Phosphine-Catalyzed Intermolecular Acylfluorination of Alkynes via a P(V) Intermediate

Article abstract of DOI:10.1021/jacs.0c08928

We report the phosphine-catalyzed intermolecular carbofluorination of alkynes using acyl fluorides as fluorinating reagents. This reaction promises to be a useful method for the synthesis of highly substituted monofluoroalkene derivatives since acyl fluor

Full text of DOI:10.1021/jacs.0c08928

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Phosphine-Catalyzed Intermolecular Acylfluorination of Alkynes via
a P(V) Intermediate
Hayato Fujimoto, Takuya Kodama, Masahiro Yamanaka, and Mamoru Tobisu*
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ABSTRACT: We report the phosphine-catalyzed intermolecular carbofluorination of alkynes using acyl fluorides as fluorinating
reagents. This reaction promises to be a useful method for the synthesis of highly substituted monofluoroalkene derivatives since acyl
fluorides can be easily prepared from the corresponding carboxylic acid derivatives and the reaction proceeds under ambient
conditions without the need for a transition-metal catalyst. Experimental and computational studies indicate that a five-coordinate
fluorophosphorane is involved as the key intermediate in the fluorination step.
luorinated molecules occupy an important place in the
pharmaceutical, medicinal, agrochemical, and materials
phorane derivative would permit this unprecedented C−F
bond-forming ligand coupling on P(V) to be successful. On
the basis of this hypothesis, we designed a phosphine-catalyzed
carbofluorination of alkynes via a P(III)/P(V) manifold
(Scheme 1e). It is well-known that phosphines can add not
only to an aryne but also to an electron-deficient alkyne such as
an alkynoate to form a carbanion species.11 If the resulting
carbanion 2 is sufficiently nucleophilic to react with an acyl
fluoride, fluorophosphorane 3 would be formed by nucleo-
philic acyl substitution (NAS). Fluorophosphorane 3 has an
equatorial ligand bearing electron-withdrawing groups, which
we hypothesized would facilitate ligand coupling to form a C−
F bond with regeneration of the phosphine catalyst.
To verify the feasibility of our hypotheses, we initially
examined the reaction between acyl fluoride 4a and alkynoate
5a using different phosphines (Table 1). Intensive screening
resulted in the identification of PCy3 as a uniquely effective
catalyst, whereas other phosphines, amines (DMAP and
DABCO), and N-heterocyclic carbenes failed to promote
this carbofluorination. The reaction of 4a (1.5 equiv) with 5a
in the presence of PCy3 (30 mol %) in toluene at room
temperature afforded monofluoroalkene 6aa in 74% isolated
yield. 19F NMR analysis indicated that the carbofluorination
product was formed as a 1:1.2 mixture of the E and Z isomers.
The isomers interconverted by reversible addition−elimination
of PCy3 under the catalytic conditions used (see Scheme S1),12
and therefore, the ratio of isomers was determined under
thermodynamic control.13−15 In addition to the fact that this
reaction represents the first catalytic intermolecular carbo-
fluorination, it features the use of acyl fluorides both as
F
sciences.1 Among the various fluorinated motifs, monofluor-
oalkene derivatives are of particular interest, partly because of
their utility as peptide bond isosteres.2 Therefore, novel,
straightforward methods for the synthesis of monofluoroal-
kenes via C−F bond formation are in great demand.3
Carbofluorination of alkynes, which proceeds via the
concomitant formation of C−C and C−F bonds, is a powerful
method for the synthesis of monofluoroalkenes. Although
some methods for the catalytic carbofluorination of alkynes
have recently been developed,4 these methods are restricted to
intramolecular reactions in which transition-metal catalysts and
highly electrophilic F+ reagents such as Selectfluor and NFSI
(Scheme 1a) are used. Herein we report the phosphine-
catalyzed intermolecular carbofluorination of alkynes via C−F
bond-forming ligand coupling on a P(V) intermediate
(Scheme 1b).
