Synthesis of 8-heteroaryl-2′-deoxyguanosine derivatives

Article abstract of DOI:10.1055/s-2007-1077795

We describe the synthesis of 8-heteroaromatic-2′-de-oxyguanosine analogues using Suzuki-Miyaura or Stille conditions. Unprotected and protected 8-bromo-2′-deoxyguanosine was coupled with commercially available heteroarylboronic acids or the trialkyltin de

Full text of DOI:10.1055/s-2007-1077795

1510
LETTER
Synthesis of 8-Heteroaryl-2¢-deoxyguanosine Derivatives
S
ynthesis of 8-(H
e
e
tAr)
d
G D
e
r
Department of Chemistry, College of Natural Sciences, University of Puerto Rico, Río Piedras Campus, San Juan 00931, Puerto Rico
Fax +1(787)7568242; E-mail: jmrivortz@mac.com
Received 14 December 2007
pense, reported instability12 and relative scarcity of com-
Abstract: We describe the synthesis of 8-heteroaromatic-2¢-de-
mercially available, functionalized 2-pyridyl boronic
oxyguanosine analogues using Suzuki–Miyaura or Stille condi-
acids we decided to use Stille conditions as an alternative
tions. Unprotected and protected 8-bromo-2¢-deoxyguanosine was
coupled with commercially available heteroarylboronic acids or the
method.13 This is not without precedent since the Stille
trialkyltin derivatives of 2-pyridylbromides either with or without methodology has been used for 2-pyridylstannane cou-
plings to various aromatic skeletons14 including a number
microwave irradiation in good yields.
of purine analogues.15 Nonetheless, to the best of our
Key words: Stille reaction, nucleosides, nucleobases, palladium,
coupling
knowledge it has never been used to make 8-(HetAr)dG
derivatives. In our hands, when we tried to couple het-
eroaromatics to 3¢,5¢-isobutyric ester of 8-bromo-2¢-de-
oxyguanosine (3¢,5¢-i-Bu-8-BrdG) using heteroaromatic
tin compounds, tetrakistriphenylphosphinepalladium in
refluxing toluene,15f the sole reaction product was that de-
rived from replacement of the bromide in the substrate
with a hydrogen atom. Under these conditions the reaction
is extremely sluggish and on this substrate dehalogenation
and hydrogenation ensues.
The development of efficient strategies for the synthesis
of nucleoside analogues is of great importance due to their
potential uses in biological applications. For example,
many nucleoside analogues have found uses as antibiotics
and antivirals,2 as probes for nucleic acid structure3 and as
chain terminators for DNA sequencing.4 Our main interest
is in guanine and its derivatives, which arises from the fact
that they can self-associate to form macrocyclic, planar
tetramers known as G-tetrads. These further associate
through p-stacking interactions to form G-quadruplexes
(GQ). These GQ can be formed from individual guanine
subunits or from G-rich oligonucleotides that fold up into
a variety of quadruplex structures.5 The cation-templated
self-assembly of guanosines into G-quadruplexes has
been recognized since the 1960s.6 More recent studies of
G-quadruplex formation have been in diverse areas such
as cancer research and nanotechnology.5,7 We have dem-
onstrated the aggregation of 8-aromatic-2¢-deoxygua-
nosine analogues in organic solvents8 and have shown
their selective binding of cations in some cases.9 We are
particularly interested in the synthesis of 8-heteroaromat-
ic-2¢-deoxyguanosine [8-(HetAr)dG] derivatives. Het-
eroatoms and functional groups in the heteroaryl moieties
can be used to increase the number of H bonds. We have
shown that functional groups within an 8-phenyl ring can
lead to supramolecular complexes with higher stability.8
Recently, the coupling of heteroaromatics to various gua-
nine analogues has been reported using Stille conditions:
refluxing in xylene at 150 °C, tetrakistriphenyl phos-
phinepalladium and triphenylbismuth as a co-ligand.15a
However, this work which parallels ours does not try the
coupling reaction on 3¢,5¢-i-Bu-8-BrdG.
Herein we report two convenient methods for the direct
functionalization of the C-8 position of 2¢-deoxygua-
nosine with heteroaromatic substituents either on 8-BrdG
using commercially available boronic acids (Suzuki–
Miyaura conditions) or via 2-pyridylstannanes and (Stille
conditions) upon 3¢,5¢-i-Bu-8-BrdG. The Stille reaction
on this substrate is accompanied by a competitive side re-
action, which by taking measures to increase the rate of
Stille Coupling, can be significantly reduced. The meth-
odology presented not only allows us to make a series of
target molecules which we believe will have novel su-
pramolecular properties but it should also be useful to oth-
ers who wish to functionalize the C-8 position of guanine
and its analogues.
