Metal-free trifluoromethylation of aromatic and heteroaromatic aldehydes and ketones

Article abstract of DOI:10.1021/jo501289v

The ability to convert simple and common substrates into fluoroalkyl derivatives under mild conditions remains an important goal for medicinal and agricultural chemists. One representative example of a desirable transformation involves the conversion of aromatic and heteroaromatic ketones and aldehydes into aryl and heteroaryl β,β,β-trifluoroethylarenes and -heteroarenes. The traditional approach for this net transformation involves stoichiometric metals and/or multistep reaction sequences that consume excessive time, material, and labor resources while providing low yields of products. To complement these traditional strategies, we report a one-pot metal-free decarboxylative procedure for accessing β,β,β- trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes. This method features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability.

Full text of DOI:10.1021/jo501289v

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Article
Metal-free Trifluoromethylation of Aromatic
and Heteroaromatic Aldehydes and Ketones
Yupu Qiao, Tuda Si, Ming-Hsiu Yang, and Ryan Alan Altman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501289v • Publication Date (Web): 08 Jul 2014
Downloaded from http://pubs.acs.org on July 14, 2014
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Metal-free Trifluoromethylation of Aromatic and Heteroaromatic
Aldehydes and Ketones
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Yupu Qiao, Tuda Si, MingꢀHsiu Yang, Ryan A. Altman*
Department of Medicinal Chemistry, The University of Kansas
Lawrence, Kansas 66045, United States
Eꢀmail: raaltman@ku.edu
TOC GRAPHIC
O
CF3
R
i) R13P+CF2CO2
ii) TBAF
•One Pot
•27 Examples
•Arenes and Heteroarenes
•Yields up to 77%
• > 1 g Scale
(Het)Ar
R
(Het)Ar
R = H, Alkyl
R = H, Alkyl
ABSTRACT: The ability to convert simple and common substrates into fluoroalkyl derivatives
under mild conditions remains an important goal for medicinal and agricultural chemists. One
representative example of a desirable transformation involves the conversion of aromatic and
heteroaromatic ketones and aldehydes into aryl and heteroaryl β,β,βꢀtrifluoroethylarenes and ꢀ
heteroarenes. The traditional approach for this net transformation involves stoichiometric metals
and/or multistep reaction sequences that consume excessive time, material and labor resources
while providing low yields of products. To complement these traditional strategies, we report a
one pot metalꢀfree decarboxylative procedure for accessing β,β,βꢀtrifluoroethylarenes and ꢀ
heteroarenes from readily available ketones and aldehydes. This method features several benefits,
including ease of operation, readily available reagents, mild reaction conditions, high functionalꢀ
group compatibility, and scalability.
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INTRODUCTION
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Recently, the synthesis of trifluoromethylated compounds has received much attention
because of the great changes that the CF3 group imparts on the physicochemical and biophysical
properties of small molecules.1 Numerous methods have been developed for the controlled
incorporation of CF3 groups into organic molecules,2 many of which have focused on the
preparation of α,α,αꢀtrifluoromethylarenes and –heteroarenes.2–3 In contrast, the ability to access
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other common fluorinated groups remain less well developed. For example, many β,β,βꢀ
trifluoroethylarenes and ꢀheteroarenes possess medicinallyꢀrelevant activity, and over 21,000
compounds bearing these substructures possess documented biological activities .4 However, the
lack of simple and general transformations to access β,β,βꢀtrifluoroethylarenes and ꢀheteroarenes
limits facile access to many desired targets.
