Two-step synthetic route to 10-substituted isoalloxazines

Article abstract of DOI:10.1080/00397910600602552

10-Substituted isoalloxazines were synthesized in two steps starting from 1,2-phenylenediamine. Monoalkylation of the diamine resulted in 2-amino-N-alkylanilines, which were subsequently condensed with alloxan in boric acid and acetic acid to give 10-subs

Full text of DOI:10.1080/00397910600602552

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Two‐Step Synthetic Route to 10‐Substituted
Isoalloxazines
Prosenjit Chattopadhyay a , Roopali Rai a & Pramod S. Pandey a
a Department of Chemistry, Indian Institute of Technology, New Delhi, India
Version of record first published: 18 Aug 2006
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Route to 10‐Substituted Isoalloxazines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:13, 1857-1861
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Synthetic Communicationsw, 36: 1857–1861, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602552
Two-Step Synthetic Route to 10-Substituted
Isoalloxazines
Prosenjit Chattopadhyay, Roopali Rai, and Pramod S. Pandey
Department of Chemistry, Indian Institute of Technology Delhi,
New Delhi, India
Abstract: 10-Substituted isoalloxazines were synthesized in two steps starting from
1,2-phenylenediamine. Monoalkylation of the diamine resulted in 2-amino-N-alkylani-
lines, which were subsequently condensed with alloxan in boric acid and acetic acid to
give 10-substituted isoalloxazines.
Keywords: Flavin mimic, flavoenzyme, isoalloxazines, monoalkylation
Flavin coenzymes represented by FAD (flavin adenine dinucleotide) and FMN
(flavin mononucleotide) play important roles in a wide variety of redox
reactions through interactions with apoproteins.[1–4] There has been considerable
debate over the reaction pathways and mechanisms utilized by these flavoproteins
because of the complexity of the native enzymatic systems.[5–9] Synthetic models
play a crucial role here, as they help us to understand the individual interactions
and reaction pathways, which become somewhat difficult with the complex
flavoenzyme systems. Isoalloxazines have been widely used by many groups
as synthetic models for flavin to observe the effects of individual interactions
on flavoenzyme behavior.[10–14] As a result, 10-substituted isoalloxazines have
been synthesized via a number of routes.[12–18] However, the methods involve
expensive starting materials as well as a number of synthetic steps. We report
here a simple two-step method for the synthesis of 10-substituted isoalloxazines.
Our synthetic strategy involves the selective monoalkylation of 1,2-pheny-
lenediamine followed by cyclization of the 2-amino-N-alkylanilines with
Received in India December 16, 2005
Address correspondence to Pramod S. Pandey, Department of Chemistry, Indian
Institute of Technology, Hauz Khas, New Delhi 110016, India. Tel: 91-11-2659-
1506; Fax: 91-11-2658-2037; E-mail: pramod@chemistry.iitd.ac.in
1857

1858
P. Chattopadhyay, R. Rai, and P. S. Pandey
Scheme 1.
alloxan in acidic conditions. Alkylation of a primary amino group normally
results in the formation of secondary, tertiary and quaternary amine salts.
However, the monoalkylated product can be selectively obtained by using
amines in large excess. Thus, 2-amino-N-alkylanilines were synthesized by
the reaction of alkyl bromides with an excess of 1,2-phenylenediamine and
anhydrous potassium carbonate in dry methanol for 12h. The reaction
mixture was concentrated in vacuo, and the residue was flash chromatographed
on silica gel (230–400 mesh) using hexane–ethyl acetate (9 : 1) as eluent to
obtain pure 2-amino-N-alkylanilines in 50–60% yields. The products were
1
characterized by IR and H NMR. The unreacted 1,2-phenylenediamine was
recovered by using methanol as a eluent. The cyclocondensation of 2-amino-
N-alkylanilines with alloxan in boric acid and acetic acid resulted in the
formation of 10-alkylated isoalloxazines. Acetic acid was removed in vacuo,
and the residue was flash chromatographed on silica gel (230–400 mesh)
using CHCl3–MeOH (97 : 3) as eluent to obtain pure 10-alkylated isoalloxa-
zines in 45–50% yields. The products were characterized by various spectro-
1
scopic data including IR, H, 13C NMR, and mass spectrometry. This is a
more efficient synthetic route because it not only helps in reducing at least
one synthetic step in the preparation of 10-alkylated isoalloxazines but also is
more economical because of inexpensive starting materials (Scheme 1).
EXPERIMENTAL
´ ´
Melting points are uncorrected. IR spectra were recorded on a Nicolet Protege
1
460 FTIR spectrometer, using potassium bromide pellets. H and 13C NMR
spectra were recorded on a Bruker Spectrospin DPX 300. Tetramethylsilane
was used as internal reference, and the chemical shifts are expressed as

