Functionalized α-oximinoketones as building blocks for the construction of imidazoline-based potential chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2015.01.011

Functionalized α-oximinoketones with β-alkoxy, β-alkyl, and β-sulfenyl groups were used as efficient synthons for the preparation of chiral 1-acyl-4-imidazolin-2-ones and 1-acylimidazolidin-2-ones. For the preparation of the former heterocycles, α-oximinoketones were transformed into their respective imidazole N-oxides by neutral treatment with a chiral triazine, followed by reaction with acetic or propionic anhydrides to furnish the desired chiral 1-acetyl- or 1-propionyl-4-imidazolin-2-ones in moderate overall yields. Upon palladium hydroxide-catalyzed hydrogenation, these series were converted into their corresponding 1-acylimidazolidin-2-ones in high diastereoisomeric ratios. Thus, these novel chiral 1-acetyl- and 1-propionyl-imidazolidin-2-ones were obtained with a variety of alkyl groups at the C-4 and C-5 positions of the heterocycle, through a three-step methodology, and can be applied as new potential chiral auxiliaries.

Full text of DOI:10.1016/j.tetasy.2015.01.011

Tetrahedron: Asymmetry 26 (2015) 230–246
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Functionalized
a-oximinoketones as building blocks for the
construction of imidazoline-based potential chiral auxiliaries
Rsuini U. Gutiérrez a, , Araceli Rebollar a, , Rafael Bautista a,b, Vanessa Pelayo a, José Luis Várgas a,
Mabel M. Montenegro a, Carlos Espinoza-Hicks a, Francisco Ayala a, Pablo M. Bernal b,
Cuauhtemoc Carrasco b, L. Gerardo Zepeda a, Francisco Delgado a, Joaquín Tamariz a,
⇑
a Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
b Departamento de Investigación y Desarrollo, Signa, S.A. de C.V., Av. Industria Automotriz No. 301, Zona Industrial Toluca, 50200 Toluca, Edo. de México, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 December 2014
Accepted 6 January 2015
Functionalized
synthons for the preparation of chiral 1-acyl-4-imidazolin-2-ones and 1-acylimidazolidin-2-ones. For
the preparation of the former heterocycles, -oximinoketones were transformed into their respective
a-oximinoketones with b-alkoxy, b-alkyl, and b-sulfenyl groups were used as efficient
a
imidazole N-oxides by neutral treatment with a chiral triazine, followed by reaction with acetic or pro-
pionic anhydrides to furnish the desired chiral 1-acetyl- or 1-propionyl-4-imidazolin-2-ones in moderate
overall yields. Upon palladium hydroxide-catalyzed hydrogenation, these series were converted into
their corresponding 1-acylimidazolidin-2-ones in high diastereoisomeric ratios. Thus, these novel chiral
1-acetyl- and 1-propionyl-imidazolidin-2-ones were obtained with a variety of alkyl groups at the C-4
and C-5 positions of the heterocycle, through a three-step methodology, and can be applied as new
potential chiral auxiliaries.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
crobial activities of the imidazole and benzimidazole parent sys-
tems.11 1H-Imidazole N-oxides have also been revealed to be
Imidazole is a five-membered aromatic heterocycle constituted
by two nitrogen atoms at the 1,3-positions.1 One of them is substi-
tuted and shares its lone pair of electrons with two conjugated
double bonds to stabilize the ring by aromaticity. The other bears
a lone pair of electrons in the plane of the ring providing a basic
character to that center of the heterocycle. This electron-density
distribution renders unique biological properties to imidazoles
among the vast number of nitrogen containing heterocycles.2 Imid-
azole-containing compounds have been used as reagents for vari-
ous synthetic transformations,3 while natural and synthetic
imidazole derivatives show a broad range of pharmacological
activities,4 such as histamine-based receptors,5 antifungal (clo-
trimazole, miconazole, sulconazole, tioconazole, luliconazole, and
ketoconazole),6 antimicrobial,7 anticonvulsant,8 and antiparasitic
drugs,9 as well as anti-tumor and anticancer agents.10
attractive synthetic building blocks,12 and as new achiral and chiral
ionic liquids.13 Among the preparation methods of chiral and race-
mic 1H-imidazole N-oxides,14 the reaction of
a-oximinoketones
with hexahydro-1,3,5-triazines is an easy and efficient proce-
dure.15 The resulting N-oxides display a diverse reactivity that
allows this skeleton to be transformed into a variety of imidazole
derivatives,16 including their isomerization into imidazolin-2-
ones.17
The great interest in the preparation of imidazol-2-ones is due to
their broad range of uses, including analogues inhibiting the MurB
enzyme,18 anti-tumor potential agents,19 and anti-oxidants.20
Recently, imidazol-2-ones have been used as key-fragments for
successfully designing new drugs through a fragment-based drug
discovery.21 Consequently, the synthesis of such heterocycles has
been reported through many procedures, which consist of the
condensation of carbonylic compounds with substituted ureas22 or
isocyanates,23 intramolecular cyclization of imino salts,24 or
transition metal-catalyzed transformations.25
Recently, the development of 1H-imidazole N-oxide derivatives
has enhanced the antitumoral, antiparasitic, antiviral, and antimi-
In spite of the growing interest in the design and preparation of
modern chiral transition-metal complex catalysts26 and organocat-
alysts,27 and their efficiency for improving asymmetric synthesis,
the use of chiral auxiliaries still represents a highly selective and
⇑
Corresponding author. Fax: +52 (55) 5396 3503.
E-mail addresses: jtamarizm@gmail.com, jtamariz@woodward.encb.ipn.mx
(J. Tamariz).
Equivalent contribution.
http://dx.doi.org/10.1016/j.tetasy.2015.01.011
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
231
O
O
We previously reported the direct conversion of enones 1a–b
into b-alkoxy and b-sulfenyl -oximinoketones 6–7 through a cas-
cade reaction or a sequential one-pot two-step process involving
an acid- (Brønsted or Lewis) or base-promoted 1,4-addition of alco-
hols or thiols 2–3 to enones 1a–b in the presence of or by the con-
secutive addition of nitrosyl chloride (Scheme 1).31 Herein we
report a study of synthetic applications of these functionalized a-
oximinoketones for the preparation of imidazole N-oxides 8 and
novel chiral 4-imidazolidin-2-ones 9.
O
O
R3
R2
a
O
N
N
O
N
N
R3
R3
R1
R2
R1
I
II
O
O
O
O
O
R4
R
R1
R
N
N
2. Results and discussion
R2
R3
2.1. Preparation of
a-oximinoketones 6a–c, 7a–c, and 12a–f
III
IV
A series of b-alkoxy
a-oximinoketones 6a–c were prepared
Figure 1. Oxazolidin-2-one-based chiral auxiliaries
I (Evans) and II (Davies,
through the optimized procedure by using BF3ꢀEt2O as the Lewis
acid catalyst in the presence of the desired alkyl alcohol 2a–c
and bubbling dry NOCl to carry out the oxa-Michael addition reac-
tions to methyl vinyl ketone 1a, followed by electrophilic addition
(Scheme 1) (Table 1, entries 1–3).31 We found that the efficiency of
the process did not significantly decrease when shortening the
reaction time from that previously reported31 (lasting for days)
to 4 h (at ꢁ78 °C for 2 h, then at room temperature for 2 h).
Table 1 also summarizes the preparation of 4-arylthio-3-
(hydroxyimino)butan-2-ones 7a–c via a one-pot two-step reaction
in good overall yields (entries 4–6).31 In some cases this procedure
resulted in the formation of both (Z)- and (E)-stereoisomers,
although the former was generally the major one. The synthesis
of 7a–c through the two-step procedure increased selectivity,
Seebach) and imidazolidin-2-one-based chiral auxiliaries III (Helmchen, Cardillo)
and IV (Davies).
easy methodology for the construction of desired non-racemic chi-
ral compounds (Fig. 1).28 In particular, oxazolidin-2-one- [e.g., I
(Evans) and II (Davies, Seebach)] or imidazolidin-2-one-based
[e.g., III (Helmchen, Cardillo) and IV (Davies)] chiral auxiliaries,
which are also associated with chiral 1,2-amino alcohols and 1,2-
diamino compounds and ligands,29 have proven to be efficient in
carrying out diverse reactions with high diastereoselectivities
while not being susceptible to nucleophilic ring opening on cleav-
age. Under conditions that do not cause racemization of the prod-
uct, the auxiliary is removed and recovered for future inductions.30
O
O
NOH
XR2
O
acid
NOCl
R2-XH
+
R1
R1
4, X = O
XR2
R1
or base
-78-25 °C
or NaNO2
-78-25 °C
, R1 = Me
, X = O
, X = S
1a
2, X = O
3, X = S
6
7
1b, R1 = Et
5
, R = S
O
O
R4
O-
+
N
N
N
N
Ph
Ph
R1
R3
R1
R3
8
9
Scheme 1.
Table 1
Acid-catalyzed hetero-Michael additions of alcohols 2a–c or base-catalyzed hetero-Michael additions of thiophenols 3a–c to enone 1a, followed by nitrosation of either the in situ
formation of 4a–c or 5a–c or of b-thioketones 5a–c
Entry
2 or 3 or 5 (R2)
Acid or basea
Solvent
T (°C)
t (h)
Productb (%)
1
2
3
4
5
6
7
8
9
2a (Me)c
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
DABCO
DABCO
DABCO
HCl
—
—
—
THF
THF
THF
THF
THF
THF
ꢁ78 (25)d
ꢁ78 (25)d
ꢁ78 (25)d
65 (25)e
65 (25)e
65 (25)e
0 (25)f
2 (2)d
6a (65)
6b (51)
6c (46)
7a (90)
7b (65)
7c (55)
7a (92)
7b (62)
7c (60)
2b (Et)c
2 (2)d
2c (i-Pr)c
3a (Ph)
3b (C6H4-4-Cl)
3c (C6H4-4-Br)
5a (Ph)
5b (C6H4-4-Cl)
5c (C6H4-4-Br)
2 (2)d
4 (12)e
4 (12)e
4 (12)e
2 (12)f
2 (12)f
2 (12)f
HCl
HCl
0 (25)f
0 (25)f
a
b
c
d
e
f
Under an N2 atmosphere, with BF3ꢀEt2O (0.16 mol equiv), or DABCO (0.2 mol equiv), or concd HCl (6.0 mol equiv).
Yields after column chromatography.
Nitrosation (HCl/NaNO2) of a mixture of 1a with the alcohol 2.
Addition of reagents at ꢁ78 °C for 2 h, then the mixture was left at 25 °C for 2 h.
The reaction was carried out with thiol 3 at 65 °C for 4 h, followed by the addition of HCl/NaNO2 at 0 °C; the mixture was then left at 25 °C for 12 h.
The addition of HCl to a mixture of ketone 5 and NaNO2 was carried out at 0 °C, followed by stirring for 2 h, then the mixture was left at 25 °C for 12 h.

232
R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
Table 2
Preparation of
and also mainly furnishing the (Z)-isomer. Thus, the DMAP-cata-
lyzed addition to 1a with the same series of substituted thiophe-
nols 3a–c gave Michael adducts 5a–c, respectively, in high yields
(83–90%). The latter were then treated with sodium nitrite and
hydrochloric acid at room temperature to afford the corresponding
4-arylthio-3-(hydroxyimino)butan-2-ones 7a–c in good overall
yields (entries 7–9).
The X-ray diffraction crystallography of 7a shows that the (Z)-
configuration and the s-trans conformation are preferred in the
crystalline state (Fig. 2). It is noteworthy that the oximino proton
does not form a hydrogen bond with the sulfur atom, whose group
adopts an orthogonal conformation with respect to the plane
formed by the conjugated hetero-atom double bonds.
a-oximinoketones 12a–12f via addition of hydroxylamine to
a
-diketones 10a–10c or via nitrosation of ketones 11a–11da
Entry
Ketone
Reagents
Solvent
t (h)
Productb (%)
1
2
3
4
5
6
7
10a
10b
11a
11b
11c
11d
10c
HONH2ꢀHClc
HONH2ꢀHClc
NOCld
MeOH
MeOH
2
2
2
2
2
12a (95)
12b (92)
12c (63)
12d (65)
12e (57)
12f (52)
12f (71)
Et2O/MeOH/HCle
Et2O/MeOH/HCle
Et2O/MeOH/HCle
MeOH
NOCld
NOCld
NOClf
192
2
HONH2ꢀHClc
MeOH
a
b
c
All reactions were carried out at room temperature.
After purification by column chromatography.
In the presence of pyridine (1.1 mol equiv).
d
Generated as gas (NaNO2/H2SO4), which was bubbled it in the substrate
Alkyl
of hydroxylamine to
of the corresponding dialkyl ketones 11a–d (Scheme 2) (Table 2).
-Oximinoketones 12a–b were efficiently prepared from 10a–b
a
-oximinoketones 12a–e were prepared by the addition
solution.
a-diketones 10a–b or by direct nitrosation
e
In a 2:3:1 ratio; HCl (37%).
HCl (37%) in MeOH was added to the substrate solution containing NaNO2
f
a
(3.0 mol equiv) at 25 °C. NaNO2 (3.0 mol equiv) was added three times each 24 h
after the first addition.
(Table 2, entries 1 and 2), although 10a is also commercially avail-
able. Non-symmetrical ketones 2-pentanone 11a and 2-hexanone
11c afforded a single chemoisomer, 12c and 12e, respectively
(entries 3 and 5). This can be accounted for by the fact that the
slowest step of the reaction mechanism is the acid-promoted enol
formation of the ketone.32 Hence, the thermodynamic enol is
preferentially formed, leading to nitrosation in the secondary car-
bon adjacent to the carbonyl group.
mation of 10c and to carry out treatment with hydroxylamine.
Although
a-diketone 10c was prepared in moderate yield (43%)
and its conversion into 12f (entry 7) did not improve the overall
yield (31%), purification of the product was easier than when using
the direct nitrosation of 11d.
The synthesis of aryl methyl a-oximinoketone 12f started from
2.2. Preparation of chiral 1H-imidazole N-oxides 8a–l and their
conversion into 1-acyl 4-oxazolin-2-ones 14d–p
the Lewis acid-promoted propionylation of anisole to yield ketone
11d in 45% yield, which was then submitted to nitrosation condi-
tions to give the desired product (Table 2, entry 6). The modest
Previously, Heimgartner et al. described the efficient synthesis
yield of the latter was due to the formation of
a side-product, which resulted from a further conversion of the
firstly obtained -oximinoketone 12f into 10c under the same
nitrosation conditions.33 Therefore, we decided to optimize the for-
a-diketone 10c as
of
-oximinoketones with hexahydrotriazines.12a,13,15 We applied
this methodology using our -oximinoketones 6a–c, 7a–c, and
a series of 1H-imidazole N-oxide derivatives by reacting
a
a
a
Figure 2. X-ray structure of
a-oximinoketone 7a (ellipsoids at the 30% probability level).
Scheme 2.

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
233
12a–f and the chiral hexahydrotriazine 13 (Table 3).13,34 Although
these described -oximinoketones have quite different structures
than those previously reported, the procedure was found to be
highly efficient for our substrates, thereby providing a series of
1H-imidazole N-oxides 8a–l in good to excellent yields.
Table 3
Preparation of 1H-imidazole N-oxides 8a–l by reacting
and 12a–f and the chiral hexahydrotriazine 13
a
-oximinoketones 6a–c, 7a–c,
a
2
1
N
+
O-
For example, the
a-oximinoketones 6a–c that bear alkoxy
Ph
N
N
Ph
N
O
NOH
R2
Ph
EtOH
methyl ethers as substituents at C-4 of the heterocycle proved to
be stable under the reaction conditions to give 1H-imidazole N-
oxides 8a–c in satisfactory yields (entries 1–3). Similarly, the series
4
5
+
N
reflux, 1-12 h
R1
R1
R2
Ph
of b-sulfenyl
a-oximinoketones 7a–c afforded the expected 1H-
6a-c, 7a-c, 12a-f
13
8a-l
imidazole N-oxides 8d–f in good yields (entries 4–6). Although
the reaction of 12a was also reported by the same authors,34 in
our hands the desired product 8g was obtained in almost quantita-
tive yield (entry 7). For most of the rest of the series 12b–f, the
desired 1H-imidazole N-oxides 8h–l were prepared in high yields
(entries 8–12). The structure of these compounds, including hexa-
hydrotriazine 13, was characterized by NMR and the signals were
assigned by 2D experiments (HMQC and HMBC), mass spectrome-
try (low and high resolution), and/or elemental analysis. The struc-
ture of 8g was also established by X-ray diffraction crystallography
(Fig. 3), which shows that the chiral auxiliary adopts a conforma-
tion in which the phenyl group is orthogonal to the plane formed
by the heterocycle ((b) view), while the proton is oriented toward
the C-5 methyl group (vide infra).
Entry
a
-Oximinoketone
R1
R2
Producta (%)
1
2
3
4
5
6
7
8
6a
6b
6c
7a
7b
7c
12a
12b
12c
12d
12e
12f
Me
Me
Me
Me
Me
Me
Me
Et
CH2OMe
CH2OEt
CH2Oi-Pr
CH2SPh
CH2SC6H4-4-Cl
CH2SC6H4-4-Br
Me
Et
Et
Me
n-Pr
Me
8a (82)
8b (81)
8c (75)
8d (85)
8e (80)
8f (79)
8g (98)
8h (93)
8i (96)
8j (91)
8k (90)
8l (96)
9
Me
Et
Me
10
11
12
C6H4-4-OMe
a
Yields after column chromatography.
We were able to obtain a monocrystal of hexahydrotriazine 13
to establish its structure by X-ray diffraction (Fig. 4). The
Figure 3. X-ray structure of 1H-imidazole N-oxide 8g (ellipsoids at the 30% probability level): (a) frontal view; (b) lateral view.
Figure 4. X-ray structure of hexahydrotriazine 13 (ellipsoids at the 30% probability level; the hydrogen atoms were removed for a better view).

