A novel biomimetic condensation of 2-deoxyribose, aryl amine and acetyl acetone to bicyclic aminols catalyzed by InCl3

Article abstract of DOI:10.1016/j.tetlet.2008.02.080

2-Deoxyribose, an aryl amine and acetyl acetone undergo smooth cyclocondensation in the presence of 10 mol % of InCl₃ under mild conditions to afford the corresponding sugar-derived bicyclic aminols in good yields with moderate diastereoselectivity. This reaction is reminiscent of the celebrated tropinone synthesis of Robinson. The structures of the products are established by using various NMR experiments and X-ray crystallographic studies.

Full text of DOI:10.1016/j.tetlet.2008.02.080

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3341–3345
A novel biomimetic condensation of 2-deoxyribose, aryl amine
and acetyl acetone to bicyclic aminols catalyzed by InCl3
a,
a
a
a
*
J. S. Yadav , B. V. Subba Reddy , G. Satheesh , G. Narasimhulu ,
Y. Portier c, C. Madhavi b, A. C. Kunwar b
a Division of Organic 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 Sciences de Chimiques de Rennes, Universite´ de Rennes, France
Received 1 November 2007; revised 31 January 2008; accepted 14 February 2008
Available online 19 February 2008
Abstract
2-Deoxyribose, an aryl amine and acetyl acetone undergo smooth cyclocondensation in the presence of 10 mol % of InCl3 under mild
conditions to afford the corresponding sugar-derived bicyclic aminols in good yields with moderate diastereoselectivity. This reaction is
reminiscent of the celebrated tropinone synthesis of Robinson. The structures of the products are established by using various NMR
experiments and X-ray crystallographic studies.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 2-Deoxysugars; Indium trichloride; Aryl amines; Heterobicycles
Multi-component, one-pot syntheses have received con-
siderable attention because of their wide range of applica-
tions in pharmaceutical chemistry for generation of
structural diversity and combinatorial libraries for drug
discovery.1 The ready availability of a wide range of carbo-
hydrates in Nature and their multi-chiral architecture, cou-
pled with their well-defined stereochemistry, make them
attractive starting materials in organic synthesis.2,3 In par-
ticular, 2-deoxy-D-ribose is a valuable synthetic intermedi-
ate for various organic transformations.4,5 Recently,
indium trichloride has emerged as a mild and water-toler-
ant Lewis acid imparting high regio-, chemo- and diastereo-
selectivity in various organic transformations.6 Compared
to conventional Lewis acids, indium trichloride, in parti-
cular, has advantages of low catalyst loading and moisture
stability.
method for the synthesis of sugar-based, bicyclic aminols
from 2-deoxyribose, an aryl amine and acetyl acetone.
Initially, we attempted a three-component reaction of
2-deoxyribose, p-anisidine and acetyl acetone in the pres-
ence of 10 mol % of InCl3. The reaction proceeded
smoothly in acetonitrile at room temperature and the prod-
uct was obtained in 91% yield as a mixture of 4c and 5c in a
1:1 ratio after acetylation (Scheme 1, Table 1).
OMe
O
N
OMe
AcO
Me
Me
H2N
2
O
O
4c
OMe
OH
a) InCl3/CH3CN
b) Ac2O/DMAP
HO
+
+
O
O
In continuation of our interest in exploring the synthetic
utility of indium(III) chloride,7 we herein disclose a novel
HO
1
N
Me
Me
AcO
Me
Me
O
O
3
5c
*
Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512.
