Preparation of Morpholines and Benzoxazines Starting from Nitroepoxides

Article abstract of DOI:10.1055/s-0035-1561466

Nitroepoxides are easily transformed into 2,3-disubstituted morpholines and 2,3-disubstituted benzoxazines in a two-step sequence by treatment with N-methylethanolamine and N-methyl-2-hydroxyaniline, respectively, in a highly stereoselective fashion.

Full text of DOI:10.1055/s-0035-1561466

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
feature
A
E. Capel et al.
Feature
Synthesis
Preparation of Morpholines and Benzoxazines Starting from
Nitroepoxides
E. Capel
A. Vidal-Albalat
O
NO2
R2
N
O
N
O
NH
MeOH
OH
TMSOTf, Et3SiH
S. Rodríguez
R1
OH
CH2Cl2
–78 °C to r.t.
F. V. González*
R1
R1
R2
R2
0 °C or r.t.
nitroepoxides
morpholinols
benzoxazinols
10 examples
anti morpholines
syn benzoxazines
6 examples
up to 97% yield
dr >95:5
Departament de Química Inorgànica i Orgànica, Universitat
Jaume I, Avda. Sos Baynat, s/n, 12071-Castelló, Spain
fgonzale@uji.es
R1 = aryl
R
2 = alkyl
up to 90% yield
dr 3:1 to 6:1 (anti/syn)
Received: 25.04.2016
Accepted after revision: 28.04.2016
Published online: 16.06.2016
pot-process by using isonitriles and amines1a (Scheme 2).
We have recently reported the preparation of quinoxalines
by reaction between nitroepoxides and 1,2-benzenedi-
amines, and also the synthesis of pyrazines when ammonia
is used as a nucleophile (Scheme 2).2
DOI: 10.1055/s-0035-1561466; Art ID: ss-2016-z0288-fa
Abstract Nitroepoxides are easily transformed into 2,3-disubstituted
morpholines and 2,3-disubstituted benzoxazines in a two-step se-
quence by treatment with N-methylethanolamine and N-methyl-2-hy-
droxyaniline, respectively, in a highly stereoselective fashion.
R3
NH
R2
Ar
N
S
N
Key words nitroepoxides, morpholinols, morpholines, benzoxazines
R1
R1
R2
imidazoles
thiazoles
Nitroepoxides are an underdeveloped class of com-
pounds with wide potential for use in chemical synthesis.1
Nitroepoxides represent strained systems displaying two
highly oxidized vicinal positions by nature of their chemical
connectivity and hence are potentially exploitable as syn-
thons with vicinal electrophilic centers.
In 1991, Vankar reported the transformation of nitro-
epoxides into amino ketones.1d Nucleophilic attack of the
amine to the β-position of the nitroepoxide followed by ni-
trite extrusion affords the amino ketone (Scheme 1).
NH2
N
R3
O
N
NO2
N
R1
N
R1
R2
R1
R2
R2
quinoxalines
2-aminoimidazoles
R2
R1
N
N
R1
R2
pyrazines
NO2
R2
O
O
N
N
Scheme 2 Nitroepoxides into aromatic heterocycles
H
reduction, reductive amination,...
R2
R1
– R1
– NO2
nitroepoxide
Nitroepoxides can be also transformed into 1,2-di-
amines3 if a reductive amination is performed on the re-
sulting amino ketone, or 1,2-amino alcohols if the resulting
amino ketone is subjected to a reduction step4 (Scheme 3).
We recently reported the preparation of saturated 1,4-
diamino-heterocycles, such as piperazines and tetrahydro-
quinoxalines (Scheme 3),2 when nitroepoxides are treated
with 1,2-diamines and then a reductive agent. The diamino
ketone intermediate resulting from the opening of the ni-
troepoxide by 1,2-diamine cyclizes to afford an amino-
imine that upon reduction affords the corresponding satu-
Scheme 1 Reactivity of nitroepoxides with amines
Resulting amino ketones can be further transformed
into interesting moieties in one-pot processes starting from
nitroepoxides. During the last few years a number of stud-
ies have appeared reporting the transformation of nitro-
epoxides into aromatic heterocycles. Hence nitroepoxides
have been transformed into thiazoles when reacted with
benzothioamides,1b imidazoles if guanidines are used as ni-
trogenated nucleophiles,1f and aminoimidazoles in a one-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
E. Capel et al.
Feature
Synthesis
rated 1,4-diamino-heterocycle (Scheme 4). Reductive ami-
nation of the amino-imine intermediate affords the syn iso-
mer as the major isomer in both cases (syn/anti ca. 3:1).
We envisioned nitroepoxides to be transformed into
morpholines if treated with 1,2-amino alcohols. It is ex-
pected that the amino group would open the nitroepoxide
and the resulting hydroxy ketone would to cyclize into a
stable morpholinol. Morpholinols could be then trans-
formed into the desired morpholines by reduction (Scheme
4). We report herein the synthetic transformation of nitro-
epoxides into morpholines and benzoxazines by reaction
with 1,2-amino alcohols and a reductive agent.
Morpholines are considered to be privileged scaffolds in
medicinal chemistry.5 Some commercial drugs display mor-
pholine moiety (Figure 1). For example, reboxetine (Edro-
Biographical Sketches
Estefanía Capel received her
B.Sc. in chemistry from Univer-
sitat Jaume I (Spain) in 2015.
She is currently an M.Sc. stu-
dent in medicinal chemistry un-
der the guidance of Prof.
Florenci V. González at Universi-
tat Jaume I. Her research focus-
es
on
the
synthetic
transformations of nitroepox-
ides.
Andreu Vidal Albalat was
born in Albocàsser (Spain). He
received his M.Sc. in medicinal
chemistry from Universitat
Jaume I (Spain), in 2012 with a
thesis on the synthesis of vicinal
diamines from nitroepoxides.
He is currently a Ph.D. student
under the supervision of Prof.