234
R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
Table 4
Preparation of 1-acyl 4-imidazolin-2-ones 14d–p by treatment of 1H-imidazole N-oxides 8a–c and 8e–l with acetic and propionic anhydrides
O
O
2
R3
2
O-
(R3CH2CO)2O
reflux, 1 h
+
3
1N
N
N
N
3N
N 1
Ph
Ph
Ph
+
5
4
4
5
R2
R1
R2
R1
R2
AcO
14a p
15a c
-
8a-c, 8e-l
-
Entry
8
R1
R2
R3
14a (%)
15a (%)
1
2
3
4
5
6
7
8
8a
8b
8c
8e
8f
8g
8h
8i
8j
8k
8l
8g
8h
8i
8k
8l
Me
Me
Me
Me
Me
Me
Et
Me
Et
Me
C6H4-4-OMe
Me
Et
Me
Me
C6H4-4-OMe
CH2OMe
CH2OEt
CH2Oi-Pr
CH2SC6H4-4-Cl
CH2SC6H4-4-Br
Me
Et
Et
Me
n-Pr
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
14a (b)
14b (b)
14c (b)
—
—
—
—
14d (94)
14e (97)
14f (54)
14g (60)
14h (53)
14i (60)
14j (39)
14k (46)
14l (54)
14m (72)
14n (60)
14o (30)
14p (50)
—
15a (20)
—
15b (18)
—
9
10
11
12
13
14
15
16
15c (16)
—
—
—
—
—
—
Et
n-Pr
Me
a
Yields after column chromatography.
A complex mixture.
b
OAc
OAc
N
six-membered ring adopts a chair-like conformation, and only two
of the chiral N-benzyl substituents assume the equatorial confor-
mation, leaving the third one in an axial position.
O
H
N
OAc
OAc
+
Ac2O
N
N
N
N
Ph
Ph
Ph
Ph
-OAc
Treated under similar conditions as those reported previ-
ously,17a the series of alkoxymethyl 1H-imidazole N-oxides 8a–c
when treated with acetic anhydride at reflux for 1 h did not pro-
duce the desired N-acetyl 4-oxazolin-2-ones 14a–c, but instead a
complex mixture of products (Table 4, entries 1–3). It is likely that
the presence of acetic acid in the middle of the reaction decom-
poses the ether group to yield diverse side-products. Unlike these
compounds, the arylsulfenylmethyl 1H-imidazole N-oxides 8e–f
reacted with acetic anhydride at reflux for 1 h to afford 1-acetyl-
4-imidazolin-2-ones 14d–e, respectively, in high yields (entries 4
and 5).
R
R
R
III
I
II
-Ac2O
O
O
2
+
O-
Ac2
O
N
5
N
N
N
N
N
3
1
+
Ph
Ph
4
reflux, 1 h
AcO
15a
R
R
R
8g, R = Me
14f
, R = Me
, R = Me
8i
, R = Et
8k
14h
15b, R = Et
15c, R = i-Pr
, R = Et
, R = i-Pr
14j, R = i-Pr
-AcO-
For the case of alkyl derivative 1H-imidazole N-oxide 8g, the
reaction with acetic anhydride at reflux for 1 h produced the
desired 1-acetyl 4-oxazolin-2-one 14f, but only in a fair yield
(54%) (Table 4, entry 6). We found that this unexpectedly modest
yield was due to the presence of a second product appearing in
the reaction mixture (Table 4). The NMR, HRMS, and elemental
analysis data revealed this to be 1H-imidazole 15a, which has an
imidazole ring substituted by an acetoxy group in the C-5 methyl
group. NOE experiments supported this assignment, showing an
enhancement of the signals attributed to the methine proton and
methyl group of the chiral auxiliary when the methylene attached
to the acetoxy group was irradiated, thus indicating the spatial
proximity of these groups.
The formation of products 14 has been previously documented,
with the mechanism suggested (Scheme 3).17 The reaction of 1H-
imidazole N-oxides 8 with acetic anhydride leads to intermediate
I, which in turn undergoes the elimination of a molecule of acetic
acid to afford intermediate II. By N-acylation with another mole
of acetic anhydride, the latter can be converted into the intermedi-
ate 2-acetoxyimidazole III, which is stabilized by losing a molecule
of acetic anhydride to furnish the observed products 14.
+
+
+
OAc
OAc
-AcOH
N
N
N
N
N
N
Ph
Ph
AcO-
Ph
AcO-
H
R
R
R
IV
V
VI
Scheme 3.
conditions.17 However, there are analogous results from the reac-
tion between 1,2-dimethylbenzimidazole 3-oxide and acetic anhy-
dride, in which the C-2 methyl group is acetoxylated.35 Evidence of
the reaction mechanism was provided, showing similarity with a
vinylogous Polonovski reaction,36 in which aliphatic tertiary amine
N-oxides are activated with acid anhydrides to form the corre-
sponding iminium ion as the key intermediate, resulting in a ter-
tiary amide and an aldehyde. Considering these mechanisms, a
proposal for the case of compounds 8 can be made (Scheme 3).
Acetylation of the imidazole N-oxides 8 leads to species IV, whose
positive charge is delocalized between both nitrogen atoms to form
intermediate V. This is stabilized by a likely concerted elimination
of the N-acetoxy group, affording a molecule of acetic acid with one
of the protons of the C-5 methyl group to form the iminium ion VI.
The latter can undergo an attack from the acetoxy anion to give the
The presence of 15a is noteworthy, since there are no reports
regarding the formation of this kind of product under similar

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
235
neutral products 15. This mechanism can be proposed for the gen-
eration of the whole 15a–c series from the starting materials 8g, 8i,
and 8k, respectively (Table 4). Even though the process was mon-
itored by NMR, we were unable to detect or isolate an intermedi-
ate, such as salt-species VI,35 and only observed the two
products 14 and 15 along with the starting material.
It is worth noting that this type of side-product 15 was exclu-
sively detected and isolated from the 1H-imidazole N-oxides
substituted by a C-5 methyl group, 8g, 8i, and 8k (Table 4, entries
6, 8, and 10). This suggests that the formation of methylenic spe-
cies VI is much more stable than that originated from the C-4
methyl group or from a C-4 or C-5 ethyl or propyl group present
in the heterocycle. Likewise, the addition of the acetoxy group to
the exocyclic methylene of the VI species would be favored by
the fact that the reactive center is not substituted. Therefore, a ste-
ric effect cannot be ruled out as a controlling factor for this reaction
together with the electronic factor.
Taking into account the interesting N-propionyl group in the 2-
oxazolidinone and 2-imidazolidinone chiral auxiliaries, which
gives rise to a second chiral center in aldol or Michael additions,37
we explored the reactions of 1H-imidazole 3-oxides 8g–i, and 8k–l
with propionic anhydride under the reaction conditions similar to
those used with acetic anhydride (Table 4, entries 12–16). The
expected N-propionyl derivatives 14l–p were obtained in moder-
ate yields. In the case of the C-5 methyl substituted 1H-imidazole
3-oxides 8g, 8i, and 8k, the side-products (e.g., 15a–c) were
detected by NMR from the crude mixtures as a series of minor-
sized signals. None of these products were isolated by their decom-
position during the purification process.
of hydrogenation and therefore obtain the best diastereoselectivity
and chemical yield. Table 5 summarizes the most representative
assays, which included a variation in catalyst, catalyst loading, sol-
vent, pressure, and reaction time. All of the assays were carried out
at room temperature. The diastereoisomeric ratio was improved by
reducing the pressure of the vessel when the reaction mixture was
catalyzed with Pd/C (10%). Methanol was the best solvent, since
ethyl acetate (entry 6), ethanol, isopropanol, and toluene ineffi-
ciently favored any form of transformation. Among the catalysts
tested, Rh/C promoted the decomposition of the substrate.
However, palladium hydroxide (20%) displayed the best profile
considering the short reaction time, diastereoselectivity, and yield
(entry 8). Therefore, these conditions were applied for a series of
representative substrates, 14f–g, 14j–m, and 14p, furnishing mod-
est to good yields and high diastereoselectivity, in which isomer 16
was favored (entries 11–17). In the case of 14p, the hydrogenation
furnished 16h as a single isomer. Despite the efficient and selective
conversion of these substrates into the desired potential chiral
auxiliaries, the sulfenyl analogues 14d and 14e did not endure
the hydrogenation conditions, giving rise to decomposition prod-
ucts. The yields of products 16 were sometimes quite modest
(entries 8, 13, and 14) because of the hydrolysis of the N-3 amide
group of the substrates, probably due to the basic aqueous medium
(Pd(OH)2 being commercially available in 50% w/w H2O), affording
imidazolin-2-ones 18 as the main by-products of the reaction
(entries 8 and 11–17). Eventually, the latter by-products can be
recycled into the corresponding chiral compound 16, through a
two-step procedure starting with hydrogenation and followed by
N-acylation.30e
The diastereoisomeric ratio was determined by 1H NMR spec-
troscopy of the crude mixtures. The structure for the major isomer
was assigned in agreement with previous theoretical and X-ray
crystallographic studies for the condensation and hydrogenation
of 4-oxazolin-2-ones bearing the same chiral auxiliary.38 These
2.3. Preparation of the potential chiral auxiliaries 16–17
Due to the difference between its C-4 and C-5 substituents,
derivative 14i was selected to establish the optimum conditions
Table 5
Preparation of chiral auxiliaries 16–17 by hydrogenation of 1-acyl 4-oxazolin-2-ones 14
O
O
O
O
O
O
O
R3
R3
R3
H2
N
N
N
N
N
N
N
NH
R2
Ph
Ph
Ph
+
+ Ph
catalyst
25 ºC
R1
R2
R1
R2
R1
R2
R1
14
16
17
18
Entry
14
Catalyst
% Mol equiv
Solvent
P (psi)
t (h)
16/17/18 (ratio)a
dr (16/17)a
Yieldb (%)
1
2
3
4
5
6
7
8
14i
14i
14i
14i
14i
14i
14i
14i
14i
14i
14f
14g
14j
14k
14l
14m
14p
Pd/C (10%)
Pd/C (10%)
Pd/C (10%)
Pd/C (10%)
Pd/C (10%)
Pd/C (10%)
Rh/C (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
Pd(OH)2 (20%)
10
10
10
15
20
20
20
20
20
50
20
20
20
20
20
20
20
MeOH
MeOH
MeOH
MeOH
MeOH
EtOAc
MeOH
MeOH
AcOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
1500
500
300
100
(d)
(d)
(d)
(d)
(d)
(d)
(d)
(d)
(d)
(d)
(d)
(d)
(d)
24
24
48
24
24
24
96
6
24
24
6
6
6
16c/17c (50:50)
16c/17c (64:36)
16c/17c (66:34)
16c/17c (76:24)
16c/17c (89:11)
(e)
—
—
—
—
—
—
—
99:1
—
—
97:3
99:1
91:9
93:7
95:5
99:1
>99:1
(c)
(c)
(c)
(c)
(c)
—
—
(f)
16c/17c/18c (64.4:0.6:35)
(f)
(f)
16a/17a/18a (90:3:7)
16b/17b/18b (74.5:0.5:25)
16d/17d/18d (72:7:21)
16e/17e/18e (76.8:6.2:17)
16f/17f/18f (90:5:5)
16g/17g/18b (69.5:0.5:30)
16h/17h/18e (74:0:26)
16c/18c (42:22)
—
9
10
11
12
13
14
15
16
17
—
16a/18a (83:0)
16b/18b (79:20)
16d/18d (44:0)
16e/18e (42:11)
16f/18d (84:0)
16g/18b (66:24)
16h/18e (61:17)
6
6
6
24
a
b
c
d
e
f
Ratio determined by 1H NMR of the crude mixture.
Yields after column chromatography.
Not determined.
Atmospheric pressure (ca. 14.68 psi).
Recovered starting material.
Decomposition.

236
R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
H
R3
R3
O
H
O
H
H
O
2
H3C
Ph
R2
N
1
5
O
N
H3C
Ph
H
N
H
N
H3
Me
R1
4
Me
H
Figure 5. Interaction sites between the imidazolin-2-one double bond of 14 and the catalytic hydrogenation framework in the alpha (disfavored) and beta (favored)
approaches, leading to the major diastereoisomers imidazolidin-2-ones 16, as confirmed by the NOE experiments carried out with derivative 16a (R3 = H).
studies suggest a conformational preference of the chiral auxiliary,
with the proton of the (S)-stereogenic center adopting an almost
coplanar position to the heterocycle, leaving the methyl and phenyl
groups above (beta) and below (alpha) this plane, respectively
(Fig. 5).30e This conformation is in agreement with the X-ray struc-
ture of 1H-imidazole N-oxide 8g (Fig. 3), in which the phenyl group
of the chiral auxiliary clearly adopts an orthogonal conformation
with respect to the double bond. It is likely that this conformation
blocks an approach by the catalyst to this face. Accordingly, the cat-
alyzed syn-hydrogenation preferentially takes place at the beta face
of the heterocycle, leaving the C-4 and C-5 substituents underneath,
as shown in isomers 16 (Table 5). This stereochemistry was also
supported by the NOE experiments of compound 16a (Fig. 5), show-
ing an enhancement of the signals attributed to the methine proton
and phenyl group of the chiral auxiliary as well as of the signal of the
H-4 proton when the methyl group of the chiral auxiliary was irra-
diated. Reciprocal enhancements of the signals attributed to the
methine proton and methyl group (but not to the phenyl ring) of
the chiral auxiliary were observed when the H-4 proton was irradi-
ated. Irradiation of the signal attributed to the C-4 methyl group
induces an enhancement of the signals of the syn C-5 methyl group,
the methine of the auxiliary, and the aromatic protons signal, indi-
cating their spatial proximity as well as the conformational prefer-
ence of the chiral auxiliary as indicated in Figure 5.
500 MHz) and 13C (75 or 125 MHz) NMR spectra were recorded
on Varian Mercury-300 or Varian VNMR System instruments, with
TMS as internal standard; chemical shifts (d) are reported in ppm.
Mass spectra (MS) and high-resolution mass spectra (HRMS) were
obtained, in electron impact (EI) (70 eV) mode, on Thermo-Finni-
gan Polaris Q and Jeol JSM-GcMateII spectrometers, respectively.
Elemental analyses were performed on a CE-440 Exeter Analytical
instrument. Optical rotations were determined on a Jasco P-200
polarimeter. X-ray crystallographic structures were obtained on
an Oxford XcaliburS diffractometer. Analytical thin-layer chroma-
tography was performed on precoated silica gel plates (Merck
60F254). Flash column chromatography was performed over silica
gel (230–400 mesh) (Natland International Co.) or pre-treated sil-
ica gel (230–400 mesh) with 10% of triethylamine (w/w, hexane).
EtOH, MeOH, i-PrOH, and THF were freshly distilled over sodium,
and CH2Cl2 over calcium hydride prior to use. All other reagents
were used without further purification. The preparation of com-
pounds 6a and 7a has been previously described.31
4.2. General procedures for the preparation of compounds 5, 6
and 7
Method A: In a two-necked round bottom flask A with a thermom-
eter and cooled to ꢁ78 °C BF3ꢀEt2O (0.16 mol equiv) was added
dropwise to a solution of 1a (1.0 mol equiv) in the corresponding
alcohol 2b–c (20 mL), and the mixture was stirred for 15 min. Then,
at the same temperature, nitrosyl chloride [generated at room tem-
perature in a two-necked round bottom flask B by adding concd
aqueous HCl (37%) (10 mol equiv) dropwise through a funnel to
NaNO2 (10 mol equiv)] was bubbled into the solution of flask A
through a glassware connector, which was packed with NaNO2
and anhydrous Na2SO4. The mixture was stirred at ꢁ78 °C for 2 h
and then at room temperature for 2 h. The solvent was removed
under vacuum and extracted with EtOAc (3 ꢂ 10 mL), the organic
layers were dried (Na2SO4), and the solvent removed under vacuum.
The residue was purified by column chromatography over silica gel
(20 g/g crude, hexane/EtOAc, 95:5) to give compounds 6b–c.
Method B: In a two-necked round bottom flask at room temper-
ature, 1a (1.0 mol equiv) was added dropwise to a solution of the
corresponding thiophenol 3a–c (1.1 mol equiv) and DMAP
(0.2 mol equiv) in CH2Cl2 (10 mL), and the mixture was stirred
for 24 h. The mixture was diluted with CH2Cl2 (20 mL) and washed
with a 5% aqueous solution of HCl (10 mL) and brine (2 ꢂ 10 mL),
the organic layer was dried (Na2SO4) and the solvent removed
under vacuum. The residue was purified by column chromatogra-
phy over silica gel (15 g/g crude, hexane/EtOAc, 90:10) to give
compounds 5a–c.
3. Conclusion
A four-step synthetic methodology has been developed to
access to a variety of novel chiral 1-acyl-3-((S)-1-phenylethyl)imi-
dazolidin-2-ones 16a–h as potential auxiliaries in asymmetric
aldol condensation, Michael addition and [4+2] cycloadditions,
among other reactions. This versatile methodology includes the
preparation of the starting materials
a-oximinoketones 6, 7, and
12, and a readily available approach to yield the imidazole N-oxi-
des 8 and the N-acyl 4-imidazolin-2-ones 14, as precursors of the
chiral derivatives 16. The latter were obtained diastereoselectively
thanks to the induction accomplished by the (S)-methylbenzyl
moiety of 14 during the hydrogenation of the heterocyclic ring.
However, this approach is limited to using
a-oximinoketones
substituted by alkyl and aryl groups, since ethers and thioethers
incorporated into these substituents were not stable enough to
endure the reaction conditions. The use of these novel and poten-
tial auxiliaries in asymmetric synthesis will be studied, and the
results will be reported in due course.
4. Experimental
4.1. General
Method C: In a two-necked round bottom flask at 0 °C, an aque-
ous concd solution of HCl (37%) (6.0 mol equiv) dissolved in THF
(5.0 mL) was added dropwise to a mixture of 5 (1.0 mol equiv)
and NaNO2 (3.0 mol equiv) in THF (10 mL), and the mixture was
Melting points were determined on an Electrothermal capillary
apparatus and are uncorrected. Infrared spectra (IR) were recorded
on a FT-IR 2000 Perkin–Elmer spectrophotometer. 1H (300 or

