Cuprate addition to a 6-substituted pentafulvene - Preparation of sec-alkyl-substituted titanocene dichlorides and their biological activity

Article abstract of DOI:10.1002/ejoc.201300474

The copper-catalysed (10 mol-% CuBr·SMe₂, CuCN·LiCl or CuI/PPh₃) addition of RMgBr to the pentafulvene 1-(cyclopenta-2,4-dien-1-ylidenemethyl)-2-methoxybenzene allows the formation of cyclopentadienyl derivatives with α-CHR(2-MeOPh)

Full text of DOI:10.1002/ejoc.201300474

FULL PAPER
DOI: 10.1002/ejoc.201300474
Cuprate Addition to a 6-Substituted Pentafulvene – Preparation of sec-Alkyl-
Substituted Titanocene Dichlorides and Their Biological Activity
Melchior Cini,[a,b] Tracey D. Bradshaw,*[b] William Lewis,[a] and Simon Woodward*[a]
Dedicated to the memory of Professor Noel Zarb Adami
Keywords: Alkylation / Titanium / Cyclopentadienyl ligands / Grignard reagents / Antitumor agents
The copper-catalysed (10 mol-% CuBr·SMe2, CuCN·LiCl or
CuI/PPh3) addition of RMgBr to the pentafulvene 1-(cyclo-
penta-2,4-dien-1-ylidenemethyl)-2-methoxybenzene allows
the formation of cyclopentadienyl derivatives with α-CHR(2-
MeOPh) sidechains (R = Me, Et, nBu, iBu, allyl, Ph) without
H– transfer. The deprotonation of these sec-alkyl-substituted
cyclopentadienyls followed by the addition of TiCl4 allows
the isolation of TiCl2{η5-C5H4CHR(2-OMePh)} as rac/meso
mixtures that show activity against human colon, breast and
pancreatic cell lines (GI50 2.3–42.4 μM).
ing hydride transfer (unless R = Me or Ar).[3] This synthetic
deficiency has left the –CHAlkylAr motif rather underrep-
resented in substituted cyclopentadienyl chemistry, for
which, in addition to any biological use, a wide range of
additional applications in organic synthesis and catalysis
has also been identified.[4]
Introduction
Since the initial disclosure of its moderate cytotoxicity to
Ehrlich ascites tumour cells,[1] the complex Cp2TiCl2 (Cp =
η5-C5H5, 1) and its derivatives have attracted considerable
attention, in part, owing to their potential against tumour
types resistant to existing treatments (especially cisplatin).
As the biological activity of 1 has proved too low for clin-
ical use,[2] numerous studies have targeted the structural
modifications summarised in Scheme 1 in a quest for com-
pounds with greater potency (lower IC50 or GI50 values).[3]
These modifications, reported by Tacke and others, have
resulted in the identification of compounds 2–4 and 5 (so
called “Titanocene-Y”) as the current “optimal” structures,
which deliver IC50 values in the range 5.5–28 μm against an
identical pig kidney tumour LLC-PK cell line (thus al-
lowing direct comparison). The secondary centres in 2–3
and the proximal oxygen atom of 4 suggested to us that
species containing [η5-C5H4CHR(2-MeOPh)] units might
be good candidates for therapeutic screening. However,
these are notably absent in the current titanocene dichloride
compound library. A closer look at the literature reveals
that additions of RLi or RMgX to 6-substituted pentafulv-
enes (the normal optimal route) suffer badly from compet-
[a] School of Chemistry, the University of Nottingham,
University Park, Nottingham NG7 2RD, UK
Fax: +44-115-9513564
E-mail: simon.woodward@nottingham.ac.uk
Homepage: www.nottingham.ac.uk/~pczsw/SWGroup
[b] School of Pharmacy, Centre for Biomolecular Sciences, the
University of Nottingham,
Scheme 1. Lead and titanocene structural optimisation. Biological
activities against identical pig kidney cancer LLC-PK cells, for
which cisplatin gives an IC50 value of 3.3 μm. In this paper, GI50
values are used, that is, the concentration that inhibits cell prolifer-
ation by 50%.
University Park, Nottingham NG7 2RD, UK
Fax: +44-115-9513412
E-mail: tracey.bradshaw@nottingham.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300474.
Based on our experiences,[5] we speculated that hydride
transfer would be avoided if a “Michael-like” organocopper
addition to yield A was employed (Scheme 2). Cyclopen-
Eur. J. Org. Chem. 2013, 3997–4007
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M. Cini, T. D. Bradshaw, W. Lewis, S. Woodward
FULL PAPER
tadienyl groups are widely regarded as “nontransferable” Table 1. Development of catalytic procedure for RMgBr additions
to fulvene 6.[a]
from transition metal ions, but CpCuI complexes are some
of the most labile.[6] We reasoned that with a suitably nu-
cleophilic terminal organometallic species it should prove
possible to close the catalytic cycle of Scheme 2.
Run
CuI [mol-%]
Additive [mol-%]
R
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
CuCN (10)
LiCl (10)
–
–
–
–
–
–
Et (7a)
Et (7a)
THF
THF
THF
THF
THF
THF
THF
tBuOMe
tBuOMe
88
85
87
92
91
27[c]
24[c]
91[d]
66
CuBr·SMe2 (10)
CuBr·SMe2 (10)
CuBr·SMe2 (10)
CuBr·SMe2 (10)
CuBr·SMe2 (10)
CuBr·SMe2 (10)
CuI (8)
nBu[b] (7b)
iBu (7c)
allyl (7d)
Me (7e)
Ph (7f)
Scheme 2. Proposed use of fulvene substrates in copper-catalysed
addition of terminal organometallics.
PPh3 (10)
PPh3 (10)
Me (7e)
Ph (7f)
Thus, our targets became: (1) to define the new catalysis
of Scheme 2 and (2) to screen the derived titanocenes in
human carcinoma cell lines.
CuI (8)
[a] Performed with 6 on a 1–10 mmol scale, isolated yields except
where noted. [b] nBuMgCl used. [c] Conversion of 6. [d] Isolated
yield from 77% conversion (10 mmol scale).
Results and Discussion
These runs could be conducted on at least 2 g scale without
reduction of yields. One limitation of the CuBr·SMe2 cata-
Synthesis
1-(Cyclopenta-2,4-dien-1-ylidenemethyl)2-methoxybenz- lyst system was that it would not provide the methyl and
ene (6) was selected for our trials and prepared by literature phenyl derivatives (7e–f) in good yield; only partial conver-
procedures from cyclopentadiene and 2-MeO(C6H4)- sions were attained (Table 1, Runs 6–7). These deficiencies
CHO.[7] The initial addition of 6 to a fivefold excess of a could be overcome through the use of tBuOMe (MTBE)
stoichiometric cuprate prepared from CuI/LiBr/EtMgBr in and PPh3 (Table 1, Runs 8–9). Presumably, the lower coor-
tetrahydrofuran (THF) at –10 °C produced the ethyl ad- dination ability of MTBE leads to a more Lewis acidic
dition product 7a in modest yield (43%) after 16 h at cuprate, which can overcome the slower transmetallation
–10 °C; no hydride-transfer byproducts were detected. In rates from these Grignard reagents from “CpCuI” (A,
particular, two overlapping multiplets at δH = 1.81–2.08 Scheme 2). Some support is given to this idea by the obser-
1
ppm in the H NMR spectrum confirmed the presence of vation that MeMgBr (Mg–C 60 kcalmol–1)[9] is the slowest
diastereotopic methylene groups from the ethyl addition. reacting system and the only one that does not give com-
Additionally, two broadened signals at δH = 2.85 and 3.00 plete conversion (ca. 80Ϯ5% depending on the reaction
ppm in a 0.8:1.2 ratio indicated the presence of two [1,5] scale). We were interested to probe if the crucial phosphane
hydrogen shift tautomers, in which the CH2 group is either in these systems is able to deliver ligand accelerated cataly-
α or β to the ipso-cyclopentadienyl carbon atom. Through sis and, thus, potentially an asymmetric synthesis. Screening
2D NMR spectroscopy [COSY, heteronuclear multiple of a small library of chiral phosphanes provided no evi-
quantum coherence (HMQC) and HMBC], near full as- dence of any induced stereoselectivity in the addition of
signment of the two sets of tautomeric signals could be EtMgBr to 6 under any of the conditions we tried. We con-
made; however, they could not be independently distin- clude that although the added PPh3 (Table 1, Runs 8 and
guished. Next, we focussed our attention on attaining a 9) stabilises the cuprate, it is not critically involved in the
viable catalytic system. Base reaction conditions of –10 °C addition transition state. All of the isolated cyclopentadiene
and 16 h with 2.5 equiv. of RMgBr were selected, and the products 7 are colourless oils and show the expected spec-
other reaction components were varied (Table 1).
troscopic properties. All are isolated as close to 1:1 mixtures
As copper(I) cynanide is known to result in highly reac- of α/β [1,5] hydrogen shift tautomers.
tive cuprates,[8] it was selected for an initial trial and pro-
With an efficient route to 7 in hand, we focussed our
vided a high yield of 7a at 10 mol-% (Table 1, Run 1). With attention on the preparation of the derived titanocenes. Ra-
EtMgBr, either no reaction at all (or slow and unclean pid quantitative deprotonation of 7a by nBuLi (1.1 equiv.)
transformations under other promotions) were observed in in THF, Et2O or MTBE at 0 °C was confirmed quenching
the absence of CuI under the conditions tried. For practical the reaction with D2O, which led to [D1]-7a as an α/β iso-
considerations (cyanide waste and the need to dry LiCl), we mer mix (Scheme 3). The direct use of these reaction mix-
sought an alternative to CuCN and were delighted to find tures with either TiCl4 or TiCl4(THF)2 led only to intracta-
that, for a range of Grignard reagents (Table 1, Runs 2–5), ble mixtures. As has been found before,[3] filtration and dry-
essentially quantitative conversion of 6 (Ͼ95%) could be ing of the intermediate organolithium species 8 is required
attained and high yields of the cyclopentadiene products 7 to attain chemoselective preparation of the titanocene di-
could be isolated by using simple commercial CuBr·SMe2. chlorides 9. Presently the nature of the impurities in the
3998
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Biological Activity of sec-Alkyl-Substituted Titanocene Dichlorides
crude deprotonation mixture that causes these issues is un- be isolated in a pure form from the mother liquor (which
known. The lower yield of 8b is caused by its higher solubil- provided only sticky intractable rac/meso mixtures). The rel-
ity in hydrocarbons containing trace tBuOMe. Recrystalli- ative rac stereochemistry of 9f could be confirmed by X-
sation of the crude titanocene reaction mixtures containing ray crystallography (Figure 1). The Ti–Cl and Ti–C(Cpave
)
9 allowed the isolation of analytically pure red-orange/ bond lengths of 2.335 and 2.392 Å, respectively, in rac-9f
brown powders containing 1:1 mixtures of rac/meso dia- compare well with those of typical titanocene dichloride
1
stereomers for 9a–e from CH2Cl2/pentane. The H NMR structures bearing a Cp-CHAr unit in the Cambridge Crys-
spectrum of the rac- and meso-9a is representative of the tallographic Database.[10] These monosubstituted titano-
class. A triplet at δH = 0.76 ppm is attributed to the methyl cene dichlorides show Ti–Cl and Ti–C(Cpave) bond lengths
3
group of one diastereomer and shows a typical JH,H of of 2.31–2.37 and 2.39–2.45 Å, respectively. Often the Ti–C
7.5 Hz. This signal is overlapped by the equivalent methyl bond length associated with the point of substitution in
group of the other diastereomer at δH = 0.77 ppm. A broad such complexes is appreciably lengthened (2.40–2.49 Å) and
signal at δH = 1.96 ppm and an associated multiplet at δH this is the case in rac-9f, which shows 2.442 Å for Ti–C(1).
