Zinc chloride-catalyzed cyclizative 1,2-rearrangement enables facile access to morpholinones bearing aza-quaternary carbons

ABSTRACT Morpholines and morpholinones are important building blocks in organic synthesis and pharmacophores in medicinal chemistry, however, C3-disubstituted morpholines/morpholinones are

extremely difficult to access. Here we show the ZnCl2-catalyzed cyclizative 1,2-rearrangement for the efficient synthesis of morpholinones bearing aza-quaternary stereocenters. A series of

structurally diverse C3-disubstituted morpholin-2-ones which are difficultly accessible by existing methods were efficiently constructed from readily available two achiral linear compounds.

Notably, mechanistic studies reveal that this reaction proceeds via an unusual sequence of direct formal [4 + 2] heteroannulation regioselectively delivering specific α-iminium/imine

hemiacetals followed by a 1,2-esters or amides shift process, which is different from the reported mechanism of the aza-benzilic ester rearrangements. SIMILAR CONTENT BEING VIEWED BY OTHERS

ASYMMETRIC SYNTHESIS OF _N_-BRIDGED [3.3.1] RING SYSTEMS BY PHOSPHONIUM SALT/LEWIS ACID RELAY CATALYSIS Article Open access 18 January 2022 STEREOSPECIFIC MOLECULAR REARRANGEMENT VIA

NUCLEOPHILIC SUBSTITUTION AT QUATERNARY STEREOCENTRES IN ACYCLIC SYSTEMS Article 19 March 2025 DESIGN, DEVELOPMENT AND APPLICATIONS OF COPPER-CATALYZED REGIOSELECTIVE (4 + 2) ANNULATIONS

BETWEEN DIARYLIODONIUM SALTS AND ALKYNES Article Open access 08 November 2022 INTRODUCTION C-substituted morpholines and morpholinones represent important building blocks1,2 in organic

synthesis and pharmacophores in medicinal chemistry, such as commercially available drugs of Finafloxacin3, Plk-2 inhibitor4 and Aprepitant5 (Fig. 1). Consequently, efficient access to these

structural targets have been in great demand. Thus far, there have been a number of methods for the synthesis of C-functionalized morpholines or morpholinones6,7,8 benefiting from

metal-catalyzed cyclization reactions9,10,11,12,13,14, allylic alkylation15, hydrogenations16,17 or other multi-step transformations18,19,20. On the contrary, approaches for the catalytic

preparation of C3-disubstituted morpholines/morpholin-2-ones are far less developed, which is due probably to the steric hindrance effect of the incoming aza-quaternary carbon and

availability of the corresponding branched starting materials21,22,23. Furthermore, asymmetric synthesis of such compounds was envisioned to be even more challenging, which must overcome the

formidable challenges in both reaction reactivity and stereoselectivity. In this regard, an elegant work by Carreira and coworkers dealing with ring expansion of 3-oxetanone-derived

spirocycles under In(III) catalysis is noteworthy (Fig. 2A)24. Mechanistically, the newly formed aza-quaternary carbon results from the Strecker reaction25 of oxazolidine with trimethylsilyl

cyanide, and a subsequent stereoselective desymmetrizing 6-_exo_-tet cyclization finally affords morpholine in high dr value. To the best of our knowledge, so far, this is the only example

of asymmetric synthesis of morpholine derivative with an aza-quaternary carbon center which is in situ formed rather than originates from a substrate. Thus, the highly useful and efficient

approaches for the de novo construction of structurally diverse C3-disubstituted morpholines/morpholin-2-ones from readily available linear compounds are highly desirable. Condensation of

arylglyoxals with vicinal amino alcohols delivering 2-acyloxazolidines which further isomerize to morpholinones is well-known26,27,28,29,30. Recently, this reaction has been applied to the

diastereoselective synthesis of morpholinones by Walczak group31. Very recently, we demonstrated an enantioselective aza-benzilic ester rearrangement for the synthesis of enantioenriched

morpholinones by chiral Brønsted acid (Fig. 2B)32. In both cases, however, only morpholinones bearing aza-tertiary stereocenters have been successfully synthesized while all efforts aimed at

the construction of C3-disubstituted morpholin-2-ones afford either oxazolidine intermediates or degradation at higher temperature31,32. To the best of our knowledge, 1,2-rearrangement for

the construction of morpholinones bearing aza-quaternary stereocenters has not been achieved in spite of the significant synthetic importance of the resulting compounds33,34. In connection

