6-Bromopurine nucleosides as reagents for nucleoside analogue synthesis

Article abstract of DOI:10.1021/jo016078v

Surprisingly facile direct substitution reactions with acetyl-protected 6-bromopurine nucleosides are described. Included in the series of bromonucleosides studied is the guanosine derivative N²-2′,3′,5′-tetraacetyl-6-bromopurine ribonucleoside, the synthesis of which is reported here for the first time. Brominated nucleosides had not previously been considered optimal substrates for SNAr reactions given the general reactivity trend for halogenated aromatic systems (i.e. F > Cl > Br > I). However, even weakly nucleophilic aromatic amines give high yields of the substitution products in polar solvents with these 6-bromopurine nucleosides. For primary aromatic amines, secondary aliphatic amines, and imidazole, reaction takes place only at C6, with no effect on the acetyl-protected ribose. In addition, we report the first synthesis of 3′,5′-di-O-acetyl-6-bromopurine-2′-deoxyribonucleoside and its reaction with an arylamine in MeOH in the absence of added metal catalyst. Thus, C6-arylamine derivatives of both adenosine and 2′-deoxyadenosine can be prepared via simple S_NAr reactions with the corresponding 6-bromo precursor. We also describe high yielding and C6-selective substitution reactions with 6-bromonucleosides using alcohol and thiol nucleophiles in the presence of added base (DBU). Finally, C6-bromonucleosides are shown to be readily hydrogenated to give purine or 2-aminopurine products in good yield. This work increases the arsenal of reactions and strategies available for the synthesis of nucleoside analogues as potential biochemical tools or new therapeutics.

Full text of DOI:10.1021/jo016078v

8592
J . Org. Chem. 2001, 66, 8592-8598
6-Br om op u r in e Nu cleosid es a s Rea gen ts for Nu cleosid e An a logu e
Syn th esis
Eduardo A. Ve´liz* and Peter A. Beal*
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112
beal@chemistry.utah.edu
Received August 31, 2001
Surprisingly facile direct substitution reactions with acetyl-protected 6-bromopurine nucleosides
are described. Included in the series of bromonucleosides studied is the guanosine derivative N2-
2′,3′,5′-tetraacetyl-6-bromopurine ribonucleoside, the synthesis of which is reported here for the
first time. Brominated nucleosides had not previously been considered optimal substrates for SNAr
reactions given the general reactivity trend for halogenated aromatic systems (i.e. F > Cl > Br >
I). However, even weakly nucleophilic aromatic amines give high yields of the substitution products
in polar solvents with these 6-bromopurine nucleosides. For primary aromatic amines, secondary
aliphatic amines, and imidazole, reaction takes place only at C6, with no effect on the acetyl-
protected ribose. In addition, we report the first synthesis of 3′,5′-di-O-acetyl-6-bromopurine-2′-
deoxyribonucleoside and its reaction with an arylamine in MeOH in the absence of added metal
catalyst. Thus, C6-arylamine derivatives of both adenosine and 2′-deoxyadenosine can be prepared
via simple SNAr reactions with the corresponding 6-bromo precursor. We also describe high yielding
and C6-selective substitution reactions with 6-bromonucleosides using alcohol and thiol nucleophiles
in the presence of added base (DBU). Finally, C6-bromonucleosides are shown to be readily
hydrogenated to give purine or 2-aminopurine products in good yield. This work increases the
arsenal of reactions and strategies available for the synthesis of nucleoside analogues as potential
biochemical tools or new therapeutics.
In tr od u ction
coupling,9,10 Pd-mediated arylaminations,5 organocuprate
cross couplings,11,12 and reactions that involve 6-oxyphos-
phonium intermediates.6 Generally, N6-substituted pu-
rine derivatives have been prepared by direct aromatic
nucleophilic displacement (SNAr) of halogens with amine
nucleophiles in the presence of a base in alcohol at
reflux.13 Following the general trend of reactivity of
halogenated aromatic systems, most syntheses employed
the 6-fluoro or 6-chloro derivative; the latter being
favored for ease of preparation. Later, other procedures
were developed to synthesize N6-substituted purine
derivatives. For instance, N6-substituted purine 2′-
deoxyribonucleosides have been synthesized via SNAr
displacement of O6-arylsulfonyl purine derivatives with
amines in DME at 50 °C.14 More recently, Robins and
Lin6 described the synthesis of N6-substituted purine
derivatives by displacing a presumed 6-oxyphosphonium
intermediate with cyclic secondary amines and imidazole.
These procedures are efficient with good nucleophiles,
such as aliphatic amines. However, less reactive nucleo-
philes (e.g., aromatic amines) rarely succeed in these
The development of new methods for the generation
of nucleoside analogues continues to be an intensively
studied research topic. Nucleoside analogues have found
use in a number of areas, including the study of the
effects of DNA-damaging reagents1 and in mechanistic
analysis of nucleoside metabolizing and nucleic acid
modifying enzymes.2,3 In addition, these compounds have
the potential to be developed into new antibacterial,
antiviral or cancer chemotherapeutic agents.4 Due to
these important applications, modern synthetic methods
are being applied to nucleoside analogue synthesis to
create simple, versatile and efficient procedures for their
generation. Purine derivatives with various substituents
at C6 have received considerable attention, at least in
part, due to their structural similarity to DNA damage
products arising from modification of N6 of 2′-deoxy-
adenosine or O6 of 2′-deoxyguanosine.5,6 Recent advances
in the synthesis of C6 modified purines include use of
such reactions as Stille coupling,7,8 Suzuki-Miyaura
* To whom correspondence should be addressed. Phone: (801) 585-
9719. Fax: (801) 581-8433.
(1) Harwood, E. A.; Sigurdsson, S. T.; Edfeldt, N. B. F.; Reid, B. R.;
Hopkins, P. B. J . Am. Chem. Soc. 1999, 121, 5081-5082.
(2) Kati, W. M.; Acheson, S. A.; Wolfenden, R. Biochemistry 1992,
31, 7356-7366.
(3) Easterwood, L. M.; Ve´liz, E. A.; Beal, P. A. J . Am. Chem. Soc.
2000, 122, 11537-11538.
(4) Suhadolnik, R. J . Nucleosides as Biological Probes; Wiley: New
York, 1979.
(5) Lakshman, M. K.; Keeler, J . C.; Hilmer, J . H.; Martin, J . Q. J .
Am. Chem. Soc. 1999, 121, 6090-6091.
(6) Lin, X.; Robins, M. J . Org. Lett. 2000, 2, 3497-3499.
(7) Hocek, M.; Masoj´ıdkova´, M.; Holy, A. Tetrahedron 1997, 53,
2291-2302.
(8) Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron 1996, 52,
5625-5638.
(9) Hocek, M.; Holy, A.; Votruba, I.; Dvora´kova´ Collect. Czech. Chem.
Commun. 2000, 65, 1683-1697.
(10) Lakshman, M. K.; Hilmer, J . H.; Martin, J . Q.; Keeler, J . C.;
Dinh, Y. Q. V.; Ngassa, F. N.; Russon, L. M. J . Am. Chem. Soc. 2001,
123, 7779-7787.
(11) Hocek, M.; Holy, A. Collect. Czech. Chem. Commun. 1999, 64,
229-241.
