unsaturated amine

Cyclic 2 or 3 amine

Mechanism:

21-26,13

The mechanism of all of the above mentioned reactions is essentially the same. However, some steps in the mechanism are still not fully understood. The following steps are believed to be involved in the Eschweiler-Clarke methylation: 1) formation of a Schiff-base (imine) from the starting primary or secondary amine and formaldehyde via an aminoalcohol (aminal) intermediate; 2) hydride transfer from the reducing agent (e.g., formic acid, cyanoborohydride, etc.) to the imine to get the corresponding N-methylated amine along with the loss of CO2; and 3) if the starting amine was primary, then steps 1 and 2 are repeated.
O H H H O H O H O H H H R1 R2 -H N H H R
2

Eschweiler-Clarke Methylation
O H N
1

H +H H R
2

O N

H H R
1

- HOH

C N

R aminal

R2

R1

Schiff base

R1 R
2

N C H

H H

R1 O O R
2

H N H TS
*

O O

R1
hydride transfer

N C

R2 H + CO2

H 2C

-H

H N-Methylated amine

generate the soft nucleophiles. However, allylic carbonates undergo decarboxylation, and in the process a sufficiently basic alkoxide is formed so no extra base is needed; 4) the range of possible soft carbon nucleophiles is also wide: 3 4 active methylene compounds with two electron-withdrawing groups (R and R ), enamines and enolates; 5) the (0) (0) catalytically active Pd species is introduced in either the form of Pd or by the in situ reduction of Pd(II) complexes; 6) the addition of the nucleophiles to the unsymmetrical -allylpalladium complexes is regioselective and favors the least substituted allyl terminus regardless of the initial position of the leaving group; 7) occasionally the regioselectivity can be influenced by the nature of the ligand and the nucleophile; 8) bis allylic substrates having two different leaving groups can be substituted with high regioselectivity; and 9) optically active substrates are substituted by soft nucleophiles with an overall retention of configuration (double inversion), while hard nucleophiles give rise to products with an overall inversion of configuration (-allylpalladium complexes are transmetallated). Nitrogen-, oxygen-, and sulfur-based soft nucleophiles can also be used in Tsuji-Trost allylation reactions.

Tsuji-Trost Allylation
R
1

R1

Pd(0) or Pd(II) complexes (catalytic) solvent / phosphine ligand base (stoichiometric) or neutral cond.

Nuc H or Nuc

R1

Nuc

Pd(II) X -allylpalladium complex

1 2

Substituted product

R1

R2

Pd(0) (cat.) hard Nuc

inversion of configuration

R X

Nuc Substituted product

or R >> R
1 2

R X

Pd(0) (cat.) soft Nuc

retention of configuration

R1

R2

Nuc Substituted product

R1-2 = H, alkyl, aryl; X = OH, OPh, OCOR, OCONHR, OCO2R, OP(O)(OR)2, Cl, NO2, SO2Ph, NR2, NR3X, SR2X soft Nuc-H = R3R4CH2, enamines, enolates; R3-4 = CO2R, CN, NO2, SO2Ph, COR, NC, N=(CMe2), SPh, alkenyl Pd-complexes: Pd(PPh3)4, Pd2(dba)3, [Pd(allyl)Cl]2; ligands: PPh3, dba

Mechanism: 38,5,39,40
Pd(0) or Pd(II) complexes (precatalysts) R1 Nuc R
1

Mechanism with soft and hard nucleophiles: X R1 X R2 R1 >> R2

LnPd(0)

coordination

oxidative addition with inversion

LnPd(0) R2 soft Nuc

Nuc

R1 Pd(0)Ln

X hard Nuc

R1

Substituted product

configuration

R >> R

configuration

Su

R1-2 = H, alkyl, aryl; X = OH, OPh, OCOR, OCONHR, OCO2R, OP(O)(OR)2, Cl, NO2, SO2Ph, NR2, NR3 soft Nuc-H = R3R4CH2, enamines, enolates; R3-4 = CO2R, CN, NO2, SO2Ph, COR, NC, N=(CMe2), SPh Pd-complexes: Pd(PPh3)4, Pd2(dba)3, [Pd(allyl)Cl]2; ligands: PPh3, dba

