Towards a flexible strategy for the synthesis of enantiomerically pure [2.2]paracyclophane derivatives: The chemistry of 4-tolylsulfinyl[2.2] paracyclophane

Article abstract of DOI:10.1055/s-0030-1258286

The use of enantiomerically enriched 4-tolylsulfinyl[2.2]paracyclophane as a precursor to a variety of mono- and di-substituted [2.2]paracyclophane derivatives is described. The goal of our research is to develop a single general precursor that permits the synthesis of the most common [2.2]paracyclophane substitution patterns. The chemistry of two diastereoisomers of 4-tolylsulfinyl[2.2]paracyclophane has been explored and it facilitates the synthesis of enantiomerically enriched 4-substituted and 4,13-disubstituted [2.2]paracyclophanes. Directed lithiations result in an unusual cyclisation reaction. Whilst the tolyl group cannot realise our goal, the chemistry outlined acts as a successful proof of concept.

Full text of DOI:10.1055/s-0030-1258286

PAPER
4177
Towards a Flexible Strategy for the Synthesis of Enantiomerically Pure
[2.2]Paracyclophane Derivatives: The Chemistry of 4-Tolylsulfinyl[2.2]para-
cyclophane
E
nantiomerically
a
Pure [2.2]
P
k
aracyclopha
e
ne Derivati
s
ves h Parmar,a Martyn P. Coles,a Peter B. Hitchcock,a Gareth J. Rowlands*a,b
a
Chemistry Division, Department of Chemistry and Biochemistry, University of Sussex, Falmer, BN1 9QJ, UK
Institute of Fundamental Sciences – Chemistry, Massey University, Private Bag 11 222, Palmerston North, New Zealand
Fax +64(6)3505682; E-mail: g.j.rowlands@massey.ac.nz
b
Received 6 August 2010
cyclophane-derived compounds show great potential in
asymmetric synthesis, yet compared to planar chiral ferro-
cenyl derivatives or h6-arene transition-metal complexes
there is a paucity of reports and the field is still in its rela-
Abstract: The use of enantiomerically enriched 4-tolylsulfi-
nyl[2.2]paracyclophane as a precursor to a variety of mono- and di-
substituted [2.2]paracyclophane derivatives is described. The goal
of our research is to develop a single general precursor that permits
the synthesis of the most common [2.2]paracyclophane substitution tive infancy. Arguably, the most significant impediment
patterns. The chemistry of two diastereoisomers of 4-tolylsulfi-
to expanding this area is the lack of attractive strategies
nyl[2.2]paracyclophane has been explored and it facilitates the syn-
for the preparation of enantiomerically enriched
thesis of enantiomerically enriched 4-substituted and 4,13-
[2.2]paracyclophane derivatives;5,7 the field is still domi-
disubstituted [2.2]paracyclophanes. Directed lithiations result in an
nated by tedious and frequently expensive resolution pro-
unusual cyclisation reaction. Whilst the tolyl group cannot realise
tocols. This shortcoming arises as the introduction of just
one substituent breaks the symmetry of [2.2]paracyclo-
phane, and, therefore, needs to be enantioselective. In fer-
rocenyl and h6-arene complexes two substituents are
required to establish planar chirality, thus allowing the
first substituent to be used to control the enantioselective
introduction of the second.8
our goal, the chemistry outlined acts as a successful ‘proof of
concept.’
Key words: asymmetric synthesis, cyclophanes, sulfoxides, enan-
tiomeric resolution
[2.2]Paracyclophane (1a; R = H, Figure 1) was first pre-
pared by Brown 60 years ago,1 but it was the pioneering
studies of Cram that initiated the field of paracyclophane
chemistry.2 The popularity of [2.2]paracyclophane, which
has seen it become one of the most studied hydrocarbons,
arises from its unique structural, physical, and electronic
properties.3
In this paper we report the full details of our first steps to-
wards a general strategy for the formation of enantiomer-
ically enriched [2.2]paracyclophane derivatives from a
common precursor. Parts of this chemistry have previous-
ly been reported.9,10
Currently, enantiomerically enriched [2.2]paracyclo-
phane compounds are either resolved on an ad hoc basis11
or are derived from one of the key precursors 1b–f and 2
(Figure 1). The optimum routes to these enantiomerically
enriched compounds appear to be; aldehyde 1b via multi-
ple recrystallisations of Schiff base derviatives12 or enzy-
matic methods;13 carboxylic acid 1c by recrystallisation of
diastereoisomeric salts;14 phenol 1d by esterification with
a chiral acid chloride,15 enzymatic resolution of the ace-
tate;16 amine 1e by multiple recrystallisations of diaste-
reoisomeric salts;17 methyl ketone 1f via HPLC18 or
diastereoisomeric hydrazone derivatives.19 Resolved 4-
bromo[2.2]paracyclophane (1g) is now available via a ki-
netic resolution-amination protocol.20 4,12-Disubstituted
[2.2]paracyclophane derivatives are invariably prepared
from 4,12-dibromo[2.2]paracyclophane 2, which can be
obtained by kinetic resolution utilising the Buchwald–
Hartwig amination protocol21 or by chiral HPLC.
7
8
6
3
Br
9
2
1
5
4
R
16
15
10
Br
11
14
12
13
1a R = H
1e R = NH2
1i R = SiMe3
1j R = P(O)Ph2
1k R = D
2
1b R = CHO
1c R = CO2H
1d R = OH
1f R = COMe
1g R = Br
1h R = Me
Figure 1 Common [2.2]paracyclophane derivatives
It was recognised as early as 1955 that appropriately sub-
stituted [2.2]paracyclophane derivatives exhibited planar
chirality,4 yet no applications in stereoselective synthesis
were reported until the early 1990s.5,6 Since that time,
enantiomerically pure [2.2]paracyclophane compounds
have been employed with varying degrees of success in all
aspects of asymmetric synthesis. It is clear that [2.2]para-
We were interested in developing a methodology that will
permit the synthesis of any of the common [2.2]paracy-
clophane substitution patterns 4–7 in enantiomerically en-
riched form from a common precursor 3 (Scheme 1). Of
all the possible chiral directing groups, the sulfoxide moi-
ety offers sufficient versatility to fulfil all these criteria.
SYNTHESIS 2010, No. 24, pp 4177–4187
Advanced online publication: 05.10.2010
DOI: 10.1055/s-0030-1258286; Art ID: P12510SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

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R. Parmar et al.
PAPER
Due to the commercial availability of the Andersen re- agent 8 permitted stereospecific sulfination and the
agent, (1R,2S,5R)-(–)-menthyl (S)-p-toluenesulfinate (8), formation of a 1:1 mixture of diastereoisomers (Rp,SS)-9
and its diastereoisomers, as well as a previous report by and (Sp,SS)-9 in good yield (Scheme 2). The two diastereo-
Reich and Yelm22 employing the tolylsulfinyl moiety to isomers were readily separated utilising gradient elution
resolve [2.2]paracyclophanes, we began investigating the column chromatography; the [2.2]paracyclophane con-
chemistry of 4-tolylsulfinyl[2.2]paracyclophane (9).
taminate is removed first before elution of (Rp,SS)-9 fol-
lowed by (Sp,SS)-9. Separation has been achieved on a 10
g scale without issue. As nucleophilic substitution of sul-
finates proceeds with inversion at sulfur, the two diaste-
reoisomers differ only by their planar chirality. This
chemistry is equally effective with the diastereoisomer of
8, (1R,2S,5R)-(–)-menthyl (R)-p-toluenesulfinate, which
gives a 1:1 mixture of (Sp,RS)-9 and (Rp,RS)-9 in 50%
yield.
R4
R1
R1
path A
path D
path B
path C
4
5
DG
Both diastereoisomers are highly crystalline and we were
able to confirm Reich and Yelm’s original assignment of
the relative stereochemistry, which was based on derivati-
sation,22 by X-ray crystallography.9,26 As highlighted in
the original synthesis, the 1H NMR shifts are highly indic-
ative of the orientation of the sulfinyl oxygen. In the
(Rp,SS)-9 diastereoisomer, the oxygen is directed towards
the bridgehead methylene group and the anisotropic influ-
ence of the sulfoxide causes H2syn to be deshielded in
comparison to the other diastereoisomer [3.84 ppm versus
R3
3
R1
R2
R1
7
6
Scheme 1 General strategy for the synthesis of enantiomerically
pure [2.2]paracyclophane derivatives from a common precursor
The sulfoxide moiety must meet two criteria: it must al- 3.50 ppm in (Sp,SS)-9]. In diastereoisomer (Sp,SS)-9, the
low simple resolution and it must undergo direct substitu- sulfinyl oxygen is orientated towards the ortho hydrogen,
tion; other auxiliaries have been employed to resolve the H5, resulting in this hydrogen displaying a downfield res-
planar chirality of [2.2]paracyclophane, but all have been onance of 7.13 versus 6.58 ppm in (Rp,SS)-9.26
retained in the final product or have required several steps
Having resolved the planar chirality, substitution of the
to remove.23,24 Therefore, the first goal was the synthesis
sulfinyl moiety was investigated (Path A; Scheme 1). In
of enantiopure 4-monosubstituted [2.2]paracyclophane
order to access an extensive range of products, sulfoxide–
derivatives 4. Treatment of racemic 4-bromo[2.2]paracy-
metal exchange to give an enantiomerically enriched 4-
metallo[2.2]paracyclophane 11 was investigated. Disap-
clophane (1g)25 with n-BuLi followed by Andersen re-
pointingly, application of Reich and Yelm’s methodolo-
gy, employing n-BuLi followed by excess DMF gave only
a trace of product 1b along with [2.2]paracyclophane 1a
O
S
R
ii
(Scheme 3; Table 1, entry 1,). Clearly, sulfoxide–metal
exchange had occurred, but protonation was faster than
addition. Deeming that a soft 4-metallo[2.2]paracyclo-
phane 11 would be less basic, we utilised the conditions
of Satoh et al.27 to convert the sulfoxide into a cuprate via
the intermediacy of a Grignard reagent, then reacted it
with MeI to give 4-methyl[2.2]paracyclophane (1h) and
starting material (Table 1, entry 2). Omitting the copper
salt from this reaction gave comparable results (Table 1,
Tol
O
S
O
S
Tol
(Sp,SS)-9
1a R = H
1g R = Br
Tol
O
(Rp,SS)-9
i
8
Scheme 2 Resolution of planar chirality. Reagents and conditions: i.
