Enantioselective aza-Henry reaction of: t -Boc protected imines and nitroalkanes with bifunctional squaramide organocatalysts

Article abstract of DOI:10.1039/c6nj04078k

An organocatalytic asymmetric aza-Henry reaction of t-Boc protected imines with nitroalkanes has been established by chiral acid-base type bifunctional Cinchona alkaloid/squaramide organocatalysts. The cooperation of a quinine motif as a base and sterical

Full text of DOI:10.1039/c6nj04078k

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Enantioselective Aza-Henry Reaction of t-Boc Protected Imines
and Nitroalkanes with Bifunctional Squaramide Organocatalysts
Received 00th January 20xx,
Accepted 00th January 20xx
Dilşad Susam, Cihangir Tanyeli*
An organocatalytic asymmetric aza-Henry reaction of t-Boc protected imines with nitroalkanes has been established by
chiral acid-base type bifunctional Cinchona alkaloid / squaramide organocatalysts. The cooperation of quinine motif as
base and sterically encumbered squaramide (H-bond donor) enabled mostly complete conversion of a range of reactants
into corresponding aza-Henry products at room temperature with good selectivities (up to 91% ee with 10 mol% catalyst
loading.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
tested several protecting groups on imine with nitromethane using
Cinchona alkaloids as catalyst.9 They obtained the best result with t-
Aza-Henry or nitro-Mannich reaction is a well-known nucleophilic Boc protected imine in 88% ee. Another quinine derived modular
addition of nitronates to the electrophilic imine species to construct thiourea was chosen in the reaction of N-Boc protected imines and
new C-C bond. The resulting nitrogen-bearing stereogenic centered nitroalkanes by Zhang et al.10 and they achieved very high
β-nitroamines are quite feasible precursors for the corresponding enantioselectivities in 12 hours with relatively high chemical yields
1,2-diamines,1 α-amino acids2 and, which are fundamental using 10 mol% organocatalyst in -20 °C. The first example of the
structural motif in many natural products and key materials of the squaramide type bifunctional organocatalyst in the aza-Henry
many pharmaceuticals. The enantiomerically enriched forms of reaction was published by Du and co-workers in 2013.11 Although
these types of β-nitroamines have been reported with in situ imines the main subject was about benzothiazole imines, additionally t-Boc
until Hurd et al. reported that they used preformed imine in their and tosyl protected imines were also tested under their optimized
reaction in 1950.3 Since then, there have been a great interest in condition. However, the enantioselectivities were very low
the synthesis of these products by using preformed imines compared with their imine bearing benzothiazole. They only
especially in the last decade involving with both metallic4 and pure achieved 15% ee with tosyl protected imines and 31% ee with t-Boc
organocatalytic5 asymmetric synthesis. In 2004, first organocatalytic imines with 5 mol% organocatalyst although they achieved 90%
reports were published by Takemoto5b and Johnston.5a Takemoto chemical yield.
developed the first bifunctional organocatalyst, a thiourea emerged There are many examples of asymmetric catalysis methods
with R,R-cyclohexyldiamine, and applied on the various N-protected developed for aza-Henry reaction, new catalyst systems are still in
imines with nitromethane, while Johnston reported
a chiral demand. Hence, quinine amine derived, sterically encumbered
bisamidine triflate salt in the reaction between N-Boc imines and squaramides12 were chosen to improve the aza-Henry reaction.
nitroethane
and
accomplished
good
enantio-
and Herein, we report the results obtained with the organocatalyst
diastereoselectivities.
developed in our group for the reaction between t-Boc protected
Moderating β-nitroaldol products with high enantioselectivities is aldimines and nitroalkanes.
not an easy procedure with any protected imines and nitromethane
by using bifunctional organocatalysts due to low conversions. The Results and Discussion
literature results show that researchers mainly prefer to use
nitroethane and/or other higher nitroalkane derivatives over Aza-Henry reaction has been initiated with the organocatalysts,
nitromethane due to their high acidity. (pKa of nitromethane,6 involving 2-aminoDMAP / squaramides I-III13 and another three
nitroethane7 and 1-nitropropane8 is 10.2, 8.6, 8.92, respectively, in quinine / squaramides IV14-VI, developed in our research group.
water at 25 °C.) Among these studies only a few of them achieved The structures of organocatalysts used in testing reactions are
high enantioselectivities with nitromethane and reactions were depicted in Figure 1.
performed with high catalyst loading scope usually. Sgarzani et al. Benzaldehyde derived N-protected imines were reacted with
nitroalkanes to test the effectiveness of organocatalysts I-VI. In the
initial trials, we used t-Boc protected imines to be catalyzed with 2-
aminoDMAP based squaramides I-III with 2 mol% catalyst loading in
toluene. The desired products were obtained in such a short time;
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Table 1. Screening of organocatalysts and optimization studies for the aza-Henry reaction
Cat.
