Synthetic strategy toward 1,9-functionalized pyrido[2,3-d:6,5-d'] dipyrimidine-2,4,6,8-tetrones

Article abstract of DOI:10.1002/jhet.37

A synthetic approach involving a solubilizing protecting group strategy is described to generate pyr-ido[2,3-d:6,5-d']dipyrimidine-2,4,6,8-tetrones functionalized at positions 1 and 9 with alkylamine substitutents.

Full text of DOI:10.1002/jhet.37

January 2009
Synthetic Strategy Toward 1,9-Functionalized Pyrido[2,3-d:6,5-
d0]dipyrimidine-2,4,6,8-tetrones
79
Gabor Borzsonyi,a,b Rachel L. Beingessner,a,b and Hicham Fenniria,b
*
aNational Institute for Nanotechnology (NINT-NRC), Edmonton, Alberta T6G 2G2, Canada
bDepartment of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
*E-mail: hicham.fenniri@nrc-cnrc.gc.ca
Received July 18, 2008
DOI 10.1002/jhet.37
Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).
A synthetic approach involving a solubilizing protecting group strategy is described to generate pyr-
ido[2,3-d:6,5-d0]dipyrimidine-2,4,6,8-tetrones functionalized at positions 1 and 9 with alkylamine
substitutents.
J. Heterocyclic Chem., 46, 79 (2009).
INTRODUCTION
ditions) after the PDP core 4 was constructed. A conver-
gent strategy was therefore proposed as shown in
Scheme 2, whereby the desired PDPs 5 would be
derived from a common intermediate aldehyde 6 via a
reductive amination reaction with the requisite amines.
Aldehyde 6 would originate from an oxidative cleavage
of di-alkene 7, which in turn would be prepared from
urea 8 containing a robust allyl group. Herein we
describe the synthesis of 5 in detail, which required
overcoming some challenging solubility constraints.
Pyrido[2,3-d:6,5-d0]dipyrimidine-2,4,6,8-tetrones (PDP)
4 illustrated in Scheme 1 are an interesting class of bian-
nulated pyridine compounds. Derivatives of 4 have been
shown to exhibit antibacterial and antiviral properties [1]
as well as NAD-type redox catalytic activity [2]. Solid-
state ribbons have also been described from the self-as-
sembly of an amine derivative of 4, which demonstrates
the potential of these heterocyclic compounds in supra-
molecular synthesis applications [3].
A typical synthetic scheme for these nitrogen-contain-
ing tricycles 4 is shown in Scheme 1 and begins with an
often low-yielding condensation reaction of functional-
ized urea 1 with cyanoacetic acid under thermal condi-
tions, followed by a base induced cyclization of 2 to
generate 6-amino-uracil 3 [4]. A second condensation
reaction between 3 and an electrophile such as triethyl
orthoformate [3] (or an aromatic aldehyde [5a], or di-
methyl sulfoxide [5b]), generates the target compound 4
(Scheme 1).
RESULTS AND DISCUSSION
The synthesis of 5 commenced according to Scheme
3, by treating commercially available N-allyl urea (8)
with cyanoacetic acid and acetic anhydride at 85ꢀC to
provide the condensed adduct 9. Cyclization of 9 in the
presence of 10% sodium hydroxide in a 2:1 mixture of
water and ethanol at 85ꢀC generated uracil 10 with a
moderate 57% yield [4c]. Finally, treatment of 10 with
triethyl orthoformate in acetic acid under refluxing con-
ditions for 2 h provided the desired allyl functionalized
PDP adduct 7 in 80% yield [3]. Unfortunately, this
adduct was found to be insoluble in many common or-
ganic solvents such as dichloromethane, ether, tetrahy-
drofuran, acetone, and methanol and could only be
maintained in solution using dimethyl sulfoxide, reflux-
ing N,N-dimethylformamide (DMF), or pyridine. This
restricted our solvent choices for the subsequent two-
As part of our research program on the hierarchical
self-assembly of a DNA-based G^C hybrid molecule
into rosette nanotubes in aqueous media [6], we required
PDP substrates 5 shown in Scheme 1, which were selec-
tively functionalized at positions 1 and 9 with a variety
of NHR3 substituents such as L-Lysine. Given the harsh
conditions required to construct the intermediate 6-ami-
nouracil 3 and 4 (Scheme 1), we reasoned that it would
be best to introduce these amine substituents (some of
which would be incompatible with the acidic/basic con-
step
dihydroxylation/sodium
periodate
oxidative
C
V
2009 HeteroCorporation

80
G. Borzsonyi, R. L. Beingessner, and H. Fenniri
Vol 46
Scheme 1
Scheme 3
in the presence of sodium triacetoxyborohydride and
N,N-diisopropylethylamine was very low yielding (5%).
