Preparation of SEMCl

SEMCl (2-trimethylsilylethyoxymethyl chloride)
expensive, 25ml $500
so just make it!

st: 2-TMS ethanol 1.o eq. (100 g, $500)
paraformaldehyde 1.1eq.
neat.
control temperature below 20C by ice bath.
Bubble HCl gas through the mixture. exothermic. HCl flow rate need to be controlled so that the INSIDE temp below 20C.
after a while, about 10-20 min, the solution became two layers and both are clear. then stop HCl gas.
separate the top layer. dilute the top layer with pentane and dried it over mgso4 at 0 C for 1 hr.
then concentrated below rt.
what you have now is pure semcl! ready to use. H-NMR showed only pure compound.

stored over CaCl2 in freezer.

deprotection of benzyl on an amine

1. pd/c, hydrogenation.
known to be slow compare to benzyl ether.
acidic solvents like HCl/MeOH or AcOH was reported to give good results.

2. CAN/MeCN/water
mild condition, but works only for tertiary amine.

3. substitute the benzyl group with a carbamate, then remove the carbamate by various ways.
ex. vinyl formate ,allyl formate, trichloro ethyl formate,

4. oxidize it to benzoyl, then hydrolysis.

an interesting reaction- a new finding

the above rxn is a total failure. No product isolated. only st remained after 12 hr.
Seems the alpha-oxygen played some rule in this coupling rxn.

KHMDS is nucleophilic ??

In this rxn, the base KHMDS removed the benzoyl group! at -20C.
I guess the bulky silane attacked the ester and the alcohol was freed.
so the conclusion is KHMDS is quite nucleophilic.

An interesting reaction

The above reaction just won't go on my hand despite excess base.
But, the following rxn is so quick that the rxn is done within 10 min at rt.

Phosphate of ketone, ester and amide

Triflate of ketone ester and amides are useful reagent for pd coupling.
When triflate is unstable (ex. lactone or lactam), phosphate can be used (PO(OPh)2Cl).
It has better stability, stable on silica gel.

Then pd coupling can happen as triflate on phosphate.

Finally, another accident revealed the source.

Something happened during an overnight refluxing methanol rxn.

There are the clues I found:

1. somehow the red alcohol in the thermometer became un-continuous. there are gas between the red-alcohol.

2. the hot plate was cold although the knob is still on the right position. Restarted the hotplate returned the heat.

3. What is more, the mineral oil bath became darker than before.
4. although cooling water is running, half of the methanol was gone. (open container reaction)


My conclusion is the hot plate is bad. It heated up to a very high temperature sometime in the night! The high temperature exceeded the range of the thermometer and destroyed it. Also it darkened the mineral oil.
This hotplate is the same one I used for the other accident! SEE PIC!
the mechanism of controlling temp of this kind of hot plate is by a electromagnetic relay. I can hear the "click" sound when it started to heat. When the temp reached a preset value, the clicking sound became intense.
It is not reliable. Never use this kind of hotplate!

Pd catalyzed coupling of halides with enolates

Some players:
James Cook, Buchwald, Hartwig,
Josep Bonjoch...

progress:
intermolecular: enolates from ketone, ester, amide, nitrile; halides can be Ar-X, vinyl bromide.
intramolecular: enolates from ketone, ester, nitrile, halides can be Ar-x, vinyl bromide/iodide.

You may notice intramolecular amide coupling is missing.
The reason is obvious that strong base is needed to deprotonate the amide which can cause server side reactions. In the intermolecuar situation, this can be avoided by exchange the strong lithium enolate of amide with Zinc enolate as done by Hartwig.

Intramolecular epoxide openings

From :
Douglass F. Taber,* Lee J. Silverberg, and Edward D. Robinson
J. Am. Chem. SOC. 1991,113,6639-6645


1. nitrile anion opening and sulfone anions.

2.Nucleophilic allylic silanes have been employed, under acid-catalyzed conditions, ln
intramolecular epoxide openings.

3. Finally, StorkM has shown that ketone and ester enolates can be used to open allylic epoxides,
to form cyclohexane derivatives.

4. The only other enolate-based opening of an epoxide has been that reported by Negishi.31

(31)Z hang, Y.;M iller, J. A.; Negishi, E.-I.J . Org. Chem. 1989,54,2 043.

protection of tertiary amine while epoxidize an alkene.

1. use NaHSO3 to reduce the amine oxide.

tert-amine can be oxidized by mcpba to amine oxide. by using NaHSO3, the oxide can be reduced to tert-amine again. So use 2 eq. mcpba , then treated with NaHSO3.

2. TFA protection.
use TFA to convert the tert-amine to TFA salt which prevented oxidation.
after mcpba, use K2CO3 to remove TFA.
this method is not good to acid sensitive compound.

preparation of methanoli HCl

very expensive if you buy it from aldrich.
easy to make.
you need HCl gas cylinder or you can prepare it from con. sulfuric acid and NaCl ( add sulfuric acid into NaCl and stirring).

then you bubble HCl gas to MeOH. heat will be generated so an ice bath can be used.
by weighing the MeOH before and after, the concentration can be easily calculated.
In my case, I can easily reach 6N .

Once again, another lab accident.

This time it is a sealed tube reaction.
solvent is methanolic HCl (about 3-6 M, 10 ml). ace galssware 50 ml seal tube (max. 60 psi) with teflon cap.
temp is only 80-90 C. magnetic stirring.
after about 5 hr, somehow, the teflon cap was unscrewed (by itself !) and popped up to the ceiling of the fume hood along with all the solvents and reactants.

the reaction was not supposed to generate any gas.
the solution was green, which was not observed in a previous run.
the magnetic stir bar was broken after the explosion. magnetic metal inside can be seen.
Luckily, nobody get injured because of a protection shield we have.
Also nothing got broken. the seal tube is still intact and looks ok.

what is going on?
I guess the defective magnetic stir bar was the reason, which generated H2 gas in the presence of HCl. this is also explained why the color is green.

What is interesting is I still can not image how the tight teflon cap managed to unscrew itself.
In an early similar accident I had half a year ago, the sealed tube was just destroyed by the inside pressure.

Another lab accident .

Here is the detail:
I put about 30 g NaH in mineral oil in a 1000ml rbf. 500 ml of DMF added at rt.
Then ethyl acrylate 50 ml added at once. The temperature remained the same. No bubbling at all.
Then I went to the balance to weight something.
After about 15 min, the mixture became very hot. At the same time, a lot of gas was released. The reaction is so violent that it didn't stop until almost half of the orange colored mixture was pushed out of the rbf. What a big fountain!

Luckily nothing got hurt.
What happened?
the gas released during the accident was H2(trapped in a balloon which went upward showing the gas has lower density than air).
The smell of acrylate disappeared.

My conclusion is anionic polymerization.
The real question is
Did NaH deprotonate the a-proton of acrylate and initiated the reacion?

puting on THP protecting group.

tetrahydropyrane is stable to basic conditions. easily removed under acidic conditions.

To protect an indole ( N-H):

dihydropyrane + camphor sulfornic acid in DCM. rt.
8hr.