Loading
(%)
Time
(h/m)
Conv
(%)
ee (%)
(anti/syn)
dr (%)
(anti:syn)
Entrya,b,c
1
R
Catalyst
I
Solvent
Me
2
Toluene
2.5 h
>99
19 / 30
78:22
2
Me
Me
Me
Me
Me
H
II
III
I
2
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
2.5 h
2.5 h
1.0 h
1.5 h
3.5 h
3.0 h
3.0 h
3.0 h
45 m
4 h
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
92
10 / 33
87:13
3
13 / 6
69:31
4
10
5
6 / 36
92:8
5
I
rac/rac
80:20
6
I
1
10 / 20
88:12
7
I
5
23
-
8
H
II
5
18
-
9
H
III
I
5
37
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Me
Me
Me
H
2
31 / 30
79:21
I
2
DCM
30 / 27
98:2
I
2
DCM
5 h
40 / 26
93:7
IV
IV
V
VI
IV
I
5
DCM
36 h
21 h
27 h
48 h
31 h
24 h
71 h
71 h
71 h
71 h
120 h
80
-
-
-
-
-
-
-
-
-
-
-
H
10
10
10
2
DCM
95
83
H
DCM
98
75
H
DCM
95
70
H
DCM
78
25
H
2
DCM
93
52
H
IV
IV
IV
IV
IV
IV
IV
IV
10
10
10
10
10
10
10
10
Tolune
Chloroform
THF
59
80
H
71
80
H
40
77
H
DCM
92
80
H
DCM
97
80
No reaction
85
H
DCM
H
DCM
24 h
71 h
96
40
-
-
H
DCM
80
a t-Boc unit is used as protecting group, except entries 17 and 18, possessing tosyl unit. b Entries 1-13 and 25 were performed in 0.1 M, entries 14-24 were
performed in 0.2 M and entry 26 was performed in 0.3 M concentration. c Reactions were performed at room temperature, except entry 11 (-15 °C), entry
12 (-30 °C),entry 22 (0 °C), entry 23 (-40 °C) and entry 24 (-60 °C).
however, the enantioselectivities were not good as expected in case enantioselectivity increase was observed with organocatalyst I and
of both syn and anti products (Table 1, entries 1-3). Nevertheless, t- nitroethane (entry 10). Furthermore, sub-zero temperatures were
butyl / 2-aminoDMAP organocatalyst I tested in different amounts screened (entries 11 and 12) and the best enantioselectivity was
again resulted in low ee values (entries 4-6). Then, nitromethane observed so far (entry 12), as 40 ee% with very good diastereomeric
was tested with 5 mol% organocatalysts I-III, the best result was ratio (93:7%). All the reactions done with organocatalysts I-III
achieved with 2-adamantyl / 2-aminoDMAP III as 37 ee% (entry 9). possessing 2-aminoDMAP basic catalophoric site completed with
The solvent was changed into dichloromethane, because of the short reaction durations (45 min up to
5 h) with low
solubility problem of the organocatalyst III in toluene. Slight enantioselectivities. Superior basic character of 2-aminoDMAP unit
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However, the direct effect of these groups on the enantioselectivity
could not be observed. All the results were quite similar in terms of
enantioselectivity, except for 3-chloro substituted imine 1d, which
was found to be 64% ee (Table 2, entry 4) and 4-methoxy
substituted imine 1b with nitroethane (entry 10).
can presumably cause uncontrollable interactions with the
reactants, even the reaction was carried out at -30 °C with full
conversion (entry 12).
Table 2. Derivation studies with the optimized condition
T
(h)
Conversion
(%)
ee
(%)
Entrya
R1
R2
Product
drb
1
2
3
4
5
6
7
8
H
H
H
2a
2b
2c
2d
2e
2f
24
71
44
21
16
28
25
22
22
70
96
91
-
-
-
-
-
-
-
-
85
75
91
64
91
91
85
82
4-OMe
2-Me
3-Cl
Figure 1. Bifunctional squaramide organocatalysts
H
>99
91
H
Since t-butyl squaramide was chosen as the best acidic moiety,
further trials were done quinine based organocatalyst IV, having t-
butyl motif. Despite the long duration of the reaction, the
enantioselectivity was quite promising with 5 mol% organocatalyst
IV and nitromethane as 80 ee% (entry 13). For further studies
quinine based organocatalyst analogues with same acidic moieties
IV-VI were also tested in 10 mol% and 0.2 M concentration to
increase the reaction rate (entries 14-16). The best result was
afforded with 10 mol% IV as 83% ee in 21 h (entry 14), whereas,
organocatalysts V and VI with 1- and 2-adamantyl motifs gave
relatively low enantioselectivities as 75% ee and 70% ee,
respectively (entries 15-16). The relatively low enantioselectivities
obtained with V and VI can be attributable to their structurally rigid
and sterically congested adamantyl moieties.
