Mixed Dialkylaluminum Chlorides and Mixed Trimethylorganoaluminates in Chemoselective 1,4 Addition Reactions to Alkylidene Malonic Acid Diethyl Ester

Article abstract of DOI:10.1002/(sici)1521-3897(200004)342:4<396::aid-prac396>3.0.co;2-v

Mixed alkyl-methyl- and aryl-methylorganoaluminum chlorides 6 were formed by reaction of methylaluminum dichloride with organolithium or Grignard compounds and used for chemoselective 1,4 addition of higher alkyl, aryl, alkenyl and alkinyl groups to alkylidine malonic esters 1 and 2. As an alternative, mixed trimethylorganoaluminates 7 can also be applied for these Michael addition reactions. For conjugate addition of alkenyl groups to alkylidene malonates 1 and 2, alkenyl diisopropylalanes 10 obtained from alkynes and diisopropylaluminum hydride proved the most efficient reagents. Using these novel mixed organoaluminum compounds, β-branched malonic (carboxylic) acid derivatives 3c, 8, 9 and 11 were obtained in good yields. The method offers a general access to β-branched carboxylic derivatives of quite diverse structure not dependent on the commercial availability of the organoluminum chlorides.

Full text of DOI:10.1002/(sici)1521-3897(200004)342:4<396::aid-prac396>3.0.co;2-v

FULL PAPER _________________________________________________________________________
Mixed Dialkylaluminum Chlorides and Mixed Trimethylorganoaluminates in
Chemoselective 1,4 Addition Reactions to Alkylidene Malonic Acid Diethyl Ester
Steffen Maas and Horst Kunz*
Mainz, Institut für Organische Chemie der Universität
Received March 2nd, 2000
Dedicated to Prof. Dr. R. R. Schmidt on the Occasion of his 65th Birthday
Keywords: Chemoselectivity, Michael additions, Synthetic methods, β-Branched carboxylic acids, (Mixed) organoalu-
minum reagents
Abstract. Mixed alkyl-methyl- and aryl-methylorganoalu-
minum chlorides 6 were formed by reaction of methylalumi-
num dichloride with organolithium or Grignard compounds
and used for chemoselective 1,4 addition of higher alkyl, aryl,
alkenyl and alkinyl groups to alkylidine malonic esters 1 and
2. As an alternative, mixed trimethylorganoaluminates 7 can
also be applied for these Michael addition reactions. For con-
jugate addition of alkenyl groups to alkylidene malonates 1
and 2, alkenyl diisopropylalanes 10 obtained from alkynes
and diisopropylaluminum hydride proved the most efficient
reagents. Using these novel mixed organoaluminum com-
pounds, β-branched malonic (carboxylic) acid derivatives 3c,
8, 9 and 11 were obtained in good yields. The method offers a
general access to β-branched carboxylic derivatives of quite
diverse structure not dependent on the commercial availabi-
lity of the organoluminum chlorides.
tallic reagents, diethyl ethylidene-malonate 1 and di-
ethyl isobutylidenemalonate 2 have been used as the
model substrates. The reactivity (in terms of conver-
sion) and the chemoselectivity of the 1,4 addition ver-
sus the β-hydride transfer (Scheme 1) of the different
reagents are shown in Table 1.
Trivalent organoaluminum reagents combine the prop-
erties of Lewis acidity with nucleophilic reactivity in
their tetracoordinated complexes [1]. The conjugate ad-
ditions of dimethylaluminum chloride and diethylalu-
minum chloride to alkylidene malonic acid derivatives
was demonstrated an efficient access to β-methyl- and
β-ethyl-branched carboxylic acid derivatives [2]. Dime-
thyl- and diethylaluminum chloride as well as diisobutyl-
aluminum chloride are commercially available, while
other dialkyl- (or diaryl)aluminum chlorides must be
prepared prior to their use in such reactions. Dipropyl-
aluminum chloride not reliably stable in solution can
be prepared by comproportionation from aluminum
trichloride and tripropylaluminum [3]. Diphenylalumi-
num chloride is accessible in a two step synthesis. First,
triphenylaluminum is synthesized from diphenylmer-
cury and aluminum and subjected to comproportiona-
tion with aluminum trichloride [4]. The synthesis of
homologous organoaluminum chlorides requires simi-
lar exertion. This situation illustrates the need for a more
general and simple access to organoaluminum reagents
which can be used in 1,4 addition reactions to Michael
acceptors. One option should consist of the application
of mixed dialkylaluminum chlorides. So far, such com-
pounds have not been described in the literature, obvi-
ously because they undergo exchange of substituents
through dimeric or oligomeric aggregates. As a conse-
quence, it is concluded that mixed dialkylaluminum
chlorides should be generated in situ prior to their use
in the conjugate addition to α,β-unsaturated carbonyl
compounds.
R
COOEt
2.5 eq. R'ÐM l
2.5 eq. R'–MI
toluene/hexane 10 : 1,
–40 °C/20 h
COOEt
R
COOEt
COOEt
COOEt
COOEt
R
+
R'
H
1 R = Me
2 R = iProp
3a R = R' = Me
4a R = Me
3b R = Me, R' = Et
3c R = Me, R' = Bu
3d R = iProp, R' = Et
4b R = iProp
3e R = iProp, R' = Me
Scheme 1 Reaction of diethyl alkylidene malonates with or-
ganometallic reagents
All reactions were carried out under standard condi-
tions at –40 °C in toluene using 2.5 equivalents of the
organometallic reagent. The reaction time was 20 h. The
crude products were determined by gas chromatogra-
phy and identified by comparison of their retention times
with those of reference compounds.