Florenci V. González at Universi-
tat Jaume I. His research focuses
on the development of new or-
ganocatalytic
epoxidation
methodologies and synthetic
applications of chiral building
blocks.
Santiago Rodríguez graduat-
ed from the School of Chemis-
try at the University of Valencia.
His Ph.D. thesis was directed by
Prof. Ana M. Costero. He had a
postdoctoral stay with Prof. J.
Fraser Stoddart at Birmingham
University. He also did a post-
doctoral stay at the University
of Basque Country in the group
of Prof. Claudio Palomo.
Florenci V. González carried
out his undergraduate studies
at Universitat de València. He
obtained his Ph.D. under the
guidance of Prof. J. Alberto
Marco and Prof. Miguel Carda at
Universitat Jaume I. He had a
postdoctoral stay at Indiana
University and University of
Michigan in the group of Prof.
William R. Roush, he also had a
postdoctoral stay at Colorado
State University in the group of
Prof. Robert M. Williams. Since
2001 he has been associate pro-
fessor at Universitat Jaume I. His
current research interests are
synthetic methodology includ-
ing organocatalytic processes
and the design and synthesis of
protease inhibitors.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
E. Capel et al.
Feature
Synthesis
OEt
O
NHR
NHR
R1
O
O
NH
N
R2
H
1,2-diamines
NH
HN
R
N
R'
HN
R1
OH
N
R1
reboxetine
NH
O
O
R2
NO2
R1
R2
O
amino alcohols
piperazines
O
CH3
R2
N
F
R
aprepitant
F3C
CH3
R = H, (+)-phenmetrazine
R = CH3, (+)-phendimetrazine
CF3
HN
Figure 1 Commercial drugs displaying a morpholine moiety
NH
R1
R2
tetrahydroquinoxalines
We began our studies of the preparation of morpholi-
nols by combining nitroepoxide 1a with N-methylethanol-
amine (1.5 equiv) in methanol. We were pleased to see that
the reaction afforded morpholinol 2a in high chemical yield
(Scheme 5). A series of morpholinols were prepared start-
ing from the corresponding nitroepoxide following the
same experimental procedure (Scheme 5). Stereochemistry
was assigned by NMR measurements: NOE effect was ob-
served between methyl group and benzylic hydrogen
(Scheme 5).
Scheme 3 Nitroepoxides into saturated compounds
NH2
NO2
R2
O
O
HN
R1
N
NH
R2
HN
R1
HN
+
NH2
NH2
R2
R1
R2
R1
1,2-diamine nitroepoxide
1,4-diamino
heterocycle
H3C
H3C
OH
This work:
N
O
N
NO2
H
R1
O
OH
O
R1
2a–f
MeOH, 2.5 h
R2
R2
OH
O
NO2
R2
HN
R1
O
O
1a–f
HN
R1
HN
R1
+
OH
R2
NH2
R2
R1
R2
HO
H3C
N
H3C
H3C
2-amino
alcohol
nitroepoxide
morpholine
benzoxazine
N
N
H
3
O
O
O
2
Scheme 4 Mechanism for the transformation of nitroepoxides into
saturated 1,4-diamino-heterocycles and for the reaction to prepare
morpholines and benzoxazines
NOE
OH
H3C
OH
OH
H3C
H3C
H3C
F
2b
2c
2a
anti/syn 82:18
anti/syn 72:28
anti/syn 86:14
83%
78%
87%
H3C
H3C
N
H3C
N
N
nax, Prolift) a selective norepinephrine reuptake inhibitor
(NRI), is an antidepressant currently approved and market-
ed in over 60 countries;6 phenmetrazine is a potent releaser
of [3H]norepinephrine and [3H]dopamine,7 phendimetra-
zine (Bontril) is an anorexigenic drug;8 aprepitant (Emend)
is a potent and orally active NK1 receptor antagonist for
chemotherapy induced emesis, depression and other po-
tential indications9 (Figure 1). Although there have been re-
ported routes for the preparation of morpholines,10 their
use is currently limited by the scarcity of methods for their
preparation, particularly for 2,3-disubstituted morpholines.
Benzoxazine moiety is displayed by compounds with a
wide range of biological activities like neuroprotective
agents,11 PPARγ agonists,12 intracellular calcium antago-
nist,13 antiangiogenic therapeutic agents,14 estrogen recep-
tor β-agonists,15 and antitumour.16
O
Cl
O
O
OH
OH
OH
H3C
H3C
F
Cl
CH3
2f
2d
anti/syn 82:18
79%
2e
anti/syn 85:15
74%
anti/syn 75:25
63%
Scheme 5 Conversion of nitroepoxides into morpholinols
The conversion of morpholinols into morpholines was
carried out by a sequence of two steps.17 Reduction of mor-
pholinol 2a with sodium borohydride afforded diol 3 as a
mixture of stereoisomers. Then sulfuric acid treatment of
compound 3 gave morpholine 4a as a 45:55 mixture of ste-
reoisomers (Scheme 6). This transformation has also been
performed in one-pot (Scheme 6).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
E. Capel et al.
Feature
Synthesis
H3C
Ph
H3C
Ph
H3C
Ph
OH
N
H3C
N
H3C
OH
N
N
O
N
1.
NO2
H2SO4
NaBH4
87%
H
O
O
Ph
OH
O
Ph
CH3
2. TMSOTf, Et3SiH
44%
1a
4a
CH3
CH3
3
CH3
4a
anti/syn > 95:5
H C OH
3
2a
anti/syn 45:55
anti/syn 73:27
1. NaBH4
Scheme 8 One-pot process for the conversion of nitroepoxide 1a into
morpholine 4a
2. H2SO4
44%
We then evaluated a one-pot procedure for the prepara-
tion of 2,3-disubstituted morpholines starting from nitro-
epoxides. Some experimental work was performed to opti-
mize the transformation. Morpholine 4a was prepared
starting from nitroepoxide 1a by treatment with N-methyl-
ethanolamine (2 equiv) followed by addition of trimethylsi-
lyl triflate (6 equiv) and triethylsilane (24 equiv) in di-
chloromethane (Scheme 8).
