Chemistry Research

Electrophilic Substitution of 3-(m-Chlorophenyl)sydnone and 3-(m-Bromophenyl)sydnone

Summer research project completed by:

- Heidelberg College's
Dr. Daniel T. Esterline (Associate Professor of Chemistry)
&
Jason Stengel (Chemistry Major)

& Wright State University's
- Dr. Kenneth Turnbull (Chemistry Professor)

Funded by:
The Petroleum Research Foundation
Aigler Faculty Grant
Heidelberg Pepsi Fund Grant

ABSTRACT

The goal of this project was to synthesis 3-(m-chlorophenyl)sydnone and 3-(m-bromophenyl) sydnone and then to test a newly discovered method of adding substituents selectively onto the phenyl and/or sydnone rings. The method involves proton removal with LDA (lithium diisopropylamine) at very cold temperatures (-63 oC) followed by addition of various electrophiles. Substitution on the ortho-position of the aryl ring (see Y in structure 1 below) and the 4-position of the sydnone ring (see Z in structure 1) would allow future preparation of fused-ring congeners (2) an active area of study.¹ The additional halogen substituent in the meta-position of the aryl ring (see X in structure 1) would allow for further modification of this tricyclic structure (2). Similar reactions have previously been studied without any substituent in the meta-position .²

Scheme 1

GENERAL PROCEDURE

The meta-substituted phenyl sydnones were synthesized by known methods (see Scheme 2).

Scheme 2

Substitution of these sydnones involved cooling a solution of the sydnone (100 mg) dissolved in freshly distilled THF (5 mL) utilizing a liquid nitrogen/chloroform bath (-63 oC) under an atmosphere of nitrogen. LDA (1.1 or 2.9 eq.) was added dropwise. After 30 minutes, an elecrophile (1.1 or 2.2 eq.) dissolved in THF (1 mL) was added dropwise. After an additional 1.5 hours, the mixture was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (sodium sulfate), decanted, and evaporated under vacuum. The resulting oily residue was purified by column chromatography employing methylene chloride as the eluent. In a few cases, the resulting purified fractions showed substantial contamination with diisopropylamine, thus they were either warmed under vacuum or dissolved in methylene chloride followed by washing with dilute HCl.

Scheme 3

Summary of Electrophilic Substitution Reactions with 3-(m-chlorophenyl)sydnone

Scheme 4

Summary of Electrophilic Substitution Reactions with 3-(m-bromophenyl)sydnone

RESULTS

Nearly every attempt at disubstitution (addition of 2.9 eq. LDA followed by 2.5 eq. electrophile) succeeded. The only exceptions involved utilization of electrophiles with questionable purity (DMF and benzaldehyde). Additionally, attempts at producing the mono-substituted product on the sydnone ring (addition of 1.1 eq. LDA followed by 1.2 eq. electrophile) worked very well. It was thought that mono-subsitution on the phenyl ring in the ortho position would work just as well (2.9 eq. LDA followed by 1.1 eq. electrophile) since it was proven that this proton is successfully removed in the disubstitution reactions and that the sydnone proton is selectively removed with 1.1 eq. LDA (see Scheme 5).

Scheme 5

Yet many attempts at selective substitution only on the phenyl ring resulted in inconclusive results. Some of these reactions showed multiple products by TLC that were not successfully separated by column chromatography, at least in amounts large enough for positive identification employing FT-IR and 60 MHz proton FT-NMR. Most likely, substitution was occurring on either the phenyl ring, the sydnone ring, or both. It was at first thought that the pKa's of the protons on these two positions varied enough for ease of selectivity, yet with the presence of the meta-halogen their pKa's may be very similar. It is possible that a greater difference in reactivity of these sites may be achieved at lower reaction temperatures.

