A Predictably Selective Aliphatic C–H Oxidation Reaction for Complex Molecule Synthesis

M. Christina White of the University of Illinois, Science 2007: Vol. 318. no. 5851, pp. 783 - 787.

1. although the yields are only moderate, selectivity is good. In all cases examined, hydroxylation occurred preferentially at the most electron-rich tertiary (3°) C–H bond, despite the fact that secondary (2°) C–H bonds have a significant statistical advantage (entries 1 to 9)
2. hydroxylation occurred with complete retention of stereochemistry (entries 6 and7)
3. This reagent showed substantial (probably steric) selectivity. Different from methyl(trifluoromethyl)dioxirane.

Interconverstion of esters

1. methylester to mentholester
menthol, dmap, m.s., toluene, refluxing temp.

2. mentholester to methylester
methol, sealed tube. 120C.

3. Ti(OEt)4/EtOH -> ethylester.

Stereoselective Olefin Isomerization Leading to Asymmetric Quaternary Carbon Construction

a good article by Prof. Scott Nelson, University of Pittsburgh, Org. Lett., 9 (12), 2325 -2328, 2007.

1. The olefin isomerization-Claisen rearrangement (ICR) sequence allow the transformation of an oxygen chirality into carbon chiralities.

2. this method allows adjacent quaternary-tertiary stereocenter relationships to be established with excellent diastereoselection.

3. Notice in the Figure 2, the only difference of the products are the quartary centers.

Dehydration of alcohol

1. MsCl, then strong base.

2. SOCl2/Py

3. POCl3/Py
some examples indicate that a primary alcohol can be kept intact when dehydrate a tertiary alcohol.

transformation of alcohol to iodide

1. TEA/MsCl/DCM, rt, then NaI/acetone, reflux.
2 steps, good yield.
2. PPh3/I2/imidazole
good yield, one step rxn, sometimes separation of pph3/pph3O is problematic.

deprotection of benzyl methyl ether.

1. BBr3.
popular.
2. BCl3, works for meta-carbonyl benzyl methyl ether.

3. alcl3,dcm
other ether can also be removed.

4. Et3SiH/(C6F5)3B then TBAF
very gentle condition.

5.HBr 48% solution, tributylhexdecylphosphonium bromide.
6. HBr, AcOH
7. PBr3.
conclusion: halide is essential. an oxygen-philic element is also important( usually an element with empty atomic orbitals).

7. LiCl/DMF/ heat
tolerates 1,2-diketone.

ortho-directed reaction of phenol

1. lewis acid-acid chloride/halides
usually no selectivity, both ortho and para product can be formed.

2 dibalH-ester
ester reduced by dibalH, then Al chelate with the phenol to give only ortho product(diol).

3. phenylboronic acid/aldehyde
boron atom formed bonds with the aldehyde and the phenol. same as dibalH, but gives boron complex, after H2O2 oxidation, gives diol.

4. alcl3/BCl3/cynide
gives phenol ketone after hydrolysis.

reduction of methylester

1.LAH

2. NaBH4 in MeOH/t-BuOH or THF, heat.
very gentle reducing condition, compatible with beta-CN.

work up of a reaction

1. usually, in small scale, dilute the rxn mixture with ether and let the rxn mixture pass through a pad of silica gel will remove all the polar/inorganic compounds. then remove the ether by rotavapor and then ready for a column.
2. MgSO4 is better than Na2SO4 as the drying reagent. Much quicker, more efficient and less water.
3. silica gel can also trap water so it is not necessary to use MgSO4 before a column.

Column technologies

silica gel size: 5-20 mesh.
1. dry pack the column. use compressed air to tighten the silica gel.
2. add P.E. from the top. push it into silica gel by compressed air. leave some p.e. on the top.
3. mix the organic compound with a little organic solvent(the solvent should dissolve your compound but not carry it through the column. ex. toluene, dichloromethane) and add the mix to the top of the column.
4. push the mix into the column. then add sand to the column.
5. P.E. as the unpolar solvent, (hexanes is better, because it has a higher boiling point than p.e., so it is less likely to make a hot circle in your column), MTBE as the polar solvent.
6.if 40% MTBE in PE is not polar enough, DCM can be added into the solvent to improve the polarity. if more polar solvent is needed, acetone can be added.
7.better separation can be achieved by using different solvent combinations.
usually, polar solvents are: ethylacetate, MTBE, diethylether,acetone, acetonitrile
unpolar solvents: p.e., hexanes, DCM

