Organosynthetic & Organometallic Chemistry

A failed reduction by LAH

2011-07-14T20:03:00.000-07:00

The reduction by LAH on the following compound failed to give the desired product.

Instead, the allyl alcohol isolated.
So mechanismly, the hydride added to the double bond and the so-formed carbon anion caused the nitrile on the alpha position to eliminate.
But whether the ester is reduced before it or after is not clear now.

Preparation of 1,2-diMagnesiummethylbenzene

2011-07-14T18:03:00.000-07:00

The 1,2-dimagnesiummethylbenzene showing below is a useful reagent for metal ligand preparation.
This di-grignard reagent can be made in high yield from corresponding dichloride compound.

1,2-Dibromomethylbenzene can't be used because it can cause problem.

steps:
1. activate Mg using 1,2-dibromoethane.
2. in diluted solution, slowly add dichloride into Mg in THF. control temperature at rt.
3. allow 8 hr stirring at rt.

yield is over 95% in reports.

Another approach to sordaricin

2011-04-05T07:13:00.000-07:00

this strategy is based on a 3+2 cycloaddition.

an indole synthesis plan from nitrile

2011-03-01T07:20:00.000-08:00

the plan is like this:

it is really plausible to me.

the additional six membered ring is required because without it, nitirle ylide will be formed instead of the azirine.

ps: sorry, the diazo compound is missing in the drawing.

preparation of thermodynamic silyl enol ethers

2011-01-28T00:46:00.000-08:00

Tetrahedron Letters,Vol.24,No.l3,pp 1345-1348,1983

There now exist a variety of mild and very selective procedures for the kinetic
deprotonation of unsymmetrical ketones employing alkali metal dialkylamides. The "kinetic"
enolates produced in this way may be efficiently trapped by trimethylsilyl chloride to
regiospecifically provide the less substituted trimethylsilyl enol ethers.1 Despite the
recent introduction of several new methods, there are still no procedures available which
allow direct3 regiospecific preparation of the more substituted "thermodynamic" enolates or
trimethylsilyl enol ethers.

this paper described a way using MeMgBr/diisopropylamine to generate the thermodynamic enolate at rt, which worked out as described.(HMPA is necessary, without it, no rxn at all).

a mild alternative nitrene generation method for C-H amination

2011-01-07T18:49:00.000-08:00

current method involve hypervalence iodine to oxidize the carbamate or sulfonamates to the imidoiodo species followed by metal incorperation to do following C-H aminations.
One problem limiting the rxn scope and catalyst preformance is the the high-oxidative potencial of the hypervalenc iodine compund such as pida, pifa.

here I propose a new oxidant which is a imidoiodo compound with a bulky blocking group attached to the imine. It is a milder oxidant than the pida/pifa and with a certain sized bulky group, the oxidant might be able to exchange its iodo with a carbamte but not able to react with the metal like rhodium.
Such a setup can increase the catalyst scope and performance and also milder the rxn condition.

Isomerization of conjugated double bond

2010-12-24T00:08:00.000-08:00

Recently found an interesting reaction which isomerized the conjugated double bond by the following sequence:
1. ketalize the ketone by acid/ethylene glycol. during which rxn the double bond isomerized to the more substituted position.
2. remove the ketal by oxalic acid which is efficient and mild enough to keep the double bond from isomerization to the more stable conjugated position.

very cool transformations, which demonstrated the author's deep understanding of those reagents and the beauty of organic transformations.
the paper was published about 30-40 years ago in jacs.

Oxidative cleavage of α-hydroxyketones

2010-11-04T00:51:00.000-07:00

Tetrahedron Letters 50 (2009) 5399–5402
"
The oxidative cleavage of vicinal diols, a-hydroxyketones, and related functionalities is a common synthetic procedure and various reagents are available to perform this reaction, such as sodium bismuthate,1 iodo triacetate,2 manganic pyrophosphate,3 KHSO5,4 calcium hypochlorite,5 basic hydrogen peroxide,6 methylrhenium trioxide,7 Bi/O2,8 sodium percarbonate,9 and vanadium-based HPA and dioxygen.10 However, the most versatile reagents for this purpose are sodium metaperiodate,11 and lead tetraacetate.12–14
Usually sodium metaperiodate is used in aqueous solutions, because the effectiveness of this oxidant in organic solvents is very limited due to its insolubility.15 Lead tetraacetate has been used in non-aqueous media to accomplish the same types of reactions effected by periodates with water-soluble compounds.15 On the
other hand, this reagent is difficult to store and handle, non-environmentally friendly and, being more reactive, can afford undesired oxidation byproducts.
Aiming to expand the versatility of sodium metaperiodate as an oxidating reagent in organic media, and to overcome the solubilityissues, variations of a silica gel-supported sodium metaperiodate reagent have been disclosed, to promote oxidative cleavage of 1,2 diols, and oxidation of hydroquinones and sulfur-containing compounds.16–18 Usually the sodium periodate is adsorbed on silica gel, and stirred with the starting material in dichloromethane, ether, or benzene.
"
One of the conditions described in the reference paper (NaIO4/SiO2/toluene) was applied to a mixture of alpha-hydroxyketone and TMS protected alpha-hydroxyketone shown below.
Surprisingly, only alpha-hydroxyketone was cleaved. The TMS protected alpha-hydroxyketone survived.
compared with HIO4 in Et2O, this condition (NaIO4/SiO2/toluene) is more neutral.

A Mask of the More Reactive Carbonyl

2010-11-03T20:05:00.000-07:00

David Colby and co-workers from Purdue have just added a useful way to selectively reduce less reactive carbonyls (ie: lactone) over more reactive ones (ie: ketone) by introducing N,O-dimethylhydroxylamine in the presence of an aluminum reducing agent (DIBAL).

deprotection of dimethyl acetal

2010-10-15T01:10:00.000-07:00

1. in a particular substrate bearing a terminal double bond at 5,6 position related to the acetal,
the following deprotection methods failed

Methods tried:                                 results:

1. TFA/water/chloroform                   unknown product, aldehyde/alkene disappeared

2. I2/acetone                                     unknown product, aldehyde/alkene disappeared

3.HCOOH, pentane                          unknown product, aldehyde/alkene disappeared

4. TESOTf, 2,6-lutidine                       no reaction

the following method is successful:

DDQ/MeCN/water rt.

preparation of 2-Bromo-3-(trimethylsillyl)-1-propene

2010-09-13T05:02:00.000-07:00

(2-Bromoallyl)trimethylsilane
Expensive.
two methods to prepare it.

1. coupling of 2,3-dibromopropene with a trimethylsilyl organocopper reagent generated by addition
of 1.5 equiv of cuprous cyanide to (trimethylsily1)lithium in a 3:l THF-HMPA mixture at 0 C.
2. Alternatively, the bromosilane was conveniently prepared according to eq 2 in 71% yield. This method has the advantage of avoiding the use of HMPA.

The resulting bromosilane can be distilled and stored in the dark for prolonged periods.

Reference:
J. Am. Chem. SOC. 1991, 113, 7350-7362.

synthesis of cyclopentanones

2010-09-11T02:47:00.000-07:00

From:
An efficient one-pot method for the synthesis of mono- and biscyclopentenones via zirconium-catalyzed cycloalumination of cyclic alkynes and diynes, Tetrahedron Letters (2010), doi: 10.1016/j.tetlet.2010.08.120

Cyclopentenones have attracted the attention of organic chemists due to their wide use as building blocks in organic synthesis. In addition, they are often encountered in drugs and flavoring compounds.1

Efficient and widely used procedures for preparing cyclopentenones include the Nazarov cyclization, the
Pauson-Khand reaction and methods based on intramolecular cyclization of dienes, enynes and diynes
catalyzed by Ru, Ir, Rh, Au, Pd or Ni complexes.2
Another method for the synthesis of cyclopentenones
includes intramolecular carbocyclization of aluminacyclopentenes3 generated in situ in Zr-catalyzed
cycloalumination reactions of alkynes and Et3Al (Dzhemilev reaction),4 and their subsequent treatment with
CO2, ClCOOEt or CO(OEt)2.

reference:

