Direct C-H borylation and C-H arylation of pyrrolo2,3-dpyrimidines: Synthesis of 6,8-disubstituted 7-deazapurines

Article abstract of DOI:10.1039/b900218a

Novel direct C-H borylations of 7-deazapurines to position 8 by B ₂pin₂ under Ir catalysis were followed by Suzuki cross-couplings with aryl halides and other functional group transformations to give diverse 8-substituted 7-deazaaden

Full text of DOI:10.1039/b900218a

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Direct C–H borylation and C–H arylation of pyrrolo[2,3-d]pyrimidines:
synthesis of 6,8-disubstituted 7-deazapurines†
Martin Klecˇka, Radek Pohl, Blanka Klepeta´rˇova´ and Michal Hocek*
Received 6th January 2009, Accepted 6th January 2009
First published as an Advance Article on the web 14th January 2009
DOI: 10.1039/b900218a
Novel direct C–H borylations of 7-deazapurines to position
8 by B2pin2 under Ir catalysis were followed by Suzuki cross-
couplings with aryl halides and other functional group trans-
formations to give diverse 8-substituted 7-deazaadenines.
explanation of this lack of reactivity is the formation of a stable
complex of purine with Ir catalyst at N7. Another problem
might be the limited stability13 of the purine-8-boronate that may
undergo protodeborylation back to the starting compound.
Therefore, our further efforts focused on 7-deazapurines (lack-
ing the N7 coordination site). The model starting compound
of choice was 9- benzyl-6-phenyl-7-deazapurine (2, 7-benzyl-
4-phenyl-7H-pyrrolo[2,3-d]pyrimidine). The reaction of 2 with
bispinacolatodiboron in presence of di-tert-butylbipyridine and
[Ir(COD)(OMe)]2 proceeded well to give selectively 8-borylated
product 6 in high yield (85%, Table 1, entry 1)‡. The regioselectivity
was in accord with the literature examples14 of borylation of
indoles at position 2 and was unequivocally proved by X-ray
diffraction analysis of 6 (Fig. 1).15
2,6,9- or 6,8,9-Trisubstituted, as well as and 2,6,8,9-tetrasub-
stituted purines display a wide range of biological activities,1
i.e. inhibition of protein kinases,2 or tubulin polymeri-
zation,3 and antagonist effects to receptors,4 etc. 6-Arylpurines
are of particular importance due to anti-HCV, cytostatic
and antimycobacterial activities.5 7-Deazapurines (pyrrolo[2,3-d]-
pyrimidines) are often used as surrogates of purine bases and
also many of them display interesting biological effects.6 However,
comparedtopurines, this class of heterocycles is under explored. In
our previous synthetic and medicinal chemistry studies of di-, tri-
and tetrasubstituted purines we have heavily utilized regioselective
cross-coupling reactions of di- and trihalopurines.7 Later on, we
have for the first time developed novel direct C–H arylation8
reactions in purine bases9 and nucleosides10 and, most recently,
we used a combination of regioselective cross-couplings, Cu-
catalyzed N-arylations and direct C–H arylations for the efficient
consecutive synthesis of small libraries of tri and tetrasubstituted
purines.11 Now we wished to explore the utility of another reaction
from the family of C–H activations: Ir-catalyzed direct C–H
borylation12 in modifications of purines and 7-deazapurines. Such
reactions should lead to hetarylboronates suitable for further
functional group transformations by the Suzuki cross-coupling
or Cu-catalyzed aminations. So far, not only have such reactions
not been reported on these two heterocyclic systems, but also the
corresponding hetarylboronates or -boronic acids are unknown.
Ir-catalyzed C–H borylation12 of aromatic compounds is a one-
step method to generate aryl boronates. The most active catalyst
for this transformation is generated from di-tert-butylbipyridine
and [Ir(COD)(OMe)]2. 9-Benzyl-6-phenylpurine (1) was chosen
as the first model substrate for studying the C–H borylation
(Scheme 1). We have employed the above mentioned catalytic
system under diverse conditions (from r.t. to 80 ◦C and MW
irradiation). Unfortunately, no formation of 8-borylated purine
was observed (mostly just the starting compound was recov-
ered accompanied by minor byproducts). The most plausible
Next, we have tried the C–H borylation of 9-benzyl-7-
deazaadenine
3
and its N-[(dimethylamino)methylidene]-
protected derivative 4 under the same conditions. However, no
C–H borylation was observed (entries 2,3). Another interesting
substrate was 9-benzyl-6-chloro-7-deazapurine (5) suitable for
further functional group transformations at position 6. In this
case, the C–H borylation worked reasonably well to give the
desired product 7 in moderate (but acceptable) 53% yield (entry 4).