an easy separation of some beta-ketoesters

beta ketoesters are quite acidic.
In some cases, shake the betaketoester with NaOH or KOH aqueous solution will make the Na or K salt of the betaketoester.
Depends on the structure of the ketoester, the salts may be soluable in water(K salt are more likely to be water-soluable than Na salt), so it can be extracted into water and then acidified by HCl to give the ketoester.
Na salt has less solubility in both water and organic solvent(ex. ether),so it will form a nice precipitation. an easy filtration can give you 99% Na salt of betaketoester, the drawback is the low yield of the precipitation.

hydrogenation opening of cyclopropane

cyclopropane is less reactive than double bond. It is possible to saturate double bond without touching cyclopropane.

PtO2/AcOH/H2
this is the general way to open the cyclopropane between the less substituted carbons.

if you run the rxn in basic or neutral solvents like MeOH will give ring opening product with less selectivity.

Convertion of alkene to ketones

1. hydroboration
alcohol on the less hindered carbon.

2.Wacker oxidation.
very gentle condition. internal alkene is still problematic.

3.alkene to epoxide, then hydride opening of the epoxide gives alcohol on the more substituted carbon. If use Cp2TiCl mediated radical reduction,then gives alcohol on the less hindered carbon.

4. Hg(OAc)2/H2O.
a very gentle condition. gives hydromercury, then NaBH4 radical reduction gives the alcohol on the more substituted carbon.

5. make bromohydrin first, then pd will eliminate the bromide and gives the ketone on the more electronphilic carbon.

trityl ether protection group

behaves like Bn ether.very bulky, so better selectivity towards primary alcohol.

forming:
trityl chloride, TEA, DCM

easily falled off when contact with Silica gel.(during column)
pretreat the silica gel with 1% TEA in P.E. can prevent it completely.

can be removed by hydrogenation(pd/c, H2), addition of Py can preserve it.

benzyl ether protection group

forming:

1.NaH, THF/DMF, BnBr.
TBAI can be used, more active BnI is formed.

2. CsOH/M.S./DMF or Cs2CO3/ DMF or DMSO, BnBr
Cs is a good base, works for very unreactive alcohol.

3. TfOH, DCM, hexane, benzyl trichloroacetimidate
acidic conditon, works for base-sensitive substrate. generally, low yield.

4. Ag2O, BnBr, solvent,( in darkness)
good selectivity between primary and secondary alcohols. very mild condition.

5. bis(butyl)tin oxide/CsF/BnBr
works for monoprotection of 1,2-diol.

6. Cu(acac)2/BnCl/reflux
only protect primary alcohols.

7.BnCHN2/HBF4
very mild condition. tolerates many functional groups.

8. benzyl chloride/Bu4NBr/NaOH aquous/

deprotection:
1. 5% Pd/c, in THF the reation is faster than MeOH.
addition of base (TEA, pyridine) can prevent benzylether from hydrogenation conditions.(H2, 1 atm, Pd/C, 5%, MeOH).
Removal of trityl ether is slower than hydrogenation of double bond. So short time (1-2hr) hydrogenation won't touch trityl group, of course, base can also be used to pretect trityl group.
removal of benzylether is 20 times quicker in THF than in MeOH(Pd/C, 1atm H2, rt).

2. O3 can oxidize Bn to Benzylester.
3. RuO2/NaIO4 oxidation can oxidize Bn to Benzyl ester.
4. DDQ.
with or without water.
UV/MeCN. (mild condition, can tolerate double bonds).
5. dissolving metal.
Na/Li in liquid ammonia.

chiral pool

1.Evans Oxazolidinone Auxiliaries
2. menthol, camphor, amino acid derivatives.
3. Myers Pseudoephedrine Auxiliaries

criegee rearrangement

1. O3 to get the ozonide, then remove solvent, Ac2O/...?/reflux
= ozonolysis/pph3 + Baeyer-Villiger rearangement.
nice reaction.

Hg(OAc)2 mediated hydrolysis of alkene

1. Hg(OAc)2/THF/H2O then NaBH4/NaOH/H2O
Hg++ acts like Br+,
NaBH4 reduces Hg to H.
gives different alcohol compared to Borane.