In order to prepare benzoxazines, nitroepoxides were
treated with 2-hydroxyanilines. The resulting benzoxazinol
would be further transformed into benzoxazines in a simi-
lar sequence as applied for the synthesis of morpholines.
Firstly nitroepoxide 2a was treated with 2-hydroxyaniline
at room temperature, compound 5a was obtained, but the
yield was not satisfactory. Then the reaction was carried
out at low temperature (0 °C) and an improvement in the
chemical yield was observed (Scheme 9). Stereochemistry
was assigned by NMR measurements: an NOE effect was
observed between the methyl group and the benzylic hy-
drogen.
Scheme 6 Conversion of morpholinol into an equimolecular mixture
of morpholines
In order to improve the chemical yield and diastereose-
lectivity of the reaction, other conditions were evaluated.
Treatment of nitroepoxide 1a with trimethylsilyl triflate (2
equivalents) and triethylsilane (8 equivalents)18 in di-
chloromethane afforded anti morpholine 4a as a single iso-
mer (Scheme 7). Morpholinols 2b–f were transformed into
the corresponding anti morpholines 4b–f (Scheme 7).
H3C
H3C
N
N
TMSOTf
Et3SiH
O
O
R1
R1
4a–f
R2
OH
R2
2a–f
H3C
H3C
N
H3C
N
N
3
O
O
2
O
CH3
CH3
CH3
R4
4c
H3C
4b
F
4a
R4
anti/syn > 95:5
72%
anti/syn > 95:5
37%
(J2,3 = 8.7 Hz)
anti/syn > 95:5
R3
57%
R3
N
O
(J2,3 = 8.8 Hz)
H3C
N
(J2,3 = 8.8 Hz)
H
NO2
H3C
R1
1a,f
OH
O
N
N
R1
R2
MeOH, 2.5 h
O
R2
O
OH
5a–d
CH3
CH3
4f
4d
Cl
Cl
anti/syn > 95:5
96%
(J2,3 = 8.7 Hz)
anti/syn > 95:5
97%
(J2,3 = 8.8 Hz)
Cl
HN
HN
H
O
O
Scheme 7 Conversion of morpholinols into morpholines
NOE
OH
OH
H3C
H3C
5a
5b
anti/syn 86:14
anti/syn 82:18
Stereochemical assignments were made by NMR cou-
pling constants and by NOE experiments (Scheme 8). Simi-
lar coupling constants were observed for anti morpholines
4a–f (Scheme 7) denoting relative anti stereochemistry. Ac-
cording to the literature anti morpholines show higher cou-
pling constants (J2,3 = 9.0 Hz for phendimetrazine10s) than
syn morpholines (J2,3 = 4.4 Hz10r). syn-4a Compound
(Scheme 7) showed coupling constant J2,3 = 3.4 Hz.
90%
55%
H3C
H3C
N
N
O
O
OH
OH
H3C
H3C
5c
5d
anti/syn 77:23
Cl anti/syn 76:24
80%
87%
Scheme 9 Conversion of nitroepoxides into benzoxazinols
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
E. Capel et al.
Feature
Synthesis
2-Hydroxybenzoxazine 5c was submitted to same reac-
tion as morpholinols with trimethylsilyl triflate and trieth-
ylsilane to furnish syn benzoxazine 6 in good chemical yield
(Scheme 10). Compound 6 was formed as a single isomer.
The relative stereochemistry of 6 was assigned as syn based
upon coupling constants and NOE experiments (Scheme
10). For 6, a coupling constant J2,3 = 2.8 Hz is in accordance
with syn benzoxazines in the literature (for anti: J2,3 = 4.5
Hz; for syn: J2,3 = 2.0 Hz).19
S
1.
SH
, KOH
HN
O
ClH3N
2. NaBH4
NO2
2
+
NH
CH3
3
S
Ph
Ph
Ph
CH3
7
28%
2,3 = 9.6Hz
1a
8
39%
syn/anti 2:1
CH3
J
Scheme 11 Conversion of nitroepoxides into thiomorpholines
and 2-hydroxybenzoxazine, followed by their transforma-
tion into morpholines and benzoxazines by reduction. The
whole process can also be performed in one-pot starting
from the nitroepoxide. Further investigations of the utility
of nitroepoxides in synthesis are ongoing and will be re-
ported in the future.
H3C
H3C
N
N
2
TMSOTf
Et3SiH
76%
O
O
3
OH
H3C
CH3
6
5c
syn/anti > 95:5
2,3 = 2.8Hz
J
1H and 13C NMR spectra were measured in CDCl3 (1H, δ = 7.24; 13C, δ =
77.0) solution at 30 °C on a 300 MHz, 400 MHz, or 500 MHz NMR
spectrometer. HRMS were measured on a QTOF I (quadrupole-hexa-
pole-TOF) mass spectrometer with an orthogonal Z-spray-electro-
spray interface. Mass spectra were measured on a GCMS (single quad-
rupole). IR spectra were recorded as oily films on KBr plates using a
FT-IR spectrophotometer. EM Science Silica Gel 60 was used for col-
umn chromatography while TLC was performed with precoated
plates (0.25 mm). Unless otherwise specified, all reactions were car-
ried out under an N2 atmosphere with magnetic stirring.
Scheme 10 Conversion of nitroepoxides into benzoxazines
Curiously same reaction by using trimethylsilyl triflate
and triethylsilane afforded the anti isomer in the case of
morpholines and the syn isomer for benzoxazines. Anomer-
ic effect is ascribed to n → s* hyperconjugation between the
nonbonding orbital on the oxygen and the antibonding or-
bital of the anomeric position.20 In the silane reaction start-
ing from morpholinols, hydride attack on the oxocarbeni-
um intermediate would occur predominantly from the axial
direction due to the kinetic anomeric effect (Figure 2).21 In
case of benzoxazinols, restricted conformation of the oxo-
carbenium intermediate directs hydride attack to the less
hindered face (Figure 2).
