Synthesis of (pyrimidin-4-yloxy)- and (pyrimidin-3-yl)acetyl azides and their rearrangement to carbamates and ureas

On nitrosation of (pyrimidin-4-yloxy)- and (pyrimidin-3-yl)acetohydrazides 2 , 3 with sodium nitrite in diluted hydrochloric acid at 0-5  C the corresponding (pyrimidinyl)acetyl azides 5 , 6 were prepared. Azides 5 , 6 undergo Curtius rearrangement in the reactions with alcohols, phenols, arylamines or water to give carbamates 7 - 9 , 11 - 14 or ureas 15 - 21 .


Introduction
In recent years naturally occurring and synthetic heterocyclic compounds are of interest in pharmaceutical and pesticide research. 13][4][5][6] On the other hand, compounds with the linkage of carbamate or urea are citied to show cytotoxic, [7][8][9][10][11][12] antimicrobial and insecticidal 13 or fatty acid amide hydrolase inhibitory 14 activity.][17][18][19] Carbamates and ureas are frequently synthesized from acyl azides via Curtius rearrangement. 13,20A number of methods for the synthesis of acyl azides have been reported.Acyl azides are commonly prepared from carboxylic acid and ethyl chloroformate via mixed anhydrides and sodium azide or by the reaction of acyl chlorides with trimethylsilyl azide. 21A. R. Katritzsky et al. recently reported a simple and safe synthesis of acyl azides from the corresponding N-acyl benzotriazoles and sodium azide. 22Acyl azides can also be prepared from hydrazides by nitrozation with sodium nitrite in acidic media. 13,20,23This approach is a convenient one, especially for readily accessible hydrazides.Hydrazide nitrosation to give acyl azides is applied for a large-scale synthesis. 24SSN 1551-7012 Page 40  ARKAT USA, Inc.
Continuing our interest in the synthesis of compounds with potential biological activity, 6,25 herein we report the synthesis of new pyrimidine-based acetyl azides and their rearrangement reactions to form carbamates and ureas.

Results and Discussion
Previously we reported the synthesis of acetyl azide 4 by nitrosation of hydrazide 1 in a 50% acetic acid or diluted hydrochloric acid. 26Performing this reaction in acetic acid the yield of azide 4 was higher, when in a diluted hydrochloric acid together with the azide 4 formation some azide 6 was obtained.In this work azides 5, 6 were successfully prepared under treatment of acetohydrazides 2, 3 with sodium nitrite at 0-5 C in a diluted hydrochloric acid solution (Scheme 1).

Scheme 1
Compounds 5, 6 were sufficiently pure to be used for further rearrangement reactions.The IR spectra of acyl azides 5, 6 display strong absorption bands characteristic for azide stretching vibrations at 2158 and 2150 cm -1 , respectively.
Acyl azides undergo thermal rearrangement in an inert solvents to give isocyanates (Curtius rearrangement), which on reaction with alcohols or amines lead to the formation of carbamates and ureas. 21Azide 5 being heated at reflux in benzene with phenols gave carbamates 7-9 (Scheme 2).

Scheme 2
Analytically pure carbamates 7-9 after recrystallization from 2-propanol were isolated in 43-59% yields.The reaction of azide 5 and benzylamine to form the corresponding urea was unsuccessful, amide 10 was isolated instead.Heating of azide 5 at reflux in benzene for 4 h to rearrange to isocyanate, then addition of benzylamine and further heating for 1 h gave a complex mixture of unidentified products.By adding azide 5 and benzylamine at one go and immediate heating in benzene for 1 h resulted in amide 10 formation in 67% yield.The 1 H NMR spectra of carbamates 7-9 show characteristic dublets at 5.50 and 5.51 ppm for OCH2 group protons and triplets for NH protons (broad singlet for comp.8) in the region of 6.53-6.56ppm.In the 1 H NMR of amide 10 singlet at 4.95 ppm for OCH2 group protons, dublet at 4.56 ppm for CH2 benzyl protons and broad singlet at 6.60 ppm due to NH proton were observed.
In contrast to azide 5, reactions of azide 6 with nucleophiles proceeded smoothly and yields of products were higher (Scheme 3).

Scheme 3
Thus, azide 6 under heating at reflux for 5 h in methanol gave carbamate 11 in 56% yield.For reactions with phenols dry solvents, benzene and dioxane, were used.In benzene azide 6 did not show any reaction with phenols, likely because of poor solubility.In dioxane on heating at reflux for 5 h azide 6 with phenols furnished carbamates 12-14 in 63-74% yields.In the 1 H NMR spectra of 11-14 the characteristic doublets for NCH2 group protons were observed at 5.09 and 5.18 ppm along with the broad singlets in the region of 7.49 and 8.17-8.25 ppm.due to NH protons.
Heating at reflux of acyl azide 6 and arylamines in dioxane for 1 h produced ureas 15-20 in 57-88% yields, while heating at reflux for 4 h of azide 6 in the presence of water gave disubstituted urea 21.In the 1 H NMR spectra of ureas 15-20 characteristic dublets for NCH2 group protons resonate at 5.22-5.25 ppm and the nearby NH proton shifts appear as triplets in the region of 6.78-7.86ppm (for comp.15 and 16 these peaks overlap with signals of aromatic protons).Besides the well-distinctive sharp one-proton peaks due to the NH group next to aromatic ring are observed downfield at 7.94-9.13ppm.The symmetrical urea 21 spectrum shows a dublet at 5.10 ppm for NCH2 group protons and neighboring NH proton as a triplet at 6.96 ppm indicating magnetic equivalency of protons in both halves of the molecule.
The newly synthesized compounds were tested for antiproliferative activity in vitro.Compounds 7-21 were inactive.
In conclusion, nitrosation of (pyrimidinyl)acetohydrazides is convenient and simple method for the synthesis of (pyrimidin-4-yloxy)-and (pyrimidin-3-yl)acetyl azides.Both of azides are suitable synthons for the new carbamate and urea synthesis.

Experimental Section
General.Melting points were determined in open capillaries and are uncorrected.NMR spectra were recorded on a Unity Varian INOVA spectrometer at 300 MHz for 1 H and 75 MHz for 13 C.Chemical shifts (δ) are reported in ppm relative to TMS.The IR spectra were recorded on a Spectrum BX FT-IR (Perkin-Elmer, Sweden) as potassium bromide pellets.The reactions and purity of compounds was controlled by tlc on Silica gel 60 F254 plates (MERCK, Germany).Elemental analyses were performed at the Microanalytical Laboratory of the Department of Organic Chemistry of Vilnius University.All solvents were dried and distilled before use.(6-Methyl-2-methylthiopyrimidin-4-yloxy)acetohydrazide 2 and (6-methyl-2,4-dioxo-1,2dihydropyrimidin-3(4H)-yl)acetohydrazide 3 were synthesized as reported in references 27,28 .