Combined transition-metal- and organocatalysis: An atom economic C3 homologation of alkenes to carbonyl and carboxylic compounds

Article abstract of DOI:10.1002/chem.200903223

A combination of regioselective room-temperature/ambient-pressure hydroformylation (transitionmetal catalysis) and decarboxylative Knoevenagel reactions (organocatalysis) allowed for the development of an efficient, one-pot C3 homologation of terminal alkenes to (E)-α,β-unsaturated acids and esters, (E)-β,γ-unsaturated acids, (E)-α-cyano acrylic acids, and α,β-unsaturated nitriles. All reactions proceed under mild conditions, tolerate a variety of functional groups, and furnish unsaturated carbonyl compounds in good yields and with excellent regioand stereocontrol. Further, an iterative C2 homologation of (E)-α,β-unsaturated carboxylic acids is possible through a combination of decarboxylative hydroformylation employing a supramolecular catalyst followed by decarboxylative Knoevenagel condensation with an organocatalyst.

Full text of DOI:10.1002/chem.200903223

FULL PAPER
DOI: 10.1002/chem.200903223
Combined Transition-Metal- and Organocatalysis: An Atom Economic C3
Homologation of Alkenes to Carbonyl and Carboxylic Compounds
[a]
ˇ
Susanne T. Kemme, Tomꢀsˇ Smejkal, and Bernhard Breit*
Abstract: A combination of regioselec-
tive room-temperature/ambient-pres-
sure hydroformylation (transition-
metal catalysis) and decarboxylative
Knoevenagel reactions (organocataly-
sis) allowed for the development of an
efficient, one-pot C3 homologation of
terminal alkenes to (E)-a,b-unsaturat-
ed acids and esters, (E)-b,g-unsaturated
acids, (E)-a-cyano acrylic acids, and
a,b-unsaturated nitriles. All reactions
proceed under mild conditions, tolerate
a variety of functional groups, and fur-
nish unsaturated carbonyl compounds
in good yields and with excellent regio-
and stereocontrol. Further, an iterative
C2 homologation of (E)-a,b-unsaturat-
ed carboxylic acids is possible through
a combination of decarboxylative hy-
droformylation employing
a supra-
Keywords:
hydroformylation
condensation
supramolecular catalysis
atom economy
·
molecular catalyst followed by decar-
boxylative Knoevenagel condensation
with an organocatalyst.
·
Knoevenagel
·
organocatalysis ·
Introduction
(Scheme 1).[6] Unfortunately these reactions suffer either
from a bad atom economy, the necessity for special reagents,
or additional steps. Accordingly, a clean byproduct-free and
An ideal target-oriented synthesis should consist of skele-
ton-constructing reactions while avoiding unnecessary func-
tional-group interconversions and protection and deprotec-
tion steps.[1] If a synthetic target contains functional groups,
those should be directly introduced in the course of the skel-
eton-expanding operation without the need for further ma-
nipulation.[2] This requires carbon–carbon bond-forming re-
actions that proceed under mild conditions and tolerate the
typical reactive functional groups of natural target struc-
tures, such as alcohols, amines, carboxylic acids, etc. Further-
more, if such reactions would satisfy the criteria of atom
economy, a highly efficient synthetic methodology should be
the result.[3] In this context we became interested in the
functional subunit of unsaturated carboxylic acid derivatives.
These moieties represent an interesting and important class
of functionalities. Typical synthetic procedures to access
these product classes employ Wittig-type olefinations,[4]
cross-alkene metathesis,[5] and the Peterson olefination
Scheme 1. Common homologation methodologies for the preparation of
unsaturated compounds.
selective methodology for the synthesis of a,b-unsaturated
carboxylic acid derivatives from aldehydes would be highly
desirable. However, due to their intrinsic reactivity, alde-
hydes are usually not particularly stable and isolation can be
troublesome. We reasoned that a solution to this problem
could be a process combining aldehyde generation in situ
with a subsequent decarboxylative Knoevenagel reaction as
a nearly atom-economic olefination process with water and
carbon dioxide being the only byproducts.[7]
In this context, we recently reported on the development
of a supramolecular self-assembly catalyst that allows for re-
gioselective hydroformylation of terminal alkenes under
mild reaction conditions. Employing the self-assembling 6-
ˇ
[a] S. T. Kemme, T. Smejkal, Prof. B. Breit
Institut fꢀr Organische Chemie und Biochemie
Freiburg Institute for Advanced Studies (FRIAS)
Albert-Ludwigs-Universitꢁt Freiburg, Albertstrasse 21
79104 Freiburg (Germany)
Fax : (+49)761-203-8715
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903223.
Chem. Eur. J. 2010, 16, 3423 – 3433
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3423

diphenyl-phosphanylpyridone (6-DPPon)/RhI catalyst the
reaction can be performed even at room temperature under
ambient pressure, thus avoiding the use of special pressure-
vessel equipment (Scheme 2).[8]
Results and Discussion
Synthesis of a,b-unsaturated carboxylic acids: a,b-Unsatu-
rated carboxylic acids represent a structural motif found in
many natural products, such as pheromones.[10] 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 criteria of atom economy. Common synthetic
methodology relies on a two-step procedure resulting from
the construction of a corresponding ester that is subsequent-
ly saponified to liberate the carboxylic acid.[11] The standard
method for the synthesis of the a,b-unsaturated carboxylic
ester is a two-carbon chain elongation of an aldehyde by the
Wittig or related Horner–Wadsworth–Emmons olefina-
tion.[4c–f] An interesting alternative is the cross-metathesis
between terminal alkenes and acrylic esters with ethylene as
the sole byproduct.[5b–e] However, the reaction is incompati-
ble with a free carboxylic acid, and hence an additional
ester hydrolysis step has to be employed. A significantly im-
proved atom economy shows the decarboxylative Knoeve-
nagel condensation because only water and carbon dioxide
are formed as byproducts. How-
Scheme 2. RTAP hydroformylation–atom-economic C1 homologation.
