Perfluoroalkyl and -aryl Zinc Ate Complexes: Generation, Reactivity, and Synthetic Application

Article abstract of DOI:10.1002/chem.201501811

A combination of dimethylzinc, perfluoroalkyl iodide, and LiCl afforded a new type of perfluoroalkyl (R_F) zinc ate complex. These complexes show much greater thermal stability than conventional perfluorinated metal species, such as R_F-lithium species and Grignard reagents, and they can be used at room temperature or higher. The results of DFT calculations on the origin of the enhanced stability are reported and the synthetic utility of R_F-zincate complexes is demonstrated. The magnificent ate: A combination of dimethylzinc, perfluoroalkyl iodide, and LiCl afforded a new type of perfluoroalkyl (R_F) zinc ate complex. These complexes show greater thermal stability than conventional perfluorinated metal species and they can be used at room temperature or higher. The results of DFT calculations on the origin of the enhanced stability are reported and the synthetic utility of R_F-zincate complexes is demonstrated.

Full text of DOI:10.1002/chem.201501811

DOI: 10.1002/chem.201501811
Communication
&
Ate Complexes |Hot Paper|
Perfluoroalkyl and -aryl Zinc Ate Complexes: Generation,
Reactivity, and Synthetic Application
Xuan Wang,[a] Keiichi Hirano,*[a, b] Daisuke Kurauchi,[a] Hisano Kato,[a] Naoyuki Toriumi,[a]
Ryo Takita,[b] and Masanobu Uchiyama*[a, b]
In memory of Prof. Dr. Manfred Schlosser
Abstract: A combination of dimethylzinc, perfluoroalkyl
iodide, and LiCl afforded a new type of perfluoroalkyl (RF)
zinc ate complex. These complexes show much greater
thermal stability than conventional perfluorinated metal
species, such as RF–lithium species and Grignard reagents,
and they can be used at room temperature or higher. The
results of DFT calculations on the origin of the enhanced
stability are reported and the synthetic utility of RF-zincate
complexes is demonstrated.
Fluoroalkyl and -aryl motifs[1] are found in biologically impor-
tant[2] as well as functional materials.[3] Although numerous
Scheme 1. Perfluoroalkyl organometallic species.
synthetic methods for the installation of fluorine atoms into or-
ganic molecules have been developed over decades, the ma-
jority of them involve fluorination or trifluoromethylation.[4]
Perfluoroalkylation has attracted significantly less attention.[5–7]
Since the halogen–metal exchange reaction of organohalides
was pioneered by Gilman and Wittig,[8] generation methods
and synthetic applications of organolithium species and
Grignard reagents have been intensively investigated. Methods
for preparation of RF–Li and RF–MgX (Grignard reagents) by
halogen–metal exchange with perfluoroalkyl iodide (RF–I) in
combination with organolithium[9] or organomagnesium[10] re-
agents have also been established. However, these reagents
are very unstable and decompose via a- or b-elimination of
fluoride anion (Scheme 1). Consequently, these reagents can
be handled only at extremely low temperature and this limits
their practical application in synthetic organic chemistry.
fluoroalkylation, we started to examine the feasibility of achiev-
ing highly efficient and operationally benign perfluoroalkyla-
tion reactions by utilizing the high tunability of organozinc re-
agents.[12] Since Naumann and Lange reported that the halo-
gen–zinc exchange reaction proceeds between dialkylzinc and
RF–I and the resulting RF–Zn reagent is stable in the presence
of Lewis base(s),[13] this strategy was extensively adopted by
several research groups, including ours, to prepare and utilize
RF–Zn reagents.[14,15] Herein, we report the generation of RF–
zincate complexes by halogen–zinc exchange and demonstrate
their utility in organic synthesis.