with our ongoing research interest in developing catalytic asymmetric cyclizative rearrangement (CACR)32,35, we herein report the successful realization of this endeavor, which delivers a

wide range of C3-disubstituted morpholin-2-ones 3 from readily available linear 2,3-diketoesters 1 and vicinal amino alcohols 2 under the catalysis of ZnCl2 complex (Fig. 2C). Moreover, a

highly diastereoselective version of such transformation has also been achieved by employing chiral vicinal amino alcohols as reaction partners. More importantly, rather than previously

reported formal [4 + 1] oxazolidination/ring-expansive hemiacetalization/1,2-aryl or alkyl shift cascade (Fig. 2B)32,35, mechanistic investigations indicated that this transformation

proceeded via a completely different reaction pathway consisting of an initial direct [4 + 2] cyclization (INT) followed by a 1,2-ester/amide shift process (Fig. 2C)36. RESULTS REACTION

DEVELOPMENT With our on-going efforts to further examine its reactivity profile35,36, the multi-functionalizable vicinal tricarbonyl compounds37,38,39,40,41,42,43,44,45,46,47 were chosen as

the reaction partner with aminoethanols. Our studies commenced with a mixture of ethyl 2,3-dioxo-3-phenylpropanoate and its hydrate (1A, 1.0 equiv), 2-((4-methoxyphenyl)amino)ethan-1-ol 2A

(1.2 equiv) in 1,2-dichloroethane (_c_ 0.1 M) at 80 °C under argon. Initially, screening of various strong Brønsted acids, such as trifluoroacetic acid, trifluoromethanesulfonic acid, and

_p_-toluenesulfonic acid, failed to give the rearranged products (entries 1-3, Table 1). Additionally, even aqueous hydrochloric acid could not give the desired product. As typical

bifunctional catalysts, chiral phosphoric acids (CPA)48,49 could not give the rearranged product 3A as well. Boron trifluoride-diethyl etherate (BF3 ∙ Et2O) was also ineffective (entry 4).

Screening of a series of strong Lewis acids, such as Mg(OTf)2, InCl3, and Zn(II) complexes (entries 5-10), in the presence of tricarbonyl compound 1A and amino alcohol 2A at 80 °C resulted

in the formation of the desired C3-disubstituted morpholin-2-one 3A, and ZnCl2 gave the best result (55% yield). Using ZnCl2 as catalyst, the reaction conditions were further optimized by

varying the solvent (entries 11–13), catalyst loading (entry 14), and reaction temperature (entries 15–16). Overall, the best conditions consisted of performing the reaction in DCE (_c_ 0.1 

M) at 100 °C in the presence of ZnCl2 (0.2 equiv). Under these conditions, C3-disubstituted morpholin-2-one 3A was isolated in 61% yield (entry 15). SUBSTRATE SCOPE EXPLORATION With the

optimized conditions in hand, this ZnCl2-catalyzed cyclizative 1,2-rearrangement was applicable to a wide range of substrates (Fig. 3). Regarding the aryl group of 3-aryl substituted

2,3-diketoesters, the presence of electron-neutral (H, Ph), electron-donating (MeO) groups and electron-withdrawing (F, CF3, CO2Et) at _para_ and _meta_ positions of the phenyl ring were

well tolerated (3A-3J). Unfortunately, an aryl group bearing an _ortho_ substituent failed to give the desired product which is due probably to the steric hinderance effect. The structure of

compound 3A was confirmed by X-ray crystallographic analysis (see Supplementary Data 1). In the presence catalytic amount of ZnCl2, (_S_)-(+)-Ibuprofen derived 2,3-diketoester could give

the corresponding C3-disubstituted morpholin-2-one 3G in moderate yield. Moreover, arylcoupled Aspirin could be smoothly functionalized with the present methodology (3H). 3,4-Dichlorophenyl,

2-naphthyl, and even heterocycles, such as benzo[_d_][1,3]dioxole, 3-thiophene and 2-thiophene, were transferred without event (3K-3O). To our delight, with aliphatic 2,3-diketoesters

(1P-1S), these rearrangement reactions efficiently afforded the corresponding product 3P-3S as well. Interestingly, instead of vicinal tricarbonyl compounds, 1,2-diketone bearing CF3 group

(1T)50 could also give the desired rearranged product (3T) with decreased yield. Furthermore, 2,3-diketoesters derived from different alcohols, such as methyl, isopropyl, and benzyl, were

all well-accepted substrates (3U-3W). Gratefully, 2,3-diketoamides participated in this ZnCl2-catalyzed cyclizative 1,2-rearrangement to provide the corresponding rearranged products 3X and

3Y in high yields. Performing the gram scale reactions of 1Y (6.78 mmol) and 2A (8.14 mmol) in the presence of ZnCl2 (20 mol%) afforded 3Y without obvious erosion of yield (75%).

