Cyclopentene-1,3-dione derivative

PROCESS, spectroscopy, SYNTHESIS Comments Off

Jul 202015

the isolated cyclopentenedione derivative may have structure 1a or 1b or even exist as an equilibrium mixture between these two enol forms showing average ¹H and ¹³C NMR spectra due to a proposed rapid interconversion between 1a and 1b.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024

Synthetic results

Our approach to cyclopentenedione derivative (1) started with the preparation of furylmethylcarbinol (3) by the reduction of commercially available 2-acetylfuran (2) with NaBH₄ (Scheme 2).⁵ Compound 3 was isolated in 98% yield and transformed into 4-hydroxy-5-methylcyclopenten-2-one (4) in 90% yield after treatment with ZnCl₂-HCl (pH 6.0) under reflux in dioxane-H₂O for 48 h.⁶ Upon treatment of 4-hydroxy-5-methylcyclopenten-2-one (4) with phosphate buffer (pH 8.0) in refluxing dioxane for 24 h, 4-hydroxy-2-methylcyclopenten-2-one (5) was obtained in 65% yield.⁷By using this strategy we were able to prepare up to gram quantities of hydroxyketone 5.

Diketone 6 was obtained in almost quantitative yield by the smooth oxidation of hydroxyketone 5 with MnO₂(Scheme 3).^8,9 At this point, all that remained was to carry out the necessary acylation coupling. It was with some gratification that we observed that the reaction between lithium enolate of diketone 6 and cinnamic anhydride 7 gave a 57:43 mixture of cyclopentenediones 1a/1b in 22% yield, after purification by flash column chromatography, together with starting material and by-products arising from O-acylation (Scheme 3).

In order to try to improve the yields for formation of 1a/1b, we tested a new synthetic route (Scheme 4). Protection of the OH-functionality in 5 with TESCl and imidazole at room temperature gave ketone 8 in 85% yield. Treatment of 8 with LDA in THF at –78 ºC, followed by slow addition of cinnamaldehyde, gave aldol adduct 9 as a mixture of diastereoisomers. Oxidation of the OH-function at C9 in allylic alcohol 9 under standard Swern¹¹ conditions followed by removal of the TES protecting group with TBAF in THF led to diol 10 in 60% overall yield. The last step involved treatment of diol 10 under standard Swern oxidation conditions, to give a 59:41 mixture of 1a/1b in 79% yield.¹¹

The correct structure for the natural product was confirmed as being 1a by the heteronuclear long-range coupling (ⁿJ_CH; n = 2,3,4) obtained by HMBC experiments in CDCl₃ as solvent. Heteronuclear long-range coupling of C11 (d_C 201.3) with H13 (d_H6.70,³J_CH) and H15 (d_H2.12, ³J_CH), as well as between C14 (d_C 191.8) with H13 (d_H6.70,²J_CH) and H15 (d_H2.12, ⁴J_CH) for 1a, together with the long-range coupling of C11 (d_C 200.7) with H12 (d_H6.61,²J_CH) and H15 (d_H2.11, ⁴J_CH), as well as between C14 (d_C 192.3) with H12 (d_H6.61,³J_CH) and H15 (d_H2.11 ppm, ³J_CH) for 1b, unambiguously established the correct structure as being 1a (Figure 10).

cyclopentenedione derivative (1) as a yellow solid. Rf 0.37 (30% EtOAc/Hexane); IR (film) n_max/cm^-1: 3428, 2965, 1632, 1589, 1266, 1103, 1023, 803, 742, 699; (HRMS) Exact mass calc. for C₁₅H₁₂O₃: 240.0786. Found: 240.0787.

Journal of the Brazilian Chemical Society

On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.16 no.3a São Paulo May/June 2005

http://dx.doi.org/10.1590/S0103-50532005000300024

Short synthesis of a new cyclopentene-1,3-dione derivative isolated from Piper carniconnectivum

Luiz C. Dias^*; Simone B. Shimokomaki; Robson T. Shiota

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024

Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas – SP, Brazil

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Flow chemistry can make processes greener….Swern oxidation

MANUFACTURING, PROCESS, SYNTHESIS Comments Off

Jul 202015

The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride,dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine.The reaction is known for its mild character and wide tolerance of functional groups.

The by-products are dimethyl sulfide (Me₂S), carbon monoxide (CO), carbon dioxide (CO₂) and — when triethylamine is used as base — triethylammonium chloride (Et₃NHCl). Two of the by-products, dimethyl sulfide and carbon monoxide, are very toxic volatile compounds, so the reaction and the work-up needs to be performed in a fume hood.Dimethyl sulfide is a volatile liquid (B.P. 37 °C) with an extremely unpleasant odour.

The first step of the Swern oxidation is the low-temperature reaction of dimethyl sulfoxide (DMSO), 1a, formally as resonance contributor 1b, with oxalyl chloride, 2. The first intermediate, 3, quickly decomposes giving off CO₂ and CO and producing chloro(dimethyl)sulfonium chloride, 4.

After addition of the alcohol 5, the chloro(dimethyl)sulfonium chloride 4 reacts with the alcohol to give the key alkoxysulfonium ion intermediate, 6. The addition of at least 2 equivalents of base — typically triethylamine — will deprotonate the alkoxysulfonium ion to give the sulfur ylide 7. In a five-membered ring transition state, the sulfur ylide 7decomposes to give dimethyl sulfide and the desired ketone (or aldehyde) 8.

