Solvent dependent reductive defluorination of aliphatic C-F bonds employing Sm(HMDS)2

Article abstract of DOI:10.1039/c3cc37828d

Sm(HMDS)₂ in n-hexane mediates fast cleavage of primary, secondary and tertiary alkyl fluorides in good to excellent yields. In n-hexane Sm(HMDS)₂ exhibits uniquely enhanced reductive ability towards the C-F bond compared to when using THF as solvent.

Full text of DOI:10.1039/c3cc37828d

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Solvent dependent reductive defluorination of
aliphatic C–F bonds employing Sm(HMDS)2†
Cite this: Chem. Commun., 2013,
4
9, 1826
Mario Janjetovic, Annika M. Tr a¨ ff, Tobias Ankner, Jenny Wettergren and
G o¨ ran Hilmersson*
Received 29th October 2012,
Accepted 9th January 2013
DOI: 10.1039/c3cc37828d
www.rsc.org/chemcomm
Sm(HMDS)
2
in n-hexane mediates fast cleavage of primary, secondary cleavage of aliphatic fluorocarbons. Initially we started off by
9
and tertiary alkyl fluorides in good to excellent yields. In n-hexane investigating SmI as a potential dehalogenation reagent. SmI
2
2
Sm(HMDS)
2
exhibits uniquely enhanced reductive ability towards the is a known and versatile reagent that has been used in several
1
0
C–F bond compared to when using THF as solvent.
functional group transformations. Its reactivity can be fine-
tuned by additives, and our group has found that by combining
Selective activation and transformation of aliphatic C–F bonds it with Et
3
N and H
2
O a powerful reducing agent is obtained.
/Et N/H O has for example been
that forms the strongest bond with carbon. The fluorocarbon utilized in reduction of ketones, alkyl and aryl halides,
is a challenge in organic chemistry, as fluorine is the element The combination of SmI
2
3
2
1
11
12
15
1
3
14
moiety is often incorporated into medicinal and pesticidal conjugated olefins, nitroalkanes, and carboxylic acids.
compounds to alter properties such as metabolic stability and Yet, when used in the reduction of simple alkylfluorides, such
lipophilicity. However, the stability of the C–F bond is both a as 1-fluorodecane, it was not reactive enough to cleave the
blessing and a curse since the strong bond renders these aliphatic C–F bond (Table 1, entry 1).
compounds chemically inert, thus making fluorinated com-
Other combinations of SmI
pounds persistent in the environment. These considerations entries 2 and 3) failed under these conditions as well. Interest-
prompted us to investigate the possibility to cleave aliphatic ingly, Sm(HMDS) was shown to mediate reductive cleavage
C–F bonds. A few studies have reported on Lewis acid C–F bond of the C–F bond. It was found that the outcome of the reac-
2
and additive mixtures (Table 1,
2
2
3
activation, e.g. using Et SiH/BF , tBu Al–H and other methods.
tion changed with the solvent and source of Sm(HMDS)2
3
3
2
However, reductive defluorination of aliphatic substrates has (Table 1, entries 4–8). Preparing Sm(HMDS)2 from SmI2
received little attention, earlier reports include the use of and potassium bis(trimethylsilyl)amide in THF, followed by
4
5
6
zirconium-complexes, magnesium metal or alkali metals.
removal of the precipitated potassium iodide (KI), yielded a
solution in THF (Table 1, entry 4).
These procedures have been shown to require either long 0.10 M deep-purple Sm(HMDS)
2
reaction times, give moderate yields or require large amounts
of the reagent.
a
Table 1 Reduction of 1-fluorodecane
Herein an efficient protocol is presented using Sm(HMDS)
2
as a single electron transfer (SET) reagent, capable of pro-
moting reductive defluorination of aliphatic C–F bonds. Pre-
viously Sm(HMDS) has been reported to mediate reduction of
2
b
e.g. an SET labile aryl nitro functional group and play a role in
the reductive coupling of imines.
