Hybrid-Type Squaramide-Fused Amino Alcohol Organocatalysts for Enantioselective Nitro-Aldol Reaction of Nitromethane with Isatins

Article abstract of DOI:10.1002/ejoc.201700138

A series of hybrid-type squaramide-fused amino alcohol (SFAA) catalysts were synthesized, and their catalytic efficiency in the enantioselective nitro-aldol reaction of various isatins with nitromethane has been described. This transformation afforded chiral 3-substituted 3-hydroxyoxindoles in excellent chemical yields (up to 99 %) with high enantioselectivities (up to 95 % ee). The resulting chiral 3-hydroxyoxindoles can be further used as synthetic precursors for the synthesis of several natural products that have a broad spectrum of fascinating biological activities.

Full text of DOI:10.1002/ejoc.201700138

A Journal of
Accepted Article
Title: New Hybrid Type, Squaramide-Fused Amino Alcohol
Organocatalysts for Enantioselective Nitro-Aldol Reaction of
Nitromethane with Isatins
Authors: Hiroto Nakano
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700138
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700138
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10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
New Hybrid Type, Squaramide-Fused Amino Alcohol
Organocatalysts for Enantioselective Nitro-Aldol Reaction of
Nitromethane with Isatins
Madhu Chennapuram, [a] U. V. Subba Reddy, [a] Chigusa Seki, [a] Yuko Okuyama, [b] Eunsang Kwon,* [c]
Koji Uwai, [a] Michio Tokiwa, [d] Mitsuhiro Takeshita, [d] and Hiroto Nakano*[a]
centers with high stereoselectivitys. Nitro-aldol reaction (Henry
ABSTRACT: A series of new hybrid type squaramide-fused amino
reaction)[5] is one of the prominent coupling reactions between a
alcohol (SFAA) catalysts were synthesized and their catalytic
carbonyl compound and a nitro alkyl compound bearing α-
efficiency in enantioselective nitro-aldol reaction of various isatins with
hydrogens, leading to the formation of a new C-C bond with the
nitromethane that afford the chiral 3-substituted 3-hydroxyoxindoles
concomitant generation of β-nitro alcohol, a new bi-functional
in excellent chemical yields (up to 99%) and high enantioselectivities
moiety, which could further provide efficient routes to highly
(up to 95% ee) is described. The resulting chiral 3-hydroxyoxindoles
valuable and functionalized derivatives such as 1,2-amino
could be used as synthetic precursors for the synthesis of several
alcohols or amino acids.[6] Importantly, asymmetric aldol reaction
natural products with a broad spectrum of fascinating biological
of cyclic ketones generates a quaternary stereocenter, which is a
activities.
challenging task in asymmetric synthesis.
S
HO
Introduction
N
H
new biologically
O
active compounds
N
H
H3CS
S
dioxibrassinin
Although the concept of utilizing organic molecules as catalysts
started long ago,[1] enantioselective organocatalysis has emerged
as one of the most intensively investigated areas in organic
chemistry since last two decades.[2] Small organic molecules as
catalysts could provide complex organic transformations with high
levels of stereoselectivity in environmentally and economically
friendly manner. Owing to their significance, the development of
new organocatalysts and evaluation of their catalytic efficiency in
organic transformations is still a challenging task. In recent years,
we have been exploring the role of simple primary amino alcohols
as new class of organocatalysts with distinctive properties such
as easy synthesis, stability on exposure to air, potential for
convenient alteration of the steric sites and ability to be used as
bi-functional (enamine activation and non-covalent activation)
catalysts.[3] Organocatalysis using chiral hydrogen-bond (H-bond)
donor catalysts, such as thioureas and squaramides,[4] has
expanded rapidly in the past few years. This type of catalysis now
efficiently addresses the issue of the formation of multiple chiral
N
O
O
R2
HO
N
H
NO2
O
*
spirobrassinin
H
*
N
N
O
asymmetric
nitro-aldol
reaction
R1
N
HO
Isatins
R1
chiral
3-alkyl-3-hydroxy-
oxindoles
O
R2
NO2
N
H
nitroalkanes
donaxaridine
O
HO
NMe
HN
O
SMe
N
N
H
O
H
Me
CPC-1
maremycin B
Scheme 1. Utility of Chiral 3-Alkyl-3-Hydroxyindoles
[a]
Division of Sustainable and Environmental Engineering, Graduate
School of Engineering, Muroran Institute of Technology, 27-1
Mizumoto, Muroran 050-8585, Japan
E-mail: catanaka@mmm.muroran-it.ac.jp
http://www3.muroran-it.ac.jp/hnakano/
Tohoku Medical and Pharmaceutical University, 4-4-1
Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Research and Analytical Center for Giant Molecules, Graduate
School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-
ku, Sendai 980-8578, Japan
Specifically, asymmetric nitro-aldol reaction of isatins with
nitroalkanes could provide chiral 3-substituted 3-
hydroxyoxindole core units[7] with nitro functional group, which
are important synthetic precursors for many biologically active
natural products such as CPC-1 (antibacterial activity),[8a]
maremycine B (cytotoxicity against K562 human leukemia cell
lines),[8b] spirobrassinin (antifungal, antitumor and oviposition
stimulation activity),[8c] donaxaridine (anticancer activity),[8d,e] and
[b]
[c]
[d]
Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053,
Japan
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ejoc.201xxxxxx.
dioxobrassinin
(Scheme
1).
Furthermore,
these
3-
hydroxyindoles could also be used as intermediates for newly
designed drugs. Although there have been a few reports[9] on the
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10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
asymmetric nitro aldol reaction of isatins with nitroalkanes, all of
them utilize the cinchona alkaloid derivatives as organocatalysts
for this transformation.
tertiary amino group, which can act as Brønsted base as well as
steric influence site along with two amino and one hydroxyl group
which could make hydrogen bonding with both isatins and
nitroalkanes (Scheme 3). Catalyst B could be easily prepared by
In continuation of our efforts towards expanding the scope
of amino alcohols and their derivatives as organocatalysts,[3] we
herein focused on the synthesis of squaramide-fused amino
alcohols A and B, which have multiple hydrogen bonding sites
and stereoinduction sites in the same molecule, and evaluated
their catalytic activity for the nitro-aldol reaction of isatins with
nitroalkanes. These simple amino alcohols with covalent and
noncovalent hydrogen bonding sites in the same molecule work
as efficient organocatalysts for many enantioselective reactions.[3]
In recent years, squaramide based catalysts containing two
amino hydrogen bonding sites in four membered ring system have
been explored rigorously.[10] Being nitrogenated derivatives of
squaric acid, squaramides are considered as vinylogous amides
(Scheme 2, structure II), whereas, the corresponding urea and
thiourea derivatives are normal (thio) amides (Scheme 2,
structure I). Hence, the rotation of C-N single bond is restricted
due to the delocalization of lone pair of electrons on nitrogen atom
through the carbon-oxygen double bond of cyclobutenedione
system and also further delocalization can occur due to the
partially aromatic character of cyclobutanedione system.[11a]
Moreover, Takemoto[11b] and Rawal[11c] groups have calculated
the distances between the two N-H groups for N,N’-
dimethylthiourea III and N,N’-dimethylsquaramide IV to be
approximately 2.13 Å and 2.72 Å, respectively. And also, the
square geometric structure of the cyclobutenedione ring also
induces a convergent orientation of the N-H groups, canting each
by approximately 6o (Scheme 2, structure VI). [11c] Because of all
these peculiar properties, squaramide moieties could have
greater linearity to make stronger hydrogen bonds with the
substrates bearing nitro, carbonyl, imino, nitrile functional groups
etc. and can provide different binding properties in the transition
states.
