Functionalization of unprotected uracil derivatives using the halogen - Magnesium exchange

Article abstract of DOI:10.1021/ol063136w

The reaction of commercially available 5-iodouracil with 2 equiv of MeMgCl in the presence of LiCl, followed by the addition of i-PrMgCl-LiCl, provides the corresponding trimagnesiated species, which reacts with various electrophiles to give selectively 5

Full text of DOI:10.1021/ol063136w

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1639-1641
Functionalization of Unprotected Uracil
Derivatives Using the
Halogen−Magnesium Exchange
Felix Kopp and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Munich, Germany
paul.knochel@cup.uni-muenchen.de
Received December 28, 2006
ABSTRACT
The reaction of commercially available 5-iodouracil with 2 equiv of MeMgCl in the presence of LiCl, followed by the addition of i-PrMgCl‚LiCl,
provides the corresponding trimagnesiated species, which reacts with various electrophiles to give selectively 5-functionalized uracil derivatives.
This method was also successfully applied to the functionalization of 6-iodouracils including the synthesis of pharmaceutically relevant Emivirine
and HEPT precursors.
The functionalization of uracil and related nucleobase
derivatives has been extensively investigated, as these
systems represent core structural elements for a broad variety
of pharmaceutically active compounds.1 Using uracil-derived
organometallic reagents, at least one of the two acidic protons
in the uracil moiety has to be protected.2
Recently, we have reported a convenient magnesiation of
phenol derivatives, avoiding the need for protection of the
acidic OH group by generating a bianionic species.3
In analogy, we reacted commercially available 5-iodouracil
(1a) with MeMgCl (2.0 equiv) in the presence of LiCl (2.0
equiv) at -20 °C, followed by the addition of i-PrMgCl‚
LiCl (1.1 equiv) at -20 °C, allowing the mixture to warm
to room temperature. The use of MeMgCl as a deprotonating
agent proves to be best. Its low activity as an exchange
reagent avoids a potential “self-protonation”. LiCl plays a
double role as it increases the rate of the exchange reaction4
and, at the same time, drastically improves the solubility5
(e.g., 5-iodouracil itself is nearly insoluble in THF), resulting
in the formation of the triple magnesiated species 2a, which
finally precipitates to give a thick, but still stirrable, slurry.
The use of 3 equiv of LiCl is essential; experiments with
fewer equivalents resulted in lower conversions. The mag-
nesium reagent 2a can be easily trapped by the reaction with
different electrophiles. Thus, the reaction with sterically
demanding, aliphatic, aromatic, or heteroaromatic aldehydes
(1.3 equiv) affords the desired products 3a-d in 55-78%
yield (Table 1, entries 1 and 3-5). Similarly, the reaction
with allyl bromide in the presence of catalytic amounts of
CuCN‚2LiCl6 (1 mol %) proceeds smoothly, giving the
(1) (a) Boudet, N.; Knochel, P. Org. Lett. 2006, 8, 3737. (b) Newkome,
G. R.; Pandler, W. W. Contemporary Heterocyclic Chemistry; Wiley: New
York, 1982. (c) Botta, M.; Saladino, R.; Lamba, D.; Nicoletti, R.
Tetrahedron 1993, 49, 6053. (d) Asakura, J.; Robins, M. J. J. Org. Chem.
1990, 55, 4928. (e) Peters, D.; Ho¨rnfeldt, A.-B.; Gronowitz, S. J. Heterocycl.
Chem. 1990, 27, 2165.
(2) For protection of only one NH function, see: (a) Aso, M.; Kaneko,
T.; Nakamura, M.; Koga, N.; Suemune, H. Chem. Commun. 2003, 1094.
Or: (b) Schinazi, R. F.; Prusoff, W. H. J. Org. Chem. 1985, 50, 841. (c)
For DABCO-mediated modification of uridine derivatives: Sajiki, H.;
Yamada, A.; Yasunaga, K.; Tsunoda, T.; Amer, M. F. A.; Hirota, K.
Tetrahedron Lett. 2003, 44, 2179.
(4) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(5) For the solubilization of lanthanide salts in the presence of LiCl,
see: Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 497.
(3) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004, 20,
2288.
(6) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
10.1021/ol063136w CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/28/2007

