Novel procedure for the coupling of sterically hindered electron-deficient anilines to the 6-position of the purine core

Article abstract of DOI:10.1080/00397911.2010.517615

Sterically hindered electron-deficient anilines are coupled to the 6-position of the purine core only when activated as their corresponding TFA-amide. The free anilines did not react under all conditions tested. After aqueous work-up, the TFA-group is los

Full text of DOI:10.1080/00397911.2010.517615

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Novel Procedure for the Coupling of
Sterically Hindered Electron-Deficient
Anilines to the 6-Position of the Purine
Core
Ruben Leenders a , Jan Heeres b , Dirk Vandenput a , Jérôme
Guillemont c & Paul Lewi b
a Mercachem BV, Nijmegen, the Netherlands
b Janssen Research Foundation, Center for Molecular Design,
Vosselaar, Belgium
c Johnson and Johnson Pharmaceutical Research and Development,
Medicinal Chemistry Department, Val de Reuil, France
Available online: 27 Jul 2011
To cite this article: Ruben Leenders, Jan Heeres, Dirk Vandenput, Jérôme Guillemont & Paul Lewi
(2011): Novel Procedure for the Coupling of Sterically Hindered Electron-Deficient Anilines to
the 6-Position of the Purine Core, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:21, 3246-3250
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Synthetic Communications1, 41: 3246–3250, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517615
NOVEL PROCEDURE FOR THE COUPLING OF
STERICALLY HINDERED ELECTRON-DEFICIENT
ANILINES TO THE 6-POSITION OF THE PURINE CORE
Ruben Leenders,1 Jan Heeres,2 Dirk Vandenput,1
´ ˆ
Jerome Guillemont, and Paul Lewi
3
2
1Mercachem BV, Nijmegen, the Netherlands
2Janssen Research Foundation, Center for Molecular Design, Vosselaar,
Belgium
3Johnson and Johnson Pharmaceutical Research and Development,
Medicinal Chemistry Department, Val de Reuil, France
GRAPHICAL ABSTRACT
Abstract Sterically hindered electron-deficient anilines are coupled to the 6-position of the
purine core only when activated as their corresponding TFA-amide. The free anilines did not
react under all conditions tested. After aqueous work-up, the TFA-group is lost.
This procedure provides a new tool in the construction of purines functionalized with a
sterically hindered electron-deficient aniline in the 6-position.
Keywords Heterocycles; HIV; medicinal chemistry
INTRODUCTION
As part of our continuing search towards HIV-inhibiting pyrimidines,[1]
triazines,[2] and purines,[3] we devised a novel procedure to prepare 2,6-dianilino-
substituted 9-H-purines of general structure A possessing 2,6-disubstituted electron-
deficient anilines in the 6-position (Fig. 1). These compounds act as nonnucleoside
reverse transcriptase inhibitors (NNRTIs). In the present article, we outline the syn-
thesis of structures B, intermediates in the synthesis of purines A.
In the first step (Scheme 1), 2,6-dichloropurine 1 was protected on the imida-
zole nitrogen[4] with 4-methoxybenzyl chloride. This resulted in a 2:1 mixture of the
Received August 12, 2010.
Dedicated to the memory of Dr. Paul Janssen.
Address correspondence to Ruben Leenders, Mercachem BV, Kerkenbos 10-13, 6546 BB
Nijmegen, the Netherlands. E-mail: ruben.leenders@mercachem.com
3246

6-ANILINO-SUBSTITUTED PURINES
3247
Figure 1.
Scheme 1.
9- and 7-PMB regioisomers 2a and 2b respectively. These were conveniently sepa-
rated by column chromatography.
In further steps, we primarily used 2a as we found that the 6-chloro atom is
more easily substituted in 2a than in 2b. In the second step (see Scheme 2), 2a is func-
tionalized on the 6-position with an aniline. When sterically hindered electron-poor
anilines are used (e.g., aniline 3, Scheme 2), however, no coupling took place under
any of the conditions tested. We tested different organic [Et3N, i-Pr2NEt, pyridine,
collidine, dimethylaminopyridine (DMAP)] and inorganic bases (K2CO3, Cs2CO3
NaOH) in tetrahydrofuran (THF), DME, dioxane, dimethylformamide (DMF),
DMA, EtOH=water 1=1, microwave irradiation and Buchwald–Hartwig coupling
conditions [Pd(OAc)2, BINAP, Cs2CO3, toluene, 80 ꢀC]. No trace of the desired pro-
duct was found using any of these conditions. Electron-deficient anilines that are not
sterically hindered, however, can be coupled to the dichloroaniline core.[5]
Alternatively, as we were successful in coupling a series of phenols to the
6-position of 2a,[3] we made the aniline NH comparably as acidic as the phenol by
preparing a series of the corresponding amides.
We found that 2a could be substituted with sterically hindered electron-poor
anilines only when the aniline nitrogen is activated by a trifluoroacetyl (TFA) group,
as exemplified in Scheme 2, compound 4. N-Acetyl or N-benzoyl activation of the
aniline did not result in any coupling. pKa calculationsꢁ show similar values for
N-TFA aniline and phenol: 9.9 and 10.0 respectively. pKa N-acetylaniline: 13.5
and pKa N-benzoylaniline: 15.7. During aqueous workup, the TFA group is hydro-
lyzed and compound 5 is isolated (see also Table 1, entry 9).
In the literature, many examples can be found where TFA anilines of general
structure 6 are N-functionalized to 7 (Scheme 3). These conversions are mainly
N-alkylations,[6] intramolecular cyclizations,[7] Mitsunobu reactions,[8] and palladium
ꢁSource: http://aceorganic.pearsoncmg.com/epoch-plugin/public/pKa.jsp

