The synthesis of homochiral ligands based on [2.2]paracyclophane

Article abstract of DOI:10.1016/S0040-4039(01)01808-1

A new ortho-lithiation of homochiral 4-N,N-diethylamido[2.2]paracyclophane 8 is the key to the production of a wide variety of 4,5-disubstituted homochiral ligands. ψ-Geminal bromination of 8 proceeds in high yields and the resulting bromide may be conver

Full text of DOI:10.1016/S0040-4039(01)01808-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8391–8394
The synthesis of homochiral ligands based on
[2.2]paracyclophane
Andrew Pelter,a,* Baldwin Mootoo,b Anderson Maxwellb and Alicia Reida,b
aDepartment of Chemistry, University of Wales Swansea, Singleton Park, Swansea, SA2 8PP, UK
bDepartment of Chemistry, University of the West Indies, St. Augustine, Trinidad and Tobago, West Indies
Received 18 July 2001; revised 11 September 2001; accepted 21 September 2001
Abstract—A new ortho-lithiation of homochiral 4-N,N-diethylamido[2.2]paracyclophane 8 is the key to the production of a wide
variety of 4,5-disubstituted homochiral ligands. c-Geminal bromination of 8 proceeds in high yields and the resulting bromide
may be converted into a variety of 4,13-disubstituted ligands. The o-lithiation and c-geminal reactions can be used sequentially
to give 4,5,12-trisubstituted compounds in which two liganding groups have the same geometrical relationship as in
‘Phanephos’™. Homochiral oxazolines with only planar chirality have been made, one of which has been shown to be an effective
catalyst for the Heck reaction. © 2001 Elsevier Science Ltd. All rights reserved.
Chiral synthesis is at the cutting edge of organic
synthesis1–3 due to the intellectual challenges posed and
its potential importance, particularly in the pharmaceu-
tical industry.4 Due to the amplification of chirality,
recent work has concentrated on catalytic reactions
involving catalysts that may be homochiral or rendered
so by ligation with homochiral ligands. Such ligands
require a reasonably rigid framework and should be
recoverable. Examples are 2,2-binaphthyls,3 ferrocenes,5
arene metal complexes6 and metal carbonyl
compounds7 of planar chirality.
groups on the [2.2]paracyclophane frame have rigidly
defined geometrical relationships and it was surprising
that the system had not received systematic investiga-
tion from the viewpoint of chiral synthesis.9,10 We
therefore incorporated the [2.2]paracyclophane (22PC)
unit into unique amino acids of planar chirality11–13 and
showed that 4-alkylamino[2.2]paracyclophanes are
effective chiral auxiliaries.14 We further showed13 that
both secondary amide and oxazolinyl groups are c-
geminal directing to give 4,13-disubstituted 22PC
derivatives and produced racemic 1 and 2 as part of the
first group of oxazolinyl[2.2]paracyclophanes (Fig. 1).
We pointed out the potential of such compounds as
chiral catalysts and indeed compound 1 has proved to
be a potent catalyst for the Heck reaction.15
Some years ago we realised that substituted
[2.2]paracyclophanes are readily available systems8 that
are chemically and chirally stable. The substituent
H
Y
2
N
O
3
PPh2
4
1
14
8
7
O
4
N
4
X
X
13
5
15
16
6
9
13
12
12
PPh2
11
10
1 X = PPh2 2 X = SPh
6 X = H 7 X = Br
4 X =H, Y = SPh
3
5 X = Ph2C(OH), Y = H
Figure 1.
Keywords: homochiral ligands; [2.2]paracyclophane; ortho-lithiation; c-geminal substitution.
* Corresponding author. Tel.: +44 (0)1792 295258; fax: +44 (0)1792 295747; e-mail: a.pelter@swansea.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01808-1

