Synthesis of 6,8,9-tri- and 2,6,8,9-tetrasubstituted purines by a combination of the Suzuki cross-coupling, N-arylation, and direct C-H arylation reactions

Article abstract of DOI:10.1021/jo8018126

(Chemical Equation Presented) Novel practical methodology of synthesis of a several types of di-, tri-, and tetraarylpurine derivatives by a combination of regioselective Suzuki cross-coupling reactions and/or Cu-catalyzed N-arylation with direct C-H arylations was developed. 6,8-Diaryl- and 2,6,8-triaryl-9- isopropylpurines were prepared by one or two cross-couplings of 6-chloro- or 2,6-dichloro-9-isopropylpurine with arylboronic acids followed by Pd-catalyzed C-H arylation by aryl halides to position 8. 6-Chloropurine and adenine underwent Cu-catalyzed N-arylation to position 9 with boronic acids, followed by cross-coupling with AlMe₃ and/or C-H arylation to obtain 8,9-diaryl-6-methylpurines or 8,9-diaryladenines (accompanied by products of partial N-arylation of adenine in position 6). The methodology is suitable for construction of small libraries of modified purines.

Full text of DOI:10.1021/jo8018126

Synthesis of 6,8,9-Tri- and 2,6,8,9-Tetrasubstituted Purines by a
Combination of the Suzuki Cross-coupling, N-Arylation, and Direct
C-H Arylation Reactions
ˇ
Igor Cernˇa, Radek Pohl, Blanka Klepeta´rˇova´, and Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Gilead Sciences & IOCB Research Center, CZ-16610, Prague 6, Czech Republic
hocek@uochb.cas.cz
ReceiVed August 13, 2008
Novel practical methodology of synthesis of a several types of di-, tri-, and tetraarylpurine derivatives
by a combination of regioselective Suzuki cross-coupling reactions and/or Cu-catalyzed N-arylation with
direct C-H arylations was developed. 6,8-Diaryl- and 2,6,8-triaryl-9-isopropylpurines were prepared by
one or two cross-couplings of 6-chloro- or 2,6-dichloro-9-isopropylpurine with arylboronic acids followed
by Pd-catalyzed C-H arylation by aryl halides to position 8. 6-Chloropurine and adenine underwent
Cu-catalyzed N-arylation to position 9 with boronic acids, followed by cross-coupling with AlMe3 and/
or C-H arylation to obtain 8,9-diaryl-6-methylpurines or 8,9-diaryladenines (accompanied by products
of partial N-arylation of adenine in position 6). The methodology is suitable for construction of small
libraries of modified purines.
Introduction
activities.7 Large combinatorial libraries of several types of tri-
and tetrasubstituted purines have been prepared by heterocy-
clizations8 or by regioselective nucleophilic substitutions of
dihalopurines with amines (sometimes in combination with one
cross-coupling reaction).9,10 In contrast to simple, efficient, and
2,6,9- or 6,8,9-Trisubstituted and 2,6,8,9-tetrasubstituted
purines display a wide range of biological activities,1 such as
inhibition of protein kinases2 or tubulin polymerization,3 and
antagonist effects to receptors,4 etc. Reversine is a purine
derivative causing a dedifferentiation of muscle cells to progeni-
tor cells5 and inducing polyploidization6 of cancer cells via
inhibition of Aurora kinases. 6-Arylpurines are of particular
importance due to anti-HCV, cytostatic, and antimycobacterial
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Y.-T.; Wignall, S. M.; Rosania, G. R.; Gray, N. S.; Hanson, S. R.; Su, A. I.;
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J. Med. Chem. 2001, 44, 4497–4500. (c) Wignall, S. M.; Gray, N. S.; Chang,
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* To whom correspondence should be addressed. Phone: +420 220183324;
fax: +420 220183559.
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Y.-T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.; Kwon, S.; Norman, T. C.;
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10.1021/jo8018126 CCC: $40.75 2008 American Chemical Society
Published on Web 10/21/2008

Synthesis of Tri- and Tetrasubstituted Purines
regioselective introduction of N- or C-substituents,10 regiose-
lective introduction of C-substituents by cross-coupling reac-
tions11 is more problematic. Although 2,6- and 6,8-dihalopurines
give regioselective cross-couplings with most types of organo-
metallics and were used for the synthesis of series of several
types of disubstituted purine bases and nucleosides,12 reactions
of 2,6,8-trichloropurine proceed unselectively, giving mixtures
of products.13 Therefore, we have started out developing the
methodology of direct C-H arylation14,15 in purines as a new
strategy complementary to the cross-couplings applicable for
regioselective multiple substitutions of purine. Recently, we have
reported16 on the new C-H arylations of 6,9-disubstituted
purines to position 8 by diverse aryl halides under Pd catalysis
in absence of ligands (in analogy to Bellina’s protocol15). As a
proof of principle, this method was applied15 in combination
with two regioselective cross-coupling reactions to get two
examples of 2,6,8-trisubstituted purines. Later on, we17 and
others18 have further developed the C-H arylation for modi-
fication of unprotected nucleosides (i.e., adenosine).
