Intramolecular direct C-H arylation approach to fused purines. Synthesis of purino[8, 9-f]phenanthridines and 5, 6-dihydropurino[8, 9-a]isoquinolines

Article abstract of DOI:10.1021/jo100111t

(Figure Presented) Intramolecular C-H arylations were employed as a key step in the synthesis of hitherto unknown fused purine systems: 13-substituted purino[8, 9-f]phenanthridines and 11-substituted 5, 6-dihydro-purino[8, 9-a]isoquinolines. The purino[8, 9-f]phenanthridines were prepared in moderate yields by double C-H arylations of 9-phenylpurines with 1, 2-diiodobenzene or, more efficiently, by con-secutive Suzuki coupling of 9-(2-bromophenyl)purines with 2-bromophenylboronic acid followed by intramolecular C-H arylation. 5, 6-Dihydropurino[8, 9-a]isoquinolines were prepared in quantita-tive yields by intramolecular C-H arylations of 9-(2-chloropnenethyl)purines.

Full text of DOI:10.1021/jo100111t

pubs.acs.org/joc
Intramolecular Direct C-H Arylation Approach to Fused
Purines. Synthesis of Purino[8,9-f]phenanthridines and
5,6-Dihydropurino[8,9-a]isoquinolines§
ꢀ
Igor Cerna, Radek Pohl, Blanka Klepetarova, and Michal Hocek*
ꢀ
ꢁꢀ ꢁ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, CZ-16610,
Prague 6, Czech Republic
hocek@uochb.cas.cz
Received January 22, 2010
Intramolecular C-H arylations were employed as a key step in the synthesis of hitherto unknown
fused purine systems: 13-substituted purino[8,9-f]phenanthridines and 11-substituted 5,6-dihydro-
purino[8,9-a]isoquinolines. The purino[8,9-f]phenanthridines were prepared in moderate yields by
double C-H arylations of 9-phenylpurines with 1,2-diiodobenzene or, more efficiently, by con-
secutive Suzuki coupling of 9-(2-bromophenyl)purines with 2-bromophenylboronic acid followed by
intramolecular C-H arylation. 5,6-Dihydropurino[8,9-a]isoquinolines were prepared in quantita-
tive yields by intramolecular C-H arylations of 9-(2-chlorophenethyl)purines.
Purine scaffolds bearing a combination of 2-4 substitu-
ents at positions 2, 6, 8, and/or 9 are an important class of
pharmacophores and many derivatives display a wide range
of biological activities,1 i.e., inhibition of protein kinases,2 or
tubulin polymerization,3 antagonist effects to receptors,4
dedifferentiation of muscle cells to progenitor cells,5 or
induction of polyploidization6 of cancer cells via inhibition
of Aurora kinases. Large combinatorial libraries of several
types of tri- and tetrasubstituted purines have been prepared
by heterocyclizations7 or by regioselective nucleophilic
substitutions of dihalopurines with amines in combination
§ Dedicated to the memory of Keith Fagnou.
*To whom correspondence should be addressed. Phone: þ420 220183324.
Fax: þ420 220183559.
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2302 J. Org. Chem. 2010, 75, 2302–2308
Published on Web 03/03/2010
DOI: 10.1021/jo100111t
r
2010 American Chemical Society

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with cross-coupling reactions.8,9 Fused purine hererocycles
have also been extensively studied10,11 and some of them
display biological effects, i.e., antiinflamatory12 or cyto-
static13 activity or phosphodiesterase inhibition.14 Unlike
N-linked fused purines which are easily available through
heterocyclizations of aminopurines,10-14 synthesis of benzo-
and extended benzo-fused purines is much more challenging
since, at least when starting from purines, some intramolecular
C-C bond forming reaction is needed. Only very scarce
examples15 of saturated f- and e-dihydro- and tetrahydroben-
zo-fused purines prepared by the building-up of the purine ring
or by radical cyclizations are known in the literature.
positions 2, 6, or 8. Recently, we17,18 and others19 have
introduced direct C-H arylations20 as an alternative for
C-substitution at position 8 of purine bases and nucleosides
and used this reaction in combination with cross-couplings
to regioselectively generate18 small libraries of purines bear-
ing multiple substituents. Intramolecular versions of C-H
arylations are often used for the construction of fused
heterocycles.21 To the best of our knowledge, no intramole-
cular C-H arylation on purine was known until the very
recent synthesis of 6H-isoindolo[2,1-f]purine published22
during the course of writing up of this paper as a single
example within a series of other Cu-catalyzed intramolecular
C-H arylations leading to 11H-isoindolo[2,1-a]benzimidazoles.