= 2.08–2.23 ppm (integrating to 4 H) are assigned to the The exact mode of anticancer therapeutic action of such
overlapping diastereomeric signals of the CH2 groups, complexes is not completely understood, but labilisation of
whereas the methoxy and α-CH groups of the two stereo- both the Cl and Cp ligands has been postulated.[2] It is un-
isomers are coincident at δH = 3.78 and 4.42 ppm, respec- known if steric factors are involved in such processes, if they
tively. The broadness of the latter indicates restricted rota- occur, but clearly such effects are present in 9f. The origin
tion within the molecule, most likely about the Cp–CHEtAr of the restricted rotation in 9 is also clear from the structure
bond. The chemical shift region between δH = 5.97 to of rac-9f, for which the C(2)–C(7) and C(5)–C(15) distances
6.73 ppm contains two sets of signals from diastereotopic (3.28 and 3.00 Å, respectively) are close to the expected
1
cyclopentadienyl methine protons. The H–1H COSY spec- C···C van der Waals contact ranges.
trum of the aromatic region (see Supporting Information)
allows assignment of two sets of four magnetically inequiva-
lent protons (δH = 5.97, 6.06, 6.46 and 6.73 and δH = 6.01,
6.17, 6.40 and 6.71 ppm) for the C5H4R units of the two
diastereomers. The phenylene signals are badly overlapped
with only slight separation on the 4-H Ar (δH = 7.22 and
7.23 ppm) and 5-H Ar (δH = 6.90 and 6.91 ppm) signals of
the diastereomers. The rac/meso signals of 3-H Ar at δ =
6.91 ppm and 6-H Ar at δ = 7.04 ppm are essentially coinci-
dent, and the latter signal is appreciably broadened at ambi-
ent temperature.
Figure 1. Molecular structure of rac-9f.
Growth Inhibitory Studies
The antiproliferative activities of the RCHAr-substituted
titanocenes (9) in comparison to the simple benzyl-substi-
tuted titanocene analogue (10),[11] titanocene dichloride (1,
Scheme 4) and cisplatin [cis-PtCl2(NH3)2] were evaluated in
vitro against HCT-116 (colorectal), MiaPaCa-2 (pancreatic)
and MDA-468 (triple negative breast) carcinoma cell lines,
which represent intractable cancers from three different or-
gan sites. Breast cancer is the most common cancer among
women (1.38 million new cases worldwide in 2008) and the
second most commonly diagnosed cancer overall; 23% of
all cancers diagnosed in 2008 were breast cancer.[12a] Triple
negative (basal-like) breast cancers, that is, those that do
not express oestrogen receptor, progesterone receptor or hu-
Scheme 3. Preparation of titanocene dichlorides 9.
For 9f, only small initial crops of crystalline rac-9f were man epidermal growth factor receptor 2, tend to affect
isolated from CHCl3/hexane, and the meso form could not younger women, are aggressive, more resistant to therapy
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M. Cini, T. D. Bradshaw, W. Lewis, S. Woodward
FULL PAPER
and associated with poor prognoses.[12b] Colorectal carci-
As can be deduced from Table 2, all chiral-substituted
noma is the third most common cancer and caused more titanocenes 9 are active against all the studied cancer cell
than 600000 deaths globally in 2008.[12a] Pancreatic carci- lines in the examined concentration range (0.01–100 μm).
noma is particularly resistant to chemotherapy, often diag- The dose–response relationships of 9a and 9e in HCT-116,
nosed with metastatic disease and has an appalling 5 year MiaPaCa-2 and MDA-468 carcinoma cell lines are high-
survival rate (Ͻ5%). Thus, the development of new therap- lighted in Figure 2.
ies for such malignant diseases represents a currently se-
verely unmet need.
Duplicate DMSO (vehicle) controls were performed on
all three cell lines, representative of DMSO content over
the whole range of concentrations; growth of cells was not
significantly inhibited (DMSO Յ1%). On direct compari-
son of 9 with 1 and 10, it can be deduced that all chiral
complexes 9 are much more active than their titanocene ref-
erence counterparts. Of particular note are 9a and 9e with
GI50 values Ͻ10 μm in all three cell lines, which makes them
some of the most active titanocenes reported in this area
and directly comparable to cisplatin (particularly against
HCT-116 and MiaPaCa-2 cells). This can be attributed to
the presence of their –CHRAr substituents, which might
lead to a significant increase in inhibitory activity, as has
been seen before.[3] MDA 468 demonstrates greater sensitiv-
ity towards 9a, 9b and cisplatin. MiaPaCa-2 is more (rela-
tively) sensitive to the growth inhibitory properties of rac-9f
and 10. Titanocenes 9d and 9e demonstrate approximately
equiactivity in all three cell lines. In an in vitro cytotoxicity
study performed with benzyl-substituted titanocenes such
as 5 against 36 human tumour cell lines from 14 different
organ sites it was found that the cytotoxicity of 5 relative
to cisplatin was comparatively much lower in colon carci-
noma cell lines, whereas it was comparable in pancreas and
breast carcinoma cell lines.[13]
Scheme 4. Species compared in growth inhibitory studies against
cisplatin.
The compound concentrations that inhibit cell growth by
50% (GI50 values) after 72 h exposure of cells to agents 9,
10 and 1 were obtained by standard MTT [3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and
are represented in Table 2. Compound stocks (10 mm) were
prepared in dimethyl sulfoxide (DMSO) and diluted in nu-
trient medium immediately prior to use. All of the com-
plexes 9 were assayed as 1:1 rac/meso mixtures of stereoiso-
mers except for 9f, which was a single rac diastereomer.
Of particular note is the effect of chain length on the
cytotoxicity of family 9, it can be seen in Table 2 and Fig-
ure 2 that the longer the chain length, the lower the cytotox-
icity values obtained. As the chain length increases, the
cytotoxicity diminishes by a factor of approximately six
from a C1/C2 side chain to an n-butyl chain. The best results
were obtained for titanocenes with an ethyl side chain (9a),
which showed GI50 values of 7.7 μm for HCT-116, 5.8 μm
for MiaPaCa-2 and 2.3 μm for MDA-468, or a methyl side
chain (9e), which has GI50 values of 5.7 μm for HCT-116,
6.6 μm for MiaPaCa-2 and 7.7 μm for MDA-468. These two
titanocenes show almost identical activity with uniform
growth inhibitory responses in all three cancer cell lines,
which are similar to the activity of standard cisplatin (GI50
Table 2. Growth inhibitory assays. GI50 values are represented as
mean standard error of mean (SEM) of three independent experi-
ments (n = 4 per experiment).
Mean GI50 [μm]
HCT-116
Compound
MiaPaCa-2
MDA-468
9a
7.7Ϯ1.4[a]
42.4Ϯ4.8
24.6Ϯ3.5
28.6Ϯ2.9
5.7Ϯ2.8
25.0Ϯ0.5
73.4Ϯ3.9
Ͼ 100
5.8Ϯ2.3
34.7Ϯ3.1
22.4Ϯ3.9
24.8Ϯ1.0
6.6Ϯ1.0
11.4Ϯ2.6
22.7Ϯ1.5
Ͼ 100
2.3Ϯ0.8
14.6Ϯ4.2
32.3Ϯ1.7
26.7Ϯ0.5
7.7Ϯ 2.6
27.5Ϯ0.5
76.2Ϯ2.6
Ͼ 100
9b
9c
9d
9e
rac-9f
10
1
cisplatin
6.9Ϯ0.1
6.8Ϯ2.4
0.6Ϯ0.1
[a] Nomenclature: mean value Ϯ standard error of the mean.
Figure 2. MTT assay profiles for inhibition of MIAPACA-2, HCT-116 and MDA-468 growth by 9a and 9e.
4000 Eur. J. Org. Chem. 2013, 3997–4007
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Biological Activity of sec-Alkyl-Substituted Titanocene Dichlorides
AV400, DPX400, AV(III)400 or AV500 spectrometers with CDCl3
as the deuterated solvent. Chemical shift values are reported in
ppm, and solvent resonances were used as internal standards
(CHCl3: δ = 7.27 ppm for 1H, δ = 77.0 ppm for 13C). Coupling
constants (J) are quoted in Hertz. Carbon NMR multiplicities and
connectivities were assigned by using DEPT and HMQC experi-
ments. IR spectra were recorded with a Nicolet Avatar 320 FTIR
spectrometer with a Nicolet Avatar 360 FTIR reflecting probe [at-
tenuated total reflectance (ATR)] or a Perkin–Elmer 1600 FTIR
spectrometer (thin films). HRMS were recorded with a Bruker Ap-
values of 6.9 μm for HCT-116, 6.8 μm for MiaPaCa-2 and
0.6 μm for MDA-468). Compounds 9a and 9e are equiactive
to cisplatin based on an unpaired t-test (P Ͻ 0.01),[14] ex-
cept for 9e vs. cisplatin in MDA-468 (for which cisplatin is
significantly more active).
The growth inhibitory range shown by the n- and iso-
butyl derivatives (9c and 9d) across HCT-116 and MDA-
468 cell lines deserves comment. Complex 9c is statistically
(unpaired t-test: P Ͻ 0.01) more active towards HCT-116
than MDA-468, whereas for 9d, the trend is reversed. It exIV FT-ICRMS instrument (EI) or a Bruker MicroTOF LC-MS
has been proposed[2] that the cyclopentadienyl ligands are
instrument (ESI). MS were recorded with a Bruker Ultraflex instru-
ment (MALDI-TOF). Elemental analyses were performed by using
removed in the cytotoxic events associated with Cp2TiCl2
an Exeter Analytical CE-440 instrument. Melting points were de-
therapeutics, and the role of the cyclopentadienyl ligand is
termined with a Stuart Scientific SMP3 melting point apparatus.