8392
A. Pelter et al. / Tetrahedron Letters 42 (2001) 8391–8394
ortho-lithiation, though occurring, was not a clean reac-
In the recent expansion of chiral [2.2]paracyclophane
investigations16 particularly apposite, from our view-
point, was the beautiful work of Pye and Rossen17 who
introduced homochiral (S)-[2.2] Phanephos™ 3 and its
enantiomer as potent ligands for a variety of transition
metal-catalysed reactions. Very recently Hou18 intro-
duced the bridge substituted oxazoline 4 for palladium-
catalysed allylic alkylations. The synthesis of 4 was
inefficient, bridge substitution occurring in only 12%
yield. The same group19 synthesised 5 and homologues
as catalysts for the chiral addition of ZnEt2 to aromatic
aldehydes. In both cases the origin of chiral induction is
not clear as more than one type of chirality is present.
tion. These results parallel those of Hou.18
We tested a variety of groups such as CH2OH,
CH2NEt2 as ortho-directors (Scheme 1) but with no
success, and we therefore turned to 4-N,N-diethyl-
amido[2.2]paracyclophane 8. Compound 8 was readily
obtained in 92% yield from 4-carboxy[2.2]para-
cyclophane. One crystallisation of 8 of 97.4% e.e. gave
an amide of >99.9% e.e. (chiral column), a very useful
feature as compared with the acid. The recrystallised
amide derived from the (−)-(R)-acid had mp 118–
119°C, [h]2D0 −97.
Iron-catalysed bromination of 8 gave the desired c-
geminal 4-bromo-13-(N,N-diethylamido)[2.2]paracyclo-
phane 9, mp 94–96°C, [h]D20 −2.1, e.e. 98% (derived from
acid of 98% e.e.) in 96% yield. Hence, we have estab-
lished that the CONEt2 group is c-geminal directing
with regard to electrophilic substitution. Low tempera-
ture (78°C) lithiation of 9 and reaction with an appro-
priate reagent gave the 4,13-disubstituted compounds
10–13 (Fig. 2, Table 1).
We now report that we have produced a novel ortho-
lithiation reaction and combined it with c-geminal
substitution to provide a flexible route to a wide variety
of homochiral [2.2]paracyclophanes of potential use as
ligands and as catalysts directly. The route is illustrated
in Scheme 1. It depends critically on finding a sub-
stituent functional group that can have a dual role as
an ortho-directing group for lithiation and is also capa-
ble of directing electrophilic substitution into the c-
geminal (C-13) position. This would then give rise to
the possibility of producing compounds belonging to
classes A, B and C, the latter containing the 4,12
substitution pattern of Phanephos™ (Scheme 1).
Snieckus21 found that lithiation of 2-methyl-N,N-
diethylamidobenzene resulted in double benzylic lithia-
tion, although in the absence of the 2-methyl group
efficient ortho-lithiation occurred. As we necessarily
have a methylene group in an ortho-position to the
amide group then bridge substitution seemed likely.
However, we were happy to find that the use of t-BuLi/
Et2O/TMEDA led to ortho-lithiation of 8 in very high
yield. Following this important discovery, we were able
to make a novel series of ortho-disubstituted[2.2]para-
cyclophanes 14–19 in good yields of which 14–17 were
derived from (−)-(R)-amide (Fig. 2, Table 1).
We had already converted 6 into 7 and thence to 1 and
2 and therefore were sure that the oxazolinyl group was
c-geminal directing. There are many examples20 show-
ing that oxazolinyl groups can direct lithiation to the
ortho-position. However, extensive studies of the lithia-
tion of 6 led only to mixtures, in which substitution at
the bridge position (C-3) was evidenced in low yield but
FG
Y
FG
FG
Y
FG
X
X
A
B
C
Scheme 1.
X
X
CONEt2
CONEt2
CONEt2
X
X
20 X = Br
21 X = OH
22 X = CO2Me
23 X = SPh
8
9
X = H
14 X = Br
X = Br
15 X = OH
10 X = OH
16 X = CO2Me
17 X = SPh
11 X = CO2Me
12 X = SPh
18 X = SnBu3
19 X = SiMe3
13 X = PPh2
Figure 2.

