The conventional amination of protected uracil in position
5 often first involves a nitration10 or harsh reaction conditions
for the substitution.11 Using our method, starting from readily
available 5-bromo-2,4-dimethoxypyrimidine (4c), a Br/Mg
exchange with i-PrMgCl·LiCl12 followed by a transmetalation
with CuCl·2LiCl led after reaction with LiHMDS (6b) or
the lithiated N-TBS 3,4,5-trimethoxyaniline (6e) to the
5-aminated uracil derivative 7e and 7f (68–79%, entries 5–6).
Commercially available 6-chloro-2,4-dimethoxypyrimidine
(4d) was metalated at C5 position (TMPMgCl·LiCl, 25 °C,
1 h; then CuCl·2LiCl) affording the corresponding organo-
copper reagent 5d (entries 7–8). The reaction with the
N-lithium amides 6a-f provided the corresponding 6-chloro-
5-amino-2,4-dimethoxypyrimidine derivatives 7g–h (78%).
Polyhalogenated pyrimidines 4e–f were regioselectively
magnesiated, 8 cuprated (5e–f) and oxidatively aminated by
the secondary lithium amides 6a–f leading to the aminated
pyrimidines (7i–j, 66–70%, entries 9–10).
Scheme 1. Direct Amination in 6-Position of Uracil
magnesiations) of pyrimidine and purine derivatives. Thus,
starting from commercially available 2,4-dimethoxypyrimi-
dine (4a, Scheme 1), the addition of TMPMgCl·LiCl8 (TMP
) 2,2,6,6-tetramethylpiperidyl; 1.1 equiv, -40 °C, 12 h) led
to an unprecedented direct C6-metalation.9 The correspond-
ing C6-magnesiated intermediate afforded after transmeta-
lation using CuCl·2LiCl (1.2 equiv, -60 °C) the correspond-
ing copper reagent (5a). After the reaction with N-lithium
morpholide (6a; 2 equiv, -60 °C, 1 h), the corresponding
amidocuprate is oxidized using chloranil (1.2 equiv, -78
°C, 12 h) giving the expected aminated product 7a in 76%
yield. A subsequently treatment of 7a under acidic conditions
provided the 6-N-morpholino-uracil (8a) in 91% yield
(Scheme 1). Similarly, starting from the organocopper
reagent 5a, the addition of LiHMDS (6b) or of the lithiated
N-TBS aniline derivative 6c, furnished after oxidation with
chloranil, the corresponding products 4-amino-2,6-dimethox-
ypyrimidine (7b, 81%, obtained after desilylation using
TBAF, THF, 25 °C, 0.3 h, entry 1 of Table 1) and 7c, a
precursor of HB-TMAU (1); (76%, entry 2).10 Interestingly,
the direct C6-magnesiation and cupration of 5-methyl-2,4-
dimethoxypyrimidine (4b, entry 3) using successively
TMPMgCl·LiCl (1.1 equiv, -5 °C, 3 h) and CuCl·2LiCl
provided the cuprated protected thymine 5b. An oxidative
amination of 5b with the sterically hindered amides
N-lithium morpholide or TMPLi (6a–d) provided the 6-N-
morpholino-thymine 8b (69%, after acidic deprotection,
entry 3) and the aminated 5- methyl-2,4-dimethoxypyri-
midine 7d (70%, entry 4).
