Three-component reaction of aldose sugars, aryl amines, and 1,3-diones: A novel synthesis of annulated pyrroles

Article abstract of DOI:10.1021/jo702012w

(Chemical Equation Presented) Aldose sugars undergo smooth coupling with enamines, generated in situ from aryl amines and 1,3-diketones, in the presence of 10 mol % of InCl₃ in water at 80°C to furnish annulated pyrrole derivatives in relativel

Full text of DOI:10.1021/jo702012w

molecular sensors and devices.4-7 Therefore, considerable
attention has been paid to develop efficient methods for the
synthesis of pyrroles.8
Three-Component Reaction of Aldose Sugars,
Aryl Amines, and 1,3-Diones: A Novel Synthesis
of Annulated Pyrroles
Naturally occurring carbohydrates and their derivatives have
been useful during the last few decades as “chiral pool”
constituents in the enantioselective synthesis of biologically
active natural and non-natural products.9 The ready availability
of a wide range of carbohydrates in nature and their multichiral
architecture, coupled with their well-defined stereochemistry,
make them attractive starting materials in organic synthesis.10
To the best of our knowledge, there have been no reports in
the literature on the formation of annulated pyrroles via
condensation of aldose sugars with enamines. In this paper, we
disclose a direct and one-pot synthesis of optically pure
annulated pyrroles via a novel cyclization of enamines with
aldose sugars. While working on the Knoevenagel condensation
of D-glucose with â-enaminoketones in the presence of InCl3,
surprisingly, we have observed the formation of annulated
pyrroles. This provided the incentive for an extensive study.
Initially, we have examined the reaction of D-glucose with
aniline and acetyl acetone in the presence of 10 mol % of
InCl3. The reaction proceeded well in water at 80 °C and
after acetylation; the product 4a was isolated in 93% yield
(Scheme 1).
Jhillu S. Yadav,*,† Basi V. Subba Reddy,† Mende Srinivas,†
Chitteti Divyavani,† Shaik Jeelani Basha,‡ and
Akella V. S. Sarma‡
DiVision of Organic Chemistry and Centre for Nuclear
Magnetic Resonance, Indian Institute of Chemical Technology,
Hyderabad 500007, India.
yadaV@iict.res.in
ReceiVed September 13, 2007
To establish the structure, the product (dihydroxyl derivative)
thus obtained was converted as its nitrobenzoate 5a and then
submitted for extensive NMR studies. In 5a, the presence of
Aldose sugars undergo smooth coupling with enamines,
generated in situ from aryl amines and 1,3-diketones, in the
presence of 10 mol % of InCl3 in water at 80 °C to furnish
annulated pyrrole derivatives in relatively good to high yields.
The use of InCl3, in combination with water, makes this
procedure quite simple, more convenient, and environmen-
tally friendly.
(3) (a) Thompson, R. B. FASEB J. 2001, 15, 1671-1676. (b) Muchowski,
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Zeng, D. X.; Chen, Y. Synlett 2006, 490-492 and references cited therein.
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Substituted pyrroles represent an important class of hetero-
cycles which are present in a wide range of natural products
such as porphyrins and bioactive molecules including the
blockbuster drug atorvastatin calcium as well as important
antiinflammatants, antitumor agents, and immunosuppressants.1-3
Similarly, polypyrroles are of growing relevance in material
science, nonlinear optics, and supramolecular chemistry as
* Address correspondence to this author. Fax: 91-40-27160512.
† Division of Organic Chemistry.
‡ Centre for Nuclear Magnetic Resonance.
(1) Reviews: (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999,
2849-2866. (b) Jones, R. A., Ed. Pyrroles Chemistry of Heterocyclic
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10.1021/jo702012w CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/21/2008
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J. Org. Chem. 2008, 73, 3252-3254

