Divergent reactivities in fluoronation of allylic alcohols: Synthesis of: Z -fluoroalkenes via carbon-carbon bond cleavage

Article abstract of DOI:10.1039/c7sc00483d

An unconventional cleavage of an unstrained carbon-carbon bond in allylic alcohols can be induced by the use of N-fluorobenzenesulfonimide (NFSI) under catalyst-free conditions. By using this simple procedure, a wide range of functionalized Z-fluoroalkenes can be accessed in high yield and selectivity from cyclic and acyclic allylic alcohols.

Full text of DOI:10.1039/c7sc00483d

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Divergent Reactivities in Fluoronation of Allylic Alcohols:
Synthesis of Z-Fluoroalkenes via Carbon-Carbon Bond Cleavage†
Received 00th January 20xx,
Accepted 00th January 20xx
Tang-Lin Liu, Ji’En Wu and Yu Zhao
An unconventional cleavage of unstrained carbon-carbon bond in allylic alcohols can be induced by the use of N-
fluorobenzenesulfonimide (NFSI) under catalyst-free conditions. By using this simple procedure, a wide range of
functionalized Z-fluoroalkenes can be accessed in high yield and selectivity from cyclic and acyclic allylic alcohols.
DOI: 10.1039/x0xx00000x
www.rsc.org/
prepare
fluorination induced ring opening of cyclopropanols was also
reported recently to deliver -fluoroketones under Ag/Cu or
β
-fluoroketones (Scheme 1a).10 Related to this, the
Introduction
β
photo-catalysis (Scheme 1b).11 We have discovered a general
and catalyst-free fluorination of allylic alcohols simply by
reacting the substrate with commercial NFSI open to air
(Scheme 1c). In particular, a conceptually new transformation
of allylic alcohols to Z-fluoroalkenes was realized through the
cleavage of non-activated carbon-carbon bond. It is
noteworthy that carbon-carbon bond activation has been
actively investigated as a new strategy in organic synthesis,
with the majority of the systems involving transition metal-
mediated opening of strained C-C bonds.12 While examples of
the activation of unstrained C-C bonds in carbonyl derivatives
The incorporation of fluorine in pharmaceuticals and
agrochemicals has become
a common practice as a
consequence of the attractive properties fluorine can confer
on them.1 Accordingly, fluorination chemistry has been
extensively explored in the past decades to deliver fluorinated
compounds of various substitution patterns.2 Despite the great
progress achieved for catalytic Csp3-F bond formation3 as well
as aryl fluoride synthesis,4 significant limitations still exist for
the preparation of certain structures such as fluoroalkenes
that are highly valuable as peptide isosteres and building
blocks.5 The preparation of fluoroalkenes through direct C-F
formation requires the use of sensitive organometallic
reagents or intermediates (such as alkenyl lithium) and are
thus limited in the substrate scope.6 Alternatively, classical
olefination reactions using fluorine-containing reagents have
been extensively explored;7 the control of olefin geometry in
these methods, however, has remained an unsolved challenge.
Only very recently the synthesis of 1,2-disubstituted Z-
fluoroalkenes was achieved through catalytic cross
β
a) Fluorinationꢀinduced rearrangement: synthesis of ꢀfluorocarbonyl
F
OH
"F+"
Rearrangement
catalyst
OH
H
O
R1
Selectfluor
R1
R2
R2
R1
R2
allylic alcohol (acyclic
or strained cyclic)
βꢀfluorocarbonyl
β
b) Fluorination of cyclopropanols: synthesis of ꢀfluorocarbonyl
O
F
OH
Ag/Cu catalyst or TCB, hv
metathesis.8 We present here
a highly efficient and
R
R
R'
R'
Selectfluor
operationally simple method that can deliver functionalized
trisubstituted Z-fluoroalkenes from readily available allylic
alcohols with excellent stereoselectivity.