We report here the use of intramolecular C-H arylations
for the synthesis of two novel types of extended e-fused
purines: purino[8,9-f]phenanthridines and 5,6-dihydropurino-
[8,9-a]isoquinolines. The e-fusion (positions 8,9) preserves the
base-pairing and major-groove facets of purine ring intact and
thus these types of compounds might be able to intercalate to
DNA or bind to adenine binding sites of some enzymes. We
intended to investigate and compare several approaches based
on C-H arylation(s) in the synthesis of e-fused derivatives of
model 6-methylpurine (containing no interfering functionality)
and biologically relevant adenine (containing an amino group
that can potentially cause some side reactions18).
During the last 3 decades, cross-coupling reactions have
become the method of first choice for C-C bond formation
in purines16 and were used for attachment of all kind of
unfunctionalized or even functionalized C-substituents at
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Three possible synthetic pathways were envisaged for the
synthesis of 13-substituted purino[8,9-f]phenanthridines
(Scheme 1): (i) oxidative coupling of 8,9-diphenylpurines,
(ii) double C-H arylation of 9-phenylpurines with 1,2-
dihalobenzenes, and (iii) the Suzuki coupling of 9-(2-bromo-
phenyl)purines with 2-bromophenylboronic acid followed
by intramolecular C-H arylation.
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Oxidative coupling of two arenes23 is the simplest and
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SCHEME 1. Retrosynthetic Analysis of Construction of the
Purino[8,9-f]phenanthridine Core
benzofurans, etc. (Pd(OAc)2-catalyzed reactions using diverse
oxidants;benzoquinone,26 air,27 Cu(OAc)2,28 Ag(OAc)23a
;
in the presence or absence of additives;Ag2CO3, K2CO3 or
pivalic acid; or FeCl3-catalyzed reaction in the presence of
m-CPBA29). Unfortunately none of these reactions proceeded
to produce even traces of the desired product 5a and, in all
cases, the starting compound 4a was recovered from the
reaction mixture.
The second attempted strategy involved the double C-H
arylation of 3a with 1,2-dihalobenzenes (Scheme 3, Table 1).
At first, we tried to employ our conditions previously
reported17 for direct arylation of purines in the reaction of
3a with 1,2-diiodobenzene 6 (entry 1). This Pd-catalyzed
reaction in the presence of CuI and Cs2CO3 led to a complex
mixture of many products from which we were able to isolate
three products. Besides the desired annulated product 5a,
formed in only 10% yield, we isolated also 6-methyl-8,9-
diphenyl-9H-purine (4a, 8%) as a product of C-H arylation
at position 8 followed by dehalogenation, and 1,2-bis(6-
methyl-9-phenyl-9H-purin-8-yl)benzene (7a, 25%) as a pro-
duct of competing intermolecular 2-fold direct C-H aryla-
tion of two purines with one diiodobenzene. The structure of
this interesting unwanted product was proved by X-ray
diffraction (Figure 1). The crystal structure of 7a showed
π-π stacking of each N(9)-phenyl group with the neighbor-
ing purine moiety. Attempts to optimize these conditions
(alteration of base and ligands, catalyst loadings, reaction
time) as well as the use of 1,2-dibromobenzene did not bring
any improvement.
SCHEME 2. Synthesis of 4a and Attempted Oxidative Coupling
Hence, we turned our attention to the recently reported
Fagnou’s protocol30 based on the addition of pivalic acid,
which acts as a proton shuttle31 to increase the reactivity of
substrates toward the CMD mechanism. Initial experiments
employed Pd(OAc)2 with P(p-FPh)3 in the presence of
PivOH (60 mol %) and K2CO3 in DMF, at 130 °C for 48 h
(Table 1, entry 2). The reaction gave low conversion but
cleanly produced the desired product 5a in 23% yield (no
formation of byproducts 4a and 7a was observed and most of
the starting 3a was recovered). The conditions were further
optimized to increase the conversion. However, the use of
P(F5Ph)3 or P(Cy)3 HBF4 ligands or a higher amount of
3
employed in an intramolecular manner, where the formation
of an extended aromatic system is the driving force. We
envisaged that in 8,9-diphenylpurines, the two phenyl rings
are in perfect orientation to facilitate the ring closure leading
to purino[8,9-f]phenanthridines. The starting model com-
pound, 6-methyl-6,8,-diphenylpurine (4a), was prepared in
three steps (Scheme 2). The synthesis started with the
N9-arylation reaction of 6-chloropurine (1) with phenylboro-
nic acid,24 followed by methylation with trimethylalumi-
num25 to give 6-methyl-9-phenylpurine (3a) in high yield.
