The first regioselective double electrophilic substitution of the C2-symmetric pseudo-meta-disubstituted [2.2]paracyclophanes

Article abstract of DOI:10.1016/j.tetlet.2006.02.003

We report here the first examples of the regioselective double electrophilic substitution of chiral C₂-symmetric pseudo-meta-disubstituted [2.2]paracyclophanes. Thus, the double acylation of 4,15-dihydroxy[2.2]paracyclophane occurs ortho-regioselectively, whereas the double acylation of its respective dimethyl ether is completely para-regioselective. Double bromination of 4,15-dicarbomethoxy[2.2]paracyclophane regioselectively generates the pseudo-gem-substitution pattern. The approaches elaborated allow the synthesis of all three possible types of chiral bis-bifunctional compounds, which have two independent, although chemically and stereochemically equal, functional fragments with pseudo-meta mutual orientation of both pairs of identical substituents.

Full text of DOI:10.1016/j.tetlet.2006.02.003

Tetrahedron Letters 47 (2006) 2357–2360
The first regioselective double electrophilic substitution of the
C2-symmetric pseudo-meta-disubstituted [2.2]paracyclophanes
Natalia V. Vorontsova, Evgenii V. Vorontsov, Elena V. Sergeeva
and Valeria I. Rozenberg*
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28, Vavilova, V-334, GSP-1,
Moscow 119991, Russia
Received 1 December 2005; revised 23 January 2006; accepted 1 February 2006
Available online 20 February 2006
Abstract—We report here the first examples of the regioselective double electrophilic substitution of chiral C2-symmetric pseudo-
meta-disubstituted [2.2]paracyclophanes. Thus, the double acylation of 4,15-dihydroxy[2.2]paracyclophane occurs ortho-regioselec-
tively, whereas the double acylation of its respective dimethyl ether is completely para-regioselective. Double bromination of 4,15-
dicarbomethoxy[2.2]paracyclophane regioselectively generates the pseudo-gem-substitution pattern. The approaches elaborated
allow the synthesis of all three possible types of chiral bis-bifunctional compounds, which have two independent, although chemi-
cally and stereochemically equal, functional fragments with pseudo-meta mutual orientation of both pairs of identical substituents.
Ó 2006 Elsevier Ltd. All rights reserved.
In our project aimed at developing chiral [2.2]paracyclo-
phane derivatives to be used as planar chiral ligands in
asymmetric catalysis,1 we have been working on regio-
selective approaches to the functionalization of several
monosubstituted [2.2]paracyclophanes.1a,c,2 In particu-
lar, we have revealed the regularities of the ortho-
and para-regioselective formylation and acylation
of 4-hydroxy[2.2]paracyclophane and its methyl
ether.1a,c,2a,c On the other hand, our recent interest in
chiral C2-symmetric bis-bifunctional [2.2]paracyclo-
phanes, that is, those which contain in their structure
two independent, although chemically and stereochemi-
cally identical functional fragments, has led us to set of
multichiral cyclohexadienols, namely (Rp,4Rc,7Rc,
4,23Ra,7,17Ra)-cis-4,7-diarylsubstituted-4,7-dihydroxy-
4,7-dihydro[2.2]paracyclophanes, which possess ele-
ments of planar, central, and axial chirality (Fig. 1).3
In these ligands, the hydroxy groups attached to the
[2.2]paracyclophane scaffold are paired with the
functional groups of the aryl substituents to form two
fragments, both of which are capable of coordination
with a metal and so could work as chiral promoters,
R
R
17
23
X
X
4
7
HO
OH
Figure 1. (Rp,4Rc,7Rc,4,23Ra,7,17Ra)-cis-4,7-Diarylsubstituted-4,7-
dihydroxy-4,7-dihydro[2.2]paracyclophanes.
as was demonstrated by the stereoselective diethylzinc
addition to benzaldehydes (ees up to 93%).3
As another method to construct chiral C2-symmetric
bis-bifunctional compounds, we envisaged the location
of both pairs of functional groups on the aromatic rings
of the [2.2]paracyclophane scaffold. Here, we present
the ortho-, para- and pseudo-gem-regioselective double
electrophilic substitution of pseudo-meta disubstituted
[2.2]paracyclophanes as a rational approach to tetrasub-
stituted [2.2]paracyclophanes, which correspond to three
structurally diverse types of chiral bis-bifunctional
compounds, two of which have never been described
to our knowledge.
Keywords: Cyclophanes; Electrophilic substitution; Regioselectivity;
Bis-bifunctional compounds.
The double electrophilic substitution of [2.2]paracyclo-
phanes with two equal functional groups looks very
attractive from the synthetic point of view, however,
*
Corresponding author. Tel.: +7 495 135 9268; fax: +7 495 135
5085; e-mail: ineos-ghkl@yandex.ru
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.003

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N. V. Vorontsova et al. / Tetrahedron Letters 47 (2006) 2357–2360
little attention has been paid to it so far. The known
examples describe pseudo-gem-regioselective double
chloromethylation of 4,7-dicarbomethoxy[2.2]paracyclo-
phane (of the para-structure),4 ortho-regioselective
double acylation of 4,12-dihydroxy[2.2]paracyclophane
(PHANOL, pseudo-ortho), and para-regioselective chlo-
rosulfonation of its diacetate.5 Dinitration of 4,12-di-
bromo[2.2]paracyclophane was para-regioselective,5
whereas acylation, oxaloylation, and formylation of this
substrate para-regioselectively produced monocarbonyl
compounds only.6
[2.2]paracyclophane (47%) and 4-hydroxy[2.2]paracyc-
lophane (44%) were isolated. Oxidation of the dilithio
derivative with nitrobenzene produced the target diphe-
nol 3 in a low chemical yield (30%). An improved yield
of 3 was achieved by application of a stepwise synthetic
technique, including initial synthesis of 4-bromo-15-
hydroxy[2.2]paracyclophane 2, followed by the synthesis
of the target diphenol 3 therefrom, carrying out each
time the room temperature monolithiation in Et2O,
Li/B exchange, and oxidation. Diphenol 3 was next con-
verted into 4,15-dimethoxy[2.2]paracyclophane 49 via a
standard methoxylation procedure.10
As a model for investigation of the regioselectivity of the
electrophilic substitution, the chiral pseudo-meta-substi-
tuted pattern was chosen. Compounds of this type,
although planar chiral, have never been used in asym-
metric synthesis, since their functional groups, situated
on different sides of the plane passing through the four
bridge carbon atoms, cannot coordinate with a metal.
As a basic synthon, we used 4,15-dibromo[2.2]para-
cyclophane 1 (pseudo-meta). This compound is prepared
by dibromination of [2.2]paracyclophane with Br2 with-
out catalyst and could be isolated with a chemical yield
of 38–43% from the regioisomeric 4,16-dibromo-
[2.2]paracyclophane (pseudo-para-, 33–40%) by frac-
tional crystallization.7
In contrast to the lack of the reactivity of the intermedi-
ate dilithio derivative with B(OMe)3, its reaction with
solid CO2 followed by acidification of the reaction
mixture smoothly produced 4,15-dicarboxy[2.2]para-
cyclophane 5.11a The target 4,15-dicarbomethoxy-
[2.2]paracyclophane 611b was obtained by methoxylation
of the respective dichloroanhydride.
In our investigation of the reactivity and regioselectivity
of electrophilic substitution of pseudo-meta-disubsti-
tuted [2.2]paracyclophane derivatives, we started with
the acylation of diphenol 3, bearing in mind the exclu-
sive ortho-regioselective acylation revealed by us for 4-
hydroxy[2.2]paracyclophane.2a Indeed, the reaction of
3 with 3 equiv of AcCl (3 equiv of TiCl4, CH2Cl2, room
temp) was ortho-regioselective producing a mixture of
the respective mono- and diacylated diphenols (5,16-di-
acetyl-4,15-dihydroxy[2.2]paracyclophane 7 and 5-acetyl-
4,15-dihydroxy[2.2]paracyclophane) and was accompa-
nied by O-acylation. To achieve the chemoselective
synthesis of the target 7 (93%), a solution of diphenol
3 was stirred with TiCl4 for 1 h, and then AcCl was
added (to avoid the formation of O-acylation products).
In order to consume 3 and the intermediate monoacyl-
ated phenol completely, excess reagents (3 equiv of
AcCl and 3 equiv of TiCl4) were added and the reaction
was carried out at 40 °C for 20 h (Scheme 2). The result-
ing C2-symmetric diacylated phenol 7 possesses two
functional fragments, each of which mimic the ortho-
disubstituted functional part of 5-acetyl-4-hydroxy-
[2.2]paracyclophane (AHPC),2a a well-known precursor
for a series of efficient imino-type ligands.12 These
fragments are pseudo-meta-oriented with respect to each
other and therefore, we refer to the compound 7 as
pseudo-meta-(bis-AHPC).
The choice of functional substituents attached to the
[2.2]paracyclophane scaffold (OH, OMe, and COOMe)
was based on known regularities of the ortho-, para-2a
and pseudo-gem-regioselective8 electrophilic substitu-
tion, revealed earlier for the monosubstituted [2.2]para-
cyclophanes. The syntheses of 4,15-dihydroxy- and 4,15-
dicarboxy[2.2]paracyclophanes (3 and 5) were carried
out from the dibromide 1 by double lithiation/electro-
philic exchange (Scheme 1). The ‘classical’ approach
for the introduction of the hydroxy-group, namely Li/
B exchange with trimethylborate and oxidation of the
respective boronic esters with H2O2/NaOH failed to
produce the expected diphenol 3, and the parent
i
Br
HO
RO
Br
Br
OR
ii
ii
1
R = H, 3
2
As expected, the diacylation of the dimethoxy-derivative
4 with AcCl/TiCl4 (1/6/6 reagents ratio, 20 h) was
para-regioselective (as was the monoacylation of 4-meth-
oxy[2.2]paracyclophane2a) and produced 7,12-diacetyl-
4,15-dimethoxy[2.2]paracyclophane 8 as the sole pro-
duct, isolated in a chemical yield of 71% (Scheme 2).
iii
R = Me,4
O
O
O
iv
O
HO
MeO
OH
OMe
v
Next, we carried out the Fe-catalyzed room temperature
bromination of the diester 6.13 The reaction with
2.4 equiv of Br2 was quite slow and after three days
1H NMR showed 80% conversion of the starting mate-
rial and formation of the monobromination product.
Therefore, a considerable excess of Br2 (7.6 equiv) was
added and the mixture was stirred for a further 10 days
6
5
Scheme 1. Reagents and conditions: (i) 2 equiv n-BuLi, Et2O, room
temp.; then PhNO2, À78 °C, 30%; (ii) 1 equiv n-BuLi, Et2O, rt; then
B(OMe)3, H2O2/NaOH, 87%; (iii) NaH/DMF, then MeI, 80%; (iv)
2 equiv n-BuLi, THF, À78 °C; then CO2, then HCl, 80%; (v) SOCl2,
CHCl3; 61 °C, then MeOH, 78%.

N. V. Vorontsova et al. / Tetrahedron Letters 47 (2006) 2357–2360
2359
3
4
6
i, 71%
i, 93%
OH
ii, 93%
O
O
MeO
Me
HO
O
OMe
Br
MeO
Br
OMe
Me
Me
Me
O
O
O
7
8
9
pseudo-meta-(bis-AHPC)
Scheme 2. Reagents and conditions: (i) 6 equiv AcCl, 6 equiv TiCl4, CH2Cl2, 40 °C, 20 h; (ii) Fe, 10 equiv Br2, CH2Cl2, room temp., 13 d, 93%.
to reach full consumption (1H NMR) of the starting 6
and of the intermediate monobromide. The only
compound isolated from the reaction mixture in 93%
yield was identified as 4,15-dibromo-8,13-dicarbometh-
oxy[2.2]paracyclophane 9, the product of regioselective
pseudo-geminal disubstitution. This compound, in our
opinion, has great potential for further chemical trans-
formations at the bromine atoms as well as at the carbo-
methoxy groups, thus providing scope for a wide range
of novel [2.2]paracyclophane derivatives.
tric,15 as well as liquid crystalline materials16 and poly-
mers17 from [2.2]paracyclophanes of types B–D.
In summary, we have for the first time investigated the
reactivity and the regioselectivity of electrophilic substi-
tution of chiral pseudo-meta-disubstituted [2.2]para-
cyclophanes. We have developed conditions for the
chemoselective disubstitution, which can occur ortho-,
para-, or pseudo-gem-regioselectively, giving rise to chi-
ral bis-bifunctional compounds of types B–D. Further
application of the regioselective double electrophilic
substitution outlined above to novel pseudo-meta-disub-
stituted substrates, the chiral 4,7-16 and the achiral 4,16-
disubstituted[2.2]paracyclophanes (para- and pseudo-
para-, respectively), and extension of the electrophilic
reactions (formylation, oxaloylation, nitration, etc.)
are underway.
It is worthy of note that any C2-symmetrical pseudo-
meta-di-X-substituted [2.2]paracyclophane A, in princi-
ple, has three possible arrangements for the adoption
of two pseudo-meta-oriented (with respect to each other)
identical functional groups Y, thus allowing for forma-
tion of three C2-symmetrical chiral tetrasubstituted pat-
terns, B–D, respectively (Fig. 2). As is clear from Scheme
2, all three compounds 7–9, being bis-bifunctional
[2.2]paracyclophanes, represent these three patterns.
Within each pattern, one could easily distinguish two
identical fragments, constructed from two different func-
tional groups (X = OH, Y = COMe in 7; X = OMe,
Y = COMe in 8; X = COOMe, Y = Br in 9), which
are situated in close proximity to each other. Thus, start-
ing from the pseudo-meta-disubstituted [2.2]paracyclo-
phanes that, due to their structure, would be unable to
undergo coordination with a metal, we have succeeded
in arriving at three types of bis-bifunctional compounds;
in each one, two independent functional fragments (X–
Y) mimic the pattern of typical disubstituted chiral
ligands, based on [2.2]paracyclophane (namely, ortho-
in B, pseudo-ortho- in C, and pseudo-gem- in D).14
Acknowledgements
This work was financially supported by the Russian
Foundation for Basic Research (Submitted Grant Ref.
No. 06-03-33086a).
References and notes
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0.3 mL of this solution and a suspension of iron powder
(0.03 g, 0.54 mmol) in CH2Cl2 (5 mL) was stirred for 1 h in
the absence of light. Then 6 (0.12 g, 0.37 mmol) in CH2Cl2
(15 mL) was added in one portion and the remaining Br2/
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excess of Br2 (0.15 mL, 2.7 mmol) was added and the
reaction mixture was stirred at room temperature for an
additional 10 days. The reaction mixture was washed with
aq NaHCO3 and dried with Na2SO4. The solvent was
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by preparative chromatography on SiO2 (eluent CH2Cl2),
to produce 4,15-dicarbomethoxy-8,13-dibromo[2.2]para-
cyclophane 9 (0.17 g, 93%). An analytically pure sample
of 9 was obtained by recrystallization from hexane.
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33.14. 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),
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200 (18), 199 (43), 198 (12), 197 (46), 189 (16), 184 (32),
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methoxy[2.2]paracyclophane (6):
A solution of Br2
(0.05 mL, 0.9 mmol) in CCl4 (2 mL) was prepared, and