Diastereoselectivity in the Ring Expansion of Tetrahydropyrimidin-2-ones into Tetrahydro-1 H-1 , 3-diazepin-2-ones

A five-step synthesis of 4-(1-mesyloxyethyl)-6-methyl-5-tosyl-1,2,3,4-tetrahydropyrimidin2-one via amidoalkylation has been developed. Reaction of this compound with C-, O-, S-, and Nnucleophiles led to the highly diastereoselective formation of polysubstituted 2,3,4,5-tetrahydro-1H1,3-diazepin-2-ones as a result of ring expansion. The diastereoselectivity of the reaction depended on the nucleophile used and changed from cis to trans. The results obtained were explained by the formation of a bicyclic cyclopropane intermediate followed by cleavage of the zero bridge and stereoselective addition of the nucleophile to the resulting dihydro-1H-1,3-diazepin-2-one under kinetic control. The prepared cis-4-alkoxy-5-methyldiazepines reacted with alcohols under acidic conditions to give thermodynamically more stable trans-isomers.

Intermediates 3 are very labile and undergo conversion into the final products 2 in the presence of nucleophiles via cleavage of the zero bridge.There are several pathways for the latter transformation.5d We hypothesized that investigation of the reaction diastereoselectivity might provide useful insights into the mechanism of the transformation.Thus, the synthesis of 4-(1-mesyloxyalk-1-yl)-1,2,3,4tetrahydropyrimidin-2-ones 1 (R ≠ H) with two stereocenters and the study of nucleophile-mediated ring-expansion of these compounds into diazepines 2 (R ≠ H) is highly desirable.Herein, we describe the preparation of 4-(1-mesyloxyethyl)-6-methyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-one and its reactions with C-, O-, S-, and N-nucleophiles to give the corresponding 1,3-diazepin-2-ones.The mechanism of this reaction is discussed on the basis of the diastereoselectivity of the process.Some aspects of the structures and reactivity of the obtained diazepines are also reported.

Results and Discussion
According to our approach to tetrahydropyrimidin-2-ones, 4 we started this work with the preparation of the amidoalkylating reagent, sulfone 4 (Scheme 2).Scheme 2. Synthesis of the starting amidoalkylating reagent, sulfone 4.
This compound was obtained from 2-benzoyloxypropanal dimethyl acetal (5), which was hydrolyzed (80% aqueous HCOOH, 40 °C, 4 h) to give the corresponding aldehyde 6, followed by addition of p-toluenesulfinic acid (1 equiv), urea (5 equiv) and water.The condensation was complete after 21 hours at room temperature to afford 4 in 88% yield as a mixture of two diastereomers in a ratio of 94:6.Sulfone 4 precipitated from the solution and was isolated in 95% purity by filtration ( 1 H NMR data).The crude product was used in the next step without further purification.Sulfone 4 reacted with the sodium enolate of tosylacetone in dry MeCN at room temperature for 8 hours to give oxoalkylurea 9 in 89% yield as a mixture of four diastereomers in a ratio of 38:36:13:13 (Scheme 3).Heating 9 in MeCN at reflux for 2 hours in the presence of TsOH (0.5 equiv) resulted in cyclization to give hydroxypyrimidine 10, dehydration of which afforded tetrahydropyrimidine 11 in 90% yield as a mixture of two diastereomers in a ratio of 52:48.We studied the reactions of pyrimidine 13 with O-, C-, S-, and N-nucleophiles under conditions similar to those previously described. 5Treatment of a 55:45 diastereomeric mixture of 13 with MeONa in MeOH (rt, 2.5 h) gave 4-methoxydiazepine 14 in 93% yield as a single cis-diastereomer (Scheme 4).4-Ethoxydiazepine 15 was prepared analogously in 97% yield with excellent cis-diastereoselectivity (cis/trans = 93/7) from 13 and EtONa in EtOH (rt, 2 h).When pyrimidine 13 was reacted with NaCN (1.98 equiv) in dry DMSO at room temperature for 3.5 hours, the isolated material contained 10% of the minor diastereomer of the starting compound 13 along with the expected product of ring expansion, cyanodiazepine 16.Reaction of compound 13 with NaCN (2.88 equiv) in DMSO at room temperature was complete in 6 hours to afford diazepine 16 in 80% yield as a 94:6 mixture of cis-and trans-diastereomers.
Pyrimidine 13 smoothly reacted with PhSNa (1.14 equiv) generated by treatment of PhSH with NaH in THF (rt, 2 h) to give the expected 4-(phenylthio)diazepine 17 in 83% yield after silica gel column chromatography.This compound was obtained as a single trans-isomer.
Full trans-diastereoselectivity was also observed in the reaction of pyrimidine 13 with potassium phthalimide (1.29 equiv) in refluxing MeCN over 1.5 hours to afford 4-(phthalimido)diazepine trans-18 in 95% yield.The use of DMSO as the solvent did not change the selectivity of this reaction and gave trans-18 in 82% yield (rt, 6 h).
A plausible pathway for the nucleophile-mediated transformation of pyrimidine 13 into diazepines 14-18 based on our DFT calculations, 5d reported experimental data, 5,6 and current results is shown in Scheme 5.