Herein, we report in full detail on the development of a
combined regioselective room-temperature/ambient-pres-
sure hydroformylation (RTAP, transition-metal catalysis)
employing our self-assembly 6-DPPon/RhI-catalyst and a de-
carboxylative Knoevenagel condensation (organocatalysis)
in a one-pot procedure (Scheme 3).[9] Thus, by starting from
ever, the application of the de-
carboxylative Knoevenagel con-
densation (Knoevenagel–Doeb-
ner) for the synthesis of a,b-un-
saturated carboxylic acids is de-
scribed as limited. Yields for
enolizable aliphatic aldehydes
are low, the E/Z-selectivity
varies, and, most importantly,
not a,b-, but rather b,g-unsatu-
rated acids are obtained.[11,22,40]
Hence, our first goal was to
identify a useful protocol for
Scheme 3. Combined transition-metal- and organocatalysis—a new approach to carbonyl and carboxylic com-
pounds.
the decarboxylative Knoevena-
gel reaction to obtain a,b-unsa-
turated carboxylic acids from
enolizable aldehydes.
simple terminal alkenes this process allows for a formal hy-
droalkenylation of an alkene leading to a C3 homologation
to furnish a wide range of unsaturated carbonyls, such as
a,b-unsaturated carboxylic acids, esters, nitriles, and b,g-un-
saturated carboxylic acids. Both catalytic processes tolerate
a variety of functional groups, proceed under mild condi-
tions, give the unsaturated products in good yields and with
excellent regio- and stereocontrol, and produce carbon diox-
ide and water as the only stoichiometric byproducts (Sche-
me 3A).
Additionally, inspired by the biosynthesis of fatty acids a
new two-carbon homologation procedure of aldehydes and
a,b-unsaturated carboxylic acids has been developed by a
combination of supramolecular transition-metal catalysis
and decarboxylative Knoevenagel condensation (Sche-
me 3B).
For this reason the influence of various reaction condi-
tions on the reaction of capronaldehyde and malonic acid
was studied (Table 1). Thus, preliminary experiments re-
vealed that a combination of pyridine and a secondary
amine catalyst gave the most promising results. When em-
ploying catalytic amounts of pyridine (0.1 equiv) and pyrro-
lidine (1 mol%) the chemoselectivity was high (a,b/b,g
96:4), but decarboxylation of the unsaturated carboxylic
diacid 3 (11%) was incomplete (Table 1, entry 1). Originally,
DMF was used as the solvent, which made the isolation of
the reaction products troublesome. Interestingly, when pyri-
dine (2 equiv) was used as the solvent and reagent in the
presence of catalytic amounts of pyrrolidine (1 mol%), (E)-
oct-2-enoic acid was obtained in an excellent yield (93%)
and with high chemo- and stereoselectivity (a,b/b,g >98:2,
E/Z >99:1) (Table 1, entry 2). Other secondary amines were
also effective as catalysts (Table 1, entries 3–5). Interestingly,
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Homologation of Alkenes to Carbonyl and Carboxylic Compounds
FULL PAPER
Table 1. Synthesis of a,b-unsaturated carboxylic acids by using a decar-
boxylative Knoevenagel reaction—reaction optimization.
Schlenk tube under ambient pressure of the synthesis gas at
room temperature. The reaction occurs with high regioselec-
tivity (99:1) in favor of the linear aldehyde. After 20 h, the
synthesis gas was replaced with argon and the base catalyst
and malonic acid were added. After an additional 20 h at
108C and 4 h at room temperature, the reaction was com-
plete and the a,b-unsaturated carboxylic acid 4 was isolated
by chromatography on silica in good overall yield (77%)
(Scheme 5). The procedure turned out to be very reliable
Entry Base 1 (equiv) Base 2 (mol%) NMR yield [%][a]
Ratio 1/2
1[b]
2
3
4
5
pyridine (0.1) pyrrolidine (1) 1 (85), 2 (4), 3 (11)
96:4
>98:2
>99:1
98:2
94:6
>99:1
–
pyridine (2)
pyridine (2)
pyridine (2)
pyridine (2)
pyridine (2)
–
pyrrolidine (1) 1 (93), 2 (1.6)
piperidine (1)
l-proline (1)
Et2NH (1)
–
1 (91), 2 (1.2)
1 (88), 2 (1.8)
1 (74), 2 (4.5)
1 (50)
6
7
pyrrolidine (1) 3 (98)
8[c]
DMAP (2)
pyrrolidine (1) 1 (22), 2 (11), 3 (66)
67:33
[a] 1H NMR spectra detected, trimethoxybenzene as standard. [b] DMF
(6m solution of the aldehydes) was added. [c] THF (1m solution of the al-
dehyde) was added. Formation of a precipitate was observed.
Scheme 5. An example of a one-pot RTAP hydroformylation/Knoevena-
gel reaction to a,b-unsaturated carboxylic acid 4.
with pyridine alone product 1 was formed with high selectiv-
ity, but in low yield (50%, Table 1, entry 6). By using pyrro-
lidine alone, we observed full conversion of the aldehyde,
but diacid 3 was the only product (Table 1, entry 7). Hence,
there is cooperativity between these two base catalysts (vide
infra). Dimethylaminopyridine, which has been described as
an excellent catalyst for the synthesis of a,b-unsaturated
esters, was not effective for this reaction (Table 1,
entry 8).[11]
and general for terminal alkenes. Many functional groups in-
cluding free-alcohol functionalities, acetals and carbamates
were tolerated (for the substrate scope see Table 5).
Synthesis of a,b-unsaturated carboxylic esters: To explore
whether such a one-pot process consisting of RTAP-hydro-
formylation and a decarboxylative Knoevenagel reaction
can be employed for the synthesis of other classes of unsatu-
rated carbonyl derivatives, we looked at the preparation of
a,b-unsaturated carboxylic esters[13] by starting from malonic
acid half esters. Their decarboxylative Knoevenagel reaction
with aldehydes was reported in 2005 by List et al. The reac-
tion has been performed in DMF at room temperature over
5 to 48 h by using 4-dimethylaminopyridine (DMAP) (10–
20 mol%) and piperidine (10 mol%) as organocatalysts.[11,14]
The drawback is indeed the formation of the aldehyde start-
ing material in a separate step. Conversely, a wide range of
functionalized alkenes are commercially available and allow
for a rapid formylation by employing our RTAP-hydrofor-
mylation protocol. Thus, transferring the conditions of the
one-pot process developed for malonic acid to the corre-
sponding methyl half ester furnished the desired a,b-unsatu-
rated ester 5 in 80% yield with high chemo- and stereoselec-
tivity (l/b 99:1, a,b/b,g >98:2, E/Z >99:1, Scheme 6). Again,
With optimized conditions in hand, a,b-unsaturated car-
boxylic acid
1 was prepared on a preparative scale
(50 mmol) and isolated in excellent yield and selectivity
(Scheme 4). In the next step, we explored whether this de-
Scheme 4. Knoevenagel reaction for the preparation of a,b-unsaturated
acids.
