One-pot etherification of purine nucleosides and pyrimidines

Article abstract of DOI:10.1021/ol101655h

A one-pot synthesis of ethers derived from inosine, guanosine, 2′-deoxyguanosine, and pyrimidinones is described. Exposure of the heterocycle to 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs₂CO₃

Full text of DOI:10.1021/ol101655h

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4478-4481
One-Pot Etherification of Purine
Nucleosides and Pyrimidines
Hari Prasad Kokatla and Mahesh K. Lakshman*
Department of Chemistry, The City College and The City UniVersity of New York,
160 ConVent AVenue, New York, New York 10031-9198
lakshman@sci.ccny.cuny.edu
Received July 16, 2010
ABSTRACT
A one-pot synthesis of ethers derived from inosine, guanosine, 2′-deoxyguanosine, and pyrimidinones is described. Exposure of the heterocycle
to 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs2CO3 produces a reactive intermediate, which
is converted to the desired ether by subsequent addition of an appropriate alcohol or phenol and Cs2CO3. Although rapid formation of HMPA
from BOP can occur in the presence of an alcohol and base, as demonstrated by the reaction with methanol, under appropriate conditions
these heteroaryl ethers can be efficiently synthesized.
Modification of the natural nucleoside scaffold offers conve-
nient access to unnatural or modified nucleosides.1 In this
context, modified nucleosides are highly important in biochem-
istry, in biology, and as pharmaceutical agents. Natural nucleo-
sides contain a pyrimidine motif, and pyrimidines themselves
are privileged structures in medicinal chemistry.2
ones by PyBroP.9 Recently, we10-16 and others17-23 have
been interested in the in situ activation of nucleosides,
purines, and other heterocycles that contain an amide linkage
as part of the cyclic system. In these cases, the heterocycle
is converted to a reactive phosphonium salt using an
appropriate reagent, and the phosphonium salt subsequently
reacts with a suitable nucleophile. Amines have been
classically used as nucleophiles in these transformations.
Although phenols have also been used as nucleophiles, only
Halogenation of nucleoside derivatives via in situ activa-
3,4
tion of their amide linkages with PPh3/CCl4 or combina-
tions of HMPT with CCl4 or CBr4 or NBS5,6 are known. A
similar principle has been used for the N6 modification of
adenine as well as 2,6-diaminopurine nucleosides by PPh3/
I27,8 and the C-2 modification of 3,4-dihydropyrimidin-2(1H)-
(2) (a) Cheng, C. C. Prog. Med. Chem. 1969, 6, 67–134. (b) Cheng,
C. C.; Roth, B. Prog. Med. Chem. 1970, 7, 285–341. (c) Cheng, C. C.;
Roth, B. Prog. Med. Chem. 1971, 8, 61–117. (d) Jain, K. S.; Chitre, T. S.;
Miniyar, P. B.; Kathiravan, M. K.; Bendre, V. S.; Veer, V. S.; Shahane,
S. R.; Shishoo, C. J. Curr. Sci. 2006, 90, 793–803.
(1) (a) Modified Nucleosides in Biochemistry, Biotechnology and Medi-
cine; Herdewijn, P., Ed.; Wiley-VCH: Weinheim, 2008. (b) Nucleic Acids
in Chemistry and Biology, 3rd ed.; Blackburn, G. M., Gait, M. J., Loakes,
D., Williams, D. M., Eds.; RSC Publishing: Cambridge, UK, 2006. (c)
Simons, C. Nucleoside Mimetics: Their Chemistry and Biological Properties;
Gordon and Breach: Amsterdam, 2001. (d) PerspectiVes in Nucleoside and
Nucleic Acid Chemistry; Kisaku¨rek, M. V., Rosemeyer, H., Eds.; Verlag
Helvetica Chimica Acta: Zurich and Wiley-VCH: Weinheim, 2000. (e)
Suhadolnik, R. J. Nucleosides as Biological Probes; Wiley Interscience:
New York, 1979.
(3) De Napoli, L.; Messere, A.; Montesarchio, D.; Piccialli, G.;
Santacroce, C. Nucleosides Nucleotides 1991, 10, 1719–1728.
