Straightforward chemo- and stereoselective fluorocyclopropanation of allylic alcohols: Exploiting the electrophilic nature of the not so elusive fluoroiodomethyllithium

Article abstract of DOI:10.1039/c9cc03394g

An unprecedented direct fluorocyclopropanation of allylic alcohols is reported. This simple method involves the not so elusive fluoroiodomethyllithium, a carbenoidic intermediate that under the developed conditions discloses its electrophilic nature. Gratifyingly, the reaction turned out to be highly chemo- and stereoselective, and DFT calculations provided insights into the structure and nature of this new type of carbenoid.

Full text of DOI:10.1039/c9cc03394g

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DOI: 10.1039/C9CC03394G
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Straightforward chemo- and stereoselective
fluorocyclopropanation of allylic alcohols: Exploiting the
electrophilic nature of the not so elusive fluoroiodomethyllithium
Received 00th January 20xx,
Accepted 00th January 20xx
Marco Colella,a,‡ Arianna Tota, Angela Großjohann , Claudia Carlucci, Andrea Aramini,
a, ‡
a
a
b
c,*
a,*
a,*
DOI: 10.1039/x0xx00000x
Nadeem S. Sheikh, Leonardo Degennaro, and Renzo Luisi,
5
An unprecedented direct fluorocyclopropanation of allylic alcohols the nucleophilic fluorination, the addition of carbene to
6
is reported. This simple method involves the not so elusive fluoroalkenes and the addition of fluorocarbene or
fluoroiodomethyllithium, a carbenoidic intermediates, that under fluorocarbenoids to alkenes. Every protocol has pros and cons
the developed conditions discloses its electrophilic nature. mainly related to the availability and the ease of preparation of
Gratifyingly, the reaction turned out to be highly chemo- and the starting materials, or the stability of the intermediates
stereoselective, and DFT calculations provided insights on the involved in the process. A rather underexploited strategy, for
structure and nature of this new type of carbenoid.
making fluorinated molecules, is based on the use of fluorinated
organometallics such as fluorinated carbenoids where both the
fluorine and the metal atoms (i.e. Li, Zn or Mg) are bound to the
same carbon. The intrinsic nature of fluorinated carbenoids
would make them suitable electrophilic reagents for the
cyclopropanation of alkenes. In fact, it has been demonstrated
that halo carbenoids could react as nucleophiles or
electrophiles depending on the reaction conditions and the
Fluorinated compounds are of paramount importance in
modern synthetic chemistry. The presence of a fluorine atom in
an organic molecule could profoundly affect some molecular
properties, and this is particularly significant in medicinal
chemistry.1 With regard to the preparation of fluorinated
molecules, several strategies have been invented in the last
decades.2 Among the fluorinated molecules of interest in
medicinal chemistry, monofluorinated cyclopropanes are
attractive scaffolds found in several biologically active
7
nature of the coupling partners. Concerning the direct
fluorocyclopropanation of alkenes, Schlosser reported that the
reactions of mono-fluorocarbenoids with alkenes furnished,
3
compounds (Figure 1).
8
albeit in low yields, the expected fluorocyclopropanes.
Similarly, Burton succeeded to generate fluorochloro-,
fluorobromocarbenoids, subsequently employed for the
preparation of 1,1´-halofluorocyclopropanes. However, these
strategies found limited synthetic applicability, and noticeably,
required very low temperatures (i.e. -116 °C) for controlling the
reactivity of such unstable intermediates. A more synthetically
useful strategy, for the preparation of mono-
fluorocyclopropanes, was introduced by Terashima, who
H
F
CO2H
F
MeO2C
HN
Cl
Cl
9
H
NH2
ODMT
O
N
O
N
S
HO2C
O
N
NHBz
Antidepressant
O
F
N
O
O
P
F
NH2
Ph
H2O3P
O
(
i-Pr)2N
OCH2CH2CN
CO2H
F
O
N
NH2
Anxiolytic
Antisense Oligonucleotide
mGluRIII agonist
Protease Inhibitor
Figure 1. Bioactive entities bearing a monofluorocyclopropyl
unit.
Notwithstanding the potential of the fluorocyclopropane unit,
the synthesis of these molecular motifs is rather difficult. The
available strategies for the preparation of mono-
exploited
a
zinc fluorocarbenoid generated from
fluorodiiodomethane in the presence of diethylzinc (Scheme 1).