Br2/Fe, CH2Cl2, >99%; ii. (a) n-BuLi (1.05 equiv), THF, –78 °C, (b)
8, THF, 61%.
O
t-Bu
O
t-Bu
S
S
M
E
O
O
S
S
M
M
R
9
10
11
12
1a–k
13a E = H
13b E = CHO
13c E = N3
Scheme 3 Formation of 4-monosubstituted [2.2]paracyclophane derivatives and the possible mechanism. Reagents and conditions: see Tables
1 and 2.
Synthesis 2010, No. 24, 4177–4187 © Thieme Stuttgart · New York

PAPER
Enantiomerically Pure [2.2]Paracyclophane Derivatives
4179
entry 3). When a less reactive electrophile was employed,
namely DMF, only 1a and unreacted starting material 9
was recovered (Table 1, entry 4). Using a large excess of
EtMgBr resulted in the consumption of more 9 but failed
to yield any product (Table 1, entry 5). 4-Metal-
lo[2.2]paracyclophanes formed by halogen–metal ex-
change are known to react efficiently, therefore, the
isolation of 1a implicates the ethylsulfoxide by-product as
the source of protons that inhibits reaction. Employing
tert-butyl organometallic reagents removes the relatively
acidic a-protons thus avoiding premature protonation.
Use of t-BuMgBr provided unsatisfactory results
(Table 1, entry 6), but t-BuLi proved more encouraging;
all starting material was rapidly consumed and, on addi-
tion of iodomethane, 1h was produced (30%) along with
1a (40%) and tert-butylsulfinyl-p-toluene (13a) (16%;
Table 1, entry 7). More auspiciously reaction with DMF
gave aldehyde 1b in good yield (62%; Table 1, entry 8)
along with 1a, 13a, and 2-(tert-butylsulfinyl)-5-methyl-
benzaldehyde (13b) (Scheme 3). Performing the reaction
at a higher temperature accelerates the detrimental side re-
actions (Table 1, entries 9 and 10). Extensive optimisation
led to conditions that minimised the formation of
[2.2]paracyclophane 1a (Table 1, entry 11).
Table 2 Synthesis of Enantiomerically Enriched Monosubstituted
[2.2]Paracyclophanes (Scheme 3)
Entry Electrophile Product
R
Yield
(%)
Yield (%) of
resolutiona
1
2
3
4
5
3
6
7
8
DMF
1b
1c
1d
1e
1h
1i
CHO
CO2H
OH
81
25 (20)13
CO2(s)
B(OMe)3
TsN3
77
24 (24)14
53b
32c
64
16 (11)15
NH2
10c (24)17
MeI
Me
–
–
–
–
–
TMSCl
TMS
P(O)Ph2
P(O)Ph2
D
44
Ph2P(O)Cl 1j
52
Ph2PCl
D2O
1j
90d
48
1k
a Overall yield from racemic ( )-4-bromo[2.2]paracyclophane to one
enantiomer of product. Literature yield is given in parentheses.
b Boron adduct was not isolated, but oxidised in situ with NMO.
c The low yield is due to a problematic reduction of 4-azido[2.2]para-
cyclophane, which occurs in only 40%.
d Phosphine is believed to oxidise on purification.
The scope of the reaction was then ascertained by varying
the electrophile (Table 2). Pleasingly, the methodology
permits the synthesis of four key enantiomerically en-
riched monosubstituted [2.2]paracyclophane precursors
1b–e in comparable or improved yields to previous reso-
lutions (Table 2, entries 1–4,). Whilst, the yield of 1e was
not ideal (32% for two steps), the reaction could be per-
formed on both a 0.3 mmol (100 mg) and a 3.0 mmol (1
g) scale without loss in yield. The methodology also per-
mitted the first reported preparation of the phosphine ox-
ide 1j in enantiomerically pure form (Table 2, entries 7
and 8);28 presumably, aerial oxidation occurs on purifica-
tion in the latter reaction.
Other electrophiles, such as iodine, bromine, and acetyl
chloride gave only [2.2]paracyclophane. Considering all
these reagents react with 4-lithio[2.2]paracyclophane
generated from 4-bromo[2.2]paracyclophane, it is fair to
assume that the basic nature of [2.2]paracyclophane in
conjunction with the formation of a comparatively acidic
Table 1 Optimisation for the Formation of 4-Monosubstituted [2.2]Paracyclophane Derivatives from 9
Entry
1
R1M (equiv)
RX (equiv)
DMF (12.0)
MeI (4.0)
Product
1b
1h
1h
–
Yield (%)
9 (%)
0
1a (%)
>95
–
Othersa (%)
n-BuLi (6.0)
EtMgBr (3.5), CuBr (0.5)
EtMgBr (3.5)
EtMgBr (3.5)
EtMgBr (9.0)
t-BuMgBr (2.0)
t-BuLi (2.0)
<5
61
62
0
–
2
36
36
52
10
53
0
–
3
MeI (4.0)
0
–
4
DMF (4.0)
DMF (12.0)
MeI (4.0)
44
66
–
–
5
–
0
–
6
–
0
–
7
MeI (4.0)
1h
1b
–
30
62
0
40
27
80
45
18
54
16 (13a)
8
t-BuLi (2.0)
DMF (4.0)
DMF (4.0)
DMF (6.0)
DMF (8.0)
TsN3 (8.0)
0
15 (13a), 29 (13b)
9b
10b
11
12
t-BuLi (2.0)
0
–
t-BuLi (3.0)
1b
1b
1e
16
81
32c
0
15 (13a), 21 (13b)
–
t-BuLi (4.0)
0
t-BuLi (4.0)
0
13 (13a), 20 (13c)
a See Scheme 3.
b Reaction performed at 0 °C.
c Yield is for two steps; azide formation and reduction with NaBH4.
Synthesis 2010, No. 24, 4177–4187 © Thieme Stuttgart · New York

4180
R. Parmar et al.
PAPER
sulfoxide by-product is the source of these disappointing Having proven the feasibility of employing the sulfoxide
results.
moiety as a ‘traceless’ resolving group, we turned our at-
tention to the synthesis of disubstituted derivatives.
We believe that the substitution reaction is not as simple
as it appears. Up to four products 1b–k, 1a, 13a and 13b, The simplest disubstituted [2.2]paracyclophane deriva-
or 13c (Scheme 3) can be isolated from these reactions tives to prepare are the pseudo-gem [2.2]paracyclophanes
and this suggests the following: It is unlikely that direct 5 (Scheme 1). The pseudo-gem effect directs electrophilic
substitution of the [2.2]paracyclophanyl moiety by the aromatic substitution reactions to the thermodynamically
tert-butyl group occurs. Due to its high basicity, disfavoured position directly opposite the original substit-
[2.2]paracyclophane is a less effective leaving group than uent. The basis of this effect is the formation of a s-com-
p-tolyllithium. The high basicity of 4-lithio[2.2]paracy- plex in which the pseudo-gem hydrogen atom (H13) is
clophane is apparent in the reaction of 11 (M = Li) with orientated towards a basic atom on the 4-substituent (e.g.,
MeI, which gives up to 34% yield of 4-iodo[2.2]paracy- 14; Scheme 4).31,32 This alignment facilitates an intramo-
clophane along with the expected 4-methyl[2.2]paracy- lecular proton transfer step and promotes deprotonation.
clophane. A similar result was observed by Cram.29 The
Our plan was to direct bromination to the C13 position
iodide arises due to a second metal–halogen exchange.
and then employ halogen–metal exchange to introduce a
Equally improbable is the sequential displacement of p-
range of electrophiles. Reich and Yelm have shown that
tolyllithium, to give 4-tert-butylsulfinyl[2.2]paracyclo-
phane, followed by a second substitution to give 11 and
di-tert-butyl sulfoxide; we have shown that 4-tert-butyl-
the sulfone moiety could direct bromination22 but sulfox-
ides have never been employed in this reaction. We were
conscious that the reactivity of the sulfoxide group could
compromise chemoselectivity in the subsequent halogen–
sulfinyl[2.2]paracyclophane does not participate in sulf-
oxide–metal exchange reactions.30 Therefore, we posit
exchange reaction, and therefore, the bromosulfone ana-
that ortho-lithiation of the tolyl moiety to give 10 occurs
logue 18 and the bromosulfide 19 were also prepared
(Scheme 5).
prior to displacement by t-BuLi. Compounds 1b–j and
13a–c are formed by reaction of 11 and 12 with an elec-
Treatment of (Sp,SS)-9 with iron and bromine furnished
trophile. [2.2]Paracyclophane 1a arises as 11 competes
the desired pseudo-gem-disubstituted [2.2]paracyclo-
with t-BuLi to form 10.
phane (Rp,SS)-15 in moderate yield (57%) along with un-
The most striking feature of the results in Table 2 is not
reacted starting material. More starting material could be
that the sulfoxide methodology compares favourably with
consumed, but at the detriment of the yield as more side-
the known resolution strategies (entries 1 to 4), but that all
products were formed. Reaction of diastereoisomer
these compounds can be prepared in enantiomerically
(Rp,SS)-9 was less successful, giving only 35% of the de-
sired bromide (Sp,SS)-15 before deoxygenation, and sub-
sequent nonselective bromination, became an issue.
Presumably, interaction between the ethylene bridge and
pure form from the same precursor. Whilst this methodol-
ogy is still a resolution, it is a significant advance due to
its versatility.
the tolyl moiety hinders rotation and the molecule cannot
adopt the correct conformation for efficient intramolecu-
Tol
lar hydrogen transfer; this unfavourable conformation can
S
O
H
be inferred by comparing the X-ray crystallographic
structures of bromides (Sp,SS)-15 and (Rp,SS)-15
(Figure 2). In (Sp,SS)-15 the sulfinyl oxygen is orientated
away from the lower ring whilst in (Rp,SS)-15 there is less
hindrance to it approaching the lower ring.
O
O
S
S
Br
Tol
Tol
Br
(Sp,SS)-9
(Rp,SS)-15
14
Scheme 4 Pseudo-gem directed functionalisation. Reagents and
conditions: Fe/Br2, CH2Cl2, 57%.
