A novel entry into a new class of cyclophane derivatives: Synthesis of (±)-[2.2]paracyclophane-4-thiol

Article abstract of DOI:10.1016/S0040-4039(00)01992-4

Two syntheses of (±)-[2.2]paracyclophane-4-thiol have been accomplished in two and five steps, with overall yields of 46 and 31%, respectively, from [2.2]paracyclophane. The strategy involves two key reactions: (a) a lithium aluminium hydride reduction of the disulphide of [2.2]paracyclophane and (b) the use of a Newman-Kwart reaction for the conversion of [2.2]paracyclophane-4-ol to [2.2]paracyclophane-4-thiol.

Full text of DOI:10.1016/S0040-4039(00)01992-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 373–376
A novel entry into a new class of cyclophane derivatives:
synthesis of ( )-[2.2]paracyclophane-4-thiol†
Vinayak V. Kane,‡* Anton Gerdes, Walter Grahn,* Ludger Ernst, Ina Dix, Peter G. Jones and
Henning Hopf*
Institut fu¨r Organische Chemie, TU Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany
Received 26 October 2000; accepted 3 November 2000
Abstract—Two syntheses of ( )-[2.2]paracyclophane-4-thiol have been accomplished in two and five steps, with overall yields of
46 and 31%, respectively, from [2.2]paracyclophane. The strategy involves two key reactions: (a) a lithium aluminium hydride
reduction of the disulphide of [2.2]paracyclophane and (b) the use of a Newman–Kwart reaction for the conversion of
[2.2]paracyclophane-4-ol to [2.2]paracyclophane-4-thiol. © 2001 Elsevier Science Ltd. All rights reserved.
The first rational synthesis of [2.2]paracyclophane
(PCP) was described a half century ago by Cram and
Steinberg.1 One of us (H.H.) has been involved in
[2.2]paracyclophane chemistry for the past thirty years
and has utilised [2.2]paracyclophane for probing theo-
ries of bonding, ring strain and p electron interactions.2
Two important developments during the past ten years
are (a) the synthesis of fluoro derivatives of
[2.2]paracyclophane3 and their possible use in polymer
industry, and (b) the use of monosubstituted
[2.2]paracyclophanes as planar chiral templates or aux-
iliaries.4 The latter development has rejuvenated the
interest in the synthesis of [2.2]paracyclophane deriva-
tives. This has resulted in numerous methods for their
enantioselective synthesis. These cyclophane enan-
tiomers are stable towards light, oxidation, base, acid
and thermal stress up to 180°C, and are finding wide-
spread applications as ligands in asymmetric catalysis,
particularly as hydroxy and P–P based ligands with
phosphorus attached to the [2.2]paracyclophane.5 How-
ever, ligands are also known with sulphur attached to
each benzene ring of PCP.6 The related enantiomeri-
Scheme 1. Synthesis of thiol 6 using the Newman–Kwart reaction.
Keywords: [2.2]paracyclophane; Newman–Kwart reaction.
* Corresponding authors. E-mail: h.hopf@tu-bs.de
†
This paper is dedicated to Professors Fritz Bickelhaupt and Willem H. De Wolf.
Present address after 1st November 2000: Ludwig-Maximilians-Universita¨t, Institut fu¨r Organische Chemie, Butenandtstr. 5-13, Haus F,
D-81377 Munich, Germany.
‡
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01992-4

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V. V. Kane et al. / Tetrahedron Letters 42 (2001) 373–376
Scheme 2. Alternate synthesis of [2.2]paracyclophane-4-thiol.
1
Scheme 3. Important H and 13C NMR chemical shifts of 6 compared to 1 and 3–5.
cally pure monothio-[2.2]paracyclophane has not yet
been reported. We reasoned that such a thio derivative
could be converted to a thioacetal in order to study an
asymmetric reaction of its anion with a,b-unsaturated
ketones, a reaction that needs to be explored since it
will open new synthetic pathways to natural products.
In the first phase of our program we developed the
highly expeditious synthesis of this so far elusive ( )-
[2.2]paracyclophane-4-thiol by two routes.
attempts to improve the yield failed. Reduction of 5
with lithium aluminium hydride in THF at 65°C gave
( )-[2.2]paracyclophane-4-thiol (6) (90%), mp 140–
141°C.
The second and shorter synthesis (Scheme 2) consists of
the treatment of the organolithium salt intermediate
with sublimed sulphur (S8). The crude product thus
obtained was not characterised but reduced with
lithium aluminium hydride in ether to give
[2.2]paracyclophane-4-thiol 6 (46%), identical in all re-
spects to the compound prepared earlier in Scheme 1
(mixed mp, NMR, IR).
The overall synthetic plan is depicted in Scheme 1. A
key requirement in the synthesis is the conversion of
O-aryl dimethylthiocarbamate 4 to S-aryl dimethyl-
thiocarbamate 5 by the use of the Newman–Kwart
reaction. Bromination of [2.2]paracyclophane 1 using
essentially the method of Cram and Day7 gave 91% of
a mixture containing mainly monobromide 2 (86% by
13C NMR), mp 203–204°C. This monobromide was
lithiated in ether with 2.2 equiv. of n-BuLi and the
resultant organolithium intermediate was treated with
trimethyl borate. Subsequent hydrolysis of the borate
ester with hydrogen peroxide and sodium hydroxide
gave phenol 3, mp 224–225°C (82%).8 Treatment of 3
with sodium hydride in DMF generated the sodium salt
and subsequent addition of dimethylthiocarbamoyl
chloride gave the desired O-aryl dimethylthiocarbamate
4 in 78% yield, mp 214–215°C.9 Difficulties were en-
countered in the conversion of the O-aryl dimethylthio-
carbamate using literature procedures.10 The best
reaction conditions found consisted of heating 4 exactly
at 208°C under N2 in diphenyl ether for 50 hours,
which gave a mixture from which the desired 5 could be
obtained in 55% yield after chromatography on silica
gel. This was not unexpected since large alkyl groups at
an ortho position slow the reaction and in general cause
a lower yield.11 Also, [2.2]paracyclophane is unstable
above 200°C over a long period of time.12 This is
clearly shown by the isolation of a mixture of two ring
opening products 7 and 8 in the ratio of 1:2. Several
1
We could fully assign the 13C and H NMR spectra of
6 including the bridge proton multiplets. Important
chemical shifts of 6 are given in Scheme 3 and are
compared with those of its precursors 1 and 3–5. Fig.
1 shows the experimental and simulated 1H NMR
spectra at 400 MHz of the aromatic protons of 6.
Fig. 2 shows the molecular structure of intermediate 4
as obtained from an X-ray diffraction measurement.13
Conclusion. This communication describes the synthesis
and properties of ( )-[2.2]paracyclophane-4-thiol. The
resolution using chiral reagents has not yet been suc-
cessful. However, previously we, Cipicani and his col-
leagues have obtained enantiomerically pure phenol
3.14,15 Its conversion to the thiol using the Newman–
Kwart reaction is in progress and will be reported at a
later date.
Acknowledgements
We thank Mrs. Petra Holba-Schulz for recording the
NMR spectra.

V. V. Kane et al. / Tetrahedron Letters 42 (2001) 373–376
375
1
Figure 1. Aromatic region of the 400 MHz H NMR spectrum of 6 in CDCl3; experimental (bottom), simulated (top).
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