Selective synthesis of 7-substituted purines via 7,8-dihydropurines

Article abstract of DOI:10.1021/ol1025525

A simple and efficient protocol for the preparation of 7-substituted purines is described. 6- and 2,6-Dihalopurines were N⁹-tritylated and then transformed to 7,8-dihydropurines by DIBAL-H. Subsequent N ⁷-alkylation followed by N⁹-trityl deprotection with trifluoroacetic acid was accompanied by spontaneous reoxidation, which led to the 7-substituted purines at 55 - 88% overall isolated yields.

Full text of DOI:10.1021/ol1025525

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5724-5727
Selective Synthesis of 7-Substituted
Purines via 7,8-Dihydropurines
Vladislav Kotek, Nadeˇzˇda Chud´ıkova´, Toma´sˇ Tobrman, and Dalimil Dvorˇa´k*
Department of Organic Chemistry, Institute of Chemical Technology, Prague,
Technicka´ 5, 166 28 Prague 6, Czech Republic
dalimil.dVorak@Vscht.cz
Received October 21, 2010
ABSTRACT
A simple and efficient protocol for the preparation of 7-substituted purines is described. 6- and 2,6-Dihalopurines were N9-tritylated and then
transformed to 7,8-dihydropurines by DIBAL-H. Subsequent N7-alkylation followed by N9-trityl deprotection with trifluoroacetic acid was
accompanied by spontaneous reoxidation, which led to the 7-substituted purines at 55-88% overall isolated yields.
The 2- and/or 6-,9-substituted purines form a vast group of
biologically active compounds.1 Moreover, some naturally
occurring 7-substituted purines also exhibit interesting
biological properties. Caffeine represents probably the best
known N7-substituted purine derivative. Other examples are
Raphanatin and 6-(benzylamino)-7-(ꢀ-D-glucopyranosyl)pu-
rine, which possess cytokinin activity2 or 2-amino-7-[(1,3-
dihydroxy-2-propoxy)methyl]purine, that exhibit high anti-
viral activity.3 Also asmarine alkaloids with their significant
cytotoxicity against various tumor cell lines can be consid-
ered as 7-substituted purines.4 The other group of N7-
substituted purines is represented by the 7,9-disubstituted
purine motif, which can be found in many biologically
relevant compounds, including the mRNA cap analogs.5
While the biological activity of 7-substituted purines has
clearly been demonstrated, the synthetic approaches to them
are rather limited in scope.
7-Substituted purines can be prepared by labored cycliza-
tion of appropriate diaminopyrimidine derivatives6 or by
direct alkylation of purine bases. It however, usually leads
to mixtures of both N7 and N9-alkyl derivatives in which the
latter predominates.7 Only a few 2- or 6-aminopurine
derivatives have been reported to undergo N7-alkylation
preferentially. Thus N3-benzyladenine can be selectively
alkylated at the N7-position and subsequent debenzylation
affords N7-substituted adenine.8 Glycosidation of trisilylated
N2-acetylguanine9 and alkylation of disilylated 2-acetamido-
6-chloropurine5 was also reported to produce 7-substituted
(1) For a recent review of naturally occurring 7- and 9-substituted purines
see: Rosemeyer, H. Chem. BiodiVersity 2004, 361.
(2) Duke, C. C.; Liepa, A. J.; MacLeod, J. K.; Letham, D. S.; Parker,
C. W. J. Chem. Soc., Chem. Commun. 1975, 964, and references cited
therein.
(3) Ja¨hne, G.; Kroha, H.; Mu¨ller, A.; Helsberg, M.; Winkler, I.; Gross,
G.; Scholl, T. Angew. Chem., Int. Ed. 1994, 33, 562.
(5) (a) Recent examples: Jemielity, J.; Kowalska, J.; Rydzik, A. M.;
Darzynkiewicz, E. New. J. Chem. 2010, 34, 829. (b) Cai, A.; Jankowska-
Anyszka, M.; Centers, A.; Chebicka, L.; Stepinski, J.; Stolarski, R.;
Darzynkiewicz, E.; Rhoads, R. E. Biochemistry 1999, 38, 8538.
(6) Montgomery, J. A.; Hewson, K. J. Org. Chem. 1961, 26, 4469.
(7) (a) Montgomery, J. A.; Temple, C. J. Am. Chem. Soc. 1961, 83,
630. (b) Lukin, K. A.; Yang, C.; Bellettini, J. R.; Narayanan, B. A.
Nucleosides Nucleotides Nucleic Acids 2000, 19, 815.