(12) Ve´liz, E. A.; Stephens, O. M.; Beal, P. A. Org. Lett. 2001, 3,
2969-2972.
(13) Fleysher, M. H.; Bloch, A.; Hakala, M. T.; Nichol, C. A. J . Med.
Chem. 1969, 12, 1056-1061.
(14) Lakshman, M. K.; Ngassa, F. N.; Keeler, J . C.; Dinh, Y. Q. V.;
Hilmer, J . H.; Russon, L. M. Org. Lett. 2000, 2, 927-930.
10.1021/jo016078v CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/10/2001

6-Bromopurine Nucleosides as Reagents
J . Org. Chem., Vol. 66, No. 25, 2001 8593
Sch em e 1
procedures. Indeed, more elaborate alternative methods
have been developed to synthesize N6-aryl substituted
purine derivatives. Lakshman and co-workers5 described
a Pd-mediated coupling of arylamines with a 6-bromopu-
rine derivative. Robins and Lin6 were successful in
synthesizing these types of compounds by allowing
aniline to react with C6-sulfonylpurine derivatives, which,
in turn, were synthesized from their corresponding
inosine nucleosides. Because of the expected general
reactivity trend of halogenated aromatic systems, the
reactivity of 6-bromopurine nucleosides has been under-
explored in SNAr reactions. Given our recent development
of a simple, efficient procedure to prepare 6-bromopurine
ribonucleoside15 and its application in the synthesis of
the tetraacetyl-protected 2-amino-6-bromopurine deriva-
tive, we wished to ascertain the general efficacy and scope
of simple substitution reactions with these compounds
and their reactivity with aromatic amines in particular.
Herein we report that direct substitution at C6 of
acetyl-protected 6-bromopurine nucleosides occurs in
high yield under mild conditions in polar solvents with
various amines, including arylamines, in the absence of
added base or metal catalyst. These reactions are typi-
cally more efficient than those of the analogous 6-chlo-
ropurine ribonucleoside, in contrast to the predicted
relative reactivity for SNAr reactions. Moreover, other
nucleophiles, such as phenol and thiophenol, react se-
lectively at C6 in the presence of DBU as added base.
The observed reactivity at the 6-position is maintained
with a 2-amino-6-bromopurine nucleoside giving substi-
tuted derivatives of guanosine or 2,6-diaminopurine
ribonucleoside. To further expand the use of this reaction
to 2′-deoxyribonucleosides, 3′,5′-di-O-acetyl-6-bromopu-
rine-2′-deoxyribonucleoside was synthesized using Nair’s
protocol.16 Importantly, it also reacts with an arylamine
in MeOH in the absence of added metal catalyst. Thus,
C6-arylamine derivatives of both adenosine and 2′-
deoxyadenosine can be prepared via simple SNAr reac-
tions with the corresponding C6-bromo precursor and do
not require the use of metal catalyst, in contrast to a
previous report.5
SNAr Rea ction s w ith 6-Br om op u r in e Nu cleosid es
a n d Am in e Nu cleop h iles. A search of the literature
found that N2-aryl-2-aminopurine derivatives had been
synthesized by the reaction of 2-bromopurines with the
appropriate aromatic amine in alcohol at reflux.18,19 This
result indicated that direct displacement of bromide from
the purine C2 could be accomplished with weak nucleo-
philes, such as aromatic amines. In addition, it was found
that 2-halo-6-bromopurine derivatives underwent sub-
stitution at the C6 position under mild conditions (25
°C),20-22 whereas, the subsequent reaction at the C2
position required more forcing conditions (120 °C).22 Little
was known, however, regarding the efficiency of direct
displacement of bromide from the 6-position of 6-bro-
mopurine nucleosides. Lakshman and co-workers5 re-
ported that 6-chloro-9-(2-deoxy-â-D-erythro-pentafurano-
syl)purine does not react with arylamines, and therefore,
the 6-bromo derivative should be even less reactive. They
also reported a Pd-catalyzed substitution reaction of bis-
O-silylated 6-bromopurine 2′-deoxyribonucleoside with
aromatic amines and found that no reaction occurred in
the absence of the Pd catalyst. This latter observation
seemed to suggest that direct displacement of bromide
from the purine C6 would fail with weak nucleophiles.
However, initial studies in our laboratory indicated that
the 6-bromopurine ribonucleoside was quite reactive and
underwent a displacement reaction under very mild
conditions (5 equiv of K2CO3, MeOH/rt/1 h) to give 6-O-
methyl inosine in 89% yield.3 Under the same conditions
and time, the 6-chloro precursor reacts to give the
substituted product in significantly lower yield.23 This
was an unexpected result given the reactivity trend for
halogenated aromatic systems in SNAr reactions (i.e.,
F > Cl > Br > I). These observations prompted us to
explore further the reactivity of 6-bromopurine nucleo-
sides in SNAr reactions.
Resu lts a n d Discu ssion
Br om in a tion of Gu a n osin e Usin g HMP T/NBS/
LiBr . We recently reported a simple, high yielding
procedure for the generation of 2′,3′,5′-tri-O-acetyl-6-
bromopurine ribonucleoside (1a ) using triacetylinosine
and HMPT/NBS/LiBr in acetonitrile.15 To determine if
this approach could be applied to other nucleosides, we
carried out a similar transformation using guanosine
protected at the ribose hydroxyls and at the 2-amino
position with acetyl groups.17 This reaction proceeded in
high yield to give N2-2′,3′,5′-tetraacetyl-6-bromopurine
ribonucleoside 1b (Scheme 1). This constitutes the first
reported synthesis of this versatile compound. Direct
reaction of 1b with various nucleophiles in polar solvents
allows ready access to a variety of 2-amino-substituted
purine derivatives (vide infra). Unfortunately, application
of our bromination conditions to protected 2′-deoxyinosine
failed due to depurination. Also, 2′,3′,5′-tri-O-acetyluri-
dine reacts under these conditions to give C5 bromination
instead of the desired C4 bromo-product.
Primary aliphatic amines react with acetyl-protected
6-bromopurine ribonucleoside at room temperature to
give high yields of the substitution products (Table 1,
entries 1-3). For instance, 4-methylbenzylamine reacts
with 1a in DME in a 3 h period to give an 87% yield of
adenosine derivative 2a . This reaction is selective for
substitution at C6 with no loss of the acetate-protecting
groups. When this reaction is carried out in THF, it takes
place at a lower rate and gives an overall lower yield
(Table 1, entry 2). The more reactive methylamine reacts
at C6 in DME to give a high yield of the substitution
(18) Wright, G. E.; Dudycz, L. W. J . Med. Chem. 1984, 27, 175-
181.
(19) Xu, H.; Maga, G.; Focher, F.; Smith, E. R.; Spadari, S.; Gambino,
J .; Wright, G. E. J . Med. Chem. 1995, 38, 49-57.
(20) Wright, G. E.; Hildebrand, C.; Freese, S.; Dudycz, L. W.;
Kazimierczuk, Z. J . Org. Chem. 1987, 52, 4617-4618.
(21) Montgomery, J . A.; Shortnacy-Fowler, A. T.; Clayton, S. D.;
Riordan, J . M.; Secrist, J . A., III J . Med. Chem. 1992, 35, 397-401.
(22) Kazimierczuk, Z.; Vilpo, J .; Hildebrand, C.; Wright, G. E. J .
