Zirconium(IV) chloride-mediated chemoselective conjugate addition of aliphatic amines to α,β-ethylenic compounds

Article abstract of DOI:10.1080/00397910500451423

Zirconium chloride efficiently catalyzes the conjugate addition of a variety of aliphatic amines to α,β-unsaturated ester, nitriles, and ketones to give the corresponding β-amino derivatives in excellent yields under mild reaction conditions. Aromatic amines do not participate in this transformation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500451423

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Zirconium(IV) Chloride–Mediated
Chemoselective Conjugate Addition of
Aliphatic Amines to α,β‐Ethylenic Compounds
H. M. Meshram a , C. Lakshindra a , P. N. Reddy a , K. Sadashiv a & J. S.
Yadav a
a Organic Chemistry Division‐I, Indian Institute of Chemical Technology,
Hyderabad, India
Published online: 16 Aug 2006.
To cite this article: H. M. Meshram , C. Lakshindra , P. N. Reddy , K. Sadashiv & J. S. Yadav (2006):
Zirconium(IV) Chloride–Mediated Chemoselective Conjugate Addition of Aliphatic Amines to α,β‐Ethylenic
Compounds, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:6, 795-801
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Synthetic Communicationsw, 36: 795–801, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500451423
Zirconium(IV) Chloride–Mediated
Chemoselective Conjugate Addition of
Aliphatic Amines to a,b-Ethylenic
Compounds
H. M. Meshram, C. Lakshindra, P. N. Reddy,
K. Sadashiv, and J. S. Yadav
Organic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad, India
Abstract: Zirconium chloride efficiently catalyzes the conjugate addition of a variety
of aliphatic amines to a,b-unsaturated ester, nitriles, and ketones to give the corre-
sponding b-amino derivatives in excellent yields under mild reaction conditions.
Aromatic amines do not participate in this transformation.
Keywords: Amines, Michael addition, a,b-unsaturated compounds, zirconium(IV)
chloride
INTRODUCTION
As a result of its vast range of applications,[1] the synthesis of b-amino
carbonyl compounds and their derivatives have attracted much attention in
organic synthesis.[2] The conjugate addition method is frequently utilized to
prepare b-amino carbonyl derivatives. However, the conjugate addition
requires basic or acid catalysts.[3] A Lewis acid–induced addition of amines
to a,b-ethylenic compounds has been reported.[4] The metal-catalyzed
reactions to prepare b-amino carbonyl compounds have been studied.[5]
Many of these methods are fraught with difficulties.
Received in the USA September 1, 2005
Address correspondence to H. M. Meshram, Organic Chemistry Division-I, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. Fax: þ091 40 7170512;
E-mail: hmmeshram@yahoo.com
795

796
H. M. Meshram et al.
Recently, zirconium(IV) chloride has gained wide popularity as a mild
and efficient Lewis acid catalyst for various organic transformations.[6–12]
In continuation of our interest in zirconium chloride–catalyzed reaction,
herein we report the chemoselective-conjugated addition of aliphatic amines
to a,b-ethylenic compounds.
RESULTS AND DISCUSSION
Treatment of morpholine with methyl acrylate in the presence of zirconium
chloride(IV) (10 mol%) in dichloromethane resulted in the formation of
addition product in almost quantitative yield at ambient temperature
(Scheme 1). A variety of aliphatic amines were reacted with a,b-unsaturated
esters, nitrites, and ketones to produce the corresponding Michael adducts. In
all the cases, the starting materials were consumed within 2–4 h at room temp-
erature, giving rise to addition products in good yields. Although the reaction
did proceed with 5 mol% of zirconium(IV) chloride, we reasoned that
10 mol% was optimum for completion of the reaction. The results are sum-
marized in Table 1.
Secondary cyclic amines such as morpholine, piperidine, pyrrolidine, and
piperizine showed higher reactivity than their acyclic counterparts. Piperazine
gave the bis-addition product. Primary amines such as benzylamine and buty-
lamine reacted smoothly, leading to the conjugated addition products.
We also demonstrated the chemoselective addition of aliphatic amines to
a,b-ethylenic compounds in the presence of aromatic amines (Scheme 2).
When an equimolar mixture of aniline and pyrrolidine was exposed to methy-
lacrylate in the presence of ZrCl4 the pyrrolidine adduct was obtained as a
single product. Several aromatic amines such as p-chloroaniline, p-hydroxya-
niline, and p-nitroaniline were subjected to this reaction, and we found that in
all cases Michael addition proceeded only at aliphatic amines. This result
clearly shows that the Lewis acidity of zirconium(IV) chloride is suitable
only for active aliphatic amines. This selectivity could be useful to distinguish
the two types of amines in synthetic applications.
In summary, we have developed a simple and efficient method for the
synthesis of b-amino derivatives using inexpensive zirconium(IV) chloride
as a mild catalyst.
Scheme 1.

Table 1. Zirconium(IV) chloride–catalyzed Michael addition of aliphatic amines with a,b-ethylenic compounds
Entry
Amines
Unsaturated
Producta
Time (h)
Yieldb (%)
Quant.
Lit.c
2a
1
1.0
2
3
2.5
92
—
2b
0.75
Quant.
4
2.0
86
—
—
5
6
1.5
2.0
78
94
—
(continued)

Table 1. Continued
Entry
Amines
Unsaturated
Producta
Time (h)
3.0
Yieldb (%)
Lit.c
2a
7
83
8
2.0
79
—
9
10
11
3.0
80
82
84
2b
—
2b
2.5
0.75
1
aAll the products were characterized by H NMR mass, and IR spectral data.
bIsolated yields.
cPhysical and spectral data agree with those reported in the literature.