The results quoted in Table 1 show that a) the reac-
tivity of dialkylalumium chlorides is generally higher
than that of monoalkylaluminum dichlorides (entry 1
versus 2, entry 5 versus 6); b) the reactivity of ethylalu-
minum chlorides is higher than that of methylalumi-
Methodical Investigations
In order to classify the mode of reactions of organome-
396 © WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 1436-9966/99/3410X-396 $ 17.50 + .50/0
J. Prakt. Chem. 2000, 342, No. 4

Chemoselective 1,4 Addition Reactions to Alkylidene Malonic Acid Diethyl Ester
___________________________________________________________________________ FULL PAPER
Table 1 Reaction of organometallic reagents with alkylidene malonic esters 1 and 2
Entry Educt
R' – M
Conversion
(%)
Ratio a)
Remark
3 :
4
1
2
3
4
5
6
7
1
1
1
1
2
2
2
Me2AlCl
MeAlCl2
EtAlCl2
BuLi
Et2AlCl
EtAlCl2
MeAlCl2
100
82
100
100
100
75
100 :
100 :
98 :
88 : 12
33 : 67
79 : 21
0
0
2
[2]
–
–
and 3 polar products
[2]
–
–
45
100 :
0
a) Determined from crude product by GC
num chlorides (entry 2 versus 3, entry 6 versus 7); this
is in agreement with the markedly different reactivity
of diethyl- and dimethylaluminum chloride towards α,β-
unsaturated N-acyl oxazolidinones [5–7]); c) the slow-
er reaction of ethylaluminum dichloride to isobutyli-
denemalonic ester 2 more selectively yields the 1,4 ad-
duct compared to the reaction of diethylaluminum chlo-
ride which preferentially forms the hydride transfer
product (entry 6 versus 5); butyllithium reacts with the
acceptor to give polar products of 1,2 addition [8] be-
sides the conjugate adducts.
The hydride transfer product 4a was the major com-
ponent as was also observed in the reaction of 1 with
diethylaluminum chloride (Table 1). Ethyl and n-butyl
were transferred in almost equal extension as can be
expected for a mixed dialkylaluminum chloride 5.
In particular, polar components from 1,2 addition of
butyllithium (see, Table 1) have not been detectable. It
can be concluded from these results, that the reacting
species are not the single components ethylaluminum
dichloride and butyllithium, but the mixed butylethyl-
aluminum chloride 5.
As a first example of a mixed dialkylaluminum chlo-
ride we synthesized n-butyl-ethylaluminum chloride (5)
from ethylaluminum dichloride (1M in n-hexane) and
n-butyllithium (1.6M in n-hexane) in toluene at – 40 °C.
Immediate precipitation of lithium chloride indicates the
formation of the mixed dialkylaluminum chloride 5.
After addition of ethylidene malonic ester 1 and 18 h at
–40 °C, gaschromatographical analysis of the crude
product showed the formation of three compounds
(Scheme 2).
The lower reactivity of methylaluminum reagents in
conjugate addition reactions [1, 5–7] (see also Table 1)
suggests that methyl containing mixed organoaluminum
reagent should be more suitable than 5 for the 1,4-addi-
ton of higher alkyl, aryl and other groups to Michael
acceptors. In this sense, n-butylmethylaluminum chlo-
ride 6a was synthesized from n-butyllithium and me-
thylaluminum dichloride and, subsequently, reacted with
ethylidenemalonic ester 1 (Scheme 3, entry 1 in Table
2).
n-BuLi
n-BuLi +
EtAlCl
2
2
CH 3
COOEt
COOEt
n-BuÐM
H3C
CH3
H3C
COOEt
COOEt
n-Bu–M
l
BuEtAlC
5 5
ttoolluueennee,,18 h18 h
toluene/hexane 10 : 1,
o
-40 C / 18 h
–40 °C/18 h
1
1
CH
H C
3
COOEt
COOEt
CH
H C
3
COOEt
3
3
3
3
CH
COOEt
COOEt
CH
COOEt
COOEt
H3C
H3C
Me
Bu
COOEt
+
3c
3a
Bu
Et
CH
COOEt
H C
3c
3
+
3b
COOEt
3
CH3
H3C
4a
H
COOEt
H
COOEt
= 14 : 15 : 71
4a
Scheme 3 1,4-Addition of n-butyl-methylaluminum reagents
to ethylidene malonic ester 1
:
:
3c 3b 4a
In this reaction, the products of butyl transfer and
methyl transfer (3a) were formed in a ratio of >3:1 (ac-
Scheme 2 Reaction of in situ-generated n-butyl-ethylalumi-
num chloride malonates
J. Prakt. Chem. 2000, 342, No. 4
397

St. Maas, H. Kunz
FULL PAPER __________________________________________________________________________
cording to GC analysis). The reduced acceptor 4a was
obtained in amounts equal to those of the butyl substi-
tuted compound 3c. In order to enhance the selectivity,
the reaction was carried out at –78 °C. At this tempera-
ture the ratio of butyl to methyltransfer increased to 8:1.
However, the hydride transfer to give 4a was not influ-
enced (Table 2).
borontrifluoride prior to the 1,4 addition reaction [2].
Under these conditions the (1-methyl-pentyl)malonic
acid ester 3c was obtained with excellent selectivity and
isolated in a yield of 74%. The products of methyl trans-
fer 3a and of hydride transfer 4a were formed in only
small amounts and could be separated from3c by flash-
chromatography.
This efficient method was adopted for the 1,4 addi-
tion of other groups from mixed organomethylalumi-
num chlorides not only to 1, but also to the isobutyli-
denemalonic ester 2 as an example of a sterically de-
manding Michael acceptor (Scheme 4).
Table 2 Conjugate addition of mixed n-butyl-methylalumi-
num reagents to ethylidene malonic ester 1
Entry Bu-M
Temp (°C)
Ratio of Products a)
3c : 3a : 4a
1
2
3
4
BuMeAlCl 6a
–40 °C
–78 °C
–40 °C
– 40 °C
42 : 13 : 45
47 : 6 : 47
57 : 14 : 30
87 b) : 7 : 6
BuMeAlCl 6a
Li+BuMe3Al 7
BuMeAlCl·BF3
R
COOEt
COOEt
R'MeAlCl ( á BF
)
3
R'MeAlCl (· BF3)
totolulueennee,,–4Ð04°0C¡C, ,202h0 h
a) Determined from crude product by GC; b) yield: 74%
1
The reactivity of the mixed organoaluminum reagents
can be modified either by enhancing their nucleophilic-
ity or by combination with a Lewis acid [2]. Alanate
complexes should exhibit enhanced nucleophilicity.