limited to modulation of drug uptake into the cell. There-
fore, the activity profiles of 9c and 9d are somewhat unex-
pected in light of the rather close structural similarity of graphic data for this paper. These data can be obtained free of
CCDC-931593 (for rac-9f) contains the supplementary crystallo-
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
these complexes. This might hint at significant molecular
recognition at some point in the mode of action rather than
simple pharmokinetic affects. Finally, we also note the sig-
nificantly increased growth inhibition evoked by class 9 in
comparison with titanocene-Y 5 in colon carcinoma cell
lines.[13]
Compound 10 was prepared according to a literature route.[11]
1-(Cyclopenta-2,4-dien-1-ylidenemethyl)-2-methoxybenzene
(6):
Compound 6 was prepared as described in the literature[7] with
minor modifications. 2-Methoxybenzaldehyde (16.3 g, 0.12 mol)
and excess freshly fractionated cyclopentadiene (38–41 °C,
25.2 mL, 0.30 mol) were dissolved in methanol (120 mL) to give a
colourless solution. On dropwise addition of pyrrolidine (15.0 mL,
0.18 mol), the solution changed from colourless to yellow and then
dark red. The reaction was left to stir at room temperature and was
monitored by TLC (pentane/CH2Cl2, 4:1). After 60 min, acetic acid
(18.0 mL, 0.32 mol) was added. The mixture was diluted with di-
ethyl ether (300 mL) and deionised water (50.0 mL). After extrac-
tion from the aqueous layer (2ϫ 100 mL of diethyl ether), the com-
Conclusions
Through the use of copper catalysis, the additions or
alkyl Grignard reagents to pentafulvene acceptors becomes
a practical process without competing hydride transfer. The
resultant cyclopentadienyl ligands are readily complexed to
TiCl4 and the resulting substituted (η5-C5H4CHRAr)2TiCl2
(R = alkyl, 9) compounds are some of the most cytotoxic bined organic portions were washed twice with brine (2ϫ 80 mL)
and once with deionised water (50 mL) and dried with anhydrous
MgSO4. The volatiles were evaporated in vacuo (CARE! 6 is highly
malodorous). The crude product (21.1 g, 95%) was obtained as a
red oil and was used immediately to avoid Diels–Alder dimeri-
sation, which was facile in the neat liquid (ca. 10% over 7 d at
–20 °C as detected by NMR spectroscopy). Alternatively, a portion
of such contaminated product (3.00 g) was filtered through a
40 mm pad of silica gel, eluted first with pentane (2ϫ 100 mL) and
then with pentane/CH2Cl2 (4:1, 2ϫ 100 mL). The last two pentane/
dichloromethane fractions were combined and evaporated in vacuo
to yield a light red oil (2.44 g, 81%), which was stored at –20 °C.
Rf = 0.34 (pentane/CH2Cl2, 4:1) 1H NMR (400.1 MHz, CDCl3,
25 °C): δ = 3.91 (s, 3 H, -OCH3), 6.43 (dt, J = 5.1, 1.8 Hz, 1 H, 4-
H), 6.58 (ddd, J = 5.1, 1.6, 0.6 Hz, 1 H, 1-H), 6.69–6.72 (m, 2 H,
2-H and 3-H), 6.95 (dd, J = 8.3, 0.6 Hz, 1 H, 3Ј-H), 7.06 (dddd, J
= 7.6, 7.5, 1.0, 0.6 Hz, 1 H, 5Ј-H), 7.39 (ddd, J = 7.3, 1.6, 1.6 Hz,
1 H, 4Ј-H), 7.62 (br., s, unresolved long range couplings, 1 H, 6-
H), 7.66 (dd, J = 7.8, 1.8 Hz, 1 H, 6Ј-H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 55.5 (OCH3), 110.5 (C-3Ј), 120.5
(C-5Ј), 120.6 (C-2 or C-3), 125.9 (C-1Ј), 126.8 (C-4), 130.5 (C-1 or
C-4Ј), 130.6 (C-1 or C-4Ј), 132.4 (C-6Ј), 133.7 (C-6), 134.7 (C-2 or
C-3), 144.9 (C-5), 158.4 (C-2Ј) ppm. This previously uncorrelated
data was obtained by using HMQC, HMBC and DEPT 90/135. IR
agents that have been found in this area. As the cyclopenta-
dienes 7 are prepared in racemic form, the complexes 9 are
attained as rac/meso mixtures of diastereomers. In principle,
organometallic reagents in the presence of chiral additives
[e.g., (–)-sparteine] offer the possibility to access enantioen-
riched samples of 7 and, hence, 9. This approach is now
being actively targeted in our laboratory as the screening of
individual stereoisomers of 9 is likely to be a useful tool in
the identification of the biological mode of action of these
titanocene dichlorides.
Experimental Section
General: All reactions involving air sensitive reagents/intermediates
were performed under an atmosphere of argon by using standard
Schlenk techniques. Reaction solvents were distilled from appropri-
ate drying agents under argon. THF, ether and methyl tert-butyl
ether were dried and distilled from sodium/benzophenone. Grig-
nard reagents were purchased from Acros and Sigma–Aldrich. All
organolithium and Grignard reagents were titrated by using the
Gilman double titration procedure before use. A saturated NH4Cl/
NH3 solution (pH 8) was prepared by mixing 35% v/v NH3 (8 mL)
in saturated NH4Cl(aq) (500 mL). All other solvents and reagents
were used as received from commercial suppliers. Column
chromatography was performed using Davisil silica gel 60, and
TLC analysis was performed with Merck silica gel 60 F254nm. NMR
spectra (1H, 13C) were recorded with either Joel EX270 or Bruker
(thin film): ν = 3070, 3002, 2937, 2836, 1622, 1597, 1489, 1464,
˜
1339, 1302, 1249, 1109, 1049, 1027, 903, 842, 753, 624 cm–1. MS
(EI+): m/z (%) = 185.1 (13.7) [M + H]+·, 184.1 (100) [M]+·, 183.1
(38.7) [M – H]+·, 169.1 (77.6) [M – CH3]+·, 153.1 (44.9) [M –
OCH3]+·. HRMS (EI+): calcd. for C13H12O [M]+· 184.0888; found
184.0881.
Eur. J. Org. Chem. 2013, 3997–4007
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4001

M. Cini, T. D. Bradshaw, W. Lewis, S. Woodward
FULL PAPER
General Procedure for CuBr·SMe2 Catalysed Additions to 6: In a
dry Schlenk tube equipped with a magnetic stirrer and a septum,
CuBr·SMe2 (206 mg, 1.00 mmol, 10 mol-%) was added to dry THF
ether solution, 25.0 mmol, 2.5 equiv.). The crude product was puri-
fied by flash column chromatography on silica gel (pentane/
CH2Cl2, 8:1, Rf = 0.32) to yield 7a as a colourless oil (1.82 g, 85%).
(30.0 mL), and the mixture was stirred at room temperature The individual α/β tautomer (0.8:1.2 ratio) signals could not be
(15 min). The solution was cooled to –10 °C, and the appropriate
Grignard reagent (25.0 mmol, 2.5 equiv., typically from a 0.50–
0.90 m THF solution, 20 wt.-% THF/toluene solution or 1.00–
3.00 m ether solution) was added dropwise. The reaction was stirred
(15 min) at –10 °C, and a colour change from yellow to purple was
noted. Neat 6 (1.84 g, 10.0 mmol, 1.0 equiv.) was dissolved in dry
uniquely identified and are referred to as tautomer 1 and tautomer
2 and integrated on this basis. 1H NMR (400.2 MHz, CDCl3,
25 °C): δ = 0.92 (t, J = 7.3 Hz, 1.2 H, CH2Me, tautomer 1) over-
lapped by 0.93 (t, J = 7.3 Hz, 1.8 H, CH2Me, tautomer 2), 1.81–
2.08 (m, 2 H, CH2Me, both tautomers), 2.82–2.87 (br., 0.8 H, CH2,
tautomer 1), 2.98–3.02 (br., 1.2 H, CH2, tautomer 2), 3.85 (s, 1.2
THF (10.0 mL) and added dropwise to the Grignard–cuprate solu- H, OMe, tautomer 1) overlapped by 3.86 (s, 1.8 H, OMe, tautomer
tion. The reaction was then stirred for 16 h at –10 °C. Saturated
NH4Cl/NH3 solution (pH 8, 25 mL) was added dropwise to quench
the reaction, which was then warmed to room temperature with
rapid stirring. The reaction mixture was diluted with diethyl ether
(60 mL), and the organic phase was extracted, and washed with
2), 4.12–4.22 (m, 1.0 H, CHEt, both tautomers), 6.10–6.15 (m, 0.6
H, Cp, tautomer 2), 6.23–6.31 (m, 0.8 H, Cp, tautomer 1), 6.36–
6.45 (m, 1.2 H, Cp, tautomer 2), 6.45–6.48 (m, 0.4 H, Cp, tautomer
1), 6.87–6.96 (m, 2.0 H, Ar, both tautomers), 7.11–7.23 (m, 2.0 H,
Ar, both tautomers) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C):
NH4Cl/NH3 solution (pH 8, 15 mL) and brine (2ϫ 40 mL). The δ = 12.5 (CH2Me, both tautomers), 27.3 (MeCH2, tautomer 2),
organic layer was then dried with MgSO4. All volatiles were re-
moved under reduced pressure to yield the crude product, which
was purified by column chromatography (pentane/CH2Cl2) to yield
the pure products.
27.8 (MeCH2, tautomer 1), 39.6 (CHEt, tautomer 2), 40.4 (CHEt,
tautomer 1), 41.0 (CH2, tautomer 2), 42.6 (CH2, tautomer 1), 55.5
(OMe, both tautomers), 110.6 (Ar, both tautomers), 120.6 (Ar,
both tautomers), 125.8 (Cp, tautomer 2), 126.3 (Cp, tautomer 1),
126.8 (Ar, tautomer 1), 126.9 (Ar, tautomer 2), 127.9 (Ar, tautomer
1), 128.0 (Ar, tautomer 2), 130.7 (Cp, tautomer 1), 132.1 (Cp, tau-
tomer 2), 132.9 (Cp, tautomer 2), 133.1 (Cp, tautomer 1), 133.6
(Cp, tautomer 1), 134.6 (Cp, tautomer 2), 149.9 (CpCCHEt, tauto-
mer 2), 152.8 (CpCCHEt, tautomer 1), 157.1 (COMe, tautomer 1),
General Procedure for CuI/PPh3 Catalysed Additions to 6: In a dry
Schlenk tube equipped with a magnetic stirrer and a septum, CuI
(152 mg, 0.80 mmol, 8.0 mol-%) and triphenylphosphane (262 mg,
1.00 mmol, 10 mol-%) were added to dry methyl tert-butyl ether
(30 mL), and the mixture was stirred at room temperature (30 min).
The solution was cooled to –10 °C, and the appropriate Grignard
reagent (25.0 mmol, 2.5 equiv., from a 2.80–3.00 m ether solution)
was added dropwise. The reaction was stirred (15 min) at –10 °C.
Neat 6 (1.84 g, 10.0 mmol, 1.0 equiv.) was dissolved in dry methyl
tert-butyl ether (10 mL) and added dropwise to the Grignard–
cuprate solution. The reaction mixture was then stirred for 16 h at
–10 °C. Quenching and work-up was performed as above for the
CuBr·SMe2 promoted reactions.
157.3 (COMe, tautomer 2) ppm. IR (thin film): ν = 3064, 2961,
˜
2932, 2874, 2835, 1598, 1490, 1463, 1241, 1031, 899, 752 cm–1.
HRMS (EI+): calcd. for C15H18O [M]+· 214.1358; found 214.1360.
C15H18O (214.31): calcd. C 84.07, H 8.47; found C 84.01, H 8.67.
Also prepared according to the CuCN/LiCl procedure (yield 2.82 g,
88%).
