Microwave-assisted synthesis of 10-substituted isoalloxazines in the presence of solid acids

Article abstract of DOI:10.1081/SCC-120017194

The microwave-enhanced synthesis of 10-substituted isoalloxazines is achieved rapidly (～4 min) and in good yield (>80-95%) via the cyclocondensation of 2-substituted aminoanilines with alloxan or N-methylalloxan monohydrate in the presence of acidic alumi

Full text of DOI:10.1081/SCC-120017194

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Microwave-Assisted Synthesis of 10-Substituted
Isoalloxazines in the Presence of Solid Acids
S. M. S. Chauhan a , Ram Singh a & Geetanjali a
a Department of Chemistry , University of Delhi , Delhi, India
Published online: 21 Aug 2006.
To cite this article: S. M. S. Chauhan , Ram Singh & Geetanjali (2003) Microwave-Assisted Synthesis of 10-Substituted
Isoalloxazines in the Presence of Solid Acids, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:7, 1179-1184, DOI: 10.1081/SCC-120017194
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1179–1184, 2003
Microwave-Assisted Synthesis of
10-Substituted Isoalloxazines in the Presence
of Solid Acids
*
S. M. S. Chauhan, Ram Singh, and
Geetanjali
Department of Chemistry, University of Delhi,
Delhi, India
ABSTRACT
The microwave-enhanced synthesis of 10-substituted isoalloxazines is
achieved rapidly (ꢀ4 min) and in good yield (>80–95%) via the
cyclocondensation of 2-substituted aminoanilines with alloxan or
N-methylalloxan monohydrate in the presence of acidic alumina or
montmorillonite clays (KSF and K10).
Key Words: Isoalloxazine; Microwave; Montmorillonite clays;
Acidic alumina.
*Correspondence: S. M. S. Chauhan, Department of Chemistry, University of
Delhi, Delhi-7, India; E-mail: smschauhan@chemistry.du.ac.in.
1179
DOI: 10.1081/SCC-120017194
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1180
Chauhan, Singh, and Geetanjali
Selective absorption of microwave irradiation in conjunction with the
use of catalysts or mineral supported reagents provide unique reaction
environments leading to enhanced yield, reaction rate and easy work up
of various organic reactions.[1,2] Supported reagents on inorganic oxide
surfaces like alumina, clays, silicas and zeolites in conjunction with
microwave irradiation have received attention in recent years.[3,4]
10-Substituted isoalloxazines (or flavins) are natural cofactors for many
enzymes, which play important roles in the versatile redox reaction[5] and
are found to possess antimalarial activity.[6] The cyclocondensation of
2-substituted aminoanilines (1) with alloxan or N-methylalloxan mono-
hydrate (2) in the presence of mineral acids in water or organic solvents is
an important method for the synthesis of 10-substituted isoalloxazines (3)
in 18–40% yield.[7–10] This conventional method involves pooryield, long
reaction times and the use of corrosive mineral acids. We report the
cyclocondensation of 2-substituted aminoanilines (1) with alloxan or
N-methylalloxan monohydrate (2) to afford 10-substituted isoalloxazines
(3) (Sch. 1) in the presence of solid acids[11,12] under microwave irradia-
tion (MWI)[13] in high yield.
The cyclocondensation of 2-substituted aminoanilines (1) with
alloxan or N-methylalloxan monohydrate (2) in boric acid and acetic
acid (10 mL) gave 10-substituted isoalloxazines (3) in 39–55% yields
(method A). The same reaction under microwave irradiation in minimum
amount of acetic acid (0.5 mL) afforded 3 in 74–84% yield (method B).
Further, the mixture of 1 and 2 under microwave irradiation in the pres-
ence of acidic alumina gave 3 in 88–97% yield (method C). The yields of 3
in the presence of montmorillonite KSF and K10 are reported in the
Table 1. Results are summarized in the Table and improvements in the
yield of the solid phase reactions in comparison with the other two meth-
ods are observed throughout. Although, the use of minimum amount of
acetic acid under microwave irradiation is giving higher yield than the
solution heating, the use of mineral acids in microwave ovens are not
advised. Hence, method C is betterin compairson with the othertwo.
Amongst the solid acid, acidic alumina gave betteryield in comparison
Scheme 1.