(4) De Napoli, L.; Messere, A.; Montesarchio, D.; Piccialli, G.;
Santacroce, C.; Varra, M. J. Chem. Soc., Perkin Trans. 1 1994, 923–925.
(5) Ve´liz, E. A.; Beal, P. A. Tetrahedron Lett. 2000, 41, 1695–1697.
(6) Ve´liz, E. A.; Beal, P. A. J. Org. Chem. 2001, 66, 8592–8598.
(7) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497–3499.
(8) Janeba, Z.; Lin, X.; Robins, M. J. Nucleosides, Nucleotides Nucleic
Acids 2004, 23, 137–147.
10.1021/ol101655h  2010 American Chemical Society
Published on Web 09/16/2010

a single one-pot reaction of quinazolin-4(3H)-one and phenol
has been reported.20 Other such etherifications were con-
ducted on preformed benzotriazol-1-yloxy and 7-azabenzo-
triazol-1-yloxy derivatives, obtained by reactions of pyrim-
idinones with BOP and PyAOP, respectively.20,24-26 The
serendipitous formation of such triazolyl derivatives was first
reported in the reaction of thymidine with a hydroxybenzo-
triazole-derived phosphorylating agent.27 Despite recent
interest in the in situ activation protocols for nucleosides and
pyrimidines, there are no examples of a general procedure
for the synthesis of alkyl ethers from these heterocycles.
Notably, our previous attempts at one-pot etherification of
nucleosides with alcohols were unsuccessful, although reac-
tions of preformed O6-(benzotriazol-1-yl) nucleoside deriva-
tives with both alcohols and phenols were eminently fea-
sible.10,16 This led us to consider a general approach for
accomplishing etherification by in situ activation, thereby
augmenting the methodological palette for one-pot transfor-
mations of nucleosides and pyrimidines.
at δ ) 143 ppm) over 1 h, indicating that BOP does not directly
react with the alcohol. However, when this experiment was
repeated in the presence of Cs2CO3, rapid formation of HMPA
was observed by 31P{1H} NMR (singlet at δ ) 25 ppm) within
1 h. This reaction led to the isolation of 1-methoxy-1H-benzo-
triazole28 in >70% yield. On its own, in comparison to existing
methods,29-32 this reaction represents facile, general entry
to hydroxybenzotriazole ethers, and our results on such a
direct etherification are forthcoming. In the context of the
present work, these results demonstrated that combining
BOP, alcohol, and base could lead to a competing reaction.
The next stage in the development was a consolidation of
the two steps, i.e., formation of the (benzotriazol-1-yl)
derivative 1 and etherification, into a one-pot operation. For
this evaluation, we were presented with several options
involving DBU or Cs2CO3 as bases and THF as solvent.
Table 2 shows the results of our analysis.
Table 2 presents several notable observations. When all
components were present at the start of the reaction, a
mixture of products was observed (entries 1 and 5), consistent
with the fact that a reaction between MeOH and BOP occurs
in the presence of base. For reasons presently unknown, when
4 molar equiv of base was present at the beginning of the
reaction, O6-(benzotriazol-1-yl) derivative 1 was seen to form
but it did not undergo further reaction when MeOH alone was
added subsequently (entries 2 and 6). On the other hand,
Our work commenced with analysis of conditions that
would provide efficient conversion of O6-(benzotriazol-1-
yl)inosine 110 to the O6-methyl ether 2. These data are shown
in Table 1. Consistent with our previous observations, in the
Table 1. Analysis of the Reaction of 1 with MeOH under
Various Conditions
(9) Kang, F.-A.; Kodah, J.; Guan, Q.; Li, X.; Murray, W. V. J. Org.
Chem. 2005, 70, 1957–1960
.
(10) Bae, S.; Lakshman, M. K. J. Am. Chem. Soc. 2007, 129, 782–789
.
