Paradigm shift from alkaline (earth) metals to early transition metals in fluoroorganometal chemistry: Perfluoroalkyl titanocene(III) reagents prepared via not titanocene(II) but titanocene(III) species

Article abstract of DOI:10.1002/chem.201303089

Perfluoroalkyl (R_F) titanocene reagents [Cp₂Ti ^IIIR_F] synthesized via [Cp₂Ti^IIICl] rather than [Cp₂Ti^II] show new types of perfluoroalkylation reactions. The [Cp₂Ti^IIIR_F] reagents exhibit a wide variety of reactivity with carbonyl compounds including esters and nitriles, and selectivities far higher than those reported for conventional R_FLi and R_FMgX reagents. Copyright

Full text of DOI:10.1002/chem.201303089

DOI: 10.1002/chem.201303089
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&
Perfluoroalkylation
Paradigm Shift from Alkaline (Earth) Metals to Early Transition
Metals in Fluoroorganometal Chemistry: Perfluoroalkyl
Titanocene(III) Reagents Prepared via Not Titanocene(II) but
Titanocene(III) Species
Motohiro Fujiu, Ryota Hashimoto, Yuzo Nakamura, Kohsuke Aikawa, Shigekazu Ito, and
Koichi Mikami*[a]
Abstract: Perfluoroalkyl (RF) titanocene reagents [Cp2TiIIIRF]
synthesized via [Cp2TiIIICl] rather than [Cp2TiII] show new
types of perfluoroalkylation reactions. The [Cp2TiIIIRF] re-
agents exhibit a wide variety of reactivity with carbonyl
compounds including esters and nitriles, and selectivities far
higher than those reported for conventional RFLi and RFMgX
reagents.
Introduction
tions: perfluoroalkylation of nitriles and carbonyl compounds
including esters. The present work can thus be regarded as
a paradigm shift from alkaline (earth) metals to early transition
metals in fluoroorganometal chemistry. The perfluoroalkyl
titanium(III) reagents show a wide range of reactivity and far
higher selectivity than conventional reactions reported for per-
fluoroalkyl lithium and Grignard reagents (Scheme 1).
Organofluorine compounds have attracted great interest in
recent years because of their important applications in materi-
als[1] and biological[2] sciences. Generally, synthetic methods for
fluorine-containing compounds are classified into 1) carbon–
fluorine bond-forming reactions with fluorinating reagents,[3]
2) carbon–carbon bond-forming reactions with fluoroalkylating
reagents,[4] and 3) carbon–carbon bond-forming reactions em-
ploying fluorine-containing building blocks, for example, fluori-
nated carbonyl compounds.[5] The carbon–carbon bond-forma-
tion (CCF) method is among the most efficient in construction
of the target carbon skeleton and fluorofunctionalization
thereof. However, the CCF method based on anionic fluoroalk-
yl metal reagents such as alkyl lithium compounds, which have
been widely employed for nonfluorinated systems, is often not
applicable to fluorinated counterparts. Perfluoroalkyl (RF) metal
reagents are generally recognized as unstable and difficult to
prepare because of facile a- or b-metal fluoride (MF) elimina-
tion.[6] Therefore, a coexisting carbonyl electrophile is em-
ployed for in situ halogen–metal exchange reactions of per-
fluoroalkyl halides and subsequent carbonyl addition of per-
fluoroalkyl lithium reagents at low temperature.[7] Herein, we
report the in situ preparation of perfluoroalkyl titanocene re-
agents not via titanocene(II) species but via titanocene(III)
monochloride, and their new types of perfluoroalkylation reac-
Scheme 1. Reactions of perfluoroalkyl titanium(III) reagents.
Results and Discussion
We first thought that perfluoroalkyl titanocene reagents with
electron-donating and sterically demanding Cp ligands could
stabilize the unstable perfluoroalkyl metal reagents by prevent-
ing a- or b-fluoride elimination through electronic and steric
shielding effects (Scheme 2).[8] The perfluoroalkyl titanocene
halide reagents would be synthesized by oxidative addition of
perfluoroalkyl halides to the widely employed titanocene(II)
species generated with two equivalents of alkyl metal species
such as alkyl lithium and Grignard reagents according to the
general preparative procedures.[9]
[a] M. Fujiu, R. Hashimoto, Y. Nakamura, Prof. Dr. K. Aikawa, Prof. Dr. S. Ito,
Prof. Dr. K. Mikami
Department of Applied Chemistry
Tokyo Institute of Technology
Tokyo 152-8552 (Japan)
Fax: (+81)3-5734-2776
E-mail: mikami.k.ab@m.titech.ac.jp
First, we attempted to synthesize perfluoroalkyl titanocene
reagents by treating titanocene(IV) dichloride with two equiva-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303089.