Only reaction with phenyl disulfide (25) and trimethylsilyl chloride (15) look as if they successfully added only to the phenyl ring and not the sydnone ring. Reaction with trimethylsilyl chloride (2.5 eq.) after addition of 2.9 equivalents of LDA gave mainly the monosubstituted product (15) with only minor amounts of the disubstituted product. This result was most likely due to using an old used bottle of TMSCl that was not freshly distilled. Yet, it did show that monosubstitution on the ortho-position of the m-chlorophenyl ring was possible with some electrophiles.

Ultimately, synthesis of a tri-substituted phenylsydnone with all three substituents being different was desired. Thus a couple of attempts at producing 3-(2-methyl-3-chlorophenyl)- 4-thiophenylsydnone (shown below) were completed with inconclusive results.

Scheme 6

The first attempt utilized 2.9 eq. LDA and the second attempt 3.5 equivalents, just in case the LDA reagent bottle was decreasing in reactivity. Proton NMR seemed to show the presence of thiophenyl group, but not the methyl group, at least with the correct integration. The same difficulty mentioned above concerning selective substitution at the meta position of the phenyl ring was most likely resulting in partial methylation at both sites yielding multiple disubstituted products. These products would be of similar polarity and thus be difficult to separate by flash chromatography.

FUTURE WORK

Since mono-substitution on the sydnone ring has been shown through this summer work to be viable, further reaction of these products with LDA to attempt substitution in the ortho-position of the aryl ring will be investigated. Also, completion of Scheme 6 starting with phenylsydnone will be attempted since the ortho-position of the phenyl ring and the sydnone hydrogen have pka's that differ by ~10, a greater difference in pKa than with m-chlorophenylsydnone. Therefore selective electrophilic substitution at each of these sites has a greater chance of success.

EXPERIMENTAL

Synthesis of N-(3-chlorophenyl)glycine [4]

To a stirred suspension of m-chloroaniline (22.0 mL, 0.209 mol) and anhydrous sodium acetate (29.04 g, 0.354 mol) was added bromoacetic acid (29.10 g, 0.209 mol) in 30 mL water. The mixture was heated at 60 ^oC for 14.5 hours and allowed to cool overnight. The solid mixture was filtered, washed with water (10 mL), digested in ether (~12 mL), and filtered again affording an off-white solid (17.98 g, 96.9 mmol, 46.4%, mp = 224-225 ^oC). IR (KBr): 3408 (N-H), 3350-2500 (CO₂H), 3060, 3031 (alkene C-H), 2950, 2919 (alkane C-H), 1724 (C=O), 1601 (C=C), 1569, 1507, 1490, 1433, 1410, 1355, 1269, 1238, 988, 898, 829.5, 763, 672.

Synthesis of N-nitroso-N-(3-chlorophenyl)glycine [5]

To a stirred solution of N-(3-chlorophenyl)glycine (4.685 g, 25.32 mmol) in 12% HCl (46.8 mL) cooled to 0-5 ^oC was added 3.5 M sodium nitrite (9.6 mL) dropwise. The mixture was left stirring in the ice bath slowly warming to room temperature overnight. The dark yellow solution with reddish-orange solid was extracted with methylene chloride (47 mL), dried with sodium sulfate, filtered, and evaporated in vacuo yielding a brown solid which was used in the next step without further purification or characterization.

Synthesis of 3-(3-chlorophenyl)sydnone [6]

The unpurified N-nitroso-N-(3-chlorophenyl)glycine was dissolved in methylene chloride (47 mL) and magnesium sulfate (small quantity) was added. The stirred mixture was cooled to 0 ^oC and trifluoroacetic anhydride (4.0 mL, 0.029 mol) was added dropwise. After stirring for 30 minutes, the red solution was neutralized with saturated aqueous sodium bicarbonate (35 mL) and the organic layer was dried, filtered and evaporated in vacuo resulting in a dark reddish-brown solid (4.636 g, 23.65 mmol, 93.42% for 2 steps, mp = 137-139 ^oC). IR matched an authentic sample. IR (KBr): 3138 (sydnone C-H), 3098, 3082, 3048 (alkene C-H), 1740 (C=O), 1472, 960, 800, 763, 726, 443. ¹H-NMR (CDCl₃): 6.759 (s, 1 H), 7.593-7.768 (m, 3 H).