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
237
stirred at this temperature for 2 h, then at room temperature for
12 h. The mixture was diluted with EtOAc (20 mL) and washed
with a saturated aqueous solution of K2CO3 until neutral and with
brine (2 ꢂ 10 mL), then the organic layer was dried (Na2SO4) and
the solvent removed under vacuum. The residue was purified by
column chromatography over silica gel (15 g/g crude, hexane/
EtOAc, 8:2) to give compounds 7a–c.
Method D: In a two-necked round bottom flask at room temper-
ature, 1a (1.0 mol equiv) was added dropwise to a solution of the
corresponding thiophenol 3a–c (1.0 mol equiv) and DABCO
(0.2 mol equiv) in THF (10 mL), and the mixture was heated to
65 °C and stirred for 4 h. At 0 °C, an aqueous concd solution of
HCl (37%) (6.0 mol equiv) and NaNO2 (3.0 mol equiv) in H2O
(5 mL) was successively added dropwise, and the mixture was stir-
red at this temperature for 2 h, then at room temperature for 12 h.
The mixture was diluted with EtOAc (20 mL) and washed with a
saturated aqueous solution of NaHCO3 until neutral and with brine
(2 ꢂ 10 mL), then the organic layer was dried (Na2SO4), and the sol-
vent removed under vacuum. The residue was purified by column
chromatography over silica gel (20 g/g crude, hexane/EtOAc, 8:2)
to give compounds 7a–c.
and acetic or propionic anhydride (5 mL) was stirred at reflux for
1 h. The remaining anhydride was removed under warm air flux
and the residue was purified by column chromatography over sil-
ica gel (20 g/g crude, hexane/EtOAc, 98:2) to give compounds
14d–p and 15a–c.
4.6. General procedures for the preparation of imidazolidin-2-
ones 16a–h/17a–h, and 1H-imidazolin-2-ones 18a–f
Method I: In a round bottom flask under an H2 atmosphere (ca.
759 mmHg (14.68 psi)), a mixture of the corresponding 1H-imidaz-
olin-2-ones 14 (1.0 mol equiv) in MeOH and Pd(OH)2/C (20%)
(0.125 mol equiv) (in w/w 50% H2O) was stirred at room tempera-
ture for 6–24 h. The mixture was filtered over Celite, the solvent
removed under vacuum, and the residue purified by column chro-
matography over silica gel (20 g/g crude, hexane/EtOAc, 98:2) to
give compounds 16a–h/17a–h and 18a–f.
4.7. 4-Ethoxy-3-(hydroxyimino)butan-2-one 6b31
Synthesized according to method A, with 1a (0.85 g, 12.1 mmol)
in EtOH (2b) (20 mL), BF3ꢀEt2O (0.28 g, 1.97 mmol), NaNO2 (8.40 g,
0.12 mol) and HCl (37%) (4.49 g, 0.123 mol), 6b (0.90 g, 51%) was
afforded as a pale yellow oil. Rf 0.50 (hexane/EtOAc, 3:2). IR (film)
4.3. General procedures for the preparation of compounds 12a–e
3273, 2979, 2879, 1692, 1444, 1365, 1263, 1089, 1024 cmꢁ1 1H
.
Method E: In a two-necked round bottom flask at room temper-
ature, pyridine (1.1 mol equiv) was added dropwise to a solution of
the corresponding a-diketone 10a–b (1.0 mol equiv) and hydroxyl-
amine hydrochloride (1.0 mol equiv) in MeOH (20 mL), and the
mixture was stirred for 2 h. The solvent was then removed under
vacuum and the residue was extracted with EtOAc (3 ꢂ 10 mL),
after which the organic layer was dried (Na2SO4) and the solvent
removed under vacuum. The residue was purified by column chro-
matography over silica gel (20 g/g crude, hexane/EtOAc, 95:5) to
give compounds 12a–b.
NMR (300 MHz, CDCl3) d 1.22 (t, J = 7.0 Hz, 3H, CH3CH2O), 2.40 (s,
3H, CH3CO), 3.59 (q, J = 7.0 Hz, 2H, CH3CH2O), 4.44 (s, 2H, H-4),
10.38 (br s, 1H, OH). 13C NMR (75 MHz, CDCl3) d 14.9 (CH3CH2O),
25.2 (C-1), 58.2 (C-4), 67.2 (CH3CH2O), 155.1 (C-3), 197.0 (C-2).
MS (70 eV) m/z 145 (M+, 7), 128 (7), 101 (61), 99 (100), 85 (47),
70 (31), 59 (64). HRMS (FAB) m/z [M+1]+ Calcd for C6H12
NO3: 146.0817. Found: 146.0818.
4.8. 3-(Hydroxyimino)-4-isopropoxybutan-2-one 6c31
Method F: In a two-necked round bottom flask A with a ther-
mometer and at room temperature, the corresponding ketones
11a–c (1.0 mol equiv) were dissolved in a mixture of Et2O/MeOH/
HCl (37%) (10:15:5 mL), and the resulting mixture was stirred for
15 min. Then at the same temperature, nitrosyl chloride [generated
at room temperature in a two-necked round bottom flask B by add-
ing concd H2SO4 (98%) (2.0 mol equiv) dropwise through a funnel
to NaNO2 (1.5 mol equiv)] was bubbled into the solution of flask
A through a glassware connector, which was packed with NaNO2
and anhydrous Na2SO4. The mixture was stirred at room tempera-
ture for 2 h, and then neutralized with NaHCO3. The solvent was
removed under vacuum and the residue was extracted with EtOAc
(3 ꢂ 10 mL), the organic layer was dried (Na2SO4), and the solvent
removed under vacuum. The residue was purified by column chro-
matography over silica gel (20 g/g crude, hexane/EtOAc, 85:15) to
give compounds 12c–e.
Synthesized according to method A, with 1a (0.85 g, 12.1 mmol)
in i-PrOH (2c) (20 mL), BF3ꢀEt2O (0.28 g, 1.97 mmol), NaNO2
(8.40 g, 0.12 mol) and HCl (37%) (4.49 g, 0.123 mol), 6c (0.89 g,
46%) was afforded as a pale yellow oil. Rf 0.51 (hexane/EtOAc,
3:2). IR (film) 3213, 3046, 2976, 2880, 1693, 1421, 1368, 1265,
1175, 1122, 1057, 1019 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.20
.
(d, J = 6.0 Hz, 6H, (CH3)2CHO), 2.40 (s, 3H, H-1), 3.73 (sept,
J = 6.0 Hz, 1H, (CH3)2CHO), 4.44 (s, 2H, H-4), 10.47 (br s, 1H, OH).
13C NMR (75 MHz, CDCl3) d 21.7 ((CH3)2CHO), 25.3 (C-1), 56.4 (C-
4), 73.2 ((CH3)2CHO), 155.3 (C-3), 197.1 (C-2). MS (70 eV) m/z
159 (M+, 4), 117 (100), 99 (49), 84 (9), 70 (7). HRMS (FAB) m/z
[M+1]+ Calcd for C7H14NO3: 160.0974. Found: 160.0964.
4.9. 4-Phenylthiobutan-2-one 5a31,39
Synthesized according to method B, with 1a (0.700 g, 0.01 mol),
3a (1.210 g, 0.011 mol) and DMAP (0.244 g, 0.002 mol), 5a (1.62 g,
90%) was afforded as a colorless oil. Rf 0.60 (hexane/EtOAc, 9:1). IR
(film) 3057, 2931, 1713, 1582, 1480, 1438, 1360, 1158, 1089, 1024,
4.4. General procedure for the preparation of chiral 1H-imidazole
N-oxides 8a–l
Method G: In a round bottom flask at room temperature, a mix-
ture of the corresponding a-oximinoketones 6a–c, 7a–c, and 12a–f
738, 690 cmꢁ1 1H NMR (500 MHz, CDCl3) d 2.11 (s, 3H, CH3CO),
.
2.73 (t, J = 7.0 Hz, 2H, H-3), 3.11 (t, J = 7.0 Hz, 2H, H-4), 7.15–7.19
(m, 1H, H-40), 7.24–7.29 (m, 2H, H-30), 7.30–7.34 (m, 2H, H-20).
13C NMR (125 MHz, CDCl3) d 27.2 (C-4), 29.8 (C-1), 42.8 (C-3),
126.0 (C-40), 128.8 (C-20), 129.2 (C-30), 135.5 (C-10), 206.2 (CO).
MS (70 eV) m/z 180 (M+, 100), 137 (20), 123 (11), 109 (24), 108
(31), 77 (5), 65 (8).
(1.0 mol equiv) and the chiral hexahydrotriazine 13 (0.5 mol e-
quiv) was dissolved in EtOH (15 mL) and stirred at reflux for 1–
12 h. The solvent was removed under vacuum and the residue
purified by column chromatography over silica gel (20 g/g crude,
hexane/EtOAc, 1:1) to give compounds 8a–l.
4.5. General procedure for the preparation of 1H-imidazolin-2-
ones 14d–p, and 1H-imidazoles 15a–c
4.10. 4-(4-Chlorophenylthio)butan-2-one 5b31
Method H: In a round bottom flask at room temperature, a mix-
ture of the corresponding 1H-imidazole N-oxides 8 (1.0 mol equiv)
Synthesized according to method B, with 1a (0.700 g, 0.01 mol),
3b (1.600 g, 0.011 mol) and DMAP (0.244 g, 0.002 mol), 5b (1.76 g,

238
R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
83%) was afforded as colorless crystals. Rf 0.59 (hexane/EtOAc,
9:1); mp 57–58 °C. IR (KBr) 1713, 1474, 1414, 1386, 1366, 1159,
as white crystals. Rf 0.40 (hexane/EtOAc, 4:1); mp 75–76 °C [Lit.40
76.8 °C]. IR (film) 3270, 3207, 3042, 2868, 1668, 1442, 1368, 1315,
1016, 981, 798 cmꢁ1. 1H NMR (500 MHz, CDCl3) d 2.00 (s, 3H, H-4),
2.40 (s, 3H, H-1), 9.26 (br s, 1H, NOH). 13C NMR (125 MHz, CDCl3) d
8.04 (C-4), 25.1 (C-1), 157.2 (C-3), 197.5 (C-2). MS (70 eV) m/z 101
(M+, 100), 86 (10), 84 (15), 58 (17), 54 (6), 51 (4).
1094, 1004, 824, 806 cmꢁ1 1H NMR (300 MHz, CDCl3) d 2.16 (s,
.
3H, CH3CO), 2.75 (t, J = 7.3 Hz, 2H, H-3), 3.11 (t, J = 7.3 Hz, 2H, H-
4), 7.27 (s, 4H, H-20, H-30). 13C NMR (75 MHz, CDCl3) d 27.7 (C-4),
30.1 (C-1), 42.9 (C-3), 129.1 (C-20), 130.9 (C-30), 132.4 (C-40),
134.2 (C-10), 206.3 (CO). MS (70 eV) m/z 216 (M++2, 47), 214 (M+,
100), 171 (18), 157 (16), 144 (34), 143 (35), 108 (27). Anal. Calcd
for C10H11ClOS: C, 55.94; H, 5.16. Found: C, 55.90; H, 5.10.
4.15. 4-(Hydroxyimino)hexan-3-one 12b
Synthesized according to method E, with 10b (1.14 g,
10.0 mmol), hydroxylamine hydrochloride (0.695 g, 10.0 mmol)
and pyridine (0.869 g, 11.0 mmol), 12b (1.19 g, 92%) was afforded
as white crystals. Rf 0.56 (hexane/EtOAc, 4:1); mp 58–59 °C. IR
(KBr) 3379, 1672, 1460, 1420, 1374, 1234, 1109, 1070, 999, 980,
4.11. 4-(4-Bromophenylthio)butan-2-one 5c31
Synthesized according to method B, with 1a (0.700 g, 0.01 mol)
in CH2Cl2 (10 mL), 3c (2.080 g, 0.011 mol) and DMAP (0.244 g,
0.002 mol), 5c (2.20 g, 86%) was afforded as colorless crystals. Rf
0.63 (hexane/EtOAc, 9:1); mp 60–61 °C (hexane). IR (film) 1714,
904, 751 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.05 (t, J = 7.7 Hz, 3H,
.
H-6), 1.12 (t, J = 7.3 Hz, 3H, H-1), 2.58 (q, J = 7.7 Hz, 2H, H-5),
2.79 (q, J = 7.3 Hz, 2H, H-2), 8.95 (br s, 1H, NOH). 13C NMR
(125 MHz, CDCl3) d 8.0 (C-1), 10.3 (C-6), 16.1 (C-5), 30.8 (C-2),
160.9 (C-4), 199.6 (C-3). MS (70 eV) m/z 129 (M+, 29), 112 (30),
101 (16), 84 (21), 72 (17), 57 (100). HRMS (EI) m/z [M+] Calcd for
C6H11NO2: 129.0790. Found: 129.0788.
1473, 1415, 1382, 1265, 1111, 1092, 1007, 823, 803, 737 cmꢁ1
.
1H NMR (500 MHz, CDCl3) d 2.15 (s, 3H, H-1), 2.75 (t, J = 7.0 Hz,
2H, H-3), 3.11 (t, J = 7.0 Hz, 2H, H-4), 7.17–7.21 (m, 2H, H-20),
7.39–7.42 (m, 2H, H-30). 13C NMR (125 MHz, CDCl3) d 27.4 (C-4),
30.0 (C-1), 42.8 (C-3), 120.1 (C-40), 130.9 (C-20), 132.0 (C-30),
135.0 (C-10), 206.2 (CO). MS (70 eV) m/z 261 (M++2, 2), 259 (M+,
2), 190 (100), 188 (93), 109 (90), 82 (8), 69 (13). Anal. Calcd for
4.16. 3-(Hydroxyimino)pentan-2-one 12c
C
10H11BrOS: C, 46.34; H, 4.28. Found: C, 46.12; H, 4.05.
Synthesized according to method F, with 11a (0.86 g,
10.0 mmol), NaNO2 (1.03 g, 15.0 mmol) and H2SO4 (1.92 g,
19.6 mmol), 12c (0.73 g, 63%) was afforded as a white solid. Rf
0.36 (hexane/EtOAc, 4:1); mp 55–56 °C. IR (film) 3202, 3045,
2978, 2947, 1668, 1432, 1377, 1248, 1074, 1051, 989, 929, 806,
4.12. 4-(4-Chlorophenylthio)-3-(hydroxyimino)butan-2-one 7b31
Synthesized according to method C, with 5b (1.070 g, 0.005 mol),
NaNO2 (1.035 g, 0.015 mol) and HCl (37%) (2.96 g, 0.03 mol), 7b
(0.75 g, 62%) was afforded as white crystals. Synthesized according
to method D, with 3b (1.45 g, 0.01 mol), DABCO (0.224 g,
0.002 mol), 1a (0.77 g, 0.011 mol), HCl (37%) (5.87 g, 0.06 mol) and
NaNO2 (2.08 g, 0.03 mol), 7b (1.59 g, 65%) was afforded as white
crystals. Rf 0.48 (hexane/EtOAc, 4:1); mp 94–95 °C. IR (KBr) 3423,
2965, 2833, 1765, 1716, 1496, 1408, 1341, 1281, 1220, 1169, 1086,
741 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.05 (t, J = 8.0 Hz, 3H, H-
.
5), 2.39 (s, 3H, H-1), 2.58 (q, J = 8.0 Hz, 2H, H-4), 9.10 (br s, 1H,
NOH). 13C NMR (125 MHz, CDCl3) d 10.3 (C-5), 15.9 (C-4), 25.3
(C-1), 161.5 (C-3), 197.2 (C-2). MS (70 eV) m/z 115 (M+, 51), 98
(100), 84 (22), 72 (20), 54 (19). HRMS (EI) m/z [M+] Calcd for
C5H9NO2: 115.0633. Found: 115.0639.
986, 837 cmꢁ1 1H NMR (300 MHz, CDCl3) d 2.34 (s, 3H, H-1), 3.92
.
4.17. 2-(Hydroxyimino)pentan-3-one 12d
(s, 2H, H-4), 7.22–7.28 (m, 2H, H-20), 7.35–7.41 (m, 2H, H-30), 8.07
(br s, 1H, NOH). 13C NMR (75 MHz, CDCl3) d 24.6 (C-4), 25.2 (C-1),
128.9 (C-20), 132.8 (C-30), 133.3 (C-40), 133.4 (C-10), 156.0 (C-3),
196.2 (C-2). MS (70 eV) m/z 243 (M+, 80), 199 (15), 183 (35), 157
(29), 143 (100), 108 (80), 75 (12). Anal. Calcd for C10H10ClNO2S: C,
49.28; H, 4.14; N, 5.75. Found: C, 49.11; H, 3.97; N, 5.61.
Synthesized according to method F, with 11b (0.86 g,
10.0 mmol), NaNO2 (1.03 g, 15.0 mmol) and H2SO4 (1.92 g,
19.6 mmol), 12d (0.75 g, 65%) was afforded as a white solid. Rf
0.36 (hexane/EtOAc, 4:1); mp 59–60 °C. IR (film) 3323, 1668,
1406, 1374, 1266, 1044, 1015, 911, 796, 731 cmꢁ1 1H NMR
.
(500 MHz, CDCl3) d 1.11 (t, J = 7.5 Hz, 3H, H-5), 2.00 (s, 3H, H-1),
2.80 (q, J = 7.5, Hz, 2H, H-4), 8.70 (br s, 1H, NOH). 13C NMR
(125 MHz, CDCl3) d 7.9 (C-5), 8.3 (C-1), 30.5 (C-4), 156.6 (C-2),
199.7 (C-3). MS (70 eV) m/z 115 (M+, 50), 98 (100), 84 (21), 72
(17), 54 (18). Anal. Calcd for C5H9N1O2: C, 52.16; H, 7.88; N,
12.17. Found: C, 52.16; H, 7.86; N, 12.18.
4.13. 4-(4-Bromophenylthio)-3-(hydroxyimino)butan-2-one 7c31
Synthesized according to method C, with 5c (1.300 g,
0.005 mol), NaNO2 (1.035 g, 0.015 mol) and HCl (37%) (2.96 g,
0.03 mol), 7c (0.86 g, 60%) was afforded as white crystals. Synthe-
sized according to method D, with 3c (1.87 g, 0.01 mol), DABCO
(0.224 g, 0.002 mol), 1a (0.77 g, 0.011 mol), HCl (37%) (5.87 g,
0.06 mol) and NaNO2 (2.08 g, 0.03 mol), 7c (1.58 g, 55%) was affor-
ded as white crystals. Rf 0.52 (hexane/EtOAc, 4:1); mp 83–84 °C. IR
(film) 3257, 3166, 3032, 2883, 1675, 1473, 1419, 1368, 1168, 1090,
1001, 807, 934 cmꢁ1. 1H NMR (500 MHz, CDCl3) d 2.34 (s, 3H, H-1),
3.94 (s, 2H, H-4), 7.30–7.33 (m, 2H, H-20), 7.36–7.40 (m, 2H, H-30),
10.63 (br s, 1H, NOH). 13C NMR (125 MHz, CDCl3) d 24.1 (C-4), 25.0
(C-1), 120.8 (C-40), 131.7 (C-20), 132.5 (C-30), 134.7 (C-10), 155.4 (C-
3), 195.9 (C-2). MS (70 eV) m/z 286 (M+, 5), 227 (40), 189 (100), 187
(65), 145 (8), 108 (92), 79 (9), 69 (19). HRMS (FAB) m/z [M+1]+
Calcd for C10H10BrNO2S: 286.9616. Found: 286.9605.
4.18. 3-(Hydroxyimino)hexan-2-one 12e
Synthesized according to method F, with 11c (1.10 g, 11.0 mmol),
NaNO2 (4.55 g, 66.0 mmol) and H2SO4 (6.857 g, 0.070 mol), 12e
(0.81 g, 57%) was afforded as a pale yellow solid. Rf 0.63 (hexane/
EtOAc, 7:3); mp 43–45 °C. IR (KBr) 3333, 2965, 1680, 1418, 1367,
1227, 1135, 1063, 986, 958, 609 cmꢁ1. 1H NMR (300 MHz, CDCl3) d
0.93 (t, J = 7.5, 3H, H-6), 1.48 (sext, J = 7.5 Hz, 2H, H-5), 2.37 (s, 3H,
H-1), 2.53 (t, J = 7.5, 2H, H-4), 8.75 (br s, 1H, NOH). 13C NMR
(125 MHz, CDCl3) d 14.2 (C-6), 19.4 (C-5), 24.3 (C-4), 25.3 (C-1),
160.5 (C-3), 197.1 (C-2). Anal. Calcd for C6H11NO2: C, 55.80; H,
8.58; N, 10.84. Found: C, 55.83; H, 8.55; N, 10.81.
4.14. 3-(Hydroxyimino)butan-2-one 12a
4.19. 1-(4-Methoxyphenyl)propan-1-one 11d
Synthesized according to method E, with 10a (0.86 g,
10.0 mmol), hydroxylamine hydrochloride (0.695 g, 10.0 mmol)
and pyridine (0.869 g, 11.0 mmol), 12a (0.96 g, 95%) was afforded
In a two-necked round bottom flask under N2 atmosphere and
at 0 °C, anisole (1.08 g, 10.0 mmol) and propionyl chloride

