α-bromination of β-enamino compounds using K-10

Article abstract of DOI:10.1055/s-2001-17702

A series of α-bromo 3-amino-5,5-dimethylcyclohex-2-en-1-ones 2a-g and α-bromo β-enamino compounds 4a, b have been conveniently prepared using NBS supported on montmorillonite (K-10). Other reaction conditions such as di-tert-butyl peroxide/NBS/CCl₄

Full text of DOI:10.1055/s-2001-17702

SHORT PAPER
1935
-Bromination of -Enamino Compounds Using K-10
M
-Bromination of -En
a
amino Com
r
pounds
a
U
sing
K
-10 E. F. Braibante,* Hugo T. S. Braibante, Giovanni B. Rosso, Juliano K. da Roza
Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil
Fax +55(55)2208031; E-mail: mara@quimica.ufsm.br
Received 6 April 2001; revised 20 June 2001
Abstract: A series of -bromo 3-amino-5,5-dimethylcyclohex-2-
en-1-ones 2a–g and -bromo -enamino compounds 4a, b have
been conveniently prepared using NBS supported on montmorillo-
nite (K-10). Other reaction conditions such as di-tert-butyl perox-
ide/NBS/CCl4, and Br2/CH2Cl2 were also studied for 3-amino-5,5-
dimethylcyclohex-2-en-1-ones 1b, e, g resulting in a mixture of
mono and di-brominated compounds 5b, f, g and 6b, e, g.
Key words: -enamino compounds, montmorillonite, bromination,
halogenation
Scheme 1
We have previously reported the efficient use of support-
ed reagents in the synthesis of a series of -amino unsat- successfully applied to -amino , -unsaturated ketone
urated ketones and esters. These compounds have been and ester 3a and 3b, respectively, resulting in -brominat-
conveniently prepared in our laboratory using a solid sup- ed compounds 4a, b (Scheme 2).
port method by dispersing primary amines and 1,3-dike-
tones or 1,3-ketoesters on K-101 coupled with an
ultrasound technique.2-4 In continuation of our investiga-
tion exploring the use of supported compounds we report
herein the results of our studies on bromination of
-
enamino ketones with the fixed configuration trans-s-
trans and acyclic enamino compounds cis-s-cis using N-
bromosuccinimide supported on montmorillonite.
The -enamino ketones 1a-g were prepared by reaction of
dimedone and the corresponding amines dispersed on K-
10 under microwave irradiation, 155 MHz for 3 minutes.
For the volatile amines (R = H, Me, i-Pr, Bn and allyl),
their acetate derivatives were used.7
Scheme 2
Bromination with N-bromosuccinimide and di-tert-butyl
peroxide were used to evaluate the reactivity of the allylic
position of the trans-s-trans -enamino ketones. The -
enamino ketones 1b, e–g were chosen for the study of
these reactions because they contain saturated acyclic
(R = Me), aromatic (R = Ph), benzylic and acyclic unsat-
urated (R = allyl) groups as the nitrogen substituents.
These starting materials gave a mixture of mono-bromi-
nated compounds in the vinylic position 2b, f, g or di-bro-
minated in the allylic position, 5b, e–g, except for the -
enamino ketone 1e for which only product 5e was isolated
(Scheme 3). The formation of only the di-brominated
compound 5e can be attributed to the conjugation of the
pair of electrons on the nitrogen atom with the aromatic
system of its substituent, which causes the vinyl amide
character to diminish. The use of NBS as bromination
agent with -enamino ketones gave only substitution
products.
The conventional methods described for the bromination
of enamino compounds use NBS/MeOH, Br2/CCl4 or
BrCN5,6 give rise to different products such as salts, mono
and di-bromination with variable yields and show a de-
pendence upon the nature of N-substituent and reaction
conditions. In this work, we describe the selective -mono
bromination of 3-amino-5,5-dimethylcyclohex-2-en-1-
one 1a–g with NBS supported on K-10 to afford -bromi-
nated 2a–g (Scheme 1). When this reaction was per-
formed without using the solid support, in MeOH/H2O
solvent, the isolation of the products was difficult. The use
of NBS/K-10 has advantages over the traditional proce-
dures; decreased reaction time of 5 hours, and the simple
work-up. The isolation is simplified because the succin-
imide formed during the reaction is adsorbed onto the sup-
port and thus filtration is sufficient. This method was
Synthesis 2001, No. 13, 08 10 2001. Article Identifier:
1437-210X,E;2001,0,13,1935,1937,ftx,en;M01901ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1936
