A direct meta-lithiation route to 1,3-disubstituted ferrocenes

Article abstract of DOI:10.1039/b314641c

Ferrocenyl sulfides afford meta-lithiation products with up to 94% regioselectivity on reaction with s-BuLi; the resulting 1,3-disubstituted ferrocenes can then be reacted with a variety of electrophiles.

Full text of DOI:10.1039/b314641c

A direct meta-lithiation route to 1,3-disubstituted ferrocenes
Christophe Pichon, Barbara Odell and John M. Brown*
Dyson Perrins Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford, UK
OX1 3QY. E-mail: john.brown@chem.ox.ac.uk
Received (in Cambridge, UK) 13th November 2003, Accepted 9th January 2004
First published as an Advance Article on the web 10th February 2004
Ferrocenyl sulfides afford meta-lithiation products with up to
94% regioselectivity on reaction with s-BuLi; the resulting
1,3-disubstituted ferrocenes can then be reacted with a variety
of electrophiles.
separated by silica chromatography and identified by NMR
spectroscopy.† The key was provided by NOEs between neigh-
bouring ferrocenyl protons and ferrocenyl substituents, e.g. H
(CHO group) and ortho-H (–S–p-Tol group), respectively.
The expected 1,2-disubstituted product 5 was the minor
component, accompanied by the 1,1A-isomer 6 and the 1,3-isomer 7,
the last being the dominant product.7 With s-BuLi, the reaction was
far more selective in favour of compound 7. No evidence for
products arising from phenyl metallation was obtained, consistent
with the higher intrinsic acidity of ferrocene over benzene.8
Through further experiments, it was established that each of
these three products could dominate, depending on the reaction
conditions. In order to promote formation of the 1,2-lithiated
species, the Schlosser superbase was needed.9 The 1,1A-isomer was
best formed under conditions of thermodynamic control (Table 1).
With s-BuLi, the same regiochemical course was observed with the
other ferrocenyl sulfides 4b and 4c.
The availability of a simple route to meta-lithiated ferrocenes
encouraged us to examine the reaction of the s-BuLi-generated
intermediate with a range of electrophiles. Trapping with D2O gave
product 8 that was 85% deuterated, and the 2H NMR spectrum of a
sample quenched at 75% metallation established the distribution
shown in Fig. 1.
In general, yields of 50–65% were obtained (Scheme 3), with the
remainder being largely recovered starting material. The re-
gioisomeric bias towards formation of the 1,3-isomer was con-
sistently in the range 90–93%, with the nature of the electrophile
exerting little influence. A range of 1,3-disubstituted ferrocenes
was obtained in this way, in 95–98+% purity.
In a recent communication, we reported a route to a ferrocene-based
pincer ligand and a simple hydridorhodium complex derived from
it.1 The synthesis involved a multistep preparation of the diol 1,
which could be phosphinated directly with t-Bu2PH in AcOH to
give the desired diphosphine 2. In turn, this was readily converted
into the desired Rh complex 3 (Scheme 1). Production of planar
asymmetric analogues for catalytic dehydrogenation was then the
goal and an improved route to 1,3-disubstituted ferrocenes became
a priority.2
In initial experiments, a sulfoxide group was employed as the
template, with the intention of employing two sequential directed
ortho-metallations to introduce two different flanking side-chains,
followed by removal of the sulfoxide.3 The first step in the
sequence is well precedented,4 whilst the rest requires novel
chemistry and proved more challenging. This led us to examine the
directing properties of different S-ferrocenyl compounds in metal-
lation and, in particular, introducing the second ring functionality
by lithiation of a ferrocenyl sulfide and electrophilic trapping of the
intermediate. Simple model ferrocenyl sulfides 4a–c were easily
prepared from ferrocenyllithium and the corresponding disulfide5
or, alternatively, via the corresponding sulfoxide (Scheme 2).6
Although the preparation of FcLi is normally undertaken following
Kagan’s procedure, we discovered that the reaction of ferrocene
with s-BuLi in THF at 0 °C is a simple clean route to
ferrocenyllithium.
In order to demonstrate the synthetic application of this
sequence, the primary alcohol 9a was converted into its tert-
butyldimethylsilyl (TBDMS) ether 12. Oxidation of the sulfide to
sulfoxide 13 was followed by reaction with t-BuLi,10 trapping with
DMF, as before, to give 14 and NaBH4 reduction to the
As part of the survey of directing effects in sequential
metallations necessary for us to achieve our stated objective, the
products were subjected to various lithiation procedures. Initial
experiments involved comparison between s-BuLi and t-BuLi as
base in THF solution, trapping the lithiated species from 4a with
DMF. With t-BuLi, there were three products, which were
Table 1 Conditions for regioselective metallation of 4a
Conditions
5
6
7
ta (%)
i-Pr2NLi, RT, 13 h
n-BuLi, RT, 13 h
s-BuLi, 0 °C, 7 h
t-BuLi, 0 °C, 7 h
s-BuLi, 0 °C, 7 h, then 30° C, 48 h
s-BuLi, t-BuOK, 278 °C, 7 h
—
—
2
13
3
—
—
4
32
85
10
—
—
94
55
12
25
3
17
84
68
83
75
65
a Conversion (%).
Scheme 1
Scheme 2 Method A: s-BuLi, 0 °C, 5 h, then R–SS–R. Method B: (i) s-
BuLi, 0 °C, 5 h, then p-TolSO2iPr (R = p-Tol) or t-BuSO–S–t-Bu (R = t-
Bu); (ii) Me2SiCl2, Zn, 0 °C, 10 min, acetone.
Fig. 1 2H NMR spectrum of deuterated 4a in C6H6 at 81.3 MHz.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
598
C h e m . C o m m u n . , 2 0 0 4 , 5 9 8 – 5 9 9

