Bifunctional organocatalysts for the enantioselective synthesis of axially chiral isoquinoline n -oxides

Article abstract of DOI:10.1021/jacs.5b04151

Bifunctional catalysts bearing amino and urea functional groups have been applied for a novel, highly enantioselective synthesis of axially chiral isoquinoline N-oxides, which are promising chiral ligands or organocatalysts in organic synthesis. This is t

Full text of DOI:10.1021/jacs.5b04151

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Communication
Bifunctional Organocatalysts for the Enantioselective
Synthesis of Axially Chiral Isoquinoline N-Oxides
Ryota Miyaji, Keisuke Asano, and Seijiro Matsubara
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 May 2015
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Bifunctional Organocatalysts for the Enantioselective Synthesis of
Axially Chiral Isoquinoline N-Oxides
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Ryota Miyaji, Keisuke Asano,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo,
Kyoto 615-8510, Japan
Supporting Information Placeholder
Scheme 1. Construction of Axially Chiral Structure by Using
Bifunctional Organocatalysts
ABSTRACT: Bifunctional catalysts bearing amino and urea
functional groups have been applied for a novel, highly enantiose-
lective synthesis of axially chiral isoquinoline N-oxides, which are
promising chiral ligands or organocatalysts in organic synthesis.
This is the first example of highly enantioselective synthesis of
axially chiral biaryls by bifunctional organocatalysts. Good-to-
excellent enantioselectivities were obtained with a range of sub-
strates.
Bifunctional organocatalysts have significantly contributed to
the field of asymmetric synthesis.1 In these catalysts, the
(thio)urea and tertiary amino functional groups cooperatively
realize the simultaneous activation of a nucleophile and an elec-
trophile in a suitable spatial configuration. Previously, we have
used these organocatalysts for several asymmetric cyclization
reactions via intramolecular hetero-Michael addition,2 in which
multipoint recognition by the catalysts stabilizes the specific con-
formations of the substrates in the transition state before the con-
struction of a chiral center. Inspired by the success of these re-
sults, we envisaged that the utility of this class of small-molecule
catalysts could be expanded by translating the molecular torsion
induced by bifunctional organocatalysts into axial chirality. Re-
cently, although some organocatalysts have been reported to be
useful for the enantioselective syntheses of axially chiral com-
pounds,3 thus far, methods employing this type of bifunctional
organocatalysts have rarely been developed.4 Here, we demon-
strate the novel competence of bifunctional organocatalysts as an
efficient avenue for the asymmetric construction of axially chiral
compounds.
In this study, we report the highly enantioselective aromatic
electrophilic bromination of 1-(3-hydroxyphenyl)isoquinoline 2-
oxides (Scheme 1). The 1-(3-hydroxyphenyl)isoquinoline 2-oxide
substrates have an isoquinoline N-oxide moiety, which can inter-
act with a hydrogen-bond donor, and a phenol moiety, which can
interact with a hydrogen-bond acceptor; such interactions are
expected to twist the molecule in one direction. Meanwhile, the
axially chiral N-oxides obtained are promising chiral ligands or
organocatalysts in organic synthesis,5 although thus far, their cata-
lytic enantioselective synthesis has been thus far underdeveloped,
to the best of our knowledge.
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Table 1. Optimization of Conditionsa
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4
5
6
Figure 1. Brominating reagents.
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Table 1 shows the optimization of reaction conditions. First,
we investigated the reaction between 1-(3-
brominating
temp. yield
ee
entry catalyst
solvent
reagent
(°C)
–40
–40
–40
–40
–40
0
(%)b
95
7
(%)
hydroxyphenyl)isoquinoline 2-oxide (1a) and N-bromoacetamide
(NBA, 4a) as the brominating reagent with 10 mol % of quini-
dine-derived bifunctional catalyst 3a6 in CH2Cl2 at –40 °C. As
expected, tribromide 2a was obtained in good yield with moderate
enantioselectivity (Table 1, entry 1). Second, the solvents were
screened, and among those tested, THF was identified to be the
most suitable solvent, demonstrating high enantioselectivity, albe-
it with an unsatisfactory product yield (Table 1, entry 5). Third,
the effect of temperature on the reaction was studied: higher tem-
peratures improved products yield while maintaining excellent
enantioselectivites (Table 1, entries 6 and 7); hence, we selected
0 °C as the reaction temperature for further investigations.