CF3
O
O
N
Ph
Ph
OH
+
N
H
H2N
MeO
CF3
squaramides
amino alcohols
steric influence
steric influence
basic site
F3C
O
O
F3C
O
O
N
R
Ph
Ph
N
H
N
H
Ph
Ph
N
H
N
H
F3C
HO
F3C
HO
hydrogen bonding site
R: alkyl or phenyl
hydrogen bonding site
B
A
new hybrid type
squaramide fused
amino alcohols
squaramide fused
amino alcohols
CF3
O
O
F3C
N
N
O
H
H
N
N
H
O
O
O
R
H
R
O
N
plausible trasition state X
Scheme 3. Concept of catalyst design
the condensation of squarate methyl ester amide with the
corresponding amino alcohols and due to the presence of multiple
hydrogen bonding sites and steric factors in one molecule, it could
show strong influence in controlling the stereoselectivity for the
reaction of isatins with nitromethane as shown in the plausible
transition state X (Scheme 3). Thus, isatins and nitromethane
could be conformationally fixed by four hydrogen bonding
interactions between the two amino groups on the squaramide
site and two carbonyl groups on isatins, between the cyclic
ammonium site and the oxygen atom on the nitro enolate moiety,
and between the cyclic ammonium site and the hydrogen on the
hydroxyl group in the ammonium alcohol intermadiate. And then,
the reaction might proceed stereoselectively to afford the nitro-
aldol product with high enantioselectivity.
Herein, we describe the synthesis of new type squaramide
fused amino alcohol organocatalysts and their catalytic efficiency
for the enantioselective nitro-aldol reaction of isatins with
nitromethane as the first example using this class of
organocatalysts to afford the corresponding aldol products with
excellent chemical yields and enantioselectivities (up to 98%, up
to 95% ee).
O
N
O
N
O
N
O
N
X
X
R
R
R
R
N
H
N
H
N
H
N
H
II
I
(X = O, S)
O
O
O
O
S
S
N
H
N
H
N
H
N
H
N
H
N
N
N
H
H
H
-2.1A
-2.7 A
III
IV
V
VI
Scheme 2. Comparison of zwitterionic forms of the urea/thiourea and
squaramide skeletons (I & II), H-bond spacing distances (III & IV), disposition of
hydrogen bonds in N,N’-dimethylthiourea and N,N’-dimethylsquaramide (V &VI).
Previously reported catalyst A containing two amino and
one hydroxyl group as hydrogen bonding sites show efficient
catalytic activity in the enantioselective allylation reaction.[12] On
the other hand, our newly designed catalyst B contains a cyclic
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10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Table 1. Nitro-Aldol Reaction of Isatins with Nitromethane Using Catalysts 4a-
d
The previous reported simple squaramide fused amino alcohol
catalyst 4c[9] and other new derivatives 4a,b,d were synthesized
by the coupling of squarate monoester amide 3 with the
corresponding β-amino alcohols 2a-d, which were obtained easily
from commercial available amino esters 1a-d via Grignard
reaction (Scheme 4).[3d-f]
O
HO
Catalysts 4a-d
(10 mol%)
NO2
O
CH3NO2
O
DMAP, Solvent
0 oC, 48 h
N
N
R
R
5a-c
6
7a-c
catalyst
4
yield
ee
entrya
5
R
base
solvent
7
CF3
(%)b
(%)c
O
O
1d
2
3
4
5
6
7
8
a
a
a
a
b
c
d
a
a
a
a
a
a
a
a
a
a
a
b
c
a
a
H
H
H
H
H
H
H
Me
Bn
H
--
TEA
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
CHCl3
--
a
a
a
a
a
a
b
c
a
a
---
12
25
83
82
83
82
62
75
92
85
---
8
R1
R1
F3C
N
H
OMe
O
Ph
Ph
OH
2a-d
DIPEA
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
11
38
32
31
32
23
11
rac
rac
PhMgBr
3
Et2O, 0 o
15 h
C
H2N
1a-d
H2N
OMe
MeOH, rt, 12 h
R1 = Me, Ph,
Bn, i-Pr
F3C
O
O
9
10
11
R1
Ph
Ph
N
H
N
H
H
aThe reactions were carried out with 5 (0.13 mmol), 6 (0.67 mmol) in mentioned
dry solvents (2.0 mL). bIsolated yields. cEnantiomeric excess was determined
by chiral HPLC on chiralpak-AD-H column.d without base.
F3C
4
HO
4a : R1 = Me, 70%
4c : R1 = Ph, 64%
4b : R1 = i-Pr, 65%
4d : R1 = Bn, 59%
To test our hypothesis, we synthesized the new hybrid type SFAA
catalysts 14a-e in few steps from commercially available L-serine
methyl ester (Scheme 5). Grignard reaction of ammonium ester 8
using PhMgBr furnished the β-amino alcohol 9 in moderate yield.
Scheme 4. Synthesis of Usual Type of SFAA Catalysts 4a-d
With the catalysts 4a-d in hand, we desire to examine the
catalytic activity of these catalysts in nitro-aldol reaction (Table 1).
Initially, we carried out the reaction of simple isatin 5a with
nitromethane 6 using catalyst 4a in THF at 0 oC in the absence of
any basic additive. However, the expected aldol product 7a was
not observed even after 48 h and the starting compound 5a could
be recovered completely (entry 1). Then we hypothesized that
addition of a basic additive might initiate the reaction. To
implement this hypothesis, the basic additives such as TEA,
DIPEA and DMAP were used in the course of reaction to abstract
the proton from nitromethane (entries 2-4). By using these basic
additives, the reaction was proceeded smoothly and the expected
aldol product 7a was obtained, but the better results observed by
using DMAP as additive (entry 4, 83%, 38% ee). Then, different
SFAA catalysts 4b-d, were tested and each catalyst showed
considerable catalytic activity and furnished the product 7a in
good yields (up to 83%), although the ee values were not
satisfactory (entry 5-7, upto 32% ee). Among the tested catalysts,
4a was found to be the best one to furnish the aldol product 7a in
good chemical yield, though the enantioselectivity was not
satisfactory. Different substituted isatins 5b, and 5c were
examined using catalyst 4a under the same reaction conditions.
The reactions of N-methylated isatin 5b and N-benzylated isatin
5c, afforded the respective aldol products 7b and 7c in moderate
chemical yields and poor enantioselectivities (entries 8-9). A quick
solvent screening was performed. The reaction proceeded
efficiently in DCM and CHCl3 furnished the aldol products 7a in
good yield, albeit in racemic form (entries 10-11). These results
revealed that catalysts 4a-d were inefficient to yield the aldol
products with satisfactory enantioinduction and that a basic
additive is necessary for the reaction to proceed. With these
results in hand, we assumed that the introduction of tertiary amino
group into the core structure of SFAA catalyst could improve the
catalytic activity and enantioselectivity of the reaction.
