A novel sugar based intramolecular Ugi 3CC for the N-alkyl-3-oxo-4-aryl- octahydrofuro[2,3-f][1,4]oxazepine-5-carboxamides

Article abstract of DOI:10.1016/j.tetlet.2012.02.048

An intramolecular Ugi reaction of 3-carboxy tethered sugar aldehyde with aryl amines and isocyanides has been accomplished to produce a novel class of carbohydrate derivatives, 3-oxo-4-aryl-octahydrofuro[2,3-f][1,4]oxazepine-5- carboxamides in good yields. The stereochemistry of the products was assigned by NMR studies. This is the first report on intramolecular Ugi reaction of 3-carboxy tethered sugar aldehyde, aryl amine, and isonitrile.

Full text of DOI:10.1016/j.tetlet.2012.02.048

Tetrahedron Letters 53 (2012) 2273–2276
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel sugar based intramolecular Ugi 3CC for the
N-alkyl-3-oxo-4-aryl-octahydrofuro[2,3-f][1,4]oxazepine-5-carboxamides
B.V. Subba Reddy a, , Nilanjan Majumder a, T. Prabhakar Rao b, B. Sridhar c
⇑
a Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Centre for X-Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An intramolecular Ugi reaction of 3-carboxy tethered sugar aldehyde with aryl amines and isocyanides
has been accomplished to produce a novel class of carbohydrate derivatives, 3-oxo-4-aryl-octahydrof-
uro[2,3-f][1,4]oxazepine-5-carboxamides in good yields. The stereochemistry of the products was
assigned by NMR studies. This is the first report on intramolecular Ugi reaction of 3-carboxy tethered
sugar aldehyde, aryl amine, and isonitrile.
Received 3 November 2011
Revised 10 February 2012
Accepted 11 February 2012
Available online 26 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ugi three component coupling
Carboxy tethered sugar aldehyde
Oxazepine derivatives
In recent years; the pharmaceutical industry has focused more
and more on diversity-oriented combinatorial libraries.1 Multi-
component reactions (MCRs) are powerful tools for generating
combinatorial libraries to drug discovery.2 MCRs are atom efficient
and are extremely convergent, producing a high molecular com-
plexity in a single step process.3 Of these, isocyanide based MCRs
such as Ugi4 and Passerini reactions are the most popular especially
in medicinal chemistry.5 The ability of isonitriles to undergo facile
addition either with nucleophile or with electrophile under mild
conditions makes them useful reactants for the development of
novel MCRs.6,7 Recently, a new version of isocyanide-based MCRs
with keto acids have been developed as bifunctional reagents.8
The coupling of keto acids with amines and isocyanides provides
the carbamoyl derivatives of four-, five-, six-, seven-, and eight-
membered lactams.9–11 However, to the best of our knowledge,
there are no reports on the isocyanide-based Ugi reaction of bifunc-
tional sugar aldehydo carboxylic acid, aryl amine, and isonitrile.
Following our interest on the synthesis of sugar annulated
heterocycles12 we herein report a novel strategy for the synthesis
of N-alkyl-3-oxo-4-aryl-octahydrofuro[2,3-f][1,4]oxazepine-5-car-
boxamide derivatives via intramolecular Ugi reaction. Initially, we
attempted the coupling of p-toluidine (1) with 3-carboxy sugar
aldehyde (2) and cyclohexyl isocyanide (3). Interestingly, the
NH
O
H1
H
5 H
H3C
4 O
O
N
O
H2
H3
O
O
H6
H6'
NC
O
HN
N
NH2
O
3
Me
MeOH
50 oC, 10h
O
O
+
O
H
O
HO2C
O
O
O
O
O
Me
1
4a
2
Scheme 1. Preparation of oxazepine 4a via three-component reaction.
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
Figure 1. Characteristic nOe’s and energy-minimized structure of 4a.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.048

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B. V. S. Reddy et al. / Tetrahedron Letters 53 (2012) 2273–2276
Figure 2. X-ray crystal structure of 4f.
Table 1
Sugar based intramolecular Ugi reaction
Entry
Aryl amine (1)
NH2
Isonitrile (3)
Producta (4)
Time (h)
Yieldb (%)
NC
Me
Me
O
HN
a
10
82
O
N
O
O
O
O
NH2
NC
Cl
Cl
O
HN
b
10
77
O
N
O
O
O
O
O
NH2
NC
O
HN
c
12
13
72
78
O
N
O
O
O
NH2
NC
NC
MeO
O
HN
MeO
d
O
N
O
O
O
O
NH2
O
HN
N
e
11
84
O
O
O
O
O

B. V. S. Reddy et al. / Tetrahedron Letters 53 (2012) 2273–2276
2275
Table 1 (continued)
Entry
Aryl amine (1)
Isonitrile (3)
Producta (4)
Time (h)
Yieldb (%)
NH2
NC
O
HN
f
10
83
O
O
O
N
O
O
O
O
O
O
O
O
NH2
NC
NC
NC
O
HN
g
13
13
75
70
N
O
O
NH2
Cl
O
HN
h
N
Cl
O
O
NH2
Me
O
HN
Me
i
13
72
O
N
O
O
O
O
O
NH2
NC
O
HN
j
10
83
N
O
O
O
O
a
All the reactions were characterized by NMR, IR, and mass spectroscopy.
Isolated yields after chromatography.
b
R-N
O
reaction proceeded smoothly in methanol at 50 °C and the desired
sugar annulated oxazepine derivative 4a was obtained in 82% yields
(Scheme 1).
The stereochemistry of 4a was confirmed by nOe studies. The
presence of strong nOe between H4 and H5 indicates that both
are cis. The nOe cross peaks between H3 and H5 also suggest that
H3 and H5 are also cis to each other. The energy-minimized struc-
ture further supports the assigned structure for 4a (Fig. 1).
The structure of product 4f was further confirmed by X-ray
crystallography (Fig. 2).13
O
O
O
O
R-NH2
H
H
HO2C
O
O
HO2C
O
O
R'-NC
R-HN
O
:
O
R-HN
O
O
R'-N
O
O
N
R'
O
O
O
O
O
O
This result provided the incentive for further study of reactions
with various aryl amines such as aniline, p-chloroaniline, p-
methoxyaniline, and o-chloroaniline (Table 1). The 3CC reaction
was also successful with benzyl amine (Table 1, entries c and e).
In all the cases, the reactions are clean and provide the desired oxa-
zepine derivatives in good yields. Other isocyanides such as t-butyl
isocyanide and 1,1,3,3-tetramethylbutyl isocyanide also partici-
pated effectively in this reaction (Table 1, entries c, d and f–i). As
solvent, methanol appeared to give the best results. A variety of
functional groups such as cyclic acetal, N-alkyl amide, and cyclic
lactam are well-tolerated.
Mechanistically, we assume that imine may be formed in situ
from sugar aldehyde and aryl amine. Followed by the attack of iso-
cyanide on imine would give iminolactone. This adduct undergoes
simultaneously an intramolecular cyclization with a secondary
amine to give the seven-membered lactam as depicted in Scheme 2.
R'
NH
O
O
O
R
O
N
O
O
Scheme 2. A plausible reaction pathway.
The products were fully characterized and confirmed by NMR,
IR, and mass spectrometry. The scope and generality of this process
is illustrated with respect to various aryl amines and isonitriles and
the results are presented in Table 1.14
In summary, we have demonstrated for the first time the sugar
based intramolecular Ugi reaction for the synthesis of highly func-
tionalized furo[2,3-f][1,4]oxazepine derivatives from readily avail-

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B. V. S. Reddy et al. / Tetrahedron Letters 53 (2012) 2273–2276
9. (a) Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591; (b) Short, K. M.; Mjalli, A.
M. M. Tetrahedron Lett. 1997, 38, 359.
10. (a) Tsaloev, A.; Ilyin, A.; Tkachenko, S.; Ivachtchenko, A.; Kravchenko, D.;
Krasavin, M. Tetrahedron Lett. 1800, 2011, 52; (b) Ghandi, M.; Zarezadeh, N.;
Taheri, A. Tetrahedron Lett. 2011, 52, 1228.
able precursors under neutral conditions. It is entirely a new strat-
egy to produce sugar annulated oxazepine derivatives in a single-
step process.
11. Ilyin, A. P.; Parchinski, V. Z.; Peregudova, J. N.; Trifilenkov, A. S.; Poutsykina, E.
B.; Tkachenko, S. E.; Kravchenkoa, D. V.; Ivachtchenko, A. V. Tetrahedron Lett.
2006, 47, 2649.
Acknowledgment
12. (a) Reddy, B. V. S.; Majumdar, N.; Gopal, A. V. H.; Chatterjee, D.; Kunwar, A. C.
Tetrahedron Lett. 2010, 51, 6835; (b) Yadav, J. S.; Reddy, B. V. S.; Gopal, A. V. H.;
Rao, R. N.; Somaiah, R.; Reddy, P. P.; Kunwar, A. C. Tetrahedron Lett. 2010, 51,
2305; Reddy, B. V. S.; Ganesh, A. V.; Krishna, A. S.; Kumar, G. G. K. S. N.; Yadav, J.
S. Tetrahedron Lett. 2011, 52, 3342.
N.M. thanks CSIR, New Delhi for the award of a fellowship.
Supplementary data
13. CCDC 862973 contains Supplementary Crystallographic Data for the structure
4f.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.048.
14. Typical procedure:
A mixture of sugar aldehydo carboxylic acid (246 mg,
1 mmol) and p-toluidine (107 mg, 1 mmol) in MeOH (5 mL) was stirred for
30 min at room temperature and then cyclohexylisocyanide (130.8 mg,
1.2 mmol) was added at room temperature and the resulting mixture was
stirred at 50 °C for 10 h. After complete conversion, as monitored by TLC, the
mixture was concentrated in vacuo and purified by column chromatography
using ethyl acetate–hexane (1:9) as eluent to afford the product as a pale
yellow solid. The spectral data can be found in Supplementary data. Compound
References and notes
1. (a) Schreiber, S.-L. Science 1964, 2000, 287; (b) Terrett, N. K. Combinatorial
Chemistry; Oxford University Press: New York, 1998.
2. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Dömling, A.
Chem. Rev. 2006, 106, 17; (c) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem. Eur. J. 2000, 3321.
4a: Solid, mp 90–95 °C. IR:
m ;
3038, 1728, 1611, 1508, 1219, 772, 686 cmÀ1 1H
NMR (300 MHz, CDCl3): d 7 7.08 (m, 4H), 6.40 (d, J = 8.2 Hz, 1H) 5.94 (d,
J = 3.6 Hz, 1H), 5.12 (dd = 4.5, 6.4 Hz, 1H), 4.60 (d, J = 3.6 Hz, 1H), 4.54 (d,
J = 16.2 Hz, 1H), 4.30 (d, J = 4.5 Hz, 1H), 4.25 (d, J = 16.2 Hz, 1H), 4.21 (d,
J = 6.4 Hz, 1H), 3.83 (m, 1H), 2.34 (s, 3H), 2.00–1.00 (m, 20H); 13C NMR
(75 MHz, CDCl3): d 171.3, 166.5, 142.2, 137.0, 129.9, 126.6, 113.8, 105.6, 84.1,
83.9, 83.1, 74.1, 62.5, 48.3, 37.1, 36.2, 33.4, 33.1, 25.6, 24.9, 24.8, 23.9, 23.6,
21.2; LC–MS: m/z: 485 (M+H). HRMS calcd for C27H36N2O6Na: 507.2471, found:
3. Weber, L. Curr. Med. Chem. 2002, 9, 1241.
4. (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810; (b) Ugi, I.; Lohberger, S.;
Karl, R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; p 1083. Vol. 2.
5. (a) Zhu, J.; Bienayme´, H. In Multi-Component Reactions; Ghn, J., Ed.; Wiley-VCH:
Weinheim, 2005; (b) Banfi, L.; Riva, R. Org. React. 2005, 65, 1; (c) Toure, B. B.;
Hall, D. G. Chem. Rev. 2009, 109, 4439.
6. (a) Ramazani, A.; Mahyari, A. T.; Rouhani, M.; Rezaei, A. Tetrahedron Lett. 2009,
50, 5625; (b) Sanudo, M.; Garcia-Valverde, M.; Marcaccini, S.; Delgado, J. J.;
Rojo, J.; Torroba, T. J. Org. Chem. 2009, 74, 2189.
7. (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899; (b) Dömling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3169.
507.2454. Compound 4b: Solid, mp 108–112 °C. IR:
m 3387, 2933, 2855, 1678,
1524, 1491, 1414, 1219, 1124, 1039, 772 cmÀ1 1H NMR (500 MHz, CDCl3): d
;
7.3 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 6.42 (d, J = 7.9 Hz, 1H), 5.94 (d,
J = 3.9 Hz, 1H), 5.10 (dd, J = 4.9,5.9 Hz, 1H), 4.60 (d, J = 3.9 Hz, 1H), 4.53 (d,
J = 16.8 Hz, 1H), 4.29 (d, J = 4.9 Hz, 1H), 4.24 (d, J = 16.8 Hz, 1H), 4.19 (d,
J = 5.9 Hz, 1H), 3.80 (m, 1H), 2.00–1.12 (m, 20H); 13C NMR (75 MHz, CDCl3): d
192.7, 171.4, 133.6, 129.4, 128.4, 113.8, 105.6, 84.0, 83.8, 74.1, 62.4, 48.3, 37.1,
36.1, 33.4, 33.1, 29.7, 28.4, 25.6, 24.8, 24.7, 23.9, 23.5, 23.1; LC–MS: m/z: 505
(M+H); HRMS calcd for C26H33N2O6Na: 527.1924, found: 527.1913.
8. (a) Ivachtchenko, A. V.; Ivanenkov, Y. A.; Kysil, V. M.; Krasavin, M. Y.; Ilyin, A. P.
Russian Chem. Rev. 2010, 79, 787; (b) Shaabani, A.; Soleimani, E.; Rezayan, A. H.;
Sarvary, A.; Khavasi, H. R. Org. Lett. 2008, 10, 2581.