Practical synthesis of (E)-α,β-unsaturated carboxylic acids using a one-pot hydroformylation/decarboxylative Knoevenagel reaction sequence

Article abstract of DOI:10.1002/adsc.200700595

Combining the regioselective room temperature/ambient pressure hydroformylation and a modification of the Doebner-Knoevenagel reaction allowed for the development of an efficient, one-pot procedure for the synthesis of (E)-α,β-unsaturated carboxylic acids. The reaction proceeds under mild conditions, tolerates a variety of functional groups and gives (E)-α,β-unsaturated carboxylic acids in good yields and with excellent regio-and stereocontrol. The practicability of this process has been demonstrated by a short protecting group-free synthesis of the queen honeybee pheromones 9-ODA[( E)-9-oxodec-2-enoic acid] and 9-HDA[( E)-9-hydroxydec-2-enoic acid].

Full text of DOI:10.1002/adsc.200700595

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DOI: 10.1002/adsc.200700595
Practical Synthesis of (E)-a,b-Unsaturated Carboxylic Acids
Using a One-Pot Hydroformylation/Decarboxylative Knoevenagel
Reaction Sequence
a
a
a,
ˇ
ˇ
Susanne T. Kemme, Tomµs Smejkal, and Bernhard Breit *
a
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104 Freiburg,
Germany
Fax : (+49)-761-203-8715; e-mail: bernhard.breit@organik.chemie.uni-freiburg.de
Received: December 18, 2007; Published online: March 10, 2008
Dedicated to Andreas Pfaltz on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Combining the regioselective room tem-
perature/ambient pressure hydroformylation and a
modification of the Doebner–Knoevenagel reaction
allowed for the development of an efficient, one-
pot procedure for the synthesis of (E)-a,b-unsatu-
rated carboxylic acids. The reaction proceeds under
mild conditions, tolerates a variety of functional
groups and gives (E)-a,b-unsaturated carboxylic
acids in good yields and with excellent regio- and
stereocontrol. The practicability of this process has
been demonstrated by a short protecting group-free
synthesis of the queen honeybee pheromones 9-
ODA[( E)-9-oxodec-2-enoic acid] and 9-HDA[( E)-
9-hydroxydec-2-enoic acid].
In this context we became interested in the func-
tional subunit of a,b-unsaturated carboxylic acids,
which represents a structural motif encountered in
many natural product structures.[4] Several a,b-unsatu-
rated acids and derivatives have been reported as
pheromones.[5] Famous examples are, e.g., the honey-
[6]
bee queen compounds 9-HDAand 9-ODA.
In spite of their widespread occurrence in synthetic
targets, to the best of our knowledge there is no
direct catalytic method for the construction of the
a,b-unsaturated carboxylic acid motif meeting the cri-
teria of atom economy.
Common synthesis methodology relies on two-step
procedures resulting from (step 1) the construction of
a corresponding a,b-unsaturated ester which is subse-
quently (step 2) saponified to liberate the acid.[5,7] The
standard method for the construction of the a,b-unsa-
turated esters is a two-carbon chain elongation of an
aldehyde by way of a Wittig or the related Horner–
Wadsworth–Emmons olefination protocol.[8a–d] Al-
though, this constitutes robust and reliable methodol-
ogy, stoichiometric amounts of organophosphorus by-
Keywords: atom economy; Doebner–Knoevenagel
reaction; hydroformylation; one-pot reaction; a,b-
unsaturated carboxylic acids
An ideal target-oriented synthesis should consist of products are formed which have to be separated and
skeleton-constructing reactions only while avoiding disposed of. In this regard more attractive is the re-
unnecessary functional group interconversions, pro- cently developed cross-metathesis protocol between
tection and deprotection steps.[1] If a synthetic target terminal alkenes and acrylic esters with ethylene as
contains functional groups, those should be directly the sole by-product.[8e,f] However, the problem of a
introduced in the course of the skeleton-expanding subsequent ester hydrolysis step to liberate the de-
operation without the need for further manipula- sired carboxylic acid remains unsolved.
tion.[2] This requires carbon-carbon bond forming re-
Based on similar considerations, a decarboxylative
actions which proceed under mild conditions and tol- Knoevenagel-type condensation was recently suggest-
erate the typical reactive functional groups of natural ed for the synthesis of a,b-unsaturated esters. This re-
target structures such as alcohols, amines, carboxylic action has a significantly improved atom economy
acids, etc. Furthermore, if such reactions would satisfy and only water and carbon dioxide are formed as by-
the criteria of atom economy, a highly efficient syn- products. Moreover it employs inexpensive starting
thesis methodology should be the result.[3]
materials – malonic acid derivatives. However, appli-
cation of this methodology for the synthesis of a,b-un-
Adv. Synth. Catal. 2008, 350, 989 – 994
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Susanne T. Kemme et al.