Br
R
ii (n = 1)
S(O)nTol iii (n = 2)
S(O)nTol
S(O)nTol
vi–ix
(Sp,SS)-9 n = 1
(Rp,SS)-9 n = 1
(Rp)-16 n = 2
(Sp)-16 n = 2
(Rp)-17 n = 0
(Rp,SS)-15 n = 1
(Sp,SS)-15 n = 1
(Rp)-18 n = 2
(Sp)-18 n = 2
(Sp,SS)-20 n = 1; R = Me
(Rp)-21 n = 2; R = Me
(Rp)-22a n = 0; R = P(O)Ph2
(Rp)-22b n = 0; R = Me
(Sp)-22c n = 0; R = I
i
iv
v
(Sp)-19 n = 0
Scheme 5 Synthesis of pseudo-gem disubstituted [2.2]paracyclophane derivatives. Reagents and conditions: i. m-CPBA, CH2Cl2 [(Rp)-16
61%; (Sp)-16 >98%]; ii. Br2/Fe, CH2Cl2 [(Sp,SS)-9 → (Rp,SS)-15 57%; (Rp,SS)-9 → (Sp,SS)-15 35%]; iii. Br2/Fe, CCl4 [(Sp)-16 → (Rp)-18 61%];
iv. HSiCl3, Et3N, THF, reflux [(Sp,SS)-15 → (Sp)-19 98%]; v. m-CPBA, CH2Cl2 [(Sp,SS)-19 → (Sp)-18 28%]; vi. (a) i-PrBu2MgLi, THF, 0 °C,
(b) MeI, THF, 0 °C [(Rp,SS)-15 → (Sp,SS)-20 48%]; vii. (a) n-BuLi, THF, –78 °C, (b) MeI, THF, 0 °C [(Sp)-18 → (Rp)-21 40%]; viii. (a) i-
PrBu2MgLi, THF, 0 °C, (b) Ph2P(O)Cl, THF, 0 °C [(Sp)-19 → (Rp)-22a 88%]; ix. (a) t-BuLi, THF, –78 °C, (b) MeI, THF, –78 °C [(Sp)-19 →
(Rp)-17 55%, (Rp)-22b 34%, (Sp)-22c 11%].
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Enantiomerically Pure [2.2]Paracyclophane Derivatives
4181
the efficiency. Reaction of the electron-rich sulfide (Sp)-
19 was highly capricious, with additions to diphenylphos-
phoryl chloride furnishing phosphine oxide (Rp)-22a with
yields varying from 10–88% (Scheme 5). Use of other
electrophiles invariably resulted in protonation and for-
mation of sulfide (Rp)-17. The sulfide moiety detrimental-
ly increases the basicity of the system, as highlighted by
the reaction of (Sp)-19 with t-BuLi and MeI. In addition to
the formation of methyl derivative (Rp)-22b (34%) and
sulfide (Rp)-17 (38%), the iodide (Sp)-22c (11%) was also
observed. The electron-deficient bromosulfone (Sp)-18
was no less idiosyncratic, furnishing both the desired
methylated (Rp)-21 (40% yield) and considerable amounts
of proto-debrominated (Rp)-16. Additionally, the NMR
spectra indicated that the sulfone had directed lithiation to
the ortho position on the tolyl moiety.
The current results serve as a ‘proof of concept’; it is pos-
sible to use the sulfoxide moiety to direct functionalisa-
tion to the second ring of [2.2]paracyclophane. The
tolylsulfinyl group is capable of directing pseudo-gem
bromination, but it is too reactive to permit selective metal
exchange. Conversion to more robust functionality, either
the sulfide or the sulfone alleviates the problem of selec-
tive exchange, but both are still hampered by side reac-
tions.
Sulfoxides are known to be excellent auxiliaries for di-
rected metallations36 and we were interested in applying
this chemistry to further functionalise the [2.2]paracyclo-
phane backbone. The issue of regioselectivity prevented
directed ortho-metallation at C5 of diastereoisomer
(Sp,SS)-9. García Ruano et al. have reported high
chemoselectivity in sulfoxide-directed metallations of
benzylic methylenes in preference to ortho-metallation37
and we believed that employing their methodology with
diastereoisomer (Rp,SS)-9 or (Sp,RS)-9, in which the sulfi-
nyl oxygen is orientated towards C2, would permit direct-
ed bridgehead metallation. Functionalisation of C2 is rare;
Hou,24 Pelter,38 and Bolm39 have all described the acci-
dental/nonselective deprotonation of C2, but only Hopf
has achieved deliberate ‘lateral’ functionalisation.40
Figure 2 X-ray crystal structure of pseudo-gem brominated sulf-
oxides (Sp,SS)-15 and (Rp,SS)-1526b
The side-products arise from the reduction of the sulf-
oxide to an electron-donating sulfide, which promotes
non-selective bromination. The major side-product in-
volves bromination of the electron rich upper ring para to
the sulfinyl moiety. Dibromination of the [2.2]paracyclo-
phane moiety deactivates it, and subsequent bromination
occurs in the ortho position of the tolyl ring. The struc-
tures were inferred from X-ray crystallography studies.33
The bromosulfone (Rp)-18 was synthesised according to
the literature22 whilst its enantiomer, (Sp)-18, was pre-
pared by the oxidation of bromosulfide (Sp,SS)-19. The
sulfide (Sp)-19 was prepared by the reduction of (Sp,SS)-15
with HSiCl3 and Et3N at reflux (Scheme 5).34
Treatment of diastereoisomer (Sp,RS)-9 with lithium diiso-
propylamide (LDA) and MeI furnished a new compound
23 (16%) along with starting material (Scheme 6). Reac-
tion of (Rp,SS)-9 with an alternative electrophile, diphe-
Treatment of sulfoxide (Rp,SS)-15 with n-BuLi followed
by MeI led to a complex mixture of products comprised of
predominantly [2.2]paracyclophane 1a and only 8% of the
desired (Sp,SS)-20 (Scheme 5). It was clear that nonselec-
tive metal exchange was occurring. After screening vari-
ous conditions, the most selective halogen–metal
exchange was achieved with Oshima’s magnesate, lithi-
umdibutylisopropylmagnesate (i-PrBu2MgLi).35 Addition
of (Rp,SS)-15 to a solution of i-PrBu2MgLi at 0 °C fol-
lowed by the addition of MeI gave (Sp,SS)-20 in an im-
proved 48% yield along with 1a (40%).
10
9
6
11
12
16
15
5
7
8
13
14
1
i
O
4
H
S
3
2
18
S
19
23
17
22
O
20
H
21
24
(Sp,RS)-9
23
Neither the sulfone 18 nor the sulfide 19 completely ame-
liorated the low yields. Whilst selective halogen–metal
exchange was possible in both cases, other issues affected
Scheme 6 Cyclisation of the C2 anion onto the tolyl moiety.
Reagents and conditions: i. (a) LDA, THF, –78 °C, (b) MeI, (23
16%).
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4182
R. Parmar et al.
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23
21
H
20
19
22
17
H
H
H
O
S
H
S
1
2
14
i or ii
18
13
15
16
3
S
S
S
4
8
7
O
O
O
12
11
10
5
6
9
(Rp,SS)-9
24
25
26
27
Scheme 7 Cyclisation of the C2 anion onto the tolyl moiety. Reagents and conditions: i. (a) LDA, THF, –78 °C, (b) Ph2PCl (24 53%), 25
10%); ii. (a) LDA, THF, –78 °C, (b) aq NH4Cl (26 30%, 27 14%).
nylphosphinic chloride, resulted in two new products, (6.52–6.49 ppm) suggesting that the electron-withdraw-
sulfoxide 24 (53%) and sulfide 25 (10%), as well as start- ing sulfinyl moiety had been reduced to the electron-rich
ing material (18%; Scheme 7). It was assumed that 24 and sulfide. The position of the alkene bonds in 26 and 27 was
25 were formed by the elimination of an adduct of a cy- ascertained with the aid of NOE experiments; interaction
clohexadienyl anion and the phosphorous reagent. Empir- between the methyl group and the CH2 group of 26, along
5
ical evidence supported this assumption as quenching the with a large J value for H17 and H20 analogous to 23
proposed anion with a weak acid resulted in the formation suggested the 1,3-diene pattern of 26. The presence of the
of 1,3-diene 26 (30%), conjugated diene 27 (14%) and un- sulfinyl moiety as opposed to a simple sulfide was implied
reacted starting material (12%). It appears that without a by the downfield resonance of H5, which at 7.14 ppm is
suitable leaving group, no re-aromatisation is possible. almost identical to dimethyl 23 (7.12 ppm). The 1H NMR
Presumably, 1,3-diene 26 predominates due to similar ar- spectrum of 27 indicated it was an isomer of 26 and NOE
guments to those proffered for the regiochemistry of the suggested the conjugated diene 27. Again, the downfield
Birch reduction.
resonance of H5 implied that the compound was in the
sulfoxide oxidation state.
Initially, identification of the polycyclic compounds was
taxing; all except 23 proved relatively unstable and thus Clearly, the sulfinyl moiety can direct deprotonation to
were only characterised by 1H and 13C NMR spectrosco- the bridgehead C2 position, but cyclisation on to the tolyl
py. The 1H NMR spectra of 23 is complex and misleading, ring is faster than reaction with external nucleophiles.
5
there is an unexpectedly large J coupling between H17
4-Tolylsulfinyl[2.2]paracyclophane shows the potential
and H20 (6.5 Hz) that presumably arises due to the doubly
of the proposed sulfoxide methodology to deliver a vari-
allylic nature of these hydrogen and their pseudo anti-
ety of enantiomerically pure [2.2]paracyclophane deriva-
tives from a common precursor. Employing this
periplanar arrangement. The structure was finally con-
firmed by X-ray crystallography (Figure 3). The presence
sulfoxide, we have prepared enantiomerically pure 4-sub-
of the sulfinyl moiety in 24 was inferred from the down-
stituted [2.2]paracyclophane derivatives and functiona-
lised the C13 position of the second aromatic ring, thus
field shift of the ortho (H5) and gem (H13) hydrogen res-
onances; H5, 7.29–7.27 ppm and H13 7.17 ppm.26 In
permitting the formation of disubstituted derivatives. Di-
[2.2]paracyclophane these equivalent protons are found at
rected metallations are possible, but the C2 anion cyclises
6.46 ppm and in the methylated polycycle 23 they are at
on to the toluene ring faster than it reacts with an external
electrophile.
