A study on the regioselectivity in N,C-acylation of β-enamino-esters

Article abstract of DOI:10.1016/j.tet.2013.04.012

With the aim to produce the new corresponding amide, amino pyrone 1 [=4-(benzylamino)-6-methyl-2H-pyran-2-one] was acylated in dichloromethane in the presence of triethylamine, obtaining an unexpected mixture of N- and C-acyl products in a 60:40 ratio, respectively. The regioselective investigation was enlarged by using a series of organic bases and taking into account both solvent effects and acyl halide structure. Conditions able to give pure amides or pure C-acyl products were established. The study also includes the reactivity of a β-enamino-ester with NH group involved in an intramolecular hydrogen bond, where pure C-acyl products were obtained.

Full text of DOI:10.1016/j.tet.2013.04.012

Tetrahedron 69 (2013) 4586e4590
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A study on the regioselectivity in N,C-acylation of b-enamino-esters
*
Andrea Defant, Ines Mancini
ꢀ
Universita di Trento, Dipartimento di Fisica, Laboratorio di Chimica Bioorganica, via Sommarive 14, I-38123 Povo Trento, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
With the aim to produce the new corresponding amide, amino pyrone 1 [¼4-(benzylamino)-6-methyl-
2H-pyran-2-one] was acylated in dichloromethane in the presence of triethylamine, obtaining an un-
expected mixture of N- and C-acyl products in a 60:40 ratio, respectively. The regioselective investigation
was enlarged by using a series of organic bases and taking into account both solvent effects and acyl
halide structure. Conditions able to give pure amides or pure C-acyl products were established. The study
Received 21 January 2013
Received in revised form 19 March 2013
Accepted 4 April 2013
Available online 10 April 2013
also includes the reactivity of a
bond, where pure C-acyl products were obtained.
b-enamino-ester with NH group involved in an intramolecular hydrogen
Keywords:
Regioselectivity
N,C-Acylation
Ó 2013 Elsevier Ltd. All rights reserved.
b-Enamino-ester
Amino pyrone
1. Introduction
We report here an investigation of the regioselectivity by
changing the organic base, the solvent polarity, and acyl agent
structure, establishing the best conditions to drive the production
of pure regioisomeric products.7
In our recent synthesis of potential antiviral agents, we became
interested in producing new amides by acylation of 4-(benzyla-
mino)-6-methyl-2H-pyran-2-one (1, Scheme 1). Attempts to obtain
suitable amides by using an acyl chloride in the presence of trie-
thylamine, resulted in the expected products by N-acylation, but in
a mixture with C-acyl compounds. These results suggested that we
look further into the N,C-acylation selectivity for the ambidentate
amino pyrone, whose reactivity is poorly known. In fact, despite
recent interest in amino-pyrone chemistry as precursors in the
synthesis of natural products,1e4 only an old theoretical study on
their N-basicity was reported.5 By a general point of view, 4-amino
2. Results and discussion
By following the general procedure for producing amides by the
reaction of an amine with acyl chloride in the presence of an or-
ganic base (to trap the formed HCl),8 amino pyrone 1 was treated
with dichloroacetyl chloride. Unexpectedly, a mixture of products
containing the desired amide 2a and 3a in a 60:40 ratio was ob-
tained, products deriving from N- and C-acylation, respectively
(Scheme 1). The structural assignment of the two regioisomers was
based on extensive NMR analysis (Experimental) and by compari-
son of values for C]O stretching deduced by experimental and DFT
calculated IR spectra (Table 1).
pyrones can be regarded cyclic conjugated b-enamino esters that
can act as 1,3-dielectrophiles or as nucleophilic reagents.6
It was reported that the reaction of primary or secondary amines
with dichloroacetyl chloride in the presence of triethylamine gave
N-acylation, producing dichloroacetamido derivatives in high
yields supposedly via dichloroketene Cl2C]C]O, which reacted
Table 1
Experimental and DFT calculated values for C]O stretching in regioisomers 2a
and 3a
Scheme 1. N,C-acylation of amino pyrone 1. Reagents and conditions: a) suitable base
(2.5 equiv) acyl chloride (2.0 equiv), suitable solvent, 0 ꢀC / rt, 18 h, 75e90% yield.
