Two-Step Cyanomethylation Protocol: Convenient Access to Functionalized Aryl- and Heteroarylacetonitriles

Figure

Two-Step Cyanomethylation Protocol: Convenient Access to Functionalized Aryl- and Heteroarylacetonitriles

Publication Date (Web): January 15, 2015 (Letter)
DOI: 10.1021/ol503479g

http://pubs.acs.org/doi/abs/10.1021/ol503479g

 

A two-step protocol has been developed for the introduction of cyanomethylene groups to metalated aromatics through the intermediacy of substituted isoxazoles. A palladium-mediated cross-coupling reaction was used to introduce the isoxazole unit, followed by release of the cyanomethylene function under thermal or microwave-assisted conditions. The intermediate isoxazoles were shown to be amenable to further functionalization prior to deprotection of the sensitive cyanomethylene motif, allowing access to a wide range of aryl- and heteroaryl-substituted acetonitrile building blocks.

Eli Lilly has officially opened new research facilities at its R&D base in Erl Wood in Surrey.

Eli Lilly and Company has announced a five year research partnership with the University of Surrey to study health outcomes, focusing on the effects of …

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Copying Nature’s Assembly Line Organic Synthesis: Successive homologation reactions let chemists tailor carbon chain’s conformation

09237-notw3-boronic_18037306-657

Reaction repeatedly inserts organolithium compound into carbon-boron bond, creating chains up to 10 carbons long.

http://cen.acs.org/articles/92/i37/Copying-Natures-Assembly-Line.html
Reaction repeatedly inserts organolithium compound into carbon-boron bond, creating chains up to 10 carbons long

Copying Nature’s Assembly Line

Organic Synthesis: Successive homologation reactions let chemists tailor carbon chain’s conformation
Organic chemists have long admired nature for its ability to perform chemistry in an assembly-line style, wherein the same reaction or sets of reactions are carried out repeatedly to create a target molecule. Polyketide natural products, for example, are biosynthesized via such an assembly-line process.
Now, chemists at England’s University of Bristol report an assembly-line reaction that can be done in a flask (Nature 2014, DOI: 10.1038/nature13711).

 

Ethyl acetoacetate 乙酰乙酸乙酯 teaches you Organic spectroscopy… brush up?????

read at

http://orgspectroscopyint.blogspot.in/2014/04/ethyl-acetoacetate-teaches-you-organic.html

Ethyl acetoacetate
Ethyl 3-oxobutanoate
Acetoacetic acid ethyl ester
Ethyl acetylacetate
3-Oxobutanoic acid ethyl ester


Ethyl acetoacetate is produced industrially by treatment of diketene with ethanol.
The preparation of ethyl acetoacetate is a classic laboratory procedure.[2] It is prepared via the Claisen condensation of ethyl acetate. Two moles of ethyl acetate condense to form one mole each of ethyl acetoacetate and ethanol.

Preparation of ethyl acetoacetate.







Structure: structure

IUPAC Name: ethyl 3-oxobutanoate (ethyl acetoacetate)

Analysis: C6H10O3: MW = 130.14

The molecule contains an oxygen, and from the analysis, contains two double bonds, carbonyls or rings.
The mass spectrum displays a molecular ion and the base peak represents the formation of the acylium ion, indicating the presence of a methyl adjacent to a carbonyl. The presence of an m-45 peak strongly suggests the presence of an ethoxy group.
The 13C spectrum contains six peaks, indicating that all carbons are unique. The quartets at  14 and 24 represent relatively simple methyl groups; the triplets at  59 and 47 represent a CH2 groups bonded to mildly electronegative groups; the singlets at  207 and 172 are in the carbonyl region, and most likely a ketone or aldehyde ( 207) and an ester ( 172).
The proton NMR shows evidence for an ethyl group and isolated CH2 and CH3 groups. The methylene of the ethyl group must be next to an electronegative atom (most likely oxygen) suggesting an -OCH2CH3 group. The isolated CH2 must also be flanked by mildly electronegative groups, and the isolated CH3 is in the region often observed for methyls adjacent to carbonyls.
The IR is consistent with a simple saturated hydrocarbon, possibly containing two carbonyls (based on the side peak at  1670 cm1). The minor peak at 3400 cm1 is too small to be an -OH.
The simplest structure which is consistent with all of these data would be a dicarbonyl compound containing an ethoxy residue and a methyl ketone (based on the presence of the acylium ion in the MS).

