Facile synthesis of α-substituted acrylate esters

Article abstract of DOI:10.1021/jo026101s

Treatment of 5-monosubstituted Meldrum's acids with dimethylmethyleneimmonium iodide (Eschenmoser's iodide salt) in methanol gives α-substituted acrylate methyl esters in good yields. Easy access to 5-monosubstituted Meldrum's acids allowed us to synthesize a wide variety of α-substituted acrylate methyl esters. The reaction conditions are mild and tolerate many functional groups commonly used in organic synthesis; thus, this new method has potential as an alternative to conventional preparative methods for α-substituted acrylate esters.

Full text of DOI:10.1021/jo026101s

F a cile Syn th esis of r-Su bstitu ted Acr yla te Ester s
Bunda Hin, Pavel Majer, and Takashi Tsukamoto*
Guilford Pharmaceuticals, Inc., 6611 Tributary Street, Baltimore, Maryland 21224
tsukamotot@guilfordpharm.com
Received J une 25, 2002
Treatment of 5-monosubstituted Meldrum’s acids with dimethylmethyleneimmonium iodide
(Eschenmoser’s iodide salt) in methanol gives R-substituted acrylate methyl esters in good yields.
Easy access to 5-monosubstituted Meldrum’s acids allowed us to synthesize a wide variety of
R-substituted acrylate methyl esters. The reaction conditions are mild and tolerate many functional
groups commonly used in organic synthesis; thus, this new method has potential as an alternative
to conventional preparative methods for R-substituted acrylate esters.
SCHEME 1
In tr od u ction
Utility of R-substituted acrylate esters as synthetic
intermediates has been well demonstrated by the 1,4-
addition reaction of various types of nucleophilic reagents
leading to several biologically important compounds. For
example, 1,4-addition reactions of phosphorus-based nu-
cleophiles to R-substituted acrylate esters have been
extensively used in the synthesis of pseudopeptides
including inhibitors of metalloproteases1-3 and ATP-
dependent ligases.4-6 One of the most common methods
for the acrylate synthesis involves a Mannich reaction
of R-monosubstituted malonic acid half esters 3 (Scheme
1).7 Although the reaction generally gives the products
4 in good yields, preparation of the starting materials 3
often suffers from low yield due to difficulties in monoalky-
lation of malonate diesters 1 and/or partial saponification
of the monosubstituted malonate diesters 2. It has been
described, however, that the R-monosubstituted malonic
acid esters 3 can be readily obtained by heating an
alcoholic (phenol,8 methanol,9 ethanol,10,11 benzyl alco-
hol,12,13 or tert-butyl alcohol14) solution of 5-monosubsti-
tuted Meldrum’s acids 5. Recent progress in the practical
synthesis of 5-monosubstituted Meldrum’s acids15-23
should enhance the utility of this alcoholysis reaction as
a new route to R-monosubstituted malonic acid half
esters. Since the alcoholysis of 5-monosubstituted Mel-
drum’s acids 5 proceeds under mild conditions, this
reaction could be combined with the subsequent Mannich
reaction. In this paper, we describe a one-pot procedure
for the preparation of R-substituted acrylate esters from
5-monosubstituted Meldrum’s acids.
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10.1021/jo026101s CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/24/2002
J . Org. Chem. 2002, 67, 7365-7368
7365