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
239
(1.39 g, 15.0 mmol) were mixed and the mixture stirred for 15 min.
Then, at the same temperature, BF3ꢀEt2O (1.42 g, 10.0 mmol) was
added dropwise and the mixture stirred for 4 h. The mixture was
washed with an aqueous saturated solution of NaHCO3 until neu-
tral, then the organic layer was extracted with EtOAc
(3 ꢂ 10 mL). The organic layer was dried (Na2SO4) and the solvent
removed under vacuum. The residue was purified by column chro-
matography over silica gel (20 g/g crude, hexane/EtOAc, 85:15) to
give 11d (0.73 g, 45%) as a yellow oil. Rf 0.36 (hexane/EtOAc,
8:2). IR (film) 2975, 2937, 1679, 1601, 1509, 1459, 1352, 1309,
113.5 (C-30), 128.8 (C-10), 132.8 (C-20), 157.0 (CH3CNOH), 163.6 (C-
40), 190.0 (CH3CNOHCO). Anal. Calcd for C10H11NO3: C, 62.17; H,
5.74; N, 7.25. Found: C, 62.13; H, 5.75; N, 7.25.
4.22. 1,3,5-Tris((S)-1-phenylethyl)-1,3,5-triazine 13
In a round bottom flask at room temperature, a mixture of (S)-
(ꢁ)-
a-methylbenzylamine (4.84 g, 0.04 mol) 1.0 mol equiv) and a
38% methanolic solution of formaldehyde (3.79 g, 0.048 mol) was
stirred for 1 h. The mixture was filtered, washing the solid phase
with MeOH (5 mL). The solid was dried under vacuum, giving 13
1257, 1227, 1171, 1030, 952, 843, 799 cmꢁ1 1H NMR (300 MHz,
.
CDCl3) d 1.18 (t, J = 7.3 Hz, 3H, CH3CH2CO), 2.95 (q, J = 7.3 Hz, 2H,
CH3CH2CO), 3.86 (s, 3H, CH3OAr), 6.90–6.95 (m, 2H, H-30), 7.92–
7.98 (m, 2H, H-20). 13C NMR (75 MHz, CDCl3) d 8.3 (CH3CH2CO),
31.4 (CH3CH2CO), 55.3 (CH3OAr), 113.6 (C-30), 129.9 (C-10), 130.2
(C-20), 163.2 (C-40), 199.5 (CH3CH2CO). Anal. Calcd for C10H12O2:
C, 73.15; H, 7.37. Found: C, 73.20; H, 7.32.
(15.3 g, 96%) as a white solid. mp 45–46 °C. [
MeOH). IR (KBr) 3013, 2970, 2800, 1491, 1452, 1370, 1350, 1303,
1283, 1206, 1114, 1082, 911, 761, 701 cmꢁ1 1H NMR (300 MHz,
a]
26 = +120.0 (c 1.15,
D
.
CDCl3) d 1.24 (d, J = 6.5 Hz, 3H, H-20), 3.34 (br s, 2H, H-2), 3.67 (q,
J = 6.5 Hz, 1H, H-10), 7.12–7.27 (m, 5H, H-200, H-300, H-400). 13C
RMN (75 MHz, CDCl3) d 20.1 (C-20), 59.4 (C-10), 70.0 (C-2), 126.7
(C-400), 127.3 (C-200 or C-300), 128.1 (C-300 or C-200), 144.3 (C-100). MS
(70 eV) m/z 399 (M+, 1), 212 (4), 156 (8), 139 (14), 106 (25), 105
(100), 103 (26), 91 (10), 79 (30), 77 (19). HRMS (EI) m/z [M+] Calcd
for C27H33N3: 399.2674. Found: 399.2691.
4.20. 1-(4-Methoxyphenyl)propane-1,2-dione 10c
In a two-necked round bottom flask under N2 atmosphere at 0 °C,
to a stirred mixture of 11d (1.64 g, 10.0 mmol) in Et2O (10 mL) and
NaNO2 (4.14 g, 60.0 mmol) a concd aqueous solution of HCl (37%)
(9.86 g, 0.1 mol) was added dropwise. The mixture was stirred at
room temperature for 24 h, then washed with an aqueous saturated
solution of NaHCO3 until neutral, and the organic layer was
extracted with EtOAc (3 ꢂ 10 mL). The combined organic layers
were dried (Na2SO4) and the solvent removed under vacuum. The
residue was purified by column chromatography over silica gel
(20 g/g crude, hexane/EtOAc, 85:15) to give 10c (0.77 g, 43%) as a
yellow solid. Rf 0.36 (Hexane/EtOAc, 8:2); mp 50–51 °C [Lit.41 44–
45 °C; Lit.42 38–39 °C]. IR (film) 2935, 1708, 1655, 1597, 1571,
4.23. (S)-4-(Methoxymethyl)-5-methyl-1-(1-phenylethyl)-1H-im
idazole 3-oxide 8a
Synthesized according to method G, with 6a (0.500 g,
3.82 mmol) and 13 (0.762 g, 1.91 mmol) and heating for 4 h, 8a
(0.77 g, 82%) was afforded as a brown oil. Rf 0.28 (hexane/EtOAc/
MeOH, 1:1:0.1). [a]
25 = +94.8 (c 0.29, MeOH). IR (film) 3397,
D
2981, 2934, 1653, 1454, 1334, 1220, 1195, 1091, 768, 703 cmꢁ1
.
1H NMR (300 MHz, CDCl3) d 1.85 (d, J = 6.9 Hz, 3H, CH3-20), 2.10
(s, 3H, CH3-5), 3.38 (s, 3H, CH3O), 4.45 (d, J = 12.3 Hz, 1H, OCH2-
4), 4.50 (d, J = 12.3 Hz, 1H, OCH2-4), 5.26 (q, J = 6.9 Hz, 1H, CH-10),
7.09–7.15 (m, 2H, H-200), 7.24–7.40 (m, 3H, H-300, H-400), 8.35 (s,
1509, 1422, 1307, 1261, 1152, 1025, 900, 841, 755, 693 cmꢁ1 1H
.
NMR (300 MHz, CDCl3) d 2.50 (s, 3H, CH3CO), 3.88 (s, 3H, CH3OAr),
6.88–7.02 (m, 2H, H-30), 7.96–8.05 (m, 2H, H-20). 13C NMR
(75 MHz, CDCl3) d 26.4 (CH3CO), 55.5 (CH3OAr), 114.0 (C-30),
124.5 (C-10), 132.6 (C-20), 164.7 (C-40), 189.9 (CH3COCO), 201.1
(CH3COCO). Anal. Calcd for C10H10O3: C, 67.41; H, 5.66. Found: C,
67.43; H, 5.65.
13
1H, H-2). C NMR (75 MHz, CDCl3) d 8.9 (CH3-5), 22.0 (CH3-20),
56.1 (CH-10), 58.2 (CH3O), 60.7 (OCH2-4), 124.2 (C-2), 125.2 (C-5),
125.6 (C-200), 127.2 (C-4), 128.4 (C-400), 129.2 (C-300), 139.4 (C-100).
MS (70 eV) m/z 246 (M+, 3), 230 (8), 200 (60), 156 (6), 105 (100),
94 (28), 77 (24). HRMS (EI) m/z [M+] Calcd for C14H18N2O2:
246.1368. Found: 246.1366.
4.21. 2-(Hydroxyimino)-1-(4-methoxyphenyl)propan-1-one 12f
4.24. (S)-4-(Ethoxymethyl)-5-methyl-1-(1-phenylethyl)-1H-im-
idazole 3-oxide 8b
Prepared according to method E, with 10c (1.78 g, 10.0 mmol),
hydroxylamine hydrochloride (0.695 g, 10.0 mmol) and pyridine
(0.87 g, 11.0 mmol), 12f (1.37 g, 71%) was afforded as a yellow
Synthesized according to method G, with 6b (0.500 g,
3.45 mmol) and 13 (0.688 g, 1.72 mmol) and heating for 4 h, 8b
(0.72 g, 81%) was afforded as a brown oil. Rf 0.30 (hexane/EtOAc/
solid. Alternatively, prepared according to
a modification of
MeOH, 1:1:0.1). [
2976, 1619, 1494, 1452, 1402, 1330, 1219, 1199, 1089, 769,
703 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.21 (t, J = 7.0 Hz, 3H, CH3-
a]
26 = +63.7 (c 0.186, MeOH). IR (film) 3390,
D
method C, with 11d (1.64 g, 10.0 mmol), NaNO2 (2.07 g,
30.0 mmol) in MeOH (30 mL), and an aqueous concd solution of
HCl (37%) (3.95 g, 40.0 mmol) in MeOH (10 mL) 12f was afforded
in the following manner. After stirring at room temperature for
24 h, NaNO2 (2.07 g, 30.0 mmol) in MeOH (30 mL), and an aqueous
concd solution of HCl (37%) (3.95 g, 40.0 mmol) in MeOH (10 mL)
were successively added and the mixture was stirred for 24 h. This
operation was repeated again. The mixture was washed with an
aqueous saturated solution of NaHCO3 until neutral, and the
organic layer was extracted with EtOAc (3 ꢂ 10 mL). The combined
organic layers were dried (Na2SO4) and the solvent removed under
vacuum. The residue was purified by column chromatography over
silica gel (20 g/g crude, hexane/EtOAc, 97:3) to give 12f (1.01 g,
52%) as a yellow solid. Rf 0.40 (Hex/AcOEt 7:3); mp 128–129 °C
[Lit.43 114–118 °C]. IR (film) 3247, 2923, 1651, 1599, 1513, 1458,
.
CH2O), 1.80 (d, J = 7.0 Hz, 3H, CH3-20), 2.13 (s, 3H, CH3-5), 3.60 (q,
J = 7.0 Hz, 2H, CH3CH2O), 4.53 (d, J = 13.0 Hz, 1H, OCH2-4), 4.61 (d,
J = 13.0 Hz, 1H, OCH2-4), 5.26 (q, J = 7.0 Hz, 1H, CH-10), 7.11 (d,
J = 6.5 Hz, 2H, H-200), 7.27–7.40 (m, 3H, H-300, H-400), 7.96 (s, 1H, H-
2). 13C NMR (125 MHz, CDCl3) d 8.8 (CH3-5), 15.0 (CH3CH2O), 21.8
(CH3-20), 55.5 (CH-10), 59.1 (OCH2-4), 65.9 (CH3CH2O), 122.8 (C-2),
124.6 (C-5), 125.5 (C-200), 127.9 (C-4), 128.3 (C-400), 129.1 (C-300),
139.5 (C-100). EM (70 eV) m/z 260 (M+, 4), 189 (12), 171 (40), 145
(83), 144 (80), 130 (36), 104 (81), 103 (100), 77 (49), 59 (29). HRMS
(EI) m/z [M+] Calcd for C15H20N2O2: 260.1525. Found: 260.1524.
4.25. (S)-4-(Isopropoxymethyl)-5-methyl-1-(1-phenylethyl)-1H-
imidazole 3-oxide 8c
1328, 1276, 1116, 1019, 899, 848, 758, 745 cmꢁ1 1H NMR
.
(300 MHz, CDCl3) d 2.17 (s, 3H, CH3CNOH), 3.87 (s, 3H, CH3OAr),
6.86–6.98 (m, 2H, H-30), 7.92–7.98 (m, 2H, H-20), 8.31 (br s, 1H,
NOH). 13C RMN (75 MHz, CDCl3) d 10.5 (CH3CNOH), 55.5 (CH3OAr),
Synthesized according to method G, with 6c (0.500 g,
3.14 mmol) and 13 (0.626 g, 1.57 mmol) and heating for 4 h, 8c

