Catalytic Iodination of the Aliphatic C-F Bond by YbI3(THF)3: Mechanistic Insight and Synthetic Utility

Article abstract of DOI:10.1021/acs.orglett.6b01022

A facile iodination protocol of unactivated alkyl fluorides using catalytic amounts of YbI₃(THF)₃ in the presence of iodotrimethylsilane as a stoichiometric fluoride trapping agent is presented. ¹H NMR spectroscopy demonstrates a two-step catalytic cycle where TMSI regenerates active YbI₃(THF)₃. Finally, the catalytic reaction is extended into a one-pot procedure to demonstrate a potential application of the method. Overall, the findings present a distinct strategy for C-F bond transformations in the presence of catalytic YbI₃(THF)₃.

Full text of DOI:10.1021/acs.orglett.6b01022

Letter
pubs.acs.org/OrgLett
Catalytic Iodination of the Aliphatic C−F Bond by YbI (THF) :
3
3
Mechanistic Insight and Synthetic Utility
Mario Janjetovic, Andreas Ekebergh, Annika M. Traff
̈
̈
, and Goran Hilmersson*
̈
Department of Chemistry and Molecular Biology, University of Gothenburg, Kemivagen 10, SE-412 96 Gothenburg, Sweden
*
S Supporting Information
ABSTRACT: A facile iodination protocol of unactivated alkyl fluorides using catalytic amounts of
YbI (THF) in the presence of iodotrimethylsilane as a stoichiometric fluoride trapping agent is
3
3
1
presented. H NMR spectroscopy demonstrates a two-step catalytic cycle where TMSI regenerates
active YbI (THF) . Finally, the catalytic reaction is extended into a one-pot procedure to demonstrate
3
3
a potential application of the method. Overall, the findings present a distinct strategy for C−F bond
transformations in the presence of catalytic YbI (THF) .
3
3
he C−F bond is the strongest single bond that can be
the first example of YbI (THF) catalyzed iodination of alkyl
3 3
1
T
formed between carbon and another element. The
fluorides in the presence of iodotrimethylsilane (TMSI) as a
stoichiometric fluoride trapping agent (Scheme 1). In addition,
the mechanism has been extensively studied to expand the
understanding of YbI (THF) and its application in C−F bond
characteristic inertness of the C −F functional group has
sp3
resulted in widespread applications, e.g., within pharmaceutical,
2
agricultural, and material sciences. This demand for fluorinated
3
3
compounds has led to the development of numerous
transformations.
Olah et al. have shown that substitution of alkyl fluorides to
3
fluorinating protocols. The fact that fluorinated compounds
are extensively used, extremely long-lived, and potentially toxic
alkyl iodides is feasible using 1.1 equiv of TMSI in
7
inspires the development of vital and novel methods for C−F
dichloromethane (CH Cl ). However, they reported that
2
2
4
−6
bond activation and transformation.
Our group has recently
displacement of primary fluorides is sluggish and incomplete
even during heating and at extended reaction times. Indeed,
when such a reaction was attempted in our laboratory, using 1-
fluorodecane as a model substrate with 3 equiv of TMSI, only a
communicated that lanthanide(III) reagents facilitate mild and
6
selective activation of aliphatic fluorides. It was proposed
therein that the strong lanthanide−fluoride interaction is
responsible for the C−F bond cleavage. Having established
YbI (THF) as a stoichiometric reagent for selective halogen
2
% yield was achieved after 13 h (Table 1, entry 1).
3
3
To test the notion that YbI (THF) could be used in
3
3
exchange transformation (F to I), we envisioned that treatment
of the lanthanide(III) reagent with a fluoride trapping agent
would allow the usage of YbI (THF) in a catalytic amount.
catalytic amounts, 1-fluorodecane was subjected to a mixture of
3
1
equiv of TMSI and 1, 5, and 10 mol % of YbI (THF) (Table
, entries 2−4). A GC yield of 95% of 1-iododecane was
3 3
3
3
The majority of synthetically valuable methods for substitution
of unactivated alkyl fluorides still apply stoichiometric amounts
of Lewis acids (Scheme 1a). Catalytic main-group Lewis acid
Table 1. Optimization of YbI (THF) Catalyzed C−F Bond
4
3
3
a
Substitution of 1-Fluorodecane in the Presence of TMSI
hydrodefluorinations of alkyl fluorides have been developed
5
(
Scheme 1b). However, catalytic halogen exchange reactions
4a
of unactivated alkyl fluorides are scarce. Herein we describe
Scheme 1. Lewis Acid Promoted C−F Bond Substitution
b
entry
YbI (THF) (mol %)
TMSI (equiv)
t (h)
yield (%)
3
3
1
2
3
4
5
6
0
3
13
13
13
13
13
8
2
21
60
95
77
95
1
3
5
3
10
10
10
3
1.5
6
a
Reaction conditions: 1a (0.04 mmol), CH Cl (0.4 mL). Dodecane
2
2
b
was used as internal standard. Analyzed by GC-FID.