Nitroepoxides 1a–f; General Procedure
To a stirred ice-bath cold suspension of the corresponding nitroalkene
(3.07 mmol) in MeOH (9.5 mL) containing 50% aq H2O2 solution (690
μL, 12.28 mmol) was added 2 M aq NaOH (770 μL, 1.54 mmol) and the
mixture was stirred at 0 °C for 10 min. Then, iced water (ca. 20 mg)
was added, the mixture was extracted with Et2O (3 × 30 mL), and the
combined organic phases were washed with brine (45 mL), dried
(Na2SO4), and concentrated under vacuum to obtain the product as
yellow oil without further purification.
O
H3
C
O
N
2-Methyl-2-nitro-3-phenyloxirane (1a)
Ph
CH3
N
+ CH3
H3C
Yellow oil; yield: 451 mg (82%).
H
Et3SiH
H–
IR (KBr): 3062, 3028, 2948, 1555, 1495, 1448, 1354, 1158, 1105, 982,
899 cm–1
.
Figure 2 Stereoelectronic effects to explain observed diastereoselec-
1H NMR (300 MHz, CDCl3): δ = 7.47–7.39 (m, 3 H), 7.34–7.28 (m, 2 H),
tivity
4.54 (s, 1 H), 1.80 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 131.0, 129.3, 128.7, 126.3, 88.8, 62.6,
12.2.
HRMS (EI): m/z [M]+ calcd for C9H9NO3: 179.0582; found: 179.0587.
Nitroepoxides have also been converted into thiomor-
pholines. When nitroepoxide 1a was treated with thioetha-
nolamine and then with sodium borohydride in a one-pot
process a mixture of regiomeric thiomorpholines 7 and 8
was obtained. Compound 7 is a sulfur analogue of the drug
phenmetrazine (Scheme 11).
In summary, we report herein that morpholines and
benzoxazines can be easily prepared by treating nitroepox-
ides with N-methylethanolamine and N-methyl-2-hy-
droxyaniline, respectively. The transformations comprise
two steps: firstly is the formation of 2-hydroxymorpholines
3-(4-Fluorophenyl)-2-methyl-2-nitrooxirane (1b)
Pale yellow oil; yield: 472 mg (78%).
IR (KBr): 3059, 3024, 2944, 1546 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.56–6.88 (m, 4 H), 4.53 (s, 1 H), 1.79
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.2 (d, J = 247.8 Hz), 128.3 (d, J = 8.4
Hz), 126.8 (d, J = 4.0 Hz), 115.8 (d, J = 22.0 Hz), 88.8, 62.1, 12.1.
HRMS (EI): m/z [M]+ calcd for C9H8NFO3: 197.0488; found: 197.0492.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
E. Capel et al.
Feature
Synthesis
2-Methyl-2-nitro-3-(p-tolyl)oxirane (1c)
1H NMR (300 MHz, CDCl3): δ = 7.49–7.27 (m, 5 H), 5.29 (s, 1 H), 4.23
(ddd, J = 15.4, 8.8, 2.6 Hz, 1 H), 3.68 (ddd, J = 12.0, 4.0, 1.1 Hz, 1 H),
3.07 (s, 1 H), 2.87 (ddd, J = 11.6, 2.9, 1.0 Hz, 1 H), 2.50 (ddd, J = 12.5,
11.7, 4.0 Hz, 1 H), 2.04 (s, 3 H), 1.10 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 137.53, 128.04, 127.85, 95.69, 77.24,
59.44, 56.15, 44.15, 25.03.
Yellow oil; yield: 444 mg (75%).
IR (KBr): 3062, 3025, 2948, 1552 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.21 (q, J = 8.5 Hz, 4 H), 4.50 (s, 1 H),
2.38 (s, 3 H), 1.80 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 139.6, 129.5, 128.0, 126.4, 89.1, 62.8,
21.1, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C12H18NO2: 208.1338; found:
208.1335.
HRMS (EI): m/z [M]+ calcd for C10H11NO3: 193.0739; found: 193.0745.
3-(4-Fluorophenyl)-2,4-dimethylmorpholin-2-ol (2b)
3-(4-Chlorophenyl)-2-methyl-2-nitrooxirane (1d)
Yellow pale solid; yield: 104 mg (83%); mp 99–101 °C; Rf = 0.66
(EtOAc/MeOH 95:5).
Pale yellow oil; yield:616 mg (94%).
IR (KBr): 3052, 2984, 1560, 1420, 1259, 894, 697 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.44–7.38 (m, 2 H), 7.29–7.22 (m, 2 H),
4.52 (s, 1 H), 1.78 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 135.47, 129.47, 129.02, 127.74, 88.60,
61.95, 12.30.
IR (KBr): 3490, 3050, 2987, 1608 cm–1
.
.
1H NMR (500 MHz, CDCl3): δ = 7.51–7.28 (m, 2 H), 7.02 (t, J = 8.3 Hz, 2
H), 4.22 (td, J = 12.1, 1.7 Hz, 1 H), 3.68 (dd, J = 12.0, 4.0 Hz, 1 H), 3.05
(s, 1 H), 2.89–2.81 (m, 1 H), 2.49 (td, J = 11.6, 2.8 Hz, 1 H), 2.02 (d, J =
1.2 Hz, 3 H), 1.10 (d, J = 1.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.03, 160.77, 133.29, 133.25, 114.71,
95.57, 76.36, 59.38, 56.10, 44.04, 25.16.
MS (EI): m/z [M – NO2]+ calcd for C9H8ClO: 167.0; found: 167.1; m/z
[M – C3H4NO3]+ calcd for C6H4Cl: 111.0; found: 111.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H17FNO2: 226.1243; found:
2-Ethyl-3-(4-fluorophenyl)-2-nitrooxirane (1e)
226.1246.
Pale yellow oil; yield: 583 mg (90%).
2,4-Dimethyl-3-(p-tolyl)morpholin-2-ol (2c)
IR (KBr): 3052, 2979, 1710, 1606, 1552, 1510 cm–1
.
