Suzuki-Miyaura cross-coupling of unprotected halopurine nucleosides in water - Influence of catalyst and cosolvent

Article abstract of DOI:10.1080/10916460600946139

Reaction conditions for the Suzuki-Miyaura cross-coupling of unprotected halopurine nucleosides with arylboronic acids in aqueous media were investigated. A series of arylated purine nucleosides was prepared in water without an organic cosolvent, using either Pd(PPh₃)₄ or Pd(OAc)₂/TPPTS as the catalyst. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10916460600946139

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Suzuki–Miyaura Cross‐Coupling of
Unprotected Halopurine Nucleosides in
Water—Influence of Catalyst and Cosolvent
Alice Collier a & Gerd K. Wagner a
a Centre for Carbohydrate Chemistry, School of Chemical Sciences and
Pharmacy, University of East Anglia , Norwich, UK
Published online: 01 Dec 2006.
To cite this article: Alice Collier & Gerd K. Wagner (2006) Suzuki–Miyaura Cross‐Coupling of Unprotected
Halopurine Nucleosides in Water—Influence of Catalyst and Cosolvent, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:24, 3713-3721, DOI:
10.1080/10916460600946139
To link to this article: http://dx.doi.org/10.1080/10916460600946139
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Synthetic Communicationsw, 36: 3713–3721, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/10916460600946139
Suzuki–Miyaura Cross-Coupling of
Unprotected Halopurine Nucleosides in
Water—Influence of Catalyst and Cosolvent
Alice Collier and Gerd K. Wagner
Centre for Carbohydrate Chemistry, School of Chemical Sciences
and Pharmacy, University of East Anglia, Norwich, UK
Abstract: Reaction conditions for the Suzuki–Miyaura cross-coupling of unprotected
halopurine nucleosides with arylboronic acids in aqueous media were investigated.
A series of arylated purine nucleosides was prepared in water without an organic
cosolvent, using either Pd(PPh3)4 or Pd(OAc)2/TPPTS as the catalyst.
Keywords: Catalysis, nucleosides, Suzuki–Miyaura reaction, water
Structural analogues of the naturally occurring purine nucleosides adenosine
and guanosine (Scheme 1) are of considerable interest as drug candidates,[1]
pharmacological and biological tools,[2] and synthetic building blocks.[3]
However, the preparation of such analogues in the laboratory is frequently
complicated by their physicochemical and structural properties e.g., the
generally poor solubility of nucleosides in organic solvents, the presence of
multiple functional groups, and the potential sensitivity of the glycosidic
bond to hydrolytic cleavage.[4] Although the use of protecting groups is a
valid strategy to circumnavigate some of these problems, the direct structural
modification of unprotected nucleosides represents a much more elegant and
efficient approach.
For an ongoing research program on carbohydrate-modifying enzymes,
we require purine nucleosides bearing additional hydrophobic substituents
Received in the UK January 14, 2006
Address correspondence to Gerd K. Wagner, Centre for Carbohydrate Chemistry,
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich
NR4 7TJ, UK. E-mail: g.wagner@uea.ac.uk
3713

3714
A. Collier and G. K. Wagner
Scheme 1. Analogues of the naturally occurring purine nucleosides adenosine and
guanosine as building blocks for the construction of nucleoside diphosphate (NDP)
sugars.
at the nucleobase as synthetic intermediates en route to the corresponding
nucleoside diphosphate (NDP) sugars (Scheme 1). The desired substituents
can be installed using palladium-catalyzed cross-coupling chemistry such as
the Suzuki–Miyaura reaction.[5] The Suzuki–Miyaura cross-coupling of aryl-
boronic acids with fully protected halopurine nucleosides and 20-deoxynucleo-
sides in organic solvents[6] and, more recently, with unprotected halopurine
nucleosides in aqueous media[7–9] using various cosolvents (e.g., MeCN[8]
or dimethoxyethane (DME)[9]) has been reported.
The scope of the Suzuki–Miyaura cross-coupling of unprotected halopur-
ine nucleosides in neat water has not previously been explored on a synthetic
scale. We were interested in testing the feasibility of such an approach for two
reasons: first, to generate the nucleoside building blocks required for our
general synthesis in an efficient manner without the use of protecting
groups, and second, to assess the potential of such a strategy for the direct
structural modification of charged, water-soluble species such as nucleotides
and NDP sugars. Western and coworkers have studied the cross-coupling of
8-bromo-20-deoxyadenosine with phenylboronic acid in different aqueous
media but reported only conversion rates based on high performance liquid
chromatography (HPLC) data for those experiments carried out in water.[8]
Therefore, we have investigated the adaptability of two standard
palladium catalysts for the Suzuki–Miyaura cross-coupling of different halo-
purine nucleosides (Scheme 2) in water on a preparative scale. Herein, we
report the first results from this study.
Our initial experiments were carried out with the traditional Suzuki–
Miyaura catalyst Pd(PPh3)4 (Table 1).[5a] In aqueous media, the use of a
palladium catalyst based on a hydrophobic triphenylphosphine ligand offers
the advantage that the catalyst can be removed from the reaction by simple
filtration. The cross-coupling of 8-bromoadenosine (8-BrA)[9] with phenyl-
boronic acid in three different aqueous solvent systems (DME/H2O,
MeCN/H2O, and water) was used as a model reaction to assess the
influence of the organic cosolvent on cross-coupling efficiency under these

