A Concise Stereoselective Synthesis of (R)-2-Benzylmorpholine and ML398 from (R)-(?)-2-Phenylglycinol

Article abstract of DOI:10.1002/jhet.3657

We describe here an efficient stereoselective method for the preparation of (R)-2-benzylmorpholine and ML398. The present method features a high diastereocontrol using an endocyclic oxidation of phenylglycinol-derived morpholine and a stereoselective alky

Full text of DOI:10.1002/jhet.3657

Month 2019
A Concise Stereoselective Synthesis of (R)-2-Benzylmorpholine and
ML398 from (R)-(À)-2-Phenylglycinol
Saúl Torres,a Manuel Velasco,a José Ángel Gallegos-Rojas,b Sylvain Bernès,c María L. Orea,a Joel L. Terán,a
d
a
a
*
Gabriela Huelgas, Víctor Gómez-Calvario, and Jorge R. Juárez
aCentro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. IC8, Complejo de
Ciencias, C.U., 72570, Puebla, Pue., Mexico
bInstituto Tecnológico de Parral, 33850, Hidalgo del Parral, Chih., Mexico
cInstituto de Física, Benemérita Universidad Autónoma de Puebla, 1IF2 (aka 110-B), Lab. 102, C.U., 72570, Puebla, Pue.,
Mexico
dDepartamento de Ciencias Químico-Biológicas, Universidad de las Américas-Puebla, Sta. Catarina Mártir, 72820,
Cholula, Pue., Mexico
*E-mail: jorge.juarez@correo.buap.mx
Received June 6, 2019
DOI 10.1002/jhet.3657
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
We describe here an efficient stereoselective method for the preparation of (R)-2-benzylmorpholine and
ML398. The present method features a high diastereocontrol using an endocyclic oxidation of
phenylglycinol-derived morpholine and a stereoselective alkylation of chiral non-racemic morpholin-3-one
as key steps.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
obtainment through oxidation have been reported.
Nevertheless, poor yields, by-products, and dependence
on the catalyst have been the main drawbacks [17–21].
Therefore, the development of new efficient oxidation
methods for the preparation of morpholin-3-one is highly
desirable. In this context, we have reported an efficient
endocyclic oxidation of phenylglycinol-derived piperidine
to generate the corresponding piperidin-2-one [22]. Thus,
the piperidin-2-one was a key intermediate in the
enantioselective synthesis of (2′S,3R)-(+)-stenusine (a,
Scheme 1). Now, in connection with our interest to
synthesize chiral non-racemic heterocyclic compounds
based on the use of (R)-(À)-2-phenylglycinol and that to
the best of our knowledge no stereoselective syntheses of
(R)-2-benzylmorpholine and ML398 have been reported,
we present here a concise stereoselective synthesis of (R)-
2-benzylmorpholine and ML398 (b, Scheme 1).
C2-substituted morpholines are important structural
cores present in many natural or synthetic compounds
that exhibit interesting biological activities [1–6]. For
example, the (R)-2-benzylmorpholine, a potent appetite
suppressant drug [7], has also proven to be useful in the
treatment of diabetes and cognitive disorders [8,9];
ML398, a potent and selective dopamine receptor
antagonist (D4R), shows activity (in vivo) to reverse
hyperlocomotion induced by cocaine (Figure 1) [10].
Interestingly, studies in the biological activities of (R)-2-
benzyl morpholine and ML398 have shown that the (R)-
enantiomers are the active isomers. To date, several
methods for the preparation of (R)-2-benzylmorpholine
have been reported, including chemoenzymatic
methodologies [11], resolution with dibenzoyl-L-tartaric
acid [7], as well as asymmetric synthesis based on α-
aminooxylation [12] or Sharpless epoxidation [13], while
ML398 has been obtained by asymmetric synthesis based
on an organocatalytic α-chlorination of aldehydes [10].
The morpholin-3-one core has proven to be a versatile
intermediate for the construction of morpholine
derivatives [14–16]. Several methodologies for its
RESULTS AND DISCUSSION
According to the retrosynthetic plan depicted in
Scheme 2, the construction of (R)-2-benzylmorpholine
and ML398 can be generated from amide derivatives 4a
© 2019 Wiley Periodicals, Inc.

