Metal-Free and User-Friendly Regioselective Hydroxyfluorination of Olefins

Article abstract of DOI:10.1021/acs.orglett.8b00681

A simple, user-friendly, metal-free protocol for the regioselective anti-Markovnikov hydrofluorination of olefins using readily available and inexpensive reagents has been developed. This new approach displays a broader scope than previously reported methodologies and has been applied to the late-stage fluorination of a complex molecule, giving rise to a fluorosteroid derivative. The stereochemistry of the process has also been studied in some detail.

Full text of DOI:10.1021/acs.orglett.8b00681

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free and User-Friendly Regioselective Hydroxyfluorination of
Olefins
Daniel M. Sedgwick,†,‡ Ines Lopez,† Raquel Roman,‡ Nanako Kobayashi,§ Otome E. Okoromoba,∥
́
́
́
Bo Xu,⊥ Gerald B. Hammond,*,∥ Pablo Barrio,*,† and Santos Fustero*,†,‡
†Departamento de Química Organ
́
ica, Universidad de Valencia, E-46100 Burjassot, Spain
Príncipe Felipe, E-46012 Valencia, Spain
‡Laboratorio de Molec
́
ulas Organicas, Centro de Investigacion
́
́
§Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
∥Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
⊥College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
S
* Supporting Information
ABSTRACT: A simple, user-friendly, metal-free protocol for the regioselective anti-
Markovnikov hydrofluorination of olefins using readily available and inexpensive reagents
has been developed. This new approach displays a broader scope than previously reported
methodologies and has been applied to the late-stage fluorination of a complex molecule,
giving rise to a fluorosteroid derivative. The stereochemistry of the process has also been
studied in some detail.
1,2-Difunctionalization of olefins and alkynes has become one
of the most powerful strategies for the rapid construction of
molecular complexity, since it allows the introduction of two
vicinal functional groups at the expense of the π-component of
a double or triple bond.1 Sharpless’ asymmetric dihydroxylation
or aminohydroxylation reactions are emblematic examples of
such processes.2 On the other hand, organofluorine compounds
have received a great deal of attention by synthetic organic
chemists in recent decades.3 The unique physical−chemical
properties brought about by the introduction of fluorine in
organic molecules and the resulting effect on their correspond-
ing pharmacological profiles,4 along with their applications in
imaging techniques5 or material science,6 has propelled the
research in this field forward. Among organofluorine com-
pounds, fluorohydrins7 stand out as an important subclass with
Figure 1. Biorelevant compounds containing the 1,2-fluorohydrin
subunit.
fludrocortisone (1A) being the first fluorine-containing mar-
keted drug (Figure 1).8 In addition to this paradigmatic
example, recently reported drugs such as the ocular anti-
inflammatory corticosteroid Difluprednate9a−c (1B, Sirion
2008) or the antihepatitis C agent Sofosbuvir9d (1C, Gilead
2013) contain the 1,2-fluorohydrin substructure. Not only
steroid and nucleotide analogs but also alkaloid-derived
fluorohydrins have been described.9e
The synthesis of fluorohydrins has mostly relied on the
nucleophilic opening of epoxides with several fluoride sources,
among which the use of HF·base reagents (e.g., Olah’s reagent)
is particularly noteworthy.10 Epoxides, in turn, are usually
derived from olefins by means of the well-known Prilezhaev
reaction using m-CPBA,11 among other methodologies.12 In
view of the wide availability and low cost of olefins, we
envisioned that the direct 1,2-difunctionalization of olefins
toward the corresponding fluorohydrins would be an ideal
synthetic approach for this subclass of biorelevant compounds
(Scheme 1).
In spite of its a priori simplicity, to the best of our knowledge,
only one report studying the compatibility of an electrophilic
epoxidating agent (m-CPBA) and a nucleophilic fluoride source
(HBF4) has been published, although this report is limited to
the use of allylic amines as substrates.13 On the other hand,
most studies of olefin hydroxyfluorination rely on electrophilic
fluorine sources (Selectfluor, NFSI) resulting, in some cases, in
the opposite regioselectivity.14 Moreover, some of these
Received: February 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the replacement of chloroform by dichloromethane as the
reaction solvent made no significant difference to the outcome
of the reaction (Table 1, entries 10 and 11). Therefore, reaction
conditions that included the simultaneous addition of 2 equiv
of m-CPBA and 7 equiv of HF·Py to the olefin in DCM at 0 °C
were determined to be optimal.
Scheme 1. 1,2-Difunctionalization Approach towards
Fluorohydrins
With the optimized conditions in hand, we investigated the
scope and limitations of this highly convenient protocol
(Scheme 2). First, styrene derivatives bearing several
a b
,
Scheme 2. Scope and Limitations
protocols proceed through radical pathways and are limited to
styrene derivatives because they are able to stabilize the radical
intermediate formed upon addition of the hydroxyl radical
(Scheme 1, eq 1).14a In addition, the recent report by Xu and
Tang suffers from complex reaction conditions (AgOTf/Sm
(OTf)3, Selectfluor, PhNO2/H2O/MeNO2).
