Chemo-, regio-, and stereo-selective perfluoroalkylations by a Grignard complex with zirconocene

Article abstract of DOI:10.1039/c5dt03039k

The synthesis of highly reactive perfluoroalkyl Grignard reagents with early transition metal zirconocene complexes and their new types of highly chemo-, regio-, and stereo-selective perfluoroalkylation reactions are reported with epoxides in particular. The zirconocene complex is advantageous in activating the perfluoroalkyl Grignard species. The zirconocene·Grignard complexes were clarified by DOSY. Both ¹H and ¹⁹F DOSY analyses show that the addition of MAO and dioxane to the mixture of R_FMgCl and Cp₂ZrCl₂ connects Cp₂Zr and R_FMg to generate the zirconocene/perfluoroalkyl-Grignard/dioxane complex.

Full text of DOI:10.1039/c5dt03039k

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Chemo-, regio-, and stereo-selective
perfluoroalkylations by a Grignard complex
with zirconocene†
Cite this: DOI: 10.1039/c5dt03039k
Received 7th August 2015,
Accepted 28th September 2015
Motohiro Fujiu,a Kazuyuki Negishi,a Jie Guang,b Paul G. Williard,b Shigeki Kurokia and
DOI: 10.1039/c5dt03039k
Koichi Mikami*a
www.rsc.org/dalton
The synthesis of highly reactive perfluoroalkyl Grignard reagents
with early transition metal zirconocene complexes and their new
types of highly chemo-, regio-, and stereo-selective perfluoro-
alkylation reactions are reported with epoxides in particular. The
zirconocene complex is advantageous in activating the perfluoro-
alkyl Grignard species. The zirconocene·Grignard complexes were
clarified by DOSY. Both 1H and 19F DOSY analyses show that the
addition of MAO and dioxane to the mixture of RFMgCl and
Cp2ZrCl2 connects Cp2Zr and RFMg to generate the zirconocene/
perfluoroalkyl-Grignard/dioxane complex.
Scheme 1 Summary of Mg/Zr-mediated perfluoroalkylations.
Organofluorine compounds have attracted current interest
because of their important applications in material and bio-
logical sciences.1 Conceptually, carbon–carbon bond for-
mation (CCF) is the most efficient to directly construct the
fluorofunctionalized carbon skeleton of organofluorine com-
pounds. Although the CCF procedures including organoalkali
and organoalkali earth metal reagents are widely utilized for
non-fluorinated compounds, the CCF method using the
corresponding perfluoroalkyl organometallic reagents is often
not applicable to fluorinated counterparts;2 perfluoroalkyl
metal reagents have been recognized unstable and difficult to
prepare because of the facile metal fluoride elimination.
Therefore, a coexisting method of carbonyl electrophile is used
for halogen–metal exchange reaction of perfluoroalkyl halides
and in situ carbonyl addition of perfluoroalkyllithium reagents
thus generated at low temperature.3 In other words, control of
such unstable perfluoroalkyl metal species by coexisting metal
complexes would be effective to synthesize desirable per-
fluoalkylated products. Here we report the synthesis of highly
reactive perfluoroalkyl (RF−) Grignard reagents with early tran-
sition metal zirconocene complex (RFMgCl·Cp2ZrCl2), and
their new types of highly chemo-, regio-, and stereo-selective
Scheme 2
perfluoroalkylation reactions with epoxides in particular. The
perfluoroalkyl heterobimetallic Grignard complexes with
zirconocene show a wide range of reactivity and high selectivity
far beyond the conventional reactions reported on the parent
Grignard reagents (Scheme 1). Although perfluoroalkyl lithium
and Grignard reagents have been used for perfluoroalkylation
of carbonyl derivatives,3 the synthetic methodology could be
developed for other functionality such as epoxides with high
selectivity; reaction of perfluoalkyl reagents with epoxides has
scarcely been studied, whereas that with alkyllithiums is
widely employed (Scheme 1).2–4
In order to explore perfluoroalkyl Grignard reagents associ-
ated with zirconocene complexes, we first examined perfluoro-
alkylation of 17-keto steroid, a problematic enolizable ketone
substrate (Scheme 2);5a in comparison with the yield obtained
only with RFMgCl (60%), the yield was much improved to 91%
with RFMgCl and zirconocene complex. Stereospecific α-face
perfluoroalkylation led to 17β-hydroxy steroid (1a); the cis-
stereochemistry was confirmed by NOE of 18-Me and 17-OH.