Table
M. E. F. Braibante et al.
SHORT PAPER
-Bromo 3-Amino-5,5-dimethylcyclohex-2-en-1-one 2a–g, 4a, b, 5b, e–g and 6a Preparation
Product Yieldb(%) Mp(°C)
1H NMR (200 MHz, CDCl3)
(ppm), J (Hz)
13C NMR (75 MHz, CDCl3)
(ppm)
2ac
2b
2c
60
74
74
38
204–206
177–179
90–92
0.97 (s, 6 H), 2.20 (s, 2 H), 2.42 (s, 2 H), 6.67 (br, 27.50, 31.74, 42.70, 50.24, 91.10, 160.83, 185.95
1 H), 7.47 (br, 1 H)
1.11 (s, 6 H), 2.39 (s, 2 H), 2.43 (s, 2 H), 3.02 (d, 28.20, 30.18, 31.76, 39.88, 50.16, 93.94, 160.18,
3 H, J = 6.0), 5.70 (br, 1 H)
186.75
1.10 (s, 6 H), 1.28 (d, 6 H, J = 6.4), 2.39 (s, 2 H), 24.03, 28.18, 32.10, 40.15, 45.11, 50.34, 94.37,
2.44 (s, 2 H), 3.77 (m, 1 H), 5.52 (br, 1 H) 158.40, 186.83
2d
140–142
0.81 (s, 3 H), 1.01 (s, 3 H), 1.90 (d, 3 H, J = 6.8), 24.54, 27.34, 28.21, 31.86, 40.19, 50.18, 53.07,
2,14 (dd, 1 H, Jab = 16.5, Ha), 2.30 (s, 2 H), 2.42 95.10, 124.98, 127.47, 128.83, 143.27, 158.92,
(dd, 1 H, Jba = 16.5, Hb), 4.74 (quint, 1 H, J = 7.0, 187.08
6.8), 5.95 (d, 1 H, J = 7.2), 7.21–7.40 (m, 5 H)
2e
2f
70
69
61
40
40
52
158–159
186–188
115–116
81–84
1.05 (s, 6 H), 2.43 (s, 2 H), 2.44 (s, 2 H), 7.12–7.43 27.91, 32.74, 41.40, 50.69, 96.75, 125.74,
(m, 5 H)
126.85, 129.52, 137.28, 157.36, 188.15
1.04 (s, 6 H), 2.38 (s, 2 H), 2.41 (s, 2 H), 4.52 (d, 28.16, 32.11, 40.10, 47.11, 50.33, 95.16, 126.55,
2 H, J = 6.0), 6.07 (br, 1 H), 7.23–7.42 (m, 5 H) 127.96, 129.04, 137.18, 159.37, 187.33
2gd
4a
4b
5b
1.09 (s, 6 H), 2.17 (s, 4 H), 3.93 (m, 2 H), 5.24 (m, 28.18, 32.08, 39.75, 45.37, 50.34, 94.91, 116.89,
2 H), 5.89 (m, 1 H)
133.67, 159.51, 187.27
2.19 (s, 3 H), 2.38 (s, 3 H), 5.58 (br, 1 H), 10.26
(br, 1 H)
25.53, 30.00, 91.58, 160.11, 195.18
68–69
1.31 (t, 3 H, J = 7.0), 2.19 (s, 3 H), 4.19 (q, 2 H,
J = 7.0)
14.33, 25.03, 60.51, 78.52, 158.84, 166.91
Oil
1.22 (s, 3 H), 1.29 (s, 3 H), 2.33 (dd, 1 H,
25.08, 29.26, 29.84, 36.18, 46.05, 52.66, 96.06,
Jab = 16.0, Jax = 1.8, Ha), 2.78 (dd, 1 H, Jba = 16.0, 158.18, 186.19
Jbx = 0.8, Hb), 3.15 (d, 3 H, J = 5.4), 4.51 (d, 1 H,
Jxa = 1.8), 5.56 (br, 1 H)
5e
5f
63
53
176–178
Oil
1.18 (s, 3 H), 1.26 (s, 3 H), 2.40 (dd, 1 H,
24.62, 28.99, 36.17, 46.72, 53.00, 98.65, 127.43,
