SuFExable NH-Pyrazoles via 1,3-Dipolar Cycloadditions of Diazo Compounds with Bromoethenylsulfonyl Fluoride

Abstract

“Click” reactions have transformed the molecular sciences. Augmenting cycloaddition reactions, sulfur(VI) fluoride exchange (SuFEx) chemistry has diversified the landscape of molecular assembly. Herein, we report a facile strategy to access SuFExable NH-pyrazoles via strain and catalyst-free 1,3-dipolar cycloadditions of stabilized diazo compounds under mild conditions. Subsequent SuFEx proceeds efficiently with various N- and O-nucleophiles. Access to SuFExable NH-pyrazoles—a class of compounds containing two common pharmacophores—enables future opportunities within drug discovery, chemical biology, materials chemistry, and related fields.

Graphical Abstract

Modularity has overwhelmed modern chemical synthesis, enabling innovative strategies within chemical biology, materials chemistry, and other disciplines within the molecular sciences. This molecular revolution has been “defined, enabled, and constrained by a handful of nearly perfect “spring-loaded” reactions”.¹

The race to disclose “perfect” chemical strategies was inspired by nature’s use of a core set of building blocks and reactions. Attractive features of pericyclic reactions, and the discovery of the copper-catalyzed azide–alkyne cycloaddition (CuAAC),² have endowed 1,3-dipolar cycloadditions as the prototype (Scheme 1A).³ The extension to chemical biology necessitated the removal of the Cu catalysts. To meet this requirement, the strain-promoted azide–alkyne cycloaddition (SPAAC),^4,5 tetrazine–trans-cylooctene inverse-demand Diels–Alder,⁶ and related reactions⁷ were developed and optimized.^8,9 In parallel, applications enabled by modularity flourished.¹⁰

Scheme 1. Exemplary Click Reactions^a.

^a(A) The 1,3-dipolar cycloaddition between an azide and an alkyne. (B) Commonly employed sulfur(VI) fluoride exchange (SuFEx) reactions. (C) Sulfonyl fluoride-containing dipolarophiles.

As the number of available reactions expands, the utility of each depends on access to reagents, reaction conditions, and efficiency, among other criteria. While the “click” strategy focuses on the modular assembly of building blocks, the properties of generated linkages is of growing interest.¹

Sulfur(VI) fluoride exchange (SuFEx) has recently been endowed a “click” reaction (Scheme 1B).¹¹ The increased stability of sulfonyl fluorides over sulfonyl chlorides and favorable attributes of the sulfonyl group enable unique opportunities.^12,13 The utility of SuFEx stems from latent reactivity that can be exploited for late-stage diversification,¹⁴ the prevalence of sulfonyl linkages in drug compounds,¹⁵ and other attractive features.¹⁶

Among methods to generate SuFEx “hubs”, various 1,3-dipoles have been reported to undergo cycloadditions with ethenylsulfonyl fluoride (ESF),¹⁷ 1-bromoethene-1-sulfonyl fluoride (Br-ESF),¹⁸ substituted alkynylsulfonyl fluorides (SASFs),¹⁹ and other dipoles (Scheme 1C).²⁰ While these reactions furnish diverse heterocyclic scaffolds able to undergo subsequent SuFEx chemistry, the requisite conditions (i.e., catalyst, base, heat, etc.) limit their utility.

We report within that the reactivity inherent to diazo compounds²¹ enables access to sulfonyl fluoride-substituted pyrazoles and pyrazolines under mild conditions via 1,3-dipolar cycloaddition with Br-ESF or ESF, respectively (Figure 1A).^17b,22 Computational analysis reveals that this dipole–dipolarophile pair is well-matched to harness stereoelectronic transition-state stabilization.^{8f-i,21d-g,23} Subsequent SuFEx reactions of the obtained NH-pyrazoles enable rapid access to diverse scaffolds containing two clinically important pharmacophores (Figure 1B).^15,24 Facile transformation of azides—ubiquitous within the “click” realm—into diazo compounds renders this strategy advantageous for the generation of SuFEx “hubs” utilizing readily available starting materials.

Figure 1.

Pyrazolyl SuFEx hubs enable access to medicinally important molecular scaffolds. (A) Ambient temperature, catalyst-free 1,3-dipolar cycloadditions of diazo compounds with ESF and Br-ESF afford pyrazolines 3 and pyrazoles 4, respectively. (B) Biologically active compounds containing both a pyrazole heterocycle and a sulfonyl fluoride or sulfonamide.