(4) (a) Yosief, T.; Rudi, A.; Stein, Z.; Goldberg, I.; Gravalos, G. M. D.;
Schleyer, M.; Kashman, Y. Tetrahedron Lett. 1998, 39, 3323. (b) Rudi,
A.; Shalom, H.; Schleyer, M.; Benayahu, Y.; Kashman, Y. J. Nat. Prod.
2004, 67, 106. (c) Rudi, A.; Aknin, M.; Gaydou, E.; Kashman, Y. J. Nat.
Prod. 2004, 67, 1932. (d) Yosief, T.; Rudi, A.; Kashman, Y. J. Nat. Prod.
2000, 63, 299.
10.1021/ol1025525  2010 American Chemical Society
Published on Web 11/19/2010

purine derivatives selectively. Another example is N6-
[(dimethylamino)methylen]adenine, which is alkylated ex-
clusively at the N7-position.10 We have recently shown that
this compound as well as N2-[(dimethylamino)methylen]-
guanine can also be arylated with high N7-selectivity.11
On the other hand, the selective N7-alkylation of 2- or 2,6-
halopurines is a troublesome procedure, because direct
alkylation leads to predominance by the N9-isomer.12 Issues
related to regioselectivity have been addressed by N7-
alkylation of 6-chloro-9H-purine and 2,6-dichloro-9H-purines
in the presence of sophisticated Co-complexes.13 In addition,
reversible Michael addition of 6-chloro-9H-purine to acry-
lonitrile provided a temporary N9-protecting group for the
N7-alkylation of 6-chloro-9H-purine during the total synthesis
of asmarines.14 Despite some progress in the area of N7-
alkylation of halopurines, studies of biological activity are
limited by the availability of such compounds from a simple,
efficient and convenient protocol.
mentioned.18 Therefore, we initially tested the ability of the
imidazoyl moiety of purine to undergo reduction under
various conditions. The results are summarized in Table 1.
Table 1. Reduction of 9-Substituted 6-Halo and
2,6-Dihalopurines under Various Conditions
entry
X, Y, R
reagenta
yield (%)b
c
1
2
3
4
5
6
7
8
Cl, H, C6H5CH2(1a)
Cl, H, C6H5CH2 (1a)
Cl, H, C6H5CH2 (1a)
Cl, H, C6H5CH2 (1a)
Cl, H, C6H5CH2 (1a)
I, H, C6H5CH2 (1b)
Cl, H, (C6H5)3C (1c)
Cl, I, C6H5CH2 (1d)
NaBH4
LiAlH4
2a (73)d 1a (27)d
2a (77)
2a (79)
LiBEt3H
e
LiAlH4
3a (67)
Therefore we envisioned that selective N7-alkylation of
7,8-dihydropurines followed by N9-deprotection and reoxi-
dation may be used as a simple route for the synthesis of
N7-substituted purine derivatives (Scheme 1).
DIBAL-H 2a (97)
DIBAL-H 2b (89)
DIBAL-H 2c (94)
DIBAL-H 2d (97)
9
10
11
MeO, H, C6H5CH2 (1e) DIBAL-H 2e (65)
Ph, H, C6H5CH2 (1f) DIBAL-H 2f (65)
NEt2, H, C6H5CH2 (1g) DIBAL-H
-
a Reaction conditions: Reducing reagent (1.2 equiv) was added to a
solution of purines 1a-g and the reaction mixture was stirred for 2 h at
room temperature. b Isolated yield. c Reaction mixture was refluxed for 2
Scheme 1. Envisaged Route to 7-Alkylated-7H-purines
d
days. 1H NMR yield. e Reaction mixture was stirred for 4 h at 60 °C.
Attempts to use the Pd-catalyzed triethylsilane reduction20
of 9-benzyl-6-chloro-9H-purine (1a) in various solvents
(DMF, THF, dioxane) at an elevated temperature led to the
full recovery of the starting compound. Repetition of the
To our surprise only a few reports have been published
dealing with the preparation of 7,8-dihydropurine derivatives.
The reported protocols for the preparation of these com-
pounds are limited mainly to the action of boron-derived
reducing reagents, for example, NaBH4,15 NaBH4/HCl,16
NaBH3CN/AcOH,17 BH3·THF,18 and NaBH4/AcOH..19 The
reduction of adenine derivatives with DIBAL-H was also
1
reported NaBH4 reduction of 1a gave 2a at 73% H NMR
yield along with the unreacted chloropurine 1a (Table 1,
Entry 1). Complete consumption of 1a was achieved with
LiAlH4 and LiBEt3H; however, the isolated yields of 2a did
not change significantly (Table 1, Entries 2,3).
