Conjugate addition of dialkylaluminum chlorides to alkylidenemalonic acid derivatives

Article abstract of DOI:10.1055/s-1999-3589

Complete regioselectivity is achieved in conjugate addition reactions of dialkylaluminum chlorides with alkylidenemalonic esters, alkylidenecyanoacetates, and alkylidenemalonodinitrile to give β-branched carboxylic acid derivatives. Sterically demanding products containing quaternary carbon atoms are obtained in good yields. In the case of diethylaluminum chloride, accompanying reductions of the substrates can be suppressed by application of boron trifluoride as an assisting Lewis acid.

Full text of DOI:10.1055/s-1999-3589

1792
PAPER
Conjugate Addition of Dialkylaluminum Chlorides to Alkylidenemalonic Acid
Derivatives
Steffen Maas, Armin Stamm, Horst Kunz*
Institut für Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10–14, D–55128 Mainz, Germany
Fax +49(6131)394786; E-mail: hokunz@mail.uni-mainz.de
Received 31 May 1999
Dedicated to Professor Herbert Meier on the occasion of his 60th birthday
a,b-unsaturated carbonyl compounds,9 although some
Abstract: Complete regioselectivity is achieved in conjugate addi-
limitations on their thermal stability and ligand transfer
tion reactions of dialkylaluminum chlorides with alkylidenemalonic
efficiency have been recognized.
esters, alkylidenecyanoacetates, and alkylidenemalonodinitrile to
give b-branched carboxylic acid derivatives. Sterically demanding
products containing quaternary carbon atoms are obtained in good
yields. In the case of diethylaluminum chloride, accompanying re-
ductions of the substrates can be suppressed by application of boron
trifluoride as an assisting Lewis acid.
The 1,4-addition of alkyl- or arylaluminum compounds to
enones is only achieved under special conditions. The
transfer of a methyl group from trimethylaluminum10 or
an aryl group from aryldimethylaluminum11 requires cat-
alytic amounts of low valent nickel, while the conjugate
addition of tripropylaluminum to cyclohexenone needs
photochemical activation.12 Alkenyl- and alkynylalumi-
num reagents are more reactive and deliver the alkenyl13
or alkynyl group14 efficiently to Michael acceptors.
Key words: Michael addition, organoaluminum halides, b-
branched carboxylic acids and nitriles, regioselective addition to
enolates, quaternary carbons, organometallic reagents
Conjugate 1,4-additions of alkyl and aryl groups have
been achieved efficiently and with high diastereoselectiv-
ity in reactions of a,b-unsaturated N-acyloxazolidinones15
and -oxazinones16 with dialkyl- or diarylaluminum chlo-
rides. A marked contrast between dimethyl- and higher di-
alkylaluminum chlorides was observed in these processes.
While the latter react at –78°C in toluene/hexane or
dichloromethane, dimethylaluminum chloride undergoes
1,4-addition only after photochemical activation or radi-
cal initiation.15,16
The 1,4-conjugate addition of carbanions to activated alk-
enes is an important carbon–carbon bond forming reac-
tion. While the addition of stabilized carbanions, e.g.
enolates (Michael addition) usually occurs with complete
1,4-regioselectivity,1 addition reactions of organometallic
compounds transferring non-stabilized alkyl (or aryl)
groups to enones and enoate often suffer from accompa-
nying side reactions. As a rule, organolithium compounds
undergo 1,2-addition to a,b-unsaturated carbonyl com-
pounds and carboxylic esters. With less reactive salts and
secondary amides of cinnamic-type carboxylic acids, they
produce mixtures of Michael and "contra-Michael" ad-
ducts.2
We report here on an efficient regioselective 1,4-addition
of dialkylaluminum chlorides which neither needs special
conditions nor N-acylurethanes as substrates. Alkylidene-
malonic esters, alkylidenecyanoacetates and alkylidene-
malonodinitrile are used as the acceptors to yield the
corresponding b-branched alkyl derivatives which are
useful precursors of b-branched carboxylic acids or ni-
triles and their conversion products. As shown in Scheme
1 for dimethylaluminum chloride, the 1,4-addition to
these acceptors 1, 2 or 3 proceeds in toluene at –40°C to
furnish the corresponding b-branched products 4, 5 or 6,
respectively, in high yield (Table 1).