Since Shaughnessy’s method10 of using the easily pre-
pared 8-bromo-2¢-deoxyguanosine (8-BrdG)11 and com-
mercially available boronic acids had proven successful in
the synthesis of 8-aromatic-2¢-deoxyguanosine analogues
(8-ArdG),8 we decided to apply it to the synthesis of 8-
(HetAr)dG targets. However, although the method is use-
ful in the coupling of a variety of heterocycles vide infra,
we quickly realized that we needed to use a different
method to couple the 2-pyridyl moiety. Because of the ex-
Boronic acids (1a–c) were found to couple efficiently to
8-BrdG using the Shaughnessy method (Scheme 1,
Table 1, entries 1–3) to yield the 8-(HetAr)dG derivatives
2a–c.16
It was found, however, that the coupling reaction was very
inefficient with the boronic acids 1d–f. Since it has been
reported that Suzuki couplings can be extremely efficient
under microwave irradiation,17 we modified the method-
ology by treating 8-BrdG with boronic acids 1d–f in aque-
ous MeCN–DMF mixtures under microwave irradiation,
obtaining the 8-(HetAr)dG products (2d–f, entries 4–6).18
SYNLETT 2008, No. 10, pp 1510–1514
x
x
.x
x
.2
0
0
8
Advanced online publication: 19.05.2008
DOI: 10.1055/s-2007-1077795; Art ID: S10207ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 8-(HetAr)dG Derivatives
1511
(i for a, b, c)
H2N
MeCN, H2O,
80 °C
NH
N
RO
O
1a–f
8-BrdG
O
N
ArB(OH)2,
Pd(OAc)2,
TPPTS,
RO
N
(ii for d, e, f)
Ar
8-ArdG
2a–f R = H
Na2CO3
MeCN, DMF,
H2O, MW (100 W) ,
120 °C
(Me2CHCO)2O,
Et3N, DMAP,
MeCN, r.t.
X
X
O
N
Ar =
a
b x = S
c x = O
d x = S
e x = O
f
8-ArdG
3a–f R = COi-Pr
Scheme 1 Synthesis of 8-(HetAr)dG derivatives
Riva-Toniolo,15b where they describe the solid-phase re-
action of 8-bromo-2,6-diaminopurines with various orga-
nostannanes. The initial coupling under homogeneous
conditions used DMF as the solvent, copper(II) oxide as
additive and much less of the ligand, bisdiphenylphosphi-
nopropane (DPPP). We found that the reaction gave a
mixture of the debrominated 7 and coupled product 4a in
a 1:1 ratio (entry 2, Table 2). Furthermore, 4a turned out
to be a 1:1 mixture of diastereomers as determined by 1H
and 13C NMR, indicating no diastereoselectivity.
However, upon changing the additive to Cu(I)oxide15b and
the equivalents of additive to two, we observed a signifi-
cant improvement in the overall rate of the reaction and on
the ratio of the two products (7/4a, entry 3).
Table 1 Results for the Synthesis of 8-(HetAr)dG Derivatives from
Commercially Available Boronic Acids and 8-BrdG
Entry
Boronic acid Product, yield (%)c Ester, yield (%)c
1
2
3
4
5
6
1aa
1ba
1ca
1db
1eb
1fb
2a, 79
2b, 88
2c, 81
2d, 77
2e, 82
2f, 94
3a, 89
3b, 91
3c, 65
3d, 89
3e, 90
3f, 80
a Conditions i, see Scheme 1.
b Conditions ii, see Scheme 1
c Isolated yield.
Changing the ligand to triphenylarsine, which has weak
donicity, led to improved yields of 4a (entry 4) with fur-
ther improvement by changing the solvent to N-meth-
ylpyrrolidinone (NMP, entry 5). The overall optimal
combination of ligand and solvent was DPPP with NMP
(entry 6). Under these conditions reducing the amount of
additive [Cu(I)O], reduction in the initial amount of tin
compound added or increasing the concentration of ligand
(DPPP) had adverse effects on the rate of formation of the
required product (data not shown). These results are in ac-
cord with those of other groups, who have sought to in-
crease the rate of the Stille coupling reaction.15b–e,13b
H2N
OR2
R = COi-Pr
NH
N
N
X
3',5'-i-Bu-8-BrdG
R1
O
O
RO
see Table 2 for
conditions
N
N
RO
6a–d X = SnBu3
Ar
OR2
i) n-BuLi, THF,
hexane, –78 °C
ii) Bu3SnCl, –78 °C
N
R1
Ar =
H
7
These results encouraged us to attempt the synthesis of
more challenging 8-(2Py)dG targets. The protected bro-
mopyridines 5b–d were converted into the tributyltin de-
rivatives 6b–d. Each of these was coupled to 3¢,5¢-i-Bu-8-
BrdG as outlined in Table 2 (entries 7–9).20 As can be
seen the coupling reaction proceeds with moderate to
good yields in all cases.
5a–d X = Br
4a–d
a R1 = Me, R2 = Bn
b R1 = Me, R2 = PMB
c R1 = H, R2 = PMB
d R1 = H, R2 = (CH2)2TMS
Scheme 2 Synthesis of 3¢,5¢-i-Bu-8-(2Py)dG analogues
We have applied a set of conditions that make the rate of
the Stille coupling reaction competitive to a problematic
side reaction, obtaining reasonable yields of the target
molecules. Using this method or the previously reported
Suzuki–Miyaura conditions and a modification of these,
we are now able to synthesize a library of 8-(HetAr)dG
derivatives. We expect that these methodologies should
also be useful to others who wish to attach functional
groups to the C-8 position of purines.