1-[1-(Cyclopenta-1,3-dien-1-yl)pentyl]-2-methoxybenzene and 1-[1-
(Cyclopenta-1,4-dien-1-yl)pentyl]-2-methoxybenzene (7b): Prepared
by the CuBr·SMe2 procedure by using nBuMgCl (14.6 g of 20 wt.-
% THF/toluene solution, 25.0 mmol, 2.5 equiv.). The crude prod-
uct was purified by flash column chromatography on silica gel
(pentane/CH2Cl2, 6:1, Rf = 0.34) to yield 7b as a colourless oil
(2.10 g, 87%). The individual α/β tautomer (0.8:1.2 ratio) signals
could not be uniquely identified and are referred to as tautomer 1
and tautomer 2 and integrated on this basis. 1H NMR (400.1 MHz,
CDCl3, 25 °C): δ = 0.88 (t, J = 7.0 Hz, 3.0 H, CH2Me, both tauto-
mers), 1.17–1.39 (m, 4.0 H, C2H4Me, both tautomers), 1.75–2.00
(m, 2.0 H, CH2C3H7, both tautomers), 2.80–2.85 (m, 0.8 H, CH2,
tautomer 1), 2.95–3.01 (m, 1.2 H, CH2, tautomer 2), 3.84 (s, 1.2 H,
OMe, tautomer 1) overlapped by 3.84 (s, 1.8 H, OMe, tautomer 2),
4.18–4.27 (m, 1.0 H, CHBu, both tautomers), 6.06–6.12 (m, 0.6 H,
Cp, tautomer 2), 6.21–6.27 (m, 0.8 H, Cp, tautomer 1), 6.36–6.47
(m, 1.6 H, Cp, both tautomers), 6.85–6.94 (m, 2.0 H, Ar, both
tautomers), 7.10–7.20 (m, 2.0 H, Ar, both tautomers) ppm. 13C
NMR (100.6 MHz, CDCl3, 25 °C): δ = 14.0 (CH2Me, both tauto-
mers), 22.7 (C2H4Me, both tautomers), 30.0 (C2H4Me, tautomer 2)
overlapped by 30.1 (C2H4Me, tautomer 1), 34.1 (CH2C3H7, tauto-
mer 2), 34.6 (CH2C3H7, tautomer 1), 37.7 (CHBu, tautomer 2),
38.5 (CHBu, tautomer 1), 41.0 (CH2, tautomer 2), 42.6 (CH2, tau-
tomer 1), 55.5 (OMe, both tautomers), 110.6 (Ar, both tautomers),
120.6 (Ar, both tautomers) 125.7 (Cp, tautomer 2), 126.2 (Cp, tau-
tomer 1), 126.7 (Ar, both tautomers), 127.9 (Ar, tautomer 1), 128.0
(Ar, tautomer 2), 130.7 (Cp, tautomer 2), 132.1 (Cp, tautomer 1),
133.1 (Cp, tautomer 2), 133.2 (Cp, tautomer 2), 133.9 (Cp, tauto-
mer 1), 134.6 (Cp, tautomer 2), 150.1 (CpCCH, tautomer 2), 153.0
General Procedure for CuCN/LiCl Catalysed Additions to 6: To a
dry Schlenk tube, equipped with a magnetic stirrer and a septum
was added dried LiCl (63.6 mg, 1.50 mmol, 5.0 mol-%) and CuCN
(134 mg, 1.50 mmol, 5.0 mol-%, TOXIC!). The mixture was then
heated under vacuum (5 min) by using a hot air gun (Ͼ100 °C),
cooled to room temperature and flushed with argon. Dry THF
(50 mL) was added, and the solution was cooled to –10 °C. A solu-
tion of ethylmagnesium bromide (0.83 m) in THF (45.0 mL,
37.5 mmol, 2.5 equiv.) was added dropwise, and the colour changed
from colourless to grey and then purple. Similar solutions were
obtained with other Grignard reagents. Neat 6 (2.76 g, 15.0 mmol,
1.0 equiv.) was dissolved in dry THF (25 mL). The latter solution
was added dropwise to the complexed Grignard solution. A colour
change from dark purple to yellow was noted. The reaction was
then stirred for 16 h at –10 °C. Saturated NH4Cl/NH3 solution (pH
8, 35 mL) was then added dropwise to quench the reaction, and
the mixture was then warmed to room temperature with rapid stir-
ring. The reaction mixture was diluted with diethyl ether (90 mL),
and the organic phase was extracted, washed with NH4Cl/NH3
solution (pH 8, 15 mL) and brine (2ϫ 50 mL). The organic layer
was then dried with MgSO4. Aqueous cyanide residues were
quenched with bleach. All volatiles were removed under reduced
pressure to yield the crude product, which was then purified by
column chromatography (pentane/CH2Cl2) to yield the purified
product.
1-[1-(Cyclopenta-1,3-dien-1-yl)propyl]-2-methoxybenzene and 1-[1-
(Cyclopenta-1,4-dien-1-yl)propyl]-2-methoxybenzene (7a): Prepared (CpCCH, tautomer 1), 157.0 (COMe, tautomer 1), 157.1 (COMe,
by the CuBr·SMe2 procedure by using EtMgBr (8.7 mL of 2.90 m tautomer 2) ppm. IR (thin film): ν = 3064, 3028, 2998, 2931, 2859,
˜
4002
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3997–4007

Biological Activity of sec-Alkyl-Substituted Titanocene Dichlorides
1598, 1491, 1463, 1439, 1367, 1288, 1242, 1117, 1052, 1032, 931,
899, 752, 676 cm–1. HRMS (EI+): calcd. for C17H22O [M]+·
242.1671; found 242.1670. C17H22O (242.36): calcd. C 84.25, H
9.15; found C 84.27, H 9.10.
tautomer 2), 39.0 (CH2CHCp, tautomer 1), 41.0 (CH2, tautomer
2), 42.7 (CH2, tautomer 1), 55.5 (OMe, both tautomers), 110.6 (Ar,
both tautomers), 115.4 (CH2C2H3CHCp, tautomer 2) overlapped
by 115.5 (CH2C2H3CHCp, tautomer 1), 120.5 (Ar, tautomer 2)
overlapped by 120.6 (Ar, tautomer 1) 126.3 (Cp, tautomer 2), 126.8
(Cp, tautomer 1), 127.0 (Ar, both tautomers), 128.1 (Ar, tautomer
1), 128.3 (Ar, tautomer 2), 131.0 (Cp, tautomer 2), 132.1 (Cp, tau-
tomer 1), 132.3 (Cp, tautomer 2), 133.1 (Cp, tautomer 1), 133.3
(Cp, tautomer 2), 134.6 (Cp, tautomer 1), 137.5 (CHCH2CHCp,
both tautomers), 149.2 (CpCCH, tautomer 2), 151.9 (CpCCH, tau-
tomer 1), 156.9 (COMe, tautomer 1), 157.0 (COMe, tautomer 2)
1-[1-(Cyclopenta-1,3-dien-1-yl)-3-methylbutyl]-2-methoxybenzene
and 1-[1-(Cyclopenta-1,4-dien-1-yl)-3-methylbutyl]-2-methoxybenz-
ene (7c): Prepared by the CuBr·SMe2 procedure by using iBuMgCl
(12.5 mL of 2.00 m ether solution, 25.0 mmol, 2.5 equiv.). The
crude product was purified by flash column chromatography on
silica gel (gradient pentane/CH2Cl2 initially 6:1, Rf = 0.38) to yield
7d as a colourless oil (2.23 g, 92%). The individual α/β tautomer
(0.8:1.2 ratio) signals could not be uniquely identified and are re-
ferred to as tautomer 1 and tautomer 2 and integrated on this basis.
1H NMR (400.1 MHz, CDCl3, 25 °C): δ = 0.89–0.93 (m, 6 H,
CH3CHCH3, both tautomers), 1.4–1.53 (m, 1.0 H, CH3CHCH3,
both tautomers), 1.68–1.83 (m, 2.0 H, CHCH2C3H7, both tauto-
mers), 2.80–2.85 (m, 0.8 H, CH2, tautomer 1), 2.95–2.99 (m, 1.2
H, CH2, tautomer 2), 3.83 (s, 1.2 H, OMe, tautomer 1) overlapped
ppm. IR (thin film): ν = 3072, 3029, 3001, 2935, 2836, 1640, 1599,
˜
1586, 1491, 1463, 1439, 1365, 1339, 1289, 1242, 1186, 1162, 1114,
1052, 1032, 995, 951, 911, 899, 808, 753, 678, 619, 572, 503, 478,
460 cm–1. HRMS (EI+): calcd. for C16H18O [M]+· 226.1358; found
226.1360. C16H18O (226.32): calcd. C 84.91, H 8.02; found C 84.90,
H 8.02.
