Synthesis of β-hydroxyacetamides from unactivated ethyl acetates under base-free conditions and microwave irradiation

Article abstract of DOI:10.1016/j.tetasy.2014.11.015

The amidation of unactivated ethyl esters with achiral and chiral 1,2-amino alcohols under microwave irradiation and base-free conditions is described. This procedure provides a convenient method for the synthesis of β-hydroxyacetamides bearing pyrazole, imidazole, and benzimidazole groups in high yields and without racemization. The protocol described herein is environmentally friendly and allows for the preparation of a wide variety of β-hydroxyacetamides, which are key intermediates in the synthesis of oxazolines and other derivatives of biological interest.

Full text of DOI:10.1016/j.tetasy.2014.11.015

Tetrahedron: Asymmetry 26 (2015) 73–78
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of b-hydroxyacetamides from unactivated ethyl acetates
under base-free conditions and microwave irradiation
a
b,
Eugenio Hernández-Fernández a, , Pedro Pablo Sánchez-Lara , Mario Ordóñez
⇑
⇑
,
Oscar Abelardo Ramírez-Marroquín b, Francisco G. Avalos-Alanís a, Susana López-Cortina a,
Víctor M. Jiménez-Pérez a, Tannya Rocio Ibarra-Rivera c
a Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, Pedro de Alba s/n, Ciudad Universitaria, 66400 San Nicolás de los Garza, Nuevo León, Mexico
b Universidad Autónoma del Estado de Morelos, Centro de Investigaciones Químicas, Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico
c Universidad Autónoma de Nuevo León, Facultad de Medicina, Fco. I. Madero s/n, Mitras Centro, 64460 Monterrey, Nuevo León, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 November 2014
Accepted 24 November 2014
The amidation of unactivated ethyl esters with achiral and chiral 1,2-amino alcohols under microwave
irradiation and base-free conditions is described. This procedure provides a convenient method for the
synthesis of b-hydroxyacetamides bearing pyrazole, imidazole, and benzimidazole groups in high yields
and without racemization. The protocol described herein is environmentally friendly and allows for the
preparation of a wide variety of b-hydroxyacetamides, which are key intermediates in the synthesis of
oxazolines and other derivatives of biological interest.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
On the other hand, Microwave-Assisted Organic Synthesis
(MAOS) has been successfully applied in the synthesis of amide
Amide bond formation is a general and versatile reaction widely
used to prepare peptides, polymers, and other complex molecules.
The mildest conditions require activation of the carboxylic acid
derivatives using stoichiometric quantities of activating or con-
densing agents.1 Amides bearing chiral 1,2-amino alcohols, which
have been used as building blocks in the synthesis of more
complex molecules,2 and as chiral ligands,3 are usually prepared
by the reaction of activated carboxylic acids with chiral 1,2-amino
alcohols. Other amides bearing chiral amino alcohols have been
obtained by reactions between mildly activated esters and
1,2-amino alcohols without the need of coupling reagents,4 or in
a single-step carbene-catalyzed reaction of esters with chiral 1,2-
amino alcohols,5 catalyzed by 2-tert-butylimino-2-diethylamino-
1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP),6 and using
K3PO4 as the catalyst.7 However, these methods suffer from one
or more disadvantages such as the use of specialized handling
techniques and tedious work-up, long reaction times, vigorous
reaction conditions, the requirement of an excess of reagents, the
use of solvent, which leads to unsatisfactory yields, and a lack of
generality.
from non-activated acids, and optically active compounds are com-
patible with these methods.8 However, the preparation of amides
bearing chiral 1,2-amino alcohols under microwave irradiation
has not been reported. Therefore, in connection with our previous
studies concerning the synthesis of amides bearing chiral
1,2-amino alcohols,9 we herein report an operationally simple,
and expeditious base-free synthesis of several b-hydroxyamides
from unactivated esters under microwave irradiation. The versatil-
ity of this method was exploited to obtain b-hydroxyamides, with
moderate to excellent yields in very short reaction times, which
can be used as key intermediates in the synthesis of more complex
molecules and as ligands.
2. Results and discussion
For the synthesis of target compound 1, we envisaged two syn-
thetic procedures: (a) reaction of easily obtained N-chloroacetamido
alcohols 2, with several cyclic amines, and (b) the reaction of ethyl
acetate derivative 3 with chiral 1,2-amino alcohols (Scheme 1).
Initially we developed a general procedure to prepare the novel
b-hydroxyacetamides 1a–f following route A. In this context, using
a recently described procedure the N-chloroacetamido alcohol 2
was readily obtained,9,10 which was then reacted with different het-
erocyclic amines such as pyrrolidine, piperidine, and morpholine in
the presence of K2CO3 in CH3CN at room temperature, obtaining the
⇑
Corresponding authors. Tel./fax: +52 818329 40 00x6293 (E.H.-F.); tel./fax: +52
7773297997 (M.O.).
