Synthesis of enantiomerically pure 2-(N-aryl, N-alkyl-aminomethyl)aziridines: a new class of ligands for highly enantioselective asymmetric synthesis

Article abstract of DOI:10.1016/j.tetasy.2017.10.018

A simple and effective synthesis of enantiomerically pure 2-(N-aryl-, N-alkyl-aminomethyl)aziridines from (2S)-N-tritylaziridine-2-carboxylic acid methyl ester has been developed. Treating of this key ester with several primary and secondary amines in the presence of AlMe₃ provided the corresponding chiral N-trityl-2-carboxamides, and their reduction performed with different reagents resulted in the formation of the expected 2-(aminomethyl)aziridines. The choice of reaction conditions allows to either keep or leave the trityl substituent in the product. Such 2-(aminoalkyl)aziridines have shown very high catalytic efficiency in the asymmetric arylation of aldehydes and in other testing asymmetric reactions. On the other hand, homochiral N-trityl-2-carboxamides are interesting building blocks for the synthesis of various biologically active compounds.

Full text of DOI:10.1016/j.tetasy.2017.10.018

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiomerically pure 2-(N-aryl, N-alkyl-aminomethyl)
aziridines: a new class of ligands for highly enantioselective
asymmetric synthesis
⇑
´
´
Szymon Jarzynski, Stanisław Lesniak, Michał Rachwalski
´
´
Department of Organic and Applied Chemistry, University of Łódz, Tamka 12, 91-403 Łódz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and effective synthesis of enantiomerically pure 2-(N-aryl-, N-alkyl-aminomethyl)aziridines
from (2S)-N-tritylaziridine-2-carboxylic acid methyl ester has been developed. Treating of this key ester
with several primary and secondary amines in the presence of AlMe3 provided the corresponding chiral
N-trityl-2-carboxamides, and their reduction performed with different reagents resulted in the formation
of the expected 2-(aminomethyl)aziridines. The choice of reaction conditions allows to either keep or
leave the trityl substituent in the product. Such 2-(aminoalkyl)aziridines have shown very high catalytic
efficiency in the asymmetric arylation of aldehydes and in other testing asymmetric reactions. On the
other hand, homochiral N-trityl-2-carboxamides are interesting building blocks for the synthesis of var-
ious biologically active compounds.
Received 12 October 2017
Accepted 25 October 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
sources of chirality in asymmetric transformations working both
as chiral ligands and auxiliaries.4 On the contrary, it is surprising
Numerous types of 1,2-diamines (primary, secondary, tertiary,
cyclic, acyclic) constitute relevant molecules for many scientific
sectors such as chemistry, biology, pharmacology and medicine,
exhibiting interesting pharmacological properties, such as antitu-
mor, anti-infective, anti-inflammatory, antidiabetic and cardiovas-
cular agents or enzyme inhibitors and immune agents. The typical
example of drug containing vicinal diamine subunits is Oxaliplatin
and other platinum based drugs.1 Based on the great importance of
such systems, a search for the synthetic approaches leading to
these valuable compounds in enantiomerically pure form is one
of the most important topics in modern organic synthesis. Addi-
tionally, 1,2-diamines are versatile ligand/catalysts in stereocon-
trolled synthesis, including both transition metal-catalyzed and
organocatalytic transformations.2
that diamines containing one aziridine ring and another amine
function are still only a little known group of organic compounds.
The first synthesis of enantiomerically pure aminoalkylaziridines
was described by Concellón in 2001.5 More recently, a new and
original method of synthesis of aziridine-containing vicinal diami-
nes from aziridine aldehyde dimers was elaborated by Yudin et al.6
The obtained amino-aziridine derivatives were then subjected to
ring-opening reactions.7 Interestingly, it should be emphasized,
that enantiomerically pure aminoalkylaziridines have never been
tested as ligands or organocatalysts in asymmetric synthesis.
The synthetic diversity and broad spectrum of applications of
chiral diamines prompted us to explore the synthesis of aziri-
dine-containing diamines and to use them for preliminary research
tests as catalysts for stereo-divergent reactions.
On the other hand, aziridines are a special kind of amine. These
nitrogen-containing heterocycles are useful building blocks in syn-
thesis and are important synthetic targets. Interest in these small
heterocycles lies either in their biological activity, mainly as antitu-
mor agents, as displayed by some naturally occurring compounds
bearing the aziridine subunit, or in their ring strain, which makes
these heterocycles useful precursors of more complex systems.3
Moreover, aziridines (especially aziridine alcohols) can act as
2. Results and discussion
2.1. Synthesis of the ligands
Taking into consideration that a stereogenic center located at
the aziridine subunit has a decisive influence on the stereochemi-
cal outcome of the asymmetric reaction as we proved earlier,4d,8
we designed vicinal diamines in which one amine function
constitutes an aziridine and the second one is the secondary or
tertiary amine. Synthesis of such systems was carried out in two
⇑
Corresponding author.
E-mail address: mrach14@wp.pl (M. Rachwalski).
https://doi.org/10.1016/j.tetasy.2017.10.018
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
´
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2
steps, starting from (2S)-N-tritylaziridine-2-carboxylic acid methyl
ester. This key starting material was prepared from homochiral
serine methyl ester. Thus, selective protection of the amino
group in serine methyl ester as the trityl derivative followed by
treatment of the protected serine methyl ester with
methanesulfonyl chloride and then with Et3N in THF using a
procedure described by Zwanenburg et al9 gave the desired methyl
(2S)-N-tritylaziridine-2-carboxylate 1 in essentially quantitative
yield (Scheme 1).
Excluding compounds 210 and 611 (obtained by other methods),
the remaining amides were unknown in the literature, thus, their
full spectroscopic characterization was performed. It should be
noted that our method of synthesis of aziridine carboxamides
using amine/AlMe3 reagents afforded products 2 and 6 in a higher
total yield (in the literature, 2 and 6 were obtained via cyclisation
of the corresponding trityl-L-serine dimethyl- or benzyl amide).
A few hitherto synthesized aziridine carboxamides have been
applied to the synthesis of pharmacologically important carbohy-
drates or peptides, e.g., several
a- and b-O-glycosyl serine
conjugates were obtained stereoselectively via aziridine 2-carbox-
amide ring-opening reactions with pyranose C1-O-nucleophiles.12
Moreover, the synthesis of new chiral thio-, seleno- and telluro-
peptides via ring-opening of aziridine carboxamides was
described.11,13
O
O
O
Me
Me
TrCl, Et3N
DCM
Me
O
Et3N, MsCl
THF
HO
O
HO
O
N
NHTrt
NH2
Trt
1
L-serine methyl ester
(R)-N-Benzyl-2-acetamido-3-methoxypropionamide, known as
Lacosamide, is a low-molecular-weight antiepileptic drug, which
was introduced in both the United States and Europe for adjuvant
treatment of partial-onset seizures in adults.14 There are a few
methods that describe its synthesis. The key starting materials
for these syntheses were enantiomerically pure methyl N-trity-
laziridine-2-carboxylate or N-tritylaziridine-2-carboxamide that
underwent aziridine ring-opening reactions. From the point of
view of Lacosamide synthesis, it is more advantageous if the open-
ing of the aziridine ring proceeds in the aziridine ester and the
amide group is introduced later than the other way around.15 Tak-
ing into account the above, it seems to be clear that the obtained
O
O
AlMe3
Me
R1
H
N
O
N
R2
CH2Cl2,rt
R1
R2
N
N
Trt
Trt
Primary and secondary
1
2-9
Scheme 1. Synthesis of aziridine amides 2–9.
Subsequent treatment of 1 equiv of aziridine ester 1 with 3
equiv of various amines in the presence of 3 equiv of trimethylalu-
minum in DCM at À10 °C for 1 h and 48–72 h at rt (progress of the
reaction was monitored by TLC) resulted in the formation of the
corresponding amides 2–9 in good yields (Table 1).
