Mild acetalisation of mono and dicarbonyl compounds catalysed by titanium tetrachloride. Facile synthesis of β-keto enol ethers

Article abstract of DOI:10.1016/S0040-4020(00)01001-2

The use of TiCl₄, as a catalyst for the acetalisation, at room temperature, of carbonyl compounds is reported. Cyclic ketones and cyclic 1,4-diketones easily afford dimethyl acetals, but cyclic 1,3-diketones give β-keto enol ethers. Additionally, aryl ketones and acyclic ketones failed to react. β-keto aldehydes can be monoprotected either as β-keto enol ethers or β-keto dimethyl acetals depending on the reaction time and catalyst amount. Some mechanistic features are accounted for.

Full text of DOI:10.1016/S0040-4020(00)01001-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 217±225
Mild acetalisation of mono and dicarbonyl compounds
catalysed by titanium tetrachloride.
Facile synthesis of b-keto enol ethers
*
Angelo Clerici, Nadia Pastori and Ombretta Porta
Dipartimento di Chimica del Politecnico, Via Mancinelli 7, 20131 Milano, Italy
Received 23 March 2000; revised 29 September 2000; accepted 19 October 2000
AbstractÐThe use of TiCl4, as a catalyst for the acetalisation, at room temperature, of carbonyl compounds is reported. Cyclic ketones and
cyclic 1,4-diketones easily afford dimethyl acetals, but cyclic 1,3-diketones give b-keto enol ethers. Additionally, aryl ketones and acyclic
ketones failed to react. b-keto aldehydes can be monoprotected either as b-keto enol ethers or b-keto dimethyl acetals depending on the
reaction time and catalyst amount. Some mechanistic features are accounted for. q 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
under very mild reaction conditions (Eq. (2)).
Acetals are not only the most widely used protective groups
for carbonyl compounds,1 but they have also been increas-
ingly employed as ef®cient chiral auxiliaries for the syn-
thesis of enantiomerically pure compounds.2 In recent
years several transition metal complexes have been
shown3 to offer major advantages over general Bronsted
acid catalysis, but the search for new Lewis acid catalysts,
to generate acetals under aprotic and milder conditions, is
still actively pursued.
ꢀ2†
As the yields are very good and the reactions very simple to
perform, it was of interest to further investigate the extent of
applicability of this protocol with ketones and dicarbonyl
compounds.
The results herein reported widen the use of TiCl4 as a
highly ef®cient and chemoselective catalyst for acetalisation
reactions, and emphasise the sharp contrast between alde-
hydes and ketones.
TiCl4, when used in slight excess, either converts dimethyl
and cyclic acetals to the corresponding carbonyl com-
pounds4 or has proven to be the Lewis acid of choice2,5 to
activate the addition of carbon nucleophiles to acetals, via a
direct displacement of a TiCl4±ether complex and/or a prior
formation of an oxocarbenium ion5,6 (Eq. (1)).
2. Results and discussion
The cycloalkanones of Table 1, when allowed to react for
1 h at room temperature in a methanolic solution containing
1 mol% of TiCl4 and 12 mol% of TEA, gave the corre-
sponding dimethyl acetals 1±12 in good to excellent yields
(Eq. (3)).
ꢀ1†
On the contrary, as we recently reported,7 a catalytic amount
of TiCl4 in methanol solution containing triethylamine
(TEA) or ammonia gas easily converts aliphatic, a,b-unsat-
urated and aromatic aldehydes to the corresponding acetals
ꢀ3†
Keywords: acetalisation; titanium tetrachloride; cyclic ketones; 1,3-dicar-
bonyl compounds; b-keto enol ethers.
* Corresponding author. Tel.: 12-2399-3063; fax: 12-233913080; e-mail:
ombretta.porta@polimi.it
In line with the mechanism already proposed,7 the ef®ciency
of the catalytic cycle will depend on the ability of TiCl4 to
act both as a dehydrating agent and as a template for the
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01001-2

218
A. Clerici et al. / Tetrahedron 57 (2001) 217±225
Table 1. TiCl4/TEA Catalysed acetalisation of aliphatic cyclic ketones
Ketone
Conversion (%)a
Isolated yield (%)
1
2
95
49
83b
3
88
80c
4
5
6
7
90
85c
95b
84c
97b
quant.
90
quant.
8
9
75
quant.
quant.d
95b
96b
10111
12e
84f
78c
1
a Conversion was determined by H NMR analysis of the crude reaction mixture (the remainder to 100% was the starting ketone).
b When the conversion was $95%, isolated yields (%) refer to the recovered crude acetal without further puri®cation.
c Puri®ed by Kugelrohr distillation.
d GC analysis of the crude acetal revealed the presence of dimethyl acetal 10 (10%) and of tetramethyl acetal 11 (90%).
e Acetalisation occurred only at the less hindered 4-position.
f NH3 gas, instead of TEA, was used.7 TEA gave a lower conversion.
simultaneous activation of the carbonyl compound and of
MeOH before coupling. Small differences in steric and elec-
tronic properties of the carbonyl impact upon the metal ion's
ability to allow formation of the reactive intermediate. As a
consequence, the equatorial8 2-Me group of 2-Me-cyclo-
hexanone sterically interferes with the Ti(IV)±carbonyl
oxygen complexation, lowering the yield of acetal 2 with
respect to the other cyclic ketones having a substituent
remote from the reaction centre.
90% conversion to the tetramethylacetal 11 and only 10%
conversion to the monoprotected ketone 10.
The more sterically hindered aromatic ketones (e.g. aceto-
phenone, propiophenone) and the conformationally more
¯exible acyclic ketones (e.g. 2-butanone, 2-hexanone)
failed to react.
Importantly, the synthetic restriction regarding these
ketones allows the use of TiCl4 as a speci®c acetalisation
catalyst to selectively protect a carbonyl group in the
presence of another more sterically hindered carbonyl unit.
