Lewis acid-catalyzed diastereoselective synthesis of multisubstituted N-acylaziridine-2-carboxamides from 2 H -Azirines via Joullié-Ugi three-component reaction

Article abstract of DOI:10.1021/acs.joc.7b03189

A ZnCl₂-catalyzed diastereoselective Joullié-Ugi three-component reaction from 2H-azirines, isocyanides, and carboxylic acids was established. The protocol allows the preparation of highly and diversely functionalized N-acylaziridine-2-carboxamide derivatives in up to 82% isolated yields. Moreover, the applicability of N-acylaziridines is demonstrated through a variety of transformations.

Full text of DOI:10.1021/acs.joc.7b03189

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Article
Lewis acid-catalyzed diastereoselective synthesis of
multisubstituted N-acylaziridine-2-carboxamides from
2H-azirines via Joullié–Ugi three-component reaction
Anikó Angyal, Andras Demjen, Edit Wéber, Anita K. Kovacs,
Janos Wolfling, Laszlo G. Puskas, and Ivan Kanizsai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03189 • Publication Date (Web): 02 Mar 2018
Downloaded from http://pubs.acs.org on March 3, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Page 1 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Lewis acid-catalyzed diastereoselective synthesis of multisubstituted N-
acylaziridine-2-carboxamides from 2H-azirines via Joullié–Ugi three-
component reaction
Anikó Angyala,b, András Demjéna,b, Edit Wéberc, Anita K. Kovácsd, János Wölflingb, László G. Puskása, Iván
Kanizsaia,*
aAVIDIN Ltd., Alsó kikötő sor 11/D, Szeged, Hꢀ6726, Hungary; bDepartment of Organic Chemistry, University of Szeged, Dóm tér
8, Hꢀ6720, Szeged, Hungary; cSZTEꢀMTA Lendület Foldamer Research Group, Institute of Pharmaceutical Analysis, University
of Szeged, Somogyi u. 4., Szeged, Hꢀ6720, Hungary; dDepartment of Medical Chemistry, University of Szeged, Dóm tér 8, Szeged
6720, Hungary
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tel.: +36ꢀ62/202107; fax: +36ꢀ62/202108; eꢀmail: i.kanizsai@avidinbiotech.com
and VI containing an active methylene group6 through
Abstract
Knoevenagel intermediate VII or from protected αꢀ
iminoglyoxylic derivatives7 VIII. However, these
A ZnCl2ꢀcatalyzed diastereoselective Joullié–Ugi threeꢀ
component reaction from 2Hꢀazirines, isocyanides and
carboxylic acids has been established. The protocol allows
the preparation of highly and diversely functionalized Nꢀ
synthetic strategies still suffer from low overall yields and
lack of diversity. It is notable, that fullyꢀsubstituted Nꢀ
acylaziridineꢀ2ꢀcarboxamides (R3, R4, R5≠H) have not
acylaziridineꢀ2ꢀcarboxamide derivatives in up to 82%
been reported yet. Therefore, the development of a rapid
isolated yields. Moreover, the applicability of Nꢀ
and straightforward approach to multisubstituted Nꢀ
acylaziridines is demonstrated through a variety of
acylaziridineꢀ2ꢀcarboxamides still remains a synthetic
transformations.
challenge.
Introduction
Aziridines are not only important building blocks and
synthetic intermediates but also present in a variety of
biologically active natural (eg. azinomycins and
mitomycins) and synthetic compounds exhibiting
antibacterial, antimalarial, anticancer and enzyme
inhibitory effects.1
Due to the structural similarity to αꢀ and βꢀamino acids,
1Hꢀaziridineꢀ2ꢀcarboxylic acid (Azy) represents an
exceptional interest among aziridines.2 This useful
building block has prompted the preparation of diꢀ and
tripeptides by consecutive amino acid couplings towards
the NH and carboxyl function of Azy.3 Following this
strategy, a great number of Nꢀacylaziridineꢀ2ꢀcarboxylates
and
ꢀcarboxamides were synthesized and tested as cysteine
protease inhibitors.4
The known synthetic approaches towards Nꢀ
acylaziridineꢀ2ꢀcarboxamides I are limited and almost
exclusively proceed through the formation of aziridine
Scheme 1. Synthetic protocols for Nꢀacylaziridineꢀ2ꢀ
carboxamides.