The final direct arylation18 of 3a with phenyl iodide in the
presence of CuI and Cs2CO3 gave the desired 8,9-diphenyl
derivative 4a in 54% yield. Oxidative coupling of 6-methyl-
8,9-diphenyl-9H-purine 4a was attempted with use of several
procedures recently published for intra- and intermolecular
oxidative couplings of diverse heterocycles, i.e., indoles,
base did not change the conversions significantly (yields
19-25%, entries 3-5). Similar low conversions were also
obtained when using 1,2-dibromobenzene (data not shown).
The last attempt was based on the protocol of Chattopadhyay
et al.32 that employed Pd(OAc)2 in the presence of tetra-
butylammonium bromide (TBAB, Aliquat100) and KOAc,
which gave the desired 13-methylpurino[8,9-f]phenanthridine
(5a) in moderate (but improved) 35% yield (entry 6). Applica-
tion of these conditions to annulation of 9-phenyladenine
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TABLE 1. Double C-H Arylations of 3a with 1,2-Diiodobenzene
entry
ligand (mol %)
additive (equiv)
base (equiv)
temp, °C
time, h
yield, %
1
2
3
4
5
6
CuI (3)
Cs2CO3 (2.5)
K2CO3 (3)
K2CO3 (3)
K2CO3 (4)
K2CO3 (4)
KOAc (4)
160
130
130
130
130
140
60
48
48
43
43
25
10a
23
19
25
24
35
P(p-FPh)3b (10)
P(F5Ph)3c (10)
P(p-FPh)3 (20)
P(Cy)3 BF4 (20)
3
PivOH (0.6)
PivOH (0.6)
PivOH (0.6)
PivOH (0.6)
TBAB (1)
aIsolated byproducts: 4a (8%) and 7a (25%). bTris(4-fluorophenyl)phosphine. cTris(Pentafluorophenyl)Phosphine.
SCHEME 3. Double C-H Arylations of 3a with 1,2-Diiodo-
benzene
SCHEME 4. Combination of the Suzuki Cross-Coupling with
Intramolecular C-H Arylation
(3b) with 1,2-diiodobenzene gave only traces of the desired
product 5b.
FIGURE 1. Molecular and crystal structure of 7a. Thermal ellip-
soids are drawn at the 50% probability level.
The third approach to the target purino[8,9-f]phenanthri-
dines 5 was based on a combination of the Suzuki cross-
coupling with direct C-H arylation (Scheme 4). The starting
6-methyl- and 6-amino-9-(2-bromophenyl)purines 9a,b were
prepared by Cu(II)-mediated N9-arylation33 of 6-methyl-
purine (8a)34 or adenine (8b) with 2-bromobenzeneboronic
acid in the presence of TMEDA (Scheme 4). Following
exactly the published procedure,33 the reactions proceeded
poorly, giving only 7% and 13% of desired products 9a,b.
However, the use of neat MeOH instead of MeOH:H2O=
4:1, described in the original protocol, improved the yields of
products 9a and 9b to already acceptable 44% and 30%,
respectively. The Suzuki cross-couplings of derivatives 9a
and 9b with 2-bromobenzeneboronic acid were performed
according to published protocol35 in the presence of Pd-
(PPh3)4, Na2CO3, and Aliquat 100 in toluene/water. Even
after prolonged time (36 h), the conversion was not complete
and the biphenylpurine intermediates were not chromato-
graphically separable from starting bromophenylpurines 9.
Therefore, we decided to perform the C-H arylation directly
with the reaction mixture after the Suzuki coupling. Thus the
reaction mixture was extracted from water to toluene and the
crude intermediate obtained by evaporation and drying of
the organic phase was used in the second step. The intra-
molecular direct C-H arylation step was performed under
conditions (Pd(OAc)2 in the presence of tricyclohexylphos-
phine (P(Cy)3 HBF4) and K2CO3 in DMF at 150 °C) deve-
3
loped by Fagnou for intramolecular direct arylation with aryl
chlorides36 recently also applied in the synthesis of higher
helicenes.37 The cascade of the two reactions starting from 9a
proceeded smoothly giving the desired annulated product 5a
in excellent 82% yield over the two steps (Scheme 4). The
same approach was also successfully used in the synthesis of
13-aminopurino[8,9-f]phenanthridine 5b, though in moderate
32% overall yield due to lower conversions observed for both
steps. Apparently, this approach is the most efficient and
convenient for the synthesis of 13-substituted purino[8,9-f]-
phenanthridines. The crystal structure of 5a by X-ray diffraction
(Scheme 4 and the SI) showed a perfectly planar extended
aromatic system of the novel purino[8,9-f]phenanthridine
system.
