N-NITROSACCHARINS

Abstract

N-nitrosaccharin of the general formula (I),

##STR00001##

wherein R is either a hydrogen (H) or a nitro group (NO.sub.2), its preparation and its use as nitrating agent.

Claims

1. N-nitrosaccharin of the general formula (I), ##STR00006## wherein R is either a hydrogen (H) or a nitro group (NO.sub.2).

2. N-nitrosaccharin according to claim 1 of the formula (Ia) ##STR00007##

3. 6-Nitro-N-nitrosaccharin according to claim 1 of the formula (Ib) ##STR00008##

4. N-nitrosaccharin according to claim 1, wherein the N-nitrosaccharin of general formula (I) is in crystalline form.

5. A method for the preparation of N-nitrosaccharin of the general formula (I) according to claim 1 comprising the following steps: reacting N-saccharin of the general formula (II), ##STR00009## wherein R is either a hydrogen or a nitro group, in the presence of nitric acid, to obtain N-nitrosaccharin of general formula (I).

6. The method according to claim 5, wherein N-saccharin of the general formula (II) is dissolved in an organic anhydride.

7. The method according to claim 5, wherein the molar ratio of N-saccharin to concentrated nitric acid is between 500 to 1 and 10 to 1.

8. The method according to claim 5, wherein solution comprising N-saccharin of the general formula (II) dissolved in the organic solvent is cooled down below 15° C., during the addition of nitric acid is completed.

9. The method according to claim 5, wherein the reaction mixture is stirred for 1 to 24 hours.

10. The method according to claim 5, wherein N-nitrosaccharin of the general formula (I) is obtained with a yield of at least 50%.

11. The method according to claim 5, wherein the solvent is removed to obtain the N-nitrosaccharin of the general formula (I) in crystalline form.

12. A method for applying N-nitrosaccharin of the general formula (I), ##STR00010## with R being either hydrogen (H) or a nitro group (NO.sub.2), as nitrating agent of a compound A in an electrophilic substitution, wherein compound A comprises at least one substituted or unsubstituted aromatic or heteroaromatic ring.

13. The method according to claim 12, wherein the electrophilic substitution is an ipso-substitution.

14. The method for applying N-nitrosaccharin according to claim 12, wherein the aromatic or heteroaromatic ring of compound A comprises a leaving group, wherein the leaving group Y is selected from the group consisting of halogen atoms (I, Br, Cl, F), SO.sub.3H, Si(CH.sub.3).sub.3, tosyl, mesyl, nosyl, brosyl, tresyl, dansyl, trifyl, hydroxides, alkoxides, amides, acetyl substituents and tert-alkyl substituents.

Description

EXAMPLE 1

[0042] The procedure for synthesis of N-nitrosaccharins:

[0043] In a 250 mL three necked round bottom flask equipped with dropping funnel, air outlet and stirring bar was placed N-saccharin (10.0 g, 54.64 mmol) in acetic anhydride (25.7 mL, 0.27 mol). The solution was cooled to 0-5° C. with ice-bath and concentrated nitric acid (25.1 mL, 0.61 mol) was added dropwise to the solution during 30 minutes, while dry air being bubbled through the solution rapidly in order to remove excess of nitrogen oxides. N-saccharin was completely dissolved once all nitric acid was added. The cooling bath was removed, and the reaction mixture was stirred at room temperate during at least 4 hours with continuous bubbling of air through the liquid. The precipitate which had formed during the reaction was collected on a sintered glass filter and dried under high vacuum until dryness (11.8 g, 95% yield). The material can be recrystallized from hot chloroform or acetonitrile and is a white crystalline compound. No decomposition of N-nitrosaccharin found after 24 hours at room temperature in CH.sub.2Cl.sub.2, CHCl.sub.3, acetone, HFIP, THF, MeCN, benzene. Full or partial decomposition of N-nitrosaccharin was found in DMF, DMSO and MeOH.

[0044] M.p./Decomposition temperature 180-182° C. (mass loss −50%, determined by termogravimetric analysis);

[0045] .sup.1H-NMR (300 MHz, CD.sub.3CN): δ=8.05 (dt, J=7.4, 1.5 Hz, 1H), 8.14 (dt, J=6.1, 1.4 Hz, 1H), 8.16-8.23 (m, 2H);

[0046] .sup.13C-NMR (75 MHz): δ=121.7, 123.1, 126.5, 134.4, 135.9, 137.6, 151.7;

[0047] IR (ATR, neat): 3097, 1781, 1717, 1601, 1463, 1292, 1176, 1068, 1007, 891, 758, 662, 582, 500;

[0048] HRMS (El) m/z calculated for C.sub.7H.sub.4N.sub.2O.sub.5S: [M+] 227.9836, found 227.9842.

