Chapter 2 Heterocyclic ortho-quinodimethanes

25

Chapter 2

Heterocyclic

ortho.Quinodimethanes

Steven J. Collier and Richard C. Storr

Chemistry Department, The University of Livelpool, Livelpool L69 7ZD, U.K.

2.1

INTRODUCTION

o-Quinodimethane 1 and derivatives have been extensively studied over the last 30 years. They are reactive dienes which can be generated in situ by a number of routes; their inter- and intramolecular Diels-Alder reactions have been the basis of the synthesis of a wide range of target molecules including steroids, alkaloids and anthracyclines. In contrast, and in spite of their considerable potential in synthesis, heterocyclic analogues have received much less attention. However, in the last ten years the situation has changed considerably and the ground rules for producing and handling such species have become much clearer. Surprisingly, few tal:get oriented applications of heterocyclic o-quinodimethanes have so fro" appeared. Most of the useful applications have been in the indole series and have followed from the imaginative use by Bergman and colleagues <77TL4663, 78TL4055> and by Magnus and his co-workers <84ACR35, 89CRV1681> of indole-2,3-quinodimethanes as intelxnediates in the synthesis of indole alkaloids. Heterocyclic o-quinodimethanes were comprehensively reviewed by Chou in 1993 <93RHA65>. The present review is more selective; it provides a current overview of their chemistry and methods of generation and is intended to stimulate the use of these species in synthesis.

2.2

S T R U C T U R E AND R E A C T I V I T Y

o-Quinodimethane itself is best considered as a reactive diene 1 although some reactions have been explained in terms of the diradical structure la.

1

la

Heterocyclic ortho-Quinodimethanes

26

The situation with the heterocyclic analogues is similar. Most m'e best considered as reactive dienes although some reactions of certain o-quinodimethanes appeal" to be more consistent with radical character. For example, the thiophene analogue 2, when generated in solution in the presence of dienophiles, gives Diels-Alder adducts <87TL6085> whereas when generated by flash vacuum pyrolysis (see Section 2.4) and then co-condensed with thiophenol it gives the sulfides 3 and 4 <88TL117>. When generated alone in solution, o-quinodimethane dimerises and gives the [4 + 2] dimer 5 at low temperatures and the [4 + 4] dimer 6 at higher temperatures. Both dimers have been accounted for in terms of biradical intermediates but it is not clear whether the kinetic [4 + 2] dimer is formed by a conventional Diels-Alder reaction. More extensive studies with the furan based species 7, which gives a [4 + 4] dimer <86JA4138>, and with the thiophene derivative 2, which gives a [14 + 2] dimer <92MI1>, have concluded that biradical intermediates are involved and imply that the o-quinodimetl'mnes have bfl'adical character.