Wacker oxidation

1. PdCl2/CuCl/DMF/H2O/O2/temp
usually only for terminal alkene, methylketone is the product.

2. internal alkene is less reactive and no regioselectivity.
If the internal alkene has an allylic alcohol, product will be only bata-alcohol ketone.

3. catalytic amount of Cu(OAc)2 can be used.
this condition is less reactive, but some acid sensitive groups can be preserved, and also yield can be higher.

selectivity of epoxidation by mcpba

electron rich alkene reacts first,
tri-sub alkene reacts first, then di-sub alkene.
NaHCO3 can be added to neutralize the acid generated.

convert ketone to alkene

wittig
basic reagent, may cause problem if ketone is enolizable.


tebbe, petasis regaent
non basic, works for enolizable and steric hindered ketones.

protection of ketone by Li enolate.

convert ketone into Li enolate by LDA in THF at -70 C.
the enolate formed is very stable below -30C, LAH can't reduct it.
LAH can't reduce ester below -40C at THF. So warm up to -40- -30C, the ester will be reduced while the ketone remained.
In one run, the Li enolate is stable even at about 0 C!

Reduction of ketone

1. Meerwein-Ponndorf-Verley Reduction
thermodynamic alcohol is formed instead of kinetic product (compare to LAH).
Al(OR)3 ,i-prOH.
lanthanides are more reactive, for example Gd.

2. LAH
solvent THF or Et2O. Exothermic, slow addition!
when quenching LAH reaction, if x gram LAH used, then add x g water, x ml of 15% NaOH in water, 3x gram of water finally. Then a easy filtering through a celite pad will remove all the metal.

3. NaBH4
reduces ketone, not ester.
solvent: MeOH/THF.

4. DIBAL-H
reduces ester to aldehyde.

cationic cyclization

initiator:
alcohol,alkene,
epoxide, ketone, ketal,
acid, acid chloride,
C=N+ -> N-C+
R-SO2Ph, R-NO2,

terminator:
alcohol,
azide, ketone, ketal, ester, beta-ketoester.
Enone, TMS enone ether, allyl silane
acytylene
alkene, C=NR,
aromatic, indole

a very good pdf about cationic cyclization:
http://cmds.kaist.ac.kr/skim/lecture/1.Cationic.pdf

making of beta-ketoester

adds methylester to a methyl ketone to form beta-ketoester:
1. NaH/toluene/dimethylcarbonate/reflux, trace of MeOH to initiate the reaction,
then add the methylketone dropwise into the reaction mixture.
reaction is very exothermic, add slowly.
KH or DMF can also be used to initiate the reaction.
kinetic enolate is formed.

2. LDA/HMPA, cyano methylcarbonate (mander's reagent). -78C.
C-alkylation. if chloro methylcarbonate was used, only O-alkylation product.

HMPA

polar aprotic solvent.

1. can chelate with Li, improves basicity of LDA.
also increase the stability of LDA. ( without hmpa, LDA in THF became gray above 0C. with HMPA, LDA in THF can go beyond 0C.)

2. can chelate with Cu for 1,4 addition.

very useful.

organomagnesium

less basic than organolithium?

usually stable in THF at rt. Can be made in reflux THF or ether.

1,2 addition. (for enolizable/stericly hindered ketones, use CeCl3)

To initiate the reaction between halides and Mg,
1. heat,
2. I2 can be used.
3. broken glass can also be used.
4. distill organohalides with CaH2 can also help.

Reaction is very exothermic.
usually, Grignard made from RBr is more reacitive than RCl.

organolithium reagent

1. vinyl lithium can't be made directly. tetravinyltin was used to make vinyllithium.
2. RLi is not stable in THF at rt, so Et2O was used as the solvent. control temp at 0C or lower.
3. High sodium Li metal is more active than low sodium Li.
4. Argon should be used instead of N2 when store Li wire in bottle, since Li can react with N2.
5. Excess Li can be used and CuCN can be added directly into the reaction mixture containing Li at -40C. The Cu+ won't be reduced by Li metal.
6. broken glass can be added with Li to improve reactivity. it works as a Li surface scratcher.
7. alky lithium is very basic, stable temp is lower than vinyl lithium.