TABLE 1. InCl3-Catalyzed Synthesis of Pyrroles from Sugers and
Enamines
SCHEME 1
prod- time yieldb
aldose
amine
1,3-dione ucta
[h]
[%]
D-glucose
D-glucose
D-glucose
D-glucose
D-glucose
C6H5NH2 (1a)
4-MeC6H4NH2 (1b)
4-MeO-C6H4NH2 (1c) acac
R-naphthylamine (1d) acac
3,4-methyleneoxy-
C6H3
acac
acac
4a
4b
4c
4d
4e
6.0
6.0
6.0
6.0
8.0
93
90
87
92
87
NH2 (1e)
D-glucose
D-manose
D-fructose
D-arabinose C6H5NH2 (1a)
D-arabinose C6H5NH2 (1a)
D-arabinose 4-MeC6H4NH2 (1b)
D-arabinose 4-MeO-C6H4NH2 (1c) maa
D-arabinose 3,4-methyleneoxy-
C6H3
4-C4H9C6H4NH2 (1f)
4-MeO-C6H4NH2 (1c) acac
C6H5NH2 (1a)
acac
4f
6.5
6.0
7.0
6.0
8.5
6.5
6.0
6.5
86
93
85
80
79
91
81
91
4g
4h
4i
4j
4k
4l
acac
acac
eaa
acac
NH2 (1e)
4m
D-arabinose 4-F-C6H4NH2 (1g)
acac
acac
acac
acac
4n
4o
4p
4a
7.0
6.0
6.0
7.5
87
92
90
47
D-xylose
D-xylose
D-sucrose
C6H5NH2 (1a)
4-Cl-C6H4NH2 (1h)
C6H5NH2 (1a)
a Products were characterized by 1H NMR,13C NMR, IR, and mass
spectrometry. b Yield refers to pure products after chromatography. c acac:
acetyl acetone. eaa: ethyl acetoacetate. maa: methyl acetoacetate.
FIGURE 1. Characteristic NOE interactions, the chemical structure,
and the energy-minimized structure of 5a.
FIGURE 3. The energy minimized structure 4h.
3
FIGURE 2. Characteristic Longe range (2JCH and JCH) correlations
from the HMBC spectrum of 5a.
NOE between aH1 and aH2 with ortho protons of the N-phenyl
group of the pyrrole ring confirms that the oxygen in the pyran
ring and nitrogen in the pyrrole ring are opposite each other.
The energy-minimized structure is shown in Figure 1 and long-
3
range (2JCH and JCH) correlations obtained from HMBC
spectrum confirming the structure as shown in Figure 2. Figure
1 shows NOE correlations observed from a NOESY spectrum.
Further the structure of 5a was confirmed by molecular
mechanics calculations.11 Initially, the structure was minimized
with steepest decent and conjugate gradient methods for 10 000
iterations. The distances calculated from the minimized struc-
tures are in good agreement with NOE data. The phenyl
connected to the nitrogen atom is oriented perpendicular to the
plane of the pyrrole ring. The ortho protons of phenyl are close
to the methyl group on the fourth carbon of the pyrrole ring as
well as to the protons aH1 and aH2. These protons are also in
proximity to dH1 and dH2. The minimized structure of 5a is
shown in Figure 1.
FIGURE 4. Characteristic NOE interactions, the chemical structure,
and the energy-minimized structure of 4i.
SCHEME 2
mannose reacted well with enaminoketone to produce the
corresponding tetrahydropyrano[3,2-b]pyrroles derivative (entry
4g, Table 1). Like aldose sugars, ketose sugar, for example,
fructose, gave the respective annulated pyrrole in 85% yield
under similar conditions (entry 4h, Scheme 2, Table 1).
The product 4a was also obtained from a disaccharide,
sucrose, under identical conditions (entry 4a, Table 1). Similarly,
(11) (a) Goto, H.; Osawa, E. J. J. Chem. Soc., Perkin Trans. 2 1993,
187. (b) Structures were calculated by using Insight II/DISCOVER modules
on a silicon graphics workstation.
The structure of 4h (Figure 3) was established by using
various NMR studies. The NMR information (NOE and HMBC)
J. Org. Chem, Vol. 73, No. 8, 2008 3253

SCHEME 3
confirms the structure as shown in the energy-minimized
structure (Figure 4). In all cases, the reactions were carried out
in water at 80 °C and the products were obtained in good to
high yields. Only a single stereoisomer was obtained in each
case, the structure of which was established by using various
1
NMR studies. The products were characterized by H and 13C
NMR, IR, and mass spectrometry. As solvent, water appeared
to give the best results. Among various Lewis acid catalysts
such as BiCl3, NbCl5, ZrCl4, TaCl5, and CeCl3·7H2O tested,
InCl3 was found to be effective in terms of conversion. The
scope and generality of this process is illustrated with respect
to various aldose sugars, aryl amines, and 1,3-dicarbonyl
compounds and the results are presented in Table 1.
SCHEME 4. A Possible Reaction Mechanism
Probably, the reaction proceeds via the condensation of
enaminoketone with sugar hemi-acetal to give an aldol product
that on subsequent cyclodehydrations followed by aromatization
would give an annulated pyrrole (Scheme 4).
In conclusion, we have demonstrated a novel, one-pot, and
efficient protocol for the preparation of annulated pyrroles via
a three-component coupling of aldose sugars, aryl amines, and
â-diketones. The use of InCl3 in water makes this procedure
quite simple, more convenient, and environmentally friendly.
The novelty and synthetic usefulness of this methodology was
demonstrated in the efficient synthesis of some interesting
optically pure annulated pyrroles.
Experimental Section
Experimental Procedure. D-Glucose (1 mmol), pentane-2,4-
dione (1 mmol), aniline (1 mmol), and InCl3 (0.1 mmol) in H2O
were stirred at 80 °C for the appropriate time (Table 1). After
completion of the reaction, as indicated by TLC, the reaction
mixture was extracted with ethyl acetate (2 × 10 mL). The
combined organic extracts were washed with water followed by
brine and dried over anhydrous Na2SO4. Removal of solvent
followed by purification on silica gel column with a mixture of
ethyl acetate:n-hexane (6:4) afforded pure product.
for 4h is very similar to that for 4a. The energy-minimized
structure of 4h is shown in Figure 3.
Acknowledgment. M. Srinivas and Ch. Divyavani thank
CSIR for the award of fellowships.
Like hexose sugars, pentose sugars such as arabinose and
xylose also reacted smoothly with â-enaminoketones to pro-
duce the corresponding annulated pyrroles in good yields
(Scheme 3).
The structure of the product 4i was determined by NMR
studies. Like 5a and 4h, in 4i also NOEs between aH1, aH2,
and ortho protons of the N-phenyl ring of pyrrole are observed.
In addition, a long range ω coupling between aH2 and cH2
Supporting Information Available: Characterization data and
1H and 13C NMR spectra for compounds 5a and 4b-q and
experimental procedure for general reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO702012W
3254 J. Org. Chem., Vol. 73, No. 8, 2008