Meanwhile, the effect of various brominating agents besides NBA
(DBH (4b), NBS (4c), and NBP (4d)) was also studied. Figure 1
shows their chemical structures. As can be seen, no significant
effects were observed with respect to the yields and enantioselec-
tivities (Table 1, entries 8–10). Next, the effect of different cata-
lysts was also investigated; other cinchona-alkaloid-derived cata-
lysts6 also exhibited good stereoselectivities similar to that ob-
tained with the use of 3a (entry 6), and the use of 3c and 3d af-
forded the opposite enantiomer of the product with high enanti-
oselectivities (Table 1, entries 11–13). Moreover, catalyst 3e,6
with a cyclohexanediamine framework, also afforded a quantitat-
tive product yield with a slightly lower enantioselectivity (Table 1,
entry 14). On the other hand, catalyst 3f,6 which has a significant-
ly less basic nitrogen atom, failed to attain enantioselectivity (Ta-
ble 1, entry 15). Moreover, quinidine (3g) also demonstrated
enantioselectivity significantly lesser than those exhibited by cata-
lysts 3a–3e (Table 1, entry 16). These results demonstrate the
significance of the bifunctionality of the catalyst containing amino
and urea functional groups toward enantioselectivity.
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1
2
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)
NBA (4a)
NBA (4a)
NBA (4a)
CH2Cl2
toluene
EtOAc
Et2O
THF
54
74
93
–
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
3
50
<5
32
99
99
99
99
99
99
85
84
99
46
91
4
5
6c
7d
8c,e
9c
10c
11c
12c
13c
14c
15c
99
99
97
98
98
98
98
–96
–94
–91
1
THF
THF
25
0
THF
THF
0
THF
0
THF
0
THF
0
THF
0
THF
0
THF
0
16c
THF
0
–42
3g
a
Reactions were run using 1a (0.1 mmol), the brominating
reagent (0.3 mmol), and the catalyst (0.01 mmol) in the solvent
(10 mL). b Isolated yields. c Reactions were run for 6 h. d Reac-
tion was run for 5 h. e 1.5 equiv of 4b was used for the reaction.
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Table 2. Substrate Scopea
good yield and stereoselectivity. Moreover, as shown in Scheme
1
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3
4
5
6
7
8
2, substrates bearing substituted phenols were also investigated.
A meta substituent on the phenol ring did not affect the reaction,
affording 2g in excellent yield and enantioselectivity. Moreover,
when the reaction was carried out using 1h, which has a substitu-
ent ortho to the hydroxy group, dibromination proceeded with
quantitative yield with excellent enantioselectivity. Meanwhile,
the absolute configuration of 2a was determined by X-ray analysis
(see the Supporting Information for details), and the configura-
tions of all other examples were assigned analogously.
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Scheme 3. Reactions of Monobrominated Substrates
a
Reactions were run using 1 (0.1 mmol), 4a (0.3 mmol), and 3a
(0.01 mmol) in THF (10 mL). b Isolated yields.
To gain insight into the reaction mechanism, the reactions were
performed using substrates previously monobrominated at the
ortho positions of the biaryl axis, and almost racemic products
were obtained in both reactions (Scheme 3). These results imply
that the bromination at an ortho position of the axis is the enanti-
odetermining step in this reaction, and once one of the ortho posi-
tions is brominated, no racemization occurs by bond rotation dur-
ing the course of further bromination.7
Scheme 2. Reactions of Substrates with Substituted Phenols
Scheme 4. Asymmetric Synthesis of Benzamide
In addition, this protocol could also be applied to the synthesis
of an axially chiral benzamide (Scheme 4),3g indicating the feasi-
bility of this method with the use of this bifunctional organocata-
lyst. By using 10 mol % 3a and 3 equiv 4a with EtOAc at –40 °C,
benzamide 5a was tribrominated to afford optically active ben-
zamide 6a in high yield and enantioselectivity.8
Next, the substrate scope was investigated, and the robustness
of this synthetic method was confirmed. Table 2 shows the re-
sults. For substrates bearing fluoro and bromo functional groups
on the isoquinoline ring, the desired products 2b and 2c were
obtained with high enantioselectivities. Moreover, a nitro group
was also tolerated, affording the corresponding product 2d in high
enantioselectivity. Furthermore, a substrate with a methyl group
near the biaryl axis yielded the brominated product 2e in excellent
yield and enantioselectivity. In addition, a derivative bearing an
expanded π-conjugate plane afforded the brominated product 2f in
In summary, we present a novel, highly enantioselective syn-
thesis of axially chiral isoquinoline N-oxides using bifunctional
organocatalysts. This method efficiently produces axially chiral
N-oxides, which are promising chiral catalysts in organic synthe-
sis. Notably, this is the first example of the use of simple bifunc-
tional organocatalysts for the asymmetric synthesis of axially
chiral biaryls. In addition, good-to-excellent enantioselectiveties
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3847. (j) Shirakawa, S.; Liu, K.; Maruoka, K. J. Am. Chem. Soc.
