Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01832

5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1′-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.

Full text of DOI:10.1021/acs.joc.6b01832

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Mechanochemical preparation of 3,5-disubstituted Hydantoins from
Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives.
Laure Konnert, Lori Gonnet, Ivan Halasz, Jean-Simon Suppo, Renata Marcia de
Figueiredo, Jean-Marc Campagne, Frédéric Lamaty, Jean Martinez, and Evelina Colacino
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01832 • Publication Date (Web): 28 Sep 2016
Downloaded from http://pubs.acs.org on September 29, 2016
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 free 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 accessible to all
readers and 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.

Page 1 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
Mechanochemical preparation of 3,5-disubstituted Hydantoins from Dipeptides and
Unsymmetrical Ureas of Amino Acid Derivatives.
7
8
9
Laure Konnert,[a] Lori Gonnet,[a] Ivan Halasz,[b] Jean-Simon Suppo,[c] Renata Marcia de
Figueiredo,[c] Jean-Marc Campagne,[c] Fredéric Lamaty,[a] Jean Martinez,[a] Evelina
Colacino*[a]
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
[a] Université de Montpellier, Institut des Biomolécules Max Mousseron
UMR 5247 CNRS – Université de Montpellier - ENSCM, Place E. Bataillon, Campus Triolet,
cc 1703, 34095 Montpellier (France), Tel. +33 (0)4 67 14 42 85; Fax +33 (0)467 14 48 66 ;
*e-mail : evelina.colacino@umontpellier.fr
[b]
Ruđer Bošković Institute, Bijenička cesta 54, Zagreb (Croatia)
[c] Institut Charles Gerhardt Montpellier (ICGM), UMR 5253 CNRS-UM-ENSCM,
Ecole Nationale Supérieure de Chimie, 8 Rue de l
Montpellier Cedex 5 (France).
’
Ecole Normale, 34296
Table of content
R1 R2
O
H
N
H2N
OR5
3 R4
R2
R
O
R1
O
O
O
Dipetides
N
N
HN
N
N
N
OR5
R1 R2
O
O
R4
R3
BALL-MILLING
OR
+
H2N
OR5
H2N
3 R4
3,5-disubstituted
Hydantoins
O
R
Amino acid derivatives
Abstract
5-substituted-3-(alkoxycarbonyl)alkyl-hydantoin
derivatives
were
prepared
by
mechanochemistry from amino esters or dipeptides, via a 1,1’-carbonyldiimidazole (CDI)-
mediated one-pot/two step cyclization reaction involving amino acid unsymmetrical urea A
and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution
were also performed. The successful preparation of an antibacterial agent precursor was also
investigated.
Keywords : Mechanochemistry, Hydantoins, Urea, Dipeptides, Ball-milling
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
3
4
Introduction
5
6
7
8
Compounds containing the 2,4-imidazolidinedione scaffold are a well-known family of
bioactive products (hydantoin family) with numerous therapeutic properties (also pesticides).1
The hydantoin core offers numerous possibilities of substitutions, allowing building a large
diversity of potential structures. In particular, 5-substituted-3-(alkoxycarbonyl)alkyl-
hydantoin derivatives (Figure 1) present a particular substitution pattern, which make them
interesting peptidomimetics2 and bioactive compounds with antiepileptic, anticonvulsant,
antiarrhythmic or antibacterial properties.1,3-5 They have been notably presented as inhibitors
of dihydro-orotate dehydrogenase from Clostridium (Zymobacterium) oroticum for the
potential treatment of parasitic diseases.6,7
9
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
Figure 1. 5-substituted-3-(alkoxycarbonyl)alkyl-hydantoin structures
From the synthetic point of view, these structures have been often reported as by-
products in peptide synthesis.8-10,11 However, their structural and biological interest have
given rise to the development of several methodologies for their preparation. The reaction of
amino acid derivatives with isocyanates led to the formation of such hydantoins, after
cyclization of the corresponding ureido derivatives in strong acidic conditions5,12,5,13 (Figure
1a). N-alkylation with halogeno acetates and their derivatives,14,7,15,16 and Michael addition17
reactions, allowed the introduction of the carboxyalkyl group at the N-3 position of
hydantoins, with a particular interest in phenytoin derivatives.3,18-20,4,17 (Figure 1b).
Miscellaneous procedures reported the reaction between acetylenic diesters and isocyanides,21
or phosphates,22 in the presence of an hydantoin molecule (Figure 1b). The rearrangement of
Boc-protected dipeptide compounds,23 diketopiperazines,24 seven-membered cyclopeptides,25
and oxazolidinones26 were also described (Figure 1c).
2
ACS Paragon Plus Environment

Page 3 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Our on-going work on the use of mechanochemistry for the preparation of carbamates
from amino acid derivatives,27-29 and biologically relevant compounds by grinding in a ball-
29-30,29,31
mill,
it seemed appealing to develop mechanochemical strategies to access 5-
substituted-3-(alkoxycarbonyl)-alkyl-hydantoins. Specifically, our previously developed
procedure on the 1,1’-carbonyldiimidazole (CDI)-mediated mechanochemical synthesis of
3,5-disubstituted hydantoins31 might be applicable to the preparation of similar structures, via
a one-pot/two step cyclization reaction involving amino acid unsymmetrical urea A (Method
A) or a carboxy-imidazolyl-dipeptide ester B (Method B) (Scheme 1).
9
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
Scheme 1. Synthesis of 5-substituted-3-(alkoxycarbonyl)alkyl-hydantoins by
mechanochemistry
To the best of our knowledge, Štrukil et al.32-35 achieved the only described mechanochemical
preparation of unsymmetrical (thio)ureas from either iso(thio)cyanates or benzotriazolyl-
activated thiocarbonyls.32 In solution, thiohydantoins were prepared from dissymmetrical
thioureas derived from amino acids.36,37 We have described the synthesis of unsymmetrical
ureas containing one amino ester, from either potassium cyanate30,29 or isocyanates,31 but no
mechanochemical desymmetrization from amino acid urea derivatives, and using CDI as an
activating agent has been reported so far. In solution, CDI has been used for the preparation
of symmetrical6 and unsymmetrical38,39 ureas from amino acid derivatives. However these
synthetic methods often require the use of toxic solvents such as DMF, the use of a base such
as triethylamine, and extra reagents such as methyl trifluoromethanesulfonate40,39 to enhance
the reactivity of the carboxamido intermediate.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
1
2
3
4
5
6
7
8
9
Amino acid ureas have been reported to cyclize into hydantoins in the presence of
concentrated HCl.6,41 In only one case the symmetrical urea was formed when using CDI.6 So
far, no study reported on the preparation of hydantoins from dissymmetrical ureas obtained
from amino acid derivatives and the safe, cheap and easy-to handle CDI (Scheme 1, method
A), neither in solution nor by mechanochemistry. Furthermore, mechanochemical reaction
conditions avoid the use of solvents and provide a strong activation in reactions involving
CDI,29 thus avoiding the addition of extra base or activating agents to the reaction mixture.