Arbitrary numbering is for convenience.
Compound
C(2)]O
C(10)]O
Exper. (cmꢁ1
)
Calcd (cmꢁ1
)
Exper. (cmꢁ1
)
Calcd (cmꢁ1
)
2a
3a
1737
1704
1759
1712
1693
1616
1694
1622
* Corresponding author. Tel.: þ39 0461 281536; fax: þ39 0461 281696; e-mail
address: ines.mancini@unitn.it (I. Mancini).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.012

A. Defant, I. Mancini / Tetrahedron 69 (2013) 4586e4590
4587
with the more nucleophilic nitrogen centre.9 C-Acylation is also
possible by the involvement of a zwitterionic resonance form,
where the charged C-nucleophile can react with acyl chloride
(Fig. 1). This is in line with the KlopmaneSalem concept that
hardehard interactions are charge controlled (and softesoft in-
teractions are orbital controlled).10
carrying out the reaction without triethylamine and any other ba-
ses, pure C-acyl compound 3a was produced. This evidence is in
agreement with the nucleophile attack of the zwitterionic pyrone
with the electrophile carbonyl group present both in dichloroacetyl
chloride and dichloroacetyl pyridinium species, as well as with the
absence of the dichloroketene, whose formation requires the base.
The evaluation of solvent effect was also investigated in two
cases of highly selective acylation: by employing pyridine, to give
pure C-acyl product 3a and by using DBU producing the N-acyl
compound 2a. The replacement of dichloromethane with
solvents having different polarity did not affect the selectivity in the
presence of pyridine. On the contrary, with DBU the selectivity in
N,C-acylation was lost in toluene or acetonitrile, whereas it was
fully reversed in acetone (Table 3).
Fig. 1. Two resonance forms of amino pyrone 1.
A further investigation took into account a series of organic
bases, chosen in order to cover a range of different basicity, as re-
ported in Table 2.
Table 3
Selectivity in N,C-dichloroacetylation of amino pyrone 1 using pyridine or DBU by
changing the solvent (at 0 ꢀC for 18 h, yield 89%) to give N-acyl 2a and C-acyl 3a
products
Table 2
Selectivity in N,C-dichloroacetylation of amino pyrone 1 by changing the base (in
CH2Cl2 at 0 ꢀC for 18 h, yield 89%) to give N-acyl 2a and C-acyl 3a products
Solvent
Pyridine
DBU
% 2aa
% 3aa
% 2aa
% 3aa
Basea
% 2ab
% 3ab
Dichloromethane
Toluene
Acetonitrile
Acetone
0
0
0
0
100
100
100
100
100
60
64
0
0
40
36
Pyridine
0
0
0
48
100
100
100
52
4-Methyl-pyridine
1-Methyl-imidazole
2,4,6-Trimethyl-pyridine
1,2-Dimethyl-imidazole
TMDM
Triethanolamine
Tributylphosphine
DABCO
TMED
DMAP
Triethylamine
DIPEA
DBU
100
a
0
100
The N- and C-acylation ratio was evaluated in the crude reaction mixture by the
¼4.55 ppm (d, PhCH2) in
c
c
signal integrals in 1H NMR spectrum recorded in CDCl3, at
3a and
¼4.90 ppm (s, PhCH2) in 2a.
d
c
c
d
0
100
0
100
66
0
60
90
100
0
34
100
40
10
0
It is evident that the presence of two electronegative atoms in
dichloroacetyl chloride is able to increase the positive charge on the
C]O group, so that to increase its electrophilicity. In order to ex-
pand the investigation, other acyl halides were studied in the re-
actions carried out in dichloromethane with pyridine or DBU. The
results reported in Table 4 indicate that selectivity is not affected by
the acyl structure.