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Scheme 3. Halogen–metal exchange with the remaining Grignard reagent.
agent gives the perfluoroalkyl Grignard reagent by halogen–
metal exchange with the perfluoroalkyl iodide at À508C
(Scheme 3), and thus a 1:1 mixture of the perfluoroalkylation
and alkylation products results. Indeed, 1H NMR analysis of
a mixture of two equivalents of the alkyl Grignard reagent, per-
fluoroalkyl iodide, and titanocene(IV) dichloride prior to the ad-
dition of benzaldehyde showed the formation of one equiva-
lent of 1-iodobutane (nBuI) by halogen–metal exchange reac-
tion.
Scheme 2. Attempted synthesis and reactions of perfluoroalkyl titanocene
reagents.
Table 1. Synthesis and reactions of perfluoroalkyl titanium(III) reagents
with benzaldehyde (1a).
The question arises why iPrMgCl gave a quantitative yield of
perfluoroalkylation product, in contrast to the 1:1 mixture of
perfluoroalkylation and alkylation products obtained with
nBuMgCl. To gain an insight into the reaction mechanism, per-
fluoroalkylation reactions of an aldehyde and a nitrile were car-
ried out with two equivalents of iPrMgCl or nBuMgCl with or
without raising the reaction temperature to ambient tempera-
ture (Schemes 4–6).
Entry
RM
Yield of 2a [%]
Yield of 3 [%]
Yield of 4 [%]
1
2
3
nBuLi
nBuMgCl
iPrMgCl
0
0
48[a]
0
40[a]
quant.
48[a]
0
0
1
[a] Determined by H NMR analysis.
lents of nBuLi, nBuMgCl, or iPrMgCl at À788C and subsequent
oxidative addition of perfluoroalkyl halides to the titanocene(II)
species formed on increasing the temperature to À508C
(Table 1).[10–13] With nBuLi, however, no perfluoroalkylation was
observed in the reaction with benzaldehyde (1a), and pinacol
coupling product 4 was obtained instead (Table 1, entry 1). The
corresponding Grignard reagent nBuMgCl led to perfluoroalky-
lation product 2a along with alkylation product 3a in a ratio
of 1:1 (Table 1, entry 2). In contrast, iPrMgCl gave a quantitative
yield of isolated perfluoroalkylation product 2a (Table 1,
entry 3).
The following findings are significant: The fact that nBuLi
solely provided the pinacol coupling product implies that
CF3(CF2)5I did not oxidatively add to the titanocene(II) species
generated with two equivalents of nBuLi. The titanocene(II)
species gave pinacol coupling product 4 by single-electron
transfer (SET) to benzaldehyde (Table 1, entry 1). Attempted re-
duction of the titanocene(IV) dihalide with two equivalents of
nBuMgBr at À788C gave no pinacol coupling product but
a 1:1 mixture of perfluoroalkylation product 2a and alkylation
product 3a (Table 1, entry 2). This result indicates no reduction
to the titanocene(II) species but halogen–metal exchange reac-
tion of CF3(CF2)5I with the Grignard reagent. Butyllithium is
more nucleophilic than the corresponding Grignard reagent
and hence bis-transmetalates the titanocene(IV) species to
eventually give the low-valent titanocene(II) species
(Scheme 2). In contrast, at low temperature (À788C), only one
equivalent of the less nucleophilic Grignard reagent transmeta-
lates [Cp2TiCl2], the remaining equivalent of the Grignard re-
Scheme 4. Temperature effect on the perfluoroalkylation of benzaldehyde.
Even with two equivalents of iPrMgCl, a mixture of perfluor-
oalkylation product 2a and alkylation product 3b was ob-
tained at À788C to room temperature (Scheme 4). At low reac-
tion temperature, the iPr group could be retained on the tita-
nium center to give isopropyl carbinol 3b, as opposed to ex-
clusive formation of perfluoroalkylation product 2a on raising
the reaction temperature to À508C.
The reaction of the nitrile with two equivalents of nBuMgBr,
which gave a 1:1 mixture of perfluoroalkylation and alkylation
products of benzaldehyde at low temperature, resulted in con-
trast in quantitative formation of perfluoroalkylation product
5a on warming to ambient temperature (Scheme 5). However,
perfluoroalkyl Grignard and monoalkyl titanocene(IV) re-
agents[14] did not give the (perfluoro)alkylation products of ni-
triles.