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
Another possible strategy to prepare 5-substituted-3-(alkoxycarbonyl)-alkyl-
hydantoins under ball-milling conditions, was to explore the reactivity of CDI towards
dipeptides, instead of single amino esters, (Scheme 1, method B). Liu et al. reported the
rearrangement of N-Boc-dipeptides into the corresponding hydantoins in solution, in the
presence of triflic anhydride.23 On solid support, the preparation of hydantoins proceeded
through the formation of an isocyanate function on resin-bound peptides. This isocyanate
could be generated after removal of the Fmoc-protecting group from the N-terminal moiety of
the peptide,42 but more generally by nucleophilic attack of this amino moiety on the
triphosgene43,44 or CDI-45,9 activated carbonyl of the carboxylic function.
The mechanochemical pathway is an interesting alternative to solid-phase synthesis, for
which the scale-up would be quite difficult (Figure 1d). We report herein two unprecedented
mechanochemical synthetic routes to access 5-substituted-3-(alkoxycarbonyl)alkyl-
hydantoins. The first one consists in the synthesis of unsymmetrical ureas (A) from amino
esters and CDI and their one-pot cyclization into the targeted hydantoins (Scheme 1, method
A). The second one describes the CDI activation of N-terminal moieties of dipeptides
followed by cyclisation (Scheme 1, method B). The disclosed methodology is a valid eco-
friendly alternative (replacing the use of triphosgene)46 to prepare 5-benzyl-3-
(methyloxycarbonyl)benzyl hydantoin 2e (Table 2, entry 5), which corresponding carboxylic
acid is an anti parasite agent, inhibitor of dihydro-orodotase dehydrogenase from Clostridium
(Zymobacterium) oroticum.6,7
Results and discussion
Synthesis of 3-substituted alkoxycarbonyl hydantoins from unsymmetrical ureas of amino
esters (Method A). We have recently reported the CDI-mediated mechanochemical
preparation of N-protected carbamates of amino esters29 and 3,5-dialkyl substituted
hydantoins,31 in a planetary ball-mill (PBM). Relying on our precedent one-pot/two steps
4
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
procedure, an amino ester hydrochloride AA1 was reacted with CDI, leading to the
corresponding 1H-imidazole-carboxamido intermediate (first step) (Table 1). Milling the
mixture in the presence of a- or b-amino tert-butyl esters AA2 added in the second step, led to
dissymmetrical carbonyl diamino esters 1, that was smoothly converted into hydantoins by a
chemoselective base-mediated intramolecular cyclization (Table 1 and 2). Therefore,
formation of regioisomeric hydantoins could be avoided when cyclizing either one-pot
generated symmetrical carbonyl diamino esters, or by means of a one-pot stepwise addition to
the grinding jar containing methyl/tert-butyl esters (Table 1).
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
Table 1. Optimization of the reaction conditions for the preparation of 5-substituted-3-
(alkoxycarbonyl)alkyl-hydantoins.a
Reaction time
Yield (%)c
Entry AAb derivative 1
AAb derivative 2
(Step 2) (h)
2a
40
47
63
1
2
3
HCl.H-Phe-OMe
HCl.H-Leu-OtBu
HCl.H-Phe-OMe
HCl.H-Leu-OtBu
HCl.H-Phe-OMe
HCl.H-Leu-OtBu
2
3
4
a
Conditions: (step 1) L-a-amino ester AA1 (1 equiv.) and CDI (1.3 equiv) at 450 rpm, 50
balls (5 mm, stainless steel, 5 mm Ø) for 40 min; (step 2) L-a-amino ester AA2 (1.6 equiv.)
and K2CO3 (3.6 equiv) at 450 rpm; b AA = Amino Acid; c Yield of isolated compounds.
Strictly applying the experimental conditions of the previously described synthesis of 5-
benzyl-3-(tert-butoxycarbonyl)isobutyl-hydantoin 2a led to only moderate yields, the
cyclization of the unsymmetrical urea 1a was incomplete (entry 1). Switching the addition
order of the amino esters did not significantly improve the reaction yield (entry 2). It was
however increased to 63% when the second step of the reaction was carried out for 4 h at 450
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
1
2
3
4
5
6
7
8
9
rpm (entry 3). From this preliminary optimization, several combinations of amino methyl and
tert-butyl esters were tested to scope the variety of substrates. Most of the corresponding
hydantoins were obtained in satisfying to good yields (Table 2), with the exception of 2b and
2e (entries 2 and 5). The grinding parameters were found to be essential. Indeed, whereas
good yields were obtained with 2a, 2c, and 2d in a PBM, no or low conversion was observed
in the case of 2b and 2e. However, moving to a vibrational ball-mill (VBM), the hydantoin 2b
could be obtained in a 58% yield (entry 5). Regardless to the milling parameters set for PBM,
the cyclization reaction into hydantoin 2b could not be improved and the yield remained
moderate. Indeed, the cyclisation reaction led to a mixture of the symmetrical carbonyl
diamino methyl ester of valine (urea formed in the first step) and the corresponding
dissymetrical urea 1b (formed in the second step), both structure attributed on the base of
LC/MS analyses of the crude mixture. The best results were obtained using the planetary ball-
mill (PBM) for 2 h (entry 2). It is noteworthy that the procedure was applicable to quaternary
amino esters (entry 3), as well as to b-amino acid derivatives (entry 4) from which the
hydantoin 2d was recovered in a 88% yield. The preparation of 2e, issued from the
symmetrical urea of phenylalanine methyl ester, could also be achieved in a satisfying yield
of 58% using VBM (entry 5). The yield was not improved by extending the reaction time up
to 6 h (52%, entry 5) or by changing the base. When Na2CO3, NaHCO3 and triethylamine
were used instead of K2CO3, conversion of the starting amino ester was not complete and the
cyclization reaction failed. Disappointingly, it was not possible to prepare hydantoin 2e by
performing the reaction in a planetary ball-milling (PBM) for 4 hours. Cyclization did not
occur and only the corresponding symmetrical urea 1 was obtained, confirming that PBM was
not suitable to prepare 2e hydantoin, probably due to the sticky texture of the milling mixture.