Lithium n-butyltrimethylalanate 7a reacted with accep-
tor 1 to form an increased amount of the 1,4-butyl addi-
tion product 3c, although the butyl moiety is competing
with three methyl groups in this reagent. The hydride
transfer was slightly reduced. However, a selective and
efficient 1,4 addition of the butyl group to the alkyli-
denemalonic ester was achieved when n-butylmethyl-
aluminum chloride 6 was mixed with one equivalent of
R
COOEt
COOEt
R
COOEt
COOEt
R'
Me
8 R = Me
8 R = Me
9 R = iProp
9 R = iProp
3a or 3e
+
R
COOEt
4
H
COOEt
Scheme 4 1,4-Addition of mixed organomethylaluminum
chlorides to alkylidene malonates
Table 3 1,4-Addition of mixed organomethylaluminum chlorides to ethylidende- (1) and isobutylidene malonic ester 2 accord-
ing to Scheme 4
Product
Reagent
Ratio of Products a)
Yield (%)
8 or 9 : 3 : 4
[conversion (5)]
COOEt
tBuMeAlCl·BF3
92 : 2 : 6
66
COOEt
8a
COOEt
COOEt
MePheAlCl
95 : 5 : 0
100 : 0 : 0
100 : 0 : 0
71
8b
COOEt
COOEt
MeVinylAlCl
HexinylMeAlCl
35 (66)
71
COOEt
8c
COOEt
COOEt
Bu
8d
9a
COOEt
COOEt
BuMeAlCl·BF3
tBuMeAlCl·BF3
HexinylMeAlCl
65 : 5 : 32
89 : 8 : 3
100 : 0 : 0
34 (84)
77 (92)
99
COOEt
COOEt
9b
COOEt
COOEt
Bu
9c
a) Determined from crude product by GC
398
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Chemoselective 1,4 Addition Reactions to Alkylidene Malonic Acid Diethyl Ester
___________________________________________________________________________ FULL PAPER
The reactions were performed in toluene at – 40 °C
within a reaction time of 18 h. In cases of competing
hydride transfer, the mixed organoaluminum chloride
was first treated with borontrifluoride prior to the addi-
tion reaction (Table 3). The results quoted in Table 3
give evidence that the 1,4 addition of mixed organome-
thylaluminum chlorides is of general use for the syn-
thesis of β-branched carboxylic acid derivatives. While
the reaction of n-butylmethylaluminum chloride 6a
(Scheme 3, Table 2) can be considered a typical exam-
ple for the transfer of n-alkyl groups, the highly selec-
tive formation of 8a from ethylidenemalonic ester 1 and
tert-butylmethylaluminum chloride 6b/borontrifluoride
illustrates that sterically demanding branched groups can
be added to the acceptor by this methodology.
During this reaction, a quaternary carbon is formed.
The product 4a of the hydride transfer was found in
only small amounts. Transfer of a β-hydrogen is not
expected in the 1,4 addition of methylphenylaluminum
chloride 6c to 1. Therefore, precomplexation with bo-
ron trifluoride was not necessary. A highly selective
transfer of the phenyl group was achieved to give ad-
duct 8b in high yield. The mixed methylvinylaluminum
chloride 6d synthesized from vinylmagnesium bromide
and methylaluminum dichloride proved less reactive
than 6a and 6b. Its reaction with 1 remained incom-
plete within the time of 18 h. However, the product 8c
of the 1,4-vinyl addition was obtained with complete
selectivity. In contrast, 1-hexinylmethylaluminum chlo-
ride 6e generated from 1-hexinyllithium and methyl-
aluminum dichloride exhibits high reactivity and un-
derwent completely selective 1,4 addition of the hexi-
nyl group to 1 to furnish product 8d.
It is expected and was shown for the 1,4 addition of
diethylaluminum chloride [2] that extensive β-hydride
transfer occurs with sterically hindered Michael accep-
tors. In order to estimate the limitations of the 1,4-addi-
tion of mixed organoaluminum chlorides to Michael
acceptors, isobutylidenemalonic ester 2 was applied as
the substrate. Selective 1,4-addition of the n-butyl group
from butylmethylaluminum chloride 6a to give the bran-
ched compound 9a was accompanied by hydride trans-
fer to form 4b even in the presence of boron trifluoride.
Surprisingly, the conjugate addition of the tert-butyl
group from tert-butylmethylaluminum chloride 6b/bo-
rontrifluoride proceeded with high selectivity, and the
multiply branched product 9b was isolated in high yield.
Once again, complete selectivity was achieved in the
1,4 addition of the rod-like 1-hexinyl group from the
reactive 1-hexinylmethylaluminum chloride 6e. The
branched carboxylic acid derivative 9c was isolated in
almost quantitative yield.
minum chloride to acceptor 1 (Table 3), the reactivity
of the mixed alkenylaluminum chlorides is lower than
that of the other reagents 6. This resulted in incomplete
conversions, e.g. in the formation of 8c. Therefore, the
use of alternative mixed alkenyl organoaluminum rea-
gents in conjugate addition reactions to Michael accep-
tors was investigated. Organoaluminum hydrides read-
ily undergo hydroalumination reactions [9–11]. There
are no experiences reported on the conjugate addition
of trialkylaluminum reagents to alkylidenemalonic de-
rivatives. In addition, hydroaluminations of alkines of-
ten are accompanied by undesired side-reactions e.g.
hydroalumination of the product or formation of the alki-
nylaluminum compound from terminal alkines, if reac-
tion temperature and ratio of components are not opti-
mized. In order to prevent such side reactions, the bulky
diisobutylaluminumhydride was used for addition re-
actions to 1-hexine, 1-octine and 3-hexine in n-heptan/
toluene at 45–50 °C to form the alkenyl diisobutylalu-
minum reagents 10 (Scheme 5). Hydroaluminations pro-
ceed with cis-stereoselectivity, to give Z-configured al-
kenylalanes (this was confirmed for the terminal alke-
nyl diisobutylalanes 10a and 10b by the coupling con-
stants J = 15.1 Hz for the olefinic protons in the NMR
spectra). To the solution of the mixed organoaluminum
compounds 10 at –40 °C the alkylidenemalonic esters
1 or 2, respectively, was added.
