Selective magnesiation of chloro-iodopurines: An efficient approach to new purine derivatives

Article abstract of DOI:10.1021/ol053013w

Both 6-chloro-2-iodo-9-isopropylpurine (1) and 2-chloro-6-iodo-9- benzylpurine (4) undergo a selective I/Mg exchange reaction with iPrMgCl at -80 °C. The reaction course at 0 °C is different. Magnesiation of 1 proceeds with the migration of magnesium to t

Full text of DOI:10.1021/ol053013w

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1291-1294
Selective Magnesiation of
Chloro-iodopurines: An Efficient
Approach to New Purine Derivatives
Toma´sˇ Tobrman and Dalimil Dvorˇa´k*
Department of Organic Chemistry, Prague Institute of Chemical Technology,
Technicka´ 5, 166 28 Prague 6, Czech Republic
dalimil.dVorak@Vscht.cz
Received December 13, 2005
ABSTRACT
Both 6-chloro-2-iodo-9-isopropylpurine (1) and 2-chloro-6-iodo-9-benzylpurine (4) undergo a selective I/Mg exchange reaction with iPrMgCl at
80 C. The reaction course at 0 C is different. Magnesiation of 1 proceeds with the migration of magnesium to the 8 position of the purine
−
°
°
nuclei. In the case of 4, substitution of iodine with an alkyl group from the Grignard reagent accompanied with a Cl/Mg exchange reaction
takes place, and 6-alkyl-2-magnesiated purines (9) are formed. Thus prepared Grignard reagents afford the corresponding alcohols by the
reaction with aldehydes.
The biological activity of structurally modified purine
derivatives is well-known. Their activities span a wide range
from antiviral and antineoplastic to hypertensive. Some
substituted purines are inhibitors of cyclin-dependent kinases1
with potential application in a large variety of pathologies
such as cancers, glomerulonephritis, restenosis, proliferation
of parasites, and neurodegenerative disorders.2 Substituted
purines also attract attention as inhibitors of estrogen
sulfotransferase3 and tubulin polymerization4 and as antago-
nists of a corticotropin-releasing hormone.5 6-(Hydroxy-
methyl)purine can be considered a homologue of hypoxan-
thine and a potential transition-state analogue for adenosin
deaminase,6 and 6-hydroxymethyl-9-(â-D-ribofuranosyl)pu-
rine was reported as an adenosine deaminase inhibitor.7
Cross-coupling of an O-protected hydroxymethyl zinc re-
agent with 6-halopurines has been recently used for the
preparation of 6-hydroxymethylpurine derivatives.8 Another
possibility of introduction of an R-hydroxy group to the
purine moiety utilizes reaction of metalated purines with
(3) 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.
(4) (a) Rosania, G. R.; Chang, Y.-T.; Perez, O.; Sutherlin, D.; Dong, H.
L.; Lockhart, D. J.; Schultz, P. G. Nat. Biotechnol. 2000, 18, 304. (b) Chang,
Y.-T.; Wignall, S. M.; Rosania, G. R.; Gray, N. S.; Hanson, S. R.; Su, A.
I.; Merlie, J.; Moon, H. S.; Sangankar, S. B.; Perez, O.; Heald, R.; Schultz,
P. G. J. Med. Chem. 2001, 44, 4497. (c) Franeˇk, F.; Siglerova´, V.; Havl´ıcˇek,
L.; Strnad, M.; Eckschlager, T.; Weigl, E. Collect. Czech. Chem. Commun.
2002, 67, 257.
(5) Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.; Gilligan,
P. Bioorg. Med. Chem. Lett. 1999, 9, 1063.
(6) Erion, M. D.; Reddy, M. R. J. Am. Chem. Soc. 1998, 120, 3295.
(7) (a) Evans, B.; Wolfenden, R. J. Am. Chem. Soc. 1970, 92, 4751. (b)
Wolfenden, R.; Wentworth, D. F.; Mitchell, G. N. Biochemistry 1977, 16,
5071.
(1) (a) Havl´ıcˇek, L.; Hanusˇ, J.; Vesely´, J.; Leclerc, S.; Meijer, L.; Shaw,
G.; Strnad, M. J. Med. Chem. 1997, 40, 408. (b) Legraverend, M.; Ludwig,
O.; Bisagni, E.; Leclerc, S.; Meijer, L. Bioorg. Med. Chem. Lett. 1998, 8,
793. (c) Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer, L.;
Giocanti, N.; Sadri, R.; Favaudon, V. Bioorg. Med. Chem. 1999, 7, 281.
(d) Gray, N. S.; Wodicka, L.; Thunnissen, A.-M. W. H.; Nornam, 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, 281, 533. (e)
Chang, Y.-T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.; Kwon, S.;
Norman, T. C.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P. G. Chem.
Biol. 1999, 6, 361.
(2) Meijer, L. Trends Cell Biol. 1996, 6, 393.
10.1021/ol053013w CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/03/2006