A result which is noteworthy, based on the sensitivity to
steric hindrance, is the clean regioselective monoacetali-
sation of 2,2,6-trimethylcyclohexan-1,4-dione at the less
hindered 4-position, whereas cyclohexan-1,4-dione gives
In fact, as expected, intermolecular competitive acetalisation

A. Clerici et al. / Tetrahedron 57 (2001) 217±225
219
Table 2. TiCl4-Catalysed synthesis of b-methoxycycloalkenones from 1,3-
cycloalkanediones
We next investigated the acetalisation reaction of b-dicar-
bonyl compounds. Treatment of cycloalkane-1,3-diones of
Table 2 with a 3 mol% of TiCl4 in a methanolic solution, for
half an hour at room temperature, invariably afforded the
corresponding b-methoxycycloalkenones 13±19 in very
high yields, rather than b-keto dimethyl acetals (Eq. (4)).
b-Diketone
Isolated yield (%)a
13
14
95
90
15
97
ꢀ4†
4,4-Dimethyl-1,3-cyclohexanedione afforded
a
77:23
16117 (77:23)
96b
mixture of 3-methoxy-6,6-dimethylcyclohex-2-enone 16/
3-methoxy-4,4-dimethylcyclohexen-2-one 17. Addition of
7
NH3 gas to the reaction mixture did not substantially
change the yields of enol ethers, but increased the isomers
ratio 16:17 to 96/4.
18
19
92
80
The TiCl4-catalysed synthesis of these compounds is
simpler, milder and higher yielding than the previously
reported techniques for the preparation of the same
compounds. Compounds 13±19 are key intermediates in
organic synthesis9±12 and they have been usually prepared
starting from cyclic-b-diketones with diazomethane9 or
prolonged re¯ux under acid catalysis10 and from 3-Cl-
cycloalkenones with methoxide.11,12
a Yields (%), based on the starting substrate, refer to the crude recovered
product, which always showed an H NMR purity $95%.
1
b
1H NMR analysis revealed a 77:23 mixture of 3-methoxy-6,6-dimethyl-
cyclohex-2-enone 16 and of 3-methyl-4,4-dimethylcyclohex-2-enone 17.
However, open chain aliphatic and aromatic 1,3-diketones
(e.g. dibenzoylmethane, acetylacetone, benzoylacetone)
remained unaffected under the reaction conditions used.
These compounds exist in solution in the cis-enol form13
and are capable of serving as bidentate ligands in the forma-
tion of very stable strongly mesomeric bis(b-diketonato)-
Ti(IV)X2 compounds14 (XˆCl, OR) where the six-
coordinative valence of the metal is fully saturated. Thus
neither coordination of methanol to the metal, nor regenera-
tion of the catalyst will be possible, conditio sine qua non
for an ef®cient catalytic cycle.
of a 1:1 mixture of either benzaldehyde/acetophenone or
4-tBu-cyclohexanone/acetophenone delivered only the
benzaldehyde or the 4-tBu-cyclohexanone dimethyl acetals
(conversion .95%) and a 1:1 mixture of cyclohexanone/
2-hexanone afforded a 92:8 mixture of cyclohexanone/
2-hexanone dimethyl acetals.
Scheme 1.

220
A. Clerici et al. / Tetrahedron 57 (2001) 217±225
Table 3. TiCl4-Catalysed synthesis of b-methoxyenones (Method A) or b-keto dimethyl acetals (Method B) from b-keto aldehydes
b-Ketoaldehyde
Method
(reaction time)
Yield (%)a
Yield (%)a
(95% enol form)15
A (5 min)
A (2 h)
B (5 min)
B (2 h)
54
40
50
traces
20
21
6
26
27
40
20
95b
A (10 min)
A (2 h)
B (5 min)
B (2 h)
76
56
61
±
traces
22
20
95b
A (5 min)
B (2 h)
63
traces
22
23
24
7
28
29
30
92b
A (5 min)
B (2 h)
78
±
6
90b
A (5 min)
B (2 h)
70
±
20
93b
A (5 min)
B (2 h)
95b
95b
25
a Yields (%) are based on 1H NMR analysis of the crude reaction mixture; the difference to 100 was the unreacted aldehyde.
1
b Yields (%) refer to the recovered crude product, which always showed an H NMR purity .95%, making further puri®cation unnecessary.
The cyclic 1,3-diones of Table 2 largely exist in the enol
form also, but enolization gives `®xed' trans-enols13
where intramolecular Ti(IV) bonding is sterically impos-
sible. As a consequence fast regeneration of the catalyst,
after water7 and product formation, allows the reaction to
proceed.
5 mol% of TiCl4, were quantitatively converted into their
dimethyl acetals 26±30.
The very interesting feature of this reaction is that it can be
stopped at the stage of enol ethers. These intermediates have
seldom been isolated on the way to b-keto acetals either
starting from b-keto vinyl chlorides16 or from the sodium
salt of b-keto aldehydes17 or from b-keto vinyl sul®des.18
Instead, they have usually been prepared by pyrolysis of the
corresponding b-keto dimethyl acetals both under strongly
basic19 or acidic16,20 catalysis. In a more recent paper,21
illustrating the synthetic potential of b-methoxy enones, a
Rh2(OAc)4 catalysed procedure starting from diazoketones
has been reported.
With b-keto aldehydes acetalisation was very straight-
forward15a (Scheme 1).
All substrates of Table 3 rapidly reacted (5 min) with metha-
nol, at room temperature, in the presence of a 1 mol% of
TiCl4 to give the corresponding trans-b-methoxyenones
20±25 as the almost exclusive products (Method A), but
prolonged reaction time (2 h) afforded a mixture of both
enol ethers and dimethyl acetals (Table 3). More speci®c-
ally, an higher amount of catalyst (5 mol%, method B) gave
instead, after 2 h, only the b-keto dimethyl acetals 26±30 in
high yields ($90%) and high purity (1H NMR, $95%),
making further puri®cation of the crude products unneces-
sary. However, 2-methyl-3-oxo-3-phenyl- propionaldehyde
constituted an exception since even under the conditions of
method B gave the b-methoxyenone 25 with only traces
amount of the acetal adduct (vide infra).
The failure of cyclic enol ethers 13±19 (Table 2) and of the
acyclic enol ether 25 (Table 3) to further react with metha-
nol, under the conditions of method B, is in strong contrast
with the successful quantitative conversion of enol ethers
20±24 into the corresponding dimethyl acetals.