Historically, β,β,βꢀtrifluoroethylarenes and ꢀheteroarenes have been most commonly
accessed from the corresponding aromatic and heteroaromatic aldehydes and ketones. This
conversion generally requires a threeꢀstep sequence involving 1,2ꢀaddition of the RupertꢀPrakash
reagent (TMSCF3),5 functionalization of the resulting alcohol, and reduction or deoxygenation
(Scheme 1A).6 Each step of this arduous sequence requires isolation and purification of products,
which diminishes the yield of final product, consumes substantial quantities of solvents and
reagents, generates excessive waste, and expends an individuals’ time. Despite these drawbacks,
this sequence still represents the most common strategy for accessing β,β,βꢀtrifluoroethylarenes
and ꢀheteroarenes.6
Several other metalꢀmediated and ꢀcatalyzed strategies provide access to β,β,βꢀ
trifluoroethylarenes and ꢀheteroarenes, but are less commonly employed. Aryltrifluoroethanes
can be accessed from benzylic electrophiles using stoichiometric “Cu–CF3” (Scheme 1B),7 and
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from aryl iodides using stoichiometric “Cu–CH2CF3” (Scheme 1C).8 In addition, Pdꢀcatalyzed
reactions of aryl boronic acids with ICH2CF3 can provide β,β,βꢀtrifluoroethylarenes (Scheme
1D).9 However, few of these methods enable access to secondary trifluoromethyl products, or Nꢀ
containing heterocycles, the latter of which remain important for the development of therapeutic
candidates and agrochemical agents. In addition, a freeꢀradicalꢀbased C–H functionalization
approach using zinc sulfonate salts can also introduce the –CH2CF3 group onto heteroaromatic
substrates at a late stage of a synthesis (Scheme 1E). 10 However using an innate C–H
functionalization strategy, certain target molecules might be difficult to access. Therefore, the
development of complementary methods to access this general substructure remains an important
goal. Herein, we report a metalꢀfree oneꢀpot process for the trifluoromethylation of aromatic and
heteroaromatic aldehydes and ketones to access privileged β,β,βꢀtrifluoroethylarenes and ꢀ
heteroarenes.
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Scheme 1. Trifluoromethylation of Aryl and Heteroaryl Aldehydes and Ketones
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8
Complements Existing Methods.
A) Multi-step Reaction Sequences
O
CF3
R
HO CF3
Ar
1) OH
2) [H]
→ LG
TMSCF3
R
Ar
R
Ar
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B) Cu-Mediated Reactions of Benzylic Electrophiles
1) OH
2) "CuCF3"
X = Cl, Br, I, O2CF3, O2CCF2Br, OC(S)SMe
→
X
OH
CF3
C) Cu-Mediated Reactions of Aryl Iodides
I
"CuCH2CF3"
CF3
D) Pd-Catalyzed Reactions of Aryl Boronic Acids
B(OH)2
CF3
Pd
R
R
X2CH2CF3
X2 = I, OTs
X1
X1
X1 = C, N
X1 = C, N
E) Reaction Via Radical Mechanism
O
H
TBHP
CF3
S
Zn
O
CH2CF3
2
R
R
X
X
F) Two-step Difluoroolefination–Hydrofluorination
F
F
O
CF3
1) Olefination
2) KF, K222
R
R
R
G) This Work: One-pot Trifluoromethylation of Aldehydes and Ketones
O
CF3
R
i) R3P+CF2CO2
ii) TBAF
Ar(Het)
R
Ar(Het)
R = H, Alkyl
R = H, Alkyl
•One Pot Transformation
•Readily Available Substrates
•Common Reagents
•Tolerates Many Functional Groups
•Tolerates Heterocycles
•Mild Reaction Conditions
•Scalable
We sought a one pot approach to the preparation of β,β,βꢀtrifluoroethylarenes and ꢀ
heteroarenes from ketones and aldehydes (Scheme 1G). Ketones and aldehydes represent
attractive groups for functionalization found in many commercially available building blocks and
natural products, and frequently serve and readily accessible by a variety of synthetic
transformations. We drew inspiration from several twoꢀstep procedures involving
difluoroolefination of ketones and aldehydes using Wittig reactions 11 or Julia–Kocienski
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reactions, 12 followed by a hydrofluorination reaction (Scheme 1F). 13 However for “green”
considerations, the ability to telescope these two reactions into a single pot process represents a
desirable goal.14
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RESULTS AND DISCUSSION
In order to develop a practical and efficient transformation for aromatic and heteroaromatic
aldehydes and ketones, we devised a oneꢀpot difluoroolefinationꢀhydrofluorination sequence to
provide access to β,β,βꢀtrifluoroethylarenes and ꢀheteroarenes (Scheme 1G). Initially, 2ꢀ
naphthaldehyde was selected as a model substrate, and quick optimization of the
difluoroolefination reaction confirmed that the use of Xiao’s stable R3P+CF2CO2 reagents15 in
–
N,Nꢀdimethylformamide (DMF) at 60–100 °C provided access to the corresponding
difluoroalkene. Subsequent work assessed several sources of fluoride for the hydrofluorination
step of the transformation. Most commonly, hydrofluorination reactions of difluoroolefins
employ metal fluorides in combination with phaseꢀtransfer catalysts (e.g. K222).16 However, the
use of these reagents (KF, CsF, TBAF•3H2O, KHF2) in the oneꢀpot process provided low yields
of the trifluoroethylarene product in DMF. In contrast, the use of commercially available
tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF), which is rarely used for this
transformation, afforded good yields of product.13b When using TBAF (THF), the water content
of the solution was crucial for success of the reaction (Table 1). Specifically, 5–8 mol% water
provided good yield of product (Table 1, entries 1–4), but increasing the water content beyond
10% decreased the yield of product (Table 1, entries 5–6). For all subsequent reactions, TBAF
(1.0 M in THF) with 5 mol% of H2O was employed.