~

~SPh ~_SPh [ ~

2

3

4

~~~C] ~ 5

6

7

There is still little, if any, substantive data on the structure-reactivity profile of different heterocyclic o-quinodimethanes, but the expected trends are supported by experience. The stability of the o-quinodimethanes appears to be related to the loss of aromatic character; oquinodimethanes derived fi'om the more stable aromatic heterocycles are the most reactive. Thus, when generated by flash vacuum pyrolysis and condensed at low temperatures, some heterocyclic o-quinodimethanes can be isolated. It is clear that the furan derived species 7 is considerably rnore stable than the thiophene analogue 2. The species 7 is sufficiently stable for NMR spectra to be recorded a t - 6 0 ~ and Diels-Alder adducts can be obtained by adding dienes to the cold finger <81JA6691>. In contrast, the species 2 can be observed directly only in an argon rnanix <88CB791 > and it readily polymerises even in the presence of dienophiles. Sirnilar qualitative trends are observed with other heterocyclic o-quinodimethanes. "Bond fixation" can affect the ease of formation and the reactivity of heterocyclic oquinodimethanes. Thus, the 3,4-quinodirnethane 8 is found to dimerise 1013 times faster than its isomer 7 <88JA4050>. Interestingly, canonical forms for this 3,4-quinodimethane of the types 8a and 8b suggest potential reactivity at the 2- and 5-positions as well as at the exocyclic methylene groups. This is found to be the case; the cycloadducts 9 and 10 are both formed in its reaction with fumaronitrile, the bridged adduct 9 predominating <89JA3659>. On the other hand, the thiophene analogue of 8 gives adducts of type 10 exclusively.

CN O~. = = O~ = =+d/-~ ~ C N O~~~,,,c CN "

8

0

9

-

8a

8b

N

9

10

One of the best routes to o-quinodimethanes involves cycloreversion with elimination of a small, thermodynamically stable, molecule. The most irnportant example is the loss of sulfur dioxide in the widely used cheletropic extrusion from sulfolenes (Section 2.4). In this allowed [c2 + c2 + ~2] process the bond order of the "backbone" sulfolene double bond is ideally 2. If the bond order is lowered by bond fixation this renders the extrusion rnore difficult and the

Heterocyclic ortho-Quinodimethanes

27

sulfolene 11 fails to give the o-quinodimethalle 8 on heating. Indeed, when the sulfolene 11 is heated in the presence of a dienophile the first product is a Diels-Alder cycloadduct with the furan from which sulfur dioxide can then be extruded more easily (Scherne 1) <93JCS(P1)2263>. The effect of bond fixation is 'also apparent in the more difficult forrnation of 2,3-quinodimethanes in the naphthalene, quinoline and quinoxaline series compared with the 1,2-naphthalene and 3,4-quinoline derivatives <95TL5983, 94T10721 >.

80 ~

i o .O. C-

+

N

NC'r'

11

Scheme 1

2.3

R E A C T I O N TYPES: AN O V E R V I E W

The types of reaction that have been observed for heterocyclic o-quinodimethanes are outlined below. Some of these, such as dimelisation and electrocyclic ring closure, involve only the o-quinodimethanes whereas the majority involve the participation of another compound. The methods of generation of o-quinodimethanes are discussed in Section 2.4; however, it is our experience that one of the cornrnonly used methods, flash vacuum pyrolysis (FVP), tends to favour intramolecular reactions and dimerisation over reactions with other species. It is best to use one of the solution methods of generation when intermolecular reactions are required.

2 . 3 . 1 Diels-Aider

Reactions

Heterocyclic o-quinodimethanes are unstable and reactive dienes that must be generated in In solution and in the presence of a dienophile the o-quinodimethanes can be intercepted in a Diels-Alder reaction, often in high yield. Most of the dienophiles investigated so far have been electron deficient: N-phenylrnaleirnide, acrylonitrile, methyl vinyl ketone, acrylate, fumarate and acetylenedicarboxylic esters are typically used. However, since the objective of most of the work was simply to establish that the o-quinodimethane was being formed, the scope of the reaction has not been adequately explored. The pyridine derived oquinodimethane 12 has recently been shown to undergo cycloaddition to ethyl vinyl ether (Scheme 2) and to dihydrofuran <96T11889>, and it is thus cleaz that the scope of the DielsAlder reaction extends beyond electron deficient alkenes and alkynes. Heterodienophiles (azodicarbonyl compounds and nitrosobenzene) have been added to indole-2,3quinodimethanes <91T 1925> and this type of hetero Diels-Alder reaction is also potentially of wider application.

situ.

CI

CI

12 Scheme 2

Heterocyclic ortho-Quinodimethanes

28

One drawback of the methodology is that the cycloaddition of unsymmetrical dienophiles to heterocyclic o-quinodimethanes is rarely completely regioselective. Some attempts have been made to relate the preferred regioselectivity to the frontier orbital coefficients of the dienes <96T11889>. A number of intramolecular reactions have been reported and, as expected, these work well even when the dienophile component does not carry activating substituents. Starting with the pioneering work on this reaction by the Magnus group, the reaction has continued to prove useful in the indole series as a route to indole alkaloids <89CRV1681>. An illustration is the formation of the indole, 13, an intermediate for the synthesis of the alkaloid (-)-vindoline, by an intramolecular Diels-Alder reaction that is high yielding, stereospecific and enantiospecific (Scheme 3) <88JA2242>. Other intramolecular Diels-Alder reactions of o-quinodimethanes derived from pyridines <82JA7609>, pyrroles <92CC1401>, pyrazoles <93JOC493>, thiophenes <91CC1287> and thiazoles <92TL4201> have been reported. In common with other intramolecular Diels-Alder reactions, steric effects are important in determining the endo/exo selectivity of the cycloaddition <83JA4739>.

SPh

SPh PhMe,heat e O ~ ~ N ~------~

--N +

MeO

, CO2Me

O~Ci

MeO2C 70-75%

S

Ph~ MeO/~"~ /

14

Scheme 3

N }" CO2Me

-"N

13

The cycioaddition of heterocyclic o-quinodimethanes to buckminsterfullerene (C60) can be regarded as a special case of the Diels-Alder reaction; cycloadducts with the general structure 14 are obtained. This type of cycloaddition has been reported with a wide range of oquinodimethanes <96MI1, 96JCS(P1)1077, 97TL2557, 97T9075>.

2 . 3 . 2 Cheletropic Addition of Sulfur Dioxide A well known reaction of conjugated dienes that is mechanistically related to the Diels-Alder reaction is the cheletropic addition of sulfur dioxide <89TL7289, 90TL 1487, 90TL1491>. We have found that the reaction is particularly efficient with heterocyclic o-quinodimethanes (Scheme 4), and that sulfur dioxide is one of the best reagents for intercepting these species at low temperatures. The reaction is reversible at higher temperatures and can be used as a method of regenerating the o-quinodimethanes (see Scheme 1 and Section 2.4).

Heterocyclic ortho-Quinodimethanes +

SO2

29

~S02

Scheme 4 2 . 3 . 3 Other Cycioaddition Reactions Tile o-quinodimethanes 15 (X = O, NCOMe and NCOPh) can be intercepted by aryl nitrile oxides and act as the 2~-electron components in a double 1,3-dipolar cycloaddition reaction leading to the cycloadducts 16 and stereoisomers <92T6059>. o-Quinodimethanes also act as the formal 2re-electron cornponents in dimerisation reactions leading to spiro dimers such as cornpound 17 <86JOC4208, 88TLl17, 91T1925, 93JOC493, 94JOC2594>. The [4 + 4] dimers, exemplified by 18 <90TL1487>, can also be regarded as the products of cycloaddition reaction between two molecules, but since such a process is symmetry forbidden, a stepwise (radical) addition is more likely. We have recently observed that the o-quinodimethane 19 reacts with tetraphenylcyclopentadienone to give not only the expected Diels-Alder adducts but also a formal [4 + 4] adduct 20 <98MI1>. AF

16

15

17

0

18 0

Ph

19

20

2 . 3 . 4 Electrocyclic Reactions and Hydrogen Shifts The simplest type of electrocyclic reaction of o-quinodimethanes is ring closure to the corresponding cyclobutenes (Scheme 5). This reaction occurs with several o-quinodimethanes derived frorn six-mernbered heterocycles, including pyridines, pyrazines, and quinoxalines <86JCS(P1)1495, 97CC205>. The ring closure can be reversed by heating (Section 2.4). The cyclisation is not generally observed with five-membered heterocyclic o-quinodimethanes but with furo-2,3-quinodirnethane <87AG(E)471> and thieno-2,3-quinodimethane <88CB791> the ring closure can be achieved by irradiation in an argon matrix at 16K.