S. Torres, M. Velasco, J. Á. Gallegos-Rojas, S. Bernès, M. L. Orea, J. L. Terán, G. Huelgas,
V. Gómez-Calvario, and J. R. Juárez
Vol 000
Scheme 3. Synthesis of 3. Reagents and conditions: (i) EtOH, 80°C,
K2CO3, (BrCH2CH2)2O, 24 h, yield 92%; and (ii) Br2, AcOH, NaOH,
0°C and then 90°C, 3 h, yield 88%.
Figure 1. Structures of (R)-2-benzylmorpholine and ML398.
stereoselective alkylations was prepared from (R)-(À)-2-
phenylglycinol in two steps. Thus, the cyclocondensation
reaction of 1 with 2-bromoethyl ether in ethanol at 80°C
afforded morpholine 2 in 92% yield [23,24]. Endocyclic
oxidation of 2 in the presence of bromine and acetic acid
led to the morpholin-3-one 3 [25] in 88% yield,
following our previously reported reaction conditions
[22,26].
and 4b, respectively. Amides 4 can be easily accessed by
asymmetric alkylation of chiral amide enolate 3. The key
intermediate 3 can be achieved by endocyclic oxidation
of morpholine 2. Morpholine 2 can be obtained by an
intramolecular
phenylglycinol 1.
SN2
reaction
using
(R)-(À)-2-
As shown in Scheme 3, the key intermediate
enantiomerically pure morpholin-3-one 3 required for the
Scheme 1. Previous studies and this work. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 2. Retrosynthetic analysis of (R)-2-benzylmorpholine and ML398.
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Total synthesis of (R)-2-benzylmorpholine.
With
compound 3 in hand, we then studied its C2-substitution;
therefore, was allowed to react with lithium
C-2, the hydrochloride salt of 5 was formed, and its X-
ray diffraction analysis was performed [28]. The absolute
configuration of the new stereogenic center C-2 of 5·HCl
was determined as (R), based on the source of chirality:
(R)-(À)-2-phenylglycinol (Figure 2). Then, the synthesis
3
diisopropylamide in tetrahydrofuran (THF), and then
benzyl bromide was added at À78°C. Under these
conditions, the desired product 4a was obtained with
good diastereoselectivity (dr = 94:6) in 92% yield [27].
Subsequently, (R)-2-benzylmorpholine was prepared
within two steps from 4a. As shown in Scheme 4, the
reduction of the morpholinone 4a with BH3·Me2S gave 5
in 84% yield. In order to determine the configuration at
of
(R)-2-benzylmorpholine
was
completed
by
hydrogenolysis of 5 in 95% yield. The spectroscopic data
of the final compound were consistent with those
reported in the literature [13]. Thus, the total synthesis of
(R)-2-benzylmorpholine was accomplished in 60%
overall yield over five steps.
Total synthesis of ML398. A similar strategy was used
for the synthesis of ML398 (Scheme 5). (R)-2-
Phenethylmorpholine 7 was readily synthesized from 3
under similar conditions to those described for the
synthesis of (R)-2-benzylmorpholine: (i) stereoselective
alkylation using (2-iodoethyl)benzene [(dr = 94:6), 75%
yield]; (ii) BH3·Me2S-mediated reduction (80% yield);
and (iii) catalytic hydrogenation (H2, Pd–C 10%, MeOH,
95% yield). Finally, alkylation of 7 with 4-chlorobenzyl
bromide provided compound ML398 in 70% yield. Thus,
the total synthesis of ML398 was accomplished in six
steps [starting from (R)-(À)-2-phenylglycinol] in 35%
overall yield.
Scheme 4. Synthesis of (R)-2-benzylmorpholine. Reagents and
conditions: (i) lithium diisopropylamide, tetrahydrofuran (THF), À78°C,
and then benzyl bromide, 6 h, yield 92%; (ii) BH3·Me2S, THF, 0°C,
8 h, yield 85%; and (iii) H2, Pd–C 10%, MeOH, 24 h, yield 95%.