carboxylative Knoevenagel reaction could be coupled with
an atom-economic in situ generation of the required alde-
hyde. For this purpose we chose our recently developed re-
gioselective room-temperature/ambient-pressure (RTAP)
hydroformylation by employing the self-assembling 6-
DPPon/RhI catalyst. Such a one-pot regioselective hydrofor-
mylation/decarboxylative Knoevenagel reaction would in-
stall a C3 extension of a terminal alkene, and would thus
correspond to a formal and hitherto unknown cross-hydroal-
kenylation of a terminal alkene with acrylic acid.[12] Initial
experiments showed that the reaction conditions of the de-
carboxylative Knoevenagel are incompatible with the condi-
tions of RTAP-hydroformylation protocol, which precluded
a Tandem process. However, a very efficient and practical
one-pot process was developed. Thus, first hydroformylation
Scheme 6. An example of a one-pot RTAP hydroformylation/Knoevena-
gel reaction to a,b-unsaturated carboxylic ester 5.
many functional groups including free-alcohol functionalities
as well as acetales and carbamates were tolerated (for sub-
strate scope see Table 5).
was performed with [RhACHTUNGTRENN(UNG acac)(CO)2]/6-DPPon (acac=ace-
tylacetonate) as the catalyst precursor in a flat-bottomed
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B. Breit et al.
Synthesis of b,g-unsaturated carboxylic acids: Simple linear
b,g-unsaturated carboxylic moieties are found in natural
products, identified among volatile constituents, isolated
from various fruits and food, and have also been reported as
pheromones and as important synthetic intermediates.[15]
Those can be easily transformed into lactones,[16] homoallylic
alcohols,[17] and unsaturated macrolides.[18] Therefore, the
preparation of b,g-unsaturated carboxylic acids is attractive
and interesting in organic synthesis. A variety of methods,
such as the cross-alkene metathesis, have been reported for
preparing b,g-unsaturated carboxylic acids, which give the
desired products in good yield but with moderate stereose-
lectivity. In many cases, specific reagents and catalysts had
to be used or the reaction suffered from severe reaction
conditions and a limited substrate tolerance.[5b,f,19] None of
these methods is as simple and atom economic as the decar-
boxylative Knoevenagel reaction. In 1998 Ragoussis et al.
reported a synthesis of b,g-unsaturated carboxylic acids in
good yields and with good selectivity by employing the de-
carboxylative Knoevenagel reaction. The reaction proceed-
ed in DMF (or DMSO) at 1008C with piperidinium acetate
(1–4 mol%) as the sole catalyst.[20] However, under these
conditions, the substrate scope is limited. To overcome these
limitations we were interested to identify milder reaction
conditions, which would allow us to run the deconjugative
and decarboxylative Knoevenagel reaction at lower temper-
atures. When we used our optimized standard conditions
and exchanged pyridine by the less nucleophilic base 2,6-lu-
tidine, the reaction of capronaldehyde with malonic acid fur-
nished a 57:43 mixture of a,b- versus b,g-unsaturated car-
boxylic acid 2 (Table 2, entry 2). Increasing the reaction
temperature to 408C led to an increased amount of the de-
conjugative product (a,b/b,g 8:92, entry 4). When using 2,6-
di-tert-butylpyridine no improvement was observed (a,b/b,g
31:69, entry 6). Interestingly, employing the stronger base
tetramethylguanidine (TMG) gave excellent chemoselectivi-
ty towards the deconjugated product, albeit the conversion
was low (a,b/b,g 1:99, entry 7). Changing towards 1,8-
diazabicycloACTHUNGETRNNU[G 5.4.0]undec-7-ene (DBU) gave both excellent
chemoselectivity and conversion (a,b/b,g 1:99, entry 8).
Interestingly, under these reaction conditions, the pres-
ence of pyrrolidine is no longer essential (Table 2, entry 9),
which suggests that these reactions proceed by a different
reaction mechanism (vide infra). Optimized reaction condi-
tions require two equivalents of DBU and a reaction tem-
perature of 408C (compare entries 9–11). With these condi-
tions in hand we again combined them with RTAP-hydrofor-
mylation in a one-pot operation, and thus prepared a wide
variety of functionalized b,g-unsaturated acids in good
yields and with high selectivities (see Scheme 7 and
Table 5).
Scheme 7. An example of a one-pot RTAP hydroformylation/Knoevena-
gel reaction to b,g-unsaturated carboxylic acid 6.
Synthesis of (E)-a-cyano acrylic acids: Our next objective
was the use of nitrile acetic acid as a methylene-active re-
agent to prepare a-cyano acrylic acids, which are interesting
intermediates for the synthesis of b2-amino acids[21] (which
are important building blocks in medicinal chemistry),[22]
and find applications as organocatalysts.[23] The most fre-
quently used access towards a-cyano acrylic acids is provid-
ed by the Knoevenagel condensation, which employs an
excess of pyridine or piperidine with heating.[24] Reports on
reaction conditions employing catalytic amounts of a base
are rare.[25] To the best of our knowledge, there is no report
on a Knoevenagel condensation of nitrile acetic acid, which
occurs without heating in the presence of a catalytic amount
of an amine base. Thus, subjection of nitrile acetic acid and
capronaldehyde to our optimized conditions for the decar-
boxylative Knoevenagel con-
densation furnished the a-
cyano acrylic acid 7 with excel-
lent E/Z selectivity (from
Table 2. Variation of the bases to furnish b,g-unsaturated carboxylic acids by starting from capronaldehyde by
using a decarboxylative Knoevenagel reaction.
>99:1) and
a
good yield.
Hence, under these conditions a
decarboxylation did not occur.