Dimethyl sulfide, a byproduct of the Swern oxidation, is one of the most foul odors known in organic chemistry. Human olfactory glands can detect this compound in concentrations as low as 0.02 to 0.1 parts per million. A simple remedy for this problem is to rinse used glassware with bleach (usually containing sodium hypochlorite), which will oxidize the dimethyl sulfide, eliminating the smell.

The reaction conditions allow oxidation of acid-sensitive compounds, which might decompose under the acidic conditions of a traditional method such as Jones oxidation. For example, in Thompson & Heathcock’s synthesis of the sesquiterpene isovelleral,the final step uses the Swern protocol, avoiding rearrangement of the acid-sensitive cyclopropanemethanol moiety.

Rapid, exothermic reactions are challenging to do in batch reactors. Reagents such as organometallics, strong bases, and highly active electrophiles are often added slowly to a reaction mixture under energy-intensive cryogenic conditions to prevent an uncontrollable exotherm. Quenching of these high-energy reagents may again require low temperature. This issue is scale dependent,1 and without proper precautions, both the likelihood and hazard of a runaway reaction increase with the size of a reactor.

The high surface area to volume ratio found in flow reactors makes heat transfer more efficient than in batch, allowing rapid removal of thermal energy given off. These features serve to give the chemist or engineer more control over reaction temperature and reduces the risk of thermal runaway.

Many instances have been reported of reactions being performed safely at 0 °C or room temperature in flow that would require cryogenic conditions in batch.^2,3,4 This has a further benefit on the overall processing time, as the reaction will occur faster at the elevated temperature and inefficient cooling and warming steps are avoided. A remarkable example demonstrating these principles is the room temperature Swern oxidation reaction by Yoshida and co-workers .⁵

The Swern reaction is a reliable procedure for converting alcohols to ketones and aldehydes using DMSOactivated by an electrophile (typically COCl₂ or TFAA) as the oxidant. In batch, the reaction takes place over three exothermic steps, each of which requires dropwise addition of reagents at cryogenic temperatures.^{6, 7}

PROCESS TO FLOW

When converting the process to flow, the Yoshida group found that the Swern oxidation could be done at room temperature with good yields and purity. Moreover, instead of having reaction times on the order of minutes or hours, the whole process was completed in seconds. They attributed the success of their process to the precise temperature control that can be obtained in flow systems, as well as the ability to quickly transfer unstable intermediates to subsequent steps. Using only a series of syringe pumps, stainless steel tubing, and commercial micromixers, they could prepare over 10 grams of material per hour. Being able to perform reactions on species with very short lifetimes is another general advantage of performing reactions in flow.⁸


	Scheme Room temperature Swern oxidation.

……………

MORE……..

http://thalesnano.com/products/IceCube

…………………

The Swern oxidation. The center column (green background) shows the desired chemical path, with added reagents shown in black boxes. The outer columns (red background) show the potential chemical pathways for side-product formation (8 and 9).

http://www.mdpi.com/2227-9717/2/1/24/htm

REF

R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. Chem., Int. Ed., 2011, 50, 7502–7519
V. Hessel, C. Hofmann, H. Löwe, A. Meudt, S. Scherer, F. Schönfeld and B. Werner, Org. Process Res. Dev., 2004, 8, 511–523 Search PubMed.
A. Nagaki, Y. Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H. Okamoto and J.-i. Yoshida, Chem.–Asian J., 2007, 2, 1513–1523
T. Gustafsson, H. Sörensen and F. Pontén, Org. Process Res. Dev., 2012, 16, 925–929 Search PubMed.
T. Kawaguchi, H. Miyata, K. Ataka, K. Mae and J.-I. Yoshida, Angew. Chem., Int. Ed., 2005, 44, 2413–2416
A. K. Sharma and D. Swern, Tetrahedron Lett., 1974, 15, 1503–1506 Search PubMed.
A. K. Sharma, T. Ku, A. D. Dawson and D. Swern, J. Org. Chem., 1975, 40, 2758–2764
J.-i. Yoshida, Chem. Rec., 2010, 10, 332–341

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Application in Febuxostat synthesis

PROCESS, SYNTHESIS, Uncategorized Comments Off

Jul 172015

………..

Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions

Abstract

Electron-rich arenes bearing methyl or methoxy groups on the aromatic ring were treated with dichloromethyl methyl ether and ZnBr₂, and then with molecular iodine and aq. ammonia to give the corresponding aromatic nitriles in good yields. Using this method, febuxostat was efficiently prepared from 4-bromophenol in four steps. The method can be used for the preparation of aromatic nitriles from arenes in one pot under metal-cyanide-free conditions.

The nitrile moiety is an important group that is found in pharmaceuticals and agrochemicals. In addition the nitrile can serve as a stable intermediate for amides, carboxylic acids, ketones, aldehydes, etc. As a result, many methods to make nitriles have been reported. In a new publication Togo et al. report their development of a one-pot metal-cyanide-free protocol to make electron-rich aromatic nitriles ( Eur. J. Org. Chem. 2015, 2023). The reaction first reacts arenes with zinc bromide (ZnBr₂) and dichloromethyl methyl ether to make in situ the (dichloromethyl)arene, that then reacts with aq. ammonia and iodine to make the nitrile. The electron-rich aromatic nitriles are formed in moderate-to-high yields (59–94%). They demonstrate usefulness of this reaction by synthesizing febuxostat.

Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions

Toshiyuki Tamura,
Katsuhiko Moriyama and
Hideo Togo^*

Article first published online: 9 FEB 2015

Tamura, T., Moriyama, K. and Togo, H. (2015), Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions. Eur. J. Org. Chem., 2015: 2023–2029. doi: 10.1002/ejoc.201403672

Author Information

Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan, http://reaction-2.chem.chiba-u.jp/index.html

Email: Hideo Togo (togo@faculty.chiba-u.jp)

^*Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan

Issue

European Journal of Organic Chemistry

Volume 2015, Issue 9, pages 2023–2029, March 2015

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201403672/abstract

UGI PRODUCT

PROCESS, spectroscopy, SYNTHESIS, Uncategorized Comments Off

Jul 052015

To synthesize a Ugi adduct from phenanthrene-9-carboxaldehyde, 1-heptylamine, tert-butylisocyanide and crotonic acid in methanol using Ugi 4CR

Procedure

To a one gram vial, charged with methanol (1mL) heptylamine, phenanthrene-9-carboxaldehyde, crotonic acid and tert-butyl isonitrile (0.5mmol each) was added in that order. After each addition, the resulting solution was vortexed for 15 seconds (or more) and confirmed that a homogeneous solution had been obtained. The vial was capped tight and left at room temperature for 3 days. The solution formed solid upon moving it to another spot. The obtained solid was washed with methanol (3 x 500uL), centrifuged each time to obtain a white residue. The wet product was set under a high vac to remove the solvent.

Characterization : White powder; M.pt~ 179-181C; H-NMR ( external image delta.gif

ppm, CDCl3) 0.30 (m, 1H), 0.54-0.95 (m, 10H), 1.05-1.2 (m, 1H ), 1.39 (s, 9H), 1.89 (d, 3H J 6.8Hz), 2.86 (bs, 1H), 3.28-3.60 (m 2H ), 5.79 (s,1H), 6.24 (d,1H J 15Hz), 6.87 (s 1H), 7.0-7.15 (m 1H), 7.56-7.76 (m 4H), 7.88 (d 1H J 7.85 Hz), 7.92-8.04 (m 2H), 8.68 (d 1H J 8.25 Hz), 8.73 (d 1H J 8.25Hz); 13C NMR ( external image delta.gif

ppm, CDCl3) 13.8, 18.2, 22.1, 26.2, 27.9, 28.6, 29.9, 31.0, 45.5, 51.7, 57.8, 122.0, 122.4, 123.1, 124.1, 126.8, 126.9, 127.43, 127.48, 128.9, 129.15, 129.16, 130.3, 130.47, 130.9, 131.0, 142.7, 166.9, 169.9; IR (KBr, 1/cm): v=3315, 3080, 2926, 2855, 1663, 1614, 1452, 1419, 748, 728; HRMS m/z calcd for C31 H40 N2 O2 : 495.298748 [M+Na]; found 495.2997.

Characterization amount: 118.5 mg

m.p. 179-181C
HNMR(50mg in 700uL CDCl3)
CNMR(50mg in 700uL CDCl3)
HRMS (FAB) [M+Na]
Nominal Mass (FAB) [M+H]
Nominal Mass (FAB) [M+Na]
IR (KBr)

Conclusion

A Ugi product was successfully synthesized in 50% yield.

9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester

spectroscopy, SYNTHESIS Comments Off

Jul 042015

9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester



Name	9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
Synonyms
Name in Chemical Abstracts	9,10-Ethanoanthracene-11,12-dicarboxylic acid, diethyl ester, trans-
CAS No	93368-53-7
EINECS No
Molecular formula	C₂₂H₂₂O₄
Molecular mass	350.42
SMILES code	c1cccc2[C@@H]3[C@H](C(=O)OCC)[C@@H](C(=O)OCC)[C@H](c12)c4ccccc43

1H NMR

¹H-NMR: 9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
250 MHz, CDCl₃
delta [ppm]	mult.	atoms	assignment
1.23	t (³J = 7.2 Hz)	6 H	CH₃ ethyl
3.45	m	2 H	11-H, 12-H (-CH-COO-)
4.08	m	4 H	CH₂ ethyl
4.75	m	2 H	9-H, 10-H

¹³C-NMR

13C NMR

¹³C-NMR: 9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
62.5 MHz, CDCl₃
delta [ppm]	assignment
14.2	CH₃ (ethyl ester)
46.7	C9, C10 (CH)
47.7	C11, C12 (CH-COO)
60.9	CH₂ (ethyl ester)
123.8	CH arom.
124.5	CH arom.
126.2	CH arom.
126.3	CH arom.
140.3	C quart. arom.
142.0	C quart. arom.
172.3	C(=O)O-
76.5-77.5	CDCl₃

IR: 9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
[KBr, T%, cm^-1]
[cm^-1]	assignment
3074, 3026	arom. C-H valence
2981	aliph. C-H valence
2935, 2897	aliph. C-H valence
1739	C=O valence, ester
1467	arom. C=C valence

; Side reactions

Synthesis of 9,10-dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester

Reaction type:	cycloaddition, Diels-Alder reaction
Substance classes:	alkene, aromatics, carboxylic acid ester, diene, dienophile, acid catalyst
Techniques:	working with moisture exclusion, heating under reflux, stirring with magnetic stir bar, filtering, evaporating with rotary evaporator, recrystallizing, use of an ice cooling bath, heating with oil bath

Equipment

	three-necked flask 1000 mL			adapter with ground-glass joint and hose coupling
	protective gas piping			reflux condenser
	drying tube			bubble counter
	powder funnel			heatable magnetic stirrer with magnetic stir bar
	rotary evaporator			ice bath
	exsiccator with drying agent			oil bath

Operating scheme

MULTAN, PAKISTAN

Mutlan is an important city of Pakistan which is also known as the city of Saints. The history of Multan begins with the Alexander and later on Kushans, Arabs, Huns, Ghaznavi, Afghans, Mongols, Sikhs, Mughals and British ruled over the city. It is the city of Sufis and Saints who preached the Islam in this region. In the South Asia Multan is the oldest city.