Entry
Sm(II) source
Solvent
Yield (%)
7
1
2
3
4
5
6
7
8
SmI
SmI
SmI
2
2
2
/Et
/TPPA
/DMPU
3
N/H
2
O
THF
THF
THF
THF
n-Hex
THF
n-Hex
THF
n/r
n/r
n/r
In a previous publication from our group a-defluorination
of polyfluorocarboxylic acid esters and amides employing
c,d
8
Sm(HMDS)
Sm(HMDS)
2
2
2
26
SmI
2
/Et
3
N/H
2
O in THF was presented. This led us to explore
c
55
whether divalent samarium reagents were capable of reductive
Sm(HMDS)
2
30
II
c
NaSm (HMDS)
3
II
NaSm (HMDS)
3
n/r
Department of Chemistry and Molecular Biology, University of Gothenburg,
Kemiv a¨ gen 10, SE-412 96, Gothenburg, Sweden. E-mail: hilmers@chem.gu.se;
Tel: +46-317869022
a
2
To Sm(HMDS) (1.0 mL, 0.1 M in solvent, 0.1 mmol) 1-fluorodecane
(
7.9 mL, 0.04 mmol) was added. n-Dodecane (9.1 mL, 0.04 mmol) was added
as an internal standard. The reaction mixture was stirred for 24 h at r.t.,
b
†
Electronic supplementary information (ESI) available: Experimental procedures
after which a sample was collected and analyzed. Measured by GC-FID.
c
d
and characterization data for all new compounds. See DOI: 10.1039/c3cc37828d
2
Further conversion was observed after 24 h. Sm(HMDS) with KI traces.
1
826 Chem. Commun., 2013, 49, 1826--1828
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a
Since this solution likely also contains a substantial amount of Table 2 Reductive defluorination of alkylfluorides
KI, which affects the reactivity (vide infra), we employed the
1
6
Evans procedure for the preparation of KI-free Sm(HMDS)2
by removing the solvent THF and dissolving the reagent in
n-hexane, thereby precipitating more of the KI (Table 1, entry 5).
Exchange of n-hexane with THF afforded KI-free THF-solvated
b
Entry
1
Substrate
Product
Time (min)
60
Yield (%)
Sm(HMDS)
vide infra). Another method from the Evans group was explored
to generate absolutely halide-free Sm(II) from Sm(HMDS) and
sodium in THF or n-hexane. This yielded deep-purple 0.10 M
2
(Table 1, entry 6), which also differs in reactivity
95
(
3
2
3
4
20
40
10
93
90
II
17
solutions of NaSm (HMDS) (Table 1, entries 7 and 8). We
3
found that Sm(HMDS) in n-hexane (Table 1, entry 5) was the
2
superior reagent for use in cleavage of the C–F bond at room
temperature.
By increasing the temperature to 100 1C using a microwave
cavity we could shorten the reaction time dramatically. With
our procedure, primary-, secondary-, and tertiary alkyl fluorides
(Table 2, entries 1, 2, and 4), as well as cyclic fluorinated
compounds (both secondary and tertiary, Table 2, entries 3
and 5), can be reduced to their corresponding hydrocarbons in
good to excellent yields in 60 min or less. Surprisingly, the gem-
difluoro compounds yielded the alkene product in 25–50%
conversion (Table 2, entries 6 and 7). The alkene was afforded,
and not the alkane in this case, probably due to a change in the
reaction pathway. We believe that this reaction proceeds either
via a vinyl fluoride or via a carbene intermediate. A vinyl
fluoride (4-tert-butyl-1-fluorocyclohexene) was reductively cleaved
in 55% conversion to the corresponding alkene (Table 2,
entry 8). This result is an indication that the gem-difluoro
compounds may proceed via the vinyl fluoride, but does
not exclude the carbene intermediate. An aromatic fluoride
89
96
5
6
30
60
d,e
25
(
(
p-fluorotoluene) was reduced yielding toluene in 75% yield
Table 2, entry 9). An excess of Sm(HMDS) was necessary in
yielded
d,e
7
8
9
60
60
60
50
2
this case. The expected 2.5 equivalents of Sm(HMDS)
2
approximately 20% toluene, regardless of time. The possibility
to reduce a trifluoroalkyl compound (Table 2, entry 10) was
examined, but (3,3,3-trifluoropropyl)benzene was shown to be
chemically inert in this case. However, the benzylic fluorides
in trifluorotoluene were reduced in moderate yield (Table 2,
entry 11) at room temperature.
d
55
Examining the selectivity of the primary, secondary, and
2
tertiary fluorides by addition of Sm(HMDS) in n-hexane to an
equimolar solution of the three fluorides (1a, 1b and 1d)
revealed the following order of reactivity: 31 > 21 > 11
f,g
75
(Scheme 1 and Scheme S2, ESI†). This implies that the reaction
most likely proceeds via a radical intermediate with the tertiary
alkyl radical being the most stable, and the one which is
reduced fastest to its corresponding anion.