Thus, the presence of pyridine,
which is essential for the decar-
boxylation process, should be
unnecessary to provide the
Entry
Base 1 (equiv)
Base 2 (mol%)
T [8C]
NMR yield [%][a]
Ratio 1/2
1[b]
2[b]
3[c]
4
5
6
7
8
9
10
11
pyridine (2)
2,6-lutidine (2)
2,6-lutidine (2)
2,6-lutidine (2)
2,6-lutidine (1)
2,6-di-tBu-pyridine (2)
TMG (2)
DBU (2)
DBU (2)
DBU (2)
DBU (1)
pyrrolidine (1)
pyrrolidine (1)
pyrrolidine (1)
pyrrolidine (1)
pyrrolidine (1)
pyrrolidine (1)
–
10
10
RT
40
40
40
40
40
40
RT
40
1 (93), 2 (1.6)
1 (4), 2 (3)
98:2
57:43
12:88
8:92
18:82
31:69
1:99
1:99
1:99
–
1 (12), 2 (88)
1 (5), 2 (90)
1 (18), 2 (82)
1 (22), 2 (50)
1 (0), 2 (57)
1 (0), 2 (93)
1 (0), 2 (94)
1 (0), 2 (0)
Knoevenagel
condensation
product 7. Indeed running the
same reaction in the absence of
pyridine led to Knoevenagel
condensation product 7 in a
similar yield (Table 3, entries 1
and 2). On the other hand,
when employing pyridine alone,
pyrrolidine (1)
–
–
–
1 (0), 2 (30)
1:99
[a] 1H NMR spectra detected, trimethoxybenzene as standard. [b] 08C/10 min, 108C/20 h, RT/4 h, direct hydro-
formylation/Knoevenagel one-pot reaction with 1-octene. [c] 4 d reaction time.
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Homologation of Alkenes to Carbonyl and Carboxylic Compounds
FULL PAPER
Table 3. Synthesis of a,b-unsaturated nitrile acetic acids by starting from capronaldehde—reaction optimiza-
tion.
lents of DBU. The correspond-
ing unsaturated nitriles 8 and
10 were obtained as a 92:8 mix-
ture, both as a mixture of cis-
and trans-alkene isomers, re-
spectively (Table 4, entry 3).
Entry
Base 1 (equiv)
Base 2 (mol%)
T [8C]
NMR yield[a] 7 [%]
Ratio 7/8
1
2
3
pyridine (2)
–
pyridine (2)
pyrrolidine (1)
pyrrolidine (1)
–
RT
RT
RT
98
97
>99:1
>99:1
–
The amount of DBU em-
ployed in the course of the re-
action had an important influ-
ence on the ratio of unsaturated
no reaction
[a] 1H NMR spectra detected, trimethoxybenzene as standard.
Table 4. Results of decarboxylative Knoevenagel condensation of capro-
naldehyde with nitrile acetic acid in the presence of varying amounts of
DBU.
the Knoevenagel condensation did not occur at all (Table 3,
entry 3).
By using these optimized Knoevenagel condensation con-
ditions, a one-pot procedure with our RTAP-hydroformyla-
tion by starting with 1-octene furnished the corresponding
a-cyano acrylic acid derivative 9 with the best selectivity
and in good yield (a,b/b,g 1:99, E/Z 99:1, 75%, Scheme 8).
Entry Base (equiv) T [8C] t [h] NMR yield [%]
Ratio 8/10[a]
7 (–), 8 (78), 10 (10) 89:11
7 (–), 8 (81), 10 (16) 83:17
7 (–), 8 (77), 10 (7) 92:8
7 (–), 8 (34), 10 (44) 44:56
7 (–), 8 (78), 10 (22) 78:22
1
2
3
4
5
6
7
DBU (3.0)
DBU (1.5)
DBU (1.5)
DBU (1.0)
DBU (0.5)
DBU (0.5)
DBU (0.1)
RT
RT
40
40
RT
40
24
24
24
24
24
24
24
7 (–), 8 (7), 10 (69)
7 (50), 8 (0), 10 (0)
9:91
–
RT
[a] Both 8 and 10 are a mixture of cis and trans isomers in a ratio of ca.
1:1, as determined by H NMR spectroscopy.
Scheme 8. One-pot RTAP hydroformylation/Knoevenagel reaction to-
wards the a-cyano acrylic acid derivative 9.
1
Alkene geometry was confirmed by NOESY experiments
(see the Supporting Information). Also here, the reaction
conditions could be applied to a wide range of functional-
ized alkenic substrates (see Scheme 8 and Table 5).
nitriles 8 and 10. While 1.5 equivalents of DBU seemed to
be the optimum amount to favor the a,b-unsaturated prod-
uct 8, decreasing the amount of DBU to 0.5 equivalents al-
lowed the selective preparation of the b,g-unsaturated nitrile
10 (Table 4, entry 6). Other bases, such as 2,6-lutidine (no
Development of a hydroformylation/decarboxylative Knoe-
venagel one-pot protocol for the synthesis of a,b-unsaturat-
ed nitriles: a,b-Unsaturated nitriles are found as a structural
motif in pheromones,[26] but they also represent versatile bi-
functional building blocks for organic synthesis. Standard
methods for the preparation of a,b-unsaturated nitriles are
Wittig and analogous olefination protocols, the Peterson ole-
fination and related elimination reactions, and the cross-
metathesis reaction.[5b,27–31] Again, these reactions often
suffer from limited substrate tolerance or require special re-
agents. With the a-cyano acrylic acids in hand we had a
closer look at whether a decarboxylative Knoevenagel con-
densation could be an alternative. Interestingly, to the best
of our knowledge, a general decarboxylative Knoevenagel
condensation of a-cyano acrylic acids resulting from the
Knoevenagel condensation with aliphatic aldehydes is un-
known. For the corresponding a-cyano cinnamic acids, re-
sulting from the Knoevenagel condensation with aromatic
aldehydes, the decarboxylation has been described to re-
quire heating to more than 1508C.[32] Surprisingly, we found
that by starting from capronaldehyde and nitrile acetic acid
a smooth decarboxylative Knoevenagel condensation oc-
curred at room temperature in the presence of 1.5 equiva-
reaction) and 1,4-diazobicycloACTHNGUTERNNU[G 2.2.2]octane (mixture of un-
known products) were not efficient.
With these conditions in hand, we again combined them
with the RTAP-hydroformylation reaction in a one-pot op-
eration, and thus could prepare a wide variety of functional-
ized a,b-unsaturated nitriles in good yields (see Table 5).
Two-carbon homologation of aldehydes and a,b-unsaturated
carboxylic acids: The two-carbon homologation of the alkyl
chain of aldehydes or carboxylic acids (Scheme 9) is a syn-
thetic problem commonly encountered in the literature. Typ-
ically Wittig or related Horner–Wadsworth–Emmons reac-
tions and subsequent functional-group interconversions are
used.[33] These methods usually suffer from bad atom econo-
my and relatively low functional-group tolerance.
Scheme 9. Two-carbon homologation of aldehydes and a,b-unsaturated
carboxylic acids, R=alkyl or aryl.
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B. Breit et al.
Table 5. RTAP hydroformylation/decarboxylative Knoevenagel one-pot reaction of functionalized terminal alkenes with the Rh/6-DPPon system and an
organocatalyst.
