Synthon approachDr. Taj Khan

Dept. of Pharmaceutical Chemistry, Oriental college of pharmacy

Sanpada, New Mumbai.

Ref: Stuart Warren , Iyer R P

Retrosynthesis is the process of “deconstructing” a target molecule into readily available starting materials by means of imaginary breaking of bonds (disconnections) and by the conversion of one functional group into another (functional group interconversions).Its useful for finding out new route for synthesis of new drugs or existing drugs and comparing them in logical & straightforward wayAn operation that involves breaking of a bond between 2 atoms to produce oppositely charged synthons.

Indicates disconnection

Functional group interconversion (FGI): process of converting 1 fun grp into another by substitution, addition, elimination, oxidn or redn. Reverse operation is used in analysis

AB A+ + B -

COOH CN Hydrolysis

NH2 NO2 Reduction

Cl OH Substitution

Terms for Synthesis Retro analysisStarting structure SM Target

Steps Rx Transformation/disconnection

Steps shown by

Stru features needed

Fun grp Retron

Prdt after the step intermediate Precursor/ Synthon

Ending stru Desired prdt Possible SM

Disconnection: An analytical operation, which breaks a bond and converts a molecule into a possible starting material. The reverse of a chemical reaction. Symbol

and a curved line drawn through the bond being broken.⇒

FGI: Functional Group Inter-conversion: The operation of writing one functional group for another so that disconnection becomes possible. The reverse of a chemical reaction. Symbol with FGI written over it. –COOH -CN, -NH⇒ ⇒ 2 NO⇒ 2 -H⇒Target Molecule: The molecule whose synthesis is being plannedFunctional grp addition: process in which functional grp is addedin the retro scheme in order to make stable fragment e.g. addition of COOEt grpFunctional grp removal: removal of fun grp in order to make stable fragment

Transform: reverse of synthetic rxRetrosynthetic analysis: Logical process of analysing stru of TM to transform the target to a sequence of progressively simpler stru along a pathway which finally give simple & comm viable SM.“process of breaking down TM into available SM by FGI & disconnection”

O

O OH

Alcohol+

Cl

O

Acyl chloride

Ester

Synthon: A generalized fragment, usually an ion (cation/anion/radical), produced by a disconnection. (some people also use synthon for a synthetic equivalent).

2 typesdn Synthon (d= donor n= distance bet FG & reactive centre) functionalized Nuan Synthon ( a= acceptor ) functionalized E+

OH

R 1

R

O

12

R

OH

12 H3C

O

12 3

a3 synthona1 synthon

d2 synthon

a3 synthon

O

Cl

O

Br

Me

O

Me

OH

Reagent: A compound which reacts to give an intermediate in the planned synthesis or to give the target molecule itself. The synthetic equivalent of a synthon. e.g. MeI is reagent for Me+

Synthetic equivalent (SE ) A reagent carrying out the function of a synthon which cannot itself be used, often because it is too unstable. Every synthon has its SE H2SO4 and HNO3 mixture is SE of NO2

+

Retron: Minimal stru in mole in TM which causes transformation e.g. in Deil’s Alder rx 6 memb ring with pie electrons B: SM and A TM

Arrow: it could be made from

A B Ph Ph

OO OO

Ph Ph

OO

Target Retron

Precursor

Synthetic tree: Set of all possible disconnections and synthons leading from TM to SM

Route 1

Route 2

C C RO2N CO2N C R+

Disconnection towards NO2

Disconnection towards R

C C RO2N CO2N C R+

Stabilizedcarbanion

unstabilizedcarbonium ion

unstabilizedcarbanion

Strategies for disconnection approach:1) Simple route: good for industrial purpose. Avoid radical and photochemistry.2) Disconnection shd be done such that it gives stable ion fragments. Break down molecule 1 bond at a time. For heterocyclic compd disconnection is done such that 2 fragments in which 1 is +ve and other is -ve fragments generated e.g disconnection of C-C bond

Strategies for disconnection approach: contdStability of ion generated governs the mode to be followedCarbanion (C-) fragment is stabilized by EWG like CN, NO2, COOEtCarbonuim ion (C+) fragment stabilized by EDG or e releasing grp like R or ORIn this case route 1 is preferred because it gives Stabilized ion fragment , whereas route 2 gives both unstabilized fragments3) No of fragments generated shd be small in number as possible i.e. few steps strategy is preferred.