E-mail addresses: eugenio.hernandezfr@uanl.edu.mx (E. Hernández-Fernández),
palacios@uaem.mx (M. Ordóñez).
http://dx.doi.org/10.1016/j.tetasy.2014.11.015
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

74
E. Hernández-Fernández et al. / Tetrahedron: Asymmetry 26 (2015) 73–78
O
R
1,2-amino alcohols in order to obtain the target compounds. In this
context, we carried out the reaction of 3a with (S)-phenylalaninol
in ethanol at 70 °C for 8 h, to obtain the desired compound 1g in
22% yield (Table 2, entry 1). We suspected that the poor yield could
be strongly influenced by the temperature at which the reaction
took place; therefore we decided to change the solvent and carry
out the reaction in toluene at reflux for 8 h, and obtained the
desired product 1g in 50% yield (Table 2, entry 2). On the other
hand, it is well known that microwave irradiation is able to speed
up certain chemical reactions and increase the yield. With this in
mind, we carried out the reaction of 3a with (S)-phenylalaninol
in toluene at 120 °C for 25 min under microwave irradiation, and
obtained compound 1g in 89% yield (Table 2, entry 3). Compound
1g was obtained in 94% yield when the reaction was conducted
at 180 °C for 10 min (Table 2, entry 4).
Cl
+
N
N
N
H
R
O
OH
OH
H
2
N
N
H
OH
R
1
O
+
H2N
OEt
3
Scheme 1. Retrosynthetic analysis of 1.
target compounds 1a–c in good yields (83–96%). Under identical
conditions, the reaction of N-chloroacetamido alcohol 2 with benz-
imidazole afforded b-hydroxyacetamide 1d in 76% yield, whereas
the reaction of 2 with benzotriazole gave a mixture of two regioi-
somers 1e and 1f in 45% and 36% yields, respectively (Table 1).
Table 2
Preparation of pyrazolyl-hydroxyacetamide 1g
Bn
Table 1
Bn
N
N
O
O
conditions
Reaction of 2 with several cyclic amines
+
N
N
H2N
OEt
N
H
O
Ph
Ph
O
OH
N
OH
3a
H
OH
Cl
OH
N
1g
N
H
N
H
K2CO3, MeCN
25 oC or Δ
Entry
Conditions
Yielda (%)
1a-f
2
1
2
3
4
EtOH, 70 °C, 8 h
PhMe, 110 °C, 8 h
MW, PhMe, 120 °C, 25 min
MW, PhMe, 180 °C, 10 min
22
50
89
94
Ph
Ph
Ph
O
O
OH
OH
N
N
N
N
a
Isolated after purification by column chromatography.
H
H
1a; 85%a
1b; 96%a
Having identified the optimal reaction conditions, we next
N
Ph
O
O
O
investigated the generality of the reaction of 3a–c with several
1,2-amino alcohols. Our results show that the reaction of 3a–c with
(S)-phenylalaninol afforded b-hydroxyacetamides (S)-1g–i in
excellent yields (91–96%). In a similar manner, the reaction of
3a–c with (R)-phenylglycinol produced the corresponding b-
hydroxyacetamides (R)-1j–l in 83–96% yield. On the other hand,
when 3a–c was reacted with ethanolamine, the achiral b-hydrox-
yacetamides 3m–o were obtained in excellent yield. Treatment
of 3a–c with (S)-alalinol under microwave irradiation gave the b-
hydroxyacetamides (S)-1p–r in 52–84% yield. Finally, the reaction
of 3a–c with (S)-valinol produced the b-hydroxyacetamides (S)-
1s–u in good to excellent yields (Table 3).
OH
OH
N
N
N
H
N
H
1d; 76%a
1c; 83%a
N
N
Ph
Ph
N
O
O
OH
OH
N
N
N
N
H
N
H
1e; 45%a
1f; 36%a
a Isolated after purification by column chromatography.
On the other hand, route B started with the nucleophilic substi-
tution reaction of ethyl bromoacetate with pyrazole, imidazole,
and benzimidazole in the presence of K2CO3 in CH3CN at reflux
for 3 h, to give compounds 3a–c in 82–92% yield (Scheme 2).
3. Conclusion
In conclusion, we have developed a rapid, practical, and effi-
cient method for the synthesis of a variety of amides bearing achi-
ral and chiral 1,2-amino alcohols and pyrazole, imidazole, and
benzimidazole, under microwave irradiation. These compounds
have great potential as key intermediates in the synthesis of
important bioactive compounds or as chiral ligands in asymmetric
catalysts. Studies on the biological activity of these compounds are
currently in progress.
O
O
N
H
Br
N
K2CO3, MeCN
OEt
O
OEt
Δ
3a-c
N
N
O
O
N
4. Experimental
4.1. General
N
N
N
OEt
OEt
OEt
3a
; 92%
3b; 82%
3c
; 83%
Scheme 2. Preparation of 3a–c.