Table 1
Synthesis of aziridine-2-carboxamides 2–9
c
Entry
1
Amine (NR1R2)
Time (h)
24
Producta
Yield (%)b
84
[a]
D
Me
Me
O
N
H
Me
N
Me
À69.8
À74.5
À55.5
N
Trt
2
O
N
H
N
2
3
72
72
88
84
N
Trt
3
O
N
N
H
N
Trt
4
O
O
N
O
4
5
6
72
48
96
90
92
78
À71.8
N
H
N
Trt
5
O
NH2
N
H
À101.0
À115.9
N
Trt
6
O
NH2
N
H
N
Trt
7
OMe
MeO
Me
NH2
O
7
8
96
96
87
85
À118.4
À104.7
N
H
N
Trt
8
Me
Me
Me
O
NH2
N
H
9
N
Me
Trt
Me
a
b
c
Reaction conditions: aziridine ester 1 (1 mmol) and appropriate amine (3 mmol) with AlMe3 (3 mmol) in CH2Cl2 (5 mL) at 25 °C during the time indicated.
Isolated yields.
In chloroform (c 0.3).
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S. Jarzynski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
aziridine-2-carboxamides 2–9 can be important building blocks for
the synthesis of biologically active substances, e.g., amide 6 was
transformed into Lacosamide in two simple steps. Treatment of 6
with TFA in a chloroform/methanol mixture at 0 °C for 2 h and then
reflux for 6 h afforded primary amine 10 in a good yield (75%). In
this ‘one pot’ reaction, detritylation and opening of the aziridine
ring took place sequentially (Scheme 2). This method of preparing
of (S)-N-benzyl-2-amino-3-methoxypropionamide 10 constitutes a
new, original and very effective approach to a very important
building blocks named C(3)-alkoxy-PAADs (Primary Amino Acid
Derivatives).15c Acetylation of 10 with AcCl gave (S)-Lacosamide
11 in a 87% yield (Scheme 2).
2.2. Asymmetric arylation of p-tolualdehyde in the presence of
chiral amines 12–22
All amines 12–22 were then investigated as catalysts in the
asymmetric arylation of p-tolualdehyde with phenylboronic acid
(Scheme 4). Diarylalcohols may act as precursors of many sub-
stances exhibiting biological and pharmacological activities; previ-
ously, we reported successful arylation of aldehydes using chiral
aziridine alcohols as catalysts.18 Herein, we demonstrated, that
diamines (aziridine amines) exhibit higher catalytic activity in
comparison with aziridine carbinols reported by us recently.18
The reactions were performed in toluene using phenylboronic
acid and p-tolualdehyde as starting materials in the presence of
ligands 12–22 (10 mol %). All the results are summarized in
Table 3.
Inspection of Table 3 reveals that all the designed amines 12–22
are prone to promote asymmetric model reaction leading to (S)-(4-
methylphenyl)phenylmethanol in good chemical yields and with
very high enantiomeric excess. Among the amines bearing a trityl
substituent on the nitrogen atom, system 16 with benzyl group led
to the best results in terms of yield and ee (Table 3, entry 5). Inter-
estingly, similar results were achieved using NH-aziridines 20–22
(without the trityl substituent). The product of arylation was
formed in yields 87–90% and with very high enantioselectivity
(ee up to 98%) (Table 3, entries 9–11). In all cases, (4-methylphe-
nyl)phenylmethanol was formed with (S)-absolute configuration
which was assigned on the basis of specific rotation measurements
and retention times in HPLC chromatograms.20
O
O
1. TFA, 0 oC
N
MeO
MeO
N
H
H
N
2. MeOH,
NH2
Trt
reflux
10
6
AcCl, Et3N
CH2Cl2, 0 oC to rt
O
N
H
NH
O
11
(S)-Lacosamide
Scheme 2. Synthesis of Lacosamide via two steps.
It should be emphasized that although our goal was to synthe-
size enantiomerically pure aminomethylaziridines as effective
ligands/catalysts for asymmetric reactions, synthesized amides
may also be very interesting building blocks for the synthesis of
many biologically relevant compounds. The ability of influencing
2.3. Asymmetric addition of diethylzinc to benzaldehyde
promoted by amines 12–22
Catalytic activity of amines 12–22 was also checked in the well-
known model reaction of addition of diethylzinc to benzaldehyde
(Scheme 5), (Table 4). Inspection of Table 4 clearly indicates, that
all the ligands 12–22 are prone to catalyze this process very effi-
ciently leading to the corresponding chiral alcohol in good chemi-
cal yields and with very high enantiomeric excess.
Moreover, it should be emphasized that a chiral alcohol was
often formed with higher values of chemical yield and enan-
tiomeric excess than using various aziridine alcohols, as we
described earlier.22
the configuration of the stereogenic center (L- or D-serine), the
diversity of substituents on the amide nitrogen atom and, the pos-
sibility of using different nucleophiles to open the ring, create very
wide synthetic possibilities.
All of the obtained amides 2–9 were then reduced to amines via
three different methods. The first method (Method A) was reduc-
tion with LAH in boiling THF in a ratio of 1 mol of amide:2 mol
of LiAlH4, 3 h of reflux. In the second method (Method B), a mixture
of triethoxysilane and Zn(OAc)2 in boiling THF was used for reduc-
tion. This method is particularly beneficial for the reduction of ter-
tiary amides.16 And, finally, the third method (C) is harsher than A,
namely LAH in boiling THF in a ratio of 1 mol of amide:4 mol of
LiAlH4, 8 h of reflux. The application of this latter method not only
resulted in the reduction of amide to amine, but detritylation of the
aziridine was also observed (Scheme 3, Table 2).
2.4. Asymmetric epoxidation of chalcone catalyzed by the most
active ligands 13, 16, 20 and 21
Finally, basing on our previous work on the asymmetric synthe-
sis of small three-membered ring heterocycles,8c,23 the most active
ligands 13, 16, 20 and 21 in the previous addition, were tested in
the asymmetric epoxidation of chalcone (Scheme 6) (Table 5).
The reactions were performed in diethyl ether using cumene
hydroperoxide (CMHP) as epoxidising agent, diethyl zinc in the
presence of the appropriate ligands (20 mol %).
R1
R1
N
R2
N
R2
Method A, B or C
N
N
X
Trt
2-9
13-20
, X = Trt
, X = H
21-22
Inspection of Table 5 clearly shows, that all the ligands exhibit a
high catalytic activity leading to the corresponding chiral epoxide
in good chemical yields and with high enantiomeric excess. In
the light of above results, chiral ligands 13, 16, 20 and 21 may be
used as useful catalysts for the synthesis of chiral epoxides, which
consist a structural part of a large variety of natural products, fra-
grances (epoxides of carvone, b-ionone), pheromones ((+)-dispar-
lure), alkaloids (scopolamine) and many others.
Scheme 3. The reduction of amides 2–9 to corresponding amines.
Regardless of the reactions of compounds 6–9 using Method C
(Table 2, entries 9–11), we performed detritylation reactions of
amines 16–19 using a well-known method with TFA.17 This reac-
tion provided the same products 20–23 in a 70–75% yield, which
proves that it is better to use the ‘one pot’ procedure C than A
and, subsequently, detritylation using TFA. On the other hand, to
the best our knowledge, this is the first example of detritylation
of aziridines using lithium aluminum hydride.
