Enantioselective direct aminalization with primary carboxamides catalyzed by chiral ammonium 1,1′-binaphthyl-2,2′-disulfonates

Article abstract of DOI:10.1039/c2cc31530k

A highly effective catalytic enantioselective direct aminal synthesis was developed. Chiral ammonium 1,1′-binaphthyl-2,2′-disulfonates, which were prepared in situ from (R)-BINSA and achiral amines, promoted the enantioselective addition of primary amides to aromatic aldimines. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc31530k

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COMMUNICATION
Enantioselective direct aminalization with primary carboxamides
catalyzed by chiral ammonium 1,10-binaphthyl-2,20-disulfonateswz
Manabu Hatano,a Takuya Ozaki,a Yoshihiro Sugiuraa and Kazuaki Ishihara*ab
Received 29th February 2012, Accepted 23rd March 2012
DOI: 10.1039/c2cc31530k
A highly effective catalytic enantioselective direct aminal synthesis
was developed. Chiral ammonium 1,10-binaphthyl-2,20-disulfonates,
which were prepared in situ from (R)-BINSA and achiral amines,
promoted the enantioselective addition of primary amides to aromatic
aldimines.
the phosphoric acid can promote deprotonation of the acidic
nucleophiles, such as sulfonamides and phthalimides, and thus a
cyclic transition state would be favored via anionic activation
with increased nucleophilicity (Fig. 1a). In sharp contrast,
since carboxamides are basically more nucleophilic and less
acidic, they cannot be easily activated through deprotonation
with the phosphoric acid catalyst. In this case, carboxamides may
directly react with aldimines through an extended transition state
(Fig 1b). Therefore, the enantiofacial stereocontrol of aldimines
with chiral acid catalysts should be very important for the
enantioselective reaction with carboxamides. To overcome this
synthetic problem, a stronger Brønsted acid catalyst might
be able to activate aldimines more effectively. In this regard,
(R)-1,10-binaphthyl-2,20-disulfonic acid (BINSA, 1)7,8 should
be attractive, since both its Brønsted acidity and bulkiness can
be easily controlled by complexation with achiral amines (2)
without substitutions at the 3,30-position in the binaphthyl
skeleton (Fig. 2). According to the theoretical calculation for
the (R)-BINSA ammonium salt in our previous work,8e it is
expected that SO3 moieties strongly coordinate to the ammonium
proton through three hydrogen bonds, and the bulky achiral
amine moiety is effective to construct a chiral reaction field
around the other SO3H moiety. We report here a catalytic
enantioselective aminal synthesis from aryl aldimines (3) and
primary carboxamides or carbamates (4) based on the use of
chiral ammonium 1,10-binaphthyl-2,20-disulfonates as acid–base
combination catalysts.9
Aminals, which are nitrogen equivalents of acetals, are synthetically
and medicinally useful compounds in natural products and
pharmaceuticals.1 In particular, acyclic N-protected chiral
aminals have often been designed in retro-inverso pseudopeptides,
by virtue of various biochemical processes through their intra-
and extracellular functions such as antibacterial, antimycotic,
antioxidant, antitumor, antiviral, sweetening, and other
properties.2,3 Nevertheless, practical catalytic methods for the
synthesis of chiral acyclic aminals are still limited, and thus the
Curtius rearrangement of chiral acyl azides and Hofmann
rearrangement of chiral a-amino amides have traditionally been
used, although serious loss of optical purity is sometimes
observed by epimerization.2 In this context, Antilla et al.
recently reported a catalytic enantioselective aminal synthesis
by the direct amidation of aldimines in the presence of a chiral
VAPOL-derived phosphoric acid as a Brønsted acid catalyst
(Fig. 1).4–6 According to their reports, acidic sulfonamides and
phthalimides could be used successfully, but the use of simple
primary carboxamides, which are less acidic and strong nucleo-
philes, showed unsatisfactory enantioselectivities (21–34% ee).4
We assumed that a strong basicity of the phosphoryl moiety in
In the course of our study on asymmetric catalysis using
chiral ammonium 1,10-binaphthyl-2,20-disulfonate catalysts,
which are prepared in situ from (R)-BINSA (1,10-binaphthyl-
2,20-disulfonic acid, 1) and achiral amines (2), N-Cbz aryl
aldimines were suitable substrates in the direct Mannich
reaction and aza-Friedel–Crafts reaction.8c,e By taking advantage
of this fact, we envisioned the catalytic enantioselective addition
of aryl carboxamide 4a to aldimine 3a with the catalytic use of
Fig. 1 Assumed activation mechanism by the phosphoric acid catalyst.
