Synthetic and Mechanistic Investigation of an Unexpected ­Intramolecular 1-5 Nitrogen to Carbon Tosyl Migration

Abstract

Controlled sulfonyl migration is considered an important transformation for total synthesis and scaffold elaboration. Accordingly, efforts to understand the underlying properties of these often serendipitously identified reactions have important implications. Following the attempted synthesis of a tetrahydroindazolone analogue, we report here an unexpected 1,5-nitrogen to carbon tosyl migration, resulting in the isolation of an unusual sulfonated dimedone. Synthetic and mechanistic investigations provide early insight into the scope of this reaction, with two potential mechanisms proposed.

Due to their broad spectrum of biological activity, tetrahydroindazolones are considered privileged scaffolds in drug discovery.[1] [2] [3] [4] This is possibly best exemplified by SNX-25a (1) and SNX-2112 (2, Figure [1]) which were identified by Huang et al. as potent and selective in inhibitors of HSP90[5] and have also proven useful for the development of molecular probes, with applications in diagnostics and mechanistic investigations.[6] [7] [8] [9] [10] Consequently, their biological utility has seen the development of several synthetic procedures to access the core tetrahydroindazolone scaffold.[11] [12] [13] [14] [15] The most commonly reported procedures typically involve introducing a hydrazine source to a suitably functionalized dimedone derivative.

For example, Claramunt et al. (Scheme [1], I) conveniently cyclized 2-acetyl dimedone (3) with hydrazine hydrate in THF in the absence of acid or base to generate a 3-methyl-tetrahydroindazolone analogue 4.[16]

Similarly, in their reported synthetic procedure of compound 1 Huang et al. cyclized 3 with a suitably functionalized phenylhydrazine under acidic conditions to form precursor compound 5 (Scheme [1], II).[5] Due to reported instability of the requisite trifluoroacetylated dimedone, the same method could not be applied for the synthesis of compound 2. Accordingly, through the adaption of a previously reported method,[17] Huang et al. introduced the required nitrogen atoms via the formation of a tosylhydrazone intermediate 6. In a two-step, one pot reaction intermediate 6 was reacted with trifluoroacetic anhydride in the presence of Et₃N in THF to form the putative C-2 acylated intermediate, followed by cyclization and detosylation in the presence of NaOH in methanol and water to yield 7 (Scheme [1], III).[5] [18] Driven by our own interests in exploring HSP90 as a therapeutic target,[19] we were curious as to whether the method described in Scheme [1] (III) may have wider substrate scope. While, in our hands, this approach led to the successful isolation of compound 7, modification of this method for the synthesis of 4 was unsuccessful instead leading to the isolation of N-acetylsulfonohydrazide (8, Figure [2]), with no evidence of formation of tetrahydroindazolone 4.

Despite the reported reactivity of the dimedone C-2 position, and the general assumption that indazolone cyclization occurs via a C-2 acylated intermediate,[18] the formation of N,N-acyltosyl hydrazide in the presence of acid anhydrides and Et₃N has been reported.[20] However, given the reported lability of tosylhydrazones under strongly basic conditions,[21] [22] the survival of compound 8 intact was unexpected. We reasoned that interrogating the circumstances leading to the formation and isolation of amide 8 would assist in the successful adaptation of Huang et al.’s method and the synthesis of 4. Mechanistically, for this reaction to proceed, the formation of the indazolone ring would likely need to progress via tetrahedral intermediate 9, which could potentially form from either anion 10 (Scheme [2], Pathway 1), or 11 (Pathway 2).

Therefore, we reasoned that amide 8 could form through either direct acetylation of the hydrazone N-9, or through Pathway 1, where tetrahedral intermediate 9a collapses into 11a and finally forming amide 8 following workup. Geometry optimization of the intermediates 9, 10, and 11 suggested that for each respective system, both amides 11a and 11b occupy a lower energy conformation than their corresponding ketones 10a and 10b (Figure [3]). However, the calculated energy barrier between the methyl ketone 10a and amide 11a (Δ60.5 kJ·mol^–1) is substantially larger than the calculated energy gap between the corresponding trifluoromethyl analogues 10b and 11b (Δ37.0 kJ·mol^–1). Similarly, the energy gaps between tetrahedral intermediate 9a and the corresponding ketone 10a (Δ40.1 kJ·mol^–1) and amide 11a (Δ100.6 kJ·mol^–1) were greater than those calculated for the formation of intermediate 9b from 10b (Δ20.9 kJ·mol^–1) and 11b (Δ57.9 kJ·mol^–1), respectively.