As shown in Scheme 1, these 8-(HetAr)dG compounds
were converted into their isobutyric esters19 3a–f for fu-
ture studies of their self-assembly in organic solvent.
We next turned our attention to the synthesis of target
molecule 4a (Scheme 2). The starting secondary alcohol
was protected as the benzyl ether 5a. This was converted
into the tributyltin compound 6a in good yield. We ap-
plied a modification of the method reported by Brill and
Synlett 2008, No. 10, 1510–1514 © Thieme Stuttgart · New York

1512
G. Hobley et al.
LETTER
Table 2 Coupling of 2-Pyridyl Stannanes to 3¢,5¢-i-Bu-8-BrdG under Various Conditions
Entrye
Tin compda Additive
(equiv)
Reaction time Ligand
(h)
Solvent
Conversion
(%)c
Ratio 7/4a
Yield
(%)
(equiv)b
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6a
6b
6c
6d
none
3.5
DPPP (0.66)
DPPP (0.66)
DPPP (1)
AsPh3 (2)
AsPh3 (2)
DPPP (1)
DPPP (1)
DPPP (1)
DPPP (1)
DMF
DMF
DMF
DMF
NMP
NMP
NMP
NMP
NMP
33
nd
1.2: 1c
1: 1d
1: 6.3c
1: 6.0c
1: 6.2c
1: 7.7c
na
Nd
CuO (1)
Cu2O (2)
Cu2O (2)
Cu2O (2)
Cu2O (2)
Cu2O (2)
Cu2O (2)
Cu2O (2)
14
1
4a 39d
4a 70c
4a 57c
4a 59c
4a 74d
4b 80d
4c 60d
4d 61d
>98
>98
>98
>98
nd
1
1
1
1
1
nd
na
1
nd
na
a In all cases, 2.0 equiv were used.
b With respect to the palladium.
c Calculated by HPLC analysis of the crude reaction mixtures; (nd) not done; (na) not applicable.
d Isolated yield.
e Other conditions: 3¢,5¢-i-Bu-8-BrdG (50 mg in 490 mL of solvent), 15 mol% Pd(OAc)2, 115 °C.
(11) (a) Gillet, L. C. J.; Scharer, O. D. Org. Lett. 2002, 4, 4205.
(b) Gannett, P. M.; Sura, T. P. Synth. Commun. 1993, 23,
1611.
(12) (a) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004,
45, 685. (b) Molander, G. A.; Biolatto, B. J. Org. Chem.
2003, 68, 4302.
Acknowledgment
We thank the NIH-SCoRE program for financial support, the Natio-
nal Science Foundation EPSCoR program for a graduate fellowship
to V.G. and the NASA PR Space Grant Consortium as well as
PRIDCO for a graduate fellowship to M.C.R.S.
(13) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(b) Farina, V. Pure Appl. Chem. 1996, 68, 73. (c) For a
recent computational analysis of the Stille Reaction,
including ligand and solvent effects, see: Alvarez, R.; Faza,
O. N.; Cardenas, D. J.; De Lera, A. R. Adv. Synth.Catal.
2007, 349, 887. (d) Alvarez, R.; Faza, O. N.; Lopez, C. S.;
De Lera, A. R. Org. Lett. 2006, 8, 35.
(14) (a) Champouret, Y. D. M.; Chaggar, R. K.; Dadhiwala, I.;
Fawcett, J.; Solan, G. A. Tetrahedron 2006, 62, 79.
(b) Galaup, C.; Couchet, J. M.; Bedel, S.; Tisnes, P.; Picard,
C. J. Org. Chem. 2005, 70, 2274. (c) Lee, S. H.; Jang, B. B.;
Kafafi, Z. H. J. Am. Chem. Soc. 2005, 127, 9071.
(d) Gronowitz, S.; Bjork, P.; Malm, J.; Hornfeldt, A.-B.
J. Organomet. Chem. 1993, 460, 127. (e) Zoppellaro, G.;
Enkelmann, V.; Geies, A.; Baumgarten, M. Org. Lett. 2004,
6, 4929. (f) Bour, C.; Suffert, J. Org. Lett. 2005, 7, 653.
(g) Kim, D. H.; Ohshita, J.; Lee, K. H.; Kunugi, Y.; Kunai,
A. Organometallics 2006, 25, 1511.
References and Notes
(1) Current address: Dublin City University, Biomedical
Diagnostics Institute, Glasnevin, Dublin 9, Ireland.
(2) (a) De Clercq, E.; Field, H. J. Br. J. Pharmacol. 2005, 147,
1. (b) Simons, C. Nucleoside Mimetics: Their Chemistry and
Biological Properties, 1st ed., Vol. 3; Gordon and Breach:
Amsterdam, 2001.
(3) (a) Benner, S. A. Acc. Chem. Res. 2004, 37, 784. (b)Henry,
A. A.; Romesberg, F. E. Curr. Opin. Chem. Biol. 2003, 7,
727. (c) Kool, E. T. Acc. Chem. Res. 2002, 35, 936.
(d) Kool, E. T.; Morales, J. C.; Guckian, K. M. Angew.
Chem. Int. Ed. 2000, 39, 990.
(4) França, L. T. C.; Carrilho, E.; Kist, T. B. L. Q. Rev. Biophys.
