Chiral trans-carboxylic trifluoromethyl 2-imidazolines by a Ag2O-catalyzed Mannich-type reaction

Article abstract of DOI:10.1016/j.tet.2017.12.029

Trifluoromethyl aldimines derived from α-amino esters have proven to be very good starting materials to obtain the title compounds. A Ag₂O-catalyzed Mannich-type/cyclization cascade reaction starting from suitable α-isocyano acetates leads to e

Full text of DOI:10.1016/j.tet.2017.12.029

Accepted Manuscript
Chiral trans-carboxylic trifluoromethyl 2-imidazolines by a Ag O-catalysed Mannich-
2
type reaction
Laura Trulli, Fabio Sciubba, Stefania Fioravanti
PII:
S0040-4020(17)31291-7
10.1016/j.tet.2017.12.029
TET 29185
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 September 2017
Revised Date: 6 December 2017
Accepted Date: 14 December 2017
Please cite this article as: Trulli L, Sciubba F, Fioravanti S, Chiral trans-carboxylic trifluoromethyl
2-imidazolines by a Ag O-catalysed Mannich-type reaction, Tetrahedron (2018), doi: 10.1016/
2
j.tet.2017.12.029.
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Graphical Abstract
Chiral trans-carboxylic trifluoromethyl 2-
imidazolines by a Ag2O-catalysed Mannich-
type reaction
Leave this area blank for abstract info.
Laura Trulli, Fabio Sciubba, Stefania Fioravanti*
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, I-00185 Roma,
Italy

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1
Tetrahedron
journal homepage: www.elsevier.com
Chiral trans-carboxylic trifluoromethyl 2-imidazolines by a Ag2O-catalyzed
Mannich-type reaction
Laura Trulli, Fabio Sciubba, Stefania Fioravanti*
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, I-00185 Roma, Italy
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Trifluoromethyl aldimines derived from α-amino esters have proven to be very good starting
materials to obtain the title compounds. A Ag2O-catalyzed Mannich-type/cyclization cascade
reaction starting from suitable α-isocyano acetates leads to enantiopure valuable trans-
carboxylic trifluoromethyl substituted 2-imidazolines by a highly stereoselective addition
without the need to add organocatalysts.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
α-amino ester
heterocycle
α-isocyano acetate
metal catalyst
trifluoromethyl aldimine
1. Introduction
In particular, the development of transition metal-catalyzed
processes provides access to both cis or trans isomers, under
mild conditions and starting from the same materials.1,7
Moreover, since the first asymmetric form of this reaction was
reported,4 a variety of enantioselective approaches have been
widely investigated.5 The structural diversity introduced on the
imidazoline ring are many, but only one example of a CF3-
substitued 2-imidazoline is reported,8 despite the relevance of the
trifluoromethyl group on the molecular behaviour.9 As is well
known, the incorporation of fluorine-containing groups into an
organic molecule often drastically perturbs the chemical,
physical, and biological properties of the parent compound.10
Given the broad utility of trifluoromethyl heterocycle
compounds in medicinal chemistry,11 our attention was directed
towards the synthesis of carboxylic trifluoromethyl-substituted 2-
imidazolines (Scheme 1) by a Mannich-type addition/cyclization
cascade reaction between trifluoromethyl aldimines12 and suitable
α-isocyano acetates.13
2-Imidazolines are an important class of heterocyclic
compounds due to their wide applications in different chemistry
fields. They can be found in natural product chemistry,
pharmaceutical chemistry, organic synthesis, coordination
chemistry, and homogeneous catalysis.1 Furthermore, carboxylic
substituted 2-imidazolines are cyclic analogues of α,β-diamino
acids,2 key structural units of several natural products, having
great relevance in the synthesis of bioactive compound
derivatives characterized by exclusive pharmacological profiles.
α,β-Diamino acids have also been used to induce specific
conformations in peptide segments, or as precursors of
imidazoline derivatives with therapeutic activity, increasing the
resistance to hydrolysis.3
Many new efficient methods to synthesize 2-imidazolines as
well as modifications of traditional methods have been reported.
Among these, a remarkable example is the reaction between
imines and both unactivated or activated isocyanides4 to give
racemic 2-imidazolines. In addition, starting from α-isocyano
acetates,5 carboxylic substituted 2-imidazolines can be obtained.
These Mannich-type/cyclization cascade reactions are usually
base5g or metal catalyzed, but the simultaneous use of both have
also been reported.6
Scheme 1. Synthesis of carboxylic trifluoromethyl substituted 2-
imidazolines.
———
*
Corresponding author.
E-mail: stefania.fioravanti@uniroma1.it

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Tetrahedron
2. Results and discussion
Further examination of the solvent effect, ranging from aprotic
polar (entries 4−7) to protic polar (entries 5−9), revealed that the
performance of the silver oxide-catalyzed addition does not seem
to be influenced by the solvent; we observed a slight decrease of
the yield only by using EtOH or iPrOH. The best result was
achieved working under solvent-free conditions (entry 10) and
trans-3a was successfully obtained within 5 h (vs 15 h, entries 5-
7) with higher yield and purity. Varying the aldimine N-
protecting group and working under the same solvent-free
conditions of entry 10, the expected trans 2-imidazoline 3b was
found in good yield (entry 11).