a Graduate School of Engineering, Nagoya University, Furo-cho,
Chikusa, Nagoya 464-8603, Japan. E-mail: ishihara@cc.nagoya-u.ac.jp;
Fax: +81-52-789-3331; Tel: +81-52-789-3222
b Japan Science and Technology Agency (JST), CREST, Furo-cho,
Chikusa, Nagoya 464-8603, Japan
w Electronic supplementary information (ESI) available: Experimental
details and product characterization. See DOI: 10.1039/c2cc31530k
z This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Fig. 2 BINSA (1) ammonium salts in situ.
c
4986 Chem. Commun., 2012, 48, 4986–4988
This journal is The Royal Society of Chemistry 2012

Table 1 Screening of catalystsa
Table 2 Catalytic enantioselective aminal synthesisa
Entry Ar
R
Product Yield (%) ee (%)
Entry 2 [mol%]
Yield (%) ee (%)
1b
2
Ph
1-Naph
p-FC6H4
p-MeOC6H4 p-MeOC6H4
Ph Ph
p-MeOC6H4 Ph
Ph
p-MeOC6H4 p-ClC6H4
Ph
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
99
80
84
81
1b
2c
3d
4
5
6
7
8
9
10
11
12
13e
—
—
96
0
82
96
89
95
88
84
499
99
499
83
—
—
1
2
5
64
42
43
78
10
82
77
84
3b
4
90 [73]c 82 [98]c
—
t-BuNH2 (2a) [5]
Et2NH (2b) [5]
Me2NBu (2c) [5]
2,6-Ph2-pyridine (2d) [5]
2,6-(3,5-t-Bu2C6H3)2pyridine (2e) [5]
2,6-(2,4,6-Me3C6H2)2pyridine (2f) [5]
2,6-(2,4,6-i-Pr3C6H2)2pyridine (2g) [3]
2g [5]
499 [92]c 87 [93]c
5
98
87
6b
7
95 [86]c 89 [98]c
p-ClC6H4
499
80
8
9
10
11
12
499d [79]c 75 [93]c
CHQCH2
499
499d
87
74
89
71
30
p-MeOC6H4 CHQCH2
Ph
Ph
5j
C(CH3)QCH2 5k
t-Bu 5l
499
2g [10]
2g [5]
a
499
Unless otherwise noted, the reaction was conducted with
(0.75 mmol) and 4 (0.5 mmol) in the presence of MgSO4 as a drying
3
a
Unless otherwise noted, the reaction was conducted with 3a
b
agent in 1,2-dichloroethane at 0 1C for 1 h. The reaction time was 2 h.
After purification of the crude mixture by washing and recrystallization
(0.75 mmol), 4a (0.5 mmol), (R)-1 (0.025 mmol), and
(0.015–0.05 mmol) in the presence of MgSO4 as a drying agent in
2
c
d
without silica gel column chromatography. Conversion yield determined
b
dichloromethane at 0 1C for 1 h. Without both (R)-1 and 2 at
by 1H NMR.
c
d
room temperature. Without both (R)-1 and 2 at 0 1C. Without 2.
1,2-Dichloroethane was used in place of dichloromethane. The
reaction time was 2 h.
e
quantitative yields with high enantioselectivity (75–89% ee)
(entries 5–8). Moreover, when aliphatic conjugate carboxamides,
acrylamide and methacrylamide were also used, good to high
enantioselectivity was observed (71–89% ee) (entries 9–11). As a
more nucleophilic non-conjugate carboxamide, pivalamide (4b)
gave the corresponding aminal 5l with low enantioselectivity
(30% ee) when the (R)-1–2g catalyst was used (entry 12).
However, another optimization of achiral amines for (R)-1
proved that more basic trioctylamine (2h) was effective in
dichloromethane at ꢀ20 1C, and the enantioselectivity was
greatly improved up to 80% ee (eqn (1)). Acyclic aminals,
unlike cyclic aminals, are often unstable, epimerize, and are
not isolable. However, the acyclic N-protected aminals (5)
obtained here were highly stable in a solid state and in general
solvents. Therefore, 5 could be thoroughly purified by silica
gel column chromatography without decomposition and/or
epimerization. Moreover, since many of the products were highly
crystalline, washing of the crude mixture with water and ethyl
acetate and subsequent recrystallization from chloroform–hexane
was a practical alternative to silica gel column chromatography
for purification. Water and ethyl acetate can dissolve and
thus remove (R)-1 and the starting materials, respectively.
For example, the enantioselectivity values of 5c, 5d, 5f, and
5h increased to 93–98% ee without any serious loss of yield
after this simple purification (Table 2, brackets in entries 3, 4,
6, and 8).