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saturated carboxylic acids is described as limited. gave most promising results. Employing catalytic
Yields for enolizable aliphatic aldehydes are low, the amounts of pyridine (0.1 equiv.) and pyrrolidine (1
E/Z-selectivity varies and, most importantly, not a,b- mol%) the chemoselectivity was high (a,b:b,g=96:4)
but rather b,g-unsaturated acids are obtained.[7,9] Ac- but decarboxylation of the unsaturated diacid 3
cordingly, a clean, by-product free and selective meth- (11.3%) was incomplete. Originally, DMF was used as
odology for the synthesis of a,b-unsaturated acids solvent, which made the isolation of the reaction
from aldehydes would be highly desirable. However, products troublesome. Interestingly, when pyridine
due to their intrinsic reactivity aldehydes are usually (2 equiv.) was used as the solvent and reagent in the
not particularly stable and isolation can be trouble- presence of catalytic amounts of pyrrolidine (1
some. Hence, a process combining an atom economic mol%), (E)-oct-2-enoic acid was obtained in excellent
in situ aldehyde generation with a subsequent olefina- yield (93%) and with high chemo- and stereoselectiv-
tion process could be an interesting solution.[10]
ity (a,b:b,g>98:2, E:Z>99:1) (Table 1, entry 2).
Herein, we report on the first one-pot hydroformy- Other secondary amines were also effective as cata-
lation/decarboxylative Knoevenagel reaction se- lysts (Table 1, entries 3–5). Interestingly, with pyridine
quence, which constitutes a practical, atom economic alone product 1 was formed highly selectively, but in
and highly selective synthesis of a,b-unsaturated car- low yield (50%, table 1, entry 6). Using pyrrolidine
boxylic acids (Scheme 1).
alone we observed full conversion of the aldehyde,
In a first step we tried to identify ideal reaction pa- but diacid 3 was the only product (Table 1, entry 7).
rameters for a clean and selective decarboxylative Hence, there is cooperativity between these two base
Knoevenagel condensation (Doebner–Knoevenagel) catalysts (vide infra). Dimethylaminopyridine, which
of aliphatic aldehydes. For this reason the influence of has been described as an excellent catalyst for the
various reaction conditions on the reaction of capro- synthesis of a,b-unsaturated esters, was not effective
naldehyde and malonic acid was studied (Table 1). for this reaction (Table 1, entry 8).[7] With the opti-
Thus, preliminary experiments revealed that a combi- mized conditions in hand a,b-unsaturated carboxylic
nation of pyridine and a secondary amine catalyst acid 1 was prepared on a preparative scale (50 mmol),
and isolated in excellent yield and selectivity
(Scheme 2).
In a next step we explored whether this decarboxy-
lative Knoevenagel reaction could be coupled with an
Scheme 2.
Scheme 1.
Table 1. Knoevenagel reaction optimization.
Entry
Base 1
Equiv.
Base 2
mol [%]
NMR yield [%][a]
Ratio 1:2
1[b]
2
3
4
5
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
-
0.1
2
2
pyrrolidine
pyrrolidine
piperidine
1
1
1
1
1
-
1 (85); 2 (3.5); 3 (11.3)
1 (93); 2 (1.6)
1 (91); 2 (1.2)
1 (88); 2 (1.8)
1 (74); 2 (4.5)
1 (50)
96:4
>98:2
>99:1
98:2
94:6
>99:1
-
2
2
-
Et2NH
-
pyrrolidine
pyrrolidine
6
7
1
1
3 (98)
1 (22); 2 (11); 3 (66)
8[c]
DMAP
2
67:33
[a]
1H NMR detected, trimethoxybenzene as standard.