Med. Chem. 1990, 33, 1683-1687.
(15) Ve´liz, E. A.; Beal, P. A. Tetrahedron Lett. 2000, 41, 1695-1697.
(16) Nair, V.; Richardson, S. G. J . Org. Chem. 1980, 45, 3969-3974.
(17) Reese, C. B.; Saffhill, R. J . Chem. Soc., Perkin Trans. 1 1972,
2937-2940.
(23) Ve´liz, E. A.; Beal, P. A. Unpublished results.

8594 J . Org. Chem., Vol. 66, No. 25, 2001
Ve´liz and Beal
period of time (16 h).24 This specific example demon-
strates the increased reactivity of the 6-bromo derivative
in comparison with its 6-chloro counterpart. Secondary
aliphatic amines react selectively at C6 in DME at room
temperature with either inosine derivative 1a or gua-
nosine derivative 1b (Table 1, entries 4-10). Given the
selectivity of this substitution reaction, an alcohol func-
tional group differentiated from those on ribose can be
easily introduced into the structure using the appropriate
amino alcohol (Table 1, entries 6 and 7). The substitution
reaction with secondary amines does have limitations as
no reaction was observed with the bulky diisopropyl-
amine in DME. Substitution with imidazole occurs in
DMF at 65 °C taking place in 8 h in 92% yield with 1a
and 65% yield for 1b. However, no reaction was observed
with imidazole in DME.
Ta ble 1. Su bstitu tion Rea ction s w ith 6-Br om op u r in e
Ribon u cleosid es a n d Am in esa
Importantly, aromatic amines react with both 1a and
1b in DMF, MeOH, or EtOH at 65 °C in 5 h to give
substitution products in good to excellent yields (Table
1, entries 13-18). Ortho-substitution on the arylamine
does not inhibit this reaction (Table 1, entries 17-18).
This procedure is the simplest, most efficient reported
to prepare arylamine derivatives of adenosine modified
at N6. The synthesis consists of three high yielding steps
from commercially available inosine (acetyl protection,
bromination, and substitution) and requires no metal for
catalysis of the substitution reaction. Interestingly, no
arylamine substitution product was observed when the
6-chloro substrate was used under the same reaction
conditions. Furthermore, less polar solvents, such as
DME or acetonitrile, do not support the substitution
reaction with arylamines.
The efficiency of SNAr reactions with the 6-bromopu-
rine ribonucleosides and arylamines was surprising given
the observation of Lakshman and co-workers.5 As de-
scribed above, they reported that no substitution product
was observed in a reaction with a 6-bromopurine 2′-
deoxyribonucleoside and arylamines in DME even after
24 h at 80 °C. There are several possible explanations
for the observed reactivity differences. First, their reac-
tion was carried out in DME and we have shown that a
more polar solvent like DMF, MeOH, or EtOH is neces-
sary for substitution with weakly nucleophilic amines.
Second, their substrate was protected as a bis-tert-
butyldimethylsilyl-derivative, whereas we used acetyl-
protected substrates. Finally, their reaction was carried
out with a 2′-deoxyribonucleoside as opposed to the
ribonucleosides discussed above. To determine if the
difference in sugar structure was important in defining
the different reactivities observed, we prepared 3′,5′-
diacetyl-6-bromopurine-2′-deoxyribonucleoside (11) as a
substrate for substitution reactions with an arylamine
(Scheme 2). To do this, we used Nair’s diazotization/
bromination procedure16 with tert-butylnitrite and bro-
moform to convert 3′,5′-diacetyl-2′-deoxyadenosine to 11
in 57% yield. This constitutes the first reported synthesis
of this derivative which we anticipate could be prepared
on a multigram scale. Interestingly, compound 11 reacted
in MeOH at 65 °C with p-toluidine to give the 2′-
deoxyadenosine derivative 12 in 91% in 12 h. Therefore,
simple, efficient substitution reactions with arylamines
observed for 6-bromopurine ribonucleosides can also take
place with 2′-deoxyribonucleosides. Thus, the use of more
a
(1) Trace H2O from addition of 40% MeNH2 in H2O. (2) Yield
of deprotected nucleoside. (3) NR ) no reaction.
product, but under these conditions, ribose deprotection
also occurs (Table 1, entry 3). The efficacy of this reaction
is noteworthy given the extremely mild conditions em-
ployed. The transformation occurs at room temperature,
whereas the 6-chloro derivative requires both high pres-
sure (Parr bomb) and temperature (80 °C) and longer
(24) J ohnson, J . A., J r.; Thomas, H. J .; Schaeffer, H. J . J . Am. Chem.
Soc. 1958, 80, 699-702.

6-Bromopurine Nucleosides as Reagents
J . Org. Chem., Vol. 66, No. 25, 2001 8595
Ta ble 3. Su bstitu tion Rea ction s w ith 6-Br om op u r in e
Ribon u cleosid es a n d Oxygen a n d Su lfu r Nu cleop h iles
Sch em e 2
Ta ble 2. Su bstitu tion of Rea ction s w ith Silyl-P r otected
6-Br om op u r in e Ribon u cleosid e
substitution reactions occur more readily when the
nucleoside is acetyl-protected as opposed to tert-bu-
tyldimethylsilyl-protected. How the ribose-protecting
group affects the reactivity of the remote C6 position is
unknown at this time. The low solubility of 13 in MeOH
prevented a test of this solvent for the arylamine sub-
stitution reaction with this compound.
SNAr Rea ction s of 6-Br om op u r in e Nu cleosid es
w ith Oxygen a n d Su lfu r Nu cleop h iles. To study
further the ability of 6-bromo derivatives 1a and 1b to
undergo nucleophilic displacement, O- and S-containing
nucleophiles were allowed to react with these compounds
(Table 3). Thiophenol reacts with 1a in the presence of
DBU in acetonitrile to give 17a in 92% yield in 8 h at
room temperature (Table 3, entry 1). The reaction is
selective for C6 with no loss of the acetyl protecting
groups. DBU was included in these reactions as a proton
acceptor and does not react directly with 1a or 1b under
these conditions. Phenol also reacts under these condi-
tions with 1a and 1b to give 18a and 18b, respectively,
in high yield. Thus, bromopurine nucleosides 1a and 1b
are useful precursors to C6-O and C6-S substituted
purines via simple substitution reactions.
Redu ction of 6-Br om opu r in e Nu cleosides by Cata-
lytic Hyd r ogen a tion . Purine and 2-aminopurine ribo-
nucleosides are important nucleoside analogues with
unique enzyme inhibitory and fluorescent properties.25,26
These compounds have been synthesized previously via
the hydrogenolysis of the corresponding 6-chloro deriva-
tive,27,28 as well as via other procedures.29,16,30 Although
the hydrogenolysis of the 6-chloro precursor is typically
high yielding, these reactions often require extended
reaction times (>24 h) to reach completion. We recently
complex procedures, such as Pd-mediated arylamina-
tions, to generate C6 arylamine derivatives of 2′-deoxy-
adenosine may not be necessary as these compounds can
likely be obtained from simpler direct substitution reac-
tions of the acetyl-protected 6-bromo substrate in MeOH.
