Symmetrically tetrasubstituted [2.2]paracyclophanes: Their systematization and regioselective synthesis of several types of bis-bifunctional derivatives by double electrophilic substitution

DOI: 10.1002/chem.200701683

Symmetrically Tetrasubstituted [2.2]Paracyclophanes: Their Systematization

and Regioselective Synthesis of Several Types of Bis-Bifunctional Derivatives

by Double Electrophilic Substitution

Natalia V. Vorontsova,^[a]Valeria I. Rozenberg,*^[a]Elena V. Sergeeva,^[a]

Evgenii V. Vorontsov,^[a]Zoya A. Starikova,^[a]Konstantin A. Lyssenko,^[a]and

Henning Hopf*^[b]

Abstract: The possible number of

chiral and achiral tetrasubstituted

[2.2]paracyclophanes possessing differ-

ent types of symmetry (C₂, C_i, C_s, C_2v,

C_2h) is evaluated and a unified inde-

pendent trivial naming descriptor

systemis introduced. The reactivity

and regioselectivity of the electrophilic

substitution of the chiral pseudo-meta-

and achiral pseudo-para-disubstituted

[2.2]paracyclophanes are investigated

in an approach suggested to be general

for the synthesis of bis-bifunctional

[2.2]paracyclophanes. The mono- and

diacylation of chiral pseudo-meta-

rivatives. The same reaction with ben-

zoylchloride is neither regio-, nor che-

moselective, and gives rise to a mixture

of ortho-/para-, mono-/diacylated com-

pounds 27–31. The double acylation of

mination may be directed towards

mono- 36 or disubstitution 37 products

chemoselectively by varying the reac-

tions conditions. The diacylation and

dibromination reactions of the respec-

tive achiral diphenol 12 and bis(me-

thoxycarbonyl) 40 derivatives of the

pseudo-para-structure retain regiose-

lectivities which are characteristic for

their pseudo-meta-regioisomers. Imino

ligands 26, 25, and 39, which were ob-

pseudo-meta-dimethoxy

A

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tive. Electrophilic substitution of

pseudo-meta-bis(methoxycarbonyl)-

A

N

generates the pseudo-gem-substitution

pattern. Formylation of this substrate

produces the monocarbonyl derivatives

35 only, whereas the Fe-catalyzed bro-

tained fromomnoacyl-

22 and

diacyldihydroxy[2.2]paracyclophanes

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21, 38, are tested as chiral ligands in

stereoselective Et₂Zn addition to ben-

zaldehyde producing 1-phenylpropanol

with ee values up to 76%.

dihydroxy[2.2]paracyclophane 14 with

G

Keywords: asymmetric catalysis

·

acetylchloride occur ortho-regioselec-

tively to produce tri- 22, 23 and sym-

metrically 21 tetrasubstituted acyl de-

cyclophanes · electrophilic substitu-

tion · regioselectivity · resolution

Introduction

Ever since [2.2]paracyclophane (1) was first prepared by

Brown and Farthing nearly 60 years ago^[1]this prototypical

layered organic molecule (and as such the sister molecule of

layered metal organic compounds: ferrocene) has attracted

the interest of numerous chemists. Whereas during the first

part of the history of this remarkable three-dimensional aro-

matic compound preparative, structural and spectroscopic

questions stood in the foreground of research, in more

recent times a shift of interest towards application of 1 and

its derivatives—often in areas far apart fromsynthetic

chemistry—is discernible. For example^[2]the use of cyclo-

phanes in materials chemistry and asymmetric catalysis are

present-day central topics in the field. The bonding of two

[a] Dr. N. V. Vorontsova, Dr. V. I. Rozenberg, Dr. E. V. Sergeeva,

Dr. E. V. Vorontsov, Dr. Z. A. Starikova, Dr. K. A. Lyssenko

A. N. Nesmeyanov Institute of Organoelement Compounds

Russian Academy of Science, Vavilova 28

119991 Moscow (Russia)

Fax : (+7)095-135-5085

E-mail: ineos-ghkl@yandex.ru

[b] Prof. Dr. H. Hopf

Institute of Organic Chemistry

Technical University of Braunschweig, Hagenring 30

38106 Braunschweig (Germany)

Fax : (+49)531-391-5388

E-mail: h.hopf@tu-bs.de

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FULL PAPER

parallel benzene rings in close proximity provides three-di-

mensional (3D) structures with unique electronic properties,

extremely useful for the design of new materials fulfilling

the requirements of nonlinear optics, optoelectronics, chemi-

cal sensing materials,^[3]liquid crystallinity,^[4]and photolumi-

nescent conjugated polymers.^[5]Substituted [2.2]paracy-

clophanes treated under chemical vapor deposition (CVD)

conditions furnish poly-para-xylylene films which impart

useful properties to the coated surface.^[6]At the same time

the planar chirality of cyclophanes, connected with high

thermal (up to 2008C) and chemical stability (towards the

action of acids and bases), has proven useful for the con-

struction of a variety of efficient chiral ligands.^[7]

Up to now the majority of the investigations in all these

areas were carried out with mono- and disubstituted paracy-

clophanes whereas the share of tri-, tetra- and polysubstitut-

ed derivatives was meagre. One of the possible reasons is

the absence of convenient techniques to prepare the respec-

tive compounds. Tetrasubstituted [2.2]paracyclophanes are

commonly approached in two general ways based on the for-

mation of the cyclophane scaffold: i) by the well-elaborated

dithiacyclophane route, that is, the initial synthesis of 2,11-

Figure 1. Bis-bifunctional cyclohexadienols 2.

In such ligands the hydroxy groups, bound to the

[2.2]paracyclophane scaffold and arranged pairwise with

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functional groups of the aryl fragments, form two independ-

ent systems, both of which are capable of coordination with

a metal or metal containing fragment. These compounds

function as chiral inductors in the enantioselective addition

of diethylzinc to benzaldehyde (up to 93.5% ee).^[15b]

Among other synthetic techniques applied for the synthe-

sis of tetrasubstituted [2.2]paracyclophanes, little attention

has so far been paid to an approach that is very attractive

fromthe synthetic point of view: the double electrophilic

substitution of suitably disubstituted [2.2]paracyclophanes

(possessing two identical functional groups), allowing the

one-step introduction of a pair of two other identical func-

tional groups and thus the synthesis of symmetrical tetrasub-

stituted compounds. This approach is illustrated in the litera-

ture by isolated examples only so far, for example para-re-

gioselective dibromination of pseudo-ortho-dibromo-

dithia[3.3]paracyclophanes already bearing the substituents

G

in appropriate positions of the aromatic rings,^[8]followed by

sulfur extrusion via pyrolysis^[9a]or photolysis^[9b]or, ii) by the

Diels–Alder cycloaddition of 1,2,4,5-hexatetraenes with

symmetrically or unsymmetrically substituted acetylenes^[10]

producing, as a rule, mixtures of regioisomers. Another ap-

proach is based on polysubstitution of [2.2]paracyclophane

(1) itself, such as, for example, direct tetrabromination with

Br₂(cat. Fe),^[11a]in liquid Br₂(cat. I₂),^[11b]or a sonication-as-

sisted tetrabromomethylation,^[3c]producing in each case

mixtures of chiral and achiral derivatives (see below), re-

spectively. Further stepwise substitution of these brominated

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homo-tetrasubstituted paracyclophanes gave rise to

a

number of regioisomeric two-donor/two-acceptor deriva-

tives.^[3c]It is clear that all these approaches suffer frompoor

regioselectivity. Only very recently has the improved Hof-

mann 1,6-elimination technique been suggested as a regiose-

lective route to synthesize several symmetrical di-, tetra-,

and octasubstituted [2.2]paracyclophane derivatives, as well

as the parent hydrocarbon itself.^[12]

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ortho-dibromo[2.2]paracyclophane is also para-regioselec-

G

tive,^[17]whereas acylation, oxaloylation, and formylation of

this substrate para-regioselectively produce the monocar-

bonyl compounds only.^[18]A single example of pseudo-gem-

regioselective bromination of unsymmetric 4-bromo-5-

In our line of research, polysubstituted [2.2]paracy-

clophane derivatives would be a further contribution to a

study of [2.2]paracyclophanes of variable structure applica-

diethylcarbamoyl

[2.2]paracyclophane is also known.^[19]

E

Here we present the first direct electrophilic substitution

of C₂-symmetrical chiral pseudo-meta-^[20]and C_i-symmetrical

achiral pseudo-para-disubstituted [2.2]paracyclophanes as an

approach to the chemo- and regioselective synthesis of tetra-

substituted [2.2]paracyclophanes. We also have evaluated

the number of all possible symmetrical tetrasubstituted

[2.2]paracyclophanes containing substituents in their aro-

matic rings, describe their symmetry properties, and intro-

duce a convenient descriptor system for naming them. First

results of the usage of some polysubstituted [2.2]paracy-

clophanes as chiral inductors in asymmetric catalysis are

also reported.

ble as planar chiral ligands in asymmetric catalysis,^[13]as

[14]

monomers for poly-para-xylylene filmsynthesis

or for the

investigation of liquid crystalline properties.^[4]As the first

example of multichiral C₂-symmetric bis-bifunctional

[2.2]paracyclophanes, diastereomerically and enantiomeri-

cally pure cyclohexadienones (R_p,4R_c,7R_c,4,23R_a,7,17R_a)-cis-

4,7-diarylsubstituted-4,7-dihydroxy-4,7-dihydro

A

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axial chirality, Figure 1) were recently synthesized by us via

a stereospecific reaction of ortho-substituted aryllithiumre-

agents with [2.2]paracyclophane-4,7-quinone.^[15]

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V. I. Rozenberg, H. Hopf et al.

Results and Discussion

carbon atoms of the upper ring now carry the lower num-

bers.^[24b]These two nomenclature systems hence give dissim-

ilar names to compound of type 3 (which is either a 4,16- or

a 4,12-disubstituted [2.2]paracyclophane). The other com-

monly used system^[8,9,25,26]numbers carbon atoms in the

second ring by ascribing the lower number to the substitu-

ent-carrying carbon atoms. However, this system does not

allow one to distinguish between the front and back sides of

the molecule and, consequently, to describe properly the re-

spective regioisomers (for example, both 3 and 4 would be

4,12-disubstituted in this case (Figure 3, right).

Statement of the problem: The rapid progress in preparative

[2.2]paracyclophane chemistry has brought forth a large

number of differently polysubstituted [2.2]paracyclophanes,

among which those with four aromatic substituents in a sym-

metrical substitution pattern have attracted the interest of

chemists because of their possible use in various areas of

modern chemistry (see below: Prospects). Such symmetrical

compounds could possess very diverse substitution patterns,

either chiral or achiral, homo- or heterosubstituted, and

comprise in their structures two chemically and, in the case

of chiral compounds stereochemically identical functional

units. We suggest to designate themas bis-bifunctional

[2.2]paracyclophanes (Figure 2). In our opinion, one of the

more important questions is the proper description of the

array of substituents in these derivatives.

The recently recommended IUPAC Phane Nomencla-

ture^[27a,b]which demands the use of the lowest locants

rule^[27c]in numbering of the respective substituents attached

to the simplified skeleton also does not discern the regioiso-

mers.^[27d]For disubstituted [2.2]paracyclophanes, the proper

description could be done by using the “pseudo”-prefixes

suggested by Cram,^[28]which unequivocally define the

mutual arrangement of two substituents (for example, disub-

stituted [2.2]paracyclophanes 3 and 4 would be pseudo-para-

and pseudo-ortho-, respectively, Figure 3).

For tetrasubstituted chiral and achiral derivatives the am-

biguities in their description prompted chemists to add dif-

ferent prefixes or epithets to designate the mutual arrange-

ment of the substituents, that we would like to illustrate by

selected examples. Thus, structures of both pairs of chiral

bis-bifunctional regioisomeric compounds 5 and 6 (4,7-dime-

thoxy-12,15-dinitro-^[9]and 4,7-dicyano-12,15-dimethoxy-,^[25]

Figure 4, left), were described as pseudo-ortho- or “stag-

gered” for 5 and pseudo-geminal or “eclipsed” for 6. On the

other hand, homo-tetrasubstituted compounds (achiral 7

and chiral 8, Figure 4, right) were discerned as either ortho–

ortho- and para–para (R=CH₂Br^[3c]or OMe^[8,9]) or pseudo-

para and pseudo-ortho- (R=Br).^[12]Nevertheless, the usage

of such prefixes does not only make the nomenclature

system more cumbersome but it also often does not provide

an unambiguous representation of the structure.

Figure 2. Examples of bis-bifunctional [2.2]paracyclophanes.

Such an extension is necessary since at least three differ-

ent nomenclature systems are used in the present chemical

literature for the naming of [2.2]paracyclophane derivatives.

In all these systems the numbering of the bridge carbon

atoms and of the aromatic carbons of the first ring are the

same and accepted as originally proposed by Cram^[21]

(Figure 3). These systems differ, however, as to how the

carbon atoms should be numbered in the second ring. Thus,

in the first numbering scheme the front-side (facing) carbon

atoms of each aromatic ring of the [2.2]paracyclophane mol-

ecule have lower numbers than their respective back-side

atoms (Figure 3, left structure 3).^{[13,19,22,23]}Working on the

numbering of multibridged [2_n]cyclophanes, Boekelheide^[24a]

suggested to number all carbons in aromatic rings in a clock-

wise manner, starting each time from the nearest bridgehead

(Figure 3, right structure 3). In the case of [2.2]paracy-

clophane this leads to a situation, in which the back-side

Figure 4. Selected examples of distinguishing between regioisomeric tet-

rasubstituted [2.2]paracyclophanes.

We have hence decided to develop a unified, comprehen-

sive, and self-consistent descriptor systemfor the naming of

symmetrical tetrasubstituted [2.2]paracyclophane derivatives

with substituents in their aromatic rings. As the first step we

calculated the possible number of such compounds by a

combinatorial approach^[29]and found that there could be 28

items: 7 structural isomers with four equal substituents X

Figure 3. Different nomenclature systems commonly used for numbering

of [2.2]paracyclophane derivatives.

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Symmetrically Tetrasubstituted [2.2]Paracyclophanes

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(homosubstituted) and 21 isomers with two pairs of different

substituents X and Y (heterosubstituted). The second step

involves the systematization of these compounds by substi-

tution patterns and types of symmetry. With this aim we ap-

proached the tetrasubstituted symmetrical [2.2]paracy-

clophanes as derivatives of the respective disubstituted

[2.2]paracyclophanes of seven possible substitution patterns

(three chiral and four achiral).^[30]The rule proposed by us

for an accurate estimation of the novel patterns (so-called

“homonymous substitution” rule) is presented below in

detail for chiral compounds and then expanded to respective

achiral compounds. The third step consist of the construc-

tion of the descriptors for each novel pattern, and for this

purpose we have decided to chose the combination of the

usual prefixes (ortho-, meta-, and para-) with Cramꢁs

“pseudo”-prefixes (pseudo-ortho-, pseudo-meta-, pseudo-

para-, and pseudo-gem-) which have been accepted and

used for a long time in [2.2]paracyclophane chemistry.

each type the C₂axis of the parent origin is retained

(Figure 5).

Homosubstitution (i.e., by a pair X–X) of each origin, A–

C, produces several additional patterns; however, only one

of these, D (a superposition of A2, B2, and C2), is chiral

and describes the single chiral homo-tetrasubstituted

[2.2]paracyclophane of D₃symmetry^[30](Figure 5).

Symmetrical achiral tetrasubstituted [2.2]paracyclophanes:

Apart fromten chiral C₂-symmetrical tetrasubstituted deriv-

atives one can consider 18 additional achiral bis-bifunctional

regioisomers. Thus the application of the “homonymous

substitution” rule to four achiral origins (ortho- (E), meta-

(F), pseudo-gem- (G) of C_ssymmetry, and pseudo-para- (H)

of C_isymmetry) produces twelve novel patterns (E1–E3 to

H1–H3) as a result of Y–Y heterosubstitution (Figure 6).

Again within each four types the symmetry of the parent

origin is retained.

The homonymous X–X homosubstitution of four achiral

disubstituted origins E–H finally gives rise to the next six re-

gioisomers I–N of C_2vand C_2hsymmetry (Figure 7).

Thus, we have specified all possible patterns of tetrasub-

stituted symmetrical [2.2]paracyclophanes as 7 homo- and

Symmetrically tetrasubstituted [2.2]paracyclophane deriva-

tives: symmetry properties and unified descriptor system for

their denotation

C₂-Symmetrical chiral tetrasub-

stituted [2.2]paracyclophanes:

The first generation of chiral

C₂-symmetrical

[2.2]paracy-

clophanes is presented by deriv-

atives which are X,X-disubsti-

tuted in their aromatic rings

and belong to three patterns

(para- (A), pseudo-ortho- (B),

and pseudo-meta- (C), differing

in the orientation of the C₂-

axis^[30](Figure 5). The next gen-

eration

[2.2]paracyclophanes (namely,

tetrasubstituted derivatives)

of

C₂-symmetrical

arises by heterosubstitution of

the parent patterns A–C (chiral

origins) by the pair of substitu-

ents Y–Y of the same substitu-

tion pattern (“homonymous

substitution”, namely para- (A)

by para-, pseudo-ortho- (B) by

pseudo-ortho-, and pseudo-

meta-substituted pattern (C) by

pseudo-meta- pair Y–Y), and

each chiral origin structure A–

C can bind the Y–Y pair in

three possible ways. Thus the

combination of three disubsti-

tuted origins (A–C) with three

possible incoming substitutions

leads to the formation of nine

tetrasubstituted chiral patterns:

Figure 5. C₂-Symmetrical planar chiral [2.2]paracyclophanes: three disubstituted origins A–C and ten tetrasub-

stituted patterns (A1–A3, B1–B3, C1–C3, and D) for bis-bifunctional derivatives. In this Figure we will use the

A1–A3, B1–B3, C1–C3; within prefix “ps-” instead of “pseudo-” for brevity.

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V. I. Rozenberg, H. Hopf et al.

21 heterosubstituted variants, among which 10 are chiral and

18 are achiral.

Construction of the descriptors: In accordance with our pro-

posal, the descriptor for every symmetrical tetrasubstituted

[2.2]paracyclophane derivative may be constructed by suc-

cessive specification of three prefixes chosen fromseven

possible patterns which describe the relationship between

substituents in the molecule of [2.2]paracyclophane (ortho-,

meta-, para-, pseudo-ortho-, pseudo-meta-, pseudo-para-,

and pseudo-gem-). Thus, the descriptor may be constructed

by successive specification of three prefixes as follows:

*

The first prefix bis- is multiplicative and indicates the

presence of two identical pairs of functional groups;

*

the last prefix in the sequence denotes the mutual ar-

rangement of these pairs and refers to the positioning of

the identical substituents (X vs X and Y vs Y); for C₂-

symmetric compounds it always describes a chiral ar-

rangement;

*

the middle prefix (in brackets) denotes the relative posi-

tions of different substituents in these pairs (X vs Y, the

so-called in pair descriptor).

There is a choice to be made between two in pair descrip-

tors possible for each of the structures (for example, para-

or pseudo-ortho- for C2, Figure 3). In principle, one may

arrive at the drawing of the same structure regardless of

which of the two prefixes is used. For the preference we sug-

gest a simple criterion, namely, the shorter path (i.e., smaller

number of chemical bonds) from X to Y along the paracy-

clophane scaffold (which is para- in the present example).

This preference is related with the lowest locant rule^[27c]of

IUPAC nomenclature according to which the pair of sub-

stituents X and Y of one functional unit would be numbered

as 4- and 7- (rather than 4- and 12-). So, the model structure

C2 would be called bis-(para)-pseudo-meta. However, for

the chemists working, for example, in asymmetric synthesis,

the other descriptor, namely bis-(pseudo-ortho)-pseudo-

meta, would be more informative, for it displays the location

of the functional groups X and Y on the same side of the

plane passing through the four bridge carbon atoms and re-

flects the ability of these groups for coordination. The de-

scriptors for all other chiral and achiral structures are pre-

sented in Figures 5 and 6. In two cases only (F2 and F3),

when both pairs of prefixes are accountable for equal

amounts of chemical bonds, the preference would be made

for those, which describe the location of the functional

groups X and Y on the same side of the plane passing

through the four bridge carbon atoms (pseudo-ortho- rather

than pseudo-para- for F2 and pseudo-gem- rather than

pseudo-meta- for F3).

Figure 6. C_s- and C_i-Symmetrical achiral [2.2]paracyclophanes: four achi-

ral disubstituted origins E–H and twelve novel patterns (E1–E3, F1–F3,

G1–G3 and H1–H3) for tetrasubstituted bis-bifunctional derivatives.

Homo-tetrasubstituted [2.2]paracyclophanes may be

named by choosing the last and the middle prefixes fulfilling

the criterion of the shorter X–X path drawn along the para-

cyclophane scaffold. In this case, the last prefix would

always describe the arrangement of two X substituents in

Figure 7. Six patterns of C_2v- and C_2h-symmetrical achiral homo-tetrasub-

stituted [2.2]paracyclophanes.

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Symmetrically Tetrasubstituted [2.2]Paracyclophanes

FULL PAPER

the same aromatic ring and would have preference over the

middle prefix in resolving the ambiguous cases. For example,

to name structure I (with all substituents in the same aro-

matic ring, Figure 5), one would choose ortho- rather than

meta- or para- for the last prefix, and then meta- rather than

para- for the middle prefix. The K and N regioisomers, with

substitution patterns resembled by F3 and F2, respectively,

would have their preferable middle prefixes as pseudo-gem-

and pseudo-ortho- in a similar way. The single chiral homo-

substituted structure D (which resembles A2, B2, and C2 at

a time) in accordance with the preference criteria could be

named as bis-(pseudo-meta)-para (Figure 5). For the full set

of these descriptors see Figures 5–7.

of an improved separation procedure (see Experimental

Section). Similar bromination and an alternative separation

technique, recently described by one of us,^[32]yielded the di-

bromides 9 and 10 in 38 and 31% yield, respectively.

These simple bromination and separation techniques^[31,32]

allow to carry out the reaction on a larger scale (up to 25 g

per single run), thus making dibromides 9 and 10 readily

available for further transformations. Dibromide 10 could

also be used for the synthesis of the pseudo-ortho-dibromide

11,^[33]a precursor for the paracyclophane derived diphos-

phine ligand PHANEPHOS, its analogues,^[34]and for a

number of promising unsymmetrical N,N-, N,P-,^[35]N,O-,

and O,O-ligands.^[36]

The proposed descriptor systemis unified and independ-

ent, and so could be used for the naming of all symmetrical

tetrasubstituted [2.2]paracyclophanes in addition to any no-

menclature. For example, compounds from Figure 4 could

be named now as bis-(pseudo-meta)-para 5, bis-(pseudo-

gem)-para-6, bis-(pseudo-meta)-ortho 7 and bis-(pseudo-

meta)-para 8, and as is clear fromthe Figure, both hetero-

and homo-tetrasubstituted paracyclophanes 5 and 8 of the

similar substituted pattern have identical descriptors.

Starting fromdibromides 9 and 10 we have carried out

the synthesis of several novel as well as already described

disubstituted [2.2]paracyclophanes. The choice of functional

substituents, attached to the [2.2]paracyclophane scaffold

(OH, OMe, and COOMe), was based on known regularities

of ortho-, para-^[13d,o]and pseudo-gem-regioselective^[13k,37]

electrophilic substitution, revealed earlier for the monosub-

stituted [2.2]paracyclophanes. Achiral pseudo-para-diphenol

12 was obtained fromdibromide 10 in accordance with the

described procedure (Scheme 1).^[11]For the synthesis of

It should be noted that the same naming principle may

also be applied to a similar classification of bis-trifunctional

and bis-tetrafunctional [2.2]paracyclophanes.

pseudo-meta-dihydroxy[2.2]paracyclophane 14 several differ-

G

ent transformations were employed (Scheme 2). First, by

analogy to the synthesis of the respective pseudo-para-dihy-

Regioselective electrophilic substitution reactions

droxy- (12)^[11a]and pseudo-ortho-dihydroxy

ACHTREUNG

AHCTREUNG

Synthesis of starting materials: As starting materials for the

synthesis of pseudo-para- and pseudo-meta-disubstituted

[2.2]paracyclophanes, the respective dibromides were select-

ed. Several years ago we have worked out a non-catalytic di-

bromination of [2.2]paracyclophane 1 with Br₂and a separa-

tion technique which allowed us to isolate pseudo-para-

of dibromide 9 followed by oxidation of the intermediate di-

lithio derivative with nitrobenzene. This reaction produced

the target diphenol 14, however in low yield (30%), attrib-

utable to formation of brownish sticky side products which

prevent easy isolation of 14. The “classical” Li/B exchange

with trimethylborate followed by oxidation of the respective

boronic esters with H₂O₂/NaOH^[39]failed to produce 14, and

dibromo[2.2]paracyclophane (10, 40%) and its pseudo-meta

A

isomer (9, 10%, Scheme 1).^[31]This is in contrast to Cramꢁs

Fe-catalyzed dibromination where the respective dibromides

10 (26%) and 11 (pseudo-ortho, 16%) were isolated as the

main products.^[11a]In the present work the pseudo-meta-di-

bromide 9 has been isolated in higher yield (43%) by means

Scheme 2. Synthesis of the starting pseudo-meta-[2.2]paracyclophanes.

a) 2.4 equiv nBuLi, Et₂O, RT, then PhNO₂, À788C; 30%; b) 1.2 equiv

nBuLi, Et₂O, RT; then B(OMe)₃, then H₂O₂/NaOH; 86%; c) 1.2 equiv

G

nBuLi, Et₂O, RT; then B

ACHTREUNG

nBuLi, THF, À788C; then B

AHCTREUNG

Scheme 1. Non-catalyzed dibromination of [2.2]paracyclophane 1. a) Br₂,

Fe, CCl₄, 98%; b) benzene, 2008C, autoclave 24 h;^[13a]c) nBuLi, THF,

PhNO₂.^[11a,37]

DMF, then MeI, 87%; f) NaH/DMF, then MeI, 80%; g) 2.4 equiv nBuLi,

Et₂O, RT; then CO₂, then HCl; 74%; h) SOCl₂, CHCl₃/DMF; then

MeOH, 78%.

Chem. Eur. J. 2008, 14, 4600 – 4617

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4605

V. I. Rozenberg, H. Hopf et al.

nothing but parent [2.2]paracyclophane (1) and 4-hydroxy-

[2.2]paracyclophane (15) were isolated fromthe reaction

mixture.

This prompted us to elaborate a stepwise synthetic proto-

col. Monolithiation of the bromide 9 with nBuLi in Et₂O at

roomtemperature, Li/B exchange and oxidation gave rise to

First we examined the acylation of the pseudo-meta-di-

phenol 14 under our standard conditions^[13d]with twofold

excess of the reagents (3 equiv of AcCl, 3 equiv of TiCl₄,

CH₂Cl₂, roomtemperature) and found that three products

(ortho-structure exclusively) were found in almost equal

amounts here, namely, the desired diacylation product: 1,1’-

ACHTREUNG

4-bromo-15-hydroxy

G

[5,16-dihydroxy[2.2]paracyclophane-4,15-diyl]diethanone

N

cal yield (Scheme 2). Due to difficulties in purification, a

portion of the phenol 16 was converted into the respective

methyl ether 17, which was then fully characterized. Crude

16 was again used in the lithiation/electrophilic substitution

reaction to produce the target diphenol 14. Roomtempera-

ture lithiation in Et₂O has been found more efficient than

that at low temperature (À788C) in THF (87 vs 18% yield).

Diphenol 14 was next transformed into the respective di-

methyl ether 18^[23]by a standard methylation procedure. It

should be noted that the intermediate brominated mono-

phenol 16 looks very attractive as a starting material for fur-

ther unsymmetrically disubstituted [2.2]paracyclophanes of

the pseudo-meta type, as reported earlier for the respective

brominated monophenol of pseudo-ortho-structure.^[34,35]

In contrast to the lack of reactivity of the intermediate di-

lithio derivative with trimethylborate, its reaction with solid

CO₂(similar to the synthesis of the respective regioisomeric

dicarboxylic acids with pseudo-para-^[40a]and pseudo-ortho-

arrangement^[33b]) occurred smoothly and produced, after

acidification of the reaction mixture, pseudo-meta-

(21, bis-(ortho)-pseudo-meta, type C1), monoacylated diphe-

nol 1-[5,16-dihydroxy-[2.2]paracyclophan-4-yl]ethanone (22),

and

its

O-acyl-derivative

16-acetyl-15-hydroxy-

[2.2]paracyclophan-4-yl acetate (23) (Scheme 3, Table 1,

1

entry 1). Their ratio was determined by H NMR analysis.

We have found that larger amounts of the reagents (Table 1,

entry 2) and longer reaction times (Table 1, entry 3) affect

the product ratio only slightly. Treatment of the reaction

mixture with a further portion of the reagents at reflux al-

lowed us to convert 22 into 21, still producing some of the

unfavorable O-acylation product 23 (Table 1, entry 4).

Finally the chemoselective synthesis of 21 (93% isolated

yield, together with 22 and 23 in trace amounts only) was

achieved as follows: a solution of 14 was stirred with TiCl₄

for 1 h (to avoid the formation of any O-acylation products),

then AcCl was added, and the reaction mixture was kept

under reflux followed by further addition of the reagents in

excess (Table 1, entry 5 and Experimental Section). From

the combined reaction mixtures of the unselective reactions

(Table 2, entries 1–4) 21, 22 and 23 have been isolated by

preparative chromatography and fully characterized. Addi-

dicarboxy

[2.2]paracyclophane (19)^[41]in high chemical yield

A

(72%, Scheme 2). Dimethyl

ester 20 was easily obtained

fromthe diacid 19 through the

methoxylation of its respective

bis(acidchloride).

ortho-Regioselective

tion of pseudo-meta-dihydroxy-

[2.2]paracyclophane (14): Re-

diacyla-

ACHTREUNG

cently we have found that the

TiCl₄-catalyzed Friedel–Crafts

acylation

of

4-hydroxy-

ACHTREUNG

AcCl and BzCl in dichlorome-

thane, and Fries rearrangement

of O-acyl-4-hydroxy[2.2]para-

N

cyclophane occur ortho-regiose-

lectively.^[13d]Later Braddock

et al. have applied this ap-

proach to the acylation of

pseudo-ortho-diphenol

13

(PHANOL).^[17]Various reac-

tion conditions were studied,

and it was demonstrated that

the double ortho-regioselective

acylation by valeroyl chloride

may be achieved in 1,2-di-

chloroethane under reflux.

Scheme 3. ortho-Regioselective acylation of 14 and synthesis of diastereomeric imino-ligands 25 and 26.

a) 6 equiv AcCl, TiCl₄, CH₂Cl₂; b) 1.2 equiv (R)-(a)-PEAM, Et₂SnCl₂; c) 2.5 equiv (R)-(a)-PEAM, Et₂SnCl₂;

d) chromatographic separation.

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Chem. Eur. J. 2008, 14, 4600 – 4617

Symmetrically Tetrasubstituted [2.2]Paracyclophanes

FULL PAPER

Table 1. ortho-Regioselective mono- and diacylation of diphenol 14

(0.1m solution in CH₂Cl₂).

Entry 14/TiCl₄/

AcCl ra-

t₁Excess por-

t₂Ratio of the products 21/

[h] tion of TiCl₄/ [h] 22/23^[d](chemical yield of

tio, equiv

AcCl

21)

1^[a]

2^[a]

3^[a]

4^[b]

5^[c]

1:3:3

1:6:6

10

20

10 6:6

–

30:35:35

40:30:30

45:35:20

10 60:35:5

10 95:3:2 (93%)

[a] Roomtemperature. [b] T=408C. [c] TiCl₄was added to a solution of

14 at RT, the mixture was stirred for 1 h, then AcCl was added and the

1

mixture was kept under reflux (T=408C). [d] By H NMR analysis.

Table 2. Asymmetric diethylzinc (2 equiv) addition to benzaldehyde with

imino ligands (L, 10 mol%), toluene, 08C.

Figure 8. X-ray crystal structure of 21. Parameters of hydrogen bonds:

O(1)-H(10)···O(2) 1.76 , O(1)···O(2) 2.522 (2) , a: O(1)H(10)O(2)

1488; O(3)-H(30)···O(4) 1.73 , O(3)···O(4) 2.491 (3) , a:

O(3)H(30)O(4) 1478.

Entry

L

Configuration

of 1-phenylpropanol

ee [%]

1

2

3

4

5

C

(S)

(R)

(S)

36

76

82^[41]

71

ried out (Figure 9); it allowed us to establish the absolute

configurations of this diastereomers as (R,S_p,R)-25.

N

7

Furthermore, we obtained the diastereomeric Schiff bases

26 fromracemic, trisubstituted 22 and (R)-(a)-PEAM to get

AHPC-based imino ligands with modified electronic proper-

ties (Scheme 3). Both (R_p,R)- and (S_p,R)-26 were isolated in

practically quantitative chemical yields after chromato-

tionally for 21 an X-ray investigation was carried out

(Figure 8). The presence of only the half set of signals in the

¹H and ¹³C spectra of 21 reveals the symmetry of the com-

pound. This characteristic spectral feature could be used for

identification of all bis-bifunctional [2.2]paracyclophanes.

As is obvious fromFigure 8 and Scheme 3, C₂-symmetri-

cal diacylated diphenol 21 comprises two chemically and ste-

reochemically identical units with mutual pseudo-meta ori-

entation, both of which mimic the functional part of the 5-

1

graphic separation (de > 99% by H NMR analysis). As for

25 (as well as for the respective AHPC derivatives 24^[13d]),

the less soluble diastereomer of 26 has the higher chromato-

graphic mobility. The X-ray investigation of this diastereo-

mer allowed us to assign its configuration as (S_p,R)

(Figure 10).

It should be noted that in contrast to (R,S_p,R)-25 in which

O-H···O intramolecular H bonds are formed, in the crystal

structure of (S_p,R)-26 the N-H···O H bond is observed. Thus

acetyl-4-hydroxy a well

[2.2]paracyclophane (AHPC),^[13d]

G

known precursor for a series of efficient imino-type ligands

like 24.^[42]This structural simi-

larity prompted us to obtain

bis-bifunctional analogues of

the imino-ligands 24.

Thus

Schiff bases 25 were obtained

(85% chemical yield,

the

diastereomeric

Scheme 2) from racemic bis-

(ortho)-pseudo-meta 21 and

(R)-(a)-phenylethylamine ((R)-

(a)-PEAM). (R,R_p,R)- And

(R,S_p,R)-25 were separated by

preparative

chromatography

(de >99% by ¹H NMR analy-

sis). For the latter diastereomer

(which is less soluble and pos-

sesses higher chromatographic

mobility in toluene/EtOH) an

À

Figure 9. X-ray crystal structure of bis-imine (R,S_p,R)-25. Selected bond lengths [] in H-bonded rings: O(1)

À

C(4) 1.356(4), O(2) C(15) 1.350(4), N(1) C(17) 1.290(5), N(2) C(27) 1.278(4), C(5) C(17) 1.484(4), C(16)

À

C(27) 1.492(4), C(4) C(5) 1.412(5), C(15) C(16) 1.418(5). Parameters of hydrogen bonds: O(1)-H(10)···N(1)

1.73 , O(1)H(10)N(1) 1498, O(1)···N(1) 2.539(4) ; O(2)-H(20)···N(2) 1.63 , O(2)H(20)N(2) 1538,

X-ray diffraction study was car- O(2)···N(2) 2.488(4) .

Chem. Eur. J. 2008, 14, 4600 – 4617

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4607

V. I. Rozenberg, H. Hopf et al.

Figure 10. X-ray crystal structure of Schiff base (S_p,R)-26. Selected bond

À

lengths []: O(1) C(4) 1.305(5), O(2) C(15) 1.368(5), N(1) C(17)

Scheme 4. Acylation of diphenol 14 with benzoylchloride. a) 6 equiv

BzCl, TiCl₄, CH₂Cl₂, RT.

À

1.308(7), C(5) C(17) 1.448 (6), C(4) C(5) 1.449(7). Parameters of hy-

drogen bond: O(1)-H(10)···N(1) 1.56 , O(1)H(10)N(1) 1608, O(1)···N(1)

2.478(9).

NOESY, ¹H-¹³C HMQC and HMBC correlation experi-

ments.

In compounds 28 and 31 two benzoyl groups are placed

opposite the pseudo-gem-position to each other, thus giving

rise to the closure of the etheno bridge with formation of a

rigid “orthogonal cyclophane”, as it was carried out for the

in the latter crystal the equilibriumbetween two possible

tautomers is shifted towards the enamine form. In addition

to the position of hydrogen which was located in the vicinity

À

of N(1) atom, the pronounced variation of the N(1) C(17),

À

C(17) C(5), C(4) C(5), C(4) O(1) bonds (Figures 9–10),

respectively, can serve as an unequivocal support of the

presence of such tautomer in 26. The stabilization of the en-

amine tautomer in 26 may be caused by the fact that an ad-

À

respective diketone pseudo-gem-dibenzoyl

phane under McMurry conditions followed by stilbene–

phenanthrene photocyclization.^[26]

[2.2]paracyclo-

AHCTREUNG

ditional intermolecular

H

bond is established: O(2)

The different chemo- and regioselectivity of the diacyla-

tion reactions of diphenol 14 towards acetyl- and benzoyl-

chloride (in contrast to the exclusive ortho-regioselectivity

of the monoacylation of monophenol 15 under the action of

aromatic and aliphatic acylchlorides^[13d]) reveals that in the

case of more complicated bifunctional compounds, no gener-

al prediction of any clear-cut regioselectivity can be made at

this time, and the reaction conditions should be adjusted

properly, by applying a certain reagent if necessary, in order

to achieve the selectivity desired.

H(2O)···O(1) (y, 2Àx, z+¹= ) (O(2)···O(1) 2.754(7) ,

4

H(2O)···O(1) 1.82 , O(2)H(2O)O(1) 1648), making the

molecules assemble into a chiral helix.

The bis-acylation technique elaborated above was next

applied to the reaction of diphenol 14 with benzoylchloride,

but the reaction was carried out at roomtemperature. In

contrast to the reaction with AcCl and to the results ob-

tained for the acylation of the monophenol 15 (leading to

the single ortho-substituted product, namely, 5-benzoyl-4-

hydroxy

[2.2]paracyclophane (BHPC)),^[13d]this one was nei-

G

ther chemo- nor regioselective, and gave rise to a number of

C/O-acylated products of both ortho- and para-structure

(Scheme 4). Preparative chromatography provided five frac-

tions: the expected ortho-C-diacylated diphenol (5,16-

para-Regioselective diacylation of pseudo-meta-dimethoxy-

AHCTREUNG

dihydroxy

none (27, bis-(ortho)-pseudo-meta, type C1), ortho-para-di-

acylated 5,16-dihydroxy[2.2]paracyclophane-4,13-diyl)bi-

s(phenyl-methanone (28) together with a small amount of

its mono-O-benzoyl derivative 7,16-dibenzoyl-15-hydroxy-

G

reagent ratio for 20 h. As expected, the reaction was para-

regioselective (as found by us for the acylation of 4-

methoxy

dimethoxy

(para)-pseudo-meta, type C2) as the sole product

A

ACHTUNG-

TERUNG

A

(Scheme 5). The substitution pattern of both functional

units in this compound mimics that of the recently obtained

A

12-hydroxy[2.2]paracyclophane-4-carbaldehyde (34, pseudo-

A

and 12-benzoyl-15-hydroxy-[2.2]paracyclophan-4-yl benzoate

(30, para-C). The substitution pattern of 28 was confirmed

by the presence of two singlets at d=5.93 and 6.87 ppm

(para-substituted aromatic ring) and two doublets (³J=

7.8 Hz) at 6.39 and 7.10 ppm( ortho-substituted aromatic

ring). The structures of the more complex O-/C-acylated

FHPC, of the pseudo-ortho-structure), a novel origin for

planar chiral diol^[13o]and iminophenol ligands.^[36b]The syn-

thesis of the bis-bifunctional compound 33 is also envisaged

by deprotection of the hydroxy-groups of 32.

Pseudo-gem-regioselective electrophilic substitution of

1

compounds 29 and 30 were established by a series of H-

pseudo-meta-bis(methoxycarbonyl[2.2]paracyclophane (20):

A

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Chem. Eur. J. 2008, 14, 4600 – 4617

Symmetrically Tetrasubstituted [2.2]Paracyclophanes

FULL PAPER

the formylation, in the bromination reaction with 2.4 mol

equiv of Br₂at room temperature the starting compound

was consumed by 80% (¹H NMR control) already in three

days. This reaction also gave the product of the pseudo-gem-

regioselective

monosubstitution,

dimethyl

8-bromo-

AHCTREUNG

pletely separated fromstarting material 20 by chromatogra-

phy. The next bromination experiment was carried out in a

similar manner, but after three days a huge excess of the re-

agents (up to 10 mol equiv of Br₂in total) was added and

Scheme 5. para-Regioselective diacylation of 18. a) 6 equiv AcCl, TiCl₄,

CH₂Cl₂, 408C, 71%.

1

the mixture was stirred for a further 10 day-period. H NMR

The regioselective pseudo-gem bromination of 4-carboxy-

spectra showed full consumption of 20 and pseudo-geminal

A

regioselective formation of the target dimethyl 8,13-

[37a]

Cramand Reich already,

dibromo[2.2]paracyclophane-4,15-dicarboxylate (37, bis-

G

used for the regioselective substitution of amide and oxazo-

(meta)-pseudo-meta, type C3). The dibromination was accel-

erated by refluxing 20 with 20 mol equiv of Br₂in a 2:1

CH₂Cl₂/CCl₄solvent system. The reaction was complete in

10 h, and the dibromide 37 was isolated by preparative chro-

matography in 88% yield. We believe this compound to be

a promising precursor of a wide range of novel [2.2]paracy-

clophane derivatives obtainable by further chemical trans-

formations of its bromine atoms and/or of its ester groups.

line derivatives of this acid^[19,43]or of 4-tosyl-

[2.2]paracyclophane.^[44]Recently the formylation of 4-

methoxycarbonyl[2.2]paracyclophane was found to be effi-

E

cient for the generation of the pseudo-gem substitution pat-

tern.^[37b]To the best of our knowledge, the only example of

a double pseudo-gem-regioselective substitution, namely, the

chloromethylation

of

para-bis(methoxycarbonyl)-

A

tetrasubstituted derivative.^[16]We have undertaken the inves-

ortho- and pseudo-gem-Regioselective double electrophilic

substitution of achiral pseudo-para-disubstituted [2.2]para-

cyclophanes 12 and 40: To expand the scope of the double

electrophilic substitution onto the synthesis of achiral bis-bi-

functional compounds, we have applied the above diacyla-

tion and dibromination techniques to the achiral 4,16-

tigation of the reactivity and regioselectivity of pseudo-

meta-bis(methoxycarbonyl)

A

(20)

in

double pseudo-geminal substitution reactions.

The formylation of 20 with Cl₂CHOCH₃(2.4 equiv) in the

presence of TiCl₄(4 equiv) in dichloromethane at room tem-

perature was extremely slow and in 13 days went halfway to

completion only. Under these conditions only monoformyla-

tion was achieved (¹H NMR control), even with the set of

the reagents being added three times. However, the process

was highly pseudo-gem-regioselective, and dimethyl 8-

dihydroxy

A

(12)

and

to

4,16-

bis(methoxycarbonyl)

AHCTREUNG

pseudo-para-structure). As expected, both reactions retained

the regioselectivities which are characteristic for their

pseudo-meta regioisomers and produced the respective 1,1’-

formyl

[2.2]paracyclophane-4,15-dicarboxylate (35) was iso-

[5,15-dihydroxy

(38, bis-(ortho)-pseudo-para, type H1) and dimethyl 7,13-

dibromo[2.2]paracyclophane-4,16-dicarboxylate (41, bis-

U

lated fromthe reaction mixture in 49% chemical yield

(Scheme 6); unreacted 20 was recovered in 40% yield.

Next, the Fe-catalyzed, room temperature bromination of

the diester 20 was investigated (Scheme 6). In contrast to

AHCTREUNG

(para)-pseudo-para, type H2, Scheme 7).

Here, we would like to touch upon some points of a spe-

cifically stereochemical interest. Ernst and Wittkowski have

proposed to consider disubstituted [2.2]paracyclophane de-

rivatives with identical groups in both aromatic rings not

only as regio- but also as stereoisomers.^[45]In such com-

pounds there are two constitutionally equal planes of chirali-

ty, passing through the planes of both aromatic rings, and

optical activity depends on the sense of chirality of these

two elements. That is the reason why, for example, biphenols

13 and 14 (with R stereochemical descriptors for both aro-

matic rings, {R_p,R_p}^[46]) may be regarded as internal (intra-

molecular) “chiral diastereomers”, whereas biphenol 12 is

described as {R_p,S_p}, and so is an internal achiral “meso-com-

pound” (Scheme 7). The same statements are true for all

compounds of chiral (A–C) and achiral patterns (E–H) as

well as for the respective symmetrical tetrasubstituted

[2.2]paracyclophanes derived fromthem.

Scheme 6. Pseudo-gem-regioselective electrophilic mono- and disubstitu-

tion of 20. a) 6 equiv Cl₂CH₂OCH₃, TiCl₄, 49%; b) 2 equiv Br₂, Fe, RT,

3 d, 80%; c) 10 equiv Br₂, Fe, RT, 10d, 93%; d) 20 equiv Br₂, Fe, T=

428C, 10 h, 88%.

However, the reaction of achiral 38 with two equivalents

of (S)-(a)-PEAM furnishes an interesting Schiff base

Chem. Eur. J. 2008, 14, 4600 – 4617

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4609

V. I. Rozenberg, H. Hopf et al.

Figure 11. Intramolecular stereochemical analogues for bis-iminoligands

25 and 38.

(R,{R_p,R_p},R)-25), may be compared with structurally and

A

stereochemically symmetrical salens such as ((S_p,R,R,S_p)-42

or (R_p,R,R,R_p)-42, Figure 11, right).

Enantioselective diethylzinc addition to benzaldehyde

To estimate the ability of the newly synthesized imino li-

gands to function as chiral inductors in asymmetric catalysis,

we have carried out the model reaction of diethylzinc addi-

tion to benzaldehyde (Table 2).

Thus, for the diastereomeric ligands 25 a matched-mis-

matched effect was observed (Table 2, entries 1, 2), and

(R,S_p,R)-25 showed a catalytic activity very close to that

shown by the respective structurally similar (R_p,S)-AHPC

analog (cf. 76% (R) against 82% (S),^[42]Table 2, entry 3).

The ligand (S_p,R)-26 (with additional hydroxy group), in

contrast, influenced the reaction in the opposite direction

providing (S)-1-phenylpropanol with good selectivity

(Table 2, entry 4). The “internal diastereomer” 39 showed

some (though very negligible) catalytic activity with the

result lying between that obtained for the two diastereomers

of the respective imino-ligands 25 (Table 2, entry 5).

Scheme 7.

(S,{R_p,S_p},S)-39 (or (S_c,S_c)-39) which formally has four chiral

A

elements and is, in this case, chiral due to the chirality of its

asymmetric centers (Scheme 7). If one considers independ-

ently both functional units of this compound ((R_p,S)-, top

ring, and (S_p,S)-, bottomring), then their similarity to the

functional fragments of diastereomers of the imino-type li-

gands derived fromAHPC and ( S)-(a)-PEAM, namely

(R_p,S)- and (S_p,S)-24 becomes clear. So (S,{R_p,S_p},S)-39 could

A

be regarded as “internal diastereomer”. Both ¹H and

¹³C NMR spectra are an excellent illustration of this phe-

nomenon. The spectra, containing two characteristic sets of

signals of equivalent intensity, appear to be those of the

equimolar diastereomeric mixture. Obviously, the individual

diastereomeric fragments could not have been separated

chemically in this case.

The other stereochemical analogy of this phenomenon

may be found among [2.2]paracyclophane derived salen li-

gands 42, described and classified (in accordance with their

structural and configurational symmetry) by us recently.^[13j,47]

These ligands also have four chiral elements (two independ-

ent planar chiral paracyclophane moieties and two chiral

centers), and in the case when they are structurally symmet-

rical, but two paracyclophanyl fragments have opposite con-

figurations (R and S), they also became chiral due to the

chirality of the diamine fragment only ((S_p,R,R,R_p)-42,

Figure 11, left). At the same time, diastereomeric bis-bifunc-

tional iminoligands (R,S_p,R)- and (R,R_p,R)-25 (Scheme 3,

Prospects

Synthesis: Our experience^[20]and the literature data^[16–19]

reveal that ortho-, para-, and pseudo-gem-regioselective

double electrophilic substitution of symmetrical chiral and

achiral disubstituted [2.2]paracyclophanes constitute a gen-

eral and useful approach to the synthesis of the different

types of tetrasubstituted derivatives. The combination of

symmetrical disubstituted origins with different substitution

patterns, certain substituents (chosen in accordance with the

known regularities of the regioselective electrophilic substi-

tution of cyclophanes), and appropriate reactions (bromina-

tion, acylation, formylation, oxaloylation, nitration, sulfona-

tion etc.) are a good way to synthesize the majority of the

28 possible symmetrical regioisomeric tetrasubstituted

[2.2]paracyclophanes. Moreover, the direct lithiation/electro-

philic exchange—a useful method for the regioselective

functionalization of either aromatic rings or ethano

bridges^[48–50]of [2.2]paracyclophanes bearing DMG substitu-

ents (DMG=direct metallation groups: phenols- and car-

which formally may be considered as (R,{S_p,S_p},R)- and

A

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Chem. Eur. J. 2008, 14, 4600 – 4617

Symmetrically Tetrasubstituted [2.2]Paracyclophanes

FULL PAPER

boxylic acids derivatives, sulfoxides etc.^[51])—looks promising

to be extended to the functionalization of disubstituted par-

acyclophanes, which, to the best of our knowledge, has

never been investigated.

The possibility to carry out mono-electrophilic substitu-

tion makes trisubstituted [2.2]paracyclophanes available for

further conversions, as modifiers for well known ligands^[18]

or bidentate ligands whose extra substituent may be used

for fixation on a solid support.^[17]

Further development may also include an unsymmetric

double electrophilic substitution of disubstituted [2.2]paracy-

clophanes and/or a stepwise condensation of carbonyl com-

ponents with configurationally opposite amines, which could

lead to a variety of structurally and configurationally unsym-

metric bis-bifunctional ligands.

The synthesis of Schiff bases of bis-carbonyl compounds

with various diamines (for example, bis-(ortho)-pseudo-meta

21 with ethylendiamine) is in progress now.

clophanes. We have developed conditions for chemoselec-

tive disubstitution and established that these reactions can

occur ortho-, para- or pseudo-gem-regioselectively, providing

for an efficient synthesis of chiral and achiral bis-bifunction-

al tetrasubstituted [2.2]paracyclophanes. The approach

worked out here may be considered as a powerful tool for

the preparation of the title compounds with diverse substitu-

tion patterns and 3D-structures. We have determined the

possible number of chiral and achiral patterns (10 and 18,

respectively), described their symmetry properties, and in-

troduced a straightforward descriptor system(based on cus-

tomary ortho-, meta-, para-, and “pseudo”-prefixes accepted

in [2.2]paracyclophane chemistry), allowing an unambiguous

designation of all these patterns. Preliminary results of the

application of several bis-bifunctional imino-type ligands in

asymmetric catalysis have also been presented. Further in-

vestigations in this area are underway, including:

1) Application of the regioselective double electrophilic

substitution outlined above to novel pseudo-meta- and

pseudo-para-disubstituted substrates (dicarboxylic acid

derivatives, sulfoxides, etc.), and to chiral para-disubsti-

tuted [2.2]paracyclophanes;

2) extension of the range of electrophilic reactions (formy-

lation, oxaloylation, nitration, etc.);

3) examination of the reactivity (mono-/disubstitution) and

regioselectivity (ortho-/lateral) of the lithiation/electro-

phile exchange of symmetrical DMG-disubstituted

[2.2]paracyclophanes.

Applications: For a long period of time the investigation of

the chemistry of tetrasubstituted cyclophanes has been re-

stricted to theoretical studies of “through space” donor–ac-

ceptor p–p interactions.^[8,9]Only recently charge transfer ef-

fects were successfully applied by Bazan et al. in materials

chemistry for the construction of nonlinearoptic and opto-

electric materials from several especially designed tetrasub-

stituted compounds.^[3]

A more detailed insight into the structures of the bis-bi-

functional [2.2]paracyclophanes reveals priorities of their

potential usefulness. It is clear fromFigure 5, that all chiral

C₂-symmetric structures look attractive as prospective chiral

ligands for asymmetric catalysis. Thus the functional groups

in the regioisomers A1–A3, B1 and C1–C3 formtwo identi-

cal (chemically and stereochemically) systems {X–Y} both of

which mimic one of the typical disubstituted chiral ligand

patterns based on [2.2]paracyclophane^[7](ortho-, pseudo-

ortho-, and pseudo-gem-) and may independently work as

chiral promoters. The structures B2 and B3, in contrast,

have two different {X–X} and {Y–Y} functional systems of

pseudo-ortho-architecture, whereas structure D consists of

two pseudo-ortho-systems with identical substituents {X–X}.

Note also that the second pair of substituents may affect the

electronic properties of the ligand. Furthermore, all symmet-

rical tetrasubstituted compounds have a great potential to

be used not only as chiral ligands for asymmetric catalysis,

but also as a useful platformfor the composition of liquid

crystalline or NLO materials, monomers for polymer synthe-

sis, objects for biological research etc. We hope that the

elaboration of useful and versatile methods for their synthe-

sis will promote the development in the titled areas.

Experimental Section

General remarks: ¹H and ¹³C NMR: Bruker AMX-400 at 400.13 and

100.61 MHz, respectively, in CDCl₃and [D₆]DMSO. Residual signals of

the solvent protons with the chemical shifts d=7.27 (CDCl₃) and 2.5 ppm

([D₆]DMSO) were used as internal standards. MS: Kratos MS 90 mass

spectrometer (70 eV) at 200 or 2508C. TLC: Sorbfil UV-254 plates

(CTX-1 A); chromatographic purification and separation of isomers were

carried out using Kieselgel 60 silica gel (Merck). Optical rotations: EPO-

1 and Perkin Elmer in thermostated cell (258C). Et₂Zn (1.1m solution in

toluene) was purchased fromAldrich and used without purification. All

asymmetric additions of diethylzinc to aldehydes were carried out in dry

glassware under argon in accordance with the standard procedure.^[12j]

Uncatalyzed bromination of [2.2]paracyclophane (1): To a suspension of

1 (21.55 g, 0.104 mmol) in CCl₄(300 mL) with vigorous stirring and heat-

ing (558C) was added dropwise a solution of Br₂(99.45 g, 0.62 mmol) in

CCl₄(30 mL), and the resulting mixture was stirred for 2 h (TLC con-

trol). Excess bromine and solvent were evaporated under reduced pres-

sure, and the residue was washed with warmhexane (45–55 8C, 75 mL)

and Et₂O (75 mL) to remove possible polybrominated byproducts. The

mixture of dibromides 9 and 10 was washed with CHCl₃(2135 mL) and

the remaining solid was recrystallized twice from dioxan to afford

pseudo-para-dibromide 10 (12.88 g, 34%). M.p. 250–2518C; lit. m.p.

248.5–2508C.^[11a]The chloroformsolution was evaporated and analytically

pure pseudo-meta-dibromide 9 (16.29 g, 43%) was isolated as a result of

fractional recrystallization of the solid fromethanol; m.p. 125–125.5 8C;

lit. m.p. 123.5–125.58C.^[11a]

Conclusion

We have for the first time investigated the reactivity and the

regioselectivity of electrophilic substitution of chiral pseudo-

meta- and achiral pseudo-para-disubstituted [2.2]paracy-

4-Bromo

A

2.73 mmol) in Et₂O (20 mL) nBuLi (1 mL of 3.27n solution in hexane,

Chem. Eur. J. 2008, 14, 4600 – 4617

ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4611

V. I. Rozenberg, H. Hopf et al.

3.27 mmol) was added dropwise at room temperature, and the resulting

suspension was stirred for 3 h. Then B(OMe)₃(0.7 mL, 5.90 mmol) was

³J=7.8 Hz, 2H, 7-, 12-H), 6.91 ppm(d, ³J=7.8 Hz, 2H, 8-, 13-H); ¹³C

NMR (75 MHz, CDCl₃): d=25.45, 30.45 (C-1, -2, -9, -10), 117.07, 120.31,

126.10 (C-5, -7, -8, -12, -13, -16), 121.52, 137.22 (C-6, -3, -11, -14),

150.02 ppm(C-4, -15); MS (70 eV): m/z (%): 241 (26) [M]⁺, 240 (60)

[M]⁺, 239 (13), 121 [MÀ119]⁺(52), 91 (100); elemental analysis calcd

(%) for C₁₆H₁₆O₂: C 79.97, H, 6.71; found: C 79.97, H 6.71.

AHCTREUNG

added and the mixture was stirred overnight at room temperature. A so-

lution of NaOH (2 g in 10 mL of H₂O, 50 mmol) and 30% H₂O₂(6.5 mL)

were added, and the reaction mixture was stirred for 1 h. The organic

phase was separated and the aqueous phase was extracted with Et₂O (3

100 mL). The combined organic phases were dried with Na₂SO₄. The sol-

vent was evaporated under reduced pressure, and the residue was sepa-

rated by preparative chromatography on silica gel with CH₂Cl₂to afford

16 (0.71 g, 86%). ¹H NMR (400 MHz, CDCl₃): d=2.79–3.07 (m, 6H,

bridge-CH₂-), 3.08–3.26 (m, 1H, bridge-CH₂-), 3.27–3.43 (m, 1H, bridge-

CH₂-), 4.45 (s, 1H, OH), 5.64 (s, 1H, 5-H), 6.22, 6.47 (brd, ³J=7.8 Hz,

2H, 7-, 12-H or 8-, 13-H), 6.57 (s, 1H, 16-H), 7.01, 7.10 ppm(2d, ³J=

7.8 Hz, 2H, 8-, 13-H or 7-, 12-H); ¹³C NMR (75 MHz, CDCl₃): d=24.77,

30.05, 30.37, 30.63 (C-1, -2, -9, -10), 117.70, 120.51, 125.59, 126.68, 126.79,

132.48 (C-5, -7, -8, -12, -13, -16), 120.94, 123.56, 135.28, 136.73 (C-6, -3,

-11, -14), 137.49, 150.28 ppm(C-4, -15); MS (70 eV): m/z (%): 304 [M]⁺

(67), 302 (68) [M]⁺, 224 [MÀBr]⁺(13), 223 (20), 200 (11), 184 (36), 120

(100).

ortho-Regioselective

diacylation

of

[2.2]paracyclophane-4,15-diol

(pseudo-meta-, 14) with acetyl chloride: To a solution of 14 (0.20 g,

0.84 mmol) in CH₂Cl₂(30 mL) TiCl₄(0.55 mL, 5.04 mmol) was added at

08C, and the reaction mixture was allowed to warm to RT. The resulting

brownish-red solution was stirred for 1 h, then acetyl chloride (0.36 mL,

5.04 mmol) was added and the mixture was stirred at 408C for 10 h. The

reaction mixture was cooled to RT, the second portions of TiCl₄

(0.55 mL, 5.04 mmol) and acetyl chloride (0.36 mL, 5.04 mmol) were

added successively, and the mixture was stirred at 408C for an additional

10 h. The reaction mixture was diluted with H₂O (10 mL) and vigorously

stirred for 15 min. The organic layer was separated, washed with H₂O

(210 mL) and dried with Na₂SO₄. The crude product was obtained after

removal of the solvent in vacuo and purified by preparative chromatogra-

phy on silica gel (CH₂Cl₂) to yield 21 (0.35 g, 93%).

4-Bromo[2.2]paracyclophan-15-yl methyl ether (17): To a solution of 16

A

(0.50 g, 1.65 mmol) in DMF (2 mL) NaH (60% in oil, 0.072 g, 1.79 mmol)

was added, the resulting brown solution was stirred at roomtemperature

for 1 h and then MeI (0.5 mL, 8.03 mmol) was added. The reaction mix-

ture was stirred for additional 2 h, diluted with H₂O (10 mL), extracted

with Et₂O (520 mL), and dried with Na₂SO₄. The solvent was evaporat-

ed at reduced pressure and the solid residue was purified by preparative

chromatography on silica gel with CH₂Cl₂to furnish 17. Recrystallization

fromhexane yielded analytically pure 17 (0.46 g, 87%). M.p. 113.5–

1,1’-[5,16-Dihydroxy[2.2]paracyclophane-4,15-diyl]diethanone (bis-(ortho)-

C

3

CH₂-), 6.09 (d, J=7.8 Hz, 2H, 7-, 12-H or 8-, 13-H), 7.02 (d, ³J=7.8 Hz,

2H, 7-, 12-H or 8-, 13-H), 12.72 ppm(s, 2H, 2 OH); ¹³C NMR (75 MHz,

CDCl₃): d=24.64, 26.64, 34.00, 117.45, 121.95, 125.93, 129.90, 135.95,

158.60, 200.45 ppm; MS (70 eV): m/z (%): 324 (81) [M]⁺, 306 (6), 288

(11), 164 (13), 163 (53), 162 (100), 161 (100); elemental analysis calcd

(%) for C₂₀H₂₀O₄: C 74.06, H 6.21; found: C 74.03, H 6.18.

1

114.58C; H NMR (400 MHz, CDCl₃): d=2.82–3.05 (m, 6H, bridge-CH₂-

), 3.20–3.36 (m, 2H, bridge-CH₂-), 3.71 (s, 3H, CH₃), 5.75 (d, ⁴J=1.8 Hz,

1H, 16-H), 6.23 (dd, ³J=7.8, ⁴J=1.8 Hz, 1H, 12-H), 6.46 (dd, ³J=7.8,

⁴J=1.8 Hz, 1H, 7-H), 6.53 (d, ⁴J=1.8 Hz, 1H, 5-H), 6.75 (d, ³J=7.8 Hz,

1H, 8-H), 7.12 ppm(d, ³J=7.8 Hz, 1H, 13-H); ¹³C NMR (75 MHz,

CDCl₃): d=29.16, 34.25, 34.40, 35.10 (C-1, -2, -9, -10), 54.22 (CH₃),

115.88 (C-16), 123.84 (C-12), 126.71, 127.48, 129.81, 130.26 (C-7, -13),

136.68 (C-5), 139.86, 140.57, 141.42, 158.11 ppm(C-3, -6, -11, -14); MS

(70 eV): m/z (%): 318 (30) [M]⁺, 316 (32) [M]⁺, 189 (11), 184 (23), 182

(25), 135 (52), 134 (100), 115 (19), 105 (41), 104 (92), 103 (90), 102 (34);

elemental analysis calcd (%) for C₁₇H₁₇BrO: C 64.37, H 5.40, Br 25.19;

found: C 64.18, H 5.36, Br 25.13.

Acylation of 14 under the conditions described in Table 2 (entries 1–4)

leads to mixtures of 21, 22 and 23. Combined reaction mixtures from

these experiments were separated by preparative chromatography on

silica gel (CH₂Cl₂/Et₂O 10:1) to produce the individual derivatives 21, 22

and 23.

1-[5,16-Dihydroxy[2.2]paracyclophan-4-yl]ethanone (22): M.p. 131.5–

G

1328C; ¹H NMR (400 MHz, CDCl₃): d=2.59 (s, 3H, CH₃), 2.60–2.77 (m,

2H, bridge-CH₂-), 2.82–2.94 (m, 2H, bridge-CH₂-), 3.06–3.22 (m, 2H,

bridge-CH₂-), 3.24–3.34 (m, 1H, bridge-CH₂-), 3.61–3.72 (m, 1H, bridge-

CH₂-), 4.63 (s, 1H, C-15(OH)), 5.64 (d, ⁴J=1.8 Hz, 1H, 16-H), 6.05 (dd,

³J=7.8, ⁴J=1.8 Hz, 1H, 12–12), 6.27 (d, ³J=7.8 Hz, 1H, 7- or 8-H), 6.87

ACHTREUNG

3

(d, J=7.8 Hz, 1H, 7- or 8-H), 7.07 (d, ³J=7.8 Hz, 1H, 13-H), 12.82 ppm

A

a

9

(s, 1H, C-4(OH)); ¹³C NMR (75 MHz, CDCl₃): d=24.89, 24.99, 26.85,

30.49, 33.22, 115.49, 118.08, 120.02, 122.00, 122.71, 125.11, 125.51, 130.39,

135.78, 137.85, 150.04, 158.67, 200.62 ppm; MS (70 eV): m/z (%): 283

(21) [M]⁺, 282 (79) [M]⁺, 163 (27), 162 (92), 147 (19), 134 (20), 121 (41),

120 (100), 115 (13); elemental analysis calcd (%) for C₁₈H₁₈O₃: C 76.57,

H 6.43; found: C 76.41, H 6.42.

2.73 mmol) in Et₂O (100 mL), nBuLi (2 mL of 3.27n solution in hexane,

6.54 mmol) was added dropwise at room temperature; the resulting sus-

pension was stirred for 3 h at roomtemperature and cooled to À788C. A

solution of PhNO₂(0.8 mL, 7.84 mmol) in Et₂O (20 mL) was added, and

the reaction mixture was stirred for 5 h at À788C. Methanol (10 mL) and

2m HCl (40 mL) were added, the mixture was stirred for 1 h and left

overnight to warmup. The organic phase was separated and washed with

H₂O (3100 mL); the aqueous phase was extracted with Et₂O (3

100 mL), and the combined organic phase was dried with Na₂SO₄. The

solvent was evaporated under reduced pressure and the residue was puri-

fied by preparative chromatography on silica gel (CH₂Cl₂) to afford 14

(0.20 g, 30%).

16-Acetyl-15-hydroxy

143.58C; H NMR (400 MHz, CDCl₃): d=2.33 (s, 3H, CH₃), 2.59 (s, 3H,

A

1

CH₃), 2.60–2.74 (m, 2H, bridge-CH₂-), 2.85–3.06 (m, 3H, bridge-CH₂-),

3.11–3.21 (m, 1H, bridge-CH₂-), 3.26–3.35 (m, 1H, bridge-CH₂-), 3.61–

3.71 (m, 1H, bridge-CH₂-), 6.11 (d, ⁴J=1.8 Hz, 1H, 5-H), 6.25–6.33 (m,

2H, 7-, 15- or 16-H), 6.70, 6.97 (2d, ³J=7.8 Hz, 2H, 8-, 15- or 16-H),

12.78 ppm(s, 1H, OH); ¹³C NMR (75 MHz, CDCl₃): d=17.18, 25.29,

25.81, 26.91, 30.55, 33.04, 118.36, 121.56, 122.80, 124.87, 125.03, 125.49,

127.78, 131.85, 135.50, 138.05, 145.38, 158.65, 164.50, 200.44 ppm; MS

(70 eV): m/z (%): 324 (38) [M]⁺, 282 (15), 264 (10), 163 (21), 161 (94),

147 (16), 134 (18), 133 (17), 115 (16), 120 (100); elemental analysis calcd

(%) for C₂₀H₂₀O₄: C 74.06, H 6.21; found: C 74.20, H 6.24.

From 4-bromo[2.2]paracyclophane-15-ol (16): To a solution of 16 (0.50 g,

A

1.65 mmol) in Et₂O (100 mL), nBuLi (1.1 mL, 3.27n solution in hexane,

3.63 mmol) was added dropwise at room temperature, and the resulting

suspension was stirred for 3 h. The reaction mixture was treated with B-

(OMe)₃(0.92 mL, 9.08 mol) and stirred overnight. Then NaOH solution

(1 g in 5 mL of H₂O, 0.03 mol) and 30% H₂O₂(3.5 mL) were added, and

the mixture was stirred for 1 h. The organic phase was separated, the

aqueous phase was extracted with Et₂O (3100 mL) and the combined

organic phases were dried with Na₂SO₄. The solvent was evaporated in

vacuo, and the residue was purified on a silica gel column (CH₂Cl₂) to

afford 14 (0.35 g, 87%). Analytically pure 14 was obtained by recrystalli-

zation from hexane/toluene 1:1. Decomp. temp. 200–2308C; ¹H NMR

(400 MHz, CDCl₃): d=2.77–2.96 (m, 6H, bridge-CH₂-), 3.13–2.26 (m,

2H, bridge-CH₂-), 4.42 (s, 2H, 2 OH), 5.57 (s, 2H, 5-, 8-H), 6.21 (brd,

Acylation of [2.2]paracyclophane-4,15-diol (pseudo-meta-, 14) with ben-

zoyl chloride: The reaction was carried out as described for acetyl chlo-

ride by double successive addition of the respective reactants, TiCl₄

(1.24 mL, 11.25 mmol) and benzoyl chloride (1.31 mL, 11.25 mmol) to 14

(0.045 g, 1.88 mmol); the reaction mixture was, however, stirred for 10 h

at roomtemperature rather than refluxed in CH ₂Cl₂. The reaction mix-

ture was diluted with H₂O (50 mL) and vigorously stirred for 15 min. The

organic layer was separated, washed with H₂O (260 mL), dried with

4612

www.chemeurj.org

ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2008, 14, 4600 – 4617

Symmetrically Tetrasubstituted [2.2]Paracyclophanes

FULL PAPER

Na₂SO₄and the solvent was evaporated in vacuo to produce a mixture of

27–31. The products were separated by preparative chromatography on

silica gel (CHCl₃(28, 30)_,CH₂Cl₂/Et₂O 10:1 (27) and cyclohexane/Et₂O

10:1 (29, 31)).

12-Benzoyl-15-hydroxy[2.2]paracyclophan-4-yl benzoate (30): Isolated

C

3.11–3.21 (m, 1H, bridge-CH₂-), 3.42–

(5,16-Dihydroxy[2.2]paracyclophane-4,15-diyl)bis(phenylmethanone)

G

3.54 (m, 2H, bridge-CH₂-), 5.82 (s,

(bis-(ortho)-pseudo-meta-, 27): Isolated yield: 0.256 g (30%); m.p. 188–

1898C; H NMR (600 MHz, CDCl₃): d=1.77–1.99 (m, 2H, bridge-CH₂-),

2.14–2.31 (m, 2H, bridge-CH₂-), 2.80–

1H, 16-H), 6.20 (d, ⁴J=1.8 Hz, 1H, 5-

H), 6.56 (dd, ³J=7.8, ⁴J=1.8 Hz, 1H,

7-H), 7.02 (d, ³J=7.8 Hz, 1H, 8-H),

2.96 (m, 2H, bridge-CH₂-), 3.29–3.44

(m, 2H, bridge-CH₂-), 6.27 (d, ³J=

7.03 (s, 1H, 13-H), 7.40–7.52 (m, 4H,

meta-Ph), 7.58 (brd, ³J=7.5 Hz, 2H, 2

7.8 Hz, 2H, 7- and 12-H or 8- and 13-

ortho-H, Ph), 7.61 (t, ³J=7.5 Hz, 1H,

3

H), 7.23 (d, J=7.8 Hz, 2H, 8- and 13-

para-Ph), 7.71 (t, ³J=7.5 Hz, 1H, para-Ph), 7.89 (d, ³J=7.5 Hz, 2H,

ortho-Ph), 10.07 ppm(s, 1H, OH); ¹³C NMR (151 MHz, DMSO): d=

30.62, 30.68, 34.74, 35.31, 124.74, 124.84, 125.29, 125.34, 125.75, 129.42,

130.06, 130.17, 130.58, 131.67, 132.37, 132.79, 135.17, 137.22, 141.13,

142.61, 145.86, 150.16, 161.17, 164.54, 196.86, 215.18 ppm; MS (70 eV):

m/z (%): 449 (39) [M]⁺, 448 (66) [M]⁺, 343 (11), 328 (13), 225 (25), 224

(74), 223 (46), 195 (16), 181 (20), 165 (18), 152 (15), 120 (10), 106 (35),

105 (100); elemental analysis calcd (%) for C₃₀H₂₄O₄: C 80.34, H 5.39;

found: C 80.08, H 5.26.

3

H or 7- and 12-H), 7.38 (t, J=7.8 HZ,

4H,

4

meta-arom.), 7.50 (dt, ³J=

7.8 Hz, 2H, 2 para-arom.), 7.65 ppm

(dd, ³J=7.8, ⁴J=1.8 Hz, 4H, 4 ortho-

arom.), 11.90 ppm (s, 2H, C-5(OH), C-16(OH)); ¹³C NMR (151 MHz,

CDCl₃): d=28.61, 37.24, 119.78, 125.22, 128.36, 128.95, 129.19, 132.44,

134.62, 140.16, 142.05, 162.44, 200.62 ppm; MS (70 eV): m/z (%): 449

(13) [M]⁺, 448 (45) [M]⁺, 447 (52) [M]⁺, 430 (23), 412 (18), 238 (20), 237

(46), 226 (15), 225 (62), 224 (82), 223 (100), 222 (17), 212 (25), 211 (22),

210 (16), 209 (54), 208 (19), 207 (16), 206 (13), 182 (12), 181 (56), 179

(18), 178 (40), 177 (24), 176 (25), 167 (29), 166 (22), 165 (51), 147 (27),

146 (11), 128 (12), 120 (50), 119 (15), 115 (14), 105 (67), 104 (35), 103

(10); elemental analysis calcd (%) for C₃₀H₂₄O₄: C 80.34, H 5.39; found:

C 80.47, H 5.34.

7,16-Dibenzoyl-15-hydroxy[2.2]paracyclophan-4-yl benzoate (31): Isolat-

E

ed yield: 0.066 g (6%); m.p. 238.5–2398C; ¹H NMR (600 MHz, DMSO):

3

d=2.65–3.35 (m, 8H, bridge-CH₂-), 6.61 (d, J=7.8 Hz, 1H, 12- or 13-H),

6.69 (s, 1H, 5- or 8-H), 7.17 (s, 1H, 8-

or 5-H), 7.33 (d, ³J=7.8 Hz, 1H, 13-

or 12-H), 7.55–7.95 (m, 13H, 3 Ph),

8.35 (d, ³J=7.5 Hz, 2H, ortho-Ph),

(5,16-Dihydroxy[2.2]paracyclophane-4,13-diyl)bis(phenylmethanone)

T

(28): Isolated yield: 0.177 g (21%); decomp. temp. < 3008C; ¹H NMR

(600 MHz, DMSO): d=2.56–2.82 (m, 4H, bridge-CH₂-), 2.83–2.97 (m,

1H, bridge-CH₂-), 2.99–3.12 (m, 1H,

11.72 ppm(s, 1H, OH);

¹³C NMR

(151 MHz, DMSO): d=29.75, 29.84,

35.00, 35.70, 119.98, 126.11, 127.43,

128.82, 128.90, 129.01, 129.79, 129.83,

130.10, 130.41, 130.52, 131.45, 132.13,

132.80, 133.01, 133.71, 134.88, 137.49, 139.19, 140.95, 143.96, 145.24,

152.52, 160.72, 161.04, 163.96, 195.29, 199.69 ppm; MS (70 eV): m/z (%):

552 (12) [M]⁺, 224 (16), 223 (31), 106 (13), 105 (100); elemental analysis

calcd (%) for C₃₇H₂₈O₅: C 80.42, H, 5.11; found: C 80.32, H 5.19.

bridge-CH₂-), 3.27–3.43 (m, 2H,

bridge-CH₂-), 5.93 (s, 1H, 16-H), 6.39

(d, ³J=7.8 Hz, 1H, 7- or 8-H), 6.87 (s,

1H, 13-H), 7.10 (d, ³J=7.8 Hz, 1H, 8-

or 7-H), 7.41–7.80 (m, 10H, 2 Ph),

9.92 (s, 1H, C-16(OH)), 11.68 ppm(s,

1H, C-5(OH)); ¹³C NMR (151 MHz,

4,15-Dimethoxy[2.2]paracyclophane (pseudo-meta, 18): To a solution of

A

DMSO): d=29.55, 30.07, 35.94, 36.45,

14 (0.240 g, 1.00 mmol) in DMF (4 mL) NaH (0.088 g, 2.2 mmol, 60% in

mineral oil) was added; the resulting brown solution was stirred at room

temperature for 2 h and MeI (0.3 mL, 0.710 g, 5 mmol) was added. The

reaction mixture was stirred for additional 2 h, diluted with H₂O

(30 mL), extracted with Et₂O (530 mL), dried with Na₂SO₄. After evap-

oration of the solvent, the solid residue was purified by preparative chro-

matography on silica gel (CH₂Cl₂) to furnish 18 (0.215 g, 80%). M.p.

1758C (lit.^[23]m.p. 175–1778C).

120.72, 124.91, 125.64, 126.66, 127.70, 128.62, 129.14, 129.47, 130.51,

130.61, 132.54, 133.43, 135.78, 136.78, 141.32, 141.98, 145.32, 145.61,

161.28, 162.27, 195.95, 200.54 ppm; MS (70 eV): m/z (%): 449 (12) [M]⁺,

448 (40) [M]⁺, 447 (47) [M]⁺, 430 (18), 419 (13), 237 (12), 226 (13), 224

(92), 223 (100), 211 (15), 209 (21), 207 (10), 196 (14), 195 (41), 181 (36),

178 (16), 177 (10), 167 (14), 166 (12), 165 (27), 153 (12), 152 (24), 147

(10), 105 (66); elemental analysis calcd (%) for C₃₀H₂₄O₄: C 80.34, H

5.39; found: C 80.08, H 5.30.

para-Regioselective diacylation of 4,16-dimethoxy[2.2]paracyclophane

A

16-Benzoyl-15-hydroxy[2.2]paracyclophan-4-yl benzoate (29): Isolated

C

(18) with acetyl chloride: To a solution of 18 (0.11 g, 0.41 mmol) in

CH₂Cl₂(10 mL) TiCl₄(0.27 mL, 2.46 mmol) and acetyl chloride (0.18 mL,

2.6 mmol) were added successively at 08C, and the resulting solution was

stirred at roomtemperature for 10 h. Then TiCl

(0.27 mL, 2.46 mmol)

4

1H, 1b-H), 3.19 (m, 1H, 1a-H), 3.41

(m, 1H, 2b-H), 6.27 (d, ⁴J=1.8 Hz,

and acetyl chloride (0.18 mL, 2.6 mmol) were added and the reaction

mixture was stirred for further 10 h. The mixture was diluted with water

(20 mL) and vigorously stirred for 45 min. The organic layer was washed

with H₂O (210 mL) and dried with Na₂SO₄. The removal of the solvent

in vacuo followed by purification of the crude product by preparative

chromatography on silica gel (C₆H₆) yielded 32 (0.10 g, 71%); analytical-

ly pure 32 was obtained by recrystallization fromtoluene.

1H, 5-H), 6.40 (d, ³J=7.8 Hz, 1H, 13-

H), 6.48 (dd, ³J=7.8, ⁴J=1.8 Hz, 1H,

7-H), 7.17 (d, ³J=7.8 Hz, 1H, 12-H),

7.19 (d, ³J=7.8 Hz, 1H, 8-H), 7.77 (d,

³J=7.5 Hz, 2H, 2 ortho-H, PhC(O)-),

7.51 (brt, ³J=7.5 Hz, 2H,

2 meta-

PhC(O)-), 7.62 (m, 3H, para-PhC(O)-, 2 meta-PhOC(O)-), 7.72 (t, ³J=

1,1’-[7,12-Dimethoxy[2.2]paracyclophane-4,15-diyl]diethanone (bis-(para)-

3

1

7.5 Hz, 1H, para-PhOC(O)-), 8.28 (d, J=7.5 Hz, 2H, ortho- PhOC(O)-),

pseudo-meta, 32): M.p. 139–1418C; H NMR (600 MHz, CDCl₃): d=2.45

11.86 ppm(s, 1H, OH); ¹³C NMR (151 MHz, DMSO): d=25.80, 26.04,

30.44, 32.51, 121.92, 122.35, 124.51, 124.59, 124.60, 124.78, 125.30, 125.62,

125.95, 127.60, 128.57, 128.60, 129.64, 132.52, 135.88, 136.39, 139.84,

145.38, 158.14, 160.26, 196.13, 196.32 ppm; MS (70 eV): m/z (%): 449

(22) [M]⁺, 448 (53) [M]⁺, 430 (16), 325 (11), 225 (18), 224 (69), 223 (87),

222 (13), 209 (15), 195 (14), 181 (14), 165 (17), 152 (14), 120 (10), 106

(43), 105 (100); elemental analysis calcd (%) for C₃₀H₂₄O₄: C 80.34, H

5.39; found: C 80.48, H 5.26.

(s, 6H, 2CH₃), 2.66–2.78 (m, 2H, bridge-CH₂), 2.94–3.05 (m, 2H, bridge-

CH₂-), 3.17–3.29 (m, 2H, bridge-CH₂-), 3.66 (s, 6H, 2 OCH₃), 3.76–3.88

(m, 2H, bridge-CH₂-), 5.77 (s, 2H, 5-, 16-H or 8-, 13-H), 7.11 ppm(s, 2H,

8-, 13-H or 5-, 16-H); ¹³C NMR (151 MHz, CDCl₃): d=24.86, 25.23,

31.27, 50.72, 112.40, 123.07, 127.19, 127.58, 141.12, 156.56, 195.80 ppm;

MS (70 eV): m/z (%): 353 (56) [M]⁺, 352 (81) [M]⁺, 351 (31), 337 (15),

334 (15), 191 (13), 189 (20), 178 (31), 177 (77), 176 (95), 175 (100), 174

(16), 169 (10), 165 (11), 163 (13), 162 (11), 161 (52), 148 (30), 147 (86),

Chem. Eur. J. 2008, 14, 4600 – 4617

ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4613

V. I. Rozenberg, H. Hopf et al.

146 (70), 145 (35), 135 (10), 133 (25), 132 (15), 131 (55), 128 (10), 119

(28), 118 (26), 117 (46), 116 (12), 115 (32), 105 (37), 104 (22), 103 (50); el-

emental analysis calcd (%) for C₂₂H₂₄O₄: C 74.98, H 6.86; found: C

74.99, H 6.97.

6.87 (d, ⁴J=1.8 Hz, 1H, 7-H), 7.20 (d, ⁴J=1.8 Hz, 1H, 12-H), 7.45 ppm

(d, ³J=1.8 Hz, 1H, 5-H); ¹³C NMR (151 MHz, CDCl₃): d=29.66, 30.05,

30.61, 30.72, 47.65, 48.28, 124.52, 125.15, 129.25, 129.91, 130.51, 130.76,

131.84, 135.06, 135.55, 136.70, 137.60, 139.16, 162.73, 163.07 ppm; HRMS:

calcd for C₂₀H₁₉O₄Br: m/z: 402.0467 [M]⁺; found: 402.0452.

[2.2]Paracyclophane-4,15-dicarboxylic acid (pseudo-meta, 19): To a solu-

tion of 9 (5.00 g, 13.66 mmol) in Et₂O (250 mL), nBuLi (10 mL, 3.27n so-

lution in hexane, 32.76 mmol) was added at 208C. After stirring the reac-

tion mixture for 3 h a considerable excess of solid CO₂was added, the re-

sulting mixture was allowed to warm up to room temperature and diluted

with H₂O (150 mL). The aqueous phase was separated, the organic phase

was washed with H₂O (100 mL), aq. NaOH (3 g in 100 mL of H₂O), H₂O

(100 mL) and acidified with 2n HCl up to pH 1. The precipitate was fil-

tered off, dissolved in 1n aq. NaOH, the solution was filtered and acidi-

fied with 2n HCl. The precipitate formed was filtered off, thoroughly

washed with H₂O (1 L) and dried in vacuo to afford diacid 19 (3.00 g,

74%). M.p. 2838C (lit.^[41]m.p. 283–283.58C).

pseudo-gem-Regioselective dibromination of dimethyl [2.2]paracy-

clophane-4,15-dicarboxylate (pseudo-meta, 20): The reaction was carried

out as described above for the monobromination of 20. After 3 d an

excess of Br₂(0.15 mL, 2.7 mmol) was added and the reaction mixture

was stirred at room temperature for further 10 d. The reaction mixture

was washed with H₂O, aq. Na₂CO₃and dried with Na₂SO₄. The solvent

was removed in vacuo and the solid residue was purified by preparative

chromatography on silica gel with CH₂Cl₂to produce 37 (0.17 g, 93%).

An analytically pure sample of 37 was obtained by recrystallization from

hexane.

An improved synthesis of 37: A solution of Br₂(0.56 mL, 1.1 mmol) in

CCl₄(1 mL) was stirred with suspended iron powder (0.030 g, 0.54 mmol)

in a light-protected reaction vessel for 1 h. Then 20 (0.035 g, 0.11 mmol)

in CH₂Cl₂(4 mL) and a solution of Br₂(0.56 mL, 1.1 mmol) in CCl₄

(1 mL) were added in one portion. The resulting mixture was refluxed

for 10 h, washed with H₂O, aq. Na₂CO₃and dried with Na₂SO₄. The sol-

vent was removed in vacuo and the solid residue was purified by prepara-

tive chromatography on silica gel (CH₂Cl₂) to yield 37 (0.046 g, 88%).

Dimethyl[2.2]paracyclophane-4,15-dicarboxylate (pseudo-meta, 20): To a

N

suspension of 19 (1.00 g, 3.38 mmol) in CHCl₃(30 mL), SO₂Cl₂(1 mL,

13.5 mmol) was added and the mixture was refluxed for 0.5 h; then DMF

(three drops) was added and the mixture was refluxed for additional

1.5 h. The cooled mixture was concentrated, diluted with CHCl₃(10 mL),

and MeOH (10 mL) was added. The reaction mixture was stirred under

reflux for 1.5 h. After removal of the solvent in vacuo, the residue was

purified by preparative chromatography (silica gel, CH₂Cl₂) to yield 20

(0.85 g, 78%). M.p. 115.58C (lit.^[10a]m.p. 1158C).

Dimethyl

8,13-dibromo

A

(bis-

(pseudo-gem)-pseudo-meta-, 37): M.p. 170.5–1718C; ¹H NMR (600 MHz,

CDCl₃): d=2.94–3.14 (m, 4H, bridge-CH₂-), 3.40–3.52 (m, 2H, bridge-

CH₂-), 3.91 (s, 6H, 2-CH₃), 4.27–4.39 (m, 2H, bridge-CH₂-), 6.78 (d, ⁴J=

1.8 Hz, 2H, 5- and 16-H), 7.41 ppm(d, ⁴J=1.8 Hz, 2H, 7- and 12-H);

¹³C NMR (151 MHz, CDCl₃): d=27.70, 28.81, 48.07, 125.82, 127.30,

128.63, 135.16, 135.82, 137.95, 162.46 ppm; MS (70 eV): m/z (%): 483

(32) [M]⁺, 482 (15) [M]⁺, 481 (59) [M]⁺, 479 (31), 466 (13), 243 (29), 242

(100), 240 (100), 239 (11), 227 (36), 226 (12), 225 (50), 223 (15), 211 (45),

210 (14), 209 (27), 203 (10), 202 (22), 201 (13), 200 (18), 199 (43), 198

(12), 197 (46), 189 (16), 184 (32), 183 (13), 182 (33), 162 (12), 129 (14),

115 (12), 104 (10), 103 (38), 102 (87); elemental analysis calcd (%) for

C₂₀H₁₈Br₂O₄: C 49.82, H 3.76, Br 33.14; found: C 49.64, H 3.64, Br 33.28.

pseudo-gem-Regioselective monoformylation of dimethyl [2.2]paracy-

clophane-4,15-dicarboxylate (pseudo-meta, 20): To

a solution of 20

(0.090 g, 0.28 mmol) in CH₂Cl₂(3 mL), TiCl₄(0.12 mL, 1.11 mmol) and

CH₃OCHCl₂(0.06 mL, 0.67 mmol) were added successively at 08C. The

resulting solution was stirred at roomtemperature for 13 d with the alky-

lating reagent and TiCl₄being added three more times. The reaction mix-

ture was diluted with CH₂Cl₂(5 mL), cooled to 08C, and H₂O (5 m L)

and 2n HCl (5 mL) were successively added. The organic layer was

washed with H₂O (210 mL), NaHCO₃solution, and dried with Na₂SO₄.

After removal of the solvent in vacuo the mixture was separated by prep-

arative chromatography on silica gel (CH₂Cl₂/MeOH 30:1) to yield 35

(0.048 g, 49%) and recovered 20 (0.036 g, 40%). An analytically pure

sample of 35 was obtained by recrystallization fromhexane.

Dimethyl

(pseudo-gem)-pseudo-para-, 41): Compound 41 was obtained by the

same method as that described above from dimethyl[2.2]paracyclophane-

7,13-dibromo

A

(bis-

Dimethyl 8-formyl[2.2]paracyclophane-4,15-dicarboxylate (35): M.p.

G

AHCTREUNG

116.5–1178C; ¹H NMR (600 MHz, CDCl₃): d=2.98–3.27 (m, 6H, bridge-

CH₂-), 3.82 (s, 3H, -CH₃), 3.96 (s, 3H, -CH₃), 4.01–4.16 (m, 2H, bridge-

CH₂-), 6.67 (d, ³J=7.8 Hz, 1H, 15-H), 6.71 (dd, ³J=7.8, ⁴J=1.8 Hz, 1H,

16-H), 7.11, 7.29, 7.31 ppm(3d, ⁴J=1.8 Hz, 3H, 5-, 7-, 12-H); ¹³C NMR

(151 MHz, CDCl₃): d=24.88, 30.16, 30.46, 31.49, 47.97, 48.27, 126.75,

129.35, 130.32, 130.79, 131.54, 131.63, 134.51, 135.83, 135.89, 135.92,

138.30, 142.85, 162.60, 162.83, 185.12 ppm; MS (70 eV): m/z (%): 353

(21) [M]⁺, 352 (68) [M]⁺, 205 (12), 203 (13), 202 (23), 201 (11), 191(24),

190 (87), 177 (11), 176 (14), 175 (11), 165 (11), 164 (11), 163 (52), 162

(100), 161 (14), 159 (15), 148 (19), 147 (95), 146 (11), 145 (15), 132 (44),

131 (87), 130 (24), 129 (16), 119 (71), 118 (18), 117 (10), 115(23), 104

(77), 103 (75), 102 (43); elemental analysis calcd (%) for C₂₁H₂₀O₅: C

71.58, H 5.72; found: C 71.73, H 5.85.

4,16-dicarboxylate 40 (0.200 g, 0.617 mmol) in 97% chemical yield

(0.288 g). An analytically pure sample was obtained by recrystallization

fromheptane/toluene (0.214 g, 72%). M.p. 235–236 8C; ¹H NMR

(600 MHz, CDCl₃): d=2.86–3.07 (m, 4H, bridge-CH₂), 3.48–3.67 (m, 2H,

bridge-CH₂), 3.90 (s, 6H, 2 CH₃), 4.29–4.43 (m, 2H, bridge-CH₂), 6.72 (s,

2H, 5-, 15-H or 8-, 12-H), 7.37 ppm(s, 2H, 8-, 12-H or 5-, 15-H); NMR

¹³C (151 MHz, CDCl₃): d=32.53(2C, bridge), 34.71 (2C, 2 CH₃, 2 C-

bridge), 128.32, 130.99, 153.71, 138.87 (4C), 143.89, 166.55 ppm(2COO);

MS (70 eV): m/z (%): 484 (40) [M]⁺, 483 (19) [M]⁺, 482 (75) [M]⁺, 481

(10) [M]⁺, 480 (37) [M]⁺, 469 (11), 467 (16), 371 (37) [MÀCH₃]⁺, 370

(10) [MÀCH₃]⁺, 369 (36) [MÀCH₃]⁺, 243 (11) [M/2]⁺, 242 (97), 241 (37),

240 (100), 239 (26), 227 (21), 225 (28), 212 (24), 211 (12), 210 (31), 202

(11), 199 (15), 197 (19), 184 (19), 182 (17),103 (10), 102 (20), 101 (10); el-

emental analysis calcd (%) for C₂₀H₁₈Br₂O₄: C 49.82, H 3.76, Br 33.14;

found: C 50.26, H 3.92, Br 33.35.

pseudo-gem-Regioselective monobromination of dimethyl [2.2]paracy-

clophane-4,15-dicarboxylate (pseudo-meta, 20): The reaction was carried

out in a light-protected reaction vessel. A solution of Br₂(0.05 mL,

0.9 mmol) in CCl₄(2 mL) was prepared, and 0.3 mL of this solution was

stirred with suspended iron powder (0.03 g, 0.54 mmol) in CH₂Cl₂(5 mL)

for 1 h. Then 20 (0.12 g, 0.37 mmol) in CH₂Cl₂(15 mL) was added in one

portion and the remaining Br₂/CH₂Cl₂solution was added dropwise. The

resulting mixture was stirred at room temperature for 3 d. The reaction

mixture was washed with H₂O, aq. Na₂CO₃and dried with Na₂SO₄. The

solvent was removed in vacuo and the solid residue was purified by pre-

ortho-Regioselective

diacylation

of

[2.2]paracyclophane-4,16-diol

(pseudo-para-, 12) with acetyl chloride: Compound 38 was obtained

from 0.20 g (0.83 mmol) of 12 in an isolated yield of 0.24 g (89%) using

the method as described for the acylation of 14.

1,1’-[5,15-Dihydroxy

A

(bis-

(ortho)-pseudo-para, 38): Decomp. temp. 210–2128C; ¹H NMR

(600 MHz, CDCl₃): d=2.32–2.45 (m, 2H, bridge-CH₂-), 2.60 (s, 6H, 2

-CH₃), 3.17–3.31 (m, 2H, bridge-CH₂-), 3.39–3.49 (m, 2H, bridge-CH₂-),

3.50–3.61 (m, 2H, bridge-CH₂-), 6.39 (d, ³J=7.8 Hz, 2H, 7-, 13-H or 8-,

12-H), 6.62 (d, ³J=7.8 Hz, 2H, 8-, 12-H or 7-, 13-H), 12.80 ppm(s, 2H,

2OH); ¹³C NMR (151 MHz, CDCl₃): d=26.97, 27.38, 30.90, 118.47,

120.44, 123.27, 133.69, 139.14, 158.52, 200.66 ppm; MS (70 eV): m/z (%):

324 (64) [M]⁺, 306 (37), 291 (14), 281 (12), 189 (12), 161 (100), 153 (12),

A

Dimethyl 8-bromo[2.2]paracyclophane-4,15-dicarboxylate (36): M.p.

C

149.5–1518C; ¹H NMR (600 MHz, CDCl₃): d=2.96–3.34 (m, 5H, bridge-

CH₂-), 3.64–3.77 (m, 1H, bridge-CH₂-), 3.87–3.94 (m, 1H, bridge-CH₂-),

3.96 (s, 3H, CH₃), 3.99 (s, 3H, CH₃), 4.33–4.45 (m, 1H, bridge-CH₂-),

6.67 (d, ³J=7.8 Hz, 1H, 15-H), 6.74 (dd, ³J=7.8, ⁴J=1.8 Hz, 1H, 16-H),

4614

www.chemeurj.org

ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2008, 14, 4600 – 4617

Symmetrically Tetrasubstituted [2.2]Paracyclophanes

FULL PAPER

147 (61), 133 (66), 119 (65), 115 (51), 105 (36); elemental analysis calcd

(%) for C₂₀H₂₀O₄: C 74.06, H 6.21; found: C 74.13, H 6.33.

evaporated under reduced pressure and the residue was subjected to

preparative chromatography on silica gel. MS (70 eV): m/z (%): 386 (46)

[M]⁺, 385 (71) [M]⁺, 280 (19), 266 (45), 265 (79), 264 (61), 263 (17), 250

(22), 249 (12), 174 (12), 162 (50), 161 (91), 160 (96), 159 (17), 133 (23),

132 (44), 131 (13), 130 (14), 122 (45), 121 (10), 120 (42), 118 (20), 117

(21), 116 (11), 115 (28), 107 (11), 106 (49), 105 (100), 104 (41), 103 (50).

The equimolar mixture of diastereomeric (R_p,R)- and (S_p,R_c)-26 was sep-

arated by preparative chromatography on silica gel (CH₂Cl₂/Et₂O 10:1)

to produce 0.052 g (85%) of diastereomerically pure (S_p,R)-26 (R_f=0.32,

CH₂Cl₂/Et₂O/Et₃N 10:1:0.1) and 0.056 g (91%) of diastereo-merically

pure (R_p,R)-26 (R_f=0.23, CH₂Cl₂/Et₂O/Et₃N 10:1:0.1).

General procedure for the synthesis of the Schiff bases of bis-

acetylhydroxy

A

a solution of bis-

acetylhydroxy

ACHTREUNG

(30 mL) enantiomerically pure a-PEAM (0.22 mL, 1.8 mmol) and a cata-

lytic amount of Et₂SnCl₂were added. The reaction mixture was refluxed

for 40 h in a flask equipped with a Dean-Stark trap filled with MgSO₄.

The solvent was evaporated under reduced pressure and the residue was

subjected to preparative chromatography on silica gel.

Separation of the diastereomeric Schiff bases of 21 with (R)-a-PEAM:

The equimolar mixture of diastereomeric (R,R_p,R)- and (R,S_p,R)-25 was

separated by preparative chromatography on silica gel (toluene/EtOH

20:1) to produce 0.18 g (92%) of diastereomerically pure (R,S_p,R)-25

(R_f=0.60) and 0.16 g (84%) of diastereomerically pure (R,R_p,R)-25 (R_f=

0.45).

(S_p,R)-4,15-Dihydroxy-5[1-(1-phenylethylimino)-ethyl][2.2]paracyclophane

T

26 ((S_p,R)-26): An analytically pure sample was obtained by recrystalliza-

tion froma toluene/hexane mixture. M.p. 154.0–154.5 8C; [a]²_D⁵=À453.48

1

3

(c=0.31 in toluene); H NMR (600 MHz, CDCl₃): d=1.75 (d, J=6.5 Hz,

3H, CH₃), 2.29 (s, 3H, CH₃), 2.46–2.58 (m, 1H, bridge-CH₂-), 2.61–2.72

(m, 1H, bridge-CH₂-), 2.75–2.86 (m, 1H, bridge-CH₂-), 2.87–3.07 (m, 2H,

bridge-CH₂-), 3.11–3.21 (m, 1H, bridge-CH₂-), 3.24–3.36 (m, 1H, bridge-

CH₂-), 3.38–3.49 (m, 1H, bridge-CH₂-), 4.43 (brs, 1H, C-15(OH)), 4.89

A

N

cyclophane (bis-(ortho)-pseudo-meta, (R,S_p,R)-25): Decomp. temp. 230–

1

2358C; [a]²_D⁵=+914.78 (c=0.23 in toluene); H NMR (600 MHz, CDCl₃):

3

(q, J=6.5 Hz, H,=N-CH), 5.70 (d, ⁴J=1.8 Hz, 1H, 16-H), 6.11 (dd, ³J=

d=1.75 (d, 6H, 2 CH₃, ³J=6.5 Hz), 2.29 (2s, 6H, 2 CH₃), 2.38–2.51 (m,

2H, bridge-CH₂-), 2.71–2.84 (m, 2H, bridge-CH₂-), 3.22–3.34 (m, 2H,

bridge-CH₂-), 3.38–3.51 (m, 2H, bridge-CH₂-), 4.89 (q, 2H, 2 CH, ³J=

6.5 Hz), 6.06 (d, ³J=7.8 Hz, 2H, 7-, 12-H or 8-, 13-H), 6.95 (d, ³J=

7.8 Hz, 2H, 8-, 13-H or 7-, 12-H), 7.21–7.29 (m, 2H, Ph), 7.31–7.40 (m,

8H, Ph), 15.89 ppm(s, 2H, 2 OH); ¹³C NMR (151 MHz, CDCl₃): d=

15.92, 21.36, 24.97, 33.89, 54.28, 116.97, 120.05, 122.25, 123.13, 124.82,

125.58, 126.87, 134.30, 139.80, 158.96, 166.37 ppm; MS (70 eV): m/z (%):

530 (2) [M]⁺, 409 (17), 304 (8), 265 (16), 161 (41), 160 (56), 132 (11), 105

(100), 104 (20); elemental analysis calcd (%) for C₃₆H₃₈N₂O₂: C 81.48, H

7.22, N 5.28; found: C 81.63, H 7.35, N 5.22.

4

7.8, J=1.8 Hz, 1H, 12-H), 6.17, 6.89, 6.95 (3d, J=7.8 Hz, 3H, 13-, -7, 8-

H), 7.13–7.40 (m, 5H, Ph), 15.91 ppm (s, 1H, C(4)-OH); elemental analy-

sis calcd (%) for C₂₆H₂₇NO₂: C 81.01, H 7.06, N 3.63; found: C 81.10, H

7.23, N 3.37.

(R_p,R)-4,15-Dihydroxy-5[1-(1-phenylethylimino)ethyl][2.2]paracyclophane

A

26 ((R_p,R)-26): An analytically pure sample was obtained by recrystalli-

zation fromheptane; m.p. 178 8C; [a]²_D⁵=+103.78 (c=0.19 in toluene);

¹H NMR (600 MHz, CDCl₃): d=1.75 (d, ³J=6.5 Hz, 3H, CH₃), 2.29 (s,

3H, CH₃), 2.46–2.58 (m, 1H, bridge-CH₂-), 2.61–2.72 (m, 1H, bridge-

CH₂-), 2.75–2.86 (m, 1H, bridge-CH₂-), 2.87–3.07 (m, 2H, bridge-CH₂-),

3.11–3.21 (m, 1H, bridge-CH₂-), 3.24–3.36 (m, 1H, bridge-CH₂-), 3.38–

(R,R_p,R)-4,15-Dihydroxy-5,16-[di-1-(1-phenylethylimino)ethyl][2.2]para-

3

3.49 (m, 1H, bridge-CH₂-), 4.43 (brs, 1H, C-15(OH)), 4.89 (q, J=6.5 Hz,

cyclophane (bis-(ortho)-pseudo-meta, (R,R_p,R)-25): M.p. 74–758C;

[a]²_D⁵=+238.88 (c=0.17 in toluene); ¹H NMR (600 MHz, CDCl₃): d=

1.67 (d, 6H, 2CH₃, ³J=6.5 Hz), 1.98–2.11 (m, 2H, bridge-CH₂-), 2.22 (s,

6H, 2CH₃), 2.69–2.87 (m, 2H, bridge-CH₂-), 3.06–3.20 (m, 2H, bridge-

CH₂-), 3.22–3.36 (m, 2H, bridge-CH₂-), 4.85 (q, ³J=6.5 Hz, 2H, 2 CH),

4

3

4

H,=N-CH), 5.70 (d, J=1.8 Hz, 1H, 16-H), 6.11 (dd, J=7.8, J=1.8 Hz,

1H, 12-H), 6.17, 6.89, 6.95 (3d, ³J=7.8 Hz, 3H, 13-, 7-, 8-H), 7.13–7.40

(m, 5H, Ph), 15.91 ppm (s, 1H, C-4(OH)); elemental analysis calcd (%)

for C₂₆H₂₇NO₂: C 81.01, H 7.06, N 3.63; found: C 81.10, H 7.23, N 3.37.

3

5.65 (d, J=7.8 Hz, 2H, 7-, 12-H or 8-, 13-H), 6.88 (d, J=7.8 Hz, 2H, 8-,

Enantioselective diethylzinc addition to benzaldehyde catalyzed by

12-H or 7-, 13-H), 7.27–7.36 (m, 2H, Ph), 7.40–7.48 (m, 4H, Ph), 7.55 (d,

(R,R_p,R)-25, (R,S_p,R)-25, (S_p,R)-26, (S,{R_p,S_p},S)-39; typical procedure:

A

³J=7.5 Hz, 4H,

4 ortho-Ph), 15.91 ppm(s, 2H, 2

OH); ¹³C NMR

To a solution of a Schiff base (0.01 mmol) in toluene (0.28 mL), Et₂Zn

(0.2 mL of 1.1m solution in toluene, 0.22 mmol) was added in one portion

at 08C. Subsequently benzaldehyde (0.1 mmol) was added dropwise and

the reaction mixture was stirred for 15 h at room temperature. The mix-

ture was quenched with 1n HCl (0.45 mL), diluted with Et₂O (2 mL) and

H₂O (1 mL). The organic layer was separated, the aqueous layer was ex-

tracted with Et₂O (32 mL) or CH₂Cl₂(32 mL) and the combined or-

ganic fractions were washed with aq. NaHCO₃(3 mL) and dried over

Na₂SO₄. The oily residue obtained after solvent removal was subjected

without further purification to chiral HPLC. Enantiomeric analysis of 1-

phenylpropanol was performed by HPLC (Varian 5000 LC) on Chiralcel

OD (250 mm4.6 mm) with hexane/isopropanol 100:4, flow rate

(151 MHz, CDCl₃): d=19.72, 24.82, 28.93, 37.70, 58.22, 120.90, 124.28,

126.57, 127.31, 128.81, 129.34, 130.66, 138.41, 144.49, 162.97, 169.97 ppm;

MS (70 eV): m/z (%): 530 (24) [M]⁺, 425 (17), 409 (48), 304 (46), 288

(36), 265 (65), 160 (82), 146 (20), 132 (24), 105 (100); elemental analysis

calcd (%) for C₃₆H₃₈N₂O₂: C 81.48, H 7.22, N 5.28; found: C 81.43, H

7.20, N 5.20.

((S,

N

G

ACHTREUNG

purification of the reaction mixture on silica gel (CH₂Cl₂/Et₂O 10:1) with

a chemical yield of 0.33 g (86%); m.p. 79–808C; [a]²_D⁵=À130.78 (c=0.28

in toluene); ¹H NMR (600 MHz, CDCl₃): d=1.74 (d, ³J=6.5 Hz, 3H,

CH₃), 1.79 (d, ³J=6.5 Hz, 3H, CH₃), 1.97–2.13 (m, 1H, bridge-CH₂-),

2.26–2.48 (m, 1H, bridge-CH₂-), 2.39 (s, 6H, 2 -CH₃), 3.08–3.57 (m, 6H,

bridge-CH₂-), 4.87–5.04 (m, 2H, 2 -CH-), 6.08 (d, ³J=7.8 Hz, 1H, 7- or

À1

1 m Lm in , temperature 208C, detector UV 254 nm: the retention times

were 9.4 (S) and 11.1 min (R), respectively.

X-ray crystallographic study of 21, (R,S_p,R)-25 and (S_p,R)-26: The struc-

tures were solved by direct methods and refined by the full-matrix least-

squares against F²in anisotropic (for non-hydrogen atoms) and isotropic

(for H atoms) approximation. All hydrogen atoms (with the exception of

the H atoms of OH-and N-H groups) were placed in geometrically calcu-

lated positions and included in the final refinement using the riding

3

13- or 8- or 12-H,), 6.45 (d, J=7.8 Hz, 1H, 7- or 13- or 8- or 12-H), 6.56

3

(d, J=7.8 Hz, 7- or 13- or 8- or 12-H), 6.60 (d, ³J=7.8 Hz, 1H, 7- or 13-

or 8- or 12-H), 7.25–7.63 (m, 10H, 2 Ph), 15.82 (brs, 1H, OH), 16.02 ppm

(brs, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): d=16.32, 16.47, 20.93,

21.43, 27.44, 27.64, 30.94, 30.98, 54.14, 54.26, 117.95, 118.05, 119.05,

119.12, 122.28, 122.46, 123.14, 123.32, 124.84 (2C), 129.09, 129.54, 137.24,

137.50, 139.85, 140.56, 158.74, 159.03, 166.60, 166.81 ppm; MS (70 eV):

m/z (%): 530 (17) [M]⁺, 425 (37), 409 (31), 304 (12), 265 (45), 160 (82),

146 (21), 132 (33), 105 (100); HRMS: calcd for C₃₆H₃₈O₂N₂: m/z:

530.2933 [M]⁺; found: 530.2687.

model with the U_iso(H) parameters equal to 1.2U_eq(C_i) or 1.5U_eq

ACHTREUNG

where

U(C_i) and U

ACHTREUNG

the sp²and sp³carbon atoms to which the respective H atoms are

bonded. The H atoms of OH and NH- groups were located from the dif-

ference Fourier synthesis and included in the final refinement using the

riding model with the U_iso(H) parameters equal to 1.2U_eq(O_i), where

U(O_ii) are the equivalent thermal parameters of the oxygen atoms to

which respective H atoms are bonded. The analysis of the Fourier elec-

tron density synthesis has revealed that toluene solvate molecules are dis-

Synthesis and separation of the diastereomeric Schiff bases of 22: To a

solution of 22 (0.09 g, 0.32 mmol) in toluene (6 mL) enantiomerically

pure (R)-a-PEAM (0.05 mL, 0.38 mmol) and

a catalytic amount of

Et₂SnCl₂were added. The reaction mixture was refluxed for 3 h in a flask

equipped with a Dean-Stark trap filled with MgSO₄. The solvent was

Chem. Eur. J. 2008, 14, 4600 – 4617

ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4615

V. I. Rozenberg, H. Hopf et al.

Table 3. Crystal data and structure refinement parameters for 21,

(R,S_p,R)-25 and (S_p,R)-26.

Chem. Soc. 2002 , 124 , 518 3 –5 196; d) J. Zyss, I. Ledoux, S. Volkov,

V. Chernyak, S. Mukamel, G. Bartholomew, G. Bazan, J. Am. Chem.

Soc. 2000 , 122 , 1195 6 –1 1962; e) J. W. Hong, H. Y. Woo, B. Liu,

G. C. Bazan, J. Am. Chem. Soc. 2005 , 127 , 743 5 –7 443, and referen-

ces therein.

21

G

empirical formula

formula weight

T [K]

C₂₀H₂₀O₄

324.36

120

C₃₆H₃₈N₂O₂

530.68

163

C₂₆H₂₇NO₂

431.55

100

[4] a) V. Rozenberg, E. Popova, H. Hopf, Helv. Chim. Acta 2002 , 85 ,

43 1 –4 41; b) E. L. Popova, V. I. Rozenberg, Z. A. Starikova, S.

Keuker-Baumann, H.-Z. Kitzerow, H. Hopf, Angew. Chem. 2002 ,

114 , 356 1 –3 564; Angew. Chem. Int. Ed. 2002 , 41 , 341 1 –3 414.

[5] a) Y. Morisaki, N. Wada, Y. Chujo, Polym. Bull. 2005 , 53 , 7 3 –8 0;

b) Y. Morisaki, Y. Chujo, Macromolecules 2004 , 37 , 409 9 –4 103;

c) H. Hopf, Angew. Chem. 2008, 120, submitted; Angew. Chem. Int.

Ed. 2008, 47, submitted.

[6] a) H.-Y. Chen, Y. Elkasabi, J. Lahann, J. Am. Chem. Soc. 2006 , 128 ,

37 4 –3 80; b) M. Herrera-Alonso, T. J. McCarthy, Langmuir 2004 , 20 ,

918 4 –9 189; c) H.-Y. Chen, J. Lahann, Anal. Chem. 2005 , 77 , 690 9 –

6914; d) J. Lahann, M. Balcells, H. Lu, T. Rodon, K. F. Jensen, R.

Langer, Anal. Chem. 2003 , 75 , 211 7 –2 122; e) J. Lahann, R. Langer,

Macromolecules 2002 , 35 , 438 0 –4 386.

[7] See ref. [2]: V. I. Rozenberg, E. V. Sergeeva, H. Hopf in Modern Cy-

clophane Chemistry, Chapter 17: Cyclophanes as Templates in Ste-

reoselective Synthesis, pp. 435–462.

[8] a) H. A. Staab, R. Reimann-Haas, P. Ulrich, C. Krieger, Chem. Ber.

1983 , 116 , 280 8 –2 826 and references therein. b) R. Gleiter, W. Schä-

fer, H. A. Staab, Chem. Ber. 1988 , 121 , 125 7 –1 264 and references

therein.

[9] a) H. A. Staab, H. Haffner, Chem. Ber. 1977 , 110 , 335 8 –3 365;

b) H. A. Staab, V. Taglieber, Chem. Ber. 1977 , 110 , 336 6 –3 376.

[10] a) H. Hopf, F. T. Lenich, Chem. Ber. 1974 , 107 , 189 1 –1 897; b) H.

Hopf, Angew. Chem. 1972 , 84 , 471; Angew. Chem. Int. Ed. Engl.

1972 , 11 , 419; c) H. Hopf, I. Bçhm, J. Kleinschroth, Org. Synth.

1981, 60, 41–48; d) I. Bçhm, H. Hermann, K. Menke, H. Hopf,

Chem. Ber. 1978 , 111 , 52 3 –5 28; e) J. Kleinschroth, H. Hopf, Angew.

Chem. 1979 , 91 , 336; Angew. Chem. Int. Ed. Engl. 1979 , 18 , 329;

f) S. Sankararaman, H. Hopf, I. Dix, P. G. Jones, Eur. J. Org. Chem.

2000 , 269 9 –2 701.

crystal system

size [mm]

space group

Z(Z’)

monoclinic

0.60.40.2

P2₁/n

orthorhombic tetragonal

0.50.40.3 0.40.030.03

P2₁2₁2₁

4(1)

P4₃

4(1)

a []

b []

c []

a [8]

7.706(1)

14.489(2)

14.376(2)

90.00

7.841(2)

15.280(5)

23.705(7)

90.00

16.641(2)

9.211(2)

90.00

b [8]

103.573(4)

90.00

1560.2(4)

1.381

90.00

2840.2(15)

1.241

90.00

2550.6(7)

1.124

g [8]

V [³]

1_calcd[gcm^À1

]

linear absorption, m

[cm^À1

(000)

0.95

0.76

0.7

]

F

G

688

1136

924

2q_max[8]

56

52

diffractometer

Smart 1000

CCD

w

Syntex P21

Smart Apex II

CCD

w

scan type

q/2q

completeness of data

set [%]

98.5

98.1

99.4

reflections measured

11687

3336

19222

[R_int=0.0612]

[R_int=0.0104] [R_int=0.0931]

independent reflections 3686

observed reflections [I 1843

> 2s(I)]

3298

2835

2787

1874

parameters

R1

wR2

GOF

D1_max, D1_min[e

217

361

297

0.0667

0.1321

1.039

0.371/À0.379

0.0548

0.1328

0.981

0.0621

0.1708

1.083

[11] a) H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 1969 , 91 , 352 7 –3 533;

b) B. Kçnig, B. Knieriem, A. de Meijere, Chem. Ber. 1993 , 126 ,

164 3 –1 650.

À3

]

0.386/À0.327 0.416/À0.237

[12] H.-F. Chou, H.-H. Low, K. Y. Wong, Synlett 2005, 2130–2134.

[13] a) V. I. Rozenberg, V. G. Kharitonov, D. Yu. Antonov, E. V. Sergee-

va, A. A. Aleshkin, N. S. Ikonnikov, S. A. Orlova, Yu. N. Belokon’,

Angew. Chem. 1994 , 106 , 10 6 –1 08; Angew. Chem. Int. Ed. Engl.

1994 , 33 , 9 1 –9 2; b) D. Yu. Antonov, Yu. N. Belokon’, N. S. Ikonni-

kov, S. A. Orlova, A. P. Pisarevsky, N. I. Raevsky, V. I. Rozenberg,

E. V. Sergeeva, Yu. T. Struchkov, V. I. Tararov, E. V. Vorontsov, J.

Chem. Soc. Perkin Trans. 1 1995, 1873–1879; c) V. Rozenberg, N.

Dubrovina, E. Vorontsov, E. Sergeeva, Yu. Belokon’, Tetrahedro n :

Asymmetry 1999 , 10 , 51 1 –5 17; d) V. Rozenberg, T. Danilova, E. Ser-

geeva, E. Vorontsov, Z. Starikova, K. Lysenko, Yu. Belokon’, Eur. J.

Org. Chem. 2000 , 329 5 –3 303; e) V. I. Rozenberg, D. Yu. Antonov,

R. P. Zhuravsky, E. V. Vorontsov, V. N. Khrustalev, V. N. Ikonnikov,

Yu. N. Belokon’, T e trahedro n : A symmetry 2000 , 11 , 268 3 –2 693;

f) N. V. Vorontsova, V. I. Rozenberg, E. V. Vorontsov, O. L. Tok,

Yu. N. Bubnov, Russ. Chem. Bull. Int. Ed. 2000, 5, 914–921; g) V. I.

Rozenberg, T. I. Danilova, E. V. Sergeeva, E. Vorontsov, Z. Stariko-

va, A. Korlyukov, H. Hopf, Eur. J. Org. Chem. 2002 , 46 8 –4 77;

h) E. V. Sergeeva, V. I. Rozenberg, D. Yu. Antonov, E. V. Vorontsov,

Z. A. Starikova, H. Hopf, Tetrahedro n : A symmetry 2002 , 13 , 112 1 –

1123; i) V. I. Rozenberg, T. I. Danilova, E. V. Sergeeva, I. A. Shou-

klov, E. Vorontsov, Z. Starikova, H. Hopf, K. Kꢂhlein, Eur. J. Org.

Chem. 2003 , 43 2 –4 40; j) T. I. Danilova, V. I. Rozenberg, Z. A. Stari-

kova, S. Bräse, Tetrahedro n : A symmetry 2004 , 15 , 22 3 –2 29; k) V. I.

Rozenberg, D. Yu. Antonov, E. V. Sergeeva, E. V. Vorontsov, Z. A.

Starikova, I. V. Fedyanin, C. Schulz, H. Hopf, Eur. J. Org. Chem.

2003 , 205 6 –2 061; l) T. I. Danilova, V. I. Rozenberg, E. V. Sergeeva,

Z. A. Starikova, S. Bräse, Tetrahedro n : A symmetry 2003 , 14 , 201 3 –

2019; m) N. Vorontsova, V. Rozenberg, E. Vorontsov, D. Antonov,

Z. Starikova, Eur. J. Org. Chem. 2003, 4, 761–770; n) V. I. Rozen-

ordered by two positions. The disordered toluene molecules were refined

as rigid groups in isotropic approximation. Crystal data and structure re-

finement parameters for 21, (R,S_p,R)-25 and (S_p,R)-26 are given in

Table 3. All calculations were performed using the SHELXTL software

[G. M. Sheldrick, SHELXTL-97, Version 5.10, Bruker AXS Inc., Madi-

son, WI-53719, USA].

CCDC 614214 (21), 614215 [(R_c,S_p,R_c)-25] and 626319 [(S_p,R)-26] contain

the supplementary crystallographic data for this paper. These data can be

obtained free of charge fromThe Cambridge Crystallographic Data

Centre via www.ccdc.cam.ac.uk/data_request/cif.

Acknowledgements

This work was financially supported by the Russian Foundation for Basic

Research (Grants Ref. No. 06-03-33086). The authors are grateful to Dr.

Mikhail M. Il’in (INEOS RAS, Moscow, Russia) for the enantiomeric

analysis.

[1] C. J. Brown, A. C. Farthing, Nature 1949, 163, 915–916.

[2] Modern Cyclophane Chemistry (Eds.: R. Gleiter, H. Hopf), Wiley-

VCH, Weinheim, 2004.

[3] For a review see: a) G. P. Bartholomew, G. C. Bazan, Acc. Chem.

Res. 2001 , 34 , 3 0 –3 9; selected original papers: b) G. P. Bartholomew,

I. Ledoux, S. Mukamel, G. C. Bazan, J. Zyss, J. Am. Chem. Soc.

2002 , 124 , 1348 0 –1 3485; c) G. Bartholomew, G. Bazan, J. Am.

4616

www.chemeurj.org

ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2008, 14, 4600 – 4617

Symmetrically Tetrasubstituted [2.2]Paracyclophanes

FULL PAPER

berg, D. Yu. Antonov, R. P. Zhuravsky, E. V. Vorontsov, Z. A. Stari-

kova, Tetrahedron Lett. 2003 , 44 , 380 1 –3 804; o) E. V. Sergeeva, V. I.

Rozenberg, D. Yu. Antonov, E. V. Vorontsov, Z. A. Starikova, I. V.

Fedyanin, H. Hopf, Chem. Eur. J. 2005 , 11 , 694 4 –6 961.

[14] a) E. Popova, D. Yu. Antonov, E. V. Sergeeva, E. V. Vorontsov, A.

Stash, V. I. Rozenberg, H. Hopf, Eur. J. Inorg. Chem. 1998 , 173 3 –

1737; b) G. N. Gerasimov, E. L. Popova, E. V. Nikolaeva, S. N. Chva-

lun, E. I. Grigoriev, L. I. Trakhtenberg, V. I. Rozenberg, H. Hopf,

Makromol. Chem. Phys. 1998 , 199 , 217 9 –2 184.

[15] a) N. V. Vorontsova, V. I. Rozenberg, E. V. Vorontsov, D. Y. Anto-

nov, Z. A. Starikova, Yu. N. Bubnov, Izv. Akad. Nauk, Ser. Khim.

2002, 8, 1369–1375 [Russ. Chem. Bull. Int. Ed. (Engl. Transl.) 2002,

8, 1483–1490]; b) N. Vorontsova, E. Vorontsov, D. Antonov, Z. Star-

ikova, K. Butin, S. Bräse, S. Hçefener, V. Rozenberg, Adv. Synth.

Catal. 2005 , 347 , 12 9 –1 35.

[16] R. Gray, V. Boekelheide, J. Am. Chem. Soc. 1979 , 101 , 212 8 –2 136.

[17] D. Ch. Braddock, I. D. MacGlip, B. G. Perry, Adv. Synth. Catal.

2004, 346, 1117–1130.

[18] B. Domingues, A. Zanotti-Gerosa, W. Hems, Org. Lett. 2001, 6,

1927–1930.

[19] A. Pelter, B. Mootoo, A. Maxwell, A. Reid, Tetrahedron Lett. 2001 ,

42 , 839 1 –8 394.

[20] Preliminary results on the double electrophilic substitution of

pseudo-meta-disubstituted [2.2]paracyclophanes: N. V. Vorontsova,

E. V. Vorontsov, E. V. Sergeeva, V. I. Rozenberg, T e trahedron Lett.

2006 , 47 , 235 7 –2 360.

[30] The symmetry properties of several [2.2]paracyclophanes mono-, di-

and tetrasubstituted in aromatic rings and ethano bridges were illus-

trated by Cramwith co-authors, using as examples the respective

bromides which were obtaind in their group at the time: D. J. Cram,

R. B. Hornby, E. A. Truesdale, H. J. Reich, M. H. Delton, J. M.

Cram, Tetrahedron 1974 , 30 , 175 7 –1 768.

[31] V. A. Nikanorov, V. G. Kharitonov, E. V. Yatsenko, D. P. Krut’ko,

M. V. Galakhov, S. O. Yakushin, V. V. Mikulꢁshina, V. I. Rozenberg,

V. N. Guryshev, V. P. Yur’ev, O. A. Reutov, Izv. Akad. Nauk, Ser.

Khim. 1992, 1837–1843 [Russ. Chem. Bull. Int. Ed. 1993, 1430–

1434].

[32] L. Bondarenko, I. Dix, H. Hinrichs, H. Hopf, Synthesis 2004, 2751–

2759.

[33] a) H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 1969 , 91 , 351 7 –3 526;

b) D. Yu. Antonov, E. V. Sergeeva, E. V. Vorontsov, V. I. Rozenberg,

Russ. Chem. Bull. 1997, 106, 1897–1900.

[34] a) P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante, P. J.

Reider, J. Am. Chem. Soc. 1997 , 119 , 620 7 –6 208; b) A. Zanotti-

Gerosa, C. Malan, D. Herzberg, Org. Lett. 2001 , 3 , 368 7 –3 690.

[35] a) T. Focken, J. Rudolph, C. Bolm, Synthesis 2005, 429–436; b) T.

Focken, G. Raabe, C. Bolm, Tetrahedro n : A symmetry 2004 , 15 ,

169 3 –1 706; c) D. K. Whelligan, C. Bolm, J. Org. Chem. 2006 , 71 ,

460 9 –4 618.

[36] a) V. I. Rozenberg, R. P. Zhuravsky, E. V. Sergeeva, Chirality 2006 ,

18 , 9 5 –1 02; b) D. Yu. Antonov, V. I. Rozenberg, T. I. Danilova,

Z. A. Starikova, H. Hopf, Eur. J. Org. Chem. 2008, 1038–1048..

[37] a) H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 1969 , 91 , 350 5 –3 516;

b) H. Zitt, I. Dix, H. Hopf, P. G. Jones, Eur. J. Org. Chem. 2002 ,

229 8 –2 307.

[21] D. J. Cram, R. H. Bauer, N. L. Allinger, R. A. Reevs, W. J. Wechter,

E. Heilbronner, J. Am. Chem. Soc. 1959 , 81 , 597 7 –5 983.

[22] a) R. G. Hegelson, T. L. Tarnovski, J. M. Titko, D. J. Cram, J. Am.

Chem. Soc. 1977, 99, 6411–6418; b) A. Pelter, H. Kidwell,

R. A. N. C. Crump, J. Chem. Soc. Perkin Trans. 1 1997 , 313 7 –3 139;

c) P. B. Hitchcock, G. J. Rowlands, P. Parmar, Chem. Commun. 2005 ,

421 9 –4 221.

[38] D. Ch. Braddock, I. MacGilp, B. G. J. Perry, J. Org. Chem. 2002, 67,

8679–8681.

[39] K. Krohn, H. Rieger, H. Hopf, D. Barrett, P. G. Jones, D. Dçring,

Chem. Ber. 1990 , 123 , 172 9 –1 732.

[23] S. Takahashi, N. Mori, J. Chem. Soc. Perkin Trans. 1 1991 , 202 9 –

2032.

[24] a) V. Boekelheide, in Cyclophanes I, 1983, Academic-Verlag, Berlin

(F. Vçgtle, ed.); b) F. Vçgtle, Cyclophane Chemistry, Wiley, Chiches-

ter, 1993.

[40] a) Y. L. Yeh, W. F. Gorham, J. Org. Chem. 1969 , 34 , 236 6 –2 370.

[41] D. Cram, J. Am. Chem. Soc. 1975, 97, 3782–3788.

[42] S. Bräse, S. Dahmen, S. Hçfener, F. Lauterwasser, M. Kreis, R. Zie-

gert, Synlett 2004 , 264 7 –2 669.

[43] a) X.-W. Wu, X.-L. Hou, L.-X. Dai, J. Tao, B.-X. Cao, J. Sun, Tetra-

hedron: Asymmetry 2001 , 12 , 52 9 –5 32; b) A. Marchand, A. Max-

well, B. Mootoo, A. Pelter, A. Reid, Tetrahedron 2000 , 56 , 733 1 –

7338.

[25] T. Furo, T. Mori, T. Wada, Y. Inoue, J. Am. Chem. Soc. 2005 , 127 ,

824 2 –8 243.

[26] H. Hopf, C. Mlynek, J. Org. Chem. 1990 , 55 , 136 1 –1 363.

[27] a) International Union of Pure and Applied Chemistry, Organic

Chemistry Division. Comission on Nomencalture of Organic

Chemistry. “Phane Nomenclature. Part I: Phane parent names

(IUPAC Recommendations 1998)”, Pure Appl. Chem. 1998, 70,

1513–1545; b) International Union of Pure and Applied Chemistry.

Organic Chemistry Division. Comission on Nomencalture of Organ-

ic Chemistry. “Phane nomenclature. Part II: Modification of the

degree of hydrogenation and substitution derivatives of phane

parent hydride (IUPAC Recommendations 2002)”, Pure Appl.

Chem. 2002, 74, 809–834; c) International Union of Pure and Ap-

plied Chemistry. Organic Chemistry Division. Comission on Nomen-

calture of Organic Chemistry. A Guide to IUPAC Nomenclature of

Organic Compounds (Eds.: R. Panico, W. H. Powell, J.-C. Richer),

Blackwell Scientific Publications, Oxford, 1993, R-0.2.4.2.

[28] H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 1968 , 90 , 136 5 –1 367.

[29] a) R. P. Stanley, Enumerative combinatorics, Wadsworth and Brooks/

Cole, Monterey, CA, 1986, v 1; b) R. L. Graham, D. E. Knuth, O.

Patashnik, Concrete mathematics, Addison-Wesley, Reading, MA,

1988.

[44] H. J. Reich, K. E. Yelm, J. Org. Chem. 1991 , 56 , 567 2 –5 679.

[45] L. Ernst, L. Wittkowski, Eur. J. Org. Chem. 1999 , 165 3 –1 663.

[46] In this particular part of the work we will use the denotations

{R_p,R_p} and {R_p,S_p} for description of the “interior” of the paracyclo-

phanyl fragment in the respective chiral and achiral di- and tetrasub-

stituted derivatives.

[47] T. I. Danilova, V. I. Rozenberg, E. V. Vorontsov, Z. A. Starikova, H.

Hopf, Tetrahedro n : A symmetry 2003 , 14 , 137 5 –1 383.

[48] H. Hopf, D. C. Barrett, Liebigs Ann. 1995, 449–452.

[49] T. Focken, H. Hopf, V. Snieckus, I. Dix, P. G. Jones, Eur. J. Org.

Chem. 2001 , 222 1 –2 228.

[50] P. B. Hitchcock, G. J. Rowlands, R. J. Seacome, Org. Biomol. Chem.

2005 , 3 , 387 3 –3 876.

[51] V. Snieckus, Chem. Rev. 1990 , 90 , 87 9 –9 33.

Received: October 24, 2007

Published online: April 2, 2008

Chem. Eur. J. 2008, 14, 4600 – 4617

ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

4617

Article Doi

Symmetrically tetrasubstituted [2.2]paracyclophanes: Their systematization and regioselective synthesis of several types of bis-bifunctional derivatives by double electrophilic substitution

DOI: 10.1002/chem.200701683

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