Gold-catalyzed oxycyclization of allenic carbamates: expeditious synthesis of 1,3-oxazin-2-ones

A combined experimental and computational study on regioselective gold-catalyzed synthetic routes to 1,3-oxazinan-2-ones (kinetically controlled products) and 1,3-oxazin-2-one derivatives (thermodynamically favored) from easily accessible allenic carbamates has been carried out.


Results and Discussion
To explore the effects of various substrates on gold-catalyzed oxycyclization reactions, a number of new allenic carbamates were synthesized as shown in Scheme 1. Starting materials, tert-butyl (prop-2-ynyl)carbamates 1a-j, were obtained both in the racemic form and in optically pure form by using standard methodologies. Thus, alkynylcarbamates 1a-g were prepared through reductive amination of the appropriate aldehyde with propargylamine, followed by Boc 2 O treatment of the corresponding N-substituted prop-2-yn-1-amine. Alkynylcarbamate 1h was prepared from Garner's aldehyde following a literature report [56,57]. Alkynylcarbamate 1i was readily accessed from (S)-prolinol by using a modified known procedure [58]. Alkynylcarbamate 1j was achieved through the reaction of 3-bromo-1H-indole-2-carbaldehyde with the Ohira-Bestmann reagent followed by the addition of Boc 2 O. Terminal alkynes 1 were conveniently converted into allenic carbamates 2 by treatment with paraformaldehyde in the presence of diisopropylamine and copper(I) bromide (Crabbé reaction) [59,60].
We employed three different gold salts in our initial screening of catalysts for the model system, allenic carbamate 2a. Initially, the use of AuCl 3 and AuCl were tested, but both failed to catalyze the reaction. Fortunately, we found that [AuClPPh 3 ]/ AgOTf was an excellent catalyst for our purpose. To our delight, the reaction of allenic carbamate 2a at room temperature afforded 3-benzyl-6-methylene-1,3-oxazinan-2-one (3a) bearing an exocyclic double bond as the sole product (Scheme 2). Adding a catalytic amount of Brønsted acid (PTSA) into the reaction system did slightly improve the yield of 3a. Solvent screening demonstrated that dichloromethane was the best choice in the reaction.
As revealed in Scheme 2, a variety of allenic carbamates 2 were also suitable for such heterocyclization reactions to afford 1,3oxazinan-2-ones 3. To increase the molecular diversity by incorporating more 1,3-oxazin-2-ones in the molecule, compound 2g having two allenic carbamate units was used. Notably, bis(allenic carbamate) 2g also undergoes this interest-ing transformation to give bis(6-methylene-1,3-oxazinan-2-one) 3g through a two-fold cyclization. This product particularly underlines the power of the present cyclization reaction, as none of the conventional methods would allow its synthesis with such great ease.
Thus, it is possible to suppress the formation of the 1,3-oxazinan-2-one ring by performing the reaction at higher temperature, yielding the 1,3-oxazin-2-one as the exclusive product. A general trend can be deduced on the basis of these results: heterocycle 4 is the thermodynamically controlled product while heterocycle 3 is the kinetically controlled product [71][72][73]. Probably, double-bond migration in compounds 3 results in the formation of the 1,3-oxazin-2-one 4. In order to verify the role of the Au(I) catalyst in the double-bond migration process, we set up two experiments. Heating a mixture of 3a with Au(OTf)PPh 3 at a loading of 2.5 mol % in dichloromethane for 1.5 h at 130 °C resulted in full conversion into 4a. Running the same reaction in the absence of any catalyst resulted in 30% conversion after two days, as determined by 1 H NMR. Treatment of 1,3-oxazinan-2-one 3a with 5 mol % TfOH in CH 2 Cl 2 at room temperature did not proceed to give an appreciable amount of 3,4-dihydro-2H-1,3-oxazin-2-one 4a after 2 h. This indicates that the Au(I) catalyst might participate in the doublebond migration process; being a possible intermediate, the π-allyl complex 5 is depicted in Scheme 3 [74]. Despite that, the isomerization process can be also viewed as an intramolecular 1,3-H shift assisted by gold.
A possible pathway for the gold-catalyzed achievement of heterocycles 3 from allenyl-tethered carbamates 2 may initially  involve the formation of a complex 6 through coordination of the gold salt to the proximal allenic double bond. Next, chemoand regioselective 6-endo-dig oxyauration of the carbamate carbonyl moiety forms species 7. Attack of the carbamate carbonyl group occurs as a result of the stability of the intermediate ammonium cation type 7. Loss of proton linked to 2-methylprop-1-ene release [75-78], generates neutral species 8, which followed by protonolysis of the carbon-gold bond affords 6-methylene-1,3-oxazinan-2-ones 3 with concurrent regeneration of the gold catalyst (Scheme 4, left catalytic cycle). In line with the above mechanistic proposal, the easy breakage of the tert-butyl group at species 7 is essential for the formation of 1,3-oxazinan-2-ones 3. Besides, the replacement of the tertbutyl group in allenic carbamates 2 by other alkyl functions, such as methyl, did not allow the preparation of heterocycles 3. In addition to the double-bond isomerization that transforms products 3 into the thermodynamically more favored compounds 4, a mechanistic scenario involving the initial coordination of the gold to the distal allenic double bond leading to complex 9, followed by a 6-exo-dig oxyauration is likely for the achievement of 1,3-oxazin-2-ones 4 from allenic carbamates 2 (Scheme 4, right-hand catalytic cycle).
Density functional theory (DFT) calculations (see Supporting Information File 1) have been carried out at the PCM-M06/ def2-SVP//B3LYP/def2-SVP level to gain more insight into the reaction mechanism of the above discussed gold-catalyzed divergent oxycyclization reaction. The corresponding computed reaction profiles of the model allene 1M with the model gold catalyst AuPMe 3 (OTf) are shown in Figure 1, which gathers the respective free energies (computed at 298 K) in CH 2 Cl 2 solution. From the data in Figure 1, it becomes obvious that the 6-endodig transformation is kinetically favored over the 6-exo-dig reaction in view of the computed lower activation barrier of the former process (ΔΔG ≠ 298 = +7.4 kcal/mol). However, the cyclic reaction product INT2-B is thermodynamically more stable than the counterpart INT2-A (ΔΔG = 2.5 kcal/mol), which is in agreement with the experimental findings (see above). The next step of the process involves the TfO − promoted elimination of isobutene to form the corresponding INT3 complexes. The driving force of this process is clearly related to the thermodynamically favored release of isobutene (ΔG R,298 = −1.9 and −5.2 kcal/mol from INT3-A and INT3-B, respectively). Finally, the protonolysis reaction of the carbon-gold bond by TfOH renders the final products 3M and 4M regenerating the catalyst. This step occurs through the transition states TS2-A and TS2-B, respectively, in an exergonic transformation (ΔG R,298 = −4.5 and −3.0 kcal/mol from INT3-A and INT3-B, respectively). Again, the data in Figure 1 indicate that the final product 4M is thermodynamically more stable than 3M, which is in line with the experimentally observed conversion of 3a into 4a by heating in the presence and also in the absence of the gold-catalyst. From the computed reaction profile, it can be concluded that the observed divergent cyclization finds its origin in the initial 6-endo versus 6-exo oxyauration reaction steps, with the former being kinetically favored whereas the latter is thermodynamically favored. At this point, it cannot be safely discarded that the formation of the thermodynamically more stable 6-exo-dig products is the result of the simple thermally promoted isomerization of the less stable 6-endo-dig species.

