A One-pot Synthesis of Cyclic Pyrido[1,2-a]quinoxaline Phosphate, a New Molecule of Biological Importance from a Quinoxaline Derivative of Sugar

Article abstract of DOI:10.1246/cl.2003.678

A five membered cyclic pyrido[1,2-a]quinoxaline phosphate has been first synthesized in one step in a good yield by phosphorylation of the quinoxaline derivative of sugar 1a with (PhO)P(O)Cl₂. Phosphorylation of the tetrols (1a and 1b) and the diol acetals with other phosphorylating agents, however, affords a dehydration product 2-(2-furyl)quinoxaline.

Full text of DOI:10.1246/cl.2003.678

678
Chemistry Letters Vol.32, No.8 (2003)
A One-pot Synthesis of Cyclic Pyrido[1,2-a]quinoxaline Phosphate, a New Molecule of
Biological Importance from a Quinoxaline Derivative of Sugar
Shyamaprosad Goswamiꢀ and Avijit Kumar Adak
Department of Chemistry, Bengal Engineering College (Deemed University), Howrah-711 103, West Bengal, India
(Received April 4, 2003;CL-030295)
A five membered cyclic pyrido[1,2-a]quinoxaline phos-
i
phate has been first synthesized in one step in a good yield by
phosphorylation of the quinoxaline derivative of sugar 1a with
(PhO)P(O)Cl2. Phosphorylation of the tetrols (1a and 1b) and
the diol acetals with other phosphorylating agents, however, af-
fords a dehydration product 2-(2-furyl)quinoxaline.
1a
2
ii or iii
3
H
HO
1
R
N
N
R' ii or iii
iv
Quinoxaline and their derivatives have found use in antitu-
mor antibiotics,1a-c potent bacteriocides,1d molecular recogni-
tion research,1e colorimetric sensors1f and consequently they
have become the subject of intense research for their biochem-
ical significance.1g,h 2-(D-arabino-Tetrahydroxybutyl)quinoxa-
line 1a is a long known molecule2 and has been used as a pter-
idine analogue3 for synthetic studies on the molybdenum
cofactor.4 Synthetic phosphoric esters of 6-hydroxyquinoxaline
and ester derivatives of 2-hydroxyquinoxaline have also found
use in insecticidal preparations and anthelmintics.1g Cyclic
phosphates are important constituents and are present in a large
number of biologically important molecules.5 However, no re-
port has been made for the synthesis of a cyclic phosphate onto
a quinoxaline system. We wish to report a simple and an effi-
cient synthesis of such a new heterocyclic phosphate triester
where the phosphate moiety is present in a five membered ring
which is attached to the pyrido[1,2-a]quinoxaline system.
H
O
5
R
O
R'
a: OH H
b: OH
H
Scheme 1. Reagent and conditions: i. (PhO)P(O)Cl2 neat, rt,
5h. ii. (EtO)3P(O) neat or POCl3/(PhO)P(O)Cl2/(p-O2N-
C6H4O)P(O)Cl2/2-phenyl-bis-triazoloyl phosphate/tris(1,2,4-
triazoloyl) phosphate in dioxane/CH3CN and Et3N or in pyri-
dine, rt, 4-6 h. iii. Hþ, rt, 4-6 h. iv. dry acetone, conc. H2SO4,
rt, 12 h.
yl phosphate6a and tris(1,2,4-triazoloyl) phosphate6b with vari-
ous solvents containing Et3N such as dioxane, CH3CN and also
in pyridine resulted a product which is solely found to be 2-(2-
furyl)quinoxaline 3. Acid treatment (concentrated H2SO4, con-
centrated HCl, HCl in absolute alcohol as well as AcOH and
H3PO4) of 1a–b also led to the formation of 3, previously which
was however wrongly assigned as glucazidone 4.7 We also first
report here the complete spectral proof (1H, 13C, MS, and IR da-
ta) in favour of the structure 3.
