Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper-N-Heterocyclic Carbene Complex

Article abstract of DOI:10.1002/anie.201506882

A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without

Full text of DOI:10.1002/anie.201506882

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201506882
German Edition: DOI: 10.1002/ange.201506882
Synthetic Methods
Catalytic Nucleophilic Fluorination of Secondary and Tertiary
Propargylic Electrophiles with a Copper–N-Heterocyclic Carbene
Complex
Li-Jie Cheng and Christopher J. Cordier*
Abstract: A catalytic method for the nucleophilic fluorination
of propargylic electrophiles is described. Our protocol involves
the use of a Cu(NHC) complex as the catalyst and is suitable
for the preparation of secondary and tertiary propargylic
fluorides without the formation of isomeric fluoroallenes.
Preliminary mechanistic investigations suggest that fluorina-
tion proceeds via copper acetylides and that cationic species are
involved.
fluorides). By contrast, catalytic methods for preparing
propargylic fluorides remain underrepresented.[16] Propar-
gylic fluorides are important motifs in biologically active
compounds[17] and are used as synthetic precursors to
fluorinated analogues of fluoroglycosides and antiviral, anti-
fungal, and anticancer agents.[18] At present, reagent-based
protocols for the dehydroxyfluorination[19] of propargylic
alcohols remain the state-of-the-art methods for the prepa-
ration of propargylic fluorides, and, to the best of our
knowledge, catalytic nucleophilic fluorination reactions of
propargylic electrophiles have not been reported. When
considering the use of fluoride anions in propargylic sub-
stitution reactions,[20] our attention was drawn to a study by
Murahashi and co-workers on the copper(I)-catalyzed ami-
nation of propargylic electrophiles.[21a] This strategy for
propargylic substitution under copper catalysis has since
been expanded to include the use of other nitrogen,[21]
carbon,[22] and oxygen[23] nucleophiles [Eq. (2)].
À
C
ompounds containing C F bonds are of vital importance
to the pharmaceutical[1] and agrochemical industries,[2] posi-
tron-emission tomography,[3] and materials science.[4] Cata-
lytic fluorination has been the focus of many investigations,[5]
in which either electrophilic or nucleophilic fluorine sources
have been used.[6] Despite these significant advances, catalytic
nucleophilic fluorination remains a challenge, particularly at
C(sp3) centers.[7] The high charge density of unsolvated
fluoride anions imparts high nucleophilicity but also strong
basicity,[8] thus enabling elimination pathways to alkenes.
Hydrogen bonding to fluoride anions by protic solvents limits
the formation of alkene by-products owing to reduced
basicity[9] but significantly reduces fluoride nucleophilicity.
This dichotomy represents a unique challenge for catalysis,
and the catalytic nucleophilic fluorination of comparatively
simple non-activated primary alkyl electrophiles is still
relatively underdeveloped.[10] Strategies for installing fluoride
substituents into organic molecules equipped with functional
groups for subsequent synthetic elaboration are of notable
utility. To meet this objective, transition-metal-catalyzed
methods for the nucleophilic fluorination of allylic electro-
philes, with Pd,[11] Ir,[12] Rh,[13] or Cu[14] complexes as catalysts,
have received considerable attention [Eq. (1)].