Results were not improved when variable quantities of inert grinding additives such as
NaCl,47-49 were added to modify the mechanical properties of the mixture. As previously
experimented for other organic transformations,29,28 the differences in grinding phenomena
and parameters occurring in the PBM with respect to VBM could be the explanation.
Noteworthy, the carboxylic acid of compound 2e is a dihydro-orotate dehydrogenase
inhibitor,6 and thus may be easily obtained from 2e. The work-up of the reaction was very
simple, as the products were recovered by precipitation/filtration by addition of water to the
crude mixture in the milling jar (2a,d,e) or by extraction in ethyl acetate (2b,c).
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
6
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
1
2
3
4
Table 2. Synthesis of 5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoins from ureas of amino esters.
5
6
7
8
9
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
Yield (%)b
Entry
1
HCl.H-AA1-OMea
HCl.H-Phe-OMe
HCl.H-AA2-OtBua
HCl.H-Leu-OtBu
Product
PBM
VBM
O
O
n.p.c
Ot-Bu
N
HN
2a
63
O
O
O
∗
2
HCl.H-Val-OMe
HCl.H-Ala-OtBu
2bd
43e
n.s.c
Ot-Bu
N
∗
HN
CH3
O
O
O
Ot-Bu
n.p.c
n.p.c
N
3
4
HCl.H-Aib-OMe
HCl.H-Met-OtBu
2c
60
88
HN
SMe
O
O
N
Ot-Bu
t-BuO
HCl.H-b-Ala-OtBu
HCl.H-Tyr(tBu)-OMe
2d
HN
O
O
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
O
O
OMe
5
6
7
8
N
5
HCl.H-Phe-OMe
HCl.H-Phe-OMe
2e
n.s.c
58f (52)g
HN
O
a
b
c
d
The amino esters were of (L)-configuration; Isolated yields; n.p. = not performed, n.s. = not successfull; Mixture
of diastereoisomers (d.r. 57:43) determined by H NMR; The second step was performed for 2 hours only;
9
1
e
f
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
Conditions: HCl.H-Phe-OMe (2 equiv.), CDI (1 equiv.) and K2CO3 (3 equiv.) were milled in a vibratory ball-mill
(VBM) at 30 Hz for 2 hours; g Yield is given for 6 h reaction in the VBM.
8
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Synthesis of 3-substituted alkoxycarbonyl hydantoins from dipeptides (Method B). Several
TFA salts of dipeptide methyl esters 3 were synthesized following usual procedures in
solution.50 Then, they were reacted with CDI in a planetary ball-mill (PBM) in neat
conditions without base. As described above, the reaction consisted in the nucleophilic attack
of the free N-terminal moiety of the peptides, on the CDI activated carboxylic acid group, to
afford activated 1H-imidazole-carboxamido species 4 that cyclized directly into the
hydantoins. At this stage, we wondered the intermediate of the reaction was either the 1H-
imidazolyl carboxamido derivative 4 (Table 3) or the corresponding isocyanate, generated in
similar procedures in solution.51 Indeed, mechanochemistry is known to induce in some cases,
different reactivities than in the corresponding reactions in solution. By in-situ Raman
spectroscopy, it was recently demonstrated that the mechanochemical reaction between
9
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
anilines
and
bis(benzotriazolyl)methanethione
afforded
the
aryl
N-
thiocarbamoylbenzotriazoles that could be isolated, species that decompose instantly into
isocyanates in solution synthesis.32 By analogy to the benzotriazole intermediates, we
assumed that the reaction went through the formation of intermediate 4. Once the 1H-
imidazole-carboxamido intermediate 4 formed, the intramolecular nucleophilic attack of the
amide peptide bond on the C-activated imidazolyl carboxamide led to intramolecular
cyclization reaction to produce unknown hydantoins 5 (Table 3).
Table 3. Preparation of 5-substituted-3-(alkoxycarbonyl)alkyl-hydantoins from
dipeptides.
Entry
Dipeptide methyl ester
TFA. H-Phe-Leu-OMe
Product
Yield (%)a
82 (76)b
51
52
53
54
55
56
57
58
59
60
O
O
OMe
N
1
3a
5a
HN
O
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
2
3
4
O
O
OMe
5
6
7
8
70 (75) c
N
2
TFA. H-Phe-Val-OMe
HCl. H-Phe-Ala-OMe
3b
3c
5b
HN
HN
HN
O
9
O
O
OMe
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
57 (96)d
N
O
3
4
5
6
5c
5d
5e
5f
CH3
O
O
OMe
BzlO
N
O
HCl. H-Asp(OBzl)-Met-OMe 3d
76
O
SMe
O
O
OMe
78 (62)d
N
TFA. H-Val-Ala-OMe
3e
3f
HN
CH3
O
O
O
NH2
CH3
29e,f
N
TFA. H-Phe-Ala-NH2
HN
O
a
b
c
d
Isolated yields; Yield after 1 hour milling; Yield is given for 6 h reaction in the PBM;
Yield is given for synthesis in solution; e 1H NMR yield; Full conversion by LC/MS analyses
f
for synthesis in solution.
The corresponding hydantoins were readily obtained in good yields under non-
optimized conditions (Scheme 1). The only by-products of the reaction identified was the
symmetrical urea of the dipeptides. Indeed, in the first trial, consisting in the milling of
TFA.H-Phe-Leu-OMe with two equivalents of CDI at 450 rpm for two hours, the hydantoin
5a was obtained in 82% yield (entry 1). NMR of the crude showed the presence of the
dipeptide urea in (8%) compared to the desired compound. A shorter time of one-hour milling
decreased the yield of 5a to 76% (entry 1), while no improvement was observed when
extending the milling time to 6 h (entry 2) for compound 5b. The reactions were performed
for two hours using dipeptide methyl esters 3b-e or the amide 3f (entries 2-6). It could be
noticed that cyclization of the postulated intermediates 4 occurred without the need of a base,
in contrast with solid-phase synthesis.45 Indeed, when prepared in solution, the intermediate
4c proved to be very unstable and difficult to isolate, undergoing fast cyclization into
hydantoin 5c. Based on our previous findings,29 we excluded an autocatalyzed/base
10
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
regenerating system, promoting the cyclization, despite the presence of one equivalent of
imidazole, generated in the mixture after the first step. Indeed, the strong activation provided
by mechanochemistry allowed the direct reaction of a non-nucleophilic dipeptide (HX salt) 3
with CDI (without the need of a base to generate in situ a free amine). It is proposed that two
sequential acid-base reactions were the driving force of the reaction, leading to intermediates
A and postulated B, each having the distal nitrogen of the imidazole nucleus activated by
protonation (Scheme 2).
