Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes

Article abstract of DOI:10.1021/acs.orglett.5b01027

(Chemical Equation Presented) "Cu-CF₃" species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu-CF₃-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate (trifluoromethyl)allenes. This method provides a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)allenes, which can be further modified to generate complex fluorinated substructures.

Full text of DOI:10.1021/acs.orglett.5b01027

Letter
pubs.acs.org/OrgLett
Ligand-Controlled Regioselective Copper-Catalyzed
Trifluoromethylation To Generate (Trifluoromethyl)allenes
Brett R. Ambler, Santosh Peddi,† and Ryan A. Altman*
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: “Cu−CF3” species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions.
Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic
intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu−CF3-mediated or -catalyzed reaction has not
been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand
controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the
regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate
(trifluoromethyl)allenes. This method provides a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)allenes, which can
be further modified to generate complex fluorinated substructures.
opper-mediated and -catalyzed nucleophilic trifluorome-
C
thylation is a popular strategy for accessing CF3-based
products.1 While the fundamental reactivity of Cu−CF3 with sp2-
and activated sp3-electrophiles has long been established,2 recent
advances have greatly improved the practical utility and
economic viability of these methods.3−5 One important
advancement involves the use of ligands to stabilize the reactive
Cu−CF3 species and to accelerate reactions with electro-
philes.3,5,6 These two features allow reactions to proceed under
milder conditions that tolerate a broad array of functional groups
and heterocycles.3,5,6 While many of these new Cu-mediated and
-catalyzed trifluoromethylation reactions display excellent
chemoselectivity, ligands have not previously influenced
regiochemical outcomes of reactions. Herein, we report the
first example of a regioselective trifluoromethylation reaction in
which a ligand overrides the intrinsic reactivity of unligated “Cu−
CF3” with electrophiles. Further, we show that the products can
serve as useful synthetic building blocks by providing access to 2°
trifluoromethanes that are otherwise difficult to synthesize.
Propargyl electrophiles, including −Br,7−9 −Cl,8−11 −OMs,12
−OTs,10 −OAc,13 and −O2CCF2X (X = F, Cl, Br),8,14,15c react
using either catalytic11,15c or stoichiometric7−10,12−14 “Cu−CF3”
to generate propargyl and/or allenyl products with minimal
control of regiochemistry. Unsubstituted propargyl electrophiles
provide (trifluoromethyl)allene;9,10,14 however, reactions of
substituted substrates display distinct selectivities. In most
cases, the product distribution is dictated by the substitution
pattern of the substrate with 1° electrophiles providing propargyl
products and with 2° and 3° electrophiles providing allenyl
products (Scheme 1, eqs 1 and 2).7,10−14 In contrast, using a Cu/
Scheme 1. Substrate and Temperature-Controlled
Regioselective Trifluoromethylation
Received: April 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01027
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Organic Letters
Letter
PPh3-based system, modulation of the reaction temperature can
control the regioisomeric ratio of branched and linear products
(Scheme 1, eqs 3 an 4).8 However, for many cases, the intrinsic
reactivity of the substrate overrides the control by temperature,
and thus, many allenyl products are not accessible.8
In our own work aimed at developing decarboxylative
strategies for fluoroalkylation,15 we reported a CuI/N,N′-
dimethylethylenediamine-catalyzed trifluoromethylation reac-
tion of propargyl bromodifluoroacetates to generate propargyl
trifluoromethanes preferentially.15c For this reaction, a wide
variety of N-, O-, and P-based ligands provided propargyl
products with modest regioselectivity (Figure 1A). However, the
Figure 2. Reactions of primary propargyl bromodifluoroacetates
generate 1,1-disubstituted (trifluoromethyl)allenes. (a) Conditions:
4a−l (1 equiv), CuI (10 mol %), phen (10 mol %), NaO2CCF2Br (25
mol %), KF (2 equiv), DMF (1.0 M), 50 °C, 14 h. The numbers in
parentheses represent the ratios of allene/alkyne in purified product as
1
determined by H NMR spectroscopy. (b) 12:1 mixture of allene/
alkyne prior to chromatographic purification as determined by 19F NMR
spectroscopy. (c) Terpy (10 mol %) employed as a ligand. (d) Reaction
conducted on a 7 mmol scale.
via other Cu-mediated or -catalyzed processes,7−14 and otherwise
requires multistep sequences that afford low yields of product.16
Propargyl electrophiles conjugated with electron-rich, -neutral,
and -deficient aromatic moieties all formed allene products in
excellent selectivity (5a−d,g−j).17 When the reaction was
conducted on a gram scale, good yield, and excellent selectivity
were maintained (5l). In contrast to substrates bearing meta- and
para-substituted aryl moieties, substrates bearing ortho-sub-
stituted aryl systems afforded products in lower selectivity (ca.