Nucleosides Cross-Coupling in Water
3715
Scheme 2. Suzuki–Miyaura cross-coupling of unprotected halopurine nucleosides
with arylboronic acids.
conditions (Scheme 2). At 808C, this influence was negligible, and 8-pheny-
ladenosine was isolated in moderate to good yield from all three reactions
(Table 1, entries 1a–c).
Likewise, the cross-coupling of phenylboronic acid with 6-chloropurine
riboside (6-ClP)[10] in water gave 6-phenylpurine riboside, albeit in very
low yield (entry 2). However, with 8-bromoguanosine (8-BrG)[11] no
reaction was observed by thin-layer chromatography (TLC) under these
Table 1. Suzuki–Miyaura cross-coupling of halopurine nucleo-
sides with phenylboronic acid (Ar ¼ phenyl) in aqueous media
a
using Pd(PPh3)4
Entry
Substrate
Solvent
Yieldb (%)
1a
1b
1c
2
8-BrA
8-BrA
8-BrA
6-ClP
8-BrG
H2O
75
90d
60
15f
0g
MeCN/H2Oc
DME/H2Oe
H2O
3
DME/H2O, MeCN/H2O,
or H2O
aReagents and conditions: 10 mol % Pd(PPh3)4, K2CO3 (6 eq.),
phenylboronic acid (1.5 eq.), 808C, 24 h.
bIsolated yields. Not optimized.
cMeCN/H2O (1 : 2).
dThis reaction was complete after 17 h.
eDME/H2O (2 : 1).
fThis reaction was complete after 7 h.
gReactions were carried out with 6–20 eq. of K2CO3 or NaOH
as the base.

3716
A. Collier and G. K. Wagner
conditions (entry 3). Neither changes in the amount or strength of base nor
addition of an organic cosolvent altered this result. Taken together with the
successful cross-coupling of phenylboronic acid with 8-BrA, the unsuccessful
reaction with 8-BrG in various aqueous media suggests that addition of an
organic cosolvent has neither a prohibitive nor a beneficial effect on cross-
coupling efficiency.
We next turned our attention to a catalytic system composed of Pd(OAc)2
as the palladium source and the water-soluble phosphine ligand TPPTS
(triphenylphosphine trisulfonic acid).[8] The reduced reactivity of guanosine
analogues in metal-catalyzed reactions has been attributed to the coordination
of the catalytic metal by the nucleobase.[8] Western and coworkers have suc-
cessfully overcome this difficulty by employing the Pd(OAc)2/TPPTS system
for the arylation of 8-bromo-20-deoxyguanosine and 8-BrG in MeCN/H2O.[8]
To test the practicability of this catalytic system in water, we set out to obtain
isolated yields for the cross-coupling of 8-BrA, 8-BrG, and 6-ClP with a range
of phenylboronic acids (Table 2).
Use of the Pd(OAc)2/TPPTS system allowed the clean cross-coupling of
8-BrA with phenylboronic acid in water, MeCN/H2O, and DME/H2O
(Table 2, entries 4a–c). Similar to the results obtained with Pd(PPh3)4, and
in contrast to Western’s observations for the Pd(OAc)2/TPPTS system based
on HPLC data,[8] we found that the use of a cosolvent did not have a discernible
Table 2. Suzuki–Miyaura cross-coupling of halopurine nucleosides with
various phenylboronic acids in aqueous media using Pd(OAc)2/TPPTSa
Entry
Substrate
Aryl (Ar)
Solvent
Yieldb (%)
4a
4b
4c
5
8-BrA
8-BrA
8-BrA
6-ClP
8-BrG
8-BrG
8-BrG
8-BrA
8-BrA
8-BrA
8-BrG
8-BrG
8-BrG
Phenyl
Phenyl
H2O
75
94
69
70
61
75
0e
MeCN/H2Oc
DME/H2Od
H2O
Phenyl
Phenyl
6a
6b
6c
7
Phenyl
Phenyl
H2O
MeCN/H2O
DME/H2O
H2O
Phenyl
4-tolyl
70
79
96
83
87
84
8
4-methoxyphenyl
4-Cl-phenyl
4-tolyl
H2O
H2O
9
10
11
12
H2O
H2O
4-methoxyphenyl
4-Cl-phenyl
H2O
aReagents and conditions: 2.5 mol % Pd(OAc)2/TPPTS (Pd : L 1 : 2.5),
K2CO3 (2 eq.), ArB(OH)2 (1.5 eq.), 808C, 1–4 h.
bIsolated yields. Not optimized.
cMeCN/H2O (1 : 2).
dDME/H2O (2 : 1).
eReaction time was 24 h.