1-[1-(Cyclopenta-1,3-dien-1-yl)ethyl]-2-methoxybenzene and 1-[1-
by 3.84 (s, 1.8 H, OMe, tautomer 2), 4.30–4.40 (m, 1.0 H, CHiBu, (Cyclopenta-1,4-dien-1-yl)ethyl]-2-methoxybenzene (7e): Prepared
both tautomers), 6.05–6.10 (m, 0.6 H, Cp, tautomer 2), 6.20–6.28
(m, 0.8 H, Cp, tautomer 1), 6.33–6.47 (m, 1.5 H, Cp, both tauto-
by the CuI/PPh3 procedure by using MeMgBr (8.3 mL of 3.00 m
ether solution, 25.0 mmol, 2.5 equiv.). The crude product was puri-
mers), 6.85–6.93 (m, 2.0 H, Ar, both tautomers), 7.09–7.19 (m, 2.0 fied by flash column chromatography on silica gel (gradient pent-
H, Ar, both tautomers) ppm. 13C NMR (100.6 MHz, CDCl3, ane/CH2Cl2 initially 10:1, Rf = 0.30) to yield 7e as a colourless oil
25 °C): δ = 22.4 (CH3CHCH3, tautomer 1), 22.5 (CH3CHCH3, tau-
tomer 2), 23.0 (CH3CHCH3, tautomer 2), 23.1 (CH3CHCH3, tau-
tomer 1), 25.8 (CH3CHCH3, both tautomers), 35.5 (CHiBu, tauto-
(1.83 g, 91%). The individual α/β tautomer (1.2:0.8 ratio) signals
could not be uniquely identified and are referred to as tautomer 1
and tautomer 2 and integrated on this basis. 1H NMR (400.2 MHz,
mer 2), 36.3 (CHiBu, tautomer 1), 41.0 (CH2, tautomer 2), 42.6 CDCl3, 2 5 °C): δ = 1.46 (d, J = 7.2 Hz, 3.0 H, CHMe, both tauto-
(CH2, tautomer 1), 43.8 (CHCH2C3H7, tautomer 2), 44.2 mers), 2.81–2.86 (m, 1.2 H, CH2, tautomer 1), 2.99–3.02 (m, 0.8
(CHCH2C3H7, tautomer 1), 55.5 (OMe, both tautomers), 110.6
(Ar, tautomer 2) overlapped by 110.7 (Ar, tautomer 1), 120.6 (Ar,
both tautomers) 125.6 (Cp, tautomer 2), 126.1 (Cp, tautomer 1),
126.7 (Ar, tautomer 1), 126.8 (Ar, tautomer 2), 128.0 (Ar, tautomer
1), 128.2 (Ar, tautomer 2), 130.7 (Cp, tautomer 2), 132.1 (Cp, tau-
tomer 1), 133.2 (Cp, both tautomers), 133.8 (Cp, tautomer 1), 134.7
H, CH2, tautomer 2), 3.85 (s, 1.8 H, OMe, tautomer 1) overlapped
by 3.86 (s, 1.2 H, OMe, tautomer 2), 4.25–4.40 (m, 1.0 H, CHMe,
both tautomers), 6.08–6.13 (m, 0.4 H, Cp, tautomer 2), 6.22–6.29
(m, 1.2 H, Cp, tautomer 1), 6.33–6.41 (m, 0.8 H, Cp, tautomer 2),
6.42–6.48 (m, 0.6 H, Cp, tautomer 1), 6.85–6.93 (m, 2.0 H, Ar,
both tautomers), 7.03–7.08 (m, 1.0 H, Ar, both tautomers), 7.14–
(Cp, tautomer 2), 150.3 (CpCCH, tautomer 2), 153.2 (CpCCH, 7.21 (m, 1.0 H, Ar, both tautomers) ppm. 13C NMR (100.6 MHz,
tautomer 1), 157.0 (COMe, tautomer 1), 157.1 (COMe, tautomer CDCl3, 25 °C): δ = 19.9 (MeCH, tautomer 2), 20.4 (MeCH, tauto-
2) ppm. IR (thin film): ν = 3064, 2954, 2868, 2835, 1598, 1491,
mer 1), 32.4 (MeCH, tautomer 2), 33.1 (MeCH, tautomer 1), 41.0
(CH2, tautomer 2), 42.7 (CH2, tautomer 1), 55.5 (OMe, both tauto-
mers), 110.5 (Ar, both tautomers), 120.6 (Ar, both tautomers),
125.5 (Cp, tautomer 2), 126.2 (Cp, tautomer 1), 126.8 (Ar, tautomer
1), 126.9 (Ar, tautomer 2), 127.7 (Ar, tautomer 1), 127.9 (Ar, tauto-
mer 2), 131.0 (Cp, tautomer 1), 132.1 (Cp, tautomer 1), 133.3 (Cp,
tautomer 2), 134.2 (Cp, tautomer 2), 134.7 (Cp, tautomer 2), 135.2
(Cp, tautomer 1), 151.1 (CpCCH, tautomer 2), 153.9 (CpCCHEt,
tautomer 1), 156.5 (COMe, tautomer 1), 156.8 (COMe, tautomer
˜
1464, 1438, 1366, 1288, 1241, 1168, 1096, 1053, 1032, 899, 807,
752, 677, 622 cm–1. HRMS (EI+): calcd. for C17H22O [M]+·
242.1671; found 242.1676. C17H22O (242.36): calcd. C 84.25, H
9.15; found C 83.85, H 9.12.
1-[1-(Cyclopenta-1,3-dien-1-yl)but-3-en-1-yl]-2-methoxybenzene and
1-[1-(Cyclopenta-1,4-dien-1-yl)but-3-en-1-yl]-2-methoxybenzene
(7d): Prepared by the CuBr·SMe2 procedure by using allylmagne-
sium bromide (25.0 mL of 1.00 m ether solution, 25.0 mmol,
2.5 equiv.). The crude product was purified by flash column
chromatography on silica gel (gradient pentane/CH2Cl2 initially
6:1, Rf = 0.28) to yield 7c as a colourless oil (2.06 g, 91%). The
individual α/β tautomer (0.9:1.1 ratio) signals could not be
uniquely identified and are referred to as tautomer 1 and tautomer
2 and integrated on this basis. 1H NMR (400.1 MHz, CDCl3,
2) ppm. IR (thin film): ν = 3061, 2962, 2835, 1599, 1491, 1463,
˜
1438, 1367, 1289, 1241. 1163, 1111, 1030, 931, 899, 808, 753, 677,
573, 503 cm–1. HRMS (EI+): calcd. for C14H16O [M]+· 200.1201;
found 200.1205.
1-[Cyclopenta-1,3-dien-1-yl(phenyl)methyl]-2-methoxybenzene and
1-[Cyclopenta-1,4-dien-1-yl(phenyl)methyl]-2-methoxybenzene (7f):
25 °C): δ = 2.55–2.77 (m, 2.0 H, CH2CHCp, both tautomers), 2.82– Prepared by the CuI/PPh3 procedure by using PhMgBr (9.0 mL of
2.86 (m, 0.9 H, CH2, tautomer 1), 2.96–3.02 (m, 1.1 H, CH2, tauto-
mer 2), 3.83 (s, 1.3 H, OMe, tautomer 1), 3.84 (s, 1.7 H, OMe,
2.80 m ether solution, 25.0 mmol, 2.5 equiv.). The crude product
was purified by flash column chromatography on silica gel (gradi-
tautomer 2), 4.26–4.37 (m, 1.0 H, CH2CHCp, both tautomers), ent pentane/CH2Cl2 initially 10:1, Rf = 0.20) to yield 7f as a colour-
4.90–4.95 (m, 1.0 H, CH2C2H3CHCp, both tautomers), 4.98–5.05 less oil (1.73 g, 66%). The individual α/β tautomer (0.9:1.1 ratio)
(m, 1.0 H, CH2C2H3CHCp, both tautomers), 5.72–5.85 (m, 1.0 H, signals could not be uniquely identified and are referred to as tau-
CHCH2CHCp, both tautomers), 6.12–6.15 (m, 0.5 H, Cp, tauto-
mer 2), 6.22–6.30 (m, 0.9 H, Cp, tautomer 1), 6.36–6.42 (m, 1.1 H, (400.2 MHz, CDCl3, 25 °C): δ = 2.99–3.04 (br., 0.9 H, CH2, tauto-
tomer 1 and tautomer 2 and integrated on this basis. 1H NMR
Cp, tautomer 2), 6.42–6.45 (m, 0.4 H, Cp, tautomer 1), 6.85–6.93
(m, 2.0 H, Ar, both tautomers), 7.08–7.20 (m, 2.0 H, Ar, both tau-
tomers) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 38.0 (CH-
allyl, tautomer 1), 38.5 (CH-allyl, tautomer 2), 38.8 (CH2CHCp,
mer 1), 3.05–3.09 (br., 1.1 H, CH2, tautomer 2), 3.81 (s, 3.0 H,
OMe, both tautomers), 5.63–5.67 (br., 0.5 H, CHPh, tautomer 2),
5.67–5.71 (br., 0.5 H, CHPh, tautomer 1), 5.81–5.84 (m, 0.5 H,
Cp), 5.98–6.02 (br., m, 0.5 H, Cp), 6.37–6.41 (m, 0.5 H, Cp), 6.43–
Eur. J. Org. Chem. 2013, 3997–4007
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4003

M. Cini, T. D. Bradshaw, W. Lewis, S. Woodward
1), 6.01 (AB, JA,B = 2.0 Hz, 1 H, Cp, isomer 2), 6.06 (AB, JA,B
2.5 Hz, 1 H, Cp, isomer 1), 6.17 (AB, JA,B = 2.5 Hz, 1 H, Cp,
isomer 2), 6.40 (AB, JA,B = 2.5 Hz, 1 H, Cp, isomer 2), 6.46 (AB,
JA,B = 2.5 Hz, 1 H, Cp, isomer 1), 6.71 (AB, JA,B = 2.5 Hz, 1 H,
FULL PAPER
6.47 (m, 0.5 H, Cp), 6.47–6.52 (m, 1.0 H, Cp), 6.91–6.99 (m, 2.0
H, Ar, both tautomers), 7.07–7.14 (m, 1.0 H, Ar both, tautomers),
7.22–7.30 (m, 4.0 H, Ar and Ph, both tautomers), 7.31–7.37 (m,
2.0 H, Ph, both tautomers) ppm. 13C NMR (100.6 MHz, CDCl3,
=
25 °C): δ = 41.0 (CH2, tautomer 2), 43.6 (CH2, tautomer 1), 44.7 Cp, isomer 2), 6.73 (AB, JAB = 2.5 Hz, 1 H, Cp, isomer 1), 6.86–
(CHPh, tautomer 2), 45.4 (CHPh, tautomer 1), 55.6 (OMe, both 6.92 (m, 4 H, 4-H and 6-H Ar, both isomers), 7.03 (br. d, J =
tautomers), 110.6 (Ar, tautomer 1), 110.7 (Ar, tautomer 2), 120.3 6.9 Hz, 2 H, 3-H Ar, both isomers), 7.20 (ddd, J = 7.5, 7.0, 1.0 Hz,
(Ar, both tautomers), 125.9 (Ph, both tautomers), 127.3 (Ar, tauto-
mer 1), 127.4 (Ar, tautomer 2), 128.0 (Ph ϫ2, both tautomers),
128.9 (Ph ϫ2, tautomer 1), 129.0 (Ph ϫ2, tautomer 2), 129.1 (Ar,
tautomer 2), 129.6 (Ar, tautomer 1), 129.7 (Cp, tautomer 2), 130.0
(Cp, tautomer 1), 131.6 (Cp, tautomer 2), 131.8 (Cp, tautomer 2),
132.0 (Cp, tautomer 2), 132.6 (Cp, tautomer 1), 133.4 (Cp, tauto-
mer 1), 135.1 (Cp, tautomer 2), 143.4 (PhCCH, tautomer 2), 143.9
(PhCCH, tautomer 1), 149.1 (CpCCH, tautomer 2), 151.6
(CpCCH, tautomer 1), 156.8 (COMe, tautomer 1), 157.0 (COMe,
1 H, 5-H Ar) overlapped by 7.25 (ddd, J = 7.5, 7.0, 1.0 Hz, 1 H,
5-H Ar) ppm. 13C NMR (125.8 MHz, CDCl3, 25 °C): δ = 11.9
(CH2Me, both isomers), 26.2 (CH2Me, isomer 1 or 2), 26.3
(CH2Me, isomer 1 or 2), 42.1 (CHEt, both isomers), 55.4 (OMe,
both isomers), 111.1 (C-6 Ar, both isomers), 115.4 (br., Cp, isomer
1), 116.4 (br., Cp, isomer 2), 117.4 (Cp, isomer 2), 118.3 (Cp, isomer
1), 118.8 (Cp, isomer 1), 119.2 (Cp, isomer 2), 120.7 (C-3 or C-4
Ar, both isomers), 120.7 (C-3 or C-4 Ar, both isomers), 121.9 (Cp,
isomer 2), 123.1 (Cp, isomer 1), 127.6 (C-5 Ar, both isomers), 129.9
(br., ipso-Cp), 131.7 (br., ipso-Cp), 142.2 (C-2 Ar, isomer 1 or 2),
142.5 (C-2 Ar, isomer 1 or 2), 157.6 (C-1 Ar, both isomers) ppm.
tautomer 2) ppm. IR (thin film): ν = 3061, 3026, 2935, 2835, 1598,
˜
1450, 1462, 1438, 1361, 1289, 1243, 1162, 1105, 1051, 1030, 900,
755, 700, 634 cm–1. HRMS (EI+): calcd. for C19H18O [M]+·
262.1358; found 262.1361.
