Cerium(IV) ammonium nitrate catalyzed synthesis of α-dehydro-β-amino esters

Article abstract of DOI:10.1016/j.tetlet.2008.02.054

α-Dehydro-β-amino esters have been synthesized regioselectively from acetates of Baylis-Hillman adducts with amines in the presence of a catalytic amount of ceric ammonium nitrate (CAN) in good yield. The regioselectivity does not differ with respect to t

Full text of DOI:10.1016/j.tetlet.2008.02.054

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2432–2434
Cerium(IV) ammonium nitrate catalyzed synthesis
of a-dehydro-b-amino esters
Moumita Paira, Samir Kumar Mandal, Subhas Chandra Roy *
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 27 November 2007; revised 5 February 2008; accepted 10 February 2008
Available online 13 February 2008
Abstract
a-Dehydro-b-amino esters have been synthesized regioselectively from acetates of Baylis–Hillman adducts with amines in the presence
of a catalytic amount of ceric ammonium nitrate (CAN) in good yield. The regioselectivity does not differ with respect to the polarity of
the solvent.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Baylis–Hillman adduct; Ceric ammonium nitrate; Amine; a-Dehydro-b-amino esters; Regioselective
Table 1
a-Dehydro-b-amino esters are useful synthetic interme-
A comparison of different reported amination reactions
diates for indenoquinoline derivatives, nonproteinogenic
Ref.
Reagent used
Yielda (%)
b-amino acids as well as b-lactams, which facilitates the
development of modern medicines.1–4 Peptide derivatives
of a-dehydro-b-amino acids exhibit intramolecular hydro-
gen bonding, which plays a significant role in biochemical
molecular recognition and mimics a b-turn.5–8 Similar to
dehydro-a-amino acids, a-dehydro-b-amino acids can pro-
vide constraint after incorporation into a peptide molecule
and thus renders a peptide more favorable to binding to its
target.9,10 It is noteworthy that the b-amino acid in a cyto-
toxic depsipeptide11 namely, kulokekahilide-1 often
requires synthesis when they are not available commer-
cially. Thus, numerous methods have been developed for
the construction of b-amino ketones, acids or esters such
as, the reduction of an aziridine ring with SmI2,12 cobalt-
catalyzed epoxide opening,13 Michael addition of amide
cuprate reagents,14 Sharpless asymmetric aminohydroxyl-
ation of olefins,15 (ZnBF4)2 mediated Mannich reaction,16
ring opening of b-lactams,17 nucleophilic substitution reac-
tions,18,19 Pd(0)-catalyzed amination5 and rearrangement
of carbamates (Table 1).20 However, to our knowledge,
5
12
13
14
15
16
17
18
19
20
a
Pd(PPh3)4
SmI2
Co(II) or Co(III)
Amide cuprate
(DHQD)2–PHAL or (DHQ)2–PHAL
Zn(BF4)2
No reagent
No reagent
57–78b
78–98
32–69
29–88
48–78
48–98
76–90
47–91b
20–95b
30–98
Et3N
CsF or DABCO or KF–AL2O3 or K2CO3
Range of yields refers to products with different substrates.
Mixture of SN2 and SN20 products.
b
only two methods21,22 are reported in the literature using
Baylis–Hillman adducts as precursors for the synthesis of
b-amino esters, (i) DABCO-catalyzed allylic amination
(40–79% yield), and (ii) thermal addition of amines to
Baylis–Hillman adducts (67–78% yield). Although some
of the reported procedures are quite elegant, many suffer
from long reaction times, use of excess and costly reagents,
low regioselectivity and low yields in some cases. So, meth-
ods for the synthesis of a-dehydro-b-amino esters are still
desirable. Herein, we disclose a simple and facile method
*
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ocscr@iacs.res.in (S. C. Roy).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.054