Curtius rearrangement

converts acid to carboxylic azides (use DPPA or acid chloride then NaN3) then upon heating rearrange to an isocyanate.

Then the isocyanate can be trapped by alcohol to form a carbamate.

related rxn: Hofmann Rearrangement, Schmidt Reaction.

Condition I used (to amine):

toluene, dppa, tea, 80C 2h,

then water added, 80C, overnight.

turned out the above transformation is not high yielding.
seems trapping the isocyanate by water is not a good idea.

generally, t-BuOH or BnOH was used to make a carbamate. then remove the carbamate by acid or hydrogenation.

2nd condition I used to make amine:
1. toluene, oxalyl chloride 60C. then concentrated invacuo.
2. acid chloride made in step 1 was dissolved in acetone, then added into NaN3 in water at zero degree. then rt. excess water was used to precipitate the product.
3. heated in toluene to 80C for 2 hr.
4. BnOH added. heated for another 2 hr.
isolate product by column.
5. MeOH, acoh, water + pd/c + H2. rt.
2 hr, then celite filtration.
K2CO3 solution was used to neutralize acoh and make free amine( pH>9). then extract the amine to DCM. the crude product is very clean. no column needed.

FIsher indole synthesis

Condition I used:
40% aquous H2SO4 + toluene
80 C, 4 hr.
phenylhydrazine + 2-methyl-1,3-cyclohexanedione.

2nd generation condition:
1. phenylhydrazine + ketone in EtOH at rt. orange colored hydrazone will be formed in 15 min.
2. remove EtOH invacuo, then add 10%H2SO4 aqueous solution. Turned blue immidiately. heated to reflux for 2-4 hr will decolorize the blue solution. Then simply collect the product by filtration after cooling down.

Oxidation of aldehyde to acid or ester

1. Jones reagent
acidic condition, strong oxidant.

2. I2/MeOH/KOH
forms methylester. mild condition, alkene is untouched.
can't make t-buylester by this way.
tert-aldehyde is more reactive than sec-aldehyde.

3. KMnO4/PH buffer/t-BuOH/water
mild condition, benzyl ether untouched.

4. NaClO2, t-BuOH, PH buffer
mild condition, works for very hindered aldehydes.
t-amlyne used to prevent alkenes from oxidation.

Intermolecular Enolate Heterocoupling

ASAP J. Am. Chem. Soc., ASAP Article, 10.1021/ja804159y
Web Release Date: August 5, 2008
Michael P. DeMartino, Ke Chen, and Phil S. Baran

The direct, convergent synthesis of unsymmetrical 2,3-disubstituted-1,4-dicarbonyl compounds from two carbonyl subunits has proven extremely difficult, several methods for the synthesis of hypothetical succinate 1 are depicted in Figure 2.9,
Efficient, enantioselective syntheses of such entities have escaped synthetic grasp, in spite of their presence in countless natural products and innumerable medicinal remedies. All of the methods depicted suffer from one or more of the following limitations: multistep sequences, installation of requisite disposable functionality on one or both of the monomers, and stereoselectivity problems with prefunctionalization methods and/or during the union of the two monomers. No stereoselectivity was observed or necessary for the most efficient of these methods, the Stetter reaction, as the product was subjected to a pyrrole synthesis. This report is a full account of a research program initiated originally to eliminate the first two of these issues and having since evolved to address the third. By taking advantage of an underutilized and underappreciated reactivity of carbonyl enolates, the oxidative heterocoupling of two enolates joins two different sp3-hybridized carbon centers in a single step without requiring prefunctionalization of the corresponding monomers.

indicator of basicity

Triphenylmethane

The pKa of the hydrogen on the central carbon is around 31. The trityl anion absorbs strongly in the visible region, making it red. This colour can be used as an indicator when maintaining anhydrous conditions with calcium hydride; the hydride reagent reacts with water to form solid calcium hydroxide, while it is also a strong enough base to generate the trityl anion. If the hydride is used up then the solution will turn colourless. The sodium salt can be prepared also from the chloride.

Before the popularization of butyllithium and related strong bases, trityl sodium was often used as a strong, non-nucleophilic base.in the lab, in small scale reaction, triphenylmethane can be used to indicate excess n-Buli or LDA.

titration of n-BuLi

Titration of BuLi (http://www.pushingarrows.com/Lab/page12/page12.html)

- Equipments and reagents needed:
dry isobutyl alcoholanhydrous ether1,10-phenanthroline (indicator)2- or 3-necks 25 ml round bottom flask (with magnetic stirrer bar)dry syringes – 5.0 ml, 2.0 ml, 1.0mlice bath(hexane to wash out needle and syringe contaminated with BuLi)- Procedures:
To a dry* 2- or 3-necks 25 ml round bottom flask with magnetic stirrer bar was added 5.0 ml of anhydrous ether under an inert atmosphere.
A crystal of indicator 1,10-phenanthroline was added and after it dissolved completely, the mixture was cooled to 0°C for about 10 minutes.
The maximum amount of dry isobutyl alcohol that is needed to quench the BuLi could be calculated as follows:

For example, if the previous titration was determined to be 3.1M then 2.0ml of this BuLi solution should contain

3.1M x 2.0ml / 1000ml = 6.2x10-3 mol of BuLi.

Since it takes 1 equivalent of isobutyl alcohol (MW 74.12; density 0.803 g/ml) to quench the BuLi, therefore

6.2x10-3 mol x 72.14g/mol / 0.803 g/ml = 0.57 ml of isobutyl alcohol was potentially needed.

2.0ml of BuLi solution was then added under an inert atmosphere and it was titrated by slow addition of approx. 1.0ml of dry isobutyl alcohol.

The colour change should be very apparent.

n-BuLi : orange-brown to bright yellow
t-BuLi : purple to bright yellow
Using the amount of isobutyl alcohol added (initial volume – final volume), the molarity of the BuLi solution can be calculated as follows:

For example, if 0.41 ml of isobutyl alcohol was used,

0.41 ml x 0.803 g/ml / 74.12 g/mol = 4.44x10-3 mol of isobutyl alcohol was used = 4.44x10-3 mol of BuLi present

The strength of the BuLi solution is therefore

4.44x10-3 mol / (2.0 ml / 1000ml) = 2.22M
(2.22M vs 3.1M makes a big difference!)
* oven dried then cooled under a stream of inert gas, or flame dried under reduced pressure then cooled under a stream of inert gas.

Reductive Decyanation

1. naphthalene/Li
liminted to nitriles which have a adjacent electron-withdrawing group.

2. LiDBB/THF
more reactive than LN.
1. addition of nitrile into LiDBB THF solution at -78C. reverse addition gave side products.
2. when making lidbb, n-BuLi was used to remove trace of water, otherwise, the concentration of lidbb is low.

who is doing this ?
Professor Scott D. Rychnovsky

Ketone to ketal

Ketal is sensitive to acid but very stable to base or radical.

forming
1. 1,2 diol or 1,3 diol, DCM(or meoh), p-TsOH hydrate(or ppts), trimethyl(or triethyl) orthoformate, rt.