This was attributed to the removal of the Bz group(s) on
12 under the basic conditions, which caused the result-
ing material to precipitate out of the solution prior to
undergoing the coupling reaction.
cleavage reaction for the preparation of 6. Diol forma-
tion was therefore attempted using catalytic osmium te-
troxide and an excess of 4-methyl-morpholine N-oxide
(NMO) co-oxidant in a mixture of dimethyl sulfoxide
and water, but only starting material was recovered.
To confer the required solubility to the PDP core 7,
various protecting groups (PGs) were installed on the
nitrogen atoms at positions 3 and 7. The benzoyl (Bz)
group was initially chosen and although it did afford the
required solubility to conduct the oxidative cleavage
reaction as illustrated in Scheme 4, the following reduc-
tive amination step of aldehyde 12 with protected lysine
Scheme 4
Scheme 2
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January 2009
Synthetic Strategy Toward 1,9-Functionalized Pyrido[2,3-d:6,5-d0]
dipyrimidine-2,4,6,8-tetrones
81
Scheme 5
ether with heating. Furthermore, the DMB group was
easily removed under both acidic (100% TFA, room
temperature, 1 h) and oxidative conditions (ceric (IV)
ammonium nitrate, acetonitrile:water (2:1), room tem-
perature, 3.5 h) in excellent yields of 90% and 85%,
respectively (Scheme 6).
With this PG strategy in hand, the synthesis was con-
tinued from compound 16. Oxidative cleavage in the
presence of catalytic osmium tetroxide and NMO fol-
lowed by treatment with sodium periodate provided
aldehyde 17 in 80% yield for the two steps. Double
reductive amination of 17 with L-Lysine furnished the
coupled adduct 18 in 89% yield. Finally, treatment of
18 with a 94:6 v/v TFA:thioanisole solution ensured
complete removal of all six PGs (i.e., benzyloxycar-
bonyl (Cbz), trimethylsilyl (TMS) and DMB) and the
desired water-soluble PDP adduct 19 was obtained in
69% yield (ꢁ94% yield per PG).
Base-stable benzyl (Bn) and p-methoxy benzyl (PMB)
PGs were subsequently installed on the PDP core 7
under standard conditions (Scheme 5). To ensure that
these groups could also be easily removed, the deprotec-
tion of 14 and 15 was attempted under radical (2,3-
dichloro-5,6-dicyano-p-benzoquinone, wet dichlorome-
thane, room temperature, 1 day), acidic (98% trifluoro-
acetic acid (TFA), 2 days) and hydrogenation (H2/
Pd(C), acetic acid, 20 psi) conditions. Surprisingly, only
starting material was recovered in all cases, except for
the latter, in which the allyl group was reduced. Only in
the presence of ceric (IV) ammonium nitrate in a 2:1
mixture of acetonitrile-water at room temperature for 14
h was the desired deprotected product 7 isolated,
although in a mere 50% and 68% yield from 14 and 15,
respectively.
In conclusion, a convergent synthetic strategy has
been developed to access PDP substrates functionalized
at positions 1 and 9 with amines such as L-lysine (i.e.,
Scheme 7
As a result of these unsatisfactory deprotection yields
and limited conditions in which to remove the PMB/Bn
groups, a fourth N-PG, DMB (di-(4-methoxyphenyl)-
methyl) was also examined. Although it is less common
than other N-PGs [7], examples of its applications can
be found in amino acid [8a], allylic amine [8b], b-lac-
tam [8c], and urethane/uridine [8d] synthesis to name a
few. Gratifyingly, installation of DMB on compound 7
proceeded smoothly in the presence of sodium hydride
and di-(4-methoxyphenyl)methyl chloride [9] in N,N-
DMF to afford the bis-protected product 16 in quantita-
tive yield (Scheme 6). Solubility tests also confirmed
that 16 was soluble in a range of solvents such as ace-
tone, dichloromethane, dimethylsulfoxide, N,N-DMF and
Scheme 6
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G. Borzsonyi, R. L. Beingessner, and H. Fenniri
Vol 46
C, 50.29; H, 5.43; N, 25.14. Found: C, 50.40, H, 5.39, N,
25.15.
