One-pot conversion of alkyl aldehydes into substituted propanoic acids via Knoevenagel condensation with Meldrum's acid

Article abstract of DOI:10.1016/j.tetlet.2010.07.054

Reaction of a range of alkyl aldehydes and Meldrum's acid in triethylammonium formate (TEAF) at 100 °C generates substituted propanoic acids in a single step.

Full text of DOI:10.1016/j.tetlet.2010.07.054

Tetrahedron Letters 51 (2010) 4972–4974
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Tetrahedron Letters
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One-pot conversion of alkyl aldehydes into substituted propanoic acids
via Knoevenagel condensation with Meldrum’s acid
*
Harminder Mudhar , Andrew Witty
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of a range of alkyl aldehydes and Meldrum’s acid in triethylammonium formate (TEAF) at 100 °C
generates substituted propanoic acids in a single step.
Received 6 May 2010
Revised 2 July 2010
Accepted 9 July 2010
Available online 15 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The Knoevenagel condensation of Meldrum’s acid with aromatic
aldehydes to produce arylidene derivatives is a well-documented
method reported by Tóth and Köver, we decided to investigate
the reaction of tetrahydro-2H-pyran-4-carbaldehyde (1a) with
Meldrum’s acid. We were gratified to obtain 3-(tetrahydro-2H-pyr-
1
reaction. Arylidene Meldrum’s acids are useful reactive intermedi-
2
11
ates, being susceptible to 1,4-addition, acting as activated dieno-
an-4-yl)propanoic acid (5a) as the exclusive product in 87% yield.
philes in Diels–Alder reactions3 and being used for the
This result encouraged us to further explore the scope of this
reaction, as summarised in Table 1. Starting with close analogues
of tetrahydo-2H-pyran-4-carbaldehyde, 3-cyclohexylpropanoic
acid (5b) and 3-(1-{[(phenylmethyl)oxy]carbonyl}-4-piperidinyl)prop-
anoic acid (5c) were obtained in good yields from cyclohexanecarbalde-
hyde (1b) and phenylmethyl 4-formyl-1-piperidinecarboxylate (1c),
respectively. In five-membered ring systems, 3-cyclopentylpropanoic
acid (5d) was obtained in an excellent yield from cyclopentanecarbal-
dehyde (1d), but 3-(N-Boc-2-pyrrolidinyl)propanoic acid (5e) was
4
preparation of heterocyclic molecules such as coumarins, benzofu-
5
rans and indoles. When the condensation of aromatic aldehydes
(1) and Meldrum’s acid (2) is carried out in triethylammonium for-
mate (TEAF) at temperatures between 20 °C and 50 °C, a transfer
6
hydrogenation of the arylidene Meldrum’s acid occurs. The double
bond in the intermediate 3 is reduced to give 4, which can be iso-
lated or converted into the corresponding 3-arylpropanoic acid 5
by heating to 80–100 °C (Scheme 1). If the reaction is carried out
at 80–100 °C, direct conversion of aryl aldehyde 1 into 3-arylprop-
anoic acid 5 is generally completed within 3 h.
only isolated in 26% yield from N-Boc-L-prolinal (1e). In this case a
small amount of a second product, believed to be 7-({[(1,1-dimeth-
ylethyl)oxy]carbonyl}amino)-4-oxoheptanoic acid, formed via ring-
opening, was also obtained. Interestingly, a similar reaction using
N-Boc-2-formylpiperidine (1f) did not show any signs of ring-open-
This facile method of generating 3-arylpropanoic acids from the
corresponding benzaldehydes has also been extended to include
7
heteroaromatic aldehydes. In contrast, the corresponding reaction
of aliphatic aldehydes with Meldrum’s acid has received little
attention. Tóth and Köver reported that the reaction of straight-
chain aldehydes with Meldrum’s acid in TEAF gave Michael ad-
6
O
O
O
R
O
O
ducts rather than the corresponding substituted propanoic acids.
O
Typically, when alkyl-substituted Meldrum’s acids have been
+
O
TEAF
O
isolated (4, where R = alkyl), reductive alkylation conditions have
R
H
8
been employed. In order to obtain substituted propanoic acids,
O
20-50 ºC
the isolated alkyl-substituted Meldrum’s acid is subsequently
decarboxylated; a one-pot conversion is yet to be reported.
1
2
3
9
Recently, we required 3-(tetrahydro-2H-pyran-4-yl)propanoic
acid (5a) as a versatile intermediate in an ongoing medicinal chem-
istry programme. This material is not readily available from com-
mercial sources and the only documented route for its
8
0-100 ºC TEAF
TEAF 20-50 ºC
O
R
O
O
O
preparation involves
methyl)tetrahydro-2H-pyran. Having previously prepared 3-(4-
a
three-step synthesis from 4-(bromo-
O
10
R
OH
80-100 ºC
cyanophenyl)propanoic acid from 4-formylbenzonitrile via the
5
4
*
Corresponding author. Tel.: +44 1279 622916; fax: + 44 1279 622260.
Scheme 1. Stepwise route for conversion of aldehydes to substituted propanoic
E-mail address: harminder.s.mudhar@gsk.com (H. Mudhar).
acids.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.054

