A new look at boron enolate chemistry: Aminative C-C bond formation using diaminoboron enolate with aldehyde

Article abstract of DOI:10.1021/ol0497436

Unlike ordinary boron enolates, such as dialkylboryl (R₂B) and dialkoxyboryl ((RO)₂B) derivatives, reactions of diaminoboryl ((R₂N)₂B) enolates with aldehydes proceed with the concurrent transfer of amino and enoxy groups from the boron to the aldehyde carbon, yielding β-amino ketones in a selective manner.

Full text of DOI:10.1021/ol0497436

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1167-1169
A New Look at Boron Enolate
Chemistry: Aminative C−C Bond
Formation Using Diaminoboron Enolate
with Aldehyde
Michinori Suginome,* Lars Uehlin, Akihiko Yamamoto, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
suginome@sbchem.kyoto-u.ac.jp
Received February 13, 2004
ABSTRACT
Unlike ordinary boron enolates, such as dialkylboryl (R B) and dialkoxyboryl ((RO)2B) derivatives, reactions of diaminoboryl ((R N)2B) enolates
2
2
with aldehydes proceed with the concurrent transfer of amino and enoxy groups from the boron to the aldehyde carbon, yielding â-amino
ketones in a selective manner.
Boron enolate is one of the most versatile reagents for the
aldol-type C-C bond formation reactions.1 Its reactions with
aldehydes proceed via compact cyclic transition states, which
are believed to be crucial for the high stereoselectivity of
the aldol formation.2,3 To attain the Lewis acidity of the boron
centers, dialkylboron (1a) and dialkoxyboron (1b) derivatives
are usually employed (Figure 1). In contrast, diaminoboron
nonbonding lone pair on the nitrogen atom to the vacant
boron p-orbital makes a carbonyl-boron interaction unfavor-
able.
Recently, we reported that bis(dialkylamino)cyanoboranes
served as a highly efficient reagent for Strecker-type ami-
native cyanation of aldehydes.4 The concurrent transfer of
both the amino and the cyano group to the carbonyl carbon
was so efficient that stoichiometric reaction of the amino-
cyanoborane afforded the corresponding R-amino nitrile in
near-quantitative yields.5 Remarkably, no cyanohydrin was
formed by simple cyanation. On consideration of the reaction
mechanism, it occurred to us that replacing the cyano group
of the aminocyanoboranes with another nucleophilic group
(2) For diastereoselectivity in boron-mediated aldol reactions, see: (a)
Masamune, S.; Mori, S.; Van Horn, D.; Brooks, D. W. Tetrahedron Lett.
1979, 20, 1665. (b) Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem.
Soc. 1979, 101, 6120. (c) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T.
R. J. Am. Chem. Soc. 1981, 103, 3099.
Figure 1.
(3) For asymmetric aldol reactions using boron enolates, see: (a)
Masamune, S.; Sato, T.; Kim, B.; Wollmann, T. A. J. Am. Chem. Soc. 1986,
108, 8279. (b) Paterson, I.; Lister, M. A.; McClure, C. K. Tetrahedron Lett.
1986, 27, 4787. (c) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B.
J. Am. Chem. Soc. 1989, 111, 5493. (d) Review: Cowden, C. J.; Paterson,
I. Org. React. 1997, 51, 1.
(4) Suginome, M.; Yamamoto, A.; Ito, Y. Chem. Commun. 2002, 1392.
(5) Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Fochi, M.; Comes-
Franchini, M.; Ricci, A. Synlett 2003, 1778.
derivatives (2) have attracted less attention, partly because
of the low acidity of their boron center. The donation of the
(1) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 2., p
239.
10.1021/ol0497436 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004