These approaches exploit the electrophilicity of metal–p-
allyl intermediates and have been elegantly engineered to
overcome significant challenges, including elimination to
[15]
À
form dienes, the reversibility of C F bond formation, and
regioselectivity (formation of branched or linear allylic
Key features of these transformations include the chemo-
selectivity of reactions of terminal alkynes, the lack of allene
formation, and the enhanced reactivity of 3-aryl substrates
relative to their 3-alkyl congeners. Mechanistic investigations
indicate nonstereospecific pathways for substitution and have
implicated copper allenylidenes[24] as key intermediates.[25]
Our objective was to identify a suitable catalyst system that
would permit the capture of such putative intermediates by
a fluoride anion, while prohibiting the displacement of
fluoride from the resulting product. In this endeavor, we
focused our attention on 3-alkyl substrates. Herein, we report
a catalytic method for the nucleophilic fluorination of
[*] Dr. L.-J. Cheng, Dr. C. J. Cordier
Department of Chemistry, Imperial College London
South Kensington, London, SW7 2AZ (UK)
E-mail: ccordier@imperial.ac.uk
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201506882.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
13734
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13734 –13738

Angewandte
Chemie
Table 1: Effect of the reaction parameters on the catalytic synthesis of
secondary propargylic fluorides.[a]
Entry Variation from “standard” conditions
Conv. [%][b] Yield [%][b]
1
2
3
4
5
6
7
none
no [(IPr)CuCl]
>98
<2
>98
>98
<2
90
<2
<2
<2
<2
72
35
55
84
90
propargylic electrophiles [Eq. (3); Ms = methanesulfonyl,
Ts = p-toluenesulfonyl].[26]
CuCl instead of [(IPr)CuCl]
[(IMes)CuCl] instead of [(IPr)CuCl]
[(IPent)CuCl] instead of [(IPr)CuCl]
[(SIPr)CuCl] instead of [(IPr)CuCl]
CuOTf·0.5PhH, L1 (20 mol%)
We began our investigations by examining 3-alkyl-sub-
stituted propargylic carboxylate esters in conjunction with
anionic fluoride sources in the presence of CuI salts. The use
of ligand-free conditions, or catalysts with diphosphine or
tridentate pyridine-based ligands, resulted in either low
substrate conversion or ester cleavage, presumably as a con-
sequence of the basic nature of the fluoride anion. To
circumvent ester cleavage, we extended our substrate survey
to include propargylic chloride 1a-Cl [Eq. (4); Tf = trifluoro-
83
>98
>98
98
>98
>98
>98
>98
96
8[c] CuOTf·0.5PhH, L2 (20 mol%)
5 mol% instead of 10 mol% [(IPr)CuCl]
10[d] 608C instead of 308C
9
11
[(IPr)CuF] instead of [(IPr)CuCl]
80
12[e] [(IPr)CuOTs] instead of [(IPr)CuCl]
90
13[f] [(IPr)CuOTf] instead of [(IPr)CuCl]
90 (77)[g]
14
mesylate instead of tosylate
80
70
15[h] trichloroacetimidate instead of tosylate >98
[a] All results shown are the average for two experiments performed with
0.1 mmol of the substrate. [b] The conversion and yield were determined
by analysis of the reaction mixture by 1H NMR spectroscopy with CH2Br2
as an internal standard. [c] The product was racemic. [d] The reaction
was complete within 1 h. [e] The reaction was complete within 5 h.
[f] The reaction was complete within 2 h. [g] The yield in parentheses is
for a reaction carried out under the standard conditions following the
premixing of [(IPr)CuCl] with AgOTf (10 mol%). [h] [(IPr)CuOTf] was
used instead of [(IPr)CuCl], and the reaction was performed at 608C.
methanesulfonyl]. Full substrate conversion was observed
when CuCl (10 mol%) was used, without significant product
formation. With CuI–binap or CuI–pybox catalyst systems,
shown previously to be suitable for the use of non-halide
nucleophiles, complete substrate consumption was possible,
but fluoride 2a was formed in very low yield along with enyne
3. Expanding our evaluation of ligand architectures, we found
that the copper–N-heterocyclic carbene (NHC) complex
[(IPr)CuCl] catalyzed the formation of fluoride 2a in 42%
yield, with 33% starting material remaining. Despite this
breakthrough, elimination (15% yield) was an alarming
drawback. Control experiments demonstrated that enyne 3a
was not formed by nBu4NF-mediated elimination from 1a-Cl
or 2a in the absence of [(IPr)CuCl]. Furthermore, when
fluoride 2a was subjected to the reaction conditions, the
formation of enyne 3 was not observed.