Nucleosides Cross-Coupling in Water
3717
effect on the formation of side products. The yields for the product 8-phenyl-
adenosine were good to excellent for all three reactions, and no side products
were isolated. In addition, reaction times were generally much shorter under
these conditions than with the Pd(PPh3)4 system. The Pd(OAc)2/TPPTS
catalyst also successfully catalyzed the cross-coupling of phenylboronic acid
with 6-ClP in water (entry 5) and, different from the Pd(PPh3)4 system, with
8-BrG in water and MeCN/H2O (entries 6a,b). Representative procedure:
a flask containing 8-BrG (99.9 mg, 0.276 mmol), potassium carbonate
(80.7 mg, 0.584 mmol), phenylboronic acid (50.4 mg, 0.413 mmol),
palladium acetate (2.1 mg, 0.009 mmol), and TPPTS (13.6 mg, 0.024 mmol)
was purged with nitrogen. Water (distilled, 6 ml) was added through a
septum, and the reaction was stirred under nitrogen at 808C until TLC
(CHCl3/MeOH 16 : 5) showed completion (3 h). The reaction was cooled to
room temperature and diluted with water (20 ml). Upon neutralization of the
aqueous solution with hydrochloric acid (10%), a precipitate formed. The pre-
cipitate was dissolved by heating, and the clear solution was kept at 08C for
several hours. The precipitate was collected by filtration and dried in vacuo to
give 8-phenylguanosine as a white powder (60.1 mg, 61%). 1H NMR (DMSO-
d6, 400 MHz, assignments based on COSY) d 10.75 (s, 1H, exchangeable, NH),
7.65–7.62 (m, 2H, ph), 7.51–7.49 (m, 3H, ph), 6.38 (bs, 2H, exchangeable,
NH2), 5.61 (d, 6.4 Hz, 1H, H-10), 5.37 (d, 6.4 Hz, 1H, OH-20), 5.05–4.97
(m, 3H, partly exchangeable, H-20, OH-30, OH-50), 4.07–4.03 (m, 1H, H-30),
3.82–3.79 (m, 1H, H-40), 3.68–3.62 (m, 1H, Ha-50), 3.55–3.49 (m, 1H, Hb-50);
13C NMR (DMSO-d6, 400 MHz) d 157.3, 153.8, 152.7, 148.2, 130.7, 130.1,
129.9, 129.3, 117.8, 89.6, 86.5, 71.3, 70.9, 62.8; HRMS (ES) m/z 360.1301,
calcd. for C16H18N5O5 [M þ H]þ: 360.1302.
However, in DME/H2O, only very slow formation of 8-phenylguanosine
was observed by TLC, and decomposition became predominant during the
course of the reaction (entry 6c).
Next, we explored the scope of the Pd(OAc)2/TPPTS protocol in water
with regard to the cross-coupling of 8-BrA and 8-BrG with several substituted
phenylboronic acids (Table 2, entries 7–12). Under these conditions, the
cross-coupling of 4-tolylboronic acid, 4-methoxyphenylboronic acid, and
4-chlorophenylboronic acid with both 8-BrA (entries 7–9) and 8-BrG
(entries 10–12) went to completion in 1–4 h. The 8-arylated nucleosides
were purified by column chromatography (adenosine analogues) or through
precipitation from aqueous solution (guanosine analogues) and were
isolated in generally good to excellent yields. To assess the potential effect
of an organic cosolvent, we also carried out all of these reactions in
MeCN/H2O under otherwise identical conditions. In agreement with the
findings for the cross-coupling of 8-BrA and 8-BrG with the parent phenyl-
boronic acid (entries 4a,b and 6a,b), the organic cosolvent did not affect
reaction times or yields for the reactions with substituted phenylboronic
acids. For comparison, the isolated yields for the cross-coupling of 8-BrA
(8-BrG) in MeCN/H2O with substituted phenylboronic acids using the

