Kunlayanee
Punjajom‡
a,
Paul P.
Sinclair‡
a,
Ishika
Saha
b,
Mark
Seierstad
b,
Michael K.
Ameriks
b,
Pablo
García-Reynaga
*b,
Terry P.
Lebold
*b and
Richmond
Sarpong
*a
aDepartment of Chemistry, University of California, Berkeley, CA 94720, USA. E-mail: rsarpong@berkeley.edu
bJanssen Research and Development, San Diego, California 92121, USA. E-mail: pgarciar@its.jnj.com; terry.lebold@gmail.com
First published on 27th November 2023
We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting from methyl ketones and primary amines. This one-pot, three-component coupling employs 2,3-dimethylimidazole-1-sulfonyl azide triflate as a coupling reagent and oxidant. The transformation is scalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to 89% yield. In addition, 15N- and 13C-labeling studies suggest a mechanism involving a 1,2-nitrogen migration. Together with the mechanistic studies, DFT calculations provide insight into the reaction pathway and set the stage for further exploration of the mechanistic nuances of reactions that use sulfamoyl azides. In combination with the demonstrated modularity of the approach reported herein, the derivatization of the thiodiazole dioxide products highlights the potential of this methodology to rapidly access diverse chemical structures.
In the course of a recent collaborative study between the Sarpong group and Janssen Research and Development to prepare aza-bicyclohexanes and bicyclopentanes,7 we identified 3 as an unexpected product of the reaction between an imine and 2,3-dimethylimidazole-1-sulfonyl azide triflate (A, Fig. 1C). We recognized that this transformation seemingly overcomes the key challenge described above by obviating the need for pre-oxidation of the α-carbon of the ketone coupling partner en route to the thiodiazole dioxide structural motif. This transformation represents a modular, three-component coupling that allows for the rapid diversification of methyl ketones and primary amines, two functional groups that are well-represented in pharmaceutical libraries.
In addition to the practical value of this discovery, we also recognized an opportunity to explore the reactivity of 2,3-dimethylimidazole-1-sulfonyl azide triflate (A).8 Sulfamoyl azides have been used in sulfonyl8 and diazo9 transfer reactions, cycloadditions,10 and even nitrogen deletion reactions.11 Because of their diverse array of reactivity, the study of these reagents with a variety of functional groups may give rise to new mechanistic insights and strategies for chemical diversification.
Entry | Temp | Solvent | Additive (1.0 equiv.) | Yielda (%) | RSM (%) |
---|---|---|---|---|---|
a Yield was determined by 1H NMR with dimethyl sulfone as an internal standard. b Decomposition was observed. c Isolated yield. CyH = cyclohexane RSM: recovered starting material MS: molecular sieves. | |||||
1 | 23 °C | MeCN | — | 15 | 59 |
2 | 60 °C | MeCN | — | 43 | 26 |
3 | 80 °C | MeCN | — | N/Ab | N/A |
4 | 60 °C | MeCN | Di-tert-butylpyridine | 71c | 18c |
5 | 60 °C | MeCN | 2,6-Lutidine | 48 | 47 |
6 | 60 °C | THF | Di-tert-butylpyridine | 61 | 15 |
7 | 60 °C | DCM | Di-tert-butylpyridine | 38 | 6 |
With optimized conditions in hand, we next investigated the scope of the coupling partners (Scheme 1). Simple allylic amines (see 3a–3b) perform well in this reaction, while cinnamyl amine results in reduced yield of the product (3c). Propargylic and homoallylic amines are also competent coupling partners giving moderate yields of the desired products (3d and 3e, respectively). Diverse benzylic amines, including those bearing electronically-disparate groups (see 3f–h) serve competently as coupling partners in the reaction, although α-substitution (see 3i) leads to decreased yields compared to other benzylic amines. Finally, aliphatic amines can also be employed, giving the products (3j–3k) in moderate to good yields. X-Ray crystallographic analysis of a single crystal of 3b provided support for the assigned structures. To further establish the practicality of this approach, a gram-scale reaction using 1a (1.00 g, 7.23 mmol) and 2a under the standard reaction conditions proceeded without any loss in efficiency to give 3a in 70% yield along with 5% of recovered methyl ketone starting material.