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
Scheme 2. Proposed mechanism to hydantoins 5.
Mechanochemistry allowed the preparation of hydantoins 5 in slightly shorter reaction times
(2 h) compared to solution-based protocols (4 h under stirring), and with no need to further
activate the reactants. Generally, the yields were higher under mechanochemistry and the
purification of the crude easier. Moreover, the reaction was versatile, as dipeptides with
various side chains and C-terminal functions (Table 3, 3f, entry 6) were transformed into
hydantoins. Product 5f was obtained in a 29% NMR yield, but we did not success in this
purification from the imidazole (entry 6). IR experiments confirmed hydantoins 5 had been
obtained, instead of dipeptide isocyanates, which can be prepared from phosgene or
triphosgene in solution.51 The typical absorbance band at 2270 cm-1 was not detectable in the
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
1
2
3
4
5
6
crude, confirming the formation of the desired hydantoins, which is in contrast with previous
reports reporting formation of stable isocyanates in solution.
7
8
9
Method B was also applied to the preparation of compound 2e, from TFA. H-Phe-Phe-
OMe, for sake of comparison with the solution procedure usually carried out in harsh
conditions (triphosgene and pyridine under reflux for 12 h).46 By mechanochemistry, the
cyclization according to Method B was not possible, with or without a base, and by modifying
the milling parameters (e.g. extending the reaction time or increasing the number of milling
balls). It is acknowledged that new compounds or novel reactivities can be accessed using
mechanochemistry, because different energetic (and mechanistic) pathways are involved
compared to the synthesis in solution. In this particular case, mechanochemistry failed where
solution chemistry was successful. As a consequence, the preparation of hydantoin 2e
according to our initial approach (Method A) remained the only new and alternative route to
this compound by mechanochemistry.
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
Overall, our procedure presented a number of advantages also over the described
solid-phase synthesis: 1) ball-milling allowed a solvent-free reaction that avoids the use of
toxic DMF; 2) No extra base was required as the hydantoins were readily obtained by the
simple mechanochemical reaction between dipeptides and CDI; 3) The postulated
intermediates 4 did not require any activation by extra reagents, 4) Only two CDI equivalents
were required, which is much less than in solution reaction;44,45 and finally 5) ball-milling
provides a cheaper alternative and possible scale-up of the reaction compared to solid-phase
synthesis, which was the only reported pathway for the preparation of the desired hydantoins
from dipeptides. These five points support the use of mechanochemistry to prepare
hydantoins with less waste production, for a more sustainable and environmental green
chemistry.
Conclusions
We present in this piece of work, two methodologies for the preparation of new structures of
5-substituted-3-(tert-butoxycarbonyl)alkyl-hydantoins, belonging to a class of biologically
active molecules, by mechanochemistry. In the first part, we have described a novel
procedure in which unsymmetrical ureas prepared from amino esters are cyclized into the
corresponding hydantoins (Method A). In the second part, we present an improved and a
more environmental-friendly procedure for the synthesis of hydantoins by intramolecular
cyclization of dipeptides (Method B). The key reagent of these synthetic methods is 1,1’-
12
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
carbonyldiimidazole (CDI), which enables the activation of the amino functionality of
dipeptides and amino acid derivatives. The syntheses require no or few optimization, allow
the use of various substrates, afford the new compounds in good yields, and are carried out
following a more sustainable synthetic route brought about by the ball-milling technology.
Moreover, compared to the previously reported methods in solution, both methodologies
display higher atom and solvent economy, also overcoming the N-1/N-3 regioselectivity
problems usually encountered for alkylation reactions of hydantoins.16 From a more general
perspective, this work contributes to advance an area recently termed as medicinal
mechanochemistry,52 with the emergence and the development of mechanochemical
techniques for the preparation of API,48,53,35 opening new trends and perspectives for the
pharmaceutical industry, in « thinking chemistry differently ».
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
Acknowledgements
L.K. is grateful to the Ministère de l’Education Nationale, de l’Enseignement Supérieure et de
la Recherche (MENR) for the Ph.D. grant; L.G., E.C., F.L. and J.M. acknowledge also the
support from Centre National pour la Recherche Scientifique (CNRS) and ENSCM; I.H. is
supported by the Croatian Science Foundation under project number UIP-2014-09-4744;
R.M.F., J.M.C. and J.S.S. gratefully thank the Agence Nationale de la Recherche for financial
support (ANR JCJC: ANR-12-JS07-0008-01) and the support from CNRS and ENSCM.
Experimental section
General Remarks
All reagents were commercially available and used without any further purification. L-a-
amino esters were used. TFA salts of dipeptide methyl esters were synthesized following
usual procedures in solution.50 NMR spectra were recorded at room temperature with the
1
appropriate deuterated solvent (CD3CN or d6-DMSO). Chemical shifts (δ) of H NMR and
13C NMR spectra are reported in ppm relative to residual solvent signals (CHCl3 in CDCl3: δ
= 7.27 ppm for 1H and CDCl3: δ = 77.04 ppm for 13C NMR); J values are given in Hz. 1H and
13C NMR spectra were registered at 300 MHz, and 400 MHz. HRMS measurements were
performed on a TOF mass analyser. Melting points were measured on a Büchi Melting Point
510 apparatus (or M-560 for compound 5c) and are uncorrected. Infrared spectra were
recorded on a FT-IR spectrometer equipped with high pressure diamond cell. Optical rotation
for compounds 2a-e and 5a-e were measured in CHCl3 at l =589 nm (Na lamp). Analytical
high performance liquid chromatography (HPLC) was performed with a variable wavelength
diode detector using a CHROMOLITH RP18 column (50 x 4.6 mm), flow 5 mL/min, linear
gradient CH3CN in water 0-100% (+ 0.1% TFA) in 4.5 min. LC-MS analysis were performed
with HPLC, column Onyx C18, (25 x 4.6 mm), flow 3 mL/min linear gradient CH3CN in
water 0-100% (+ 0.1% HCO2H) in 2.5 min. The ball-milling experiments were performed in a
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
3
4
5
vibrational ball using 5 mL mill steel jar (2 stainless steel balls, 5 mm Ø), and in a planetary
mill, 12 mL steel jar (25 or 50 stainless steel balls, 5 mm Ø).