iBu AlH
iBu22AlH
+
R3
R2
n-heptane/
n-heptane/
toluene 45–50 °C
10a R2 = Bu, R 3 = H
toluene 45 - 50¡C
AliBu
2
AliBu2
10a R2 = Bu, R 3 = H
10a R2 = Bu, R3 = H
R1
COOEt
10b R2 = Hex, R3 = H
R3
10a R2 = Bu, R 3 = H
R2
10c R2 = R3 = Et
–40 °C/18 h
o
-40 C / 18 h
COOEt
1 or 2
R2
= H
= H
R1
COOEt
COOEt
R2
R3
11 and by-products
Scheme 5 1,4-Addition of mixed alkenyl diisobutylalanes
to alkylidene malonates
The conjugate addition reactions of the mixed 1-alke-
nyl organoalanes proceeded with high selectivity and
gave the branched alkenylmalonic esters 11a –c in high
yield (Table 4).
1,4 -Addition Reactions of Mixed Alkenyl Diisobutyl-
alanes
Only small amounts of the β-alkinyl substituted de-
rivatives 8d, 8e, 9c formed from the corresponding alki-
As already outlined for the addition of methylvinylalu-
J. Prakt. Chem. 2000, 342, No. 4
399

St. Maas, H. Kunz
FULL PAPER __________________________________________________________________________
Table 4 1,4-Additon of mixed alkenyl diisobutylalanes 10 to alkylidene malonic esters 1/2 to give substituted C-allylmalonic
esters 11 (Scheme 5)
Product
R1
R2
R3
Ratio a) of
11 : (by-product)
Yield of 11 (%)
11a
11b
11c
11d
11e
CH3
CH(CH3)2
CH3
CH3
CH(CH3)2
n-C4H9
n-C4H9
n-C6H13
C2H5
H
H
H
C2H5
C2H5
97 : 3 (8d)
97 : 3 (9c)
93 : 7 (8e) b)
79 : 21 (4a)
80 : 20 (4b)
84
74
82
43
47
C2H5
a) Determined by gas chromatography from crude product;
COOEt
b) 8e:
COOEt
tained for most of the new compounds and those incomplete-
ly characterized in the literature.
nyl diisobutylalane as the by-product of the hydroalu-
mination were detectable and could easily be removed
by flash-chromatography.
Methodical Investigations
The 1,4 addition of 3-hexenyl diisobutylalane 10c to
the acceptors 1/2 was accompanied by β-hydride trans-
fer to give reduced acceptors 4. Nevertheless, the 1,4
adducts 11d and 11e were the mayor product (ratio 4:1)
and could be isolated in pure form and acceptable yield.
The results show that mixed alkenyl diisobutylalanes
are alternative reagents to the alkenyl methylaluminum
chlorides. Their complementary use with the mixed
alkylmethylaluminum chlorides, arylmethylaluminum
chlorides and alkinyl methylaluminum chlorides in 1,4-
additon reactions to alkylidene malonic esters constitu-
ents a general efficient method for the synthesis of β-
branched carboxylic acid derivatives of diverse struc-
ture.
For reactions of diethyl alkylidene malonates 1 and 2 with
dimethyl- and diethylaluminum chlorides, see ref [2].
Reaction of Methyl- and Ethylaluminum Dichloride with
Alkylidenemalonic Esters 1 and 2 (General Procedure)
A solution of methylaluminum dichloride or ethylaluminum
dichloride (3 mmol, 3 ml of 1M solution in n-hexane) in dry
toluene (50 ml) under argon atmosphere was stirred at
–40 °C, and the diethyl alkylidenemalonate 1 or 2 (1.2 mmol)
was added. The mixture was stirred at –40 °C for 20 h and
then poured into sat. aqueous ammonium chloride solution
(100 ml). The aqueous layer was extracted three times with
dichloromethane (30 ml). The combined organic layers were
washed with sat. ammonium chloride solution and dried with
magnesium sulfate. After evaporation of the solvent in va-
cuo, the remaining crude products were analyzed by gaschro-
matography. Diethyl ethylmalonate 4a and diethyl isobutyl-
malonate 4b were identified by comparison with authentic
material synthesized according to ref. [12]. The products of
conjugate addition 3a, 3b, 3d and 3e were identified by com-
parison with authentic substances described in ref. [2] (see,
Table 1).
This work was supported by the Deutsche Forschungsgemein-
schaft and by the Fonds der Chemischen Industrie.
Experimental
Toluene and heptane were dried before use by distillation from
potassium benzophenone ketyl. Alkylidenemalonic diethyl
esters 1 and 2 were synthesized according to published pro-
cedures [12]. Dimethyl- and diethylaluminum chloride as well
as methyl- and ethylaluminum dichlorides and diisobutylalu-
minumhydride (1.5M, toluene) were purchased from Aldrich
and used as 1M solutions in n-hexane. Petroleum ether refers
to b.p. 40–70 °C. Flash-chromatography was carried out us-
ing silica gel 60 (Merck, Darmstadt, Germany), 0.04 –
0.063 nm. TLC was performed on silica gel (Kieselgel
60 F254, Merck, Darmstadt, Germany). Gaschromatography
was carried out with a fused silica-column (PERMABOND
SE-30-DF-0.25, 25m × 0.32 mm ID, Machery & Nagel,
Diethyl Isopropylmalonate (3a) [2, 5]
GC analysis: 80 °C (5 min) → 150 °C (5 °C/min): Rt =
6.73 min.
Diethyl (1-Methylpropyl)malonate (3b) [2, 13]
GC analysis: 80 °C (5 min) → 150 °C (5 °C/min): Rt =
5.08 min (4a); 9.58 min (3b).
Diethyl (1,2-Dimethyl-propyl)malonate (3e) [2, 5]
GC analysis: 100 °C (5 min) → 200 °C (5 °C/min): Rt =
7.27 min.
