A practical synthesis of α-substituted tert-butyl acrylates from meldrum's acid and aldehydes

Article abstract of DOI:10.1055/s-0028-1083351

An expeditious synthesis of α-substituted tert-butyl acrylates from commercially available aldehydes and Meldrum's acid has been established. The method benefits from a telescoped condensation-reduction sequence to afford 5-monosubstituted Meldrum's acid

Full text of DOI:10.1055/s-0028-1083351

PAPER
627
A Practical Synthesis of a-Substituted tert-Butyl Acrylates from Meldrum’s
Acid and Aldehydes
a
-Substituted tert
h
-Butyl
A
cryl
r
ates from
i
Meld
s
r
um’s
A
ci
t
d
and A
o
ldehydes pher G. Frost,*a Stephen D. Penrose,a Robert Gleaveb
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
Fax +44(1225)386231; E-mail: c.g.frost@bath.ac.uk
b
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline,
New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 29 August 2008
difficulties with the hydrolysis of the corresponding di-
ester. The a-functionalisation of acrylates employing the
Baylis–Hillman reaction (Scheme 1) or aza variant is well
documented, but limited to a-hydroxy- or a-amino-substi-
Abstract: An expeditious synthesis of a-substituted tert-butyl
acrylates from commercially available aldehydes and Meldrum’s
acid has been established. The method benefits from a telescoped
condensation–reduction sequence to afford 5-monosubstituted Mel-
drum’s acid derivatives followed by a Mannich-type reaction trig- tuted products.4 The methylenation of functionalised
gered by a rapid cycloreversion of the dioxinone ring on heating
phosphonates via
a Wittig–Horner reaction using
with tert-butyl alcohol.
paraformaldehyde (Scheme 1) allows convenient access
to a-methylene adipate derivatives, although, surprising-
ly, this route is rarely utilised.5 Palladium and nickel com-
plexes have been studied in the catalytic synthesis of a-
aryl-a,b-unsaturated carbonyl compounds by the cross-
Key words: alkenes, Mannich bases, acrylate derivatives, tandem
reactions, aldehydes
Functionalised a-substituted acrylic acid esters are of in- coupling of a-organometallics with aryl halides or the
creasing importance in the design and synthesis of new complementary combination of an a-halocarbonyl com-
polymer-based materials for a wide variety of applications pound and an sp2-carbon-derived organometallic com-
in different areas of chemistry, biotechnology, nanotech- pound (Scheme 1).6 However, in the context of preparing
nology, and material science.1 Furthermore, they are valu- a-substituted acrylates, there are few reported examples,
able intermediates for the 1,4-addition reaction of and mixtures of products are often isolated.7
nucleophiles in both biological systems and for organic
Herein, we report a practical and scalable synthesis of a
wide range of a-substituted tert-butyl acrylates 4 from
commercially available aldehydes 2 and Meldrum’s acid
synthesis.2 Consequently, a number of methods have been
developed to allow access to structurally diverse a-substi-
tuted acrylates, and some of the reported approaches are
illustrated in Scheme 1.
(1) (Scheme 2); this approach is complementary to estab-
lished routes from carboxylic acids.8 The method entails a
telescoped condensation–reduction sequence to afford 5-
HO
O
O
monosubstituted Meldrum’s acid derivatives 3, followed
by a Mannich-type reaction triggered by a rapid cyclore-
version of the dioxinone ring on heating (Scheme 2).9
Mannich
catalytic coupling
R1O
R1O
R1O
R2
R2
Br
R2M
O
O
Baylis–Hillman
Wittig–Horner
RCHO 2
H2O
O
O
O
O
R
P(O)(OR3)2
R2
O
O
NaBH4
O
O
R1O
R2CHO
+
+ R1O
1
3
(HCHO)n
[Me2N=CH2]+I–
O
O
t-BuOH
Scheme 1
t-BuO
R
The classical method for acrylate synthesis involves a
Mannich reaction of a-monosubstituted malonic half es-
ters (Scheme 1).3 This route can be problematic, with dif-
ficulties in the selective formation of the monosubstituted
malonate diester. Furthermore, it is not possible to obtain
the a-substituted tert-butyl acrylate by this method, due to
4
O
Scheme 2
A number of methods for the synthesis of a,b-unsaturated
Meldrum’s acid derivatives has been reported, including
the use of strong base and N,N-dimethylformamide as a
solvent,10 neat aldehyde,11 zinc dust,12 and, more recently,
pyridinium acetate.13 A remarkably expedient method is
the uncatalysed Knoevenagel condensation of aldehydes
and 1 in water, reported by Bigi et al.14 This protocol of-
SYNTHESIS 2009, No. 4, pp 0627–0635
x
x
.
x
x
.2
0
0
9
Advanced online publication: 02.02.2009
DOI: 10.1055/s-0028-1083351; Art ID: P09408SS
© Georg Thieme Verlag Stuttgart · New York

628
C. G. Frost et al.
PAPER
fers significant advantages over existing methods for the
preparation of a-substituted tert-butyl acrylates, as it cir-
cumvents the use of expensive coupling reagents and the
generation of side products. Thus, the Knoevenagel con-
densation of thiophene-2-carbaldehyde (2a) and 1 in wa-
ter afforded a bright-yellow, solid condensation product
after two hours at 75 °C (Scheme 3). The compound was
isolated by simple filtration, and washed with water and
hexane to give the desired a,b-unsaturated Meldrum’s
acid derivative 5a. The crude product could be used in the
next step without further purification. Consequently, 5a
was cooled to 0 °C and dissolved in dichloromethane, and
acetic acid was introduced. After the reaction mixture had
stirred for 15 minutes, sodium borohydride was added in
small portions over one hour. A rapid colour change oc-
curred in 15 minutes, corresponding to the loss in conju-
gation and completion of the reaction. After a simple
aqueous workup, the 5-monosubstituted Meldrum’s acid
derivative 3a was obtained in high yield (Scheme 3).
O
O
MeO
HO
CHO
1, H2O
O
O
75 °C, 2 h
21%
2b
5b
1. 1, H2O, 75 °C, 2 h
CH2Cl2 extraction
NaBH4
AcOH
OH
OMe
2. NaBH4, AcOH,
CH2Cl2, 0 °C, 1 h
CH2Cl2, 0 °C, 1 h
54%
87% (from 2b)
O
O
O
O
3b
OH
OMe
Scheme 4
Table 1 Synthesis of 5-Substituted Derivatives of Meldrum’s Acid
1, H2O
O
O
CHO
S
88%
O
O
S
1. RCHO 2
H2O, 75 °C, 2 h
2a
O
O
O
O
5a
CH2Cl2 extraction
O
O
NaBH4
AcOH
O
O
2. NaBH4, AcOH,
CH2Cl2, 0 °C, 1 h
1
3
CH2Cl2
98%
R
O
O
Product
3a
R
Yielda (%)
88
O
O
2-thienyl
3a
S
3b
3c
3-MeO-4-HOC6H3
3-thienyl
87
88
Scheme 3
3d
3e
3-methyl-2-thienyl
PMP
91
This two-step route proved to be effective for a range of
aldehydes, notably those that are liquids at room temper-
ature.15 However, problems arose when solid aldehydes
with poor solubility in water were used or when the inter-
mediate a,b-unsaturated Meldrum’s acid derivatives were
not easily isolated as crystalline solids. This was rectified
by telescoping the two operations by a simple extraction
with dichloromethane. The improved procedure is illus-
trated for vanillin (2b) (Scheme 4). In this case, separation
of the Knoevenagel condensation product 5b from the
starting aldehyde proved difficult and resulted in low
yields of isolated product.
87
3f
2-MeOC6H4
1,3-benzodioxol-4-yl
1,3-benzodioxol-5-yl
2,3,4-(MeO)3C6H2
2-F-4-MeOC6H3
3-Cl-4-MeOC6H3
4-FC6H4
94
3g
73
3h
3i
76
64
3j
82
3k
3l
63
61
The telescoped procedure involved taking the dichlo-
romethane extracts from the Knoevenagel condensation
and drying them over magnesium sulfate before they were
cooled to 0 °C for the conjugate reduction step
(Scheme 4). This afforded product 3b in 87% yield after a
single recrystallisation from hot ethyl acetate. Using this
telescoped method, 20 compounds were synthesised in
good to excellent yields (Table 1). The products isolated
were air and moisture stable, making them suitable for
large-scale synthesis. The method was not suitable for
certain heteroaromatic aldehydes such as furan and pyr-
3m
3n
3o
2,6-F2C6H3
98
4-MeSC6H4
Tol
89
95
3p
3q
3r
2,6-Me2C6H3
1-naphthyl
92
97
i-Pr
92
a Isolated yield.