Hin et al.
SCHEME 2
SCHEME 4
SCHEME 3
SCHEME 5
Resu lts a n d Discu ssion
5-Monosubstituted Meldrum’s acids, key materials for
this synthetic study, can be readily prepared from Mel-
drum’s acid and carboxylic acids by using a previously
reported method.17 Thus, DCC-mediated coupling of
isophthalic acid monomethylester 6a to Meldrum’s acid
followed by reduction with sodium borohydride afforded
compound 7a in 75% yield (Scheme 2). Using compound
7a as a substrate and methanol as a solvent, we evalu-
ated various different Mannich reaction conditions
(Scheme 3). In most cases (e.g., diethylamine and form-
aldehyde), acrylate methyl ester 8a was obtained as a
For example, Michael addition of benzyl acrylate to
Meldrum’s acid gives 3-(2,2-dimethyl-4,6-dioxo-1,3-di-
oxan-5-yl)propionic acid benzyl ester 7j (Scheme 4). The
compound 7j was subsequently converted into differen-
tially protected 2-methyleneglutarate derivative 8j, which
is not accessible by direct dimerization of acrylate esters.
As an extension to this methodology, we speculated
that we could introduce other ester groups by changing
solvent from methanol to other alcohols. Thus, compound
7a was treated with Eschenmoser’s iodide salt in benzyl
alcohol or tert-butyl alcohol (with THF as a cosolvent).
In both cases, the reactions proceeded smoothly while the
original benzoate methyl ester group remained intact,
providing orthogonally protected R-substituted acrylate
benzyl ester 9 and tert-butyl ester 10, respectively
(Scheme 5). This modification provides additional value
to our method since these acrylate esters have not been
prepared through the conventional approach in Scheme
1 due to difficulty in obtaining malonic acid monobenzyl
and mono-tert-butyl esters by direct hydrolysis of the
corresponding diesters.
1
major product even though H NMR analyses of the crude
materials indicate the formation of other minor products.
Several reaction conditions were evaluated, and dimeth-
ylmethyleneimmonium iodide24 (Eschenmoser’s iodide
salt) produced the best results. In fact, when a solution
of 7a in methanol was stirred at 65 °C in the presence of
Eschenmoser’s iodide salt, the desired compound 8a was
obtained as the sole product in 95% yield.
To explore the scope and utility of this reaction, we
prepared a variety of 5-monosubstituted Meldrum’s acids
7a -j, which were subsequently converted into R-substi-
tuted acrylate methyl esters 8a -j using this new method.
The results are summarized in Table 1. In all cases, the
reaction provides the products in good yields (72-98%).
The reaction conditions are mild and tolerate many
functional groups commonly used in organic synthesis.
For example, S-triphenylmethyl thioether, tert-butyl
carbamate, and benzyl and tert-butyl esters remained
intact under the reaction conditions. This allowed us to
prepare more complex molecule 8h , a fully protected
derivative of (R)-2-amino-6-methyleneheptanedioic acid.
Although similar compounds have been previously syn-
thesized in multiple steps for the purpose of studying the
diaminopimelate (DAP) pathway,25,26 our route requires
fewer steps and offers higher total yield from com-
mercially available materials.
Con clu sion
We have developed a highly efficient method for the
one-pot synthesis of R-substituted acrylate esters from
the corresponding 5-monosubstituted Meldrum’s acids.
We demonstrated that the new method provides a wide
variety of R-substituted acrylate esters in high yields. The
mild conditions, simple procedure, clean reaction, and
high yields of the products coupled with ready access to
various 5-monosubstituted Meldrum’s acids make the
present method a very attractive alternative to the
previously known methods for the synthesis of R-substi-
tuted acrylate esters.
In addition to the method described in Scheme 2, there
are several other practical synthetic methods for 5-mono-
substituted Meldrum’s acids,18-23 which would provide
access to a wider range of R-substituted acrylate esters
by combining with our new acrylate synthetic method.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed under
nitrogen. Unless otherwise noted, all materials were obtained
from commercial suppliers and used without further purifica-
tion. Melting points were obtained on a Mel-Temp apparatus
and are uncorrected. 1H NMR spectra were recorded at 300
or 400 MHz and 13C NMR spectra at 75 or 100 MHz. Elemental
analyses were obtained from Atlantic Microlabs, Norcross, GA.
The preparation of (R)-5-[(2-tert-butoxycarbonylamino-3-me-
thyl)butyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (7f) and (R)-5-
(24) Kleinman, E. F. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L., Ed.; Wiley: New York, 1995; pp 2090-2093.
(25) Zeng, B.; Wong, K. K.; Pompliano, D. L.; Reddy, S.; Tanner, M.
E. J . Org. Chem. 1996, 61, 10081-10086.
(26) Sutherland, A.; Caplan, J . F.; Vederas, J . C. J . Chem. Soc.,
Chem. Commun. 1999, 555-556.
7366 J . Org. Chem., Vol. 67, No. 21, 2002

