Exploring the versatility of the Johnson-Claisen rearrangement: access to functionally versatile δ-ethoxycarbonyl-α,β-unsaturated nitriles

Article abstract of DOI:10.1016/j.tet.2010.02.045

A practical entry into δ-ethoxycarbonyl-α,β-unsaturated nitriles is described. α,β-Unsaturated aldehydes were converted to cyanohydrins, by employing either KCN in aqueous acid, or by using TMSCN with catalytic K₂CO₃, followed by acid hydrolysis of the TMS ether. These cyanohydrins underwent a Claisen rearrangement employing a modified Johnson-Claisen protocol to yield unsaturated nitriles in good yields and with moderate E/Z selectivity.

Full text of DOI:10.1016/j.tet.2010.02.045

Tetrahedron 66 (2010) 3050–3057
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploring the versatility of the Johnson–Claisen rearrangement: access to
functionally versatile d-ethoxycarbonyl-a,b-unsaturated nitriles
,b,
Kelly L. Cosgrove a, Ross P. McGeary a
*
a The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Queensland 4072, Australia
b The University of Queensland, School of Pharmacy, Brisbane, Queensland 4072, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical entry into d-ethoxycarbonyl-a,b-unsaturated nitriles is described. a,b-Unsaturated aldehydes
Received 23 November 2009
Received in revised form 21 January 2010
Accepted 8 February 2010
were converted to cyanohydrins, by employing either KCN in aqueous acid, or by using TMSCN with
catalytic K2CO3, followed by acid hydrolysis of the TMS ether. These cyanohydrins underwent a Claisen
rearrangement employing a modified Johnson–Claisen protocol to yield unsaturated nitriles in good
yields and with moderate E/Z selectivity.
Available online 13 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Johnson–Claisen rearrangement
Cyanohydrins
Unsaturated nitriles
Allylic alcohols
1. Introduction
subsequently undergoes a thermal [3,3] sigmatropic rearrange-
ment to give a
g
,d
-unsaturated ester 5.2
Carbon–carbon bond forming reactions are fundamental tools in
synthetic organic chemistry. Foremost among these is the Claisen
rearrangement, which describes a thermally allowed concerted
rearrangement of an allyl vinyl ether into an unsaturated aldehyde
or ketone.1 The numerous variants of the Claisen rearrangement
attest to the importance of this powerful transformation. Of the
different modifications, the Johnson–Claisen variant is a well-
established and reliable method for converting allylic alcohols
OEt
O
EtO
OEt
H+
OH
OEt
R
- EtOH
R
3
OEt
2
1
- EtOH
OEt
O
OEt
O
[3,3]
into g,d
-unsaturated esters.2,3 The effectiveness of this method can
R
R
5
4
be attributed to the execution of several steps in a one-pot pro-
cedure, without recourse to strictly anhydrous conditions. The
standard procedure typically involves heating an allylic alcohol in
the presence of an excess of orthoester (typically trimethyl or tri-
ethyl ortho acetate) and a catalytic amount of a weak protic acid at
temperatures ranging from 140 to 200 ꢀC.3 As depicted in Scheme 1,
an allylic alcohol 1 condenses with the orthoester 2 under acid
catalysis to form a mixed orthoester intermediate 3 (which is
generally not isolated). This process is however reversible and the
equilibrium can be shifted in the forward direction by distilling off
the low-boiling alcohol by-product. Further acid-catalysed elimi-
nation of alcohol from 3 gives a ketene acetal intermediate 4, which
Scheme 1. The Johnson–Claisen rearrangement.
While useful, the Johnson–Claisen rearrangement requires
rather harsh reaction conditions4 and these high reaction temper-
atures, acid catalysis and long reaction times may not always be
compatible with sensitive substrates. To date, development of
methodology for milder reaction conditions has received limited
attention. Johnson–Claisen reactions performed under microwave
irradiation are reported to reduce reaction times and improve
yields, however they too are performed at elevated temperatures.5
For some time we have been interested in developing methodology
to reduce these harsh reaction conditions of the Johnson–Claisen
reaction and we have recently reported a variation, promoted by
triisobutylaluminium (TIBAL), that occurs at room temperature
(Scheme 2).6 We wished to complement this methodology by
* Corresponding author. Tel.: þ61 7 33653955.
E-mail address: r.mcgeary@uq.edu.au (R.P. McGeary).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.045

K.L. Cosgrove, R.P. McGeary / Tetrahedron 66 (2010) 3050–3057
3051
examining an alternative approach, which did not require TIBAL,
and so would be compatible with substrates containing reducible
functional groups.
deprotection to the cyanohydrins, albeit over two steps, gave con-
sistently better yields (Scheme 4).
O
OTMS
OH
CN
16
OMe
O
OMe
O
OMe
O
OH
a
c
b
MeO
R
[3,3]
R
TIBAL
r.t.
TIBAL
R
14
R
CN
R
15
R
R
6
7
8
9
Scheme 4. Reagents and conditions: (a) TMSCN, K2CO3, neat, rt, 6 h; (b) 5% HCl, MeCN,
rt; (c) KCN, 16% HCl, Et2O, rt, 3 h.
Scheme 2. A room temperature triisobutylaluminium-promoted Johnson–Claisen
rearrangement.6
As a model substrate for the Johnson–Claisen reaction, we ex-
amined the allylic cyanohydrin 17, readily prepared from 2-octenal
18. To our dismay, subjecting 17 to the standard Johnson–Claisen
conditions (excess of triethyl ortho acetate, catalytic propionic acid
at reflux) resulted in a complex mixture with the predominant
Substituent effects on the rate of the Claisen rearrangement
have been extensively investigated, both experimentally and the-
oretically.7–10 The most impressive substituent-induced rate
enhancement of the Claisen rearrangement is observed for the 4-
cyano-substituted allyl vinyl ether, which leads to a 270-fold rate
enhancement, relative to an unsubstituted allyl vinyl ether.7,8
Remarkably, this impressive increase in rate caused by a 4-cyano
substituent appears never to have been exploited synthetically. We
therefore sought to apply the rate enhancement promoted by the
4-cyano group to the Johnson–Claisen rearrangement, with the
expectation that by lowering the activation energy of this reaction,
it could be executed under milder conditions and so be applied to
thermally-sensitive substrates (Scheme 3).
product being the
cyanohydrin was derived (Scheme 5). Trace amounts of the desired
-alkoxycarbonyl- -unsaturated nitrile were formed and isolated
a,b-unsaturated aldehyde 18 from which the
d
a,b
by flash column chromatography, however yields were poor.
Employing strictly anhydrous conditions increased the yield of the
rearranged nitrile only slightly. We tried using commonly
employed solvents such as toluene, xylene and DMF with limited
improvements. Both trimethyl ortho acetate and triethyl ortho
acetate were tested along with catalysts such as acetic acid,
trifluoroacetic acid, sulfuric acid and hydroquinone without any
major improvement in yields. Various reaction temperatures and
times were trialled along with changing the order of reagent ad-
dition to the reaction and the number of molar equivalents of
orthoester, all without significant improvement in yields. Different
allylic cyanohydrins were also tested but they all decomposed to
their respective enals. The reaction was also tested in a microwave
reactor using conditions similar to those we had trialled under
conventional heating, and with equally limited success. A literature
search revealed a report by Gerrits et al. who found that cyano-
hydrins rapidly decompose in water and simple alcohols to give
the parent aldehyde.11 We thought it likely that the low-boiling
alcohol evolved during the Johnson–Claisen reaction, in conjunc-
tion with the high reaction temperatures, was responsible for the
decomposition of the cyanohydrins. We therefore tried a protocol,
which used trimethyl ortho acetate and activated 4 Å sieves, so
that we could remove the methanol as it was formed. Un-
fortunately we did not observe a significant improvement in yield.