6
7
8
9
General procedure for the synthesis of 5-substituted-3-(tert-butoxycarbonyl)alkyl-
hydantoins (method A). Conditions in a Planetary Ball-Mill (PBM): (Compounds 2a-d): the
amino acid methyl ester (1 equiv.) and CDI (1.3 equiv.) were added to a 12 mL stainless steel
milling jar with 50 stainless steel milling balls (5 mm diameter). The reactants were milled for
40 minutes at 450 rpm. The amino acid tert-butyl ester (1.6 equiv.) and K2CO3 (3.6 equiv.)
were added to the jar and the reaction mixture was milled for 4 hours at 450 rpm. Conditions
in a Vibratory Ball-Mill (VBM): (Compound 2e) 5 mL stainless steel milling jar with 2
stainless steel milling balls (5 mm diameter) were used at 30 Hz for the specified time (Table
1). Distilled water was added to the jar and the desired compounds precipitated. They were
recovered either by filtration (2a,d), or by extraction of the aqueous layer with ethyl acetate
(2b,c). The organic layer was washed three times with 10% aq. citric acid and brine, dried
over anhydrous MgSO4 and concentrated in vacuo. The crudes compounds 2a-c were further
purified by column chromatography (linear gradient of EtOAc in cyclohexane from 0-80%).
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
(S)-tert-butyl 2-((S)-4-benzyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoate 2a (Table
2, entry 1). The reaction scale was 0.83 mmol; (188.3 mg, 63% yield). White solid, m.p. 160-
1
28
162°C, [a]D – 8.77 (c = 5.2, CHCl3); H NMR (300 MHz, CDCl3) d (ppm): 7.34-7.19 (m,
5H), 5.90 (s, 1H), 4.56 (dd, J = 11.5 Hz, J = 4.4 Hz, 1H), 4.28 (dd, J = 8.0 Hz, J = 3.3 Hz,
1H), 3.28 (dd, J = 13.9 Hz, J = 3.6 Hz, 1H), 2.90-2.83 (m, 1H), 2.16-2.04 (m, 1H), 1.77-1.68
13
(m, 1H), 1.44 (s, 9H), 0.84 (d, J = 6.6 Hz, 6H); C{1H} NMR (300 MHz, CDCl3) d (ppm):
172.7, 168.6 ,156.3, 135.5, 129.4, 129.1, 127.6, 82.5, 58.3, 52.0, 38.3, 36.8, 28.1, 25.0, 23.3,
21.2; MS ESI-(+): m/z 361 [M+H]+, 337, 305, 259; HRMS ESI-(+): calcd. for C20H28N2O4
[M+H]+ 361.2127, found 361.2127.
(S)-tert-butyl 2-((S)-4-isopropyl-2,5-dioxoimidazolidin-1-yl)propanoate 2b (Table 2,
entry 2). The reaction scale was 1.49 mmol; (175.2 mg, 43% yield). Mixture of
1
28
diastereoisomers (maj.:min. 57:43). Colourless oil, [a]D + 0.40 (c = 2.0, CHCl3); H NMR
(300 MHz, CDCl3) d (ppm): 6.57-6.55 (m, 1H), 4.66-4.60 (m, 1H, maj. and min.), 3.93-3.91
(m, 1H, maj. and min.), 2.25-2.21 (m, 1H, maj. and min.), 1.54 (d, J = 7.3 Hz, 3H, maj.), 1.52
(d, J = 7.3 Hz, 3H, min.), 1.43 (s, 1H, maj.), 1.42 (s, 1H, min.), 1.05 (d, J = 7.0 Hz, 3H, maj.),
13
1.04 (d, J = 7.0 Hz, 3H, min.), 0.95-0.92 (m, 3H, maj. and min.); C{1H} NMR (300 MHz,
CDCl3) d (ppm): maj.: 173.1, 168.7, 157.8, 82.6, 62.6, 48.9, 30.6, 28.2, 19.2, 16.4, 15.1;
14
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
min.: 173.1, 168.7, 157.7, 82.6, 62.7, 48.9, 30.6, 28.2, 19.1, 16.3, 15.1; MS ESI-(+): m/z 271
[M+H]+, 247, 215, 197, 169; HRMS ESI-(+): calcd. for C13H22N2O4 [M+Na]+ 293.1477,
found 293.1474.
9
(S)-tert-butyl 2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-4-(methylthio)butanoate 2c
(Table 2, entry 3). The reaction scale was 0.86 mmol; (161.9 mg, 60% yield) Waxy white
solid, m.p. 83-85°C, [a]D28 –8.82 (c = 4.2, CHCl3); 1H NMR (300 MHz, CDCl3) d (ppm): 6.21
(s, 1H), 4.69 (t, J = 7.3 Hz, 1H), 2.54-2.36 (m, 4H), 2.08 (s, 3H), 1.45, 1.44 and 1.43 (s x 3,
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
13
15H, 2 x CH3 and t-Bu); C{1H} NMR (300 MHz, CDCl3) d (ppm): 177.0, 167.8, 156.0,
82.7, 58.8, 52.2, 31.1, 28.1, 28.0, 25.1, 15.5; MS ESI-(+): m/z 317 [M+H]+, 261, 243, 215,
167; HRMS ESI-(+): calcd. for C14H24N2O4S [M+H]+ 317.1535, found 317.1533.
(S)-tert-butyl
3-(4-(4-tert-butoxybenzyl)-2,5-dioxoimidazolidin-1-yl)propanoate
2d
(Table 2, entry 4). The reaction scale was 0.83 mmol; (286 mg, 88% yield). White solid,
m.p. 129-131°C, [a]D28 – 8.26 (c = 5.4, CHCl3); 1H NMR (300 MHz, CDCl3) d (ppm): 7.08 (d,
J = 8.3 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 5.45 (s, 1H), 4.21-4.18 (m, 1H), 3.69 (t, J = 6.5 Hz,
2H), 3.21 (dd, 13.9 Hz, J = 2.7 Hz, 1H), 2.83-2.76 (m, 1H), 2.46 (t, J = 7.8 Hz, 2H), 1.43 (s,
13
9H), 1.33 (s, 9H); C{1H} NMR (300 MHz, CDCl3) d (ppm): 173.1, 170.1, 156.9, 155.2,
130.1, 124.8, 81.4, 79.0, 58.7, 37.7, 34.8, 33.8, 29.2, 28.4; MS ESI-(+): m/z 391 [M+H]+, 335,
279, 261; HRMS ESI-(+): calcd. for C21H30N2O5 [M+H]+ 391.2233, found 391.2231.