Like those of organolithium compounds, the reactions of
Grignard reagents with a,b-unsaturated carbonyl com-
pounds generally afford 1,2-addition products. Conjugate
1,4-addition of Grignard reagents occurs with unsaturated
N,N-disubstituted amides as the substrates.3 This reaction
was extended to diastereoselective formations of b-
branched carboxylic acid derivatives,4 however, this strat-
egy needs subsequent cleavage of the stable amide groups
prior to further chemical transformations. Regioselective
1,4-addition was also reported for reactions of Grignard
reagents with alkylidenemalonates and -cyanoace-
tates.3,5,6 If ethyl- and higher alkylmagnesium halides are
used, Grignard reduction occurs to a considerable ex-
tent.5a,b In the case of phenylmagnesium bromide, poly-
merization of the alkylidenemalonates was found to be a
serious problem.5 Organocopper intermediates are the re-
active species in the copper-catalyzed Grignard additions
to enones, enolates and doubly activated alkenes which
often proceed with high 1,4-regioselectivity.7,8 Organocu-
prates are the most widely applied reagents in order to
achieve a selective 1,4- versus the 1,2-mode of addition to
E1
E2
2.5 eq. Me2AlCl
R
E1
E2
R
toluene/n-hexane 10 : 1,
-40°C
Me
4 E1 = E2 = COOEt
5 E1 = CN; E2 = COOEt
6 E1 = E2 = CN
1 E1 = E2 = COOEt
2 E1 = CN; E2 = COOEt
3 E1 = E2 = CN
Scheme 1
Synthesis 1999, No. 10, 1792–1798 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conjugate Addition of Dialkylaluminum Chlorides to Alkylidenemalonic Acid Derivatives
1793
Table 1 Conjugate Addition of Me2AlCl to Malonic Acid Deriva-
tives 1, 2 and 3
2.5 eq. Et2AlCl
R
CO2Et
CO2Et
CO2Et
CO2Et
R
CO2Et
R
+
toluene/n-hexane
10 : 1, -40oC
Et
H
CO2Et
Sub-
R
Reaction Time Product
(h)
Yield (%)
strate
10
9
1a
1b
1c
1d
1e
1f
CH3
15
16
20
4a
4b
4c
4d
4e
4f
84
79
Scheme 3
CH2CH3
CH(CH3)2
100
79
CH2CH(CH3)2 18
taining branching in g-position (1c, 1e, 1f) result in ac-
companying formations of byproducts formed by b-
hydride transfer and release of ethylene (Table 2).
c-C6H11
C(CH3)3
C6H5
15
18
6
81
63
The results given in Table 2 show that d-branching in sub-
strate 1d also affects the selectivity of the addition reac-
tion, while the phenyl group in benzylidenemalonate 1g
does not exert sterical hindrance. The (1-phenyl)propyl-
malonic ester 9g is obtained almost quantitatively.
1g
2a
2b
3
4g
5a
5b
6
100
81
CH(CH3)2
C(CH3)3
CH(CH3)2
16
18
17
77
The reaction of diethylaluminum chloride to alkylidene-
Meldrum acids 7 shows the same feature. Complete selec-
tive 1,4-addition occurs with benzylidene-Meldrum acid
7a, whereas the reaction with the isobutylidene derivative
7b produces a mixture of the 1,4-adduct 11b and the re-
duced compound 12b (Scheme 4).
73
In contrast to the corresponding reactions with the N-acyl-
urethane-type acceptors, no photochemical activation,
radical initiation or transition metal catalysis is required.
Branching in g-position (1c, 1e, 2a) does not hinder the
conversion. Even with the tert-butyl substituted alkyl-
idenemalonate 1f and -cyanoacetate 2b, the 1,4-adducts 4f
and 5b are obtained in good yield. Benzylidenemalonate
1g is slightly more reactive than the other alkylidenema-
lonates presumably because of its lower LUMO. The re-
activity of the isobutylidenemalonodinitrile 3 is not
significantly different from those of the corresponding
malonate 1c and cyanoacetate 2a. Knoevenagel products
of Meldrum acid 7 also smoothly undergo 1,4-addition of
dimethylaluminum chloride to yield branched-chain com-
pounds 8 in high yield (Scheme 2).
O
O
O
O
O
O
O
O
O
O
Et
R
H
R
2.5 eq. Et2AlCl
+
R
toluene/n-hexane
10 : 1, -40°C
O
O
7a,b
11a R = Ph; 83%
11b R = CHMe2; 63%
12a
12b
ratio 11a/12a 100:0
ratio 11b/12b 77:23
Scheme 4
Table 2 Conjugate Addition of Et2AlCl to Alkylidene Malonic
Esters 1
O
O
O
O
O
O
Me
R
2.5 eq. Me2AlCl
Sub-
R
Reaction Product
Product Yield
(%)
toluene/n-hexane
10 : 1, -40°C
R
strate
Time (h) Ratio 9/10a
O
O
1a
1b
1c
1d
1e
1f
CH3
14
16
22
100:0
100:0
33:67
88:12b
42:58b
38:62b
100:0
9a
88
82
7a R = Ph
8a R = Ph; 88%
7b R = CHMe2
8b R = CHMe2; 93%
CH2CH3
CH(CH3)2
9b
Scheme 2
9c/10cc
9d/10dc
9e/10ec
9f
95
CH2CH(CH3)2 15
50
The reaction of diethylaluminum chloride as an example
of higher alkylaluminum chlorides with Michael accep-
tors 1 first was investigated under conditions identical to
those applied in the addition reactions of dimethylalumi-
num chloride (Scheme 3).
c-C6H11
C(CH3)3
C6H5
15
16
21
29
19
1g
9g
100
a Determined by 1H NMR spectra.
Selective conjugate addition and high yields of 1,4-ad-
ducts are obtained with non-branched alkylidenemalonic
esters (1a, 1b). Analogous conversions of substrates con-
b Additionally determined by gas chromatography.
c Not separable.
Synthesis 1999, No. 10, 1792–1798 ISSN 0039-7881 © Thieme Stuttgart · New York

1794
S. Maas et al.
PAPER
The most selective reaction is observed if alkylidenecy- tio of products 9c/10c from 1:2 (Table 2) to 1:1. If the re-
anoacetates 2 are used as the acceptors (Scheme 5). In no action is carried out in diethyl ether instead of toluene,
case (Table 3) was the formation of the reduced acceptor preferred formation of the 1,4-addition product 9c is
14 found.
achieved (ratio 9c/10c = 4:1). The obvious influence of
the donor quality of the solvent on the chemoselectivity of
the conjugate addition can be rationalized by the breaking
effect of Lewis basic donors on organoaluminum chloride
aggregates present in non-polar solutions.10 Complexation
of the substrates 1 or 3 by boron trifluoride etherate prior
to addition of the diethylaluminum chloride markedly im-
proved the chemoselectivity of the reaction in favour of
preferred formation of the 1,4-conjugate adducts. The b-
ethyl branched malonate 9d and malonodinitrile 13f were
formed with complete selectivity and isolated in yields of
73 and 92%, respectively. The more hindered malonates
1c, 1e and 1f gave ratios for 9/10 of about 10:1 to 20:1. In
spite of this improved chemoselectivity the byproducts 10
have to be separated by chromatography in these cases.