Synthesis of N-(3-bromophenyl)glycine, methyl ester [8]

To a stirred solution of 3-bromoaniline (5.0 mL, 46 mmol) and anhydrous sodium acetate (3.75 g, 77.6 mmol) was added methyl bromoacetate (4.4 mL, 46 mmol) in ethanol (20 mL) and heated (~120 ^oC) for 2 hours. The yellow mixture was cooled to room temperature upon which a flocculent white solid formed. The entire mixture was poured into water (20 mL) and filtered washing with copious amounts of water affording an off-white solid (7.90 g, 32.4 mmol, 70.5%, mp = 80-90 ^oC). IR (KBr): 3385 (N-H), 3218, 3061, 3025 (alkene C-H), 2952, 2845 (alkane C-H), 1740 (C=O), 1620, 1598, 1573 (C=C), 1481, 1217 (C-O), 1069, 988, 864, 768, 681.

Synthesis of N-(3-bromophenyl)glycine [9]

To a solution of N-(3-bromophenyl)glycine, methyl ester (7.89 g, 32.1 mmol) in ethanol (4.0 mL) was added 10% aqueous sodium hydroxide (19.5 mL) and the mixture was heated to reflux for 30 minutes. The light-brown solution was cooled to room temperature and extracted with methylene chloride (19.5 mL). The aqueous layer was then acidified to pH 4 with 3 M sulfuric acid and extracted with methylene chloride (3 x 25 mL). The combined organic layers were dried with sodium sulfate, filtered, and evaporated in vacuo yielding a caramel-colored oil (3.857 g, 16.77 mmol, 52.23%). IR (KBr): 3409 (N-H), 3070-2350 (CO₂H), 3063 (alkene C-H), 2976, 2920 (alkane C-H), 1728 (C=O), 1599 (C=C), 1504, 1481, 1434, 1220 (C-O), 1070, 986, 766, 681.

Synthesis of N-nitroso-N-(3-bromophenyl)glycine [10]

To a stirred solution of N-(3-bromophenyl)glycine (5.25 g, 22.8 mmol) in 12% hydrochloric acid (22.8 mL) cooled to 0-5 ^oC was added dropwise 3.5 M sodium nitrite (8.7 mL) turning the pink solution to an off-white color. After stirring in an ice bath overnight, slowly warming to room temperature, the mixture as extracted with methylene chloride (4 x 20 mL). The combined organic layers were dried with sodium sulfate, filtered, and evaporated in vacuo leaving an orangish-red semi-solid which was used in the next step without further purification or characterization.

Synthesis of 3-(3-bromophenyl)sydnone [11]

N-nitroso-N-(3-bromophenyl)glycine was dissolved in methylene chloride (20 mL) and magnesium sulfate (small amount) was added. After cooling to 0 ^oC, trifluoroacetic anhydride (1.90 mL, 13.5 mmol) was added dropwise. After stirring at 0 ^OC for 30 minutes, the maroon-colored mixture was neutralized with saturated aqueous sodium bicarbonate (16 mL) and the aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were dried with sodium sulfate, filtered through a pad of silica gel, and eluent was evaporated in vacuo affording a light-orange solid (21.85 g, 90.66 mmol, 77.50%, mp = 149-150 ^oC). IR (KBr): 3139 (sydnone C-H), 3101 (alkene C-H), 1735 (C=O), 1467, 1350, 957, 741, 725, 692.¹H-NMR (CDCl₃): 7.92-7.48 (m, 4 H), 6.76 (s, 1 H).

