Samarium diiodide catalyzed aza-michael reactions for the formation of β-amino amides

Article abstract of DOI:10.2174/157017810790796255

Samarium diiodide is an efficient Lewis acid type catalyst for the 1,4-addition of aromatic amines onto α,β- unsaturated N-benzoyl amides affording new β-amino amides. These reactions are compared with similar aza-Michael additions involving α,β-unsaturat

Full text of DOI:10.2174/157017810790796255

94
Letters in Organic Chemistry, 2010, 7, 94-97
Samarium Diiodide Catalyzed Aza-Michael Reactions for the Formation of
ꢀ-Amino Amides
Iréna Reboule, Sophie Bezzenine-Lafollée, Jacqueline Collin*, Richard Gil and Myriam Martin
Equipe de Catalyse Moléculaire, ICMMO, UMR 8182, Université Paris-sud 11, 91405 Orsay, France
Received November 06, 2009: Revised December 24, 2009: Accepted January 02, 2010
Abstract: Samarium diiodide is an efficient Lewis acid type catalyst for the 1,4-addition of aromatic amines onto ꢀ,ꢁ-
unsaturated N-benzoyl amides affording new ꢁ-amino amides. These reactions are compared with similar aza-Michael
additions involving ꢀ,ꢁ-unsaturated-N-acyloxazolidinones.
Keywords: Samarium diiodide, catalysis, amines, Aza-Michael reaction, carbon-nitrogen bond formation.
INTRODUCTION
ꢁ,ꢂ-Unsaturated N-benzoylamides have been introduced
by Jacobsen et al. as useful chelating substrates for
enantioselective catalysis [10]. They have been successfully
employed in enantioselective aza-Michael reactions
involving cationic palladium catalysts [11]. With the aim to
increase the chemio- and enantioselectivities of aza-Michael
reactions we decided to investigate ꢁ,ꢂ-unsaturated N-
benzoylamides as substrates. p-Anisidine was selected as
ꢁ-Aminoacids are important building blocks for the
synthesis of biologically active molecules, [1] and can be
easily prepared by Mannich or aza-Michael reactions [2,3].
The latter are catalyzed by a variety of Lewis acids such as
transition metal [4] or lanthanide complexes [5]. We have
previously reported that samarium diiodide used in
MeO
OMe
MeO
O
O
10% SmI2(THF)2
CH2Cl2
OMe
NH
O
O
NH
O
R
N
O
R
N
R
N
O
H
NH2
1
4
2
3
Scheme 1.
methylene chloride is an efficient pre-catalyst for the
formation of carbon-nitrogen bonds [6]. Recently we studied
samarium diiodide-catalyzed aza-Michael additions of
amines onto ꢀ,ꢁ-unsaturated N-acyloxazolidinones which
afford two products, the aza-Michael adduct 3 and the amide
4 resulting from an amidation reaction by a second
equivalent of amine on the former (Scheme 1) [7]. The ratio
of adducts depends on the amine but also on the substituent
in the 4-position of the ꢁ,ꢂ-unsaturated N-acyloxazolidinone.
nucleophile since carbon–nitrogen bond of the adducts can
be easily cleaved [12]. Furthermore this amine furnished the
highest selectivities and enantioselectivities during our
previous investigations [9].
O
.(THF)2
I
Sm
O
With the aim to prepare enantioenriched products we
studied the catalysis of the above reactions by samarium
iodobinaphtholate 5 [8] Scheme 2 and reported high
enantiomeric excesses in some cases for aza-Michael
reactions [9]. N-acyloxazolidinone derived from fumaric
5
Scheme 2.
In this paper, we present studies concerning samarium
diiodide-catalyzed additions of p-anisidine onto ꢁ,ꢂ-
unsaturated N-benzoylamides and compare the results with
those obtained with unsaturated N-acyloxazolidinones.
ethyl ester afforded selectively the adduct
3
with
enantiomeric excesses up to 88% while mixtures of
compounds 3 and 4 were obtained using substrates with
electron-donor substituents. The use of an excess of amine
gave selectively the amide 4 but under racemic form.
RESULTS AND DISCUSSION
*Address correspondence to this author at the Equipe de Catalyse
Moléculaire, ICMMO, UMR 8182, Université Paris-sud 11, 91405 Orsay,
