Palladium-catalyzed aryl amination reactions of 6-bromo- and 6-chloropurine nucleosides

Article abstract of DOI:10.1002/adsc.200900728

Palladium-catalyzed C-N bond forming reactions of 6-bromo- as well as 6-chloropurine ribonucleosides and the 2′-deoxy analogues with arylamines are described. Efficient conversions were observed with palladium(II) acetate/Xantphos/cesium carbonate, in toluene at 100°C. Reactions of the bromonucleoside derivatives could be conducted at a lowered catalytic loading [5 mol% Pd(OAc)₂/7.5 mol% Xantphos], whereas good product yields were obtained with a higher catalyst load [10mol% Pd(OAc)₂/ 15 mol% Xantphos] when the chloro analogue was employed. Among the examples evaluated, silyl protection for the hydroxy groups appears better as compared to acetyl. The methodology has been evaluated via reactions with a variety of arylamines and by synthesis of biologically relevant deoxyadenosine and adenosine dimers. This is the first detailed analysis of aryl amination reactions of 6-chloropurine nucleosides, and comparison of the two halogenated nucleoside substrates.

Full text of DOI:10.1002/adsc.200900728

FULL PAPERS
DOI: 10.1002/adsc.200900728
Palladium-Catalyzed Aryl Amination Reactions of 6-Bromo- and
6-Chloropurine Nucleosides
Paul F. Thomson,a Pallavi Lagisetty,a Jan Balzarini,b Erik De Clercq,b
and Mahesh K. Lakshmana,*
a
Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, New
York 10031, U.S.A.
Fax : (+1)-212-650-6107; phone: (+1)-212-650-7835; e-mail: lakshman@sci.ccny.cuny.edu
Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000, Leuven, Belgium
b
Received: October 21, 2009; Revised: May 30, 2010; Published online: July 2, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900728.
À
Abstract: Palladium-catalyzed C N bond forming re- tection for the hydroxy groups appears better as
actions of 6-bromo- as well as 6-chloropurine ribonu- compared to acetyl. The methodology has been eval-
cleosides and the 2’-deoxy analogues with arylamines uated via reactions with a variety of arylamines and
are described. Efficient conversions were observed by synthesis of biologically relevant deoxyadenosine
with palladium(II) acetate/Xantphos/cesium carbon- and adenosine dimers. This is the first detailed analy-
ate, in toluene at 1008C. Reactions of the bromonu- sis of aryl amination reactions of 6-chloropurine nu-
cleoside derivatives could be conducted at a lowered cleosides, and comparison of the two halogenated
catalytic loading [5 mol% Pd
phos], whereas good product yields were obtained
with a higher catalyst load [10 mol% Pd(OAc)2/
15 mol% Xantphos] when the chloro analogue was Keywords: amination; C N bond formation; ligands;
employed. Among the examples evaluated, silyl pro- nucleosides; palladium; Xantphos
ACHTUNGRTENUN(NG OAc)2/7.5 mol% Xant- nucleoside substrates.
AHCTUNGTRENNUNG
À
Introduction
to be useful in gaining access to N6-(6-benzo[a]pyren-
yl)-2’-deoxyadenosine.[7]
À
Palladium-catalyzed C N bond forming reactions
In all these cases, the halopurine nucleoside tested
have become an important type of transformation in and used was 6-bromo-9-[2-deoxy-3,5-di-O-(tert-butyl-
the synthetic repertoire.[1] In this context, we have dimethylsilyl)-b-d-ribofuranosyl]purine. In compari-
been gaining an understanding of and exploiting such son, there are fewer analyses of the use of the 6-
catalyzed amination reactions of nucleosides.[2] The chloro
ACTHNUGRTENUNGpurine nucleoside analogues in Pd-mediated
high biochemical, physiological and medicinal value amination reactions. Among these, reactions of 6-
of compounds that can arise by alteration of the nu- chloro-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-b-d-ribo-
cleoside scaffold adds significant importance to the furanosyl]purine using Pd
development of methods for nucleoside modifica- Cs2CO3 or t-BuOK were evaluated.[8] Although reac-
tion.[3,4]
tions of alkylamines proceeded well, comparable reac-
2ACHTNUGTREN(UNGN dba)3/BINAP with either
In 1999 we demonstrated, for the first time, that tions of arylamines were not efficient. Using Pd-
N6-aryl-2’-deoxyadenosine analogues could be effi-
G
À
ciently synthesized via C N bond-formation using a nation of silyl-protected 6-chloro-9-[2-deoxy-3,5-di-O-
suitable Pd-ligand complex.[5] Subsequently, we ana- (tert-butyldimethylsilyl)-b-d-ribofuranosyl]purine with
À
À
lyzed a series of ligands for C C and C N bond for- a sterically-demanding alkylamino derivative of a
mation.[6] This led to the identification of specific li- polycyclic aromatic hydrocarbon.[9] Subsequently we
gands that were effective for aryl amination. These in- have synthesized more elaborate carcinogen-nucleo-
cluded 2-(dicyclohexylphosphino)-2’-(N,N-dimethyla- side adducts using this chloronucleoside.[10] We have
mino)-1,1’-biphenyl and (Æ)-BINAP. In subsequent also studied C N
aryl amination work the same two ligands also proved bromo- and 6-chloropurine nucleosides with azoles.[11]
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Palladium-Catalyzed Aryl Amination Reactions of 6-Bromo- and 6-Chloropurine Nucleosides
Despite these results, there has not been the devel-
opment of effective Pd-catalyzed aryl amination
methods to involve 6-chloropurine nucleosides. Also,
no comparative performance evaluation of 6-bromo-
and 6-chloropurine nucleosides under Pd-catalyzed
aryl amination conditions has been conducted. In this
context it should be noted that SNAr displacement re-
actions between a 6-bromopurine nucleoside and two
arylamines have been accomplished, but reactions of
corresponding 6-chloro compound are stated to be in-
effective.[12]
Pd catalysis appears to offer a simple, unifying
method for involving both 6-bromo- and 6-chloropur-
ine nucleosides in aryl amination reactions. This
paper reports our studies on such reactions of these
nucleoside derivatives.