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Table 1. Excess Water Decreases the Yield of β,β,β-Trifluoroethylarene.a
5
6
7
–
i) Ph3P+CF2CO2
CF3
O
DMF, 60 °C, 130 min
H
H
8
9
ii) TBAF (mol% H2O)
THF, 60 °C, 10 min
2
1
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yield (%)b
entry
1c
mol% H2O
5.0
5.2
75
76
80
75
69
60
2c
3c
5.6
4d
8.0
5c
10.5
15.0
6d
a
–
Reactions were performed with 0.400 mmol aldehyde, 0.800 mmol Ph3P+CF2CO2 , in 1.6 mL DMF, followed by
addition of 1.2 mL TBAF solution (1.0 M in THF). b 19F NMR yield using
α,α,αꢀtrifluorotoluene as an internal
standard. c The content of water was determined by KarlꢀFischer titration. d The content of water was determined by
adding a known quantity of deionized H2O to the solution of TBAF employed in entry 3.
The present one pot trifluoromethylation reaction of aromatic aldehydes tolerated a broad
variety of useful and important functional groups, including including nitro, ester, amide,
aliphatic ether, and aliphatic amine groups (Table 2). Monoꢀ, diꢀ, and trisubstituted aromatic
aldehydes with distinct electronic characters all underwent trifluoromethylation under mild
conditions (60–80 °C) and in short reaction times (< 2 h). Electronꢀ neutral and ꢀrich substrates
(Table 2, entries 5–9) typically required the use of higher temperatures and shorter reaction times
than substrates bearing strong electronꢀwithdrawing groups (Table 2, entries 1–3). Using this
procedure on a larger scale, 1.33 g of material could be obtained in 74% yield (Table 2, entry 7).
The trifluoromethylation of polysubstitued aromatic aldehydes and an orthoꢀsubstitued aldehyde
also proceeded efficiently (Table 2, entries 8–10).
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Table 2. Trifluoromethylation of Aldehydes Tolerates Many Important Functional
Groups.a
O
CF3
i) Ph3P+CF2CO2–, DMF
H
R1
R1
ii) TBAF, THF
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4
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entry
1c
1st step
2nd step
product
yield (%)b
52 (45)
O2N
CF3
60 °C, 40 min
60 °C, 60 min
60 °C, 60 min
60 °C, 120 min
60 °C, 10 min
O
CF3
CF3
2c
3
60 °C, 10 min
60 °C, 10 min
60 °C, 10 min
61 (50)
67 (57)
67 (56)
nBuO
O
(nPr)2N
BnO
CF3
4
CF3
5
60 °C, 130 min
60 °C, 10 min
76 (63)
83 (76)
CF3
6
60 °C, 120 min
60 °C, 180 min
90 °C, 120 min
90 °C, 160 min
O
N
CF3
7d
(74)
1.33 g
O
N
MeO
CF3
8
60 °C, 120 min
60 °C, 60 min
84 (68)
MeO
OMe
MeO
BnO
CF3
CF3
60 °C, 120 min
80 °C, 100 min
68 °C, 120 min
60 °C, 10 min
82 (72)
78 (68)
9
MeO
MeO
Br
10e
Reactions were performed with 0.400 mmol aldehyde, 0.800 mmol Ph3P+CF2CO2 , in 1.6 mL DMF, followed by
addition of 1.2 mL TBAF (1.0 M in THF). Times and temperatures for each step are reported in the table. b 19F NMR
a
–
c
yield using
α,
α,
α
ꢀtrifluorotoluene as an internal standard, the number in parentheses indicates the yield. 5.4 mL
DMF was employed. d Largeꢀscale reaction, 1.33 g product was obtained. e 0.80 mL DMF was employed.