IR (ATR.): ν = 3118, 2962, 2933, 2875, 2835, 1597, 1583, 1490,
˜
1459, 1434, 1379, 1334, 1290, 1242, 1183, 1157, 1117, 1080, 1048,
1025, 908, 838, 829, 797 775, 752, 740, 712 cm–1. HRMS (ESI+):
calcd. for C30H34Cl2NaO2Ti+ [M + Na]+ 567.1308; found 567.1319.
C30H34Cl2O2Ti (545.40): calcd. C 66.07, H 6.28; found C 65.94, H
6.28.
General Procedure for the Synthesis of rac/meso-Substituted Titano-
cenes 9: A flame-dried Schlenk tube was left to cool under vacuum
for 30 min and then weighed under vacuum. Under a stream of
argon, 7 (1.0 equiv.) was added, followed by dry ether or methyl
tert-butyl ether (4.00 mL per 1.00 mmol of 7). The mixture was
cooled to 0 °C, and nBuLi (1.60 m in hexane, 1.1 equiv.) was added.
The solution was left to stir for 30 min at 0 °C to yield a white
precipitate of the lithium substituted-cyclopentadienide 8 in a faint
yellow solution. The solvent was removed from 8 by cannula fil-
tration, and the solid was washed twice with dry ether (2ϫ 1.0 mL
per 1.0 mmol of 7) and refiltered under argon. The precipitate was
dried under vacuum at 0.1 Torr for 1 h and weighed under vacuum.
The lithium substituted-cyclopentadienide 8 (2.0 equiv.) was dis-
solved in dry THF (4.0 mL per 1.0 mmol of 8) to give a colourless
solution. In another Schlenk tube, titanium tetrachloride (1.00 m
in toluene, 1.0 equiv.) was dissolved in dry THF (8.0 mL per
1.0 mmol of titanium tetrachloride) to give a yellow solution. The
solution of titanium tetrachloride was added to the solution of 8
by cannulation at room temperature to give a dark red solution,
which was heated to reflux for 16 h at 85 °C. The resultant solution
was then cooled, and the solvent was removed under reduced pres-
sure. The remaining brown residue was extracted with chloroform,
which was filtered through Celite to remove LiCl. The solvent was
removed in vacuo to yield the crude solid material. Purification was
performed by direct infusion of pentane on top of a saturated solu-
tion of 9 in CH2Cl2 (final mixture ca. 5:1 pentane/CH2Cl2).
rac/meso-Dichloridobis[1-pentyl-1Ј-(2-methoxyphenyl)-η5-cyclopen-
tadienyl]titanium (9b): Prepared by using 7b (606 mg, 2.50 mmol,
1.0 equiv.), dry methyl tert-butyl ether (10 mL) and nBuLi (1.7 mL,
2.75 mmol, 1.1 equiv.) to yield 8b (170 mg, 27% yield). This inter-
mediate (0.69 mmol, 2.0 equiv.) was dissolved in dry THF (2.8 mL)
to give a colourless solution. Titanium tetrachloride (0.34 mmol,
0.34 mL, 1.0 equiv.) was dissolved in dry THF (2.8 mL) to give a
yellow solution. After purification, a red solid was obtained
(143 mg, 69% based on titanium). The individual rac and meso
diastereomers (1:1 ratio) signals could not be uniquely identified
and are thus identified as isomer 1 or 2, m.p. 121–123 °C. 1H NMR
(500.1 MHz, CDCl3, 22 °C): δ = 0.82 (t, J = 7.5 Hz, 6 H, CH2Me,
both isomers) 0.95–1.08 (br., 2 H, C2H4Me, both isomers), 1.10–
1.40 (m, 6 H, C2H4Me, both isomers), 1.85–2.16 (m, 2.0 H,
CH2C3H7, both isomers), 3.78 (s, 6 H, 2ϫ OMe, both isomers),
4.49 (br., 2 H, CHBu, both isomers), 5.95 (s, 1 H, Cp, isomer 1),
6.01 (s, 2 H, Cp, both isomers), 6.16 (s, 1 H, Cp, isomer 2), 6.39
(s, 1 H, Cp, isomer 2), 6.48 (s, 1 H, Cp, isomer 1), 6.69 (s, 1 H, Cp,
isomer 2), 6.74 (s, 1 H, Cp, isomer 1), 6.82–6.95 (m, 4 H, 4-H and
6-H Ar, both isomers), 7.03 (br. d, J = 6.0 Hz, 2 H, 3-H Ar, both
isomers), 7.20 (br. t, J = 7.5 Hz, 2 H, 5-H Ar, both isomers) ppm.
13C NMR (125.8 MHz, CDCl3, 25 °C): δ = 14.1 (CH2Me, both
isomers) 22.6 (CH2Me, both isomers), 29.4 (CH2CH2Me, both iso-
rac/meso-Dichloridobis[1-propyl-1Ј-(2-methoxyphenyl)-η5-cyclopen-
tadienyl]titanium (9a): Prepared by using 7a (535 mg, 2.50 mmol, mers), 33.0 (CHCH2C3H7, isomer 1 or 2) overlapped by 33.1
1.0 equiv.), dry ether (10 mL) and nBuLi (1.7 mL, 2.75 mmol,
1.1 equiv.) to yield lithium substituted-cyclopentadienide 8a
(410 mg, 1.86 mmol, 74 %). This intermediate (1.86 mmol,
2.0 equiv.) was dissolved in dry THF (7.5 mL) to give a colourless
solution. Titanium tetrachloride (0.93 mmol, 0.93 mL, 1.0 equiv.)
was dissolved in dry THF (7.5 mL) to give a yellow solution. After
purification, a red solid was obtained (359 mg, 71% based on tita-
nium). The individual rac and meso diastereomers (1:1 ratio) sig-
nals could not be uniquely identified and are thus identified as
isomer 1 or 2, m.p. 173–174 °C. 1H NMR (500.1 MHz, CDCl3,
(CHCH2C3H7, isomer 1 or 2), 39.5–40.5 (CHBu, both isomers),
55.5 (OMe, both isomers), 111.1 (C-6 Ar both isomers), 115.2 (br.,
Cp, isomer 1 or 2), 116.8 (br., Cp, isomer 2), 117.6 (Cp, isomer 2),
118.1 (Cp, isomer 1), 119.2 (Cp, isomer 1 or 2), 119.6 (Cp, isomer
1), 120.7 (C-3 or C-4 Ar, isomer 1 or 2) overlapped by 120.8 (C-3
or C-4 Ar, isomer 1 or 2), 121.3 (Cp, isomer 2), 123.0 (Cp, isomer
1), 127.6 (C-5 Ar, both isomers), 129.9 (br., ipso-Cp), 132.2 (br.,
ipso-Cp), 142.3 (C-2 Ar, isomer 1 or 2), 142.8 (C-2 Ar, isomer 1 or
2), 157.5 (C-1 Ar, both isomers) ppm. IR (ATR): ν = 3105, 2954,
˜
2928, 2869, 1596, 1585, 1491, 1463, 1438, 1336, 1288, 1240, 1189,
22 °C): δ = 0.76 (t, J = 7.5 Hz, 3 H, CH2Me, isomer 1 or 2) over- 1162, 1124, 1088, 1051, 1029, 949, 843, 826, 804, 782, 753, 735,
lapped by 0.76 (t, J = 7.5 Hz, 3 H, CH2Me, isomer 1 or 2), 1.88– 714, 702, 685, 675 cm–1. MS (MALDI-TOF, DCTB matrix, 10%
2.03 (br., 2 H, CH2Me, both isomers), 2.08–2.23 (m, 2 H, CH2Me, laser): m/z (%) = 565.3 (100) [M – Cl]+, 530.3 (3) [M – 2Cl]+.
both isomers), 3.78 (s, 6 H, 2ϫ OMe, both isomers), 4.42 (br., 2
H, CHEt, both isomers), 5.97 (AB, JA,B = 2.0 Hz, 1 H, Cp, isomer
C34H42Cl2O2Ti (601.51): calcd. C 67.89, H 7.04; found C 67.80, H
7.08.
4004
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3997–4007

Biological Activity of sec-Alkyl-Substituted Titanocene Dichlorides
rac/meso-Dichloridobis[1-(3-methylbutyl)-1Ј-(2-methoxyphenyl)-η5- (125.8 MHz, CDCl3, 25 °C): δ = 37.5 (CH2CHCp, isomer 1 or 2)
cyclopentadienyl]titanium (9c): Prepared by using 7c (735 mg,
3.00 mmol, 1.0 equiv.), dry ether (12.1 mL) and nBuLi (2.1 mL,
overlapped by 37.5 (CH2CHCp, isomer 1 or 2), 40.6 (CpCHPh,
both isomers), 55.4 (OMe, both isomers), 111.0 (C-6 Ar, both iso-
3.34 mmol, 1.1 equiv.) to yield 8d (706 mg, 2.84 mmol, 94% yield). mers), 115.2 (br., Cp, isomer 1), 116.1 (CH2C2H3CH, both isomers)
This intermediate (2.84 mmol, 2.0 equiv.) was dissolved in dry THF
(11.5 mL) to give a colourless solution. Titanium tetrachloride
(1.42 mmol, 1.42 mL, 1.0 equiv.) was dissolved in dry THF
(11.5 mL) to give a yellow solution. After purification, a red solid
was obtained (682 mg, 80% based on titanium). The individual rac
and meso diastereomers (1:1 ratio) signals could not be uniquely
identified and are thus identified as isomer 1 or 2, m.p. 161–162 °C.
overlapped by 116.1 (Cp, isomer 2), 117.4 (Cp, isomer 2), 118.4
(Cp, isomer 1), 118.6 (Cp, isomer 1), 119.3 (Cp, isomer 2), 120.6
(C-3 or C-4 Ar, both isomers), 121.8 (Cp, isomer 2), 122.8 (Cp,
isomer 1), 127.8 (C-5 Ar, both isomers), 130.1 (br., ipso-Cp), 131.3
(br., ipso-Cp), 136.4 (CH2CHCH2, both isomers), 141.5 (C-2 Ar,
isomer 1 or 2), 141.7 (C-2 Ar, isomer 1 or 2), 157.2 (C-1 Ar, both
isomers) ppm. IR (ATR): ν = 3074, 2939, 2836, 1639, 1598, 1588,
˜
1H NMR (500.1 MHz, CDCl3, 50 °C): δ = 0.84 (d, J = 6.4 Hz, 6 1492, 1462, 1438, 1421, 1337, 1288, 1275, 1244, 1177, 1123, 1093,
H, CH3CHCH3, both isomers), 0.93 (d, J = 6.8 Hz, 6 H,
1078, 1052, 1030, 995, 960, 907, 847, 816, 786, 753, 732, 718 cm–1.