Note:
1. 2,2-dimethyl -1,3-diol is more reactive than ethylene glycol, because ketal so formed is more stable. On my congested aldehyde, ethylene glycol failed , but 2,2-dimethyl1,3-diol succeed.
2. you can premix p-TsOH, trimethylorthoformate and 2,2-dimethyl-1,3-diol to form a stable compound. Then isolate this compound and add your aldehyde or ketone. In this procedure, "only a small amount of acid is needed to complete the reaction". cited from a JOC paper. 1993, 5479.

2. diol, toluene or benzene, p-TsOH, Dean-Stark to remove water.
high temp.

removal
acid. equilibrium reaction.

aldehyde to terminal alkyne

1. OhiraReagent and derivatives
diazoketophosphonium ester.

2. Corey-Fuchs Reaction
tetrabromomethane/pph3, then base.
or
trichloroacetic acid /base

Tandem Semipinacol/Schmidt Reaction

Org. Lett., 8 (23), 5271 -5273, 2006.





A TiCl₄-promoted tandem semipinacol/Aube's type intramolecular Schmidt reaction of -siloxy-epoxy-azide has been designed and developed to be a general method for efficient construction of azaquaternary carbon units. As applicable examples, some key tricyclic azaquaternary skeletons incorporated in many important alkaloids, such as cephalotaxine, stemonamine, erythrinan, and homoerythrinan alkaloids, have been constructed.

Epoxide-Initiated Electrophilic Cyclization of Azides

Org. Lett., 5 (4), 583 -585, 2003.

Cation-induced cyclization is one of the most powerful techniques used in the synthesis of polycyclic frameworks.¹ With the advent of more efficient cation terminators, the importance of the epoxide-initiated electrophilic cyclization in the stereoselective synthesis of natural products is expanding rapidly.² In recent years, azide has gained remarkable attention as a cation terminator, since the subsequent skeletal rearrangement (Schmidt reaction) after cyclization offers a novel approach to azabicyclic ring systems.^3,4 Acid-mediated inter- and intramolecular Schmidt reaction of azidoalkenes³ and azidoketones⁴ has been extensively studied; however, the synthetic potential of the corresponding epoxide-initiated Schmidt reaction is yet to be explored.

The azabicyclic ring skeleton is an important structural subunit present in numerous biologically active natural products.⁵ In this family, indolizidine alkaloids are the most important class of compounds, known for their wide range of pharmaceutical applications (Scheme 1).⁶ Herein, for the first time, we report a general and highly diastereoselective approach for the construction of 5-hydroxymethyl azabicyclic compounds and its application in the synthesis of indolizidine alkaloids based on epoxide-initiated electrophilic cyclization of azides.

Oxidation of organoboranes

1. H2O2

2. trimethylamine N-oxide
3. sodium perborate
4. sodium percarbonate
5. pcc
6. NMO-TPAP
7. Molybdenum peroxide.

preparation of LN (lithium naphthalenide)

Tetrehedron P370, year ??
0.66 m solution:
Li 0.82 g, naphthalene 16.6 g, THF 180 mL.
Ar protected.
rt. stirred for 1 day.
dark blue solution.
stored in fridge.

A novel synthesis of silyl enol ethers from a-silylbenzylthiols and carboxylic acid derivatives via C---C bond formation

Tetrahedron Letters
Volume 42, Issue 52, 24 December 2001, Pages 9221-9223

A new procedure for the synthesis of silyl enol ethers from S--silylbenzyl thioesters without need for either bases or catalysts via C---C bond formation is described. Solutions of S--silylbenzyl thioesters were simply heated at 180°C for 24 h in a sealed tube to give silyl enol ethers in good yields with high stereoselectivity. Cyclization of the dipoles generated by thermal rearrangement of the silyl group and elimination of sulfur afforded silyl enol ethers.

The method represents a new preparative method of silyl enol ethers under completely neutral conditions with no need for any catalyst or additives.

LDBBA, a new and efficient reducing agent for the conversion of esters to aldehydes

Lithium diisobutyl-t-butoxyaluminum hydride (LDBBA), easily prepared by reaction of lithium t-butoxide with DIBALH, readily reacts with common aromatic and aliphatic esters to give the corresponding aldehydes in 74–88% yield at 0 °C. Especially, this reagent proved to be the most effective partial reducing agent for conversion of isopropyl esters to aldehydes, in most cases, with >90% yield under the same reaction temperature.

Ruthenium-Catalyzed [2 + 2 + 2] Cocyclization of Diene-yne

J. Am. Chem. Soc., 129 (25), 7730 -7731, 2007.

Transition metal-catalyzed cyclizations are useful methods for the synthesis of carbo- and heterocycles.¹ Among them, [2 + 2 + 2] cocyclization is a unique and an atom-economical method. It has been shown that [2 + 2 + 2] cocyclization of ,-diyne and an alkyne or intramolecular cocyclization of triyne using a cobalt, rhodium, iridium, or ruthenium complex is a useful method for the synthesis of benzene derivatives.² However, there are a few reports of [2 + 2 + 2] cocyclization of enyne and an alkene or intramolecular reaction of diene-yne.
Publish Post

Heck Coupling with Nonactivated Alkenyl Tosylates and Phosphates

Angewandte Chemie International Edition Volume 45, Issue 20, Pages 3349-3353

Considerable efforts have been undertaken by numerous groups in academia and industry over the past decade to expand the repertoire of coupling reagents in palladium(0)-catalyzed cross-coupling reactions.[1] In particular, alkenyl phosphates and tosylates have proven their worth in various cross-coupling reactions, such as the Stille,[2] Suzuki,[2e],[f], [3] Negishi,[2b] Kumada,[2b], [3e], [4] Sonogashira,[2b],[e],[f], [5] Buchwald-Hartwig,[4a], [6] carbonyl enolate,[3d] and Heck couplings,[7] as effective alternatives to the less stable and typically more expensive alkenyl triflates and nonaflates.[8] However, the majority of this work has focused on the use of activated vinyl phosphates and tosylates, such as ,-unsaturated systems or -heteroatom-substituted alkenes, for which the oxidative-addition step is nonproblematic with palladium(0) catalysts bearing aryl phosphine ligands. Less attention has been devoted to nonactivated counterparts, most likely because of the greater difficulty in carrying out the first step of the catalytic cycle, namely the oxidative addition.[3d], [4], [5], [9]

We now report on catalyst systems composed of a palladium complex with a basic, hindered alkyl phosphine that can promote the Heck coupling of nonactivated vinyl tosylates and phosphates with electron-deficient alkenes in good yields, thereby increasing the scope of this important cross-coupling reaction. Furthermore, during these studies we observed an interesting 1,2-isomerization with certain alkenyl tosylates and phosphates under reaction conditions that provide coupling yields as high as 95 %

Iridium-Catalyzed Enantioselective Synthesis of Allylic Alcohols

Angewandte Chemie International Edition, 45, Issue 37, Pages 6204-6207

The development of efficient processes that give rapid and easy access to optically active building blocks is of great importance, particularly for the synthesis of complex molecules. The metal-catalyzed asymmetric allylic substitution reaction, which involves the addition of a range of diverse nucleophiles to an allylmetal intermediate, is one of the most studied processes.[1] The use of Ir complexes in this transformation provides access to products that are complementary to those obtained from Pd catalysis.[2], [3] The types of nucleophiles that have been employed in Ir-catalyzed processes have included enolates derived from malonates, but recently other nucleophiles such as amines, phenols, and alkoxides have been used.[4]-[6] Omitted from this list is the use of hydroxide, or its equivalent, to give the corresponding product with a free alcohol. Herein, we describe the first example of an iridium-catalyzed enantioselective allylation involving the use of silanolates as nucleophiles, which allows convenient access to chiral allylic alcohols, useful building blocks in asymmetric synthesis [Eq. (1)]. The isolated products are formed in useful yields and 92-99 % ee.