The electrophilic fluorination of enolate intermediates and
alkenes has proven to be a highly successful strategy for C-F
bond formation.3 By utilizing allylic alcohols as the substrate, a
tandem metal-catalyzed isomerization to the enolate followed
c) General, catalystꢀfree fluorination of allylic alcohols to access fluoroalkenes (this work)
F
R = aryl,
alkenyl, alkynyl
O
OH
n
H
H
CHO
n+1
R = alkyl
R
alkyl
R
F
fluoroalkenes
27 examples
β-fluoroketones
3 examples
+
NFSI
+
by fluorination has been reported to prepare
fluoroketones.9 Alternatively, fluorination of the alkene moiety
followed by semi-pinacol rearrangement was realized to
α-
F
O
OH
Ar'
R = H or alkyl
R = aryl
Ar
aryl
R
R
F
Ar Ar'
Ar
allylic alcohol
fluoroalkenes
6 examples
β-fluoroaldehydes
6 examples
general fluorination of allylic alcohols
novel Z-fluoroalkene synthesis
catalyst-free cleavage of unstrained C-C bond
broad substrate scope
Scheme 1. Fluorination of Allylic Alcohols and Cyclopropanols
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Table 1. Optimization of Fluoroalkene Synthesis.a
are known under transition metal- or photocatalytic
conditions,13 our method represents an unprecedented
reactivity of allylic alcohols, in which the non-activated C-C
bond undergoes cleavage induced by NFSI. The stereoselective
formation of fluoroalkenes also renders this system a valuable
tool in chemical synthesis.
OH
2 mol % catalyst
OH
with or w/o additive
CHO
or
Ph
Ph
Ph
F
F
1.5 equiv. NFSI
2a
4a
1a
PhMe, 4 Å MS, temp, 20 h
entry
catalyst
F+ (equiv.)
NFSI (1.5)
NFSI (1.5)
T (°C) Yield (%)b
1
2
[Rh(cod)2]BF4
23
23
58
60
[Ir(cod)Cl]2
Results and discussion
[RuCl2(p-
3
NFSI (1.5)
23
59
cymeme)]2
In the past few years, our laboratory has been exploring
catalytic enantioselective redox-neutral processes for the
preparation of important chiral entities.14 During our
investigation of a Rh-catalyzed isomerization of allylic alcohol
4
5
/
NFSI (1.5)
Selectfluor
NFSI (1.5)
NFSI (1.5)
NFSI (1.5)
NFSI (1.5)
NFSI (1.5)
NFSI (2.0)
NFSI (2.0)
23
23
23
23
23
23
40
40
40
61
<5
/
K2CO3
In dark
Ag2CO3
CuCl
/
6
55
7
60
1a to the corresponding
α-benzyl cyclopentanone (Scheme
8
54
2),14e as a mechanistic probe we attempted the synthesis of 3a
by trapping the proposed enolate intermediate with an
electrophilic fluorinating reagent such as NFSI. To our great
surprise, none of 3a could be accessed under this set of
conditions and a completely unexpected product 2a was
formed instead. This transformation involves the cleavage of
an unstrained carbon-carbon (C-C) bond in a five-membered
ring and delivers synthetically versatile fluoroalkene 2a as a
single Z-isomer (determined by the JH-F value as well as 2D
NMR; see SI for details). Intrigued by this discovery, we
decided to explore this transformation in detail.
9
50
10
11
12
66
/
70
82 (4a)c
/
a
The reactions were carried out with 0.2 mmol 1a and 100 mg 4Å molecular
sieve in 2 mL toluene open to air using commercially available NFSI. Isolated
b
yields. ] The isolated yield of alcohol 4a after the reduction of aldehyde.
To further optimize the reaction, the loading of NFSI and
the reaction temperature were varied. The use of 2.0 equiv. of
NFSI at 40 °C proved to be the optimal (entries 10-11). Overall,
a simple and effective procedure that involves a simple mixing
of the substrate and NFSI with gentle heating proved to be the
most effective. Finally, a more convenient procedure was
adopted that included an in situ reduction of 2a using NaBH4;
the corresponding primary alcohol 4a could be isolated in a
high yield of 82% (entry 12). The scale-up of this reaction
proved to be straightforward as well. A similar yield of 78%
was obtained for 4a on a 5 mmol scale (Scheme 3).
Scheme 2. Discovery of fluoroalkene synthesis from allylic alcohol.
With the optimal conditions in hand, we moved on to
explore the scope of this ring-opening fluorination reaction.
For the ring-opening of cyclopentanols (n = 1), various
substituted aryl groups can be well-tolerated (Scheme 3a). A
As summarized in Table 1, a series of transition metal
complexes based on Rh, Ir, Ru, etc were examined first.
