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From the Principle of Areno-Analogy to Heterocyclopolyaromatic Compounds.

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Volume 18
a
Number 1
January 1979
Pages 1 - 9 0
International Edition in English
From the Principle of Areno-Analogy to Heterocyclopolyaromatic
Compounds[**]
By Thomas Kauffmann[*]
Dediuited to Georg Wittig
Organometallic linkage of heteroaromatic compounds provided a means of synthesizing
complicated combinations of heteroaromatic compounds; not only nucleophilic aromatic substitution, but also “Ar-Cu/Ar-Hal
linkage”, “organometallic oxidative linkage”, and “metal
amide linkage” have been employed. The heterocyclopolyaromatic compounds are made of
one, two, or three kinds of heteroaromatic species as ring members. These syntheses illustrate
the construction of heterocycles from large, preformed structural units. Competition experiments
showed that the reactivity typical of the individual species is enhanced in open-chain combinations
(ArNJn and (Ar& (ATNu,ATE: nucleo- and electrophilic heteroaromatic systems, respectively);
the opposite situation is mostly encountered in the case of ArN,-AE combinations.-Cycloocta[ I .2-h :4.3-h’: 5,6-b”: 8,7-h’”]tetrathiophene, the only heterocyclopolyaromatic system yet
to have been studied in detail, proved surprisingly inclined to undergo monosubstitution
reactions.
1. Motivating Influence of the Principle of ArenoAnalogy
The existence of nucleophilic and electrophilic functional
groups permits highly selective reactions to be performed
in organic chemistry and biochemistry. Carbon chains
furnished with groups of one kind or the other can be linked
together without interference by formation of side products
( e .g. ester formation from carboxylic acids and alcohols).
A second set of nucleophiles and electrophiles is available
in the nucleophilic and electrophilic heteroaromatic compounds (rc-electron-excess and rc-electron-deficient heteroaromatic compounds“]). With regard to their reactions and the
effect on their substituents, they show a clear resemblance
to nucleophilic and electrophilic functional groups (see below)
and thus call for analogous applications in organic synthesis
(principle of areno-analogy”. 31).
The underlying reason for the relationship between heteroaromatic compounds and functional groups-the analogy
between pyridine and the carbonyl group had already been
pointed out prior to the formulation of the principle of areno-
.
[*I
P r d Dr. Th Kauflmann
Orpnisch-Chemisches Institut der Unlversitit
Orleans-Ring 23, 0-4400 Munster (Germany)
[**I l~etrrocyclopolyaromaticCompounds. Part 8.-Part
-OH
7 : ref. [40a].
Scheme 1. Functional group5 and their areno-analogs
1
analogy[41-can be consideredr3] to lie in the possibility of
formally deriving the simple heteroaromatic systems from
the functional groups by incorporation of a C4 unit possessing
471 electrons (Scheme 1). Although this leads to a drastic
modification of the properties of the system, its nucleophilic
or electrophilic activity and other essential featuresf2. are
retained.
As may be seen in Scheme 2, areno-analogy corresponds
rather to hetero-analogy than to vinylogy. We therefore prefer
the term "areno-analogy" over the originally chosen term
"arenology"l's 3 1 . Scheme 2 also underlines the difference
between areno-analogy and phenylogy, thienylogy. etc. (see
Section 2.2).
P heny logy
Vinylogy
\ 1, /
Thienylogy
F u 1-ylogy
Pyrrolylogy
N
0
II
/
Helero-analogy
K-x
\
2.1.1. Linkage of Heteroaromatic Units by Nucleophilic Substitution
*
Areno-analogy
Scheme 7 . Heuristicall) valuable analogies a s illustrated for the C" double
bond.
Use of the principle of areno-analogy often involves several
conceptual steps; the pairs of reactions shown in Scheme
3 serve as examples. If classical heteroaromatic compounds
=
Unlike functional groups, nucleophilic and electrophilic
heteroaromatic compounds do not react together without
prior activation. However, the activity of the nucleophilic
heteroaromatic systems can readily be enhanced by introduction of a metal atom; such an example is seen in the reaction
of thiophene with n-BuLi to give 2-lithiothiophene or with
n-BuLi + CuCI to form 2-cuprothiophene. This enhancement
of nucleophilicity is straightforward because nucleophilic
heteroaromatic compounds exhibit a relatively high C H
acidity and-in contrast to electrophilic heteroaromatic compounds-show no tendency to add the metalation reagent
or the product of metalation.
Addition of one of the more strongly electrophilic heteroaromatic systems to a lithiated nucleophilic heteroaromatic unit
generally leads to fast specific linkage.
At the outset of our studies seven years ago, little was
known about the combinations of nucleophilic and electrophilic heteroaromatic compounds. The simplest uncharged representative, riz. 2-(2-furyl)pyridine was unknown and ( I ), the
corresponding thiophene derivative. was accessible in only
about 1 ?< yield (Scheme 4)"'. Replacement of the magnesium
iodide group by lithiuml"'] or copper[l01, as well as an H
atom of the electrophilic component by halogen significantly
raised the yield of ( I ) (Scheme 4).
805
Scheme 3. Normal and areiio-analogous benzoin and Claisen condensatlons
[ 5 . 31
2
2. Heteropolyaromatic Compounds
2.1. Syntheses
II
-c -x
are viewed as higher homologs of functional groups, a number
of interesting questions arise: Is the reactivity of the individual
systems altered on linking heteroaromatic compounds to give
open-chain or macrocyclic compounds in the same way as
in the case of functional groups (see Section 2.2)? Are there
hetero-aromatic counterparts of important specific reactions
of organic molecules containing functional groups (see Scheme
3 ) ? What heteroaromatic groups are particularly well suited
for the linkage of hydrocarbon chains to give compounds
such as Alk-ArN,-ArE-Alk
(see Section 2. I .4)? Can the
bond between a nucleophilic and an electrophilic heteroaromatic unit be broken specifically (see Section 3.3.3)?
Questions of this kind and the favorable synthetic scope
to be expected from the very existence of nucleophilic and
electrophilic heteroaromatic compounds instigated the studies
surveyed in the present article"!
Scheme 4. Synthesis of 2-(?-thienyl)pyridine ( I
Angew. Chrrii.
)
Iiit.
Ed. Eiigi. IX. I - 1 9 ( I 979 i
While the reaction of anionic nucleophiles such as 2-lithiothiophene with halogenuteil electrophilic heteroaromatic compounds like 2-fluoropyridine is known to proceed in full analogy to nucleophilic substitution with addition-elimination
mechanism of acyl halides, the reaction of non-halogenated
electrophilic heteroaromatic substances corresponds to the
nucleophilic substitution ofaldehydes which is much less familiar t o the organic chemist (Scheme 5 ) : in each case a stable
adduct is formed which must be oxidized to regenerate the
6rc- and 2rc-electron system. Regeneration of the 671 system
is usually easier (oxidation with nitrobenzene or with K M n 0 4
in acetone) and sometimes even occurs of its own accord.
Substitution with aldehyde-analogous electrophilic heteroaromatic compounds is of great importance in heteropolyaromatic
chemistry; pyrimidine, quinoxaline, and quinoline are particularly well suited for this purpose.
of linkage products are mostly lower than from corresponding
substitutions with lithiated ntccleophilic, heteroaromatic compounds.
The syntheses of (Za)["I and ( Z ~ I ) [ ' ~ ] are examples of
substitutions with electrophilic heteroaromatic compounds
after umpolung.
2.1.2. Other Methods of Linking Heteroaromatic Units
the mechanism of which has
Ar-Cu/Ar-Hal
still not been elucidated[' 'I, has been used primarily by Nilsson
er d.['
6l to join nucleophilic aromatic compounds (benzene
and its derivatives, nucleophilic heteroaromatic compounds)
symmetrically and unsymmetrically. We found the method
to be suitable for the synthesis of ArNu-ArE combinations
(an example is shown in Scheme 4), and to permit
a convenient ring-linking synthesis of ull-a-terthiophene
(3 ) [ l o . '*I (Scheme 6): pathway A proves much more favorable
than B for reasons that are still not fully understood.
H
Scheme 5 Nucleophilic substitution
aromatic compounds.
non-halogenated electrophilic hetero-
in
Scheme 6. Ring-linking synthesis of terthiophene
As may be seen in Table 1 (second line), electrophilic heteroaromatic compounds can be linked analogously if one of
the two components-preferably
that of lower electrophilicity-is first subjected to "umpolung". In contrast to the
carbonyl compounds[' 'I, direct umpolung generally proceeds
without difficulty at low temperatures. However, the yields
Organometallic oxidatice linkage is employed for symmetrically uniting nucleophilic heteroaromatic compounds. The
reaction is normally accomplished smoothly by reaction of
the lithium or magnesium compounds with CuCI,, CuC1/02,
NiCI2, or FeC1, (for a survey, see ref. ["I). Ring-linking synthesis of 2,2'-bifuran ( 4 ) (yield 85 % ) [ I 9 ] , the best synthesis
presently available for this sensitive compound[*"], is particularly instructive: the reaction temperature should be about
- 10°C; n-BuLi may only be used in the given molar ratio
in order to ensure its complete consumption and to preclude
its participation in the linkage process. Moreover, the bifurancopper complex formed must be decomposed under mild conditions (addition of glycine). Analogous linkages led to the
formerly unknown all-a-quaterfuran (53 %)['"I, but for poorly
understood reasons not to a//-a-octifuran'2'1(for further applications, see Sections 2.1.4, 3.2, and 3.4).
Table I . Proven methods or linking heteroaromatic unitb.
K i n d 01 lmkagc
Keactanlc
Nucleophilic
aromatic
substitution
ArN,,-Li
ArE-Li
Ar-Cu:Ar-Hal
Iinkagc
ArN,,-Cu
ArN,-Cu
Organoinetnllic
oxldallve
lin kagc
ArN,,-M + transition metal halide
( M = Li. MgX)
Ark- M + transition metal halide
Metal amide
linkapc
Ar,
Areno-analogous
benzoin
condenhation
(scc Schcme 3)
Ark + K C N
~~
~
l'roduct
+ ArE (or H a l F A r , )
+ ATE. ( o r Hal - ~ A r , , )
+ Hal-Art
+ Hal
~~
( H a l = Br. I )
ATNu.(Hal = Br, I )
+ LiN(iPrIl
A r l geu. Clierii l i l t .
