aldehyde to terminal alkyne

1. OhiraReagent and derivatives
diazoketophosphonium ester.

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

Tandem Semipinacol/Schmidt Reaction

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





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

Epoxide-Initiated Electrophilic Cyclization of Azides

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

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

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

Oxidation of organoboranes

1. H2O2

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

preparation of LN (lithium naphthalenide)

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

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

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

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

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

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

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

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

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

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

Heck Coupling with Nonactivated Alkenyl Tosylates and Phosphates

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

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

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

Iridium-Catalyzed Enantioselective Synthesis of Allylic Alcohols

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

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

Direct preparation of copper organometallics bearing an aldehyde function

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

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

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

The First Negishi Cross-Coupling Reaction of Two Alkyl Centers

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

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

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

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

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

Acyclic Diastereocontrol and Asymmetric Transmission via Anionic Oxy-Cope Rearrangement

JOC, 1991.5973.

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

Bisoxazoline ligands

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

very good article about this kind of popular ligands.

Some online resources

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

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

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

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

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

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

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

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

Meerwein–Ponndorf–Verley alkynylation of aldehydes

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

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

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

enantioselective reduciton of ketones by thichlorosilane

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

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

beta-alkylation of alcohols by Cp*Ir complex

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

very efficient coupling rxn.

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

C-C bond forming by Si-C cleavage

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

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

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

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

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

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

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

Synthesis of Silyl Enol Ethers by Mg/TMSCl

Tetrahedron Letters 40 (1999) 1349-1352

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

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

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

LAH explosions

Accidents happen without sign. really?

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

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

How to open a lactone?

1. MeOH/MeONa
forms methylester and free alcohol.

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