Diethyl (1-Ethyl-2-methyl-propyl)malonate (3d) [2, 14]
1
Düren, Germany). H and 13C NMR-spectra were recorded
GC analysis: 100 °C (5 min) → 200 °C (5 °C/min): Rt =
5.05 min (4b); 9.23 min (3d). The reaction of diethyl ethyli-
denemalonate 1 (1.2 mmol) with n-butyllithium (3.0 mmol,
1.9 ml 1.6M in n-hexane) in toluene (50 ml) under conditions
on a Bruker AC 200 or on a Bruker AM 400 NMR spectro-
meter. All NMR spectra have been recorded in CDCl3 using
TMS as the standard. Satisfactory microanalyses were ob-
400
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Chemoselective 1,4 Addition Reactions to Alkylidene Malonic Acid Diethyl Ester
___________________________________________________________________________ FULL PAPER
as described in the general procedure for the reactions of the
alkylaluminum dichloride gave a crude product that consist-
ed of 5 components of which 2 could be determined by gas
chromatography: 80 °C (5 min) → 150 °C (5 °C/min): Rt =
5.09 min (4a); 14.37 (3c, vide infra).
c) analogous to b), however, reaction temperature –78 °C,
reaction time 3 h: conversion 30%. Ratio of products see Ta-
ble 2.
d) By method B from trimethylaluminum (1.5 ml, 2M in n-
hexane, 3.0 mmol), n-butyllithium (1.9 ml, 1.6M in n-hexane,
3.0 mmol) and 222 mg (1.19 mmol) of diethyl ethylidene-
malonate 1. Yield 288 mg (crude product mixture), yellowish
oil; GC analysis: Rt = 5.17 min (4a), 6.63 min (3a) and
14.42 min (3c). 4a:3a:3c = 30:14:56.
e) Preparative synthesis by method A from methylaluminum
dichloride (9.0 ml, 1M in n-hexane, 9.0 mmol), n-butyllithi-
um (5.7 ml, 1.6M in n-hexane, 9.1 mmol) and borontrifluo-
ride etherate (1.2 ml, 9.76 mmol) and then diethyl ethylide-
nemalonate (666 mg, 3.58 mmol). Yield 649 mg (74% pure,
colourless oil, Rt = 0.75 (petroleum ether/ethyl acetate 10:1).
(GC analysis: Rt = 5.07 min (4a), 6.58 min (3a), and
14.37 min (3c). 4a:3a:3c = 6:7:87)). – 1H NMR (200 MHz,
CDCl3): d/ppm = 4.11 (q, 4H, J = 7.0 Hz, CH2O), 3.14 [d,
1H, J = 8.3 Hz, CH(COOEt)2], 0.90 (d, 3H, J = 6.8 Hz, CH–
CH3), 0.80 (t, 3H, J = 5.6 Hz, (CH2)3CH3). – 13C NMR (50.3
MHz, CDCl3): δ/ppm = 168.95, 168.77 (C=O), 61.00, 60.95
(CH2O).
Mixed Organoaluminum Compounds (General Proce-
dures)
Method A: Mixed dialkylaluminum chlorides 5 and 6: In a
dry two-neck flask under argon atmosphere dry toluene (50
ml) was cooled to –40 °C. Methyl- or ethylaluminum dichlo-
ride (vide infra, 1M solution in n-hexane) and the organolith-
ium- or organomagnesium compound (vide infra) were add-
ed using a syringe through a septum. The mixture is stirred
for 1 h. In the indicated cases (vide infra) 1 equivalent of
boron trifluoride etherate is added and the mixture stirred for
an additional hour.
Method B: Ate complex 7 To a solution of trimethylalumi-
num (2M in n-hexane) in dry toluene (50 ml) under argon
atmosphere at –40 °C an equimolar amount of a solution of
the organolithium compound (or Grignard compound) in an
appropriate inert solvent was added. The solution was stirred
at –40 °C for 1 hour prior to its use in the 1,4 addition reac-
tion.
C13H24O4
(224.3)
Calcd.: C 63.91 H 9.90
Found: C 63.81 H 9.87.
Diethyl (1,2,2-Trimethylpropyl)malonate (8a) [2]
1,4 Addition Reaction of Mixed Organoaluminum Com-
pounds with Diethyl Alkylidenemalonates 1/2 (General
Procedure)
This compound was synthesized according to method A from
methylaluminum dichloride (3.0 ml, 1M in hexane, 3.0 mmol),
tert-butyllitium (2.0 ml, 1.5M in n-pentane, 3.0 mmol), bo-
rontrifluoride etherate (0.36 ml, 2.9 mmol) and diethyl ethyl-
idenemalonate 1 (222 mg, 1.19 mmol). GC analysis: 80 °C
(5 min) → 150 °C (5 °C/min): Rt = 4.98 min (4a), 6.48 min
(3a), and 13.12 min (8a). Ratio 4a:3a:8a = 6:2:92. Yield
193 mg (66%), pure, colourless oil, Rf = 0.58 (petroleum ether/
ethyl acetate 5:1). The product is identical with the one de-
scribed in ref. [2].
To the in situ generated solution of the mixed organoalumi-
num compound 5, 6 or 7, respectively, in toluene under argon
atmosphere at –40 °C, the diethyl alkylidenemalonate was
added. After stirring at –40 °C for 18–20 h, the mixture was
poured into sat. aqueous ammonium chloride solution. The
aqueous solution was extracted three times with dichlorometh-
ane (30 ml). The combined organic layers were washed with
sat. aqueous ammonium chloride solution, dried with mag-
nesium sulfate, and the solvent was evaporated. The remain-
ing crude product was analyzed by gas chromatography and
the components identified by comparison with authentic sam-
ples [2]. Products of the most efficient method were purified
by flash-chromatography in petroleum ether/ethyl acetate
(25:1) and characterized (see also Tables 2 and 3).