Jab = 17.0, Jax = 1.8, Ha), 2.78 (d, 1 H, Jba = 17.0, 128.04, 129.70, 136.32, 156.93, 187.15
Hb), 4.49 (d, 1 H, Jxa = 1.8, Hx), 7.13 (br, 1 H),
7.27–7.49 (m, 5 H)
1.02 (s, 3 H), 1.26 (s, 3 H), 2.31 (dd, 1 H,
24.66, 29.08, 36.11, 46.02, 46.71, 52.90, 96.72,
Jab = 16.8, Jax = 1.7, Ha), 2.74 (d, 1 H, Jba = 16.8, 126.56, 128.06, 129.02, 137.24, 157.65, 186.34
Hb), 4.44 (d, 1 H, Jxa = 1.7, Hx), 4.65 (dd, 1 H,
Jcd = 15.8, Hc), 4.67 (dd, 1 H, Jdc = 15.8, Hd), 6.07
(br, 1 H), 7.29–7.41 (m, 5 H)
5g
6
50
32
104–106
165–168
1.18 (s, 3 H), 1.26 (s, 3 H), 2.32 (dd, 1 H, Jax = 1.8, 24.52, 28.92, 35.97, 44.84, 45.88, 52.47, 95.93,
Jab = 16.8, Ha), 2.75 (dd, 1 H, Jbx = 0.8,
Jba = 16.8, Hb), 4.12 (m, 2 H), 4.51 (d, 1 H,
Jxa = 1.8, Hx), 5.25 (m, 2 H), 5.98 (m, 2 H)
116.52, 133.98, 157.87, 186.06
1.03 (s, 6 H), 2.25 (s, 2 H), 2.52 (s, 2 H), 3.71 (m, 27.54, 27.86, 35.30, 38.88, 39.48, 47.55, 50.10,
1 H), 3.83 (m, 1 H), 3.94 (m, 2 H), 4.61 (m, 1 H), 52.97, 93.49, 159.41, 185.85
6.89 (br, 1 H)
a All compounds gave satisfactory elemental analyses.
b Yield of pure isolated product.
c DMSO-d6.
d 1H and 13C NMR spectra were recorded on a 400 MHz spectrometer.
Synthesis 2001, No. 13, 1935–1937 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
-Bromination of -Enamino Compounds Using K-10
1937
Bromination with N-Bromosuccinimide/K-10; -Bromo -
Enamino Ketones 2a–g, 4a and -Bromo -Enamino Ester 4b;
General Procedure
N-Bromosuccinimide (3.5 mmol) was suspended in MeOH (6 mL)
and added to 3-amino-5,5-dimethylcyclohex-2-en-1-one 1a–g, 4-
amino penten-2-one 4a or ethyl 3-amino butenoate 3b (3 mmol) dis-
persed on K-10 (0.9 g; Fluka). The mixture was stirred at r.t. for 5
h. After completion of the reactions (TLC/CH2Cl2), the products
were extracted by washing the K-10 with CH2Cl2 (4 10 mL). The
combined organic layers were washed with sat. NaHCO3 (13 mL),
dried (MgSO4), filtered, and the solvent was removed under vacu-
um to yield the crude products. Solid compounds were recrystal-
lized from diisopropyl ether. Compound 2d was purified by column
chromatography on silica gel (Aldrich, 230–400 mesh) using
EtOAc–CH2Cl2 (1:1). Yields and NMR data are repoorted in the ta-
ble.