4-Br
H
>99
>99
98
4-Me
3-OMe
2-Br
H
H
2g
2h
3a
3b
H
93
9
H
Me
Me
85
72:28 90d
75:25 44d
62:38 66d
78:22 89e
62:38 77d
10
11
12c
4-OMe
76
2-Me
H
H
Me
Et
CH2Ph
3c
4a
5a
26
20
26
>99
96
nd
13
a
All of the experiments were performed 0.1 M concentration. Conversions
were calculated with GC-MS. b diastereomeric ratios of anti/syn. c anti & syn
configurations cannot be determined. d ee % of anti isomer. e ee % of major
diastereomer.
We also changed the protecting group into tosyl unit; however, we
couldn’t get a better result (entries 17 and 18). Solvent screening
was done by three other solvents (entries 19-21). Although the
enantioselectivities are quite similar, we did not choose them
because the reactions were much slower than it used to be.
The absolute configurations of the products 2a-h were assigned as
(S) by comparing the specific rotation values determined at equal
concentrations in the same solvent and also HPLC results with same
chiral columns, eluent systems and flow rates which have been
already reported in literature.15,16 Syn and anti diastereomeric signal
sets of the products 3a-c and 5a were also determined by
comparing the HPLC chromatograms by using the same chiral
columns, eluent systems and flow rates which have been already
reported in literature. 15-17
As the final attempt for the optimization studies, different
concentrations and temperatures have been tested with 10 mol%
organocatalyst IV (entries 22-26), the best result was achieved with
0.1 M concentration in DCM as 85 ee% with 92% conversion in 24 h
(entry 25).
Consequently, aforementioned conditions were determined as the
best condition for this aza-Henry reaction between the t-Boc
protected aldimines and nitromethane. With the optimized reaction
condition, the scope of this enantioselective organocatalytic aza-
Henry reaction was examined further by varying t-Boc protected
imine derivatives 1a-h with nitroalkanes. All the reactions were
conducted in DCM at room temperature, molar concentration with
0.1 M. The results are summarized in Table 2. Most of the aza-
Henry products were obtained in high to excellent conversions (76-
100%) and good selectivities up to 91% ee. It is noteworthy that the
reaction worked very well with ortho-, para- methyl and para-
bromo substituted imine derivatives (1c, 1e, 1f) in 91% ee with full
conversion. It appears that, the electron donating groups on the Figure 2. Proposed transition state model
phenyl ring cause elongation of reaction durations, whereas the
electron withdrawing groups cause a decrease in reaction duration.
In order to understand the selectivity of the aza-Henry reaction of
nitromethane with t-Boc protected imines catalyzed by bifunctional
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quinine derived squaramide organocatalyst IV we proposed a reactant, directly loaded into column chromatography.
transition-state model. Based on the proposed activation modes of EtOAc:Hexane mixtures was used as eluent to purify the products.
nucleophile and electrophile of Jacobsen’ study,18 a plausible The following GC-MS method was performed on Thermo TR-5MS
transition state model was designed to show the origin of the 30m x 0.25 mm ID x 0.25 um film, 5% Phenyl Polysilphenylene-
enantioselectivity. In the transition state, the deprotonation of siloxane column (260F142P) to track the reactions: Flow = 1.0
nitroalkane is achieved by interaction via H bond while, the mL/min, oven = 0.1 min at 50 °C, to 200 °C at 20 °C/min, 0.1 min at
squaramide moiety activated the t-Boc imine through double 200 °C; to 260 °C at 10 °C/min, 3.0 min at 260 °C, inlet=220 °C, MS-
hydrogen bonding. Nitromethane anion could attack the activated Transfer Line=250 °C.
imine from the Si-face (Figure 2).
