Remote functionalisation via sodium alkylamidozincate intermediates: Access to unusual fluorenone and pyridyl ketone reactivity patterns

Article abstract of DOI:10.1039/c1cc10193e

Treating fluorenone or 2-benzoylpyridine with the sodium zincate [(TMEDA)·Na(μ-^tBu)(μ-TMP)Zn(^tBu)] in hexane solution, gives efficient ^tBu addition across the respective organic substrate in a highly unusual 1,6-fashion, p

Full text of DOI:10.1039/c1cc10193e

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Remote functionalisation via sodium alkylamidozincate intermediates:
access to unusual fluorenone and pyridyl ketone reactivity patternsw
James J. Crawford,z*a Ben J. Fleming,b Alan R. Kennedy,b Jan Klett,b Charles T. O’Hara*b
and Samantha A. Orrb
Received 11th January 2011, Accepted 4th February 2011
DOI: 10.1039/c1cc10193e
Treating fluorenone or 2-benzoylpyridine with the sodium
zincate [(TMEDA)ꢀNa(l-tBu)(l-TMP)Zn(tBu)] in hexane
solution, gives efficient tBu addition across the respective organic
substrate in a highly unusual 1,6-fashion, producing isolable
organometallic intermediates which can be quenched and
aerobically oxidised to give 3-tert-butyl-9H-fluoren-9-one and
2-benzoyl-5-tert-butylpyridine respectively.
work up) in 51% yield.4 The selective functionalisation of
pyridines has and continues to attract a great deal of interest,
as the resultant N-heterocycles have a high pharmacological
importance.5 Pertinent to the work presented herein, Maron
and Okuda have recently highlighted that by utilizing
a calcium bis(allyl) complex, 1,4-dihydropyridines can be
regioselectively prepared6 and Hill has reduced pyridine to
dihydropyridide anions using
hydride complex.7
a well-defined magnesium
Fluorenone and its derivatives are currently attracting
widespread interest due to their utilization in several diverse
fields. For instance, because of their attractive luminescent
properties, fluorenone-based materials are employed as photo-
chemical sensitizers, organic and polymer light-emitting
diodes, as well as bulk heterojunction solar cells. In addition,
fluorenones are of high pharmacological importance and are
key building blocks of many natural products. The synthesis
of substituted fluorenones is therefore an important topic for
synthetic chemists. Various methods have been developed for
this purpose. For example, one approach has involved intra-
molecular Friedel–Crafts acylation of biaryls.1 Using alternative
directed metallation methodologies; Snieckus and co-workers
have prepared a range of substituted fluorenones.2 Langer
et al., have recently reported the synthesis of fluorenones using
Alkali metal zincates have recently come to the fore as
efficient synthetic reagents. Of particular note, Mulvey has
recently exploited the sodium amidodialkylzincate [(TMEDA)ꢀ
Na(m-tBu)(m-TMP)Zn(tBu)], 1 (where TMEDA is N,N,N0,N0-
tetramethylethylenediamine and TMP is 2,2,6,6-tetramethyl-
piperidide) in a range of regioselective sodium-mediated zincation
reactions (towards arenes8 and heterocycles9). In one study this
zincate behaved anomalously, resulting in addition to benzo-
phenone in a novel 1,6-manner.10 To investigate whether this
surprising one-off reactivity could be extended to other systems,
we have probed the reaction of this zincate with fluorenone and
2-benzoylpyridine. Could this represent a new synthetic method
for the preparation of alkyl-substituted fluorenones and carbonyl-
substituted pyridines?
Utilising 1 in a 1 : 1 stoichiometric reaction with fluorenone
t
in hexane solution gave the selective 1,6-addition of a Bu
a
[3+3] cyclisation/Suzuki cross-coupling/Friedel–Crafts
acylation route starting from a 1,3-bis-silyl enol ether and a
silyloxypentenone.3 In contrast, the synthesis of substituted
fluorenones (particularly alkyl-substituted examples) from the
parent fluorenone is more unusual. To the best of our knowledge,
thus far it has not been possible to synthesize alkyl-substituted
fluorenones directly from fluorenone. When fluorenone is
treated with nBuLi in THF at ambient temperature, the
product, as expected, is the 1,2-nucleophilic addition complex,
9-n-butyl-9H-fluoren-9-ol which is formed (after aqueous
group across the tricyclic ketone (Scheme 1).y The resultant
yellow, crystalline organometallic complex, [(TMEDA)ꢀ
Na(m-OC13H8-3-tBu)(m-TMP)Zn(tBu)], 2 contains a 3-(tert-
butyl)-3H-fluoren-9-olate anion, whereby one of the aromatic
rings of fluorenone has been concomitantly dearomatized on
tBu addition. The unit cell of 2 contains two crystallographi-
cally unique molecules, with essentially identical connectivities;
however, one molecule contains a disordered TMP group.
Structural discussions will focus on the non-disordered molecule.
The molecular structure of 2 (Fig. 1) consists of a NaNZnO
four-atom four-element ring and retains the majority of the
a AstraZeneca R&D Charnwood, Loughborough, Leicestershire,
LE11 5RH, UK. E-mail: crawford.james@gene.com
b WestCHEM, Department of Pure and Applied Chemistry, University
of Strathclyde, Glasgow G1 1XL UK.
t
structural integrity of 1, except that the Bu ‘bridge’ in 1 has
been replaced by the aforementioned enolate anion. The Na
centre in 2 adopts a distorted tetrahedral (N3O) geometry
(mean angle around Na atom, 107.96 A) binding to one TMP
and two TMEDA-N atoms, and the enolato-O atom. The
four-atom four-element Na–N–Zn–O ring is effectively planar
and the carbon skeleton of the substituted fluorenone
E-mail: charlie.ohara@strath.ac.uk
w Electronic supplementary information (ESI) available: X-ray data,
full experimental details, NMR spectra. CCDC 807682–3 (2 and 3).
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc10193e
z Current address: Genentech, Inc.,
1 DNA Way, South San
Francisco, CA 94080, USA.
c
3772 Chem. Commun., 2011, 47, 3772–3774
This journal is The Royal Society of Chemistry 2011