Heteroaryltrifluoroethanes also represent important structural motifs found in many
pharmaceutical candidates and agrochemicals,4 and the ability to access these substructures from
the respective heteroaryl aldehydes would complement other approaches.7 To this end, a variety
of heteroaromatic aldehydes were subjected to the optimized reaction conditions (Table 3).
Trifluoromethylation of electronꢀrich heteroaryl aldehydes including 2ꢀfuran, 7ꢀbenzothiophene,
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5ꢀpyrazole, and 3ꢀindole provided products in good yields (Table 3, entries 1–5). Reactions of
electronꢀdeficient quinoline and pyridineꢀbased aldehydes also generated the corresponding
products (Table 3, entries 6–7). Again, these reactions demonstrated compatibility with
important protecting groups (Bn and Boc), and aryl halides (Br and Cl), all of which might be
useful for further synthetic elaboration (Table 3, entries 1, 3–4, 6–7). In order to further
demonstrate the potential for largerꢀscale application of this process, a trifluoromethylation
reaction of a 3ꢀformyl indole was conducted on a 1 g scale, and provided 77% yield (Table 3,
entry 5). However, on this scale, each step of the reaction required slightly longer time to reach
full conversion (Table 3, entry 4 vs. entry 5). Thus, this oneꢀpot procedure enabled easy access to
a variety of heteroaryl trifluoromethanes, and demonstrated useful potential for drug and
agrochemical applications.
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Table 3. Trifluoromethylation of Aldehydes Tolerates Many Important Heterocycles.a
3
4
5
6
7
CF3
O
i) Ph3P+CF2CO2–, DMF
ii) TBAF, THF
H
Het
Het
8
9
6
5
yield (%)b
63 (58)
entry
1
1
st step
2nd step
product
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O
BnO
CF3
80 °C, 40 min
80 °C, 110 min
60 °C, 40 min
60 °C, 15 min
60 °C, 40 min
55 (53)
66 (61)
2
3
CF3
S
CF3
N
60 °C, 60 min
N
Bn
CF3
Br
60 °C, 60 min
60 °C, 10 min
4
81 (71)
N
N
Boc
CF3
Br
5c
93 (77)
Gram Scale
60 °C, 80 min
90 °C, 50 min
60 °C, 60 min
60 °C, 45 min
Boc
CF3
60 °C, 10 min
49 (40)
47 (47)
6
N
CF3
7
60 °C, 10 min
Cl
N
Reactions were performed with 0.400 mmol aldehyde, 0.800 mmol Ph3P+CF2CO2 , in 1.6 mL DMF, followed by
addition of 1.2 mL TBAF (1.0 M in THF). Times and temperatures for each step are reported in the table. b 19F NMR
a
–
c
yield using
α,
α,
α
ꢀtrifluorotoluene as an internal standard, the number in parentheses indicates the yield. Reaction
conducted on 1.00 g starting material.