R2
R3
CN
R1
R2
Et
CN
R1
R2
H
CN
R1
2.5 eq. Et2AlCl
R3
R3
+
toluene/n-hexane
10 : 1, -40°C
13
14
2 R1 = COOEt
3 R1 = CN
Scheme 5
Results given in Table 3 also illustrate, that acceptors 2
carrying two substituents in b-position (2c, 2d, 2e) are
converted completely selectively into the 1,4-adducts 13c,
13d or 13e, respectively, all containing a newly formed
quaternary carbon atom.
Therefore, we were interested in a completely chemose-
lective 1,4-addition of diethylaluminum chloride even to
these sterically more demanding alkylidenemalonates 1.
Because neither coordination of diethyl ether to the orga-
noaluminum reagent nor that of boron trifluoride to the
substrates resulted in the desired effect, diethylaluminum
chloride itself was pretreated with equimolar amounts of
boron trifluoride etherate in toluene at –40°C for 2 hours.
After additon of the alkylidenemalonates 1 complete
chemoselective 1,4-addition of the ethyl group is achieved
(Scheme 6, Table 4).
It appears particularly remarkable that the conjugate ad-
duct 13e which contains a g-branching next to the quater-
nary carbon in b-position is formed without
accompanying reduction of the substrate. Nevertheless,
the sterical hindrance in this conjugate addition must be
overcome by a long reaction time although excess of the
diethylaluminum chloride is used.
In general, the described conjugate additions proceed with
one equivalent of the organoaluminum chloride. In order
to accelerate the reactions, 2.5 equivalents are uniformly
applied. It is astonishing that isobutylidenemalonodini-
trile 3 carrying two slim electron-withdrawing groups re-
acts with lower chemoselectivity compared to the
cyanoacetates 2.
2.5 eq. (Et2AlCl
.BF3 OEt2)
.
R
E
E
R
E
E
toluene/n-hexane
10 : 1, -40°C
Et
In order to improve the ratio of the 1,4-addition versus re-
duction for alkylidenemalonic esters 1 and the dinitrile 3,
the influence of the solvent on the reaction of diethylalu-
minum chloride with isobutylidenemalonic ester 1c was
investigated. Addition of one equivalent of diethyl ether
(related in the amount of) Et2AlCl slightly changes the ra-
1 E = COOEt
3 E = CN
9
E = COOEt
13f E = CN
Scheme 6
Compared to the results obtained with diethylaluminum
chloride alone (Table 2), the effect of boron trifluoride on
the chemoselectivity is decisive. Without BF3∑OEt2 (Ta-
ble 2), the reaction of Et2AlCl with all three acceptors 1c,
1e and 1f yields mixtures of 1,4-adduct 9 and prevailing
reduction product 10. In contrast, after pretreatment with
BF3∑OEt2 the conjugate additon of Et2AlCl furnishes se-
lectively the 1,4-adducts 9 (Table 4).
Table 3 Conjugate 1,4-Addition of Et2AlCl to Alkylidene Cyanoac-
etates 2 and Malonodinitrile 3
Sub- R1
strate
R2
R3
Reaction Product Prod- Yield
Time (h) Ratio
uct
(%)
13/14a
2a
2b
2c
2d
2e
3
CO2Et CH(CH3)2
CO2Et C(CH3)3
CO2Et CH3
H
H
16
18
100:0 13a 81
100:0 13b 85
We assume that BF3 forms heterodimeric complexes with
Et2AlCl and thus breaks the oligomeric structures of the
organoaluminum
reagents.
The
heterodimeric
CH3 40
100:0
100:0
100:0
94:6
13c
65
Et2AlCl∑BF3 complexes are responsible for the chemo-
and regioselective 1,4-addition of the dialkylaluminum
chloride even to sterically hindered acceptors. This con-
clusion is confirmed by the reaction of Et2AlCl•BF3 with
isobutylidene Medrum acid 7b giving selectively the con-
jugate adduct 11b.
CO2Et CH2CH3 CH3 44
CO2Et CH(CH3)2 CH3 168
13d 88
13e
13f
87
67
CN
CH(CH3)2
H
17
a Determined by 1H NMR spectra.
Synthesis 1999, No. 10, 1792–1798 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conjugate Addition of Dialkylaluminum Chlorides to Alkylidenemalonic Acid Derivatives
1795
solution in hexane) was injected by a syringe. After stirring for the
reaction time given in Table 1, 2 or 3 (TLC monitoring), aq sat.
NH4Cl solution (100 mL) was added. After separation of the layers,
the aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were washed with NH4Cl solution (50 mL)
and dried (MgSO4). The solvent was removed by distillation and
the crude product purified by flash chromatography using petro-
leum ether (PE)/EtOAc (20:1) as eluent (Tables 1–3).