would lead to the development of new aminative C-C
formation reactions.6 Herein, we report on a Mannich-type
reaction of bis(dialkylamino)boron enolates 2 with aldehydes,
which leads to the highly selective formation of â-amino
ketones.7
There are a few precedents of reactions of aminoboron
enolates with aldehydes. It has been reported that ordinary
aldol products were obtained in good yields in the reaction
of cyclohexenoxybis(dimethylamino)borane with aldehydes.8
Similarly, chloro(dialkylamino)boron enolates have been
reported to yield aldol products in their reaction with
aldehydes.9 Despite these rather discouraging precedents, we
carried out experiments to verify our hypothesis.
We prepared bis(diethylamino)boron enolate 2a by react-
ing the lithium enolate of acetophenone with chlorobis-
(diethylamino)borane. The boron enolate was isolated by
distillation in a high yield. Although the reaction of 2a with
benzaldehyde (2 equiv) was sluggish at room temperature
in THF, heating the reaction mixture to 50 °C for 5 h led to
the complete consumption of 2a. We found that â-amino
ketone was formed in a good yield, with no formation of
the corresponding aldol product (Table 1, entry 1). Further-
lidino groups successfully afforded the corresponding amino
ketones (entries 5 and 6). In these reactions, use of DMF as
a solvent moderately accelerated the Mannich-type reaction,
allowing the reaction to proceed to completeness within 2 h
at 50 °C. It is important to note, however, that the
decomposition of the â-amino ketone products to R,â-
unsaturated ketones via the elimination of amines becomes
the dominant reaction in DMF if long reaction times or higher
reaction temperatures are used.11 Remarkably, aminative
C-C bond formation also took place at the geminally
disubstituted carbon atom of enolate 2d (entry 7). In this
particular case, use of DMF as a solvent at 80 °C was
essential to drive the reaction to completion. Boron enolate
2e, derived from acetone, also reacted with benzaldehyde to
afford good yields (entry 8).
It is interesting to note that the R-amino acid derivatives
bearing γ-keto functions were synthesized by this reaction
protocol. Thus, reactions of 2a and 2d with polymeric
glyoxylic acid ethyl ester (3e) in DMF at 50 °C led to the
formation of 4ae and 4de, respectively, in high yields
(Scheme 1).
Scheme 1
Table 1. Reactions of Diaminoboron Enolates 2 with
Aldehydesa
entry
enolate (R1, R2, NR2)
aldehyde (R3)
% yieldb
These results prompted us to reinvestigate Hoffmann’s
aldol system, in which boron enolate 5a was reacted with
benzaldehyde in THF (Table 2).8 We did reproduce their
results, in which the aldol product 6 was obtained as the
1
2
3
4c
5c
6c
7c,e
8
2a (Ph, H, NEt2)
2a
2a
2a
2b (Ph, H, N(allyl)2)
2c (Ph, H, pyrrolidino)
2d (Ph, Me, NEt2)
2e (Me, H, NEt2)
3a (Ph)
3b (p-MeOC6H4)
3c (p-NCC6H4)
3d (H)d
3a
3a
3a
3a
84 (4a a )
87 (4a b)
97 (4a c)
90 (4a d )
88 (4ba )
66 (4ca )
63 (4d a )
84 (4ea )
Table 2. Reactions of Diaminoboron Enolates 2 with
Aldehydesa
a A mixture of boron enolate 2 (0.25 mmol) and aldehyde 3 (0.5 mmol)
in THF (0.5 mL) was stirred at 50 °C for 5 h unless otherwise noted. b NMR
yield (2,6-dimethylanisol or benzyl acetate as an internal standard). c In
DMF. d Paraformaldehyde. e At 80 °C.
more, the reactions of p-substituted benzaldehydes with 2a
afforded the corresponding â-amino ketones 3b and 3c in
high yields (entries 2 and 3). Boron enolate 2a also reacted
with paraformaldehyde to afford 4ad in a high yield (Table
1, entry 4).
Reactions of a series of aminoboron enolates 2b-e with
benzaldehyde 3a were also tested.10 Acetophenone-derived
boron enolates 2b and 2c bearing diallylamino and pyrro-
boron
% yieldb % yieldc
entry
enolate
solvent
T, °C
6
7
1
2
3
4
5
6
5a (R ) Me)
THF
THF
DMF
DMF
THF
DMF
-78∼20
50
-70 to 20
50
-78 to 20
50
63
57
61
5
trace
trace
20
5a
5a
5a
50
5b (R ) Et)
47
28
5b
72
a Boron enolate 5 (0.25 mmol), benzaldehyde 3a (0.5 mmol), and the
solvent (0.5 mL) were used. b NMR yield (using 2,6-dimethylanisol or
benzyl acetate as an internal standard). The diastereomeric ratios were
10:1-15:1. c NMR yield. The diastereomeric ratios were in the range
2.5:1∼1:1.
(6) Sugasawa, T.; Toyoda, T. Synth. Commun. 1979, 9, 553.
(7) Recent review of the Mannich reaction: Arend, M.; Westermann,
B.; Risch, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 1044.
(8) Hoffmann, R. W.; Ditrich, K.; Fro¨ch, S. Ann. Chem. 1987, 977.
(9) Sugasawa, T.; Toyoda, T.; Sakakura, K. Synth. Commun. 1979, 9,
583.
1168
Org. Lett., Vol. 6, No. 7, 2004

