Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides

Article abstract of DOI:10.3762/bjoc.13.151

Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantioselective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatilit

Full text of DOI:10.3762/bjoc.13.151

Bifunctional organocatalysts for the asymmetric synthesis of
axially chiral benzamides
Ryota Miyaji, Yuuki Wada, Akira Matsumoto, Keisuke Asano* and Seijiro Matsubara*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1518–1523.
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510,
Japan
doi:10.3762/bjoc.13.151
Received: 21 April 2017
Accepted: 18 July 2017
Published: 02 August 2017
Email:
Keisuke Asano* - asano.keisuke.5w@kyoto-u.ac.jp;
Seijiro Matsubara* - matsubara.seijiro.2e@kyoto-u.ac.jp
Associate Editor: M. Rueping
* Corresponding author
© 2017 Miyaji et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
axial chirality; benzamide; bifunctional organocatalyst; molecular
conformation; multipoint recognition
Abstract
Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantiose-
lective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatility of
bifunctional organocatalysts for the enantioselective construction of axially chiral compounds. Moderate to good enantioselectivi-
ties were afforded with a range of benzamide substrates. Mechanistic investigations were also carried out.
Introduction
Bifunctional organocatalysts have significantly contributed to axes [17-24], dynamic kinetic resolution [25-41], kinetic resolu-
the field of asymmetric synthesis [1-6]. In these catalysts, tion [42-47], desymmetrization [48-54], de novo annulation
(thio)urea and tertiary amino functional groups cooperatively [55-61], and point-to-axial chirality transfer [58,59] (for
activate a nucleophile and an electrophile simultaneously, in a reviews, see references [31,62,63]), motivated us to expand on
suitable spatial configuration. Thus, they enable various stereo- the utility of this class of small-molecule catalysts. We have
selective addition reactions to occur. Organocatalysts have also recently demonstrated that bifunctional organocatalysts can also
been employed in several asymmetric cyclization reactions via be applied to the asymmetric synthesis of axially chiral com-
intramolecular hetero-Michael addition [7-16]. In these reac- pounds (biaryls bearing isoquinoline N-oxides or quinolines and
tions, multipoint recognition by the catalysts favors the specific phenolic moieties) by translating a specific conformation,
conformations of the substrates in the transition state. Several recognized by bifunctional organocatalysts, into axial chirality
successful results and a recent trend in organocatalytic atropose- [36,37]. Thus, we assumed that this method could be further
lective reactions, including enantioselective formation of chiral applied to the enantioselective synthesis of a range of axially
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chiral compounds. In this study, we present the enantioselec- tribrominated product 2a was formed enantioselectively
tive synthesis of 3-hydroxybenzamides via aromatic electrophil- (Table 1, entry 1). Although a lower temperature did not
ic bromination [28,29]. The 3-hydroxybenzamide substrates improve the enantioselectivity (Table 1, entry 2), lowering the
comprise both amide and phenolic moieties. These can interact concentration of the reaction mixture was effective (Table 1,
with a hydrogen-bond donor and a hydrogen-bond acceptor, re- entry 3). The screening of solvents identified ethyl acetate as
spectively. Such interactions are expected to recognize a specif- the most suitable solvent (Table 1, entries 4–7). Other brominat-
ic conformation of the substrate molecule to realize the enantio- ing reagents (Figure 1) were also investigated; however, NBA
selective construction of axially chiral benzamides [36,37].
(4a) still afforded the best enantioselective results (Table 1,
entries 8–10). In addition, other bifunctional organocatalysts
derived from easily available cinchona alkaloids exhibited simi-
Results and Discussion
We initiated our investigations using 3-hydroxy-N,N-diiso- larly good enantioselectivities; 3c and 3d afforded the opposite
propylbenzamide (1a) and N-bromoacetamide (NBA, 4a) as a enantiomer of the product (Table 1, entries 11–13, results of
brominating reagent, with 10 mol % quinidine-derived bifunc- further catalyst screening are described in the Supporting Infor-
tional catalyst 3a, in toluene, at −40 °C. As expected, the mation File 1).
Table 1: Optimization of conditions.a
Entry
Catalyst
Brominating reagent
Solvent
Yield (%)b
ee (%)
1c
2c,d
3
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
NBA (4a)
NBA (4a)
NBA (4a)
NBA (4a)
NBA (4a)
NBA (4a)
NBA (4a)
DBH (4b)
NBS (4c)
NBP (4d)
NBA (4a)
NBA (4a)
NBA (4a)
toluene
toluene
toluene
CHCl3
Et2O
88
48
58
73
66
69
84
99
99
99
56
89
76
78
78
84
84
42
82
87
77
51
72
84
−81
−80
4
5
6
THF
7
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
8e
9
10
11
12
13
aReactions were run using 1a (0.1 mmol), the catalyst (0.01 mmol), and the brominating reagent (0.3 mmol) in the solvent (10 mL). bIsolated yields.
cReactions were run in 0.5 mL of toluene. dReaction was run at −45 °C. e1.5 equiv of 4b was used for the reaction.