Direct preparation of copper organometallics bearing an aldehyde function

• Chem. Commun., 2006, 2486-2488
• DOI: 10.1039/b604259g

Polyfunctionalized organometallics are versatile intermediates in modern organic chemistry, since they allow the formation of multifunctional products.¹ One of the best preparation methods of these organometallic reagents is the halogen–metal exchange reaction.^1e,2 The halogen–magnesium³ and halogen–copper⁴ exchanges have recently been extensively investigated. They allow the convenient preparation of polyfunctional aryl, heteroaryl and alkenyl organometallic reagents that bear various functional groups. The formyl group is present in numerous compounds, but has been regarded as being incompatible with most organometallic reagents.⁵ Only scarce examples of formyl-substituted aryl organometallic compounds have been reported.⁶ In most cases, tedious protection and deprotection steps or an additional oxidation step are required to introduce this sensitive function in a target molecule.

Iodine–copper exchange reaction allows the direct preparation of various new aryl, heteroaryl and alkenyl cuprates bearing an aldehyde group, thus expanding the applications of functionalized copper organometallic species in organic synthesis.

The First Negishi Cross-Coupling Reaction of Two Alkyl Centers

Org. Lett., 7 (17), 3805 -3807, 2005.

Palladium-catalyzed cross-coupling reactions of unsaturated organohalides and sulfonates with organometallic reagents are well established and powerful methods for construction of carbon-carbon bonds.¹ While coupling of alkyl organometallic reagents has been known for some time, the use of unactivated alkyl chlorides, bromides, or tosylates as coupling partners posed a greater challenge,² isolated early examples notwithstanding.³ Until recently, there was no general and efficient catalytic protocol for alkyl-alkyl cross-coupling reactions.

Previous work by Fu and co-workers demonstrated that Pd(PR₃)₂ (R = cyclohexyl, cyclopentyl) is an effective catalyst for Negishi⁴ and Suzuki⁵ cross-couplings of primary alkyl halides (Cl, Br, I) and tosylates. Kambe and co-workers disclosed Pd-1,3-diene catalysts for Kumada couplings of unactivated alkyl halides (Cl, Br) and tosylates.⁶ In addition, catalysts based on Ni^6,7 or other transition metals (Fe, Cu)^3,8 have been used successfully in alkyl-alkyl cross-coupling protocols.

The main problems when attempting to couple haloalkanes are the reluctance of saturated carbon-halogen bonds to undergo oxidative addition^2b compared to aryl, vinyl, or allyl halides and competing -H elimination from the oxidative addition intermediate, which results in unwanted alkene formation.

Further, this is also the first reported room-temperature palladium-catalyzed Negishi alkyl-alkyl coupling reaction.

Acyclic Diastereocontrol and Asymmetric Transmission via Anionic Oxy-Cope Rearrangement

JOC, 1991.5973.

The anionic oxy-Cope rearrangement is widely utilized
as a versatile class of bond reorganization in synthesis.'
In the context of acyclic stereocontrol, however, the acyclic
oxy-Cope methodology still occupies a much lower position
than that of its Claisen counterpart? although several
oxy-Cope rearrangements of rigid, cyclic substrates have
been reported to provide high levels of stereo~ontrol.'~~
The key stereochemical issue inherent in the acyclic oxy-
Cope process is associated with the oxyanion orientation
(axial vs equatorial) in the chairlike transition states.
Related studies4 have shown that the oxyanion stereochemistry
in acyclic systems cannot be effectively controlled
unless other steric demand(s) such as favorable
Ir-facial selectivity is imposed on the pericyclic array. We
now disclose that the acyclic oxy-Cope rearrangement,
when the proper substrate stereochemistry is generated
by the [2,3]Wittig rearrangement: provides a synthetically
useful level of diastereoselection and asymmetric transmission
(Scheme I).

Bisoxazoline ligands

http://en.wikipedia.org/wiki/Bisoxazoline_ligand

very good article about this kind of popular ligands.

Some online resources

1. Evan's group seminar pdf
http://www2.lsdiv.harvard.edu/labs/evans/cgi-bin/seminar.cgi

2. Hans J. Reich 's chem547 handouts
http://www.chem.wisc.edu/areas/reich/chem547/

3. myers chem115 handouts
http://www.chem.harvard.edu/groups/myers/chemistry115handouts.htm

4. Dr. Rovias link
http://www.chem.colostate.edu/rovis/links.html

5.William Reusch the Virtual Textbook of Organic Chemistry
http://www.cem.msu.edu/~reusch/VirtualText/intro1.htm

Direct Condensation of Carboxylic Acids with Alcohols Catalyzed by Hafnium(IV) Salts

Science 10 November 2000:
Vol. 290. no. 5494, pp. 1140 - 1142

The replacement of current chemical processing with more environmentally benign alternatives is an increasingly attractive subject (1). Esterification is one of the most fundamental and important reactions in organic synthesis [(2), and references cited therein]. Although several methods have been explored and developed [(2), and references cited therein], the use of large amounts of condensing reagents and activators should be avoided in order to promote green chemistry and atom efficiency. The direct condensation of carboxylic acids with alcohols using small amounts of catalysts is the most ideal method, but in most cases, large excess amounts of either carboxylic acids or alcohols are used in this condensation to give esters in high yield (3-18). We describe highly efficient and direct ester condensation with equimolar amounts of carboxylic acids and alcohols catalyzed by hafnium(IV) chloride and alkoxides (19-21).

Meerwein–Ponndorf–Verley alkynylation of aldehydes

Org. Biomol. Chem., 2004, 2, 3312 - 3319,

In 1925 Meerwein1 and Verley2 independently reported the reduction of aldehydes with primary alcohols in the presence of aluminium ethoxide, and in the next year Ponndorf3
extended the scope to the reduction of ketones using second-ary alcohols and their aluminium alkoxides, particularly aluminium isopropoxide (Al(OPri)3). This type of reaction, i.e., Meerwein–Ponndorf–Verley (MPV) reduction is believed to proceed via a six-membered transition state [A] and can be performed under mild conditions both in the laboratory and on a large scale without sophisticated experimental technique, generally exhibiting high chemoselectivity (Scheme 1).4
Accordingly, numerous studies have been carried out to expand the inherent potential of this classical yet important organic transformation as exemplified by the recent elaborations of
lanthanides and transition metal catalysts as well as modified aluminium alkoxides.5,6 During our continuous effort toward the development of new MPV reduction systems, we have been
interested for some time in the possibility of alkyl transfer through the MPV process, which should provide a practical, nonorganometallic way for carbonyl alkylation.7–9 However, developing the MPV alkylation seemed to be a great challenge because of the inertness of alkyl transfer [B] compared to the facile hydride transfer [A] in the MPV reduction.