major product (entry 1). In the reaction mixture, however, a
trace amount of â-dimethylamino ketone 7a was also
detected. This preference for the formation of the aldol
product was unchanged either by using a higher reaction
temperature (50 °C, 5 h) (entry 2) or by use of DMF as a
solvent at low temperature (-70 to 20 °C, 18 h) (entry 3).
To our surprise, however, a dramatic change of the reaction
course was observed when the reaction was carried out in
DMF at 50 °C (1.5 h). The amino ketone 7a was obtained
as the major product with a minor formation of 6 (6:7a )
1:10) (entry 4). We also observed that the corresponding
diethylamino derivative 5b favored the amino ketone forma-
tion more than 5a. Even when using Hoffmann’s conditions
(i.e., THF and low temperature), the ratio of 7b to 6 was
found to be greater than 1:2 (entry 5). Applying the optimized
conditions (DMF, 50 °C) increased the yield of 7b to 72%,
without any detectable formation of 6 (entry 6). We
confirmed that 7 and 6 are derived by independent reaction
pathways. Thus, before aqueous treatment of the reaction
mixture obtained under the reaction conditions for entry 5
(Table 2), the solvent (THF) was replaced with DMF, and
the resultant DMF solution was heated at 50 °C for 1.5 h.
Aqueous workup resulted in the major formation of the aldol
product 6 in a ca. 2:1 ratio (6:7).
We propose the following explanation for the observed
Mannich-type reaction. A direct aldol-type reaction via a
cyclic transition state may be suppressed by the unfavorable
coordination of the carbonyl group to the di(amino)boron
center as a result of its low Lewis acidity. Instead, an iminium
intermediate is generated via nucleophilic attack of the boron-
bound nitrogen to the aldehyde followed by deoxygenation,
with corresponding formation of a B-O bond (Scheme 2).
A boron enolate then attacks the iminium intermediate, for
which a cyclic transition state is unlikely. The existence of
the iminium ion pair may be supported by the crossover
experiment shown in Scheme 3. Thus, a mixture of the boron
enolates 2b and 2e (1:1) was reacted with excess benzalde-
hyde in DMF at 50 °C for 2 h. It had been confirmed that
no exchange of the amino groups between the two boron
enolates took place in the absence of the aldehyde under
otherwise identical reaction conditions. The reaction of
benzaldehyde with the mixture of the boron enolates yielded
two â-amino ketones. One of these â-amino ketones was
4ea, in which both functionalities were derived solely from
the boron enolate 2e. Unexpectedly, the other product was
Scheme 2
found to be a crossover product 4aa, whose amino and
carbonyl functionalities were derived from 2e and 2b,
respectively. No amino ketones bearing the diallylamino
group were detectable. The selective transfer of a diethyl-
amino group over a diallylamino group was also observed
in the reaction of benzaldehyde with the (diallylamino)-
(diethylamino)boron enolate of acetophenone. The boron
enolate with mixed amino groups yielded diethylamino
ketone 4aa exclusively in good yield.The formation of 4aa
suggests that the amino and enoxy groups are derived from
two independent boron components, as shown in Scheme 2.
Scheme 3
In summary, we have reported a new Mannich-type
reaction using bis(amino)boron enolates, which yield syn-
thetically useful â-amino ketones. In addition to their
synthetic importance, this demonstrates the generality of the
aminative C-C bond formations using diaminoboryl-
substituted nucleophiles. We are currently investigating the
mechanistic details to expand the scope of the reaction.
(10) The boron enolates 2a, 2b, 2d, and 2e were prepared from the
corresponding lithium enolates with chlorobis(dialkylamino)boranes and
used after distillation. The enolate 2c was prepared via amino exchange by
reaction of 2a with pyrrolidine (3-4 equiv). The boron enolates generated
by the amino exchange reaction were used after evaporation of volatile
materials in vacuo.
Acknowledgment. A.Y. thanks the Japan Society of
Promotion of Science for the fellowship support.
(11) All of the â-amino ketones reported in this work decompose
gradually on storage at room temperature, even under an inert atmosphere.
Moreover, owing to chromatographic instability, the amino ketones could
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds This material
is available free of charge via the Internet at http://pubs.acs.org.
1
not be isolated in the pure state. The yields were determined by H NMR
with an internal standard for crude â-amino ketones, which were obtained
by acid/base extraction (see Supporting Information). In all cases, a purity
>90% was achieved.
OL0497436
Org. Lett., Vol. 6, No. 7, 2004
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