CH3CHCH3, both isomers), 1.4–1.53 (m, 2 H, CH3CHCH3, both MS (MALDI-TOF, DCTB matrix, 10% laser): m/z (%) = 533.2
isomers), 1.75–2.15 (m, 4 H, CH2CHCp, both isomers), 3.79 (s, 6 (100) [M – Cl]+, 430.3 (6) [M – 2Cl]+. HRMS (ESI+): Calcd. for
H, 2ϫ OMe, both isomers), 4.45–4.85 (br., 2 H, CHiBu, both iso-
mers), 5.94 (s, 1 H, Cp, isomer 1), 6.00 (s, 2 H, Cp, both isomers),
6.16 (s, 1 H, Cp, isomer 2), 6.37 (s, 1 H, Cp, isomer 2), 6.48 (s, 1
H, Cp, isomer 1), 6.65 (s, 1 H, Cp, isomer 2), 6.72 (s, 1 H, Cp,
isomer 1), 6.85–6.95 (m, 4 H, 4-H and 6-H Ar, both isomers), 7.00–
7.15 (br., 2 H, 3-H Ar, both isomers), 7.20 (t, J = 7.6 Hz, 2 H, 5-
H Ar, both isomers) ppm. 13C NMR (125.8 MHz, CDCl3, 25 °C):
δ = 21.8 (CH3CHCH3, both isomers), 24.1 (CH3CHCH3, both iso-
mers), 25.7 (CH3CHCH3, both isomers), 42.8 (CH2CHCp, both
isomers), 55.5 (OMe, both isomers), 111.3 (C-6 Ar, both isomers),
117.5 (br., Cp, isomer 1 or 2), 117.9 (br., Cp, isomer 2), 119.2 (Cp,
isomer 2), 119.8 (Cp, isomer 1), 120.7 (C-3 or C-4 Ar, isomer 1 or
2), 120.9 (Cp, both isomers), 122.7 (Cp, isomer 1), 127.6 (C-5 Ar,
both isomers), 129.9 (br., ipso-Cp, isomer 1 or 2), 132.4 (br., ipso-
Cp, isomer 1 or 2), 142.6 (C-2 Ar, isomer 1 or 2), 143.0 (C-2 Ar,
C32H34Cl2O2TiNa [M + Na]+ 591.1308; found 591.1313.
C32H34Cl2O2Ti (569.43): calcd. C 67.50, H 6.02; found C 67.86, H
6.02.
rac/meso-Dichloridobis[1-ethyl-1Ј-(2-methoxyphenyl)-η5-cyclopenta-
dienyl]titanium (9e): Prepared by using 7e (802 mg, 4.00 mmol,
1.0 equiv.), dry ether (16.0 mL) and nBuLi (2.70 mL, 4.40 mmol,
1.1 equiv.) to yield 8e (738 mg, 89 %). This intermediate
(3.58 mmol, 2.0 equiv.) was dissolved in dry THF (14.0 mL) to give
a colourless solution. Titanium tetrachloride (1.80 mmol, 1.80 mL,
1.0 equiv.) was dissolved in dry THF (14.0 mL) to give a yellow
solution. After purification, a red solid was obtained with a yield
(based on titanium) of 51% (472 mg, 0.91 mmol). The individual
rac and meso diastereomer (1:1 ratio) signals could not be uniquely
identified and are thus identified as isomer 1 or 2, m.p. 144–145 °C.
1H NMR (500.1 MHz, CDCl3, 25 °C): δ = 1.54 (d, J = 7.0 Hz, 3
H, CHMe, isomer 1 or 2) overlapped by 1.55 (d, J = 7.0 Hz, 3 H,
CHMe, isomer 1 or 2), 3.81 (s, 3 H, OMe, isomer 1 or 2) overlapped
by 3.82 (s, 3 H, OMe, isomer 1 or 2), 4.67–4.75 (m, 2 H, CHMe,
both isomers), 6.06 (JA,B = 2.5 Hz, 1 H, Ap, Cp, isomer 1) over-
lapped by 6.08 (AB, JA,B = 2.5 Hz, 1 H, Cp, isomer 2), 6.29 (AB,
isomer 1 or 2), 157.6 (C-1 Ar, both isomers) ppm. IR (ATR): ν =
˜
3105, 2953, 2868, 2838, 1653, 1596, 1586, 1491, 1464, 1438, 1384,
1364, 1327, 1287, 1242, 1187, 1168, 1119, 1097, 1051, 1043, 1028,
906, 848, 828, 806, 754, 717, 702 cm–1. MS (MALDI-TOF, DCTB
matrix, 10% laser): m/z (%) = 565.3 (100) [M – Cl]+, 530.3 (11)
[M – 2Cl]+. C34H42Cl2O2Ti (601.51): calcd. C 67.89, H 7.04; found
C 67.73, H 7.10.
JA,B = 2.5 Hz, 1 H, Cp, isomer 1) overlapped by 6.31 (AB, JA,B
=
2.5 Hz, 1 H, Cp, isomer 2), 6.43–6.46 (m, 2 H, Cp, both isomers),
6.72–6.76 (m, 2 H, Cp, both isomers), 6.84–6.90 (m, 4 H, 4-H and
6-H Ar, both isomers), 6.94 (dd, J = 7.0, 1.5 Hz, 1 H, 3-H Ar,
isomer 1 or 2) overlapped by 6.95 (dd, J = 7.0, 1.5 Hz, 1 H, 3-H
Ar, isomer 1 or 2), 7.19 (ddd, J = 7.0, 6.5, 1.0 Hz, 1 H, 5-H Ar]
overlapped by 7.20 (ddd, J = 7.0, 6.5, 1.0 Hz, 1 H, 5-H Ar) ppm.
13C NMR (125.8 MHz, CDCl3, 25 °C): δ = 19.3 (CHMe, both iso-
mers), 34.5 (CHMe, isomer 1 or 2) overlapped by 34.5 (CHMe,
isomer 1 or 2), 55.4 (OMe, both isomers), 110.9 (C-6 Ar, both iso-
mers), 116.3 (Cp, isomer 1), 116.3 (Cp, isomer 2), 117.2 (Cp, isomer
1), 117.4 (Cp, isomer 2), 119.0 (Cp, isomer 1), 119.4 (Cp, isomer
2), 120.7 (C-3 or C-4 Ar, both isomers), 121.8 (Cp, isomer 2), 122.0
(Cp, isomer 1), 127.5 (C-5 Ar, both isomers), 128.7 (C-3 or C-4 Ar,
both isomers), 134.6 (ipso-Cp, both isomers), 142.2 (C-2 Ar, isomer
1 or 2), 142.5 (C-2, Ar isomer 1 or 2), 156.6 (C-1 Ar, both isomers)
rac/meso-Dichloridobis[1-but-3-en-1-yl-1Ј-(2-methoxyphenyl)-η5-cy-
clopentadienyl]titanium (9d): Prepared by using 7d (1.09 g,
4.8 mmol, 1.0 equiv.), dry methyl tert-butyl ether (19.2 mL) and
nBuLi (3.3 mL, 5.28 mmol, 1.1 equiv.) to yield 8c (785 mg, 71%
yield). This intermediate (3.38 mmol, 2.0 equiv.) was dissolved in
dry THF (13.5 mL) to give a colourless solution. Titanium tetra-
chloride (1.70 mmol, 1.70 mL, 1.0 equiv.) was dissolved in dry THF
(13.5 mL) to give a yellow solution. After purification, a brown
solid was obtained (713 mg, 74% based on titanium). The individ-
ual rac and meso diastereomer (1:1 ratio) signals could not be
uniquely identified and are thus identified as isomer 1 or 2, m.p.
1
139–140 °C. H NMR (500.1 MHz, CDCl3, 25 °C): δ = 2.71–2.83
(m, 2 H, CH2CHCp, isomer 1 or 2), 2.87–2.97 (m, 2 H, CH2CHCp,
isomer 1 or 2), 3.78 (s, 6 H, 2ϫ OMe, both isomers), 4.55–4.70 (m,
2 H, CH2CHCp, both isomers), 4.80–4.85 (br. s, 1 H, CH2C2H3CH,
isomer 1 or 2), 4 (br. s, 1 H, CH2C2H3CH, isomer 1 or 2), 4.92–
4.95 (br. m, 1 H, CH2C2H3CH, isomer 1 or 2), 4.95–4.97 (br. m, 1
H, CH2C2H3CH, isomer 1 or 2), 5.58–5.67 (m, 2 H, CH2CHCH2,
both isomers), 5.98 (AB, JA,B = 2.0 Hz, 1 H, Cp, isomer 1), 6.02
(AB, JA,B = 2.5 Hz, 1 H, Cp, isomer 2), 6.08 (AB, JA,B = 2.0 Hz,
1 H, Cp, isomer 1), 6.18 (AB, JA,B = 2.0 Hz, 1 H, Cp, isomer 2),
ppm. IR (ATR): ν = 3110, 2936, 2834, 1598, 1586, 1491, 1461,
˜
1437, 1421, 1366, 1334, 1290, 1241, 1179, 1123, 1110, 1076, 1043,
1031, 986, 917, 861, 851, 827, 812, 753, 706 cm–1. MS (MALDI-
TOF, DCTB matrix, 10% laser): m/z (%) = 481.1 (100) [M – Cl]+,
446.1 (29) [M – 2Cl]+. HRMS (ESI+): calcd. for C28H30Cl2O2TiNa
[M + Na]+ 539.0995; found 539.1004. C28H30Cl2O2Ti (517.35):
calcd. C 65.01, H 5.85; found C 65.33, H 6.14.
6.41 (AB, JA,B = 2.5 Hz, 1 H, Cp, isomer 2), 6.45 (AB, JA,B
=
rac-Dichloridobis[1-(phenyl)methyl-1Ј-(2-methoxyphenyl)-η5-cyclo-
pentadienyl]titanium (9f): Prepared by using 7f (707 mg, 2.70 mmol,
1.0 equiv.), dry ether (10.8 mL) and nBuLi (1.90 mL, 2.97 mmol,
1.1 equiv.) to yield 8f (568 mg, 78 % yield). This intermediate
2.5 Hz, 1 H, Cp, isomer 1), 6.71–6.73 (2ϫ AB, JA,B = 2.5 Hz, 2 H,
C5H4, both isomers), 6.85–6.91 (m, 4 H, 4-H and 6-H Ar, both
isomers), 6.99–7.05 (t, J = 6.5 Hz, 2 H, 3-H Ar, both isomers), 7.20
(ddd, J = 8.0, 7.5, 1.5 Hz, 2 H, 5-H Ar) ppm. 13 C NMR (2.12 mmol, 2.0 equiv.) was dissolved in dry THF (8.5 mL) to give
Eur. J. Org. Chem. 2013, 3997–4007
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4005

M. Cini, T. D. Bradshaw, W. Lewis, S. Woodward
FULL PAPER
a colourless solution. Titanium tetrachloride (1.05 mmol, 1.05 mL,
1.0 equiv.) was dissolved in dry THF (8.5 mL) to give a yellow solu-
tion. Purification involved the dissolution of the crude red solid
(0.350 g, 66%) in a saturated solution of chloroform (1 part), which
was layered with hexane (4 parts) to give red crystals of rac-9f (con-
firmed by X-ray data) with a yield (based on titanium) of 93.0 mg
(14%). The mother liquors contained a rac/meso mixture of 9f that
could not be brought to a state of analytical purity despite repeated
were calculated by performing MTT assays at time of drug addition
as well as after 72 h exposure.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all compounds prepared in this
study.