Scheme 5 A rnore common process its a 6~-electron electrocyclic ring closure in which two of the ~electrons are part of an aromatic ring. This type of ring closure requires high temperatures but it has nevertheless provided a useful method of synthesis of several fused ring systems. An

Heterocyclic ortho-Quinodimethanes

30

early exarnple is a synthesis of ellipticene which is illustrated in Scheme 6 <77TL4663; see also 81JOC2979, 82JOC3566>. + Bu

350 ~

~

H

,~

H

Scheme 6

Such electrocyclisations occur more cleanly under the unimolecular conditions of FVP. Examples include the formation of naphthothiophenes from a phenyl-substituted thiophene oquinodimethane (Scheme 7). At these high temperatures hydrogen shifts in the intermediate dihydroaromatic products can lead to skeletal rearrangements prior to dehydrogenation, as shown. The extent of the rearrangement increases with temperature so that the product distribution can be controlled to some extent <88TL117>. Analogous hydrogen shifts in the corresponding thiazole species lead to an unproductive fragmentation of the heterocyclic ring system (see Scheme 12) <94TL5293>.

H 11,5] H

H Scheme 7

[ 1,5] Hydrogen shifts can also interfere in other reactions when the o-quinodimethane is generated thermally. An example is shown in Scheme 8: here the o-quinodimethane is generated by elimination of sulfur dioxide fi'om a sulfolene, and a [1,5] hydrogen shift competes with the desired intramolecular Diels-Alder reaction <93JOC493>.

63%

24%

Scheme 8 2 . 3 . 5 Addition Reactions

The addition of thiols to o-quinodimethanes was illustrated earlier by the formation of the adducts 3 and 4 from the o-quinodimethane 2 and thiophenol. We have found that, although thiols react readily with several o-quinodimethanes, other simple nucleophiles such as alcohols and amines are ineffective. This may reflect the radical character of the reaction with thiols.

Heterocyclic ortho-Quinodimethanes

31

The reaction of o-quinodimethanes with other radical precursors and with elecuophiles remains largely unexplored.

2.4

METHODS

OF G E N E R A T I O N

2 . 4 . 1 Generation from Cyclobutaheterocycles Thennal ring opening of benzocyclobutenes has been widely used in the generation of oquinodimethanes. The temperature required for ring opening of the parent benzocyclobutene is c a . 200 ~ but tends to be lower when there are substituents in the four-membered ring. Exuapolation of this approach to five-membered heterocyclic analogues is not possible as the COlTesponding cyclobutaheterocycles are extremely unstable, being even less stable than their o-quinodimethane valence tautomers. Indeed, they have only been observed spectroscopically when isolated in an argon matrix at 16K <8TAG(E)471, 88CB791>. On the other hand, the six-membered heteroaryl fused cyclobutenes are comparable in stability to benzocyclobutene and indications are that, where available, they are excellent o-quinodimethane precursors (Table). Synthesis of the cyclobutenes is not always straightforward and each heterocyclic system has to be considered ill its own right. A recent example involving a pyrimidine oquinodimethane 21 is shown in Scheme 9 <97TL4873>.

O,~

,"h--n

R,.,~N +

2

RCN

-

N.

"

-y-

R = Me, Ph

R....I~N.~

180 ~

IJ__._]

R

Adductswith

N.\..,~,.

= c6oN-phenylmaleimide

T"

naphthoquinone

R

21

Scheme 9 As expected, the ease of ring opening is affected by "bond-fixation"; this is illustrated by the extreme conditions required for generation of quinoxaline o-quinodilnethane <94T10721>. In some cases, cyclobutaheterocycles result fi'om ring closure of o-quinodirnethanes produced by other routes, especially by flash pyrolysis or in solution in the absence of trapping agents. Regeneration of the o-quinodimethane under conditions more amenable for trapping can then offer advantages. An example from our own work involves the pyrimidine derivative 22 (Scheme 10) <95MI1>. O F vP

22

O

O

0

-196~

l

heat in solution

O Scheme 10

O

Heterocyclic ortho-Quinodimethanes

32 2.4.2

1,4-Eliminations

A large number of heterocyclic o-quinodimethanes have been produced by eliminations of the type shown in Scheme 11.

~

X= H,Y=

CI, OCOR

X

X = halogen, Y = halogen

Y

X = R3 N + , Y = s i M e 3 X = SnBu3, Y = OAc

Scheme 11

Pyrolytic Elimination:

The majority of purely thermal 1,4-eliminations of this type have involved FVP. This entails passage of the precursor through a hot tube (500-700 ~ at low pressure (10 -3 mmHg) and condensation of the pyrolysate at low temperature (-196 ~ or lower). Under these conditions, the o-quinodimethane can be detected or isolated on the cold surface but in the case of substituted o-quinodimethanes inu'amoleculm" reactions can occur in the hot zone prior to condensation. For example, electrocyclisation occurs with aryl and heteroaryl substituted derivatives and provides a route to fused heterocycles (Section 2.3.4) With the relatively very stable furan derivative 7, spectral data have been obtained and cycloadducts isolated by introduction of dienophiles on to the cold surface. Other more reactive o-quinodirnethanes tend to dirnerise or polymerise on warrning and since they are present in high local concentration these reactions preclude interception even when the species are co-condensed with reactive dienophiles. However, co-condensation of such oquinodimethanes with thiophenol leads to adducts and SO2 has also proved to be an efficient trap even with the most reactive o-quinodimethanes <88TL117, 90TL1487>. In'adiation, at low temperature, of furan and thiophene o-quinodirnethanes produced by FVP provides a route to the extremely unstable and otherwise inaccessible cyclobutene valence tautomers (Scheme 5, X = O, S) <8TAG(E)471, 88CB791>. During studies with the thiazole o-quinodirnethane 23 it was found that thermal elimination of acetic acid occurred in refluxing dichlorobenzene (180 ~ to give the o-quinodimethane which underwent head to head [4 + 4] dimerisation or gave Diels-Alder adducts with added dienophiles. Significantly, under these conditions no products derived from electrocyclisation involving the phenyl substituent were observed. This contrasts with the results of flash pyrolysis and highlights the difference between the two sets of conditions. In solution the prefected Z-o-quinodimethane is rapidly consumed by dimerisation or cycloaddition whereas in the higher energy, unimolecular conditions of the pyrolysis tube equilibration of the Z form with the rnore hindered E forrn occurs and so leads to electrocyclisation (Scheme 12) <94TL5293>.

33

Heterocyclic ortho-Quinodimethanes

m

23(E) m

/

23(Z)

solution ~

Diels-Alder adducts

ph.~N~ N~,--ph S~",,~J-" S Ph Ph S c h e m e 12

In summary, flash pyrolysis can be extremely valuable if the objective is to isolate and study the o-quinodimethanes at low temperature or if intramolecular cyclisations are required. For intermolecular reactions, methods producing the species in situ in solution at low standing concentration are much better. Also such methods do not suffer from the problerns of scale inherent with the flash pyrolysis technique where there is normally an upper limit of ca. 0.5 g.

R e d u c t i v e Dehalogenation: This was the first method used to produce an oquinodimethane and has been widely applied to the formation of both 5- and 6-membered heterocyclic analogues as can be seen from the Table and from the examples in Scheme 3. The normal procedure uses NaI in DMF at temperatures ranging fi'om ambient to 150 ~ Activated zinc has been used extensively for non-heterocyclic o-quinodimethanes but has found little application with heterocyclic systems <91SC1055>. Yields of Diels-Alder adducts from 5membered heterocyclic o-quinodimethanes generated by this method tend to be low to moderate and are accompanied by polymers. However, use of molecular sieves has been shown to give irnproved yields <92TL4499>. The elirnination is most commonly cazried out on the dibromo compounds but the dichloro compounds can also be used; both most likely proceed via the diiodo derivative. Fh Ph