Synthesis 2009, No. 4, 627–635 © Thieme Stuttgart · New York

PAPER
a-Substituted tert-Butyl Acrylates from Meldrum’s Acid and Aldehydes
629
Table 3 Synthesis of a-Substituted tert-Butyl Acrylates 4 from 5-
Substituted Derivatives 3 of Meldrum’s Acid
role, due to sensitivity to acid and light, respectively. Oth-
er problematic aldehydes are straight-chain aliphatics,
which tended to react with a second equivalent of
Meldrum’s acid to afford an insoluble solid.
[Me2N=CH2]+I–
O
O
R
6
t-BuO
R
With the 5-monosubstituted Meldrum’s acid derivatives
3a–r in hand, the Mannich-type reaction with N,N-di-
methylmethyleneiminium iodide (6) to install the exo-
methylene could be explored.16 Initially, the reaction of 3a
with tert-butyl alcohol and 6 was optimised as shown in
Table 2. The reaction proceeds by rapid cycloreversion of
the dioxinone ring to establish the tert-butyl ester and trig-
ger the Mannich-type reaction. A significant advantage of
this method is that the reaction byproducts (acetone, car-
bon dioxide, and dimethylamine) are volatile, resulting in
clean conversion to product. Using neat tert-butyl alcohol
as a solvent led to incomplete dissolution of 6 and lower
yields (Table 2, entries 1 and 2). The quantity of 6 was
also critical, with 1.1 equivalents giving poor yields,
t-BuOH, THF, 70 °C
O
O
O
4a–r
3a–r
Product
4a
R
Yielda (%)
92
2-thienyl
4b
3-MeO-4-HOC6H3
3-thienyl
57
4c
82
4d
3-methyl-2-thienyl
PMP
78
4e
95
4f
2-MeOC6H4
94
while the use of an excess, 2.6–3.5 equivalents, afforded 4g
1,3-benzodioxol-4-yl
1,3-benzodioxol-5-yl
2,3,4-(MeO)3C6H2
2-F-4-MeOC6H3
3-Cl-4-MeOC6H3
4-FC6H4
90
excellent yields of product 4a (Table 2, entries 3–6).
4h
87
Table 2 Optimisation of the Reaction of 3a with tert-Butyl Alcohol
and 6
4i
88
4j
83
O
O
4k
4l
91
[Me2N=CH2]+I–
6
t-BuO
S
t-BuOH, THF, 70 °C
O
O
S
84
3a
4a
O
4m
4n
4o
4p
4q
4r
2,6-F2C6H3
84
4-MeSC6H4
98
Entry
6
Ratio
t-BuOH/THF (°C)
Temp
Yielda (%)
of 4a
Tol
82
(equiv)
2,6-Me2C6H3
1-naphthyl
85
1
2
3
4
5
6
1.1
2.0
2.6
2.6
2.6
3.5
1:0
1:0
1:0
1:1
1:1
1:1
65
28
73
81
89
68
91
92
65
i-Pr
98
70
a Isolated yield.
70
reflux
70
In conclusion, a practical synthesis of a-substituted tert-
butyl acrylates from commercially available aldehydes
and Meldrum’s acid is presented. The reaction conditions
are mild and tolerate many functional groups commonly
used in organic synthesis. The method complements exist-
ing routes to a-substituted acrylates and is anticipated to
be of particular utility for applications that require the
tert-butyl ester.
a Isolated yield.
The scope of the method was investigated with 5-mono-
substituted Meldrum’s acid derivatives 3a–r (Table 3).
When substrate 3 and reagent 6 were dissolved in a mix-
ture of anhydrous tetrahydrofuran and tert-butyl alcohol
for optimum solubility, and the mixture was heated to
70 °C overnight, the desired product was obtained in
>95% purity after aqueous workup. Simple purification
by short flash column chromatography afforded analyti-
cally pure materials. Pleasingly, a-substituted tert-butyl
acrylates 4a–r were all formed in good to excellent yields
(Table 3), and all products were stable to air and moisture
with no isomerisation to the tert-butyl 2-methyl-3-phenyl-
acrylate species.
Commercially available solvents and reagents were obtained from
Sigma-Aldrich Company Ltd, Lancaster Synthesis Ltd and Fisher
Scientific Ltd and were used without further purification, with the
exception of Meldrum’s acid which was recrystallised from EtOH.
CH2Cl2 and THF were dried and degassed under an argon at-
mosphere over activated alumina columns using an Innovative
Technology Solvent Purification System (SPS). Melting points
were determined on a Buchi 235 melting point apparatus. IR spectra
were recorded on a Nicolet Nexus FTIR spectrometer, over the ran-
ge 4000–200 cm–1 and averaged over 32 scans, using KBr discs or
NaCl plates. 1H NMR (300 MHz) and 13C NMR (75.5 MHz) spec-
troscopic measurements were carried out on Bruker AV300 or
Synthesis 2009, No. 4, 627–635 © Thieme Stuttgart · New York

630
C. G. Frost et al.
PAPER
AVANCE 400 spectrometers. MS determinations were obtained on
Fisons VG autospec Finnigan MAT 8340 (EI/CI MS) and Bruker
micrOTOF-Q (CI-HRMS) instruments. Elemental analyses were
carried out at the University of Bath using an Exeter Analytical CE
440 elemental analyser.
CH Ar), 3.74 (t, J = 4.6 Hz, 1 H, CH), 3.50 (d, J = 4.6 Hz, 2 H, CH2),
1.73 (s, 3 H, CCH3), 1.51 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.2, 136.7, 129.2, 125.4,
123.9, 105.1, 47.5, 28.2, 27.1, 26.5.
MS (EI/CI): m/z (%) = 258 (55) [M + NH4 ], 240 (5) [MH+], 173
+
+
(45) [C8H10OS + NH4 ].
5-Monosubstituted Meldrum’s Acid Derivatives 3a–r; General
Procedure
+
HRMS (CI): m/z [M + NH4 ] calcd for C11H16O4NS: 258.0795;
2,2-Dimethyl-1,3-dioxane-4,6-dione (1; 1.5 g, 10.5 mmol) was add-
ed portionwise to a stirred suspension of aldehyde 2 (10.0 mmol) in
H2O (25 mL) at 23 °C. A reflux condenser was attached and the
mixture was stirred at 75 °C for 2 h. After cooling of the mixture to
r.t., the precipitated solid was dissolved in CH2Cl2 (100 mL), and
the soln was passed through a hydrophobic frit into a second round-
bottomed flask. The crude arylidene 5 was subsequently cooled to
0 °C (NaCl/ice), and AcOH (5 mL) was added with stirring of the
mixture for 5 min under N2. NaBH4 (4 equiv) was added portion-
wise over 1 h or until the soln turned colourless. The reaction mix-
ture was quenched with H2O (50 mL) and extracted with CH2Cl2
(50 mL). The combined organic extracts were washed with brine
(2 × 75 mL) and H2O (2 × 75 mL) and dried (MgSO4), yielding the
title compound, which could be used without further purification.
Recrystallisation from hot EtOAc–hexanes afforded analytically
pure compounds.
found: 258.0789.
Anal. Calcd for C11H12O4S: C, 55.0; H, 5.03. Found: C, 54.4; H,
4.98.
2,2-Dimethyl-5-[(3-methyl-2-thienyl)methyl]-1,3-dioxane-4,6-
dione (3d)
Cream solid; yield: 83%; mp 78–80 °C (EtOAc).
IR (KBr): 3108, 3007, 2987 (C–H), 1785, 1741 (C=O), 1298 (C–S)
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.98 (d, J = 4.9 Hz, 1 H, Ar), 6.64
(d, J = 4.9 Hz, 1 H, Ar), 3.78 (t, J = 4.6 Hz, 1 H, CH), 3.53 (d, J =
4.6 Hz, 2 H, CH2), 2.18 (s, 3 H, CH3), 1.69 (s, 3 H, CCH3), 1.54 (s,
3 H, CCH3.
13C NMR (75.5 MHz, CDCl3): d = 165.5, 136.2, 132.8, 130.6,
123.5, 105.7, 48.6, 48.5, 28.8, 27.5, 25.0, 16.0.