Cu mediated 1,4 and 1,5 addition

1. 1,5 addition means opening of cyclopropane conjugated with a beta-ketoester.
organocupper made by organolithium works better than organocupper made by organomagnesium halide. The reason is believed that the Li can chelate with oxygen.
Cu2R made by MgR gives only 1,2 addition while Cu2R made by RLi only gives 1,5 addition.
R is 1-bromo-2-methylpropene. reaction condition: R, Li,broken glass,Et2O, 0C, then -40C, THF,HMPA,CuCN, substrate.
half eq. of CuCN is used to make the active Cu2R.

1. dummy ligand can be used to save half the bromide.

cleavage of double bond to diol

OsO4/NMO/acetone/water
K2OsO4 can be used instead of OsO4, purple powder, easy to handle.
OsO4 dissolves in CCl4. very toxic.
don't use excess NMO. In my case, some unknown compound isolated if large excess NMO used. Since OsO4/oxone can cut double bond just as ozonolysis, not a surprise.

Hydrocarboxylation of alkene

several conditions available.
1. Pd /ligand /CO/MeOH/TsOH or MsOH
elevated temp, CO >1 atm,
if you have a isopropyl group on the terminal, then ester adds to the 2-carbon!
2. Ru2(CO)12

internal alkene can be isomerized and forms terminal carboxylate.

Hydroboration of alkenes

BH3, thexylborane, Sia2BH ,9-BBN

Boron atom adds to the less hindered carbon. Sia2BH gives aldehyde(alkyne addition).
after quenching by base, oxidation removes the boron and gives an alcohol.

H2O2, sodium borate can be used to oxidize the borane.

dimethyl sulfide/1,4-dioxane can stabilize BH3 in THF.

Borane can easily chelate with oxygen atom(ex. protected alcohol). In some case, may give unexpected product.

BH3 took off TBS in my case.

Oxidation of alcohol

several conditions and there limitations:
1. Dess-Martin
very good.
2. Swern oxidaion
gives low yield when you have an alpha-benzyl alcohol.
control temp below -65C is important for success of this rxn.
3. P2O5/DMSO
forms sticky solid in the bottle. P2O5 is very sensitive to water, hard to handle.
slightly low yield compared to swern. but works for alpha-benzyl alcohol.
4. TBAP/NMO/M.S.
good.
5. PCC/H5IO6
very good for some substrate, ex. alpha-benzyl alcohol.
6. Jone's reagent
acidic condition, gives acid.
7. PCC/NaOAc/M.S.(1:1:1)
better work up than PCC along.

ozonolysis

Usually in DCM/MeOH at -78C.
Why MeOH?
literature said MeOH can keep ozone longer in solution. Actually once I did it without MeOH, big scale, The result is that I can't see the blue color! So MeOH can also serve as an indicator!
If you have another functional group which is also sensitive to ozone, you can use an indicator, sudan III is one.
Triphenylphosphine or dimethyl sulfide can be used to workup the ozonide if you want a ketone.
Zinc dust is also OK.
NaBH4 is used to reduce the ozonide to alcohol. Now MeOH is important because it can dissolve NaBH4.

A good alternative way to cut the double bond is to use PhIO in water. J. Am. Chem. Soc., 129 (10), 2772 -2773, 2007.

alkylidene carbene insertion

formation: vinyl halide (-70C, DME, KHMDS).
or ketone + (Li-TMSdiazomethane), aldehyde will give (alkyne?)
the above reactions are very sensitive to steric hinderance. In my experience, ketone with a alpha quartary center can't react.

transformation of Ketone to Nitrile.

1. TOSMIC
ketone sensitive to MeO- will be destroyed during the reaction. for example beta-ketoester.

2. 1. tosylhydrazine/MeOH to form the hydrazone, then 2. KCN, MeOH, heat.
1. triisopropylbenzylsulfonylhydrazones or trimethylbenzylsulfonylhydrazones have quicker decompose rate than tosylhydrzones. To form the hydrazone, acid (eg. sulfuric acid) usually used to catalyze the reaction. Addition of water can also make the hydrazone formation faster.
2. In the second reaction, acid usually used to make HCN in situ from KCN, which is more reactive.
3. works even for very hindered ketone, for example, ketone with two alpha quaternary carbon center.
4. If temp. goes too high, elimination will happen and you will get an alkene if the ketone has a-hydrogen.

3. reduce the ketone to alcohol, make a leaving group (MsO-),
then treated with NaCN/DMF/water. Sn2 rxn.