Synthesis of 3-(3-chlorophenyl)-4-thiophenylsydnone [12]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (100 mg, 0.509 mmol) in dry THF (5 mL) was added 2 M LDA (1.2 eq, 0.310 mL, 0.611 mmol) dropwise under a nitrogen atmosphere. After 30 minutes, phenyl disulfide (1.2 eq, 108 mg, 0.611 mmol) in dry THF (0.5 mL) was added slowly. After an additional 1.5 hours at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried in sodium sulfate, filtered, and evaporated in vacuo leaving a light-brown oil. Column chromatography (CH₂Cl₂) yielded off-white crystals (112 mg, 0.368 mmol, 72.4%, mp = 76-79 ^oC). IR (KBr): 3076 (alkene C-H), 1770 (C=O), 1590 (C=C), 1479, 1442, 1240, 1045, 874, 790, 761, 742, 726, 681, 558. ¹H-NMR (CDCl₃): 7.591-7.466 (m, 4 H), 7.259 (s, 5 H).

Synthesis of 3-(3-chlorophenyl)-4-methylsydnone [13]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (100 mg, 0.509 mmol) in dry THF (5 mL) was added 2 M LDA (1.2 eq., 0.310 mL, 0.611 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, methyl iodide (1.1 eq., 0.029 mL, 0.56 mmol) was added dropwise. After an additional 1.5 hours at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated in vacuo affording a brown oily solid. Purification via column chromatography (CH₂Cl₂) resulted in a tan solid (57 mg, 0.27 mmol, 53%). IR (KBr): 3065 (alkene C-H), 2921 (alkane C-H), 1741 (C=O), 1461, 1237, 1080, 788, 670.¹H-NMR (CDCl₃): 7.721-7.505 (m, 4 H), 2.171 (s, 3 H).

Attempted Synthesis of 3-(3-chloro-2-methylphenyl)sydnone [14]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (102 mg, 0.519 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.75 mL, 1.5 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, methyl iodide (1.1 eq., 0.035 mL, 0.57 mmol) was added dropwise. After an additional 1.5 hours at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated in vacuo affording a brown oily solid (68 mg). Purification via column chromatography (CH₂Cl₂) followed TLC of the fractions showed multiple close-running products. NMR of several fractions showed a small sydnone hydrogen and possibly multiple methyl peaks. IR showed lots of alkane C-H bands. Combined fractions 13-16 (16 mg, 14.6%) looked the most promising. Digested in ether affording a tan solid (5 mg, 4.6%, mp = 71-75 ^oC) yet still showed extra peaks on NMR and alkane C-H on IR. IR (KBr): 3132 (sydnone C-H), 3107 (alkene C-H), 2921 (alkane C-H), 1773, 1731 (C=O), 1457, 1352, 1166, 1091, 792, 724. ¹H-NMR (CDCl₃): 7.793-7.355 (m, 5.37), 6.766 (s, 0.28), 6.501 (s, 0.57), 2.338 (s, 2.11), 2.222 (s, 1.14, matches methyl singlet on dimethylated product but integration too small), 1.982 (s, 1.56, matches methyl singlet on dimethylated product but integration too small).