Substrate 1
CH
(CO2H)Rꢃ
Rꢃ=CO2H[b] 4a–e
Rꢃ=CO2H[c] 6a–e
Rꢃ=CO2Me[b] 5a–e
Rꢃ=CN[d] 9a–e
Rꢃ=CN[e] 11a–e
l/b 99:1[f]
yield [%][g]
77
98:2
75
1:99
80
98:2
80
99:1
70
85:15
a,b/b,g[h]
l/b 99:1
l/b 99:1
l/b 99:1
l/b 99:1
l/b 99:1
yield [%]
a,b/b,g
72
98:2
59
1:99
68
97:3
82
99:1
48
85:15
yield [%]
a,b/b,g
75
99:1
89
1:99
80
94:6
57
99:1
60
81:19
yield [%]
a,b/b,g
68
99:1
78
1:99
60
92:8
72
99:1
45
88:12
yield [%]
a,b/b,g
68
98:2
76
1:99
62
98:2
69
99:1
67
86:14
yield [%]
69
53
69
63
55
a,b/b,g
98:2
1:99
98:2
99:1
87:13
[a] Conditions (RTAP hydroformylation): [RhACHTUNGTREN(NGNU acac)(CO)2] (0.66 mol%), 6-DPPon (3.33 mol%), alkene (1.0 equiv), CO/H2 (1:1) 1 atm., THF (c0-
ACHTUNGTRENNUNG
pyridine (2.0 equiv), pyrrolidine (1 mol%), 20 h at 108C then 4 h at RT. [c] Conditions (decarboxylative Knoevenagel): malonic acid (1.0 equiv), DBU
(2.0 equiv), 24 h at 408C. [d] Conditions (Knoevenagel): nitrile acetic acid (1.1 equiv), pyrrolidine (1 mol%), 24 h at RT, no Z isomer was determined in
the 1H NMR spectra. [e] Conditions (decarboxylative Knoevenagel): nitrile acetic acid (1.1 equiv), pyrrolidine (1 mol%), 24 h at RT, DBU (2.0 equiv),
24 h at RT, a mixture of cis and trans isomers in a ratio of 1:1 was observed, as determined by the 1H NMR spectra. [f] Ratio of the intermediate alde-
1
hyde regioisomers of the hydroformylation, (isomerization to the internal alkene <5%), H NMR spectra detected. [g] Isolated yield of the unsaturated
1
product. [h] Ratio of the two regioisomers of the Knoevenagel reaction, H NMR spectra detected.
In the previous chapters, two-carbon elongation of alde-
hydes to give a,b-unsaturated carboxylic acid by a decarbox-
ylative Knoevenagel reaction was described. Recently, our
group reported a new catalytic transformation of a,b-unsatu-
rated carboxylic acids to aldehydes (decarboxylative hydro-
formylation).[34] We envisaged the combination of these two
catalytic methods as a homologation process for both alde-
hydes and a,b-unsaturated carboxylic acids (Scheme 10). In-
spiration for this concept came from the biosynthesis of
fatty acids carried out by a multifunctional enzyme com-
plex–fatty acid synthase (Scheme 11).[35] The fatty acid is
Scheme 10. Concept for the homologation of a,b-unsaturated carboxylic
anchored to the acyl-carrier protein (ACP) and the acyl
acids and aldehydes.
3428
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Homologation of Alkenes to Carbonyl and Carboxylic Compounds
FULL PAPER
Scheme 12. One-pot C2 homologation of oct-2-enoic acid 1.
Scheme 11. Biosynthesis of fatty acids.
synthesis gas was removed by bubbling argon through the
solution. Malonic acid (1 equiv), pyridine (2 equiv), and pyr-
rolidine (1 mol%) were added and the reaction mixture was
stirred for a further 24 h at RT to furnish dec-2-enoic acid
14.
chain grows by two carbon atoms in each cycle. Two reduc-
tions and one dehydration are required to convert the b-
keto group to an alkyl group forming a substrate, which can
again enter the cycle. Although the synthetic and natural
cycle employ completely different chemical reactions and
catalysts, the stoichiometric byproducts of both processes
are the same (CO2 and H2O). Obviously the atom economy
is similar in both cases. To explore the synthetic potential of
our method, aliphatic aldehydes were subjected to the two-
step homologation procedure by using guanidine ligand 13
for the decarboxylative hydroformylation.[34] Aldehydes
(12a–e) were obtained in 62–84% yields over two steps
(Table 6).
Mechanistic discussion: Accordingly, the decarboxylative
condensation of malonic acid derivatives presents an inter-
esting, atom-economic alternative to the more traditional
carbon–carbon bond-forming reactions. These and analo-
gous processes are relatively rarely synthetically exploited
so far because of the dominating controversy concerning the
mechanism.
Our results confirm a correlation between the catalyst nu-
cleophilicity, the basicity, and the chemoselectivity of the de-
carboxylative Knoevenagel reaction (Table 7).[36] On the one
hand, a weak but nucleophilic base like pyridine afforded
the decarboxylation to a,b-unsaturated carboxylic acids
(Table 7, entry 1); on the other hand, a rather strong but
less nucleophilic base, such as DBU led to the b,g-isomer se-
lectively (Table 7, entry 4). Bases with pKa values between
these two bases led either to bad selectivity (Table 7,
entry 2, 2,6-lutidine) or low conversion (Table 7, entry 3,
TMG). We reasoned that under these conditions two differ-
ent mechanisms are operating (Scheme 13). The first step is
in both cases A and B a classical Knoevenagel condensation
that is catalyzed by the secondary amine, which here is pyr-
rolidine, via the formation of highly electrophilic iminium
ion intermediates from the corresponding aldehyde with for-
mation of diacid 15. The same intermediate, alkylidenma-
lonic acid 15, could be isolated when pyrrolidine was used
as the sole catalyst. This step is fast and shows over 50%
conversion after 30 min at 108C. When 15 was treated with
pyridine, a smooth decarboxylation occurred and furnished
the a,b-unsaturated carboxylic acid 1.[9a] Hence, a two-step
mechanism is most likely. We propose that pyridine func-
tionalities (see pathway A) as a Lewis basic catalyst that un-
dergoes conjugate addition to Knoevenagel product 15 fol-
lowed by decarboxylation via the indicated transition-state
16. In pathway B, diacid 15 undergoes a base-catalyzed
double-bond isomerization to the b,g-unsaturated carboxyl-
ate 17. We assume that more than one equivalent of base is
necessary due to the deprotonation of acid 15. Mechanistic
studies by Corey et al. led to the proposal that decarboxyla-
tion of a,b-unsaturated malonic acids 1 can only proceed via
b,g-unsaturated intermediate 18, which then smoothly decar-
boxylates to the b,g-unsaturated carboxylic acid 2.[37] This
mechanism probably also operates during the condensation
of malonic acid and aliphatic aldehydes catalyzed by piperi-
Table 6. Two-carbon homologation of aliphatic aldehydes.[a]
Entry
1
Substrate
Product
Yield [%][b]
84[c]
2
3
76[d]
83[d]
4
5
62[e]
73[e,f]
[a] Conditions: (decarboxylative Knoevenagel): malonic acid (1.0 equiv),
pyridine (2.0 equiv), pyrrolidine (1–3 mol%), RT to 608C, 24 h. Condi-
tions: (decarboxylative hydroformylation): [RhACTHNUTRGNEN(UG acac)(CO)2]/13/substrate
1:10:200, c0(substrate)=0.2m, CH2Cl2 (8 mL), 13 bar CO/H2 (1:1), 258C,
24 h. [b] Yields of aldehyde products over two steps. [c] GC yield.