[0049] Analytically calculated for C.sub.7H.sub.4N.sub.2O.sub.5S: C 36.85, H 1.77, N 12.28 found: C 36.88, H 1.87, N 12.41.

[0050] Colorless crystals of compound Ia were obtained by slow evaporation from a saturated solution in chloroform/acetonitrile 1:1.

[0051] Crystal data and structure refinement of compound IA:

[0052] Empirical formula C.sub.7H.sub.4N.sub.2O.sub.5S

[0053] Formula weight 228.18

[0054] Temperature/K 100.0

[0055] Crystal system Monoclinic

[0056] Space group IT number 15

[0057] Space group name C 1 2/c 1

[0058] a/Å 12.1513(6)

[0059] b/Å 10.0288(5)

[0060] c/Å 14.5625(8)

[0061] α/° 90.0

[0062] β/° 102.979(2)

[0063] γ/° 90.0

[0064] Volume/Å.sup.3 1729.29(15)

[0065] Z 8

[0066] ρ.sub.calcg/cm.sup.3 1.753

[0067] μ/mm.sup.−1 0.378

[0068] F(000) 928.0

[0069] Crystal size/mm.sup.3 0.076×0.199×0.202

[0070] Radiation Monα (λ=0.71073)

[0071] 2θ range for data 2.662 to 28.282

[0072] collection/°

[0073] Index ranges −16≤h≤16, −13≤k≤13, −19≤1≤19

[0074] Reflections collected 35975

[0075] Independent reflections 2154

[0076] Data/restraints/parameters 2154/0/136

[0077] Goodness-of-fit on F.sup.2 1.101

[0078] Final R indexes [I>=2σR.sub.1=0.0466, wR.sub.2=0.0975 (I)]

[0079] Final R indexes [all data] R.sub.1=0.0394, wR.sub.2=0.1026

[0080] Largest diff. peak/hole/0.859/−0.508

[0081] e A.sup.−3

[0082] The sensitivity of the reagent was tested by hammer blow and with a drop-weight impact machine. The hammer test is an initial indication of the sensitivity of the molecule to an outside impact stimulus. Reagent in amount of 1 g were placed on a clean steel surface of a witness plate and hit with a hammer (250 g). No fume, heavy smoke, sparks, explosion, or heat were recorded, suggesting that this molecule is shock insensitive. For the fall-hammer test, MP-3 Falling Hammer equipment was used. Sample of the reagent (200 mg) was placed on a clean steel surface and a 1 kg hammer was raised to a predetermined height (0.5 m and 0.8 m) by a manual crank. The hammer was dropped from various height onto the striker. No effects have been recorded.

[0083] Although we encountered no incidents while synthesizing this molecule or products reported herein, safety precautions must be taken such as wearing safety glasses, protected shield, full body protective clothing, etc. Safety regulation of acyl nitrate is well documented in the following reference:Louw, R. e-EROS Encycl. Reagents Org. Synth. 2001, DOI: 10.1002/047084289X.ra032. For the use of multi kilograms of acetyl nitrate in the synthesis, see the following reference: Hoare, J.; Duddu, R.; Damavarapu, R. Org. Process Res. Dev. 2016, 20, 683-686).

EXAMPLE 2

[0084] The procedure for synthesis of 6-nitro-N-nitrosaccharins:

[0085] In a 250 mL three necked round bottom flask equipped with dropping funnel, air outlet and stirring bar was placed N-saccharin (10.0 g, 36.63 mmol) in acetic anhydride (28.2 mL, 0.30 mol). The solution was cooled to 0-5° C. with ice-bath and concentrated nitric acid (28.2 mL, 0.67 mol) was added dropwise to the solution during 30 minutes, while dry air being bubbled through the solution rapidly in order to remove excess of nitrogen oxides. 6-nitrosaccharin was completely dissolved once all nitric acid was added. The reaction mixture was stirred at 5-10° C. during 4 hours with constant bubbling of air through the liquid. The reaction mixture was placed to freezer for hours to complete precipitation of the product. The precipitate was collected on a sintered glass filter, washed with cold chloroform and dried under high vacuum until dryness (9.6 g, 96% yield). The product is a light-yellow (almost white) powder/crystalline compound.

