Synthesis and reactions of N-acetyl- and N-(2-chloroacetyl)-N-[(2E)-1- methylbut-2-en-1-yl]-2-iodoanilines

Article abstract of DOI:10.1134/S1070363213020217

The reaction of N-(1-methylbut-2-en-1-yl)-2-iodaniline with Ac₂O or ClCH₂C(O)Cl results in a mixture of syn- and anti-atropisomers of N-acetyl- and N-chloroacetyl-N-(1-methylbut-2-en-1-yl)-2-iodaniline in a ratio of 1:1. Ozonolysis of the latter followed by reduction with dimethyl sulfide in CH₂Cl₂ gives rise to the atropisomers mixture of 2-[N-(chloroacetyl)-N-(2-iodophenyl)]aminopropanal in a ratio of 1:3. When heated in boiling benzene, the mixture of atropoisomeric aldehydes reacts with triphenylphosphine to afford a mixture of 2-[(N-acetyl)-N-(2-iodophenyl)] aminopropanal atropisomers in 1:3 ratio.

Full text of DOI:10.1134/S1070363213020217

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 2, pp. 368–372. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © D.A. Skladchikov, R.R. Gataullin, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 2, pp. 313–317.
Synthesis and Reactions of N-Acetyl-
and N-(2-Chloroacetyl)-N-[(2E)-1-methylbut-2-en-1-yl]-
2-iodoanilines
D. A. Skladchikov and R. R. Gataullin
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054 Russia
e-mail: gataullin@anrb.ru
Received March 1, 2012
Abstract―The reaction of N-(1-methylbut-2-en-1-yl)-2-iodaniline with Ac2O or ClCH2C(O)Cl results in a
mixture of syn- and anti-atropisomers of N-acetyl- and N-chloroacetyl-N-(1-methylbut-2-en-1-yl)-2-iodaniline
in a ratio of 1:1. Ozonolysis of the latter followed by reduction with dimethyl sulfide in CH2Cl2 gives rise to the
atropisomers mixture of 2-[N-(chloroacetyl)-N-(2-iodophenyl)]aminopropanal in a ratio of 1:3. When heated in
boiling benzene, the mixture of atropoisomeric aldehydes reacts with triphenylphosphine to afford a mixture of
2-[(N-acetyl)-N-(2-iodophenyl)]aminopropanal atropisomers in 1:3 ratio.
DOI: 10.1134/S1070363213020217
The substituted N-(1-methylbut-2-en-1-yl)anilines
are used to obtain a wide range of ortho-derivatives via
the aromatic Claisen aminorearrangement of the
hindered indolines and substances with the pronounced
anti-phytophthora activity [1]. The presence of olefin
C=C bonds in these compounds make it possible to
perform a number of oxidation reactions. The products
of ozonation of these compounds can be reduced with
borohydride to give phenylaminopropanal [2]. The N-
allylaniline derivatives are known to be used in the
construction of heterocyclic compounds via the metal-
catalyzed cyclization, and most of publications in this
respect are reviewed in [3].
I
I
O
O
PPh3 _Ph3P=O
N
N
O
CH3
H3C
II
I
(2-iodophenyl)-N-[(2E)-1-methylbut-2-en-1-yl]acetamide
[syn- and anti-IVa] in a 1:1 ratio in a 85% yield. Since
the subsequent studies revealed some unusual
transformation, we have also obtained atropisomers of
N-(2-iodophenyl)-N-[(2E)-1-methylbut-2-en-1-yl]acet-
amide (syn- and anti-IVb) containing acetyl group at
the nitrogen atom by the reaction of amine III with
acetic anhydride. An individualization of atropisomers
syn-IV and anti-IV is not possible due to the low
energy barrier to transition into each other, although
they can be detected on the TLC plates due to the
slightly different Rf values.
The 1H NMR spectrum of a mixture of atro-
pisomers IVa and IVb contains a double set of the
signals. The signals of methyl groups of pentenyl
moiety are differentiated most clearly. The signals of
the methyl group at the C4' carbon atom of atropisomer
IVa are observed at 1.02 (d, J 7.2 Hz) and 1.35 ppm
(d, J 6.7 Hz). The signals at 1.46 (d. d, J1 1.0, J2
6.5 Hz) and 1.63 ppm (d, J 6.2 Hz) belong to the
In this work we present some results on acylation of
N-(1-methylbut-2-en-1-yl)-2-iodoanilines, ozonation
of the obtained derivatives followed by reduction to
the aldehydes, and on the reaction of the resulting alde-
hydes with triphenylphosphine.