First, the addition was tested by reaction of an equimolar
mixture of trifluoromethyl aldimine 1a and methyl 2-
isocyanoacetate (
2
) in THF at rt without catalyst,14 but no
reaction occurred and both reagents were quantitatively
recovered (48 h). Even when changing the reaction
conditions (solvent, temperature, molar ratios), no addition
product was observed. Then, a base-promoted Mannich-type
reaction was attempted and several tertiary amines (Et3N,
DBU, DMAP, DABCO) have been examined. Only
performing the reaction in THF using a stoichiometric
amount of Et3N, 2-imidazoline trans-37b,15 was obtained,
although in long reaction times and low yields (Scheme 2).
On the basis of the collected results and supported by the data
reported in the literature,13,14a,b,18 a mechanism for the silver(I)-
catalyzed Mannich-type reaction is depicted in Scheme 3.
Scheme 2. Base-promoted Mannich-type reaction.
Next, we focused our attention on
a metal-catalyzed
addition/cyclization cascade reaction. Given our success in the
ZrCl4-catalyzed additions of nucleophiles to trifluoromethyl
aldimines,16 zirconium tetrachloride was considered as a suitable
Lewis acid, also because it is easy to handle, cheap and
environmentally friendly.17 However, its catalytic use at room
temperature failed in the reaction between α-isocyano acetate 2
and aldimine 1a and only a complex crude mixture was
recovered, even working at lower temperature (0 °C).
Furthermore, other different Lewis acids such as CuCl2, Cu2O
and ZnCl2 were tested by us under different conditions, but with
no results in any case.
Scheme 3. Proposed mechanism for the silver(I)-catalyzed Mannich-
type addition/cyclization cascade reaction.
Finally, we envisioned the catalytic activity of silver(I)
derivatives, considering their efficiency in the 2-imidazoline
formation.5a-e,14c Working in THF at room temperature, Ag2O (10
mol %) provided the best result, affording the desired product
trans-3a in higher yield and in shorter reaction time (Table 1,
entry 3).
After deprotonation of the activated isocyanide I, the
formed enolate leads to II. The ring closure reaction
followed by silver(I) cation/proton exchange provides the
trans 2-imidazoline, as has been widely reported for the
analogous reaction on unfluorinated aldimines.4b,c,f,5c,g,f
Next, three different α-substituted isocyano acetates 4-6
Table 1. Optimization of the addition/cyclization cascade reaction of
2 on achiral trifluoromethyl aldimines
were synthesized starting from α-amino acid methyl ester
hydrochlorides, through slight modifications of the standard
protocol,14a,19 and then tested in the reaction with 1a
aldimine 1c derived from β-alanine (Table 2).
,b and
Table 2. Silver(I)-catalyzed Mannich-type reactions of α-isocyano
methyl esters 4-6 to achiral aldimines
Entry
1
Pg
Bn
3
Catalyst
AgOAc
Solvent
THF
Time (h) Yielda (%)
a
22
24
18
20
15
15
15
16
15
5
46
52
60
62
66
63
65
45
40
85
88
2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
PMP
a
a
a
a
a
a
a
a
a
b
AgNO3
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
THF
THF
CH2Cl2
DMSO
NMP
DMF
EtOH
iPrOH
−
3
Entry
1
R
R'
Product Solvent Time (h) Yieldb (%)
4
Bn
7/7'a
7/7'b
8/8'a
8/8'b
9/9'a
9/9'b
−
4
60
58
54
56
48
50
5
Me
2
3
4
5
6
PMP
Bn
−
4
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16
16
12
10
7
iBu
Bn
PMP
Bn
8
9
PMP
10
11b
a After flash chromatography on silica gel.
−
5
While the reactions involving 4 proceeded as expected under
solvent-free conditions (entries 1‒2), starting from 5 or 6 the use
of CH2Cl2 was specifically required to afford the desired products
a
b
After flash chromatography on silica gel. No reaction occurred
without catalyst

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3
(entries 3‒6).20 The data reported in Table 2 seems to show that
proposed for aldimine 1c (Figure 1, IV). In fact, starting
the presence of a steric hindrance on the pronucleophile carbon
only partially influence the reaction yields, but significantly
controls the reaction diastereoselectivity.21 Actually, the
substituent on the nucleophile carbon could be responsible for the
similar energy between E/Z enolates, resulting in a total loss of
geometric selectivity.22
from the latter, a low induction was observed.
Once better conditions were identified, we focused our efforts
on obtaining asymmetric induction in the model reaction. Thus, we
decided to perform the silver oxide catalyzed Mannich-type
addition starting from optically pure trifluoromethyl aldimines,
hoping that the presence of a chiral resident center on the
electrophilic aldimine could control the facially stereoselective
addition.5 Therefore, aldimine 1c, derived from (R)-α-methyl
Fig 1. Model for preferred face-selective addition reaction.
3. Conclusions
In conclusion, we have reported the first example of a Ag2O-
catalyzed Mannich-type/cyclization cascade reaction between
trifluoromethyl aldimines and α-isocyano acetates. The process
offers a simple and efficient route for the synthesis of trans-
carboxylic trifluoromethyl substituted 2-imidazolines without it
being necessary to add a base.6 The methodology works very
well under solvent-free conditions starting from methyl isocyano
acetate (2) and the use of silver oxide as catalyst leads to total
geometric stereoselective control. In addition, large-scale (250
mg) synthesis of 3a was realized in good yields and high
selectivity (see SI).
Moreover, the reactivity of α-substituted isocyano acetates
was also studied, for which few examples are reported in the
literature.5h,28 The results showed that the presence of an alkyl
group on the nucleophilic site is responsible of the total loss of
geometric selectivity.
benzylamine,23 and aldimines 1d-f, deriving from
L-α-amino
esters24 were considered in the addition reactions with 2 (Table 3).