H. Mudhar, A. Witty / Tetrahedron Letters 51 (2010) 4972–4974
4973
Table 1
1
1
Synthesis of substituted propanoic acids
O
O
O
TEAF
O
R
H
100 ºC
R
OH
O
O
Entry
1
Aldehyde
Product
Yield (%)
O
O
H
OH
OH
87
78
O
O
1
a
c
5a
5b
O
O
2
H
1
b
O
O
H
OH
3
4
5
90
89
N
N
Cbz
Cbz
1
5c
5d
O
O
H
H
OH
1
d
O
O
OH
26a
N
N
Boc
1
e
Boc
5
e
O
O
H
OH
41b
87
89
93
6
7
8
9
N
N
Boc
Boc
1
f
5f
O
O
O
O
H
OH
1
g
5g
O
O
H
OH
1
h
5h
O
O
n-C H
H
n-C H
OH
7
15
7
15
1
i
5i
O
O
H
OH
1
0
N
N
93
N
N
N
N
1
j
5j
a
Another product, believed, but not confirmed to be 7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-oxoheptanoic acid was isolated along with 5e.
Required additional purification by flash column chromatography, recovery lower than expected based on the crude yield.
b
ing, 3-(N-Boc-2-piperidinyl)propanoic acid (5f) being obtained in
anal (1h) gave 4-(tetrahydro-2H-pyran-4-yl)butanoic acid (5g)
and 5-phenylpentanoic acid (5h), respectively. We were delighted
to find that n-octanal (1i) gave decanoic acid (5i) in 93% yield, with
no Michael addition products observed.
4
1% yield.
Other N-Boc-protected amino aldehydes such as Boc-L-alaninal
and N-Boc-D-phenylalaninal were not tolerated and complex mix-
tures of products were obtained. Similarly, a reaction using (S)-per-
illaldehyde failed, suggesting that sensitive substrates are not
suitable when using these conditions.
The reaction using 1-(5-methyl-2-pyrazinyl)-4-piperidinecarb-
aldehyde (1j) gave 3-[1-(5-methyl-2-pyrazinyl)-4-piperidi-
1
2
nyl]propanoic acid (5j) in 93% yield.
This product was
We also investigated the chain length as a factor in this reaction.
Tetrahydro-2H-pyran-4-ylacetaldehyde (1g) and 3-phenylprop-
previously unreported and represents a novel drug-like template
for further medicinal chemistry exploration.