Together, this data implied that cyclization to form compound 7 via tetrahedral intermediate 9b was more energetically favorable in comparison to forming 4 via intermediate 9a. Furthermore, while the minimized energy calculations indicated a preference for the amides over the corresponding ketones, the comparatively small energy gap between 10b and 11b, in conjunction with the even smaller energy gap between 10b and intermediate 9b, suggest that either pathway is plausible for the formation of compound 7. Conversely, the large, predicted energy gap between 10b and 11b suggests the formation of 8 would most likely occur via direct amide formation, rather than acetyl migration. Furthermore, this information implies that overcoming the energy barrier required to form 9a from amide 11a would require substantial energy input, such as harsher reaction conditions. Given these scenarios, we opted to deviate from the one-pot strategy and attempt to elucidate conditions for indazolone formation directly from amide 8. Accordingly, following its formation,[23] 8 was subjected to varying reaction conditions based around steps 1 and 2 of the method of Huang et al. (Table [1]). Entries 1–4, which featured methanol as the partial or lone solvent all resulted in amide hydrolysis and the recovery of tosylhydrazone 6.

Table 1 Attempted Optimization of Cyclization Conditions^a

Entry	Starting material	Solvent	Base (M)	Major product	Yield (%)b
1	8	MeOH/H20 (1:1)	NaOH (0.25)	6	90
2	8	MeOH	NaOH (0.5)	6	82
3	8	MeOH	Et3N (0.25)	6	92
4	8	MeOH	NaOMe (0.25)	6	66
5	8	THF	Et3N (0.25)	NRc	NAd
6	8	THF	pyridine (0.25)	NR	NA
7	8	THF	NaOH (0.25)	12	76
8	8	THF	NaH (0.25)	12	17
9	8	THF	KOH (0.25)	12	59
10	8	THF	K2CO3 (0.25)	12	39
11	6	THF	NaOH (0.25)	NR	NA
12	13	THF	NaOH (0.25)	19	77
13	14	THF	NaOH (0.25)	20	35
14	15	THF	NaOH (0.25)	21	73

^a Reagents and conditions: either one of starting materials 6, 8, 13–15 (0.285 mmol) and an appropriate base were dissolved/suspended in 6 mL of solvent as indicated and stirred at room temperature for 16 h.

^b Isolated yields.

^c No reaction.

^d Not applicable.

Assuming that the nucleophilic solvent was partly responsible for this reaction, we reverted to THF. While no reaction was observed in the presence of either Et₃N or pyridine (entries 5 and 6), introduction of NaOH (entry 7) resulted in the formation of an unexpected sulfonyl compound 12 (Figure [4]), presumably occurring via a 1,5-­nitrogen-to-carbon tosyl migration.[24] This same phenomenon was observed in the presence of NaH, KOH, and K₂CO₃ (entries 8–10), albeit not as effectively. Interestingly, no reaction was observed when tosylhydrazone 6 was treated with NaOH in THF (entry 11) indicating an important role for the amide functionality in this transformation.

We reasoned that additional amide analogues could help uncover greater details of the tosyl migration (Table [2]).[23] Accordingly, we were able to generate the butyric (13, entry 1), isobutyric (14, entry 2), and isovaleric (16, entry 3) amide homologues in moderate to low yields.

Table 2 Attempted Expansion of Amide Analogues^a

Entry	R	Product	Yield (%)b
1		13	51
2		14	35
3		15	35
4		16	17
5		17	45
6		18	36
7		7	15

^a Reagents and conditions as per ref. 23.

^b Isolated yields

Reaction of 6 with crotonic (entry 4), methacrylic (entry 5), and acrylic anhydride (entry 6) did not result in the desired amides, but rather three highly substituted pyrazolidinone ring containing compounds (16–18, Figure [5]), which presumably formed from initial Michael addition at N-9, followed by amide formation at N-8, and were not investigated further.

In addition, attempts to isolate the putative trifluoroacetate amide were unsuccessful, with cyclization and detosylation occurring after only the single step, and compound 7 forming in a 15% yield (entry 7). Following this, amides 13–15 were subjected to previously observed tosyl migration conditions (Table [1], entries 12–14).[24] Compounds 19 and 21 formed in good yields, with a substantial drop off in yield noted for 20, which was possibly due to congestion of the reaction center as a result of the extra α-carbon on amide 14.