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10-Substituted Isoalloxazines
1181
Table 1. Yields (%) of 10-substituted isoalloxazines* under different reaction
conditions.
Yield (%)
Lit# M.p.
(ꢁC)
C
a/b/c
Compd.
R
R0
M.p. (ꢁC)
A
B
3a
3b
3c
3d
3e
3f
C6H5
H
>340
>300
>300
>300
>340
>340
247
>360[14]
>300[14]
>300[14]
>300[14]
>360[15]
347[15]
55 78 93/84/89
50 80 89/87/89
39 79 90/84/84
45 81 97/80/83
51 79 92/84/85
53 84 95/86/88
20-CH3C6H4
20-OCH3C6H4
40-OCH3C6H4
CH3
H
H
H
H
CH2CH3
H
3g
3h
3i
(CH2)9CH3
(CH2)11CH3
C6H5
H
246–247[14] 52 78 90/84/84
262–263[16] 50 78 89/85/85
H
262
CH3
CH3
>340
>340
>340
333
>360[6]
>360[6]
353[6]
334[15]
156[7]
53 80 94/85/86
49 75 88/86/86
44 72 95/79/81
50 79 90/85/86
51 80 89/86/87
3j
20-CH3C6H4
3k
3l
40-OCH3C6H4 CH3
CH3
(CH2)9CH3
(CH2)11CH3
CH3
CH3
CH3
3m
3n
156
177
177–179[16] 53 74 89/84/84
*The products were well characterized by normal spectroscopic data.
#see references.
Asolution heating.
Bsolution phase MWI.
Csolid phase MWI.
aacidic alumina.
bMont. KSF.
cMont. K10.
with montmorillonite clays. Hence, the microwave irradiation in conjunc-
tion with solid acids is solvent free, easy and convenient method for the
synthesis of 10-substituted isoalloxazines in high yield.
EXPERIMENTAL
Melting points were determined on a Thomas Hoover Capillary
melting point apparatus and are uncorrected. The purities of the com-
pounds were determined on silica-coated Al plates (Merck). All the
microwave-assisted reactions were carried out in a Padmini Essentia
domestic microwave oven, Model Brownie. Montmorillonite clays and
Acidic alumina were obtained from Fluka (Switzerland) and s.d. fine-

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1182
Chauhan, Singh, and Geetanjali
chem Ltd. (Mumbai) respectively. Alloxan monohydrate was obtained
from Acros (Belgium) and N-methylalloxan was synthesized from
theobromine (M.p. 150ꢁC, lit.[17] M.p. 150–151ꢁC). 2-Substituted
aminoanilines were prepared by the reduction of corresponding nitro
compounds with SnCl2/HCl.[14,16]
General Procedure for the Synthesis of 10-Substituted
Isoalloxazines (3)
Method A: The Condensation of 1 and 2 in Acidic Solutions
In a typical example, a mixture of 2-phenylaminoaniline (1a, 0.092 g,
0.5 mmol), alloxan monohydrate (2, 0.096 g, 0.6 mmol) and boric acid
(0.031 g, 0.5 mmol) was refluxed in glacial acetic acid (10 mL) for
1 h at 120ꢁC. The reaction mixture was allowed to cool to room
temperature. The excess acetic acid was removed under reduced
pressure. The residue was chromatographed on silica gel (60–120
mesh) using CHC13:CH3OH (97:3) as eluent to get 10-phenylisoallox-
azine (3a).
Method B: Solution Phase Microwave Irradiation
A paste of 2-phenylaminoaniline (1a) (0.092 g, 0.5 mmol), alloxan
monohydrate (2) (0.096 g, 0.6 mmol), boric acid (0.031 g, 0.5 mmol) and
glacial acetic acid (0.5 mL) was subjected to microwave irradiation in
a borosil beaker (25 mL) for 4 min with an interval after every 1 min.
The temperature inside the beaker was found to be 100–110ꢁC after
removing it from the microwave oven. The reaction mixture was allowed
to cool to room temperature. The crude product chromatographed
on silica gel (60–120 mesh) using CHCl3:CH3OH (97:3) as eluent to
get 10-phenylisoalloxazine (3a).
Method C: Solid Phase Microwave Irradiation
2-Phenylaminoaniline (1a) (0.092 g, 0.5 mmol), alloxan monohydrate
(2) (0.096 g, 0.6 mmol) and solid acid (1.5 g) was thoroughly grounded
and subjected to microwave irradiation in a borosil beaker (25 mL)

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10-Substituted Isoalloxazines
1183
for 4 min with an interval after every 1 min. The temperature inside
the beakerwas found to be 110–120 ꢁC after removing it from the
microwave oven. The reaction mixture was allowed to cool to room
temperature. The crude product was dissolved in CH3OH:CHCl3 (1:1)
and filtered through celite. The filtrate was concentrated to dryness and
the crude product was recrystallized from ethanol affording 3a as yellow
solid.
ACKNOWLEDGMENTS
Financial assistance as SRF to RS by UGC and JRF to G by CSIR,
New Delhi, India is gratefully acknowledged.
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Received in the USA May 15, 2002