Scheme 1 Substrate scope of amine. aReaction conditions: see Table 1, entry 4. bp-Fluoroacetophenone. c(E)-Cinnamylamine. Isolated yield reported. Yield in parenthesis refer to recovered starting material. CyH: cyclohexane MS: molecular sieves. |
We then investigated the substrate scope of the ketone coupling partner. Para- and meta-substitution is well tolerated on the ketone coupling partner (see 3m–3n), while ortho-substitution significantly reduces reaction efficiency (see 3o). Electron-neutral and electron-poor ketones react well (see 3l–3q), whereas decreased yields are observed for an electron-rich ketone (see 3p). Various heteroaryl substituted ketones are competent substrates and deliver the corresponding products (3r–3u) in up to 89% yield. A series of cyclic aromatic ketones, including 5-fluoro-1-indanone, α-tetralone, and β-tetralone were successful substrates as well. Notably, α-tetralone and β-tetralone led to the same product (3w), presumably through diverging pathways (vide infra). Finally, vinyl and aliphatic ketones were competent substrates, giving 3x and 3y–3ab, respectively. Ketones bearing α-branched, cyclic, groups are superior substrates, whereas linear substrates (e.g., 1aa) gave lower yields of the desired products (e.g., 3aa).
There are also several limitations in the scope of this reaction. Specifically, we found that ketones bearing α-substitution were poor substrates. For example, 3ac was not formed from the corresponding ketone even upon extended reaction times. Amino acids and anilines also proved to be unsuccessful amine coupling partners.
We hypothesized that inefficient formation of the intermediate imine could account for the poor reaction outcomes observed in several cases. To probe this possibility, we monitored the imine formation for one successful substrate (i.e., to form 3a) and two unsuccessful substrates (to form 3ac and 3ad) as well as one low yielding product (3o). As shown in Scheme 2, for substrates that reacted poorly or unsuccessfully, only partial conversion of the ketone to the imine was observed. When these ketone/imine mixtures were treated with A, product was only obtained from imines 4a and 4o. The mixtures containing imines 4ac and 4ad returned only starting ketone after treatment with A and workup. We then synthesized pure 4o and subjected it to reaction with A. The product (3o) was isolated in a much improved 43% yield. From these experiments, we conclude that for some ketone substrates, low yields of the product might result due to incomplete imine formation. However, in some cases (e.g., 3ac), even substrates that form the imine intermediate efficiently can lead to low yields of the products due to other incompatibility issues (e.g., difficulty with enamine formation).
To gain insight into the reaction mechanism, we chose to conduct a series of studies with isotopically labeled substrates. The use of α-13C acetophenone (13C-1l) provided thiodiazole dioxide 13C-3l (Scheme 3A) bearing the 13C label at the imine carbon, which suggests that the carbon chain remains intact (i.e., a phenyl migration does not occur). Next, we conducted the reaction with 15N labelled allyl amine, which gave 15N-3a (Scheme 3B) where the 15N label was incorporated only at the amine position and not at the imine nitrogen. This observation indicates that the imine nitrogen in 4 undergoes a 1,2 migration during the course of the reaction. Notably, the nitrogen also migrates when an aliphatic ketone (1y) is used to give 15N-3y—further evidence that the aromatic system is not involved or critical to the rearrangement.
Scheme 3 (A) Outcome of reaction with 13C-acetophenone. (B) Outcome of reaction with 15N-allylamine for conditions see Table 1 entry 4. |
Nitrogen migrations of this type are known for enamine/azide cycloadditions.12 These cycloadditions can generate amino-triazolines which can in turn generate amino-aziridines (Fig. 2A). Each of these species can further transform in several ways, including through C–C bond cleavage (Type I)13 and migration of a carbon (Type II),13a–d,14 nitrogen (Type III),13e,14b,c,15b or hydride (Type IV)10,13e,14a,15 substituent (Fig. 2A). Product mixtures are often observed, and the selectivity is dictated by the nature of the substituents on both the enamine and the azide components. Importantly, our system differs from those described in the literature in several ways. Most notably, our reaction proceeds through an imine formed from a primary amine (see Scheme 3A) rather than an enamine formed from a secondary amine (see ref. 12–15). Additionally, sulfamoyl azide A is able to react with the imine at sulfur, to generate a sulfamoyl enamine. These key differences, as well as the superb selectivity for the Type III nitrogen migration that we observe, led us to further investigate the reaction pathway with DFT. For ease of computation, calculations were performed with a model enamine (5), where the N-allyl group is modified to N-Me. Structure minima were generated with DFT or UDFT in the gas phase in Jaguar (B3LYP-D3/6-31G+*). Transition structures were identified using coordinate scans, linear synchronous transit, quadratic synchronous transit, or a combination thereof, at the same level of theory.
