Sodium phenoxide-phosphine oxides as extremely active Lewis base catalysts for the Mukaiyama aldol reaction with ketones

Article abstract of DOI:10.1021/ol702052r

(Chemical Equation Presented) A highly efficient Mukaiyama aldol reaction between ketones and trimethylsilyl enolates catalyzed by sodium phenoxide-phosphine oxides as simple homogeneous Lewis base catalysts (0.5-10 mol %) was developed, which minimized c

Full text of DOI:10.1021/ol702052r

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4527-4530
Sodium Phenoxide−Phosphine Oxides
as Extremely Active Lewis Base
Catalysts for the Mukaiyama Aldol
Reaction with Ketones
Manabu Hatano, Eri Takagi, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya UniVersity, Furo-cho,
Chikusa, Nagoya, 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received August 21, 2007
ABSTRACT
A highly efficient Mukaiyama aldol reaction between ketones and trimethylsilyl enolates catalyzed by sodium phenoxide
simple homogeneous Lewis base catalysts (0.5 10 mol %) was developed, which minimized competing retro-aldol reaction. For a variety of
aromatic ketones and aldimines, aldol and Mannich-type products with an -quaternary carbon center were obtained in good to excellent
yields. Up to 100 mmol scale of benzophenone and trimethylsilyl enolate with 0.5 mol % of catalyst was established in 97% yield (34.8 g).
−phosphine oxides as
−
r
The catalytic aldol reaction is one of the most important and
useful reactions for synthesizing a â-hydroxy carbonyl
structural scaffold, which is often found in natural products
and pharmaceuticals.1 Remarkably, however, an efficient
synthesis of tertiary aldols (aldol adducts of enolates with
ketones) is still limited.2 This is because (1) the reactivity
of ketones is low due to electronic and steric reasons and
(2) the intrinsic retro-aldol reactions are generally rapid.2b,d
Actually, according to our preliminary experiments, the direct
aldol reaction of Na enolate (2)3 with benzophenone (1a)
gave the desired product (3a-OH) in only 1% yield (eq 1).
Surprisingly, 87% of the corresponding Na aldolate quickly
decomposed to 1a within 1 min due to the rapid retro-aldol
reaction even at -78 °C (eq 2). Moreover, a poor result (0%
yield) was obtained in an exemplary Lewis acid-catalyzed
Mukaiyama aldol reaction between 1a and trimethylsilyl
(TMS) enolate (4a) by using 10 mol % of TMSOTf even at
60 °C (eq 3).4 Thus, there are many difficulties in tertiary
aldol synthesis from, particularly, diaryl ketones. However,
we considered that, in principle, rapid TMS protection to
the corresponding tertiary aldolate via anionic activation to
TMS enolate by Lewis base catalysts might minimize the
retro-aldol reaction (eq 4). We report here, for the first time,
simple and highly effective Lewis base catalysts such as
(1) (a) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. (b)
Mahrwald, R. Chem. ReV. 1999, 99, 1095. (c) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. (d) Palomo, C.; Oiarbide,
M.; Garc´ıa, J. M. Chem. Soc. ReV. 2004, 33, 65. (e) Mahrwald, R. Modern
Aldol Reactions; Wiley-VCH: Weinheim, Germany, 2004. (f) Farina, V.;
Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. ReV. 2006, 106, 2734.
(2) Cl3Si- or (RO)3Si enolates with ketones: (a) Denmark, S. E.; Fan,
Y. J. Am. Chem. Soc. 2002, 124, 4233. (b) Oisaki, K.; Suto, Y.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5644. (c) Denmark, S. E.;
Fan, Y.; Eastgate, M. D. J. Org. Chem. 2005, 70, 5235. (d) Oisaki, K.;
Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7164.
(3) Lochmann, L.; Trekoval, J. J. Organomet. Chem. 1975, 99, 329.
(4) Pioneering Lewis acid or Lewis base catalysis with Si enolates with
aldehydes: (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,
1011. (b) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am.
Chem. Soc. 1996, 118, 7404. (c) Matsukawa, S.; Okano, N.; Imamoto, T.
Tetrahedron Lett. 2000, 41, 103. (d) Fujisawa, H.; Mukaiyama, T. Chem.
Lett. 2002, 31, 182. (e) Nakagawa, T.; Fujisawa, H.; Nagata, Y.; Mukaiyama,
T. Bull. Chem. Soc. Jpn. 2004, 77, 1555. (f) Fujisawa, H.; Nakagawa, T.;
Mukaiyama, T. AdV. Synth. Catal 2004, 346, 1241. (g) Nakagawa, T.;
Fujisawa, H.; Nagata, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2005, 78,
236.
10.1021/ol702052r CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/26/2007