Concerning a transition state model of the enantioselective pro-
cesses, we assume, that all the asymmetric reactions involving zinc
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S. Jarzynski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 2
Synthesis of aziridine-2-methylamines
d
Entry
Amide
Method Aa, Bb or Cc
Product
[a]
D
Yield (%)
Me
O
N
Me
A: 77
B: 82
N
Me
N
1
À17.4
Trt
N
12
Me
Trt
2
O
N
A: 81
B: 90
N
N
2
3
4
À22.3
À19.7
À20.5
Trt
N
13
Trt
3
O
N
A: 82
B: 88
N
N
N
Trt
14
N
Trt
4
O
N
O
A: 76
B: 91
O
N
Trt
N
15
Trt
5
O
N
H
N
N
H
Trt
5
6
A: 84
A: 81
À32.6
À41.3
16
N
Trt
6
O
O
N
H
N
H
N
N
Trt
Trt
17
7
OMe
Me
OMe
Me
N
H
18
7
N
H
8
A: 86
À45.8
N
N
Trt
Trt
Me
Me
O
O
O
N
H
N
H
8
A: 83
C: 70
C: 68
À39.7
+11.9
+14.0
N
Me
N
Me
Trt
9
Trt
19
N
H
20
N
H
9
N
H
N
Trt
7
OMe
Me
OMe
Me
N
H
21
N
H
10
N
H
N
Trt
8
Me
Me
O
N
H
N
H
22
11
C: 74
+12.7
N
N
H
Me
Me
Trt
9
a
b
c
Method A: reaction conditions: 1 mmol of amide:2 mmol of LiAlH4, 3 h, reflux.
Method B: reaction conditions: HSi(OEt)3/Zn(OAc)2 in THF, 6 h, reflux, then stirred 3 h in 1 M NaOH at rt.
Method C: reaction conditions: 1 mmol of amide:4 mmol of LiAlH4, 8 h, reflux.
In chloroform (c 0.3).
d
Table 3
Asymmetric arylation of p-tolualdehyde with phenylboronic acid in the presence of
amines 12–22
eea
Config.b
[a]
D
c
OH
Entry
Ligand
Yield (%)
B(OH)2
ZnEt
Et2Zn
Ligand 12-22
1
2
3
4
5
6
7
8
12
13
14
15
16
17
18
19
20
21
22
77
84
80
92
94
86
85
81
90
89
87
91
97
94
93
97
91
95
95
98
98
98
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
À2.1
À2.8
À2.5
À2.7
À3.0
À3.2
À3.3
À3.5
À3.4
À2.2
À2.9
toluene
p-tolualdehyde
Me
60 oC, 12h
0 oC, 48h
Scheme 4. Asymmetric arylation catalyzed by amines 12–22.
9
10
11
ions proceed in accordance with transition state models describing
for aziridine alcohols25 and aziridine sulfides26 in which zinc
atom is complexed by both heteroatoms. It seems probably that
in the case of aminoalkylaziridine this interaction is the most
effective.
a
b
c
Determined using chiral HPLC on Chiralcel OD column.
Absolute configuration was determined as S according to literature.19
In chloroform (c 0.3).
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S. Jarzynski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
OH
availability of various enantiomerically pure aziridine amides, we
can greatly expand a library of Lacosamide analogues.
Ligand 12-22
Toluene, 24h
H
Et2Zn
4. Experimental
4.1. General
Scheme 5. Asymmetric addition of diethylzinc to benzaldehyde promoted by
ligands 12–22.
Toluene and tetrahydrofuran were distilled from a sodium ben-
zophenone ketyl radical. Other reagents were purchased from
commercial suppliers and used without further purification.
1H/13C NMR spectra were recorded on a Bruker instrument at
600/150 MHz, respectively or Varian-Gemini 200 MHz, using CDCl3
as solvent and TMS as internal standard. Data are reported as s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s =
broad singlet. Optical rotation measurements were performed on
a Anton Paar MCP500 polarimeter with a sodium lamp at room
temperature (c 0.3). Column chromatography was carried out
using Merck 60 silica gel. TLC was performed on Merck 60 F254 sil-
ica gel plates. Visualization was accomplished with UV light (254
nm) or using iodine vapors. The enantiomeric excess (ee) values
were determined via chiral HPLC (Chiralcel OD or OD-H column).
Table 4
Asymmetric addition of Et2Zn to benzaldehyde catalyzed by ligands 12–22
eea
Config.b
[a]
D
c
Entry
Ligand
Yield (%)
1
2
3
4
5
6
7
8
12
13
14
15
16
17
18
19
20
21
22
82
93
89
90
95
84
87
92
91
88
86
83
97
95
94
98
87
94
97
98
98
97
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
À10.9
À15.0
À14.1
À12.7
À14.5
À11.1
À13.4
À13.9
À14.7
À15.2
À14.8
9
10
11
a
b
c
Determined using chiral HPLC on Chiralcel OD-H column.
Absolute configuration was determined as S according to literature.21
In chloroform (c 0.3).
4.2. Synthesis of amides 2–9—General procedure
To a suspension of corresponding amine (3 mmol) in anhydrous
CH2Cl2 (10 mL) at À10 °C trimethylaluminum (3 mmol) was added
dropwise under a nitrogen atmosphere. The reaction mixture was
warmed to 25 °C and stirred for 1 h. After this time, the reaction
mixture was again cooled to À10 °C and methyl (2S)-N-trity-
laziridine-2-carboxylate 1 (1 mmol) was added dropwise in anhy-
drous CH2Cl2 (5 mL). The resulting mixture was stirred at room
temperature for the indicated time. Then, the reaction was cooled
to 0 °C and carefully quenched with aqueous satd NaHCO3 and
extracted with Et2O (3 Â 10 mL), the combined organic layers were
dried over MgSO4, filtered and the solvents were removed under
reduced pressure. The crude products were purified by flash chro-
matography on silica gel (AcOEt/hexane 1:4).
1. Ligand (0.1 mmol) , Et2O
O
O
2. Zn2Et (0.2 mmol), 0 o
C
O
3. CMHP (0.6 mmol), 0 oC to r.t.
Scheme 6. Asymmetric epoxidation of chalcone in the presence of chiral amines.
Table 5
Asymmetric epoxidation of chalcone
eea
Config.b
[a]
D
c
Entry
Ligand
Yield (%)
1
2
3
4
13
16
20
21
85
94
90
88
87
95
98
98
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
À185.3
À190.4
À187.8
À189.2
4.2.1. (S)-N,N-Dimethyl-1-tritylaziridine-2-carboxamide 2
Yield 84%, colorless solid; mp 96–98 °C; [
a
]
23 = À69.8 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.35 (dd, 1H, JH,H = 1.5, JH,H
= 6.0 Hz), 1.94 (dd, 1H, JH,H = 3.0, JH,H = 6.0 Hz), 2.36 (dd, 1H, JH,H
= 1.5, JH,H = 3.0 Hz), 2.81 (s, 3H), 3.00 (s, 3H), 7.20–7.23 (m, 3H),
7.26–7.29 (m, 6H), 7.54–7.55 (m, 6H) ppm.
a
b
c
Determined using chiral HPLC on Chiralcel OD-H column.
Absolute configuration was determined as (2R,3S) according to literature.24
In chloroform (c 0.3).
13C NMR (151 MHz, CDCl3): d: 27.2 (CH2 azir), 30.6 (CHazir),
36.0 (CH3), 36.9 (CH3), 74.5 (Cq), 126.8 (Car), 127.5 (Car), 129.4
(Car), 144.0 (Cq ar), 169.8 (C@O) ppm.
3. Conclusions
IR (KBr): 3080, 3054, 3017, 2997, 1655, 1593, 1488, 1449, 1420,
1350, 1242, 1157, 1013, 908, 763, 710 cmÀ1; ESI-MS: m/z: 358 (40),
379 (100, [M+Na]+), 395 (15, [M+K]+); Anal. Calcd for C24H24N2O
(356.46): C, 80.87; H, 6.79; N, 7.86. Found: C, 80.91; H, 6.68; N, 7.72.