Then we have attempted hydrolysis of the boronate ester 6 to more
reactive boronic acid. The hydrolysis proceeded quantitatively
but the final free boronic acid was rather unstable and readily
decomposed.
Scheme 1
Table 1 Direct C–H borylation of deazapurines
Entry
Starting compound
R
Yield (%)
Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences
of the Czech Republic, Gilead & IOCB Research Center, Flemingovo nam.
2, CZ-16610, Prague 6, Czech Republic. E-mail: hocek@uochb.cas.cz;
Fax: +420 220183559; Tel: +420 220183324
1
2
3
4
2
3
4
5
Ph-
NH2
(CH3)2NCH N-
Cl
6 (85%)a
no reactiona
no reactiona
7 (53%)b
=
† Electronic supplementary information (ESI) available: Experimental
details and characterization data. CCDC reference numbers 703631 (6) and
703632 (8b). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b900218a
a 1.2 equiv. B2pin2, 5 mol% [Ir(COD)OMe]2, 10 mol% dtbpy, THF, 80 ◦C,
20 h. b 1.5 equiv. B2Pin2, 8 mol% [Ir(COD)(OMe)]2, 16 mol% dtbpy.
866 | Org. Biomol. Chem., 2009, 7, 866–868
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Having access to the boronates, we have further explored their
synthetic applications. The most obvious use was in the Suzuki
cross-coupling reaction. Thus the reactions of the boronate 6 with
diverse aryl halides were performed under conditions previously
optimized16 for other hetarylboronates (Pd(dppf)Cl2 and K2CO3
in DMF) (Scheme 2). Generally, all the aryl halides (diverse aryl
iodides and 2-bromopyrene) reacted well to give the desired 8-
aryl products 8a–8g in very high yields (Table 2). One example
(8b) was also characterized by X-ray diffraction.15 Interesting
products 8e and 8g arose from the coupling with methylated 5- or 6-
iodouracils (entries 4 and 6) as novel types of Janus-nucleobases17
or fleximers.18
Fig. 1 ORTEP drawing with the atom numbering scheme. Thermal
ellipsoids are drawn at the 50% probability level.
In the case of compound 8g, the acid hydrolysis gave the free
9-benzyl-6-phenyl-8-(uracil-6-yl)-7-deazapurine 8h. The overall
yields of the 6,8-diaryl-7-deazapurines over the two steps (C–H
borylation and cross-coupling, Table 2 - Route I) were very good
(67–81%). As a complementary alternative method, we have also
tried direct C–H arylation of 2 with the same aryl halides under
the conditions optimized9 for arylation of purines (Table 2, Route
II). However, these reactions did not proceed well giving very
low yields (entries 1–3) or no reaction what so ever (entries
4–7). Comparison of the two routes to diaryl-7-deazapurines 8
revealed that the two step sequence (Route I) is much more efficient
(Table 2).
Finally, we were interested in the synthesis of 8-aryl-7-
deazaadenines. As the direct C–H activations of 7-deazaadenine
3 were unsuccessful, we have envisaged the use of the 6-chloro
derivative that can be readily transformed to 6-amino compounds
(Table 3). The two-step arylation (C–H borylation followed
by the Suzuki coupling) of 9-benzyl-6-chloro-7-deazapurine (5)
with three different aryl iodides proceeded with acceptable 31–
42% overall yields (the yield of the first step was the moderate
Scheme 2 Reagents and conditions: i) B2pin2, [Ir(COD)OMe]2, dtbpy,
THF, 80 ◦C, 20 h; ii) Ar-X, Pd(dppf)Cl2, K2CO3, DMF, 90 ◦C, 1 h;
iii) Ar-X, Pd(OAc)2, Cs2CO3, CuI, DMF, 160 ◦C, 60 h.
Table 2 Synthesis of 8-arylated deazapurines by C–H activation
Route I – couplinga
(overall yield)b
Route II
(yield)
Entry Ar-X
1
Product
8a
87%a (74%)b
90%a (76%)b
79%a (67%)b
39%
41%
35%
2
3
8b
8c
Scheme 3 Reagents and conditions: i) B2pin2, [Ir(COD)OMe]2, dtbpy,
THF, 80 ◦C, 20 h; ii) Ar-X, Pd(dppf)Cl2, K2CO3, DMF, 90 ◦C, 1 h; (iii) a)
NH3/MeOH, 120 ◦C, overnight b,c) R-NH2, butanol, reflux, overnight d)
phenol, KOt-Bu, K2CO3, DMF, 110 ◦C, 16 h.