We first sought to confirm the utility of ethenylsulfonyl fluorides as dipolarophiles in reactions with stabilized diazo compounds under mild conditions. Both ESF and Br-ESF undergo rapid 1,3-dipolar cycloadditions with N-benzyldiazoa-cetamide 1a and ethyl diazoacetate 1b, yielding the pyrazoline 3 and pyrazole 4 cycloadducts, respectively (Figure 1A). Regioselectivity was determined utilizing J-coupling values (²J_HH, ³J_HH, ⁴J_HF) from ¹H NMR spectroscopy and (²J_CF) from ¹³C NMR spectroscopy. The latter enables additional structural data afforded by heteronuclear single quantum coherence (see the Supporting Information). As expected, the nucleophilic character inherent to diazo compounds enforces high regioselectivity with the “perfect” Michael acceptor,²⁵ providing 3,5-disubstituted pyrazoles and pyrazolines.^21b,26

Notably, organic azides do not react with ESF or Br-ESF under these conditions (7 h; room temperature) and require heating, as was previously reported.^17,18 This chemoselective reactivity of diazo compounds enables cycloadditions in the presence of the azido group, broadening the scope and diversity of potential substrates for this reaction.^10c,d,21c-e

To understand the increased reactivity of diazo compounds over azides in the reaction with ESF and Br-ESF, we performed quantum chemical calculations. We optimized starting materials and transition states and examined frontier molecular orbital energies (Figure 2A,B). The higher-energy HOMO of ethyl diazoacetate 1b, relative to ethyl azidoacetate 2b, facilitates the normal-demand (type I) 1,3-dipolar cyclo-additions. The matched FMOs of 1b and Br-ESF result in lower free energies of activation relative to the reaction of 2b, in agreement with the distortion/interaction analysis (see Table S1).^26b,27

Figure 2.

Diazo compounds provide a distinct advantage in the generation of heterocyclic SuFEx hubs. (A) Matched frontier molecular orbital energies facilitate the diazo–Br-ESF cycloaddition. (B) Transition-state geometries optimized at the M06-2X/6-311++G(d,p) level of theory. NBO charges (italics) indicate the degree of charge transfer in the TS. (C) Depiction of stabilizing orbital interactions in the 1b–Br-ESF TS: alignment of the S─F antibonding orbital (σ*_SF) with the Br-ESF π-system facilitates bond formation.

We performed natural bonding orbital (NBO) analysis²⁸ to reveal specific interactions responsible for the increased reactivity of diazo compounds with ethenylsulfonyl fluorides. Charge transfer from the 1,3-dipole to ESF was quantified by examining the NBO charges on each species in the TS (Figure 2B).^21e In agreement with FMO energies, increased charge transfer is observed in the 1b–Br-ESF TS, where the dominant interaction is from the HOMO of 1b to the LUMO of ESF. Stabilization to the TS is provided by the sulfonyl fluoride. Directional charge transfer results in a partially filled π*_CC, which is delocalized into the S─F bond antibonding orbital (σ*_SF; Figure 2C). This π*_CC → σ*_SF interaction facilitates bond formation. Analogous interactions with C─X bonds (X = O, N, S) provide both an effective strategy to accelerate 1,3-dipolar cycloadditions of cyclic alkynes^{8f-i,21d-g,23} and the stereoelectronic basis for the Felkin–Anh model of asymmetric induction.²⁹ Reaction development for the assembly of SuFEx hubs^18-20 can be accelerated by harnessing this design principle.

The favorable electronics of the diazo group, the pyrazole products obtained, and the mild reaction conditions—which enable diazo-selective reactivity in the presence of azides—render the reported 1,3-dipolar cycloadditions an attractive route to pyrazolyl SuFEx hubs for broad applications. Moreover, the brightly colored solutions of diazo compounds 1a and 1b rapidly decolorize upon the addition of Br-ESF, providing a colorimetric indicator of reaction progress. Still, to solidify a place within the “click” arsenal, these pyrazolyl sulfonyl fluorides must also display efficient SuFEx reactivity. To demonstrate the scope and diversity of this modular scaffold for molecular assembly, we next examined conditions to determine general protocols for SuFEx with both nitrogen- and oxygen-based nucleophiles (Table 1).

Table 1.

Optimization of SuFEx Reaction Conditions with Primary Amines, Aryl Alcohols, and Silyl Ethers

entry	nucleophile	equiv	base	equiv	additive	equiv	time, h	T, °C	yield, %a
1	BnNH2	2	—	—	—	—	24	r.t.	—
2	BnNH2	2	—	—	—	—	24	80	—
3	BnNH2	2	DIPEA	2	—	—	72	r.t.	19
4	BnNH2	2	DIPEA	2	—	—	24	80	50
5	BnNH2	1.1	DABCO	2.1	—	—	18	r.t.	29
6	BnNH2	1.1	DABCO	2.1	Ca(NTf2)	1.4	2	r.t.	94
7	3,4-diMe-PhO-TMS	1.1	DABCO	2.1	Ca(NTf2)	1.4	48	r.t.	>99
8	3,4-diMe-PhOH	1.1	DABCO	3.1	Ca(NTf2)	1.4	18	r.t.	93
9	3,4-diMe-PhO-TMS	1.1	DBU	3	—	—	48	80	77

^aDetermined by HPLC.