Tsuji-Trost Allylation
Pd(0) or Pd(II) complexes (precatalysts)

Mechanism: 38,5,39,40

Mechanism with soft and hard nuc R

1

Nuc

LnPd(0)

R1 X

R2

R1 >

coordination

oxidative addition with inversion

LnPd(0) R2

Nuc Pd Ln
(0)

R1 Pd(0)Ln

X hard Nuc
transmetallation with retention then reductive elimination

R1 Pd(II) L X

substitution then reductive elimination

oxidative addition

Nuc

R1 L Pd
(II)

+L -X

R1 Pd(II) L X

R1

R2 Nuc

ligand exchange

3 4

aryl; X = OH, OPh, OCOR, OCONHR, OCO2R, OP(O)(OR)2, Cl, NO2, SO2Ph, NR2, NR3X, SR2X R CH2, enamines, enolates; R3-4 = CO2R, CN, NO2, SO2Ph, COR, NC, N=(CMe2), SPh, alkenyl Pd-complexes: Pd(PPh3)4, Pd2(dba)3, [Pd(allyl)Cl]2; ligands: PPh3, dba

Tsuji-Trost Allylation
Mechanism with soft and hard nucleophiles: R1 X R1 X
coordination oxidative addition with inversion

Pd(II) complexes (precatalysts)

R2

LnPd(0)

R1 >> R2

LnPd(0) R2

R1 Pd(0)Ln

X hard Nuc
transmetallation with retention then reductive elimination

R1 Pd(II) L X

soft Nuc
substitution with inversion then reductive elimination

oxidative addition

Pd(II) L L

+L -X

R1 Pd(II) L X

R1

R2 Nuc

R1

R2 Nuc

ligand exchange

two possible ways: I) addition of the aldehyde (1 equivalent) to a mixture of triphenylphosphine (4 equivalents) and carbon tetrabromide (2 equivalents) in CH2Cl2, at 0 C in 5 minutes;6 or II) addition of the aldehyde to a reagent, which is prepared by mixing zinc dust (2 equivalents) with Ph3P (2 equivalents) and CBr4 (2 equivalents) in CH2Cl2 at 23 C for 24-30h (the reaction time to form the alkyne is 1-2h). Yields are typically 80-90% for this first Wittig-type step. Procedure II, using zinc dust and less Ph3P, tends to give higher yields of dibromoolefins and simplifies the isolation procedure. In the second step, the conversion of the prepared dibromoolefins to the corresponding terminal alkynes is accomplished by treatment with 2 equivalents of n-butyllithium at -78 C (lithium-halogen exchange and elimination), followed by simple hydrolysis. The intermediate is a lithium acetylide, which can be treated with a number of electrophiles to produce a wide variety of useful derivatives. Recently, a one-pot modified procedure using t-BuOK/(Ph3PCHBr2)Br followed by the addition of excess n-BuLi was published.5

Corey-Fuchs Alkyne Synthesis

O R H

CBr4 (2 equiv) / Ph3P (4 equiv) CH2Cl2 / 0 C, 5 min or CBr4 (2 equiv) / Ph3P (2 equiv) Zn dust (2 equiv) CH2Cl2 / 0 C, 1-2h; 80-90%

Br R

C C

Br

n-BuLi (2 equiv) 82-90%

Li C C R lithium acetylide hydrolysis 80-95%

H C C R Terminal alkyne

aldehyde R = aryl, alkyl

dibromoolefin

Mechanism:

6,1

The mechanism of dibromoolefin formation from the aldehyde is similar to the mechanism of the Wittig reaction. However, there is very little known about the formation of the alkyne from the dibromoolefin. The mechanism below is one possible pathway to the observed product.
Generation of the phosphorous ylide:

Br3C

Br

PPh3

Br

PPh3 + CBr3

Br PPh3 CBr2 Br PPh3

Br Ph3P ylide Br

Ph3PBr2

Reaction of the phosphorous ylide with the aldehyde:

acetylide

alkyne

Mechanism:

6,1

The mechanism of dibromoolefin formation from the aldehyde is similar to the mechanism of the Wittig reaction. However, there is very little known about the formation of the alkyne from the dibromoolefin. The mechanism below is one possible pathway to the observed product.
Generation of the phosphorous ylide:

Corey-Fuchs Alkyne Synthesis

Br PPh3 + CBr3

Br3C

Br

PPh3

Br PPh3 CBr2 Br PPh3

Br Ph3P ylide Br

Ph3PBr2

Reaction of the phosphorous ylide with the aldehyde: R Br Ph3P Br Ph3P ylide Br Br O H R Br Br O PPh3 R Br Br O PPh3 - Ph3P=O R Br C C H

Br

dibromoolefin

Conversion of dibromoolefin to terminal alkyne: R - n-BuBr Br Li n-Bu Li H C C R - n-Bu-H - LiBr Br C C Li lithium acetylide H O H R C C H Terminal alkyne

Li n-Bu

C C

Br

dibromoolefin

isoquinoline

isoquinoline-3-carboxylic acid

Pictet & Spengler (1911): CH Pictet-Spengler reaction: 2(OMe)2 HCl (aq.) R2 NH NH2 3 100 C O C protic or Lewis acid R HO 40% H2 + R1 protic or aprotic phenylethylamine R5 R4 1,2,3,4-tetrahydroNH2 solvent isoquinoline heat Substituted carbonyl compound -arylethylamine CH2(OMe)2 CO2H HCl (aq.) R2 NH2 R3 100 C 75%
N R5 R2

CO2H

Pictet-Spengler Tetrahydroisoquinoline synthesis

R1

tyrosine

R4 Schiff base

NH R3 C H2 NH 7-hydroxy-1,2,3,4-tetrahydroR4 R5 isoquinoline-3-carboxylic acid Substituted tetrahydroisoquinoline HO R1

Pictet-Spengler reaction: R2 R1 = H, alkyl , aryl, O-alkyl, usually an electron-donating group (EDG); R2-3 = H, alkyl ,aryl; R4-5 = H, alkyl ,aryl; protic acid: 2 R 3 R R2 HCl, H2SO4, TFA, silica gel; Lewis acid: BF3OEt2 3 R 3 O protic or Lewis acid R1 R 1 + NH R R1 protic or aprotic 2,9 N 5 R5 R4 Mechanism: NH2 R solvent R4 R5 heat Substituted R4 carbonyl The firstSubstituted Pictet-Spengler reaction is the formation of a Schiff base. The amine and aldehyde give rise to an step of the tetrahydroisoquinoline -arylethylamine Schiff base aminal, which is dehydratedcompound under acidic conditions to afford the corresponding imine. Protonation of the imine

results in the formation of an iminium ion, which reacts with the electron-rich aromatic ring in a 6-endo-trig cyclization to afford = H, six-membered heterocycle. The same type ofgroup (EDG); R2-3 = H, alkyl ,aryl; R4-5 the Bischler-Napieralski R1 the alkyl , aryl, O-alkyl, usually an electron-donating reactive intermediate is involved in = H, alkyl ,aryl; protic acid: isoquinoline synthesis, but that cationic species ,is more electrophilicacid: BF OEt HCl, H2SO4 TFA, silica gel; Lewis and the aromatic ring does not need to be 3 2 activated to achieve cyclization. The loss of proton restores the aromatic ring, thus giving rise to the product.
R2 Mechanism:

2,9

3 R - HOH H +H 1 R1 RThe first step of the R R1is the formation of a Schiff base. The amine and aldehyde give rise to an HN O NHis aminal, which 2 dehydrated under acidic conditions HN afford the corresponding imine. Protonation - H the imine to OH of O H 5 results in the formation of an iminium ion, which reacts with the electron-rich aromatic ring in a 6-endo-trig cyclization R R5 R5 to afford the six-membered heterocycle. The same type of R4 reactive intermediate is involved in R4 Bischler-Napieralski the

R3

R2

P.T. 4 Pictet-Spengler reaction

R3

R2

isoquinoline synthesis, but that cationic species is more electrophilic and the aromatic ring does not need to be activated R2 achieve cyclization. The loss 2of proton restores the aromatic ring, thus giving rise to the product. to 2 2

R3

R1

R1

R2 N

+H

R3

6-endo-trig 2 R

R3

R4 NH 2 Schiff base

R4 R5 O

P.T. R5

N R4

H R1

R1 3

-H

HN R4

OH R
5

N +H H H 4 5 R1 R R

R2 R1

R3

R3 H R4 HN O

NH HOH -

R4 R2
3

R5

-H

R2

R2
3

R2
3

and the regioselectivity depends on a combination of factors: acidity of the medium, substitution of the hydrazine, Japp-Klingemann reaction provides an easy way to unsymmetrical ketones indolization usually -dicarbonyls and steric effects in the ketone and in the ene-hydrazines; 3) with obtain the starting arylhydrazones from occurs at thearenediazonium -carbon atom in strongly acidic medium, whereas weak acids give rise to the other regioisomer; least substituted salts. 4) indolization of ,-unsaturated ketones is generally unsuccessful due to the formation of unreactive pyrazolines; 5) 1,2-diketones can give both mono- and bis-indoles and the mono-indoles are usually formed with strong acid R1 R2 catalysts in refluxing alcohols; 6) 1,3-diketones and -keto esters are 1 ideal substrates, since their arylhydrazones R not 1 R2 1. used R2 formRpyrazoles and pyrazol-3-ones, respectively; 7) due to their sensitivity, aldehydes are [3,3] in their4 protected R forms (acetal, aminal, or bisulfite addition product), and they give rise to 3-substituted indoles; 8) hydrazines are often O R1 R2 N R3 2. - NH2H R4 used as their HCl salt or in their Boc protected form (they are not very stable in their free base form); 9) electron- N withdrawing substituents on the aromatic ring of the hydrazine causes N indolization to become low-yielding and R3 the acid catalyst H + slow; 10) ortho-substituted arylhydrazines generally react much slower than the meta-substituted ones; and 11) the 3 R + + - 2O Japp-Klingemann reactionHprovides an N N way to obtain the starting1 arylhydrazones from -dicarbonyls and easy R3 NH2 R arenediazonium salts. R2 N R2 1. [3,3] R1 R4 2 R R R4 1 4 R4 2. - NH2H N R3 RR1 1 2 R2 N 1. [3,3] R R 4 N R R3 O 3 R1 R2 N RH 2. - NH H R4

Fischer-Indole Synthesis

acid catalyst NH2

22-39

arylhydrazone
N R3

Mechanism: N

- H2O

The currently accepted mechanism of the Fischer indole synthesis was originally proposed by R. Robinson in 1924. R R4 2. - NH H N R3 R4 There are five distinct steps: 1) coordination of the Lewis acid (e.g., proton) to2the imine nitrogen; 2) tautomerization N of the hydrazone to the corresponding ene-hydrazine; N disruption of the aromatic ring by a 3[3,3]-sigmatropic 3) R H rearrangement; 4) rearomatization via a proton shift and formation of the 5-membered ring by a favored 5-exo-trig arylhydrazone ene-hydrazines regioisomeric indoles cyclization; and 5) the loss of a molecule of ammonia to finally give rise to the indole system.
4

R4

R2

H + R1

ene-hydrazines N

regioisomeric indoles R3
R2

+ 1. [3,3] R1

22

Mechanism: 1 2
R R

22-39

R H Robinson in 1924. H The currently accepted mechanism of the Fischer indole synthesis R1 originally proposed by R. H was H R1 H R1 N H N coordination of the Lewis acid (e.g., proton) to the imine nitrogen; 2) tautomerization R3 There are five distinct steps: 1)N N R3 R3 N R3 - H [3,3] of the N hydrazone to the corresponding ene-hydrazine; 3) P.T. disruption of the aromatic ring by N [3,3]-sigmatropic a - NH2H R2 N R3 N H N H rearrangement; 4) rearomatization via a proton shift and formation of the 5-membered ring by a favored 5-exo-trig R2 2 R2 2 cyclization; and 5) the loss of a molecule of ammonia to finally give rise to the indole system. R R H
R
1

R1 H

1 22

R3 N

ene-hydrazine
R1 H R3 R2 N H N R
3

Substituted indole
R1 H N R2 H N R1 R3 P.T. R2 H N H N R R2 Substituted indole
1

H N

H N R3 - NH2H

R1 N R2

R3

[3,3] H

R3 - H H

ene-hydrazine