We started our study by optimizing the number of
equivalents of both HF and m-CPBA (used as received from
the commercial source), the HF source, and the delay in HF
addition (Table 1, t). Regarding the number of equivalents
Table 1. Optimization of the Reaction Conditions
ab
,
entry
n
m
t (h)
HF·base
solvent
yield (%)
1
1.1
1.2
1.5
2
2.2
2.4
3
1
HF·DMPU
HF·DMPU
HF·DMPU
HF·DMPU
HF·DMPU
HF·DMPU
HF·DMPU
HF·DMPU
HF·TEA
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
32
44
48
55
76
77
75
75
NR
74
75
2
1
3
1
4
4
1
5
2
7
1
6
2
7
4
a
b
Isolated yields. Diastereomeric ratio in parentheses, when observed.
7
2
7
0.5
0
c
3:1 mixture of cis/trans isomers.
8
2
7
9
2
7
0
10
11
2
7
0
HF·Py
HF·Py
substituents at the para position were evaluated 2a−j (Scheme
2). To our delight, we found that several electron-withdrawing
substituents were well tolerated, affording the corresponding
fluorohydrins 3a−g in moderate to good yields (Scheme 2). On
the other hand, electron-donating substituents at the para
position 2h−j (Scheme 2) hampered the reaction, possibly due
to the diminished electrophilicity of the benzylic carbon (the
intermediate epoxide was the main species identified in the
crude reaction mixture).15 This explanation is supported by the
moderate yield obtained for the m-methoxy substituted
substrate 2k, in which the −I effect of the electronegative
oxygen atom overrides its +R effect due to lack of conjugation
with the benzylic position (Scheme 2).16 Next, allylbenzene
substrates 2l−n were tested (Scheme 2).
In these cases, the introduction of a fluorine atom at the para
position resulted in a somewhat diminished regioselectivity,
while a para-methoxy substituent improved the regioselectivity,
although at the expense of chemical yield. Aliphatic
unfunctionalized substrates, both cyclic and linear, also afforded
the corresponding fluorohydrins 3o−r in good to excellent
yields (Scheme 2). Regarding the substitution pattern, a
2
7
0
a
b
NMR yield. Minor amounts (ca. 5%) of the product arising from the
nucleophilic ring opening by 3-chlorobenzoic acid were observed in
the crude reaction mixture.
(Table 1, entries 1−5), an excess of HF·DMPU (N,N′-
Dimethylpropyleneurea or 1,3-Dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone) with respect to m-CPBA was necessary;
we found that the use of 2 and 7 equiv, respectively, afforded
the highest yield (Table 1, entry 5). On the other hand,
allowing the olefin to react with m-CPBA prior to the addition
of HF·DMPU did not lead to any advantage (Table 1, entries
5−8); thus, we decided to establish the addition of both
reagents from the onset as the optimized conditions seeking
maximum practicality (Table 1, entry 8).
In addition, given that only minor differences were observed
between HF·DMPU or HF·Py as the fluoride source (Table 1,
entries 8 and 10) we decided to continue our study with Olah’s
reagent, as it is readily available and inexpensive. No reaction
took place when HF·TEA was used (Table 1, entry 9). Lastly,
B
DOI: 10.1021/acs.orglett.8b00681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dramatic drop in chemical yield was observed when switching
from cyclohexene to 1-methylcyclohexene 3q vs 3r (Scheme 2),
while the reaction with 1,2-dimethylcyclohexene did not afford
the desired product. Finally, in order to study the suitability of
this new methodology for the late-stage functionalization of
complex organic molecules, cholesterol 2s produced the
corresponding fluorohydrin 3s in high yield and with high
regio- and diastereoselectivity (Scheme 2).17 The latter result
showcases the amenability of our approach for late-stage
fluorination of complex natural products and pharmaceuticals.
Recently, we reported the HF·DMPU-mediated ring opening
of aziridines in detail.18 From this study, we concluded that the
stereochemical outcome of this reaction was more complex
than anticipated. Therefore, we investigated the stereochemical
aspects of our new protocol, namely, its double stereo-
specificity. We selected cis- and trans-stilbene (cis-2t and
trans-2t) as model substrates (Scheme 3). Unexpectedly,
Table 2. Ring Opening of Enantioenriched Ia
a
entry
HF-amine
base
ee %
1
2
3
4
HF·Py
−
−
Et3N
15
10
20
11
HF·DMPU
HF·DMPU
HF·DMPU
Py
a
Determined by HPLC.