Ed. Eiigl. 18. 1-19 (1974)
Ari\,,-ArE
Ar,,,-Ary,
Ar,"-ArNU
Arb --Arb
A r , -Arb
ArE-ArE
.
~~~~
Ar,,-ArE
A rr- A rr
u
(4), 8 5 "
After umpolung, elertropfiilic iieteroaromuric compounds can
be linked analogously["1 (a recent example is the synthesis
of 5,5'-bipyrimidine, see Section 3.4).
Metulamide linkage permits linkage of electrophilic heteroaromatic compounds (pyridine, quinoline. isoquinoline) by reaction with LiN(iPr)2 in tetrahydrofuran (THF)/hexamethylphosphoric triamide (HMPA) according to Clarke, McNamaru, and M e t h - C o / ~ r i [ 'Analogous
~~.
linkages of quinoxahe
(NaNH, in dimethylaniline['31) and 3-fluoropyridine (NaNHZ
in liquid NH3IZ41)have been described on previous occasions.
The formation of a carbanion assumed to occur in the initial
reaction step (e.y. formation of 2-lithiopyridine) should then
3
initiate a nucleophilic addition or substitution[22.3(11. However,
trapping experiments failed to reveal carbanionic intermediates1221.
We have applied the linkage reaction with LiN(iPr),
to 3-bromopyridine, quinoline (see Section 3.2), 5,S-bipyrimidine, 3,3’-bi- and 4,4’-bipyridine, and to the tri- and tetraaro) Section 3.4). In some
matic compounds ( 5 2 ) and ( 4 9 ~ (see
case a dihydro-product, requiring oxidation to the aromatic
system, was formed, while in other cases the desired aromatic
system is obtained directly. In spite of modest yields, these
linkages are of preparative value because they provide ready
access to suitable starting materials for heterocyclo-polyaromatic compounds and to such compounds themselves.
and benzo[h]thiophene-quinoxaline combinations ( 7 h ) . n=
2 4 (yields 24. 1 1.4 ”{,)[”. 2 7 1 (Schemes 7 and 8).
Attempts to link four, five. or even six different aromatic
species. undertaken with the aim of developing the synthetic
approach. gave the desired products[’ 2.
(Scheme 9). The
resulting compounds. which contain a benzene ring (hatching
in the formulae emphasizes the alternance between ArNuand
ATF) show the term “heteropolyaromatic” to be a more fitting
general designation than “polyheteroaromatic”.
2.1.3. Linkage of Several Nuclei
It is relatively easy, by means of the methods described
in Section 2.1.2, to prepare heteropolyaromatic compounds.
Apart from compounds having ntrcleophilic rzuclei of’ the ~ u i i i e
kind, which are conveniently preparable by organometallic oxidative linkage (see Sections 2.1.2 and 2.1.4), combinations of
heteroaromatic systems having an ulternunt arrangement of
nucleophilic and electrophilic nuclei are most readily accessible. The pyrimidine and quinoxaline systems are especially
suited as electrophilic structural units, and thus permitted p r e p
aration of, e. y.. the yellow thiophene-pyrimidine combinations
( 5 u ) and ( 5 h)[’31 and the likewise yellow thiophene-quinoxalinecombinations(6b),n=2-6(yields 22, 12, 13,9, 5‘){,y2’],
1. THF:
4 6ob
Q-xpQLl
%4
+
3. Nitrobenzene
Scheme 9. Heteropolyaromatic compounds made u p of many different components.
Scheme 7. Allernant thtophene-pyrimidine combinations.
3 KMn04
The low yield of the hexaaromatic compound ( 8 h ) IS probably due, at least in part, to crowding on the quinoxaline
grouprzy1].Crowding on the quinoxaline group appears to
have a much less pronounced effect in the synthesis of the
polyaromatic compounds ( 6 h ) and ( 7 h ) and of the protophane formulated in Scheme 14, possibly due to the greater
mobility of the groups: in the synthesis of compounds ( 6 h )
and ( 7 h ) n - 1 quinoxaline groups are present in the dihydro
form prior to the oxidation step.
2.1.4. Fundamental Difficulties Besetting Synthesis
1. THF; 30%
2. HzO
3 KMn04
Scheme 8. Allernant thiophene-quinoxaline and benzo[h]thiophene-qiitnoxaline combinations (see Section 3.3.1 regarding the mechanism of o h g o m e r i m
tion).
4
Deucticution h j r , o m p l r . ~ ~ r r i o rOn
l : attempted linkage of a
lithiated nucleophilic heteroaromatic system with a combination of two or more heteroaromatic compounds, it was not
uncommon for the lithiated species to be deactivated by complexation. This danger is particularly acute when two electrophilic heteroaromatic nuclei are joined together directly in
the substrate.
Scheme 10 illustrates the deactivation of 2-lithiothiophene
by bipyridines: the reaction with quinoline to give ( 9 ) is
largely suppressed by addition of 2,2‘- and 3J-bipyridine.
The reason is undoubtedly to be sought in complexation
since hardly any thienyl-bipyridine is formed.
2%
L
Qumolme+
4,4'-Bipyridine [1:1]
(9) 42%
Scheme 10. Deactivation of 2-lithiothiophene by bipyridines [ Y ]
Complexation of 2-lithiothiophene by 2,T-bipyridine also
explains why this diaromatic species, although extremely reactive towards n-BuLi (see Section 2.2), shows a similar resistance
towards 2-lithiothiophene as pyridine (Scheme 1 I)[']. Lithiated
rleciruphilic heteroaromatic compounds appear to be less
readily deactivated by 2,2'-bipyridine and similar systems than
are lithiated nucleophilic heteroaromatic compounds. Thus,
attempts to link lithiated pyridine with 2,2'-bipyridine by
nucleophilic substitution are relatively successful (Scheme
enon can be utilized in the synthesis of condensed heteroaromatic c o r n p o ~ n d s341.[ ~ ~ ~
In contrast, the diaromatic compound ( I I a ) possesses two
positions of comparable acidity. The site of lithiation is
strongly influenced by the solvent: in THF u-BuLi metalates
almost exclusively in the cc- position, and in ether mainly
in the y-position (y :cc-lithiation = 62 : 13)[32.3 4 1 ; t-BuLi even
effects exclusive y-lithiation in ether1341.
The lithioalkanes are
presumably first attached as shown in ( I 1 h ) and then effect
H/Li exchange at the spatially proximate y-C atom. I t appears
plausible that the tendency to form complex ( I 1 h ) is rcduced
on use of the better-coordinating solvent THF. On heating
of the ethereal solution of the ylithiation product to boiling,
the lithium atom gradually shifts to thex-position, thus indicating kinetic control of ylithiationl351.
Solvent-controlled lithiations permit synthesis of the isoas
meric triaromatic compounds shown in Scheme 12132~341,
well as the photocyclization product133,341 (for further solventdependent lithiations and preparative applications, see ref.
132,361)
11730."1
0
a
1.
s
N
LI
o-0
N
N
0"'
6 @o
Q--O ri
+
EtZO
-40°C
Schcme 12. Solvent-controlled
Scheinu I I . Reactivity of 22-bipyridine towards lithiatcd heteroaromatic
compounds.
Norispecific lithiation: If the nucleophilic component to be
activated in a synthesis consists of two or more heteroaromatic
units. then specific lithiation of a single position often proves
impossible because two or more CH bonds of comparable
acidity are present. This does not apply to compound ( I 0 1
because lithiation at C-2 of the thiophene ring gives a thermodynamically stable chelated lithium compound. This phenom-
1-
3 4%
and ./-lithiation of 7-(7-thirnyI)pyridine.
Polyaromatic compounds containing more than two heteroaromatic members usually possess several CH groups of
comparable acidity. In such cases, it is advisable to introduce
the lithium atom in the manner shown for the synthesis of
( 12)[13], i. L'. by hulogeri/li e.uchunge (essentially quantitative
in this example; other examples are given in ref. [lil).
1 n-BuLi (- 90°C)
Rr
..A.
,
Pansmetalation: Translithiations frequently impair the
yields of heteropolyaromatic syntheses, and lead to undesired
A i l y e a . Cheiii. Iiit. Ed. Engl. 18. 1 - 1 9 ( I Y 7 Y )
5
side products. In the synthesis of the triaromatic compound
( 1 3 c ) selected as example, the less acidic five-membered ring
was first linked to pyrimidine, thus hindering further complication due to translithiation. Nevertheless, there is some interference from a transmetalation reaction: the adduct ( 2 3 b ) is
lithiated by 2-lithiothiophene and reacts to give the side product (13d)"31.
Translithiation is a very real danger when dealing with
trlkq'l-substituted elecrrophilic heteroaromatic compounds.
Instead of linkage between heteroaromatic compounds, translithiation usually occurs (Scheme 13, below) and initiates
secondary reactions. The linkage of two alkyl groups according
to
Alk-ArN,-Li
+ Ar,-Alk
+
Alk-Arh,-ArL-Alk
which is areno-analogous to the formation of carboxylic esters
or carboxamides (see Section 1) is possible only in exceptional
+
L
iS a
-
tallic syntheses of polyaromatic systems owing to their modest
acidity. Thus alkyl groups can be joined cia a group of three
heteroaromatic nuclei (ArN,-Art-Arh,,)
(Scheme 14,
above)[']. which is areno-analogous to the formation of carboxylic diesters according to
2Alk-OH
+ CI--0--CI
+ Alk-0-CO-0-Alk
It also follows from Scheme 14'"8] that this mode of
linkage can be utilized in protophane syntheses.
Sparing solubility: Organometallic syntheses of heteropolyaromatic compounds have often been thwarted by the sparing
solubility of the polyaromatic precursors in THF, benzene,
or ether. Thus it proved impossible to effect oxidative
linkage of all-r-octithiophene to give ull-sc-sexidecithiophenel3"]. all-a-Octi(N-methylpyrrole), which is much more
soluble owing to the methyl groups, underwent linkage to
give the hexadecamer (Table 2). In general, alkyl groups
attached to ArNurings, and thus non-acidic, should help to
overcome solubility problems in organometallic syntheses of
heteropolyaromatic compounds.
till-z-Poly(N-methylpyrrole) (Table 2), of which only the
representative having f i = 2 was formerly
differ
not only in their solubility but expectedly also in their melting
points (Table 2) and UV spectra (Fig.4) from the all-r-polythiophenes known as far as the octamer.