(11) Bae, S.; Lakshman, M. K. J. Org. Chem. 2008, 73, 1311–1319
(12) Bae, S.; Lakshman, M. K. J. Org. Chem. 2008, 73, 3707–3713
(13) Bae, S.; Lakshman, M. K. Org. Lett. 2008, 10, 2203–2206
(14) Lakshman, M. K.; Choudhury, A.; Bae, S.; Rochttis, E.; Pradhan,
P.; Kumar, A. Eur. J. Org. Chem. 2009, 152–159
.
.
.
.
(15) Bae, S.; Chaturvedi, S.; Lakshman, M. K. Current Protocols in
Nucleic Acid Chemistry; John Wiley and Sons, Inc.: New York, 2009;
Supplement 36, 1.22.
(16) Lakshman, M. K.; Frank, J. Org. Biomol. Chem. 2009, 7, 2933–
2940
.
(17) Wan, Z.-K.; Binnun, E.; Wilson, D. P.; Lee, J. Org. Lett. 2005, 7,
5877–5880
(18) Wan, Z.-K.; Wacharasindhu, S.; Binnun, E.; Mansour, T. Org. Lett.
entry
conditionsa
timeb
24 h
% yieldc
NRd
.
1
2
MeOH (20 molar equiv)
MeOH (20 molar equiv),
(i-Pr)2NEt (2 molar equiv)
MeOH (20 molar equiv),
DBU (2 molar equiv)
2006, 8, 2425–2428
(19) Pritz, S.; Wolf, Y.; Klemm, C.; Bienert, M. Tetrahedron Lett. 2006,
47, 5893–5896
(20) Wan, Z.-K.; Wacharasindhu, S.; Levins, C. G.; Lin, M.; Tabei, K.;
Mansour, T. S. J. Org. Chem. 2007, 72, 10194–10210
(21) Levins, C. G.; Wan, Z.-K. Org. Lett. 2008, 10, 1755–1758
.
.
24 h
NRd
75
3
4
.
45 min
.
MeOH (20 molar equiv),
(22) Ashton, T. D.; Scammells, P. J. Aust. J. Chem. 2008, 61, 49–58
(23) For recent reviews, see: (a) Kang, F.-A.; Sui, Z.; Murray, W. V.
.
Cs2CO3 (2 molar equiv)
45 min
77
Eur. J. Org. Chem. 2009, 461–479. (b) Mansour, T. S.; Bardhan, S.; Wan,
a Reactions were conducted using 70 µmol of 1 in MeOH. b Reactions
were monitored by TLC. c Yields reported are of isolated and purified
product. d No reaction was observed, and only 1 was observed by TLC.
Z.-K. Synlett 2010, 1143–1169
.
(24) Wacharasindhu, S.; Bardhan, S.; Wan, Z.-K.; Tabei, K.; Mansour,
T. S. J. Am. Chem. Soc. 2009, 131, 4174–4175
(25) Bardhan, S.; Wacharasindhu, S.; Wan, Z.-K.; Mansour, T. S. Org.
Lett. 2009, 11, 2511–2514
(26) Bardhan, S.; Tabei, K.; Wan, Z.-K.; Mansour, T. S. Tetrahedron
Lett. 2009, 50, 5733–5736
.
.
.
absence of base, no methanolysis was observed even after
24 h at room temperature, and (i-Pr)2NEt was ineffective
for this transformation (entries 1 and 2).10,11 DBU and
Cs2CO3 proved to be effective for the rapid conversion of 1
to ether 2 (entries 3 and 4).
Once this understanding was gained, the next step in the
development of a one-pot method was to determine whether
any reaction occurred between alcohol and BOP. Exposure of
a THF solution of BOP to excess MeOH led to no discernible
change in the 31P{1H} NMR (singlet at δ ) 46 ppm and septet
(27) Reese, C. B.; Richards, K. H. Tetrahedron Lett. 1985, 26, 2245–
2248
.
(28) 1-Methoxy-1H-benzotriazole. 1H NMR (500 MHz, CDCl3): δ 8.02
(d, 1H, Ar-H, J ) 8.4 Hz), 7.59 (d, Ar-H, J ) 8.3 Hz), 7.52 (t, 1H, Ar-H,
J ) 7.6 Hz), 7.40 (t, 1H, Ar-H, J ) 7.2 Hz), 4.38 (s, 3H, OCH3).
