Catalytic Diastereo- and Enantioselective Synthesis of 2-Imidazolinones

Article abstract of DOI:10.1021/acs.orglett.9b01244

Chiral cyclic ureas (2-imidazolinones) were prepared by the reaction of nitrones and isocyanoacetate esters using a multicatalytic system that combines a bifunctional Br?nsted base-squaramide organocatalyst and Ag⁺ as a Lewis acid. The reaction could be achieved with a range of nitrones derived from aryl- and cycloalkylaldehydes with moderate diastereo- and good enantioselectivity. A plausible mechanism involving an initial formal [3 + 3] cycloaddition of the nitrone and isocyanoacetate ester, followed by rearrangement to an aminoisocyanate and cyclization to the imidazolinone, is proposed.

Full text of DOI:10.1021/acs.orglett.9b01244

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Diastereo- and Enantioselective Synthesis of
2‑Imidazolinones
́
Pablo Martínez-Pardo, Gonzalo Blay,* Alba Escriva-Palomo, Amparo Sanz-Marco, Carlos Vila,
́
and Jose R. Pedro*
̀
̀
Departament de Química Organica, Facultat de Química, Universitat de Valencia, C/Dr. Moliner 50, 46100-Burjassot, Spain
S
* Supporting Information
ABSTRACT: Chiral cyclic ureas (2-imidazolinones) were prepared by the reaction of nitrones and isocyanoacetate esters using
a multicatalytic system that combines a bifunctional Brønsted base−squaramide organocatalyst and Ag+ as a Lewis acid. The
reaction could be achieved with a range of nitrones derived from aryl- and cycloalkylaldehydes with moderate diastereo- and
good enantioselectivity. A plausible mechanism involving an initial formal [3 + 3] cycloaddition of the nitrone and
isocyanoacetate ester, followed by rearrangement to an aminoisocyanate and cyclization to the imidazolinone, is proposed.
Scheme 1. Synthesis of Imidazolines and Imidazolinones
from Imine Derivatives
yclic ureas, in particular 2-imidazolinones, are structural
1
Cunits often found in natural products,
as well as
biologically and pharmacologically interesting molecules,
including HIV protease inhibitors,2 5-HT3 receptor and
PX27 receptor antagonists,3 NK1 antagonists,4 and ACE
inhibitor hypertensive drugs.5 Chiral imidazolidin-2-ones have
also been widely utilized as chiral auxiliaries,6 chiral ligands,7
and intermediates in organic synthesis.8 For these reasons,
many methodologies have been developed to generate these
molecules. Examples include the carboxylation of 1,2-
diamines,9 intramolecular amidation reactions,10 intermolecu-
lar diamidation reactions,11 or reactions involving isocya-
nates.12 However, only few procedures allow the enantiose-
lective formation of the 2-imidazolinone ring and a C−C bond
simultaneously.13
In recent years, isocyanoacetate esters have emerged as
formal 1,3-dipoles that can react with different electrophilic
unsaturated functional groups to give five-membered, nitrogen-
containing heterocycles.14 Thus, chiral imidazolines have been
prepared by several authors from isocyano acetates and imines
under different conditions (Scheme 1).15 Within this area, our
group has contributed with the development of a highly
enantioselective synthesis of 2-oxazolines from ketones and
isocyanoacetate esters using a multicatalytic system that
combines a bifunctional squaramide−Brønsted base and silver
as a Lewis acid.16 Wishing to extend the structural diversity of
compounds that can be prepared enantioselectively with this
chemistry, we became interested in studying other nitrogen-
containing electrophiles. Herein we report the reaction of
isocyanoacetates with nitrones, which are typical 1,3-dipoles
used in cycloaddition reactions. The reaction provided chiral 2-
imidazolinones instead of the expected [3 + 3] cycloaddition
products.17
The reaction of nitrone 1a and tert-butyl isocyanoacetate
(2a) was chosen to optimize the reaction conditions (Table 1).
Following our methodology previously developed for the
reaction with ketones, we tested different chiral squaramide
organocatalysts in the presence of silver oxide in tert-butyl
methyl ether as the solvent (Table 1). SQ3 and SQ4, which
are derivatives of dihydro 9-deoxy-9-epi-9-aminoquinine and
2,6-disubstituted anilines, provided the highest enantioselec-
Received: April 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01244
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
attention back to squaramide SQ4. This organocatalyst was
tested in dioxane as the solvent under identical conditions as
those previously used for SQ3 providing compound 3aa as a
1:1 mixture of diastereomers in 78% ee (Table 2, entry 9).
