Pd-Xantphos-catalyzed direct arylation of nucleosides

Article abstract of DOI:10.1021/ol0619516

Direct arylation of the exocyclic amino groups of nucleosides represents a simple approach to N-aryl nucleoside derivatives. To date, one limitation has been that only electron-deficient aryl bromides and triflates possessed adequate reactivity for effici

Full text of DOI:10.1021/ol0619516

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4613-4616
Pd−Xantphos-Catalyzed Direct Arylation
of Nucleosides
Felix N. Ngassa,*,† Kyle A. DeKorver,† Theothora S. Melistas,†
Edmund A.-H. Yeh,‡ and Mahesh K. Lakshman*,‡
Department of Chemistry, Grand Valley State UniVersity, Allendale, Michigan 49401,
and Department of Chemistry, The City College and The City UniVersity of New York,
138th Street at ConVent AVenue, New York, New York 10031
ngassaf@gVsu.edu; lakshman@sci.ccny.cuny.edu
Received August 7, 2006
ABSTRACT
Direct arylation of the exocyclic amino groups of nucleosides represents a simple approach to N-aryl nucleoside derivatives. To date, one
limitation has been that only electron-deficient aryl bromides and triflates possessed adequate reactivity for efficient, direct N-arylation of
nucleosides. We demonstrate herein that Pd−Xantphos catalytic systems lead to successful N-arylation of suitably protected 2′-deoxyadenosine
and 2 -deoxyguanosine with a wide range of aryl bromides.
′
Palladium-catalyzed C-N bond formation is emerging as a
powerful technique for the synthesis of unusual and biologi-
cally important nucleoside derivatives.1 This method has
yielded nucleoside conjugates of carcinogens and mutagens
at the C-6, C-2, and C-8 positions that can be used for
structural, biochemical, and biological studies.2-9
Generally, the most effective method for aryl amination
of nucleosides involves the reaction between a halogenated
nucleoside and an arylamine, mediated by a suitable Pd-
ligand complex.2-12 Although there are also recent examples
of aryl amination by a direct displacement of halides or other
leaving groups from the C-6 position of purine nucleosides,
the applicability of these reactions to electron-deficient
aniline derivatives is presently unknown.13-15
† Grand Valley State University.
‡ The City College and The City University of New York.
(1) Reviewed in: Lakshman, M. K. Curr. Org. Synth. 2005, 2, 83-112.
(2) (a) Wang, Z.; Rizzo, C. J. Org. Lett. 2001, 3, 565-568. (b) Stover,
J. S.; Rizzo, C. J. Org. Lett. 2004, 6, 4985-4988. (c) Elmquist, C. E.; Stover,
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(10) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. J. Am.
Chem. Soc. 1999, 121, 6090-6091.
(11) Harwood, E. A.; Sigurdsson, S. T.; Edfeldt, N. B. F.; Reid, B. R.;
Hopkins, P. B. J. Am. Chem. Soc. 1999, 121, 5081-5082.
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10.1021/ol0619516 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/02/2006