Removal of the low-boiling alcohol by-product under standard
refluxing conditions was ineffective, and so we tested a Dean–
Stark type attachment containing 4 Å molecular sieves under both
atmospheric and reduced pressure, however there were no sig-
nificant gains in yield.
111
k
rel
0.9
O
O
-CN
4
0.11
270
15.6
OEt
O
OEt
O
O
OH
CN
11
CN
CN
10
12
13
Scheme 3. Effects of cyano substituents on the rate of the Claisen reaction, relative to
the unsubstituted allyl vinyl ether, and proposed Johnson–Claisen rearrangement of
allylic cyanohydrins.
Retro-synthetically the starting substrate for a Johnson–Claisen
reaction bearing a 4-cyano substituent (12) is an allylic cyanohydrin
11, readily prepared from enal 10, and the expected product would
be a thermodynamically stable
d-alkoxycarbonyl-
a,b-unsaturated
nitrile 13 (Scheme 3). -Alkoxycarbonyl-a,b
d
-unsaturated nitriles 13
are potentially very versatile synthetic intermediates in organic
chemistry. These densely functionalised molecules may find use as
precursors for further synthetic transformations such as conjugate
additions and carbon–carbon double-bond reactions, and are also
capable of a multitude of functional group transformations at both
the nitrile and ester functionalities.
Surprisingly, the Johnson–Claisen reaction has not yet been
applied to allylic cyanohydrins. In view of the potential for milder
OH
CN
O
a
reaction conditions, combined with the utility of
d-alkoxycarbonyl-
17
18
a,b
-unsaturated nitriles, we decided to explore the Johnson–
Scheme 5. Reagents and conditions: (a) MeC(OEt)3, Hþ(cat.),
D
.
Claisen rearrangement of allylic cyanohydrins. Herein we report
our results.
Clearly a change of approach was required; we sought then to
eliminate methanol from an isolated allylic mixed orthoester 19
(Scheme 6),12 forming the mixed ketene acetal, which we expected
would immediately undergo sigmatropic rearrangement to the
Claisen product 20.6 This method would minimise exposure of
the allylic cyanohydrin to the destabilising low-boiling alcohol. The
standard Johnson–Claisen rearrangement utilises protic acid to
eliminate a molecule of alcohol from the mixed orthoester to form
the mixed ketene acetal intermediate. We added 19 to a solution of
toluene and propionic acid at reflux (Scheme 6), predominantly
yielding again regenerated allylic cyanohydrin 17 and forming only
a small quantity of the rearranged ester 20. This suggested that
2. Results and discussion
Syntheses of allylic cyanohydrins 16 are frequently accom-
plished by the reaction of an
a,b-unsaturated aldehyde 14 with
HCN, generally formed in situ from KCN and aqueous acid. Usually,
the reaction equilibrium favours formation of products, but yields
can be maximised by adding TMSCN and trapping the cyanohydrin
irreversibly as its TMS ether 15. The TMS group of 15 can then be
readily hydrolysed with mild acid to give the cyanohydrins 16. We
utilised both methods to synthesise a range of allylic cyanohydrin
substrates, and found that addition of TMSCN and then

3052
K.L. Cosgrove, R.P. McGeary / Tetrahedron 66 (2010) 3050–3057
there was a greater likelihood of elimination of the allylic alcohol
moiety from 19, rather than methanol, as was required to form the
mixed ketene acetal intermediate.
propionic acid in toluene-d8 and the temperature was increased to
80 ꢀC. Spectrawerethenacquiredduringseveralhours. To ourdelight
we discovered that the addition of an excess of propionic acid dras-
tically slowed the rate of cyanohydrin decomposition. After opti-
mising the reaction conditions we found that the best yields of the
OMe
MeO
OH
CN
O
a
b
d-ethoxycarbonyl-a,b-unsaturated nitrile products were obtained by
CN
employing an excess of triethyl ortho acetate and a large excess of
propionic acid in xylenes at 130 ꢀC. Whilst rearranged product 20
could be observed at temperatures as low as 90 ꢀC, efficient conver-
sion required higher reaction temperatures. We are now pleased to
report a modified Johnson–Claisen protocol, which we have applied
to various allylic cyanohydrins, as shown in Table 1.
17
19
b
OMe
O
CN
20
The reaction products predominantly consisted of the desired
d
-ethoxycarbonyl-
a,b-unsaturated nitriles, however they also
Scheme 6. Reagents and conditions: (a) CH2]C(OMe)2, neat, rt, 30 min; (b) propionic
acid, toluene,
D
.
contained smaller amounts of allylic aldehyde and ethyl pro-
pionate. That the expected
a,b-unsaturated nitriles had in fact
formed was confirmed by peaks in the 13C NMR spectra of the
products at around 117 ppm, along with peaks at around 171 ppm,
typical for ethyl esters. Characteristic bands in the IR spectra at
We then decided to carefully examine the decomposition of the
allylic cyanohydrin 17 by 1H NMR spectroscopy. The allylic cyanohy-
drin was added to an NMR tube containing trialkyl ortho acetate and
Table 1
Yields and isomer ratios of
d
-ethoxycarbonyl-
a
,
b-unsaturated nitriles
Entry
1
Cyanohydrin
Yield, % (method)a
d
-Ethoxycarbonyl-
a
,
b
-unsaturated nitrilesb
Ratioc (Z/E)
Yield,d
76
%
CO2Et
CN
OH
CN
17
21
96 (A)
72 (A)
20
22
24:76
CO2Et
CN
OH
CN
2
3
24:76
30:70
66e
59
OH
CN
CO2Et
CN
23
25
62 (B)
90 (B)
24
26
OH
CN
CO2Et
CN
4
24:76
73
OH
CN
CO2Et
CN
5
6
7
27
29
31
78 (B)
60 (B)
72 (B)
28
30
32
26:74
7:93
7:93
73
76
76
OH
CN
CO2Et
CN
OH
CN
CO2Et
CN
OH
CN
CO2Et
CN
8
33
35
37
73 (B)
78 (A)
63 (A)
34
36
38
30:70
22:78
20:80
75
73
40
OH
CN
CO2Et
CN
9
OH
CN
CO2Et
CN
10
OH
CN
CO2Et
11
39
41
13 (A)
50 (B)
40
42
100:0
13
0
CN
Br
Br
CO2Et
OH
CN
NO2
12
d
CN
NO2
a
Method A: KCN, aq HCl, Et2O, rt. Method B: (i) TMSCN, K2CO3, rt (ii) aq HCl, MeCN, rt.
b
c
Optimised method: EtCO2H (12.3 equiv), MeC(OEt)3 (24 equiv), xylenes,
The E/Z ratio was measured by 1H NMR spectroscopy.
Isolated uncorrected yields.
D, 24 h.
d
e
Lower yield due to evaporative losses.

K.L. Cosgrove, R.P. McGeary / Tetrahedron 66 (2010) 3050–3057
3053
around 2200 cmꢁ1 for the nitrile group (and at around 1730 cmꢁ1
for the ethyl ester functional group) were also observed. As is
typical for cyanohydrins, nitrile bands in the IR spectra of the
peak (1H NMR 7.24 ppm, 13C NMR 77.0 ppm for CDCl3; 1H NMR
7.15 ppm, 13C NMR 128 ppm for C6D6; 1H NMR 1.94 ppm, 13C NMR
118.3 for CD3CN). Coupling constants (J) are reported in hertz.