(33) Yue, Y.; Zheng, Z.-G.; Wu, B.; Xia, C.-Q.; Yu, X.-Q. Eur. J. Org.
Chem. 2005, 5154–5157.
(34) Hocek, M.; Dvorakova, H. J. Org. Chem. 2003, 68, 5773–5776.
(35) Wang, T. F.; Lin, C. L.; Chen, C. N.; Wang, T. C. J. Chin. Chem. Soc.
2007, 54, 811–816.
(36) Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581–590.
(37) Cote, J.; Collins, S. K. Synthesis 2009, 1499–1505.
J. Org. Chem. Vol. 75, No. 7, 2010 2305

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TABLE 2. Absorption and Emission Spectra of Compounds 5 and 11
compd
absorption λmax, nm (ε, L mol-1 cm-1
)
Φ
emission λ (nm)
3
346 (8 200), 330 (10 000), 316 (15 000), 304 (15 000), 263 (43 000)
3
5a
5b
11a
11b
0.22
0.33
0.019
0.45
358, 375
395
322, 337, 353
363, 380
345 (13 000), 329 (16 000), 315 (15 000), 301 (16 000), 284 (18 000), 268 (25 000), 237(42 000)
333 (22 000), 280 (28 000), 233 (9 500)
309 (25 000), 229 (16 000)
oxidants (MnO2,39 Pd/C,40 DDQ41) failed. Crystal structures
of both 5,6-dihydropurino[8,9-a]isoquinolines 11a,b (Scheme 5
and the SI) revealed a small distortion of the planarity caused
by the saturated ethylene bridge (torsion angles of purine and
benzene rings were ca. 8° or 12° for 11a and 11b, respectively).
Crystal packings of both compounds show head-to-tail π-π
stacking of the heteroaromatic systems (see the SI).
SCHEME 5. Synthesis of 5,6-Dihydropurino[8,9-a]isoquino-
lines 11
Electronic absorption and emission spectra of the novel
fused aromatic systems 5 and 11 were also studied (Table 2
and the SI). The purino[8,9-f]phenanthridines 5 showed a
very complex pattern of absorption with 5-7 distinct bands
of similar absorbance in the UV region, while the 5,6-
dihydropurino[8,9-a]isoquinolines 11 revealed standard
2-3 absorption bands. All compounds were shown to be
luminescent. Adenine derivative 5b and 11b possess higher
quantum yields and longer wavelengths of emission com-
pared to the 6-methylpurines 5a and 11a.
In conclusion, three approaches relying on Pd-catalyzed
C-H arylations have been investigated in the quest for
synthesis of purino[8,9-f]phenanthridines. While oxidative
couplings of 8,9-diphenylpurines did not work, double C-H
arylations of 9-phenylpurines with 1,2-diiodobenzene gave
moderate yields of the desired products (up to 35%) and, in
some cases, side products were detected. The most efficient
approach was based on consecutive Suzuki coupling of
9-(2-bromophenyl)purines with 2-bromophenylboronic acid
followed by intramolecular C-H arylation. Analogous
intramolecular C-H arylation was used in a simple two-
step synthesis of 5,6-dihydropurino[8,9-a]isoquinolines
from purines. The cyclizations of 9-(2-chlorophenethyl)-
purines proceeded quantitatively. The novel fused hetero-
cyclic systems of purino[8,9-f]phenanthridines 5 and 5,6-
dihydropurino[8,9-a]isoquinolines 11 showed interesting
absorption spectra and luminescence. Compounds 5a,b, 7a,
and 11a,b did not show any considerable cytostatic activity in
several tested cancer and leukemia cell lines (CCRF-CEM,
HL60, HeLaS3, HCT116, HS578, DU145, and H23)42 most
probably due to very limited solubility in water. However,
this synthetic approach may find applications in straight-
forward preparation of other novel extended heterocyclic
systems.