In order to rationalize the role of these phosphorylating
agents, we have tested the phosphorylation reactions on diol
acetals8 (5a and 5b) under the similar conditions and we isolat-
ed 3 as the sole product in each case in good yields. From the
above findings (Scheme 1), we have reasoned that instead of
phosphorylation, triethyl phosphate, triazolides and other phos-
phorus acid chlorides that are used, favoured the side chain de-
hydration of the tetrols (1a and 1b) and their diol acetals (5a
and 5b) resulting the formation of furan ring attached to qui-
noxaline 3. The five membered pyrido[1,2-a]quinoxaline phos-
phate 2 was synthesized in one step from the tetrol 1a by reac-
tion with neat (PhO)P(O)Cl2 in a good yield (85%).
HO H H
OH
O
O
O
N
P
N
N
OPh
R
R'
OH
N
1
R
R'
a: OH H
b: OH
2
3
2
O
H
4
N
N
1
O
11
3 N
N
4
In continuation5 of our work, we have investigated the pos-
sibility of phosphorylation reaction with the tetrol 1a to obtain
an ꢀ-hydroxyphosphate where the phosphate would be present
in a six membered ring under a variety of reaction conditions.
Thus when the tetrol 1a is subjected to reaction with
The structure 2 is established9 on the basis of detailed spec-
tral analysis (FTIR, 1H, 13C (normal & DEPT), 31P and MS)
which is also supported from the following plausible mecha-
nism (Scheme 2). Phenylphosphorodichloridate phosphorylates
the tetrol 1a while initially attacking the terminal alcohol6a
which follows cyclization to 6a, through pyrazine ring nitrogen
or cyclization followed by dehydrations to 3 through benzylic
hydroxyl group. Dehydration of 6a follows the stereoelectroni-
cally more favourable path a than path b (to 6b) which, may
give 2 exclusively.
(PhO)P(O)Cl2,
16-phenoxy-13H-15,17-dioxa-6,9-diaza-16-
phosphacyclopenta[a]phenanthrene16-oxide 2, an unprecedent-
ed five membered cyclic phosphate, was obtained in a good
yield. This one step procedure thus efficiently creates both six
and five membered fused heterocyclic rings onto a quinoxaline
system resulting a novel cyclic pyrido[1,2-a]quinoxaline phos-
phate by ring closure followed by dehydration of the tetrol 1a
with (PhO)P(O)Cl2 (Scheme 1).
However, treatment of 1a–b with (EtO)3P(O) or POCl3,
(PhO)P(O)Cl2, (p-O2N-C6H4O)P(O)Cl2, 2-phenyl-bis-triazolo-
Copyright ꢀ 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.8 (2003)
679
see B. Bradshaw, A. Dinsmore, D. Collison, C. D. Garner, and J.
A. Joule, J. Chem. Soc., Perkin Trans. 1, 2001, 3232.
OH
O
OPh
OH
OH
OH
P
Cl
cyclization
through ring
N atom
4
a) J. A. Pateman, D. J. Coves, B. M. Rever, and D. B. Roberts, Na-
ture, 201, 58 (1964). b) R. Hille, Chem. Rev., 96, 2757 (1996). c) D.
Collison, C. D. Garner, and J. A. Joule, Chem. Soc. Rev., 1996, 25. d)
R. S. Pilato, K. A. Erickson, M. A. Greaney, E. I. Stiefel, S. P.
Goswami, L. Kilpatric, T. G. Spiro, E. C. Taylor, and A. L.
Rhiengold, J. Am. Chem. Soc., 113, 9372 (1991). e) S. P. Goswami,
Heterocycles, 35, 1552 (1993). f) B. Bradshaw, A. Dinsmore, W.
Ajana, D. Collison, C. D. Garner, and J. A. Joule, J. Chem. Soc., Per-
kin Trans. 1, 2001, 3239. g) For the recent paper in this series, see B.
