Workbook for organic synthesis the disconnection approach i

worlfor
•

organlc
synthesis

Warren


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 workbook . 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 , C hichester, 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.

Cambridge 1982

Stuart Warren


Author's Note

Cross References: Cross references marked T, e.g. ' chapter T 20' or 'page T
145' refer lo the m ain text o Other c ross-references refer lo Ihis workbook .

Index: The text and th e workbook each have theirown indexo Al the end of this
Norkbook there is also a formula index of all target molecul es in both Ihe tex!
md the workbook.

vii


Contents

Thc Disconncction Appr03Ch

Chapter

Chapter 2 Basic Principies: Synt hesis of Aromatic Compounds

5

Chapter 3

Stratcgy 1: Thc Orde r of Events .

15

Chapter 4

One-G roup

e- x Disconncctions

29

Chapter S
Chapter

•

Chapter 7

Strategy 11 : Chemoselectivity

38

Two-G roup e-x Disconncctions

4S

Stratcgy 111 : Reve rsa! of Polarity, Cyclisation Rcactions,
Surnmary of Stfatcgy

62

Chapler 8

Aminc $ynt hcsis

70

Chapter 9

Strategy IV: Protccling G roups

80

Chapter 10

One-G roup C-C Disconncctions l· Alcohols

89

Chapter 11

General Stratcgy A: Choosing a Disconneclion

96

Chapter 12

Stral cgy V : Stc reose lectivil y

Chapler 13

Onc-G roup C-C Disconneclions 11 : Carbonyl Compounds .

123

Chapter 14

Strategy V I: Rcgioselcclivity .

134

Chapter 15

A lkenc Synt hesis

145

Chapter 16

Stralegy V II : Use of Acctylcncs

160

Chapter 17

Two-Group Oisconncclions l : Oicls-Alder Reactions .

175

Chapter 18

Rcvision Examplcs and Problcms

188

Chapter 19

Two-Group Oisconncctions 11: 1,J-Oifunctionaliscd Compounds
and a ,fi- Unsatu rated Carbonyl Compounds

200

Chapter20

Stralegy IX: Control in Carbonyl Condensations

209

Chapter 21

Two-G roup Oisconncclions 111: 1,5-0ifullcti Ullalised
Compounds: Michael Addilion and Robinson Annelation

229

Chapter22

Strategy X: Use of Aliphatic Nitro Compounds in Synthesis .

241

Chapter23

Two-G roup Oisconnections IV: 1,2-Difunctionalised
Compounds

252

Stralegy XI: Radical Reaclions in Synthesis: FGA and its
Reverse

267

Two-G roup Disconnections V: 1,4-Difunclionalised
Compounds

284

Chapter24
Chapter2S

107

¡,


ChapterU

Strategy XII : .Reconnections: Synthesis 01 1,2- and 1,4Oifunctionalised Compounds by C::C Cleavage

299

Two-Gro up Oisconnectio ns VI : 1,6-0ifunctionaliscd
Compounds

311

Chapter28

Gencr:ll Stnlcgy R: Str:ltegy of Carbonyt Oisconncctions

323

Chapler29

Stralegy XIII : Jntroduction lO Ring Synlhesis: Sal uraled
Heterocycles

335

Chapter 27

Chapter 30 Three-Membcred Rings

353

Chapler3 1 Stratcgy XIV : Rearrangemcnls in Synthesis

368

Chapter 32

Fo ur-Mcmbered Ring.'I: Pholochcmislry in Synlhesis

376

Chapter33

Slnltegy XV: Use of Ketenes in Synthesis

389

Chapter 34

Fivc- Menl bcrcd Ri ngs .

397

Chapter3S

Slralcgy XVI: Pericyclic Rearrangemenls
Special Methods for Five- Mcmbcred Rings

In

Synlhesis:
407

Chapter36

Six-Membcred Rings

.