Attempted Synthesis of 3-(3-chloro-2-trimethylsilylphenyl)sydnone [15]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (100 mg, 0.509 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.75 mL, 1.5 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, trimethylsilylchloride (2.5 eq., 0.160 mL, 1.27 mmol) was added dropwise and the reaction was allowed to warm to room temperature over 1.5 hours. The reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (MgSO₄), filtered, and evaporated in vacuo yielding a brown solid (217 mg). Digested in ether resulting in a tan solid (30 mg). IR and NMR matches diisopropylamine. IR (KBr): 3436 (N-H), 2972, 2904, 2837, 2752, 2718, 2473 (alkane C-H), 1579, 1469, 1398, 1179, 1149, 1099, 501. ¹ H-NMR (CDCl₃): 3.417 (m, ~2 H), 1.50 (d, ~12 H).
TLC (CH ₂Cl₂) of the ether filtrate (brown oil) vs. an authentic sample showed the definite presence of desired product along with some starting material, baseline impurities, and a minor high running component. Therefore the filtrate was dissolved in methylene chloride (20 mL) and washed with 5% HCl (20 mL) in an attempt to remove any remaining diisopropylamine contamination. The organic layer was dried (sodium sulfate), decanted, and evaporated in vacuo affording a brown oil (141 mg, 81.4%). Column chromatography (methylene chloride) was completed collecting 8 fractions. Fractions 1-5: red oil (10 mg). Fractions 4-5: light-brown oil (85 mg) TLC showed a minor component (matched authentic dimethyl product) and a lower-running major component. IR (neat): 3438 (large O-H), 3149 (sydnone C-H), 2954, 2899 (alkane C-H), 1774, 1751 (C=O), 1654, 1560 (C=C), 1253, 1105, 848 (large, matches authentic dimethyl product). ¹H-NMR (CDCl₃): 7.710-7.319 (m, 1.3 cm), 6.576 (s, 0.3 cm, sydnone C-H), 6.471 (s, 0.2 cm), 1.264 (m, 0.7 cm0.322 (s, 4.5 cm), 0.198 (s, 3.5 cm). Fractions 7-8: tan solid (36 mg, 26.3%, mp = 68-75 ^o C). IR (KBr): 3429 (large O-H), 3110.5 (sydnone C-H), 2963, 2924 (alkane C-H), 1741 (C=O), 1652, 1578, 1558 (C=C), 1427, 1385, 1257, 1121, 1075, 850, 796. ¹H-NMR (CDCl₃): 7.715-7.270 (m, 3 H), 6.553 (s, 1 H), 0.314 (s, 9 H).

Attempted Synthesis of 3-[3-chloro-2-(diphenylhydroxylmethyl)phenyl]-4-(diphenylhydroxylmethyl ) sydnone [16]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (100 mg, 0.509 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.75 mL, 1.5 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, benzophenone (2.5 eq., 238 mg, 1.27 mmol) in freshly distilled THF (1.0 mL) was added dropwise and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturated brine (1 mL) and stored in a freezer for 2 days. To the mixture was added more saturated brine (19 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (MgSO₄), decolorized (activated charcoal), filtered through a pad of silica gel, evaporated in vacuo, and dried overnight in a P₂O₅ dessicator yielding a red oil (248 mg, 86.9%). TLC (CH₂Cl₂) showed 2 spots matching both starting materials. Column chromatography (CH₂Cl₂) afforded a red oil [213 mg, IR and TLC matched benzophenone; IR (neat): 3083, 3061, 3028 (alkene C-H), 2927, 1659 (C=O), 1599 (C=C), 1578, 1448, 1318, 1278, 942, 920, 764, 699, 639] and a tan solid [12 mg, IR and TLC matched m-chlorophenylsydnone; IR (KBr): 3135 (sydnone C-H), 3102, 3045 (alkene C-H), 1737 (C=O), 1587 (C=C), 1469, 1348, 1169, 1105, 1028, 959, 874, 797, 764, 724].

Attempted Synthesis of 3-(3-chloro-2-formylphenyl)-4-formylsydnone [17]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (100 mg, 0.509 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.75 mL, 1.5 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, freshly distilled (but not dried) DMF (2.5 eq., 0.099 mL, 1.3 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturated brine (1 mL) and stored in a freezer for 2 days. To the mixture was added more saturated brine (19 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (MgSO₄), filtered through a pad of silica gel, and evaporated in vacuo yielding a brown oil (44 mg, 44% recovery). IR (neat): 3334 (O-H), 3063, 3027 (alkene C-H), 2961, 2928, 2856 (alkane C-H, large), 1754 (C=O), 1658, 1597 (C=C), 1482, 1454, 778, 750, 700, 683.