The MPV reduction was largely supplanted in the late 1950s by methods utilizing boro and aluminum hydrides

enantioselective reduciton of ketones by thichlorosilane

Org. Lett., 8 (17), 3789 -3792, 2006

Enantioselective reduction of ketones has been one of central topics in asymmetric synthesis over the past two decades.¹ Although a variety of reducing reagents have been used for the purpose,² there have been few studies on the use of trichlorosilane (Cl₃SiH),³ which is an economical and easy to handle reagent.⁴⁵ Because Cl₃SiH does not have the ability to reduce ketones by itself, appropriate activators are necessary for the reduction of ketones by Cl₃SiH with high efficiency. Organic chiral activators are in particular of interest in this respect because they provide a route for asymmetric reduction of ketones. We have reported a first enantioselective reduction of ketones by Cl₃SiH using chiral N-formylpyrrolidines (1q,r) as organic activators (up to 43% ee),⁴ and recently isoquinolinyloxazoline (2) was reported to work well as a chiral activator (up to 94% ee).⁶⁷

beta-alkylation of alcohols by Cp*Ir complex

Org. Lett., 7 (18), 4017 -4019, 2005.

very efficient coupling rxn.

Alcohols are one of the most basic and important classes of organic compounds because they have a wide variety of uses in industrial and laboratory chemistry. Although a huge number of methods for the synthesis of alcohols are known,¹² the synthesis of a variety of alcohols having intricate structures through alkylation of simple alcohols usually requires tedious processes using many reagents. For example, -alkylation of a secondary alcohol can usually be accomplished via three-step transformations (oxidation,³ alkylation,⁴ and reduction^2,5)

C-C bond forming by Si-C cleavage

J. Org. Chem., 61 (20), 6901 -6905

Carbon-carbon bond formation is often considered the most difficult challenge in synthetic organic chemistry, and new or improved solutions to carbon-carbon bond-forming reactions are continuously being sought. One of the most useful categories of reagents for this purpose is the organometallic carbon nucleophiles, including organolithium, organomagnesium, and organocopper compounds.¹ Unfortunately, these reagents do have limitations. Since they are extremely strong bases as well as potent nucleophiles, their use with base sensitive substrates is precluded. Organolithium and -magnesium reagents are incompatible with halo, nitro, and cyano functionalities. Finally, benzylic and allylic organometallics are notoriously difficult to generate and prone to homocoupling.¹

An alternative methodology that circumvents these limitations is the generation of stabilized carbanions or carbanoids by cleavage of silicon-carbon bonds using fluoride anion.² The most commonly used fluoride source for this purpose is tetrabutylammonium fluoride (TBAF). The superiority of tetrabutylammonium triphenyldifluorosilicate (TBAT) to TBAF as a fluoride source for nucleophilic fluorination³ is described.

Alkylation to Ketones with Grignard Catalyzed by Zinc(II) Chloride

J. Am. Chem. Soc., 128 (31), 9998 -9999, 2006.

For carbon-carbon bond-forming reactions, the addition of organometal reagents to ketones is a versatile method for synthesizing tertiary alcohols.^1,2 However, Grignard and alkyllithium reagents for ketones give the desired adducts along with (1) competitive reduction products due to the -hydride transfer of alkyl groups and (2) aldol adducts due to enolization by their strong basicity (eq 1).³ Recently, the addition of stoichiometric or an excess amount of CeCl₃,³ LiCl,⁴ LiClO₄,⁵ FeCl₂,⁶ and LnCl₃·2LiCl⁷ with Grignard reagents has shown good results with smooth alkylations and minimum side products. These additive effects were based on either a stoichiometric Lewis acid activation of carbonyl compounds or enhancement of the nucleophilicity of stoichiometric alkylation reagents (e.g., RCeCl₂, RMgCl₂·Li, etc.), which were prepared in situ from oligomeric Grignard reagents by binary metal complexations or transmetalations. While somewhat expensive LnCl₃ (Ln = La, Ce) salts have been the best alternatives to date, these stoichiometric compounds must be synthesized prior to use.^3,7 In our previous research, trialkylmagnesium(II) ate complexes, as good alkylation reagents with weak basicity, namely, R₃MgLi, which can be easily prepared from Grignard reagents (RMgX) and alkyllithiums (RLi) in situ,⁸ have improved the efficiency of alkylation to ketones (eq 1).⁹

However, in that case, more than equimolar amounts of expensive RLi (1-2 equiv) were indispensable. To overcome these problems, we report here the highly efficient alkylation to ketones and aldimines with Grignard reagents in the presence of catalytic trialkylzinc(II) ate complexes (R₃ZnMgCl) derived from ZnCl₂ in situ. The catalytic use of simple and inexpensive ZnCl₂ without further purification, instead of above stoichiometric additives, would offer significant advantage over the existing technologies.

Synthesis of Silyl Enol Ethers by Mg/TMSCl

Tetrahedron Letters 40 (1999) 1349-1352

Synthetic utility and importance of silyl enol ethers have been well established [1-2]. The
numerous methods for their preparation have been reported [3-14] although some difficulties
have been encountered in the actual preparation, especially in the large-scale production,
owing to requirement of troublesome procedure, low temperature such as -78"C, special
equipment, carcinogenic solvent and/or expensive reagents.

In this study, we wish to present novel Mg-promoted coupling of aliphatic carbonyl
compounds with trimethylsilyl chloride (TMSCI) at room temperature to give the
corresponding silyl enol ethers in excellent to good yields. This
reaction may provide a highly convenient method for the stereoselective preparation of (Z)-isomers.

ref.
[ll Brownbridge P., Synthesis, 1983, 1 and 85.
[2] Reefs yon M.T., Angew. Chem., 94, 97 (1982).
[3] Colvin E.W., Silicon in Organic Synthesis, Butterworths, London, 1981.
[4] Pawkinko S., Organo Silicon Chemistry, Walter de Gruyter, Berlin, 1986.
[5] Weber W.P., Silicon Reagents for Organic Synthesis, Spring-Verlag, Berlin, 1983.
]6] Negishi E., Organometallics in Organic Synthesis, John Wiley & Sons, New York, Vol.l, Chap. 6, 1980.
[7] Bonafoux D., Bordeau M., Biran C., Cazeau P., and Dunogues J., J. Org. Chem., 6 1,5532 (1996).
[81 Bunafoux D., Bordeau M., Biran C., and Dunogues J., J. Organomet. Chem., 4 9 3, 27 (1995).
[9] Davis F.A., Sheppard A.C, Chen B.C., and Haque M., J. Am. Chem. Soc., I 12,6679 (1990).
[10] Takai K., Kataoka Y., Okazoe T.,and Utlmoto K., Tetrahedron Left., 29, 1065 (1988).
[ I 1
] Davis F.A., Lal G.S., and Wei J., Tertahedron Left., 2 9, 4269 (1988).
[12] Dedier J., Gerval P., and Frainnet E., J. Organomet. Chem., lS$, 183 (1980).
[13] House ]t.O., Czuba L.J., Gall M.,and Olmstead H.D., J. Org. Chem., 34, 2324 (1969).
[14] Cazeau P., Duboudin F., Moulines F., Babot O., Dunogues J., Tetrahedron., 43, 2075 (1987).
[15] Ishino Y., Maekawa It., Takeuchi H., Sukata K., and Nishiguchi I., Chem. Lett., 1995, 829.