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C210–C211 and C211–C212 bond distances [range,
1.377(4)–1.386(4) A].
Realising that the sodium alkylzincate-induced 1,6-addition
could be applied to other ketones, we decided to design an
approach to prepare further molecules which are not easily
obtainable using conventional methods of synthesis. Our
molecule of choice was 2-benzoylpyridine. Again we hoped
to induce a 1,6-addition with respect to the carbonyl functional
group; however, even more interestingly, if the addition
occurred on the pyridine ring, this would amount to a C-3
addition with respect to its nitrogen atom. To elaborate, in
‘normal’ nucleophilic additions to pyridine rings, the nucleophile
will generally add to the C-2 or C-4 positions [as C-3 (or C-5)
addition is not favoured since the negative charge on the
intermediate cannot be delocalized onto the electronegative
nitrogen atom]. Addition at the C-3 position is generally only
accomplished when this carbon carries a good leaving group.
In our system, we can dupe the ligand into conducting a C-3
pyridyl addition since we generate an enolate anion—that is a
canonical form where the negative charge still resides on an
electronegative atom, this time an O atom. As now described,
selective addition to C-3 was easily accomplished using this
strategy. In the reaction, 1 was treated with 2-benzoylpyridine
in a 1 : 1 molar ratio. The yellow crystalline product was
characterised by X-ray crystallography as [(TMEDA)ꢀNa{m-
O(Ph)-2-C5H4N-4-tBu)(m-TMP)Zn(tBu)], 3 (Fig. 2). These
data revealed that the branched alkyl group had indeed added
across the pyridyl ring of the ligand, leaving the phenyl ring
untouched.
Scheme 1 Synthesis of 2 and 3.
Complex 3 was isolated in moderate to good yield (non-
t
optimized yield, 56%). The added Bu-group is positioned
b- to the pyridyl–N atom and para- to the COPh group. In
keeping with the previous two examples of this 1,6-carbonyl
addition, loss of aromaticity in the six-membered pyridyl ring
is evident due to alternating short and long bonds (and in this
case also C–N bonds). Both the Na and Zn atoms in 3 adopt a
distorted tetrahedral geometry (sum of angles around the
metal, 663.26 and 640.481 respectively). The zinc has undergone
a coordination expansion with respect to that in 2 due to the
additional dative pyridyl-N interaction which is possible with
2-benzoylpyridine. The facile syntheses of 2 and 3 are a
significant advance showing that the selective 1,6-addition
reaction can be extended to different arenes and heteroarenes.
To investigate whether these complexes could be used to
Fig. 1 Molecular structure of 2.w
fragment does not deviate far from planarity [deviations of
C23, C24, C25 and C26 from the plane defined by the five C
atoms of the central ring are 0.168(6), 0.183(7), ꢁ0.089(7) and
ꢁ0.014(6) A respectively]. This enforced planarity has struc-
tural implications when it is compared to its benzophenone
analogue. For instance, the plane of the fluorenyl ligand in 2
adopts a perpendicular stance between the two metal centres
[dihedral angle between NaNZnO ring plane and that of the
5-membered ring is 82.95(9)1], thus not favouring one metal
over the other. This is in stark contrast to the situation in the
benzophenone complex, where the aromatic and substituted
rings are not constrained. Instead, the tBu-substituted ring lies
towards the zinc and the unsubstituted less-sterically demand-
ing phenyl ring favours the Na centre. Returning to 2, the tBu
group protrudes from its adjoining sp3 carbon on the sodium
side of the molecule and the loss of aromaticity in the six-atom
ring is evident due to the alternate short and long bond
distances [C21–C22, 1.375(4); C22–C23, 1.442(4); C23–C24,
1.353(4); C24–C25, 1.523(5); C25–C26, 1.516(5); C26–C27,
1.335(4); C27–C28, 1.473(4) A] consistent with localized C–C
bonding. The unsubstituted ring of fluorenone remains
aromatic as gauged by the similarity of the C29–C210,
Fig. 2 Molecular structure of 3.w
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Chem. Commun., 2011, 47, 3772–3774 3773