Table 3. Reactions of 2 on chiral trifluoromethyl aldimines
Entry
1
1
R
Solvent Product Dra
10/10’ 0.6:0.4
Yieldb (%)
50
c
−
2
3
d
e
f
CH2Cl2 11
CH2Cl2 12
CH2Cl2 13
>0.99:0.1 49
Finally, starting from α-amino ester functionalized chiral
aldimines, a complete stereoselective induction without the need
for other added organocatalysts was observed, and enantiopure
valuable trans-carboxylic trifluoromethyl 2-imidazolines,
enriched by an α-amino ester residue, were obtained.
>0.99:0.1 45
4
>0.99:0.1 38
4. Experimental section
a
Determined by 1H and 19F NMR spectroscopy performed on the crude
mixtures. b After flash chromatography on silica gel.
4.1. General information
The Mannich-type reaction between methyl 2-isocyanoacetate
(2) and aldimine 1c took place under solvent-free conditions but
IR spectra were recorded on a Fourier transform infrared (FT/IR)
spectrophotometer in CHCl3 as solvent and are reported in
reciprocal centimeters.1H, 13C, and 19F NMR spectra were
recorded on a Varian-Mercury 300 instrument and on a Bruker
Avance III 400 instrument and reported in δ units. CDCl3 was
used as the solvent and CHCl3 (δ = 7.26 ppm for 1H NMR),
afforded trans-2-imidazolines 10/10' with
a
very low
diastereomeric ratio (entry 1), even when the addition was
attempted at lower temperatures (from −20 to 0 °C). However,
pure diastereomerically compounds 10 (major) and 10' (minor)
were obtained by HPLC purification. So, following our already
reported methodology,16b,c two-dimensional nuclear Overhauser
spectroscopic analyses (2D NOESY) coupled with computational
studies (see SI) allowed us to assign the S,S and the R,R absolute
configurations to the new chiral centers of 10 and 10', respectively.
Unexpectedly, the reactions starting from aldimines 1d-f did not
occur under solvent-free conditions but required the use of CH2Cl2
as the best solvent (entries 2-4).
CDCl3 (δ = 77.0 ppm for 13C NMR) and C6F6 (δ = −164.9 for 19
F
NMR) were used as internal standard. The NOESY experiments
were performed by a 400 MHz instrument using CDCl3 as the
solvent and CHCl3 as the internal standard and used to assist in
structure elucidation.29 ESI-MS analyses were performed using a
quadrupole-time of flight (Q-TOF) mass spectrometer equipped
with an ESI source and a syringe pump. The experiments were
conducted in the positive ion mode. Optical rotation was
determined at 25 °C at a wavelength of 589 nm, using a quartz
cell of 1 cm length. Imines 1a-f were prepared by reaction of
trifluoroacetaldehyde ethyl hemiacetal and an the relevant
primary amine, following the reported procedures.24,30 Methyl 2-
isocyanoacetate (2) is commercially available and used as
received.
Under these conditions, the Ag2O-catalyzed Mannich-
type addition/cyclization cascade reactions occurred with
very high diastereoselectivity, forming in all cases only the
configured S,R,R
diastereomer.25
A possible explanation for the stereochemical results27
seems to be the presence of the ester moiety on the aldimine.
An interaction could be generated between the silver-
isocyano acetate complex and aldimines deriving from L-α-
4.2. General procedure for the synthesis of α-isocyano acetates
4-6.
amino esters (Figure 1, III), making for
a greater
discrimination of aldimine enantiotopic faces. In fact, this
interaction could create a well-defined chiral pocket that can
readily favor the enolate attack preferentially on the Re
imine face so giving enantiopure valuable trifluoromethyl
imidazolidines. Obviously, a similar interaction cannot be
The methyl esterꢀHCl salt (100 mmol) was added to a semi-
saturated Na2CO3 (aq) (100 mL) solution and the mixture was
extracted with CH2Cl2 (4 × 100 mL). The organic layers were
combined and dried over MgSO4. Removal of the solvent under
reduced pressure allowed isolation of the corresponding methyl
ester. Acetic formic anhydride (110 mmol), prepared by stirring 1

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Tetrahedron
equiv of acetic anhydride (10.4 mL) and 1.1 equiv of formic
282.4 Hz), 76.8, 62.9 (q, J = 30.5 Hz), 53.0, 50.7, 19.8 (q, J =3.0
Hz). IR: 3201, 2875, 1747, 1594 cm-1. HR-MS (ESI Q-TOF)
(m/z) [M + H]+ calcd for C14H16F3N2O2 301.1164, found
301.1189.
acid (4.6 ml) for 2 h at 55 °C, was added dropwise at 0 °C to a
stirred solution of the appropriate methyl ester (50 mmol) in
CH2Cl2 (135 mL), and the mixture was stirred for 2 h at room
temperature. All volatiles were evaporated under reduced
pressure, and the corresponding formamides were isolated (68-
95%). Then, a solution of POCl3 (2.9 mL, 4.8 g, 31 mmol) in
CH2Cl2 (20 mL) was added dropwise to a solution of formamide
(25 mmol) in Et3N (17 mL) and CH2Cl2 (60 mL) at −25 °C. The
reaction mixture was stirred for 5 h at the same temperature, and
the resulting red mixture was added to cold H2O (60 mL) and
extracted with Et2O (3 × 60 mL). The organic layers were
combined, washed with H2O (2 × 50 mL), dried (MgSO4),
filtered, and concentrated in vacuo to yield the desired α-
isocyano acetates 4-614c (64-93%), which were obtained as pure
compounds and directly used in follow-up chemistry.