PhMgBr
Et2O
(Boc)2O
Et3N
HO
HN
O
HO
H2N
Ph
Ph
OH
HO
Ph
Ph
OH
0 °C to rt
15 h
54%
DCM, 0 °C to rt
5 h, 91%
OMe
BocHN
HCl
8
9
10
NH
X
n
(X = CH2, O, S)
(n = 0, 1, 2)
MsO
Ph
Ph
OH
MsCl, Et3N
R
Ph
Ph
OH
DCM, 0 °C to rt
4 h, 81%
BocHN
neat, 80 ˚C
12 h
55% to 65%
BocHN
11
12a-e
F3C
O
O
F3C
O
O
N
OMe
R
R
Ph
Ph
OH
F3C
TFA, DCM
H
3
0 ˚C, 5 h
85% to 95%
N
H
14a-e
N
H
sealed tube
MeOH, 120 o
Ph
Ph
H2N
13a-e
C
F3C
HO
14a: 56%, 14b: 52%, 14c: 62%
14d: 78%, 14e: 81%
N
12b : 13b : 14b : R =
12a : 13a : 14a : R = N
12c : 13c : 14c : R =
12e : 13e : 14e : R =
N
N
12d : 13d : 14d : R = N
O
S
Scheme 5. Synthesis of New SFAA Catalysts 14a-e
The free amino function of 9 was protected with Boc group
by treatment with (Boc)2O in the presence of Et3N to afford 10,
followed by the protection of primary hydroxyl group to result in
the O-mesylated derivative 11 in good yield. Subsequently, mesyl
function of 11 was replaced with various cyclic amines (pyrrolidine,
piperidine, azepane, morpholine and thiomorpholine) under the
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10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
neat reaction conditions to provide the compounds 12a-e in
moderate to good yields. De-protection of Boc group of 12a-e by
treating with TFA furnished 13a-e, and a further coupling with
squarate monoester amide 3 afforded the targeted new type
organocatalysts 14a-e in good overall yields (Scheme 5).
poor to moderate enantioselectivities were observed (entries 7-
12). Furthermore, the effect of polar solvents such as TFE, ACN,
DMA, DMF, DMSO and MeOH were also investigated.
Unfortunately,
satisfactory
chemical
yields
and
enantioselectivities were not obtained (entries 13-18). The
reaction was also conducted in water and in neat conditions
(nitromethane used as solvent and reactant). Although, the
product 7a was obtained in fairly good chemical yields, good
enantioinduction was not observed (entries 19 and 20).
Next, we examined the catalytic activity of synthesized
catalysts 14a-e using the best solvent i.e. THF (Table 2). As the
first attempt, catalyst 14a bearing pyrrolidine ring system as a
basic site was tested for the nitro-aldol reaction of simple isatin 5a
with nitromethane 6 at 0°C. Surprisingly, respective aldol product
7a was obtained in excellent chemical yield (99%) with better
enantioselectivity (64% ee) (entry 1). Inspired by these results, we
decided to examine the catalytic activity of other synthesized
SFAA catalysts in this reaction. Catalyst 14b bearing piperidine
ring system as a basic site afforded 7a with excellent chemical
yield but with low enantioselectivity (39%) (entry 2). The best
enantioselectivity (81% ee) with good chemical yield (92%) was
obtained by using catalyst 14c bearing azepane ring system
(entry 3). On the other hand, other two catalysts 14d bearing
morpholine and 14e bearing thiomorpholine ring systems,
afforded the aldol product 7a in only trace amounts (entries 4-5).
Fortunately, performing these reactions at room temperature
successfully afforded the desired aldol product 7a in good
chemical yields with moderate enantioselectivities (14d: 85%,
61% ee; 14e: 98%, 59% ee) (entries 6-7), but these results were
not better than those obtained with 14c.
Table 3. Optimization of Nitro-Aldol Reaction Using Catalyst 14c
HO
NO2
Catalyst 14c
5a
6
O
Solvent, Temp.
60 h
N
H
7a
catalyst
(mol%)
5
20
10
10
10
10
10
yield
(%)b
82
93
70
89
98
95
86
entrya
solvent
temp. (oC)
ee (%)c
1
2
3
4
5
THF
THF
THF
Toluene
Benzene
m-Xylene
DCM
0
0
-20
0
0
0
74
64
78
rac
rac
rac
2
6
7
0
8
9
10
10
10
10
10
10
10
10
10
10
10
10
Diisopropylether
CPME
1,4-Dioxane
Et2O
0
0
0
0
0
0
0
0
0
RT
0
RT
0
93
86
94
93
trace
94
91
43
57
trace
92
92
96
2
rac
55
21
--
rac
53
74
64
--
10
11
12
13
14
15
16
17
18
19
20
THP
TFE
ACN
DMA
Table 2. Nitro-Aldol Reaction Using Catalysts 14a-e
O
HO
Catalysts 14a-e
(10 mol%)
NO2
O
DMF
CH3NO2
O
DMSO
MeOH
Water
N
H
N
H
THF, 60 h
rac
rac
rac
5a
6
7a
10
Neat
aThe reactions were carried out with 5a (0.13 mmol), 6 (0.67 mmol) in mentioned
dry solvents (2.0 mL).bIsolated yields. cEnantiomeric excess was determined by
chiral HPLC on chiralpak AD-H column
entrya
1
catalyst 14
temp. (oC)
yield (%)b
99
ee (%)c
64
a
0
2
3
4
b
c
d
0
0
0
92
92
trace
39
81
--
After rigorous screening of catalysts, catalyst loadings,
additives, solvents and reaction temperatures, we decided to set
the conditions in entry 3 of Table 2 as our optimal conditions for
this reaction and started to explore the substrate scope. The
generality of this protocol was fully demonstrated by evaluating a
variety of isatins and nitromethane and the respective nitro-aldol
products 7b-k were accomplished in good to excellent yields and
poor to good enantioselectivities (Scheme 6). The reactions of N-
alkylated isatins i.e N-methyl-isatin 5b, N-benzyl-isatin 5c and N-
allyl-isatin 5d with afforded the desired aldol products 7b-d,
respectively, in excellent chemical yields (95-98%) but with low to
moderate enantioselectivity (26-67% ee). On the other hand, the
reaction of N-Boc isatin 5e proceeded smoothly and
accomplished the respective product 7e in good chemical yield
(82%) with excellent enantioselectivity (95% ee). 5-Methyl-isatin
5f provided the aldol product 7f in excellent chemical yield (96%)
with low selectivity (35% ee). Moreover, only trace amount of the
aldol product 7g was obtained from the reaction of 5-NO2-isatin
5g with 6, although the exact reason was not clear. The use of
halogenated isatins 5h-k provided the corresponding nitro aldol
products 7h-k with fairly good to excellent chemical yields (89-
5
6
7
e
d
e
0
RT
RT
trace
85
98
--
61
59
a The reactions were carried out with 5a (0.13 mmol), 6 (0.67 mmol) in
dry THF (2.0 mL). bIsolated yields. cEnantiomeric excess was determined
by chiral HPLC on chiralpak AD-H column
We next inspected the effect of solvent, the molar ratio of
catalyst, and reaction temperature (Table 3, entries 1-20).