A simple synthesis of chiral aziridine amides and three methods
of their reduction leading to the corresponding enantiomerically
pure 2-(N-aryl, N-alkyl-aminomethyl)aziridines has been
described. We proved that all the newly synthesized aziridine
derivatives are versatile catalysts exhibiting high catalytic activity
in some asymmetric reaction in the presence of zinc ions like
asymmetric arylation, addition of diethylzinc to benzaldehyde or
asymmetric epoxidation of chalcone. It should be stressed, that
such diamines exhibited higher catalytic activity in comparison
with those showed by aziridine alcohols reported previously. The
investigations on the use of these new aziridine systems in another
asymmetric processes are in progress.
4.2.2. (S)-Pyrrolidin-1-yl(1-tritylaziridin-2-yl)methanone 3
Yield 88%, colorless solid; mp 122–124 °C; [
a]
23 = À74.5 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.32 (dd, 1H, JH,H = 1.5, JH,H
=
6.0 Hz), 1.78–1.84 (m, 5H), 2.43 (dd, 1H, JH,H = 1.5, JH,H = 3.0 Hz),
3.08–3.11 (m, 1H), 3.22–3.26 (m, 1H), 3.48–3.51 (m, 1H), 3.57–
3.61 (m, 1H), 7.20–7.23 (m, 3H), 7.26–7.29 (m, 6H), 7.53–7.54 (m,
6H) ppm; 13C NMR (151 MHz, CDCl3): d 24.1 (CH2), 26.0 (CH2),
27.1 (CH2 azir), 31.6 (CHazir), 46.0 (CH2), 46.1 (CH2), 74.5 (Cq),
126.8 (Car), 127.5 (Car), 129.4 (Car), 144.0 (Cq ar), 168.4 (C@O) ppm;
IR (KBr): 3055, 3018, 2981, 2948, 1648, 1597, 1488, 1352, 1228,
1188, 1154, 1081, 1042, 901, 866, 710, 563 cmÀ1; ESI-MS: m/z:
405 (100, [M+Na]+), 421 (17.5, [M+K]+); Anal. Calcd for C26H26N2O
(382.50): C, 81.64; H, 6.85; N, 7.32. Found: C.81.44;H. 6.90, N. 7.40.
On the other hand, all the obtained chiral aziridine carboxam-
ides, being intermediates, can act as versatile building blocks for
the synthesis of biologically relevant compounds, such as
Lacosamide (an antiepileptic drug). Taking into account the broad
´
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S. Jarzynski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
6
4.2.3. (S)-Piperidin-1-yl(1-tritylaziridin-2-yl)methanone 4
(d, 1H, JH,H = 2.6 Hz), 2.17 (dd, 1H, JH,H = 2.6, JH,H = 6.6 Hz), 3.84 (s,
3H), 6.93–6.95 (m, 2H), 7.28–7.30 (m, 3H), 7.33–7.35 (m, 6H),
7.46–7.47 (m, 6H), 7.52–7.54 (m, 2H), 8.57 (s, 1H, NH) ppm; 13C
NMR (151 MHz, CDCl3): d 30.0 (CH2 azir), 34.8 (CHazir), 55.5
(CH3), 74.6 (Cq), 114.3 (Car), 121.7 (Car), 127.3 (Car), 127.9 (Car),
129.3 (Car), 130.6 (Cq ar), 143.2 (Cq ar), 156.6 (Cq ar), 168.5 (C@O)
ppm; IR (KBr): 3304, 3277, 3143, 3051, 2993, 2951, 2830, 1681,
1659, 1608, 1595, 1510, 1462, 1447, 1311, 1244, 1176, 1036,
1002, 905, 828, 707, 634, 514 cmÀ1; ESI-MS: m/z: 457 (100, [M
+Na]+), 473 (7.5, [M+K]+); Anal. Calcd for C29H26N2O2 (434.53): C,
80.16; H, 6.03; N, 6.45. Found: C, 79.96; H, 6.01; N, 6.48.
Yield 84%, colorless solid; mp 128–130 °C; [
a]
23 = À55.5 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.34–1.35 (m, 3H), 1.54–
1.59 (m, 4H), 1.92 (dd, 1H, JH,H = 3.0, JH,H = 6.0 Hz), 2.38 (dd, 1H,
JH,H = 1.5, JH,H = 3.0 Hz), 3.19–3.27 (m, 2H), 3.55–3.58 (m, 1H),
3.63–3.66 (m, 1H), 7.20–7.23 (m, 3H), 7.27–7.29 (m, 6H), 7.54–
7.56 (m, 6H) ppm; 13C NMR (151 MHz, CDCl3): d: 24.5 (2CH2),
25.6 (CH2), 26.2 (CH2), 27.0 (CH2 azir), 30.5 (CHazir), 43.4 (CH2),
46.3 (CH2), 74.5 (Cq), 126.8 (Car), 127.5 (Car), 129.4 (Car), 144.0
(Cq ar), 168.0 (C@O) ppm; IR (KBr): 3083, 3055, 3032, 2999, 2932,
2854, 1641, 1594, 1488, 1465, 1446, 1351, 1251, 1189, 1141,
1076, 1017, 903, 851, 759, 707, 565 cmÀ1; ESI-MS: m/z: 419 (100,
[M+Na]+), 435 (52.5, [M+K]+); Anal. Calcd for C27H28N2O (396.52):
C, 81.78; H, 7.12; N, 7.06. Found: C, 81.61; H, 7.16; N, 7.10.
4.2.8. (S)-N-Mesityl-1-tritylaziridine-2-carboxamide 9
Yield 85%, colorless solid; mp 156–158 °C; [
a
]
23 = À104.7 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.63 (d, 1H, JH,H = 6.6 Hz), 2.19
(d, 1H, JH,H = 2.6 Hz), 2.27 (dd, 1H, JH,H = 2.6, JH,H = 6.6 Hz), 2.30 (s,
9H), 6.96 (s, 2H), 7.26–7.29 (m, 3H), 7.31–7.34 (m, 6H), 7.50–
7.52 (m, 6H), 8.10 (s, 1H, NH) ppm; 13C NMR (151 MHz, CDCl3) d:
18.5 (2 CH3), 20.9 (CH3), 30.4 (CH2 azir), 34.5 (CHazir), 74.7 (Cq),
127.3 (Car), 127.8 (Car), 129.1 (Car), 129.4 (Car), 130.4 (Cq ar), 135.3
(Cq ar), 137.2 (Cq ar), 143.2 (Cq ar), 169.3 (C@O) ppm; IR (KBr):
3085, 3059, 2979, 2952, 2855, 1675, 1660, 1596, 1493, 1447,
1375, 1220, 1188, 1010, 904, 848, 762, 707, 634 cmÀ1; ESI-MS:
m/z: 469 (100, [M+Na]+), 485 (37.5, [M+K]+); Anal. Calcd for
4.2.4. (S)-Morpholino(1-tritylaziridin-2-yl)methanone 5
Yield 90%, colorless solid; mp 132–134 °C; [
a
]
23 = À71.8 (c 0.3,
D
CHCl3); 1H NMR(600 MHz, CDCl3) d: 1.37 (dd, 1H, JH,H = 1.5, JH,H
6.0 Hz), 1.89 (dd, 1H, JH,H = 3.0, JH,H = 6.0 Hz), 2.41 (dd, 1H, JH,H
=
=
1.5, JH,H = 3.0 Hz), 3.25–3.28 (m, 1H), 3.30–3.33 (m, 1H), 3.43–
3.46 (m, 1H), 3.49–3.51 (m, 1H), 3.55–3.58 (m, 1H), 3.66–3.70
(m, 2H), 3.77–3.80 (m, 1H) 7.22–7.24 (m, 3H), 7.28–7.30 (m, 6H),
7.53–7.54 (m, 6H) ppm; 13C NMR (151 MHz, CDCl3): d 27.2 (CH2
azir), 30.2 (CHazir), 42.5 (CH2), 45.6 (CH2), 66.5 (CH2), 66.9 (CH2),
74.5 (Cq), 126.9 (Car), 127.6 (Car), 129.3 (Car), 143.8 (Cq ar), 168.6
(C@O) ppm; IR (KBr): 3056, 3032, 2986, 2968, 2898, 1644, 1595,
1489, 1465, 1447, 1385, 1330, 1233, 1157, 1117, 1068, 1043,
1019, 951, 901, 845, 760, 745, 707, 575 cmÀ1; ESI-MS: m/z: 421
(100, [M+Na]+), 437 (10, [M+K]+); Anal. Calcd for C26H26N2O2
(396.52): C, 78.36; H, 6.58; N, 7.03. Found: C, 78.39; H, 6.59; N, 7.05.
