Catalytic electronic activation as a tool for the addition of stabilised nucleophiles to allylic alcohols

Article abstract of DOI:10.1016/j.tet.2004.10.009

This paper describes the activation of 2-cyclohexen-1-ol (1) and 2-cyclopenten-1-ol (11) through the use of aluminium-catalysed transfer hydrogenation. The electronically activated substrates are demonstrated to undergo facile conjugate addition and, when the alcohol functional group is subsequently restored in a one-pot procedure, this leads to an indirect addition of nucleophiles to allylic alcohols. This novel methodology has been termed catalytic electronic activation. The aluminium tert-butoxide catalysed conversion of 2-cyclohexen-1-ol (1) into 2-(3-hydroxycyclohexyl)-2- methylmalononitrile (18) and 2-cyclopenten-1-ol (11) into 2-(3- hydroxycyclopentyl)-2-methylmalononitrile (16) in 90 and 60% yield, respectively has been demonstrated through an efficient domino Oppenauer/Michael addition/Meerwein-Ponndorf-Verley process.

Full text of DOI:10.1016/j.tet.2004.10.009

Tetrahedron 61 (2005) 1363–1374
Catalytic electronic activation as a tool for the addition of
stabilised nucleophiles to allylic alcohols
*
Phillip J. Black, Michael G. Edwards and Jonathan M. J. Williams
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 31 May 2004; revised 8 September 2004; accepted 1 October 2004
Abstract—This paper describes the activation of 2-cyclohexen-1-ol (1) and 2-cyclopenten-1-ol (11) through the use of aluminium-catalysed
transfer hydrogenation. The electronically activated substrates are demonstrated to undergo facile conjugate addition and, when the alcohol
functional group is subsequently restored in a one-pot procedure, this leads to an indirect addition of nucleophiles to allylic alcohols. This
novel methodology has been termed catalytic electronic activation.The aluminium tert-butoxide catalysed conversion of 2-cyclohexen-1-ol
(1) into 2-(3-hydroxycyclohexyl)-2-methylmalononitrile (18) and 2-cyclopenten-1-ol (11) into 2-(3-hydroxycyclopentyl)-2-methylmalo-
nonitrile (16) in 90 and 60% yield, respectively has been demonstrated through an efficient domino Oppenauer/Michael addition/Meerwein–
Ponndorf–Verley process.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
concept has been applied by this group to indirect Wittig
reactions on alcohols2,3 and other processes.4–7
The reactivity of an alkene is highly dependent upon the
nature of any nearby substituents. For example, whilst
alkenes conjugated to electron-withdrawing groups can be
susceptible to nucleophilic addition reactions, alkenes
attached to electron-donating groups are more susceptible
to electrophilic addition. Conversion of electron-donating
groups and electron-withdrawing groups would achieve
reversible catalytic electronic activation of the alkene, and
enable a cross-over in the reactivity of alkene substrates
(Scheme 1). Thus, alkenes attached to electron-withdrawing
groups (EWG) could undergo indirect electrophilic
addition, and alkenes attached to electron donating groups
(EDG) could undergo indirect nucleophilic addition.
Transfer hydrogenation reactions have been used widely in
the reduction of carbonyl compounds, as well as the reverse
process.8–12 One of the hallmarks of these reactions is their
reversibility, which has been exploited in the racemisation
of secondary alcohols.13 Whilst there are many reagents and
catalysts capable of effecting a reversible oxidation/
reduction sequence, we reasoned that the use of aluminium
catalysts would be less likely to promote isomerisation of
allylic alcohol substrates than many transition metal
catalysts.14,15
2. Results and discussion
2.1. Use of malonate nucleophiles
Aluminium alkoxides have been used extensively to carry
out reversible hydride transfer to a carbonyl acceptor.16–18
The most commonly used reagent, aluminium isopropoxide,
is available commercially and promotes both the
Meerwein–Ponndorf–Verley (MPV) reduction and
Oppenauer oxidation effectively under suitable reaction
conditions, generally employing an excess of either oxidant
(acetone, 2-butanone) or reductant (propan-2-ol).
Scheme 1. Reversible crossover of alkene reactivity.
By designing a reaction whereby an alcohol is reversibly
oxidised to a carbonyl compound, we have reported
preliminary results which show that it is possible to effect
indirect nucleophilic addition to allylic alcohols.1 A related
Keywords: Aluminium; Catalytic electronic activation; Homogeneous
catalysis; Hydrogenation; Michael addition.
It was envisaged that the catalytic electronic activation
process would only require a catalytic amount of ketone
added at the start of the reaction. Equilibrium would then be
* Corresponding author. Tel.: C44 1225 383942; fax: C44 1225 826231;
e-mail: j.m.j.williams@bath.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.009

1364
P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
After 6 h, 1H NMR analysis of the crude product indicated a
O95% conversion into 2-cyclohexen-1-one (3) and alcohol
4 in both tetrahydrofuran and dichloromethane (Table 1,
entries 1 and 2), thus proving conclusively that the
equilibrium position for the transfer hydrogenation reaction
lies firmly to the right, that is, towards the thermodynami-
cally more favourable conjugated ketone. This is beneficial
for ensuring a constant supply of enone ready for conjugate
addition. Surprisingly, aluminium tert-butoxide also exhib-
ited excellent activity at substoichiometric levels (Table 1,
entry 3); a property not normally associated with MPV-type
systems.16 However, a repeat experiment conducted at room
temperature gave no conversion into the desired products
after 6 h, while the use of a sodium isopropoxide catalyst22
(Table 1, entry 5) provided equally disappointing results.
Scheme 2. Principal of catalytic domino Oppenauer/Michael addition/MPV
reduction.
maintained between the alcohol and ketone components
during the course of the reaction (Scheme 2).
The data collected thus far suggested that the following
reaction scheme could be envisaged (Scheme 5).
Preliminary studies indicated that both dimethyl malonate
derived nucleophiles and the corresponding Michael
addition adducts were susceptible to aluminium isoprop-
oxide mediated trans-esterification (Scheme 3).19,20 The
labile methoxy ester groups are replaced readily by the
isopropoxide ligands on the aluminium catalyst.
A series of experiments was designed in order to test this
hypothesis: the general procedure involved the addition
of 2-cyclohexen-1-ol (1) and a catalytic amount of
2-cyclohexen-1-one (3) to a stirred solution of di-tert-
Scheme 3. Aluminium isopropoxide catalysed trans-esterification of dimethyl malonate.
In an attempt to block trans-esterification and base-
catalysed hydrolysis reactions, the more robust tert-butyl
ester was chosen; for these substrates trans-esterification
proceeds almost exclusively through alkyl-oxygen
cleavage.21
Scheme 5. Malonate derived domino Oppenauer/Michael addition/MPV
process.
In order to ascertain the equilibrium position for the desired
transfer hydrogen reaction, arguably the most important
factor in catalytic electronic activation, a 1:1 mixture of
2-cyclohexen-1-ol (1) and ketone 2 was heated to reflux in
solvent into which aluminium tert-butoxide was added
dropwise (Scheme 4, Table 1).
butyl malonate (5) and base in dichloromethane. This
solution was subsequently heated at reflux into which
aluminium tert-butoxide was added slowly over 30 min
(Table 2).
Table 2. Results of malonate derived domino Oppenauer/Michael
addition/MPV process
Entry
Basea
(mol%)
Malonate Al(OtBu)3
(mol%)
t
(h)
Conv. 4:2:3
(%)b
(mol%)
1
2
3
4
5
6
7
NaH (20)
NaH (20)
NaH (10)
KOtBu (10)
NaH (30)
NaH (50)
NaH (20)
200
200
200c
100d
200
500
200
100
100
100
100
10
1
6
12:14:1
19:12:5
0:0:10
0:0:10
0:29:0
0:43:0
10:2:6
24
24
24
24
72
Scheme 4. Aluminium catalysed Oppenauer/MPV crossover reaction.
Table 1. Results of malonate derived Oppenauer/MPV crossover reaction
100
100
Entry Catalyst
(mol%)
Solventa
t
(h)
Conv.
(%)b
Recovery
(%)c
a The reactions were carried out on a 1 mmol scale in CH2Cl2 (5–8 mL) at
reflux.
b Analysed by 1H NMR.
1
2
3
4
Al(OtBu)3 (100)
THF
6
O95
O95
O95
!5
96
99
100
76
c Added portionwise over 7 h.
Al(OtBu)3 (100)
Al(OtBu)3 (10)
Na(OiPr) (100)
CH2Cl2
CH2Cl2
CH2Cl2
24d
24
24
d Heated at 100 8C in an ACE pressure tube.
a The reactions were carried out on a 1 mmol scale in solvent (10 mL) at
reflux.
The initial results were rather disappointing: under a variety
of experimental conditions, only low conversions (10–19%;
Table 2, entries 1, 2 and 7) into alcohol 4 were obtained, even
after 72 h. Of some concern was the presence of ketone 2 in
1
b Analysed by H NMR.
c Crude recovery upon work-up.
d Reaction reached completion in 6 h.