7.12 and 6.98 ppm, respectively. The reduced sulfide 25
exhibits a high field resonance for the ortho H5 hydrogen
We are currently modifying the sulfoxide substituent in
the hope of overcoming these limitations. The tert-butyl-
sulfinyl group has proven successful in directed lithiation
reactions, but is not without its own deficiencies,30 and
studies are now focussing on other sulfoxides. We are also
interested in developing more efficient routes to various
enantiomerically pure sulfoxides including oxidative ki-
netic resolution of racemic sulfides. The results of these
studies will be reported in due course.
Et2O and THF were obtained by distillation from sodium/benzophe-
none. CH2Cl2, toluene, and MeCN were distilled from CaH2. Petro-
leum refers to the fraction of hexanes of boiling point 60–80 °C. All
other chemicals were purchased from Avocado, Acros, or Sigma-
Aldrich and were used without further purification.
Melting points were measured on a Kofler hot-stage apparatus and
Figure 3 X-ray crystal structure of cyclisation product 2326b
are uncorrected. Optical rotations were recorded using a Perkin-
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Enantiomerically Pure [2.2]Paracyclophane Derivatives
4183
Elmer PE241 polarimeter using a 1 dm path length cell and a con-
centration, c, in g/100 mL. IR spectra were recorded on a Perkin-
Elmer 1710 Fourier transform spectrometer. NMR spectra were re-
corded on a Bruker DPX 300 Fourier transform instrument or by the
late Dr. A. G. Avent using a Bruker AMX 500 Fourier transform in-
strument. Chemical shifts are given in ppm using residual undeuter-
ated solvent peaks and TMS as internal references. Mass spectra
were recorded at the University of Sussex by Dr. A. Abdul-Sada us-
ing a Kratos MS 80RF (FAB), VG Autospec (EI), Bruker BioApex
III (ESI) double focussing spectrometers or a 4.7 FT-ICR (Bruker
BioApex III) spectrometer.
13C NMR (75 MHz): d = 144.3, 142.1, 141.9, 141.3, 139.6, 139.0,
136.5, 135.8, 135.3, 133.1, 132.9, 132.8, 131.5, 129.9, 127.8, 125.7,
35.2, 35.2, 34.6, 32.9, 21.3.
MS (EI+): m/z = 346 [M]+, 329 [M – O]+, 283, 257, 242, 225, 211,
178, 165, 150, 137, 121, 104, 91.
HRMS-EI: m/z found 346.138971 [M]+; C23H22OS requires
346.139137.
4-Substituted [2.2]Paracyclophane Derivatives; General Proce-
dure
A solution of t-BuLi (1.5 M in pentane; 0.48 mmol, 4.0 equiv) was
X-ray crystallographic structure analysis experiments were con-
ducted at the University of Sussex by Dr. P. B. Hitchcock using a
Bruker-Nonius Kappa CDD diffractometer.
added dropwise to
a solution of (Sp,RS)-4-p-toluenesulfinyl
[2.2]paracyclophane (0.12 mmol, 1 equiv) in THF (0.1 M) at
–78 °C. The resulting orange solution was stirred at –78 °C for 10
min, whereupon the electrophile (0.96 mmol, 8 equiv) was added.
Liquids were added neat and solids added as a solution in THF. The
reaction mixture became a pale yellow colour and was stirred at
–78 °C for a minimum of 3 h. Sat. aq NH4Cl (5 mL) was added and
the reaction mixture warmed to r.t. The organic layers were separat-
ed and the aqueous phase extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (MgSO4) and concentrated.
The crude material was purified by column chromatography on sil-
ica gel using gradient elution (petrol to petrol–EtOAc).
(Rp,Ss)-4-p-Toluenesulfinyl[2.2]paracyclophane [(Rp,Ss)-9] and
(Sp,Ss)-4-p-Toluenesulfinyl[2.2]paracyclophane [(Sp,Ss)-9]22
n-BuLi (2.5 M solution in hexane, 14.6 mL, 36.90 mmol) was added
dropwise to a solution of ( )-4-bromo[2.2]paracyclophane (10.0 g,
34.80 mmol) in THF (174 mL) at –78 °C. The resulting yellow so-
lution was stirred for 2 h at –78 °C, then added via cannula to a so-
lution of (1R,2S,5R)-(–)-menthyl (S)-p-toluenesulfinate (10.8 g,
36.60 mmol) in THF (183 mL) at –78 °C. The solution was warmed
to r.t. over 18 h. Sat. aq NH4Cl (150 mL) was added and the organic
phase was separated. The aqueous phase was extracted with Et2O
(3 × 150 mL) and the combined organics dried (MgSO4), then con-
centrated under reduced pressure to yield a yellow residue, which
was purified by column chromatography on silica gel using gradient
elution (petrol to 9:1 petrol–EtOAc) to give (Rp,Ss)-9 as a white
crystalline solid (3.7 g, 31%), and (Sp,Ss)-9 as white needles (3.6 g,
30%).
(Sp)-4-Formyl[2.2]paracyclophane (1b)13,41
Prepared according to the general procedure and isolated as a white
crystalline solid (0.02 g, 81%); data in general agreement with liter-
ature. See Supporting Information.13,41
(Rp)-4-Carboxy[2.2]paracyclophane (1c)14,32
Prepared according to the general procedure except for purification,
which was performed by forming the carboxylate anion with aq 1 M
NaOH, washing with CH2Cl2 (3 × 15 mL) before acidification with
concd HCl and filtering the white percipitate (0.28 g, 77%); data in
general agreement with literature. See Supporting Information.14,32
(Rp,Ss)-9
Mp 175–177 °C (Lit. mp 176–177 °C); Rf = 0.4 (2:1 petrol–EtOAc);
[a]D25 –51.4 (c 1.1, CHCl3) {Lit. [a]D –51 (c 0.2, CHCl3)}.
IR (nujol): 2923, 2725, 1903, 1585, 1459, 1377, 1303, 1155, 1079,
1035, 942, 910, 896, 727, 694 cm–1.
(Sp)-4-Hydroxy[2.2]paracyclophane (1d)11,15
Prepared according to the general procedure except after reacting
with trimethyl borate for 30 min at –78 °C and r.t. for 1 h, N-meth-
ylmorpholine-N-oxide (10 equiv) was added and the reaction mix-
ture heated to reflux for 2 days. Standard purification gave 1d as a
white solid (0.02 g, 53%); data in general agreement with literature.
See Supporting Information.11,15
1H NMR (300 MHz): d = 7.39 (2 H, d, J = 8.1 Hz, H-Tol), 7.25 (2
H, d, J = 7.7 Hz, H-Tol), 6.88 (1 H, d, J = 6.6 Hz, H13), 6.60–6.53
(4 H, m, H5, H7, H15, H16), 6.46 (1 H, d, J = 8.3 Hz, H8), 6.37 (1
H, d, J = 8.1 Hz, H12), 3.84 (1 H, ddd, J = 13.0, 10.6, 2.4 Hz, H2),
3.36 (1 H, ddd, J = 12.8, 10.6, 5.0 Hz, H1) 3.21–2.89 (5 H, m, H1,
2 × H9, 2 × H10), 2.79 (1 H, ddd, J = 12.9, 10.8, 5.2 Hz, H2), 2.38
(3 H, s, CH3).
13C NMR (75 MHz): d = 142.0, 142.0, 141.8, 140.8, 140.7, 139.9,
139.1, 137.5, 136.5, 133.1, 132.7, 132.6, 132.5, 132.4, 129.6, 125.2,
35.5, 35.1, 34.9, 32.9, 21.4.
(Sp)-4-Amino[2.2]paracyclophane (1e)42
A solution of t-BuLi (1.8 M in hexane; 8.45 mL, 15.21 mmol, 4.0
equiv) was added dropwise to a solution of sulfoxide 10 (1.05 g,
3.04 mmol, 1.0 equiv) in THF (30.41 mL) at –78 °C. The bright yel-
low solution was stirred for 3 min and then a solution of TsN3 (6.00
g, 30.41 mmol, 10.0 equiv) in THF (10.00 mL) was added in one
portion. The reaction mixture was warmed to r.t. overnight. The re-
action was poured into brine (50 mL) and extracted with Et2O
(3 × 100 mL). The combined organics were dried (MgSO4) and con-
centrated. The crude residue was dry loaded and filtered through sil-
ica using petrol (60–80) as eluent. The azide (0.84 g, 3.37 mmol, 1.0
equiv), NaBH4 (2.50 g, 67.40 mmol, 20.0 equiv), and Bu4NI (0.50
g, 1.35 mmol, 0.4 equiv) were suspended in 2:1 THF–H2O (102
mL) and stirred at r.t. for 12 h. The reaction mixture was poured into
brine (50 mL) and extracted with Et2O (3 × 60 mL). The combined
organic phases were dried (MgSO4) and concentrated. The residue
was purified by column chromatography (gradient neat petrol then
4:1 petrol–EtOAc) to give amine 1e (0.20 g, 30%); data in general
agreement with literature. See Supporting Information.42
HRMS-ESI: m/z found 346.139135 [M]+; C23H22OS requires
346.139137.
(Sp,Ss)-9
Mp 148–150 °C (Lit. mp 151–155 °C); Rf = 0.3 (2:1 petrol–EtOAc);
[a]D25 +104.8 (c 1.2, CHCl3) {Lit. [a]D +85 (c 0.4, CHCl3) contain-
ing ~8% other diastereoisomer}.
IR (nujol): 2921, 2725, 1903, 1584, 1459, 1377, 1303, 1180, 1077,
1055, 1035, 942, 897, 846, 815, 846, 815, 792, 727, 694 cm–1.
1H NMR (300 MHz): d = 7.37 (2 H, d, J = 8.1 Hz, H-Tol), 7.17 (2
H, d, J = 8.0 Hz, H-Tol), 7.13 (1 H, d, J = 1.9 Hz, H5), 6.97 (1 H, d,
J = 8.0 Hz, H13), 6.63 (1 H, d, J = 8.0 Hz, H12), 6.60 (1 H, dd, J =
7.9, 1.5 Hz, H7), 6.53 (2 H, s, H15, H16), 6.44 (1 H, d, J = 7.7 Hz,
H8), 3.50 (1 H, ddd, J = 13.2, 10.3, 2.4 Hz, H2) 3.34 (1 H, ddd, J =
13.1, 9.9, 5.3 Hz, H1), 3.22–3.02 (5 H, m, H1, 2 × H9, 2 × H10),
2.87 (1 H, ddd, J = 13.5, 10.7, 5.3 Hz, H2), 2.30 (3 H, s, CH3).
