Design of New Amino Tf-Amide Organocatalysts: Environmentally Benign Approach to Asymmetric Aldol Synthesis

Article abstract of DOI:10.1055/s-0037-1610408

A new type of optically pure primary amino aromatic Tf-amide organocatalyst can be easily prepared from 8-amino-1-tetralone, and its chemical behavior was investigated in the context of asymmetric aldol and Mannich reactions. Most notably, the asymmetric

Full text of DOI:10.1055/s-0037-1610408

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
H.-J. et al.
Letter
Synlett
Design of New Amino Tf-Amide Organocatalysts: Environmental-
ly Benign Approach to Asymmetric Aldol Synthesis
Hyo-Jun Leea
O
OH
Natarajan Arumugamb
Abdulrahman I. Almansourb
Raju Suresh Kumarb
Ar-CHO
Ar
O
NH2 NHTf
~98% (94:6 to 99:1),
97–99% ee
PMP
Keiji Maruoka*a,c
0
0
0
0-0
0
0
2-0
0
4
4-6
4
1
1
O
HN
a Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo, Kyoto 606-8502, Japan
(5 mol%)
CO2Et
maruoka@kuchem.kyoto-u.ac.jp
EtO2C
C
H
N PMP
b Department of Chemistry, College of Science, King Saud University,
P.O. Box 2455, Riyadh, 11451, Saudi Arabia
96% (93:7), 95% ee
c School of Chemical Engineering and Light Industry, Guangdong University
of Technology, No.100, West Waihuan Road, HEMC, Panyu District,
Guangzhou, 510006, P. R. of China
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 08.10.2018
Accepted after revision: 13.11.2018
Published online: 19.12.2018
strategy is based on the enhancement of the reactivity of
the acidic Tf-amide moiety by introducing an aromatic Tf-
amide moiety as illustrated in primary amino Tf-amide or-
ganocatalysts of type 5, which could accelerate asymmetric
aldol and Mannich reactions.
DOI: 10.1055/s-0037-1610408; Art ID: st-2018-b0644-l
License terms:
Abstract A new type of optically pure primary amino aromatic Tf-am-
ide organocatalyst can be easily prepared from 8-amino-1-tetralone,
and its chemical behavior was investigated in the context of asymmetric
aldol and Mannich reactions. Most notably, the asymmetric aldol reac-
tion proceeded smoothly in brine.
NHTf
NHTf
H
NHTf
NHTf
NH2
H2N
H
MeO
MeO
NH
NH
(S)-1
(S)-2
(S,S)-3
(S,S)-4
Key words asymmetric synthesis, aldol reaction, organocatalyst,
brine, Mannich reaction
NH2
NHTf
Among various types of amine-based, chiral, and bi-
functional organocatalysts, amino Tf-amide organocatalysts
are very reliable in various asymmetric transformations
that include asymmetric aldol, Mannich, and conjugate ad-
dition reactions.1,2 In 2005, we reported the design of chiral
binaphthyl-modified secondary amino Tf-amide organocat-
alysts of the type 1, which effectively promote anti-selec-
tive direct asymmetric Mannich reactions and syn-selective
direct asymmetric cross-aldol reactions (Figure 1).3 Later,
we prepared structurally similar chiral biphenyl-modified
secondary amino Tf-amide organocatalysts of type 2.4
Moreover, we also designed primary amino Tf-amide or-
ganocatalysts of the type 3 and 4 for asymmetric aldol reac-
tions and asymmetric conjugate additions.5,6 Compared to
primary amino aliphatic Tf-amide organocatalysts of the
type 3 and 4, which are not applicable to asymmetric
Mannich-type reactions, the catalysts 1 and 2 exhibit a high
nucleophilicity of the secondary amino moiety in addition
to the acidic, aromatic Tf-amide hydrogen atom. However,
due to the laborious synthesis of 1 and 2,3,4 the design and
synthesis of easily accessible reactive amine Tf-amide or-
ganocatalysts represent a desirable research target.7,8 Our
R
(R)-5
Figure 1 Previously and newly designed amino Tf-amide organocata-
lysts 1–5
Initially, we prepared various types of primary amino
aromatic Tf-amide organocatalysts (6–10) and evaluated
their reactivity and selectivity in asymmetric direct aldol
reactions (Table 1). For this purpose, a series of aldol reac-
tions between 4-nitrobenzaldehyde and cyclohexanone
was carried out in the presence of catalysts 6–10 in aque-
ous THF at room temperature (Table 1, entries 1–5).9
Among these catalysts, 9 afford the highest stereoselectivi-
ty, giving the anti-aldol product (anti-11a) with 97% anti-
selectivity and 99% ee, albeit that 120 h are required for 60%
yield (Table 1, entry 4). Subsequently, we carried out a sol-
vent screening in order to improve the reactivity (Table 1,
entries 6–11). Among the solvents tested, aqueous solvents,
in particular brine, dramatically accelerated the rate of the
asymmetric aldol reactions (Table 1, entries 9 and 10), fur-
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
H.-J. et al.