To gain further knowledge about the reaction, the choice of
2
solvent and the mode of preparation of Sm(HMDS) (Table 1)
h
10
60
30
n/r
h,i
were studied. It was found that the outcome of the reaction 11
65
improved greatly with n-hexane as solvent. In addition, the
source of Sm(HMDS) influenced the reaction to a large extent.
We initially started off investigating the solvent effect by addi-
2
a
b
c
For reaction conditions see ref. 18. Measured by GC-FID. 1-Decene,
2
-E-decene, and 2-Z-decene were formed in B0.1 : 0.3 : 1.0 mixture.
tion of increasing amounts of THF to Sm(HMDS)
2
in n-hexane
d
f
e
Conversion of the starting material. 5 equiv. of Sm(HMDS)
2
in n-hexane.
with 1-fluorodecane as the substrate. The yield steadily decreased
when the concentration of THF increased (Table S2, ESI†). of Sm(HMDS) in n-hexane. r.t.
2
g
h
Starting material left. 10 equiv. of Sm(HMDS)
2
in n-hexane. 7.5 equiv.
i
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2
the mechanism indicates that reduction with Sm(HMDS) in
n-hexane most likely proceeds via direct cleavage of the carbon–
fluorine bond. Sm(HMDS) in n-hexane has been shown to be
2
the optimal reagent in this case. Owing to its increased reacti-
vity compared to KI-free Sm(HMDS)2 in THF, it is not only
valuable for defluorination reactions, but also an interesting
candidate in reductive processes in general. Further mecha-
nistic studies of the reagent and its use in C–F bond cleavage
are ongoing.
Scheme 1 Selectivity between 11-, 21-, and 31-alkyl fluorides.
Financial support from Vetenskapsrådet and AstraZeneca is
gratefully acknowledged.
THF seems to affect the reducing ability of the reagent to such
an extent that the reaction is inhibited at room temperature.
For reduction to occur we believe that the strong C–F bond
needs to be weakened by an interaction with samarium, thus
highlighting the importance of an inner vs. outer sphere
mechanism. Flowers et al. have previously presented results,
showing that reduction of alkyl halides with Sm(HMDS)2
in THF goes through an inner-sphere mechanism. Our
results indicate that the reductive cleavage of the C–F bond is
inhibited in THF (Table 1, entries 6, and 8). The strong
coordination between the THF molecule and samarium pro-
vides a reagent incapable of interaction with the substrate.
Hence, the reaction most likely proceeds via an inner-sphere
Notes and references
1
2
3
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(
mechanism when Sm(HMDS) is dissolved in n-hexane (Table 1,
2
6
7
8
entries 5, and 7).
Another observation was the difference in yield when com-
paring entries 4, 6, and 8 (Table 1), all reactions run with
(
44, 5025; (c) T. Ohsawa, T. Takagaki, A. Haneda and T. Oishi,
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A. Dahl ´e n, G. Hilmersson and R. A. Flowers II, Tetrahedron, 2003,
2
Sm(HMDS) in THF. Entry 4 gave 26% yield while only traces of
decane were obtained in entries 6 and 8. The difference
between these entries was the amount of residual potassium
iodide present in the reaction mixture. Even though KI is
filtered off in the preparation of Sm(HMDS) from SmI and
5
9, 10397.
J. Wettergren, T. Ankner and G. Hilmersson, Chem. Commun., 2010,
6, 7596.
