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Rapid and Chemodivergent Synthesis of NHeterocyclic Sulfones and Sulfides: Mechanistic and Computational Details of the Persulfate-Initiated Catalysis Viet D Nguyen, Vu T. Nguyen, graham haug, Hang Dang, Hadi D. Arman, Walter C. Ermler, and Oleg V. Larionov ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00464 • Publication Date (Web): 28 Mar 2019 Downloaded from http://pubs.acs.org on March 28, 2019
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ACS Catalysis
Rapid and Chemodivergent Synthesis of N-Heterocyclic Sulfones and Sulfides: Mechanistic and Computational Details of the Persulfate-Initiated Catalysis Viet D. Nguyen,† Vu T. Nguyen,† Graham C. Haug,† Hang T. Dang,† Hadi D. Arman,† Walter C. Ermler,†,‡ and Oleg V. Larionov†* † ‡
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States Division of Chemistry, National Science Foundation, 2415 Eisenhower Avenue, Alexandria, Virginia 22314, United States
ABSTRACT: N-Heterocyclic sulfones and sulfides are key functional motifs in medicinal and agricultural chemistry, and important building blocks in organic synthesis. Currently available methods produce N-heterocyclic sulfones in low yields and under harsh conditions. Here, we describe a rapid sulfone synthesis under ambient conditions that is initiated by persulfate with water as a cosolvent. The reaction has a broad scope and is readily expanded to the chemodivergent synthesis of symmetrical Nheterocyclic sulfones and sulfides. The products can be isolated by simple filtration. Our combined experimental and computational study suggests that the remarkable persulfate-initiated acceleration of the sulfone formation in the biphasic system that enables the otherwise sluggish reaction under ambient conditions is due to the combination of the previously unknown rapid acidification of the persulfate‒sulfinate system, the self-catalysis of the reaction of sulfinic acid with halo-N-heterocycles, and the substantial acceleration of the reaction in the aqueous phase. KEYWORDS biphasic catalysis, chemodivergent reactions, N-heterocycles, persulfate, reaction kinetics, sulfinate, sulfone. and high temperatures cannot be avoided even with 2- and 4halopyridines, despite their ability to participate in nucleophilic aromatic substitution (SNAr) reactions that bypass such limitations as the frequently kinetically sluggish oxidative insertion of a transition metal into the C–X bond and deactivation of metal catalysts by N-heterocycles. The low reactivity of sulfinates towards halogenated N-heterocycles has been a significant and unresolved synthetic problem,9 and a general method for N-heterocyclic sulfone synthesis under mild conditions and at room temperature has remained elusive. Although transition metal catalysis has played a dominant role in the development of carbon–heteroatom bond-forming reactions in the past several decades, recent advances in transition metal-free reactions have highlighted the potential synthetic impact of this emerging methodology, especially in C–B, C–C, C–Si, and C–S bond-forming processes.10 However, the mechanistic underpinnings of many metal-free reactions remain poorly understood. We present herein a simple persulfate-initiated synthesis of N-heterocyclic sulfones that proceeds at room temperature, and can be complete within 15 min. Despite the major role of persulfates as radical initiators,11 we also present mechanistic evidence that the rapid persulfate-initiated reaction of sulfinates with halo-N-heterocycles is not a radical process. In addition, we show that the new method can be successfully extended to the synthesis of symmetrical N-heterocyclic sulfones and sulfides in a divergent manner and under mild conditions.