In order to obtain N-(1-methyl-2-oxoethyl)-N-(2-
iodophenyl)-2-(Р,Р,Р-triphenyl)phosphinydeneacetamide
I, which could be used for the preparation of 1-(2-
iodophenyl)-5-methyl-1,5-dihydrogen-2H-pyrrol-2-one
II by the Wittig reaction, we synthesized the chloro-
acetyl derivative of N-(2-iodophenyl)-N-[(2E)-1-methyl-
but-2-en-1-yl]amine III.
The reaction of amine III with chloroacetyl chlo-
ride results in an atropisomers mixture of 2-chloro-N-
368

SYNTHESIS AND REACTIONS OF N-ACETYL-...
369
ClCH2COCl
CH3
CH3
O
CH3
O
CH3
K2CO3
or
Ac2O
H
N
H
N
I
X
X
CH3
CH3
+
CH2Cl2
I
I
N
H
syn-IVa, IVb
X = Cl (a), X = H (b).
anti-IVa, IVb
III
protons of CH3-group located at the С2' carbon atom of
phosphine in benzene, transformation into the ylides I
of N-(2-iodophenyl)-N-[(2E)-1-methylbut-2-en-1-yl]acet-
amide phosphonium salts VI and subsequent Wittig
olefination failed. The compound VI was not obtained.
the double bond. The CH2Cl-protons are magnetically
1
non-equivalent, so in the H NMR spectrum there are
two groups of the well-resolved signals at 3.51 (d, Jgem
13.4 Hz) and 3.72 ppm (d, Jgem 13.4 Hz) for one, and at
3.57 (d, Jgem 13.5 Hz) and 3.78 ppm (d, Jgem 13.05 Hz)
for the other atropisomer of IVa. Assignment to the
atropisomers was done based on the geminal spin-spin
coupling constants of the protons. Other proton signals
of these molecules resonate in the overlapping areas.
In the 13C NMR spectrum of an atropisomers IVb
mixture, as in the case of N-chloroacetyl analog, the
signals are also doubled. The C2 carbon atom of the
aromatic rings resonates as a singlet at 103.3 ppm. In
addition, some signals of the aromatic carbon atoms
are overlapped. For this reason, the 13C NMR spectrum
does not contain a double set of the signals for the С3,
С4, С5, С6, С2' and С3' atoms.
Moreover, a reduction reaction occurred where the
halogen atom was replaced with a hydrogen atom.
When recovering the unreacted compound V we
isolated a significant amount of a mixture of syn- and
anti-atropisomers of N-(2-iodophenyl)-N-(1-methyl-2-
hydroxyethyl)acetamide VII. Since the heating in
benzene was performed without isolation from
atmospheric moisture, the water molecule may
participate in this reaction. One proton of the water
molecule is involved into the atropisomers formation
and the other “leaves” with the chlorine anion as HCl.
The oxygen atom migrates to triphenylphosphine and
facilitates the separation of the latter as triphenyl-
phosphine oxide. During the prolonged heating of the
reaction mixture we registered by TLC the formation
of a large amount of Ph3P=O. The reduction of
phosphonium ylide into a methyl group was observed
in [7], but the occurrence of such process at the stage
of the formation of quaternary triphenylphosphonium
salt was not previously described.
The reduction of the ozonated atropisomers IVa
with dimethyl sulfide results in a mixture of syn- and
anti-atropisomers of 2-chloro-N-(2-iodophenyl)-N-(1-
methyl-2-hydroxyethyl)acetamide V in a ratio of 1:3.
By analogy with the known fact that in the spectrum of
the syn-atropisomer the signal of the proton at the
carbon atom bound to the nitrogen atom is in a
stronger field than in the anti-isomer V [4–6], it was
concluded that the syn-isomer of V (δ 4.11 ppm) is the
minor one. The quartet signal at δ 4.33 ppm is assigned
to the H2' proton of the major anti-isomer. There is no
spin-spin coupling between this proton and the proton
of the aldehyde group.