L-(-)-Menthol derived 2,3-diketoesters gave the corresponding product 3Z in good yield as well. Alternatively, other _N_-substituted amino alcohols bearing phenyl, 2-methylphenyl, methyl and

benzyl groups were also examined, affording the corresponding products 3AA-3AD without event. Notably, amino alcohol bearing electron-withdrawing protecting group on nitrogen, such as Ts

and Ns, failed to afford the desired product 3. Furthermore, _N_-unsubstituted amino alcohols could give the corresponding rearranged products (3AE-3AF) smoothly. STRATEGY EXTENSION

Asymmetric catalytic construction of multi-functionalized morpholin-2-ones bearing aza-quaternary stereocenters represents a formidable challenge. To further exploit the structural diversity

of the products, we divert our attention to the diastereoselective synthesis of C3-disubstituted morpholin-2-ones by employing optically pure _N_-substituted 2-aminoethan-1-ols. Gratefully,

without any modifications to the reaction conditions, this protocol was applicable to a wide range of chiral amino alcohols delivering structurally diverse products bearing

multi-stereocenters in high stereoselectivities (Fig. 4). Various _N-_substituted 2-aminoethan-1-ol, such as (_S_)-2-aminopropan-1-ol, (_R_)-2-amino-3-phenylpropan-1-ol and

(_R_)-2-amino-3-methylbutan-1-ol, underwent this rearrangement reaction smoothly affording the desired products 3AG-3AI in high diastereoselectivities. 2,3-Diketoamides 1AJ and 1AK were also

well tolerated leading to the formation of the products 3AJ and 3AK in good yields with excellent stereoselectivities (>20/1 d.r.). Moreover, C2-phenyl substituted amino alcohol 1AL

afforded the product 3AL in excellent d.r. value as well. _N_-benzyl substituted amino alcohol 1AM delivered decreased stereoselectivity (6/1 d.r.). Subsequently, Other more challenging

chiral amino alcohols were further examined. Interestingly, even _N_-PMP substituted (_S_)-1-aminopropan-2-ol 1AN where the original stereocenter was far away from the newly formed

aza-quaternary carbon could also afford the product 3AN in good diastereoselectivity (4/1 d.r.). Substrates 1AO and 1AP derived from cyclic amino alcohols underwent the cyclizative

1,2-rearrangement without event, which furnished the corresponding products (3AO-3AP) bearing three stereocenters in excellent and good diastereoselectivities. The absolute configurations of

the products 3AG, 3AM, 3AN and 3AO were determined to be (3_S_,5_S_), (3_R_,5_R_), (3_S_,6_S_), and (3 _R_,4a_R_,8a_R_), respectively (see Supplementary Data 2–5). Consequently, the

absolute configurations for other morpholinones (3AH-3AL and 3AP) were assigned accordingly (Fig. 4). Unfortunately, all efforts aimed at developing a catalytic enantioselective version of

this rearrangement gave almost racemic products (see Supplementary Table S1 for details). MECHANISTIC STUDIES A series of control experiments were performed to gain insight into the reaction

mechanism. In the presence of _p_-toluenesulfonic acid (_p_-TSA), a formal [3 + 2] reaction of 1A with 2A occurred at 80 °C affording an oxazolidine compound 4A in moderate yield (Fig. 5a).

Further treating intermediate 4A with catalytic amount of _p_-TSA (20 mol%) gave trace of the product 3A (Fig. 5a). To our surprise, however, resubmitting 4A to the standard reaction

conditions also afforded only trace of the rearranged product 3A with concurrent formation of a linear compound 5 in 43% yield and some decomposition species (Fig. 5b). As 2-aminoethan-1-ol

derivatives 2 are capable of serving as bidentate ligands to Zn(II)51, we further examine the reactivity of (2A)∙ZnCl2 complex. Under the catalysis of the in situ formed (2A)∙ZnCl2 complex,

the reaction of the intermediate 4A gave product 3A in very low yield (10%) and a linear compound 5 was formed as a main product (Fig. 5c). Alternatively, a set of experiments were performed

with 2,3-diketoester 1A and amino alcohol 2A under the standard conditions and the yields of both 3A and 4A were detected at different time. As it is seen clearly from the diagram shown in