Scheme 1. Preparation of 4c and 5c.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.080

3342
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3341–3345
Table 1
InCl3-catalyzed three-component coupling of 2-deoxy-ribose, acetyl acetone and aryl amines
Entry
a
Substrate
Aryl amine
Productsa
Time (h)
5.0
Yieldb,c (%)
93
NH2
O
2-Deoxy-D-ribose + acetyl acetone
O
N
N
AcO
Me
AcO
Me
Me
O
Me
O
Me
Me
NH2
O
O
N
N
b
c
2-Deoxy-D-ribose + acetyl acetone
2-Deoxy-D-ribose + acetyl acetone
5.5
5.0
85
91
Me
AcO
AcO
AcO
AcO
Me
Me
Me
Me
O
O
OMe
OMe
NH2
O
O
N
N
MeO
Me
Me
Me
Me
O
O
MeO
MeO
OMe
OMe
OMe
OMe
NH2
MeO
MeO
O
O
d
2-Deoxy-D-ribose + acetyl acetone
6.0
5.5
83
80
N
N
AcO
AcO
AcO
AcO
Me
Me
OMe
Me
Me
O
O
OMe
OMe
NH2
O
O
e
2-Deoxy-D-ribose + acetyl acetone
N
N
OMe
OMe
Me
OMe
MeO
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
O
NH2
O
O
N
N
f
2-Deoxy-D-ribose + acetyl acetone
2-Deoxy-D-ribose + acetyl acetone
4.5
6.0
85
82
AcO
AcO
AcO
AcO
Me
Me
Me
O
O
Br
Br
NH2
O
O
N
N
g
Br
Me
Me
Me
O
O
Me
Me
Br
Br
NH2
Br
O
O
N
N
h
2-Deoxy-D-ribose + acetyl acetone
5.0
87
Me
Me
AcO
AcO
AcO
AcO
Me
Me
Me
O
O
Me
O
Me
O
N
N
NH2
i
2-Deoxy-D-ribose + acetyl acetone
2-Deoxy-D-ribose + acetyl acetone
5.5
6.5
75
73
Me
Me
Me
Me
O
O
F
F
NH2
O
O
N
N
j
F
AcO
AcO
Me
Me
Me
Me
O
O
a
All products were characterized by NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
Diastereomers were formed in 1:1 ratio.
b
c

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3341–3345
3343
OMe
These diastereoisomers, 4c and 5c could be easily sepa-
OMe
rated by column chromatography and characterized by
extensive NMR experiments. Compound 4c was character-
ized thoroughly with the help of various NMR experiments
including 2-D nuclear Overhauser effect spectroscopy
(NOESY), heteronuclear single-quantum correlation spec-
troscopy (HSQC) and heteronuclear multiple bond correl-
ation spectroscopy (HMBC). The NMR data suggest that
the molecular structure of 4c consists of a [1.3.3]bicyclo-
nonene-like structure. The bridgehead protons H3 and
H5 and the methylene group in the bridge (H4(pro-R) and
H4(pro-S)) all showed small couplings (JH2–H3 = 4.4 Hz,
O
DMP (1.5 eq)
O
N
N
HO
Me
Me
°
O
CH2Cl2, 0 C-r.t., 1 h
Me
Me
m.p. 123-125
O
O
4c
°
6c (91%)
C
25
[α]D = - 413 (
c
= 1, CHCl3)
OMe
OMe
O
O
O
N
DMP (1.5 eq)
N
HO
O
Me
Me
Me
Me
m.p. 123-124 C
°
CH2Cl2, 0 C-r.t., 1 h
JH3–H4(pro-S) = 4.6 Hz, JH4(pro-S)H3 = 2.2 Hz, JH3–H4(pro-R)
=
O
°
7c (89%)
3.0 Hz, and JH4(pro-R)-H5 = 3.0 Hz; Fig. 1). The two
six-membered rings of the bicyclononene moiety differ in
their conformations. The chair conformation of the oxy-
gen-containing six-membered ring is supported by the
NOESY cross peak H2/H4(pro-S) as well as the large diaxial
coupling JH1(pro-R)–H2 = 10.4 Hz and other small couplings
mentioned above. NOE correlations, H5/Hortho and
H1(pro-R)/Hortho further confirm that the N–Ph group is
on the same side as the ring oxygen, while the location of
the methyl group adjacent to the ring nitrogen was sup-
ported by the NOE correlation H6/Hortho. Additionally,
HMBC correlations, C11/H5, C1/H5, C1/H3, C7/H5,
C8/H2 and C8/H4(pro-R) are in complete agreement with
the proposed structure. The minimum energy structure
supporting these conclusions is shown in Figure 1.8
Further, the structure of 4c was established by chemical
correlation. Thus, the oxidation of both 4c and 5c with
Dess–Martin periodinane gave the corresponding ketones
6c and 7c which exhibit identical NMR spectra and mps
but opposite optical rotation which confirms the structure
of 4c (Scheme 2).
5c
25
[α]D = + 413 (c = 1, CHCl3)
Scheme 2. Oxidation of 4c and 5c.
correlation H6/Hortho. Additionally, HMBC correlations,
C11/H5, C1/H5, C1/H3, C7/H5, C8/H2 and C8/H4(pro-S)
are in complete agreement with the proposed structure.