+
2,2-Dimethyl-5-(2-thienylmethyl)-1,3-dioxane-4,6-dione (3a)
Cream solid; yield: 98%; mp 128 °C (EtOAc).
HRMS (CI): m/z [M + NH4 ] calcd for C12H18O4NS: 272.0957;
found: 272.0924
IR (KBr): 3100, 3014, 2936 (C–H), 1778, 1744 (C=O), 1298 (C–S)
cm–1.
Anal. Calcd for C12H14O4S: C, 56.7; H, 5.55. Found: C, 56.2; H,
5.49.
1H NMR (300 MHz, CDCl3): d = 8.03 (dd, J = 5.0, 1.3 Hz, 1 H, CH
Ar), 7.10–7.02 (m, 1 H, CH Ar), 6.94–6.90 (m, 1 H, CH Ar), 3.76
(t, J = 4.6 Hz, 1 H, CH), 3.72 (d, J = 4.6 Hz, 2 H, CH2), 1.76 (s, 3
H, CCH3), 1.59 (s, 3 H, CCH3).
5-(4-Methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3e)17
White solid; yield: 98%; mp 82–85 °C (EtOAc) (Lit.17 85–86 °C).
IR (KBr): 3006, 2961, 2915 (C–H), 1787, 1746 (C=O) cm–1.
13C NMR (75.5 MHz, CDCl3): d = 164.9, 138.1, 127.9, 126.8,
1H NMR (300 MHz, CDCl3): d = 7.24 (d, J = 8.7 Hz, 2 H, CH Ar),
6.81 (d, J = 8.7 Hz, 2 H, CH Ar), 3.77 (s, 3 H, OCH3), 3.72 (t, J =
4.9 Hz, 1 H, CH), 3.44 (d, J = 4.9 Hz, 2 H, CH2), 1.72 (s, 3 H,
CCH3), 1.48 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.3, 158.6, 130.8, 129.0,
113.8, 105.1, 55.1, 48.1, 31.3, 28.3, 27.1.
125.0, 105.3, 48.2, 28.3, 27.1, 26.4.
+
MS (EI/CI): m/z (%) = 258 (45) [M + NH4 ], 240 (5) [M + H+], 173
+
(50) [C8H10OS + NH4 ].
+
HRMS (CI): m/z [M + NH4 ] calcd for C11H16O4NS: 258.0795;
found: 258.0791.
+
MS (EI/CI): m/z (%) = 282 (45) [M + NH4 ], 265 (5) [M + H+], 198
Anal. Calcd for C11H12O4S: C, 55.0; H, 5.03. Found: C, 54.2; H,
4.96.
(50) (C10H12O3 + NH4).
+
HRMS (CI): m/z [M + NH4 ] calcd for C14H20NO5: 282.3118;
5-(4-Hydroxy-3-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3b)
Cream solid; yield: 66%; mp 133 °C (EtOAc).
found: 282.3114.
Anal. Calcd for C14H16O5: C, 63.6; H, 6.10. Found: C, 63.1; H, 6.06.
IR (KBr): 3400 (O–H), 2831 (C–O–CH3), 1778, 1754 (C=O) cm–1.
5-(2-Methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3f)
1H NMR (300 MHz, CDCl3): d = 6.85 (br s, 1 H, CH Ar), 6.81–6.79
(m, 2 H, CH Ar), 5.56 (s, 1 H, OH), 3.82 (s, 3 H, OCH3), 3.72 (t, J =
4.9 Hz, 1 H, CH), 3.42 (d, J = 4.9 Hz, 2 H, CH2), 1.72 (s, 3 H,
CCH3), 1.47 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.5, 146.2, 144.7, 128.8,
122.5, 114.3, 112.6, 105.2, 55.9, 48.3, 31.9, 28.4, 27.3.
Cream solid; yield: 92%; mp 97–100 °C (EtOAc).
IR (KBr): 3000, 2940, 2886 (C–H), 1772, 1751 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36 (dd, J = 7.5, 1.9 Hz, 1 H, CH
Ar), 7.25 (td, J = 7.9, 1.9 Hz, 1 H, CH Ar), 6.93 (td, J = 7.5, 1.1 Hz,
1 H, CH Ar), 6.85 (d, J = 7.9 Hz, 1 H, CH Ar), 4.03 (t, J = 6.0 Hz,
1 H, CH), 3.83 (s, 3 H, OCH3), 3.40 (d, J = 6.0 Hz, 2 H, CH2), 1.77
(s, 3 H, CCH3), 1.73 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 170.4, 164.9, 156.7, 131.1,
127.8, 125.3, 120.0, 110.0, 104.4, 59.8, 54.7, 45.5, 28.0, 27.3, 25.8,
20.4, 13.7.
ESI-HRMS: m/z [M + Na+] calcd for C14H16Na1O6: 303.0845;
found: 303.0822.
Anal. Calcd for C14H16O6: C, 60.0; H, 5.75. Found: C, 60.8; H, 5.81.
+
MS (EI/CI): m/z (%) = 282 (40) [M + NH4 ], 265 (10) [M + H+], 198
(50) (C10H12O3 + NH4).
2,2-Dimethyl-5-(3-thienylmethyl)-1,3-dioxane-4,6-dione (3c)
Cream solid; yield: 91%; mp 81–83 °C (EtOAc).
+
IR (KBr): 3102, 3014, 2936 (C–H), 1774, 1744 (C=O), 1298 (C–S)
cm–1.
HRMS (CI): m/z [M + NH4 ] calcd for C14H20NO5: 282.3118;
found: 282.3112.
1H NMR (300 MHz, CDCl3): d = 7.22 (dd, J = 4.9, 3.0 Hz, 1 H, CH
Ar), 7.18–7.72 (m, 1 H, CH Ar), 7.02 (dd, J = 4.90, 1.13 Hz, 1 H,
Anal. Calcd for C14H16O5: C, 63.6; H, 6.10. Found: C, 62.8; H, 6.01.
Synthesis 2009, No. 4, 627–635 © Thieme Stuttgart · New York

PAPER
a-Substituted tert-Butyl Acrylates from Meldrum’s Acid and Aldehydes
631
5-(1,3-Benzodioxol-4-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3g)
Cream solid; yield: 73%; mp 127–128 °C (EtOAc).
5-(3-Chloro-4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3k)
Cream solid; yield: 63%; mp 142 °C (EtOAc).
IR (KBr): 1755, 1725 (C=O), 1276 (O–C–O) cm–1.
IR (KBr): 2837 (C–O–CH3), 1784, 1741 (C=O), 7584 (C–Cl) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.81 (d, J = 2.3 Hz, 1 H, Ar), 6.77
(d, J = 6.8 Hz, 1 H, Ar), 6.72 (dd, J = 6.8 Hz, 1 H, 2.3 Hz, Ar), 5.93
(s, 2 H, OCH2O), 3.99 (t, J = 5.7 Hz, 1 H, CH), 3.42 (d, J = 5.7 Hz,
2 H, CH2), 1.80 (s, 3 H, CCH3), 1.72 (s, 3 H, CCH3).
1H NMR (300 MHz, CDCl3): d = 7.35 (s, 1 H, CH Ar), 7.21 (d, J =
8.3 Hz, 1 H, CH Ar), 6.84 (d, J = 8.3 Hz, 1 H, CH Ar), 3.87 (s, 3 H,
OCH3), 3.71 (t, J = 4.9 Hz, 1 H, CH), 3.40 (d, J = 4.9 Hz, 2 H, CH2),
1.75 (s, 3 H, CCH3), 1.58 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 147.5, 145.6, 123.6, 122.2,
119.4, 107.8, 105.4, 101.0, 46.4, 29.0, 27.0, 26.7.
13C NMR (75.5 MHz, CDCl3): d = 165.0, 154.1, 131.5, 130.1,
129.3, 122.2, 111.9, 105.2, 56.1, 48.1, 30.8, 28.4, 27.1.
ESI-HRMS: m/z [M + Na+] calcd for C14H14O6Na1: 301.0688;
ESI-HRMS: m/z [M + Na+] calcd for C14H15Cl1O5Na1: 321.0506;
found: 301.0671.
found: 321.0503.
Anal. Calcd for C14H12O6: C, 60.9; H, 4.40. Found: C, 59.9; H, 4.30.