No base
100
a
TMDM¼N,N,N0,N0-tetramethyldiaminomethane, DABCO¼1,4-diazabicyclo[2.2.2]
octane, TMED¼N,N,N0,N0-tetramethyl-ethylenediamine, DMAP¼4-(dimethylamino)
pyridine, DIPEA¼N-ethyldiisopropylamine, DBU¼1,8-diazabicyclo[5.4.0]undec-7-
ene.
Table 4
b
The N- and C-acylation ratio was evaluated in the crude reaction mixture by the
Selectivity in N,C-acylation of amino pyrone 1 using pyridine or DBU by changing the
relative signal integrals in 1H NMR spectrum recorded in CDCl3, at
d
¼4.55 ppm
acyl halide (in CH2Cl2 at 0 ꢀC for 18 h, yields 78e90%)
(d, PhCH2) in 3a and
d
¼4.90 ppm (s, PhCH2) in 2a.
c
No products were obtained; starting amino pyrone 1 was practically recovered
Acyl halide
Pyridine
DBU
in quantitative amount.
% C-Acyl
% N-Acyl
% C-Acyl
% N-Acyl
producta
producta
producta
producta
By replacing triethylamine with DBU, DABCO, and diisopropy-
lethylamine (DIPEA), the expected amide 2a were obtained in pure
form, in agreement with the probable involvement of the soft
dichloroketene electrophile, produced by dehydrochlorination of
dichloroacetyl chloride induced by hindered and non-nucleophile
bases.
Dichloroacetyl chloride
Propionyl chloride
Isobutyryl chloride
100
93
100
100
0
7
0
0
0
12
100
88
0
100
b
b
2-Bromo-propionyl bromide
a
The ratio of N- and C-acylation was evaluated in the crude reaction mixture by
the signal integrals of benzylic protons in ketones and amides in 1H NMR spectrum
recorded in CDCl3.
An interesting completely reversed selectivity was given by
using pyridine, 4-methylpyridine, 4-dimethylaminopyridine
(DMAP), 1-methylimidazole, and 1,2-dimethylimidazole) and trib-
utylphosphine, to produce pure C-acyl product 3a. It can be
explained by the hardehard interaction between the pyrone sub-
strate in its zwitterionic form and a probable N-dichloroacetyl
pyridinium species acting as electrophile. It is in line with the re-
port of acylammonium salts isolated from the reaction of acyl
chlorides and amines including pyridine, DMAP, picoline, and
triethylamine.11 The low selectivity observed by using triethyl-
amine, TMED, and 2,4,6-trimethylpyridine is attributable to the
involvement of both mechanisms.8 In order to rationalize the effect
of base structure, their proton affinity, defined as the tendency of
a base to accept a proton in gas phase and reported as the difference
between the energy values for protonated (BHþ) form and free base
(B),12 has been evaluated by density functional theory (DFT) cal-
culations, but no correlation was found. It is noteworthy that
b
No products were obtained and tars were recovered.
The regioselectivity was further evaluated on (Z)-ethyl 3-(ben-
zylamino)but-2-enoate (4). It was treated in dichloromethane
with dichloroacetyl chloride in the presence of different bases
(Scheme 2). Each reaction, carried out with triethylamine, pyridine,
DBU or without any base, always gave a complete regioselectivity in
favor of the C-acyl product 5. The (Z)-configuration of b-enamino
ester 4 was secured by an intramolecular hydrogen bond between
NH and C]O groups and forming a stable six membered ring, as
established by the presence of a broad singlet at 8.94 ppm in 1H
NMR spectrum of 4 recorded in CDCl3. Otherwise the enamino-like
double bond present in the structure of amino pyrone 1 has an
(E)-configuration avoiding any similar reactivity. In addition, the
presence of the benzyl moiety may have inhibited N-acylation as
a result of steric hindrance.13

4588
A. Defant, I. Mancini / Tetrahedron 69 (2013) 4586e4590
vibrational energy calculations, resulting in IR wavenumbers to-
gether with intensities and force constants. For each optimized
structure, no imaginary wavenumber modes were obtained, prov-
ing that a local minimum on the potential energy surface was ac-
tually found. The computed wavenumbers were scaled by factor
0.9613, suggested for B3LYP/6e31G(d) calculations.15 Similarly,
proton affinity of the organic bases was calculated at DFT B3LYP/
aug-ccpVDZ level of theory.