P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
1365
the reaction mixture (Table 2, entries 5 and 6). This suggested
that the efficient aluminium catalysed transfer hydrogenation
between ketone 2 and allylic alcohol 1 (Scheme 4) was
inhibited by the presence of di-tert-butylmalonate (5).
MPV reduction, respectively. In each case, the reaction
proceeded at room temperature to give the desired products
in excellent yield.
In view of this evidence dimethylaluminium chloride
appeared to be an excellent candidate for the domino
Oppenauer/Michael addition/MPV process. Thus, the
transfer hydrogenation capabilities of dimethylaluminium
chloride were investigated for the crossover
Oppenauer/MPV process (Scheme 4, Table 4).
Surprisingly, a repeat experiment using 10 mol% of ketone
intermediate 2 as oxidant (Scheme 5) provided appreciably
enhanced, yet still moderate, conversions into alcohol 4
(Table 3). We are not sure why the choice of ketone has such
a pronounced effect on conversion, however a possible
solution is postulated (vide infra).
These promising results prompted further investigation
towards the domino Oppenauer/Michael addition/MPV
process. The general procedure involved adding dimethyl-
aluminium chloride to a nitrogen-purged dichloromethane
solution of 2-cyclohexen-1-ol (1). After 20 min, a catalytic
amount of 2-cyclohexen-1-one (3), di-tert-butyl malonate
(5) and sodium hydride were added and the reaction
maintained at room temperature (Scheme 6, Table 5).
Table 3. Results of domino Oppenauer/Michael addition/MPV process
using catalytic ketone 2
Entry
Solventa
(mL)
Malonate
(mol%)
Al(OtBu)3
(mol%)
t
(h)
Conv. 4:2:3
(%)b
1
2
3
4
5
6
THF (10)
THF (10)
CH2Cl2 (10)
CH2Cl2 (5)
CH2Cl2 (5)
CH2Cl2 (25)e
100
100c
200
200
200
120
100
10
100
100
100
100
96
24
72
10
10
24
43:20:5
29:67:0d
38:0:0
0:23:0
10:0:9
24:0:1
a The reactions were carried out on a 1 mmol scale in CH2Cl2 (5–25 mL) at
reflux.
b Analysed by 1H NMR.
c 0.1 equiv KOtBu.
d Main product consistent with malonic acid dicyclohex-2-enyl ester.
e 5 mmol in CH2Cl2 at reflux.
Scheme 6. Dimethylaluminium chloride catalysed Domino Oppenauer/
Michael addition/MPV reaction.
Both Wilds17 and Okano23 have reported that b-diketones
deactivate aluminium and lanthanide(III) catalysts by strong
chelate formation. Furthermore, Okano and co-workers were
able to isolate the acetylacetonate complex gd(acac)3 from
the reaction mixture which displayed no catalytic activity. It
is therefore probable that the low conversions to date are
attributed to an analogous complex formation (Fig. 1, A).
Table 5. Dimethylaluminium chloride catalysed Domino Oppenauer/
Michael addition/MPV reaction
Entry
NaH
(mol%)
Malonatea
(mol%)
t
(h)
Conv. 4:2:3
(%)b
1
2
3
4
5
10
20
10
20
20
100c
100c
100d
100c
200c
6
6
24
72
72
9:1:15
22:12:11
25:1:5
11:1:20
23:12:10
a The reactions were carried out on a 1 mmol scale in CH2Cl2 (7–10 mL) at
room temperature.
b Analysed by H NMR.
1
c
˚
2-Cyclohexen-1-one (0.2 equiv) and 4 A MS were added.
d 2-Cyclohexen-1-ol and catalyst stirred for 1 h.
Figure 1. Comparison of proposed aluminium complex and aluminium
acetylacetonate.
Unfortunately, the conversions into alcohol 4 were still low
(9–25%), even after prolonged reaction times (Table 5,
entries 4 and 5). However, the presence of unreacted
2-cyclohexen-1-one (2) (Table 5, entries 2 and 5), again
suggests that the malonate salt may be forming an acac-type
complex (Fig. 1, A) with the aluminium catalyst, inhibiting
both the Michael addition and Meerwein–Ponndorf–
Verley–Oppenauer (MPVO) chemistry.
This idea is reinforced by the fact that aluminium
acetylacetonate (Fig. 1, B) was demonstrated to be an
ineffective promoter in the Oppenauer/MPV crossover
reaction (Scheme 4, Table 4).
Snider24 and more recently Node25,26 demonstrated that
dimethylaluminium chloride was able to catalyse both an
Oppenauer/ene annelation and a domino Michael addition/
Yager and co-workers27 have demonstrated that the rates of
MPVO reactions were affected directly by the degree of pre-
association of the aluminium complex and the alcohol
substrate. Thus, a final experiment was performed in order
to discover whether prior reaction of cyclohexenol with the
aluminium promoter could lead to an improved yield. Thus,
reaction of 2-cyclohexen-1-ol (1) with dimethylaluminium
chloride for 1 h presumably forms an aluminium cyclo-
hexenyl alkoxide intermediate, and this was found to
provide an increase in the rate of reaction (Scheme 7).
Table 4. Results of dimethylaluminium chloride catalysed Oppenauer/
MPV crossover reaction
Entry
Catalysta
(mol%)
Temperature
(8C)
Conv.
(%)b
1
2
3
Al(acac)3 (100)
Me2AlCl (10)
Me2AlCl (120)
44
25
25
!5
O95
O90
a The reactions were carried out on a 1 mmol scale in solvent (5 mL).
b Analysed by 1H NMR.

1366
P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
The next objective was to establish the equilibrium position
for the transfer hydrogenation reaction. Thus, dimethyl-
aluminium chloride and aluminium tert-butoxide were
investigated for their ability to effect transfer hydrogenation
between 2-cyclohexen-1-ol (1), 2-cyclopenten-1-ol (11) and
the corresponding ketone intermediates (Scheme 9,
Table 7).
Scheme 7. In situ generated aluminium alkoxide domino Oppenauer/Mi-
chael addition/MPV reaction.
After 90 h an increased conversion into alcohol 4 (51%) was
realised. The formation of the desired product, at room
temperature, albeit at moderate conversion, was considered
a notable improvement.
Table 7. Results of aluminium catalysed Oppenauer/MPV crossover
reaction of malononitrile derived substrates
Entry
Substrate Catalysta
(mol%)
Temperature
(8C)
t
(h)
Conv.
(%)b
1
2
3
4
14
15
12
13
Me2AlCl (10)
25
44
44
44
15
6
24
24
O95
O95
41
2.2. Use of malononitriles as nucleophiles
Al(OtBu)3 (10)
Al(OtBu)3 (10)
Al(OtBu)3 (100)
68
In order to realise high conversions in the allylic alcohol
catalytic electronic activation procedure it was proposed
that an alternative non-chelating nucleophile should be
investigated. Malononitrile (6) is a useful building block in
synthetic chemistry28 and it is therefore an appealing
substrate for the domino Oppenauer/Michael addition/
MPV process. However competitive Knoevenagel conden-
sation/dehydration was found to occur either preferentially
or subsequent to the desired conjugate addition (Scheme 8,
Table 6).29,30
a Reactions were performed on a 1 mmol scale in solvent (5 mL).
b Analysed by 1H NMR.
Whilst the equilibrium position for the transfer hydrogen-
ation reaction between cyclohexyl derivatives lies firmly to
the right (Table 7, entries 1 and 2), the effect is not quite as
pronounced for the cyclopentyl adducts (Table 7, entries 3
and 4). This suggests that the thermodynamic driving force
to produce the conjugated ketone is less well defined.
Feringa33 and Pfaltz34 have also observed an analogous
significant difference in reactivity between 2-cyclohexen-1-
one (3) and 2-cyclopenten-1-one (20) towards asymmetric
conjugate addition.
Based on the conditions needed for conjugate addition and
for transfer hydrogenation an indirect nucleophilic addition
of methylmalononitrile (9) and benzylmalononitrile (10) to
2-cyclohexen-1-ol (1) and 2-cyclopenten-1-ol (11) was
attempted (Scheme 10, Table 8). These experiments
employed the aluminium reagent in stoichiometric amounts.
Scheme 8. Addition of malononitrile to 2-cyclohexen-1-one.
Table 6. Results of the addition of malononitrile to 2-cyclohexen-1-one
Entry
Malononitrilea
(mol%)
t
(h)
Conv. 7:8
(%)b
These data demonstrated for the first time an efficient
domino Oppenauer/Michael addition/MPV process
(Table 8, entries 5 and 6); it is worth noting that the
maximum expected yield is 90%. However, significantly
poorer yields were obtained when using the dimethyl-
aluminium chloride catalyst (Table 8, entries 1 and 2) and in
the cyclopentyl system (Table 8, entries 7–9).
1
2
3
100
200
100
1
4
8
O90:0
43:57
29:71
a Reactions were performed on a 1 mmol scale in solvent (10–20 mL).
b Analysed by H NMR.
1
It was proposed that a simple solution to prevent the
aldol/dehydration reaction was to place a substituent at the
acidic (pKaZ11.2)31 a-position of malononitrile (6). Thus,
methylmalononitrile (9) and benzylmalononitrile (10) were
Nevertheless, it was hoped that a fully catalytic reaction
could be employed. Thus, both aluminium tert-butoxide and
dimethylaluminium chloride were investigated for their
ability to effect a catalytic electronic activation process
(Scheme 10, Table 9).
synthesised according to a recent procedure reported by
´
32
Dıez-Barra and co-workers. This procedure was adopted
as other simple base-catalysed routes are known to lead to
di-substituted products.
Poor results were obtained initially when using substoichio-
metric amounts of catalyst (Table 9, entries 1–3). To address
these problems the reactions were studied at elevated
temperatures using ACE pressure tubes (Table 9, entries
4–9). Thus we were able to realise the catalytic reaction
within 8 h when the higher temperatures were employed;
even when using 10 mol% of cyclohexanone as an
alternative catalytic oxidant (Table 9, entry 5). Under the
same conditions a 57% yield of alcohol 18 could be
obtained using 5 mol% cyclohexanone.
Scheme 9. Aluminium catalysed Oppenauer/MPV crossover reaction of
malononitrile derived substrates.
The initial results for the attempted domino Oppenauer/