We considered two possible pathways to access the amino-aziridine precursor to the Type III product. Pathway 1 involving loss of nitrogen followed by (2 + 1) cycloaddition, and Pathway 2 involving (3 + 2) cycloaddition followed by nitrogen extrusion (Fig. 2B). To interrogate Pathway 1, we first identified a transition state corresponding to loss of nitrogen from 5 (TS1) to form nitrene 6 in one of three spin states. At this stage, (2 + 1) cycloaddition would generate aziridine 8 through the respective transition structure, which subsequently undergoes exothermic rearrangement viaTS5 to give final product 9. For Pathway 2, we were able to identify a transition state for the intramolecular cycloaddition of the azide and enamine (TS2) in 5, which results in the formation of triazoline 7. A transition structure for the direct conversion of 7 to 9 by either a concerted or stepwise mechanism could not be identified. However, TS4 was identified, corresponding to loss of nitrogen from triazoline 7 to give 8. Analogous to the first pathway, 8 could undergo exothermic rearrangement to give the final product (9). The computationally computed barrier for the (3 + 2) cycloaddition at TS2 is 3.5 kcal mol−1 lower than the barrier for loss of nitrogen at TS1, suggesting the former is the favored pathway. Consistent with the isotope labelling experiments discussed above, one of the C–N aziridine bonds is lengthened at TS5, and the imaginary frequency at this transition structure corresponds to atomic motion of the C and N atoms involved in the bond rearrangement.
We hypothesize that the preference for Type III reactivity over either Type I or Type II arises from the sulfur dioxide group connecting the two nitrogens. This tether would make amidine formation difficult due to developing strain en route to a four-membered heterocycle. Although we cannot rule out an intermolecular enamine/azide cycloaddition, the product selectivity suggests that the S–N bond forms prior to rearrangement. Additionally, we propose that the nitrogen rearrangement accounts for the convergent reactivity of α- and β-tetralone. In the case of α-tetralone, the expected Type III nitrogen migration is observed (as confirmed by 15N NMR; see Fig. 2C). In the β-tetralone system, however, the nitrogen does not migrate. Instead, the observed product results from Type IV hydride migration (see Fig. 2A and C). We posit that in this case, the nitrogen shift is disfavored by developing “peri-strain” between the ortho hydrogen on the aromatic ring and the N-allyl substituent. In all other cases, the migrating group is moving away from the aromatic ring, leading instead to a lessening of any unfavorable interactions between the nitrogen substituent and the aromatic protons. On the basis of this hypothesis, we anticipated that a linear analog of β-tetralone (e.g., phenylacetone) should give only the expected nitrogen shift product because of the absence of “peri-strain” in this conformationally flexible system. Indeed, using 10 and 2a in the thiadiazole dioxide forming reaction, we isolated only the two expected products that involve a nitrogen shift (i.e., 11, arising from an intermediate benzylic enamine and 12, arising from a terminal enamine intermediate). This observation supports our hypothesis that the conformational rigidity of the α-tetralone system leads to the unique reactivity that is observed in that case.
With empirical and computational support for our proposed mechanism secured, we then set out to demonstrate the synthetic utility of our dihydro-1,2,5-thiodiazole 1,1-dioxides (Scheme 4). For example, tetrahydro-1,2,5-thiodiazole dioxide 13 is obtained through either reduction with sodium borohydride or enantioselective transfer hydrogenation using ruthenium catalyst B to give 13 in high yield and, in the case of the transfer hydrogenation, good enantiomeric excess (91% ee).6 In addition to hydrides, 3a is a competent electrophile for carbon nucleophiles, exemplified by the addition of ethyl magnesium bromide to form 14. The cyclic sulfamide moiety can also be opened to 1,2 diamine 15 by heating with hydrazine. This process allows for easy and modular access to diamines which are precursors to a variety of biologically relevant structural motifs (imidazolidinones, etc.).16
Scheme 4 Synthetic transformations of dihydro-1,2,5-thiodiazole dioxide. FA/TEA: formic acid/triethylamine (∼5:2). |
Sulfonyl imines are well-established precursors to N-sulfonyl oxaziridines, a very useful class of oxygen-transfer reagents.17 Accordingly, the dihydro-1,2,5-thiodiazole dioxide 3f was readily converted to the corresponding oxaziridine (16) by oxidation with meta-chloroperoxybenzoic acid (mCPBA). The modular nature of our method should allow for the synthesis of a diverse array of oxaziridines which could aid in the discovery of new reagents for oxygen transfer.
Footnotes |
† Electronic supplementary information (ESI) available. CCDC 2284144 for 3b. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc04478e |
‡ These authors contributed equally to this work. |
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