The type of reactivity of trans-b-methoxy enones may be
strongly affected by varying the rigidity and coplanarity of
the conjugated system.9a The conjugation is most effective
in a near planar system causing signi®cant resonance
stabilisation, which is crucial for elimination rather than
for further methanol addition.
As expected, enol ethers 20±24, but not 25, upon standing
2 h at room temperature in a methanolic solution containing

A. Clerici et al. / Tetrahedron 57 (2001) 217±225
221
corresponding ethyl (25A and 13A) or deuterated methyl
enol ethers (25B and 13B) in almost quantitative yields
(.95%) according to Scheme 2 (shown for 25).
However, when 25 was allowed to react in a CH2Cl2
solution containing 1.4 equiv. of d,l-2,3-butanediol and
5 mol% of TiCl4, the more stable 1,3-dioxolane 31 was
obtained in 85% yield, via internal displacement of metha-
nol. Under comparable experimental conditions, enol ether
13 gave instead a mixture of 1,3-cyclohexanedione mono-
and bis-cyclic acetal,24 even starting from an equimolar
amount of d,l-2,3-butanediol. Thus 1,3-diketones of Table
2 can be selectively monoprotected as enol ethers but double
protection occurs in the formation of cyclic acetals.
3. Conclusions
Chart 1.
On considering the very simple and mild reaction con-
ditions, the high conversions and yields, this methodology
for the synthesis of acetals and/or b-keto enol ethers
represents a valid alternative to the existing procedures,
especially for carbonyl compounds bearing acid-sensitive
groups.
By comparing enol ethers 20±24 with 13±19 and 25 (Chart
1), it is clear that 20±24 are the least rigid molecules since
both the methoxy and the R±CO groups are free to rotate.
However, if the substituent in the a-position is a methyl
group, instead of an hydrogen atom, the non-bonded inter-
actions with the phenyl group in the trans/s-cis rotamer 25
dramatically19b increase, resulting in an equilibrium shifted
towards the energetically favoured trans/s-trans rotamer, as
clearly shown by the 1H NMR spectrum15b and NOE experi-
ments15c carried out on compound 25. Because of the
restricted rotation around the Csp2±Csp2 single bond, the
two double bonds in 25 s-trans are held nearly coplanar in
a favourable position for conjugation, as it is for cyclic enol
ethers 13±19, where no part of the conjugated system can
rotate.
The success of this method lies in the use of TiCl4, which
acting both as a catalyst and as dehydrating agent, makes
unnecessary the azeotropic removal of the water generated
during the reaction and allows the acetalisation to occur at
room temperature.
4. Experimental
4.1. General remarks
As a consequence for these near planar and resonance
stabilised b-methoxy enones TiCl4-assisted addition-elimi-
nation22,23 at the b-carbon can be observed. In fact, we
proved that both 13 and 25 reacted with ethanol or deuter-
ated methanol, under conditions of method B, yielding the
All reactions were carried out at room temperature without
protection from moisture or oxygen. NMR spectra were
recorded in CDCl3 solution on a Bruker AC-250 MHz
instrument with Me4Si as an internal standard. Mass spectra
were taken on a Finnigan MAT-TS Q70 spectrometer.
Scheme 2.

222
A. Clerici et al. / Tetrahedron 57 (2001) 217±225
Melting points (uncorrected) were taken on a Ko¯er appa-
ratus. Flash column chromatography was performed by
using Silica gel 60 (particle size 0.004±0.063).
layer was again extracted with diethyl ether. The combined
ether extracts were washed with sodium bicarbonate solution,
dried and evaporated to dryness. The crude b-Keto aldehydes
(purity .95% by 1H NMR) was employed at once.
Triethylamine (TEA) was distilled prior to use. TiCl4 (1.0 M
solution in CH2Cl2) and methanol ACS (HPLC grade) were
purchased from Aldrich and used as received. Ketones of
Tables 1 and 2 are commercially available and were used
without further puri®cation. The b-Keto aldehydes of
Table 3 were readily prepared by acylation of the appro-
priate ketones using slight modi®cations of the standard
methods.25a,b Procedure A was adopted for solid b-Keto
aldehydes and procedure B for liquid b-Keto aldehydes.
4.2. General procedure for the TiCl4/Et3N catalysed
synthesis of cyclic dimethyl acetals 1±12 (Table 1)
50 mL (5£1022 mmol) of a 1.0 M TiCl4 solution in CH2Cl2
was added in one portion with a syringe, to a stirred solution
of the cyclic ketone (5 mmol) in MeOH (10 mL) at room
temperature. After ca 10 min, Et3N (83 mL, 0.6 mmol) was
added to the resulting solution, which was stirred for an
additional 45 min before the addition of H2O (3 mL). The
reaction mixture was then extracted with diethyl ether
(3£10 mL) and the combined organic layers were succes-
sively washed with H2O, dried over Na2SO4 and evaporated
Procedure A. Sodium methoxide (5.40 g, 0.10 mol) was
suspended in THF (100 mL) and treated at room tempera-
ture with ethyl formate (8.1 mL, 0.10 mol), followed by
dropwise addition of the appropriate ketone (8£1022 mol
of 4-methoxyacetophenone or 4-chloroacetophenone or
propriophenone). The reaction mixture was stirred for
2.5 h at room temperature, quenched by the addition of
water (300 mL), and extracted with two 100 mL portions
of diethyl ether. These extracts were discarded. The aqueous
phase was acidi®ed with 18 mL of 6 M H2SO4 and extracted
with diethyl ether (2£100 mL). This extract was washed
with water and brine, dried, and concentrated to give a
thick yellow oil, which was puri®ed by crystallization
from the appropriate solvent to afford the b-Keto aldehydes
reported in succession.
1
under reduced pressure. Conversion was determined by H
NMR analysis of the crude reaction mixture (the remainder
to 100% was the starting ketone, by-product have never
been detected). When the crude residue showed an 1H
NMR purity $95%, no further puri®cation was undertaken,
and the isolated yields (%) of Table 1 refer to the recovered
1
crude acetals. When the H NMR purity was ,95%, the
crude residue was puri®ed by Kugelrohr distillation.