C31H30N2O (446.58): C, 83.37; H, 6.77; N, 6.27. Found: C, 83.32;
H, 6.83; N, 6.11.
4.3. Synthesis of compounds 10 and 11
4.3.1. (S)-2-Amino-N-benzyl-3-methoxypropanamide 10
(S)-N-Benzyl-1-tritylaziridine-2-carboxamide
6
(0.84 g,
2
4.2.5. (S)-N-Benzyl-1-tritylaziridine-2-carboxamide 6
mmol) was dissolved in a mixture of chloroform (5 mL) and metha-
nol (5 mL). A solution was cooled to 0 °C and TFA (3.2 mL) was
added dropwise. The resulting solution was stirred for 2 h at 0 °C.
After this time, an additional portion (5 mL) of methanol was
added and the mixture was refluxed for 6 h, then cooled to room
temperature, neutralized with 3 M aqueous NaOH and extracted
with Et2O (3Â). The combined organic layers were dried over anhy-
drous MgSO4 and the crude product was obtained after evapora-
tion of the solvent in vacuo. Purification via column
chromatography (SiO2, CHCl3:MeOH 9/1) gave a pure 10. Yield
Yield 92%, colorless solid; mp 142–144 °C; [
a
]
D
23 = À101.0 (c 0.3,
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.30 (d, 1H, JH,H = 6.6 Hz), 2.04
(d, 1H, JH,H = 2.6 Hz), 2.11 (dd, 1H, JH,H = 2.6, JH,H = 6.6 Hz), 4.36 (dd,
1H, JH,H = 5.0, JH,H = 15.0 Hz), 4.78 (dd, 1H, JH,H = 7.5, JH,H = 15.0 Hz),
7.11–7.13 (m, 1H), 7.25–7.28 (m, 9H), 7.33–7.35 (m, 1H), 7.37–7.43
(m, 9H) ppm; 13C NMR (151 MHz, CDCl3): d 29.9 (CH2 azir), 34.2
(CHazir), 43.0 (CH2), 74.6 (Cq), 127.2 (Car), 127.5 (Car), 127.6 (Car),
127.7 (Car), 128.8 (Car), 129.3 (Car), 138.5 (Cq ar), 143.2 (Cq ar),
170.7 (C@O) ppm; IR (KBr): 3085, 3057, 3030, 2988, 2927, 1648,
1596, 1545, 1489, 1447, 1357, 1286, 1223, 1187, 1081, 1032,
1011, 965, 903, 745, 708, 632, 592 cmÀ1; ESI-MS: m/z: 441 (100,
[M+Na]+), 457 (5, [M+K]+); Anal. Calcd for C29H26N2O (418.53): C,
83.22; H, 6.26; N, 6.69. Found: C, 83.10; H, 6.20; N, 6.70.
75%, colorless oil, [a]
23 = 1.3 (c 0.3, CHCl3); 1H NMR (600 MHz,
D
CDCl3) d: 3.38 (s, 3H), 3.61–3.65 (m, 3H), 4.46 (dd, 2H, JH,H = 6.0,
JH,H = 15.0 Hz), 7.25–7.28 (m, 3H), 7.31–7.34 (m, 2H), 7.73 (br s,
1H) ppm. The spectroscopic data are in full agreement with those
reported in the literature.27a
4.2.6. (S)-N-Phenyl-1-tritylaziridine-2-carboxamide 7
Yield 78%, colorless solid; mp 133–135 °C; [
a
]
23 = À115.9 (c 0.3,
4.3.2. (S)-2-Acetamido-N-benzyl-3-methoxypropanamide 11
((S)-Lacosamide)
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.63 (d, 1H, JH,H = 6.6 Hz), 2.16
(d, 1H, JH,H = 2.6 Hz), 2.18 (dd, 1H, JH,H = 2.6, JH,H = 6.6 Hz), 7.16–
7.19 (m, 1H), 7.28–7.30 (m, 3H), 7.33–7.35 (m, 6H), 7.39–7.41
(m, 2H), 7.46–7.47 (m, 6H), 7.62–7.64 (m, 2H), 8.69 (s, 1H, NH)
ppm; 13C NMR (151 MHz, CDCl3): d 30.0 (CH2 azir), 34.9 (CHazir),
74.7 (Cq), 119.8 (Car), 124.4 (Car), 127.3 (Car), 127.9 (Car), 129.1
(Car), 129.3 (Car), 137.5 (Cq ar), 143.2 (Cq ar), 168.7 (C@O) ppm; IR
(KBr): 3315, 3277, 3054, 3031, 2994, 2926, 1690, 1659, 1602,
1533, 1490, 1443, 1411, 1362, 1314, 1263, 1220, 1180, 1034,
1008, 904, 764, 749, 707, 632, 512 cmÀ1; ESI-MS: m/z: 405 (17.5,
[M+H]+), 427 (100, [M+Na]+), 443 (5, [M+K]+); Anal. Calcd for
C29H26N2O (404.50): C, 83.14; H, 5.98; N, 6.93. Found: C, 82.99;
H, 6.11; N, 6.97.
Acetylation of amine 10 was performed according to literature
procedure.27b Yield 87%, Colorless oil, [
a]
23 = À7.4 (c 0.3, CHCl3);
D
1H NMR (600 MHz, CDCl3) d: 2.03 (s, 3H), 3.38 (s, 3H), 3.44 (dd,
1H, JH,H = 7.5, JH,H = 9.0 Hz), 3.81 (dd, 1H, JH,H = 4.0, JH,H = 9.0 Hz),
4.43–4.51 (m, 2H), 4.51–4.56 (m, 1H), 6.41 (br s, 1H), 6.72 (br s,
1H), 7.22–7.30 (m, 3H), 7.32–7.35 (m, 2H) ppm. The
spectroscopic data were in full agreement with those reported in
the literature.27b
4.4. Reduction of amides 2–9 to amines 12–22—General
procedures
Method A: The corresponding amide (1 mmol) was dissolved in
anhydrous THF (15 mL). The mixture was cooled to 0 °C and solu-
tion of LiAlH4 (2 mmol, 1.0 M in THF) was added under a nitrogen
atmosphere. After refluxing for 3 h, the mixture was cooled to
room temperature and aqueous 2 M NaOH was added until the
4.2.7. (S)-N-(4-Methoxyphenyl)-1-tritylaziridine-2-carboxamide
8
Yield 87%, colorless solid; mp 144–146 °C; [
a]
23 = À118.4 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.62 (d, 1H, JH,H = 6.6 Hz), 2.15
´
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S. Jarzynski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
hydrogen bubbling stopped. The resulting mixture was filtered and
extracted with Et2O (3 Â 10 mL). The combined organic layers
were dried over MgSO4, and the solvent was evaporated under vac-
uum. A crude product was purified by column chromatography
(silica gel, hexane with ethyl acetate in gradient 1:9) to afford
the corresponding products; Method B: In a round-bottomed flask,
zinc acetate (1 mmol), triethoxysilane (3 mmol) and anhydrous
THF (5 mL) were mixed. The mixture was stirred for 30 min under
argon followed by the addition of corresponding secondary amide
(2–5) (1 mmol) in THF (3 mL). After refluxing for 7 h, the mixture
was cooled to room temperature and treated with aqueous 1 M
NaOH (5 mL). After stirring for 3 h, the mixture was extracted with
ethyl acetate (4 Â 10 mL) and the combined organic phases were
dried over anhydrous MgSO4 and concentrated in vacuo. The resi-
due was purified by column chromatography (silica gel, hexane
with ethyl acetate in gradient 1:9) to afford the corresponding
products; Method C: The corresponding amide (1 mmol) was dis-
solved in anhydrous THF (15 mL). The mixture was cooled to 0 °C
and solution of LiAlH4 (4 mmol, 1.0 M in THF) was added under a
nitrogen atmosphere. After refluxing for 8 h, the mixture was
cooled to room temperature and aqueous 2 M NaOH was added
until the hydrogen bubbling stopped. The resulting mixture was
filtered and extracted with Et2O (3 Â 10 mL). The combined
organic layers were dried over MgSO4, and the solvent was evapo-
rated under vacuum. A crude product was purified by column
chromatography (silica gel, methanol/ethyl acetate in gradient
1:9) to afford the corresponding products.