Baking Yeast Reduction

enantioselective, reduce beta-keto ester to beta-hydroxy ester.

brand : red star active dry baking yeast.

fermented yeast (sucrose or ethanol) reacts really slow and not efficient. and after the reaction, separation procedure is really time costing.

Use P.E. and water as the solvent and non-fermented yeast works better. shorter time and higher yield. work up is greatly improved. Acetone was used to extract the reaction mixture, works great.

xanthate chemistry

1.formation
1. DBU in DMSO, CS2, MeI.
this condition can't isomerize an ester.
2. NaH/THF.

2.thermal elimination
heated to 180C, syn elimination happened, double bond formed.
3. reductive elimination.
with Bu3SnH.aibn. radical rxn.
can be done at rt with water, described by John Wood.

CeCl3 assisted Grignard rxn

Organomagnisum compound can react with CeCl3 to form some complex so the basisity is reduced.
both hinded and enoliazable ketones can be reactive under CeCl3.
1,2 addtion in most of the cases.
CeCl3 drying process: 90C 4hr, 140-150C 2hr under high vacuum. (0.1-0.2 Torr)
several conditions available:
1.CeCl3/THF
sonication is better than stirring, 1 hr at rt is good enough.
grignard added into CeCl3 at -78C, then ketone.
2.CeCl3 with TiCl4
Even beta-ketone ester can be alkylated to the the beta-alcohol ester! Only successful when gama position is phenyl.
3.CeCl3.2xLiCl in THF

C-alkylation vs. O-alkylation

canion effect:
Li, Na, K, Cs
C---------O
smaller canion like Li can chelate with Oxygen, so carbon is more active compared to the oxygen atom. But at the same time, both C and O are less reactive compared to bigger canion!

solvent effect:
hexane, toluene, THF, acetone, DMF, DMSO
C----------------------O
substrate is less solvated in less polar solvent.

temperature
high temp seems favor O alkylation.

leaving group
OTs, Br, I
soft leaving group favors C-alkylation.

a good article about research

1.一半时间做实验，一半时间看文献。half time doing experiments, half time reading!
千万不能把时间全部消耗在实验台上。看文献、看书、看别人的操作、听别人的经验、
研究别人的思路，边做边思考。要学会比较，不要盲从。否则，会被一些小小的问题困
扰许久。

2.准备越充分，实验越顺利。better preparation makes your experiment better.
古人云，磨刀不误砍柴工。前期的知识储备、文献储备、材料准备、方法准备可以避免
手忙脚乱，充分的预实验使你充满信心。一步一个脚印，就不必“从头再来”。最不能
容忍的是在开始的几步偷懒，造成后面总有一些无法排除的障碍。

3.记录真实详尽。record everything.
人总是有一点虚荣心的。只把成功的步骤或漂亮的结果记到实验记录里，是很多人的做
法。殊不知，许多宝贵经验和意外发现就这样与你擦肩而过。客观、真实、详尽的记录
是一笔宝贵的财富。

4.不要为老板省钱。Don't try to save money for your boss!
效率为先。整天算计着省钱，一旦用了不可靠的东西，只会浪费时间，遭受打击，到头
来一分钱也省不了。

5.把握心理优势。Keep your mind optimistic.
做过实验的人都经历过失败和挫折。有些失败应当在预实验阶段发生，你这时能坦然接
受。假如不做预实验，在正式的实验中遇到，你的挫折感就很明显。假如你因为赶时间
而误操作，你会沮丧。假如你能因为目前心浮气燥而果断地放一放，就可以避免悲剧的
发生。假如你早上进入实验室之前还不知道今天要干什么，你最好想好了再去。最大的
错误是重复犯同样的错误。记住，屡教不改者不适合做实验。

6.先看综述，后看论著. Read reviews first, then articles.
看综述搞清概念，看论著掌握方法

10.两手准备. choose research area which can be published even you get negtive result.
设计课题要为了阐明问题，即不论结果为阳性或阴性，都能写文章。阳性结果说明什么
，阴性结果说明什么。假如课题要求得出阳性结果，你可能要事先设计几部分，万一第
一部分得不出预期结果，可以用其它部分弥补损失。

14.准备引用的文章要亲自看过。Read every paper cited by you.
转引造成的以讹传讹不胜枚举。

17.交流是最好的老师. communication is the best teacher.
做实验遇到困难是家常便饭。你的第一反应是什么？反复尝试？放弃？看书？这些做法
都有道理，但首先应该想到的是交流。对有身份的人，私下的请教体现你对他的尊重；
对同年资的人，公开的讨论可以使大家畅所欲言，而且出言谨慎。千万不能闭门造车。
一个实验折腾半年，后来别人告诉你那是死路，岂不冤大头？

