The Synthesis of Unsubstituted Cyclic Imides Using Hydroxylamine under Microwave Irradiation†

Unsubstituted cyclic imides were synthesized from a series of cyclic anhydrides, hydroxylamine hydrochloride (NH2OH∙HCl), and 4-N,N-dimethylamino-pyridine (DMAP, base catalyst) under microwave irradiation in monomode and multimode microwaves. This novel microwave synthesis produced high yields of the unsubstituted cyclic imides for both the monomode (61 - 81%) and multimode (84 - 97%) microwaves.


Introduction
The unsubstituted cyclic imide is an important functionality which has been found to maintain significant biological activity [1][2][3]. The synthesis of unsubstituted cyclic imides either by conventional methods or microwave irradiation is often carried out under harsh conditions thereby increasing byproduct formation [4]. Currently, there are several conventional and microwave techniques to produce unsubstituted cyclic imides. Many conventional syntheses of unsubstituted cyclic imides use the reaction of cyclic anhydrides with reactants including ammonia, urea, formamide, and lithium nitride [5][6][7]. Other conventional reactions catalyze the cyclization of acidamide functionalities forming unsubstituted cyclic imides.
The application of microwave technology in many conventional syntheses offers many advantages including increased product yields and decreased reaction times [16][17][18][19]. We wish to report the synthesis of a series of unsubstituted cyclic imides using cyclic anhydrides, NH 2 OH·HCl, and DMAP via a novel microwave technique. This novel microwave synthesis produced unsubstituted cyclic imides in good yields within minutes.

Microwave Synthesis
The novel syntheses were conducted under microwave irradiation using hydroxylamine hydrochloride, DMAP, and an array of cyclic anhydrides yielding the corresponding unsubstituted cyclic imide. (Scheme 1) [20]. Although modifications of several experimental parameters gave moderate yields of the N-hydroxy cyclic imides (~30 percent), repeated studies found that the unsubstituted cyclic imides were the major products. Increased N-hydroxy cyclic imides yields were identified at lower temperatures and shorter reaction times. These results contradict Sugamoto et al., whoreported that N-hydroxy cyclic imides were synthesized in high yield under similar conditions [20]. The current data supports research done by Consonni et al., which found that cyclic Nhydroxyimides are converted to unsubstituted cyclic imides under basic conditions [21]. Application of this novel microwave technique can be used to synthesize many biologically important molecules including that of streptimidone, a glutarimide antibiotic [22]. Whereas this novel microwave synthesis produced high yields of the unsubstituted cyclic imides, no definite mechanism has been identified. One possible mechanism for unsubstituted cyclic imide formation is the breakdown of hydroxylamine·HCl into ammonia and water (Scheme 2). Ammonia production then promotes unsubstituted cyclic imide formation. A second possibility is the conversion of cyclic N-hydroximide to the unsubstituted cyclic imide. Unsubstituted cyclic imides formation appears to be enhanced by the addition of a base catalyst and additional heating.

Monomode Microwave Synthesis
The monomode microwave synthesis furnished unsubstituted cyclic imides using hydroxylamine as a source for nitrogen, DMAP, and cyclic anhydrides for the cyclic carbon backbone. The microwave synthesis was done at 150 °C over 5 minutes with a maximum energy output of 300W, producing between 61 and 81 isolated percent yields.

Multimode Microwave Synthesis
A series of multimode microwave reactions were used to identify a cost effective alternative to the more expensive monomode synthesis. This technique used similar reaction conditions and anhydrides to that of the monomode microwave syntheses. The reaction times ranged from 1 to 3 minutes at full power until the material melted and started to vigorously bubble. Isolated percent yields were between 84 and 97 percent.

84
Unsubstituted cyclic imides were produced in good yields in both the multimode and monomode microwaves. Slightly higher isolated yields were found in the multimode reactions compared to the monomode result. This variation may stem from energy output differences for the multimode (1100 W) and the monomode (300 W) microwaves.
Crystals isolated from this and previous unsubstituted cyclic imide syntheses were analyzed by single crystal X-ray diffraction generating good structural data for the desired cyclic imide products [23]. Specifically, the unsubstituted cyclic imide 3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione (4, Figure 1) was characterized by X-ray diffraction studies [24]. The crystal structure of this compound has previously been reported by Wang and co-workers [25]. Our unpublished crystal data found an unsubstituted cyclic imide bound in the cis position of a well defined cyclohexane ring (R factor = 0.0393).