4.3.4. Methyl 1-benzyl-4-methyl-5-(trifluoromethyl)-4,5-dihydro-
1H-imidazole-4-carboxylate (trans-7'a). Method A.
Yellow oil (14 mg, 31%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). H NMR (CDCl3): δ 7.42–7.14 (m,
6H), 4.65 (d, J = 14.5 Hz, 1H), 4.23 (d, J = 14.7 Hz, 1H), 3.74 (s,
3H), 3.51 (q, J = 7.1 Hz, 1H), 1.41 (s, 3H). 19F NMR (CDCl3): δ
–69.3 (d, J = 7.0 Hz). 13C NMR (CDCl3): δ 171.5, 156.5, 134.4,
129.1 (2C), 128.6, 128.2 (2C), 124.2 (q, J = 279.4 Hz), 77.2, 67.9
(q, J = 31.1 Hz), 52.8, 50.7, 27.5. IR. 3199, 2835, 1751, 1253 cm-
1. HR-MS (ESI Q-TOF) (m/z) [M + H]+ calcd for C14H16F3N2O2
301.1164, found 301.1145.
1
4.3.5. Methyl 1-(4-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-
4,5 dihydro-1H-imidazole-4-carboxylate (cis-7b). Method A.
Red oil (14 mg, 29%). Purified by flash chromatography on
4.3. General procedure for the Ag2O-catalyzed Mannich-type
reactions.
1
Method A: To a mixture of trifluoromethyl aldimines 1a-c
(0.18 mmol) and Ag2O (0.015 mmol), α-isocyano acetates 2 or 4
(0.15 mmol) were added. The reactions were performed under
solvent-free conditions and stirred at room temperature (3-5 h,
see Tables 1 and 2). EtOAc was added and the mixtures were
filtered through a pad of celite. After solvent evaporation, the
crude mixtures were purified by flash chromatography on silica
gel or by HPLC.
silica gel (eluent: hexane/ethyl acetate = 3:7). H NMR (CDCl3):
7.13 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.89 (d, J = 8.9 Hz, 2H),
5.08 (q, J = 7.3 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 1.71 (s, 3H).
19F NMR (CDCl3): –67.8 (d, J = 7.5 Hz). 13C NMR (CDCl3):
173.2, 158.3, 154.1, 131.7, 124.9 (2C), 124.5 (q, J = 281.2 Hz),
114.8 (2C), 65.4 (q, J = 30.2 Hz), 60.3, 55.5, 53.3, 19.5 (q, J =
2.9 Hz). IR: 3256, 2917, 1769, 1240, 1150 cm-1. HR-MS (ESI Q-
TOF) (m/z) [M + H]+ calcd for C14H16F3N2O3 317.1113, found
317.1154.
Method B: To a mixture of trifluoromethyl aldimines 1a-b or
1d-f (0.18 mmol) and Ag2O (0.018 mmol) in CH2Cl2, α-isocyano
acetates (0.18 mmol) were added. The reactions were stirred at
room temperature (see Tables 2 and 3). EtOAc was added and the
mixtures were filtered through a pad of celite. After solvent
evaporation, the crude mixtures were purified by flash
chromatography on silica gel or by HPLC.
4.3.6. Methyl 1-(4-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-
4,5 dihydro-1H-imidazole-4-carboxylate (trans-7'b). Method A.
Red oil (14 mg, 29%). Purified by flash chromatography on
1
silica gel (eluent: hexane/ethyl acetate = 3:7). H NMR (CDCl3):
7.17 (s, 1H), 7.09 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H),
4.23 (q, J = 6.9 Hz, 1H), 3.81 (s, 6H), 1.68 (s, 3H). 19F NMR
(CDCl3): –69.5 (d, J = 6.9 Hz). 13C NMR (CDCl3): 170.7, 158.0,
153.9, 131.7, 124.1 (2C), 123.8 (q, J = 282.3 Hz), 114.9 (2C),
76.0, 70.8 (q, J = 30.4 Hz), 55.5, 53.0, 27.6. IR. 3189, 2850,
1735, 1256, 1140 cm-1. HR-MS (ESI Q-TOF) (m/z) [M + H]+
calcd for C14H16F3N2O3 317.1113, found 317.1137.
4.3.1.
Methyl
1-benzyl-5-(trifluoromethyl)-4,5-dihydro-1H-
imidazole-4-carboxylate (trans-3a). Method A.
Colorless oil (36 mg, 85%). Purified by flash chromatography
on silica gel (eluent: hexane/ethyl acetate = 3:7). 1H NMR
(CDCl3): δ 7.41–7.22 (m, 6H), 4.77 (d, J = 15.1 Hz, 1H), 4.70 (d,
J = 7.0, 1H), 4.36−4.27 (m, 2H), 3.77 (s, 3H). 19F NMR (CDCl3):
δ –74.6 (d, J = 6.9 Hz). 13C NMR (CDCl3): δ 169.9, 157.4, 134.5,
129.0 (2C), 128.4, 128.0 (2C), 124.8 (q, J = 280.3 Hz), 70.3, 60.9
(q, J = 31.9 Hz), 52.9, 50.6. IR: 3019, 2869, 1754, 1588 cm-1.
HR-MS (ESI Q-TOF) (m/z) [M + H]+ calcd for C13H14F3N2O2
287.1007, found 287.1068.
4.3.7.