Several types of cytostatic natural products (e.g., colchicine,
podophyllotoxin, and combretastatine) displaying antimitotic
effect through inhibition of tubulin polymerization possess a
common structural feature of two heavily methoxylated aromatic
rings in the vicinity. Many diverse non-natural compounds of
such and related structures (diarylpyrroles,19 -triazoles,20 -imi-
dazoles,21 -thiophenes22 etc.) were prepared and were also found
to be potent inhibitors of tubulin polymerization. Myoseverin3
is a related cytostatic purine derivative, 2,6-bis[(4-methoxy-
benzyl)amino]-9-isopropylpurine, with the same mechanism of
action. Our own study23 on analogous 2,6-diaryl- and -diben-
zylpurines did not show significant activities except for 2,6-
diarylethynylpurines. Now, we have decided to further combine
the stuctural features of three classes of cytostatic com-
poundss2,6,9-trisubstituted purines, 6-arylpurines, and com-
bretastatine analoguessand use a purine ring as a scaffold for
attachment of two or three methoxylated phenyl groups in other
positions and their combinations. Therefore, our target com-
pounds were novel 9-isopropyl-6,8-diarylpurines, -2,6,8-tri-
arylpurines, 6-methyl-8,9-diarylpurines, and 8,9-diaryladenines,
and our synthetic methodology of choice involved a combination
of the cross-coupling reactions in positions 2 and/or 6, N-
arylations in position 9, and C-H arylation in position 8.
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Results and Discussion
As mentioned above, our synthetic strategy toward the target
compounds was based on a combination of the Pd-catalyzed
Suzuki-Miyaura cross-coupling reactions of (di)halopurines
with arylboronic acids, Pd-calatyzed C-H arylations of purines
with aryl halides, and Cu-catalyzed N-arylations of 9H-pur-
ines with arylboronic acids. Therefore a set of five methoxylated
phenylboronic acids (1a-e) and four methoxylated phenyl
iodides and bromides (2a-d) has been chosen (Chart 1) as the
reagents for the particular arylations in different position.
The first class of compounds of our interest were 9-isopropyl-
6,8-diarylpurines envisaged to be prepared by a two-step
sequence of the Suzuki reaction in position 6 followed by the
C-H arylation in position 8. Thus 6-chloro-9-isopropylpurine
(3) underwent the Pd-catalyzed Suzuki-Miyaura cross-coupling
reactions with four arylboronic acids 1a-d under classical
conditions12c,23 in toluene in presence of Pd(PPh3)4 and K2CO3
to get a series of 6-aryl-9-isopropylpurines (4a-d, Scheme 1)
isolated in good yields (except for the 3,4,5-trimethoxyphenyl
derivative 4d isolated in rather moderate yield of 66%). In the
second step, each of these intermediates 4a-d was used in a
series of C-H arylation16 experiments with methoxyphenyl
halides (2a-d) to generate a small library of 16 6,8-diarylpu-
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J. Org. Chem. Vol. 73, No. 22, 2008 9049

ˇ
Cernˇa et al.
CHART 1. Set of arylboronic acids and aryl halides
the second step varied between 23 and 80% depending on the
aryl halide used. Somewhat surprisingly we did not observe
significant differences in reactivity between substituted phenyl
iodides and bromides, but the least reactive was the most
electron-rich 3,4,5-trimethoxyphenyl iodide (yields 23-40%).
The moderate yields were mostly caused by incomplete conver-
sion of the starting materials rather than by formation of side-
products.16 Formation of minor 8,8′-bis(purine) side-products16
has been observed in several cases with yields of <5%, but in
the case of reaction of 4a or 4b with 2a, the bis(purines) were
isolated in 24 and 10%, respectively (see Supporting Informa-
tion), in addition to the desired major products 5aa (64%) and
5ba (80%). The overall yields of the desired title 6,8-diarylpu-
rines 5xy over the two steps ranged from moderate (15%) to
excellent (71%), and the methodology was quite efficient for a
facile generation of the 4 × 4 library of derivatives.
