Stereoselective synthesis of enones from the reaction of aldehydes with sterically hindered dimethylaluminum enolates

Article abstract of DOI:10.1016/j.jorganchem.2005.04.040

The equimolar reaction between Me₃Al and the methyl ketones (2,4,6-R₃-C₆H₂)C(O)CH₃, where R = Me or ⁱPr, results in exclusive formation of the enolization products [{Me₂AlOC(2,4,6-R₃-C₆H₂)CH ₂}₂], 1 and 2, upon heating to reflux temperature in toluene solution. The property of Me₃Al acting as a base rather than a nucleophile in these reactions is due to the sterically hindered nature of the ketones. Crystallographic analysis of 2 revealed a dimeric complex where the metal centers are bridged by the enolate anions, consistent with the previous studies of 1. Addition of a series of aldehydes to hexane solutions of 1 and 2, followed by heating to reflux for several hours gave enone products in generally high conversions. The presumed aluminum aldolate intermediates were not detected by in situ monitoring studies and are presumably short-lived under the reaction conditions. The enone products from the addition reactions were formed predominantly as the E-isomers with good to excellent stereoselectivities.

Full text of DOI:10.1016/j.jorganchem.2005.04.040

Journal of Organometallic Chemistry 690 (2005) 3474–3478
www.elsevier.com/locate/jorganchem
Stereoselective synthesis of enones from the reaction of
aldehydes with sterically hindered dimethylaluminum enolates
*
Zachary S. Sales, Roger Nassar, J. Jacob Morris, Kenneth W. Henderson
Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46656, USA
Received 13 April 2005; revised 27 April 2005; accepted 27 April 2005
Available online 15 June 2005
Abstract
The equimolar reaction between Me3Al and the methyl ketones (2,4,6-R3–C6H2)C(O)CH3, where R = Me or iPr, results in exclu-
sive formation of the enolization products [{Me2AlOC(2,4,6-R3–C6H2)@CH2}2], 1 and 2, upon heating to reflux temperature in tol-
uene solution. The property of Me3Al acting as a base rather than a nucleophile in these reactions is due to the sterically hindered
nature of the ketones. Crystallographic analysis of 2 revealed a dimeric complex where the metal centers are bridged by the enolate
anions, consistent with the previous studies of 1. Addition of a series of aldehydes to hexane solutions of 1 and 2, followed by heat-
ing to reflux for several hours gave enone products in generally high conversions. The presumed aluminum aldolate intermediates
were not detected by in situ monitoring studies and are presumably short-lived under the reaction conditions. The enone products
from the addition reactions were formed predominantly as the E-isomers with good to excellent stereoselectivities.
ꢀ 2005 Elsevier B.V. All rights reserved.
Keywords: Enolates; Aluminum; Enones; Crystal structure
1. Introduction
hours [6,7]. The behavior of Me3Al as a base rather than
a nucleophile to give exclusive enolization was somewhat
unexpected considering the small size of the organic moi-
ety [8,9]. The key to this selectivity was found to be
dependant on the steric encumbrance of the aromatic ke-
tone, where disubstitution at the ortho positions of the
ring by methyl groups was required for enolization to
be the dominant reaction pathway. We now report an
extension to this work, investigating the reaction chemis-
try of two aluminum enolates derived by this direct eno-
lization route with a series of aldehydes. In addition, the
crystal structure of a new dimethylaluminum enolate
intermediate has been elucidated.
The reaction between triorganoaluminum compounds
and ketones commonly results in four outcomes:
acid-base complex formation, reduction via b-hydride elim-
ination, direct alkylation across the carbonyl, and enoli-
zation [1]. The product distribution is influenced by all
the expected factors including the nature of the organic
anions, the size and electronics of the ketone, the temper-
ature of the reaction and the solvent media used [2,3]. In
general, these reactions produce a mixture of products
and hence their utility in synthesis has remained limited
[4,5]. We previously reported that the reaction between
Me3Al and 2,4,6-trimethylacetophenone in toluene un-
der ambient temperature resulted in formation of the
complex [Me3AlÆO@C(2,4,6-Me3–C6H2)Me], which
cleanly converted to the enolate [{Me2AlOC(2,4,6-
Me3–C6H2)@CH2}2], 1 upon heating to reflux for several
2. Results and discussion
2.1. Syntheses and structural characterization
*
The enolate complex [{Me2AlOC(2,4,6-Me3–C6H2)@
CH2}2], 1, was prepared as previously described [6]. For
Corresponding author. Tel.: +574 631 8025; fax: +574 631 6652.