Synthesis of tert-butyl (S)-(2-nitro-1-phenylethyl) carbamate (2a)
Experimental
General procedure starting from nitromethane and tert-butyl
(phenylmethylene) carbamate afforded to desired chiral product
1H NMR and 13C NMR spectra were recorded in CDCl3 on Bruker with 96% conversion and 85% ee in 24 h as a white solid. Optical
Spectrospin Avance DPX-400 spectrometer. The chemical shifts rotation was determined as [α]ꢃꢂꢄ = +18.48° (c=0.25, CH2Cl2). 1H
1
were reported in ppm relative to CDCl3 (δ 7.26 and 77.0 for H and NMR (400 MHz, CDCl3): δ 7.38-7.35 (m, 2H), 7.32-7.27 (m, 3H), 5.37
13C NMR, respectively) as the internal standard, and the data are (bs, 2H), 4.83 (bs, 1H), 4.73-4.65 (m, 1H), 1.43 (s, 9H).13C NMR (100
specified as s (singlet), bs (broad singlet), d (doublet), dd (doublet of MHz, CDCl3): δ154.9, 136.9, 129.3, 128.8, 126.5, 80.8, 79.0, 52.9,
doublet), ddd (doublet of doublet of doublet), bd (broad doublet), t 28.4. HPLC: Chiralpak ADH column, 95:5 (n-hexane/i-PrOH), flow
(triplet), td (triplet of doublet, tt (triplet of triplet), m (multiplet) rate 1.0 mL/min, 210 nm, temp=25 °C, tmajor= 29.3 min, tminor= 31.6
and coupling constants (J) in Hertz (Hz). HPLC chromatograms were min. GC-MS: Retention time: 10.57 min. [m/z]+= 57.08, 91.04,
recorded on Dionex & Thermo-Finnigan HPLC system. Daicel ADH, 117.05, 119.05, 132.06, 164.03, 177.03, 224.01. IR(neat): 3376,
IA, ODH, ASH, OJH chiral columns were used with different solvent 2977, 1685, 1545, 1517, 1255, 1165, 1025, 796, 699 cm-1.
systems. The mass spectra were recorded on Thermo Scientific DSQ
II Single Quadrupole GC/MS. Infrared measurements were done on Synthesis of tert-butyl (S)-(1-(4-methoxyphenyl)-2-nitroethyl)
Thermo Nicolet IS10 ATR / FT-IR spectrophotometer. Optical carbamate (2b)
rotations were measured with Rudolph Scientific Autopol III
polarimeter and reported as follows [α]ꢁꢀ (c is in gram per 100 mL General procedure starting from nitromethane and N-Boc-4-
solvent). Using Merck Silica Gel 60, flash column chromatographies methoxy benzylideneamine afforded to desired chiral product with
were performed. Reactions were monitored by thin layer 91% conversion and 75% ee in 71 h as a white solid. Optical rotation
chromotography using precoated silica gel plates (Merck Silica Gel was determined as [α]ꢃꢂꢄ = +19.36° (c=0.25, CH2Cl2). 1H NMR (400
PF-254), visualized by UV-light and polymolybden phosphoric acid in MHz, CDCl3): δ 7.24 (d, 2H), 6.91 (d, 2H), 5.36-5.30 (m, 1H), 5.24 (d,
ethanol and potassium permanganate stain as appropriate. All J=7.3 Hz, 1H), 4.85 (bs, 1H), 4.68 (dd, J= 12.5, 5.8 Hz, 1H), 3.82 (s,
extracts were dried over anhydrous magnesium sulphate and 3H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3): δ159.7, 154.7, 128.9,
solutions were concentrated under vacuum by using rotary 127.6, 114.5, 136.9, 129.2, 128.7, 126.3, 80.5, 55.3, 52.5, 28.3.
evaporator. Compounds names were written with ChemBioDraw HPLC: Chiralpak OJH, 92:8 (n-hexane/i-PrOH), flow rate 1.0 mL/min,
14.0.
210 nm, temp=25 °C, tmajor= 43.7 min, tminor= 48.9 min. GC-MS:
Retention time: 10.99 min. [m/z]+= 57.09,77.03, 104.03, 106.05,
120.05, 149.99, 162.92, 164.05. IR(neat): 3362, 2983, 1689, 1551,
1513, 1247, 1164, 1020, 830, 541 cm-1.
General Procedure for Aza-Henry Reaction: Nitromethane
Addition to t-Boc Protected Imines
Slightly modified literature procedure was performed to synthesize
N-Boc imine derivatives.19-21
Synthesis of tert-butyl (S)-(2-nitro-1-(o-tolyl)ethyl) carbamate (2c)
Racemic synthesis;
General procedure starting from nitromethane and tert-Butyl N-[(2-
methylphenyl)methylene] carbamate afforded to desired chiral
product with full conversion and 91% ee in 44 h as a white solid.