Bradshaw, D. Collison, C. D. Garner, and J. A. Joule, Org. Biomol.
Chem., 1, 129 (2003).
S. P. Goswami and A. K. Adak, Tetrahedron Lett., 43, 503 (2002)
and references cited therein.
a) C. Broka, T. Hozumi, R. Arentzen, and K. Itakurea, Nucleic Acids
Res., 8, 5461 (1980). b) A. Kraszewski and J. Stawinski, Tetrahedron
Lett., 21, 2935 (1980).
a) A. G. Sanchez, M. Y. Antinolo, and A. G. Gonzalez, An. R. Soc.
Esp. Fis. Quim., 51B, 431 (1954); Chem. Abstr., 50, 11078 (1958). b)
A. G. Sanchez, A. G. Gonzalez, and M. Y. Antinolo, An. R. Soc. Esp.
Fis. Quim., 51B, 659 (1955); Chem. Abstr., 50, 10108 (1958). c) K.
Maurer, B. Schiedt, and H. Schroeter, Ber., 68B, 1716 (1935); Chem.
Abstr., 29, 1822 (1935).
Compounds 1 and 5 are prepared by the similar procedure reported in
Refs. 2b and 3a respectively. Selected physical data for compound
5a: mp 129-131 ꢂC [lit3a 145-146 ꢂC]. 1H NMR (CDCl3,
500 MHz): d 9.0 (s, 1H, quinoxalin-2-yl), 8.16–8.14 (m, 2H), 8.07-
8.05 (m, 2H), 5.24 (dd, 1H, J ¼ 2:0, 2.0 Hz), 4.30–4.25 (m, 2H,
OH and c4-H), 4.19 (m, 1H), 4.09 (m, 2H), 3.07 (brs, OH), 1.46
and 1.38 (2 ꢃ s, 6H, 2 ꢃ CH3). MS (FD): m=z (%): 290 (Mþ,
100), 275 (50), 189 (40). The spectroscopic data for compound 5b
is in accord with the structure given. For a recent preparation of 1a
and 1b see: S. P. Goswami and A. K. Adak, Tetrahedron Lett., 43,
8371 (2002).
O
OH
OH
N
N
(PhO)P(O)Cl2
N
N
1a
H
(PhO)P(O)Cl2
cyclization
cyclization through
benzylic hydroxyl
group and then
dehydrations
OH
a
O
O
H
O
P
O
b
N
H
P
O
OPh
N
N
3
O
OPh
b
a
2
N
6b
6a
5
6
Scheme 2. Plausible mechanism for the formation of 2.
The 1H NMR spectrum however shows a cis coupling con-
stant (J ¼ 6:9 Hz) for the vicinal olefin protons which is consis-
tent with the structure 2. Further, DEPT-135 experiment has al-
so suggested that the double bonds are present between C11-C1
and C3-C4 atoms. The ESI MS shows an intense peak at m=z
353.9 (MHþ). Thus, careful analysis of all the spectral data con-
firms the structure 2 for the product.
X-ray crystallographic studies10a of several five membered
cyclic phosphate esters have established that alkoxy group on
phosphorus is directed away from the ring. The large negative
(ꢁ30:12 ppm) 31P chemical shift value of 2 and those found
in other five membered cyclic phosphate esters10b,c suggest that
the compound 2 exists as a single conformer at room tempera-
ture.
In conclusion, the first one-pot synthesis of a cyclic pyri-
do[1,2-a]quinoxaline phosphate 2, a new heterocyclic phos-
phate triester of biological significance is reported by a simple
and an efficient method. Interestingly, on reaction with acids
and other phosphorylating agents, the tetrols and the diol acetals
formed 3 as the sole product.