54.9 (CH2), 62.7 (CH2), 73.9 (Cq), 126.5 (Car), 127.4 (Car), 129.6
(Car), 144.7 (Cq ar) ppm; IR (KBr): 3080, 3058, 2982, 2941, 2925,
2853, 2752, 1595, 1489, 1446, 1336, 1257, 1151, 1098, 1043,
1032, 912, 775, 710, 634 cmÀ1; ESI-MS: m/z: 383 (100, [M+H]+);
Anal. Calcd for C27H30N2 (382.54): C, 84.77; H, 7.90; N, 7.32. Found:
C, 84.78; H, 7.79; N, 7.29.
4.4.4. (R)-4-((1-Tritylaziridin-2-yl)methyl)morpholine 15
Yield 91%, colorless solid, mp 186–188 °C; [
a
]
D
23 = À20.5 (c 0.3,
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.20 (d, 1H, JH,H = 6.0 Hz),
1.37–1.40 (m, 1H), 1.67 (d, 1H, JH,H = 3.0 Hz), 2.26 (dd, 1H, JH,H
=
8.0, JH,H = 12.5 Hz), 2.35–2.36 (m, 2H), 2.47–2.49 (m, 2H), 3.07
(dd, 1H, JH,H = 4.0, JH,H = 12.5 Hz), 3.63–3.68 (m, 4H), 7.19–7.22
(m, 3H), 7.26–7.27 (m, 6H), 7.49–7.51 (m, 6H) ppm; 13C NMR
(151 MHz, CDCl3): d 27.7 (CH2 azir), 30.3 (CHazir), 54.0 (CH2),
62.2 (CH2), 66.9 (CH2), 73.9 (Cq), 126.6 (Car), 127.4 (Car), 129.5
(Car), 144.6 (Cq ar) ppm; IR (KBr): 3084, 3031, 2957, 2927, 2853,
2796, 1648, 1596, 1489, 1447, 1330, 1290, 1239, 1155, 1118,
1069, 1010, 910, 866, 747, 707 cmÀ1; ESI-MS: m/z: 385 (35, [M
+H]+), 407 (100, [M+Na]+); Anal. Calcd for C26H28N2O (384.51): C,
81.21; H, 7.34; N, 7.29. Found: C, 81.10; H, 7.34; N, 7.33.
4.4.5. (R)-N-Benzyl-1-(1-tritylaziridin-2-yl)methanamine 16
Yield 84%, colorless solid, mp 221–223 °C; [
a
]
23 = À32.6 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.01 (d, 1H, JH,H = 6.0 Hz),
1.38–1.39 (m, 1H), 1.46 (sbr, 1H, NH), 1.67 (d, 1H, JH,H = 3.0 Hz),
2.73 (dd, 1H, JH,H = 5.0, JH,H = 12.0 Hz), 2.87 (dd, 1H, JH,H = 5.0, JH,H
= 12.0 Hz), 3.70 (s, 2H), 7.10–7.12 (m, 3H), 7.15–7.19 (m, 9H),
7.22–7.25 (m, 1H), 7.38–7.40 (m, 6H) ppm; 13C NMR (151 MHz,
CDCl3): d 25.5 (CH2 azir), 32.5 (CHazir), 51.5 (CH2), 54.0 (CH2),
73.9 (Cq), 126.6 (Car), 126.9 (Car), 127.4 (Car), 128.1 (Car), 128.4
(Car), 129.5 (Car), 140.4 (Cq ar), 144.6 (Cq ar) ppm; IR (KBr): 3057,
3030, 2979, 2922, 2891, 2829, 1680, 1595, 1489, 1448, 1359,
1236, 1153, 1086, 901, 746, 696, 632 cmÀ1; ESI-MS: m/z: 405
(100, [M+H]+), 427 (27.5, [M+Na]+); Anal. Calcd for C29H28N2
(404.55): C, 86.10; H, 6.98; N, 6.92. Found: C, 86.01; H, 7.21; N, 6.76.
4.4.1. (R)-N,N-Dimethyl-1-(1-tritylaziridin-2-yl)methanamine
12
Yield 82%, colorless solid; mp 159–161 °C; [
a]
23 = À17.4 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.20 (d, 1H, JH,H = 6.0 Hz),
1.36–1.39 (m, 1H), 1.68 (d, 1H, JH,H = 1.5), 2.10–2.14 (m, 1H), 2.19
(s, 6H), 3.09 (d, 1H, JH,H = 12.0 Hz), 7.19–7.22 (m, 3H), 7.25–7.28
(m, 6H), 7.49–7.50 (m, 6H) ppm; 13C NMR (151 MHz, CDCl3): d
27.7 (CH2 azir), 31.3 (CHazir), 45.9 (2 CH3), 62.7 (CH2), 73.9 (Cq),
126.6 (Car), 127.4 (Car), 129.5 (Car), 144.6 (Cq ar) ppm; IR (KBr):
3017, 2995, 2960, 2854, 1487, 1446, 1386, 1231, 1214, 1150,
1041, 1031, 900, 773, 753, 706 cmÀ1; ESI-MS: m/z: 343 (100, [M
+H]+), 365 (32.5 [M+Na]+); Anal. Calcd for C24H26N2 (342.48): C,
84.17; H, 7.65; N, 8.18. Found: C, 84.09; H, 7.71; N, 8.20.