Table 4 Conjugate 1,4-Addition of Et2AlCl Pretreated with
Equimolar BF3◊OEt2
Substrate
R
Reaction Time Product Yield (%)
(h)
1c
1d
1e
1f
3
CH(CH3)2
18
9c
9d
9e
93
73
93
87
92
CH2CH(CH3)2 16
1
Characteristic H NMR signals of all malonic esters 4, 9 and 10:
c-C6H11
20
20
16
d = 1.20–1.22 (t, 3 H, J = 7.0–7.2 Hz, CH3CH2O), 4.11–4.14 (q, 4
H, J = 7.0–7.2 Hz, CH3CH2O), and for cyanoacetic esters 5 and 13:
d = 1.27–1.29 (t, 3 H, J = 7.0–7.3 Hz, CH3CH2O), 4.20–4.22 (q, 2
H, J = 7.1 Hz, CH3CH2O).
C(CH3)3
CH(CH3)2
9f
13f
Diethyl Isopropylmalonate (4a)19
Colorless oil; Rf 0.36 (PE/EtOAc, 10:1).
1H NMR: d = 0.95 (d, 6 H, J = 6.8 Hz, CH3), 3.05 [d, 1 H, J = 8.8
Hz, CH(CO2Et)2].
13C NMR: d = 14.0 (CH3CH2O), 20.3 (CHCH3), 28.6 (CHMe2),
59.1 [CH(CO2Et)2], 60.9 (CH2O), 168.7 (C=O).
Diethyl (1-Methylpropyl)malonate (4b)18
Colorless oil; Rf 0.49 (PE/EtOAc, 10:1).
1H NMR: d = 0.84 (t, 3 H, J = 7.4 Hz, CH3CH2), 0.91 (d, 3 H,
J = 6.8 Hz, CH3CH), 3.16 [d, 1 H, J = 8.3 Hz, CH(CO2Et)2].
13C NMR: d = 11.1 (CH3CH2), 14.0 (CH3CH2O), 16.4 (CH3CH),
57.5 [CH(CO2Et)2], 60.9, 61.0 (CH2O), 168.7, 168.9 (C=O).
Diethyl (1,2-Dimethylpropyl)malonate (4c)19
O
O
O
2.5 eq. (Et2AlCl
O
O
.
.BF3 OEt2)
O
O
Et
toluene/n-hexane
10 : 1, -40°C
O
7b
11b; 86%
Scheme 7
Colorless oil; Rf 0.63 (PE/EtOAc, 5:1).
1H NMR: d = 0.79 [d, 3 H, J = 6.8 Hz, CH(CH3)2], 0.85 [d, 3 H,
J = 7.0 Hz, CH(CH3)2], 0.92 (d, 3 H, J = 6.8 Hz, CHCH3), 1.66 (m,
1 H, CHMe2), 3.31 [d, 1 H, J = 9.4 Hz, CH(CO2Et)2].
13C NMR: d = 11.4, 13.7, 16.3, 20.9 (CH3), 60.7, 60.8 (CH2O),
Comparison of this result with that shown in Scheme 4
also illustrates the general efficiency of the novel reaction
in this optimized modification for the conjugate addition
of alkyl groups to alkylidenemalonic acid derivatives. The
reactions are conveniently carried out in homogenous so- 168.6, 168.8, (C=O).
lution and do not need assistance by transition metal com-
ponents. Compounds containing multiple branchings or
quaternary carbon centers are efficiently accessible.
Diethyl (1,3-Dimethylbutyl)malonate (4d)
Colorless oil, Rf 0.44 (PE/EE 10:1).
1H NMR: d = 0.83 and 0.84 each [d, 3 H, J = 6.5 Hz, CH(CH3)2],
0.92 (d, 3 H, J = 6.8 Hz, CHCH3), 3.15 [d, 1 H, J = 7.9 Hz,
CH(CO2Et)2].
Toluene and Et2O were dried before use by distillation from potas-
sium/benzophenone ketyl. Alkylidenemalonic diethyl esters 1,
alkylidene-Meldrum acids 7, ethyl alkylidenecyanoacetates 2 and
isobutylidenemalonodinitrile 3 were synthesized according to pub-
lished procedures.17 Dimethyl- and diethylaluminum chloride were
purchased from Aldrich and used as 1 M solutions in hexane. Petro-
leum ether refers to the fraction with bp 40–70°C. Flash chromatog-
raphy was carried out using silica gel 60 (Merck, Darmstadt,
Germany), 0.04–0.063 nm. TLC was performed on silica gel (Kie-
selgel 60 F254, Merck, Darmstadt, Germany). Gas chromatography
was carried out with a fused silica-column (PERMABOND SE-30-
DF-0.25, 25m × 0.32mm ID, Machery & Nagel, Düren, Germany).
13C NMR: d = 14.1 (CH3CH2O), 17.0, 21.6, 23.6 (CH3), 60.9, 61.0
(CH2O), 168.8, 168.9 (C=O).
Diethyl (1-Cyclohexylethyl)malonate (4e)20
Colorless oil; Rf 0.40 (PE/EtOAc, 10:1).
1H NMR: d = 0.85 (d, 3 H, J = 6.9 Hz, CHCH3), 2.12 (m, 1 H,
CHMe), 3.34 [d, 1 H, J = 9.2 Hz, CH(CO2Et)2].
13C NMR: d = 12.9 (CH3), 14.1 (CH3CH2O), 26.4, 26.5, 26.7, 27.6,
31.5, 38.5 (c-C6H11), 60.9, 61.0 (CH2O), 169.0 169.2 (C=O).
Diethyl (1,2,2-Trimethylpropyl)malonate (4f)19
Colorless oil; Rf 0.37 (PE/EtOAc, 10:1).
