Enantioselective amination of nitroolefins under base-free and water-rich conditions using chiral bifunctional phase-transfer catalysts

Article abstract of DOI:10.1039/c8ob00583d

The direct enantioselective amination of nitroolefins has been performed with l-tert-leucine-derived squaramide-scaffold bifunctional phase-transfer catalysts under base-free and water-rich conditions with low catalyst loading (0.5-1 mol%) to provide 2-am

Full text of DOI:10.1039/c8ob00583d

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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Enantioselective amination of nitroolefins under base-free and
water-rich conditions by chiral bifunctional phase-transfer
catalysts
Received 00th January 20xx,
Accepted 00th January 20xx
‡
Junchao Zhu,a,† Dongxiao Cui,b,c,† Yuedan Li,a Jingxu He,a Weiping Chena,‡ and Pingan Wanga,
DOI: 10.1039/x0xx00000x
The direct enantioselective amination of nitroolefins has been performed with L-tert-leucine-derived squaramide-scaffold
bifunctional phase-transfer catalysts under base-free and water-rich conditions with low catalyst-loading (0.5~1 mol%) to
provide 2-aminonitroalkanes in good yields (up to 96%) and enantioselectivities (up to 93% ee).
www.rsc.org/
Introduction
Bn
N
The Chiral phase-transfer catalysis (CPTC) plays an important
role in modern organic synthesis both in academies and
industries for providing numerous chiral intermediates and
building blocks1. However, most of phase-transfer catalytic
reactions such as alkylation and Michael addition were usually
performed under basic conditions, some substrates and chiral
phase-transfer catalysts such as ammonium and phosphonium
salts are unstable in the presence of these basic additives2. In
order to overcome this problem, neutral phase-transfer
catalytic reactions have been discovered by chemists, but this
type of reactions is less investigated except Maruoka and
colleagues’ research works3.
H
H
Br
Br
PPh2
N
N
Ph
O
O
HO
H
H
N
N
N
CF3
O
MeO2C
O
CO2Me
CF3
Bn
N
NH
O
NH
NH
Br
Br
NH
I
NMe2
Br
On one hand, the synthesis and application of bifunctional
chiral phase-transfer catalysts with various privileged
skeletons including Cinchona alkaloids, binols, 1,2-
diaminocyclohexane and amino acids are booming in recent
years (Figure 1)4, 5. Commonly, this type of catalysts not only
possess quaternary onium salt centre but also hydrogen-
bonding functional group such as free OH, (thio)urea and
squaramide, which are used in asymmetric Henry reaction,
epoxidation, Michael addition, alkylation, Mannich reaction
and so on to achieve good enantioselectivities. On the other
hand, the organocatalyzed amination of active carbonyl
compounds at α-position with azodicarboxylates has provided
an efficient strategy for C-N bond formation6, 7, and the direct
Figure 1. The representative chiral bifunctional phase-transfer
catalysts developed in recent literatures.
neutral amination of nitroolefins in water-rich solvents has
also been found to afford 2-aminonitroalkanes in high yields
and enantioselectivities with chiral binaphthyl-based
bifunctional tetraalkylammonium salts (Scheme 1a, CPTC-1
under phase-transfer conditions8. Although the latter is
regarded as powerful and environmental benign C-N
)
a
formation reaction, it is rarely investigated except this above-
mentioned example, and the catalysts used in this reported
amination were synthesized over 10 steps with a low overall
yield9. Herein we have prepared a plenty of chiral bifunctional
phase-transfer catalysts in good yields from commercially
available materials in simple synthetic routes through 3~5
steps with easily handling reagents, and the direct
enantioselective aminations of nitroolefins have been
performed by using these chiral bifunctional phase-transfer
catalysts under base-free and water-rich conditions with only
0.5-1.0 mol% of catalyst-loading to generate 2-
aminonitroalkanes in good to excellent yields and
enantioselectivities (Scheme 1b, OC-11).
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catalyst OC-1 is essential for obtaining good yield in this
reaction (Table 1, entry 1 vs entry 2). When cinchonine-derived
OC-3 was used as phase-transfer catalyst, 3a was obtained in
moderate yield (56%) and low enantiselectivity (Table 1, entry
3). In our previous reports10, a series of ferrocene-based
organocatalysts have been prepared for enantioselective
Michael reaction and Morita–Baylis–Hillman reaction to afford
good performance, these researches demonstrate that
ferrocene could be an excellent scaffold for construction of
chiral organocatalysts. With the continuation of our works, the
ferrocene-based chiral bifunctional quaternary phosphonium
salts OC-4 and OC-5 are synthesized and tested in this direct
amination, respectively. Unexpectedly, these two phase-
transfer catalysts have shown low efficiency in this amination
to produce 3a with moderate yields and low enantiselectivities.