P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
1367
Scheme 10. Aluminium catalysed domino Oppenauer/Michael addition/MPV process using malononitrile derived substrates.
Spectroscopic analysis on the intractable mixtures was
inconclusive.
Table 8. Results of malononitrile derived domino Oppenauer/Michael
addition/MPV process
Entry
Product
Catalysta
Temperature
(8C)
t
(h)
Yield
(%)b
In order to address these problems, two further approaches
were explored: organic and fluoride bases (Scheme 11,
Table 10).
1
2
3
4
5
6
7
8
9
18
18
18
18
18
19
16
16
17
Me2AlCl
25
25
44
44
44
44
44
44
44
24
24
24
8
48
24
6
43
46
78
69
90
81
10
31e
19
Me2AlClc
Al(OiPr)3
Al(OtBu)3
Al(OtBu)3
Al(OtBu)3
Al(OtBu)3
Al(OtBu)3
Al(OtBu)3
d
24
24
a Reactions were performed on a 1 mmol scale in CH2Cl2 (5–10 mL).
b Yield of isolated product after flash-column chromatography.
c Tetrabutylammonium bromide (0.04 equiv) added to increase dissolution
of malononitrile salt.
Scheme 11. 2-Cyclopenten-1-ol domino Oppenauer/Michael addi-
tion/MPV process.
d Reaction carried out on a 5 mmol scale.
e NaOtBu (0.1 equiv) used as base.
Table 10. Results of 2-Cyclopenten-1-ol domino Oppenauer/Michael
addition/MPV process
Entry Product Al(OtBu)3 Base (mol%) Tempera-
(mol%)a
t
ture (8C) (h)
Conv.
(%)b
Table 9. Results of malononitrile derived catalytic domino Oppenauer/
Michael addition/MPV process
1
2
3
4
5
6
16
16
16
16
17
17
100
10
CsF (10)
CsF (100)
DBUd (10)
MTBDe (10)
—
100
100
44
100
100
100
20
24
24
24
24
72
71
!5
!5
48f
44
Entry
Product Catalysta
(mol%)
Temperature
(8C)
t
(h)
Yield
(%)b
100c
100
100
100
1
2
3
4
5
6
7
8
9
18
18
18
18
18
19
16
16
17
Me2AlCl (10)
Me2AlCl (30)
25
25
44
100
100
100
100
150
100
24
24
24
8
8
8
24
24
24
!5
37
!5
90
70
64
60
61
—
60f
Al(OtBu)3 (10)c
Al(OtBu)3 (10)c
Al(OtBu)3 (10)c,d
Al(OtBu)3 (10)c
Al(OtBu)3 (100)c
Al(OtBu)3 (100)c
Al(OtBu)3 (100)c
a Reactions were performed on a 1 mmol scale in an ACE pressure tube.
1
b Analysed by H NMR.
c Reaction was performed on a 1 mmol scale in solvent at reflux.
d 1,8-Diazabicyclo[5.4.0]undec-7-ene.
e 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.
f
21
Yield of isolated product after flash column chromatography.
a Reactions were performed on a 1 mmol scale in CH2Cl2 (3–10 mL).
b Yield of isolated product after flash column chromatography.
c Reactions were performed on a 1 mmol scale in an ACE pressure tube.
d Cyclohexanone (0.1 equiv) used as oxidant.
Catalytic caesium fluoride (Table 10, entry 1) was
demonstrated to be an excellent base in the domino
Oppenauer/Michael addition/MPV process. Michael
addition reactions using caesium fluoride do have literature
precedent: Yamaguchi and co-workers35 have reported
previously the stereoselective addition of di-tert-butyl
malonate (5) to 2-cyclohexen-1-one (3) catalysed by
20 mol% caesium fluoride. In addition, fluoride bases
provided a very ‘clean’ reaction profile appearing to
suppress the minor side-reactions which were previously
observed. This trend was also reflected in the result obtained
using the strong organic base, MTBD (pKaw23).36 Whereas
the weaker organic base DBU (pKa 11–12), did not
display any activity in the allylic alcohol catalytic elec-
tronic activation process (Table 10, entry 3), MTBD was
Michael addition/MPV process between 2-cyclopenten-1-ol
(11) and malononitrile derivatives were disappointing
(Table 9, 7–9), although an increase in temperature does
provide an appreciable enhancement in yield (Table 9,
entries 7 and 8 cf. Table 8, entries 7–9). Nevertheless, these
yields are moderate in comparison with the cyclohexyl
system (vide supra) and require a stoichiometric amount of
catalyst. Unidentified by-products were formed when
2-cyclopenten-1-ol (11) was employed as a substrate. This
may be attributable to self-condensation of the enone,
malononitrile or to Ritter or Pinner reactions on the nitrile.

1368
P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
able to catalyse the reaction in moderate yield (Table 10,
entry 4).
The application of the current procedure towards acyclic
substrates is, at present, unfulfilled. The required reaction
was found to be fatally inhibited by both poor crossover
transfer hydrogenation, and undesired cyclisation
processes.38
Whilst the yield of alcohol 17 was low at reflux and elevated
temperatures (Tables 8 and 9, entries 9), a moderate yield
was finally obtained through using a system in which the
potassium tert-butoxide base was omitted (Table 10, entries
5 and 6). It therefore appeared that under the prolonged high
temperatures, the aluminium catalyst was able to form the
desired malononitrile nucleophile,37 whilst not possessing
sufficient basicity to facilitate the formation of base-
catalysed by-products.
3. Conclusion
In summary, it has been demonstrated that whilst nucleo-
philes will not normally add to allylic alcohols, this reaction
becomes possible by a procedure involving catalytic
electronic activation of the substrate.
An issue not discussed thus far is product diastereoselec-
tivity. For the cyclohexyl-derived substrates an approximate
60:40 ratio of product diastereomers was delivered, whereas
the cyclopentyl-derived products displayed a moderate bias
towards the cis configuration (Fig. 2). The ratio of
diastereoisomers was established by analysis of the 1H
NMR spectra. Absolute stereochemistry was confirmed
through X-ray crystallographic analysis of the individual
diastereomers.
The concept of temporarily oxidising alcohols to carbonyl
compounds as an approach to catalytic electronic activation
processes is under further investigation.
4. Experimental
4.1. General procedures
All reactions were performed under an atmosphere of dry
nitrogen using oven-dried (150 8C) glassware. Dichloro-
methane was distilled from CaH2 before use. THF was
distilled from the anion of benzophenone ketyl radical.
Unless preparative details are provided all chemicals were
available commercially and were purchased from Acros,
Fluka, Lancaster or Sigma-Aldrich. Methylmalononitrile
(9) and benzylmalononitrile (10) were prepared by the
´
32
method of Dıez-Barra. 2-Cyclopenten-1-ol (11) was
prepared by the method of Larock.39
Melting points were recorded on a Bu¨chii 535 Series
instrument and are uncorrected.
IR spectra were recorded as thin films, solutions (CDCl3) or
KBr discs using a Perkin–Elmer 1600 Series FT-IR
spectrophotometer in the range 4000–600 cmK1, with
internal background scan. Absorption maxima are recorded
in wavenumbers (cmK1).
Figure 2. Axial/equatorial product ratios.
Proton (d 1H) NMR spectra were run in CDCl3 using either a
Bruker AM-300 (300 MHz), Jeol (270 MHz), or Jeol
(400 MHz) instrument. Chemical shifts are reported relative
to Me4Si (d 0.00 ppm) as internal standard. Coupling
constants (J) are given Hz and multiplicities denoted as
singlet (s), doublet (d), triplet (t), multiplet (m), or broad
(br). Carbon-13 (d 13C) NMR spectra were run in CDCl3 and
were recorded using a Bruker WH-400 (100 MHz) or a
Bruker AM-300 (75 MHz).
The thermodynamic product distribution was explored
through the equilibration of pure axial alcohol (trans-16)
in 1:1 acetone/propan-2-ol at reflux (Scheme 12).
Thus, the axial alcohol (trans-16) was converted into a
thermodynamic product ratio (62:38 equatorial/axial) effi-
ciently under aluminium tert-butoxide catalysis within 12 h.
This is essentially the same ratio that is observed in the
overall domino process.
Mass spectra, including high-resolution spectra, were
Scheme 12. Equilibration of axial alcohol.