1. (a) Surburg, H.; Panten, J. Common Fragrance and Flavor Materials: Preparation, Properties and Uses. Willey&Sons, 2006, pp. 330. (b) Hendrickson, J. B.; Palumbo, P. S. J. Org.Chem. 1985, 50, 2110. (c) Ceccherelli, P.; Curini, M.;Marcotullio, M. C.; Rosati, O.; Wenkert, E. J. Org. Chem.1990, 55, 311. (d) Conti, M. Anti-Cancer Drugs 2006, 17,1017.
2. (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003,125, 14278. (b) Grant, T. N.; West, F. G. J. Am. Chem. Soc.2006, 128, 9348. (c) Shindo, M.; Yaji, K.; Kita, T.; Shishido,K.; Choueiry, D. Synlett 2007, 1096. (d) Saito, A.; Umakoshi,M.; Yagyu, N.; Hanzawa, Y. Org. Lett. 2008, 10, 1783. (e)Magnus, P. Tetrahedron Lett. 1985, 26, 4851. (f) Deng, L.-J.;Liu, J.; Hung, J.-Q.; Hud, Y.; Chen, M.; Lan, Y.; Chen, J.-H.;Lei, A.; Yang, Z. Synthesis 2007, 2565. (g) Park, K.H.; Song,S.U.; Chung, Y.K. Tetrahedron Lett. 2003, 44, 2827. (h)Shibata, T.; Toshida, N.; Yamasaki, M.; Maekawa, S.;Kagaki, K. Tetrahedron 2005, 61, 9974; (j) Rausch, B.;Gleiter, R. Tetrahedron Lett. 2001, 42, 1651; (k) Gleiter, R.;Schulte, J.H.; Werz, D.B. Eur. J. Org. Chem. 2004, 4077; (l)Oh, C.H.; Karmakar, S. J. Org. Chem. 2009, 74, 370.
3. Negishi, E.; Montchamp, J.-L.; Anastasia, L.; Elizarov, A.;Choueiry, D. Tetrahedron Lett. 1998, 39, 2503.
4. (a) Name Reactions and Reagents in Organic Synthesis.Mundy, B. P.; Ellerd, M. G.; Favaloro, F. G. Jr. Eds. Wiley-Interscience. New Jersey. 2005, pp. 882; (b) Dzhemilev, U.M. Tetrahedron 1995, 51, 4333. (c) Dzhemilev, U. M.Mendeleev Commun., 2008, 18, 1. (d) Dzhemilev, U. M.;Ibragimov, A. G. J. Organomet. Chem., 2010, 695, 1085. (e)D’yakonov, V. A. Dzhemilev Reaction in Organic and
Organometallic Synthesis, New-York.: NOVA Sci. Publ.,2010. p. 96.

activation of Magnesium for grignard reaction

2010-09-11T02:35:00.001-07:00

Grignard: Initiating the reaction is the tricky part, people have used 1,2-dibromomethane, iodine, TMSCl - but for me the best working initiation technique is to place few equivalents of Mg turnings into an oven-dried flask with a large egg-shaped stirbar, flush it thoroughly with dry argon, add few drops of Br2 and dry-stir the Mg turnings in the Br2 vapors overnight. Then add freshly distilled ether solvent via canula (the bromine color disappears) and then carefully your substrate. I got some Grignards like BrMg(CH2)3MgBr by this technique that are hard to make by other methods (unless you want to mess with Rieke Mg). The Mg turnings are fairly fragile and crushing them in oxygen-free and nitrogen-free environment uncovers a highly-reactive newly-formed surface which is further protected by MgBr2 formation. MgBr2 is soluble in ether. Please note that one has to use Ar because N2 reacts with fresh Mg surfaces, to produce dark Mg nitride.

http://chemknowhow.com/forum/viewtopic.php?t=448

Prepartion of magnesium bromide diethyl etherate solution

2010-09-10T18:55:00.000-07:00

Once I was going to make a MgBr2-OEt2 1M solution in Ether.
When the ether was added into MgBr2-OEt2 powder, two layers of liquid was resulted.

Turned out the button layer contains MgBr2 at 39%wt. the top layer contains 3%wt.
addition of some benzene can increase the solubility and make a clear solution.

reference:
digital.library.okstate.edu/OAS/oas_pdf/v32/p79_82.pdf

note:
In a preparation, 1.5 M clear solution was made using 27 ml of Et2O and 4 mL of benzene at 25 C.

2010-09-08T19:47:00.000-07:00

Don M. Coltart

http://fds.duke.edu/db/aas/Chemistry/faculty/don.coltart

Assistant professor, Duke
NSERC, AHFMR, and CRI Postdoctoral Fellow, Memorial Sloan-Kettering Cancer Center, 2001–2004
Ph.D. Chemistry, University of Alberta, 2000
M.S. Chemistry, University of Manitoba, 1995
B.S. Biochemistry, University of Manitoba, 1993

Research Interests

Asymmetric α-Alkylation of Ketones via Activated Hydrazones

Direct Carbon-Carbon Bond Formation via Soft Enolization of Thioesters

Natural Products Total Synthesis

A proposal for the synthesis of cortistatin A

2010-08-03T22:34:00.000-07:00

The proposal is as following:

The discussion of key steps:

1. the c-h insertion to form the five-membered ring is well known.

2. The oxygen bridge can then be formed through epoxidation and epoxide ring expantion which might be the biological way also.

3. alternatively the oxygen bridge can be formed by the diazo insertion into C=O and then 3+2 addition.

4.the 7-membered quadene can be constructed by carbene/carbenoid inerstion into aromatic rings followed by elimination of OAc.

Enantioselective Fp mediated alkene addition?

2010-07-31T00:33:00.000-07:00

the above reaction is from wiki
http://en.wikipedia.org/wiki/Cyclopentadienyliron_dicarbonyl_dimer

I am just wondering whether it is possible to make it enantioselective?
anyone did it already? not as I know.

A proposal for englerin A synthesis

2010-07-29T23:56:00.001-07:00

A hot molecular.
here I proposed a synthesis of Englerin A.

1. it is known we can open the epoxide from the more hindered/more stable site.

2. Single electron reduction then can form the required C-C bond and hopefully set the secondary alcohol.

The starting material can be prepared by C-H insertion. It is known to give trans fused 5,6 rings.

One method to enhance the power of the lab sonicator

2010-07-28T00:01:00.000-07:00

Besides of getting a more powerful sonicator, there is a simple method you can try to get more power out of the old sonicator.
the method is described in a journal paper by a Japanese researcher.
The method is simple: just add detergent to the water bath.
The result is substantial.
the reason is ovbious that the polymer has big molecular weight than water so the long-distance energy-transfer-ability is better.

Don't believe ? try it! and post the result here.

Proposal of synthesis of mayamycin

2010-06-22T23:01:00.000-07:00

Johannes Imhoff and co-workers at IFM-GEOMAR inn Germany have isolated a polyketide that had an IC50 value of 0.3 micromolar against HT-29 (colon adenocarcinoma) cell lines.

preparation of derivatives of Calicheamicin by enzyme ？

2010-06-13T19:10:00.001-07:00

1. The gene for the biosynthesis of calicheamicin is known. As I can remember, the calicheamicinone is constructed and attached to a sugar by an enzyme.
2. Calicheamicin is cheap by biosynthesis. calicheamicinone is difficult to make by chemical synthesis.
3. no known way to cleave Calicheamicinone from calicheamicin.

So is it possible to make new derivatives by mixing a new sugar with calicheamicin in the presense of some enzymes ?

reductive deoxygenation of vinlyl or aryl triflate

2010-05-28T20:28:00.000-07:00

Some conditions:

1. pd(PPh3)4/Bu3SnH/THF.
works for vinyl triflate.

2. pd(OAc)2/DPPF/Formic acid/TEA/Bu3SiH/DMF, 50C
works for electron-rich aryl triflate.

a graphic rss feed of wiley publications

2010-05-28T18:27:00.000-07:00

You can subscribe on these tuned feeds:

Angewandte Chemie International Edition
Advanced Materials
ChemInform
Chemistry - A European Journal
Chemistry - An Asian Journal
European Journal of Organic Chemistry
Advanced Synthesis Catalysis

You can get a completed description in the following page:

http://sulflower.com/?page_id=5040

proposal of synthesis of namenamicin

2010-05-26T01:11:00.000-07:00

Namenamicin is a enediyne.
the construction of the sulfur-containing quartery center is the critical part of the synthesis. This proposal uses a thionium ion to directly form the quartery center which can lead to the desired structure in an efficient way.

proposal of synthesis of dictyolactone

2010-05-25T23:48:00.000-07:00

1.The target is quite an interesting molecular.
2. This proposal mainly aims at the application of C-H insertion in total synthesis.