electrophile (3.3 equiv) was used. After acidic aqueous
workup, the desired product, bearing only one TMS group,
is isolated in 72% yield (entry 8). The introduction of a sulfur
functionality is conveniently accomplished by reacting 2a
with thiosulfonates of the type R2SSO2R2.7 The correspond-
ing thioethers 3h and 3i are prepared in 77% and 64% yield,
respectively (entries 9 and 10). Also, the cheaper 5-bromo-
uracil (1b) can be magnesiated using i-Pr2Mg‚LiCl8 (1.1
equiv). The reactions with standard electrophiles such as
t-BuCHO or methallyl bromide (2.8 equiv) provide lower
yields than using 5-iodouracil (1a) as the substrate (compare
entries 2 and 7). Similarly, 6-iodouracil9 (1c) can be smoothly
metalated using the same reaction sequence. The reactions
with allyl bromide and t-BuCHO proceed smoothly and give
access to the expected products 3j and 3k in 64% and 69%
yield, respectively (entries 11 and 12).
Table 1. Functionalization of Unprotected Uracil Derivatives
by Triple Magnesiation and Subsequent Reaction with
Electrophiles
Artificial nucleobase derivatives have found important
applications as drugs, especially for the treatment of HIV,
and a broad variety of uracil derivatives have been tested
for their activity. Many active compounds bear an alkyl
substituent in the 5-position and variable groups in the
adjacent position 6.10 Encouraged by our results with 6-iodo-
uracil (1c) as a substrate, we investigated the magnesiation
of unprotected 5-alkyl-6-iodouracil derivatives of type 6.
These substrates are easily obtained in a two-step process
starting from readily available 5-alkyl barbituric acids (4).11
The chlorination with POCl3 and catalytic amounts of H3PO4
at reflux gives access to the 5-alkyl-chlorouracils of type 5
in good yields (Scheme 1).12 Treatment with sodium iodide
in the presence of HI at room temperature affords the cor-
responding iodides 6a,b in 71-74% yield. The magnesiation
according to our protocol occurs smoothly in the case of
both the methyl (6a) and the isopropyl derivatives (6b),
affording the triple magnesiated species of type 7. However,
the introduction of a thioether moiety by treating 7a with
PhSSO2Ph affords 8 in only 40% yield.13 More efficiently,
the reaction of 7b with benzyl bromide after transmetalation
using CuI‚2LiCl furnishes the uracil derivative 9 in 57% yield
(Scheme 1). The resulting products 8 and 9 are precursors
(7) (a) These electrophiles are easily available: Fujili, K.; Tanifuji, N;
Sasaki, Y.; Yokoyama, T. Synthesis 2002, 343. (b) The installation of
thioether moieties was also recently accomplished by the reaction of
chlorouracils with thiolates: Fang, W.-P.; Chedng, Y.-T.; Cheng, Y.-R.;
Cherng, Y.-J. Tetrahedron 2005, 61, 3107.
(8) Krasovskiy, A.; Straub, B.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 15.
(9) Pfleiderer, W.; Deiss, H. Isr. J. Chem. 1968, 6, 603.
(10) (a) Sun, G.-F.; Chen, X.-X.; Chen, F.-E.; Wang, Y.-P.; De Clercq,
E.; Balzarini, J.; Pannecouque, C. Chem. Pharm. Bull. 2005, 53, 886. (b)
Tanaka, H.; Baba, M.; Hayakawa, H.; Sakamaki, T.; Miyasaka, T.; Ubasawa,
M.; Takashima, H.; Sekiya, K.; Nitta, I.; Shigeta, S.; Walker, R. T.;
Balzarini, J.; De Clercq, E. J. Med. Chem. 1991, 34, 349. (c) Tanaka, H.;
Takashima, H.; Ubasawa, M.; Sekiya, K.; Nitta, I.; Baba, M.; Shigeta, S.;
Walker, R. T.; De Clercq, E.; Miyasaka, T. J. Med. Chem. 1992, 35, 4713.
(d) El-Brollosoy, N.; Pedersen, E. B.; Nielsen, C. Arch. Pharm. Pharm.
Med. Chem 2003, 336, 236.
(11) 4b is commercially available, and 4a was synthesized from diethyl
2-methylmalonate, according to: Puckett, W. E.; Pews, R. G. J. Fluorine
Chem. 1989, 42, 179.
(12) (a) Koroniak, H.; Jankowski; A.; Krasnowski, M. Org. Prep. Proced.
Int. 1993, 25, 563. (b) Gauri, K. K.; Partenheimer, H. Ger. Offen. 1962,
1250829.
a Isolated yields of analytically pure compounds. b(i-Pr)2Mg‚LiCl (1.1
equiv), -20 °C to rt, 2 h. c The reaction was conducted in the presence of
d
CuCN‚2LiCl (1 mol %). Steps 1 and 2 conducted at -25 °C.
(13) The main side product is the protonolysis product of the organo-
magnesium reagent 7a, which suggests the reagent to be quite sensitive
and possibly unstable.
product 3e in 84% yield (entry 6). The reagent 2a can also
be reacted with TMSCl. In this case, a larger excess of the
1640
Org. Lett., Vol. 9, No. 9, 2007