sodium phenoxide (5b) with phosphine oxides (L) (eqs 4
and 5), which were designed for tertiary aldol syntheses with
an R-quaternary carbon center between ketones and easily
available TMS enolates.
(entries 1-5).7 The reactions did not proceed in the absence
of either 5b or L (entries 6 and 7). To our delight, the reaction
proceeded with 1 mol % of 5b and 1-3 mol % of L (entries
8-10).
Under the optimized reaction conditions, a 100 mmol scale
amount of the desired tertiary aldol 3a with an R-quaternary
carbon center was obtained in 97% yield (34.8 g) from 1a
and 4a with 0.5 mol % of 5b‚L2 in THF at -78 °C for 6 h
(eq 6).
Scheme 1. Toward Aldol Reaction with Benzophenone 1a
Next, we examined the aldol synthesis of other TMS
enolates (4a-h) with 1a in the presence of a mixed cata-
lyst 5b‚L2 (1 mol %) in THF at -78 °C for 2 h, in which
tertiary aldols with an R-quaternary or R-tertiary carbon
would be formed (Table 2). In particular, the reaction of R,R-
Table 2. 5b‚L2-Catalyzed Mukaiyama Aldol Reactions
First of all, Mukaiyama aldol reactions between 1a and
TMS enolate (4a) were examined in the presence of alkaline
metal phenoxide (PhOM, 5) as a Lewis base catalyst.5,6 We
found that the co-presence of phosphine oxides, especially
bidentate 1,2-(OdPPh2)2C6H4 (L), remarkably increased the
activity of the catalysts. Table 1 shows the results with simply
mixed homogeneous catalysts of 5 and L in TMS aldol (3a)
syntheses from 1a and 1.2 equiv of 4a in THF at -78 °C
for 5 min-2 h. With 10 mol % each of 5 and L, PhONa
(5b) showed high reactivity among alkaline metal phenoxides
Table 1. Mukaiyama Aldol Reactions of 4a with
Benzophenone (1a) Catalyzed by Alkaline Metal
Phenoxide-Phosphine Oxides (5‚Ln)
entry
5 [M]a
La yieldb entry
5 [M]a
La yieldb
a 5 mol % of 5b‚L2 was used.
1
2
3
4
5
5a [Li], 10 10 69 [40]c
5b [Na], 10 10 84 [86]c
5c [K], 10 10 80 [79]c
5d [Rb], 10 10 76
6
7
8
9
5b [Na], 10
-, 0
5b [Na], 1
5b [Na], 1
0
10
1
2
3
0
0
92 [22]d
97 [34]d
89 [38]d
disubstituted TMS ketene acetals with 1a proceeded with
yields of 87-99% in 3a-d. â-Lactone 3g′ was obtained in
5e [Cs], 10 10 73
10 5b [Na], 1
a Units: mol %. b Units: %. c Reaction time was 15 min. d Reaction time
was 5 min.
(5) Ba(OPh)2-catalyzed direct aldol reactions: Saito, S.; Kobayashi, S.
J. Am. Chem. Soc. 2006, 128, 8704.
4528
Org. Lett., Vol. 9, No. 22, 2007

>99% yield from the phenyl ester-derived enolate. O-TMS
N,O-ketene acetal also reacted with 1a, and 3h was obtained
in 86% yield. Encouraged by the good reactivities for
commonly used TMS enolates with 1a, we further examined
the reactions between other ketones and 4a or 4h by using
1-10 mol % of 5b‚L2 (Table 3). Unfortunately, the reactivity
quaternary carbon centers were obtained in 83% and 92%
yield, respectively (entries 8 and 9).
We next examined aldimines (6) with TMS enolates (4)
in the presence of 5-10 mol % of 5b‚L2 (Table 3). In
principle, aldimines are not much reactive due to their weak
electrophilic nature, and moreover, deactivation was expected
particularly in the case of Lewis acid catalysts because of
the increasing basicity of the corresponding products. Anionic
Lewis base catalyst 5b‚L2, however, showed high catalytic
activities with N-Bz, N-Boc, and N-Cbz protected aldimines
(6a-c) in Mannich-type reactions with 4, and the corre-
Table 3. 5b‚L2-Catalyzed Mukaiyama Aldol Reactions
Table 4. Mannich-Type Reactions of 4 with Aldimine 6
a 1 mol % of 5b‚L2 was used. b 5 mol % of 5b‚L2 was used. c 10 mol %
of 5b‚L2 was used.
a Reaction was examined at 0 °C for 2 h. b 10 mol % of 5b‚L2 was used.
c 5 mol % of 5b‚L2 was used.
of acetophenone with enolizable R-proton was not high,
probably due to the basicity of the catalyst, and 3i was
obtained in moderate yield (entry 1). In sharp contrast,
diphenylpropynone, enolizable heteroaromatic ketones, diaryl
ketones, and ferrocenyl ketone provided the desired corre-
sponding aldols in 71-99% yield (entries 2-7). An R-dike-
tone and an R-ketoester also reacted with 4, and polyfunc-
tionalized aldol compounds (3p and 3q) with vicinal
sponding adducts (7) were obtained in up to >99% yield.
Deprotection of the N-Boc product 7b smoothly proceeded
under AcCl-MeOH conditions to give the primary amine
compound in quantitative yield.
Finally, we turned our attention to the study of the active
catalysts. When 3a-OH (10 mol %), NaN(SiMe3)2 (10 mol
%), and L (20 mol %) were used, 3a was obtained in only
8% yield while an estimated maximum yield was 110% (eq
7). Therefore, the possibility of self-catalysis by the corre-
sponding aldolate (3a-O-) was denied.4f However, addition
(6) (a) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. J. Am. Chem.
Soc. 2005, 127, 10776. (b) Hatano, M.; Miyamoto, T.; Ishihara, K. J. Org.
Chem. 2006, 71, 6474.
(7) AcONa‚L2 or t-BuONa‚L2 (10 mol %) with low solubility showed
no catalytic activity under the same reaction conditions.
Org. Lett., Vol. 9, No. 22, 2007
4529