19) from the common intermediate aldehyde 17. Central
to this strategy is the protection of the nitrogen atoms at
positions 3 and 7 on compound 7 with the base-stable
DMB group. This PG provides the necessary solubility
to the parent compound for the alkene cleavage and
double reductive amination reactions and yet is suffi-
ciently labile on the PDP core under both oxidative and
acidic conditions for its eventual removal (Scheme 7).
1,9-Diallylpyrido[2,3-d:6,5-d0]dipyrimidine-2,4,6,8 (1H, 3H,-
7H,9H)-tetrone (7). A mixture of 10 (51.5 g, 0.308 mol),
triethyl orthoformate (118 mL, 0.709 mol) and glacial acetic
acid (1.2 L, 21 mol) was heated to reflux for 2 h. After cooling
to room temperature, the precipitate was washed with glacial
acetic acid, isolated by filtration and dried under high vacuum
to provide 7 as a white solid (C15H13N5O4, 41.2 g, 80%). mp
1
¼ 351.6–353.2ꢀC (decomposes); H NMR (500 MHz, DMSO-
d6) d (ppm): 11.87 (s, 2H), 8.58 (s, 1H), 5.95–5.87 (m, 2H),
5.19–5.12 (m, 4H), 4.72–4.71 (m, 4H); 13C NMR (125 MHz,
DMSO-d6) d (ppm): 160.1, 154.0, 150.1, 137.6, 132.3, 116.9,
106.7, 43.8; HRMS: m/z 327.0971 (Mþ). Anal. Calcd. for
C15H13N5O4: C, 55.05; H, 4.00; N, 21.40. Found: C, 55.11, H,
4.03, N, 21.53.
EXPERIMENTAL
General. All commercial reagents and solvents were used
without further purification except for dichloroethane which
was purified on an MBraun solvent purification system. Reac-
tions were monitored by TLC analysis using silica-coated TLC
plates (Merck F 60254) and visualized under UV light. Flash
chromatography was carried out using Merck 60 (0.040–0.063
mm) or Merck 60 (0.063–0.2 mm) silica. 1H and 13C NMR
spectra were recorded on Varian Inova NMR spectrometers
(300, 400, 500, or 600 MHz) with the solvent as the internal
reference. The NMR data is presented as follows: chemical
shift, multiplicity, coupling constant, integration. The mass
spectra were performed at the Mass Spectrometry Laboratory
at the Department of Chemistry, University of Alberta, or at
the Analytical Laboratory of The National Institute for Nano-
technology, University of Alberta.
N-(Allylcarbamoyl)-2-cyanoacetamide (9). A mixture of all-
ylurea (104.8 g, 1.046 mol), cyanoacetic acid (89.03 g, 1.046
mol) and acetic anhydride (197.4 mL, 2.092 mol) was heated
for 3 h at 85ꢀC. On cooling to room temperature, ether (530
mL) was added and the mixture was placed in an ice-bath for
2 h. The resulting solid was isolated, washed with ether and
dried on the high vacuum to yield 9 as a white powder
(C7H9N3O2, 98 g, 58%). Rf ¼ 0.6 (SiO2, 75% ethyl acetate/
hexane); mp 140.1–141.9ꢀC; 1H NMR (300 MHz, DMSO-d6)
d (ppm): 10.56 (brs, 1H), 8.03 (brs, 1H), 5.83 (ddt, J ¼ 17.1,
10.2, 5.1 Hz, 1H), 5.16–5.05 (m, 2H), 3.90 (s, 2H), 3.78 (ddd,
J ¼ 5.1, 2.4, 1.5 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) d
(ppm): 165.0, 152.2, 134.9, 115.2, 115.0, 41.3, 26.7; MS: m/z
168.40 (Mþ þ 1). Anal. Calcd. for C7H9N3O2: C, 50.29; H,
5.43; N, 25.14. Found: C, 49.90, H, 5.35, N, 24.83.