General
The monomode microwave reactions were carried out in a CEM Discover Microwave. Multimode microwave reactions were done in a Kennmore Microwave Oven (Household) Output: 1100 Watts (Frequency: 2450 MHz). All Gas Chromatograph Mass Spectrometry (GC-MS) was performed using a Shimadzu GC-17A and GCMS-QP5050A Labsolutions system. All reagents were purchased from Aldrich Chemical Company and were used without further purification. Since two different methods are described in this article Method 1 will refer to synthesis carried out under monomode conditions, while, Method 2 will refer to synthesis under multimode conditions. Only the GCMS data is given, however unsubstituted cyclic imides data matched that reported earlier [15].
Phthalimide (1): Method 1. Phthalic anhydride (0.20 g, 1.35 mmol), NH 2 OH·HCl (0.09 g, 1.30 mmol), and DMAP (0.04 g, 0.33 mmol) were thoroughly mixed in a CEM vial with a stirrer. This was capped and heated in a CEM Discover microwave for 5 minutes at 150 o C. This was rapidly cooled to room temperature yielding a dark brown solid. The reaction mixture was dissolved in AcOEt (4 mL) and was washed with distilled water (2 x 2 mL). The organic layer was concentrated to obtain a white solid (0.14 g, 70%); MS m/z 147 (M + ) 104, 76, 50.
Phthalimide (1): Method 2. Phthalic anhydride (1.0 g, 6.75 mmol), NH 2 OH·HCl (0.54 g, 7.7 mmol), and DMAP (0.08 g, 0.65 mmol) were mixed in an 8 mL Teflon capped vial. The mixture was allowed to heat for 4 minutes and 11 seconds at 30 percent power in the multimode microwave and then cooled to room temperature. The sample was dissolved in acetone and flash chromatographed using silica (~30 g) with pure acetone as the mobile phase to obtain a yellow solid. Yield: 0.96 g (97%); MS m/z 147 (M + ) 104, 76, 50.
Succinimide (2): Method 1. Succinic anhydride (0.20 g, 2.00 mmol), NH 2 OH·HCl (0.14 g, 2.0 mmol), and DMAP (0.04 g, 0.33 mmol) were thoroughly mixed in a CEM vial with a stirrer. This was capped and heated in a CEM Discover microwave for 5 minutes at 150 °C. This was rapidly cooled to room temperature yielding a dark brown solid. The reaction mixture was dissolved in AcOEt (4 mL) and was washed with distilled water (2 x 2 mL). The organic layer was concentrated to obtain a white solid (0.14 g, 71%); MS m/z 99 (M + ) 56.
Succinimide (2): Method 2. Succinic anhydride (1.0 g, 10 mmol), NH 2 OH·HCl (0.80 g, 11 mmol), and DMAP (0.12 g, 0.98 mmol) were mixed in an 8 mL Teflon capped vial. The mixture was allowed to heat for 1 minute 49 seconds at full power in the multimode microwave and then cooled to room temperature. The sample was dissolved in acetone and flash chromatographed using silica (~30 g) with pure acetone as the mobile phase to obtain a yellow solid (0.95 g, 96%); MS m/z 99 (M + ) 56. (3): Method 1. cis-1,2-Cyclobutanedicarboxylic acid anhydride (0.20 g, 1.59 mmol), NH 2 OH·HCl) (0.11 g, 1.58 mmol), and DMAP (0.04 g, 0.33 mmol) were thoroughly mixed in a CEM vial with a stirrer. This was capped and heated in a CEM Discover microwave for 5 minutes at 150 °C. This was rapidly cooled to room temperature yielding a white solid. The reaction mixture was dissolved in AcOEt (4 mL) and was washed with distilled water (2 x 2 mL). The organic layer was concentrated to obtain a white solid (0.12 g, 61%); MS m/z 125 (M + ) 82, 54.