Scheme 2. Acylation of
b-enamino ester 4 by using different bases. Reagents and
conditions: a) triethylamine, or pyridine, or DBU, or no base, dichloroacetyl chloride,
CH2Cl2, 0 ꢀC / rt, 18 h, 78e90% yield.
4.1.1. 4-(Benzylamino)-6-methyl-2H-pyran-2-one (1). A mixture
containing 6-methyl-2-oxo-2H-pyran-4-yl 4-tosylate (280.3 mg,
3. Conclusions
1 mmol), benzylamine (120
mL, 1.1 mmol), and Et3N (210 mL,
The acylation of 4-(benzylamino)-6-methyl-2H-pyran-2-one
with dichloroacetyl chloride in dichloromethane was investigated
by using different organic bases. It produced the regioisomers by N-
and C-attack, with a high selectivity in favor of the expected amide
by using DABCO, DBU, and DIPEA, and fully reversed reactivity giv-
ing C-acyl product in the presence of pyridine, 4-methylpyridine,
DMAP, 1-methylimidazole, 1,2-dimethylimidazole, and tribu-
tylphosphine, or in absence of any bases. Both the solvent polarity
and the acyl halide structure did not effectively affect the selectivity.
1.5 mmol) in absolute ethanol (60 mL) was stirred at room tem-
perature for 60 h monitoring by TLC (hexane/ethyl acetate/
Et3N¼20:79:1). After concentration in vacuo, purification by flash
chromatography using hexane/ethyl acetate by gradient, gave the
title compound 1 (118 mg, 55%) as viscous transparent oil. 1H NMR
(400 MHz, CDCl3)
H-3), 5.16 (1H, br s, NH), 4.99 (1H, s, H-5), 4.27 (2H, d, J 5.2 Hz, H-10),
2.12 (3H, s, MeeC(6)). 13C NMR (100 MHz, CDCl3)
(ppm): 165.5
d (ppm): 7.47e7.14 (5H, m, C6H5e), 5.57 (1H, s,
d
(C-4), 161.3 (C-2 and C-6), 136.7 (C-20), 129.0 (C-40 and C-60), 127.9
(C-30 and C-70), 127.5 (C-50), 99.2 (C-5), 81.11 (C-3), 46.8 (C-10), 19.9
(MeeC(6)). EI-MS m/z (%): 215 ([Mþꢄ], 40),187 (30),106 (22); HR(EI)
MS: 215.09448 (C13H13NO2, calcd 215.09463). The data are consis-
tent with the ones reported by McLaughlin et al.3
The study on an (Z)-acyclic
b-enamino ester taken as a model
compound, gave only the corresponding C-acyl product, probably
due to the involvement of a stable intramolecular hydrogen bond, as
established by NMR analysis. The reactivity here investigated rep-
resents an effective and versatile access to practically pure
regioisomers, otherwise difficult to be produced.