Changing the molar ratio of catalyst 14c to 5 mol% and 20 mol%
also provided the aldol product 7a in good chemical yields and
enantioselectivity (5 mol%: 82%, 74 % ee, 20 mol%: 93%, 64%
ee), respectively (entries 1-2). At lower reaction temperature i.e -
o
20 C, both the chemical yield and enantioselectivity dropped to
70% and 78% ee respectively (entry 3). The use of non-polar
aromatic solvents also gave 7a with excellent chemical yields (89-
95%), but completely in racemic form (entries 4-6). Furthermore,
the reaction in chlorinated solvents and different ethereal solvents
afforded 7a in good to excellent chemical yields (86-94%) (except
THP, in which case only trace amount of 7a was formed), but very
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10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
97%), but with moderate enantioselectivity (52-64% ee). We also
tried this protocol for superior nitroalkanes (Nitroethane,
Nitropropane), but unfortunately does not yield the corresponding
products with stereoselectivity (corresponding products were
obtained in complete racemic form), although the reason was not
clear.
H
H
H
N
N
H
H
N
H
H
O
O
O
O
O
O
O
N
(a)
(b)
N
H
O
N
H
VII
6
5a
VII
Complex A
Complex B
ꢃꢁꢂ
ꢃ ꢂ
ꢀꢁꢂ
ꢀ ꢂ
ꢀꢁꢂ
ꢃꢁꢂ
ꢃ ꢂ
NO2
O
HO
CH3NO2
6
R2
R2
O
ꢀ ꢂ
O
Catalyst 14c
(10 mol %)
N
N
R1
R1
THF, 0 o
C
E(2) / kcal·mol-1 = 0.25
E(2) / kcal·mol-1 = 1.56
7b-k
5b-k
60 h
HO
ꢃꢅ ꢆ ꢇꢈꢂꢉꢂ
ꢂꢄ ꢅꢆꢇꢂꢁꢈꢁ
HO
HO
HO
NO2
O
NO2
NO2
O
NO2
O
ꢄꢁꢂ
ꢀꢁꢂ
ꢀ ꢁ
ꢃ ꢁ
O
N
(c)
N
N
N
Me
Bn
Boc
ꢃꢂꢁ
ꢀꢂꢁ
ꢂꢄ ꢅꢉꢆꢇꢁꢈꢁ
ꢀꢃꢂ
ꢄꢃꢂ
7b: 97%, 26% ee
7c: 95%, 67% ee
7d: 98%, 41% ee
7e: 82%, 95% ee
ꢃꢅ ꢈꢊꢃꢊꢂꢉꢂ
HO
HO
HO
HO
Complex 2ꢀ
Complex B
Complex 1 ꢀ
NO2
NO2
O
NO2
Cl
NO2
Complex A
Me
O2N
F
O
O
O
N
N
H
N
N
H
H
H
ꢂꢃ ꢄꢅꢆꢁ
7f: 96%, 35% ee
7g: trace
7h: 96%, 64% ee
7i: 89%, 55% ee
ꢂꢃ ꢄꢇꢅꢁ
ꢃ ꢈꢄꢃꢁ
HO
HO
ꢀꢁ
NO2
NO2
O
Br
I
O
N
N
H
H
Mulliken Charge Distribution
7j: 92%, 52% ee
7k: 97%, 62% ee
Figure 1. (a) The calculated second order perturbation energies (E (2) / kcal,
Eamol-1) of the second donor (H-bond donor of squaramides) and acceptor
(Oxygenatoms of Isatins 5a and nitrate 6) interaction for the complexes A and
B, (b) the calculated hydrozen bond distances of the complexes A and B, (c)
The electron density map and Mulliken charge distribution of isatins 5a.
Scheme 6. Substrate Scope of Nitro-Aldol Reaction
Finally, the enantioselective reaction mechanistic pathway of
this reaction using our squaramide-fused amino alcohol catalyst
14c was considered based on both the high enantiopurity (81%
ee) of the chiral aldol product (S)-7a which was obtained from the
reaction of isatin 5a with nitromethane 6 and the calculation
analysis (a: natural bonding orbital (NBO)[13] analysis of the
hydrogen bonding of simple squaramide VII with isatin 5a or
nitrometane 6, b: the hydrogen bonding distance calculations of
complexes A or B, c: electron density of isatin 5a) (Figure 1). Thus,
(a) NBO analysis was performed subsequently on the optimized
structures to quantify the donor-acceptor. The stabilization
energies (E (2)) of intermolecular interactions of all complexes
(complexes A and B) were performed by using second order
perturbation theory. As the calculation result, the stability of A
(E(2) / kcal·mol-1 = 1.56) was increased as compared with that of
B (E(2) / kcal·mol-1 = 0.25). This result might be consistent with the
stability of the complexes. Furthermore, (b) the hydrogen bonding
distance of complex A was also shorter than that of complex B.
In addition, (c) the place of the highest electron density (Mulliken
charge distribution) was on oxygen of amide in isatin 5a.
5a + 6
F3C
O
O
N
N
H
N
H
Ph
Ph
F3C
HO
14c
CF3
CF3
O
O
O
O
F3
C
F3
C
N
N
N
O
H
H
N
H
N
N
H
H
O
H
O
O
O
H
O
H
O
N
HN
O
HN
O
N
O
TS-I
Disfavoured
TS-II
Favoured
81% ee
O
O
O
O
N
N
O
HO
HO
O
N
H
N
From these knowledge, a model for the enantioselective
reaction mechanistic pathway is proposed as follows (Scheme 7).
First, the active methylene proton of nitromethane is abstracted
by basic tertiary amino group on azepane ring in catalyst 14c to
form nitro enolate, which might also induce the strong hydrogen
bonding interaction between the hydrogen atom of the ammonium
H
(R)-7a
Minor isomer
(S)-7a
Major isomer
Scheme 7. Plausible reaction course.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
13C-NMR (125 MHz) spectra were measured in CDCl3, (CD3)2SO. 1H-NMR
spectra data were reported as follows: chemical shifts in ppm from
tetramethylsilane (0.0 ppm) or the residual solvent as an internal standard
((CD3)2SO; 2.50 ppm), integration, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet-doublet, m = multiplet and br = broad),
coupling constants (Hz), and assignment. 13C-NMR spectra were
measured with complete proton decoupling. Chemical shifts were reported
in ppm from the residual solvent as an internal standard (CDCl3: 77.16
ppm). High performance liquid chromatography (HPLC) was performed
using the chiral columns AD-H, AS-H 4.6 mm x 25 cm columns. Optical
rotations were measured with a digital polarimeter. HRMS spectra were
performed by EI and FAB using sector instruments.
moiety on azepane ring in catalyst and oxygen atom of nitro
enolate. Next, isatin 5a might fixed with catalyst 14c through two
hydrogen bonds between two carbonyl oxygen atom on isatin 5a
and two primary amino groups on squaramide site in catalyst.