240
R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
(0.65 g, 75%) was afforded as a brown oil. Rf 0.31 (hexane/EtOAc/
MeOH, 1:1:0.1). [
26 = +58.6 (c 0.11, MeOH). IR (film) 3398,
2973, 1624, 1454, 1382, 1369, 1328, 1220, 1200, 1123, 1052,
767, 704 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.19 (d, J = 6.0 Hz,
1091, 1067, 1008, 813, 764, 701 cmꢁ1 1H NMR (500 MHz, CDCl3)
.
a
]
D
d 1.73 (s, 3H, CH3-5), 1.77 (d, J = 7.0 Hz, 3H, CH3-20), 4.07 (d,
J = 14.0 Hz, 1H, SCH2-4), 4.15 (d, J = 14.0 Hz, 1H, SCH2-4), 5.15 (q,
J = 7.0 Hz, 1H, CH-10), 7.01 (dd, J = 7.5, 1.5 Hz, 2H, H-200), 7.22–
7.26 (m, 2H, H-2000), 7.26–7.30 (m, 2H, H-3000), 7.33–7.39 (m, 3H,
H-300, H-400), 7.97 (s, 1H, H-2). 13C NMR (125 MHz, CDCl3) d 8.7
(CH3-5), 21.8 (CH3-20), 25.9 (SCH2-4), 55.7 (CH-10), 121.2 (C-4000),
122.8 (C-2), 123.4 (C-5), 125.4 (C-200), 126.6 (C-4), 128.4 (C-400),
129.2 (C-300), 131.8 (C-2000), 133.5 (C-3000), 134.1 (C-1000), 139.6 (C-
100). MS (70 eV) m/z 402 (M+, 1), 378 (17), 376 (27), 297 (5), 189
(100), 187 (97), 108 (69), 69 (11). HRMS (EI) m/z [M+] Calcd for C19-
H19N2OSBr: 402.0401. Found: 402.0391.
.
3H, (CH3)2CH), 1.20 (d, J = 6.0 Hz, 3H, (CH3)2CH), 1.82 (d,
J = 7.0 Hz, 3H, CH3-20), 2.13 (s, 3H, CH3-5), 3.76 (sept, J = 6.0 Hz,
1H, (CH3)2CH), 4.53 (d, J = 12.5 Hz, 1H, OCH2-4), 4.61 (d,
J = 12.5 Hz, 1H, OCH2-4), 5.27 (q, J = 7.0 Hz, 1H, CH-10), 7.13 (br d,
J = 7.0 Hz, 2H, H-200), 7.28–7.39 (m, 3H, H-300, H-400), 8.17 (s, 1H,
13
H-2). C NMR (125 MHz, CDCl3) d 8.8 (CH3-5), 21.87 (CH3-20),
21.89 ((CH3)2CH), 22.0 (CH3)2CH), 55.6 (CH-10), 57.1 (OCH2-4),
71.4 ((CH3)2CH), 123.3 (C-2), 124.5 (C-5), 125.6 (C-200), 128.1 (C-
4), 128.3 (C-400), 129.1 (C-300), 139.6 (C-100). EM (70 eV) m/z 200
(M+ꢁ74, 46), 156 (6), 120 (6), 105 (100), 95 (37), 77 (24). HRMS
(EI) m/z [M+] Calcd for C16H22N2O2: 274.1681. Found: 274.1692.
4.29. (S)-4,5-Dimethyl-1-(1-phenylethyl)-1H-imidazole 3-oxide 8g
Synthesized according to method G, with 12a (0.505 g,
5.00 mmol) and 13 (1.00 g, 2.5 mmol) and heating for 12 h, 8g
(1.05 g, 98%) was afforded as a white solid. Rf 0.41 (hexane/EtOAc/
MeOH, 1:1:0.1); mp 105–106 °C [Lit.12a 105–106 °C; Lit.34b 230 °C].
4.26. (S)-5-Methyl-1-(1-phenylethyl)-4-(phenylthiomethyl)-1H-
imidazole 3-oxide 8d
[a]
26 = +134.7 (c 0.835, MeOH) [Lit.34b +131.5 (c 1.02, MeOH)]. IR
D
Synthesized according to method G, with 7a (0.500 g, 2.39 mmol)
and 13 (0.477 g, 1.20 mmol) and heating for 1 h, 8d (0.66 g, 85%) was
afforded as a brown oil. Rf 0.18 (hexane/EtOAc/MeOH, 1:1:0.1).
(film) 3394, 3058, 2983, 1631, 1453, 1407, 1379, 1332, 1196, 1147,
751, 698 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.79 (d, J = 7.0 Hz, 3H,
.
CH3-20), 2.00 (s, 3H, CH3-5), 2.18 (s, 3H, CH3-4), 5.23 (q, J = 7.0 Hz,
1H, CH-10), 7.08 (dd, J = 7.5, 1.5 Hz, 2H, H-200), 7.28–7.33 (m, 1H, H-
400), 7.33–7.38 (m, 2H, H-300), 7.94 (s, 1H, H-2). 13C NMR (125 MHz,
CDCl3) d 7.1 (CH3-4), 8.9 (CH3-5), 21.9 (CH3-20), 55.4 (CH-10), 121.1
(C-5), 122.4 (C-2), 125.5 (C-200), 127.1 (C-4), 128.2 (C-400), 129.1 (C-
300), 140.0 (C-100). MS (70 eV) m/z 216 (M+, 19), 116 (28), 111 (33),
105 (100), 103 (38), 77 (41). HRMS (EI) [M++1] Calcd for
[a
]
D
27 = ꢁ39.1 (c 0.0197, MeOH). IR (film) 3412, 1646, 1494, 1438,
1407, 1338, 1245, 1218, 1024, 889, 746, 696 cmꢁ1
.
1H NMR
(300 MHz, CDCl3) d 1.59 (s, 3H, CH3-5), 1.75 (d, J = 6.9 Hz, 3H, CH3-
20), 4.05 (d, J = 14.0 Hz, 1H, SCH2-4), 4.13 (d, J = 14.0 Hz, 1H, SCH2-
4), 5.13 (q, J = 6.9 Hz, 1H, CH-10), 7.01 (dd, J = 7.8, 2.1 Hz, 2H, H-200),
7.10–7.22 (m, 3H, H-2000, H-4000), 7.30–7.40 (m, 5H, H-300, H-400, H-
3000), 8.00 (s, 1H, H-2). 13C NMR (75 MHz, CDCl3) d 8.3 (CH3-5), 21.7
(CH3-20), 26.2 (SCH2-4), 55.3 (CH-10), 122.6 (C-2), 123.2 (C-5),
125.3 (C-200), 126.7 (C-4), 127.1 (C-4000), 128.1 (C-400), 128.6 (C-2000),
128.9 (C-300), 132.4 (C-3000), 134.6 (C-1000), 139.5 (C-100). MS (70 eV)
m/z 324 (M+, 7), 311 (5), 274 (8), 230 (9), 205 (12), 186 (17), 160
(11), 109 (100), 88 (16), 65 (25). HRMS (EI) m/z [M+] Calcd for C19H20-
N2OS: 324.1296. Found: 324.1294.
C13H17N2O: 217.1341. Found: 217.1340.
4.30. (S)-4,5-Diethyl-1-(1-phenylethyl)-1H-imidazole 3-oxide 8h
Synthesized according to method G, with 12b (0.500 g,
3.88 mmol) and 13 (0.773 g, 1.94 mmol) and heating for 12 h, 8h
(0.88 g, 93%) was afforded as a white solid. Rf 0.45 (hexane/EtOAc/
MeOH, 1:1:0.1). [
2974, 2936, 1664, 1454, 1403, 1380, 1352, 1314, 1258, 1216, 1185,
860, 764, 702 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.00 (t, J = 7.5 Hz,
a]
24 = +99.8 (c 0.489, MeOH). IR (film) 3378,
D
4.27. (S)-4-((4-Chlorophenylthio)methyl)-5-methyl-1-(1-phenyl
ethyl)-1H-imidazole 3-oxide 8e
.
3H, CH3CH2-5), 1.23 (t, J = 7.5 Hz, 3H, CH3CH2-4), 1.80 (d, J = 7.0 Hz,
3H, CH3-20), 2.38–2.53 (m, 2H, CH3CH2-5), 2.58–2.74 (m, 1H, CH3-
CH2-4), 5.26 (q, J = 7.0 Hz, 1H, CH-10), 7.09 (br d, J = 7.0 Hz, 2H, H-
200), 7.28–7.33 (m, 1H, H-400), 7.33–7.40 (m, 2H, H-300), 7.96 (s, 1H,
H-2). 13C NMR (125 MHz, CDCl3) d 13.1 (CH3CH2-4), 14.3 (CH3CH2-
5), 15.4 (CH3CH2-5), 16.5 (CH3CH2-4), 22.3 (CH3-20), 55.1 (CH-10),
122.7 (C-2), 125.4 (C-200), 126.6 (C-5), 128.3 (C-400), 129.1 (C-300),
131.7 (C-4), 140.3 (C-100). MS (70 eV) m/z 244 (M+, 1), 228 (100),
199 (40), 124 (29), 109 (25), 105 (85). Anal. Calcd for C15H20N2O:
C, 73.74; H, 8.25; N, 11.47. Found: C, 73.76; H, 8.19; N, 11.49.
Synthesized according to method G, with 7b (0.500 g,
2.06 mmol) and 13 (0.410 g, 1.05 mmol) and heating for 1 h, 8e
(0.583 g, 80%) was afforded as a pale yellow oil. Rf 0.19 (hexane/
EtOAc/MeOH, 1:1:0.1). [
a]
D
25 = ꢁ61.1 (c 0.157, MeOH). IR (film)
3392, 1673, 1475, 1454, 1387, 1338, 1094, 1012, 817, 764,
702 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.70 (s, 3H, CH3-5), 1.77
.
(d, J = 7.0 Hz, 3H, CH3-20), 4.05 (d, J = 14.0 Hz, 1H, SCH2-4), 4.14
(d, J = 14.0 Hz, 1H, SCH2-4), 5.15 (q, J = 7.0 Hz, 1H, CH-10), 7.01
(dd, J = 8.0, 2.0 Hz, 2H, H-200), 7.10–7.14 (m, 2H, H-2000), 7.27–7.31
(m, 2H, H-3000), 7.32–7.38 (m, 3H, H-300, H-400), 8.04 (s, 1H, H-2).
13C NMR (125 MHz, CDCl3) d 8.5 (CH3-5), 21.6 (CH3-20), 26.1
(SCH2-4), 55.7 (CH-10), 123.0 (C-2), 123.4 (C-5), 125.3 (C-200),
126.2 (C-4), 128.2 (C-400), 128.7 (C-2000), 129.0 (C-300), 132.9 (C-4000),
133.2 (C-1000), 133.5 (C-3000), 139.4 (C-100). MS (70 eV) m/z 358 (M+,
3), 278 (100), 245 (24), 230 (46), 214 (50), 199 (14), 139 (84),
124 (73), 96 (71). HRMS (EI) m/z [M+] Calcd for C19H19N2OSCl:
358.0907. Found: 358.0902.
4.31. (S)-4-Ethyl-5-methyl-1-(1-phenylethyl)-1H-imidazole 3-
oxide 8i
Synthesized according to method G, with 12c (0.50 g, 4.4 mmol)
and 13 (0.868 g, 2.20 mmol) and heating for 12 h, 8i (0.96 g, 96%)
was afforded as a pale yellow oil. Rf 0.42 (hexane/EtOAc/MeOH,
1:1:0.1). [
a]
23 = +6.8 (c 1.614, MeOH). IR (film) 3410, 2981, 1647,
D
1494, 1455, 1352, 1316, 1265, 1218, 1145, 851, 765, 704 cmꢁ1
.
1H NMR (500 MHz, CDCl3) d 1.21 (t, J = 7.5 Hz, 3H, CH3CH2-4),
1.79 (d, J = 7.0 Hz, 3H, CH3-20), 2.02 (s, 3H, CH3-5), 2.58–2.74 (m,
2H, CH3CH2-4), 5.22 (q, J = 7.0 Hz, 1H, CH-10), 7.08 (br d,
J = 8.0 Hz, 2H, H-200), 7.28–7.33 (m, 1H, H-400), 7.33–7.38 (m, 2H,
H-300), 7.91 (s, 1H, H-2). 13C NMR (125 MHz, CDCl3) d 8.7 (CH3-5),
12.8 (CH3CH2-4), 15.3 (CH3CH2-4), 22.0 (CH3-20), 55.5 (CH-10),
120.8 (C-5), 122.6 (C-2), 125.5 (C-200), 128.3 (C-400), 129.1 (C-300),
132.3 (C-4), 140.0 (C-100). MS (70 eV) m/z 230 (M+, 1), 214 (16),
4.28. (S)-4-((4-Bromophenylthio)methyl)-5-methyl-1-(1-phenyl
ethyl)-1H-imidazole 3-oxide 8f
Synthesized according to method G, with 7c (0.500 g,
1.74 mmol) and 13 (0.339 g, 0.85 mmol) and heating for 1 h, 8f
(0.55 g, 79%) was afforded as a pale yellow oil. Rf 0.19 (hexane/
EtOAc/MeOH, 1:1:0.1). [
3368, 3085, 2981, 1673, 1620, 1473, 1452, 1385, 1336, 1245,
a
]
28 = ꢁ57.4 (c 0.19, MeOH). IR (film)
D

