An efficient mixed-ligand Pd catalytic system to promote C-N coupling for the synthesis of N-arylaminotriazole nucleosides

Article abstract of DOI:10.1002/chem.201103918

Make it unique! A mixed-ligand system of Pd/Synphos/Xantphos promotes effective C-N coupling in the synthesis of various N-arylaminotriazole and N-arylaminopurine nucleoside analogues. This catalytic system is strikingly powerful and efficient, allowing f

Full text of DOI:10.1002/chem.201103918

COMMUNICATION
DOI: 10.1002/chem.201103918
À
An Efficient Mixed-Ligand Pd Catalytic System to Promote C N Coupling
for the Synthesis of N-Aryl
N
Yuting Fan,[a, b] Yi Xia,[b] Jingjie Tang,[a] Fabio Ziarelli,[c] Fanqi Qu,[a] Palma Rocchi,[d]
Juan L. Iovanna,[d] and Ling Peng*[b]
Nucleoside analogues are an important family of candi-
dates in the search for antiviral and anticancer agents.[1] We
have been recently engaged in developing various triazole
nucleosides bearing aryl moieties on the triazole ring be-
cause members of this nucleoside family show extremely
promising antiviral and anticancer activity.[2] Of particular
interest are the N-arylaminotriazole nucleoside analogues,
which displayed potent anticancer activity against drug-re-
sistant cancer forms with novel modes of action.[3] However,
the synthesis of N-arylaminotriazole nucleosides is nontrivial
and requires distinct conditions for different substrates with
varying reactivity and stability on the reaction sites of the
triazole ring and the sugar components.[3–4] Very recently,
Xantphos to synthesize various N-arylaminotriazole nucleo-
sides and N-arylaminopurine nucleosides. This catalytic
À
system is extremely powerful, even promoting C Cl bond
À
activation for C N coupling.
We started our evaluation of the reaction parameters for
mixed-ligand-system-promoted C N coupling with 5-bro-
motriazole ribonucleoside (1) and aniline as model sub-
strates and by using the two phosphor ligands, Synphos and
Xantphos (Table 1 and the Supporting Information, Table
[7]
À
Table 1. Evaluation of Pd/Synphos/Xantphos systems for arylamination
of 5-bromotriazole ribonucleoside (1).[a]
Buchwald et al. proposed a mixed-ligand Pd catalyst to pro-
[5]
À
mote C N coupling. Such mixed-ligand systems are able
to provide enhanced reactivity and selectivity by combining
the benefits of single-ligand systems when the ligands are ju-
diciously selected.[6] We therefore wished to develop a gen-
À
eral and powerful mixed-ligand catalytic system towards C
Entry
Catalyst
loading [mol%]
Synphos/Xantphos[b]
Yield
[%][c]
42[d]
21[e]
80
N coupling to synthesize various N-arylaminotriazole nu-
cleosides with wide substrate scope. It is notable that tria-
zole nucleosides are particularly challenging for metal-cata-
lyzed cross-coupling reactions due to the low reactivity of
the heterocyclic triazole ring, the multiple coordinating N-
and O-atoms and the labile glycosidic bond. In this work,
we report a unique mixed-ligand system of Pd/Synphos/
1
2
3
4
5
5
5
5
5
0:1
1:0
1:1
2:1
2:1
92
2.5
88[f]
[a] The reaction conditions were: 1 (0.1 mmol), aniline (0.2 mmol), [Pd]/
[Ligand]=1:1.2, K2CO3 (0.2 mmol), toluene (2 mL). [b] Molar ratio.
ACHTUNG-
TERNNUG
[a] Y. Fan, J. Tang, Prof. F. Qu
State Key Laboratory of Virology
College of Chemistry and Molecular Sciences
Wuhan University
[c] Isolated product yield. [d] Formation of several by-products. [e] A
large amount of 1 was recovered. [f] Reaction time was 14 h.
