1 Base-Promoted Ring Contraction of Dihydrodiazepinones to Pyrrolinones

A novel synthesis of 2,3-dihydro-1H-1,3-diazepin-2-ones based on thermal elimination of methanol from 4-methoxy-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones has been developed. The prepared dihydrodiazepinones underwent a new rearrangement under basic conditions to give 3(aminomethylene)-2,3-dihydro-1H-pyrrol-2-ones. Plausible mechanism for the rearrangement is proposed.


Results and discussion
We previously developed a general five-step synthesis of 6-functionalized 2,3,4,5-tetrahydro-1H-1,3diazepin-2-ones 1 based on the ring expansion of 1,2,3,4-tetrahydropyrimidin-2-ones 2 mediated by nucleophiles (Scheme 1). 5 Initially, we studied the thermolysis of compounds 3a-f using 1 H NMR spectroscopy.We heated DMSO-d 6 solutions of 3a-f in NMR tubes at different temperatures and time intervals, and then determined the compositions of the reaction mixtures (at 25 o C).Selected data are summarized in Table 1.
Table 1 shows that thermolysis of tetrahydrodiazepinones 3a-f resulted in the corresponding dihydrodiazepinones 4a-c as the major products.Conversion of the starting material strongly depended on the substituent at the C4 position.The rate of transformation of phenylthio diazepinones 3d-f was lower than those of methoxy derivatives 3a-c (entries 1, 2 and 6 vs entries 10, 11 and 13, respectively), probably due to the poorer leaving group ability of the phenylthio group compared with a methoxy group.Some other products, 1-carbamoyl-1H-pyrroles 5a-c, 1H-pyrroles 6a-c, 3-(aminomethylene)-2,3dihydro-1H-pyrrol-2-ones 7a-c, and bis-diazepinone 8 (from 3b) always formed along with products 4a-c.The amounts of these products obtained depended on the structure of the starting material, the temperature and the reaction time.In general, increasing the temperature and decreasing the reaction time led to an increase in the relative amounts of 4a-c (entries 3-6 and entries 8-10).Under the optimized conditions (entries 1, 2 and 6) the yields of 4a-c from 3a-c determined by 1 H NMR spectroscopy were 71-91%.These conditions were used for the preparative synthesis of diazepinones 4a-c.Heating 3a-c in DMSO at 135 o C for 30 minutes followed by the addition of water and filtration of the formed precipitate gave products 4a-c in 53-73% yields after silica gel column chromatography.Scheme 2 illustrates possible routes for the transformation of substrates 3 into compounds 4-8 upon heating.The additional 1 H NMR experiments showed that prolonged heating of dihydrodiazepinones 4a-c in DMSO-d 6 at 136 o C led to their slow conversion, mainly into pyrrolones 7a-c (entries 14-16).The summarized 1 H NMR spectroscopic data in Table 1 confirms that the thermolysis of 3a-f proceeds via two independent pathways.Pathway A gives diazepinones 4a-c followed by their slow transformation into pyrrolones 7a-c; pathway B affords carbamoylpyrroles 5a-c and then pyrroles 6a-c.Formation of bis-diazepinone 8 upon heating of 3b can be explained as a result of the reaction of 4b with its imine tautomer 9b (see refs 5a,b).We suppose that thermal elimination of MeOH from 3a-c proceeds through formation of imine intermediates 9a-c followed by a tautomeric shift of hydrogen to produce more stable enamines 4a-c.Bis-diazepine 8 was not observed in the thermolysis of phenylthio-substituted diazepine 3e (entries 11 and 12), presumably due to the short life-time of 9b in the presence of strongly nucleophilic thiophenol.The rearrangement of dihydrodiazepinones 4a-c into pyrrolones 7a-c seems quite intriguing; its mechanism is currently under investigation and will be briefly described below.
There are several possible mechanisms underlying the transformation of tetrahydrodiazepinones 3a-f into pyrroles 5a-c.One of them could include hydrolysis of 3a-f with traces of residual water in DMSO to produce hydroxy diazepines 3 (R 1 X = OH) followed by ring-opening and recyclization.
However, thermolysis of diazepines 3a,c,f in refluxing toluene or xylene under strictly anhydrous conditions also gave significant amounts (up to 30%) of pyrroles 5a,c in addition to diazepines 4a,c and other products.Therefore, we think that compounds 5a-c result from transannular attack of the N1 nitrogen at the carbon atom C4 of imine intermediates 9a-c to produce derivatives of 1,6-diazabicyclo[3.2.0]hept-2-en-7-one followed by C5-N6 cleavage (Scheme 3).Previously, we found that tetrahydropyrimidines 2, in the presence of strong non-nucleophilic bases, were transformed into dihydrodiazepinones (e.g., 4 and 9) via cyclopropane bicyclic intermediates (e.g., 12).5e Reflux of 11 in pyridine for six hours in the presence of DBU (0.25 equiv) resulted in a mixture of pyrroles 5a, 6a and 7a, and pyridinium salt 13 in a ratio of 1:13:78:8, respectively.Pyrrolone 7a was isolated from this mixture using column chromatography in 37% yield.