Scheme 3
The use of elementary bromine (Br2/Et2O) with enamines
to give mono-brominated products has been reported in
the literature.8 In order to analyze the effect of this reagent
on bromination of the -enamino ketones in this study, we
reacted Br2/CH2Cl2 with the -enamino ketones 1b, g. For
1b (R = Me), a mixture of substitution products 2 and 5
(1:2) was isolated; and for 1g (R = allyl), compound 6 re-
sulting from addition ( system of N-allyl) and substitu-
tion (on vinylogous carbon) was isolated (Scheme 4).
Bromination with Di-tert-butyl peroxide/N-Bromosuccinimide;
General Procedure
To a solution of 3-amino-5,5-dimethylcyclohex-2-en-1-one 1b, e–g
(2.1 mmol) in CCl4 (15 mL) was added di-tert-butyl peroxide (0.06
mmol) and N-bromosuccinimide (2.3 mmol, 0.40 g). The mixture
was heated with stirring at 120 °C for 15 h. The products were fil-
tered, washed with sat. NaHCO3, extracted with CH2Cl2 (4 10
mL), dried (MgSO4), filtered, and the solvent was removed under
vacuum to yield the crude products. For 5e the purification was per-
formed by recrystallization from diisopropyl ether–CH2Cl2. The
mixture of 2b and 5b, 2f and 5f, 2g and 5g were separated by col-
umn chromatography on silica gel (Aldrich, 230–400 mesh) using
hexane–CH2Cl2 (1:1) to give 2b (29%) and 5b (52%), 2f (23%), 5f
(53%), 2g (13%) and 5g (50%).
Bromination with Bromine; General Procedure
A solution of bromine (20 mmol) in CH2Cl2 (20 mL) was added
dropwise to a stirred solution of 1b or 1g under ice cooling, Pyridine
(20 mmol) in CH2Cl2 was added dropwise and the mixture was
stirred for 1 h. The reaction mixture was washed with H2O, then 0.1
M HCl, extracted with CH2Cl2 (4 10 mL), dried (MgSO4), and fil-
tered. The solvent was removed under vacuum to afford a mixture
(1:2) of 2b (25%), 5b (55%), or 6 (32%).
Acknowledgement
Scheme 4
We are grateful to the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), Brazil, for financial support. Ju-
liano K. da Roza thanks CNPq for a fellowship (PBIC).
The structures of the compounds were unambiguously es-
tablished based on their 1H and 13C NMR spectra (Table).
The use of the NBS/K-10 method for the bromination of
-enamino ketones compared with the other systems em-
ployed resulted in the regioselective synthesis of -bro-
mo-enaminones. The use of the solid support, K-10, in
these reactions facilitated the isolation of the products due
to adsorption of the succinimide formed during the reac-
tion.
References
(1) Braibante, M. E. F.; Braibante, H. S.; Missio, L.;
Andricopulo, A. Synthesis 1994, 898.
(2) Braibante, M. E. F.; Braibante, H. S.; Valduga, C. J.;
Squizani, A. Synthesis 1998, 1019.
(3) Braibante, M. E. F.; Braibante, H. S.; Valduga, C. J. J.
Heterocycl.Chem. 1997, 34, 1453.
(4) Braibante, M. E. F.; Braibante, H. S.; Valduga, C. J. J.
Heterocycl. Chem. 1998, 35, 189.
Mps were determined with a Microquímica APF-301 apparatus and
are uncorrected. 1H and 13C NMR spectra were recorded on a Bruk-
er DPX 200 and Bruker DPX 400 spectrometers in CDCl3 / TMS.
Elemental analyses were carried out on a Vario CHN-standard ana-
lyzer. Capillary GC analyses were performed on a Carlo Erba,
Mega Series 5400 chromatograph equipped with a split/splitless in-
jector and FID detector.
(5) Jirkovsky, I. Can. J. Chem. 1974, 55.
(6) Alberola, A.; Andrés, C.; Ortega, G. A.; Pedrosa, R.;
Vicente, M. Synth. Commun. 1986, 16, 1161.
(7) Rosso, G. B. M. Sc. Dissertation; Universidade Federal de
Santa Maria: Brazil, 2000.
(8) Pitchumani, K.; Venkatachlapathy, C. Tetrahedron 1997,
53, 2581.
Synthesis 2001, No. 13, 1935–1937 ISSN 0039-7881 © Thieme Stuttgart · New York