Solvent-free Mukaiyama aldol reaction of O-silyl dienolates catalyzed by benzoic acid

Article abstract of DOI:10.1016/j.tetlet.2005.06.152

The vinylogous aldol reaction of O-silyl dienolates deriving from 2,2-dimethyl-[1,3]-dioxin-4-ones proceeds in moderate to excellent yields in the presence of catalytic amounts of PhCOOH under solvent-free conditions. Modest to good yields can be obtained by using silica gel or 3 ? molecular sieves as heterogeneous catalysts.

Full text of DOI:10.1016/j.tetlet.2005.06.152

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6141–6144
Solvent-free Mukaiyama aldol reaction of O-silyl
dienolates catalyzed by benzoic acid
Maria Rosaria Acocella, Antonio Massa, Laura Palombi,
Rosaria Villano and Arrigo Scettri*
Dipartimento di Chimica, Universit a` di Salerno, 84081 Baronissi (Salerno), Italy
Received 23 May 2005; revised 28June 2005; accepted 28June 2005
Available online 14 July 2005
Abstract—The vinylogous aldol reaction of O-silyl dienolates deriving from 2,2-dimethyl-[1,3]-dioxin-4-ones proceeds in moderate
to excellent yields in the presence of catalytic amounts of PhCOOH under solvent-free conditions. Modest to good yields can be
˚
obtained by using silica gel or 3 A molecular sieves as heterogeneous catalysts.
ꢀ
2005 Elsevier Ltd. All rights reserved.
In these last years an ever increasing interest has been
aimed to solvent-free organic syntheses. In fact, avoid-
1
O
O
RCHO
1) cat
2) H+
+
2
ing the use of volatile, often flammable, expensive and
toxic solvents strongly reduces the waste production
and many fundamental processes have proven to be
achievable through efficient procedures characterized
by high simplicity of set-up and work-up.
OSiMe3
R’
1
Scheme 2.
silyl dienolates 1 promoted by Lewis acids such as
As well-documented in the literature, racemic and chiral
2b,5
6
TiCl4
or BF ÆEt O (Scheme 2).
3 2
compounds 2 are versatile intermediates in preparative
2
organic synthesis and, particularly, their easy conver-
7
A recent investigation on the reactivity of compounds
of type 1 pointed out their significant nucleophilic prop-
erties, so that the conversion 1 ! 2 was found to take
place in efficient way in the presence of a very weak
3
sion in d-hydroxy-b-ketoesters 3 (Scheme 1) has been
conveniently exploited, as the key-step, in the prepara-
4
tion of several bio-active compounds.
Lewis acid as SiCl . Since solvent-free reactions very
4
One of the typical approaches leading to compounds 2 is
based on a Mukaiyama-type aldol condensation of O-
often exhibit rather high reaction rates, it seemed inter-
esting to examine the reactivity of 1a,b (Scheme 3) in
Mukai- yama aldol condensations performed in the
absence of solvent.
Nevertheless, a preliminary control experiment, carried
out by using neat 1a (E/Z mixture in a 3/5 ratio) and
OH O
O
R''OH
OH
O
O
∆
R
OR''
R
O
R'
R'
OP
O
O
2
3
1)PhCOOH, 20˚C
1a,b
+
RCHO
2
)CF COOH
R
O
3
Scheme 1.
R’
2a,b: P= H
2'a,b: P= SiMe3
1
a: R'= Me
Keywords: Aldol reaction; Molecular sieves; Silica gel; Silyl dienolates.
1b: R'= H
*
Corresponding author. Tel.: +39 089 965 374; fax: +39 089 965
96; e-mail: scettri@unisa.it
2
Scheme 3.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.152