Scheme 4. Ring Opening of Enantioenriched Io
Scheme 3. Stereochemical Outcome with Stilbenes
develop an enantioselective version of this hydrofluorination
reaction.20
In conclusion, we have developed a convenient and user-
friendly hydrofluorination of olefins that uses readily available,
inexpensive reagents (m-CPBA and HF·Py) and mild reaction
conditions (CH2Cl2, 0 °C, under air). The reaction has shown
good functional group tolerance and is suitable for the late-
stage fluorination of complex organic molecules bearing a
double bond. An additional benefit of our one-pot protocol is
the stereospecific nature of the two processes, namely syn
epoxidation and anti epoxide opening, as well as from extremely
practical and economical reaction conditions. The development
of an asymmetric version of this methodology is currently
under study in our laboratories.
although trans-2t afforded exclusively the anti-3t product, cis-
2t furnished a 1:1 mixture of syn- and anti-3t using our optimal
conditions. We suspect this result is due to the ring opening of
strained cis-epoxide intermediate cis-It, resulting in the
stabilized benzylic carbocation IIt (Scheme 3). The lack of
stereoselectivity observed suggests that the α stereocenter is
unable to direct the nucleophilic attack by the fluoride anion.
These results made us question whether the ring opening of
the intermediate epoxide could have proceeded with erosion of
optical purity if the starting material was enantiomerically
enriched, which was similar to our observations with
aziridines.18 Hence, commercially available (R)-styrene oxide
was subjected to a nucleophilic ring opening with HF·Py under
identical conditions to the one-pot procedure (Table 2, entry
1). Indeed, a major loss of optical purity was observed (>99%
to 15% ee). The use of the more acidic HF·DMPU gave rise to
a higher degree of racemization (Table 2, entry 2).
Furthermore, the use of an external base did not improve the
optical purity of the product to a satisfactory degree (Table 2,
entries 3 and 4).
The stabilization of the benzylic carbocation again explains
the aforementioned results. Thus, in order to find further
support to this assumption, enantiomerically enriched (S)-1-
dodecene oxide (S)-Io was synthesized, according to a reported
procedure,19 and was subjected to nucleophilic ring opening
with HF·Py (Scheme 4). To our satisfaction, an improved 76%
ee was obtained, demonstrating complete conservation of the
optical purity. These results must be taken into account to
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00681.
Experimental procedures, characterization of all new
compounds, copies of HPLC chromatograms and NMR
spectra (H, C, and F) (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: santos.fustero@uv.es.
*E-mail: pablo.barrio@uv.es.
*E-mail: gb.hammond@louisville.edu.
C
DOI: 10.1021/acs.orglett.8b00681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
I.; Olah, J. A. J. Org. Chem. 1979, 44, 3872. (i) Olah, G. A.; Meidar, D.
Isr. J. Chem. 1978, 17, 148.
Bo Xu: 0000-0001-8702-1872
Gerald B. Hammond: 0000-0002-9814-5536
Santos Fustero: 0000-0002-7575-9439
Author Contributions
(11) Prilezhaev, N. Ber. 1909, 42, 4811.
(12) For some recent reviews on alternative epoxidation methods,
see: (a) Ujwaldev, S. M.; Sindhu, K. S.; Thankachan, A. P.; Anilkumar,
G. Tetrahedron 2016, 72, 6175. (b) Krishnan, K. K.; Thomas, A. M.;
Sindhu, K. S.; Anilkumar, G. Tetrahedron 2016, 72, 1. (c) Cusso, O.;
Ribas, X.; Costas, M. Chem. Commun. 2015, 51, 14285. (d) Davis, R.
L.; Stiller, J.; Naicker, T.; Jiang, H.; Jorgensen, K. A. Angew. Chem., Int.
Ed. 2014, 53, 7406. (e) Zhu, Y.; Wang, Q.; Cornwall, R. G.; Shi, Y.
Chem. Rev. 2014, 114, 8199. (f) Saisaha, P.; de Boer, J. W.; Browne, W.
R. Chem. Soc. Rev. 2013, 42, 2059. (g) De Faveri, G.; Ilyashenko, G.;
Watkinson, M. Chem. Soc. Rev. 2011, 40, 1722. (h) Weiss, K. M.;
Tsogoeva, S. B. Chem. Rec. 2011, 11, 18.
(13) (a) Cresswell, A. J.; Davies, S. G.; Lee, J. A.; Morris, M. J.;
Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2012, 77, 7262. For the
use of the m-CPBA/HF combination in other types of trans-
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J. J. Org. Chem. 2017, 82, 11721. (c) Suzuki, S.; Kamo, T.; Fukushi, K.;
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(16) This behavior has recently been reported by our group in the
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the Spanish MINECO (CTQ2013-
43310 and CTQ2017-84249-P) and Generalitat Valenciana
(PROMETEOII/2014/073) for their financial support. G.B.H.
acknowledges the support of the National Institutes of Health
(Grant R01GM121660). D.M.S. expresses his thanks to the
Spanish Government and Generalitat Valenciana for a
predoctoral fellowship.
DEDICATION
■
In memory of Prof Kenji Uneyama.
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DOI: 10.1021/acs.orglett.8b00681
Org. Lett. XXXX, XXX, XXX−XXX