Synthesis of 4-(alkoxyamino)chroman-2-ones via 6-exo-trig cyclization of carbon-centered radicals into oxime ethers

Article abstract of DOI:10.1007/s10593-016-1857-z

[Figure not available: see fulltext.] 4-(Alkoxyamino)chroman-2-ones were synthesized via a 6-exo-trig cyclization of alkyl radicals obtained from α-bromoesters containing an oxime ether group. In the case of secondary bromides, the best results were achie

Full text of DOI:10.1007/s10593-016-1857-z

DOI 10.1007/s10593-016-1857-z
Chemistry of Heterocyclic Compounds 2016, 52(3), 177–182
Synthesis of 4-(alkoxyamino)chroman-2-ones via 6-exo-trig cyclization
of carbon-centered radicals into oxime ethers
Carlos A. Bejarano1, John E. Díaz1, Alix E. Loaiza1*
1 Departamento de Química, Facultad de Ciencias, Pontificia Universidad Javeriana,
Cra. 7 No. 40-62, Edificio Carlos Ortiz, 11001000, Bogotá, Colombia
e-mail: aloaiza@javeriana.edu.co
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(3), 177–182
Submitted December 4, 2015
Accepted after revision February 10, 2016
4-(Alkoxyamino)chroman-2-ones were synthesized via a 6-exo-trig cyclization of alkyl radicals obtained from α-bromoesters containing
an oxime ether group. In the case of secondary bromides, the best results were achieved using tris(trimethylsilyl)silane as the chain
transfer agent and Et3B as the initiator in dichloromethane at room temperature; the corresponding chromanones were produced in
58–70% yield. Low yields of the cyclized compounds were obtained in the case of tertiary alkyl bromides (20–25%). Products of
premature reduction of carbon-centered radicals and addition of ethyl radicals to C=N bond were also observed.
Keywords: 4-(alkoxyamino)chroman-2-ones, oxime ethers, 6-exo-trig radical cyclizations.
Oxime ethers are useful and versatile compounds in
organic synthesis. They are easily prepared and relatively
stable to moisture, so that they can be stored during long
periods in air.1 Reductive addition of alkyl radicals to
oxime ethers is by far the most exploited application of this
class of compounds in radical chemistry. Since the first
pinacol-type radical cyclization into an oxime ether was
reported in 1983,2 many interesting methodologies that
involve inter- and intramolecular versions of this
transformation have been published.3,4 For instance, Naito
and coworkers reported the synthesis of 4-(benzyloxy-
amino)furan-2-ones and 4-(benzyloxyamino)pyran-2-ones
from oxime ethers connected with acryloyl and meth-
acryloyl moieties. The synthesis was carried out via tandem
intermolecular addition of secondary alkyl radicals to the
C=C bond of a carbonyl α,β-unsaturated system, followed
by intramolecular addition of the stabilized α-ester radical
to the C=N bond, using Et3B and alkyl iodides in a variety
of solvents including water.4c
4-(Alkoxyamino)chroman-2-ones are known as important
building blocks of biologically active compounds and are
considered privileged molecular moieties present in a variety
of natural products.5 With the aim of extending the
application of reductive addition of alkyl radicals to
oximes, we explored in this work the synthesis of
4-(alkoxyamino)chroman-2-ones from salicylaldehyde
oxime ethers connected to α-bromoesters via 6-exo-trig
radical cyclization of secondary and tertiary alkyl radicals
at the electrophilic carbon atom of C=N–OR group. In
order to evaluate the feasibility of this approach, the
requisite oxime ethers were obtained in two steps starting
from the reaction of salicylaldehyde (1) with O-benzyl- or
O-methylhydroxylamine hydrochloride to obtain com-
pounds 2a,b which were reacted with 2-bromoacyl-
bromides 3a–c to provide the oxime ethers 4a–f in yields
up to 69% in two steps (Scheme 1).
Scheme 1
CHO
OH
1
i
OR1
Br
OR1
O
N
N
ii
R2
R3
R2
+
Br
R3
Br
3a–c
OH
2a,b
O
O
4a–f
i: H2NOR1·HCl, Na2SO4, Py, MeOH, rt;
ii: Et3N, CH2Cl2, 0°C, 2–3 h
1
1
2a 4a c e
2b 4b d f
, , , R = Me
,
, ,
R
= Bn;
R
,
,
2 = H, R3 = Me;
3a 4a b
2
,
,
R
2 = H, R3 = Et;
,
, R = R3 = Me
3b 4c d
3c 4e f
009-3122/16/52(3)-0177©2016 Springer Science+Business Media New York
177

Chemistry of Heterocyclic Compounds 2016, 52(3), 000–000
Table 1. Conditions and product ratios for radical cyclization of oxime 4a
Entry
X3MH
Initiator
Solvent Temperature Reaction time, h
Ratio 5a : 6a : 7a*
1
2
3
Bu3SnH
(Me3Si)3SiH
(Me3Si)3SiH
AIBN
AIBN
Et3B
PhMe
C6H12
CH2Cl2
Reflux
Reflux
rt
14
12
1
9:91:0
17:83:0
58:37:5
* Product ratios established by GC-MS and ¹H NMR spectroscopy.
Table 2. Structures and yields for products of radical cyclization of oximes 4a–f
Product yield, %
Entry
Products 5–7
R1
R2
R3
5 (ratio trans : cis)
58 (8 : 1)
67 (7 : 1)
63 (4.6 : 1)
70 (6.6 : 1)
25
6
7
5
7
6
5
6
6
1
2
3
4
5
6
Bn
Me
Bn
Me
Bn
Me
H
H
H
H
Me
Me
Me
Me
Et
Et
Me
Me
37
26
31
25
69
74
a
b
c
d
e
f
20
In order to establish the most favorable reaction con-
ditions for the 6-exo-trig cyclization to generate 4-(alkoxy-
amino)chroman-2-ones, we carried out preliminary
experiments with compound 4a (Table 1). The reaction
with tri(n-butyl)tin hydride (TBTH) and azobisiso-
butyronitrile (AIBN) in toluene proceeded through the
direct reduction of C–Br bond giving rise to compound 6a
(91%) as the main product (entry 1).