1,9-Diallyl-3,7-(bis(4-methoxyphenyl)methyl)pyrido[2,3-d:6,5-
d0] dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetrone (16). Compound
7 (1.3 g, 3.8 mmol) was slowly added to a mixture of NaH
(183 mg, 7.63 mmol) in N,N-DMF (26 mL) at 0ꢀC. After stir-
ring for 1 h, di-(4-methoxyphenyl)methyl chloride (2.0 g, 7.6
mmol) was added and the reaction was slowly warmed to
room temperature and stirred for 5 h. After re-cooling to 0ꢀC,
saturated aqueous ammonium chloride (50 mL) was added and
the product was extracted with dichloromethane (3ꢂ). The
combined organic phases were washed with water, dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo
to provide 16 as a white foam (C45H41N5O8, 3.09 g, quantita-
tive yield). Rf ¼ 0.8 (50% ethyl acetate/hexane). 1H NMR
(600 MHz, CD2Cl2) d (ppm): 9.06 (s, 1H), 7.36 (s, 2H), 7.33–
7.30 (m, 8H), 6.87–6.86 (m, 8H), 5.95 (ddt, J ¼ 22, 10.8, 5.4
Hz, 2H), 5.24–5.20 (m, 4H), 4.88 (d, J ¼ 5.5 Hz, 4H), 3.80 (s,
12H); 13C NMR (125 MHz, CD2Cl2) d (ppm): 160.2, 159.3,
153.7, 150.6, 141.9, 132.0, 130.7, 130.3, 118.0, 113.7, 107.3,
59.9, 55.6, 45.7; MS: m/z 752.6 ((Mþ þ 1)-C2H3). Anal.
Calcd. for C45H41N5O8: C, 69.31; H, 5.30; N, 8.98. Found: C,
69.68, H, 5.53, N, 8.74.
1,9-Diacetaldehyde-3,7-(bis(4-methoxyphenyl)methyl)pyr-
ido [2,3-d:6,5-d0]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetrone
(17). A solution of 16 (1 g, 1.3 mmol) in acetone/water (4:1,
50 mL) was treated with 50% aqueous N-methylmorpholine N-
oxide (1.9 mL, 7.8 mmol) at room temperature. After stirring
for 5 min, OsO4 (4 mL, 0.1M solution in t-BuOH, 0.4 mmol)
was added over a period of 5 min and the resulting solution
was stirred at room temperature for 48 h. Sodium sulfite
(ꢁ500 mg) was then added to quench the reaction and stirring
was continued for an additional 1 h. The solvent was subse-
quently removed under reduced pressure, water was added and
the product was extracted with dichloromethane (3ꢂ). The
combined organic phases were washed with brine, dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo
to provide 1.1 g of crude tetrol. Rf ¼ 0.3 (5% methanol/
dichloromethane). A solution of the tetrol (1.1 g, 1.3 mmol)
and sodium periodate (1.11 g, 5.2 mmol) in dichloromethane:-
water (4:1, 200 mL) was stirred at room temperature for 48 h.
The organic layer was then separated, washed with water,
dried over anhydrous sodium sulfate, filtered, and concen-
trated. Purification by flash chromatography on silica gel (0–
2% methanol in dichloromethane) provided the desired product
which was subsequently re-dissolved in dichloromethane and
1-Allyl-6-aminopyrimidine-2,4(1H,3H)-dione (10). A mix-
ture of 9 (91 g, 0.54 mol) in water (248 mL) and ethanol (124
mL) was warmed to 85ꢀC and slowly treated with 10% aque-
ous sodium hydroxide until a pH of 10 was obtained and the
starting material was fully dissolved. After 10 min, the desired
product 10 began to precipitate out of solution. The reaction
mixture was stirred for an additional 2 h at 85ꢀC and then
treated with 1 N hydrochloric acid until the solution was
slightly acidic. On cooling to room temperature, the resulting
solid was isolated and dried on the high vaccum to furnish 10
as a white powder (C7H9N3O2, 51.5 g, 57%). Rf ¼ 0.6 (SiO2,
1
