Mechanism of the double aldol reaction: The first spectroscopic characterization of a carbon-bound boron enolate derived from carboxylic esters

Article abstract of DOI:10.1021/ja0260014

The novel doubly borylated enolate is identified as an intermediate of the double aldol reaction of acetate esters. As a precursor to the formation of the doubly borylated enolate, carbon-bound boron enolates of carboxylic esters are spectroscopically cha

Full text of DOI:10.1021/ja0260014

Published on Web 08/15/2002
Mechanism of the Double Aldol Reaction: The First
Spectroscopic Characterization of a Carbon-Bound Boron
Enolate Derived from Carboxylic Esters
Atsushi Abiko,*,† Tadashi Inoue,† and Satoru Masamune‡
Contribution from the Venture Laboratory, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto, 606-8585 Japan, and Department of Chemistry,
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 22, 2002
Abstract: The novel doubly borylated enolate is identified as an intermediate of the double aldol reaction
of acetate esters. As a precursor to the formation of the doubly borylated enolate, carbon-bound boron
enolates of carboxylic esters are spectroscopically characterized for the first time. When 2,6-diisopropylphenyl
acetate (10d) is treated with c-Hex2BOTf (1.3 equiv) and triethylamine (1.5 equiv) in CDCl3, the corresponding
mono-enolate is formed as a mixture of oxygen- (11d) and carbon-bound (12d) forms in 71% and 20%
yields, respectively. The structures of these enolates have been unambiguously determined by NMR
spectroscopy. Investigation of the enolization of a series of substituted aryl acetates shows that the steric
factor of the acetate affects the degree of the mono-enolate (as a mixture of oxygen- and carbon-bound
enolates) and the doubly borylated enolate formation. Studies also revealed that oxygen- and carbon-
bound boron enolates exist as equilibrium mixtures and that a proton transfer process occurs between
oxygen- and carbon-bound enolates. The doubly borylated enolate formation is general for a variety of
carbonyl compounds. Besides acetate esters, carbonyl containing compounds, such as acetic acid,
dimethylacetamide, methoxyacetone, and 3-acetyl-2-oxazolidinone, also produce the doubly borylated
enolates when treated with c-Hex2BOTf (2.5 equiv) and triethylamine (3.0 equiv). A plausible pathway of
the double aldol reaction involving a carbon-bound boron enolate as a key intermediate is proposed.
Scheme 1
Introduction
Since the discovery of a convenient and reliable procedure
for the enolization of carbonyl compounds with dialkylboron
triflate and a tertiary amine,1 the boron-mediated aldol reaction
has been undoubtedly one of the most successful variants of
the modern aldol methodology. As a substrate of this reaction,
however, carboxylic esters have been scarcely used, as compared
with ketones, thioesters, or imides. Recently, we have found
that there are a number of unique features to the boron-mediated
aldol reaction of carboxylic esters,2a which are summarized as
follows: (i) the stereochemistry of an enolate of propionate ester
could be controlled by the judicious selection of the enolization
conditions, (ii) facile isomerization of an E-enolate3 to the
Z-enolate was observed, and (iii) the boron-mediated aldol
reaction of acetate esters proceeded in an unusual manner to
produce bis-aldols. More specifically, we have reported that anti-
and syn-â-hydroxy-R-methyl carbonyl adducts can be con-
a (i) c-Hex2BOTf (2.5 eq), Et3N (3 eq), (ii) RCHO. b(i) n-Bu2BOTf (2.5
eq), i-Pr2EtN (3 eq), (ii) RCHO. Mes ) 2,4,6-trimethylphenyl, OHA )
1,2,3,4,6,7,8,9-octahydroanthracenyl
* Address correspondence to this author. E-mail: abiko@ipc.kit.ac.jp.
† Kyoto Institute of Technology.