Interestingly, lithium aluminum hydride reduction carried
out at 60 °C furnished pyrimidine derivative 3a (Table 1,
Entry 4). In contrast, DIBAL-H selectively and efficiently
reduced 6-halopurines 1a,b,c and 2,6-dihalopurine 1d to the
corresponding 7,8-dihydropurines 2a-d almost quantitatively
(Table 1, Entries 5-8). The outcome of the reduction was
considerably influenced by the nature of the substituent in
position 6. While purines bearing 6-MeO (1e) and 6-Ph (1f)
groups were reduced at somewhat lower yield, the 6-NEt2(1g)
derivative failed to give any dihydropurine derivative (Table
1, Entries 9-11). The character of the substituent also
influenced the stability of the obtained dihydropurine. Thus,
halogen-bearing dihydropurines 2a, 2b, and 2d showed
excellent stability in air and no traces of reoxidized product
1 were observed after several months of storage in air in the
(8) (a) Leonard, N. J.; Fujii, T.; Saito, T. Chem. Pharm. Bull. 1986, 34,
2037. (b) Fujii, T.; Saito, T.; Inoue, I.; Kumazawa, Y.; Leonard, N. J. Chem.
Pharm. Bull. 1986, 34, 1821–1825.
(9) Garner, P.; Ramakanth, S. J. Org. Chem. 1988, 53, 1294.
(10) Hockova´, D.; Budeˇsˇ´ınsky´, M.; Marek, R.; Marek, J.; Holy´, A. E. J.
Org. Chem. 1999, 2675.
(11) Keder, R.; Dvorˇáková, H.; Dvorˇák, D. Eur. J. Org. Chem. 2009,
1522.
(12) For examples, see: (a) Toyota, A.; Katagiri, N.; Kaneko, C. Chem.
ˇ
Pharm. Bull. 1992, 40, 1039. (b) Cesnek, M.; Holy´, A.; Masoj´ıdkova´, M.
Tetrahedron 2002, 58, 2985. (c) Landli, G.; Gundersen, L.-L.; Rise, F.
Tetrahedron 1996, 52, 5625. (d) Brik, A.; Wu, C.-Y.; Best, M. D.; Wong,
C.-H. Bioorg. Med. Chem. 2005, 13, 4622.
(13) Dalby, C.; Bleasdale, C.; Clegg, W.; Elsegood, M. R. J.; Golding,
B. T.; Griffin, R. J. Angew. Chem., Int. Ed. 1993, 32, 1696.
(14) Pappo, D.; Shimony, S.; Kashman, Y. J. Org. Chem. 2005, 70,
199.
(15) Kelley, J. L.; Linn, J. A. J. Org. Chem. 1986, 51, 5435.
(16) Pendergast, W.; Hall, W. R. J. Heterocyclic Chem. 1989, 26, 1863.
(17) Sako, M.; Saito, T.; Kameyama, K.; Hirota, H.; Maki, Y. J. Chem.
Soc., Chem. Commun. 1987, 1298.
(20) For recent examples of Pd-catalyzed triethylsilane reduction, see:
(a) Luo, F.; Pan, C.; Wang, W.; Ye, Z.; Cheng, J. Tetrahedron 2010, 66,
1399. (b) Mandal, P. K.; McMurray, J. S. J. Org. Chem. 2007, 72, 6599.
(c) Nakanishi, J.; Tatamidani, H.; Fukumoto, Y.; Chatani, N. Synlett 2006,
869.
(18) Trafelet, H.; Stulz, E.; Leumann, C. HelV. Chim. Acta 2001, 84,
87.
(19) Maki, Y.; Suzuki, M.; Ozeki, K. Tetrahedron Lett. 1976, 17, 1199.
Org. Lett., Vol. 12, No. 24, 2010
5725

solid state at room temperature. In contrast, dihydropurines
containing electron-donating substituents 2e,f and also the
9-trityl derivative 2c were easily oxidized to 1e,f and 1c upon
exposure to air within a couple of weeks. For their instability,
the compounds 2e and 2f were not included in the further
study.