We assume the good diastereoselectivity observed in the
alkylation step can be rationalized through the formation of
Figure 2. Oak Ridge Thermal Ellipsoid Plot diagram of hydrochloride salt of 5. The chloride ion is disordered over two sites, one of which is omitted in
the figure. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 5. Synthesis of ML398. Reagents and conditions: (i) lithium diisopropylamide, tetrahydrofuran, À78°C, and then (2-iodoethyl)benzene, 6 h,
yield 75%; (ii) BH3·Me2S, tetrahydrofuran, 0°C, 8 h, yield 80%; (iii) H2, Pd–C 10%, MeOH, 24 h, yield 95%; and (iv) CH3CN, 20°C, K2CO3, 4-
chlorobenzyl bromide, 12 h, yield 70%.
Journal of Heterocyclic Chemistry
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S. Torres, M. Velasco, J. Á. Gallegos-Rojas, S. Bernès, M. L. Orea, J. L. Terán, G. Huelgas,
V. Gómez-Calvario, and J. R. Juárez
Vol 000
Scheme 6. Chelated model applied to the diastereoselective alkylation of 3 leading to enantiopure amides 4. [Color figure can be viewed at
wileyonlinelibrary.com]
a bicyclic chelated transition state (I) where the β-face is
much easier to attack, allowing the observed
stereochemistry (Scheme 6) [29,30]. This hypothesis is
consistent with the conformation of the heterocycle
observed in the solid state for 3 and 5·HCl: due to the
presence of the sp2-hybridized C-3 atom in 3, the N atom
has a trigonal planar geometry, and the morpholinone
adopts a half-chair conformation [31], with a puckering
amplitude of 0.59(2) Å, favoring the differentiation
between α and β faces in the transition state I. Once the
alkylation proceeded, and after reduction at C-3, the chair
conformation is restored for the heterocycle in 5·HCl, as
is observed in the vast majority of morpholinium salts for
which X-ray structures have been determined [32].
(1H, dd, J = 10.9, 8.7 Hz, CH2OH), 3.66–3.74 (m, 5H,
CH2OH, OC2H4), 3.59 (1H, dd, J = 8.7, 5.2 Hz,
NCHAr), 2.53–2.59 (2H, m, NC2H4), 2.35–2.42 (2H, m,
NC2H4); 13C NMR (125 MHz, CDCl3) δC 135.7, 128.8,
128.3, 128.0, 70.5, 67.2, 60.5, 49.8; high-resolution mass
spectrometry (HRMS) Fast atom bombardment (FAB+)
calcd for C12H18NO2 [M + H]+ 208.1338; found 208.1332.
Synthesis of (R)-4-(2-hydroxy-1-phenylethyl)morpholin-3-
one (3).
To a solution of compound 2 (0.70 g,
3.37mmol) in acetic acid (3.5 mL, 80%) at 0°C was
added dropwise a solution of bromine (10.80 mmol) in
acetic acid (3.5 mL). The mixture was stirred for 20 min,
and water (23 mL) was then added and stirred for 3 h.
Afterwards, the reaction was treated with a solution of
sodium hydroxide (150 mL, 0.5 M), warmed to 90°C,
and stirred for 2 h. Then, the mixture was cooled,
saturated with sodium chloride, and extracted with
dichloromethane (3 × 80 mL); and the combined organic
mixture was dried (sodium sulfate) and concentrated
under reduced pressure. The crude mixture was purified
by column chromatography on silica gel (EtOAc) to give
compound 3: white solid; yield 0.65 g (88%); mp 122°C;
[α]2D0 = À87.5 (c 1.00, CHCl3); IR (cmÀ1): vmax 3391
CONCLUSION
In conclusion, an efficient stereoselective total synthesis
of (R)-2-benzylmorpholine and ML398 has been achieved
in five (60% overall yield) and six (35% overall yield)
steps, respectively. In both routes, a stereoselective
alkylation of chiral non-racemic morpholin-3-one was
used as a key step. The diastereocontrol observed during
the formation of 4a and 4b can be explained by the
1
(OH), 1637 (C═O), 1489; H NMR (500 MHz, CDCl3)
formation of
a
bicyclic chelated transition state.