Conclusion
In conclusion, efficient gold-catalyzed synthetic routes to 1,3oxazinan-2-one and 1,3-oxazin-2-one derivatives from easily accessible allenic carbamates under mild conditions have been reported. The oxycyclization reactions were found to proceed with complete control of regioselectivity. The mechanism of these processes has additionally been investigated by a computational study showing that heterocycles 3 are the kinetically controlled products whereas heterocycles 4 are thermodynamically favored.

Experimental
General Information 1 H NMR and 13 C NMR spectra were recorded on 700, 500, 300, or 200 MHz spectrometers. NMR spectra were recorded in CDCl 3 solutions, except were otherwise stated. Chemical shifts are given in parts per million relative to TMS ( 1 H, 0.0 ppm) or CDCl 3 ( 13 C, 76.9 ppm). Low-and high-resolution mass spectra were taken on a QTOF LC-MS spectrometer using the electronic impact (EI) or electrospray modes (ES) unless otherwise stated. Specific rotation [α] D is given in 10 −1 deg cm 2 g −1 at 20 °C, and the concentration (c) is expressed in grams per 100 mL. All commercially available compounds were used without further purification.
Typical procedure for the Au(I)-catalyzed preparation of 1,3-oxazin-2-ones, 4 [AuClPPh 3 ] (0.00475 mmol), AgOTf (0.00475 mmol), and p-toluenesulfonic acid (0.019 mmol) were sequentially added to a stirred solution of the allenic carbamate 2a (50 mg, 0.19 mmol) in dichloromethane (1.9 mL). The resulting mixture was heated in a sealed tube at 130 °C until disappearance of the starting material (TLC, 1.5 h). The reaction was allowed to cool to room temperature and filtered through a pack of celite. The filtrate was extracted with dichloromethane (3 × 5 mL), and the combined extracts were washed twice with brine. The organic layer was dried (MgSO 4 ), concentrated under reduced pressure, and purified by flash column chromatography on silica gel (hexanes/ethyl acetate 4:1) to afford product 4a (27 mg, 70%) as a colorless oil. 1

Supporting Information
Supporting Information File 1 Experimental details, analytical data of new compounds, copies of 1 H NMR and 13 C NMR spectra and computational details.