20% methanol/dichloromethane); mp 271.2–273.1ꢀC; H NMR
(400 MHz, DMSO-d6) d (ppm): 10.38 (s, 1H), 6.71 (s, 2H),
5.79 (ddt, J ¼ 17.2, 10.2, 4.5 Hz, 1H), 5.12–5.03 (m, 2H),
4.55 (s, 1H), 4.39–4.38 (m, 2H); 13C NMR (125 MHz,
DMSO-d6) d (ppm): 162.5, 155.7, 151.0, 132.4, 115.7, 75.2,
42.5; HRMS: m/z 167.0699 (Mþ). Anal. Calcd. for C7H9N3O2:
precipitated with hexane, filtered and dried under reduced
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January 2009
Synthetic Strategy Toward 1,9-Functionalized Pyrido[2,3-d:6,5-d0]
dipyrimidine-2,4,6,8-tetrones
83
pressure to provide 17 (C43H37N5O10, 812 mg, 80%) as a
white solid. Rf ¼ 0.2 (90% ethyl acetate/hexane); mp 172.8–
173.9ꢀC; 1H NMR (500 MHz, acetone-d6) d (ppm): 9.63 (s,
2H), 8.94 (s, 1H), 7.33–7.30 (m, 10H), 6.87–6.85 (m, 8H),
5.11 (s, 4H), 3.77 (s, 12H); 13C NMR (125 MHz, acetone-d6)
d (ppm): 196.8, 161.1, 160.5, 154.8, 151.9, 142.3, 131.8,
(m, 4H), 1.75–1.69 (m, 4H), 1.57–1.45 (m, 4H); 13C NMR
(150 MHz, D2O) d (ppm): 173.1, 162.1, 154.8, 152.1, 140.2,
108.0, 62.6, 44.5, 39.3, 39.0, 29.6, 26.7, 21.8; HRMS: m/z
592.2838 (Mþ). Anal. Calcd. for C25H37N9O8ꢄ3.2CF3-
COOHꢄ0.5H2O: C, 39.06; H, 4.30; N, 13.06. Found: C, 38.66,
H, 4.69, N, 13.39.
131.4, 114.8, 108.6, 60.8, 56.1, 53.4; MS: m/z 784.6 (Mþ
þ
Acknowledgment. This work was supported by the National
Research Council of Canada, University of Alberta, Natural Sci-
ences and Engineering Research Council of Canada and the Ca-
nadian Foundation for Innovation.
1). Anal. Calcd. for C43H37N5O10: C, 65.89; H, 4.76; N, 8.94.
Found: C, 65.98, H, 4.93, N, 8.60.
1,9-Di((S)-2-(trimethylsilyl)ethyl-2-amino-6-(benzyloxy-car-
bonylamino)hexanoate)-3,7-(bis(4-methoxyphenyl)methyl)pyr-
ido[2,3-d:6,5-d0]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetrone
(18). A solution of 17 (200 mg, 0.26 mmol) in dichloroethane
(20 mL) was treated with N-Cbz-L-Lysine-OCH2CH2TMS (250
mg, 0.65 mmol) at room temperature. After stirring for 15
min, Na(AcO)3BH (165 mg, 0.78 mmol) was added and stir-
ring was continued for an additional 48 h. The reaction was
then quenched with water and the product was extracted with
dichloromethane (2ꢂ). The combined organic layers were
washed successively with 10% aqueous citric acid, water, 5%
aqueous sodium bicarbonate and brine, dried over anhydrous
sodium sulfate. Concentration under reduced pressure followed
by purification by silica gel preparative thin layer chromatog-
raphy (90% ethyl acetate/hexane) yielded compound 18 as
white foam (C81H101N9O16Si2, 346 mg, 89%). Rf ¼ 0.8 (90%
ethyl acetate/hexane); 1H NMR (600 MHz, CD2Cl2) d (ppm):
9.02 (s, 1H), 7.34–7.29 (m, 20H), 6.85–6.84 (m, 8H), 5.03 (s,
4H), 4.98 (s, 2H), 4.35 (dt, J ¼ 13.2, 6.6 Hz, 4H), 4.16–4.13
(m, 4H), 3.77 (s, 12H), 3.15 (t, J ¼ 6.6 Hz, 2H), 3.06 (dt, J ¼
13.2, 6.6 Hz, 4H), 2.97 (dt, J ¼ 13.0, 6.0 Hz, 2H), 2.80–2.76
(m, 2H), 2.0 (broad s, 2H), 1.60–1.25 (m, 12H), 0.96–0.93 (m,
4H), 0.02 (s, 18H) 13C NMR (150 MHz, CD2Cl2) d (ppm):
175.8, 160.4, 159.6 , 156.8, 154.2, 151.4, 141.9, 137.7, 131.0,
130.9, 130.5, 128.9, 128.5, 113.9, 107.5, 66.8, 63.4, 61.7, 60.0,
55.8, 46.1, 43.6, 41.4, 33.6, 30.2, 23.6, 17.9, ꢃ1.2; MS: m/z
1512.8 (Mþ þ 1). Anal. Calcd. for C81H101N9O16Si2: C,
64.31; H, 6.73; N, 8.33. Found: C, 64.05, H, 6.78, N, 7.93.