2002, 35, 169.
(5) Burge, S.; Parkinson, G. N.; Hazel, P.; Todd, A. K.; Neidle,
S. Nucleic Acids Res. 2006, 34, 5402.
(15) (a) Arsenyan, P.; Ikaunieks, M.; Belyakov, S. Tetrahedron
Lett. 2007, 48, 961. (b) Brill, W. K. D.; Riva-Toniolo, C.
Tetrahedron Lett. 2001, 42, 6515. (c) Mamos, P.; Van
Aerschot, A. A.; Weyns, N. J.; Herdewijn, P. A. Tetrahedron
Lett. 1992, 33, 2413. (d) Kaucher, M. S.; Davis, J. T.
Tetrahedron Lett. 2006, 47, 6381. (e) Chi, T.; Keane, C.;
Eaton, B. E. Nucleosides Nucleotides 1995, 14, 1631.
(f) Sessler, J. L.; Wang, B.; Harriman, A. J. Am. Chem. Soc.
1995, 117, 704. (g) Ozola, V.; Persson, T.; Gronowitz, S.;
Horfeldt, A.-B. J. Heterocycl. Chem. 1995, 32, 863.
(h) Moriarty, R. M.; Epa, W. R.; Awasthi, A. K. Tetrahedron
Lett. 1991, 31, 5877.
(6) Gellert, M.; Lipsett, M. N.; Davies, D. R. Proc. Natl. Acad.
Sci. U.S.A. 1962, 48, 2013.
(7) (a) Riou, J. F.; Morjani, H.; Trentesaux, C. Ann. Pharm. Fr.
2006, 64, 97. (b) Davis, J. T. Angew. Chem. Int. Ed. 2004,
43, 668. (c) Pitchiaya, S.; Krishnan, Y. Chem. Soc. Rev.
2006, 35, 1111. (d) Feldkamp, U.; Niemeyer, C. M. Angew.
Chem. Int. Ed. 2006, 45, 1856. (e) Beissenhirtz, M. K.;
Willner, I. Org. Biomol. Chem. 2006, 4, 3392.
(8) Gubala, V.; Betancourt, J. E.; Rivera, J. M. Org. Lett. 2004,
6, 4735.
(9) Gubala, V.; De Jesus, D.; Rivera, J. M. Tetrahedron Lett.
2006, 47, 1413.
(10) Western, E. C.; Daft, J. R.; Johnson, E. M.; Gannett, P. M.;
(16) Suzuki couplings were performed according to the
procedures outlined in ref. 8 and 10.
Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767.
Analytical Data
Compound 2a: yield 79% (391 mg, 1.14 mmol); mp 225 °C.
1H NMR (300 MHz, DMSO-d6): d = 10.89 (br s, 1 H), 8.85
Synlett 2008, No. 10, 1510–1514 © Thieme Stuttgart · New York

LETTER
(d, J = 2 Hz, 1 H), 8.71 (dd, J = 5, 1 Hz, 1 H), 8.09 (dt, J = 8,
Synthesis of 8-(HetAr)dG Derivatives
1513
(neat): 1688, 1619, 1527, 1446, 1379, 951 cm–1.
2 Hz, 1 H), 7.59 (dd, J = 8, 5 Hz, 1 H), 6.50 (s, 2 H), 6.06 (t,
J = 7 Hz, 1 H), 5.19 (d, J = 5 Hz, 1 H), 4.96 (t, J = 6 Hz, 1
H), 4.33 (br m, 1 H), 3.80 (m, 1 H), 3.64 (m, 1 H), 3.53 (m,
Compound 2f: grey solid, yield 94% (45 mg, 135 mmol). 1H
NMR (500 MHz, DMSO-d6): d = 10.76 (br s, 1 H), 8.17 (s,
1 H), 7.86 (t, J = 1 Hz, 1 H), 6.87 (br d, J = 1 Hz, 1 H), 6.43
(br s, 2 H), 6.17 (t, 1 H), 5.22 (d, 1 H), 5.00 (t, 1 H), 4.40 (br
dt, J = 3 Hz, 1 H), 3.81 (m, 1 H), 3.64 (m, 1 H), 3.55 (m, 1
1 H), 3.17 (m, 1 H), 2.08 (ddd, J = 13, 6, 2 Hz, 1 H). 13
C
NMR (80 MHz, DMSO-d6): d = 174.1, 173.6, 153.7, 151.1,
149.6, 118.8, 115.9, 83.3, 79.8, 72.1, 61.1, 31.9, 31.2, 27.1,
16.5. IR (neat): 3206, 1677, 1631, 1560, 1244 cm–1. Anal.
Calcd for C15H16N6O4: C, 52.32; H, 4.68; N, 24.41. Found:
C, 51.65; H, 4.73; N, 24.16.