In recent years, ligand coupling on P(V) species5 has
attracted renewed interest as an alternative to transition-metal-
mediated cross-coupling reactions. For example, McNally and
co-workers reported the ligand coupling of pyridine derivatives
on a P(V) species that was generated by the reaction of
heterocyclic phosphonium salts with heteronucleophiles6
(Scheme 1c) and heterobiaryl synthesis7 via a P(V)
intermediate. Vilotijevic and co-workers also reported a related
phosphine-mediated C2-functionalization of benzothiazole
derivatives.8 Despite the significant advances in P(V)-mediated
reactions over the past years, a P(V)-mediated C−F bond-
formation reaction has not been achieved to date.9
Quite recently, we reported the first synthesis of a stable
tetraarylfluorophosphorane by the reaction of fluorine-
substituted phosphines with an aryne via tandem nucleophilic
addition and nucleophilic aromatic substitution (Scheme
1d).10 Phosphine-mediated C−F bond formation would be
possible if ligand coupling on fluorophosphorane 1 were to
take place. However, all of our attempts to achieve ligand
coupling on 1 were unsuccessful. We envisaged that increasing
the electrophilicity of the equatorial ligand in the fluorophos-
Received: August 19, 2020
https://dx.doi.org/10.1021/jacs.0c08928
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© XXXX American Chemical Society
A

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Scheme 1. Carbofluorination of Alkynes: Background and
Working Hypothesis
Table 1. Catalyst Optimization for Carbofluorination
between 4a and 5a
a
b
c
entry
1
2
3
4
5
6
7
catalyst
yield (%)
52
E:Z
PCy3
PCy3
PCyp3
1:1.2
1:1.2
d
e
76 (74 )
f
4
6
0
0
0
f
dcype
PnBu3, PtBu3, PAd3, PAd2 Bu, PPhMe2, PPhCy2
DMAP, DABCO
n
f
IPr
a
Reaction conditions: 4a (0.30 mmol), 5a (0.20 mmol), catalyst (0.04
b
mmol), and toluene (1.0 mL) in a sealed tube at 80 °C for 24 h. 1H
c
d
NMR yields. Determined by 19F NMR analysis. The reaction was
conducted at room temperature in the presence of PCy3 (0.06 mmol).
e
f
Yield of the isolated product. Catalyst structures:
carbofluorination proceeded when alkynes bearing a different
electron-withdrawing group such as an ethyl ester (5i), tert-
butyl ester (5j), or benzoyl (5k) group were used instead of
methyl ester 5a, affording the corresponding coupling products
6ki−kk. This organocatalyic carbofluorination can be used in
the late-stage functionalization of pharmaceuticals containing a
carboxylic acid functionality, as shown by the reactions of
probenecid and febuxostat to form the corresponding
monofluoroalkene derivatives 6ma and 6na.
acylating and fluorinating reagents in an atom-economical
manner, which is also unprecedented.
With the optimized reaction conditions in hand, we
subsequently examined the scope of the carbofluorination
reaction (Scheme 2). With regard to acyl fluorides, electron-
neutral (4b) as well as electron-deficient substrates bearing
trifluoromethyl (4c), nitro (4d), cyano (4e), and benzoyl (4f)
groups readily participated in this reaction to produce the
corresponding monofluoroalkenes. Halogen groups such as p-
chloro (4g), o-iodo (4h), and m-bromo (4i) were compatible,
allowing the resulting monofluoroalkenes to be amenable to
further structural elaboration via common C−X bond
functionalization reactions. The electron-rich substrate 4j
also participated in this reaction, although it required a longer
reaction time (72 h). Acyl fluorides bearing a heteroaryl (4k)
or π-extended aryl (4l) group also underwent the carbo-
fluorination successfully. Aromatic alkynoates bearing a methyl
(5b), methoxy (5c), fluoro (5d), bromo (5e), or chloro (5f)
group reacted to afford the corresponding monofluoroalkenes.
Although aliphatic alkynoates bearing alkyl groups such as n-
pentyl, cyclopropyl, and tert-butyl failed to form the
corresponding carbofluorinated products, 3-thienyl- and 2-
pyridyl-substituted alkynoates (5g, 5h) were compatible.