Anal. Calcd for C14H15Cl1O5: C, 56.3; H, 5.06. Found: C, 56.0; H,
4.94.
5-(1,3-Benzodioxol-5-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3h)
Cream solid; yield: 76%; mp 114–116 °C (EtOAc).
5-(4-Fluorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3l)18
White solid; yield: 97%; mp 107–110 °C (EtOAc).
IR (KBr): 1772, 1751 (C=O), 1256 (O–C–O) cm–1.
IR (KBr): 3014, 2954, 2893 (C–H), 1786, 1744 (C=O), 1514 (C–F)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.27 (m, 2 H, CH Ar), 6.97
(t, J = 8.7 Hz, 2 H, CH Ar), 3.73 (t, J = 4.9 Hz, 1 H, CH), 3.46 (d,
J = 4.9 Hz, 2 H, CH2), 1.79 (s, 3 H, CCH3), 1.74 (s, 3 H, CCH3).
1H NMR (300 MHz, CDCl3): d = 8.31 (s, 1 H, CH Ar), 8.06 (d, J =
1.9 Hz, 1 H, CH Ar), 7.54 (dd, J = 8.3, 1.9 Hz, 1 H, CH Ar), 6.09 (s,
2 H, OCH2O), 4.12 (t, J = 6.1 Hz, 1 H, CH), 3.40 (d, J = 6.1 Hz, 2
H, CH2), 1.76 (s, 3 H, CCH3), 1.71 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 164.3, 160.7, 153.6, 148.7,
13C NMR (75.5 MHz, CDCl3): d = 173.9, 165.1, 163.5, 160.3,
132.6, 132.6, 131.5, 131.4, 130.2, 115.4, 115.3, 115.1, 105.2, 48.0,
31.1, 28.3, 27.1.
134.6, 126.8, 111.7, 108.9, 104.7, 102.8, 54.1, 32.7.
HRMS (EI/CI): m/z [M + Na+] calcd for C14H12O6Na1: 301.0688;
found: 301.0692.
ESI-HRMS: m/z [M + Na+] calcd for C13H13F1O6 Na1: 275.0696;
found: 275.0690
Anal. Calcd for C14H12O6: C, 60.9; H, 4.40. Found: C, 60.2; H, 4.37.
Anal. Calcd for C13H13F1O4: C, 61.9; H, 5.19; found: C, 61.8; H,
5.16.
2,2-Dimethyl-5-(2,3,4-trimethoxybenzyl)-1,3-dioxane-4,6-di-
one (3i)
Cream solid; yield: 79%; mp 91–94 °C (EtOAc).
IR (KBr): 2895, 2845, 2828 (C–O–CH3), 1775, 1742 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.02 (d, J = 8.7 Hz, 1 H, CH Ar),
6.61 (d, J = 8.7 Hz, 1 H, CH Ar), 4.03 (t, J = 5.7 Hz, 1 H, CH), 3.91
(s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.31 (d,
J = 5.7 Hz, 2 H, CCH2), 1.77 (s, 3 H, CH3), 1.71 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.2, 152.9, 151.6, 141.8,
125.4, 123.4, 107.0, 104.8, 60.7, 60.6, 55.8, 47.0, 28.5, 27.2, 26.4.
HRMS (EI): m/z [M + Na+] calcd for C16H20O7Na: 347.1107; found:
347.1100.
5-(2,6-Difluorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(3m)
White solid; yield: 98%; mp 125–127 °C (EtOAc).
IR (KBr): 3004, 2954, 2909 (C–H), 1782, 1748 (C=O), 1625, 1593
(C–F) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26–7.14 (m, 1 H, Ar), 6.97 (t,
J = 8.3 Hz, 2 H, CH Ar), 3.98 (t, J = 6.9 Hz, 1 H, CH), 3.43 (d, J =
6.9 Hz, 2 H, CH2), 1.81 (s, 3 H, CCH3), 1.77 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 164.4, 163.0, 159.7, 128.5,
113.4, 111.4, 111.1, 105.1, 45,1, 28.5, 26.4, 19.8.
+
HRMS (EI/CI): m/z [M + NH4 ] calcd for C13H16F2O4N: 288.1047;
Anal. Calcd for C16H20O7: C, 59.3; H, 6.22. Found: C, 58.8; H, 6.17.
found: 288.1042.
5-(2-Fluoro-4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3j)
Anal. Calcd for C13H12F2O4: C, 57.8; H, 4.48; found: C, 57.9; H,
4.45.
Cream solid; yield: 82%; mp 128–130 °C (EtOAc).
5-[4-(Methylsulfanyl)benzyl]-2,2-dimethyl-1,3-dioxane-4,6-di-
one (3n)
Cream solid; yield: 89%; mp 96–98 °C (EtOAc).
IR (KBr): 2840 (C–O–CH3), 1786, 1744 (C=O), 1514 (C–F) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.23 (t, J = 8.67 Hz, 1 H, CH Ar),
6.59 (dd, J = 8.67, 2.64 Hz, 1 H, CH Ar), 6.53 (dd, J = 12.1, 2.64
Hz, 1 H, CH Ar), 3.72 (t, J = 6.03 Hz, 1 H, CH), 3.71 (s, 3 H, OCH3),
3.32 (d, J = 6.03 Hz, 2 H, CH2), 1.72 (s, 3 H, CCH3), 1.64 (s, 3 H,
CCH3).
13C NMR (75.5 MHz, CDCl3): d = 164.9, 163.1, 160.1, 159.9,
159.8, 132.3, 132.2, 116.2, 109.8, 109.8, 105.1, 101.7, 101.4, 55.5,
46.9, 46.9, 28.6, 26.6, 25.2, 25.2.
IR (KBr): 2996, 2945, 2897, 2875 (C–H), 1789, 1747 (C=O), 1498
(S–CH3) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25 (d, J = 6.4 Hz, 2 H, CH Ar),
7.17 (d, J = 6.4 Hz, 2 H, CH Ar), 3.73 (t, J = 4.9 Hz, 1 H, CH), 3.44
(s, 3 H, SCH3), 3.44 (d, J = 4.9 Hz, 2 H, CH2), 1.73 (s, 3 H, CCH3),
1.54 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.1, 137.3, 133.8, 130.3,
126.7, 105.1, 48.1, 31.5, 28.4, 27.2, 15.8.
HRMS (CI): m/z [M + Na+] calcd for C14H16O4Na1S: 303.0662;
found: 303.0651.
ESI-HRMS: m/z [M + Na+] calcd for C14H15O5F1Na1: 305.0801;
found: 305.0810.
Anal. Calcd for C16H20O7: C, 59.6; H, 5.36. Found: C, 59.1; H, 5.32.
Anal. Calcd for C14H16O4S: C, 59.9; H, 5.75; found: C, 59.9; H,
5.72%
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632
C. G. Frost et al.
PAPER
2,2-Dimethyl-5-(4-methylbenzyl)-1,3-dioxane-4,6-dione (3o)19
White solid; yield: 95%; mp 110–112 °C (EtOAc) (Lit.19 112–
113 °C).
tert-Butyl 2-(2-Thienylmethyl)acrylate (4a)
Acrylate 4a was prepared by the general procedure described
above, from Meldrum’s acid derivative 3a (0.50 g, 2.08 mmol) and
6 (1.24 g, 6.69 mmol).
IR (KBr): 3004, 2942, 2896 (C–H), 1786, 1751 (C=O) cm–1.
Colourless oil; yield: 0.43 g (92%); Rf = 0.55 (petrol–CH2Cl2, 2:1).
IR (neat): 2979, 2931 (C=CH2), 1711 (C=O), 1368 (C–S) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.0 (dd, J = 5.3, 1.1 Hz, 1 H, Ar),
7.0 (dd, J = 3.4, 5.3 Hz, 1 H, Ar), 6.82 (dd, J = 3.4, 1.1 Hz, 1 H, Ar),
6.16 (s, 1 H, CHH), 5.50 (s, 1 H, CHH), 3.79 (s, 2 H, CH2), 1.47 [s,
9 H, C(CH3)3].
1H NMR (300 MHz, CDCl3): d = 7.19 (d, J = 7.9 Hz, 2 H, CH Ar),
7.08 (d, J = 7.9 Hz, 2 H, CH Ar), 3.78 (t, J = 4.9 Hz, 1 H, CH), 3.60
(d, J = 4.9 Hz, 2 H, CH2), 2.29 (s, 3 H, CH3), 1.72 (s, 3 H, CCH3),
1.50 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.2, 162.8, 136.5, 134.0,
129.4, 129.0, 106.0, 105.0, 47.9, 35.9, 31.4, 28.2, 27.3, 26.9, 20.8.