DMF (6M solution of the aldehydes) was added.
THF (1M solution of the aldehyde) was added. Formation of a precipitate was observed.
[b]
[c]
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Practical Synthesis of (E)-a,b-Unsaturated Carboxylic Acids
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atom economic in situ generation of the required al-
dehyde. For this purpose we chose our recently devel-
oped regioselective room temperature/ambient pres-
sure (RTAP) hydroformylation employing the self-as-
sembling 6-DPPon/rhodium catalyst.[11]
Such a one-pot regioselective hydroformylation/de-
carboxylative Knoevenagel reaction would install a C3
extension of a terminal alkene, and would thus corre-
spond to a formal and hitherto unknown cross-hydro-
alkenylation of a terminal alkene with acrylic acid (or
related electron-poor alkenes) (Scheme 3).[12]
Scheme 3.
sure of synthesis gas at room temperature.[11] After
Initial experiments showed that the reaction condi- 20 h the synthesis gas was replaced with argon and
tions of the decarboxylative Knoevenagel are incom- the nitrogen bases and malonic acid were added.
patible with the conditions of the RTAP hydroformy- After additional 20 h at 108C and 4 h at room temper-
lation protocol, which precluded a tandem process. ature the reaction was complete and the a,b-unsatu-
However, a very efficient and practical one-pot pro- rated carboxylic acids were isolated by chromatogra-
cess was developed. Thus, first hydroformylation was phy on silica in good overall yields and in high
performed with [Rh(CO)2acac]/6-DPPon as the cata- chemo- and stereoselectivity (Table 2, Experimental
lyst precursor in a Schlenk tube under ambient pres- Section). The procedure turned out to be very reliable
Table 2. One-pot hydroformylation/Knoevenagel reaction.[a]
Entry
R
Conversion [%][b,c]
l:b[c]
Yield [%][d]
5:6[b]
1
2
3
4 (quant.); 5 (quant.)
4 (quant.); 5 (quant.)
4 (quant.); 5 (quant.)
>99:1
99:1
77
78
68
>98:2
97:3
>99:1
98:2
4
4 (quant.); 5 (quant.)
95:5
67
99:1
5
6
4 (quant.); 5 (quant.)
4 (quant.); 5 (quant.)
99:1
98:2
75
69
99:1
98:2
7
4 (quant.); 5 (quant.)
4 (70); 5 (quant.)
99:1
99:1
68
71
99:1
98:2
8[e]
9
4 (quant.); 5 (98)
99:1
99:1
72
77
98:2
98:2
10
4 (quant.); 5 (quant.)
[a]
Conditions (hydroformylation): [Rh(CO)2acac] (0.66 mol%), 6-DPPon (3.33 mol%), alkene (1 equiv.), CO/H2 (1:1) 1
atm, THF [co(alkene)=1.0M], room temperature, 20 h, Conditions (Knoevenagel): malonic acid (1 equiv.), pyridine
ACHTREUNG
(2 equiv.), pyrrolidine (1 mol%), 20 h at 108C then 4 h at room temperature.
Of alkene 4 (isomerization to the internal alkene <5%), NMR detected.
Of the intermediate aldehyde 5, NMR detected.
[b]
[c]
[d]
Isolated yield of product 6.[e] Isolated yield referred to the Knoevenagel reaction.
Adv. Synth. Catal. 2008, 350, 989 – 994
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991

Susanne T. Kemme et al.
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and general for terminal alkenes. Many functional acid and aliphatic aldehydes catalyzed by piperidinum
groups including, free alcohol functions as well as ke- acetate in dimethyl sulfoxide at 1008C (Scheme 6).[9a]
tones, acetals, esters, amides and carbamates were tol-
erated.
We reasoned that under our conditions an alterna-
tive mechanism is operative (Scheme 7). Thus, using
To demonstrate the practicability of our methodol- pyrrolidine as the sole catalyst alkylidenemalonic acid
ogy, a protecting group-free synthesis of the two 3 has been isolated and characterized. When 3 was
honey bee pheromones, 9-ODAand 9-HDA, was en-
visioned (Scheme 4).[13,14] Thus, alkenes 8 and 9 were
Scheme 6.
