31002-87-6

Usage

Physical state

White solid

Odor

Slightly floral

Common uses

Intermediate in production of pharmaceuticals and other organic compounds; chiral auxiliary in asymmetric synthesis

Potential impurity

In drugs like chlorthalidone

Preccursor

In synthesis of certain pesticides and herbicides

Safety concerns

Potential health hazards if mishandled

InChI:InChI=1/C9H11ClO/c1-9(2,11)7-4-3-5-8(10)6-7/h3-6,11H,1-2H3

Upstream product

• 67-64-1 acetone 
• 36229-42-2 (3-chlorophenyl)magnesium bromide 
• 108-37-2 1-bromo-3-chlorobenzene 
• 40473-10-7 2-chloro-2-(3'-chlorophenyl)propane 
• 99-02-5 3'-Chloroacetophenone 
• 1017478-92-0 3-(3-chlorophenyl)-3-methylbutan-2-one 
• 1309380-81-1 3-methyl-3-(m-chlorophenyl)-2-butanone oxime 
• 1309380-99-1 C₂₁H₂₀ClNO₃S 
• 7073-93-0 m-chlorocumene 
• 74-88-4 methyl iodide 
• 75-16-1 methylmagnesium bromide 
• 1712-71-6 3-chloro-α-methylstyrene 
• 917-64-6 methyl magnesium iodide 
• 1128-76-3 3-chloro-benzoic acid ethyl ester 

Downstream Products

• 69261-42-3 1-Chloro-3-(1,1,2,2-tetramethyl-propyl)-benzene 
• 64798-37-4 m-chloro-α,α-dimethylbenzyl isocyanate 
• 35658-85-6 tert-butyl 3-chlorocumyl peroxide 
• 3972-55-2 1-tert-butyl-3-chloro-benzene 
• 97872-10-1 2-Benzo[d]isoxazol-3-yl-N-[1-(3-chloro-phenyl)-1-methyl-ethyl]-acetamide 
• 17790-50-0 α,α-dimethyl-3-chlorobenzylamine 
• 412048-36-3 3-chlorocumyloxy radical 
• 90862-24-1 p-Tolyl-carbamic acid 1-(3-chloro-phenyl)-1-methyl-ethyl ester 
• 90862-08-1 Phenyl-carbamic acid 1-(3-chloro-phenyl)-1-methyl-ethyl ester 
• 1712-71-6 3-chloro-α-methylstyrene 
• 40473-10-7 2-chloro-2-(3'-chlorophenyl)propane 

Relevant academic research and scientific papers

Stepwise benzylic oxygenation via uranyl-photocatalysis

Stepwise oxygenation at the benzylic position (1°, 2°, 3°) of aromatic molecules was comprehensively established under ambient conditions via uranyl photocatalysis to produce carboxylic acids, ketones, and alcohols, respectively. The accuracy of the stepwise oxygenation was ensured by the tunability of catalytic activity in uranyl photocatalysis, which was adjusted by solvents and additives demonstrated through Stern–Volmer analysis. Hydrogen atom transfer between the benzylic position and the uranyl catalyst facilitated oxygenation, further confirmed by kinetic studies. Considerably improved efficiency of flow operation demonstrated the potential for industrial synthetic application.

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the gem-dimethyl group.

One-Pot C-H Arylation/Lactamization Cascade Reaction of Free Benzylamines

An efficient method has been developed for the synthesis of seven-membered biaryl lactams involving Pd-catalyzed, native amine-directed, ortho-arylation of benzylamines followed by in situ lactamization. This cascade sequence is enabled by the use of 2-iodobenzoates, which facilitates C-H arylation from the free amine under conditions that typically require an improved directing group approach. This reaction is characterized by a broad substrate scope with good functional group tolerance. The need for an ester versus carboxylic acid-functionalized coupling partner is also explored, as is the potential for synthesizing eight-membered biaryl lactams. Various applications are also investigated, including access to the aza-brassinolide core.

Carbon Dioxide-Mediated C(sp2)-H Arylation of Primary and Secondary Benzylamines

C-C bond formation by transition metal-catalyzed C-H activation has become an important strategy to fabricate new bonds in a rapid fashion. Despite the pharmacological importance of ortho-arylbenzylamines, however, effective ortho-C-C bond formation of free primary and secondary benzylamines using PdII remains an outstanding challenge. Presented herein is a new strategy for constructing ortho-arylated primary and secondary benzylamines mediated by carbon dioxide (CO2). The use of CO2 with Pd is critical to allowing this transformation to proceed under relatively mild conditions, and mechanistic studies indicate that it (CO2) is directly involved in the rate-determining step. Furthermore, the milder temperatures furnish free amine products that can be directly used or elaborated without the need for deprotection. In cases where diarylation is possible, an interesting chelate effect is shown to facilitate selective monoarylation.