(R)-1 and 2 in the presence of MgSO4 as a drying agent
(Table 1). Since 4a is highly nucleophilic than sulfonamides and
phthalimides,10 this reaction easily proceeded without catalysts at
room temperature (entry 1). However, the reaction did not
proceed without catalysts at 0 1C (entry 2). Therefore, the strong
activation of aldimines with the chiral BINSA salts should be
effective at 0 1C without the competitive thermodynamic racemic
pathways. First, we optimized the catalysts by screening 2
(5 mol%) for (R)-1 (5 mol%). Poor enantioselectivities (o5% ee)
were observed for the product (5a) when the reaction was
conducted in the absence of 2 (entry 3) or in the presence of
primary and secondary amines (2a and 2b in entries 4 and 5).
In sharp contrast, Me2NBu (2c)8e and 2,6-diphenylpyridine
(2d)8c as tertiary amines improved the enantioselectivity of 5a
(64% ee in entry 6 and 42% ee in entry 7, respectively). We
eventually found that more sterically hindered 2,6-dimesityl-
pyridine (2e) and 2,6-(2,4,6-i-Pr3C6H2)2pyridine (2g) were effective
(78% ee in entry 9 and 82% ee in entry 11, respectively), although
2,6-(3,5-t-Bu2C6H3)2pyridine (2e) was less effective (entry 8).
Therefore, we decided to use 2g as an optimal achiral amine for
(R)-1 in further examinations. For this catalysis, more or less than
a 1 : 1 molar ratio of (R)-1 and 2g was not effective (entries 10–12).
With regard to other solvents, 1,2-dichloroethane gave better
enantioselectivity (84% ee) (entry 13), while low enantioselectivity
(0–o50% ee) was observed when other common solvents, such as
toluene, diethyl ether, THF, and propionitrile, were used.
Next, we examined the scope of the aryl aldimine and
primary carboxamide under the optimum reaction conditions
(Table 2). When aryl aldimines with an electron-donating or
electron-withdrawing group were used with 4a, the desired
products (5b–d) were obtained with high enantioselectivity
(81–87% ee) (entries 2–4). Other benzamides were also used
and the corresponding products (5e–h) were obtained in almost
ð1Þ
Unfortunately, N-protecting groups other than N-Cbz
did not give better results in these reactions. However, one
improved result was observed in the synthesis of 5m with
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4986–4988 4987

from (R)-BINSA and bulky 2,6-(2,4,6-i-Pr3C6H2)2pyridine as
an achiral amine, promoted the direct addition of primary
carboxamides to aromatic aldimines. The corresponding
optically active peptidomimetic non-cyclic N-protected aminals
were obtained without decomposition or epimerization in high
yields with high enantioselectivities after simple purification by
recrystallization without silica gel column chromatography.
Financial support was partially provided by MEXT, KAKENHI
(21200033), the Global COE Program of MEXT, Yazaki
Memorial Foundation for Science and Technology.
Fig. 3 Possible extended transition state.
3,5-dimethylbenzyl carbamate (92% ee) in place of benzyl
carbamate (eqn (2)).
Notes and references
1 (a) A. Alexakis and P. Mangeney, in Advanced Asymmetric Synthesis,
ed. G. R. Stephenson, Springer, London, 1996, ch. 5, pp. 93–110;
(b) C. Ko, Synthesis Methods Using Cyclic Acetals and Aminals,
ProQuest, Ann Arbor, 2011.
2 For reviews, see: (a) M. Goodman and M. Chorev, Acc. Chem. Res.,
1979, 12, 1; (b) M. Chorev and M. Goodman, Acc. Chem. Res.,
1993, 26, 266; (c) M. D. Fletcher and M. M. Campbell, Chem. Rev.,
1998, 98, 763; (d) J. M. Lozano, L. P. Lesmes, L. F. Carreno,
G. M. Gallego and M. E. Patarroyo, Molecules, 2010, 15, 8856.
3 (a) R. Amoroso, G. Cardillo and C. Tomasini, Tetrahedron Lett.,
1991, 32, 1971; (b) R. Granados, M. Alvarez, F. Lopez-Calahorra
and M. Salas, Synthesis, 1983, 329; (c) V. V. Sureshbabu and
N. Narendra, Int. J. Pept. Res. Ther., 2008, 14, 201; (d) G. Verardo,
C. D. Venneri, G. Esposito and P. Strazzolini, Eur. J. Org. Chem.,
2011, 1376.
ð2Þ
In place of carboxamide (4), allyl carbamate 6 was used in the
reaction of 3a. Fortunately, the reaction proceeded smoothly in
1,2-dichloroethane at 0 1C within 2 h, and the corresponding
product 7 was obtained in 499% yield with 77% ee (eqn (3)).