Scheme 4.
prepared by copper-catalyzed acylation and alkylation
of the corresponding Grignard reagents, respective-
ly.[15,16] Using our one-pot homologation the corre-
sponding (E)-a,b-unsaturated acids 9-ODAand 9-
HDAwere obtained in good yields and perfect selec-
tivity. To the best of our knowledge these are the
shortest synthesis of these two honey bee pheromones
which are completely free of protecting groups.[13,14]
Scheme 7.
Accordingly, the decarboxylative condensation of
malonic acid presents an interesting, atom economic treated with pyridine a smooth decarboxylation took
alternative to the more traditional carbon-carbon place and furnished the a,b-unsaturated acid 1.
bond forming reactions. These and analogous process-
Hence, a two-step mechanism is most likely. The
es are relatively rarely synthetically exploited because first step is a classical Knoevenagel condensation
of the dominating controversy concerning the mecha- which is catalyzed by the secondary amine via forma-
nism.
tion of highly electrophilic iminium ion intermediates
Mechanistic studies by Corey led to the proposal from the corresponding aldehyde with formation of
that decarboxylation of a,b-unsaturated malonic acids diacid 3. This step is fast (over 50% conversion after
10 can only proceed via b,g-unsaturated intermediate 30 min at 108C) and is followed by the much slower
11 which then smoothly decarboxylates to the b,g-un- decarboxylation step initiated by pyridine (38% con-
saturated acid 12 (Scheme 5).[17] This mechanism version after 10 h at 108C).[18] We propose that pyri-
probably operates during the condensation of malonic dine functions as a Lewis basic catalyst which under-
goes conjugate addition to Knoevenagel product 3
followed by decarboxylation via the indicated transi-
tion state (Scheme 7).
In summary, conditions for the first general and
highly selective decarboxylative Knoevenagel conden-
sation with aliphatic aldehydes have been identified.
This enabled the development of a new one-pot
method for the direct synthesis of (E)-a,b-unsaturated
acid starting from terminal alkenes. Thus, combining
room temperature, ambient pressure regioselective
Scheme 5.
hydroformylation with the decarboxylative Knoevena-
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Practical Synthesis of (E)-a,b-Unsaturated Carboxylic Acids
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particular examples of, e.g., Peterson olefination, see:
b) P. A. Grieco, C. L. J. Wang, S. D. Burke, J. Chem.
Soc., Chem. Commun. 1975, 537–538. For aldehyde re-
action with dibromacetic acid promoted by SmI2, see:
c) J. M. Concellón, C. Concellón, J. Org. Chem. 2006,
71, 1728–1731. For reaction of trimethylsilylketene
acetal and aldehydes, see: d) M. Bellassoued, M. Gau-
demar, Tetrahedron Lett. 1988, 29, 4551–4554.
gel condensation (E)-a,b-unsaturated acids were ob-
tained in good yields and with high chemo- and ste-
reoselectivity. The process is mild, efficient, practical,
atom economic and tolerates many functional groups.
Interestingly, the overall transformation represents a
formal cross-hydroalkenylation between a terminal
alkene and acrylic acid, a reaction which is hitherto
unknown. Future studies in our group will focus on
exploring the full scope of this and related one-pot
processes.
[5] S. Schulz, The Chemistry of Pheromones and other
Semiochemicals, in: Topics in Current Chemistry,
Springer Verlag, Heidelberg, Berlin, 2004, p 154.
[6] A. Brockmann, D. Dietz, J. Spaethe, J. Tautz, J. Chem.
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[7] a) B. List, A. Doehring, M. T. Hechavarria Fonseca, A.
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Wobser, H. van Thienen, R. R. Torres, P. L. Galilea,
Adv. Synth. Catal. 2005, 347, 1558–1560.
Experimental Section
General Procedure for the One-Pot
Hydroformylation/Knoevenagel Reaction
Under an atmosphere of argon the olefin (150 equiv.) was
[8] For some examples for Wittig and HWE reaction, see:
a) D. Ok, C. Li, T. L. Shih, S. Salva, M. B. Ayer, S. L.
Colletti, P. K. Chakravarty, M. J. Wyvratt, M. H. Fisher,
L. Gregory, M. Zakson-Aiken, W. L. Shoop, D. M.
Schmatz, P. T. Meinke, Bioorg. Med. Chem. Lett. 2002,
12, 1751–1754; b) H. J. Bestmann, R. Dostalek, R.
