A novel one-pot two-component synthesis of tricyclic pyrano[2,3-b] quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2004.11.084

Tricyclic pyrano[2,3-b]quinoxalines 6 have been synthesized in one step by the reaction of o-phenylenediamine and phenylhydrazone derivatives 8a-c in good yields. A one-pot two-component synthesis of tricyclic pyrano[2,3-b]quinoxalines with a pendant hydr

Full text of DOI:10.1016/j.tetlet.2004.11.084

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 221–224
A novel one-pot two-component synthesis of tricyclic
pyrano[2,3-b]quinoxalines
Shyamaprosad Goswami* and Avijit Kumar Adak
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103, India
Received 20 September 2004; revised 9 November 2004; accepted 15 November 2004
Available online 30 November 2004
Abstract—A one-pot two-component synthesis of tricyclic pyrano[2,3-b]quinoxalines with a pendant hydroxymethyl fuction at the
2-position relevant to molybtopterin is described by the reaction of o-phenylenediamine and phenylhydrazone derivatives of sugars
in good yields.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The metal-binding tetrahydropyranopterin enedithiolate
or molybdopterin (MPT) is the organic ligand of the
molybdenum co-factor (Moco), which has a reduced tri-
cyclic pyranopterin nucleus that carries a terminal phos-
phate group and a Mo atom bound to an enedithiolate
system 1.1 Detailed spectroscopic analysis and structural
characterization2a recently demonstrated that the fully
reduced pyranopterin system is present in the precursor
Z, 2 of Moco, which is different from compound Z.2b In
1990, Pfleiderer and co-workers reported elegant work
on the synthesis of pyranotetrahydropteridines, 3 from
various 5,6-diaminopyrimidines and phenylhydrazones
of pentoses.3 Joule and co-workers have recently dem-
onstrated the synthesis of the organic proligand 4
related to MPT in its protected and masked form.4
Pyrano[2,3-b]quinoxalines have proven to be the most
promising model substrates related to the MPT of
Moco.4,5 Joule and co-workers have described a linear
synthesis of pyranoquinoxalines and the cobalt complex
5 as a model complex related to MPT.5 Thus, the devel-
opment of pyrano[2,3-b]quinoxalines has been a field of
intense investigation over recent years.4–6 Herein we
describe the synthesis of pyranoquinoxalines 6, which
involved in situ cyclization of a side-chain hydroxyl
group of sugar hydrazones resulting in the pyran ring
with the desired side-chain length as found in MPT.
O
H
N
Mo(W)
S
HOOH
O
H
N
S
H
H
H
O
O
HN
P
HN
4
R3
R
R1
OH
Co
S
H
N
5
O
OP(OH)(OR)
H
R2
R
H
N
H
H
H2N
N
N
H
O
H2N
N
N
H
O
S
4
H
H
S
4a
10a
H
H
3
2
2
1
10
(R = H or nucleoside)
(other ligands on the metal not shown)
N
H
OH
O
1
(Precursor Z)
N
H
O
H
H
O
H
6 (R = H, CH2OH)
5 (Quinoxaline analog)
O
O
H
N
O
OH
H
H
H
N
H
S
OH
t-Bu
Me2N
O
N
HN
In our synthetic studies7 on Moco, we recently reported
a microwave-mediated Gabriel–Isay condensation for
the fusion a pyrazine ring onto a preformed pyrimidine
for the synthesis of 6-substituted pterins, and also onto a
benzene ring for 2-substituted quinoxalines by reaction
with D-glucose or D-galactose with appropriate diam-
ines.8 However, the use of phenylhydrazone derivatives
of these aldohexoses for the synthesis of pyranoquinox-
alines, and 6-substituted pteridines remains relatively
unexplored, although the analogous phenylhydrazones
OH
N
N
N
H
O
R
N
N
H
O
H
H
4
3 (R = NH2, SMe)
Keywords: Pyrano[2,3-b]quinoxalines; Phenylhydrazones; Molyb-
dopterin.
*
Corresponding author. Tel.: +91 33 26684561; fax: +91 33
26682916; e-mail: spgoswamical@yahoo.com
Previously named as Bengal Engineering College (Deemed
University).