Having established that the tosyl migration occurred consistently across four related substrates, our attention then shifted to a potential mechanism underlying this reaction. Aryl migrations involving sulfonamides are commonly associated with the Truce–Smiles rearrangement. However, this reaction typically involves the migration of a phenyl moiety, often with the extrusion of SO₂ rather than full sulfone migration.[25] Given a previously reported observation that tosylhydrazones are subject to base-mediated extrusion of a nucleophilic tosyl species,[26] we also considered the possibility of nucleophilic attack from the sulfur center. However, given our finding in Table [1], entry 11, we were unable to rationalize a suitable mechanistic reason as to why the presence of the amide would be required for sulfur nucleophilicity. Furthermore, dimedone is not vulnerable to nucleophilic attack at the C-2 position,[27] [28] therefore, nucleophilic attack was also discounted as a possibility. Related nitrogen–carbon sulfonyl shifts have been reported to occur in the presence of metal catalysts, radical inducing or photosensitizing reagents, as well as through pericyclic rearrangements.[29–31] However, given the absence of obvious conditions for the aforementioned reactions and no plausible pericyclic or homolytic reaction pathway, we hypothesized that tosyl migration occurs via a heterolytic cascade, following deprotonation of N-8 and nucleophilic attack on the sulfur atom. This could plausibly occur though a stepwise process, via intermediate 22 (Scheme [3], Pathway 1), which is analogous to common hydrolysis mechanisms, or through a concerted single step via transition state 23 (Scheme [3], Pathway 2).

Both proposed reaction mechanisms are reliant on the presence of the amide as the critical element. The amide acts as an electron shuttle, facilitating S–N bond cleavage upon formation of imidate 24, which presumably undergoes tautomerization and amide rearrangement to form the compounds 12, 19–21. Importantly, this observation is in agreement with the experimentally observed result in Table [1], where tosyl migration did not occur in the absence of the amide.

Finally, in order to deduce whether the tosyl may migrate onto alternative electron-rich species, the reaction was repeated with the addition of one equivalent of pyrrole (Scheme [4]). However, this reaction only resulted in the formation of compound 12, in a typical yield, with the desired substituted pyrrole 25 not being observed.

In conclusion, the utility of sulfones as protecting or activating groups in organic synthesis, as well as their ubiquity in biologically active compounds renders serendipitously discovered migrations of this nature as potentially valuable synthetic transformations.[29] [30] [31] Our efforts to deconstruct and optimize Huang et al.’s tetrahydroindazolone synthesis resulted in an unexpected 1,5-nitrogen-to-carbon tosyl migration and a new and unusual class of sulfonated dimedone derivatives. Insights gained from this study will potentially prove useful for understanding controlled sulfonyl migrations in other systems as well as expanding the structural diversity of this class through alternative sulfonyls, dimedone analogues, or amides.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

