InBr3-Catalyzed Cyclization of Glycals with Aryl Amines

Article abstract of DOI:10.1002/anie.200351267

A new class of carbohydrate analogues, benzo-fused heterobicycles 1, can be prepared by cyclization of D-glucals with aryl amines in the presence of 10 mol% indium tribromide under mild and convenient reaction conditions [Eq. (1)]. The structure and configuration of the products were established by extensive NMR experiments and molecular modeling studies.

Full text of DOI:10.1002/anie.200351267

Communications
catalyst recycling.[4] C-Glycosides bearing carbon-linked het-
erocycles have attracted great attention owing to their potent
antiviral and antitumor behavior.[5] Because of these proper-
ties of aryl glycosides, we have attempted C-glycosidation
with aryl amines to synthesize aryl C-glycosides with a free
amino functionality for further derivatization. Interestingly,
we observed for the first time an unusual formation of benzo-
fused heterobicycles in the aminoglycosidation.
In our continuing research on glycoside synthesis,[6] we
have made unprecedented observations in the aminoglycosi-
dation reactions of glycals with aryl amines, which we report
here. Initially, we attempted the aminoglycosidation reaction
of d-glucal with aniline using 10 mol% indium(iii) bromide as
a novel glycosyl activator. Interestingly, the unusual bicyclic
adduct 3a (R = H) was isolated in 85% yield with high
stereoselectivity (Scheme 1).
Glycal Cyclization
InBr3-Catalyzed Cyclization of Glycals with Aryl
Amines**
Jhillu S. Yadav,* Basi V. S. Reddy, Katta V. Rao,
Kavuda Saritha Raj, Atlaluri R. Prasad,
Singarapu Kiran Kumar, Ajit C. Kunwar,
Panjula Jayaprakash, and Bulusu Jagannath
Scheme 1. Reaction of 3,4,6-tri-O-acetyl-d-glucal (2) with aryl amines.
The product 3a was characterized thoroughly by various
NMR experiments including double-quantum-filtered corre-
lation spectroscopy (DQFCOSY), nuclear Overhauser effect
spectroscopy (NOESY), heteronuclear single-quantum cor-
Dedicated to Professor Goverdhan Mehta
on the occasion of his 60th birthday
3
relation spectroscopy (HSQC),[7] and JCH-optimized HMBC
Glycals are ambident electrophiles capable of reacting with
various nucleophiles such as alcohols, malonates, and silyl
nucleophiles under the influence of acid catalysts or oxidants
to produce 2,3-unsaturated glycosides.[1,2] In recent times,
indium halides have emerged as versatile Lewis acid catalysts
imparting high regio-, chemo-, and diastereoselectivity to a
variety of organic transformations.[3] Compared to conven-
tional Lewis acids, indium tribromide, in particular, has
advantages of low catalyst loading, moisture stability, and
experiments.[8] The edited HSQC spectrum showed the
presence of two methylene groups in addition to eight
methine and two methyl groups. The location of the
methylene group in the bridge of a bicyclononene-like
structure was confirmed by the presence of small couplings
between these protons and the bridgehead protons H1 and
H3 (JH1-H2(pro-S) = 3.7 Hz,
JH1-H2(pro-R) = 1.8 Hz, JH2(pro-S)-H3 =
2.4 Hz, and JH2(pro-R)-H3 = 4.6 Hz; Figure 1)). Fusion of the
À
À
bicyclononene and the aromatic ring at C1 C11 and NH C3
was confirmed by nOe interactions between H1 and H12.