Interestingly, when 5h was used, products 6kh, 6ah, and 6gh
were obtained with high Z selectivity.16 The structure of 6kh
was confirmed by single-crystal X-ray analysis.17 This
To gain additional insights into the reaction mechanism,
some control experiments were performed (Scheme 3). Apart
from the mechanism shown in Scheme 1e, an alternative
pathway that is initiated by the reaction of PCy3 with the acyl
fluoride is also possible. This would lead to the formation of an
acylphosphonium fluoride, which could function as a fluoride
ion source to induce the subsequent addition to the alkynoate
to form fluoroallenoate 7 as a key intermediate.18 However,
external fluoride sources such as CsF and tetrabutylammonium
difluorotriphenylsilicate (TBAT) failed to promote the
carbofluorination of 4b and 5a, thus excluding the alternative
fluoride-mediated mechanism (Scheme 3a). In an attempt to
observe the postulated fluorophosphorane intermediate 3, the
reaction of 4b and 5a in toluene-d8 using 1.0 equiv of PCy3 was
monitored by 19F NMR spectroscopy (Scheme 3b). However,
no resonances assignable to P(V) species were observed, and
6ba was formed in 43% yield (E:Z = 1.6:1), indicating that
ligand coupling on 3 is rapid compared with the formation of
3. When the same reaction was conducted in CD3CN instead
of toluene-d8, 6ba was not formed in an appreciable amount,
and instead, PCy3F2 (8) and the hydroacylated product 9 were
produced in 28% and 34% yield, respectively. R4PF-type
compounds can exist as both four-coordinate ionic (phospho-
nium fluoride) and five-coordinate neutral (fluorophosphor-
B
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a
Scheme 2. Scope of the Phosphine-Catalyzed Carbofluorination of Alkynoates
a
Reaction conditions: acyl fluoride (0.30 mmol), alkyne (0.20 mmol), PCy3 (0.06 mmol), and toluene (1.0 mL) in a sealed tube at room
b
temperature for 24 h. Yields of isolated products are shown. E:Z ratios were determined by 19F NMR analysis and are shown in parentheses. The
reaction was run for 72 h. The reaction was run at 50 °C.
c
ane) species, with the phosphonium fluoride form being more
stable in polar solvents.19 Therefore, fluorophosphorane 3
ionizes in CD3CN, thus making it susceptible to undergoing
decomposition,9,20 which would eventually lead to the
formation of 8 and 9 via protonation.21 These results suggest
that the phosphonium fluoride is not a competent intermediate
for C−F bond formation.22
Scheme 3. Control Experiments
To further verify the intermediacy of fluorophosphorane 3 in
the PCy3-catalyzed carbofluorination, density functional theory
(DFT) calculations (ωB97X-D/6-31+G(d,p) with PCM
(toluene)) were conducted for the C−F bond-forming ligand
coupling process (Scheme 4). INT1 and INT1′ are the most
stable fluorophosphoranes among the suite of isomers, having a
trigonal-bipyramidal geometry in which fluorine occupies the
apical position.9,10,23 Since INT1 and INT1′ have nearly the
same free energy (ΔG = −0.3 kcal/mol), they can be
interconverted. C−F bond formation from INT1 occurs in a
C
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chloride 10 and KF to afford monofluoroalkene 6ca in 57%
yield on a gram scale (Scheme 5).
Scheme 4. Calculated Energy Diagram for the Ligand
Coupling on a Phosphorane Intermediate
a
Scheme 5. Gram-Scale Reaction Using an Acyl Chloride and
KF
In conclusion, we have reported the first catalytic
intermolecular carbofluorination reaction. This reaction
operates under mild conditions and in the absence of metals,
thus showing a wide functional group tolerance. DFT
calculations revealed that a C−F bond is formed via ligand
coupling on a phosphorus, which has not been achieved to
date.9 The development of novel fluorination reactions using
the fluorophosphorane platform is currently being investigated
in our laboratory.29
a
The Gibbs free energies of intermediates and transition states
relative to the sum of the free energies of the starting materials are
presented.
stepwise fashion, similar to C−C bond-forming ligand coupling
on a P(V) intermediate.7a In the C−F bond-forming step, an
apical P−F bond breaks, allowing the fluorine atom to migrate
to the equatorial β-carbon (TS1) to form the zwitterionic
intermediate INT2. In the C−P bond-breaking step, the
fluorinated product (E)-P is generated by the dissociation of
PCy3. This energy diagram indicates that the process from
INT1 to (E)-P is a reversible process (the highest activation
barrier for the reverse reaction is ΔG⧧ = 21.7 kcal/mol), which
leads to the E/Z isomerization of the product.24 Considering
that the addition of a phosphine to an alkyne has a high
activation barrier (∼19 kcal/mol),14 the ligand coupling
process (∼8.5 kcal/mol) would be relatively facile.25 This
view is consistent with the failure to observe a fluorophosphor-
ane intermediate, such as INT1 (Scheme 3b). To investigate
the steric effect of the phosphine catalyst, the energy diagram
using PMe3 as a model of a relatively small catalyst was
calculated. The results indicated that the process is less favored
than that using PCy3 both in terms of kinetics (ΔG⧧ = 16.7
kcal/mol) and thermodynamics (ΔG = −3.6 kcal/mol). The
steric bulk of PCy3 is particularly effective in facilitating the C−
P bond cleavage step (INT2 → (E)-P) in comparison with
PMe3, as evidenced by the longer P−Cβ bond in INT2
(Scheme S4).26
Another mechanistic possibility involves the formation of
INT2 by outer-sphere attack of fluoride to a four-coordinate
phosphonium intermediate. However, no stable phosphonium
fluoride ion pair structures were formed in our calculations.