The conventional amination of purines in positions-2, –6
and –813 involves high temperature for the substitution,14
or Pd-catalyzed amination from halogenated purines.15
However, the chloranil-mediated oxidation proceeds under
much milder conditions. We have concentrated our efforts
on the amination of these positions. Thus, a selective
magnesiation in position-8 could be achieved by the reaction
of the purines 4g and 4h with TMPMgCl·LiCl under
convenient reaction conditions (THF, -10 °C, 2–3 h) giving
after transmetalation the 8-cuprated purines 5g–h which by
oxidative amination with N-lithium morpholide (6a) or
Et2NLi (6g) provided the expected 8-aminated purines 7k–l
(63–66%, entries 11–12). Using DVor˘ák’s conditions16 for
the selective magnesiation in position 2 on the iodopurine
4i and a copper-(I) transmetalation, the reaction of the lithium
amide 6a to the corresponding organocopper reagent 5i
followed by the treatment with chloranil (-78 °C, 2 h), gave
the desired 2-aminopurine 7m in 69% yield (entry 13). The
mild amination conditions allowed also an alternative method
to the nucleophilic substitution for the amination at C6
position.17 Thus, the 6-iodopurine nucleoside 4j18 was
successively magnesiated, cuprated and finally aminated with
6f furnishing the adenosine derivative 7n (70%, entry 14).
Via a chemoselective I/Mg exchange reaction using
i-PrMgCl·LiCl on the 9-alkylated 2-chloro-6-iodopurine 4k
(11) Ozerov, A. A.; Novikov, M. S.; Brel’, A. K.; Solodunova, G. N.
Chem. Heterocycl. Compd. 1998, 34, 611.
(7) (a) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 7838. For the use of other oxidants, see: (b)
Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739. (c) Casarini,
A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.; Ricci, A.; Seconi,
G. J. Org. Chem. 1993, 58, 5620. (d) Bernardi, P.; Dembech, P.; Fabbri,
G.; Ricci, A.; Seconi, G. J. Org. Chem. 1999, 64, 641.
(12) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(13) For a recent method of C8-arylamino substitution on purines, see:
Bookser, B. C.; Matelich, M. C.; Ollis, K.; Ugarkar, B. G. J. Med. Chem.
2005, 48, 3389.
(14) (a) Kurimito, A.; Ogino, T.; Ichii, S.; Isobe, Y.; Tobe, M.; Ogita,
H.; Takaku, H.; Sajiki, H.; Hirota, K.; Kawakami, H. Bioorg. Med. Chem.
2003, 11, 5501. (b) de Ligt, R. A. F.; van der Klein, P. A. M.; Frijtag
Drabbe Künzel, J. K.; Lorenzen, A.; El Maate, F. A.; Fujikawa, S.; van
Westhoven, R.; van den Hoven, T.; Brussee, J.; IJzerman, Ad. P. Bioorg.
Med. Chem. 2004, 12, 139.
(8) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
(9) The deprotonation at C5 position of 2,4-dimethoxypyrimidine was
described using lithiated bases: (a) Wada, A; Yamamoto, J.; Kanatomo, S.
Heterocycles 1987, 3, 585. (b) Wada, A.; Yamamoto, J.; Hamoaka, Y.;
Ohki, S.; Nagai, S.; Kanamoto, S. J. Heterocycl. Chem. 1990, 27, 1831.
(c) Turck, A.; Plé, N.; Quéguiner, G. Heterocycles 1994, 3, 2149.
(10) (a) Isobe, Y.; Tobe, M.; Inoue, Y.; Isobe, M.; Tsuchiya, M.;
Hayashi, H. Biooorg. Med. Chem. 2003, 11, 4933. (b) Cushman, M.;
Sambaiah, T.; Jin, G.; Illarionov, B.; Fischer, M.; Bacher, A. J. Org. Chem.
2004, 69, 601.
(15) (a) Dai, Q.; Ran, C.; Harvey, R. G. Org. Lett. 2005, 7, 99. (b)
Jacobsen, M. I.; Meier, C. Synlett 2006, 15, 2411. (c) Schoffers, E.; Olsen,
P. D.; Means, J. C. Org. Lett. 2001, 3, 4221.
(16) Tobrman, T.; Dvorˇák, D. Org. Lett. 2006, 8, 1291.
(17) Véliz, E. A.; Beal, P. A. J. Org. Chem. 2001, 66, 8592.
(18) For the preparation of 4j, see: Hocek, M.; Holy, A. Collect. Czech.
Chem. Commun. 1999, 64, 229.
1716
Org. Lett., Vol. 10, No. 9, 2008