After deducing that basic fluoride sources should be
avoided, we turned to acidic fluoride sources, such as
Et3N·3HF, but chloride 1a-Cl was unreactive under such
conditions. Since related propargylic substitution reactions
are performed in the presence of a base, thus implicating the
possible formation of a copper acetylide, we were uncertain as
to the viability of propargylic substitution reactions under
acidic conditions. However, we found that [(IPr)CuCl]
catalyzed the formation of propargylic fluoride 2a in good
yield from propargylic tosylate 1a-OTs in the presence of
Et3N·3HF as the fluoride source at 308C,[27] with the
formation of only a trace amount of enyne 3 (Table 1,
entry 1). To our knowledge, Cu(NHC) complexes have not
previously been demonstrated as catalysts for propargylic
substitution reactions of this kind.[28] In the absence of
[(IPr)CuCl], no reaction was observed (Table 1, entry 2).[29]
The use of ligand-free conditions led to consumption of the
substrate without fluorination, and the structure of the NHC
ligand had a significant effect on reaction efficiency (Table 1,
entries 3–6). By comparison with copper–ligand systems
successfully used in propargylic substitution reactions with
other nucleophiles (Table 1, entries 7 and 8), [(IPr)CuCl]
displayed pronounced efficiency. The catalyst loading could
be reduced to 5 mol% with little change in the product yield
(Table 1, entry 9). The fluorination was complete in 1 h when
the reaction was performed at 608C (Table 1, entry 10).
Curious about anion exchange in the (IPr)Cu complex, we
treated of a solution of [(IPr)CuCl] in [D8]THF with
Et3N·3HF [Eq. (5)]. Although [(IPr)CuF] was not detected
1
by H or 19F NMR spectroscopy, this complex did catalyze
fluoride formation when used as
a catalyst (Table 1,
entry 11).[30] Conversely, [(IPr)CuOTs] and [(IPr)CuOTf]
Angew. Chem. Int. Ed. 2015, 54, 13734 –13738
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13735

.
Angewandte
Communications
containing substrate proceeded in 56% yield to give 2m, and
fluorination in the presence of an aldehyde occurred
smoothly to give 2n. In contrast, many reagents used for
dehydrofluorination are incompatible with unprotected alde-
hydes and alcohols.
The extension of our method to the formation of tertiary
propargylic fluorides required an assessment of electrophile
stability. To this end, we found that tertiary propargylic
trichloroacetimidates could be readily prepared and fluori-
nated within 2 h with [(IPr)CuOTf] as the catalyst
(Scheme 2). The acyclic fluoride 5a was formed in 64%
were shown to be highly active and led to fluorination in 5 and
2 h, respectively (Table 1, entries 12 and 13).[31] The corre-
sponding propargylic mesylate was fluorinated in 80% yield
(Table 1, entry 14). The corresponding trichloroacetimidate
was a suitable substrate when [(IPr)CuOTf] was used as the
catalyst; in this case, the best results were obtained at 608C
(Table 1, entry 15). To our knowledge, this acid-activated
leaving group has not been deployed in related propargylic
substitution reactions.[21–23]
Having identified an appropriate ligand architecture and
fluoride source, we elected to move forward with the
commercially available complex [(IPr)CuCl] to explore the
scope of this fluorination protocol (Scheme 1). Fluoride 2a
Scheme 2. Scope of the catalytic synthesis of tertiary propargylic
fluorides with respect to the substituents on the electrophile. Yields
are for the purified product and are the average for two experiments
with 0.5 mmol of the substrate. [a] The yield in parentheses is for
a reaction with [(IPr)CuCl] as the catalyst (a reaction time of 24 h was
required).