Melting points were determined on a Stuart SMP11 Melting Point
apparatus and are uncorrected. Low- and high-resolution EIMS were
measured on a Finnigan MAT 900 XL-Trap mass spectrometer in
positiveionisation mode. LR-ESI datawere recorded on a Bruker HCT
3D Ion Trap and HR-ESI data were recorded on a Bruker MicrOTof-Q
with the DIONEX Ultimate 3000 LC in positive electrospray ionisa-
tion mode. GC/MS data were recorded on a Shimadzu GC-17A Ver.3,
mass spectrometer. IR spectra were recorded on a Perkin–Elmer FT-
IR spectrometer (Spectrum 2000) and are only reported for the
rearranged nitriles, because cyanohydrins have a very weak nitrile
stretching frequency.13 Spectroscopic data for the allylic cyanohy-
drins have generally beenpreviously reported. Unfortunately, all the
allylic cyanohydrins underwent dehydrocyanation when subjected
to GC–MS or ESI-MS, using acetonitrile, methanol or diethyl ether as
the solvent. Notably, mass spectral data are frequently not reported
for cyanohydrins.14–18 In addition, several accounts, which have
reported mass spectral data, identify peaks corresponding to
dehydrocyanation of cyanohydrins.19–23 All of the unsaturated al-
dehydes were purchased from Sigma–Aldrich, except for (E)-3,7-
dimethylocta-2,6-dienal (geranial) and 3-methylbut-2-enal, which
were prepared from known literature procedures.24 Only the NMR
resonances of the major product isomers are reported. Light pe-
troleum refers to the fraction boiling at 40–60 ꢀC.
starting materials were very weak or not observed. Isolation of the
d-
ethoxycarbonyl- -unsaturated nitriles was readily achieved by
a,b
flash column chromatography. Presumably the large excess of protic
acid decreases the amount of free ethanol by sequestering it as ethyl
propionate, thereby limiting the likelihood of the cyanohydrin
reconverting to the aldehyde. Anhydrous conditions were necessary
for the reactions to proceed in high yields; all of the reagents were
dried by distillation prior to reaction, the cyanohydrin was dried
under high vacuum, and the xylene was dried over molecular sieves.
The majority of allylic cyanohydrins we examined were con-
verted to d-ethoxycarbonyl-a,b-unsaturated nitriles in yields greater
than 70%. The unsaturated nitrile products are very stable and NMR
analysis showed that storage at room temperature for several
months did not lead to decomposition. Allylic cyanohydrins pos-
sessing di-, and tri-substituted alkenes were capable of rearrange-
ment and the reaction conditions are compatible with the presence
of an additional double bond and a benzyl group. The Johnson–
Claisen rearrangement of allylic cyanohydrins (entries 1–10)
predominantly led to formation of the E-isomer. The E-selectivity of
the reaction is fairly consistent for entries 1–5, 9 and 10. In-
terestingly, allylic cyanohydrins possessing b-disubstituted double
bonds (entries 6 and 7) yielded higher proportions of the E-isomers
of the products. The geometry around the double bonds of com-
pounds 38 and 40 were confirmed by NOESY experiments. Notably,
the reaction seems to be sensitive to an increased steric hindrance
around the double bond imposed by an aromatic group and methyl
group, leading to a low yield of 38. In comparison, the absence of
4.2. General procedure for the preparation of allylic
cyanohydrins Method A
a methyl group at the
a
-position did little to hinder the reaction as
The general procedure of Anderson et al.25 was used for the
preparation of allylic cyanohydrins. The preparation of 2-hydroxy-
3-pentenenitrile 21 is representative. A chilled (0 ꢀC) solution of
potassium cyanide (CAUTION, highly toxic; 9.83 g, 151 mmol) in
water (20 mL) was added dropwise over 10 min to a stirred and
chilled solution (ꢁ10 ꢀC, ice/salt bath) of (E)-but-2-enal (5.00 mL,
4.23 g, 60.4 mmol) in diethyl ether (40 mL). Hydrochloric acid
(40 mL, 16% aqueous) was added dropwise to the reaction over 2 h.
The reaction was allowed to warm to room temperature and stir for
3 h. The ether layer was separated from the aqueous layer and
washed with distilled water (2ꢂ100 mL), before being dried over
MgSO4, filtered and evaporated in vacuo to afford a yellow oil. The
title compound was purified by flash column chromatography (20%
EtOAc in light petroleum), to yield a colourless oil (4.19 g, 72%), Rf
0.38 (20% EtOAc in light petroleum). dH (500 MHz, CDCl3) 6.07 (1H,
dqd, J 15.3, 6.6, 1.4 Hz), 5.61 (1H, ddq, J 15.3, 6.1 and 1.8 Hz), 4.90
(1H, m), 1.77 (3H, m); dC (125 MHz, CDCl3) 132.9, 125.0, 118.5, 61.7,
17.5. NMR data are in agreement with that previously reported.15
shown for product 36, however further increase in steric bulk by
replacement of the methyl group with a bromo-group as in 39 led to
a further reduction in yield. The absolute stereochemistry of the
isomers of compound 34 has not been unequivocally determined;
however it has been tentatively assigned on the basis of COSY and
NOESY correlations. The minor isomer was able to be partially pu-
rified from the other isomers and is assigned the following structure
34a. The remaining two isomers, which were unable to be separated
chromatographically have been assigned the following structures
34b and 34c (Fig. 1).
CO2Et
CN
CO2Et
CN
CO2Et
CN
34a
26%
34b
44%
34c
30%
Figure 1. Stereochemical assignments of isomers 34a–c.
3. Conclusion
4.2.1. (E)-2-Hydroxynon-3-enenitrile (17). The title compound was
prepared as indicated in the representative procedure (Method A).
Flash column chromatography (10% EtOAc in light petroleum)
afforded the pure cyanohydrin as a colourless oil (990 mg, 96%).
Anal. Calcd for C9H15NO: C, 70.55; H, 9.87; N, 9.14. Found: C, 70.40;
H, 10.08; N, 9.28, Rf 0.3 (10% EtOAc in light petroleum). dH (CDCl3,
400 MHz) 6.06 (1H, dtd, J 15.4, 6.8 and 1.2 Hz), 5.59 (1H, ddt, J 15.4,
6.0 and 1.5 Hz), 4.92 (1H, m), 2.35 (1H, br s), 2.09 (2H, m,), 1.43–1.36
(2H, m), 1.35–1.22 (4H, m), 0.87 (3H, br t, J 6.9 Hz). dC (CDCl3,
400 MHz) 138.2, 123.7, 118.4, 61.9, 31.7, 31.3, 28.1, 22.4, 13.9. NMR
data are in agreement with that previously reported.26
The Johnson–Claisen reaction fails for allylic cyanohydrins when
the standard conditions are employed. The reaction may be suc-
cessfully accomplished, however, by using a large excess of acid
catalyst and a large excess of triethyl ortho acetate in hot xylenes,
giving good yields of
These reactions can be performed on a diverse range of allylic cy-
d-ethoxycarbonyl-a,b-unsaturated nitriles.
anohydrins and display moderate E/Z selectivity.