Due to this unfavorable result, we decided to replace
TBTH by a weaker hydrogen donor tris(trimethylsilyl)-
silane (TTMSS), retaining AIBN as the initiator (entry 2).
In this case, the yield of cyclized product 5a increased,
however, the main product as before was the undesired
open-chain compound 6a (83%).
addition of ethyl radicals (donated by Et3B) to the C=N
bond of the oxime function.
Guided by the results of the preliminary experiments, we
synthesized a series of 4-(alkoxyamino)chroman-2-ones 5b–f
using TTMSS and Et3B, since these conditions gave rise to
a good product ratio 5a : 6a (Table 1, entry 3) and required
the simplest experimental procedure.
As shown in Table 2, the cyclization of oximes 4a–d
took place with diastereoselectivity favoring the trans-
isomer due to the steric repulsion between the alkyl group
tethered to the carbon-centered radical and the oxime ether
group NOR1. The assignment of cis/trans configuration to
the cyclized products 5a–d was made by NOESY
3
experiments and examining the JHH coupling constants in
1
In an attempt to improve the yield of compound 5a we
carried out a third experiment (entry 3) using Et3B as the
initiator, trying to take advantage of its well-known weak
Lewis acid character along with the simplification of the
experimental procedure, since no heating and deoxy-
the H NMR spectra (Table 3). The magnitude of coupling
Table 3. 3J coupling constant values between protons of 3-CH
and 4-CH groups in the 1H NMR spectra of compounds 5a–d
1
genating processes are needed. The H NMR spectrum of
the crude mixture after aqueous work-up showed that under
these conditions, the desired heterocyclic compound 5a
was generated as the main product (yield 58%), in addition
to reduction product 6a (37%) and a small amount of open-
chain product 7a (5%), likely produced by intermolecular
178

Chemistry of Heterocyclic Compounds 2016, 52(3), 000–000
1
constants in trans-isomer showed protons 3-CH and 4-CH
in pseudo-equatorial positions.
pleasant odor. H NMR spectrum, δ, ppm (J, Hz): 1.95
(3H, d, J = 6.9, CH3); 4.59 (1H, q, J = 6.9, CHBr); 5.26
(2H, s, OCH2Ph); 7.17 (1H, dd, J = 8.1, J = 1.3, H-6 Ar);
7.24–7.38 (1H, m, H-5 Ar); 7.33–7.51 (6H, m, H-4 Ar,
H Ph); 7.85 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.33 (1H, s,
HC=N). 13C NMR spectrum, δ, ppm: 21.4 (CH3); 39.3
(CHBr); 76.6 (OCH2Ph); 122.4 (C-6 Ar); 124.7 (C-1 Ar);
126.6 (C-5 Ar); 127.9 (C-3 Ar); 128.1 (C-2,6 Ph); 128.3
(C-4 Ph); 128.5 (C-3,5 Ph); 130.8 (C-4 Ar); 137.4 (C-1 Ph);
144.1 (C=N); 148.3 (C-2 Ar); 168.4 (C=O). Found, m/z:
362.0398 [M(79Br)+H]+. C17H17BrNO3. Calculated, m/z:
362.0387.
In the case of oximes 4e,f, the steric hindrance of the
tertiary radical precluded the cyclization to proceed in an
efficient way, leading to the formation of chromanones 5e,f
in only 20–25% yield, and reduced open-chain compounds
6e,f as the major products.
In conclusion, the synthesis of 4-(alkoxyamino)chroman-
2-ones via radical cyclization was achieved with
reasonably good yields and diastereoselectivity in the case
of precursors containing a secondary alkyl bromide and
low yields in the case of those containing tertiary alkyl
bromides. The experimental protocol to carry out the
radical reactions is simple, as is the synthesis of the starting
materials.
2-{[(Methoxy)imino]methyl}phenyl 2-bromopropanoate
1
(4b). Yield 0.255 g (89%). Light-yellow liquid. H NMR
spectrum, δ, ppm (J, Hz): 1.97 (3H, d, J = 6.9, CH3); 3.99
(3H, s, OCH3); 4.65 (1H, q, J = 6.9, CHBr); 7.14 (1H, d,
J = 8.1, H-6 Ar); 7.29 (1H, t, J = 7.6, H-5 Ar); 7.42 (1H, t,
J = 7.7, H-4 Ar); 7.83 (1H, d, J = 7.8, H-3 Ar); 8.23 (1H, s,
HC=N). 13C NMR spectrum, δ, ppm: 21.4 (CH3); 39.4
(CHBr); 62.2 (OCH3); 122.4 (C-6 Ar); 124.7 (C-1 Ar);
126.7 (C-5 Ar); 127.7 (C-3 Ar); 130.7 (C-4 Ar); 143.6
(C=N); 148.2 (C-2 Ar); 168.4 (C=O). Mass spectrum, m/z
(Irel, %): 285 [M(79Br)]+ (5), 152 (9), 151 (100), 120 (23),
119 (41), 107 (17), 91 (37). Found, m/z: 286.0073
[M(79Br)+H]+. C11H13BrNO3. Calculated, m/z: 286.0074.
2-{[(Benzyloxy)imino]methyl}phenyl 2-bromobutanoate
(4c). Yield 0.301 g (80%). Pale-yellow liquid with a plea-
Experimental
1H and 13C NMR spectra were acquired on a Bruker
Avance spectrometer (300 and 75 MHz, respectively) in
CDCl3. All chemical shifts are quoted in respect to residual
proton signals of CDCl3 (7.28 ppm for 1H nuclei and 77.0 ppm
for 13C nuclei). Chemical shifts were assigned with the help
of HSQC-edit, HMBC, and COSY experiments. The
assignment of cis/trans configuration was made by
NOESY experiments (mixing time 300 ms) and examining
the 3JHH coupling constants in the 1H NMR spectra.
High-resolution mass spectra were recorded on an
Agilent 6520 q-TOF-MS instrument with orthogonal ESI.