SCHEME 1. Preparation of
6,8-disubstituted-9-isopropyl-9H-purines
The second class of compounds under study were 9-isopropyl-
2,6,8-triarylpurines. To access these compounds, we decided
to combine two regioselective Suzuki-Miyaura cross-couplings
with direct C-H arylation. In our previous communication, we
have demonstrated, as a proof-of-principle, on two examples
that, starting from 9-substituted 2,6-dichloropurine, one can
perform consecutively two cross-couplings followed (without
isolation of intermediates) by the C-H arylation. We have now
applied the approach for the synthesis of our target 2,6,8,9-
tetrasubstituted purines. Thus, the starting 2,6-dichloro-9-
isopropylpurine 6 was reacted successively in one pot with two
arylboronic acids, and then, without isolation, the reaction
mixture was just filtered through a pad of celite, evaporated,
and directly used for C-H arylation reaction (Scheme 2). Both
reactions were performed under the same conditions as discussed
above in the previous series of compounds. The first aryl group
was regioselectively introduced to position 6 (using arylboronic
acids 1a, 1b, and 1e), the second to position 2 (using 1a and
1b), and the third one to position 8 (using aryl halides 2a and
2b). Using this methodology, we prepared 9 examples of desired
2,6,8,9-tetrasubstituted purines (7xyz) in very good total yields
(average yield 48% over three steps). Reactions proceeded
relatively cleanly with only one major product, easily separable
from minor impurities (presumably mono- and diarylated
purines) by column chromatography.
In the third series of compounds, 6-methyl-8,9-diarylpurines,
we used a combination of N9-arylation, cross-coupling with
trimethylaluminum, and direct C-H arylation. This time the
intermediates after each step were isolated from the reaction
mixture on a pad of silica gel due to incompatible reagents used
in each step. The N9-arylations of 6-chloropurine 8 with
arylboronic acids (1a, 1b) were performed according to the
Gundersen procedure24 in presence of anhydrous Cu(OAc)2,
phenanthroline and molecular sieves in dichloromethane gave
desired products 9a and 9b in ca. 50% yields (Scheme 3).
Methylation of intermediates 9a and 9b with trimethylaluminum
was performed in analogy to literature25 in the presence of
Pd(PPh3)4 in THF to give the 6-methyl-9-arylpurines 10a and
10b in 63 and 80% yields, respectively. The last step, C-H
arylation in position 8 of 10a,b with aryl halides 2a, 2b, and
2d proceeded smoothly under the same conditions as above to
give six examples of the target compounds 11x,y in 52-97%
rines (5xy, Scheme 1). The direct C-H arylation reactions were
performed under the previously reported16 optimized conditions
in the presence of Pd(OAc)2 (without any ligand) and excess
of CuI and Cs2CO3 in DMF at 160 °C for 60 h. The yields of
(24) Bakkestuen, A. K.; Gundersen, L. L. Tetrahedron Lett. 2003, 44, 3359–
3362.
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57, 5268–5270. (b) Cesnek, M.; Hocek, M.; Holy´, A. Collect. Czech. Chem.
Commun. 2000, 65, 1357–1373.
9050 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Tri- and Tetrasubstituted Purines
SCHEME 2. Consecutive synthesis of
2,6,8-trisubstituted-9-isopropyl-9H-purines
SCHEME 3. Synthesis of
8,9-disubstituted-6-methyl-9H-purines
yielding procedure was still quite practical. The second step,
C-H arylation of 12a with 2a, led to complex mixture of three
major products. Besides the desired 8-arylated adenine 13aa,
two byproducts were also isolated arising from single (14aa)
and double (15aa) Cu-mediated N6-arylation of 13aa (Scheme
4). This phenomenon was also observed in direct C-H arylation
on adenosine,17 where partial (in this case only one-fold) N6-
arylation of the product also took place. Under the standard
conditions mentioned above, we isolated 45% of desired product
13aa and 29 (14aa) and 17% (15aa) of the byproducts (Table
1, entry 1), which were easily separable from each other by
flash chromatography. Several optimization experiments have
been performed in order to suppress the side reaction. Shortened
reaction time led to lower conversion (entry 2), whereas a lower
temperature (120 °C, Table 1, entry 3) slighty increase the yield
of desired product 13aa. Decreasing or increasing of the amount
of copper iodide did not bring any improvements (Table 1,
entries 4 and 5). The use of piperidine as base (entry 6) gave
the best selectivity and yield of formation of 8-aryladenine 13aa
(79%), accompanied only by 10% of minor product 14aa (15aa
was not observed). We took advantage of the good separation
of the three products (13, 14, and 15) to diversity-oriented
synthesis of several derivatives in parallel and used the
conditions giving good yields of all of them (Table 1, entry 3)
in arylation of 12a,b with a series of aryl halides 2a, 2b, and
2d. These six arylation reactions gave 18 compounds (Scheme
4, Table 2). The yields of the 8,9-diaryladenines 13x,y ranged
from 21 to 50%, whereas the N-arylated products 14 and 15
were isolated in 5-31% yields. It is interesting to mention that
although the arylation of 12 with mono- and dimethoxyphenyl
halides 2a and 2b produced the 8-aryladenines 13 as major
products, the reaction with trimethoxyphenyl iodide 2d led to
preferential formation of N6,8-diarylated products 14ad and
14bd (Table 2, entries 3 and 6).
yields of the third step. Again, reactions with 5-iodo-1,2,3-
trimethoxybenzene 2d gave lower conversions to give the
products 11ad and 11bd in 53 and 52%, respectively.