Scheme 5.
A plausible pathway for the ring expansion of pyrimidine 13 to give diazepines 14-18.
All the above ring-expansion reactions proceeded with full diastereoselectivity (for 14, 17, and 18) or excellent diastereoselectivity (for 15, 16).Therefore, the formation of diazepines 14-18 from a 55:45 diastereomeric mixture of starting pyrimidine 13 proceeds through the same indermediate with one stereogenic center.Presumably, this intermediate could be dihydrodiazepine 19 arising from zerobridge cleavage in bicyclic compound 20.Thus, the diastereoselectivity of the ring-expansion reaction depends on the addition of nucleophiles to the C=N double bond of intermediate 19.
To confirm the proposed mechanism, we attempted to detect presumed intermediates in the reaction of pyrimidine 13 (a 55:45 diastereomeric mixture) with NaCN (1.3 equiv) in DMSO-d 6 at 25 °C using 1 H NMR spectroscopy.The reaction was complete in 2.5 hours to give a 95:5 mixture of cis-and trans-16.After 70 minutes, 7% of starting material 13 (unreacted minor isomer) was observed.No intermediates were detected in the NMR experiment because of their short lifetimes under the experimental conditions employed.
Unexpectedly, the diastereoselectivity of the ring expansion was dependent on the nucleophile used and changed from a cis-process (for MeONa, EtONa, and NaCN) to a trans-process (for PhSNa and potassium phthalimide).This can be explained by the reactions of intermediate 19 with nucleophiles under kinetic control.Bulky aryl-containing nucleophiles attack at C-4 of 19 exclusively from the side opposite to the 5-Me group to give trans-diazepines 17 and 18, while smaller nucleophiles attack from the same side of the 5-Me group to afford predominantly cis-diazepines 14-16.Although the reasons behind the cis-selectivity are not clear, we consider that stereoelectronic effects might be one possibility.
Kinetic control of the reaction of compound 13 with MeONa and EtONa was confirmed by isomerization of the resulting cis-14 and cis-15 into the corresponding trans-isomers.Indeed, we have found that stirring cis-14 in MeOH (rt, 30 min) or cis-15 in EtOH (reflux, 30 min) in the presence of TsOH (0.1 equiv) gave trans-14 or trans-15 in 87% and 97% yields, respectively (Scheme 6).Scheme 6. Acid-catalyzed transformation of cis-14 and cis-15 into trans-14 and trans-15.
We assume that this isomerization proceeds by an S N 1 mechanism through the formation of an acyliminium cation followed by addition of the nucleophile.Similarly, cis-14 was converted into trans-15 in 76% yield by heating in EtOH at reflux for 30 minutes.
The above data demonstrate that cis-14 and cis-15 resulting from the ring expansion of 13 are thermodynamically less stable than the corresponding trans-isomers.This was confirmed by the DFT calculations (B3LYP/6-31+G(d,p)) performed for various conformers of cis-14 and trans-14 in the gas phase and DMSO solution using the polarizable continuum model (PCM).The calculations showed that trans-14 was more stable than cis-14 (2.08 and 3.73 kcal/mol for the gas phase and DMSO solution, respectively).Analogously, we found that trans-16 was more stable than cis-16 (1.31 kcal/mol in the gas phase).
The stereochemistry of the diazepines 14-18 obtained was determined using 1 H NMR spectroscopy.
Proton couplings in the N(3)H-C(4)H-C(5)H fragment of these compounds were the most diagnostic.
For example, the values of the vicinal coupling constant between N(3)H and H-4 for cis-14,15 (1.3-1.4Hz) compared with those for trans-14,15 (6.2 Hz) in DMSO-d 6 prove, that these compounds exist predominantly in puckered conformations with pseudo equatorial and pseudo axial orientation of the alkoxy groups, respectively.The position of the 5-Me group in cis-14,15 and trans-14,15 is pseudo axial, which follows from the absence of long-range coupling between H-5 and 7-CH 3 (see refs 5a-d).