E-mail address: khenders@nd.edu (K.W. Henderson).
0022-328X/$ - see front matter ꢀ 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.04.040

Z.S. Sales et al. / Journal of Organometallic Chemistry 690 (2005) 3474–3478
3475
comparative purposes, the enolate [{Me2AlO-
C(2,4,6-iPr3–C6H2)@CH2}2], 2, was targeted and suc-
cessfully prepared as the sole product from the
equimolar reaction of Me3Al with 2,4,6-triisopropylace-
tophenone in toluene solution after heating to reflux for
3 h (Eq. (1)).
H2C
R
O
O
O
toluene
Me
Me
Me
Al
Al
2Me3Al + 2
+ 2CH4
R
Me
reflux, 3h
Me
R
CH2
i
Me
R =
Me
iPr
Pr
Me
iPr
ð1Þ
Removal of the solvent in vacuo and replacement by
hexane followed by cooling the solution to ꢀ45 ꢁC re-
sulted in the precipitation of high quality crystals of 2.
1
In turn, this allowed the characterization of 2 by H
and 13C NMR spectroscopy, and also by single-crystal
X-ray diffraction. The 1H NMR spectrum of 2 in
C6D6 shows a single set of signals for the aromatic
meta-Hs and also for the methyl groups attached to
the aluminum, consistent with the expected composi-
tion. A pair of doublets due to the olefinic protons are
i
present and two independent sets of Pr groups in a
2:1 ratio arising from the ortho- and para-units, respec-
tively, complete the spectrum. A somewhat different pat-
tern is found in the 13C NMR spectrum of 2. Three
independent methyl resonances at d 23.35, 24.48 and
27.07 are found, along with two methine signals at d
31.23 and 35.15. This pattern suggests that the methyl
carbons of the ortho-isopropyl groups are inequivalent.
Indeed, the recent characterization by Kunicki of the
closely related complex [Ph2AlOC(2,4,6-iPr3–C6H2)@
CH2}2], 3, displays a very similar 13C NMR spectrum
[10]. This pattern of signals can be explained by re-
stricted rotation of the aromatic groups locking the iso-
propyl units into asymmetrical environments [11].
Fig. 1. Crystal structure of the two independent molecules of 2,
showing two alternative views of the dimers. Hydrogen atoms are
removed for clarity.
˚
(range 1.949–1.952 A) are within the ranges of those
found in 1 and 3. Also the mean Al–O–Al and O–Al–
O angles of 100.75ꢁ and 79.25ꢁ in 2 are within 1.5ꢁ of
those in 1 and 3. In all three complexes 1–3 the enolate
group sits approximately in the same plane as the Al2O2
ring, with Al–O–C@CH2 dihedral angles of 23.3 and
22.0ꢁ in 1 and 3, whereas the two independent dimers
of 2 have these angles at 28.1ꢁ and 31.8ꢁ. The overall
similarity of 1–3 indicates that the increase in steric hin-
drance at the ortho-positions of the aromatic ring in 2
and 3 compared to 1, or the increased size of the organic
anion of 3 compared to that in 1 and 2 has little notable
effect on the structures adopted. Nevertheless, the struc-
tural characterization of 2 represents an addition to the
small handful of crystal structures that have been suc-
cessfully completed for aluminum enolates derived from
simple ketones [13].
1
Interestingly, the H NMR spectrum of 3 also displays
this behavior whereas that of 2 shows only a single set
of resonances for the ortho-units. This suggests greater
flexibility in 2 due to smaller methyl groups being at-
tached to the metal compared with phenyl groups in 3.