P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
1369
recorded on a Micromass Autospec Spectrometer using
electron impact (EIC) ionisation, chemical impact (CIC,
iso-butane) ionisation, electrospray (ESC) ionisation
and/or Fast Atom Bombardment (FABC) ionisation.
anhydrous methanol (5 mL) was cooled to 0 8C whilst
sodium borohydride (0.038 g, 1.0 mmol) was added gradu-
ally over 0.1 h. After 1 h, the reaction was quenched with
distilled water (50 mL) and extracted with dichloromethane
(3!50 mL). The combined organic extracts were washed
with brine (100 mL), dried (Na2SO4) and concentrated in
vacuo. Purification by flash-column chromatography (SiO2,
4:1 petroleum ether/ethyl acetate) gave cis/trans-5 as
colourless oil (0.311 g, 99%, 80:20 cis/trans) (Fig. 4).
Elemental analyses were performed using a Carlo Erba 1106
Elemental Analyser or an Exeter Analytical Inc. CE-440
Elemental Analyser.
4.1.1. Aluminium isopropoxide catalysed trans-esterifi-
cation of dimethyl malonate. Dimethyl malonate (0.132 g,
1.0 mmol) and aluminium isopropoxide (0.204 g,
1.0 mmol) were heated to 62 8C in THF (8 mL). After 6 h
under nitrogen, the reaction was cooled, diluted with diethyl
ether (50 mL), and washed with 10% v/v aqueous HCl
(25 mL). The aqueous phase was separated and extracted
with diethyl ether (3!50 mL). The combined organic
extracts were washed with brine, dried (Na2SO4) and
concentrated in vacuo to give a mixture of iso-propyl-
methylmalonate and di-iso-propylmalonate (1:3) as yellow
oil (80% conversion determined by 1H NMR). An authentic
sample of iso-propylmethylmalonate was prepared by the
method of Wakasugi.40
Figure 4.
Compound cis/trans-4. 1H NMR (400 MHz, CHCl3, 25 8C):
dZ0.90–1.22 (m, 2H), 1.24–1.40 (m, 1H), 1.43 (br s, 18H),
1.50–1.64 (m, 3H), 1.66–1.77 (m, 1H), 1.78–1.83 (m, 1H),
1.93–2.11 (m, 1H), 2.98 (d, JZ9 Hz, 1H, H3), 2.98 (d, JZ
9 Hz, 1H, H3), 3.59 (m, 1H, H10ax), 4.09 (br s, 1H, H10eq); 13
C
NMR (100 MHz, CDCl3, 25 8C): dZ23.6, 27.9 (C6), 27.9
(C6), 35.2, 35.9, 39.7, 59.5 (C3), 70.0 (C10), 81.3 (C5), 81.3
(C5), 167.5 (C4), 167.6 (C4); IR (CHCl3): n (cmK1)Z3436
(O–H); 1750 (C]O); MS (FABC): m/z 315 [M%C];
C17H30O5 requires C 64.92%, H 9.62%, found C 64.40%,
H 9.62%.
4.1.2. Preparation of 2-(3-oxo-cyclohexyl)-malonic acid
di-tert-butyl ester (2). 2-Cyclohexen-1-one (3) (1.00 g,
10 mmol) in THF (2 mL) was added dropwise to a
suspension of sodium hydride (0.025 g, 1.0 mmol) and
di-tert-butyl malonate (5) (2.25 g, 10 mmol) in THF
(10 mL). After 6 h at room temperature, the reaction was
quenched with acetic acid, diluted with diethyl ether
(100 mL) and washed with water (2!50 mL). The aqueous
phase was separated and extracted with diethyl ether (3!
100 mL). The combined organic extracts were washed with
brine (100 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (SiO2, 4:1
petroleum ether/ethyl acetate) gave 2 as a white crystalline
solid (3.05 g, 94%) (Fig. 3).
4.1.4. General procedure for the aluminium tert-
butoxide catalysed crossover transfer hydrogenation
reaction between 2-cyclohexen-1-ol (1) and 2-(3-oxo-
cyclohexyl)-malonic acid di-tert-butyl ester (2)
(Scheme 4, Table 1). Aluminium tert-butoxide (0.246 g,
1.0 mmol) in dichloromethane (2 mL) was added dropwise
over a period of 30 min to a stirred solution of 2-cyclo-
hexen-1-ol (1) (0.098 g, 1.0 mmol) and 2-(3-oxo-cyclo-
hexyl)-malonic acid di-tert-butyl ester (2) (0.312 g,
1.0 mmol) in dichloromethane (8 mL) at 44 8C under
nitrogen. After 24 h, the reaction was cooled, diluted with
diethyl ether (50 mL), and washed with 10% v/v aqueous
HCl (25 mL). The aqueous phase was separated and
extracted with diethyl ether (3!50 mL). The combined
organic extracts were washed with brine (50 mL), dried
(Na2SO4) and concentrated in vacuo to give 3/4 as a yellow
oil (0.387 g, 94% recovery, O95% conversion determined
Figure 3.
1
Compound 2. Mp 67–68 8C; H NMR (400 MHz, CDCl3,
1
by H NMR).
25 8C): dZ1.42 (br s, 9H, H6), 1.42–1.75 (m, 2H), 1.94–
2.03 (m, 1H), 2.04–2.12 (m, 1H), 2.20–2.32 (m, 2H), 2.36–
2.50 (m, 3H), 3.09 (d, JZ8 Hz, 1H, H3); 13C NMR
(100 MHz, CDCl3, 25 8C): dZ24.7, 28.0 (C6), 28.0 (C6),
37.9, 41.2, 45.2, 58.8 (C3), 81.8 (C5), 81.8 (C5), 167.0 (C4),
209.7 (C10); IR (CHCl3): n (cmK1)Z1740 (C]O), 1724
(C]O); MS (FABC): m/z 313 [M%C]; HRMS (FABC):
C17H28O5 requires 313.2015, found 313.2028; C17H28O5
requires C 65.36%, H 9.03%, found C 65.60%, H 9.05%.
4.1.5. General procedure for the dimethylaluminium
chloride catalysed crossover transfer hydrogenation
reaction between 2-cyclohexen-1-ol (1) and 2-(3-oxo-
cyclohexyl)-malonic acid di-tert-butyl ester (2)
(Scheme 4, Table 4). Dimethylaluminium chloride
(0.1 mL, 1.0 M solution in hexane, 0.1 mmol) was added
to a nitrogen-purged solution of 2-cyclohexen-1-ol (1)
(0.098 g, 1.0 mmol) in dichloromethane (3 mL). The
reaction was stirred at room temperature for 0.25 h followed
by the addition of 2-(3-oxo-cyclohexyl)-malonic acid
di-tert-butyl ester (2) (0.312 g, 1.0 mmol) in dichloro-
methane (2 mL). After 24 h, the reaction was quenched with
4.1.3. Preparation of cis/trans-2-(3-hydroxy-cyclohexyl)-
malonic acid di-tert-butyl ester (4). 2-(3-Oxo-cyclohexyl)-
malonic acid di-tert-butyl ester (4) (0.312 g, 1.0 mmol) in

1370
P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
saturated aqueous NH4Cl (1 mL), diluted with diethyl ether
(50 mL) and washed with 10% v/v aqueous HCl (25 mL).
The aqueous phase was separated and extracted with diethyl
ether (3!50 mL). The combined organic extracts were
washed with brine (50 mL), dried (MgSO4) and concen-
trated in vacuo to give 3/4 as a yellow oil (0.369 g, 90%
4.1.9. Preparation of 2-(3-dicyanomethyl-cyclohexyl-
idene)-malononitrile (8). 2-Cyclohexen-1-one (3)
(0.192 g, 2.0 mmol) in THF (10 mL) was added dropwise
to a suspension of sodium tert-butoxide (0.019 g, 0.2 mmol)
and malononitrile (6) (0.264 g, 4.0 mmol) in THF (10 mL).
After 4 h at room temperature, the reaction was quenched
with acetic acid, diluted with dichloromethane (50 mL) and
washed with water (100 mL). The aqueous phase was
separated and extracted with dichloromethane (3!50 mL).
The combined organic extracts were washed with brine
(100 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (SiO2, 50:50
petroleum ether/diethyl ether) gave 8 as a yellow gum
(0.306 g, 67%) (Fig. 5).
1
recovery, O95% conversion determined by H NMR).
4.1.6. General procedure for the aluminium tert-
butoxide catalysed domino Oppenauer/Michael addi-
tion/MPV process (Scheme 5, Table 2). 2-Cyclohexen-1-
ol (1) (0.098 g, 1.0 mmol) and 2-cyclohexen-1-one (3)
(0.010 g, 0.1 mmol) in dichloromethane (1 mL) were added
to a suspension of di-tert-butyl malonate (5) (0.624 g,
2.0 mmol) and NaH (0.005 g, 0.2 mmol) in dichloro-
methane (5 mL) at room temperature. The solution was
heated to 44 8C and aluminium tert-butoxide (0.246 g,
1.0 mmol) in dichloromethane (2 mL) was added dropwise.
After 6 h, the reaction was cooled, diluted with diethyl ether
(50 mL) and washed with 10% v/v aqueous HCl (25 mL).
The aqueous phase was separated and extracted with diethyl
ether (3!50 mL). The combined organic extracts were
washed with brine (50 mL), dried (Na2SO4) and concen-
trated in vacuo to give 4/2/3 as a yellow oil (0.673 g, 92%
Figure 5.
1
recovery, 19:12:5% conversion determined by H NMR).
Compound 8. 1H NMR (300 MHz, CDCl3, 25 8C): dZ1.60–
1.76 (m, 2H), 2.18–2.46 (m, 5H), 3.12–3.26 (m, 2H), 3.85
(d, JZ5 Hz, 1H, H3); 13C NMR (75 MHz, CDCl3, 25 8C):
dZ25.4, 28.2, 28.8, 30.7, 40.0, 75.3 (C3), 85.7 (C9), 111.5
(C4), 111.5 (C10), 111.6 (C4), 111.8 (C10), 179.3 (C8); IR
(CHCl3): n (cmK1)Z2339 (C^N), 2232 (C^N), 1598
(C]C); MS (EIC, 70 eV): m/z (%) 210 (23) [M%C]; HRMS
(EIC, 70 eV): C12H10N4 requires 210.0906, found
210.0910.
4.1.7. General procedure for the dimethylaluminium
chloride catalysed domino Oppenauer/Michael addi-
tion/MPV process (Scheme 6, Table 5). Dimethylalumi-
nium chloride (1.2 mL, 1.0 M solution in hexane, 1.2 mmol)
was added to nitrogen-purged solution of 2-cyclohexen-1-ol
(1) (0.098 g, 1.0 mmol), 2-cyclohexen-1-one (3) (0.010 g,
0.1 mmol), di-tert-butyl malonate (5) (0.216 g, 1.0 mmol)
and sodium hydride (0.002 g, 0.1 mmol) in dichloromethane
(3 mL). After 24 h, the reaction was quenched with
saturated aqueous NH4Cl (1 mL), diluted with diethyl
ether (50 mL) and washed with 10% v/v aqueous HCl
(25 mL). The aqueous phase was separated and extracted
with diethyl ether (3!50 mL). The combined organic
extracts were washed with brine (50 mL), dried (MgSO4)
and concentrated in vacuo to give 4/2/3 as a yellow oil
(0.309 g, 93% recovery, 25:1:5% conversion determined by
1H NMR).
4.1.10. Preparation of 2-(3-oxo-cyclohexyl)-malononi-
trile (7). 2-(3-Oxo-cyclohexyl)-malonic acid dimethyl
ester41 (1.00 g, 4.38 mmol) was stirred for 18 h in 35%
aqueous NH4OH (5 mL) at room temperature. The aqueous
phase was concentrated in vacuo to give 2-(3-oxo-
cyclohexyl)-malonamide as an off-white solid (0.966 g,
97% recovery). Phosphoryl chloride (0.91 mL, 9.75 mmol)
was added to a stirred suspension of 2-(3-oxo-cyclohexyl)-
malonamide in anhydrous acetonitrile (25 mL). After 5 h at
82 8C, the solution was filtered and concentrated in vacuo.
The oily residue was dissolved in chloroform (100 mL) and
extracted with a saturated solution of Na2CO3 (2!50 mL).
The combined aqueous phases were neutralised with 10%
v/v aqueous HCl and NaCl added until a saturated solution
was obtained. The aqueous phase was extracted with
chloroform (4!50 mL), dried (MgSO4) and concentrated
in vacuo. Purification by flash column chromatography
(SiO2, 50:50 petroleum ether/diethyl ether) gave 2-(3-oxo-
4.1.8. General procedure for the dimethylaluminium
chloride catalysed domino Oppenauer/Michael addi-
tion/MPV process (Scheme 7). Dimethylaluminium chlor-
ide (1.2 mL, 1.0 M solution in hexane, 1.2 mmol) was added
to nitrogen-purged (0.25 h) stirred solution of 2-cyclohexen-
1-ol (1) (0.098 g, 1.0 mmol) in dichloromethane (2 mL).
After 1 h at room temperature, 2-(3-oxo-cyclohexyl)-malo-
nic acid di-tert-butyl ester (2) (0.031 g, 0.1 mmol), di-tert-
butyl malonate (5) (0.216 g, 1.0 mmol) and sodium hydride
(0.002 g, 0.1 mmol) in dichloromethane (3 mL) were added.
After 90 h, the reaction was quenched with saturated aqueous
NH4Cl (1 mL), diluted with diethyl ether (50 mL) and
washed with 10% v/v aqueous HCl (25 mL). The aqueous
phase was separated and extracted with diethyl ether (3!
50 mL). The combined organic extracts were washed with
brine (50 mL), dried (MgSO4) and concentrated in vacuo to
give (4) as a yellow oil (0.304 g, 91% recovery, 51%
conversion determined by 1H NMR).
Figure 6.