13C NMR (75.5 MHz, CDCl3): d = 165.8, 141.6, 141.1, 126.8,
5-(2,6-Dimethylbenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(3p)
White solid; yield: 92%; mp 112–115 °C (EtOAc).
IR (KBr): 3000, 2960, 2867 (C–H), 1776, 1739 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.13–7.01 (m, 3 H, CH Ar), 3.70
(t, J = 6.0 Hz, 1 H, CH), 3.50 (d, J = 6.0 Hz, 2 H, CH2), 2.42 (s, 6
H, CH3), 1.79 (s, 3 H, CCH3), 1.77 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.0, 137.0, 134.9, 128.6,
126.8, 104.9, 47.0, 28.7, 26.6, 26.4, 20.2.
125.5, 126.8, 123.8, 80.9, 32.3, 28.8, 28.0.
+
MS (EI/CI): m/z (%) = 242 (25) [M + NH4 ], 225 (25) [M + H+], 186
+
(50) [C8H7O2S + NH4 ].
HRMS (CI): m/z [M + H+] calcd for C12H17O2S: 225.0944; found:
225.0943.
tert-Butyl 2-2-(4-Hydroxy-3-methoxybenzyl)acrylate (4b)
Acrylate 4b was prepared by the general procedure described
above, from Meldrum’s acid derivative 3b (0.50 g, 1.79 mmol) and
6 (0.875 g, 4.73 mmol).
HRMS (CI): m/z [M + Na+] calcd for C15H18O4Na1: 285.1097;
found: 285.1091.
White semisolid; yield: 0.27 g (57%); Rf = 0.20 (petrol–CH2Cl2,
2:1); mp 41–43 °C (hexanes).
IR (neat): 2979 (C=CH2), 1711 (C=O), 1493 (O–CH3) cm–1.
Anal. Calcd for C15H18O4: C, 68.6; H, 6.92; found: C, 68.4; H,
6.88%
1H NMR (300 MHz, CDCl3): d = 6.84 (dd, J = 7.2, 1.1 Hz, 1 H, CH
Ar), 6.70 (s, 1 H, CH Ar), 6.68 (dd, J = 7.2, 1.9 Hz, 1 H, CH Ar),
6.12 (dd, J = 1.5, 0.75 Hz, 1 H, C=CH2), 5.37 (dd, J = 3.0, 1.5 Hz,
1 H, C=CH2), 3.85 (s, 3 H, OCH3), 3.53 (s, 2 H, CH2), 1.46 [s, 9 H,
C(CH3)3].
2,2-Dimethyl-5-(1-naphthylmethyl)-1,3-dioxane-4,6-dione
(3q)20
Cream solid; yield: 97%; mp 135–137 °C (EtOAc).
IR (KBr): 3057, 3000, 2869 (C–H), 1781, 1750 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08 (d, J = 8.3 Hz, 1 H, CH Ar),
7.90 (d, J = 8.3 Hz, 1 H, CH Ar), 7.79 (d, J = 8.3 Hz, 1 H, CH Ar),
7.65 (d, J = 7.2 Hz, 1 H, CH Ar), 7.61–7.47 (m, 2 H, CH Ar), 7.44
(t, J = 7.2 Hz, 1 H, CH Ar), 3.93 (d, J = 5.3 Hz, 2 H, CH2), 3.81 (t,
J = 5.3 Hz, 1 H, CH), 1.70 (s, 3 H, CCH3), 1.69 (s, 3 H, CCH3).
13C NMR (75.5 MHz, CDCl3): d = 165.3, 134.0, 133.9, 131.2,
129.2, 128.4, 127.8, 126.7, 125.7, 125.5, 122.7, 105.1, 47.7, 28.7,
28.6, 26.4.
13C NMR (75.5 MHz, CDCl3): d = 166.2, 146.3, 143.9, 142.0,
130.8, 124.7, 121.6, 114.1, 111.4, 80.6, 55.7, 37.7, 27.9.
+
MS (EI/CI): m/z (%) = 282 (35) [M + NH4 ], 264 (15) [M + H+], 208
+
(50) [C11H12O4 + NH4 ].
ESI-HRMS: m/z [M + Na+] calcd for C15H20O4Na1: 287.1259;
found: 287.1258
tert-Butyl 2-(3-Thienylmethyl)acrylate (4c)
Acrylate 4c was prepared by the general procedure described above,
from Meldrum’s acid derivative 3c (0.50 g, 2.08 mmol) and 6 (1.24
g, 6.69 mmol).
5-Isobutyl-2,2-dimethyl-1,3-dioxane-4,6-dione (3r)20
White solid; yield: 92%; mp 119–120 °C (EtOAc) (Lit.20 120 °C).
IR (KBr): 3003, 2893, 2861 (C–H), 1797, 1748 (C=O) cm–1.
Colourless oil; yield: 0.41 g (82%); Rf = 0.55 (petrol–CH2Cl2, 2:1).
IR (neat): 2976, 2934 (C=CH2), 1709 (C=O), 1366 (C–S) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.23 (dd, J = 5.0, 3.0 Hz, 1 H, Ar),
6.97 (s, 1 H, Ar), 6.91 (dd, J = 5.0, 1.1 Hz, 1 H, Ar), 6.12 (s, 1 H,
CHH), 5.39 (s, 1 H, CHH), 3.60 (s, 2 H, CH2), 1.44 [s, 9 H,
C(CH3)3].
1H NMR (300 MHz, CDCl3): d = 3.43 (t, J = 5.7 Hz, 1 H, CH), 1.8–
2.15 [m, 3 H, CH(CH3)2, CH2 overlap], 1.77 (s, 3 H, CH3), 1.72 (s,
3 H, CH3), 0.85 [d, J = 6.0 Hz, 6 H, CH(CH3)2].
13C NMR (75.5 MHz, CDCl3): d = d 165.9, 104.8, 44.1, 35.2, 28.5,
26.7, 25.8, 22.0.
13C NMR (75.5 MHz, CDCl3): d = 166.1, 141.2, 139.3, 128.4,
a-Substituted tert-Butyl Acrylates 4a–r from 5-Monosubstitut-
ed Meldrum’s Acid Derivatives 3a–r; General Procedure
An oven-dried 50-mL round-bottomed flask was charged under N2
with the appropriate 3 (2.08 mmol) and 6 (1.00 g, 5.41 mmol). The
solids were dissolved in THF (12 mL) and anhyd t-BuOH (12 mL).
The reaction mixture was then heated to 70 °C and stirred at that
temperature for 18 h. Upon cooling of the mixture to r.t., the solvent
was removed in vacuo, and the yellow residue was taken up in Et2O
(25 mL), extracted with a sat. NaHCO3 soln (20 mL), 10% aq
KHSO4 (20 mL), and a sat. NaCl soln (20 mL), and dried (MgSO4).
The solvent was removed in vacuo and the resulting oils were puri-
fied by flash column chromatography [silica gel, petrol (40–60)
CH2Cl2, 2:1]; this gave the corresponding product 4.
125.2, 124.7, 121.4, 80.6, 65.7, 32.6, 15.2, 27.9.
+
MS (EI/CI): m/z (%) = 242 (20) [M + NH4 ], 225 (20) [M + H+], 186
+
(60) [C8H7O2S + NH4 ].
HRMS (CI): m/z [M + H+] calcd for C12H17O2S: 225.0944; found:
225.0943.
tert-Butyl 2-[(3-Methyl-2-thienyl)methyl]acrylate (4d)
Acrylate 4d was prepared by the general procedure described
above, from Meldrum’s acid derivative 3d (0.50 g, 1.97 mmol) and
6 (1.05 g, 5.91 mmol).
Colourless oil; yield: 0.38 g (78%); Rf = 0.5 (petrol–CH2Cl2, 2:1).
IR (neat): 2977, 2929 (C=CH2), 1712 (C=O), 1392 (C–S) cm–1.