Fig. 5d, the yield of 3A increased steadily as the reaction proceeded with the concurrent formation of the low yield of 4A. These results revealed that, in this case, oxazolidine

intermediate 4A resulted from formal [4 + 1] condensation of 1A and 2A is not a major reservoir for product 3A, which is different from the reported Brønsted acid catalyzed aza-benzilic

ester rearrangements31,32. Notably, during the screening of the reaction conditions, another benzilic ester rearrangement product 636 was observed in the presence of catalytic amount of

Zn(OTf)2 (Fig. 6a). However, ZnCl2 complex only gave a trace of compound 6 (Fig. 6b). Furthermore, resubmitting 6 to our standard reaction conditions failed to give the desired product 3A

(Fig. 6c). These results indicate that an intramolecular aza-cyclization to the final product 3A via a possible in situ formed carbocation intermediate 6’ derived from dehydration of 6 could

be excluded. Subsequently, we realized that, at the first step of this tandem reaction, a direct formal [4 + 2] reaction might be competitive to the [4 + 1] cyclization of 1A and 2A. All

our efforts aimed at trapping the key intermediate of the rearrangement by employing various excessive nucleophilic reagents failed to give the corresponding products. To our delight, when

the reaction of 1A and _N_-unsubstituted amino alcohol 2AE was performed at lower temperature (60 °C), a unique α-imine hemiacetal intermediate 7 was successfully isolated in good yield

(Fig. 6d). Surprisingly, the imine moiety was formed from the condensation of primary amine with the carbonyl group linked to phenyl rather than with the middle one, which is also different

from the previous reports31,32,35. Notably, no oxazolidine intermediate 4AE was detected throughout the whole reaction process26,27,28,29,30. Interestingly, a predictable regioisomer 8

resulted from the formal [4 + 2] reaction was actually not observed as well, which is due probably to the relatively high thermodynamic stability of the α-imine hemiacetal 7. Importantly,

under the standard condition, the six-membered ring compound 7 underwent the rearrangement reaction smoothly, which delivered the corresponding product 3AE in high yield (Fig. 6e). In the

absence of ZnCl2 catalyst, intermediate 7 failed to give 3AE. The reaction of 1A with another branched amino alcohol 2AF gave similar results (Fig. 6f, g). The structure of the important

α-imine hemiacetal 9 was further confirmed by X-ray single crystal diffraction technique (see Supplementary Data 6). These results clearly suggested that a six-membered ring intermediate

resulting from a direct formal [4 + 2] cyclization should be the real reservoir for product 3. Moreover, treating compound 9 with catalytic amount of either _p_-TSA or (_R_)-TRIP-CPA at 100 

°C failed to yield the product 3AF, which not only underlined the great importance of ZnCl2 catalyst in triggering the key 1,2-ester shift step but also highlighted the difference in the

reaction mechanism between current rearrangement and Brønsted acid-catalyzed benzilic ester-type rearrangement (Fig. 6h)31,32,35. Finally, the reaction of diphenyl-substituted 1,2-diketone

10 with the amino alcohol 2A gave neither the rearranged product nor any intermediates (Fig. 6i), which indicated that the extra ester group is of vital importance for this rearrangement.

For all NMR spectra of the new compounds, see Supplementary Data 7. As the conversion of 1 and 2 to the five-membered oxazolidine intermediates 4 is extremely low, and the transformation of

4 to the products 3 is also highly difficult (see Fig. 5b–d), the compound 4 should be not the preferred intermediates under the conditions. Moreover, the isolation of the only [4 + 2]

cyclization products 7 and 9 which could be smoothly transformed into the rearranged products 3AE and 3AF clearly indicates the real reaction pathway as well. Therefore, on the basis of the

mechanistic experiments, this rearrangement reaction is proposed to proceed via an unprecedent direct [4 + 2] cyclization/1,2-ester or amide migration sequence (Fig. 7a). Initially, the

2,3-diketoester 1A and amino alcohol 2A predominately undergo a formal [4 + 2] heteroannulation reaction to generate a cyclic α-iminium hemiacetal A. Subsequently, the key intermediate A

then participate in a 1,2-ester shift reaction under the catalysis of in situ formed (2A)∙ZnCl2 complex affording the final C3-disubstituted morpholin-2-one 3A. The in situ formed a small

amount of 4A is more inclined to generate compound 5 rather than the rearrangement product 3A, which is due probably to the driving force differences to these two compounds, respectively.

