diazomethane.pdf

DIAZOMETHANE 1

Diazomethane1

+ –H2C=N=N

[334-88-3] CH2N2 (MW 42.04)InChI = 1/CH2N2/c1-3-2/h1H2InChIKey = YXHKONLOYHBTNS-UHFFFAOYAZ

(methylating agent for various functional groups including car-boxylic acids, alcohols, phenols, and amides; reagent for the syn-thesis of α-diazo ketones from acid chlorides, and the cyclopropa-

nation of alkenes1)

Physical Data: mp −145 ◦C; bp −23 ◦C.Solubility: diazomethane is most often used as prepared in ether,

or in ether containing a small amount of ethanol. It is less fre-quently prepared and used in other solvents such as dichloro-methane.

Analysis of Reagent Purity: diazomethane is titrated2 by adding aknown quantity of benzoic acid to an aliquot of the solution suchthat the solution is colorless and excess benzoic acid remains.Water is then added, and the amount of benzoic acid remainingis back-titrated with NaOH solution. The difference betweenthe amount of acid added and the amount remaining reveals theamount of active diazomethane present in the aliquot.

Preparative Methods: diazomethane is usually prepared by thedecomposition of various derivatives of N-methyl-N-nitroso-amines. Numerous methods of preparation have beendescribed,.3 but the most common and most frequentlyemployed are those which utilize N-Methyl-N-nitroso-p-toluenesulfonamide (Diazald©R ; 1),4 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG, 2),5 or N-methyl-N-nitrosourea (3)2

(1) (2) (3)

MeN NH2N

NO

NH

N

O

NO

Me NO2

HN S

O

O

Me

ON

The various reagents each have their advantages and disadvan-tages, as discussed below. The original procedure6 for the synthe-sis of diazomethane involved the use of N-methyl-N-nitrosourea,and similar procedures are still in use today. An advantage ofusing this reagent is that solutions of diazomethane can be pre-pared without distillation,7 thus avoiding the most dangerous op-eration in other preparations of diazomethane. For small scalepreparations (1 mmol or less) which do not contain any alcohol,a kit is available utilizing MNNG which produces distilled di-azomethane in a closed environment. Furthermore, MNNG is astable compound and has a shelf life of many years. For largerscale preparations, kits are available for the synthesis of up to 300mmol of diazomethane using Diazald as the precursor. The shelflife of Diazald (about 1–2 years), however, is shorter than thatof MNNG. Furthermore, the common procedure using Diazaldproduces an ethereal solution of diazomethane which containsethanol; however, it can be modified to produce an alcohol-freesolution. Typical preparations of diazomethane involve the slowaddition of base to a heterogeneous aqueous ether mixture con-taining the precursor. The precursor reacts with the base to lib-erate diazomethane which partitions into the ether layer and is

concomitantly distilled with the ether to provide an ethereal so-lution of diazomethane. Due to the potentially explosive natureof diazomethane, the chemist is advised to carefully follow theexact procedure given for a particular preparation. Furthermore,since diazomethane has been reported to explode upon contactwith ground glass, apparatus which do not contain ground glassshould be used. All of the kits previously mentioned avoid the useof ground glass.Handling, Storage, and Precautions: diazomethane as well as the

precursors for its synthesis can present several safety hazards,and must be used with great care.8 The reagent itself is highlytoxic and irritating. It is a sensitizer, and long term exposurecan lead to symptoms similar to asthma. It can also detonateunexpectedly, especially when in contact with rough surfaces,or on crystallization. It is therefore essential that any glasswareused in handling diazomethane be fire polished and not containany scratches or ground glass joints. Furthermore, contact withcertain metal ions can also cause explosions. Therefore metalsalts such as calcium chloride, sodium sulfate, or magnesiumsulfate must not be used to dry solutions of the reagent. The rec-ommended drying agent is potassium hydroxide. Strong lightis also known to initiate detonation. The reagent is usually gen-erated immediately prior to use and is not stored for extendedperiods of time. Of course, the reagent must be prepared andused in a well-ventilated hood, preferably behind a blast shield.The precursors used to generate diazomethane are irritants andin some cases mutagens and suspected carcinogens, and careshould be exercised in their handling as well.