Synthesis 2009, No. 4, 627–635 © Thieme Stuttgart · New York

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a-Substituted tert-Butyl Acrylates from Meldrum’s Acid and Aldehydes
633
1H NMR (300 MHz, CDCl3): d = 7.06 (d, J = 4.9 Hz, 1 H, Ar), 6.81
(d, J = 4.9 Hz, 1 H, Ar), 6.15 (s, 1 H, CHH), 5.33 (s, 1 H, CHH),
3.69 (s, 3 H, CH2), 2.14 (s, 3 H, CH3), 1.50 [s, 9 H, C(CH3)3].
ESI-HRMS: m/z [M + Na+] calcd for C15H18O4Na1: 285.1103;
found: 285.1101
tert-Butyl 2-(1,3-Benzodioxol-5-ylmethyl)acrylate (4h)
Acrylate 4h was prepared by the general procedure described
above, from Meldrum’s acid derivative 3h (0.51 g, 1.83 mmol) and
6 (0.961 g, 5.20 mmol).
13C NMR (75.5 MHz, CDCl3): d = 165.8, 140.4, 134.1, 133.9,
129.9, 124.8, 122.0, 80.8, 29.8, 27.9, 13.5, 53.3.
+
MS (EI/CI): m/z (%) = 256 (10) [M + NH4 ], 239 (20) [M + H+], 200
+
(80) [C9H10O2S + NH4 ].
Colourless oil; yield: 0.41 g (87%); Rf = 0.35 (petrol–CH2Cl2, 1:1).
IR (neat): 1708 (C=O), 1251 (O–C–O) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.74 (dd, J = 15.1, 7.5 Hz, 1 H,
CH Ar), 6.70 (dd, J = 7.5, 1.5 Hz, 1 H, CH Ar), 6.66 (dd, J = 7.5,
1.5 Hz, 1 H, CH Ar), 6.16 (dd, J = 2.6, 1.1 Hz, 1 H, C=CH2), 5.91
(s, 2 H, OCH2O), 5.39 (dd, J = 2.6, 1.1 Hz, 1 H, C=CH2), 3.56 (s, 2
H, CH2), 1.46 [s, 9 H, C(CH3)3].
HRMS (CI): m/z [M + H+] calcd for C13H18O2S: 239.1100; found:
239.1099
tert-Butyl 2-(4-Methoxybenzyl)acrylate (4e)
Acrylate 4e was prepared by the general procedure described above,
from Meldrum’s acid derivative 3e (0.50 g, 1.89 mmol) and 6 (1.05
g, 5.68 mmol).
Colourless oil; yield: 0.45 g (95%); Rf = 0.35 (petrol–CH2Cl2, 2:1).
IR (neat): 2979 (C=CH2), 1710 (C=O), 1512 (O–CH3) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.10 (d, J = 6.8 Hz, 2 H, CH Ar),
6.82 (d, J = 6.8 Hz, 2 H, CH Ar), 6.11 (dd, J = 1.5, 0.75 Hz, 1 H,
C=CH2), 5.40 (dd, J = 3.4, 1.5 Hz, 1 H, C=CH2), 3.79 (s, 3 H,
OCH3), 3.53 (s, 2 H, CH2), 1.44 [s, 9 H, C(CH3)3].
13C NMR (75.5 MHz, CDCl3): d = 165.9, 147.0, 145.5, 139.8,
125.0, 122.8, 121.2, 120.4, 106.7, 100.4, 80.5, 31.4, 27.9.
MS (EI/CI): m/z (%) = 280 (15) [M + NH4 ], 262 (25) [M + H+], 224
+
+
(60) [C11H10O4 + NH4 ].
ESI-HRMS: m/z [M + Na+] calcd for C15H18O4Na1: 285.1103;
found: 285.1091
13C NMR (75.5 MHz, CDCl3): d = 158.0, 142.1, 131.1, 129.9,
tert-Butyl 2-(2,3,4-Trimethoxybenzyl)acrylate (4i)
Acrylate 4i was prepared by the general procedure described above,
from Meldrum’s acid derivative 3i (0.50 g, 1.54 mmol) and 6 (0.856
g, 4.62 mmol).
124.8, 113.7, 80.6, 55.2, 37.3, 28.0.
MS (EI/CI): m/z (%) = 282 (30) [M + NH4 ], 266 (80) [M + H+], 210
+
+
(50) [C11H12O3 + NH4 ].
+
HRMS (CI): m/z [M + NH4 ] calcd for C15H24O3N: 266.1751;
Yellow oil; yield: 0.42 g (88%); Rf = 0.3 (CH2Cl2).
found: 266.1750.
IR (neat): 2976, 2937 (C=CH2), 1712 (C=O) 1627, 1618 (O–CH3)
cm–1.
tert-Butyl 2-(2-Methoxybenzyl)acrylate (4f)
Acrylate 4f was prepared by the general procedure described above,
from Meldrum’s acid derivative 3f (0.50 g, 1.89 mmol) and 6 (0.875
g, 4.73 mmol).
1H NMR (300 MHz, CDCl3): d = 6.80 (d, J = 8.7 Hz, 1 H, CH Ar),
6.60 (H, d, J = 8.7 Hz, CH Ar), 6.14 (dd, J = 2.6, 1.1 Hz, 1 H,
C=CH2), 5.38 (dd, J = 3.4, 1.5 Hz, 1 H, C=CH2), 3.86 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.53 (s, 2 H, CH2),
1.46 [s, 9 H, C(CH3)3].
13C NMR (75.5 MHz, CDCl3): d = 166.3, 152.3, 151.9, 142.2,
141.6, 125.0, 124.5, 124.4, 107.0, 80.5, 60.8, 60.6, 55.9, 31.6, 28.7,
28.0.
Colourless oil; yield: 0.43 g (94%); Rf = 0.35 (petrol–CH2Cl2, 2:1).
IR (neat): 2979 (C=CH2), 1711 (C=O), 1493 (O–CH3) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.21 (td, J = 7.9, 1.5 Hz, 1 H, CH
Ar), 7.12 (dd, J = 7.5, 1.5 Hz, 1 H, CH Ar), 6.89 (td, J = 7.5, 1.1 Hz,
1 H, CH Ar), 6.86 (d, J = 7.9 Hz, 1 H, CH Ar), 6.10 (dd, J = 2.6, 1.1
Hz, 1 H, C=CH2), 5.26 (dd, J = 3.4, 1.5 Hz, 1 H, C=CH2), 3.80 (s, 3
H, OCH3), 3.59 (s, 2 H, CH2), 1.47 [s, 9 H, C(CH3)3].
+
MS (EI/CI): m/z (%) = 326 (10) [M + NH4 ], 309 (10) [M + H+], 210
+
(80) [C13H16O5 + NH4 ].
HRMS (CI): m/z [M + H+] calcd for C17H25O3N: 309.1697; found:
309.1698.
13C NMR (75.5 MHz, CDCl3): d = 208.5, 192.0, 181.5, 178.6,
175.6, 171.4, 161.4, 131.5, 106.4, 82.9, 79.0.
+
MS (EI/CI): m/z (%) = 282 (10) [M + NH4 ], 266 (80) [M + H+], 210
(50) [C11H12O3 + NH4 ].
tert-Butyl 2-(2-Fluoro-4-methoxybenzyl)acrylate (4j)
Acrylate 4j was prepared by the general procedure described above,
from Meldrum’s acid derivative 3j (0.50 g, 1.77 mmol) and 6 (0.875
g, 4.73 mmol).
+
+
HRMS (CI): m/z [M + NH4 ] calcd for C15H24O3N: 266.1751;
found: 266.1749.
Pale yellow oil; yield: 0.39 g (83%); Rf = 0.35 (petrol–CH2Cl2, 2:1).
tert-Butyl 2-(1,3-Benzodioxol-4-ylmethyl)acrylate (4g)
Acrylate 4g was prepared by the general procedure described
above, from Meldrum’s acid derivative 3g (0.51 g, 1.83 mmol) and
6 (0.961 g, 5.20 mmol).
IR (neat): 2978 (C=CH2), 1708 (C=O), 1627 (O–CH3), 1509 (C–F)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.06 (t, J = 8.7 Hz, 1 H, CH Ar),
6.60 (dd, J = 8.7, 2.6 Hz, 1 H, CH Ar), 6.51 (s, 1 H, CH Ar), 6.12
(dd, J = 2.6, 1.1 Hz, 1 H, C=CH2), 5.32 (dd, J = 1.5, 0.74 Hz, 1 H,
C=CH2), 3.76 (s, 3 H, OCH3), 3.53 (s, 2 H, CH2), 1.45 [s, 9 H,
C(CH3)3].
