6-Magnesiated Purines: Preparation and Reaction with Aldehydes

Article abstract of DOI:10.1021/ol0355027

(Equation presented) Halogen-metal exchange reaction of 9-benzyl-6-iodopurine with iPrMgCl in toluene at -80°C proceeds almost quantitatively. Such a purine-derived Grignard reagent reacts selectively with aldehydes in toluene, giving the corresponding alcohols in 25-62% yield, while other functional groups such as ketones, esters, and nitriles do not react under these conditions. The reaction can be extended to protected 6-iodopurine ribonucleoside.

Full text of DOI:10.1021/ol0355027

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4289-4291
6-Magnesiated Purines: Preparation and
Reaction with Aldehydes
Toma´sˇ Tobrman and Dalimil Dvorˇa´k*
Department of Organic Chemistry, Prague Institute of Chemical Technology,
Technicka´ 5, 166 28 Prague 6, Czech Republic
dVorakd@Vscht.cz
Received August 8, 2003
ABSTRACT
Halogen−metal exchange reaction of 9-benzyl-6-iodopurine with iPrMgCl in toluene at −80 °C proceeds almost quantitatively. Such a purine-
derived Grignard reagent reacts selectively with aldehydes in toluene, giving the corresponding alcohols in 25−62% yield, while other functional
groups such as ketones, esters, and nitriles do not react under these conditions. The reaction can be extended to protected 6-iodopurine
ribonucleoside.
Many structurally modified purine bases, nucleosides, and
nucleotides are biologically active. Their activities range from
antiviral and antineoplastic to antihypertensive activities, and
many of these compounds are clinically used drugs. Purine
derivatives bearing carbon substituents attached to ring
carbon atoms at the 2-, 6-, and 8-positions are of special
interest because such substitution should dramatically influ-
ence their base-pairing ability, binding to receptors, or
interaction with other molecules. For example, significant
cytostatic activity was found for several 6-aryl and 6-benzyl
ribonucleosides,1 and 6-hydroxymethylpurine ribonucleoside
is a strong reversible inhibitor of adenosine deaminase.2 High
inhibitory activity against Mycobacterium tuberculosis was
found for 9-benzylpurines carrying a phenylethynyl-, trans-
styryl, or aryl substituent in the 6-position.3 An important
feature of purines, containing substituents attached with a
C-C bond, is their expected stability toward enzymatic
degradation. Currently, the most frequently used methods
for introduction of C-substituents to the 2-, 6-, and 8-positions
are transition metal-catalyzed cross-coupling reactions of
purine halides. These methods employ organozinc, orga-
noaluminum, Grignard, organotin, and organoboron re-
agents.4 An opposite approach, coupling of metalated purines
with appropriate C-electrophiles, has been less developed.
Only preparation and reactivity of lithiated and 6-zincated
purines has been reported. 6-Lithiated purines can be
prepared and are stable at -130 °C, but at -78 °C rearrange
to 8-derivatives.5 8-Lithiated purines can be obtained by
halogen-metal exchange reaction6 and by BuLi-7 or LDA-
mediated8 lithiation. 6-Chloro-8-silylated purines were lithi-
ated at the 2-position. Lithio derivatives prepared by the
above methods were converted to C-substituted purines by
(4) For a recent review on the synthesis of C-substituted purines by metal-
or organometal-mediated reactions, see: Hocek, M. Eur. J. Org. Chem.
2003, 245.
(5) Leonard, N. J.; Bryant, J. D. J. Org. Chem. 1979, 44, 4612.
(6) Cong-Dahn, N.; Beacourt, J.-P.; Pichat, L. Tetrahedron. Lett. 1979,
20, 2385.
(1) (a) Hocek, M.; Holy´, A.; Votruba, I.; Dvorˇa´kova´, H. J. Med. Chem.
2000, 43, 1817. (b) Hocek, M.; Holy´, A.; Votruba, I.; Dvoˇra´kova´, H. Collect.
Czech. Chem. Commun. 2001, 66, 483.
(2) (a) Evans, B.; Wolfenden, R. J. Am. Chem. Soc. 1970, 92, 4751. (b)
Frieden, C.; Kurz, L. C.; Gilbert, H. R. Biochemistry 1980, 19, 5303.
(3) (a) Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Liu, F.; Nolsøe,
J. M. J. Bioorg. Med. Chem. Lett. 2000, 10, 1207. (b) Gundersen, L.-L.;
Nissen-Meyer, J.; Spilsberg, B. J. Med. Chem. 2002, 45, 1383.
(7) Barton, D. H. R.; Hedgecock, C. J. R.; Lederer, E.; Motherwell, W.
B. Tetrahedron Lett. 1979, 20, 279.
(8) (a) Tanaka, H.; Uchida, Y.; Shinozaki, M.; Hayakawa, H.; Matsuda,
A.; Miyasaka, T. Chem. Pharm. Bull. 1983, 31, 787. (b) Hayakawa, H.;
Haraguchi, K.; Tanaka, H.; Miyasaka, T. Chem. Pharm. Bull. 1987, 35,
72. (c) Hayakawa, H.; Tanaka, H.; Sasaki, K.; Haraguchi, K.; Saitoh, T.;
Takai, F.; Miyasaka, T. J. Heterocycl. Chem. 1989, 26, 189. (d) Czechtizky,
W.; Vasella, A. HelV. Chim. Acta 2001, 84, 594.
10.1021/ol0355027 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/11/2003