Multan Things to Do

See all 10 Things to Do in Multan

Baha-ud-din Zakariya Mazar

Sheikh Baha-ud-din Zakariya (1170-1267) was a sufi saint who for several years travelled the region from Baghdad, Iraq to India preaching Islam, and made his final abode in Multan. His offsprings and disciples travelled all over India to preach. His most famous descendant is Shah… more
Shah Rukn-e-Alam’s tomb

Situated on top of a small hillock, behind the old ruins of Multan Fort, the Mazar and its majestic dome is the first landmark visible when you enter proper Multan. Shah Rukn-e-Alam (1251-1335) was a Sufi saint in Multan. He was revered by his followers, and to this date thousands of pilgrims from all over… more
Other Saints and Sufis Mazars

Multan is known as City of Saints, and this is evident by the number of Masuleums, Mazars, Dargas, or tombs situated in this city. Some of them are listed below.1 Hazrat Baha-ud-Din Zakaria2 Shah Rukn-i-Alam3 Shah Shams Sabzwari4 Shah Gardez5 Musa Pak Shaheed6 Hazrat Hafiz Muhammad… more
Ghanta Ghar (Clock Tower house)

Ghanta Ghar whch is situated in the city center is the city government head quarter. (not a great picture, taken from a moving car)

more
Multan Fort

The Multan Fort on a high mound of earth which separated it from the old branch of the river Ravi. There are now only remnant of this old fort, which was considered as one of the best fort (defense wise) built in the sub-continent. The fort was destroyed when the British took over. During its haydays the fort walls were was almost 1.6… more
King mosque Eid Gah

This Masjid is a marvelous piece of architecture of multan.it is a very beautiful masjid and must to visit place of Multran city

more
Shrines must to visit

Given below is list of must to visit shrines in Multan1.Shrine B.B Pak Damman2.Shrine Hameed-ud-Din Hakim3.Shrine Qutab-al-quteeb’Moj Daryan’4.Shrine-Syed Pir Sakhi Shah Hasan Prwana5.Shrine-Qazi Qutab-ud-Din Kashani6.Shrine-Syed Hasan Kanjzee7.Shrine-Hazarat Shah Dana Shaheed8.Shrine-Abu… more
Shrines of the sufi hermits

Hi Awais,All the destinations in Pakistan, they’ve their own attraction or somethijng very special in that area, likewise in Hunza, you can’t find the shrines of the sufi hermits, or in Multan, the mountains like Nanga parbat or Kalash tribes in Lahore?Multan, Medina-tul-awlia, the city of saints, famous all over the… more
Visiting Historical Places

As I describe before that Multan is the city of Saints so there r so many Tombs to Visit and explore the history.

more

Multan Hotels

Ramada Multan

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Nonanedioic acid, Azelaic acid

spectroscopy, SYNTHESIS Comments Off

Jun 292015

148

Nonanedioic acid

Azelaic acid



Name	Nonanedioic acid
Synonyms	Azelaic acid
Name in Chemical Abstracts	Nonanedioic acid
CAS No	123-99-9
EINECS No	204-669-1
Molecular formula	C₉H₁₆O₄
Molecular mass	188.23
SMILES code	O=C(O)CCCCCCCC(=O)O

KMnO₄ / KOH

; Side reactions

1H NMR

¹H-NMR: Nonanedioic acid
250 MHz, DMSO-d₆
delta [ppm]	mult.	atoms	assignment
1.25	m	6 H	4-H, 5-H, 6-H
1.47	m	4 H	3-H, 7-H
2.18	t (³J = 7.3 Hz)	4 H	2-H, 8-H
ca. 12	broad s	2 H	COOH
2.49			DMSO

¹³C-NMR

13C NMR

¹³C-NMR: Nonanedioic acid
62.5 MHz, DMSO-d₆
delta [ppm]	assignment
23.9	C3, C7
27.6	C5
27.8	C4, C6
33.1	C2, C8
173.4	COOH
39.5	DMSO-d₆

Azelaic acid(123-99-9)¹³CNMR

IR: Nonanedioic acid
[KBr, T%, cm^-1]
[cm^-1]	assignment
3300-2500	O-H valence, superimposed on C-H valence
2962, 2887	aliph. C-H valence
1724	C=O valence, carboxylic acid

Oxidation of ricinoleic acid (from castor oil) with KMnO4 to azelaic acid

Reaction type:	oxidation
Substance classes:	alkene, carboxylic acid, renewable resources
Techniques:	heating under reflux, stirring with magnetic stir bar, stirring with KPG stirrer, adding dropwise with an addition funnel, shaking out, extracting, evaporating with rotary evaporator, filtering, recrystallizing, heating with oil bath
Degree of difficulty:	Medium