Further support for the structure came from HMBC peaks for
H1/C12, H1/C11, H1/C16 and H12/C1. The two six-mem-
bered rings of the bicyclononane moiety have two different
conformations. The one containing oxygen takes a chair form,
[*] Dr. J. S. Yadav, Dr. B. V. S. Reddy, K. V. Rao, K. Saritha Raj,
Dr. A. R. Prasad
Division of Organic Chemistry
Indian Institute of Chemical Technology
Hyderabad-500 007 (India)
Fax: (+91)40-2716-0512
E-mail: yadav@iict.ap.nic.in
S. Kiran Kumar, Dr. A. C. Kunwar
Centre for Nuclear Magnetic Resonance
Indian Institute of Chemical Technology
Hyderabad-500 007 (India)
P. Jayaprakash, Dr. B. Jagannath
Molecular Modelling and Drug Design
Indian Institute of Chemical Technology
Hyderabad-500 007 (India)
[**] B.V.S.R., K.V.R., K.S.R., and S.K.K. thank the Council of Scientic and
Industrial Research (CSIR), New Delhi, for the award of fellowships.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Figure 1. a) Characteristic nOe interactions, b) the chemical structure,
and c) the energy-minimized structure of 3a.
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DOI: 10.1002/anie.200351267
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Angewandte
Chemie
whereas the other ring with nitrogen and fused to the
aromatic ring exists in half-chair form. HMBC peaks for
H2(pro-S)/C11 and H2(pro-R)/C4 are consistent with this structure.
The large coupling constant JH4-H5 = 10.4 Hz and the NOESY
cross peak for H2(pro-S)/H4 further support the chair form for
the ring containing these protons. The ring current of the
aromatic ring causes high-field chemical shifts for H2(pro-R)
(d = 1.96 ppm) and H5 (d = 3.58 ppm). Further the structure
of 3a was confirmed by molecular mechanics calculations.[9]
These unexpected results encouraged us to extend this
process to other glycals and aryl amines. Interestingly, a-
naphthylamine and substituted aryl amines such as electron-
rich as well as electron-deficient aniline derivatives reacted
efficiently with d-glucal under similar conditions to produce
the corresponding cyclic adducts in fairly good yields
(Table 1). Similarly, l-rhamnal also underwent cyclization
with aryl amines to produce derivatives 3p and 3q. Under
similar reaction conditions d-xylal also underwent cyclization
with aryl amines to afford the corresponding cyclic adducts 3r
and 3s.
Figure 2. Characteristic nOe interactions, the chemical structure, and
the energy-minimized structure of 3p.
the product. However, the reac-
tion of aniline and 2 in D2O at
808C gave the isomeric deuter-
ated products [2pro-R-D1]-3a and
[2pro-S-D1]-3a in equal amounts,
Table 1: Synthesis of oxaazatricyclotridecatrienyl derivatives from d-glucal and aryl amines (see
Scheme 1).
Glucal
Amine
Product[a] InBr3 (10 mol%) TMSOTf (1 equiv)
t [h] Yield [%][b] t [h]
Yield [%][b]
which
was
confirmed
by
1H NMR and FAB mass spectros-
copy.[10] This clearly indicates
that protons were abstracted
from the solvent and not from
aniline.
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
d-glucal
C6H5NH2 (1a)
2-MeC6H4NH2 (1b)
4-FC6H4NH2 (1c)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
6.0 85
5.5 82
7.0 78
6.0 84
8.0 75
9.0 80
7.5 82
7.0 78
6.0 80
5.5 85
6.0 80[c]
5.0 83
8.0 n.r.[d]
7.0 77
6.0 79
5.0 87
4.5 82
6.0 89
5.0 85
3.5
4.0
5.0
4.5
6.0
5.0
4.5
4.0
5.0
4.5
5.0
4.5
6.0
6.0
5.0
5.0
4.0
3.5
4.0
87
85
81
85
82
75
84
78
83
89
82[c]
85
n.r.[d]
78
81
85
84
82
80
4-ClC6H4NH2 (1d)
2-Br-4-Me-C6H3NH2 (1e)
a-naphthylamine (1 f)
4-Br-C6H4NH2 (1g)
4-MeO-C6H4NH2 (1h)
2-Cl-C6H4NH2 (1i)
4-MeC6H4NH2 (1j)
3-Cl-C6H4NH2 (1k)
2,5-(CH3)2-C6H3NH2 (1l)
We also found that 2 does not
react with 2,6-dimethylaniline
(Table 1), which clearly indicates
that one of the ortho positions of
aniline should be free from sub-
stitution for the success of the
reaction. Accordingly, a plausi-
ble mechanism for the formation
of product 3 may be depicted[11]
as in Scheme 2.