REFERENCES AND NOTES
[1] (a) Nasr, M. N.; Gineinah, M. M. Arch. Pharm Pharm Med
Chem 2002, 6, 289; (b) Suresh, T.; Kumar, R. N.; Mohan, P. S. Heter-
ocycl Commun 2003, 9, 203.
[2] (a) Nagamatsu, T.; Yamato, H.; Ono, M.; Takarada, S.;
Yoneda, F. J Chem Soc Perkin Trans 1992, 1, 2101; (b) Yoneda, F.;
Yamato, H.; Ono, M. J Am Chem Soc 1981, 103, 5943.
[3] Petersen, P. M.; Wu, W.; Fenlon, E. E.; Kim, S.; Zimmer-
man, S. C. Bioorg Med Chem 1996, 4, 1107.
[4] (a) Traube, W. Ber 1900, 33, 3095; (b) Speer, J. H.; Ray-
mond, A. L. J Am Chem Soc 1953, 75, 114; (c) Papesch, V.;
Schroeder, E. F. J Org Chem 1951, 16, 1879; (d) Bredereck, H. Pharm
Ztg 1971, 116, 780.
[5] (a) Dabiri, M.; Arvin-Nezhad, H.; Khavasi, H. R.; Bazgir,
A. Tetrahedron 2007, 63, 1770; (b) Elderfield, R. C.; Wharmby, M. J
Org Chem 1967, 32, 1638.
[6] (a) Fenniri, H.; Deng, B.-L.; Ribbe, A. E. J Am Chem Soc
2002, 24, 11064; (b) Fenniri, H.; Deng, B.-L.; Ribbe, A. E.; Hallenga,
K.; Jacob, J.; Thiyagarajan, P. Proc Natl Acad Sci USA 2002, 99,
6487; (c) Fenniri, H.; Mathivanan, P.; Vidale, K. L.; Sherman, D. M.;
Hallenga, K.; Wood, K. V.; Stowell, J. G. J Am Chem Soc 2001, 123,
3854; (d) Moralez, J. G.; Raez, J.; Yamazaki, T.; Kishan, M. R.;
Kovalenko, A.; Fenniri, H. J Am Chem Soc 2005, 127, 8307; (e)
Raez, J.; Moralez, J. G.; Fenniri, H. J Am Chem Soc 2004, 126,
16298; (f) Johnson, R. S.; Yamazaki, T.; Kovalenko, A.; Fenniri, H. J
Am Chem Soc 2007, 129, 5735; (g) Beingessner, R. L.; Deng, B.-L.;
Fanwick, P. E.; Fenniri, H. J Org Chem 2008, 73, 931.
1,9-Di((S)-2,6-diaminohexanoic
acid)pyrido[2,3-d:6,5-
d0]dipyrimidine-2,4,6,8 (1H,3H,7H,9H)-tetrone (19). A 94:6
v/v solution of TFA:thioanisole (10 mL) was added to 18 (70
mg, 0.046 mmol) at room temperature. After stirring for 70 h,
ether (50 mL) was added and the resulting precipitate was fil-
tered, washed with ether and dried under vacuum to provide
[7] Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, NY, 1999.
[8] (a) Hanson, R. W.; Law, H. D. J Chem Soc 1965, 7285; (b)
Trost, B. M.; Keinan, E. J Org Chem 1979, 44, 3451; (c) Kawabata,
T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetrahedron Lett 1986, 27,
6241; (d) AbuSbeih, K.; Bleasdale, C.; Golding, B. T.; Kitson, S. L.
Tetrahedron Lett 1992, 33, 4807.
1
19 as a white solid (31 mg, 69%). H NMR (500 MHz, D2O)
d (ppm): 8.93 (s, 1H), 4.69–4.65 (m, 4H), 3.82 (t, J ¼ 6.5 Hz,
´
[9] Jonsson, D.; Unden, A. Tetrahedron Lett 2002, 43, 3125.
¨
2H), 3.58–3.44 (m, 4H), 3.01 (t, J ¼ 7.5 Hz, 4H), 2.02–1.90
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet