Hydrogen-Bonding-Assisted α-F Elimination from Cu-CF3 for in Situ Generation of R3N·HF Reagents: Reaction Design and Applications

Article abstract of DOI:10.1021/acs.orglett.9b02516

We report herein a strategy of ammonium hydrogen-bonding-assisted α-F elimination from Cu-CF₃ compounds that generates R₃N·HF reagents in situ. Combining this strategy and Cu(III)-CF₃ chemistry with alkynes, dual fluorination and trifluoromethylation of terminal alkynes is enabled by a single Cu(III)-CF₃ compound assisted by a tertiary amine with excellent regio- and stereoselectivity. This strategy also enables the development of other reaction types involving trapping of the in situ-formed R₃N·HF reagents by other electrophilic groups and can be used for the late-stage functionalization of estrone derivatives.

Full text of DOI:10.1021/acs.orglett.9b02516

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Hydrogen-Bonding-Assisted α‑F Elimination from Cu−CF for in Situ
3
Generation of R N·HF Reagents: Reaction Design and Applications
3
Song-Lin Zhang* and Jia-Jia Dong
Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan
University, Wuxi, Jiangsu 214122, China
*
S Supporting Information
ABSTRACT: We report herein a strategy of ammonium hydrogen-bonding-
assisted α-F elimination from Cu−CF3 compounds that generates R N·HF
3
reagents in situ. Combining this strategy and Cu(III)−CF chemistry with alkynes,
3
dual fluorination and trifluoromethylation of terminal alkynes is enabled by a
single Cu(III)−CF compound assisted by a tertiary amine with excellent regio-
3
and stereoselectivity. This strategy also enables the development of other reaction
types involving trapping of the in situ-formed R N·HF reagents by other
3
electrophilic groups and can be used for the late-stage functionalization of estrone
derivatives.
he conversion of alkali-metal- or alkaline-earth-metal-
This strategy was designed during our development of
Cu(III)−CF reactivity with terminal alkynes (Scheme
T
bound CF complexes to fluoride and difluorocarbene in
3
3
12,13
solution has been observed under certain conditions in
dynamic equilibrium, involving a formal α-F elimination
Scheme 1a). Such conversion has been utilized as an efficient
1c).
The reaction was found to generate the Ar−CC−
CF product in up to quantitative yield at 100 °C in DMF with
3
12c,13a
the strong base NaOtBu.
Interestingly, when excess CsF
(
was used to replace NaOtBu, selective alkyne fluorotrifluor-
strategy for the generation of difluorocarbene, which can be
1
,2
omethylation was achieved, producing 3a in 81% yield, where
introduced into various organic compounds, in particular
13a
3
CsF was a preferred fluoride source (Scheme 1c). From the
alkenes, alkynes, carbonyl compounds in the presence of
4
reaction balance and mechanistic studies, a vinyl cation
phosphine, and nucleophiles (Nu−H, where Nu is a
I
−
5
,6
intermediate B and a [Cu (CF ) ] anionic species D were
3 2
13
nucleophilic group, e.g., C, O, S, N, etc.), leading to the
proposed (Scheme 2). We reasoned that if a tertiary amine is
used as the base, then a protonated ammonium ion would be
generated. This ammonium ion would engage in substantial
formation of important difluorinated structural motifs. In
14
addition, α-F elimination of transition-metal-bound CF
compounds is also known for Mo, Ru, etc., but synthetically
3
7
,8
hydrogen bonding to the F atom of the bound CF ligand to
3
useful transformations remain very limited.
Herein we report a strategy of hydrogen-bonding-assisted
weaken the C−F bond, and thus, C−F bond cleavage might
occur under appropriate conditions, generating the crucial
R3N·HF reagents (red box in Scheme 2) that may further be
trapped by other electrophilic groups. This is synthetically
attractive to avoid the use of stoichiometric toxic and corrosive
R3N·HF reagents.
C−F bond cleavage of copper-bound CF for efficient in situ
3
generation of R N·HF reagents (Scheme 1b). Specifically, a
3
+
3
protonated tertiary amine, HNR , can efficiently cleave the
C−F bond of the copper-bound CF ligand, promoted by
3
15
significant H···F hydrogen bonding between the ammonium
ion and a fluorine atom. This leads to the in situ generation of
DFT computational studies were performed to verify the
feasibility of this hydrogen-bonding-assisted α-F elimination
9
,10
the R N·HF reagent, a classic nucleophilic fluoride reagent,
(Scheme 3 and Figure 1). The anionic intermediate D and
3
+
which then undergoes known hydrofluorination with alkyne,
Et NH first combine to form an initial complex CP1 with a
3
aldehyde, and epoxide functionalities in a one-pot operation
weak hydrogen bond, which is slightly exergonic by 5.9 kcal/
(
Scheme 1d). The in situ generation and utilization of the
mol. In CP1 there is weak yet significant hydrogen bonding
+
R3N·HF reagent avoids the safety problem and inconvenience
of manipulating highly toxic and erosive R N·HF reagents. Our
strategy combines the trifluoromethylation and hydrofluorina-
between the Et
CF
3
NH hydrogen and one fluorine atom of one
ligand, as reflected by the bond distances of 1.82 and 1.45
3
3
Å for the H−F and C−F bonds (Figure 1), indicating
tion reactions of a substrate by a single Cu(III)−CF
3
1
1,12
compound
task.
in one pot, which is a novel and challenging
Received: July 19, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02516
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Strategy of α-F Elimination of Organometallic
Scheme 3. Computational Rationalization of Hydrogen-
a
M−CF Reagents
Bonding-Assisted C−F Bond Cleavage
3
a
Values in parentheses are relative free energies in kcal/mol.
Scheme 2. Concept Design
Figure 1. Optimized key structures for ammonium-assisted α-F
elimination to generate Et N·HF. The values depicted are bond
3
lengths in Å and bond angles and dihedral angles in degrees.
elimination to produce Et N·HF in situ is in principle very
3
+
facile in the presence of Et NH .
3
Indeed, when Et N, one of the simplest tertiary amines, was
3
used instead of the inorganic salts, the desired reaction of path
a (Scheme 2) occurred very efficiently to produce the
fluorotrifluoromethylated product 3a (Scheme 4) without the
16
need for an external fluoride salt/reagent. Other tertiary
amines were also evaluated, and TMEDA and DABCO were
also good organic bases for promoting this reaction (see the
Supporting Information for more details about the screening of
the reaction conditions).
This strategy was found to be generally applicable to various
terminal alkynes to achieve the dual fluorination−trifluor-
omethylation reaction (Scheme 4). A range of functional
groups can be tolerated, including alkyl, alkoxy, chloro, bromo,
nitro, carbonyl, ester, and even an unprotected amine group
(3l). The halo, carbonyl, ester, and unprotected amine groups
provide useful synthetic handles that can be further function-
alized to broaden the diversity and scope of the products.
Furthermore, 2-naphthylacetylene 2m and heteroaryl acety-
lenes, including 3-pyridyl- (2n) and 2-thiophenylacetylene
activation and elongation of the C−F bond. Then, a crucial α-
C−F bond cleavage occurs for the CF ligand with hydrogen
3
bonding through the key transition state TS1 to generate CP2,
I
which is a complex of (phen)Cu (CF )(CF ) (E) and Et N·
2
3
3
HF (Figure 1). This α-C−F bond cleavage has an activation
free energy of only 13.8 kcal/mol. Further dissociation of Et N·
3
HF from intermediate E releases an additional 5.1 kcal/mol,
making the overall α-C−F elimination process to form Et N·
3
HF only slightly endergonic by 2.4 kcal/mol from D and
ammonium. Subsequent trapping of Et N·HF would provide
3
additional thermodynamic driving force for the α-F cleavage.
These results verify that the hydrogen-bonding-assisted α-F
B
DOI: 10.1021/acs.orglett.9b02516
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Dual Fluorination−Trifluoromethylation of an
Scheme 5. Dual Functionalization of Two Functional
Groups
Alkyne Functionality by a Single Cu(III)−CF
3
,
a b
Compound
acetylene as substrates. The expected product 6 was produced
in an excellent 98% NMR yield and an 82% isolated yield
(
Scheme 5b). This observation supports the mechanistic
proposal in Scheme 5a. The reaction of o-epoxide-substituted
phenylacetylene gave product 7 in a low yield of 18%, where a
formal β-elimination occurs after the expected nucleophilic
addition of benzyl oxide to the o-alkyne (Scheme 5c).
Finally, the synthetic potential of the fluorination−
trifluoromethylation chemistry was demonstrated by the triple
functionalization of 1,3,5-tris(ethynyl)benzene (Scheme 6)
a
Method A: 1 (0.3 mmol), 2 (0.3 mmol), Et N (0.6 mmol), and
3
DMF (2.5 mL) stirred at 100 °C for 12 h under N . Method B: using
DABCO (0.6 mmol) and dicarbonyl A2 (0.3 mmol) instead of Et N
in method A. Both F NMR and isolated yields (in parentheses) are
given if available. Reaction time of 18 h. See the Supporting
2
3
b
19
c
d
Scheme 6. Triple syn-Fluorotrifluoromethylation of a Triyne
e
Information for more details. Dicarbonyl A1 was used in place of A2.
(
7
2o), are also good substrates, producing the desired 3m−o in
6%, 63%, and 55% yield, respectively. Notably, the reaction is
also amenable to aliphatic alkynes (3p).
With the above success of this hydrogen-bonding-assisted α-
F elimination strategy, we next envisioned that if there were a
second electrophilic group present on the alkyne substrate that
is more reactive than the alkyne functionality, the in situ-
generated R N·HF might react preferentially with the second
3
and late-stage modification of an estrone derivative (Scheme
), producing star-shaped tristyrene 8 and functionalized
estrone product 10 in 48% and 58% isolated yield, respectively.
These results show that this hydrogen-bonding-assisted α-F
elimination strategy is anticipated to find applications in
materials science and pharmaceuticals.
group instead, thus achieving dual functionalization of two
functional groups (path b in Scheme 2). With this
consideration in mind, we then tested the o-ethynylbenzalde-
hyde as the substrate because aldehyde is a preferred
7
electrophilic group for reaction with R N·HF. We were
3
delighted to see that product 5 was obtained in 81% NMR
yield, where both CF and F are incorporated into the product
3
Scheme 7. Application to the Modification of Estrone
(Scheme 5a). The formation of 5 is attributed to nucleophilic
addition to the o-alkyne by the benzyl oxide generated by
nucleophilic fluoride addition to the aldehyde by in situ-
1
7
generated R N·HF. This result provides nice evidence
3
supporting the strategy designed.
Inspired by the reaction in Scheme 5a, we then directly used
o-ethynylbenzyl alcohol and o-epoxide-substituted phenyl-
C
DOI: 10.1021/acs.orglett.9b02516
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In conclusion, a novel reactivity of a Cu(III)−CF
X.-Y.; Lin, J.-H.; Zheng, J.; Xiao, J.-C. Chem. Commun. 2015, 51, 8805.
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(
1
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compound has been developed to enable one-pot fluorination
and trifluoromethylation of terminal alkynes and o-ethynyl-
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(
7) For Mo α-F elimination, see: Reger, D. L.; Dukes, M. D. J.
Organomet. Chem. 1978, 153, 67−72.
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assisted α-F elimination is involved to provide R N·HF
3
(
reagents in situ that can further be trapped by the substrates.
This is advantageous to avoid the use of toxic and corrosive
R3N·HF reagents. The synthetic potential of this strategy was
demonstrated by the triple fluorotrifluoromethylation of a
triyne and the late-stage functionalization of a complex estrone
derivative.
(
9) For a review of Et N·HF, see: McClinton, M. A. Aldrichimica
3
Acta 1995, 28, 31−35.
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3
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ASSOCIATED CONTENT
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*
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The Supporting Information is available free of charge on the
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glett.9b02516.
(
(
f) O’Connor, T. J.; Toste, F. D. ACS Catal. 2018, 8, 5947.
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AUTHOR INFORMATION
Corresponding Author
(11) For related Cu(III)−CF
M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc., Chem. Commun.
989, 1633. (b) Naumann, D.; Roy, T.; Tebbe, K.-F.; Crump, W.
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Chem., Int. Ed. 2019, 58, 8510.
3
compounds, see: (a) Willert-Porada,
■
*
1
slzhang@jiangnan.edu.cn
ORCID
Song-Lin Zhang: 0000-0002-5337-8600
Notes
The authors declare no competing financial interest.
(12) (a) Zhang, S.-L.; Bie, W.-F. RSC Adv. 2016, 6, 70902.
(
b) Zhang, S.-L.; Bie, W.-F. Dalton Trans 2016, 45, 17588. (c) Zhang,
ACKNOWLEDGMENTS
■
S.-L.; Xiao, C.; Wan, H.-X. Dalton Trans 2018, 47, 4779. (d) Xiao, C.;
Zhang, S.-L. Dalton Trans 2019, 48, 848.
(13) (a) Zhang, S.-L.; Wan, H.-X.; Bie, W.-F. Org. Lett. 2017, 19,
6372. (b) Zhang, S.-L.; Xiao, C. J. Org. Chem. 2018, 83, 10908.
(c) Xiao, C.; Wan, H.-X.; Zhang, S.-L. Asian J. Org. Chem. 2019, 8,
This study was supported by the National Natural Science
Foundation of China (21472068). Financial support from
MOE&SAFEA for the “111 Project” (B13025) and national
first-class discipline program of Food Science and Technology
6
54. (d) Zhang, S.-L.; Xiao, C.; Wan, H.-X.; Zhang, X. Chem.
Commun. 2019, 55, 4099.
14) Reaction of amine with metal−trifluoromethyl reagents, e.g.,
(
JUFSTR20180204) is also gratefully acknowledged.
(
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(
(
D
DOI: 10.1021/acs.orglett.9b02516
Org. Lett. XXXX, XXX, XXX−XXX