The strategy was found successful for the cyclopropanation of
1
0
enamines. More recently, Charette reported the use of
difluoroiodomethane as starting material for the genesis of the
same zinc fluorocarbenoids reported by Terashima but
4
fluorocyclopropanes rely on the Michael initiated ring closure,
a
Department of Pharmacy – Drug Sciences, University of Bari “A. Moro” Via E. exploiting an unusual F/I exchange reaction (Scheme 1). The
Orabona 4 - 70125 Bari, Italy.
Department of Discovery Dompé Farmaceutici S.p.A., Via Campo di Pile, L’Aquila
Charette’s methodology allowed for a direct and effective
b
6
7100, Italy
fluorocyclopropanation of allylic alcohols with high
stereocontrol, nevertheless a long reaction time was required
c
Department of Chemistry, College of Science, King Faisal University, P.O. Box 380,
Al-Ahsa 31982, Saudi Arabia
(
15 hours stirring at -40 °C), and the use of dichloromethane as
‡
These authors contributed equally.
Electronic Supplementary
DOI: 10.1039/x0xx00000x
1
1
Information
(ESI)
available:.
See solvent. In continuation of a research plan on the chemistry of
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Page 2 of 5
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Journal Name
fluorinated
fluorocarbenoids, we recently reported that the very unstable values of the
fluoroiodomethyllithium could be generated by deprotonation comparison with already reported molecules (see
organometallics,
and
in
particular fluorinated cyclopropane was ascertained on the basis of the
View Article Online
DOI: 10.1039/C9CC03394G
1
2
3
3
JH-H and
JH-F coupling constants, and by
1
3
of fluoroiodomethane with a suitable lithium amide.
Supplementary Material). The optimization was continued,
According to Moss and Burton’s studies, such fluorinated searching for the optimal conditions to maximize the yield of
carbenoid was considered highly unstable and difficult to the desired fluorocyclopropane. Parameters such as the
1
4
generate for synthetic exploitation. We have successfully stoichiometry of the reagents, the nature of the solvent, and the
demonstrated that, under internal quenching conditions, temperature were judiciously screened (see Supporting
fluoroiodomethyllithium could react, as a nucleophile, with Information). As a result of this study, a dramatic role of the
carbonyls or imines to provide unusual and synthetically useful solvent was observed – ethereal solvents such as THF likely
1
3
fluoroepoxides and fluoroaziridines (Scheme 1). Herein, we exalted the electrophilic nature of the carbenoid – and the
report an efficient direct fluorocyclopropanation of allylic effect of the concentration and temperature. The optimal
alcohols, exploiting the unprecedented electrophilic behavior of conditions provided fluorocyclopropane 4b up to 80% yield
the same fluoroiodomethyllithium carbenoid (Scheme 1). using 1/LDA/2b in 1:3:2 molar ratio respectively, and running
Pleasingly, our approach has exhibited an excellent chemo- and the reaction at -50 °C (see Supporting Information). With the
stereoselectivity, adopting a fast and easy procedure en route optimal conditions in hand, the role of the unsaturated acceptor
to monofluorocyclopropanes.
was evaluated (Scheme 3). The use of a preformed lithium
alcoholate 5 was not beneficial leading to 4b in only 20% yield.
The use of allylic ether 6 resulted in unfruitful reaction as well
as in the case of cynammic acid 7, homoallylic alcohol 8, styrene
9, and propargyl alcohol 10 (Scheme 3). These experiments
would rule out the involvement of a carbolithiation sequence.
In addition, although the alcohol is expected to be not
compatible with organolithium species, these data strongly
suggested that the hydroxyl group at the allylic position is an
Terashima, 1994
COOR
HN
H
I
I
N
COOR
Et2Zn
F
I
F
ZnF
CH Cl2
F
2
-
40 °C, 1h
Charette, 2013
OH
F
F
F
I
EtZnI
F
I
F
ZnI
F
ZnF
CH2Cl2
OH
-40 °C, 15h
X
R3
Luisi, Pace 2019
R1 R2
R1
O
R1
R2
N
or
nucleophilic
route
R2
F
F
1
7
essential requirement for the process.