S1). According to our previous work, Synphos and Xant-
phos exercised a selective and effective impact on Pd-cata-
430072 Wuhan (P.R. China)
[b] Y. Fan, Dr. Y. Xia, Dr. L. Peng
Centre Interdisciplinaire de Nanoscience de Marseille
CNRS UMR 7325, Aix-Marseille Universitꢀ
13288 Marseille (France)
À
lyzed C N coupling with the 5- and 3-bromotriazole acyclo-
nucleoside isomers, respectively.[3a] However, using the
single-ligand system based on either Xantphos or Synphos,
we got rather disappointing results for synthesizing the cor-
responding triazole ribonucleoside 1a (Table 1, entries 1 and
Fax : (+33)4-91-82-93-01
E-mail: ling.peng@univmed.fr
[c] Dr. F. Ziarelli
À
2). Xantphos, the most remarkable ligand to promote C N
Aix-Marseille Universitꢀ
Fꢀdꢀration des Sciences Chimiques, Spectropole
13013 Marseille (France)
coupling of 3-bromotriazole acyclonucleoside in our previ-
ous study,[3a] gave a poor yield of 1a (Table 1, entry 1);
whereas Synphos, which efficiently enhances the arylamina-
tion reaction of 5-bromotriazole acyclonucleoside,[3a] led to
an even worse result (Table 1, entry 2). A close analysis of
the reactions brought to light the possible reasons for the
low yields. When Xantphos was used, many unknown by-
[d] Dr. P. Rocchi, Dr. J. L. Iovanna
Centre de Recherche en Cancꢀrologie de Marseille
UMR1068 Inserm, Institut Paoli-Calmettes
Aix-Marseille Universitꢀ, 13288 Marseille (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103918.
Chem. Eur. J. 2012, 18, 2221 – 2225
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2221

products were also formed, although 1 was completely con-
sumed (as indicated by TLC analysis). This implies that the
Pd/Xantphos combination resulted in an active but unselec-
tive catalytic system. In the case of Synphos, no by-product
was observed; however large amounts of starting material
remained. This suggests that while being specific, the Pd/
Synphos system was an inefficient catalyst.
scope of both the amines and the nucleosides, the represen-
tative results of which are summarized in Table 2 and
Table 3.
As shown in Table 2, the Pd/Synphos/Xantphos system
proved to be widely efficient for the arylamination of 1 with
Table 3. Arylamination of different bromotriazole and halopurine nu-
cleoside substrates using the mixed-ligand catalytic system of Pd/Syn-
phos/Xantphos.[a]
On the basis of these findings, we expected that a mixed-
ligand Pd catalytic system based on the combination of
Xantphos and Synphos might allow the promotion of cata-
lytic reactivity by overcoming the limitations of selectivity
and efficiency manifested by the use of the individual ligand
systems. We hence developed the mixed-ligand system using
Synphos and Xantphos at a 1:1 molar ratio and obtained an
excellent yield of 80% for 1a (Table 1, entry 3). Further ad-
justment of the ligand ratio led us to obtain the best yield
with Synphos and Xantphos at a ratio of 2:1 (Table 1,
entry 4 and the Supporting Information, Table S1). Most im-
portantly, the starting material 1 was completely consumed,
with a significant reduction in by-product formation. More-
over, reducing the catalyst loading to 2.5 mol% still led to
the generation of the product in an 88% yield, although a
longer reaction time was required (Table 1, entry 5). We
À
Ar’ X
Entry
Product
Yield
[%][b]
1
1
2
1a
92[c]
also tried to premix Pd2ACHTUNTRGNEUNG(dba)3, Synphos/Xantphos (2:1) and
2
2a
91
K2CO3 with a small volume of toluene for preactivation
during 1 h before the reaction. This considerably reduced
the reaction time to 2 h (see the Supporting Information,
Table S1, entry 4). Consequently, we chose the preactivated
catalyst system for subsequent studies on the substrate