M. Paira et al. / Tetrahedron Letters 49 (2008) 2432–2434
2433
for the synthesis of a-dehydro-b-amino esters by the reac-
O
tion of Baylis–Hillman acetates with various primary
amines catalyzed by ceric ammonium nitrate (CAN).
Acetates of Baylis–Hillman adducts are of valuable syn-
thetic intermediates for the synthesis of a number of com-
plex molecules.23 It is well documented in the literature24–26
that CAN is a useful catalyst for C–C and C–N bond
formation in synthetic organic chemistry. In continuation
of our efforts27–30 to develop novel methodologies for
organic transformations using cheap and commercially
available CAN as a catalyst, we report that CAN acts as
an effective catalyst for the addition–elimination reaction
to furnish b-amino esters from amines and Baylis–Hillman
acetates.
Ce(III)
OMe
OAc
O
O
R
NH2
CO2Me
Ar
Ar
Ce(IV)
NH2
1
+
R
O
CO2Me
NHR
O
Ar
Ar
Ce(III)
O
3
NHR
OMe
A
Scheme 2. Proposed mechanism for the formation of the E-isomer
predominantly.
Thus, in a preliminary study,31 benzyl amine was reacted
with acetate 1a in THF at 60–65 °C for 3 h using a catalytic
amount of CAN (10 mol %) to give amino ester 3a (Scheme
1, Table 2).
O
Ref. 1(b)
Ar
CO2Me
NHR
Ar
Thus, a series of amines were treated with various
Baylis–Hillman acetates and the results are summarized
in Table 2.
N
R
4
3
Scheme 3. Conversion of amino esters to b-lactams.
The stereochemistry of the products was established by
comparing the signal of the vinylic proton in H NMR
1
spectra with the literature values.2,5 The appearance of
the vinylic proton of the E-isomer in the range of d 7.63–
7.94 and that of the Z-isomer in the range of d 6.56–6.70
depending on the substrates used is in good agreement with
the reported values. It was observed that the reaction in
methanol or in THF resulted in the best yield compared
to other solvents. 4-Chloro-substituted aromatic moieties
in the Baylis–Hillman acetates enhanced the yield of the
products with aromatic amines (Table 2, entries o and p).
Aliphatic amines also underwent smooth amination under
similar reaction conditions resulting in moderate to good
yields of the amino esters. Aromatic amines required a little
more reaction time compared to aliphatic amines, which
may be due to the lower reactivity of aromatic amines. It
was clear from the results that aromatic amines and benzyl
amine gave relatively better yields than aliphatic amines
and also showed higher E-selectivity. All products were
characterized by NMR, IR and HRMS studies and were
compared with those of the reported data.
OAc
CO2Me
10 mol % CAN / THF
CO2Me
Ar
R
NH2
+
Ar
60-65 oC, 3 h
53-92%
NHR
3
2
1
R = Aryl, alkyl, benzyl
Scheme 1. Synthesis of b-amino esters.
Table 2
CAN catalyzed synthesis of a-dehydro-b-amino esters
Amines undergo Michael type addition followed by b-
acetoxy elimination in the presence of CAN. The E-selec-
tivity can be explained by the formation of the chelated
intermediate (A) with cerium(IV) and the carbomethoxy
group (Scheme 2).
Entry
Ar
R
Yield of 3a (%)
E/Z ratiob
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
84
85
92
89
78
73
57
72
55
65
95
79
87
53
90
91
74
100:0
92:8
100:0
100:0
94:6
4-MeC6H4
4-MeOC6H4
3-Cl-4-MeC6H3
a-Naphthyl
Me
n-C8H17
n-C16H33
Cyclo-C6H11
4-MeC6H4
3-O2NC6H4
Bn
Some of the amino esters 3 have already been proved2 as
versatile precursors for the synthesis of biologically active
b-turn inducers and b-lactams 4 (Scheme 3).
91:9
78:22
86:14
85:15
98:2
100:0
89:11
88:12
80:20
100:0
96:4
In conclusion, we have developed an efficient and regio-
selective method for the synthesis of a-dehydro-b-amino
esters in a stereoselective manner from Baylis–Hillman
acetates and various primary amines catalyzed by ceric
ammonium nitrate.
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
Ph
Bn
n-C8H17
Acknowledgements
83:17
We sincerely thank DST, New Delhi, for financial
support. M.P. and S.K.M. thank CSIR, New Delhi, for
awarding the fellowships.
Yield refers to pure isolated yield.
Isomeric ratio was determined from 1H NMR spectra of the crude
b
reaction mixture.

2434
M. Paira et al. / Tetrahedron Letters 49 (2008) 2432–2434
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