These studies are also consistent with the expected di-
meric aggregation remaining intact in solution.
X-ray crystallographic studies of 2 revealed the ex-
pected dimeric arrangement, with a central Al2O2 ring
(Fig. 1). This structure is in accord with those previously
reported for 1 and 3 [6,10]. Two almost identical but
independent dimers are formed within the unit cell of
2 and their key bond lengths and angles are given in Ta-
ble 1. In general, the geometric parameters in 2 are sim-
ilar to those reported for related Al2O2 ring systems [12].
2.2. Reaction of enolates 1 and 2 with aldehydes
We were interested in determining the reactivity of
the aluminum enolates 1 and 2 with aldehydes. From
our perspective the most desirable reaction was aldol
addition, due to the importance of this transformation
in the stereoselective formation of new carbon–carbon
˚
For example, the mean Al–O distance of 1.870 A (range
˚
1.863–1.878 A), and the mean Al–C distance of 1.950 A
˚

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Z.S. Sales et al. / Journal of Organometallic Chemistry 690 (2005) 3474–3478
Table 1
Encouraged by these results a series of reactions using
a
˚
Selected bond lengths (A) and angles (ꢁ) for 2
1 and 2 as enolate synthons and pivaldehyde, benzalde-
hyde, mesitylaldehyde, isobutyraldehyde and isovaleral-
dehyde as electrophiles were performed. In each instance
the reactions were conducted on a 1-mmol scale in hex-
ane solution and the products were determined by
GCMS and 1H NMR spectroscopy after aqueous work-
up. The results of the reactions are outlined in Tables 2
and 3, and in all the cases the major product was deter-
mined to be the E-enone derivatives by their character-
istic NMR spectra. In most instances the enolates were
converted to the enones in high yields, with only the
reactions using the bulky mesitylaldehyde requiring ex-
tended reaction times (entries 3 in Tables 2 and 3). No
alkylation products were detected from GCMS analyses
of the crude reaction mixtures. Similarly, no b-hydroxy-
ketones were found, presumably due to the instability of
the aluminum aldolate intermediates under the reaction
conditions. In comparison, Barron has reported that the
bulky alkoxide EtAl(2,6-tBu2-4-Me–C6H2O)2 reacts
with a variety of ketones to yield stable aluminum
aldolates [17]. In Barronꢀs system no intermediate
enolates could be identified and hydrolysis resulted in
non-selective fragmentation of the aldolate backbone.
Finally, in all cases, the dominant stereoisomer
formed in the reactions was the E-enone. This outcome
is in accord with the E-enones being the thermodynam-
ically favored isomers [14]. Indeed, using 1 as enolate re-
sulted in exclusive formation of the E-isomer when
pivaldehyde and mesitylaldehyde were used as electro-
phile. Moreover, all of the reactions using 2 as enolate
gave exclusive E-enone, with the exception of isovaleral-
dehyde (97:3 E/Z, entry 5, Table 3). Clearly, the
Al(1)–O(1)
Al(1)–C(19)
O(1)–C(1)
1.8721(10)
1.9487(15)
1.3918(13)
1.8648(11)
1.9490(14)
1.3919(14)
1.8626(10)
1.9516(16)
1.3305(16)
1.8783(10)
1.9505(15)
1.3286(17)
Al(2)–O(2)#2
Al(2)–C(37)
O(2)–C(20)
Al(1)–O(1)#1
Al(1)–C(18)
C(1)–C(2)
Al(2)–O(2)
Al(2)–C(38)
C(20)–C(21)
O(1)#1–Al(1)–O(1)
O(1)–Al(1)–C(19)
O(1)–Al(1)–C(18)
Al(1)#1–O(1)–Al(1)
C(1)–O(1)–Al(1)
O(2)#2–Al(2)–O(2)
O(2)–Al(2)–C(37)
O(2)–Al(2)–C(38)
Al(2)#2–O(2)–Al(2)
C(20)–O(2)–Al(2)
O(1)#1–Al(1)–C(19)
O(1)#1–Al(1)–C(18)
C(19)–Al(1)–C(18)
C(1)–O(1)–Al(1)#1
C(2)–C(1)–O(1)
79.17(5)
112.36(6)
109.32(6)
100.83(4)
127.35(7)
79.33(5)
114.40(6)
107.81(6)
100.67(5)
126.93(7)
114.46(6)
112.10(6)
121.54(7)
131.81(7)
120.47(10)
114.24(6)
112.12(6)
121.25(6)
132.40(7)
120.28(10)
O(2)#2–Al(2)–C(37)
O(2)#2–Al(2)–C(38)
C(37)–Al(2)–C(38)
C(20)–O(2)–Al(2)#2
C(21)–C(20)–O(2)
a
Symmetry transformations used to generate equivalent atoms: #1
ꢀx + 1, ꢀy + 2, ꢀz + 1, #2 ꢀx + 1, ꢀy + 2, ꢀz + 2.
