Synthesis of ( R ) and ( S )-3-Chloro-5-(3-methylmorpholino)-4 H -1,2,6-thiadiazin-4-ones

: Reaction of 3,5-dichloro-4 H -1,2,6-thiadiazin-4-one with ( R ) and ( S )-3-methylmorpholines (2 equiv), in THF, at ca. 20 °C gave ( R ) and ( S )-3-chloro-5-(3-methylmorpholino)-4 H -1,2,6-thiadiazin-4-ones in 95 and 97% yields, respectively. The new compounds were fully characterized.


Introduction
Morpholines are important saturated nitrogen-containing heterocycles and are utilized in a number of clinically used pharmaceuticals [1]. Among the nitrogen-containing heterocycles, morpholines rank as 17th in the most frequently used in U.S. FDA approved drugs [2], while other uses include insecticides [3] and corrosion inhibitors [4]. Examples of morpholine containing drugs include the analgesic phenadoxone, the analeptic doxapram, the β blocker timolol, and the Epidermal Growth Factor Receptor (EGFR) kinase inhibitor gefitinib [5] (Figure 1). The further tuning of the morpholine's properties by using an asymmetric 3-methylmorpholine has been demonstrated to improve a compound's biological activity and enhance its physicochemical characteristics. There are a number of reports of 3-methylmorpholines, exhibiting a variety of biological activities, including anti-cancer [6], anti-HIV [7], and antidiabetic agents [8].
The introduction of 3-methylmorpholines in the design of kinase inhibitors can not only enhance the potency of a compound, but the methyl group can act as a steric handle to increase the torsion between adjacent ring systems. There are a number of examples in the literature where having a substituted methylmorpholine has enhanced the potency on target, as well as the selectivity profile over close kinome family members ( Figure 2) [9][10][11]. The effects of introducing a methyl group are not always additive [12], and the precise addition of the stereochemistry can be critical [13]. These steric effects can also be achieved by fluorine [14], by adding a carbon spirocycle [15], or by altering the electronics of the ring system [16]. There are even examples where manipulation of the atropisomerism can directly affect the kinome selectivity profile [17]. These methods all alter the electronics of the system and hence can radically influence the selectivity profile of the kinase inhibitor, while the addition of a methyl group is a more subtle modification with limited electronic character. Our interest in the 3-methylmorpholine moiety is part of our ongoing effort to investigate the biological activity of novel 1,2,6-thiadiazines. Non-S-oxidized 1,2,6-thiadiazines are relatively unexplored heterocycles that have applications as plant protectants [18][19][20][21][22], liquid crystals [23], organic photovoltaics (OPVs) [24], and potential anti-cancer agents [25]. The chemistry of non-Soxidized 1,2,6-thiadiazines has recently been reviewed [26]. Currently, we are developing a series of new 1,2,6-thiadiazine building blocks to expand our library of a drug like compounds with potential kinome selectivity profiles. For this work, we investigated the 3-methylmorpholine moiety as a substituent of 4H-1,2,6-thiadiazin-4-one. We planned to introduce this moiety by a selective nucleophilic displacement of the first chloride of dichlorothiadiazinone 1 by 3-methylmorpholine to yield 3-methylmorpholine-substituted thiadiazines 2a and 2b. This displacement could occur under mild conditions owing to the electrophilic nature of the starting thiadiazine.
In the future, we plan to further elaborate thiadiazines 2a and 2b by introducing a second substituent via displacement of the remaining chloride. The second substituent could be either an aryl, amino, alkoxy, or thioaryl group (Scheme 1). Substitutions with alkoxy or thioaryl groups on chlorothiadiazines are known [27], while Pd catalysis can be used to introduce aryl (Suzuki or Stille [28][29][30]) or amino groups (Buchwald [31]).

Results and Discussion
We reacted 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1) with 1 equiv. of 3-methylmorpholines and 1 equiv. of 2,6-lutidine in EtOH at ca. 20 °C [25]. While both reactions led to complete consumption of the starting thiadiazine 1 to give the desired products, we noted problems with the isolation and stability of products. In particular, the crude product from both reactions after purification by dry flash column chromatography showed the presence of unreacted morpholine. This led to the degradation of the thiadiazines 2 in a solution that was clearly shown by decoloration of the yellow solution. To avoid this problem, we altered the reaction conditions to use 2 equiv. of 3-methylmorpholine [27] in dry tetrahydrofuran (THF), at ca. 20 °C, which led to complete consumption of the starting thiadiazinone 1 after 1 h. Dilution of the reaction mixture with dichloromethane (DCM), followed by extraction with 1 M HCl to remove unreacted morpholine, led to the isolation of the desired products 2a and 2b as yellow oils in 95 and 97% yields, respectively (Scheme 2, see SI for NMR spectra). The products, which were isolated without the need for chromatography, were free of any residual amines and showed improved stability both neat and in solution. The optical rotation data showed that the two products were indeed enantiomers ([α] 20 D −31 and +32, respectively, for 2a and 2b, see Materials and Methods). We noted that the stereochemistry of the products 2a and 2b was attributed to the enantiomeric purity of the starting (R)-and (S)-3-methylmorpholines, [α] 20 D −13.8 (c 1, CHCl3) and +13.4 (c 1, CHCl3), respectively. To the best of our knowledge, and in particular, under the mild reaction conditions used for the above nucleophilic substitutions, chiral 3-methylmorpholines do not epimerize. The possibility of hindered rotation of the methylmorpholino group and the thiadiazine C(5) position, which could lead to atropoisomerism and mixtures of diastereoisomers, was not observed by NMR: each compound showed only five narrow C-signals in the 13 C NMR spectra, representative of a rapidly rotating 3-methylmopholino substituent.
This synthetic effort successfully gave the chiral (R) and (S) 3-methylmorpholines 2a and 2b, which can be of interest to the medicinal and materials science sectors. The chemistry of these two aminothiadiazines will be further investigated to assess the potential applications.