3
4
3
4
3a
4a
88
89
Table 2. Mixed-ligand system of Pd/Synphos/Xantphos to promote the
À
C N coupling of 5-bromotriazole ribonucleoside (1) with various aryl-
A
amines.[a]
5
6
5
6
5a
6a
86[d]
Entry
Ar
Product
Yield
[%][b]
85[d]
1
2
3
4
5
6
7
8
Ph
1a
1b
1c
1d
1e
1 f
1g
1h
1i
92
82
73
86
90
89
86
90
88
85
73
83
4-MePh
4-n-C7H15Ph
4-OMePh
3-OMePh
2-OMePh
4-FPh
3-FPh
2-FPh
4-CF3Ph
4-ClPh
1-pyrenyl
7
7
5a
70[e](90[f])
9
10
11
12
1j
1k
1l
[a] The reaction conditions were: nucleoside (0.1 mmol), aniline
(0.2 mmol), Pd2A(dba)3 (0.005 mmol), Synphos (0.008 mmol), Xantphos
(0.004 mmol), K2CO3 (0.2 mmol), toluene (2 mL). Pd2A(dba)3, ligands and
K2CO3 were premixed in toluene (1 mL) for 1 h before reaction. [b] Iso-
lated product yield. [c] Reaction time was 2 h. [d] Reaction time was 4 h.
CTHUNGTRENNUNG
[a] The reaction conditions were: 1 (0.1 mmol), arylamine (0.2 mmol),
Pd2A(dba)3 (0.005 mmol), Synphos (0.008 mmol), Xantphos (0.004 mmol),
K2CO3 (0.2 mmol), toluene (2 mL). Pd2A(dba)3, ligands and K2CO3 were
CHTUNGTRENNUNG
G
CTHUNGTRENNUNG
premixed in toluene (1 mL) for 1 h before reaction. [b] Isolated product
yield.
[e] Reaction time was 20 h. [f] 10% Pd
time was 14 h.
2ACHTUNGRTEN(NUNG dba)3 (0.01 mmol) and reaction
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Chem. Eur. J. 2012, 18, 2221 – 2225

An Efficient Mixed-Ligand Pd Catalytic System
COMMUNICATION
a multitude of aryl amines bearing various substituents. No-
tably, arylamines bearing either electron-donating (Table 2,
entries 2–6) or electron-withdrawing groups (Table 2, en-
tries 7–11) at various positions (Table 2, entries 4–6 and 7–9)
À
yielded excellent results. The C N coupling reactions pro-
ceeded very smoothly even with the sterically hindered
ortho-substituent arylamines and pyrenylamine (Table 2, en-
tries 6, 9, and 12). Consequently, a variety of N-arylamino-
triazole ribonucleoside analogues could be generated effec-
tively through this procedure (Table 2).
Most importantly, this catalytic system is also highly effi-
cient for different nucleoside substrates (Table 3). It is
worth mentioning that structural isomers of bromotriazole
nucleosides have notoriously different reactivity and require
[3–4]
À
very different conditions for C N coupling.
Using the
mixed-ligand system of Pd/Synphos/Xantphos, we achieved,
for the first time, efficient arylamination of triazole nucleo-
sides with different isomeric structures and different sugar
components (Table 3, entries 1–4). Importantly, the 6-bro-
mopurine ribo- and deoxyribonucleosides 5 and 6[8] could
also deliver the corresponding products in excellent yields
(Table 3, entries 5 and 6). Even the much less reactive 6-
chloropurine ribonucleoside 7[9] delivered the corresponding
product smoothly, with a spectacularly higher yield of 90%
being attained with a higher catalyst loading (Table 3,
entry 7). Consequently, our mixed-ligand system appears to
be a peculiarly powerful catalyst, exhibiting extraordinary
Figure 1. 31P NMR spectra of the Pd/ligand systems in the absence (A)
and presence (B) of the substrate 1. i) free Synphos, ii) free Xantphos,
iii) Pd
Xantphos, vi) Pd
viii) Pd2A(dba)3/Synphos/Xantphos/1. The spectra were obtained in
2A
R
2ACHTUNGTREN(NUNG dba)3/Synphos/
2A(dba)3/Synphos/1, vii) Pd
CHTUNGTRENNUNG
CTHUNGTRENNUNG
[D8]Toluene. All the reaction mixtures (in the absence of substrate 1)
were first refluxed at 1108C for 1 h under protection of argon and then
cooled at RT. The solutions were subsequently transferred to NMR tubes
in a glovebox directly. One more hour was required if substrate 1 was
À
reactivity and wide substrate scope in catalyzing the C N
coupling of various triazole and purine nucleosides.