All commercial materials were used as received unless noted
otherwise. Melting points were registered using a Mel-Temp II
apparatus and are uncorrected. Flash chromatography was per-
formed using 230–400 mesh Silica Flash 60Ò silica gel. Thin layer
After the preparation of acetate derivatives 3a–c, the next step
was to explore the scope of the substitution reaction with several

E. Hernández-Fernández et al. / Tetrahedron: Asymmetry 26 (2015) 73–78
75
Table 3
Synthesis of b-hydroxyacetamides 1g–u under microwave irradiation
R
R
O
O
+
PhMe, MW
OH
N
N
OH
OEt
H2N
N
H
180 ºC, 10 min
3a-c
1g-u
N
N
N
Bn
Bn
N
N
O
Bn
Ph
N
N
N
O
O
OH
N
OH
N
OH
N
H
N
H
N
H
a
a
a
1g
1h
1i
(S)- ; 94%
(S)- ; 96%
(S)- ; 91%
Ph
Ph
N
N
O
O
O
N
N
OH
OH
OH
OH
OH
OH
N
H
N
N
H
H
a
a
1j
1k
(R)-1l; 96%a
(R)- ; 83%
(R)- ; 84%
N
N
O
O
O
N
N
N
N
H
N
H
a
H
; 97%
1n; 92%a
1o; 87%a
1m
N
N
Me
Me
O
Me
O
N
N
N
N
O
OH
N
N
OH
OH
OH
OH
N
H
N
H
N
H
a
a
a
1q
1r
1p
(S)- ; 84%
(S)- ; 81%
(S)- ; 52%
O
O
O
N
N
N
N
OH
N
N
H
N
H
H
(S)-1u; 94%a
a
a
1s
(S)- ; 79%
1t
(S)- ; 83%
a Isolated after purification by column chromatography.
chromatography was carried out on pre-coated TLC sheets of silica
gel 60 F254 (E. Merck). NMR spectra were recorded on Varian Sys-
tem instrument (400 MHz for 1H and 100 MHz for 13C. The spectra
were obtained in CDCl3, CD3OD, and DMSO-d6 solution using TMS
as the internal reference. Chemical shifts (d) are reported in parts
per million. Multiplicities are recorded as follows: s = singlet,
d = doublet, t = triplet, dd = doublet of doublets, td = triplet of dou-
blets, bs = broad singlet, q = quartet and m = multiplet. Coupling
constants (J) are given in Hz. High resolution CI+ and FAB+ mass
experiments were carried out in a JEOL HRMStation JHRMS-700.
Optical rotations were measured with an Anton-Paar MCP 300
polarimeter in a 2.5 mm cell. Reactions carried out with stirring
under microwave irradiation in the closed-vessel were all per-
formed with a Microwave Synthesis Reactor (Monowave 300/
Anton Paar).
obtained was purified by flash chromatography on silica gel using
EtOAc as eluent or by crystallization in hot EtOAc for 1a–c or by
flash column chromatography using EtOAc/Hex/MeOH (5:4:1) as
eluent for 1d–f.
4.2.1. (S)-N-(2-Hydroxy-1-phenylethyl)-2-(pyrrolidin-1-yl)acet-
amide 1a
(211 mg, 85%) as a white solid, mp 114 °C, [a]D = +30.7 (c 3.0,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.74–1.83 (m, 4H),
2.57–2.66 (m, 5H), 3.19 (AB system, J = 16.4 Hz, 2H, CH2C@O),
3.85–3.88 (m, 2H, CH2OH), 5.05–5.09 (m, 1H, CHPh), 7.27–7.31
(m, 3H, Harom), 7.35–7.39 (m, 2H, Harom), 7.8 (d, J = 6.7 Hz, 1H,
NH). 13C NMR (100 MHz, CDCl3): d = 24.1, 54.7, 56.0, 59.5, 66.9
(CH2OH), 126.8, 128.0, 129.0, 139.2, 171.9 (C@O). HRMS (FAB+):
calculated for
C
14H21N2O2 [M+H]+, m/z 249.1603; found for
[M+H]+, m/z 249.1607.
4.2. General procedure for the synthesis of compounds 1a–c
4.2.2. (S)-N-(2-Hydroxy-1-phenylethyl)-2-(piperidin-1-yl)acet-
To a suspension of (S)-2-chloro-N-(2-hydroxy-1-phenylethyl)
acetamide 210 (1.0 equiv) and K2CO3 (1.2 equiv) in acetonitrile
(4 mL) at 0 °C, the corresponding amine (1.0 equiv) was added
dropwise. The reaction mixture was allowed to warm to room tem-
perature and then stirred overnight or heated at reflux. The solvent
was evaporated under reduced pressure, and water (10 mL) was
added. The mixture was extracted with EtOAc (3 Â 20 mL). The
combined organic extracts were dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. The solid
amide 1b
(252 mg, 96%) as a light yellow oil, [a]
D = +28.0 (c 3.0, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 1.45 (bs, 2H), 1.55–1.59 (m, 4H), 2.47
(m, 5H), 3.01 (AB system, J = 16.4 Hz, 2H, CH2C@O), 3.87 (d,
J = 5.2 Hz, 2H, CH2OH), 5.04–5.09 (m, 1H, CHPh), 7.27–7.40 (m,
5H,
H
arom), 8.01 (bs, 1H, NH). 13C NMR (100 MHz, CDCl3):
d = 23.6, 26.1, 54.9, 56.0, 62.2, 67.2 (CH2OH), 126.5, 127.9, 128.9,
138.9, 171.7 (C@O). HRMS (FAB+): calculated for C15H23N2O2
[M+H]+, m/z 263.1760; found for [M+H]+, m/z 263.1752.