In the last series we focused on synthesis of 8,9-disubstituted-
adenines. The first step was N9-arylation of adenine with
arylboronic acids 1a and 1b according to the literature26 in
presence of Cu(OAc2)·H2O and TMEDA (Scheme 4). These
reactions proceeded very slowly to give the 9-aryladenines 12a,b
in moderate yields of 37 and 28%, respectively (Table 2), after
separation from unreacted starting material by a simple filtration
through a short pad of silica gel. Considering the low cost of
the starting adenine and simple separation of products, the low-
All the intermediates and final compounds were fully
characterized by NMR spectroscopy (including C,H-HSQC and
C,H-HMBC experiments for complete assignment of all signals,
(26) Yue, Y.; Zheng, Z.-G.; Wu, B.; Xia, C.-Q.; Yu, X.-Q Eur. J. Org. Chem.
2005, 515, 4–5157.
J. Org. Chem. Vol. 73, No. 22, 2008 9051

ˇ
Cernˇa et al.
SCHEME 4. Synthesis of 8,9-disubstituted-adenines
TABLE 1. Reaction of 12a with 2a. Optimization of conditions
coupling reactions of (di)chloropurines with arylboronic acids
in position(s) 6 (and 2), the Cu-catalyzed N-arylation in position
9 and direct C-H arylation in position 8. The 2-3 step synthetic
sequences in principle can be performed without isolation of
intermediates (but not one-pot due to incompatibility of the
reagents and solvents in each step). The approach is efficient
and suitable for parallel synthesis of combinatorial libraries of
purines bearing several aryl groups in different position. The
compounds under study were inactive in cytostatic activity
screening and in tubulin assay; however, the cross-couplings,
N and C-H arylations should be suitable for combination with
amination(s) in position(s) 6 (and/or 2) to generate the second
generation of compounds with a better solubility in water.
CuI
13aa 14aa 15aa
Entry T (°C) t (h)
base
(equiv)
(%)
(%)
(%)
1
2
3
4
5
6
160
160
120
120
120
150
48
21
42
42
42
14
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
piperidine
3
3
3
1
6
3
45
39
46
37
21
79
29
27
24
28
17
10
17
15
16
24
18
0
see Supporting Information). Selected examples of compounds
were also characterized by single-crystal X-ray diffraction.
Figure 1 shows the ORTEP plots for structures of compounds
7eaa, 13ad, and 15aa. It demonstrates a low steric hindrance
in the 2,6,8-arylpurines, where in 7eaa all the three aryl groups
are nearly coplanar to the purine ring. On the other hand, in
8,9-diarylpurines, the two bulky adjacent aryl groups cannot
adopt planar conformation, and the one in position 9 is
perpendicular to the purine plane (13ad and 15aa), similarly to
the two aryl groups of diarylamino group in compound 15aa.
All the title substituted purines 4, 5, 7, 10, 11, 13, 14, and
15 were subjected to biological activity screening. The cytostatic
activity in vitro (inhibition of cell growth)7a was studied on the
following cell cultures: (i) mouse leukemia L1210 cells (ATCC
CCL 219); (ii) human promyelocytic leukemia HL60 cells
(ATCC CCL 240); (iii) human cervix carcinoma HeLaS3 cells
(ATCC CCL 2.2), and (iv) human T lymphoblastoid CCRF-
CEM cell line (ATCC CCL 119). The cytostatic activities of
compounds were determined by XTT analysis. None of the
studied compounds showed any significant cytostatic effect at
c ) 1-10 µM (depending on the solubility in water). In addition,
inhibition of polymerization of tubulin27 was performed on all
the compounds and again, no significant effect was found. The
very limited solubility in water was definitely a limitation for
this class of compounds.
Experimental Section
General Procedure for Suzuki Cross-coupling Reactions of
3 with 1a-d. Toluene (5 mL) was added through a septum to an
argon-purged vial containing 6-chloro-9-isopropyl-9H-purine (3,
196.6 mg, 1 mmol), Pd(PPh3)4 (27.7 mg, 0.024 mmol), arylboronic
acid (1a-d, 1.3 mmol), and K2CO3 (172.7 mg, 1.25 mmol). The
reaction mixture was heated to 100 °C for 19 h. The solvent was
evaporated under reduced pressure. Products were isolated by flash
column chromatography (gradient elution hexanes f ethyl acetate/
hexanes 1:1).