417

Chapter 37

General Strategy C: Strategy of Ring Synthcsis

429

Chapter38 Slralegy XVII : Ste rcoscleclivity B _
Chapter 39

Aromat ic Heterocycles

440
452

Chapter40

General Slralegy O: Advanced Stralegy

470

Rcfcrcnces

49 1

Formula Jlldex

511

tlldex

527


CHAPTE R 1

The Disconnection Approach

( 1)

Two sy ntheses of keto ne ( 1 ) are described i n Chapter TI.
The starting materials for the two sy ntheses are
differe n t: ( 2), (3) , a n d (4) were

u s e~

for the

indust r ial s ynthesis , (5) and (6) f o r the laboratory
~y n thC3iQ.

Analy s is shOW$ that the

sa~e

bond (a) was

made i n bo th sy nth eses .
Ind us triaZ Synthesis

Laboratory Synthesis

I ~ a H
~
I ,
I
,
,,

(2 )

(3 )

,,
,,,
(4 )
(5 )

(6 )

If you can analyse published sy nth eses lik e this,
you will inc r e a se yo ur understanding o f good places to
make good disco nnections.

1

Pr oblem

Two syn th eses of mu l t is triati n f ollow. For th ese and
f or th e syn th es i s in th e main t e xt (p T 3)
draw
diagrams like th ose above t o show whi ch part s o f mu l ti s triati n carne fr om whi ch s tart ing materials in each
syn th esis . Do no t be t oo con cerned about the details of
each s t e p in th e syn thescs .
Syn t hesis 1 2

acctal
fo rmation

H~

"Mc- U

HO-J -e~p~O~X~i~d~a~t~i~o~n~)~

)

1 .TsCl,pyr

Hel

)

)

2.Na I

H
H

1

+

~

~

(7 )

SnC1 4

)

~
mul tistriatin

(8 )

~


SYrlthesis 2 3

1.CH 20,Me 2NH,HCl
~.

K CU
2 3

)

3. Me !
4 . KOH

(9)

(7 )

56%

Quinoline,AleOH

OH
(lO)

71 %

--»

Arl s wel"

In each case,

slrnpl ~'

(8)

draw th e st ructur e (8) and

t race wh ic h atoms carne from which original starting
rnaterials.

Sy n thesi s 1

,,

,

' C0 2 '
,

a

b

~Br
(7 )


Synth68is

8

a,

( 7)

e,

Iole l

~j

Bond (a) is mad e i n all thre c sy nthe ses and bond
( b ) in two of them. We shall see latcr tha t thc
syrnmetry of ke tone (7) is a r eason for (a) an d thc
bran chpoints in thc molcculc a rcason for (a) an d (b) .
Synth e sis J
I CH 0 I
2 ,
,

•

-:r
( 7)

a,

•

,b

~

I
111

~OH


CHAPTER 2

Basic PrincipIes: Synthesis of Aromatic
Compounds

Diseonnection and FG1
t:J:amp~ e

:

Steps i n the sy n thes is of mult ist r iati n give n

on pago T 3

correspo nd to dis co nn ections or FGls as

follows: -

This 18 a r ea rra ngeme n t a nd ls bes t describad as a o FG l
si nce no ncw e-e bonds a r e forma d a nd all ca rbon atoms
r etai n the s ame numbe r o f bonds to oxyge n atams.
Could be de sc riba d as

twa e-o di sco nn ect ions
or as FG l (olcfi n to
epoxlde by o xidatton ) .

Dc fi n it ely t he majar
di sconn cc tion - a new
e -e bo nd 15 f orme d .
5


Could be desc ribed as a
djsconnect .io n o r as
a n FGl-conv e r s i on of 0 11

HO

e-o

~)

Lu

OT~

uy

s u bs tjtu tio n.

FGl: C0 211 convertcd t o
CII 0H by reductio n

2
LiACII ,
4

IVj~h

I t may s urpr ise you t hat t here is not always a cut nnd - dr icd o.nswcr to \\' hothor oac h s top corrosponds to F Gl

or d isconnecti o n, but thi s i s so, particular]y when e -x

(X - 0 , N, S etc.) bond s are t o be f o rmed . Di scuss ing
the type o í logic involved in eac h stop helps ya u to
undcrstand the logic oí the synthesis : both aspccts
(FGl aud dlsr..:ullllcctlou)
see~s

a n~

hcJpful - choase whjchcvcr

the more helpful in the c ircumstanCeS.

Pr ob Ze m :
Repeat this exercise f o r sy nthesis 2 on pago W 2 ,

Gi ve

each FGl a full descript io n (ox i ctation etc.) and la be1
eac h di sconnection

e-o

e t c . acco rding to tha bo nd formad.

Anaw er
As bcforo - a r oa rranao-

n c nt bast d ascri bc d as
FGl.


=9

~

11

+

l~',\\ 11

y:

The majar e-e di s connection in the
sy nthesis.

11

IIO~'

"dI

==9

(via OT s)

lf

C-I d i s connection o,
lwo FGls (alcohol to

tos ylate to iodide by
sub s ti tutions).

x"--"t'
J OII

Rearrangement : helpfu l
to call this FGl.

Me Cu Li A
2

e-e

disconnection.

Two e - o disconnections
or FGI (ole!in to
epo xide by oxidation).

+

II0--n
IJ

Two

e-o

disconnections

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

descr iption.


Aromatic

E~ectrophilic

Substitution

Examples

DDT (1) is a very usefu l in sect icide but builds up in
the e nvironment with unacceptable effects on wild life .
A biodegradable ve r s ion of DOT suc h a s (2) might sol ve
these problems . 1

MeO

el

(2 )

(1)

DiSConnect ion of (2) at the bonds joining the
aromatic rings to the aliphatic part of the molecul e 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 alre ady have three halogen
a toms in (3) . Th e answe r is to use the alde hyde (4) chloral - in acid solution. On e addition gives th e
al cohol (5) whi ch dehydrat es an d r e a c ts a gain via a
carbonium i on. In practice ( 5 ) need not be isolat e d.
Synthe$i$ ~

M
eo,© __"_2_50_4_» Me0'r61
Cl C . CIIO

3

_ 11

)

~

(4 )

(5 )

M
eowO

011+

2

~

M
eo'©¡
O

----:;. TM ( 2 )

+

CC1"

"

AS mo re and more waste ~ ro du cts are re- cycled,
met hods oi e x tracti ng contaminants from t hem are needed .
neagent (6) i s used to re~o v e boron compounds from
alkaline b ri ne wastes. 5


AnaZyaia
0 11

011

OH

011

( 7)

(8)

el

(6)

Remov al of the one"': carbo n e lectrophiliC f o rmaldehyde (ef p T 10) l ea ves a c hl o r o ph e no l (7) made b y
direc t ehlorination of (8) . The long all y l c hain of (8)
cann ot be pu t in by Fri edel-Crafts alkylatton o r r earra/lg:~r!lt:" IL will VCL:ur (p T 9)
so acylation and

r ea uct i on are preferred .
Synthesis 5

OH

0 11

6
(8)

+

OC l

--»

(7 )

)

)

redu ce


P"!'ob~ems

:

1. H. C. Brown 6 used este r (9) to test a new r edu cing

ngcnt which did indced for~ alcohol (10).
How migh t he
have made the es ter (9)?

el

C02Me
--©r

-~
NaBH
4

)

Ale1 3
(lO) 8 4'%

(9)
A nswe r

Ester (9) can easily be made fro m acid (11).
cons ide r two approaches to this

You might

a one- carbon elec tro -

phile addition via chIoromethylation (Table T

2 . ~)

and

oxidatio n or FG1 (TabIe 2.3) back to E- ehlor otoluene

( 12).

The latter i s eas i er on a Iarge seaIe .

The E-

chlorotol u e n e (12) can be made either by direet
c hIorination of toluene or by the diazotisation route
(p T

12)

again from toluene.

Ana~ysis

d

FGl
o xidation

==;=:;:=;»
( a)

,02

(9)

reY

==}N
el

"2C1=:;> ~"

el

11

ehloro- el
melhy l alion

Fel

~Me

O

O:üdallOn
(11)

;.

(b)

Cl

dia~OtiSationll

(12)

.~

e-el

~

--©ri
O le

11

~

e-N

reduell~
-on
!

rt)f"e 'O!, O e

IIN~
2

0 2N


Chlorination wit h a Le wis aeid eatalyst ' at low
t empe rature avoids ehlorination in the me thyl g r oup bu t
the diazotis ation r out e,' though longer, i s perhaps
eas i er .•

cato

)~(e
el
s e para t e from
ortho compound

1,eoll ,lI'
U I( 9 )

separa t e from
ortho compound
Si l1lpZe Pr obZel1l8

Fo r practic e , e spe c i ally for be ginne rs. lIow would you
ma k€ T"'s (1::l ) _ ( 15 ) . ~ h i e h w~ r ~ needed for t he r e a s on s
g ive n on t he right?
geranium odour in

s oa p~

TM ( 13 )

TM ( 14)

s tudy of c ycli s ation
r e a c tions in ac id
so lu t i on lO

'" In fa c t, all these c ompounds , even l'M (9) , ar e
availabl e cornrnercially .


13

exploration of
ind ustri a l uses of Por l l

mle
TM ( 15 )

_':;l.u t i ona to Sim p le Pro b'LS1II G :
7~,1

(13)

:

This syrnmetrical

~lecule

cffers only o ne dis -

: a nnec tion (a, below) corres ponding to a Friede l-Craft s
:llkylation (p T

8 ) ã.

x

âf'â ~ âr ++'rQ) . ~
ll

(I3a)

AICl

3

---~) T"(13)

ni ( 14 ) : This time the usual di sconnec ti on corre s po nd s
tO a Fri ede l-Crafts acylation (p T 7 ) .

( 14a)


..,
Synthesis

Cl~

PhU +

T!.l (1 5)

II

AICl!1

---..,»

nl( 14 )

60t;

: Di oconnect t h e ni tro grQup and t h e alkyl ¡;roup

in either a rde r .
Ana Zysis

a

mle

C-N

>
nitratlan

p

OMO

b ~ F ri edel­
e-e
e ra fts

C~Cll!~;Ylat10n

alky la ti on

6fOM.

©rOMO

a

C-N

;.

nitrat i an

TM (15) h as been made by nitratian followed by Friedel-

Craf t s alkylation with UF as catalyst.

alternativ e route would be successful

No doubt the

too.

Synthesis

)--oH
-..:...,:=-~) Tll (15 )

IIF

separate from
para compound


CHAPTER 3

Strategy 1: The Order of Events

Ge neraZ Strategy ExampZe a (see table of guidelines)
i~ow

that you appreciate the reasan s why a particular

arder of e vents is followed, study the s ynth eses of
b e n zocaine (p T O)

and piperanal (p T 9) ,

The

benzocaine synthesis involves a gr e at deal of FG l : two
of the four steps are FGI s .

This i s because two FGs
r equi r ed fer tbe sy nthes i s (N0 2 and C02 H) a r e ~­

directin¡;:

~nri!'lO

(',annot be used to d irect subs tit ution

wh ere i t is needed (l?) .

(guideline 1 in Chapte r T 3) .

Nitro 15 the group to put i n last (guideline 2) and FG I
sa lves the orientation problem (guideline 3).
Th e piperonal s ynth es i s (p T 9)
where th e

tWQ

i s an e xamp l e

ortho oxyge n s ubs ti tuen t s would be very

difficult to set up. We therefore (guide lin e 1 ) start
with avail ab le catecho l (E- dihydroxYbenzene).

Table 3.1

Guid el ines [rom Chapt er T J
1.

Examine t he relationship betwee n the groups, l ooking
for groups which direct to the right position.

15


2.

If there is a c hoi ce, dis connect fil'ot (that ts add
last) the most electron-withdrawing substituent.

3.

If FGl is needed during the synt hesis , 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
s ubstitution on a diazonium salt, made from an amine .
AddinC- oth er 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 sol ve 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 r e quire d r elati onship, and
then r emoved by diazotisation and reducti on.

6.

Look for substituents whi c h 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
t he TM and in a r eadil y available starting material.

8.

Avoid sequences wh ic h may lead to unwanted reactions
at other sites in the molecule .

9.

I f Q,E-substitution is involved, one st r ategy may

avoid separ ation of isomer s in t hat t he ot her
position bccomcs blockcd.
Guidelines may well cont r adict one anot he r - use

your judgement!


Gene ra l Strategy ProbZema
1.

Analyse the syntheses of (a) AH'f (page Ta )

eb) phenOl (1) (p T 12 )

and

and see wh1ch gu1de11nes

they follow.
H

rAT°

Me~Br
An8w er

2.

(I:t)

7 I:tnd 9 in pl:trticular

(b)

3, 4, and 9 in particular.

(1 )

In the trifluralin synthe s1s (p T 13) ,

what 1s

wron & w1th this order events, suggested by guidelines 2 and 9?

e-N
nitra tíon

An8We l'

>

~ e tc

- nuc leophili c substitution n o l o ng e r possible

- CF 3

~-dire ct ing,

so díffi c ult t o ma k e (2)

(guideline 15
- nitration might ox idi se ami n e ( guíd el ine 8).

Furthe r WOl' ked Examp les
1.

In 1979, wo rkers inv e sti~ating!~ the di c no n c - ph c n ol
r earr angement treated ( 3) with a cet i c anhyd ride and
got a n unknown compound believed t o be ( 4).

Trea t -

ment w1th strong ac íd gave (5), t h ey supposed, 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 ignment.

This 1s a t r1 c ky prob1en


lB
as non e al the substituents can be easily disconnected.

OAe

OH

CF C0 H
3 2

Ac 0
2

(3)

O

)

)
Ph

OH
H2 QfH

Ph

Ph

(4)?

(5 )?

We r ea lly would prefer to keep the two OH groups
and start from c ate c hol( g u 1dp.line 7). This torces u s to

tor s ynthon
(6) and the obvioll$ c hoi ce 15 the diazonium salt (7).

dis co nnection (3a).

We require a

r ~ agent

AnaZysis

Th e OH graups must be p rot ected agaiost oxidat1on
during the nitration step and the methyl e ther (8) i s a
convení ent starting material. Treatment with HOr at the
e nd of t hp. synthesis, TeIDOves the rnethy l groups .


Synthesis 1 ~
OMe

OMe

rArOOlie ~> ~"e

~OMe

Q

OMe

y

(8)

N0

H2 , Pd, C

V

NH 2

2

OMe
OMe

l.HONO

2.PhH

>

HOr

---'»)

TM (5)

Th e pro duct of th i s syn t hes i s proved t o be
identi ca l wi th the unknown compo und from the dienonephenal seq ue nce and the structures ar e co nf i rme d.
SimpLe i'l'obLems
Suggest syntheses for TM s (9) a nd ( 10) needed as in termediates: TM (9) in the sy nthesis of bror.ü nat ed hydroxyben zoic ac id s 1S and r~ (10) i n the s yn t hes i s af mod el
compou nd s fo r s t udy i ng biologi

ca l mec hani sms of est er
,
hydrol ysis.

l'

rd(0H
~CHO
(9)

(10)

So luti ons to Simple Problems
TU

(9)

With two elect r o n-w i t hdrawi ng groups, FGl is


essential to get sorne control over orientation (guideline 3), The easiest is C02 H to CH 3 , Then disconnection of either Sr or N0 2 is possible,
AnaZysis
H
3

==F=G=I=~>02N~
arA/O
ar
b

oxidation

....

(11)

b~c-ar

©(H3
(12)

Sr

~CH3

°N
2

(13)

The n itration 01 (12) would probably glve (11), but
bromination at one of the two identical r eactive
positions of (13) is the logi cal route (guideline 9).
Nitric aeid oxidises the methyl group to C02 H.
Synthesis1 5 , 1 7

( 11)

70$

(13)
separate from
ortho isomer
HN0

3

(II) ----)~

TM(9)