LiNR2
Li
F
I
F
I
F
OH
LDA
(3 equiv)
Ph
(2 equiv)
Li
F
This work
electrophilic
route
F
I
Ph
THF
-50 °C
I
F
in situ quenching
OH
1
1-Li
THF, -50 °C, 15 min
(1 equiv)
0.03 M
Scheme 1. Strategies for accessing fluorocyclopropanes.
OH
OLi
OBn
OLi
Ph
Ph
Ph
Ph
O
This investigation began while studying the reactivity of
fluoroiodomethyllithium 1-Li with ,-unsaturated carbonyls.
With the aim to prepare unsaturated fluoroepoxides, traces of
compound 4a were detected during the analysis of the crude
2b
5
6
7
80%
dr =90:10
20%
0%
<5%
OH
H
Ph
OH
Ph
Ph
8
9
10
0%
1
9
0%
0%
reaction mixture by F NMR ( = -218 ppm) (Scheme 2).
1
1
Scheme 3. Testing unsaturated systems in the
fluorocyclopropanation.
Inspired by the Charette’ reports, we hypothesized that LDA
would have reduced ketone 2, providing lithiated alkoxide 2-Li
that smoothly underwent cyclopropanation in the presence of
With the aim to apply this unprecedented and simple method
to the stereoselective synthesis of fluorocyclopropanes, the
scope of the reaction was investigated (Scheme 4). First the use
of trans-aryl substituted allylic alcohols (2b-2j) was considered,
observing the expected fluorocyclopropanes 4b-4j in good
yields and high stereoselectivity (dr >90:10). Electron-donating
groups as well as halogens were tolerated as substituents of the
aromatic ring. Interestingly, no interference was observed with
the dimethylamino functionality (4g) or the bromine (4j) as aryl’
substituents. The presence of electron-withdrawing groups, as
the substituents of the aromatic ring, affected the
cyclopropanation reaction. In fact, no reaction was observed in
the presence of the NO
the presence of the CF
ad (Scheme 4) was obtained in 15% yield although as a single
diastereoisomer. The presence of an additional substituent at
the carbinolic carbon, as for allylic alcohols 2k-n, resulted in
moderate yields of the corresponding fluorocyclopropanes 4k-
1
5
the fluorocarbenoid 1-Li.
expected
not observed
O
LDA
Li
2-Li
F
I
F
-
78 °C
THF
I
F
1
OH
1-Li
F
N
H
H
4a
O
OLi
Li
-78 °C
2
2-Li
Scheme 2. LDA mediated fluorocyclopropanation.
In order to verify our hypothesis, and demonstrate the
electrophilic nature of the fluorocarbenoid 1-Li,
fluoroiodomethane 1 (4 equiv) was reacted with LDA (4 equiv)
in the presence of cinnamyl alcohol 2b (1 equiv) in a 1/1 mixture
2
-substituent (4ac, in Scheme 4), while
-group was tolerated but the product
3
1
6
2
of THF/Et O at -78 °C. With our delight, the expected
4
fluorocyclopropane 4b was found in the reaction mixture in 28%
yield. Surprisingly, only one main diastereoisomer was detected
1
9
by F NMR analysis (dr 90:10). The stereochemistry of the
2
| J. Name., 2012, 00, 1-3
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COMMUNICATION
n and an almost unexpected high stereocontrol (dr >95:5), The use of conjugate allylic alcohol 2p resulted in a high chemo-
View Article Online
DOI: 10.1039/C9CC03394G
leading to a single stereoisomer.
and stereoselective reaction leading to 4p (Scheme 4). The use
of allylic alcohols 2q-x furnished alkyl substituted derivatives
4q-x in good yields, and a stereoselectvity depending on the
configuration of the double bond. Very high stereoselectivity
was observed using trans-configured alkenes (dr >95:5), while a
slightly lower stereoselectivity was observed with the use of cis-
configured allylic alcohols (i.e. 2v, 2x). In derivatives 4v (dr
80:20) and 4x (dr 70:30) the double bond configuration was
preserved, while the C-F configuration was likely affected by the
alkene geometry. Almost unexpectedly, the use of terminal
allylic alcohol 2ab didn’t provide the corresponding
cyclopropane 4ab. The stereochemistry at the C-F carbon was
also affected by the degree of substitution of the double bond
of the allylic alcohol. In fact, the use of either cis- or trans-
geraniol (Scheme 4) led to fluorocyclopropanes 4y and 4z
respectively, with good yields but low stereoselectivity. In
addition, the reaction was found highly chemoselective, with
the cyclopropanation occurring only at the allylic position.