1H and 13C NMR spectra were recorded on a Bruker AC 200 or on
a Bruker AM 400 NMR spectrometer. All NMR spectra were re-
corded in CDCl3 using TMS as the standard. Melting points are un-
corrected. Satisfactory micoanalyses were obtained for all new
compounds and those incompletely characterized in the literature.
1H NMR: d = 0.84 [s, 9 H, C(CH3)3], 0.95 (d, 3 H, J = 7.3 Hz,
CHCH3), 3.45 [d, 1 H, J = 5.4 Hz, CH(CO2Et)2].
13C NMR: d = 12.0 (CH3), 14.0 (CH3CH2O), 27.5 [C(CH3)3], 33.6
(CMe3), 42.6 (CHMe), 60.8, 61.2 (CH2O), 169.4, 170.1 (C=O).
Diethyl (1-Phenylethyl)malonate (4g)18
Colorless oil; Rf 0.60 (PE/EtOAc, 5:1).
Conjugate Addition of Dimethylaluminum Chloride or Diethyl-
aluminum Chloride to Malonic Acid Derivatives 1, 2, or 3;
General Procedure
Anhyd toluene (50 mL) was distilled into a two-neck flask under ar-
gon atmosphere. After addition of the alkylidenemalonic acid deriv-
ative 1, 2, 3 or 7, respectively (3 mmol), the mixture was cooled to
–40°C. The dialkylaluminum chloride (7.5 mmol; 7.5 mL of a 1 M
1H NMR: d = 3.45–3.60 [m, 2 H, CH(CO2Et)2, CHPh], 3.89 (q, 2 H,
J = 7.2 Hz, CH2O), 4.21 (q, 2 H, J = 7.2 Hz, CH2O), 7.07–7.30 (m,
5 H, C6H5).
13C NMR: d = 13.7, 14.1 (CH3CH2O), 20.1 (CH3), 40.0 (CHPh),
61.0, 61.4 (CH2O), 143.2 (C-ipso, C6H5), 167.9, 168.4 (C=O).
Synthesis 1999, No. 10, 1792–1798 ISSN 0039-7881 © Thieme Stuttgart · New York

1796
S. Maas et al.
PAPER
Ethyl 2-Cyano-3,4-dimethylpentanoate (5a)
Colorless oil; Rf 0.32 (PE/EtOAc, 10:1); mixture of diastereomers.
1H NMR: d = 0.85 and 1.01 each (d, 3 H, J = 6.8 Hz, 3-CH3), 0.93
[m, 6 H, CH(CH3)2], 1.62 (m, 1 H, H-3), 1.91 (m, 1 H, H-4), 3.35
and 3.60 each (d, 1 H, J = 4.7 and 7.6 Hz, CHCO2Et].
13C NMR: d = 13.4, 13.9 (CH3CH2O), 42.1, 42.7 (CHCO2Et), 62.4,
62.5 (CH2O), 115.4, 116.1 (CN), 165.9, 166.4 (C=O).
Ethyl 2-Cyano-3,4,4-trimethylpentanoate (5b)21
Colorless oil; Rf 0.35 (PE/EtOAc, 10:1); mixture of diastereomers.
1H NMR: d = 0.94, 0.95 each [s, 9 H, C(CH3)3], 1.06 (d, 3 H,
J = 7.0 Hz, CH3CH), 1.99 and 2.12 each (dq, 1 H, J = 2.1 and 5.0
Hz, CHBu-t), 3.47 and 3.66 each (d, 1 H, J = 2.1 and J = 5.0 Hz,
CHCO2Et).
13C NMR: d = 27.4, 27.6 C(CH3) 3, 33.4, 33.9 C(CH3) 3, 39.8, 40.4
(CHBu-t), 43.8, 44.7 (CHCO2Et), 62.4, 62.7 (CH2O), 116.1, 117.4
(CN), 166.4, 167.0 (C=O).
1H NMR: d = 0.91 (t, 3 H, J = 7.3 Hz, CH3CH2), 1.09 [s, 3 H,
(CH3)2C], 1.59 [s, 3 H, (CH3)2C], 3.62 (m, 1 H, CHPh), 3.70 [d, 1
H, J = 3.2 Hz, CH(CO)2], 7.15–7.31 (m, 5 H, C6H5).
13C NMR: d = 12.4 (CH3), 25.6 (CH2CH3), 27.9, 28.3 [C(CH3)2],
48.1 (CHPh), 50.9 [CH(CO)2], 105.3 (CMe2), 139.5 (C-ipso, C6H5),
164.6, 165.8 (C=O).
2,2-Dimethyl-5-(1-ethyl-2-methylpropyl)-1,3-dioxane-4,6-
dione (11b)
Separated from 12b by flash chromatography; yield: 63%; colorless
crystals; mp 54°C (PE/EtOAc); Rf 0.14 (PE/EtOAc, 10:1).
1H NMR: d = 0.86–0.97 (m, 9 H, CH3), 1.73 [s, 6 H, (CH3)2C], 2.18
(m, 1 H, CHEt), 3.49 [d, 1 H, J = 2.5 Hz, CH(CO)2].
13C NMR: d = 15.1, 20.9, 21.3 (CH3), 23.3 (CH2), 27.6, 28.1
[C(CH3)2], 30.2 (CHMe2), 46.2 (CHEt), 47.9 [CH(CO)2], 104.7
(CMe2), 166.1 (C=O).