aDepartment of Applied Chemistry, Tokyo Institute of Technology, Ookayama 2-12-1,
Meguro-ku, Tokyo 152-8552, Japan. E-mail: mikami.k.ab@m.titech.ac.jp
bDepartment of Chemistry, Brown University, Providence, Rhode Island, USA
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5dt03039k
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Several carbonyl substrates including aldehydes, ketones
and esters were thus investigated (Table 1). Perfluoroalkyl
groups such as C3F7, C6F13 and C8F17 gave perfluoroalkylation
products in good yields (up to 99% isolated yields) (entries
1–5). Another enolizable ketone substrate such as tetralone5b
(1f) afforded virtually quantitative yield (entry 6). Enone
substrates, which present the 1,2- vs. 1,4-regioselectivity
problem, gave 1,2-addition products exclusively in 84% and
95% yields, respectively (entries 7 and 8). Perfluoroalkylation
of aldehydes and ketones gave high yields, even in the steri-
cally demanding adamantanone (1j) (entry 10); the fluorinated
products such as 2j could be used as a more efficient photo-
resistant material than the non-fluorinated counterparts.1,6,7
In contrast to the reaction with C2F5Li,3a the ester (1k) showed
lower reactivity with the Mg·Zr-supported perfluoroethyl anion
and gave the corresponding ketone product in 75% yield (entry
11); the addition of methylaluminoxane (MAO, (Al(CH3)O)n)
led to the increase in yield up to quantitative (vide infra).
More reactive ester, diethyloxalate (1l) gave higher (81%) yield
(entry 12).
The low reactivity of ester enabled us to examine the chemo-
selective perfluoroalkylation (ester vs. aldehyde or ketone)
(Scheme 3). In the presence of the zirconocene complex,
highly chemoselective perfluoroalkylation with formyl and
keto esters (1m and 1n) proceeded to give 2m and 2n. No
addition product to the ester functionality in 1m and 1n was
observed. In the case of cyclic keto ester (1n), remarkably high
diastereoselectivity (>99%) was observed via chelation control.
Relative chelation cis-stereochemistry was determined by NOE
correlation between OH and Me groups in 2n.
Combination of RFMgCl and Cp2ZrCl2 has turned out to be
the efficient perfluoroalkylation system. However, no perfluoro-
alkylation product was obtained when RFLi was used instead
of RFMgCl with Cp2ZrCl2 (Scheme 4).8 These results support
that perfluoroalkyl groups are transmetalated not from mag-
nesium but from lithium to end up with the reported facile
Zr–F elimination;9 because of the strong electron-withdrawing
nature of fluorine, perfluoroalkyl groups are not nucleophilic
enough to promote efficient transmetalation from magnesium
to zirconium. Furthermore, alkylzirconocene reagents have
been reported to be not reactive with carbonyl electrophiles in
the absence of silver salts (e.g. AgClO4).10,11
Since the perfluoroalkylation gave high yields with carbonyl
substrates, this reaction system was applied to epoxides. To
our delight, the perfluoroalkylation product was obtained in
moderate yield (Scheme 5), however, not as the direct opening
product (5) but as the migratory perfluoroalkylation product
(4a). Small amount of chlorohydrine (6) was also observed as a
side product.
Table 1 Perfluoroalkylation of carbonyl compounds
Entry
1
Substrate
Product
% Yield [ ]a
91 [99]
2
3
99 [99]
97 [91]
4
5
96 (67 : 33) [79]
72 [52]
6
7
93 [99]
95 [80]
8
9
84 [94]
83 [76]
10
11
84 [92]
75 (99)b [71]
The selectivity of perfluoroalkylcarbinol (4a) and chloro-
hydrine (6) can be rationalized by benzyl cation intermediates
associated with zirconocene complexes (Scheme 6) leading to
the formation of aldehydes via pinacol-type 1,2-hydride
shift11,12 and eventually perfluoroalkylcarbinol (4a) (path 1).
Chlorohydrine (6) may be formed by trapping with chloride
(Cl−) (path 2).
12
81 [69]
a Ref. 4. b With methylaluminoxane (MAO, (Al(CH3)O)n).
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Table 2 Screening of additives
Entry
Additive
Yield/%
1
2
3
4
—
43
0
27
75
88
60
78
AgClO4
BF3·Et2O
Et2AlCl
MAO
MAO
MAO
Scheme 3
5
6a
7b
a Without 1,4-dioxane. b Without Cp2ZrCl2.
nol (entry 4). Furthermore, MAO (vide supra), which has been
reported to generate cationic zirconocene species by abstraction
of one chloride and promotes olefin polymerizations14 and
carbometalations of alkynes,15 gave the highest yield of 4a
(entry 5), by the highly active cationic zirconocene complexes
(see diffusion-ordered NMR spectroscopy (DOSY) experiments).
