Convenient procedure of Horner-Wadsworth-Emmons olefination for the synthesis of simple and functionalized α,β-unsaturated nitriles

Article abstract of DOI:10.1016/S0040-4039(02)02880-0

A mild and practical procedure of Horner-Wadsworth-Emmons olefination promoted by lithium hydroxide and α-cyano phosphonates has been set up for the synthesis of α,β-unsaturated nitriles. The reaction conditions are tolerated by functionalized ketones and the exclusive formation of E-γ-hydroxy α,β-unsaturated nitriles has been observed.

Full text of DOI:10.1016/S0040-4039(02)02880-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1333–1337
Convenient procedure of Horner–Wadsworth–Emmons olefination
for the synthesis of simple and functionalized a,b-unsaturated
nitriles
Alessandra Lattanzi,a Liliana R. Orelli,b Patrizia Barone,a Antonio Massa,a Patrizia Iannecea and
Arrigo Scettria,*
aDipartimento di Chimica, Universita` di Salerno, Via S. Allende 84081 I Baronissi, Salerno, Italy
bDepartamento de Quimica Organica, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Junin 956 Buenos Aires,
1113 Argentina
Received 18 December 2002; revised 19 December 2002; accepted 20 December 2002
Abstract—A mild and practical procedure of Horner–Wadsworth–Emmons olefination promoted by lithium hydroxide and
a-cyano phosphonates has been set up for the synthesis of a,b-unsaturated nitriles. The reaction conditions are tolerated by
functionalized ketones and the exclusive formation of E-g-hydroxy a,b-unsaturated nitriles has been observed. © 2003 Elsevier
Science Ltd. All rights reserved.
a,b-Unsaturated nitriles have proved to be versatile
intermediates in organic synthesis; in fact they can be
converted into carbocycles1 and heterocycles,2 and fur-
thermore they constitute the starting compounds for
conjugate additions leading to functionalized nitriles.3
One of the straightforward routes to a,b-unsaturated
nitriles is the Horner–Wadsworth–Emmons olefination
of carbonyl compounds with a-cyano phosphonates.4
Several studies have pointed out that from the stereo-
chemical point of view a-cyano phosphonates are less
selective compared to carbalkoxy reagents since they
furnish mixtures of Z/E isomers in the range of 1/4 to
2/1.5 In the case of bis(2,2,2-trifluoroethyl) a-cyano
phosphonate the prevalent formation of the Z (in some
cases exclusive) olefin is generally observed.6 When a
bulky isopropyl group is placed on the a-carbon of
a-cyano phosphonate, the Z-selectivity is comparable
to that obtained using the bis(2,2,2-trifluoroethyl) a-
cyano phosphonate.7
same system for the HWE olefination of a-hydroxy
ketones to butenolides,9 and of 1,2-diketones to 4-
hydroxy-cyclopent-2-en-1-ones.10
Finally,
more
recently, Takacs and co-workers11 reported the use of
,
lithium hydroxide/4 A MS to promote the dienylation
of aldehydes and ketones using 4-phosphonocrotonate.
LiOH showed to be superior to the classical bases such
as LDA, LiHMDS and NaH, commonly used for this
type of reaction, furnishing high yields as well as good
E-stereoselectivity for the dienoates. In all the olefina-
tion procedures described, one of the most important
features is that even in excess of LiOH no competing
ester hydrolysis or keto–enol tautomerization processes
have been observed, rendering the methodology simpler
and more selective than the one implying the use of
strong bases.
These results prompted us to further explore the HWE
olefination of carbonyl compounds promoted by LiOH
with commercial a-cyano phosphonates 2 (Table 1) for
the synthesis of a,b-unsaturated nitriles.
We reported a useful and simple procedure for the
preparation of a,b-unsaturated esters (E-isomer highly
,
prevalent), using lithium hydroxide and 4 A MS to
At first, we investigated the reactivity with aldehydes.
Aromatic, aliphatic and unsaturated aldehydes were
reacted in THF at room temperature with phospho-
nates 2 (Table 1). Unsaturated nitriles were isolated in
quite good yields with satisfactory E/Z selectivity. At
70°C, reaction times can be further reduced, increasing
the yield of the olefin and marginally affecting the E/Z
ratio (compare entries 3 and 4).
promote the olefination of aldehydes and ketones.8 The
mild reaction conditions allowed the employment of the
Keywords: Horner–Wadsworth–Emmons olefination; a,b-unsaturated
nitriles; lithium hydroxide.
* Corresponding author. Tel.: +39-089-965374; fax: +39-089-965296;
e-mail: scettri@unisa.it
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02880-0