Optical rotation was determined as [α]ꢃꢂꢄ= +28.08° (c=0.25, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ 7.22 (bs, 4H), 5.65 (d, J=5.49 Hz, 1H),
5.22 (bs, 1H), 4.79 (bs, 1H), 4.75 (bs, 1H), 4.66 (bs, 1H), 2.44 (s, 3H),
1.42 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 154.8, 135.9, 135.4,
131.3, 128.6, 126.9, 125.1, 78.1, 49.5, 29.3, 19.2. HPLC: Chiralpak
ODH, 90:10 (n-hexane/i-PrOH), flow rate 1.0 mL/min, 210 nm,
temp=25 °C, tminor= 17.0 min, tmajor= 31.1 min. GC-MS: Retention
time: 11.02 min. [m/z]+= 57.09, 59.07, 91.05, 117.06, 119.07,
132.07, 164.04, 177.05, 224.03. IR(neat): 3363, 2980, 1688, 1541,
1526, 1251 cm-1.
t-Boc Imine (0.1 mmol), nitromethane (3.5 mmol) and Et3N (0.01
mmol) were dissolved in DCM (0.8 mL) and stirred at room
temperature. The reaction was monitored with GC-MS upon the
consumption of limiting reactant, directly loaded into column
chromatography. EtOAc:Hexane mixtures was used as eluent to
purify the products.
Asymmetric synthesis;
Imine (0.1 mmol), t-butyl/quinine IV (0.01 mmol) was dissolved in
DCM (0.8 mL) for half an hour. Then nitromethane (0.35 mmol) was
added to solution and stirred at room temperature. The reaction
was monitored with GC-MS upon the consumption of limiting
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Synthesis of tert-butyl (S)-(1-(3-chlorophenyl)-2-nitroethyl)
13C NMR (100 MHz, CDCl3): δ 160.2, 154.9, 138.7, 130.4, 118.5,
113.9, 112.5, 80.8, 78.9, 55.4, 52.9, 28.4. HPLC: Chiralpak IA, 90:10
(n-hexane/i-PrOH), flow rate 1.0 mL/min, 210 nm, temp=25 °C,
carbamate (2d)
General procedure starting from nitromethane and tert-Butyl N-[(3- tmajor= 17.6 min, tminor= 25.2 min. GC-MS: Retention time: 12.26 min.
chlorophenyl)methylene] carbamate afforded to desired chiral [m/z]+= 57.08, 59.05, 77.04, 105.05, 119.05, 134.04, 150.07, 193.01,
product with 91% conversion and 64% ee in 21h as a white solid. 194.04. IR(neat): 3318, 2972, 2850, 2372, 1749, 1716, 1489, 1474,
Optical rotation was determined as [α]ꢃꢂꢄ= +16.16° (c=0.25, CH2Cl2). 1396, 1068, 1073 cm-1.
1H NMR (400 MHz, CDCl3): δ 7.32-7.31 (m, 3H), 7.21-7.18 (m, 1H),
5.41 (bs, 1H), 5.36 (bs, 1H), 4.82 (bs, 1H), 4.70-4.68 (m, 1H), 1.44 (s, Synthesis of tert-butyl (S)-(1-(2-bromophenyl)-2-nitroethyl)
9H). 13C NMR (100 MHz, CDCl3): δ154.9, 139.1, 135.1, 130.4, 128.9, carbamate (2h)
126.6, 124.5, 80.9, 78.6, 52.3, 28.2. HPLC: Chiralpak ADH, 90:10 (n-
hexane/i-PrOH), flow rate 1.0 mL/min, 210 nm, temp=25 °C, tmajor
=
General procedure starting from nitromethane and N-[(2-
10.5 min, tminor= 13.9 min. GC-MS: Retention time: 11.95 min. bromophenyl)methylene] carbamate afforded to desired chiral
[m/z]+= 57.09, 59.06, 77.03, 103.04, 138.00, 196.95. IR(neat): 3362, product with 93% conversion and 82% ee in 22 h as a white solid.
2978, 2929, 1687, 1556, 1367, 1248, 1158, 696 cm-1.