Notes and references
†
Typical procedure for meta-lithiation of 4a: the reaction was carried out
under an anhydrous argon atmosphere using standard vacuum line and
Schlenk techniques. To a solution of 4a (716 mg, 2 mmol) in anhydrous
THF (8 mL) under Ar was added dropwise at 210 °C a commercial solution
of s-BuLi (1.4 M; 1.6 mL, 2.24 mmol; 1.12 eq.). Next, the solution was
stirred at 0 °C for 7 h until it become opaque yellow–orange. After cooling
to 230 °C, acetone (0.4 mL) was then added and the solution stirred for 5
min. NH4Cl (sat. in H2O; 10 mL) was then added and the aqueous layers
were extracted with Et2O (3 3 15 mL). The combined organic layers were
washed with water (20 mL) and brine (20 mL), and dried over MgSO4. After
concentration in vacuo, a reddish oil was obtained, which was purified by
silica chromatography (40 : 1; CH2Cl2–Et2O from 99 : 1 to 80 : 20). Some
unreacted starting material was easily recovered (87 mg, 12%). The
1,2-isomer was then eluted (9 mg, 1%), then 9b (476 mg, 65%) and finally
the 1,1A-isomer (21 mg, 3%).
Selected characterisation data. 7: red solid, m.p. 104–105 °C. nmax/cm21
3005, 2995, 2975, 1720, 1550, 1320, 1100. Rf 0.51 (CH2Cl2). dH (400 MHz,
CDCl3) 2.28 (s, 3H, CH3), 4.35 (s, 5H, CpA-H), 4.76 (dd, 1H, J 2.6, 1.3 Hz,
Cp-H5), 4.90 (dd, 1H, J 2.6, 1.3 Hz, Cp-H4), 4.99 (t, 1H, J 1.3 Hz, Cp-H3);
7.04 (dAAABBA, 2H, J 8.4 Hz, Ar-H), 7.09 (dAAABBA, 2H, J 8.3 Hz, Ar-H), 9.91
(s, 1H, CHO). dC (100 MHz, CDCl3) 21.0, 70.8, 71.3, 75.0, 78.6, 80.3, 83.9,
128.2, 129.7, 134.6, 136.1, 192.7. HRMS m/z calc. for C18H16OSFe [M +
Scheme 3 Meta-lithiation of 4a: (a) s-BuLi, THF, 0 °C, 7 h; (b) the
electrophile used is listed in brackets before the isolated yield.
H]+ 337.0349, found 337.0341. 9b: yellow solid, m.p. 151–153 °C. nmax
/
cm21 3225, 3005, 1650, 1420, 1310, 1220. Rf 0.41 (CH2Cl2–Et2O 8 : 2). dH
(400 MHz, C6D6) 1.44 (s, 3H, Me), 1.47 (s, 3H. Me), 2.08 (s, 3H, Ar–CH3),
4.17 (s, 5H, CpA-H), 4.19 (dd, 1H, J 2.4, 1.3 Hz, Cp-H4), 4.38 (dd, 1H, J 2.4,
1.3 Hz, Cp-H5), 4.48 (t, 1H, J 1.3 Hz, Cp-H2), 6.92 (dAAABBA, 2H, J 8.1 Hz,
Ar-H), 7.34 (dAAABBA, 2H, J 8.1 Hz, Ar-H). dC (100 MHz, C6D6) 20.9, 31.1,
31.5, 67.6, 68.7, 70.5 (5C), 72.8, 74.8, 77.4, 102.5, 127.4, 130.0, 135.2,
137.8. HRMS m/z calc. for C20H22OSFe [M + H]+ 367.0819, found
368.0821. 15: orange oil. nmax/cm21 3200 (br), 1510, 1410, 1210. Rf 0.15
(CH2Cl2). dH (400 MHz, CDCl3) 1.50 (t, 1H, J 5.8 Hz, OH); 4.16 (s, 5H,
CpA-H), 4.20 (m, 1H, Cp-H), 4.23 (m, 1H, Cp-H), 4.28 (m, 1H, CH2O), 4.29
(m, 1H, Cp-H), 4.30 (m, 1H, CH2O), 4.39 (s, 2H, CH2OSi). dC (100 MHz,
CDCl3) 25.1, 18.4, 26.0, 60.7, 61.1, 67.6, 67.8, 68.1, 68.9 (5C), 88.3, 88.4.
HRMS m/z calc. for C18H28O2SiFe [M + NH4]+ 378.1552, found
378.1559.
1 E. J. Farrington, E. M. Viviente, B. S. Williams, G. van Koten and J. M.