4.1.2. (Z)-Ethyl 3-(benzylamino)but-2-enoate (4). A mixture of ethyl
acetoacetate (0.5 mL, 3.9 mmol), benzylamine (0.43 mL, 3.9 mmol),
4. Experimental section
4.1. General
and acetic acid (25 mL, 0.44 mmol) was placed in an ultrasound bath
at a temperature never exceeding 30 ꢀC, for 1 h. Later ethanol
(10 mL) was added, the resulting solution was dried on anhydrous
Na2SO4, filtered, and concentrated in vacuo to give pure product
(850 mg, quantitative yield). Yellow oil. 1H NMR (400 MHz, CDCl3)
All evaporations were carried out at reduced pressure at room
temperature. Yields are given on the reacted compounds. Solvents
and reagents were purchased from SigmaeAldrich Europe and
from Alfa Aesar and were used without purification. Thin-layer
chromatography (TLC) was carried out on Merck Kieselgel 60
PF254 and flash chromatography (FC) was carried on Merck silica
d
(ppm): 8.94 (1H, br s), 7.31e7.20 (5H, m), 4.52 (1H, s), 4.42 (2H, d, J
6.4 Hz), 4.09 (2H, q, J 7.0 Hz), 1.9 (3H, s), 1.25 (3H, t, J 7.0 Hz). The
data are consistent with the ones reported by Brandt et al.16
4.2. General procedure for the synthesis of compounds 2aec,
3aed and 5
gel (Si-60, 15ꢂ25 m). Preparative TLC was realized on 20ꢃ20 cm
m
Merck Kieselgel 60 F254 0.5 mm plates. Ultrasound bath Badelin
Sonorex RK510, 35 KHz, 160 W was used for the synthesis of
compound 4. IR spectra were acquired by FT-IR Equinox 55 Bruker,
equipped with ATR device in zinc selenide. NMR spectra were
recorded by an Avance 400Bruker spectrometer: 1H at 400 MHz
To a solution of compound 1 (5 mg, 0.02 mmol) or 4 (5 mg,
0.02 mmol) dissolved in anhydrous CH2Cl2 (0.5 mL), the suitable
amine (0.05 mmol) was added and the solution cooled at 0 ꢀC for
30 min. The proper acyl chloride (0.04 mmol) was slowly added at
this temperature. The mixture was stirred at room temperature for
18 h monitoring by TLC (hexane/ethyl acetate¼6:4). After concen-
tration in vacuo, the crude products were analyzed by 1H NMR
analysis.
and 13C at 100 MHz in CDCl3.
d values are reported in parts per
million relative to the solvent residual signals dH¼7.25 and
dC¼77.00 ppm for CDCl3, relative to SiMe4 (¼0 ppm); J values in
Hertz. 13C NMR assignments come from heteronuclear single
quantum correlation (HSQC) and heteronuclear multiple bond
correlation (HMBC) experiments. For NMR assignments a number-
ing for convenience was adopted. Electron impact (EI) mass spectra
(m/z; rel%) and high-resolution EI data (ꢂ0.003) were taken with
a Kratos-MS80 mass spectrometer with a home-built computerized
acquisition software. Electrospray ionization (ESI)-MS mass spectra
and tandem fragmentation spectra (MS/MS) were taken with
a Bruker Esquire-LC spectrometer equipped with an electrospray
ion source used in positive or negative ion mode by direct infusion
of a methanolic solution of the sample, under the following con-
ditions: source temperature 300 ꢀC, drying gas N2, 4 L/min, positive
ion mode, ISV 4 kV, OV 38.3 V, scan range m/z 100e1000. Quantum
chemical calculations were performed using the Gaussian 03W
revision E.01 package program set.14 The basis set of choice was
6e31 G(d) for geometry optimization and the optimized structural
parameters were employed in the vibrational energy calculations at
the DFT levels to characterize all stationary points as minima. Then,
vibrational averaged nuclear positions were adopted for harmonic
4.2.1. N-Benzyl-2,2-dichloro-N-(6-methyl-2-oxo-2H-pyran-4-yl)
acetamide (2a). Yield 82%. Oil, Rf (40% EtOAc/hexane) 0.31. nmax
(neat) 3070e2850 (br), 1737, 1693, 1641, 1562, 1215, 700 cmꢁ1. 1H
NMR (400 MHz, CDCl3) d
(ppm): 7.38e7.30 (3H, m, H-400, H-500, and
H-600), 7.23e7.17 (2H, m, H-300 and H-700), 6.19 (1H, s, H-20), 5.93 (1H,
s, H-3), 5.88 (1H, s, H-5), 4.90 (2H, s, H-100), 2.26 (3H, s, MeeC(6)).