4. Experimental
4.1. General experimental
4.2.2. (E)-2-Hydroxy-4-phenylbut-3-enenitrile (35). The title com-
pound was prepared as indicated in the representative procedure
(Method A). Purification by trituration with hexane gave a white
solid (469 mg, 78%), mp 71–72 ꢀC (lit.27 mp 73–74 ꢀC). dH (500 MHz,
CDCl3) 7.42–7.39 (2H, m), 7.37–7.30 (3H, m), 6.91 (1H, dd, J 15.9 Hz
All NMR experiments were recorded on Bruker AVANCE 500, 400
or 300 MHz spectrometers. Chemical shifts are reported in parts per
million (ppm) on a
d scale, and referenced to the residual solvent

3054
K.L. Cosgrove, R.P. McGeary / Tetrahedron 66 (2010) 3050–3057
and 1.3 Hz), 6.25 (1H, dd, J 15.9 Hz and 5.9 Hz), 5.15 (1H, br d,
J 5.6 Hz), 2.60 (1H, br s). dC (125 MHz, CDCl3) 135.4, 134.6, 129.1,
128.8, 127.1, 122.2, 118.0, 61.9. NMR data are in agreement with that
previously reported.16,17
(480 mg, 62%), Rf 0.21 (30% Et2O in light petroleum). dH (300 MHz,
C6D6) 6.14 (dd J 15.2 and 10.4 Hz), 5.72–5.63 (1H, m), 5.46–5.34 (1H,
m), 5.05 (dd, J 15.0 and 5.6 Hz), 4.10 (1H, br t, J 7.0 Hz), 1.44 (3H, m),
1.24 (1H, br d, J 7.0 Hz). dC (100 MHz, C6D6) 134.8, 133.4, 129.7, 123.7,
118.4, 61.4, 18.0. NMR data are in general agreement with that
previously reported.11,23
4.2.3. (E)-2-Hydroxy-3-methyl-4-phenylbut-3-enenitrile (37). The ti-
tle compound was prepared as indicated in the representative
procedure (Method A). Purification by flash column chromatogra-
phy (25% Et2O in light petroleum), gave a waxy white solid (1.49 g,
63%), mp 28–29 ꢀC, Rf 0.13 (20% Et2O in light petroleum). dH
(500 MHz, CDCl3) 7.38–7.34 (2H, m), 7.29–7.26 (3H, m), 6.79 (1H, br
s), 5.01 (1H, s), 2.51 (1H, br s), 2.02 (3H, d, J 1.4 Hz). dC (125 Hz,
CDCl3) 135.7, 131.8, 130.3, 129.0, 128.4, 127.7, 118.1, 67.2, 14.2. NMR
data are in agreement with that previously reported.22
4.3.2. (E)-3,7-Dimethylocta-2,6-dienal. The enal was prepared from
geraniol using literature procedures24 and purified by Et3N-washed
silica flash column chromatography (2% Et3N in 2:8 Et2O/light pe-
troleum) to afford the product as a clear oil (750 mg, 85%), Rf 0.63
(20% Et2O in light petroleum). dH (400 MHz, C6D6) 9.86 (1H, d,
J 7.8 Hz), 5.82 (1H, m), 4.94 (1H, m), 1.86 (2H, m), 1.74 (2H, m), 1.59
(3H, d, J 0.8 Hz),1.51 (3H, d, J 1.2 Hz),1.42 (3H, s). dC (100 MHz, C6D6)
189.7, 161.2, 132.3, 127.7, 123.3, 40.4, 25.9, 25.6, 17.6, 16.8. NMR data
are in general agreement with that previously reported.29
4.2.4. (Z)-3-Bromo-2-hydroxy-4-phenylbut-3-enenitrile (39). The ti-
tle compound was prepared as indicated in the representative
procedure (Method A). Purification by flash column chromatogra-
phy (20% Et2O in light petroleum) to yield a waxy light-yellow solid
(300 mg, 13%), mp 51–52 ꢀC. Anal. Calcd for C10H8BrNO: N, 5.88; C,
50.45; H, 3.39. Found: N, 5.77; C, 50.31; H, 3.29, Rf 0.12 (20% Et2O in
light petroleum). dH (400 MHz, C6D6) 7.35–7.32 (2H, m), 7.07–7.00
(3H, m), 6.72 (1H, s), 4.22 (1H, d, J 8.2 Hz), 1.88 (1H, d, J 8.2 Hz). dC
(100 MHz, C6D6) 134.0 131.9, 129.4, 129.2, 128.5, 118.9, 117.1, 67.4.
LRMS showed peaks corresponding only to the enal.
4.3.3. (E)-4,8-Dimethyl-2-(trimethylsilyloxy)nona-3,7-dieneni-
trile. The title compound was prepared as indicated in the repre-
sentative procedure (Method B). Purified by flash column
chromatography (20% Et2O in light petroleum) to yield a pink oil
(267 mg, 76%), Rf 0.9 (20% Et2O in light petroleum). dH (400 MHz,
CDCl3) 5.32 (1H, doublet of sextets, J 8.4 and 1.3 Hz), 5.08 (1H, d, J
8.4 Hz), 5.04 (1H, m), 2.13–2.02 (4H, m), 1.70 (3H, d, J 1.4 Hz), 1.66
(3H, d, J 1.2), 1.58 (3H, s), 0.19 (9H, s). dC (100 MHz, CDCl3) 142.7,
132.3, 123.2, 120.7, 119.4, 58.5, 39.2, 25.9, 25.7, 17.7, 16.8, ꢁ0.1. NMR
data are in agreement with that previously reported.30
4.3. General procedure for the preparation of allylic
cyanohydrins Method B
4.3.4. (E)-2-Hydroxy-4,8-dimethylnona-3,7-dienenitrile (31). The title
compound was prepared as indicated in the representative procedure
(Method B). Purified by flash column chromatography (20% EtOAc in
light petroleum) to yield a clear yellow oil (170 mg, 95%), Rf 0.3
(15:10:75 EtOAc/CHCl3/light petroleum). dH (400 MHz, CDCl3) 5.39
(1H, doublet of sextets, J 5.9 and 1.3 Hz), 5.11 (1H, dd, J 8.5 and 6.0 Hz),
5.06–5.02 (1H, m), 2.14 (1H, d, J 8.4 Hz), 2.19–2.03 (4H, m),1.75 (3H, d,
J 1.4 Hz), 1.67 (3H, d, J 1.1 Hz), 1.59 (3H, br s). dC (100 MHz, CDCl3)
145.7, 132.5, 123.0, 119.2 (2C), 58.0, 39.2, 25.9, 25.6, 17.7, 16.9. NMR
data are in agreement with that previously reported.23
The general procedure of He et al.28 was used for the preparation
of allylic cyanosilyl ethers. The preparation of the silyl-protected
cyanohydrin 25 is representative. Dried potassium carbonate
(4.2 mg, 0.03 mmol) was added to a 10 mL flask, which was sub-
sequently heated with a heat-gun to ensure dry reaction condi-
tions. Once the flask was cooled under high vacuum it was placed
under argon. (E)-2-Methylpent-2-enal (0.12 mL, 0.1 g, 1 mmol) and
TMSCN (0.15 mL, 0.12 g, 1.2 mmol) were then added and the re-
action was stirred vigorously. The reaction became warm. After 6 h
TLC indicated complete consumption of the starting material. The
title compound was concentrated under reduced pressure and
purified by flash column chromatography (20% Et2O in light pe-
troleum) yielding a light pink oil in quantitative yield (200 mg), Rf
0.79 (20% Et2O in light petroleum). dH (500 MHz, C6D6) 5.37 (1H,
triplet of quintets, J 7.2 and 1.2 Hz), 4.42 (1H, br s), 1.75 (2H, quintet,
J 7.5 Hz),1.58 (3H, m), 0.74 (3H, t, J 7.5 Hz), 0.03 (9H, s); dC (125 MHz,
C6D6) 132.1, 130.7, 119.0, 67.6, 21.1, 13.4, 11.8, ꢁ0.44. ESI-MS m/z 220
(MþNa)þ HRMS calculated for C10H19NOSiNaþ 220.1128, found
220.1127.