To determine if the ribose-protecting group played a
role in determining the reactivity of the brominated
nucleosides in substitution reactions, we generated tris-
O-(tert-butyldimethylsilyl)-6-bromopurine ribonucleoside
13 by deprotection of 1a with NH3/MeOH at room
temperature and silylating the resulting riboside (Table
2). Morpholine reacts readily with 13 in DME at room
temperature to give the substitution product 14 in 87%
yield (Table 2, entry 1). However, the reaction is slower
than that of 1a (9 h to reach completion compared to 3 h
for 1a ), suggesting that the silyl-protecting groups may
be adversely affecting the substitution reaction. Weak
nucleophiles such as imidazole can also displace bromide
from 13 in DMF at 65 °C to give 15 in 93% yield (Table
2, entry 3). Again, no reaction with imidazole was
observed in DME (Table 2, entry 2). When the arylamine
p-toluidine was used with 13, no substitution product was
observed in DMF up to 12 h at 65 °C, whereas the
p-toluidine substitution product was obtained in 65%
yield in 5 h in DMF when 1a is used as the substrate
(Table 2, entry 4; Table 1, entry 14). Thus, direct
(25) Ward, D. C.; Reich, E. J . Biol. Chem. 1969, 244, 1228-1237.
(26) J ones, W.; Kurz, L. C.; Wolfenden, R. Biochemistry 1989, 28,
1242-1247.
(27) Vickers, R. S.; Gerster, J . F.; Robins, R. K. In Synthetic
Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S.,
Eds.; Wiley-Interscience: New York, 1968; Vol. 1, pp 244-245.
(28) Schaeffer, H. J .; Thomas, H. J . J . Am. Chem. Soc. 1958, 80,
4896-4899.
(29) Fox, J . J .; Wempen, I.; Hampton, A.; Doerr, I. L. J . Am. Chem.
Soc. 1958, 80, 1669-1675.
(30) Nair, V.; Young, D. A.; DeSilvia, R., J r. J . Org. Chem. 1987,
52, 1344-1347.

8596 J . Org. Chem., Vol. 66, No. 25, 2001
Ve´liz and Beal
amines were present in 2.5 equiv. The reaction mixture was
stirred at room temperature until completion by TLC (see
Table 1). The reaction mixture was diluted with EtOAc (10
mL) and washed with brine (1 × 15 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude products were purified by flash column
chromatography on silica gel using appropriate solvent sys-
tems (listed under individual compound headings, vide infra).
2′,3′,5′-Tr i-O-a cetyl-N6-(p-m eth ylben zyl)a d en osin e (2a ).
Chromatography, 2% MeOH/CHCl3. Yellow syrup (87%). 1H
NMR (CDCl3, 300 MHz): δ (ppm) 8.41 (br s, 1H), 7.87 (s, 1H),
7.27 (d, J ) 8.1 Hz, 2H), 7.14 (d, J ) 7.8 Hz, 2H), 6.18 (d, J )
5.4 Hz, 1H), 6.08 (br t, J ) 4.8 Hz, 1H), 5.92 (t, J ) 5.4 Hz,
1H), 5.67 (dd, J ) 5.4, 4.5 Hz, 1H), 4.81 (br s, 2H), 4.47-4.41
(m, 2H), 4.36 (dd, J ) 12.9, 5.7 Hz, 1H), 2.33 (s, 3H), 2.14 (s,
3H), 2.12 (s, 3H), 2.08 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ
(ppm) 170.4, 169.6, 169.4, 154.7, 153.5, 138.0, 137.2, 135.2,
129.3, 127.7, 86.1, 80.2, 73.1, 70.6, 63.1, 44.3, 21.1, 20.8, 20.5,
20.4. HRFABMS: calcd for C24H28N5O7 (M + H)+ 498.1989,
obsd 498.2007.
Sch em e 3
reported that a copper-mediated coupling reaction to form
a 6-trifluoromethylpurine derivative occurred much more
readily with the 6-bromo precursor12 than with the
6-chloro compound.31 Given this observation, we wished
to ascertain the efficacy of Pd-catalyzed hydrogenolysis
of 1a and 1b. Indeed, we found that excellent yields of
purine derivatives 19a and 19b were obtained in 8 h in
MeOH at room temperature with 2.5 atm of H2 (Scheme
3).
These results indicate that 6-bromopurine nucleosides
are excellent substrates for substitution reactions with
N-, O-, and S-containing nucleophiles in polar solvents
and are good candidates for transition metal catalyzed
reactions, often superior to the 6-chloro alternatives.
N-Meth yla d en osin e (3a ). Triturated with EtOAc. White
solid (94%). Spectral data agreed with reported values.32
2′,3′5′-Tr i-O-a cetyl-N6,N6-(d ieth yl)a d en osin e (4a ). Chro-
1
matography, 2% MeOH/CHCl3. Light yellow syrup (94%). H
NMR (CDCl3, 300 MHz): δ (ppm) 8.30 (s, 1H), 7.86 (s, 1H),
6.19 (d, J ) 5.7 Hz, 1H), 5.89 (t, J ) 5.7 Hz, 1H), 5.63 (dd,
J ) 5.4, 3.9 Hz, 1H), 4.44-4.39 (m, 2H), 4.34 (dd, J ) 12.9,
5.1 Hz, 1H), 3.93 (br s, 4H), 2.12 (s, 6H), 2.05 (s, 3H), 1.26 (t,
J ) 6.9 Hz, 6H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.3,
169.6, 169.4, 153.7, 152.8, 150.3, 136.1, 119.9, 85.6, 80.1, 73.0,
70.4, 63.2, 43.0, 20.8, 20.5, 20.4, 13.4. HRFABMS: calcd for
Exp er im en ta l Section
Gen er a l. Glassware for all reactions was oven dried at 125
°C overnight and cooled in a desiccator prior to use. Reactions
were carried out under an atmosphere of dry nitrogen when
anhydrous conditions were necessary. All reagents were
obtained from commercial sources and were used without
further purification unless noted otherwise. Liquid reagents
were introduced by oven-dried microsyringes. Tetrahydrofuran
was distilled from sodium metal and benzophenone. Thin-layer
chromatography (TLC) was performed with Merck silica gel
60 F254 precoated plates, eluting with the solvents indicated.
Short- and long-wave visualization was performed with a
Mineralight multiband ultraviolet lamp at 254 and 365 nm,
respectively. Flash column chromatography was carried out
using Mallinckrodt Baker silica gel 150 (60-200 mesh). 1H
and 13C nuclear magnetic resonance spectra of pure compounds
were acquired at 300 and 75 MHz, respectively. Chemical
shifts are reported in parts per million in reference to the
solvent peak. The abbreviations s, d, dd, t, td, q, m, and brs
stand for singlet, doublet, doublet of doublets, triplet, triplet
of doublets, quartet, multiplet, and broad singlet, in that order.
High-resolution mass spectra were obtained on a Finnigan
Mat 95.
C
20H28N5O7 (M + H)+ 450.1989, obsd 450.1997.