How to convert indole to tryptamine ?

2010-05-02T21:53:00.001-07:00

1. POCl3-DMF to make the indole aldehyde,
2.nitromethane to make unsaturated nitro indole.
3. LAH reduction to give you tryptamine.

to save one step, step 1 and 2 can be made into one step:
TFA, (CH3)2N-CH=CH-NO2, DCM to make the unsaturated nitro indole.

to increase the functional group compatibility of this sequence,
the LAH reduction step can be replaced by a 2 step sequence:
1. NaBH4/SiO2 reduction to take off the double bond.
2. Fe/AcOH reduction to convert the nitro group to amine.

How to reduce 2-oxyindole ?

2010-04-22T00:12:00.000-07:00

1. BH3. 0C.
slow reaction, low yielding, but can tolerate many functional groups, like ester.
can over reduced to indoline.

2. LAH
of course, amide can be reduced.

3. triflation first, then Pd/Et3SiH remove triflate.

4. lawesson's reagent to convert oxygen to sulfur, then reduce it by
Raney Ni.

5. some reducing reagent (red-al, super hydride...) under the help of acid (TFA, BF3-OEt2...)

How to prevent N-Cbz from falling off in hydrogenation condition ?

2010-03-11T16:35:00.000-08:00

N-Cbz is sensitive to H2/pd/c even in basic condition (TEA).
Known methods to prevent N-Cbz from falling off when doing hydrogenation reactions are not many.

1. Pd/c (en), H2, THF by Kosaku Hirota
pd/c (en) is pd/c deactivated by ethylenediamine. It is developed for chemoselective hydrogenation of reducible functionalities such as olefin, acetylene, nitro, azide, aromatic bromine or benzyl ester moieties, in the presence of O-Bn or N-Z protective
groups.
alkyl N-cbz is stable while double bonds are saturated.
aryl-N-cbz is unstable under this catalyst.
H. Sajiki, K. Hattori and K. Hirota, J. Org. Chem., 1998, 63, 7990.

2. Pd(OAc)2, DPPF,TEA, dmf,formic acid
Can do deoxygenation of phenol by OTf in the presences of N-Zbz.

3. squaric acid derivative/pd/c/H2
works ok, can saturate double bond without touch n-cbz.

4. pd/c/ph2s/H2
also can saturate double bond without touching n-cbz.

5. Pd(OAc)2, DPPF, TEA, dmf,formic acid, Et3SiH
works for deoxygenation of phenol triflate in the presense of N-Cbz.

Note:
1. pd/c(en) was tried. but n-cbz falled off quickly.
2. dppe/pd/formic acid method is OK.
3. ph2s/pd/c/h2 didn't touch N-cbz in my hand. but can't do deoxygenation of a phenol.

Making of N-methyl tryptamine

2010-01-27T21:15:00.000-08:00

United States Patent: 4946840

Preparation of 1-methyl tryptamine

This step began with a solution of:

(1) 1.6 g (10 mmol) of tryptamine; and (2) 20 ml of dimethylformamide. This solution was added dropwise to a suspension of: (1) 440 mg (11 mmol) of sodium hydride oil in (2) 30 ml of dimethylformamide. A dark brown solution resulted.

The dark brown solution was then stirred for 30 minutes at room temperature, cooled to 0.degree. C., and mixed with methyl iodide. (The methyl iodide was purified before use by passing it through a column of basic alumina.) After stirring for an hour at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated brine and then dried by sodium sulfate filtration. The filtrate was concentrated, the filtration residue loaded onto a 5.times.25 cm silicon dioxide column, and the column eluted with dichloromethane:methanol:triethylamine, 95:4:1. Pure fractions were concentrated to afford 970 mg (a 56% yield) of the first intermediate as a yellow oil.

note:
1. usual procedure requires protection of NH2 then alkylation on the indole Nitrogen which is unnecessary if you follow the above procedure.
the reaction works fine although the yield is not high and product separation is difficult.

Sonogashira Coupling

2010-01-19T19:02:00.000-08:00

he reaction was first reported by Kenkichi Sonogashira and Nobue Hagihara in 1975.

The coupling of terminal alkynes with aryl or vinyl halides is performed with a palladium catalyst, a copper(I) cocatalyst, and an amine base. Typically, the reaction requires anhydrous and anaerobic conditions, but newer procedures have been developed where these restrictions are not important.

solvent/base : tea or other amine, DMF, MeCN
Pd (0) is needed, pd(pph3)4, also pd (II) can be used which will be reduced to pd (0) by alkyne. pdcl2(pph3)2.
CuI.
some additive can increase the rate and yields: ex. Bu4NI,
temp: rt or heat.

note:
1. electron deficient aromatic halides gave better yields. electron rich aromatics don't react well.

Preparation of 2,3-dihydroxycyclopentanone

2010-01-19T00:37:00.001-08:00

The title compound seems easy to make, but actually costs a lot of steps, especially in enantiomeric form.

In the following paper, the auther had a new preparaion method.

Syntheses of (-)-Oleocanthal
by AB Smith III
J. Org. Chem. 2007, 72, 6891-6900

We began by adopting a protocol developed by Borchardt14 et al. (Scheme 6). Exhaustive
oxidation of 16 employing pyridinium chlorochromate (PCC) (4 equiv) provided lactone 17 in 62% yield. This transformation involves both oxidation of the primary alcohol and cleavage of
a C-C bond. Treatment of the resultant lactone (17) with the lithium anion derived from dimethyl methylphosphate produced enone (-)-18, which upon hydrogenolysis furnished ketone (-)- 11. The overall yield of (-)-11 from D-lyxose was reproducibly 50% on a 10 gram scale. Although D-lyxose is more expensive (ca. 3 times) than D-ribose, the starting material utilized in the first-generation synthesis, this sequence eliminates three steps, reduces the use of several expensive reagents, and is scalable. Equally important, only a single chromatographic separation is required after hydrogenolysis. Alkylation as achieved in the firstgeneration synthesis then afforded (-)-12 in 55-60% yield.

Is the new way really good?
I don't know. But at least there is a big drawback they didn't say it here.
In the experimental, they described the pcc reaction which needs a lot of benzene (cause cancer) as solvent.

Maze Solving by Chemotactic Droplets

2010-01-11T17:14:00.000-08:00

a very interesting paper.
in jacs asap.

Solving maze problems is not only relevant to the everyday issues
of urban transportation1 and to experimental psychology2 but is
also one of the model problems of network and graph theory3 as
well as robotics.4 With the advent of computers, algorithms for
maze solving have become automated, but the solution times still
scale unfavorably with maze size/complexity.5 Several groups have
thus explored the possibility of maze solving by physical, chemical,
or even biological systems: microfluidic networks,6 chemical waves7
or plasmas,8 or microorganisms growing in response to food
gradients within the maze.9 Inspired by the latter example, we
wished to create a system in which an inanimate/chemical construct
would be self-propelled and solve mazes in response to chemical
stimuli. Here we describe one such system comprising small
droplets powered by the combination of acid/base chemistry and
surface tension effects. When subject to a pH gradient within a
maze, these droplets move toward regions of low pH and find the
shortest of multiple possible paths. Taxis in our system is over
distances of several centimeters and derives from the convection
flows developed outside of the droplets.1

preparation of 4-t-butyldiphenol

2009-12-04T23:21:00.001-08:00

the following procedure seems to be the easiest.
from a chinese patent. application number:99124902

1. liquifiy pure diphenol by warming. no solvent needed.
2. add 1-5% TsOH-H2O.
3. keep temp at 135C, add 1 eq. MTBE dropwise in 2-3 hr (a cold condenser needed).
4. 1 hr later, you get the title compound with a yield >75%

note:
I tried the reaction, everything worked out as described.

a Convenient Procedures for Birch reduction

2009-11-24T02:55:00.000-08:00

Turk J Chem
29 (2005) , 513 - 518.
http://journals.tubitak.gov.tr/chem/issues/kim-05-29-5/kim-29-5-7-0504-3.pdf

The reduction of aromatic rings by solutions of alkali metals in liquid ammonia was discovered by Wooster and Godfrey14, who reacted toluene with sodium in ammonia followed by the addition of water. They reported a "highly unsaturated liquid product", which was not identied further. However, the real development of this reaction was to follow in the work by Birch15. This reaction is generally referred to as the Birch reduction, although in some cases it is simply called metal-ammonia reduction. Wild and Nelson16 found adding alcohol last to be advantageous, as opposed to having it present when the metal is added, and it was subsequently discovered that it should be avoided altogether with polynuclear compounds.