3248
R. LEENDERS ET AL.
Scheme 2.
Table 1. Overview of compounds B prepared by method I or II
No.
R1
R2
R3
Method; yield (%)
1
2
Me
Me
Me
Me
Me
Me
OMe
Me
Me
Me
OMe
Cl
Me
Me
Me
Me
Me
Me
OMe
Me
Me
Me
Me
Me
Me
t-Bu
I; 84
I; 69
3
OMe
OEt
O-CH2-CN
I; 64
4a
5
I; 63a
I; 75
6
CH2-CH2-CN
OMe
CN
=
CH CH-CN
=
CH CH-C(O)-morpholinyl
I; 49
I; 99
7
8
II; 41
II; 54
II; 51
II; 72
II; 53
9
10
11
12
=
CH CH-CN
=
CH CH-CN
Method I: EtOH/water 80ꢀC; method II: see General Procedure below.
aThe dichloropurine-7-PBM 2b (see Scheme 1) was used instead of 2a.
Scheme 3.
Scheme 4.

6-ANILINO-SUBSTITUTED PURINES
3249
cross-coupling reactions.[9] To the best of our knowledge, substitution on a 2-chloro-
N-heterocycle as reported here has not been described elsewhere.
Finally, in a further modification, the 2-position of the intermediates is substi-
tuted with 4-cyanoaniline in a classical Buchwald–Hartwig coupling Pd2(dba)3,
BINAP, Cs2CO3, toluene 80 ꢀC, 12 h and the PMB group is removed in TFA at
60 ꢀC to obtain structures A (see Fig. 1).
General Procedure for Coupling TFA-Activated Anilines 6 to Purine
2a Resulting in Products B
The TFA aniline 6 (1.0 mmol, 1.0 eq.) and the protected dichloropurine 2a (1.0 eq.)
were dissolved in dimethoxyethane (DME; 20 mL), and K2CO3 (3.0 eq) was added.
The reaction mixture was stirred vigorously at 60–80 ꢀC and checked by thin-layer
chromatography (TLC) and liquid chromatography–mass spectrometry (LCMS).
After observing an acceptable conversion, the reaction was worked up.
The solvent was evaporated, and the residue was dissolved in EtOAc and
washed with aqueous NaHCO3 (sat.). The layers were separated, and the water layer
was re-extracted with EtOAc. The combined EtOAc layer was dried (brine and
Na2SO4) and concentrated.
The residue was purified by trituration with ethanol or by preparative TLC
using n-heptane=DME 2:3 as the eluent.
1H NMR of 5 (Scheme 2) (300 MHz, [d6]DMSO, 25 ꢀC, TMS): d ¼ 9.88 (s, 1H;
NH), 8.37 (s, 1H; purine-H), 7.59 [d, 3J(H,H) ¼ 16.6 Hz, 1H; ¼ CH-], 7.43 (s,
3
3
2H; ArH2), 7.32 (d, J(H,H) ¼ 8.8 Hz, 2H; ArH2), 6.92 [d, J(H,H) ¼ 8.8 Hz, 2H;
3
ArH2], 6.42 [d, J(H,H) ¼ 16.6 Hz, 1H; ¼ CH-], 5.28 (s, 2H; ArCH2), 3.72 (s, 3H;
OCH3), 2.13 ppm (s, 6H; 2 CH3).
REFERENCES
1. Leenders, R.; Heeres, J.; Guillemont, J.; Lewi, P. A. Novel route to 2,4-dianilino-
substituted pyrimidines. Tetrahedron Lett. 2010, 51, 543–544, and the literature cited there
in as Refs. 1 and 2.
2. (a) Lewi, P.; Janssen, P.; de Jonge, M.; Koymans, L.; Vinkers, H.; Daeyaert, F.; Heeres, J.;
Leenders, R.; Hoornaert, G..; Kilonda, A.; Ludovici, D. HIV-inhibiting 1,2,4-triazines.
WO Patent 2004=074266, 2004; (b) Hoornaert, G.; Kilonda, A.; Heeres, J.; Lewi, P.; de
Jonge, M.; Daeyaert, F.; Vinkers, H.; Koymans, L.; Janssen, P. HIV-inhibiting 1,2,4-
triazin-6-one derivatives. WO Patent 2006=015985, 2006; (c) Leenders, R.; Heeres, J.;
Vandenput, D.; Zijlmans, R.; Guilemont, J.; Lewi, P. 3-(Arylamino)-1,2,4-triazin-5-one:
A novel synthesis and its use. Eur. J. Org. Chem. 2010, 15, 2852–2854.
3. Janssen, P.; Lewi, P.; de Jonge, M.; Koymans, L.; Daeyaert, F.; Heeres, J.; Vinkers, H.;
Leenders, R.; Vandenput, D. HIV replication inhibiting purine derivatives. WO Patent
2005=028479, 2005.
4. Kelley, J.; Linn, J.; Krochmal, M.; Selway, J. 9-Benzyl-6-(dimethylamino)-9H-purines with
antirhinovirus activity. J. Med. Chem. 1988, 31, 2001–2004. Here 2 is prepared in 59% yield.
5. (a) Kelley, J.; Linn, J.; Selway, J. Antirhinovirus activity of 6-anilino-9-benzyl-2-chloro-9H-
purines. J. Med. Chem. 1990, 33, 1360–1363; (b) Mott, B.; Ferreira, R.; Simeonov, A.;
Jadhav, A.; Kean-Hooi Ang, K.; Leister, W.; Shen, M.; Silveira, J.; Doyle, P.; Arkin,
M.; McKerrow, J.; Inglese, J.; Austin, C.; Thomas, C.; Shoichet, B.; Maloney, D.

3250
R. LEENDERS ET AL.
Identification and optimization of inhibitors of trypanosomal cysteine protease: Cruzain,
rhodesain, and TbCatB. J. Med. Chem. 2010, 53, 52–60.
6. (a) Yoshihisa, I.; Nobuhiro, F.; Michiyo, G.; Tatsumi, M. Furoisoquinoline derivative and
use thereof. EP1541576 A1; (b) Yamada, M.; Yura, T.; Morimoto, M.; Harada, T.;
Yamada, K.; Honma, Y.; Kinoshita, M.; Sugiura, M. 2-[(2-Aminobenzyl)sulfinyl]-
1-(2-pyridyl)-1,4,5,6-tetrahydrocyclopent[d]imidazoles as a novel class of gastric Hþ=Kþ-
ATPase inhibitors. J. Med. Chem. 1996, 39, 596–604; (c) Bosch, J.; Roca, T.; Armengol,
M.; Fernandez-Forner, D. Synthesis of 5-(sulfamoylmethyl)indoles. Tetrahedron 2001,
57, 1041–1048.
7. (a) Wang, J.-Y.; Guo, X.-F.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. New strategy for
the synthesis of 1,4-benzodiazepine derivatives based on the tandem N-alkylation–ring
opening–cyclization reactions of methyl 1-arylaziridine-2-carboxylates with N-[2-bromo-
methyl(phenyl)]trifluoroacetamides. J. Org. Chem. 2008, 73, 1979–1982; (b) Kobayashi,
K.; Miyamoto, K.; Morikawa, O.; Konishi, H. Synthesis of benzazetine derivatives by
intramolecular iodoamination of O-(acylamino)styrene derivatives. Bull. Chem. Soc. Jpn.
2005, 78, 886–889; (c) Cacchi, S.; Fabrizi, G.; Parisi, L. Preparation of indoles from
O-alkynyltrifluoroacetanilides through the aminopalladation-reductive elimination process.
Synthesis 2004, 11, 1889–1894.
8. Kurkin, A.; Nesterov, V.; Karchava, A.; Yurovskaya, M. Synthesis of nonracemic
9-(1-methoxycarbonylethyl)-1,2,3,4-tetrahydrocarbazole. Chem. Heterocycl. Comp. 2003,
39, 1466–1477.
9. Cacchi, S.; Fabrizi, G.; Pace, P. Palladium-catalyzed cyclization of O-alkynyltrifluoroace-
tanilides with allyl esters: A regioselective synthesis of 3-allylindoles. J. Org. Chem. 1998,
63, 1001–1011.