‡ Massachusetts Institute of Technology.
structed from chiral propionate esters 12b,d and 22c,d (Scheme
1a and 1b), and acetate ester 3 undergoes novel double aldol
reaction to give 4 selectively (Scheme 1c).4 Furthermore, bis-al-
dol 4 provided an efficient route to chiral triols of C3-symmetry.
(1) Mukaiyama, T.; Inoue, T. Bull. Chem. Soc. Jpn. 1980, 53, 174.
(2) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Org. Chem. 1996, 61, 2590. (b)
Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586.
(c) Liu, J.-F.; Abiko, A.; Pei, Z.; Buske, D. C.; Masamune, S. Tetrahedron
Lett. 1998, 39, 1873. (d) Inoue, T.; Liu, J.-F.; Buske, D. C.; Abiko, A. J.
Org. Chem. 2002, 67, 5250.
(3) In this paper the Z and E stereochemical descriptors of enol borinates are
defined on the assignment of the highest priority designation to the OBR2
group.
(4) Abiko, A.; Liu, J.-F.; Buske, D. C.; Moriyama, S.; Masamune, S. J. Am.
Chem. Soc. 1999, 121, 7168.
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J. AM. CHEM. SOC. 2002, 124, 10759-10764
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A R T I C L E S
Abiko et al.
Scheme 2
BOTf (2.5 equiv) were mixed in CDCl3 (0.27 M for MeOAc,
1
0.68 M for c-Hex2BOTf), the H NMR spectrum showed a
downfield shift of the chemical shift because of complexation
(Figure 1b). Addition of triethylamine (3.0 equiv) to the mixture
produced the doubly borylated enolate 5 (Figure 1c and d). The
structure of 5 was unequivocally established using modern NMR
techniques.5 (Detailed discussion is given in ref 5.) The order
of mixing of the reagents (acetate, boron triflate, and amine)
did not affect the results. 5, in turn, was proved to be an
intermediate of the double aldol reaction by the reaction with
isobutyraldehyde to give 6 (Figure 1e). The doubly borylated
enolate is unusual in that two dicyclohexylboron moieties are
incorporated in the enolate involving formation of a carbon-
boron bond. Double borylation in the doubly borylated enolate
was further confirmed by a deuteration experiment. When the
corresponding doubly borylated enolate derived from benzyl
acetate was treated with D2O-MeOD two deuteriums were
incorporated in the recovered acetate at the acetyl group
quantitatively. The corresponding doubly borylated enolates
could be prepared from methyl acetate with n-Bu2BOTf, 9-BBN
triflate, or c-Hex2BI under the same reaction conditions.
Chiral acetate ester 3 also afforded the doubly borylated
enolate 8 with c-Hex2BOTf (2.5 equiv) and triethylamine (3.0
equiv) (Scheme 2). At -73 °C in CD2Cl2-CDCl3, 8-E was
formed as a single isomer, which isomerized to a mixture of
8-E and 8-Z upon warming; 8-E: 8-Z ) 1:1 at -23 °C, 1:3 at
-3 °C (Figure 2). The facile isomerization of the doubly
borylated enolate is particularly noteworthy (vide infra). The
similar Z-isomer preference on the isomerization of the boron
enolate was observed for the chiral propionate ester 1. The E:Z
ratios of 8 at -73 °C (8-E only) and -3 °C (8-E: 8-Z ) 1:3)
were in good agreement with the ratios of the double aldol
products obtained by enolization at -78 °C (9a:9b:9c )
88:9:3) and at 0 °C (9a:9b:9c ) 23:67:10) (Scheme 2). 8-E
mainly produced 9a, whereas 8-Z afforded 9b as a major
product. Thus, the same chiral auxiliary group exhibited the
oposite sense of diastereofacial selection with its E and Z
enolates. The similar reversal of the facial selectivity was
observed in the related anti- and syn-selective asymmetric aldol
reactions (see Scheme 1i and ii).2b
1
1
Figure 1. (a) H NMR of methyl acetate, (b) H NMR of (a) + c-Hex2-
BOTf (2.5 eq), (c) H NMR of (b) + Et3N (3 eq), (d) 13C NMR of (b) +
Et3N (3 eq), (e) H NMR of (c) + i-PrCHO (3 eq).