6142
M. R. Acocella et al. / Tetrahedron Letters 46 (2005) 6141–6144
Table 1. Benzoic acid-catalyzed Mukaiyama reaction of 1a on RCHO
cause quenching or decomposition of the used nucleo-
philes, such as silyl enol ethers. However, recent re-
a
b
Entry
R
Reac.
Prod. 2a Yield syn/anti dr
1
0
time (h)
(%)
ports have shown that several nucleophiles sensitive
to acidic conditions could be successfully reacted with
carbonyl compounds, suitably activated by mild protic
organo-catalysts through single or double hydrogen
c
1
Ph
2-Furyl
Ph
3
2.5
3
18
24
2
24
2
2
2aa
2ab
2aa
2aa
2ac
2ad
2ae
2af
62
82
/3 12 868
72
96
96
50
62
60
68/32
51/49
c
2
d
3
d
11
4
Ph
71/29
58/42
57/43
56/44
60/40
54/46
bonding. The possible involvement in the conversion
5
6
7
8
9
p-MeC
p-MeOC
PhCH
p-BrC
p-CNC
6
H
4
of type 1 ! 2 of a hydrogen bond-promoted aldol reac-
tion seemed to be reasonably confirmed by performing
the experiment of entry 4 in the presence of rac-BINOL
6
H
4
2
CH
2
6
H
4
(3% mol) since aldol 2aa was obtained in 73% yield (58/
6
H
4
2ag
4
2 syn/anti ratio). Furthermore, the employment of the
a
All the yields refer to isolated chromatographically pure compounds,
whose structures were confirmed by comparison of the spectroscopic
hindered 2,6-di-tert-butyl phenol (3% mol), as activator,
required higher temperature (40 ꢁC, reaction time 20 h)
to change p-anisaldehyde into 2ad, isolated in 74% yield,
as 52/48 syn/anti mixture.
1
13
9
data ( H and C NMR) with the ones reported in the literature. In
all entries RCHO/1a were used in 1/2 stoichiometric ratio. Typical
experimental procedure: in a dried vial diene 1 (2 equiv, 1 mmol),
benzoic acid (0.025 equiv) and aldehyde (1 equiv, 0.5 mmol) were
mixed and stirred at 20 ꢁC. The reaction was quenched by water
The same procedure showed to be successful with O-silyl
dienolate 1b, as confirmed by the data reported in Table
(
2 ml) and the organic layer extracted in Et
was desilylated by Kruger and Carreiraꢀs procedure and the result-
ing mixture purified by silica gel chromatography (eluent: CHCl
Et O 9/1).
syn/anti diastereoisomeric ratios were calculated by
400 MHz) analysis on the crude products 2a by accurate integration
2
O (3 · 5 ml). The crude
8
2
(entries 1–6).
3
–
2
It is noteworthy that preliminary experiments performed
on linear O-silyl dienolates, such as Chanꢀs diene 4 and
Danishefskyꢀs diene 5 (Fig. 1) gave very poor results: in
fact, under the typical conditions of entry 1 (Table 2) no
b
1
H
NMR
(
9
of the signals relative to CHOH protons.
c
In these entries undistilled aldehydes were used.
In this entry freshly distilled benzaldehyde was used.
evidence of formation of the corresponding vinylogous
d
1
aldols could be detected and H NMR analysis (CDCl )
3
performed directly on the crude reaction mixtures, with-
out any previous work-up, revealed only the presence of
unreacted benzaldehyde and the products of decomposi-
tion of 4 and 5 (methyl 3-trimethylsilyloxy crotonate
and 4-methoxy-but-3-en-2-one, respectively).
benzaldehyde as representative reagents, afforded a
rather surprising result: in fact, under the conditions re-
ported in Table 1 (entry 1, no catalyst added) the forma-
0
tion of the O-silylated aldol 2 aa was found to occur in
rather fast way: the following desilylation by acidic
0
treatment of the crude 2 aa, according to Kruger and
The employment of solvent-free conditions proved to be
particularly convenient: in fact the experiment of entry 1
was repeated in CH Cl solution (1 ml) and after 3.5 h a
mixture of aldol 2ba and O-silylated 2 ba was isolated.
The desilylation procedure afforded 2ba in only 46%
yield.
8
Carreira procedure, afforded the free aldol 2aa in
appreciable yield and moderate diastereosectivity. An
even better efficiency was observed by reacting 1a with
-furaldehyde under the same conditions (entry 2),
although the corresponding aldol 2ab was isolated in
1/1 diastereoisomeric ratio. However, it is noteworthy
that using freshly distilled benzaldehyde resulted in a
dramatic drop of yield (entry 3). This latter result sug-
gested the possibility that in entries 1 and 2 the presence
of benzoic or furoic acids, deriving from the auto-oxida-
tion of the corresponding aldehydes, could be responsi-
ble of the formation of the Mukaiyama aldols 2aa,ab. In
fact, undistilled benzaldehyde used in entry 1 was found
to be contaminated by benzoic acid in a significant way
2
2
0
2
ꢀ
Table 2. Solvent-free benzoic acid-catalyzed Mukaiyama reaction of
1b on RCHO
a
Entry
R
Reac. time (h) Prod. 2b Yield (%)
1
2
3
4
5
6
Ph
p-MeC
p-MeOC
PhCH
p-BrC
p-CNC
2
2
2
24
24
2
2ba
2bc
2bd
2be
2bf
2bg
70
72
85
40
64
61
6
H
4
6
H
4
(
9%). The determining role exerted by the carboxylic
2
CH
2
acid was confirmed by performing the solvent-free reac-
tion by using freshly distilled benzaldehyde in the pres-
ence of 0.025 equiv of PhCOOH (entry 4): in fact,
after the usual treatment, the aldol 2aa was isolated in
good yield and appreciable diastereoisomeric ratio. In
order to assess the level of general validity of this find-
ing, several aldehydes were submitted to reaction with
6
H
4
6
H
4
a
All the yields refer to isolated chromatographically pure compounds,
whose structures were confirmed by comparison of the spectroscopic
data ( H and C NMR) with the ones reported in the literature. In
1
13
9
all entries RCHO/1b were used in 1/2 stoichiometric ratio.
1
a and in all the reported entries 4–9 the formation of
the expected aldols 2a was found to take place in mod-
erate to very good yields, although a poor syn/anti selec-
tivity was usually observed. These results are
particularly interesting since many important prepara-
tive processes, including C–C bond formation reactions,
may suffer the presence of protic acids since they often
OSiMe3
Me SiO
OSiMe3
OMe
3
OMe
4
5
Figure 1.