Similar intramolecular C-H arylation was used for the
synthesis of another novel type of fused purines: 5,6-
dihydropurino[8,9-a]isoquinolines (Scheme 5). The key in-
termediates, 9-(2-chlorophenethyl)purines 10a,b, were envi-
saged to be suitable substrates for the intramolecular aryla-
tion. They were prepared by alkylation of purines 8a,b with
2-chlorophenethyl bromide in the presence of K2CO3 (in
analogy to ref 38) in 84% and 56% yield, respectively. Intra-
molecular direct C-H arylation of methylpurine derivative
10a was then performed under the aforementioned Fagnou
conditions.36 The reaction proceeded smoothly within 17 h
to afford the desired 11-methyl-5,6-dihydropurino[8,9-a]-
isoquinoline 11a in quantitative yield. Similarly, the same
intramolecular cyclization of adenine derivative 10b gave
quantitative conversion to 11-amino-5,6-dihydropurino[8,9-a]-
isoquinoline 11b. The higher yields of this intramolecular
C-H arylation compared to the synthesis of purino[8,9-f ]-
phenanthridines are probably due to the flexible saturated
linker in intermediates 10 that makes the C-H arylation
more efficient even for ethylene-tethered chlorobenzene
compared to o-phenylene-tethered bromobenzene. Attempts
to oxidize 5,6-dihydropurino[8,9-a]isoquinolines 11 to fully
aromatic purino[8,9-a]isoquinolines with use of diverse
Experimental Section
Double Direct Arylation of 3a with 1,2-Diiodobenzene
6. Method A (Table 1, entry 1): DMF (6 mL) was added through
ꢁ
(40) (a) Sridharan, V.; Avendano, C.; Menendez, J. C. Tetrahedron 2007,
63, 673–681. (b) Boekelheide, V.; Godfrey, J. C. J. Am. Chem. Soc. 1953, 75,
3679–3685. (c) Nunez, A.; Abarca, B.; Cuadro, A. M.; Alvarez-Builla, J.;
Vaquero, J. J. J. Org. Chem. 2009, 74, 4166–4176.
(41) (a) Sun, J.; Xia, E. Y.; Zhang, L. L.; Yan, C. G. Eur. J. Org. Chem.
2009, 5247–5254. (b) Ma, L. J.; Li, X. X.; Kusuyama, T.; El-Sayed, I. E. T.;
Inokuchi, T. J. Org. Chem. 2009, 74, 9218–9221.
(38) Raboisson, P.; Lugnier, C.; Muller, C.; Reimund, J.-M.; Schultz, D.;
Pinna, G.; Bec, A.; Basaran, H.; Desaubry, L.; Gaudiot, F.; Seloum, M.;
Bourguignon, J. Eur. J. Med. Chem. 2003, 38, 199–214.
ꢀ
(42) Naus, P.; Pohl, R.; Votruba, I.; Dzubak, P.; Hajduch, M.; Ameral,
R.; Birkus, G.; Wang, T.; Ray, A. S.; Mackman, R.; Cihlar, T.; Hocek, M.
ꢀ
ꢁ
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(39) Mısek, J.; Teply, F.; Stara, I. G.; Tichy, M.; Saman, D.; Cı
sek, P.; Stary, I. Angew. Chem., Int. Ed. 2008, 47, 3188–3191.
ꢁ
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ꢁ
sarova, I.;
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´
´
ꢀ
ꢁ
Vojtı
´
J. Med. Chem. 2010, 53, 460–470.
2306 J. Org. Chem. Vol. 75, No. 7, 2010

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a septum to an argon-purged vial containing 6-methyl-9-phenyl-
9H-purine 3a (210 mg, 1 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol,
5 mol %), CuI (571 mg, 3 mmol), 1,2-diiodobenzene (260 μL, 2
equiv), and Cs2CO3 (814 mg, 2.5 mmol). The reaction mixture
was heated to 160 °C for 60 h. The solvent was evaporated under
reduced pressure. Products 5a (10% yield), 4a (8% yield), and 7a
(25% yield) were isolated by flash column chromatography
(gradient elution THF/hexanes 1:9 f THF/hexanes 4:6).
Method B (Table 1, entry 2): DMF (3 mL) was added through
a septum to an argon-purged vial containing 6-methyl-9-phenyl-
9H-purine 3a (105 mg, 0.5 mmol), Pd(OAc)2 (11.2 mg, 0.05
mmol), P(p-FPh)3 (15.8 mg, 0.05 mmol), PivOH (30.6 mg,
0.3 mmol), 1,2-iodobenzene (130 μL, 1 mmol), and K2CO3
(207 mg, 1.5 mmol). The reaction mixture was heated to
130 °C for 48 h. The solvent was evaporated under reduced
pressure. Product 5a (23% yield) was isolated by flash column
chromatography (gradient elution hexanes f ethyl acetate/
hexanes 2:8).