76
E. Hernández-Fernández et al. / Tetrahedron: Asymmetry 26 (2015) 73–78
4.2.3. (S)-N-(2-Hydroxy-1-phenylethyl)-2-morpholin-acetamide 1c
(220 mg, 83%) as a colorless oil, [
D = +36.0 (c 3.0, CHCl3). 1H
CH@CHAN), 7.48 (d, J = 2.3 Hz, 1H, CH@N), 7.56 (d, J = 1.8 Hz, 1H,
CHAN). 13C NMR (100 MHz, CDCl3): d = 14.1 (CH3CH2), 53.1
(CH2C@O), 61.8 (CH2O), 106.5 (CH@CHAN), 130.6 (CHAN), 140.1
(CH@N), 168.0 (C@O). HRMS (CI+): calculated for C7H11N2O2
[M+H]+, m/z 155.0821; found for [M+H]+, m/z 155.0815.
a]
NMR (400 MHz, CDCl3): d = 2.48–2.60 (m, 5H), 3.05 (AB system,
J = 16.3 Hz, 2H, CH2C@O), 3.7 (t, J = 4.6 Hz, 4H), 3.82 (dd, J = 11.6,
6.4 Hz, 1H, CH2OH), 3.86 (dd, J = 11.2, 4.4 Hz, 1H, CH2OH), 5.05–
5.09 (m, 1H, CHPh), 7.27–7.32 (m, 3H, Harom), 7.35–7.39 (m, 2H,
H
arom), 7.83 (d, J = 7.4 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3):
4.3.2. Ethyl 2-(1H-imidazol-1-yl)acetate 3b
(1.56 g, 82%) as a light yellow oil. 1H NMR (400 MHz, CDCl3):
d = 1.29 (t, J = 7.2 Hz, 3H, CH3CH2O), 4.24 (q, J = 7.2 Hz, 2H,
OCH2CH3), 4.70 (s 2H, CH2C@O), 6.96 (s, 1H, NCH@CH), 7.09 (s,
1H, NCH@CH), 7.50 (s, 1H, N@CHN). 13C NMR (100 MHz, CDCl3):
d = 14.0 (CH3), 48.0 (CH2C@O), 62.0 (OCH2CH3), 120.0, 129.6,
137.9, 167.4 (C@O). HRMS (FAB+): calculated for C7H11N2O2
[M+H]+, m/z 155.0821; found for [M+H]+, m/z 155.0822.
d = 53.9, 55.6, 62.0, 66.7 (CH2OH), 67.1, 126.7, 128.1, 129.0, 139.1,
170.6 (C@O). HRMS (FAB+): calculated for C14H21N2O3 [M+H]+, m/
z 265.1552; found for [M+H]+, m/z 265.1547.
4.2.4. (S)-N-(2-Hydroxy-1-phenylethyl)-2-(1H-benzo[d]-imidazol-
1-yl)acetamide 1d
(215 mg, 76%) as a white solid, mp 217–219 °C, [a]D = +86.8 (c
3.0, DMSO). 1H and 13C NMR data are identical to those described
in the literature11 HRMS (FAB+): calculated for C17H18N3O2
[M+H]+, m/z 296.1399; found for [M+H]+, m/z 296.1413.
4.3.3. Ethyl 2-(1H-benzo[d]imidazol-1-yl)acetate 3c
(2.81 g, 83%) as a white solid, mp 63–64 °C. 1H NMR (400 MHz,
CDCl3): d = 1.23 (t, J = 7.1 Hz, 3H, CH3CH2O), 4.20 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.83 (s, 2H, CH2C@O), 7.26–7.33 (m, 3H, Harom),
7.78–7.83 (m, 1H,
H
arom), 7.88 (s, 1H, N@CHAN). 13C NMR
4.2.5. (S)-N-(2-Hydroxy-1-phenylethyl)-2-(2H-benzo[d]-[1,2,3]
triazol-2-yl)acetamide 1e
(100 MHz, CDCl3): d = 14.1 (CH3CH2O), 46.1 (CH2C@O), 62.2
(OCH2CH3), 109.3, 120.5, 122.5, 123.4, 143.5, 167.3 (C@O). HRMS
(FAB+): calculated for C11H13N2O2 [M+H]+, m/z 205.0977; found
for [M+H]+, m/z 205.0977.