France; Fax: +33 1 69154680; E-mail: jacollin@icmo.u-psud.fr
Aza-Michael additions of p-anisidine onto a variety of
ꢁ,ꢂ-unsaturated N-benzolyamides 6 were performed in
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Samarium Diiodide Catalyzed Aza-Michael Reactions
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
95
methylene chloride using 10 mol% of samarium diiodide at
room temperature [13]. Two adducts can be formed, the aza-
Michael addition 7 and the amide 4 resulting from an
amidation reaction onto adduct 7 (Scheme 3 and Table 1).
We first examined the reaction of substrate 6a with methyl
substituted double bond using amine in stoichiometric or
substoichiometric quantities to avoid the formation of amide
4a. In these conditions both products 7a and 4a were formed
(entries 1 and 2). An increase in the amount of amine led to a
higher ratio of amide 4a (entry 4). Yet a large excess of
amine did not allow to prepare 4a selectively (entry 5). A
decrease in reaction temperature did not improve
significantly the selectivity in 7a (entry 3). Similarly the
substrate 6b with an isopropyl substituent on the double
bond afforded mixtures of adducts 7b and 4b whatever ratio
amine/substrate was employed (entries 6-9). With phenyl-
substituted substrate 6c the same ratio 7c/4c was observed
with different quantities of amine (entries 10, 11, 13). A
decrease in temperature allowed a slight increase in the
amount of 7c (entry 12). The 2-pyridinyl substituted
substrate 7d was selectively transformed in amide 4d
whatever quantity of amine 2 was employed (entries 14-16).
The N-benzoylamide 6e derived from fumarate ester
furnished equal amounts of adducts 7e and 4e using
stoichiometric amount of p-anisidine while amide 4e was
obtained as the sole product with an excess of this amine
(entries 17 and 18). For all reactions total conversion was
observed after 48 h. Interestingly using 5 mol% catalyst with
substrate 6a led to total conversion within 72 h and the ratio
7a/4a was not modified. The use of ꢀ,ꢁ-unsaturated N-
benzoylamides 6 led to mixtures of aza-Michael adducts 7
and amidation products 4 in nearly all cases. Adducts 7 have
thus been isolated in low yields due to difficulties of
separation from 4 and decomposition of products during
preparative chromatography.
During our previous investigations, we observed that
additions of p-anisidine onto ꢀ,ꢁ-unsaturated N-
acyloxazolidinones depend on the amount of amine and on
the nature of the substrate. Some results of reactions of p-
anisidine with ꢀ,ꢁ-unsaturated N-acyloxazolidinones in
similar conditions than with N-benzoylamides are reported in
the Table 1 for a comparison of the two Michael acceptors.
MeO
OMe
MeO
O
O
10% SmI2(THF)2
CH2Cl2
OMe
NH
O
O
NH
O
R
N
H
R
N
R
N
H
H
NH2
6
7
4
2
Scheme 3.
Table 1. Aza-Michael Reactions Catalyzed by Samarium Diiodide
Entry
2/6
or
R
Ratio 7/4 d
Ratios 3/4 c
Reaction
Products from 6
Reaction
Products from 1
2/1
1
2
0.8/1a
1.05/1 a,b
1.05/1 c
1.2/1 a
5/1 a
64/36
59/41
0/100
0/100
Me
7a, 4a
3a/4a
3
55/45
0/100 (93)
4
51/49
5
22/78
6
0.8/1 a
1.05/1 a
1.05/1 c
2/1 a
41/59
7
iPr
7b, 4b
7c, 4c
50(12)/50
70/30
8
9
24/76
10
11
12
13
14
15
16
17
18
0.8/1 a
28/72
a
1.05/1
Ph
3c/4c
Nrf
Nrf
25(8)/75(22)
50/50e
1.05/1 c
2/1 a
0.8/1 a
1.05/1 a
2/1 a
28/72
0/100
0/100 (27)
0/100
2-Py
7d, 4d
7e, 4e
1.2/1 a
5/1 a
CO2Et
50 (24)/50(45)
3e/4e
100/0
0/100
0/100 (70)
aReactions performed at room temperature using 10 mol% SmI2(THF)2 in CH2Cl2, see reference 13 for a typical procedure. bSame ratio 7/4 was obtained using 5 mol% SmI2(THF)2.
e
f
cReaction performed at 0°C. dRatios 7/4 and 3/4 were measured by NMR on crude products (yield, %). For this substrate at 0°C, 50% of starting material 6c was recovered. No
reaction.