18.最高层次的能力是表达能力. expression of your self is a top ability.
再好的工作最终都要靠别人认可。表达能力，体现为写和说的能力，是需要长期培养的
素质。比如发现一个罕见病例，写好了发一篇论著；写不好只能发一个病例报道。比如
做一个课题，写好了发一篇或数篇论著；写不好只能发一个论著摘要或被枪毙。一张图
,一张表,无不是表达能力的体现。寥寥几百上千字的标书，可以赢得大笔基金；虽然关
系很重要，但写得太差也不行。有人说，我不学PCR，不学spss，只要学会ppt（
powerpoint）就可以了。此话有一点道理，实验室的boss 们表面上就是靠一串串ppt
行走江湖的。经常有研究生因思维敏捷条例清楚而令人肃然起敬。也经常有研究生不理
解“为什么我做了大部分工作而老板却让另一个没怎么干活的人写了文章？让他去大会
发言？”你没有看到人家有张口就来的本事吗？

Computer aid Rh(II) catalyst design and synthesis

before I enter the project, the first generation cat. Rh2Ln2 was already made successfully, can catalyze C-H insertion, high ee but very low yield. We believe the very big and interconnected ligands blocked the active site of the Rh metal and were the reason for the low reactivity.

In the 2nd generation cat. Rh2T2, the ligand was smaller and interconnected by less number of carbons than the first generation. The only problem is the synthesis of the ligand was not successful.


So we did a little change to the ligand, which made the synthesis easier. The ligand was synthesized by diels-alder reaction of Evan's chiral auxiliary. But the reaction between Rh2(TFA)4 and the ligand is not successful. polymer like material was resulted, poor solubility in almost all organic solvents. Poor reactivity toward C-H insertion.

The reason I think is that the two carboxyl group of the ligand connected with two molecular of Rh2 instead of one Rh2. So you get a big molecular, a polymer.

Pd catalyzed rxn

Heck reaction
Pd/phosphine ligand. Although Pd(OAc)2 was used, Pd (0) is the real catalyst. pd mirror was formed on the wall of the reaction vessel when I did the reaction.

Pd(MeCN)Cl2 mediated cyclization of beta-ketoester was not successful in my hand. probably the reason is the unpure homemade cat.

Pd(OAc)2 catalyzed cyclization of TES enolate to alkenes.

Indole synthesis

Fisher indole synthesis
started with N-substituted benzene, C-C bond is formed by an intramolecular rearrangement.
finished with elimination of NH3.


Neber-Taber indole synthesis
started with C-substituted benzene, C-N bond is formed by N* attack the benzene. finished with proton transfer from benzene to N.

The intermediate azirine is very stable and under elevated temp. or rt with some metal catalyst (rh dimer for example), the azirine smoothly rearranged to indole.

Radical cyclization

In general, halides can be reduced to radical by aibn. Bu3SnH is used to reduce the radical to R-H.

1. Mn(OAc)3
Mn3+ oxidizes the enone form of a beta-ketoester. A stablized carbon/oxygen radical is formed,
then it cyclizes to a double bond, the secondary carbon radical then can be oxidized by Cu2+, gives a cation, then finally, cation eliminates to give a double bond.
thermodynamically most stable isomer is the major product.
LiCl can be used instead of Cu(OAc)2 to give a chloride.
For some hindered double bond, Mn/Cu or Mn/LiCl do not work. O2 in the air reacted with the initial radical and R-OOH was the final product. if LiCl was used, R-Cl was formed.
In some case, push away O2 by Argon instead of N2 gives better yield.
Mn/EtOH gives reduced product instead of oxidized product. only works when you formed a methyl radical after cyclization.
AcOH is a good solvent, MeCN is also OK.

2. Iodine transfer reaction
treat a beta-ketoester with LDA/I2 gives the iodide. then aibn/heat/benzene gives cyclized product.
This method worked better for hindered double bond than Mn,
AIBN along with some heat is enough to initiate the rxn.
Lewis acid (for ex. Mg(ClO4)2 ) can be used to catalyze the reaction.
gives thermodynamic product.