H3C CH3

OO

TM

H3C CO

H3C OEt

O

+

CH3

O

MgBr

O

GR

FGI

OH

O

O +

O

O

1

2

3

4

5

Total fragments 5

Route 1

2 3

2-3 disconnection

H3C CH3

OO

TM

OMichael Rx O+

Total fragments 2so preffered route

Route 2

3

4

3-4disconnection

Examine 1) mole as whole 2) watch various fun grps and 3) positional relationship between fun grps

4) C-C db can be considered to result from dehydration, dehydrohalogenation or Elimination of NH3, NH2OH....etc.Addition of mole of water or NH3 to db can set up the target for further disconnection

5) A bond joining a C atom to hetero atom (O, N, S) is always broken with electron pair remaining on hetero atom i.e. hetero atom shd have –ve charge

In this case disconnection follows principle of electronegativity i.e O, N, S > C

C N C

C Cl

N

HN

C-N+

6) Sometimes disconnection does not generate stable fragments in such cases FGI concept can be used to generate stabilized ion fragmentse.g. synthesis of alkylamine

R NH2 R + NH3

ab a

R Clb

R

R Cl

+ H2C NH2

UnstableFGI/FGC

H2C NO2 H3C NO2

Ana

lysi

s

H3C NO2Base

R Cl

RCH2

O2NReduction

R NH2

7) Fun grp addition: Sometimes disconnection does not generate sufficiently stable fragments in such cases stability could be achieved by introducing additional EWG & removing after use.

Ana

lysi

sS

y nth

esis

R

O

R CH2

O+ Cl

Unstable

FGA/carboethoxy

REtO

O

O

R

O

OEt

OBase

Cl

REtO

O

O H

-CO2-EtOH

R

O

TM

TM

8) In some cases reconnection of acyclic fragments can help to generate cyclic fragments that could result in simpler starting material & Rxn sequences. Of course, strategy must be in place for conversion of acyclic to cyclic fragments during synthetic sequence.

Diel's Alder Rxn

OMe

COOHOH

FGI

OH & COOH on same sideso can be reconnected to form lactone

OMe

O

O

OMe

O

O

OMe

O

OMeOMe OH

+

1) DA2) Oxidn3)BV oxidn

O

12

3 4

12

3 45

5

12

5

67

834

O

+vely charged alkyl fragments:

RCH2RCH2Cl or RCH2OH or RCH2OEt

+vely charged acyl fragments: acid chloride, acid, acid ester

OR Cl R

OOr

R OH

OOr R OEt

O

-vely charged fragments Corresponding protonated species

NO2

R

NO2

RR N

H

HR N

H

R O RO

HR

OEtO

R

OEtO

Retro analysis followed by synthesis:

One grp disconnection (C-X disconnection)Disconnection of simple alcohols, alkyl halide, ethers

Alkyl halide:

C-X disconnection in aliphatic compds gives a Nu (XH) &E+ carbon species usually represented by alkyl halide, tosylate and mesylate

R XC-X

X + R RY

XH

cationic C synthon

Y=Br, OTs good leaving grps

Following types of compds can be made using alcohols

Base Hal-R'OH

NuR'SH/base

R-XROH

R-OR'

RHal

RNu

R-S-R'

Ether

Alkyl halide

Other deri

SulphidesX= halOTs (tosylate)OMs (mesylate)

ROHTSClPyr

PBr3/HBr

MSCl

TEAROTsROMs

RBr

Methyl & 1o alkyl deri : SN2 mech so powerful Nu and non polar solvent effective.3o SN1 Polar solvents and catalysise.g. 1)

R1R3

R2

OHR1

R3R2

R1

R2

R3

R1R3

R2

X

R1R3

R2

Br

X-

C-C+

Cl

FGI

OH

A(TM)