P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
1371
cyclohexyl)-malononitrile (7) as a colourless oil (0.593 g,
75%) (Fig. 6).
washed with brine (100 mL), dried (Na2SO4) and concen-
trated in vacuo. Purification by flash column chromatography
(SiO2, 100% diethyl ether) gave cis/trans-18 as a white solid
(0.037 g, 32%, 94:6 cis/trans) (Fig. 8).
Compound 7. 1H NMR (400 MHz, CHCl3, 25 8C): dZ1.67–
1.82 (m, 2H), 2.18–2.27 (m, 2H), 2.29–2.54 (m, 4H), 2.53–
2.60 (m, 1H, H2), 3.75 (d, JZ5 Hz, 1H, H3); 13C NMR
(75 MHz, CDCl3, 25 8C): dZ24.0, 28.4, 39.7, 40.7, 44.6,
75.3 (C3), 111.5 (C4), 111.6 (C4), 206.9 (C8); IR (thin film):
n (cmK1)Z2251 (C^N), 1700 (C]O); MS (EIC, 70 eV):
m/z (%) 162 (7) [M%C]; HRMS (EIC, 70 eV): C9H10N2O
requires 162.0793, found 162.0790.
Compound cis/trans-18. Mp 75–76 8C; 1H NMR (300 MHz,
CHCl3, 25 8C): dZ1.20 (app dq, JZ4, 16 Hz, 2H), 1.41
(app ddt, JZ2, 4, 16 Hz, 2H), 1.55–1.80 (m, 3H), 1.71
(s, 3H, H5), 1.89–2.10 (m, 2H), 2.22 (app ddt, JZ3, 3,
12 Hz, 1H), 3.50–3.65 (m, 1H, H9ax), 4.23 (br s, 1H, H9eq);
13C NMR (75 MHz, CDCl3, 25 8C, single diastereomer):
dZ22.7 (C5), 23.2, 27.5, 35.0, 37.0, 37.4, 43.9 (C3), 69.9
(C9), 70.0 (C9), 115.9 (C4), 116.0 (C4); IR (CHCl3): n(cmK1)Z
3383 (O–H), 2249 (C^N); MS (CIC): m/z (%) 179 (88)
[MHC]; HRMS (CIC): C10H15N2O requires 179.1184, found
179.1177.
4.1.11. Preparation of 2-methyl-2-(3-oxo-cyclohexyl)-
malononitrile (14). 2-Cyclohexen-1-one (3) (0.144 g,
1.50 mmol) in THF (3 mL) was added dropwise to a
suspension of sodium tert-butoxide (0.014 g, 0.15 mmol)
and methylmalononitrile (9) (0.120 g, 1.50 mmol) in THF
(7 mL). After 4 h at room temperature, the reaction was
quenched with acetic acid, diluted with diethyl ether (50 mL)
and washed with water (2!25 mL). The aqueous phase was
separated and extracted with diethyl ether (3!50 mL). The
combined organic extracts were washed with brine
(100 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (SiO2, 100%
diethyl ether) gave 14 as a white solid (0.202 g, 83%) (Fig. 7).
4.1.13. General procedure for the dimethylaluminium
chloride catalysed crossover transfer hydrogenation
reaction between 2-cyclohexen-1-ol (1) and 2-methyl-2-
(3-oxo-cyclohexyl)-malononitrile (14) (Scheme 9,
Table 7). Carried out following the procedure described
above. After 15 h, the reaction was quenched with saturated
aqueous NH4Cl (1 mL), diluted with diethyl ether (50 mL)
and washed with 10% v/v aqueous HCl (25 mL). The
aqueous phase was separated and extracted with diethyl
ether (3!50 mL). The combined organic extracts were
washed with brine (50 mL), dried (MgSO4) and concen-
trated in vacuo to give 3/16 as a yellow solid (0.294 g, 100%
1
recovery, O95% conversion determined by H NMR).
4.1.14. General procedure for the aluminium tert-but-
oxide catalysed domino Oppenauer/Michael addition/
MPV process (Scheme 10, Table 8). 2-Cyclohexen-1-ol
(1) (0.098 g, 1.0 mmol) and 2-cyclohexen-1-one (3)
(0.009 g, 0.1 mmol) were added to a suspension of
methylmalononitrile (9) (0.080 g, 1.0 mmol) and potassium
tert-butoxide (0.012 g, 0.1 mmol) in dichloromethane
(5 mL). The solution was heated to 44 8C under nitrogen
and aluminium tert-butoxide (0.246 g, 1.0 mmol) in
dichloromethane (3 mL) was added dropwise. After 24 h,
the reaction was cooled, diluted with ether (50 mL) and
washed with 10% v/v aqueous HCl (25 mL). The aqueous
phase was separated and extracted with ether (3 x 50 mL).
The combined organic extracts were washed with brine,
dried (MgSO4) and concentrated in vacuo. Purification by
flash column chromatography (SiO2, 50:50 petroleum ether/
diethyl ether) gave cis/trans-18 as a white crystalline solid
(0.153 g, 85%).
Figure 7.
1
Compound 14. Mp 59–61 8C; H NMR (300 MHz, CDCl3,
25 8C): dZ1.63–1.80 (m, 2H), 1.81 (s, 3H), 2.16–2.41 (m,
5H), 2.46–2.54 (m, 1H), 2.67–2.74 (m, 1H); 13C NMR
(75 MHz, CDCl3, 25 8C): dZ22.5 (C5), 23.7, 27.2, 40.5,
42.7, 45.3 (C3), 114.5 (C4), 115.0 (C4), 206.2 (C9); IR
(CHCl3): n (cmK1)Z2360 (C^N), 1700 (C]O); MS (EIC,
70 eV): m/z (%) 176 (32) [M%C]; HRMS (EIC, 70 eV):
C10H12N2O requires 176.0950, found 176.0952;
C10H12N2O requires C 68.16%, H 6.86%, N 15.90%,
found C 68.10%, H 6.88% N 15.80%.
4.1.12. Preparation of cis/trans-2-(3-hydroxy-cyclo-
hexyl)-2-methyl-malononitrile cis/trans-(18). 2-Methyl-
2-(3-oxo-cyclohexyl)-malononitrile (14) (0.016 g, 0.71
mmol) in anhydrous methanol (15 mL) was cooled to 0 8C
whilst sodium borohydride (0.027 g, 0.71 mmol) was added
portionwise over 0.1 h. After 1 h, the reaction was quenched
with distilled water (50 mL) and extracted with dichloro-
methane (3!50 mL). The combined organic extracts were
4.1.15. General procedure for the dimethylaluminium
chloride catalysed domino Oppenauer/Michael addition/
MPV process (Scheme 10, Table 8). Dimethylaluminium
chloride (1.0 mL, 1.0 M solution in hexane, 1.0 mmol) was
added to nitrogen-purged solution of 2-cyclohexen-1-ol (1)
(0.098 g, 1.0 mmol), 2-cyclohexen-1-one (3) (0.010 g,
0.1 mmol), methylmalononitrile (9) (0.080 g, 1.0 mmol)
TBAB (0.012 g, 0.04 mmol) and potassium tert-butoxide
(0.012 g, 0.1 mmol) in dichloromethane (3 mL). After 24 h,
the reaction was quenched with saturated aqueous NH4Cl
(1 mL), diluted with diethyl ether (50 mL) and washed with
10% v/v aqueous HCl (25 mL). The aqueous phase was
separated and extracted with diethyl ether (3!50 mL). The
Figure 8.

