Workbook for organic synthesis the disconnection approach i

ChapterU Strategy XII: .Reconnecti ns: Synthesis 01 1,2- and 1,4-Oifuncti nalised Compounds by C::C Cleavage 299 Chapter 27 Two-Group Oisconnectio s VI: 1,6-0ifunctionalscd Chapter28 Gen

Preface

This workbook accompanies the text Organic Synthesis: The Disconnection

Appmach Tt contains fllrther examples, problems, and solutions undee the same chaplee headings as those of the maio texto 1 assume lha! you have read the corresponding chaplee in the tex! before tackling the chaplee in the work-book You should then find examples and problems 10 help you understand each parl oC the chapler in the maio text

Within each chapler, the problems and examples are arranged either 10 follow lhe same organisatioll as Ihal oC lhe main lexl Uf lu presen! a series graded in difficulty Particularly easy or difficult problems are so labelled tha! you can avoid Ihem ir you wanl too My prograrnmed text Designing Organic Syntheses, Wiley, Chichester, 1978, provides another graded series of problems and solutions within a similar framework

My chief thanks go to Oenis Marrian who gave me vigorous encouragement

as well as checking all the text, diagrams and references and providing index and formula indexo His hard work and that of Marilyn Buck, who typed the printed words, enabled this workbook to be produced at the same time as the main text 1 am deeply grateful to them both

Contents

Chapter Thc Disconncction Appr0 C h

Chapter 2 Basic Principies: Synthesis of Aromatic Compounds 5 Chapter 3 Stratcgy 1: T h c Orde r o f ve nt s 1 5 Chapter 4 One - G r oup e- x Disconncc ti n s 29 Chapter S Strategy 11 : Chemoselectivity 38 Chapter • Two - Group e- x Disco nn cc ti n s 4S Chapter 7 Stratcgy 111 : Reve r sa! of P o larit y Cyclisa ti n Rcac ti ns,

Chapter 9 Strategy IV: Protccling G roups 80 Chapter 10 One - G r oup C-C Di sconncctions l· Alcohols

Chapter 11 General Stratcgy A: Ch osing a Discon ecli n

Chapter 12 Stralcgy V : St c reose lectiv ily

89

96

107 Chapler 13 Onc - G r oup C-C Di sconnec li n s : Ca rb o y Compounds 1 23 Chapter 14 Strategy VI : Rcg iose l ccli ity

Chapter 15 A lk enc Synt hesis

Chapter 16 Stralegy VII : Use of Acc t y lc n cs

134

145

160 Chapter 17 Two- Group Oiscon ccli n s l : Oicls-Alde r Reactions 1 75 Chapter 18 Rcvision Examplcs and Problcms 1 88 Chapter 19 Two-Group Oisconncction s 11: 1,J- Oifuncti naliscd Compounds

and a , fi- U n satu rated Ca r bo n l Co mp o un ds 200 Chapter20 Stralegy IX : Co ntrol in Carbony Co nd e n sat ons 209 Chapter 21 Two - G r o up Oisconnccli n s 111: 1 ,5- 0ifullctiU llali se d

Compo un ds: Micha l Addilio n a nd Robinson Annela ti n 229 Chapter22 S tr a t egy X: Use of Aliphatic Nitro Compo und s in Sy nth esi s 241 Chapter23 Two- Group Oisconnections IV: 1 ,2- Difunction a sed

ChapterU Strategy XII: Reconnecti ns: Synthesis 01 1,2- and 1

,4-Oifuncti nalised Compounds by C::C Cleavage 299

Chapter 27 Two-Group Oisconnectio s VI: 1,6-0ifunctionalscd

Chapter28 Gencr:ll Stnlcgy R: Str:ltegy of Carbon t Oisconncctio s 323

Chapler29 Stralegy XIII: Jntroducti n lO Ring Synlhesis: Saluraled

Chapter 30 Three-Membcred Rings 353

Chapler31 Stratcgy XIV: Rearrangemcnls in Synthesis 368

Chapter 32 Four-Mcmbered Ring.'I: Pholochcmislry in Synlhesis 376 Chapter33 Slnltegy XV: Use of Ketenes in Synthesis 389

Chapter34 Fivc-Menlbcrcd Rings 397

Chapter3S Slralcgy XVI: Pericyclic Rearrangemenls In Synlhesis:

Special Methods for Five-Mcmbcred Rings 407 Chapter36 Six-Membcred Rings

Chapter 37 General Strategy C: Strategy of Ring Synthcsis

Chapter38 Slralegy XVII: Stercoscleclivity B _

C HAPT E R 1 The Disconnection Approach

( 1 ) Two syntheses of ketone (1) are described in Chapter TI The starting materials for the two syntheses are

differe n t: ( 2), (3) , a n d (4) were us e~ for the

industrial synthesis , (5) and (6) for the laboratory

~y n thC3iQ Analy s is shOW$

(6 )

If you can analyse published syntheses like this, you wi l l incre se your understanding of good places to make good disconnections

1

Pr oblem

Two syntheses of mul istriatin follow For these and

for the synthesis in the main text (p T 3) draw

diagrams like those above to show which parts of multi

-striatin carne from which starting materials in each

synthesis D n t be too con cerned about the details of

each step in the synthescs

H

~

A rl s w el" In each case, slrnpl ~ draw the structure (8) and

trace which atoms carne from which original starting rnaterials

Sy n thesi s 1

', , C02 , , '

a b

Synth68is 8

a , e , Iol l

Bond (a) is made in all threc syntheses and bond

(b) in two of them We shall see latcr that thc syrnmetry of ketone (7) is a reason for (a) and thc

branchpoints in thc molcculc a rcason for (a) and (b)

CHAPT E R 2

Basic PrincipIes: Synthesis of Aromatic

Compounds

Diseonnection and FG1

t:J:amp~ e : Steps in the synthesis of multistriatin given

on pago T 3 correspond to disconnections or FGls as

follows:

-This 18 a rearrangemen and ls best describad as ao FGl

since no ncw e - e bonds are formad and all carbon atoms

retain the same number of bonds to oxygen atams

5

Could be describad as twa e-o disconnections

or as FGl (olcfin to epoxlde by oxidatton)

Dcfinitely the majar

disconncction - a new

e-e bond 15 formed

(FGl aud dlsr :ullllcctlou) a n hcJpful - choase whjchcvcr see~s the more helpful in the circumstanCeS

Two e-o disconnections

1 5 t he mu:::;L IH :ll pIul description

Aromatic E~ectrophilic Substitution

DiSConnection of (2) at the bonds joining the

aromatic rings to the aliphatic part of the molecule will need a reagent for the doubly charged synthon (3)

Analysis

Me

(2a)

(3)

A diha1ide wi11 not do as it would be unreactive

towards substitution and we already have three halogen

atoms in (3) The answer is to use the aldehyde (4) chloral - in acid solution One addition gives the

-alcohol (5) which dehydrates and re cts again via a

carbonium ion In practice (5) need not be isolated

AnaZyaia

el

Removal of the one"':carbon electrophiliC fo

rmalde-hyde (ef p T 10) leaves a chlorophen l (7) made by direct ehlorination of (8) The long ally chain of (8)

cannot be put in by Friedel-Crafts alkylatton or r

e-arra/lg:~r!lt :" IL will VCL:ur (p T 9) so acylation and

P"!'ob~ems :

1 H C Brown 6 used ester (9) to test a new reducing ngcnt which did indced for~ alcohol (10) How might he have made the es ter (9)?

Ester (9) can easily be made from acid (11) You might

consider two approaches to this a one-carbon electrophile addition via chIoromethylation (Table T 2 ~) and oxidation or FG1 (TabIe 2.3) back to E-ehlorotoluene (12) The latter is easier on a Iarge seaIe The E-chlorotoluene (12) can be made either by direet

-chIorination of toluene or by the diazotisation route (p T 12) again from toluene

Chlorination with a Lewis aeid eatalyst' at low

temperature avoids ehlorination in the methy group but

the diazotisation route,' though longer, is perhaps easier •

available cornrnercially

1 3

mle

exploration of industrial uses of Porl l

TM ( 15 )

_':;l.u t o a to Sim ple Pro b'LS 1II G :

7~ , 1 (13) : This syrnmetrical ~lecule cffers only one dis:annection (a, below) corresponding to a Friedel-Crafts :llkylation (p T 8 ) •

tO a Friedel-Crafts acylation (p T 7 )

( 14a)

- : ,:=-~) Tll (15 ) IIF

C HAPT E R 3 Strategy 1: The Order of Events

G e neraZ Strategy E xampZe a (see table of guidelines)

i~ow that you appreciate the reasans why a particular

benzocaine (p T O) and piperanal (p T 9), The

of the four steps are FGIs This is because two FGs

required fer tbe synthesis (N02 and C02H) are ~­

directin¡;: ~nri!'lO (',annot be used to direct substitution

where i t is needed (l?) (guideline 1 in Chapter T 3)