Since dioxane seemed not to be a good solvent for this catalyst,
the reaction was repeated in MTBE under dilute conditions
yielding the expected urea 3aa with fair diastereoselectivity (dr
= 68:32) and high enantioselectivity (88% ee), without
detriment in the yield (Table 1, entry 10). Attempts to
improve the stereoselectivity by changing the reaction
temperature were unsuccessful (Table 1, entries 11 and 12).
Finally, a small increase of diastereo- and enantioselectivity
could be obtained by further dilution of the reaction mixture
(Table 1, entry 13).
Table 1. Screening of Organocatalysts
Given the similar results obtained either with SQ3 in
dioxane (Table 2, entry 3) or with SQ4 in MTBE (Table 2,
entry 13), both reaction condition manifolds were tested with
two nitrones 3b and 3c derived from p-substituted aldehydes
(Scheme 2). The SQ3/dioxane system provided the expected
ureas 3ba and 3ca with similar or lower stereoselectivities to
those obtained with SQ4/MTBE, and in significant lower
yields. Accordingly, the study of the reaction scope was
continued under the optimized conditions for SQ4 in MTBE.
In general, the reaction conditions could be applied to the
addition of tert-butyl isocyanoacetate (2a) with a large range of
N-phenylnitrones derived from substituted benzaldehydes
bearing substituents of different electronic nature in different
positions of the aromatic ring. The chiral 2-imidazolinones
3aa−3ka were obtained with fair to good diastereoselectivity
(62:38 to 78:22) and high enantiomeric excesses (67−94%).
The presence of electron-donating groups (Me, MeO) (3ba,
3ea, 3fa, 3ia) favored higher enantioselectivities than electron-
withdrawing groups (Br, NO2) (3ca, 3da, 3ga, 3ha, 3ja, 3ka)
regardless of the position of these groups on the aromatic ring.
The reaction also worked with the N-phenyl nitrone derived of
the bulky 2-naphthylcarbaldehyde delivering urea 3la with
good yield, good dr, and excellent ee. 2-Pyridine-derived
nitrone 1m reacted with tert-butyl isocyanoacetate to give
compound 3ma in quantitative yield, with good diastereose-
lectivity (dr = 88:12) and excellent enantioselectivity (95%
ee). This result contrasts with those obtained with nitrones
derived from nitrobenzaldehydes, and it is quite surprising
since both the pyridine and the nitrophenyl are electron-poor
rings. Furthermore, the enantiomer of 3ma could be also
obtained with a very good result by using squaramide SQ7,
derived from dihydroquinidine, in place of SQ4. Cycloalkyl-
carbaldehyde-derived nitrones were also suitable substrates for
the reaction.18 Compounds 3na and 3oa, bearing a cyclohexyl
or cyclopropyl substituent, respectively, were obtained with
very high enantiomeric excesses. The effect of the substituent
on the N atom of the nitrone was also tested. N-(4-
Chlorophenyl) imine reacted with tert-butyl isocyanoacetate
to give compound 3pa with good yield but moderate diastereo-
and enantioselectivity. On the other hand, the N-(4-
methoxyphenyl) nitrone provided compound 3qa with good
enantioselectivity (91% ee) but in very low yield (24%),
unfortunately. Finally, we tested the reaction with benzyl (2b)
and methyl (2c) isocyanoacetates, yet neither performed better
than tert-butyl isocyanoacetate. The reaction could be carried
out at 1 mmol scale without noticeable effect on the results
(Scheme 2, footnote c).
b
c
d
entry
SQ
t (d)
yield (%)
trans/cis
eetrans (%)
1
2
3
4
5
6
SQ1
SQ2
SQ3
SQ4
SQ5
SQ6
1
1
1
2
2
7
83
73
75
89
70
43
46:54
48:52
71:29
61:39
55:45
52:48
70
70
84
84
58
83
a
Conditions: 1a (0.13 mmol), 2a (0,17 mmol), SQ (0.013 mmol),
b
Ag2O (0.0063 mmol), TBME (1 mL), room temperature. Isolated
c
yield after column chromatography. Determined by 1H NMR.
d
Determined by HPLC over chiral stationary phases.
tivity for the major trans diastereomer (Table 1, entries 3 and
4).