added in the reaction mixture. In mixed-ligand samples, [Synphos]/ACHTUNGTRENNUNG[Xant-
To gain a better understanding of the reason for the cata-
lytic power shown by the Pd/Synphos/Xantphos system, we
performed a 31P NMR investigation (Figure 1). In the Pd/
Synphos system, we observed that a considerable amount of
Synphos existed as free ligand and only a small amount of
phos]=2:1. The label b denotes the Pd complex in which Synphos works
as monodentate ligand; label c denotes the Pd complex in which Xant-
phos works as monodentate ligand (see ref. [13]).
(Synphos)Pd
suggests that the formation of the (Synphos)Pd
plex is slow and inefficient. As (Synphos)Pd(dba) is the pre-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[10]
À
cursor of the active catalytic species for C N coupling,
this finding may explain in part why the Pd/Synphos system
was not efficient for arylamination of 1 (Table 1, entry 2).
As for the Pd/Xantphos system, all of the Xantphos coordi-
nated to Pd and no free ligand was detected (Figure 1A, iv).
These results suggest that Xantphos is more efficient at
forming complexes with Pd2ACTHNUTRGNE(UNG dba)3 than Synphos. This differ-
ence might be ascribed to the more flexible structure and
larger bite angle of Xantphos,[11] which makes it more ready
to form complexes with Pd compared with the structurally
rigid Synphos, which has a small bite angle. Using the
mixed-ligand Pd/Synphos/Xantphos system,[12] we surprising-
ly found no free ligand of Synphos and considerably in-
Scheme 1. Proposed ligand exchange at the level of A) the Pd/ligand
complex formation and B) the oxidative insertion.
creased amounts of (Synphos)PdACTHNUGTRNEUNG(dba) were detected (Fig-
ure 1A, v). It is also important to note that Xantphos mono-
dentate-ligated Pd complex,[13] which formed in the single-
ligand system of Pd/Xantphos (peak c in Figure 1A, iv), was
diminished completely in the mixed-ligand system (Fig-
ure 1A, v).[14] Collectively, these findings led us to hypothe-
size that, in the Pd/Synphos/Xantphos system, Xantphos
promoted the complex formation between Pd and Synphos
through a rapid exchange of ligand at the level of Pd com-
plexes in the mixed-ligand system (Scheme 1A), and the
considerably increased formation of the (Synphos)Pd
ACHTUNGTRENNUNG(dba)
complex thus resulted in a more efficient catalytic system.
Chem. Eur. J. 2012, 18, 2221 – 2225
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L. Peng et al.
We further studied the oxidative addition step by adding
5-bromotriazole ribonucleoside (1) into the mixed-ligand
catalyst system (Figure 1B, viii). Interestingly, in the pres-
ence of Xantphos, compound 1 preferentially formed the
adduct (Synphos)Pd(1) (Figure 1B, viii) compared with the
single-ligand system with Synphos (Figure 1B, vi). As a
result, the ligand exchange equilibrium could again be shift-
tremely important compounds in the continued quest for an-
tiviral and anticancer drug candidates.
Acknowledgements
ed towards the formation of the (Synphos)PdACTHNURTGNEU(GN dba) complex
Financial support was from the National Mega Project on Major Drug
Development (2009ZX09301-014), Wuhan University, CNRS and
INSERM. YTF is supported by the China Scholarship Council, and YX
by la Fondation pour la Recherche Mꢀdicale. We thank Drs. Gilles Quꢀl-
ꢀver, Hervꢀ Clavier and Ms. Roseline Rosas for their help in the synthe-
sis and 31P NMR investigation.
(Scheme 1B), thus further promoting the reaction. Based on
these results, we could reasonably conclude that, in the Pd/
Synphos single-ligand system, it is not that the catalytic spe-
cies has lower catalytic activity, but rather that the single-
ligand system with Synphos generates only a limited amount
of active catalytic species. In the mixed-ligand system, Xant-
phos promotes the formation of active catalytic species
formed between Pd and Synphos, thus leading to powerful
catalytic activity (Scheme 1A). In addition, using this mixed-
ligand system, the substrate preferentially formed adduct
Keywords: antitumor agents
·
arylamination
·
cross-
coupling · nucleosides · palladium
with the (Synphos)PdACHTNUGRTENUNG(dba) complex, further favoring the
[1] a) Modified Nucleosides in Biochemistry Biotechnology and Medi-
cine, (Ed.: P. Herdewijn), Wiley-VCH, Weinheim, Germany, 2008;
b) C. M. Galmarini, F. Popowycz, B. Joseph, Curr. Med. Chem. 2008,
15, 1072–1082.
equilibrium shift towards the formation of active catalyst
(Scheme 1B). Altogether, the 31P NMR studies provided
crucial data with which we were able to better understand
the origin of the enhanced catalytic effect displayed by this
[2] a) Y. Xia, F. Qu, L. Peng, Mini-Rev. Med. Chem. 2010, 10, 806–821;
b) J. Wan, Y. Xia, Y. Liu, M. Wang, P. Rocchi, J. Yao, F. Qu, J.
Neyts, J. L. Iovanna, L. Peng, J. Med. Chem. 2009, 52, 1144–1155;
c) Y. Xia, Y. Liu, J. Wan, M. Wang, P. Rocchi, F. Qu, J. L. Iovanna,
L. Peng, J. Med. Chem. 2009, 52, 6083–6096; d) Y. Liu, Y. Xia, W.
Li, M. Cong, A. Maggiani, P. Leyssen, F. Qu, J. Neyts, L. Peng,
Bioorg. Med. Chem. Lett. 2010, 20, 3610–3613; e) M. Wang, R. Zhu,
Z. Fan, Y. Fu, L. Feng, J. Yao, A. Maggiani, Y. Xia, F. Qu, L. Peng,
Bioorg. Med. Chem. Lett. 2011, 21, 354–357; f) Y. Xia, P. Rocchi,
J. L. Iovanna, L. Peng, Drug Discov. Today 2011, 17, 35–43.
[3] a) Y. Fan, Y. Xia, J. Tang, P. Rocchi, F. Qu, J. Iovanna, L. Peng, Org.
Lett. 2010, 12, 5712–5715; b) Y. Liu, Y. Xia, Y. Fan, A. Maggiani, P.
Rocchi, F. Qu, J. L. Iovanna, L. Peng, Bioorg. Med. Chem. Lett.
2010, 20, 2503–2507.
À
mixed-ligand system to promote C N coupling. Based on all
these results presented above, we hence proposed a general
mechanism of this mixed-ligand system assisted C-N cou-
pling involving two independent catalytic cycles between
which Pd is shuttled (see the Supporting Information,
Scheme S1). This mechanism parallels the one proposed by
Buchwald et al, which was formulated on the basis of prod-
uct analysis by trapping the reactive intermediates.[5]
Finally, we also assessed the newly synthesized N-arylami-
notriazole ribonucleosides for their anticancer activity
against drug-resistant pancreatic cancer MiaPaCa-2 cells.