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1H NMR
NMR Spectrum
The proton NMR has a quartet coupled to a triplet, indicative of an ethyl group. The CH2 must be adjacent to an electron withdrawing group since it is shifted to  4.1. The two singlets at  2.2 and 3.2 suggest isolated CH2 and CH3 groups and the CH2 must be adjacent to one or more electronegative groups.

 

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http://orgspectroscopyint.blogspot.in/2014/04/ethyl-acetoacetate-teaches-you-organic.html
……………………………………………………….
13C NMR
13C NMR Assignments: C-13 assignments
13C NMR Data: q-13.6; q-24.2; t-59.2; t-46.6; s-172.0; s-207.1
The 13C spectrum contains six peaks, indicating that all carbons are unique. The quartets at  14 and 24 represent relatively simple methyl groups; the triplets at  59 and 47 represent a CH2 groups bonded to mildly electronegative groups; the singlets at  207 and 172 are in the carbonyl region, and most likely a ketone or aldehyde ( 207) and an ester ( 172).

spectrum for Ethyl acetoacetate

ethyl acetoacetate CH3COCH2COOCH2CH3

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MASS SPECTROSCOPY
Mass Spectrum


Mass Spectrum Fragments: C-13 assignments
The mass spectrum consists of a molecular ion at 130, an m-15 peak at 115, which is consistent with loss of a CH3 group, an m-43 peak (loss of acylium), an m-45 peak (loss of CH3CH2O-), and a base peak at m-43(m/e = 43) which suggests the formation of an acylium ion (CH3-CO). The spectrum is consistent with a molecule which can lose methyl or ethoxy radicals, or can undergo fragmentation to form the acylium radical cation.

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IR

3400-3200 cm1: no OH peak (too small) 3100 cm1: no significant peak, suggesting no unsaturated CH 2900 cm1: strong peak suggesting saturated CH 2200 cm1: no unsymmetrical triple bonds 1710 cm1: strong carbonyl with a second peak at 1670 cm1, suggesting a the possibility of two carbonyls 1600 cm1: no significant peaks, suggesting no carbon-carbon double bonds

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2D [1H,1H]-TOCSY

spectrum for Ethyl acetoacetate

spectrum for Ethyl acetoacetate1D DEPT135





spectrum for Ethyl acetoacetate2D [1H,13C]-HSQC



spectrum for Ethyl acetoacetate2D [1H,13C]-HMBC





spectrum for Ethyl acetoacetate2D [1H,1H]-COSY


spectrum for Ethyl acetoacetate2D [1H,13C]-HMQC

 

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The Chemistry of Love

There are a lot of chemicals racing around your brain and body when you’re in love. Researchers are gradually learning more and more about the roles they play both when we are falling in love and when we’re in long-term relationships. Of course, estrogen and testosterone play a role in the sex drive area . Without them, we might never venture into the “real love” arena.

That initial giddiness that comes when we’re first falling in love includes a racing heart, flushed skin and sweaty palms. Researchers say this is due to the dopamine, norepinephrine and phenylethylamine we’re releasing. Dopamine is thought to be the “pleasure chemical,” producing a feeling of bliss. Norepinephrine is similar to adrenaline and produces the racing heart and excitement. According to Helen Fisher, anthropologist and well-known love researcher from Rutgers University, together these two chemicals produce elation, intense energy, sleeplessness, craving, loss of appetite and focused attention. She also says, “The human body releases the cocktail of love rapture only when certain conditions are met and … men more readily produce it than women, because of their more visual nature.”

Researchers are using functional magnetic resonance imaging (fMRI) to watch people’s brains when they look at a photograph of their object of affection. According to Helen Fisher, a well-known love researcher and an anthropologist at Rutgers University, what they see in those scans during that “crazed, can’t-think-of-anything-but stage of romance” — the attraction stage — is the biological drive to focus on one person. The scans showed increased blood flow in areas of the brain with high concentrations of receptors for dopamine — associated with states of euphoria, craving and addiction. High levels of dopamine are also associated with norepinephrine, which heightens attention, short-term memory, hyperactivity, sleeplessness and goal-oriented behavior. In other words, couples in this stage of love focus intently on the relationship and often on little else.