4.3. General procedure for competition acetalisation
experiments
50 mL (5£1022 mmol) of a 1.0 M TiCl4 solution in CH2Cl2
was added in one portion with a syringe, to a stirred solution
containing a 1:1 mixture of benzaldehyde and acetophenone
(2.5 mmol each) in 10 mL of MeOH. After 10 min, Et3N
(83 mL, 0.6 mmol) was introduced, and stirring was con-
tinued for an additional 45 min. GLC analysis of the reac-
tion mixture was performed on sample taken up in diethyl
ether and washed with small quantity of water. By com-
parison of the retention times with those of authentic
samples,7a the GLC analysis con®rmed that the benzalde-
hyde dimethyl acetal was the only reaction product.
4.1.1. 3-(4-Methoxyphenyl)-3-oxo-propionaldehyde.
Yield 60%, yellow crystals; mp 53±568C (hexane). Lit.25c
54±568C.
4.1.2. 3-(4-Chlorophenyl)-3-oxo-propionaldehyde. Yield
72%, yellow crystals; mp 45±478C (hexane). Lit.25d 46±488C.
4.1.3. 2-Methyl-3-oxo-3-phenyl-propionaldehyde. Yield
67%, yellow crystals; mp 118±1208C (chloroform). Lit.25e
1188C.
Procedure B. The reactions were conducted according to the
procedure given in A, but the products were obtained pure
by ®rst preparing the copper derivatives. The crude residue,
obtained after work-up as in procedure A, was dissolved in
MeOH (10 mL) and treated with a hot ®ltered solution of
10 g of copper acetate in 100 mL of water. The copper salt
of the b-Keto aldehyde separated out on cooling (one night
at 08C).
Comparable experimental conditions were adopted for
the competitive acetalisations of 4-tBu-cyclohexanone/
acetophenone and cyclohexanone/2-hexanone.7b
4.4. General procedure for the TiCl4-catalysed synthesis
of b-methoxy-cycloalkenones 13±19 (Table 2)
0.15 mL (0.15 mmol) of a 1.0 M TiCl4 solution in CH2Cl2
was added in one portion with a syringe, at room tempera-
ture, to a well stirred solution of the cyclic 1,3-diketone
(5 mmol) in MeOH (10 mL). The reaction mixture was
then stirred for an additional 30 min before the addition of
H2O (3 mL). Further work up was similar to the preceding
procedure. The isolated yields(%) of Table 2 refer to the crude
recovered products, which always showed an 1H NMR purity
$95%, making further puri®cation unnecessary.
4.1.4. Copper salt of 3-oxo-3-phenyl-propionaldehyde.
Yield 68%, dark green needles; mp 210±2158C, dec.
Lit.25f 212±2138C, dec.
4.1.5. Copper salt of 4,4-dimethyl-3-oxo-pentanal. Yield
52%, blue crystals; mp 124±1268C. Lit.25g 125±1268C.
4.1.6. Copper salt of 5-methyl-3-oxo-hex-4-enal. Yield
50%, black crystals; mp 1348C. Lit.25h 1348C.
4.5. General procedure for the TiCl4-catalysed synthesis
of b-methoxyenones 20±25 (Method A) and of b-keto
dimethyl acetals 26±30 (Method B) (Table 3)
The free b-Keto aldehyde was prepared from the copper deri-
vative by shaking with diethyl ether, dilute sulphuric acid, and
ice until the salt was completely decomposed. The aqueous
Method A. The b-keto aldehyde (10 mmol) was dissolved in

A. Clerici et al. / Tetrahedron 57 (2001) 217±225
223
20 mL of MeOH. To the stirred solution was added in one
portion with a syringe, at room temperature, 0.1 mL
(1.0£1021 mmol) of a 1.0 M TiCl4 solution in CH2Cl2.
After 5±10 min, the reaction was quenched with H2O
(5 mL). Work up was as in the preceding procedures.
Compounds 20±24 were puri®ed by ¯ash column chroma-
tography (hexane/EtOAc, 8:2) and the solid b-methoxy-
enone 21 was recrystallized from hexane. The crude 25
showed an 1H NMR purity .95%, making its further
puri®cation unnecessary. Method B. A larger amount
(0.5 mL, 0.5 mmol) of the TiCl4 solution in CH2Cl2 was
added to the methanolic solution (20 mL) of the b-keto
aldehyde (10 mmol) and stirring was continued for 2 h (or
5 min; see Table 3) at room temperature. Work up was as in
the preceding procedures. The purity of the b-keto dimethyl
acetals 26±30 was judged to be .95% by 1H NMR analysis.
white solids all the synthesized new compounds are pale
yellow liquids.
4.9.1. 2,6,6-Trimethyl-4,4-dimethoxycyclohexan-1-one
1
(12). H NMR (CDCl3) d 1.03 (3H, CH3, d, Jˆ6.5 Hz),
1.06 (3H, CH3, s), 1.26 (3H, CH3, s), 1.49 (1H, d,
Jˆ13.9 Hz), 1.65 (1H, d, Jˆ13.9 Hz), 2.17 (1H, dd,
Jˆ3.9, 14.2 Hz), 2.25±2.35 (1H, m), 2.80±2.90 (1H, m),
3.22 (3H, OCH3, s), 3.28 (3H, OCH3, s); proton-decoupled
13C NMR (CDCl3) d 14.5, 26.3, 27.0, 36.6, 40.9, 43.5, 45.2,
47.9, 102.9, 216.3; IR (neat) nmax 2966, 1713, 1100,
1050 cm21; MS (EI) m/e (relative intensity) 185 (M121,
40), 170 (30), 169 (25), 153 (25), 125 (60), 109 (85), 99
(100), 88 (70), 83 (50), 69 (70), 59 (58); Anal. Calcd for
C10H18O3: C 64.49; H 9.77%. Found: C 64.47; H 9.80%.
4.9.2. 3-Deuteromethoxycyclohex-2-en-1-one (13B). Mp
44±468C; 1H NMR (CDCl3) d 1.93 (2H, dt, Jˆ6.3,
9.5 Hz), 2.30 (2H, t, Jˆ6.1 Hz), 2.36 (2H, t, Jˆ6.1 Hz),
5.30 (1H, s); proton-decoupled 13C NMR (CDCl3) d 20.8,
28.4, 36.3, 55.3, 101.8, 178.5, 199.3; HRMS Calcd for
C7H7D3O2 (M1) 129.0680, found 129.0682.