Optical rotation was determined as [α]ꢃꢂꢄ = +27.48° (c=0.25,
CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.52 (d, J=8.0 Hz, 2H), 7.27 (d,
J=4.85, 2H), 7.16-7.11 (m, 1H), 5.68-5.63 (m, 2H), 4.77-4.71 (m, 2H),
1.36 (s, 9H). 13C NMR (100 MHz, CDCl3): δ154.6, 135.5, 133.8, 130.3,
128.3, 128.1, 122.9, 80.9, 77.6, 52.7, 28.4. HPLC: Chiralpak ADH,
Synthesis of tert-butyl (S)-(1-(4-bromophenyl)-2-nitroethyl)
carbamate (2e)
General procedure starting from nitromethane and tert-Butyl N-[(4- 85:15 (n-hexane/i-PrOH), flow rate 1.0 mL/min, 210 nm, temp=25
bromo)methylene] carbamate afforded to desired chiral product °C, tmajor= 9.1 min, tminor= 13.0 min. GC-MS: Retention time: 12.18
with full conversion and 91% ee in 16 h as a white solid. Optical min. [m/z]+= 57.08, 59.05, 77.05, 103.06, 118.05, 147.99, 181.94,
rotation was determined as [α]ꢃꢂꢄ= +18.23° (c=0.25, CH2Cl2). 1H 183.94, 185.94, 208.99, 277.90. IR(neat): 3353, 2981, 2933, 1700,
NMR (400 MHz, CDCl3): δ 7.51 (d, J=8.5, 2H), 7.19 (d, J=8.5, 2H), 1558, 1488, 1369, 1325, 1162, 1126, 1068 cm-1.
5.33 (bs, 2H), 4.82 (bs, 1H), 4.74-4.65 (m, 1H), 1.43 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ154.8, 137.5, 132.4, 131.6, 128.2, 127.8, 122.8, Synthesis of tert-butyl ((1R,2S)-2-nitro-1-phenylpropyl) carbamate
81.2, 78.7, 52.3, 28.4. HPLC: Chiralpak ADH, 95:5 (n-hexane/i-PrOH), (3a)
flow rate 1.0 mL/min, 210 nm, temp=25 °C, tmajor= 30.4 min, tminor
=
41.3 min. GC-MS: Retention time: 13.00 min. [m/z]+= 57.08, 59.06, General procedure starting from nitroethane and tert-butyl
77.05, 102.40, 183.93, 197.96, 240.90, 243.93. IR(neat): 3337, 2977, (phenylmethylene) carbamate afforded to desired chiral product
2928, 2855, 1697, 1556, 1487, 1367, 1157, 1010 cm
mixture of syn/anti-isomers with ratio 72:28 (anti/syn) with 85%
conversion in 22 h as a white solid. 1H NMR (400 MHz, CDCl3): δ
7.38-7.32 (m, 3H, overlapping signals of anti and syn), 7.25-7.21 (m,
2H, overlapping signals of anti and syn), 5.32 (bd, J= 8.7 Hz, 1H,
Synthesis of tert-butyl (S)-(2-nitro-1-(p-tolyl)ethyl) carbamate (2f)
General procedure starting from nitromethane and N-[(4- anti), 5.19 (dd, J=8.9, 5.6 Hz, 1H, overlapping signals of anti and
methylphenyl)methylene] carbamate afforded to desired chiral syn), 5.10 (bs, 1H, syn), 4.92 (bs, 1H, overlapping signals of anti and
product with full conversion and 91% ee in 28h as a white solid. syn), 1.53 (d, J= 6.8 Hz, 3H, overlapping signals of anti and syn), 1.46
Optical rotation was determined as [α]ꢃꢂꢄ= +21.92° (c=0.25, CH2Cl2). (s, 9H, syn), 1.43 (s, 9H, anti). 13C NMR (100 MHz, CDCl3): (anti
1H NMR (400 MHz, CDCl3): δ 7.18 (s, 4H), 5.33 (bs, 2H), 4.82 (bs, 1H), product) δ155.1, 136.6, 129.1, 128.7, 127.0, 85.9, 80.6, 57.6, 23.8,
4.72-4.62 (m, 1H), 2.33 (s, 3H), 1.43 (s, 9H). 13C NMR (100 MHz, 15.3. (syn product) δ155.1, 136.6, 129.1, 128.5, 126.6, 86.8, 80.6,
CDCl3): δ154.9, 138.7, 134.0, 129.9, 126.4, 80.7, 79.1, 52.8, 28.4, 57.5, 25.4, 17.1. HPLC: Chiralpak ADH, 95:5 (n-hexane/i-PrOH), flow
21.2. HPLC: Chiralpak ADH, 75:25 (n-hexane/i-PrOH), flow rate 1.0 rate 1.0 mL/min, 210 nm, temp=25 °C, tmajor,anti= 19.3 min, tminor,anti
=
mL/min, 210 nm, temp=5 °C, tmajor= 15.5 min, tminor= 18.1 min. GC- 22.2 min, tminor,syn= 25.5 min, tmajor,syn= 32.4 min. GC-MS: Retention
MS: Retention time: 11.35 min. [m/z]+= 57.09, 59.06, 91.04, 118.05, time: 10.46 min (anti) / 10.63 min (syn) [m/z]+= 57.08, 59.06, 78.04,
120.06, 164.00, 177.04, 178.05. IR(neat): 3365, 2979, 2929, 1685, 104.03, 106.04, 117.06, 150.02, 177.00, 206.05. IR(neat): 3370,
1554, 1515, 1367, 1251, 1164, 817 cm-1.