Operating scheme

Equipment

	round bottom flask 250 mL			three-necked flask 1000 mL
	reflux condenser			internal thermometer
	addition funnel with pressure balance			heatable magnetic stirrer with magnetic stir bar
	KPG stirrer			beaker 400 mL
	beaker 250 mL			Erlenmeyer flask 250 mL
	separating funnel			rotary evaporator
	suction filter			suction flask
	exsiccator with drying agent			oil bath

Chromatogram

crude product chromatogram

TLC: crude product
TLC layer	Merck silica gel 60 F254, 5 x 10 cm
mobile phase	EtOH
staining reagent	0.1% solution of 2,6-dichlorophenolindophenol sodium salt in 95% ethanol
Rf (educt)	0.70
Rf (product)	0.60

PESHAWAR, PAKISTAN FOOD

Peshawar is one the oldest cities of South Asia. It is an entrance point of Pakistan from the Afghanistan. It was an important city of Subcontinent and a meeting and marketing place for the public of Middle East, India and central Asia. Afghan warriors used this way to enter into subcontinent.

NALLI GOSHT

Pakistani cooks prepare food for refugees in the Jalozai camp in Peshawar,

Food being prepared at Qissa Khuwani Bazaar in Peshawar on the eve of Eid Milad-

The Big Pot Tea Man of Peshawar

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Pd(II) catalyzed ortho C–H iodination of phenylcarbamates at room temperature using cyclic hypervalent iodine reagents

spectroscopy, SYNTHESIS Comments Off

Jun 292015

A novel approach to access ortho iodinated phenols using cyclic hypervalent iodine reagents through palladium(II) catalyzed C–H activation has been developed through weak coordination. The reaction showed excellent regioselectivity, reactivity and good functional group tolerance. A unique mechanism was proposed.

Pd(II) catalyzed ortho C–H iodination of phenylcarbamates at room temperature using cyclic hypervalent iodine reagents

Xiuyun Sun,^a Xia Yao,^a Chao Zhang^a and Yu Rao*^a

*Corresponding authors

^aMOE Key Laboratory of Protein Sciences, Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China

E-mail: yrao@mail.tsinghua.edu.cn

Chem. Commun., 2015,51, 10014-10017

DOI: 10.1039/C5CC02533H

http://pubs.rsc.org/en/content/articlelanding/2015/cc/c5cc02533h#!divAbstract

yu rao

Zhang Chao

Tsinghua University, Beijing

///

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions

SYNTHESIS Comments Off

Jun 162015

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions Steffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley DOI: 10.1039/C4OB02105C, Paper From themed collection Recent Advances in Flow Synthesis and Continuous Processing

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions

Steffen Glöckner,^a Duc N. Tran,^a Richard J. Ingham,^a Sabine Fenner,^a Zoe E. Wilson,^a Claudio Battilocchio^a and Steven V. Ley*^a

*Corresponding authors

^aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

E-mail: svl1000@cam.ac.uk Web: http://www.leygroup.ch.cam.ac.uk/

Org. Biomol. Chem., 2015,13, 207-214

DOI: 10.1039/C4OB02105C

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide


	Fig. 1 Oxazoline- and oxazole-containing natural products.


	Scheme 1 Optimised conditions for the flow synthesis of oxazolines.


	Scheme 2 Microchip reaction for the preparation of oxazolines.


	Scheme 3 Platform set up for the scale up experiment.


	Scheme 4 Flow oxidation of aryl-oxazolines using activated MnO₂.


	Scheme 5 Flow oxidation of 2-alkyl-oxazolines using amorphous MnO₂. ^aDeprotection was observed.


	Scheme 6 Automated oxidation of oxazolines using a Raspberry Pi® computer and a multiple position valve.

Table 1 Flow cyclodehydration of β-hydroxy amides using Deoxo-Fluor®

Entry^a			Isolated yield^b
a Reactions were run on a 2 mmol scale. b Compounds were isolated without purification. c The crude material was passed through a plug of calcium carbonate/silica in place of an aqueous work up. d Total flow rate = 10 mL min⁻¹ with 2.6 eq. of Deoxo-Fluor®.
1	1a	2a	98%
2	1b	2b	98%
3	1c	2c	79%^c
4	1d	2d	98%
5	1e	2e	99%
6	1f	2f	95%
7	1g	2g	98%
8	1h	2h	92%
9	1i	2i	95%
10	1j	2j	60%
11	1k	2k	85%^d
12	1l	2l	92%^d

……………………………………… 2a

General protocol for the preparation of oxazoline in flow

A solution of Deoxo-Fluor® (1 mL, 50% in toluene) in CH₂Cl₂ (7.0 mL) and a solution of β-hydroxy amide (2 mmol) in CH₂Cl₂ (8 mL) were combined at a T-piece (each stream run at 3.0 mL min⁻¹) and reacted at rt in a 10 mL PFA reactor coil. The combined stream was then directed to an aqueous quenching stream (9 mL min⁻¹) and the solution directed to a liquid/liquid separator.²²

(4S,5S)-5-Methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (2a).