13-Aminopurino[8,9-f]phenanthridine (5b): white solid, from
CHCl3/heptane, mp >300 °C; 1H NMR (600.1 MHz, DMSO-
d6) δ 7.62 (ddd, 1H, J6,5=8.4 Hz, J6,7=7.1 Hz, J6,8=1.3 Hz,
H-6), 7.63 (br s, 2H, NH2), 7.78 (ddd, 1H, J2,1=7.9 Hz, J2,3=7.0
Hz, J2,4=1.0 Hz, H-2), 7.81 (ddd, 1H, J7,8=8.3 Hz, J7,6=7. Hz1,
J
J
7,5=1.2 Hz, H-7), 7.84 (ddd, 1H, J3,4=8.3 Hz, J3,2=7.0 Hz,
3,1=1.3 Hz, H-3), 8.42 (s, 1H, H-11), 8.67 (dd, 1H, J1,2=7.9 Hz,
J1,3=1.3 Hz, H-1), 8.68 (br d, 1H, J4,3=8.3 Hz, H-4), 8.71 (dd,
1H, J5,6=8.4 Hz, J5,7=1.2 Hz, H-5), 9.76 (dd, 1H, J8,7=8.3 Hz,
J
8,6=1.3 Hz, H-8); 13C NMR (150.9 MHz, DMSO-d6) δ 118.2
(CH-8), 120.3 (C-13a), 121.2 (C-4b), 123.0 (C-14b), 123.7 (CH-
4), 124.5 (CH-5), 124.8 (CH-1), 125.9 (CH-6), 129.3 (CH-2),
129.4 (C-4a), 129.8 (CH-7), 131.0 (CH-3), 133.3 (C-8a), 143.1
(C-14a), 148.7 (C-9a), 152.4 (CH-11), 156.7 (C-13); TOF MS
(EIþ), m/z (% rel intensity) 151 (6), 178 (19), 214 (20), 258 (29),
285 (M, 100); HR MS (EIþ) 285.1024 (calcd for C17H11N5
285.1014). Anal. Calcd for C17H11N5 0.4H2O: C, 69.8; H,
3
4.07; N, 23.94. Found: C, 70.0; H, 3.89; N, 23.77.
Method C (Table 1, entry 6): A mixture of Aliquat 100 (158
mg, 0.5 mmol) and KOAc (184 mg, 2 mmol) in dry degassed
DMF (20 mL) was stirred for 20 min. This solution was added
through a septum to an argon-purged vial containing 6-methyl-
9-phenyl-9H-purine 3a (105 mg, 0.5 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), and 1,2-iodobenzene (130 μL, 1 mmol). The reac-
tion mixture was heated to 140 °C for 25 h. The solvent was
evaporated under reduced pressure. Product 5a, 50.3 mg (35%
yield), was isolated by flash column chromatography (gradient
elution hexanes f ethyl acetate/hexanes 2:8).
General Procedure for Intramolecular Direct Arylation of 10a
and 10b. DMF (3 mL) was added through a septum to an argon-
purged vial containing purine (10a or 10b, 0.5 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol), P(Cy)3 HBF4 (18.4 mg, 0.05 mmol), and
3
K2CO3 (172 mg, 1.25 mmol). The reaction mixture was heated to
150 °C for 17 h. The crude mixture was diluted with CHCl3 (20
mL) and the solvents were evaporated under reduced pressure.
Products 11a and 11b were isolated by flash column chroma-
tography (gradient elution CHCl3 f 10% of MeOH in CHCl3).
5,6-Dihydro-11-methylpurino[8,9-a]isoquinoline (11a): yield
99%, colorless crystals from CHCl3/heptane, mp 156-157 °C;
1H NMR (600.1 MHz, CDCl3) δ 2.91 (s, 3H, CH3), 3.30 (t, 2H,
13-Methylpurino[8,9-f]phenanthridine (5a): brownish crystals
from CHCl3/tBuOMe, mp 252-255 °C; 1H NMR (600.1 MHz,