M. R. Acocella et al. / Tetrahedron Letters 46 (2005) 6141–6144
6143
5
˚
As previously reported, in the past years TiCl has rep-
the capability of commercially available 3 A molecular
4
0
resented the catalyst of choice for Lewis acid-catalyzed
conversion 1 ! 2. For example, the formation of the
aldol 2ba was found to occur in 99% by performing
the reaction in CH Cl solution at ꢁ78 ꢁC in the pres-
sieves to catalyze the conversion 1a,b ! 2 a,b similarly
to silica gel and the moderate efficiency can be reason-
ably attributed to the reduced pore dimensions, forcing
therefore the reaction to take place only on the external
surface of the heterogeneous catalyst.
2
2
5
b
ence of stoichiometric amounts of the catalyst. In the
attempt to compare the catalytic properties of PhCOOH
and TiCl4 the experiment of entry 1 (Table 2) was
carried out under solvent-free conditions at room tem-
In conclusion, the vinylogous aldol reaction of acid-la-
bile masked forms of b-ketoesters was found to occur
in satisfactory way under solvent- and metal-free condi-
tions by activating the carbonyl functionality with ben-
zoic acid; similar catalytic properties were exhibited by
different protic organo-catalysts, such as rac-BINOL
and 2,6-di-t-butyl phenol, although in all cases a modest
stereoselectivity was usually observed. Alternatively,
both activated silica gel and commercially available
molecular sieves, characterized by the presence of
Brønsted acidic sites on their surface, promoted the for-
mation of the vinylogous aldols under heterogeneous
conditions with acceptable yields.
perature in the presence of 0.05 equiv of TiCl (reaction
time 2 h). It is noteworthy that the above treatment
again led to a mixture of 2ba and 2 ba and, after desily-
lation, pure 2ba could be obtained in 68% yield, pointing
out a very similar catalytic activity for both PhCOOH
and TiCl in the absence of solvent.
4
0
4
Keeping in mind that the employment of a heteroge-
neous catalyst could have allowed a significant improve-
ment of the free-solvent procedure especially in terms of
work-up and products isolation, the possibility to ex-
ploit the catalytic properties of Brønsted acidic silanol
groups situated on the surface of silica gel was exam-
ined. The preliminary results reported in Table 3 pointed
out that, in spite of the weakly acidic character of the sil-
1
2
Acknowledgement
0
We are grateful to Ministero dellꢀ Istruzione, Universita`
e Ricerca Scientifica (MIUR) for financial support.
anol groups, the formation of O-silylated products 2 a
took place in the presence of pre-activated silica gel;
the usual desilylation procedure afforded the free aldols
2
a in acceptable yields although a modest diastereoselec-
References and notes
tivity was usually observed (entries 1–5).
1
. (a) Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J.
L. J. Am. Chem. Soc. 2001, 123, 8701–8708; (b) Cave, G.
W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001,
2159–2169; (c) Tanaka, K.; Toda, F. Chem. Rev. 2000,
100, 1025–1074; (d) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding,
K. J. Am. Chem. Soc. 2002, 124, 10–11; (e) Toda, F. Acc.
Chem. Res. 1995, 28, 480–486; (f) Toda, F. Synlett 1993,
303–312; (g) Firouzabadi, H.; Iranpoor, N.; Sobhani, S.
Synthesis 2004, 16, 2692–2696.
As known, untreated molecular sieves exhibit intrinsic
catalytic properties which are generally associated with
the presence of Lewis and Brønsted acidic sites situated
on the external and, most of all, internal surface. In par-