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
241
199 (13), 123 (9), 105 (100), 95 (15), 77 (24). HRMS (EI) [M+] Calcd
for C14H18N2O: 230.1419. Found: 230.1427.
as a colorless oil. Rf 0.60 (hexane/EtOAc, 7:3). [
a
]
27 = +26.8 (c
D
0.306, MeOH). IR (film) 1711, 1474, 1409, 1361, 1313, 1236,
1179, 1093, 1012, 820, 699 cmꢁ1 1H NMR (300 MHz, CDCl3) d
.
1.21 (s, 3H, CH3-4), 1.73 (d, J = 7.1 Hz, 3H, CH3-20), 2.73 (s, 3H, CH3-
CO-1), 4.11 (s, 2H, SCH2-5), 5.50 (q, J = 7.1 Hz, 1H, CH-10), 7.10–7.15
(m, 2H, H-2000), 7.19–7.26 (m, 4H, H-200, H-3000), 7.30–7.40 (m, 3H, H-
4.32. (S)-5-Ethyl-4-methyl-1-(1-phenylethyl)-1H-imidazole 3-
oxide 8j
13
400, 300). C NMR (75 MHz, CDCl3) d 8.8 (CH3-4), 18.0 (CH3-20), 26.3
Synthesized according to method G, with 12d (0.500 g,
4.35 mmol) and 13 (0.867 g, 2.17 mmol) and heating for 12 h, 8j
(1.00 g, 91%) was afforded as a yellow oil. Rf 0.34 (hexane/EtOAc/
(CH3CO-1), 32.0 (SCH2-5), 50.6 (CH-10), 113.8 (C-5), 121.9 (C-4),
126.4 (C-200), 127.6 (C-400), 128.7 (C-300), 128.9 (C-2000), 132.7
(C-4000), 134.4 (C-1000), 135.8 (C-3000), 139.9 (C-100), 152.3 (C-2),
170.9 (CH3CO-1). MS (70 eV) m/z 400 (M+, 1), 144 (100), 109
(55), 82 (25), 69 (54). HRMS (EI) m/z [M+] Calcd for C21H21ClN2O2S:
400.1012. Found: 400.1021.
MeOH, 1:1:0.1). [
2979, 1651, 1622, 1454, 1406, 1384, 1336, 1218, 1145, 766,
705 cmꢁ1 1H NMR (300 MHz, CDCl3) d 0.97 (t, J = 7.5 Hz, 3H, CH3-
a]
26 = +101.7 (c 0.168, MeOH). IR (film) 3400,
D
.
CH2-5), 1.80 (d, J = 6.9 Hz, 3H, CH3-20), 2.21 (s, 3H, CH3-4), 2.35–
2.55 (m, 2H, CH3CH2-5), 5.27 (q, J = 6.9 Hz, 1H, CH-10), 7.06–7.15
(m, 2H, H-200), 7.28–7.40 (m, 3H, H-300, H-400), 7.93 (s, 1H, H-2).
13C NMR (75 MHz, CDCl3) d 7.1 (CH3-4), 13.7 (CH3CH2-5), 16.7
(CH3CH2-5), 22.3 (CH3-20), 55.1 (CH-10), 122.4 (C-2), 125.4 (C-200),
126.7 (C-4), 126.9 (C-5), 128.3 (C-400), 129.1 (C-300), 140.3 (C-100).
MS (70 eV) m/z 230 (M+, 7), 215 (12), 214 (20), 181 (7), 126 (14),
110 (60), 106 (100), 103 (21), 96 (30), 79 (22), 77 (16). HRMS
(EI) [M+] Calcd for C14H18N2O: 230.1419. Found: 230.1416.
4.36. (S)-1-Acetyl-5-((4-bromophenylthio)methyl)-4-methyl-3-
(1-phenylethyl)-1H-imidazol-2(3H)-one 14e
Synthesized according to method H, with 8f (0.500 g,
1.24 mmol) and acetic anhydride, 14e (0.535 g, 97%) was afforded
as a colorless oil. Rf 0.80 (hexane/EtOAc, 8:2). [
a
]
25 = ꢁ65.7 (c
D
0.087, MeOH). IR (film) 1709, 1655, 1472, 1409, 1361, 1312,
1235, 1179, 1009, 816, 699 cmꢁ1 1H NMR (500 MHz, CDCl3) d
.
1.24 (s, 3H, CH3-4), 1.74 (d, J = 7.5 Hz, 3H, CH3-20), 2.73 (s, 3H, CH3-
CO2), 4.11 (s, 2H, SCH2-5), 5.50 (q, J = 7.5 Hz, 1H, CH-10), 7.14–7.17
(m, 2H, H-3000), 7.22 (br d, J = 8.0 Hz, 2H, H-200), 7.26–7.29 (m, 2H, H-
2000), 7.28–7.33 (m, 1H, H-400), 7.34–7.39 (m, 2H, H-300). 13C NMR
(125 MHz, CDCl3) d 8.8 (CH3-4), 18.0 (CH3-20), 26.2 (CH3CO-1),
31.8 (SCH2-5), 50.6 (CH-10), 113.8 (C-5), 121.9 (C-4), 122.4 (C-4000),
126.4 (C-200), 127.6 (C-400), 128.7 (C-300), 131.9 (C-2000), 133.5 (C-
1000), 135.9 (C-3000), 139.9 (C-100), 152.3 (C-2), 170.8 (CH3CO-1); MS
(70 eV) m/z 444 (M+, 1), 190 (100), 188 (93), 109 (99), 84 (16),
69 (13). HRMS (EI) m/z [M+] Calcd for C21H21BrN2O2S: 444.0507.
Found: 444.0512.
4.33. (S)-5-Methyl-1-(1-phenylethyl)-4-propyl-1H-imidazole 3-
oxide 8k
Synthesized according to method G, with 12e (0.500 g,
3.88 mmol) and 13 (0.773 g, 1.94 mmol) and heating for 12 h, 8k
(0.85 g, 90%) was afforded as a pale yellow solid. Rf 0.40 (hexane/
EtOAc/MeOH, 1:1:0.1); mp 60–61 °C. [
IR (film) 3393, 2962, 2932, 1676, 1495, 1455, 1383, 1359, 1329,
1216, 1027, 765, 703 cmꢁ1 1H NMR (300 MHz, CDCl3) d 0.92 (t,
a]
24 = +97.6 (c 0.101, MeOH).
D
.
J = 7.5 Hz, 3H, CH3(CH2)2-4), 1.67 (sext, J = 7.5 Hz, 2H, CH3CH2CH2-
4), 1.79 (d, J = 7.0 Hz, 3H, CH3-20), 2.00 (s, 3H, CH3-5), 2.50–2.70 (m,
2H, CH3CH2CH2-4), 5.23 (q, J = 7.0 Hz, 1H, CH-10), 7.04–7.11 (m, 2H,
H-200), 7.27–7.41 (m, 3H, H-300, H-400), 7.99 (s, 1H, H-2). 13C NMR
(75 MHz, CDCl3) d 8.9 (CH3-5), 13.7 (CH3CH2CH2-4), 21.3 (CH3CH2-
CH2-4), 22.0 (CH3-20), 23.7 (CH3CH2CH2-4), 55.6 (CH-10), 121.6
(C-5), 122.8 (C-2), 125.5 (C-200), 128.3 (C-400), 129.2 (C-300), 130.8
(C-4), 140.1 (C-100). Anal. Calcd for C15H20N2O: C, 73.74; H, 8.25;
N, 11.47. Found: C, 73.71; H, 8.35; N, 11.42.
4.37. (S)-1-Acetyl-4,5-dimethyl-3-(1-phenylethyl)-1H-imidazol-
2(3H)-one 14f
4.37.1. (S)-5-(Acetoxymethyl)-4-methyl-1-(1-phenylethyl)-1H-
imidazole 15a
Synthesized according to method H, with 8g (0.500 g,
2.31 mmol) and acetic anhydride, 14f (0.32 g, 54%) was afforded
as a yellow oil and 15a (0.12 g, 20%) as a yellow oil.
4.34. (S)-5-(4-Methoxyphenyl)-4-methyl-1-(1-phenylethyl)-1H-
imidazole 3-oxide 8l
Data of 14f: Rf 0.63 (hexane/EtOAc, 7:3). [
a
]
25 = ꢁ52.25 (c 1.68,
D
MeOH). IR (film) 1711, 1669, 1450, 1370, 1312, 1176, 1026, 751,
700 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.68 (d, J = 0.9 Hz, 3H,
.
Synthesized according to method G, with 12f (1.93 g,
10.0 mmol) and 13 (2.00 g, 5.0 mmol) and heating for 12 h, 8l
(2.95 g, 96%) was afforded as a pale yellow oil. Rf 0.36 (hexane/
CH3-4), 1.79 (d, J = 7.2 Hz, 3H, CH3-20), 2.19 (d, J = 1.2 Hz, 3H,
CH3-5), 2.67 (s, 3H, CH3CO-1), 5.56 (q, J = 7.2 Hz, 1H, CH-10),
7.22–7.37 (m, 5H, PhH). 13C NMR (75 MHz, CDCl3) d 9.1 (CH3-4),
11.6 (CH3-5), 18.1 (CH3-20), 26.2 (CH3CO-1), 50.3 (CH-10), 114.0
(C-5), 117.7 (C-4), 126.3 (C-200), 127.3 (C-400), 128.5 (C-300), 140.4
(C-100), 152.4 (C-2), 171.0 (CH3CO-1). MS (70 eV) m/z 258 (M+,
30), 216 (55), 112 (100), 105 (75), 77 (14). HRMS (EI) m/z [M+]
Calcd for C15H18N2O2: 258.1368. Found: 258.1379.
EtOAc/MeOH, 1:1:0.1). [
a
]
27 = ꢁ37.3 (c 0.26, MeOH). IR (film)
D
3289, 2977, 2932, 1713, 1603, 1513, 1453, 1418, 1326, 1252,
1175, 1021, 833, 762, 700 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.73
.
(d, J = 7.1 Hz, 3H, CH3-20), 2.13 (s, 3H, CH3-4), 3.85 (s, 3H, CH3O),
5.19 (q, J = 7.1 Hz, 1H, CH-10), 6.88–6.95 (m, 2H, H-3000), 6.96–7.08
(m, 4H, H-200, H-2000), 7.16–7.38 (m, 3H, H-300, H-400), 8.23 (s, 1H,
Data of 15a: Rf 0.50 (hexane/EtOAc, 7:3). [
a
]
22 = ꢁ44.1 (c 0.068,
D
13
H-2). C NMR (75 MHz, CDCl3) d 7.58 (CH3-4), 21.9 (CH3-20), 55.3
MeOH). IR (film) 2935, 1736, 1494, 1454, 1382, 1367, 1226, 1022,
(CH3O), 55.6 (CH-10), 114.3 (C-3000), 119.1 (C-1000), 123.8 (C-2),
125.8 (C-200), 126.5 (C-5), 127.7 (C-4), 128.3 (C-400), 129 (C-300),
131.8 (C-2000), 140.1 (C-100), 160.4 (C-4000). HRMS (EI) [M+] Calcd for
962, 761, 700 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.85 (s, 3H, CH3-
.
CO2CH2-5), 1.86 (d, J = 7.1 Hz, 3H, CH3-20), 2.26 (s, 3H, CH3-4),
4.75 (d, J = 13.7 Hz, 1H, CH3CO2CH2-5), 5.02 (d, J = 13.7 Hz, 1H, CH3-
CO2CH2-5), 5.36 (q, J = 7.1 Hz, 1H, CH-10), 7.01–7.07 (m, 2H, H-200),
7.23–7.36 (m, 3H, H-300, H-400), 7.67 (s, 1H, H-2). 13C NMR (75 MHz,
CDCl3) d 12.7 (CH3-4), 20.6 (CH3CO2CH2-5), 22.6 (CH3-20), 54.5
(CH3CO2CH2-5), 55.0 (CH-10), 121.7 (C-5), 125.5 (C-200), 127.8
(C-400), 128.9 (C-300), 134.9 (C-2), 139.5 (C-4), 141.8 (C-100), 170.6
(CH3CO2CH2-5). HRMS (EI) m/z [M+] Calcd for C15H18N2O2:
258.1368. Found: 258.1357.
C19H20N2O2: 308.1525. Found: 308.1520.
4.35. (S)-1-Acetyl-5-((4-chlorophenylthio)methyl)-4-methyl-3-
(1-phenylethyl)-1H-imidazol-2(3H)-one 14d
Synthesized according to method H, with 8e (0.300 g,
0.84 mmol) and acetic anhydride, 14d (3.15 g, 94%) was afforded

242
R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
4.38. (S)-1-Acetyl-4,5-diethyl-3-(1-phenylethyl)-1H-imidazol-
2(3H)-one 14g
(q, J = 7.5 Hz, 2H, CH3CH2-4), 2.65 (s, 3H, CH3CO-1), 5.38 (q,
J = 7.5 Hz, 1H, CH-10), 7.22–7.40 (m, 5H, PhH). 13C NMR (75 MHz,
CDCl3) d 11.7 (CH3-5), 13.6 (CH3CH2-4), 16.2 (CH3CH2-4), 18.0
(CH3-20), 26.3 (CH3CO-1), 50.8 (CH-10), 113.8 (C-5), 123.4 (C-4),
126.4 (C-200), 127.3 (C-400), 128.5 (C-300), 140.4 (C-100), 152.7 (C-2),
171.1 (CH3CO-1). Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40; N,
10.29. Found: C, 70.57; H, 7.38; N, 10.27.
Synthesized according to method H, with 8h (0.500 g,
2.05 mmol) and acetic anhydride, 14g (0.35 g, 60%) was afforded
as a yellow solid. Rf 0.63 (hexane/EtOAc, 7:3); mp 76–78 °C.
[a]
26 = +46.5 (c 0.142, MeOH). IR (film) 2974, 2935, 1713, 1452,
D
1407, 1369, 1334, 1309, 1289, 1271, 1255, 1115, 754, 698 cmꢁ1
.
1H NMR (300 MHz, CDCl3) d 0.89 (t, J = 7.5 Hz, 3H, CH3CH2-4),
1.10 (t, J = 7.3 Hz, 3H, CH3CH2-5), 1.86 (d, J = 7.5 Hz, 3H, CH3-20),
2.28 (q, J = 7.5 Hz, 2H, CH3CH2-4), 2.65 (s, 3H, CH3CO-1), 2.68 (qd,
J = 7.3, 0.9 Hz, 2H, CH3CH2-5), 5.34 (q, J = 7.5 Hz, 1H, CH-10), 7.24–
7.39 (m, 5H, PhH). 13C NMR (75 MHz, CDCl3) d 14.3 (CH3CH2-4),
14.9 (CH3CH2-5), 16.2 (CH3CH2-4), 18.0 (CH3-20), 18.5 (CH3CH2-5),
26.5 (CH3CO-1), 51.0 (CH-10), 119.8 (C-5), 123.5 (C-4), 126.5 (C-
200), 127.4 (C-400), 128.5 (C-300), 140.5 (C-100), 152.5 (C-2), 170.8 (CH3-
CO-1). Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found:
C, 71.33; H, 7.75; N, 9.76.
4.41. (S)-1-Acetyl-4-methyl-3-(1-phenylethyl)-5-propyl-1H-
imidazol-2(3H)-one 14j
4.41.1. (S)-5-(Acetoxymethyl)-1-(1-phenylethyl)-4-propyl-1H-
imidazole 15c
Synthesized according to method H, with 8k (0.500 g,
2.05 mmol) and acetic anhydride, 14j (0.228 g, 39%) was afforded
as a yellow oil and 15c (0.099 g, 16%) as a yellow oil.
Data of 14j: Rf 0.63 (hexane/EtOAc, 7:3). [
MeOH). IR (film) 2962, 2934, 1710, 1454, 1369, 1307, 1291,
1234, 1026, 754, 699 cmꢁ1 1H NMR (300 MHz, CDCl3) d 0.86 (t,
a]
28 = +46.5 (c 0.142,
D
.
4.39. (S)-1-Acetyl-5-ethyl-4-methyl-3-(1-phenylethyl)-1H-imid-
azol-2(3H)-one 14h
J = 7.5 Hz, 3H, CH3(CH2)2-5), 1.47 (sext, J = 7.5 Hz, 2H, CH3CH2CH2-
5), 1.71 (s, 3H, CH3-4), 1.81 (d, J = 7.3 Hz, 3H, CH3-20), 2.62 (br t,
J = 7.5 Hz, 2H, CH3CH2CH2-5), 2.68 (s, 3H, CH3CO-1), 5.57 (q,
J = 7.3 Hz, 1H, CH-10), 7.24–7.39 (m, 5H, PhH). 13C NMR (75 MHz,
CDCl3) d 9.3 (CH3-4), 13.5 (CH3(CH2)2-5), 18.2 (CH3-20), 22.8 (CH3-
CH2CH2-5), 26.5 (CH3CO-1), 26.6 (CH3CH2CH2-5), 50.4 (CH-10),
118.3 (C-4), 118.5 (C-5), 126.3 (C-200), 127.4 (C-400), 128.6 (C-300),
140.4 (C-100), 152.7 (C-2), 170.8 (CH3CO-1). HRMS (EI) m/z [M+]
Calcd for C17H22N2O2: 286.1681. Found: 286.1675.
4.39.1. (S)-5-(Acetoxymethyl)-4-ethyl-1-(1-phenylethyl)-1H-im-
idazole 15b
Synthesized according to method H, with 8i (0.500 g,
2.17 mmol) and acetic anhydride, 14h (0.31 g, 53%) was afforded
as a yellow oil and 15b (0.106 g, 18%) as a yellow oil.
Data of 14h: Rf 0.56 (hexane/EtOAc, 7:3). [
a
]
22 = ꢁ50.0 (c 0.13,
D
MeOH). IR (film) 1710, 1661, 1407, 1368, 1316, 1267, 1175,
Data of 15c: Rf 0.50 (hexane/EtOAc, 7:3). [
a
]
29 = ꢁ14.4 (c 0.202,
D
1099, 966, 753, 699 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.05 (t,
.
MeOH). IR (film) 2960, 2934, 1737, 1493, 1454, 1368, 1234, 1021,
J = 7.5 Hz, 3H, CH3CH2-5), 1.72 (s, 3H, CH3-4), 1.81 (d, J = 7.2 Hz,
3H, CH3-20), 2.63–2.69 (m, 2H, CH3CH2-5), 2.67 (s, 3H, CH3CO-1),
5.55 (q, J = 7.2 Hz, 1H, CH-10), 7.24–7.37 (m, 5H, PhH). 13C NMR
(75 MHz, CDCl3) d 10.2 (CH3-4), 14.5 (CH3CH2-5), 18.1 (CH3-20),
18.2 (CH3CH2-5), 26.4 (CH3CO-1), 50.4 (CH-10), 117.6 (C-4), 120.0
(C-5), 126.4 (C-200), 127.3 (C-400), 128.5 (C-300), 140.4 (C-100), 152.6
(C-2), 170.6 (CH3CO-1). MS (70 eV) m/z 272 (M+, 54), 230 (100),
126 (79), 105 (64), 77 (14). HRMS (EI) m/z [M+] Calcd for
962, 761, 700 cmꢁ1 1H NMR (500 MHz, CDCl3) d 0.92 (t, J = 7.5 Hz,
.
3H, CH3CH2CH2-4), 1.67 (sext, J = 7.5 Hz, 2H, CH3CH2CH2-4), 1.85
(s, 3H, CH3CO2CH2-5), 1.86 (d, J = 7.0 Hz, 3H, CH3-20), 2.55
(t, J = 7.5 Hz, 2H, CH3CH2CH2-4), 4.77 (d, J = 13.8 Hz, 1H, CH3CO2-
CH2-5), 5.02 (d, J = 13.8 Hz, 1H, CH3CO2CH2-5), 5.37 (q, J = 7.0 Hz,
1H, CH-10), 7.00–7.04 (m, 2H, H-200), 7.24–7.28 (m, 1H, H-400),
7.29–7.34 (m, 2H, H-300), 7.67 (s, 1H, H-2). 13C NMR (125 MHz,
CDCl3) d 13.8 (CH3CH2CH2-4), 20.6 (CH3CO2CH2-5), 22.6 (CH3-20),
23.1 (CH3CH2CH2-4), 29.0 (CH3CH2CH2-4), 54.5 (CH3CO2CH2-5),
55.0 (CH-10), 120.3 (C-5), 125.4 (C-200), 127.7 (C-400), 128.9 (C-300),
135.1 (C-2), 142.0 (C-100), 143.8 (C-4), 170.6 (CH3CO2CH2-5). HRMS
(EI) m/z [M+] Calcd for C17H22N2O2: 286.1682. Found: 286.1681.
C
16H20N2O2: 272.1525. Found: 272.1532.
Data of 15b: Rf 0.40 (hexane/EtOAc, 7:3). [
a
]
D
26 = ꢁ18.1 (c 0.086,
MeOH). IR (film) 3374, 2975, 2935, 1738, 1493, 1454, 1367, 1226,
1020, 954, 761, 700 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.24 (t,
.
J = 7.5 Hz, 3H, CH3CH2-5), 1.85 (s, 3H, CH3CO2CH2-4), 1.86 (d,
J = 6.9 Hz, 3H, CH3-20), 2.60 (q, J = 7.5 Hz, 2H, CH3CH2-5), 4.76 (d,
J = 13.8 Hz, 1H, CH3CO2CH2-4), 5.02 (d, J = 13.8 Hz, 1H, CH3CO2CH2-
4), 5.36 (q, J = 6.9 Hz, 1H, CH-10), 7.01–7.06 (m, 2H, H-200), 7.23–
7.36 (m, 3H, H-300, H-400), 7.68 (s, 1H, H-2). 13C NMR (75 MHz,
CDCl3) d 14.5 (CH3CH2-4), 20.3 (CH3CH2-4), 20.7 (CH3CO2CH2-5),
22.7 (CH3-20), 54.4 (CH3CO2CH2-5), 55.0 (CH-10), 120.9 (C-5),
125.5 (C-200), 127.8 (C-400), 128.9 (C-300), 135.1 (C-2), 141.9 (C-100),
145.3 (C-4), 170.6 (CH3CO2CH2-5). MS (70 eV) m/z 272 (M+, 10),
213 (23), 212 (89), 197 (20), 125 (30) 108 (26), 105 (100), 97
(23), 85 (26), 79 (30), 71 (31), 57 (32). HRMS (EI) m/z [M+] Calcd
for C16H20N2O2: 272.1525. Found: 272.1528.
4.42. (S)-1-Acetyl-4-(4-methoxyphenyl)-5-methyl-3-(-1-phenyl
ethyl)-1H-imidazol-2(3H)-one 14k
Synthesized according to method H, with 8l (0.500 g, 1.62 mmol)
and acetic anhydride, 14k (0.26 g, 46%) was afforded as a yellow oil.
Rf 0.40 (hexane/EtOAc, 7:3). [
a]
26 = ꢁ10.2 (c 0.188, MeOH). IR (KBr)
D
2924, 2853, 1731, 1605, 1511, 1456, 1373, 1306, 1253, 1173, 1030,
845, 762, 699 cmꢁ1. 1H NMR (300 MHz, CDCl3) d 1.72 (d, J = 7.2 Hz,
3H, CH3-20), 2.15 (s, 3H, CH3-5), 2.69 (s, 3H, CH3CO-1), 3.83 (s, 3H,
CH3OAr), 5.08 (q, J = 7.2 Hz, 1H, CH-10), 6.83–6.90 (m, 2H, H-3000),
6.97 (br s, 2H, H-2000), 7.15–7.36 (m, 5H, PhH). 13C NMR (75 MHz,
CDCl3) d 12.6 (CH3-5), 17.8 (CH3-20), 26.3 (CH3CO-1), 52.1 (CH-10),
55.3 (CH3OAr), 113.9 (C-3000), 115.8 (C-5) 120.2 (C-1000), 123.5 (C-4),
126.7 (C-200), 127.3 (C-400), 128.3 (C-300), 132.2 (C-2000), 140.7 (C-100),
151.9 (C-2), 159.9 (C-4000), 171.3 (CH3CO-1). HRMS(EI) m/z [M+] Calcd
for C21H22N2O3: 350.1631. Found: 350.1615.
4.40. (S)-1-Acetyl-4-ethyl-5-methyl-3-(1-phenylethyl)-1H-imid-
azol-2(3H)-one 14i
Synthesized according to method H, with 8j (0.500 g,
2.17 mmol) and acetic anhydride, 14i (0.35 g, 60%) was afforded
as a yellow solid. Rf 0.56 (hexane/EtOAc, 7:3); mp 49–51 °C.
4.43. (S)-4,5-Dimethyl-3-(1-phenylethyl)-1-propionyl-1H-imid-
azol-2(3H)-one 14l
[
a
]
26 = ꢁ6.0 (c 0.133, MeOH). IR (KBr) 2978, 2934, 1708, 1497,
D
1454, 1370, 1318, 1234, 1205, 1174, 1108, 1030, 950, 753,
701 cmꢁ1
.
1H NMR (300 MHz, CDCl3) d 0.84 (t, J = 7.5 Hz, 3H, CH3-
Synthesized according to method H, with 8g (0.500 g,
2.31 mmol) and propionic anhydride, 14l (0.34 g, 54%) was affor-
CH2-4), 1.85 (d, J = 7.5 Hz, 3H, CH3-20), 2.23 (s, 3H, CH3-5), 2.26