Methyl
1-benzyl-4-isobutyl-5-(trifluoromethyl)-4,5-
dihydro-1H-imidazole-4-carboxylate (cis-8a). Method B.
Colorless oil (18 mg, 29 %). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 7.37–7.28 (m,
3H), 7.15 (d, J = 6.6, 2H), 7.06 (s, 1H), 4.58 (d, J = 15.2 Hz, 1H),
4.21 (d, J = 15.2 Hz, 1H), 3.84 (q, J = 7.6 Hz, 1H), 3.62 (s, 3H),
2.02 (dd, J = 5.7, 13.5 Hz, 1H), 1.92–1.83 (m, 1H), 1.72 (dd, J =
5.2, 13.9 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz,
3H). 19F NMR (CDCl3): –66.9 (d, J = 7.4 Hz). 13C NMR
(CDCl3): 174.1, 155.7, 135.1, 128.9 (2C), 128.3, 128.0 (2C),
124.8 (q, J = 283.7 Hz), 80.2, 52.6, 64.6 (q, J = 30.0 Hz), 50.6 (q,
J = 1.4 Hz), 41.3 (q, J = 2.5 Hz), 25.3, 24.5, 23.4. IR: 3027,
2834, 1764, 1413, 1115 cm-1. HR-MS (ESI Q-TOF) (m/z) [M +
H]+ calcd for C17H22F3N2O2 343.1633, found 343.1659.
4.3.2.
Methyl
1-(4-methoxyphenyl)-5-(trifluoromethyl)-4,5-
dihydro-1H-imidazole-4-carboxylate (trans-3b). Method A.
Red oil (40 mg, 88%). Purified by flash chromatography on
silica gel (eluent: hexane/ethyl acetate = 3:7) 1H NMR (CDCl3): δ
7.17 (s, 1H), 7.11 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H),
4.96−4.89 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H). 19F NMR (CDCl3):
δ –74.8 (d, J = 6.1 Hz). 13C NMR (CDCl3): δ 170.0, 158.1, 155.5,
131.3, 124.4 (q, J = 281.2 Hz), 123.8 (2C), 114.9 (2C), 70.3, 63.1
(q, J = 31.7 Hz), 55.5, 53.2. IR: 3030, 2973, 1750, 1499 cm-1.
HR-MS (ESI Q-TOF) (m/z) [M + H]+ calcd for C13H14F3N2O3
303.0957, found 303.0905.
4.3.8.
Methyl
1-benzyl-4-isobutyl-5-(trifluoromethyl)-4,5-
dihydro-1H-imidazole-4-carboxylate (trans-8′a). Method B.
Colorless oil (15.6 mg, 25%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 7.45–7.29 (m,
3H), 7.21 (d, J = 6.6, 2H), 7.09 (s, 1H), 4.61 (d, J = 15.0 Hz, 1H),
4.21 (d, J = 15.1 Hz, 1H), 3.74 (s, 3H), 3.45 (q, J = 7.2 Hz, 1H),
1.93 (dd, J = 6.6, 13.6 Hz, 1H), 1.70–1.66 (m, 1H), 1.19 (dd, J =
5.3, 13.5 Hz, 1H), 0.83 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H).
19F NMR (CDCl3): –69.2 (d, J = 6.7 Hz). 13C NMR (CDCl3):
170.8, 156.0, 134.6, 129.0 (2C), 128.5 (3C), 124.5 (q, J = 283.2
Hz), 79.7, 67.4 (q, J = 30.4 Hz), 52.6, 50.9, 49.8, 24.6, 24.2, 23.1.
4.3.3. Methyl 1-benzyl-4-methyl-5-(trifluoromethyl)-4,5-dihydro-
1H-imidazole-4-carboxylate (cis-7a). Method A.
Yellow oil (12 mg, 27 %). Purified by HPLC (eluent:
1
hexane/ethyl acetate = 7:3). H NMR (CDCl3): δ 7.39–7.19 (m,
5H), 6.94 (s, 1H), 4.59 (d, J = 15.0 Hz, 1H), 4.37 (q, J = 7.6 Hz,
1H), 4.25 (d, J = 15.1 Hz, 1H), 3.71 (s, 3H), 1.59 (s, 3H). 19F
NMR (CDCl3): δ –67.0 (d, J = 7.5 Hz). 13C NMR (CDCl3): δ
173.0, 155.5, 134.8, 128.9 (2C), 128.3, 128.1 (2C), 124.9 (q, J =

ACCEPTED MANUSCRIPT
5
IR: 3157, 2765, 1758, 1456, 1200 cm-1. HR-MS (ESI Q-TOF)
(m/z) [M + H]+ calcd for C17H22F3N2O2 343.1633, found
343.1602.
(2C), 80.9, 66.8 (br), 55.5, 52.7, 39.5. IR: 3010, 2900, 1787,
1533, 1416 cm-1. HR-MS (ESI Q-TOF) (m/z) [M + H]+ calcd for
C20H20F3N2O3 393.1426, found 393.1432.
4.3.9. Methyl 4-isobutyl-1-(4 methoxyphenyl)-5-(trifluoromethyl)-
4,5-dihydro-1H-imidazole-4-carboxylate (cis-8b). Method B.
Brown oil (17.6 mg, 27%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 7.16 (s, 1H), 7.06
(d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 4.67 (q, J = 7.1 Hz,
1H), 3.82 (s, 3H), 3.80 (s, 3H), 2.11 (dd, J = 5.1, 13.3 Hz, 1H),
2.00–1.89 (m, 1H), 1.85–1.83 (m, 1H), 1.04 (d, J=6.5 Hz, 3H),
0.92 (d, J=6.5 Hz, 3H). 19F NMR (CDCl3): –67.2 (d, J = 8.3 Hz).