Next, we focused on the alkylation of the obtained
dihydropurines 2. For optimization of the alkylation condi-
tions, the reaction of 2a and 2b with iodomethane was carried
out. The first experiments confirmed the previously reported
low stability of 7,8-dihydropurines in the presence of a
base.15 Thus, attempts to alkylate 2a in the presence of
sodium hydride in THF afforded a 3:1 mixture of the desired
7-methylated purine 4a and 9-benzyl-9H-purine (5) as the
product of dehydrohalogenation at low yield (Table 2, Entry
dihydropurine (2a), 6-chloro-7,8-dihydro-9-tritylpurine (2c)
and 9-benzyl-6-chloro-7,8-dihydro-2-iodopurine (2d) reacted
smoothly with highly reactive benzyl (Table 3, Entries 1-3),
Table 3. Preparation of the 7,9-Disubstituted Dihydropurines 4
Table 2. Optimization of the Reaction of
9-Benzyl-6-halo-7,8-dihydropurines 2 with CH3I
base, temp
(°C), time (h)
entry compound solvent
yield (%)a
1
2
3
4
5
6
7
8
9
a
2a
2a
2b
2a
2a
2a
2a
2a
2a
THF
NaH, -78 to rt 4a (30) 5 (10)
DMF
DMF
HMPA
HMPA
MeCN
DMF
DMF
DMF
NaH, rt, 1b
1a (60)c 5 (21)c
NaH, rt, 1b
1b (14)c 5 (71)c
d
K2CO3, rt, 24
K2CO3, 60, 20
K2CO3, 60, 20
DBU, 0 to rt
LiTMP, rt, 0.5
NaH, rt, 0.5
a Isolated yield. b Reaction conditions: A solution of the alkylhalide
(1.5 equiv) in dry DMF was added to a mixture of NaH (1.2 equiv) and
7,8-dihydropurine 2. The resulting mixture was stirred for 2 h at room
temperature. c “One-pot” protocol was used: DIBAL-H (1.2 equiv) was
added to a solution of 1 and the mixture was stirred for 2 h at room
temperature, quenched by Na2SO4·10H2O, filtrated through Celite and
concentrated in vacuo. The crude product was mixed with NaH (1.2 equiv)
followed by addition of a solution of RX (1.5 equiv) in dry DMF. The
resulting mixture was stirred for 2 h at room temperature.
4a (25) 5 (<10)
4a (15) 5 (<10)
4a (51) 5 (<10)
4a (92)c
4a (88)c
1H NMR yield. b Reaction without CH3I. Reaction conditions: dry
DMF was added to a mixture of 2a or 2b (1.0 equiv) and NaH (1.2 equiv).
The resultant mixture without addition of CH3I was stirred for 1 h at room
temperature. c Isolated yield. d Unreacted starting 2a was recovered.
1). The tendency of 2a and 2b to elimination was confirmed
by the reaction with NaH without CH3I. 9-Benzyl-9H-purine
(5) was isolated at 21 and 71% yield, respectively, in this
case (Table 2, Entries 2,3). Other bases such as K2CO3 and
DBU suppressed the dehydrohalogenation, but the yield of
4 did not exceed 51% (Table 2, Entries 4-7). Acceptable
isolated yields of 4 were obtained when 2a was alkylated in
the presence of LiTMP or NaH in dry DMF; however, to
avoid a side-reaction, DMF and iodomethane had to be mixed
with a mixture of 2a and the base simultaneously (Table 2,
Entries 8,9). Since NaH is readily available and gives
comparable results to lithium 2,2,6,6-tetramethylpiperidine,
it was used for further alkylation experiments.
allyl (Table 3, Entries 4-8) and propargyl halides (Table 3,
Entries 9,10). High yields of 7-alkylated products were also
obtained with unactivated primary and secondary alkyl
halides (Table 3, Entries 11-13). An attempt to simplify
the above procedure by combining the reduction and alky-
lation steps was made. Thus, simple concentration of the
reaction mixture after the reduction of 1a, followed by the
addition of NaH, dry DMF and benzyl chloride gave 4b at
54% isolated yield. However, a different workup including
quenching of the reaction mixture with Na2SO4·10H2O after
reduction, filtration through Celite and concentration in vacuo
followed by alkylation gave the desired 4b at 86% yield
(Table 3, Entry 14). Similarly, “one-pot” alkylation of 1c
with allyl bromide or 3,3-dimethylallyl bromide gave 4e or
4f at fairly good yields (Table 3, Entries 15,16). Moreover,
the synthesis of N7-substituted-6-iodo-7,8-dihydropurine
nucleoside 4o was accomplished at 60% isolated yield using
Since adenine itself and adenosine derivatives were not
reduced by DIBAL-H, we focused on 6-halo and 2,6-
dihalopurines as precursors of adenine and guanine deriva-
tives. Under the above conditions 9-benzyl-6-chloro-7,8-
5726
Org. Lett., Vol. 12, No. 24, 2010

this protocol starting from 6-iodo-9-(2,3-O-isopropylidene-
5-O-trityl-ꢀ-D-ribofuranosyl)-9H-purine (1h)21 (Table 3,
Entry 17).