4
9 Y. Yamaki, A. Shigenaga, K. Tomita, T. Narumi, N. Fujii and
A. Otaka, J. Org. Chem., 2009, 74, 3272.
2
2
potassium bis(trimethylsilyl)amide in THF, traces will always
be present in the solution. Sm(HMDS) free from potassium
10 (a) D. J. Procter, R. A. Flowers II and T. Skrydstrup, Organic Synthesis
2
using Samarium Diiodide
A Practical Guide, RSC, Cambridge,
1
6
iodide was prepared according to the Evans procedure, where
solvent THF was removed and the reagent was dissolved in
n-hexane, thereby precipitating even more KI yielding KI-free
2010; (b) H. B. Kagan, Tetrahedron, 2003, 59, 10351; (c) K. C.
Nicolaou, S. P. Ellery and J. S. Chen, Angew. Chem., Int. Ed.,
2
2
009, 48, 7140; (d) P. G. Steel, J. Chem. Soc., Perkin Trans. 1,
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2
in n-hexane. Changing the solvent from hexane to
1996, 96, 307; ( f ) A. Dahl ´e n and G. Hilmersson, Eur. J. Inorg. Chem.,
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427.
2
THF afforded KI-free Sm(HMDS) in THF. Investigation of how
potassium iodide affected the reductive cleavage of the C–F
2
1
bond could now be done by adding substoichiometric amounts 11 A. Dahl ´e n and G. Hilmersson, Tetrahedron Lett., 2002, 43, 7197.
1
2 (a) A. Dahl ´e n, G. Hilmersson, B. W. Knettle and R. A. Flowers II,
J. Org. Chem., 2003, 68, 4870; (b) A. Dahl ´e n and G. Hilmersson, J. Am.
Chem. Soc., 2005, 127, 8340.
of KI to the KI-free Sm(HMDS)
amounts of KI, the yield of decane increased up to 50% when
2
in THF. With increasing
1
eq. of KI was added (Table S3, ESI†). Not only was the product 13 A. Dahl ´e n and G. Hilmersson, Tetrahedron Lett., 2003, 44, 2661.
formed, but traces of 1-iododecane were observed as well.
These results led us to believe that KI in the presence of
1
1
1
4 T. Ankner and G. Hilmersson, Tetrahedron Lett., 2007, 48, 5707.
5 M. Szostak, M. Spain and D. J. Procter, Org. Lett., 2012, 14, 840.
6 W. J. Evans, D. K. Drummond, H. Zhang and J. L. Atwood, Inorg.
Chem., 1988, 27, 575.
Sm(HMDS) in THF somehow performs a halogen exchange,
forming alkyl iodide which then is reductively cleaved. These
2
1
7 (a) W. J. Evans, M. A. Johnston, R. D. Clark, R. Anwander and
J. W. Ziller, Polyhedron, 2001, 20, 2483; (b) W. J. Evans, D. S. Lee,
D. B. Rego, J. M. Perotti, S. A. Kozimor, E. K. Moore and J. W. Ziller,
J. Am. Chem. Soc., 2004, 126, 14574.
findings indicate that the two Sm(HMDS) species, KI contami-
2
nated and KI-free (Table 1, entries 4 and 6), operate through
different pathways.
1
8 To Sm(HMDS)
the substrate (0.04 mmol) was added. n-Dodecane (9.1 mL,
.04 mmol) was added as the internal standard. The reaction was
2
in n-hexane (1.0 mL, 0.1 M in n-hexane, 0.1 mmol)
In conclusion, we have developed a protocol for the facile
0
removal of alkyl fluorides using Sm(HMDS)
2
in n-hexane. At
primary,
heated in the microwave cavity at 100 1C for the time stated in
Table 2, after which a sample was collected and analyzed.
9 (a) E. Prasad, B. W. Knettle and R. A. Flowers II, J. Am. Chem. Soc.,
100 1C with stoichiometric amounts of Sm(HMDS)
2
1
secondary, and tertiary alkyl fluorides can be reduced in short
reaction times in good to excellent yields. Initial investigation of
2
002, 124, 14663; (b) E. Prasad, B. W. Knettle and R. A. Flowers II,
J. Am. Chem. Soc., 2004, 126, 6891.
1
828 Chem. Commun., 2013, 49, 1826--1828
This journal is c The Royal Society of Chemistry 2013