Chemoselective Conjugate Addition of Aliphatic Amines
799
Scheme 2.
EXPERIMENTAL
Melting points were determined on Buchi R535 apparatus and are uncor-
rected. IR spectra were recorded on either a Perkin-Elmer spectrophotometer
1
or the IR Nicole 740 FT-IR. H NMR was recorded on a Gemini 200-MHz
instrument using TMS as an internal standard. M/s were recorded on a
Micromass 7070 h or a Finnigan Mat 1020 B mass spectrometer operating
at 70 eV. Thin-layer chromatography was done on precoated silica-gel 60f
254 (0.5 mm) glass plates.
General Procedure
A mixture of morpholine (1 mmol), methyl acrylate (1.2 mmol), and
zirconium(IV) chloride (10 mol%) in anhydrous dichloromethane (10 mL)
was kept at ambient temperature under stirring for 1 h. It was quenched
with water and the organic layer separated. The aqueous layer was extracted
with dichloromthane. The combine organic layer was washed with water,
dried over sodium sulphate, and concentrated to give the crude product,
which was purified by silica-gel column chromatography using ethyl
acetate–pet. ether (1 : 9).
SPECTRAL DATA FOR UNKNOWN COMPOUNDS
Ethyl 3-(4-phenylhexahydro-1-1pyrazinyl) propanoate (entry 2): 1H NMR
(200 MHz, CDCl3) d: 1.25 (t, J ¼ 7.2 Hz, 3 H), 2.52 (t, J ¼ 7.5 Hz, 2 H), 2.64
(t, J ¼ 4.9 Hz, 4 H), 2.74 (t, J ¼ 7.5 Hz, 2 H), 3.02 (t, J ¼ 4.9 Hz, 4 H), 4.10
(q, J ¼ 7.2 Hz, 2 H), 7.27–7.45 (m, 5 H); 13C NMR: d 13.8, 32.6, 49.4,
47.2, 53.4, 59.6, 116.4, 120.7, 127.1, 148.0, 171.2; mass (EI) m/z: 262
(Mþ); anal. calcd for C15H22N2O2: C, 68.67; H, 8.45; N, 10.68; found: C,
68.80; H, 8.24; N, 10.47%.
3-[(tert-Butoxycarbonyl) amino] hexahydro-1-1pridinyl-ethyl cyanide
(entry 4): 1H NMR (200 MHz, CDCl3) d: 1.42 (s, 9 H), 2.22–2.70
(m, 12 H), 3.70(brs, 1 H), 4.95 (m, 1 H); 13C NMR: (14.9, 20.2, 28.2, 29.4,
46.2, 53.0, 53.2, 60.1, 156.6; mass (EI) m/z: 253 (Mþ); anal. calcd for
C13H23N3O2: C, 61.63; H, 9.15; N, 16.59; found: C, 61.69; H, 9.33; N, 16.77%.

800
H. M. Meshram et al.
4-Hexahydro-1-pyridinyl-2-butanone (entry 5): 1H NMR (CDCl3,
200 MHz,) d: 1.38–1.50 (m, 6 H), 2.25–2.36(m, 4 H), 2.52 (s, 3H), 2.61–
2.86 (m, 4 H); 13C NMR: d 24.5, 26.2, 29.3, 39.8, 52.6, 55.4, 206.2; mass
(EI) m/z: 155 (Mþ); anal. calcd. for C9H17NO: C, 69.63; H, 11.04; N, 9.02;
found: C, 69.52; H, 11.06; N, 9.04%.
Ethyl 3-tetrahydro-1H-1-pyrrolylpropanoate (entry 6): 1H NMR (CDCl3,
200 MHz) d: 1.22 (t, J ¼ 7.0 Hz, 3 H), 1.62–1.83 (m, 4 H), 2.64–2.72
(m, 2 H), 2.79–2.90 (m, 4 H), 2.96–3.10 (m, 2 H), 4.08 (q, J ¼ 7.0 Hz, 2 H);
13C NMR: d 14.2, 23.6, 32.7, 47.2, 52.4, 58.8, 169.2; mass (EI) m/z: 171
(Mþ); anal. calcd. for C9H17NO2: C, 63.13; H, 10.01; N, 8.18: Found: C,
63.26; H, 10.28; N, 8.24%.
Methyl 3-(2-methoxycarbonylethylanilino) propanoate (entry 8): 1H NMR
(CDCl3, 200 MHz,) d: 2.45 (t, J ¼ 6.8 Hz, 4 H), 2.80 (t, J ¼ 6.8 Hz, 4 H), 3.59
(s, 2 H), 3.62 (s, 6 H), 7.15–7.32 (m, 5 H); 13C NMR: d 32.6, 49.2, 51.4, 58.3,
63.6, 127.0, 128.2, 128.6, 172.8; mass (EI) m/z: 279 (Mþ); anal. calcd. for
C15H21NO4: C, 64.50; H, 7.58; N, 5.01: found: C, 64.25; H, 7.62; N, 5.11%.
Methyl 3-butyl (2-methyloxycarbonylethyl) aminopropanoate (entry 10):
1H NMR (CDCl3, 200 MHz,) d: 0.88 (t, J ¼ 6.8 Hz, 3 H), 1.23–1.45 (m, 4 H),
2.35–2.44 (m, 6 H), 2.75 (t, J ¼ 6.9 Hz, 4 H), 3.65 (s, 6 H); 13C NMR: d 13.6,
20.1, 29.1, 32.3, 49.1, 53.3, 172.5; mass (EI) m/z: 245 (Mþ); anal. calcd. for
C12H23NO4: C, 58.75; H, 9.45; N, 5.71; found: C, 58.60; H, 9.49; N, 5.75%.
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