Figure 2. Six ligands selected for analysis.
phenyl (L1), (Æ)-BINAP (L2), Xantphos (L3), 2-(di-
cyclohexylphosphino)biphenyl (L4), 2-(di-tert-butyl-
phosphino)biphenyl (L5) and 4-(diphenylphosphino)-
Results and Discussion
For the current work, 6-bromo- and 6-chloropurine ri- 9,9-dimethylxanthene (L6) shown in Figure 2. The
bonucleosides as well as the 2’-deoxy analogues were first three were chosen since these have previously
chosen for analysis. We also wanted to assess silyl and yielded effective amination catalysts for nucleo-
acetyl protecting groups for the sugar moieties. Thus, sides,[2,5–11,18–24] whereas L4 and L5 were included due
six compounds 1a–2c (Figure 1) became the choices to their similarity to L1. Monophosphane L6 was in-
for the initial experiments. The overall goal was not cluded for comparison to L3. PdACHTNUTRGENNG(U OAc)2 and Pd2ACHTUNGTRENNUNG(dba)3
the determination of the best conditions for reactions were the metal sources, K3PO4 and Cs2CO3 were
of each substrate, but rather to find generally optimal chosen as bases.
conditions for the aryl amination reactions that can
Our initially reported work on 1a[5,6] was the start-
be applied to the synthesis of a broad class of N6-aryl- ing point upon which the newer results were devel-
A
oped. Using p-toluidine as a representative amine in
Bromo nucleosides 1a–c were conveniently synthe- the initial test reactions, the most significant results
sized through
a diazotization-bromination proto- (product yields >50%) from several experiments are
col[11,12] by appropriate modification of a literature shown in Table 1.
route.[13] Chloro nucleoside 2a[14] was prepared by sily-
Our first attempt was to further tune conditions in
lation of 6-chloro-9-(2-deoxy-b-d-ribofuranosyl)pur- entry 1 using substrate 1a. Use of 10 mol% PdACTHUNTRGNE(UNG OAc)2/
ine[15] whereas 2b[11,16] and 2c were prepared by silyla- 15 mol% L1, under otherwise comparable conditions
tion and acetylation of commercially available 6- to entry 1, resulted in a poor yield (37%, 9 h). Use of
chloro-9-(b-d-ribofuranosyl)purine. Alternatively, 2c 10 mol%
can be prepared by chlorination of inosine triace- Cs2CO3 in toluene at 1008C, did not produce an im-
tate.[17]
provement (41% yield in 4 h). This led us to consider
With these compounds, we began to evaluate condi- L2 as well as L3. Initial reactions were conducted
tions for aryl amination. We selected six ligands, 2-(di- with 10 mol% Pd(OAc)2/15 mol% L2 or L3/1.5 molar
cyclohexylphosphino)-2’-N,N-(dimethylamino)-1,1’-bi-
Pd
G
L1/1.5 molar equiv.
AHCTUNGTRENNUNG
equiv. Cs2CO3, in toluene at 1008C. Under these con-
ditions, the reaction utilizing L2 gave a 64% yield of
product, whereas that involving L3 gave 89% yield
(entries 2 and 3). We next considered reducing the
Pd/L3 loading by half, and this modification produced
essentially no difference, resulting in an excellent
90% yield of the amination product (entry 4). Under
these best conditions, replacing L3 with L4 or L5 re-
sulted in poorer results (entries 5 and 6).