were accomplished with a range of substrates. Thus, this method-
ology demonstrates utility for further application in the synthesis
of various axially chiral compounds. Further studies regarding
the detailed clarification of the reaction mechanism and applica-
tion of this methodology to the construction of other axially chiral
structures are currently underway and will be reported in due
course.
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ASSOCIATED CONTENT
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Supporting Information
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Experimental procedures including spectroscopic and analytical
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(4) For enantioselective syntheses of axially chiral allenes by bi-
functional organocatalysts, see: (h) Inokuma, T.; Furukawa, M.;
Uno, T.; Suzuki, Y.; Yoshida, K.; Yano, Y.; Matsuzaki, K.;
Takemoto, Y. Chem.—Eur. J. 2011, 17, 10470. (i) Inokuma, T.;
Furukawa, M.; Suzuki, Y.; Kimachi, T.; Kobayashi, Y.; Take-
moto, Y. ChemCatChem 2012, 4, 983.
AUTHOR INFORMATION
Corresponding Author
asano.keisuke.5w@kyoto-u.ac.jp;
u.ac.jp
matsubara.seijiro.2e@kyoto-
(5) For selected examples of chiral N-oxide catalysts, see: (a)
Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem.
Soc. 1998, 120, 6419. (b) Saito, M.; Nakajima, M.; Hashimoto,
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X.; Dong, Z.; Xie, M.; Feng, X. Angew. Chem., Int. Ed. 2008, 47,
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X. Angew. Chem., Int. Ed. 2008, 47, 7079. (f) Hrdina, R.; Ope-
kar, F.; Roithová, J.; Kotora, M. Chem. Commun. 2009, 2314.
(g) Malkov, A. V.; Ramírez-Lόpez, P.; Biedermannová, L.;
Rulíšek, L.; Dufková, L.; Kotora, M.; Zhu, F.; Kočovský, P. J.
Am. Chem. Soc. 2008, 130, 5341. (h) Traverse, J. F.; Zhao, Y.;
Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2005, 7, 3151. For
reviews, see: (i) Karayannis, N. M.; Pytlewski, L. L.; Mikulski,
C. M. Coord. Chem. Rev. 1973, 11, 93. (j) Chelucci, G.; Mu-
rineddu, G.; Pinna, G. A. Tetrahedron: Asymmetry 2004, 15,
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(6) Catalysts 3a–3e were prepared according to previous studies
(see the Supporting Information for details): for 3a–3d, see ref
1c; for 3e, see ref 1a. Catalyst 3f was purchased from Aldrich;
see: Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558.
(7) The reaction conducted using 1 equiv of NBA (4a) afforded a
mixture of multiple products including monobromide 1i, while
few amount of 1j was generated; the ee of 1i was >95% ee (see
the Supporting Information for details). Thus, we currently con-
sider that the bromination at the ortho position of the hydroxy
group occurs before the bromination at the para position of the
hydroxy group.
(8) The reaction of 3-hydroxy-N,N-dicyclohexylbenzamide (5b)
afforded the corresponding tribromide, 2,4,6-tribromo-N,N-
dicyclohexyl-3-hydroxybenzamide (6b) in 99% yield with 79%
ee; the absolute configuration of 6b was determined by X-ray
analysis (see the Supporting Information for details).
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Professor Takuya Kurahashi (Kyoto University) for X-
ray crystallographic analysis. This work was supported financial-
ly by the Japanese Ministry of Education, Culture, Sports, Science
and Technology. K.A. also acknowledges the Asahi Glass Foun-
dation, Toyota Physical and Chemical Research Institute, and
Tokyo Institute of Technology Foundation.
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