Facile Synthesis of R-Substituted Acrylate Esters
TABLE 1. Syn th esis of r-Su bstitu ted Acr yla te Meth yl Ester s fr om Ca r boxylic Acid s
a
b
Reference 17. Commercially available.
[(2-tert-butoxycarbonylamino-3-phenyl)propyl]-2,2-dimethyl-
1,3-dioxane-4,6-dione (7g) has been previously described.17
Gen er a l P r oced u r e for th e P r ep a r a tion of 5-Mon o-
su bstitu ted Meld r u m ’s Acid s: 3-(2,2-Dim eth yl-4,6-d ioxo-
1,3-d ioxa n -5-ylm eth yl)ben zoic Acid Meth yl Ester (7a ). A
solution of DCC (4.74 g, 23 mmol) in dichloromethane (50 mL)
was added to a solution of carboxylic acid 6a (3.60 g, 20 mmol),
Meldrum’s acid (3.20 g, 22 mmol), and DMAP (3.85 g, 32 mmol)
in dichloromethane (100 mL) at 0 °C over a period of 1 h. The
reaction mixture was kept at 0 °C overnight, and the resulting
white precipitate (dicyclohexylurea, DCU) was removed by
filtration. The filtrate was washed with aq 10% KHSO4 (100
mL × 4) and brine (100 mL) and then dried over MgSO4. The
solution was acidified by acetic acid (13.5 mL) at 0 °C, and
NaBH4 (1.85 g, 50 mmol) was added over a period of 1 h. The
reaction mixture was kept at 0 °C overnight, washed with
brine (100 mL × 2) and water (100 mL × 2), dried over MgSO4,
and concentrated in vacuo. The resulting mixture was purified
by recrystallization from EtOAc/hexanes to give 4.40 g of 7a
2H), 3.80 (t, J ) 5.2 Hz 1H), 3.89 (s, 3H), 7.33-7.39 (m, 1H),
7.52-7.57 (m, 1H), 7.88-7.92 (m, 1H), 7.96-7.99 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 26.8, 28.3, 31.5, 47.9, 52.0, 105.1,
128.2, 128.5, 130.3, 130.5, 134.3, 137.7, 164.9, 166.8. Anal.
Calcd for C15H16O6: C, 61.64; H, 5.52. Found: C, 61.89; H,
5.52. 5-Monosubstituted Meldrum’s acids 7b-h were prepared
using the same procedure and purified by either recrystalli-
zation from EtOAc/hexanes (7e-h ) or silica gel chromatogra-
phy using EtOAc/hexanes as eluent (7b-d ). The product
characterization data for compounds 7b -h are provided in
Supporting Information.
3-(2,2-Dim eth yl-4,6-dioxo-1,3-dioxan -5-yl)pr opion ic Acid
Ben zyl Ester (7j). To a solution of Meldrum’s acid (1.44 g,
10 mmol) in acetonitrile (15 mL) were added K2CO3 (1.38 g,
10 mmol, 1.0 equiv) and benzyltriethylammonium chloride
(2.28 g, 10 mmol, 1.0 equiv) at rt. The suspension was stirred
at rt for 15 min, and benzyl acrylate (2.43 g, 15 mmol, 1.5
equiv) was added to the suspension at rt. The resulting
mixture was stirred at 60 °C for 12 h. The solvent was removed
under reduced pressure, and the residue was taken up in
EtOAc (50 mL). The organic solution was washed with aq 10%
1
as a white solid (75% yield): mp 129-132 °C; H NMR (400
MHz, CDCl3) δ 1.59 (s, 3H), 1.75 (s, 3H), 3.50 (d, J ) 5.2 Hz,
J . Org. Chem, Vol. 67, No. 21, 2002 7367