When isatin 5 makes the hydrogen bonding to catalyst, one
carbonyl oxygen atom of amide on isatin 5a might binds with the
hydrogen atom of amino group with 3,5-Bis(trifluoromethyl)phenyl
group as an electron-withdrawing group on squaramide site in
catalyst and other carbonyl oxygen atom on isatins 5a might binds
with the hydrogen atom of another amino group on squaramide in
catalyst. In addition, the side chain containing ammonium alcohol
moiety on catalyst might be fixed by the hydrogen bonding
interaction between hydrogen atom on the hydroxyl group and
ammonium moiety on azepane ring on the side chain. Among the
possible two transition states TS-I and TS-II, TS-II has less steric
interaction than that of TS-I, which has strong steric repulsion
between four membered squaramide skeleton and di-phenyl
groups on catalyst. Hence the reaction might proceed via the
transition state TS-II, in which nitroenolate coordinated to
ammonium moiety on azepane ring could attack the isatin from
the upper side (Si face) leading to the formation of (S)-7a as major
enantiomer, whereas minor isomer (R)-7a might be obtained via
the unfavorable transition state TS-I.
General procedure for synthesis of catalysts 4a-d. To a stirred solution
of squarate mono amide ester 3 (149 mg, 1 mmol) in dry MeOH (5 mL)
was added corresponding β-aminoalcohol 2a-d (1 mmol) at room
temperature and allowed the reaction mixture to stirred for 12 h at same
temperature. After completion of reaction indicated by TLC, the excess
MeOH was evaporated under reduced pressure results the crude reaction
mixture, which was purified by flash column chromatography using
Hexane:EtOAC (6:4) as eluent to afforded the targeted organocatalysts
4a-d as pure compounds in moderate to good yields.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-
diphenylpropan-2-yl)amino)cyclobut-3-ene-1,2-dione (4a). Pale yellow
solid (MeOH). 170 mg, 70% yield. m.p. 202-205 °C. [α]D24 = -38 (c = 0.5,
MeOH). IR (neat) = 3223, 2980, 1687, 1417, 1115, 825 cm-1. 1H NMR (500
MHz, DMSO-d6): δ 10.40 (s, 1H), 8.03 (s, 2H), 7.99 (d, J = 10.50 Hz, 1H),
7.62 (s, 1H), 7.51 (t, J = 7.00 Hz, 3H), 7.40 (t, J = 7.50 Hz, 2H), 7.26-7.20
(m, 3H), 7.09 (t, J = 7.50 Hz, 1H), 6.42 (s, 1H), 1.00 (d, J = 7.0 Hz, 3H),
0.83 (d, J = 7.00 Hz, 3H). 13C NMR (125 MHz, DMSO-d6): δ 184.6, 180.0,
170.1, 161.8, 146.2, 145.3, 141.1, 128.3, 127.8, 126.8, 126.4, 125.7, 125.6,
124.2, 122.1, 117.9, 114.6, 81.1, 63.6, 28.7, 22.3, 17.5. EI-MS m/z: 534
(M)+, 556.8 (M + Na)+. HRMS (EI) calcd for C27H20F6N2O3 m/z: 534.1378
(M)+ found: 534.1390.
Conclusions
In summary, we have synthesized squaramide-fused amino
alcohol (SFAA) catalysts 4a-d and newly designed SFAA
catalysts 14a-e from commercial available amino esters via
simple organic transformations and demonstrated their catalytic
efficiency in the asymmetric nitro aldol reaction of various isatins
and nitromethane. This protocol provides the chiral 3-substituted
3-hydroxyoxindoles in excellent chemical yields (up to 99%) and
high enantioselectivities (up to 95% ee). Catalyst 14c bearing
azepane ring system as basic site showed best catalytic activity
for this reaction among all synthesized catalysts. The resulted 3-
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-3-
methyl-1,1-diphenylbutan-2-yl)amino)cyclobut-3-ene-1,2-dione (4b).
White solid (ether). 150 mg, 65% yield. m.p. 197-198 °C. [α]D24 = -647 (c =
0.5, MeOH). IR (neat) = 3215, 2986, 1696, 1497,740 cm-1. 1H NMR (500
MHz, DMSO-d6): δ 8.28 (s, 1H), 8.21 (d, J = 11.00 Hz, 1H), 8.04 (d, J =
10.50 Hz, 1H), 7.50-7.43 (m, 4H), 7.34-7.23 (m, 4H), 7.20-7.11 (m, 1H),
5.76 (s, 1H), 5.68 (s, 1H), 5.12-5.10 (m, 1H), 4.40 (s, 1H), 4.19 (s, 1H),
0.93 (d, J = 7.00 Hz, 3H), 0.75 (t, J = 6.50 Hz, 3H). 13C NMR (125 MHz,
DMSO-d6): δ 189.8, 182.4, 177.3, 173.1, 146.8, 130.2, 129.3, 128.8, 128.3,
128.1, 127.9, 127.5, 126.6, 126.0, 125.8, 125.6, 125.5, 125.0, 80.5, 63.7,
28.5, 22.4, 17.7. EI-MS m/z: 562 (M)+. HRMS (EI) calcd for C29H24F6N2O3
m/z: 562.1691 (M)+ found: 562.1705.
alkylsubstituted
3-hydroxyoxindoles
could
be
crucial
intermediates for the synthesis of many significant biologically
active scaffolds. The feasible mechanistic path of this reaction
using our newly synthesized catalyst 14c was also explained by
calculated the second order perturbation energies of second
donor [H-bond donor of squaramide] and acceptor [oxygen atoms
of isatin 5a and nitromethane 6] and hydrogen bond distances
between catalyst 14c and isatin 5a, and nitromethane 6.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1,3-
triphenylpropan-2-yl)amino)cyclobut-3-ene-1,2-dione (4d). White solid
(MeOH). 100 mg, 59% yield. m.p. 253-255 °C. [α]D24 = -25 (c = 0.5, MeOH).
IR (neat) = 3265, 2986, 1686, 1446, 855 cm-1. 1H NMR (500 MHz, DMSO-
d6): δ 10.15 (s, 1H), 8.05 (d, J = 10.00 Hz, 1H), 7.93 (s, 2H), 7.66 (d, J =
7.50 Hz, 2H), 7.60 (s, 1H), 7.54 (d, J = 7.50 Hz, 2H), 7.46 (t, J = 7.50 Hz,
2H), 7.29 (t, J = 7.50 Hz, 1H), 7.19 (t, J = 7.50 Hz, 4H), 7.15-7.05 (m, 4H),
6.62 (s, 1H), 5.47-5.41 (m, 1H), 2.83 (d, J = 7.00 Hz, 2H). 13C NMR (125
MHz, DMSO-d6): δ 183.8, 179.6, 169.6, 160.9, 145.4, 145.1, 141.0, 137.9,
131.5, 131.2, 129.3, 128.6, 128.2, 127.9, 127.0, 126.4, 125.5, 124.2, 122.0,
117.6, 79.7, 62.2, 36.8. EI-MS m/z: 610 (M)+, 633 (M + Na)+. HRMS (EI)
calcd for C33H24F6N2O3 m/z: 610.1691 (M)+ found: 610.1697.