10:1; 5e−f). Using phen as a ligand, a 1° aliphatic-substituted
substrate was not effectively converted to product; however, the
use of terpy as a ligand provided (trifluoromethyl)allene 5k in
synthetically useful yield and selectivity. The reaction tolerated
many important functional groups, including carbonyl groups
(5a, 5b, 5h, 5j), nitro groups (5d, 5e), nitriles (5f), and ethers
(5i). The carbonyl-containing groups are particularly interesting
because they are prone to react with free CF3− to provide β,β,β-
trifluoroethyl alcohols.1d,4,18 Since products of 1,2-addition were
not observed in these reactions, free −CF3 must not have existed
in solution. Therefore, generation of the reactive (phen)Cu-CF3
Figure 1. Ligand-controlled regioselective trifluoromethylation.
use of 1,10-phenanthroline-based and 2,2′-bipyridine-based
ligands reversed the regioselectivity of the transformation and
afforded (trifluoromethyl)allene 3 with high regioselectivity
(Figure 1B). For these bipyridines and phenanthrolines, the use
of ligands bearing electron-donating aliphatic and methoxy
groups did not significantly modulate the selectivity of reactions.
Thus, the geometric influence of the bipyridyl substructure
presumably controlled the regioselectivity of the transformation.
However, these electron-donating groups decreased the activity
of the catalysts. Thus, 1,10-phenanthroline (phen) and
terpyridine (terpy) were identified as the optimal ligands for
the current transformation.
Employing phen as a ligand, various 1° propargyl bromodi-
fluoroacetates were converted to 1,1-disubstituted (trifluoro-
methyl)allenes with good to excellent selectivity (Figure 2).
Initial efforts focused on the synthesis of 1-aryl-1-
(trifluoromethyl)allenes,which cannot be selectively accessed
B
DOI: 10.1021/acs.orglett.5b01027
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Organic Letters
Letter
species likely involved an inner-sphere process that does not
generate free −CF3.
Allenes can serve as a useful building block for accessing
complex substructures,19 and in recent years, considerable
attention has focused on both the synthesis of allenes20 and
transformations of allene-based building blocks.21 Given the
synthetic potential of allenes, (trifluoromethyl)allenes should be
useful synthetic precursors for various fluorinated motifs.
However, few modern transformations of (trifluoromethyl)-
allenes have been disclosed,16c,22 which restricts the use of these
fluorinated substructures as intermediates in synthetic sequen-
ces. To showcase the potential synthetic utility of (trifluoro-
methyl)allenes, 5l was subjected to metal-catalyzed hydro-
functionalization reactions to generate C−B,23 C−O,24 C−N,25
and C−C16c bonds (Scheme 2). In all cases, the reactions of 5l
Utilizing similar reaction conditions to those used for 1°
bromodifluoroacetates, 2° and 3° propargyl electrophiles were
also regioselectively converted to di- and trisubstituted
(trifluoromethyl)allenes in high regioisomeric ratios (Figure
3). Generally, 2° 1-aryl propargyl substrates provided 1,3-
Scheme 2. Direct Conversion of (trifluoromethyl)allenes to
Functionalized Trifluoromethylated Motifs
a
B2(pin)2 (1.1 equiv), CuCl (5 mol %), IPr·HCl (5 mol %), NaOtBu
b
(40 mol %), MeOH (6 equiv), THF, 23 °C. 2-Phenylethanol (1.1
equiv), AuIPrCl (10 mol %), AgOTf (10 mol %), PhMe, 23 °C.
c
(CH2O)n (2 equiv), RuHCl(CO)(PPh3)3 (5 mol %), dppm (5 mol
d
%), iPrOH (4 equiv), PhMe, 105 °C. Imidazole (1.2 equiv),
[PdCl(C3H5)]2 (2.5 mol %), dppf (5 mol %), THF, 80 °C.