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Scheme 5. Quantitative perfluoroalkylation of a nitrile.
Scheme 7. Reaction of a perfluoroalkyl titanocene(III) species with a nitrile.
cies, which is now reactive even with nitriles (step 4). These re-
sults indicate the formation of perfluoroalkyl titanocene(III)
species.
Scheme 6. Temperature effect on the perfluoroalkylation of a nitrile.
The Lewis acidity of perfluoroalkyl titanocene reagents was
found to be increased by the electron-withdrawing perfluor-
oalkyl group, and they smoothly underwent addition reactions
to carbonyl compounds and nitriles (Scheme 1). The high reac-
tivity of perfluoroalkyl titanocene reagents is in sharp contrast
to alkyl zirconocene and titanocene reagents, which did not
react with these electrophiles in the absence of methylalumi-
noxane or silver perchlorate.[9,16] We have thus developed reac-
tive perfluoroalkyl titanocene(III) reagents, starting from two
equivalents of isopropyl Grignard reagent, titanocene dichlor-
ide, and perfluoroalkyl halides, not by oxidative addition of
perfluoroalkyl halides to the widely employed titanocene(II)
species but via titanocene(III) monochloride.
On increasing the reaction temperature to ambient tempera-
ture, the active perfluoroalkyl titanocene species could be gen-
erated even with two equivalents of nBuMgCl (Scheme 6). This
transformation is quite similar to that in the mixture of two
equivalents of isopropyl Grignard reagent, perfluoroalkyl
iodide, and [Cp2TiCl2].
The question remains whether b-hydride elimination or re-
duction of Cp2TiIV to Cp2TiIII provides the active perfluoroalkyl
titanocene species on raising the reaction temperature. The
1H NMR spectrum of a mixture of two equivalents of iPrMgCl,
perfluoroalkyl iodide, and titanocene(IV) dichloride did not
show any formation of propene (dꢀ4.8–5.8 ppm) by b-hydride
elimination. Moreover, the use of two equivalents of cyclohexyl
Grignard reagent instead of iPrMgCl did not result in a signal
for the higher-boiling cyclohexene at dꢀ5.7 ppm.
Several carbonyl substrates 1 including aldehydes and ke-
tones were then investigated (Table 2). The addition to aromat-
ic and aliphatic aldehydes of other perfluoroalkyl groups such
as C3F7 and C4F9 also gave perfluoroalkylated products in 81
and 79% yield, respectively (Table 2, entries 1 and 2). Even
ketone substrates such as a-tetralone and 17-keto steroid,
which are problematic owing to their easily enolizable
nature,[17] afforded virtually quantitative yields, much higher
than those obtained with the corresponding lithium and
Grignard reagents (Table 2, entries 4 and 9). a-Face-selective
perfluoroalkylation leading to 17b-hydroxy steroid 2j was con-
firmed by NOE correlation of 18-Me and 17-OH. Enone sub-
strates, which show the problem of 1,2- versus 1,4-addition,
chemoselectively gave 1,2-addition products in 80 and 94%
yield, respectively (Table 2, entries 5 and 6).
To clarify the intermediacy of perfluoroalkyl titanium(III) re-
agents, [Cp2TiIIICl] was prepared as a green solution according
to the literature procedure[15] from [Cp2TiCl2] and one equiva-
lent of iPrMgCl at room temperature. The separately prepared
perfluoroalkyl Grignard reagent was added to the solution of
[Cp2TiIIICl] at À788C. After stirring the mixture at À508C for
2 h, b-phenylpropionitrile was added to give perfluoroalkyla-
tion product 5a in 57% yield (Scheme S1 in the Supporting In-
formation). Alternatively,
a mixture of [Cp2TiCl2], iPrMgCl
(2 equiv), and perfluorohexyl iodide prepared at À508C gener-
ated a paramagnetic species that was observable by EPR spec-
troscopy at ambient temperature and indicated the presence
of TiIII species. These findings could be explained as follows: As
shown in Scheme 7, only one of the two equivalents of the
Grignard reagent transmetalates [Cp2TiIVCl2] at low temperature
(step 1). Addition of RFI to the mixture containing the remain-
ing Grignard reagent leads to the formation of the perfluor-
oalkyl Grignard reagent via halogen–metal exchange reaction
(step 2). On increasing the reaction temperature, [Cp2TiIVRCl] is
reduced to [Cp2TiIIICl][15] (step 3). Transmetalation of the per-
fluoroalkyl Grignard reagent provides the active [Cp2TiIIIRF] spe-
The reaction of ester 6a with more than two equivalents of
perfluoroalkyl titanocene(III) species selectively provided per-
fluoroalkyl ketone 7a in high yield rather than the tertiary alco-
hol (Scheme 8). There has been no report, however, on the re-
action of esters with alkyl or even allyl titanocene(III or IV) re-
agents. The specific formation of perfluoroalkyl ketones is in
sharp contrast to reports by Gassman and O’Reilly on perfluor-
oalkyl lithium species providing ketones or tertiary alcohols,
depending on the aliphatic and aromatic ester substrates em-
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Table 2. Perfluoroalkylation of
a
variety of carbonyl compounds.