carbonyl compounds. This approach is limited to lithiated9
and magnesiated10 purine derivatives. In our previous paper,
we have shown that 6-iodo-9-substituted purines (but not
6-chloro derivatives) can be converted to 6-magnesiated
purines by an I/Mg exchange reaction.10 This methodology
allowed us to prepare purines bearing R-hydroxyalkyl groups
in the 6 position. Herein, we wish to report results of our
continuing research concerning the I/Mg exchange reaction
of 2,6-dihalopurines leading to new hydroxyalkylpurine
derivatives with potential biological activity.
Because chlorine cannot be exchanged in the reaction of
6-chloropurine derivatives with iPrMgCl,10 selective ex-
change of iodine for magnesium in mixed chloro-iodopurine
derivatives was expected. Products of such a reaction would
bear a chlorine atom suitable for further synthetic transfor-
mations such as cross-coupling reactions or nucleophilic
substitution. We started our study of the halogen-magnesium
exchange reaction with 6-chloro-2-iodo-9-isopropylpurine
(1).11 Reaction of 1 with iPrMgCl at -80 °C followed by
addition of benzaldehyde at the same temperature smoothly
afforded the expected 6-chloro-2-(phenylhydroxymethyl)-
purine derivative 2a in 85% yield (Scheme 1, Table 1, entry
Table 1. Formation of 6-Chloro-9-isopropyl-2-substituted
Hydroxymethylpurines 2 (Scheme 1)
entry
R
product (yield %)
1
2
3
4
5
6
7
Ph
(CH3)2CH
2a (85)
2b (76)
2c (69)
2d (73)
2e (79)
2f (49)
2g (48)
3-NO2C6H4
4-MeOC6H4
PhCHdCH
PhCH2OCH2
MeCO2CH2
(Scheme 1). This is similar to the behavior of 6-lithiated
purines that isomerize to the thermodynamically more stable
8-isomers even at -80 °C.8a In agreement with Scheme 1,
quenching the reaction mixture after magnesiation at 0 °C
with D2O at the same temperature resulted in the formation
of 8-D-6-chloro-9-isopropylpurine. The reaction most prob-
ably proceeds via bimolecular transmetalation where a
2-magnesiated derivative traps the H-8 of another one.
Reaction of isomeric 9-benzyl-2-chloro-6-iodopurine12 (4)
with iPrMgCl at -80 °C also proceeded with selective
exchange of iodine for magnesium. 9-Benzyl-2-chloropurine
(5) was obtained after quenching the reaction mixture with
water in almost quantitative yield, and the reaction with
benzaldehyde afforded the corresponding alcohol (6) in 50%
yield (Scheme 2). In contrast, when the reaction was run
Scheme 1
Scheme 2
1). Other aromatic and aliphatic aldehydes behave similarly
under these conditions (Table 1, entries 2-7). Even alde-
hydes bearing nitro or acetoxy groups (Table 1, entries 3
and 7) reacted selectively on the aldehyde function furnishing
the corresponding secondary alcohols 2f and 2g in good
yields. However, when the I/Mg exchange reaction was
performed at 0 °C, purine derivative 3 bearing the secondary
alcohol moiety at the 8 position of the purine nuclei was
obtained, after addition of benzaldehyde, in 47% yield
(8) Sˇilha´r, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Lett. 2004, 6, 3225.
(9) (a) Leonard, N. J.; Bryant, J. D. J. Org. Chem. 1979, 44, 4612. (b)
Cong-Dahn, N.; Beacourt, J.-P.; Pichat, L. Tetrahedron Lett. 1979, 20, 2385.
(c) Barton, D. H. R.; Hedgecock, C. J. R.; Lederer, E.; Motherwell, W. B.
Tetrahedron Lett. 1979, 20, 279. (d) Tanaka, H.; Uchida, Y.; Shinozaki,
M.; Hayakawa, H.; Matsuda, A.; Miyasaka, T. Chem. Pharm. Bull. 1983,
31, 787. (e) Hayakawa, H.; Haraguchi, K.; Tanaka, H.; Miyasaka, T. Chem.
Pharm. Bull. 1987, 35, 72. (f) Hayakawa, H.; Tanaka, H.; Sasaki, K.;
Haraguchi, K.; Saitoh, T.; Takai, F.; Miyasaka, T. J. Heterocycl. Chem.
1989, 26, 189. (g) Czechtizky, W.; Vasella, A. HelV. Chim. Acta 2001, 84,
594.
with 2 equiv of iPrMgCl at -80 °C, then allowed to warm
to 0 °C, and quenched with water, 9-benzyl-6-isopropylpurine
(7a) was obtained as the only product in high yield (Scheme
(12) This compound was prepared by benzylation of 2-chloro-6-
iodopurine, which was prepared from 2,6-dichloropurine by an exchange
reaction with concentrated hydroiodic acid: Elion, G. B.; Hitchings, G. H.
J. Am. Chem. Soc. 1956, 78, 3508. The position of halogens in the above
paper was only estimated. Thus, the reaction described in Scheme 2 is also
proof that the compound obtained from 2,6-dichloropurine by reaction with
hydroiodic acid is 2-chloro-6-iodopurine and not isomeric 6-chloro-2-
iodopurine.
(10) Tobrman, T.; Dvoˇra´k, D. Org. Lett. 2003, 5, 4289.
(11) Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer, L.;
Giocanti, N.; Sadri, R.; Favaudon, V. Bioorg. Med. Chem. 1999, 7, 1281.
1292
Org. Lett., Vol. 8, No. 7, 2006