A. Pelter et al. / Tetrahedron Letters 42 (2001) 8391–8394
8393
Table 1. Physical characteristics of paracyclophanes 10–23 (Fig. 2) and 1, 2, 6, 7 (Fig. 1)
Entry
Compound
Reagent
X−
Mp (°C)
Yield (%)a
[h]2D0
e.e. (%)
1
2
3
4
5
6
7
8
10b
11
B(OMe)3/H2O2
ClCO2Me
PhSO2SPh
ClPPh2
OH
CO2Me
SPh
PPh2
Br
OH
CO2Me
SPh
SnBu3
SiMe3
Br
OH
CO2Me
SPh
152–155
103–104
139–141
190–191
94–96
67–69
110–111
92–95
57 (77c)
85
83
−150.6
+3.50
ꢀ0.00
–
−38.5
−17.9
+13.8
−51.5
–
\99.9d
98e
12b
13
\99.9d
52
99
14b,h
15
16
Br2
98e
98e
98e
98d
B(OMe)3/H2O2
ClCO2Me
PhSO2SPh
ClSnBu3
ClSiMe3
Br2
B(OMe)3/H2O2
ClCO2Me
PhSO2SPh
CCl4/PPh3
Br2
82 (94c)
87 (96c)
92
17
9
18f
19b,f
20i
21b
22b
23j
6
Oil
94
10
11
12
13
14
15
16
17
18
147–149
153–155
115–116
139–142
193–194
82–84
136–142
174–175
111–112
91 (96c)
84 (98c)
80
–
−28.8
−121.1
+30
+8.2
+105.4
−30.6
−22.9
−12.7
\99.9d
\99.9d
\99.9d
\99.9d
94g
72
76
97
H
Br
SPh
PPh2
7
2
1
82 (85c)
58
94g
PhSO2SPh
ClPPh2
94g
54
94g
a Isolated yield of pure product.
b X-Ray structure obtained.
c Yield taking recovered starting material into account.
d From (−)-(R)-amide of >99.9% e.e.
e From (−)-(R)-amide of 98% e.e.
f From racemic amide.
g From (+)-(S)-acid of 94% e.e.
h 8 (2.22 mmol), t-BuLi (5.33 mmol), TMEDA (5.3 mmol), Et2O (80 ml), −78°C then Br2 (1.2 mmol).
i 14 (1.71 mmol), Br2 (1.84 mmol), Fe (0.1 mmol), CH2Cl2 (35 ml), 40°C.
j 20 (0.43 mmol), t-BuLi (1.08 mmol), TMEDA (1.04 mmol), Et2O (35 ml), −78°C then PhSO2SPh (2.16 mmol).
A key process in our approach (Scheme 1) to com-
pounds of type C was the bromination of 14 to give 20.
In fact, as envisaged, this iron catalysed bromination
proceeded in very good yield (Table 1, entry 11). Fur-
thermore, double lithiation of 20 was successful and
enabled us to produce essentially homochiral com-
pounds 21–23 in good isolated yields (Table 1, entries
12–14, Figs. 3 and 4). In these compounds the two
substituents (X) have the same relationship as in
Phanephos™ and our approach thus constitutes a
flexible route to a wide variety of such compounds.
Additionally to the above results, we here report that
we have produced optically active 1 and 2 starting with
(+)-(S)-4-carboxy[2.2]paracyclophane of 94% e.e. using
methodology we have previously described.13 We have
already shown that one of these, 1, is an efficient
catalyst for the Heck reaction and for the addition of
ZnEt2 to benzaldehyde. We are now embarking on a
systematic study of the catalytic properties of the com-
pounds described above plus certain derivatives. Not all
Figure 4. X-Ray structure of 22.
Figure 3. X-Ray structure of 21.

8394
A. Pelter et al. / Tetrahedron Letters 42 (2001) 8391–8394
are designed as transition metal ligands. Compounds
derived from 10, 11, 17, 21 and 22 will be tested for
cooperative catalysis in biomimetic reactions.
12. Pelter, A.; Crump, R. A. N. C.; Kidwell, H. Tetra-
hedron: Asymmetry 1997, 8, 3873.
13. Marchand, A.; Maxwell, A.; Mootoo, B.; Pelter, A.;
Reid, A. Tetrahedron 2000, 56, 7331.
The ortho-lithiation procedure described will have con-
sequences far beyond those outlined above and will be
of importance to all workers in the field of
[2.2]paracyclophanes.
14. Pelter, A.; Crump, R. A. N. C.; Kidwell, H. Tetra-
hedron: Asymmetry 1997, 8, 3173.
15. Pelter, A.; Beletskaya, I., unpublished experiments.
16. (a) Antonov, D. Y.; Belokon, Y. N.; Ikonnikov, N. S.;
Orlova, S. A.; Pisarevsky, A. P.; Raevski, N. I.; Rozen-
berg, V. I.; Sergeeva, E. V.; Struchkov, Y. T.; Tararov,
V. I.; Vorontsov, E. V. J. Chem. Soc., Perkin Trans. 1
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Vorontsov, E. V.; Danilova, T. I.; Starikova, Z. A.;
Yanovsky, A. I.; Belokon, Y. N.; Hopf, H. Tetrahedron:
Asymmetry 1996, 7, 3445; (c) Belokon, Y.; Moscalenko,
M.; Ikonnikov, N.; Yashkina, L.; Antonov, D.;
Vorontsov, E.; Rozenberg, V. Tetrahedron: Asymmetry
1997, 8, 3245; (d) Vetter, A. H.; Berkessel, A. Tetra-
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Dubrovina, N. V.; Vorontsov, E. V.; Sergeeva, E. V.;
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(f) Wo¨rsdo¨rfer, U.; Vo¨gtle, F.; Nieger, M.; Waletzke,
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Acknowledgements
We thank the Leverhulme Trust, the British Council,
the University of Wales, Swansea and UWI, St.
Augustine for financial support of this work.
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