2,2-Dimethyl-5-(2-methylpropyl)-1,3-dioxane-4,6-dione (12b)22
Separated from 11b; yield: 23%; colorless crystals; mp 120°C
(PE/EtOAc); Rf 0.18 (PE/EtOAc, 10:1).
1H NMR: d = 0.89 (d, 6 H, J = 6.4 Hz, CH3), 1.70 [s, 3 H, (CH3)2C],
1.75 [s, 3 H, (CH3)2C], 1.92–2.07 (m, 3 H, CH2, CHMe2), 3.42 [t, 1
H, J = 5.4 Hz, CH(CO)2].
(1,2-Dimethylpropyl)malonodinitrile (6)
Colorless oil; Rf 0.26 (PE/EtOAc, 10:1).
1H NMR: d = 0.93–1.01 [m, 6 H, CH(CH3)2], 1.20 (d, 3 H, J = 5.6
Hz, CHCH3), 3.75 [dd, 1 H, 3J = 5.6 Hz, 4J = 1.2 Hz, CH(CN)2].
13C NMR: d = 13.5, 18.0, 20.6 (CH3), 27.5 (CHMe2), 30.4 (C-b),
41.4 (CCN), 111.9, 112.8 (CN).
2,2-Dimethyl-5-(1-phenylethyl)1,3-dioxane-4,6-dione(8a)22
Yield: 88%; colorless crystals; mp 101°C (); Rf 0.25 (PE/EtOAc,
10:1).
1H NMR: d = 3.68 [d, 1 H, J = 3.2 Hz, CH(CO)2], 3.98 (dq, 1 H,
J = 7.3, 3.0 Hz, CHPh), 7.20–7.34 (m, 5 H, C6H5).
13C NMR: d = 22.1 (CH3), 25.9 (CHMe2), 26.8, 28.6 [C(CH3)2],
44.2 [CH(CO)2], 35.3 (CH2), 104.8 (CMe2), 166.0 (C=O).
Ethyl 2-Cyano-3-ethyl-4-methylpentanoate (13a)
Colorless oil; mixture of diastereomers; Rf 0.30 (PE/EtOAc, 10:1).
1H NMR: d = 0.87–0.97 (m, 9 H, CH3) 1.25–1.95 (m, 4 H, CHEt,
CH2, CHMe2), 3.59 and 3.60 each (d, 1 H, J = 5.4 and 6.8 Hz,
CHCO2Et).
13C NMR: d = 11.9, 12.1 (CH3), 13.9 (CH3CH2O), 18.5, 19.2 (CH3),
20.2, 21.2 (CH3), 21.5, 22.6 (CH2), 39.5, 40.3 (CHEt), 46.7, 46.8
(CHCO2Et), 62.5, 62.6 (CH2O), 115.9, 116.1 (CN), 166.8, 167.0
(C=O).
13C NMR: d = 17.8 (CH3), 28.0, 28.3 [C(CH3)2], 38.7 (CHPh),
105.2 [C(CH3)2], 164.7, 165.0 (C=O).
2,2-Dimethyl-5-(1,2-dimethylpropyl)-1,3-dioxane-4,6-dione
(8b)
Yield: 93%; colorless crystals; mp 89°C (PE/EtOAc); Rf 0.18 (PE/
EtOAc, 10:1).
Ethyl 2-Cyano-3-ethyl-4,4-dimethylpentanoate (13b)
Colorless oil; mixture of diastereomers; Rf 0.35 (PE/EtOAc, 10:1).
1H NMR: d = 0.89 [d, 3 H, J = 7.1 Hz, CH(CH3)2], 0.91 [d, 3 H,
J = 6.7 Hz, CH(CH3)2], 1.00 (d, 3 H, J = 6.7 Hz, CH3), 1.69 and
1.70 each [s, 3 H, C(CH3)2], 2.02 (m, 1 H, CHMe2), 2.16 (m, 1 H,
CHCH3), 3.55 [d, 1 H, J = 2.9 Hz, CH(CO)2].
13C NMR: d = 15.1, 20.9, 21.3, (CH3), 27.8, 28.2 [C(CH3)2], 41.3
(CHMe), 48.8 [CH(CO)2], 104.6 (CMe2), 164.7, 166.3 (C=O).
1H NMR: d = 0.87 (t, 3 H, J = 7.5 Hz, CH3), 0.96 and 0.97 each [s,
9 H, C(CH3)3], 1.53–1.75 (m, 2 H, CH2), 1.89–1.95 (m, 1 H, CHBu-
t), 3.61 and 3.69 each (d, 1 H, J = 1.0 and 3.0 Hz, CHCO2Et).
13C NMR: d = 13.1, 13.2 (CH3). 13.8, 13.9 (CH3CH2O) 20.9, 21.7
(CH2), 27.8, 28.0 [C(CH3)3], 34.0, 34.4 (CMe3), 37.8, 38.5 (CHBu-
t), 50.7, 51.3 (CHCO2Et), 62.6, 62.7 (CH2O), 116.2, 116.6 (CN),
167.4, 167.6 (C=O).
Diethyl (1-Methylpropyl)malonate (9a)
Identical to 4b; Rf 0.49 (PE/EtOAc, 10:1).
Diethyl (1-Ethylpropyl)malonate (9b)23
Ethyl 2-Cyano-3,3-dimethylpentanoate (13c)
Colorless oil; Rf 0.35 (PE/EtOAc, 10:1).
1H NMR: d = 0.86 (t, 3 H, CH2CH3),1.04 (s, 3 H, CH3), 1.08 (s, 3 H,
CH3), 1.46 (m, 2 H, CH2), 3.31 (s, 1 H, CHCO2Et).