In the 13C NMR spectrum of this atropisomers
mixture there is a similar doubling of all the signals of
the carbon atoms. The aldehyde carbon atom appears
at 197.5 (anti-isomer) and 198.3 ppm (syn-isomer).
The assignment is done by an explicit predominance of
the first signal.
The reduction of the ozonated atropisomers IVb
mixture under similar conditions gives rise to a
mixture of syn- and anti-atropisomers of VII in a ratio
of 1:3 in 61% yield.
Thus, the substitution of the chlorine atom by the
hydrogen atom was revealed in obtaining a quaternary
phosphonium salt from PPh3 and 2-chloro-N-(2-
iodophenyl)-N-(1-methyl-2-hydroxyethyl)acetamide.
EXPERIMENTAL
The IR spectra were recorded on a FT-IR Prestige-
21 Shimadzu spectrophotometer. The 1H and 13C NMR
spectra were taken on a Bruker AM 300 (300.13 and
75.45 MHz) and Bruker Avance III 500 (500.13 and
125.73 MHz) instruments with respect to internal
The attempts to obtain N-phenylpyrrole II from the
atropisomers V via the reaction with triphenyl-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 2 2013

370
SKLADCHIKOV, GATAULLIN
O
CH3
O
O
H
H
CH3
CH3
(1) O3, _5oC
(2) Me2S
O
O
Cl
Cl
Cl
N
CH3
N
N
+
I
I
I
CH2Cl2
_5oC
syn-IVa, anti-IVa
syn-V
anti-V
PPh3
benzene
reflux
Cl_
Ph3P+
O
H
Cl_
Ph3P+
O
H
CH3
CH3
O
O
N
N
+
I
I
syn-VI
anti-VI
_HCl
_Ph3P=O
H2O
O
CH3
O
O
H
H
N
CH3
CH3
(1) O3, _5oC
(2) Me2S
O
O
H3C
N
CH3
H3C
N
H3C
I
+
I
I
CH2Cl2
_5oC
syn-IVb, anti-IVb
syn-VII
X = Cl (a), X = H (b).
anti-VII
1
TMS. The elemental analysis was performed on a
CHN Analyzer M-185B. The purity of the samples
was determined on a Chromos GC-1000 complex
using helium as a carrier gas, flame-ionization
detector, column 1 m × 3 mm, 5% SE 30 on a Chro-
maton N-AW carrier. TLC analysis was performed
using Sorbfil plates (Sorbpolimer, Krasnodar) and
detecting with UV irradiation (λ 254 nm) or in iodine
vapor.
(2 mm Hg). Н (CDCl3), δ, ppm: 1.30 d (3H, CH3, J
6.7 Hz), 1.55 d (3H, CH3, J 6.2 Hz), 3.85 m (1H, H4'),
4.05 br. s (1H, NH), 5.35 d. d (1H, H3, J 4.4, 15.5 Hz),
5.55 d. q (1H, H2, J 6.2, 15.5 Hz), 6.35 d. d (1H, ArH,
J 7.2, 7.8 Hz), 6.52 d (1H, ArH, J 8.3 Hz), 7.05 d. d
(1H, ArH, J 7.2, 8.3 Hz), 7.55 d (1H, ArH, J 7.8 Hz).
13С NMR spectrum (CDCl3), δС, ppm: 16.9, 17.7, 17.9,
19.8 (CH3); 43.5, 43.6 (CH2Cl); 54.2, 56.5 (C4'), 103.3
(С2); 127.8, 128.3, 128.6, 129.5, 130.4, 130.7, 130.9,
131.1, 140.4 (С3, С4, С5, С6, С2', С3'), 141.0, 141.6
(C1), 165.2, 165.5 (N–C=O). Found, %: C 45.90; H
4.88; I 44.07; N 4.82. C11H14IN. Calculated, %: C
46.01; H 4.91; I 44.20; N 4.88.