Yellow solid; yield: 97 mg (78%); mp 105–107 °C; Rf
(EtOAc/MeOH, 95:5).
= 0.56
1H NMR (300 MHz, CDCl3): δ = 7.42–7.23 (m, 2 H), 7.21–7.05 (m, 2 H),
4.50 (s, 1 H), 2.47 (dq, J = 14.9, 7.4 Hz, 1 H), 1.68 (td, J = 14.9, 7.5 Hz, 1
H), 1.08 (t, J = 7.4 Hz, 3 H).
IR (KBr): 3526, 3050, 2987, 1608 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.54–6.98 (m, 4 H), 4.21 (td, J = 12.2,
3.0 Hz, 1 H), 3.65 (dd, J = 11.9, 4.0 Hz, 1 H), 3.01 (s, 1 H), 2.83 (dd, J =
11.6, 2.8 Hz, 1 H), 2.46 (td, J = 12.0, 3.9 Hz, 1 H), 2.32 (s, 3 H), 2.01 (s, 3
H), 1.09 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.2 (d, J = 247.5 Hz), 128.2 (d, J = 8.3
Hz), 127.0 (d, J = 2.3 Hz), 115.9 (d, J = 21.8 Hz), 92.37, 62.62, 19.44,
7.53.
HRMS (EI): m/z [M]+ calcd for C10H10FNO3: 211.0645; found:
211.0651.
13C NMR (75 MHz, CDCl3): δ = 137.49, 134.45, 130.77, 128.74, 128.40,
95.76, 76.91, 59.44, 56.20, 44.10, 25.12, 21.05.
3-(3-Chlorophenyl)-2-methyl-2-nitrooxirane (1f)
HRMS (ESI): m/z [M + H]+ calcd for C13H20NO2: 222.1494; found:
222.1493.
Yellow oil; yield: 213 mg (86%).
IR (KBr): 3052, 2982, 1559, 1419, 1259, 893, 700, 698 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.43–7.29 (m, 3 H), 7.24–7.18 (m, 1 H),
4.52 (s, 1 H), 1.80 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 134.97, 133.03, 130.12, 129.66,
.
3-(4-Chlorophenyl)-2,4-dimethylmorpholin-2-ol (2d)
White solid; yield: 106 mg (79%) mp 128–130 °C; Rf
(EtOAc/MeOH, 95:5).
= 0.65
IR (KBr): 3488, 3052, 2985, 1599 cm–1
.
126.46, 124.59, 88.54, 61.72, 12.40.
1H NMR (300 MHz, CDCl3): δ = 7.43–7.24 (m, 4 H), 4.19 (td, J = 12.2,
3.0 Hz, 1 H), 4.06 (bs, 1 H), 3.65 (ddd, J = 11.9, 3.9, 1.0 Hz, 1 H), 3.01 (s,
1 H), 2.83 (dd, J = 12.1, 2.4 Hz, 1 H), 2.45 (td, J = 12.3, 4.0 Hz, 1 H), 1.99
(s, 3 H), 1.08 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 136.12, 133.64, 130.70, 128.23, 95.44,
76.46, 59.40, 56.01, 44.11, 25.19.
MS (EI): m/z [M – NO2]+ calcd for C9H8ClO: 167.0; found: 167.0; m/z
[M – C3H4NO3]+ calcd for C6H4Cl; 111.0; found: 111.0.
Morpholinols 2a–f; General Procedure
To an ice-bath cold solution of the corresponding nitroepoxide 1a–f
(0.56 mmol) in MeOH (1 mL), N-methylethanolamine (90 μL, 1.12
mmol) was added. The resulting mixture was stirred for 3.5 h at r.t.,
then H2O (5 mL) was added; the mixture was extracted with EtOAc (3
× 20 mL), washed with brine (20 mL), dried (Na2SO4), and concentrat-
ed under vacuum. The resulting crude oil was purified through flash
liquid chromatography (silica gel, hexanes/EtOAc, 1:1, EtOAc, and
EtOAc/MeOH, 9:1) to afford the desired product.
HRMS (ESI): m/z [M + H]+ calcd for C12H17ClNO2: 242.0948; found:
242.0945.
2-Ethyl-3-(4-fluorophenyl)-4-methylmorpholin-2-ol (2e)
Yellow solid; yield: 84 mg (63%); mp 61–63 °C; Rf
(EtOAc/MeOH, 95:5).
= 0.53
IR (KBr): 3491, 3056, 2986, 1602 cm–1
.
2,4-Dimethyl-3-phenylmorpholin-2-ol (2a)
1H NMR (500 MHz, CDCl3): δ = 7.51–7.28 (m, 2 H), 7.02 (t, J = 8.3 Hz, 2
H), 4.22 (td, J = 12.1, 1.7 Hz, 1 H), 3.68 (dd, J = 12.0, 4.0 Hz, 1 H), 3.05
(s, 1 H), 2.89–2.81 (m, 1 H), 2.49 (td, J = 11.6, 2.8 Hz, 1 H), 2.02 (d, J =
1.2 Hz, 3 H), 1.23 (d, J = 1.3 Hz, 2 H), 1.10 (d, J = 1.3 Hz, 3 H).
White solid; yield: 101 mg (87%); mp 64–66 °C; Rf = 0.43 (EtOAc).
IR (KBr): 3500, 3049, 2985, 1601 cm–1
.
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E. Capel et al.
Feature
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13C NMR (126 MHz, CDCl3): δ = 163.37, 161.41, 133.21, 131.01,
IR (KBr): 3049, 2986, 1634, 1455, 1048 cm–1
.
114.55, 96.54, 96.54, 75.24, 59.31, 56.21, 44.12, 30.67, 6.42.
HRMS (ESI): m/z [M + H]+ calcd for C13H19FNO2: 240.1400; found:
240.1399.
