5-Carbonyl-1,3-oxazine-2,4-diones from N-Cyanosulfoximines and Meldrum&#39;s Acid Derivatives

Meldrum ’s Acid Derivatives

Letter

‑Carbonyl-1,3-oxazine-2,4-diones from N‑Cyanosulfoximines and

Felix Brosge, Johannes Florian Kochs, Mariela Bregu, Khai-Nghi Truong, Kari Rissanen,

and Carsten Bolm *

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02504

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sı Supporting Information

ABSTRACT: At elevated temperatures, N-cyanosulfoximines react with

Meldrum’s acid derivatives to give sulfoximines with N-bound 5-

carbonyl-1,3-oxazine-2,4-dione groups. A representative product was

characterized by single-crystal X-ray structure analysis. The product

formation involves an unexpected molecular reorientation requiring

several sequential bond-forming and -cleaving processes.

or centuries, organic chemists have discovered unprece-

particular role. They can easily be accessed by well-established

6 7

dented reaction pathways. Many of those have become the

synthetic protocols, and their deﬁned stability allows them to

basis for “name reactions”. Serendipity, rational design, and

be applied as useful intermediates in the preparation of other

computational reaction prediction have all proven fruitful in

N-functionalized sulfoximine derivatives. Direct applications

expanding the preparative boundaries of organic chemistry.

of N-cyanosulfoximines include the aforementioned use of

Because of their valuable chemical features and broad

bioactivity proﬁles, sulfoximines have continuously been

investigated and developed for applications in both crop

sulfoxaﬂor (1) as insecticide and various attempts to aﬀect

enzyme actions in a range of biomedical test systems. To

modify the N-cyano group of 3, several 1,3-dipolar cyclo-

additions have been developed (Scheme 1) providing

sulfoximines with various N-bound heterocyclic substituents

protection and medicinal chemistry. For example, the N-

cyano sulfoximine sulfoxaﬂor (1) is an insecticide developed by

−13

Dow AgroSciences, which exhibits a high eﬃciency against a

such as 4−7 (Scheme 1).

We now wondered about

wide range of sap-feeding insects. In medicinal chemistry,

reactions of N-cyanosulfoximines with another type of

Bayer Pharma introduced Pan-CDK inhibitor BAY 10000394

cycloaddition partner: Meldrum’s acid derivatives 8.

(

2), which entered clinical trials (Scheme 1).

The physicochemical properties of sulfoximines can be ﬁne-

In general, Meldrum’s acid derivatives such as 8 have widely

been used as acylation agents and precursors for acylketenes

tuned by functionalizing the S-bound nitrogen. In the series of

the respective products, N-cyanosulfoximines 3 play a very

9. The latter compounds are of interest because they easily

undergo [4 + 2] cycloaddition reactions. Accordingly, we

expected the formation of 2-sulfoximidoyl-substituited 4H-1,3-

oxazine-4-one 10aa when 8a and N-cyanosulfoximine 3a were

heated in toluene (Scheme 2). To our surprise, however, the

NMR data of the product were inconsistent with the structure

of 10aa, suggesting that sulfoximine 11aa was formed.

Although unexpected, the generation of 11aa appeared

reasonable taking into account the general reaction behavior

of Meldrum’s acid derivatives, which also involves the cleavage

of ketonic components providing dipolar intermediates 12

Scheme 1. Bioactive Sulfoximines and N-Cyano Derivatives

in 1,3-Dipolar Cycloaddition Reactions

14,15

(

Scheme 2).

In order to unequivocally conﬁrm the product structure, an

X-ray crystal structure analysis of the sulfoximine obtained

Received: July 28, 2020

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 2. Reactivity of Meldrum’s Acid Derivatives,

8d bearing an electron-donating ether group on the arene,

which gave 13ad in only 28%. The moderate yield of 13af

(48%) is a result of the water sensitivity of 8f, which rapidly

hydrolyzes. On a 4 mmol scale, 13aa was obtained in 90%

yield.

Assumed Compounds 10aa and 11aa and Obtained Product

3aa

Next, the sulfur component was varied, and several other N-

cyanosulfoximines were applied in reactions with Meldrum’s

acid derivative 8a (Scheme 3). Again, the yields of the

corresponding products 13ba−ia spanned a wide range (from

5% to 87%). Among the S-alkyl S-aryl derivatives, S-

cyclopropyl S-phenyl sulfoximine 3b performed best providing

3ba in 87% yield. For unknown reasons, the presence of a

para substituent on the arene reduced the product yields

(

13ca−ga). Distinct electronic eﬀects were not identiﬁed. An

interesting observation was made in the reaction of 8a with p-

formyl-substituted sulfoximine 3g. In this case, we expected the

formation of 13ga, but instead compound 14 was obtained

(

13% yield). Presumably, 14 stemmed from 13ga, which had

undergone a subsequent aldol reaction with in situ formed

acetone resulting from the degradation of Meldrum’s acid

derivative 8a. NMR spectroscopy suggested an exclusive

formation of the Z isomer of 14, which contrasted observations

by Bhat and co-workers, who found high E selectivities in

related organocatalytic reactions providing α,β-unsaturated

from the reaction of 3a with 8a was performed (Scheme 2).