1
1
From the detailed investigation of the double aldol reaction of
methyl acetate, the novel doubly borylated enolate 5 was identi-
fied as an intermediate enolate species (Figure 1). Herein, we
disclose further efforts to delineate the mechanism of the double
aldol reaction, including the characterization of the first carbon-
bound boron enolate of carboxylic esters. Part of the work
appeared earlier in preliminary form.5
Results and Discussion
NMR Spectroscopic Characterization of a Carbon-Bound
Boron Enolate. Mechanistic considerations concerning the
formation of a doubly borylated enolate naturally led to the
assumption of the intermediacy of an R-borylester. From a
structural point of view, three distinct types of “enolates” are
possible depending on the nature of the metal-enolate bond; an
oxygen-bound enolate, an R-metalocarbonyl compound (a
The Doubly Borylated Enolate as an Intermediate of the
Double Aldol Reaction. To elucidate the pathway of the double
aldol reaction, the reaction was monitored by NMR spectros-
copy. When methyl acetate (1.0 equiv) (Figure 1a) and c-Hex2-
(5) Abiko, A.; Inoue, T.; Furuno, H.; Schwalbe, H.; Fieres, C.; Masamune, S.
J. Am. Chem. Soc. 2001, 123, 4605.
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Mechanism of Double Aldol Reaction
A R T I C L E S
Figure 3. (a) Enolate mixture derived from 10d, c-Hex2BOTf (1.3 eq),
Et3N (1.5 eq). (b) Enolate mixture derived from 1-13C-10d, c-Hex2BOTf
(1.3 eq), Et3N (1.5 eq).
Scheme 4
Figure 2. 1H NMR spectrum (partial) of the doubly borylated enolate
mixture (8) from 3.
Scheme 3
of c-Hex2BOTf. This indicates that the doubly borylated enolate
is formed in a stepwise manner via a mono-enolate, presumably
via a carbon-bound enolate, and that the difference in the
distribution of mono- and doubly borylated enolates is attribut-
able to the difference in the rate of the first and the second
enolization steps (see below for detailed discussion).
From an extensive survey of acetate esters with the purpose
of detecting the possible “carbon-bound boron enolate” inter-
mediate, we found that certain aryl acetates afforded the
corresponding mono-boron enolates as a mixture of oxygen-
and carbon-bound forms. When 2,6-diisopropylphenyl acetate
(10d) was treated with 1.3 equiv of c-Hex2BOTf and 1.5 equiv
of triethylamine in CDCl3 at 0 °C, the 1H NMR spectrum
showed formation of two enolate species (oxygen- (11d) and
carbon-bound (12d) enolates) in a 7:2 ratio with 90% conversion
(see signals at 3.43 and 2.78 ppm in Figure 3 a, respectively)
(Scheme 4).The structures of these enolates were determined
using two-dimensional NMR techniques. The major species
exhibited a set of doublets (J ) 2.5 Hz) at 3.43 and 3.06
(concealed) ppm (CdCH2), which correlated to the 13C signal
a c-Hex2BOTf (1.0 eq), Et3N (1.3 eq), CDCl3 0 °C 5 min. bc-Hex2BOTf
(1.0 eq), Et3N (1.3 eq), CDCl3 -65 °C 5 min
carbon-bound enolate), and a η3-oxaallyl complex. Although
R-borylcarbonyl compounds have been described as a hypo-
thetical intermediate of certain reactions,6 boron enolates are
believed to exist only as oxygen-bound enolates, and carbon-
bound boron enolates have never been characterized as such.7
Assuming a two-step enolization process toward doubly
borylated enolates, treatment of an acetate ester with a decreased
amount of boron triflate should produce an intermediate mono-
boron enolate. Unexpectedly, when methyl acetate was treated
with 1.0 equiv of c-Hex2BOTf and 1.3 equiv of triethylamine,
1
1
at 68.1 ppm (CdCH2) in the [13C, H] COSY and [1H, 13C]
the H NMR spectrum showed the formation of the doubly
HMBC spectra (1J doublet) [(a) in Figure 4a and 4b], suggesting
the structure of the oxygen-bound enolate (11d) (Scheme 4).
