Study on the thermolysis of 5′-O-trityl-2′,3′-O-triphenylphosphoranediyluridine

Article abstract of DOI:10.1081/SCC-100000592

A new method is introduced by thermolysis of 5′-O-trityl2′,3′-O-triphenylphosphoranediyluridine (4) with or without the presence of methanol to afford the 3-N-methyl-5′-O-trityluridine (9) and 5′-O-trityl-2,2′-cyclouridine (5), respectively. Mechanism for this thermolysis is also proposed.

Full text of DOI:10.1081/SCC-100000592

Synthetic Communications
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STUDY ON THE THERMOLYSIS OF 5′-O-TRITYL-2′,3′-
O-TRIPHENYL-PHOSPHORANEDIYLURIDINE
Yi-Sui Zhou , Zhi-Wei Miao , Yu-Ping Feng & Yu-Fen Zhao
To cite this article: Yi-Sui Zhou , Zhi-Wei Miao , Yu-Ping Feng & Yu-Fen Zhao (2001) STUDY
ON THE THERMOLYSIS OF 5′-O-TRITYL-2′,3′-O-TRIPHENYL-PHOSPHORANEDIYLURIDINE,
Synthetic Communications, 31:4, 631-636, DOI: 10.1081/SCC-100000592
To link to this article: http://dx.doi.org/10.1081/SCC-100000592
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Date: 22 May 2017, At: 15:04

SYNTHETIC COMMUNICATIONS, 31(4), 631–636 (2001)
STUDY ON THE THERMOLYSIS
OF 5ꢀ-O-TRITYL-2ꢀ,3ꢀ-O-TRIPHENYL-
PHOSPHORANEDIYLURIDINE
Yi-Sui Zhou, Zhi-Wei Miao, Yu-Ping Feng,
and Yu-Fen Zhao∗
Key Laboratory for Bioorganic Phosphorus Chemistry
of Education Ministry, Department of Chemistry,
School of Life Science and Engineering, Tsinghua
University, Beijing, 100084, China
ABSTRACT
A new method is introduced by thermolysis of 5ꢀ-O-trityl-
2ꢀ,3ꢀ-O-triphenylphosphoranediyluridine (4) with or without the
presence of methanol to afford the 3-N-methyl-5ꢀ-O-trityluridine
(9) and 5ꢀ-O-trityl-2,2ꢀ-cyclouridine (5), respectively. Mechanism
for this thermolysis is also proposed.
Substituted 1,2-diols reacted with diethoxytriphenylphosphorane (DTPP) to
give the stable 1,3,2-dioxaphospholanes in neutral media, which were then cleaved
to epoxides, ketones, or allylic alcohol and triphenylphosphine oxide when heated
(1–3). For example, trans-1,2-cyclohexanediol afforded essentially quantitative
yields (>95%) of cyclohexene oxide via an oxyphosphonium betaine intermediate.
On the other hand, cis-1,2-cyclohexanediol reacted with pentaethoxyphosphorane
to give a stable dioxyphosphorane (31P-NMR δ −37.7 PPM), which was decom-
posedundervacuumthermolysisconditions(180◦C, 10torr)togivecyclohexanone
∗Corresponding author.
631
Copyright ꢁ 2001 by Marcel Dekker, Inc.
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C

