Conversion of a (sp3)C-F bond of alkyl fluorides to (sp 3)C-X (X = Cl, C, H, O, S, Se, Te, N) bonds using organoaluminium reagents

Article abstract of DOI:10.1039/b613641a

A simple method for the conversion of (sp³)C-F bonds of alkyl fluorides to (sp³)C-X (X = Cl, C, H, O, S, Se, Te, N) bonds has been achieved by the use of a hexane solution of organoaluminum reagents having Al-X bonds. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613641a

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Conversion of a (sp3)C–F bond of alkyl fluorides to (sp3)C–X (X = Cl,
C, H, O, S, Se, Te, N) bonds using organoaluminium reagents{
Jun Terao,* Shameem Ara Begum, Yoshiaki Shinohara, Masahiro Tomita, Yoshitaka Naitoh and
Nobuaki Kambe*
Received (in Cambridge, UK) 19th September 2006, Accepted 27th October 2006
First published as an Advance Article on the web 23rd November 2006
DOI: 10.1039/b613641a
A simple method for the conversion of (sp3)C–F bonds of alkyl
fluorides to (sp3)C–X (X = Cl, C, H, O, S, Se, Te, N) bonds has
(1%) was formed as a by-product probably via 1,2-hydride shift of
the 1-octyl carbocation (Table 1, entry 1). When dichloromethane
was used as solvent instead of hexane, a mixture of 1-octyl chloride
and secondary octyl chlorides was obtained in 78% and 21%
yields, respectively, under similar conditions, but no reaction took
place in THF or diethyl ether. When cyclohexyl fluoride and
adamantyl fluoride were treated similarly in hexane, the corre-
sponding chlorides 12 and 13 were obtained in 74% and 76%
yields, respectively (entries 2 and 3). These results may suggest that
substitution reaction proceeds in either an SN1 or SN2 fashion
depending on the substrates and solvents. It should be noted that
n-octyl fluoride can react with triethylaluminium at 25 uC, giving
rise to alkyl–alkyl cross-coupling product 14 in good yield (entry
4). Recently, construction of the (sp3)C–(sp3)C linkage with
cleavage of non-activated (sp3)C–F bonds has been achieved by
the use of organoaluminiums10b or magnesium enamide,2a or
BF3?OEt210c as mediators or catalysts. Reaction of n-octyl fluoride
with alkenyl(diisobutyl)aluminium (3), prepared in situ from
iBu2AlH and 1-octyne, in hexane at 25 uC for 6 h afforded a
coupling product (15) in 90% yield with an E/Z ratio of 90/10
(entry 5). When diethyl(1-octynyl)aluminium (4) was used,
7-hexadecyne (16) was obtained in 94% yield (entry 6). These
results indicate the selective transfer of the alkenyl or alkynyl
group on the aluminium center over alkyl groups.10b Under the
same conditions, a primary alkyl fluoride was readily defluorinated
to an alkane by the use of DIBALH (entry 7). When
organoaluminium reagents containing aluminium–chalcogen (O,
S, Se, and Te) bonds were employed, the corresponding
chalcogenides were obtained in good yields (entries 8–11).
Replacement of the fluorine atom by an amino group has also
been achieved by the use of a hexane solution of organoalu-
minum reagents having Al–X bonds.
Organic fluorides, especially those having an (sp3)C–F bond, have
been recognized as the most inert class of organic compounds due
to the strong C–F bonds. Hence, to develop reactions which
replace fluorine atoms with other atoms or groups is a challenging
subject in organic chemistry.1,2 It is known that (sp3)C–F bonds
would be cleaved when treated with a strong hard acid in polar
solvent and/or at elevated temperatures. Organoaluminium
reagents or aluminium salts can also be employed, but in many
cases the substrates employed are limited to tertiary alkyl fluorides
or activated ones having a halogen,3 chalcogen,4 CF3,5 or Ph6
group at the a-position. The use of primary alkyl fluorides usually
gives unsatisfactory results due mainly to the H–F elimination,
hydride shift, and skeleton rearrangement7 from primary alkyl
cation intermediates since these reactions proceed via an SN1
mechanism. During the course of our study on the synthetic
application of alkyl halides, we have recently developed Ni- or Cu-
catalyzed C–C bond forming reactions using primary or secondary
alkyl fluorides8 Here, we disclose that C–F bonds of non-activated
alkyl fluorides can be converted efficiently into C–Cl,7,9 C–C,10–12
C–H,13 C–O,14 C–N,15 C–S,12b C–Se, and C–Te bonds by using
organoaluminum reagents (R2Al–X) in hexane under mild
conditions (Scheme 1).
For example, when a reaction of n-octyl fluoride (1.0 mmol)
with diethylaluminium chloride (1.2 equiv., 1 M in hexane) was
performed at 278 uC for 3 h, n-octyl chloride 11 was obtained in
98% yield. In this reaction, only a trace amount of 2-octyl chloride
i
been achieved by the use of Bu2Al–NEt2 (entry 12).
It is worth noting that the present reaction is unique to only
alkyl fluorides and the corresponding alkyl bromides and iodides
are tolerant to this reaction as shown below. To a mixture of
equimolar amounts of n-octyl fluoride, n-decyl bromide, and
n-undecyl iodide was added a hexane solution of diethylaluminum
chloride. GC analysis of the resulting mixture indicated the
selective formation of n-octyl chloride in 98% yield (Scheme 2). No
evidence for the formation of other alkyl chlorides was obtained by
GC analysis. We also carried out reaction of diethylaluminum
chloride with n-octyl iodide or bromide under the identical
conditions as entry 1 in Table 1, and confirmed that n-octyl
chloride was not obtained at all in either case and unreacted
starting materials were recovered. These results suggest that
activation of C–F bond by coordination of Al to F is essential
to promote the present substitution reaction.16
Scheme 1 Conversion of C–F Bond of Alkyl–F to C–X bonds using
organoaluminium reagents.
Science and Technology Centre for Atoms, Molecules and Ions Control,
Graduate School of Engineering, Osaka University, Department of
Applied Chemistry, Graduate School of Engineering, Osaka University,
Yamadaoka 2-1, Suita, Osaka, 565-0871.
E-mail: terao@chem.eng.osaka-u.ac.jp; kambe@chem.eng.osaka-
u.ac.jp; Fax: +81-6-6879-7390; Tel: +81-6-6879-7389
Tel: +81-6-6879-7388
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b613641a
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 855–857 | 855