4.6. General procedure for the TiCl4-catalysed
conversion of enol ethers 20±24 to the corresponding
dimethyl acetals 26±30
The enol ether (5 mmol) was dissolved in 10 mL of MeOH.
To the stirred solution was added in one portion with a
syringe, 0.25 mL (0.25 mmol) of a 1.0 M TiCl4 solution in
CH2Cl2 and stirring was continued for 2 h at room tempera-
4.9.3. 3-Methoxy-1-phenyl-2(E)-propen-1-one (20).21 1
H
NMR (CDCl3) d 3.81 (3H, OCH3, s), 6.35 (1H, CH, d, Jˆ
12.4 Hz), 7.4±7.6 (3H, PhH, m), 7.80 (1H, CH, d, Jˆ
12.4 Hz), 7.9±8.0 (2H., PhH, m);15b IR (neat) nmax 1644,
1600, 1583, 1206 cm21; MS (EI) m/e (relative intensity)
162 (M1z, 5), 105 (100), 85, 77, 51.
1
ture. After work up as in the preceding procedures, the H
NMR analysis of the crude residue revealed the quantitative
conversion of the enol ether into the corresponding dimethyl
acetal.
4.9.4. 3-Methoxy-1-(4-chlorophenyl)-2(E)-propen-1-one
(21). Mp 63±58C (lit.27 63±48C); 1H NMR (CDCl3) d
3.80 (3H, OCH3, s), 6.3 (1H, CH, d, Jˆ11.9 Hz), 7.4 (2H,
ArH, A2B2), 7.78 (1H, CH, d, Jˆ11.9 Hz), 7.85 (2H., ArH,
A2B2); IR (KBr) nmax 1655, 1580, 1260, 1205 cm21; Anal.
Calcd for C10H9ClO2: C 61.07; H 4.58%. Found: C 60.95; H
4.61%.
4.7. Transacetalisation of b-keto enol ethers 13 and 25 to
the corresponding ethyl ethers 13A and 25A or
deuterated methyl ethers 13B and 25B (Scheme 2)
The reactions were performed under the conditions of
method B: dissolution of 13 or 25 (5 mmol) in EtOH
(10 mL) or CD3OH (10 mL), followed by addition of
0.25 mL (0.25 mmol) of the TiCl4 solution in CH2Cl2,
quenching of the reaction after 2 h and usual work up.
4.9.5. 3-Methoxy-1-(4-methoxyphenyl)-2(E)-propen-1-
one (22). H NMR (CDCl3) d 3.82 (3H, OCH3, s), 3.85
1
(3H, OCH3, s), 6.33 (1H, CH, d, Jˆ11.9 Hz), 6.92 (2H,
ArH, m), 7.75 (1H, CH, d, Jˆ11.9 Hz), 7.9 (2H., ArH,
m); IR (neat) nmax 2937, 1660, 1603, 1257, 1209,
1171 cm21; proton-decoupled 13C NMR (CDCl3) d 55.3
(OCH3), 57.9 (OCH3), 101.0 (vCH), 113.6 (2CHarom),
130.5 (2CHarom), 132.5 (Carom), 163.6 (Carom), 164.0
(vCH),188.0 (CvO); MS (EI) m/e (relative intensity)
192 (M1, 20), 135 (100); Anal. Calcd for C11H12 O3: C
68.74; H 6.29%. Found: C 68.78; H 6.31%.
4.8. Transacetalisation of 25 to the cyclic acetal 31
(Scheme 2)
The reaction was performed under the conditions of method
B: dissolution of 25 (5 mmol) in a CH2Cl2 (10 mL) solution
containing d,l-2,3-butanediol (7 mmol), followed by
addition of the TiCl4 (0.25 mL, 0.25 mmol) solution and
quenching of the the reaction after 2 h. Usual work up
afforded 31 in 85% isolated yield, as an inseparable 50:50
mixture of two diastereoisomers.
4.9.6. 1-Methoxy-4,4-dimethyl-1(E)-penten-3-one (23).19
1H NMR (CDCl3) d 1.08 (9H, 3CH3, s), 3.70 (3H, OCH3, s),
5.77 (1H, CH, d, Jˆ11.9 Hz), 7.47 (1H, CH, d, Jˆ11.9 Hz);
4.9. Spectroscopic data
IR19b (CH2Cl2) nmax 1689, 1611, 1596 cm21
.
With the exception of 2,6,6-trimethyl-4,4-dimethoxycyclo-
hexan-1-one 12, all the products listed in Tables 1 and 2 are
known compounds, and their spectroscopic and physical
data are in accord with those reported in the literature.26
We include the spectroscopic data for all the compounds
of Table 3, and for 13B, 25A, 25B and 31 (Scheme 2)
because most of them are new compounds and/or their
spectral data in the literature is incomplete.
4.9.7. 1-Methoxy-5-methylhexan-1(E),4-dien-3-one (24).
1H NMR (CDCl3) d 1.19 (6H, 2CH3, s), 3.68 (3H, OCH3, s),
5.30 (1H, CH, s), 5.55 (1H, CH, d, Jˆ12.4 Hz); 7.45 (1H,
CHv, d, Jˆ12.4 Hz); proton-decoupled 13C NMR (CDCl3)
d 24.9 (CH3), 27.8 (CH3), 53.5 (OCH3), 119.3 (vCH),
123.8 (vCH), 156.5 (vC), 159.1 (vCH), 196.8 (CvO);
IR (neat) nmax 2976, 1622, 1075 cm21; MS (EI) m/e
(relative intensity) 140 (M1z, 5), 100 (5), 85 (100);
With the exception of compounds 13B and 21 which are

224
A. Clerici et al. / Tetrahedron 57 (2001) 217±225
Anal. Calcd for C8H12 O2: C 68.55; H 8.63%. Found: C
68.61; H 8.72%.