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• 23 General Procedure for the Preparation of Compounds 7, 8, 13–18 Acid anhydride (1 equiv) was added to a suspension of 6 (500 mg, 1.59 mmol, 1 equiv) in Et₃N (13 equiv) and THF (9 mL). The reaction mixture was heated to 55 °C, forming an orange solution, which was stirred for 2 h. After cooling to room temperature, the mixture was quenched with sat. NH₄Cl (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic fractions were washed with sat. brine (20 mL), dried over anhydrous MgSO₄, concentrated in vacuo to yield an orange-brown oil, and purified with silica gel chromatography to yield compounds 7, 8, 13–18. N-Acetyl-N′-(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)-4-methylbenzenesulfonohydrazide (8) White solid (1.32 g, 60% yield). ¹H NMR (DMSO, 400 MHz): δ = 9.84 (1 H, s, NH-8), 7.87 (2 H, d, J = 8.5 Hz, H-14, H-19), 7.46 (2 H, d, J = 8.5 Hz, H-15, H-18), 4.96 (1 H, s, H-2), 2.42 (3 H, s, H-17), 2.30 (2 H, s, H-6), 2.10 (2 H, s, H-4), 2.05 (3 H, s, H-11), 1.04 (3 H, s, H-7a), 1.02 (3 H, s, H-7b). ¹³C NMR (DMSO, 100 MHz): δ = 195.6 (CO, C-3), 170.5 (CO, C-10), 162.0 (q_c, C-1), 145.3 (q_c, C-16), 135.0 (q_c, C-13), 129.5 (CH, C-15, C-18), 128.7 (CH, C-14, C-19), 97.4 (CH, C-2), 50.3 (CH₂, C-4), 38.7* (CH₂, C-6), 32.7 (q_c, C-5), 27.6 (CH₃, C-7), 27.6 (CH₃, C-7), 21.9 (CH₃, C-11), 21.1 (CH₃, C-17) ppm. HRESMS: m/z calcd for C₁₇H₂₃N₂O₄S [M + H]⁺ 351.1379; found: 351.1377. Spectral data for compounds 7, 13–18 are available in the Supporting Information.
• 24 General Procedure for the Preparation of Compounds 12, 19–21 NaOH (5.3 equiv) was added to a suspension of 8 (100 mg, 0.285 mmol, 1 equiv) in THF (6 mL) and stirred at room temperature for 16 h. Thereafter, the mixture was quenched with sat. NH₄Cl (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic fractions were washed with sat. brine (15 mL), dried over anhydrous MgSO₄, concentrated in vacuo, and purified with silica gel chromatography to yield compounds 12, 19–21. N′-(5,5-Dimethyl-3-oxo-2-tosylcyclohex-1-en-1-yl)acetohydrazide (12) Pale yellow solid (76 mg, 76% yield). ¹H NMR (DMSO, 500 MHz): δ = 10.45 (1 H, s, NH-8), 10.42 (1 H, s, NH-9), 7.76 (2 H, d, J = 8.2 Hz, H-14, H-19), 7.34 (2 H, d, J = 8.2 Hz, H-15, H-18), 2.53 (2 H, s, H-6), 2.37 (3 H, s, H-17), 2.05 (2 H, s, H-4), 1.96 (3 H, s, H-11), 0.90 (6 H, s, H-7). ¹³C NMR (DMSO, 125 MHz): δ = 189.2 (CO, C-3), 169.0 (CO, C-10), 167.7 (q_c, C-1), 142.8 (q_c, C-16), 140.6 (q_c, C-13), 128.8 (CH, C-15, C-18), 126.8 (CH, C-14, C-19), 105.1 (q_C, C-2), 50.0 (CH₂, C-4), 38.3 (CH₂, C-6), 30.5 (q_C, C-5), 27.3 (CH₃, C-7), 20.9 (CH₃, C-17), 20.4 (CH₃, C-11) ppm. HRESMS: m/z calcd for C₁₇H₂₃N₂O₄S [M+H]⁺: 351.1379; found: 351.1378. Spectral data for compounds 19–21 are available in the Supporting Information.
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Corresponding Author