yield, and the method was shown to be compatible with an
acetal and a carbamate during preparation of the cyclic
tertiary fluorides 5b and 5c. The synthesis of tertiary fluorides
by known protocols is highly challenging, and methods to
form tertiary propargylic fluorides often suffer from side
reactions, including elimination and 1,2-alkyl shifts. For the
synthesis of fluoride 5c, protection of the alkyne as a cobalt
complex has been required previously to circumvent these
problems.[32]
We performed a series of control experiments to examine
some mechanistic features of this process. Under our standard
conditions, the enantiomerically enriched tosylate (R)-
1a-OTs (e.r. > 99:1) was converted into racemic 2a
[Eq. (6)].[33] The attempted fluorination of tosylate 6, bearing
Scheme 1. Scope of the catalytic synthesis of secondary propargylic
fluorides with respect to the substituents on the electrophile. For
reaction conditions, see Table 1. Yields are the average for two experi-
ments with 0.5 mmol of 1. [a] Yield of the purified product of a reaction
performed with 10 mmol of 1a-OTs. Bn=benzyl, Boc=N-tert-butoxy-
carbonyl.
was formed in 87% yield under the standard reaction
conditions. A reaction on a 10 mmol scale provided 1.5 g of
the product (90%). Fluorination in the presence of a furan, an
unfunctionalized alkyl chain, an alkene, and a 3-benzyl-
substituted substrate proceeded well to give products 2b–e.
We next explored the tolerance of our method towards steric
an internal alkyne, did not occur, even at elevated temper-
atures [Eq. (7)]. To investigate the possible formation of
congestion adjacent to the reacting carbon atom.
A
3-cyclohexyl substituent was tolerated without modification
of the procedure (product 2 f), and fluorination adjacent to an
adamantyl unit occurred in 88% yield (product 2g). The
method functioned well with substrates containing a primary
chloride, a benzyl ether, an acetal, a methyl ester, and
a carbamate (products 2h–l). The fluorination of an alcohol-
a copper acetylide, we prepared a (IPr)Cu–phenylacetylide
complex. Under standard conditions, the use of this complex
13736 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13734 –13738

Angewandte
Chemie
of Cu(NHC) complexes in propargylic substitution reactions
are under way.
Acknowledgements
as a catalyst, in place of [(IPr)CuCl], led to fluoride formation
in just 1 h [Eq. (8)]. On the basis of these results, our current
hypothesis is that the transformation probably occurs via
copper acetylides, and achiral cationic species are key
intermediates.
The synthetic importance of terminal alkynes is widely
appreciated. We were keen to showcase the synthetic utility of
propargylic fluorides and to examine the stability of the
fluoride during subsequent modifications (Scheme 3). Sono-
We gratefully acknowledge financial support from Imperial
College London and the EPSRC (EP/L00352X/1), as well as
the Royal Society for a University Research Fellowship
(C.J.C.). We thank Prof. Alan Spivey for helpful comments,
and his research group for useful discussions following
a double-blind repetition of the reaction in Table 1, entry 1.
Keywords: alkynes · carbene ligands · copper · fluorine ·
homogeneous catalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13734–13738
Angew. Chem. 2015, 127, 13938–13942
[1] For reviews, see: a) K. Müller, C. Faeh, F. Diederich, Science
2007, 317, 1881 – 1886; b) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320 – 330; c) J. Wang, M.
Sµnchez-Roselló, J. L. AceÇa, C. del Pozo, A. E. Soronchinsky,
S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114,
2432 – 2506; d) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305 –
321.
[2] For a review, see: P. Jeschke, ChemBioChem 2004, 5, 570 – 589.
[3] For reviews, see: a) A. F. Brooks, J. J. Topczewski, N. Ichiishi,
M. S. Sanford, P. J. H. Scott, Chem. Sci. 2014, 5, 4545 – 4553;
b) S. M. Ametamey, M. Honer, P. A. Schubiger, Chem. Rev.
2008, 108, 1501 – 1516.
[4] M. H. Hung, W. B. Farnham, A. E. Feiring, S. Rozen in
Fluoropolymers: Synthesis, Vol. 1 (Eds.: G. Hougham, P. E.