Jˆ5.4 Hz), 3.41 (6H, 2OCH3, s), 3.89 (3H, OCH3, s), 5.00
(1H, CH, t, Jˆ 5.4 Hz), 6.95 (2H, ArH, m), 7.95 (2H., ArH,
m); proton-decoupled 13C NMR (CDCl3) d 42.2 (CH2), 54.1
(2OCH3), 55.4 (OCH3), 102.3 (CH), 113.7 (2CHarom), 129.5
(Carom), 130.5 (2CHarom), 163.6 (Carom), 195.3 (CvO); IR
(neat) nmax 2937, 1678, 1602, 1092, 1316, 1172, 1122,
1053 cm21; M (EI) m/e (relative intensity) 224 (M1, 4),
209 (25), 135 (100), 92 (50), 77 (50); HRMS Calcd for
C12H16O4 (M1) 224.1048, found 224.1045.
4.9.8. 3-Methoxy-2-methyl-1-phenyl-2(E)-propen-1-one
1
(25). H NMR (CDCl3) d 1.88 (3H, CH3, d, Jallˆ1.1 Hz),
3.80 (3H, OCH3, s), 6.92 (1H, CHv, q, Jallˆ1.1 Hz), 7.36±
7.48 (3H, PhH, m), 7.50±7.59 (2H, PhH, m);15b 13C NMR
1
(CDCl3) d (and J C-1, H-1) 8.9 (CH3, q, Jˆ129 Hz), 61.5
(OCH3, q, Jˆ145 Hz), 117.3 (vC, s), 128.1 (2CHarom, d,
Jˆ160 Hz), 128.6 (2CHarom, d, Jˆ161 Hz), 130.6 (CHarom
,
4.9.14. 1,1-Dimethoxy-4,4-dimethylpentan-3-one (29).19a
1H NMR (CDCl3) d 1.10 (9H, 3CH3, s), 2.63 (2H, CH2, d,
Jˆ 5.4 Hz), 3.29 (6H, 2OCH3, s), 4.71 (1H, CH, t,
Jˆ5.4 Hz).
d, Jˆ130 Hz), 139.3 (Carom, s), 164.4 (vCH, d, Jˆ177 Hz),
197.1 (CvO, s); IR (neat) nmax 2940, 1677, 1626, 1247,
1143 cm21; MS (EI) m/e (relative intensity) 176 (M1z,
60), 175 (M121, 70), 105 (100), 77 (73); HRMS Calcd
for C11H12O2 (M1) 176.0837, found 176.0839.
1
4.9.15. 1,1-Dimethoxy-5-methylhex-4-en-3-one (30). H
NMR d 1.18 (6H, 2CH3, s), 2.63 (2H, CH2, d, Jˆ5.6 Hz),
3.28 (6H, 2OCH3, s), 4.67 (1H, CH, t, Jˆ5.6 Hz), 5.30 (1H,
CHv, s); IR (neat) nmax 2976, 1710, 1619, 1366, 1190,
1123, 1075 cm21; proton-decoupled 13C NMR (CDCl3) d
24.7 (CH3), 27.6 (CH3), 47.6 (CH2), 53.6 (2OCH3), 101.8
(CH), 124.0 (vCH), 155.9 (vC), 206.4 (CvO); MS (EI)
m/e (relative intensity) 172 (M1z, 3), 157 (10), 131 (10), 99
(18), 75 (80), 73 (100); HRMS Calcd for C9H16O3 (M1)
172.1099, found 172.1096.
4.9.9. 3-Ethoxy-2-methyl-1-phenyl-2(E)-propen-1-one
1
(25A). H NMR (CDCl3) d 1.32 (3H, CH3, t, Jˆ7.1 Hz),
1.89 (3H, CH3, d, Jallˆ1.1 Hz), 4.00 (2H, CH2, q,
Jˆ7.1 Hz), 6.99 (1H, CHv, q, Jallˆ1.1 Hz), 7.35±7.48
(3H, PhH, m), 7.50±7.56 (2H, PhH, m);15b proton-
decoupled 13C NMR (CDCl3) d, 8.8 (CH3), 15.3 (CH3),
67.9 (OCH2), 117.3 (vC), 128.2 (2CHarom), 128.6
(2CHarom), 130.5 (CHarom), 139.3 (Carom), 150.3 (vCH),
197.3 (CvO); IR (neat) nmax 2982, 1676, 1625, 1212,
1143, 1014 cm21; MS (EI) m/e (relative intensity) 190
(M1z, 52), 161 (40), 113 (18), 105 (100), 77 (80). Anal.
Calcd for C12H14O2: C 75.76; H 7.42%. Found C 75.80; H
7.50%.
4.9.16. 1-Phenyl-2-[4,5-(trans)dimethyl-k1,3l-dioxolan-2-
yl]propan-1-one (31). Isolated in 85% yield as an insepar-
able 50:50 mixture of two diastereomers; 1H NMR d 1.17±
1.24 (6H, 2CH3, 4d, Jˆ5.8, 5.8, 5.4, 5.4 Hz), 1.29 (3H, CH3,
d, Jˆ6.9 Hz), 3.60 (2H, CH2, m), 3.65±3.77 (1H, CH, 2qd,
Jˆ6.9, 3.8; 6.9, 4.2 Hz), 5.31±5.36 (1H, CH, 2d, Jˆ4.2,
3.8 Hz), 7.42±7.60 (3H, PhH, m), 7.95±8.01 (2H, PhH,
m); IR (neat) nmax 2977, 1683, 1597, 1216, 1104,
968 cm21; MS (EI) m/e (relative intensity) 234 (M1z, 1),
219 (11), 179 (13), 161 (6), 146 (8), 134 (10), 133 (18),
105 (100), 101 (99), 77 (92), 73 (44), 55 (31); HRMS
calcd for the mixture of isomers C14H18O3 (M1) 234.1256,
found 234.1260.
4.9.10.