The side product 5 might result from the carbon-carbon cleavage of intermediate B to produce a carbene species which is quenched by water and a potential hydride transfer reagent 2A52,53. A

plausible pathway leading to the observed stereochemical outcome is also illustrated in Fig. 7b. Because the ester moiety of the intermediate A1 is remote from benzyl group, the _Re_ face of

the iminium moiety is open to the ester group 1,2-migration, thus favorably affording 3AH. In contrast, the _Si_ face of the iminium moiety is shielded by benzyl group in A2, thus making

the 1,2-ester shift disfavored and resulting in the formation of the enantiomer _ent_-3AH in a minor amount. This scenario is in accordance with the configuration of the products as

established by X-ray crystal structure analysis of four representative morpholines (3AG, 3AM, 3AN and 3AO, see Fig. 4). In conclusion, we have developed the first examples of ZnCl2-catalyzed

cyclizative 1,2-rearrangement for the asymmetric synthesis of morpholinones bearing aza-quaternary stereocenters which are far more challenging to obtain efficiently by existing methods. A

series of structurally diverse C3-disubstituted morpholin-2-ones were efficiently constructed from readily available two achiral linear compounds. Importantly, on the basis of mechanistic

studies, this rearrangement proceeds via an unprecedent sequence of direct formal [4 + 2] heteroannulation followed by a 1,2-ester or amide migration process, which is highly distinct from

the reported reaction mechanism of aza-benzilic acid-type rearrangements. METHODS (SUPPLEMENTARY METHODS IN THE SI) GENERAL PROCEDURE FOR THE SYNTHESIS OF 3 To a mixture of 1 (0.1 mmol, 1.0

equiv), 2 (0.12 mmol, 1.2 equiv), and ZnCl2 (0.02 mmol, 0.2 equiv) was added 1,2-dichloroethane (1.0 mL) under argon. The reaction mixture was stirred at 100 °C for indicated hours. After

completion of the reaction (monitored by TLC), the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel, eluting with petroleum ether/ethyl

acetate to afford the products 3 in moderate to high yields. DATA AVAILABILITY Cif. files (see Supplementary Data 1–6); all NMR spectra of new compounds (see Supplementary Data 7). All data

generated and analyzed during this study are included in this article, its Supplementary Information, and also available from the authors upon reasonable request. The X-ray crystallographic

coordinates for structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 2225996, 2246927, 2246928, 2246926,

2246925 and 2266070 (see Supplementary Notes and Supplementary Tables S2-43 for details). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via

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of Stevens [1,2]-shifts of cyclic ammonium ylides. A Route to Morpholin-2-ones, J. Org. Chem. 1994, 59, 6051–6056. Download references ACKNOWLEDGEMENTS Financial support for this work was

provided by the National Natural Science Foundation of China (Grant No. 22101172, 22371183), and startup funding from Shanghai Jiao Tong University (SJTU). Dr. Y.-P. He thanks the China

Postdoctoral Science Foundation (grant no. 2022M710094). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai, 200240,

China Xing-Zi Li, Yu-Ping He & Hua Wu Authors * Xing-Zi Li View author publications You can also search for this author inPubMed Google Scholar * Yu-Ping He View author publications You

can also search for this author inPubMed Google Scholar * Hua Wu View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS X.L. Y.H. and H.W.

conceived the work, designed the experiments and analyzed the data. X.L. optimized the reaction conditions and performed the experiments. H.W. conceived and directed the project and wrote

the paper. All the authors discussed the results and commented on the manuscript. CORRESPONDING AUTHOR Correspondence to Hua Wu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare

no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Communications Chemistry_ thanks the anonymous reviewers for their contribution to the peer review of this work. ADDITIONAL

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CITE THIS ARTICLE Li, XZ., He, YP. & Wu, H. Zinc chloride-catalyzed cyclizative 1,2-rearrangement enables facile access to morpholinones bearing aza-quaternary carbons. _Commun Chem_ 6,

216 (2023). https://doi.org/10.1038/s42004-023-01016-y Download citation * Received: 19 July 2023 * Accepted: 29 September 2023 * Published: 07 October 2023 * DOI:

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