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Figure 1: Brominating reagents.
We then investigated substrates bearing other substituents on
the amino group (Scheme 1). Dimethyl- and diisobutylamide
groups resulted in much lower enantioselectivities (2b and 2c).
Substrates bearing cyclohexyl groups or a piperidinyl moiety
provided the corresponding products in high yields; however,
the enantioselectivities were not as high as that of 2a. The
absolute configuration of 2d was determined by X-ray analysis
(see the Supporting Information File 1 for details), and the con-
figurations of all other examples were assigned analogously.
Once the optimal conditions for the transformation were estab-
lished, we next proceeded to explore the substrate scope
(Scheme 2). The substrate bearing a phenyl group yielded the
product with the highest enantioselectivity (Scheme 2, 2f).
However, a decrease in enantioselectivity was observed when
the phenyl group was replaced by substituted phenyl groups
(Scheme 2, 2g and 2h). The substrate bearing a naphthyl group
afforded the corresponding product in moderate enantioselectiv-
ity (Scheme 2, 2i). In addition, a benzamide with a cyclopropyl
group also provided the product in good enantioselectivity
(Scheme 2, 2j). Furthermore, when the reaction was carried out
Scheme 2: Substrate scope. Reactions were run using 1 (0.1 mmol),
3a (0.01 mmol), and 4a (0.3 mmol) in EtOAc (10 mL). Yields represent
material isolated after silica gel column chromatography.
Scheme 1: Optimization of the substituents of the amide group. Reactions were run using 1 (0.1 mmol), 3a (0.01 mmol), and 4a (0.3 mmol) in EtOAc
(10 mL). Yields represent material isolated after silica gel column chromatography.
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Beilstein J. Org. Chem. 2017, 13, 1518–1523.
using 1k and 1l with 2 equiv of NBA (4a), dibromination
proceeded in high yields and moderate enantioselectivities
(Scheme 3); both 1k and 1l comprise a substituent ortho to the
hydroxy group. These brominated axially chiral benzamides can
further be derivatized for the synthesis of functional molecules
[64].
Scheme 4: Reactions of monobrominated substrates.
Scheme 3: Reactions of substrates with substituted phenols.
To gain insight into the reaction mechanism, the reactions were
performed using substrates 1m and 1n, previously monobromi-
nated at the ortho-positions of the rotational axis. Much lower
enantioselectivities than that afforded by 1a were observed in
both reactions (Scheme 4). In addition, the reaction was also
carried out with 1 equiv of NBA (4a). The sole product afforded
was 1m and most of the starting material was recovered (see
Supporting Information File 1 for details). These results imply
that the first bromination, occurring at the ortho-position of the
axis (probably at the 2-position), is the enantiodetermining step
of the reaction. Moreover, once one of the ortho-positions is
Scheme 5: Rotational barriers of substrates and intermediates calcu-
lated at the B3YLP/6-31G(d) level of theory.
brominated, racemization through bond rotation is negligible temperature. Furthermore, it is also important to employ sub-
during further brominations [65]. Indeed, the rotational barrier strates bearing bulky substituents on the nitrogen atom. Such
of substrate 1a, calculated at the B3YLP/6-31G(d) level of substrates limit the bond rotation about the chiral axis to realize
theory, is only 7.6 kcal/mol; on the other hand, that of the high enantioselectivity (Scheme 1). The rotational barriers of
monobrominated intermediate 1m is 19.0 kcal/mol (Scheme 5). monobrominated compounds 1p and 1q (bearing methyl and
However, this latter value is not high enough to inhibit bond isobutyl groups, respectively, on the amide moiety) are lower
rotation at room temperature. This explains why the reactions than that of 1m. Although racemization of 2b, the rotational
must be carried out at such a low temperature (−40 °C) to afford barrier of which is 22.9 kcal/mol, was observed after a lot of
high enantioselectivities. Compound 1o, with both ortho-posi- months, it is enough slow to enable the immediate analysis of
tions brominated, has a rotational barrier that is high enough to the reaction selectivity (the decrease of the enantiomeric purity
enable the isolation of the optically active form, even at room of 2b was negligible after a day).
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Beilstein J. Org. Chem. 2017, 13, 1518–1523.
Furthermore, the reaction of benzamide 5, bearing a protected Science and Technology (15H05845 and 16K13994). K.A. also
phenol, was carried out (Scheme 6). It failed to give the corre- acknowledges the Asahi Glass Foundation, Toyota Physical and
sponding product 6, indicating the significance of multipoint ac- Chemical Research Institute, Tokyo Institute of Technology
tivation involving the phenolic hydroxy group.
Foundation, the Naito Foundation, Research Institute for Pro-
duction Development, the Tokyo Biochemical Research Foun-
dation, the Uehara Memorial Foundation, and the Kyoto
University Foundation. R.M. and A.M. also acknowledge the
Japan Society for the Promotion of Science for Young Scien-
tists for the fellowship support.
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