In the initial screening to find suitable reagents, we pre-
pared various RF–organozinc reagents and assessed their reac-
tivity in the iodine–zinc exchange reaction with nonafluorobu-
tyl iodide at 08C, followed by in situ trapping with benzalde-
hyde at room temperature (Table 1). However, initial attempts
using various zincates, including mono-anionic zincates such
as Me3ZnLi (Table 1, entry 1) and di-anionic zincates such as
Me4ZnLi2 developed in our laboratory (entry 2),[11i] were unsuc-
cessful at room temperature, although at À788C 1a was ob-
tained in 73% and 62% yield, respectively. Gratifyingly, Me2Zn
prepared from ZnCl2 and 2 equivalents of MeLi afforded the
desired perfluoroalkylated product 1a in 62% yield without
any methylated byproduct formation (Table 1, entry 4), where-
as MeZnCl did not work (entry 3). The LiCl-free solution of
Me2Zn was totally unproductive (Table 1, entry 5). Addition of 2
equivalents of LiCl to the reaction of entry 3 gave 1a in 43%
yield (Table 1, entry 6).[16] Given Koszinowski’s reports[17] on the
formation of [Bu2ZnCl]Li as the sole species by complexation
of Bu2Zn with LiCl and our experimental results, we hypothe-
For over a decade, we have been working on organozincate
chemistry[11] and, given the paucity of general methods of per-
[a] Dr. X. Wang, Dr. K. Hirano, D. Kurauchi, H. Kato, N. Toriumi,
Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: k1hirano@mol.f.u-tokyo.ac.jp
uchiyama@mol.f.u-tokyo.ac.jp
[b] Dr. K. Hirano, Dr. R. Takita, Prof. Dr. M. Uchiyama
Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable
Resource Science, and Elements Chemistry Laboratory, RIKEN
2-1 Hirosawa, Wako-shi, Saitama 351-0198 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501811.
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(15.2 kcalmolÀ1) are small, allowing the reactions to proceed
easily even at low temperature [Figure 1, Eq. (1) and (2)]. How-
ever, b-elimination of [C2F5ZnMeCl]Li is not likely to occur at
room temperature [DE=28.5 kcalmolÀ1; Figure 1, Eq. (3)] and
this result is in agreement with our experimental results.
C2F5ZnMe2Li has a larger activation barrier than C2F5Li and
C2F5MgCl (DE=23.8 kcalmolÀ1), but is not sufficiently stabilized
to prevent the extrusion of tetrafluoroethylene at room tem-
perature [Figure 1, Eq. (4)].
Table 1. Preparation of RF–zinc reagents via the iodine–zinc exchange re-
action and their trapping with benzaldehyde.
Entry
Zinc reagent
Prepared from:
Yield [%][a]
1
2
3
4
5[d]
6[d]
Me3ZnLi
Me4ZnLi2
MeZnCl
Me2Zn
Me2Zn
Me2Zn·LiCl
ZnCl2 +3MeLi
ZnCl2 +4MeLi
ZnCl2 +MeLi
ZnCl2 +2MeLi
–
0[b] (73)[c]
0[b] (62)[c]
0
62
0
After exhaustive optimization of alkyl ligands on zinc, sol-
vents, and salts for activation, the combination of Me2Zn and
LiCl in THF was found to be optimal[21] and the scope of the
perfluoroalkylation with [RFZnMeCl]Li was examined (Table 2).
Nonafluorobutyl iodide and its higher analogues afforded the
corresponding products in high yields (Table 2, entries 1–3).
Me2Zn+2LiCl
43
[a] Yield of isolated product. [b] Iodine–zinc exchange was carried out at
À788C. [c] The reaction mixture was kept at À788C. [d] Commercial LiCl-
free Me2Zn solution was used.
Table 2. Reaction with various perfluoroalkyl/aryl halides.
sized that the chloride anion coordinates to dimethylzinc to
afford a zinc ate complex, [Me2ZnCl]Li,[14a,b] which is reactive
enough to undergo iodine–zinc exchange[11i,18] to form
[RFZnMeCl]Li, thereby enabling the subsequent addition reac-
tion to benzaldehyde.[19]
Entry
RF–X
Yield [%][a]
89
Entry
RF–X/ArF–X
n-C8F17Br
C6F5I
Yield [%][a]
The unusual stability of [RFZnMeCl]Li in comparison with RF–
lithium species and RF–Grignard reagents was investigated by
means of DFT calculations on the b-elimination pathway at the
B3LYP/631SVP level of theory (Figure 1).[20] Pentafluoroethyl
group (C2F5) and dimethyl ether were used as simplified
models of the RF groups and THF, respectively. Activation barri-
ers for b-elimination of C2F5Li (13.9 kcalmolÀ1) and C2F5MgCl
1
2
3
n-C4F9I
n-C6F13I 90
n-C8F17I 91
4
5
35
92
[a] Yield of isolated product. [b] Iodine–zinc exchange was carried out at
À788C. [c] The reaction mixture was kept at À788C. [d] Commercial LiCl-
free Me2Zn solution was used.
The reaction with nonafluorobu-
tyl bromide gave the product in
a lower yield of 35%, possibly
due to sluggish bromine–zinc
exchange at 08C (Table 2,
entry 4). Surprisingly, a branched
perfluoroalkyl iodide, i-C3F7I, did
not give the desired product.