[d] NMR yield. [e] Isolated yield. [f] Over 3 steps by starting from 4-phe-
nylbut-1-ene (RTAP hydroformylation–decarboxylative Knoevenagel–de-
carboxylative hydroformylation).
Of course, the order of reactions can be also changed
giving an efficient two-carbon elongation of a,b-unsaturated
carboxylic acids. More interestingly, this transformation
could be also performed as
a
one-pot procedure
(Scheme 12). Decarboxylative hydroformylation of (E)-oct-
2-enoic acid 1 was conducted as described.[34] After 24 h,
Chem. Eur. J. 2010, 16, 3423 – 3433
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www.chemeurj.org
3429

B. Breit et al.
Table 7. Correlation between the strength of the base used and the regioselectivity of the Knoevenagel reaction.
[a]
Entry
Base
pKa
Ratio 1/2 at 108C
Ratio 1/2 at 408C
1
2
3
4
pyridine
2,6-lutidine
TMG
12.3
13.9
23.3
24.2
98:2 full conversion
57:43 good conversion
n.d.[b]
n.d.[b]
8:92 good conversion
1:99 low conversion
1:99 full conversion
DBU
no conversion
[a] pKa of the conjugated acid in CH3CN. [b] Not determined.
Scheme 13. Proposed mechanism, which is dependent upon the base used.
dinium acetate in dimethyl sulfoxide at 1008C as described
Experimental Section
by Ragoussis et al.[25,38]
Typical procedure for the synthesis of a,b-unsaturated carboxylic acids
(Table 5, 4a–e, (E)-undec-2-enoic acid (4)): Under an atmosphere of
argon, 1-octene (785 mL, 5.00 mmol, 150 equiv) was added to a solution
Conclusion
of 6-DPPon (46.7 mg, 167 mmol, 5.00 equiv) and [RhACHTUNTGRNENG(U acac)(CO)2]
(8.50 mg, 33.0 mmol, 1.00 equiv) in THF (5 mL, 1m according to the
alkene) at room temperature in a flat-bottomed Schlenk tube. The argon
atmosphere was replaced by synthesis gas (balloon). The reaction mix-
ture was stirred at room temperature and ambient pressure for 20 h. Sub-
sequently, the synthesis gas was removed over 20 min by bubbling argon
through the solution. The solution was cooled to 08C and malonic acid
(520 mg, 5.00 mmol, 150 equiv), pyridine (809 mL, 10.0 mmol, 300 equiv),
and pyrrolidine (4.00 mL, 50.0 mmol, 1.50 equiv) were added. The reaction
mixture was warmed to 108C and stirred for 20 h at this temperature,
and then an additional 4 h at room temperature. The reaction was finish-
ed by the addition of aqueous H3PO4 (20%, 10 mL). After phase separa-
tion, the aqueous phase was extracted three times with ethyl acetate and
the combined organic phases were dried over MgSO4. The solvent was
removed in vacuo. Purification by flash chromatography (silica gel, petro-
leum ether/diethyl ether/acetic acid 100:20:1) furnished 710 mg (77%) of
the acid as a colorless oil. 1H NMR (400.132 MHz, CDCl3): d=0.88 (t,
J=7.0 Hz, 3H), 1.20–1.36 (m, 10H), 1.43–1.50 (m, 2H), 2.23 (tdd, J=7.2,
7.2, 1.6 Hz, 2H), 5.82 (dt, J=15.6, 1.6 Hz, 1H), 7.09 (dt, J=15.6, 7.0 Hz,
1H), 11.9 ppm (brs, 1H); 13C{1H} NMR (100.626 MHz, CDCl3): d=14.1,
22.7, 27.9, 29.2, 29.2, 29.4, 31.9, 32.3, 120.6, 152.5, 172.3 ppm; MS (CI,
NH4Cl, 130 eV): m/z (%): calcd for C11H20O2: 184.15; found: 202.1 (100)
[M+NH4]+; elemental analysis calcd (%) for: C 71.20, H 10.94; found: C
71.53, H 10.98.
Traditionally, each unit operation advances the synthesis by
a single step, which wastes solvents, time, and energy. The
efficient synthesis of unsaturated (carboxylic) compounds
and the “homologation process” described in this work rep-
resent examples of the new paradigm of sustainable chemis-
try: multiple reactions carried out in a single vessel promot-
ed by compatible catalysts.[39] Thus, combining our recently
developed regioselective room-temperature/ambient-pres-
sure hydroformylation (transition-metal catalysis) with a
new variant of the decarboxylative Knoevenagel reaction
(organocatalysis) allowed for the development of an effi-
cient, one-pot C3 homologation of terminal alkenes to fur-
nish (E)-a,b-unsaturated acids and esters, (E)-b,g-unsaturat-
ed acids, (E)-a-cyano acrylic acids, and a,b-unsaturated ni-
triles. All reactions proceed under mild conditions, tolerate
a variety of functional groups, and furnish unsaturated car-
bonyl compounds in good yields and with excellent regio-
and stereocontrol. Further, inspired by fatty-acid biosynthe-
sis an iterative two-carbon homologation of the (E)-a,b-un-
saturated carboxylic acid is possible through a combination
of a decarboxylative hydroformylation by employing a
supramolecular catalyst system followed by a decarboxyla-
tive Knoevenagel condensation, which makes use of an or-
ganocatalyst.