1H NMR (500 MHz, CDCl3): δ = 7.39 (s, 1 H), 7.32–7.23 (m, 5 H), 3.95–
3.84 (m, 2 H), 3.59–3.51 (m, 1 H), 2.82 (d, J = 11.8 Hz, 1 H), 2.64 (d, J =
8.8 Hz, 1 H), 2.41 (tt, J = 11.3, 5.6 Hz, 1 H), 1.98 (s, 3 H), 0.87 (d, J = 6.2
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 140.01, 128.4, 127.7, 126.9, 76.99,
3-(3-Chlorophenyl)-2-methylmorpholin-2-ol (2f)
75.9, 66.8, 55.5, 44.0, 18.5.
Yellow solid; yield: 100 mg (74%); mp 63–65 °C; Rf
= 0.52
HRMS (ESI): m/z [M + H]+ calcd for C12H18NO: 192.1388; found:
192.1384.
(EtOAc/MeOH, 95:5).
IR (KBr): 3418, 3051, 2983, 1602 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.35 (dd, J = 38.4, 16.9 Hz, 3 H), 7.24 (s,
1 H), 4.19 (td, J = 12.2, 3.0 Hz, 1 H), 3.64 (dd, J = 11.4, 4.5 Hz, 1 H), 2.99
(s, 1 H), 2.82 (dd, J = 13.1, 1.4 Hz, 1 H), 2.52–2.35 (m, 1 H), 1.99 (s, 3
H), 1.09 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 139.78, 133.92, 129.22, 128.04, 95.37,
76.69, 59.37, 55.95, 44.19, 25.31.
3-(4-Fluorophenyl)-2,4-dimethylmorpholine (4b)
Yellow oil; yield: 26 mg (57%); Rf = 0.47 (EtOAc).
IR (KBr): 3048, 2933, 1637, 1508, 1453, 1226, 1068 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.26–7.15 (m, 1 H), 7.07–6.87 (m, 2 H),
3.89–3.73 (m, 1 H), 3.51–3.34 (m, 1 H), 2.79–2.71 (m, 1 H), 2.57 (d, J =
8.8 Hz, 1 H), 2.39–2.29 (m, 1 H), 2.28 (s, 3 H), 0.79 (d, J = 6.3 Hz, 3 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C12H17ClNO2: 242.0948; found:
242.0953.
13C NMR (75 MHz, CDCl3): δ = 162.2 (d, J = 262.6 Hz), 135.7 (d, J = 3.0
Hz), 129.2 (d, J = 8.4 Hz), 115.32 (d, J = 20.3 Hz), 77.0, 75.0, 66.7, 55.4,
43.8, 18.5.
1-[(2-Hydroxyethyl)(methyl)amino]-1-phenylpropan-2-ol (3)
HRMS (ESI): m/z [M + H]+ calcd for C12H17FNO: 210.1294; found:
210.1291.
To an ice-bath cooled solution of 2a (30 mg, 0.14 mmol) in a mixture
of EtOH/H2O (360 μL each), a cold solution of NaBH4 (22 mg, 0.58
mmol) in H2O (250 μL) was added dropwise. The mixture was allowed
to warm up to r.t. and stirred overnight. The mixture was cooled to 0
°C and concd HCl (200 μL) was added dropwise. Then EtOH was re-
moved under reduced pressure and the crude mixture was diluted
with water (3 mL), chilled to 0 °C, and made basic with 40% aq NaOH
(tested with litmus). It was then extracted with CH2Cl2 (3 × 15 mL),
washed with brine (20 mL), dried (anhyd Na2SO4), and finally concen-
trated under vacuum. The crude product was purified with flash liq-
uid chromatography [silica gel, hexane/EtOAc, 1:1 (impurities), then
pure EtOAc, and EtOAc/MeOH, 7:3 (product)] to give a pale yellow oil;
yield: 26 mg (87%); Rf = 0.83 (CH2Cl2/MeOH, 95:5).
2,4-Dimethyl-3-(p-tolyl)morpholine (4c)
Yellow oil; yield: 17 mg (37%); Rf = 0.49 (EtOAc).
IR (KBr): 3049, 2985, 1631, 1455, 1283, 1283, 1071 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–6.98 (m, 4 H), 3.86 (d, J = 7.1 Hz, 1
H), 3.56–3.45 (m, 1 H), 2.79 (d, J = 11.6 Hz, 1 H), 2.58 (d, J = 8.7 Hz, 1
H), 2.37 (dt, J = 11.6, 7.6 Hz, 1 H), 2.27 (s, 3 H), 1.95 (s, 3 H), 0.82 (d, J =
6.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 137.43, 129.21, 76.91, 75.61, 66.65,
55.57, 43.83, 21.13, 18.58.
IR (KBr): 3049, 2986, 1634, 1455, 1048 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C13H20NO: 206.1545; found:
206.1541.
1H NMR (500 MHz, CDCl3): δ = 7.32–7.16 (m, 4 H), 7.07 (d, J = 7.9 Hz, 1
H), 4.34–4.28 (m, 1 H, major), 4.15 (dt, J = 15.8, 5.9 Hz, 1 H, minor),
3.71–3.42 (m, 2 H), 3.27 (d, J = 10.1 Hz, 1 H, minor), 3.18 (d, J = 5.8 Hz,
1 H, major), 2.47 (t, J = 5.5 Hz, 2 H, major), 2.60–2.25 (m, 2 H, minor),
2.15 (s, 3 H, major), 2.11 (s, 3 H, minor), 1.02 (d, J = 6.3 Hz, 3 H, major),
0.96 (d, J = 6.0 Hz, 1 H, minor).
3-(4-Chlorophenyl)-2,4-dimethylmorpholine (4d)
Yellow oil; yield: 48 mg (97%); Rf = 0.47 (EtOAc).