13C NMR (100 MHz, CDCl3)
d
(ppm): 171.5 (C-10), 164.9 and 164.8
(C-2 and C-6), 154.7 (C-4), 134.6 (C-200), 128.7 (C-400 and C-600), 127.6
(C-300 and C-700), 126.6 (C-500), 108.6 (C-5), 103.1 (C-3), 63.3 (C-20),
51.5 (C-100), 20.6 (MeeC(6)). ESI-MS (positive mode): 348
([MþNa]þ). EI-MS m/z (%): 325 ([Mþꢄ], 4), 214 (10), 91 (100); HR(EI)
35
MS: 325.0267 (C15
H Cl2NO3, calcd 325.02725).
13
4.2.2. 4-(Benzylamino)-3-(2,2-dichloroacetyl)-6-methyl-2H-pyran-
2-one (3a). Yield 89%. White solid (from hexane/ethyl acetate), mp
94e95 ꢀC, Rf (40% EtOAc/hexane) 0.44. nmax (neat) 3232e2930 (br),
1704, 1659, 1616, 1568, 1498, 1456, 1363, 1338, 1296, 1230,

A. Defant, I. Mancini / Tetrahedron 69 (2013) 4586e4590
4589
700 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
(ppm): 11.43 (1H, br s, NH),
(C-3), 45.2 (C-100), 37.3 (C-20), 20.7 (MeeC(6)), 10.1 (C-30). ESI-MS
(positive mode): m/z 272 ([MþH]þ), 294 ([MþNa]þ). 564
([2MþNa]þ); MS/MS (272): m/z 216 ([MþHꢁC3H4O]þ); MS3
(216): m/z 138 ([MþHꢁC6H6]þ). EI-MS m/z (%): 271 ([Mþꢄ], 33), 242
(71), 180 (21), 91 (100); HR(EI)MS: 271.12072 (C16H17NO3,
calcd 271.12084).
7.67 (1H s, H-20), 7.46e7.32 (3H, m, H-400, H-500, and H-600), 7.32e7.26
(2H, m, H-300 and H-700), 5.93 (1H, s, H-5), 4.57 (2H, d, J 5.6 Hz, H-100),
2.210 (3H, s, MeeC(6)). 13C NMR (100 MHz, CDCl3)
d (ppm): 188.4
(C-1 ), 166.9 and 166.8 (C-2 and C-6), 163.2 (C-4), 135.2 (C-200), 129.1
(C-400 and C-600), 127.0 (C-500), 126.9 (C-300 and C-700), 95.3 (C-5), 90.4
(C-3), 69.8 (C-20), 47.0 (C-100), 20.6 (MeeC(6)). EI-MS m/z (%): 325
([Mþꢄ], 4), 290 (16), 254 (23), 242 (86); HR(EI)MS: 325.02575
(C15H13Cl2NO3, calcd 325.02725).
4.2.7. 4-(Benzylamino)-3-(2-bromopropanoyl)-6-methyl-2H-pyran-
2-one (3d). Yield 85%. Pale yellow oil, Rf (40% EtOAc/hexane) 0.41.
nmax (neat) 3300e2800 (br), 1706, 1657, 1604, 1562, 1495, 1454,
1367, 1338, 1242, 1167, 1012, 920, 806, 735 cmꢁ1. 1H NMR (400 MHz,
4.2.3. N-Benzyl-N-(6-methyl-2-oxo-2H-pyran-4-yl)isobutyramide
(2b). Yield 78%. Oil, Rf (40% EtOAc/hexane) 0.29. nmax (neat) 2957,
CDCl3) d
(ppm): 11.69 (1H, br s, NH), 7.42e7.32 (3H, m, H-400, H-500,
2854, 1720, 1676, 1639, 1556, 1452, 1414, 1379, 1319, 1198, 700 cmꢁ1
.