4
5
8d
8e
95%a (81%)b
92%a (78%)b
traces
0%
Table 3 Two-step synthesis of 6,8-disubstituted 7-deazapurines
Entry
1
Ar
Product (yield)
X
Product (yield)
9a (42%)
NH2
10aa (83%)
2
3
4
5
NH-Ph
NH-Bn
O-Ph
10ab (65%)
10ac (77%)
10ad (93%)
10b (85%)
6
7
8f
91%a (77%)b
0%
0%
9b (31%)
9c (36%)
NH2
8g
92%a,c (78%)b,c
6
NH2
10c (79%)
a Cross coupling. b Overall yield after two steps (C–H borylation and cross
coupling). c Overall yield after acidic deprotection to free uracil 8h.
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54% as mentioned above). The follow-up aminations of the 6-
chloro-7-deazapurines with methanolic ammonia gave the 8-aryl-
7-deazaadenines 10aa, 10b and 10c in very good yields (Scheme 3,
Table 3). Other nucleophilic substitutions were also pursued with
6-chloro-7-deazapurine 9a. Its reactions with aniline, benzylamine,
as well as with sodium phenolate gave the corresponding 6-N- or
6-O-substituted products 10ab, 10ac and 10ad, respectively.
In conclusion, the Ir-catalyzed C–H borylation of 7-
deazapurines proceeded selectively in position 8. The follow-
up Suzuki cross-coupling reactions can be efficiently used for
the introduction of aryl groups to position 8. This is the first
efficient methodology for 8-arylation of important 7-deazapurines
(so far the 8-substituted 7-deazapurines were only prepared by
multistep heterocyclizations6). The methodology can be combined
with nucleophilic substitutions of 6-chloro-7-deazapurines to give
an efficient way to synthesise diverse 6-substituted 8-aryl-7-
deazapurines.
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Acknowledgements
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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.).
Notes and references
‡ General procedure for C–H borylation. 7-Deazapurines
2 or 5
(2 mmol, 1 equiv.), bispinacolatodiboron (0.609 g, 2.4 mmol, 1.2 equiv.),
[Ir(COD)OMe]2 (66 mg, 0.1 mmol, 5 mol%) and 4,4¢-di-tert-butyl-2,2¢-
bipyridine (54 mg, 0.2 mmol, 10 mol%) were dissolved in dry THF (15 ml)
under Ar. The solution was heated at 80 ◦C in a septum-sealed flask for
20 hours. The solvent was evaporated and the residue was purified by silica
gel flash chromatography (hexane/EtOAc 5:1→ ethyl acetate/hexanes 1:1)
to give product 6 (698 mg, 85%) or 7 (390 mg, 53%). Compound 6: M.p.
ˇ
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ˇ
◦
11 I. Cernˇa, R. Pohl, B. Klepeta´rˇova´ and M. Hocek, J. Org. Chem., 2008,
128–134 C.1H NMR (600 MHz, CDCl3): 1.28 (s, 12H, CH3); 5.81 (s,
73, 9048–9054.
2H, CH2); 7.17–7.26 (m, 5H, H-o,m,p-Bn); 7.46 (s, 1H, H-5); 7.50 (m,
1H, H-p-Ph); 7.54 (m, 2H, H-m-Ph); 8.16 (m, 2H, H-o-Ph); 9.02 (s, 1H,
H-2). 13C NMR (151 MHz, CDCl3): 24.65 ((CH3)2C); 47.17 (CH2Ph); 84.39
(C(CH3)2); 113.54 (CH-5); 115.44 (C-4a); 127.14 (CH-p-Bn); 127.28 (CH-
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(CH-p-Ph); 132.15 (C-6); 138.16 (C-i-Ph); 138.79 (C-i-Bn); 152.94 (CH-2);
154.25 (C-7a); 158.73 (C-4). IR (CHCl3): 2983, 1562, 1525, 1468, 1449,
1428, 1382, 1374, 1335, 1139. HRMS (ESI) calculated for C25H26BN3O2:
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◦
412.2191; found: 412.2192. Compound 7: M.p. 172–175 C.1H NMR
(500 MHz, CDCl3): 1.28 (s, 12H, CH3); 5.75 (s, 2H, CH2); 7.16–7.25 (m, 6H,
H-5 and H-o,m,p-Bn); 8.68 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3):
24.62 ((CH3)2C); 47.60 (CH2Ph); 84.56 (C(CH3)2); 112.23 (CH-5); 117.21
(C-4a); 127.22 (CH-o-Bn); 127.34 (CH-p-Bn); 128.30 (CH-m-Bn); 132.79
(C-6); 138.12 (C-i-Bn); 151.91 (CH-2); 153.28 and 153.42 (C-4 and C-7a).
IR (CHCl3): 2984, 1579, 1541, 1525, 1469, 1430, 1374, 1355, 1330, 1259,
1177, 1137. HRMS (ESI) calculated for C19H21BClN3O2: 370.1499; found:
370.1488.
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This journal is
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