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(Rp)-4-Methyl[2.2]paracyclophane (1h)32,43
Prepared according to the general procedure and isolated as a white
solid (0.03 g, 75%); data in general agreement with literature. See
Supporting Information.32,43
then added dropwise via cannula and the suspension stirred at r.t. for
20 h. The reaction mixture was poured into sat. aq NH4Cl (100 mL).
The organic layer was separated and the aqueous phase extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with aq 10% Na2S2O3 (250 mL), brine (250 mL), dried
(MgSO4), and concentrated to yield a pale yellow residue. The res-
idue was purified by recrystallisation (toluene–petrol) to give a
white solid (38%) and (Rp)-4,12-dibromo-7-p-tolylsulfa-
nyl[2.2]paracyclophane, which was purified by recrystallisation
(CH2Cl2–Et2O) to give a white solid (11%). In addition a molecule
that appears to be (Sp)-4,12,18-tribromo-7-p-tolylsulfanyl[2.2]para-
cyclophane co-crystallised with the dibromide in about a 2:1 ratio.33
(Rp)-4-Trimethylsilyl[2.2]paracyclophane (1i)
Prepared according to the general procedure and isolated as a white
solid (0.38 g, 44%); mp 89–90 °C; Rf = 0.6 (2:1 petrol–EtOAc);
[a]D32 –59.01 (c 1.49, CHCl3).
IR (CH2Cl2 film): 3435, 2952, 2854, 2893, 2107, 1638, 1464, 1435,
1243, 1180, 1066, 901, 832, 791, 753, 665 cm–1.
1H NMR (300 MHz): d = 6.69 (1 H, d, J = 1.5 Hz, H5), 6.58 (2 H,
br s, H15, H16), 6.43 (1 H, dd, J = 7.6, 1.5 Hz, H7), 6.39–6.28 (3 H,
m, H12, H13, H8), 3.31–2.91 (8 H, m, 2 × H1, 2 × H2, 2 × H9,
2 × H10), 0.31 (9 H, s, 3 × CH3).
(Sp,Ss)-15
29
Mp 201–203 °C; Rf = 0.1 (2:1 petrol–Et2O); [a]D +92.5 (c 0.52,
CHCl3).
13C NMR (75 MHz): d = 145.6, 139.5, 139.4, 138.9, 137.8, 137.1,
134.0, 133.6, 132.8, 132.5, 132.2, 132.1, 35.7, 35.5, 35.2, 35.2, 0.4.
IR (nujol): 3435, 2109, 1644, 1473, 1394, 1081, 1031, 665 cm–1.
1H NMR (300 MHz): d = 7.67 (2 H, d, J = 8.1 Hz, H-Tol), 7.31 (2
H, d, J = 7.9 Hz, H-Tol), 6.63–6.52 (4 H, m, H7, H8, H15, H16),
6.40 (1 H, s, H5), 5.85 (1 H, s, H12), 4.35 (1 H, ddd, J = 13.9, 9.7,
4.5 Hz, H1), 3.73 (1 H, ddd, J = 13.2, 10.1, 3.2 Hz, H2), 3.21 (1 H,
ddd, J = 13.7, 10.1, 3.2 Hz, H9), 3.07–2.89 (5 H, m, H1, H2, H9,
2 × H10), 2.41 (3H, s, CH3).
13C NMR (75 MHz): d = 147.3, 142.0, 141.6, 140.4, 140.0, 139.7,
139.8, 137.5, 136.3, 135.3, 132.0, 130.3, 128.4, 127.3, 127.2, 36.3,
35.2, 34.8, 32.3, 22.0.
MS (EI+): m/z = 426 [M]+, 408, 345 [M – 81Br]+, 318, 242, 225, 135,
91.
HRMS-EI: m/z found 425.0569250 [M]+; C23H22BrOS [M]+ re-
quires 425.0593280.
MS: m/z not available as the compound did not ionise.
(Rp)-Diphenyl([2.2]paracyclophan-4-yl)phosphine Oxide (1j)11
Prepared according to the general procedure and isolated as a pale
yellow solid (0.03 g, 49%); mp 192–194 °C (Lit.11 mp 205–
207 °C); Rf = 0.1 (2:1 petrol–EtOAc); [a]D32 –68.3 (c 1.88, CHCl3)
{Lit.11 [a]D20 –24.1 (c 1.05, CHCl3)}.
IR (neat): 3583, 3430, 2925, 2853, 1637, 1501, 1456, 1437, 1178,
1116, 1104, 1069, 1027, 998, 916, 851, 794, 752, 720, 707, 695, 665
cm–1.
1H NMR (300 MHz): d = 7.72–7.68 (2 H, m, C6H5), 7.56–7.44 (6 H,
m, C6H5), 7.38–7.35 (2 H, m, C6H5), 7.18 (1 H, dd, J = 7.88, 1.6 Hz,
H5), 6.62 (1 H, d, J = 7.6 Hz, H7), 6.57 (1 H, dd, J = 7.9, 1.8 Hz,
H15), 6.55 (1 H, d, J = 3.6 Hz, H8), 6.53 (1 H, dd, 7.8, 1.7 Hz, H16),
6.29 (1 H, dd, J = 2.1, 2.1 Hz, H12), 6.27 (1 H, dd, J = 3.5, 1.7 Hz,
H13), 3.55–3.50 (2 H, m, H1, H2), 3.13–2.74 (6 H, m, H1, H2,
2 × H9, 2 × H10).
(Rp)-4,12-Dibromo-7-p-tolylsulfanyl[2.2]paracyclophane
31
Mp 161–162 °C; Rf = 0.7 (2:1 petrol–Et2O); [a]D +75.0 (c 0.88,
CHCl3).
IR (nujol): 3401, 3053, 2931, 2855, 2305, 1584, 1490, 1462, 1390,
1354, 1264, 1207, 1115, 1063, 1032, 907, 895, 876, 862, 844, 802,
750, 705, 665 cm–1.
13C NMR (75 MHz): d = 146.1, 146.0, 140.0, 139.5, 139.4, 136.9,
136.7, 136.2, 134.8, 132.7, 132.3, 132.1, 132.0, 131.8, 131.5, 131.4,
131.3, 128.4, 128.3, 128.2, 128.1, 35.6, 35.1, 35.0, 29.7.
1H NMR (300 MHz): d = 7.20 (1 H, dd, J = 8.0, 1.2 Hz, H15), 6.97
(2 H, d, J = 7.9 Hz, H-Tol), 6.89 (2 H, d, J = 8.5 Hz, H-Tol), 6.71 (2
H, br s, H5, H13), 6.59 (1 H, s, H8), 6.51 (1 H, d, J = 7.9 Hz, H16),
3.79–3.67 (2 H, m, H2, H10), 3.40 (1 H, ddd, J = 12.9, 10.5, 2.1 Hz,
H9), 3.16 (1 H, ddd, J = 13.0, 10.0, 6.1 Hz, H1), 3.06–2.94 (2 H, m,
H1, H9), 2.89–2.68 (2 H, m, H2, H10), 2.24 (3 H, s, CH3).
31P NMR (300 MHz): d = 28.12 (P).
MS (EI+): m/z = 408 [M+], 304, 234, 225, 201, 178, 165, 152, 125,
104, 77.
HRMS-EI: m/z found 431.1535230; C28H25PO + Na requires
431.1535230.
13C NMR (75 MHz): d = 143.7, 143.4, 142.8, 142.6, 139.8, 139.8,
139.2, 139.0, 136.6, 136.6, 134.4, 133.2, 130.0, 128.9, 128.5, 124.1,
35.5, 35.0, 33.3, 32.8, 21.4.
(Rp)-4-Deuterio[2.2]paracyclophane (1k)44
Prepared according to the general procedure and isolated as a white
solid (0.15 g, 48%); mp 279–280 °C (Lit.44 mp 280–285 °C); Rf =
MS (EI+): m/z 488 [M]+, 444, 410, 304, 225, 192, 149, 105, 84.
0.7 (2:1 petrol–EtOAc); [a]D32 +5.91 (c 0.16, CHCl3) {Lit.44 [a]D
25
–4 (c 0.87, CHCl3) for the S-enantiomer}.
HRMS-EI: m/z found 508.9526950 [M]+; C23H2Br2S + Na [M +
Na]+ requires 508.9544676.
1H NMR (300 MHz): d = 7.14 (7 H, s, H5, H7, H8, H12, H13, H15,
H16), 3.74 (8 H, s, 2 × H1, 2 × H2, 2 × H9, 2 × H10).
(Sp)-4-Bromo-13-p-tolylsulfanyl[2.2]paracyclophane [(Sp)-19]
To a solution of (Sp,SS)-15 (0.30 g, 0.71 mmol, 1.0 equiv) in THF
(9.4 mL) was added Et3N (0.93 mL, 7.06 mmol, 10 equiv) followed
by trichlorosilane (1.07 mL, 10.59 mmol, 15 equiv). The reaction
was heated to reflux for 20 h. The reaction was carefully (Caution!)
poured into a rapidly stirred mixture of aq 2 M NaOH (30 mL) and
CH2Cl2 (30 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 30 mL). The combined organ-
ic layers were dried (MgSO4) and concentrated to yield a white sol-
id, which was purified by recrystallisation (CH2Cl2–Et2O), to
furnish (Sp)-19 as colourless crystals (0.28 g, 98%); mp 148–
150 °C; Rf = 0.7 (2:1 petrol–EtOAc); [a]D31 +10.2 (c 0.98, CHCl3).
13C NMR (75 MHz): d = 139.6, 133.0, 35.7.
MS (EI+): m/z = 209 [M]+, 104.