ticular, catalytic sites characterized by strong Brønsted
acidity are origined by readily enolizable hydroxyl
1
3
groups. The experiments of entries 6–8highlighted
2
. (a) Katritzky, A. R.; Wang, Z.; Wang, M.; Hall, C. D.;
Suzuki, K. J. Org. Chem. 2005, 70, 4854–4856; (b) Morris,
W. J.; Custar, D. W.; Scheidt, K. Org. Lett. 2005, 6, 1113–
Table 3. Solvent-free Mukaiyama aldol reaction of 1a,b on RCHO
˚
promoted by silica gel and 3 A molecular sieves
1
1
116; (c) Dritz, J. H.; Carreira, E. M. Tetrahedron Lett.
997, 38, 5579–5582.
a
b
Entry
R
Reac.
Prod. 2a,b Yield syn/anti dr
3
. Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995,
17, 12360–12361.
. (a) Soriente, A.; De Rosa, M.; Apicella, A.; Scettri, A.;
time (h)
(%)
1
c
1
p-MeC
6
H
4
18
24
24
2ac
2af
2ag
2ah
2ae
2aa
2bc
2bd
49
55
57
40
3851/49
45
40
80/20
61/39
54/46
55/45
4
c
2
6
p-BrC H
4
Sodano, G. Tetrahedron: Asymmetry 1999, 10, 4481–4484;
c
3
p-CNC
6
H
4
(
b) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J.
A.; Charette, A. B.; Lautens, M. Angew. Chem., Int. Ed.
998, 37, 2354–2359; (c) Brennan, C. J.; Campagne, J.-M.
c
4
PhCH@CH 24
c
5
PhCH
Ph
2
CH
2
24
20
20
20
1
d
6
59/41
—
—
Tetrahedron Lett. 2001, 42, 5195–5197; (d) Hagiwara, H.;
Kimura, K.; Uda, H. J. Chem. Soc., Perkin Trans. 1 1992,
d
7
p-MeC
6
H
4
d
8
p-MeOC
6
H
4
50
6
93–700; (e) Hagiwara, H.; Kon-no, M.; Uda, H. J. Chem.
a
All the yields refer to isolated chromatographically pure compounds,
whose structures were confirmed by comparison of the spectroscopic
data ( H and C NMR) with the ones reported in the literature. In
Soc., Chem. Commun. 1992, 866–868.
5. (a) Jhan, U.; Hartmann, P.; Dix, I.; Jones, P. G. Eur. J.
Org. Chem. 2002, 718–735; (b) Bach, T.; Kirsch, S. Synlett
2001, 1974–1976; (c) Sato, M.; Sugita, Y.; Abiko, Y.;
Kaneko, C. Tetrahedron: Asymmetry 1992, 3, 1157–1160.
6. Enders, D.; Piva, O.; Burkamp, F. Tetrahedron 1996, 52,
2893–2908.
7. Acocella, M. R.; De Rosa, M.; Massa, A.; Palombi, L.;
Villano, R.; Scettri, A. Tetrahedron 2005, 61, 4091–4097.
8. Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120,
837–838.
1
13
9
all entries RCHO/1a,b were used in 1/2 stoichiometric ratio.
b
c
1
syn/anti Diastereoisomeric ratios were calculated by H NMR analy-
sis (400 MHz) on the crude products 2a by accurate integration of the
9
signals relative to CHOH protons.
Entries 1–5 were carried out on 0.5 mmol scale of RCHO in the
presence of pre-activated (48h at 120 ꢁC) Merck chromatographic
silica gel 60 (63–200 lm) (0.1 g).
Entries 6–8were carried out on 0.5 mmol scale of RCHO in the
presence of activated (48h at 120 ꢁC) commercially available 3 A˚
molecular sieves purchased from Aldrich (pellets, 0.5 g).
d
9. De Rosa, M.; Acocella, M. R.; Rega, M. F.; Scettri, A.
Tetrahedron: Asymmetry 2004, 15, 3029–3033.

6144
M. R. Acocella et al. / Tetrahedron Letters 46 (2005) 6141–6144
1
0. (a) Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed.
005, 44, 1924–1942; (b) Bolm, C.; Rantanen, T.; Schiffers,
I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44, 1758–1763;
c) the same activation of the carbonyl function by
11. Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062–
2
2064.
12. Butters, M. In Zeolite Assisted Organic Synthesis, A
Survey in Solid Supports and Catalysts in Organic Synthe-
sis; Smith, K., Ed.; Ellis Horwood PTR, Prentice Hall:
New York, 1992, p 8.
(
carboxylic acids was proposed for the allylation of
aldehydes by allyl stannanes: see Li, G.; Zhao, G. J.
Org. Chem. 2005, 70, 4272–4278.
13. See Ref. 12, p 32.