Synthesis of 3-(2-bromo-3-chlorophenyl)-4-bromosydnone [18]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (100 mg, 0.509 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.75 mL, 1.5 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, bromine (2.5 eq., 0.065 mL, 1.27 mmol) in freshly distilled THF (1.0 mL) was added dropwise and the reaction was allowed to warm to room temperature over 1.5 hours. The reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (MgSO₄), filtered, and evaporated in vacuo yielding a dark semi-solid (327 mg, >100%). TLC (CH₂Cl₂) showed no starting material. Flushed through a pad of silica gel (CH₂Cl₂) affording a reddish-brown oil (206 mg, >100%). Digested in ether resulting in a light-brown solid (28 mg, 0.079 mmol, 16%, mp = 106-118 ^oC). IR (KBr): 3073 (alkene C-H), 1777 (C=O), 1655, 1419, 1204, 1027, 977, 787, 758, 698. ¹H-NMR (CDCl₃): 7.93-7.26 (m).

Synthesis of 3-(3-chloro-2-iodophenyl)-4-iodosydnone [19]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (100 mg, 0.509 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.75 mL, 1.5 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, iodine (2.5 eq., 0.323 g, 1.27 mmol) in freshly distilled THF (1.0 mL) was added dropwise and the reaction was allowed to warm to room temperature over 1.5 hours. The reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (MgSO₄), passed through a pad of silica gel, evaporated in vacuo, and dried in a P₂O₅ dessicator affording a brown solid. Digested in ether and then in methylene chloride leaving off-white crystals (142mg, 62.2%, mp = 137-141 ^oC). IR matched authentic sample. IR (KBr): 3065 (alkene C-H), 1735 (C=O), 1558 (C=C), 1457, 1402, 1192, 1040, 1019, 792. ¹H-NMR (CDCl₃): 7.736-7.256 (m).

Synthesis of 3-(3-bromophenyl)-4-thiophenylsydnone [20]

To a cooled (-63 ^oC) solution of 3-(3-bromophenyl)sydnone (100 mg, 0.415 mmol) in dry THF (5 mL) was added 2 M LDA (1.2 eq., 0.255 mL, 0.498 mmol) dropwise under an atmosphere of nitrogen. After stirring for 30 minutes, phenyl disulfide (1.2 eq., 90 mg, 0.50 mmol) dissolved in dry THF (0.5 mL) was slowly added. After an additional 1.75 hours at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated in vacuo affording a caramel-colored oil. Purification via column chromatography (CH₂Cl₂) resulted in a light-yellow solid (61 mg, 0.18 mmol, 42%, mp = 86-87 ^oC). IR (KBr): 3083, 3067, 3000 (alkene C-H), 1773, (C=O), 1579 (C=C), 1471, 1388, 1250, 1034, 867, 792, 742, 725, 713, 675, 550, 505. ¹H-NMR (CDCl₃): 7.731-7.390 (m, 4 H), 7.275 (s, 5 H).

Attempted Synthesis of 3-(3-bromo-2-methylphenyl)sydnone [21]

To a cooled (-63 ^oC) solution of 3-(3-bromophenyl)sydnone (100 mg, 0.415 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.60 mL, 1.2 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, methyl iodide (1.1 eq., 0.028 mL, 0.46 mmol) was added dropwise. After an additional 1.5 hours at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated in vacuo affording a brown oil. TLC (CH₂Cl₂) showed only starting material. Digested in ether affording a tan solid which was dried in vacuo (211 mg). IR [(KBr): 3436, 1120, 635, 313] and NMR [(CDCl₃): 2.144 (s), 1.346-1.102 (m)] looked like an inorganic salt (no sign of sydnone). Dissolved in methylene chloride (40 mL) and extracted with dilute HCl (20 mL) in order to remove salts and diisopropylamine. Dried the organic layer (Na₂SO ₄), decanted and evaporated in vacuo affording a dark brown oil (81 mg). TLC (CH₂Cl₂) shows very strong alkane C-H bands. IR (KBr): 3063, 3082, 3027 (alkene C-H), 2925, 2853 (alkane C-H), 1594 (C=C), 1496, 1454, 699, 428.