13C NMR (CDCl3): 174.2, 157.9, 153.6, 131.9, 124.3 (q, J =
284.9 Hz), 124.2 (2C), 114.8 (2C), 80.3, 67.4 (q, J = 29.4 Hz),
55.5, 52.9, 41.5, 25.2, 24.5, 23.7. IR: 3076, 2748, 1765, 1433 cm-
1. HR-MS (ESI Q-TOF) (m/z) [M + H]+ calcd for C17H22F3N2O3
359.1583, found 359.1553.
4.3.14. Methyl 4-benzyl-1-(4-methoxyphenyl)-5-(trifluoromethyl)-
4,5-dihydro-1H-imidazole-4-carboxylate (trans-9′b). Method B.
Brown oil (19 mg, 27%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 7.33–7.22 (m,
6H), 6.69 (d, J = 8.9 Hz, 2H), 6.40 (d, J = 8.8 Hz, 2H), 4.39 (q, J
= 6.8 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.46 (d, J=13.7 Hz,
1H), 3.34 (d, J=13.9 Hz, 1H). 19F NMR (CDCl3): –68.7 (d, J =
7.0 Hz). 13C NMR (CDCl3): 170.2, 158.4, 155.3, 134.4, 130.0,
131.3 (2C), 128.5 (2C), 127.5, 125.2 (2C), 123.8 (q, J = 287.7
Hz), 114.5 (2C), 79.1, 67.6 (q, J=30.8 Hz,), 55.4, 53.2, 44.2. IR:
2900, 1765, 1516 cm-1. HR-MS (ESI Q-TOF) (m/z) [M + H]+
calcd for C20H20F3N2O3 393.1426, found 393.1468.
4.3.15. Methyl (4S,5S)-1-[(R)-1-phenylethyl]-5-(trifluoromethyl)-
4,5-dihydro-1H-imidazole-4-carboxylate (10). Method A.
Colorless oil (12 mg, 26%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). [α]D = +33.9 (c = 2 g/100 mL,
CHCl3). 1H NMR (CDCl3): 7.43–7.34 (m, 5H), 6.91 (s, 1H), 4.78
(d, J = 5.6 Hz, 1H), 4.69 (q, J = 6.8 Hz, 1H), 4.60−4.51 (m, 1H),
3.82 (s, 3H), 1.62 (d, J = 6.9 Hz, 3H). 19F NMR (CDCl3): –75.0
(d, J = 7.7 Hz). 13C NMR (CDCl3): 169.5. 156.4, 138.6, 129.1
(2C), 128.6, 127.2 (2C), 124.6 (q, J = 280.7 Hz), 68.9, 61.7 (q, J
= 31.5 Hz), 56.2, 53.3, 18.4. IR: 3076, 2750, 1762, 1567 cm-1.
HR-MS (ESI Q-TOF) (m/z) [M + H]+ calcd for C14H16F3N2O2
301.1164, found 301.1103.
4.3.10.
Methyl
4-isobutyl-1-(4
methoxyphenyl)-5-
(trifluoromethyl)-4,5-dihydro-1H-imidazole-4-carboxylate
(trans-8′b). Method B.
Brown oil (19 mg, 29%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 7.20 (s, 1H), 7.07
(d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 4.20 (q, J = 7.3 Hz,
1H), 3.81 (s, 6H), 2.21 (dd, J = 13.4, 6.7 Hz, 1H), 1.99–1.90 (m,
1H), 1.67 (dd, J = 5.1, 13.3 Hz, 1H), 1.00 (d, J=6.7 Hz, 3H), 0.94
(d, J=6.7 Hz, 3H). 19F NMR (CDCl3): –69.5 (d, J = 7.0 Hz). 13C
NMR (CDCl3): 170.7, 157.7, 153.3, 132.1, 123.4 (q, J = 284.3
Hz), 123.4 (2C), 114.9 (2C), 79.6, 70.4 (q, J = 29.9 Hz), 55.5,
52.7, 50.2, 24.7, 24.5, 23.2. IR: 3189, 2753, 1763, 1421 cm-1.
HR-MS (ESI Q-TOF) (m/z) [M + H]+ calcd for C17H22F3N2O3
359.1583, found 359.1565.
4.3.16.
Methyl
(4R,5R)-1-[(R)-1-phenylethyl]-5-
(trifluoromethyl)-4,5-dihydro-1H-imidazole-4-carboxylate (10′).
Method A.
4.3.11. Methyl 1,4-dibenzyl-5-(trifluoromethyl) 4,5-dihydro-1H-
imidazole-4-carboxylate (cis-9a). Method B.
Colorless oil (11 mg, 24 %). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). [α]D = +23.6 (c = 2 g/100 mL,
CHCl3). H NMR (CDCl3): 7.39–7.15 (m, 6H), 4.73 (d, J = 5.9
Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.12−4.09 (m, 1H), 3.72 (s,
3H), 1.71 (d, J = 7.0 Hz, 3H). 19F NMR (CDCl3): –74.9 (d, J =
7.5 Hz). 13C NMR (CDCl3): 160.5, 154.5, 137.7, 129.1 (2C),
128.4, 126.2 (2C), 69.8, 61.3 (q, J = 34.5 Hz), 56.8, 52.9, 22.1
[note: the CF3 signal was obscured due to its low intensity.]. IR:
3056, 2754, 1759, 1557 cm-1. HR-MS (ESI Q-TOF) (m/z) [M +
H]+ calcd for C14H16F3N2O2 301.1164, found 301.1153.