N R

E

OH

Ph

R

Ph

/

Ph

~,,,,s

N

CO2Me

R

.N.~./B r

N

Ph

N

R N

-

"N ~,,,,~N.. E R S c h e m e 13

R R

O

<94H(37)967>

Heterocyclic ortho-Quinodimethanes

34

Reductive debromination of bis(dibromomethyl) compounds, for example 24, in the presence of dienophiles such as N-phenylmaleimide leads to loss of HBr and aromatisation of the adducts under the reaction conditions (Scheme 14) <86JCS(P1)1495>.

~

CHBr2,

~CHBr

CHBr2

Br O ~ } ~ N p h

O

. ~ N P h

"N" "CH Br

24

Br

O

O

Scheme 14 One of the main problems with this approach is synthesis of the starting bis(halomethyl) heterocycles. Two main routes have been used: free radical halogenation of the appropriate bis(methyl) compound (usually using N-bromosuccinimide) or transformation of the bis(hydroxymethyl) derivative which in turn can be obtained from the con'esponding diacid or diester as, for example, in Scheme 13. Lack of selectivity in the formation of the desired dihalo compound can be a problem in the former case. A different approach to bis(halomethyl)pyridines involves cycloaddition of chloroalkylacetylenes to oxazinones (Scheme 15) <96T11889>.

RlCH(OH)CN

+ COCI2

R_I O. O CI

N

CI

R1 O -O ClH2C

- 7CI. SN

R2

r.-Ct c~

CH2Cl R , 1 1 1 Cl

2

Scheme 15 Toxicity and lack of stability is also a problem in the use of bis(halomethyl) heterocycles as precursors to o-quinodimethanes. Another drawback is lack of flexibility in that the dihalides are not amenable to further modification to produce substituted o-quinodimethane derivatives. Nevertheless, in spite of these problems, its directness and simplicity have made this one of the most widely used approaches to o-quinodimethanes. It is also interesting to note that this method has led to the formation of Diels-Alder adducts in the difficult case of quinoxaline oquinodimethane where other routes have failed. However, the isolation of products incorporating both halogen and trap in the case of N-phenylmaleimide raises the question of whether "free" o-quinodimethane is involved (Scheme 16) <95TL6777>.

Other 1,4-Eliminations:

Fluoride ion induced desilylation is a very mild method that allows generation of heterocyclic o-quinodimethanes at ambient temperature and is suitable for inter- and intramolecular Diels-Alder adduct formation (Scheme 17). However, the presence of F - can be a problem, leading to epimerisation of optically active centres <85CJC3526>. Long routes required for the synthesis of the silylated precursors and purification problems detract somewhat from this otherwise excellent method.

Heterocyclic ortho-Quinodimethanes

N~ N

35

Br Br

Nal I DMF N

E

E ~

E L~/"-~ E-N=N-E v -N- -...~ / o~~_~ Ph o

E = CO2Me

N/-.x....../N..E E= CO2Et [~N.~

CHO O

~ NZ

- ~ O NPh +

~NZ

N.~.~oNPh

~ - ~ O NPh

Scheme 16

+ csF

k,~N~/SiMe 3

z

=

=

NMe3Br- CsF ~ SiMe3 ~

~.. F ~e~'-

["~ ]~ ~..../SiMe3 ~"~,./~"N R

Z <82JA7609>

~

TBAF

~ = <82TL2745> R

Scheme 17 A new type of elimination involving destannylation is shown in Scheme 18. So far it has been used for the furan o-quinodimethane but promises wider application <96CC2251>.

O2Me NBS,hv CCI4

OAc .CO2Me (ii)(i)IZn'BLu3SnCI "i ~A' ~ I BF3"Et2O H 4= I ~ Br

(iii) AcCI,Py

SnBu3

l

Scheme 18

Dieis-Alderadducts

There are surprisingly few simple base induced 1,4-eliminations leading to oquinodimethanes. The first reports of furan and thiophene o-quinodimethanes involved Hofmann elimination of quaternary amines 25 (X = O, S) <60JA1428> and treatment of the

Heterocyclic ortho-Quinodimethanes

36

pyrrole 25 (X = NH) with NaNH2 gave a [4 + 4] dimer of the o - q u i n o d i m e t h a n e <68BSF2134> but in no case was there any interception of the o-quinodimethane. One successful example is the formation of the indole o-quinodimethane 26 by elimination of 2,6dichlorobenzoic acid (Scheme 19) <87TL3423>. +

NMe3 I-

OCOAr

25

N R R = MeOC6H4SO2

PhCN 135~

N R 26 Scheme 19

Related Methods: Methods that ale closely related to these 1,4-elimination reactions involve the removal of a proton at one site of a molecule that bears a x-acceptor group at the other site of the potential o-quinodirnethane. The methodology is most clearly exemplified in the indole2,3-quinodimethane series, this being the strategy introduced by Magnus and his colleagues for the synthesis of indole alkaloids <84ACR35>. An imine function at C-3 is acylated and this prornotes the loss of a proton from a methyl substituent at C-2. The initial experiment of this type is illustrated in Scheme 20. The method has also been used by van Leusen and coworkers to generate pyn'ole-2,3-quinodimethanes <92CC1401 >.

Ac-N

I• Ac20, heat ,. SO2Ar

64% ___ SO2Ar

~

H

~

~! SO2Ar

Scheme 20 Some methods that are fonnally of a similar type include thermally induced isomefisations such as that used to generate ellipticene and analogues (Scheme 21) <78TLA055, 82JOC3566> and the desilylation of the thienyloxazolium salt 27, a procedure used by Chadwick and Plant to generate thiophene-2,3-quinodimethanes (Scheme 22) <87TL6085>.

.ea,

r

products H

N H Scheme 21

Heterocyclic ortho-Quinodimethanes

CsF

37

products

27

Scheme 22

2 . 4 . 3 E x t r u s i o n of Sulfur Dioxide from Heterocyclic Sulfones

S02

-"

The cheletropic extrusion of SO2 fi'om heterocyclic sulfones is now the most widely used and flexible route to the o-quinodimethanes. The sulfones m'e stable, easily handled and readily synthesised. The ease of this thermal elimination depends on the bond order of the sulfolene 3,4-bond. It is norrnally in the range 150-200 ~ for a typical aromatic heterocyclic fused system but can be much higher for 2,3-naphtho fused and other systems, e.g. 11, where this bond order is reduced by bond fixation. The extrusion temperature for the 2-substituted pyrazoles 29 is significantly higher than for the 1-substituted isomers 30 and, in contrast to the 1-isomers, the 2-phenyl and 2-tosyl pyrazole derivatives shown in Scheme 26 could not be induced to lose SO2. The pyrimidones 34 lose SO2 at 150 ~ compared with 200 ~ for the aromatic pyrimidines 35. An exceptionally facile extrusion takes place in the case of the oxazole fused sulfone shown in Scheme 28. This has been attributed to greater strain in the sulfone ring arising from fusion of the oxazole ring compared to other five-membered heterocycles and also to the low aromaticity of the oxazole ring <94JOC2241, 97JOC7882>. The extrusions can be carried out in refluxing 1,2-dichlorobenzene or 1,2,4-trichlorobenzene but, especially where volatile trapping agents are to be used, sealed tube reactions are preferable. Sulfolane is a convenient water miscible solvent. One of the great advantages of the use of heterocyclic sulfones as o-quinodimethane precursors is the acidity of the hydrogens adjacent to the sulfone group. This allows functionalisation and provides access to o-quinodimethanes bearing substituents on the exocyclic methylene groups. Thus introduction of alkenyl groups for intramolecular DielsAlder reactions has been widely accomplished; an example is given in Scheme 27. Stability of the sulfone ring also allows for derivatisation of the heterocyclic ring. For example, electrophilic substitutions have been accomplished on a thiophene fused sulfone <96T12459>. There are three main routes to heterocyclic fused sulfones: (i) Addition of SO2 to the o-quinodimethane (ii) Fon'nation fi'om bis(halomethyl) heterocycles (iii) Building the heterocyclic ring on to a dihydrothiophene. The first route is lmgely of acadernic interest and is likely to be of practical use only when the sulfones are inaccessible by other routes or when the o-quinodimethane can be produced readily by FVP but is too reactive for direct interception by co-condensation with dienophiles (Section 2.3.2) <89TL7289, 90TL1487, 90TL 1491>. Where the bis(halornethyl) heterocycles are available, reaction with freshly prepared sodium sulfide leads to the cyclic sulfide which can be readily oxidised to the sulfone with m-

Heterocyclic ortho-Quinodimethanes

38

chloroperbenzoic acid (Scheme 23) <90TL1491>. We have also prepared the pyridine fused sulfone by this route and produced and trapped the o-quinodimethane (Scheme 24) <95MI1>.

.••

(i) Na2S (ii) mCPBA

CI CI

MeO2C

.~jS

. ~

02

=

MeO2C

Diels= Alder adducts

MeO2C

Scheme 23

Ph

~'~CI

CI

(i) Na2S (ii) mCPBA ~ S

O ~ ~N"

O

02

=-

O

~~~NPh O

Scheme 24

The third route, involving annulation of a suitable dihydrothiophene, has received considerable attention over the last few years, most notably by Chou and his co-workers <93RHA65>. We first applied this approach with the sulfolene 28 (Scheme 25). Cycloaddition of diazomethane and elimination of sulfinic acid with KOH gave the pyrazole sulfone. Methylation or benzoylation led to the isomeric sulfones which on heating in trichlorobenzene gave the two pyrazole o-quinodimethanes <91TL7609, 92T8101>. Unfortunately this cycloaddition approach was not very general and other attempted dipolar additions and Diels-Alder reactions to 28 were disappointing. The situation was not improved by replacing the benzenesulfonyl group by other activating/leaving groups such as CN and NO2.

PhSO2 ~SO2

PhS02 " N~SO2

H

N'~~SO2 kN

28 R R~SO

o _o R

NPh ~

N'~,~~SO2 Nk

2

-

R

R

O~" N""~O

R

O

NPh

O

O Scheme 25

Chou used an alternative route to a number of pyrazole sulfones starting from the dihydrothiophene 31 (Scheme 26) <93JOC493; 93H(35)2839>. The same dihydrothiophene was also used as the starting point for isoxazole <92TL8121> and pyrrole <92CC549> fused sulfones as precursors for the respective o-quinodimethanes (Scheme 26).

Heterocyclic ortho-Quinodimethanes (i) RNHNH2

39

R

N.

N

R = H, Ph, Tosyl, PhNHCO

(ii) H +

(iii) mCPBA

NH2ON

O~

NOH

m,.

N§

H +

mCPBA

~Ph3P=CHOMe

31

~~,..~

OU

CHO

(i) PhSO2NH2

.so2P.

(ii) mCPBA S c h e m e 26

The dihydrothiophene dioxide 32 is a common precursor to thiophene <91CC1287> (Scheme 27), pyrrole <93MI1> and furan <92H(34)663> sulfones. Other simple dihydrothiophenes that have been converted to heterocyclic sulfones and hence to oquinodirnethanes are shown in Scheme 28.

Ci~Br

AC c A ~ . ~ OH AcS HO (i) KCN, NaHCO3 Zn (ii) MsCI,Et3N 02 ,

02

~..

32

200~

Scheme 27

02 I (i) BuLi, HMPA

40

Heterocyclic ortho-Quinodimethanes R

O

Br

NLS~ =

02 O

SPh ~ COR = TosN~,~ R = <96SC569> 02

<92TL4201>

02 R CI NHCOR NJ"O = <94JOC2241> Br

COR

S~t~R =

Br

<96TL4189>

Br

Br

=. O 2 S ~

<97TL5315>

Scheme 28 Reaction of the keto ester 33 with amidines followed by oxidation provides access to pyrimidone fused sulfones 34. Standard manipulation of the pyrimidone ring via the 4-chloro compound leads to pyrimidines 35 (X = H, OMe, NEt2, SPh, OTPP) (TPP = mesotetraphenylporphyrin). Both the pyrimidone and pyrimidine sulfones lead to oquinodimethanes which can be intercepted with dienophiles (Scheme 29) <96T1723, 96T1735, 97TL2753>. The initial 1:1 adducts with N-phenylmaleimide 36 give 2:1 adducts with an excess of dienophile and these adducts were assigned the novel 8-membered ring structures 37 <93TL6639>. Subsequent studies in our laboratories have shown that these 2:1 adducts actually have structures of the type 38 <98MI1>. In the light of this, the structures of analogous 8-membered 2:1 adducts reported from the quinoxaline o - q u i n o d i m e t h a n e <97CC205> and from the azaquinodimethane 39 <97TL4667> should be reconsidered.

e

O•CO2M 33

(i) N H

O Me R N_~SO2 34

(ii) mCPBA

O Mel ~-~SO2 K2CO3 RH~N

X

(i) POCI3 ,~~S (ii) XR

02 35

Heterocyclic ortho-Quinodimethanes

x

i

Ph

lo

ox

R

41

o

R

O

36 x

0

R

0

0 ~-N

37

0

0 ~

38

39

Scheme 29 Six-membered heterocyclic fused sulfones produced by annulation of dihydrothiophenes include the quinoxaline sulfone 40 derived from 3-bromo-4-oxotetrahydrothiophene dioxide and 1,2-diaminobenzene <94T10721>. The difficulty in extrusion of SO2 from this sulfone has already been discussed. We found similar problems in attempts to generate the quinoline 2,3-quinodimethanes 44 fiom sulfones 42 (X - CI, Me). The quinolone derivative 41 (R Me), however, underwent loss of SO2 in refluxing trichlorobenzene and the corresponding oquinodimethane 43 was trapped successfully (Scheme 30). The unsubstituted quinolone sulfone is more difficult to handle because of its insolubility but behaves similarly. This, therefore, constitutes a "masked" quinoline 2,3-quinodimethane precursor since, in principle, the adducts can be converted to the aromatic quinolines < 96T3117 >.

40 As expected, no problerns in extrusion of SO2 were encountered with the quinoline 3,4fused sulfone 45 obtained as shown in Scheme 31. The coumm'in o-quinodimethane was also generated from a sulfone 46 produced by annulation of a dihych'othiophene <96T3117>. Clearly a wide range of heterocyclic fused sulfones can be obtained by annulation of a limited number of readily available dihydrothiophenes, the scope only being limited by the imagination of the synthetic chemist.

Heterocyclic ortho-Quinodimethanes

42

O~02M e H

R X

O

SO2

R = H ~-h,.~'~~S O ~

R

2

42

41

1

O

r x

44

43 0

X

R Scheme 30

H

NHBoc

i~~O

~.~OMeso2

B(OH)2

Pd(0) j , . 1 TfO

Me

=

"" S

45

CO2Me

-.... B(OH)2 Pd(0)

~CO2Me 'kS""

~

o o

@o

2 46

Scheme 31

2 . 4 . 4 Other Cycloeliminations One of the few problems with the sulfone route to o-quinodimethanes is the relatively high temperature required for cheletropic extrusion of S02. Loss of S02 from the benzosultine 47

Heterocyclic ortho-Quinodimethanes

43

by a retro Diels-Alder reaction occurs more readily than from the isomeric sulfone. The benzosultine is readily produced by the reaction of bis(bromomethyl)benzene or bis(iodomethyl)benzene with Rongolite (HOCH2SO2Na.2H20). There are a few examples where heterocyclic sultines have been prepared similarly and used successfully as oquinodimethane precursors. Significantly, these have so far all involved sultines with a low 4,5-bond order, for example 48 <97CC205> and 49 <95CC2537>, and it would appear that other heterocyclic sultines may be too unstable.

~

47

48

49 X= O, S, NTos

There are few other retro Diels-Alder reactions that have been used for the generation of oquinodimethanes. Examples are shown in Scheme 32. The azo compounds used in the formation of the furan and thiophene 3,4-quinodimethanes lose nitrogen thermally below 0 ~ or photochemically at low temperature <89JA3659>.

O

O

R'

R'

R

-002

R

R' R

<89TL7289> ~,,..

X ~

z

NCO2Me NCO2Me

=X ~

NH NH <89JA3659>

X = O, S; Z = CI, Br Scheme 32

2.5

C O N C L U S I O N AND F U T U R E D E V E L O P M E N T S

It is clear from the foregoing discussion that heterocyclic o-quinodimethanes can now take their place in the standard armoury of the synthetic chemist. The flexibility available for the generation of such species should allow them to fonn the basis of routes to a wide variety of fused heterocycles. There is, however, still scope for improvements such as even milder, general approaches towards their generation and there are notable gaps in the list of analogues which have so far been produced. For example, there is as yet no convenient route to the potentially very useful imidazole derivatives. Space has limited our ability to give comprehensive coverage to this rapidly expanding field and we apologise for omissions. Nevertheless we hope that this review will stimulate further developments and the routine use of such species.

44

2 9 "I

"N

L

i

=

2

~ "~ .-;

~i~

"-

.~-

"i

~

"-

:

~

,-.~ "~1"

- ~

,.-1

~1

~

'-q

I=I

ej ~(".l

:

:

'

t~

o

,j E-, "~

0

:t'~ er

INN

".

-.

'

t~

i

i

,

".

.

1

im

I

l

N I

".

:

'

"-'

".