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.084

222
S. Goswami, A. K. Adak / Tetrahedron Letters 46 (2005) 221–224
of sugars (e.g., D-arabinose phenylhydrazone) have
found applications in the synthesis of 6-poly-
hydroxyalkylpteridines or pyranopteridines.9 Our syn-
thesis represents for the first time, a one-step entry to
the tricyclic pyranoquinoxaline system having the de-
sired hydroxymethyl function as found in MPT.
phenylhydrazones is always involved in the cyclization
process resulting in a pyran ring and also the formation
of one diastereoisomer almost exclusively. Polyhydroxy-
pyranoquinoxalines 6b–c are soluble in alcohol and
DMSO, which make isolation of the products difficult,
so the more soluble penta-acetyl derivatives 9a–b were
prepared (acetic anhydride, DMAP, 60–80 ꢁC, 6–8 h)
in 68–80% yield for ease of purification.13
We have synthesized pyrano[2,3-b]quinoxalines using
phenylhydrazones 8a–c, which in turn were prepared
according to a literature procedure10 (Scheme 1).
The structures of tricyclic pyrano[2,3-b]quinoxalines 6
and 9 were established by spectroscopic studies.11,12 In
their 1H NMR spectra, the three methine protons
appeared in the range of 6.22–6.06 ppm (H-10a),
5.86–5.78 ppm (H-2), and 5.54–5.34 ppm (H-4a),
which are consistent with this class of compounds.5
To this end we started with D-arabinose 7a and D-glu-
cose 7b, which upon reaction with phenylhydrazine
(freshly prepared from sodium acetate and phenylhydra-
zine hydrochloride) in water at 22 ꢁC gave phenylhydra-
zones 8a and 8b in 40% and 42% yields. D-Galactose 7c
afforded D-galactose phenylhydrazone 8c in 80% yield.11
The stereochemistry at the two chiral centers (C3 and
C4) of 6 and 9 were already known from the configura-
tion of the starting phenylhydrazones of D-arabinose,
D-glucose, and D-galactose used. The cis stereochemistry
of the pyrazine/pyran ring junction was established
The synthesis of pyranoquinoxalines 6a–c was achieved
starting from these phenylhydrazones 8a–c (Scheme 2).
1
Thus the condensation reaction between o-phenylenedi-
amine and phenylhydrazones 8a–c in methanol–water
(1:1), concd HCl and 2-mercaptoethanol at 50–60 ꢁC
led to the formation of pure pyrano[2,3-b]quinoxalines
6a–c in moderate yields.12 Formation of pyranoquinox-
alines 6b–c suggests that the C5 hydroxyl group of the
using H NMR data based on both the coupling con-
stant values and also by observations from the selective
NOESY experiments (Fig. 1).
In compound 9b, the proton at H-4a (d 5.54 ppm, dd,
J = 2.0, 2.0 Hz), showed a strong NOE to the two
H
N
N
H
CHO
R6
R4
R2
R5
R3
R1
phenylhydrazine
20 oC, 4 h
R6
R4
R2
R5
R3
R1
R
R
7a: R = CH2OH, R1 = OH, R2 = H,
8a: R = CH2OH, R1 = OH, R2 = H,
R3 = OH, R4 = H, R5 = H, R6 = OH
R3 = OH, R4 = H, R5 = H, R6 = OH
(40%)
(42%)
(80%)
7b: R = CH(OH)CH2OH, R1 = OH, R2 = H,
8b: R = CH(OH)CH2OH, R1 = OH, R2 = H,
R3 = H, R4 = OH, R5 = OH, R6 = H
R3 = H, R4 = OH, R5 = OH, R6 = H
7c: R = CH(OH)CH2OH, R1 = H, R2 = OH,
8c: R = CH(OH)CH2OH, R1 = H, R2 = OH,
R3 = H, R4 = OH, R5 = OH, R6 = H
R3 = H, R4 = OH, R5 = OH, R6 = H
Scheme 1.
R3
R4
R1
H
N
H
NH2
R2
phenylhydrazones 8a-c
4
3
methanol-water (1:1),
5N HCl (0.5-1.0 mL),
2-mercaptoethanol
(2-3 drops),
NH2
N
H
O
R
H
H
6a: R = H,
R1 = H, R2 = OH, R3 = H, R4 = OH (38%)
50-60 oC, 4-6 h
6b: R = CH2OH,
R1 = H, R2 = OH, R3 = OH, R4 = H (40%)
6c: R = CH2OH,
R1 = OH, R2 = H, R3 = OH, R4 = H (58%)
OAc
Ac
N
R1
H
H
R2
6b
or
6c
Ac2O, DMAP
4
3
OAc
N
O
60-80 oC, 6-8 h
H
Ac
9a: R1 = H, R2 = OAc (68%)
9b: R1 = OAc, R2 = H (80%)
Scheme 2.