Compared to the other reduction procedures of converting benzene and its derivatives to corresponding nonconjugated dienes, the new reduction procedures have certain advantages. These include the following:
1) These reduction reactions are carried out at room temperature, avoiding the low temperatures, under -33oC, needed to obtain liquid NH3.
2) The procedures are environmentally friendly30−34. Much more NH3 is needed when liquid NH3 is used as solvent. Evaporation of liquid NH3 may damage the environment.
3) Control of moisture is easier in our method, and the reaction may go on for longer periods. When the reaction is conducted with liquid ammonia, it may be quenched by the developing moisture.
4) Evaporation of liquid NH3 may take a long time and some side reactions such as isomerization and reoxidation may be observed. \
5) It is unnecessary for the researcher to observe the reaction carefully and continuously in the
present method because temperature control is not necessary, whereas the temperature must be checked in the reaction with liquid NH3.

Procedure 1: Reduction of benzene to 1,4-cyclohexadine.
In a 500-mL, 2-necked, round-bottomed flask tted with a reflux condenser and a stirring bar were placed tert-butanol (72 g, 0.963 mol, 2.85 equivalents), dry benzene (27.3 g, 0.35 mol, 1 equivalent) and dry THF (120 mL). The flask was attached to gas ammonia (NH3) whose pressure was approximately 1 atmosphere (atm) and the resulting solution was stirred. The reaction mixture was cooled in an icewater bath and then freshly cut lithium (7.35 g, 1.05 g-atom, 3 equivalents) was added over 3-5 min. The temperature of the bath was allowed to rise gradually to room temperature. After the addition of lithium was completed, the reaction mixture was stirred for 5 h. Two phases appeared in the reaction mixture.
The top and bottom phases were brown and gray, respectively. The mixture was cooled in an ice-water bath again. Cold water was added slowly and carefully to the flask until all the lithium was consumed, as evidenced by the conversion of the colors to white. The reaction mixture was poured into a mixture (250 g) of water and ice and was acidied with the addition of 2 N cold hydrochloric acid. The organic layer was separated and washed with cold water (100 mL), a solution of NaHCO3 (5%, 50 mL) and water (75 mL), in order that. The reduction product, 1,4-cyclohexadiene, was dried over CaCl2 and ltered. The yield (23.5 g) and conversion of the reaction were 84% and 100%, respectively.

Note:
checked this reaction by myself, it really works.

substrates scope:
obviously, product of entry 5 and 6 should be switched.

All-Up Reactive Conformation of Chiral Rhodium(II) Carboxylate Catalysts

2009-11-06T01:33:00.000-08:00

by
Vincent N. G. Lindsay, Wei Lin, and Andre´ B. Charette*
doi: 10.1021/ja9044955

Chiral Rh(II)-carboxylate catalysts have found widespread use in the field of metal carbene transformations, including asymmetric cyclopropanation reactions.1 Though several enantioselective transformations have been developed to date, little evidence is known
on how the chirality is projected near the reaction center by the chiral carboxylates. Davies et al. have suggested that four main possible symmetries have to be considered, from which only two
possess equivalent catalyst faces (Figure 1, C2 and D2).2 It has been postulated that catalysts having two different carbene-formation sites should not be effective in inducing enantioselectivity, since the more kinetically active and accessible face is apparently achiral (C1 andC4).

However, Fox et al. recently contradicted this concept by reporting the highly efficient asymmetric cyclopropanation of alkenes with R-alkyl-R-diazoesters using such a catalyst, where DFT calculations demonstrated that the all-up conformation of the catalyst plays a prominent role in these reactions.

All our experiments suggest that the halogenated rhodium carboxylate catalysts used in this process react through an all-up conformation, which is consistent with Fox’s DFT calculations made on non-halogenated analogues.

C-3 arylation of indole

2009-11-04T19:38:00.000-08:00

Challenging chemical architectures of natural origin often point to gaps in synthetic methodology. For instance, there is a shortage of methods for C-3 quaternization of indoles with an aryl appendage. A number of natural products including haplophytine,1 bipleiophylline,2 hodgkinsine,3 and leptosin D4 (Fig. 1) contain a quaternary indole C-3 with an aryl appendage or a structure theoretically derived from such a motif as with haplophytine.1h Recent efforts by Nicolaou and co-workers,5 and Fukuyama and coworkers6 in the context of haplophytine have demonstrated the feasibility of the synthetic union of a substituted indole C-3 with an
aryl nucleophile,6 or a pseudo-aryl electrophile,5 however, both approaches were highly substrate specific and proceed in less than 25% yield.
In a much simpler context, Barton and co-workers have shown that treatment of skatole with tert-butyl tetramethylguanidine (BTMG) in the presence of 1.5 equiv of Ph4BiOTs results in
95% conversion to the C-3 disubstituted indolenine 1 (Fig. 2).7 This approach suffers from the required use of 4 equiv of aryl donor for each aryl group transfer. Additionally, extensive studies in these laboratories have shown that this bismuth mediated protocol does not have broad substrate scope and requires a tedious five-step reagent preparation.8

Baran reaported this method:
Tetrahedron 65 (2009) 3149–3154

The strategy has been generalized and performs well with a wide variety of substrate and reagent combinations. While this strategy is somewhat limited with respect to efficiency in appending very electron rich arene rings to C-3 of indole substrates, other than highly substrate dependent cases of Nicolaou5 and Fukuyama,6 there are no comparable methods in the
literature that allow for the direct C-3 quaternization of indoles with an arene ring.

Scott Phillips, pen state university

2009-10-30T00:53:00.000-07:00

Assistant Professor of Chemistry, Pennsylvania State University, 2008-

Research Fellow, George Whitesides Group, Harvard University, 2006-2008

Developed new materials and detection platforms with applications in
medicine, drug development, and less-industrialized nations.

Post-Doctoral Fellow, Matthew Shair Group, Harvard University, 2004-2006

Designed, synthesized, and analyzed the behavior of beta-strand and beta-sheet mimics.
Determined the energies associated with amino acid interactions in beta-sheets.
Developed chemical hosts to recognize peptide guests sequence-selectively in
water.

Education

Ph.D., University of California, Berkeley, 2004
boss Paul A. Bartlett

B.S., California State University, San Bernardino, 1999

research area:

Chemistry for Resource-Limited Environments

We are using organic chemistry to create autonomous diagnostics--that is, diagnostic devices that provide all of the functions typically obtained with instruments i.e., (selectivity, sensitivity, quantitative measurements, and clearly displayed information), but using only organic reactions on a piece of paper. Our goal is to devise chemistry that forms the basis for exceedingly simple and disposable diagnostics devices. These systems will be useful in the developing world, emergency rooms, and other applications requiring portable and inexpensive devices for detecting disease or pollution. Projects in this area include: (i) Developing new reagents and strategies for signal and target amplification; (ii) developing new reactions for activity–based detection; and (iii) developing new strategies and new reagents for stabilizing biomolecules.

Designing Living Materials

We are developing materials that respond to external signals by changing shape, function, and/or surface properties. This work can be extended to developing materials that grow, and possibly divide. One aspect of this work includes the design and synthesis of environmentally–friendly plastics.

Unconventional Reaction Methodology

As the price of crude oil continues to rise, so too will prices of bulk chemicals derived from oil. We are developing reactions that use CO₂ as an inexpensive carbon source (in place of oil) for making bulk chemical building blocks.

A second program in this area focuses on reaction networks that are self-perpetuating, the simplest of which is an autocatalytic reaction (where a molecule makes more of itself). We plan to expand autocatalytic behavior into more complex reaction networks, with the goal of developing systems that provide useful function and/or byproducts.

Donald A. Watson, University of Delaware

2009-10-20T23:40:00.000-07:00

Donald A. Watson was born in California in 1976. He received his BS in Chemistry from UC San Diego in 1998. During his undergraduate years, he worked in the laboratories of Professors K.C. Nicolaou and Emmanuel Theodorakis, working on natural products synthesis.

He completed his PhD in Organic Chemistry at UC Irvine in 2004, working under the direction of Professor Larry E. Overman. His dissertation work focused on stereochemical problems in palladium catalyzed transformations.