N-(2-Iodophenyl)-N-[(2E)-1-methylbut-2-en-1-
yl]amine (III). To a solution of 20.5 g (94 mmol) of 2-
iodoaniline in 50 ml of triethylamine were added 15 g
of chloropentene. The reaction mixture was boiled for
10 h. The triethylamine excess was removed on a
rotary evaporator. To the residue was added a solution
of 20 g of NaOH in 100 ml of H2O. The organic layer
was separated, dried with KOH, concentrated. and
distilled in a vacuum. Yield 24 g (89%), bp 135–140°C
2-Chloro-N-(2-iodophenyl)-N-[(2E)-1-methylbut-
2-en-1-yl]acetamide (IVa) (atropisomers mixture). To
a solution of 5.94 g (20 mmol) of amine III in 30 ml of
anhydrous CH2Cl2 was added 2.5 g of chloroacetyl
chloride (1.8 ml) in 5 ml of CH2Cl2 and 2.76 g
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 2 2013

SYNTHESIS AND REACTIONS OF N-ACETYL-...
371
(40 mmol) of K2CO3 under stirring. The reaction
progress was monitored by TLC (C6H6–EtOAc, 95:5).
After the disappearance of the starting amine, to the
reaction mixture was added H2O, the product was
extracted with CH2Cl2 (100 ml). The organic layer was
washed with water, dried over Na2SO4. The solvent
was evaporated, and the residue was chromatographed
on a silica gel eluting with benzene. Yield 6.2 g (85%),
kept for 2 h. Then the solvent was evaporated, and the
residue was chromatographed on a silica gel eluting
with a С6H6–EtOAc mixture (10:1). Yield 1.9 g (54%),
1
viscous substance, Rf 0.3 (С6H6:EtOAc = 19:1). H
NMR spectrum (CDCl3), δ, ppm: 1.55 d (3H, CH3, J
7.3 Hz), 3.77 d (1H, H2'''A, Jgem 13.7 Hz), 3.78 d (1H,
minor, H2''A, J 13.5 Hz), 3.87 d (1H, H2''B, J 13.7 Hz),
3.92 d (1H, minor, H2''B, J 13.5 Hz), 4.11 q (1H, minor,
H2, J 7.3 Hz), 4.33 q (1H, H2, J 7.3 Hz), 7.15–7.55 m
(ArH), 7.97–8.03 m (ArH), 9.82 s (1H, minor, CHO),
9.87 s (1H, CHO). 13C NMR spectrum (CDCl3), δС,
ppm: 11.2, 13.6 (CH3); 42.1, 42.4 (CH2Cl); 63.2, 65.2
(C2); 101.0, 101.1 (C2'); 128.1, 130.1, 130.3, 130.4,
130.6, 130.8, 131.0, 140.4 (C3', C4', C5', C6'), 140.6,
141.1 (C1'); 166.2, 166.3 (N–C=O); 197.5, 198.3
(CHO). Found, %: C 37.47; H 3.11; Cl 10.01; I 36.00;
N 3.93. C11H11ClINO2. Calculated, %: C 37.58; H
3.15; Cl 10.08; I 36.10; N 3.98.
1
Rf 0.5 (C6H6). Н (CDCl3), δ, ppm: 1.02 d (3Н, СН3, J
7.2 Hz), 1.35 d (3Н, СН3, J 6.7 Hz), 1.47 d. d (3Н,
СН3, J1 1.0, J2 6.5 Hz), 1.64 d (3Н, СН3, J 6.2 Hz);
3.51 d, 3.55 d, 3.71 d, 3.79 d (2Н, СH2Cl, Jgem 13.2
Hz), 4.85–5.69 m (3Н, Н4', H2'C=CH3'), 7.03 t. t (ArH,
J1 1.5, J2 7.5 Hz), 7.20 d. t (ArH, J1 1.5, J2 7.5 Hz),
7.32–7.39 m (1Н, ArН), 7.84–7.90 m (ArH). 13С NMR
spectrum (CDCl3), δС, ppm: 16.9, 17.7, 17.9, 19.8
(СН3), 43.5, 43.6 (СН2Cl); 54.2, 56.5 (С4'), 103.3 (С2);
127.8, 128.6, 129.5, 130.4, 130.7, 130.9, 131.1, 140.4
(С3, С4, С5, С6, С2', С3'); 141.0, 141.6 (С1), 165.2,
165.5 (N–C=O). Found, %: C 42.82; H 4.11; Cl 9.68; I
34.78; N 3.80. C13H15ClINO. Calculated, %: C 42.94;
H 4.16; Cl 9.75; I 34.90; N 3.85.