Received: April 8, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01022
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Organic Letters
Letter
successfully obtained utilizing 10 mol % of YbI (THF) within
3
3
1
4
3 h at room temperature without any rearrangements (entry
). Using only 1.5 equiv of TMSI gave a somewhat lower yield
of 77% within 13 h (entry 5), while increasing TMSI to 6 equiv
afforded 1-iododecane in 95% yield within 8 h (entry 6).
Optimized reaction conditions were found to be 10 mol % of
YbI (THF)3 and 3 equiv of TMSI in CH Cl2 at room
3
2
temperature.
With H and 19F NMR spectroscopy we could confirm the
1
regeneration of active YbI (THF) by TMSI. 1-Fluoro-
3
3
adamantane (1b) was chosen as a model substrate, and all
reagents were added in stoichiometric amounts. NMR spectra
acquired directly after adding 1 equiv of YbI (THF) to 1 equiv
3
3
of 1-fluoroadamantane in CD Cl showed full conversion of
2
2
starting material to 1-iodoadamantane (2b) (Figure 1A to B; no
1
Figure 2. H NMR spectra of (A) THF signals from LaI (THF) in
3
4
CD Cl . (B) Spectra obtained 5 min after addition of TMSI showing
2
2
quantitative ring opening of THF to yield (4-iodobutoxy)-
trimethylsilane. (C) Spectra showing after an additional 18 h only
1
,4-diiodobutane and hexamethyldisiloxane are detected.
extended time, the (4-iodobutoxy)trimethylsilane (confirmed
by GC-MS) was further substituted to 1,4-diiodobutane and
hexamethyldisiloxane (Figure 2C). These NMR results show
that it is possible to form a catalytic reagent which is free of
THF.
To further understand the effect THF ligands have on the
catalytic reagent system, the stereochemical outcome of the
iodo substitution of syn-fluoropyran 1c was studied. As
previously reported by us, the reaction between syn-1c and
YbI (THF) in stoichiometric amounts favors the formation of
Figure 1. 1H NMR spectra of (A) 1-fluoroadamantane (1b) in
CD Cl ; (B) instantaneous and quantitative conversion of 1b to 1-
3
3
2
2
anti-iodopyran (syn/anti 10:100), indicative of an S 2-type
N
6c
iodoadamantane (2b) upon addition of YbI (THF) to A; and (C)
3
3
mechanism.
further addition of TMSI revealing instantaneous formation of TMSF.
A striking difference in selectivity was observed when
reacting THF-free YbI , generated in situ through extended
3
premixing of YbI (THF) and TMSI, with syn-1c (Scheme 2,
fluorine signal present in 19F NMR) and most likely forming
3
3
the paramagnetic “YbI F(THF) ” in situ. Based on previous
2
3
Scheme 2. Study of the THF Effect on the YbI (THF)
Substitution of syn-1c
3
3
results, it is known that “YbI F(THF) ” is inactive and cannot
2
3
6
c
participate in C−F bond substitution. When adding 1 equiv of
TMSI to this unreactive reagent, a new set of signals appeared
1
instantaneously, corresponding to TMSF, as determined by H
19
and F NMR spectroscopy (Figure 1C). These findings
confirm that TMSF, formed upon addition of TMSI, is a direct
result of the subtraction of fluorine from the “YbI F(THF) ”
2
3
8
complex. Thus, TMSI acts as a trapping agent which facilitates
the regeneration of YbI (THF) in this case. Again, with full
3
3
conversion of TMSI to TMSF, the only iodination source
present is YbI (THF) . So when 1b was added a second time,
3
3
full conversion of starting material to 2b occurred (see
Supporting Information (SI)).
To gain insight into the catalytic reagent system and how
TMSI influences the surroundings of the catalyst, we exchanged
the paramagnetic YbI (THF) for the closely related but
pathway I). The ratio between the two stereoisomers now
slightly favored the syn-configuration, possibly indicating an
SN1-type mechanism with a short-lived carbocation. The
influence of THF was further validated by deliberate addition
of THF to YbI , regenerating “YbI (THF) ”, followed by syn-1c
3
3
diamagnetic LaI (THF) and were thereby able to study the
3
4
1
process by H NMR spectroscopy (Figure 2). Analysis of the
H NMR spectrum acquired after mixing 8 equiv of TMSI and
1
3
3
3
1
equiv of LaI (THF) in CD Cl showed a new set of signals
(pathway II). This process reverted the stereoisomeric
selectivity to the original ratio. Thus, the reactivity of the
catalyst is clearly affected by THF and its cleavage product in
the presence of TMSI.
3
4
2
2
corresponding to (4-iodobutoxy)trimethylsilane (Figure 2B).
Thus, we have confirmed that the LaI (THF) complex readily
undergoes ring opening of the THF ligands, most likely9
resulting in a THF free oligomeric complex of LaI3.