1. INTRODUCTION Organosulfur compounds are among the most synthetically versatile and widely used reagents in organic synthesis.1 Sulfur is also the third most common heteroatom after oxygen and nitrogen in the FDA-approved small molecule drugs.2 At the functional group level, the sulfonyl group (-SO2-) is the most common sulfur-containing medicinally-relevant functionality. Given the central role of organosulfur compounds in chemistry and biology, significant efforts have recently been directed towards the development of efficient and chemoselective methods of their synthesis.3 N-Heterocyclic sulfones have key roles in medicinal and agricultural chemistry,4 organic synthesis,1,5 and materials science.6 Two approaches are typically used to synthesize Nheterocyclic sulfones (Figure 1). The first approach takes advantage of the high nucleophilicity of thiols and thiolates in reactions with halogenated N-heterocycles. However, it necessitates oxidation of the intermediate sulfides to sulfones that can give rise to side products due to over- and underoxidation7. The poor step economy, in addition to the environmental and toxicological liabilities of thiols, as well as the side reactions have inspired development of a direct sulfone synthesis from sulfinates and halogenated Nheterocycles that is enabled by transition metal catalysts, e.g., Pd, Ni, and Cu.7,8 Although these methods have afforded a more straightforward route to pyridine sulfones, they require harsh conditions (100–150 °C in polar high-boiling solvents) and give lower yields. Remarkably, transition metal catalysts
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b N
O O S Me Cl Cl Cl
N
S O O EtO2C
H N
algophase (antifouling)
Cl N
O
H N
S
O O GSK3787 (potent and selective hPPAR antagonist) N N
O R S O
O R S O N
R
O
R R
S
O
N
N
R
R
N
N
S
R N
PD 122860 (cardiovascular diseases)
F3C
H 2N
rapid room-temperature synthesis of sulfones and sulfides
CN CF3
Cl TM
Me
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OMe
S OMe N O O NH2 antibiotic dihydrofolate reductase inhibitor
RSH
use of thiols
RSO2Na
R
two-step sequence R N
SR
requires TM catalysts
X
N
Pd, Ni, Cu catalysts high-boiling solvents (DMF, DMAc)
RSO2Na persulfate initiator aqueous-organic mixtures rapid reaction at rt
over- and underoxidation
lower yields
elevated temperatures O [O] S O N R Simple, transition metal-free protocol for rapid sulfone synthesis at room temperature R
Mechanistic studies of the role of persulfate initiator point to a non-radical pathway Broad scope for sulfinates, halopyridines and other N-heterocycles Synthesis of sulfones and sulfides enables structural diversification
O O S CO2H N CO2H
divergent synthesis of symmetrical sulfones and sulfides
CO2H N
X
N
CO2H 4PSPyMTA (protein spin labeling)
R
HOCH2SO2Na
R
N
Na2S2O8
N
O
S
O
R N
R or
R
S
N
N
Figure 1. Applications and synthesis of N-heterocyclic sulfones and sulfides. a. Biomedical applications of N-heterocyclic sulfones. b. Synthetic strategies toward N-heterocyclic sulfones.
2. RESULTS AND DISCUSSION Reaction optimization. In our initial experiments, we found that the reaction of chloroquinoline 1 and sulfinate 2 was unexpectedly greatly accelerated when sodium persulfate was added as an initiator (Table 1). While no reaction was observed in 15 min without sodium persulfate in the biphasic dichloromethane-water mixture, sulfone 3 was rapidly formed in 83% in the presence of 20 mol% persulfate. Other water-immiscible solvents (EtOAc, toluene) were equally suitable. The persulfate-initiated reaction was even faster in the ethanol-water mixture: the reaction was complete within 15 min, and proceeded to 77% in 8 min. In all cases, water was crucial for achieving rapid conversion to the sulfone. The reactions proceeded cleanly, and no by-products were formed. Transition metal catalysts (e.g., AgNO3, CuCl, CuCl2) had no effect on the reaction, nor was it affected by exclusion of light. Substrate scope. We then proceeded with the evaluation of the reaction scope (Figure 2). Several classes of nitrogen heterocycles were investigated. Substituted 4haloquinolines reacted smoothly and produced the sulfones in good and excellent yields (3-14). 2-Bromo- and 2chloroquinoline were also suitable substrates (15). 4Halopyridines bearing substituents in the 2- and 3-positions were studied next, and the corresponding pyridine sulfones were readily obtained in good yields (16-23). Interestingly, 4-fluoro group was efficiently displaced by a sulfinate in preference to the 2-chloro group (18).
1-Haloisoquinolines were converted to the corresponding sulfones as well (24-27). Diazines of quinoxaline and quinazoline series also afforded the sulfones (28-30). Interestingly, a regioselective C1-substitution took place with 1,3-dichloroquinazoline (product 30), and the C3regioisomer or 1,3-disulfone were not observed. The reaction scope also included benzothiazole sulfone 31, indicating that it is not limited to six-membered nitrogen heterocycles. Table 1. Reaction conditions for the sulfone synthesis Cl
Cl
N 1
SO2Tol
TolSO2Na (2) Na2S2O8 (20 mol%) CH2Cl2/H2O (2.5 : 1) 15 min, rt
Cl
Change in the reaction conditions
N 3
Yield, %
No change
83
No Na2S2O8 added