9-Isopropyl-6-(4-methoxyphenyl)-9H-purine (4a). Yield 98%,
white crystals from CHCl3/heptane, 89-92 °C. 1H NMR (600 MHz,
CDCl3): 1.68 (d, 6H, Jvic ) 6.8, (CH3)2CH); 3.91 (s, 3H, CH3O);
4.98 (h, 1H, Jvic ) 6.8, CH(CH3)2); 7.08 (m, 2H, H-3′,5′); 8.16 (s,
1H, H-8); 8.81 (m, 2H, H-2′,6′); 8.97 (s, 1H, H-2). 13C NMR (151
MHz, CDCl3): 22.6 ((CH3)2CH); 47.1 (CH(CH3)2); 55.4 (CH3O);
114.0 (CH-3′,5′); 128.4 (C-1′); 130.9 (C-5); 131.4 (CH-2′,6′); 141.4
(CH-8); 151.9 (C-4); 152.0 (CH-2); 154.4 (C-6); 161.9 (C-4′). MS
(FAB), m/z (% relative intensity): 184 (10), 227 (40), 269 (MH+,
100). HR MS (MH+) 269.140558 (calcd for C15H16N4O 269.140236).
Anal. calcd for C15H16N4O: C, 67.15; H, 6.01; N, 20.88. Found: C,
67.07; H, 5.90; N, 20.69.
In conclusion, we have developed the synthetic strategy for
the preparation of several novel classes of tri- and tetrasubsti-
tuted purines by a combination of the Suzuki-Miyaura cross-
General Procedure for C-H Arylation of 6-Aryl-9-isopropyl-
purines 4a-d with 2a-d. DMF (6 mL) was added through a
septum to an argon-purged vial containing a 6-aryl-9-isopropyl-
TABLE 2. Synthesis of 8,9-disubstituted-adenines
9052 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Tri- and Tetrasubstituted Purines
FIGURE 1. ORTEP drawings of crystal structures of 7eaa (a), 13ad (b), and 15aa (c) with atom numbering scheme. Thermal ellipsoids are drawn
at the 50% probability level.
9H-purine (1 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol %),
CuI (571.3 mg, 3 mmol), aryl halide (2a-d, 2 mmol), and Cs2CO3
(814.6 mg, 2.5 mmol). Reaction mixture was stirred at 160 °C for
60 h and, after cooling to rt, it was diluted with chloroform (20
mL) and solvents were evaporated under reduced pressure. Products
were isolated by flash column chromatography (gradient elution
hexanes f ethyl acetate/hexanes 1:1).
General Procedure for Consecutive Synthesis of 2,6,8,9-
Tetrasubstituted Purines 7xyz. Toluene (3 mL) was added through
a septum to an argon-purged vial containing a 2,6-dichloro-9-
isopropyl-9H-purine (6, 231.1 mg, 1 mmol), arylboronic acid
(1a,1b,1e, 1.05 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol, 5 mol %),
and K2CO3 (414.6 mg, 3 mmol). Reaction mixture was heated to
100 °C for 18 h. After cooling to rt, the second arylboronic acid
(1a,1b, 2 mmol) and toluene (6 mL) were added. The reaction
mixture was heated to 100 °C for 12 h, and after being cooled to
rt it was diluted with CHCl3 (100 mL) and filtered through a pad
of celite. The solvents were evaporated, and the residue was dried
at room temperature under vacuum for 14 h. The crude reaction
mixture was transferred into a vial and Pd(OAc)2 (11.2 mg, 0.05
mmol, 5 mol %), CuI (571.3 mg, 3 mmol), aryl halide (2a,2b, 2
mmol), and Cs2CO3 (814.6 mg, 2.5 mmol) were added. The vial
was closed with a pressure cap, evacuated and filled with argon.