LAH explosions

Accidents happen without sign. really?

1. LAH explosion.
years ago when we still have LAH pellets in the lab, you have to powder it to use.
One day I was puhching it in an open container. Suddenly there was an explosion. Not a big one, but really scaring. Hopfully there was only 1 pellet of LAH. only the powder of LAH cautht on fire, the pellet was still intact.

2. another LAH story.
when I quench a LAH reduction(big scale), water was first used. You are supposed to add water slowly. But how slow? I don't konw. One day, addition of water was a little quicker , but still under control, I thought. Then suddenly, boom... liquid in the bottle jumped out. Hopfully, there was no stopper on the neck and I was not touched. What happened? the water added was coated by LAH, when the stirring is not quick enough to break the water drop, it will explode.

How to open a lactone?

1. MeOH/MeONa
forms methylester and free alcohol.

2. KOH/MeOH water
free acid and free alcohol.

Nitrile to acid

hydrolysis of nitrile is very sensitive to the hinderance around the nitrile.

1. KOH in MeOH/water.
140C
2. KOH in ethylene glycol. or diethylene glycol.
200C or 250C.
3. KOH/H2O2/water/EtOH
100C, more reactive toward hindered nitrile.

4. HCl or H2SO4 in water or MeOH
strong acid needed. not compatible with ether, alkene.

5. DIBAlH then oxidation.
6. o-phthalic anhydride.
7. Microwave/ phthalic acid.
8. reductive removal of the nitrile by LidBB or LN, then trap the anion by CO2.

allylic oxidation

1. MnO2/DCM.rt
can selectively oxidize allylic alcohols with primary alcohols untouched.

2. SeO2
selectively oxidize allylic H to alcohol.
1. 95% EtOH, reflux
2. DCM, t-BuOOH
3. 1,4-dioxane, t-BuOOH.
4. xylene(toluene), reflux
Acid is known to accelerate the rxn rate.

How do you prepare nmr shifts for publication?

Found a new software which can format the peaks/integration/J coupling for you.
acd/1d nmr assistant.

you only need to assign the desired peaks, sometimes the integration, j constant will be calculated automatically.
example output:
¹H NMR (CHLOROFORM-d) d ppm 0.58 (3 H, d, J=7.0 Hz), 0.88 (9 H, m), 0.95 (11 H, m), 1.05 (6 H, m), 1.28 (6 H, m), 1.46 (2 H, m), 1.83 (9 H, m), 2.19 (6 H, m), 2.44 (2 H, m), 3.04 (1 H, d, J=9.0 Hz), 3.13 (1 H, m), 3.80 (1 H, d, J=5.1 Hz), 7.28 (15 H, m), 7.42 (9 H, m)

READY for publication!!!!!!!!!!!!!!!!!!

For carbon nmr, you can also get a peak list:
example output:
(ppm)
20.0
25.1
28.2
31.2
32.4
33.7
52.7
58.2
61.1
67.0
87.4
117.6
143.4
174.9


added (7-2009)
both mestrec and mestrenova have the function of generating decent NMR formatted report for acs or wiley.

what PCC can do?

R. A. Fernandes, P. Kumar / Tetrahedron Letters 44 (2003) 1275–1278


Before the studies of Corey and co-workers,1 the reactivity of PCC had been little investigated. PCC is well known to convert alcohols into aldehydes or ketones with high efficiency.2a This reagent also converts tertiary cyclopropyl carbinols into the corresponding , -unsaturated ketones,2b 1,4-dienes into dienones,2c,d hydroquinone silyl ethers into quinones,2e enol ethers toesters and lactones2f and oximes to ketones.2g Other known important conversions using this reagent are: (i)furan rings undergo oxidative ring expansion,3a (ii) 5-3 -tetrahydropyranyl ethers are oxidized to the corresponding carbonyl 4-3,6-diones,3b (iii) olefins are oxidized to carbonyl compounds via the oxidation of organoboranes.3c–g Furthermore, PCC is well known
for selective oxidation of steroidal allylic alcohols,4a oxidative cleavage of aryl substituted olefins,4b specific oxidative cleavage of allylic and benzylic ethers,4c oxidation of benzylic4d and active methylene compounds,4e oxidative cleavage of 1,4-dioxenyl carbinols to - hydroxy acids and -ketoacids,4f one-pot oxidation of glycals to lactams,4g cleavage of vicinal diols4h and modified oxidation of aldehydes to carbamoyl azides/ acyl azides or carboxylic acids.4i Thus, the varied and numerous oxidative reactions of PCC makes it a versatile oxidant in organic synthesis.5


references;
1. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647–2650.
2. (a) Augustine, R. L. Oxidation; Marcel Dekker: New York, 1969; Vol. 1; (b) Wada, E.; Okawara, M.; Nakai, T. J. Org. Chem. 1979, 44, 2952–2954; (c) Wender, P. A.;
Eissenstat, M. A.; Filosa, M. P. J. Am. Chem. Soc. 1979, 101, 2196–2198; (d) Marshall, J. A.; Wuts, P. G. M. J. Org. Chem. 1977, 42, 1794–1798; (e) Willis, J. P.; Gogins, K. A. Z.; Miller, L. L. J. Org. Chem. 1981, 46, 3215–3218; (f) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron
Lett. 1977, 18, 3483–3484; (g) Maloney, J. R.; Lyle, R. E. Synthesis 1978, 212–213.
3. (a) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron Lett. 1977, 18, 2199–2200; (b) Parish, E. J.; Kizito, S. A.; Heidepriem, R. W. Synth. Commun. 1993, 23, 223–230; (c) Ramana Rao, V. V.; Devaprabhakara, D.; Chandrasekaran, S. J. Organomet. Chem. 1978, 162, C9–C10;
(d) Rao, C. G.; Kulkarni, S. U.; Brown, H. C. J. Organomet. Chem. 1979, 172, C20–C22; (e) Brown, H. C.; Kulkarni, S. U.; Rao, C. G. Synthesis 1980, 151–153; (f) Brown, H. C.; Kulkarni, S. U.; Rao, C. G. Synthesis 1979, 702–704; (g) Brown, H. C.; Rao, C. G.; Kulkarni, S. U.
Synthesis 1979, 704–705.
4. (a) Parish, E. J.; Schroepfer, G. J., Jr. Chem. Phys. Lipids 1980, 27, 281–288; (b) Narasimhan, V.; Rathore, R.; Chandrasekaran, S. Synth. Commun. 1985, 15, 769–774; (c) Cossy, J.; Bouzbouz, S.; Lachgar, M.; Hakiki, A.; Tabyaoui, B. Tetrahedron Lett. 1998, 39, 2561–2594; (d)
Rathore, R.; Saxena, N.; Chandrasekaran, S. Synth. Commun. 1986, 16, 1493–1498; (e) Bonadies, F.; Bonini, C. Synth. Commun. 1988, 18, 1573–1580; (f) Fetizon, M.; Goulaouic, P.; Hanna, I. Tetrahedron Lett. 1988, 29, 6261– 6264; (g) Rollin, P.; Sinay, P. Carbohydr. Res. 1981, 98, 139–142; (h) Cisneros, A.; Fernandez, S.; Hernandez, J. E. Synth. Commun. 1982, 12, 833–838; (i) Reddy, P. S.; Yadagiri, P.; Lumin, S.; Shin, D.-S.; Falck, J. R. Synth.
Commun. 1988, 18, 545–551.
5. Piancatelli, G.; Scettri, A.; D’ Auria, M. Synthesis 1982, 245–258.

