Facile synthesis of planar chiral N-oxides and their use in Lewis base catalysis

Article abstract of DOI:10.1039/c0cc02216k

A rapid and versatile method for the preparation of planar chiral [2.2]paracyclophane-derived pyridines and pyridine N-oxides is reported. The potential utility of these compounds in Lewis base catalysis is briefly introduced.

Full text of DOI:10.1039/c0cc02216k

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Facile synthesis of planar chiral N-oxides and their use in Lewis base
catalysiswzy
J. Robin Fulton, Jean E. Glover, Lamin Kamara and Gareth J. Rowlands*
a
b
a
ab
Received 29th June 2010, Accepted 2nd September 2010
DOI: 10.1039/c0cc02216k
A rapid and versatile method for the preparation of planar chiral
2.2]paracyclophane-derived pyridines and pyridine N-oxides is
The simplest route to 2-([2.2]paracyclophan-4-yl)pyridines 1
involves the cross coupling of suitably functionalised
[2.2]paracyclophane derivative 2 or 4 with its complementary
2-pyridinyl unit 3 or 5 (Scheme 1); frustratingly, such
chemistry is problematic. Whilst 2-halopyridines 3 readily
[
reported. The potential utility of these compounds in Lewis base
catalysis is briefly introduced.
Chiral heteroaromatics are a valuable motif in enantioselective
participate in the cross coupling reactions, the corresponding
13
4-[2.2]paracyclophanyl boronic acids 2 are unstable.
1
–4
catalysis and related disciplines. Planar chiral heterocycles
are uncommon, with the majority based on ferrocene or
related complexes. Chiral cyclophane-based heteroaromatics
Reversing the functionality fails to overcome this problem;
4-halo[2.2]paracyclophanes 4 are suitable precursors but
2-pyridyl boronic acids 5 are inherently unstable and rarely
employed in cross-coupling reactions. The direct arylation
chemistry of Fagnou et al. appeared to offer an effective
solution to these limitations, permitting the coupling of
4
–8
is a field ripe for exploration.
We are interested in the
9
synthesis of planar chiral [2.2]paracyclophane derivatives
and in this communication, we disclose a rapid route to planar
chiral pyridine N-oxides and reveal their potential as Lewis
base catalysts.
1
4–16
4-halo[2.2]paracyclophanes 4 and pyridine N-oxides 6.
A multitude of [2.2]paracyclophane-derived heterocycles
have been reported, but have found little utility as the
To evaluate the utility of this methodology in [2.2]para-
cyclophane chemistry, racemic 4-bromo[2.2]paracyclophane 4
and pyridine N-oxide 6a were treated with tri-tert-butyl-
phosphonium tetrafluoroborate, palladium(II) acetate and
potassium carbonate at reflux in toluene (Scheme 2; Table 1;
Entry 1).y The desired 10a was isolated in 66% yield with the
remainder of the material comprising of [2.2]paracyclophane,
the product of proto-debromination. A perfunctory attempt
was made to optimise the reaction but the only improvement
was obtained by increasing the catalyst loading. Use of the
more reactive 4-iodo[2.2]paracyclophane with the addition of