Scheme 3
Table 2. Preparation of 6-Alkylpurines 7 (Scheme 2)
entry
R
product (yield %)
1
2
3
4
5
6
7
(CH3)2CH
but-2-yl
cyclopentyl
CH3CH2
C6H5CH2
(CH3)3C
C6H5
7a (80)
7b (65)
7c (79)
7d (50)
7e (30) 5 (12)
5 (33)
5 (21)
2, Table 2, entry 1). This reaction was successfully used for
the preparation of 6-alkylpurine derivatives 7a-d. As can
be seen from Table 2, the reaction allows smooth introduction
of secondary (Table 2, entries 1-3) and primary (Table 2,
entry 4) alkyl groups into the 6 position of the purine nuclei.
Benzylmagnesium bromide, however, formed an inseparable
mixture of 9-benzyl and 6,9-dibenzylpurine derivatives
(Table 2, entry 5). In contrary, in the case of tert-butylmag-
nesium chloride and phenylmagnesium chloride, only the
I/Mg exchange reaction proceeds resulting in the formation
of 9-benzyl-2-chloropurine (5) as the only product (Table
2, entries 6 and 7). Allylmagnesium bromide reacted
completely differently giving derivatives 8 and 9 (Figure 1),
prior to the addition of iPrMgCl did not result in the
formation of the 6-sec-butylpurine derivative, and only
formation of the 6-isopropyl derivative was observed. It
therefore seems that substitution of iodine to the alkyl group
proceeds via an addition-elimination mechanism rather than
via the reaction of a primarily formed Grignard reagent with
an alkyl iodide originated from the exchange reaction.13
Table 3. Preparation of Trisubstituted Purines 10 (Scheme 3)
R
R1
product (yield %)
(CH3)2CH
cyclopentyl
but-2-yl
C6H5
3,4-CH2O2C6H3
3-NO2C6H4
10a (59)
10b (68)
10c (54)
Although Pd-,14 Ni-,15 and Fe-catalyzed16 coupling of
halopurines with Grignard reagents has been reported, the
noncatalyzed process has never been observed. Smooth
coupling of Grignard reagents with 4 is probably a result of
the activation of iodine by the chlorine atom at the 2 position
of the purine nuclei. The reason the Cl/Mg exchange does
proceed easily in this case and the reason the formed
2-magnesiated purine 9 does not isomerize to the 8-derivative
remain the objects of our further study.17
Figure 1. Products of the reaction of 4 with allylmagnesium
bromide.
the products of addition of the Grignard reagent, to the 8
position of the purine nuclei.
Evidently, the chlorine to magnesium exchange reaction
proceeds in the reaction of 4 with 2 equiv of the Grignard
reagent. This is unexpected because the Cl/Mg exchange
reaction has not been observed on purines, yet. Surprisingly,
such formed 2-magnesiated purine 9 is stable and does not
rearrange to the 8-derivative in contrast to the above-
discussed magnesiation of 6-chloro-2-iodo-9-isopropylpurine
(1). This can be documented using D2O as an electrophile.
Quenching the reaction mixture after reaction of 4 with 1
equiv of iPrMgCl at -80 °C with D2O at the same
temperature afforded 6-D-5. The reaction of 4 with 2 equiv
of iPrMgCl at -80 °C and addition of D2O after warming
to 0 °C gave exclusively 2-D-7a. 2-Magnesiated intermediate
9 can be trapped by the reaction with aldehyde giving
disubstituted purine 10 in acceptable yield (Scheme 3, Table
3). The structure of such obtained derivatives 10 was
unambiguously confirmed by 2D-NMR experiments (HMQC,
HMBC).
(13) The outcome of the reaction with 1 equiv of RMgCl strongly
depends on the reaction temperature. Thus, the reaction with iPrMgCl at
-80 °C followed with addition of water at -80 °C affords exclusively 5,
whereas the same reaction at higher temperatures gives mixtures of 5 and
7a in a different ratio. Interestingly, formation of 9-benzyl-6-iodopurine or
6-isopropyl-2-chloropurine was not observed. It suggests that a Cl/Mg
exchange reaction is connected with the introduction of an alkyl group to
the 6 position. However, all attempts to prepare 6-alkyl-2-chloro-9-
benzylpurines as putative intermediates of the formation of 9 failed.
(14) Nguyen, C.-D.; Beaucourt, J.; Pichat, L. Tetrahedron Lett. 1979,
20, 3159.
(15) (a) Bergstrom, D. E.; Reddy, P. A. Tetrahedron Lett. 1982, 23, 4191.
(b) Estep, K. G.; Josef, K. A.; Bacon, E. R.; Carabates, P. M.; Rumney, S.;
Pilling, G. M.; Krafte, D. S.; Volberg, W. A.; Dillon, K.; Dugrenier, N.;
Briggs, G. M.; Canniff, P. C.; Gorczyca, W. P.; Stankus, G. P.; Ezrin, A.
M. J. Med. Chem. 1995, 38, 2582. (c) Sugimura, H.; Takei, H. Bull. Chem.
Soc. Jpn. 1985, 58, 664.
(16) (a) Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem.
Soc. 2002, 124, 13856. (b) Hocek, M.; Dvorˇa´kova´, H. J. Org. Chem. 2003,
68, 5773. (c) Hocek, M.; Hockova´, D.; Dvoˇra´kova´, H. Synthesis 2004, 889.
(d) Hocek, M.; Pohl, R. Synthesis 2004, 2869.
(17) Preliminary results show that 2-magnesiated purines are stabilized
by electron-donating substituents in the 6 position of purine nuclei.
The mechanism of the formation of 9 is not clear. The
addition of an excess of 2-iodobutane to the reaction mixture
Org. Lett., Vol. 8, No. 7, 2006
1293