Then DMF (6 mL) was added under argon atmosphere, and the
reaction mixture was heated to 160 °C for 60 h. The crude mixture
was diluted with CHCl3 (50 mL), and the solvents were evaporated
9-Isopropyl-6,8-bis(4-methoxyphenyl)-9H-purine (5aa). Yield
1
52%, white crystals from CHCl3/heptane, mp 151-152 °C. H
NMR (600 MHz, CDCl3): 1.78 (d, 6H, Jvic ) 6.9, (CH3)2CH); 3.89
(s, 3H, CH3O-4′); 3.91 (s, 3H, CH3O-4′′); 4.83 (h, 1H, Jvic ) 6.9,
CH(CH3)2); 7.06 (m, 2H, H-3′,5′); 7.09 (m, 2H, H-3′′,5′′); 7.68
(m, 2H, H-2′′,6′′); 8.88 (m, 2H, H-2′,6′); 8.93 (s, 1H, H-2). 13C
NMR (151 MHz, CDCl3): 21.1 ((CH3)2CH); 49.7 (CH(CH3)2); 55.3
(CH3O-4′); 55.5 (CH3O-4′′); 113.9 (CH-3′,5′); 114.3 (CH-3′′,5′′);
122.4 (C-1′′); 128.8 (C-1′); 130.9 (C-5); 131.0 (CH-2′′,6′′); 131.4
(CH-2′,6′); 151.0 (CH-2); 153.3 (C-6); 153.9 (C-4); 154.5 (C-8);
161.3 (C-4′′); 161.6 (C-4′). MS (FAB), m/z (% relative intensity):
134 (35), 290 (5), 303 (6), 319 (5), 333 (59), 345 (6), 359 (5), 375
(MH+, 100). HR MS (MH+) 375.183958 (calcd for C22H22N4O2
375.182101). Anal. calcd for C22H22N4O2: C, 70.57; H, 5.92; N,
14.96. Found: C, 70.59; H, 5.84; N, 14.64.
(27) (a) Castoldi, M.; Popov, A. V. Protein Expr. Purif. 2003, 32, 83–88.
(b) Hamel, E. Cell Biochem. Biophys. 2003, 38, 1–21.
J. Org. Chem. Vol. 73, No. 22, 2008 9053

ˇ
Cernˇa et al.
under reduced pressure. Products 7xyz were isolated by flash
column chromatography (gradient elution 5% ethyl acetate in
hexanes f 30% ethyl acetate in hexanes).
C26H23N5O3 ·1CHCl3: C, 56.61; H, 4.22; N, 12.22. Found: C, 56.61;
H, 4.19; N, 12.08.
N6,N6,8,9-Tetrakis(4-methoxyphenyl)adenine (15aa). Yield
16%, colorless crystals from CHCl3/heptane, Rf 0.73 (EtOAc), mp
8-(3,4-Dimethoxyphenyl)-9-isopropyl-2,6-bis(4-methoxyphe-
1
215-218 °C. H NMR (600 MHz, CDCl3): 3.77 (s, 3H, CH3O-
nyl)-9H-purine (7aab). Yield 54%, white crystals from CHCl3/
1
4′′); 3.85 (s, 6H, CH3O-4′); 3.87 (s, 3H, CH3O-4′′′); 6.71 (m, 2H,
H-3′′,5′′); 6.94 (m, 4H, H-3′,5′); 7.02 (m, 2H, H-3′′′,5′′′); 7.23 (m,
2H, H-2′′,6′′); 7.25 (m, 2H, H-2′′′,6′′′); 7.29 (m, 4H, H-2′,6′); 8.43
(s, 1H, H-2). 13C NMR (151 MHz, CDCl3): 55.2 (CH3O-4′′); 55.5
(CH3O-4′); 55.6 (CH3O-4′′′); 113.6 (CH-3′′,5′′); 114.3 (CH-3′,5′);
115.0 (CH-3′′′,5′′′); 121.0 (C-5); 122.0 (C-1′′); 128.3 (C-1′′′); 128.4
(CH-2′,6′); 128.7 (CH-2′′′,6′′′); 130.4 (CH-2′′,6′′); 138.1 (C-1′);
148.8 (C-8); 152.6 (CH-2); 154.0 and 154.6 (C-4,6); 157.6 (C-4′);
159.7 (C-4′′′); 160.5 (C-4′′). IR (KBr): 2835, 1609, 1574, 1508,
1455, 1418, 1341, 1293, 1250, 1179, 1107, 1091, 1030, 838, 745,
712, 634. MS (ESI), m/z (% relative intensity): 288.3 (5), 316.4
(3), 376.3 (2), 560.3 (MH+, 100). HR MS (MH+) 560.2286 (calcd
for C33H30N5O4 560.2292). Anal. calcd for C33H29N5O4 ·0.1 CHCl3:
C, 69.56; H, 5.13; N, 12.25. Found: C, 69.83; H, 5.10; N, 12.29.