Interestingly, OC-5 with a thiourea group generated 3a in an
opposite configuration which compared to OC-4 with a urea
group (Table 1, entries 4 and 5) in this reaction. Kowalczyk11
and Oriyama12 have reported asymmetric Michael reaction of
thiols to electro-deficiency alkenes by using chiral (thio)urea
and squaramide organoccatalysts derived from commercially
available (S)- or (R)-3-amino-1-benzylpyrrolidine. We have
prepared four chiral bifunctional quaternary ammonium salts
OC-6 to OC-9 based (R)-3-amino-1-benzylpyrrolidine and these
phase-transfer catalysts are also applied in the water-rich
Scheme 1. Enantioselective amination by chiral bifunctional phase-
transfer catalysts.
Results and discussion
As illustrated in Figure 2, twelve chiral phase-transfer
catalysts (OC-1 to OC-12) are synthesized from commercially
available reagents such as L-tartaric acid, cinchonine, ugi’s
amine, (R)-3-amino-1-benzylpyrrolidine, L-valine and L-tert-
leucine in good yields (see the Supplementary Information for
details), respectively. All synthetic catalysts are screened in
amination reaction of
1 and 2a. OC-6 containing a urea motif
with p-trifluoromethyl group at phenyl ring afforded 3a in
moderate yield but low ee value (Table 1, entry 6). By replacing
p-trifluoromethylphenyl with 3,5-bistrifluoromethylphenyl in
OC-6 to furnish OC-7, and OC-7 results in no significant
increase of enantioselectivity but with higher yield of 3a than
OC-6 under the same conditions (Table 1, entry 7 vs entry 6).
OC-8 with a thiourea group as a catalyst has provided 3a in
good yield and moderate ee value (Table 1, entry8). When
squaramide-containing catalyst OC-9 has been used in the
model reaction of BocNHOBn
1 and trans-β-nitrostryene 2a
under neutral water-rich conditions, and the results are listed
in Table 1. The racemic product 3a was obtained in moderate
yield (45%) by using catalyst OC-1 from L-tartaric acid. OC-2
was prepared by masking two hydroxyl groups in OC-1 with
MsCl, and only trace amination product was detected from TLC
under the same base-free conditions with OC-2 as catalyst.
These results clearly indicate that free hydroxyl groups of
amination reaction of 2a
,
an expected increase
Figure 2. Chiral bifunctional phase-transfer catalysts.
2 | J. Name., 2012, 00, 1-3
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Table 1. The screening of catalysts.
oC, the ee value of 3a was promoted slightly from 84% to 87%
with a little decrease of yield and an acceptable prolongation
of reaction time (Table 1, entry 13 vs entry 12). Increasing the
amount of amination reagent from 3.0 eq. to 5.0 eq., no
significant improvement of enantioselectivity of 3a was
observed (Table 1, entry14 vs entry 13). The decrease of the
amount of amination reagent from 5.0 eq. to 1.5 eq. resulted
Entrya NH(eq.)b
Cat.
Tc
Yieldd[%]
45
trace
56
eee[%]
rac-
1
2
5.0
5.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
5.0
1.5
3.0
3.0
OC-1
OC-2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0oC
r.t.
0oC
0oC
0oC
r.t.
0oC
in somewhat lower yield of 3a but with
a very little
-
enhancement of ee value (Table 1, entry 15 vs entry 14).
Besides pyrrolidine, morpholine was also embedded in the
structure of catalyst to furnish OC-12, which demonstrated a
similar catalytic ability with OC-11 in this direct amination
3
OC-3
-21(R)
19(S)
-21(R)
31(S)
30(S)
40(S)
45(S)
60(S)
67(S)
84(S)
87(S)
87(S)
88(S)
83(S)
89(S)
4
OC-4
53
5
OC-5
50
6
OC-6
62
7
8
OC-7
OC-8
70
78
reaction at room temperature.
A slight increase of
enantioselectivity was found when the reaction was
performed at 0 oC to give 3a in 89% ee (Table 1, entries 16 and
17 vs entry 15). Based on the results of screening of catalysts,
OC-11 and OC-12 have shown very similar catalytic and
enantioselective abilities in this water-rich amination.
9
OC-9
90
10
11
12
13
14
15
16
17
OC-10
OC-10
OC-11
OC-11
OC-11
OC-11
OC-12
OC-12
93
90
96
91
Next, we have performed the model reaction of 2a and 1 in
various solvent systems (Table 2). The hydrophobic organic sol-
92
85
96
Table 2. The screening of solvents and additives.