5
syntheses are either convoluted or of limited generality. To
overcome this limitation, we sought a versatile route to rapidly
prepare 2-([2.2]paracyclophan-4-yl)pyridines 1 (Scheme 1).
Pyridines and pyridine N-oxides have an excellent pedigree as
ligands for catalysis, photoelectronic dyes and metal–organic
1
,2,10,11
frameworks as well as being common organocatalyst.
-([2.2]Paracyclophan-4-yl)pyridines and related compounds
are known; Hopf has reported a simple route to a pyridinyl-
2.2]paracyclophane by a nitrone cycloaddition, but the
2
[
1
2
generality of this reaction has not been assessed, whilst
8
2 3
Ag CO led to a slight improvement (Entry 4) but this did not
6
Pfaltz et al. and Andrus et al. have accessed derivatives of
2](1,4)benzeno[2](2,5)pyridinophane in generally low yields.
offset the additional steps required to form the iodide from the
bromide. Reducing the amount of pyridine N-oxide to less
than 3 eq. results in a dramatic decrease in yield. The reaction
appears general, with both the electron rich 4-methoxypyridine
N-oxide 6b and the electron deficient 4-nitropyridine N-oxide
[
6
c undergoing coupling in respectable yields (Entries 5 and 6).
The initial attempt to form a bis(pyridine N-oxide) utilised
pseudo-para 4,16-dibromo[2.2]paracyclophane 7, thus minimising
any inter-deck interactions. As expected a mixture of the
desired bis(pyridine N-oxide) 11 and debromo mono(pyridine
N-oxide) 10a was formed (Entry 7). More rewarding was the
successful coupling of the pseudo-ortho 4,12-dibromo[2.2]-
paracyclophane derivative 12. Under our standard reaction
conditions, all three pyridine N-oxides, 6a, 6b and 6c, reacted
to give mixtures of mono- and bis(pyridine N-oxides) (Entries
Scheme
1 Possible syntheses of 2-([2.2]paracyclophane-4-yl)-
pyridines.
a
Department of Chemistry, University of Sussex, Falmer,
BN1 9QJ, UK
8
, 9 and 10). Generally, the combined yields are excellent.
b
Institute of Fundamental Sciences – Chemistry, Massey University,
Private Bag 11 222, Palmerston North, New Zealand.
E-mail: g.j.rowlands@massey.ac.nz; Fax: +64 6 350 5682;
Tel: +64 6 356 9099 extn 3566
w Dedicated to the memory of Keith Fagnou.
Cz hT ehmi sCa or mt i cml e. is part of the ‘Emerging Investigators’ themed issue for
It is unclear if the variation in ratio of mono- to bis(pyridine
N-oxide) is due to steric hindrance or an electronic effect
affecting the rate of proto-debromination. Interestingly, only
1
6
in the reaction of more reactive nitro derivative was the
bromo pyridine N-oxide observed (Entry 10). The optimum
yield of the bis(pyridine N-oxide) 11/12 was obtained by
doubling the number of equivalents of all reagents. Currently,
the major limitation to this methodology is associated with
y Electronic supplementary information (ESI) available: Full
1
experimental for all new compounds along with copies of the
and C NMR spectra. See DOI: 10.1039/c0cc02216k
H
13
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 433–435 433

