Efficient and regioselective 4-amino-de-chlorination of 2,4,6- trichloropyrimidine with N-sodium carbamates

Article abstract of DOI:10.1016/S0040-4039(00)00048-4

4-N-Alkoxycarbonyl-2,6-dichloropyrimidines have been synthesized with good to excellent regioselectivity and yields from 2,4,6-trichloropyrimidine and N-sodium carbamates in DMF, at room temperature, in 15-30 minutes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00048-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1757–1761
Efficient and regioselective 4-amino-de-chlorination of 2,4,6-
trichloropyrimidine with N-sodium carbamates
Matteo Zanda,a Patrice Talaga,b Alain Wagner a,∗ and Charles Mioskowski a,∗
aUniversité Louis Pasteur de Strasbourg, UMR 7514 du CNRS, Laboratoire de Synthèse Bioorganique, Faculté de Pharmacie,
74 Route du Rhin, 67401 Illkirch-Graffenstaden, France
bUCB S.A. Pharma Sector, Chemin du Foriest, B-1420, Braine-l’Alleud, Belgium
Received 25 November 1999; accepted 4 January 2000
Abstract
4-N-Alkoxycarbonyl-2,6-dichloropyrimidines have been synthesized with good to excellent regioselectivity and
yields from 2,4,6-trichloropyrimidine and N-sodium carbamates in DMF, at room temperature, in 15–30 minutes.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: pyrimidines; carbamates; amination; regioselection.
Aminopyrimidines are biologically important molecules (remarkable examples are cytosine, thiamine
and vitamin B-1) and valuable heterocyclic nuclei for the design of pharmaceutical agents.1 Recently,
we became interested in preparing N-alkoxycarbonylamino-dichloropyrimidines from commercially
available and cheap 2,4,6-trichloropyrimidine. Desired properties of this synthesis include: high regio-
selectivity, high yields, general applicability, extreme experimental simplicity, and one-pot introduction
of the protected amine function. Surprisingly, an overview of the literature revealed that a general
and efficient methodology to prepare N-acylamino dichloropyrimidines was not available.2 Herein we
disclose a tailor-made procedure, featuring all the requirements above, to perform the one-step synthe-
sis of 4-N-alkoxycarbonylamino-2,6-dichloropyrimidines from 2,4,6-trichloropyrimidine (TCP) and the
corresponding carbamates (Scheme 1).
The known approach to the target compounds is in two steps: aromatic nucleophilic substitution (SNAr)
of TCP with free amines, followed by N-alkoxycarbonylation. Unfortunately, the former step is generally
not regioselective, as witnessed by literature data as well as by our own experience (Scheme 2 and Table
1).3 Ammonia4 and alkylamines, like benzylamine,5 cyclopropylamine and ethanolamine,6 invariably
provide nearly equimolar ratios of the two possible regioisomers 1 and 2, under different experimental
conditions (entries 1–5). Interestingly, aniline in ethanol (Na2CO3 as base) gives rise to a regioselective
chlorine displacement, producing 4-anilino-2,6-dichloropyrimidine (entry 6).7
∗
Corresponding authors. Fax: +00 33 3 88 67 88 91; e-mail: alwag@aspirine.u-strasbg.fr (A. Wagner), mioskow@aspirine.u-
strasbg.fr (C. Mioskowski)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00048-4
tetl 16328

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Scheme 1.
Scheme 2.
Table 1
Reaction of 2,4,6-trichloropyrimidine with free amines
However, we found that replacement of ethanol/Na2CO3 with THF/C6H5NH2 induces a dramatic
drop in regioselectivity (entry 7). Concerning the second step, our experiments, supported by analogous
literature reports,8 evidenced that N-acylation of aminodichloropyrimidines under standard conditions
(acyl chloride, pyridine, CH2Cl2) is unsatisfactory, due to the low nucleophilicity of the amine function.
For example, acetyl chloride gave rise to a largely incomplete reaction and massive formation of by-
products upon reaction forcing.
We therefore turned our attention to the reaction of TCP with carbamates (Scheme 3). To the best of
our knowledge a single example of nucleophilic hetero-aromatic substitution of chlorine by action of a
N-metalated carbamate has been described,9 therefore almost no data on the feasibility, regioselectivity
and synthetic potential of this reaction were available. Satisfactorily, this approach proved to be very
efficient, operatively simple, regio- and chemo-selective, since O-substitution was never found to be
competitive. Portion-wise addition of solid NaH (60%) (usually 1.1 equiv., see Table 2) to an equimolar
mixture of carbamate 3 and TCP in dry DMF at rt afforded in all cases high yields of the corresponding 4-
alkoxycarbonylamino-2,6-dichloropyrimidines 4 within 15–30 min (Table 2).10,11 The method is general,