Experimental Section
General Methods. All commercial reagents were purchased and used
without further purification. All reactions were carried out under an argon
atmosphere in flame-dried glassware with magnetic stirring. Thin layer
chromatography (TLC) was performed on silica gel 60 F254 and analytes
were detected using UV light (254 nm) and iodine vapor. Column
chromatography was carried out on silica gel 60N (40–100 µm) and
preparative TLC was carried out on silica gel 60 F254. Melting points were
measured using a micro-melting point apparatus. Infrared (IR) spectra
were measured with a FT/IR spectrophotometer. 1H-NMR (500 MHz) and
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
General procedure for Synthesis of compounds 13a-e. Compound 11
(1 mmol) compound was charged in 50 mL round bottomed flask and the
corresponding cyclic amine (5 mmol) was added drop-wise at room
temperature. After 5 min stirring the temperature was raised to 70° C and
allowed to stirred for 12 h. After completion of the reaction, crude reaction
mixture was purified by flash column chromatography using
Hexane:EtOAc (7:3) as eluent to give the compounds 12a-e (55% - 65%),
Next, the compounds 12 (1 mmol) compounds were dissolved in DCM (10
mL) followed by slow addition of TFA (0.382 mL, 10 mmol) at 0 oC and
stirred for 1 h at room temperature. After completion of reaction the residue
was basified using with saturated aq. NaHCO3 solution and extracted in
DCM (3x15 mL) and the combined organic layers were washed with brine
and dried over Na2SO4. The solvent was evaporated under reduced
pressure to yield the resulted g-tertiary amine aminoalcohols 13a-e (85% -
95%) as pure compounds without further purification.
CD3OD): δ 147.4, 146.8, 129.5, 129.3, 127.9, 127.8, 127.2, 126.2, 126.9,
80.7, 61.5, 57.2, 54.9, 28.9. EI-MS m/z: 328 (M)+. HRMS (EI) calcd for
C19H24N2OS m/z: 328.1609 (M)+: found: 328.1608.
General procedure for synthesis of compounds 14a-e. The
squaramide mono-ester amide 3 (100 mg, 1 mmol) and g-tertiaryamine
aminoalcohol 13 (1 mmol) were charged in sealed tube in 20 mL MeOH
solvent and the sealed tube was closed tightly without any air gap and the
reaction mixture was stirred for 12 h at 120° C. After completion of the
reaction indicated by TLC, the excess solvent was evaporated under
reduced pressure resulted the crude mass, which was purified directly by
flash column chromatography using CHCl3:MeOH (9:1) as eluent to give
the compound 14a-e (56% - 81%).
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-
diphenyl-3-(pyrrolidin-1-yl)propan-2-yl)amino)cyclobut-3-ene-1,2-
25
(S)-2-Amino-1,1-diphenyl-3-(pyrrolidin-1-yl)propan-1-ol (13a). Light
yellow solid (Ether). 135 mg, 90% yield. m.p. 113-115 °C. [α]D24 = -74 (c =
1.09, EtOH). IR (neat) = 2933, 2803, 1556, 1448, 1355 cm-1. 1H NMR (500
MHz, CDCl3): δ 7.64 (d, J = 8.50 Hz, 2H), 7.53 (d, J = 8.50 Hz, 2H), 7.33-
7.25 (m, 4H), 7.20-7.13 (m, 2H), 3.92 (q, J1 = 3.50, 7.00 Hz, 1H), 2.76 (q,
J1 = 7.00, 13.00 Hz, 1H), 2.62-2.60 (m, 2H), 2.42-2.40 (m, 2H), 2.28 (dd,
J1 = 3.50, 13.00 Hz, 1H), 1.76-1.70 (m, 4H). 13C NMR (125 MHz, CDCl3):
δ 146.3, 145.8, 128.4, 128.2. 126.6, 126.5, 125.9, 125.6, 79.9, 57.6, 55.1,
55.0, 23.7; FAB-MS m/z: 297 (M+H)+. HRMS (FAB) calcd for C19H25N2O
m/z: 297.1967 (M+H)+ found: 297.1963.
dione (14a). Brown solid (Ether). 99 mg, 56% yield. m.p. 145-146 °C. [α]D
= -45 (c = 1.0, CHCl3). IR (neat): 3566, 3250, 3198, 2965, 1680, 1596 cm-
1
.
1H NMR (500 MHz, CD3OD): δ 8.02 (s, 2H), 7.63 (d, J = 8.50 Hz, 2H),
7.55 (t, J = 7.50 Hz, 3H), 7.39 (t, J = 8.00 Hz, 2H), 7.26 (t, J = 7. 50 Hz,
1H), 7.21 (t, J = 7.50 Hz, 2H), 7.11 (t, J = 7.50 Hz, 1H), 5.45 (d, J = 6.50
Hz, 1H), 3.00 (d, J = 8.50 Hz, 1H), 2.77 (s, 2H), 2.60 (d, J = 13.00 Hz, 1H),
2.46 (s, 2H), 1.78 (s, 4H). 13C NMR (125 MHz, CD3OD): δ 186.1, 182.0,
171.6, 164.0, 146.5, 146.3, 142.6, 129.7, 129.2, 128.4, 128.1, 127.0, 126.8,
127.0, 126.8, 125.8, 123.7, 119.2, 116.4, 58.9, 56.0, 24.5. EI-MS m/z: 603
(M)+. HRMS (EI) calcd for C31H27F6N3O3 m/z: 603.1957 (M)+: found:
603.1948.
(S)-2-Amino-1,1-diphenyl-3-(piperidin-1-yl)propan-1-ol (13b). Pale
yellow solid (Ether). 145 mg, 95% yield. m.p. 125-126 °C. [α]D25 = -66 (c =
1.38, EtOH). IR (neat) = 3432, 2836, 2321, 1561, 1446 cm-1. 1H NMR (500
MHz, CDCl3): δ 7.60 (d, J = 7.50 Hz, 2H), 7.51 (d, J = 7.50 Hz, 2H), 7.33-
7.24 (m, 4H), 7.20-7.15 (m, 2H), 3.96 (q, J1 = 4.50, 6.50 Hz, 1H), 2.62-2.39
(m, 3H), 2.20-2.16 (m, 3H), 1.57-1.50 (m, 4H), 1.38 (s, 2H). 13C NMR (125
MHz, CDCl3): δ 146.9, 145.2, 128.3, 128.2, 126.6, 126.5, 126.1, 125.8,
79.5, 59.1, 56.3, 54.0, 28.5, 26.3. FAB-MS m/z: 310 (M+H)+. HRMS (FAB)
calcd for C20H27N2O m/z: 311.2123 (M+H)+: found: 311.2126.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-
diphenyl-3-(piperidin-1-yl)propan-2-yl)amino)cyclobut-3-ene-1,2-
dione (14b). Brown solid (Ether). 100 mg, 54% yield. m.p. 125-126° C.