carboxamide intermediate IV (Scheme 1). Most of the
described methods start from protected amino acids serine
and threonine II and transform the OH functionality to
form the aziridine ring via multiꢀstep processes.5,3b In
An efficient opportunity for reducing the number of
reaction steps and avoiding protective group strategies is
represented by highlyꢀconvergent multicomponent
reactions (MCRs).8 The isocyanideꢀbased Ugi fourꢀ
addition, a careful choice of protective groups and peptide
component reaction is one of the most relevant MCRs,
coupling techniques are required, while the achievable
which allows the construction of complex αꢀaminoacyl
amide peptidomimetics in a oneꢀstep operation.9 Although
substitution pattern on the aziridine ring is very limited
(R3=H; R4=H or Me; R5=H). Alternatively, aziridineꢀ2ꢀ
the classical Ugi reaction provides linear products, various
carboxamide IV can also be obtained from compounds V
ACS Paragon Plus Environment

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
The Journal of Organic Chemistry
Page 2 of 19
1
2
3
4
5
6
7
8
9
heterocycles (rarely aziridine)10, can also be accessed
either through postꢀcondensation reactions or by the
application of bifunctional inputs.9,11 For example,
utilization of cyclic imines in the threeꢀcomponent Joullié–
Ugi reaction12 (JUꢀ3CR) affords diverse fiveꢀ,13 sixꢀ13,14 or
sevenꢀmembered13,15 Nꢀacylated heterocycles.
Here, we describe the first utilization of 2Hꢀazirines in the
JUꢀ3CR, leading to heavily substituted Nꢀacylaziridineꢀ2ꢀ
carboxamides in a straightforward oneꢀpot procedure.
moderate catalytic activity (Table 1, Entries 16 and 17). In
contrast, ZnCl2 was found to be a superior catalyst
providing the desired Nꢀacylaziridines 4{1} and 5{1} in
71% combined HPLC yield. Applying both lower (10
mol%) and higher (50 mol%) loadings of ZnCl2 resulted in
decreased yields (Table 1, Entries 19 and 20). All reactions
gave predominantly transꢀaziridine 4{1} with high
diastereoselectivity (from 87:13 to 94:6 trans:cis dr), but
the amount of catalyst did not influence the stereochemical
outcome. The stereochemistry of racꢀ4{1} and racꢀ5{1}
diastereomers was determined by NOESY experiments
(see Supporting Information).
Next, we focused on exploring the effect of solvents,
temperature and concentration (Table 2). The reaction was
found to tolerate a wide range of media with no distinct
changes in the dr (from 89:11 to 93:7; trans:cis). The
developed JUꢀ3CR is mostly favored in nonꢀpolar (toluene
and 1,4ꢀdioxane) and polar aprotic solvents (CHCl3, THF
and MeCN). The only exception is DMF, which was not
tolerated (Table 2, Entries 3–8). Of all solvents applied,
THF was found to be the best solvent to form aziridine in
72% combined HPLC yield. Additionally, we attempted to
accelerate the reaction by using microwave irradiation
(Table 2, Entries 9–11). By raising the reaction
temperature (80–120 °C) a clear trend of decreased yields
and dr was observed. On the other hand, by lowering the
concentration of azirine (±)ꢀ1a, improvements in combined
yields and diastereomeric ratios could be achieved (Table
2, Entries 13 and 14).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
Preliminary investigations were started by examining the
reaction of racemic ethyl 3ꢀmethylꢀ2Hꢀazirineꢀ2ꢀ
carboxylate16a (1a) with tertꢀbutyl isocyanide (2a) and
benzoic acid (3a) under the reported Joullié–Ugi 3CR
conditions (MeOH, toluene; rt or reflux).14a,17 However, no
conversion was observed. Gratifyingly, performing the
model reaction in refluxing THF offered the target product
in 8% isolated yield after two days (Table 1, Entry 1).
Since Lewis acids could increase the reactivity of
azirines,18 we tested several Lewisꢀ and Brønsted acids as
promoters in the model reaction (Table 1, Entries 2–18).