(29) Serve´, M. P.; Seybold, P. G.; Feld, W. A.; Chao, M. A. J. Het-
erocycl. Chem. 1976, 13, 509–512
.
(30) Grochowski, E.; Falent-Kwastowa, E. J. Chem. Res. (S) 1978, 300–
301
.
(31) Ma¨rky, M.; Schmid, H.; Hansen, H.-J. HelV. Chim. Acta 1979, 62,
2129–2153
.
(32) Feld, W. A.; Paessun, R. J.; Serve´, M. P. J. Macromol. Sci.-Chem.
1981, A15, 891–896
.
Org. Lett., Vol. 12, No. 20, 2010
4479

Table 2. Evaluation of Conditions for a One-Pot Conversion of
Trisilyl Inosine 3 to the O6-Methyl Ether 2
entry
1
conditionsa
timeb
24 h
% yieldc
d
DBU (4 molar equiv), BOP
(2 molar equiv), MeOH
(20 molar equiv), THF, rt
DBU (4 molar equiv), BOP
(2 molar equiv), THF, rt
then evaporate solvent and
add MeOH (20 molar
equiv), rt
DBU (2 molar equiv), BOP
(2 molar equiv), THF, rt
then add DBU (2 molar
equiv) and MeOH (20
molar equiv), rt
DBU (2 molar equiv), BOP
(2 molar equiv), THF, rt
then evaporate solvent and
add DBU (2 molar equiv)
and MeOH (20 molar
equiv), rt
Cs2CO3 (4 molar equiv),
BOP (2 molar equiv),
MeOH (20 molar equiv),
THF, rt
-
2
3
4
step 1: 2 h
e
step 2: 24 h
-
step1: 2 h
step 2: 8 h
74
76
Figure 1.
Nucleoside O6-ethers synthesized. (Step 1: 10 min for
inosine and 1 h for guanosine as well as 2′-deoxyguanosine, at room
temperature. Step 2: reaction temperatures and times are shown
above.)
step 1: 2 h
step 2: 4 h
d
Cs2CO3 to the reaction mixture after formation of the O6-
(benzotriazol-1-yl) ether (step 1) without evaporation of the
mixture, and the displacement (step 2) was conducted at 70
°C.
5
6
48 h
-
Cs2CO3 (4 molar equiv),
BOP (2 molar equiv),
THF, rt
then add MeOH (20 molar
equiv), rt
step 1: 20 min
e
As seen from Figure 1, reactions proceeded with tert-
butyldimethylsilyl protected ribo and 2′-deoxyribonucleo-
sides. Reactions with alcohols proceeded at room tempera-
ture. In the reaction of ethylene glycol and 3, a small amount
(15%) of the bisetherification product of ethylene glycol by
3 was isolated. Notably, the electron-deficient p-nitrophenol
reacted well, leading to 8. Yields of products obtained were
generally comparable to our previously reported two-step
procedures.10,16 Reactions of silylated guanosine and 2′-
deoxyguanosine in MeCN were superior to those in THF
(yields were 10-15% lower in THF). This is consistent with
our previous observation on the superiority of MeCN for
the reactions of guanine nucleosides with BOP.16
step 2: 24 h
step 1: 2 h
step 2: 1 h
-
7
8
9
DBU (2 molar equiv), BOP
(2 molar equiv), THF, rt
then evaporate solvent and
add Cs2CO3 (2 molar
equiv) and MeOH (20
molar equiv), rt
Cs2CO3 (2 molar equiv),
BOP (2 molar equiv),
THF, rt
then add Cs2CO3 (2 molar
equiv) and MeOH (20
molar equiv), rt
Cs2CO3 (2 molar equiv),
BOP (2 molar equiv),
THF, rt
77
step 1: 10 min
step 2: 2 h
94
94
step 1: 10 min
step 2: 10 min
then evaporate solvent and
add Cs2CO3 (2 molar
equiv) and MeOH (20
molar equiv), rt
We next considered the application of this method for a
general synthesis of ethers derived from pyrimidines. Typically,
such ethers are prepared by an SNAr displacement reaction
between chloropyrimidines and alkoxides33 or alternatively by
more complex procedures such as oxidation of a hydrazone,34
displacement of a trichloromethyl group,35 or a direct alkylation
where N- and O-alkyl products are formed.36,37 By comparison,
the present method would offer significant operational
simplicity. Therefore, for evaluation we selected three
representative substrates shown in Figure 2: quinazolin-
4(3H)-one (13), 4-methylpyrimidin-2(1H)-one hydrochloride
(14·HCl), and 5-bromopyrimidin-2(1H)-one (15).