GC-MS analyses were performed on an Agilent 6850 series II
gas chromatograph coupled to an Agilent 5975B VL mass
spectrometer (electron ionization, 70 eV) equipped with
split/splitless inlet (split relation 15:1, 260°C), Agilent
6850 series automatic injector, and Agilent HP-5MS
column (30 m × 0.25 mm × 0.25 μm); initial oven temperature
80°C for 1 min, then a temperature ramp of 10°C/min to
320°C (hold 3 min); total run time 28 min. Melting points
were determined on a Thermo Fisher Scientific IA 9100
apparatus.
1
sant odor. H NMR spectrum, δ, ppm (J, Hz): 1.16 (3H, t,
J = 7.3, CH2CH3); 2.07–2.34 (2H, m, CH2CH3); 4.41 (1H,
dd, J = 7.9, J = 6.5, CHBr); 5.26 (2H, s, OCH2Ph); 7.13–
7.18 (1H, m, H-6 Ar); 7.26–7.47 (7H, m, H-4,5, H Ph);
7.88 (1H, dd, J = 7.8, J = 1.5, H-3 Ar); 8.34 (1H, s,
HC=N). 13C NMR spectrum, δ, ppm: 11.9 (CH2CH3); 28.1
(CH2CH3); 47.1 (CHBr); 76.6 (OCH2Ph); 122.3 (C-6 Ar);
124.7 (C-1 Ar); 126.6 (C-5 Ar); 127.6 (C-3 Ar); 128.0
(C-4 Ph); 128.3 (C-3,5 Ph); 128.5 (C-2,6 Ph); 130.7 (C-4 Ar);
137.4 (C-1 Ph); 143.9 (C=N); 148.3 (C-2 Ar); 167.9
(C=O). Found, m/z: 376.0561 [M(79Br)+H]+. C18H19BrNO3.
Calculated, m/z: 376.0543.
2-[(Benzyloxyimino)methyl]phenol (2a) and 2-[(methoxy-
imino)methyl]phenol (2b) were synthesized according to
previously reported procedures.4g,6 Oxime 2a was obtained
as a white solid, mp 62–63°C (MeOH) (mp 62.5–63.0°C
(AcOEt–hexane)4g), and oxime 2b was obtained as a
colorless solid, mp 30–32°C (MeOH) (mp ≤ 30°C (cyclo-
hexane–EtOAc)6). The 1H NMR spectra of both com-
pounds were consistent with those reported in literature.
Coupling of oxime ethers with α-bromoesters (Gene-
ral method). A solution of oxime 2a (0.227 g, 1.0 mmol) or
2b (0.151 g, 1.0 mmol), an appropriate α-bromoacyl
bromide 3a–c (1.5 mmol), and triethylamine (0.28 ml,
2 mmol) in dichloromethane (3.3 ml) was stirred at 0°C for
2–3 h. The reaction mixture was treated with distilled water
and extracted with dichloromethane. The organic phase
was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude mixtures were purified by
column chromatography (silica gel, hexane–CH2Cl2, 4:1) to
provide products 4a–f.
2-{[(Methoxy)imino]methyl}phenyl 2-bromobutanoate
1
(4d). Yield 0.267 g (89%). Light-yellow liquid. H NMR
spectrum, δ, ppm (J, Hz): 1.16 (3H, t, J = 7.3, CH2CH3);
2.08–2.37 (2H, m, CH2CH3); 4.00 (3H, s, OCH3); 4.44 (1H,
dd, J = 8.0, J = 6,6, CHBr); 7.14 (1H, dd, J = 8.1, J =1.3,
H-6 Ar); 7.26–7.33 (1H, m, H-5 Ar); 7.39–7.46 (1H, m,
H-4 Ar); 7.86 (1H, dd, J = 7.8, J = 1.8, H-3 Ar); 8.24 (1H,
s, HC=N). 13C NMR spectrum, δ, ppm: 12.0 (CH2CH3);
28.1 (CH2CH3); 47.0 (CHBr); 62.2 (OCH3); 122.4
(C-6 Ar); 124.7 (C-1 Ar); 126.7 (C-5 Ar); 127.5 (C-3 Ar);
130.7 (C-4 Ar); 143.4 (C=N); 148.2 (C-2 Ar); 167.9 (C=O).
Mass spectrum, m/z (Irel, %): 299 [M(79Br)]+ (4), 152 (9), 151
(100), 120 (19), 119 (35), 91 (24). Found, m/z: 300.0235
[M(79Br)+H]+. C12H15BrNO3. Calculated, m/z: 300.0230.
2-{[(Benzyloxy)imino]methyl}phenyl 2-bromo-2-methyl-
propanoate (4e). Yield 0.275 g (73%). Clear yellow
1
liquid. H NMR spectrum, δ, ppm (J, Hz): 2.14 (6H, s,
CBr(CH3)2); 5.31 (2H, s, OCH2Ph); 7.20 (1H, d, J = 8.1,
H-6 Ar); 7.33 (1H, t, J = 7.6, H-5 Ar); 7.39–7.52 (6H, m,
H-4 Ar, H Ph); 7.95 (1H, d, J = 7.8, H-3 Ar); 8.42 (1H, s,
2-{[(Benzyloxy)imino]methyl}phenyl 2-bromopropanoate
(4a). Yield 0.286 g (79%). Pale-yellow liquid with a
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Chemistry of Heterocyclic Compounds 2016, 52(3), 000–000
HC=N). 13C NMR spectrum, δ, ppm: 30.6 (C(CH3)2); 55.2
(C-7); 128.1 (C-4 Ph); 128.6 (C-3,5 Ph); 128.7 (C-2,6 Ph);
129.6 (C-5); 130.2 (C-6); 137.0 (C-1 Ph); 151.8 (C-8a);
170.7 (C=O). Found, m/z: 284.1293 [M+H]+. C17H18NO3.
Calculated, m/z: 284.1281.