Synthesis of 3-(3-bromo-2-methylphenyl)-4-methylsydnone [22]

To a cooled (-63 ^oC) solution of 3-(3-bromophenyl)sydnone (100 mg, 0.415 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.60 mL, 1.2 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, methyl iodide (1.1 eq., 0.029 mL, 0.456 mmol) was added dropwise. After an additional 1.5 hours at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated in vacuo affording a brown oily solid which was dried in a P₂O₅ dessicator (129 mg). Purification by column chromatography (CH₂Cl₂) afforded a reddish semi-solid (73 mg, 65%). Digested in ether leaving a tan solid (3 mg, 2.7%, mp = 124-128 ^o C) TLC, IR and NMR matched an authentic sample of the dimethylated product. IR (KBr): 3073 (alkene C-H), 1734 (C=O), 1492, 1448, 1243, 1058, 792, 655. ¹H-NMR (CDCl₃): 7.90 (t, 1 H), 7.35 (d, 2 H), 2.241 (s, 3 H), 1.976 (s, 3 H).

Synthesis of 3-[3-bromo-2--(diphenylhydroxymethyl)phenyl]sydnone [23]

To a cooled (-63 ^oC) solution of 3-(3-bromophenyl)sydnone (100 mg, 0.415 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.60 mL, 1.2 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, benzophenone (1.2 eq., 91 mg, 0.498 mmol) in dry THF (1.0 mL) was added dropwise. After an additional 95 minutes at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), decanted, and evaporated in vacuo affording a green oil which was dried in a P₂O₅ dessicator (211 mg). TLC (CH₂Cl₂) showed starting material and one higher running product with baseline material. Purification by column chromatography (CH₂Cl₂) afforded a tan solid (5 mg, IR (KBr) and TLC matched m-bromophenylsydnone starting material) and green crystals (8 mg, 4.6% yield, mp = half ~60 ^oC matching phenyl disulfide and half turned dark brown 140-270 ^oC without completely melting). IR (KBr): 3462 (O-H), 3062, 3028 (alkene C-H), 2969, 2929 (alkane C-H impurities?), 1725 (sydnone C=O), 1660, 1599, 1578 (C=C), 1494, 1448, 1319, 1277, 1177, 1028, 942, 920, 764, 697, 639. ¹H-NMR (CDCl₃): 7.344-7.208 (m, ~14 H), 5.858 (s, ~1 H), 1.276-1.113 (m, impurities?).

Synthesis of 3-(3-bromo-2-iodophenyl)-4-iodosydnone [24]

To a cooled (-63 ^oC) solution of 3-(3-bromophenyl)sydnone (100 mg, 0.415 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.60 mL, 1.2 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, iodine (2.5 eq., 0.264 g, 1.04 mmol) in dry THF (1.0 mL) was added dropwise. After an additional 95 minutes at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), decanted, and evaporated in vacuo affording a brown oil. Dried in a P₂O₅ dessicator (266 mg). TLC (CH₂Cl₂) showed no starting material and only one higher running product with baseline material. Thus, the oil was flushed through a pad of silica gel (CH₂Cl₂) affording a tan oil which was then digested in ether affording a red solid (89 mg, 44% yield, mp = 114-119 ^o C). IR (KBr): 3065 (alkene C-H), 2925, 2852 (alkane C-H impurities?), 1736 (C=O), 1561 (C=C), 1459, 1403, 1196, 1014, 787, 704. ¹H-NMR (CDCl₃): 8.025-7.198 (m).