Notably, perfluoroarylation pro-
ceeded cleanly in 92% yield with
pentafluoroiodobenzene
(Table 2, entry 5). Pentafluoro-
phenyllithium is known to de-
compose to afford tetrafluoro-
benzyne, and must be handled
at low temperature.[22] Our zin-
cate can be utilized at room
temperature without formation
of any byproduct and this enor-
mously enhances the practicality
of this method.
Perfluoroalkylation and -aryla-
tion under these conditions ex-
hibits a broad substrate scope
for electrophiles (Table 3). ortho-
Substitution of benzaldehyde
Figure 1. Stability of RF–metal species accessed by DFT calculations at the B3LYP/631SVP level. Energy changes are
shown in kcalmolÀ1 and bond lengths in Š.
was not deleterious (1b and
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hexane, 1.0 mmol) were added. Nonafluorobutyl iodide (415 mg,
1.2 mmol) was then added to the mixture at 08C and stirred for
1 h. Benzaldehyde (127 mg, 1.2 mmol) was then added at 08C and
the resultant mixture was stirred at room temperature for 3 h, fol-
lowed by quenching with saturated aqueous NH4Cl solution
(5 mL). The crude mixture was extracted with diethyl ether (2”
30 mL), the combined organic phases were washed with brine
(30 mL) and dried over MgSO4. After removal of volatiles under re-
duced pressure, the residue was purified by silica-gel column chro-
matography (hexane/ethyl acetate=96:4) to give 1-phenyl-
Table 3. Perfluoroalkylation and -arylation of carbonyl compounds.
2,2,3,3,4,4,5,5,5,-nonafluoropentan-1-ol (1a) as
a colorless oil
(290 mg, 89%).
Acknowledgements
This work was supported by funding from JSPS KAKENHI (S)
(No. 24229011), Takeda Science Foundation, The Asahi Glass
Foundation, Daiichi-Sankyo Foundation of Life Sciences, Mochi-
da Memorial Foundation, Tokyo Biochemical Research Founda-
tion, Foundation NAGASE Science Technology Development,
and the Sumitomo Foundation to M.U., a JSPS Grant-in-Aid for
Young Scientists (Start-up) (No. 24850005) and a JSPS Grant-in-
Aid for Young Scientists (B) (No. 26860010) to K.H., and a JSPS
Grant-in-Aid for Young Scientists (A) (No. 25713001) to R.T. The
calculations were performed on the Riken Integrated Cluster of
Clusters (RICC). We gratefully acknowledge Advanced Center
for Computing and Communication (RIKEN) for providing pre-
cious computational resources.
2b). The presence of an electron-donating (OMe) or an elec-
tron-withdrawing (CN) substituent had little effect on the reac-
tion efficiency (>90% yields, 1c, 2c, 1d and 2d). Methyl ester
remained intact (1e and 2e). 3-Iodobenzaldehyde was convert-
ed into the desired adducts without iodine–zinc exchange (1 f
and 2 f), whereas perfluoroalkylated and -arylated tertiary alco-
hols with a pyridine ring were obtained in moderate yields (1g
and 2g). A thiophene ring was well tolerated, giving the prod-
ucts 1h and 2h in 86% and 97% yields, respectively. This
method is also applicable to the functionalization of activated
ketone substrates. a-Perfluoroarylated-a-hydroxyacid derivative
(2i) and a-perfluoroarylated-a-hydroxyoxindole (2j) were ob-
tained in good yields. Moreover, phthalic anhydride was per-
fluoroalkylated to give the adduct 1i in 80% yield.
In summary, we have developed a method for generation of
novel perfluoroalkyl zincates ([RFZnMeCl]Li), as a perfluoroalkyl
anion equivalent, from dialkylzinc in combination with per-
fluoroalkyl halides and LiCl, and demonstrated their utility in
perfluoroalkylation reactions with carbonyl compounds. These
RF–zincates showed unprecedented stability and could be used
even at room temperature. DFT calculations confirmed the su-
perior stability of [RFZnMeCl]Li over the lithium and magnesi-
um counterparts. Further studies on the reaction mechanism,
enantioselective addition reaction to carbonyl compounds, and
more general cross-coupling reactions are in progress and will
be reported in due course.
Keywords: ate complexes
·
chemoselectivity
·
density
functional calculations · perfluoroalkylation · zinc
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Chem. Eur. J. 2015, 21, 10993 – 10996
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Received: May 8, 2015
[14] Vicic and co-workers elegantly demonstrated the construction of fluo-
roalkyl-containing rings utilizing (RF)2–Zn reagents with the aid of CuCl:
Published online on June 30, 2015
Chem. Eur. J. 2015, 21, 10993 – 10996
www.chemeurj.org
10996
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