13C NMR: d = 8.1 (CH3CH2C) 14.0 (CH3CH2O), 24.1, 24.7 (CH3),
33.0 (CH2), 37.7 (EtCMe2), 47.8 (CHCO2Et), 62.3 (CH2O), 116.0
(CN), 165.4 (C=O).
Colorless oil; Rf 0.55 (PE/EtOAc, 10:1).
1H NMR: d = 0.83 (t, 6 H, J = 7.5 Hz, CH3CH2CH), 2.00 (m, 1 H,
CHEt2), 3.34 [d, 1 H, J = 8.1 Hz, CH(CO2Et)2].
13C NMR. d = 10.8 (CH3), 14.0 (CH3CH2O), 23.0 (CH2), 40.9
(CHEt2), 55.1 [CH(CO2Et)2], 60.9 (CH2O), 169.0 (C=O).
Diethyl (1-Phenylpropyl)malonate (9g)24
Colorless oil; Rf 0.60 (PE/EtOAc, 5:1).
Ethyl 2-Cyano-3-ethyl-3-methylpentanoate (13d)
Colorless oil; Rf 0.41 (PE/EtOAc, 10:1).
1H NMR: d = 0.83 (t, 3 H, J = 7.6 Hz, CH3CH2), 0.84 (t, 3 H, J = 7.3
Hz, CH3CH2), 1.04 (s, 3 H, CH3), 1.39 (dq, 2 H, J = 7.5, 1.7 Hz,
CH2), 1.50 (q, 2 H, J = 7.5 Hz, CH2), 3.41 (s, 1 H, CHCO2Et).
13C NMR: d = 7.6, 7.8 [(CH3CH2)2C] 13.9 (CH3CH2O), 21.7 (CH3),
28.8 (CH2), 29.5 (CH2), 40.3 (Et2CMe), 46.1 (CHCO2Et), 62.2
(CH2O), 116.1 (CN), 165.5 (C=O).
1H NMR: d = 0.68 (t, 3 H, J = 6.0 Hz, CH3CH2CH), 3.22 (dt, 1 H,
J = 3.7, 10.9 Hz, CHPh), 3.60 [d, 1 H, J = 11.0 Hz, CH(CO2Et)2],
3.84 (q, 2 H, J = 7.1 Hz, CH2O), 4.19 (q, 2 H, J = 7.1 Hz, CH2O),
7.11–7.26 (m, 5 H, C6H5).
13C NMR: d = 11.7 (CH3), 13.6, 14.1 (CH3CH2O), 47.3 (CHPh),
61.0, 61.4 (CH2O), 140.6 (C-ipso, C6H5), 167.8, 168.5 (C=O).
Ethyl 2-Cyano-3-ethyl-3,4-dimethylpentanoate (13e)
Colorless oil; mixture of diastereomers; Rf 0.43 (PE/EtOAc, 10:1).
2,2-Dimethyl-5-(1-phenylpropyl)-1,3-dioxane-4,6-dione (11a)
Yield: 83%; colorless oil; Rf 0.46 (PE/EtOAc, 5:1).
Synthesis 1999, No. 10, 1792–1798 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conjugate Addition of Dialkylaluminum Chlorides to Alkylidenemalonic Acid Derivatives
1797
1H NMR: d = 0.81–1.09 (m, 12 H, CH3), 1.37–2.03 (m, 3 H, CH2,
CHMe), 3.46 and 3.49 each (s, 1 H, CHCO2Et).
13C NMR: d = 8.3, 8.4 (CH3CH2). 14.0 (CH3CH2O), 17.2, 17.4,
17.6, 20.0, 20.9 (CH3), 28.0, 29.3, 32.7, 34.2 (CHMe2, CH2), 42.9,
43.1 (i-PrCMeEt), 44.8, 45.0 (CHCO2Et), 62.9 (CH2O), 116.7
(CN), 166.0 (C=O).
13C NMR: d = 13.7 (CH3CH2CH), 14.1 (CH3CH2O) 22.0, 26.6,
26.8, 26.9, 29.4, 30.8 (CH2), 40.3 (CHEtCH), 45.5 (CHEt), 54.5
[CH(CO2Et)2], 61.0, 61.1 (CH2O), 169.4 169.7 (C=O).
Diethyl (1-Ethyl-2,2-dimethylpropyl)malonate (9f)
Colorless oil; Rf 0.46 (PE/EtOAc, 10:1).
1H NMR: d = 0.86 [s, 9 H, C(CH3)3], 0.89 (t, 3 H, J = 7.5 Hz,
CH3CH2CH), 1.22 (t, 3 H, J = 7.1 Hz, CH3CH2O), 1.23 (t, 3 H,
J = 7.1 Hz, CH3CH2O), 1.48–1.63 (m, 2 H, CH2CH3), 1.93 (m, 1 H,
CHEt), 3.54 (d, 1 H, J = 4.2 Hz, CH(CO2Et)2).
(1-Ethyl-2-methylpropyl)malonodinitrile (13f)
Yield: 67%; separated from 14 by flash chromatography; colorless
oil; Rf 0.30 (PE/EtOAc, 10:1).
1H NMR: d = 1.00 [d, 6 H, J = 6.8 Hz, CH(CH3)2], 1.04, (t, 3 H,
J = 7.3 Hz, CH3CH2), 1.52–2.05 (m, 4 H, CH2, CHEt, CHMe2), 3.82
(d, 1 H, J = 3.9 Hz, CHCN).