Cassidy, K. John, T. Davidson), Plenum, New York, 1999,
pp. 51 – 66.
[5] For a review of catalytic fluorination methods, see: T. Furuya,
A. S. Kamlet, T. Ritter, Nature 2011, 473, 470 – 477.
[6] For reviews, see: a) T. Furuya, C. A. Kuttruff, T. Ritter, Curr.
Opin. Drug Discovery Dev. 2008, 11, 803 – 819; b) T. Liang, C. N.
Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214 – 8264;
Angew. Chem. 2013, 125, 8372 – 8423.
Scheme 3. Synthetic transformations of propargylic fluoride 2a. Yields
are for the isolated product of reactions performed with 0.5 mmol of
2a. Reagents and conditions: [a] [Pd(PPh3)4] (10 mol%), CuI
(10 mol%), PhI, Et3N, 608C, 8 h; [b] CuI (50 mol%), N,N-dicyclohexyl-
amine, paraformaldehyde, dioxane, 1108C, 24 h; [c] H2 (1 atm), Lindlar
catalyst, quinoline, EtOAc, room temperature, 22 h; [d] AgSbF6
(10 mol%), MeOH–H2O (10:1), 758C, 24 h; [e] CuSO4·5H2O
(10 mol%), sodium ascorbate (20 mol%), PhN3, tBuOH–H2O (1:1),
room temperature, 24 h; [f] [Cp*Ru(cod)Cl] (5 mol%), N,N-bis(propar-
gyl)toluenesulfonamide, DCE, room temperature, 15 min. cod=1,5-
cycloctadiene, Cp*=1,2,3,4,5-pentamethylcyclopentadienyl, DCE=1,2-
dichloroethane.
gashira coupling, one-carbon homologation, and hydrogena-
tion allowed the formation of internal alkyne 7, allene 8, and
allylic fluoride 9, respectively. Alkyne hydration with AgSbF6
gave methyl ketone 10 in 58% yield. Conversion of the alkyne
group in 2a into aromatic moieties was straightforward:
Copper-catalyzed cycloaddition with phenyl azide to form
triazole 11 proceeded in good yield, and a ruthenium-
catalyzed [2+2+2] annulation provided hydroisoindole deriv-
ative 12.
In summary, we have described the first catalytic method
for nucleophilic propargylic fluorination. The commercially
available, air- and moisture-insensitive Cu(NHC) complex
[(IPr)CuCl] was used for this transformation, which is suitable
for the fluorination of readily available propargylic electro-
philes in the presence of a range of functional groups to give
secondary and tertiary propargylic fluorides without fluo-
roallene formation. The transformation is selective for
terminal alkynes, and preliminary mechanistic investigations
suggest cationic pathways for fluorination. Propargylic fluo-
rides serve as versatile synthetic precursors to a variety of
fluorinated building blocks. Efforts to expand the application
[7] For reviews, see: a) J. Wu, Tetrahedron Lett. 2014, 55, 4289 –
4294; b) C. Hollingworth, V. Gouverneur, Chem. Commun.
2012, 48, 2929 – 2942.
[8] J. H. Clark, Chem. Rev. 1980, 80, 429 – 452.
[9] J. Emsley, Chem. Soc. Rev. 1980, 9, 91 – 124.
[10] H. Dang, M. Mailig, G. Lalic, Angew. Chem. Int. Ed. 2014, 53,
6473 – 6476; Angew. Chem. 2014, 126, 6591 – 6594.
[11] For examples of palladium-catalyzed reactions, see: a) M. H.
Katcher, A. G. Doyle, J. Am. Chem. Soc. 2010, 132, 17402 –
17404; b) M. H. Katcher, A. Sha, A. G. Doyle, J. Am. Chem.