3-Deuteromethoxy-2-methyl-1-phenyl-2(E)-
1
propen-1-one (25B). H NMR (CDCl3) d 1.89 (3H, CH3,
d, Jˆ1.1 Hz), 6.91 (1H, CHv, q, Jˆ1.1 Hz), 7.35±7.45
(3H, PhH, m), 7.50±7.60 (2H, PhH, m); proton-decoupled
13C NMR (CDCl3) d 8.9(CH3), 61.4 (OCD3), 117.3 (vC),
128.1 (2CHarom), 128.5 (2CHarom), 130.6 (CHarom), 139.0
(Carom), 164.4 (vCH),197.2 (CvO); IR (neat) nmax 2940,
1678, 1625, 1248, 1143 cm21; MS (EI) m/e (relative inten-
sity) 179 (M1z, 58), 177 (60), 105 (100), 77 (70); HRMS
Calcd for C11H9D3O2 (M1) 179.0837, found 179.0831.
Acknowledgements
4.9.11. 3,3-Dimethoxy-1-phenylpropan-1-one (26). 181H
NMR d 3.30 (2H, CH2, d, Jˆ5.2 Hz), 3.45 (6H, 2OCH3,
s), 5.02 (1H, CH, t, Jˆ5.2 Hz), 7.40±7.60 (3H, PhH, m),
7.9±8.0 (2H., PhH, m); IR (neat) nmax 1685, 1600, 750,
690 cm21; MS (EI) m/e (relative intensity) 194 (M1z, 2),
163 (M12OCH3), 136, 105 (100), 85, 77, 75 (MeO1v
CHOMe), 58, 51.
We gratefully acknowledge the ®nancial support for this
Á
work from Ministero dell'Universita e della Ricerca
Scienti®ca e Tecnologica (Co®n. 1998).
References
4.9.12. 3,3-Dimethoxy-1-(4-chlorophenyl)propan-1-one
1. For reviews on the acetalisation reaction see: (a) Meskens,
A. J. Synthesis 1981, 501. (b) Green, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New
York, 1991. (c) Kociensky, P. J. Protecting Groups; Georg
Thieme: Stuttgart/New York, 1994.
1
(27). H NMR (CDCl3) d 3.22 (2H, CH2, d, Jˆ5.4 Hz),
3.41 (6H, 2OCH3, s), 4.97 (1H, CH, t, Jˆ5.4 Hz), 7.44
(2H, ArH, A2B2), 7.90 (2H, ArH, A2B2); proton-decoupled
13C NMR (CDCl3) d 42.7 (CH2), 54.3 (2OCH3), 102.3 (CH),
128.8 (2CHarom), 129.8 (2CHarom), 135.5 (Carom), 139.8
(Carom), 195.8 (CvO); IR (neat) nmax 2940, 1686, 1594,
1092, 1012 cm21; MS (EI) m/e (relative intensity) 230±
228 (M1z, 4), 213 (13), 182 (13), 181 (13), 139 (53), 111
(23), 75 (100); HRMS Calcd for C11H13ClO3 (M1, Cl-35
isotope) 228.0553, found 228.0557.
2. For reviews see: (a) Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 477. (b) Whitesell, J. K. Chem. Rev. 1989,
89, 1581. (c) D. Seebach, D.; Imwinkelried, R.; Weber, T.
Modern Synthetic Methods; Springer: Berlin/Heidelberg,
1986; Vol. 4, pp 125±259.
3. For acetalisation promoted by Lewis acid catalysts see: (a)
Luche, J.-L.; Gemal, A. L. J. Chem. Soc., Chem. Commun.
1978, 976. (b) Gemal, A.-L; Luche, J.-L. J. Org. Chem. 1979,
44, 4187. (c) Ott, J.; Tombo, G. M. R.; Shmid, B.; Venanzi,
4.9.13. 3,3-Dimethoxy-1-(4-methoxyphenyl)propan-1-
one (28). 1H NMR (CDCl3) d 3.22 (2H, CH2, d,

A. Clerici et al. / Tetrahedron 57 (2001) 217±225
225
L. M.; Wang, G.; Ward, T. R. Tetrahedron Lett. 1989, 30,
6151. (d) Gorla, F.; Venanzi, L. M. Helv. Chim. Acta 1990,
73, 690. (e) Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto,
H. Synlett 1996, 839 and references quoted therein.
oxy group (4%), whereas the methyl group does not show a
NOE effect, indicating that it is remote from the irradiated
vinylic proton and that compound 25 has the conformation
trans/s-trans reported in Chart 1. Additional NOE experi-
ments show that the methyl group sterically interacts with
the methoxy group also, causing restricted rotation around
the Csp2±O single bond: in fact, irradiation of the methyl
group does not show a NOE effect either with the vinylic
proton or with the methoxy group, thus the energetically
favoured rotamer 25 has the conformation trans/s-trans/O-s-
trans (for nomenclature see Ref. 19b).
Â
4. Balme, G.; Gore, J. J. Org. Chem. 1983, 48, 3336.
5. This reaction has been studied deeply by a numbers of workers
since it provides non-racemic products starting from chiral
acetals: (a) Elliot, J. D.; Choi, V. M. F.; Johnson, W. S. J.
Org. Chem. 1983, 48, 2294. (b) Elliot, J. D.; Choi, V. M. F.;
Johnson, W. S. Tetrahedron Lett. 1984, 25, 591. (c) Denmark,
E. S.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089 and
references quoted therein. (d) Davis, A. P. Angew. Chem., Int.
Ed. Engl. 1997, 36, 591. (e) Wu, H.-J.; Chern, J-H. J. Chem.
Soc., Chem. Commun. 1997, 547.
16. Poland, A. E.; Benson, W. Chem. Rev. 1966, 66, 161 (refer-
ences quoted therein).
17. Royals, E. E.; Brannock, K. C. J. Am. Chem. Soc. 1953, 75,
2050.
18. Nishio, T.; Omote, Y. Synthesis 1980, 1013.
6. Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915
(references quoted therein).
7. (a) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 1998, 54,
15679. (b) Bassetti, M.; Floris, B. J. Chem. Soc., Perkin Trans.
2 1988, 227.
19. (a) Royals, E. E.; Brannock, K. C. J. Am. Chem. Soc. 1954, 76,
3041. (b) Dabrowski, J.; Tencer, M. Bull. Chem. Soc. Jpn
1975, 48, 1310.
8. Free energy difference between equatorial and axial Me
groups in a cyclohexanone ring is 1.74 kcal mol21, which
corresponds to a 5% of axial and to a 95% of equatorial
conformations: Booth, H.; Everett, J. R. J. Chem. Soc.,
Chem. Commun. 1976, 278.