Compound 2b: white solid, yield 88% (164 mg, 304 mmol);
mp 203 °C. 1H NMR (500 MHz, DMSO-d6): d = 10.87 (s, 1
H), 8.05 (m, 1 H), 7.97 (m, 1 H), 7.94 (s, 1 H), 7.46 (m, 2 H),
6.59 (s, 2 H), 6.45 (t, J = 7 Hz, 1 H), 5.24 (d, J = 5 Hz, 1 H),
5.04 (t, J = 6 Hz, 1 H), 4.46 (m, 1 H), 3.88 (q, J = 9, 5 Hz, 1
H), 3.72 (m, 1 H), 3.62 (m, 1 H), 3.27 (m, 1 H), 2.15 (m, 1
H). 13C NMR (125 MHz, DMSO-d6): d = 157.1, 153.7,
152.8, 141.9, 132.6, 129.3, 128.8, 128.6, 117.8, 88.5, 85.2,
71.8, 62.7, 37.1. IR (neat): 2928, 1679, 1631, 1101, 940
cm–1.
Compound 2c: grey solid, yield 81% (179.4 mg, 468.0
mmol). 1H NMR (500 MHz, DMSO-d6): d = 10.89 (br s, 1 H),
7.79 (br d, J = 7 Hz, 1 H), 7.70 (br d, J = 8 Hz, 1 H), 7.46 (br
s, 1 H), 7.43 (br t, J = 8 Hz, 1 H), 7.36 (br t, J = 7 Hz, 1 H),
6.57 (br s, 2 H), 6.50 (t, 1 H), 5.25 (br s, 1 H), 4.97 (br s, 1
H), 4.45 (br s, 1 H), 3.85 (br s, 1 H), 3.68 (m, 1 H), 3.54 (m,
1 H), 3.23 (quin, J = 7 Hz, 1 H), 2.17 (br ddd, J = 7 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 157.1, 154.8, 154.0,
152.6, 146.5, 137.9, 128.2, 126.2, 124.2, 122.4, 118.3, 11.9,
108.5, 88.4, 84.9, 71.6, 62.5, 37.7. IR (KBr): 3144, 2949,
1678, 1566, 750 cm–1.
H), 3.22 (q, J = 7 Hz, 1 H), 2.09 (ddd, J = 7, 3 Hz, 1 H). 13
C
NMR (125 MHz, DMSO-d6): d = 157.3, 153.6, 152.6, 144.6,
143.3, 140.9, 117.6, 117.0, 111.6, 88.4, 84.7, 71.4, 62.5,
37.2. IR (KBr): 3341, 3143, 2919, 1678, 1568, 877 cm–1.
(19) Esterifications were performed according to the procedures
outlined in ref. 8.
Analytical Data
Compound 3a: yield 89% (63.0 mg, 129 mmol); mp 126 °C.
1H NMR (500 MHz, DMSO-d6): d = 11.0 (br s, 1 H), 8.88 (d,
J = 2 Hz, 1 H), 8.74 (dd, J = 5, 1 Hz, 1 H), 8.10 (d, J = 8 Hz,
1 H), 7.68 (dd, J = 5, 8 Hz, 1 H), 6.61 (s, 2 H), 6.13 (t, J = 7
Hz, 1 H), 5.50 (q, J = 3 Hz, 1 H), 4.45 (dd, J = 11, 5 Hz, 1
H), 4.30 (dd, J = 11, 7 Hz, 1 H), 4.20 (m, 1 H), 3.57 (q, J = 7
Hz, 1 H), 2.57 (m, 2 H), 2.44 (q, J = 5 Hz, 1 H), 1.12 (d, J = 2
Hz, 1 H) 1.10 (s, 6 H), 1.08 (s, 3 H). 13C NMR (125 MHz,
DMSO-d6): d = 176.0, 175.7, 156.7, 153.3, 152.1, 150.2,
139.3, 144.2, 136.5, 126.3, 123.6, 117.4, 84.72, 81.8, 74.7,
63.5, 34.0, 33.1, 33.0, 18.71, 18.68, 18.60, 18.59. IR (neat):
1727, 1689, 1627, 1150 cm–1. Anal. Calcd for C23H28N6O6:
C, 57.02; H, 5.82; N, 17.35. Found: C, 54.86; H, 5.99; N,
15.51.
Compound 3b: yield 91% (128 mg, 237 mmol); mp 201 °C.
1H NMR (500 MHz, DMSO-d6): d = 10.83 (s, 1 H), 8.01 (m,
1 H), 7.93 (m, 2 H), 7.42 (m, 2 H), 6.54 (s, 2 H), 6.41 (t, J = 7
Hz, 1 H), 5.00 (t, J = 6 Hz, 1 H), 4.42 (m, 1 H), 3.68 (m, 1
H), 3.57 (m, 1 H), 3.23 (m, 1 H), 2.53 (m, 2 H), 2.09 (m, 1
H), 1.10 (m, 6 H), 1.05 (m, 6 H). 13C NMR (125 MHz,
DMSO-d6): d = 206.9, 175.8, 175.6, 156.9, 153.7, 153.0,
141.4, 140.1, 139.8, 132.9, 126.0, 125.3, 125.0, 122.7,
117.8, 88.3, 84.6, 71.2, 62.1, 37.2, 31.1, 18.5, 18.4. IR
(neat): 1734, 1683, 1635, 1597, 1190, 1156 cm–1. Anal.
Calcd for C26H29N5O6S: C, 57.87; H, 5.42; N, 12.96. Found:
C, 58.03; H, 5.67; N, 12.59.