Similarly, the use of peryllil alcohol produced a 70:30 mixture of
fluorocyclopropane 4aa (Scheme 4).
OH
F
LDA
Li
(
3 equiv)
(2 equiv)
(
1 equiv)
F
I
OH
0.03 M
THF
I
F
in situ quenching
4
1
-50 °C
1-Li
15 min
F
F
F
F
OCH3
OH
OH
OH
OH
4b
4c
4d
4e
H3CO
8
0%
78%
dr= 90:10
48%
64%
dr> 95:5
dr= 90:10
dr= 90:10
F
F
F
F
H3CO
H3CO
OH
OH
OH
Cl
OH
4f
N
4g
F
4h
4i
OCH3
50%
60%
54%
dr> 95:5
40%
dr> 95:5
dr> 95:5
dr> 95:5
F
F
F
F
OH
OH
OH
OH
Ph
Bu
Me
H
H
H
4
j
4k
34%
4l
4m
Br
54%
35%
dr> 95:5
38%
dr= 80:20
dr> 95:5
dr= 80:20
F
HO Bu
HO Bu
F
OH
H
H
H
Bu
Me
F
F
OH
H
4n
4p
4
o
3
6%
dr= 90:10
73%
dr> 95:5
4
1%
dr= 60:40
A) Structural analysis for 1 and 1-Li species
F
F
F
OH
OH
OH
4
r
4s
60%
dr> 95:5
4
7
q
0%
57%
dr> 95:5
dr> 95:5
F
t
F
F
B) Charge distribution analysis using electrostatic potential
map
OH
OH
OH
4
4u
4v
6
4%
dr> 95:5
81%
dr> 95:5
8
0%
dr= 80:20
F
F
OH
OH
4w
4x
5
5%
81%
dr= 70:30
dr> 95:5
F
F
F
OH
C) Proposed model to rationalize observed stereochemistry
OH
Ph
F3C
OH
OH
Li
I
I
H
F
F
F
I
F
F
H
Ph
4ac
0%
4ad
5%
dr> 95:5
4ab
2ab
O2N
Li
OX
Li
OX
+
OH
minor stereoisomer
1
OH
OH
major stereoisomer
0%
proprosed favored TS
unfavored TS
F
F
OH
F
Figure 2. DFT studies [B3LYP/6-311++G(d,p) – LanL2DZ basis set
for I-atom] and proposed model for the observed
stereoselectivity.
OH
OH
OH
OH
4
y-(major)
4z-(major)
F
4aa-(major)
F
OH
F
Once established the synthetic utility of this strategy, we were
keen to find an explanation to the high level of chemo- and
stereocontrol of the reaction, as well as to rationalize the
electrophilic behaviour of such highly reactive carbenoid. To
4
y-(minor)
4%, dr= 70:30
from cis-geraniol
4z-(minor)
4aa-(minor)
7
88%, dr= 55:45
from trans-geraniol
36%, dr= 70:30
from peryllil alcohol
Scheme 4. Scope of the direct fluorocyclopropnation.
It is worth noting that while the presence of the substituent at this end, DFT calculations were used to get insights on the
the carbinolic carbon affected the yield of the reaction, the structure of 1-Li in the gaseous and the solvent (THF) phases
(
Figure 2A, see supporting information for further details). The
additional stereogenic centre did not affected the
stereoselectivity. This suggests that a very well organized
transition state must likely be involved (see infra). The use of
cyclic allylic alcohols such as 2a and 2o was also successful
leading to 4a and 4o in reasonable yields although with a
different stereocontrol with reference to the stereochemistry
of the C-F carbon of the cyclopropane (see supporting
information). Later, alkyl substituted allylic alcohols were also
considered.