Because the 2JC-1 H-2 is nearly 0 Hz, the [1H, 13C] HMBC cross-
peak between C-1 (161.1 ppm) and H-2 (3.43 and 3.06 ppm)
could not be observed (Figure 4b). The presence of the
keteneacetal substructure was proved using 1-13C-10d, where
C-2 appeared as a doublet (J ) 100 Hz) at 68.1 ppm (see
Supporting Information) and H-2 appeared as a doublet (2JC-1 H-2
) 0 Hz) at 3.43 ppm (Figure 3b). The minor component
exhibited a broad singlet at 2.78 ppm (COCH2B), which
correlated to the 13C signal at 32.7 ppm (COCH2B) in the [13C,
1H] COSY spectra [(b) in Figure 4a] and to the 13C signals at
35.7 ppm (COCH2BCH) and 172.1 (COCH2B) in the [1H, 13C]
HMBC spectra [(b) and (c) in Figure 4b, respectively]. The
borylated enolate 5 (43%) and unreacted acetate (57%) (Scheme
3a). In contrast to this, by the same treatment of 3 at -65 °C,
the intermediate mono-enolate 78 could be detected in the
reaction mixture [7, 15%; 8, 40% (E:Z ) 1:2); 3, 45%] (Scheme
3b).9 The difference in the product distribution (the degree of
the mono-enolate formation) between these substrates is note-
worthy (vide infra). In both cases, the mixture was quantitatively
converted to the doubly borylated enolate with another 1.3 equiv
(6) (a) Brown, H. C.; Rogic, M. M.; Rathke, M. W. J. Am. Chem. Soc. 1968,
90, 6218. (b) Hooz, J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 5936. (c)
Brown, H. C.; Rogic, M. M.; Rathke, M. W. Kabalka, G. W. J. Am. Chem.
Soc. 1968, 90, 818. (d) Pasto, D. J.; Wojtkowski, P. W. J. Org. Chem.
1971, 36, 1790. (e) Mukaiyama, T.; Murakami, M.; Oriyama, T.; Yamagu-
chi, M. Chem. Lett. 1981, 1193.
(7) Computational study of O- and C-bound boron enolate, see Ibrahim, M.
R.; Bu¨hl, M.; Knab, R.; von Rague Schleyer, P. J. Comput. Chem. 1992,
13, 423.
1
assignment of this peak was confirmed by the H NMR of the
(8) Because of a minute quantity and instability of 7, the structure was
enolate sample derived from 1-13C-10d (doublet at 2.78 ppm,
J ) 7.4 Hz) (Figure 3b). The 13C signal at 35.7 ppm
(COCH2BCH) showed a cross-peak between a proton around
determined using a 13C-enriched sample.
(9) To obtain a higher yield of 7, the enolization was conducted at -65 °C.
NMR spectra were recorded at -23 °C for better resolution. The E:Z ratio
of 8 slowly changed to 1:3 upon standing at -23 °C. See above.
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A R T I C L E S
Abiko et al.