From 2004 to 2006 he was a NIH Postdoctoral Fellow in the laboratories of Professor Robert G. Bergman at UC Berkeley. During this time he developed zirconium-based catalysts for asymmetric intramolecular hydroaminations. He then moved to the Massachusetts Institute of Technology as to take a position as a Postdoctoral Associate in Professor Stephen L. Buchwald's laboratory, where he studied metal catalyzed processes C-F bond formation.

He joined the Chemistry and Biochemistry faculty at the University of Delaware as an Assistant Professor in July 2009.

1. Bimetallic Complexes for Remote Substrate-Directed Catalysis.

2.New Methods for the Preparation of a-Chiral Amines.

3. Electrocatalysts for the Reduction of CO2 to Methanol.

Publications:
pending

Bischler-Napieralski reaction

2009-10-15T23:04:00.000-07:00

reagent: pocl3
solvent: mecn, benzene, toluene, dcm, dmpu.
temp: rt - reflux
time: several hours.

not a nice and clean reaction. usually low yielding because of the strong acidic condition.
the product imine is sometimes not stable.

some milder conditions:
1. pph3/ccl4/reflux
2. Tf2O

a nice link:

http://www.organic-chemistry.org/namedreactions/bischler-napieralski-reaction.shtm

Mary Watson, University of Delaware

2009-08-27T13:44:00.000-07:00

Mary Waterson,
BS, 2000, Harvard University, phd, 2006 with Larry E. Overman, 2006–2009, postdoc with Eric N. Jacobsen. During her postdoc, she developed a nickel-catalyzed method for olefin arylcyanation via activation of C–CN bonds. She joined the faculty at the University of Delaware in July 2009.
Research:
centered on the discovery of new catalytic, stereoselective methods for organic synthesis by utilizing the power of both transition metal and Brønsted acid catalysts.
1. Selective Activation of Relatively Strong Bonds
C-H activation.
2. Brønsted Acid-Catalyzed Reactions of Unactivated Olefins
enantioselective additions of H–X (X = C, O, N, etc.) across olefins.

publication:
pending

A proposal of synthesis of maoecrystal V

2009-08-20T14:37:00.000-07:00

In 2004, islolated was the maoecrystal V with a novel C19 skeleton from the leaves of a Chinese medicinal herb, Isodon eriocalyx. it is remarkably active against HeLa cells (IC50) 0.02 ug/mL).
The two chiral quaternary carbons and a tertiary alcohol in a contiguous setting served to pose interesting challenges to the science of chemical synthesis.
So far, no total synthesis. the following are just my thoughts.

another one. not better.

or umpolung chemistry.(sorry, one methyl is missing in the product).

what can you do if your precious compound spilled?

2009-08-17T21:12:00.000-07:00

My precious compound spilled out of a bottle and sticked onto a piece of plastic foam. the foam was dissolved by the dcm which is the solvent with my compound.
Discard it ? no, the boss will kill me.

1 I cut the foam off and dissolved the foam (with my compound) with DCM/EtoAc.
The foam dissolved without problem. concentrated. passed a pad of silica gel, eluting with etoac, nothing can be removed.
2. checked the structure of the foam through internet, it is polystyrene,
http://en.wikipedia.org/wiki/Polystyrene
tried to run a TLC with pure polystyrene, no obvious spots.

3. tested the solubility of the foam in organic solvents.
soluble: dcm, etoac, ether
unsoluable: meoh, hexanes,
4. so meoh was added to precipitate the polystyrene, and a simple filtration with silica gel removed the plastic.

The radical reactions of imine radicals

2009-08-07T10:13:00.001-07:00

Tetrahedron
Volume 65, Issue 36, 5 September 2009, Pages 7415-7421

In conclusion, imine radicals 5 and 15 can be generated from the manganese(III), silver(II) oxidation of 2-amino-1,4-benzoquinones. These free radical reactions provide efficient methods for the generation of the dimeric products 4 and 14. In the presence of styrene, twistane 17 was afforded from 2-phenylamino-1,4-benzoquinone 1 via a radical annulation reaction of imine radical 5.

mechanism:

Peptide–Dirhodium Ligation

2009-08-05T13:02:00.000-07:00

Controlling Peptide Structure with Coordination Chemistry: Robust and
Reversible Peptide–Dirhodium Ligation
DOI: 10.1002/chem.200901266
Chem. Eur. J. 2009, 00, 0 – 0

interesting paper.

A novel iodine-mediated tandem cyclization

2009-08-05T11:54:00.000-07:00

Chem. Commun., 2009DOI: 10.1039/b910232a

A novel iodine-catalyzed tandem cyclization–cycloaddition reaction of ortho-alkynyl-substituted benzaldehydes leading to polyoxacyclic ring systems has been developed, which represents a useful approach towards the synthesis of the oxabicyclo-[3.2.1]octane ring skeleton found in a variety of natural products.

mechanism:

Stereoelectronic Effect for the Selectivity in C−H Insertion of Alkylidene Carbenes

2009-08-01T11:19:00.000-07:00

Stereoelectronic Effect for the Selectivity in C−H Insertion of Alkylidene Carbenes and Its Application to the Synthesis of Platensimycin

Sang Young Yun, Jun-Cheng Zheng and Daesung Lee* Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061J. Am. Chem. Soc., 2009, 131 (24), pp 8413–8415DOI: 10.1021/ja903526g

High selectivity in the insertion between two competing C-H bonds was observed and is believed to be the manifestation of a strong stereoelectronic effect of oxygen substituents.

bromination with POBr3 POCl3

2009-07-31T08:39:00.000-07:00

usual condition use Phosphorus(V) oxybromide or Phosphorus(V) oxychloride
in toluene, xylene and heat to over 120 C.
during the rxn, HBr/Br2 can be generated.
sometimes bring side reactions and low yields.

the following paper has a better procedure:
J. Chem. Soc., Perkin Trans. 1, 2002, 529–532

The use of phosphorus oxychloride to prepare compound 12 was sometime fraught with side reactions. Although a very efficient procedure has been recently reported,16 we developed a robust method, also using phosphorus oxychloride or bromide, but in the presence of potassium carbonate in boiling acetonitrile. Thus the troublesome hydrolysis of the reaction mixture takes
place under neutral conditions, without heat evolution, and avoids unwanted decomposition. The 1-halogenated derivatives 13 or 14 were thus routinely prepared in 82–85% yields.

Oxidation of Secondary Alcohols by Sodium Hydride ?

2009-07-21T12:37:00.000-07:00

author:
Xinbo Wang, Bo Zhang and David Zhigang Wang

School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China 518055

J. Am. Chem. Soc., Article ASAP

DOI: 10.1021/ja904224y

Publication Date (Web): July 21, 2009

In this recent paper, a novel oxidation of Secondary Alcohols by Sodium Hydride was described.

. they said "Uncovered here are some unprecedented reactivities of this classical reagent under very mild conditions, including alcohol oxidation, tandem allylic alcohol oxidation−hydride conjugate reduction, and aldehyde oxidative amidation. These readily implementable transition-metal-free processes feature exceptional material accessibility, operational simplicity, and environmental compatibility."

very nice work.
while reading this paper, some thoughts popped out of my little brain.
Could it be some other metal species instead of NaH really catalized the rxn?

it is known that nah is a base, sometimes can be a hydride donor, but Na+ never seen as a hydride acceptor.
I guess there is something else which catalized the rxn.
1. although nah is catalyst and all recoved after rxn, they still need a huge amount.
2. nah is made from na metal, presence of trans metal such as Pd is very possible.
3. there is an example by a japanese group which found a heck coupling rxn without pd, but finally they said the base they used (t-buOK, K2CO3?) contains trace of pd which did the trick.
(can't really remember all the detail, sorry).

anyway, this is still a very useful rxn and I hope to see more detailed research on this topic which may answer my question.

news:23,07,2009
http://totallysynthetic.com/blog/?p=1903
They already found O2 is essential for the rxn to happen.

Haouamine biosynthesis ?

2009-07-13T14:10:00.000-07:00

Baran found out biosynthesis of haouamine 1 via 4 is not possible .fig. 1, so turned down a proposed biosynthesis route by a french group. scheme 2.
here I propose a revised synthetic route a-[b]-c based on the biosynthesis scheme.
the reasoning is to make a bigger sized macro ring b first, then the center six membered ring should be accessable.

synthesis of the highly strained 3-aza-[7]-paracyclophane core of haouamines

2009-07-11T15:20:00.000-07:00

by Pete Wift
organic letters 2006 1901.

failed methods:
1. various macrolactamization conditions (Scheme 1).
2. synthesis of medium-ring biaryl compounds by organocuprate oxidation also failed (Scheme 2).
3. ring contraction strategy. (Scheme 3)

finally successful method:
As an alternative to the more traditional strategies for overcoming the kinetic barriers of ring closure, we envisioned the preparation of a macrocyclic ring composed of a tetrahydro derivative and subsequently an introduction of the ring strain by altering the hybridization of C from sp3
to sp2 by elimination of methanol. Tautomerization to the phenol would result in the formation of the biaryl system(Scheme 4).