The foregoing results formed the basis for subse-
quent experiments, and a similar trend was observed
with the ribose derivative 1b, where the lower Pd-
AHCTUNGTRENNUNG
Figure 1. Six nucleoside substrates selected for analysis.
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Paul F. Thomson et al.
FULL PAPERS
À
Table 1. Initial results from C N bond-forming reactions of substrates 1a–2c with p-toluidine.
Entry Substrate Pd source (mol%) Ligand (mol%) Base (1.5 molar equiv) Solvent Temp. [8C] Time [h][a] Yield [%][b]
Reactions of bromonucleosides 1a, b with p-toluidine
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
(dba)3 (10)
L1 (30)
L2 (15)
L3 (15)
L3 (7.5)
L4 (7.5)
L5 (7.5)
L2 (15)
L3 (7.5)
L6 (7.5)
K3PO4
DME
80
3
1
1
1
6
24
2
1
7
69[c]
64
89
T
E
E
R
E
AHCTUNGTRENNUNG
T
N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
90
70
56[d]
76
93
66
Reactions of chloronucleosides 2a, b with p-toluidine
10
11
12
13
14
15
16
17
18
19
20
21
22
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
G
L1 (30)
L1 (30)
L1 (30)
L1 (15)
L2 (15)
L2 (7.5)
L3 (15)
L3 (7.5)
L2 (15)
L2 (7.5)
L3 (15)
L3 (7.5)
L6 (15)
K3PO4
DME
DME
80
80
22
26
1
1
1
1
1
1
2
2
1
1
5
49
52
80
59
88
67
86
86
88
88
92
74
60
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
PhMe 100
A
R
E
E
E
N
G
T
R
A
Reactions of chloronucleoside 2b with o-toluidine
23
24
25
2b
2b
2b
Pd
Pd
Pd
N
L2 (15)
L2 (7.5)
L3 (15)
Cs2CO3
Cs2CO3
Cs2CO3
PhMe 100
PhMe 100
PhMe 100
1
1
1
86 (87[e])
73 (76[e])
92
Reactions of acetate-protected nucleosides 1c and 2c with p-toluidine
26
27
1c
2c
Pd
Pd
N
L3 (7.5)
L3 (15)
Cs2CO3
Cs2CO3
PhMe 100
PhMe 100
1.5
1.5
82
62
Reactions of 1a and 2a with p-toluidine using PdCAHTUNGTRENNNUG
28
29
1a
2a
Pd
Pd
N
none
none
PhMe 100
PhMe 100
4
5
56
62
Cs2CO3
[a]
[b]
[c]
[d]
[e]
Reactions were monitored by TLC for complete disappearance of the halonucleoside.
Where reported, yield is of isolated and purified products.
Reported in ref.[5]
Reaction was incomplete.
Reaction time was 2 h.
units in L3 are critical for an effective catalyst was load produced identical, good results (entries 16 and
next queried. Use of L6 in place of L3 (entry 9) clear- 17). On the basis of these experiments, substrate 2b
ly showed that L3 was superior.
was then investigated. At 10 mol% PdACTHGNUTRENNU(G OAc)2/
Next, optimization of amination conditions with the 15 mol% L2, again an excellent 88% yield of aminat-
chloronucleosides was conducted, starting with 2a. ed product was obtained (entry 18), which remained
Use of 10 mol% Pd2ACHTNUTRGENNUG(dba)3/30 mol% L1 with either unaltered when the catalyst load was decreased
K3PO4 or Cs2CO3 in DME gave ca. 50% product (entry 19). Upon replacement of L2 with L3, some
yields (entries 10 and 11). In contrast, this catalytic other differences emerged. Use of the higher
system with Cs2CO3 in PhMe gave a high 80% yield 10 mol% Pd
(entry 12), but replacing Pd2A(dba)3 with 10 mol% Pd- lent 92% yield of product, but reduction of the cata-
(OAc)2 lowered the yield to 59% (entry 13). We next lytic load by half produced only a 74% yield (com-
investigated the use of L2. At 10 mol% Pd(OAc)2/ pare entries 20 and 21). Here again presence of 2
ACHTUNGRTEN(NUNG OAc)2/15 mol% L3 resulted in an excel-
CTHUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
15 mol% L2 an excellent 88% product yield was real- phosphane units in L3 proved essential as shown by
ized (entry 14), which decreased to 67% when the cat- the poorer result with L6 (entry 22)
alytic load was reduced by half (entry 15). When L2
These results indicated some differences in the re-
was replaced with L3, the higher and lower catalyst actions of 2a and 2b. With 2a, the higher and lower
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Palladium-Catalyzed Aryl Amination Reactions of 6-Bromo- and 6-Chloropurine Nucleosides
Table 2. Amination reactions of the bromo- (1a and 1b) and chloronucleosides (2a and 2b) with several amines.