and H-600), 7.29e7.26 (2H, m, H-300 and H-700), 6.13 (1H, q, J 6.7 Hz,
H-20), 5.87 (1H, s, H-5), 4.53 (d, J 5.7 Hz, H-100), 2.19 (3H, s, MeeC(6)),
1H NMR (400 MHz, CDCl3)
d
(ppm): 7.41e7.26 (3H, m, H-400, H-500,
and H-600), 7.20e7.13 (2H, m, H-300 and H-700), 5.99 (1H, s, H-3), 5.77
(1H, s, H-5), 4.85 (2H, s, H-100), 2.83 (1H, septet, J 6.6 Hz, H-20), 2.23
(3H, s, MeeC(6)), 1.15 (6H, d, J 6.6 Hz, H-30). 13C NMR (100 MHz,
1.79 (2H, d, J 6.7 Hz, 3H, H-30). 13C NMR (100 MHz, CDCl3)
d (ppm):
197. 2 (C-10), 166.2 and 166.1 (C-2 and C-6), 162.9 (C-4), 135.6 (C-200),
128.7 (C-400and C-600), 127.1 (C-500), 127.0 (C-300 and C-700), 94.9 (C-5),
91.8 (C-3), 47.7 (C-20), 46.9 (C-100), 20.8 (MeeC(6)), 20.4 (C-30). ESI-
MS (positive mode): m/z 350/352 ([MþH]þ), 372/374 ([MþNa]þ),
388/390 ([MþK]þ); MS/MS (252): m/z 270 ([MþHꢁH81Br]þ), 180
CDCl3) d
(ppm): 177. 8 (C-10), 162.7 (C-2 and C-6), 157.2 (C-4), 136.4
(C-200), 128.5 (C-400 and C-600), 127.1 (C-500), 127.0 (C-300 and C-700),
105.5 (C-5), 103.3 (C-3), 51.4 (C-100), 32.0 (C-20), 20.6 (MeeC(6)),
19.0 (two C-30). ESI-MS (positive mode): m/z 286 ([MþH]þ),
308 ([MþNa]þ), 593 ([2MþNa]þ); MS/MS (286): m/z 216
([MþHꢁC4H6O]þ). EI-MS m/z (%): 285 ([Mþꢄ], 17), 214 (47), 91 (75),
43 (100); HR(EI)MS: 285.13607 (C17H19NO3, calcd 285.13649).
([MþHꢁH81BrꢁC7H6]þ). EI-MS m/z (%): 349 ([Mþꢄ], 1.5), 270 (51),
79
242 (27), 91 (100); HR(EI)MS: 349.02959 (C16
349.03136).
H BrNO3, calcd
16
4.2.8. (Z)-Ethyl 3-(benzylamino)-2-(2,2-dichloroacetyl)but-2-enoate
(5). Yield 82%. Yellow oil, Rf (40% EtOAc/hexane) 0.35. nmax (neat)
3068, 2977, 2935, 1703, 1657, 1603, 1562, 1493, 1454, 1340, 1234,
4.2.4. 4-(Benzylamino)-3-isobutyryl-6-methyl-2H-pyran-2-one
(3b). Yield 79%. Oil, Rf (40% EtOAc/hexane) 0.40. nmax (neat) 2970,
2933, 2873, 1707, 1658, 1603, 1560, 1495, 1454, 1379, 1342, 1232,
1176, 1009, 914, 814, 735, 698 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
1157, 1011, 918, 866, 806, 750, 737, 700 cmꢁ1
.