25
[α]D = -23.00 (c = 1.0, EtOH). IR (neat): 3554, 3447, 1794, 1733, 1671,
1558 cm-1. 1H NMR (500 MHz, CD3OD): δ 8.02, (s, 2H), 7.64 (d, J = 7.00
Hz, 2H), 7.56 (d, J = 9.00 Hz, 2H), 7.50 (s, 1H), 7.40 (t, J = 8.00 Hz, 2H),
7.27 (t, J = 7.50 Hz, 2H), 7.11 (t, J = 7.50 Hz, 1H), 5.53 (d, J = 7.50 Hz,
1H), 3.17-2.80 (m, 3H), 2.58 (s, 2H), 1.73-1.44 (m, 4H), 1.31-1.25 (m, 2H),
0.88 (t, J = 11.00 Hz, 1H). 13C NMR (125 MHz, CD3OD): δ 186.1, 182.0,
171.6, 164.2, 145.8, 142.4, 129.9, 129.3, 128.6, 128.3, 127.1, 126.8, 125.8,
123.6, 119.2, 116.7, 81.4, 60.9, 59.4, 56.1, 32.9, 26.0, 23.9, 14.6. FAB-MS
m/z: 618 (M+H)+. HRMS (FAB) calcd for C32H30F6N3O3 m/z: 618.2191
(M+H)+: found: 618.2203.
(S)-2-Amino-3-(azepan-1-yl)-1,1-diphenylpropan-1-ol
(13c).
Pale
yellow solid (Ether). 131 mg, 86% yield. m.p. 145-146 °C. [α]D23 = -40 (c =
2.4, EtOH). IR (neat) = 3504, 2933, 2326, 1615, 1452 cm-1. 1H NMR (500
MHz, CDCl3): δ 7.60 (d, J = 8.50 Hz, 2H), 7.51 (d, J = 8.50 Hz, 2H), 7.33-
7.24 (m, 4H), 7.21-7.155 (m, 2H), 3.92 (q, J1= 4.50, 7.50 Hz, 1H), 3.71 (s,
3H), 2.69-2.65 (m, 2H), 2.57-2.52 (m, 3H), 2.48 (dd, J1 = 4.50, 13.50 Hz,
1H), 1.63-1.56 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 146.3, 145.5, 128.4,
128.3, 127.3, 126.6, 126.1, 125.7, 79.8, 59.9, 56.8, 54.5, 28.0, 27.1. FAB-
MS m/z: 325 (M+H)+. HRMS (FAB) calcd for C21H29N2O m/z: 325.2280
(M+H)+: found: 325.2279.
(S)-3-((3-(Azepan-1-yl)-1-hydroxy-1,1-diphenylpropan-2-yl)amino)-4-
((3,5-bis(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione
(14c). Yellow solid (Ether). 117 mg, 62% yield. m.p. 161-162° C. [α]D23 = -
23.00 (c = 1.0, EtOH). IR (neat): 3522, 3493, 1793, 1648 cm-1. 1H NMR
(500 MHz, CDCl3): δ 7.93 (s, 1H), 7.64-7.52 (m, 4H), 7.46 (d, J = 6.00 Hz,
2H), 7.36 (t, J = 7.50 Hz, 3H), 7.23 (t, J = 6.00 Hz, 2H), 7.17-7.14 (m, 2H),
7.05 (t, J = 7.00 Hz, 1H), 5.44 (s, 1H), 3.12 (d, J = 14.00 Hz, 1H), 2.94 (s,
1H), 2.60 (s, 2H), 2.41 (s, 2H), 1.61-1.35 (m, 8H). 13C NMR (125 MHz,
CDCl3): δ 182.4, 181.7, 171.6, 162.4, 143.6, 143.0, 139.7, 129.2, 128.8,
127.7, 127.6, 125.2, 124.9, 124.0, 121.9, 117.7, 116.5, 115.3, 80.3, 59.7,
59.3, 57.8, 54.0, 27.1, 26.8, 23.6, 22.5. FAB-MS m/z: 632 (M+H)+. HRMS
(FAB) calcd for C33H32F6N3O3 m/z: 632.2342 (M+H)+: found: 632.2341.
(S)-2-Amino-3-morpholino-1,1-diphenylpropan-1-ol (13d). Light yellow
23
solid (Ether). 130 mg, 85% yield. m.p. 110-113 °C. [α]D = -66 (c = 1.0,
EtOH). IR (neat) = 3386, 3324, 2950, 1599, 1449, 1259 cm-1. 1H NMR (500
MHz, CD3OD): δ 7.29 (d, J = 8.00 Hz, 2H), 7.18 (d, J = 8.00 Hz, 2H), 6.98
(t, J = 8.00 Hz, 2H), 3.76 (dd, J1 = 3.00, 9.00 Hz, 1H), 2.20 (s, 2H), 2.10 (q,
J = 9.00, 13.00 Hz, 1H), 1.88 (s, 2H), 1.83 (dd, J = 3.00, 12.50 Hz, 1H).
13C NMR (125 MHz, CD3OD) δ: 147.6, 146.8, 129.5, 129.3, 127.9, 127.8,
127.2, 126.8, 80.7, 68.2, 61.2, 55.4, 54.6. FAB-MS m/z: 313 (M+H)+.
HRMS (FAB) calcd for C19H25N2O2 m/z: 313.1916 (M+H)+: found:
313.1904.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-3-
morpholino-1,1-diphenylpropan-2-yl)amino)cyclobut-3-ene-1,2-
dione (14d). White solid (Ether). 142 mg, 78% yield. m.p. 238-240 °C.
25
[α]D = -8.00 (c = 1.10, EtOH). IR (neat): 3589, 3423, 1797, 1568, 1541
(S)-2-Amino-1,1-diphenyl-3-thiomorpholinopropan-1-ol (13e). White
solid (Ether). 131 mg, 85% yield. m.p. 94-96 °C. [α]D = -74 (c = 1.09,
cm-1. 1H NMR (500 MHz, CD3OD): δ 8.03 (s, 2H), 7.58 (t, J = 7.50 Hz, 4H),
7.53 (s, 1H), 7.37 (t, J = 7.50 Hz, 2H), 7.26-7.21 (m, 3H), 7.11 (t, J = 7.00
Hz, 2H), 5.48 (t, J = 4.50 Hz, 1H), 3.63-3.54 (m, 4H), 2.70 (q, J1 = 9.50 Hz,
13.50 Hz, 3H), 2.54 (d, J = 12.00 Hz, 1H), 2.24 (s, 2H). 13C NMR (125
MHz, CD3OD): δ 186.3, 181.8, 171.8, 163.4, 146.6, 146.4, 142.6, 129.7,
129.3, 128.4, 128.0, 126.7, 125.8, 123.7, 119.2, 116.6, 80.8, 68.2, 61.4,
25
EtOH). IR(neat) = 3582, 2952, 2359, 1673, 1491 cm-1. 1H NMR (500 MHz,
CD3OD): δ 7.73 (s, 1H), 7.48 (d, J = 7.50 Hz, 2H), 7.39 (d, J = 7.50 Hz,
2H), 7.20-7.12 (m, 2H), 3.93 (s, 1H), 2.64 (s, 2H), 2.48 (s, 2H), 2.35 (s,
2H), 2.30-2.25 (m, 3H), 2.12 (d, J = 13.00 Hz, 1H). 13C NMR (125 MHz,
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10.1002/ejoc.201700138
European Journal of Organic Chemistry
FULL PAPER
60.0, 55.5. FAB-MS m/z: 620 (M+H)+. HRMS (FAB) calcd for
Yamada, G. Otani. Tetrahedron Lett. 1969, 10, 4237–4240; d) Z. G.