(17) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(18) General Procedure for a Microwave-Assisted Suzuki
Coupling Using the Synthesis of Compound 2d as an
Example
Palladium(II) acetate (2.10 mg, 9.30 mmol), TPPTS (13.0
mg, 23.1 mmol), Na2CO3 (69.5 mg, 656 mmol) and 8-BrdG
(125 mg, 345 mmol) were placed in a microwave reaction
vessel. To this was added H2O–MeCN–DMF (2:1:1). The
corresponding boronic acid (0.5 equiv of 1d) was added and
the mixture irradiated with microwaves at 100 W, 120 °C
with constant cooling for 5 min. The addition of the boronic
acid and microwave irradiation was repeated until TLC
revealed that the starting material was consumed. The
reaction mixture was then poured into H2O (25 mL) and pH
was adjusted to 6–7 (0.1 M HCl). The precipitate formed
was stirred at 0 °C for another 30 min, filtered, and dried in
vacuo to give compound 2d as a solid.
Compound 3c: yellow solid, yield 65% (133.8 mg, 256
mmol). 1H NMR (500 MHz, DMSO-d6): d = 11.04 (br s, 1 H),
7.78 (d, J = 7 Hz, 1 H), 7.69 (d, J = 8 Hz, 1 H), 7.44 (br s, 1
H), 7.43 (br t, J = 8 Hz, 1 H), 7.36 (t, J = 7 Hz, 1 H), 6.66 (br
s, 2 H), 6.65 (m, 1 H), 5.56 (br d, 1 H), 4.45 (br d, 1 H), 4.28
(br d, 1 H), 4.24 (m, 1 H), 3.58 (br quin, 1 H), 2.61 (br quin,
J = 7 Hz, 1 H), 2.50 (m, 1 H), 2.47 (m, 1 H), 1.14 (d, J = 7
Hz, 1 H), 1.05 (d, 1 H). 13C NMR (125 MHz, DMSO-d6):
d = 176.8, 176.5, 157.8, 155.0, 154.5, 152.8, 146.6, 138.1,
128.3, 126.42, 124.41, 122.6, 118.5, 112.0, 108.5, 85.3,
82.5, 75.3, 64.3, 35.2, 33.9, 33.8, 19.3, 19.3. IR (KBr): 3308,
3138, 2973, 2935, 2877, 1737, 1687, 1570, 1258, 751 cm–1.
Compound 3d: yield 89% (113 mg, 231 mmol); mp 134 °C.
1H NMR (500 MHz, DMSO-d6): d = 10.85 (s, 1 H), 7.76 (d,
J = 5 Hz, 1 H), 7.48 (d, J = 5 Hz, 1 H), 7.10 (dd, J = 5, 4 Hz,
1 H), 6.53 (s, 2 H), 6.32 (t, J = 7 Hz, 1 H), 5.50 (m, 1 H), 4.32
(m, 1 H), 4.30 (m, 1 H), 4.20 (m, 1 H), 3.64 (m, 1 H), 2.57
Analytical Data
Compound 2d: yield 77% (88.2 mg, 265 mmol). 1H NMR
(500 MHz, DMSO-d6): d = 10.81 (s, 1 H), 7.75 (d, J = 6 Hz,
1 H), 7.50 (d, J = 4 Hz, 1 H), 7.22 (dd, J = 5, 4 Hz, 1 H), 6.47
(s, 2 H), 6.27 (t, J = 8 Hz, 1 H), 5.20 (d, J = 5 Hz, 1 H), 4.96
(t, J = 5 Hz, 1 H), 4.39 (d, J = 3 Hz, 1 H), 3.83 (t, J = 3 Hz,
1 H), 3.64 (m, 1 H), 3.54 (m, 1 H), 3.33 (m, 1 H), 2.09 (m, 1
H). 13C NMR (125 MHz, DMSO-d6): d = 156.9, 153.8,
153.0, 141.4, 140.1, 139.8, 132.9, 126.0, 125.3, 125.0,
122.7, 117.8, 88.3, 84.6, 71.2, 62.1, 31.1. IR (neat): 1687,
1612, 1437, 999 cm–1.
(m, 2 H), 2.43 (m, 1 H), 1.11 (m, 6 H), 1.05 (m, 6 H). 13
C
NMR (125 MHz, DMSO-d6): d = 176.6, 176.4, 157.1, 153.8,
152.7, 141.9, 132.5, 129.4, 128.7, 128.5, 117.7, 85.3, 82.5,
75.4, 64.1, 34.5, 33.7, 19.3. IR (neat): 1733, 1672, 1593,
1152 cm–1. Anal. Calcd for C22H27N5O6S: C, 53.98, H, 5.56;
N, 14.31. Found: C, 53.84; H, 6.01; N, 14.27.
Compound 3e: yield 90% (111 mg, 234 mmol); mp 167 °C.