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Table 1 Conversion of C–F bond to C–X bond using R2Al–X in hexane
Entry
Alkyl–F
R2Al–X
Time
Product
Yield (%)b
1c
2c
nOct–F
cHex-F
Et2Al–Cl 1
Et2Al–Cl 1
3 h
10 min
nOct–Cl 11
98
74
12
3c
1-Adamantyl-F
Et2Al–Cl 1
10 min
76
13
4
5
6
nOct–F
nOct–F
nOct–F
nOct–F
nOct–F
nOct–F
nOct–F
nOct–F
nOct–F
Et2Al–Et 2
1.5 h
6 h
16 h
1.5 h
100 h
1 h
1 h
1 h
108 h
nOct–Et 14
93
iBu2Al–CHLCHnHex 3
Et2Al–CMC–nHex 4
iBu2Al–H 5
nOct–CHLCHnHex 15 (E/Z = 90/10)
nOct–CMC–nHex 16
nOct–H 17
90 (75)
94 (67)
97
7
8d
9
iBu2Al–OPh 6
iBu2Al–SPh 7
nOct–OPh 18
78
nOct–SPh 19
99 (77)
99 (66)
92 (67)
85 (71)
10
11
12d
a
iBu2Al–SePh 8
iBu2Al–TePh 9
iBu2Al–NEt2 10
nOct–SePh 20
nOct–TePh 21
nOct–NEt2 22
b
Alkyl fluorides (1 mmol), organoaluminum reagents (1.2–1.5 mmol), hexane (1.0–1.2 mL), 25 uC. Determined by GC based on alkyl
c
d
fluorides used. Isolated yield is in parentheses. Reaction was carried out at 278 uC. Alkyl fluorides (2 mmol), organoaluminum reagents
(6 mmol), hexane (6 mL), 25 uC.
In order to examine the relative reactivities of alkyl fluorides in
the present reaction, we carried out the following competitive
reaction. A mixture of 0.5 mmol of n-octyl fluoride, cyclohexyl
fluoride, and 1-adamantyl fluoride was allowed to react with
Et2Al–Cl (1.2 equiv.) at 278 uC for 15 min. GC analysis of the
resulting mixture revealed that 1-adamantyl chloride was obtained
predominantly along with cyclohexyl chloride as a minor product
and n-octyl fluoride remained unchanged (Scheme 3). This result
suggests that the order of reactivity for chlorination is tertiary .
secondary . primary alkyl fluorides.
that the attacking chloride, which would not be a free anion, does
not act as a strong nucleophile in the present reaction.
Results of Scheme 3 and 4 suggest that the present reaction
proceeds via SN1 mechanism. We then examined stereochemistry
of the reaction of primary alkyl fluoride in order to gain insight
into the possibility of an SN2 mechanism (Scheme 5).
Diastereometrically pure a,b-d2-b-adamantylethyl fluorides 27
was treated with Et2AlCl and the 1H-NMR analysis of the
products indicated that substitution occurs primarily with inver-
sion of configuration with ca. 10 : 1 selectivity from both
diastereomers. These results suggest that the present substitution
reaction of unactivated primary alkyl fluorides proceeds principally
via an SN2 mechanism.
We next examined the reaction of a-d1-b-phenylethyl fluoride 23
under our conditions in order to prove the reaction mechanism
(Scheme 4). When 23 was treated with Et2Al–Cl in hexane at
278 uC, a-d1-b-phenylethyl chloride (24) and b-d1-b-phenylethyl
chloride (25) were formed in nearly 1 : 1 ratio probably via a
phenonium ion intermediate (26).17 This result indicates that the
phenyl group also exerts strong anchimeric assistance suggesting
In conclusion, we have developed a simple method for the
conversion of (sp3)C–F bonds of alkyl fluorides to (sp3)C–X (X =
Cl, C, H, O, S, Se, Te, N) bonds using a hexane solution of
organoaluminum reagents having Al–X bonds. The first evidence
for a SN2 mechanism for substitiution of F in alkyl fluorides with
nucleophiles has been shown by the stereochemistry based on 1H-
NMR analysis.
This study was supported by Industrial Technology Research
Grant Program in 2006 from New Energy and Industrial
Technology Development Organization (NEDO) of Japan and
Grant-in-Aid for Scientific Research on Priority Areas from
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
Scheme 2 Competitive reaction of alkyl halides with Et2AlCl.
Scheme 4 The F–Cl exchange reaction of b-phenylethyl fluoride with
Et2AlCl.
Scheme 3 Competitive reaction of alkyl fluorides with Et2AlCl.
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Scheme 5 The F–Cl exchange reaction of a,b-d2-b-adamantylethyl
fluorides with Et2AlCl.
Notes and references
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17 It is known that F–Cl substitution of 23 with BCl3 in CH2Cl2 proceeds
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This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 855–857 | 857