Two-Step Synthetic Route to 10-Substituted Isoalloxazines
1859
displacement (d) in ppm downfield from tetramethylsilane. Mass spectrum for
3a was recorded on a quadrupole mass spectrometer (VG Platform-II) using
acetonitrile–water (1 : 1) as mobile phase. Mass spectra for 3b, c were
recorded on a Quadrupole-TOF Ultima on ESI mode using acetonitrile con-
taining 0.1% formic acid. Elemental analyses were taken on a Perkin-Elmer
2400C elemental analyzer. Column chromatography was carried out using
Spectrochem silica gel 230–400 mesh for flash chromatography. The solid
compounds were dried under vacuum in the presence of P2O5.
General Procedure for the Synthesis of 2-Amino-N-alkylanilines
o-Phenylenediamine 1 (4.00 g, 37 mmol) was dissolved in methanol (20 ml).
To this, benzyl bromide (1.36 g, 8.0 mmol) and K2CO3 (3.0 g, 21.7 mmol)
were added. The reaction mixture was allowed to stir at rt for 20 h. The
solvent was evaporated, and the residue was flash chromatographed on a
silica-gel column (230–400 mesh) [5–20% (v/v) ethyl acetate in hexane]
to give 2-amino-N-benzylaniline 2a as a dark brown viscous liquid.
General Procedure for the Synthesis of 10-Alkyl Isoalloxazines
2-Amino-N-benzylaniline 2a (0.59 g, 3.0 mmol) was dissolved in acetic acid
(10 ml), and the contents were heated to 50 8C. To this, a preheated (50 8C)
mixture of alloxan monohydrate (0.48 g, 3.0 mmol) and boric acid (0.22 g,
3.5 mmol) in acetic acid was added. The reaction mixture was stirred overnight
at 50–55 8C. Acetic acid was removed in vacuo, and the solid obtained was
flash chromatographed on a silica-gel column (230–400 mesh) [1–3% (v/v)
methanol in chloroform] to give the product 3a as bright yellow solid.
Data
1-(N-Benzylamino)-2-aminobenzene (2a): Yield 0.78 g, 50%; IR nmax
(KBr)/cm21 3335, 1057; dH (300 MHz, CDCl3) 7.37–7.23 (m, 5H, Ph),
6.81 (m, 1H, Ph), 6.68 (m, 3H, Ph), 4.26 (s, 2H, –CH2Ph), 3.37 (br, 3H,
–NH– and –NH2).
10-Benzylisoalloxazine (3a): mp 273–276 8C; yield 0.40 g, 45%; IR nmax
(KBr)/cm21 3446, 1717, 1683, 1243; dH (300 MHz, DMSO-d6) 11.47
(s, 1H, NH), 8.16 (d, 1H, Ph), 7.84–7.79 (m, 1H, Ph), 7.68–7.57 (m, 2H,
Ph), 7.36–7.25 (m, 5H, Ph), 5.90 (br s, 2H, –CH2Ph); 13C NMR (DMSO-
d6) d 47.22, 116.71, 126.18, 126.90, 127.60, 128.74, 131.86, 132.38,
134.62, 134.89, 139.38, 151.23, 155.91, 159.89; ESI mass: 327.38
(Mþ þ Na), 305.40 (Mþ þ H). Anal. calcd. for C17H12N4O2: C, 67.10; H,
3.97; N, 18.41. Found C, 67.12; H, 4.17; N, 18.27.