Diethyl (1-Phenylethyl)malonate (8b) [2]
The compound was obtained by method A from methylalu-
minum dichloride (3 ml, 1M in hexane, 3.0 mmol), phenyl-
lithium (1.9 ml, 1.6M in cyclohexane, 3.0 mmol) and diethyl
ethylidenemalonate 1 (222 mg, 1.19 mmol). GC analysis of
the crude product: 80 °C (5 min) → 150 °C (5 °C/min): Rt =
6.58 min (3a) and 19.28 min (8b). Ratio 3a:8b = 5:95. Yield
222 mg (71%, pure), colourless oil, Rf = 0.45 (petroleum ether/
ethyl acetate 5:1). The product is identical with the compound
described in ref. [2].
Diethyl (1-Methyl-pentyl)malonate (3c)
a) The product was formed in a mixture with the hydride trans-
fer product 4a (vide supra) and the 1,4 ethyl adduct 3b ac-
cording to method A from ethylaluminum dichloride (3 ml,
1M in n-hexane, 3.0 mmol), n-butyllithium (1.9 ml, 1.6M in
n-hexane, 3.0 mmol) and diethyl ethylidenemalonate 1
(222 mg, 1.19 mmol). Yield 246 mg (crude product mixture),
yellowish oil; GC analysis: 80 °C (5 min) → 150 °C (5 °C/
min): Rt = 5.21 min (4a); 9.46 min (3b) and 14.31 min (3c);
4a:3b:3c = 71:15:14.
b) By method A from methylaluminum dichloride (3 ml, 1M
in n-hexane, 3.0 mmol), n-butyllithium (1.9 ml, 1.6M in n-
hexane, 3.0 mmol) and diethyl ethylidenemalonate 1 (222 mg,
1.19 mmol). Yield 294 mg (crude product mixture), yello-
wish oil; GC analysis: 80 °C (5 min) → 150 °C (5 °C/min):
Rt = 5.19 min (4a), 6.64 min (3a) and 14.39 min (3c). 4a:3a:3c
= 45:13:42.
Diethyl (1-Methylallyl)malonate (8c)
According to method A, the mixed methylvinylaluminum
chloride was formed from methylaluminum dichloride (6 ml,
1M in n-hexane, 6 mmol) and vinylmagnesium bromide
(6 ml, 1M in tetrahydrofuran, 6 mmol) and reacted with di-
ethyl ethylidenemalonate 1 (444 mg, 2.4 mmol). GC analysis
of the crude product (conversion 69%): 80 °C (5 min) M
150 °C (5 °C/min): Rt = 8.65 min (8c), see Table 3. Yield
178 mg (35%), colourless oil, Rf = 0.65 (petroleum ether/
1
ethyl acetate 5:1). – H NMR (200 MHz, CDCl3): δ/ppm =
5.47 (ddd, 1H, Jtrans = 17.6 Hz, Jcis = 10.0 Hz, Jvic = 7.8 Hz,
-CH=), 5.01 (m, 2H, CH2=), 4.15 (q, 2H, J = 7.0 Hz, CH2O),
4.11 (q, 2H, J = 7.2 Hz, CH2O), 3.22 [d, 1H, J = 9.3 Hz,
J. Prakt. Chem. 2000, 342, No. 4
401

St. Maas, H. Kunz
FULL PAPER __________________________________________________________________________
CH(COOEt)2]. – 13C NMR (50.3 MHz, CDCl3): δ/ppm =
139.83 (-CH=), 115.33 (CH2=), 61.24, 61.16 (CH2O), 57.71
[CH(COOEt)2].
(2.4 ml, 1M in n-hexane, 2.4 mol), 1-hexynyllithium (2.4 mmol
in toluene/n-hexane, see 8d) and diethyl isobutylidene-
malonate (204 mg, 0.95 mmol). – GC analysis: 100 °C
(5 min) → 200 °C (5→°C/min): Rt = 17.06 min (9c). Yield
278 mg (99%), colourless oil, Rf = 0.43 (petroleum ether/
ethyl acetate 10:1). – 1H NMR (200 MHz, CDCl3): δ/ppm =
4.16, 4.14 (2 q, 2×2H, J = 7.2 HZ, CH2O), 3.07 (ddd, 1H, J =
10.9 Hz, J = 5.7 Hz, 5J = 2.3 Hz, CHiPr), 2.09 (dt, 2H, J =
6.7 Hz, 5J = 2.3 Hz, CH2C≡), 1.68 (d sept, 1H, J = 6.7 Hz, J =
3.6 Hz, CHMe2). – 13C NMR (50.3 MHz, CDCl3): δ/ppm =
167.88, 167. 72 (C=O), 84.54, 76.61 (C≡C), 38.78 (CHiPr),
28.86 (CHMe2).
C11H18O4
(214.3)
Calcd.: C 61.66 H 8.47
Found: C 61.68 H 8.40.
Diethyl (1-Methyl-hept-2-ynyl)malonate (8d)
Obtained by method A from methylaluminum dichloride
(3 ml, 1M in n-hexane, 3.0 mmol), 1-hexynyllithium
(3.0 mmol, from 1-hexyne in toluene and 1.05 equiv. n-butyl-
lithium) and diethyl ethylidenemalonate 1. GC analysis of
the crude product: 80 °C (5 min) → 150 °C (5 °C/min): Rt =
18.80 min (8d). Yield 200 mg (71%), colourless oil, Rf = 0.52
C17H28O4
(296.4)
Calcd.: C 68.89 H 9.52
Found: C 69.14 H 9.54.
1
(petroleum ether/ethyl acetate 10:1). – H NMR (200 MHz,
CDCl3): δ/ppm = 4.16, 4.15 2(q, 2H, J = 7.2 Hz, CH2O), 3.29
[d, 1H, J = 9.3 Hz, CH(COOEt)2], 3.14 (m, 1H, CHMe), 2.07
Generation and 1,4-Addition Reactions of Alkenyl Di-
isobutylalanes (10)
5
(dt, J = 6.6 Hz J = 2.0 Hz, CH2–C≡C). – 13C NMR (50.3
MHz, CDCl3): δ/ppm = 167.76, 167.62 (C=O), 82.32, 80.56
(C≡C), 58.17 [CH(COOEt)2], 30.92 (CH2), 26.40 (CHMe),
21.76 (CH2). No correct elemental analysis was obtained,
because a by-product <5% formed during work up could not
be separated.
n-Heptane (10 ml) was distilled from potassium/benzophe-
none under argon atmosphere into a Schlenk tube. Through a
septum, the alkyne (3 equivalents related on the alkylidene
malonate to be reacted) and diisobutylaluminumhydride (also
3 equivalents, 1.5M in toluene) were added. In the case of
terminale alkynes, the mixture was heated to 40–45 °C for
2 h. For reaction of 3-hexyne with diisobutylaluminumhy-
dride, the mixture was heated to 50 °C for 3 h. Then, the
solution was cooled to –40 °C and the diethyl alkylidene-
malonate (1 equivalent) was added. The reactions were con-
ducted and work up was carried as described for the addition
reactions with mixed dialkylaluminum chlorides (vide supra).