DFT studies for the monomeric species of 1-Li in THF disclosed
a singular structure for the carbenoid. In particular, a
remarkable change in the geometry of the lithiated carbon was
noticed in going from 1 to 1-Li. Furthermore, a pronounced
effect was observed, when the calculations were carried out
using THF as a solvent. The optimized geometry of 1-Li (in THF)
clearly reveals that the Li, H and F atoms lie on the same plane,
with the iodine sticking out from this plane. Pleasingly, analysis
of the computed electronic density distribution also confirms
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J. Name., 2013, 00, 1-3 | 3
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Journal Name
the electrophilic behavior of fluoroiodomethyllithium 2014, 114, 2432; T. Ahrens, J. Kohlmann, M. AhrensVaienwdATrti.cBlerOanulinne,
Chem. Rev., 2015, 115, 931; F. Menaa, B. Menaa and O. N. Sharts,
carbenoid 1-Li in THF as a solvent (Figure 2B). These results are
perfectly in line with our experimental results, where the role
of THF is believed to enhance the electrophilic nature of the
involved carbenoid species. However, a detailed investigation is
still underway to explore the possibilities of alkyllithium-lithium
alkoxide aggregates.1
DOI: 10.1039/C9CC03394G
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Musci, C. Carlucci, S. Lillini, M. Tomassetti, A. Aramini, L.
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V. Gouverneur, R. Szpera, D. F. J. Moseley, L. B. Smith and A. J.
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doi.org/10.1002/anie.201814457; S. Preshlock, M. Tredwell and
On the basis of the computed structure, assuming a planar V. Gouverneur, Chem. Rev., 2016, 116, 719; C. Ni, M. Hu and J. Hu,
arrangement of Li, H and F atoms, it is reasonable to propose Chem. Rev., 2015, 115, 765.
3
A. Pons, T. Poisson, X. Pannecoucke, A. B. Charette and P.
that the carbenoid would approach the double bond from the
less hindered face (Figure 2C). It is likely that the oxygen atom
of the hydroxy group would be playing a role in coordinating the
Jubault, Synthesis, 2016, 48, 4060; E. David, G. Milanole, P.
Ivashkin, S. Couve-Bonnaire, P. Jubault and X. Pannecoucke,
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1
9
observed stereoselectivity. The lower stereocontrol, observed Angew. Chem. Int. Ed., 2012, 51, 6966; P. Ivashkin, S. Couve-
Bonnaire, P. Jubault and X. Pannecoucke, Org. Lett., 2012, 14,
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in some cases, could be due to the impossibility to realize such
ordered transition state (favored TS, Figure 2C), so promoting
an attack of the 1-Li with inverted stereochemistry at the C-F
2
5
M. Zhang, Y. Gong and W. Wang, Eur. J. Org. Chem., 2013, 7372.
carbon (unfavored TS, Figure 2C). The hypothesis of a well- 6 V. N. G. Lindsay, C. Nicolas and A. B. Charette, J. Am. Chem. Soc.,
organized transition state, involved in this process, was further 2011, 133, 8972; T. Shibue and Y. Fukuda, J. Org. Chem., 2014, 79,
7
226; B. Zhang and A. Studerol, Org. Lett., 2014, 16, 1790; A. Pons,
confirmed by using the optically active allylic alcohol (R)-2m (er
92:8) which provided the corresponding cyclopropane
R,S,R,R’)-4m with absolute preservation (er = 92:8) of the
P. Ivashkin, T. Poisson, A. B. Charette, X.ꢀPannecoucke and P.
Jubault, Chem Eur. J., 2016, 22, 6239.
=
(
7
V. Capriati, Modern Lithium Carbenoid Chemistry. In
enantiopurity (Scheme 6). This particular result is quite Contemporary Carbene Chemistry; Moss, R.A., Doyle, M.P., Eds;
remarkable, because the chiral allylic alcohol was able to induce John Wiley & Sons, Inc.: Hoboken, NJ 2013; Chapter 11, pp 327-
3
62; V. H. Gessner, Chem. Commun., 2016, 52, 12011; L. Castoldi,
stereoselectivity in the reaction of the fluorocarbenoid that
S. Monticelli, R. Senatore, L. Ielo and V. Pace, Chem. Commun.,
018, 54, 6692.
2
0
formally consisted in a racemic mixture.