S. Goswami, A. K. Adak / Tetrahedron Letters 46 (2005) 221–224
223
Schwarz, G. J. Biol. Chem. 2004, 279, 15994–15999; (b)
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Ac
OAc
Ac 5 N
H
H
4
3
O1
Ac
N
OAc
N
10
5
4a
10a
2
4a
H
H
2
10
OAc
OAc
3. (a) Soyka, von R.; Pfleiderer, W.; Prewo, R. Helv. Chim.
Acta 1990, 73, 808–826; (b) Soyka, R.; Pfleiderer, W.
Pteridines 1990, 2, 63–74.
10a
4
H
OAc
OAc
H
N
O
1
H
H
9b
Ac
4. For recent examples, see: (a) Bradshaw, B.; Collison, D.;
Garner, C. D.; Joule, J. A. Chem. Commun. 2001, 123–
124; (b) Bradshaw, B.; Dinsmore, A.; Ajana, W.; Collison,
D.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 2001, 3239–
3244; (c) Bradshaw, B.; Dinsmore, A.; Collison, D.;
Garner, C. D.; Joule, J. A. Org. Biomol. Chem. 2003, 1,
129–133.
5. (a) Bradshaw, B.; Dinsmore, A.; Garner, C. D.; Joule, J.
A. Chem. Commun. 1998, 417–418; (b) Bradshaw, B.;
Dinsmore, A.; Collison, D.; Garner, C. D.; Joule, J. A.
J. Chem. Soc., Perkin Trans. 1 2001, 3232–3238.
6. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.;
Litvinov, I. A.; Levin, Ya. A. Chem. Heterocyl. Compd.
2003, 39, 96–100.
7. (a) Taylor, E. C.; Goswami, S. P. Tetrahedron Lett. 1991,
32, 7357–7360; (b) Pilato, R. S.; Eriksen, K. E.; Greaney,
M. A.; Stiefel, E. I.; Goswami, S.; Kilpatrick, L.; Spiro, T.
G.; Taylor, E. C.; Rheingold, A. R. J. Am. Chem. Soc.
1991, 113, 9372–9374; (c) Goswami, S. P. Heterocycles
1993, 35, 1551–1572; (d) Goswami, S. P.; Adak, A. K.
Tetrahedron Lett. 2002, 42, 503–505; (e) Goswami, S. P.;
Adak, A. K. Chem. Lett. 2003, 32, 678–679.
Figure 1. Key NOESY interactions observed in 9b.
methine proton signals at d 6.22 ppm (d, J = 3.0 Hz, H-
10a) and at d 5.78 ppm (dd, J = 3.0, 3.0 Hz, H-2), for H-
10a and H-2, respectively, and thus established their cis
relationships. The small coupling constant values
(J = 2.0–3.0 Hz) of H-4a with H-10a, and H-2 also sug-
gested that these protons are cis with an axial–equatorial
arrangement in a chair conformation (see Fig. 1).9d
The instabilities of pyranoquinoxalines or pyranopter-
idines are mainly due to the reversible proton-catalyzed
cleavage of the N–C–O system followed by irreversible
aerial oxidation, which ultimately produces 2- and
6-substituted derivatives.14 Therefore, protection is re-
quired in order to avoid such oxidation of the tricyclic
form. The pyranoquinoxalines 6 are relatively stable
compounds and did not undergo such oxidative cleav-
age to 2-substituted dihydro- or fully oxidized systems
during acetylation as suggested from the 1H NMR stud-
ies of 9.
8. Goswami, S. P.; Adak, A. K. Tetrahedron Lett. 2002, 43,
8371–8373.
9. (a) Viscontini, M.; Provenzale, R.; Olhgart, S. Helv. Chim.
Acta 1970, 53, 1202–1207; (b) Russell, J. R.; Garner, C.
D.; Joule, J. A. Synlett 1992, 711–712, and references cited
therein; (c) Low, J. N.; Lopez, M. D.; Quijano, M. L.;
Sanchez, A.; Nogueras, M. Acta Cryst. 1999, C55, 452–
454; (d) Lopez, M. D.; Quijano, M. L.; Sanchez, A.;
Nogueras, M.; Low, J. N. J. Heterocyl. Chem. 2001, 38,
727–736; (e) For a recent report in this series, see: Guiney,
D.; Gibson, C. L.; Suckling, C. J. Org. Biomol. Chem.