Zimmermann, Chem. Ber. 1992, 125, 2081–2084;
c) D. R. Britelli, J. Org. Chem. 1981, 46, 2514–2520;
d) P. Coutrot, M. Snoussi, P. Savignac, Synthesis 1978,
133–134. For metathesis, see: e) T.-L. Choi, C. W. Lee,
A. K. Chatterjee, R. H. Grubbs, J. Am. Chem. Soc.
2001, 123, 10417–10418; f) F. Thortsensson, I. Kvarn-
strçm, D. Mussil, I. Niolsson, B. Samuelsson, J. Med.
Chem. 2003, 46, 1165–1179.
[9] a) N. Ragoussis, V. Ragoussis, J. Chem. Soc., Perkin
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Naik, A. B. Mandal, N. Chowdappa, V. B. Praveen, J.
Org. Chem. 2007, 72, 9854–9856.
[10] For the first domino hydroformylation/Knoevenagel/
hydrogenation reaction with dimethyl malonate, see
a) B. Breit, S. K. Zahn, Angew. Chem. 2001, 113, 1964–
1967; Angew. Chem. Int. Ed. 2001, 40, 1910–1913; b) B.
Breit, S. K. Zahn, Tetrahedron 2005, 61, 6171–6179.
[11] a) W. Seiche, A. Schuschkowski, B. Breit, Adv. Synth.
Catal. 2005, 347, 1488–1494; b) W. Seiche, B. Breit, J.
Am. Chem. Soc. 2003, 125, 6608–6611.
[12] For some examples of hydroalkenylation see: a) T. V.
Rajan Babu, T. Koike, Chem. Rev. 2003, 103, 2845–
2860; b) G. Takahashi, E. Shirakawa, T. Tsuchimoto, Y.
Kawakami, Adv. Synth. Catal. 2006, 348, 837–840; c) N.
Tsukada, H. Setoguchi, T. Mitsuboshi, Y. Inoue, Chem.
Lett. 2006, 35, 1164–1166; d) A. K. Gupta, K. S. Kim,
C. H. Oh, Synlett 2005, 3, 457–461; e) C. H. Oh, J. H.
Ryu, Bull. Korean Chem. Soc. 2003, 24, 1563; f) T.
Fujii, T. Koike, A. Mori, K. Osakada, Synlett 2002, 2,
295–298.
[13] For further information and other syntheses of 9-HDA
see: a) A. S. Pawar, S. S. Chattopadhyay, S. Chattopad-
hyay, Tetrahedron: Asymmetry 1995, 6, 2219–2226;
b) R. Y. Kharisov, O. V. Botsman, L. P. Botsman, N. M.
Ishmuratova, G. Y. Ishmuratov, G. A. Tolstikov, Chem.
Nat. Compd. 2002, 38, 145–148.
added to
a
solution of 6-DPPon (5 equiv.) and
[Rh(CO)2acac] (1 equiv.) in THF (1M according to the
olefin) at room temperature. The argon atmosphere was re-
placed by synthesis gas (balloon). The reaction mixture was
stirred at room temperature and ambient pressure for
20 h.[11] Subsequently, synthesis gas was removed over
20 min by bubbling argon through the solution. The solution
was cooled to 08C and malonic acid (150 equiv.), pyridine
(300 equiv.) and pyrrolidine (1.5 equiv.) were added. The re-
action mixture was warmed to 108C and stirred for 20 h at
this temperature, and additional 4 h at room temperature.
The reaction was finished by the addition of aqueous H3PO4
(20%, 10 mL). After phase separation, the aqueous phase
was extracted three times with ethyl acetate and the com-
bined organic phases were dried over MgSO4. The solvent
was removed under vacuum. The product was purified by
chromatography (SiO2, petroleum ether:diethyl ether:acetic
acid=100:25:1 to 100:100:2).
Acknowledgements
This work was supported by DFG(International Research
Training Group: “Catalysts and Catalytic Reactions for Or-
ganic Synthesis” GRK 1038), the Alfried Krupp Foundation.
T.S. is grateful to the state of Baden-Württemberg for a
Landes-graduierten Fellowship.
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Adv. Synth. Catal. 2008, 350, 989 – 994