Entry
Amine
Substrate
Conditions,[a] time[b]
Product: Yield [%][c]
1
2
3
4
5
6
7
8
1a
1b
2a
2b
1a
1b
2a
2b
A, 1 h
A, 1 h
B, 1 h
B, 1 h
A, 1 h
A, 1 h
B, 1 h
B, 1 h
3a: 90
4a: 93
3a: 86
4a: 92
3b: 88
4b: 92
3b: 92
4b: 92
9
1a
1b
2a
2b
A, 1 h
A, 1.5 h
B, 1 h
3c: 79
4c: 87
3c: 72
4c: 91
10
11
12
B, 1 h
13
14
15
16
17
18
19
20
21
22
23
24
1a
1b
2a
2b
1a
1b
2a
2b
1a
1b
2a
2b
A, 1 h
A, 1 h
B, 1 h
B, 1 h
A, 1 h
A, 1 h
B, 1 h
B, 1 h
A, 1 h
A, 1 h
B, 1 h
B, 1 h
3d: 68
4d: 84
3d: 78
4d: 92
3e: 87
4e: 86
3e: 87
4e: 93
3f: 91
4f: 88
3f: 95
4f: 89
25
26
27
28
1a
1b
2a
2b
A, 1 h
A, 1 h
B, 1 h
B, 1 h
3g: 88
4g: 84
3g: 92
4g: 99
[a]
Reactions were performed at a nucleoside concentration of 0.1M in the reaction solvent. Conditions A: 5 mol%
Pd(OAc)2/7.5 mol% L3/1.5 molar equiv. Cs2CO3, PhMe, 1008C. Conditions B: 10 mol% Pd(OAc)2/15 mol% L3/1.5 molar
N
ACHTUNGTRENNUNG
equiv. Cs2CO3, PhMe, 1008C.
Reactions were monitored by TLC for complete disappearance of the halonucleoside.
Yield of isolated and purified products.
[b]
[c]
PdACHTUNGTRENNUNG
whereas this was not the case with PdACTHUNGTRENNNUG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
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Paul F. Thomson et al.
FULL PAPERS
former. We also compared reactions of acetate-pro- ing.[28,29] Among the various nucleoside dimers, deoxy-
tected derivatives 1c and 2c using the best conditions guanosine-deoxyguanosine (dG–dG), deoxyadeno-
identified for reactions of the bromo- and chloronu- sine-deoxyguanosine (dA–dG), and deoxyadenosine-
cleosides (entries 26 and 27). In both cases, although deoxyadenosine (dA–dA), the synthesis of dA–dA
reasonable product yields were attained, the results posed particular challenges. For instance, reaction of
were not superior to those involving the silyl-protect- 1a and 5a using several Pd/L2 complexes were report-
ed derivatives. Finally we tested 5 mol% PdACTHNUGTRNEUGN(PPh3)4 ed to be low yielding, and thus use of the iodo ana-
under otherwise identical conditions. This Pd(0) cata- logue of 1a was necessary.[29] On the basis of our re-
lyst has been used for Suzuki–Miyaura cross-coupling sults, we wanted to reassess the reaction of 1a with 5a
reactions of nucleosides.[23,25] Both 1a and 2a reacted and analyze reactivity of the chloro analogue 2a for
with p-toluidine, but these reactions (entries 28 and synthesis of dA–dA dimer. We also wanted to com-
29) were inferior to the low catalyst loading experi- pare these reactions to those leading to the adeno-
ments with L2 and L3. On the basis of these results, sine-adenosine (A–A, ribose) dimers (Scheme 1). The
we then evaluated the amination reactions using the results of these experiments are shown in Table 3.
silylated nucleoside substrates and several amines
with varying electronic and steric properties. These sides 1a and 1b are good substrates for Pd-catalyzed
results are displayed in Table 2. amination reactions with the more complex amines 5a
From the results in Table 2, it is evident that both and 5b. Good yields were obtained with 5 mol% Pd-
bromo- (1a, b) and chloronucleosides (2a, b) are ef- (OAc)2/7.5 mol% L3 (entries 1 and 2), and some im-
fective substrates for amination with a variety of aryl- provement was attained with the increased catalyst
amines. For reactions of the bromonucleosides 1a and load of 10 mol% Pd(OAc)2/15 mol% L3 (entries 3
1b, conditions A [5 mol% Pd(OAc)2/7.5 mol% L3] and 4). More interestingly, chloropurine analogues 2a
From Table 3 it becomes clear that 6-bromonucleo-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
are reasonable for efficient reactions, and good-to-ex- and 2b are also highly effective in these reactions and
cellent yields were observed. Only the reaction of o-
toluidine with 1a gave <70% yield (entry 13). On the
other hand, all reactions with o-anisidine gave satis-
factory results (entries 17–20). The electron-deficient
p-acetylaniline reacted very well (entries 5–8), and
good results were also obtained with m-cyanoaniline
(entries 9–12).