4.4.6. (R)-N-((1-Tritylaziridin-2-yl)methyl)aniline 17
Yield 81%, colorless oil, [
a
]
D
23 = À41.3 (c 0.3, CHCl3); 1H NMR
(600 MHz, CDCl3) d: 1.18 (d, 1H, JH,H = 6.0 Hz), 1.62–1.65 (m, 1H),
1.87 (d, 1H, JH,H = 3.10 Hz), 3.32–3.34 (m, 1H), 3.42–3.44 (m, 2H),
3.99 (s, 1H, NH), 6.57–6.59 (m, 2H), 6.73–6.75 (m, 1H), 7.18–7.21
(m, 2H), 7.25–7.27 (m, 3H), 7.30–7.33 (m, 6H), 7.52–7.53 (m, 6H)
ppm; 13C NMR (151 MHz, CDCl3): d 25.3 (CH2 azir), 31.8 (CHazir),
45.8 (CH2), 74.0 (Cq), 113.0 (Car), 117.4 (Car), 126.8 (Car), 127.5
(Car), 129.2 (Car), 129.5 (Car), 144.4 (Cq ar), 148.3 (Cq ar) ppm; IR
(film): 3053, 3019, 2980, 2929, 2893, 1603, 1505, 1489, 1446,
4.4.2. (R)-1-((1-Tritylaziridin-2-yl)methyl)pyrrolidine 13
Yield 90%, colorless solid, mp 178–180 °C; [
a
]
23 = À22.3 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.18 (d, 1H, JH,H = 6.0 Hz),
1.42–1.44 (m, 1H), 1.68 (d, 1H, JH,H = 3.0 Hz), 1.70–1.75 (m, 4H),
2.21 (dd, 1H, JH,H = 8.5, JH,H = 12.0 Hz), 2.40–2.43 (m, 2H), 2.50–
2.52 (m, 2H), 3.34 (dd, 1H, JH,H = 8.5, JH,H = 12.0 Hz), 7.18–7.21
(m, 3H), 7.25–7.27 (m, 6H), 7.49–7.50 (m, 6H) ppm; 13C NMR
(151 MHz, CDCl3): d 23.4 (CH2), 27.5 (CH2 azir), 31.8 (CHazir),
54.5 (CH2), 59.5 (CH2), 73.9 (Cq), 126.5 (Car), 127.3 (Car), 129.5
(Car), 144.7 (Cq ar) ppm; IR (KBr): 3053, 3031, 2971, 2956, 2920,
2875, 1595, 1490, 1446, 1349, 1244, 1156, 1143, 1047, 936, 900,
769, 748, 707, 632, 524 cmÀ1; ESI-MS: m/z: 369 (100, [M+H]+);
Anal. Calcd for C26H28N2 (368.51): C, 84.74; H, 7.66; N, 7.60. Found:
C, 84.69; H, 7.64; N, 7.58.
1316, 1253, 1233, 1152, 1032, 902, 869, 747, 708, 693, 633 cmÀ1
;
HRMS (EI) m/z calcd for C28H26N2: 390.2099, found 390.2096.
4.4.7. (R)-4-Methoxy-N-((1-tritylaziridin-2-yl)methyl)aniline 18
Yield 86%, brown solid, mp 216–218 °C; [
a]
D
23 = À45.8 (c 0.3,
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.14 (d, 1H, JH,H = 6.0 Hz),
1.58–1.61 (m, 1H), 1.84 (d, 1H, JH,H = 3.0 Hz), 3.23 (dd, 1H, JH,H
=
5.5, JH,H = 12.0 Hz), 3.36 (dd, 1H, JH,H = 4.0, JH,H = 12.0 Hz), 3.70
(sbr, 1H, NH), 3.76 (s, 3H), 6.50–6.52 (m, 2H), 6.76–6.78 (m, 2H),
7.21–7.24 (m, 3H), 7.26–7.29 (m, 6H), 7.49–7.50 (m, 6H) ppm;
13C NMR (151 MHz, CDCl3): d 25.3 (CH2 azir), 32.0 (CHazir), 47.0
(CH2), 55.9 (CH3), 73.9 (Cq), 114.4 (Car), 114.9 (Car), 126.7 (Car),
4.4.3. (R)-1-((1-Tritylaziridin-2-yl)methyl)piperidine 14
Yield 88%, colorless solid, mp 186–188 °C; [
a
]
23 = À19.7 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.18 (d, 1H, JH,H = 6.0 Hz),
1.40–1.42 (m, 3H), 1.50–1.53 (m, 4H), 1.66 (d, 1H, JH,H = 3.0 Hz),
127.5 (Car), 129.5 (Car), 142.6 (Cq ar), 144.5 (Cq ar), 152.2 (Cq
)
ar
ppm; IR (KBr): 3054, 3030, 2993, 2931, 2901, 2829, 1595, 1513,
1489, 1464, 1447, 1309, 1235, 1179, 1034, 901, 818, 747, 708,
633, 521 cmÀ1; ESI-MS: m/z: 443 (100, [M+Na]+); Anal. Calcd for
2.17 (dd, 1H, JH,H = 8.0, JH,H = 12.5 Hz), 2.28 (sbr, 2H), 2.41 (sbr
,
2H), 3.10 (dd, 1H, JH,H = 4.0, JH,H = 12.5 Hz), 7.19–7.21 (m, 3H),
7.25–7.27 (m, 6H), 7.48–7.50 (m, 6H) ppm; 13C NMR (151 MHz,
CDCl3): d 24.3 (CH2), 25.9 (CH2), 28.2 (CH2 azir), 30.7 (CHazir),
C29H28N2O (420.55): C, 82.82; H, 6.71; N, 6.66. Found: C, 82.67;
H, 6.72; N, 6.71.
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8
4.4.8. (R)-2,4,6-Trimethyl-N-((1-tritylaziridin-2-yl)methyl)
the aqueous phase was extracted three times with diethyl ether.
The combined organic layers were dried over anhydrous Na2SO4,
filtered and the solvents were evaporated in vacuo. (S)-(4-Methyl-
phenyl)phenylmethanol was purified via column chromatography
(silica gel, hexane with ethyl acetate in gradient). Yield and enan-
tiomeric excess values are listed in Table 3.
aniline 19
Yield 83%, colorless solid, mp 202–204 °C; [
a]
23 = À39.7 (c 0.3,
D
CHCl3); 1H NMR (600 MHz, CDCl3) d: 1.12 (d, 1H, JH,H = 6.2 Hz),
1.54–1.57 (m, 1H), 1.68 (d, 1H, JH,H = 3.1 Hz), 2.23 (s, 3H), 2.24 (s,
6H), 3.13 (dd, 1H, JH,H = 4.6, JH,H = 12.4 Hz), 3.27 (dd, 1H, JH,H
=
4.6, JH,H = 12.4 Hz), 6.81 (s, 2H), 7.21–7.23 (m, 3H), 7.27–7.29 (m,
6H), 7.51–7.54 (m, 6H) ppm; 13C NMR (151 MHz, CDCl3): d 18.3
(2 CH3), 20.5 (CH3), 24.8 (CH2 azir), 33.0 (CHazir), 50.3 (CH2),
74.0 (Cq), 126.7 (Car), 127.5 (Car), 129.4 (Car), 129.5 (Car), 131.1
(Cq ar), 143.5 (Cq ar), 144.6 (Cq ar) ppm; IR (KBr): 3057, 3032,
2975, 2939, 2897, 1595, 1489, 1448, 1346, 1263, 1236, 1151,
1032, 902, 847, 746, 696, 632 cmÀ1; HRMS (EI) m/z calcd for
C31H32N2: 432.2599, found 432.2565.
4.5.1. (S)-(4-Methylphenyl)(phenyl)methanol
Colorless oil; 1H NMR (600 MHz, CDCl3) d: 2.15 (d, 1H, J = 3.6
Hz), 2.34 (s, 3H), 5.83 (d, 1H, J = 3.6 Hz), 7.14–7.16 (m, 2H), 7.25–
7.27 (m, 3H), 7.32–7.35 (m, 2H), 7.38–7.39 (m, 2H) ppm; ee deter-
mination conditions: Chiralcel OD, hexane:iPrOH = 95/5, flow = 0.5
mL/min, retention time: 16.4 min (major), 18.4 min (minor).