Table 4. Overall Transformation of 6-Chloro- and
2,6-Dichloro-9H-purine to 7-Substituted Purines 6
The selective synthesis of 7-substituted purines was
subsequently accomplished. Selection of the appropriate
protecting group for the protection of position 9 of the purine
ring plays a crucial role. After several attempts, the trityl
group was chosen because it can be introduced with high
N9-regioselectivity and deprotection proceeds easily under
mild conditions. Thus, 6-chloro-9H-purine reacted with TrCl
in the presence of triethylamine furnishing 9-trityl-6-chloro-
9H-purine (1c) at 97% isolated yield. Subsequent reduction
to 2c (94%) followed by alkylation (Table 3, Entries 4,5,11)
gave dihydropurines 4e,f,l at 87, 73 and 79% overall yield
(three steps). Subsequent deprotection by trifluoroacetic acid
was accompanied by spontaneous oxidation22 affording the
7-alkyl-6-chloro-9H-purines 6e, 6f, and 6l at 82, 70 and 79%
overall yield respectively starting from 6-chloro-9H-purine
(Table 4, Entries 1-3).
deprotection
4 f 6 (%)
overall
entry
Z
R
yielda (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
CH2dCHCH2
(CH3)2CdCHCH2
Me
C6H5CH2
HCt CCH2
(CH3)2CH
MeO2CCH2
(CH3)2CH
4-CH3OC6H4CH2
95
96
99
-
-
-
-
-
-
6e (82)
6f (70)
6l (79)
6b (86)
6j (55)b
6n (73)
6p (72)
6q (80)
6r (87)
H
Clc
Cl
In this case the overall number of separation steps can
also be reduced. The starting halopurine was converted to
6-chloro-9-trityl-9H-purine (1c) or 2,6-dichloro-9-trityl-9H-
purine (1i) followed by alkylation according to the above
“one-pot” procedure and the crude alkylated dihydropurines
4 were directly treated with trifluoroacetic acid giving the
desired 7-substituted purines 6. Thus, benzyl, propargyl,
isopropyl and (methoxycarbonyl)methyl derivatives were
cleanly and selectively obtained at overall yields ranging
from 55 to 86% (Table 4, Entries 4-7) using column
chromatography only for the isolation of 1c and the final
7-substituted purines 6. Similar results were obtained for the
N7-alkylation of 2,6-dichloropurine by 2-iodopropane and
4-methoxybenzyl bromide (Table 4, Entries 8,9).
a Overall isolated yield starting from 6-chloro-9H-purine or 2,6-dichloro-
9H-purine. b MnO2 had to be used to oxidize the 6-chloro-7-propargyl-7,8-
dihydropurine 4j to 6j quantitatively. c 2,6-Dichloro-9-trityl-9H-purine was
obtained at 89% yield.
preparation of 6-halo and 2,6-dihalopurines bearing prim.
or sec. alkyl, benzyl, allyl and propargyl groups in the
position N7 at 55-88% overall yield starting from the
corresponding halopurine. Further studies to extend the scope
of this methodology, screening of biological activity and
study of the reactivity of novel 7,8-dihydropurines and
7-substituted purines are underway in our laboratory.
In summary, we have developed a new simple and
selective protocol for the synthesis of 7-substituted purines.
This methodology is based on the successive N9-protection,
reduction, N7-alkylation and N9-deprotection accompanied
by reoxidation of the starting purine derivative. It allows the
Acknowledgment. This project was supported by the
Research Centre “The Structure and Synthetic Applications
of Transition Metal Complexes-LC06070” of the Ministry
of Education, Youth and Sports of the Czech Republic and
by the Grant Agency of the Czech Republic (grant no. 203/
09/1552).
(21) Hocek, M.; Holy´, A. Collect. Czech. Chem. Commun. 1999, 64,
229.
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) The oxidation of dihydropurine derivatives 4 to the purines 6 was
practically quantitative in all described cases. Only in the preparation of
7-propargyl derivative 6j was a mixture of dihydropurines 4j and 6j
obtained. The oxidation of the above mixture was easily achieved by stirring
the CH2Cl2 solution with MnO2 for 1 h (see Supporting information).
OL1025525
Org. Lett., Vol. 12, No. 24, 2010
5727