Table 1. Catalyst screen.a
O
O
COOH
N
O
N
N
NC
catalyst
H
H
+
+
+
THF
55 °C, 6 h
Ar
COOEt
HN
COOEt
HN
COOEt
O
(±)-1a
2a
3a
(±)-4{1}
(±)-5{1}
Entry
Catalyst
ꢀ
PTSA
HClO4
In(OTf)3
Yield (%)b
dr (trans:cis)c
93:7
ꢀ
ꢀ
Table 2. Optimization of the reaction conditions.a
1d
2
8e
0
3
4
0
0
ꢀ
5
6
7
Mg(OTf)2
Dy(OTf)3
InF3
0
0
0
ꢀ
ꢀ
ꢀ
8
9
CuBr2
CuCl2
0
0
ꢀ
ꢀ
Entry
1
2
3
4
Solvent
EtOH
IPA
MeCN
DMF
Temp. (°C)
55
55
55
55
Yield (%)b
dr b
10
11
12
13
14
15
16
17
18
19
20
AlCl3
SnCl2
FeCl3
In(OAc)3
Zn(OAc)2
ZnO
InCl3
ZnBr2
0
ꢀ
12
40
56
0
91:9
93:7
89:11
ꢀ
12
13
16
20
23
51
56
71
61
54
92:8
92:8
88:12
90:10
87:13
94:6
92:8
93:7
93:7
94:6
5
6
7
8
THF
55
55
55
55
72
61
64
57
64
58
55
68
77
81
93:7
90:10
92:8
91:9
94:6
91:9
88:12
91:9
94:6
96:4
CHCl3
1,4ꢀDioxane
Toluene
THF
THF
THF
ZnCl2
ZnCl2
ZnCl2
9
80 c
100 c
120 c
55
f
10
11
12
13
14
g
d
aReaction conditions: 2Hꢀazirine (0.25 mmol), tertꢀbutyl isocyanide (1.1
equiv.), benzoic acid (1.1 equiv.), anhydrous THF (0.5 mL), catalyst (25
mol%), argon atmosphere, 55 °C, 6 h. bCombined yield of 4{1} and 5{1}.
Determined by HPLC analysis. cThe diastereomeric ratio (dr) was
determined by HPLC analysis. Both diastereomers were calibrated. d48 h,
reflux. eIsolated yield. f10 mol% catalyst was used. g50 mol% catalyst was
used.
THF
THFe
55
55
THF f
aReaction conditions: 2Hꢀazirine (0.25 mmol), tertꢀbutyl isocyanide (1.1
equiv.), benzoic acid (1.1 equiv.), anhydrous solvent (0.5 mL), anhydrous
ZnCl2 (25 mol%), argon atmosphere, 3 h. bCombined yield and dr were
determined by HPLC analysis. cMW conditions: 30 min, 250 W. d0.25 mL
e
anhydr. solvent was applied. 1 mL anhydr. solvent was applied. f2 mL
anhydr. solvent was applied and 4 h reaction time was necessary for full
conversion.
Most of the applied catalysts proved to be ineffective
(Table 1, Entries 2–15), except InCl3 and ZnBr2 showing
ACS Paragon Plus Environment

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Page 3 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
In further studies, we reacted racemic ethyl 3ꢀmethylꢀ
2Hꢀazirineꢀ2ꢀcarboxylate (1a) and tertꢀbutyl isocyanide
(2a) with varied carboxylic acids (3a–j) using the optimal
reaction conditions (anhydr. ZnCl2, anhydr. THF, argon
atmosphere, 55 °C, 4 h) (Table 3, Entries 1–10). Benzoic
acids bearing electron donating (3ꢀMeO, 4ꢀOH) or
electronꢀwithdrawing (2ꢀCl) substituents afforded the
desired products in moderate to good yields (Table 3,
Entries 1–4). Good yields were obtained as well, when
phenylacetic acid (3e) and 3,4,5ꢀtrimethoxycinnamic acid
(3f) were reacated, providing 4{5} and 4{6} in 69% and
60% yields, respectively (Table 3, Entries 5 and 6).
Moreover, nicotinic acid, a heteroaromatic carboxylicꢀ
acid, could also be subjected to the reaction (Table 3,
Entry 7). Gratifyingly, the reaction also tolerated aliphatic
carboxylic acids such as acetic and chloroacetic acids
giving good yields (Table 3, Entries 8 and 9). To our
delight, utilization of the weakly nucleophilic
trifluoroacetic acid smoothly afforded the desired Nꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
acylaziridine 4{10}
in 54% isolated yield, which
demonstrates the robustness of the carboxylic acid scope.