Single Crystal X-ray Structure Analysis. X-ray crystallographic
analysis of single crystals of 7eaa (colorless, 0.14 × 0.19 × 0.44
mm), 15aa (colorless, 0.18 × 0.29 × 0.60 mm), and 13ad (light
brown, 0.18 × 0.31 × 0.50 mm) was performed with Xcalibur
X-ray diffractometr with CuKR (λ)1.54180 Å), data collected at
150K (7eaa) and 298 K (15aa, 13ad). All three structures were
solved by direct methods with SIR9228 and refined by full-matrix
least-squares on F with CRYSTALS.29 The hydrogen atoms were
located in a difference map, but those attached to carbon atoms
were repositioned geometrically and then refined with riding
constraints, and all non-hydrogen atoms were refined anisotropically
in all three cases.
heptane, mp 198-201 °C. H NMR (500 MHz, CDCl3): 1.85 (d,
6H, Jvic ) 6.8, (CH3)2CH); 3.90 (s, 3H, CH3O-4′′); 3.91 (s, 3H,
CH3O-4′); 3.98 (s, 3H, CH3O-4′′′); 3.99 (s, 3H, CH3O-3′′′); 4.86
(h, 1H, Jvic ) 6.8, CH(CH3)2); 7.04 (d, 1H, J5′′′,6′′′ ) 8.2, H-5′′′);
7.05 (m, 2H, H-3′,5′); 7.08 (m, 2H, H-3′′,5′′); 7.27 (dd, 1H, J6′′′,5′′′
) 8.2, J6′′′,2′′′ ) 2.0, H-6′′′); 7.31 (d, 1H, J2′′′,6′′′ ) 2.0, H-2′′′); 8.64
(m, 2H, H-2′,6′); 9.01 (m, 2H, H-2′′,6′′). 13C NMR (125.7 MHz,
CDCl3): 21.3 ((CH3)2CH); 49.6 (CH(CH3)2); 55.35 and 55.38
(CH3O-4′,4′′); 56.09 and 56.13 (CH3O-3′′′,4′′′); 111.1 (CH-5′′′);
112.7 (CH-2′′′); 113.7 (CH-3′,5′); 113.8 (CH-3′′,5′′); 122.3 (CH-
6′′′); 122.9 (C-1′′′); 129.3 (C-5); 129.4 (C-1′′); 129.7 (CH-2′,6′);
131.5 (CH-2′′,6′′); 131.8 (C-1′); 149.3 (C-3′′′); 150.8 (C-4′′′); 152.8
(C-6); 154.3 (C-8); 154.9 (C-4); 157.0 (C-2); 161.1 (C-4′); 161.5
(C-4′′′). IR (KBr): 2937, 2909, 2839, 1608, 1566, 1513, 1462, 1376,
1305, 1248, 1165, 1027, 867, 619. MS (ESI), m/z (% relative
intensity): 316.4 (3), 469.3 (2), 511.2 (MH+, 100). HR MS (MH+)
511.23368 (calcd for C30H31N4O4 511.23453). Anal. calcd for
C30H30N4O4: C, 70.57; H, 5.92; N, 10.97. Found: C, 70.37; H, 6.09;
N, 10.62.
General Procedure for C-H Arylation of 9-Aryl-adenines
12a,b with 2a, 2b, and 2d. DMF (6 mL) was added through a
septum to an argon-purged vial containing a 9-aryl-adenine (1
mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol %), CuI (571.3 mg,
3 mmol), aryl halide (2 mmol), and Cs2CO3 (814.6 mg, 2.5 mmol),
and the reaction mixture was heated to 120 °C for 42 h. The crude
mixture was diluted with CHCl3 (50 mL), and the solvents were
evaporated under reduced pressure. Products 13xy, 14xy, and 15xy
were isolated by flash chromatography on silica gel (gradient elution
40% ethyl acetate in hexanes f ethyl acetate).
Crystal Data - 7eaa. C29H27F1N4O3, orthorhombic, space group
P212121, a ) 7.1004(1) Å, b ) 17.4319(2) Å, c ) 19.7015(2) Å,
V ) 2438.52(5) Å3, Z ) 4, M ) 498.55, 38154 reflections
measured, 4993 independent reflections. Final R ) 0.0317, wR )
0.0430, GoF ) 1.0768 for 3587 reflections with I > 2σ(I) and 336
parameters. CCDC 698313.
Crystal Data - 13ad. C21H21N5O4.CHCl3, monoclinic, space
group P21/c, a ) 10.1515(12) Å, b ) 13.1309(11) Å, c )
18.5570(17) Å, ꢀ ) 91.195(9) °, V ) 2473.1(4) Å3, Z ) 4, M )
526.80, 29663 reflections measured, 5219 independent reflections.
Final R ) 0.0488, wR ) 0.0780, GoF ) 1.1339 for 2510 reflections
with I > 2σ(I) and 308 parameters. CCDC 698558.