'

r-

9

_~

~_

i=

0

o t"l

,-.,

t"l'

Heterocyclic ortho-Quinodimethanes

r~

I"6I:I:1

~

o~

i=.,

~

.=

oo

!E--~

i("l

t",?'l <~

f---,

o i,-,i

~<

E-,

("l

.,-~ ,'-~

" -~ ~ ~

e,I

r~

<

L

9- - -

<~

).

0

~

c~

c~.u

"

~

~,

9

r'l

tr

{",I

~,q

~ 0

~u

.;-

~

t~

t.) r,.)

r.g3

('-I

,-.l

<~ ~

0

0

|

,

,...,

,...,

o

.,..,

.,..,

_=

,...,

==

o

2~ =_

o

o

-6

r.~

,...,

,!

N

2:

.,-,

0

'-7

o

,

m

---_

|

|

~:

~ ,-

m

._q

,--.

m

~

N_N_ .-.l

,-I ~ ,

[---.

Heterocyclic ortho-Quinodimethanes

("I~

!~ ...-.,

3::

"~

45

46 60JA 1428 67CC296 68BSF2134 74H(11)171 77TL4663 78JOC4882 78TL4055 79AG(E)411 80TL1645 81JA6691 81JOC2979 81T3889 82CC613 82H(19)1033 82H(19)1673 82JA7609 82JOC3566 82TL2745 83JA4739 84ACR35 84TL5429 85CJC3526 86CC1756 86JA4138 86JCS(PI)I495 86JOC4208 87 AG(E)471 87TL3423 87TL6085 88CB791 88CB 1203 88JA2242 88JA4050 88JHC205 88TL 117 88TL2689

Heterocyclic ortho-Quinodimethanes H.E. Winberg, F.S. Fawcett, W.E. Mochel and C.W. Theobald, J. Am. Chem. Sot'., 1960, 82, 1428. J.H. Markgraf and W.L. Scoll, J. Chem. Sot:., Chem. Commun., 1967, 296. R. Paul and S. Tchelitcheff, Bull. Soc. Chins. Fr., 1968, 2134. T. Kamelani, Y. Ichikawa, T, Suzuki and K. Fukumoto, Heterocycles, 1974, 11, 171. J. Bergman and R. Carlsson, Tetrahedron Lett., 1977, 4663. R. P. Thummel and D.K. Kohli, ,I. Org. Chem., 1978, 43, 4882. J. Bergman and R. Carlsson, Tetrahedron Lett., 1978, 4055. A. Naiman and K.P.C. Vollhardl, Angew. Chem., Int. Ed. Engl., 1979, 18, 411. C, Kaneko, T. Naito and M. Ito, Tetrahedron Lett., 1980, 21, 1645. W.S. Trahanovsky, T.J. Cassady and T.L. Woods, J. Ant. Chem. Sot., 1981, 103,6691. S. Kano, E. Sugino, S. Shibuya and S. Hibino, J. Org. Chem., 1981, 46, 2979. T.Gallagher and P. Magnus, Tetrahedron, 1981, 37, 3889. C. Exon, T. Gallagher and P. Magnus, J. Chem. Soc., Chem. Commun., 1982, 613. S. Kano, N. Mochizuki, Y. Yuasa, S. Hibino and S. Shibuya, Heterocycles, 1982, 19, 1033. S. Kano, E. Sugino and S. Hibino, Heterocycles, 1982, 19, 1673. Y. Ito, M. Nakatsuka and T. Saegusa, J. Ant. Chem. Sot., 1982, 104, 7609. S. Kano, N. Mochizuki, S. Hibino and S. Shibuya, J. Org. Chem., 1982, 47, 3566. E.R. Marinelli, Tetrahedron Lett., 1982, 23, 2745. C. Exon, T. Gallagher and P. Magnus, J. Am. Chem. Soc., 1983, 105, 4739. P. Magnus, T. Gallagher, P. Brown and P. Pappalardo, Acc. Chem. Res., 1984, 17, 35. B. Saroja and P.C. Srinivasan, Tetrahedron Lett., 1984, 25, 5429. S. Askari, S. Lee, R.R. Perkins and J.R. Scheffer, Can. J. Chem., 1985, 63, 3526. M. Ladlow, P.M. Cahns and P. Magnus, J. Chem. Soc., Chem. Commun., 1986, 1756. C.--H. Chou and W.S. Trahanovsky, J. Ant. Chem. Soc., 1986, 108, 4138. M.K. Shepherd, ,I. Chem. Sot., Perkin 7)'ans 1, 1986, 1495. C.-H. Chou and W.S. Trahanovsky, J. Org. Chem., 1986, 51, 4208. N. Munzel and A. Schweig, Angew. Chem., Int. Ed. Engl., 1987, 26, 471. M. Herslof and A.R. Martin, Tetrahedron Lett., 1987, 28, 3423. D.J. Chadwick and A. Plant, Tetrahedron Lett., 1987, 28, 6085. N. Munzel and A. Schweig, Chem. Bet'., 1988, 121,791. G. Dyker and R.P. Kreher, Chem. Bet., 1988,121, 1203. K. Cardwell, B. Hewitt, M. Ladlow and P. Magnus, J. Am. Chem. Soc., 1988, 110, 2242. J.C. Scaiano, V. Winlgens, A. Bedell and J.A. Berson, ,I. Ariz. Chem. Soc., 1988, 110, 4050. M. Noguchi, K. Sakamolo, S. Nagata and S. Kajigaeshi, J. Heterocycl. Chem., 1988, 25, 205. P.M.S. Chauhan, G. Jenkins, S.M. Walker and R.C. Storr, Tetrahedron Lett., 1 9 8 8 . 2 9 , 117. A.M. van Leusen and K.J. van den Berg, Tetrahedron Lett., 1988, 29, 2689.

Heterocyclic ortho-Quinodimethanes 89CRV1681 89JA3659

U. Pindur and H. Erfanian-Abdous! Chem. Rev., 1989, 89, 1681. K.J. Stone, M.M. Greenberg, S.C. Blackslock and J.A. Berson, J. Am. Chem.

89TL7289

Sot., 1989, 11 I, 3659. S.F. Vice, H. N. de Carvalho, N.G. Taylor and G.I. Dmitrienko, Tetrahedron Lett.,

90BCJ2938 90JHC 1751 90TL 1487 90TL 1491 90TL5197 91CC 1287 91SC1055 91 SL627 91T1925 91TL4603 91TL7(~9 92CC549 92CC1401

1989, 30, 7289. M. Noguchi, Y. Kiriki, T. Ushijima and S. Kajigaeshi, Bull. Chem. Soc. Jim., 1990, 63, 2938. S. Hibino and E. Sugino, J. lteterocycl. Chem., 1990, 27, 1751. P.M.S. Chauhan, A.P.A. Crew, G. Jenkins, R.C. Storr, S.M. Walker and M. Yelland, Tetrahedron Left., 1990, 31, 1487. A.P.A. Crew, G. Jenkins, R.C. Storr and M. Yelland, Tetrahedron Lett., 1990,

31, 1491. S. Mitkidou and J. Stephanidou-Slephanatou, Tetrahedron Lett., 1990, 31, 5197. T.-s. Chou and C.-Y. Tsai, J. Chem. Sot., Chem. Commun., 1991, 1287. R.J. Heffner and M. Joullid, Svnth. Commtm., 1991, 21, 1055. S.B. Bedford, M.J. Begley, P. Cornwall and D.W. Knight, Synlett, 1991, 627. M. Haber and U. Pindur, Tetrahedron, 1991, 47, 1925. S. Mitkidou and J. Slephanidou-Slephanalou, Tetrahedron Lett., 1991, 32, 4603. L.M. Chaloner, A.P.A. Crew, R.C. Slorr and M. Yelland, Tetrahedron Lett., 1991,32, 7609. T.-s. Chou and R.C. Chang, J. Chem. Soc., Chem. Commun., 1992, 549. F. R. Leusink, R. ten Have, K.J. van den Berg and A.M. van Leusen, ,l. Chem. Sot.. Chem. Commu;1., 1992, 1401.

92TL812 l

T.-s. Chou and C. Y. Tsai, Heterocycles, 1992, 34,663. C.-.C. Peng, Y.-C. Lin and C.-H. Chou, J. Chin. Chem. Soc., 1992, 39, 319. S. Mitkidou and J. Slephanidou-Stephanatou, Tetrahedron, 1992, 48, 6059. L.M. Chaloner, A.P.A. Crew, P.M. O'Neill, R.C. Slorr and M. Yelland, Tetrahedron, 1992, 48, 8101. T.-s. Chou and C.Y. Tsai, Tetrahedron Lett., 1992, 33,4201. G.E. Mertzanos, J. Stephanidou-Stephanatou, C.A. Tsoleris trod N.E. Alexandrou, Tetrahedron Lett., 1992, 33, 4499. T.-s. Chou and R.C. Chang, Tetrahedron Lett., 1992, 33, 8121.

93H(35)2839

T.-s. Chou and R.C. Chang, lteterocycles, 1993, 35, 2839.

93JCS(PI)2263

K. Ando, N. Akadegawa and H. Takayama, J. Chem. Soc., Perkin Trans 1, 1993, 2263. T.-s. Chou and R.-C. Chang, ,l. Org. Chem., 1993, 58, 493. U. Pindur and M. Haber, J. Prakt. Chem., 1993, 335, 12. M. Drager, M. Haber, H. Erfanianalxloust, U. Pindur and K. Sattler, Monatsh. Chem., 1993, 124, 559.

92H(34)663 92MI1 92T6059 92T8101 92TL4201 92TL4499

93JOC493 93JPR 12 93M559 93MI1

T.-:,;. Chou and C.-Y. Tsai, ,I. Chin. Chenl. Sot., 1993, 40, 581.

93RHA65

T.-s. Chou, Re~'. lleteroatom. Chenl., 1993, 8, 65.

93SL347

A.C. Tom6, P.M. O'Neill, R.C. Slorr and J.A.S. Cavaleiro, Synlett, 1993, 347.

93TL6639

A.C. Tomd, J.A.S. Cavaleiro and R.C. Storr, 7"etrahedron Lett., 1993, 34, 6639.

94H(37)967

G. E. Merlzanos, N. E. Alexandrou, C. A. Tsoleridis, S. Milkidou and J.

94JOC2241 94JOC2594

T.-s. Chou, H.-C. Chen and C.-Y. Tsai, J. Org. Chem., 1994, 59, 2241. W. S. Trahanovsky, Y.C.J. Huang and M.K. Leung, J. Org. Chem., 1994, 59, 2594. M. AI Hariri, F. Paulet and H. Fillion, Synlett, 1994, 459.

Stephanidou-Slephanalou, Heterocycles, 1994, 37, 967.

94SL459

47

48

Heterocyclic ortho-Quinodimethanes

94T1072 l 94TL5293

T.-s. Chou and C.-W. Ko, Tetrahedron, 1994, 36, 10721. A. J. Poller and R.C. Storr, 7"etrahedron Lett., 1994, 35, 5293.

95CC2537

W.-S. Chung, W.-J. Lin, W.-D. Liu and L.-G. Chen, J. Chem. Sot., Chem. Commun., 1995, 2537. L.A. White, PhD Thesis, University of Liverpool, 1995.

95MI1 95TL2113 95TL3385 95TL5983 95TL6777 96CC2251 96JCS(Pl)1077 96JCS (P 1)2827 96MI 1 96SC569 96SL531 96T1723 96T1735 96T3117 96T 11889 96T 12459 96TL4189 97CC205 97JOC405 97JOC7882 97T9075 97TL2557

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97TL2753 97TL4(-~i7 97TL4873 97TL5315 98MI 1

J.P.C.Tom6, A.C. Tom6, M.G.P.M.S. Neves and J.A.S. Cavaleiro, Tetrahedron Lett., 1997, 38, 2753. K. Wojciechowski and S. Kosinski, Tetrahedron Lett., 1997, 38, 4667. A. Herrera, R. Mart/nez, B. Gonz;ilez, B. Illescas, N. Martfn and C. Seoane, "l'etrahedron Lett., 1997, 38, 4873. C.-W. Ko and T.-s. Chou, Tetrahedron Lett., 1997, 38, 5315. S.J. Collier and R.C. Storr, unpublished observations.