Table 1. Enolization of Acetate Estersa
product composition [%]
entry
10
11
12
13b
1
2
3
4
5
6
7
8
10a (R1)H; R2)H)
10b (R1)Me; R2)H)
10c (R1)Et; R2)H)
10d (R1)i-Pr; R2)H)
10e (R1)Ph; R2)H)
10f (R1)Me; R2)t-Bu)
10g (R1)Me; R2)Br)
10h (R1)Me; R2)MeO)
54
17
10
7
10
27
11
18
0
52
56
71
46
37
63
46
0
14
15
20
43
13
15
13
46 (5:1)
17 (9:1)
19 (9:1)
2 (>20:1)
1 (1:1)
23 (4:1)
18 (9:1)
3 (12:1)
a A solution of acetate ester (0.5 mmol) and Et3N (0.75 mmol) in CDCl3
(2.5 mL) was treated with c-Hex2BOTf (0.65 mmol) at 0 °C. After 5 min,
the product composition was determined by 1H NMR. b Isomer ratio
(stereochemistry not determined) in parentheses.
to persist. 2,6-Dimethylphenyl esters with the substituents of
different electronic nature on the 4-position gave the mono-
enolate in comparable yields (Entries 2 and 6-8).
Chemical Properties of the Carbon-Bound Boron Enolate.
Carbon- and oxygen-bound enolates may exist as separable,
interconvertible species (e.g., Si enolates11) or equilibrium
mixtures (e.g., Sn enolates12) depending on the metals. To
elucidate the nature of the carbon-bound boron enolate species,
the chemical reactivity of the enolate mixture was examined.
With additional 1.3 equiv of c-Hex2BOTf (and 1.5 equiv of
Et3N), the mono-enolate mixture of 11d and 12d (prepared as
described above, see Table 1, entry 4) was quantitatively
converted to the doubly borylated enolate 13d (1:3, stereo-
chemistry not determined).13 When the same mono-enolate
mixture was treated with 0.5 equiv of benzaldehyde at 0 °C,
1H NMR showed formation of the boron aldolate 15d (43%)
leaving 11d (37%) and 12d (10%), whereas the treatment with
1.3 equiv of benzaldehyde afforded the mono-aldol product 16d
in 71% yield after workup (Scheme 5).
Scheme 5
Figure 4. (a) [13C, 1H] COSY of the enolate mixture. (b) [1H, 13C] HMBC
of the enolate mixture.
1
1.7 ppm (COCH2BCH) in the [13C, H] COSY spectra [(c) in
Figure 4a], proving the methine of the cyclohexyl group, while
a [1H, 13C] HMBC cross-peak was observed between ∼1.7
(COCH2BCH) and 32.7 ppm (COCH2BCH) [(d) in Figure 4b].
Accordingly, the structure was assigned as carbon-bound enolate
12d (Scheme 4).
As were the cases of methyl acetate and 3, the degree of
formation of mono-enolate was highly dependent on the steric
factor of the acetate. Formation of the mono-enolate became
less favorable with the less sterically demanding substituents
on the 2- and 6-positions; the lower analogues (2,6-diethyl- (10c)
and 2,6-dimethylphenyl (10b) acetates) gave less mono-enolates
(Table 1, entries 2 and 3) and phenyl acetate (10a) did not afford
the mono-enolate (Entry 1).10 This difference can be attributed
to steric factors; for the bulkier esters, the coordination of the
second molecule of boron triflate to the carbonyl group of the
R-borylester becomes too unfavorable to allow the mono-enolate
The aldol reaction presumably proceeded via the oxygen-
bound enolate.14 Thus, the indistinguishable reactivity of 11d
(11) Rearrangement of R-silyl carbonyl to silyl enol ether; e.g., Kwart, H.;
Barnette, W. E. J. Am. Chem. Soc. 1977, 99, 614 and references therein.
(12) Pereyre, M.; Bellegrade, B.; Mendelsohn, J.; Valade J. J. Organomet. Chem.
1968, 11, 97. Kobayashi, K.; Kawanisi, M.; Hitomi, T.; Kozima S. Chem.
Lett. 1984, 497l. Yasuda, M.; Katoh, Y.; Shibata, I.; Baba, A.; Matsuda,
H.; Sonoda N. J. Org. Chem. 1994, 59, 4386.