92
aReaction was performed using 1 mol% of catalysts in a 0.1
mmol scale in the 2.2 mL mixed solvent of toluene/H2O = 1/10
b
c
(v/v); NH = BocNHOBn; Reaction time: 8 h for r.t. and 12 h for
0oC; dIsolated yield based on 2a; eDetermined by HPLC on a
chiral stationary phase and the absolute configuration of 3a was
assigned according to ref. 8.
Entrya solv.
Yieldh[%]
85
eei[%]
1
CH2Cl2/H2O (v/v = 1/10)
89
2
CHCl3/H2O (v/v = 1/10)
Et2O/H2O (v/v = 1/10)
EtOAc/H2O(v/v = 1/10)
CH3CN/H2O(v/v = 1/10)
EtOH/H2O(v/v = 1/10)
THF/H2O(v/v = 1/10)
toluene
toluene/H2O(v/v = 1/10)
toluene/H2O(v/v = 1/10)
H2O
89
90
89
68
62
56
87
92
95
n.r.e
n.r.
90
85
83
84
81
77
82
88
76
rac-
-
in yield and enantioselectivity of product 3a is observed, and
3
4
this reveals that quaternary ammonium salts with
a
squaramide motif are beneficial to this water-rich amination
5
both in yield and enantioselectivity (Table 1, entry 9 vs entry 8).
Jiang and coworkers13 have developed
6
7
a category of
(thio)urea- and squaramide-tertiary amine organocatalysts for
asymmetric conjugated additions in high efficiency, and they
have also prepared L-tert-leucine-derived urea-ammonium
salts as chiral phase-transfer catalysts for enantioselective
alkylation of 5H-oxazol-4-ones. Inspired by Jiang’s work, three
8
9b
10c
11d
12f
13g
brine
-
toluene/H2O(v/v = 1/10)
89
squaramide-containing catalysts OC-10, OC-11 and OC-12 have
aReaction was performed using 1 mol% of OC-11 in a 0.1 mmol
scale in the various solvents; b1 mol% solid K2CO3 as an additive;
c1 mol% solid KOH as an additive; dThe reaction was performed
in 2.2 mL of water; en.r. means no reaction under these
been prepared from L-valine or L-tert-leucine with pyrrolidine
or morpholine in five steps, respectively. To our delight, OC-10
derived from L-valine and pyrrolidine has shown good catalytic
performance to give 3a in high yield and acceptable
enantioselectivity at 0 oC (Table 1, entries 10 and 11 vs entry 9,
67% ee vs 45% ee). Instead of L-valine in OC-10, L-tert-leucine
conditions. The reaction was performed in 2.2 mL of brine; g1
f
mol% solid KI as an additive; hIsolated yield based on 2a;
iDetermined by HPLC on a chiral stationary phase and the
absolute configuration of 3a was assigned according to ref. 8.
is introduced to generate OC-11
,
the yield and
enantioselectivity of 3a are enhanced remarkably (Table 1,
entry 12 vs entry 11). When the reaction was performed at 0
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vent systems (Table 2). The hydrophobic organic solvents such as result in no reaction (Table 2, entries 11 and 12) due to the
dichloromethane (DCM), chloroform, ether, and ethyl acetate insolubilities of substrates and catalysts in water. Interestingly, the
provide good results both in yields and enantioselectivites of amination product 3a was furnished both in high yield and
amination product 3a (Table 2, entries 1~4). However, when enantioselectivity by using 1 mol% solid KI as an additive (Table 2,
hydrophilic organic solvents like ethanol, acetonitrile or THF was entries 13). The reaction is not sensitive to the change of reaction
used as a component of reaction solvent system, both yields and temperature from 0 oC to room temperature. Therefore, the
enantioselectivities of 3a are found to be obviously decreased optimum reaction conditions were established as follows: 1 mol%
(Table 2, entries 5~7). The high yield and enantioselectivity of 3a OC-11 or OC-12, 0.1 mmol trans-β-nitrostyrene, 0.3 mmol
were obtained with toluene as sole solvent (Table 2, entry 8). When BocNHOBn, 2.2 mL mixed solvent of toluene/H2O = 1/10 (v/v).
1 mol% solid K2CO3 was used as an additive under standard reaction
With the optimal reaction conditions in hand, various trans-
conditions, 3a was obtained in high yield but with a moderate ee β-nitrostryenes (2b-m) were used as substrates for water-rich
value (Table 2, entry 9), and instead of K2CO3 with solid KOH, the enantioselective amination reactions. Because of the
racemic product of 3a was obtained (Table 2, entry 10). comparative catalytic abilities of OC-11 and OC-12, both of
Unfortunately, the reaction was performed in water or brine to them were applied as chiral bifunctional phase-transfer
Table 3. Substrates scope of the direct enantioselective amination.