Interestingly, all these catalysts led to the formation of 2a in
similar yields of 58-60% (entries 1-3). The addition of ligands
such as triphenylphosphine had no effect at all (results not
shown). When the reaction was carried out by simply mixing
1a and NFSI at ambient temperature in the absence of any
catalyst, a 61% yield was obtained for 2a (entry 4)! Clearly this
intriguing C-C bond cleavage of allylic alcohols proceeds under
transition metal-free conditions. The use of other fluorinating
reagents such as Selectfluor provided no conversion to 2a at all
(entry 5). The effect of various bases as the additive was
examined next, which led to reduced reaction efficiency (e.g.,
use of K2CO3 in entry 6). Considering the important precedent
on photo-catalyzed fluorination reactions from the Lectka
group,13b we tested the effect of light for our reaction. By
carrying out the same reaction in the dark. The same reaction
efficiency was obtained, thus excluding the possibility of
photocatalysis (entry 7). When Ag- or Cu-based salts that are
known to promote single electron transfer were examined, no
improvement was observed for our reaction either (entries 8-
9).11
wide range of fluoroalkenes bearing electron-deficient (4b-4e),
electron-neutral (4f-g) and electron-rich (4h) substitutions at
the para-position of the arene were prepared in good to
excellent yield. Reactive functionalities such as ester or cyano
groups could be well tolerated to produce (4i
as a single isomer. Meta-substituted arenes such as 4k worked
out similarly well. For ortho-substituted substrates (4l 4n), only
-4j) in good yield
-
moderate yields were obtained probably due to steric
hindrance of these substrates. Naphthyl- and heterocycle-
substituted fluoro-alkenes (4o-4r) could also be prepared in
reasonable yields. While alkyl-substituted allylic alcohols failed
to produce the desired products, alkenyl- and alkynyl-
substituted substrates underwent fluorination smoothly to
produce fluoro-substituted diene 4s and enyne 4t. Such highly
functionalized fluoroalkenes are accessed for the first time and
could prove highly valuable as building blocks in chemical
synthesis.
In addition to cyclopentanols, this fluorination method is
also applicable to the opening of different sized rings, including
4, 6, 7, and 8-membered substrates (Scheme 3b). In this way a
series of fluoroalkenes bearing a formyl or alcohol
functionality in different distances can be accessed
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Scheme 3. Scope of Fluorination-Induced Ring Opening of Cyclic Allylic
Alcohols
conveniently, although the efficiency gradually drops for
longer tethers (4u-4x). In addition to the generation of simple
linear products, substitution at different positions in the
cycloalkanol substrates (such as 1y and 1z) was well-tolerated
Finally, a double fluorination of bis-allylic alcohol
worked out smoothly to produce bis-fluoroalkene
5
also
in
6
to produce α- or β-branched fluoroalkene-containing alcohols
4y and 4z with excellent Z-selectivity (Scheme 3c).
moderate yield as
transformation, however, failed to produce ketone products
by the reaction of tertiary allylic alcohols related to 1a
a single isomer (Scheme 3d). This
.
Although tertiary alcohols are more popular substrates in
carbon-carbon bond activation, in our case the more serious
steric hindrance in these substrates are likely the culprit for
this lack of reactivity.
The success of the opening of large-ring substrates
suggested that acyclic substrates might undergo similar
transformation as well. Substituted acyclic allylic alcohols were
examined next. As shown in Scheme 4a, this type of substrates
underwent the same C-C bond cleavage to produce
trisubstituted fluoroalkenes,7,8 while producing benzaldehyde
as the side product. It is noteworthy the alternative semi-
pinacol rearrangement product (Scheme 1b) was not observed
at all. The efficiency of this process, however, leaves much
room for further optimization. While 8a bearing an electron-
rich aryl substituent was obtained in a good yield of 70%, most
fluoroalkenes were produced in yields ranging from 14-33%.
The stereoselectivity of this process, however, is uniformly
high to produce the fluoroalkenes as a single Z-isomer. Related
fluoroalkenes of the same substitution pattern have been
popular targets in medicinal chemistry15 and our method
represents an alternative method for their synthesis with
unparalleled stereoselectivity.
In addition, this fluorination of allylic alcohols can be
extended to benzylic alcohols (Scheme 4b). A proof-of-
principle reaction involves the fluorination of indole-
substituted benzylic alcohol 9, which produced 3-fluoroindole
10 in 24% yield. This greatly expanded the scope of this
fluorination method and further application is currently under
investigation.
a) fluorination of acyclic allylic alcohols
OH
R2
Ph
4 Å MS
PhO2S
PhO2S
+
N F
R1
F
toluene, 40 °C, 20 h
R1
2.0 equiv.
R2
7
8, Z/E = >20:1
F
F
F
MeO
Me
8a, 70%
8b, 33%
8c, 28%
Cl
F
F
F
Cl
8d, 33%
8e, 16%
8f, 14%
b) fluorination of benzylic alcohol
HO
Ph
F
PhO2S
N
same as above
+
F
PhO2S
N
N
Ts
10, 24%
Ts
2.0 equiv.