δH 7.26–7.38 (5H, m, Ar–H); 5.69 (1H, t, J = 7.0 Hz,
NCHAr), 4.28 (2H, d, J = 4.5 Hz, OCH2), 4.15–4.16
(2H, m, CH2OH), 3.86 (1H, ddd, J = 11.9, 6.3, 3.8 Hz,
OCH2), 3.78 (1H, ddd, J = 11.9, 6.3, 3.8 Hz, OCH2),
3.32 (1H, ddd, J = 12.1, 6.3, 3.8 Hz, NCH2), 3.06 (1H,
ddd, J = 12.2, 6.2, 3.9 Hz, NCH2); 13C NMR (125 MHz,
CDCl3) δC 168.2, 135.8, 128.2, 127.8, 128.03, 68.1,
63.9, 61.6, 59.0, 42.5; HRMS (FAB+) calcd for
Application to the synthesis of 2,3-disubstituted
morpholines is under investigation and will be reported in
due course.
EXPERIMENTAL
C12H16NO3 [M + H]+ 222.1085; found 222.1079.
Alkylation of compound 3. General procedure.
Synthesis of (R)-2-morpholino-2-phenylethan-1-ol (2).
A
mixture of (R)-phenylglycinol (2.50 g, 18.22 mmol),
K2CO3 (13.85 g, 100.23 mmol), and 2-bromoethyl ether
(8.45 g, 36.45 mmol) dissolved in EtOH (130 mL) was
refluxed for 24 h. The reaction was cooled and filtered,
and the solvent was dried (sodium sulfate) and removed
under reduced pressure. The crude mixture was purified
by column chromatography on silica gel (EtOAc) to give
compound 2: oil yellow; yield 3.46 g (92%); [α]
A solution of diisopropylamine (0.66 mL, 4.74 mmol) in
dry THF (15 mL) was cooled at À78°C under nitrogen
atmosphere. A 2.5 M hexane solution of n-BuLi
(2.16 mL, 5.42 mmol) was carefully added, and the
reaction was stirred at À78°C for 30 min. A solution of
(R)-4-(2-hydroxy-1-phenylethyl)morpholin-3-one (0.3 g,
1.35 mmol) and hexamethylphosphoric triamide (0.6 mL)
in THF (5 mL) was slowly added, and the resulting
solution was stirred at À78°C for 45 min. An electrophile
(0.41 mL, 3.52 mmol) was added dropwise, and the
20 = À28.5 (c 1.05, CHCl3), {lit.1 [α]2D0 = À31.7 (c 1.05,
D
1
CHCl3)}; IR (cmÀ1): vmax 3422 (OH), 1450; H NMR
(500 MHz, CDCl3) δH 7.12–7.48 (5H, m, Ar–H), 3.97
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reaction mixture was stirred at À78°C for 6 h. The mixture
was treated with saturated aqueous solution of NH4Cl,
extracted twice with AcOEt, dried (sodium sulfate), and
then removed under reduced pressure. Chromatographic
purification on silica gel (EtOAc–petroleum ether 9:1)
provided the compound 4a or 4b.
2.20 (1H, dd, J = 11.0, 10.0 Hz, NHCH2), 1.99 (1H, td,
J = 11.3, 3.2 Hz, NHCH2); 13C NMR (125 MHz, CDCl3)
δC 137.7, 135.4, 129.1, 128.7, 128.3, 128.2, 127.9, 126.2,
76.8, 70.2, 66.8, 60.3, 56.5, 46.6, 40.1; HRMS (EI+) calcd
for C19H23NO2 [M + H]+ 297.1729; found 297.1712.
Synthesis
of
(R)-2-((R)-2-phenethylmorpholino)-2-
20
phenylethan-1-ol (6).