Compound 13 was the major product when pyrimidine 11 was refluxed in pyridine without DBU for two hours (5a:6a:7a:13 = 4:5:39:52).Therefore, we assume that the basicity of pyridine is not sufficient for proton abstraction from N (1) H, which promotes the ring expansion.5e The base-mediated rearrangement of diazepinones 4a,b into pyrrolones 7a,b seems to be extraordinary.To our knowledge, there are no reports concerning this type of transformation.In order to understand its mechanism we performed quantum chemical calculations at the B3LYP/6-31+G(d,p) level of theory for the simplest model reaction, namely the rearrangement of diazepinone 14 into pyrrolone 15 (Scheme 5).First, we studied the structure of 14 and its conjugated base 16, from which the rearrangement presumably starts.The calculations showed that these compounds are the most stable among all the possible tautomers (seven for 14 and three for 16) in the gas phase and in DMSO or pyridine solutions using the polarizable continuum model (PCM).They are fully conjugated and their planar conformations could be expected to be anti-aromatic 8π-electron systems, 6 especially for 16.
The nuclear-independent chemical shift 7 (NICS) values of 14 and 16 in the optimized and planar conformations were used as a magnetic criterion of aromaticity.The NICS(0) values in the gas phase calculated at the HF/6-31+G(d) level (2.55 and 1.29 ppm for the optimized conformations of 14 and 16; 5.45 and 11.85 ppm for the planar conformations of 14 and 16, respectively) show that molecules of 14 and 16 in the planar conformations are anti-aromatic.To avoid anti-aromaticity these compounds adopt boat-like conformations with the nitrogen of the NH group and carbons of the opposite double bond out of the plane.The B3LYP/6-31+G(d,p) calculations in the gas phase, DMSO or pyridine solutions including the intrinsic reaction coordinate 8 (IRC) analysis demonstrated that the planar conformations of 14 and 16 are transition states with only one imaginary vibrational frequency and energy barriers of 1.23-1.35and 3.65-3.82kcal/mol for 14 and 16, respectively.
The anion 16 possesses an extraordinarily long (practically single) C2-NH bond (e.g., 1.490 Å in the gas phase) and a rather short C2-N bond (e.g., 1.331 Å in the gas phase) compared with the length of the C2-N bond (1.386 Å) in 14.Therefore, cleavage of the C2-NH bond in 16 is most probably the first step of the rearrangement.
The B3LYP/6-31+G(d,p) calculations also using the PCM solvation model showed that the most favorable pathway for the rearrangement, after deprotonation of the NH group of 14, is a concerted, one-step process including the C2-NH bond cleavage in 16 with simultaneous rotation around the C4-C5 single bond and proceeding via anionic transition states (TS) (Scheme 5).The IRC analysis demonstrated that the found transition states connect the desired minima.The energy barriers (from 16 to TS) were 30.27,34.01 and 33.70 kcal/mol for the gas phase, DMSO and pyridine solutions, respectively (VZPE uncorrected).The product of this reaction, imino-derivative 17, after the imineenamine tautomerization into 18 followed by protonation was converted into the target compound 15.
We assume that the above one-step mechanism is also valid for the base-promoted rearrangement of dihydrodiazepinones 4a,b into pyrrolones 7a,b.Indeed, the B3LYP/6-31+G(d,p) calculated structures of these compounds and their conjugated bases (the gas phase, DMSO and pyridine solutions) are close to those of 14 and 16.In particular, the N (3) H deprotonated forms of 4a,b adopt boat-like conformations with extraordinarily long C2-NH bonds (1.480-1.490Å).The remarkable regioselectivity of the reaction proceeding exclusively via the N (3) H deprotonated forms of 4a,b can be explained by the higher acidity of the N (3) H group compared with that of the N (1) H group (0.54-2.32 kcal/mol).The calculations also showed that pyrrolones 7a,b are much more stable (13.56-14.72 kcal/mol) than the corresponding dihydrodiazepinones 4a,b.

Scheme 5 .
Scheme 5. A plausible pathway for the rearrangement of 14 into 15 and the calculated geometry of the transition state in pyridine solution (TS-1) (the C-C-C-C dihedral angle = -77.67°).

Table 1 .
Product distribution upon thermolysis of
a Oil bath temperature (±1.5 o C). b According to 1 H NMR spectroscopic data.