(125 mg, 45%) as a white solid, mp 202–203 °C, [a]D = +128.0 (c
3.0, DMSO). 1H NMR (400 MHz, DMSO-d6): d = 3.58–3.68 (m, 2H,
CH2OH), 4.83–4.91 (m, 1H, CHPh), 5.05 (t, J = 5.6 Hz, 1H, OH),
5.58 (s, 2H, CH2C@O), 7.23–7.29 (m, 1H, Harom), 7.31–7.38 (m,
4H, Harom), 7.43 (dd, J = 6.4, 3.2 Hz, 2H, Harom), 7.91 (dd, J = 6.6,
4.4. General procedure for the synthesis of compounds 1g–u
3.0 Hz, 2H,
H
arom), 8.94 (d, J = 8.4 Hz, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): d = 55.5 (CH2C@O), 58.4 (CHPh), 64.6
(CH2OH), 117.9, 126.6, 127.0, 127.1, 128.3, 140.6, 144.0, 164.7
(C@O). HRMS (FAB+): calculated for C16H17N4O2 [M+H]+, m/z
297.1352; found for [M+H]+, m/z 297.1344.
In a capped 10 mL MW-vessel, the ethyl azolyl-acetate deriva-
tives 3a–c (1.0 equiv), the corresponding 1,2-amino alcohol
(1.0 equiv) and toluene (3 mL) were mixed. The tube was posi-
tioned in the irradiation cavity and the mixture was heated with
stirring under microwave irradiation at 180 °C and held for approx-
imately 10 min. The vessel was cooled to room temperature, and
the residue was dissolved in methanol and then concentrated
under vacuum. The crude product was purified either by flash
chromatography on silica gel using EtOAc/Hex/MeOH (5:4:1) as
eluent or by crystallization under ethyl acetate. The purity of the
final products was determined by 1H NMR spectroscopy.
4.2.6. (S)-N-(2-Hydroxy-1-phenylethyl)-2-(1H-benzo[d]-[1,2,3]
triazol-1-yl)acetamide 1f
(101 mg, 36%) as a white solid, mp 233–234 °C, [a]D = +130.65
(c 3.0, DMSO). 1H NMR (400 MHz, DMSO-d6): d = 3.59–3.68 (m,
2H, CH2OH), 4.85–4.90 (m, 1H, CHPh), 5.07 (t, J = 5.4 Hz, 1H, OH),
5.56 (s, 2H, CH2C@O), 7.23–7.27 (m, 1H, Harom), 7.31–7.35 (m,
4H, Harom), 7.37–7.41 (m, 1H, Harom), 7.52 (ddd, J = 8.4, 6.8,
0.8 Hz, 1H, Harom), 7.74–7.77 (m, 1H, Harom), 8.02–8.04 (m, 1H,
4.4.1. (S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-2-(1H-pyrazol-1-
yl)acetamide 1g
H
arom), 9.02 (d, J = 8.4 Hz, 1H, NH). 13C NMR (100 MHz, DMSO-
d6): d = 50.4 (CH2C@O), 55.9 (CHPh), 65.0 (CH2OH), 111.4, 119.4,
124.3, 127.3, 127.4, 127.7, 128.6, 134.1, 141.0, 145.5, 165.7
(C@O). HRMS (FAB+): calculated for C16H17N4O2 [M+H]+, m/z
297.1352; found for [M+H]+, m/z 297.1344.
(318 mg, 94%) as a white solid, mp 113–114 °C. [
a
]
D = À24.0
(c 1.0, MeOH). 1H NMR (400 MHz, CD3OD): d = 2.73 (dd, J = 13.6,
8.4 Hz, 1H, CH2Ph), 2.89 (dd, J = 13.6, 6.4 Hz, 1H, CH2Ph), 3.49
(dd, J = 11.2, 5.6 Hz, 1H, CH2OH), 3.54 (dd, J = 11.2, 4.8 Hz, 1H,
CH2OH), 4.11 (m, 1H, CHBn), 4.79 (AB system, J = 13.6 Hz, 2H,
CH2C@O), 6.31 (m, 1H, CHACH@N), 7.18–7.27 (m, 5H, Harom),
7.52 (d, J = 1.2 Hz, 1H, CH@N), 7.56 (d, J = 2.4 Hz, 1H, CHAN). 13C
NMR (100 MHz, CD3OD): d = 38.0 (CH2Ph), 54.60 (CHBn), 55.1
(CH2C@O), 63.9 (CH2OH), 107.2, 127.6, 129. 6 (2C), 130.5 (2C),
133.1, 139.7, 141.2, 169.2 (C@O). HRMS (FAB+): calculated for
C14H18N3O2 [M+H]+, m/z 260.1399; found for [M+H]+, m/z
260.1398.
4.3. General procedure for the synthesis of compounds 3a–c
A solution of the corresponding azole (imidazole, pyrazole, and
benzimidazole) (1.0 equiv) in CH3CN (30 mL) was treated with
K2CO3 (2.1 equiv) and ethyl bromoacetate (1.0 equiv). The reac-
tion mixture was stirred at reflux for 3 h, after which the reaction
mixture was quenched by the addition of a saturated NH4Cl solu-
tion (20 mL) and extracted with ethyl acetate (3 Â 30 mL). The
organic extracts were combined, dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure. The crude prod-
uct was purified by column chromatography using hexane-ethyl
acetate (7:3) for derivatives bearing a pyrazole and imidazole,
or ethyl acetate/hexane/methanol (5:4:1) for the benzimidazole
derivative.