Soc. 2011, 133, 15902 – 15905; c) M. H. Katcher, P.-O. Norrby,
A. G. Doyle, Organometallics 2014, 33, 2121 – 2133.
[12] For an example of an iridum-catalyzed reaction, see: J. J.
Topczewski, T. J. Tewson, H. M. Nguyen, J. Am. Chem. Soc.
2011, 133, 19318 – 19321.
[13] For an example of a rhodium-catalyzed reaction, see: J. Zhu,
G. C. Tsui, M. Lautens, Angew. Chem. Int. Ed. 2012, 51, 12353 –
12356; Angew. Chem. 2012, 124, 12519 – 12522.
[14] For an example of a copper-catalyzed reaction, see: Z. Zhang, F.
Wang, X. Mu, P. Chen, G. Liu, Angew. Chem. Int. Ed. 2013, 52,
7549 – 7553; Angew. Chem. 2013, 125, 7697 – 7701.
[15] A. Hazari, V. Gouverneur, J. M. Brown, Angew. Chem. Int. Ed.
2009, 48, 1296 – 1299; Angew. Chem. 2009, 121, 1322 – 1325.
Angew. Chem. Int. Ed. 2015, 54, 13734 –13738
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13737

.
Angewandte
Communications
[16] For an example of catalytic electrophilic fluorination to form
propargylic fluorides, see: H. Jiang, A. Falcicchio, K. L. Jensen,
M. W. Paix¼o, S. Bertelsen, K. A. Jørgensen, J. Am. Chem. Soc.
2009, 131, 7153 – 7157.
[27] When we conducted the fluorination of 1a at room temperature,
a similar yield was observed. In view of developing a general
protocol, we found that a reaction temperature of 308C ensured
the full conversion of all other substrates.
[28] For reviews on metal–NHC complexes in catalysis, see: a) S.
Díez-Gonzµlez, S. P. Nolan, Synlett 2007, 2158 – 2167; b) M. N.
Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014,
510, 485 – 496; c) for the fluorination of an unactivated primary
triflate with [(IPr)CuOTf] in the presence of basic fluoride
sources in reactions believed to proceed through phase-transfer
catalysis involving [(IPr)CuF], see Ref. [10]; d) the reaction of 3-
phenyl-1-propyl triflate under the conditions shown in Table 1
resulted in full substrate conversion without fluorination; e) the
reaction of 3-phenyl-1-propyl tosylate under the same conditions
resulted in less than 2% conversion.
[17] V. Kumar, C. Rodger, M. R. Bell, J. Org. Chem. 1995, 60, 4591 –
4594.
[18] For a review concerning propargylic fluorides and leading
references to biologically active compounds, see: M. C. Pacheco,
S. Purser, V. Gouverneur, Chem. Rev. 2008, 108, 1943 – 1981.
[19] For a review of sulfur-based dehydroxyfluorination reagents,
see: C. Ni, M. Hu, J. Hu, Chem. Rev. 2015, 115, 765 – 825.
[20] For reviews of catalytic propargylic substitution reactions, see:
a) D.-Y. Zhang, X.-P. Hu, Tetrahedron Lett. 2015, 56, 283 – 295;
b) Y. Miyake, S. Uemura, Y. Nishibayashi, ChemCatChem 2009,
1, 342 – 356.
[29] See the Supporting Information for details.
[21] For selected examples of N nucleophiles, see: a) Y. Imada, M.
Yuasa, I. Nakamura, S.-I. Murahashi, J. Org. Chem. 1994, 59,
2282 – 2284; b) R. J. Detz, M. M. E. Delville, H. Hiemstra, J. H.
van Maarseveen, Angew. Chem. Int. Ed. 2008, 47, 3777 – 3780;
Angew. Chem. 2008, 120, 3837 – 3840; c) G. Hattori, H. Matsu-
zawa, Y. Miyake, Y. Nishibayashi, Angew. Chem. Int. Ed. 2008,
47, 3781 – 3783; Angew. Chem. 2008, 120, 3841 – 3843; d) G.