1
Yellow oil (17 mg, 24%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 7.51 (s, 1H),
7.33–7.14 (m, 10H), 4.75 (d, J = 15.2 Hz, 1H), 4.30 (d, J = 15.1
Hz, 1H), 4.13 (q, J = 7.5 Hz, 1H), 3.37–3.34 (m, 4H), 3.13 (d,
J=13.1 Hz, 1H). 19F NMR (CDCl3): –67.3 (d, J = 9.9 Hz). 13C
NMR (CDCl3): 172.6, 156.6, 135.2, 134.6, 130.4 (2C), 129.0
(2C), 128.4, 128.1 (2C), 128.0 (2C), 127.1, 124.6 (q, J = 284.0
Hz), 80.2, 64.2 (q, J = 30.5 Hz), 52.5, 51.0, 39.2. IR: 3065, 2734,
1748, 1548, 1400, 1213 cm-1. HR-MS (ESI Q-TOF) (m/z) [M +
H]+ calcd for C20H20F3N2O2 377.1477, found 377.1405.
4.3.17. Methyl (4R,5R)-1-[(S)-1-methoxy-3-methyl-1-oxobutan-2-
yl]-5-(trifluoromethyl)-4,5-dihydro-1H-imidazole-4-carboxylate
(11). Method B.
4.3.12. Methyl 1,4-dibenzyl-5-(trifluoromethyl) 4,5-dihydro-1H-
imidazole-4-carboxylate (trans-9′a). Method B.
Colorless oil (27.6 mg, 49 %). Purified by flash
chromatography on silica gel (eluent: hexane/ethyl acetate = 3:7).
Yellow oil (17 mg, 24%). Purified by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 8.03 (s, 1H),
7.37–7.18 (m, 10H), 4.95 (d, J = 14.8 Hz, 1H), 4.39 (d, J = 15.0
Hz, 1H), 4.30 (q, J = 7.3 Hz, 1H), 3.40‒3.39 (m, 4H), 3.20 (d, J =
13.3 Hz, 1H). 19F NMR (CDCl3): –68.5 (d, J = 9.9 Hz). 13C NMR
(CDCl3): 171.8, 157.7, 134.3, 133.9, 130.3 (2C), 129.1 (2C),
128.7, 128.4 (2C), 128.2 (2C), 127.4, 124.2 (q, J = 284.2 Hz),
78.8, 64.6 (q, J = 30.8 Hz), 52.9, 51.4, 38.8. IR: 3065, 2734,
1748, 1545, 1400, 1213 cm-1. HR-MS (ESI Q-TOF) (m/z) [M +
H]+ calcd for C20H20F3N2O2 377.1477, found 377.1428.
1
[α]D = +38.6 (c = 1 g/100 mL, CHCl3). H NMR (CDCl3): 7.14
(s, 1H), 4.70 (dd, J = 1.97, 6.5 Hz, 1H), 4.35–4.29 (m, 1H), 3.81
(s, 3H), 3.75 (s, 3H), 3.52 (d, J = 10.4 Hz, 1H), 2.29−2.20 (m,
1H), 1.09 (d, J = 6.6 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H). 19F NMR
(CDCl3): –75.3 (d, J = 6.4 Hz). 13C NMR (CDCl3): 171.1, 169.9,
154.7, 124.8 (q, J = 279.9 Hz), 69.9, 67.3, 62.7 (q, J = 31.8 Hz),
53.1, 52.4, 29.8, 19.6, 19.2. IR: 3056, 2830, 1765, 1745, 1178
cm-1. HR-MS (ESI Q-TOF) (m/z) [M
+
H]+ calcd for
C12H18F3N2O4 311.1219, found 311.1274.
4.3.13. Methyl 4-benzyl-1-(4-methoxyphenyl)-5-(trifluoromethyl)-
4,5-dihydro-1H-imidazole-4-carboxylate (cis-9b). Method B.
Brown oil (16 mg, 23%). Separated by HPLC (eluent:
hexane/ethyl acetate = 7:3). 1H NMR (CDCl3): 7.35–7.22 (m,
6H), 7.10 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.93 (br,
1H), 3.80 (s, 3H), 3.52 (s, 3H), 3.45 (d, J=13.2 Hz, 1H), 3.26 (d,
J=12.6 Hz, 1H). 19F NMR (CDCl3): –67.4 (d, J = 7.5 Hz). 13C
NMR (CDCl3): 173.2, 158.0, 153.7, 135.5, 131.5, 130.3 (2C),
128.2 (2C), 127.1, 124.3 (q, J = 286.0 Hz), 124.0 (2C), 114.8
4.3.18. Methyl (4R,5R)-1-[(S)-1-methoxy-4-methyl-1-oxopentan-
2-yl]-5-(trifluoromethyl)-4,5-dihydro-1H-imidazole-4-
carboxylate (12). Method B.
Colorless oil (15.5 mg, 45 %). Purified by flash
chromatography on silica gel (eluent: hexane/ethyl acetate = 3:7).
1
[α]D = +20.6 (c = 2 g/100 mL, CHCl3). H NMR (CDCl3): 7.07
(s, 1H), 4.74 (dd, J = 6.9, 1.9 Hz, 1H), 4.38 (quintet, J = 6.6 Hz,
1H), 4.03 (dd, J = 10.3, 5.0 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H),
1.76−1.87 (m, 3H), 0.99 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.1 Hz,

ACCEPTED MANUSCRIPT
6
Tetrahedron
3H). 19F NMR (CDCl3): –75.2 (d, J = 6.7 Hz). 13C NMR
9. (a) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed.