ORDER
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632
ZHOU ET AL.
HO
HO
HO
A
A
A
O
O
O
OH
O
HO
OH
OH
1
3
2
Scheme 1.
via 1,2-hydride migration (1,4). In an earlier report (5), triphenylphosphoranediyl-
nucleosides were prepared by reaction of 9-(β-D-furanosyl)adenine derivatives
with triphenylphosphine. Both 9-(β-D-Arabinofuranosyl)adenine (1) and 9-(β-D-
Xylofuranosyl)adenine (2), containing the trans-2ꢀ,3ꢀ-diol system, gave the
epoxides (3) at 70◦C (Scheme 1). However, there was no report on the ther-
molysis of 2ꢀ,3ꢀ-O-triphenylphosphoranediylribonucleoside, which contained the
cis-2ꢀ,3ꢀ-diol. In this paper, we describe the results of thermolysis of 5ꢀ-O-trityl-
2ꢀ,3ꢀ-O-triphenylphosphoranediyluridine (4) and 4-N-benzoyl-5ꢀ-O-trityl-2ꢀ,3ꢀ-O-
triphenylphosphoranediylcytidine (6).
2ꢀ,3ꢀ-O-Triphenylphosphoranediylnucleosides were traditionally prepared
by the reaction of diethyl azodicarboxylate and triphenylphosphine (5,6). In this
paper, N-chlorodiisopropylamine (ClNPri2), an excellent reagent for the synthe-
sis of spirophosphoranes (7,8), was employed for the reaction of 5ꢀ-O-trityluridine
with triphenylphosphine. Although the procedure for the preparation of spirophos-
phorane involving ClNPri2 generally is carried out under low temperature, such as
−78◦C, we found that 5ꢀ-O-trityluridine reacted quantitatively with equivalent
amounts of ClNPr2i and triphenylphosphine in THF at room temperature. The 31P-
NMR spectra supported the phosphorane structure (4) (−27.6 PPM), which was
consistent with the chemical shift reported in the literature (5,9). This phosphorane
intermediate (4) was applied to thermolysis without further isolation.
After overnight refluxing in THF, as indicated by 31P-NMR spectrum, (4)
remained unchanged. However, as the temperature of themolysis was raised by
refluxing in xylene (140◦C), 5ꢀ-O-trityl-2,2ꢀ-cyclouridine (5) was afforded in 84%
yield. Since by TLC, there was no 5ꢀ-O-trityl-2ꢀ (or 3ꢀ)-ketouridine detected in
the reaction mixture, it would be a different mechanism from the 1,2-hydride
migration. Therefore, this finding implied that O-2 of the uridine base attacked
C-2ꢀ with the elimination of triphenylphosphine oxide (Scheme 2). Similarly, 4-N-
benzoyl-5ꢀ-O-trityl-2ꢀ,3ꢀ-O-triphenylphosphoranediylcytidine (6) was also applied
to thermolysis under vacuum conditions (140◦C, <0.1 mmHg) for half an hour.
5ꢀ-O-trityl-2,2ꢀ-cyclocytidine (7) was afforded in 42% yield (Scheme 2).
Interestingly, when phosphorane (4) was refluxed in THF/MeOH mixed
1
solvent, a new product (9) was afforded in 56% yield. FAB-MS and H-NMR
indicated that it was a methylated derivative of 5ꢀ-O-trityluridine. In the 13C-NMR
spectrum, the methyl group displayed a signal at a higher field shift (27.2 PPM)
than the representative chemical signal of CH3-O. Thus, it could be concluded that
the product (9) was 3-N-methyl-5ꢀ-O-trityluridine. LR-13C-1H COSY (in inverse

ORDER
REPRINTS
5ꢀ-O-TRITYL-2ꢀ,3ꢀ-O-TRIPHENYLPHOSPHORANEDIYLURIDINE
633
O
O
O
N
H
HN
N
N
O
O
O
TrO
TrO
TrO
O
O
N
N
CINPri2
O
+
∆
Ph3P
O
xylene
Ph3P/THF
OH
OH
O
O
OH
P
Ph
Ph
Ph
4
5
+
−
.
NH2Cl
NHBz
N
NHBz
N
N
N
N
O
O
O
O
O
TrO
TrO
TrO
N
CINPri2
Ph3P/THF
O
+
∆
Ph3P
O
OH
O
O
OH
OH
P
Ph
Ph
Ph
6
7
Scheme 2.
mode) also supported the structure of (9), in which the methyl group of 1H-NMR
had cross peaks with 2- and 4-carbonyl gruops of 13 C-NMR. In order to conirm
its strucure, compound (9) was compared with authentic material. It was found
that they had the same 1H, 13C-NMR spectra, and Rf value in TLC.
The formation of product (9) implied that the methyl group at 3-N should
come from a good methyl donor. Since the methanol was the key reagent for
this transformation, it was proposed that phosphorane (4) proceeded an ester
exchange reaction with methanol (Scheme 3). This type of ester exchange re-
action had been investigated intensively in our laboratory (10,11). It is worth
noting that the resultant phosphorane (8) could act as the methylation reagent
for uridine derivatives (Scheme 3), which is similar to the mechanism of Mit-
sunobu reaction (12–14). In the latter reaction, the phosphorane, Ph3P(OR)2, had
been proved to be the intermediate (12,13). Similar alkylation on phthalimides
and succinimides in Mitsunobu reaction had been reported in previous literature
(14).
EXPERIMENTAL
All glassware was dried in an oven for at least 8 h at 120◦C before use. Air-
sensitive materials were transferred under nitrogen atmosphere. THF and xylene
were dried by refluxing with sodium. 1H, 13C NMR, and 31P-NMR spectra were