Hajos, D. R. Parrish. J. Org. Chem. 1974, 39, 1615–1621.
C31H28F6N3O4 m/z: 620.1984 (M+H)+: found: 620.1984.
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a) P. I. Dalko in Asymmetric Organocatalysis: A New Stream in Organic
Synthesis, in Enantioselective Organocatalysis: Reactions and
Experimental Procedures (Eds.: P. I. Dalko), Wiley-VCH Verlag GmbH &
Co. KGaA, Weinheim, Germany. 2007, pp. 1-64; b) C. Bolm, J. A.
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(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-
diphenyl-3-thiomorpholinopropan-2-yl)amino)cyclobut-3-ene-1,2-
dione (14e). White solid (Ether). 151 mg, 81% yield. m.p. 234-236 °C.
25
[α]D = -11.00 (c = 1.0, EtOH). IR (neat): 3522, 3462, 1800, 1652, 1573
cm-1. 1H NMR (500 MHz, CD3OD): δ 8.03 (s, 2H), 7.58 (t, J = 7.50 Hz, 4H),
7.53 (s, 1H), 7.37 (t, J = 7.50 Hz, 2H), 7.26-7.21 (m, 3H), 7.11 (t, J = 7.00
Hz, 1H), 5.46 (m, 1H), 2.91 (t, J = 7.50 Hz, 2H), 2.69-2.49 (m, 8H). 13C
NMR (125 MHz, CD3OD) δ: 186.2, 181.8, 171.8, 163.4, 146.7, 146.4,
142.5, 129.7, 126.3, 128.4, 128.0, 126.9, 126.6, 125.8, 123.6, 119.1, 116.6,
80.8, 61.6, 60.3, 57.2, 29.0. FAB-MS m/z: 636 (M+H)+. HRMS (FAB) calcd
for C31H28F6N3O3S m/z: 636.1756 (M+H)+: found: 636.1760.
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a) U. V. Subba Reddy, M. Chennapuram, C. Seki, Y. Okuyama, E. Kwon,
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Subba Reddy, Y. Kohari, C. Seki, Y. Mawatari, K. Uwai, Y. Okuyama, E.
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General Procedure for the nitro-aldol reaction. To the stirred solution
of isatin 5 (20 mg, 1.0 equiv.) and catalyst 14c (0.1 equiv.) in THF (2 mL)
was added nitromethane 6 (5.0 equiv.) at 0 oC and stirring was continued
for appropriate times at same temperature. After completion of reaction
indicated by TLC, the excess solvent was removed under reduced
pressure yields the crude mass, which was purified by flash column
chromatography using Hexane:EtOAC (6:4) solvent system to give the
nitro aldol product as pure compounds. The chemical yields of compound
5
were calculated after isolation by column chromatography. The
enantiomeric excess and diastereoselctivity values were determined by
chiral HPLC using ChiralPak AD-H and AS-H columns.
(S)-tert-Butyl 3-hydroxy-3-(nitromethyl)-2-oxoindoline-1-carboxylate
(7e). Yellow solid. 24 mg, 98% yield. m.p. 134 -136 °C. [α]D23 = +2.88 (c =
1.0, EtOH). The ee was determined by HPLC [DAICEL chiralpak AD-H
column, hexane/2-propanol = 85/15, flow rate: 1.0 mL/min, tr(major) =
10.27 min, tr(minor) = 17.46 min, ee = 95 %]. IR (neat): 3995, 1732, 1616,
1540, 1191, 720 cm-1. (1H NMR, 500 MHz, CDCl3): δ 10.19 (s, 1H), 7.77
(t, J = 8.00 Hz, 1H), 7.66 (t, J = 8.00 Hz, 1H), 7.44 (t, J = 9.00 Hz, 1H),
7.25-7.19 (m, 1H), 7.08 (s, 1H), 5.22 (q, J1 = 14.00, 19.00 Hz, 2H), 1.58 (s,
9H). 13C NMR (125 MHz, CDCl3): δ 173.5, 148.9, 140.3, 131.2, 127.1,
125.3, 125.0, 115.3, 84.7, 78.5, 72.6, 28.4. EI-MS m/z: 308 (M)+. HRMS
(EI) calcd for C9H8N2O4 m/z: 208.0484 (M-Boc)+: found: m/z: 208.0491 (M-
Boc)+.
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(S)-3-Hydroxy-5-iodo-3-(nitromethyl)indolin-2-one (7k). Brown solid.
21
24 mg, 97% yield. m.p. 160-161 °C. [α]D = +53.33 (c = 0.3, EtOH). The
ee was determined by HPLC DAICEL chiralpak AD-H column, hexane/2-
propanol = 85/15, flow rate: 1.0 mL/min, tr(minor) = 12.51 min, tr(major) =
16.89 min, ee = 62 %]. IR (neat): 3991, 1730, 1615, 1543, 1182, 825 cm-
1. 1H NMR (500 MHz, DMSO-d6): δ 10.23 (s, 1H), 7.71 (d, J = 1.50 Hz, 1H),
7.57 (dd, J1 = 1.50, 8.00 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H),
5.02 (q, J1 = 8.00, 39.50 Hz, 2H). 13C NMR (125 MHz, DMSO-d6): δ 175.3,
142.4, 138.6, 133.1, 130.7, 112.5, 84.6, 77.8, 72.4; EI-MS m/z: 333.9 (M)+.
HRMS (EI) calcd for C9H7N2O4I m/z: 333.9450 (M)+: found: 333.9460.
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We thank Adaptable & Seamless Technology Transfer Program
through Target-driven R&D from Japan Science and Technology
Agency (JST) (AS231Z01382G and AS221Z01186D) for partial
financial support to this research.
Keywords: squaramide fused amino alcohol • organocatalysts •
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10.1002/ejoc.201700138
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Layout 2:
FULL PAPER
Squaramide-Fused Amino Alcohol
Organocatalyst
Madhu Chennapuram, U. V. Subba
Reddy, Chigusa Seki, Yuko Okuyama,
Eunsang Kwon, Koji Uwai, Michio
Tokiwa, Mitsuhiro Takeshita, and Hiroto
Nakano*
New hybrid type squaramide-fused amino alcohol organocatalysts were synthesized
and their catalytic efficiency in asymmetric nitro-aldol reaction of nitromethane with
isatins to afford the chiral 3-alkyl-3-hydroxyoxindoles with high stereoselectivitys was
described
Page No. – Page No. s
New Hybrid Type, Squaramide-Fused
Amino Alcohol Organocatalysts for
Enantioselective Nitro-Aldol Reaction
of Nitromethane with Isatins
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