(C(CH3)2); 76.6 (OCH2Ph); 122.3 (C-6 Ar); 124.9 (C-1
Ar); 126.6 (C-5 Ar); 127.5 (C-3 Ar); 128.1 (C-4 Ph); 128.4
(C-3,5 Ph); 128.5 (2C, C-2,6 Ph); 130.8 (C-4 Ar); 137.5
(C-1 Ph); 143.9 (C=N); 148.7 (C-2 Ar); 169.8 (C=O).
Found, m/z: 376.0559 [M(79Br)+H]+. C18H19BrNO3. Calcu-
lated, m/z: 376.0543.
cis-4-[(Benzyloxy)amino]-3-methylchroman-2-one
1
(cis-5a). Yield 0.008 g (6%). H NMR spectrum, δ, ppm
(J, Hz): 1.50 (3H, d, J = 7.0, 3-CH3); 2.99 (1H, qd, J = 7.0,
J = 5.1, 3-CH); 4.05 (1H, d, J = 5.1, 4-CH); 4.38 (1H, d,
J = 11.7) and 4.45 (1H, d, J = 11.6, OCH2Ph); 7.08–7.13
(1H, m, H-8); 7.16–7.21 (1H, m, H-6); 7.30–7.43 (7H, m,
H-5,7, H Ph). 13C NMR spectrum, δ, ppm: 11.5 (3-CH3);
37.3 (C-3); 60.6 (C-4); 76.9 (OCH2Ph); 116.8 (C-8); 122.7
(C-4a); 124.2 (C-6); 127.9 (C-4 Ph); 128.3 (C-2,6 Ph);
128.9 (C-3,5 Ph); 129.5 (C-5); 129.9 (C-7); 136.6 (C-1 Ph);
152.1 (C-8a); 170.4 (C=O). Found, m/z: 284.1293 [M+H]+.
C17H18NO3. Calculated, m/z: 284.1281.
2-{[(Methoxy)imino]methyl}phenyl 2-bromo-2-methyl-
propanoate (4f). Yield 0.276 g (92%). Light-yellow liquid.
1H NMR spectrum, δ, ppm (J, Hz): 2.11 (6H, s, CBr(CH3)2);
4.00 (3H, s, OCH3); 7.14 (1H, dd, J = 8.1, J = 1.4, H-6 Ar);
7.29 (1H, t, J = 7.6, H-5 Ar); 7.43 (1H, t, J = 7.7, H-4 Ar);
7.87 (1H, d, J = 7.8, H-3 Ar); 8.26 (1H, s, OCH3).
13C NMR spectrum, δ, ppm: 30.6 (2C, C(CH3)2); 55.1
(C(CH3)2); 62.2 (OCH3); 122.3 (C-6 Ar); 124.8 (C-1 Ar);
126.6 (C-5 Ar); 127.4 (C-3 Ar); 130.7 (C-4 Ar); 143.4
(C=N); 148.5 (C-2 Ar); 169.8 (C=O). Mass spectrum, m/z
(Irel, %): 299 [M(79Br)]+ (12), 151 (60), 123 (80), 121 (86),
120 (44), 119 (100), 91 (55). Found, m/z: 300.0236
[M(79Br)+H]+. C12H15BrNO3. Calculated, m/z: 300.0230.
Radical cyclization of compounds 4a–f (General
method). A. Experiments using AIBN: a solution of oxime
ether 4a (0.181 g, 0.5 mmol), TTMS or TBTH (0.5 mmol),
AIBN (0.025 g, 0.15 mmol) in cyclohexane or toluene
(20 ml) was deoxygenated for 1 h by bubbling dry argon
and stirred at reflux temperature for 6–8 h. The reactions
were monitored by TLC and GC-MS until consumption of
starting material. After cooling to room temperature, the
solution was concentrated under low pressure. In the case
of reaction carried out with TBTH, the crude mixture was
dissolved in ethyl acetate (5 ml) and treated with a 20%
aqueous solution of KF (5 ml) to eliminate brominated
organotin by-products. The crude mixtures were analyzed
by 1H NMR spectroscopy and GC-MS.
trans-4-(Methoxyamino)-3-methylchroman-2-one
(trans-5b). Yield 0.061 g (59%). 1H NMR spectrum,
δ, ppm (J, Hz): 1.22 (3H, d, J = 7.4, 3-CH3); 3.29 (1H, qd,
J = 7.4, J =2.8, 3-CH); 3.50 (3H, s, OCH3); 3.96 (1H, d,
J = 2.8, 4-CH); 7.06–7.12 (1H, m, H-8); 7.18 (1H, td,
J = 7.4, J = 1.1, H-6); 7.32 (1H, dd, J = 7.4, J = 1.5, H-5);
7.38 (1H, td, J = 7.9, J = 1.7, H-7). 13C NMR spectrum,
δ, ppm: 14.1 (3-CH3), 38.3 (C-3); 62.6 (C-4); 63.3 (OCH3);
116.8 (C-8); 119.5 (C-4a); 124.6 (C-6); 129.4 (C-5); 130.2
(C-7); 151.7 (C-8a); 170.7 (C=O). Found, m/z: 208.0966
[M+H]+. C11H14NO3. Calculated, m/z: 208.0968.
cis-4-(Methoxyamino)-3-methylchroman-2-one (cis-5b).
Yield 0.008 g (8%). 1H NMR spectrum, δ, ppm (J, Hz):
1.50 (3H, d, J = 6.9, 3-CH3); 2.93–3.01 (1H, m, 3-CH);
3.30 (3H, s, OCH3); 4.01 (1H, d, J = 5.3, 4-CH); 7.09 (1H,
d, J = 8.2, H-8); 7.17 (1H, t, J = 7.5, H-6); 7.30–7.38 (2H,
m, H-5,7). 13C NMR spectrum, δ, ppm: 11.5 (3-CH3); 37.3
(C-3); 60.8 (C-4); 62.6 (OCH3); 116.8 (C-8); 124.2 (C-6);
128.6 (C-5); 129.9 (C-7); 143.4 (C-4a); 152.3 (C-8a); 170.8
(C=O). Found, m/z: 208.1001 [M+H]+. C11H14NO3. Calcu-
lated, m/z: 208.0968.