IR (KBr): 3052, 2988, 1635, 1491, 1234, 1090 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.13 (m, 4 H), 3.92–3.75 (m, 2 H),
3.50–3.34 (m, 1 H), 2.75 (d, J = 11.7 Hz, 1 H), 2.57 (d, J = 8.8 Hz, 1 H),
2.35 (td, J = 11.6, 3.9 Hz, 1 H), 1.91 (s, 3 H), 0.81 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 136.0, 129.7, 128.2, 127.8, 75.0, 66.2,
58.6, 56.1, 38.5, 20.4.
MS (ESI): m/z [M + H]+ calcd for C12H20NO2: 210.2; found: 210.2.
13C NMR (101 MHz, CDCl3): δ = 138.6, 133.3, 128.7, 128.7, 128.5,
128.4, 76.9, 75.1, 66.9, 55.3, 43.9, 18.4.
HRMS (EI): m/z [M + H]+ calcd for C12H17ClNO: 226.0999; found:
226.0994.
Morpholines 4a–f; General Procedure
The corresponding morpholin-2-ol (0.22 mmol) was dissolved with
freshly distilled CH2Cl2 (5 mL) and cooled to –78 °C under N2 atmo-
sphere. Et3SiH (290 μL, 1.76 mmol) was added dropwise to the cool
mixture followed by the dropwise addition of TMSOTf (80 μL, 0.44
mmol). The mixture was allowed to warm up to r.t. and stirred over-
night. The mixture was then cooled to 0 °C, quenched by the addition
of sat. aq NaHCO3 (5 mL), and extracted with CH2Cl2 (3 × 15 mL); the
combined organic phases were washed with brine (20 mL), dried (an-
hyd MgSO4), filtered, and concentrated under vacuum to afford a yel-
low oil that was purified by flash liquid chromatography (silica gel,
CH2Cl2).
3-(3-Chlorophenyl)-2,4-dimethylmorpholine (4f)
Yellow oil; yield: 47 mg (96%); Rf = 0.59 (EtOAc).
IR (KBr): 3063, 2978, 1636, 1453, 1233, 1123 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.39–7.07 (m, 4 H), 3.93–3.77 (m, 2 H),
3.53–3.39 (m, 1 H), 2.77 (d, J = 11.7 Hz, 1 H), 2.59 (d, J = 8.7 Hz, 1 H),
2.37 (td, J = 11.4, 4.5 Hz, 1 H), 1.94 (s, 3 H), 0.83 (d, J = 6.3 Hz, 3 H).
.
13C NMR (101 MHz, CDCl3): δ = 137.9, 134.5, 129.8, 128.0, 125.0, 76.8,
75.3, 66.7, 55.3, 43.9, 18.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H17ClNO: 226.0999; found:
2,4-Dimethyl-3-phenylmorpholine (4a)
Yellow oil; yield: 30 mg (72%); Rf = 0.83 (CH2Cl2/MeOH, 95:5).
226.0997.
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H
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Feature
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Benzoxazinols 5a,b; General Procedure
1H NMR (400 MHz, CDCl3): δ = 7.26–7.03 (m, 4 H), 6.93–6.79 (m, 2 H),
6.76–6.70 (m, 1 H), 6.62 (dd, J = 8.0, 1.3 Hz, 1 H), 4.01 (s, 1 H), 2.75 (s,
3 H), 1.32 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 141.13, 139.17, 134.38, 133.18,
130.00, 129.92, 129.38, 128.78, 128.45, 128.43, 125.92, 122.68,
122.27, 119.51, 119.34, 117.21, 117.13, 111.90, 94.62, 68.92, 36.71,
24.44.
To a cooled solution (0 °C) of 2-aminophenol (67 mg, 0.60 mmol) in
MeOH (1 mL), a solution of nitroepoxide (0.40 mmol) in MeOH (3 mL)
was added and the mixture was stirred at 0 °C for 2 d. Then, water (3
mL) was added, and the mixture was extracted with CH2Cl2 (3 × 20
mL); the combined organic phases were washed with brine (20 mL),
dried (anhyd Na2SO4), filtered, and concentrated under vacuum. The
crude product was purified by flash chromatography (silica gel, hex-
anes/EtOAc, 7:3).
MS (ESI): m/z [M + H]+ calcd for C16H17ClNO2: 290.1; found: 290.2.
2,4-Dimethyl-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (6)
Prepared using the procedure for morpholines 4a–f.
Yellow oil; yield: 40 mg (76%); Rf = 0.74 (CH2Cl2).
2-Methyl-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-2-ol (5a)
Brown oil; yield: 87 mg (90%); Rf = 0.38 (hexane/EtOAc, 7:3).
IR (KBr): 3562, 3387, 3021, 2981, 1441, 1172, 1085 cm–1
.
IR (KBr): 3029, 2984, 1505, 1225, 1044 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.27 (m, 4 H), 7.17 (d, J = 10.7 Hz,
1 H), 6.85–6.70 (m, 3 H), 6.64–6.59 (m, 1 H), 4.02 (s, 1 H), 1.31 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 141.9, 137.4, 132.5, 128.8, 128.6,
128.4, 127.7, 121.5, 120.9, 117.6, 115.4, 96.3, 62.3, 23.6.
HRMS (EI): m/z [M + H]+ calcd for C15H16NO2: 242.1181; found:
242.1174.
1H NMR (400 MHz, CDCl3): δ = 7.22–7.15 (m, 3 H), 7.05–7.01 (m, 2 H),
6.87–6.81 (m, 1 H), 6.80–6.77 (m, 1 H), 6.60–6.55 (m, 2 H), 4.39 (qd,
J = 6.5, 2.8 Hz, 1 H), 4.08 (d, J = 2.8 Hz, 1 H), 2.73 (s, 3 H), 1.03 (d, J = 6.5
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 143.9, 138.1, 135.7, 128.4, 128.3,
127.7, 122.3, 116.7, 115.9, 110.6, 71.9, 66.3, 36.7, 17.9.
MS (ESI): m/z [M + H]+ calcd for C16H18NO: 240.1; found: 240.2.
7-Chloro-2-methyl-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-2-ol
(5b)
Thiomorpholines 7 and 8; General Procedure
Brown oil; yield: 53 mg (55%); Rf = 0.72 (hexane/EtOAc, 7:3).
