Merging domino and redox chemistry: Stereoselective access to di- and trisubstituted β,γ-unsaturated acids and esters

Article abstract of DOI:10.1002/chem.201103763

Merging is the game! The coupling of a domino reaction and an internal neutral redox reaction constitutes an excellent manifold for the stereoselective synthesis of di- and trisubstituted olefins featuring a malonate unit, an ester, or a free carboxylic acid as substituents at the allylic position (see scheme; MW=microwave). The reaction utilizes simple starting materials (propargyl vinyl ethers), methanol or water as solvents, and a very simple and bench-friendly protocol. Copyright

Full text of DOI:10.1002/chem.201103763

DOI: 10.1002/chem.201103763
Merging Domino and Redox Chemistry: Stereoselective Access to Di- and
Trisubstituted b,g-Unsaturated Acids and Esters
David Tejedor,* Gabriela Mꢀndez-Abt, Leandro Cotos, and Fernando Garcꢁa-Tellado*[a]
The regio- and stereocontrolled access to multisubstituted
alkenes bearing reactive functionalities constitutes a current
topic in organic synthesis. These alkenes are appreciated
building blocks for molecular construction and versatile
platforms for diversity-oriented synthesis.[1] The most devel-
oped and used synthetic approaches to these structural
motifs comprise the olefination of suitable carbonyl deriva-
tives (carbonyl olefination)[2] and the transition-metal-cata-
lyzed cross-coupling reactions of stereodefined alkenyl de-
rivatives.[3] Whereas carbonyl olefination methodologies
present stereochemical limitations and often stereocontrol
problems,[4] the transition-metal-catalyzed cross-coupling ap-
proach requires the previous access to stereodefined alkenyl
derivatives, which adds to the process an extra number of
synthetic transformations and a second synthetic challenge,
the synthesis of the precursor itself. Modern tendencies in
synthetic chemistry demand efficient protocols able to
achieve the molecular construction in a fast manner with
atom and step economy, in a simple and bench-friendly pro-
cess.[5] In this sense, the discovery of metal-free, domino
Scheme 1. Microwave (MW)-assisted rearrangement of PVEs 1.
manifolds for the regio- and stereocontrolled access to mul-
tisubstituted alkenes from easily accessible starting materials
constitutes an important challenge.[5] We report herein the
discovery and development of a novel approach to this chal-
lenge, which is based on the microwave-assisted (MWA) re-
arrangement of propargyl vinyl ethers (PVEs) 1 and utilizes
a [3,3]-propargyl Claisen rearrangement and a [1,5]-hydro-
gen shift as key chemical transformations.
PVE 1a (R=Ph; R1 =nPr) in the presence of molecular
sieves (MS 4 ꢀ) directly afforded the corresponding salicyl-
aldehyde derivative 2a (R=Ph, R2 =Et; 76%), through a
complex domino process involving a sequential [3,3]-pro-
pargyl Claisen rearrangement/pseudo-pericyclic [1,3]-H/eno-
lization/6p-electrocyclization and aromatization set of dis-
crete reactions. Overall, the process generated one equiva-
lent of methanol per equivalent of salicylaldehyde produced.
In the absence of MS 4 ꢀ (an efficient methanol scavenger),
the domino process delivered the corresponding salicylalde-
hyde 2a (41%) and the b,g-unsaturated malonate ester 3a
(50%). We envisioned that the formation of 3a could be
mediated by the formation of the redox active hemiacetal
6a through a [1,5]-hydrogen shift from the hemiacetal
center to the terminus of the conjugated diene with the con-
comitant rearrangement of the dienic chain. Although ex-
amples of formation of activated carboxylates by direct in-
ternal redox reactions from a,b,g,d-unsaturated aldehydes
have been described,[7,8] in only a few cases have they shown
some preparative value.[8] Evidently, this is not the case of
dienal 5a whose hydricity[9] is not enough to launch a direct
internal redox reaction in the presence of a methanol scav-
enger (MS 4 ꢀ). Thus, the productive formation of the inter-
nal redox reaction product 3a seems to be strongly related
The chemical foundation for this domino manifold was
discovered while exploring the microwave-assisted rear-
rangement of PVEs
1 leading to salicylaldehydes 2
(Scheme 1).[6] We found that the microwave irradiation of
[a] Dr. D. Tejedor, G. Mꢁndez-Abt,+ L. Cotos,+ Dr. F. Garcꢂa-Tellado
Departamento de Quꢂmica Biolꢃgica y Biotecnologꢂa
Instituto de Productos Naturales y Agrobiologꢂa
Consejo Superior de Investigaciones Cientꢂficas
Astrofꢂsico Francisco Sꢄnchez 3
38206 La Laguna, Tenerife (Spain)
Fax : (+34)922-210-635
E-mail: dtejedor@ipna.csic.es
fgarcia@ipna.csic.es
Homepage: http://www.ipna.csic.es/dept/qbb/qb/
[+] These authors have contributed equally to this work
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103763.
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Chem. Eur. J. 2012, 18, 3468 – 3472

COMMUNICATION
with the capacity of the system to selectively produce hemi-
acetal 6a. This issue was experimentally corroborated by
performing the microwave-assisted reaction in methanol, a
solvent unable to react with the starting PVE but highly re-
active toward the intermediate a,b,g,d-unsaturated aldehyde
5. When irradiated in methanol (300 W, 1758C, 1 h, closed
vessel), PVE 1a cleanly afforded the corresponding b,g-un-
saturated malonate 3a in 83% yield with complete regio-
and stereoselectivity (3a was obtained as the unique isomer;
Table 1, entry 1). It deserves to be highlighted how the
Scheme 2. Isotopic labeling experiment.
allylic (C5) position. This fact proved that the hydride mi-
grated directly from the hemiacetalic position (C1) onto the
conjugated diene (C5). The high acidic methine of the malo-
nate function (C2), which largely incorporated deuterium in
the reaction (93% of D incorporation), suffered a large
D/H exchange in the chromatography process, giving an
overall 11% of total deuterium incorporation (see the Sup-
porting Information for details).
Table 1. Stereoselective synthesis of b,g-unsaturated malonates 3 from
PVEs 1.[a]
From a preparative point of view, the reaction offers the
following advantages: 1) the substituted PVEs 1 are readily
available;[10] 2) the substituted (E,E)-dienals 5 are assembled
directly from the corresponding PVEs in a regiocontrolled
manner,[11] and 3) the experimental protocol is operationally
simple and bench-friendly. These advantages are highlighted
when this reaction is compared with the recently described
direct oxidation of the dienals 7 to carboxylic esters 8
(Scheme 3),[8b] which requires the previous formation of
these dienals by a sequential Pd-catalyzed cross-coupling re-
action of stereodefined vinyl iodide derivatives and (E)-
vinyl stannanes, and the corresponding allylic oxidation to
the aldehyde level.
Entry
R
R1
3 [%][b]
1
2
3
4
5
6
7
8
Ph
H
H
Ph
nBu
nBu
Ph
CO2Me
CO2Me
CO2Me
nPr
nPent
Ph
Ph
Ph
nPr
H
tBu
mXylyl
cHex
a
b
c
d
e
f
g
h
i
83
86
90
85
70
91
75[c]
93
94
50
9
10
j
[a] See the Experimental Section for details. [b] Isolated material. [c] 3 h.
chemical efficiency of this reaction involves a complete re-
building of the original carbon–carbon connectivity pattern.
The generality and scope of this redox domino reaction was
studied using the set of PVEs shown in Table 1.[10] In gener-
al, the reaction was tolerant with a broad functional diversi-
ty at the propargylic and sp-terminal positions of the PVE
units. Different combinations of alkyl/aryl/hydrogen sub-
stituents at the propargyl position and ester/alkyl/aromatic/
hydrogen at the sp-terminal position uniformly afforded the
corresponding di- or trisubstituted b,g-unsaturated esters
3b–h in good to excellent yields and with the same stereo-
chemical pattern than 3a (only the isomers bearing the R
and R1 substituents in a trans relationship were observed).