Interestingly, when the reaction mixture was left for an
3
4
The difference in stereochemical outcome of syn-1c, when
subjected to YbI (THF) -TMSI, is seemingly influenced by the
3
3
B
DOI: 10.1021/acs.orglett.6b01022
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Organic Letters
Letter
presence of coordinated THF. This became even more evident
when investigating the importance of premixing time between
YbI (THF) and TMSI. syn-1c was added to eight separate
experiments with premix times ranging from 1 to 180 min.
Each reaction was quenched after 30 s and analyzed. Various
syn/anti ratios were obtained (Figure 3). In addition, subjecting
defined reactivity. Furthermore, TMSF formed upon regener-
ation of YbI (THF)3 from a “YbI F(THF) ” complex
demonstrates that TMSI acts as a stoichiometric fluoride
trapping agent as hypothesized (Figure 1).
To show the applicability of the reagent system, a one-pot,
two-step reaction system was designed by using 3-fluoropropyl
benzene (1d) as a model substrate (Scheme 4). Various
3
2
3
3
3
Scheme 4. One-Pot Two-Step Substitution Reaction of 3-
Fluoropropyl Benzene to Various Substituted Propyl
Benzene Derivatives Using Cat. YbI (THF) and TMSI As a
3
3
Key Step
Figure 3. Analysis of syn/anti ratio from the stereochemical outcome
of syn-1c by varying the premix time of YbI (THF) and TMSI.
3
3
syn-1c to YbI (THF) −TMSI with a premix time of 180 min
3
3
led to a constant syn/anti ratio (16:10) over the course of the
reaction (see SI). A premix time of 30 min resulted in a
variation of syn/anti ratio (from 22:10 to 16:10) when
analyzing 2c over time. Consequently, different reactive
catalytic species are generated over the course of the reaction
as a result of the ring opening of THF.
nucleophiles could be introduced, and the corresponding
products were isolated in high to excellent yield by substitution
of the corresponding 3-iodopropyl benzene, formed in situ by
reacting 1d with YbI (THF) −TMSI for 24 h at room
Overall, the mechanistic investigation supports the proposed
catalytic cycle presented in Scheme 3. The ring opening of
3
3
temperature. Our method now allows us to incorporate various
common functional groups from an inert alkyl fluoride via a
highly reactive iodo-intermediate.
Scheme 3. Proposed Mechanism of YbI (THF) Catalyzed
3
x
C−F Bond Substitution in the Presence of TMSI (x = 0−3
THF Molecules Coordinated)
Finally, a selectivity test between fluoro-, chloro-, and
bromoalkane was conducted. The substitution promoted by
catalytic YbI (THF) showed excellent selectivity toward the
3
3
alkyl fluoride, with 95% conversion of 1-fluorodecane within 16
h, and less than 2% conversion of 1-chloro- and 1-
bromodecane, respectively (see SI).
In conclusion, we have developed a novel YbI (THF)
3
3
catalyzed C−F bond activation method in the presence of
stoichiometric TMSI. The reaction proceeds under mild
conditions and expands the usage of YbI (THF) as a versatile
3
3
and powerful reagent for C−F bond activation. The method-
ology allows the usage of fluorine as a small, sterically
unhindered surrogate protecting group. In comparison to
hydrodefluorination processes, our approach enables a direct
and powerful route for late-stage incorporation of iodine, in
which the highly reactive iodo-compound can be converted into
other functional groups. Mechanistic investigations have
presented results supporting a two-step catalytic cycle, where
TMSI regenerates the active catalyst. In addition, YbI (THF)
undergoes ring-opening of THF in the presence of TMSI over
time, which is a process that clearly affects the stereochemical
outcome of a reaction. It still needs to be determined whether
the catalytic reaction has a broad substrate scope. For this
purpose, we are currently exploring this reagent system with
other classes of alkyl fluorides.
THF, upon addition of TMSI, generates ligand-free YbI . Such
ring opening was detected by H NMR of the closely related
3
1
3
3
lanthanide LaI (THF) (Figure 2). The desolvation of
3
4
YbI (THF)3 promoted by TMSI results in the altered
3
stereochemical outcome of syn-1c (Scheme 2). When subjected
to YbI (THF)3 the reaction proceeds via an S 2-type
3
N
mechanism, while the THF-free YbI reagent predominantly
3
proceeds via an S 1-type mechanism. Notably, both
N
YbI (THF)3 and ligand-free YbI3 reagents are catalytically
3
ASSOCIATED CONTENT
Supporting Information
active species. It is also important to note that the cleavage of
coordinated THF is rapid, since 1 min of premixing time is
sufficient to significantly change the stereochemical outcome of
syn-1c (Figure 3). However, a premix time of 180 min is
necessary to generate a THF-free catalytic complex with a well-
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01022.
C
DOI: 10.1021/acs.orglett.6b01022
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Preparation of catalyst, general experimental procedure,
Letter
and mechanistic data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hilmers@chem.gu.se.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the Swedish Research
Council for financial support.
■
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DOI: 10.1021/acs.orglett.6b01022
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