4.3.5. (E)-3-Methyl-2-(trimethylsilyloxy)pent-3-enenitrile. The title
compound was prepared as indicated in the representative pro-
cedure (Method B). Purified by flash column chromatography (20%
Et2O in light petroleum) to yield a pink oil (1.3 g, 99%), Rf 0.82 (20%
Et2O in light petroleum). dH (400 MHz, CDCl3) 5.71 (1H, m), 4.75
(1H, m), 1.73 (3H, quintet, J 1.2 Hz), 1.65 (3H, m), 0.18 (9H, s). dC
(100 MHz, CDCl3) 131.4, 125.1, 118.9, 67.2, 13.3, 11.8, ꢁ0.34. ESI-MS
m/z 206 (MþNa)þ HRMS calculated for C9H17NOSiNaþ 206.0972,
found 206.0970.
3-Methyl-2-(trimethylsilyloxy)hex-3-enenitrile (1.66 g, 8.5 mmol)
was stirred in a solution of 5% HCl (aqueous, 1 mL in CH3CN
(10 mL)) until TLC indicated complete removal of the silyl ether.
TMSOH, CH3CN and water were then removed in vacuo, purifica-
tion by flash column chromatography (20% Et2O in light petroleum)
afforded (E)-2-hydroxy-3-methylhex-3-enenitrile 25 as a light-
yellow oil (96 mg, 90%), Rf 0.14 (20% Et2O in light petroleum). dH
(500 MHz, CDCl3) 5.73 (1H, m), 4.81 (1H, s), 2.08 (2H, m), 1.77 (3H,
m), 0.99 (3H, t, J 7.6 Hz); dC (125 MHz, CDCl3) 133.6, 129.2, 118.4,
66.9, 21.1, 13.4, 12.3. NMR data are in agreement with that pre-
viously reported.26
4.3.6. (E)-2-Hydroxy-3-methylpent-3-enenitrile (27). The title com-
pound was prepared as indicated in the representative procedure
(Method B). Purified by flash column chromatography (20% EtOAc in
light petroleum) to yield a clear yellow oil (620 mg, 79%), Rf 0.13 (20%
Et2O in light petroleum). dH (400 MHz, CDCl3) 5.82 (1H, m), 4.81 (1H,
m), 2.80 (1H, m), 1.77 (3H, m), 1.67 (3H, m). dC (100 MHz, CDCl3)
130.5,126.3,118.5, 66.8,13.3,12.1. NMR data are in general agreement
with that previously reported.17
4.3.7. (E)-4-(2-Nitrophenyl)-2-(trimethylsilyloxy)but-3-eneni-
trile. The title compound was prepared as indicated in the repre-
sentative procedure (Method B). Purification by flash column
chromatography (100% DCM) gave a yellow oil, which crystallised
upon standing to a yellow solid (610 mg, 63% yield), mp 51–52 ꢀC, Rf
0.33 (20% Et2O in light petroleum). Anal. Calcd for C13H16N2O3Si: C,
56.50; H, 5.84; N, 10.14. Found: C, 56.71; H, 5.66; N, 10.28. dH
(500 MHz, CDCl3) 8.01 (1H, dd, J 8.2 and 1.3 Hz), 7.61–7.56 (2H, m),
4.3.1. (3E,5E)-2-Hydroxyhepta-3,5-dienenitrile (23). The title com-
pound was prepared as indicated in the representative procedure
(Method B) with the following exception: the silyl ether was im-
mediately carried onto the next step without purification. Depro-
tected cyanohydrin was purified by flash column chromatography
(30% Et2O in light petroleum) to yield the product as a yellow oil

K.L. Cosgrove, R.P. McGeary / Tetrahedron 66 (2010) 3050–3057
3055
7.48–7.45 (1H, m), 7.31 (1H, br dd, J 15.5 and 1.5 Hz), 6.13 (1H, dd,
J 15.5 and 5.8 Hz), 5.14 (1H, dd, J 5.8 and 1.5 Hz), 0.26 (9H, s). dC
(125 MHz, CDCl3) 147.8, 133.5, 131.2, 129.7, 129.3, 129.1, 128.5, 124.8,
118.0, 61.8, ꢁ0.2. ESI-MS m/z 299 (MþNa)þ HRMS calculated for
C13H16N2O3SiNaþ 299.0822, found 299.0828.
column chromatography (30% Et2O in light petroleum) gave the
product as a light-yellow oil, as a 1:1 mixture of diastereomers
(510 mg, 93%), Rf 0.2 (30% Et2O in light petroleum). dH (400 MHz,
CDCl3) 6.09–6.05 (2H, m), 4.83 (2H, br t, J 7.5 Hz), 4.74 (2H, quintet, J
1.5 Hz), 4.70 (2H, m), 2.28–1.88 (14H, m), 1.73–1.72 (6H, m), 1.55–
1.46 (2H, m). dC (100 MHz, CDCl3) 148.7 (2ꢂC), 132.5, 132.4, 128.2,
128.0, 118.23, 118.19, 109.3 (2ꢂC), 65.5, 65.4, 40.4, 40.3, 30.31, 30.29,
27.0, 26.9, 24.7, 24.6, 20.73, 20.71. NMR data are in agreement with
that previously reported.31,32
4.3.8. (E)-2-Hydroxy-4-(2-nitrophenyl)but-3-enenitrile (41). The ti-
tle compound was prepared as indicated in the representative
procedure (Method B). Purification by flash column chromatogra-
phy (50% EtOAc in light petroleum) gave a yellow solid (350 mg,
80% yield), mp 80–81 ꢀC. Anal. Calcd for C10H8N2O3: C, 58.82; H,
3.95; N, 13.72. Found: C, 58.77; H, 3.61; N, 13.44, Rf 0.63 (50% EtOAc
in light petroleum). dH (400 MHz, CD3CN) 7.97 (1H, m), 7.71–7.66
(2H, m), 7.55–7.51 (1H, m), 7.25 (1H, m), 6.30 (1H, dd, J 15.7 and
5.6 Hz), 5.25 (1H, dd, J 5.6 and 1.6 Hz). dC (100 MHz, CD3CN,) 148.8,
134.5, 131.7, 130.3, 129.9, 129.7, 129.3, 125.5, 119.6, 61.5. Due to the
instability of this compound the 13C NMR spectrum was collected at
10 ꢀC. The carbon attached to the nitro group was very deshielded,
and only observable by using 30 mg of compound and the following
4.4. General procedure for the preparation of
d-ethoxycarbonyl-
a,b-unsaturated nitriles
Freshly distilled propionic acid (4.1 equiv) was added to a so-
lution containing allylic cyanohydrin (100 mg, freshly prepared
and dried), triethyl ortho acetate (freshly distilled, 8 equiv) and
xylenes (30 mL, dried over molecular sieves). The solution was
immediately heated to 135–140 ꢀC for 24 h whilst under an at-
mosphere of argon. During this time a further two additions of
triethyl ortho acetate (8 equiv) and propionic acid (4.1 equiv) were
made to the reaction, such that the total amount of triethyl ortho
acetate added equalled 24 equiv and the total amount of propionic
acid was 12.3 equiv. The reaction mixture was then cooled to room
temperature and concentrated to give a yellow oil. Purification of
the product was achieved by flash column chromatography.