Although further study is
needed to settle the reaction
mechanism, this method is a
highly stereoselective, one-pot
synthesis of unusual tricyclic het-
erocycles under mild conditions.
3j
3k
3l
2,6-(CH3)2-C6H3NH2 (1m) 3m
3-Cl-4-F-C6H3NH2 (1n)
2,4-Cl2-C6H3NH2 (1o)
3n
3o
3p
3q
3r
l-rhamnal C6H5NH2 (1a)
l-rhamnal 4-MeC6H4NH2 (1j)
d-xylal
d-xylal
C6H5NH2 (1a)
4-MeC6H4NH2 (1j)
3s
[a] Products were characterized by 1H NMR, 13C NMR, IR spectroscopy and mass spectrometry. [b] Yield
refers to pure products after chromatography. [c] Ratio of regioisomers 7:3. [d] No reaction.
The conformation of product 3p was similar to that of 3a
(Figure 2). The appearance of small coupling constants,
H1-H2(pro-R) = 3.6 Hz, JH1-H2(pro-S) = 1.9 Hz, JH2(pro-R)-H3 = 2.6 Hz,
and JH2(pro-S)-H3 = 4.4 Hz, indicates that the observed confor-
mation is like bicyclononene, with the middle six-membered
ring in a half-chair conformation. The nOe cross peak for
The efficacy of various Lewis acids such as InBr3, InCl3,
CeCl3·7H2O, YCl3, and YbCl3 was tested for this conversion.
Indium tribromide was found to be the most effective catalyst
in terms of conversion and selectivity. For instance, treatment
of 2 with aniline in the presence of 10 mol% InBr3 and
10 mol% InCl3 for 6 h afforded the 3a yields of 85% and
72%, respectively. However, in the absence of InBr3 or InCl3,
the reaction did not proceed even after an extended time.
Various triflates were screened—TMSOTf, Sc(OTf)3,
Bi(OTf)3, Yb(OTf)3, Ce(OTf)3 and Sm(OTf)3—and a stoi-
chiometric amount of TMSOTf was found to be best for this
reaction.
J
H1/H8, and H2(pro-R)/H4 as well as coupling constant JH4-H5
=
10.1 Hz confirms that the six-membered ring is in a chair
conformation.
To elucidate the mechanistic pathway, we carried out the
reaction with deuterated aniline and 3,4,6-tri-O-acetyl-d-
glucal (2), but no deuterium incorporation was observed in
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Communications
Experimental Section
A
mixture of d-glucal (1 mmol), aryl amine
(1 mmol), and indium tribromide (10 mol%) or
TMSOTf (1 mmol) in dichloromethane (10 mL)
was stirred at 278C for the appropriate time
(Table 1). After completion of the reaction as
indicated by TLC, the reaction mixture was diluted
with water and extracted with dichloromethane
(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 pure cyclic adduct.
Characterization of selected products: 3a:
liquid, [a]D = 95.5 (c = 1.0, CHCl3), 1H NMR
Scheme 2. A possible reaction mechanism.
(500 MHz, CDCl3): d = 7.16 (dt, J = 1.5, 7.9 Hz,
1H, H13), 7.13 (dd, J = 1.5, 7.9 Hz, 1H, H15), 6.69
(dt, J = 1.5, 7.9 Hz, 1H, H14), 6.61 (dd, J = 1.5,
7.9 Hz, 1H, H12), 4.84 (dd, J = 3.1, 10.4 Hz, 1H,
The scope and generality of this process is illustrated with
various glycals and aryl amines (Table 1). It is important to
mention that the simple cyclic enol ethers such as 3,4-dihydro-
2H-pyran and 2,3-dihydrofuran afforded the corresponding
tetrahydroquinoline derivatives under similar reaction con-
ditions.[12] The coupling reaction of aryl amines with d-glucal
also proceeded smoothly in the presence of 10 mol% InBr3 in
water at 808C with similar yields and selectivity although with
longer reaction times (8–12 h). Furthermore, the reaction also
proceeded with protic acid, specifically montmorillonite KSF,
at 808C in 1,2-dichloroethane to yield the desired product.