20. (a) Hills, R.; Mc Quillin, F. J. Chem. Soc. 1953, 4060. (b)
Burness, D. M. J. Org. Chem. 1956, 21, 97.
21. Hudlicky, T.; Olivo, H. F.; Natchus, M. G. J. Org. Chem.
1990, 55, 4767.
22. Stabilized carbanions react with 13 via exclusive addition±
elimination at the b-carbon to give products resulting from the
substitution of the methoxy group by the nucleophiles (see
Ref. 11).
9. (a) Marshall, D. R.; Roberts, T. R. J. Chem. Soc. (B) 1971,
797. (b) House, H. O.; Rasmusson, G. H. J. Org. Chem. 1963,
28, 27. (c) Chen, B.-C.; Weismiller, M. C.; Davis, F. A. Tetra-
hedron 1991, 47, 173. (d) Takahashi, K.; Tanaka, T.; Suzuki,
T.; Hirama, M. Tetrahedron 1994, 50, 1327.
23. Most probably, the mechanism depicted in Scheme 2 is also
operative in the formation of b-methoxyenones, either from
1,3-cyclohexanediones (Eq. 4) or b-keto aldehydes (Scheme
1), that is: Ti(IV)-assisted MeOH addition to the ole®nic bond
of the enol form, followed by Ti(IV)-assisted water departure.
24. Instead, the susceptibility of carbonyl groups of 13±19 to
nucleophilic attack by MeOH is strongly attenuated by elec-
tron donation of the OCH3 group through the conjugated
double bond.
10. Zimmerman, H. E.; Wang, P. A. J. Am. Chem. Soc. 1993, 115,
2205.
11. Mphahlele, M. J.; Modro, T. A. J. Org. Chem. 1995, 60, 8236.
12. Nelson, P. H.; Nelson, J. T. Synthesis 1992, 1287.
13. (a) Forsen, S.; Nilsson, M. The Chemistry of the Carbonyl
Group; Patai, S., Ed.; Wiley: New York/London, 1970; Vol.
2, pp 198±220. (b) Yogev, A.; Mazur, Y. J. Am. Chem. Soc.
1967, 89, 2162.
25. (a) Org. Syn. Coll. 1963, Vol. IV, 536. (b) Org. React. 1954,
Vol. VIII, 164. (c) Wagner, B. D.; Arnold, B. R.; Brown, G. S.;
Lusztyk, J. J. Am. Chem. Soc. 1998, 120, 1827. (d) Wright, S.
W.; Harris, R. R.; Kerr, J. S.; Green, A. M.; Pinto, D. J.; Bruin,
E. M.; Collins, R. J.; Dorow, R. L.; Mantegna, L. R.; Sherk, S.
R.; Covington, M. B.; Nurnberg, S. A.; Welch, P. K.; Nelson,
M. J.; Magolda, R. L. J. Med. Chem. 1992, 35, 4061. (e)
Aspart-Pascot, L.; Lematre, J. Bull. Soc. Chim. Fr. 1971,
483. (f) House, H. O.; Reif, D. J.; Wasson, R. L. J. Am.
Chem. Soc. 1957, 79, 2490. (g) Levine, R.; Conroy, J. A.;
Adams, J. T.; Hauser, C. R. J. Am. Chem. Soc. 1945, 67,
1510. (h) Conturier, F. Comput. Rend. 1910, 150, 705;
Chem. Abstr. 4, 2093.
14. Fay, R. C.; Lindmark, A. F. J. Am. Chem. Soc. 1983, 105, 2118
(references quoted therein).
15. (a) It should be underlined that b-keto aldehydes of Table 3
were shown to be in the cis-enol form to an extent of about
1
90±95%, by H NMR, with the aldehydic carbonyl enolized.
Thus, on the basis of their reactivity, we must deduce that they
will form much less stable Ti(IV)-complexes in methanolic
solution than the unreactive acyclic 1,3-diketones do. (b) In
1
the H NMR spectra of 20±22 (see Spectroscopic data), the
signal of the two aromatic protons ortho to the carbonyl group
occurs at ca 7.9 ppm as expected, whereas in that of 25 there
are two different signals for the two ortho-aromatic protons,
the more intense H (ù95%) occurring at ca 7.5 ppm and the
other H (ù5%) at ca 8 ppm. This fact can be interpreted in
terms of an equilibrium shifted in favour of the resonance
stabilised trans/s-trans rotamer (Chart 1). In fact, in the s-
trans rotamer, the two aromatic protons ortho to the carbonyl
group lie in the shielding zone of both the carbonyl group and
the C±C double bond, thus, adsorbing at much higher ®eld
(7.5 ppm) than those of the trans/s-cis rotamer (8 ppm). For a
similar reason, the two ortho-aromatic protons of b-ethoxy-2-
methyl-1-phenylprop-2-en-1-one 25A are found at ca 7.5 ppm
(see Spectroscopic data). (c) Irradiation of the vinylic proton
of compound 25 raises the two aromatic protons ortho to the
carbonyl group (7%) and the methylenic protons of the meth-
26. For each known compound of Tables 1 and 2, the relevant
reference is given in succession: 1: commercial product
(Aldrich); 2, 3, 4, 5 and 11: Tateiwa, J.; Hiroki, H.; Sakae,
U. J. Org. Chem. 1995, 60, 4039; 6: Takeshi, O.; Yuichi, I.;
Gen, K. Bull. Chem. Soc. Jpn 1991, 64, 2581; 7: commercial
product (Fluka); 8: Kropp, P. J.; McNeely, S.; Davis, R. D. J.
Am. Chem. Soc. 1983, 105, 6907; 9: Zajac, W. W.; Byrne, K. J.
Á
J. Org. Chem. 1970, 35, 3375; 10: Nilsson, A.; Ronlan, A.
Tetrahedron Lett. 1975, 16, 1107; 13A: commercial product
(Aldrich); 13, 18 and 19: see Ref. 11; 14: see Ref. 9d; 15: see
Ref. 12; 16 and 17: see Ref. 10.
27. Fedor, L. R.; De, N. C.; Gurwara, S. K. J. Am. Chem. Soc.
1973, 95, 2905.