Even the PVE 1j bearing a hydrogen atom at the homopro-
pargylic position and an ester group at the sp-terminal posi-
tion afforded the corresponding triester 3j in a convenient
50% yield (Table 1, entry 10). The combination of these two
substituents generates a particular reactivity profile in the
intermediate a,b,g,d-unsaturated aldehyde 5j (R=CO2Me;
R1 =cHex), which allows the formation of other redox inac-
tive intermediates,[6] and consequently, it reduces the effi-
ciency of the internal redox reaction (Scheme 1).
Scheme 3. Direct oxidation of dienal 7 to carboxylic ester 8.
With these results in hand, we envisioned the feasibility to
perform this reaction under aqueous conditions to access
these valuable synthetic building blocks in a more benign
and sustainable manner.[12] It was expected that the dienal
molecule 5 should express in water the same reactivity pat-
tern as it exhibits in MeOH, affording the corresponding hy-
drates,[13] which should oxidize to the corresponding carbox-
ylic acids. In Nature, aldehyde oxidations to carboxylates
are performed by the NAD+-dependent aldehyde dehydro-
genases (ALDHs) enzymes. The mechanism of these oxida-
tions involves the transformation of the aldehyde in a more
oxidizable thiohemiacetal derivative (ALDHs use cysteine
residues to perform this task) and a hydride transfer to the
NAD+ unit, which plays the role of an activated reducible
functional group.[14] Although we have not found precedents
for the [1,5]-H shift-mediated oxidation of dienals under
aqueous conditions, which gives an added value to this
study,[15] we were concerned with the possibility that the free
carboxylic acid would act as an internal acid catalyst for the
The intermediacy of a [1,5]-hydrogen shift in these reac-
tions was established by isotopic labeling experiments
(Scheme 2). Deuterium incorporation from the solvent re-
sulted in the expected labile positions (esters, C2 and C4).
Therefore, the deuterium label was not incorporated at the
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D. Tejedor, F. Garcꢂa-Tellado et al.
Table 2. Stereoselective synthesis of di- and trisubstituted b,g-unsaturat-
ed esters/acids 10:11 under aqueous conditions.[a]
Scheme 4. Acid-catalyzed transformations of the half-ester malonate in-
termediate.
Entry
R
R1
[%][b]
65[c]
58
82
92
10:11
Stereoselectivity
1
2
3
4
5
6
7
8
Ph
H
H
Ph
nBu
nBu
CO2Me
CO2Me
CO2Me
CO2Me
cHex
nPr
nPent
Ph
Ph
Ph
nPr
tBu
mXyl
cHex
nBu
Ph
a
b
c
d
e
f
h
i
j
1:6
3:1
9:1
15:1
19:1
3.2:1
6:1
3.1:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
6.3:1
2.6:1
1:2.1
1:1.6
1:5.2
2:1
2.4:1
1:1.7
1:12
1:2
hydrolysis of the geminal ester and for the Z/E isomeriza-
tion of the distal double bond, introducing a certain grade
of instability to the redox product (Scheme 4). However, the
characteristic protodecarboxylation reaction of the half-
ester malonates was also expected to occur under micro-
wave irradiation in water. If this reaction were fast enough,
then the side H+-catalyzed reactions could be inhibited and
the expected monoester derivative could be accumulated in
the reaction medium without suffering chemical deteriora-
tion.
69
56[d]
96
96
9
10
11
68[e]
66[f]
57
k
l
[a] See the Experimental Section for details. [b] Isolated material.
[c] H2O (1 mL), 2a (10%). [d] 2 f (12%). [e] 12j (8%). [f] 12k (7%).