CDCl3) δ 3.04 (s, 3H, CH3), 7.51 (ddd, 1H, J6,5=8.2 Hz, J6,7
=
J
J
J
5,6=6.9 Hz, H-5), 4.47 (t, 2H, J6,5=6.9 Hz, H-6), 7.37 (ddq, 1H,
4,3=7.4 Hz, J4,2=1.6 Hz, J4,1=J4,5=0.8 Hz, H-4), 7.45 (tdt, 1H,
2,1=J2,3=7.4 Hz, J2,4=1.6 Hz, J2,5=0.7 Hz, H-2), 7.48 (td, 1H,
7.1 Hz, J6,8=1.2 Hz, H-6), 7.64 (ddd, 1H, J2,1=7.9 Hz, J2,3=7.2
Hz, J2,4=1.0 Hz, H-2), 7.66 (ddd, 1H, J7,8=8.4 Hz, J7,6=7.1 Hz,
J7,5=1.3 Hz, H-7), 7.76 (ddd, 1H, J3,4=8.1 Hz, J3,2=7.2 Hz,
J3,2=J3,4=7.4 Hz, J3,1=1.6 Hz, H-3), 8.32 (ddd, 1H, J1,2=7.4
Hz, J1,3=1.6 Hz, J1,4=0.8 Hz, H-1), 8.81 (s, 1H, H-9); 13C NMR
(150.9 MHz, CDCl3) δ 19.6 (CH3), 27.9 (CH2-5), 39.3 (CH2-6),
125.6 (C-12b), 126.0 (CH-1), 127.9 (CH-2), 128.4 (CH-4), 131.4
(CH-3), 133.9 (C-11a), 135.4 (C-4a), 150.0 (C-12a), 151.0 (C-7a),
151.7 (CH-9), 157.9 (C-11); MS (ESI), m/z (% rel intensity) 195
(4), 237 (MHþ, 100); HR MS (MHþ) 237.1134 (calcd for
J3,1=1.4 Hz, H-3), 8.30 (d, 1H, J4,3=8.1 Hz, H-4), 8.33 (dd, 1H,
J5,6=8.2 Hz, J5,7=1.3 Hz, H-5), 8.74 (ddd, 1H, J1,2=7.9 Hz,
J1,3=1.4 Hz, J1,4=0.4 Hz, H-1), 8.99 (s, 1H, H-11), 9.64 (dd, 1H,
J
8,7=8.4 Hz, J8,6=1.2 Hz, H-8); 13C NMR (150.9 MHz, CDCl3)
δ 19.2 (CH-3), 118.6 (CH-8), 121.3 (C-4b), 122.2 (C-14b), 122.5
(CH-4), 123.4 (CH-5), 125.9 (CH-6), 126.1 (CH-1), 128.8 (CH-
2), 129.6 (CH-7), 130.3 (C-4a), 131.8 (CH-3), 132.8 (C-8a), 133.6
(C-13a), 147.7 (C-14a), 149.6 (CH-11), 149.8 (C-9a), 158.1 (C-
13); MS (ESI), m/z (% rel intensity) 224 (2), 257 (3), 267 (3), 285
(MHþ, 100); HR MS (MHþ) 285.1135 (calcd for C18H13N4
C14H13N4 237.1135). Anal. Calcd for C14H12N4 1.5H2O: C,
3
63.86; H, 5.74; N, 21.28. Found: C, 63.85; H, 5.6; N, 21.14.
11-Amino-5,6-dihydropurino[8,9-a]isoquinoline (11b): yield
99%, colorless crystals from CHCl3/heptane, mp >300 °C; 1H
NMR (600.1 MHz, DMSO-d6) δ 3.24 (t, 2H, J5,6 = 6.9 Hz,
H-11), 4.30 (t, 2H, J6,5=6.9 Hz, H-10), 7.27 (br s, 2H, NH2),
7.41-7.47 (m, 3H, H-2,3,4), 8.05 (m, 1H, H-1), 8.14 (s, 1H, H-9);
13C NMR (150.9 MHz, DMSO-d6) δ 27.4 (CH2-5), 39.1 (CH2-
6), 119.7 (C-11a), 124.4 (CH-1), 126.3 (C-12b), 127.6 (CH-2),
128.8 (CH-4), 130.4 (CH-3), 135.60 (C-4a), 145.7 (C-12a), 150.0
(C-7a), 152.5 (CH-9), 155.8 (C-11); HR MS (ESI, MHþ)
238.1088 (calcd for C13H12N5 238.1087). Anal. Calcd for
C13H11N5: C, 65.81; H, 4.67; N, 29.52. Found: C, 65.50; H,
4.69; N, 29.32.
285.1135). Anal. Calcd for C18H12N4 0.25H2O: C, 74.85; H,
4.36; N, 19.4. Found: C, 74.95; H, 4.24; N, 19.16.
3
General Procedure for Combination of Suzuki Cross-Coupling
Reaction with Intramolecular Direct C-H Arylation: Method D.