Figure 3. Reactions of substituted propargyl bromodifluoroacetates
provide di- and trisubstituted (trifluoromethyl)allenes. (a) Conditions:
6a−i (1 equiv), CuI (10 mol %), phen (10 mol %), NaO2CCF2Br (25
mol %), KF (2 equiv), DMF (1.0 M), 50 °C, 14 h. The numbers in
parentheses represent the ratios of allene:alkyne in purified product as
determined by 1H NMR spectroscopy. (b) 60 °C, 24 h. (c) Terpy (10
mol %) employed as a ligand. (d) Estimated by 19F NMR spectroscopy.
provided products (8−11) in good yields and excellent
regioselectivity,26 with minimal optimization of previously
reported systems.27 In most cases, the regioselectivities of the
transformations matched those of previous reports;23,24 however,
the product of the hydroamination reaction did not match the
predicted regiochemical outcome,25 indicating that some
reactions of (trifluoromethyl)allenes may generate unique
products (Scheme 2, d). Nonetheless, all functionalization
reactions provide trifluoromethyl-containing products that might
otherwise be challenging to prepare.
In conclusion, the use of bipyridyl-derived ligands overrode
the intrinsic regioselectivity of Cu-catalyzed trifluoromethylation
reactions of propargyl electrophiles and provided di-, tri-, and
tetrasubstituted (trifluoromethyl)allenes bearing synthetically
important functional groups. More broadly, this transformation
serves as the first example of a Cu-catalyzed trifluoromethylation
reaction in which a ligand controls the regiochemical outcome.
Ongoing work in our laboratory aims to understand the basis by
which the ligands control the regiochemistry of the reaction.
disubstituted (trifluoromethyl)allenes in synthetically useful
yields and excellent selectivities (7a−e). In addition, the standard
conditions converted a 2° substrate to a trisubstituted allene
product (7e); however, the standard conditions did not
effectively transform several challenging substrates. For example,
substrates bearing aliphatic groups at the α position reacted
sluggishly and provided low yields of allene products (7f−j). For
these less reactive 2° and 3° alkyl-substituted bromodifluor-
oacetates, the use of terpyridine as a ligand and/or more forcing
conditions (60 °C, 24 h) facilitated the formation of
trisubstituted (7f−g,i) and tetrasubstituted (7h) allenes.
Notably, the decarboxylative trifluoromethylation reaction
tolerated aryl bromides (7b,c,e), which can undergo Cu-
catalyzed nucleophilic trifluoromethylation under similar con-
ditions.3a Although substrates bearing free amines decomposed
under the reaction conditions, protection of these groups as
amides, carbamates, and sulfonamides permitted catalyst turn-
over (5h,j, 7g−h). Finally, the catalyst system tolerated several
important heterocycles, including indole (5j), pyrazole (7d), and
furan (7d), which may be useful for the design of biological
probes and agrochemicals.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental protocols and characterization data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
DOI: 10.1021/acs.orglett.5b01027
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Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: raaltman@ku.edu.
Present Address
†Department of Pharmacology and Pharmaceutical Sciences,
University of Southern California, 1985 Zonal Avenue, Los
Angeles, CA 90033.
Chem. Commun. 2013, 49, 7809.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the donors of the Herman Frasch Foundation for
Chemical Research (701-HF12) and the American Chemical
Society Petroleum Research Fund (52073-DNI1) for support of
this project. We gratefully acknowledge the NIGMS Training
Grant on Dynamic Aspects of Chemical Biology (T32
GM08545) for a graduate traineeship (B.R.A.). Additional
financial assistance was provided by the University of Kansas,
Office of the Provost, Department of Medicinal Chemistry, and
General Research Fund (2301795). The NMR instruments were
supported by NIH Shared Instrumentation Grant No.
S10RR024664 and NSF Major Research Instrumentation
Grant No. 0320648. We gratefully acknowledge Aspira Scientific
for providing HO2CCF2Br. We thank Casey L. Henderson and
Caleb D. Vogt of The University of Kansas, Department of
Medicinal Chemistry, for assistance with the preparation of
substrates.
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