Methylation of Heteroatoms. The most widely used featureof the chemistry of diazomethane is the methylation of carboxylicacids. Carboxylic acids are good substrates for reaction with di-azomethane because the acid is capable of protonating the dia-zomethane on carbon to form a diazonium carboxylate. The car-boxylate can then attack the diazonium salt in what is most likelyan SN2 reaction to provide the ester. Species which are not acidicenough to protonate diazomethane, such as alcohols, require an ad-ditional catalyst, such as Boron Trifluoride Etherate, to increasetheir acidity and facilitate the reaction. The methylation reactionproceeds under mild conditions and is highly reliable and veryselective for carboxylic acids. A typical procedure is to add a yel-low solution of diazomethane to the carboxylic acid in portions.When the yellow color persists and no more gas is evolved, thereaction is deemed complete. Excess reagent can be destroyed bythe addition of a few drops of acetic acid and the entire solutionconcentrated to provide the methyl ester.

Esterification of Carboxylic Acids and Other Acidic Func-tional Groups. A variety of functional groups will tolerate theesterification of acids with diazomethane. Thus α,β-unsaturatedcarboxylic acids and alcohols survive the reaction (eq 1),9 asdo ketones (eq 2),10 isolated alkenes (eq 3),11 and amines(eq 4).12

(1)HO OH

O O

OMeHO( )6 ( )6

CH2N2

Avoid Skin Contact with All Reagents

2 DIAZOMETHANE

(2)O

OH H

OHO O OMe

HHO

O

CH2N2

(3)

O

OMeOH

OCH2N2

O

N

PhMEMO MEMO

Ph

N

O

OOH

OOMe

(4)CH2N2

Other acidic functional groups will also undergo reactionwith diazomethane. Thus phosphonic acids (eq 5)13 and phenols(eq 6)14 are methylated in high yields, as are hydroxytropolones(eq 7)15 and vinylogous carboxylic acids (eq 8).16 The origin ofthe selectivity in eq 6 is due to the greater acidity of the A-ringphenol.

P

O

Ph

OH P

O

Ph

OMe (5)CH2N2

O

OOH OH

OH

OH

OHOMe O

O

HO

HO

O

O

(6)

CH2N2

(7)

OOH

OH

MeO

OH OH

MeO

OH

OMeO

CH2N2

(8)

O OO

O OMe

MeO OO

CH2N2

Selective monomethylation of dicarboxylic acids has been re-ported using Alumina as an additive (eq 9).17 It is thought that oneof the two carboxylic acid groups is bound to the surface of the alu-mina and is therefore not available for reaction. Carboxylic acidsthat are engaged as lactols will also undergo methylation withdiazomethane to provide the methyl ester and aldehyde (eq 10).18

HO OH

O O

HO OMe

O O(9)

alumina

CH2N2

(10)O

O

HO

O

MeO

OHC

CH2N2

Methylation of Alcohols and Other Less Acidic FunctionalGroups. As previously mentioned, alcohols require the additionof a catalyst in order to react with diazomethane. The most com-monly used is boron trifluoride etherate (eq 11),19 but Tetrafluo-roboric Acid has been used as well (eq 12).20 Mineral acids arenot effective since they rapidly react with diazomethane to pro-vide the corresponding methyl halides. Acids as mild as silica gelhave also been found to be effective (eq 13).21 Monomethylationof 1,2-diols with diazomethane has been reported using variousLewis acids as promoters, the most effective of which is Tin(II)Chloride (eq 14).22

O OBz

OHBzO

BzOBF3•OEt

O OBz

OMeBzO

BzO (11)CH2N2

(12)

HO

H

C8H17

H

H

H H

H

H

C8H17

H

MeO

CH2N2

HBF4

OHOH

OCO2Me

OMeOMe

OCO2Me

3 3

44

(13)silica

CH2N2

(14)O Base

HO

OHHO MeO OH

HO

BaseO O Base

HO

OMeHO

+CH2N2

SnCl2

An interesting case of an alcohol reacting with diazomethaneat a rate competitive with a carboxylic acid has been reported(eq 15).23 In this case, the tertiary structure of the molecule isthought to place the alcohol and the carboxylic acid in proximityto each other. Protonation of the diazomethane by the carboxylicacid leads to a diazonium ion in proximity to the alcohol as wellas the carboxylate. These species then attack the diazonium ion atcompetitive rates to provide the methyl ether and ester. No reactionis observed upon treatment of the corresponding hydroxy esterwith diazomethane, indicating that the acid is required to activatethe diazomethane.

