High-pressure induced domino-Horner-Wadsworth-Emmons (HWE) -Michael reactions

Article abstract of DOI:10.1055/s-2001-16786

A new protocol for the alkenylation of carbonyl compounds with phosphonates (Horner-Wadsworth-Emmons reaction) is described. Aldehydes react with phosphonates already at room temperature in the presence of triethylamine without further activation by Lewis-acids if high-pressure (8 kbar) is applied to the system. Based on this protocol a domino process was developed combining the HWE reaction with a Michael reaction, thus allowing the one-pot synthesis of β-amino esters, β-thio esters or β-thio nitriles.

Full text of DOI:10.1055/s-2001-16786

LETTER
1395
High-Pressure Induced Domino-Horner-Wadsworth-Emmons (HWE) –
Michael Reactions
Senay Has-Becker,a Kerstin Bodmann,a Reinhard Kreuder,a Gabriella Santoni,b Tobias Rein,c Oliver Reiser*, a
a Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
b Dipartimento Di Chimica Organica, Universita Degli Studi di Padova, Italy.
c AstraZeneca R&D, Discovery Chemistry, 15185 Sodertalje, Sweden.
Fax +49-9419434121; E-mail: Oliver.Reiser@chemie.uni-regensburg.de
Received 22 May 2001
The Horner-Wadsworth-Emmons reaction (HWE)7 is one
of the most versatile methods for the synthesis of alkenes.
The common protocol for this reaction calls for the depro-
tonation of the phosphonate by a base such as metal hy-
Abstract: A new protocol for the alkenylation of carbonyl com-
pounds with phosphonates (Horner-Wadsworth-Emmons reaction)
is described. Aldehydes react with phosphonates already at room
temperature in the presence of triethylamine without further activa-
tion by Lewis-acids if high-pressure (8 kbar) is applied to the sys- drides, silazides, or alkoxides, and the subsequent
addition of the carbonyl compound.8 Alternatively, a mix-
tem. Based on this protocol a domino process was developed
combining the HWE reaction with a Michael reaction, thus allow-
ture of stoichiometric amounts of a base such as 1,8-diaz-
ing the one-pot synthesis of -amino esters, -thio esters or -thio
abicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropyl-
nitriles.
ethylamine (DIPEA) or triethylamine and lithium or mag-
Key words: Horner-Wadsworth-Emmons reaction, Michael addi-
nesium salts serving as Lewis acids under rigorous anhy-
tion, domino reaction, -amino esters, -thio esters, -thio nitriles,
drous conditions has been successfully applied.9 For the
high-Pressure
condensation of phosphorylglycine esters the use of a
Lewis acid was demonstrated to be superfluous and often
disadvantageous, and that DBU or tetramethylguanidine
The development of new domino reactions to achieve
transformations of multiple components in a defined and
controlled way is an important challenge to arrive at eco-
nomical chemical processes.1 With the advent of combi-
natorial chemistry,2 domino reactions that create new
reactive functionalities by subsequent addition of compo-
nents appear to be especially valuable to readily arrive at
libraries of molecules with high diversity.
High pressure (1-12 kbar) in liquid phases3 has been rec-
ognized to greatly activate substrates for addition reac-
tions,4 most notably in Diels-Alder reactions.5 Moreover,
high-pressure reactions are commonly carried out by in-
troducing the reactants, being sealed in small teflon ves-
sels, into a high-pressure cell. A standard high-pressure
cell has typically a reaction volume of 20-50 cm3 that can
easily hold around 10-20 individual teflon vessels at a
time, and larger cells for industrial applications are also
available. Therefore, reactions carried out under high-
pressure appear to be well suited for parallel synthesis and
might therefore find their place in the rapidly growing ar-
senal of new techniques in combinatorial chemistry. A
few pioneering approaches towards the application of
high-pressure in combinatorial chemistry have been re-
cently disclosed.6
suffice as bases.10 We have now discovered that HWE re-
actions of aromatic aldehydes 1 with phosphonates 2 pro-
ceed smoothly at room temperature in the absence of any
Lewis acid using triethylamine as the base if high-pres-
sure (8 kbar) is applied to the system (Scheme 1, Table 1).
It has been shown previously that the parent Wittig reac-
tion can be accelerated by pressure,11 however, in con-
trast to our work no advantage of such high-pressure
conditions with respect to a more economical use of re-
agents had been demonstrated.
O
(EtO)2P
O
NEt3, CH3CN
8 kbar, 24 h
FG
FG
+
Ar
Ar
H
R
R
2a: FG = CO2Et, R = H
2b: FG = CO2Et, R = Br
2c: FG = CN, R = H
3a-3h
1a: Ar = Ph
1b: Ar = 4-NO2-Ph
1c: Ar = 4-OMe-Ph
Scheme 1
The electronically differentiated aldehydes 1a-c could be
alkenylated in good yields with the phosphonates 2a-c in
the presence of triethylamine at 8 kbar, in distinct contrast
to reactions carried out at ambient pressure (Table 1).
Moreover, excellent E-selectivity was observed with 2a in
all cases, while the phosphonates 2b-2c gave rise to E/Z-
mixtures depending on the aldehyde 1. Interestingly, the
reaction of 1a, b with 2c yielded the alkenes 3f and 3g (en-
tries 11-14) with better selectivities under pressure condi-
We report here a three-component process by combining
a Horner-Wadsworth-Emmons reaction (HWE) with a
Michael reaction to obtain -amino esters, -thio esters or
-thio nitriles starting from aldehydes, phosphonates and
amines or thiols. Pressure plays a pivotal role to be able to
carry out the title reactions under conditions that are com-
patible with the four classes of substrates employed.
Synlett 2001, No. 9, 1395–1398 ISSN 0936-5214 © Thieme Stuttgart · New York