The scope of this method was investigated with respect to
various glycals and a wide range of anilines including ortho-,
meta-, para-, mono-, and disubstituted anilines, and the results
are presented in the Table 1. However, in case of meta-
chloroaniline, the product obtained was a mixture of two
regioisomers 3k and 3k’ in 7:3 ratio; the reaction with 3-
chloro-4-fluoroaniline gave only a single product 3n.
H4), 4.81 (dd, J = 1.8, 3.7 Hz, 1H, H1), 4.44 (brs, 1H, NH), 4.19 (dd,
J = 4.2, 12.0 Hz, 1H, H6), 3.99 (dd, J = 2.2, 12.0 Hz, 1H, H6’), 3.84
(ddd, J = 2.4, 3.1, 4.6 Hz, 1H, H3), 3.58 (ddd, J = 2.1, 4.2, 10.4 Hz, 1H,
H5), 2.29 (ddd, J = 2.4, 3.7, 13.2 Hz, 1H, H2(pro-S)), 2.10 (s, 3H, 10-Me),
2.06 (s, 3H, 8-Me), 1.96 ppm (ddd, J = 1.8, 4.6, 13.2 Hz, 1H, H2(pro-
R));13C NMR (proton decoupled, 75 MHz, CDCl3): d = 170.8 (C7),
169.8 (C9), 145.0 (C11), 130.5 (C15), 129.9 (C13), 118.8 (C16), 117.2
(C14), 112.9 (C12), 71.8 (C4), 68.5 (C1), 67.4 (C5), 63.0 (C6), 46.6
(C3), 27.9 (C2), 21.0 (C10), 20.7 ppm (C8); FAB MS: m/z: 305 [M+],
259, 191, 144, 130, 119, 91, 69, 57.
1
3p: solid; m.p. 1478C; [a]D = À172.3 (c = 1.0, CHCl3); H NMR
(500 MHz, CDCl3): d = 7.14 (dt, J = 1.3, 7.4 Hz, 1H, H9), 7.13 (dd, J =
1.3, 7.4 Hz, 1H, H11), 6.68 (dt, J = 1.3, 7.4 Hz, 1H, H10), 6.60 (dd, J =
1.3, 7.4 Hz, 1H, H8), 4.71 (dd, J = 1.9, 3.6 Hz, 1H, H1), 4.60 (dd, J =
3.2, 10.1 Hz, 1H, H4), 4.41 (brs, 1H, NH), 3.76 (ddd, J = 2.6, 3.2,
4.4 Hz, 1H, H3), 3.47 (dq, J = 6.1, 10.1 Hz, 1H, H5), 2.25 (ddd, J = 2.6,
3.6, 13.2 Hz, 1H, H2(pro-R)), 2.21 (s, 3H, COCH3), 1.95 (ddd, J = 1.9,
4.4, 13.2 Hz, 1H, H2(pro-S)), 1.08 ppm (d, J = 6.1 Hz, 3H, 6-Me).
13C NMR (proton decoupled, 75 MHz, CDCl3): d = 170.1 (C13), 145.2
(C7), 130.4 (C11), 129.6 (C9), 119.7 (C12), 117.0 (C10), 112.8 (C8),
78.1 (C4), 68.3 (C1), 64.9 (C5), 46.8 (C3), 28.3 (C2), 21.1 (C14),
18.0 ppm (C6). FAB MS: m/z: 247 [M+], 188, 176.
Received: February 24, 2003
Revised: July 11, 2003 [Z51267]
Keywords: aminoglycosidations · aryl amines · carbohydrates ·
.
glucals · Lewis acids
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In summary, we disclose a novel one-pot synthesis of new
carbohydrate derivatives, benzo-fused heterobicycles, from
glycals and aryl amines using a catalytic amount of indium
tribromide under extremely mild and convenient conditions.
Alternatively, a stoichiometric amount of TMSOTf can also
be used to produce these products with an unusual tetrahy-
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À
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