Yellow oil, 0.08 g (80%); [α]D
= À34.5 (c 4, CHCl3); IR (cmÀ1): vmax 3429 (OH), 1452,
1H NMR (500 MHz, CDCl3) δH 7.50–7.03 (10H, m, Ar–
H), 3.98 (1H, dd, J = 10.6, 9.5 Hz, CH2OH), 3.86 (1H,
ddd, J = 11.2, 2.9, 1.5 Hz, OCH2), 3.68 (1H, dd,
J = 10.8, 5.1 Hz, NHCH2Ar), 3.61 (1H, ddd, J = 13.7,
8.1, 2.4 Hz, NHCH2Ar), 3.57–3.52 (1H, m, OCH2),
2.81–2.76 (1H, m, NHCH2), 2.76–2.71 (1H, m, CH2Ar),
2.68–2.64 (1H, m, NCH2), 2.64–2.60 (1H, m, CH2Ar),
2.21–2.16 (1H, m, NCH2), 1.99 (1H, td, J = 11.4, 3.1 Hz,
NCH2), 1.81–1.73 (1H, m, CH2CH2), 1.70–1.63 (1H, m,
CH2CH2), 13C NMR (125 MHz, CDCl3) δC 141.7, 134.8,
128.8, 128.3, 128.2, 128.0, 125.7, 75.0, 70.0, 66.7, 60.0,
57.0, 46.3, 35.1, 31.4; HRMS (EI+) calcd for C20H25NO2
[M + H]+ 311.1885; found 311.1868.
(R)-2-Alkyl-4-((R)-2-hydroxy-1-phenylethyl)morpholin-3-
one (4a).
Yellow oil, 0.38 g (92%); [α]2D0 = À39.6 (c
2.5, CHCl3); IR (cmÀ1): vmax 3394 (OH), 1626 (C═O),
1
1495; H NMR (500 MHz, CDCl3) δH 7.24–7.32 (8H, m,
Ar–H); 6.93–6.96 (2H, m, Ar–H), 5.53 (1H, dd, J = 8.6,
5.2 Hz, NCHAr), 4.53 (1H, dd, J = 6.4, 3.6 Hz, OCH),
4.05–4.12 (2H, m, CH2OH), 3.89 (1H, ddd, J = 11.9, 4.0,
2.2 Hz, OCH2), 3.71 (1H, ddd, J = 11.9, 10.3, 3.3 Hz,
OCH2), 3.26 (1H, dd, J = 14.1, 3.6 Hz, CH2Ar), 3.17
(1H, dd, J = 14.1, 6.4 Hz, CH2Ar), 2.85–2.96 (2H, m,
NCH2), 13C NMR (125 MHz, CDCl3) δC 170.2, 137.2,
135.4, 130.0, 128.6, 128.1, 127.9, 127.7, 126.5, 78.5,
62.7, 61.7, 59.1, 43.2, 38.2; HRMS Electron Impact (EI+)
calcd for C19H21NO3 [M + H]+ 311.1521; found 312.1504.
Hydrogenolysis of compounds
5
and 6. General
(R)-2-Phenethyl-4-((R)-2-hydroxy-1-phenylethyl)
procedure. To a solution of 5 or 6 (0.12 g, 0.41 mmol)
in MeOH (5 mL) under hydrogen atmosphere was added
Pd–C 10%, and the mixture reaction was stirred at room
temperature for 24 h. Afterwards, the reaction was
filtered, and the solvent was evaporated under reduced
20
morpholin-3-one (4b).
Yellow oil, 0.33 g (75%); [α]D
= À35.3 (c 1.0, CHCl3); IR (cmÀ1): vmax 3406 (OH), 1630
1
(C═O), 1495; H NMR (500 MHz, CDCl3) δH 7.10–7.28
(10H, m, Ar–H); 5.63 (1H, dd, J = 8.2, 5.4 Hz, NCHAr),
4.11 (1H, dd, J = 8.1, 3.4 Hz, OCH), 4.04 (2H, dt,
J = 14.7, 7.1 Hz, CH2OH), 3.86 (1H, ddd, J = 11.9,
3.4, Hz, OCH2), 3.72–3.64 (1H, m, OCH2), 3.11–3.01
(2H, m, NCH2), 2.66 (2H, dd, J = 9.4, 6.7 Hz, CH2Ar),
2.25–2.17 (1H, m, CH2CH2), 2.09–2.00 (1H, m,
CH2CH2); 13C NMR (125 MHz, CDCl3) δC 170.8, 141.3,
135.9, 128.8, 128.5, 128.3, 128.0, 127.7, 125.8, 76.9,
62.4, 61.2, 58.6, 42.9, 33.9, 31.1; HRMS (FAB+) calcd for
C20H24NO3 [M + H]+ 326.1756; found 326.1751.
pressure to afford (R)-2-benzylmorpholine or 7.