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Scheme 2 Synthesis of mono- and bis(pyridine N-oxides). See Table 1 for yields.
Table 1 Synthesis of [2.2]paracyclophane-based pyridine N-oxides
Entry
1
Halide
R
Product(s) (yield %)
4
4
4
9
4
4
7
H
H
H
H
OMe
NO
H
H
OMe
NO
66 (10a)
41 (10a)
74 (10a)
65 (10a)
62 (10b)
59 (10c)
38 (10a)
a
2
3
4
b
c
5
6
7
8
9
2
38 (11)
(R)-8
(R)-8
(ꢁ)-8
29 ((R)-10a)
53 ((R)-10b)
32 ((ꢁ)-10c), 15 ((ꢁ)-10d)
54 ((R)-12a)
32 ((R)-12b)
25 ((ꢁ)-12c)
10
2
a
b
Reaction employed Cy
a, 0.1 eq. Pd(OAc) , 0.3 eq. t-Bu
.0 eq. 6a, 0.05 eq. Pd(OAc) , 0.15 eq. t-Bu
.0 eq. K CO
3
PꢂHBF
4
as ligand. Reaction employed 8 eq.
6
c
2
3
PꢂHBF
4
and 8.0 eq. K
, 0.5 eq. Ag
2
CO
CO
3
.
,
3
2
3
PꢂHBF
4
2
3
2
2
3
.
purification; all the products and by-products display limited
solubility precluding simple chromatography or recrystallisation
techniques. Purification withstanding, this chemistry is extremely
practicable; it requires no special precautions, such as inert
atmosphere, and permits the coupling of aryl bromides
and pyridine N-oxides simply by heating in the presence of
palladium(II) acetate and an air-stable phosphine salt.
Scheme 3 Reagents and conditions: (i) Cl
CH Cl
, reflux (13, 88%); (ii) TMSCN (2 ꢃ 3 eq.), diethylcarbamoyl
chloride (2 ꢃ 3 eq.), CH Cl , rt (14, 51%); (iii) mCPBA (1.1 eq.),
3 3
SiH (15 eq.), Et N (10 eq.),
2
2
2
2
CH
reflux (16, 80%); (v) TMSCN (2 ꢃ 3 eq.), diethylcarbamoyl chloride
2 ꢃ 3 eq.), CH Cl , rt (17, 60%); (vi) 6 M HCl, reflux (18, 93%).
2 2 3 3 2 2
Cl , rt (15, 65%); (iv) Cl SiH (15 eq.), Et N (10 eq.), CH Cl ,
(
2
2
The mono- and bis(pyridine N-oxides) are readily modified
to form various pyridines. Simple reduction of 10a and 12a is
best achieved by treatment with trichlorosilane and triethylamine,
although other methods also furnish the products
1
5,16
(
Scheme 3).
The dipyridine 13 can be selectively oxidised
to the mixed pyridine/N-oxide–pyridine 15 by reaction with
mCPBA. The N-oxide functionality permits functionalisation
of C6 of the pyridine moiety. Treatment of either 10a or 12a
1
7
with diethylcarbamoyl chloride and trimethylsilyl cyanide
Scheme 4 Reagents and conditions: (i) N-oxide (R)-10a, 10b, 12a, 12b
or 15 (0.1 eq.), iPr NEt, CH Cl
, ꢀ78 1C.
results in the formation of the nitriles 17 and 14 in moderate
yield. Simple acid hydrolysis furnishes potentially valuable
chiral pyridine-2-carboxylic acids such as 18 (Scheme 3).
Curiously, addition of the nitrile moiety to 11 has proven
impossible under these conditions.
2
2
2
N-oxide in CH
Cl
2
at ꢀ78 1C (Scheme 4); no attempt was
2
made to optimise the conditions. All the N-oxides tested
displayed high activity and whilst only modest enantio-
selectivities were observed, the results exhibit an intriguing
electronic effect. Both the mono- and bis-unsubstituted
pyridine N-oxides (R)-10a and (R)-12a gave homoallylic alcohol
(R)-21 with identical enantioselectivities (38% ee). The electron
rich, methoxy substituted pyridine N-oxides (R)-10b and (R)-12b
furnished the opposite enantiomer, (S)-21, with comparable
enantioselectivity (36% ee and 28% ee, respectively).
The utility of these novel N-oxides was demonstrated in the
Lewis base-mediated allylation of benzaldehyde with allyl-
1
,11,18,19
trichlorosilane.
Enantiomerically pure mono- and
bis(pyridine N-oxides) (R)-10a,b, (R)-12a,b and (R)-15 were
prepared from (R)-4,12-dibromo[2.2]paracyclophane. For
these preliminary tests, benzaldehyde 19 was treated with
allyltrichlorosilane 20, diisopropylethylamine and 10 mol%
4
34 Chem. Commun., 2011, 47, 433–435
This journal is c The Royal Society of Chemistry 2011

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Most interestingly, the unsubstituted mixed pyridine/pyridine
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1
2a providing (S)-21 with 30% ee. Simple steric factors do not
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1
9
factors play a crucial role. It is unlikely that either of the
bis(pyridine N-oxides) are bidentate as they give the same
enantioselectivity as their monodentate counterparts.
In conclusion, we have outlined a new strategy for the
preparation of planar chiral pyridines and pyridine N-oxides.
The route is based on Fagnou’s direct arylation methodology
and permits the synthesis of these potentially valuable
compounds in just two steps from [2.2]paracyclophane. These
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Further studies will be directed at delineating the electronic
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these compounds in other applications, such as palladacycle
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Chem. Commun., 2011, 47, 433–435 435