Under the optimized reaction conditions, the migratory
and, hence, regioselective perfluoroalkylation of epoxides was
further executed with a variety of perfluoroalkyl Grignard
reagents (Table 3). In the reaction of styrene oxide (3a) in the
presence of MAO, the epoxide opening gave good yield (entry
1). In the epoxide (3b) with an electron-donating p-OMe substi-
tuent, perfluoroalkylation reaction proceeded even in the
absence of MAO though in slightly lower yield (entry 2).
Epoxide substrates, generating allylic or propargylic cations,
also gave high yields of the migratory perfluoroalkylation pro-
ducts in the presence of MAO (entries 3–5 and 8–10). Ketonic
intermediate derived from epoxide 3f also provided good yield
of perfluoroalkylation product (entry 6). However, epoxide
without conjugated olefin or acetylene didn’t provide any
product (entry 11).
Scheme 4
Scheme 5
The zirconocene complex16 is thus advantageous in activat-
ing the perfluoroalkyl Grignard species, as reported for
MeMgCl·MgCl2 in the Schlenk equilibrium.17 The zirconocene/
Grignard complexes were clarified by DOSY at −70 °C (see
ESI†).18,19 Both 1H and 19F DOSY analyses were performed
with the standard programs, employing a double stimulated
echo sequence, bipolar gradient pulses for diffusion, and 3
spoil gradients (dstebpgp3s).20 In 19F DOSY, MW of C4F9Mg
was increased by 18% through adding 1 eq. of MAO and
by 24% through adding MAO and dioxane (1 eq. each). In
1H DOSY, MW of Cp2Zr was also increased via addition of
dioxane.21,22 By combining these experimental observations,
we support that MAO and dioxane connect the Zr and Mg
species to form a unique heterobimetallic (Zr and Mg)
system with higher reactivity and selectivity, although we have
indirect evidence from the diffusion experiments.17 It is thus
likely that the addition of MAO and dioxane to the mixture of
Scheme 6
Screening of an additive led to the significant increase in
yields of perfluoroalkylation products of epoxides (Table 2). Use
of AgClO4 gave no perfluoroalkyl adduct (entry 2). BF3·Et2O13
provided a small amount of the perfluoroalkylated product
(entry 3), and Et2AlCl increased the yield of perfluoroalkyl carbi-
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RfMgCl and Cp2ZrCl2 connects Cp2Zr and RfMg to generate
the zirconocene/perfluoroalkyl Grignard/dioxane complex.
In conclusion, we have reported the highly chemo-, regio-,
and stereo-selective heterobimetallic perfluoroalkyl Grignard
zirconocene complexes. The unique reactivity and high selecti-
vity of the heterobimetallic complexes are thus highlighted by
the new type of highly regioselective perfluoroalkylation of
epoxides, in particular.
Table 3 Perfluoroalkylation of epoxides
Entry Substrate
1
Product
% Yield [ ]a
88 [27]
Notes and references
2b
74
71
78
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Avance III HD 600 MHz spectrometer. For DOSY experi-
ments, a z-axis gradient amplifier was equipped with
a z-axis gradient coil with maximum gradient strength
0.5 T m−1. A standard pulse program dstebpgp3s was
selected, employing a double stimulated echo sequence,
bipolar gradient pulses for diffusion, and three spoil
gradients.
20 For 1H DOSY: Diffusion time was 100 ms, and the rectangu-
lar gradient pulse duration was 1000 μs. For 19F DOSY:
Diffusion time was 60 ms, and the rectangular gradient
pulse duration was 800 μs.
21 To a test tube equipped with a magnetic stir bar was added
Cp2ZrCl2 (70.2 mg, 0.24 mmol), Et2O (2.4 ml), 2M nBuMgCl
in Et2O (0.12 ml, 0.24 mmol), 1,4-dioxane (21 μL,
0.24 mmol), and nC3F7I (35 μl, 0.24 mmol) at −78 °C under
argon atmosphere. After stirring at −78 °C for 1 h, methyl-
aluminoxane (10 wt% in toluene, 0.16 mL, 0.24 mmol) and
benzotrifluoride (10 μl as an internal standard) were
added. The mixture was stirred at 0 °C for 2 min, and
cooled to −78 °C again. The reaction mixture was trans-
ferred to NMR tube cooled to −78 °C by cannula under
argon atmosphere.
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no (RF)2Mg was observed in the perfluoroalkyl case.
Furthermore, no methylation product was observed in the
presence of MAO.
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