Reactions of the chloronucleosides 2a and 2b under
conditions B [10 mol% PdACHTNUGRTENUNG(OAc)2/15 mol% L3] gave
good-to-excellent results. These data clearly indicate
that such chloronucleosides are excellent coupling
À
partners in Pd-catalyzed C N bond-forming reactions.
When comparing these catalyzed transformations
to the SNAr chemistry of 6-halopurine nucleosides,
the following are notable. The Pd-catalyzed reactions
of 1b produced comparable yields to displacement re-
actions on 1c,[12] but require 3 times less arylamine.
Also, Pd-catalyzed reactions with the chloronucleo-
sides resulted in amination products, whereas such
chloronucleosides were reported to be unreactive
under SNAr conditions.[12]
Arylation of nucleosides by aryl bromides had been
challenging until our recent report.[24] Thus, reactivity
properties of nucleosides often do not follow known
trends of simpler aryl systems. With the reactions of
the simple arylamines completed, we next analyzed
the use of nucleosides themselves as the arylamine in
coupling reactions with the halonucleosides. Nucleo-
side dimers are of interest since they can be formed
in vitro by nitrous acid-induced DNA cross-linking.
Such a process could have a physiological role due to
the presence of nitrite in cured meats.[26,27] Pd-cata-
lyzed approaches have been used for the non-biomim-
Scheme 1. Application of the PdACHTUNRGTNEUNG(OAc)2/Xantphos system
etic synthesis of adducts produced by DNA cross-link- for the synthesis of the adenine nucleoside dimers.
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Palladium-Catalyzed Aryl Amination Reactions of 6-Bromo- and 6-Chloropurine Nucleosides
Table 3. Results from the reactions leading to the dA–dA,
and A–A dimers.
chloropurine nucleosides are also excellent substrates
for such reactions, requiring 10 mol% Pd(OAc)2/
AHCTUNGTRENNUNG
15 mol% Xantphos, under otherwise comparable con-
ditions. Finally, the method has been applied to the
synthesis of deoxyadenosine-deoxyadenosine and ade-
nosine-adenosine dimers. Bromo- as well as chloro-
purine ribo- and deoxyribonucleosides are effective
substrates for reactions with protected 2’-deoxyadeno-
sine and adenosine. Therefore, the methodology de-
scribed appears to present broad generality and scope
Entry Partners Conditions,[a] time[b] Product: Yield [%][c]
1
2
3
4
3
4
1a+5a
1b+5b A, 1 h
1a+5a B, 1 h
1b+5b B, 1 h
2a+5a B, 1 h
2b+5b B, 1 h
A, 1 h
6a: 65
6b: 70
6a: 79
6b: 84
6a: 77
6b: 81
[a]
Reactions were performed at a nucleoside concentration for nucleoside modification with both 6-bromo and 6-
of 0.1M in the reaction solvent. Conditions A: 5 mol%
Pd(OAc)2/7.5 mol% L3/1.5 molar equiv. Cs2CO3, PhMe,
1008C. Conditions B: 10 mol% Pd(OAc)2/15 mol% L3/
chloropurine nucleosides.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
1.5 molar equiv. Cs2CO3, PhMe, 1008C.
Reactions were monitored by TLC for complete disap-
pearance of the halonucleoside.
Experimental Section
[b]
[c]
Thin layer chromatography was performed on 250 mm silica
plates and column chromatographic purifications were per-
formed on 200–300 mesh silica gel. Ligands L1–L5 and Pd-
Yield of isolated and purified products.
AHCTUNGRTEGNUN(N OAc)2 were purchased from commercial suppliers. All
provide comparable product yields to the bromopur-
ine nucleoside derivatives at the higher catalyst load-
other reagents were obtained from commercial sources and
were used without further purification. Toluene was distilled
over Na. Nucleoside substrates were prepared as described
previously. Characterization data for all compounds are pro-
ing of 10 mol% PdACTHNUTRGNEUNG(OAc)2/15 mol% L3. Thus, contra-
ry to prior results,[29] our data indicate that it is unnec-
essary to involve the iodo nucleosides in Pd-catalyzed
syntheses of nucleoside dimers.
1
vided in the Supporting Information. H NMR spectra were
recorded at 500 MHz in the solvents indicated (when CDCl3
was used, it was deacidified by percolating the solvent
through a bed of solid NaHCO3 and basic alumina). All
proton spectra are referenced to residual protonated solvent
resonance. No attempt has been made to ascertain the posi-
tion of the arylamino proton (NHAr) in the products.
Therefore, this and the aromatic protons are collectively as-
signed as Ar-H. The sugar protons are numbered 1’–5’ be-
ginning at the anomeric carbon and proceeding via the
carbon chain to the primary carbinol carbon.