ORDER
REPRINTS
634
ZHOU ET AL.
−
RO
U
TrO
+
RO
O
P
Ph
CH3OH
Ph
Ph
P
Ph P+ OCH3
Ph
∆
OCH3
O
Ph
O
O
NH
Ph
Ph
O
N
Ph
4
TrO
O
8
O
O
P
U
U
Ph
Ph
4
TrO
R =
TrO
Ph
O
O
O
or
CH3
N
OH
OH
O
TrO
N
O
+
2
Ph3P
O
OH
OH
9
Scheme 3.
recorded on a Bruker AC200P spectrometer. 31P chemical shifts are reported in
PPM downfield (+) or upfield (−) from external 85% H3PO4.
Thermolysis of 5ꢀ-O-trityl-2ꢀ,3ꢀ-O-
triphenylphosphoranediyluridine (4)
ClNPri2 0.272 g (2 mmol) in 2 mL THF was added dropwise to a solution
of 5ꢀ-O-trityluridine 1.0 g (2 mmol) and triphenylphosphine 0.539 g (2 mmol) in
THF 10 mL. The mixture was stirred at room temperature for 0.5 h. After the
filtration of HCl·HNPri2 and removal of the solvent, compound (4) was afforded
quantitatively as shown by 31P-NMR spectrum (a single peak at −27.6 ppm). With-
out further isolation, this phosphorane intermediate was applied to the following
thermolysis.
The resulting compound (4) was refluxed in xylene under N2; precipita-
tion took place shortly afterwards. After 4 h, the precipitation was collected
and washed with CHCl3. Elemental analytical pure 5ꢀ-O-trityl-2,2ꢀ-cyclouridine
(5) was afforded in 84% yield. δH (200 M Hz, (CD3)2SO)): 7.94 (d, 1H, J5,6
7.5 Hz, H-6), 7.32–7.ꢀ23 (m, 15H, Ar-H), 6.32 (d, 1H, J1 ,2 5.6 Hz, H-1ꢀ ), 5.98
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(d, 1H, JOH,3 4.3Hz, 3 -OH), 5.86(d, 1H, J5,6 7.5Hz, H-5), 5.21(d, 1H, J1 ,2 5.6Hz,
H-2ꢀ), 4.40–4.21 (m, 2H, H-3ꢀ, 4ꢀ), 2.96 (dd, 1H, J5 a,4 5.97, J5 a,5 b 10.1 Hz, H-5ꢀa),
ꢀ
ꢀ
ꢀ
2.82 (dd, 1H, J5 b,4 7.34, J5 a,5 b 10.1 Hz, H-5ꢀb); m.p. 203–205◦C; ESI-MS: M/Z
ꢀ
ꢀ
ꢀ