The minimum energy structure supporting these conclu-
sions is shown in Figure 2.8
The structure of 5c was further confirmed by X-ray
crystallographic studies (Fig. 3).10
OMe
O
H
1
m
H
2
11
5
N
o
AcO
7
4
Me
H
3
8
6
The NMR data for 5c supports a structure with opposite
configuration at C3 and C5 compared to 4c. However, due
to the opposite configuration at C3 and C5 the six-mem-
bered chair flips and the acetyl group at C2 adopts an axial
position. The bridgehead protons H3 and H5 and the meth-
ylene group in the bridge (H4(pro-R) and H4(pro-S)) all show
H
9
O
Me
10
Fig. 2. Important NOEs and energy-minimized structure of 5c.
small couplings (JH3–H4(pro-S) = 3.1 Hz, JH4(pro-S)–H3
=
3.0 Hz, JH4(pro-R)–H5 = 2.2 Hz, and JH4(pro-R)–H5 = 3.8 Hz).
The NOE correlations, H5/Hortho and H1(pro-S)/Hortho
confirm that the N–Ph group is on the same side as the ring
oxygen as in 4c, while the location of the methyl group
adjacent to the ring nitrogen was supported by the NOE
OMe
O
H
11
H
m
H
1
H
N
5
o
4
7
AcO
2
Me
3
6
8
H
Me10
9
O
Fig. 1. Important NOEs and energy-minimized structure of 4c.
Fig. 3. X-ray crystal structure of 5c.

3344
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3341–3345
H
+
O
O
In(III)
HO
HO
HO
Ar-NH2
OH
O
NXAr
NXAr
HO
HO
+
HO
X= H or CH=CHCOMe
HO
O
O
Me
Me
OH
CHO
HO
Ar
+
OH
Ar
N
Me
Me
..
OH
6e electrocyclic
ring closure
+
N
NXAr
Me
Me
HO
H
In(III)
OH
O
HO
+
HO
O
OH
Ar
N
Ar
+
O
OH
..
Me
Me
Ar
O
O
N
N
+
HO
Me
Me
HO
Me
Me
O
HO
O
Scheme 3. A plausible reaction mechanism.
This result provided the incentive for further study of
reactions with various other aryl amines and lactols. Inter-
estingly, a wide range of aryl amines including ortho-,
meta-, and para-substituted anilines participated well in
this reaction. As seen from Table 1, methoxy-substituted
aryl amines gave comparatively higher yields than halo-
gen-substituted aromatic amines. However, the reaction
did not proceed with aliphatic amines under similar condi-
tions because aliphatic amines are more basic and probably
quench the Lewis acidity of InCl3. Unlike alcohols and
thiols, the aminoglycosidation with aliphatic amines is
generally problematic even under drastic conditions.
Furthermore, 2-deoxy-D-glucose and 2-deoxy-D-galactose
failed to undergo cyclization with enamines to give the
corresponding bicyclic aminols. Instead, both 2-deoxy-D-
glucose and 2-deoxy-D-galactose underwent cyclodehydra-
tion in the presence of InCl3 resulting in the formation of
2-furylethane-1,2-diol in 63% and 47% yields, respectively.9
The scope and generality of this process is illustrated in
Table 1.11
acetyl acetone and aryl amines using a catalytic amount
of InCl3 under mild conditions. This method is quite simple
and convenient to prepare a wide range of sugar-fused
heterobicycles in a single step.
Acknowledgements
G.S., G.N. and C.M. thank CSIR, New Delhi for the
award of fellowships and the authors thank Dr. K. Ravi-
kumar and Dr. B. Sridhar for providing the X-ray crystal
structure.
References and notes
1. Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley: Weinheim,
2005.
2. Hanessian, S. Total Synthesis of Natural Products: The ‘Chiron’
Approach. In Organic Chemistry Series; Pergamon: Oxford, 1983;
Vol. 3. Fraser-Reid, B.; Anderson, R. C. Fortschr. Chem. Org. Nat.
1980, 39, 1.
Simple lactols such as 2-hydroxytetrahydro-2H-pyran
and 2-hydroxytetrahydrofuran failed to undergo cycli-
zation with enamines. The solvent acetonitrile gave the best
results. The effects of various indium(III) reagents such as
InF3, InCl3, In(ClO4)3 and In(OTf)3 were tested. Of these,
indium trichloride was found to be the most effective cata-
lyst in terms of conversion. Alternatively, 10 mol % of
InBr3 was found to be an equally effective catalyst for this
conversion. A possible mechanism is depicted in Scheme 3.
In summary, we have described a direct one-pot proce-
dure for the synthesis of sugar-derived bicyclic aminols
involving a three-component coupling of 2-deoxyribose,
3. Postema, M. H. D. Tetrahedron 1992, 48, 8545.
4. (a) Reese, C. B.; Wu, Q. Org. Biomol. Chem. 2003, 1, 3160; (b)
Zammit, S. C.; Ferro, V.; Hammond, E.; Rizzacasa, M. A. Org.
Biomol. Chem. 2007, 5, 2826.
5. (a) Yadav, J. S.; Reddy, B. V. S.; Meraj, S.; Vishnumurthy, P.;
Narsimulu, K.; Kunwar, A. C. Synthesis 2006, 2923; (b) Yadav, J. S.;
Reddy, B. V. S.; Satheesh, G. Tetrahedron Lett. 2004, 45, 3673.
6. (a) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149; (b) Babu, G.;
Perumal, P. T. Aldrichim. Acta 2000, 33, 16; (c) Ghosh, R. Indian J.
Chem. 2001, 40B, 550.
7. (a) Yadav, J. S.; Sunny, A.; Reddy, B. V. S.; Sabitha, G. Tetrahedron
Lett. 2001, 42, 8063; (b) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M.
Synlett 2001, 1781; (c) Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.;
Prabhakar, A.; Kunwar, A. C. Tetrahedron Lett. 2003, 44, 2221; (d)

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3341–3345
3345
Yadav, J. S.; Reddy, B. V. S.; Reddy, Ch. S. Tetrahedron Lett. 2004,
45, 4583.
8. Molecular mechanics calculations were carried out using the SYBYL 6.8
programme on a Silicon Graphics O2 workstation.
4.6, 2.2 Hz, 1H, H4(pro-S)); 13C NMR (75 MHz, CDCl3): d 196.1,
169.8, 158.3, 154.9, 135.9, 128.7, 114.2, 106.2, 81.4, 70.7, 58.9, 55.0,
30.3, 29.4, 29.2, 27.9, 20.4, 19.7; ESI-MS: m/z: 368 (M+Na), 346
(M+H), 286, 242; HRMS calcd for
C19H23NO5Na (M+Na):
9. Babu, B. S.; Balasubramanian, K. K. J. Org. Chem. 2000, 65, 4198.
10. Compound 5c was crystallized by slow evaporation from hexanes–
dichloromethane (1:1); crystal data: C19H23NO5, M = 345.38, ortho-
368.1473. Found: 368.1460. Compound 5c: solid, mp 156–158 °C;
20
½aꢂD +254 (c 1.0, MeOH); IR (KBr): mmax 2924, 2852, 1739, 1635,
1509, 1483, 1372, 1238, 1039, 957, 840 cmꢀ1 1H NMR (500 MHz,
;
˚
˚
rhombic, space group P212121, a = 8.0633(6) A, b = 12.7088(10) A,
CDCl3): d 7.05 (d, J = 9.0 Hz, 2H, ortho), 6.91 (d, J = 9.0 Hz, 2H,
meta), 4.99 (br s, 1H, H5), 4.70 (br s, 1H, H2), 3.83 (s, 3H, OMe),
3.77–3.82 (m, 2H, H1), 3.25 (br s, 1H, H3), 2.51 (dt, J = 12.6, 3.0 Hz,
1H, H4(pro-S)), 2.36 (s, 3H, 10-Me), 2.21 (s, 3H, 6-Me), 2.17 (s, 3H,
OAc), 1.62 (dt, J = 12.6, 3.2 Hz, 1H, H4(pro-R)); 13C NMR (75 MHz,
CDCl3): d 196.4, 170.6, 158.8, 156.8, 136.2, 129.1, 114.6, 106.8, 83.0,
70.0, 61.2, 55.4, 31.0, 29.6, 29.3, 24.7, 21.3, 19.9; ESI-MS: m/z: 368
(M+Na), 346 (M+H), 286, 242, 226; HRMS calcd for C19H23NO5Na
(M+Na): 368.1473. Found: 368.1478. Compound 4i: solid, mp 151–
3
c = 17.2754(13) A, V = 1770.3(2) A , Z = 4, Dcalcd = 1.296 mg mꢀ3
,
˚
˚
T = 294(2) K, l = 0.094 mmꢀ1, F(000) = 736, k = 0.71073 A. Data
collection yielded 17,066 reflections resulting in 1809 unique, averaged
reflections, 1746 with I > 2r(I). Full matrix least-squares refinement
led to a final R = 0.0297, wR = 0.0872 and GOF = 1.054. Intensity
data were measured on a Bruker Smart Apex with CCD area detector.