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as witnessed by the fact that alkylamino, arylamino and even ammonia-derived carbamates underwent
the reaction smoothly.
Scheme 3.
Table 2
Reaction of 2,4,6-trichloropyrimidine with N-sodium carbamates (3)
N-Sodium carbamates of alkylamines 3a,b,e (entries 1, 5 and 8), ammonia 3f (entry 9) and etha-
nolamine 3g (entry 10) added regioselectively to 2,4,6-trichloropyrimidine, in contrast with the parent
free amines (see Table 1). Very efficient reaction was achieved also with aniline carbamate 3c (entry
6). A functionalized and chiral non-racemic carbamate, like N-Boc-L-phenylalanine methyl ester 3d
(entry 7), afforded remarkably good results as well.12 Different alkoxycarbonyl residues were tested,
namely Boc (3a–d), Cbz (3e,f) and the oxazolidinone (3g). The best results, both in terms of yields and

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regioselectivity, were obtained with Boc-carbamates. The influence of several experimental parameters
like solvent, temperature and counter-ion was investigated. Use of THF (entries 3, 12, 13) instead of
DMF produced much slower reactions and lower yields. Below 0°C no reaction was observed, moreover
the regioselectivity was found to be independent from the temperature (entry 4).
Interestingly, the regiocontrol was found to be superior with K+ (entry 2), Li+ (entry 13) and Cs+
(entry 11) as counter-ions. Unfortunately, a remarkable drop of yields was experienced in the first two
cases. Good yields were obtained in the case of Cs+, but the longer reaction time and the high cost of
Cs2CO3 as compared with NaH, represent two drawbacks of this protocol. Attempts to employ EtN(i-
Pr)2 as base in the reaction of TCP with 3f (benzene, 20 h, reflux) did not afford any detectable trace of
the corresponding products 4,5f. The order of addition of reagents and substrates was also found to play
a key-role. Slow addition of TCP to preformed N-sodium carbamate 3e afforded a complex mixture of
products, containing minor amounts of 4,5e. Otherwise, inverse addition of N-sodium 3e to TCP gave rise
to a clean but largely incomplete formation of 4,5e. To extend the scope of the reaction, commercial N-
potassium phthalimide 6 was also tested under identical conditions: the corresponding 4-phthalimido and
2-phthalimido-dichloropyrimidines were formed in 85:15 ratio and ca. 70% overall yield after 24 h at rt.13
Disappointingly, attempts to react TCP with δ-valerolactam using NaH or Cs2CO3 under the optimized
conditions afforded complex mixtures of products. Since Boc and Cbz are easily removable protecting
groups, the present methodology also represents a useful and regioselective protocol to the synthesis of
N-monosubstituted 4-amino-2,6-dichloropyrimidines. Indeed, treatment of 3b with trifluoroacetic acid
produced 4-benzylamino-2,6-dichloropyrimidine trifluoroacetate in 87% yield (Scheme 4).
Scheme 4.
In summary, a regioselective, high yielding and practical 4-amino-de-chlorination of 2,4,6-
trichloropyrimidine has been disclosed and optimized. Its application for the combinatorial synthesis of
a library of aminopyrimidines as well as its extension to other activated aromatic and heteroaromatic
chlorides are currently under investigation.
References
1. For some examples, see: (a) Chen, C.; Dagnino Jr., R.; De Souza, E. B.; Grigoriadis, D. E.; Huang, C. Q.; Kim, K.-I.; Liu,
Z.; Moran, T.; Webb, T. R.; Whitten, J. P.; Xie, Y. F.; McCarthy, J. R. J. Med. Chem. 1996, 39, 4358–4360. (b) Maggiali,
C.; Morini, G.; Mossini, F.; Morini, G.; Barocelli, E.; Impicciatore, M. Farmaco, Ed. Sci. 1987, 43, 277–291 and references
cited therein. (c) Williams, M.; Kowaluk, E. A.; Arneric, S. P. J. Med. Chem. 1999, 42, 1481–1500. (d) Ban, M.; Taguchi,
H.; Katsushima, T.; Aoki, S.; Watanabe, A. Bioorg. Med. Chem. 1998, 6, 1057–1068. (e) Drugs Fut. 1997, 22, 208–210.
2. See, for example: (a) Taylor, E. C.; Gillespie, P.; Patel, M. J. Org. Chem. 1992, 57, 3218–3225. (b) Temple, C.; Rener, G.
A. J. Med. Chem. 1992, 35, 4809–4812. (c) Boldyrev, I. V.; Vladimirtsev, I. F.; Romanenko, E. A.; Korzhenevskaya, N. G.;
Titov, E. V.; Cherkasov, V. M. Chem. Heterocycl. Compd. (Engl. Transl.) 1977, 13, 1006–1009.
3. (a) Vorbruggen, H. Adv. Heterocycl. Chem. 1990, 49, 117–192 and references cited therein. Interestingly, the reaction of
2,4,6-trichloropyrimidine with guanidine has been reported to produce regioselectively 2-guanidino-4,6-dichloropyrimidine:
(b) Ladd, D. L. J. Heterocyclic Chem. 1982, 19, 917–921. (c) Zawadzki, H.; Penkowski, M. Polish J. Chem. 1995, 69,
1409–1416 and references cited therein.
4. (a) Gabriel, S. Chem. Ber. 1901, 34, 3362–3366. (b) Büttner, E. Chem. Ber. 1903, 36, 2227–2235.
5. Mossini, F.; Maggiali, C.; Morini, G.; Impicciatore, M.; Morini, G.; Molina, E. Farmaco, Ed. Sci. 1984, 39, 189–199.