Diethyl (1-Isopropyl-pentyl)malonate (9a)
Obtained by method A from methylaluminum dichloride
(2.4 ml, 1M in n-hexane, 2.4 mmol), n-butyllithium (1.5 ml,
1.6M in n-hexane, 2.4 mmol), borontrifluoride etherate
(0.3 ml, 2.44 mmol) and diethyl isobutylidenemalonate 2
(204 mg, 0.95 mmol). – GC analysis of the crude product
mixture (conversion 84%): 100 °C (5 min) → 200 °C (5 °C/
min): Rt = 5.04 min (4b), 7.16 min (3e, Scheme 1), 13.18 min
(9a); ratio 4b:3e:9a = 32:5:63. Yield 87 mg (34%, still con-
tains <3% of 4b), colourless oil, Rf = 0.46 (petroleum ether/
ethyl acetate). – 1H NMR (200 MHz, CDCl3): δ/ppm = 4.14
(q, 4H, J = 7.0 Hz, CH2O), 3.37 [d, 1H, J = 7.8 Hz,
CH(COOEt)2], 1.76 (d sept., 1H, J = 6.8 Hz, J = 2.4 Hz,
CHMe2), 0.90–0.81 (m, 9H, 3CH3-). – 13C NMR (50.3 MHz,
CDCl3): δ/ppm = 169.59, 169.42 (C=O), 44.10 (CHBu), 31.35
(CH2), 29.74 (CHMe2), 20.34, 18.50 [(CH3)2CH].
Diethyl (E-1-Methyl-hept-2-enyl)malonate (11a)
Obtained from 1-hexyne (0.6 ml, 5.33 mmol), diisobutylalu-
minumhydride (3.6 ml, 5.4 mmol) and diethyl ethylidene-
malonate 1 (333 mg, 1.8 mmol). – GC analysis of the crude
product: 80 °C (5 min) → 150 °C (5 °C/min): Rt = 18.28 min
(11a), 18.55 min (8d). Yield 407 mg (84%, pure), colourless
oil, Rf = 0.65 (petroleum ether/ethyl acetate 5:1). – 1H NMR
(200 MHz, CDCl3): δ/ppm = 5.46 (dt, 1H, Jtrans = 15.1 Hz,
J = 6.4 Hz, CH2–CH=CH), 5.28 (dd, 1H, Jtrans = 15.4 Hz, J =
8.1 Hz, CH·CH=CH). – 13C NMR (50.3 MHz, CDCl3):
δ/ppm = 131.70, 131.24 (HC=CH), 58.30 [CH(COOEt)2].
Diethyl (1-Isopropyl-2,2-dimethyl-propyl)malonate (9b)
This compound was synthesized by method A from methyl-
aluminum dichloride (2.4 ml, 1M in n-hexane, 2.4 mmol),
tert-butyllithium (1.6 ml, 1.5M in n-pentane, 2.4 mmol), bo-
rontrifluoride (0.3 ml, 2.44 mmol) and diethyl isobutylidene-
malonate 2 (204 mg, 0.95 mmol). – GC analysis of the crude
product (conversion 92%): 100 °C (5 min) → 200 °C (5 °C/
min): Rt = 4.95 min (4b), 7.10 min (3e); 12.28 min (9b). Yield
199 mg (77%), colourless oil, Rf = 0.50 (petroleum ether/
ethyl acetate 10:1). – 1H NMR (200 MHz, CDCl3): δ/ppm =
4.13, 4.12 (2 q, 2×2H, J = 7.0 Hz, J = 7.2 Hz, CH2O), 2.14
(dd, 1H, J = 5.4 Hz, J = 2.0 Hz, CHtBu), 2.08 (d sept., 1H,
J = 7.1 Hz, J = 1.6 Hz, CHMe2), 0.95 (s, 9H, C(CH3)3). –
13C NMR (50.3 MHz, CDCl3): δ/ppm = 170.55 (C=O), 61.24,
61.13 (CH2O), 35.50 (CMe3), 29.07 [C(CH3)3], 28.32
(CHMe2).
C15H26O4
(270.4)
Calcd.: C 66.64 H 9.69
Found: C 66.42 H 9.64.
Diethyl (E-1-Isopropyl-hept-2-enyl)malonate (11b)
Obtained from 1-hexyne (0.48 ml, 4.27 mmol), diisobutyl-
aluminumhydride (2.9 ml, 4.35 mmol) and diethyl isobutyli-
denemalonate 2 (306 mg, 1.43 mmol). – GC analysis of the
crude product: 100 °C (5 min) → 200 °C (5 °C/min): Rt =
16.64 min (11b), 16.78 (9c). Yield 352 mg (82%), colourless
oil, Rf = 0.77 (petroleum ether/ethyl acetate 5:1). – 1H NMR
(200 MHz, CDCl3): δ/ppm = 5.43 (dt, 1H, Jtrans = 15.1 Hz,
J = 6.6 Hz, CH2CH=CH), 5.22 (dd, 1H, J = 15.4 Hz, J =
9.5 Hz, CHCH=CH), 1.67 (d sept., 1H, J = 6.8 Hz, J =
4.9 Hz, CHMe2). – 13C NMR (50.3 MHz, CDCl3): δ/ppm =
135.02, 125.80 (CH=CH), 49.18 (CHiPr), 29.16 (CHMe2).
C15H28O4
(272.4)
Calcd.: C 66.14 H 10.36
Found: C 66.16 H 10.34.