magnesiation in position 6 without the need for a protecting
group. Thus, 6-iodopurine (12) is, after deprotonation,
subjected to an iodine/magnesium exchange to produce the
magnesium reagent 13, which reacts with PhSSO2Ph to give
the desired product 14 in 55% yield (Scheme 2).
Scheme 1. Synthesis of Emivirine and HEPT Precursors
Scheme 2. Functionalization of 6-Iodopurine
In conclusion, we have developed a new protocol for the
selective functionalization of uracil derivatives employing a
triple-anionic species as an intermediate. The method was
successfully applied during the course of a short synthesis
of Emivirine (11) and HEPT (10) precursors and was also
extended to the purine system.
Acknowledgment. We thank the Fonds der Chemischen
Industrie and the G.I.F. (German-Israeli Foundation for
Scientific Research and Development; grant I-535-083.05/
97) for financial support. We are grateful to Chemetall GmbH
(Frankfurt) and BASF AG (Ludwigshafen) for generous gifts
of chemicals.
Supporting Information Available: Experimental pro-
cedures and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL063136W
(14) (a) Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Inouye,
N.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T. J.
Med. Chem. 1995, 38, 2860. (b) Pedersen, O. S.; Pedersen, E. B. AntiViral
Chem. Chemother. 1999, 10, 2860.
(15) Tobrman, T.; Dvorˇa´k, D. Org. Lett. 2006, 8, 1291; Org. Lett. 2003,
5, 4289. For further recent work on the functionalization of the purine
core: Cˇ ernˇa, I.; Pohl, R.; Klepeta´rˇova´, B.; Hocek, M. Org. Lett. 2006, 8,
5389. Kucharˇ, M.; Pohl, R.; Votruba, I.; Hocek, M. Eur. J. Org. Chem.
2006, 5083.
of HEPT (10) and Emivirine (11), both highly potent agents
for the treatment of HIV.14 Finally, we have applied our
protocol to the purine core. An elegant magnesiation of
purine derivatives with functionalization of the 6-position
has been recently developed by Dvorˇa´k and co-workers.15
Using the “LiCl effect”, it is now possible to achieve the
Org. Lett., Vol. 9, No. 9, 2007
1641