reduction of ester to methane

1. LAH reduce ester to alcohol.

Then
1. two electron reduction
MsCl/TEA converts the alcohol to a leaving group. Then LAH or NaBH4/high temp will remove the MsO.
note: a more gentle condition: NaBH4/t-BuOH/DME refluxing temp will not touch nitrile.

2. One electron reduction
xanthate then aibn.
note: usually selectivity between sec-OH and tert-OH is good.

Hydrogenation of double bond

1. heterogeneous metal catalyst.

1. pd/c is better than pt. because it won't hydrogenate aromatic rings.
2. Benzyl ether and trityl ether can be kept by addition of nitrogen containing base (Py, TEA, ...), the selectivity is very good.
3. Benzyl ether reduced quicker in THF than in MeOH.
3. Ir black gives better facial selectivity than Pd/c, PtO2.
4. hydrogenation in polar solvents is quicker. AcOH>MeOH>EtOH>THF. But facial selectivity is worse.
5. trace of water can activate the metal surface. Good for both hydrogenation and benzyl removal.

2. homogeneous catalysts
wilkinson's catalyst, facial selectivity is bad.

3. hydrazine reduction.
active NH=NH generated by heating tosylhydrazine with base.
very useful when a gental touch is desired.
can reduce triple bond to double bond.

preparation of Dess Martin reagent

recently made about 50 g of it.
here is the detail.

1. oxone 2 eq. and 2-iodobenzylacid? 1 eq. mixed together with deionized water.
stirred at 70-73C for about 4 hr. during the stirring, the insoluable iodoacid will get into the water solution. Finally a nearly clear solution will be seen with some precipitation on the bottom. good stirring is necessary.

2. cool the temp down to 0-5C for 2hr, filter out the white precipitation. wash with acetone.
The ibx is potencially explosive, it is stable at rt and should be dried at rt and 1 atm.

3. pour in Ac2O and catalytic amount of psOH-H2O solid. heated to 80C for 3 hr, a clear solution resulted. cooled it down to 0-5 C, then liquid filtered. washed with ether.
also explosive, dried in vacuo briefly.
stored in freezer.

reduction of nitrile

DibalH.
reduce nitrile to aldehyde imine or amine.

LAH can also reduce the nitrile to imine . usually, low yielding.

alkene to alkyne

1. dibromination.
DCM. 0 C or -78C if you have bromine sensitive group( for example: benzyl ether)

2. 2 eq. Base.
strong base is needed.
LDA or KHMDS.
n-BuLi is not good.


note: if you have a heteroatom ( oxygen ) alpha to you dibromide, you can use weaker base to make it into alkyne (DBU)

What data you need to publish a new compound?

The following is what I did to characterize organic compounds for ACS publication.

Unknown compounds.
1. TLC Rf.
2. melting point ( for solid)
3. IR (5 or 6 typical peaks)
4. NMR (proton and jvert)
5. high resolution MS.
6. alpha D ( for optical pure compound)

known compounds
1. tlc
2. mp.
3. nmr.
4. alpha D.

How to put both 1H and 13C nmr into one page?

in topspin.
1. bring up your 1H nmr.
2. "edc2" to setup up your 13C nmr.
3. open xwinplot.
4. set up the proton layout. then add a new spectra, choose the data set to your 13C nmr.
5. print.

How to insert NMR spectra into word.

software: topspin(unix), microsoft word( windows).
use xwinplot to setup the layout, then
"print as file" the spectra as *.png file. (jpg is bigger sized, pdf can't be inserted into word)
then transfer the png file into windows., you can directly insert pic from file into word.
the spectra made this way is very clear (600 dpi),
and very small size (~50k each page).

purification of mcpba

commercial mcpba contains ~77% mcpba. the rests are acids and water.
To get a 99% mcpba:

Purification of MCPBA
35 g MCPBA (Aldrich 57–86%) was dissolved in 250 ml ether
and washed with 3×150 ml buffer solution (410 ml 0.1 M
NaOH, 250 ml 0.2 M KH2PO4 made up to 1 l, pH 7.5).
The ether layer was dried over MgSO4 and carefully evapor-
ated under reduced pressure to give ca. 17 g pure MCPBA
(CAUTION! potential explosive).

reference:
J. Chem. Soc., Perkin Trans. 1, 1998 2771

one carbon elongation

1. aldehyde to aldehyde
step 1. aldehyde + PPh3Cl-CH2OMe/t-BuOK
step 2. Formic acid.

Wiki is a good source of infomation:

Examples of homologation reactions include:

• Seyferth-Gilbert homologation
• Displacement of a halide by a cyanide group, which can be reduced to an amine, see: Kolbe nitrile synthesis
• Kiliani-Fischer synthesis, where an aldose molecule is elongated through a three-step process consisting of:
  1. Nucleophillic addition of cyanide to the carbonyl to form a cyanohydrin
  2. Hydrolysis to form a lactone
  3. Reduction to form the homologous aldose
• Wittig reaction of an aldehyde with methoxymethylenetriphenylphosphine, which produces a homologous aldehyde.
• Arndt-Eistert synthesis is a series of chemical reactions designed to convert a carboxylic acid to a higher carboxylic acid homologue (ie. contains one additional carbon atom)
• Kowalski ester homologation, an alternative to the Arndt-Eistert synthesis. Has been used to convert β-amino esters from α-amino esters through an ynolate intermediate.^[2]

Some reactions increase the chain length by more than one unit. For example, the following are considered two-carbon homologation reactions:

• Nucleophilic addition to ethylene oxide, resulting in a ring-opening and producing a primary alcohol with two extra carbons.
• Malonic ester synthesis, which produces a carboxylic acid with two extra carbons.

