Microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines

Article abstract of DOI:10.1016/S0040-4039(02)01271-6

In an attempt to discover a high-throughput method for the synthesis of 2,6,9-trisubstituted purines, it was found that microwave irradiation was beneficial in accelerating the nucleophilic displacement of halogens by amines at the C-2 position of the purine nucleus. A method for microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines is presented.

Full text of DOI:10.1016/S0040-4039(02)01271-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6169–6171
Microwave-assisted solid-phase synthesis (MASS) of
,6,9-trisubstituted purines
2
Richard E. Austin, John F. Okonya, Daniel R. S. Bond and Fahad Al-Obeidi*
Selectide, A Subsidiary of Aventis Pharmaceuticals Inc., 1580 E. Hanley Blvd, Tucson, AZ 85737, USA
Received 13 June 2002; revised 24 June 2002; accepted 28 June 2002
Abstract—In an attempt to discover a high-throughput method for the synthesis of 2,6,9-trisubstituted purines, it was found that
microwave irradiation was beneficial in accelerating the nucleophilic displacement of halogens by amines at the C-2 position of
the purine nucleus. A method for microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines is presented.
©
2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
considering an approach to the synthesis of 2,6,9-
trisubstituted purines, it was this challenge that would
be our focus.
Purines have received much attention recently owing to
their ubiquity and ability to mediate biological pro-
cesses. The facility of protocols for synthesizing substi-
tuted purines has attracted chemists interested in
The use of microwave irradiation as an alternative
mode of heating reaction mixtures has been observed to
dramatically reduce reaction times and affect product
1
–10
preparing collections of these molecules.
A common
11
theme among published sequences for preparing purine
derivatives substituted at the C-2 position by amine
displacement of a halogen is long reaction times. In
ratios and yields. Although the source of the enhance-
ments observed by employing microwave irradiation
12
techniques has been debated, this mode of heating has
Scheme 1.
*
0
Corresponding author.
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01271-6

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R. E. Austin et al. / Tetrahedron Letters 43 (2002) 6169–6171
been applied to resin bound molecules with positive
results relative to conventional heating techniques.
3. Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1998, 39,
1827–1830.
13–18
We wish to report the results of our investigation of the
synthesis of 2,6,9-tribsubstituted purines on solid phase
employing microwave irradiation to enhance observed
reaction rates.
4. Chang, Y.-T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D.
P.; Kwon, S.; Norman, T. C.; Sarohi, R.; Leost, M.;
Meijer, L.; Schultz, P. G. Chem. Biol. 1999, 6, 361–375.
5. Legraverend, M. O.; Ludwig, O.; Bisagni, E.; Leclerc, S.;
Meijer, L.; Giocanti, N.; Sadri, R.; Favaudon, V. Bioorg.
Med. Chem. 1999, 7, 1281–1293.
2
. Results and discussion
6. Dorff, P. H.; Garigipati, R. S. Tetrahedron Lett. 2001, 42,
2
771–2773.
. Brill, W. K.-D.; Riva-Toniolo, C. Tetrahedron Lett. 2001,
2, 6515–6518.
As a scaffold, we chose a 2,6-dihalopurine. Early exper-
iments had indicated that the relative reactivities of
7
8
9
4
2
-halopurines, toward nucleophilic displacement by
. Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron
Lett. 2001, 42, 8161–8164.
. Ding, S.; Gray, N. S.; Ding, Q.; Schultz, P. G. Tetra-
hedron Lett. 2001, 42, 8751–8755.
aliphatic amines, followed the order of I>F>Cl under
microwave irradiation. The requisite 2-iodosubsti-
tuted scaffold was available in multi-gram quantities in
1
9
20
three steps from 2-amino-6-chloropurine (Scheme 1).
1
1
1
1
1
1
1
1
0. Ding, S.; Gray, N. S.; Ding, Q.; Wu, X.; Schultz, P. G. J.
Comb. Chem. 2002, 4, 183–186.
1. Krstenansky, J. L.; Cotterill, I. Curr. Opin. Drug Discov-
ery Dev. 2000, 3, 454–461.
2. Camelia, G.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.;
Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213–223.
3. Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R.
J. Comb. Chem. 2002, 4, 95–105.
As examples, two closely related literature compounds
were prepared to highlight the contribution of
microwave irradiation to increase the efficiency of dis-
placement of the C-2 iodo substituent by aliphatic
2
1
amines. The resin we employed was AMEBA-linked
polystyrene that had undergone reductive amination to
2
2
deliver 4. The loading of 4 was determined by cou-
pling Fmoc-B-Ala to an aliquot of the resin and mea-
suring Fmoc release upon treatment with piperidine. A
stoichiometric portion of the scaffold 3 was added to
the resin in NMP with DIEA and heated at 60°C for 7
hours to deliver 5. Mitsunobu alkylation with isopropyl
alcohol was achieved in the presence of diisopropyl
azodicarboxylate and triphenylphosphine in THF to
provide 6. The key displacement of the C-2 iodine was
4. Hoel, A. M. L.; Nielsen, J. Tetrahedron Lett. 1999, 40,
3
941–3944.
5. Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron
Lett. 1996, 37, 8219–8222.
6. Yu, H.-M.; Chen, S.-T.; Wang, K.-T. J. Org. Chem.
1992, 57, 4781–4784.
7. Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623–1626.
18. Larhed, M. G.; Lindeberg, G.; Halberg, A. Tetrahedron
Lett. 1996, 37, 8219–8222.
23
accomplished under microwave irradiation for 30
minutes with either diethanolamine or propanolamine
to deliver, after release from the resin, the known
1
9. Unpublished results.
2
4
25
20. Synthesis of 3. Boc anhydride (164 g, 750 mmol) was
added to a slurry of 2-amino-6-chloropurine (101 g, 600
mmol) and K CO (99 g, 720 mmol) in DMF (600 mL) at
compounds 7a and 7b. HPLC analysis of the crude
products indicated that both displacements had gone to
completion and the purities were 77% and 89%, respec-
tively, for 7a and 7b. These materials were purified to
homogeneity by flash chromatography to provide the
pure products in good yield. To compare conventional
heating techniques in the acceleration of C-2 displace-
ments analogous to the transformation of 6 to 7, long
2
3
room temperature. The mixture was stirred overnight.
Added 1 L water and stirred for 1 h. The precipitate was
removed by filtration, triturated with diethyl ether,
filtered again, and air-dried to recover the Boc protected
purine (140 g, 520 mmol, 87%) as a white solid. The Boc
protected purine (53.8 g, 200 mmol) was dissolved in a
solution of dry THF (1 L) and CH2I2 (168 mL, 2.08
3,6,26
reaction times of up to 48 hours are typical.
mmol). 4 A
mixture heated to 50°C under nitrogen. Isoamyl nitrite
84 mL, 620 mmol) was added and the mixture stirred
,
molecular sieves (40 g) were added and the
As a result of this investigation, we produced a large
collection of 2,6,9-trisubstituted purines employing
microwave irradiation in a parallel fashion to affect C-2
halogen displacement with aliphatic amines. Purities for
these molecules are typically greater than 75% and
(
overnight. The reaction mixture was filtered and concen-
trated under reduced pressure to a thick syrup. The
material was loaded directly onto a large flash column
and eluted with 95:5 toluene:EtOAc to recover 2 (27.9 g,
1
9
isolated yields range from 30% to 80%.
73 mmol, 37%) as a light brown solid. The iodinated
References
purine 2 (54.2 g, 143 mmol) was dissolved in CH Cl (700
2
2
mL). Trifluoroacetic acid (4.3 mL, 56 mmol) was added
at 24 h intervals for 3 days (12.9 mL TFA total). The
resulting precipitate was removed by filtration (36.4 g,
92.3 mmol). The filtrate was concentrated under reduced
pressure and the resulting solid triturated with 2:1 hex-
ane:diethyl ether. The second crop (17.9 g, 45.4 mmol)
was recovered by filtration. The total yield of 3 was 54.3
g (138 mmol, 96%).
1
. Nugiel, D. A.; Cornelius, L. A. M.; Corbett, J. W. J. Org.
Chem. 1997, 62, 201–203.
. Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.;
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man, D.; Nelson, M. G.; Wang, X.; Wick, M. M.; Zhang,
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2
702.