pulse settings, p1¼5.95 s, D1¼10 s, ns¼216.
m
4.3.9. 3-Methylbut-2-enal. This enal was prepared from 3-methyl-
but-2-enol using known procedures24 and purified by flash column
chromatography (30% Et2O in light petroleum) to yield a clear
volatile oil (1.96 g, 65%), Rf 0.9 (30% Et2O in light petroleum). dH
(400 MHz, CDCl3) 9.94 (1H, d, J 8.1 Hz), 5.86 (1H, doublet of septets,
J 8.1 and 1.3 Hz), 2.15 (3H, d, J 1.3 Hz), 1.96 (3H, d, J 1.3 Hz). dC
(100 MHz, CDCl3) 191.1, 160.5, 128.1, 27.2, 18.9. NMR data are in
general agreement with that previously reported.29
4.4.1. (E)-Ethyl 3-(2-cyanovinyl)octanoate (20). The title com-
pound was prepared as indicated in the representative pro-
cedure. Purification by flash column chromatography (10% EtOAc
in light petroleum) gave the title compound a yellow oil as
a mixture of Z/E (24:76) isomers (125 mg, 76%), Rf 0.38 (10%
4.3.10. 4-Methyl-2-(trimethylsilyloxy)pent-3-enenitrile. The
title
compound was prepared as indicated in the representative pro-
cedure (Method B). Purification by flash column chromatography
(20%Et2Oin lightpetroleum) yielded theproductasa pinkoil(1.24 g,
95%), Rf 0.81 (20% Et2O in light petroleum). dH (400 MHz, CDCl3) 5.33
(1H, doublet of septets, J 8.6 and 1.4 Hz), 5.06 (1H, d, J 8.5 Hz), 1.76
(3H, d, J 1.4 Hz),1.71 (3H, d, J 1.4 Hz), 0.19 (9H, s). dC (100 MHz, CDCl3)
139.5, 120.9, 119.4, 58.4, 25.6, 18.3, ꢁ0.1. ESI-MS m/z 206 (MþNa)þ
HRMS calculated for C9H17NOSiNaþ 206.0972, found 206.0970.
EtOAc in light petroleum). IR neat
n
(cmꢁ1) 2224, 1731. dH
(400 MHz, CDCl3) 6.53 (1H, dd, J 16.4 and 8.9 Hz), 5.34 (1H, dd, J
16.4 and 1.0 Hz), 4.11 (2H, q, J 7.1 Hz), 2.69–2.62 (1H, m), 2.41 (1H,
dd, J 15.6 and 5.6 Hz), 2.29 (1H, dd, J 15.6 and 8.6 Hz), 1.42–1.18
(8H, m), 1.23 (3H, t, J 7.1 Hz), 0.87 (3H, t, J 7.0 Hz). dC (100 MHz,
CDCl3) 171.3, 157.7, 117.2, 100.4, 60.7, 40.0, 38.7, 33.6, 31.5, 26.5,
22.4, 14.2, 13.9. ESI-MS m/z 246 (MþNa)þ HRMS calculated for
C13H21NO2Naþ 246.1465, found 246.1466.
4.3.11. 2-Hydroxy-4-methylpent-3-enenitrile (29). The title com-
pound was prepared as indicated in the representative procedure
(Method B). Purification by flash column chromatography (20%
EtOAc in light petroleum) gave the product as a yellow oil (500 mg,
63%), Rf 0.13 (20% Et2O in light petroleum). dH (400 MHz, C6D6) 4.94
(1H, doublet of septets, J 8.4 and 1.4 Hz), 4.36 (1H, br dd, J 8.3 and
5.8 Hz), 1.26 (3H, br d, J 1.3 Hz), 1.21 (1H, br d, J 5.9 Hz), 1.12 (3H, br
d, J 1.3 Hz). dC (100 MHz, C6D6) 140.2, 120.2, 119.2, 57.7, 24.8, 17.5.
NMR data are in general agreement with that previously reported.17
4.4.2. (E)-Ethyl 5-cyano-3-methylpent-4-enoate (22). The title
compound was prepared as indicated in the representative
procedure. Purification by flash column chromatography (20%
Et2O in light petroleum) gave the title compound as a clear oil,
as a mixture of Z/E (24:76) isomers (113 mg, 66%), Rf 0.21 (20%
Et2O in light petroleum). IR neat
n
(cmꢁ1) 2224, 1730. dH
(400 MHz, CDCl3) 6.65 (1H, dd, J 16.4 and 7.4 Hz), 5.34 (1H, dd, J
16.4 and 1.4 Hz), 4.12 (2H, q, J 7.2 Hz), 2.84 (1H, septet of dou-
blets, J 7.0 and 1.4 Hz), 2.35 (1H, d J 7.2 Hz), 2.34 (1H, d, J 7.0 Hz),
1.24 (3H, t, J 7.1 Hz), 1.10 (3H, d, J 6.8 Hz). dC (100 MHz, CDCl3)
171.1, 158.5, 117.2, 99.3, 60.7, 40.0, 34.1, 18.6, 14.2. ESI-MS m/z 190
(MþNa)þ HRMS calculated for C11H17NO2Naþ 190.0838, found
190.0837.
4.3.12. (S,R)-2-((S)-4-(Prop-1-en-2-yl)cyclohex-1-enyl)-2-(trime-
thylsilyloxy)acetonitrile. The title compound was prepared as in-
dicated in the representative procedure (Method B). Purification by
flash column chromatography (20% Et2O in light petroleum) to yield
the product as a yellow oil, as a 1:1 mixture of diastereomers
(780 mg, 78%), Rf 0.91 (20% Et2O in light petroleum). dH (400 MHz,
C6D6) 5.70 (1H, m), 5.64 (1H, m), 4.74 (2H, m), 4.67 (2H, m), 4.44
(2H, m), 2.10–1.58 (12H, m),1.53 (6H, m),1.25–1.19 (2H, m), 0.06 and
0.05 (9H, 2s). dC (100 MHz, C6D6) 149.0, 148.9, 133.7, 133.4, 126.9,
126.5, 118.9, 118.8, 109.4, 109.3, 66.0, 65.9, 40.8, 40.7, 30.5, 30.4, 27.2,
27.1, 24.5, 24.2, 20.7, 20.6, ꢁ0.42, ꢁ0.44. ESI-MS m/z 272 (MþNa)þ
HRMS calculated for C14H23NOSiNaþ 272.1441, found 272.1439.