Extension of the present method to trifluoromethylation reactions of aromatic and
heteroaromatic ketones required thorough reoptimization, and future users of this method are
encouraged to consider the attached flow diagram to assist in the optimization of their own
reactions (Scheme 2). Attempts to optimize the difluoromethylenation reaction of acetophenones
using Ph3P+CF2CO2 provided low yields of intermediate 8. However, employment of a more
–
reactive reagent, [tris(dimethylamino)phosphonio]difluoroacetate [(Me2N)3P+CF2CO2 ],15 in
–
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DMF helped overcome this problem, but the previously reported conditions, provided low yields
of product. Though reevaluation of the reaction conditions identified toluene (PhMe) as an
7
8
9
–
optimal solvent for the difluoroolefination reaction using (Me2N)3P+CF2CO2 , although DMA
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also provided good yield of the difluoroalkene. Further optimization using PhMe identified lower
concentration, shorter reaction time, and 100 °C as improved conditions. After successfully
optimizing the first step of the transformation, efforts focused on hydrofluorination of the
difluoroolefin intermediate 8. Evaluation of different sources and equivalents of TBAF revealed
that 3 equivalents of commercially available TBAF (1.0 M in THF) provided partial conversion
to product. However, the biphasic combination of PhMe/TBAF/THF inhibited efficient
conversion to the trifluoroethane product. In order to overcome the problem, the use of coꢀ
solvents was investigated. Specifically, studies focused on employment of PhMe/DMA (DMA
also facilitated the first step of the reactions), and eventually use of a solvent mixture of
PhMe/DMA (3:1) more effectively converted difluoroalkenes 8 to trifluoromethane 9. On the
basis of subsequent optimization, three parameters (concentration, temperature and solvent
system) proved crucial for successful reactions, and future users of the method are encouraged to
reevaluate these parameters for any particular substrate.
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Scheme 2. Strategy for Troubleshooting Trifluoromethylation of Substituted Acetophenone.
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6
7
8
F
F
O
CF3
Me
–
R3P+CF2CO2
step 1
TBAF (THF)
step 2
Me
Me
R
R
R
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Step 1 Problem: Poor Reactivity of Ph3P+CF2CO2
Step 1 Solution: Employment of (Me2N)3P+CF2CO2
–
–
Step 1 Problem: Poor Reactivity in DMF
Step 1 Solution: Employment of PhMe
Step 2 Problem: Biphasic Mixture of PhMe and TBAF (THF)
Step 2 Solution: Employment of DMA as a Co-solvent
Step 2 Problem: Conditions not General for Substrates with
Varying Electronic Characters
Step 2 Solution: Reoptimization of Concentration,
Temperature and Time for Each Substrate
The oneꢀpot trifluoromethylation reaction of ketones demonstrated high functional group
tolerance, but the success of individual substrates generally required optimization of
concentration and reaction time (Table 4). In general, the difluoroolefination reactions using
(Me2N)3P+CF2CO2 completed in less than 3 h at 100 °C, whereas the hydrofluorination of the
–
difluoroalkene required extended reaction times (generally 20–30 h) at 100 °C. For the
preparation of branched trifluoroethanes, extended heating did not generally decompose the final
products. Electronꢀneutral (aromatic), inductively electronꢀdeficient (3ꢀiodo, 3ꢀalkoxy), and
electron rich (3ꢀSMe) aryl ketones readily underwent trifluoromethylation in moderate yields
(Table 4, entries 1–7); however, reoptimization of the concentrations of each reaction was
required to provide reasonable yields. A ketone containing a dibenzothiophene ring system also
provided the trifluoromethylated product in good yield (Table 4, entry 8), and an extended chain
ketone, valerophenone, also generated the desired trifluoromethylated product in lower yield,
possibly because of the increased steric hindrance of the aliphatic chain (Table 4, entry 9).
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Finally, reactions of activated acetophenones bearing strong resonanceꢀdestabilized electronꢀ
5
6
t
–
withdrawing groups (4ꢀCN, 4ꢀCO2 Bu) did not provide product using (Me2N)3P+CF2CO2 , but
7
8
9
–
the use of Ph3P+CF2CO2 at short reaction times and reduced temperature afforded moderate
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yields of the desired products (Table 4, entries 10–11). For these last two examples, reduced
reaction times and decreased temperatures for both steps helped avoid decomposition of the
intermediates and the products.