Again, we were caught by surprise because none of the so far

considered structures were correct. Instead of 10aa or 11aa, an

isomer of 11aa (product 13aa) representing a sulfoximine with

an N-bound 5-carbonyl-1,3-oxazine-2,4-dione group was

found.

ketones. While the use of S,S-diphenyl sulfoximine 3h led to

3ha in 83% yield, S,S-dialkyl-substituted substrate 3i aﬀorded

3ia in only 30% yield.

Scheme 4 shows a tentative multistep reaction sequence

converting N-cyanosulfoximines 3 and Meldrum’s acid

Varying the reaction parameters revealed that 13aa could be

obtained in 99% yield when a 1:4 mixture of 3a and 8a in

Scheme 4. Proposed Reaction Mechanism

toluene was kept for 2 h at 120 °C. Under these conditions,

other Meldrum’s acid derivatives reacted with 3a analogously

providing the corresponding products 13ab−af in yields

ranging from 28% to 86% yield (Scheme 3). In this series,

the best results were obtained with substrates 8a and 8b having

as R a methyl or a benzyl group, respectively. Lower yields

were observed with Meldrum’s acid derivatives 8c−f having

aryl substituents at that position. This was particularly true for

Scheme 3. Substrate Scope

derivatives 8 to the observed products 13. Because none of

the depicted intermediates A−G could be isolated or detected,

the proposed transformation has to be taken with great care.

The process is initiated by elimination of acetone from 8

providing zwitterion A. (Note that A could loose CO leading

to acylketene 9. Then, however, CO would have to re-enter at

a later stage because it is part of the product.) Regioselective

addition of A on N-cyanosulfoximine 3 yields intermediate B.

Initially, we hypothesized that the formation of the N-acyl

group of 13 involved the addition of water to B (or B′) to give

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

https://pubs.acs.org/10.1021/acs.orglett.0c02504

Letter

C. Results from reactions under strictly anhydrous conditions

and experiments with H₂¹⁸O, however, which did not result in

any detectable incorporation of O in the product (as

Notes

determined by MS analysis), made this ﬁrst assumed reaction

The authors declare no competing ﬁnancial interest.

pathway unlikely. Taking B as starting point, an alternative

reaction path was considered beginning with a ring-opening of

heterocycle of B leading to acylketene D. Converting D into 13

requires a signiﬁcant molecular rearrangement with several C−

N bond cleavage and formation events. A potential reaction

path could involve hypothetic structures such as E and F

leading to acyl isocyanate G, which cyclized by attack of the

ketonic oxygen of G onto the acyl isocyanate group followed

ACKNOWLEDGMENTS

■

F.B. thanks Sinah Schmidt (RWTH Aachen University) for

support through practical experiments and Dr. Christoph

Rauber (RWTH Aachen University) for helpful NMR

discussions. The Alexander von Humboldt Foundation is

acknowledged for support of K.R. (AvH research award). We

also thank the anonymous reviewer for the excellent comments

on the mechanism (see ref 20).

by proton shift to give to the observed product 13.

The irreversibility of the process was shown by a crossover

experiment, which also revealed that there was no

intermolecular exchange. Thus, neither 13ab nor 13ha were

detected by ESI MS upon stirring of 3h and 8b at 120 °C in

the presence 13aa.

In summary, reactions between N-cyanosulfoximines 3 and

Meldrum’s acid derivatives 8 aﬀorded unexpected products

with 5-carbonyl-1,3-oxazine-2,4-dione groups at the sulfox-

imine nitrogen. X-ray crystal structure analysis revealed the

molecular details of a representative product. A multistep

reaction sequence starting with a [4 + 2] cycloaddition

followed by several scaﬀold reorientations has been proposed.

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ASSOCIATED CONTENT

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■

The Supporting Information is available free of charge at

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CCDC 1993374 contains the supplementary crystallographic

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AUTHOR INFORMATION

Corresponding Author

■

Carsten Bolm − Institute of Organic Chemistry, RWTH Aachen

University, D-52074 Aachen, Germany; orcid.org/0000-

001-9415-9917 ; Email: carsten.bolm@oc.rwth-aachen.de

Authors

Felix Brosge − Institute of Organic Chemistry, RWTH Aachen

University, D-52074 Aachen, Germany; orcid.org/0000-

002-4636-0517

Johannes Florian Kochs − Institute of Organic Chemistry,

RWTH Aachen University, D-52074 Aachen, Germany

Mariela Bregu − Institute of Organic Chemistry, RWTH Aachen

University, D-52074 Aachen, Germany

(

09−112.

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