4.4.3. (E)-Ethyl 3-((E)-2-cyanovinyl)hex-4-enoate (24). The title
compound was prepared as indicated in the representative pro-
cedure. Purification by flash column chromatography (20% Et2O in
light petroleum) gave the title compound as a clear oil, as a mixture
of Z/E (30:70) isomers (83 mg, 59%), Rf 0.21 (20% Et2O in light
petroleum). IR neat
n
(cmꢁ1) 2222, 1731. dH (400 MHz, CDCl3) 6.64
(1H, dd, J 16.4 and 7.0 Hz), 5.55 (1H, dqd, J 15.3, 6.5 and 1.0 Hz), 5.36
(1H, dd, J 16.4 and 1.5 Hz), 5.28 (1H, ddq, J 15.3, 7.5 and 1.6 Hz), 4.12
(2H, q, J 7.1 Hz), 3.35 (1H, br quintet, J 6.9 Hz), 2.43 (1H, d, J 7.0 Hz),
2.42 (1H, d, J 7.6 Hz), 1.67 (3H, ddd, J 6.5, 1.7, 0.8 Hz), 1.23 (3H, t,
J 7.1 Hz). dC (100 MHz, CDCl3) 170.8, 156.1, 129.2, 128.4, 117.2, 100.1,
4.3.13. (S,R)-2-Hydroxy-2-((S)-4-(prop-1-en-2-yl)cyclohex-1-enyl)a-
cetonitrile (33). The title compound was prepared as indicated in
the representative procedure (Method B). Purification by flash

3056
K.L. Cosgrove, R.P. McGeary / Tetrahedron 66 (2010) 3050–3057
60.8, 42.3, 38.6, 18.0, 14.2. ESI-MS m/z 216 (MþNa)þ HRMS calcu-
quintet, J 1.4 Hz), 4.67 (1H, appears as a septet, J 0.8 Hz), 4.20–4.08
(2H, m), 3.57 (1H, m), 2.56 (2H, d, J 7.9 Hz), 2.40 (1H, br tdd, J 13.7,
4.9 and 2.0 Hz), 2.31–2.24 (2H, m), 1.94 (1H, m), 1.86 (1H, m), 1.68
(3H, m), 1.59 (1H, m), 1.32 (1H, br td, J 12.9 and 4.1 Hz), 1.26 (3H, J
7.1 Hz). dC (100 MHz, CDCl3) 170.9, 167.8, 116.2, 109.7, 94.2, 60.9,
38.5, 37.6, 37.5, 36.4, 32.7, 31.7, 20.7, 14.1. ESI-MS m/z 270 (MþNa)þ
HRMS calculated for C15H21NO2Naþ 270.1465, found 270.1463.
lated for C11H15NO2Naþ 216.0995, found 216.0994.
4.4.4. (E)-Ethyl 5-cyano-3-ethyl-4-methylpent-4-enoate (26). The
title compound was prepared as indicated in the representative
procedure. Purification by flash column chromatography (10%
EtOAc in light petroleum) gave the title compound as a clear oil, as
a mixture of Z/E (24:76) isomers (122 mg, 73%), Rf 0.27 (10% EtOAc
in light petroleum). IR neat
n
(cmꢁ1) 2218, 1731. dH (400 MHz,
4.4.9. (E)-Ethyl 5-cyano-3-phenylpent-4-enoate (36). The title
compound was prepared as indicated in the representative pro-
cedure. Purification by flash column chromatography (20% Et2O in
light petroleum) gave the title compound as a yellow oil, as a mix-
ture of Z/E (22:78) isomers (100 mg, 73%), Rf 0.16 (10% EtOAc in light
CDCl3) 5.16 (1H, m), 4.13–4.07 (2H, m), 2.64–2.57 (1H, m), 2.42 (1H,
dd, J 15.3 and 6.2 Hz), 2.34 (1H, dd, J 15.3 and 8.8 Hz), 1.98 (3H, d, J
1.1), 1.53–1.38 (2H, m), 1.22 (3H, t, J 7.1 Hz), 0.82 (3H, t, J 7.4 Hz). dC
(100 MHz, CDCl3) 171.4, 165.7, 116.8, 97.0, 60.7, 46.1, 38.1, 25.9, 17.4,
14.2, 11.5. ESI-MS m/z 218 (MþNa)þ HRMS calculated for
C11H17NO2Naþ 218.1151, found 218.1146.
petroleum). IR neat n
(cmꢁ1) 2224, 1729. dH (400 MHz, CDCl3) 7.35–
7.31 (2H, m), 7.29–7.23 (1H, m), 7.16–7.13 (2H, m), 6.84 (1H, dd, J
16.4 and 7.0), 5.27 (1H, dd, J 16.4 and 1.6), 4.13–4.05 (2H, m, AB
system and peak mixing with cis isomer), 4.00 (1H, qd, J 7.3 and
1.6), 2.75 (2H, m), 1.18 (3H, t, J 7.1). dC (100 MHz, CDCl3) 170.6, 156.2,
139.0, 129.1, 127.8, 127.6, 117.0, 100.6, 60.9, 45.0, 39.1, 14.1. ESI-MS m/
z 252 (MþNa)þ HRMS calculated for C14H15NO2Naþ 252.0995,
found 252.0996.
4.4.5. (E)-Ethyl 5-cyano-3,4-dimethylpent-4-enoate (28). The title
compound was prepared as indicated in the representative pro-
cedure. Purification by flash column chromatography (20% Et2O in
light petroleum) gave the title compound as a clear oil, as a mixture
of Z/E (26:74) isomers (120 mg, 73%), Rf 0.22 (20% Et2O in light
petroleum). IR neat
n
(cmꢁ1) 2218, 1730. dH (400 MHz, CDCl3) 5.16
(1H, quintet, J 1.0 Hz), 4.11 (2H, q, J 7.1 Hz), 2.81 (1H, sextet of
doublets, J 7.0 and 0.6 Hz), 2.42 (1H, dd, J 15.3 and 7.4 Hz), 2.32 (1H,
dd, J 15.3 and 7.3 Hz), 2.03 (3H, d, J 1.1 Hz), 1.23 (3H, t, J 7.1 Hz) and
1.10 (3H, d, J 6.9 Hz). dC (100 MHz, CDCl3) 171.3, 167.4, 116.9, 95.5,
60.7, 39.5, 38.6, 18.9, 18.3, 14.2. ESI-MS m/z 204 (MþNa)þ HRMS
calculated for C15H23NO2Naþ 204.0995, found 204.0998.
4.4.10. (E)-Ethyl 5-cyano-4-methyl-3-phenylpent-4-enoate (38). The
title compound was prepared as indicated in the representative
procedure. Purification by flash column chromatography (10%
EtOAc in light petroleum) gave the product as a clear oil, as mixture
of Z/E (20:80) isomers (70 mg, 40%), Rf 0.24 (10% EtOAc in light
petroleum). IR neat n
(cmꢁ1) 2219, 1730. dH (500 MHz, CDCl3) 7.34–
7.29 (2H, m), 7.27–7.25 (1H, m), 7.15–7.12 (2H, m), 5.28 (1H, quintet,
J 1.1 Hz), 4.10–4.02 (2H, m, AB system), 3.96 (1H, br t, J 7.8), 2.81 (1H,
dd, J 15.5 and 8.2 Hz), 2.75 (1H, dd, J 15.5 and 7.5), 1.94 (3H. d, J
1.0 Hz), 1.16 (3H, t, J 7.3). dC (125 MHz, CDCl3) 170.8, 165.2, 139.1,
128.9, 127.7, 127.6, 116.8, 96.1, 60.9, 49.2, 38.1, 19.9, 14.1. The ste-
reochemistry was confirmed with the aid of a NOESY experiment.
ESI-MS m/z 266 (MþNa)þ HRMS calculated for C15H17NO2Naþ
266.1151, found 266.1146.
4.4.6. (E)-Ethyl 5-cyano-3,3-dimethylpent-4-enoate (30). The title
compound was prepared as indicated in the representative pro-
cedure. Purification by flash column chromatography (20% Et2O in
light petroleum) gave the title compound as a clear oil, as a mixture
of Z/E (7:93) isomers (123 mg, 76%), Rf 0.3 (20% Et2O in light pe-
troleum). IR neat
n
(cmꢁ1) 2224, 1729. dH (400 MHz, CDCl3) 6.81
(1H, d, J 16.6 Hz), 5.27 (1H, d, J 16.6 Hz), 4.10 (2H, q, J 7.1 Hz), 2.33
(2H, s), 1.23 (3H, t, J 7.1 Hz), 1.16 (6H, s). dC (100 MHz, CDCl3) 170.4,
162.6, 117.5, 97.2, 60.5, 45.9, 37.0, 26.1, 14.2. ESI-MS m/z 204
(MþNa)þ HRMS calculated for C10H15NO2Naþ 204.0995, found
204.0998.