Attempted Synthesis of 3-[3-bromo-(2-thiophenyl)phenyl]sydnone [25]

To a cooled (-63 ^oC) solution of 3-(3-bromophenyl)sydnone (100 mg, 0.415 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.60 mL, 1.2 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, phenyl disulfide (1.1 eq., 100 mg, 0.456 mmol) dissolved in dry THF (0.5 mL) was added dropwise. After an additional 1.5 hours at -35 ^oC, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated in vacuo affording a brown oil. After purification via column chromatography (CH₂Cl₂), NMR analysis showed substantial contamination by diisopropylamine, mostly removed by heating under vacuum resulted in a brown oil (77 mg, 0.221 mmol, 53%). Could be the desired product. IR (KBr): 3437 (super-large O-H), 2973, 2933 (alkane C-H from diisopropylamine?), 1758 (C=O), 1608 (C=C), 1502, 1440, 1370, 1242, 740, 689. ¹H-NMR (CDCl₃): 7.58-7.08 (m, ~8 H), 6.757 (s, ~1 H); both 3.711 (m) and 1.20 (d) shrank dramatically after heating under vacuum. IR (neat): 3342 (O-H, very small), 3062 (Sydnone C-H?), 2972, 2930, 2874 (alkane C-H, strong), 1770 (C=O), 1607, 1504, 1455.5, 1418, 1371, 1243. 743, 689.

Attempted Synthesis of 3-(3-chloro-2-methylphenyl)-4-thiophenylsydnone [29]

To a cooled (-63 ^oC) solution of 3-(3-chlorophenyl)sydnone (102 mg, 0.519 mmol) in dry THF (5 mL) was added 2 M LDA (2.9 eq., 0.75 mL, 1.5 mmol) dropwise under an atmosphere of nitrogen. After 30 minutes, methyl iodide (1.0 eq., 0.032 mL, 0.52 mmol) was added dropwise. After an additional 1.5 hours at -35 ^oC, phenyl disulfide (1.1 eq., 125 mg, 0.573 mmol) in freshly distilled THF (0.5 mL) was added dropwise. After an additional 1.5 hours, the reaction was quenched with saturated brine (20 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated in vacuo affording a brown oily solid (376 mg). Purification via column chromatography (CH₂Cl₂) yielded 3 products: (1) fractions 2-4 (68 mg) matched 3-(3-chlorophenyl)-4-thiophenylsydnone IR (KBr): 3073 (alkene C-H), 2972, 2930, 1764 (C=O), 1579 (C=C), 1478, 1440, 1242, 1040, 792, 737, 686. ¹H-NMR (CDCl₃): 7.95-7.124 (m). (2) fraction 5-6 is a green oil (24 mg) and matches desired product except the integration for the methyl peak is too small. IR (KBr): 3075 (alkene C-H), 2966, 2919, 2850, 1770 (C=O), 1582 (C=C), 1479, 1442, 1242, 1043, 795, 742, 689. ¹H-NMR (CDCl₃): 7.880-7.205 (m, ~9.0 cm), 1.259 (s, 1.5 cm). (3) fractions 7-8 looks inorganic by IR and NMR. IR (KBr): 3417 (O-H), 3061 (alkene C-H), 2973, 2918 (alkane C-H), 1747 (C=O), 1599 (C=C), 1477, 1441, 1265, 1244, 1044, 772, 738, 689. ¹H-NMR (CDCl₃): 7.27-7.18 (m), 1.264 (m).

INSTRUMENTS USED

Perkin Elmer Spectrum BX-II, FT-IR Spectrometer

Anasazi Eft-60 proton-NMR Spectrometer (Varian anaspect EM360, 60 MHz magnet)

FUNDING

Petroleum Research Foundation, summer supplemental grant

Aigler Faculty Grant, Heidelberg College

Pepsi Fund, Heidelberg College

REFERENCES

1. Preston, P.N.; Turnbull, K. J. Chem. Soc., Perkin Trans. 1 1977, 1229

2. Turnbull, K.; Krein, D.M. Tet. Lett. 1997, 38, 1165

Chemistry Home Page