13C NMR (75.5 MHz, CDCl3): d = 165.9, 163.0, 159.5, 159.4,
140.4, 131.3, 131.2, 124.8, 117.5, 109.5, 101.5, 80.6, 55.3, 30.3,
27.9.
Colourless oil; yield: 0.43 g (90%); Rf = 0.35 (petrol–CH2Cl2, 1:1).
IR (neat): 1712 (C=O), 1247 (O–C–O) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.81 (s, 1 H, CH Ar), 6.72 (dd, J =
7.5, 1.9 Hz, 1 H, CH Ar), 6.61 (dd, J = 8.3, 1.9 Hz, 1 H, CH Ar),
6.19 (dd, J = 2.6, 1.1 Hz, 1 H, C=CH2), 5.87 (s, 2 H, OCH2O), 5.43
(dd, J = 2.6, 1.1 Hz, 1 H, C=CH2), 3.54 (s, 2 H, CH2), 1.45 [s, 9 H,
C(CH3)3].
+
MS (EI/CI): m/z (%) = 284 (10) [M + NH4 ], 266 (20) [M + H+], 228
13C NMR (75.5 MHz, CDCl3): d = 165.9, 148.7, 145.8, 139.8, 130.8
125.0, 122.4, 120.4, 115.2, 114.1 106.7, 100.4, 80.5, 31.4, 27.9.
+
(70) [C11H11F1O3 + NH4 ].
ESI-HRMS: m/z [M + Na+] calcd for C15H19O3F1Na1: 289.1216;
found: 289.1204
+
MS (EI/CI): m/z (%) = 280 (15) [M + NH4 ], 262 (25) [M + H+], 224
+
(60) [C11H10O4 + NH4 ].
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C. G. Frost et al.
PAPER
tert-Butyl 2-(3-Chloro-4-methoxybenzyl)acrylate (4k)
Acrylate 4k was prepared by the general procedure described
above, from Meldrum’s acid derivative 3k (0.50 g, 1.67 mmol) and
6 (0.875 g, 4.73 mmol).
1H NMR (300 MHz, CDCl3): d = 7.20 (d, J = 8.3 Hz, 2 H, CH Ar),
6.11 (d, J = 8.3 Hz, 2 H, CH Ar), 6.14 (d, J = 1.5, 0.75 Hz, 1 H,
C=CH2), 5.38 (dd, J = 3.0, 1.5 Hz, 1 H, C=CH2), 3.53 (s, 2 H, CH2),
2.46 (s, 3 H, SCH3), 1.42 [s, 9 H, C(CH3)3].
Yellow oil; yield: 0.43 g (91%); Rf = 0.30 (petrol–CH2Cl2, 2:1).
13C NMR (75.5 MHz, CDCl3): d = 141.5, 135.8, 129.4, 126.9,
125.1, 80.6, 53.3, 37.6, 27.9, 16.1.
IR (neat): 2979 (C=CH2), 1711 (C=O), 1590 (O–CH3) 756 (C–Cl)
cm–1.
+
MS (EI/CI): m/z (%) = 282 (10) [M + NH4 ], 265 (80) [M + H+], 226
+
(50) [C11H12O2S + NH4 ].
1H NMR (300 MHz, CDCl3): d = 7.17 (d, J = 2.3 Hz, 1 H, CH Ar),
7.02 (dd, J = 8.3, 2.3 Hz, 1 H, CH Ar), 6.82 (d, J = 8.3 Hz, 1 H, CH
Ar), 6.12 (dd, J = 1.5, 0.75 Hz, 1 H, C=CH2), 5.37 (dd, J = 3.0, 1.5
Hz, 1 H, C=CH2), 3.84 (s, 3 H, OCH3), 3.48 (s, 2 H, CH2), 1.42 [s,
9 H, C(CH3)3].
HRMS (EI/CI): m/z [M + H+] calcd for C15H20O2S: 265.1257;
found: 265.1255
tert-Butyl 2-(4-Methylbenzyl)acrylate (4o)
Acrylate 4o was prepared by the general procedure described
above, from Meldrum’s acid derivative 3o (0.50 g, 2.01 mmol) and
6 (1.08 g, 6.04 mmol).
13C NMR (75.5 MHz, CDCl3): d = 165.8, 153.3, 141.3, 132.1,
130.5, 128.0, 125.1, 121.9, 111.8, 80.6, 55.9, 37.0, 27.8.
+
MS (EI/CI): m/z (%) = 300 (10) [M + NH4 ], 282 (10) [M + H+], 244
Colourless oil; yield: 0.38 g (82%); Rf = 0.65 (petrol–CH2Cl2, 2:1).
IR (neat): 2971, 2964 (C=CH2), 1704.1 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.15–7.06 (m, 4 H, Ar), 6.13 (dd,
J = 1.5, 0.75 Hz, 1 H, C=CH2), 5.36 (dd, J = 3.0, 1.5 Hz, 1 H,
C=CH2), 3.56 (s, 2 H, CH2), 2.33 (s, 3 H, CH3), 1.45 [s, 9 H,
C(CH3)3].
+
(80) [C11H11Cl1O3 + NH4 ].
ESI-HRMS: m/z [M + Na+] calcd for C15H19Cl1O3Na1: 305.0920;
found: 305.0919
tert-Butyl 2-(4-Fluorobenzyl)acrylate (4l)
Acrylate 4l was prepared by the general procedure described above,
from Meldrum’s acid derivative 3l (0.52 g, 2.20 mmol) and 6 (0.925
g, 5.00 mmol).
13C NMR (75.5 MHz, CDCl3): d = 166.2, 141.9, 135.9, 135.5,
128.9, 128.8, 124.9, 80.5, 37.6, 27.9, 20.9.
Colourless oil; yield: 0.46 g (84%); Rf = 0.55 (petrol–CH2Cl2, 2:1).
IR (neat): 2983, 3052 (C=CH2), 1712 (C=O), 1510 (C–F) cm–1.
+
MS (EI/CI): m/z (%) = 250 (32) [M + NH4 ], 233 (8) [M + H+], 194
(60) [C11H16O2 + NH4 ].
+
+
1H NMR (300 MHz, CDCl3): d = 7.14 (dd, J = 8.7, 5.7 Hz, 2 H, CH
Ar), 6.97 (t, J = 8.7 Hz, 2 H, CH Ar), 6.14 (dd, J = 1.5, 0.75 Hz, 1
H, C=CH2), 5.37 (dd, J = 3.0, 1.5 Hz, 1 H, C=CH2), 3.56 (s, 2 H,
CH2), 1.35 [s, 9 H, C(CH3)3].
13C NMR (75.5 MHz, CDCl3): d = 165.9, 163.0, 159.8, 141.5,
134.6, 130.3, 130.2, 125.2, 115.1, 114.9, 80.7, 37.4, 27.9.
HRMS (CI): m/z [M + NH4 ] calcd for C15H24O2N: 250.1807;
found: 250.1802.
tert-Butyl 2-(2,6-Dimethylbenzyl)acrylate (4p)
Acrylate 4p was prepared by the general procedure described
above, from Meldrum’s acid derivative 3p (0.50 g, 1.91 mmol) and
6 (1.06 g, 5.72 mmol).
+
MS (EI/CI): m/z (%) = 254 (34) [M + NH4 ], 237 (15) [M + H+], 198
Colourless oil; yield: 0.40 g (85%); Rf = 0.5 (petrol–CH2Cl2, 3:1).
IR (neat): 2978, 2964 (C=CH2), 1708 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d =7.12–7.00 (m, 3 H, Ar), 6.02 (dd,
J = 3.4, 1.9 Hz, 1 H, C=CH2), 4.85 (dd, J = 3.8, 1.9 Hz, 1 H,
C=CH2), 3.59 (s, 2 H, CH2), 2.33 (s, 6 H, CH3), 1.56 [s, 9 H,
C(CH3)3].
+
(50) [C10H9F1O2 + NH4 ].
+
HRMS (CI): m/z [M + NH4 ] calcd for C14H21O2F1N: 254.1551;
found: 254.1551
tert-Butyl 2-(2,6-Difluorobenzyl)acrylate (4m)
Acrylate 4m was prepared by the general procedure described
above, from Meldrum’s acid derivative 3m (0.52 g, 2.20 mmol) and
6 (0.925 g, 5.00 mmol).