Since modified nucleosides could possess interest-
ing biological properties, the amination products were
desilylated (see the Supporting Information for de-
tails, and Table S1). The deprotected compounds from
this study as well as those obtained from previously
synthesized compounds[11,23,30] were subjected to a
wide variety of antiviral assays. Unfortunately, none
showed specifically interesting activity at subtoxic
concentrations as shown in Tables S2–S5 of the Sup-
porting Information. Instead, several compounds
showed a mild cytostatic and/or cytotoxic activity
against a variety of cell lines (CC50 or MIC in the 10
to 100 mgmLÀ1 range). Only the desilylated product
from 4f was endowed with a marked cytostatic activi-
ty against CRFK cells (CC50: 4.32 mM). This com-
pound should be further explored for its potential an-
tiproliferative activity against a broad variety of
À
C N Bond-Formation under Conditions A
PdACHTNURGTNENUG(OAc)2 (5 mol%), Xantphos (7.5 mol%) and Cs2CO3 (1.5
molar equiv.) were premixed in a small volume of toluene in
an oven-dried, screw-cap vial equipped with a stirring bar.
Bromonucleoside (1 molar equiv., 0.08 mmol of 1a or 1b),
arylamine (2 molar equiv.) and toluene were then added to
the vial so that the final reaction mixture was 0.1M in nu-
cleoside. The vial was flushed with nitrogen gas, sealed with
a Teflon-lined cap, and placed in a sand bath that was main-
tained at 101–1028C. Reactions were monitored by TLC.
Upon completion, the mixtures were diluted with Et2O
(7 mL) and washed with brine (5 mL). The organic phase
was separated, dried (Na2SO4) and concentrated. Products
were purified by column chromatography on silica gel using
appropriate solvents (listed under individual headings),
evaporated and finally dried under high vacuum to remove
traces of solvent.
À
À
tumor cell lines. Pd-catalyzed C N and C C bond-
forming reactions have led to this diverse set of com-
pounds for antiviral and cytostatic analysis that would
otherwise not be available.
Conclusions
À
In conclusion, Pd-catalyzed C N bond formation is
an effective method for access to N6-aryl adenosine
À
C N Bond-Formation under Conditions B
analogues. Herein we show that 5 mol% PdACTHNUGTRENUNG(OAc)2/
7.5 mol% Xantphos is a generally effective catalyst in
combination with Cs2CO3 in PhMe at 1008C for reac-
tions of 6-bromopurine ribonucleosides as well as the
PdACHTNURGTNENUG(OAc)2 (10 mol%), Xantphos (15 mol%) and Cs2CO3 (1.5
molar equiv.) were premixed in a small volume of toluene in
an oven-dried, screw-cap vial equipped with a stirring bar.
2’-deoxy analogues. Remarkably, the corresponding 6- Chloronucleoside (1 molar equiv., 0.08 mmol of 2a or
Adv. Synth. Catal. 2010, 352, 1728 – 1735
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1733

Paul F. Thomson et al.
FULL PAPERS
0.085 mmol of 2b), amine (2 molar equiv.) and toluene were References
then added to the vial so that the final reaction mixture was
0.1M in nucleoside. The vial was flushed with nitrogen gas,
sealed with a Teflon-lined cap, and placed in a sand bath
that was maintained at 101–1028C. Reactions were moni-
tored by TLC. Upon completion, work-up as above and
column chromatography on silica gel using appropriate sol-
vents yielded the amination products.
[1] a) D. S. Surrey, S. L. Buchwald, Angew. Chem. 2008,
120, 6438–6461; Angew. Chem. Int. Ed. 2008, 47, 6338–
6361; b) J. F. Hartwig, in: Modern Arene Chemistry,
(Ed.: D. Astruc), Wiley-VCH, Weinheim, 2002,
pp 107–168; c) B. Schlummer, U. Scholz, Adv. Synth.
Catal. 2004, 346, 1599–1626; d) A. R. Muci, S. L. Buch-
wald, in: Topics in Current Chemistry, Vol. 219, (Ed.:
N. Miyaura), Springer-Verlag, Berlin, 2002, pp 131–
209; e) J. F. Hartwig, in: Modern Amination Methods,
(Ed.: A. Ricci), Wiley-VCH, Weinheim, 2000, pp 195–
262; f) B. H. Yang, S. L. Buchwald, J. Organomet.
Chem. 1999, 576, 125–146.