We first attempted the reaction of 4a with benzylamine (2 equiv) in acetonitrile; however, no reaction was observed via HPLC after 24 h at room temperature or at reflux (entries 1 and 2, respectively). The use of DIPEA (2 equiv) was found to facilitate the reaction, albeit sluggishly, as only 19% conversion was observed after 72 h (entry 3). Heating to 80 °C was moderately beneficial, resulting in 50% conversion after 24 h (entry 4).

A promising result was obtained upon substituting DIPEA with DABCO, where 29% conversion was observed after only 18 h at room temperature (entry 5). Further optimization gave a 94% yield of the desired sulfonamide 6d within 2 h at room temperature (entry 6). This result was achieved by slight modifications to protocols developed by the Ball group³⁰—benzylamine (1.1 equiv) with a combination of DABCO (2.1 equiv) and calcium bistriflimide (1.4 equiv) to activate the sulfonyl fluoride.

Analogous reactions of aryl silyl ethers proceeded smoothly, though noticeably slower. The room-temperature reaction of 4a with 3,4-xylenyl trimethylsilyl ether in the presence of DABCO (2.1 equiv) and Ca(NTf₂)₂ (1.4 equiv) gave a quantitative yield of sulfonate 5a within 48 h (entry 7). Interestingly, reactions proceeded equally well utilizing the unprotected 3,4-xylenol and were completed within 18 h. In addition to Ca(NTf₂)₂ (1.4 equiv), an extra equivalent of DABCO was required (entry 8).³¹ Alternately, DBU can be used without addition of Ca(NTf₂)₂ in reactions of aryl silyl ethers within the same timespan. However, this method requires elevated temperatures (80 °C) and furnished 5a in decreased yield (entry 9).

We next examined the scope of nucleophiles compatible with these pyrazolyl SuFEx hubs (Scheme 2). Employing optimized conditions (entries 6 and 8), we synthesized pyrazolyl sulfonates 5 and pyrazolyl sulfonamides 6. Aryl alcohols bearing both electron-donating and electron-with-drawing substituents gave the corresponding pyrazolyl sulfonates 5a–e in 77–92% yields. Benzyl and phenylamine afforded the corresponding sulfonamides in >81% yield (6a,c,d), while the morpholine yielded 6b in 74%. Overall, these newly reported pyrazolyl SuFEx hubs react quite efficiently.

Scheme 2.

Synthesis of Pyrazolyl Sulfonates and Pyrazolyl Sulfonamides via SuFEx Reactions Illustrating the Scope of Reported Pyrazolyl SuFEx Hubs

We envisioned that—in addition to selective 1,3-dipolar cycloaddition reactions (i.e., diazo compounds over azides; vide supra)—selective SuFEx reactivity will enable multistage diversification strategies. We examined the fluoride exchange reaction of 4a with excess benzyl amine (2 equiv) and 3,4-xylenol (2 equiv), both in the presence and absence of Lewis acid (Ca(NTf₂)₂) (Scheme 3A). We found near perfect chemoselectivity favoring the sulfonamide 6d over 5c (95:1) in the absence of Lewis acid. As expected, activating the electrophile decreased the selectivity to 3:1, still favoring 6d. This differentiation between nucleophiles can be exploited for chemoselective SuFEx reactivity.

Scheme 3.

(A) Amine-Selective SuFEx Reaction in the Presence of Aryl Alcohol and (B) Base-Promoted Formation of Monosubstituted NH-Pyrazoles via −SO₂F Elimination from Pyrazoline 3a

Monosubstituted NH-pyrazole 7a was generated from pyrazoline 3a (Scheme 3B). Analogous aromatization was previously observed in reactions of azides.^17a The mild reaction conditions (i.e., ambient temperatures) enable isolation of pyrazoline product 3a, whereas the azido cycloadduct spontaneously aromatized via loss of SO₂ and HF in previous reports. While attempts at SuFEx with N- and O-nucleophiles (with and without base) triggered pyrazole formation, this mild synthesis of monosubstituted NH-pyrazoles avoids the use of harsh reagents (e.g., hydrazine) and/or conditions and metal catalysts that are commonly employed. We are currently exploring the utility of on-demand base-triggered aromatization, which simultaneously generates a fluoride ion while planarizing a tetrahedral carbon atom.

In conclusion, NH-pyrazole sulfonyl fluorides (SuFEX hubs) were generated via 1,3-dipolar cycloadditions of 1-bromoe-thene-1-sulfonyl fluoride (Br-ESF) with stabilized diazoacetamides and diazoacetates—electronically matched 1,3-dipoles—under ambient conditions. Subsequent sulfur(VI) fluoride exchange was optimized for both nitrogen- and oxygen-based nucleophiles, affording sulfonamides and sulfonates, respectively. Selectivity was observed at each step in the reported “double-click” strategy, enabling future design of “click hubs” containing both a sulfonyl fluoride and an azido group. Overall, facile generation of starting materials from readily available precursors,³² distinct advantages of diazo compounds²¹ (and the resulting NH-pyrazole),³³ and highly selective reactivity enable myriad opportunities for multistage diversification strategies that remain true to the “click” mantra.