(S)-methyl 2-((S)-4-benzyl-2,5-dioxoimidazolidin-1-yl)-3-phenylpropanoate 2e (Table 2,
entry 5). HCl.H-Phe-OMe (0.46 mmol, 2 equiv.), CDI (1 equiv.) and K2CO3 (3 equiv.) were
added to a 5 mL stainless steel milling jar with two stainless steel milling balls. The reactants
were milled in a vibratory ball-mill at 30 Hz for 2 hours. Water was then added to the reaction
mixture and the desired compound 2e precipitated. The precipitate was recovered by filtration
(47.1 mg, 58% yield). CAS [1634670-17-9].46 White solid, m.p. 142-144°C, [a]D28 – 9.41 (c =
1
5.1, CHCl3); H NMR (300 MHz, CDCl3) d (ppm): 7.31-7.09 (m, 10H), 5.19 (s, 1H), 4.06
(dd, J = 10.7 Hz, J = 3.4 Hz, 1H), 3.79 (s, 3H), 3.50-3.46 (m, 1H), 3.06 (dd, J = 13.9 Hz, J =
3.11 Hz, 3H), 2.14 (dd, J = 13.8 Hz, J = 10.7 Hz, 1H); 13C{1H} NMR (300 MHz, CDCl3) d
(ppm): 172.4, 169.1, 155.7, 136.6, 135.8, 129.3, 129.2, 129.1, 128.8, 127.6, 127.2, 58.3, 53.3,
53.1, 38.4, 34.3; MS ESI-(+): m/z 416 [M+Na+ACN]+, 375 [M+Na]+, 353 [M+H]+, 322, 293.
General procedure for the synthesis of 5-substituted-3-(methoxycarbonyl)alkyl-
hydantoins (method B) (Compounds 5a-e). Dipeptide 3 (1 equiv.) and CDI (2 equiv.) were
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
1
2
3
4
5
6
7
8
9
added to a 12 mL stainless steel milling jar with 25 stainless steel milling balls (5 mm
diameter). The reactants were milled for 2 hours at 450 rpm. Dichloromethane (2 mL) was
added to the reaction mixture and the organic layer was washed three times with 10% aq.
citric acid and brine, dried over anhydrous MgSO4 and concentrated in vacuo.
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
General procedure for the synthesis of 5-substituted-3-(methoxycarbonyl)alkyl-
hydantoins (method in solution) (Compounds 5c, 5e and 5f). A solution of dipeptide TFA
salts 3c, 3e and 3f (100 mg, 1 equiv.) in CH2Cl2 (3 mL) with DIPEA (1 equiv.) was added
dropwise into a solution of CDI (1.2 equiv.) in CH2Cl2 (3 mL) at 0 °C. After complete
addition (30 min), the reaction was stirred for 3 h at room temperature. Reaction work-up was
performed as previously described for milling conditions.
(S)-methyl 2-((S)-4-benzyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoate 5a (table 3,
entry 1). The reaction scale was 0.62 mmol; (162.5 mg, 82% yield). The crude was purified
by column chromatography (linear gradient of EtOAc in cyclohexane from 0-20%). Sticky
1
28
colouress oil, [a]D –1.45 (c = 5.6, CHCl3); H NMR (300 MHz, CDCl3) d (ppm): 7.36-7.20
(m, 5H), 5.32 (s, 1H), 4.69 (dd, J = 11.6 Hz, J = 4.3 Hz, 1H), 4.32 (ddd, J = 8.6 Hz, J = 3.8
Hz, J = 1.3 Hz, 1H), 3.73 (s, 3H), 3.29 (dd, J = 14.0 Hz, J = 3.8 Hz, 1H), 2.88 (dd, J = 14.0
Hz, J = 8.7 Hz, 1H), 2.22-2.13 (m, 1H), 1.84-1.75 (m, 1H), 1.17-1.10 (m, 1H), 0.86 (d, J = 6.5
Hz, 6H); 13C{1H} NMR (300 MHz, CDCl3) d (ppm): 171.9, 169.3, 155.4, 134.4, 128.7,
128.3, 126.8, 57.5, 52.1, 50.4, 37.2, 35.9, 24.1, 22.5, 20.4; MS ESI-(+): m/z 319 [M+H]+, 287,
259; HRMS ESI-(+): calcd. for C17H22N2O4 [M+H]+ 319.1658, found 319.1661.
(R)-methyl 2-((S)-4-benzyl-2,5-dioxoimidazolidin-1-yl)-3-methylbutanoate 5b (Table 3,
entry 2). The reaction scale was 0.25 mmol; (53.3 mg, 70% yield). The product was
28
recovered by precipitation from 10% aq. citric acid. Colourless oil, [a]D + 1.05 (c = 2.0,
1
CHCl3); H NMR (300 MHz, CDCl3) d (ppm): 7.34-7.20 (m, 5H), 5.68 (s, 1H), 4.33 (d, J =
3.0 Hz, 1H), 4.30 (d, J = 6.0 Hz, 1H), 3.70 (s, 3H), 3.29 (dd, J = 14.0 Hz, J = 3.8 Hz, 1H),
2.86 (dd, J = 14.0 Hz, J = 8.6 Hz, 1H), 2.65-2.57 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H), 0.72 (d, J
= 6.8 Hz, 3H); 13C{1H} NMR (300 MHz, CDCl3) d (ppm): 172.9, 169.3, 156.7, 135.4, 129.7,
129.3, 127.8, 58.6, 58.4, 52.8, 38.3, 28.4, 21.1, 19.5; MS ESI-(+): m/z 305 [M+H]+, 273, 245;
HRMS ESI-(+): calcd. for C16H20N2O4 [M+H]+ 305.1501, found 305.1502.
(S)-methyl 2-((S)-4-benzyl-2,5-dioxoimidazolidin-1-yl)propanoate 5c (Table 3, entry 3).
Dipeptide 3c was used as a hydrochloric salt. The reaction scale was 0.87 mmol; (137.0 mg,
16
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
1
2
57% yield). White solid, m.p. 96-97.7°C, [a]D24 – 149 (c = 1.53, CHCl3); 1H NMR (300 MHz,
CDCl3) d (ppm): 7.31-7.18 (m, 5H), 6.07 (s, 1H), 4.68 (q, J = 7.2 Hz, 1H), 4.30-4.27 (m, 1H),
3.72 (s, 1H), 3.26 (dd, J = 13.9 Hz, J = 3.7 Hz, 1H), 2.92-2.87 (m, 1H), 1.46 (d, J = 7.3 Hz,
3
4
5
6
7
8
9
13
3H); C{1H} NMR (300 MHz, CDCl3) d (ppm): 172.5, 169.9, 156.5, 135.0, 129.5, 128.8,
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
127.4, 58.3, 52.8, 47.8, 37.8, 14.5; MS ESI-(+): m/z 277 [M+H]+, 245, 217; HRMS ESI-(+):
calcd. for C14H17N2O4 [M+H]+ 277.1188, found 277.1189.