3009, 2977, 2914, 2360, 1681, 1548, 1520, 1170, 701 cm-1.
Synthesis of tert-butyl (S)-(1-(3-methoxyphenyl)-2-nitroethyl)
Synthesis of tert-butyl ((1R,2S)-1-(4-methoxyphenyl)-2-
carbamate (2g)
nitropropyl) carbamate (3b)
General procedure starting from nitromethane and N-[(3- General procedure starting from nitroethane and N-Boc-4-
methoxyphenyl)methylene] carbamate afforded to desired chiral methoxybenzylideneamine afforded to desired chiral product
product with 98% conversion and 85% ee in 25 h as a white solid. mixture of syn/anti-isomers with ratio 75:25 (anti/syn) with 76%
Optical rotation was determined as [α]ꢃꢂꢄ = +17.16° (c=0.25, CH2Cl2). conversion in 70 h as a white solid. 1H NMR (400 MHz, CDCl3): δ
1H NMR (400 MHz, CDCl3): δ 7.28 (t, J=7.8 Hz, 1H), 6.89-6.82 (m, 7.16 (d, J=8.7 Hz, 2H, syn), 7.15 (overlapping signals, 2H, anti), 6.87
3H), 5.36 (bs, 2H), 4.81 (bs, 1H), 4.72-4.63 (m, 1H), 3.79 (s, 3H), 1.43 (d, J=8.7 Hz, 2H, syn), 7.86 (overlapping signals, 2H, anti), 5.58 (d, J=
(s, 9H).
9.3 Hz, 1H, syn), 5.35 (bs, 1H, anti), 5.10 (dd, J= 8.7, 6.1 Hz, 1H,
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ARTICLE
Journal Name
anti), 5.01 (bs, 1H, syn), 4.90 (bs, 1H, overlapping signals of anti and Synthesis of tert-butyl (2-nitro-1,3-diphenylpropyl)carbamate
syn), 3.78 (s, 3H, syn), 3.77 (s, 3H, anti), 1.51 (d, J= 6.7 Hz, 3H, anti),
1.49 (bs, 3H, syn), 1.42 (s, 9H, anti), 1.40 (s, 9H, syn). 13C NMR (100
General procedure starting from 1-nitro-2-phenylethane and tert-
butyl (phenylmethylene) carbamate afforded to desired chiral
MHz, CDCl3): (anti product) δ159.8, 155.2, 128.2, 127.8, 114.4, 86.1,
80.5, 57.1, 55.7, 29.8, 15.6. (anti product) δ159.7, 155.0, 129.6,
127.1, 114.5, 86.9, 80.5, 56.9, 55.4, 28.4, 17.0. HPLC: Chiralpak IA,
85:15 (n-hexane/i-PrOH), flow rate 0.5 mL/min, 210 nm, temp=25
°C, tminor,anti= 18.2 min, tmajor,anti= 19.6 min, tminor,syn, = 20.8 min,
tmajor,syn= 24.9 min. GC-MS: Retention time: 12.54 min (anti) / 12.66
min (syn) [m/z]+= 57.10, 59.07, 77.07, 109.07, 136.10, 148.11,
180.06, 207.13. IR(neat): 3340, 2979, 2933, 2237, 1683, 1550, 1516,
1252, 1174, 1028, 837 cm-1.
product mixture of syn/anti-isomers with ratio 62:38 (anti/syn) with
1
in 26 h as a white solid. H NMR of anti product(400 MHz, CDCl3): δ
7.38-7.35 (m, 3H) , 7.33-7.28 (m, 4H), 7.24 (bs, 1H), 7.14 (bd, J=6.8
Hz, 2H), 5.79 (bs, 1H) 5.20 (bs, 1H), 5.03 (bs, 1H), 3.33 (dd, J=14.4,
9.5, 1H), 3.12 (dd, J=14.7, 3.4, 1H), 1.46 (s, 9H). HPLC: Chiralpak
ADH, 85:15 (n-hexane/i-PrOH), flow rate 1.0 mL/min, 220 nm,
temp=25 °C, tmajor,anti= 19.0 min, tminor,anti= 28.7 min.