Another possible explanation for the intense focus and idealizing view that occurs in the attraction stage comes from researchers at University College London. They discovered that people in love have lower levels of serotonin and also that neural circuits associated with the way we assess others are suppressed. These lower serotonin levels are the same as those found in people with obsessive-compulsive disorders, possibly explaining why those in love “obsess” about their partner.

 

 

Pfizer Announces Availability Of Quillivant XR™ (methylphenidate hydrochloride) CII For Extended-Release Oral Suspension In The United States

methyl phenyl(piperidin-2-yl)acetate

Methylphenidate (MPH; MPD) is a psychostimulant drug approved for treatment of ADHD or attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It is better known by its 1948 trademarked name of Ritalin (original owner CIBA, now Novartis Corporation), was first licensed by the FDA in 1955 for treating ADHD, prescribed from 1960, and became heavily prescribed in the 1990s, when ADHD itself became more widely accepted.[1]

ADHD and some other conditions are believed to be linked to sub-performance of the dopamine, norepinephrine, and glutamate processes in the brain responsible for self-regulation functions, leading to self-regulation disorders compromising the sufferer’s attention, self-control, behaviour, motivation, and executive function; methylphenidate primarily works by reducing the reuptake of dopamine and norepinephrine which improves the levels and utility of these neurotransmitters in the brain. Methylphenidate possesses some structural and pharmacological similarities to cocaine, though methylphenidate is less potent and longer in duration.[2][3][4]

January 14, 2013

Pfizer Inc.  today announced that Quillivant XR™ (methylphenidate hydrochloride) CII for extended-release oral suspension is now available in the U.S. for the treatment of attention deficit hyperactivity disorder (ADHD). Quillivant XR is the first once-daily, extended-release liquid methylphenidate for ADHD and is now available by prescription.

“We also recognize that caring for and treating a child with ADHD goes beyond medication. We look forward to working with mothers and other caregivers of children with ADHD to provide meaningful resources to the ADHD community.”

“In order to effectively treat patients with chronic conditions such as ADHD, it is important to consider individual patient needs, including options for medication administration,” said Ann Childress, M.D., president of the Center for Psychiatry and Behavioral Medicine, Las Vegas, who was an investigator in the Quillivant XR laboratory classroom study. “As the first once-daily, extended-release liquid medication for patients with ADHD, Quillivant XR represents a new alternative to other ADHD treatments.”

Quillivant XR was approved by the U.S. Food and Drug Administration (FDA) on September 27, 2012 for the treatment of ADHD in patients aged 6 years and above. The efficacy of Quillivant XR was evaluated in a randomized, double-blind, placebo-controlled, crossover, multicenter, laboratory classroom study of 45 children with ADHD. Quillivant XR significantly improved ADHD symptoms compared to placebo at the primary endpoint of four hours post-dose, and in a secondary analysis, showed significant improvement at every time point measured, from 45 minutes to 12 hours after dosing.

Chemistry

Four isomers of methylphenidate are known to exist. One pair of threo isomers and one pair of erythro are distinguished, from which only d-threo-methylphenidate exhibits the pharmacologically usually desired effects. When the drug was first introduced it was sold as a 3:1 mixture of erythro:threo diastereomers. The erythro diastereomers are also pressor amines. “TMP” is referring only to the threo product that does not contain any erythro diastereomers. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotary methylphenidate is called d-TMP. A review on the synthesis of enantiomerically pure (2R,2′R)-(+)-threo-methylphenidate hydrochloride has been published.

Methylphenidate preparation according to Jeffrey M. Axten et al. (1998)

Methylphenidate production

  1. http://www.ehow.com/about_5374709_ritalin-invented.html When Was Ritalin Invented?, citing Lawrence Diller: “Running on Ritalin”, 1999
  2.  “Ritalin & Cocaine: The Connection and the Controversy”. Learn.genetics.utah.edu. Retrieved on 2011-10-16.
  3. Mary Ann Boyd (2005). Psychiatric nursing: contemporary practice. Lippincott Williams & Wilkins. pp. 160–. ISBN 978-0-7817-4916-9. Retrieved 30 April 2011.
  4. Peter Doskoch (2002). “Why isn’t methylphenidate more addictive?”. NeuroPsychiatry Rev. 3 (1): 19. Archived from the original on 2009-03-30.