(15)

O O OR

OHHO

OH

HH OHH

OHOH

HO OMe

H OHH H

OH

MeO OH

ROOO

CH2N2

Amides can also be methylated with diazomethane in the pres-ence of silica gel; however, the reaction requires a large excess ofdiazomethane (25–60 equiv, eq 16).24 The reaction primarily pro-vides O-methylated material; however, in one case a mixture of O-and N-methylation was reported. Thioamides are also effectivelymethylated with this procedure to provide S-methylated com-pounds. Finally, amines have been methylated with diazomethane

A list of General Abbreviations appears on the front Endpapers

DIAZOMETHANE 3

in the presence of BF3 etherate, fluoroboric acid,25 or copper(I)salts;26 however, the yields are low to moderate, and the methodis not widely used.

NH

O

N

OMe

(16)silica

CH2N2

The Arndt–Eistert Synthesis. Diazomethane is a usefulreagent for the one-carbon homologation of acid chlorides via asequence of reactions known as the Arndt–Eistert synthesis. Thefirst step of this sequence takes advantage of the nucleophilicityof diazomethane in its addition to an active ester, typically anacid chloride,27 to give an isolable α-diazo ketone and HCl. TheHCl that is liberated from this step can react with diazomethaneto produce methyl chloride and nitrogen, and therefore at least2 equiv of diazomethane are typically used. The α-diazo ketoneis then induced to undergo loss of the diazo group and insertioninto the adjacent carbon–carbon bond of the ketone to providea ketene. The ketene is finally attacked by water or an alcohol(or some other nucleophile) to provide the homologated car-boxylic acid or ester. This insertion step of the sequence is knownas the Wolff rearrangement28 and can be accomplished either ther-mally (eq 17)29 or, more commonly, by treatment with a metal ion(usually silver salts, eq 18),30 or photochemically (eq 19).31 It hasbeen suggested that the photochemical method is the most effi-cient of the three.32 As eqs 18 and 19 illustrate, retention of stere-ochemistry is observed in the migrating group. The obvious limi-tations of this reaction are that there must not be functional groupspresent in the molecule which will react with diazomethane morerapidly than it will attack the acid chloride. Thus carboxylic acidswill be methylated under these conditions. Furthermore, electron-deficient alkenes will undergo [2,3] dipolar cycloaddition with di-azomethane more rapidly than addition to the acid chloride. Thuswhen the Arndt–Eistert synthesis is attempted on α,β-unsaturatedacid chlorides, cycloaddition to the alkene is observed in the prod-uct. In order to prevent this, the alkene must first be protected byaddition of HBr and then the reaction carried out in the normalway (eq 20).33 Cycloaddition to isolated alkenes, however, is notcompetitive with addition to acid chlorides.

O

Cl OBnO

(17)1. CH2N2

2. 180 °C collidine BnOH

Cl

O O

N2

O

OMe(18)

PhCO2AgCH2N2

MeOH

ClO

H

H

H

H1. CH2N2

O

OMe

(19)2. hν, MeOH

1. HBr2. (COCl)2

O

OH

ON2

Br(20)