Interestingly, this paper came out about the same time as Baran's first total synthesis (receive date).

Overmann synthesis of Actinophyllic Acid

2009-07-07T08:54:00.000-07:00

Overman, Martin and Rohde. JACS, 2008, ASAP. DOI: 10.1021/ja803158y.

although it is racemic, it still went to jacs.
key step:

aza-Cope Mannich.

some molecular accomplished by this method:

an interesting paper from Eun Lee

2009-06-24T14:35:00.000-07:00

A Carbonyl Ylide Cycloaddition Approach to Platensimycin
Lee, Kim, Jang, Choi and Chung. ACIEE, 2008,

why interesting?
"they knew that a terminal olefin would have the incorrect electronic configuration to lead to the desired product in the [3+2] before attempting the chemistry. However, they did the reaction anyway, and ended out with a cracking yield of the wrong isomer and only a trace of the desired. Playing with the HOMO coefficient by using a vinyl halide in place of the terminal olefin allowed the chemistry to proceed in a tasty 83% yield, with small amounts of the competing products."
from http://totallysynthetic.com/blog/?p=976

A proposal to make 7-Methylomuralide

2009-06-22T16:57:00.000-07:00

Corey recently published the synthesis of (-)-7-Methylomuralide. very short synthesis. Here is my proposal. Also short, but racemic.

A way to make diazo compounds

2009-06-22T16:22:00.000-07:00

From:
jac_2004_126_12222
Michael E. Furrow and Andrew G. Myers*

The bimolecular reaction of carboxylic acids with diazoalkanes
to form esters is among the mildest and most efficient of organic
transformations but is seldom used in synthesis beyond the
important case of methyl esterification.1 This is largely a consequence
of the inaccessibility and poor stability of higher diazoalkanes
as substrates.2 In this work we describe a new method for
the synthesis of diazoalkanes by the oxidation of N-tert-butyldimethylsilylhydrazones
(TBSHs) with (difluoroiodo)benzene,3 a reagent
heretofore unexplored in the context of hydrazone oxidation.
When conducted in the presence of a carboxylic acid substrate,
the oxidation leads to efficient esterification in situ (Scheme 1). In
addition to greatly extending the range of diazoalkanes that are
now available for esterifications, this new protocol offers significant
advantages with regard to safety, for diazo intermediates are neither
isolated nor achieve appreciable concentrations during the reaction.

deprotection/protection of allylether

2009-06-08T14:34:00.000-07:00

1. formation of allyl ether.
allylbromide/base

2. deprotection.
1. pdcl2/acoh/Naoac/water. heated to 70C for 2 hr.
works ok, but sometimes cause decomposition of my sugar compound.
2. pd(PPh3)4/acoh, 80C. 2hr.
works great, high yield. rxn started even before heating at rt!

Swern oxidation typical procedure

2009-05-05T11:31:00.000-07:00

Procedure: 25 mL 1-neck flask, stirbar, septum, N2 inlet

Dissolved 0.077 mL of oxalylchloride (II) in 4.0 mL of dry CH2Cl2. Stirred; cooled to -78 C. Added 0.125 mL of DMSO. Stirred 10 min. Added a solution of 0.096 g of alcohol I in 1.0 mL of CH2Cl2. Stirred 15 min. Added 0.250 mL Et3N. After 15 min, warmed to 0 C. After 10 min TLC showed complete reaction. The reaction mixture was placed on a silica gel column and the product was isolated by flash chromatography .

notes

1. temp is critical for high yielding.
2. other than oxalylchloride, many activator can be used to overcome problem caused by oxalylchloride (ex. Cl-), ex. P2O5.

cited from
http://www.alsnotebook.com/oxidswern.html

an approach to Actinophyllic Acid

2009-05-04T13:19:00.000-07:00

This synthesis plan was made by me about half a year before Overmann's beautiful synthesis of the same molecular.

An approach to Sordaricin

2009-05-04T12:33:00.000-07:00

This proposal is just another application of carbene chemistry in the total synthesis of natural products.

The armed–disarmed concept

2009-04-30T11:06:00.000-07:00

The armed–disarmed concept refers to the relative ease
or difficulty of activating a sugar as a glycosyl donor in
glycosylation reactions.1 Disarmed glycosyl donors have
highly electron withdrawing protecting groups (e.g., esters,
amides) that destabilize the formation of the oxycarbenium
ion/ion pair2 during the course of the glycosylation,
whereas less electron withdrawing protecting groups (e.g.,
ethers) are less destabilizing and therefore arm the glycosyl
donor.

Tetrahedron Letters 49 (2008) 2546–2551

preparation of [Me2SSMe+][BF4-] (DMTSF)

2009-04-24T15:29:00.000-07:00

what DMTSF can do?
electrophilic sulfenylation reagent capable of reacting with nucleophilic atoms;² reacts with electron-rich alkenes to promote addition reactions,³ cyclizations;⁴ activates dithioacetals,⁵ trithioorthoesters,⁶ and thioglycosides⁷ for carbon–carbon or carbon–heteroatom bond forming reactions). from e-EROS Encyclopedia of Reagents for Organic Synthesis.

Inorganic Chemistry, Vol. 42, No. 8, 2003
Following the published procedure,
solution containing 0.74 mL of methyl disulfide (8.06 mmol) in
7 mL of CH3CN was added dropwise to an equimolar amount of
Me3O+BF4- (1.04 g, 8.06 mmol) dissolved in 8 mL of CH3CN
at 0 °C. After the mixture had been stirred for 2 h at 0 °C, dry
ether was added to precipitate dimethylthiomethylsulfonium fluoroborate
([Me2SSMe+][BF4-]) as a white solid that was stored in
the glovebox at -36 °C (1.1 g; yield, 69%).

An example of protection of alkene by Diels-alder rxn

2009-04-24T10:48:00.000-07:00

New approaches for the synthesis of erythrinan alkaloids

Org. Biomol. Chem., 2009, 7, 1963–1979

retro d-a reaction happened by heating in vacuum. 80% yield.

A synthetic proposal of calicheamicinone

2009-04-22T08:52:00.000-07:00

This synthetic plan features a rhodium mediated cyclopropanation and a curtius rearrangement. the overall steps is about 16 which is almost half of the existing synthesis!
The biggest problem I can forsee is the stability of the enediyne before the cyclopropanation.

keyword: calicheamicin, calicheamicinone, retrosynthetic plan, proposal, synthesis

solvents for developing of TLC plates

2009-04-10T09:09:00.000-07:00

1. The expected elution order of organic classes

alkanes
alkenes
ethers
halogenated hydrocarbons
aromatic hydrocarbons
aldehydes and ketones
esters
alcohols
amines
carboxylic acids

2. Eluting power of organic solvents

alkanes (hexanes, petroleum ether)
toluene
halogenated hydrocarbons (methylene chloride)
diethyl ether
ethyl acetate
acetone
alcohols
acetic acid

3. some useful combinations:

EtOAc in hexanes
MTBE in petroleum ether
EtOAc in benzene
MeOH in methylene chloride
acetone in methylene chloride

chiral building blocks - Others

2009-04-07T13:14:00.001-07:00

chiral building blocks - Amines

2009-03-29T21:16:00.000-07:00

chiral building blocks - Amino Alcohols

2009-03-29T21:15:00.001-07:00

chiral building blocks - Simple Alcohols

2009-03-29T21:12:00.000-07:00

chiral building blocks - Isocyanates

2009-03-29T21:08:00.000-07:00

chiral building blocks - amides

2009-03-28T14:53:00.001-07:00

chiral building blocks - esters

2009-03-28T14:43:00.001-07:00

chiral building blocks - acids

2009-03-28T14:40:00.000-07:00

Preparation of Ethyl Diazoacetate

2009-03-28T14:37:00.001-07:00

A solution containing 140g glycine ethyl ester hydrochloride (1mol) in 250ml water is placed in a 2L four- neck flask. 600 ml dichloromethane is added and the mixture is cooled to -5ºC under a nitrogen atmosphere. A solution containing 83g sodium nitrite in 250ml water is cooled to 0ºC and added with stirring to the reaction mixture. While keeping the reaction temperature below -9ºC, 95g 5% sulfuric acid is added dropwise to the reaction over a 3 minute period. After ten minutes addition stirring the reaction is transferred to a 2L separatory funnel while cold. The isolated yellow-greenish organic phase is poured into a cooled 1L 5% sodium carbonate solution, then placed into a separatory funnel and shaken. The isolated aqueous phase is extracted with 75ml dicholoromethane, dried over 15g anhydrous sodium sulfate, and concentrated under reduced pressure (350mmHg). Futher concentration at 20mmHg and a bath temperature of 35ºC gives 90 ~ 100g (79 ~ 80%) yellow oily substance.