Crystallographic data have been deposited for compound 5c with the
Cambridge Crystallographic Data Centre, [CCDC No. 675996].
Copies of the data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving. html or CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: (+44) 1223 336 033; e-mail: deposit@
ccdc.cam.ac.uk).
˚
20
153 °C; ½aꢂD ꢀ128, (c 1.0, MeOH); IR (KBr): mmax 2950, 1724, 1630,
1517, 1438, 1379, 1298, 1241, 1196, 1121, 1039, 858, 771, 729,
671 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.20–7.28 (m, 3H, Ar-H),
;
7.04–7.12 (m, 1H, Ar-H), 5.10 (ddd, J = 10.2, 5.6, 4.4 Hz, 1H), 4.65
(br s, 1H), 3.77–3.88 (m, 1H), 3.40–3.58 (m, 2H), 2.21–2.25 (m, 1H),
2.20 (s, 3H), 2.18 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.90 (ddd,
J = 12.6, 4.4, 2.1 Hz, 1H); 13C NMR, (75 MHz, CDCl3): d 197.6,
170.6, 155.6, 142.2, 135.9, 131.5, 129.7, 128.6, 127.4, 106.0, 80.8, 71.6,
59.9, 31.0, 30.2, 28.4, 21.3, 19.6, 17.9; ESI-MS: m/z: 352 (M+Na), 330
(M+H), 226; HRMS calcd for C19H23NO4Na (M+Na): 352.1524.
11. General procedure: A mixture of 2-deoxyribose (1 mmol), aniline
(1 mmol), acetyl acetone (1 mmol) and InCl3 (10 mol %) in aceto-
nitrile (10 mL) was stirred at room temperature for the specified time
required to complete the reaction (Table 1). After complete conver-
sion, as indicated by TLC, the reaction mixture was diluted with water
and extracted with ethyl acetate (2 ꢁ 10 mL). The combined organic
layers were dried over anhydrous Na2SO4, concentrated in vacuo and
purified by column chromatography on Silica Gel (Merck, 100–200
mesh, ethyl acetate–hexane, 1:9) to afford the pure bicyclic aminol.
20
Found: 352.1511. Compound 5i: solid, mp 188–190 °C; ½aꢂD +210, (c
1.0, MeOH); IR (KBr): mmax 2924, 2858, 1737, 1637, 1522, 1434, 1375,
1335, 1241, 1193, 1143, 1050, 966, 870, 766 cmꢀ1
;
1H NMR
20
Compound 4c: solid, mp 132–134 °C; ½aꢂD ꢀ214 (c 1.0, MeOH); IR
(200 MHz, CDCl3): d 7.20–7.29 (m, 3H, Ar-H), 7.02–7.08 (m, 1H,
Ar-H), 4.72 (br s, 2H), 3.70–3.94 (m, 2H), 3.25 (br s, 1H), 2.50 (dt,
J = 12.4, 3.0 Hz, 1 H), 2.35 (s, 3H), 2.16 (s, 6H), 2.10 (s, 3H), 1.60 (dt,
J = 12.6, 3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 196.2, 170.6,
156.8, 141.7, 135.4, 131.2, 129.6, 128.3, 127.1, 106.0, 84.2, 81.6, 70.0,
61.3, 30.9, 29.3, 24.4, 21.3, 18.8; ESI-MS: m/z: 352 (M+Na), 330
(M+H), 270, 242, 226; HRMS calcd for C19H23NO4Na (M+Na):
352.1524. Found: 352.1511.
(KBr): mmax 2924, 2852, 1739, 1635, 1509, 1483, 1372, 1238, 1039, 957,
840 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.05 (d, J = 9.0 Hz, 2H,
;
ortho), 6.91 (d, J = 9.0 Hz, 2H, meta), 5.13 (ddd, J = 10.3, 5.6, 4.4 Hz,
1H, H2), 4.94 (br t, J = 3.0 Hz, 1H, H5), 3.75–3.80 (m, 1H, H1(pro-S)),
3.82 (s, 3H, OMe), 3.50–3.54 (m, 1H, H3), 3.40 (t, J = 10.8 Hz, 1H,
H1(pro-R)), 2.23 (dt, J = 12.9, 3.0 Hz, 1H, H4(pro-R)), 2.25 (s, 3H,
10-Me), 2.18 (s, 3H, 6-Me), 2.03 (s, 3H, OAc), 1.91 (ddd, J = 12.8,