Instead, a stable pentavalent geometry was formed for the
fluorophosphorane. Indeed, a four-coordinate phosphonium
intermediate was found to be considerably more unstable than
the corresponding phosphorane form in toluene solution (see
Scheme S3).27 Therefore, there is no energetic benefit for an
outer-sphere mechanism compared with the inner-sphere
ligand coupling mechanism shown in Scheme 4. In fact, all
of our calculations that were intended to explore an outer-
sphere fluorination pathway converged on TS1.28
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c08928.
■
sı
Detailed experimental procedures, characterization of
new compounds, and computational details (PDF)
Crystallographic data for 6kh (CIF)
Crystallographic data for 8 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Mamoru Tobisu − Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan; orcid.org/0000-0002-8415-2225;
Email: tobisu@chem.eng.osaka-u.ac.jp
Authors
Hayato Fujimoto − Department of Applied Chemistry,
Graduate School of Engineering, Osaka University, Suita, Osaka
565-0871, Japan; orcid.org/0000-0002-2046-4596
Takuya Kodama − Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan; orcid.org/0000-0001-8275-2393
Masahiro Yamanaka − Department of Chemistry, Faculty of
Science, Rikkyo University, Toshima-ku, Tokyo 171-8501,
Japan; orcid.org/0000-0001-7978-620X
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c08928
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (18H01978)
and Scientific Research on Innovative Area “Hybrid Catalysis”
(20H04818) from MEXT, Japan. M.T. thanks the Hoansha
Foundation for their financial support. H.F. is thankful for
support through a JSPS Research Fellowship for Young
Scientists and the Program for Leading Graduate Schools:
“Interactive Materials Science Cadet Program”. We also thank
A synthetic advantage of acid fluorides is that they are
directly accessible from the corresponding carboxylic acids and
acyl chlorides. Phosphine-catalyzed carbofluorination can be
performed using an acyl fluoride produced in situ from acyl
D
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(11) Review: (a) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O.
Chem. Rev. 2018, 118, 10049−10293. Selected examples of vicinal
difunctionalization of alkynoates by nucleophilic catalysis: (b) Weiss,
R.; Bess, M.; Huber, S. M.; Heinemann, F. W. Nucleophilic β-
Oniovinylation: Concept, Mechanism, Scope, and Applications. J. Am.
Chem. Soc. 2008, 130, 4610−4617. (c) Nagao, K.; Ohmiya, H.;
Sawamura, M. Phosphine-Catalyzed Anti-Carboboration of Alky-
noates with Alkyl-, Alkenyl;, and Arylboranes. J. Am. Chem. Soc. 2014,
136, 10605−10608. (d) Nagao, K.; Ohmiya, H.; Sawamura, M. Anti-
Selective Vicinal Silaboration and Diboration of Alkynoates through
Phosphine Organocatalysis. Org. Lett. 2015, 17, 1304−1307.
(e) Murayama, H.; Nagao, K.; Ohmiya, H.; Sawamura, M.
Phosphine-Catalyzed Vicinal Acylcyanation of Alkynoates. Org. Lett.
2016, 18, 1706−1709. (f) Fritzemeier, R. G.; Nekvinda, J.; Vogels, C.
M.; Rosenblum, C. A.; Slebodnick, C.; Westcott, S. A.; Santos, W. L.
Organocatalytic trans Phosphinoboration of Internal Alkynes. Angew.
Chem., Int. Ed. 2020, 59, 14358−14362.
(12) For selected examples of phosphine-catalyzed isomerization of
alkenes, see ref 11e and: (a) Larpent, C.; Meignan, G. Chemistry in
water - Part VI Catalytic isomerization and stereochemistry of
reduction of acetylenics mediated by water-soluble phosphines.
Tetrahedron Lett. 1993, 34, 4331−4334. (b) Pierce, B. M.; Simpson,
B. F.; Ferguson, K. H.; Whittaker, R. E. Phosphine-mediated partial
reduction of alkynes to form both (E)- and (Z)-alkenes. Org. Biomol.