Brown, Chem. Commun., 2002, 308.
2 A. N. Nesmeyanov, E. V. Leonova, N. S. Kochetkova, A. I. Malkova
and A. G. Makarovskaya, J. Organomet. Chem., 1975, 96, 275and refs.
therein; W. E. Lindsell and L. Xinxin, J. Chem. Res., 1998, (S)462;
(M)423; P. Bickert, B. Hildebrandt and K. Hafner, Organometallics,
1984, 3, 653.
3 F. Rebière, O. Riant, L. Ricard and H. B. Kagan, Angew. Chem., Int. Ed.
Engl., 1993, 32, 568.
4 N. M. Lagneau, Y. Chen, P. M. Robben, H.-S. Sin, K. Takasu, J.-S.
Chen, P. D. Robinson and D. H. Hua, Tetrahedron, 1998, 54, 7301.
5 P. Diter, S. Taudien, O. Samuel and H. B. Kagan, J. Org. Chem., 1994,
59, 370.
Scheme 4 (a) TBDMS–Cl, DBU (98%); (b) MCPBA (94%); (c) t-BuLi (2.5
eq.), 278 °C, then DMF (91%); (d) NaBH4 (97%).
6 K. Nagasawa, Heterocycles, 1987, 26, 2607.
7 For assignments, see: T. E. Pickett and C. J. Richards, Tetrahedron Lett.,
1999, 40, 5251.
monoprotected diol 15, in 29% overall yield from ferrocene
(Scheme 4).
There are no precedents for this selective lithiation chemistry in
ferrocenes. Diphenyl sulfide is known to undergo ortho-metallation
or double ortho-metallation with n-BuLi·TMEDA.11 The chro-
mium tricarbonyl complexes of phenyl silyl ethers or alkylamino-
benzenes are known to undergo selective meta-lithiation with
different RLi bases, however.12 More general approaches to meta-
lithiation are desirable.
Attempts to carry out the metallation of ferrocenyl sulfides in the
presence of (2)-sparteine gave both low yields and low ee. As far
as our original goal is concerned, the chemistry described can only
be used after an initial enantioselective sulfoxide-driven step, and
efforts are continuing along these lines.
8 F. S. Yakushin, V. N. Setkina, E. A. Yakovleva, A. I. Shatenshtein and
D. N. Kursanov, Izv. Akad. Nauk SSSR, Ser. Khim., 1967, 206.
9 M. Schlosser, J. H. Choi and S. Takagishi, Tetrahedron, 1990, 46, 5633;
M. Schlosser, Pure Appl. Chem., 1988, 60, 1627; M. Schlosser and S.
Strunk, Tetrahedron Lett., 1984, 25, 741.
10 E.g.: M. A. M. Capozzi, C. Cardellicchio, F. Naso and V. Rosito, J. Org.
Chem., 2002, 67, 7289; J. Clayden, D. Mitjans and L. H. Youssef, J. Am.
Chem. Soc., 2002, 124, 5266; O. Riant, G. Argouarch, D. Guillaneux, O.
Samuel and H. B. Kagan, J. Org. Chem., 1998, 63, 3511.
11 A. Chopra, D. C. Dorton and C. A. Ogle, Main Group Metal Chem.,
1997, 20, 783; L. Horner, A. J. Lawson and G. Simons, Phosphorus,
Sulfur Relat. Elem., 1982, 12, 353.
12 M. Fukui, T. Ikeda and T. Oishi, Tetrahedron Lett., 1982, 23, 1605; N.
F. Masters and D. A. Widdowson, J. Chem. Soc., Chem. Commun.,
1983, 955; H. G. Schmalz, T. Volk, D. Bernicke and S. Huneck,
Tetrahedron, 1997, 53, 9219.
We thank the EC through RTN Network HPRN-CT-
2001-00172, and the Leverhulme Trust F08341A for support of C.
P.
C h e m . C o m m u n . , 2 0 0 4 , 5 9 8 – 5 9 9
599