Crystal Data - 15aa. C33H29N5O4, triclinic, space group P1j,
a ) 9.8920(8) Å, b ) 10.9199(7) Å, c ) 15.2855(9) Å, R )
97.982(5)°, ꢀ ) 101.901(6)°, γ ) 112.999(7)°, V ) 1442.4(2) Å3,
Z ) 2, M ) 559.61, 44274 reflections measured, 6065 independent
reflections. Final R ) 0.0403, wR ) 0.0554, GoF ) 1.0621 for
4137 reflections with I > 2σ(I) and 380 parameters. CCDC 698314.
8,9-Bis(4-methoxyphenyl)-adenine (13aa). Yield 46%, white
crystals from CHCl3/heptane, Rf 0.17 (EtOAc), mp 127-130 °C.
1H NMR (600 MHz, CDCl3): 3.80 (s, 3H, CH3O-4′); 3.86 (s, 3H,
CH3O-4′′); 6.09 (bs, 2H, NH2); 6.83 (m, 2H, H-3′,5′); 7.00 (m,
2H, H-3′′,5′′); 7.22 (m, 2H, H-2′′,6′′); 7.46 (m, 2H, H-2′,6′); 8.33
(s, 1H, H-2). 13C NMR (151 MHz, CDCl3): 55.3 (CH3O-4′); 55.6
(CH3O-4′′); 113.9 (CH-3′,5′); 115.0 (CH-3′′,5′′); 119.0 (C-5); 121.4
(C-1′); 127.6 (C-1′′); 128.5 (CH-2′′,6′′); 130.6 (CH-2′,6′); 150.5
(C-8); 152.3 (C-4); 152.9 (CH-2); 154.8 (C-6); 159.7 (C-4′′); 160.8
(C-4′). IR (KBr): 3490, 3288, 3151, 2976, 2910, 2841, 1639, 1598,
1567, 1515, 1469, 1449, 1416, 1331, 1304, 1254, 1173, 1102, 1031,
839, 812, 684. MS (ESI), m/z (% relative intensity): 288.3 (20),
316.4 (9), 348.2 (MH+, 100). HR MS (MH+) 348.14454 (calcd
for C19H18N5O2 348.14550). Anal. calcd for C19H17N5O2 ·1CHCl3:
C, 51.47; H, 3.89; N, 15.0. Found: C, 51.13; H, 3.83; N, 14.86.
N6,8,9-Tris(4-methoxyphenyl)-adenine (14aa). Yield 24%,
brownish crystals from CHCl3/heptane, Rf 0.79 (EtOAc), mp 94-98
Acknowledgment. This work is a part of the research project
Z4 055 0506. It was supported by the Centre for Chemical
Genetics (LC06077) and by Gilead Sciences, Inc. (Foster City,
CA, USA).
1
°C. H NMR (600 MHz, CDCl3): 3.82 (s, 3H, CH3O-4′′); 3.83 (s,
3H, CH3O-4′); 3.87 (s, 3H, CH3O-4′′′); 6.86 (m, 2H, H-3′,5′); 6.96
(m, 2H, H-3′,5′); 7.02 (m, 2H, H-3′′′,5′′′); 7.27 (m, 2H, H-2′′′,6′′′);
7.51 (m, 2H, H-2′′,6′′); 7.70 (m, 2H, H-2′,6′); 7.75 (bs, 1H, NH);
8.48 (s, 1H, H-2). 13C NMR (151 MHz, CDCl3): 55.3 (CH3O-4′′);
55.5 and 55.5 (CH3O-4′,4′′′); 114.0 (CH-3′′,5′′); 114.3 (CH-3′,5′);
115.0 (CH-3′′′,5′′′); 119.7 (C-5); 121.6 (C-1′′); 122.4 (CH-2′,6′);
127.8 (C-1′′′); 128.6 (CH-2′′′,6′′′); 130.6 (CH-2′′,6′′); 131.7 (C-
1′); 150.3 (C-8); 151.96 and 151.97 (C-4,6); 153.0 (CH-2); 156.0
(C-4′); 159.7 (C-4′′′); 160.8 (C-4′′). IR (KBr): 3417, 3075, 3038,
2934, 2909, 2834, 1620, 1590, 1513, 1465, 1346, 1300, 1229, 1173,
1079, 1031, 971, 916, 834, 802, 739. MS (ESI), m/z (% relative
intensity): 288.3 (14), 316.4 (5), 454.3 (MH+, 100). HR MS (MH+)
454.18611 (calcd for C26H24N5O3 454.18737). Anal. calcd for
Supporting Information Available: Complete experimental
part and characterization of all compounds, copies of all NMR
spectra and cif files for 7eaa, 13ad, and 15aa are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8018126
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(29) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487–1487.
9054 J. Org. Chem. Vol. 73, No. 22, 2008