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prepare their respective enol and ketone, we subjected 2 and 3
to a NMR spectroscopic study in d6-benzene solution. The
respective 1H NMR spectra show the expected resonances for
the enolate complexes, the most indicative features being the
presence of vinyl and allyl protons due to dearomatisation of
the aryl/pyridyl rings.w Solutions of 2 and 3 in d6-benzene were
reacted with D2O to give the respective D-enol product which
was subsequently oxidized in air11 to produce the 3-tert-butyl-
9H-fluoren-9-one and 2-benzoyl-5-tert-butylpyridine in essen-
tially quantitative yield (as measured by NMR spectroscopic
analysis). Full NMR spectroscopic analyses of 2 and 3, and
their subsequent enol and ketone products are given in the
ESI.w To the best of our knowledge, 3-tert-butyl-9H-fluoren-
9-one has not previously been prepared directly from fluorenone.
Longer syntheses involving indirect methods are known
including the non-selective tert-butylation of fluorene using a
Friedel–Crafts alkylation procedure, followed by oxidation;12
and, a six-step process starting from 2-bromo-4-tert-butylto-
luene.13 As far as we can ascertain, 2-benzoyl-5-tert-butylpyridine
is a new compound never previously prepared. Its methyl-
homologue was prepared (in 60% yield) by C-6 metallation
of 3-picoline using BuLi–LiDMAE (DMAE, dimethyl-
aminoethoxide) followed by electrophilic quenching with
Me2NCOPh.14
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In summary, we have shown that sodium zincate mediated
1,6-addition is a viable methodology for the preparation of
substituted fluorenones and pyridyl ketones. Future studies
will determine the scope of this work in terms of screening new
substrates, nucleophiles and other reagents such as alkali metal
magnesiates.15 We would like to thank EPSRC (doctoral
training grant, BJF) and AstraZeneca (summer placement,
SAO) for funding this work, and Prof. Robert Mulvey and
Dr Eva Hevia for insightful discussions.
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Notes and references
y All reactions were carried out under a protective argon atmosphere.
Synthesis of [(TMEDA)ꢀNa(m-OC13H8-3-tBu)(m-TMP)Zn(tBu)] (2): a
solution of tBu2Zn (0.36 g, 2 mmol) in hexane (10 mL) was transferred
by cannula to a suspension of NaTMP in hexane [prepared in situ by
reaction of nBuNa (0.16 g, 2 mmol) with TMP(H) (0.34 mL, 2 mmol)].
TMEDA (0.30 mL, 2 mmol) was then added. The resultant suspension
was gently heated to produce a homogenous yellow solution to yield
an in situ mixture of 1. Fluorenone (0.36 g, 2 mmol) was added to the
solution and the reaction mixture was allowed to stir at ambient
temperature for 30 min. The resulting deep red solution was placed in
a freezer (ꢁ28 1C). Large yellow crystals of 2 were formed after 24 h
(0.84 g, 66%). Full spectroscopic analysis is provided in the ESI.w
Synthesis of [(TMEDA)ꢀNa{m-O(Ph)-2-C5H4N-4-tBu)(m-TMP)-
Zn(tBu)] (3): A solution of tBu2Zn (0.36 g, 2 mmol) in hexane
(10 mL) was transferred by cannula to a suspension of NaTMP in
hexane [prepared in situ by reaction of nBuNa (0.16 g, 2 mmol) with
TMP(H) (0.34 mL, 2 mmol)]. TMEDA (0.30 mL, 2 mmol) was then
added. The resultant suspension was gently heated to produce a
homogenous yellow solution to yield an in situ mixture of 1.
2-Benzoylpyridine (0.37 g, 2 mmol) was added to the solution and
the reaction mixture was allowed to stir at ambient temperature for 30 min.
The resulting green solution was placed in a freezer (ꢁ28 1C). Yellow
crystals of 3 were formed after 24 h (0.72 g, 56%). Full spectroscopic
analysis is provided in the ESI.
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c
3774 Chem. Commun., 2011, 47, 3772–3774
This journal is The Royal Society of Chemistry 2011