R. E. Austin et al. / Tetrahedron Letters 43 (2002) 6169–6171
6171
2
1. Scaffold coupling. Resin 4 (553 mg, 0.60 mmol/g, 0.332
mmol) was treated with a solution of 6-chloro-2-iodo-
purine (3, 131 mg, 0.332 mmol) and DIEA (177 mL, 0.995
mmol) in N-methylpyrrolidinone (NMP, 5 mL). The
mixture was heated at 60°C for 7 h. The resin was washed
five times with DMF, five times with THF, and dried
under vacuum to provide 5. Mitsunobu alkylation. To a
solution of triphenylphosphine (435 mg, 1.66 mmol) in
THF (6 mL) was added diisopropyl azodicarboxylate
three times with THF, three times with MeOH, and dried
under vacuum. The final products were released from the
resin by cleavage with 92:8 TFA:water at 60°C. The
products were extracted using a 50:30:20 mixture of
water:THF:MeOH. And purified by normal phase flash
chromatography, eluting with a 95:5 mixture of CH Cl :7
2
2
N NH in MeOH. The final products 7a and 7b exhibited
3
spectral and mass data consistent with their structures.
22. Austin, R. E.; Waldraff, C. A.; Al-Obeidi, F. Tetrahedron
Lett. 2002, 43, 3555–3556.
(DIAD, 327 mL, 1.66 mmol) followed by isopropyl alco-
hol (127 mL, 1.66 mmol). The solution was added to the
resin. After 24 h, the resin washed four times with DMF,
three times with THF, three times with MeOH, and dried
under vacuum to provide 6. Nucleophilic displacement and
release. Resin 6 was placed in a Teflon reaction vessel.
The resin was covered with a 1 M solution of amine (10
mL per mg of resin). The mixture was heated in a
23. CEM Corporation, PO Box 200, Matthews, NC 28106,
USA.
24. Verdugo, D. E.; Cancilla, M. T.; Ge, X.; Gray, N. S.;
Chang, Y.-T.; Schultz, P. G.; Negishi, M.; Leary, J. A.;
Bertozzi, C. R. J. Med. Chem. 2001, 44, 2683–2686.
25. Otyepka, M.; Krystof, V.; Havlicek, L.; Siglerova, V.;
Strnad, M.; Koca, J. J. Med. Chem. 2000, 43, 2506–2513.
26. Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett.
1997, 38, 1161–1164.
23
microwave oven to a temperature of 200°C for a period
of 30 min. The resin was washed four times with DMF,