N2,2′,3′,5′-Tetr a a cetyl-N6,N6-(d ieth yl)-2,6-d ia m in on ebu -
la r in e (4b). Chromatography, 2% MeOH/CHCl3. Light yellow
1
syrup (90%). H NMR (CDCl3, 300 MHz): δ (ppm) 7.83 (br s,
1H), 7.73 (s, 1H), 6.02 (d, J ) 4.8 Hz, 1H), 5.90 (t, J ) 5.1 Hz,
1H), 5.69 (t, J ) 5.1 Hz, 1H), 4.46-4.37 (m, 2H), 4.35-4.28
(m, 1H), 4.11 (br s, 2H), 3.67 (br s, 2H), 2.54 (s, 3H), 2.11 (s,
3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.24 (t, J ) 4.5 Hz, 6H). 13C
NMR (CDCl3, 75 MHz): δ (ppm) 170.4, 169.5, 169.3, 153.6,
152.4, 151.0, 135.9, 116.8, 86.2, 79.6, 72.9, 70.4, 63.0, 43.4, 42.6,
24.9, 20.7, 20.5, 20.4, 14.1, 13.0. HREIMS: calcd for C22H30N6O8
506.2118, obsd 506.2138.
2′,3′,5′-Tr i-O-a cetyl-N6-(m eth yl)-N6-(2-h yd r oxyeth yl)a d -
en osin e (5a ). Chromatography, 5% MeOH/CHCl3. White foam
(87%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.29 (br s, 1H),
7.88 (s, 1H), 6.17 (d, J ) 5.7 Hz, 1H), 5.86 (t, J ) 5.7 Hz, 1H),
5.61 (dd, J ) 5.7, 4.2 Hz, 1H), 4.42-4.37 (m, 2H), 4.33 (dd,
J ) 12.6, 4.8 Hz, 1H), 4.06 (br s, 2H), 3.92 (t, J ) 4.8 Hz, 2H),
3.49 (br s, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 170.3, 169.6, 169.3, 155.4, 152.5,
150.3, 136.5, 120.2, 85.8, 80.1, 73.0, 70.6, 63.1, 61.3, 53.5, 29.5
20.7, 20.5, 20.3. HRFABMS: calcd for C19H26N5O8 (M + H)+
452.1781, obsd 452.1759.
N2,2′,3′,5′-Tetr a a cetyl-N6-(m eth yl)-N6-(2-h yd r oxyeth yl)-
2,6-d ia m in on ebu la r in e (5b). Chromatography, 5% MeOH/
CHCl3. Light yellow syrup (90%). 1H NMR (CDCl3, 300 MHz):
δ (ppm) 8.08 (br s, 1H), 7.73 (s, 1H), 6.00 (d, J ) 4.8 Hz, 1H),
5.89 (t, J ) 4.2 Hz, 1H), 5.70 (t, J ) 4.2 Hz, 1H), 4.46-4.31
(m, 3H), 4.11 (br s, 2H), 3.90 (br s, 2H), 3.32 (br s, 3H), 2.41
(br s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 170.5, 169.6, 169.3, 155.4, 152.0,
151.0, 136.3, 117.1, 86.4, 79.7, 72.8, 70.4, 63.0, 61.0, 52.9, 29.6,
25.0, 20.7, 20.5, 20.3. HRFABMS: calcd for C21H29N6O9 (M +
H)+ 509.1996, obsd 509.2002.
N2-2′,3′,5′-Tetr aacetyl-2-am in o-6-br om on ebu lar in e (1b).
The 6-bromo derivative was synthesized according to our
modified bromination procedure (NBS 2.1 equiv, HMPT 2.0
equiv, LiBr 2 equiv)15 with guanosine tetraacetate17 (540 mg,
1.20 mmol) to afford, after flash column purification (2%
MeOH/CHCl3), 461.4 mg (75%) of the product as a pale yellow
foam. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.62 (br s, 1H),
8.12 (s, 1H), 6.07 (d, J ) 4.5 Hz, 1H), 5.89 (dd, J ) 5.7, 4.5
Hz, 1H), 5.78 (t, J ) 5.4 Hz, 1H), 4.51-4.35 (m, 3H), 2.40 (s,
3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H). 13C NMR (CDCl3,
75 MHz): δ (ppm) 170.3, 169.5, 169.5, 151.8, 150.5, 143.4,
142.8, 131.0, 87.3, 80.2, 73.3, 70.3, 70.4, 63.1, 25.0, 20.7, 20.4,
20.3. HRFABMS: calcd for C18H21N4O8Br (M + H)+ 514.0574,
obsd 514.0577.
2′,3′,5′-Tr i-O-a cetyl-6-(m or p h olin -4-yl)n ebu la r in e (7a ).
Chromatography, 2% MeOH/CHCl3. Pale yellow foam (99%).
1H NMR (CDCl3, 300 MHz): δ (ppm) 8.30 (s, 1H), 7.87 (s, 1H),
6.17 (d, J ) 5.7 Hz, 1H), 5.87 (t, J ) 5.4 Hz, 1H), 5.61 (dd,
J ) 5.4, 4.5 Hz, 1H), 4.42-4.37 (m, 2H), 4.32 (dd, J ) 12.6,
5.1 Hz, 1H), 4.25 (br s, 4H), 3.78 (t, J ) 4.8 Hz, 4H), 2.10 (s,
Gen er a l P r oced u r e for th e Rea ction of 6-Br om op u r in e
Der iva tives w ith Alip h a tic Am in es. The amine was added
to a solution of the 6-bromopurine derivative (0.109-0.116
mmol) in the appropriate solvent (5 mL). With the exception
of methylamine (40% aqueous solution, 6 equiv), all other
(31) Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano, M.; Kumadaki,
I. J . Chem. Soc., Perkin Trans. 1 1980, 2755-2761.
(32) Mikkola, S.; Koissi, N.; Ketoma¨ki, K.; Rauvala, S.; Neuvonen,
K.; Lo¨nnberg, H. Eur. J . Org. Chem. 2000, 12, 2315-2323.

6-Bromopurine Nucleosides as Reagents
J . Org. Chem., Vol. 66, No. 25, 2001 8597
3H), 2.09 (s, 3H), 2.03 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ
(ppm) 170.2, 169.5, 169.3, 153.8, 152.6, 150.6, 136.5, 120.3,
85.8, 80.0, 73.0, 70.6, 66.9, 63.0, 45.4, 20.7, 20.5, 20.3. HRE-
IMS: calcd for C20H25N5O8 463.1697, obsd 463.1692.
3H), 2.14 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H). 13C NMR (CDCl3,
75 MHz): δ (ppm) 170.4, 169.5, 169.4, 152.8, 152.4, 149.7,
138.4, 135.4, 133.7, 129.4, 121.0, 117.4, 86.7, 79.8, 73.1, 70.4,
63.1, 25.1, 20.8, 20.7, 20.5, 20.4. HREIMS: calcd for C25H28N6O8
540.1969, obsd 540.1948.
N2,2′,3′,5′-Tetr a a cetyl-6-(m or p h olin -4-yl)-2-a m in on ebu -
la r in e (7b). Chromatography, 2% MeOH/CHCl3. Colorless
syrup (91%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.91 (s, 1H),
7.75 (s, 1H), 6.02 (d, J ) 4.5 Hz, 1H), 5.87 (t, J ) 4.8 Hz, 1H),
5.68 (br t, J ) 5.1 Hz, 1H), 4.45-4.32 (m, 3H), 4.22 (br s, 4H),
3.78 (br t, J ) 4.8 Hz, 4H), 2.46 (br s, 3H), 2.11 (s, 3H), 2.07
(s, 3H), 2.06 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.4,
169.5, 169.3, 153.8, 152.3, 151.4, 136.2, 117.1, 86.4, 79.7, 73.0,
70.4, 66.8, 63.0, 29.6, 25.1, 20.7, 20.5, 20.3. HRFABMS: calcd
for C22H29N6O9 (M + H)+ 521.1996, obsd 521.1988.
