nucleosides as the essential first step. In recent years,
Buchwald-Hartwig palladium-catalyzed amination6,7 has
been extensively used to synthesize many carcinogen-DNA
adducts.8,9 In this approach a bromo derivative of dG, dI, or
dA at the 8-, 2-, or 6-position, respectively, is coupled with
an alkyl or aralkylamine.8 DNA-DNA cross-links have also
been synthesized by a slight modification of this strategy.9
Significant success has been achieved in the synthesis of the
C8 dG and dA adducts of aromatic amine carcinogens,8d-g
and recently the C8 dG adduct of 1-NP (i.e., C8-AP-dG in
Scheme 1) has been prepared in 51% yield.8g A general
method for synthesizing N2 dG adducts has been reported
by Johnson and co-workers,8b which was utilized by others
as well.8c,9a However, none of the arylamines contained a
polycyclic ring system. An alternate strategy, in which the
N2 amino functionality of dG was coupled with 2-nitroaryl
bromides or triflates, was also used successfully by Johnson.10
However, it was unclear if this approach would be applicable
to aryl or aralkyl halides that did not contain an activating
group at the ortho or para position. Hopkins compared the
coupling between phenyl bromide/protected dG and phen-
ylamine/protected 2-Br-dI and found that the latter approach
provides a better yield except when the phenyl ring contains
a nitro group at the para position.9a It is noteworthy that,
unlike the substrates used by Johnson10 and Hopkins,9a the
N2 dG adducts of 1-NP contain an amino group on a distal
phenyl ring of the pyrene moiety, which, in principle, can
be easily derived by reduction of a nitro group. The objective
of the current work is to evaluate the two approaches of Pd-
catalyzed couplings under various conditions, and herein we
report a high-yielding method of synthesis of these adducts.
Our preliminary experiments involved coupling between
2-bromo-O6-benzyl-3′,5′-bis-O-tert-butyldimethylsilyl-2′-
deoxyinosine and 1-aminopyrene. This was compared with
the coupling between O6-benzyl-3′,5′-bis-O-tert-butyldim-
ethylsilyl-2′-deoxyguanosine and 1-bromopyrene. To monitor
the progress of the reaction, we followed disappearance of
the pyrene derivative by reverse-phase HPLC. After 80-
90% disappearance of the 1-bromopyrene or 1-aminopyrene,
the coupled product was isolated to assess the actual yield.
For the coupling between protected 2-Br-dI and 1-amino-
pyrene, we found that Pd(OAc)2/Cs2CO3 was superior to Pd2-
(dba)3 (dba ) trans,trans-dibenzylidenacetone) with either
NaOtBu or K3PO4, when BINAP was used as the ligand and
the reaction was carried out in toluene at 80 °C. The catalytic
system of 10 mol % Pd(OAc)2, 15 mol % racemic BINAP,
with 1.5 equiv of the base Cs2CO3 in toluene at 80 °C gave
88% conversion of 1-aminopyrene and 80% isolated yield
of the coupled product in 16 h. For the opposite strategy of
coupling between protected dG and 1-bromopyrene, we
found that similar conditions with an increase in BINAP to
70 mol % gave 83% conversion of 1-bromopyrene, though
the isolated yield was 57%.11 Allowing the reaction to
continue for a longer period and increasing the temperature
up to 100 °C were not helpful and led to partial decomposi-
tion of the product. While the reaction of 2-bromo dG with
1-aminopyrene provided a much better yield, an attractive
feature of the coupling between dG and 1-bromopyrene is
that it reduces a step.
With these encouraging results, we attempted coupling of
the protected dG with 1-bromo-8-nitropyrene (Table 1).
Table 1. Comparison of Coupling of Protected dG with
1-bromo-8-nitropyrene
Pd reagent
(mol %)
ligand temp time
yield
(%)
base
(mol %) (°C)
L-2 (30) 80
Pd2(dba)3 (10) Cs2CO3 L-2 (30) 100
(h)
1
2
3
4
5
6
7
Pd2(dba)3 (10) K3PO4
16
16
3
<30
15
Pd(OAc)2 (2)
P-3 (0.5)
P-3 (0.5)
Pd(OAc)2 (10) Cs2CO3 L-1 (70)
Pd2(dba)3 (10) tBuONa L-1 (70)
tBuONa L-3 (4)
tBuONa L-4
tBuONa L-5
80
60
60
80
80
decomp
<30
<30
6
6
8
3
88
multiple
products
a Key: L-1 ) (()-BINAP; L-2 ) 2-(dicyclohexylphosphino)-2′-(N,N-
dimethylamino)-1,1′-biphenyl;
P-3 ) [{PdBrL*}2]; L* ) L-4 or L-5; L-4 ) P(1-Ad)tBu2; L-5 ) PtBu3
Lakshman successfully applied the electron-rich ligand,
2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)-1,1′-bi-
phenyl), L2, with Pd2(dba)3 and K3PO4 in 1,2-DME for the
synthesis of N6-aryl dA adducts,8a whereas Rizzo achieved
a decent yield of the C8-dG arylamine adducts using the
same.8d However, coupling of protected dG with 1-bromo-
8-nitropyrene proceeded very slowly to ∼30% in 16 h (entry
1, Table 1), whereas changing the base to Cs2CO3 and
increasing the temperature to 100 °C decreased the yield to
15% (entry 2, Table 1). The bicyclic triaminophosphine
ligand L3, used successfully by Verkade and co-workers,12
(6) For reviews, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (c) Hartwig, J. F. Acc. Chem. Res. 1998,
31, 852.
(7) For reviews on the use of Pd-catalyzed cross-coupling methods in
nucleoside synthesis, see: (a) Lakshman, M. K. J. Organomet. Chem. 2002,
653, 234. (b) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. ReV. 2003,
103, 1875.
(8) (a) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. J.
Am. Chem. Soc. 1999, 121, 6090. (b) Bonala, R. R.; Shishkina, I. G.;
Johnson, F. Tetrahedron Lett. 2000, 41, 7281. (c) Lakshman, M. K.; Gunda,
P. Org. Lett. 2003, 5, 39. (d) Wang, Z.; Rizzo, C. J. Org. Lett. 2001, 3,
565. (e) Schoffers, E.; Olsen, P. D.; Means, J. C. Org. Lett. 2001, 3, 4221.
(f) Meier, C.; Gra¨sl, S. Synlett 2002, 802. (g) Gillet, L. C. J.; Scha¨rer, O.
D. Org. Lett. 2002, 4, 4205. (h) Bonala, R.; Tawde, D.; Torres, M. C.;
Iden, C. R.; Johnson, F. Chem. Res. Toxicol. 2002, 15, 1489.
(9) (a) Harwood, E. A.; Hopkins, P. B.; Sigurdsson, S. T. J. Org. Chem.
2000, 65, 2559. (b) Harwood, E. A.; Sigurdsson, S. T.; Edfeldt, N. B. F.;
Reid, B. R.; Hopkins, P. B. J. Am. Chem. Soc. 1999, 121, 5081. (c) De
Riccardis, F.; Johnson, F. Org. Lett. 2000, 2, 193.
(11) After completion of this work but before submission of our
manuscript, we became aware of a preprint (Lakshman, M. K.; Ngassa, F.
N.; Bae, S.; Buchanan, D. G.; Hahn, H.-G.; Mah, H. J. Org. Chem., in
press) in which the coupling efficiency between 1-bromopyrene/protected
dG and 1-aminopyrene/protected 2-Br-dI had been compared. The yield
(10) De Riccardis, F.; Bonala, R. R.; Johnson, F. J. Am. Chem. Soc.
1999, 121, 10453.
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Org. Lett., Vol. 5, No. 16, 2003