Table 3. Perfluoroalkylation
of
a
variety
of
esters.
Entry
1
Substrate
Product
Yield [%]
71
Entry Substrate
1
Product
Yield [%]
81
2
3
quant.
80
2
3
79 (68:32)[a]
52
4
5
69
90
4
quant.
5
6
80
94
6
69
7
8
76
92
smoothly proceeded to provide the corresponding perfluoroal-
kylated ketones 7, irrespective of the type of ester substrate
(Table 3). Aromatic and aliphatic esters led to the desired prod-
ucts in good to excellent yields (Table 3, entries 1–3). In addi-
tion, diethyl oxalate and lactones afforded the hydrate (Table 3,
entry 4) and hemiacetals (Table 3, entries 5 and 6), respectively.
quant.
(>99:1)[a]
9
Conclusion
[a] Ratio of diastereomers.
We have uncovered the synthesis of perfluoroalkyltitanocene
reagents, not via titanocene(II) species but via titanocene(III)
monochloride. The unique reactivity and high selectivity of the
perfluoroalkyltitanocene(III) reagents is highlighted by new
types of perfluoroalkylation reactions of carbonyl compounds
including esters and nitriles. This new and unique method can
be applied for (asymmetric) trifluoromethylation, which will be
reported in due course. The perfluoroalkyltitanocene(III) re-
agents are thus instrumental in initiating a paradigm shift in
fluoroorganometal chemistry.
Scheme 8. Specific perfluoroalkylation of esters leading to ketones.
Experimental Section
General procedure for perfluoroalkylation of aldehydes, ke-
tones, and esters
ployed, respectively.[7] In addition to the strong affinity of tita-
nium for oxygen, the highly electron-withdrawing nature of
the perfluoroalkyl group and steric shielding effect of the Cp
ligand on titanium are the key to stabilizing the tetrahedral in-
termediate A leading eventually to perfluoroalkyl ketones such
as 7a in high yield (Scheme 8). Reactions with esters 6
iPrMgCl (2.0m in Et2O, 0.24 mL, 0.48 mmol), 1,4-dioxane (46 mL,
0.54 mmol), and perfluorohexyl iodide (78 mL, 0.36 mmol) were
added to a solution of [Cp2TiCl2] (59.8 mg, 0.24 mmol) in Et2O
(2.4 mL) at À788C. After stirring at À508C for 2 h, benzaldehyde
(1a; 20 mL, 0.20 mmol) was added and the mixture stirred at room
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temperature for 2 h. The mixture was quenched with 1N HCl and
extracted three times with Et2O. The combined organic layers were
dried over Na2SO4 and the solvent was removed in vacuo. The
crude product was purified by silica-gel column chromatography
(hexane/AcOEt 20/1) to give 2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-1-
phenylheptan-1-ol (2a) in quantitative yield (85.2 mg).
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iPrMgCl (2.0m in Et2O, 0.24 mL, 0.48 mmol) and then perfluorohex-
yl iodide (78 mL, 0.36 mmol) were added to a solution of [Cp2TiCl2]
(59.8 mg, 0.24 mmol) in Et2O (2.4 mL) at À788C. After stirring at
À508C for 2 h, b-phenylpropionitrile (26 mL, 0.20 mmol) was added
and the mixture stirred at room temperature for 2 h. The mixture
was quenched with 1N HCl and extracted three times with Et2O.
The combined organic layers were dried over Na2SO4 and the
solvent was removed in vacuo. The crude product was purified
by silica-gel column chromatography (hexanes) to give
4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-1-phenylnonan-3-one (5a) in
quantitative yield (90.4 mg).
Keywords: alkylation · fluorine · metallocenes · synthetic
methods · titanium
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Published online on January 23, 2014
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