¹H-NMR (600 MHz, CDCl₃) δ = 7.98–7.96 (m, 2H), 7.49–7.46 (m, 1H), 7.40–7.38 (m, 2H), 5.05 (dq, 1H, J= 10.2, 6.4 Hz), 4.97 (d, 1H, J = 10.2 Hz), 3.76 (s, 3H), 1.37 (d, 3H, J = 6.5 Hz);

¹³C-NMR (151 MHz, CDCl₃) δ = 170.5, 166.2, 131.9, 128.6, 128.4, 127.3, 77.7, 71.8, 52.2, 16.3;

HR-MS (ESI+) for C₁₂H₁₄NO₃⁺ [M + H]⁺ calc.: 220.0974, found: 220.0981;

FT-IR neat, [small nu, Greek, tilde]

(cm⁻¹) = 2953, 1736, 1645, 1603, 1580, 1496, 1450, 1384, 1349, 1244, 1197, 1174, 1067, 1045, 1001, 973, 934, 904, 886, 851, 778, 695;

specific rotation: [α]^24.1_D = +58.58° cm³ g⁻¹ dm⁻¹ (c = 8.5 in ethanol). Lit.: [α]²⁰_D = +69.4° cm³ g⁻¹ dm⁻¹ (c = 8.5 in EtOH).³⁹

39…………H. Aït-Haddou, O. Hoarau, D. Cramailére, F. Pezet, J.-C. Daran and G. G. A. Balavoine, Chem. – Eur. J., 2004, 10, 699–707

Dr Zoe Wilson

Post Doctoral Research Associate in the group of Professor Steven V. Ley working on the synthesis of complex natural products and synthetic methodology.

College Lecturer and Fellow at Murray Edwards College.

Research Group

Ley Group Website

Telephone number

01223 336698 (shared)

Email address

zw261@cam.ac.uk

College

Murray Edwards College

Email: zw261@cam.ac.uk LinkedIn Profile

Zoe grew up on a farm in the small town of Warkworth, New Zealand. After completing her studies she moved to Auckland, New Zealand to attend the University of Auckland where she completed a Bachelor of Science in Medicinal Chemistry then a BSc (Hons) in Medicinal Chemistry under the supervision of Professor Margaret Brimble, working on the synthesis of anti-Helicobacter pylori compounds. She was then funded by a University of Auckland scholarship to carry out Ph.D. research with Professor Brimble into the synthesis of the extremophile natural product berkelic acid. Upon completion of her Ph.D. she was awarded a Newton International Fellowship from the Royal Society to move to the United Kingdom and join the research group of Professor Steven V. Ley in the Department of Chemistry, University of Cambridge. Upon completion of the two year Newton Fellowship, she was then employed as a Post-Doctoral Research Associate to continue working in the Ley group. While in Cambridge, she has been working on the total synthesis of the complex natural products azadirachtin and plantazolicins A and B, in the process developing novel chemistry. In October 2013 Zoe was appointed as a College Lecturer and Fellow at Murray Edwards College.

Teaching

Graduate Lecture Series – Reduction in Organic Chemistry (2 lectures) (2014, 2013)

Senior demonstrator Chemistry II laboratories (2014/2015)

Senior demonstrator Chemistry IB laboratories (2012/2013, 2013/2014)

College Lecturer at Murray Edwards College

Publications

12. Zoe E. Wilson, Sabine Fenner and Steven V. Ley, “Total syntheses of linear poly-thiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B”, Angew. Chem. Int. Ed., 2015, 54, 1284 – 1288 DOI: 10.1002/anie.201410063R1

11. Steffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley, “The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions”, Org. Biomol. Chem.,2015, 13, 207–214, DOI: 10.1039/c4ob02105c

10. Michael C. McLeod, Zoe E. Wilson and Margaret A. Brimble, “Formal synthesis of berkelic acid: a lesson in α-alkylation chemistry”, J. Org. Chem., 2012, 77, 1, 400–416, DOI: 10.1021/jo201988m

9. Michael C. McLeod, Margaret A. Brimble, Dominea C. K. Rathwell, Zoe E. Wilsonand Tsz-Ying Yuen, “Synthetic approaches to [5,6]-benzannulated spiroketal natural products”, Pure Appl. Chem., 2012, 84, 6, 1379-1390, DOI: 10.1351/PAC-CON-11-08-06

8. Michael C. McLeod, Zoe E. Wilson and Margaret A. Brimble, “An enantioselective formal synthesis of berkelic acid”, Org. Lett., 2011, 13, 19, 5382 – 5385, DOI: 10.1021/ol202265g

7. Zoe E. Wilson, Jonathan G. Hubert, Margaret A. Brimble, “A flexible approach to 6,5-benzannulated spiroketals”, Eur. J. Org. Chem., 2011, 3938-3945, DOI: 10.1002/ejoc.201100345

6. Jonathan Sperry, Yen-Cheng (William) Liu, Zoe E. Wilson, Jonathan G. Hubert, Margaret A. Brimble, “Synthesis of benzannulated spiroketals using an oxidative radical cyclization”, Synthesis, 2011, 9, 1383-1398, DOI: 10.1055/s-003001259981

5. Jonathan Sperry, Zoe E. Wilson, Dominea C. K. Rathwell and Margaret A. Brimble, “Isolation, biological activity and synthesis of benzannulated spiroketal natural products”, Nat. Prod. Rep., 2010, 27, 1117-1137, DOI: 10.1039/b911514p

4. Zoe E. Wilson and Margaret A. Brimble, “A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a novel Horner-Wadsworth-Emmons/oxa-Michael cascade”, Org. Biomol. Chem., 2010, 8, 1284-1286, DOI: 10.1039/B927219B