Letter
Synlett
nishing anti-11a in high yield with excellent stereoselectiv-
ity.10 However, the low reactivity and selectivity were ob-
served in the reaction in anhydrous DMSO (Table 1, entry
11).5b Lowering the catalyst loading to 5 mol% did not affect
the anti- or enantioselectivity (Table 1, entry 12). However,
carrying out the reaction with 2 mol% of 9 slightly dimin-
ished the reactivity and afforded anti-11 with lower stereo-
selectivities (Table 1, entry 13).
and isonicotinic aldehydes afforded 11 in excellent yield
and selectivity (Table 2, entries 8 and 9). Even though the
reactivity for 4-halobenzaldehydes was slightly lower, these
reactions still showed excellent stereoselectivity (Table 2,
entries 10 and 11). When benzaldehyde was employed, the
corresponding aldol product 11l (Ar = Ph; R1 and R2 = -(CH2)4-)
was obtained in moderate yield with high anti- and enanti-
oselectivity (Table 2, entry 12). The use of cyclopentanone
as the aldol donor also showed high reactivity and stereose-
lectivity for the corresponding aldol product 11m (Ar = 4-
NO2-C6H4; R1 and R2 = -(CH2)3-; Table 2, entry 13). Cyclo-
heptanone and acetone provided the corresponding aldol
products in good yield with high stereoselectivity, though
10 mol% of 9 were required (Table 2, entries 14 and 15).
Table 1 Optimization of the Catalysts and Reaction Conditions in the
Asymmetric Direct Aldol Reactions between 4-Nitrobenzaldehyde and
Cyclohexanonea
O
OH
O
OH
O
catalyst 6–10
(x mol%)
OHC
+
+
solvent
NO2
Table 2 Asymmetric Direct Aldol Reaction of Cycloalkanone and Sub-
stituted Benzaldehydes Catalyzed by Organocatalyst 9a
rt
NO2
NO2
anti-11a
syn-11a
NH2
NH2
NH2
NH2
NH2
NHTf
NHTf
NHTf
NHTf
NHTf
H2N
NHTf
Me
iPr
Ph
OH
OH
O
O
O
O
9 (5 mol%)
catalyst 6
catalyst 7
catalyst 8
catalyst 9
catalyst 10
+
R1
R1
Ar
Ar
R1
brine, rt
H
Ar
R2
anti-11
R2
syn-11
R2
Entry Catalyst
Solvent
Time
(h)
Yield
(%)b
anti/sync ee
(%)d
(x mol%)
Entry Ar, R1, R2
11
Time Yield an-
(h)
ee
1
2
6 (10)
7 (10)
8 (10)
9 (10)
10 (10)
9 (10)
9 (10)
9 (10)
9 (10)
9 (10)
9 (10)
9 (5)
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
DMSO/H2O
EtOH/H2O
neat
168
168
48
32
8
75:25
45:55
90:10
97:3
93:7
97:3
87:13
94:6
97:3
97:3
95:5
97:3
97:3
89
(%)b
ti/sync (%)d
11
97
99
86
99
83
99
99
99
98
99
99
1
2
4-NO2-C6H4, –(CH2)4–
4-CF3-C6H4, –(CH2)4–
4-CN-C6H4, –(CH2)4–
11a
24
92
96
96
88
88
84
88
92
98
55
72
47
89
92
80
97:3
95:5
97:3
97:3
97:3
98:2
99:1
96:4
94:6
97:3
97:3
94:6
91:9
88:12
–
99
99
98
99
99
99
97
99
99
99
99
98
99
89
87
3
96
60
96
92
72
69
91
91
62
92
92
11b
11c
30
30
48
24
48
30
36
20
48
48
48
18
48
48
4
120
120
40
3
5
4
4-CO2Me-C6H4, –(CH2)4– 11d
6
5
2-NO2-C6H4, –(CH2)4–
3-NO2-C6H4, –(CH2)4–
C6F5, –(CH2)4–
11e
11f
7
120
24
6
8
7
11g
11h
11i
9
H2O
20
8
3-pyridyl, –(CH2)4–
4-pyridyl, –(CH2)4–
4-Cl-C6H4, –(CH2)4–
4-Br-C6H4, –(CH2)4–
C6H5, –(CH2)4–
10
11
12
13
brine
12
9
DMSO
72
10
11
12
13
14e
15e
11j
brine
24
11k
11l
9 (2)
brine
48
a Unless otherwise specified, the asymmetric direct aldol reaction between
cyclohexanone and 4-nitrobenzaldehyde was carried out in the presence of
2–10 mol% of 6–10 at room temperature.
4-NO2-C6H4, –(CH2)3–
4-NO2-C6H4, –(CH2)5–
4-NO2-C6H4, CH3, H
11m
11n
11o
b Isolated yield.
c The anti/syn ratio was determined by 1H NMR analysis.
d % ee of major anti-isomer.
a Unless otherwise specified, the asymmetric direct aldol reaction between
cycloalkanone and the substituted benzaldehydes was carried out in brine
in the presence of 5 mol% of 9 at room temperature.
b Isolated yield.
Subsequently, the scope of the asymmetric direct aldol
reaction between cycloalkanones and various benzalde-
hydes in brine solvent was investigated under the opti-
mized conditions using 5 mol% of 9 (Table 2).11 The reac-
tions involving benzaldehydes bearing strong electron-
withdrawing substituent(s) at any position of the phenyl
group furnished the corresponding aldol products 11 in
high yields, with excellent anti- and enantioselectivity (Ta-
ble 2, entries 1–7). Especially the heteroaromatic nicotinic
c The anti/syn ratio was determined by 1H NMR analysis.
d % ee of major anti-isomer.
e 10 mol% of 9 was used.
In order to demonstrate the applicability of the catalyst
9 in asymmetric transformations, we carried out asymmet-
ric direct Mannich reaction between cyclic ketones and α-
imino ester 12 in the presence of catalytic amounts of 9 in
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
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Letter
Synlett
THF at room temperature (Scheme 1), which afforded the
anti-Mannich products 13a (anti/syn = 93:7; 95% ee (anti)),
13b (anti/syn = 96:4; 97% ee (anti)), and 13c (anti/syn =
97:3; 92% ee (anti)) in high yield.12
(3) (a) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 16408. (b) Kano, T.; Yamaguchi, Y.; Tanaka, Y.;
Maruoka, K. Angew. Chem. Int. Ed. 2007, 46, 1738. (c) Kano, T.;
Yamamoto, A.; Maruoka, K. Tetrahedron Lett. 2008, 49, 5369.
(d) Kano, T.; Yamaguchi, Y.; Maruoka, K. Angew. Chem. Int. Ed.
2009, 48, 1838. (e) Kano, T.; Yamaguchi, Y.; Maruoka, K. Chem.
Eur. J. 2009, 15, 6678. See also: (f) Kano, T.; Ueda, M.; Takai, J.;
Maruoka, K. J. Am. Chem. Soc. 2006, 128, 6046.
(4) (a) Kano, T.; Sugimoto, H.; Maruoka, K. J. Am. Chem. Soc. 2011,
133, 18130. (b) Kano, T.; Song, S.; Maruoka, K. Angew. Chem. Int.
Ed. 2012, 51, 1191. (c) Kano, T.; Song, S.; Maruoka, K. Chem.
Commun. 2012, 48, 7037.
NH2
NHTf
O
PMP
PMP
O
X
HN
O
X
HN
9 (5 mol%)
PMP
H
CO2Et
CO2Et
X
N
THF
rt, 12 h
anti-13
syn-13
EtO2C
(5) (a) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130,
17666. (b) Moteki, S. A.; Maruyama, H.; Nakayama, K.; Li, H.-B.;
Petrova, G.; Maeda, S.; Morokuma, K.; Maruoka, K. Chem. Asian.
J. 2015, 10, 2112. (c) Lee, H.-J.; Moteki, S. A.; Arumugam, N.;
Almansour, A. I.; Kumar, R. S.; Liu, Y.; Maruoka, K. Asian J. Org.
Chem. 2017, 6, 1226. (d) Lee, H.-J.; Arumugam, N.; Almansour,
A. I.; Kumar, R. S.; Maruoka, K. Tetrahedron 2018, 74, 5263.
(6) Moteki, S. A.; Xu, S.; Arimitsu, S.; Maruoka, K. J. Am. Chem. Soc.
2010, 132, 17074.
12
PMP
PMP
PMP
O
HN
O
HN
O
HN
CO2Et
CO2Et
CO2Et
S
13a
96% yield
anti/syn = 93:7
13b
92% yield
anti/syn = 96:4
13c
88% yield
anti/syn = 97:3
92% ee
O
O
95% ee
97% ee
(7) The synthesis of the primary amino aromatic Tf-amide organo-
catalysts 6–10 was carried out according to Scheme 2 (see Sup-
porting Information for details).
Scheme 1 Asymmetric Mannich reaction between cyclic ketone and
α-imino ester 13 catalyzed by organocatalyst 9.
O
S
O
S
O
S
Funding Information
(R)
tBu
NH2
tBu
tBu
N
NH2
NH NH2
a
b
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from MEXT, Japan (Grant Number JP26220803, JP17H06450).
The authors also extend their gratitude to the International Scientific
Partnership Program (ISPP) at the King Saud University for financial
support via ISPP#0072.()
+
O
NH2
R1
R1
R1
R2
R2
R2
15
NH NH2
Boc
6 : R1 = Me, R2 = H
7 : R1 = iPr, R2 = H
8 : R1 = Ph, R2 = H
9 : R1, R2 = –CH2CH2CH2–
10 : R1, R2 = –CH2CH2–
NH2
NHTf
c
d
Supporting Information
R1
R1
R2
R2
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610408.
6–10
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
Scheme 2 Reagents and conditions: (a) Ti(OEt)4, THF, 70 °C or 90 °C; (b)
DIBAL-H, THF, –78 °C; (c) (i) HCl, dioxane, MeOH, rt; (ii) Boc2O, CH2Cl2,
rt; (d) (i) Tf2O, Et3N, CH2Cl2, –78 °C; (ii) TFA, CH2Cl2, rt.
References and Notes
(1) Recent reviews on amine-based organocatalysts: (a) Kano, T.;
Maruoka, K. Chem. Commun. 2008, 5465. (b) Lui, X.; Lin, L.;
Feng, X. Chem. Commun. 2009, 6145. (c) Yang, H.; Carter, R. G.
Synlett 2010, 2827. (d) Giacalone, F.; Gruttadauria, M.;
Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41, 2406.
(e) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 52, 9748. (f) Kano,
T.; Maruoka, K. Chem. Sci. 2013, 4, 907. (g) Duan, J.; Li, P. Catal.
Sci. Technol. 2014, 4, 311. (h) Kumar, P.; Sharma, B. M. Synlett
2018, 29, 1994. (i) Zhu, L.; Wang, D.; Jia, Z.; Lin, Q.; Huang, M.;
Luo, S. ACS Catal. 2018, 8, 5466.
(2) Recent reviews on amino-catalyzed asymmetric aldol and
Mannich reactions: (a) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev.
2010, 39, 1600. (b) Hernández, J. G.; Juaristi, E. Chem. Commun.
2012, 48, 5396. (c) Heravi, M. M.; Zadsirjan, V.; Dehghani, M.;
Hosseintash, N. Tetrahedron: Asymmetry 2017, 28, 587.
(d) Saranya, S.; Harry, N. A.; Krishnan, K. K.; Anilkumar, G. Asian
J. Org. Chem. 2018, 7, 613. (e) Yamashita, Y.; Yasukawa, T.; Yoo,
W.-J.; Kitanosono, T.; Kobayashi, S. Chem. Soc. Rev. 2018, 47,
4388.
(8) The absolute configurations of the catalysts were assigned
based on the X-ray diffraction analysis of the sulfonamide inter-
mediate of catalyst 9b. The corresponding data have been
deposited at the Cambridge Crystallographic Data Center and
can be obtained free of charge via www.ccdc.cam.ac.uk/get-
structures. CCDC 1870339 contains the supplementary crystal-
lographic data for this paper.
(9) Reviews of amino-catalyzed asymmetric aldol reaction in
aqueous media: (a) Bhowmick, S.; Bhowmick, K. C. Tetrahedron:
Asymmetry 2011, 22, 1945. (b) Kitanosono, T.; Kobayashi, S. Adv.
Synth. Catal. 2013, 355, 3095. (c) Mlynarski, J.; Bas, S. Chem. Soc.
Rev. 2014, 43, 557. (d) Bhowmick, S.; Mondal, A.; Ghosh, A.;
Bhowmick, K. C. Tetrahedron: Asymmetry 2015, 26, 1215.