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A. Lattanzi et al. / Tetrahedron Letters 44 (2003) 1333–1337
Table 1. LiOH-promoted HWE olefination of aldehydes with a-cyano phosphonates 2
More interestingly, the mono-olefination (entry 7) or
Next, we turned out our attention to the olefination of
ketones, which are known to be considerably less reac-
tive than aldehydes. On the basis of our previous work8
for the synthesis of a,b-unsaturated esters we carried
diolefination of 1,2-dicarbonyl compounds could be
achieved by a suitable choice of the stoichiometric
ratios, allowing an easy and convenient approach to
mucononitriles15 (entries 8–9).
,
out the reactions in the presence of activated 4 A MS.
Unfunctionalized ketones were converted in high yields
(entries 1–2) into the corresponding olefins with moder-
ate to good E/Z stereoselectivities.
Remarkable results, from the synthetic point of view,
were observed in the olefination of a-hydroxy ketones
(entries 10–13): g-hydroxy unsaturated nitriles were
obtained with complete E-stereoselectivity. A previous
report16 on the Wittig olefination of a-hydroxyketones
with stabilized phosphonium ylides (Ph3PCHCO2Me)
and HWE reaction envisaged the hydroxyl-directed17
effect to account for the formation of E-trisubstituted
olefins. Two plausible transition states which may jus-
tify the stereochemical results in Table 2 (entries 10–13)
are depicted in Scheme 1.
Treatment of cyclohexanone with phosphonate 2b (1.1
,
mmol) in the presence of LiOH (2.4 mmol)/4 A MS at
70°C for 21 h furnished the corresponding nitrile in
80% yield.
Interestingly, in absence of molecular sieves (entry 3) at
room temperature, acetophenone was converted into 5b
in good yield and with the same E/Z ratio. Surpris-
ingly, the presence of molecular sieves was not strictly
necessary in order to obtain satisfactory yields of alke-
nes as we indeed found in the case of the olefination8 of
ketones with triethyl phosphonoacetate.
The possible interaction of the OH group of the ketone
with the phosphonate oxygen in I gives rise to a stabi-
lized transition state, which after syn elimination of
phosphate group would furnish the E olefin. An alter-
native possibility is that the hydrogen-bond between the
OH group and the carbonyl function could activate it
toward the ylide attack, affording the less sterically
encumbered transition state II. This provides, after
elimination, the E olefin.
In fact, this was further confirmed comparing experi-
ments in entries 4–6, where the functionalized ketones
(with the acetal moiety in a and b position) were
transformed in short reaction times to 3 in high yields
and satisfactory stereoselectivities at 70°C in absence of
,
4 A MS. The E-stereoselective monolefination of 2,3-
Some experiments were performed on a-hydroxycyclo-
hexanone 4j to ascertain the involvement of the OH
directing effect (Table 3).
butandione was accomplished when using 1 equiv. of
2a.

A. Lattanzi et al. / Tetrahedron Letters 44 (2003) 1333–1337
1335
Table 2. LiOH-promoted HWE olefination of ketones with a-cyano phosphonate 2aa
(compare with entry 1) decreased and more importantly
substantial erosion of E-stereoselectivity was
a
observed. Next, we performed two reactions in the
presence of lithium chelating agents (entries 6–7), in
order to verify whether the stereoselectivity would be
affected by the lithium cation coordinating effect. In
both cases, the E-unsaturated nitrile was isolated in
very good yield, confirming the hypothesis of the
unique OH group directing-effect.
Scheme 1.
No solvent dependence of the stereoselectivity was
observed when using acetonitrile and methanol (entries
2–3) which furnished the E-isomer. These results
appear to be consistent with a directed reaction.18
In conclusion, a practical procedure of HWE olefina-
tion of aldehydes and ketones for the synthesis of
a,b-unsaturated nitriles has been developed using LiOH
as a mild base. The E-stereoselectivity is predominant
and the olefins are obtained in good to high yields.
Other experimental support for the above hypothesis
was obtained in entries 4 and 5 on the OH-protected
acetate and silylated derivatives. The rate of reaction
,
Activated 4 A MS have been shown to shorten reaction
times with ketones, but they are not necessary to secure

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A. Lattanzi et al. / Tetrahedron Letters 44 (2003) 1333–1337
Table 3. LiOH-promoted HWE olefination of 4 with 2aa
good yields of the final products, rendering the method-
ology even simpler. Finally, a complete control of the
stereoselectivity has been achieved in the case of a-
hydroxy ketones, where the directing effect of the
hydroxyl group is reasonably considered to be responsi-
ble of the observed exclusive formation of the E-
isomer.
10. Bonadies, F.; Scettri, A.; Di Campli, C. Tetrahedron Lett.
1996, 37, 1899.
11. Takacs, J. M.; Jaber, M. R.; Clement, F.; Walters, C. J.
Org. Chem. 1998, 63, 6757.
12. 5c: unseparable mixture of E/Z isomers. IR (KBr) 2937,
2835, 2222, 1444, 1156, 969 cm−1; E distinct signals: 1H
NMR (400 MHz, CDCl3) l 5.60 (q, 1H, J=1.3 Hz), 4.70
(s, 1H), 3.27 (s, 6H), 2.00 (d, 3H, J=1.3 Hz); 13C NMR
(100 MHz, CDCl3) l 158.6, 116.3, 102.0, 98.6, 52.9, 16.9.
1
Z distinct signals: H NMR (400 MHz, CDCl3) l 5.32 (q,
Acknowledgements
1H, J=1.4 Hz), 5.03 (s, 1H), 3.41 (s, 6H), 1.88 (d, 3H,
J=1.4 Hz). 13C NMR (100 MHz, CDCl3) l 160.0, 103.4,
97.8, 55.2. Anal. calcd for C7H11NO2: C, 59.56; H, 7.85;
N 9.92. Found: C, 59.70; H, 7.71; N 9.80. In general the
vinylic proton of the Z-isomer exhibits signal that is
upfield compared to the E-isomer. See: Ando, K. J. Org.
Chem. 1998, 63, 8411.
We are grateful to MIUR for financial support.
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13. 5d: unseparable mixture of E/Z isomers. IR (KBr) 2938,
2834, 2218, 1443, 1082, 965 cm−1; E distinct signals: 1H
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1337
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