C17H30O4
(298.4)
Calcd.: C 68.42 H 10.13
Found: C 68.51 H 10.27.
Diethyl (1-Isopropyl-hept-2-ynyl)malonate (9c)
Diethyl (E-1-Methyl-non-2-enyl)malonate (11c)
Obtained by method A from methylaluminum dichloride
Obtained from 1-octyne (0.89 ml, 5.42 mmol), diisobutylalu-
402
J. Prakt. Chem. 2000, 342, No. 4

Chemoselective 1,4 Addition Reactions to Alkylidene Malonic Acid Diethyl Ester
___________________________________________________________________________ FULL PAPER
minumhydride (3.6 ml, 5.4 mmol) and diethyl ethylidene-
malonate 1. – GC analysis of the crude product: 80 °C
(5 min) → 150 °C (5 °C/min): Rt = 22.61 min (11c), 22.69
min (8c, Table 4). Yield 396 mg (74%, pure), colourless oil,
J = 7.3 Hz, CH2CH=C), 2.74 (dd, 1H, J = 11.2 Hz, J =
4.9 Hz, CHiPr), 2.45–1.67 (m, 5H, CH2CH=CCH2, CHMe2).
– 13C NMR (50.3 MHz, CDCl3): δ/ppm = 138.02 (C=), 129.95
(CH=), 50.29 (CHiPr), 29.99 (CHMe2). The product contained
>5% of 4b. ESI-MS: m/z = 321.4 (M+Na).
1
Rf = 0.68 (petroleum ether/ethyl acetate 5:1). – H NMR
(200 MHz, CDCl3): δ/ppm = 5.45 (dt, 1H, Jtrans = 15.3 Hz,
J = 6.5 Hz, CH2CH=CH), 5.27 (dd, 1H, Jtrans = 15.1 Hz, J =
7.8 Hz, CHCH=CH), 1.91–1.79 (m, 2H, CH2CH=C), 1.01
(d, 3H, J = 6.8 Hz, CH3–CH-). – 13C NMR (50.3 MHz,
CDCl3): δ/ppm = 131.74, 131.23 (CH=CH), 37.32 (CHMe2).
References
[1] P. A. Chaloner, in: The Chemistry of the Metal Carbon Bond
(R. F. Holey, Ed.), Vol. 4, J. Wiley, New York 1987, p. 411
[2] S. Maas, A. Stamm, H. Kunz, Synthesis 1999, 1792
[3] K. Ziegler, H. G. Gellert, in: Methoden der Organischen
Chemie (Houben-Weyl) Vol. XIII/4, Thieme Verlag, Stutt-
gart 1970, p. 60
[4] T. A. Neely, W. W. Schwarz, H. V. Vaughan jr., Org. Synth.
1965, 45, 107
[5] K. Rück, H. Kunz, Synthesis 1992, 1018
[6] K. Rück, H. Kunz, Angew. Chem. 1991, 103, 712; Angew.
Chem. Int. Ed. Engl. 1991, 30, 694
[7] H. Kunz, K. J. Pees, J. Chem. Soc., Perkin Trans. 1 1989,
1168
[8] G. Cahiez, M. Alami, Tetrahedron 1989, 45, 4163
[9] K. Ziegler, H.-G. Gellert, H. Lehmkuhl, W. Pfohl, K. Zosel,
Liebigs Ann. Chem. 1960, 628, 1
[10] G. Zweifel, J. A. Miller, Org. React. 1984, 32, 1
[11] G. Wilke, H. Müller, Liebigs Ann. Chem. 1960, 629, 222
[12] Organikum, Johann Ambrosius Barth Verlag Leipzig, 20th
Ed., 1996, p 501
C17H30O4
(298.4)
Calcd.: C 68.42 H 10.13
Found: C 68.49 H 10.17.
Diethyl (E-2-Ethyl-1-methyl-pent-2-enyl)malonate (11d)
This compound was synthesized from 3-hexyne (0.61 ml,
5.37 mmol), diisobutylaluminumhydride (3.6 ml, 5.4 mmol)
and diethyl ethylidenemalonate 1 (333 mg, 1.8 mmol). – GC
analysis of the crude product: 80 °C (5 min) → 150 °C (5 °C/
min): Rt = 5.04 min (4a), 17.30 min (11d). Yield 206 mg
(43%), colourless oil, Rf = 0.66 (petroleum ether/ethyl ace-
tate 5:1). – 1H NMR (200 MHz, CDCl3): δ/ppm = 5.12 (t, 1H,
J = 7.1 Hz, CH2CH=C), 2.83 (dq, 1H, J = 10.9 Hz, J = 6.8 Hz,
CHMe), 2.12 – 1.86 (m, 4H, CH2CH=CCH2-). –
13C NMR (50.3 MHz, CDCl3): δ/ppm = 141.62 (C=CH),
127.57 (CH=C), 22.62, 20.83 (CHC=CCH2).
C15H26O4
(270.4)
Calcd.: C 66.64 H 9.69
Found: C 66.64 H 9.56.
Diethyl (E-2-Ethyl-1-isopropyl-pent-2-enyl)malonate (11e)
Address for correspondence:
Prof. Dr. Horst Kunz
Institut für Organische Chemie
Universität Mainz
Duesbergweg 10–14
D-55099 Mainz
The compound was obtained from 3-hexyne (0.49 ml,
4.31 mmol), diisobutylaluminumhydride (2.9 ml, 4.35 mmol)
and diethyl isobutylidenemalonate 2 (306 mg, 1.43 mmol). –
GC analysis of the crude product: 100 °C (5 min) → 200 °C
(5 °C/min): Rt = 4.91 min (4b), 15.92 (11e). Yield 202 mg
(47%), colourless oil, Rf = 0.70 (petroleum ether/ethyl ace-
tate 5:1). – 1H NMR (200 MHz, CDCl3): δ/ppm = 5.03 (t, 1H,
Fax: Internat. code (0)6131-3924786
e-Mail: hokunz@mail.uni-mainz.de
J. Prakt. Chem. 2000, 342, No. 4
403