3. CH2N2

Other Reactions of α-Diazo Ketones Derived from Dia-zomethane. Depending on the conditions employed, the Wolffrearrangement may proceed via a carbene or carbenoid interme-diate, or it may proceed by a concerted mechanism where theinsertion is concomitant with loss of N2 and no intermediate isformed. In the case where a carbene or carbenoid is involved,other reactions which are characteristic of these species can oc-cur, such as intramolecular cyclopropanation of alkenes. In fact,the reaction conditions can be adjusted to favor cyclopropanationor homologation depending on which is desired. Thus treatmentof the dienoic acid chloride shown in eq 21 with diazomethanefollowed by decomposition of the α-diazo ketone with silver ben-zoate in the presence of methanol and base provides the homolo-gated methyl ester. However, treatment of the same diazoketoneintermediate with CuII salts provides the cyclopropanation prod-ucts selectively.34 This trend is generally observed; that is, silversalts as well as photochemical conditions (eqs 18 and 19) favorthe homologation pathway while copper or rhodium salts favorcyclopropanation.35 Using copper salts to decompose the diazocompounds, hindered alkenes as well as electron-rich aromaticscan be cyclopropanated as illustrated in eqs 22 and 23,36,37 re-spectively.

H

ClO O

N2

OH

H

O

OMe

Cu(acac)2benzene (21)PhCO2Ag

NEt3, MeOH

CH2N2

1. CH2N2(22)Cl

O

Br BrO

H

2. Cu, ∆

OAc

COCl

O

O

1. CH2N22. Na2CO3

(23)3. CuCl2 PhH, ∆

In addition to these reactions, α-diazo ketones will undergoprotonation on carbon in the presence of protic acids38 to pro-vide the corresponding α-diazonium ketone. These species arehighly electrophilic and can undergo nucleophilic attack. Thus ifthe proton source contains a nucleophile such as a halogen thenthe corresponding α-halo ketone is isolated (eq 24).39 However,if the proton source does not contain a nucleophilic counterionthen the diazonium species may react with other nucleophiles thatare present in the molecule, such as alkenes (eq 25)40 or aromaticrings (eq 26).41 Note the similarity between the transformationsin eqs 26 and 23 which occur using different catalysts and by dif-ferent pathways. Also, eq 26 illustrates the fact that other activeesters will undergo nucleophilic attack by diazomethane.


4 DIAZOMETHANE

Cl

O O

(24)Br

1. CH2N2

2. HBr

1. CH2N2(25)

CO2ClO

2. HClO4

1. CH2N2(26)

NO

O

CF3

O O

NH

CF3

O

OMe2. H+

Lewis acids are also effective in activating α-diazo ketones to-wards intramolecular nucleophilic attack by alkenes and arenes.42

The reaction has been used effectively for the synthesis of cy-clopentenones (eq 27) starting with β,γ-unsaturated diazo ketonesderived from the corresponding acid chloride and diazomethane.It has also been used to initiate polyalkene cyclizations (eq 28).Typically, boron trifluoride etherate is used as the Lewis acid, andelectron-rich alkenes are most effective providing the best yieldsof annulation products.

1. CH2N2(27)Cl

O

C5H11

OC5H11

2. BF3•OEt

1. CH2N2

(28)

ClO

OH

O

+

2. BF3•OEt

The Vinylogous Wolff Rearrangement. The vinylogousWolff rearrangement43 is a reaction that occurs when theArndt–Eistert synthesis is attempted on β,γ-unsaturated acid chlo-rides using copper catalysis. Rather than the usual homologationproducts, the reaction proceeds to give what is formally the prod-uct of a [2,3]-sigmatropic shift, but is mechanistically not derivedby this pathway.44 The mechanism is thought to proceed by an ini-tial cyclopropanation of the alkene by the α-diazo ketone to givea bicyclo[2.1.0]pentanone derivative. This compound then under-goes a fragmentation to a ketene alkene before being trapped bythe solvent (eq 29). Inspection of the products reveals that theyare identical with those derived from the Claisen rearrangementof the corresponding allylic alcohols, and as such this method canbe thought of as an alternative to the Claisen procedure. However,the stereoselectivity of the alkene that is formed is not as high asis typically observed in the Claisen rearrangement (eq 30), and insome substrates the reaction proceeds with no selectivity (eq 31).