Publication History

Received: 14 April 2022

Accepted after revision: 07 July 2022

Accepted Manuscript online:
07 July 2022

Article published online:
05 August 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1 Nunn AJ, Rowell FJ. J. Chem. Soc., Perkin Trans. 1 1975; 4: 2435
  CrossrefSearch in Google Scholar
• 2 Strakova I, Turks M, Strakovs A. Tetrahedron Lett. 2009; 50: 3046
  CrossrefSearch in Google Scholar
• 3 Ju HQ, Xiang YF, Xin BJ, Pei Y, Lu JX, Wang QL, Xia M, Qian CW, Ren Z, Wang SY, Wang YF, Xing GW. Bioorg. Med. Chem. Lett. 2011; 21: 1675
  CrossrefPubMedSearch in Google Scholar
• 4 Lee JC, Hong KH, Becker A, Tash JS, Schönbrunn E, Georg GI. Eur. J. Med. Chem. 2021; 214: 113232
  CrossrefPubMedSearch in Google Scholar
• 5 Huang KH, Veal JM, Fadden RP, Rice JW, Eaves J, Strachan JP, Barabasz AF, Foley BE, Barta TE, Ma W, Silinski MA, Hu M, Partridge JM, Scott A, DuBois LG, Freed T, Steed PM, Ommen AJ, Smith ED, Hughes PF, Woodward AR, Hanson GJ, McCall WS, Markworth CJ, Hinkley L, Jenks M, Geng L, Lewis M, Otto J, Pronk B, Verleysen K, Hall SE. J. Med. Chem. 2009; 52: 4288
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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• 16 Claramunt RM, López C, Pérez-Medina C, Pinilla E, Torres MR, Elguero J. Tetrahedron 2006; 62: 11704
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  CrossrefSearch in Google Scholar
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• 23 General Procedure for the Preparation of Compounds 7, 8, 13–18 Acid anhydride (1 equiv) was added to a suspension of 6 (500 mg, 1.59 mmol, 1 equiv) in Et₃N (13 equiv) and THF (9 mL). The reaction mixture was heated to 55 °C, forming an orange solution, which was stirred for 2 h. After cooling to room temperature, the mixture was quenched with sat. NH₄Cl (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic fractions were washed with sat. brine (20 mL), dried over anhydrous MgSO₄, concentrated in vacuo to yield an orange-brown oil, and purified with silica gel chromatography to yield compounds 7, 8, 13–18. N-Acetyl-N′-(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)-4-methylbenzenesulfonohydrazide (8) White solid (1.32 g, 60% yield). ¹H NMR (DMSO, 400 MHz): δ = 9.84 (1 H, s, NH-8), 7.87 (2 H, d, J = 8.5 Hz, H-14, H-19), 7.46 (2 H, d, J = 8.5 Hz, H-15, H-18), 4.96 (1 H, s, H-2), 2.42 (3 H, s, H-17), 2.30 (2 H, s, H-6), 2.10 (2 H, s, H-4), 2.05 (3 H, s, H-11), 1.04 (3 H, s, H-7a), 1.02 (3 H, s, H-7b). ¹³C NMR (DMSO, 100 MHz): δ = 195.6 (CO, C-3), 170.5 (CO, C-10), 162.0 (q_c, C-1), 145.3 (q_c, C-16), 135.0 (q_c, C-13), 129.5 (CH, C-15, C-18), 128.7 (CH, C-14, C-19), 97.4 (CH, C-2), 50.3 (CH₂, C-4), 38.7* (CH₂, C-6), 32.7 (q_c, C-5), 27.6 (CH₃, C-7), 27.6 (CH₃, C-7), 21.9 (CH₃, C-11), 21.1 (CH₃, C-17) ppm. HRESMS: m/z calcd for C₁₇H₂₃N₂O₄S [M + H]⁺ 351.1379; found: 351.1377. Spectral data for compounds 7, 13–18 are available in the Supporting Information.
• 24 General Procedure for the Preparation of Compounds 12, 19–21 NaOH (5.3 equiv) was added to a suspension of 8 (100 mg, 0.285 mmol, 1 equiv) in THF (6 mL) and stirred at room temperature for 16 h. Thereafter, the mixture was quenched with sat. NH₄Cl (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic fractions were washed with sat. brine (15 mL), dried over anhydrous MgSO₄, concentrated in vacuo, and purified with silica gel chromatography to yield compounds 12, 19–21. N′-(5,5-Dimethyl-3-oxo-2-tosylcyclohex-1-en-1-yl)acetohydrazide (12) Pale yellow solid (76 mg, 76% yield). ¹H NMR (DMSO, 500 MHz): δ = 10.45 (1 H, s, NH-8), 10.42 (1 H, s, NH-9), 7.76 (2 H, d, J = 8.2 Hz, H-14, H-19), 7.34 (2 H, d, J = 8.2 Hz, H-15, H-18), 2.53 (2 H, s, H-6), 2.37 (3 H, s, H-17), 2.05 (2 H, s, H-4), 1.96 (3 H, s, H-11), 0.90 (6 H, s, H-7). ¹³C NMR (DMSO, 125 MHz): δ = 189.2 (CO, C-3), 169.0 (CO, C-10), 167.7 (q_c, C-1), 142.8 (q_c, C-16), 140.6 (q_c, C-13), 128.8 (CH, C-15, C-18), 126.8 (CH, C-14, C-19), 105.1 (q_C, C-2), 50.0 (CH₂, C-4), 38.3 (CH₂, C-6), 30.5 (q_C, C-5), 27.3 (CH₃, C-7), 20.9 (CH₃, C-17), 20.4 (CH₃, C-11) ppm. HRESMS: m/z calcd for C₁₇H₂₃N₂O₄S [M+H]⁺: 351.1379; found: 351.1378. Spectral data for compounds 19–21 are available in the Supporting Information.
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