2
Li
I
H
8 M. Schlosser and G. Heinz, Angew. Chem. Int. Ed., 1968, 7, 820;
M. Schlosser, L. Van Chau and B. Spahić, Helv. Chim. Acta, 1975,
58, 2575; M. Schlosser and G. Heinz, Chem. Ber., 1971, 104, 1934.
OH
F
F
OH
I
*
F
Li
(S)
(R)
Ph
(R) Me
Ph
OX
Ph (R) (R) Me
30%
(
R)-2m
er = 92:8
H
9
D. J. Burton and J. L. Hahnfeld, J. Org. Chem., 1977, 42, 828.
Me
(
R,S,R,R')-4m
10 O. Tamura, M. Hashimoto, Y. Kobayashi, T. Katoh, K. Nakatani,
M. Kamada, I. Hayakawa, T. Akiba and S. Terashima, Tetrahedron,
1994, 50, 3889.
er = 92:8
Scheme 5. Validation for the observed stereoselectivity.
1
1 C. Navuluri and B. Charette, Org. Lett., 2015, 17, 4288; L.-P. B.
Beaulieu, J. F. Schneider and A. B. Charette, J. Am. Chem. Soc.,
In conclusion, an unprecedented and efficient chemo- and
stereoselective synthesis of fluorocyclopropanes has been
reported. The process resulted simple, fast, and highly
2
1
013, 135, 7819.
2 G. Parisi, M. Colella, S. Monticelli, G. Romanazzi, W. Holzer, T.
Langer, L. Degennaro, V. Pace and R. Luisi, J. Am. Chem. Soc.,
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explain the observed stereochemistry. Interestingly, the model 13 S. Monticelli, M. Colella, V. Pillari, A. Tota, T. Langer, W. Holzer,
L. Degennaro, R. Luisi and V. Pace, Org. Lett., 2019, 21, 584.
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absolute preservation of the enantiopurity of the starting allylic
1
4 D. J. Burton, Y. Zhen-Yu, and Q. Weiming, Chem. Rev., 1996,
6, 1641; W. B. Farnham, Chem. Rev., 1996, 96, 1633; D. L. S.
9
Brahms, W. P. Dailey, Chem. Rev., 1996, 96, 1585; R. A. Moss, G.
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1
5 L. Degennaro, A. Giovine, L. Carroccia and R. Luisi, Practical
enantioselectivity, is underway and will be reported in due
course. This research was supported by the project Laboratorio
Sistema code PONa300369 financed by MIUR, MISE, Horizon
Aspects of Organolithium Chemistry in Lithium Compounds in
Organic Synthesis: From Fundamentals to Application, 1st ed.;
Luisi, R., Capriati, V., Eds.; Wiley-VCH: Weinheim, 2014; Chapter
2
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of Bari. N.S.S. thanks the Deanship of Scientific Research, King 16 See Supporting information for optimization study.
1
7 C. Bolm and D. Pupowicz, Tetrahedron. Lett., 1997, 38, 7349;
Faisal University for the research support.
M. J. Durán-Peña, M. E. Flores-Giubi, J. M. Botubol-Ares, L. M.
Harwood, I. G. Collado, A. J. MacÍas-Sánchez and R. Hernández-
Galán, Org. Biomol. Chem., 2016, 14, 2731.
Conflicts of interest
There are no conflicts to declare.
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2
1
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8 L. M. Pratt, O. Kwon, T. C. Ho and N. V. Nguyen, Tetrahedron,
008, 64, 5314.
9 R. A. Moss, J. Org. Chem., 2017, 82, 2307.
0 The low yield, could likely be resulting from a sort of kinetic
resolution of racemic fluorocarbenoid 1-Li. This intriguing aspect
Notes and references
1
J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
of the reactivity is still under investigation in our laboratory.
Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev.,
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| J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C9CC03394G
TOC
X
R
N
previous work
Nucleophilic behaviour
R
R
R
R
O
R
R
or
F
F
H
H
Li
LiNR2
50 °C

I
F
I
F
OH
I
-
F
H
not so elusive
carbenoid
F
Li
OX
OH
3
0 examples
this work
Electrophilic behaviour
R
yields up to 88%
dr up to >95:5
er up to 92:8
 Highly stereoselective
Highly chemoselective

DFT calculations
 Wide scope


Simple and direct method
Valuable scaffolds
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