1. CH2N2O

N2

OR2

R1

R2

R1R1

R2

•O

OR2

R1 OR3

R3OH (29)

2. CuII

1. CH2N2

53%

Ph

Cl

O

PhOBn

O O

OBnPh

+ (30)

13%

2. Cu(OTf)2 BnOH

(31)

1. CH2N2Cl

O

CO2MeCO2Me+

29% 26%

2. Cu(acac)2 MeOH

Insertions into Aldehyde C–H Bonds. The α-diazo ketones(and esters) derived from diazomethane and an acid chloride(or chloroformate) will also insert into the C–H bond of aldehydesto give 1,3-dicarbonyl derivatives.45 The reaction is catalyzed bySnCl2, but some simple Lewis acids, such as BF3 etherate, alsowork. The reaction works well for aliphatic aldehydes, but givesvariable results with aromatic aldehydes, at times giving none ofthe desired diketone (eq 32). Sterically hindered aldehydes willalso participate in this reaction, as illustrated in eq 33 with the reac-tion of ethyl α-diazoacetate and pivaldehyde. In a related reaction,α-diazo phosphonates and sulfonates will react with aldehydes inthe presence of SnCl2 to give the corresponding β-keto phospho-nates and sulfonates.46 This reaction is a practical alternative tothe Arbuzov reaction for the synthesis of these species.

R1N2

O

H R2

O SnCl2

PhPhPhCH2CH2

HPhCH2Ph

R1 R2

O O

(32)+

88900

R1 R2 Yield (%)

EtON2

O

H R2

O SnCl2

t-BuPh

EtO R2

O O

(33)+

6550

R2 Yield (%)

Additions to Ketones. The addition of diazomethane toketones47 is also a preparatively useful method for one-carbon


DIAZOMETHANE 5

homologation. This reaction is a one-step alternative to theTiffeneau–Demjanow rearrangement48 and proceeds by the mech-anism shown in eq 34. It can lead to either homologation or epox-idation depending on the substrate and reaction conditions. Theaddition of Lewis acids, such as BF3 etherate, or alcoholic cosol-vents tend to favor formation of the homologation products overepoxidation.

R1 R2

O

R2

R1

R1 N

O–N

R2O

R1

R2

O

R1 R2

O

+

(34)

CH2N2

However, the reaction is limited by the poor regioselectivityobserved in the insertion when the groups R1 and R2 in thestarting ketone are different alkyl groups. What selectivity is ob-served tends to favor migration of the less substituted carbon,49

a trend which is opposite to that typically observed in rearrange-ments of electron-deficient species such as in the Baeyer–Villigerreaction. Furthermore, the product of the reaction is a ketoneand is therefore capable of undergoing further reaction with di-azomethane. Thus, ideally, the product ketone should be lessreactive than the starting ketone. Strained ketones tend to re-act more rapidly and are therefore good substrates for this re-action (eq 35).50 This method has also found extensive use incyclopentane annulation reactions starting with an alkene. Theoverall process begins with dichloroketene addition to the alkeneto produce an α-dichlorocyclobutanone. These species are ideallysuited for reaction with diazomethane because the reactivity ofthe starting ketone is enhanced due to the strain in the cyclobu-tanone as well as the α-dichloro substitution. Furthermore, thepresence of the α-dichloro substituents hinders migration of thatgroup and leads to almost exclusive migration of the methylenegroup. Thus treatment with diazomethane and methanol leads toa rapid evolution of nitrogen, and produces the corresponding α-dichlorocyclopentanone, which can be readily dehalogenated tothe hydrocarbon (eq 36).51 Aldehydes will also react with dia-zomethane, but in this case homologation is not observed. Rather,the corresponding methyl ketone derived from migration of thehydrogen is produced (eq 37).

OO

(35)CH2N2

CH2N2MeOH

O

ClCl

H

Cl

Cl

OH

Zn

AcOH

Cl Cl

O

H

(36)

+

O

•

(37)H

O OCH2N2

Cycloadditions with Diazomethane. Diazomethane will un-dergo [3 + 2] dipolar cycloadditions with alkenes and alkynes togive pyrazolines and pyrazoles, respectively.52 The reaction pro-ceeds more rapidly with electron-deficient alkenes and strainedalkenes and is controlled by FMO considerations with the HOMOof the diazomethane and the LUMO of the alkene serving as thepredominant interaction53 In the case of additions to electron-deficient alkenes, the carbon atom of the diazomethane behavesas the negatively charged end of the dipole, and therefore theregiochemistry observed is as shown in eq 38. With conjugatedalkenes, such as styrene, the terminal carbon has the larger lobe inthe LUMO, and as such the reaction proceeds to give the productshown in eq 39. Pyrazolines are most often used as precursorsto cyclopropanes by either thermal or photochemical extrusion ofN2. In both cases the reaction may proceed by a stepwise mecha-nism with loss of stereospecificity. As shown in eq 40, the thermalreaction provides an almost random product distribution, whilethe photochemical reaction provides variable results ranging from20:1 to stereospecific extrusion of nitrogen.54

(38):+

:_C N N

H OMe

OH N N

OMe

O+

:+

:_C N N

H

H

+ (39)NN

1.2:1 20:1

to >100:1

∆hν

NN

CO2Me CO2MeCO2Me

(40)+

Cyclopropanes can also be directly synthesized from alkenesand diazomethane, either photochemically or by using transi-tion metal salts, usually Copper(II) Chloride or Palladium(II)Acetate, as promoters. The metal-mediated reactions are morecommonly used than the photochemical ones, but they are not aspopular as the Simmons–Smith procedure. However, they do occa-sionally offer advantages. Of the two processes, the Cu-catalyzedreaction produces a more active reagent.55 which will cyclo-propanate a variety of alkenes, including enamines as shown ineq 4156 These products can then be converted to α-methyl ketonesby thermolysis. The cyclopropanation of the norbornenol deriva-tive shown in eq 42 was problematic using the Simmons–Smithprocedure and provided low yields, but occurred smoothly usingthe CuCl2/diazomethane method.57

N NO

∆, MeOH(41)

CH2N2

CuCl2 H2Osealed tube


6 DIAZOMETHANE

(42)

OH OHCH2N2

CuCl2

The Pd(OAc)2-mediated reaction can be used to cyclopropanateelectron-deficient alkenes as well as terminal alkenes. Thus selec-tive reaction at a monosubstituted alkene in the presence of oth-ers is readily achieved using this method (eq 43).58 The exampleshown in eq 44 is one in which the Simmons–Smith procedurefailed to provide any of the desired product, whereas the currentmethod provided a 92% yield of cyclopropane.59

(43)CH2N2

Pd(OAc)2

(44)

O

C5H11

OOPB

O O

OPB O

C5H11

OCH2N2

Pd(OAc)2

In the case of the photochemical reaction, irradiation of dia-zomethane in the presence of cis-2-butene provides cis-1,2-di-methylcyclopropane with no detectable amount of the trans iso-mer (eq 45).60 This reaction is thought to proceed via a singletcarbene. However, if the same reaction is carried out via a tripletcarbene, generated via triplet sensitization, then a 1.3:1 mixtureof trans to cis dimethylcyclopropane is observed (eq 46).61 Theyields in the photochemical reaction are typically lower thanthe metal-mediated processes, and are usually accompanied bymore side products.

(45)hν

CH2N2

(46)+

1:1.2

hνsensitized

CH2N2

Additions to Electron-deficient Species. Diazomethane willalso add to highly electrophilic species such as sulfenes or im-minium salts to give the corresponding three-membered ring hete-rocycles. When the reaction is performed on sulfenes, the productsare episulfones which are intermediates in the Ramberg–Backlundrearrangement, and are therefore precursors for the synthesis ofalkenes via chelotropic extrusion of SO2. The sulfenes are typi-cally prepared in situ by treatment of a sulfonyl chloride with amild base, such as Triethylamine (eq 47).62 Similarly, the addi-tion of diazomethane to imminium salts has been used to methyle-nate carbonyls.63 In this case, the intermediate aziridinium salt istreated with a strong base, such as Butyllithium, in order to induceelimination (eq 48).