2012, 51, 5048‒5050;
(b) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011,
111, 455‒529;
(c) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
4475‒4521;
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470‒477;
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Soc. Rev. 2008, 37, 320‒330.
(CDCl3): 171.6, 169.3, 155.3, 124.6 (q, J = 279.6 Hz), 68.8, 62.8
(q, J = 31.5 Hz), 58.5, 53.3, 52.8, 39.5, 24.5, 22.8, 21.0. IR:
2945, 2830, 1784, 1747, 1156 cm-1. HR-MS (ESI Q-TOF) (m/z)
[M + H]+ calcd for C13H20F3N2O4 325.1375, found 325.1342.
4.3.19. Methyl (4R,5R)-1-[(S)-1-methoxy-1-oxo-3-phenylpropan-
2-yl]-5-(trifluoromethyl)-4,5-dihydro-1H-imidazole-4-
carboxylate (13). Method B.
Colorless oil (14.4 mg, 38 %). Purified by flash
chromatography on silica gel (eluent: hexane/ethyl acetate = 3:7).
10. (a) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432‒2506;
1
[α]D = +19.3 (c = 1 g/100 mL, CHCl3). H NMR (CDCl3): 7.28–
7.12 (m, 5H), 6.98 (s, 1H), 4.61 (dd, J = 2.0, 6.7 Hz, 1H), 4.33
(quintet, J = 6.5 Hz, 1H), 4.20 (dd, J = 6.7, 8.6 Hz, 1H), 3.76 (s,
3H), 3.67 (s, 3H), 3.31 (d, J = 6.6, 14.2 Hz, 1H), 3.10 (dd, J =
8.6, 14.2 Hz, 1H). 19F NMR (CDCl3): –75.6 (d, J = 7.5 Hz). 13C
NMR (CDCl3): 170.8, 169.9, 154.3, 135.5, 128.9 (2C), 128.7
(2C), 127.3, 124.6 (q, J = 279.9 Hz), 70.1, 62.6 (q, J = 31.6 Hz),
58.6, 53.1, 52.7, 37.2. IR: 3100, 2838, 1768, 1747, 1589, 1156
(b) Nakajima, T. J. Fluorine Chem. 2013, 149, 104‒111;
(c) Bremer, M.; Kirsch, P.; Klasen-Memmer, M.; Tarumi, K.
Angew. Chem., Int. Ed. 2013, 52, 8880‒8896;
(d) Salwiczek, M.; Nyakatura, E. K.; Gerling, U. I. M.; Ye, S.;
Koksch, B. Chem. Soc. Rev. 2012, 41, 2135‒2171;
(e) Cametti, M.; Crousse, B.; Metrangolo, P.; Milani, R.; Resnati,
G. Chem. Soc. Rev. 2012, 41, 31‒42;
(f) Littich, R.; Scott, P. J. H. Angew. Chem., Int. Ed. 2012, 51,
1106‒1109;
(g) Egli, M. Acc. Chem. Res. 2012, 45, 1237‒1246;
(h) Ojima, I. Fluorine in Medicinal Chemistry and Chemical
Biology; Blackwell: Oxford, 2009;
cm-1. HR-MS (ESI Q-TOF) (m/z) [M
+
H]+ calcd for
C16H18F3N2O4 359.1219, found 359.1258.
Acknowledgments
(i) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley: New York, 2008;
(j) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford,
2006;
(k) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell:
Oxford, 2004;
We are grateful for financial support from the Università degli
Studi di Roma “La Sapienza”.
11. (a) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071‒1081;
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Both activated and unactivated isocyanides can successfully be
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18. Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V.
G. Chem. Rev. 2010, 110, 5235–5331.
19. Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400–402.
20. Using THF as a solvent, the products 8/8'a, 8/8'b, 9/9'a and 9/9'b
were obtained in lower yields.
21. Even by changing the reaction conditions (molar ratios, silver
catalysts, and temperature) no improvements of stereoselectivity
were observed.
22. The cis/trans relative configurations were assigned by comparing
between them the 1H NMR chemical shift values of HC-CF3.
23. Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J.
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Vergari, M. C. Chirality 2015, 27, 571–575.
25. For the latter, the absolute configurations were determinate using
the same previously described methodology involving
computational studies coupled with the data obtained from 2D
NOESY NMR spectra.
26. The Mannich-type cyclization-cascade reactions between
aldimines 1c-f and α-isocyano acetates 4-6 were also performed.
However, the presence of an α-alkyl substituent on the imine
nitrogen coupled with an R group on the nucleophile carbon of
isocyano acetates 4-6 seems to approach the limits for these
reactions. In fact, the expected products were obtained only in
traces.
27. To completely exclude a possible influence of the solvent on the
stereochemical outcome, 1c was reacted with 2 in CH2Cl2, but
only a decreasing in yield was observed.
28. Zhao, M.-X.; Zhu, H.-K.; Dai, T.-L.; Shi, M. J. Org. Chem. 2015,
80, 11330−11338.
29. Claridge, T. D. W. High-Resolution NMR Techniques in Organic
Chemistry, Third Ed.; Elsevier Science: Amsterdam, The
Netherlands, 2016.
30. Carroccia, L.; Fioravanti, S.; Pellacani, L.; Tardella, P. A.
Synthesis 2010, 4096−4100.
Supplementary Material
Supplementary data related to this article can be found at
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