Synthesis of tert-butyl ((1R,2S)-2-nitro-1-(o-tolyl)propyl)
Conclusions
carbamate (3c)
In this work, sterically hindered – squaramide type bifunctional
organocatalysts, developed in our research group were tested in
aza-Henry reaction of t-Boc protected imines and nitroalkanes. In
the same reaction, tosyl protected imine 21 was also tested;
however, ee value did not exceed 52% with t-butyl / 2-aminoDMAP
organocatalyst I. The best result for the t-Boc protected imine and
nitroalkane reaction was obtained with 10 mol% of organocatalyst
IV, 0.1 M concentration in DCM at room temperature. Under this
condition, derivatization studies were done with different imines
and nitroalkanes. The enantioselectivities were found up to 91% ee
with full conversions for o-methyl 2c, p-bromo 2e and p-methyl 2f
substituted imine derivatives with nitromethane.
General procedure starting from nitroethane and N-[(2-
methylphenyl)methylene] carbamate afforded to desired chiral
product mixture of syn/anti-isomers with ratio 62:38 (anti/syn) with
full conversion in 26 h as a colorless solid. 1H NMR (400 MHz,
CDCl3): δ 7.22-7.17 (bs, overlapping signals of anti and syn, 4H)
5.59-55.3 (m, 1H, syn), 5.35 (bs, 1H, anti), 5.38 (bs, 1H, syn), 4.90-
4.80 (bs, overlapping signals of anti and syn), 2.46 (s, 3H, anti), 2.45
(s, 3H, syn), 1.61 (d, J= 6.7 Hz, 3H, overlapping signals of anti and
syn), 1.42 (s, 9H, anti), 1.99 (s, 9H, syn).
13C NMR (100 MHz, CDCl3): (anti product) δ155.1, 136.3, 135.7,
131.2, 128.4, 126.8, 125.4, 85.2, 80.5, 53.6, 28.3, 19.7, 16.9. (syn
product) δ155.1, 136.3, 135.8, 131.4, 128.5, 127.0, 125.1, 86.8,
80.5, 53.5, 29.8, 19.5, 15.5. HPLC: Chiralpak ADH, 80:20 (n-hexane/i-
PrOH), flow rate 0.5 mL/min, 210 nm, temp=25 °C, tminor,anti= 13.5
min, tmajor,anti= 14.5 min, tminor,syn= 15.6 min, tmajor,syn= 23.7 min. GC-
MS: Retention time: 10.89 min (anti) / 11.08 min (anti) [m/z]+=
57.11, 59.09, 91.05, 120.11, 164.08. IR(neat): 3335, 2977, 2929,
2362, 1700, 1554, 1365, 1165 cm-1.
Acknowledgements
We are grateful for the financial support for TÜBİTAK (113Z156) and
METU-SRPC.
Keywords: asymmetric synthesis • aza-Henry reaction • imines •
Synthesis of tert-butyl (2-nitro-1-phenylbutyl)carbamate (4a)
organocatalysis • squaramide
General procedure starting from 1-nitropropane and tert-butyl
(phenylmethylene) carbamate afforded to desired chiral product
mixture of isomers with 72:28 diastereomeric ratio with 96%
conversion in 20 h as a white solid. 1H NMR (400 MHz, CDCl3): δ
7.38-7.30 (m, 3H, overlapping signals of anti and syn), 7.25-7.22 (m,
2H, overlapping signals of anti and syn), 5.71 (bd, J=7.2 Hz, 1H, syn)
Notes and references
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[2]
2
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[3]
1H, anti), 1.84-1.73 (m, 1H, syn), 1.46 (s, 9H, syn), 1.42 (s, 9H, anti),
0.98 (t, J= 7.0 Hz, 3H, anti), 0.97 (t, J= 7.3 Hz, 3H, syn)
13C NMR (100 MHz, CDCl3): (anti product) δ154.9, 137.7, 128.9,
128.7, 126.9, 93.0, 80.4, 56.8, 29.7, 24.9, 10.5. (syn product) δ155.1,
137.7, 129.0, 128.4, 126.3, 93.8, 80.4, 55.9, 28.3, 24.9, 10.3. HPLC:
Chiralpak ASH, 95:5 (n-hexane/i-PrOH), flow rate 0.5 mL/min, 214
nm, temp=25 °C, tmajor,ds1= 19.0 min, tmajor,ds2= 23.7 min, tminor,ds2
=
26.5 min, tminor,ds1= 28.7 min. GC-MS: Retention time: 10.89 min
(ds1)/ 11.02 min (ds2) [m/z]+= 57.10, 59.08, 104.07, 106.08, 150.05,
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1169, 701 cm-1.
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Table of Contents
Quinine derived sterically encumbered squaramide
organocatalyst afforded high enantioselectivity and
excellent conversion in aza-Henry reaction done by
imines and nitroalkanes.