1H NMR (500 MHz, DMSO-d6): d = 10.88 (s, 1 H), 7.90 (d,
J = 5 Hz, 1 H), 6.96 (d, J = 5 Hz, 1 H), 6.69 (dd, J = 5, 4 Hz,
1 H), 6.54 (s, 2 H), 6.44 (t, J = 7 Hz, 1 H), 5.46 (m, 1 H), 4.40
(m, 1 H), 4.22 (m, 1 H), 4.16 (m, 1 H), 3.50 (m, 1 H), 2.57
Compound 2e: yield 82% (98.8 mg, 283 mmol). 1H NMR
(500 MHz, DMSO-d6): d = 11.11 (s, 1 H), 7.92 (s, 1 H), 6.96
(d, J = 4 Hz, 1 H), 6.70 (dd, J = 3, 2 Hz, 1 H), 6.56 (s, 2 H),
6.38 (t, J = 7 Hz, 1 H), 5.21 (d, J = 4 Hz, 1 H), 5.10 (br s, 1
H), 4.40 (br s, 1 H), 3.81 (t, J = 3 Hz, 1 H), 3.64 (m, 1 H),
3.51 (m, 1 H), 3.18 (m, 1 H), 2.10 (m, 1 H). 13C NMR (125
MHz, DMSO-d6): d = 152.4, 145.0, 144.9, 138.2, 120.4,
118.2, 116.8, 112.6, 111.5, 88.6, 85.3, 71.9, 62.9, 37.8. IR
Synlett 2008, No. 10, 1510–1514 © Thieme Stuttgart · New York

1514
G. Hobley et al.
LETTER
(m, 2 H), 2.41 (m, 1 H), 1.12 (m, 6 H), 1.03 (m, 6 H). 13
C
H, 6.15; N, 12.98.
NMR (125 MHz, DMSO-d6): d = 176.6, 176.3, 157.1, 153.9,
152.3, 145.1, 144.7, 138.4, 117.9, 112.9, 112.5, 85.1, 82.3,
75.3, 64.3, 35.0, 33.7, 19.3. IR (neat1): 1732, 1681, 1153,
1077, 764 cm–1. Anal. Calcd for C22H27N5O7: C, 55.81; H,
5.75; N, 14.79. Found: C, 55.44; H, 6.02; N, 14.67.
Compound 3f: yellow solid, yield 80% (228 mg, 481 mmol).
1H NMR (500 MHz, DMSO-d6): d = 10.83 (br s, 1 H), 8.14
(s, 1 H), 7.87 (t, J = 1 Hz, 1 H), 6.88 (d, J = 1 Hz, 1 H), 6.50
(br s, 2 H), 6.22 (t, 1 H), 5.49 (quin, J = 7, 4 Hz, 1 H), 4.40
(m, 1 H), 4.24 (m, 1 H), 4.19 (br ddd, J = 7 Hz, 1 H), 3.61
(quin, J = 7 Hz, 1 H), 2.59 (quin, J = 7 Hz, 1 H), 2.52 (br
quin, J = 7 Hz, 1 H), 2.43 (ddd, J = 7, 4 Hz, 1 H), 1.12 (dd,
J = 7 Hz, 1 H), 1.05 (dd, J = 7 Hz, 1 H). 13C NMR (125 MHz,
DMSO-d6): d = 176.4, 176.2, 157.0, 153.5, 152.3, 144.6,
142.7, 140.8, 117.5, 116.7, 111.3, 84.8, 82.1, 75.1, 64.0,
34.4, 33.6, 33.6, 19.2, 19.2, 19.1, 19.1. IR (KBr): 1738,
1687, 1596, 1254, 875 cm–1.
Compound 4b: white solid, yield 80% (253 mg, 398 mmol);
mp 209 °C. 1H NMR (500 MHz, DMSO-d6): d = 10.89 (s, 1
H), 8.01 (m, 2 H), 7.55 (m, 2 H), 7.28 (d, J = 8 Hz, 2 H), 6.91
(d, J = 8 Hz, 2 H), 6.54 (s, 2 H), 5.45 (m, 1 H), 4.64 (m, 1 H),
4.48 (m, 1 H), 4.45 (d, J = 14 Hz, 1 H), 4.43 (d, J = 14 Hz, 1
H), 4.07 (m, 1 H), 3.58 (m, 1 H), 2.35 (m, 1 H), 1.49 (t, J = 6
Hz, 3 H), 1.09 (d, J = 7 Hz, 6 H), 1.07 (d, J = 7 Hz, 6 H). 13
C
NMR (125 MHz, DMSO-d6): d = 176.0, 175.6, 161.4, 158.7,
156.6, 153.2, 149.0, 143.6, 138.2, 130.3, 129.09, 129.07,
122.3, 120.1, 117.4, 113.59, 113.57, 85.4, 81.4, 76.94,
76.90, 74.9, 69.7, 63.7, 55.0, 48.4, 33.9, 33.1, 30.1, 29.0,
21.4, 21.3, 18.6, 18.53, 18.49, 17.2. IR (neat): 1724, 1681,
1635, 1566, 1153, 817 cm–1. Anal. Calcd for: C33H40N6O8:
C, 61.10; H, 6.22; N, 12.96. Found: C, 60.61; H, 6.20; N,
12.88.