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(13) The E isomer is the major product at the initial stage of this
reaction, and the E:Z ratio converges to 1:1 as the reaction proceeds
(Figure S1).
(14) Wang, W.; Wang, Y.; Zheng, L.; Qiao, Y.; Wei, D. A DFT Study
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(15) The fluoroalkene products can be made Z-rich by photo-
isomerization. See the Supporting Information for details.
(16) Computational experiments indicated that the pyridine-
substituted Z-form products are stabilized by stereoelectronic
interactions between nitrogen lone pair and a π*CO orbital (see
Scheme S2).
(17) Crystal data for 6kh (CCDC 1999458): monoclinic, space
group P21/c (No. 14), a = 6.91739(14) Å, b = 23.4940(4) Å, c =
9.63136(19) Å, β = 104.644(2)°, V = 1514.42(5) Å3, T = 123 K, Z =
4, R1 (wR2) = 0.0379 (0.1075) for 899 parameters and 19566 unique
reflections, GOF = 1.048.
the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for their assistance with HRMS.
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(b) Trost, B. M.; Xu, J.; Schmidt, T. Palladium-Catalyzed
Decarboxylative Asymmetric Allylic Alkylation of Enol Carbonates.
J. Am. Chem. Soc. 2009, 131, 18343−18357.
(23) Fluorine is known as an atom with one of the highest
apicophilicities. See: Schmutzler, R. Chemistry and Stereochemistry of
Fluorophosphoranes. Angew. Chem., Int. Ed. Engl. 1965, 4, 496−508.
(24) The activation barrier for the addition of PCy3 to (Z)-P is 22.7
kcal/mol, which also makes its isomerization energetically feasible
under the reaction conditions used. The energy difference between
(E)-P and (Z)-P is small, which is consistent with the E:Z ratio of the
products obtained experimentally (see the Supporting Information for
details).
(25) (a) Compared with the related heteroaryl-substituted
fluorophosphoranes reported by McNally,9 the C−F bond-forming
ligand coupling from INT1 is facile, presumably because this process
does not require dearomatization. (b) We also calculated a pathway
from the hypothetical fluorophosphorane INT5, which contains only
one electron-withdrawing group on the alkene moiety (Scheme S5),
to obtain insight into the effect of the electrophilicity of the ligand on
the P(V) ligand coupling process. Interestingly, the ligand coupling
from INT5 could proceed with an activation barrier similar to that for
INT1 (6.9 kcal/mol), indicating that two electron-withdrawing
groups are not essential for the ligand coupling to occur. INT1 and
INT5 would be expected to have similar electrophilicities since the
CO bonds in INT1 are twisted from the CC bond plane,
possibly as a result of steric repulsion with cyclohexyl groups, which
inhibits efficient electron withdrawal by a resonance effect.
(26) The steric bulk of PCy3 might also be effective in facilitating the
C−F bond formation step (INT1 → INT2) because the Wiberg bond
order of the P−F bond in INT1 was calculated to be 0.31, which is
actually smaller than that for a related tetraorganofluorophosphorane
that has a shorter P−F bond (∼1.8 Å).9,10 The extended P−F bond in
INT1 could be attributed to steric repulsion induced by the bulky
cyclohexyl groups, which facilitates the C−F bond formation step.
(27) We also carried out relaxed-scan calculations, and the results
suggested that the free energy of fluorophosphorane INT1 increases
as the P−F bond distance increases (Figure S3). In contrast, a
phosphonium form is more stable than the five-coordinate
phosphorane in the case of the corresponding chloride (see the
Supporting Information for details). These results are in agreement
with McNally’s work on related heteroaryl-substituted phosphorus
compounds (see ref 9).
(28) Moreover, no other intermediates were found along the
reaction pathway between INT1 and INT2 on the basis of an intrinsic
reaction coordinate (IRC) analysis starting from TS1 (Figure S4).
(29) A prior version of the present article was deposited as a preprint
on ChemRxiv. See: Fujimoto, H.; Kodama, T.; Yamanaka, M.;
Tobisu, M. Phosphine-Catalyzed Intermolecular Acylfluorination of
Alkynes via a P(V) Intermediate. ChemRxiv 2020, DOI: 10.26434/
chemrxiv.12471665.
F
https://dx.doi.org/10.1021/jacs.0c08928
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX