
C6H5CH2N3 (5g)
n-C6H13N3 (5h)
70
75
O
CH3
6f
N
O
N
N
N
N
Bn
O
H3C
H3C
50
60
84
79
O
CH3
6g
N
O
N
n-C6H13
O
H3C
H3C
O
CH3
6h
N
O
N
O
H3C
9
c-C6H11N3 (5i)
80
50
78
74
O
CH3
N
H3C
6i
6j
N
O
N
n-C8H17
O
10
n-C8H17N3 (5j)
H3C
O
CH3
H3C
a
1.2 equiv of R1–N3.
Isolated yield of pure product.
b
After the highly functionalized triazoles (5a–j) were obtained
through the 1,3-dipolar cycloaddition reaction, a ring-opening
reaction was performed on two of the products to demonstrate
the versatility and applicability of these triazole compounds. These
ring-opening reactions converted the 1,4-disubstitutes-1,3-dioxin-
N
O
O
O
O
N
N
R1
Bn-OH (1.2 eq)
110 ºC, 4 h
O
CH3
O
H3C
R
N
N
CH3
H3C
N
4-ones into their corresponding a-substituted 1,3-dicarbonyl com-
7
6
R1
pounds, which have great applicability in the field of synthetic or-
ganic chemistry, as they can be used in variations of the acetoacetic
ester synthesis.
1 = n-C12H25 (6a)
7a, 72% yield
7h, 65% yield
R2 = C6H5 (6h)
The ring-opening reactions9f were run under simple conditions,
by combining an alcohol with the 1,4-disusbstituted-1,2,3-triazole
in the absence of an external solvent, and heating the reaction to
110 °C under nitrogen atmosphere (Scheme 4).
Scheme 4. Ring-opening reactions of 1,2,3-triazoles.
quired the use of the related Sonogashira cross-coupling reaction,
which was performed according to the conditions specified in the
literature.13 The Sonogashira cross-coupling reaction formed prod-
uct 3h with an isolated yield of 56% (Scheme 3).
Product 3h was converted via the Huisgen 1,3-dipolar cycloaddi-
tion and azides (5a–j) in the corresponding 1,4-disubstituted-1,2,3-
triazole compounds (6a–j) by a simple ‘click chemistry’ reaction
mediated by a copper catalyst as is shown in Table 3.
The yields of these deprotections were moderate to good,15
depending on the substitutions on the triazole ring. While the
two examples of these reactions are representative of the many
applications possible using 2,2,6-trimethyl-1,3-dioxin-4-one sub-
strate, further investigations are required to fully understand any
trends in yields based on the various R groups, and to fully opti-
mize these reaction conditions.
While this reaction is generally sluggish, the reaction time was
significantly reduced by sonicating the reaction,14 as is shown in
the literature.10 The short reaction time associated with this ver-
sion of the Huisgen reaction under ultrasonic waves makes the
methodology much more synthetically and industrially useful.
Though many different substitutions were tested, the results
showed no preference to any specific functional groups on the
azide reagents (5a–j). While some variation is seen in the yields,
all of the yields were reasonably good. It seems that the aromatic
azides had slightly higher yields than nonaromatic ones, although
there are exceptions.
3. Conclusion
We have shown the wide versatility and reasonable yield of the
optimized conditions for the Suzuki–Miyaura cross-coupling reac-
tion of potassium alkynyl trifluoroborates with 1,3-dioxin-4-ones.
This methodology is preferred over many other organometallic-
compound-based cross-coupling reactions because potassium
organotrifluoroborate salts are readily available, very stabile, non-
toxic, mildly nucleophilic in character, because they have a unique
compatibility with aqueous media. It was observed that while

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 4256–4261
4261
Botteselle, G. V.; Hough, T. L. S.; Venturoso, R. C.; Cella, R.; Vieira, A. S.; Stefani,
H. A. Aust. J. Chem. 2008, 61, 870; (f) Vieira, A. S.; Cunha, R. L. O. R.; Klitzke, C. F.;
Zukerman-Schpector, J.; Stefani, H. A. Tetrahedron 2010, 66, 773.
Suzuki–Miyaura reaction did not work for all examples it can be
substituted by the Sonogashira reaction giving highly functional-
ized 1,4-disubstituted-1,2,3-triazole-containing compounds.
The short reaction time associated with our variation on the
1,3-dipolar cycloaddition reaction using ultrasound waves makes
the methodology much more synthetically useful.
10. Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952.
11. General procedure for the cross-coupling reaction of potassium
alkynyltrifluoroborates with 5-iodo-2,2,6-trimethyl-1,3-dioxin-4-one. To
a
solution of the alkynyl potassium trifluoroborate (1.1 mmol, 1.1 equiv) in
degassed THF/water (3:1, 3 mL) was added solid K2CO3 (1.5 mmol, 1.5 equiv).
The mixture was stirred vigorously for 1 min under a nitrogen atmosphere
after which PdCl2 (0.01 mmol, 1.0 mol %) was added, followed by 5-iodo-2,2,6-
trimethyl-1,3-dioxin-2-one (1) (268 mg, 1.0 mmol, 1.0 equiv). The reaction
was heated to 80 °C and stirred vigorously, while being monitored by TLC until
the starting material had been completely consumed. The reaction mixture
was cooled to room temperature and was then extracted from the reaction
mixture using ethyl acetate (20 mL). Additional product was extracted from
the aqueous phase with ethyl acetate (3 Â 15 mL), and the combined organic
phases were dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography (hexanes/ethyl acetate,
10:1) to afford the product.
Acknowledgments
The authors would like to acknowledge Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq 300.613/2007-5)
and Fundação de Amparo à Pesquisa do Estado de São Paulo (FA-
PESP 06/50190-7, 07/02382-7 and 07/59404-2) for their financial
support.
5-Phenylethynyl-2,2,6-trimethyl-4H-1,3-dioxin-4-one (3a). Following the
general procedure: 78% yield, white solid, mp = 51–52 °C. 1H NMR (300 MHz,
Supplementary data
CDCl3) d 1.78 (s, 6H), 1.98 (s, 3H), 7.28–7.43 (m, 3H), 7.84 (d, J = 8.5 Hz, 2H). 13
C
NMR (75 MHz, CDCl3) d 18.8, 25.9, 87.8, 92.7, 101.1, 104.0, 128.4, 128.6, 129.3,
133.2, 163.0, 168.8. GC/MS (relative intensity): m/z 242 (10) [M+], 184 (45), 156
(34), 77 (20), 43 (100).
Supplementary data (experimental procedures, spectral data
and copies of spectra for all compounds) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2011.04.072.
12. Caracelli, I.; Zukerman-Schpector, J.; Vieira, A. S.; Stefani, H. A.; Tiekink, E. R. T.
Acta Crystallogr. 2009, E65, O2736.
13. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
14. General procedure for the cross-coupling reaction of potassium
alkynyltrifluoroborates with 5-iodo-2,2,6-trimethyl-1,3-dioxin-4-one. To
a
References and notes
solution of the alkynyl potassium trifluoroborate (1.1 mmol, 1.1 equiv) in
degassed THF/water (3:1, 3 mL) was added solid K2CO3 (1.5 mmol, 1.5 equiv).
The mixture was stirred vigorously for 1 min under a nitrogen atmosphere
after which PdCl2 (0.01 mmol, 1.0 mol %) was added, followed by 5-iodo-2,2,6-
trimethyl-1,3-dioxin-2-one (1) (268 mg, 1.0 mmol, 1.0 equiv). The reaction
was heated to 80 °C and stirred vigorously, while being monitored by TLC until
the starting material had been completely consumed. The reaction mixture
was cooled to room temperature and was then extracted from the reaction
mixture using ethyl acetate (20 mL). Additional product was extracted from
the aqueous phase with ethyl acetate (3 Â 15 mL), and the combined organic
phases were dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography (hexanes/ethyl acetate,
10:1) to afford the product.
1. (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed.; Wiley-VHC: Weinheim, 2004; (b) Negishi, E. Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley: New York, 2002.
2. For reviews concerning Suzuki–Miyaura cross-coupling reactions, see: (a)
Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633; (b) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457; (c) Darses, S.; Genêt, J.-P. Chem. Rev. 2008,
108, 288; (d) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623; (e)
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5-Phenylethynyl-2,2,6-trimethyl-4H-1,3-dioxin-4-one (3a). Following the
general procedure: 78% yield, white solid, mp = 51–52 °C. 1H NMR (300 MHz,
CDCl3) d 1.78 (s, 6H), 1.98 (s, 3H), 7.28–7.43 (m, 3H), 7.84 (d, J = 8.5 Hz, 2H). 13
C
NMR (75 MHz, CDCl3) d 18.8, 25.9, 87.8, 92.7, 101.1, 104.0, 128.4, 128.6, 129.3,
133.2, 163.0, 168.8. GC/MS (relative intensity): m/z 242 (10) [M+], 184 (45), 156
(34), 77 (20), 43 (100).
15. General procedure for reaction of 5-(1-phenyl-1,2,3-triazol-4-yl)-2,2,6-
trimethyl-1,3-dioxin-4-one (6a) with benzyl Alcohol. The synthesis of benzyl-
6. Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V. V. Org. Lett.
2010, 12, 4217.
3-oxo-2-(1-phenyl-1H-1,2,3-triazol-4-yl)butanoate (7a) is representative.
A
solution of 2,2,6-trimethyl-5-(1-phenyl-1H-1,2,3-triazol-4-yl)-4H-1,3-dioxin-
4-one (6a) (142.5 mg, 0.5 mmol, 1.0 equiv) and benzyl alcohol (65 mg, 0.6 mmol,
1.2 equiv) was stirred well under an atmosphere of nitrogen for 8 h at 110 °C. The
crude product was purified by column chromatography on a silica column
(hexane/ethyl acetate, 95:5), giving the pure benzyl 3-oxo-2-(1-phenyl-1H-
1,2,3-triazol-4-yl)butanoate with a 65% yield.
Benzyl-3-oxo-2-(1-phenyl-1H-1,2,3-triazol-4-yl)butanoate (7a). 65% yield,
yellow oil, 1H NMR (300 MHz, CDCl3) d 2.44 (s, 3H), 4.27 (s, 1H), 5.52 (s, 2H),
7.27–7.54 (m, 8H), 7.76–7.80 (m, 2H), 8.52 (s, 1H). 13C NMR (75 MHz, CDCl3) d
25.1, 61.1, 71.1, 120.4 (2C), 121.7, 128.8 (2C), 129.4 (2C), 129.7, 130.9 (2C), 130.9,
137.0, 140.5, 167.9, 200.5.
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