Access to "friedel-Crafts-Restricted" tert -alkyl aromatics by activation/methylation of tertiary benzylic alcohols

Herein we describe a two-step protocol to prepare m-tert-alkylbenzenes. The appropriate tertiary benzylic alcohols are activated with SOCl2 or concentrated HCl and then treated with trimethylaluminum, affording the desired products in 68-97% yields (22 examples). This reaction sequence is successful in the presence of a variety of functional groups, including acid-sensitive and Lewis-basic groups. In addition to t-Bu groups, 1,1-dimethylpropyl and 1-ethyl-1-methylpropyl groups can also be installed using this method.

Dynamic path bifurcation in the Beckmann reaction: Support from kinetic analyses

The reactions of oximes to amides, known as the Beckmann rearrangement, may undergo fragmentation to form carbocations + nitriles when the migrating groups have reasonable stability as cations. The reactions of oxime sulfonates of 1-substituted-phenyl-2-propanone derivatives (7-X) and related substrates (8-X, 9a-X) in aqueous CH3CN gave both rearrangement products (amides) and fragmentation products (alcohols), the ratio of which depends on the system; the reactions of 7-X gave amides predominantly, whereas 9a-X yielded alcohols as the major product. The logk-logk plots between the systems gave excellent linear correlations with slopes of near unity. The results support the occurrence of path bifurcation after the rate-determining TS of the Beckmann rearrangement/fragmentation reaction, which has previously been proposed on the basis of molecular dynamics simulations. It was concluded that path-bifurcation phenomenon could be more common than thought and that a reactivity-selectivity argument based on the traditional TS theory may not always be applicable even to a well-known textbook organic reaction.

Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy

Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene (SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.

2,4-DIAMINOQUINAZOLINES FOR SPINAL MUSCULAR ATROPHY

2,4-Diaminoquinazolines of formulae I-IV and VI (I, II, III, IV and VI) are useful for treating spinal muscular atrophy (SMA).

Spectral properties and absolute rate constants for β-scission of ring-substituted cumyloxyl radicals. A laser flash photolysis study

A laser flash photolysis study of the spectral properties and β-scission reactions of a series of ring-substituted cumyloxyl radicals has been carried out. All cumyloxyl radicals display a broad absorption band in the visible region of the spectrum, which decays on the microsecond time scale, leading to a strong increase in absorption in the UV region of the spectrum, which is attributed to the corresponding acetophenone formed after β-scission of the cumyloxyl radicals. The position of the visible absorption band is red-shifted by the presence of electron-donating ring substituents, while a blue-shift is observed in the presence of electron-withdrawing ring substituents, suggesting that + R ring substituents promote charge separation in the excited cumyloxyl radical through stabilization of the partial positive charge on the aromatic ring of an incipient radical zwitterion. Along this line, an excellent Hammett-type correlation between the experimentally measured energies at the visible absorption maxima of the cumyloxyl radicals and σ+ substituent constants is obtained. A red-shift is also observed on going from MeCN to MeCN/H2O for all cumyloxyl radicals, pointing toward a specific effect of water. The ring substitution does not influence to a significant extent the rate constants for β-scission of the cumyloxyl radicals, which varies between 7.1 × 105 and 1.1 × 106 s-1, a result that suggests that cumyloxyl radical β-scission is not governed by the stability of the resulting acetophenone. Finally, κβ increases on going from MeCN to the more polar MeCN/H2O 1:1 for all cumyloxyl radicals, an observation that reflects the increased stabilization of the transition state for β-scission through increased solvation of the incipient acetophenone product.

Insecticidal substituted-2,4-diamino-5,6,7,8-tetrahydroquinazolines

There is provided an insecticidal composition comprising, in admixture with an agriculturally acceptable carrier, an insecticidally effective amount of a tetrahydroquinazoline compound of the formula STR1 wherein R, R1, R2, R3, R5, R6, R7, R8, and R9 are as defined herein, and methods of using the same. Certain novel substituted-phenyl tetrahydroquinazoline compounds per se are also identified.