A simple synthesis of N-aryl nucleosides is through
the use of the nucleoside as the amine donor in Pd-
mediated amination reactions. Although this has been
tested with protected adenine and guanine nucleosides,
typically only activated (electron-deficient) aryl bromides
and triflates produced good yields.9,16,17 In our own work,
we have encountered only limited applicability of this
method.8
Recently, we have been studying the use of Pd-Xantphos
complexes for amination reactions of nucleosides with
azoles.18 In this context, we decided to reevaluate the use of
protected nucleosides in amination reactions with aryl
bromides. Pd-Xantphos combinations have been utilized for
the synthesis of aryl amino 2′-deoxyguanosine derivatives,19
but only limited success has been realized for N2-arylation.20
This communication demonstrates a generally good utility
of Pd-Xantphos complexes in effecting arylation at the
exocyclic C-6 and C-2 amino groups of purine 2′-deoxyri-
bonucleosides.
PO4 lowered the yield (45%).22 Finally, combinations of Pd2-
(dba)3 and ligands L-1, L-2, and L-3 with Cs2CO3 or K3PO4
were tested. In these cases, no product formation to low
levels of product formation were observed (see the Support-
ing Information for a comprehensive table of results).
Formation of a N6,N6-dimer has previously been observed
when stoichiometric amounts of 1 were employed that could
be suppressed by use of 1 in excess.16 Therefore, in the
present study, 30% excess 1 was used.
These initial experiments helped establish the combination
of Pd2(dba)3/L-4/Cs2CO3 as optimal for successful reaction.
The special properties of L-4 such as the possible trans
coordination and the presence of the apical oxygen atom that
can enable cis-trans isomerization of oxidative-addition
complexes are likely contributions to the effectiveness of
this ligand when compared to L-3, which like L-4 is also
capable of bis coordination.
Next, the generality of this direct arylation was probed.
Aryl bromides of varied electronic nature and substituents
were utilized, and the results of these experiments are
collected in Table 1. The results in Table 1 clearly show
that good to excellent yields of N6-aryl 2′-deoxyadenosine
analogues can be obtained. The reaction works well with
ortho-substituted aryl bromides (entries 2, 4, 9, and 12). As
expected, electron-deficient aryl bromides undergo amination,
but more remarkably, electron-rich aryl halides also react
quite well. The naphthalene systems are slower reacting
(entries 10-12), and among the three, the least-hindered
2-bromonaphthalene reacts fastest. It is currently not clear
why the 4-acetyl and 4-formyl bromobenzenes react slowly
compared to the 4-cyano. Nevertheless, good conversions
were observed in each case.
Initial experimentation began by assessing conditions for
the amination of bromobenzene with the easily prepared 3′,5′-
bis-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine.21 Four
ligands were selected for this analysis (Figure 1). Pd(OAc)2
Confirmation of the arylation site was obtained via two
methods. Because we have synthesized 2c, 2d, 2g, and 2m
via a C-N bond formation between an arylamine and a C-6
bromo nucleoside,8,10 unequivocally established 1H NMR data
could be directly compared in these cases. Second, as
representative examples, 13C NMR spectra of 2c and 2g were
compared to those of the products obtained via C-N bond
formation of the C-6 bromo nucleoside with the respective
arylamines10 (see the Supporting Information). These com-
parisons indicated the arylation reactions to occur at the N6.
Attention was next focused on 2′-deoxyguanosine. Al-
though unprotected 2′-deoxyguanosine has been utilized for
efficient C-C bond-forming reactions in an aqueous me-
dium,23 it was subsequently demonstrated that O6-unprotected
guanine may retard the rates of C-C bond formation via N1
and/or O6 coordination.24 On the basis of these results, we
chose the use of an O6-protected 2′-deoxyguanosine deriva-
tive and decided to conduct initial experimentation on the
Figure 1. Four ligands selected for analysis.
and Pd2(dba)3 were utilized as the metal source, and toluene
was chosen as solvent. At 90 °C, the combination of Pd-
(OAc)2, any one of the ligands L-1, L-2, or L-3, and either
Cs2CO3 or K3PO4 as base led to no discernible product
formation over a 24 h period. On the other hand, 10 mol %
of Pd(OAc)2/15 mol % of L-4 with either Cs2CO3 or K3PO4
(1.4 equiv) led to low yields of the desired product (∼20%),
and 10 mol % of Pd(OAc)2/10 mol % of L-4/1.4 equiv of
Cs2CO3 gave a 48% yield. Interestingly, 10 mol % of Pd2-
(dba)3/15 mol % of L-4/1.4 equiv of Cs2CO3 led to some
yield improvement (59%), but replacing Cs2CO3 with K3-
(16) De Riccardis, F.; Bonala, R. R.; Johnson, F. J. Am. Chem. Soc.
1999, 121, 10453-10460.
(17) Harwood, E. A.; Hopkins, P. B.; Sigurdsson, S. T. J. Org. Chem.
2000, 65, 2959-2964.
(18) Lagisetty, P.; Russon, L. M.; Lakshman, M. K. Angew. Chem., Int.
Ed. 2006, 45, 3660-3663.
(22) It has been demonstrated that a 2:1 ligand-Pd complex forms even
at a 1:l 4,7-di-tert-butylXantphos/Pd ratio. This 2:1 complex is a relatively
unreactive precatalyst: Klingensmith, L. M.; Strieter, E. R.; Barder, T. E.;
Buchwald, S. L. Organometallics 2006, 25, 85-91. In an attempt to favor
a greater proportion of a 1:1 Xantphos-Pd complex, only 15 mol % of
ligand was used with 10 mol % of Pd2(dba)3.
(23) Western, E. C.; Daft, J. R.; Johnson, E. M.; Gannett, P. M.;
Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767-6774.
(24) Western, E. C.; Shaughnessy, K. H. J. Org. Chem. 2005, 70, 6378-
6388.
(19) (a) Takamura-Enya, T.; Ishikawa, S.; Mochizuki, M.; Wakabayashi,
K. Tetrahedron Lett. 2003, 44, 5969-5973. (b) Takamura-Enya, T.;
Ishikawa, S.; Mochizuki, M.; Wakabayashi, K. Nucleic Acids Res. Suppl.
3 2003, 23-24.
(20) While this manuscript was under review, arylation of unprotected
dG derivatives with an activated aryl iodide was reported: Takamura-Enya,
T.; Enomoto, S.; Wakabayashi, K. J. Org. Chem. 2006, 71, 5599-5606.
An aryl bromide was reported as unreactive for the arylation.
(21) Gao, X.; Jones, R. A. J. Am. Chem. Soc. 1987, 109, 1275-1278.
4614
Org. Lett., Vol. 8, No. 20, 2006

Table 1. Reactions of Various Aryl Bromides with
3′,5′-Bis-O-(tert-butyldimethyl)-2′-deoxyadenosinea
Table 2. N2-Arylation of 3′,5′-Bis-O-(tert-butyldimethylsilyl)-
O6-methyl-2′-deoxyguanosine with Bromobenzenea
time,b
result
entry 3:Ph-Br
catalytic system, solvent, temp
1
2
3
4
5
6
7
8
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
10 mol % of Pd(OAc)2, 10 mol % of L-4, 24 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C 33% yieldc
10 mol % of Pd(OAc)2, 10 mol % of L-4, 1 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C 88% yieldc
10 mol % of Pd(OAc)2, 10 mol % of L-4, 24 h,
1.5 equiv of tert-BuONa, DME, 85 °C
traced
20 mol % of Pd(OAc)2, 20 mol % of L-4, 1 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C 89% yieldc
30 mol % of Pd(OAc)2, 30 mol % of L-4, 1 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C 68% yieldc
10 mol % of Pd(OAc)2, 15 mol % of L-4, 24 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C traced
10 mol % of Pd(OAc)2, 20 mol % of L-4, 24 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C incompleted
10 mol % of Pd(OAc)2, 30 mol % of L-4, 24 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C incompleted
a Reactions conducted with 0.08 mmol of nucleoside in 1 mL of solvent.
b Reactions were monitored by TLC. c Yield is of isolated, purified product.
d Product formation was observed by TLC but was not isolated.
as for the arylation of 1, the results were inferior in
comparison to Pd(OAc)2. Other critical factors also came to
light in Table 2: (a) in contrast to the reactions of 1, a 1:2
ratio of 3 to bromobenzene is necessary for effective
conversion (entry 1 vs 2); (b) use of PhMe as solvent is
critical (entry 2 vs 3); (c) a 1:1 stoichiometry of Pd/ligand
results in reasonably good product yields (entries 2, 4, and
5); and (d) an increase in ligand concentration relative to Pd
is detrimental to the reaction (entry 2 vs 6-8).
With these results in hand, we conducted the next series
of experiments with O6-benzyl-3′,5′-bis-O-(tert-butyldi-
methylsilyl)-2′-deoxyguanosine 5,11 where the O6 protecting
group can be readily removed by catalytic debenzylation.
The results from the arylation of 5 with bromobenzene are
shown in Table 3.
Results in Table 3 parallel those in Table 2 and lead to
some additional understandings. As with 3, the ratio of
nucleoside to bromobenzene is important (entry 1 vs 2), and
use of PhMe as solvent continued to be a critical factor (entry
2 vs 3). A 1:1 ratio of Pd/ligand provided satisfactory results,
although in this case both 10 mol % of Pd(OAc)2/10 mol %
of L-4 and 30 mol % of Pd(OAc)2/30 mol % of L-4 produced
comparable yields (entries 2 and 4). Use of the weaker bases
K3PO4 and Cs2CO3 was ineffective for the arylation reaction
(entries 5 and 6). Interestingly, a good yield of 6a could be
realized even at a catalyst loading of 5 mol % of Pd(OAc)2/5
mol % of L-4, although the reaction was a little slower and
produced a lowered yield.
a Reaction conditions: 0.42 mmol of nucleoside in 3 mL of PhMe, 10
mol % of Pd2(dba)3, 15 mol % of L-4, 1.4 equiv of Cs2CO3, 90 °C.
b Reactions were monitored for completion by TLC. c Yield is of isolated,
purified product.
easily prepared 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-meth-
yl-2′-deoxyguanosine 3.25 The results from these experiments
are summarized in Table 2.
The initial experimentation made it evident that the Pd-
(OAc)2/L-4/tert-BuONa combination was suitable for N2-
arylation of 3. Although Pd2(dba)3 was useable in this case,
Having completed the optimization experiments with two
O6-protected 2′-deoxyguanosine derivatives 3 and 5, the next
set of experiments involved an assessment of the generality
(25) 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.
Org. Lett., Vol. 8, No. 20, 2006
4615

Table 3. N2-Arylation of O6-Benzyl-3′,5′-bis-O-
(tert-butyldimethylsilyl)-2′-deoxyguanosine with Bromobenzenea
Table 4. Reactions of Various Aryl Bromides with
O6-Benzyl-3′,5′-bis-O-(tert-butyldimethyl)-2′-deoxyguanosinea
time,b
result
entry 5:Ph-Br
catalytic system, solvent, temp
1
2
3
4
5
6
7
1:1
1:2
1:2
1:2
1:2
1:2
1:2
10 mol % of Pd(OAc)2, 10 mol % of L-4, 24 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C 40% yieldc
10 mol % of Pd(OAc)2, 10 mol % of L-4, 1 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C 89% yieldc
10 mol % of Pd(OAc)2, 10 mol % of L-4, 24 h,
1.5 equiv of tert-BuONa, DME, 85 °C
incompleted
30 mol % of Pd(OAc)2, 30 mol % of L-4, 1 h,
1.5 equiv of tert-BuONa, PhMe, 85 °C 91% yieldc
30 mol % of Pd(OAc)2, 30 mol % of L-4, 24 h,
1.5 equiv of K3PO4, PhMe, 85 °C
traced
10 mol % of Pd(OAc)2, 10 mol % of L-4, 24 h,
1.5 equiv of Cs2CO3, PhMe, 85 °C
incompleted
3.5 h,
5 mol % of Pd(OAc)2, 5 mol % of L-4,
1.5 equiv of tert-BuONa, PhMe, 85 °C 78% yieldc
a Reactions conducted with 0.07 mmol of nucleoside in 1 mL of solvent.
b Reactions were monitored by TLC. c Yield is of isolated, purified product.
d Product formation was observed by TLC but was not isolated.
of this arylation chemistry. The results from these experi-
ments are displayed in Table 4.
As seen from Table 4, 5 not only undergoes reaction with
electron-deficient aryl bromides (entries 4, 9, and 10) but
also undergoes reaction with unsubstituted, alkyl-substituted,
and polyaromatic systems (entries 1, 2, and 5-7) and, more
importantly, the electron-rich ones (entries 3 and 8). Notably,
reported reactions of 5 with bromobenzene and 4-bromoani-
sole involving (+)-BINAP as the ligand provided a 57%
yield of 6a and a 0% yield of 6c.17 In contrast to the
successful reaction of 4-bromoanisole, 2-bromoanisole did
not yield product, and electronic factors alone are perhaps
not the reason for this. In the case of 4-bromobenzonitrile,
a secondary product arising from bisarylation was observed
and it is possible that with electron-deficient aryl bromides
bisarylation could be a competing reaction. Allowing the
reaction of 4-bromobenzonitrile to proceed longer resulted
in a lowered yield, possibly due to bisarylation.
In summary, we have demonstrated that Pd catalysts with
Xantphos as the supporting ligand are effective for direct
N-arylation of 2′-deoxyadenosine as well as 2′-deoxygua-
nosine and that these are superior to BINAP-based ones.
Although there are subtle differences in the reactions of two
purine nucleosides, the methods appear to be reasonably
general. Further studies on Pd-Xantphos complexes are
being conducted in our laboratories.
a Reaction conditions: 0.07 mmol of nucleoside in 1 mL of PhMe, 10
mol % of Pd(OAc)2, 10 mol % of L-4, 1.5 equiv of tert-BuONa, 85 °C.
b Reactions were monitored for completion by TLC. c Yield is of isolated,
purified product.
istration department of Grand Valley State University
(F.N.N.), and by NSF Grant CHE-0314326 and a PSC
CUNY-37 award (M.K.L.). Acquisition of a mass spectrom-
eter has been funded by NSF Grant CHE-0520963 (M.K.L.).
Drs. P. Lagisetty and S. Bae (CCNY) are thanked for their
assistance.
Supporting Information Available: Experimental details
1
and H NMR spectra of 2a-m, 4, and 6a-j. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a Grants-
in-Aid award from the Graduate Studies and Grants Admin-
OL0619516
4616
Org. Lett., Vol. 8, No. 20, 2006