N-(2-Iodophenyl)-N-(-1-methyl-2-oxoethyl)acet-
amide (VII) (atropisomers mixture, 1:3). a. A solution
of 1.41 g (4 mmol) of amide V and 1.05 g (4 mmol) of
PPh3 in 8 ml of toluene was refluxed for 39 h. Then the
solvent was evaporated, and the residue was
chromatographed on a silica gel eluting with a С6H6–
EtOAc mixture (10:1). 0.6 g (43%) of the starting
amide V was recovered. Yield 0.31 g (24%).
N-(2-Iodophenyl)-N-[(2E)-1-methylbut-2-en-1-yl]-
acetylamide (IVb) (atropisomers mixture). To a
solution of 1.59 g (5.78 mmol) of amine III in 30 ml
of anhydrous CH2Cl2 was added 1 ml (12 mmol) of
Ac2O. After 24 h, the reaction mixture was diluted
with H2O (20 ml) and then extracted with CHCl3
(100 ml). The organic layer was washed with water
and dried over Na2SO4. The solvent was evaporated,
and the residue was chromatographed on a silica gel
eluting with benzene. Yield 0.97 g (55%), Rf 0.5
b. Compound VII was obtained similarly to amide
V via the ozonation and subsequent reduction with
dimethylsulfide, 3.29 g (13 mmol) of atropisomers
mixture IVb in CH2Cl2. Yield 1.9 g (61%), amorphous
powder, Rf 0.2 (С6H6:EtOAc=19:1). 1H NMR spectrum
(CDCl3), δ, ppm: 1.40 d (3H, CH3, J 7.2 Hz), 1.77 s
(3H, CH3), 1.82 s (3H, CH3), 3.99 q (1H, minor, H2, J
7.4 Hz), 4.07 q (1H, H2, J 7.4 Hz), 7.05–7.35 m (ArH),
7.40 d (1H, syn-, ArH, J 8.0 Hz), 7.83 d (1H, anti-,
ArH, J 8.0 Hz), 9.75 s (1H, syn-, CHO), 9.80 s (1H,
anti-, CHO). 13C NMR spectrum (CDCl3), δС, ppm:
11.6, 14.0 (CH3); 22.6, 22.8 (CH3); 62.9, 64.4 (C2);
101.3, 101.5 (C–I); 128.8, 129.2, 130.0, 130.1, 130.3,
130.4, 138.8, 140.4 (C3', C4', C5', C6'); 143.2, 144.4
(C1'); 170.6, 170.9 (N–C=O); 198.3, 199.2 (CHO).
Found, %: C 41.56; H 3.75; I 39.87; N 4.35.
C11H12INO2. Calculated, %: C 41.66; H 3.81; I 40.02;
N 4.42.
1
(C6H6). Н NMR spectrum (CDCl3), δ, ppm: 1.09 d
(3Н, СН3, J 7.1 Hz), 1.40 d (3Н, СН3, J 6.5 Hz), 1.55
d (3Н, СН3, J 6.4 Hz), 1.72 d (3Н, СН3, J 5.9 Hz),
1.78 s (3H, CH3), 1.82 s (3H, CH3), 5.05 quintet (1H,
CH, J 7.1 Hz), 5.19–5.33 m (2H, CH, HC=C), 5.54–
5.67 m (3H, HC=CH, C=CH), 7.07 t (ArH, J 7.5 Hz),
7.22 d (ArH, J 7.7 Hz), 7.36–7.45 m (ArH), 7.92–7.99
m (ArH). Found, %: C 47.31; H 4.85; I 38.41; N 4.18.
C13H15ClINO. Calculated, %: C 47.43; H 4.90; I 38.55;
N 4.26.
2-Chloro-N-(2-iodophenyl)-N-(-1-methyl-2-oxo-
ethyl)acetamide (V) (atropisomers mixture). Through
a solution of 3.63 g (10 mmol) of the atropisomers IVa
mixture in 40 ml of CH2Cl2 was passed an ozone-
oxygen mixture for 11.1 min (54 mmol h–1) at –5°C.
Then the reaction mixture was purged with argon for
1 min. After 20 min, to the reaction mixture was added
2 ml of dimethyl sulfide, and the reaction mixture was
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