2-Aminoethanethiol hydrochloride (55 mg, 0.47 mmol) was dissolved
with a solution of KOH (53 mg, 0.95 mmol) in EtOH (1.2 ml) at 0 °C
and under inert conditions. To this mixture, a previously purged solu-
tion of nitroepoxide 1a (85 mg, 0.47 mmol) in dry EtOH (0.4 ml) was
added and the mixture was stirred below 5 °C until consumption of
the nitroepoxide (ca. 3 h). Then, solid NaBH4 (37 mg, 0.95 mmol) was
added to the cold mixture and stirring maintained for 1.5 h. Then, the
mixture was quenched with 5% aq NH4Cl (5 mL) and extracted with
CH2Cl2 (3 × 10 mL); the combined organic phases were washed with
brine, dried (MgSO4), filtered, and finally concentrated under vacuum
to afford a yellow oil. The crude product was purified by flash column
chromatography (silica gel, EtOAc/MeOH, 9:1 to 7:3) to afford 7 and 8.
IR (KBr): 3565, 3390, 3054, 2987, 1448, 1186, 1092 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.46–7.37 (m, 5 H), 6.80 (d, J = 8.6 Hz, 1
H), 6.76 (d, J = 2.3 Hz, 1 H), 6.70 (d, J = 2.3 Hz, 1 H), 4.13 (s, 1 H), 1.41
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 140.5, 136.9, 133.4, 130.3, 129.4, 128.9,
128.7, 128.3, 127.6, 120.5, 118.5, 115.0, 96.2, 62.0, 23.6.
MS (ESI): m/z [M + H]+ calcd for C15H15ClNO2: 276.1; found: 276.2.
Benzoxazinols 5c,d; General Procedure
To a solution 2-(methylamino)phenol22 (0.80 mmol) in MeOH (1 mL),
a solution of nitroepoxide (0.40 mmol) in MeOH (3 mL) was added
and the mixture was stirred at r.t. until consumption of the starting
nitroepoxide. Then, water (3 mL) was added and the mixture was ex-
tracted with CH2Cl2 (3 × 20 mL); the combined organic phases were
washed with brine (20 mL), dried (anhyd Na2SO4), filtered, and con-
centrated under vacuum. The crude product was purified by flash
chromatography (silica gel, CH2Cl2).
3-Methyl-2-phenylthiomorpholine (7)
Pale yellow solid; yield: 26 mg (28%); Rf = 0.48 (EtOAc/MeOH, 7:3).
IR (KBr): 3360, 3032, 2940, 1574, 1404, 1268, 1070, 707 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.27 (m, 5 H), 3.60 (d, J = 9.6 Hz, 1
H), 3.44 (dt, J = 12.0, 2.7 Hz, 1 H), 3.25–3.12 (m, 2 H), 3.10–2.98 (m, 1
H), 2.63 (bs, 1 H), 2.59–2.50 (m, 1 H), 0.91 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 139.77, 128.61, 128.22, 127.66, 58.14,
52.00, 48.09, 30.18, 20.57.
2,4-Dimethyl-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-2-ol (5c)
Brown oil; yield: 58 mg (80%); Rf = 0.52 (CH2Cl2).
IR (KBr): 3500, 3053, 2986, 1608, 1422, 1220, 1002 cm–1
.
MS (EI): m/z [M]+ calcd for C11H15NS: 193.1; found: 193.1.
1H NMR (300 MHz, CDCl3): δ = 7.28–7.12 (m, 3 H), 7.02 (dt, J = 4.8, 1.9
Hz, 2 H), 6.92–6.79 (m, 2 H), 6.75–6.68 (m, 1 H), 6.62 (dd, J = 7.9, 1.4
Hz, 1 H), 4.04 (s, 1 H), 2.74 (s, 3 H), 1.32 (s, 3 H).
2-Methyl-3-phenylthiomorpholine (8)
Yellow oil; yield: 35 mg (39%); Rf = 0.36 (EtOAc/MeOH, 7:3).
13C NMR (75 MHz, CDCl3): δ = 141.4, 137.0, 133.7, 129.2, 128.7, 128.6,
IR (KBr): 3307, 3022, 2918, 1595, 1448, 1268, 1024, 707 cm–1
.
128.2, 128.0, 122.5, 119.1, 117.1, 111.8, 95.0, 69.3, 36.7, 24.4.
MS (ESI): m/z [M + H]+ calcd for C16H18NO2: 256.1; found: 256.2.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.14 (m, 10 H), 4.16 (dd, J = 8.3,
1.7 Hz, 1 H, minor), 4.06 (d, J = 3.2 Hz, 1 H, major), 3.49 (qd, J = 6.6, 3.3
Hz, 1 H, major), 3.32–3.24 (m, 1 H), 3.14–3.05 (m, 1 H), 2.90 (m, 3 H),
2.84–2.68 (m, 4 H), 1.07 (d, J = 6.7 Hz, 1 H, major), 0.91 (d, J = 6.4 Hz, 1
H, minor).
3-(3-Chlorophenyl)-2,4-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-
2-ol (5d)
Brown oil; yield: 53 mg (87%); Rf = 0.54 (CH2Cl2).
13C NMR (75 MHz, CDCl3): δ = 141.9, 128.3, 127.8, 127.2, 127.0, 77.7,
77.2, 60.1, 54.3, 48.2, 45.2, 42.5, 39.1, 27.2, 16.6, 15.4.
MS (EI): m/z [M]+ calcd for C11H15NS: 193.1; found: 193.1.
IR (KBr): 3501, 3008, 2942, 1502, 1217, 1042 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
E. Capel et al.
Feature
Synthesis
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Acknowledgment
We thank Universitat Jaume I for funding and Serveis Centrals d’In-
strumentació Cientifíca from Universitat Jaume I for technical sup-
port. A.V.-A. thanks Generalitat Valenciana for a Ph.D. research grant
under the VALi+D Program.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561466.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I