9
Scheme 4. Scope of Fluorination of Acyclic Allylic and Benzylic Alcohols
It is worth noting that an aryl (or sp2-hybridized)
substituent on the alkene moiety of the allylic alcohol
See SI for detailed procedure. The product Z/E ratios were determined by crude
NMR. All yields are isolated yields. a 5 mmol scale reaction
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substrates is required for the synthesis of fluoroalkenes as formed preferentially on the more electron-rich benzylic
shown in scheme 3 and 4. When allylic alcohols bearing an position, which explained why 8g was not formed. This
alkyl substituent were examined (11 or 12), an intriguing, observation also indicated that oxetane is likely a side reaction
complete switch of reactivity was observed (Scheme 5). In the pathway in the fluoroalkene synthesis instead of being an
case of cyclopentanols 11
conditions led to the formation of
moderate to good yields, which should be formed via
fluorination followed by a hydride migration. In contrast, the
acyclic allylic alcohols 12 underwent -fluorination followed by
, fluorination under identical intermediate for the formation of 8g or other fluoroalkenes
shown in scheme 4.
β
-fluoroketones 13a-c in
β
-
β
a more classical semi-pinacol rearrangement to deliver
fluoroaldehydes 14a-f in uniformly good yield.10 While these
β
β
-
-
fluoroketones 13 and 14 are valuable compounds for their
own sake, their synthesis also provided important insight for
the mechanism of this catalyst-free fluorination of allylic
alcohols. More intriguingly, a small amount of fluoroalkene 8a
was obtained during the synthesis of 14e and 14f. The
formation of 8a from 12, a formally cleavage of the alkene
moiety of the substrate, led us to hypothesize the involvement
of a key oxetane intermediate in the fluoroalkene synthesis.
See SI for detailed procedure. The product d.r. ratios were determined
by crude NMR. All yields are isolated yields. a The reaction was carried
out at 80 oC.
Scheme 6 Preliminary mechanistic studies and the proposed reaction
pathway.
Scheme 5. Fluorination of alkyl-substituted allylic alcohols.
Based on the above observations and taken all the types of
fluorination products into consideration, we propose the
general mechanism for fluorination of allylic alcohols using
NFSI shown in scheme 6c. For the substrates bearing an aryl
substituent (or alkenyl, alkynyl as in 5s and 5t), the
electrophilic fluorination generates a zwitterion II, in which the
formation of a more stable benzylic carbocation serves as the
driving force for this regio-selectivity. Fragmentation of II then
leads to the formation of fluoroalkenes. Oxetane formation
In an effort to better understand the limitation in the
fluorination of acyclic allylic alcohols, the reaction of 7g was
carried out in a larger scale and the product mixture was
analyzed carefully (Scheme 6a). In addition to the desired
fluoroalkene 8g, β-fluoroaldehyde 17 was isolated in a low
yield, indicating that two fluorination pathways were in
competition. More interestingly, a small amount of oxetane 15
and the alternative Z-fluoroalkene 16 were also isolated, which
could be linked to the formation of 8a from fluorination of
(
III) is a side pathway from this reaction, which could undergo
fragmentation through zwitterion II or the alternative species
to deliver the more electron-rich fluoroalkene product (e.g.,
16).16 For the substrates bearing an alkyl substituent, on the
12e/12f as shown in scheme 5.
When oxetane 15 was subjected to the fluorination
conditions (scheme. 6b), however, only a slow conversion to
16 was observed; no formation of 8g could be detected. We
hypothesized that the conversion of 15 to 16 likely proceeded
through a zwitterionic intermediate and the carbocation is
other hand, the electrophilic fluorination takes place at the β-
position to generate zwitterion IV. Again the stability of
carbocation is likely the determining factor. A migration (either
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Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev.,
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Milani and G. Resnati, Chem. Soc. Rev., 2012, 41, 31.
a hydride or aryl group) will then follow to deliver the more
traditional β-fluorocarbonyl products.
The products from this reaction can be used as versatile
building blocks to prepare various organofluorine compounds
(scheme 7). In addition to the reduction of 2a to yield alcohol
4a, reductive amination or Wittig olefination of 2a worked out
smoothly in one-pot with fluorination to yield amine 18 or
enone 19 in good yield (Scheme 7a). The alcohol functionality
in 4a could also be converted to ester or bromide
functionalities as in 20 and 21 without optimization (Scheme
7b). More importantly, the fluoroalkene moiety has proven to
be a synthetically versatile building block to access a diverse
range of fluoro-containing compounds.17 As representative
examples, hydrogenation and dibromination of 4a were
carried out to produce alkyl fluoride 22 and multiple-halogen-
2
(a) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473,
470; (b) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem.