13C NMR: d = 13.9 (CH3CH2O), 14.8 (CH3CH2), 20.4 (CH2CH3),
28.0 [C(CH3)3], 34.4 (CMe3), 50.8 (CHEt), 52.3 [CH(COOEt)2],
60.7, 61.2 (CH2O), 169.5, 170.6 (C=O).
13C NMR: d = 11.8, 19.0, 19.8 (CH3), 21.8 (CH2), 24.7 (CHMe2),
29.6 (CHEt), 47.4 (CHCN), 112.5, 112.9 (CN)
(1-Ethyl-2-methylpropyl)malonodinitrile (13f)
Colorless oil; Rf 0.30 (PE/EtOAc, 10:1). Identification vide supra.
(2-Methylpropyl)malonodinitrile (14)
Separated from 13f; yield: 5.6%; colorless oil; Rf 0.24 (PE/EtOAc,
2,2-Dimethyl-5-(1-ethyl-2-methylpropyl)-1,3-dioxane-4,6-
dione (11b)
10:1).
Yield: 86%; colorless crystals; mp 54°C (PE/EtOAc); Rf 0.14 (PE/
EtOAc, 10:1). Identification vide supra.
1H NMR: d = 0.98 [d, 6 H, J = 6.4 Hz (CH(CH3)2], 1.78–1.97 (m, 3
H, CH2, CHMe2), 3.72 (t, 1 H, J = 7.3 Hz, CHCN).
13C NMR: d = 20.9 (CH2), 21.5 [CH(CH3)2], 26.1 (CHMe2), 39.0
Acknowledgement
(CCN), 112.9 (CN).
This work was supported by the Deutsche Forschungsgemeinschaft
and Fonds der Chemischen Industrie.
Conjugate Addition of Diethylaluminum Chloride Precoordi-
nated to Boron Trifluoride Etherate to Alkylidenemalonic Es-
ters 1,Isobutylidenemalonodinitrile
Derivative 7b; General Procedure
3 or Meldrum Acid
References
Toluene (50 mL) was distilled into a two neck flask under argon at-
mosphere and cooled to –40°C. BF3∑OEt2 (0.93 mL, 7.5 mmol) and
Et2AlCl (7.5 mmol, 7.5 mL of 1 M solution in hexane) were added
by a syringe. After strirring for 2 h, the alkylidenemalonic ester 1,
dinitrile 3, or Meldrum acid derivative 7b, respectively, was added
and the solution stirred for the time given in Table 4. The solution
was then poured into aq satd NH4Cl solution (100 mL). After sepa-
ration of the layers, the aqueous phase was extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were washed with aq
satd NH4Cl solution and dried (MgSO4). The solvent was removed
by distillation and the crude product purified by flash chromatogra-
phy in petroleum ether/EtOAc (25:1) (Table 4).
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Diethyl (1-Ethyl-2-methylpropyl)malonate (9c)23
Colorless oil; Rf 0.59 (PE/EtOAc, 10:1).
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1H NMR: d = 0.78–0.88 (m, 9 H, CH3), 1.19 and 1.20 each (t, 3 H,
J = 7.1 Hz, CH3CH2O), 1.16–1.48 (m, 2 H, CH2CH3), 1.72 (m, 1 H,
CHMe2) 1.91 (m, 1 H, CHEt), 3.34 [d, 1 H, J = 7.8 Hz,
CH(CO2Et)2].
13C NMR: d = 13.5 (CH3CH2), 14.0 (CH3CH2O), 18.6, 20.2
[CH(CH3)2], 29.5 (CHMe2), 45.7 (CHEt), 54.6 [CH(CO2Et)2], 61.0,
61.1 (CH2O), 169.3, 169.5 (C=O).
Diethyl (1-Ethyl-3-methylbutyl)malonate (9d)
Colorless oil; Rf 0.46 (PE/EtOAc, 10:1).
1H NMR: d = 0.82 (t, 3 H, J = 7.3 Hz, CH2CH3), 0.83 (d, 6 H,
J = 6.8 Hz, CH(CH3)2), 1.00–1.66 (m, 5 H, CH2CH3, CH2CHMe2),
2.11 (m, 1 H, CHEt), 3.36 (d, 1 H, J = 7.3 Hz, CH(CO2Et)2].
13C NMR: d = 10.5 (CH3CH2), 14.1 (CH3CH2O), 22.0, 23.3, 23.7
(CH2CH3, CH3), 25.3 (CH2CHMe2), 37.2 (CHMe2), 40.1 (CHEt),
55.0 [CH(CO2Et)2], 61.0 (CH2O), 169.1 (C=O).
Diethyl (1-Cyclohexylpropyl)malonate (9e)
Colorless oil; Rf 0.46 (PE/EtOAc, 10:1).
1H NMR; d = 0.87 (t, 3 H, J = 7.6 Hz, CH3CH2CH), 0.90–1.79 (m,
13 H, c-C6H11, CH2), 1.23 (t, 3 H, J = 7.1 Hz, CH3CH2O), 1.95 (m,
1 H, CHEt), 3.42 [d, 1 H, J = 7.8 Hz, CH(CO2Et)2].
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Synthesis 1999, No. 10, 1792–1798 ISSN 0039-7881 © Thieme Stuttgart · New York

1798
S. Maas et al.
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1437-210X,E;1999,0,10,1792,1798,ftx,en;H03399SS.pdf
Synthesis 1999, No. 10, 1792–1798 ISSN 0039-7881 © Thieme Stuttgart · New York