1372
P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
combined organic extracts were washed with brine (50 mL),
dried (MgSO4) and concentrated in vacuo. Purification by
flash column chromatography (SiO2, 50:50 petroleum ether/
diethyl ether) gave cis/trans-18 as a white crystalline solid
(0.076 g, 45%).
2-(3-oxo-cyclohexyl)-malononitrile
(15)
(0.590 g,
2.34 mmol) in THF (2 mL) was added dropwise to a
nitrogen-purged 1.0 M solution of L-Selectride (2.81 mL,
2.81 mmol) in THF (3 mL) at K78 8C. After 3 h, aqueous
3 M NaOH (0.17 mL, 0.5 mmol) was added dropwise
followed by slow addition of 30% H2O2 (0.55 mL,
12.0 mmol). After a further 0.5 h stirring at room tempera-
ture the mixture was diluted with water (50 mL), extracted
with ethyl acetate (5!30 mL). The combined organic
phases were washed with brine (100 mL), dried (Na2SO4)
and concentrated in vacuo. Purification by flash column
chromatography (SiO2, 50:50 petroleum ether/diethyl ether)
gave trans-2-benzyl-2-(3-hydroxy-cyclohexyl)-malononitrile
(19) as a white crystalline solid (0.244 g, 41%) (Fig. 10).
4.1.16. General procedure for the catalytic aluminium
tert-butoxide catalysed domino Oppenauer/Michael
addition/MPV process (Scheme 10, Table 9). 2-Cyclo-
hexen-1-ol (1) (0.098 g, 1.0 mmol) and 2-cyclohexen-1-one
(3) (0.009 g, 0.1 mmol) were added to a suspension of
methylmalononitrile (9) (0.080 g, 1.0 mmol), potassium
tert-butoxide (0.012 g, 0.1 mmol) and aluminium tert-
butoxide (0.025 g, 1.0 mmol) in dichloromethane (3 mL).
The solution was heated to 100 8C in an ACE pressure tube.
After 8 h, the reaction was cooled, diluted with ether
(50 mL) and washed with 10% v/v aqueous HCl (25 mL).
The aqueous phase was separated and extracted with ether
(3!50 mL). The combined organic extracts were washed
with brine, dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (SiO2, 50:50
petroleum ether/diethyl ether) gave cis/trans-18 as a white
crystalline solid (0.160 g, 90%).
Figure 10.
Compound trans-19. Mp 106–108 8C; 1H NMR (500 MHz,
C6D6, 25 8C): dZ0.35 (br s, 1H, OH), 0.81 (app. ddt, JZ2,
4, 13.5 Hz, 1H, H6ax), 0.96 (app. dq, JZ4, 13 Hz, 1H, H4ax),
1.12 (app. dt, JZ2, 13 Hz, 1H, H2ax), 1.17–1.21 (m, 1H,
4.1.17. Preparation of 2-benzyl-2-(3-oxo-cyclohexyl)-
malononitrile (15). 2-Cyclohexen-1-one (3) (0.096 g,
1.0 mmol) in THF (2 mL) was added dropwise to a
suspension of potassium tert-butoxide (0.011 g, 0.1 mmol)
and benzylmalononitrile (10) (0.156 g, 1.0 mmol) in THF
(3 mL). After 4 h at room temperature, the reaction was
quenched with acetic acid, diluted with diethyl ether
(50 mL) and washed with water (2!25 mL). The aqueous
phase was separated and extracted with diethyl ether (3!
50 mL). The combined organic extracts were washed with
brine (100 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (SiO2, 50:50
petroleum ether/diethyl ether) gave 15 as a cubic white solid
(0.217 g, 86%) (Fig. 9).
H
5eq), 1.25 (br d, JZ14 Hz, 1H, H6eq), 1.37 (app. tq, JZ4,
13 Hz, 1H, H5ax), 1.64 (br d, JZ12.5 Hz, 1H, H4eq), 1.70 (br
d, JZ13 Hz, 1H, H2eq), 1.99 (app. tt, JZ3, 12 Hz, 1H,
H
3ax), 2.41 (d, JZ14 Hz, 1H, H7), 2.51 (d, JZ14 Hz, 1H,
H7), 3.53 (br s, 1H, H1eq), 7.02–7.25 (m, 5H, H10); 13C NMR
(75 MHz, CDCl3, 25 8C): dZ19.6, 28.7, 32.4, 35.3, 38.7,
40.9, 45.6, 66.0 (C1), 66.1 (C1), 115.0 (C8), 129.1, 129.3,
130.6, 132.8; IR (C6D6): n (cmK1)Z3592 (O–H), 2282
(C^N); MS (EIC, 70 eV): m/z (%) 254 [M%C], 91 (100)
[PhCHC2 ]; C16H18N2O requires C 75.56%, H 7.13%, N
11.01%, found C 74.8%, H 7.34% N 11.30%.
4.1.19. Preparation of 2-methyl-2-(3-oxo-cyclopentyl)-
malononitrile (12). 2-Cyclopenten-1-one (20) (0.082 g,
1.0 mmol) in THF (2 mL) was added dropwise to a
suspension of potassium tert-butoxide (0.011 g, 0.1 mmol)
and methylmalononitrile (9) (0.080 g, 1.0 mmol) in THF
(3 mL). After 4 h at room temperature, the reaction was
quenched with acetic acid, diluted with diethyl ether
(50 mL) and washed with water (2!25 mL). The aqueous
phase was separated and extracted with diethyl ether (3!
50 mL). The combined organic extracts were washed with
brine (100 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (SiO2, 50:50
Figure 9.
Compound 15. Mp 132–134 8C; 1H NMR (300 MHz,
CDCl3, 25 8C): dZ1.68 (dddd, JZ2, 12, 12, 12 Hz, 1H),
1.83 (app dtq, JZ1, 4, 12 Hz, 1H), 2.22–2.54 (m, 5H), 2.77–
2.84 (m, 1H), 3.16 (d, JZ14 Hz, 1H, H5), 3.15 (d, JZ14 Hz,
1H, H5), 7.36–7.43 (m, 5H, H6); 13C NMR (75 MHz,
CDCl3, 25 8C): dZ23.8, 27.5, 40.6, 43.2, 43.8, 44.7, 44.7,
113.6 (C4), 114.0 (C4), 128.9, 128.9, 129.0, 130.0, 130.0,
131.4, 206.2 (C10); IR (thin film): n (cmK1)Z2241 (C^N),
1716 (C]O); MS (EIC, 70 eV): m/z (%) 252 (37) [M%C];
HRMS (EIC, 70 eV): C16H16N2O requires 252.1263, found
252.1251; C16H16N2O requires C 76.16%, H 6.39%, N
11.10%, found C 76.0%, H 6.41% N 11.10%.
4.1.18. Preparation of trans-2-benzyl-2-(3-hydroxy-
cyclohexyl)-malononitrile (19). A solution of 2-benzyl-
Figure 11.

P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
1373
petroleum ether/diethyl ether) gave 12 as a white solid after
recrystallisation from acetonitrile (0.139 g, 86%) (Fig. 11).
1
Compound 12. Mp 37–40 8C; H NMR (400 MHz, CDCl3,
25 8C): dZ1.86 (br s, 3H, H5), 1.90–2.02 (m, 1H), 2.22–
2.39 (m, 2H), 2.41–2.50 (m, 1H), 2.52–2.74 (m, 3H); 13C
NMR (100 MHz, CDCl3, 25 8C): dZ23.5 (C5), 25.8, 35.8
(C3), 38.2, 40.6, 44.5 (C2), 114.6 (C4), 114.7 (C4), 212.1
(C8); IR (thin film): n (cmK1)Z2245 (C^N), 1747 (C]O);
MS (EIC, 70 eV): m/z (%) 162 (21) [M%C]; HRMS (EIC,
70 eV): C9H10N2O requires 162.0793, found 162.0795;
C9H10N2O requires C 66.65%, H 6.21%, N 17.27%, found C
66.40%, H 6.22% N 17.26%.
Figure 13.
Compound 13. Mp 122–123 8C; 1H NMR (300 MHz,
CDCl3, 25 8C): dZ2.00–2.14 (m, 1H), 2.25–2.41 (m, 3H),
2.42–2.78 (m, 3H), 3.23 (d, JZ14 Hz, 1H, H5), 3.24 (d, JZ
14 Hz, 1H, H5), 7.38–7.61 (m, 5H, H6); 13C NMR (75 MHz,
CDCl3, 25 8C): dZ25.8, 37.8, 40.5, 41.6, 42.4, 43.6, 113.8
(C4), 113.8 (C4), 128.8, 129.0, 129.8, 131.5, 212.5 (C9); IR
(thin film): n (cmK1)Z2245 (C^N), 1747 (C]O); MS
(CIC): m/z (%) 239 (67) [MHC]; HRMS (CIC):
C15H15N2O requires 239.1184, found 239.1193;
C15H14N2O requires C 75.61%, H 5.92%, N 11.76%,
found C 74.80%, H 5.96% N 11.60%.
4.1.20. Preparation of cis/trans-2-(3-hydroxy-cyclopen-
tyl)-2-methyl-malononitrile (16). 2-Methyl-2-(3-oxo-
cyclopentyl)-malononitrile (12) (0.415 g, 2.6 mmol) and
aluminium tert-butoxide (0.640 g, 2.6 mmol) were heated to
82 8C in anhydrous propan-2-ol (10 mL). After 18 h under
nitrogen, the reaction was cooled, diluted with diethyl ether
(50 mL) and washed with 10% v/v aqueous HCl (25 mL).
The aqueous phase was separated and extracted with diethyl
ether (3!50 mL). The combined organic extracts were
washed with brine, dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography (SiO2,
50:50 petroleum ether/diethyl ether) gave cis/trans-12 as
pale yellow oil (0.401 g, 94%, 75:25 cis/trans) (Fig. 12).
4.1.22. Preparation of cis/trans-2-benzyl-2-(3-hydroxy-
cyclopentyl)-malononitrile (17). 2-Benzyl-2-(3-oxo-
cyclopentyl)-malononitrile (13) (0.265 g, 1.11 mmol) and
aluminium tert-butoxide (0.274 g, 1.11 mmol) were heated
to 82 8C in anhydrous propan-2-ol (10 mL). After 13 h
under nitrogen, the reaction was cooled, diluted with diethyl
ether (50 mL) and washed with 10% v/v aqueous HCl
(25 mL). The aqueous phase was separated and extracted
with diethyl ether (3!50 mL). The combined organic
extracts were washed with brine, dried (Na2SO4) and
concentrated in vacuo. Purification by flash column
chromatography (SiO2, 50:50 petroleum ether/diethyl
ether) gave cis/trans-17 as a white crystalline solid
(0.214 g, 80%) (Fig. 14).
Figure 12.
Compound cis/trans-12. 1H NMR (300 MHz, CDCl3,
25 8C): dZ1.50–1.70 (m, 1H), 1.72 (br s, 3H, H5), 1.90–
2.20 (m, 3H), 2.25–2.38 (m, 2H), 2.59–2.71 (m, 1H), 4.30–
4.34 (m, 1H, H8eq), 4.42–4.45 (m, 1H, H8ax); 13C NMR
(75 MHz, CDCl3, 25 8C): dZ23.8 (C5), 24.3 (C5), 26.9,
26.9, 31.3, 31.3, 34.9, 36.1, 36.3, 39.1, 45.8, 46.3, 72.6 (C3),
73.1(C3), 115.0 (C4), 115.1 (C4), 115.2 (C4), 116.1 (C4); IR
(thin film): n (cmK1)Z3610 (O–H), 2250 (C^N); MS
(CIC): m/z (%) 165 (100) [MHC]; HRMS (CIC):
C9H13N2O requires 165.1028, found 165.1026.
Figure 14.
4.1.21. Preparation of 2-benzyl-2-(3-oxo-cyclopentyl)-
malononitrile (13). 2-Cyclopenten-1-one (20) (0.164 g,
2.0 mmol) in THF (2 mL) was added dropwise to a
suspension of potassium tert-butoxide (0.022 g, 0.1 mmol)
and benzylmalononitrile (10) (0.312 g, 2.0 mmol) in THF
(3 mL). After 6 h at room temperature, the reaction was
quenched with acetic acid, diluted with diethyl ether
(50 mL) and washed with water (2!25 mL). The aqueous
phase was separated and extracted with diethyl ether (3!
50 mL). The combined organic extracts were washed with
brine (100 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (SiO2, 50:50
petroleum ether/diethyl ether) gave 13 as a cubic white solid
(0.280 g, 61%) (Fig. 13).
1
Compound trans-17. Mp 84–86 8C; H NMR (300 MHz,
CDCl3, 25 8C): dZ1.61–1.82 (m, 3H), 1.90–2.10 (m, 2H),
2.13–2.23 (m, 1H), 2.66–2.77 (m, 1H), 3.09 (d, JZ14 Hz,
1H, H5), 3.10 (d, JZ14 Hz, 1H, H5), 4.44 (br s, 1H, H9),
7.24–7.60 (br s, 5H, H6).
Compound cis-17. 4.26–4.35 (m, 1H, H9); 13C NMR
(75 MHz, CDCl3, 25 8C, cis/trans-17): dZ27.2, 34.8,
35.2, 38.9, 39.3, 42.5, 42.8, 44.4, 44.6, 44.7, 72.5 (C9),
72.9 (C9), 115.3 (C4), 115.3 (C4), 129.2, 129.4, 130.5, 132.6,
132.7; IR (thin film): n (cmK1)Z3396 (O–H), 2245 (C^N);
MS (ESC): m/z 263 [MNaC]; HRMS (CIC): C15H17N2O