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For a selected recent review, see: X. Yang, T. Wu, R. J. Phipps
and F. D. Toste, Chem. Rev., 2015, 115, 826.
For a selected recent review, see: M. G. Campbell and T.
Ritter, Chem. Rev., 2015, 115, 612.
For a selected review on fluoroalkenes, see: S. Couve-
Bonnaire, D. Cahard and X. Pannecoucke, Org. Biomol.
Chem., 2007, 5, 1151. For selected reviews on fluoroalkene
synthesis, see: (b) D. J. Burton, Z.-Y. Yang and W. Qiu, Chem.
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Chem. Soc., Perkin Trans. 1, 2002, 2117; (d) G. Landelle, M.
Bergeron, M.-O. Turcotte-Savard and J.-F. Paquin, Chem. Soc.
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3
4
5
containing 23
.
6
7
M.-H. Yang, S. S. Matikonda and R. A. Altman, Org. Lett.,
2013, 15, 3894 and references therein.
For selected reviews on fluoroalkene synthesis via
olefination, see: (a) B. Zajc and R. Kumar, Synthesis, 2010,
1822; (b) E. Pfund, T. Lequeux and D. Gueyrard, Synthesis,
2015, 47, 1534; (c) Y. Zhao, F. Jiang and J. Hu, J. Am. Chem.
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8
9
M. J. Koh, T. T. Nguyen, H. Zhang, R. R. Schrock and A. H.
Hoveyda, Nature, 2016, 531, 459.
N. Ahlsten and B. Martin-Matute, Chem. Commun., 2011, 47
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,
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F. Romanov-Michailidis, L. Guénée and A. Alexakis, Angew.
Chem. Int. Ed., 2013, 52, 9266.
11 (a) H. Zhao, X. Fan, J. Yu and C. Zhu, J. Am. Chem. Soc., 2015,
137, 3490; (b) S. Bloom, D. D. Bume, C. R. Pitts and T. Lectka,
Chem. Eur. J., 2015, 21, 8060; (c) S. Ren, C. Feng and T.-P.
Loh, Org. Biomol. Chem., 2015, 13, 5105.
Scheme 7 Derivatization of Fluoroalkenes.
12 For selected reviews, see: a) G., Dong, Topics in Current
Chemistry. Springer, 2014; (b) I. Marek, A. Masarwa, P.-O.
Conclusions
Delaye and M. Leibeling, Angew. Chem. Int. Ed., 2015, 54
414; (c) L. Souillart and N. Cramer, Chem. Rev., 2015, 115
9410.
,
,
We have discovered a general fluorination of allylic alcohols
and in particular, a conceptually new and practical method to
access functionalized Z-fluoroalkenes with good to excellent
geometry control. This operationally simple procedure involves
the reaction of readily available allylic alcohols and NFSI open
to air with gentle heating to produce the versatile
functionalized fluoroalkenes. Current efforts in our laboratory
are focused on the application of this method to the
preparation of other valuable fluorinated compounds.
13 For selected reviews, see: (a) F. Chen, T. Wang and N. Jiao,
Chem. Rev., 2014, 114, 8613; For a recent elegant example of
fluorination-induced photo-catalytic cleavage of unstrained
C-C bond, see: (b) C. R. Pitts, M. S. Bloom, D. D. Bume, Q. A.
Zhang and T. Lectka, Chem. Sci., 2015, 6, 5225.
14 (a) Y. Zhang, C.-S. Lim, D. S. B. Sim, H.-J. Pan and Y. Zhao,
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Zhang, R. H. B. Chua, H.-J. Pan and Y. Zhao, J. Am. Chem. Soc.,
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Acknowledgements
We are grateful for the generous financial support from
Singapore National Research Foundation (NRF Fellowship R-
143-000-477-281) and the Ministry of Education (MOE) of
Singapore (R-143-000-613-112).
16 (a) J. R. Ludwig, P. M. Zimmerman, J. B. Gianino and C. S.
Schindler, Nature 2016, 533, 374; (b) L. Ma, W. Li, H. Xi, X.
Bai,E. Ma, X. Yan, Z. Li, Angew. Chem. Int. Ed. 2016, 55
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,
17 For selected examples, see: (a) M. Engman, J. S. Diesen, A.
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Notes and references
1
For selected recent reviews, see: (a) K. Müller, C. Faeh and F.
Diederich, Science, 2007, 317, 1881; (b) S. Purser, P. R.
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8377.
,
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