The product is pure enough to be used for ordinary synthesizing purposes. It is explosive, and distillation under even reduced pressure is hazardous.

*Ethyl diazoacetate is explosive and very toxic. Wear protective gloves, protective goggles, protective mask, and use a safety screen. Work in a well ventilated fume hood.

Preparation of Diazomethane

2009-03-28T14:26:00.000-07:00

From: http://www.tcieurope.eu/en/product/synthetic-chem/S026.shtml

A reaction and distillation apparatus is assembled by connecting an addition funnel and condensor to a 100ml long-neck distillation flask. Two in series receiving flasks are connected to the apparatus with the second flask containing an induction tube. A solution containing 6g potassium hydroxide in 10ml water, and a solution containing 35ml Carbitol (Diethylene glycol monoethyl ether) and 10ml of ether are placed in the distillation flask. 20 ~ 30ml ether is placed in the second receiving flask making sure the induction tube is immersed into the ether. Both receiving flasks are cooled to 0ºC. A solution containing p-toluenesulfonyl-N- methyl-N-nitrosamide (21.5g, 0.1mol) in 140ml ether is placed in the addition funnel. Heat the distillation flask to 70ºC in a warm water bath. As the ether begins to boil, start adding the p-toluenesulfonyl-N-methyl-N-nitrosamide solution dropwise over a 20 minute period. Swirl distillation flask from time to time. About 3g of diazomethane (0.07mol) is dissolved in ether distillate.
　The reagent should be used at once without storing it.
* Diazomethane is explosive and highly toxic. Wear protective gloves, protective goggles, protective mask and work in a well ventilated fume hood. Also place a safety shield in front of distillation apparatus. Diazomethane may explode upon contact with ground glass joints or other scratched glass surfaces, so avoid handling or preparing this compound with such surfaces. Ordinarily, diazomethane is used as a solution in ether.
*We have TMS diazomethane available. This reagent is analogous in reactivity to diazomethane, but less explosive and less toxic. Please consider using this reagent prior to preparing diazomethane.
-----------------------
Note:
0. diazomethane is yellow colored, easy to know when to stop ether distillation.
1. the diazomethane distilled by this way contains water, if anhydrous diazomethane needed, KOH pellets can be added into the diazomethane ether solution and put in freezer overnit to get dry diazomethane.
2. TMS diazomethane can't replace diazomethane, although in most case, it is a good substitutuion.
3. dry diazomethane ether solution can be stored in freezer for a while (several days). when diazomethane decomposed, the yellow color will disappear.

Preparation of Cyclopentadiene

2009-03-28T14:21:00.001-07:00

From: http://www.tcieurope.eu/en/product/synthetic-chem/S026.shtml

The reaction apparatus (Figure 1) is assembled by attaching a thermometer, Vigreaux distilling column and Liebig condenser to a 500ml two necked flask. The receiver is cooled by means of a refrigerants or freezing mixtures.
Dicyclopentadiene (195g) is placed in the two necked flask and heated to about 160ºC with an electric heating mantle or oil bath. Thermal decomposition begins at about 150ºC and distillates at 43 ~ 46ºC can be obtained (addition of iron powder expedites the thermal decomposition rate of Cyclopentadiene). Heating is applied slowly, because rapid temperature increases cause dicyclopentadiene to distill prior to undergoing thermal decomposition. In such a case, re-distillation allows narrow boiling-point distillates.
Cyclopentadiene dimerzes rapidly at room temperature and should be used immediately.

Di-n-butyltin Oxide

2009-03-05T13:49:00.000-08:00

1. in sugar chemistry, equatorial OH of a cis-diol (6 membered sugar) can be selectively protected by BuSnO then benzylbromide/allylbromide in dmf.

2. axial OH of a cis-diol can be oxidized by (BuSnO/MeOH then BuSnOMe/Br2) to ketone selectively.

How to make beta anomer of sugar?

2009-02-19T16:23:00.000-08:00

anomeric effect is effective when you have free -OH ( or ether protected) around the sugar ring.

So when you make a glycoside at the anomeric position, you will get a mixture of alpha and beta anomers.
Alghough alpha anomer is thermodynamically more stable, beta anomer formation is quicker.

how do you make beta anomer selectively?
one way is to protect the -OH on the sugar ring with ester (ex. acetate) which have small anomeric effect when you do reaction at anomeric position.

why methyl alpha-D-glucopyranoside is more stable than beta?

2009-02-05T15:23:00.000-08:00

methyl alpha-D-glucopyranoside is so cheap, 1 kg =$50 ,
methyl beta-d-glucopyranoside is so expensive, 5 g=$50

alpha-D-glu has an axial methoxy, but more stable,
beta-D-glu has the methoxy equatorial, but less stable,

why?
answers are in this link:

http://www.cem.msu.edu/~reusch/VirtualText/carbhyd.htm

looking for: anomeric effect.

The Hydrolytic Kinetic Resolution – Jacobsen’s Catalyst

2009-01-30T15:02:00.000-08:00

An Introduction

Enantiomerically pure epoxides are extremely valuable
chemical compounds due to controllable but high reactivity of
epoxides coupled with the vast array of reactions they can
undergo with retention of stereochemical integrity. One can
envision a number of direct routes to asymmetric epoxides
(Figure 1). Asymmetric carbene addition has never achieved
broad applicability due to both the instability of the carbenes,
low yields and low enantioselectivities. The most common
methods for epoxide formation is controlled addition of
activated oxygen to an alkene. For some olefins, this process
can be made enantioselective, an achievement for which K.
Barry Sharpless was awarded 1/2 of the Nobel prize in 2001.
The Sharpless asymmetric epoxidation is restricted to internal
olefins with pendent functionality such as an alcohol which
helps direct the reaction. In 1990, Jacobsen, fresh of a postdoc with Sharpless and at the beginning of his
independent career at UIUC, introduced a system which obviated the use of a directing group, but the
enantioselctivies were not phenomenal and yields were not spectacular. Furthermore, terminal olefins were still
difficult. Simultaneously and independently, Katsuki (a Sharpless postdoc from ten years prior) revealed a
closely related system which suffered the same drawbacks.
In the mid 1990’s, having moved to Harvard, Jacobsen
was exploring the use of a variety of metal catalysts all based
around a chiral “salen” ligand scaffold (Figure 2). The first
breakthrough came with the desymmetrization of meso
epoxides with Me3SiN3 catalyzed by a complex where M =
CrCl (Figure 3). While it is generally easily controlled on the
laboratory scale, the potentially explosive nature of Me3SiN3
makes it a poor choice for industrial processes. Furthermore, the resolution of terminal epoxides remained
elusive. Thus the search of a better both a better catalyst and a better nucleophile continued. The hydrolytic
kinetic resolution (Figure 3) was discovered due to a fortunate accident. Jacobsen had been working with a
reduced for of a chromium-salen complex. Surprisingly, 1,2-epoxyhexane (Figure 3, R = n-Bu) proved to be an
extraordinarily good substrate. Furthermore, the
solid residue isolated from the end of reactions
with that substrate worked extraordinarily well to
resolve others! Careful investigation led to the
discovery that acetic acid, left from the industrial
synthesis of epoxyhexane, had served to catalyze
the air-oxidation of the metal, increasing the activity of the catalyst. At long last, enantiomerically pure terminal
epoxides were readily available through a simple two step process – epoxidation of a terminal olefin and
selective hydrolysis of one enantiomer of the resulting epoxide. This was an event dramatic enough to warrant
publication in Science, an extreme rarity for a synthetic methodology.
Jacobsen has proceeded to exploit this ligand framework, and some variations on it, to enantioselectively
catalyze a broad range of reactions including an array of nucleophilic epoxide opening reactions,
hydrocyanation of aldehydes and imines, conjugate addition of HCN, aldol variations and Diels-Alder
variations, to name a few. In fact, the ligand shown in Figure 2 has become known simply as “Jacobsen’s
ligand”. The technologies developed in Jacobsen’s lab have been commercialized by Rhodia ChiRex, a joint
venture between Jacobsen and global chemical giant Rhodia. The catalysts have been used in many
pharmaceutical syntheses and, it sometimes seems, by nearly every synthetic organic chemist alive. Other
researchers too numerous to name have also used these ligands and catalysts in developing other reactions too
numerous to count. Truly it is a phenomenal impact for an accidental discovery barely a decade old.