B C

Synthesis:C B

PhH

AlCl3FC rxn

A(TM)

Ethers: 1)

C-O

Syn

thes

i s:

Ana

lysi

s

H3C O CH3 H3C O +ether

CH3Y

H3C OHMe2SO4

NaOH H3C O CH3

Ethers: 2)

Ph OPh O +

X

A route could lead to Elimination to give alkeneperfumeBpreffered

X

Ph+ HO

Benzyl alcohol is reactive but still preffered SM

C-O

C-O

Ph OH

AAB

Ether Synthesis: SN2 so base catalyst helps

HOBase

OPh Cl

OPh

Ana

lysi

sS

ynth

esis

OPh Ph OHC-O

+ HO

HO OPhBase

PhCH2Br

TM

TM

Acids:

Syn

thes

is:COOH

Br

+ H2CCOOH

COOEt

COOEtDiethyl malonate

Ana

lysi

s

COOEt

COOEt

NaOEt/EtOH

Br

COOEt

COOEtTM

KOH/H2O

H+, Heat

TM

C-C

Carbonyl compd synthesis by Michael additionR' R2

O C-C-R1 + R2

OGR/RLi

O

RC-C

O

+ R-

ORLi

n-Bu3P/ CuI

TM

Branch ponit at Beta and gamma C

O

RTM

Ana

lysi

sSy

nthe

sis

Ph

PhCOOH

C-C PhCOOH

Cinnamic acid

+ Ph-

Ph COOH

Cinnamic acid

PhHTM

AlCl3

Rings (5 & 6 membered), fused heterocyclic rings –more common in drugs3 & 4 memb less common tranyl cypromine (3 C) Beta lactum ring (4C)Retrosynthesis: 1) Follow similar rules with additional possibilities.2) Rich in functional grps so handle only readily predictable fragments like NH3, NH2NH2, NH2OH, guanidine, thiourea, (NH2)2(CH2)2, HO(CH2)2NH2

3)Break C-Het 4) Addition of H2O to db ( NH3, NH2OH etc)

5) 3-component cyclization, DA rxn, 1,3 dipolar rxn

C+ + - Hetero atom

Sulfides:

SPh Ph SHS-O

+ HO

TM

R1 S R2 R1S- + R2YUndergoes easy SN2

SH have low pKa than alcoholR1S- softer anion than RO-

so more Nu towards SP3 C

Ana

lysi

sS

ynth

esis

S

Cl

ClS

Cl

Cl

Cl

+

TMChlorbenzide-Acaricide

C-S

SH

Cl

Cl

Cl

+S

Cl

Cl

NaOEt

EtOH

TM

One grp C-C dix Alcohol: Best mtd is GR addition to ald/ketone

R1

R2

R

OH

R1

R2

OH+ R-

R1 R2

ORMgBr

1)

C-C

One grp C-C dix Alcohol contd…

+

R-

RLi

2)

OR1

ROH

R1

Epoxide ring opening

Ana

lysi

sS

ynth

esis

OR1 RLi+

ROH

R1

One grp C-C dix Carbonyl compounds (Ester, ketone, acid):

OCOCl

C-CCOOH

pheromone

Dix of heterocyclic rings: Any 1 eg1)Pyridine e.g. Nifedipine

C-N

OHOH

N

N

N

2H

N ONH2 ONH2

+

CHHC

CHHC CH

N

3 component cyclization

1,5 di-CO

Michael CHO

+ CHO

C-N Stork enamine Rxn

Michael rxn

a)

b)

c)

d) Stork enamine Rxn followed by cyclization rxn is aviable route for synthesis of pyridine

ONH2

+ ONH NH2N NO

-2H

Dix of Het. Pyridine Contd..

Pyrimidine: eg barb, anticancer (MTX, 5FU), Anti viral AZT

N

NH2N

H2N NH2

NH+

H

HO

OMalonaldehyde

N

NH2N

H2O N

NH2N

O HH O

NH

H2N

NHH2N NH2

NH

+

H OH O

OEtH

H O

OEtO

H O

OEtO

H

H

N

N

N

NH2N

H2N NH2

NH+

H

HO

OMalonaldehyde

Syn

thes

is

Dix of Het. Pyrimidine Contd..

Pyrrole: less common eg. Zomepirac (anti inflammatory)

NH

R1

R2 R3

COOEt

O O

R1 COOEt

R2 R3

Michaelrxn

O

NH2R2

R1+

R3

COOEtb)

a)

NH

Imidazole: Metro (anti bacterial, cimetidine H2 blocker

N

NH

H3C

H3C CH3

NH

O O

H3C

H3CCH3

NH2H3C

H3C+

H2O

-NH3

H3C NH2

OCl

b)

NH3

O

O

H3C

H3C+ +

H

CH3

O

Glyoxal acetaldehyde

a)

N

NH

Indole: Indomethacin

NH

R

R

H2O

H2O+H2O

NH

R

ROH

NH

R

R

HO

NH2O

R RFriedel C

NHAc

+R

RCl

O

FGI R

NO2

+Cl R

O

NH

O R

R

NH2

+R

RCl

O

Cl

NO2

+ RO

R

Fischer indole synthesis: 1,5 diene cope rearrangement Addition of NH3 in place of H2O

NH

R

RNH2 NH2

NH

R R

NHNH

R RH

NH

NH

RR

Dix of Het. Indole Contd..

Quinoline: Anitimalarial(prima, chloro) ciprofloxacin

N

N

O

CH3H2O

CH3ONH2

O

NH2

+

OEt

CH3

O

O

NH2

+

OEt

CH3

O

O

Diphenyl ether

250 0 C N

O

CH3

Ana

lysi

sS

ynth

esis

Piperazine: meclizine, cyclizine Cinnarizine (Valodailator)

NH

HN

NH

HN

OH

NH22

NH2

NH2

Cl

Cl

+

NH2

NH2+ O

C-N

C-N

+NH3

O

H2N

OHN

OHMe

Me

O

H2N

O H2N

O

Me

Me+

OH

H2N

O OCl+

OH

Cl

O

OH

HO

O

FGI

+ NH3

SOCl2

NH3

Base

2-(4-hydroxyphenyl)acetic acid

Atenolol

Epicholrhydrin

Dix of drugs

Sulfadiazine

H2N SO2NHN

N

H2N SO2ClN

N

H2N

H2N+

Free NH2 can react with ClSO2OH so need to be protected by acetyl grp and deprotected by aqs HCl

Malonaldehyde (unstable)

OHCCHO

+

H2N NH2

NH.HCl

OMeMeO

MeO

OMeDiacetal of Malonaldehyde (stable)

Ana

lysi

s

Dix of drugs contd..

Synt

hesi

s

Diacetal of Malonaldehyde + Guanidine HClN

NH2N

Aniline + Acetyl chloride HN SO2ClC

OCl

ClSO2OH

I

II

I + II H2N SO2NHN

NH2N SO2NH

N

NAqs HCl

Ibuprofen Dix of drugs contd..

Strategies:Guiding principles for selection of transform so as to keep size of retero-synthetic tree in controlTypes of strategies in disconnection:1)Transform based strategies depend on application of powerfully simplifying transformation like DA, Robbinsons annulation, Birch rx

2)Structure based strategies depend on recognition of possible SM /key intermediate for synthesis

3) Functional grp based strategies identify functional grp as key structural subunitOH, C=O , = etc can be useful for identifying suitable pts for disconnection

4) Topological based strategies depends on identification of 1/more individual bond disconnectionOr correlated bond-pair disconnection.There are several types of strategic bonds e.g. bonds in polycyclic syst, poly fused ring syst, bond connecting chai to ring, chain to fun grp5) Stereochemical based strategies remove stereocenters stereorelationships under control. Stereocontrol can be achieved by mechanistic or by substrate. Reconnection that moves stereocenters from chain (where they r difficult to introduce) or into rings (where introduction is much easier)