With the pyrimidinone substrates, the reaction with 2 molar
equiv each of BOP and Cs2CO3 was performed in THF, at room
temperature. This step was typically complete within 50 min.
The second step, leading to the formation of the pyrimidine
ethers, was conducted with a variety of alcohols (20 molar
equiv) or 4-methoxyphenol (2 molar equiv) and Cs2CO3 (2
a Reactions were conducted using 0.16 mmol of 3 in THF (2 mL).
b Reactions were monitored by TLC. c Yields reported are of isolated and
purified product. d Mixture of products. e Formation of the O6-(benzotriazol-
1-yl) derivative 1 was complete as observed by TLC.
addition of base and MeOH as a separate operation, after the
formation of 1, gave the desired result. Here, base and MeOH
can be added either directly to the reaction mixture (entries 3
and 8) or after evaporation of the reaction mixture (entries 4,
7, and 9). As can be expected, reactions were faster when
MeOH and base were added after evaporation of the solvent
(compare entries 3 and 4, as well as entries 8 and 9). From
these data, the best protocol that emerges is entry 9, where a
high product yield was attained within an overall reaction time
of 20 min. A variety of nucleoside alkyl ethers were generated
via this procedure (Figure 1). Aryl ethers 8, 10, and 12 were
synthesized by adding 2 molar equiv each of the phenol and
4480
Org. Lett., Vol. 12, No. 20, 2010

substrates (13-15), followed by reaction with a range of
hydroxyl nucleophiles. Although these reactions proceeded
with 1° and 2° alcohols, we did not obtain successful
reactions with t-BuOH. This contrasts with the successful
reaction of 13 with t-BuNH2.18 Some reactivity differences
between the pyrimidinones were observed. For example,
4-methylpyrimidin-2(1H)-one (14) required elevated tem-
perature for complete reaction with ethylene glycol, whereas
quinazolin-4(3H)-one (13) and 5-bromopyrimidin-2(1H)-one
(15) underwent reaction with this alcohol at room temper-
ature, within 4 h. In comparison to the reaction of nucleoside
3 with ethylene glycol, there was no discernible formation
of a dimeric product with the pyrimidines. Despite the
intrinsic reactivity differences of the various pyrimidines
toward SNAr displacement, the method appears general.
Finally, we evaluated whether the etherification could be
accomplished via in situ formation of a phosphonium salt from
the tautomerizable heterocycle rather than the benzotriazolyl
ether. Thus, in one unoptimized experiment, 13 was exposed
to PyBroP and Cs2CO3 (2 molar equiv each) in THF at room
temperature for 12 h. Although 13 was not fully consumed,
the mixure was evaporated and exposed to 20 molar equiv of
MeOH and 2 molar equiv of Cs2CO3. In addition to the expected
16a, the less than clean product contained another inseparable,
presently uncharacterized impurity.
In summary, we have developed a simple, one-pot method
for the etherification of hypoxanthine as well as guanine
nucleosides and pyrimidinones. Reaction of these heterocyclic
amides with BOP produces reactive intermediates in situ, which
can be made to undergo reactions with alcohols and phenols
by appropriate control of reaction conditions.
For nucleoside modification, this direct route obviates separate
syntheses of electrophilic nucleoside precursors such as halo
nucleosides and nucleoside sulfonates or the Mitsunobu reaction.
