Yb(OTf)3-catalyzed intermolecular imino Diels-Alder reaction of 2-azetidinone-tethered aryl imines as azadienes

Article abstract of DOI:10.1080/00397910500522157

Yb(OTf)3 is an efficient catalyst for the intermolecular imino Diels-Alder reaction of aldimines derived from 2-azetidinone-tethered aryl imines and electron-rich dienophiles to afford the quinoline-β-lactams. Copyright Taylor & Francis Group, LLC.

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Yb(OTf)3‐Catalyzed Intermolecular
Imino Diels–Alder Reaction of
2‐Azetidinone‐Tethered Aryl Imines as
Azadienes
E. Ramesh a , E. Elamparuthi a & R. Raghunathan a
a Department of Organic Chemistry , University of Madras , Guindy Campus,
Chennai, India
Published online: 16 Aug 2006.
To cite this article: E. Ramesh , E. Elamparuthi & R. Raghunathan (2006) Yb(OTf)3‐Catalyzed Intermolecular
Imino Diels–Alder Reaction of 2‐Azetidinone‐Tethered Aryl Imines as Azadienes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:10, 1431-1436
To link to this article: http://dx.doi.org/10.1080/00397910500522157
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Synthetic Communicationsw, 36: 1431–1436, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500522157
Yb(OTf)3-Catalyzed Intermolecular Imino
Diels–Alder Reaction of 2-Azetidinone-
Tethered Aryl Imines as Azadienes
E. Ramesh, E. Elamparuthi, and R. Raghunathan
Department of Organic Chemistry, University of Madras,
Guindy Campus, Chennai, India
Abstract: Yb(OTf)3 is an efficient catalyst for the intermolecular imino Diels–Alder
reaction of aldimines derived from 2-azetidinone-tethered aryl imines and electron-
rich dienophiles to afford the quinoline-b-lactams.
Keywords: Ytterbium triflate, b-lactam, imino Diels-Alder
INTRODUCTION
The 2-azetidinone nucleus has been recognized as the central motif of the so-
called b-lactam antibiotics, the most widely employed family of antimicrobial
agents to date.[1] Furthermore, the recent discoveries of some azetidinones that
display a broad range of enzyme-inhibitory activity justify a renewed interest
in these compounds. Beside their significance as bioactive agents, they are
important as synthetic intermediates.
Imino Diels–Alder reactions involving aza-dienes are widely used in the
construction of nitrogen-containing compound.[2] The Lewis acid–catalyzed
aza-Diels–Alder reaction of N-arylimines with dienophiles has shown to be
a very powerful tool for the synthesis of tetrahydroquinoline derivatives.
The inter- and intramolecular imino Diels–Alder reaction of imines with
Received in India October 10, 2005
Address correspondence to R. Raghunathan, Department of Organic Chemistry,
University of Madras, Guindy Campus, Chennai 600025, India. E-mail:
ragharaghunathan@yahoo.com
1431

1432
E. Ramesh. E. Elamparuthi, and R. Raghunathan
electron-rich dienophiles has been catalyzed by Lewis acids such as
[3,4]
transition-metal carbonyls,[5] InCl3[6], and so forth.
.
BF3 Et2O,
Herein we describe the catalytic activity of Yb(OTf)3 in the synthesis of
quinoline-b-lactams from b-lactam imines and various electron-rich dieno-
philes via intermolecular imino Diels–Alder reaction in acetonitrile at room
temperature in a short time with excellent yields. Synthesis of b-lactam
imine from glyoxal dimethylacetal imine leads to 4-dimethylacetal
b-lactams, which, on acid hydrolysis, give 4-formyl-b-lactams (Scheme 1).
In the presence of 20 mol% Yb(OTf)3, b-lactams imines derived from
anisidine and various dienophiles in acetonitrile at room temperature give
quinoline-b-lactam in 87–98% yield as a mixture of diastereoisozners 3
and 4. In all cases, the products were obtained as a mixture of diastereo-
isomers, which can be separated by column chromatography on silica gel.
Several other b-lactam imines underwent smooth cycloaddition to give the
corresponding quinoline-b-lactams in good yields (Table 1). The (þ)3a–c
and (þ)4a–c stereochemistry of the products was assigned on the basis of
1
coupling constants of the protons in the H NMR spectra (Scheme 2).
CONCLUSION
We found that the intermolecular imino Diels reaction can be carried out very
conveniently starting from the various electron-rich dienophiles and
b-lactams imines. This would be a highly desirable method for the preparation
Scheme 1.

Table 1. Synthesis of tricyclic quinoline b-lactamsa
Overall yield, %
(3a þ 4a)b
Overall yield, %
(3b þ 4b)b
Overall yield, %
(3c þ 4c)b
Time,
min
3a
4a
3b
4b
3c
4c
36%
51%
87
46%
49%
95
47%
51%
97
20
1
aAll the products were characterized by IR, H and 13C NMR.
bYield refers to the mixture of diastereoisomers of products 3a pure forms by column chromatography.

1434
E. Ramesh. E. Elamparuthi, and R. Raghunathan
Scheme 2.
of heteropolycyclic systems. We conclude that Yb(OTf)3 is an efficient
catalyst for cyclization of b-lactams imines with various electron-rich dieno-
philes derivatives.
EXPERIMENTAL
General Procedure for the Preparation of Imine
A solution of p-anisidine (1.50 mmol) in dichloromethane (10 mL) was added
dropwise to a stirred suspension of 4-oxoazetidine-2- carbaldehyde 1
(1.0 mmol) and anhydrous sodium sulfate (1.50 mmol) in dichloromethane
(100 mL) at room temperature. After stirring for 12 h at room temperature,
the mixture was filtered, and the solvent was removed under reduced

2-Azetidinone-Tethered Aryl Imines
1435
pressure. The residue was recrystallized with chloroform to yield the analyti-
cally pure compound (mp 1248C).
General Procedure for the Synthesis of Derivatives 3 and 4
A solution of the corresponding imine (1 mmol) in acetonitrile (5 mL) was
added dropwise to a stirred suspension of Yb(OTf)3 (0.2 mmol) in acetonitrile
(13 mL) at room temperature for 5 min, and then electron-rich dienophile
(1.20 mmol) was introduced. The reaction was decomposed with saturated
aqueous NaHCO3 (10 mL), and the mixture was extracted with chloroform
(3 ꢀ 20 mL). The combined organic extract was washed with brine, dried
(MgSO4), and concentrated on silica gel under reduced pressure. Chromato-
graphy of the residue eluting with ethyl acetate/hexanes mixture (3 : 7)
gives 3 and 4.
Data
1
Cycloadduct (3c): white solid; mp 1688C, H NMR (500 MHz, CDCl3):
d ¼ 6.80 and 7.20 (m, each 2H), 6.43 (m, 3H), 5.70 (m, 1H), 5.56 (m, 1H),
4.68 (d, J ¼ 5.3 Hz, 1H), 4.17 (dd, J ¼ 9.0, 5.3 Hz, 1H), 3.71 (m, 4H), 3.63
(m, 7H), 2.54 (m, 2H), 2.11 ppm (m, 1H); 13C NMR (125 MHz, CDCl3):
d ¼ 165.6, 157.7, 153.2, 138.4, 133.9, 130.1, 129.4, 127.1, 122.4, 117.3,
114.4, 113.9, 112.5, 83.2, 59.8, 59.3, 56.0, 55.7, 55.5, 46.1, 40.6, 31.4 ppm;
IR (CHCl3): 3345, 1743 cm21; MS: m/z: 452(M)þ. Elemental analysis
calcd. for C29H28N2O3: C, 76.97; H, 6.24; N, 6.19; found: C, 77.26; H,
6.41; N, 5.88.
1
Cycloadduct (4c): white solid; mp 1728C, H NMR (300 MHZ, CDCl3):
d ¼ 6.94 and 7.51 (m, each 2H), 6.57 (d, J ¼ 2.8 Hz, 1H), 6.46 (ddd,
J ¼ 8.6, 2.9, 0.5 Hz, 1H), 6.21 (d, J ¼ 8.6 Hz, 1H), 5.86 (m, 1H), 5.75
(m, 1H), 4.68 (d, J ¼ 5.5 Hz, 1H), 4.34 (dd, J ¼ 9.8, 5.5 Hz, 1H), 3.98
(m, 1H), 3.83 (m, 4H), 3.67 and 3.71 (s, each 3H), 3.06 (qd, J ¼ 10.8,
2.9 Hz, 1H), 2.81 (m, 1H), 2.38 ppm (m, 1H); 13C NMR (75 MHz, CDCl3):
d ¼ 166.0, 157.1, 153.3, 138.1, 134.3, 130.9, 130.1, 127.1, 120.2, 117.3,
114.6, 113.9, 112.3, 82.8, 60.5, 59.8, 59.7, 56.1, 55.7, 55.6, 46.2, 39.1,
31.6 ppm; IR (KBr): 3342, 1744 cm21; MS: m/z (%): 452(Mþ). Elemental
analysis calcd. for C29H28N2O3: C, 76.97; H, 6.24; N, 6.19; found: C,
77.16; H, 6.38; N, 596.
Cycloadduct (3b): pale yellow solid; mp 1808C, 1H NMR (500 MHz,
CDCl3): d ¼ 7.48 (m, 2H), 7.25 (m, 2H), 6.97 (m, 3H), 6.74 (m, 3H), 6.56
(ddd, J ¼ 8.7, 2.9, 0.5 Hz, 1H), 6.18 (d, J ¼ 8.7 Hz, 1H), 5.00 and 5.37
(d, J ¼ 5.4 Hz, each 1H), 4.63 (dd, J ¼ 9.8, 5.4 Hz, 1H), 3.92 (m, 1H), 1.46
(m, 4H), 3.67 and 3.77 (s, each 3H), 3.51 (m, 2H), 2.40 ppm (m, 1H);

1436
E. Ramesh. E. Elamparuthi, and R. Raghunathan
13C NMR (125 MHz, CDCl3): d ¼ 164.2, 157.5, 157.0, 153.2, 137.9, 130.4,
129.6, 122.6, 121.5, 120.1, 116.4, 115.8, 114.9, 114.3, 111.6, 79.5, 71.5,
60.9, 57.8, 56.6, 55.6, 55.4, 33.0, 24.9, 18.8 ppm; IR (KBr): 3418,
1751 cm21; MS (CI): m/z (%): 470 (Mþ). Elemental analysis calcd. for
C29H30N2O4 (%): C, 74.02; H, 6.43; N, 5.95; found: C, 74.27; H, 6.64; N, 5.65.
Cycloadduct (4b): pale yellow solid; mp 1778C, 1H NMR (500 MHz,
CDCl3): d ¼ 7.18 (m, 6H), 6.84 (m, 3H), 6.65 (dd, J ¼ 8.7, 2.9 Hz, 1H),
6.37 (d, J ¼ 8.7 Hz, 1H), 4.93 and 5.46 (d, J ¼ 5.2 Hz, each 1H), 4.51 (dd,
J ¼ 9.4, 5.2 Hz, 1H), 4.07 (m, 1H), 3.68 and 3.77 (s, each 3H), 3:41 (m,
3H); 1.57 ppm (m, 4H); 13C NMR (125 MHz, CDCl3): d ¼ 163.6, 157.6,
157.0, 153.3, 137.9, 129.7, 129.6, 129.1, 122.8, 121.7, 116.3, 115.7, 115.1,
114.4, 111.4, 80.4, 71.7, 60.6, 57.2, 56.7, 55.6, 55.4, 33.7, 24.9, 18.6 ppm;
IR (KBr): 3422, 1750 cm21; MS: m/z: 470 (Mþ). Elemental analysis calcd.
for C29H30N2O4: C, 74.02; H, 6.43; N, 5.95; found: C, 74.28; H, 6.60; N, 5.74.
ACKNOWLEDGMENTS
E. Ramesh thanks CSIR, New Delhi, for the fellowship. R. Raghunathan
thanks Council of Scientific and Industrial Research (CSIR), New Delhi, for
the financial support.
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