Biological Assays
The antiviral assays, other than the anti-HIV assays, were
based on inhibition of virus-induced cytopathicity in HEL
[herpes simplex virus type 1 (HSV-1) (KOS), HSV-2 (G),
vaccinia virus, vesicular stomatitis virus, cytomegalovirus
(HCMV) and varicella-zoster virus (VZV)], Vero (parain-
fluenza-3, reovirus-1, Sindbis virus and Coxsackie B4),
HeLa (vesicular stomatitis virus, Coxsackie virus B4, and
respiratory syncytial virus), Crandel–Rees feline kidney
(CRFK) [feline coronavirus (FIPV) and feline herpes virus]
or MDCK [influenza A (H1N1; H3N2) and influenza B] cell
cultures. Confluent cell cultures (or nearly confluent for
MDCK cells) in microtiter 96-well plates were inoculated
with 100 CCID50 of virus (1 CCID50 being the virus dose to
infect 50% of the cell cultures) in the presence of varying
concentrations (100, 20, 4, … mgmLÀ1) of the test com-
pounds. Viral cytopathicity was recorded as soon as it
reached completion in the control virus-infected cell cul-
tures that were not treated with the test compounds. The
minimal cytotoxic concentration (MCC) of the compounds
was defined as the compound concentration that caused a
microscopically visible alteration of cell morphology. The
CC50 was defined as the compound concentration that re-
sulted in a 50% reduction of the MTT- or MTS-directed
(blue) viability staining of the (CRFK and MDCK) cell cul-
tures. The methodology of the anti-HIV assays was as fol-
lows: human lymphocyte MT-4 cells (ca. 3ꢁ105 cells/mL)
[2] For a review see: M. K. Lakshman, Curr. Org. Synth.
2005, 2, 83–112.
[3] a) Modified Nucleosides in Biochemistry Biotechnology
and Medicine, (Ed. P. Herdewijn), Wiley-VCH, Wein-
heim, 2008; b) Nucleic Acids in Chemistry and Biology,
3rd edn., (Eds.: G. M. Blackburn, M. J. Gait, D. Loakes,
D. M. Williams), RSC Publishing, Cambridge, UK,
2006; c) C. Simons, Nucleoside Mimetics: Their Chemis-
try and Biological Properties, Gordon and Breach, Am-
sterdam, 2001; d) Perspectives in Nucleoside and Nucle-
ic Acid Chemistry, (Eds.: M. V. Kisakꢂrek, H. Rose-
meyer), Verlag Helvetica Chimica Acta, Zurich and
Wiley-VCH, Weinheim, 2000; e) R. J. Suhadolnik, Nu-
cleosides as Biological Probes, Wiley, New York, 1979.
[4] a) L. A. Agrofoglio, S. P. Nolan, Curr. Top. Med. Chem.
2005, 5, 1541–1558; b) L. A. Agrofoglio, I. Gillaizeau,
Y. Saito, Chem. Rev. 2003, 103, 1875–1916; c) E. Ichi-
kawa, K. Kato, Curr. Med. Chem. 2001, 8, 385–423;
d) J. Zemlicka, Pharmacol. Ther. 2000, 85, 251–266;
e) D. M. Huryn, M. Okabe, Chem. Rev. 1992, 92, 1745–
1768.
[5] M. K. Lakshman, J. C. Keeler, J. H. Hilmer, J. Q.
Martin, J. Am. Chem. Soc. 1999, 121, 6090–6091.
[6] M. K. Lakshman, J. H. Hilmer, J. Q. Martin, J. C.
Keeler, Y. Q. V. Dinh, F. N. Ngassa, L. M. Russon, J.
Am. Chem. Soc. 2001, 123, 7779–7787.
[7] M. K. Lakshman, F. N. Ngassa, S. Bae, D. G. Buchanan,
H.-G. Hahn, H. Mah, J. Org. Chem. 2003, 68, 6020–
6030.
were infected with 100 CCID50 of HIV
ACHTUNGTREN(NGNU IIIB) or HIV-2-
ACHTUNGTRENNUNG(ROD)/mL and seeded in 200 mL wells of a microtiter plate
containing appropriate dilutions of the test compounds.
After 4 days of incubation at 378C, virus-induced cytopa-
thicity was recorded with the MTT dye staining method.
[8] J. Barends, J. B. van der Linden, F. L. van Delft, G.-J.
Koomen, Nucleosides Nucleotides 1999, 18, 2121–2126.
[9] M. K. Lakshman, P. Gunda, Org. Lett. 2003, 5, 39–42.
[10] E. Champeil, P. Pradhan, M. K. Lakshman, J. Org.
Chem. 2007, 72, 5035–5045.
[11] P. Lagisetty, L. M. Russon, M. K. Lakshman, Angew.
Chem. 2006, 118, 3742–3745; Angew. Chem. Int. Ed.
2006, 45, 3660–3663.
[12] E. A. Vꢃliz, P. A. Beal, J. Org. Chem. 2001, 66, 8592–
8598.
[13] V. Nair, S. G. Richardson, J. Org. Chem. 1980, 45,
3969–3974.
[14] H. Maruenda, A. Chenna, L.-K. Liem, B. Singer, J.
Org. Chem. 1998, 63, 4385–4389.