Table 3. Scope of isocyanides and carboxylic acids.a
Entry
2 (R1)
3 (R2)
4
Yield (%)b
drc
1
2
3
4
5
6
7
8
2a R1=tꢀBu
3a R2= Ph
4{1}
4{2}
4{3}
4{4}
4{5}
4{6}
4{7}
4{8}
69 (78)
72 (79)
56 (62)
61 (74)
69 (75)
60 (69)
28 (38)
75 (79)
55 (60)
54 (58)
78 (82)
71 (75)
58 (60)
38 (40)
60 (69)
77 (80)
79 (82)
68 (76)
60 (71)
80 (85)
77 (86)
67 (69)
58 (60)
22 (34)
36 (40)
29 (36)
56 (62)
28 (38)
96:4
95:5
93:7
94:6
94:6
95:5
>99
2a R1= tꢀBu
3b R2= 3ꢀMeOC6H4
3c R2= 4ꢀHOC6H4
3d R2= 2ꢀClC6H4
3e R2= Bn
2a R1= tꢀBu
2a R1= tꢀBu
2a R1= tꢀBu
2a R1= tꢀBu
3f R2=3,4,5ꢀMeOC6H2CHCH
3g R2= 3ꢀpyridyl
3h R2= Me
2a R1= tꢀBu
2a R1= tꢀBu
95:5
94:6
97:3
94:6
93:7
94:6
97:3
97:3
95:5
95:5
96:4
93:7
96:4
93:7
93:7
96:4
99:1
97:3
97:3
96:4
96:4
9
2a R1= tꢀBu
3i R2= ClCH2
3j R2= CF3
4{9}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
2a R1= tꢀBu
4{10}
4{11}
4{12}
4{13}
4{14}
4{15}
4{16}
4{17}
4{18}
4{19}
4{20}
4{21}
4{22}
4{23}
4{24}
4{25}
4{26}
4{27}
4{28}
2b R1= tꢀOctyl
2c R1= cꢀHex
2d R1= Bn
3a R2= Ph
3a R2= Ph
3a R2= Ph
2e R1= 3,4,5ꢀMeOC6H2
2f R1=4ꢀNO2C6H4
2b R1= tꢀOctyl
2g R1= nꢀPentyl
2c R1= cꢀHex
2c R1= cꢀHex
2c R1= cꢀHex
2c R1= cꢀHex
2d R1= Bn
3a R2= Ph
3a R2= Ph
3e R2= Bn
3e R2= Bn
3b R2= Me
3e R2= Bn
3k R2= 2,4,6ꢀMe C6H2
3l R2= 3ꢀFC6H4
3e R2= Bn
2d R1= Bn
3f R2=3ꢀMeOC6H4
3b R2= Me
2e R1= 3,4,5ꢀMeOC6H2
2e R1= 3,4,5ꢀMeOC6H2
2e R1= 3,4,5ꢀMeOC6H2
2f R1= 4ꢀNO2C6H4
2f R1= 4ꢀNO2C6H4
3e R2=Bn
3a R2= 4ꢀCF3C6H4
3c R2= ClCH2
3l R2= 3ꢀFC6H4
aReaction conditions: 2Hꢀazirine (0.5 mmol), anhydrous THF (4 mL) isocyanide (1.1 equiv.), carboxylic acid (1.1 equiv.), anhydrous ZnCl2 (25 mol%),
b
argon atmosphere, 55 °C, 4 h. Isolated yield of the major trans diastereomer (NMR yield in parenthesis). NMR yield was determined by 1HꢀNMR with
1,3,5ꢀtrimethoxybenzene as internal standard. ctrans/cis diastereomeric ratio (determined from crude reaction mixture by LCꢀMS)
Then, the scope of the reaction with respect to the
isocyanide reagent was investigated using (±)ꢀ1a and 3a as
coupling partners (Table 3, Entries 11–15). When aliphatic
isocyanides 2b and 2c were applied, the reactions also
proceeded smoothly leading to 4{11} and 4{12} in 78%
and 71% yields. When benzylic 2d and aromatic
isocyanides 2e and 2f were subjected to the reaction, lower
yields were observed (Table 3, Entries 13–15, 38–60%
yields). Interestingly, aromatic isocyanide 2f bearing the
electronꢀwithdrawing nitro group provided a better isolated
yield (60%, Entry 15), than the more nucleophilic 3,4,5ꢀ
trimethoxyphenyl isocyanide 2e (38%, Entry 14).
To evaluate the general performance of our method, we
carried out further tests with other combinations of the
isocyanide and carboxylic acid components (Table 3,
Entries 16–28). The protocol allowed the use of a wide
range of functional groups and furnished the corresponding
Nꢀacylaziridines 4 in up to 80% yields with high
ACS Paragon Plus Environment