Basic rules of disconnection:Rule 1: Bond shd be disconnected such that stable fragment(ion) obtd

Route A ok as carbcation stabilized by EDG like OR Carbanions are stabilized by EWG like NO2, Cl

O2N C C OR

A

B

CO2N C OR

CO2N C OR

+

+

Rule 2: Total no of fragments shd be as min as possible i.e. synthesis shd be short. Disconnectionshd be made in middle of mole/ at branch pt

Analysis

OH

C-CCHO

+

BrMg

Br

i) Mg, Et2O

ii) CH3CHO OH

Synthesis

TM

TM

Rule 3: compds with 2 parts joined with hetero atom, disconnection shd be next to hetero atom,e pair remain with het atom (het atom more negative than C & so accommodate -ve charge easily)

AnalysisPh O Ph

C-O+

PyridineSynthesis

TM

O

Ph O

Ph

O

Ph O Ph

TM

O

PhCOClPh OH

Rule 3: If disconnection doesn’t give stable fragment then FGI done/ simple grps introduced soas to give stable fragments

Analysis RC-C

+

Synthesis

TM

NH2

R

TM

NH2

R CH2

R CH2Cl

H2C NH2

Unstable as NH2 is e rich

FGI

H2C NO2

Stable as NO2 is EWG

CH3NO2 + ClCH2CH2R R NO2

Reduction

Rule 5: Use disconnections corresponding to known reliable rx with high yields. +ve & -ve fragments generated by disconnection r replaced by known available chemicals.

H2C C CH

A

B

PhC CHH2C+

PhCH2+ C CH

Route B ok as acetylene forms anion with sodamide in liq NH3

R1HN R2

FGIR1

HN R2

O

C-NR1 NH3 Cl R2

O

+

OR

R1HN R2

FGIR1 N R2

C=NR1 NH2 Cl R2

O

+

h

Amine r converted to less reactiveamide/imine before disconnection

Positive fragments: +ve charge fragments equvt to good leaving grp/EWG

R CH2

H2C XR Alkyl halide

H2C OHR Alcohol

H2C OEtR Ether

+ve charged alkyl

R C

C XR Acyl halide

C OHR Acid

C OEtR Ester+ve charged acyl

O

O

O

O

C OR

O

C

O

R Anhydride

Positive fragments: -ve charge fragments equvt to their protonated species

O2NHC R O2N

H2C R

RO ROH

RNH RNH2

ROCOCHR' ROCOCH2R'

Rule 6: Disconnection route that avoid chemoselectivity (Rx of 1 fun grp in presence of other) shd be selected. For this reactive grps r disconnected first & 2 grp disconnection is done.

OPh

OH

a b

a

b

HO

OH

Ph

OH

OH

Ph

+

+

Route a involve 2 OH selectivity problem so route b is better

Guidelines for disconnection:G1: Examine relation bet grps in TM. Disconnect grp which is proper directive at last

COCH3

CH3

COCH3

CH3

TM

a

b

Acetophenone

Toluene

CH3+

+COCH3

Route b is better since in route a COCH3 is meta director & rx is not possible

Guidelines for disconnection:G2: Most EWG grp is to be disconnect first (It is to be added in last in synthesis)

CH3

TM

CH3H3C

NO2O2N

C-N

CH3

CH3H3C

C-C

CH3

OCH3 OCH3 OCH3

+ t-BuCl

CH3

CH3H3C

OCH3

OH

OCH3

Me2SO4

Base

CH3

OCH3

t-BuCl

AlCl3

CH3

TM

CH3H3C

NO2O2N

OCH3

HNO3

CH3

CH3

CH3 CH3

Analysis:

Synthesis

Guidelines for disconnection:G3: If FGI I needed it shd be done at proper stage to get right orientation. Other subs added either before or after FGI

Analysis

Synthesis

Cl

Cl3C

TM

Cl

Cl3C

TM

Cl

H3C

FGI C-Cl

H3C

H3C

Cl2

FeCl3H3C

Cl

Cl2PCl5

CCl3 is meta director (it is introduced by FGI)CH3 is para director so FGI shd be done before C-Cl disconnection

Guidelines for disconnection:G4: Avoid sequences that lead to unwanted rx at other site of mole

Route b is preferred as nitration e.g. benzaldehyde may lead to oxidation CHO oxidise to COOH

O2N CHO

ab

CHOCH3

O2N COOH COOH CH3

a

b

FGI

FGIFGIC-N

C-N

Guidelines for disconnection:G5: when fun grp of unequal reactivity present in mole, more reactive grp to be considered for Rxe.g. In Phenyl ring containing both OH and COOH grps in basic soln (pH> 10) phenolate ion is more reactive than carboxylate ion.

O

OO NH2

O

COOH

OH

COOH

+

I

C-O C-O

TM

Guidelines for disconnection:G6: For adding 2 O/ a P directing grp M to each other, dummy NH2 grp is added, which could be removed by diazotization and reduction

EtOH/H

RRRRR

NO2 NH2 NH2

X X

Guidelines for disconnection:G7: Grps like OH OR difficult to introduce so not disconnected instead use SM containing them

NH2

COOH COOH

OH

O

O

OSalicylic acidAnthranilic acid Phthaleic anhydride

Guidelines for disconnection:G8: If 1 fun grp can react twice then SM & final prdt compete for same reagent. Rx will be successful only when first prdt is less reactive than SM. Both contain COCl

Above Rx works as half ester TM is less reactive than phosgene b’se of conjugation

Phosgene

Cl

O

ClPh O Cl

O

Ph OH +C-O

TM

Guidelines for disconnection:G9: If both O, P subst involved, avoid separation of isomers. P can be blocked

TM

HC

H3C CH3

OH

O2N NO2a a

b

HC

H3C CH3

OH

OHOH

O2N NO2

OHC-C

C-N

b

a

OH

HNO3

OH

O2N NO2

AlCl3

Cl

TM

HC

H3C CH3

OH

O2N NO2

Route b preffered as it blocks P position

Guidelines for disconnection:G10: Disconnect rings from chain

N

HO

CH3

OCH3

N

CH3

O

+

MgBr

OCH3

C-C

Disconnection involving 1 functional grp: C-X Disconnection:1) C-X means C joining to hetero atom X. It gives cationic Carbon syst

R-X X + RC-X

The reagent for R+ is good leaving grp attached to R

R = RY where Y= Br, OTs

R C

O

X C-X

R Y

O

+ XH

Order of reactivity:Acid chloride > Anhydride > Ester > Amide

Cl

Cl

HN

O

C-N

Cl

O

+

Cl

Cl

NH2

Cl

Cl

NO2

FGI

C-N

Cl

Cl

2) In case of Carbonyl deri RCOX

3) In case of Amine, prdt usually more reactive than SM

R2HNR1

C-NR2NH2R1 X+

R2NH2R1 X+ R2

HNR1

R3X

R2NR1

R3

R2NR1

R3

R4X

R4

Secondary amine are more reactive than primary amine

4) In case of alcohol, ether & alkyl halide

RX XH + R

R = ROMs alkyl mesylate or ROTs (Alkyl Tosylate)

Analsis

Me

OMe

Me

O

+ Me

Me

OH(Me)2SO4

Me

OMe

NaOH

C-O

Synthesis

5) In case of sulfide & alkyl halide

R1-S-R2 R1-S + R2X

S

Cl

Cl

C-SS

Cl

Cl

Cl

+

TM

Disconnection involving 1 functional grp: C-C Disconnection:a) Disconnection should be of C-C bond adjacent to fun grp specially next to -OH, -C=O

CH3C

OH

H

H2C CHO

C-C CH3CHOH

CH3CHO

+ CH2CHO (Synthons)

CH3CHO (Synthetic eqt)

Disconnection involving 1 functional grp: (Contd)C-C Disconnection:b) If C=C is a part of conjugated system involving hetero atom then C=C may be converted to C(OH)-CH before disconnection

H2C CH

C

O

CH3

FGIH2C

H2C C

O

CH3

OH

c) If there is a branching branch pt shd be disconnected to get unbranched C synthon

H3CH2C

HC

H2C

H2C CH3

CH3

C-CH3C

H2C CH H2C

H2C CH3

CH3

+

Disconnection involving 1 functional grp: (Contd)C-C Disconnection:d) In a conjugated/ non conjugate system, of double bond the disconnection of C=C can be done without adding H2O to C=C part

e) It is better to cut TM in middle rather than making uneven parts

H3C

C

H3C

C

H

CH3

C OH H2C CH3+

H3C

H2C

CH2

H2C

CH2

CH3C-C

CH3CH2CH2 + CH2CH2CH3

CuLi

H2C

CH2

H3C

CH2H2C

H3C

BrCH2CH2CH3

Disconnection involving 1 functional grp: (Contd)C-C Disconnection:f) Branches must be disconnected from rings

g) Disconnect C-C bond bet 2 fung grp separated by NMT 3 other C atoms

C-CCH3

O

+ C

O

CH3

PhH2C OEt

Ph

OO

C-C

PhH2CC HC

COEt

Ph

OO

+

Disconnection involving 2 functional grps:1,1-dix: Synthons are obtd by 2 grp disconnection on single C atom. Acetal, cyanohydrin,α hydroxy acid, α Amino acid, halohydrin r prepared from ald & ketone these TM need 1,1,dix

PhC

H

O

OPh

CHO +

HO

HO

Benzaldehyde Ethylene glycol

Disconnection involving 2 functional grps: Contd1,2-dix: When 2 heteroatom r present on 2 adjacent C compound called 1,2 difunctionalised e.g.

HO OH H2N NH2

C C

HO OH

O O

COOH

OH

H3CCOOH

NH2

R

Ethylene glycol Ethylenediamine oxalic acid

Lactic Amino acid

OPh

OHC-O O C

OH

H2C PhH

+

OHO

Ph+

Disconnection involving 2 functional grps: ContdDisconnect C-C bond which has 1 hetero atom on each C

CH CH

Y

CH3H3C

XC-C X

CH

H3C

Y

HC

CH3

Both X & Y could be same or dif f t

If you want to introduce 2 fun grp at C=C, TM can be obtd from corresponding alkene

OH

OH

Disconnection involving 2 functional grps: Contd1,3-dix (1,3 difunctionalized compounds)In 3 carbon compound 2 het atom on 2 C at 1,3 position it is 1,3 difunctional compd

PhC

CH2

CCH3

O O

12

3

RO NH2

12

3

Such compounds synthesized by condensation Rx Aldol, claisen, Knovengel, Michael, Reformatsky

O NH2 OCN

FGI

O

NH2

OH

+

CN

TM

Disconnection involving 2 functional grps: Contd1,4-dix (1,4 difunctionalized compounds)In 4 carbon compound 2 het atom on 2 C at 1,4 position it is 1,4 difunctional compd

RC

CH2

H2C

CH2

O

32

1

Such compounds synthesized by Michael, Robinsons reaction

OEt

4O

O O1 4

Maleic anhydride

C C

COOH

H

H

HOOC

Fumaric acid

COOH

OHOH

1

2

3

4

O

+COOH

CH2

EtOOCCOOEt

C-C

Disconnection involving 2 functional grps: Contd1,5-dix (1,5 difunctionalized compounds)1,5 Dicarbonyl compound can be disconnected at either α, β bond in reverse Michael Rx to give Michael acceptor (a3 synthon)

R1 R2

O O

12

34

5

1,5 diketone

O

HOOC

TM

C-CHOOC +

O

O

12

3d2 synthon

a3 synthon

12

3

45

Disconnection involving 2 functional grps: Contd1,6-dix (1,6 difunctionalized compounds)Such compound can be synthesised from Diels Alder Rx. Difficult synthon as C=O is Electrophilic. Instead of disconnection Fun grp reconnection can be used.

H3C

O

12

34

5CH3

O

6

H3C

O

+

O

CH3

H3C

O

CH3

O

CH3

CH3