(S)-methyl
2-((S)-4-(2-(benzyloxy)-2-oxoethyl)-2,5-dioxoimidazolidin-1-yl)-4-
(methylthio)butanoate 5d (Table 3, entry 4). Dipeptide 3d was as a hydrochloric salt. The
28
reaction scale was 0.25 mmol; (74.5 mg, 76% yield). Sticky colourless oil, [a]D – 3.60 (c =
1
5.2, CHCl3); H NMR (300 MHz, CDCl3) d (ppm): 7.45-7.17 (m, 5H), 6.50 (s, 1H), 5.15 (s,
2H), 4.89-4.85 (m, 1H), 4.40-4.37 (m, 1H), 3.72 (s,1H), 3.08-3.02 (m, 1H), 2.75-2.44 (m,
13
5H), 2.06 (s, 3H); C{1H} NMR (300 MHz, CDCl3) d (ppm): 172.5, 170.4, 169.5, 156.5,
135.4, 129.0, 128.9, 128.7, 67.6, 53.7, 53.2, 51.9, 36.7, 31.1, 27.6, 15.6; MS ESI-(+): m/z 395
[M+H]+, 363, 257. HRMS ESI-(+): calcd. for C16H20N2O4 [M+H]+ 305.1501, found
305.1502.
(S)-methyl 2-((S)-4-isopropyl-2,5-dioxoimidazolidin-1-yl)propanoate 5e (Table 3, entry
5). The reaction scale was 0.32 mmol; (56.9 mg, 78% yield). The crude was recovered either
by column filtration on silica gel (EtOAc 100%) or precipitated by Me-THF. White solid,
m.p. 160-162°C, [a]D28 + 2.40 (c = 5.4, CHCl3); 1H NMR (300 MHz, CDCl3) d (ppm): 5.82 (s,
1H), 4.75 (q, J = 7.3 Hz, 1H), 3.97 (dd, J = 1.2 Hz, J = 3.6 Hz, 1H), 3.74 (s, 1H), 2.30-2.22
(m, 1H), 1.61 (d, J = 7.3 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H); 13C{1H}
NMR (300 MHz, CDCl3) d (ppm): 172.9, 170.2, 157.1, 62.5, 53.0, 48.2, 30.6, 19.2, 16.1,
15.1; MS ESI-(+): m/z 229 [M+H]+, 197, 169; IR (cm-1) 3299, 2964, 1684, 1432, 1225, 1085;
HRMS ESI-(+): calcd. for C10H16N2O4 [M+H]+ 229.1188, found 229.1188.
(S)-2-((S)-4-benzyl-2,5-dioxoimidazolidin-1-yl)propanamide 5f (Table 3, entry 6) . Only
the peaks corresponding to hydantoin are described. The reaction scale was 0.29 mmol (22.1
mg, 29% 1H NMR yield). White solid. 1H NMR (300 MHz, DMSO-d6) d (ppm): 8.32 (s, 1H),
7.26-7.07 (m, 5H), 4.30 (t, J = 4.4 Hz, 1H), 4.13 (q, J = 7.4 Hz, 1H), 2.95 (d, J = 4.7 Hz, 2H),
1.08 (d, J = 7.3 Hz, 3H); 13C{1H} NMR (300 MHz, DMSO-d6) d (ppm): 173.0, 170.6, 156.1,
129.9, 128.1, 126.8, 56.7, 48.2, 36.4, 14.0; MS ESI-(+): m/z 262 [M+H]+, 245, 217; HRMS
ESI-(+): calcd. for C13H15N3O3 [M+H]+ 262.1192, found 262.1194.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
1
2
3
4
Supporting Information
5
6
7
1H and 13C NMR spectra for compounds 2a-e and 5a-e.
8
9
References
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
1.
2.
3.
Meusel, M.; Gutschow, M. Org. Prep. Proced. Int. 2004, 36, 391--443.
Xiao, X.-y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968-6973.
Dylag, T.; Zygmunt, M.; Maciag, D.; Handzlik, J.; Bednarski, M.; Filipek, B.; Kiec-
Kononowicz, K. Eur. J. Med. Chem. 2004, 39, 1013-1027.
Handzlik, J.; Bajda, M.; Zygmunt, M.; Maciag, D.; Dybala, M.; Bednarski, M.; Filipek, B.;
Malawska, B.; Kiec-Kononowicz, K. Bioorg. Med. Chem. 2012, 20, 2290-2303.
Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.; Klingler, O.; Koenig, W.; Wehner, V.; Zoller,
G. J. Med. Chem. 2001, 44, 1158-1176.
Buntain, I. G.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc., Perkin Trans. 1 1988, 3175-82.
Howie, C.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc., Perkin Trans. 1 1990, 3129-35.
Abo-Dya, N. E.; Biswas, S.; Basak, A.; Avan, I.; Alamry, K. A.; Katritzky, A. R. J. Org.
Chem. 2013, 78, 3541-3552.
Verhelst, S. H. L.; Witte, M. D.; Arastu-Kapur, S.; Fonovic, M.; Bogyo, M. ChemBioChem
2006, 7, 943-950.
Savrda, J.; Chertanova, L.; Wakselman, M. Tetrahedron 1994, 50, 5309-22.
Danger, G.; Boiteau, L.; Cottet, H.; Pascal, R. J. Am. Chem. Soc. 2006, 128, 7412-7413.
Ohmoto, K.; Yamamoto, T.; Okuma, M.; Horiuchi, T.; Imanishi, H.; Odagaki, Y.; Kawabata,
K.; Sekioka, T.; Hirota, Y.; Matsuoka, S.; Nakai, H.; Toda, M.; Cheronis, J. C.; Spruce, L. W.;
Gyorkos, A.; Wieczorek, M. J. Med. Chem. 2001, 44, 1268-1285.
Wehner, V.; Blum, H.; Kurz, M.; Stilz, H. U. Synthesis 2002, 2023-2036.
Da Settimo, F.; Primofiore, G.; La Motta, C.; Salerno, S.; Novellino, E.; Greco, G.; Lavecchia,
A.; Laneri, S.; Boldrini, E. Bioorg. Med. Chem. 2004, 13, 491-499.
Takeuchi, Y.; Kirihara, K.; Shibata, N.; Kirk, K. L. Chem. Commun. (Cambridge) 2000, 785-
786.
Tzvetkov, N. T.; Euler, H.; Mueller, C. E. Beilstein J. Org. Chem. 2012, 8, 1584-1593, No.