ORDER
REPRINTS
5ꢀ-O-TRITYL-2ꢀ,3ꢀ-O-TRIPHENYLPHOSPHORANEDIYLURIDINE
635
469.1 (M + 1); 491.2 (M + Na+); 507.1 (M + K+); Anal. calc. For C25H24N2O5:
C, 71.78; H, 5.6; N, 5.98. Found: C, 71.40; H, 5.09; N, 6.22.
Thermolysis of 4-N-Benzoyl-5ꢀ-O-trityl-2ꢀ,3ꢀ-O-
triphenylphosphoranediyl-cytidine (6)
Phosphorane (6) was prepared by the same procedure, however, without
the filtration of HCl·HNPri2. After removal of THF, compound (6) was applied to
thermolysis under vacuum conditions (140◦C, <0.1 mmHg) for half an hour. When
diluted with CHCl3, a precipitaion was afforded as an elemental analytical pure
product in 42% yield, which was characterized as 5ꢀ-O-trityl-2,2ꢀ-cyclocytidine
(7). δH (200 M Hz, (CD3)2SO)): 9.68 and 9.40 (br, 2H, = NH+2), 8.38 (d, 1H, J5.6
7.3 Hz, H-6), 7.36–7.20 (m, 15H, Ar-H), 6.60 (d, 1H, J5.6 7.3 Hz, H-5), 6.56 (d, 1H,
J1 ,2 5.7 Hz, H-1ꢀ), 6.27 (d, 1H, JOH,3 4.0 Hz, 3ꢀ-OH), 5.43 (d, 1H, J1 ,2 5.7 Hz, H-
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2ꢀ), 4.42–4.20(m, 2H, H-3ꢀ,4ꢀ), 2.97(dd, 1H, J5 a,4 5.97, J5 a,5 b 10.1Hz, H-5’a), 2.70
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(dd, 1H, J5 b,4 7.34, J5 a,5 b 10.1 Hz, H-5’b); ESI-MS: M/Z 468.2 (M+1); Anal. calc.
For C28H26N3O4Cl:C, 66.73; H, 5.20; N, 8.34; Found: C, 66.32; H, 5.33; N, 8.52.
Thermolysis of 5ꢀ-O-trityl-2ꢀ,3ꢀ-O-
triphenylphosphoranediyluridine (4) in Methanol
Phosphorance (4) 1.2 g was prepared as described above and dissolved in a
mixture of 15 mL THF and 5 mL CH3OH. After refluxing for 5 h, a new product
was found by TLC and chromatography on silica gel with CHCl3 afforded 3-N-
methyl-5ꢀ-O-trityluridine (9) in 56% yield. δH (200 M Hz, CDCl3): 7.76 (d, 1H,
J
5.6 8.0 Hz, H-6), 7.38–7.25 (m, 15H, Ar-H), 5.80 (d, 1H, J1 ,2 3.0 Hz, H-1ꢀ), 5.53
ꢀ ꢀ
(d, 1H, J5,6 8.0 Hz, H-5), 4.34 (m, 2H, H-2ꢀ,3ꢀ), 4.26–4.23 (m, 1H, H-4ꢀ), 3.50
(dd, 1H, J5 a,4 2.7, J5 a, 5ꢀb 10.9 Hz, H-5ꢀa), 3.41 (dd, 1H, J5 b,4 2.7, J5 a,5 b 10.9 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
H-5ꢀb), 3.33 (s, 3H, CH3-N); (200 M Hz, (CD3)2SO)): 5.60 (d, 1H, JOH,3 , 4.0
ꢀ
Hz, 3ꢀ-OH), 5.21 (d, 1H, JOH,2 4.0 Hz, 2ꢀ-OH): δC (200 M Hz, (CD3)2SO)): δ
ꢀ
143.4, 128.3,127.9 and 127.1 (Ph3C-, Ar-C), 90.1 (Ph3C-C), 161.9 (C-4), 150.6
(C-2), 138.8 (C-6), 100.4 (C-5), 86.4 (C-1ꢀ), 82.2 (C-2ꢀ), 73.5 (C-4ꢀ), 69.3 (C-3ꢀ),
63.0 (C-5ꢀ), 27.2 (CH3-N); FAB-MS (C29H28N2O6): M/Z 501 (M + 1)
ACKNOWLEDGMENTS
The authors would like to acknowledge the financial support from the
National Natural Science Foundation of China (No. 39870415, No. 29632004),
the Ministry of Science and Technology, Ministry of Education of China, and
Tsinghua University.

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