Hattori, K. Sakata, H. Matsuzawa, Y. Tanabe, Y. Miyake, Y.
Nishibayashi, J. Am. Chem. Soc. 2010, 132, 10592 – 10608.
[22] For selected examples of C nucleophiles, see: a) F.-L. Zhu, Y.
Zou, D.-Y. Zhang, Y.-H. Wang, X.-H. Hu, S. Chen, J. Xu, X.-P.
Hu, Angew. Chem. Int. Ed. 2014, 53, 1410 – 1414; Angew. Chem.
2014, 126, 1434 – 1438; b) F.-L. Zhu, Y.-H. Wang, D.-Y. Zhang, J.
Xu, X.-P. Hu, Angew. Chem. Int. Ed. 2014, 53, 10223 – 10227;
Angew. Chem. 2014, 126, 10387 – 10391; c) C. Zhang, X.-H. Hu,
Y.-H. Wang, Z. Zheng, J. Xu, X.-P. Hu, J. Am. Chem. Soc. 2012,
134, 9585 – 9588; d) W. Shao, H. Li, C. Liu, C.-J. Liu, S.-L. You,
Angew. Chem. Int. Ed. 2015, 54, 7684 – 7687; Angew. Chem. 2015,
127, 7794 – 7797.
[30] In stoichiometric studies, the treatment of 1a-OTs with
[(IPr)CuF] (1.0 equiv) in THF for 24 h at 308C led to full
conversion and the formation of fluoride 2a in 34% yield and
enyne 3 in 20% yield. Under the same conditions in the presence
of a base (N,N-diisopropylethylamine, 2.0 equiv), 2a was formed
in 40% yield, and 3 was formed in 43% yield.
[31] Following a suggestion by a referee, we explored the influence of
extraneous chloride anion: The reaction of 1a-OTs under
standard conditions (Table 1, entry 1), but with the inclusion of
tetra-n-butylammonium chloride (1.5 equiv), led to only 17%
conversion, no detectable formation of fluoride 2a, and the
formation of chloride 1a-Cl in 4% yield.
[32] For more information on stoichiometric methods for the syn-
thesis of tertiary propargylic fluorides, see: M. B. van Niel, I.
Collins, M. S. Beer, H. B. Broughton, S. K. F. Cheng, S. C.
Goodacre, A. Heald, K. L. Locker, A. M. MacLeod, D. Morri-
son, C. R. Moyes, D. O’Connor, A. Pike, M. Rowley, M. G. N.
Russell, B. Sohal, J. A. Stanton, S. Thomas, H. Verrier, A. P.
Watt, J. L. Castro, J. Med. Chem. 1999, 42, 2087 – 2104 and
Ref. [17].
[23] K. Nakajima, M. Shibata, Y. Nishibayashi, J. Am. Chem. Soc.
2015, 137, 2472 – 2475.
[33] At 52% conversion, the enantiomeric ratio of recovered 1a-OTs
was only slightly diminished (96.5:3.5). To assess possible
product racemization, we subjected the enantiomerically
enriched fluoride (S)-2a (e.r. 97:3) to our standard reaction
conditions; no change in the enantiomeric ratio was detected for
the recovered fluoride (S)-2a.
[24] For a review on the reactivity of metal – allenylidene complexes,
see: V. Cadierno, M. P. Gamasa, J. Gimeno, Eur. J. Inorg. Chem.
2001, 571 – 591.
[25] For computational and experimental evidence relating to copper
allenylidenes as well as bimetallic intermediates, see
Refs. [21d,23].
[26] For an iron-catalyzed olefin aminofluorination, as demonstrated
with two enyne substrates, see: D.-F. Lu, G.-S. Liu, C.-L. Zhu, B.
Yuan, H. Xu, Org. Lett. 2014, 16, 2912 – 2915.
Received: July 24, 2015
Published online: September 25, 2015
13738 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13734 –13738