The piperonal synthesis (p T 9) is an example where the tWQ ortho oxygen substituents would be very difficult to set up We therefore (guideline 1) start with available catechol (E-dihydroxYbenzene)

Table 3.1

Guid el ines [rom Chapt e r T J

1 Examine the relationship between the groups, looking

15

2 If there is a choice, disconnect fil'ot (that ts add

last) the most electron-withdrawing substituent

3 If FGl is needed during the synthesis, it may well alter the directing effect of the group and other substituents may be added befo re or after the FG1

4 ~Iany groupS can be added by nudeophilia

substitution on a diazonium salt, made from an amine

AddinC- other group.<:; at thf'> amine stagf'> raay he

advisable as the amino group is strongly Q,E

-directing

5 As a last resort, there is a trick to solve sorne difficult problems, such as adding two Q,E-directing groups, ~ is one another A 'duwmy' aQino group is added, used to set up the required relationship, and then removed by diazotisation and reduction

6 Look for substituents which are difficult to add It

is often good strategy not to disconnect these at all, but to use a starting material containing the substituents

7 Look for a aombination of substituents present in

the TM and in a readily available starting material

8 Avoid sequences which may lead to unwanted reactions

at other sites in the molecule

9 If Q,E-substitution is involved, one strategy may avoid separation of isomers in that the other

position bccomcs blockcd

Guidelines may well contradict one another - use your judgement!

Gene ra l Strategy ProbZema

1 Analyse the syntheses of (a) AH'f (page Ta ) and eb) phenOl (1) (p T 12)

e - N

nitra tíon

An8We l' - nu c leophili c substitution n o l o ng e r po ssible

- CF3 ~-dire ct ing, so díffi c ult t o m a k e (2) (g uidelin e 15

- nitration might ox idi se ami n e ( guíd el ine 8)

Furthe r WOl' ked E xamp les

1 In 1979, w o rkers inv e sti~ating!~ the di c n n c - ph c n ol

r ea rr angeme nt treated ( 3) with a cet i c anhyd ride and got a n unknown compou nd believed t o be ( 4) Trea t - ment w1th strong ac íd gave (5), t h ey suppo sed, but

th ey wanted to synth e si s e an authentic samp l e of (5)

t o c he c k the ir ass ign ment This 1s a t r1 c k y prob1en

lB

as non e al the substituents can be easily

dis-connected

OH OAe O

H 2

)

) Ac

We really would prefer to keep the two OH group s

and start from c ate c hol( g 1dp.line 7) This torce s u s to

disconnection (3a) We require a r agent tor synthon

(6) and the obvioll$ choice 15 the diazonium salt (7)

AnaZysis

The OH graups must be protected agaiost oxidat1on

during the nitration step and the methyl ether (8) is a

conveníent starting material Treatment with HOr at the

e d of thp synthesis, TeIDOves the rnethyl groups

The product of this synthesis proved to be

identical with the unknown compound from the dienonephenal sequence and the structures are confirmed

-SimpLe i'l'obLems

Suggest syntheses for TMs (9) and (10) needed as mediates: TM (9) in the synthesis of bror.ünated hydroxy-benzoic acids1S and r~ (10) in the synthesis af model compounds for

inter-hydrol ysis l' studying biologi, cal mechanisms of ester

essential to get sorne control over orientation (guideline 3), The easiest is C02H to CH3, Then dis-

-connection of either Sr or N02 is possible,

(13)

separate from

ortho isomer

( 11) 70$

An alternative synthesis of (11) r~lies on the partial reduction of m-di-nitro groups (9 T 38) but thc-yie1d is poor

orientation is correct for either (Q, E- to the most electron-donating group -O ) (guideline 1) Guidelines

2 and 9 suggest disconnecting CHO first

-;

CUCla , c:._» TM( 1 0)

NaOH

Mo r e A dvano e d fxamp ~ e

2 The tetracyclines are important antibiotics often

resistance In 1980, a synthesis of sorne sulphur

containing tetracyclines10 required thiol (14) as an intermediate The SH group co ld be introduced by

nucleophilic displacement of a diazonium salt

(guideline 4) so amine (15) is an essential inter

chlarination or by diazonium displacement The most obviaus disconnection i~ to remove the chlorine Un-fortunately chlorination af the very electron-rich

amine (16) oxidises it to black tars : it would in any

case give a mixture of isomers as all positions in the ring in (16) are a tivated

Q" NH2

OMe (16)

One other possible short cut is to disconnect the

~ino group, hoping to add it by a benzyne mechanism

from easily made (17) In fact, this reaction gives a

~ixture of three isomers of (15) in which (15) do es not predominate.2 1

neither of the obvious disconnections (ISa and b) is any good In both reactions, the stron ly electron-donating OMe group will dominate and reaction will occur or t ho

to it21 ,22 (b) or give a mixture (a)

Thp- chlo rinp- c~n he d i ~conn ec t e d with th

p-alternative polarity vía the diazoníum salt to amine

(19) (guideline 4) The amino group is mor e powerfully

electron-donating than OMe so we can disconnect the N0

2 group The arnino group is itself derived from another nitro group

It will be wise to protect the amino group of (20)

by acetylation to prevent oxidation during the nitration step (ef p T 12)

1 POlyurethanes are often polymerised onto rigid

diamines Compound (21) was needed for a new pOurethane.2~ Suggest a synthesis for it

the required positions The best place is E to the methyl group

2S04 EtOIl

The dreadful tropical discase bilharzia is carried

by water snails and one way to tackle the disease is to kilI the snails with a r.'Iolusc1cide harm]css to mammals and fish Bo.yluscido (25) i8 made by Baoyer 25 fnr t.his

a tivating OH graup and E- should predominate far steric

reasons Th1s turns out ta be correet

D isconnection of e h l oro or nit r o groups ia

satisfactory as the amina group will direct very stronsly

••

Q ~ Guideline 2 suggests route (b), gutdeline 9

route (e) The published synthesis uses route (b)

H a

( hN-SCCI 3

H a ( 2) , he ga rd e n (un g :l c id e 'c aptan' (2) i s made from (1)

This is an imide - a double a~ide - and so bot h bonds

~etween carbonyl and nitrogen can be disconnected

~ >¡aty8i8

2 CoN a H cax

>

The hest reagent f a r thp doubl c acyl d e r ivativo (3)

is tbe anbydride (4) whose synthcsis is discussed in Chapter T 17 Reaction oí (4) with arnmonia gives TM (1)

Synthesis 2 '

(4)

29

e st e 8

In ~aking esters, either the alcoholar acid rnay be

largc excess of the alcohol (e.g as solvent) with

r.lineral acid catalysis

The potential analgesic (5) is an ester of the

alcohol (6), which has to be made (see p T 77), and acid EtC02H Tbe chosen reagent was the anhydride whicb

1 Mark all the c -x bonds you would wish to disconnect

in these molecules and say why

Not all of these bonds would be disconnected in any one synthesis but it i9 lmportant that you learn to see

the possibilities quickly

2 Choose starting materials for a one-step synthesis

of ether (10) sayinc why you chose these particular compounds

whereas the secondary halide (ll) in route (b) 18

relatively unre ctlve toward8 SN2 and can elimina te

Synthe sis I I

base

-,» TM ( 1 0)

.'.fOl'e advanced example

Methyl dar.1ascanine (12) has a nutrncg-like smell and

is used in perfumery Ea h group on the arOr.1atie ring [¡as an alkyl group attached - ether aminc, and ester

are all presento

(12 )

'I'he ester is the easiest to make so we can

dis-conncet that lirst 'i'he alkyl amine wi11 ue made by

metbylation of tbe aromatlc amine (13) (see Cbapter T 8)

and we are left witb a familiar problem of aromatic

synthesis

~ 'la lysis 1

e -o ester

( 12 a)

The amino group must come from a nitro group and

direct diseonneetion oí (14) has the correet orientation thou gh w h th o r ( 1 5) wi11 nitra t c a t ~ it CD (a) (b) o r (e)

is doubtíul

conditions could be found3~ to nitrate (15) at position

(a) Disconnection oí the methyl group írom the eth r

must th refore be the last step in the analysis

MeOH

- - - - 7 ) TM(12) Hel

Suggest a synthesis of the local anaesthetic

ambucaine (17) This time carry the analysis of the aromatic starting material further, for revision.*

Alcohol (18) is available (and is discussed in Chapter

by nitration and we already know (p 34) that we need

the free acid (16) for this The ether must therefore

be disconnected first

oxidation of o, rI , or f'-hydroxy toluenes is not a '-; 00-:

way to make the corresponding benzoic acids as other reactions occur