[0086] M.p./Decomposition temperature 174-176° C. (mass loss −50%, determined by thermogravimetric analysis);

[0087] .sup.1H-NMR (500 MHz, CD3CN) : δ=9.07 (d, J=2.1 Hz, 1H), 8.76 (dd, J=8.5, 2.0 Hz, 1 H), 8.43 (d, J=8.4 Hz, 1H);

[0088] .sup.13C-NMR (125 MHz, CD.sub.3CN): δ=118.3, 112.8, 128.5, 130.6, 135.4, 150.3, 152.9;

[0089] IR (ATR, neat):3073, 1732, 1601, 1529, 1424, 1347, 1180, 1064, 1024, 786, 737, 649, 490;

[0090] Analytically calculated for C.sub.7H.sub.3N.sub.3O.sub.7S: C 3.78, H 1.11, N 15.38 found: C 30.81, H 1.19, N 15.50.

[0091] Colorless crystals of compound Ib were obtained by slow evaporation from a saturated solution in chloroform/acetonitrile 1:1.

[0092] Crystal data and structure refinement of compound Ib:

[0093] Empirical formula C7H3N3O7S

[0094] Formula weight 273.18

[0095] Temperature/K 100.0

[0096] Crystal system orthorhombic

[0097] Space group IT number 61

[0098] Space group name P b c a

[0099] a/Å 9.4437(3)

[0100] b/Å 13.7774(5)

[0101] c/Å 14.6729(6)

[0102] α/° 90.0

[0103] β/° 90.0

[0104] γ/° 90.0

[0105] Volume/Å3 1909.09(12)

[0106] Z 8

[0107] ρcalcg/cm3 1.901

[0108] μ/mm−1 0.377

[0109] F(000) 1104.0

[0110] Crystal size/mm3 0.16×0.3×0.41

[0111] Radiation MoKα (λ=0.71073)

[0112] 2θ range for data 2.174 to 29.565 collection/°

[0113] Index ranges −9≤h≤9, −11≤k≤11, −26≤1≤26

[0114] Reflections collected 22172

[0115] Independent reflections 2778

[0116] Data/restraints/parameters 2778/0/163

[0117] Goodness-of-fit on F2 1.174

[0118] Final R indexes [I>=2σR1=0.0586, wR2=(I)] 0.1093

[0119] Final R indexes [all data] R1=0.0436, wR2=0.1320

[0120] Largest diff. peak/hole/0.597/−0.576

[0121] e Å-3

EXAMPLE 3

[0122] Representative general procedure I for nitration of arenes:

[0123] A 50 mL vessel was charged with compound Ia (1.3 equiv., 6.5 mmol) and sealed under nitrogen atmosphere. Arene (1.0 equiv., 5 mmol) and HFIP (10 mL) were added and the reaction mixture was heated at 55° C. for 2-19 hours, depending on the substrate. After cooling to room temperature, the solvent was removed in vacuum, and the product was purified by flash column chromatography (SiO.sub.2, ethyl acetate/n-hexane gradient).

EXAMPLE 4

[0124] Representative general procedure II for nitration of arenes:

[0125] A 50 mL vessel was charged with compound Ib (1.3 equiv., 6.5 mmol), Mg(ClO.sub.4).sub.2 (0.5 mmol) and sealed under nitrogen atmosphere. Arene (1.0 equiv., 5 mmol) and CH.sub.3CN (10 mL) were added and the reaction mixture was heated at 85° C. for 5-19 hours depending on the substrate. After cooling to room temperature, the solvent was removed in vacuum, and the product was purified by flash column chromatography (SiO2, ethyl acetate/n-hexane gradient).

EXAMPLE 5—Comparative Experiment

[0126] The following procedure described by Kozlova et al. was investigated: An equimolar amount of nitronium tetrafluoroborate was added at −30° C. to a stirred suspension of 2 g of the imide salt of saccharin in 20 mL of the absolute acetonitrile, and the mixture was stirred at this temperature for 20-30 minutes. The precipitate was removed by filtration, and the filtrate was evaporated. The solid residue was washed with a mixture of hexane with methylene chloride. Despite multiple attempts, the proposed synthesis was never successful since no product formation could be observed at all.