the reaction with electrophiles such as aldehydes, ketones,
and alkyl halides. 6-Zincated purines were prepared by
reaction of 6-iodopurines with activated zinc and used for
the introduction of aryl and alkenyl substituents using Pd-
mediated reactions or alkyl substituents using Cu-mediated
reactions.9 We assumed, that purine-derived Grignard re-
agents might have higher stability compared to lithium
reagents and higher reactivity compared to the zinc deriva-
tives. Herein we report on our results on the preparation and
reactivity of 6-magnesiated purines.
esters of carboxylic acids, nitriles, and iron pentacarbonyl),
only aldehydes reacted, giving the corresponding alcohols.12
Thus, the reaction of 2 with benzaldehyde afforded the
corresponding alcohol 3a in fair isolated yield (Table 1, entry
Table 1. Optimization of the Reaction of 2 with Benzaldehyde
9-Benzyl-6-iodopurine10 (1) was used as a model com-
pound. An attempt to obtain purine-derived Grignard reagent
directly from 1 and Rieke magnesium was unsuccessful
giving exclusively the product of dehalogenation. However,
the exchange reaction with i-PrMgCl in THF11 at -80 °C
smoothly afforded the desired Grignard reagent 2 in less than
30 min (Scheme 1). An almost quantitative yield of 2 was
entry
additive
solvent
HPLC yield (%)
1
2
3
4
5
6
none
THF
THF
THF
THF
52 (24)a
29
22
28
77 (59)a
CeCl3
BF3‚Et2O
TiCl4
none
none
toluene
THF/toluene (1:1)
Scheme 1
68
a Isolated yield.
1). Therefore, the procedure had to be optimized.13 While
addition of BF3‚Et2O, CeCl3, or TiCl4 (Table 1, entries 2-4)
had no effect, lowering the polarity of the solvent by
replacing THF with toluene raised the yield to 77% (HPLC
yield, Table 1, entry 5). Dilution of the THF solution with
toluene (Table 1, entry 6) had a similar effect.
obtained after 30 min, which could be detected by 1H NMR
of the reaction quenched with D2O. At 0 °C, the metalation
was finished within several minutes. A yellowish solution
of 2 is stable at -80 °C, but above 0 °C, slow decomposition
to unidentified products accompanied by a color change to
brownish yellow occurred. Migration of magnesium to the
8-position of purine nuclei even at room temperature was
not observed. 9-Benzyl-6-chloropurine was completely un-
reactive under the above conditions.
Therefore, toluene was used as a solvent for the reaction
of 2 with other aldehydes (Table 2). Low reactivity of 2
Table 2. Reaction of 2 with Aldehydes
Scheme 2
entry
R
product
isolated yield (%)
1
2
3
4
5
6
7
8
9
C6H5
H
(CH3)2CH
4-CF3C6H4
3-NO2C6H4
4-pyridyl
3,4-(CH2O2)C6H3
4-(CHO)C6H4
4-(CHO)C6H4
3a
3b
3c
3d
3e
3f
3g
3h
3h
59
34
25
62
54
46
26
27a
91b
a Ratio of 2 to aldehyde ) 1:1.6. b Ratio of 2 to aldehyde ) 2.2:1.
The reactivity of the Grignard reagent 2 was surprisingly
low. From common C-electrophiles (aldehydes, ketones,
allowed us to accomplish the reaction with aldehydes
containing groups that are generally not compatible with
Grignard reagent like a nitro group. Table 2 demonstrates
that the yield of the alcohol depends on the nature of the
aldehyde used. Thus, aliphatic aldehydes gave lower yields
of the corresponding alcohols compared to the aromatic ones
(9) (a) Stevenson, T. M.; Prasad, A. S. B.; Citineni, J. R.; Knochel, P.
Tetrahedron Lett. 1996, 37, 8375. (b) Prasad, A. S. B.; Stevenson, T. M.;
Citineni, J. B.; Nyzam, V.; Knochel P. Tetrahedron 1997, 53, 7237.
(10) Gundersen, L.-L.; Bakkestuen, A. K.; Aasen, A. J.; Øverås, H.; Rise,
F. Tetrahedron 1994, 50, 9743.
(11) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 4414.
4290
Org. Lett., Vol. 5, No. 23, 2003