B. Experiments using Et3B: a solution of oxime ether 4a–f
(0.5 mmol), TTMS (0.159 ml, 0.5 mmol), and Et3B (1 M in
hexane, 0.75 ml, 0.75 mmol) in dichloromethane (20 ml)
was stirred at room temperature under air atmosphere for
1–2 h. The reaction mixture was treated with 10% aqueous
NaHCO3 solution and extracted with dichloromethane. The
organic phase was dried over Na2SO4, filtered, and
concentrated. The products were preliminarily identified by
trans-4-[(Benzyloxy)amino]-3-ethylchroman-2-one
(trans-5c). Yield 0.077 g (52%). 1H NMR spectrum,
δ, ppm (J, Hz): 1.05 (3H, t, J = 7.5, 3-CH2CH3); 1.47–1.58
(2H, m, 3-CH2CH3); 3.15 (1H, td, J = 7.8, J = 2.1, 3-CH);
4.10 (1H, d, J = 2.1, 4-CH); 4.59 (1H, d, J = 11.5,
OCH2Ph); 4.69 (1H, d, J = 11.5, OCH2Ph); 7.08 (1H, dd,
J = 8.1, J =1.1, H-8); 7.15 (1H, td, J = 7.5, J = 1.1, H-6);
7.24–7.40 (7H, m, H-5,7, H Ph). 13C NMR spectrum,
δ, ppm: 11.8 (3-CH2CH3); 22.1 (3-CH2CH3); 45.7 (C-3);
61.2 (C-4); 77.7 (OCH2Ph); 116.8 (C-8); 119.4 (C-4a);
124.5 (C-6); 128.0 (C-4 Ph); 128.4 (C-3,5 Ph); 128.7
(C-2,6 Ph); 129.6 (C-5); 130.3 (C-7); 137.0 (C-1 Ph); 151.9
(C-8a); 169.7 (C=O). Found, m/z: 298.1444 [M+H]+.
C18H20NO3. Calculated, m/z: 298.1438.
1
GC-MS and H NMR spectroscopy. Purification by flash
column chromatography using silica gel (hexane–AcOEt,
4:1) afforded compounds 5a–f which were characterized by
1
HR-MS and H and 13C NMR spectroscopy, except com-
pounds 5c-cis and 5d-cis, which were detected and quanti-
fied from the crude mixtures. Compounds 6a–f, 7a,b,d
were likewise isolated by chromatography and characte-
rized.
trans-4-[(Benzyloxy)amino]-3-methylchroman-2-one
(trans-5a). Yield 0.074 g (52%). 1H NMR spectrum,
δ, ppm (J, Hz): 1.22 (3H, d, J = 7.4, 3-CH3); 3.36 (1H, qd,
J = 7.4, J = 2.9, 3-CH); 4.01 (1H, d, J = 2.9, 4-CH); 4.61
(1H, d, J = 11.5, OCH2Ph); 4.70 (1H, d, J = 11.5,
OCH2Ph); 7.10 (1H, dd, J = 8.1, J =1.1, H-8); 7.17 (1H, td,
J = 7.5, J = 1.1, H-6); 7.27–7.41 (7H, m, H-5,7, H Ph).
13C NMR spectrum, δ, ppm: 14.0 (3-CH3); 38.3 (C-3); 62.6
(C-4); 77.6 (CH2Ph); 116.9 (C-8); 119.4 (C-4a); 124.6
cis-4-[(Benzyloxy)amino]-3-ethylchroman-2-one (cis-5c).
1
Yield 0.016 g (11%). H NMR spectrum, δ, ppm (J, Hz):
1.12 (3H, t, J = 7.5, 3-CH2CH3); 1.76–1.88 (2H, m,
3-CH2CH3); 2.65–2.72 (2H, m, 3-CH); 4.18 (1H, d, J = 4.8,
4-CH); 4.45 (1H, d, J = 11.7) and 4.48 (1H, d, J = 11.7,
OCH2Ph); 7.06–7.21 (2H, m, H-6,8); 7.30–7.43 (7H, m,
H-5,7, H Ph). Mass spectrum, m/z (Irel, %): 297 [M]+ (3),
265 (6), 175 (30), 119 (20), 91 (100).
180

Chemistry of Heterocyclic Compounds 2016, 52(3), 000–000
trans-3-Ethyl-4-(methoxyamino)chroman-2-one
J = 1.2, H-6 Ar); 7.25 (1H, td, J = 7.5, J = 1.2, H-5 Ar);
7.40 (1H, td, J = 7.8, J = 1.7, H-4 Ar); 7.79 (1H, dd,
J = 7.8, J = 1.7, H-3 Ar); 8.12 (1H, s, HC=N). 13C NMR
spectrum, δ, ppm: 9.0 (CH2CH3); 27.6 (CH2CH3); 62.1
(OCH3); 123.0 (C-6 Ar); 124.5 (C-1 Ar); 126.1 (C-5 Ar);
127.7 (C-3 Ar); 130.6 (C-4 Ar); 144.04 (C=N); 148.7
(C-2 Ar); 172.7 (C=O). Found, m/z: 230.0798 [M+Na]+.
C11H13NO3Na. Calculated, m/z: 230.0788.
(trans-5d). Yield 0.067 g (61%). 1H NMR spectrum,
δ, ppm (J, Hz): 1.01 (3H, t, J = 7.4, 3-CH2CH3); 1.43–1.56
(2H, m, 3-CH2CH3); 3.05 (1H, td, J = 7.8, J = 2.1, 3-CH);
3.45 (3H, s, OCH3); 4.03 (1H, d, J = 2.1, 4-CH); 7.04 (1H,
dd, J = 8.1, J = 1.2, H-8); 7.13 (1H, td, J = 7.5, J = 1.2,
H-6); 7.27 (1H, dd, J = 7.5, J = 1.7, H-5); 7.34 (1H, td,
J = 7.8, J = 1.7, H-7). 13C NMR spectrum, δ, ppm: 11.7
(3-CH2CH3); 22.1 (3-CH2CH3); 45.6 (C-3); 61.2 (C-4);
63.3 (OCH3); 116.7 (C-8); 119.6 (C-4a); 124.5 (C-7); 129.5
(C-5); 130.2 (C-6); 151.9 (C-8a); 169.6 (C=O). Found, m/z:
222.1125 [M+H]+. C12H16NO3. Calculated, m/z: 222.1125.
cis-3-Ethyl-4-(methoxyamino)chroman-2-one (cis-5d).
2-{[(Benzyloxy)imino]methyl}phenyl butyrate (6c).
1
Yield 0.046 g (31%). H NMR spectrum, δ, ppm (J, Hz):
1.06 (3H, t, J = 7.4, (CH2)2CH3); 1.76–1.85 (2H, m,
CH2CH2CH3); 2.56 (2H, t, J = 7.4, CH2CH2CH3); 5.25 (2H,
s, OCH2Ph), 7.12 (1H, d, J = 8.1, H-6 Ar); 7.26 (2H, t,
J = 7.5, H-5 Ar); 7.36–7.45 (6H, m, H-4 Ar, H Ph); 7.83
(1H, d, J = 7.8, H-3 Ar); 8.24 (1H, s, HC=N). 13C NMR
spectrum, δ, ppm: 13.7 (CH2)2CH3); 18.3 (CH2CH2CH3);
36.0 (CH2CH2CH3); 76.5 (OCH2Ph); 123.0 (C-6 Ar); 124.6
(C-1 Ar); 126.1 (C-5 Ar); 127.6 (C-3 Ar); 128.0 (C-4 Ph);
128.4 (C-2,6 Ph); 128.5 (C-3,5 Ph); 130.6 (C-4 Ar); 137.3
(C-1 Ph); 144.4 (C=N); 148.8 (C-2 Ar); 171.8 (C=O).
Found, m/z: 298.1453 [M+H]+. C18H20NO3. Calculated, m/z:
298.1438.
1
Yield 0.010 g (9%). H NMR spectrum, δ, ppm (J, Hz):
1.05 (3H, t, J = 7.5, 3-CH2CH3); 1.47–1.57 (2H, m,
3-CH2CH3); 3.09 (1H, td, J = 7.7, J = 2.1, 3-CH); 3.49 (3H,
s, OCH3); 4.06 (1H, d, J = 2.1, 4-CH); 7.08 (1H, dd,
J = 8.2, J =1.1, H-8); 7.16 (1H, td, J = 7.4, J = 1.2, H-6);
7.30–7.41 (2H, m, H-5,7). Mass spectrum, m/z (Irel, %): 221
[M]+ (2), 176 (12), 175 (100), 147 (21), 133 (27), 119 (20),
91 (53).
4-[(Benzyloxy)amino]-3,3-dimethylchroman-2-one (5e).
1
Yield 0.037 g (25%). H NMR spectrum, δ, ppm (J, Hz):
2-{[(Methoxy)imino]methyl}phenyl butyrate (6d).
1
1.22 (3H, s, 3-CH3); 1.52 (3H, s, 3-CH3); 3.69 (1H, s,
4-CH); 4.29 (1H, d, J = 11.7) and 4.39 (1H, d, J = 11.7,
OCH2Ph); 7.06–7.10 (1H, m, H-8); 7.14–7.20 (3H, m, H-6,
H Ph); 7.33–7.41 (5H, m, H-5,7, H Ph). 13C NMR
spectrum, δ, ppm: 20.8 (3-CH3); 24.8 (3-CH3); 40.4 (C-3);
66.7 (C-4); 76.8 (OCH2Ph); 116.2 (C-8); 122.1 (C-4a);
124.3 (C-6); 127.8 (C-4 Ph); 128.3 (C-3,5 Ph); 128.4
(C-2,6 Ph); 129.7 (C-5); 129.8 (C-7); 136.8 (C-1 Ph); 151.8
(C-8a); 173.1 (C=O). Found, m/z: 298.1447 [M+H]+.
C18H20NO3. Calculated, m/z: 298.1438.
Yield 0.028 g (25%). H NMR spectrum, δ, ppm (J, Hz):
1.07 (3H, t, J = 7.4, (CH2)2CH3); 1.78–1.88 (2H, m,
CH2CH2CH3); 2.61 (2H, t, J = 7.4, CH2CH2CH3); 3.99 (3H,
s, OCH3); 7.09–7.13 (1H, m, H-6 Ar); 7.23–7.29 (1H, m,
H-5 Ar); 7.38–7.44 (1H, m, H-4 Ar); 7.81 (1H, dd, J = 7.8,
J = 1.7, H-3 Ar); 8.13 (1H, s, HC=N). 13C NMR spectrum,
δ, ppm: 13.7 ((CH2)2CH3); 18.3 (CH2CH2CH3); 36.1
(CH2CH2CH3), 62.2 (OCH3); 123.0 (C-6 Ar); 124.5
(C-1 Ar); 126.1 (C-5 Ar); 127.5 (C-3 Ar); 130.6 (C-4 Ar),
143.9 (C=N); 148.7 (C-2 Ar); 171.8 (C=O). Found, m/z:
244.0955 [M+Na]+. C12H15NNaO3. Calculated, m/z: 244.0944.
2-{[(Benzyloxy)imino]methyl}phenyl isobutyrate (6e).
4-(Methoxyamino)-3,3-dimethylchroman-2-one (5f).
1
Yield 0.022 g (20%). H NMR spectrum, δ, ppm (J, Hz):
1
1.22 (3H, s, 3-CH3); 1.52 (3H, s, 3-CH3); 3.24 (3H, s,
OCH3); 3.65 (1H, s, 4-CH); 7.05–7.09 (1H, m, H-8); 7.18
(1H, td, J = 7.4, J =1.2, H-6); 7.32–7.37 (2H, m, H-5,7).
13C NMR spectrum, δ, ppm: 20.8 (3-CH3); 24.7 (3-CH3);
40.2 (C-3); 62.6 (C-4); 66.8 (OCH3); 116.2 (C-8); 122.1
(C-4a); 124.4 (C-6); 129.5 (C-5); 129.7 (C-7); 151.8
(C-8a); 173.1 (C=O). Found, m/z: 222.1150 [M+H]+.
C12H16NO3. Calculated, m/z: 222.1125.
Yield 0.10 g (69%). H NMR spectrum, δ, ppm (J, Hz):
1.36 (6H, d, J = 6.8, CH(CH3)2); 2.85 (1H, hept, J = 6.8,
CH(CH3)2); 5.25 (2H, s, OCH2Ph), 7.10 (1H, d, J = 8.1,
H-6 Ar); 7.26 (1H, t, J = 7.5, H-5 Ar); 7.35–7.47 (6H, m,
H-4 Ar, H Ph), 7.87 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.24
(1H, s, HC=N). 13C NMR spectrum, δ, ppm: 18.9 (2C,
CH(CH3)2); 34.2 (CH(CH3)2); 76.6 (OCH2Ph); 122.9
(C-6 Ar); 124.6 (C-1 Ar); 126.1 (C-5 Ar); 127.3 (C-3 Ar);
128.1 (C-4 Ph); 128.4 (C-3,5 Ph); 128.5 (C-2,6 Ph); 130.7
(C-4 Ar); 137.3 (C-1 Ph); 144.1 (C=N); 148.9 (C-2 Ar); 175.2
(C=O). Found, m/z: 298.1454 [M+H]+. C18H20NO3. Calcu-
lated, m/z: 298.1438.
2-{[(Benzyloxy)imino]methyl}phenyl propionate (6a).
1
Yield 0.052 g (37%). H NMR spectrum, δ, ppm (J, Hz):
1.26 (3H, t, J = 7.5, CH2CH3); 2.60 (2H, q, J = 7.4,
CH2CH3); 5.23 (2H, s, OCH2Ph); 7.11 (1H, d, J = 8.1,
H-6 Ar); 7.23 – 7.29 (1H, m, H-5 Ar); 7.35 – 7.45 (6H, m,
H-4 Ar, H Ph); 7.81 (1H, d, J = 7.8, H-3 Ar); 8.22 (1H, s,
HC=N). 13C NMR spectrum, δ, ppm: 9.0 (CH2CH3); 27.6
(CH2CH3); 76.6 (OCH2Ph); 123.0 (C-6 Ar); 124.6
(C-1 Ar); 126.1 (C-5 Ar); 127.8 (C-3 Ar); 128.1 (C-4 Ph);
128.4 (C-2,6); 128.5 (C-3,5); 130.7 (C-4); 137.2 (C-1 Ph);
144.5 (C=N); 148.8 (C-2 Ar); 172.7 (C=O). Mass
spectrum, m/z (Irel, %): 283 [M]+ (1), 210 (10), 91 (100).
2-{[(Methoxy)imino]methyl}phenyl propionate (6b).
2-{[(Methoxy)imino]methyl}phenyl isobutyrate (6f).
1
Yield 0.08 g (74%). H NMR spectrum, δ, ppm (J, Hz):
1.35 (6H, d, J = 7.0, CH(CH3)2); 2.86 (1H, hept, J = 7.0,
CH(CH3)2); 3.97 (3H, s, OCH3); 7.07 (1H, dd, J = 8.1,
J = 1.2, H-6 Ar); 7.23 (1H, t, J = 7.3, H-5 Ar); 7.35–7.41
(1H, m, H-4 Ar); 7.82 (1H, dd, J = 7.8, J = 1.8, H-3 Ar);
8.12 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 18.9 (2C,
CH(CH3)2); 34.1 (CH(CH3)2); 62.1 (OCH3); 123.0 (C-6 Ar);
124.8 (C-1 Ar); 126.0 (C-5 Ar); 127.2 (C-3 Ar); 130.6
(C-4 Ar); 143.6 (C=N); 148.5 (C-2 Ar); 169.8 (C=O). Mass
spectrum, m/z (Irel, %): 221 [M]+ (7), 152 (11), 151 (100),
120 (24), 119 (38), 91 (39).
1
Yield 0.027 g (26%). H NMR spectrum, δ, ppm (J, Hz):
1.29 (3H, t, J = 7.5, CH2CH3); 2.65 (2H, q, J = 7.5,
CH2CH3); 3.98 (3H, s, OCH3); 7.11 (1H, dd, J = 8.1,
181

Chemistry of Heterocyclic Compounds 2016, 52(3), 000–000
2-{1-[(Benzyloxy)amino]propyl}phenyl propionate (7a).
13C NMR spectrum, δ, ppm: 11.2 (CHCH2CH3); 13.8
(CH2CH2CH3); 18.0 (CH2CH2CH3); 22.1 (CHCH2CH3);
33.7 (CH2CH2CH3); 56.5 (CHNH); 65.2 (OCH3); 117.7
(C-6 Ar); 119.6 (C-5 Ar); 125.2 (C-1 Ar); 126.9 (C-3 Ar);
129.6 (C-4 Ar); 155.7 (C-2 Ar); 176.8 (C=O). Found, m/z:
274.1424 [M+Na]+. C14H21NNaO3. Calculated, m/z: 274.1414.
1
Yield 0.008 g (5%). H NMR spectrum, δ, ppm (J, Hz):
1.01 (3H, t, J = 7.2, CHCH2CH3); 1.15 (3H, t, J = 7.5,
COCH2CH3); 2.02–2.16 (1H, m, CHCH2CH3); 2.30–2.53
(2H, m, COCH2CH3); 2.56–2.70 (1H, m, CHCH2CH3);
4.60 (1H, d, J = 10.2) and 4.65 (1H, d, J = 10.3, OCH2Ph);
5.51 (1H, dd, J = 9.7, J = 5.4, CHNH); 6.91 (1H, t, J = 7.5,
H-5 Ar); 7.00 (1H, d, J = 8.0, H-6 Ar); 7.21–7.40 (7H, m,
H-3,4 Ar, H Ph); 8.86 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 8.8 (COCH2CH3); 11.3 (CHCH2CH3); 22.3
(CHCH2CH3); 25.5 (COCH2CH3); 57.2 (CHNH); 79.1
(OCH2Ph); 117.7 (C-6 Ar); 119.7 (C-5 Ar); 125.1 (C-1 Ar);
126.9 (C-3 Ar); 128.7 (C-4 Ph); 128.9 (C-2,6 Ph); 129.0
(C-3,5 Ph); 129.8 (C-4 Ar); 134.0 (C-1 Ph); 156.0
(C-2 Ar); 178.1 (C=O). Found, m/z: 336.1587 [M+Na]+.