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
243
ded as a white solid. Rf 0.80 (hexane/EtOAc, 7:3); mp 36–37 °C.
(CH3-20), 22.7 (CH3CH2CH2-5), 26.6 (CH3CH2CH2-5), 31.4 (CH3CH2-
CO-1), 50.2 (CH-10), 118.1 (C-4), 118.3 (C-5), 126.2 (C-200), 127.2
(C-400), 128.4 (C-300), 140.4 (C-100), 152.4 (C-2), 174.6 (CH3CH2CO-
1). HRMS (EI) m/z [M+] Calcd for C18H24N2O2: 300.1838. Found:
300.1832.
[
a]
D
29 = ꢁ55.2 (c 0.290, MeOH). IR (film) 2980, 2935, 1711, 1668,
1496, 1451, 1359, 1288, 1215, 1095, 1076, 1026, 955, 890, 751,
700 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.20 (t, J = 7.5 Hz, 3H, CH3-
.
CH2CO-1), 1.70 (d, J = 1.0 Hz, 3H, CH3-4), 1.80 (d, J = 7.3 Hz, 3H,
CH3-20), 2.21 (d, J = 1.0 Hz, 3H, CH3-5), 3.14 (q, J = 7.5 Hz, 2H, CH3-
CH2CO-1), 5.57 (q, J = 7.3 Hz, 1H, CH-10), 7.25–7.36 (m, 5H, PhH).
13C NMR (125 MHz, CDCl3) d 8.4 (CH3CH2CO-1), 9.1 (CH3-4), 11.7
(CH3-5), 18.2 (CH3-20), 31.3 (CH3CH2CO-1), 50.4 (CH-10), 114.2
(C-5), 117.7 (C-4), 126.4 (C-200), 127.3 (C-400), 128.6 (C-300), 140.5
(C-100), 152.4 (C-2), 175.0 (CH3CH2CO-1). HRMS (EI) m/z [M+] Calcd
for C16H20N2O2: 272.1525. Found: 272.1525.
4.47. (S)-4-(4-Methoxyphenyl)-5-methyl-3-(1-phenylethyl)-1-
propionyl-1H-imidazol-2(3H)-one 14p
Synthesized according to method H, with 8l (0.500 g,
1.62 mmol) and propionic anhydride, 14p (0.30 g, 50%) was affor-
ded as a yellow oil. Rf 0.73 (hexane/EtOAc, 7:3). [
a
]
26 = ꢁ10.4 (c
D
0.091, MeOH). IR (film) 2977, 2936, 1714, 1606, 1514, 1358,
4.44. (S)-4,5-Diethyl-3-(1-phenylethyl)-1-propionyl-1H-imidaz-
ol-2(3H)-one 14m
1295, 1249, 1175, 1032, 940, 831, 751, 697 cmꢁ1 1H NMR
.
(300 MHz, CDCl3) d 1.20 (t, J = 7.2 Hz, 3H, CH3CH2CO-1), 1.72 (d,
J = 7.2 Hz, 3H, CH3-20), 2.15 (s, 3H, CH3-5), 3.16 (q, J = 7.2 Hz, 2H,
CH3CH2CO-1), 3.83 (s, 3H, CH3OAr), 5.08 (q, J = 7.2 Hz, 1H, CH-10),
6.82–6.91 (m, 2H, H-3000), 6.92–7.05 (m, 2H, H-2000), 7.15–7.32 (m,
5H, PhH). 13C NMR (75 MHz, CDCl3) d 8.3 (CH3CH2CO-1), 12.6
(CH3-5), 17.8 (CH3-20), 31.4 (CH3CH2CO-1), 52.1 (CH-10), 55.3
(CH3OAr), 113.9 (C-3000), 115.8 (C-5), 120.3 (C-1000), 123.4 (C-4),
126.7 (C-200), 127.2 (C-400), 128.3 (C-300), 132.2 (C-2000), 140.7
(C-100), 151.8 (C-2), 159.9 (C-4000), 175.2 (CH3CH2CO-1). HRMS (EI)
m/z [M+] Calcd for C22H24N2O3: 364.1787. Found: 364.1779.
Synthesized according to method H, with 8h (0.500 g,
2.05 mmol) and propionic anhydride, 14m (0.44 g, 72%) was affor-
ded as a yellow solid. Rf 0.71 (hexane/EtOAc, 7:3); mp 33–34 °C.
[
a]
D
26 = ꢁ8.25 (c 0.257, MeOH). IR (film) 2976, 2937, 1711, 1453,
1367, 1290, 1249, 1114, 1065, 753, 698 cmꢁ1
.
1H NMR (500 MHz,
CDCl3) d 0.89 (t, J = 7.5 Hz, 3H, CH3CH2-4), 1.10 (t, J = 7.5 Hz, 3H,
CH3CH2-5), 1.18 (t, J = 7.5 Hz, 3H, CH3CH2CO-1), 1.86 (d,
J = 7.5 Hz, 3H, CH3-20), 2.29 (q, J = 7.5 Hz, 2H, CH3CH2-4), 2.69 (qd,
J = 7.5, 3.0 Hz, 2H, CH3CH2-5), 3.11 (q, J = 7.5 Hz, 3H, CH3CH2CO-
1), 5.34 (q, J = 7.5 Hz, 1H, CH-10), 7.24–7.36 (m, 5H, PhH). 13C
NMR (125 MHz, CDCl3) d 8.4 (CH3CH2CO-1), 14.3 (CH3CH2-4),
14.9 (CH3CH2-5), 16.3 (CH3CH2-4), 18.0 (CH3-20), 18.6 (CH3CH2-5),
31.5 (CH3CH2CO-1), 51.0 (CH-10), 119.9 (C-5), 123.4 (C-4), 126.5
(C-200), 127.3 (C-400), 128.5 (C-300), 140.6 (C-100), 152.3 (C-2), 174.7
(CH3CH2CO-1). HRMS (EI) m/z [M+] Calcd for C18H24N2O2:
300.1838. Found: 300.1830.
4.48. (4S,5R)-1-Acetyl-4,5-dimethyl-3-((S)-1-phenylethyl)imida-
zolidin-2-one 16a
Synthesized according to method I, with 14f (0.050 g,
0.194 mmol) and Pd(OH)2/C (20%)/H2O (50%) (0.027 g,
0.024 mmol) and stirring for 6 h, 16a (0.042 g, 83%) was afforded
as a yellow oil. Rf 0.37 (hexane/EtOAc, 7:3). [
MeOH). IR (film) 2981, 1717, 1680, 1375, 1258, 937, 778, 756,
699 cmꢁ1 1H NMR (300 MHz, CDCl3) d 0.82 (d, J = 6.6 Hz, 3H,
a]
26 = +1.7 (c 0.241,
D
4.45. (S)-5-Ethyl-4-methyl-3-(1-phenylethyl)-1-propionyl-1H-
imidazol-2(3H)-one 14n
.
CH3-4), 1.14 (d, J = 6.3 Hz, 3H, CH3-5), 1.71 (d, J = 7.2 Hz, 3H, CH3-
20), 2.54 (s, 3H, CH3CO-1), 3.86 (dq, J = 7.7, 6.6 Hz, 1H, H-4), 4.33
(dq, J = 7.7, 6.3 Hz, 1H, H-5), 5.22 (q, J = 7.2 Hz, 1H, CH-10), 7.24–
7.40 (m, 5H, PhH). 13C NMR (75 MHz, CDCl3) d 13.1 (CH3-5), 14.2
(CH3-4), 15.7 (CH3-20), 24.2 (CH3CO-1), 49.8 (CH-10), 50.8 (C-4),
51.1 (C-5), 126.6 (C-200), 127.2 (C-400), 128.3 (C-300), 141.8 (C-100),
155.5 (C-2), 170.2 (CH3CO-1). HRMS (EI) m/z [M+] Calcd for
Synthesized according to method H, with 8i (0.500 g,
2.17 mmol) and propionic anhydride, 14n (0.37 g, 60%) was affor-
ded as a yellow oil. Rf 0.63 (hexane/EtOAc, 7:3). [
a]
D
26 = ꢁ46.35 (c
0.255, MeOH). IR (film) 2978, 2938, 1708, 1660, 1450, 1363,
1249, 1179, 1116, 753, 698 cmꢁ1 1H NMR (300 MHz, CDCl3) d
.
1.06 (t, J = 7.4 Hz, 3H, CH3CH2-5), 1.20 (t, J = 7.2 Hz, 3H, CH3CH2-
CO-1), 1.72 (s, 3H, CH3-4), 1.81 (d, J = 7.3 Hz, 3H, CH3-20), 2.67
(qd, J = 7.4, 1.8 Hz, 2H, CH3CH2-5), 3.15 (q, J = 7.2 Hz, 2H, CH3CH2-
CO-1), 5.56 (q, J = 7.3 Hz, 1H, CH-10), 7.23–7.39 (m, 5H, PhH). 13C
NMR (75 MHz, CDCl3) d 8.4 (CH3CH2CO-1), 9.0 (CH3-4), 14.5 (CH3-
CH2-5), 18.1 (CH3-20), 18.3 (CH3CH2-5), 31.4 (CH3CH2CO-1), 50.4
(CH-10), 117.6 (C-4), 120.0 (C-5), 126.4 (C-200), 127.3 (C-400), 128.5
(C-300), 140.5 (C-100), 152.4 (C-2), 174.6 (CH3CH2CO-1). HRMS (EI)
m/z [M+] Calcd for C17H22N2O2: 286.1681. Found: 286.1674.
C15H20N2O2: 260.1525. Found: 260.1525.
4.49. (4S,5R)-1-Acetyl-4,5-diethyl-3-((S)-1-phenylethyl)imidazolidin-
2-one 16b
4.49.1. (S)-4,5-Diethyl-1-(1-phenylethyl)-1H-imidazol-2(3H)-
one 18b
Synthesized according to method I, with 14g (0.200 g,
0.70 mmol) and Pd(OH)2/C (20%)/H2O (50%) (0.100 g, 0.089 mmol)
and stirring for 6 h, 16b (0.16 g, 79%) was afforded as a yellow oil
and 18b (0.034 g, 20%) as a pale yellow oil.
4.46. (S)-4-Methyl-3-(1-phenylethyl)-1-propionyl-5-propyl-1H-
imidazol-2(3H)-one 14o
Data of 16b: Rf 0.52 (hexane/EtOAc, 7:3). [a D
]
25 = ꢁ11.6 (c 0.093,
Synthesized according to method H, with 8k (0.500 g,
2.05 mmol) and propionic anhydride, 14o (0.184 g, 30%) was affor-
MeOH). IR (film) 2971, 1718, 1684, 1457, 1375, 1355, 1316, 1253,
1219, 966, 756, 698 cmꢁ1 1H NMR (300 MHz, CDCl3) d 0.79 (t,
.
ded as a yellow oil. Rf 0.67 (hexane/EtOAc, 7:3). [
a
]
26 = ꢁ48.6 (c
D
J = 7.2 Hz, 3H, CH3CH2-4), 0.95 (t, J = 7.5 Hz, 3H, CH3CH2-5), 0.93–
1.08 (m, 1H, CH3CH2-5), 1.30–1.48 (m, 1H, CH3CH2-4), 1.49–1.64 (m,
1H, CH3CH2-5), 1.66 (d, J = 7.2 Hz, 3H, CH3-20), 1.70–1.88 (m, 1H, CH3-
CH2-4), 2.57 (s, 3H, CH3CO-1), 3.61 (ddd, J = 11.7, 7.2, 3.3 Hz, 1H, H-4),
4.40–4.48 (m, 1H, H-5), 5.30 (q, J = 7.2 Hz, 1H, CH-10), 7.24–7.37 (m,
5H, PhH). 13C NMR (75 MHz, CDCl3) d 9.6 (CH3CH2-5), 10.2 (CH3CH2-
4), 15.2 (CH3-20), 19.9 (CH3CH2-4), 20.3 (CH3CH2-5), 24.0 (CH3CO-1),
49.7 (CH-10), 53.4 (C-5), 57.8 (C-4), 126.5 (C-200), 127.0 (C-400), 128.2
0.195, MeOH). IR (film) 2962, 2936, 1709, 1660, 1455, 1404,
1364, 1281, 1229, 1022, 752, 698 cmꢁ1 1H NMR (300 MHz, CDCl3)
.
d 0.87 (t, J = 7.3 Hz, 3H, CH3(CH2)2-5), 1.20 (t, J = 7.2 Hz, 3H, CH3-
CH2CO-1), 1.49 (sext, J = 7.3 Hz, 2H, CH3CH2CH2-5), 1.72 (s, 3H,
CH3-4), 1.81 (d, J = 7.2 Hz, 3H, CH3-20), 2.63 (t, J = 7.3 Hz, 2H, CH3-
CH2CH2-5), 3.15 (q, J = 7.2 Hz, 2H, CH3CH2CO-1), 5.57 (q,
J = 7.2 Hz, 1H, CH-10), 7.22–7.38 (m, 5H, PhH). 13C NMR (75 MHz,
CDCl3) d 8.3 (CH3CH2CO-1), 9.2 (CH3-4), 13.4 (CH3(CH2)2-5), 18.0