Similarly, etherification of pyrimidinones can be accomplished
without additional steps or application of other types of
chemistry. We believe that the method described herein will
find broad applicability in the development of pharmacologically
important entities from precursors containing cyclic amides,
such as those used in this study.
Figure 2. Pyrimidine ethers synthesized. (Step 1: 50 min at room
temperature. Step 2: reaction temperatures and times are shown above.)
molar equiv). Structures of the 20 compounds synthesized via
this route are displayed in Figure 2. Reaction times (when
reactions were observed to be complete by TLC analysis but
which were not further optimized), reaction temperatures, and
product yields are shown under each compound.
As evidenced by Figure 2, etherification can be achieved
by the in situ activation of the amide group in all three
Acknowledgment. This work was partially supported by
NIH Grant S06 GM008168-30 and by a PSC CUNY award
to M.K.L. Infrastructural support at CCNY was provided by
NIH/NCRR/RCMI Grant G12 RR03060. We thank Dr. Cliff
Soll (Hunter College), Dr. Bill Boggess, and Nonka Sevova
(University of Notre Dame) for HRMS analyses, as well as
NSF Grant CHE-0741793.
(33) See for examples: (a) Sasse, K. Synthesis 1978, 379–382. (b)
Trybulski, E. J.; Benjamin, L. E., Sr.; Earley, J. V.; Fryer, R. I.; Gilman,
N. W.; Reeder, E.; Walser, A.; Davidson, A. B.; Horst, W. D.; SepZinwall,
J.; O’Brien, R. A.; Dairman, W. J. Med. Chem. 1983, 26, 1589–1596. (c)
Pe´rez, M. A.; Soto, J. L.; Guzma´n, F. J. Chem. Soc., Perkin Trans. 1 1985,
87–91. (d) Ohno, S.; Mizukoshi, K.; Komatsu, O.; Kunoh, Y.; Nakamura,
Y.; Katoh, E.; Nagasaka, M. Chem. Pharm. Bull. 1986, 34, 4150–4165. (e)
Arukwe, J.; Keilen, G.; Undheim, K. Acta Chem. Scand. 1988, B42, 530–
536. (f) Solberg, J.; Undheim, K. Acta Chem. Scand. 1989, 43, 62–68. (g)
Warrener, R. N.; Golic, M.; Butler, D. N. Synlett 1997, 1105–1107. (h)
Decicco, C. P.; Nelson, D. J. Tetrahedron Lett. 1993, 34, 8213–8216. (i)
Zanatta, N.; Pacholski, I. D. L.; Faoro, D.; Bonacorso, H. G.; Martins, M. A. P.
Synth. Commun. 2001, 31, 2855–2863. (j) Atwal, K. S.; O’Neil, S. V.;
Ahmad, S.; Doweyko, L.; Kirby, M.; Dorso, C. R.; Chandrasena, G.; Chen,
B.-C.; Zhao, R.; Zehler, R. Bioorg. Med. Chem. Lett. 2006, 16, 4796–4799.
(k) Lee, A. H. F.; Kool, E. T. J. Am. Chem. Soc. 2006, 128, 9219–9230.
Supporting Information Available: General experimental
considerations, general procedure for the etherification using
alcohols and phenols, characterization data, and copies of
1H NMR spectra of 2, 4-12, the dimeric byproduct from
the reaction of 3 with ethylene glycol, 16a-16k, 17a-17d,
˘
(34) Stefane, B.; Polanc, S. Synlett 2008, 1279–1282.
1
18a-18e, and H-1H COSY spectra of 8, 9, and 11. This
(35) Mencarelli, P.; Stegel, F. J. Org. Chem. 1985, 50, 5415–5417.
(36) Zanatta, N.; Faoro, D.; Fernandes, L. D. S.; Brondani, P. B.; Flores,
D. C.; Flores, A. F. C.; Bonacorso, H. G.; Martins, M. A. P. Eur. J. Org.
Chem. 2008, 5832–5838.
material is available free of charge via the Internet at
http://pubs.acs.org.
(37) Hirohashi, T.; Inaba, S.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1975,
48, 147–156.
OL101655H
Org. Lett., Vol. 12, No. 20, 2010
4481