Hin et al.
KHSO4 (50 mL × 3), dried over Na2SO4, and concentrated. The
crude product was purified by silica gel column chromatogra-
phy (EtOAc/hexanes, 3:7) to give 3.0 g of 7j as a white solid
(98% yield): mp 56-57 °C; 1H NMR (300 MHz, CDCl3) δ 1.72
(s, 3H), 1.74 (s, 3H), 2.34-2.43 (m, 2H), 2.68 (t, J ) 7.2 Hz,
2H), 3.88 (t, J ) 5.6 Hz, 1H), 5.10 (s, 2H), 7.28-7.38 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 21.2, 26.3, 28.4, 30.3, 44.7, 66.4,
105.0, 128.2, 128.3, 128.5, 135.6, 165.0, 172.6. Anal. Calcd for
taken up in diethyl ether (15 mL). The organic solution was
washed with aq saturated NaHCO3 (15 mL), aq 10% KHSO4
(15 mL), and brine (15 mL). The organic layer was dried over
Na2SO4 and concentrated. The residual oil was purified by
silica gel column chromatography (EtOAc/hexanes, 3:7) to give
0.27 g of 9 as a colorless oil (85% yield): 1H NMR (400 MHz,
CDCl3) δ 3.69 (s, 2H), 3.89 (s, 3H), 5.15 (s, 2H), 5.52 (s, 1H),
6.32 (s, 1H), 7.25-7.40 (m, 7H), 7.86-7.92 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 37.9, 52.0, 66.5, 127.1, 127.7, 128.0, 128.1,
128.4, 130.0, 130.2, 133.6, 135.7, 139.0, 139.4, 166.3, 167.0.
Anal. Calcd for C19H18O4: C, 73.53; H, 5.85. Found: C, 73.52;
H, 5.92.
3-(2-ter t-Bu toxyca r bon yla llyl)ben zoic Acid Meth yl Es-
ter (10). A solution of 7a (0.30 g, 1.0 mmol) and dimethyl-
methyleneimmonium iodide (0.49 g, 2.6 mmol) in tert-butyl
alcohol and THF (1:1 by volume, 8 mL) was stirred at 65 °C
overnight. The reaction mixture was concentrated under
reduced pressure, and the residue was taken up in diethyl
ether (15 mL). The organic solution was washed with aq
saturated NaHCO3 (15 mL), aq 10% KHSO4 (15 mL), and brine
(15 mL). The organic layer was dried over Na2SO4 and
concentrated to give 0.23 g of 10 as a colorless oil (81% yield):
1H NMR (300 MHz, CDCl3) δ 1.41 (s, 9H), 3.62 (s, 2H), 3.89
(s, 3H), 5.39 (s, 1H), 6.16 (s, 1H), 7.31-7.41 (m, 2H), 7.85-
7.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 27.9, 38.1, 52.0,
80.9, 125.6, 127.5, 128.4, 130.1, 130.2, 133.5, 139.6, 141.2,
165.9, 167.1. Anal. Calcd for C16H20O4‚0.1H2O: C, 69.09; H,
7.32. Found: C, 68.98; H, 7.29.
C
16H18O6: C, 62.74; H, 5.92. Found: C, 63.03; H, 5.89.
Gen er a l P r oced u r e for th e Syn th esis of R-Su bstitu ted
Acr yla te Meth yl Ester s: 3-(2-Meth oxyca r bon yla llyl)-
ben zoic Acid Meth yl Ester (8a ). A solution of 5-monosub-
stituted Meldrum’s acid 7a (0.125 g, 0.43 mmol) and dimethyl
methyleneimmonium iodide (0.20 g, 1.1 mmol, 2.5 equiv) in
anhydrous methanol (5 mL) was stirred at 65 °C overnight.
The reaction mixture was concentrated under reduced pres-
sure, and the residue was taken up in diethyl ether (15 mL).
The organic solution was washed with aq saturated NaHCO3
(15 mL), aq 10% KHSO4 (15 mL), and brine (15 mL). The
organic layer was dried over Na2SO4 and concentrated to give
0.096 g of 8a as a colorless oil (95% yield): 1H NMR (300 MHz,
CDCl3) δ 3.68 (s, 2H), 3.73 (s, 3H), 3.90 (s, 3H), 5.50 (s, 1H),
6.27 (s, 1H), 7.40-7.48 (m, 2H), 7.85-7.92 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 37.7, 51.7, 51.9, 126.6, 127.5, 128.3, 129.9,
130.1, 133.5, 138.9, 139.3, 166.8, 166.9. Anal. Calcd for
C
13H14O4: C, 66.67; H, 6.02. Found: C, 66.59; H, 6.05.
R-Substituted acrylate methyl esters 8b-j were prepared
using the same procedure. The product characterization data
for compounds 8b-j are provided in Supporting Information.
3-(2-Ben zyloxyca r bon yla llyl)ben zoic Acid Meth yl Es-
ter (9). A solution of 7a (0.30 g, 1.0 mmol) and dimethylm-
ethyleneimmonium iodide (0.49 g, 2.6 mmol) in benzyl alcohol
(3 mL) was stirred at 65 °C overnight. The reaction mixture
was concentrated under reduced pressure, and the residue was
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O026101S
7368 J . Org. Chem., Vol. 67, No. 21, 2002