2003, 1, 664–675.
In conclusion, we have developed a novel one-step pro-
cedure for the synthesis of tricyclic pyrano[2,3-b]quinox-
alines, which have the desired side-chain length as found
in MPT of the molybdenum co-factor. Further work on
pteridine derivatives is underway.
Acknowledgements
10. (a) Wolform, M. L.; Christman, C. C. J. Am. Chem. Soc.
1931, 53, 3413–3419; (b) Mester, L.; Messmer, A. Methods
Carbohydr. Chem. 1963, 2, 117–118.
We are thankful to the Council of Scientific and Indus-
trial Research (CSIR), Government of India for finan-
cial support and the Bose Institute, Kolkata for access
to a 500 MHz NMR instrument. A.K.A. acknowledges
CSIR, Government of India for a research fellowship.
11. All compounds gave satisfactory spectroscopic data.
Selected physical data for compound 8c: Pale-yellow solid.
Mp 150–153 ꢁC [lit.10b 154–155 ꢁC]. UV/vis (CHCl3): kmax
(log e): 274 nm (5.0). FT-IR (KBr): 3480, 2925, 1751, 1435,
1374, 1221, 1046, 746 cmÀ1
500 MHz):
.
1H NMR (DMSO-d6,
(ppm) = 10.13 (s, 1H), 7.63 (d, 1H,
d
References and notes
J = 6.3 Hz), 7.51 (t, 2H, J = 7.9 Hz), 7.28 (d, 2H,
J = 7.6 Hz), 7.03 (t, 1H, J = 7.2 Hz), 5.10 (d, 1H, J =
6.2 Hz), 4.79 (t, 2H, J = 5.2 Hz), 4.72 (t, 1H, J = 6.3 Hz),
4.53 (t, 2H, J = 8.9 Hz), 4.10 (q, 1H, J = 6.5 Hz), 3.89
(p, 2H, J = 8.7 Hz), 3.82–3.74 (m, 2H). 13C NMR
(DMSO-d6, 125 MHz): dC (ppm) = 146.72 (d), 143.28,
129.80, 118.82, 112.45, 73.29 (d), 71.08 (d), 70.70 (d), 70.04
(d), 63.92 (d). MS (ESI): m/z (%) = 270 (M+, 8), 149 (32),
108 (9), 93 (100), 65 (10), 28 (27).
1. (a) Chan, M. K.; Mukund, S.; Kletzin, A.; Adams, M. M.
W.; Rees, D. C. Science 1995, 267, 1463–1469; (b) Romao,
M. J.; Archer, M.; Moura, I.; Moura, J. J. G.; LeGall, J.;
Engh, E.; Schneider, M.; Hof, P.; Huber, R. Science 1995,
270, 1170–1176; (c) Schindelin, H.; Kisker, C.; Hilton, J.;
Rajagopalan, K. V.; Rees, D. C. Science 1996, 272, 1615–
1621; (d) Hille, R. Chem. Rev. 1996, 96, 2757–2816; (e)
Boyington, J. C.; Gladyshev, V. N.; Khangulov, S. V.;
Stadtman, T. C.; Sun, P. C. Science 1997, 275, 1305–1308;
(f) Baugh, P. E.; Collison, D.; Garner, C. D.; Joule, J. A.
In Comprehensive Biological Catalysis, 1998; Vol. III, pp
377–400; (g) Hille, R.; Retey, J.; Bartlewski-Hof, U.;
Reichenbecher, W.; Schink, B. FEMS Microbiol. Rev.
1999, 22, 489–501; (h) Li, H.-K.; Temple, C.; Rajagopa-
lan, K. V.; Schindelin, H. J. Am. Chem. Soc. 2000, 122,
7673–7680.
12. Typical experimental procedure for the condensation of
o-phenylenediamine with D-galactose phenylhydrazone.