Compound 1c exhibited particularly interesting anticancer
activity (see the Supporting Information, Figure S1), with
superior potency compared to gemcitabine, the current clini-
cal drug used to treat pancreatic cancer.[15] This finding fur-
ther confirmed and warranted the interest in and impor-
tance of developing efficient catalytic systems for synthesiz-
ing this special family of nucleoside analogues.
[4] W. Li, Y. Fan, Y. Xia, P. Rocchi, R. Zhu, F. Qu, J. Neyts, J. L. Iovan-
na, L. Peng, Helv. Chim. Acta 2009, 92, 1503–1513.
[5] B. P. Fors, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, 15914–
15917.
[6] a) M. T. Reetz, Angew. Chem. 2008, 120, 2592–2626; Angew. Chem.
Int. Ed. 2008, 47, 2556–2588; b) C. Moldoveanu, D. A. Wilson, C. J.
Wilson, P. Corcoran, B. M. Rosen, V. Percec, Org. Lett. 2009, 11,
4974–4977; c) D. A. Wilson, C. J. Wilson, C. Moldoveanu, A. M. Re-
smerita, P. Corcoran, L. M. Hoang, B. M. Rosen, V. Percec, J. Am.
Chem. Soc. 2010, 132, 1800–1801; d) W. Tang, S. Keshipeddy, Y.
Zhang, X. Wei, J. Savoie, N. D. Patel, N. K. Yee, C. H. Senanayake,
Org. Lett. 2011, 13, 1366–1369.
[7] We first tried the Pd/Ruphos/Brettphos system reported by Buch-
wald (see Ref. [5]). However, no satisfactory results were obtained
for synthesizing N-aryltriazole nucleosides. This might be ascribed
to the particularly reluctant reactivity of the heterocyclic triazole
system.
In conclusion, we have disclosed a highly efficient mixed-
ligand Pd catalytic system for arylamination of triazole nu-
cleoside analogues. It is worth mentioning that the Pd/Syn-
phos/Xantphos catalytic system displayed the unparalleled
À
advantage of catalyzing C N cross-coupling of different tria-
zole nucleosides and arylamines. In addition, this catalytic
À
system was also powerful at effectively promoting C N cou-
[8] E. Champeil, P. Pradhan, M. K. Lakshman, J. Org. Chem. 2007, 72,
5035–5045.
[9] P. F. Thomson, P. Lagisetty, J. Balzarini, E. De Clercq, M. K. Laksh-
man, Adv. Synth. Catal. 2010, 352, 1728–1735.
[10] C. Amatore, G. Broeker, A. Jutand, F. Khalil, J. Am. Chem. Soc.
1997, 119, 5176–5185.
[11] L. M. Klingensmith, E. R. Strieter, T. E. Barder, S. L. Buchwald, Or-
ganometallics 2006, 25, 82–91.
[12] The total ligand concentration remained the same in the multi-
ligand system as in the single-ligand systems.
[13] C. Amatore, A. Jutand, A. Thuilliez, Organometallics 2001, 20,
3241–3249.
pling with other halopurine nucleosides including the notori-
ously less reactive chloropurine ribonucleoside. Further-
more, 31P NMR studies provided us with an insightful under-
standing of the mechanism underlying the catalytic power
displayed by the Pd/Synphos/Xantphos system in promoting
arylamination. We anticipate a fueled interest in the mixed-
ligand approach, which may be applicable to other cross-
coupling reactions for the synthesis of structurally diverse
nucleoside analogues, which are currently a class of ex-
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Chem. Eur. J. 2012, 18, 2221 – 2225

An Efficient Mixed-Ligand Pd Catalytic System
COMMUNICATION
[14] We speculate that this monodentate Xantphos-ligated Pd species
might be responsible for the by-product formation observed with
the single-ligand system of Pd/Xantphos (Table 1, entry 1).
[15] J. Berlin, A. B. Benson, Nat. Rev. Clin. Oncol. 2010, 7, 135–137.
Received: December 14, 2011
Published online: January 20, 2012
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