(10) With 2,6-di-tert-butylphenyl acetate (10i), the enolization proceeded up to
the mono-enolate stage, and none of the doubly borylated enolate was
observed even with excess amount of c-Hex2BOTf (3 equiv, 98%
conversion after 2 h).
(13) 13d afforded 14d in 76% yield (meso: dl ) 2:1) after addition of
benzaldehyde.
9
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Mechanism of Double Aldol Reaction
A R T I C L E S
Table 2. Enolization of Acetyl Derivativesa
R
conditionsa
mono-e nolate
doubly borylated enolate
R ) MeOCH2
R ) HO
[A]
[A]b
[A]
[A]
[A]
[A]
[A]
[A]
[A]
[A]
[B]
[B]
[C]
[C]
0%
0%
0%
0%
0%
>98%
>98%
>98%
>98%
>98%
0%
R ) Me2N
R ) 2-Py
R ) 2-Oxazolidione
R ) PhS
>98%
>98%
>98%
>98%
>98%
72%
>98%
0%
R ) Ph
R ) Et
0%
0%
0%
R ) 2-MeOC6H4
R ) 4-MeOC6H4
R ) 2-Oxazolidione
R ) MeOCH2
R ) PhS
0%
11%c
0%
>98%
>98%
R ) 2-MeOC6H4
0%
a Conditions: [A] Carbonyl compound (1.0 eq), c-Hex2BOTf (2.5 eq)
and Et3N (3.0 eq) in CDCl3 at 0 °C 5 min. [B] Carbonyl compound (1.0
eq), c-Hex2BOTf (1.0 eq) and Et3N (1.3 eq) in CDCl3 at -65 °C 10 min.
[C] Carbonyl compound (1.0 eq), c-Hex2BOTf (3.5 eq) and Et3N (4.0 eq)
in CDCl3 at 0 °C 24 h. b c-Hex2BOTf (4.0 eq) and Et3N (5.0 eq) were
employed. c Starting material 17%.
Figure 5. VT-NMR experiment of the enolate mixture prepared from 10d.
and 12d in these reactions suggests rapid equilibrium between
the oxygen- and carbon-bound boron enolates, and this was
confirmed by the variable temperature NMR experiments. The
oxygen and carbon-bound enolates existed as an equilibrium
mixture at -43 to ∼27 °C for 11d and 12d (Figure 5).15 The
equilibrium was established within the NMR acquisition time
and the ratio of 11d and 12d at equilibrium was only dependent
on the temperature and not on time; at higher temperatures the
enolate mixture consisted of more oxygen-bound enolate 11d.
These results imply that the activation energy of the isomer-
ization is very small and the product ratios are mostly
determined by the difference in the stability of both forms of
the enolates.16
Doubly Borylated Enolate Formation from Various Car-
bonyl Compounds. The doubly borylated enolate chemistry was
further examined (Table 2). Upon treatment with c-Hex2BOTf
(2.5 equiv) and Et3N (3.0 equiv) in CDCl3 at 0 °C for 5 min
(condition [A]), a variety of carbonyl compounds, such as
methoxyacetone, acetic acid, dimethylacetamide, 2-acetylpyri-
dine, and 3-acetyl-2-oxazolidinone,17 gave the corresponding
doubly borylated enolates. Only an oxygen-bound mono-enolate,
however, was detected from PhSCOCH3, acetophenone, 2-
butanone, 4-methoxyacetophenone, or 2-methoxyacetophenone.
