Utility of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine. Part 2: Solution phase synthesis of tetrasubstituted purines

Article abstract of DOI:10.1016/j.tetlet.2003.09.112

A simple synthesis of tetrasubstituted purines is disclosed based on the solution phase elaboration of 4,6-dichloro-2-methylthio-5-nitropyrimidine. One-pot sequential C4 and C6 chloride substitution by secondary and primary amines yields 4,6-diamino-2-methylthio-5-nitropyrimidines. mCPBA-mediated oxidation of the methylthio moiety to the corresponding sulfone allows facile substitution at the 2-position. CrCl₂ assisted reduction of the nitro group, followed by acid catalyzed orthoester cyclization, then provides novel tetrasubstituted purines not accessible by other methods.

Full text of DOI:10.1016/j.tetlet.2003.09.112

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8361–8363
Utility of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine. Part 2:
Solution phase synthesis of tetrasubstituted purines†
Lars G. J. Hammarstro¨m,‡ Michael E. Meyer, David B. Smith* and Francisco X. Talama´s
Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
Received 2 September 2003; revised 16 September 2003; accepted 16 September 2003
Abstract—A simple synthesis of tetrasubstituted purines is disclosed based on the solution phase elaboration of 4,6-dichloro-2-
methylthio-5-nitropyrimidine. One-pot sequential C4 and C6 chloride substitution by secondary and primary amines yields
4,6-diamino-2-methylthio-5-nitropyrimidines. mCPBA-mediated oxidation of the methylthio moiety to the corresponding sulfone
allows facile substitution at the 2-position. CrCl2 assisted reduction of the nitro group, followed by acid catalyzed orthoester
cyclization, then provides novel tetrasubstituted purines not accessible by other methods.
© 2003 Elsevier Ltd. All rights reserved.
Due to an emerging general interest in synthetic puri-
nes as inhibitors of various biological processes,2
method for the utilization of pyrimidine 1 in the syn-
thesis of fully substituted purines 4.
a
number of solution and solid-phase methodologies for
their construction have recently been advanced.3 As
part of our own work in this area, we recently
reported on the first example of a solid-phase method-
ology applicable to the regioselective synthesis of fully
substituted purine libraries (Fig. 1).1 In that paper,
Our optimized procedure is exemplified in the synthe-
sis of 9-isopropyl-8-methyl-6-N,N-methylbenzylamino-
2-piperidinylpurine 7 according to the conditions set
forth in Scheme 1. Reaction of 1 at room temperature
with 1 equiv. of methylbenzylamine, followed after 20
min by treatment of the reaction mixture with 3 equiv.
of isopropylamine for 3 h, provided intermediate 5.
Oxidation of the methylthio moiety to the sulfone was
carried out with mCPBA, then piperidine was added
to the crude reaction to effect a third displacement
affording 6. Finally, reduction of the nitro functional-
ity according to the Miller5 procedure was followed
by acid catalyzed cyclization using trimethylorthoace-
tate to yield purine 7. Analytically pure purine 7 was
4,6-dichloro-2-(methylthio)-5-nitropyrimidine4
1
was
loaded onto resin by displacement at C-4, and then
efficiently elaborated into a resin bound purine 2.
Cleavage from the resin was then conducted to
provide purines 3. Due to the linkage of the purine on
the resin, a minor limitation of our solid-phase
method is the inability to prepare compounds such as
4 (R1, R7"H) containing a fully substituted amine at
position 6. Herein, we disclose a simple solution phase
Figure 1. 2,6,8,9-Tetrasubstituted purines 3 and 4 accessible from the starting material 4,6-dichloro-(2-methylthio)-5-nitropyrim-
idine 1.
* Corresponding author. E-mail: dave.smith@roche.com
† See Ref. 1.
‡ Roche Palo Alto Postdoctoral Fellow, 2001–2002.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.112

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L. G. J. Hammarstro¨m et al. / Tetrahedron Letters 44 (2003) 8361–8363
Scheme 1. Solution-phase synthesis of a 2,6,8,9-substituted purine. Reagents and conditions: (i) methylbenzylamine (1 equiv.),
THF, Hunig’s base, 20 min, rt, then; isopropylamine (3 equiv.), 3 h, rt; (ii) mCPBA, DCM, 16 h, rt, then; piperidine, 2 h, rt; (iii)
CrCl2 (10 equiv.), 20:1 DMF:MeOH, 4 h, rt, then; MeC(OCH3)3, MeSO3H (cat.), 24 h, 100°C.
obtained in an overall yield of 73% after recrystallization
(see experimental section).
4-(N,N-Benzylmethylamino)-6-(N-isopropylamino)-2-
methylthio-5-nitropyrimidine(5). 1(0.31g;1.29mmol)was
dissolved in THF and diisopropylethylamine (0.83 g; 6.46
mmol) was added. After stirring for 2 min, methylbenzy-
lamine (0.16 g; 1.29 mmol) was added dropwise. The
solution was allowed to stir for 20 min at room temper-
ature after which 2-propylamine (0.23 g; 3.87 mmol) was
added in one portion. The solution was stirred for an
additional 3 h at room temperature. The THF was
removed by rotary evaporation and the reaction crude
distributed between diethyl ether and 10% NH4Cl solu-
tion. The organic portion was washed with two additional
portions 10% NH4Cl solution and one portion saturated
NaCl solution. The organic layer was dried over MgSO4
and concentrated in vacuo to yield 5 as a yellow crystalline
solid (0.44 g; 98% yield).
Noteworthy in this methodology is the ability to obtain
final products 4 in high purity and good yield after a single
purification at the end of the six-step three-pot sequence.
This compares well with the overall efficiency of our
nine-step solid-phase method, which can deliver final
products 3 in good to excellent yield and purity after
chromatography following cleavage from the solid sup-
port.1 Further examples of fully substituted purines were
prepared following our optimized procedure and are
shown in Figure 2.6 Note that even anilines can be utilized
with our protocol, providing 9-aryl purines (8, 9) difficult
to obtain using other methods.
Our current solution-phase procedure requires the use of
a secondary amine in one of the initial displacement steps
in order to avoid a regiochemical complication in the
purine formation step. As a result of this, products
following this protocol are purines with fully substituted
amines at position 6 (4, 7–10). Our previously reported1
solid-phase method requires the use of a primary amine
in the initial reductive amination, thereby leading after
cleavage to purines with a mono-substituted amine at
position 6 (3). Thus these procedures are highly compli-
mentary and allow ready access to all manner of fully
substitutedpurines, representingareadytooltothosewho
wish to prepare them. A further manuscript describing
an application to library synthesis is in progress.
4-(N,N-Benzylmethylamino)-6-(N-isopropylamino)-5-
nitro-2-piperidinylpyrimidine(6). 5(0.44g;1.27mmol)was
dissolved in anhydrous dichloromethane and m-chloro-
perbenzoicacid(0.66g;77%max. purity, 2.94mmolmax.)
was added in one portion. The reaction was stirred at
room temperature for 16 h. The reaction was quenched
with 2 mL piperidine and allowed to stir for an additional
2 h, after which the dichloromethane was removed in
vacuo. The crude was dissolved in diethyl ether and
washed with two portions 10% NH4Cl solution, two
portions saturated Na2CO3, and one portion saturated
NaCl solution. The ether layer was dried over MgSO4 and
concentrated in vacuo to yield 6 as a yellow crystalline
solid (0.43 g; 88% yield).
Experimental
9-Isopropyl-8-methyl-6-N,N-methylbenzylamino-2-pipe-
ridinylpurine (7). 6 (0.43 g; 1.12 mmol) was dissolved in
20 mL 20:1 DMF:MeOH. Anhydrous CrCl2 (1.40 g; 11.2
mmol) was added in one portion and the reaction allowed
to stir at room temperature for 4 h. Trimethylortho-
4,6-Dichloro-2-methylthio-5-nitropyrimidine (1). The
starting material can be prepared according to the
procedure of Harnden and Hurst or that of Brown and
Jacobsen.4
Figure 2. Additional examples of purines prepared by the present method.6

L. G. J. Hammarstro¨m et al. / Tetrahedron Letters 44 (2003) 8361–8363
8363
acetate (3 mL) was added to the reaction, followed by
4 drops of methane sulfonic acid, and the reaction was
stirred at 100°C for 24 h. After cooling, the resulting
solution was quenched with 200 mL water and
extracted with three portions ethyl acetate. The com-
bined ethyl acetate layers were washed with two por-
tions 5% HCl, two portions NaHCO3, one portion
water and one portion saturated NaCl solution. The
organic layer was dried over MgSO4, and after filtration
the solvents were removed in vacuo. The compound
was then recrystallized from MeOH/H2O to yield 7 as a
6169; (b) Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz,
P. G. J. Am. Chem. Soc. 2002, 124, 1594; (c) Ding, S.;
Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Comb.
Chem. 2002, 4, 183; (d) Ding, S.; Gray, N. S.; Ding, Q.;
Schultz, P. G. Tetrahedron Lett. 2001, 42, 8750; (e) Ding,
S.; Gray, N. S.; Ding, Q.; Schultz, P. G. J. Org. Chem.
2001, 66, 8273; (f) Brill, W. K.-D.; Riva-Toniolo, C.;
Mu¨ller, S. Synlett 2001, 7, 1097; (g) Brun, V.; Legraverend,
M.; Grierson, D. S. Tetrahedron Lett. 2001, 42, 8161; (h)
Brill, W. K.-D; Riva-Toniolo, C. Tetrahedron Lett. 2001,
42, 6515; (i) Dorff, P. H.; Garigipati, R. S. Tetrahedron
Lett. 2001, 42, 2771; (j) Brill, W. K.-D.; Riva-Toniolo, C.;
Mu¨ller, S. Synlett 2001, 7, 1097; (k) Chang, Y.-T.; Gray,
N. S.; Rosania, G. R.; Sutherlin, D. P.; Norman, T. C.;
Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P. G. Chem.
Biol. 1999, 6, 361; (l) Gray, N. S.; Wodicka, L.; Thunnis-
sen, A.-M. W. H.; Norman, T. C.; Kwon, S.; Espinoza, F.
H.; Morgan, D. O.; Barnes, G.; LeClerc, S.; Meijer, L.;
Kim, S.-H.; Lockhart, D. J.; Schultz, P. G. Science 1998,
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R.; Gilbert, I. H.; Floyd, C. D. J. Comb. Chem. 2000, 2,
249. Solution-phase methodologies have also been
reported. For two recent examples, see: (purines from
polyhalo purines); (q) Bakkestuen, A. K.; Gundersen,
L.-L.; Langli, G.; Lui, F.; Nolsoe, J. M. J. Bioorg. Med.
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1
light yellow solid (0.36 g; 85%). H NMR (300 MHz,
CDCl3) l 7.33–7.21 (m, 5H), 5.20 (s, 2H), 4.57 (m, 1H),
3.69 (dd, 4H), 3.31 (s, 3H), 2.42 (s, 3H), 1.59 (d, 6H),
1.57–1.44 (m, 6H). 13C NMR (75 MHz, CDCl3) 157.38,
154.12, 153.60, 144.14, 139.22, 128.76, 127.76, 127.22,
112.46, 52.56, 47.06, 45.29, 25.52, 24.91, 21.03, 14.84.
MS (ESI) m/z calcd 378.25. Found: 379 (M+H)+. Anal.
calcd for C22H30N6: C, 69.81; H, 7.99; N, 22.20. Found:
C, 69.81; H, 7.94; N, 22.02. umax 297.0 nm, 245.5 nm.
Mp: 130.9–132.6°C.
References
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