[15] M. J. Robins, G. L. Basom, Can. J. Chem. 1973, 51,
3161–3169.
[16] D. E. Bergstrom, P. A. Reddy, Tetrahedron Lett. 1982,
23, 4191–4194.
Acknowledgements
This work was supported by National Science Foundation
grant CHE-0640417 and a PSC CUNY award to MKL. JB
received support of the K.U.Leuven (GOA 10/014). PFT ac-
knowledges support via Ruth L. Kirschstein National Re-
search Service Award 5 F31 GM082025-02 from the National
Institutes of Health. We thank Mr. Mark Nuqui (undergradu-
ate research participant) for some preliminary experiments
and Prof. Mark Biscoe (CCNY) for a sample of L6. Infra-
structural support was provided by Research Centers at Mi-
nority Institutions grant NIH/NCRR/RCMI grant G12
RR03060. We thank Dr. Cliff Soll (Hunter College) for
HRMS data of new compounds, and Mrs. Leentje Persoons,
Mrs. Frieda De Meyer, Mrs. Kristien Erven, Mrs. Lies Van
den Heurck, Mr. Steven Carmans and Mrs. Anita Camps for
dedicated technical assistance.
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asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1728 – 1735

Palladium-Catalyzed Aryl Amination Reactions of 6-Bromo- and 6-Chloropurine Nucleosides
[17] a) E. A. Vꢃliz, P. A. Beal, Tetrahedron Lett. 2000, 41,
1695–1697; b) J. F. Gerster, J. W. Jones, R. K. Robins, J.
Org. Chem. 1963, 28, 945–948.
2004, 43, 6372–6377 (also see corrigendum: P. Gunda,
L. M. Russon, M. K. Lakshman, Angew. Chem. 2005,
117, 1178; Angew. Chem. Int. Ed. 2005, 44, 1154).
[18] a) N. Bçge, M. I. Jacobsen, Z. Szombati, S. Baerns, F.
Di Pasquale, A. Marx, C. Meier, Chem. Eur. J. 2008,
14, 11194–11208; b) N. Bçge, S. Grꢄsl, C. Meier, J.
Org. Chem. 2006, 71, 9728–9738.
[19] a) T. Takamura-Enya, S. Enomoto, K. Wakabayashi, J.
Org. Chem. 2006, 71, 5599–5606; b) T. Takamura-
Enya, S. Ishikawa, M. Mochizuki, K. Wakabayashi, Tet-
rahedron Lett. 2003, 44, 5969–5973.
[20] a) C. E. Elmquist, J. S. Stover, Z. Wang, C. J. Rizzo, J.
Am. Chem. Soc. 2004, 126, 11189–11201; b) J. S.
Stover, C. J. Rizzo, Org. Lett. 2004, 6, 4985–4988; c) Z.
Wang, C. J. Rizzo, Org. Lett. 2001, 3, 565–568.
[21] D. Chakraborti, L. Colis, R. Schneider, A. K. Basu,
Org. Lett. 2003, 5, 2861–2864.
[24] F. N. Ngassa, K. A. DeKorver, T. S. Melistas, E. A.-H.
Yeh, M. K. Lakshman, Org. Lett. 2006, 8, 4613–4616.
´
[25] See, for example: a) M. Hocek, A. Holy, I. Votruba, H.
ˇ
Dvorꢅkovꢅ, J. Med. Chem. 2000, 43, 1817–1825; b) M.
ˇ
ˇ
Havelkovꢅ, M. Hocek, M. Cesnek, D. Dvorꢅk, Synlett
1999, 1145–1147.
[26] R. Shapiro, S. Dubelman, A. M. Feinberg, P. F. Crain,
J. A. McCloskey, J. Am. Chem. Soc. 1977, 99, 302–303.
[27] a) J. J. Kirchner, S. T. Sigurdsson, P. B. Hopkins, J. Am.
Chem. Soc. 1992, 114, 4021–4027; b) J. J. Kirchner, P. B.
Hopkins, J. Am. Chem. Soc. 1991, 113, 4681–4682.
[28] E. A. Harwood, P. B. Hopkins, S. T. Sigurdsson, J. Org.
Chem. 2000, 65, 2959–2964.
[29] F. De Riccardis, F. Johnson, Org. Lett. 2000, 2, 293–
295.
[30] M. K. Lakshman, P. Gunda, P. Pradhan, J. Org. Chem.
2005, 70, 10329–10335.
[22] L. C. J. Gillet, O. D. Schꢄrer, Org. Lett. 2002, 4, 4205–
4208.
[23] P. Gunda, L. M. Russon, M. K. Lakshman, Angew.
Chem. 2004, 116, 6532–6537; Angew. Chem. Int. Ed.
Adv. Synth. Catal. 2010, 352, 1728 – 1735
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1735