181.
Imanzadeh, G.; Rezaee-Gatar, S. Arkivoc 2015, 5, 121-133.
Handzlik, J.; Maciag, D.; Kubacka, M.; Mogilski, S.; Filipek, B.; Stadnicka, K.; Kiec-
Kononowicz, K. Bioorg. Med. Chem. 2008, 16, 5982-5998.
Abdulrahman, L. Q.; Mohammed, M. A.; Qasim, M. L. Int. Res. J. Pharm. 2014, 5, 155-158,
4 pp.
Ozturk, S.; Yildirim, A.; Cetin, M. Appl. Surf. Sci. 2013, 265, 895-903.
Adib, M.; Hosein Sayahi, M.; Behnam, B.; Sheibani, E. Monatsh. Chem. 2006, 137, 191-196.
Marandi, G.; Maghsoodlou, M. T.; Hazeri, N.; Heydari, R.; Habibi-Khorassani, S. M.;
Torbati, N. A.; Sajadikhah, S. S.; Saravani, D.; Rakhshanipour, M.; Gholamipour, S.;
Rostami-Charati, F.; Skelton, B. W.; Makha, M.; Zare, Z.; Lashkari, M. Heteroat. Chem.
2011, 22, 630-639.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Liu, H.; Yang, Z.; Pan, Z. Org. Lett. 2014, 16, 5902-5905.
Chaubet, G.; Cazals, G.; Lebrun, A.; Martinez, J.; Parrot, I. Synlett 2014, 25, 574-578.
Jenhi, A.; Lavergne, J. P.; Rolland, M.; Martinez, J.; Hasnaoui, A. Synth. Commun. 2001, 31,
1707-1714.
Wehner, V.; Stilz, H.-U.; Osipov, S. N.; Golubev, A. S.; Sieler, J.; Burger, K. Tetrahedron
2004, 60, 4295-4302.
Konnert, L.; Gauliard, A.; Lamaty, F.; Martinez, J.; Colacino, E. ACS Sustainable Chem. Eng.
2013, 1, 1186-1191.
Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E. J. Org. Chem. 2014, 79, 4008-4017.
Lanzillotto, M.; Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E. ACS Sustainable Chem.
Eng. 2015, Ahead of Print.
26.
27.
28.
29.
18
ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
30.
Konnert, L.; Reneaud, B.; de Figueiredo, R. M.; Campagne, J.-M.; Lamaty, F.; Martinez, J.;
Colacino, E. J. Org. Chem. 2014, 79, 10132-10142.
Konnert, L.; Dimassi, M.; Gonnet, L.; Lamaty, F.; Martinez, J.; Colacino, E. RSC Adv. 2016,
6, 36978-36986.
Strukil, V.; Gracin, D.; Magdysyuk, O. V.; Dinnebier, R. E.; Friscic, T. Angew. Chem., Int.
Ed. 2015, 54, 8440-8443.
Strukil, V.; Igrc, M. D.; Eckert-Maksic, M.; Friscic, T. Chem. - Eur. J. 2012, 18, 8464-8473,
S8464/1-S8464/42.
Strukil, V.; Igrc, M. D.; Fabian, L.; Eckert-Maksic, M.; Childs, S. L.; Reid, D. G.; Duer, M. J.;
Halasz, I.; Mottillo, C.; Friscic, T. Green Chem. 2012, 14, 2462-2473.
Tan, D.; Strukil, V.; Mottillo, C.; Friscic, T. Chem. Commun. 2014, 50, 5248-5250.
Kokotos, C. G.; Limnios, D.; Triggidou, D.; Trifonidou, M.; Kokotos, G. Org. Biomol. Chem.
2011, 9, 3386-3395.
31.
32.
33.
34.
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
35.
36.
37.
38.
39.
Vega-Pecaloza, A.; Sa nchez-Antonio, O.; vila-Ortiz, C. G.; Escudero-Casao, M.; Juaristi, E.
Asian J. Org. Chem. 2014, 3, 487-496.
Halland, N.; Broenstrup, M.; Czech, J.; Czechtizky, W.; Evers, A.; Follmann, M.; Kohlmann,
M.; Schiell, M.; Kurz, M.; Schreuder, H. A.; Kallus, C. J. Med. Chem. 2015, 58, 4839-4844.
Maresca, K. P.; Hillier, S. M.; Femia, F. J.; Keith, D.; Barone, C.; Joyal, J. L.; Zimmerman, C.
N.; Kozikowski, A. P.; Barrett, J. A.; Eckelman, W. C.; Babich, J. W. J. Med. Chem. 2009, 52,
347-357.
40.
Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R. S.; Batey, R. A. Tetrahedron
2005, 61, 7153-7175.
41.
42.
43.
44.
Granacher, C.; Landolt, H. Helv. Chim. Acta 1927, 10, 799-815.
Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40, 2493-2496.
Henkel, B.; Sanofi-Aventis Deutschland GmbH, Germany . 2014; p. 31pp.
Nefzi, A.; Ostresch, J. M.; Giulianotti, M.; Houghten, R. A. Tetrahedron Lett. 1998, 39, 8199-
8202.
Vazquez, J.; Royo, M.; Albericio, F. Lett. Org. Chem. 2004, 1, 224-226.
Wang, G.; Wang, Y.; Wang, L.; Han, L.; Hou, X.; Fu, H.; Fang, H. Bioorg. Med. Chem. 2015,
23, 7359-7365.
45.
46.
47.
48.
49.
Do, J.-L.; Mottillo, C.; Tan, D.; S
2479.
̌trukil, V.; Friščić, T. J. Am. Chem. Soc. 2015, 137, 2476-
Konnert, L.; Dimassi, M.; Gonnet, L.; Lamaty, F.; Martinez, J.; Colacino, E. RSC Advances
2016, 6, 36978–36986.
Konnert, L.; Gauliard, A.; Lamaty, F.; Martinez, J.; Colacino, E. ACS Sustainable Chem. Eng.
2013, 1, 1186−1191.
Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-8.
Nowick, J. S.; Holmes, D. L.; Noronha, G.; Smith, E. M.; Nguyen, T. M.; Huang, S.-L. J.
Org. Chem. 1996, 61, 3929-3934.
Tan, D.; Loots, L.; Friscic, T. Chem. Commun. 2016, 52, 7760-7781.
Konnert, L.; Reneaud, B.; Marcia de Figueiredo, R.; Campagne, J.-M.; Lamaty, F.; Martinez,
J.; Colacino, E. J. Org. Chem. 2014, 79, 10132−10142.
50.
51.
52.
53.
19
ACS Paragon Plus Environment