3. Zoe E. Wilson and Margaret A. Brimble, “Molecules derived from the extremes of life”, Nat. Prod. Rep., 2009, 26, 44–71, DOI: 10.1039/b800164m

Featured as an Instant insight article in Chemical Biology (“Life at the extremes”,Chemical Biology, 2008, 3, B95) and featured on the cover of the issue (Nat. Prod. Rep.,2009, 26, 1-2, DOI: 10.1039/B821737H)

2. Fiona J. Radcliff, John D. Fraser, Zoe E. Wilson, Amanda M. Heapy, James E. Robinson, Christina J. Bryant, Christopher L. Flowers, and Margaret A. Brimble, “Anti-Helicobacter pylori activity of derivatives of the phthalide-containing antibacterial agents spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015”, Bioorg. Med. Chem., 2008, 16, 6179–6185, DOI: 10.1016/j.bmc.2008.04.037

1. Zoe E. Wilson, Amanda M. Heapy and Margaret A. Brimble, “Synthesis of indole analogues of the anti-Helicobacter pylori compounds CJ-13,015, CJ-13,102, CJ-13,104 and CJ-13,108”, Tetrahedron, 2007, 63, 5379–5385, DOI: 10.1016/j.tet.2007.04.067

Flow Synthesis of Fluorinated α-Amino Acids

SYNTHESIS Comments Off

Jun 102015

Dr. Susan Wilkinson, Deputy Editor for the European Journal of Organic Chemistry, talks to Professor Beate Koksch, Freie Universität Berlin, Germany, and Professor Peter Seeberger, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany, about their article on the synthesis of fluorinated amino acids recently published in the European Journal of Organic Chemistry.

Flow Synthesis of Fluorinated α-Amino Acids

Dr. Wilkinson, European Journal of Organic Chemistry, talks to Professors Koksch and Seeberger about fluorinated amino acids

http://www.chemistryviews.org/details/ezine/7956531/Flow_Synthesis_of_Fluorinated_-Amino_Acids.html

Professor Beate Koksch, Freie Universität Berlin, Germany,

.Prof. Dr. Beate Koksch

Institute of Chemistry and Biochemistry – Organic Chemistry
Freie Universität Berlin
Takustr. 3
14195 Berlin

Working Group: AG Koksch

Space: 32.18

Tel .: + 49-30-838-55344, Fax -55 644

Secretariat:
Tel .: + 49-30-838-55880
(woman Skowronski, room 32.17)

Email: Beate.Koksch (At) fu-berlin.de

++49 – 30 – 838 55344

e-mail

homepage (http://userpage.chemie.fu-berlin.de/~akkoksch/)

Free University of Berlin
Takustr. 3
14195 Berlin
Germany

Nominated by

German Research Foundation (DFG)
AcademiaNet member since 13.03.2015

Employed by

Freie Universität Berlin

Academic Discipline/Fields

Natural sciences/ Engineering/ Agricultural sciences

Field

Chemistry

Area of specialisation

Organic and Natural Product Chemistry

Research interests

folding mechanisms occuring in neurodegenerative diseases
developing new multivalent scaffolds
investigating the impact of fluorine on amino acids, peptides and proteins

Distinctions and Awards

Georg Thieme publisher’s award, 2002Lessing medal in gold, 1986

………………………………………………..

Professor Peter Seeberger, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

Since 2011, Professor Peter H. Seeberger, Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, is Editor-in-Chief of the Beilstein Journal of Organic Chemistry.

Editor-in-Chief of the Beilstein Journal of Organic Chemistry is Professor Peter H. Seeberger, Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, who is supported by a distinguished board of associate editors, each of whom is responsible for a particular subject area within the journal’s scope. Over 40 scientists from all over the world, including several Nobel Prize laureates, support the Beilstein Journal of Organic Chemistry as Advisory Board members.

Prof. Dr. Peter H. Seeberger

Director

Phone:+49 30 838-59301Fax:+49 30 838-59302

Email:boehme@…

German researchers develop cheap and high-yield process to manufacture anti-malaria drug

Jan 18, 2012

Researchers at the Max Planck Institute of Colloids and Interfaces in Potsdam and the Freie Universität Berlin have developed a very simple process for the synthesis of artemisinin – the best anti-malaria drug – more economically and in sufficient volumes for all patients. This means that it will be possible to provide medication for the 225 million malaria patients in developing countries at an affordable price.

An Anopheles female mosquito that transmits malaria(© picture alliance/dpa Fotografia)Over one million people die of malaria each year because they do not have access to effective drugs.Millions, especially in the developing world, cannot afford the combination drug preparation, which consists mainly of artemisinin.

Moreover, the price for the medication varies, as this substance is isolated from sweet wormwood (Artemisia annua) which grows mainly in China and Vietnam, and varies seasonally in its availability.

Pharmaceutical companies could only obtain the drug from plants up to now. The chemists use a waste product from current artemisinin production as their starting substance. This substance can also be produced biotechnologically in yeast, which the scientists convert into the active ingredient using a simple yet very ingenious method.

This may be about to change. Peter H. Seeberger, Director at the Max Planck Institute of Colloids and Interfaces in Potsdam and Professor of Chemistry at the Freie Universität Berlin and his colleague François Lévesque have discovered a very simple way of synthesising the artemisinin molecule, which is known as an anti-malaria drug from traditional Chinese medicine and has an extremely complex chemical structure. “The production of the drug is therefore no longer dependent on obtaining the active ingredient from plants,” says Peter Seeberger.