C19H23NNaO3. Calculated, m/z: 336.1570.
The authors thank Pontificia Universidad Javeriana
(PUJ) and COLCIENCIAS for the financial support
through the projects ID 5564 and 120365843351. John
Díaz thanks PUJ for the teaching assistantship.
References
1. Mikhaleva, A. I.; Zaitsev, A. B.; Trofimov, B. A. Russ. Chem.
Rev. 2006, 75, 797. [Usp. Khim. 2006, 75, 884.]
2. Corey, E.; Pyne, S. Tetrahedron Lett. 1983, 24, 2821.
3. For some reviews of radical addition to oxime ethers, see:
(a) Friestad, G. Tetrahedron 2001, 57, 5461. (b) Subramanian, H.;
Landais, Y.; Sibi, M. P. In Comprehensive Organic Synthesis II;
Molander, G.; Knochel, P., Eds.; Elsevier: Amsterdam, 2014,
Vol. 4, p. 699.
2-[1-(Methoxyamino)propyl]phenyl propionate (7b).
1
Yield 0.008 g (7%). H NMR spectrum, δ, ppm (J, Hz):
0.99 (3H, t, J = 7.2, CHCH2CH3); 1.19 (3H, t, J = 7.4,
COCH2CH3); 1.96–2.11 (1H, m) and 2.55–2.69 (1H, m,
CHCH2CH3); 2.34–2.50 (2H, m, COCH2CH3); 3.57 (3H, s,
OCH3); 5.42 (1H, dd, J = 9.7, J = 5.6, CHNH); 6.88 (1H, t,
J = 7.6, H-5 Ar); 6.95 (1H, d, J = 8.2, H-6 Ar); 7.22 (1H, t,
J = 7.6, H-4 Ar); 7.33 (1H, d, J = 7.6, H-3 Ar); 8.80 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 8.8 (COCH2CH3); 11.3
(CHCH2CH3); 22.1 (CHCH2CH3); 25.3 (COCH2CH3); 56.6
(CHNH); 65.2 (OCH3); 117.7 (C-6 Ar); 119.6 (C-5 Ar);
125.2 (C-1 Ar); 126.9 (C-3 Ar); 129.6 (C-4 Ar); 155.7
(C-2 Ar); 177.6 (C=O). Found, m/z: 260.1272 [M+Na]+.
C13H19NNaO3. Calculated, m/z: 260.1257.
4. For some examples of radical addition to oxime ethers, see:
(a) Miyata, O.; Takahashi, S. A.; Tamura, U. M.; Naito, T.
Tetrahedron. 2008, 64, 1270. (b) Jaramillo-Gómez, L. M.;
Loaiza, A. E.; Martin, J.; Ríos, L. A.; Wang, P. G.
Tetrahedron Lett. 2006, 47, 3909. (c) Miyabe, H.; Ueda, M.;
Fujii, K.; Nishimura, A.; Naito, T. J. Org. Chem. 2003, 68,
5618. (d) Miyabe, H.; Ueda, M.; Yoshioko, N.; Yamakawa, K.;
Naito, T. Tetrahedron 2000, 56, 2413. (e) Miyabe, H.; Ueda, M.;
Naito, T. J. Org. Chem. 2000, 65, 5043. (f) Miyabe, H.;
Tanaka, H.; Naito, T. Tetrahedron Lett. 1999, 40, 8387.
(g) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.; Naito, T.
Tetrahedron 1998, 54, 11431. (h) Miyabe, H.; Shibata, R.;
Ushiro, C.; Naito, T. Tetrahedron Lett. 1998, 39, 631.
2-[1-(Methoxyamino)propyl]phenyl butyrate (7d).
1
Yield 0.007 g (5.5%). H NMR spectrum, δ, ppm (J, Hz):
5. (a) Dong, S.; Liu, X.; Zhang, Y.; Lin, L.; Feng, X. Org. Lett.
2011, 13, 5060. (b) El-Saghier, A. M.; Naili, M. B.;
Rammash, B. Kh.; Saleh, N. A.; Kreddan, K. M. ARKIVOC
2007, (xvi), 83. (c) Di Braccio, M.; Grossi, G.; Roma, G.;
Marzano, C.; Baccichetti, F.; Simonato, M.; Bordin, F.
Farmaco 2003, 58, 1083. (d) Roma, G.; Di Braccio, M.;
Carrieri, A.; Grossi, G.; Leoncini, G.; Signorello, M.; Carotti, A.
Biorg. Med. Chem. 2003, 11, 123.
0.98 (3H, t, J = 7.4, CH2CH2CH3); 0.99 (3H, t, J = 7.3,
CHCH2CH3); 1.72 (2H, hept, J = 7.3, CH2CH2CH3); 1.96–
2.11 (1H, m, CHCH2CH3); 2.32–2.46 (2H, m,
CH2CH2CH3); 2.51–2.64 (1H, m, CHCH2CH3); 3.57 (3H,
s, OCH3); 5.44 (1H, dd, J = 9.6, J = 5.5, CHNH); 6.87 (1H,
td, J = 7.5, J = 1.3, H-5 Ar); 6.95 (1H, dd, J = 8.2, J = 1.3,
H-6 Ar); 7.22 (1H, ddd, J = 8.2, J = 7.3, J = 1.7, H-4 Ar);
7.33 (1H, dd, J = 7.3, J = 1.7, H-3 Ar); 8.77 (1H, s, NH).
6. Otto, N.; Opatz, T. Beilstein J. Org. Chem. 2012, 8, 1105.
182