Compound 4c: white solid, yield 60% (192 mg, 302 mmol);
mp 182 °C. 1H NMR (500 MHz, DMSO-d6): d = 10.91 (s, 1
H), 8.00 (m, 2 H), 7.54 (m, 2 H), 7.33 (d, J = 8 Hz, 2 H), 6.93
(d, J = 8 Hz, 2 H), 6.57 (s, 2 H), 5.50 (m, 1 H), 4.65 (s, 2 H),
4.58 (s, 2 H), 4.88 (dd, J = 12, 6 Hz, 1 H), 4.29 (dd, J = 12,
7 Hz, 1 H), 4.09 (m, 1 H), 3.76 (s, 3 H), 3.50 (m, 1 H), 2.52
(m, 2 H), 2.35 (m, 1 H), 1.10 (d, J = 7 Hz, 6 H) 1.07 (d, J = 7
Hz, 6 H). 13C NMR (125 MHz, DMSO-d6): d = 176.0, 175.5,
158.8, 157.3, 156.7, 153.3, 152.7, 149.1, 143.5, 138.1,
130.0, 129.2, 122.4, 121.1, 117.3, 113.7, 85.1, 81.4, 74.8,
71.9, 71.6, 63.8, 55.0, 34.4, 33.12, 33.09, 18.7, 18.6. IR
(neat): 1734, 1691, 1629, 1588, 1571, 1249 cm–1. Anal.
Calcd for C32H38N6O8: C, 60.56; H, 6.03; N, 13.24. Found:
C, 60.65; H, 6.00; N, 13.12.
(20) General Procedure for a Stille Coupling Using the
Synthesis of Compound 4a as an Example
3¢,5¢-i-Bu-8-BrdG (50.0 mg, 103 mmol), DPPP (6.35 mg,
15.4 mmol), Pd(OAc)2 (3.45 mg, 15.4 mmol), Cu2O (29.5 mg,
206 mmol), and NMP (490 mL) were mixed. After this,
compound 6a (115 mg, 206 mmol) was added to the mixture.
The mixture was heated to 115 °C for 1 h after which HPLC
analysis of the crude reaction mixture showed that the
starting material was consumed. Therefore, the mixture was
filtered through Celite and the solvents removed under
reduced pressure. The product was isolated by column
chromatography (50% EtOAc in Et2O) yielding 4a as a
white solid.
Compound 4d: white solid, yield 61% (187 mg, 305 mmol);
mp 193 °C. 1H NMR (500 MHz, DMSO-d6): d = 10.88 (s, 1
H), 7.99 (m, 2 H), 7.56 (t, J = 7 Hz, 1 H), 7.47 (d, J = 7 Hz,
1 H), 6.55 (br s, 2 H), 5.50 (m, 1 H), 4.59 (s, 1 H), 4.47 (dd,
J = 12, 6 Hz, 1 H), 4.26 (dd, J = 12, 7 Hz, 1 H), 4.09 (m, 1
H), 3.66 (t, J = 8 Hz, 2 H), 3.49 (m, 1 H), 2.60 (m, 1 H), 2.52
(m, 1 H), 2.37 (m, 1 H), 1.14 (dd, J = 7, 3 Hz, 6 H), 1.06 (d,
Analytical Data
Compound 4a: white solid, yield 74% (47.0 mg, 75.9 mmol);
mp 169 °C. 1H NMR (500 MHz, DMSO-d6): d = 10.89 (s, 1
H), 8.02 (m, 2 H), 7.58 (m, 2 H), 7.36 (m, 4 H), 7.30 (m, 1
H), 6.54 (s, 2 H), 5.46 (m, 1 H), 4.67 (q, J = 7 Hz, 1 H), 4.53
(s, 1 H), 4.51 (s, 1 H), 4.47 (m, 1 H), 4.31 (m, 1 H), 4.06 (m,
1 H), 3.59 (m, 1 H), 2.50 (m, 2 H), 2.34 (m, 1 H), 1.53 and
1.51 (d, J = 7 Hz, 3 H), 1.15–1.06 (m, 12 H). 13C NMR (125
MHz, DMSO-d6): d = 176.0, 175.5, 161.27, 156.6, 153.2,
152.7, 149.0, 143.7, 143.6, 138.4, 138.1, 128.19, 128.17,
127.39, 127.36, 122.3, 120.1, 117.3, 85.4, 81.4, 77.3, 74.9,
70.1, 63.6, 33.9, 33.1, 21.4, 21.3, 18.7, 18.6, 18.5. IR (neat):
1732, 1690, 1631, 1587, 1156 cm–1. Anal. Calcd for
C32H38N6O7: C, 62.12; H, 6.19; N, 13.58. Found: C, 60.88;
J = 7 Hz, 6 H), 0.99 (t, J = 8 Hz, 2 H), 0.03 (s, 9 H). 13
C
NMR (125 MHz; DMSO-d6): d = 175.9, 175.5, 157.6, 156.6,
153.3, 152.7, 148.9, 143.5, 138.0, 122.2, 120.6, 117.3, 85.1,
81.4, 74.8, 72.4, 67.6, 63.8, 34.5, 33.2, 33.1, 18.69, 18.65,
17.7, –1.30. IR (neat): 1731, 1671, 1564, 1460, 1189 cm–1.
Anal. Calcd for C29H42N6O7Si: C, 56.66; H, 6.89; N, 13.67.
Found: C, 56.59; H, 6.89; N, 12.85.
Synlett 2008, No. 10, 1510–1514 © Thieme Stuttgart · New York

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