4.4.2. (S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-2-(1H-imidazol-
1-yl)acetamide 1h
(131 mg, 96%) as a white solid, mp 189–190 °C. [
a
]
D = À10.0 (c
1.0, MeOH). 1H NMR (400 MHz, CD3OD): d = 2.72 (dd, J = 13.6,
8.4 Hz, 1H, CH2Ph), 2.92 (dd, J = 14.0, 6.0 Hz, 1H, CH2Ph), 3.52
(dd, J = 10.8, 5.6 Hz, 1H, CH2OH), 3.58 (dd, J = 10.8, 4.8 Hz, 1H,
CH2OH), 4.14 (m, 1H, CHBn), 4.63 (AB system, J = 16.0 Hz, 2H,
CH2C@O), 6.94 (bs, 2H, CH@CHAN), 7.19–7.28 (m, 5H, Harom),
7.53 (s, 1H, N@CHAN). 13C NMR (100 MHz, CD3OD): d = 38.0 (CH2-
Ph), 50.3 (CH2C@O), 54.5 (CHBn), 64.0 (CH2OH), 121.6, 127.5 (2C),
128.9, 129.5 (2C), 130.3 (2C), 139.6, 168.9 (C@O). HRMS (FAB+):
4.3.1. Ethyl 2-(1H-pyrazol-1-yl)acetate 3a
(1.70 g, 92%) as a light yellow oil, 1H NMR (400 MHz, CDCl3):
d = 1.28 (t, J = 7.2 Hz, 3H, CH3CH2O), 4.23 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.92 (s, 2H, CH2C@O), 6.33 (dd, J = 2.2, 2.1 Hz, 1H,

E. Hernández-Fernández et al. / Tetrahedron: Asymmetry 26 (2015) 73–78
77
calculated for C14H18N3O2 [M+H]+, m/z 260.1399; found for [M+H]+,
m/z 260.1398.
OH), 110.6, 119.8, 121.9, 122.8, 134.8, 143.7, 145.3, 167.1 (N@CH)
(C@O). HRMS (CI+): calculated for C11H14N3O2 [M+H]+, m/z
220.1086; found for [M+H]+, m/z 220.1085.
4.4.3. (S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-2-(1H-benzo[d]
imidazol-1-yl)acetamide 1i
4.4.10. (S)-N-(1-Hydroxypropan-2-yl)-2-(1H-pyrazol-1-yl)acet-
amide 1p
(206 mg, 91%) as a white solid, mp 222–224 °C. [
a]
D = À12.0 (c
1.0, MeOH). 1H and 13C NMR data are identical to those described
in the literature.11 HRMS (FAB+): calculated for C18H20N3O2
[M+H]+, m/z 310.1556; found for [M+H]+, m/z 310.1544.
(123 mg, 52%) as a white solid, mp 121–122 °C. [
a
]
D = À15.3 (c
1.0, MeOH). 1H NMR (400 MHz, CD3OD): d = 1.14 (d, J = 6.8 Hz,
3H, CH3), 3.49 (d, J = 4.8 Hz, 2H, CH2OH), 3.94 (m, 1H, CHCH3),
4.84 (s, 2H, CH2C@O), 6.33 (m, 1H, CH@CHAN), 7.53 (d,
J = 1.6 Hz, 1H, CH@N), 7.67 (d, J = 2.0 Hz, 1H, CHAN). 13C NMR
(100 MHz, CD3OD): d = 17.2 (CH3), 48.9 (CHCH3), 55.2 (CH2C@O),
66.0 (CH2OH), 107.1, 133.2, 141.2, 169.1 (C@O). HRMS (FAB+): cal-
culated for C8H14N3O2 [M+H]+, m/z 184.1086; found for [M+H]+, m/
z 184.1084.
4.4.4. (R)-N-(2-Hydroxy-1-phenylethyl)-2-(1H-pyrazol-1-yl)acet-
amide 1j
(312 mg, 83%) as a white solid, mp 146–147 °C. [
a
]
D = À96.0 (c
1.0, MeOH). 1H NMR (400 MHz, DMSO-d6): d = 3.38 (bs, 1H, OH),
3.59 (br, 2H, CH2OH), 4.88 (s, 2H, CH2C@O), 4.98 (m, 1H, CHPh),
6.24 (t, J = 2.0 Hz, 1H, CH@CHAN), 7.22–7.38 (m, 5H, Harom), 7.43
(d, J = 1.8 Hz, 1H, CH@N), 7.70 (d, J = 2.2 Hz, 1H, CHAN), 8.55 (d,
J = 8.6 Hz, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d = 53.9 (CHPh),
55.1 (CH2C@O), 64.5 (CH2OH), 105.2, 126.9 (3C), 128.1 (2C), 131.4,
138.8, 140.8, 166.3 (C@O). HRMS (FAB+): calculated for C13H16N3O2
[M+H]+, m/z 246.1243; found for [M+H]+, m/z 246.1244.