3718
A. Collier and G. K. Wagner
Pd(OAc)2/TPPTS system were as follows: 4-tolylboronic acid 83% (89%);
4-methoxyphenylboronic acid 66% (87%); 4-chlorophenylboronic acid 84%
(78%).
A certain limitation of the Pd(OAc)2/TPPTS protocol became apparent
when this system was applied to the cross-coupling of 8-BrA with 4-hydroxy-
phenylboronic acid (Table 3). In water and DME/H2O, the cross-coupling
reaction did take place but was accompanied by cleavage of the glycosidic
bond (Table 3, entries 13a,c). After chromatographic purification, the deribo-
sylated nucleobase 8-(p-hydroxyphenyl)adenine was obtained as the only
product from both reactions. In MeCN/H2O, no cross-coupled product was
detected at all (entry 13b). Phenol was isolated in 15% yield as the only
product from this reaction, indicating that under these conditions deboronation
occurs as an important side reaction that prevents cross-coupling.
The successful conversion of 8-BrA into 8-(p-hydroxyphenyl)adenosine
was finally accomplished with Pd(PPh3)4 as the catalyst. In water, MeCN/
H2O, and DME/H2O, this approach cleanly provided the cross-coupled nucleo-
side (entries 14a–c). The comparatively low yields of 8-(p-hydroxyphenyl)-
adenosineisolated from all three reactions can be attributed to the loss of the
very polar material during chromatography, as TLC indicated complete
consumption of starting material and only minor formation of side products.
In summary, we have identified suitable reaction conditions for the cross-
coupling of unprotected halopurine nucleosides with phenylboronic acids in
Table 3. Suzuki–Miyaura cross-coupling of 8-bromoadenosine and
4-hydroxyphenylboronic acid (Ar ¼ 4-hydroxyphenyl) in aqueous media
Yielda (%)
Entry
Conditions
Solvent
H2O
MeCN/H2Oe
DME/H2Og
H2O
Productb
Side product
13a
13b
13c
14a
14b
14c
Ac
A
0
0
55d
15f
45d
0
A
0
Bh
B
26
35
25
MeCN/H2O
DME/H2O
0
B
0
aIsolated yields. Not optimized.
b8-(p-Hydroxyphenyl)adenosine.
cSystem A: 2.5 mol % Pd acetate/TPPTS (2.5 : 1 L : Pd), K2CO3 (2 eq.),
4-hydroxyphenylboronic acid (1.5 eq.), 808C, 24 h.
d8-(p-Hydroxyphenyl)adenine.
eMeCN/H2O (1 : 2).
fPhenol.
gDME/H2O (2 : 1).
hSystem B: 10 mol % Pd(PPh3)4, K2CO3 (6 eq.), 4-hydroxyphenylboronic
acid (1.5 eq.), 808C, 24 h.

Nucleosides Cross-Coupling in Water
3719
water. Pd(PPh3)4 is a useful catalyst for the cross-coupling of a range of phe-
nylboronic acids including 4-hydroxyphenylboronic acid with 8-BrA and, to a
lesser extent, with 6-ClP, but fails with the less reactive 8-BrG. The
Pd(OAc)2/TPPTS system allows the cross-coupling of all three halopurine
nucleosides with the same family of phenylboronic acids, apart from 4-hydro-
xyphenylboronic acid. Interestingly, with neither Pd(PPh3)4 nor Pd(OAc)2/
TPPTS does the presence of an organic cosolvent have a pronounced effect
on cross-coupling efficiency, and the target arylnucleosides were generally
isolated from reactions in water in good to excellent yields.
We are currently applying the cross-coupling protocols described herein
to the direct structural modification of the corresponding nucleotides and NDP
sugars under similar conditions, and results from these studies will be reported
in due course.
EXPERIMENTAL
8-Phenyladenosine (Entry 1a)
A flask containing 8-BrA (109.7 mg, 0.476 mmol), potassium carbonate
(271.6 mg, 1.97 mmol), phenylboronic acid (61.0 mg, 0.500 mmol) and
Pd(PPh3)4 (51.4 mg, 0.044 mmol) was purged with nitrogen. Water
(distilled, 6 ml) was added through a septum and the reaction was stirred
under nitrogen at 808C until TLC (CHCl3/MeOH 16 : 5) showed completion
(24 h). The reaction was cooled to room temperature and filtered through
Celite. The solvent was removed under reduced pressure and the residue
was purified by column chromatography (silica, CHCl3/MeOH 8 : 1) to give
1
8-phenyladenosine as a white powder (82.0 mg, 75%). H NMR (DMSO-d6,
400 MHz, assignments based on COSY) d 8.13 (s, 1H, H-2), 7.74–7.72 (m,
2H, ph), 7.57–7.56 (m, 3H, ph), 7.50 (bs, 2H, exchangeable, NH2), 5.81
(dd, 2.8/8.9 Hz, 1H, exchangeable, OH-50), 5.74 (d, 7.2 Hz, 1H, H-10), 5.47
(d, 6.4 Hz, 1H, exchangeable, OH-20), 5.18–5.15 (m, 1H, H-20), 5.13 (d,
3.9 Hz, 1H, exchangeable, OH-30), 4.14 (m, 1H, H-30), 3.92 (m, 1H, H-40),
3.70–3.66 (m, 1H, Ha-50), 3.56–3.50 (m, 1H, Hb-50); 13C NMR (DMSO-d6,
400 MHz) d 156.9, 152.7, 151.6, 150.5, 130.8, 130.3, 130.1, 129.4, 119.8,
89.8, 87.4, 71.9, 71.8, 63.0; HRMS (ES) m/z 344.1356, calcd. for
C16H18N5O4 [M þ H]þ: 344.1353.
8-Phenylguanosine (Entry 6a)
A flask containing 8-BrG (99.9 mg, 0.276 mmol), potassium carbonate
(80.7 mg, 0.584 mmol), phenylboronic acid (50.4 mg, 0.413 mmol),
palladium acetate (2.1 mg, 0.009 mmol) and TPPTS (13.6 mg, 0.024 mmol)
was purged with nitrogen. Water (distilled, 6 ml) was added through a

3720
A. Collier and G. K. Wagner
septum and the reaction was stirred under nitrogen at 808C until TLC (CHCl3/
MeOH 16: 5) showed completion (3 h). The reaction was cooled to room temp-
erature and diluted with water (20 ml). Upon neutralisation of the aqueous
solution with hydrochloric acid (10%) a precipitate formed. The precipitate
was dissolved by heating and the clear solution was kept at 08C for several
hours. The precipitate was collected by filtration and dried in vacuo to give
1
8-phenylguanosine as a white powder (60.1 mg, 61%). H NMR (DMSO-d6,
400 MHz, assignments based on COSY) d 10.75 (s, 1H, exchangeable, NH),
7.65–7.62 (m, 2H, ph), 7.51–7.49 (m, 3H, ph), 6.38 (bs, 2H, exchangeable,
NH2), 5.61 (d, 6.4 Hz, 1H, H-10), 5.37 (d, 6.4 Hz, 1H, OH-20), 5.05–4.97 (m,
3H, partly exchangeable, H-20, OH-30, OH-50), 4.07–4.03 (m, 1H, H-30),
3.82–3.79 (m, 1H, H-40), 3.68–3.62 (m, 1H, Ha-50), 3.55–3.49 (m, 1H,
Hb-50); 13C NMR (DMSO-d6, 400 MHz) d 157.3, 153.8, 152.7, 148.2, 130.7,
130.1, 129.9, 129.3, 117.8, 89.6, 86.5, 71.3, 70.9, 62.8; HRMS (ES) m/z
360.1301, calcd. for C16H18N5O5 [M þ H]þ: 360.1302.
ACKNOWLEDGMENT
We thank the University of East Anglia for a studentship, the Nuffield
Foundation for financial support, and the EPSRC National Mass Spectrometry
Service Centre, Swansea, for the recording of mass spectra.
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