2′,3′,5′-Tr i-O-a cetyl-N6-(o-a n isyl)a d en osin e (10a ). Chro-
matography, 2% MeOH/CHCl3. Light yellow foam (91%). 1H
NMR (CDCl3, 300 MHz): δ (ppm) 8.73-8.70 (m, 1H), 8.53 (s,
1H), 8.22 (br s, 1H), 7.99 (s, 1H), 7.04-7.00 (m, 2H), 6.93-
6.87 (m, 1H), 6.20 (d, J ) 5.4 Hz, 1H), 5.95 (t, J ) 5.4 Hz,
1H), 5.68 (dd, J ) 5.7, 4.2 Hz, 1H), 4.47-4.41 (m, 2H), 4.36
(dd, J ) 13.2, 5.4 Hz, 1H), 3.92 (s, 3H), 2.13 (s, 3H), 2.11 (s,
3H), 2.06 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.3,
169.5, 169.3, 153.0, 152.1, 149.1, 148.4, 138.8, 128.0, 122.9,
121.2, 120.8, 119.9, 109.9, 86.0, 80.2, 73.0, 70.6, 63.0, 55.6, 20.7,
20.5, 20.3. HREIMS: calcd for C23H25N5O8 499.1702, obsd
499.1691.
Gen er a l P r oced u r e for th e Rea ction of 6-Br om op u r in e
Der iva tives w ith Ar om a tic Am in es. The aromatic amine
(6 equiv) was added to a solution of the 6-bromopurine
derivative (0.109-0.116 mmol) in the appropriate solvent (5
mL). The reaction mixture was heated at 65 °C for 5 h or until
completion by TLC (see Table 1). The mixture was concen-
trated under reduced pressure, the resulting residue dissolved
in EtOAc, and the solution was successively washed with 10%
aqueous citric acid (1 × 25 mL) and brine (1 × 25 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude products were purified by
flash column chromatography on silica gel using appropriate
solvent systems (listed under individual compound headings,
vide infra). A different workup procedure was employed when
DMF was used as the solvent. The reaction mixture was
diluted with EtOAc/hexanes (7:3, 25 mL) and washed succes-
sively with water (1 × 15 mL) and brine (1 × 15 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude products were purified by
flash column chromatography on silica gel using appropriate
solvent systems (listed under individual compound headings,
vide infra).
2′,3′,5′-Tr i-O-a cet yl-6-(im id a zol-1-yl)n eb u la r in e (8a ).
Chromatography, 2% MeOH/CHCl3. Yellow foam (92%). 1H
NMR (CDCl3, 300 MHz): δ (ppm) 9.41 (br s, 1H), 8.78 (s, 1H),
8.36 (br s, 1H), 8.27 (s, 1H), 7.24 (br s, 1H), 6.26 (d, J ) 5.1
Hz, 1H), 5.97 (t, J ) 5.4 Hz, 1H), 5.66 (t, J ) 5.1 Hz, 1H),
4.51-4.46 (m, 1H), 4.39 (dd, J ) 12.3, 4.8 Hz, 2H), 2.15 (s,
3H), 2.13 (s, 3H), 2.08 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ
(ppm) 170.2, 169.5, 169.3, 153.0, 152.5, 145.9, 142.7, 137.6,
130.7, 122.9, 117.3, 86.6, 80.4, 73.1, 70.5, 62.9, 20.7, 20.5, 20.3.
HRCIMS: calcd for C19H21N6O7 (M + H)+ 445.1468, obsd
445.1462.
N2-2′,3′5′-Tetr a a cetyl-N6-(o-a n isyl)-2,6-d ia m in on ebu la -
r in e (10b). Chromatography, 2% MeOH/CHCl3. Light tan
1
foam (95%). H NMR (CDCl3, 300 MHz): δ (ppm) 8.65 (br d,
J ) 7.8 Hz, 1H), 8.21 (br s, 2H), 7.85 (s, 1H), 7.04-6.97 (m,
2H), 6.90 (dd, J ) 7.5, 2.1 Hz, 1H), 6.05 (d, J ) 4.8 Hz, 1H),
5.97 (dd, J ) 11.7, 4.8 Hz, 1H), 5.74 (t, J ) 5.1 Hz, 1H), 4.51-
4.36 (m, 3H), 3.90 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H), 2.08 (s,
3H), 2.07 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.4,
169.5, 169.3, 152.6, 152.1, 149.5, 148.5, 138.3, 127.6, 123.3,
120.7, 120.2, 118.0, 109.9, 86.6, 79.8, 73.0, 70.4, 63.0, 55.6, 25.1,
20.7, 20.5, 20.4. HREIMS: calcd for C25H28N6O9 556.1914, obsd
556.1911.
3′,5′-Di-O-a cetyl-6-br om o-2′-d eoxyn ebu la r in e (11). A
purged solution of 3′,5′-di-O-acetyl-2′-deoxyadenosine33 (367
mg, 1.09 mmol), in CHBr3 (10 mL) was heated at 65 °C. To
this hot solution was added t-BuONO (2.26 g, 21.9 mmol, 20
equiv) and the mixture was stirred at this temperature for
1.5 h. The mixture was purified by flash column chromatog-
raphy. The column was first eluted with CHCl3 and then with
2% MeOH/CHCl3 to afford 249 mg (57%) of the product as a
1
thick yellow syrup. H NMR (CDCl3, 300 MHz): δ (ppm) 8.65
(s, 1H), 8.31 (s, 1H), 6.44 (dd, J ) 8.1, 6.6 Hz, 1H), 5.41-5.39
(m, 1H), 4.37-4.29 (m, 3H), 2.96 (ddd, J ) 14.1, 7.5, 6.3 Hz,
1H), 2.64 (ddd, J ) 14.1, 6.0, 2.7 Hz, 1H), 2.09 (s, 3H), 2.02 (s,
3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.2, 170.1, 151.8,
149.7, 143.3, 143.2, 134.7, 85.0, 82.7, 74.1, 63.4, 37.4, 20.8, 20.6.
HRCIMS: calcd for C14H16N4O5Br (M + H)+ 399.0304, obsd
399.0272.
3′,5′-Di-O-a cet yl-N6-(p -t olyl)-2′-d eoxya d en osin e (12).
Chromatography, 1-2% MeOH/CHCl3. Light yellow syrup
N2-2′,3′,5′-Tet r a a cet yl-6-(im id a zol-1-yl)-2-a m in on eb u -
la r in e (8b). Chromatography, 5% MeOH/CHCl3. Yellow foam
(65%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.04 (br s, 1H),
8.66 (br s, 1H), 8.28 (br s, 1H), 8.07 (s, 1H), 7.22 (br s, 1H),
6.11 (d, J ) 4.5 Hz, 1H), 5.93 (t, J ) 4.5 Hz, 1H), 5.80 (br t,
J ) 5.1 Hz, 1H), 4.53-4.42 (m, 3H), 2.51 (s, 3), 2.15 (s, 3H),
2.10 (s, 3H), 2.10 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm)
170.4, 169.6, 169.5, 154.0, 152.4, 146.0, 142.2, 137.4, 130.8,
119.5, 117.4, 87.2, 80.2, 73.3, 70.5, 63.2, 25.2, 20.8, 20.5, 20.4.