4.4.11. (Z)-Ethyl 4-bromo-5-cyano-3-phenylpent-4-enoate (40). The
title compound was prepared as indicated in the representative
procedure. Purification by flash column chromatography (10%
EtOAc in light petroleum) gave the product as a single isomer, as
a clear yellow oil (14 mg, 13%), Rf 0.2 (10% EtOAc in light petroleum).
4.4.7. (E)-Ethyl 3-(2-cyanovinyl)-3,7-dimethyloct-6-enoate (32). The
title compound was prepared as indicated in the representative
procedure. Purification by flash column chromatography (20% Et2O
in light petroleum) gave the title compound as a clear oil, as
a mixture of Z/E (7:93) isomers (115 mg, 76%), Rf 0.42 (20% Et2O in
IR neat n
(cmꢁ1) 2227, 1729. dH (500 MHz, CDCl3) 7.37–7.30 (3H, m),
7.22–7.19 (2H, m), 6.01 (1H, d, J 0.9 Hz), 4.32 (1H, br t, J 7.5 Hz), 4.14–
4.06 (2H, m, AB system), 3.05 (1H, dd, J 16.1 and 7.9 Hz), 2.86 (1H,
dd, J 16.1 and 7.3 Hz), 1.18 (3H, dd, J 7.5 and 7.0 Hz). dC (100 MHz,
CDCl3) 170.1, 152.3, 137.4, 129.1, 128.3, 127.7, 115.7, 103.1, 61.2, 51.7,
38.3, 14.1. Stereochemistry confirmed with the aid of a NOESY ex-
periment. ESI-MS m/z 330 (MþNa)þ HRMS calculated for
C14H14BrNO2Naþ 330.0100, found 330.0107.
light petroleum). IR neat n
(cmꢁ1) 2224, 1730. dH (400 MHz, CDCl3)
6.76 (1H, d, J 16.7 Hz), 5.25 (1H, d, J 16.7 Hz), 5.01 (1H, m), 4.12–4.07
(2H, m, AB system), 2.38 (1H, d, J 14.2 Hz), 2.32 (1H, d, J 14.2 Hz),
1.93–1.82 (2H, m), 1.65 (3H, m), 1.56 (3H, m), 1.46 (2H, br t, J 8.7 Hz),
1.23 (3H, t, J 7.2 Hz), 1.15 (3H, s). dC (100 MHz, CDCl3) 170.4, 162.0,
132.4, 123.2, 117.6, 98.0, 60.5, 44.3, 40.2, 40.1, 25.6, 22.7, 22.4, 17.6,
14.2. ESI-MS m/z 272 (MþNa)þ HRMS calculated for C15H23NO2Naþ
272.1621, found 272.1618.
References and notes
1. Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002.
2. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.;
Faulkner, D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741–743.
3. Langlois, Y. In The Claisen RearrangementdMethods and Applications; Hier-
semann, M., Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, 2007; pp 301–366.
4. Giardina, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001,
713–718.
5. Srikrishna, A.; Nagaraju, S. J. Chem. Soc., Perkin Trans. 1 1992, 311–312.
6. Cosgrove, K. L.; McGeary, R. P. Synlett 2009, 1749–1752.
7. Burrows, C. J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103, 6983–6984.
8. Burrows, C. J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103, 6984–6986.
9. Aviyente, V. J. Org. Chem. 1997, 62, 6121–6128.
10. Yoo, H. Y.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 2877–2884.
11. Gerrits, P. J.; Zumbragel, F.; Marcus, J. Tetrahedron 2001, 57, 8691–8698.
12. Cosgrove, K. L.; McGeary, R. P. Synlett 2008, 2425–2428.
13. Willams, D. H.; Fleming, I. Spectroscopic Methods in Organic Chemistry, 5th ed.;
McGraw-Hill: London, Sydney, 1995.
4.4.8. Ethyl 2-((1S,5S,E)-2-(cyanomethylene)-5-(prop-1-en-2-yl)cy-
clohexyl)acetate (34). The title compound was prepared as in-
dicated in the representative procedure. Purification by flash
column chromatography (20% Et2O in light petroleum) gave the
title compound as a yellow oil, as mixture of Z/E (30:70) isomers,
where the trans isomer was a mixture of diastereomers (106 mg,
75%), Rf 0.38 (20% Et2O in light petroleum). The minor trans isomer
(26% of the total product) was partially purified from the other
isomers and tentatively assigned the above structure based on
NOESY and COSY correlations of the allylic proton. IR neat
2218, 1731. dH (400 MHz, CDCl3) 5.11 (1H, d, J 1.9 Hz), 4.72 (1H,
n )
(cmꢁ1

K.L. Cosgrove, R.P. McGeary / Tetrahedron 66 (2010) 3050–3057
24. Piancatelli, G.; Leonelli, F. Org. Synth. 2006, 83, 18–23.
3057
14. Solis, A.; Luna, H.; Manjarrez, N.; Perez, H. I. Tetrahedron 2004, 60, 10427–10431.
15. Jacobson, R.; Lahm, G.; Clader, J. J. Org. Chem. 1980, 45, 395–405.
16. Kim, S. S.; Lee, S. H. Synth. Commun. 2005, 35, 751–759.
17. Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Org. Chem. 1993, 58, 1515–1522.
18. Kiljunen, E.; Kanerva, L. T. Tetrahedron: Asymmetry 1996, 7, 1105–1116.
19. Lu, W.; Chen, P.; Lin, G. Tetrahedron 2008, 64, 7822–7827.
20. Brussee, J.; Loos, W. T.; Kruse, C. G.; Van der Gen, A. Tetrahedron 1990, 46, 979–986.
21. Kirsten, C. N.; Herm, M.; Schrader, T. H. J. Org. Chem. 1997, 62, 6882–6887.
22. Black, P. J.; Jenkins, K.; Willams, J. M. J. Tetrahedron: Asymmetry 2002, 13,
317–323.
25. Anderson, J. R.; Edwards, R. L.; Whalley, A. J. S. J. Chem. Soc., Perkin Trans. 1 1982,
215–221.
26. Nanda, S.; Kato, Y.; Asano, Y. Tetrahedron: Asymmetry 2006, 17, 735–741.
27. Kantam, M. L.; Mahendar, K.; Sreedhar, B.; Kumar, K. V.; Choudary, B. M. Synth.
Commun. 2008, 38, 3919–3936.
28. He, B.; Li, Y.; Feng, X.; Zhang, G. Synlett 2004, 1776–1778.
29. Zgani, I.; Menut, C.; Seman, M.; Gallois, V.; Laffont, V.; Liautard, J.; Liautard, J.-P.;
Criton, M.; Montero, J.-L. J. Med. Chem. 2004, 47, 4600–4612.
30. Rajagopal, G.; Kim, S. S.; George, S. C. Appl. Organomet. Chem. 2007, 21, 198–202.
31. Braish, T. F.; Fuchs, P. L. Synth. Commun. 1985, 15, 549–567.
32. McGuirk, P. R.; Collum, D. B. J. Org. Chem. 1984, 49, 843–852.
23. Ognyanov, V. I.; Datcheva, V. K.; Kyler, K. S. J. Am. Chem. Soc. 1991, 113,
6992–6996.