(Sp,Ss)-4-Bromo-13-p-tolylsulfinyl[2.2]paracyclophane [(Sp,Ss)-
15] and (Rp)-4,12-Dibromo-7-p-tolylsulfanyl[2.2]paracyclo-
phane
A solution of Br2 (2.53 mL, 49.04 mmol, 10.5 equiv) in CH2Cl2
(490 mL) was covered with aluminum foil. Part of this solution (49
mL) was added iron filings (0.78 g, 14.01 mmol, 3 equiv) in a foil-
coated flask and stirred at r.t. for 40 min. (Rp,Ss)-p-Tolylsulfi-
nyl[2.2]paracyclophane (1.61 g, 4.67 mmol, 1 equiv) in THF (94
mL) was added in one portion. The remaining bromine solution was
Synthesis 2010, No. 24, 4177–4187 © Thieme Stuttgart · New York

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Enantiomerically Pure [2.2]Paracyclophane Derivatives
4185
IR (neat): 3411, 2926, 2859, 2111, 1640, 1490, 1389, 1031, 804,
666 cm–1.
1H NMR (300 MHz): d = 7.05 (2 H, d, J = 8.1 Hz, H-Tol), 6.97 (2
H, d, J = 8.3 Hz, H-Tol), 6.87 (1 H, s, H5), 6.78 (1 H, s, H12), 6.70–
6.57 (4 H, m, H7, H8, H15, H16), 3.92–3.61 (2 H, m, H1, H2), 3.20–
2.96 (6 H, m, H1, H2, 2 × H9, 2 × H10), 2.33 (3 H, s, CH3).
13C NMR (75 MHz): d = 142.4, 141.1, 139.8, 138.7, 138.1, 136.0,
135.9, 135.2, 135.1, 134.8, 134.5, 133.7, 131.9, 129.5, 127.9, 126.3,
35.1, 34.7, 34.6, 32.9, 20.9.
1H NMR (500 MHz): d = 7.53 (2 H, d, J = 8.4 Hz, H-Tol), 7.32 (1
H, d, J = 1.8 Hz, H5), 7.13 (2 H, d, J = 8.0 Hz, H-Tol), 6.73 (1 H, br
s, H7), 6.56–6.43 (3 H, m, H8, H15, H16), 6.26 (1 H, br s, H12),
3.63–3.58 (2 H, m, H1, H2), 3.22–3.12 (2 H, m, H9, H10), 3.01–
2.85 (4 H, m, H1, H2, H9, H10), 2.34 (3 H, s, CH3-C13), 2.30 (3 H,
s, CH3-Tol).
MS (EI+): m/z = 376 [M]+, 193, 179, 156, 139, 119, 104, 91, 77.
HRMS-EI: m/z found 399.1422657 [M + Na]+; C24H24O2S [M +
Na]+ requires 399.1557580.
MS (EI+): m/z = 408 [M]+, 383, 328, 305, 290, 224, 210, 192.
HRMS-EI: m/z found 408.054001 [M]+; C23H21BrS [M]+ requires
(Rp)-Diphenyl(4-p-tolylsulfanyl[2.2]paracyclophan-13-yl)phos-
phine Oxide [(Rp)-22a]
408.054734.
n-BuLi (2.5 M in hexanes; 0.12 mL, 0.29 mmol, 2.4 equiv) was add-
ed dropwise to a solution of i-PrMgCl (0.07 mL, 0.14 mmol, 1.2
equiv) in THF (0.2 mL) at 0 °C and the resulting solution stirred at
0 °C for 10 min. A solution of (Sp)-19 (0.05 g, 0.12 mmol, 1.0 equiv)
in THF (1.2 mL) was added dropwise to the dibutylisopropylmag-
nesate solution, and the resulting pale yellow solution stirred for 1
h at 0 °C. Diphenylphosphinic chloride (0.07 mL, 0.37 mmol, 3.0
equiv) was added in one portion and the reaction warmed to r.t.
slowly over 72 h. The reaction mixture was poured into sat. aq
NH4Cl (10 mL) and the layers separated. The aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with sat. aq NaHCO3 (2 × 40 mL), dried (MgSO4), and
concentrated to yield (Rp)-22a as a white crystalline solid (0.06 g,
(Sp,Ss)-4-p-Tolylsulfinyl-13-methyl[2.2]paracyclophane
[(Sp,Ss)-20]
To a solution of i-PrMgCl (0.07 mL, 0.14 mmol, 1.2 equiv) in THF
(0.24 mL) at 0 °C was added n-BuLi (2.5 M in hexanes; 0.11 mL,
0.28 mmol, 2.3 equiv) and the resulting solution stirred at 0 °C for
10 min. A solution of (Rp,SS)-15 (0.05 g, 0.12 mmol, 1 equiv) in
THF (1.2 mL) was added dropwise to the dibutylisopropylmagne-
sate solution. The resulting bright yellow solution was stirred for 30
min at 0 °C. MeI (0.01 mL, 0.16 mmol, 1.3 equiv) was added to give
a pale yellow solution. After 1 h, more MeI (0.05 mL, 0.08 mmol,
0.7 equiv) was added to produce a colourless solution. The reaction
mixture was poured into sat. aq NH4Cl (10 mL) and the organic
phase was separated. The aqueous phase was extracted with CH2Cl2
(3 × 10 mL) and the combined organic layers were washed with
brine (50 mL), dried (MgSO4), and concentrated. The crude residue
was purified by column chromatography (gradient elution; petrol to
petrol–EtOAc, 2:1) to yield (Sp,Ss)-20 as a white solid (0.02 g,
48%); mp 162–163 °C; Rf = 0.2 (2:1 petrol–EtOAc); [a]D31 +12.6 (c
1, CHCl3).
24
88%); mp 222–223 °C; Rf = 0.14 (petrol); [a]D –1.5 (c 0.4,
CHCl3).
IR (neat): 3500, 2933, 1638, 1478, 1416, 1390, 1327, 1216, 1123,
1094, 1032, 977, 891, 868, 749, 708, 665 cm–1.
1H NMR (300 MHz): d = 7.73–7.57 (4 H, m, C6H5), 7.40–7.22 (6 H,
br s, C6H5), 6.79 (2 H, d, J = 7.3 Hz, H-Tol), 6.70 (2 H, d, J = 7.3
Hz, H-Tol), 6.61 (1 H, s, H12), 6.52 (1 H, s, H5), 6.40 (4 H, br s,
H7, H8, H15, H16), 3.96–3.35 (4 H, m, H1, H2, H9, H10), 2.96–
2.67 (4 H, m, H1, H2, H9, H10), 2.07 (3 H, s, CH3).
13C NMR (75 MHz): d = 142.9, 141.5, 140.3, 139.1, 138.5, 136.4,
136.3, 135.6, 135.7, 135.5, 135.3, 134.1, 132.5, 132.3, 132.1, 132.0,
129.9, 129.0, 128.9, 128.9, 128.4, 126.8, 35.5, 35.1, 35.0, 33.4,
21.3.
IR (neat): 3052, 2927, 2852, 2305, 1579, 1490, 1470, 1449, 1265,
1087, 1051, 1017, 947, 896, 871, 838, 810, 748, 704, 665 cm–1.
1H NMR (500 MHz): d = 7.26 (2 H, d, J = 8.3 Hz, H-Tol), 7.21 (1
H, d, J = 1.9 Hz, H5), 7.10 (2 H, d, J = 7.9 Hz, H-Tol), 6.60 (1 H,
dd, J = 7.7, 1.9 Hz, H7), 6.50 (1 H, d, J = 7.7 Hz, H15), 6.77 (1 H,
d, J = 1.9 Hz, H12), 6.44 (1 H, dd, J = 7.7, 0.7 Hz, H16), 6.29 (1 H,
d, J = 1.5 Hz, H8), 3.70 (1 H, ddd, J = 13.7, 10.0, 5.3 Hz, H2), 3.55
(1 H, ddd, J = 13.3, 10.2, 2.7 Hz, H1), 3.16–3.02 (5 H, m, H2,
2 × H9, 2 × H10), 2.93 (1 H, ddd, J = 13.4, 10.7, 5.3 Hz, H1), 2.36
(3 H, s, CH3), 2.26 (3 H, s, CH3-Tol).
MS: m/z not available as the compound did not ionise.
(Rp)-4-p-Tolylsulfanyl[2.2]paracyclophane [(Rp)-17], (Rp)-4-p-
Tolylsulfanyl-13-methyl[2.2]paracyclophane [(Rp)-22b] and
(Sp)-4-Iodo-13-p-tolylsulfanyl[2.2]paracyclophane [(Sp)-22c]
t-BuLi (1.5 M in pentane; 0.16 mL, 0.24 mmol, 2.0 equiv) was add-
13C NMR (75 MHz): d = 144.1, 143.4, 141.0, 140.9, 139.5, 138.1,
137.3, 136.4, 136.1, 135.5, 134.7, 134.0, 129.9, 129.8, 125.1, 124.7,
35.1, 34.7, 33.4, 30.8, 21.3, 19.8.
ed dropwise to
a solution of (Sp)-4-bromo-13-p-tolylsulfa-
nyl[2.2]paracyclophane (0.05 g, 0.12 mmol) in THF (2.4 mL) at
–78 °C to give a bright yellow solution. The reaction mixture was
stirred for 10 min at –78 °C before MeI (0.02 mL, 0.37 mmol, 3.0
equiv) was added in one portion. The reaction warmed to r.t. over
20 h. The reaction mixture was poured into sat. aq NH4Cl (10 mL)
and the organic layer separated. The aqueous phase was extracted
with CH2Cl2 (3 × 10 mL) and the combined organic layers were
washed with brine (10 mL), dried (MgSO4), and concentrated under
reduced pressure to yield a white residue. The crude mixture was
purified by column chromatography on silica gel (gradient elution
petrol to petrol–EtOAc 2:1) to yield (Rp)-4-p-tolylsulfa-
nyl[2.2]paracyclophane [(Rp)-17] as colourless crystals (0.02 g,
55%), (Rp)-4-p-tolylsulfanyl-13-methyl[2.2]paracyclophane [(Rp)-
22b] as a white solid (0.01 g, 34%), and (Sp)-4-iodo-13-p-tolylsul-
fanyl[2.2]paracyclophane [(Sp)-22c] as a white solid (0.01 g, 11%).
MS (EI+): m/z = 360 [M]+, 242, 224, 211, 178, 140, 119, 105, 92,
77.