HRCIMS: calcd for C21H24N7O8 (M + H)+ 502.1681, obsd
502.1679.
1
(91%). H NMR (CDCl3, 300 MHz): δ (ppm) 8.48 (s, 1H), 7.99
(s, 1H), 7.85 (br s, 1H), 7.61 (d, J ) 8.4 Hz, 2H), 7.17 (d, J )
8.4 Hz, 2H), 6.43 (dd, J ) 7.8, 6.0 Hz, 1H), 5.44-5.42 (m, 1H),
4.41-4.32 (m, 3H), 2.96 (ddd, J ) 14.4, 7.8, 6.6 Hz, 1H), 2.62
(ddd, J ) 14.1, 6.0, 2.4 Hz, 1H), 2.33 (s, 3H), 2.12 (s, 3H), 2.06
(s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.4, 170.2,
153.0, 152.4, 149.0, 138.5, 135.7, 133.5, 129.5, 120.9, 120.7,
84.5, 82.5, 74.5, 63.7, 37.5, 20.8, 20.8, 20.7. HRCIMS: calcd
for C21H24N5O5 (M + H)+ 426.1784, obsd 426.1758.
2′,3′,5′-Tr is-O-(ter t-b u t yld im et h ylsilyl)-6-br om on eb u -
la r in e (13). To a solution of 6-bromopurine ribonucleoside (90
mg, 0.272 mmol) in freshly distilled anhydrous THF (3 mL)
was added sequentially imidazole (92.5 mg, 1.36 mmol) and
TBDMSCl (135.2 mg, 0.897 mmol) and stirred at room tem-
perature overnight. The reaction mixture was diluted with
EtOAc (25 mL) and washed successively with 5% NaHCO3-
(aq) (1 × 30 mL) and brine (1 × 30 mL). The organic layer
was dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (30%
EtOAc/hexanes) afforded 128.2 mg (70%) of the product as a
white foam. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.68 (s, 1H),
8.54 (s, 1H), 6.11 (d, J ) 5.1 Hz, 1H), 4.58 (t, J ) 4.8 Hz, 1H),
4.29 (t, J ) 3.9 Hz, 1H), 4.15 (q, J ) 2.7 Hz, 1H), 4.01 (dd,
J ) 11.7, 3.6 Hz, 1H), 3.79 (dd, J ) 11.4, 2.4 Hz, 1H), 0.95 (s,
2′,3′,5′-Tr i-O-a cetyl-N6-(p-tolyl)a d en osin e (9a ). Chroma-
tography, 5% MeOH/CHCl3. Light yellow foam (85%). 1H NMR
(CDCl3, 300 MHz): δ (ppm) 8.49 (s, 1H), 7.98 (s, 1H), 7.81 (br
s, 1H), 7.61 (d, J ) 8.1 Hz, 2H), 7.18 (d, J ) 8.4 Hz, 2H), 6.20
(d, J ) 5.4 Hz, 1H), 5.94 (t, J ) 5.4 Hz, 1H), 5.68 (t, J ) 5.7
Hz, 1H), 4.47-4.42 (m, 2H), 4.37 (dd, J ) 12.9, 5.4 Hz, 1H),
2.33 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 170.3, 169.6, 169.4, 153.3, 152.5,
149.2, 138.7, 135.6, 133.6, 129.5, 120.9, 120.6, 86.1, 80.2, 73.1,
70.6, 63.1, 20.8, 20.7, 20.5, 20.4. HRFABMS: calcd for
C
23H26N5O7 (M + H)+ 484.1832, obsd 484.1837.
N2-2′,3′,5′-Tetr a a cetyl-N6-(p-tolyl)-2,6-d ia m in on ebu la -
r in e (9b). Chromatography, 2% MeOH/CHCl3. Light yellow
syrup (90%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.18 (s, 1H),
7.83 (br s, 2H), 7.59 (d, J ) 8.4 Hz, 2H), 7.17 (d, J ) 8.1 Hz,
2H), 6.02 (d, J ) 4.5 Hz, 1H), 5.96 (t, J ) 5.1 Hz, 1H), 5.74 (br
t, J ) 4.8 Hz, 1H), 4.46-4.35 (m, 3H), 2.43 (br s, 3H), 2.33 (s,
(33) van der Wenden, E. M.; Ku¨nzel, J . K. v. F. D.; Mathoˆt, R. A.
A.; Danhof, M.; IJ zerman, A. P.; Soudijn, W. J . Med. Chem. 1995, 38,
4000-4006.

8598 J . Org. Chem., Vol. 66, No. 25, 2001
Ve´liz and Beal
9H), 0.92 (s, 9H), 0.77 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), 0.09
(s, 3H), 0.08 (s, 3H), -0.05 (s, 3H), -0.27 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 151.8, 150.2, 143.9, 143.0, 134.6,
88.5, 85.7, 76.3, 71.8, 62.4, 26.1, 25.8, 25.6, 18.5, 18.0, 17.8,
-4.4, -4.7, -4.8, -5.1, -5.3, -5.4. HRFABMS: calcd for
(CDCl3, 300 MHz): δ (ppm) 8.51 (s, 1H), 8.18 (s, 1H), 7.48-
7.43 (m, 2H), 7.32-7.25 (m, 3H), 6.24 (d, J ) 5.1 Hz, 1H), 5.98
(t, J ) 5.4 Hz, 1H), 5.67 (t, J ) 5.1 Hz, 1H), 4.49-4.44 (m,
2H), 4.37 (dd, J ) 12.6, 5.1 Hz, 1H), 2.15 (s, 3H), 2.13 (s, 3H),
2.09 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.3, 169.5,
169.3, 160.4, 152.5, 152.4, 152.2, 141.4, 129.6, 125.9, 122.3,
121.8, 86.6, 80.3, 73.1, 70.5, 62.9, 20.7, 20.5, 20.4. HR-
FABMS: calcd for C22H23N4O8 (M + H)+ 471.1516, obsd
471.1499.
N2-2′,3′,5′-Tetr aacetyl-O6-(ph en yl)gu an osin e (18b). Chro-
matography, 2% MeOH/CHCl3. White foam (80%). 1H NMR
(CDCl3, 300 MHz): δ (ppm) 7.97 (br s, 1H), 7.43 (t, J ) 7.5
Hz, 2H), 7.28 (t, J ) 7.2 Hz, 1H), 7.21 (t, J ) 7.5 Hz, 2H), 6.87
(dd, J ) 14.7, 7.5 Hz, 1H), 6.10 (d, J ) 4.2 Hz, 1H), 5.92 (t,
J ) 5.1 Hz, 1H), 5.72 (t, J ) 5.1 Hz, 1H), 4.51-4.44 (m, 2H),
4.38 (dd, J ) 13.2, 6.0 Hz, 1H), 2.14 (s, 3H), 2.12 (s, 3H), 2.10
(s, 6H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.4, 169.5,
169.4, 156.0, 152.2, 152.1, 129.5, 125.9, 121.9, 120.2, 115.3,
87.0, 80.0, 73.2, 70.4, 63.0, 24.8, 20.7, 20.5, 20.4. HRCIMS:
calcd for C24H25N5O9 527.1652, obsd 527.1667.