With these concerns in mind, we undertook the study of
these reactions under aqueous conditions[16] by using the hy-
drophobic PVE 1a as a model. After some trials, a set of re-
action conditions were selected for the heterogeneous reac-
tion (Scheme 5). Under these conditions, 1a was trans-
tion conditions, there is no significant double-bond migra-
tion to give the corresponding a,b-unsaturated esters/acids.
Consequently, this procedure becomes a simple, metal-free
stereoselective access to di- and trisubstituted b,g-unsaturat-
ed esters/acids, which are valuable synthetic building blocks.
A mechanistic proposal for this reaction is outlined in
Scheme 6A. Three experimental evidences confirm this
mechanistic picture. Firstly, the intermediacy of a [1,5]-H
migration in these reactions was again established by isotop-
ic labeling experiments when the reaction was carried out in
Scheme 5. Microwave-assisted rearrangement of PVE 1a under aqueous
conditions.
formed into the 1:6 mixture of trisubstituted b,g-unsaturated
methyl ester 10a and carboxylic acid 11a in a combined
yield of 65%. Three main characteristics of this reaction de-
serve to be highlighted: Firstly, the stereoselectivity of the
process is good (90% of the E isomer); secondly, the ex-
pected H+-catalyzed ester hydrolysis is achieved with a low
erosion of the alkene stereochemistry (10%), and thirdly,
the expected protodecarboxylation of the half-ester malo-
nate function takes place without significant alkene reorder-
ing.
Once a proof of concept was established, we studied the
scope of this reaction with regard to the nature of the PVE
(Table 2). Three conclusions could be extracted from the
data of Table 2: 1) the reaction showed good tolerance with
regard to the substituents, affording the desired products as
mixtures of the carboxylic acids or esters; 2) the stereoselec-
tivity of the reaction is governed by the nature of the alkyne
substituent R, which is optimal for R=H or CO2Me (up to
90%; Table 2, entries 2, 3, and 7–10); and 3) the isolated
product yields of the products range from good to excellent.
Furthermore, it is worth mentioning that under these reac-
Scheme 6. Microwave-assisted domino-redox rearrangement of PVE 1
under aqueous conditions.
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Merging Domino and Redox Chemistry
COMMUNICATION
Representative procedure for the microwave-assisted reaction of pro-
pargyl vinyl ether in water. Synthesis of b,g-unsaturated carboxylic esters/
acids (10/11): Propargyl vinyl ether 6i (1.00 mmol) and water (0.5 mL)
were placed in a microwave-special closed vial and the solution was irra-
diated for 90 min in a single-mode microwave oven (300 Watt, 1758C).
The products were extracted with CH2Cl2 and the solvent was removed
at reduced pressure. The products were purified by flash column chroma-
tography (silica gel, appropriate mixtures of n-hexane/EtOAc) to yield
10i/11i (2.4:1) (96%).
D2O (see the Supporting Information for details). Secondly,
the allylic ester functionality is stable to hydrolysis in the ab-
sence of a geminal carboxylic acid (Scheme 6B). Lastly, the
isolation of diacids 12j and 12k (Table 2, entries 9 and 10)
establishes that the allylic ester needs to be hydrolyzed
before the protodecarboxylation reaction of the geminal car-
boxylic acid takes place to give the monoacid 11 (H+-cata-
lyzed ester hydrolysis). The free carboxylic acid in 11 could
catalyze the hydrolysis of the vinylic ester to render the
diacid 12.
(E)-dimethyl
1H NMR (400 MHz, CDCl3, 258C) : d=2.28 (s, 6H), 3.52 (d, 3J
6.8, 2H), 3.52 (s, 2H), 3.71 (s, 3H), 3.72 (s, 3H), 6.82 (t, 3J
(H,H)=6.8,
2-(2-(2,6-dimethylphenyl)ethylidene)succinate
(10i):
ACHTUNGTRENNUNG(H,H)=
AHCTUNGTRENNUNG
1H), 7.01–7.08 ppm (m, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=
20.0, 29.5, 32.4, 51.9, 52.0, 125.8, 126.6, 128.3, 135.2, 136.4, 143.5, 167.1,
171.0 ppm; IR (CHCl3) n˜ =3027.6, 2952.7, 1736.8, 1710.9, 1469.1, 1332.5,
1306.7, 1267.4 cmÀ1; MS (70 eV): m/z (%): 244 (8.6) [M+ÀCH3OH], 230
(49), 201 (18), 184 (30), 157 (100), 143 (54), 142 (35), 141 (24), 128 (24),
115 (17), 91 (16); elemental analysis calcd (%) for C16H20O4: C 69.54, H
7.30; found: C 69.35, H 7.10.