In conclusion, the I/Mg exchange reaction of 6-chloro-2-
iodo-9-isopropylpurine (1) with iPrMgCl at -80 °C proceeds
selectively with the formation of the corresponding 2-mag-
nesiated derivative, which, at 0 °C, isomerizes to the
8-magnesiated derivative. Similarly, the I/Mg exchange
reaction of 9-benzyl-2-chloro-6-iodopurine (4) at -80 °C
gives exclusively the 6-magnesiated compound. However,
with 2 equiv of a primary or secondary Grignard reagent at
0 °C, unprecedented alkylation in the 6 position and the Cl/
Mg exchange reaction proceed. All prepared purine-derived
Grignard reagents react with aldehydes giving new trisub-
stituted purine derivatives. Thus, the presented magnesiation
methodology allows an easy access to new purine derivatives,
which are not easily accessible by other methods. The
mechanistic aspects of these reactions, further reactivity of
obtained compounds, and activity tests are now under study
in our laboratory.
Acknowledgment. Financial support from the Grant
Agency of the Czech Republic (grant No. 203/03/0035) is
gratefully acknowledged.
Note Added after ASAP Publication. There was a
nitrogen missing in the six-membered ring in structure 4 of
Scheme 2 in the version published ASAP March 1, 2006;
the corrected version was published March 7, 2006.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 2a-g, 3, 5,
6, 7b, 7c, 8, 9, and 10a-c. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL053013W
1294
Org. Lett., Vol. 8, No. 7, 2006