Typical procedure for the synthesis of a,b-unsaturated carboxylic esters
(Table 5, 5a–e, (E)-methyl-2-undecenoate (5)): Under an atmosphere of
argon, 1-octene (785 mL, 5.00 mmol, 150 equiv) was added to a solution
of 6-DPPon (64.7 mg, 167 mmol, 5.00 equiv) and [RhACHTUNTGRNENG(U acac)(CO)2]
(8.50 mg, 33.0 mmol, 1.00 equiv) in THF (5 mL, 1m according to the
alkene) at room temperature in a flat-bottomed Schlenk tube. The argon
atmosphere was replaced by synthesis gas (balloon). The reaction mix-
ture was stirred at room temperature and ambient pressure for 20 h. Sub-
sequently, the synthesis gas was removed over 20 min by bubbling argon
through the solution. The solution was cooled to 08C and malonic acid
methyl ester (556 mL, 5.50 mmol, 165 equiv), pyridine (809 mL,
3430
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Chem. Eur. J. 2010, 16, 3423 – 3433

Homologation of Alkenes to Carbonyl and Carboxylic Compounds
FULL PAPER
10.0 mmol, 300 equiv), and pyrrolidine (2.00 mL, 24.0 mmol, 1.50 equiv)
were added. The reaction mixture was warmed to 408C and stirred for
20 h at this temperature, and then an 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 combined organic phases were dried
over MgSO4. The solvent was removed in vacuo. Purification by flash
chromatography (silica gel, short column with CH2Cl2) furnished 793 mg
(80%) of the ester 5 as a colorless oil. 1H NMR (400.132 MHz, CDCl3):
d=0.88 (t, J=6.9 Hz, 3H), 1.24–1.31 (m, 10H), 1.41–1.48 (m, 2H), 2.20
(m, 2H), 3.72 (s, 3H), 5.79–5.84 (dt, J=15.7, 7.0 Hz, 1H), 6.93–7.01 ppm
(dt, J=15.7, 1.5 Hz, 1H); 13C{1H} NMR (100.626 MHz, CDCl3): d=24.2,
72.7, 28.1, 29.2, 29.3, 29.4, 31.9, 32.3, 51.5, 65.9, 120.9, 150.0, 167.3 ppm;
the analytical data match with those reported in literature.[40]
Typical procedure for the synthesis of a,b-unsaturated nitriles (Table 5,
11a–e, undec-2-enenitrile (11)): Under an atmosphere of argon, 1-octene
(314 mL, 2.00 mmol, 150 equiv) was added to a solution of 6-DPPon
(18.6 mg, 66.6 mmol, 5.00 equiv) and [RhACTHNUTRGNEG(NU acac)(CO)2] (3.40 mg,
13.3 mmol, 1.00 equiv) in THF (2 mL, 1m according to the alkene) at
room temperature in a flat-bottomed Schlenk tube. The argon atmos-
phere was replaced by synthesis gas (balloon). The reaction mixture was
stirred at room temperature and ambient pressure for 20 h. Subsequently,
the synthesis gas was removed over 20 min by bubbling argon through
the solution. At room temperature, nitrile acetic acid (187 mg,
2.20 mmol, 165 equiv) and pyrrolidine (2.00 mL, 0.02 mmol, 1.5 equiv)
were added and the reaction mixture was stirred at room temperature for
24 h. Then DBU (450 mL, 3.00 mmol, 225 equiv) was added and the reac-
tion mixture was stirred for an additional 24 h at room temperature. The
reaction was finished by the addition of aqueous NaOH (1m, up to
pH 11). After phase separation, the aqueous phase was extracted three
times with ethyl acetate and the combined organic phases were dried
over MgSO4. The solvent was removed in vacuo. Purification by flash
chromatography (silica gel, cyclohexane/ethyl acetate 20:1, Rf =0.45) fur-
nished 233 mg (70%) of the nitrile 11 as a colorless liquid. 1H NMR
(400.132 MHz, CDCl3): d=0.88 (t, J=6.9 Hz, 3H), 1.27–1.4 (m, 10H),
1.49–1.51 (m, 2H), 2.21 (tdd, J=7.0, 7.0, 1.7 Hz, 2H; trans), 2.42 (tdd, J=
7.4, 7.4, 1.4 Hz, 2H; cis), 5.31 (dt, J=11.0, 1.4 Hz, 1H; cis), 5.31 (dt, J=
16.3, 1.7 Hz, 1H; trans), 6.47 (dt, J=10.9, 7.7 Hz, 1H; cis), 6.72 ppm (dt,
J=16.3, 7.0 Hz; trans); 13C{1H} NMR (100.626 MHz, CDCl3): d=14.2,
22.7, 27.7, 28.3, 29.1, 29.2, 29.3, 31.9, 32.0, 33.4, 99.5, 116.2, 117.7, 155.4,
156.3 ppm; MS (EI, 70 eV): m/z (%): calcd for C11H19N: 165.28; found
164.2 (23) [MÀH]+, 150.1 (46) [MÀNH]+, 136.1 (100) [MÀCH3N]+,
122.1 (92) [MÀC3H7]+, 108.1 (32) [MÀC4H9]+, 94.1 (47) [MÀC5H11]+,
Typical procedure for the synthesis of b,g-unsaturated carboxylic acids
(Table 5, 6a–e, (E)-2-cyanoundec-2-enoic acid (6)): Under an atmosphere
of argon, 1-octene (785 mL, 5.00 mmol, 150 equiv) was added to a solu-
tion of 6-DPPon (64.7 mg, 167 mmol, 5.00 equiv) and [RhACHTUNGRTNEUNG(acac)(CO)2]
(8.50 mg, 33.0 mmol, 1.00 equiv) in THF (5 mL, 1m according to the
alkene) at room temperature in a flat-bottomed Schlenk tube. The argon
atmosphere was replaced by synthesis gas (balloon). The reaction mix-
ture was stirred at room temperature and ambient pressure for 20 h. Sub-
sequently, the synthesis gas was removed over 20 min by bubbling argon
through the solution. At room temperature malonic acid (520 mg,
5.00 mmol, 150 equiv) and DBU (1.50 g, 10.0 mmol, 300 equiv) were
added. The reaction mixture was stirred for 24 h at room temperature.
The reaction was finished by the addition of aqueous NaOH (1m, up to
pH 11). After phase separation, the aqueous phase was extracted three
times with ethyl acetate and the aqueous phase was acidified by adding
aqueous H3PO4 (20%, down to pH 2). This aqueous phase was extracted
three times with ethyl acetate and the combined organic phases were
dried over MgSO4. The solvent was removed in vacuo to furnish 688 mg
94.1 (47) [MÀC6H13]+, 80.1 (53) [MÀC6H13]+; HRMS: m/z: (CI, Cl
130 eV, 300 mA): calcd for C11H19N: 164.1440; found: 164.1439.