bonds [14]. However, potentially problematic alternative
reaction pathways include nucleophilic addition of the
methyl groups across the highly reactive carbonyl
groups and also for the complexes to act as bases to pro-
duce bisenolate species [15,16]. Initially, a test reaction
between 1 and pivaldehyde in d6-benzene solution was
Table 2
Products from the reaction of 1 with a series of aldehydes
Entry
Aldehyde
Major Product
Conv.a
(E):(Z)
100:0
1
O
monitored by H NMR spectroscopy. No reaction was
O
H
1
84.3%
(4)
(5)
observed over several hours at ambient temperature
and the chemical shift positions indicated no discernable
interaction between the species present in solution.
NMR analysis of the mixture following heating to reflux
temperature for 3 h revealed remarkably clean conver-
sion to an enone product along with traces of unreacted
enolate 1 (Eq. (2)).
O
O
O
H
2
3
4
>99.0%
64.1%b
85.8%
67.8%
92:8
O
H
100:0
90:10
89:11
(6)
(7)
O
O
H2C
R
O
H
O
O
O
O
hexane
Me
Me
Me
+
Al
Al
R1
H
reflux, 3h
Me
R
R1
O
H
5
(8)
R
CH2
a
Conversion after 3 h reflux.
After 22 h reflux, 80.8%.
b
ð2Þ

Z.S. Sales et al. / Journal of Organometallic Chemistry 690 (2005) 3474–3478
3477
13C NMR spectra were referenced internally to the deu-
terated solvents. Elemental analyses were performed by
Midwest Microlab, Indianapolis, IN.
Table 3
Products from the reaction of 2 with a series of aldehydes
Entry
Aldehyde
Major Product
Conv.a
(E):(Z)
100:0
O
O
H
1
90.0%
4.2. Syntheses
(9)
O
O
O
H
The enone compounds were prepared in a similar
manner and the synthesis of 4 is given as a representative
example. Once prepared, the enone compounds were
purified after aqueous workup by crystallization from
either hexane or ether, or alternatively by column chro-
matography using a solvent system of 90% methylene
chloride and 10% hexane. Compound 1 was prepared
as reported previously [6].
2
3
4
93.1%
10.8%b
100:0
100:0
(10)
O
H
(11)
(12)
O
O
O
H
90.3%
88.1%
100:0
97:3
O
H
5
4.3. Synthesis of [Me2AlOC(2,4,6-(CH(CH3)2)3–
C6H2)@CH2] (2)
(13)
a
Conversion after 3 h reflux.
After 42 h reflux, 74.8%.
b
2,4,6-Triisopropylacetophenone (1.05 g, 4.2 mmol)
was added dropwise to a ꢀ78 ꢁC cooled solution of
Me3Al (6.4 mmol) in 12 ml of toluene. The reaction mix-
ture was allowed to warm to ambient temperature with
constant stirring and subsequently heated to reflux for 3
h. Solvents were removed in vacuo, the residue dissolved
in 12 ml of hexane and a solid was obtained upon cool-
ing the mixture to ꢀ45 ꢁC for 24 h. Isolated yield 80.2%.