Toluene (2 mL) and water (1 mL) were added through a septum
to an argon-purged vial containing 9a or 9b (0.5 mmol), 2-
bromobenzeneboronic acid (150 mg, 0.75 mmol), Pd(PPh3)4
(23.5 mg, 0.02 mmol), Aliquat 100 (25 mg, 0.08 mmol), and
Na2CO3 (212 mg, 1.5 mmol). The reaction mixture was heated to
110 °C for 36 h. After being cooled to room temperature the
resulting reaction mixture was diluted with water (10 mL) and
extracted with toluene (3 ꢀ 10 mL). Combined organic extracts
were dried over MgSO4 and filtered, then solvent was evapo-
rated and residue was dried at room temperature in vacuo for
14 h. The crude residue was then dissolved in DMF (4 mL) and
transferred through a septum to an argon-purged vial contain-
Single Crystal X-ray Structure Analysis. The diffraction data
of single crystals of 5a (colorless, 0.01 ꢀ 0.09 ꢀ 0.60 mm3), 7a
(colorless, 0.11 ꢀ 0.20 ꢀ 0.42 mm3), 11a (colorless, 0.07 ꢀ 0.32 ꢀ
0.60 mm3), and 11b (colorless, 0.02 ꢀ 0.29 ꢀ 0.60 mm3) were
collected on Xcalibur X-ray diffractometer with Cu KR (λ =
1.54180 A). All three structures were solved by direct methods
with SIR9243 and refined by full-matrix least-squares on F with
CRYSTALS.44 All hydrogen atoms were located in a difference
map, but those attached to carbon atoms were repositioned
ing Pd(OAc)2 (5.6 mg, 0.025 mmol), P(Cy)3 HBF4 (18.4 mg,
3
0.05 mmol), and K2CO3 (173 mg, 1.25 mmol). The reaction
mixture was heated to 150 °C for 20 h (30 h for 9b). The crude
mixture was diluted with CHCl3 (20 mL) and the solvents were
evaporated under reduced pressure. Products 5a (116 mg, 82%
overall yield starting from 9a) and 5b (45 mg, 32% overall yield
starting from 9b) were isolated by flash column chromatography
(gradient elution hexanes f ethyl acetate/hexanes 2:8).
(43) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla,
M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435–435.
(44) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.;
Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487–1487.
J. Org. Chem. Vol. 75, No. 7, 2010 2307

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geometrically and then refined with riding constraints, while all
other atoms were refined anisotropically in all cases.
Crystal data for 11b: C13H11N5, triclinic, space group P1, a=
7.3513(6) A, b = 10.8273(10) A, c = 13.9340(10) A, R =
103.269(7)°, β = 93.029(6)°, γ = 91.387(7)°, V = 1077.20(16)
A3, Z = 4, M = 237.26, 35870 reflections measured, 4541
independent reflections. Final R=0.050, wR=0.056, GoF=
1.079 for 3288 reflections with I > 2σ(I) and 326 parameters.
The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no.
762122.
Crystal data for 5a: C18H12N4, orthorhombic, space group
Pnn2, a=17.463(3) A, b=18.850(4) A, c=3.9169(10) A, V=
1289.4(5) A3, Z=4, M=284.32, 11932 reflections measured, 1561
independent reflections. FinalR=0.057, wR=0.068, GoF=1.090
for 1199 reflections with I > 1.5σ(I) and 199 parameters. The
crystallographic coordinates have been deposited with the Cam-
bridge Crystallographic Data Centre; deposition no. 762123.
Crystal data for 7a: C30H22N8, monoclinic, space group C2/c,
a = 15.3485(11) A, b = 9.7269(4) A, c = 18.4269(13) A, β =
119.133(9)°, V=2403.0(3) A3, Z=4, M=247.28, 27606 reflections
measured, 2530 independent reflections. Final R = 0.048, wR =
0.056, GoF=1.099 for 2009 reflections with I>2σ(I) and 172 para-
meters. The crystallographic coordinates have been deposited with
the Cambridge Crystallographic Data Centre; deposition no. 762121.
Crystal data for 11a: C14H15N4O1.5, triclinic, space group P1,
a=10.2023(13) A, b=11.7179(15) A, c=11.9757(16) A, R=
84.147(11)°, β=65.064(13)°, γ=82.177(11)°, V=1284.6(3) A3,
Z=4, M=263.30, 27466 reflections measured, 5385 indepen-
dent reflections. Final R=0.051, wR=0.063, GoF=0.940 for
4003 reflections with I > 2σ(I) and 353 parameters. The crystal-
lographic coordinates have been deposited with the Cambridge
Crystallographic Data Centre; deposition no. 767124.
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, U.S.A.). The cytostatic activity was tested
by Dr. I. Votruba (IOCB) and Dr. Tomas Cihlar and co-
workers (Gilead Sciences, Inc).
Supporting Information Available: Complete experimental
details and characterization of all compounds, copies of all
NMR spectra, UV and fluorescence spectra, additional figures
of ORTEPs and crystal packing, and CIF files for 7a, 5a, 10a,
and 10b. This material is available free of charge via the Internet
at http://pubs.acs.org.
2308 J. Org. Chem. Vol. 75, No. 7, 2010