Moreover, a single recrystallization increased the enantiopurity
up to 95% ee. In sharp contrast, the conventional synthesis of 7
from N-Cbz-L-phenylglycine via the Curtius rearrangement to
azide carbonyl compound 811 failed (eqn (4)). Compound 7 was
obtained in 17% yield with a significant loss of enantiopurity
(29% ee) in addition to the generation of racemic N,O-acetal 9,
since 8 is unstable under basic conditions. Therefore, direct
enantioselective aminal synthesis with such a chiral Brønsted
acid catalyst under mild reaction conditions is highly useful.
4 (a) G. B. Rowland, H. Zhang, E. B. Rowland, S. Chennamadhavuni,
Y. Wang and J. C. Antilla, J. Am. Chem. Soc., 2005, 127, 15696;
(b) Y. Liang, E. B. Rowland, G. B. Rowland, J. A. Perman and
J. C. Antilla, Chem. Commun., 2007, 4477.
5 After Antilla’s report, List and Rueping independently reported
a
catalytic enantioselective synthesis of cyclic aminals from
2-aminobenzamides and aldehydes with the use of chiral BINOL-
derived phosphoric acid catalysts. (a) X. Cheng, S. Vellalath,
R. Goddard and B. List, J. Am. Chem. Soc., 2008, 130, 15786;
(b) M. Rueping, A. P. Antonchick, E. Sugiono and K. Grenader,
Angew. Chem., Int. Ed., 2009, 48, 908.
6 Enantioselective synthesis of N,O- and N,S-acetals using chiral
phosphoric acid catalysts. (a) G. Li, F. R. Fronczek and
J. C. Antilla, J. Am. Chem. Soc., 2008, 130, 12216; (b) S. Vellalath,
I. Coric and B. List, Angew. Chem., Int. Ed., 2010, 49, 9749;
(c) G. K. Ingle, M. G. Mormino, L. Wojtas and J. C. Antilla, Org.
Lett., 2011, 13, 4822.
7 (a) H. J. Barber and S. Smiles, J. Chem. Soc., 1928, 1141; (b) W. L. F.
Armarego and E. E. Turner, J. Chem. Soc., 1957, 13.
ð3Þ
8 (a) D. Kampen, A. Ladepeche, G. Claßen and B. List, Adv. Synth.
Catal., 2008, 350, 962; (b) S. C. Pan and B. List, Chem.–Asian J.,
2008, 3, 430; (c) M. Hatano, T. Maki, K. Moriyama, M. Arinobe
and K. Ishihara, J. Am. Chem. Soc., 2008, 130, 16858;
(d) M. Hatano, Y. Hattori, Y. Furuya and K. Ishihara, Org. Lett.,
2009, 11, 2321; (e) M. Hatano, Y. Sugiura, M. Akakura and
K. Ishihara, Synlett, 2011, 1247.
9 For reviews on acid–base chemistry, see: (a) M. Kanai, N. Kato,
E. Ichikawa and M. Shibasaki, Synlett, 2005, 1491; (b) K. Ishihara,
A. Sakakura and M. Hatano, Synlett, 2007, 686; (c) K. Ishihara,
Proc. Jpn. Acad., Ser. B, 2009, 85, 290.
ð4Þ
10 Interestingly, the reaction between 3a and phthalimide did not
proceed with (R)-1–2 catalysts, while the reaction between 3a and
p-toluenesulfonamide proceeded with (R)-1–2 catalysts (o50% ee).
These results strongly suggest that (R)-1–2 might act as a strong
Brønsted acid catalyst with low Brønsted basicity, which can
anionically activate p-toluenesulfonamide (pKa = 10.2) but not
phthalimide (pKa = 10.4) and 4a (pKa = 16.0). Estimated pKa
values were reported by SciFinder with ACD Software V11.02.
11 G. Verardo, C. D. Venneri, G. Esposito and P. Strazzolini, Eur. J.
Org. Chem., 2011, 1376.
Based on the absence of a nonlinear effect between the
enantioselectivity of (R)-1 and that of aminal product 5a
(see the ESIw) and the theoretical calculation for the 3a–(R)-
BINSA ammonium salt,8e a postulated extended transition
state is shown in Fig. 3 as a working model.12 The predominant
attack to the re-face of the aldimine by carboxamide can explain
the absolute S-configuration of the products.
In summary, we have developed a highly effective catalytic
enantioselective direct aminal synthesis. A chiral ammonium
1,10-binaphthyl-2,20-disulfonate, which was prepared in situ
12 Preliminary analysis of the catalysts from (R)-1 (1 equiv.) and 2
(0–2 equiv.) by 1H NMR (CDCl3) also suggested the generation of
a 1 : 1 complex in situ. See the ESIw.
c
4988 Chem. Commun., 2012, 48, 4986–4988
This journal is The Royal Society of Chemistry 2012