With 1 equiv of the boron triflate, methoxyacetone and 3-acetyl-
2-oxazolidinone afforded the oxygen-bound mono-enolate in
>98% and 72% yields, respectively (condition [B]). The mono-
enolate of PhSCOCH3 and 2-methoxyacetophenone were slowly
converted to the doubly borylated enolates after prolonged
reaction at 0 °C with excess boron triflate (condition [C]). From
these results, it is conceivable that the formation of the doubly
borylated enolate, and the success of the double aldol reaction,
should be attributed to the stability of the carbon-bound boron
enolate species.18 Resonance stabilization of the carbon-bound
enolates of carboxylic ester, thioester, and ketone diminished
in this order, and the nearby chelating functional group stabilized
the carbon-bound enolate intermediate of methoxyacetone,
2-acetylpyridine, and 2-methoxyacetophenone.
Proton-Transfer Process in the Boron Enolate. The mono-
enolates of aryl acetates were reasonably stable but underwent
disproportionation to produce the starting acetate and the doubly
borylated enolates upon standing (Table 3, Scheme 6).21 The
rate of disproportionation was affected by the steric factor of
the substrate. Thus, a 15:56:14:15 mixture of 10c:11c:12c:13c
changed to a 35:30:8:27 mixture after 6 h, whereas a 6:72:20:2
mixture of 10d:11d:12d:13d changed to a 22:53:15:10 mixture
after 24 h. The ratio of oxygen- and carbon-bound enolates was
constant during the disproportionation process.
When 1-13C-10d (1 equiv) was added to the enolate mixture
prepared from 1-12C-10d (cf. Table 1, entry 4), 1H NMR showed
gradual formation of 1-13C-12d and 1-12C-10d. The dispropor-
tionation was suppressed at 24 h (Table 4). It is evident from
these results that there exists an equilibrium process between
the oxygen- and the carbon-bound enolates (and also between
the doubly borylated enolate and the acetate) via proton transfer
as described in Scheme 6.
Plausible Pathway of the Double Aldol Reaction. Now a
plausible pathway of the double aldol reaction can be sum-
marized as shown in Scheme 7. A boron triflate forms a complex
with both a carbonyl compound and an amine reversibly. When
the boron triflate-carbonyl compound complex 17 is more
(14) The higher reactivity of oxygen-bound metal enolates toward aldol reactions
has been reported. For Si enolate: Hong, Y.; Norris, D. J.; Collins, S. J.
Org. Chem. 1993, 58, 359. For Sn enolate: Kobayashi, K.; Kawanisi, M.;
Hitomi, T.; Kozima, S. Chem. Lett. 1983, 851. Labadie, S. S.; Stille, J. K.
Tetrahedron 1984, 40, 2329.
(18) It is known that the carbon-bound silyl enolate of esters are more stabilized
than those of ketones presumably by resonance stabilization. See Larson,
G. L.; Fuentes, L. M. J. Am. Chem. Soc. 1981, 103, 248.
(19) The boron enolate of ketones were reported to isomerize under rather forcing
conditions; (a) Masamune, S.; Mori, S.; van Horn, D.; Brooks, D. W.
Tetrahedron Lett. 1979, 1665. (b) Evans, D. A.; Nelson, J. V.; Vogel, E.;
Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099.
(15) The similar results were obtained with the enolate of 10e. See Supporting
Information.
(16) From the data in Figure 5, thermodynamic parameters were calculated:
(20) The double aldol reaction of 3 can be done with two different aldehydes
in a stepwise manner. See ref 4.
∆S0 ) -0.013 kcalmol-1 and ∆H0 ) -2.81 kcalmol-1
.
(17) The asymmetric double aldol reaction of chiral acetyloxazolidinones
proceeded with high selectivity. Furano, H.; Inoue, T.; Abiko, A. Submitted
for publication.
(21) During the disproportionation process, more starting acetates than the doubly
borylated enolates were produced. The reason of this phenomena is not
clear.
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A R T I C L E S
Abiko et al.