ACHTUNGTRENNUNG(NH3),
Procedure for the one-pot decarboxylative hydroformylation/decarboxy-
lative Knoevenagel reaction to (E)-dec-2-enoic acid (14) (Scheme 12):
Decarboxylative hydroformylation of (E)-oct-2-enoic acid (227 mg,
1.60 mmol) was carried out according to the literature procedure.[34] Sub-
sequently, the autoclave was depressurized and the synthesis gas was re-
moved over 20 min by bubbling argon through the solution. The solution
was cooled to 08C and malonic acid (167 mg, 1.60 mmol), pyridine
(259 mL, 253 mg, 3.20 mmol), and pyrrolidine (1.30 mg, 16.0 mmol) were
added. The reaction mixture was warmed to RT and stirred for 24 h at
this temperature (76% conversion of the Knoevenagel reaction). The re-
action was finished by the addition of aqueous H3PO4 (20%, 10 mL) at
08C. It was extracted three times with CH2Cl2, the combined organic
phases were dried (Na2SO4), and the solvent was removed in vacuo. Pu-
rification by chromatography (silica gel, petroleum ether/Et2O/AcOH
100:20:1) furnished 183 mg (67%) of the acid 14 as a colorless liquid.
1H NMR (400.132 MHz, CDCl3): d=0.88 (t, J=7.0 Hz, 3H); 1.17–1.38
(m, 8H); 1.41–1.56 (m, 2H); 2.23 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 5.82 (dt,
J=15.7, 1.5 Hz, 1H), 7.09 (dt, J=15.7, 7.0 Hz, 1H), 12.0 ppm (brs, 1H);
13C{1H} NMR (100.626 MHz, CDCl3): d=14.0, 22.5, 27.8, 29.0, 29.6, 31.6,
32.2, 120.5 (s, 1C; C2), 152.4 (s, 1C; C3), 172.3 ppm (s, 1C; COOH); the
analytical data match with those reported in the literature.[9f]
(75%) of the acid
6 as a
colorless solid. M.p. 48–508C; 1H NMR
(400.132 MHz, CDCl3): d=0.88 (t, J=5.8 Hz, 3H), 1.22–1.32 (m, 10H),
2.00–2.05 (m, 2H), 3.05–3.08 (m, 2H), 5.46–5.62 ppm (m, 2H);
13C{1H} NMR (100.613 MHz, CDl3): d=14.1, 22.7, 27.8, 29.1, 29.2, 29.3,
31.8, 32.4, 109.4, 113.1, 166.3, 166.4 ppm; MS (EI, 70 eV, 500 mA): m/z
(%): calcd for C12H19NO2: 209.14; found: 210.1 (19) [M+H]+, 166.1 (35)
[MÀCNÀOH]+, 164.1 (25) [MÀCO2H]+, 138.0 (58) [MÀCOOHÀCN]+;
HRMS (CI, ClACHTUNGTRENNUNG(NH3), 130 eV, 300 mA): m/z: calcd for C12H19NO2+NH4:
227.17595; found: 277.17580.
Typical procedure for the synthesis a-cyano acrylic acids (Table 5, 9a–e,
(E)-undec-3-enoic acid (9)): Under an atmosphere of argon, the alkene
(5.00 mmol, 150 equiv) was added to a solution of 6-DPPon (167 mmol,
5 equiv) and [RhACHTUNGTRENNUNG(acac)(CO)2] (33.0 mmol, 1 equiv) in THF (5 mL, 1m ac-
cording to the alkene) at room temperature. The argon atmosphere was
replaced by synthesis gas (balloon). The reaction mixture was stirred at
room temperature and ambient pressure for 20 h. Subsequently, the syn-
thesis gas was removed over 20 min by bubbling argon through the solu-
tion. At room temperature, nitrile acetic acid (486 mg, 5.5 mmol,
165 equiv) and pyrrolidine (4.00 mL, 50.0 mmol, 1.5 equiv) were added
and the reaction mixture was stirred at room temperature for 24 h. The
reaction was finished by the addition of aqueous NaOH (1m, up to
pH 11). After phase separation, the aqueous phase was extracted three
times with ethyl acetate and the aqueous phase was acidified by adding
aqueous H3PO4 (20%, down to pH 2). This aqueous phase was extracted
three times with ethyl acetate and the combined organic phases were
dried over MgSO4. The solvent was removed in vacuo to furnish 640 mg
Acknowledgements
(77%) of the acid
9 as a
colorless solid. M.p. 63–658C; 1H NMR
This work was supported by the DFG (International Research Training
Group: “Catalysts and Catalytic Reactions for Organic Synthesis”, GRK
1038) and the Alfried Krupp Foundation.
(400.132 MHz, CDCl3): d=0.88 (t, J=6.6 Hz, 3H), 1.27–1.36 (m, 10H),
1.53–1.61 (tt, J=7.2, 7.2 Hz, 2H), 2.57–2.62 (td, J=7.5, 7.5 Hz, 2H), 7.74
(t, J=7.9 Hz, 1H), 10.74 ppm (brs, 1H); 13C{1H} NMR (100.613 MHz,
CDl3): d=14.1, 22.7, 27.8, 29.1, 29.2, 29.3, 31.8, 32.4, 109.4, 113.1, 166.3,
166.4 ppm; MS (EI, 70 eV, 500 mA): m/z (%): calcd for C12H19NO2:
209.14; found: 210.1 (19) [M+H]+, 166.1 (35) [MÀCNÀOH]+, 164.1 (25)
[1] R. W. Hoffmann, Synthesis 2006, 3531–3541.
[2] a) J. B. Hendrickson, J. Am. Chem. Soc. 1975, 97, 5763–5784; J. B.
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[MÀCO2H]+, 138.0 (58) [MÀCOOHÀCN]+; HRMS (CI, Cl
ACHTUNGTNER(NUGN NH3),
130 eV, 300 mA): m/z: calcd for C12H19NO2+NH4: 227.17595; found:
277.17580.
Chem. Eur. J. 2010, 16, 3423 – 3433
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www.chemeurj.org
3431

B. Breit et al.
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Received: November 25, 2009
Published online: February 3, 2010
Chem. Eur. J. 2010, 16, 3423 – 3433
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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