244
R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
(C-300), 141.6 (C-100), 156.4 (C-2), 170.3 (CH3CO-1). HRMS (EI) m/z [M+]
4.52. (4S,5R)-1-Acetyl-4-(4-methoxyphenyl)-5-methyl-3-((S)-1-
Calcd for C17H24N2O2: 288.1838. Found: 288.1837.
phenylethyl)imidazolidin-2-one 16e
Data of 18b: Rf 0.45 (hexane/EtOAc, 7:3). [
a]
D
25 = ꢁ11.4 (c 0.109,
MeOH). IR (film) 3237, 2974, 2935, 1712, 1672, 1449, 1410, 1378,
4.52.1. (S)-5-(4-Methoxyphenyl)-4-methyl-1-(1-phenylethyl)-
1H-imidazol-2(3H)-one 18e
1076, 1027, 756, 698 cmꢁ1 1H NMR (300 MHz, CDCl3) d 0.81 (t,
.
J = 7.5 Hz, 3H, CH3CH2-5), 1.12 (t, J = 7.5 Hz, 3H, CH3CH2-4), 1.85
(d, J = 7.2 Hz, 3H, CH3-20), 2.22 (q, J = 7.5 Hz, 2H, CH3CH2-5), 2.32
(q, J = 7.5 Hz, 2H, CH3CH2-4), 5.39 (q, J = 7.2 Hz, 1H, CH-10), 7.17–
7.40 (m, 5H, PhH), 10.15 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3)
d 13.7 (CH3CH2-4), 14.8 (CH3CH2-5), 16.7 (CH3CH2-5), 17.4 (CH3-
CH2-4), 18.7 (CH3-20), 50.5 (CH-10), 118.8 (C-4), 119.1 (C-5), 126.5
(C-200), 126.9 (C-400), 128.3 (C-300), 141.6 (C-100), 154.3 (C-2). HRMS
(EI) m/z [M+] Calcd for C15H20N2O: 244.1576. Found: 244.1561.
Synthesized according to method I, with 14k (0.249 g,
0.71 mmol) and Pd(OH)2/C (20%)/H2O (50%) (0.100 g, 0.089 mmol)
and stirring for 24 h, 16e (0.105 g, 42%) was afforded as a yellow oil
and 18e (0.024 g, 11%) as a pale yellow oil.
Data of 16e: Rf 0.48 (hexane/EtOAc, 8:2). [
a]
22 = ꢁ15.8 (c 0.061,
D
MeOH). IR (film) 2981, 2937, 1721, 1682, 1613, 1514, 1407, 1374,
1353, 1339, 1246, 1218, 1174, 1030, 910, 841, 729, 699 cmꢁ1 1H
.
NMR (500 MHz, CDCl3) d 0.87 (d, J = 6.5 Hz, 3H, CH3-5), 1.84 (d,
J = 7.5 Hz, 3H, CH3-20), 2.53 (s, 3H, CH3CO-1), 3.82 (s, 3H, CH3OAr),
4.36–4.46 (m, 2H, CH-10, H-5), 4.67 (d, J = 9.0 Hz, 1H, H-4), 6.83–
6.89 (m, 2H, H-3000), 7.01–7.08 (m, 2H, H-2000), 7.18–7.35 (m, 5H,
4.50. (4S,5R)-1-Acetyl-4-ethyl-5-methyl-3-((S)-1-phenylethyl)im
idazolidin-2-one 16c
13
PhH). C NMR (125 MHz, CDCl3) d 15.7 (CH3-5), 18.1 (CH3-20),
24.5 (CH3CO-1), 52.0 (C-5), 54.1 (CH-10), 55.3 (CH3OAr), 61.0 (C-
4), 114.0 (C-3000), 126.5 (C-1000), 127.57 (C-200), 127.60 (C-400), 128.4
(C-300), 129.6 (C-2000), 140.5 (C-100), 155.8 (C-2), 159.7 (C-4000), 170.6
(CH3CO-1). HRMS (EI) m/z [M+] Calcd for C21H24N2O3: 352.1787.
Found: 352.1790.
4.50.1. (S)-5-Ethyl-4-methyl-1-(1-phenylethyl)-1H-imidazol-2
(3H)-one 18c
Synthesized according to method I, with 14i (0.050 g,
0.184 mmol) and Pd(OH)2/C (20%)/H2O (50%) (0.026 g,
0.023 mmol) and stirring for 6 h, 16c (0.021 g, 42%) was afforded
as a yellow oil and 18c (0.093 g, 22%) as a pale yellow oil.
Data of 18e: Rf 0.16 (hexane/EtOAc, 8:2). [
a]
26 = ꢁ12.5 (c 0.401,
D
MeOH). IR (film) 3219, 2934, 1676, 1607, 1514, 1374, 1287, 1249,
Data of 16c: Rf 0.43 (hexane/EtOAc, 7:3). [
a
]
26 = ꢁ15.35 (c 0.057,
D
1175, 1037, 833, 754, 698 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.70
.
MeOH). IR (film) 2971, 2927, 1721, 1682, 1450, 1375, 1355, 1260,
(d, J = 7.5 Hz, 3H, CH3-20), 1.89 (s, 3H, CH3-4), 3.81 (s, 3H, CH3OAr),
5.20 (q, J = 7.5 Hz, 1H, CH-10), 6.77–6.84 (m, 2H, H-3000), 6.87–6.94
(m, 2H, H-2000), 7.12–7.32 (m, 5H, PhH), 10.21 (br s, 1H, NH). 13C
NMR (75 MHz, CDCl3) d 9.8 (CH3-4), 18.5 (CH3-20), 51.7 (CH-10),
55.2 (CH3OAr), 113.6 (C-3000), 114.9 (C-4) 119.9 (C-5), 121.8 (C-
1000), 126.7 (C-200), 126.8 (C-400), 128.1 (C-300), 132.2 (C-2000), 142.0
(C-100), 154.2 (C-2), 159.3 (C-4000). HRMS (EI) m/z [M+] Calcd for
1219, 1174, 758, 698 cmꢁ1 1H NMR (500 MHz, CDCl3) d 0.75
.
(t, J = 7.5 Hz, 3H, CH3CH2-4), 0.92–1.02 (m, 1H, CH3CH2-4), 1.15
(d, J = 6.5 Hz, 3H, CH3-5), 1.35–1.44 (m, 1H, CH3CH2-4), 1.68 (d,
J = 7.5 Hz, 3H, CH3-20), 2.54 (s, 3H, CH3CO-1), 3.57 (ddd, J = 12.0,
7.7, 3.5 Hz, 1H, H-4), 4.42 (dq, J = 7.0, 6.5 Hz, 1H, H-5), 5.29 (q,
J = 7.5 Hz, 1H, CH-10), 7.24–7.37 (m, 5H, PhH). 13C NMR
(125 MHz, CDCl3) d 9.9 (CH3CH2-4), 12.2 (CH3-5), 15.5 (CH3-20),
20.4 (CH3CH2-4), 24.1 (CH3CO-1), 49.6 (CH-10), 49.9 (C-5), 57.3
(C-4), 126.4 (C-200), 127.1 (C-400), 128.4 (C-300), 142.0 (C-100), 155.8
(C-2), 170.1 (CH3CO-1). HRMS (EI) m/z [M+] Calcd for
C19H20N2O2: 308.1525. Found: 308.1530.
4.53. (4S,5R)-4,5-Dimethyl-3-((S)-1-phenylethyl)-1-propionylim
idazolidin-2-one 16f
C
16H22N2O2: 274.1681. Found: 274.1685.
Data of 18c: Rf 0.51 (hexane/EtOAc, 8:2). [a]
26 = +6.1 (c 0.053,
D
Synthesized according to method I, with 14l (0.200 g,
0.735 mmol) and Pd(OH)2/C (20%)/H2O (50%) (0.103 g,
0.092 mmol) and stirring for 6 h, 16f (0.17 g, 84%) was afforded
MeOH). IR (film) 3264, 2977, 2935, 1683, 1434, 1376, 1113,
1027, 758, 698 cmꢁ1 1H NMR (500 MHz, CDCl3)
0.80
.
d
(t, J = 7.5 Hz, 3H, CH3CH2-5), 1.84 (d, J = 7.0 Hz, 3H, CH3-20), 1.93
(s, 1H, CH3-4), 2.16–2.22 (m, 2H, CH3CH2-5), 5.42 (q, J = 7.0 Hz,
1H, CH-10), 7.20–7.37 (m, 5H, PhH), 8.94 (br s, 1H, NH). 13C NMR
(125 MHz, CDCl3) d 9.4 (CH3-4), 14.2 (CH3CH2-5), 16.9 (CH3CH2-
5), 18.7 (CH3-20), 50.5 (CH-10), 112.3 (C-4), 120.0 (C-5), 126.5
(C-200), 127.0 (C-400), 128.4 (C-300), 141.7 (C-100), 154.0 (C-2). HRMS
(EI) m/z [M+] Calcd for C14H18N2O: 230.1419. Found: 230.1416.
as a yellow oil. Rf 0.67 (hexane/EtOAc, 7:3). [
MeOH). IR (film) 2980, 2939, 1716, 1681, 1449, 1375, 1250,
1218, 1170, 1067, 1018, 929, 779, 758, 699 cmꢁ1 1H NMR
(300 MHz, CDCl3) 0.82 (d, J = 6.9 Hz, 3H, CH3-4), 1.14 (d,
a]
25 = +7.6 (c 0.651,
D
.
d
J = 6.6 Hz, 3H, CH3-5), 1.65 (t, J = 7.5 Hz, 3H, CH3CH2CO-1), 1.70
(d, J = 7.3 Hz, 3H, CH3-20), 2.84–3.12 (m, 2H, CH3CH2CO-1), 3.85
(dq, J = 7.5, 6.9 Hz, 1H, H-4), 4.33 (dq, J = 7.5, 6.6 Hz, 1H, H-5),
5.21 (q, J = 7.3 Hz, 1H, CH-10), 7.23–7.41 (m, 5H, PhH). 13C NMR
(75 MHz, CDCl3) d 8.6 (CH3CH2CO-1), 13.0 (CH3-5), 14.2 (CH3-4),
15.6 (CH3-20), 29.3 (CH3CH2CO-1), 49.7 (CH-10), 50.8 (C-4), 51.1
(C-5), 126.6 (C-200), 127.1 (C-400), 128.3 (C-300), 141.8 (C-100), 155.4
(C-2), 174.0 (CH3CH2CO-1). HRMS (EI) m/z [M+] Calcd for
4.51. (4S,5R)-1-Acetyl-4-methyl-3-((S)-1-phenylethyl)-5-propyl-
imidazolidin-2-one 16d
Synthesized according to method I, with 14j (0.200 g, 0.70 mmol)
and Pd(OH)2/C (20%)/H2O (50%) (0.100 g, 0.089 mmol) and stirring
for 6 h, 16d (0.089 g, 44%) was afforded as a yellow oil. Rf 0.46 (hex-
C16H22N2O2: 274.1681. Found: 274.1683.
ane/EtOAc, 8:2). [
a
]
21 = ꢁ21.15 (c 0.101, MeOH). IR (film) 2961,
D
4.54. (4S,5R)-4,5-Diethyl-3-((S)-1-phenylethyl)-1-propionylimid
azolidin-2-one 16g
1717, 1682, 1450, 1373, 1353, 1253, 1224, 756, 699 cmꢁ1. 1H NMR
(300 MHz, CDCl3) d 0.89 (t, J = 6.9 Hz, 3H, CH3(CH2)2-5), 0.90 (d,
J = 6.9 Hz, 3H, CH3-4), 1.10–1.53 (m, 3H, CH3(CH2)2-5), 1.60–1.73
(m, 1H, CH3(CH2)2-5), 1.71 (d, J = 7.2 Hz, 3H, CH3-20), 2.56 (s, 3H, CH3-
CO-1), 3.89 (dq, J = 7.1, 6.9 Hz, 1H, H-4), 4.27–4.35 (m, 1H, H-5), 5.23
(q, J = 7.2 Hz, 1H, CH-10), 7.24–7.46 (m, 5H, PhH). 13C NMR (75 MHz,
CDCl3) d 14.1 (CH3-4), 14.2 (CH3(CH2)2-5), 15.7 (CH3-20), 18.8 (CH3-
CH2CH2-5), 24.2 (CH3CO-1), 30.6 (CH3CH2CH2-5), 50.0 (CH-10), 51.4
(C-4), 54.4 (C-5), 126.7 (C-200), 127.2 (C-400), 128.3 (C-300), 141.7 (C-
100), 156.0 (C-2), 170.4 (CH3CO-1). HRMS (EI) m/z [M+] Calcd for
4.54.1. (S)-4,5-Diethyl-1-(1-phenylethyl)-1H-imidazol-2(3H)-one
18b
Synthesized according to method I, with 14m (0.200 g,
0.67 mmol) and Pd(OH)2/C (20%)/H2O (50%) (0.093 g, 0.083 mmol)
and stirring for 6 h, 16g (0.133 g, 66%) was afforded as a yellow oil
and 18b (0.039 g, 24%) as a pale yellow oil.
Data of 16g: Rf 0.87 (hexane/EtOAc, 7:3). [
a
]
26 = ꢁ16.1 (c 0.259,
D
MeOH). IR (film) 2973, 2939, 1719, 1685, 1459, 1375, 1242, 1216,
1162, 756, 699 cmꢁ1. 1H NMR (300 MHz, CDCl3) d 0.79 (t, J = 7.2 Hz,
C17H24N2O2: 288.1838. Found: 288.1839.

R. U. Gutiérrez et al. / Tetrahedron: Asymmetry 26 (2015) 230–246
245
Table 6
Crystal data and structure refinement for 7a, 8g, and 13
Structure
7a
1032284
10H11NO2S
209.26
292(2)
0.51 ꢂ 0.47 ꢂ 0.45
Orthorhombic
Pca21
8g
13
CCDC No.
1032149
C13H16N2O
216.28
1032287
C27H33N3
399.56
292(2)
0.74 ꢂ 0.14 ꢂ 0.12
Monoclinic
P21
Empirical formula
Molecular weight
Temperature (K)
Crystal size (mm3)
Crystal system
Space group
C
292(2)
0.60 ꢂ 0.40 ꢂ 0.39
Monoclinic
P21
Unit cell parameters
a = 22.5929(2) Å,
a
= 90°
a = 6.8435(2) Å,
a
= 90°
a = 12.3636(16) Å, a = 90°
b = 4.92380(10) Å, b = 90°
b = 7.2959(2) Å, b = 106.336(3)°
b = 6.0130(11) Å, b = 96.813(12)°
c = 9.2068(2) Å,
1024.19(3)
4
1.357
0.288
3.61–32.64
40,351
3588
c
= 90°
c = 11.9794(4) Å,
573.98(3)
2
1.251
0.081
3.102–32.519
6564
3533
c
= 90°
c = 15.949(2) Å,
1177.3(3)
2
1.127
0.066
3.223–32.624
13,454
7283
c = 90°
Volume (Å3)
Z
Density (mg/m3)
Absorption coefficient (mmꢁ1
Theta range (°)
)
Reflections collected
Independent reflections
Observed reflections
Final R indices
3369
3273
1660
R1 = 0.0343; wR2 = 0.0861
1.114
R1 = 0.0387; wR2 = 0.1007
1.045
R1 = 0.0713; wR2 = 0.0923
0.845
Goodness-of-fit on F2
3H, CH3CH2-4), 0.90 (t, J = 7.5 Hz, 3H, CH3CH2-5), 0.94–1.10 (m, 1H,
CH3CH2-5), 1.19 (t, J = 7.5 Hz, 1H, CH3CH2CO-1), 1.34–1.47 (m, 1H,
CH3CH2-4), 1.45–1.59 (m, 1H, CH3CH2-5), 1.66 (d, J = 7.3 Hz, 3H,
CH3-20), 1.70–1.89 (m, 1H, CH3CH2-4), 2.85–3.15 (m, 1H, CH3CH2-
CO-1), 3.60 (ddd, J = 11.7, 6.9, 3.3 Hz, 1H, H-4), 4.38–4.48 (m, 1H,
H-5), 5.29 (q, J = 7.3 Hz, 1H, CH-10), 7.24–7.36 (m, 5H, PhH). 13C
NMR (75 MHz, CDCl3) d 8.9 (CH3CH2CO-1), 9.7 (CH3CH2-5), 10.3
(CH3CH2-4), 15.3 (CH3-20), 20.1 (CH3CH2-4), 20.4 (CH3CH2-5), 29.3
(CH3CH2CO-1), 49.7 (CH-10), 53.5 (C-5), 58.0 (C-4), 126.6 (C-200),
127.0 (C-400), 128.2 (C-300), 141.8 (C-100), 156.5 (C-2), 170.2 (CH3CH2-
CO-1). HRMS (EI) m/z [M+] Calcd for C18H26N2O2: 302.1994. Found:
302.1994.
(graphite crystal monochromator, k = 71073 Å) at room tempera-
ture. Three standard reflections were monitored periodically with
no change found during data collection. Intensities were corrected
for Lorentz and polarization effects. Multi-scan absorption correc-
tion was applied. Anisotropic temperature factors were introduced
for all non-hydrogen atoms. Hydrogen atoms were placed in ideal-
ized positions and their atomic coordinates refined. Unit weights
were used in the refinement (Table 6). Structures were solved
using the SHELXS-201344 program as implemented in the WinGX
suite,45 and refined using SHELXL-201346 within WinGX, on a per-
sonal computer. In all cases ORTEP and packing diagrams were
made with the ORTEP package.
4.55. (4S,5R)-4-(4-Methoxyphenyl)-5-methyl-3-((S)-1-phenyleth
yl)-1-propionylimidazolidin-2-one 16h
Acknowledgments
We thank Daniel Zárate, Pablo Montoya, and Eder I. Martínez-
Mora for their help in spectrometric measurements. We thank
Bruce Allan Larsen for proofreading the manuscript. J.T. gratefully
acknowledges SIP-IPN (Grants 20110172, 20120830, 20130686,
and 20140858) and CONACYT (Grants 83446, 178319, and PEI-
181/2012) for financial support. A.R., R.U.G., R.B., J.L.V., M.S., and
F.M. thank CONACYT for graduate scholarship awarded, and also
thank SIP/IPN (PIFI) and Ludwig K. Hellweg Foundation for scholar-
ship complements. L.G.Z., F.D., and J.T. are fellows of the EDI-IPN
and COFAA-IPN programs.
4.55.1. (S)-5-(4-Methoxyphenyl)-4-methyl-1-(1-phenylethyl)-
1H-imidazol-2(3H)-one 18e
Synthesized according to method I, with 14p (0.260 g,
0.71 mmol) and Pd(OH)2/C (20%)/H2O (50%) (0.100 g, 0.089 mmol)
and stirring for 24 h, 16h (0.162 g, 61%) was afforded as a yellow
oil, and 18e (0.029 g, 17%) as a pale yellow oil.
Data of 16h: Rf 0.63 (hexane/EtOAc, 7:3). [
a
]
26 = ꢁ23.3 (c 0.171,
D
MeOH). IR (film) 2979, 2937, 1725, 1683, 1613, 1514, 1457, 1406,
1374, 1354, 1341, 1250, 1216, 1175, 1032, 843, 757, 700 cmꢁ1 1H
.
NMR (300 MHz, CDCl3) d 0.85 (d, J = 6.3 Hz, 3H, CH3-5), 1.12
(t, J = 7.2 Hz, 3H, CH3CH2CO-1), 1.83 (d, J = 7.5 Hz, 3H, CH3-20),
2.95 (qd, d, J = 7.2, 2.2 Hz, 2H, CH3CH2CO-1), 3.78 (s, 3H, CH3OAr),
4.32–4.46 (m, 2H, CH-10, H-5), 4.66 (d, J = 8.7 Hz, 1H, H-4), 6.81–
6.87 (m, 2H, H-3000), 7.01–7.08 (m, 2H, H-2000), 7.22 (br s, 5H, PhH).
13C NMR (75 MHz, CDCl3) d 8.6 (CH3CH2CO-1), 15.5 (CH3-5), 17.9
(CH3-20), 29.6 (CH3CH2CO-1), 51.9 (C-5), 53.8 (CH-10), 55.1 (CH3-
OAr), 61.0 (C-4), 113.8 (C-3000), 126.4 (C-1000), 127.4 (C-200, C-400),
128.2 (C-300), 129.3 (C-2000), 140.3 (C-100), 155.7 (C-2), 159.5 (C-4000),
174.2 (CH3CH2CO-1). HRMS (EI) m/z [M+] Calcd for C22H26N2O3:
366.1944. Found: 366.1942.
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