C
28H54N4O4BrSi3 (M + H)+ 673.2636, obsd 673.2644.
2′,3′,5′,-Tr is-O-(t-b u t yld im et h ylsilyl)-6-(m or p h olin -4-
yl)n ebu lar in e (14). Chromatography, 2% MeOH/CHCl3. Thick
syrup (87%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.32 (s, 1H),
8.02 (s, 1H), 6.02 (d, J ) 5.4 Hz, 1H), 4.71 (t, J ) 5.1 Hz, 1H),
4.30 (t, J ) 3.6 Hz, 4H), 4.10 (q, J ) 3.3 Hz, 1H), 4.01 (dd,
J ) 11.1, 4.2 Hz, 1H), 3.82 (t, J ) 4.5 Hz, 4H), 3.76 (dd, J )
11.4, 3.0 Hz, 1H), 0.94 (s, 9H), 0.92 (s, 9H), 0.79 (s, 9H), 0.12
(s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), -0.06 (s, 3H),
-0.23 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 153.9, 152.2,
150.9, 137.7, 120.5, 88.1, 85.4, 75.4, 72.1, 67.0, 62.6, 45.6, 26.1,
25.8, 25.7, 18.5, 18.1, 17.8, -4.4, -4.7, -4.7, -5.0, -5.4, -5.4.
HRCIMS: calcd for C32H62N5O5Si3 (M + H)+ 680.4043, obsd
680.4081.
2′,3′,5′-Tr is-O-(t-bu tyld im eth ylsilyl)-6-(im id a zol-1-yl)-
n ebu la r in e (15). Chromatography, 1% MeOH/CHCl3. Light
yellow syrup (93%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.19
(br s, 1H), 8.77 (s, 1H), 8.54 (s, 1H), 8.41 (br s, 1H), 7.25 (br s,
1H), 6.15 (d, J ) 4.8 Hz, 1H), 4.62 (t, J ) 4.8 Hz, 1H), 4.33 (t,
J ) 4.2 Hz, 1H), 4.17 (dd, J ) 6.3, 3.6 Hz, 1H), 4.04 (dd, J )
11.4, 3.6 Hz, 1H), 3.81 (dd, J ) 11.4, 2.4 Hz, 1H), 0.97 (s, 9H),
0.93 (s, 9H), 0.81 (s, 9H), 0.17 (s, 3H), 0.15 (s, 3H), 0.10 (s,
3H), 0.10 (s, 3H), -0.02 (s, 3H), -0.21 (s, 3H). 13C NMR (CDCl3,
75 MHz): δ (ppm) 153.3, 152.1, 145.6, 143.4, 137.7, 130.6,
122.9, 117.4, 88.5, 85.5, 76.2, 71.7, 62.3, 26.1, 25.8, 25.6, 18.5,
18.0, 17.8, -4.4, -4.7, -4.7, -5.0, -5.4, -5.4. HRCIMS: calcd
for C31H57N6O4Si3 (M + H)+ 661.3735, obsd 661.3785.
Gen er a l P r oced u r e for th e Rea ction of 6-Br om op u r in e
Der iva tives w ith O- a n d S-Nu cleop h iles. To a solution of
the 6-bromopurine derivative (0.164-0.109 mmol) in anhy-
drous acetonitrile (7 mL) was added sequentially DBU (1.5
equiv) and the nucleophile (5 equiv, see Table 3). The reaction
mixture was stirred at room temperature for 8 h. It was then
concentrated and the resulting residue dissolved in EtOAc (20
mL). The organic layer in each case was successively washed
with 5% NaOH(aq) (1 × 25 mL) and brine (1 × 25 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure.
The crude products were purified by flash column chromatog-
raphy on silica gel using appropriate solvent systems (listed
under individual compound headings, vide infra).
Gen er a l P r oced u r e for th e Ca ta lytic Deh a logen a tion
of 6-Br om op u r in e Der iva tives. The 6-bromopurine deriva-
tive (1.94-2.19 mmol) was dissolved in MeOH (30 mL), and
10% Pd-C (0.050 g) and anhydrous NaOAc (2 equiv) were
added to the mixture. The flask was evacuated and refilled
with hydrogen gas. The mixture was shaken in
a Parr
apparatus for 8 h and under 2.5 atm of pressure. The mixture
was filtered through Celite, and the residue was washed with
MeOH. The filtrate was concentrated under reduced pressure.
The residue was redissolved in EtOAc (15 mL) and washed
with brine (1 × 10 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude
products were purified by flash column chromatography on
silica gel using appropriate solvent systems (listed under
individual compound headings, vide infra).
2′,3′,5′-Tr i-O-a cetyl-n ebu la r in e (19a ). Chromatography,
2% MeOH/CHCl3. Pale yellow foam (85%). Spectral data
agreed with reported values.16
N2-2′,3′,5′-Tetr a a cetyl-2-a m in on ebu la r in e (19b). Chro-
matography, 5% MeOH/CHCl3. Pale yellow syrup (96%). 1H
NMR (CDCl3, 300 MHz): δ (ppm) 9.10 (br s, 1H), 8.92 (s, 1H),
8.09 (s, 1H), 6.09 (d, J ) 3.9 Hz, 1H), 5.96 (t, J ) 4.5 Hz, 1H),
5.83 (br s, 1H), 4.54-4.37 (m, 3H), 2.43 (s, 3H), 2.14 (s, 3H),
2.09 (s, 3H), 2.06 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm)
170.4, 169.6, 169.5, 152.9, 151.5, 149.9, 143.0, 131.1, 86.9, 80.1,
73.3, 70.5, 63.2, 25.0, 20.7, 20.5, 20.4. HRFABMS: calcd for
2′,3′,5′-Tr i-O-a cetyl-S6-(p h en yl)th ioin osin e (17a ). Chro-
matography, 2% MeOH/CHCl3. Pale yellow foam (92%). 1H
NMR (CDCl3, 300 MHz): δ (ppm) 8.61 (s, 1H), 8.16 (s, 1H),
7.66-7.63 (m, 2H), 7.48-7.45 (m, 3H), 6.21 (d, J ) 5.4 Hz,
1H), 5.95 (t, J ) 5.4 Hz, 1H), 5.65 (t, J ) 5.4 Hz, 1H), 4.47-
4.42 (m, 2H), 4.36 (dd, J ) 12.9, 5.1 Hz, 1H), 2.13 (s, 3H), 2.12
(s, 3H), 2.07 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) 170.2,
169.5, 169.3, 161.4, 152.5, 148.4, 141.3, 135.6, 131.2, 129.6,
129.3, 126.8, 86.4, 80.3, 73.0, 70.5, 62.9, 20.7, 20.5, 20.3.
HRFABMS: calcd for C22H23N4O7S (M + H)+ 487.12875, obsd
487.13064.
C
18H22N5O8 (M + H)+ 436.1468, obsd 436.1477.
Ack n ow led gm en t. This research was funded in
part by a grant from the National Institutes of Health
to P.A.B. (GM 61115).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectral
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
2′,3′,5′-Tr i-O-a cetyl-O6-(p h en yl)in osin e (18a ). Chroma-
tography, 2% MeOH/CHCl3. White foam (82%). 1H NMR
J O016078V