4.6. Asymmetric addition of diethylzinc to benzaldehyde—
General procedure8a
4.4.9. (S)-N-(Aziridin-2-ylmethyl)aniline 20
Yield 70%, colorless oil, [a]
23 = +11.9 (c 0.3, CHCl3); 1H NMR (600
D
MHz, CDCl3) d: 1.52 (d, 1H, JH,H = 3.0 Hz), 1.86 (d, 1H, JH,H = 6.0 Hz),
2.30–2.34 (m, 1H), 3.05 (dd, 1H, JH,H = 6.0, JH,H = 13.0 Hz), 3.36 (dd,
1H, JH,H = 4.0, JH,H = 13.0 Hz), 6.64–6.66 (m, 2H), 6.70–6.73 (m, 1H),
7.16–7.19 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3): d 23.5 (CH2
azir), 29.1 (CHazir), 46.9 (CH2), 113.0 (Car), 117.7 (Car), 129.2 (Car),
148.2 (Cq ar) ppm; IR (film): 3354, 3307, 3108, 3051, 2924, 2850,
1604, 1506, 1435, 1321, 1261, 1180, 1072, 991, 870, 754, 694
cmÀ1; HRMS (EI) m/z calcd for C9H12N2: 148.1003, found 140.1000.
The corresponding amine 12–22 (0.1 mmol) and toluene (10 mL)
were placed in a round bottomed flask. To ensure dryness, 5 mL of
toluene were distilled off. The solution was cooled to 0 °C and
diethylzinc solution (1.0 M in hexane, 3 mmol) was added under
argon. After the complete precipitation of an amorphous white solid,
benzaldehyde (1 mmol) was added at 0 °C and the mixture was stir-
red at room temperature overnight. Then, a 5% aqueous solution of
hydrochloric acid was added, layers were separated and the aqueous
phase was extracted with diethyl ether (4 Â 10 mL). The combined
organic layers were washed with brine (10 mL) and dried over anhy-
drous MgSO4. The solvents were evaporated in vacuo to afford a
crude (S)-1-phenyl-1-propanol, which was purified via column
chromatography (silica gel, hexane with ethyl acetate in gradient
95:5). Yield and enantiomeric excess values are listed in Table 4.
(S)-1-Phenyl-1-propanol: Yellow oil; 1H NMR (600 MHz, CDCl3) d:
0.96 (t, 3H, J = 7.4 Hz), 1.72–1.91 (m, 2H), 1.94 (s, 1H), 4.63 (t, 1H,
J = 6.6 Hz), 7.29–7.40 (m, 5H) ppm; ee determination conditions:
Chiralcel OD-H, hexane:iPrOH = 98/2, flow = 0.7 mL/min, retention
time: 19.7 min (minor), 23.5 min (major).
4.4.10. (S)-N-(Aziridin-2-ylmethyl)-4-methoxyaniline 21
Yield 68%, yellow oil, [
MHz, CDCl3) d: 1.51 (d, 1H, JH,H = 3.0 Hz), 1.86 (d, 1H, JH,H = 6.0 Hz),
2.31 (dd, 1H, JH,H = 3.0, JH,H = 6.0 Hz), 2.98 (dd, 1H, JH,H = 6.0, JH,H
a]
23 = +14.0 (c 0.3, CHCl3); 1H NMR (600
D
=
13.0 Hz), 3.31 (dd, 1H, JH,H = 4.0, JH,H = 13.90 Hz), 3.73 (sbr, 1H, NH),
3.74 (s, 3H), 6.61–6.63 (m, 2H), 6.77–6.79 (m, 2H) ppm; 13C NMR
(151 MHz, CDCl3): d 23.5 (CH2 azir), 29.3 (CHazir), 48.1 (CH2),
55.8 (CH3), 114.4 (Car), 115.0 (Car), 142.5 (Cq ar), 152.4 (Cq
)
ar
ppm; IR (film): 3356, 3309, 3275, 3065, 3033, 2996, 2852, 2830,
1618, 1513, 1465, 1402, 1287, 1234, 1179, 1035, 903, 821, 708,
669, 526 cmÀ1; ESI-MS: m/z: 179 (100, [M+H]+); Anal. Calcd for
C
10H14N2O (178.23): C, 67.39; H, 7.92; N, 15.72. Found: C, 67.37;
4.7. Enantioselective epoxidation of chalcone—General
procedure24
H, 7.91; N, 15.69.
4.4.11. (S)-N-(Aziridin-2-ylmethyl)-2,4,6-trimethylaniline 22
The corresponding amine (0.1 mmol) and anhydrous Et2O (4
mL) were placed in a round bottomed flask under nitrogen atmo-
sphere. After cooling to 0 °C in an ice-bath, Et2Zn (0.2 mmol, 1 M
solution in toluene) was added while stirring. After the complete
precipitation of an amorphous white solid, chalcone (0.5 mmol)
and CMHP (0.6 mmol, 80% solution in cumene) were added and
the mixture was stirred at 0 °C overnight. The reaction was
quenched with aq. sat. NaHCO3 and extracted with Et2O. The
organic layer was washed with aqueous Na2CO3 and brine. The
combined organic layers were dried with MgSO4, and the solvent
was evaporated in vacuo. A crude product was purified by column
chromatography (silica gel, hexane with ethyl acetate in gradient
95:5). Yield and enantiomeric excess values are listed in Table 5.
Yield 74%, colorless oil, [
(600 MHz, CDCl3) d: 1.48 (d, 1H, JH,H = 3.0 Hz), 1.85 (d, 1H, JH,H
a]
D
23 = +12.7 (c 0.3, CHCl3); 1H NMR
=
6.0 Hz), 2.22–2.23 (m, 4H), 2.26 (d, 1H, JH,H = 6.0 Hz), 2.28 (s, 6H),
2.78 (dd, 1H, JH,H = 7.0, JH,H = 13.0 Hz), 3.12 (dd, 1H, JH,H = 4.5, JH,H
= 13.0 Hz), 6.82 (sbr, 2H) ppm; 13C NMR (151 MHz, CDCl3): d 18.3
(2 CH3), 20.5 (CH3), 23.4 (CH2 azir), 30.1 (CHazir), 52.3 (CH2),
129.4 (Car), 129.9 (Car), 131.5 (Cq ar), 143.0 (Cq ar) ppm; IR (film):
3356, 3301, 2994, 2943, 2915, 2856, 1751, 1593, 1487, 1444,
1375, 1306, 1233, 1157, 1032, 853, 754 cmÀ1; ESI-MS: m/z: 189
(100, [MÀH]À); Anal. Calcd for C12H18N2 (190.28): C, 75.74; H ,
9.53; N, 14.72. Found: C, 75.58; H, 9.40; N, 14.53.
4.5.
Asymmetric
arylation
of
p-tolualdehyde
with
phenylboronic acid in the presence of Et2Zn—General
4.7.1. [(2R,3S)-3-Phenyloxiran-2-yl]-phenylmethanone
White solid; 1H NMR (600 MHz, CDCl3) d: 4.09 (d, 1H, J = 2.0
Hz), 4.29 (d, 1H, J = 2.0 Hz), 7.33–7.46 (m, 5H), 7.49–7.51 (m, 2H),
7.62–7.64 (m, 1H), 8.02–8.03 (m, 2H) ppm; ee determination con-
ditions: Chiralcel OD-H, hexane:iPrOH = 95/5, flow = 1.0 mL/min,
retention time: 10.0 min (minor), 11.2 min (major).
procedure18
A solution of diethylzinc (2.5 mmol) was added dropwise to a
solution of phenylboronic acid (0.5 mmol) in toluene (1.5 mL)
under nitrogen atmosphere. After stirring for 15 min. at 60 °C,
the mixture was cooled to ambient temperature and the solution
of the corresponding amine 12–22 (10 mol %) in toluene (1 mL)
was added. After the complete precipitation of an amorphous
white solid, a mixture was cooled to 0 °C and p-tolualdehyde
(0.5 mmol) was added. After stirring for 24 h, the reaction was
quenched with 15 ml of saturated NH4Cl aqueous solution and
Acknowledgement
Financial support by the National Science Centre (NCN), Poland,
Grant Preludium No. 2014/15/N/ST5/02897 for S. J. is gratefully
acknowledged.
´
Please cite this article in press as: Jarzynski, S.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.018

´
9
S. Jarzynski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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