The efficiency of this transformation is highlighted when
we take into account that it enables a domino process con-
sisting of a [3,3]-propargyl Claisen rearrangement/pseudo-
pericyclic [1,3]-H shift reaction/diene E/E to E/Z isomeriza-
tion/water addition/redox [1,5]-H shift/ester hydrolysis and
protodecarboxylation.
Finally, the ester–acid mixture (10/11) can be selectively
converted in just one of the two derivatives by the chemical
transformation shown in Scheme 7.
(E)-5-(2,6-dimethylphenyl)-3-(methoxycarbonyl)pent-3-enoic acid (11i):
1H NMR (400 MHz, CDCl3, 258C): d=2.27 (s, 6H), 3.54 (d, 3J
ACHTUNGTRENNUNG(H,H)=
6.8, 2H), 3.56 (s, 2H), 3.72 (s, 3H), 6.84 (t, 3J
ACTHNUTRGNEUNG(H,H)=6.8, 1H), 7.01–
7.08 ppm (m, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=20.1, 29.6,
32.6, 52.1, 125.3, 126.7, 128.4, 135.1, 136.5, 144.0, 167.4, 175.9 ppm; IR
(CHCl3) n˜ =3024.0, 2952.2, 1712.9, 1437.5, 1296.9, 1266.8, 1200.8 cmÀ1
.
MS (70 eV): m/z (%): 262 (5.6) [M+], 230 (37), 201 (25), 184 (31), 157
(100), 143 (56), 142 (49), 141 (30), 128 (30), 115 (28), 91 (26); HRMS
calcd for C15H18O4: 262.1205; found: 262.1205.
Scheme 7. Controlled acid–ester interconversion of the acid–ester mix-
ture 10/11.
Acknowledgements
In summary, we have shown how the coupling of a MWA
domino reaction and an internal neutral redox reaction con-
stitutes an excellent manifold for the stereoselective synthe-
sis of di- and trisubstituted olefins featuring a malonate unit,
an ester, or a free carboxylic acid at the allylic position.
These reactive functionalities can be used as convenient
chemical handles for the development of enantioselective
transformations at the double bond or for the chemical ho-
mologation of these unsaturated platforms. The reaction uti-
lizes simple starting materials (propargyl vinyl ethers),
methanol or water as solvents, and a very simple and bench-
friendly experimental protocol. The reaction in methanol is
highly efficient, rendering the b,g-unsaturated malonate
with complete stereoselectivity. The use of water as the reac-
tion medium changes the chemical outcome of the reaction
to give the corresponding trisubstituted b,g-unsaturated acid
(ester) with high stereoselectivity (up to 19/1).
This research was supported by the Spanish MICINN and the European
RDF (CTQ2008–06806-C02–02), the Spanish MSC ISCIII (RETICS
RD06/0020/1046), FUNCIS (REDESFAC PI01/06). G. M.-A. and L. C.
thank Spanish MEC for FPU and FPI grants, respectively.
Keywords: alkenes · domino reactions · redox chemistry ·
stereoselectivity · water
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Representative procedure for the microwave-assisted reaction of pro-
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column chromatography (silica gel, appropriate mixtures of n-hexane/
EtOAc) to yield 3a (83%).
Chem. Eur. J. 2012, 18, 3468 – 3472
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Received: November 30, 2011
Published online: February 22, 2012
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Chem. Eur. J. 2012, 18, 3468 – 3472