Further optimization was carried out first with organo-
catalyst SQ3 (Table 2). From the different solvents tested
a
Table 2. Effect of Solvents and Concentration
yield
c
eetrans
e
b
d
entry
SQ
solvent
[1a]
t (d) (%)
trans/cis
(%)
1
2
3
4
5
6
7
8
9
10
SQ3
SQ4
SQ3
SQ3
SQ3
SQ3
SQ3
SQ3
SQ4
SQ4
SQ4
SQ4
SQ4
MTBE
MTBE
dioxane
toluene
Et2O
0.13
0.13
0.13
0.13
0.13
0.13
0.13
0.063
0.063
0.063
0.063
0.063
0.042
1
1
2
2
2
2
2
2
3
2
4
1
4
75
83
70
71
70
60
39
46
60
84
78
60
78
71:29
61:39
71:29
70:30
69:31
65:35
41:59
73:27
50:50
68:32
67:37
66:33
71:29
84/−6
84/−13
90/30
87/3
79/6
79/6
59:12
99/3
EtOAc
DCM
dioxane
dioxane
MTBE
MTBE
MTBE
MTBE
78/21
88/−9
88/−3
88/−2
90/−3
f
11
g
12
13
a
Conditions: 1a (0.13 mmol), 2a (0.17 mmol), SQ (0.013 mmol),
Ag2O (0.0063 mmol), solvent, room temperature. Molar concen-
b
c
tration of 1a. Isolated yield after column chromatography.
d
e
Determined by 1H NMR. Determined by HPLC over chiral
f
g
stationary phases. Reaction carried out at 0 °C. Reaction carried out
at 35 °C
(Table 2, entries 3−7), dioxane allowed the best diastereo-
(trans:cis 71:29) and enantioselectivity (90%) to be obtained.
By performing the reaction under more dilute conditions, the
ee could be raised up to 99%, however with a huge detriment
to yield (Table 2, entry 8). Other attempts to increase the yield
and/or stereoselectivity with SQ3 in dioxane were unsuccessful
(see Supporting Information). Therefore, we turned our
Scheme 3 outlines some synthetic modifications of
compounds 3. Deprotection of the tert-butyl ester can be
B
DOI: 10.1021/acs.orglett.9b01244
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the Reaction of Nitrones 1 and
Isocyanoacetates 2
Scheme 3. Synthetic Modifications and Determination of
the Absolute Stereochemistry of Compounds 3
a
a
a
Reaction conditions: (a) CF3CO2H/CH2Cl2, rt, 5h, 89%; (b) BH3·
SMe2, THF, rt, 24 h, 76%; (c) CAN (3.0 equiv), MeCN/H2O, 0 °C
to rt, 1 h, 75%; (d) CF3CO2H/CH2Cl2, rt, 7 h, 87%; (e) H2SO4
(cat.), MeOH, reflux, 6 h, 89%.
known stereochemistry (Scheme 3). Thus, the N atom in
compound 3qa was deprotected with CAN to give compound
6, which after hydrolysis of the tert-butyl ester with
trifluoroacetic acid yielded acid 7. Finally, Fisher esterification
gave the ester 8, which showed identical spectroscopic features
and optical rotation sign as those described in the literature for
(4R,5S)-8,19 allowing assignment of the stereochemistry of
compound 3qa. The absolute stereochemistry of the remaining
compounds 3 was assigned upon the assumption of a uniform
mechanistic pathway.
Scheme 4 shows a plausible mechanism for the formation of
cyclic ureas 3. Thus, deprotonation of the isocyanoacetate 2 by
the basic bifunctional squaramide assisted by silver would give
the corresponding enolate I that would undergo nucleophilic
addition to the C−N double bond of nitrone 1 to give
Scheme 4. Proposed Catalytic Cycle for the Synthesis of 2-
Imidazolinones
a
Reaction conditions: 1 (0.25 mmol), 2 (0.33 mmol), SQ4 (0.025
b
mmol), Ag2O (0.013 mmol), MTBE (6 mL), rt. Reaction
conditions: 1 (0.13 mmol), 2 (0.17 mmol), SQ3 (0.013 mmol),
c
Ag2O (0.0063 mmol), dioxane (1 mL), rt. Reaction carried out with
d
1 mmol of 1a. Reaction carried out with squaramide SQ7. Yields
after column chromatography, dr determined by 1H NMR, ee
determined by HPLC.
achieved with trifluoroacetic acid to give acid 4 which can be
converted into alcohol 5 after reduction with borane. On the
other hand, the absolute stereochemistry of compounds 3 was
determined by chemical correlation with a compound of
C
DOI: 10.1021/acs.orglett.9b01244
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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intermediate II, followed by intramolecular alkoxide addition
to the isocyanide giving the formal [3 + 3] cycloaddition
product III. This would rearrange to the amino isocyanate IV,
which after amide addition would give the deprotonated
imidazolinone V. Finally, protonation by the catalyst conjugate
acid provides product 3 and releases the catalyst.