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6. Delia, T. J.; Stark, D.; Glenn, S. K. J. Heterocycl. Chem. 1995, 32, 1177–1180.
7. For further examples of amino-de-chlorinations of 2,4,6-pyrimidine see the references cited in Ref. 6. See also: (a) D’Atri,
G.; Gomarasca, P.; Resnati, G.; Tronconi, G.; Scolastico, C.; Sirtori, C. R. J. Med. Chem. 1984, 27, 1621–1629. (b) Koga,
M.; Schneller, S. W. J. Heterocyclic Chem. 1992, 29, 1741–1747.
8. Giovanninetti, G.; Garuti, L.; Cavrini, V.; Roveri, P.; Mannini Palenzona, A.; Sinibaldi, P.; Fusco, P. A. Farmaco, Ed. Sci.
1980, 35, 879–886.
9. Bridges, A. J.; Sanchez, J. P. J. Heterocyclic Chem. 1990, 27, 1527–1536.
10. General experimental. To a solution of TCP and carbamate 3 (1.42 mmol both) in dry DMF (5 mL) solid NaH (60%) (1.56
mmol) was added portionwise over 5 min at rt. The resulting slurry was kept under stirring for 15–30 min at rt. The reaction
was quenched with a saturated aqueous NH4Cl solution, extracted three times with diethyl ether, the collected organic layers
were washed twice with water, dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo. Pure products 4
were obtained via silica gel chromatography, generally using n-hexane:ethyl acetate 9:1 as eluant. In the case of the primary
carbamate 3f (entry 6) 2.2 equiv. of NaH were used, since the corresponding products 4,5f also undergo N-metalation. All
new compounds were characterized by 1H and 13C NMR, FT IR and mass spectrometry.
11. The proton H-5 of 4-alkoxycarbonylamino-2,6-dichloropyrimidines 4 resonates at extraordinarily low fields (δ 7.8–8.3).
This could be explained by an intramolecular C–H···O_C–N hydrogen bonding, which is confirmed by preliminary X-ray
diffraction experiments.
12. Although the ee of the product 4d was not measured, a high value of optical activity was recorded: [α]2D0 (c 1.0,
CHCl3)=−77.8.
13. For a quite recent example of SNAr reaction of N-metalated phtalimide with an activated aromatic chloride: Zhao, W.-Y.;
Liu, Y.; Huang, Z.-T. Synth. Commun. 1993, 23, 591–599.