1374
P. J. Black et al. / Tetrahedron 61 (2005) 1363–1374
7. Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.;
Ishii, Y. J. Am. Chem. Soc. 2003, 126, 72–73.
8. Brieger, G.; Nestrick, T. J. Chem. Rev. 1974, 74, 567–580.
9. Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. Rev.
1985, 85, 129–170.
requires 241.1333, found 241.1335; C15H16N2O requires C
74.97%, H 6.71%, N 11.66%, found C 74.70%, H 6.79% N
11.60%.
4.1.23. General procedure for the aluminium tert-
butoxide catalysed domino Oppenauer/Michael
addition/MPV process (Scheme 11, Table 10). 2-Cyclo-
penten-1-ol (11) (0.084 g, 1.0 mmol) and 2-cyclopenten-1-
one (20) (0.008 g, 0.1 mmol) were added to a suspension of
benzylmalononitrile (10) (0.156 g, 1.0 mmol) in dichloro-
methane (3 mL). Aluminium tert-butoxide (0.246 g,
1.0 mmol) was added and the solution heated to 100 8C in
an ACE pressure tube. After 72 h, the reaction was cooled,
diluted with ether (50 mL) and washed with 10% v/v
aqueous HCl (25 mL). The aqueous phase was separated
and extracted with ether (3!50 mL). The combined organic
extracts were washed with brine, dried (MgSO4) and
concentrated in vacuo. Purification by flash column
chromatography (SiO2, 50:50 petroleum ether/diethyl
ether) gave cis/trans-17 as a white crystalline solid
(0.144 g, 60%).
10. Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev. 1992,
92, 1051–1069.
¨
11. Pamies, O.; Backvall, J. E. Chem. Eur. J. 2001, 7, 5052–5058.
¨
12. Backvall, J. E. J. Organomet. Chem. 2002, 652, 105–111.
¨
13. Pamies, O.; Backvall, J. E. Chem. Rev. 2003, 103, 3247–3261
and references therein.
¨
14. Backvall, J. E.; Andreasson, U. Tetrahedron Lett. 1993, 34,
5459–5462.
15. Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1993, 115,
2027–2036.
16. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J.
Synthesis 1994, 1007–1017.
17. Wilds, A. L. In Adams, R., Ed.; Organic Reactions; Wiley:
New York, 1944; Vol. 2; pp 178–223.
18. Djerassi, C. In Organic Reactions, Vol. 6; Wiley: New York,
1951; pp 207–235.
19. Otera, J. Chem. Rev. 1993, 93, 1449–1470.
20. Rehberg, C. E.; Fisher, C. H. J. Org. Chem. 1947, 12, 226–231.
21. Smith, M. B.; March, J. March’s Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, 5th ed.;
Wiley: New York, 2001.
4.1.24. Meerwein–Ponndorf–Verley equilibration of
trans-2-(3-hydroxy-cyclohexyl)-2-methyl-malononitrile
trans-18. trans-2-(3-Hydroxy-cyclohexyl)-2-methyl-malo-
nonitrile trans-18 (0.134 g, 0.75 mmol) and aluminium tert-
butoxide (0.246 g, 1.0 mmol) were heated to 82 8C in a 1:1
mixture of anhydrous propan-2-ol/acetone (10 mL). After
12 h under nitrogen, the reaction was cooled, diluted with
diethyl ether (50 mL) and washed with 10% v/v aqueous
HCl (25 mL). The aqueous phase was separated and
extracted with diethyl ether (3!50 mL). The combined
organic extracts were washed with brine, dried (Na2SO4)
and concentrated in vacuo. Purification by flash column
chromatography (SiO2, 50:50 petroleum ether/diethyl ether)
gave cis/trans-18 (62:38 cis/trans, determined by 1H NMR)
as a white crystalline solid (0.145 g, 100% recovery).
22. Woodward, R. B.; Wendler, N. L.; Brutschy, F. J. J. Am.
Chem. Soc. 1945, 67, 1425–1429.
23. Okano, T.; Matsuoka, M.; Konishi, H.; Kiji, J. Chem. Lett.
1987, 181–184.
24. Snider, B. B.;Goldman,B.E. Tetrahedron1986, 42, 2951–2956.
25. Nishide, K.; Shigeta, Y.; Obata, K.; Node, M. J. Am. Chem.
Soc. 1996, 118, 13103–13104.
26. Node, M.; Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K.
J. Am. Chem. Soc. 2000, 122, 1927–1936.
27. Yager, B. J.; Hancock, C. K. J. Org. Chem. 1964, 30,
1174–1179.
28. Freeman, F. Chem. Rev. 1969, 69, 591–624.
29. Murahashi, S. I.; Naota, T.; Taki, H.; Mizuno, M.; Takaya, H.;
Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka, M.; Hirano,
M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117, 12436–12451.
30. Baty, J. D.; Jones, G.; Moore, C. J. Org. Chem. 1969, 34,
3295–3302.
Acknowledgements
We wish to thank the University of Bath, Roche Discovery
(P. J. B.), and the E. P. S. R. C. (M. G. E.) for their generous
financial support.
31. Isaacs, N. S. Physical Organic Chemistry, 2nd ed.; Wiley:
New York, 1995; pp 166, 247.
´
32. Dıez-Barra, E.; de la Hoz, A.; Moreno, A.; Sanchez-Verdu, P.
J. Chem. Soc. Perkin Trans. 1 1991, 2589–2592.
33. Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de
Vries, A. H. M. Angew. Chem. Int. Ed. 1997, 36, 2620–2623.
34. Zhou, Q. L.; Pfaltz, A. Tetrahedron Lett. 1993, 34, 7725–7728.
35. Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996,
61, 3520–3530.
References and notes
1. Black, P. J.; Harris, W.; Williams, J. M. J. Angew. Chem. Int.
Ed. 2001, 40, 4475–4476.
36. Schwesinger, R. Chimia 1985, 39, 269–272.
37. Heinsohn, G. E.; Ashby, A. E. J. Org. Chem. 1973, 38,
4232–4236.
2. Edwards, M. G.; Williams, J. M. J. Angew. Chem. Int. Ed.
2002, 41, 4740–4743.
3. Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.; Shermer, D. J.;
Whittlesey, M. K.; Williams, J. M. J.; Edney, D. D. Chem.
Commun. 2004, 90–91.
38. Hamada, Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T.
Tetrahedron 1991, 47, 8635–8652.
39. Larock, R. C.; Yum, E. K.; Yang, H. S. Tetrahedron 1994, 50,
305–321.
4. Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Tetrahedron
Lett. 2002, 43, 7987–7989.
40. Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y. Tetra-
hedron Lett. 2000, 41, 5249–5252.
5. Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J. Org. Chem.
2001, 66, 9020–9022.
6. Cami-Kobeci, G.; Williams, J. M. J. Synlett 2003, 124–126.
41. Bartlett, P. D.; Woods, G. F. J. Am. Chem. Soc. 1940, 62,
2933–2938.