(10) Selected examples for asymmetric aldol reaction in water or
brine: (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, J.; Barbas, C. F. III J. Am. Chem. Soc. 2006, 128, 734.
(b) Ma, X.; Da, C.-S.; Yi, L.; Jia, Y.-N.; Guo, Q.-P.; Che, L.-P.; Wu,
F.-C.; Wang, J.-R.; Li, W.-P. Tetrahedron: Asymmetry 2009, 20,
1419. (c) Miura, T.; Kasuga, H.; Imai, K.; Ina, M.; Tada, N.; Imai,
N.; Itoh, A. Org. Biomol. Chem. 2012, 10, 2209. (d) Qiao, Y.; Chen,
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

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Q.; Lin, S.; Ni, B.; Headley, A. D. J. Org. Chem. 2013, 78, 2693.
(e) Hu, X.-M.; Zhang, D.-X.; Zhang, S.-Y.; Wang, P.-A. RSC Adv.
2015, 5, 39557.
30.7, 27.6, 24.6. HRMS (ESI): m/z calcd for C13H15O4NNa:
272.0893 [M + Na]+; found: 272.0895. [α]D24 –11.2 (CHCl3, c 0.9,
99% ee).
(11) General Procedure for the Asymmetric Aldol Reaction Using
the Catalyst 9 for the Preparation of 11
(12) General Procedure for the Asymmetric Mannich Reaction
Using Catalyst 9 for the Preparation of 13
To a mixture of catalyst 9 (3 mg, 5 mol%) and benzaldehyde (0.2
mmol) in brine (1.2 mL) was added ketone (6.0 mmol). The
homogenous mixture was stirred at room temperature for the
appropriate time until the reaction was completed (TLC). Then,
a saturated NH4Cl solution was added, and the mixture was
extracted with dichloromethane. The organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The residue
was then purified by silica gel column chromatography
(EtOAc/hexane = 1:3) to afford the product 11.
To a mixture of catalyst 9 (3 mg, 5 mol%) and α-imino ester 12
(42 mg, 0.2 mmol) in THF (1.2 mL) was added ketone (6.0
mmol). The mixture was stirred at room temperature for 12 h.
Then, a saturated NH4Cl solution was added, and the mixture
was extracted with EtOAc. The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
then purified by silica gel column chromatography (EtOAc/hex-
ane = 1:4) to afford the product 13.
Ethyl
(R)-2-[(4-Methoxyphenyl)amino]-2-[(S)-2-oxocyclo-
(R)-2-[(S)-Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one
(anti-11a)
hexyl]-acetate (anti-13a)
Colorless oil. 1H NMR (CDCl3, 500 MHz): δ = 6.77–6.73 (m, 2 H),
6.64–6.61 (m, 2 H), 4.24 (br s, 1 H), 4.18–4.10 (m, 2 H), 3.98 (d,
J = 4.5 Hz, 1 H), 3.73 (s, 3 H), 3.12–3.08 (m, 1 H), 2.45–2.40 (m, 1
H), 2.35–2.29 (m, 1 H), 2.13–2.09 (m, 1 H), 2.07–2.02 (m, 1 H),
1.96–1.87 (m, 2 H), 1.78–1.62 (m, 2 H), 1.21 (t, J = 7.5 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 210.9, 173.0, 152.7, 142.1, 115.6,
114.7, 61.1, 59.0, 55.7, 53.5, 41.8, 30.5, 26.8, 24.5, 14.1. HRMS
(ESI): m/z calcd for C17H23O4NNa: 328.1519 [M + Na]+; found:
328.1526. [α]D24 –22.4 (CHCl3, c 0.7, 95% ee).
White solid. 1H NMR (CDCl3, 500 MHz): δ = 8.22–8.11 (m, 2 H),
7.52–7.49 (m, 2 H), 4.90 (d, J = 8.0 Hz, 1 H), 4.07, (br s, 1 H),
2.61–2.56 (m, 1 H), 2.52–2.47 (m, 1 H), 2.40–2.33, (m, 1 H),
2.14–2.08 (m, 1 H), 1.85–1.80 (m, 1 H), 1.72–1.62 (m, 1 H),
1.60–1.51 (m, 2 H), 1.42–1.33 (m, 1 H). 13C NMR (CDCl3, 125
MHz): δ = 214.7, 148.3, 147.5, 127.8, 123.5, 74.0, 57.1, 42.6,
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D