Synthesis of (R)-2-benzylmorpholine. Yellow oil, 0.07 g
(95%); [α]2D5 = +1.35 (c 5, CHCl3); {lit.8a [α]2D5 = +1.31 (c
1
5, CHCl3)}; IR (cmÀ1): vmax 3456 (NH), 1633, H NMR
(500 MHz, CDCl3) δH 7.39–7.18 (5H, m, Ar–H), 3.94–
3.86 (1H, m, OCH2), 3.77–3.71 (1H, m, OCH2), 3.65 (1H,
td, J = 11.2, 3.1 Hz, OCH), 3.29 (1H, s, NH), 2.95–2.87
(2H, m, NHCH2), 2.86–2.83 (2H, m, NHCH2), 2.68 (1H,
dd, J = 13.9, 6.5 Hz, CH2Ar), 2.65–2.59 (1H, m, CH2Ar).
13C NMR (125 MHz, CDCl3) δC 137.5, 129.2, 128.3,
127.0, 126.3, 77.0, 67.5, 50.2, 45.2, 40.2. HRMS (EI+)
Reduction of compounds 4a and 4b. General
procedure.
To a stirred solution of 4a or 4b (0.1 g,
calcd for C11H15NO [M + H]+ 177.1154; found 177.1137.
0.32 mmol) in anhydrous THF (10 mL) at 0°C was added
a solution of BMS (0.12 mL, 1.28 mmol). Then, the
reaction mixture was stirred at room temperature for 8 h.
The reaction was quenched with methanol (2 mL) and
stirred at room temperature for 1 h. Finally, the solvents
were evaporated under reduced pressure. Chromatographic
purification on silica gel (EtOAc–petroleum ether 1:1)
Synthesis of (R)-2-phenethylmorpholine (7). Yellow oil,
0.07 g (95%); [α]D25 = +46.3 (c 1, CHCl3); IR (cmÀ1):
1
vmax 3456 (NH), 1633; H NMR (500 MHz, CDCl3) δH
7.30–7.24 (2H, m, Ar–H), 7.20–7.15 (3H, m, Ar–H),
3.90 (1H, m, OCH2), 3.67–3.59 (1H, m, OCH2), 3.45
(1H, dddd, J = 10.5, 8.3, 4.3, 2.3 Hz, OCH), 2.92–2.89
(1H, m, NHCH2), 2.88–2.86 (2H, m, NHCH2), 2.81–2.74
(1H, m, CH2Ar), 2.64 (1H, ddd, J = 13.8, 9.7, 6.9 Hz,
CH2Ar), 2.58 (1H, dd, J = 12.2, 10.4 Hz, NHCH2), 1.83–
1.73 (1H, m, CH2CH2), 1.69–1.61 (1H, m, CH2CH2);
13C NMR (125 MHz, CDCl3) δC 141.6, 128.2, 125.7,
75.2, 67.1, 50.3, 45.1, 35.1, 31.2. HRMS (EI+) calcd for
C19H23NO2 [M + H]+ 191.1310; found 191.1293.
provided the reduced compound 5 or 6.
Synthesis of (R)-2-((R)-2-alkylmorpholino)-2-phenylethan-1-
ol (5). Yellow oil, 0.08 g (84%); [α]2D0 = À81.8 (c 4,
CHCl3); IR (cmÀ1): vmax 3364 (OH), 1494; 1H NMR
(500 MHz, CDCl3) δH 7.14–7.35 (10H, m, Ar–H); 3.93
(1H, dd, J = 10.8, 9.1 Hz, OCH2), 3.76–3.81 (2H, m,
OCH), 3.61–3.65 (1H, m, CH2OH), 3.53–3.58 (2H, m,
OCH2), 2.83 (1H, dd, J = 13.8, 7.0 Hz, CH2Ar), 2.74 (1H,
dt, J = 11.1, 1.8 Hz, NHCH2), 2.63 (1H, dd, J = 13.8,
6.5 Hz, CH2Ar), 2.56 (1H, dd, J = 11.4, 1.8 Hz, NHCH2),
Synthesis of ML398.