Synthesis from a by-product of artemisinin production

As a starting point, the chemists use artemisinic acid – a substance produced as a hitherto unused by-product from the isolation of artemisinin from sweet wormwood, which is produced in volumes ten times greater than the active ingredient itself. Moreover, artemisinic acid can easily be produced in genetically modified yeast as it has a much simpler structure. “We convert the artemisinic acid into artemisinin in a single step,” says Peter Seeberger. “And we have developed a simple apparatus for this process, which enables the production of large volumes of the substance under very controlled conditions.”

The effect of the molecule, which not only targets malaria but possibly also other infections and even breast cancer, is due to, among other things, a very reactive chemical group formed by two neighbouring oxygen atoms – which chemists refer to as an endoperoxide. Peter Seeberger and François Lévesque use photochemistry to incorporate this structural element into the artemisinic acid. Ultraviolet light converts oxygen into a form that can react with molecules to form peroxides.

800 photoreactors should suffice to cover the global requirement for artemisinin

Dr. Peter H. Seeberger, Director at the Max Planck Institute of Colloids and Interfaces in Potsdam and Professor of Chemistry at the Freie Universität Berlin(© dpa)“Photochemistry is a simple and cost-effective method. However, the pharmaceutical industry has not used it to date because it was so difficult to control and implement on a large scale,” explains Peter Seeberger.

“The fact that we do not carry out the synthesis as a one-pot reaction in a single vessel, but in a continuous-flow reactor enables us to define the reaction conditions down to the last detail,” explains Peter Seeberger.

After just four and a half minutes a solution flows out of the tube, in which 40 percent of the artemisinic acid has become artemisinin. “We assume that 800 of our simple photoreactors would suffice to cover the global requirement for artemisinin,” says Peter Seeberger. And it could all happen very quickly. Peter Seeberger estimates that the innovative synthesis process could be ready for technical use in a matter of six months. This would alleviate the global shortage of artemisinin and exert considerable downward pressure on the price of the associated drugs…….see http://www.india.diplo.de/Vertretung/indien/en/__pr/Edu__Science__News/Malaria__drug.html

Max Planck Institute for Colloids and Interfaces

Peter Seeberger

Department of Biomolecular Systems
Max Plank Institute for Colloids and Interfaces
(Potsdam, Germany)
peter.seeberger@mpikg.mpg.de

http://www.peter-seeberger.de/

The core interests our research program currently address the following areas:

Automated oligosaccharide synthesis

Rapid access to monosaccharide by de-novo synthesis
New protecting groups
New Glycosylating Agents
New linkers for solid phase carbohydrate synthesis
Assembly of complex structures (in particular N-Glycans, O-Glycans)
Optimization of steps followingthe assembly, like deprotection, modification and conjugation

Total Synthesis of Biologically Important Oligosaccharides

Tumor-associated antigens
HIV-related oligosaccharides
Bacterial cell-surface antigens
N-linked glycoproteins

Chemical Synthesis and Biochemistry of Proteoglycans

Modular synthesis of heparin/heparan sulfates
Creation of heparin microarray
Optimization of the building blocks synthesis
Study of the SAR (structure-activity relationship) and the interactions between Proteoglycans and proteins
Automated synthesis of heparin fragments

Total Synthesis and Biological Activity of Glycosylphosphatidylinositols (GPIs)

Total syntheses of GPIs
Development of a synthetic GPI malarial vaccine
Elucidation of the biosynthesis of GPI
Immunological response to synthetic GPIs

Development of Cabohydrate-based Vaccines

A fully synthetic malaria vaccine
Leishmania vaccine
Synthetic HIV vaccine
Synthetic TB vaccine

Microreactors for Organic Synthesis

(Automated) Synthesis in continuous flow Microreactors
Photochemistry in Microflow reactors
Catalysis in Microreactors

Carbohydrate Microarrays

De novo synthesis

Nanoparticules and Colloidal Polymers

Quantum dots
Supramolecular dendrimers
Emulsion polymerization of nanoparticules

http://www.theguardian.com/technology/2012/feb/05/malaria-drug-synthesis-peter-seeberger

take a tour

Potsdam, Germany

Potsdam – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Potsdam

Potsdam (German pronunciation: [ˈpɔtsdam] ( listen)), is the capital city of the German federal state of Brandenburg. It directly borders the German capital Berlin …

‎Potsdam Conference – ‎Sanssouci – ‎City Palace, Potsdam – ‎New Palace

Map of potsdam germany

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Synthesis of Phospholipopeptides

SYNTHESIS Comments Off

Jun 102015

Synthesis of Phospholipopeptides

A crosslinking approach for the synthesis of phospholipopeptides under mild conditions

http://www.chemistryviews.org/details/news/7984971/Synthesis_of_Phospholipopeptides.html

Bonan Li and Jun F. Liang, Stevens Institute of Technology, Hoboken, NJ, USA, report an approach to synthesize phospholipopeptides. They use a crosslinker with a thiol-reactive maleimide and an amine-reactive N-hydroxysuccinimide ester (pictured). Hence, the molecule is able to link the thiol group of the amino acid cystein in the peptide and the amine group of the phospholipid (phosphatidylamine).