(47)

SO2ClO O

O2SO

NEt3 ∆CH2N2

1. CH2N2(48)

+N

OH

H

H

H

HH

2. BuLi

Miscellaneous Reactions. Diazomethane has been shown toreact with vinylsilanes derived from α,β-unsaturated esters to pro-vide the corresponding allylsilane by insertion of CH2 into theC–Si bond (eq 49).64 The reaction has been shown to be stereospe-cific, with cis-vinylsilane providing cis-allylsilanes; however, themechanism of the reaction has not been defined. Diazomethanehas also been used in the preparation of trimethyloxonium salts.Treatment of a solution of dimethyl ether and trinitrobenzenesul-fonic acid with diazomethane provides trimethyloxonium trini-trobenzenesulfonate, which is more stable than the fluoroboratesalt.65

OMe

OO

OMe

TMSTMS

(49)CH2N2

Related Reagents. 2-Diazopropane; Diphenyldiazomethane;Phenyldiazomethane; 1-Diazo-2-propene.

1. (a) Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis;Academic: Orlando, 1986. (b) Black, T. H., Aldrichim. Acta 1983, 16, 3.(c) Pizey, J. S. Synthetic Reagents; Wiley: New York, 1974; Vol. 2, p 65.

2. Arndt, F., Org. Synth., Coll. Vol. 1943, 2, 165.

3. Moore, J. A.; Reed, D. E., Org. Synth., Coll. Vol. 1973, 5, 351. Redemann,C. E.; Rice, F. O.; Roberts, R.; Ward, H. P., Org. Synth., Coll. Vol. 1955,3, 244. McPhee, W. D.; Klingsberg, E., Org. Synth., Coll. Vol. 1955, 3,119.

4. De Boer, Th. J.; Backer, H. J., Org. Synth., Coll. Vol. 1963, 4, 250.Hudlicky, M., J. Org. Chem. 1980, 45, 5377. See also Aldrich ChemicalCompany Technical Bulletins Number AL-121 and AL-131. Note thatthe preparation described in Fieser & Fieser, 1967, 1, 191. is flawed andneglects to mention the addition of ethanol Failure to add ethanol canresult in a buildup of diazomethane and a subsequent explosion.

5. McKay, A. F., J. Am. Chem. Soc. 1948, 70, 1974. See also AldrichChemical Company Technical Bulletin Number AL-132.

6. von Pechman, A., Chem. Ber. 1894, 27, 1888.

7. Ref. 2, note 3.

8. For a description of the safety hazards associated with diazomethane,see: Gutsche, C. D., Org. React. 1954, 8, 391.

9. Fujisawa, T.; Sato, T.; Itoh, T., Chem. Lett. 1982, 219.

10. Nicolaou, K. C.; Paphatjis, D. P.; Claremon, D. A.; Dole, R. E., J. Am.Chem. Soc. 1981, 103, 6967.

11. Fujisawa, T.; Sato, T.; Kawashima, M.; Naruse, K.; Tamai, K.,Tetrahedron Lett. 1982, 23, 3583.

12. Kozikowski, A. P.; Sugiyama, K.; Springer, J. P., J. Org. Chem. 1981,46, 2426.

13. De, B.; Corey, E. J., Tetrahedron Lett. 1990, 31, 4831. Macomber, R. S.,Synth. Commun. 1977, 7, 405.

14. Blade, R. J.; Hodge, P., J. Chem. Soc., Chem. Commun. 1979, 85.

15. Kawamata, A.; Fukuzawa, Y.; Fujise, Y.; Ito, S., Tetrahedron Lett. 1982,23, 1083.

16. Ray, J. A.; Harris, T. M., Tetrahedron Lett. 1982, 23, 1971.


DIAZOMETHANE 7

17. Ogawa, H.; Chihara, T.; Taya, K., J. Am. Chem. Soc. 1985, 107, 1365.

18. Frimer, A. A.; Gilinsky-Sharon, P.; Aljadef, G., Tetrahedron Lett. 1982,23, 1301.

19. Chavis, C.; Dumont, F.; Wightman, R. H.; Ziegler, J. C.; Imbach, J. L.,J. Org. Chem. 1982, 47, 202.

20. Neeman, M.; Johnson, W. S., Org. Synth., Coll. Vol. 1973, 5, 245.

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Tarek SammakiaUniversity of Colorado, Boulder, CO, USA


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