In summary, we have developed an unprecedented catalytic
diastereo- and enantioselective synthesis of cyclic ureas (2-
imidazolinones) by reaction of isocyanoacetate esters and
nitrones. The reaction is catalyzed by a bifunctional Brønsted
base−squaramide organocatalyst and Ag+ as a Lewis acid and
provides the chiral trans-2-imidazolinones with good diaster-
eoselectivity and high enantioselectivity in most of the
examples tested, applicable to nitrones derived from aromatic
and heteroaromatic aldehydes as well as nitrones derived from
cycloalkylcarbaldehydes. The reaction most probably involves
the initial formal [3 + 3] cycloaddition of the nitrone and
isocyanoacetate ester, followed by rearrangement to an amino
isocyanate and cyclization to the imidazolinone.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01244.
Experimental procedures, characterization data, NMR
spectra, and HPLC traces (PDF)
(10) (a) Hinds, E. M.; Wolfe, J. P. J. Org. Chem. 2018, 83, 10668−
10676. (b) Rao, W.-H.; Yin, X. S.; Shi, B. F. Org. Lett. 2015, 17,
̈
̃
3758−3761. (c) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K.
J. Am. Chem. Soc. 2005, 127, 14586−14587.
AUTHOR INFORMATION
■
(11) (a) Wu, M.-S.; Fan, T.; Chen, S.-S.; Han, Z.-Y.; Gong, L.-Z.
Org. Lett. 2018, 20, 2485−2489. (b) Song, J.; Zhang, Z.-J.; Chen, S.
S.; Fan, T.; Gong, L.-Z. J. Am. Chem. Soc. 2018, 140, 3177−3180.
(12) (a) Struble, T. J.; Lankswert, H. M.; Pink, M.; Johnston, J. N.
ACS Catal. 2018, 8, 11926−11931. (b) Rajesh, M.; Puri, S.; Kant, R.;
Sridhar Reddy, M. J. Org. Chem. 2017, 82, 5169−5177. (c) Youn, S.
W.; Kim, Y. H. Org. Lett. 2016, 18, 6140−6143. (d) Kondoh, A.;
Terada, M.; Kamata, Y. Org. Lett. 2017, 19, 1682−1685.
Corresponding Authors
*E-mail: gonzalo.blay@uv.es.
*E-mail: jose.r.pedro@uv.es.
ORCID
Gonzalo Blay: 0000-0002-7379-6789
Carlos Vila: 0000-0001-9306-1109
Jose R. Pedro: 0000-0002-6137-866X
(13) Kobayashi, Y.; Yoshida, T.; Uno, T.; Tsukano, C.; Takemoto,
Y. Heterocycles 2017, 95, 980−993.
́
Notes
(14) (a) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.;
Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235−5331. (b) Blay, G.;
Vila, C.; Martínez-Pardo, P.; Pedro, J. R. Targets in Heterocyclic
Systems 2018, 22, 165−193.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) Selected examples: (a) Nakamura, S.; Maeno, Y.; Ohara, M.;
Yamamura, A.; Funahashi, Y.; Shibata, N. Org. Lett. 2012, 14, 2960−
2963. (b) Shao, P.-L.; Liao, J.-Y.; Ho, Y. A.; Zhao, Y. Angew. Chem.,
Int. Ed. 2014, 53, 5435−5439. (c) Ortin, I.; Dixon, D. J. Angew.
Chem., Int. Ed. 2014, 53, 3462−3465. (d) Hayashi, M.; Iwanaga, M.;
Shiomi, N.; Nakane, D.; Masuda, H.; Nakamura, S. Angew. Chem., Int.
Ed. 2014, 53, 8411−8415. (e) Zhao, M.-X.; Dong, Z.-W.; Zhu, G.-Y.;
Zhao, X.-L.; Shi, M. Org. Biomol. Chem. 2018, 16, 4641−4649.
́
Agencia Estatal de Investigacion and Fondo Europeo de
Desarrollo Regional (FEDER, EU) (CTQ2017-84900-P).
Access to NMR and MS facilities from SCSIE-UV. C.V.
thanks the Spanish Government for a Ramon y Cajal contract
(RyC-2016-20187). A.S.-M. thanks the Generalitat Valenciana
and FEDER-EU for a postdoctoral grant (APOST/2016/139).
(16) (a) Martínez-Pardo, P.; Blay, G.; Mun
Sanz-Marco, A.; Vila, C. Chem. Commun. 2018, 54, 2862−2865.
(b) Martínez-Pardo, P.; Blay, G.; Munoz, M. C.; Pedro, J. R.; Sanz-
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