4.4.11. (S)-N-(1-Hydroxypropan-2-yl)-2-(1H-imidazol-1-yl)acet-
amide 1q
(417 mg, 84%) as a white solid, mp 172–173 °C. [
a
]
D = À8.0 (c
1.0, MeOH). 1H NMR (400 MHz, CD3OD): d = 1.14 (d, J = 6.8 Hz,
3H, CH3CH), 3.47 (dd, J = 11.2, 5.2 Hz, 1H, CH2OH), 3.51 (dd,
J = 11.2, 5.2 Hz, 1H, CH2OH), 3.95 (m, 1H, CHCH3), 4.72 (s, 2H, CH2-
C@O), 6.97 (bs, 1H, CH@CHAN), 7.10 (bs, 1H, CH@CHAN), 7.65 (bs,
1H, N@CHAN). 13C NMR (100 MHz, CD3OD): d = 17.1 (CH3), 30.0
(CH2C@O), 50.4 (CHCH3) 66.0 (CH2OH), 121.9, 129.0, 139.6, 169.0
(C@O). HRMS (FAB+): calculated for C8H14N3O2 [M+H]+, m/z
184.1086; found for [M+H]+, m/z 184.1092.
4.4.5. (R)-N-(2-Hydroxy-1-phenylethyl)-2-(1H-imidazol-1-yl)
acetamide 1k
(120 mg, 84%) as a white solid, mp 180–181 °C. [
a
]D = À105.2 (c
1.0, MeOH). 1H NMR (400 MHz, DMSO-d6): d = 3.47 (bs, 1H, OH),
3.57 (dd, J = 9.4, 5.5 Hz, 1H, CH2OH), 3.61 (dd, J = 9.5, 4.0 Hz, 1H,
CH2OH), 4.74 (s, 2H, CH2C@O), 4.86 (m, 1H, CHPh), 6.87 (bs, 1H,
CH@CHAN), 7.08 (bs, 1H, CH@CHAN), 7.22–7.27 (m, 1H, Harom),
4.4.12. (S)-N-(1-Hydroxypropan-2-yl)-2-(1H-benzo[d]-imidazol-
1-yl)acetamide 1r
7.30–7.32 (m, 4H,
Harom), 7.58 (s, 1H, N@CHAN), 8.68 (d,
(276 mg, 81%) as a white solid, mp 187–189 °C. [
a
]
D = À12.0 (c
J = 8.2 Hz, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d = 48.8 (CH2-
C@O), 55.3 (CHPh), 64.6 (CH2OH), 120.4, 126.9 (3C), 127.9,
128.14 (2C), 138.09, 140.7, 166.5 (C@O). HRMS (FAB+): calculated
for C13H16N3O2 [M+H]+, m/z 246.1243; found for [M+H]+, m/z
246.1240.
1.0, MeOH). 1H NMR (400 MHz, DMSO-d6): d = 1.07 (d, J = 6.8 Hz,
3H, CH3), 3.30 (dd, J = 10.6, 5.8 Hz, 1H, CH2OH), 3.38 (dd, J = 10.6,
5.3 Hz, 1H, CH2OH), 3.79 (m, 1H, CHCH3), 4.91 (AB system,
J = 16.3 Hz, 2H, CH2C@O), 7.17–7.29 (m, 2H, Harom), 7.43–7.46 (m,
1H, Harom) 8.17 (s, 1H, N@CHAN), 8.28 (d, J = 7.9 Hz, 1H, NH). 13C
NMR (100 MHz, DMSO-d6): d = 17.0 (CH3), 46.9 (CH2C@O and
CHNH), 64.2 (CH2OH), 110.2, 119.3, 121.4, 122.3, 134.2, 143.2,
144.9, 165.84 (C@O). HRMS (FAB+): calculated for C12H16N3O2
[M+H]+, m/z 234.1243; found for [M+H]+, m/z 234.1251.
4.4.6. (R)-N-(2-Hydroxy-1-phenylethyl)-2-(1H-benzo[d]-imi-
dazol-1-yl) acetamide 1l
(427 mg, 96%) as a white solid, mp 218–220 °C, [
a]
D = À108.0 (c
1.0, MeOH). 1H and 13C NMR data are identical to those described
in the literature.11
4.4.13. (S)-N-(1-Hydroxy-3-methylbutan-2-yl)-2-(1H-pyrazol-1-
yl)acetamide 1s
4.4.7. N-(2-Hydroxyethyl)-2-(1H-pyrazol-1-yl)acetamide 1m
(213 mg, 97%) as a white solid, mp 111–112 °C. 1H NMR
(400 MHz, CD3OD): d = 3.35 (t, J = 5.6 Hz, 2H, CH2NH), 3.61 (t,
J = 5.6 Hz, 2H, CH2OH), 4.89 (s, 2H, CH2C@O), 6.36 (t, J = 2.2 Hz,
1H, CH@CHAN), 7.56 (d, J = 1.8 Hz, 1H, CH@N), 7.70 (d, J = 2.2 Hz,
1H, CHAN). 13C NMR (100 MHz, CD3OD): d = 41.7 (CH2NH), 53.6
(CH2C@O), 59.9 (CH2OH), 105.7, 131.7, 139.9, 168.4 (C@O). HRMS
(FAB+): calculated for C7H12N3O2 [M+H]+, m/z 170.0930; found for
[M+H]+, m/z 170.0927.