3. selenide transfer rxn.
in my case, starting material - beta ketoester phenylselenide is not stable on silica gel.
usually, UV light, lewis acid can catalyze the reaction.

C-H Insertion/cyclopropanation (Rh, Cu...)

1. C-H insertion -> cyclopentane/cyclohexane
the biggest side product is the dimer ( two diazo ketone lost one N2). usually unstable carbenoid gives less dimer, for example carbenoid with two electron withdrawing group or the rhodium dimer have electron-withdrawing ligand( for ex. Rh2(pttl)4).
stablized carbenoid reacts slowly so more dimmer, but better selectivity. for example,
In some situation, cyclohexane is formed instead of cyclopentane, rh2(piv)4 gives best 6/5 ratio.

2. double bond inerstion -> cyclopropane

The yield is usually higher than C-H inserstion. if the double bond is in a ring before the reaction, open the cyclopropane by hydrogenation will give CIS-ring fusion product.

3. O-H/N-H insertion.

Common catalysts:

hashimoto's cat.
rh2(pttl)4 , ptpa,....
very active toward intra. C-H insertion of ketones. higgest ee so far.

Davies' cat.
Rh2(DOSP)4, ...
intermolecular C-H or cyclopropanation.
intramolecular also ok.

Doyle's cat.
Rh2(MEOX)4 , mppim....
good for diazo esters. less reactive for diazoketones.

Taber's cat.
two ligands instead of four. ligand stability increased.
no good results so far.

DuBois's cat.
Rh2(ESP)2
very electron rich ligand. N-H insertion. derived from taber's cat.

diazo transfer reaction
ketone, beta-ketoester:
base: TEA, DBU
diazotransfer reagent: MsN3, AABSA, PNBSA, TIBSA
solvent: DCM, MeCN, Toluene
for a-aryl ketone, TIBSA/toluene/DBU works better.
for beta-ketoester, TEA/MeCN/MsN3 works OK. 1N NaOH can wash away excess MsN3.

ester:
Danheiser's method J. Org. Chem. 1990, 55, 1959.
introduced 2,2,2-trifluoroethyl trifluoroacetate and lithium bis(trimethylsilyl) amide as an efficient acylation method.

Taber's method
The TiCl4-mediated reaction of an ester with benzoyl chloride results in high yields of the R-benzoylated ester. Diazo transfer of the benzoylated ester utilizing p-acetoamidobenzenesulfonyl azide affords the R-diazo ester in good yield

acid->acid chloride then treated with diazomethane. TMSdiazomethane is a good substitution, but not in all cases. I did a reaction where TMSdiazomethane is not successful but diazomethane works.

ketone-> hydrazone->

benzylic functionalization

1.super base (deprotonation directly)
t-BuOK/n-BuLi.
In hexanes, you get both deprotonation on benzylic and on the benzene ring, selectivity is bad.
Change the solvent to THF, only benzylic deprotonation resulted.

2. activated Zn + benzylic bromide
Zn can be activated by many methods, for example, TMSCl, dibromoethane, HCl or ultrasound, The activation reaction is hard to repeat.
other metal can be added to increase the reactivity of the benzylic anion.(Mn,Cu)

3. benzylic bromide + Mg (barbier type rxn)
works for some particular substrates only.

4. SmI2
ex. benzylic bromide + aldehyde.
barbier type, yield is only 50%, pivaldehyde can be added into the reaction mix to convert the alcohol to ketone in one pot.
using of Sm metal is also described in the literature.

5. Mn

Carbonyl umpolung

dithiane
really bad smell. can attack ketone/aldehyde.

Baldwin's hydrazone
hydraone is not stable, easily go back to aldehyde. reactive, can attack benzyl bromide.

protected cyanohydrin

thiazolium salt catalyzed reaction

oximes

nitronate anion

metalated enol derivatives

commercially available chiral building blocks

pulegone (both enantiomers)

menthol (both -, +)
citronellal(both en.)

carvone

asymmetric epoxidation

Sharpless epoxidation
allylic alcohol only.
homoallylic alcohol can also be reactive using some more active metal.

Jacobsen epoxidation

not limited to allylic alcohol, tetra-sub alkene gives low ee.

Shi epoxidation


Sulfur Ylide Epoxidation

cordova's epoxidation
works for electron deficient olefins.

taber's mandelic acid approachbased on column separation of two mandelic ester diasteromers.
Works on Terminal alkenes.