Catalytic Activation of the Leaving Group in the SN2 Reaction

Org. Lett., 9 (20), 4029 -4032
Hirofumi Yamamoto, Ghanshyam Pandey, Yumiko Asai, Mayo Nakano, Atsushi Kinoshita, Kosuke Namba, Hiroshi Imagawa, and Mugio Nishizawa

They had very good idea here.







the mechanism proposed:

Making of Cu(acac)2, Ni(acac)2.

2 eq. of acetylacetone + 2eq. of NaOMe in MeOH
then CuCl2 2H2O 1eq. in MeOH added slowly at rt.
color changed immediately from green to blue when you add CuCl2 into the solution.
1hr, then concentrated. DCM added to dissolve cu(acac)2. fitered. then concentrated.
Can be recrystallized in MeOH/DCM.

the blue solid can dissolve in DCM, chloroform. can't dissolve in water, very limited solubility in MeOH.
H-NMR is a crab. you can't see any sharp peaks. only a broad peak at about 1 ppm.
IR can be used to characterized it.
Ni(acac)2 can be made similarly.

General ways to make a methyl ester.

1. MeI/base

2. MeOH/H+

3.CH2N2 or TMSCHN2.
diazomethane is more reactive and smaller than tmsdiazomethane.
sometimes, tmsdiazomethane gave side products, while diazomethane gave clean product.

making of beta ketoester.

from aldehyde:
1. diazo ethylacetate + Tin (II) chloride.
2. beta-OH ester by enolate attack, then oxidize the beta-OH to ketone.
3. three carbon homologation. ex. the aldehyde attacked by deprotonated 3-Nitroproponic methyl ester, then dehydration of the alcohol to alkene , you get beta alkene beta-NO2 ester. Then replace NO2 group to -OH by radical procedure. you get beta-ketoester.

from ketone:
dimethyl carbonate +NaH/toluene or THF. reflux

from alpha,beta unsaturated ester
Na2PdCl4, t-BuOOH

triethylsilane ether

formation:
1. TESCl/base
converts free alcohol to TES ether.

2. triethylsilane/(C6F5)3B
converts benzylether or methylether etc. to TES ether.

removal
TBAF.

t-butyldimethylsilane ether

Formation:
tbdmsCl/TEA/DMF, 4-dmap, rt.
primary alcohol protected selectively.

under acid condition (trace h2so4 in mecn, 50C) the silane ether can fall off.

deprotection:
TBAF.

unsaturated ketone/ester to beta-ketoester/ketone

Na2pdCl4/t-BuOOH. t-BuOH/AcOH/water
temp: 55C.

converts unsaturated ester/ketone into betaketoester/ketone.

aliphatic acid to methylester without touching aromatic acid

TMSCl, MeOH, 2,2-dimethoxypropane.
aliphatic acid can be converted to methylester in high yield.
aromatic acid remains.

THP ether protective group

Tetrahydrohydropyranyl (THP) ether
is not a leaving group. stable under basic conditions.
can't eliminate even bata to Grigyard anion.

Formation:
catalytic amount of con. HCl + alcohol + 3,4-dihydro-2H-pyran
no solvent. 0 C to rt. overnight.
CeCl3-7H2O 5%, NaI 5%, no solvent. 1-10hr. a new way to make the thp ether.

deprotection:
1. TsOH in EtOH/MeOH.

sacrificing ester

The idea of sacrificing ester.
NaH or KH usually contains some NaOH/KOH which will hydrolyze esters.
Trace of water can also react with KH/NaH to form NaOH/KOH.

a non enoliazable ester can be used to remove the metal hydroxide.
methylbenzoate works fine.

convertion of 3,4-alkene ester to conjugated ester

Base: DBU or NaH
solvent: Et2O or toluene or MeCN
rt. long reaction time.


methyl benzoate can be used as sacrificed ester to prevent the ester from hydrolysis.

Bromination on aromatic ring

o-Bromination of phenol.
: iPr-NH, slow addition of 1 eq. of NBS in DCM at 0 C.

optical rotation calculation

d: sodium line.
temperature: Celsius.
1. a neat = a/densiy

2. for a solution:
a = 100a/c (c= xx g/100ml)
ex: a 20 d = +6.2 (c 1.2, EtOH)

making of diazotransfer reagents

ex. 2,4,6-triisopropylbenzenesulfonyl azide

1. reaction can be monitored by TLC. the azide is slightly less polar than the sulfonylchloride.

2. detailed reaction:
1. dissolve the tipscl in acetone.
2. add NaN3 into the reaction mixture. vigrous stirring for at least 20 min. NaN3 can't dissolve, a cloudy solution.
3. add water dropwise into the solution, until clear.
4. 1 hr, st gone.
5. wash with water, extracted into ether. dried, concentrated. sticky oil.
6. can be recrystallized in hexanes.

Note: if water was added at the very beginning, reaction can't go because tipscl can't dissolve in water.

Drying reagents MgSO4 vs. Na2SO4

MgSO4 is more expansive, but as a drying reagent, it is much quicker and more complete than Na2SO4.
when a lot of water is present, MgSO4 generates heat, Na2SO4 does not.

petasis reagent: (cp)2Ti(cyclopropane)2

Cp2Ti(cyclopropane)2 is used to convert a ketone into cyclopropane-alkene.

1. making of this reagent.
Li,Et2O, 0 C, add cyclopropanebromide dropwise into the solution.( very exothermic).
low sodium Li can be used. 1hr at rt, then the solution was transfered into a Et2O solution of Cp2TiCl2 at 0 C. stirred for 90 min, quenched by ice water. washed, dried over MgSO4, concentrated. red solid. dissolved in toluene (0.5-0.8 mol/l). The solubility is poor in toluene, so can't make more concentrated). stored in freezer. Solid will be precipitated from the solution in the freezer, so warm it up before use.

2. reaction.
usually, 3-5 eq. of the reagent, toluene as solvent, 50-55C. overnight.
the product is very easy to isomerize to other alkene-isomers. So during the reaction, some NaHCO3 solid can bee added to prevent isomerization.

Diastereoselective Intermolecular Pauson-Khand Reactions of Chiral Cyclopropenes

Joesph M. Fox of University of Delaware.

1. the unusual reactivity of cyclopropenes can increase the scope and utility of intermolecular Pauson-Khand reactions.
2. The well-defined chiral environment of cyclopropenes has a powerful influence on the diastereoselectivity of the reactions
and leads to the production of a single cyclopentenone in each of the described cases.
3. The cyclopropane ring strongly influences the stereochemistry of reactions at the enone
4. the three-membered ring can subsequently be cleaved under mild conditions.

5. Notably, the types of products that are accessible via cyclopropene Pauson- Khand/reductive cleavage complement those that can be formed using directed Pauson-Khand methodology
.

Pd-Catalyzed alpha-Arylation of Trimethylsilyl Enol Ethers with Aryl Bromides and Chlorides

By John F. Hartwig, Angewandte Chemie International Edition, 2006, 5852-5855

1. these conditions allow the coupling of bromoarenes with functionalities that are not tolerated by the basic alkali-metal enolates.

2. Entry 3, 6 showed this method has very good regioselectivity.