4
974
H. Mudhar, A. Witty / Tetrahedron Letters 51 (2010) 4972–4974
5. Baxter, G. J.; Brown, R. F. C.; McMullen, G. L. Aust. J. Chem. 1974, 27, 2605.
In conclusion, we have reported the efficient one-pot conver-
6
7
.
.
Tóth, G.; Köver, K. E. Synth. Commun. 1995, 25, 3067.
sion of a range of alkyl aldehydes into substituted propanoic acids
via Knoevenagel condensation with Meldrum’s acid in TEAF. The
reaction works well for straight-chain and branched aldehydes.
N-Cbz protection is well tolerated. N-Boc-protected aldehydes gave
much lower yields but it is inconclusive whether the protecting
group was responsible for this outcome.
(a) Reddy, G. J.; Rao, K. S.; Khalilullah, M.; Thirupathaiah, C.; Latha, D.
Heterocycl. Commun. 2006, 12, 423; (b) Erwan, A.; Gloanec, P.; Berge, G.; de
Nanteuil, G.; Mennecier, P.; Rupin, A.; Verbeuren, T. J.; Fulcrand, P.; Martinez, J.;
Hernandez, J.-F. Bioorg. Med. Chem. Lett. 2009, 19, 1386.
8.
(a) Hubowchak, D. M.; Smith, F. X. Tetrahedron Lett. 1983, 24, 4951; (b)
Ramachary, D. B.; Kishor, M.; Ramakumar, A. Tetrahedron Lett. 2006, 47, 651.
9. (a) Helavi, V. B.; Solabannavar, S. B.; Desai, U. V.; Mane, R. B. J. Chem. Res. 2003,
74; (b) Obaza, J.; Smith, F. X. Synth. Commun. 1982, 12, 19.
1
1
1
0. Prelog, V.; Cerkovnikov, E. Liebigs Ann. Chem. 1937, 532, 83.
1. General method for the preparation of substituted propanoic acids: 3-(tetrahydro-
Acknowledgements
2
3
H-pyran-4-yl)propanoic acid (5a). Et N (3.36 mL, 24.11 mmol) was added
dropwise to formic acid and (2.26 mL, 58.9 mmol) cooled in an ice bath to give
triethylammonium formate. This was added to tetrahydro-2H-pyran-4-
carbaldehyde (1a) (250 mg, 2.190 mmol) and Meldrum’s acid (316 mg,
2.190 mmol), and the mixture was heated at 100 °C for 5 h. The reaction
mixture was treated with 2 M NaOH (40 ml), and the aqueous layer extracted
This research was carried out during a Nuffield Science Bursary
Scheme summer placement. We would like to thank the Nuffield
Foundation and SETPOINT Hertfordshire for helping to make this
possible.
with Et
with 5 M aq HCl and the aqueous layer was extracted with CH
The combined organics were dried (MgSO ), filtered and evaporated to give the
2
O (3 Â 40 ml). The combined organic layer was then acidified to pH 4
2
Cl
2
(3 Â 40 ml).
References and notes
4
1
title compound 5a, as a white solid (301 mg, 87%). H NMR (400 MHz, CDCl ): d
3
1
.
.
(a) McNab, H. Chem. Soc. Rev. 1978, 7, 345; (b) Chen, B. C. Heterocycles 1991, 32,
29; (c) Dumas, A. N.; Fillion, E. Acc. Chem. Res. 2010, 43, 440.
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P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 9682; (c) Ziegler, F.
E.; Guenther, T.; Nelson, R. V. Synth. Commun. 1980, 10, 661.
(a) Pałasz, A.; Jelska, K.; O z_ óg, M.; Serda, P. Monatsh. Chem. 2007, 138, 481; (b)
Borah, H. N.; Deb, M. L.; Boruah, R. C.; Bhuyan, P. J. Tetrahedron Lett. 2005, 46,
1.30 (m, 2H), 1.52 (m, 1H), 1.60 (m, 4H), 2.39 (m, 2H), 3.37 (dt, 2H, J = 11.8,
2.0 Hz), 3.97 (m, 2H). 13C NMR (400 MHz, DMSO-d
5
6
): d 30.7, 31.4, 32.3, 33.8,
2
66.9, 174.5.
12. 3-[1-(5-Methyl-2-pyrazinyl)-4-piperidinyl] propanoic acid (5j). Prepared via the
above method. Obtained as a pale yellow solid (296 mg, 93% yield). 1H NMR
3
4
.
.
6
(400 MHz, DMSO-d ): d 1.06 (m, 2H), 1.46 (m, 3H), 1.72 (m, 2H), 2.25 (m, 5H),
2.77 (dt, 2H, J = 12.7, 2.4 Hz), 4.32 (m, 2H), 7.66 (s, 1H), 8.08 (s, 1H), 12.06 (br s,
+
3
391.
1H). LC/MS [M+H] = 250.
Mahulikar, P. P.; Mane, R. B. J. Chem. Res. 2006, 12.