1H NMR spectrum, d ꢀ0.52 (s, 6H, AlCH3), 1.17 (d,
J = 6.9 Hz, 12H, o-C(CH3)2), 1.42 (d, J = 6.6 Hz, 6H,
p-C(CH3)2), 2.73 (sept, J = 6.9 Hz, 1H, p-CH(CH3)2),
3.38 (sept, J = 6.9 Hz, 2H, o-CH(CH3)2), 4.32 (d,
J = 2.1 Hz, 1H, C@CH2), 5.01 (d, J = 2.1 Hz, 1H,
C@CH2), 7.09 (s, 2H, m-C6H2). 13C NMR spectrum, d
ꢀ9.13 (AlCH3), 23.35 (CH3), 24.48 (CH3), 27.07
(CH3), 31.23 (CH), 35.15 (CH), 98.76 (C@CH2),
121.46, 132.02, 147.94, 151.27(Ar–C), 153.07(OC@CH2).
Theoretical elemental analysis for C38H62-O2Al2: C,
75.46; H, 10.33. Found C, 73.70; H, 10.05%.
stereoselectivity of the reaction is promoted by increas-
ing the steric bulk of both the enolate and the aldehyde.
3. Conclusions
Trimethylaluminum can act as a selective base in the
enolization of sterically hindered ketones. In particular,
aromatic ketones substituted at the 2- and 6-positions
with methyl or isopropyl groups, react with Me3Al upon
heating to exclusively yield the respective dimethylalu-
minum enolates. The enolates adopt dimeric structures
featuring central Al2O2 rings in the solid state and also
in solution. Reaction of these enolates with a series of
simple aldehydes at elevated temperatures results in en-
one formation presumably via an aldol addition reaction
followed by an elimination step. The enones are pro-
duced in high yields and as predominantly the E-
isomers.
4.4. Synthesis of E-[(2,4,6-Me3–C6H2)C(O)CH@CHC-
(CH3)3] (4)
2,4,6-Trimethylacetaldehyde (0.207 g, 2.3 mmol) was
added dropwise to a solution of 12 ml hexane and 1
(0.500 g, 1.15 mmol) at 0 ꢁC. The reaction mixture
was allowed to warm to ambient temperature and then
heated at reflux for 3 h. The solution was quenched with
deionized water, extracted into ether (3 · 15 mL) and
purified using column chromatography (9:1 methylene
chloride/hexane).
4. Experimental
4.1. General
All experiments were carried out under a dry nitrogen
atmosphere and scrupulously anhydrous conditions
using standard Schlenk techniques [18]. Toluene and
hexane were purified by passage through a solvent puri-
fication system (Innovative Technology). The Me3Al
was supplied by Aldrich as 1.6 M solutions in hexane
and used as received. The NMR experiments were re-
4.5. X-ray crystallography
Table 4 contains information on the data collection
for 2. A crystalline sample of 2 was placed in inert oil,
mounted on a glass pin, and transferred to the cold
1
corded on Varian-300 and -500 spectrometers. H and

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Z.S. Sales et al. / Journal of Organometallic Chemistry 690 (2005) 3474–3478
Table 4
Crystallographic parameters for 2
Acknowledgments
Chemical formula
Formula weight
Crystal size (mm)
Crystal system
C38H62Al2O2
604.84
We thank the National Science Foundation (CHE03-
45713) and the University of Notre Dame for funding.
We also thank Professor Bruce C. Noll for training in
small molecule X-ray crystallography.
0.36 0.28 0.25
Triclinic
ꢀ
Space group
Unit cell dimensions
P1
˚
a (A)
8.0860(16)
14.768(3)
17.659(4)
66.62(3)
86.19(3)
82.43(3)
1918.5(7)
2
˚
b (A)
References
˚
c (A)
a (ꢁ)
b (ꢁ)
d (ꢁ)
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