1396
S. Has-Becker et al.
LETTER
Table 1 Synthesis of alkenes under high-pressure15
O
Nu
(EtO)2P
FG
NEt3, CH3CN
FG
ArCHO +
Nu–H
+
Ar
8 kbar, 3 d
R
X
40 °C or 80 °C
X = H, Nu
R = H, Br
1
2
4
5
Scheme 2
Indeed, -amino esters 5a-5g could be obtained in this
way in moderate to good yields (Table 2, entries 1-9). It
became readily apparent that the second step, i.e. the 1,4-
addition of the amine, was the limiting step of the se-
quence. Only secondary amines would give addition prod-
ucts, while with primary amines only the HWE-products
are formed. Moreover, sterically hindered secondary
amines (entry 10) and aromatic amines (entry 11) failed to
give the desired amino esters at all. Using the phosphonate
2b, the 1,2-diaminoester 5d was obtained, in which the
bromine substituent underwent another substitution by the
nucleophile (entry 5). No aminolysis of the ethyl ester
groups was observed at any point, however, when the
amino alcohol 4b was employed as the nucleophile, lac-
tonization takes place after 1,4-addition to give rise to 5e
(entry 6).
When thiols are used as nucleophiles instead of amines,
-thio esters and -thio nitriles are obtained (Table 2, en-
tries 12-18). In contrast to the amine nucleophiles, there
seem to be no limitations in the type of thiols being em-
ployed, i.e. aryl, benzyl and alkyl thiols all gave the ex-
pected addition products 5j-5p in generally high yields.
1
aThe ratio was determined by H NMR integrals of the olefinic
protons.
bIsolated Yield.
In conclusion, a new three-component process leading to
-amino esters, -thio esters or -thio nitriles was devel-
oped. Further developments of new domino reactions to
explore the potential of high-pressure for multi-compo-
nent reactions and their application to parallel synthesis
are under investigation in our laboratories.
tions, marking one of the few examples in which pressure
does not decrease selectivity under otherwise unchanged
conditions.12
The mild conditions used in this new alkenylation proto-
col opened up the possibility to design a domino process
by combining the HWE-reaction with a Michael addition.
We expected that pressure will not only have a beneficial
effect on the HWE reaction but also on the Michael reac-
tion.13 Thus, subjecting a mixture of an aldehyde 1, a
phosphonate 2 and a nucleophile 4 in the presence of tri-
ethylamine to 8 kbar, we envisioned a one pot synthesis of
compounds with the general structure 5 (Scheme 2).
Acknowledgement
This work was supported by the DAAD (International Quality Net-
work Program (IQN)) and the Fonds der Chemischen Industrie.
References and Notes
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Synlett 2001, No. 9, 1395–1398 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
High-Pressure Induced Domino-Horner-Wadsworth-Emmons (HWE) – Michael Reactions
1397
Table 2 Domino-HWE-Michael-Reactions[16,17]
a Isolated Yield. b A ratio of syn:anti isomers of 1:1 was found. c In addition 46% 4-NO2-cinnamic ester (3b) were isolated. d In addition 29%
cinnamic ester (3a) were isolated. e In addition 69% cinnamic ester (3a) were isolated.
Synlett 2001, No. 9, 1395–1398 ISSN 0936-5214 © Thieme Stuttgart · New York

1398
S. Has-Becker et al.
LETTER
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Article Identifier:
1437-2096,E;2001,0,09,1395,1398,ftx,en;G09301ST.pdf
Synlett 2001, No. 9, 1395–1398 ISSN 0936-5214 © Thieme Stuttgart · New York