1860
P. Chattopadhyay, R. Rai, and P. S. Pandey
1-(N-Hexylamino)-2-aminobenzene (2b): Yield 0.90 g, 57%; IR nmax (KBr)/
cm21 3330, 2920, 1599, 1515, 1453, 1265, 730; dH (300 MHz, CDCl3)
6.83–6.79 (m, 1H, Ph), 6.71–6.62 (m, 3H, Ph), 3.39–3.28 (br m, 3H,
–NH– and –NH2), 3.10–3.04 (t, 2H, –CH2), 1.70–1.61 (m, 2H, –CH2),
1.43–1.26 [m, 6H, –(CH2)3], 0.91–0.85 (t, 3H, –CH3).
10-Hexylisoalloxazine (3b): mp 246-247 8C; yield 0.44 g, 48%; IR nmax
(KBr)/cm21 3440, 2920, 1715, 1681, 1240; dH (300 MHz, CDCl3) 10.51
(s, 1H, NH), 8.24–8.21 (d, 1H, Ph), 7.88–7.82 (m, 1H, Ph), 7.60–7.54
(m, 2H, Ph), 4.62 (t, 2H, –CH2), 1.84–1.74 (m, 2H, –CH2), 1.45–1.18 [m,
6H, –(CH2)3], 0.86–0.81 (t, 3H, –CH3); 13C NMR (DMSO-d6) d 13.88,
22.03, 25.82, 26.41, 30.97, 44.20, 116.34, 125.95, 131.83, 132.35, 134.88,
134.97, 138.66,þ 150.35, 155.71, 159.75; ESI-LRMS calcd. for
.
(C16H18N4O2 H) 299.159, found 299.106. Anal. calcd. for C16H18N4O2:
C, 64.41; H, 6.08; N, 18.78. Found C, 64.85; H, 6.20; N, 18.47.
1-(N-Octylamino)-2-aminobenzene (2c): Yield 0.93 g, 60% IR nmax (KBr)/
cm21 3329, 3044, 2923, 1599, 1513, 1454, 1268, 737; dH (300 MHz, CDCl3)
6.84–6.80 (m, 1H, Ph), 6.72–6.64 (m, 3H, Ph), 3.40-3.30 (br m, 3H, –NH–
and –NH2), 3.11–3.06 (t, 2H, –CH2), 1.71–1.61 (m, 2H, –CH2), 1.42–1.28
[m, 10H, –(CH2)5], 0.90–0.86 (t, 3H, –CH3).
10-Octylisoalloxazine (3c): mp 248–249 8C; yield 0.43 g, 50%; IR nmax
(KBr)/cm21 3443, 2922, 1714, 1683, 1242; dH (300 MHz, CDCl3) 8.54
(s, 1H, NH), 8.35–8.33 (d, 1H, Ph), 7.96–7.91 (m, 1H, Ph), 7.66–7.64
(m, 2H, Ph), 4.71 (t, 2H, –CH2), 1.87 (br m, 2H, –CH2), 1.58–1.28 [m,
10H, –(CH2)5], 0.88 (t, 3H, –CH3); 13C NMR (DMSO-d6) d 13.98, 22.13,
26.19, 26.48, 28.65, 28.78, 31.24, 44.23, 116.38, 125.99, 131.86, 132.39,
134.91, 135.00, 138.70, 138.99, 150.38, 155.76, 159.80; ESI-LRMS calcd.
þ
.
for (C18H22N4O2 H)
327.182, found 327.160. Anal. calcd. for
C18H22N4O2: C, 66.24; H, 6.79; N, 17.17. Found C, 66.45; H, 7.06; N, 16.91.
ACKNOWLEDGMENT
P. C. and R. R. are thankful to the Council of Scientific and Industrial
Research, New Delhi, and Indian Institute of Technology, Delhi, respectively,
for research fellowships.
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