of 10 mol % of PhOTMS under the same conditions
promoted the reaction, and 3a was obtained quantitatively
(eq 7). These results show the importance of the PhO- moiety
in situ. Fortunately, a single crystal could be obtained for
X-ray analysis of tetrahedral Li complex (8‚OH) bearing Li+
and L2 as a cation moiety and HO- as an anion moiety
(Figure 1).8 As an analogy from 8‚OH in the X-ray analysis,
Figure 2. Postulated catalytic cycle including initial precursor
5b‚L2.
In summary, we have developed a highly efficient Mu-
kaiyama aldol reaction between ketones and TMS enolates
catalyzed by sodium phenoxide-phosphine oxides as a
simple Lewis base. Aldol products with an R-quaternary
carbon center were obtained in high yields with prevention
of the serious retro-aldol reactions, by rapidly protecting the
corresponding aldolates with TMS. Further studies of the
application to other catalyses and a challenge toward
enantioselective catalyses, are now underway.
Figure 1. ORTEP drawing of the cationic moiety of Li complex
(8‚OH).
we can predict the structure of 5b‚L2 as a possible active
catalyst,9 although 8‚OH should not be the active species
because no catalytic activity was observed by LiOH‚L2 or
NaOH‚L2 in the reaction of 1a and 4a. In particular, for
5b‚L2, the Na+ moiety wrapped by L2 should make the
counteranion (i.e., PhO-) naked and hypervalent silicate 9
would be generated (Figure 2).10,11 Thus, activated enolate
9 could ultimately increase the nucleophilicity enough to
attack even ketones. Presumably, the naked PhO- as 5b‚L2
could be regenerated from PhOTMS in continuous catalytic
cycles (see also eq 7).12
Acknowledgment. This paper is dedicated to the memory
of Professor Yoshihiko Ito. Financial support for this project
was provided by Grant-in-Aid for Young Scientists B
(19750072) of MEXT, Toray Science Foundation, Tatematsu
Foundation, Toyoaki Schlorship Foundation, General Sekiyu
Research & Development Encouragement & Assistance
Foundation, and Ichihara International Scholarship Founda-
tion.
Supporting Information Available: Experimental pro-
cedures and spectral data, as well as copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Due to adventitious water during the recrystallization of 5a‚L2, the
phenol moiety was interchanged by hydroxide in the crystal structure.
(9) HRMS(FAB+) analysis of 5b‚L2 also assisted in determining the
structure of the 1:2 complex (calcd for [Na‚L2]+ 979.2401, found 979.2408).
(10) (a) Chuit, C. C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem.
ReV. 1993, 93, 1391. (b) Rendler, S.; Oestreich, M. Synthesis 2005, 1727.
(c) Orito, Y.; Nakajima, M. Synthesis 2006, 1391.
OL702052R
(11) Anionic fluoride-promoted reactions with RSi(OMe)3 or RSiMe3:
(a) Hosomi, A.; Shirahata, A.; Sakurai, H. Tetrahedron Lett. 1978, 19, 3043.
(b) Aoyama, N.; Hamada, T.; Manabe, K.; Kobayashi, S. Chem. Commun.
2003, 676. (c) Biddle, M. M.; Reich, H. J. J. Org. Chem. 2006, 71, 4031.
(12) Addition of PhOTMS (1 mol %) in the presence of 2 mol % of L
was not effective in the reaction between 1a and 2, and therefore, PhO- is
essential for the activation of TMS enolates but not Na enolates.
4530
Org. Lett., Vol. 9, No. 22, 2007