Ent.a
1
2
3
R
Cat.
T.
Time
8 h
4 h
8 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
12 h
8 h
12 h
8 h
12 h
8 h
12 h
Yieldb[%]
3a, 91
3a, 96
3a, 92
3a, 96
3b, 94
3b, 95
3b, 92
3b, 96
3c, 92
3c, 96
3c, 92
3c, 95
3d, 93
3d, 96
3d, 96
3d, 96
3e, 82
3e, 90
3e, 81
3e, 91
3f, 82
3f, 86
3f, 84
eec[%] Ent.a
R
Cat.
T.
Time
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8h
Yieldb[%] eec[%]
2a, Ph
2a, Ph
2a, Ph
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
87
84
89
83
86
85
86
84
91
85
89
84
90
88
88
85
89
86
87
82
91
88
87
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
2f, 3-CF3C6H4
2g, 4-MeC6H4
2g, 4-MeC6H4
2g, 4-MeC6H4
2g, 4-MeC6H4
2h, 4-OMeC6H4
2h, 4-OMeC6H4
2h, 4-OMeC6H4
2h, 4-OMeC6H4
2i, 2-furyl
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-11 r.t.
OC-12 0 oC
OC-12 r.t.
OC-11 0 oC
OC-12 r.t.
3f, 85
3g, 90
3g, 91
3g, 91
3g, 90
3h, -d
3h, -d
3h, -d
3h, -d
3i, 93
3i, 92
3i, 93
3i, 95
3j, -d
85
92
87
90
82
89
75
91
80
91
82
93
74
89
84
89
82
93
92
92
90
-
4
2a, Ph
5
6
2b, 4-FC6H4
2b, 4-FC6H4
2b, 4-FC6H4
2b, 4-FC6H4
2c, 4-ClC6H4
2c, 4-ClC6H4
2c, 4-ClC6H4
2c, 4-ClC6H4
2d, 4-BrC6H4
2d, 4-BrC6H4
2d, 4-BrC6H4
2d, 4-BrC6H4
2e, 3-ClC6H4
2e, 3-ClC6H4
2e, 3-ClC6H4
2e, 3-ClC6H4
2f, 3-CF3C6H4
2f, 3-CF3C6H4
2f, 3-CF3C6H4
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2i, 2-furyl
2i, 2-furyl
2i, 2-furyl
2j, piperonyl
2j, piperonyl
2j, piperonyl
2j, piperonyl
2k, iPr
3j, -d
3j, -d
3j, -d
3k, 92
3k, 95
3k, 92
3k, 93
n.r.e
2k, iPr
2k, iPr
8h
2k, iPr
8h
2l, 2,4-Cl2C6H3
2l, 2,4-Cl2C6H3
36 h
36 h
n.r.
-
aReaction was performed in a 0.1 mmol scale with 3.0 eq. of BocNHOBn; Isolated yields based on 2a-k; cDetermined by HPLC on a chiral stationary
phase and the absolute configurations of 3a-k were assigned according to ref. 8; dThe pure products 3h and 3j couldn’t be separated through a flash
column chromatography, but all TLC results indicated full conversion of various substrates in amination processes; en.r. means no reaction under the
optimal conditions.
b
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catalysts in the reactions. The corresponding amination under the same conditions, and it is probably due to the
products were obtained both in excellent yields and repulsive effect between bulky Boc group in amination reagent
enantioselectivities in most cases and the results are
1
and ortho-Cl at phenyl ring of substrate 2l
We proposed that dual activation of both nitroolefin 2a and
2c and BocNHOBn by OC-12 is responsible for the highly efficient
3c and 3d) in chiral induction in this amination process. The substrate 2a
.