Scheme 7. A Plausible Pathway of the Double Aldol Reaction
Table 3. Disproportionation of Enolatesa
product composition [%]
time
10c
11c
12c
13c
5 min
1 h
2 h
4 h
6 h
15
15
22
31
35
44
56
57
48
35
30
17
14
15
13
10
8
15
13
17
24
27
35
24 h
4
product composition [%]
time
10d
11d
12d
13d
5 min
1 h
4 h
8 h
12 h
24 h
6
6
10
13
16
22
72
71
68
63
59
53
20
20
18
17
16
15
2
3
4
7
9
10
a A solution of acetate ester (0.5 mmol) and Et3N (0.75 mmol) in CDCl3
(2.5 mL) was treated with c-Hex2BOTf (0.65 mmol) at 0 °C. The product
1
composition was determined by H NMR at the indicated times.
even with 1 equivalent of boron triflate. For larger esters, “step
2” becomes slower because of steric hindrance. For acetophe-
none or 2-butanone, the concentration of the carbon-bound
enolate is too small to form 19 for further enolization to the
doubly borylated enolate. In the enolization of acetate esters
with sufficiently large R, the configuration of the initially formed
doubly borylated enolate is E (20a) at low temperature, which
may isomerize to Z-isomer (20c) upon warming. This facile
isomerization19 implies that it also proceeds through a carbon-
bound boron enolate (20b). The aldol reaction naturally proceeds
in a stepwise manner to afford R-boryl â-boryloxy carbonyl
intermediate 21, which isomerizes to the second (oxygen-bound)
enolate with E configuration 22.20 Then the bis-aldol 23 is
produced after reaction with the second equivalent of the
aldehyde.
Scheme 6
Table 4. Disproportionation of Enolates of 10d with 1-13C-10da
product composition [%]
time
1-13C-10d
1-12C-10d
11db
1-12C-12d
1-13C-12d
13d
5 min
1 h
4 h
8 h
12 h
24 h
50
50
46
44
44
42
8
10
14
19
22
25
32
30
30
27
26
24
9
7
6
5
4
4
1
1
1
1
1
1
2
3
4
3
4
Summary
Mechanistically, the boron-mediated aldol reaction has been
considered a “straightforward reaction”. However, our recent
research on the boron aldol reaction of carboxylic esters has
revealed its rather complex nature and, more importantly,
dramatically expanded its utility toward complementary anti-
and syn- selective asymmetric aldol reactions and the double
aldol reaction, with the identification of a “carbon-bound boron
enolate” as a key player. Further studies on the boron-enolate
chemistry are in progress in our laboratory.
a 10d (0.5 mmol) and Et3N (0.75 mmol) in CDCl3 (2.5 mL) was treated
with c-Hex2BOTf (0.65 mmol) at 0 °C. After being stirred for 5 min, 1-13C-
10d (0.5 mmol) was added to the reaction mixture. Then, 1H NMR was
recorded at the indicated times. b 1-13C- and 1-12C-11d are indistinguishable
1
in H NMR (JC-1 H-1 ) 0 Hz).
favorable than the boron triflate-amine complex and the acidity
of the R-proton of the boron-carbonyl complex is high enough
to be deprotonated with the amine, enolization proceeds (step
1). The initial product, an oxygen-bound mono-enolate 18a,
rapidly equilibrates with the carbon-bound enolate 18b, and the
latter is again enolized with the aid of boron triflate and amine
(step 2). This second enolization proceeds with an acetate ester
(and a thioacetate, acetyl-2-oxazolidinone and certain ketones)
irrespective of the amount of the carbon-bound enolates. For
acetates with smaller alcohol residue, “step 2” is faster than
“step 1”, thus only the doubly borylated enolate is produced
Acknowledgment. A.A. was supported by a grant from the
Ministry of Education, Culture, Sports, Science, and Technology
of Japan (Grant-in-Aid 10640578 and 13640533).
Supporting Information Available: Experimental detail and
1
NMR spectra (1H, 13C, [13C, H] COSY, [1H, 13C] HMBC) of
enolate mixtures. This material is available free of charge via
the Internet at http://pubs.acs.org.
JA0260014
9
10764 J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002