Acknowledgments
1
trials, m.p. 244–245 °C. H NMR (500.1 MHz, CDCl3, 25 °C): δ =
3.67 (s, 6 H, 2ϫ OMe), 4.87 (AB, JA,B = 2.5 Hz, 2 H, Cp), 5.97
(br. s, 2 H, CHPh), 5.99 (AB, JA,B = 2.5 Hz, 2 H, Cp), 6.42 (AB,
JA,B = 2.5 Hz, 2 H, Cp), 6.68 (dd, J = 7.5, 1.5 Hz, 2 H, Ph), 6.76
(AB, JA,B = 2.5 Hz, 2 H, Cp), 6.78–6.83 (m, 4 H, 4-H and 6-H Ar),
7.17 (dd, J = 7.5, 1.5 Hz, 1 H, 3-H Ar), 7.18–7.23 (m, 7 H, Ph and
Ar), 7.25 (br. s, 2 H, Ph), 7.26–7.27 (m, 2 H, Ph), 7.27–7.28 (m, 1
H, Ph) ppm. 13C NMR (125.8 MHz, CDCl3, 25 °C): δ = 45.9
(CHPh) 55.4 (OMe), 110.3 (Cp), 110.8 (C-6 Ar), 116.0 (Cp), 120.0
(Ar), 123.7 (Cp), 126.6 (Ar or Ph), 127.9 (Ar or Ph) overlapped by
127.9 (Ar or Ph), 128.8 (Ph), 129.6 (Ph or Ar), 131.8 (Cp), 132.7
(Ph), 140.5 (Ar or Ph), 141.5 (Ar or Ph), 158.7 (C-1 Ar) ppm. IR
M. C. is grateful to the European Union (EU), European Social
Fund for a Strategic Educational Pathways Scholarship (Malta)
(scholarship part-financed by the EU), to the Schools of Chemistry
and Pharmacy University of Nottingham and to the Edith Johnson
Bequest for the provision of studentship support at M.Sc. and
Ph.D. levels, respectively.
[1] H. Köpf, P. Köpf-Maier, Angew. Chem. 1979, 91, 509; Angew.
Chem. Int. Ed. Engl. 1979, 18, 477–478.
[2] For biology overviews, see: a) S. Gómez-Ruiz, D. Maksimovic´-
Ivanic´, S. Mijatovic´, G. N. Kalueerovic´, Bioinorg. Chem. and
Appl. 2012, 140284; b) U. Olszewski, G. Hamilton, Anti-Cancer
Agents Med. Chem. 2010, 10, 302–311.
(ATR): ν = 3119, 2838, 1599, 1584, 1488, 1461, 1452, 1436, 1341,
˜
1319, 1290, 1246, 1187, 1162, 1008, 1075, 1058, 1050, 1029, 953,
940, 898, 847, 837, 826, 794, 783, 765, 751, 735, 728, 700, 686 cm–1.
MS (MALDI-TOF, DCTB/NaI matrix, 25 % laser): m/z (%) =
605.2 (100) [M – Cl]+, 570.2 (7) [M – 2Cl]+. HRMS (ESI+): calcd.
for C38H34Cl2O2TiNa [M + Na]+ 663.1308, found 663.1315.
C39H36Cl4O2Ti (9f dichloromethane monosolvate from CH2Cl2/
hexanes, 726.42): calcd. C 64.49, H 5.00; found C 64.61, H 5.00.
Dichloridobis-1-(2-methoxyphenyl)-(η5-cyclopentadienyl)titanium
(10): Procedure as in literature.[11] The compound had properties
identical to those in the primary literature (13C NMR, IR, MS,
CHN analyses), but its 1H NMR spectrum showed differences in
the multiplicities of the C5H4 “Cp” protons: 1H NMR (500.1 MHz,
CDCl3, 22 °C): δ = 3.84 (s, 6.0 H, 2ϫ OMe), 4.03 (s, 4 H, 2ϫ
CpCH2), 6.33 (t, J = 5.5 Hz, 4 H, 2ϫ Cp), 6.40 (t, J = 5.0 Hz, 4
H, 2ϫ Cp), 6.85–6.92 (m, 4 H, 2ϫ Ar), 7.16 (dd, J = 7.5, 1.5 Hz,
2 H, 6Ј-H), 7.23 (dt, J = 7.5, 1.5 Hz, 2 H, Ar) ppm.
[3] For structure optimisation reviews, see: a) M. Hogan, M.
Tacke, in: Topics in Organometallic Chemistry (Eds.: G. Jaouen,
N. Metzler-Nolte), Springer, New York, 2010, vol. 32, p. 119–
140; b) K. Strohfeldt, M. Tacke, Chem. Soc. Rev. 2008, 37,
1174–1187. Selected recent synthetic developments: c) J. Claf-
fey, H. Müller-Bunz, M. Tacke, J. Organomet. Chem. 2010, 695,
2105–2117; d) M. Napoli, C. Saturnino, E. Sirignano, A. Po-
polo, A. Pinto, P. Longo, Eur. J. Med. Chem. 2010, 46, 122–
128; e) L. M. Gao, J. L. Vera, J. Matta, E. Meléndez, J. Biol.
Inorg. Chem. 2010, 15, 851–859; f) J. Zagermann, A. Deally, N.
Metzler-Nolte, H. Müller-Bunz, D. Wallis, M. Tacke, Polyhe-
dron 2011, 30, 2387–2390; g) J. Ceballos-Torres, S. Gomez-
Ruiz, G. N. Kaluderovic, M. Fajardo, R. Paschke, S. Prashar,
J. Organomet. Chem. 2012, 700, 188–193; h) M. L. Hlavinka,
Q. Yang, M. M. Murph, PCT Int. Appl. WO/2012/170384 A1
20121213, 2012 ; i) A. Deally, F. Hackenberg, G. Lally, H.
Müller-Bunz, M. Tacke, Organometallics 2012, 31, 5782–5790.
[4] For overviews, see: a) R. L. Halterman, Chem. Rev. 1992, 92,
965–94; b) M. Hapke, C. C. Tzschucke, Angew. Chem. Int. Ed.
2013, 52, 3317–3319. for selected recent applications of substi-
tuted CpTi species, see: c) D. J. Cho, C. J. Wu, S. Sujith, W.-S.
Han, S. O. Kang, B. Y. Lee, Organometallics 2006, 25, 2133–
2134; d) A. Gansäuer, M. Otte, L. Shi, J. Am. Chem. Soc. 2011,
133, 416–417; e) A. Gansäuer, A. Okkel, D. Worgull, G.
Schnakenburg, Organometallics 2010, 29, 3227–3230; f) T.
Janssen, R. Severin, M. Diekmann, M. Friedemann, D. Haase,
W. Saak, S. Doye, R. Beckhaus, Organometallics 2010, 29,
1806–1817.
[5] a) M. Welker, S. Woodward, A. Alexakis, Org. Lett. 2010, 12,
576–579; b) X. Tang, A. J. Blake, W. Lewis, S. Woodward, Tet-
rahedron: Asymmetry 2009, 20, 1881–1891; c) X. Tang, S.
Woodward, N. Krause, Eur. J. Org. Chem. 2009, 2836–2844.
[6] For displacement of Cp from CpCu, see: a) A. L. Johnson,
A. M. Willcocks, P. R. Raithby, M. R. Warren, A. J. Kingsley,
R. Odedra, Dalton Trans. 2009, 922–924; b) M. Swart, Inorg.
Chim. Acta 2007, 360, 179–189; c) A. N. Shoshkin, L. N. Boch-
karev, S. Ya. Khorshev, Russ. J. Gen. Chem. 2002, 72, 715–716;
d) A. J. Edwards, M. A. Paver, P. R. Raithby, M.-A. Rennie,
C. A. Russell, D. S. Wright, Organometallics 1994, 13, 4967–
4972; e) H. K. Shin, M. J. Hampden-Smith, E. N. Duesler, T. T.
Kodas, Polyhedron 1991, 10, 645–647; J. E. Maansson, T. Ols-
son, O. Wennerstroem, Acta Chem. Scand., Ser. B 1979, 33,
307–308.
Growth Inhibitory Studies in Vitro: The antiproliferative activity
was evaluated by an MTT [3-(4,5-dimethyl-thiazol-2-yl)-2,5-di-
phenyltetrazolium bromide] assay on three different human carci-
noma cell lines; colon (HCT-116), pancreas (MiaPaCa-2), and
breast (MDA-468). The carcinoma cell lines were maintained in
RPMI 1640 medium supplemented with 10% (v/v) foetal bovine
serum (FBS). The cells were seeded into 96-well plates at a density
of 3ϫ103 per well (180 μL per well) and allowed to adhere for 24 h
at 37 °C/5% CO2. A 10 mm top stock solution in DMSO was then
freshly made. Serial dilutions were prepared in RMPI 1640 medium
supplemented with 10% FBS. Control wells received vehicle alone
(20 μL per well). The final concentrations in the wells were; 0.01,
0.1, 0.5, 1, 5, 10, 50 and 100 μm. The final concentration of DMSO
in the wells never exceeded 1%. Vehicle control assays were per-
formed (0.0001–1% DMSO). Experimental plates were incubated
for a further 72 h period at 37 °C/5% CO2. Cell viability was re-
corded at the time of agent addition (T0) and after 72 h exposure:
following addition of MTT solution (2 mg/mL in PBS: 50 μL per
well), experimental plates were incubated for 3 h to allow reduction
of MTT to insoluble dark purple formazan crystals. The superna-
tant in each well was then aspirated, and cellular formazan was
solubilised by addition of DMSO (150 μL per well). Absorbance
was read at a wavelength of 550 nm by using an Anthos Labtec
systems plate reader. The measured intensity is proportional to
metabolic activity, which correlates to cellular viability. Agent GI50
values (the concentration of agent which inhibits growth by 50%)
[7] J. Honzicek, I. Klepalova, J. Vinklarek, Z. Padelkova, I. Cisa-
rova, P. Siman, M. Rezacova, Inorg. Chim. Acta 2011, 373, 1–
7.
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www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3997–4007

Biological Activity of sec-Alkyl-Substituted Titanocene Dichlorides
[8] B. H. Lipshutz, R. S. Wilhelm, D. M. Floyd, J. Am. Chem. Soc.
1981, 103, 7672–7674.
[13]
G. Keltera, N. J. Sweeney, K. Strohfeldt, H.-H. Fiebig, M.
Tacke, Anti-Cancer Drugs 2005, 16, 1091–1098.
[9] S. Woodward, Tetrahedron 2002, 58, 1017–1050.
[14] Unpaired t-tests were performed by using GraphPad Prism for
Windows, version 6.00, GraphPad Software, San Diego,
www.graphpad.com.
[10] Cambridge
Crystallographic
Data
Centre
(CCDC,
www.ccdc.cam.ac.uk). Structures used were: ECUHEQ, ECU-
JAO, KEDKEJ, MAJMAM and VATWAO.
[11] J. Claffey, M. Hogan, H. Müller-Bunz, C. Pampillón, M.
Tacke, J. Organomet. Chem. 2008, 693, 526–536.
Received: April 2, 2013
Published Online: May 15, 2013
[12] For summaries of cancer therapy data, see: a) www.cancerrese-
archuk.org ; b) K. R. Bauer, M. Brown, R. D. Cress, C. A. Par-
ise, V. Caggiano, Cancer 2007, 109, 1721–1728.
Eur. J. Org. Chem. 2013, 3997–4007
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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