summarized in Table 3. Substrates with an electron-
withdrawing group at para-position of phenyl ring (2b
,
2d) furnished the corresponding products (3b
,
excellent yields and ee values within 4 hours except substrate was activated by the hydrogen-bonding interactions between
2m with a para-nitro group at phenyl ring. Substrates with an the two NH in squaramide catalyst OC-12 and the nitro-group
electron-donating group at para-position of phenyl ring (2g in substrate 2a, while BocNHOBn was activated through the
and 2h) were fully converted to be the corresponding static electronic interaction of the cationic ammonium center
amination products (3g and 3h) in high enantioselectivities in OC-12 to attack from the Si-face to produce 3a in high yield
within 8 hours (Table 2, entries 25~32). However, the pure 3h and enantioselectivity (Figure 3). When hydrophilic organic
couldn’t be separated from a flash column chromatography solvents like ethanol, acetonitrile or THF was used as a component
even though TLC results indicated full conversion of substrate 2h in of reaction solvent system, the yields and enantioselectivities of 3a
amination processes. The product 3h and amination reagent are found to be significantly decreased (Table 2, entries 5~7),
BocNHOBn were eluted at the same time in 1/1 ratio which because the hydrogen-bonding interactions between OC-12 and 2a
1
can be found in NMR spectrum. Substrates with an electron- of the biphasic interface were deteriorated by these hydrophilic
withdrawing group at meta-position of phenyl ring (2e and 2f
)
solvent systems
.
need longer reaction time than the other substrates to give
In order to demonstrate the practicability of this above
the amination products 3e and 3f in good yields and enantioselective amination protocol, 5.0 mmol of 2a has been
enantioselectivities (Table 3, entries 17~24). 2-Furyl and used in the reaction under optimal conditions with only 0.5
piperonyl trans-β-nitrostryenes 2i and 2j are also suitable to mol% catalyst-loading to deliver the corresponding product 3a
this water-rich neutral amination reaction to generate the in 95% yield and 90% ee (Scheme 2).
corresponding products 3i and 3j in excellent ee values (Table
3, entries 33~40). Although TLC results showed full conversion
of 2j, the pure amination product 3j was not obtained from a
flash column chromatography with various ratios of petroleum
and EtOAc as eluent systems. Alkyl substituted substrate (E)-3-
methyl-1-nitrobut-1-ene 2k was underwent amination
smoothly to afford 3k in excellent yield and enantioselectivity
Scheme 2. Gram-scale preparation of 3a.
(Table 3, entries 41~44). Unfortunately, substrate 2l couldn’t
provide the corresponding product even with the prolongation
of reaction time up to 36 hours (Table 3, entries 45 and 46)
Experimentals
General procedure for the neutral asymmetric amination of trans-
β-nitrostyrenes
Catalysts OC-11 or OC-12 (0.65 mg for OC-11 or 0.67 mg for OC-12,
1 mol%), trans-β-nitrostyrenes 2 (0.1 mmol) and BocNHOBn 1 (67
mg, 0.3 mmol) were added to a 10-mL vial equipped with a stirring
bar, the mixed solvent of toluene (0.2 mL) and H2O (2.0 mL) was
added subsequently. The mixture was stirred at 0 oC or room
temperature for the indicated time which illustrated in Table 2 and
then the mixture was extracted by EtOAc (3×5.0 mL), the combined
organic layers were dried over anhydrous Na2SO4 and evaporated
under reduced pressure to yield a light yellow glue which was
purified by flash column chromatography on silica gel, eluting with
mixtures of petroether/EtOAc (50/1 to 20/1, v/v). The ee of pure
Figure 3. The proposed transition state model of this amination.
product was determined by HPLC using a chiral column (Daicel
Chiralpak AS-H, see details in the supplementary information).
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In conclusion, we have prepared
a series of chiral
bifunctional phase-transfer catalysts based various skeletons
and their performances in asymmetric neutral amination of
trans-β-nitrostyrenes under water-rich conditions are
investigated to produce 2-aminonitroalkanes in high yields and
enantioselectivities. Applications of these chiral bifunctional
phase-transfer catalysts in other neutral C-C or C-X bond
formation processes are currently under studied and will be
reported in due course.
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Conflicts of interest
There are no conflicts to declare.
For recent examples on asymmetric aminations, see: a) Y.
Wei, H. Zhang, J. Zeng, J. Nie, J. Ma, Org. Lett., 2017, 19
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We thank the National Science Foundation of China (no.
21372259 and 81503028) for financial support of this work.
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OBn
NO2
Boc
N
Boc
O
OBn
0.5~1 mol% CPTCs
+
NO2
F3C
N
R
H
R
H2O-toluene (v/v = 10:1)
0 oC or r.t., 12 h
up to 96% yield
and 93 % ee
O
O
F3C
O
O
CPTCs =
or
F3C
N
N
N
H
N
H
N
N
H
H
F3C
Br
Bn
Bn
Br
base-free
low catalyst-loading
water-rich
The direct enantioselective amination of nitroolefins has been performed with L-tert-leucine derived squaramide-scaffold
bifunctional phase-transfer catalysts under base-free and water-rich conditions to provide 2-aminonitroalkanes in excellent yields
and enantioselectivities.
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