96
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Reboule et al.
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Interestingly in the case of phenyl substituted substrates
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are currently under study.
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unsaturated N-benzoylamide
6 or ꢁ,ꢂ-unsaturated N-
acyloxazolidinones 1. The former substrates afford in most
cases a mixture of the Michael adduct 7 and its amidation
product 4. For a selective formation of the simple Michael
adduct oxazolidinone template should be preferred in the
case of substrates with electron withdrawing substituent on
the double bond. In the case of a donor substituent, higher
Michael adduct/amide ratio is obtained with N-
benzoylamides 6. Higher reactivity for aza-Michael reactions
is observed with ꢁ,ꢂ-unsaturated N-benzoylamides 6 than
with ꢁ,ꢂ-unsaturated N-acyloxazolidinones 1. Samarium
diiodide allows the preparation in mild conditions of various
ꢁ-aminoacid derivatives and especially of ꢁ-aminoamides by
aza-Michael reactions.
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ACKNOWLEDGEMENTS
The Centre National de la Recherche Scientifique
[CNRS] is acknowledged for financial support and Ministère
National de l’Enseignement et de la Recherche [MNESER]
for PhD grants for I. R. and M. M.
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Samarium Diiodide Catalyzed Aza-Michael Reactions
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
97
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Ethyl 4-(benzoylamino)-2-(4-methoxyphenylamino) 4-oxo but-
anoate 7e : Oil. 1H NMR (360 MHz, CDCl3): ꢂ (ppm) 9.27 (s, 1H),
7.83 (d, 2H, J = 7.8 Hz), 7.50 (m, 3H), 6.70 (m, 4H), 4.40 (t, 1H, J
= 4.9 Hz), 4.17 (q, 2H, J = 7.3 Hz), 3.70 (s, 3H), 3.50 (m, 2H), 1.20
[12]
[13]
(t, 3H, J = 7.3 Hz). 13C NMR (90.6 MHz, CDCl3): ꢂ 173.5, 172.6,
165.7, 153.1, 140.4, 133.3, 132.3, 128.9, 127.8, 115.8, 114.8, 61.5,
55.6, 54.4, 40.5, 14.0. MS (ESI): 371.2 (M+1). HRMS: calcd for
C20H22N2O5Na 393.1421, found 393.1427.
Ethyl N-(4-methoxyphenyl) -2-(4-methoxyphenylamino)-succi-
1
namate 4e: solid, dec 115°C. H NMR (250 MHz, CDCl3): ꢂ 8.42
Typical procedure for aza-Michael reactions: preparation of 7e and
4e. SmI2(THF)2 (55 mg, 0.1 mmol) and p-anisidine (148 mg, 1.2
mmol) were weighed in a glove-box and introduced in a Schlenk
tube. Dichloromethane (5 mL) was added followed by a solution of
ethyl 4-(benzoylamino)-4-oxo but-2-enoate 6e (251 mg, 1 mmol) in
CH2Cl2 (1 mL) at room temperature. The reaction mixture was
stirred for 24h, quenched by addition of 10 mL of HCl 0.1 N
aqueous solution and extracted by CH2Cl2.The crude product was
purified by flash chromatography on silica gel using
(s, 1H), 7.32 (d, 2H, J = 8.8 Hz), 6.78 (m, 6H), 4.35 (m, 1H), 4.18
(m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 2.80 (m, 2H), 1.20 (t, 3H, J =
7.6 Hz). 13C NMR (62.9 MHz, CDCl3): ꢂ 172.8, 167.8, 156.4,
153.7, 139.9, 130.8, 121.8, 116.8, 114.9, 114.0, 56.0, 55.6, 55.4,
53.4, 39.5, 14.1. MS (ESI): 395.2 (M+23), 373.3 (M+1). HRMS:
calcd for C20H24N2O5Na 395.1577, found 395.1580.