(Rp)-4-p-Tolylsulfonyl-13-methyl[2.2]paracyclophane [(Rp)-21]
n-BuLi (2.5 M in hexanes; 0.05 mL, 0.12 mmol, 1.0 equiv) was add-
ed dropwise to (Sp)-18 (0.05 g, 0.12 mmol, 1.0 equiv) in THF (2.5
mL) at –78 °C to form a bright red solution. The reaction mixture
was stirred for 5 min at –78 °C, then MeI (0.04 mL, 0.61 mmol, 5.0
equiv) was added to give a colourless solution. The reaction mixture
was poured into sat. aq NH4Cl (5 mL), the organic phase separated,
and the aqueous layer extracted with CH2Cl2 (3 × 5 mL). The com-
bined organic layers were dried (MgSO4) and concentrated. The
crude residue was purified by column chromatography on silica gel
(gradient elution petrol to petrol–EtOAc, 2:1) to yield (Rp)-21 as a
yellow solid (0.02 g, 40%); mp 230–231 °C; Rf = 0.4 (2:1 petrol–
EtOAc); [a]D22 –2.4 (c 0.6, CHCl3).
(Rp)-17
Mp 167–168 °C; Rf = 0.1 (petrol); [a]D27 +48.3 (c 0.53, CHCl3).
IR (nujol): 3583, 2930, 2854, 1719, 1585, 1538, 1493, 1476, 1393,
1315, 1305, 1192, 1084, 1057, 1032, 1120, 960, 909, 877, 839, 816,
733, 708, 688, 664 cm–1.
IR (neat): 3429, 2925, 2854, 2115, 1638, 1491, 1456, 1215, 1087,
757, 666 cm–1.
Synthesis 2010, No. 24, 4177–4187 © Thieme Stuttgart · New York

4186
R. Parmar et al.
PAPER
1H NMR (300 MHz): d = 7.15 (2 H, d, J = 8.3 Hz, H-Tol), 7.12 (1
H, d, J = 2.0 Hz, H5), 7.07 (2 H, d, J = 8.3 Hz, H-Tol), 6.58–6.45 (4
H, m, H7, H8, H13, H15), 6.40 (1 H, dd, J = 7.7, 2.0 Hz, H16), 6.30
(1 H, d, J = 1.7 Hz, H12), 3.40 (1 H, ddd, J = 12.4, 10.2, 1.9 Hz, H2),
3.27 (1 H, ddd, J = 15.5, 12.1, 5.7 Hz, H1), 3.13–2.83 (5 H, m, H1,
2 × H9, 2 × H10), 2.76 (1 H, ddd, J = 13.0, 10.6, 5.5 Hz, H2), 2.32
(3 H, s, CH3).
13C NMR (75 MHz): d = 141.4, 141.1, 140.0, 139.6, 136.8, 136.7,
135.5, 133.7, 133.3, 132.8, 132.4, 132.3, 130.4, 130.2, 129.5, 128.6,
35.7, 35.3, 34.8, 34.2, 21.5.
IR (neat): 3490, 3155, 2926, 2856, 1784, 1700, 1621, 1463, 1413,
1387, 1244, 1212, 1155, 1033, 1081, 911, 895, 730 cm–1.
1H NMR (500 MHz): d = 7.12 (1 H, d, J = 1.8 Hz, H5), 6.98 (1 H,
dd, J = 8.0, 1.9 Hz, H13), 6.64 (1 H, dd, J = 7.7, 1.9 Hz, H16), 6.61
(1 H, dd, J = 7.8, 1.9 Hz, H15), 6.47 (1 H, dd, J = 7.8, 1.8 Hz, H7),
6.45 (1 H, dd, J = 3.0, 1.6 Hz, H19), 6.37 (1 H, dd, J = 8.0, 1.8 Hz,
H12), 6.33 (1 H, dd, J = 7.8, 0.9 Hz, H8), 5.86 (1 H, ddd, J = 4.7,
3.0, 1.5 Hz, H22), 3.99 (1 H, dddd, J = 6.5, 4.9, 3.2, 1.6 Hz, H17),
3.47–3.41 (2 H, m, H1, H2), 3.33 (1 H, dd, J = 13.5, 9.4 Hz, H1),
3.03–3.39 (4 H, m, 2 × H9, 2 × H10), 2.81–2.77 (1 H, m, H20), 1.83
(3 H, s, CH3-24), 1.24 (3 H, d, J = 7.3 Hz, CH3-23).
13C NMR (75 MHz): d = 141.0 (C), 139.4 (C), 138.7 (C), 138.3 (C),
137.6 (CH), 137.7 (CH), 137.0 (C), 134.5 (CH), 134.2 (CH), 134.2
(C), 134.1 (CH), 132.6 (CH), 132.1 (CH), 130.8 (CH), 121.9 (CH),
50.8 (CH), 44.4 (CH2), 35.5 (CH), 35.1 (CH2), 35.0 (CH), 34.7
(CH2), 21.2 (CH3), 19.3 (CH3).
MS (EI+): m/z = 330 [M]+, 315 [M – CH3]+, 226, 211, 134, 105, 91.
HRMS-EI: m/z found 353.1334425 [M + Na]+; C23H22S + Na [M +
Na]+ requires 353.1337260.
(Rp)-22b
Mp 172–173 °C; Rf = 0.7 (2:1 petrol–EtOAc).
MS (EI+): m/z = 359 [M]+, 343 [M – O]+, 329, 255, 238, 224, 207,
192, 178, 165, 150, 138, 124, 104, 91.
HRMS-EI: m/z found: 361.1643080 [M + H]+; C24H25SO [M + H]+
IR (neat): 3583, 3400, 3052, 2927, 2852, 2305, 1579, 1490, 1470,
1449, 1265, 1087, 1051, 1017, 947, 896, 871, 838, 810, 700, 704,
665 cm–1.
requires 361.1620625.
1H NMR (500 MHz): d = 6.98 (2 H, d, J = 8.0 Hz, H-Tol), 6.91 (2
H, d, J = 8.2 Hz, H-Tol), 6.71 (1 H, d, J = 1.8 Hz, H12), 6.58 (1 H,
d, J = 7.7 Hz, H15), 6.55 (1 H, d, J = 7.8 Hz, H16), 6.50 (1 H, d,
J = 1.7 Hz, H8), 6.46 (1 H, d, J = 1.8 Hz, H7), 6.27 (1 H, d, J = 1.7
Hz, H5), 3.70 (1 H, ddd, J = 9.1, 9.1, 10.6 Hz, H2), 3.50 (1 H, ddd,
J = 10.9, 8.1, 8.1 Hz, H1), 3.11–2.87 (6 H, m, H1, H2, 2 × H9,
2 × H10), 2.38 (3 H, s, CH3-C13), 2.26 (3H, s, CH3-Tol).
13C NMR (75 MHz): d = 142.4, 140.0, 139.0, 138.1, 138.0, 137.5,
135.4, 135.1, 134.0, 134.0, 133.9, 133.4, 132.4, 130.2, 129.5, 127.9,
34.9, 34.8, 32.9, 32.7, 20.9, 20.6.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are X-ray crystallographic data for all diastereoisomers of sulfoxide
9, bromides (Sp,SS)-15 and (Rp,SS)-15 and polycyclic 23, as well as
figures highlighting salient 1H NMR shifts for sulfoxide 9 and poly-
cyclic compounds 23–27 and full experimental for all compounds.
References
MS (EI+): m/z = 344 [M]+, 330, 256, 226, 211, 193, 178, 149, 141,
127, 119, 111, 95.
(1) Brown, C. J.; Farthing, A. C. Nature 1949, 164, 915.
(2) (a) Cram, D. J.; Cram, J. M. Acc. Chem. Res. 1971, 4, 204.
(b) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73,
5691.
(Sp)-4-Iodo-13-p-tolylsulfanyl[2.2]paracyclophane [(Sp)-22c]
Rf = 0.4 (2:1 petrol–EtOAc).
(3) (a) de Meijere, A.; Konig, B. Synlett 1997, 1221. (b) Bräse,
S. In Asymmetric Synthesis - The Essentials; Christmann,
M.; Bräse, S., Eds.; Wiley-VCH: Weinheim, 2007, 67.
(c) Modern Cyclophane Chemistry; Gleiter, R.; Hopf, H.,
Eds.; Wiley-VCH: Weinheim, 2004. (d) Cyclophane
Chemistry; Vögtle, F., Ed.; Wiley: Chichester, 1993.
(e) Classics in Hydrocarbon Chemistry; Hopf, H., Ed.;
Wiley-VCH: Weinheim, 2000. (f) Aly, A. A.; Brown, A. B.
Tetrahedron 2009, 65, 8055. (g) Vu, T. T.; Badre, S.;
Dumas-Verdes, C.; Vachon, J. J.; Julien, C.; Audebert, P.;
Senotrusova, E. Y.; Schmidt, E. Y.; Trofimov, B. A.; Pansu,
R. B.; Clavier, G.; Meallet-Renault, R. J. Phys. Chem. C
2009, 113, 11844. (h) Bazan, G. C. J. Org. Chem. 2007, 72,
8615. (i) Kattnig, D. R.; Mladenova, B.; Grampp, G.; Kaiser,
C.; Heckmann, A.; Lambert, C. J. Phys. Chem. C 2009, 113,
2983. (j) Morisaki, Y.; Murakami, T.; Sawamura, T.; Chujo,
Y. Macromolecules 2009, 42, 3656. (k) Schlotter, K.;
Boeckler, F.; Hubner, H.; Gmeiner, P. J. Med. Chem. 2006,
49, 3628. (l) Bondarenko, L.; Hentschel, S.; Greiving, H.;
Grunenberg, J.; Hopf, H.; Dix, I.; Jones, P. G.; Ernst, L.
Chem. Eur. J. 2007, 13, 3950. (m) Furo, T.; Mori, T.; Wada,
T.; Inoue, Y. J. Am. Chem. Soc. 2005, 127, 8242.
(4) Cram, D. J.; Allinger, N. L. J. Am. Chem. Soc. 1955, 77,
6289.
1H NMR (500 MHz): d = 7.00 (1 H, d, J = 1.8 Hz, H5), 6.97 (2 H,
d, J = 8.0 Hz, H-Tol), 6.91 (2 H, d, J = 8.3 Hz, H-Tol), 6.74 (1 H, d,
J = 1.9 Hz, H12), 6.61 (1 H, d, J = 7.9 Hz, H15), 6.58 (1 H, d, J =
1.3 Hz, H7), 6.55 (1 H, d, J = 1.8 Hz, H16), 6.52 (1 H, dd, J = 7.7,
0.6 Hz, H8), 3.80 (1 H, ddd, J = 13.5, 9.9, 3.8 Hz, H2), 3.61 (1 H,
ddd, J = 13.7, 9.9, 3.7 Hz, H1), 3.16–2.94 (6 H, m, H1, H2, 2 × H9,
2 × H10), 2.25 (3 H, s, CH3)
MS (EI+): m/z = 456 [M]+, 225, 211, 178, 113.
Limited data due to decomposition of the product.
<2>(1,4)-Benenzo-<1>(6,9)-2,3-dimethyl-9,9a-dihydro-3H-
thioxanthenophane-10-oxide (23)
n-BuLi (2.5 M in hexanes, 0.21 mL, 0.52 mmol, 2.2 equiv) was add-
ed dropwise to (i-Pr)2NH (0.68 mL, 0.52 mmol, 2.2 equiv) in THF
(1.7 mL) at 0 °C. The mixture was stirred for 40 min at 0 °C and 20
minutes at –78 °C. (Sp,Rs)-4-p-Toluenesulfinyl[2.2]paracyclophane
[(Sp,Rs)-9; 0.08 g, 0.23 mmol, 1.0 equiv] in THF (2.9 mL) was add-
ed via cannula to produce a deep red colouration. The reaction mix-
ture was stirred at –78 °C for 70 min, then MeI (0.02 mL, 0.23
mmol, 1.0 equiv) was added dropwise causing the reaction mixture
to clear. The reaction was stirred for 4 h, whilst the cold bath slowly
warmed, before sat. aq NH4Cl (5 mL) was added. The organic phase
was separated and the aqueous layer was extracted with CH2Cl2
(3 × 5 mL). The combined organics layers were washed with brine
(3 × 5 mL), dried (MgSO4) and concentrated. The residue was puri-
fied by column chromatography on silica gel (gradient elution
petrol to petrol–EtOAc, 2:1) to yield 23 as light brown crystals (0.03
g, 16%); mp 194–195 °C; Rf = 0.1 (2:1 petrol–EtOAc).
(5) Gibson, S. E.; Knight, J. D. Org. Biomol. Chem. 2003, 1,
1256.
(6) Rozenberg, V.; Sergeeva, E.; Hopf, H. In Modern
Cyclophane Chemistry; Gleiter, R.; Hopf, H., Eds.; Wiley-
VCH: Weinheim, 2004, 435.
(7) This argument was originally stated in reference 5. Chemists
that have worked with [2.2]paracyclophane might argue that
Synthesis 2010, No. 24, 4177–4187 © Thieme Stuttgart · New York

PAPER
the greatest impediment to advancing this field is the
Enantiomerically Pure [2.2]Paracyclophane Derivatives
4187
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223)336033; or
deposit@ccdc.cam.ac.uk.
mercurial nature of these molecules that can hinder even the
most simple-looking syntheses.
(8) (a) Arrayas, R. G.; Adrio, J.; Carretero, J. C. Angew. Chem.
Int. Ed. 2006, 45, 7674. (b) Hou, X. L.; You, S. L.; Tu, T.;
Deng, W. P.; Wu, X. W.; Li, M.; Yuan, K.; Zhang, T. Z.;
Dai, L. X. Top. Catal. 2005, 35, 87. (c) Atkinson, R. C. J.;
Gibson, V. C.; Long, N. J. Chem. Soc. Rev. 2004, 33, 313.
(d) Gibson, S. E.; Ibrahim, H. Chem. Commun. 2002, 2465.
(e) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry
1998, 9, 2377. (f) Ferber, B.; Kagan, H. B. Adv. Synth.
Catal. 2007, 349, 493.
(27) Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S. Tetrahedron
2001, 57, 3891.
(28) (a) Bhalla, R.; Boxwell, C. J.; Duckett, S. B.; Dyson, P. J.;
Humphrey, D. G.; Steed, J. W.; Suman, P. Organometallics
2002, 21, 924. (b) Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L.
Tetrahedron: Asymmetry 2007, 18, 1990. (c) Zhang, T.-Z.;
Dai, L.-X.; Hou, X.-L. Tetrahedron: Asymmetry 2007, 18,
251.
(9) Hitchcock, P. B.; Parmar, R.; Rowlands, G. J. Chem.
Commun. 2005, 4219.
(29) Cram, D. J.; Hefelfinger, D. G. J. Am. Chem. Soc. 1971, 93,
4754.
(30) Hitchcock, P. B.; Rowlands, G. J.; Seacome, R. J. Org.
Biomol. Chem. 2005, 3, 3873.
(10) Rowlands, G. J. Org. Biomol. Chem. 2008, 6, 1527.
(11) Zhang, T. Z.; Dai, L. X.; Hou, X. L. Tetrahedron:
Asymmetry 2007, 18, 251.
(12) Banfi, S.; Manfredi, A.; Montanari, F.; Pozzi, G.; Quici, S.
(31) Hopf, H. In Modern Cyclophane Chemistry; Gleiter, R.;
Hopf, H., Eds.; Wiley-VCH: Weinheim, 2004, 189.
(32) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3505.
(33) The crystal appears to contain the tribromo product co-
crystallised with the dibromo product in a 2:1 ratio. There
are two independent molecules with different conforma-
tions. In both the occupancy of the Br(3) atom is 0.67.
(34) Mancheno, O. G.; Priego, J.; Cabrera, S.; Arrayas, R. G.;
Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679.
(35) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2001, 66, 4333.
(36) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
Angew. Chem. Int. Ed. 2004, 43, 2206. (b) Quesnelle, C.;
Iihama, T.; Aubert, T.; Perrier, H.; Snieckus, V. Tetrahedron
Lett. 1992, 33, 2625. (c) Snieckus, V. Chem. Rev. 1990, 90,
879.
(37) (a) García Ruano, J. L.; Carreño, M. C.; Toledo, M. A.;
Aguirre, J. M.; Aranda, M. T.; Fischer, J. Angew. Chem. Int.
Ed. 2000, 39, 2736. (b) García Ruano, J. L.; Aleman, J.;
Parra, A. J. Am. Chem. Soc. 2005, 127, 13048.
(c) García Ruano, J. L.; Aranda, M. T.; Aguirre, J. M.
Tetrahedron 2004, 60, 5383. (d) García Ruano, J. L.;
Aleman, J.; Soriano, J. F. Org. Lett. 2003, 5, 677.
(38) Pelter, A.; Mootoo, B.; Maxwell, A.; Reid, A. Tetrahedron
Lett. 2001, 42, 8391.
J. Mol. Catal. A: Chem. 1996, 113, 77.
(13) Pamperin, D.; Hopf, H.; Syldatk, C.; Pietzsch, M.
Tetrahedron: Asymmetry 1997, 8, 319.
(14) Rozenberg, V.; Dubrovina, N.; Sergeeva, E.; Antonov, D.;
Belokon, Y. Tetrahedron: Asymmetry 1998, 9, 653.
(15) Rozenberg, V.; Danilova, T.; Sergeeva, E.; Vorontsov, E.;
Starikova, Z.; Korlyukov, A.; Hopf, H. Eur. J. Org. Chem.
2002, 468.
(16) (a) Cipiciani, A.; Bellezza, F.; Fringuelli, F.; Silvestrini, M.
G. Tetrahedron: Asymmetry 2001, 12, 2277. (b) Pamperin,
D.; Ohse, B.; Hopf, H.; Pietzsch, M. J. Mol. Catal. B:
Enzym. 1998, 5, 317.
(17) Cipiciani, A.; Fringuelli, F.; Mancini, V.; Piermatti, O.;
Pizzo, F.; Ruzziconi, R. J. Org. Chem. 1997, 62, 3744.
(18) Tanji, S.; Ohno, A.; Sato, I.; Soai, K. Org. Lett. 2001, 3, 287.
(19) Minuti, L.; Taticchi, A.; Marrocchi, A. Tetrahedron:
Asymmetry 2000, 11, 4221.
(20) Kreis, M.; Friedmann, C. J.; Bräse, S. Chem. Eur. J. 2005,
11, 7387.
(21) Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. J. Org.
Chem. 1997, 62, 6462.
(22) Reich, H. J.; Yelm, K. E. J. Org. Chem. 1991, 56, 5672.
(23) (a) Bolm, C.; Whelligan, D. K. Adv. Synth. Catal. 2006, 348,
2093. (b) Whelligan, D. K.; Bolm, C. J. Org. Chem. 2006,
71, 4609. (c) Wu, X. W.; Zhang, T. Z.; Yuan, K.; Hou, X. L.
Tetrahedron: Asymmetry 2004, 15, 2357. (d) Bolm, C.;
Focken, T.; Raabe, G. Tetrahedron: Asymmetry 2003, 14,
1733. (e) Wu, X. W.; Yuan, K.; Sun, W.; Zhang, M. J.; Hou,
X. L. Tetrahedron: Asymmetry 2003, 14, 107. (f) Wu, X.
W.; Hou, X. L.; Dai, L. X.; Tao, J.; Cao, B. X.; Sun, J.
Tetrahedron: Asymmetry 2001, 12, 529.
(39) Bolm, C.; Wenz, K.; Raabe, G. J. Organomet. Chem. 2002,
662, 23.
(40) Focken, T.; Hopf, H.; Snieckus, V.; Dix, I.; Jones, P. G. Eur.
J. Org. Chem. 2001, 2221.
(41) Brink, M. Synthesis 1975, 807.
(42) (a) Cram, D. J.; Allinger, N. L. J. Am. Chem. Soc. 1955, 77,
6289. (b) Duan, W.; Ma, Y.; Xia, H.; Liu, X.; Ma, Q.; Sun,
J. J. Org. Chem. 2008, 73, 4330.
(24) Hou, X. L.; Wu, X. W.; Dai, L. X.; Cao, B. X.; Sun, J. Chem.
Commun. 2000, 1195.
(43) Nugent, M. J.; Weigang, O. E. J. Am. Chem. Soc. 1969, 91,
(25) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3534.
(26) (a) Supporting Information contains X-ray crytallographic
data, full experimental, and figures showing select NMR
data. (b) CCDC-276960–276961 and CCDC-772176–
772181 contain the supplementary crystallographic data for
4556.
(44) Hoffman, P. H.; Ong, E. C.; Weigang, O. E.; Nugent, M. J.
J. Am. Chem. Soc. 2002, 96, 2620.
Synthesis 2010, No. 24, 4177–4187 © Thieme Stuttgart · New York