Synthesis of pyrano[2,3-b]quinoxaline 6c. To a stirred
solution of o-phenylenediamine (0.12 g, 1.11 mmol) in a
50% mixture of methanol–water (20 mL) were added
freshly prepared D-galactose phenylhydrazone (0.33 g,
1.21 mmol), two drops of 2-mercaptoethanol and HCl
(5 N, 0.5 mL). The reaction mixture was heated for 4 h at
50 ꢁC and then allowed to cool to room temperature and
then cooled at 0 ꢁC. The resulting brown precipitate was
collected by filtration, washed with cold water, acetone,
2. For a recent discussion, see: (a) Santamaria-Araujo, J. A.;
Fischer, B.; Otte, T.; Nimtz, M.; Mendel, R. R.; Wray, V.;

224
S. Goswami, A. K. Adak / Tetrahedron Letters 46 (2005) 221–224
and ether, dried, which consisted of mainly the title
in methylene chloride afforded the penta-acetyl derivative
9b as a light-yellow solid. Mp 144–145 ꢁC; UV/vis
(CHCl3): kmax (log e): 271 (8.3), 245 nm (8.3). FT-IR
compound 6c (0.14 g, 58%). Mp 240 ꢁC (dec); UV/vis
(CH3OH): kmax (log e): 280 (3.2), 273 (3.2), 243 nm (3.2).
FT-IR (KBr): 3558, 3399, 2926, 1624, 1433, 1269, 1105,
1
(KBr): 3479, 2925, 1752, 1435, 1374, 1220, 1047 cmÀ1. H
1036 cmÀ1
.
1H NMR (DMSO-d6, 300 MHz):
d
NMR (CDCl3, 500 MHz): d (ppm) = 7.27–7.23 (m, 4H),
6.22 (d, 1H, J = 3.0 Hz), 5.78 (dd, 1H, J = 3.0, 3.0 Hz),
5.54 (dd, 1H, J = 2.0, 2.0 Hz), 5.32 (dt, 1H, J = 2.0, 4.0,
2.2 Hz), 4.30 (dd, 1.5H, J = 5.1, 5.1 Hz), 3.90 (dd, 1.5H,
J = 7.3, 7.3 Hz), 2.19, 2.09, 2.05, 2.02, and 1.97 (5 · s,
15H, 2 · NHCOCH3 and 3 · OCOCH3). 13C NMR
(CDCl3, 125 MHz): dC (ppm) = 170.86, 170.71, 170.48,
170.34, 169.46, 148.51, 131.32, 129.25, 69.37, 68.47, 68.02,
67.92, 62.39, 21.11, 21.07, 21.03, 20.91, 20.88. MS (FAB):
m/z (%) = 479 (M++NH3, 100), 419 (M–Ac, 10), 377
(M À 2 · Ac, 10), 317 (15), 257 (5), 203 (10), 161 (40), 147
(35). Anal. Calcd for C22H26N2O9: C, 57.13; H, 5.66; N,
6.05. Found: C, 57.01; H, 5.78; N, 5.99.
(ppm) = 7.58–7.56 (m, 2H), 7.16–7.08 (m, 2H), 6.90 (d,
1H, J = 7.8 Hz), 6.50 (dd, 1H, J = 3.4, 2.1 Hz), 6.38 (dd,
1H, J = 3.5, 2.2 Hz), 5.52 (d, 1H, J = 6.5 Hz), 5.14 (d, 2H,
J = 6.0 Hz), 3.91 (t, 2H, J = 7.7 Hz), 3.75 (br s, 2H), 3.62
(d, 2H, J = 9.3 Hz). 13C NMR (DMSO-d6, 125 MHz): dC
(ppm) = 158.53, 148.51, 123.69, 122.02, 73.59, 70.78,
70.03, 68.35, 63.98. MS (ESI): m/z (%) = 269.2
(M++NH3, 100), 251.2 (20), 215.4 (10), 174.9 (15), 161.2
(25), 147.2 (30).
13. The pyrano[2,3-b]quinoxaline 6c (0.08 g, 0.23 mmol), ace-
tic anhydride (1.0 mL), and DMAP (10 mg) were heated at
60–80 ꢁC for 4–6 h and then evaporated under reduced
pressure. The residue was dissolved in methylene chloride,
washed with 5% NaHCO3, water, and dried (Na2SO4).
The organic layer after evaporation and purification by
preparative thin layer chromatography using 1% methanol
14. For a discussion on the stability of reduced pyranoquin-
oxalines or pyranopteridines, see: (a) Ref. 4a; (b) Great-
banks, S. P.; Hillier, I. H.; Garner, C. D.; Joule, J. A. J.
Chem. Soc., Perkin Trans. 2 1997, 1529–1534.