13C NMR (75.5 MHz, CDCl3): d = 166.5, 139.3, 137.0, 135.4,
127.9, 126.3, 123.0, 80.7, 31.1, 28.0, 19.7.
Colourless oil; yield: 0.46 g (84%); Rf = 0.6 (petrol–CH2Cl2, 2:1).
+
MS (EI/CI): m/z (%) = 264 (25) [M + NH4 ], 247 (5) [M + H+], 208
(70) [C12H14O2 + NH4 ].
+
IR (neat): 2980, 2934 (C=CH2), 1712 (C=O), 1594, 1470 (C–F)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26–7.14 (m, 1 H, Ar), 6.97 (t,
J = 7.6 Hz, 2 H, CH Ar), 6.12 (d, J = 1.1 Hz, 1 H, C=CH2), 5.19 (d,
J = 0.75 Hz, 1 H, C=CH2), 3.64 (s, 2 H, CH2), 1.49 [s, 9 H,
C(CH3)3].
+
HRMS (CI): m/z [M + NH4 ] calcd for C16H26O2N: 264.1958;
found: 264.1959.
tert-Butyl 2-(1-Naphthylmethyl)acrylate (4q)
Acrylate 4q was prepared by the general procedure described
above, from Meldrum’s acid derivative 3q (0.50 g, 1.76 mmol) and
6 (0.875 g, 4.73 mmol).
13C NMR (75.5 MHz, CDCl3): d = 165.7, 163.2, 159.9, 138.8,
128.3, 124.3, 114.8, 111.0, 80.9, 27.9, 24.5.
Orange oil; yield: 0.43 g (92%); Rf = 0.55 (petrol–CH2Cl2, 3:1).
IR (neat): 2978 (C=CH2), 1711 (C=O) cm–1.
+
MS (EI/CI): m/z (%) = 272 (30) [M + NH4 ], 255 (10) [M + H+], 216
(60) [C10H8F2O2 + NH4 ].
+
+
HRMS (CI): m/z calcd for C14H20O2F2N [M + NH4 ]: 272.1457;
found: 272.1459.
1H NMR (300 MHz, CDCl3): d = 7.96–7.89 (m, 1 H, CH Ar), 7.89–
7.83 (m, 1 H, CH Ar), 7.77 (d, J = 8.3 Hz, 1 H, CH Ar), 7.53–7.44
(m, 2 H, CH Ar), 7.42 (d, J = 8.3 Hz, 1 H, CH Ar), 7.34 (d, J = 7.2
Hz, 1 H, CH Ar), 6.14 (dd, J = 2.6, 1.5 Hz, 1 H, C=CH2), 5.10 (dd,
J = 3.0, 1.5 Hz, 1 H, C=CH2), 4.06 (s, 2 H, CH2), 1.51 [s, 9 H,
C(CH3)3].
13C NMR (75.5 MHz, CDCl3): d = 166.4, 140.9, 135.0, 133.8,
131.9, 129.1, 128.6, 127.3, 127.2, 125.8, 125.5, 125.4, 125.2, 124.2,
124.2, 80.8, 34.7, 28.0.
tert-Butyl 2-[4-(Methylsulfanyl)benzyl]acrylate (4n)
Acrylate 4n was prepared by the general procedure described
above, from Meldrum’s acid derivative 3n (0.50 g, 1.78 mmol) and
6 (1.01 g, 5.35 mmol).
Yellow oil; yield: 0.46 g (98%); Rf = 0.4 (petrol–CH2Cl2, 2:1).
IR (neat): 2978, 2934 (C=CH2), 1712 (C=O), 1137 (C–S) cm–1.
Synthesis 2009, No. 4, 627–635 © Thieme Stuttgart · New York

PAPER
a-Substituted tert-Butyl Acrylates from Meldrum’s Acid and Aldehydes
635
+
MS (EI/CI): m/z (%) = 286 (12) [M + NH4 ], 269 (3) [M + H+], 230
(75) [C14H12O2 + NH4 ].
(3) Stetter, H.; Kuhlmann, H. Synthesis 1979, 29.
(4) For reviews, see: (a) Basavaiah, D.; Rao, J. A.;
+
Satyanarayana, T. Chem. Rev. 2003, 103, 811. (b) Ciganek,
E. In Organic Reactions, Vol. 51; Paquette, L. A., Ed.;
Wiley: New York, 1997, 201–350. (c) Basavaiah, D.; Rao,
P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(d) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653.
HRMS (CI): m/z calcd for C18H21O2 [M + H+]: 269.1536; found:
269.1538.
tert-Butyl 4-Methyl-2-methylenepentanoate (4r)
Acrylate 4r was prepared by the general procedure described above
from Meldrum’s acid derivative 3r (0.50 g, 1.91 mmol) and 6 (1.06
g, 5.72 mmol).
(5) (a) Samarat, A.; Fargeas, V.; Villieras, J.; Lebreton, J.; Amri,
H. Tetrahedron Lett. 2001, 42, 1273. (b) Le Notre, J.;
van Mele, D.; Frost, C. G. Adv. Synth. Catal. 2007, 349, 432.
(6) Negishi, E.; Tan, Z.; Liou, S. Y.; Liao, B. Q. Tetrahedron
2000, 56, 10197.
(7) (a) Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron Lett.
2003, 44, 8487. (b) Xi, C.; Chen, C.; Lin, J.; Hong, X. Org.
Lett. 2005, 7, 347.
Colourless oil; yield: 0.348 g (98%); Rf = 0.55 (petrol–CH2Cl2, 4:1).
IR (neat): 2959 (C=CH2), 1710 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.05 (d, J = 1.9 Hz, 1 H, C=CH2),
5.39 (dd, J = 1.9, 1.1 Hz, 1 H, C=CH2), 2.13 (dd, J = 6.8, 1.1 Hz, 2
H, CH2), 1.77 [tsept, J = 6.8, 3.4 Hz, 1 H, CH(CH3)2], 1.48 [s, 9 H,
C(CH3)3], 0.88 [d, J = 6.4 Hz, 6 H, CH(CH3)2].
(8) (a) Hin, B.; Majer, P.; Tsukamoto, T. J. Org. Chem. 2002,
67, 7365. (b) Hargrave, J. D.; Bish, G.; Frost, C. G. Chem.
Commun. 2006, 4389.
13C NMR (75.5 MHz, CDCl3): d = 167.2, 141.8, 125.0, 80.7, 41.8,
28.5, 27.8, 22.7.
(9) (a) Sato, M.; Ogasawara, H.; Sekiguchi, K.; Kaneko, C.
Heterocycles 1984, 22, 2563. (b) Sato, M.; Ogasawara, H.;
Kato, T. Chem. Pharm. Bull. 1984, 32, 2602. (c) Sato, M.;
Yoneda, N.; Katagiri, N.; Watanabe, H.; Kaneko, C.
Synthesis 1986, 672. (d) Sato, M.; Ban, H.; Kaneko, C.
Tetrahedron Lett. 1997, 38, 6689. (e) Frost, C. G.; Hartley,
B. C. Org. Lett. 2007, 9, 4259.
(10) Schuster, P.; Polansky, O. E.; Wessely, F. Monatsh. Chem.
1964, 53.
(11) Lu, J.; Li, Y. Y.; Bai, Y. J.; Tian, M. Heterocycles 2004, 63,
583.
+
MS (EI/CI): m/z (%) = 202 (45) [M + NH4 ], 184 (5) [M + H+], 146
(50) [C7H12O2 + NH4 ].
+
+
HRMS (CI): m/z [M + NH4 ] calcd for C11H24O2N: 202.1802;
found: 202.1803.
Acknowledgment
We are grateful to the EPSRC and GlaxoSmithKline Limited
(CASE award to S.D.P.) for funding. Dr Anneke Lubben (Mass
Spectrometry Service at the University of Bath) and the EPSRC
Mass Spectrometry Service at the University of Wales Swansea are
thanked for valuable assistance.
(12) Rao, P. S.; Venkataratnam, R. V. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1993, 32, 484.
(13) Dumas, A. M.; Seed, A.; Zorzitto, A. K.; Fillion, E.
Tetrahedron Lett. 2007, 48, 7072.
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Synthesis 2009, No. 4, 627–635 © Thieme Stuttgart · New York