The (R)-2-phenethylmorpholine
(0.03 g, 0.14 mmol) was suspended in anhydrous
acetonitrile (7.7 mL) and cooled at 20°C. To this solution
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S. Torres, M. Velasco, J. Á. Gallegos-Rojas, S. Bernès, M. L. Orea, J. L. Terán, G. Huelgas,
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was
dried
with
magnesium
sulfate,
filtered,
and concentrated. The crude mixture was purified using
flash column chromatography (5% methanol in
dichloromethane) to afford the product ML398: yellow oil,
0.08 g (70%); [α]D25 = +31.2 (c 1, CH3OH); {lit.10 [α]D
20
1
= +29.3 (c 1, CH3OH)}; H NMR (500 MHz, CDCl3) δ
7.34–7.22 (m, 7H), 7.19–7.15 (m, 3H), 3.87 (1H, ddd,
J = 11.2, 3.1, 1.4 Hz, OCH2), 3.64 (1H, td, J = 11.4,
2.3 Hz, OCH2), 3.52–3.46 (1H, m, OCH), 3.43 (2H, s,
NCH2), 2.82–2.70 (1H, m, CH2Ar), 2.69–2.66 (1H, m,
NCH2), 2.65–2.62 (1H, m, NCH2), 2.61–258 (1H, m,
NCH2), 2.16 (1H, td, J = 11.4, 3.3 Hz, NCH2), 1.87 (1H, t,
J = 10.4, NCH2), 1.83–1.75 (1H, m, CH2CH2), 1.68–1.59
(1H, m, CH2CH2); 13C NMR (125 MHz, CDCl3) δC 141.9,
136.3, 132.8, 130.4, 129.6, 129.0, 128.6, 128.4, 128.3,
125.7, 74.8, 66.6, 62.4, 58.5, 53.1, 35.2, 31.5. HRMS
(EI+) calcd for C19H22ClNO [M + H]+ 315.1390; found
315.1373.
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2012, 44, 1625.
[25] Crystal structure 3 was deposited at the Cambridge Crystallo-
graphic Data Centre, deposit number CCDC 1847513.
[26] The oxidation of 2 following the methodologies reported by
Griffiths et al. (I2, NaHCO3, aqueous THF or DMSO), and Chamorro-
Arenas et al. (TEMPO, NaClO2, NaH2PO4, NaOCl, CH3CN) afforded
compound 3 in 57% and 30% yield, respectively; (a) Griffiths, R. J.; Bur-
ley, G. A.; Talbot, E. P. A. Org. Lett 2017, 19, 870; (b) Chamorro-Arenas,
D.; Osorio-Nieto, U.; Quintero, L.; Hernández-García, L.; Sartillo-Piscil,
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Acknowledgments. The authors gratefully acknowledge
financial support from CONACyT (project 268178) and VIEP-
BUAP. S. T. (304685) and M. V. (277416) were supported by
CONACyT doctoral fellowships. The authors also thank Ana G.
Machorro-Juárez for her technical assistance.
[27] The diastereomeric ratio of 4 was measurement by HPLC anal-
ysis using a chiral column (Chiralpak AD-H; hexane-i-PrOH, 90:10;
1.0 mL/min; detection 210 nm), tR (min) = 20.5 (major isomer) and
28.3 (minor isomer).
[28] Crystal structure 5·HCl was deposited at the Cambridge Crys-
tallographic Data Centre, deposit number CCDC 1847514.
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SUPPORTING INFORMATION
[8] Bentley, J. M.; Dawson, C. E.; Guba, W.; Hebeisen, P.;
Monck, N.; Pratt, R. M.; Richter, H.; Roever, S.; Ruston, V. PCT Int.
Appl, WO 2006/077025A2 2006.
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet