Synthesis of bromo-substituted 4-hydroxy[2.2]paracyclophanes and [2.2]paracyclophane-4,7-quinones as versatile chiral building blocks

Article abstract of DOI:10.1002/ejoc.201403316

Approaches to a number of bromo-substituted derivatives of 4-hydroxy[2.2]paracyclophane, including the regioselective mono- and dibromination of this phenol, were investigated. The applicability of the regioisomeric monobromo-substituted phenols for the synthesis of substituted [2.2]paracyclophane-4,7-quinones through a one-pot diazonium coupling/reduction/oxidation sequence was demonstrated. The compounds obtained possess various substitution patterns and could be used for the synthesis of a wide range of [2.2]paracyclophane derivatives by transformation of the bromine, hydroxy, and quinoid fragments.

Full text of DOI:10.1002/ejoc.201403316

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403316
Synthesis of Bromo-Substituted 4-Hydroxy[2.2]paracyclophanes and
[2.2]Paracyclophane-4,7-quinones as Versatile Chiral Building Blocks
Natalia V. Atman (Vorontsova),*[a] Roman P. Zhuravsky,[a] Dmitrii Yu. Antonov,[a]
Elena V. Sergeeva,[a] Ivan A. Godovikov,[a] Zoya A. Starikova,[a] and Anna V. Vologzhanina[a]
Keywords: Cyclophanes / Regioselectivity / Bromination / Chirality / Building blocks / Quinones
Approaches to a number of bromo-substituted derivatives of
4-hydroxy[2.2]paracyclophane, including the regioselective
mono- and dibromination of this phenol, were investigated.
The applicability of the regioisomeric monobromo-substi-
tuted phenols for the synthesis of substituted [2.2]paracyclo-
phane-4,7-quinones through a one-pot diazonium coupling/
reduction/oxidation sequence was demonstrated. The com-
pounds obtained possess various substitution patterns and
could be used for the synthesis of a wide range of [2.2]para-
cyclophane derivatives by transformation of the bromine,
hydroxy, and quinoid fragments.
mic or enantiomerically enriched form[5e,7] (Figure 1). In
the course of our investigations[8] we required several re-
gioisomeric monobromo-substituted phenols. To our sur-
prise, para regioisomer 5 had not been reported, even
though its methyl ether was previously synthesized by para-
regioselective bromination of 4-methoxy[2.2]paracyclo-
Introduction
The success in using [2.2]paracyclophane derivatives as
chiral promoters in various stereoselective processes[1] and
as building blocks in polymer and materials science[2] has
prompted chemists to seek out novel compounds possessing
definitive structural features.[3] Owing to the unique rigidity
of the [2.2]paracyclophane scaffold and the variety of pos-
sible patterns (mono- and polysubstituted aromatic rings,
aliphatic bridges, and their combinations), one can govern
the parameters of the molecules, including the number of
attached functional groups, their electronic and steric fea-
tures, relative orientation, rigid or flexible connection, to
provide a certain distance between them. Directing effects
of various substituents uncovered by Cram in the 1960s[4]
and the extension of this early chemistry to new ap-
proaches[5] has permitted the controlled synthesis of a mul-
titude of mono- and polysubstituted achiral and planar/cen-
tral chiral [2.2]paracyclophanes. This chemistry in conjunc-
tion with the development of new resolution techniques[6]
has allowed the number of useful ligands and building
blocks in enantiomerically pure form to grow continually.
The conversion of bromo substituents attached to a [2.2]-
paracyclophane moiety is the foundation of most syntheses
providing introduction of various functionalities.[1,3a]
A
number of bromo- and polybromo-substituted phenols and
diphenols 1–9 have previously been reported in either race-
[a] A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Science,
Vavilova 28, 119991 Moscow, Russia,
E-mail: ghkl-ineos@yandex.ru
http://www.ineos.ac.ru/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403316.
Figure 1. Bromo-substituted phenols of [2.2]paracyclophane series.
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SHORT COMMUNICATION
phane.[9] Additionally, whereas pseudo-para derivative 6 has described.[12] The phthalimide sulfenylation of 11 produced
been reported by Cram,[7e] its synthesis was not efficient.
a mixture of ortho- and para-substituted phenols in a 3:2
In this communication we would like to disclose the syn- ratio or the single ortho,para-disubstituted phenol, de-
thesis of new members of the bromophenol series and to pending on the amount of the reagent used. We investigated
demonstrate the reactivity of several regioisomeric mono- the mono- and dibromination of phenol 11 as a possible
bromo-substituted 4-hydroxy[2.2]paracyclophanes in the route for the synthesis of the novel derivatives (Scheme 2).
synthesis of novel substituted quinones.
Results and Discussion
There is no general approach to the synthesis of all the
possible regioisomeric monobromo-substituted 4-hydroxy-
[2.2]paracyclophanes (Figure 1). The synthesis of 12-
bromo-4-hydroxy[2.2]paracyclophane and 15-bromo-4-
hydroxy[2.2]paracyclophane (pseudo-ortho 1 and pseudo-
meta 2) is based on the selective low-temperature[7a] or
room-temperature monolithiation[7c] of the respective re-
gioisomeric dibromides followed by standard treatment
with B(OMe)3 and oxidation of the intermediate boronic
esters with H2O2/NaOH. 13-Bromo-4-hydroxy[2.2]para-
Scheme 2. Mono- and dibromination of 4-hydroxy[2.2]paracyclo-
phane 1.
cyclophane (pseudo-gem 3) is obtainable through
a
Reaction of 11 with an equimolar amount of Br2 at 0 °C
produced a mixture of para and ortho isomers {novel 7-
bromo-4-hydroxy[2.2]paracyclophane (5) and known 4},
which were separated by preparative chromatography to
give yields of 57 and 17%, respectively. Performing the
bromination at room temperature allowed us to increase the
para regioselectivity, which resulted in the formation of 5 in
a yield of 83%, whereas the yield of 4 was low. The latter
compound could not be purified by chromatography or
multistep synthesis that culminates in converting the amino
group of the respective bromo-substituted amine into a
hydroxy group.[7d] 5-Bromo-4-hydroxy[2.2]paracyclophane
(ortho-4) can be prepared in several steps from the product
of the palladium-directed halogenation of imines.[5e] To
complete a series of preparatively available regioisomeric
monobromo-substituted 4-hydroxy[2.2]paracyclophanes 1–
6, we turned our attention to the synthesis of 5 and 6.
16-Bromo-4-hydroxy[2.2]paracyclophane (pseudo-para
6) was obtained[7e] together with three other products upon
treatment of dibromide 10[4a,10] with potassium tert-butox-
ide in DMSO followed by acidic ether hydrolysis. The syn-
thetic procedure was laborious and 7 was not fully charac-
terized. On the other hand, it is known that the reaction of
10 with nBuLi in Et2O at room temperature occurs with
exchange of only one bromine atom by lithium.[11] To im-
prove the preparation of 6, we monolithiated 10, which was
followed by introduction of a hydroxy group by a standard
procedure (Scheme 1). The low yield of 6 can be explained
by the poor solubility of starting material 10 and the in-
creased solubility of the monolithiated species, which re-
sults in a further, undesired, dilithiation reaction. The mix-
ture of lithio derivatives after the workup gave rise to target
6 together with 4-hydroxy[2.2]paracyclophane (11) and par-
ent [2.2]paracyclophane (both well detectable by TLC) as
products of the partial and full hydrolysis of the dilithio
derivative.
1
recrystallization because in the H NMR spectrum of the
TLC-pure samples we always observed a considerable
amount of the admixture product of presumable further
bromination, which has a very close Rf, and it could not be
removed by crystallization.
The reaction of 11 with 2 equivalents of Br2 proceeded
smoothly at room temperature to produce a mixture of re-
gioisomeric dibromo-substituted phenols 12 and 13
(Scheme 2) that were easily separable by preparative
chromatography. The structure of 12 was supported by X-
ray diffraction analysis (Figure 2). Compound 12 is a rare
example of a [2.2]paracyclophane that has three substitu-
ents on a single ring. This result is analogous to the chemis-
try of N-thiophthalamide.[12] Earlier, we described a tri-
bromo-substituted [2.2]paracyclophane with all bromine
atoms in one aromatic rings that was formed in a trace
amount only.[10] Dialkyl- and diallylphenols of such a type
were obtained as minor products (4–22%) in the acid-cata-
lyzed dehydration of cis-4,7-disubstituted 4,7-dihydro-4,7-
dihydroxy[2.2]paracyclophanes.[13] If one considers the
known directing effects in the substitution reactions of
[2.2]paracyclophane derivatives[4a,10] then it is likely that
major product 12 arises from both 5 and 4 by further
bromination of the substituted aromatic ring (ortho and
para outcome of the second substituent with respect to the
hydroxy group, Figure 1). Minor phenol 13 is the product
of substitution of the lower ring. The regiochemistry of this
Scheme 1. Synthesis of 16-bromo-4-hydroxy[2.2]paracyclophane
(6).
To the best of our knowledge, only one example of the reaction is driven by steric hindrance and not by electronics,
electrophilic aromatic substitution of phenol 11 has been so bromination occurs at the most accessible position. The
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[2.2]Paracyclophane Derivatives as Versatile Chiral Building Blocks
high yield of 12 is probably the result of the highly activa- of substituted planar chiral quinones by applying this se-
ting effect of the hydroxy group. Similar effects were ob- quence of reactions to regioisomeric bromophenols 1, 2,
served during the bis-sulfenylation of 11, which was proven and 6 (Scheme 3).
to be the unique example of a double substitution product
in a series of approximately 50 phenols. Its formation was
attributed to stereoelectronic effects of the [2.2]paracyclo-
phane moiety, which allowed the withdrawing effect of the
first thiophthalimide group to be overcome.[12]
Figure 2. Molecular view of 5,7-dibromo-4-hydroxy[2.2]paracyclo-
phane (12); thermal ellipsoids given with p = 50%.
[2.2]Paracyclophane-derived quinones, quinhydrones,
and their esters were traditionally used as attractive models
to investigate the dependence of donor–acceptor (D-A) in-
teractions with respect to the mutual arrangement of the
D and A substituents.[14] Multistereogenic bis-bifunctional
ligands 15, obtainable by stereoselective addition of
organolithium compounds to enantiomers of [2.2]para-
cyclophane-4,7-quinone (14),[15] were applied as chiral li-
gands in the asymmetric diethylzinc addition to alde-
hydes.[15b] Recently, the respective para-ditriflate obtained
from (Sp)-14 was found to be a suitable precursor for the
synthesis of diaryl derivatives (Sp)-16 by double Suzuki
coupling[16] (Figure 3).
Scheme 3. Synthesis of bromo-substituted [2.2]paracyclophane
quinones.
In analogy with the behavior of unsubstituted phenol
11,[7e] the reaction was expected to occur by the para-selec-
tive coupling of diazonium and phenol followed by re-
duction of an intermediate azo derivative to an unstable
aminophenol and its further oxidation with formation of
the para-quinoid fragment. Thus, para-diazonium coupling
in pseudo-ortho-bromophenol (1) and in pseudo-meta-
bromophenol (2) would produce azo compounds 1a and 2a,
respectively, which after reduction would give intermediate
amines 1b and 2b (Scheme 3). Notably, both of them should
furnish the same product as a result of oxidation, namely,
12-bromo[2.2]paracyclophane-4,7-quinone (17). Indeed,
phenols 1 and 2 showed the predicted reactivity and pro-
duced 17 in yields of 68 and 57%, respectively. These reac-
tions are complementary to each other in the synthesis of
Figure 3. Enantiomerically pure [2.2]paracyclophane-4,7-quinone
(14) and compounds 15 and 16 obtained therefrom.
Previously, substituted [2.2]paracyclophane-derived 17. Thus, the total three-step synthesis of racemic 17 from
quinones were prepared by multistep procedures involving [2.2]paracyclophane is more efficient because pseudo-meta
the synthesis of dithia[3.3]paracyclophanes from the respec- dibromide could be obtained in good yield by direct bromi-
tive suitably substituted molecular halves followed by nation of the parent hydrocarbon,[10] and further, the syn-
photoextrusion of sulfur.[17] For the synthesis of unsubsti- thesis of 2 did not require low temperatures. In turn, for the
tuted quinone 14, either racemic[7e,18] or in enantiomerically synthesis of nonracemic 17, enantiomers of 1 are the start-
pure form,[15,16] an efficient one-pot diazonium coupling/ ing materials of choice. pseudo-para-Bromophenol (7) did
reduction/oxidation sequence starting from 11 was used. As not react as predicted and gave rise to 15-bromo-5-hydroxy-
the next step, we evaluated the possibility of the synthesis [2.2]paracyclophane-4,7-quinone (18) bearing a hydroxy
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N. V. Atman (Vorontsova) et al.
SHORT COMMUNICATION
group in addition to the para-quinoid fragment. The struc- whereas derivatives of para and pseudo-para substitution
tures of substituted quinones 17 and 18 were unequivocally patterns are of great interest for applications in polymer
established by X-ray diffraction analysis (Figure 4).
and materials chemistry.[2,3b,24]
Conclusions
We elaborated efficient procedures for the gram-scale
synthesis of several novel monobromo- and dibromo-sub-
stituted 4-hydroxy[2.2]paracyclophanes with various substi-
tution patterns, including a quite rare example with two
bromine atoms positioned meta to each other. The applica-
tion of the one-pot diazonium coupling/reduction/oxidation
sequence to monobromo-substituted phenols allowed us to
obtain substituted [2.2]paracyclophane-4,7-quinones. The
newly synthesized planar chiral building blocks combine
bromine atoms, hydroxy group, and/or a quinoid fragment
in their structures, and they are ready for a number of other
transformations (including resolution into enantiomers).
Figure 4. Molecular view of 12-bromo-4,7-dihydro[2.2]paracyclo-
phane-4,7-quinone (17, left) and 15-bromo-5-hydroxy-4,7-dihydro-
[2.2]paracyclophane-4,7-quinone (18, right); thermal ellipsoids
given with p = 50%.
To rationalize the formation of 18 one can assume that
diazonium coupling in 6 occurs at the ortho position rather
than the para position with respect to the hydroxy group
with formation of intermediate azo derivative 6a owing to
steric hindrance exerted by the bromine atom. The re-
duction of 6a should produce ortho-aminophenol 6b, which
in turn should be transformed into ortho-quinone 6c under
oxidation conditions, as is known for the oxidation of aro-
matic ortho-aminophenols.[19] However, ortho-quinones
formed as intermediates during oxidation of sterically hin-
dered diphenols (such as 3,6-di-tert-butylcatechol) in aque-
ous protic media or under the influence of FeIII salts could
suffer hydroxylation followed by several transformations to
yield hydroxy-substituted para-quinones.[20] These reactions
occur by ionic and/or radical mechanisms, respectively. In
our case, whereas all successive transformations from 6 to
Experimental Section
Bromination of 4-Hydroxy[2.2]paracyclophane (11): A solution of
Br2 (0.50 mL, 1.6 g, 10 mmol) in CH2Cl2 (15 mL) was added drop-
wise to a solution of 11 (2.24 g, 10 mmol) in dichloromethane
(50 mL), and the mixture was stirred at room temperature for 4 h.
The solution was washed with H2O (20 mL) and saturated aqueous
NaHCO3 solution (2ϫ 30 mL). The aqueous layer was extracted
with CH2Cl2 (3ϫ 15 mL), and the combined organic solution was
dried with Na2SO4 and concentrated in vacuo to yield a mixture of
compounds 4 and 5, which were separated by column chromatog-
raphy (CH2Cl2/hexane, 3:2).
Dibromination of Phenol 11: A solution of Br2 (0.55 mL, 1.76 g,
11 mmol) in CH2Cl2 (5 mL) was added to a solution of 11 (1.12 g,
18 are performed as a one-pot reaction, intermediate ortho- 5 mmol) in dichloromethane (30 mL), and the mixture was stirred
at room temperature for 4 h. The solution was washed with H2O
(20 mL) and saturated aqueous NaHCO3 solution (2ϫ 30 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ 15 mL), and
the combined organic solution was dried with Na2SO4 and concen-
trated in vacuo to produce a mixture of 12 and 13, which were
separated by column chromatography (benzene/hexane, 7:3).
quinone 6c could be hydroxylated by H2O and the hydroxy
group would add to the position that is not shielded by the
bromine atom. Subsequent oxidation of 6d under the action
of the FeIII salt that is present in the reaction mixture in
excess amounts would lead to hydroxylated para-quinone
18.
General Synthesis of Substituted [2.2]Paracyclophane-4,7-quinones
from Phenols 1, 2, and 6: Sodium nitrite (0.245 g, 3.55 mmol) was
added to a solution of sulfanilic acid (0.56 g, 3.24 mmol) and
Na2CO3 (0.171 g, 1.62 mmol) in H2O (15 mL) cooled to +15 °C.
The mixture was stirred for 30 min and poured into a mixture of
ice (15 g) and concentrated HCl (0.36 mL, 4.26 mmol). A yellow
solution of the diazonium salt was stirred at 0 °C for 30 min. A
solution of the respective 12/15/16-bromo-4-hydroxy[2.2]paracyclo-
The synthesis of the novel bromo-substituted phenols
was performed on a gram scale. All transformations were
performed with racemic compounds with the aim to study
the reactivity of the substrates in the reactions under inves-
tigation. There is no doubt that all of the compounds could
be obtained in enantiomerically pure form (if needed for
certain applications) starting from nonracemic precursors
(e.g., 2, 11) or by resolution and other chiral transforma- phane 1, 2, or 6 (0.65 g, 2.15 mmol) in MeOH (75 mL) was mixed
tions fairly well developed for both bromine[21] and the
with a solution of NaOH (0.47 g, 11.81 mmol) in H2O (10 mL),
hydroxy group.[22] Stepwise application of classical synthetic
and the mixture was cooled to 5 °C. Then, a solution of the diazo-
nium salt was added under vigorous stirring, and the temperature
techniques, for example, bromine–lithium exchange reac-
was maintained at no higher than +5 °C. The dark-scarlet solution
tions, and novel approaches, such cross-coupling reactions
of the azo compound was stirred at +5 °C for 1 h, warmed to room
(Suzuki, Sonogashira, etc.),[23] as well as transformations
temperature, and left overnight. Concentrated HCl (10 mL) and a
solution of SnCl2·2H2O (3.35 g, 14.85 mmol) in concentrated
HCl (13 mL) were successively added to the solution of the
azo compound, and the mixture was heated at reflux for 1 h.
of the quinoid fragment opens up broad prospects for the
synthesis of novel polysubstituted compounds with desired
structures and properties. Thus, ortho, pseudo-ortho, and
pseudo-gem substitution of [2.2]paracyclophane plays an
Fe2(SO4)3·9H2O (29.51 g, 52.5 mmol) was added, and the mixture
important role in the construction of chiral promoters,[1,3a] was heated at reflux with stirring for 8 h. The bromoquinones were
4
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[2.2]Paracyclophane Derivatives as Versatile Chiral Building Blocks
S. Höfener, F. Lauterwasser, M. Kreis, R. E. Ziegert, Synlett
2004, 2647–2669; d) J. Paradies, Synthesis 2011, 3749–3766; e)
G. J. Rowlands, Isr. J. Chem. 2012, 52, 60–75.
extracted with CHCl3 and dried with Na2SO4. The solution was
concentrated in vacuo, and the residue was purified by column
chromatography (CHCl3).
[2]
a) G. C. Bazan, J. Org. Chem. 2007, 72, 8615–8635; b) H. Hopf,
Angew. Chem. Int. Ed. 2008, 47, 9808–9812; Angew. Chem.
2008, 120, 9954–9958; c) E. Elacqua, L. R. MacGillivray, Eur.
J. Org. Chem. 2010, 6883–6894; d) Y. Morisaki, Y. Chujo,
Polym. Chem. 2011, 2, 1249–1257; e) A. Marrocchi, I. Tomasi,
L. Vaccaro, Isr. J. Chem. 2012, 52, 41–52.
a) O. R. P. David, Tetrahedron 2012, 68, 8977–8993; b) M.
Montanari, A. Bugana, A. K. Sharma, D. Pasini, Org. Biomol.
Chem. 2011, 9, 5018–5020.
12-Bromo[2.2]paracyclophane-4,7-quinone (17): Yield 0.46 g (68%),
from pseudo-ortho-bromophenol (1), yield 0.39 g (57%) from
pseudo-meta-bromophenol (2). Rf = 0.71 (CH2Cl2). Analytically
pure 17 was obtained by crystallization from a mixture of toluene/
hexane as yellow crystals, m.p. 197.5–198.5 °C. 1H NMR
(400.13 MHz, CDCl3): δ = 2.24–2.39 (m, 1 H, -CH2-CH2-), 2.56–
2.69 (m, 1 H, -CH2-CH2-), 2.90–3.19 (m, 4 H, -CH2-CH2-), 3.20–
3.31 (m, 1 H, -CH2-CH2-), 3.31–3.42 (m, 1 H, -CH2-CH2-), 5.90 (s,
[3]
[4]
[5]
a) H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 1969, 91, 3505–
3516; b) H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 1969, 91,
3527–3533.
3
4
1 H, 5-H), 6.42 (s, 1 H, 8-H), 6.73 (dd, J = 7.8 Hz, J = 1.8 Hz, 1
H, 12-H), 6.88 (d, 3J = 7.8 Hz, 1 H, 13-H), 6.93 ppm (d, 4J =
1.8 Hz, 1 H, 16-H). 13C NMR (CDCl3): δ = 26.93, 29.16, 32.89,
33.81, 127.87, 132.11, 132.41, 133.18, 135.26, 135.51, 138.83,
a) For reviews, see ref.[1,3a] For selected publications, see: b)
G. J. Rowlands, Org. Biomol. Chem. 2008, 6, 1527–1534; c) P.
Lennartz, G. Raabe, C. Bolm, Adv. Synth. Catal. 2012, 354,
3237–3249; d) P. Schaal (née Lennartz), H. Baars, G. Raabe, J.
Atodiresei, C. Bolm, Adv. Synth. Catal. 2013, 355, 32506–2512;
e) J. J. P. Kramer, C. Yildiz, M. Nieger, S. Bräse, Eur. J. Org.
Chem. 2014, 1287–1295.
140.93, 149.66, 150.04, 186.50, 187.40 ppm. IR (CH Cl ): ν = 1654,
˜
2
2
1667 (C=O) cm–1. MS (70 eV): m/z (%) = 318 (23) [M]+, 317 (6)
[M]+, 316 (28) [M]+, 300 (7), 298 (8), 290 (16) [M – CO]+, 289 (5)
[M – CO]+, 288 (19) [M – CO]+, 275 (12), 273 (21), 259 (7), 257
(7), 238 (14) [M – Br]+, 237 (100) [M – Br – H]+, 222 (50), 221 (19),
220 (10), 219 (33), 209 (52), 208 (18), 207 (9), 195 (17), 194 (29),
192 (14), 191 (38), 190 (9), 189 (6), 184 (8), 181 (27), 180 (9), 179
(6), 178 (6), 169 (10), 167 (15), 166 (43), 165 (44), 153 (8), 152 (9),
141 (16), 140 (6), 139 (6), 115 (21), 103 (21), 102 (6). C16H13BrO2
(317.18): calcd. C 60.59, H 4.13, Br 25.19; found C 60.67, H 4.13,
Br 25.02.
a) For reviews, see ref.[1,3a] For selected publications, see: b) N.
Dendele, F. Bisaro, A.-C. Gaumont, S. Perrio, Ch. J. Richards,
Chem. Commun. 2012, 48, 1991–1993; c) Y. Morisaki, R. Hif-
umi, L. Lin, K. Inoshita, Y. Chujo, Chem. Lett. 2012, 41, 990–
992; d) D. Enders, M. Ludwig, G. Raabe, Chirality 2012, 24,
215–222; e) R. P. Zhuravsky, T. I. Danilova, D. Yu. Antonov,
E. V. Sergeeva, Z. A. Starikova, I. A. Godovikov, M. M. Il’in,
V. I. Rozenberg, Isr. J. Chem. 2012, 52, 156–170; f) F. He, Y.
Ma, L. Zhao, W. Duan, J. Chen, Zh. Zhao, Tetrahedron: Asym-
metry 2012, 23, 809–817; g) Y. Morisaki, M. Gon, T. Sasamori,
N. Tokitoh, Y. Chujo, J. Am. Chem. Soc. 2014, 136, 3350–3353.
2: a) T. Focken, J. Rudolph, C. Bolm, Synthesis 2005, 3, 429–
436; b) R. Zhuravsky, Z. Starikova, E. Vorontsov, V. Rozen-
berg, Tetrahedron: Asymmetry 2008, 19, 216–222; 3: c) N. V.
Vorontsova, V. I. Rozenberg, E. V. Sergeeva, E. V. Vorontsov,
Z. A. Starikova, K. A. Lyssenko, H. Hopf, Chem. Eur. J. 2008,
14, 4600–4617; 4: d) D. Xin, Y. Ma, F. He, Tetrahedron: Asym-
metry 2010, 21, 333–338; 5: see ref.[5e]; 7: e) D. J. Cram, A. C.
Day, J. Org. Chem. 1966, 31, 1227–1232; 8: f) D. C. Braddock,
I. D. MacGilp, B. G. Perry, Adv. Synth. Catal. 2004, 346, 1117–
1130; 9: g) B. Dominguez, A. Zanotti-Gerosa, W. Hems, Org.
Lett. 2004, 6, 1927–1930; 10: see ref.[6g]
D. Yu. Antonov, M. M. Ilyin, E. V. Sergeeva, Z. A. Starikova,
E. V. Vorontsov, N. V. Vorontsova, R. P. Zhuravsky, V. I. Roz-
enberg, Metal-Mediated Reactions in the Synthesis of [2.2]-
Paracyclophane Derivatives with Different Types of Chirality,
CRC International Symposium in Moscow, Cross-Coupling and
Organometallics, September 18, 2009, Moscow, Abstract of pa-
pers, p. 28.
a) V. Rozenberg, R. Zhuravsky, E. Sergeeva, Chirality 2006, 18,
95–102; b) B. Wang, J. W. Graskemper, L. Qin, S. G. DiMagno,
Angew. Chem. Int. Ed. 2010, 49, 4079–4083; Angew. Chem.
2010, 122, 4173–4177.
a) V. A. Nikanorov, V. G. Kharitonov, E. V. Yatsenko (Ser-
geeva), D. P. Krut’ko, M. V. Galakhov, S. O. Yakushin, V. V.
Mikul’shina, V. I. Rozenberg, V. N. Guryshev, V. P. Yur’ev,
O. A. Reutov, Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl.
Transl.) 1992, 41, 1430–1434 (Izv. Acad. Nauk SSSR, Ser.
Khim. 1992, 1837–1843).
Y. L. Yeh, W. F. Gorham, J. Org. Chem. 1969, 34, 2366–2370.
S. Menichetti, C. Faggi, G. Lamanna, A. Marrocchi, L. Minuti,
A. Taticchi, Tetrahedron 2006, 62, 5626–5631.
N. Vorontsova, V. Rozenberg, E. Vorontsov, D. Antonov, Z.
Starikova, Eur. J. Org. Chem. 2003, 761–770.
a) A. R. Wartini, J. Valenzuela, H. A. Staab, F. A. Neugebauer,
Eur. J. Org. Chem. 1998, 221–227; b) H. M. Muchall, Modern
Cyclophane Chemistry (Eds.: R. Gleiter, H. Hopf), Wiley-VCH,
Weinheim, Germany, 2004, p. 259–274; c) P. Rademacher, Mod-
[6]
[7]
[8]
15-Bromo-5-hydroxy[2.2]paracyclophane-4,7-quinone (18): Yield
0.53 g (74%). Rf = 0.07 (CH2Cl2). Analytically pure 18 was ob-
tained by crystallization from toluene as dark-red crystals, m.p.
192.5–193.5 °C. 1H NMR (400.13 MHz, CDCl3): δ = 2.61–2.68 (m,
1 H, -CH2-CH2-), 2.70–2.77 (m, 1 H, -CH2-CH2-), 2.83–2.90 (m, 2
H, -CH2-CH2-), 2.90–2.97 (m, 1 H, -CH2-CH2-), 2.99–3.10 (m, 2
H, -CH2-CH2-), 3.34–3.41 (m, 1 H, -CH2-CH2-), 6.39 (br. s, 1 H,
OH), 6.61 (d, 3J = 7.8 Hz, 1 H, 13-H), 6.66 (s, 1 H, 8-H), 6.86 (dd,
4
4
3J = 7.8 Hz, J = 1.8 Hz, 1 H, 12-H), 6.91 ppm (d, J = 1.8 Hz, 1
H, 16-H). 13C NMR (CDCl3): δ = 21.82, 26.22, 32.46, 33.36,
122.59, 126.76, 129.43, 132.85, 134.81, 134.82, 137.82, 142.71,
145.25, 150.93, 183.35, 186.53 ppm. IR (CH Cl ): ν = 1644, 1660
˜
2
2
(C=O), 3421 (OH) cm–1. MS (70 eV): m/z (%) = 334 (21) [M]+, 333
(5) [M]+, 332 (25) [M]+, 317 (6) [M – OH]+, 306 (7) [M – CO]+,
305 (5), 304 (6), 303 (6), 254 (18) [M – Br]+, 253 (100) [M – Br –
H]+, 235 (8), 225 (26), 209 (5), 208 (6), 207 (14) (170), 197, 184
(24), 183 (6), 182 (28), 181 (9), 180 (5), 179 (29), 178 (12), 169
(17), 154 (5), 153 (6), 152 (6), 141 (10), 115 (11), 104 (6), 103 (22).
C16H13BrO3 (333.18): calcd. C 57.68, H 3.93, Br 23.98; found C
58.05, H 4.25, Br 23.53.
[9]
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental details, analytical data for key compounds, H
NMR and 13C NMR spectra, and crystallographic data.
[10]
Acknowledgments
Financial support for this work by the Russian Foundation for Ba-
sic Research (project number 13-03-01041) is gratefully acknowl-
edged. The authors would like to thank Dr. E. V. Vorontsov,
Dr. J. V. Nelubina, and A. A. Aleshkin for their assistance with
some NMR, crystallographic, and synthetic experiments.
[11]
[12]
[13]
[14]
[1] a) S. E. Gibson, J. D. Knight, Org. Biomol. Chem. 2003, 1,
1256–1269; b) V. Rozenberg, E. Sergeeva, H. Hopf, Modern
Cyclophane Chemistry (Eds.: R. Gleiter, H. Hopf), Wiley-VCH,
Weinheim, Germany, 2004, p. 435–462; c) S. Bräse, S. Dahmen,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. V. Atman (Vorontsova) et al.
SHORT COMMUNICATION
ern Cyclophane Chemistry (Eds.: R. Gleiter, H. Hopf), Wiley-
VCH, Weinheim, Germany, 2004, p. 275–310.
[15] a) N. V. Vorontsova, V. I. Rozenberg, E. V. Vorontsov, D. Y.
Antonov, Z. A. Starikova, Yu. N. Bubnov, Russ. Chem. Bull.
2002, 1483–1490; b) N. Vorontsova, E. Vorontsov, D. Antonov,
Z. Starikova, K. Butin, S. Bräse, S. Höfener, V. Rozenberg, Adv.
Synth. Catal. 2005, 347, 129–135.
[16] M. Cakisi, S. Bräse, Eur. J. Org. Chem. 2012, 6132–6135.
[17] a) H. A. Staab, G. H. Knaus, H.-E. Henke, C. Krieger, Chem.
Ber. 1983, 116, 22785–2807; b) H. A. Staab, R. Reimann-Haas,
P. Ulrich, C. Krieger, Chem. Ber. 1983, 116, 2808–2826.
[18] N. V. Vorontsova, V. I. Rozenberg, E. V. Vorontsov, D. Yu. An-
tonov, Z. A. Starikova, Yu. N. Bubnov, Russ. Chem. Bull. 2000,
51, 1483–1490.
[19] a) Houben-Weyl, Methoden der Organischen Chemie, Chinone
II, o-Chinone, Thieme, Stuttgart, Germany, 1979, p. 64–65; b)
H. Brockmann, F. Seela, Chem. Ber. 1971, 104, 2751–2771; c)
H. Musso, K. H. Bantel, Chem. Ber. 1969, 102, 686–695.
[20] V. B. Vol’eva, T. I. Prokof’eva, I. S. Belostotskaya, N. L. Kom-
issarova, V. V. Ershov, Russ. Chem. Bull. 1998, 47, 1952–1955.
[21] Synthesis of the diastereomeric sulfoxides starting from bromo-
substituted derivatives followed by sulfoxide–metal exchange:
a) H. J. Reich, K. E. Yelm, J. Org. Chem. 1991, 56, 5672–5679;
b) P. B. Hitchcock, G. J. Rowlands, R. Parmar, Chem. Com-
mun. 2005, 4219–4221; c) see ref.[6c]; d) followed by reduction:
G. J. Rowlands, R. J. Seacome, Beilstein J. Org. Chem. 2009, 5,
9; e) followed by reduction and Suzuki coupling, see ref.[6d]
For the resolution of [2.2]paracyclophane-derived phenols via
diastereomeric esters with (–)-(1S,4R)-camphanic acid, see: a)
V. Rozenberg, T. Danilova, E. Sergeeva, E. Vorontsov, Z. Stari-
kova, A. Korlyukov, H. Hopf, Eur. J. Org. Chem. 2002, 468–
477; b) see ref.[7b]; c) see ref.[6g]; enzymatic resolution: d) A.
Cipiciani, F. Fringuelli, V. Mancini, O. Piermatti, A. M. Scap-
pini, R. Ruzziconi, Tetrahedron 1997, 53, 11853–11858; e) D.
Pamperin, B. Ohse, H. Hopf, M. Pietzsch, J. Mol. Catal. B
1998, 5, 317–319; f) D. C. Braddock, I. D. MacGilp, B. G.
Perry, J. Org. Chem. 2002, 67, 8679–8681.
[22]
[23]
For a review, see: H. Hopf, Tetrahedron 2008, 64, 11504–11516.
[24] a) V. I. Rozenberg, E. L. Popova, H. Hopf, Helv. Chim. Acta
2002, 85, 431–441; b) Y. J. Chang, M. Watanabe, P.-T. Chou,
T. J. Chow, Chem. Commun. 2012, 48, 726–728.
Received: October 7, 2014
Published Online: ᭿
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Pages: 7
[2.2]Paracyclophane Derivatives as Versatile Chiral Building Blocks
Cyclophane Phenols and Quinones
N. V. Atman (Vorontsova),*
R. P. Zhuravsky, D. Yu. Antonov,
E. V. Sergeeva, I. A. Godovikov,
Z. A. Starikova,
A. V. Vologzhanina ............................ 1–7
The syntheses of a number of mono- and
disubstituted 4-hydroxy[2.2]paracyclo-
phanes and substituted [2.2]paracyclo-
phane-4,7-quinones with various substi-
tution patterns are elaborated. The planar
chiral building blocks combine bromine
atoms, hydroxy groups, and/or quinoid
fragments in their structures, and they are
ready for further transformations (includ-
ing resolution into enantiomers).
Synthesis
of
Bromo-Substituted
4-
Hydroxy[2.2]paracyclophanes and [2.2]-
Paracyclophane-4,7-quinones as Versatile
Chiral Building Blocks
Keywords: Cyclophanes / Regioselectivity /
Bromination / Chirality / Building blocks /
Quinones
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7