1H NMR (400 MHz,
d
(ppm): 12.65 (1H, br s, NH), 7.44e7.36 (3H, m, H-400, H-500, and
CDCl3)
d
(ppm): 12.03 (1H, br s, NH), 7.42e7.31 (3H, m, H-400, H-500,
H-600), 7.32e7.22 (2H, m, H-300 and H-700), 6.92 (1H, s, H-20), 4.57 (2H,
and H-600), 7.30e7.24 (2H, m, H-300 and H-700), 5.81 (1H, s, H-5), 4.50
d, J 5.6 Hz, H-100), 4.25 (2H, q, J 7.1 Hz, eOCH2e), 2.29 (3H, s, C-4),
(2H, d, J 5.6 Hz, H-100), 2.16 (3H, s, MeeC(6)), 1.11 (6H, d, J 6.7 Hz,
1.34 (3H, t, J 7.1 Hz, CH3CH2). 13C NMR (100 MHz, CDCl3)
d (ppm):
H-30). 13C NMR (100 MHz, CDCl3)
d
(ppm): 208. 8 (C-10), 165.5 and
173.7 (C-10), 171.3 (C-3), 168.2 (C-1), 135.3 (C-200), 128.1 (C-400,
and C-600), 127.6 (C-300 and C-700), 127.3 (C-500), 98.8 (C-2), 71.7 (C-20),
60.9 (eOCH2e), 47.8 (C-100), 17.9 (Mee(C-3)), 13.89 (CH3e). ESI-MS
(positive mode): m/z 330 ([MþH]þ), 352 ([MþNa]þ); MS/MS (330):
165.1 (C-2 and C-6), 162.7 (C-4), 136.0 (C-200), 128.5 (C-400 and C-600),
127.4 (C-300 and C-700), 127.3 (C-500), 94.5 (C-5), 93.2 (C-3), 46.7
(C-100), 37.7 (C-20), 20.6 (MeeC(6)), 18.5 (two C-30). ESI-MS (positive
mode): m/z 286 ([MþH]þ), 308 ([MþNa]þ); MS/MS (286): m/z 268
([MþHꢁH2O]þ), 216 ([MþHꢁC4H6O]þ). EI-MS m/z (%): 285 ([Mþꢄ],
9), 242 (63), 194 (42), 91 (100); HR(EI)MS: 285.13652 (C17H19NO3,
calcd 285.13649).
m/z 284 ([MþHꢁC2H6O]þ). EI-MS m/z (%): 329 ([Mþꢄ], 2), 246 (55),
35
91 (100); HR(EI)MS: 329.05801 (C15
H Cl2NO3, calcd 329.05855).
17
Acknowledgements
4.2.5. N-Benzyl-N-(6-methyl-2-oxo-2H-pyran-4-yl)propionamide
(2c). Yield 73%. Colorless oil, Rf (40% EtOAc/hexane) 0.27. nmax
(neat) 2952, 2854, 1720, 1676, 1639, 1556, 1452, 1414, 1379, 1319,
We are grateful to Mr. A. Sterni and D. Avi for recording mass and
FT-IR spectra, respectively.
1198, 700 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d (ppm): 7.37e7.27 (3H,
Supplementary data
m, H-400, H-500, and H-600), 7.20e7.13 (2H, m, H-300 and H-700), 6.13
(1H, s, H-3), 5.77 (1H, s, H-5), 4.88 (2H, s, H-100), 2.43 (2H, q, J 7.4 Hz,
H-20), 2.23 (3H, s, MeeC(6)), 1.16 (3H, t, J 7.4 Hz, H-30). 13C NMR
Supplementary data associated with this article, including NMR
spectra of 2aec and 3aed and IR spectra of 2a and 3a, can be found
in the online version. Supplementary data related to this article can
be found at http://dx.doi:10.1016/j.tet.2013.04.012.
(100 MHz, CDCl3)
d
(ppm): 174.1 (C-10), 162.4 and 164.3 (C-2 and
C-6), 157.2 (C-4), 136.1 (C-200), 127.9 (C-400 and C-600), 127.1 (C-500),
126.8 (C-300 and C-700), 103.2 (C-5), 51.5 (C-100), 28.5 (C-20), 20.6
(MeeC(6)), 18.1 (C-30). ESI-MS (positive mode): m/z 272 ([MþH]þ),
294 ([MþNa]þ); MS/MS (272): m/z 216 ([MþHꢁC3H4O]þ). EI-MS m/
z (%): 271 ([Mþ], 33), 242 (66), 180 (20), 91 (100); HR(EI)MS:
271.12064 (C16H17NO3, calcd 271.12084).
References and notes
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