7
8
9
A suspension of the tetrol 1a (1.0 g, 3.98 mmol) and (PhO)P(O)Cl2
(1.0 mL) was stirred under nitrogen atmosphere at ice bath (0–
5 ꢂC) for 1 h and then at rt for 4 h. Water (40 mL) was then added
and the mixture was extracted with CH2Cl2 (2 ꢃ 50 mL). The organic
layer was washed well with brine, dried (MgSO4) followed by evap-
oration with rotary evaporator afforded a brown solid which was pu-
rified on silica gel (100-200 mesh) column chromatography eluting
with pertoleum ether : CH2Cl2 (3:2) gave 2 (0.88 g, 85%) as a brown
crystalline solid. mp 84–86 ꢂC. UV (CHCl3) ꢁmax (log "): 369 (4.09)
and 284 (4.23) nm. FT-IR (KBr): 3137, 2925, 1612, 1588, 1552,
1497, 1297, 1189, 1083, 1058, 1002, 963, 917, 775, 758, 688,
We acknowledge the Bose Institute, Kolkata for the paid fa-
cility of a Bruker 500 MHz NMR instrument and Professor Tho-
mas Schrader of Philipps Universitat, Marburg, Germany for the
mass spectra. AKA thanks CSIR, Govt. of India for a Senior Re-
search Fellowship.
594 cmꢁ1 1H NMR (CDCl3, 500 MHz): d 9.23 (s, 1H, quinoxalin-
.
2-yl), 8.09 (d, 1H, J ¼ 8:8 Hz), 8.05 (d, 1H, J ¼ 8:8 Hz), 7.75-7.70
(m, 2H), 7.67 (d, 1H, J ¼ 6:9 Hz), 7.35-7.30 (m, 4H), 7.24 (d, 1H,
J ¼ 8:4 Hz), 7.20 (t, 1H, J ¼ 7:3 Hz), 6.61 (qt, 1H, J ¼ 1:7, 1.7,
1.7 Hz). 13C NMR (CDCl3, 125 MHz): 152.00, 150.87 (d,
J ¼ 7:3 Hz), 145.49, 144.25, 142.48, 142.45, 141.68, 130.84,
130.25 (d, J ¼ 0:8 Hz), 129.72, 129.61, 126.0 (d, J ¼ 1:2 Hz),
120.54, 120.50, 112.90, 112.23. 1H decoupled 31P NMR (CDCl3,
202 MHz): ꢁ30:12. MS (ESI): m=z (%): 353.9 (MHþ, 20), 349.0
(100), 327 (30), 196 (25). Calcd. for C18H13N2O4P: required C,
61.37;H, 3.72;N, 7.95%. Found C, 61.35;H, 3.78;N, 7.99%. Select-
ed physical data for compound 3: Yield: (80%);off-white solid;mp
76–78 ꢂC. FT-IR (KBr): 3136, 3116, 1736, 1612, 1552, 1497, 1224,
1169, 1082, 916, 657, 594, 589 cmꢁ1. 1H NMR (CDCl3, 500 MHz): d
9.25 (s, 1H, quinoxalin-2-yl), 8.11 (d, 1H, J ¼ 8:3 Hz), 8.07 (d, 1H,
J ¼ 8:3 Hz), 7.77-7.72 (m, 2H), 7.69 (d, 1H, J ¼ 7:3 Hz), 7.33 (d,
1H, J ¼ 3:4 Hz), 6.64 (qt, 1H, J ¼ 1:6, 1.7, 1.7 Hz). 13C NMR
(CDCl3, 125 MHz): 151.97, 145.55, 144.23, 142.47, 142.43,
141.67, 130.93, 129.77, 129.61 (d, J ¼ 1:2 Hz), 129.53, 112.88,
112.19. MS (ESI): m=z (%): 196 (Mþ, 100), 168 (30). Calcd. for
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2
3
C12H8N2O: required C, 73.46;H, 4.11;N, 14.28%. Found C,
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Published on the web (Advance View) July 7, 2003;DOI 10.1246/cl.2003.678