(114 mg, 79%) as a white solid, mp 120–122 °C. [
a]D = À32.0 (c
1.0, MeOH). 1H NMR (400 MHz, CD3OD): d = 0.89 (d, J = 6.8 Hz,
3H, (CH3)2CH), 0.93 (d, J = 6.8 Hz, 3H, (CH3)2CH), 1.86 (m, 1H,
CH(CH3)2), 3.54 (dd, J = 11.6, 5.2 Hz, 1H, CH2OH), 3.59 (dd,
J = 11.2, 4.4 Hz, 1H, CH2OH), 3.68 (m, 1H, CHN), 4.88 (AB system,
J = 13.2 Hz, 2H, CH2C@O), 6.34 (2d, 1H, CH@CHAN), 7.53 (d,
J = 1.6 Hz, 1H, CH@N), 7.68 (d, J = 2.0 Hz, 1H, CHAN). 13C NMR
(100 MHz, CD3OD): d = 18.8 (CH3), 20.1 (CH3), 30.1 (CH(CH3)2),
55.2, 58.4, 63.1, 107.2, 133.2, 141.2, 169.7 (C@O). HRMS (FAB+):
4.4.8. N-(2-Hydroxyethyl)-2-(1H-imidazol-1-yl)acetamide 1n
(544 mg, 92%) as a white solid, mp 135–136 °C (literature12
132.8–134 °C). 1H and 13C NMR data are identical to those
described in the literature12 HRMS (FAB+): calculated for
C7H12N3O2 [M+H]+, m/z 170.0930; found for [M+H]+, m/z 170.0934.
calculated for C
10H18N3O2 [M+H]+, m/z 212.1399; found for
[M+H]+, m/z 212.1406.
4.4.14. (S)-N-(1-Hydroxy-3-methylbutan-2-yl)-2-(1H-imidazol-
1-yl)acetamide 1t
(142 mg, 83%) as a white solid, mp 160–161 °C. [
a
]
D = À13.8 (c
4.4.9. N-(2-Hydroxyethyl)-2-(1H-benzo[d]imidazol-1-yl)acet-
amide 1o
0.5, MeOH). 1H NMR (400 MHz, CD3OD): d = 0.91 (d, J = 7.2 Hz,
3H, (CH3)2CH), 0.94 (d, J = 7.2 Hz, 3H, (CH3)2CH), 1.86 (m, 1H,
CH(CH3)2), 3.55 (dd, J = 11.2, 6.4 Hz, 1H, CH2OH), 3.63 (dd,
J = 11.6, 4.4 Hz, 1H, CH2OH), 3.71 (m, 1H, CHN), 4.76 (AB system,
J = 13.2 Hz, 2H, CH2C@O), 6.98 (s, 1H, CH@CHAN), 7.12 (s, 1H,
CH@CHAN), 7.67 (s, 1H, N@CHAN). 13C NMR (100 MHz, CD3OD):
d = 18.9 (CH3), 20.1 (CH3), 30.2 [CH(CH3)2], 50.5 (CH2C@O), 58.5
(CHNH), 63.1 (CH2OH), 121.9, 129.1, 139.6, 169.5 (C@O). HRMS
(187 mg, 87%) as a white solid, mp 211–212 °C. 1H NMR
(400 MHz, DMSO-d6): d = 3.18 (q, J = 5.8 Hz, 2H, CH2NH), 3.38 (bs,
1H, OH), 3.44 (m, 2H, CH2OH), 4.93 (s, 2H, CH2C@O), 7.18–7.26
(m, 2H, Harom), 7.44–7.46 (m, 1H, Harom), 7.64–7.66 (m, 1H, Harom),
8.17 (s, 1H, N@CHAN), 8.40 (t, J = 5.4 Hz, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): d = 42.2 (CH2NH), 47.3 (CH2C@O), 60.1 (CH2-

78
E. Hernández-Fernández et al. / Tetrahedron: Asymmetry 26 (2015) 73–78
(FAB+): calculated for C10H18N3O2 [M+H]+, m/z 212.1399; found for
[M+H]+, m/z 212.1393.
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Crabbe, T.; Deltent, M.-F.; Driessens, F.; Gill, A.; Harris, S.; Hutchinson, G.;
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4.4.15. (S)-N-(1-Hydroxy-3-methylbutan-2-yl)-2-(1H-benzo[d]
imidazol-1-yl)acetamide 1u
(365 mg, 94%) as a white solid, mp 213–215 °C. [
a]
D = À8.0 (c
1.0, MeOH). 1H and 13C NMR data are identical to those described
in the literature11 HRMS (FAB+): calculated for C14H20N3O2
[M+H]+, m/z 262.1556; found for [M+H]+, m/z 262.1562.
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Acknowledgements
The authors thank CONACYT of México, for their financial sup-
port via projects 101898 and 181816 and PAICYT for project
CN886-11. We thank V. Labastida-Galván for determination of
the HRMS. F.G.A.A. and O.A.R.M. also thank CONACYT for a Gradu-
ate Scholarship.
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