(Table 2, entries 2 and 3). Among aromatic aldehydes,
benzaldehyde itself and those bearing electron-withdrawing
substituents such as NO2 or CF3 and also 4-pyridinecarbox-
aldehyde gave the best yields (Table 2, entries 1 and 4-6).
Electron-rich 3,4-(methylenedioxy)benzaldehyde afforded
only a low yield of the corresponding alcohol (Table 2, entry
7). From this point of view, the reaction of 2 with tereph-
thalaldehyde is interesting. When an excess (1.6 equiv) of
aldehyde was used, exclusive formation of monoaddition
product (3h) in 27% yield was observed. With excess of
Grignard reagent (2.2 equiv), again only monoaddition
product (3h) was formed, however, in 91% yield (calculated
with respect to terephthalaldehyde) (Table 2, entries 8 and
9). Evidently, the negative charge, being developed after
addition of 2 to the first aldehyde group, deactivates the
second carbonyl to such an extent that the second addition
does not occur.
Selective reaction of 6-magnesiated purines with aldehydes
can be demonstrated on the triacetylated nucleoside 4.14 This
compound can be smoothly converted to the Grignard reagent
with iPrMgCl at -80 °C, and further reaction with 4-tri-
fluorobenzaldehyde in toluene affords the expected alcohol
(3i) in 26% yield.
Acknowledgment. Financial support from the Grant
Agency of the Czech Republic (Grant 203/03/0035) is
gratefully acknowledged. The authors thank Dr. Michal
Hocek for helpful discussion.
(12) Several 6-hydroxymethyl and substituted hydroxymethyl purine
derivatives were previously prepared by the reaction of 6-lithiated purines
with aldehydes and ketones (ref 5) by photochemical addition of methanol
with subsequent oxidation (ref 2a): Buffel, D. K.; McGuigan, C.; Robins,
M. J. J. Org. Chem. 1985, 50, 2664. Also, conversion of 6-trichlorometh-
ylpurine to hydroxyphenyl-substituted 6-hydroxymethyl purines has been
reported: Cohen, S.; Thom, E.; Bendich, A. J. Org. Chem. 1963, 28, 1379.
(13) (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (b) Reetz, M. T.; Kyung,
S. H.; Hu¨llmann, M. Tetrahedron 1986, 42, 2931. (c) Canonne, P.; Foscolos,
G.; Caron, H.; Lemay, G. Tetrahedron 1982, 38, 3563.
Supporting Information Available: Detailed experi-
mental procedures and characterization of products 3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0355027
(14) Nair, V.; Richardson, S. G. J. Org. Chem. 1980, 45, 3969.
Org. Lett., Vol. 5, No. 23, 2003
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