Table 2. Melting points of u//-1-polythiophene [41] and ~r//-rr-poly(N-methyIpyrroles) [40].
X = NCH,, yield [ '7.1
CUCI] [a]
NiCI] [a]
M.p. ["C]
I1
X=S
X = NCH,
33
214
253
305 -307
338
14-15
I34
145
16(1
178-- 1x2
240-256
.
7
4
5
6
~~~
~
-~
XZ
52
40
53
0.3[b]
1.0 [c]
29
10
21
7
Scheme I 3 Interference by tranalithiation
X
16
In contrast, alkyl groups attached to nucleoplzilic heteroaromatic systems d o not have any interfering effect in organome-
[a] Oxidative linkage with CuCll or NICI] analogous to the synthesis of
( 4 ) . [b] Side product in the oxidative linkage of ?-lithio(M-methylpyrrole).
[ c ] Side product in the oxidative linkage of S-lithio-2,2'-bi(N-methyIpyrrole).
-
~
.
29%
23%
Scheme 14. Linkage ofalkyl groups L'IU heteroaromatic groups and protophane aynthesea.
6
Anyew. Chrm. lnt. Ed. Eiiyl. 18, 1-19 ( l Y 7 9 )
substitution products. The individual results are shown in
Schemes 17-20. The figures above the brackets are the ratios
in which the monosubstitution products are formed in the
competition experiments (slow dropwise addition of reagent
2.2. Reactivity[421
Combinations of functional groups are of considerable significance in organic chemistry. The results compiled in the upper
part of Scheme 15 thus belong to the basic armamentarium
of thc organic chemist: linkage of groups of the same kind
(nucleophilic or electrophilic), for instance of amine or carbony1 functions, leads to an enhancement of the reactivity
typical of the individual group; on linkage of a nucleophilic
group with an electrophilic one, however, the reactivity of
individual groups is lowered by mesomeric interaction. In
this connection, the reader's attention is called to the
pronounced electrophilicity of triketones, which is manifested
in their tendency to add water at the central carbonyl group.
:N-N:
0
,
N-N :
.
0N-
:N*-
.N-
,NtC-
I
Q
CH&OCl/SnQ [ I :11
22 "c
3 h benzene a t
*
2:98 [54%]
I
53%
1"0
Scheme 16. Typical competition experiment [43]
0
-C
0 0 0
0 0
I1
II
II
I1
II
-c<-
-
-C
II
II
-c-c-
0
0 ;II
Q
*
4
I n c r e a s i n g nucleophilic c h a r a c t e r
I n c r e a s i n g electrophilic c h a r a c t e r
1
4
I n c r e a s i n g nucleophilic c h a r a c t e r
towards CH,COCl/SnCq
I
*
I n c r e a s i n g electrophilic c h a r a c t e r
towards n-BuLi
QQ
O
Q
Schemc IS. Relative reactivity of combinations of functional groups and of heteroaroniatic compounds.
Our studies have shown that the question, raised in the
Introduction, whether an analogous situation is encountered
in heteroaromatic combinations can be answered essentially
in the affirmative if thiopkene and pyridine are chosen as
representative systems and acetyl chloride/SnCI, and n-BuLi
as reagents. The only deviation from the situation described
in the upper part of Scheme 15 is that all-cx-terpyridine lies
between pyridine and 2,2'-bipyridine on the electrophilicity
scale. This deviation is probably due to the formation of
the very stable n-BuLi-terpyridine complex (15) and the mposition of the terminal nuclei on thecentral ring of terpyridine,
which hinders mesomeric interaction between the terminal
rings.
The information shown in the lower part of Scheme 15
was gained in competition experiments with the reagents mentioned according to Scheme 16, giving practically only mono-
solution to the aromatic
the overall yields of the
two monosubstitution products are given in square brackets.
We attribute the apparent drastic weakening of the w c h philic activity in the combination of nucleophilic and electrophilic nuclei as compared with thiophene (Schemes 17 and
19) to the formation of N-acetyl compounds, e.g. ( 1 6 ) , in
which the electron-withdrawing effect of the electrophilic nucleus is greatly increased. Accordingly, acetylation of one mole
A
CI 0-C H3
CO-CH3
I
Bu
(15)
116)
of this combination requires two moles of acetyl chloride
(but only one mole of SnC14)[431.
-
%I
,
51:49[74%]
55:45 [ 8 9 %]
9 8 2 154 %]
> 99:l 199 81
75:25 [ 5 2
Scheme 17. Competition experiments with CH3COCI;SnCI, as reagent (acetylation at a).
A I I ~ P M Cl~cwi.
..
l i l t . Ed. Eilgl. 18. 1 - I Y ( 1 9 7 9 )
7
4 4 5 6 [66 %]
I
22:78 [21%]
24:76 (20 %]
25:75 [29
- 1
-
I
461
37.1
1
‘
J 4;
Nm
I
3:97 [21 961
::[32?4]
Cx2 1
[45
%I
N
Scheme 18. Competition experiments with n-BuLi as reagent (butylation at
0)
they have only one site susceptible to attack by n-BuLi compared with the two of pyrimidine’451.
Scheme 19 shows that the drop in nucleophilicity at the
thiophene nucleus of ( 1 7 a ) , n = O , due to the pyrimidine nucleus can extend over two further thiophene nuclei and is
completelyattenuated only after the third additional nucleus[39!
The ratio of 32 : 68 almost corresponds to the statistical ratio
since (I 7 a ) , n = 3, possesses one nucleophilic a-position
whereas ( 1 8 ) has two such positions; acetylation is apparently
subject to kinetic control.
.-.
,N-CO-
-x-c 0x=o,s
-c 0-
-co-co-
Increasing electrophilic
character
see Scheme 19
x=o,s
Scheme 19. Competition experiments on “thienylogous pyrimldines” with
CH3COCI/SnCI4 as reagent (acetylation at 0 ) [39].
n=o
24:76
149 X I
<1:99
[99 X ]
[99 XI
32:68
[96 %]
Compounds (I 7 a ) can be regarded as thienylogs of pyrimidine (cf. Scheme 2). The nucleophilicity of their terminal thiophene nuclei does not exhibit umpolung under the influence
of the pyrimidine nucleus-no formation of adducts ( 1 9 a )
has been observed so far-but is significantly lowered, partly
due to charge shifts according to ( 1 9 b ) .
wNu
N
S
(19a)
W
H
H
(19b)
Further results of competition experiments are summarized
in Scheme 20 (for details see ref. [421): the increase in carbonyl
activity on going from left to right in line 1 has long been
known. The “pyridine activity” (towards n-BuLi) of the compounds in line 2 show a similar gradation. However, the
“pyrimidine activities” (towards n-BuLi) in the compounds
of line 3 do not correspond entirely to expectation, for reasons
yet unknown[44], since in competition experiments with pyrimidine ( 1 7 b ) the diaromatic compounds ( 1 7 6 ) underwent
butylation almost to the same extent as pyrimidine although
8
6Hq
(17b), X = 0 , S
I1 = 3
<l:99
R
1
Increasing electrophilic
character towards n-BuLi
Scheme 20. Electrophilicity of carbonyl compounds and areno-analogous
systems (butylation at 0 ) [42].
It was established in the competition experiments with
CH3COCI/SnC14 that the resulting monoacetyl compounds
are stable under the experimental conditions. In competition
experiments with n-BuLi the lithium derivatives of dihydroheteroaromatic compounds appear as primary products, and
have to be hydrolyzed and oxidized for the synthesis of the
aromatic monosubstituted products. Presumably the lithiated
dihydroheteroaromatic species are largely stable under the
experimental conditions and are transformed into the substitution products on hydrolysis and oxidation. However, this
assumption has yet to be confirmed.
2.3. Spectra
2.3.1. NMR Spectra[491
The diminished chemical reactivity of ArNu-ArE combinations usually observed on comparison with the individual
aromatic compounds suggests that electron density is transferred from the nucleophilic to the electrophilic nuclei. This
can be confirmed by ‘H-NMR spectro~copy’~~].
The 2-H atom
of the pyrimidine nucleus is particularly suitable as a probe
because its signal (Table 3) is hardly ever masked by other
proton signaIs[’3.431.
Angew. Chem. I n t . E d . Engl. 18, 1-19 ( 1 9 7 9 )
Table 3. ' H - N M R s~gnalof ?-H i n pyrimidine derivatives A
0.11 hl wIu1ion. TMS :IS int. standard. 10°C. in CDCIJ) [J3].
:tiid
5 ( <( i .
R
2-(iV-i\.lethylpyrrol~ll
2-Thieiiyl
?-Furl1
H
2-Pyridyl
2-Pyritnidinyl
9.04
9.13
9. I4
9.22
9 29
9.35
8.94
9.03
2.3.2. UV Spectra
In this Section mention is made only of the difference in
on the one
spectra between u//-c~-poly(N-methyIpyrroles)[~"J
hand and ir//-x-polythiophenes[4Xl, - f u r a d ' "I, and -pyron the other (Fig. 3). The convergence of the absorproles~48]
tion wavelengths in d/-x-poly(N-methylpyrroles), which is
more pronounced than in the case of the poly-p-benzenes"8',
is due to the greater torsional angle between the planes of
adjacent nuclei.
9 00
9.22
The redistribution of electron density is even clearer in
the "C-NMR spectra[471:the chemical shifts shown in Figures
1 and 3 can be viewed, to a first approximation, as a measure
of the change in electron density at the C atoms. The signals
of C-3 and C-5 of the pyridine ring (Fig. 1) and of C-5 of
the pyrimidine ring (Fig. 2) are shifted upfield owing to
enhanced electron density and those of the nucleophilic heteroaromatic nuclei downfield. The effects are very pronounced
in the triaromatic systems of Figure 2 because a stronger
acceptor nucleus is linked to two donor nuclei.
Fig. 3. i,,, in the U V spectrum of combinations (Ar,")": solbent CHC13.
2.3.3. Mass Spectra[49]
3t
2
Fig. I . ' 'C-NMR of diaromatic compounds: chemical shifts relative t o furan.
thiophcne. N-methylpyrrole. o r pyridine (m.0.4 M solution, 20°C. in [D,]dimcthql ,olfoxide. standard TMS. upfield shift shown positive) [47].
The mass spectra (70 eV) of heteropolyaromatic compounds
do riof normally contain fragment ions indicating the elimination of individual aromatic nuclei; intranuclear bonds are
apparently broken much faster than internuclear ones. Exceptions are encountered in heterotetrdaromatic compounds with
terminal nuclei in the o,o'-position relative to the central
internuclear bond ("o,o'-linkage"). In such a case. e. y. in ( 2 0 ) ,
an intense ( M +-Ar) peak regularly appears which is usually
also the base peak (Table 4). Knowledge of this phenomenon
is useful in structure elucidation.
The mass number of the (M+-Ar) peak of tetraaromatic
compounds which consist, like ( 2 0 ) , of two kinds of aromatic
species, show that one turrnirzd nucleus each is eliminated.
A fused aromatic compound is probably formed, Tor an intense
peak for ( M t -Ar) occurs only if cyclization to give
a condensed aromatic molecule is formally possible (further
arguments, see [491).
4
-2
-
-4
-8
-6
1
Fig. 2. I ' C - N M R of triaromatic compounds: chemical shifts relative t o r u m ,
thiophcnc. .Y-methylpyrrole. or pyrimidine ( 1 , ~ . 0.4 M solution, 20°C. i n
[D,]diinethyl sulfoxide. standard TMS. upfield shift shown positive) [47].
Heterotetraaromatic compounds having o,o'-linkage in
which the terminal nuclei are attached by C N bonds to the
central portion also eliminate a terminal nucleus in the mass
spectrometer (Table 4). However, the ( A 4 - A r ) peaks are
relatively weak owing to competition by more favorable
decomposition pathways [H elimination, HCN elimination,
formation of fragments such as ( 2 1
)I.
9
Table 4. (M' -Arl peaks i n the mass spectra of heternaromatic compounds with "o.n'-linkage"
Compound
Relative intensity
(.W+)
2.2'-DiiZ-pqridyl)-3,3'-hithiophene
(20 1
3.3'-DiiZ-pyridyl)-?.2'-bithiophene
3.3'-Di(4-pyrimidinylj.2,2'-bithiophene
3.3'- Dii2-pyrazinyl)-2.2-hithiophene
?.?'-Di(2-quinoxalin~l~-2,2'-bithiophene
2,Z'-D1(?-qu1nolyl~-~.3'-bi(ben~~[~]~hioplienej
5,5'-Di(5-pyrimidinyI)-4.4'-bipyrimidine
[a]
3.3'-Di(3-pyridyll-4.3'-hipyridine [h]
1 . I '-Di(l-p)ridyl)-2.2'-hiimi~az~~le
1.1 '-D1i3-pyridyI)-Z.Z'-biimid~zole
I , 1 '-Di(2-pyridyl)-5.5'-bipyrazole
I . 1 '-Di(?-pyridyI)-5,5'-hi(1,?,4-triazole)
(M-i)
9
6
IX
16
64
??
35
x7
M'-HCN
100
I00
I00
1
100
5
100
I00
15
53
I00
44
37
100
I00
[":,I
(M'-Ar)
I00
87
~
23
_7 _7
39
i 00
65
45
6
22
90
72
7
[a] 5,5':4',4":5"'-Quaterpyrimidine. [h] 3,3':4'.4":3",3'"-Quaterpyridine.
3. Heterocyclopolyaromatic Compounds
3.1. An Unattractive Class of Compounds?
In contrast to the field of organoelement compounds, there
are probably only few regions left to be discovered in the
field of organic compounds proper. Nevertheless, the wellpopulated class of heterocyclopolyaromatic compounds was
still unknown in 1973, apart from the heterocyclodiaromatic[sz21
compounds such as ( 2 2 ~ ) or
[ ~(22b)["].
~ ]
BrMg
BrMg
/
Carbocyclic cyclopolyaromatic compounds have been
known for several decades. The first example, cyclotetrabenzene (tetraphenylene) ( 2 3 a ) was prepared in 1943 by Rnpson,
Shurtleworth, and van Niekerk[s31 by oxidative coupling of
a di-Grignard compound (Scheme 21). Further syntheses and
studies were performed primarily by research teams led by
Wirriyfs4]and S t ~ a h [The
~ ~ carbocyclic
~ .
compounds were
obtained mainly in modest yield by oxidative linkage of metalated starting compounds with transition metal halides; the
properties of the products, r . g . ( 2 3 h ) , correspond largely to
expectations.
We attempted to gain an entry to heterocyclopolyaromatic
compounds, which promise to be more interesting than their
carbocyclic analogues with regard to their chemical reactivity
because they are also expected to exhibit the interactions
between neighboring nuclei (see Section 2.2) observed in openchain heteropolyaromatic compounds. It might be expected
that the reactivity typical of the individual nuclei would be
enhanced in ( 2 4 u ) and ( 2 5 ) , whereas mutual deactivation
10
"
H
H
H
(23b?
Scheme 21. Cyclopolybenzenes (polyphenylenes).
of the aromatic nucleophiles and electrophiles constituting
the ring members could occur in ( 2 6 a ) and especially ( 2 6 b ) .
Aiiyen.
C h m . I i i r . Ed. Eiiyl. IX. 1-19 ( 1 9 7 9 )
3.2. Organometallic Oxidative Linkage as Cyclization Step
3.2.1, Similar Aromatic Ring Members
The method of oxidative linkage which proved of value
in the preparation of cyclotetrabenzene was successfully
applied to heterocyclic starting materials. Starting from the
d i b r o m i d e ~ [ ~Br/Li
~ ' , exchange and oxidative coupling initially
gave the cyclotetrathiophenes ( 2 4 0 ) and (28) (Scheme
22)[9.13.5?.58]. cyclohexathiophene ( 2 7 ) was formed as side
product in one case. Cyclodithiophenes, i. P. products analogous to ( 2 2 0 ) . could not be detected.
Two further nucleophilic cyclotetraaromatic compounds
(Scheme 23) could be prepared analogously['. 1 3 * 5 7 . s81 from
known precursors[62,h31.
The difficult synthesis of cyclotetraf ~ r a n [could
~ ~ ] be reproduced only after several attempts[651.
3I . 2 n-B"L1
2. C"CI2
Scheme 23. Further homotypic 1661 heterocyclotetrdaromatic compounds
by oxidative coupling: Top, aromatic nucleophiles as ring members: bottom,
aromatic electrophiles as ring members.
Scheme 12 Cyclopolythiophene syntheses
The three-dimensional structure ( 2 8 ' ) was found for ( 2 8 )
by X-ray structure analysis[591.The angle between the planes
of adjacent nuclei is 53.7" and is thus considerably smaller
than in cyclotetrabenzene (23 a ) (ca. 70")[601.This complies
with expectations, because less deformation of the bond angles
is required to planarize (28') than ( 2 3 a ) . Analogous nonnlanar s t r u p r e s are assurnedfor.fl224nLmd the other heterocyclotetraaromatic compounds synthesized. The H-NMR
spectrum of the cyclohexathiophene ( 2 7 ) is almost identical
with that of ( 2 8 ' ) . Hence ( 2 7 ) probably has the three-dimensional structure ( 2 7 ' ) rather than (27")[6'1.
The mechanism of the linkages leading to ( 2 4 a ) and analogous compounds is still unclear. A reaction route analogous
to that proposed and experimentally supported by Wirtig
rt u/.l s4cl for the formation of cyclotetrabenzene would involve
the intermediacy of the ate complex ( 2 4 b ) and metallocyclic
species ( 2 4 ~ in
) the formation of ( 2 4 a ) by oxidation with
CUCIZ.
Etiyl. 18.1-19 ( 1 9 7 9 )
Analogous attempts to synthesize cyclopolyaromatic
compounds made upexclusively of heteroaromatic c+xtrophiles
as ring members have so far succeeded only in the case of
cyclotetrapyridine (25). Metal amide linkagr of 3-bromopyridiiie (cf. Section 2.1.2) led to (29)L3'1, which reacted with
n-BuLi to form the corresponding dilithium compound.
AdditionofFeCI3 gave the cyclotetrapyridine (25 ). In contrast,
only traces of (25) were formed on use of C U C I ~ [ ~ ~ ]
3.2.2. Two Different Kinds of Aromatic Ring Members
On synthesis of ( ~ O C ) , the first heterocyclopolyaromatic
compound containing unlike aromatic ring members (Scheme
24)[h8.h9],selective linkage of pyrazole and benzene proved
feasible because 1 -phenylpyrazole is metalated specifically at
the phenyl group by Grignard
and the tetraaromatic compound (3Oa) specifically at the pyrazolyl group
by n-BuLir"M1.CuCI,, which is usually the reagent of choice
for oxidative linkage cia organocopper compounds, fails to
effect cyclization of the dilithium compound ( 3 0 h ) ; it acts
as a chlorinating agent instead. There is a danger of explosion
when cyclization is performed with C U I ~ O ~ ~ " ~ .
Cyclic pyrrole-benzene combinations were much more readily accessible (Scheme 24, below). O n linkage of the dilithium
compound (31 a ) , which arises almost quantitatively on reaction of t mol of t-phenylpyrrole with 2mol of ti-Buliltetramethylethylenediamine (TMEDA)[40b.721, the question
whether (31 h ) or (31 c ) is formed preferentially was of particular interest. It is still unclear why the macrocycle with alternant
arrangement of the nuclei happens to predominate. Structural
assignment of the twocyclization
proved possible
only after the isomer ( 3 1 ~ )had been synthesized from
(31 d)[731.
It was not possible to isolate the expected cyclohexaaromatic
analog of ( 3 6 b ) or the cyclotetraaromatic compound ( 3 2 ~ )
from the mixture obtained on reaction[40biof the triaromatic
11
2 n-BuLi
THF/- 100°C
I;r
Br
1
CUCI2
(31b), 3Oob
1 3 1 ~ ) 16%
.
4
Scheme 25. Heterocyclohexaaromatic compounds with a crown-type sIructu1.e.
X-Ray structure analysis of ( 3 3 ) d s o shows that a clear
distinction in bond length remains (C-Caromatlc:1.38 CCilltelnUcleilr:
1.40 A) in the internal ring, which formally corresponds to an [ I Rlannulene ring. Thus. as expected, the aromatic character of the individual benzene rings is not weakened
in favor of an aromatic [18]annulene system. Any formulation
as a condensed aromatic system ( 3 3 ' ) is therefore erroneous.
The IH-NMR spectrum of hexa-m-phenylene ( 2 3 h )
(Scheme 21) contains the signals of the internal protons at
ii= 8.85. The corresponding signals of the tetraaza compound
(33) at b = 9.42 (Hi)and 9.51 (Hi ) show a significant downfield
shift. This is probably partly due to the stronger mutual
interaction (van der Waals). In the case of octaazahexa-mphenylene ( 3 4 ) (synthesis in Section 3.4), the signals of the
internal protons Hi and H,, appear at 6 = 9.75, i. e. even further
downfield. This cyclohexaaromatic compound should therefore also be planar. which is understandable in view of the
absence of steric hindrance between external 0.o'-pairs of protons.
Since compounds ( 3 5 t r ) and ( 3 5 b ) are k n ~ w n ~ ' ' . ' ~ ' ,it
was to be expected that not only crown-type cyclohexaaromatic compounds (Scheme 25) should be possible in which two
nuclei are arranged face to face. The question of their chemical
and spectroscopic properties makes such compounds interesting synthetic objectives.
It proved possible to synthesize compound ( 3 6 b ) as the
first representative of this type in acceptable yield (Scheme
26y4"'.Attempted preparation of an analogous heterobicyclooctaaromatic compound having benzene rings linked cia
three bispyrazolyl bridges did not give the desired product
but instead a disubstituted cyclohexaaromatic compound to
A;
i3Idi
3 570
Scheme 24. Heterotypic [66] heterocyclotetraaromatlc compounds by oxidatiye linkage.
species ( 3 2 ~ ) [ ~ ~Compound
1].
( 3 2 ~ should
)
be formed less
readily for steric reasons than the colorless, fairly soluble
isomer ( 3 2 h ) formed in relatively good yield; the compound
has the basic ring system of (31 h i .
ONxgN0
(32b)* 31";
i3ZaJ
On synthesis of (33) (Scheme 25)F6y.-41. the first heterocyclo1wsuaromatic compound having different kinds of ring
members, the double Br/Li exchange shown in the scheme
must be carried out with cooling owing to the competing
ri-BuLi addition at the pyrimidine nucleus.
While the planes of adjacent benzene rings are twisted
by CU. 30" relative to each other in hexa-m-phenylene ( 2 3 b )
(Scheme 21)L751, the corresponding angle in tetraazahexa-niphenylene (33) is shown by X-ray structure analysis""' not to
exceed I". This is probably because six pairs of o,o'-protons
in the outer sphere of ( 2 3 b ) hinder planarization while only
two such pairs are present in the tetraaza compound. Intramolecular hydrogen bonds from benzene moieties to nitrogen
atoms may also be effective.
12
A I I ~ C MChein.
..
I i i t Ed. Engl. 1 8 . 1-19 ( 1 9 7 9 )
which we assign structure (37b)[791. The yield of (37h) was
only 1 ":, on oxidative coupling of the precursor with CuClz
instead of with 02[40b1.
(36b), 43%
(36 a ) , 7 9%
Lie
of two molecules of a monolithiated diaromatic compound
appears highly promising if it contains a strongly iiucleophilic
and a strongly electrophilic center like (39a). This kind of
cyclization proved successful in four cases.
Especially smooth cyclization was observed with lithiated
3-(1-imidazolyl)quinoline(3Ya) (Scheme 27)[68.x'.821.
A contributory role is probably played by the chelate bridge assumed
to occur in the intermediate (39 b ) which forces the terminal
nuclei into spatial proximity. Unlike the syntheses of ( 4 0 b ),
(41 c), and ( 4 2 ) , that of (39c) fails to give better yields
on addition of CuF2 or NiF2.
The analogous benzimidazole derivative (40a) gives the
cyclotetraaromatic compound mentioned in a yield of only
3 %, for reasons which are still unknown: addition of 2 equiv.
of NiF2 (vide infia) to the reaction mixture raises the yield
to over 15 %[68.81]. The higher electrophilicity of benzimidarole, compared with imidazole, is probably responsible for
formation of the above side product (addition of ( 4 0 a ) to
the corresponding nonlithiated compound).
( 3 7 a / , 90%
A
J.
CCL
N
0 "C
THF
Scheme 26. Heterocycloaromatic compounds with face-to-face arrangement
of two rings.
1. HzO
The signals of the phenylene protons (singlet, b = 6.97) in
the 'H-NMR spectrum (in CDC13) of (36b) are distinctly
shifted upfield relative to those of the precursor (36a)
(O= 7.80). This corresponds to the situation in [2.2]paracyclophane'*'', in (35h)[781, and in other phanes, and can be
explained in terms of the anisotropic effect of the neighboring
pheny lene group[ 'I.
In the syntheses of heterocyclopolyaromatic compounds
by oxidative linkage considered so far, the yield of the cyclization step was at most 31 %.The high yield of (36b)-43 %---is
therefore surprising. Since the two CC bonds will hardly be
formed simultaneously, we have to assume that the intermediate hexaaromatic compound occurs in the cisoid conformation ( 3 8 ~ 1 or
) as metallocycle (38b), or readily transforms
into these structures (cf. ref. [49j).
2 KMn04
p
( 3 9 ~ / 5640
,
Scheme 27. Cyclization of imidazolide-analogous [X3] diheteroaromatic compounds.
The corresponding cyclization of the lithiated thiophenequinoxalinecombination ( 6 a ) could not initially be performed
since only the open-chain oligomers (6 h ) mentioned in Section
/38ai
M = Li,C u
(38b)
3.3. Nucleophilic Aromatic Substitution as Cyclization Step
3.3.1. 2 + 2 Linkage
Since linkage of a heteroaromatic nucleophile with an electrophile is particularly facile (see Section 2.1.1), the cyclization
A i i ~ g c i v . Cliein. ijii.
Ed. Enyl. I N . 1-15 ( 1 9 7 5 )
13
2.1.3 were formed on heating. We attribute this to the chelate
bridges in ( 6 u ) and (6c) and analogous intermediates because
they fix the two active centers (marked by a point) in the
t r u i s orientation which is unfavorable for cyclization.
The desired cyclization to (41 c) (yield 9
occurred only
on treatment of the THF solution of ( 6 a ) with 2 equiv.
of CuF2 (Scheme 28)r26,27!The effect of the CuF2 can be
rationalized by assuming it to complex the N atoms of the
quinoxaline system according to (41 a), which should overcome the fixing of the “wrong” conformation of ( 6 a ) and
also raise the electrophilicity. The speculative formula (41 h )
should illustrate the complexity of the reaction course.
The benzohomolog ( 7 a ) likewise mentioned in Section
2.1.3 also cyclizes without addition of CuF2. Addition of 2
equiv. of anhydrous CuF2 or NiFZcS4]raised the yield of
cyclization product ( 4 2 ) from 12% to 63 and 26%, respectively[26,271. 63y, is the highest yield yet obtained in a heterocyclopolyaromatic synthesis. It is remarkable that this yield and
the second-best one [56‘%, of ( 3 9 c ) ] were both achieved
by ArNU-ArE linkages, which have also proved especially
valuable in the synthesis of open-chain systems (cf. Section
2. I .3).
I%))
The reaction of a dilithiated nucleophilic diaromatic compound with an electrophilic diaromatic species, e.g. according
to Scheme 29, also appeared promising as a method for the
synthesis of heterocyclotetraaromatic compounds, but all
attempts to carry out this reaction were unsuccessful. We
suspect the dilithium compound to be deactivated by complexation, e.g. according to ( 4 3 ) (cf. Section 2.1.4).
3.3.2. 3 + 1 Linkage
The quinoxaline system, whose adjacent electrophilic centers
make it appear to be such a favorable structural unit for
cyclotetraaromatic syntheses, is particularly advantageous for
the critical cyclization step in cyclotetraaromatic syntheses.
If one of the two electrophilic centers is attacked with formation of an adduct (44), then the electrophilicity of the second
center increases, since the “aromatic” C N double bond has
been transformed into a “normal” C N double bond. Thus
special measures are required (very slow addition of nucleophile to quinoxaline’*51) if single nucleophilic addition to the
2. H20
3. K M n 0 4
1. HzO
t
2. KMn04
0 s
+
2 LiN(iPr),
L. CuF2
2. A
3. HzO/KMn04
___)
- 15 “C
(7a)
( 4 2 ) , 63%
Scheme 28. Cup,-assisted cyclotetraaromatic syntheses.
’ZLix
+
S
o Li
Heterocyclo-
* tetraaromatic
0
compound
N w N
(46 C) , 16‘10
Scheme 29. Unaccomplished cyclizations [ 13.261
14
Scheme 30. Heterocyclotetraaromatic syntheses with dilithium compounds.
Angeb<. Chetn. I i i f . E d . Eiiyl. 18. 1-19 ( 1 9 7 Y )
quinoxaline system is to be accomplished rather than double
addition. Reaction of the lithiated triaromatic compound
( 4 5 ~ 1with
) quinoxaline does lead to the desired compound
( 4 5 b ) (Scheme 30), but only in poor
The dilithium compound ( 4 6 a ) prepared analogously is
a far better starting material[26~69].
Presumably, crowding
of groups in the conformations 1 4 6 ~ ' and
)
( 4 6 ~ " leads
)
to
population of conformation (46cr) which is more favorable
for cyclization. The reaction temperature has a marked
influence on the product ratio: at 20 instead of - 15°C (Scheme
30) the yield of ( 4 6 b ) and 146c) is 18 and 69 %, respectively.
X-Ray structure analysis[761confirms the expected doubleboat structure analogous to (28').
Reaction of ( 4 7 a ) with quinoxaline gives ( 4 7 b ) , the first
heterocyclotetraaromatic compound to contain three kinds
of ring members (Scheme 31)12']. The by-product ( 4 7 c ) justifies the conclusion that the benzothienyl group is initially
linked to the quinoxaline. This is expected, because chelation
not occur specifically at the site given (cf. Section 2.1.4)["'.
A further detrimental effect on the yield is exerted by the
unusual intramolecular nucleophilic substitution leading to
the fused system ( 4 5 c ) , in which a 3-thienyl group replaces
a 2-quinoxalinyl moiety (Scheme 32). Elimination of a nucleus
from ( 4 8 ) (two terminal nuclei located in an o,o'-relationship
to the central internuclear bond) is comparable with elimination of nuclei in the mass spectrometry of structurally analogous tetraaromatic compounds (cf. Section 2.3.3).
(4SC)> 7%
T
: -s
/
Li
(46a'j
( 4 6a ")
to an N atom of the quinoxaline leading to a drop in nucleophilicity is more likely for steric reasons in the case of the thienyl
group of ( 4 7 ~ 1 than
)
for the benzothienyl group.
1870
Scheme 32. Cycliration of tetraaromatic compounds and replacement of
one nucleus by another (see also Scheme 30).
In only one other case have we observed a similar nuclear
substitution : the by-product ( 4 5 c ) of the reaction formulated
in Scheme 30 must have been formed in this way. That such
reaction must also be able to proceed intermolecularly follows
from the 1-pyrazolyl/2-thienyl exchange shown in the bottom
part of Scheme 3218'1. A common feature of these substitutions,
which probably proceed via an addition-elimination
mechanism, is their occurrence at a strongly electrophilic nucleus.
.1
+
( 4 7 d ) , 7%
Scheme 31. Heterocyclotetraaromatic compound having three differcnl kinds
of ring members.
3.3.3. 4 + 0 Linkage
The yield obtained on cyclization of the lithiated tetraaromatic compound ( 4 8 ) to give the compound ( 4 5 b ) already
mentioned was surprisingly low[261.This may be partly because
lithiation with lithium diisopropylamide leading to (48) does
Anges C'lirm lnr Ed E n g l 18. 1-19 11979)
3.4. Metal Amide Linkage as a Cyclization Step"]
The 5,5'-bipyrimidine obtained (57 %, Scheme 33)' 13. 57b. 581
by oxidative linkage of 5-lithi0pyrimidine[~~]
was transformed
into quaterpyrimidine ( 4 9 a) and cyclotetrapyrimidine (49 h )
on addition of lithium diisopropylamide. On further reaction
with lithium diisopropylamide[13.57b.58J, (49tI) underwent
cyclization, possibly involving fixation of the cisoid conformation by complexation with lithium diisopropylamide according
to ( 4 9 c ) . This would explain why quaterpyridine (50), which
lacks the two nitrogen atoms required for such a complexation,
cannot be cyclized analogously[311.
led to only a very modest
Linkage of 3,3'-bipyridine[31~57"l
yield ofcyclotetrapyridine (Scheme 33). The much more readily
[*] C I Section 2.1.2.
15
accessible cyclotetrapyridine (25) was mentioned in Section
3.1.
3.5. Detailed Studies on the Heterocyclotetraaromatic Compound ( 2 4 ~ )
Among the heterocyclotetraaromatic compounds synthesized, only the cyclotetrathiophene cycloocta[ I ,2-h:4,3-h’:5,6b”:8,7-b”’]tetrathiophene ( 2 4 ~ 1 has
) been studied in detail.
Nonavailability of suitable crystals precluded X-ray structure
analysis; however, the three-dimensional structure will no
doubt closely resemble that found for the isomer (28)[591
(see Section 3.2.1). In the U V spectrum (CHC13) of (24a)
i,,, is observed at 278nm, and thus lies between i,,, of
3,3‘-bithiophene (263nm) and of 2,2‘-bithIophene (297 nm).
Noncoplanarity of the nuclei apparently prevents extensive
interaction between the n-electrons.
LiN(iPr12
R
(50). 2 570
Rr
Br
1541
(24a), R = H
i53a), R = CO-CH,
(53b), R = -(&CO-CH,
XQ
j53c), K = B r
0.7%
Scheme 33. Cycliration of electrophilic heterodiaromatic compounds.
Attempts to obtain cyclohexapyridine ( 5 1 c) by treatment
of 4,4‘-bipyridine, alone or in admixture with (51 a ) , or of
sexipyridine ( 5 1 b ) with lithium diisopropylamide were unsuccessful. Linkage gave only open-chain polypyridine~[~’].
-41
N
Reaction of ( 2 4 u ) with one mol. equiv. each of acetyl
chloride and SnCI4 leads to a 45 ”/, yield of the monoacetyl
compound ( 5 3 0 ) ;less than 3 % of diacetyl compounds were
formed[*’, 901. Introduction of the electron-attracting acetyl
group thus significantly reduces the nucleophilic character,
not only of the acetylated thiophene ring but of the entire
macrocycle, which seems surprising in view of the markedly
nonplanar structure.-Competitive experiments with acetyl
chloride/SnCI4 show (Scheme 34) that ( 2 4 0 ) lies between
thiophene and 2,2’-bithiophene[’’l on the nucleophilicity scale
(regarding experimental conditions, see ref. 14’]).
I
Q8,
31:69 [57 %]
17:83 [84 %]
1
I
D:
(240)
Scheme 34. Relative nucleophiliclty towards acetyl chloride;SnCI,: results
of competitive experiments analogous to Scheme 16 [91].
i5lc~
In contrast, the triaromatic compound ( 5 2 ) reacts to give
octaazahexa-ni-phenylene ( 3 4 ) already mentioned (see Section
3.2.2)[”l. The product of linkage was obtained directly in
the “fully aromatic” form, albeit in very low yield.
The deactivating effect of electron-withdrawing substituents
on the entire macrocycle manifests itself even more clearly
in the failure of an excess of acetyl chloride and SnCI4 to
acetylate even one of the C atoms of the macrocyclic system
of the pyrimidinyl-substituted cyclotetrathiophene ( 5 3 r )
(Scheme 3.9, whereas the pyrimidinyl-substituted (open-chain)
quaterthiophene (1 7 a ) , n = 3, is readily acetylatable under
the same conditions (see Section 2.2). This is probably due
to the formation of the N-acetyl compound ( 5 3 b ) and the
resulting strongly enhanced electron attraction of the pyrimidinyl group.
A ~ r g m . .Clrrm. Int. Ed E n g i IX. 1-19 ( 1 9 7 9 )
While 2-bromothiophene effectively cannot be obtained by
the action of bromine on thiophene, owing to fast incorporation of further bromine atoms["'], the reaction of ( 2 4 ~ with
)
one mol. equiv. of bromine leads to a 29 % yield [48 'y, based
on reacted ( 2 4 u ) I of the monobromine derivative ( 5 3 ~ ) .
Reaction with an excess of bromine under more drastic conditions gave the tetrabromide ( 5 4 ) in 82 ?d, yield[*"].
W u k electrophiles can be linked to the macrocycle by
reaction with lithiated ( 2 4 a ) . It is most fortunate that the
reaction of ( 2 4 u ) with one equivalent of n-BuLi surprisingly
affords essentially only a monolithium d e r i ~ a t i v e ~ It
~ ,also
~~'.
proves possible, ria this compound (53ri), to oxidatively link
two molecules of ( 2 4 a ) or to join them together by way
of a linking
(Scheme 35).
The mass spectrum of the bridged products, r . y . ( 5 5 0 )
and ( 5 5 h ) , contain intense peaks suggestive of cyclization'"';
(55c.l and ( 5 5 d ) (each of relative intensity 100%) are two
Lq
contains two sets of four equivalent nucleophilic and CH
acid positions, monosubstitution products could be obtained
with a surprising degree of selectivity by direct electrophilic
substitution. by lithiation, or by electrophilic substitution of
the lithiation product. The nonplanar structure endows the
molecule with a relatively good solubility (r.cq. 29.4g/I in
CHC131931),
while still not effecting mutual isolation of the
nuclei which would be of disadvantage on substitution of
equivalent positions by random attack. The results suggest
that selective and hence preparatively valuable reactions are
also possible with other heteropolyaromatic compounds.
4. Outlook
The principle of areno-analogy, which prompted our investigations, will continue to stimulate research into organic
COOH
so os
4 1010
CH,-Si-CH,
79%
(SSb), 7 %
Scheme 35. Products obtained from Iithiocyclotetrathiophcne ( S 3 d 1.
characteristic examples. We may expect that uncharged metallocycles analogous to ( 5 5 a ) will one day become readily
accessible on a preparative scale from heterocyclopolyaromatic compounds.
The information obtained from a detailed study of cyclotetrathiophene ( 2 3 u ) isencouraging: although this macrocycle
chemistry. Developing trends can be seen in protophane (see
Section 2.1.4) and phane syntheses['], in which heteroatoms
linked cia carbon chains serve as nucleophilic and electrophilic
functional groups; however, transmetalation reactions (see
Section 2.1.4) could set narrow limits to the utility of these
reactions. A further limitation comes from the generally irreversible nature of linkages between two heteroaromatic groups
(exception: see Scheme 32) which contrasts with the linkage
of most functional groups.
It should be mentioned in connection with the heterocyclopolyaromatic compounds that the large number of known
hetero- and carbocyclic aromatic compounds and the great
variety of possible linkages must, in principle, give rise to
thousands of such compounds. In the long term, chemists
will not wish to forgo this enormous potential. The years
to come will therefore see the synthesis of many new compounds of this kind. After introduction of suitable substituents
to raise their solubility, some compounds of this class may
also exhibit interesting physiological properties.
As shown in Section 3.5, monosubstitution does not cause
any fundamental difficulties. Concerning the introduction of
several substituents or side chains, we can expect that tetrasubstituted derivatives of ( 2 4 u ) should be preparable, e.g. from
the tetrabromo compound ( 5 4 ) , by Br/Li exchange and reaction with electrophiles. Apart from subsequent introduction
of substituents, it should also be possible to cyclize substituted
di- and triaromatic compounds.
A11 the syntheses carried out so far are organometallic in
nature, and often unsatisfactory with regard to yield. Thus,
another future task is the development of less complicated,
productive syntheses.
The pathway leetdirtg to keterocyclopol~aromaticcompounds
hj' u team of capable co-workers, whose names
are mentioned in the references cited. This report is their report.
I wish to express my gratitude to c111 of them-Thanks are
also due to Prof: Dr. H . G . Con Schnering, Max-Planck-Institut
fur Fe.stkBrperfbrschung, Stuttgart, and PriwDoz. Dr. H . Irngurtirtyer, Orgaiiisch-chemisclies Institut eler Uniuersitiit Heidelberg,ji)r X-ray structure analyses. I am indebted to H . Niewind,
Organisch-Clzeiiiisches Institut der Uniuersitat Miinster, ,for preparation of starting ti~ateriuls.-Financial support of this work
by the Deutsche Forschuiigsgemeinschaft ( K u 144127 and Ku
144/30), the Ministerium f u r Wssenschaft und Forschung des
Laiides Norclrhein- W e ~ t f a l e n ' and
~ ~ ~the
, Fonds der Chemischen
Indtrstrie is gratefully acknordedged.
HYIS smoothed
Received: January 2, 1978 [A 252 I E ]
German version: Angew. Chem. 91, 1 (1979)
A . Alhert: HeterocyclicChemistry. Athlone Press, London 1959; Chemie
der Heterocyclen. Verlag Chemie. Weinheim 1962. Nucleophilic and
electrophilic aromatic moieties are designated as Ar,,, and ArE, respectively.
[?I 711.Knuffrnuriri, Angew. Chem. 83. 798 (1971); Angew. Chem. Int. Ed.
Engl. 10, 743 (1971).
[3] Tli. Kuu/finann. Chimia 26, 511 (1972).
[4] Cf. A . R. Kutririkv, J . M . Lrrgoit~.ski.The Principles of Heterocyclic
Chemistry. Methnen, London 1967.
[5] W L. F . Armureao. R. E. Willctrr. J. Chem. Soc. 1965. 1258; 7:Hiuushino.
M .Gio, E . Hajashi. Chem. Pharm. Bull. 22. 2493 (1974)
For studies on protophanes, phanes, heteroprotophanes, and heterophanes stimulated by the principle of areno-analogy, see: a) Th. Kuu/fl
ininin. A . Wolterniunn, Angew. Chem. 84. 824 (1972); Angew. Chem.
Int. Ed. Engl. 11, 842 (1972); h) Th. Kuu/fniunii, J . Juckiscli, A . Wo1rrrrnuriri. P. Riirwmeirr, rhid. 84. 826 (1972) and I 1 , 844 (1972). respectively;
c) 7h. Koirffmarin, ibirl. 86. 321 (1974) and 13. 291 (1974). respectively;
d l Th. Kuiiffrnunn, G. BeircJler, W Sulrm. A . Wolrrrniunn,ihid. 82, 81 5
J ~ IBeiss~ier.
I.
R. Muihaurn,
(1970) and 9, 808 (1970); e) Th. K U U ~ / I ? I ~ G.
rbid. 83, 795 (1971) and 10, 740 (1971). respectively: f) Th. Kuuffmunn,
K H . Kniese. Tetrahedron Lett. 1973, 4043.
H Wwhrrg. 7: J. L'UII Beryeri, R M . Keilogy, J . Org. Chem. 34, 3175
[I]
( I 969).
Th. Kauffmaini. E. Wiediiifer, A . W~~lrer~nuini,
Angew. Chem. 83, 796
(1971); Angew. Chem. Int. Ed. Engl. 10, 741 (1971).
4 . W~~lterriiairri,
Universitit Miinster. experiments 1971 1976.
H . Liickirig. Diplomarbeit, Universitit Miinster 1977.
Indirect umpolung of carbonyl compounds: B. 7 Grhhrl, D. Srebncii,
Synthesis lY77, 357, and refcrcnces cited therein.
E. Wierihiiftr, Dissertation. Universitit Miinster 1974.
B. Greririy, Dissertation. Universitat Miinster 1976.
A . C a i r ~ i ~ r ~W~ . ~4 . ~Slirppurd,
.
J Am. Chem. SOC. 90, 2186 (1968).
Addition-elimination mechanism in reactions of hetero-arylcopper compounds uith 1.3.5-trinitrobenzeiie: M. !Vi/sson, C. L'lli~nius. 0.
Werni~~rsrr~jni.
Tetrahedron Lett 1971. 271 3.
a ) M. Niksori, C. Ulleriiu%. Acta Chem. Scand. 24. 2379 (1970): h)
,M.i ~ l / s s o n 0
,
Werinerstriirri, ibid 24, 482 (I970): c ) N . Gjos. S. GroJloitrr:,
rhrd. 26, 3383 (1972).
ibid. 25. 2596 (1971); d) C. Lr1l~~riir~.s.
Analogy. reactions of phenylcopper with acyl halidcs: H . Gilniari. J .
M . Srrulry. Rec. Trav. Chim. Pays-Bas 5 5 , 821 (1936)
Six-step ring-forming synthesis (overall yield 14
If. Pi'vnhrrg. Rec. Trav. Chim. Pays-Bas 86. 37 (1967).
H. k y j , Diplomarbeit, Universitit Munster 1975.
Four-step ring-forming synthesis (overall yield 16 ':,a): 7: Reichstriri,
A . Griiwit'r. H Z d i o k , Helv. Chirn. Acta 15, 1066 (19321. R. Grrgg,
J . A . Kmghr, M . I! Sargrrit, J. Chem. Soc. C 1966, 976.
IUPAC rule A-54.1 requires use of the numerical prefixes hi, ter, quater.
quinque, sexi. ere. for open and unbranched chains made up of identical
ring systems. These requirements are not fulfilled hy most of the conceivable polyaromatic systems o*ing to non-identical aromatic chain
members. to cyclic or branched structures. In these cases and in the
gcneral terms auch as tetraaromatic compounds or cyclotetraaromatic
compounds we employ the set of prefixes di. tri. tetra, ('re.
A . J . Clirrkr. S. ,'blc,~urnuru,0. Mrrli-Cohn, Tetrahedron Lett. /Y74.
2373.
B. C . Plutr, Nature 157, 439 (1946). Dehydrodimerization products
of electrophilic heteroaromatic compounds have been obtained on
several occasions as side products of the Chichihabin reaction (cf. If.
T Lcf/kr, Ore. React. 1. 91 (1942)).
R. J. M m t w s , H . J. drii Herroq, .%I. ruri .Aninirr. Tetrahedron Lett.
1964, 3207.
The yields given are the highest yields obtained in several experiments.
Heating of ( 6 u ) in boiling ether afforded all the oligomers listed.
while only 1 6 b ) . H = I and 2, were formed if ( h u ) was allowed to
react in T H F at 0°C.
R. Orrrr, Dissertation. Universitit Miinster 1978.
TI,. Kuii/f~nuiiri,R. Orrer, Angew. Chem. 88, 513 (1976); Angew. Chem.
Int. Ed. Engl. l j , 500 (1976).
E. Wiriikufrr-.71%Kauf~niunii,Tetrahedron Lett. 1974, 2347
The reaction temperature cannot be increased since ( X u ) otherwise
undergoes increased self-addition.
Th. Ka1~ffn1ann,J. Kiinig, A . W f ~ / r e r m u ~Chem.
ni,
Ber. 109, 3864 (1976).
J. Kiiiiig, Dissertation, Universitat Miinster 1977.
Th. Kuuffmurin, .4. Mirschker, Tetrahedron Lett. 1973. 4039.
A. Mitsclikur, L'. BruJid/. Th. Kauflmunri, Tetrahedron Lett. I Y74, 2343.
4 . Mirschker, Dissertation. Universitit Miinster 1974.
A. Vahr~.ti/ior.st.
Universitiit Miinuter, experiments 1977.
P. Rlhrr@ou.G. Nrcer,, G . Q U P ~ I I I Jlecture
I Y ~ . at Reunion du Groupe
F r a n p i s de Chimie Hktkrocyclique in Lille, Sept. 1977; P. Rihereou,
G. Nrvers, G. Qut~giiinur.P. Pusfour, C. R. Acad. Sci. Ser. C 280, 293
(1975).
J. Juckisrh, Dissertation, Universitit Munster 1973.
L'. Prager, Dissertation, Universitiit Munster 1977.
D. Kiirher, Dissertation, Universitiit Miinster 1977.
a ) Th. Kmfinarrn. H . L r ~ yAngew.
,
Cheni. YO, 804 (1978); Ange*. Chein.
Int. Ed. Engl. 17. 755 (1978); b) H . Lerj-. Dissertation, Universitat
Miinster 1978.
The melting points given by W S t e i ~ i k f ~ pR.f , Lritsmari, K . H. Hqfniari,
Justus Liehigs Ann. Chem. 546, IS0 (1941), for all-r-polythiophenes
have been improved on the basis of our own results [39]. all-r-Octithiophene [39] was previously unknown. The melting points given in Table
2 are corrected values.
Th. Ku~rffntririri. .I. Kiiuig, D. Kijrhrr, H . Lrxy, H.-J. Srreitbrrger, A .
Vulirri~horsr.A . Wultwmuini. Tetrahedron Lett. 1977. 389.-1n the conipetition experiments, several factors (failure of reaction to occur at
low reagent concentrations owing to N-acetylation or H;Li exchange;
poor availability of some compounds; necessity of high yields to facilitate
evaluation) precluded choice of reaction conditions required for determination of competition constants (large excess of substrates relative
to reagent: cf. R. H u i s g e n , W M u d , L. Miihius, Tetrahedron Y, 29
(1960)). Neverthcless. our aim of gaining some idea about the relative
nucleo- o r elcctropliilicity of the rubstrates has probably been accomplished.
H:J. Strrirber,qer. Dissertation. Unibersitat Miinster 1975. and unpuhlished measurements performed in 1976.
Calculations (Pariser-Parr-Pople) by .bl. Klessirrger and 7: lacheheck
( T /.sc/irhr~ck,Diplomarbeit. Universitat Miinster 1974) show that the
nucleophilicity and electrophilicity of a combination ArNu-Arb should
he greater than those of ArN,, and Art.
[45] Given therinodynamic control, the nunibcr of sites open to attack
would not play any role However, kinetic control is to be assumed
since no n-BuLi adduct of the diaromatic compound ( 1 7 h ) . X-S.
was formed on its addition to the ri-BuLi adduct of pyrimidine under
the conditions of competition experiments [35].
[46] Th. Kuuffmann. P. Bundi, W BrirrLiwrrh, B. Greciriy. Angew. Chem.
84. 830 (1972); Angew. Chem. Int. Ed. Engl. / I , 848 (1972).
[47] H. Stdckel~narin,Diplomarbeit. Universitit Munster 1976
Arigeit. Cliern.
Iiir.
Ed. EngI. 111. 1-19 ( 1 9 7 9 )
U V spectra of ull-r-polythiophenes (in CHCI,), see [39] : of ~ l l - r - p o l y pyrroles (in CHCI,), see [40b]; of poly-/~-hcnzenes(in CHCI,), see A
E. Gillon, D. H . Hey, J . Chem. Soc. IY3Y. 1170: 4 E. Gillun. D. H.
Her, 4 . Lanihrrr, ibid. 1Y41, 364.
711. Kuuffmunii, A . Mitscbkrr, Tetrahedron Lett. 1977, 393.- According
to the 'H-NMR spectra, heterotetraaromatic compounds with "o,o'-linkage", e. g. i 2 0 ) , exist preferentially in thecisoid conformation in solution
[Job, 681.
P. J . G ~ r r ~Kt ., P. C. Vollhurdt, J. Am. Chem. Soc. 94, 7087 (1972).
J hl. Krumrr, R S. Brrrr, J. Am. Chem. Soc. Y3, 1303 (19711.
~ieterocyclotriaromaticcompounds such ab the phOtOcydizdIiOn product in Scheme 12 number among the fused heterocyclic compounds.
W S. Rupsoii. R . G. Shurtleiwrth. J . N . w i i Niekerk, J . Chem. Soc.
lY43. 326.
a ) G. Wirtig, G. Lehmanii, Chem. Ber. 90, 875 (1957); b) G. Witrig.
0. Rev. Chem. Soc. 20. 205 (1966): c) G. Wirtig, G. Klur. Justus Liebigs
Ann. Chein. 704. 91 (1967); d ) G. Witrig, K.-D. Riinipler. ibid. 751,
I (1971): e ) G. Wittrg, S. Fiscber, G. Rriff; ibid. 1973, 495.
a ) H. A . Sruuh, F . Buiiiig, Chem. Ber. 100, 293, 889 (1967); b) H .
4. Stuuh. H . Bruuiiliny. K . Schiwider. Chem. Ber. I ( J 1 , 879 (1968).
S.Groriowitz, H . - 0 . Kurlsson, Ark. Kemi 17, 89 (1961): R . M . Kellogg,
d P. S c h ~ u p H
. . W!vnhery, J . Org. Chem. 3 4 , 343 (1969): S. Gronowitz,
Acta Chem. Scand. I S , 1393 ( I 961 J.
a) B. Greciiiy, A. Woltcrmaiin, Th. Kauffmunn, Angew. Chem. 86, 475
(1974): Angeu Chem. Int. Ed. Engl. 13, 467 (1974); b) Th. Kauffmunn,
LI. Grrriny. J . Kijniy, A . Mirschker. A. W~ilrermunii,ibid. 87, 745 (1975)
and 1 4 , 713 (1975), respectively.
711.Kofr//manii.B. Greoing. R . Kriegc,smunn, A. Mirschker. A . Wolrermunn,
C'hem. Ber. 1 1 1 , 1330(1978).
H . Irtrgurringrr. 1976. personal communication. The results will be
puhlished in full.
The value is taken from a molecular model [54d] based on electron
diffraction studies by I . L. Kurlr, L. 0. Brotkivny, J. Am. Chem. Soc.
66, I974 ( I 944).
Cf. the analogous alternative for cyclohexa-o-benzene (hexa-o-phenylene): [54d] and L. Ernst. A. Mannsrhreck. K.-D. Riiinpler, Org. Magn.
Reson. 5. 125 (1973).
G. hi. Dat'irs. P S . Daoies, Tetrahedron Lett. 1972, 3507.
L J . P a i i d ~ a ,D. S . Ruu. 8. D. Rlak, J. Sci. Ind. Res. Sect. B 18, 516
(1939); Chem. Abstr. 54, 1739d (1960); for an improved preparation,
see [ 5 8 ] .
A . . W r r . d i k r r , Universitiit Miinster, experiments performed in 1975.
R Krirg<,.\mann, Diplomarbeit, Universitit Miinster 1976.
We designate cyclopolyaromatic compounds having aromatic ring
member, of the same kind (not necessarily joined by the same kind
of bond) as "homotypic" and those with different kinds of aromatic
ring inembers as "heterotypic".
F R . S u p Dissertation, Universitat Miinster, projected for 1979.
D. 71glrr, Dissertation, Universitat Miinster 1977.
Tli. Kuuffniuiin, B. M u k e , R. Otrer, D. Tiyler, Angew. Chem. 87, 746
(1975): Angew. Chem. Int. Ed. Engl. 14, 714 (1975).
A . Marrrr, M. Sieqrist, Helv. Chim. Acta 57, 1988 (1974).
After passage of oxygen into T H F solutions of organocopper(1) compounds (c.y. 2-cuprothiophene) at cu. -60°C the mixture exploded
on three occasions when warmed to room temperature in our laboratory,
probably due to decomposition of peroxides of THF. We have found
room temperature oxidation of the organocopper(1) compounds with
oxygen to be a more favorable method.
D. '4. S b i r h , B. H . Gross, P. A . Roussel, J . Org. Chem. 20, 225 (1955).
Preparation of the new compound (31 d ) by reaction of o-bromoaniline
with 2.5-dimethoxytetrahydrofuran in glacial acetic acid (yield 93 %)
Anyew. C'licn. lnt. E d . Enql. 18, 1-19 (1979)
[40b]; corresponding preparation of ( 3 2 ~ )(yield 36
N. Elmiiig,
3. Cluu.soii-Kuus, Acta Chem. Scand. 6. 867 (1952).
[74] B. Muke, Dissertation, Universitat Miinster 1976.
[75] H . Irngartiriger. L . Lriserowrz, G. M. J . Schmidt, Chem. Ber. 103,
1132 (1970).
[76] X-Ray structure analysis of ( 3 3 ) and 1 4 6 h ) : H . G . roii Schnwing.
G . Sawir:ki, 1976177, personal communication. The results will be published in detail elsewhere.
1771 H . A. Stuab, E . Wehinger, Angew. Chem. 80, 240 (1968): Angew. Chem.
Int. Ed. Engl. 7, 225 (1968).
[78] F. K;gile, M . Arzmiillrr, W Wt'hner, J . Griirze, Angew. Chem. 89. 33X
(1977): Angew. Chem. Int. Ed. Engl. 16. 325 (1977).
[79] The low yield of ( 3 7 h ) is probably due in part to the fact that ( 3 7 0 )
is also lithiated at the benzene nucleus (threelold "external lithiation"
is accompanied by double "internal lithiation"). The
of the two I-pyrazole groups in ( 3 7 b ) is supported the significant
upfield shift of the 'H-NMR signals (in CDCI,) of the pyrazole protons
of 1 3 7 b ) (d=7.79) relative to those of ( 3 7 ~ (6=7.98)
)
(cf. ref. [XI).
[80] 'H-NMR signals (in CDCI,) of the phenylene groups of [2.2]paracyclophane. [2.3]paracyclophane, and p-xylene: (5 =6.37. 6.48, and 7.05 ( H .
Hopf, Angew. Chem. 84, 471 (1972); Angew. Chem. Int. Ed. Engl. 11,
419 (1972); D. J . Cram, R. C. Helgeson, J. Am. Chem. Soc. X8, 3515
(1966); High Resolution NMR, NMR Spectra Catalog, Instrument Division of Varian Associates, Palo Alto, California 19621.- Concerning
interpretation of the upfield shift for aromatic rings arranged face to
face in phanes, see M . Huenel, H . A . Sruub, Chem. Ber. 106. 2203
(1973): C. E . Johiison, Jr.. F. A . Bouer. J. Chem. Phys. 29, I012 (1958).
[81] Th. Kuuffmunn, D. Tigler, A . Wiltermuiin, Tetrahedron Lett. 1Y77, 741.
[82] Increase in yield from 35 % 1681 to 56 % by lowering the reaction
temperature from 20 to 0 °C ; H. Rohkriiliinrr. Diplomarbeit. Universitit
Mhnster 1977.
[X3] The N-acylimidazoles designated as imidazolides (see H . A Stuoh,
Angew. Chem. 74, 407 (1962): Angew. Chem. Int. Ed. Engl. 1. 351
(1962)) have a carbonyl activity resembling that of acyl halides. The
electrophilicity ofthe electrophilic heteroaromatic species is correspondingly enhanced in heterodiaromatic compounds analogous to imidazolides [81].
[84] The favorable effect of CuF, o r NiF, on cyclizations was discoved
by accident on attempted coupling of lithiated heterodiaromatic compounds with these nuorides [26].
[ 8 5 ] Synthesis of Arh,-Arb combinations of quinoxaline under these conditions, see: M . Ghanem. Diplomarbeit, Universitht Miinster 1974.
[86] Owing t o the unfavorable position of this signal the site of lithiation
could not be determined by 'H-NMR spectroscopy of the deuterolysis
product in this case.
[87] W. Briiikwertk, Dissertation, Universitat Miinster 1975.
[ 8 8 ] S. Gronowirz, J . Riie, Acta Chem. Scand. 19, 1741 (1965).
[89] H . P. Mackowiuk, Dissertation, Universitat Miinster 1977.
[90] The position of the acetyl groups in the two diacetyl compounds accessible in 20 "/, yield each under more drastic conditions could not be
elucidated [89].
[YI] The molar ratio ( 2 4 ~: )thiophene (bithiophene): acetyl chloride: SnCI4
is 0.5: 1 : 1 : I in the competition experiments with ( 2 4 a ) + thiophene
o r 2,2'-bithiophene. This ratio was chosen in order that the substrates
should present equal numbers of active sites to attack by acetyl chloride
(cf. ref. 1423).
[92] Monobromination succeeds with N-bromosuccinimide: N g . Pli. Buu-Hoi,
Justus Liebigs Ann. Chem. 556, 1 (1944).
[93] H . P. M u c k w i u k , Universitiit Miinster, unpublished measurements performed in 1977.
[94] Research report: Th. Kuuffinunii, Forschungsberichte des Landes Nordrhein-Westfalen. No. 2450. Westdeutscher Verlag, Opladen 1975.
19
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