From: http://www.chem.colostate.edu/rovis/

Stains for TLC

2009-01-30T11:51:00.000-08:00

Although the recipes can be found on internet, here are some I used in the lab.

Ceric Ammonium Molybdate (CAM): This stain is prepared by dissolving 2.5 g of (NH4) 6-Mo7O24 and 1.0 g Ce(SO4)2 in 90 mL of water and 10 mL of conc. H2SO4. The plate is developed by heating on a hot plate. This stain chars blue and is good for polyhydroxylated compounds.

Potassium Permanganate: This stain is prepared by dissolving 3 g of KMnO4 and 20 g of K2CO3 in 5 mL of 5% NaOH and 300 mL of water.

p-Anisaldehyde: This clear tan stain is prepared by dissolving 0.7 mL of p-anisaldehyde in 250 mL of EtOH containing 9.5 mL of conc. H2SO4 and 2.7 mL of acetic acid. The plate is developed by heating on a hot plate. This stain chars lavender and is good for oxygenated compounds.

Sometimes, I found PMA is the only one that can show me the spot.

Phosphomolybdic acid (PMA): This green-yellow stain is prepared by dissolving ~3-4 g of PMA in 100 mL of EtOH. The plate is developed by heating on a hot plate. PMA is the most commonly used stain for organic materials, since it reacts with a wide variety of functional moieties. The spots are usually black against a yellow-green background. PMA is also effective with extremely dilute reaction samples and in this regard can be used semi-quantitatively.

Sulfur containing quaternary carbon center

2009-01-29T21:36:00.000-08:00

How to build a S-containing quaternary carbon center
like this:

ways I can find out:
1. enolate attack a S-nucleophile. ex. MeSSMe.
2. 3,3-sigmatropic rearrangement.
3. thioketone attacked by a Nu-.
4. thiol 1,4-addition.
5. thionium ions (ex. from thiolketal) attacked by a Nucleophile.
6. methoxyphenylthiomethyllithium addition to ketone, then rearrange using SOCl2 in py or MeSO2Cl /TEA.

Some pdf from group of Professor Scott Denmark

2009-01-29T08:58:00.000-08:00

very good presentations, very broad topics.

http://www.scs.uiuc.edu/denmark/presentations/

List of 2008:

Transition Metal‐Catalyzed Carbon‐Carbon Bond Cleavage (C‐C Activation)

The Petasis-Ferrier Union/Rearrangement

Interrupted Nazarov Cyclizations

Nickel Catalyzed sp3-sp3 Couplings

Rhodium Catalyzed [5+2] Cycloaddition

The 5 W's of Chiral Dienes as Ligands for Asymmetric Catalysis

Theory and Design of Mobius Molecules

Alois Fürstner: Applying Organometallic Chemistry in Total Synthesis

Pyrrole-Imidazole Alkaloids

Go With the Flow. . . Microfluidics and Microreactors: An Organic Chemist's New Round Bottomed Flask

Catalytic Carbonylative Ring Expansion of Epoxides and Aziridines

Conbinatorial Approaches in Homogeneous Catalysis Development: Case Studies

Biology as a Tool for Synthetic Chemistry

Enantioselective Protonation

The Mechanism of Rhenium Catalyzed Olefination of Aldehydes

Gold Activation of pi-Systems [Propargylic Esters] What Makes Gold Special Relativity Speaking

Frustrated Lewis Pairs: Novel Reactivity and Mechanism

benzylidene acetal of glucopyranoside

2009-01-26T14:49:00.000-08:00

formation:
1. bnezaldehyde -ZnCl2
2. benzaldehyde dimethyl acetal 3 eq.- TsOH 0.1 eq. in MeCN, refluxing. 2hr.
works great. >60% yield.
workup procedure:
remove mecn to about half invacuo, then NaHCO3 aq. solution added to quench TsOH. Further remove meCN completely invacuo.
EtOAc used to dissolve the product. wash with naHCO3,brine. then concentrated.
Add acetone to dissolve the solid. Add hexanes to precipitate the product. product collected by filtration.
(EtOAc is not a good solvent for the product, so have to use acetone, benzaldehyde dimethyl acetal can dissolve in hexanes).

the rxn is reversible, so base should be used to destroy the catalyst after done.

3. phCHBr2 -base

4. benzaldehyde dimethylacetal , I2 in MeCN ,rt. 1-2 hr.
although the author claimed more than 90% yield, I can only get about 30-40% yield after workup( Na2S2O3 quenching). the author also claimed a simple workup by vacuum away MeCN and I2, but removal of I2 by vacuum is really not practical.

removal:
1. MeOH, I2, reflux, 2 hr
works great, >80%
2. MeOH, TsOH, rt

Titrating n-buLi,s-buli, t-buli

2009-01-16T09:56:00.000-08:00

method 1:

Take a briquette of menthol (usually about 80-100 mg), dissolve that in dry THF (~2 mL) and then add 1-2 mg (you don't need to really weight it) of triphenylmethane. You can roughly calculate how much of your lithium reagent you will need, and then add it dropwise to the solution of menthol/Ph₃CH/THF. When all the menthol is deprotonated the triphenylmethane will be deprotonated abnd the solution will turn pink (eventually dark red if you add to much), then you can back calculate the concentration based on the volume of alkyl lithium you added. I usally carry this procedure out in triplicate ad average the results. It really only takes about 30 mins start to finish and it doesn't take much material either.

note:
1,1'-dipyridyl can also be used instead of triphenylmethane.

a link:
http://www.chemistry.mcmaster.ca/emslie/Titrating%20Alkyllithium%20Reagents%202.pdf

preparation of Methyl triphenyl Phosphonium Acetate

2009-01-08T13:40:00.000-08:00

the correspongind phosphonium bromide 1 eq.
dissolve in DCM. (0.5 M)
NaOH 2 eq. dissolve in water. 1 M.
then put the two solutions together in a separatory funnel, shake vigorously for 10 min at rt.
then organic layer separated. washed with nahco3, brine.
concentrated to 50 ml or until solid started to showup.
then hexanes 100 ml added. further remove dcm in vacuo.
this will percipitate the product.
after all dcm removed, solid can be easily collected by filtration. washing with hexanes.

use:
ex: mecn, 3 eq. phosphonium, 60C.

petasis reagent cp2TiMe2

2009-01-04T12:01:00.000-08:00

titanocene dichloride 1 eq.
meli 2 eq. (can use excess)
-5 C, meli in Et2O was added dropwise into titanocene dichloride in toluene (0.1-0.2 M) during 10 min.
upon addition, red insoluable TiCP2Cl2 disappeared slowly.
an intermediate TiCp2ClMe is soluable and red colored.
the product ticp2me2 is also soluable but orange colored.

although standard prodcedure require 2 eq. of meli. I found out excee meli won't affect anything.

quench the rxn by nh4Cl solution;, then extract with Et2O. dried over mgso4 and concentrated to 0.5M (toluene). stored in freezer.

Preparation of SEMCl

2008-12-29T15:15:00.000-08:00

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

2008-12-23T09:19:00.000-08:00

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

2008-12-12T12:21:00.000-08:00

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 ??

2008-12-11T15:06:00.000-08:00

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

2008-12-08T17:32:00.000-08:00

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

2008-11-24T13:54:00.000-08:00

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.

2008-11-17T21:15:00.000-08:00

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

2008-11-16T09:46:00.000-08:00

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

2008-11-11T13:08:00.000-08:00

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.

2008-11-09T11:25:00.000-08:00

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

2008-11-09T10:47:00.000-08:00

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.

2008-11-09T10:23:00.001-08:00

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 .

2008-10-28T21:07:00.000-07:00

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.

2008-10-16T22:15:00.000-07:00

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

2008-10-08T20:41:00.000-07:00

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.