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Table 4. Trifluoromethylation of Ketones Tolerates Many Important Functional Groups.a
3
4
5
6
–
i) (Me2N)3P+CF2CO2
O
CF3
R2
PhMe/DMA (3:1)
ii) TBAF, THF
R2
R1
R1
7
8
10
11
9
yield (%)b
58 (46)
product
concentration
entry
1
1st step
100 °C, 1 h
2nd step
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
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CF3
Me
I
100 °C, 2 h
0.074 M
0.25 M
CF3
Me
BnO
2
3
100 °C, 20 h
100 °C, 1 h
100 °C, 2 h
70 (62)
68 (58)
CF3
Me
MeO
100 °C, 14 h
100 °C, 26 h
0.25 M
OMe
OMe
CF3
Me
MeO
MeO
67 (57)
61 (59)
4
5
100 °C, 2 h
0.50 M
CF3
Me
100 °C, 3 h 100 °C, 30 h
0.074 M
Ph
CF3
Me
6
7
100 °C, 24 h
62 (53)
54 (46)
100 °C, 3 h
0.074 M
0.074 M
CF3
Me
100 °C, 3 h 100 °C, 30 h
100 °C, 1.5 h 100 °C, 24 h
MeS
75 (70)
42 (27)
0.25 M
0.50 M
8
9
S
CF3
Me
CF3
nBu
100 °C, 3 h
100 °C, 78 h
CF3
Me
10c 60 °C, 1.33 h 60 °C, 0.5 h
0.25 M
0.25 M
59 (46)
55 (47)
NC
O
CF3
Me
11c
60 °C, 8 h
60 °C, 1 h
tBuO
a Reactions were performed with 0.400 mmol aldehyde and 0.800 mmol (Me2N)3P+CF2CO2– in PhMe : DMA (3:1),
followed by addition of 1.2 mL TBAF (1.0 M in THF). Times and temperatures for each step are reported in the
table. b 19F NMR yield using
α
,
α,
α
ꢀtrifluorotoluene as an internal standard; the number in parentheses indicates the
yield. c Ph3P+CF2CO2 was used instead of (Me2N)3P+CF2CO2 , DMF was used as solvent.
–
–
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The proposed efficiency, functional group compatibility, and operational simplicity of the
trifluoromethylation of aldehydes and ketones should provide rapid access to important target
compounds. For example, the present transformation provides an improved route to fluorinated
compound 14, a Tebufenpyrad analog with acaricidal activity (Scheme 3). Previously, aldehyde
12 was converted to fluorinated intermediate 13 in 3 steps and 41% overall yield.6a However,
using the present reaction, 13 was readily accessed in 69% yield in a oneꢀpot transformation.
Benefits of the present approach include: 1) an improved overall yield; 2) decreased operational
costs associated with time and labor cost; 3) generation of less waste from workup and
purification of multiꢀstep sequences; 4) no metal contamination; 5) operational simplicity; 6)
usage of stable and nontoxic reagents. Because of these beneficial features, this reaction should
provide improved access to a wide variety of aryl and heteroaryltrifluoroethyl analogs of target
molecules.
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Scheme 3. Improved Protocol for Trifluoromethylation of Heteroaromatic Aldehydes.
Previous Work: Three Steps, 41% Overall Yield
Cl
O
N
F3C
F3C
H
H
a, b, c
N
N
O
N
N
O
N
41%
(3 steps)
O
N
Me
Me
Me
14
tBu
12
13
Fluorinated Analog
of Tebufenpyrad
This Work: One Step, 69% Yield
O
F3C
H
d
O
N
O
N
N
N
82% 19F NMR Yield
69% Yield
Me
Me
(1 step)
12
13
(a) Me3SiCF3, TBAF (cat.), THF, rt. (b) PhOCSCl, DMAP, PhMe, 50–60 °C. (c) Bu3SnH, cat. AIBN, PhMe,
–
80 °C. (d) i) Ph3P+CF2CO2 , DMF, 60 °C, 1 h; ii) TBAF (1.0 M in THF), 6 h, 60 °C.
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CONCLUSION
5
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8
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A practical oneꢀpot protocol was developed for converting aryl and heteroaryl aldehydes and
ketones into β,β,βꢀtrifluoroethylarenes and ꢀheteroarenes. This transformation should provide
rapid and efficient access to fluorinated analogs of agricultural chemicals and therapeutic
candidates. The benefits of the present reaction (ease of operation, mild reaction conditions,
inexpensive and readily available substrates and reagents, tolerance of many functional groups
and heterocycles, potential for application on larger scales) should be useful for the discovery of
therapeutics and agrochemical agents.
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EXPERIMENTAL SECTION
All reactions were performed under an atmosphere of dry N2 using ovenꢀdried glassware.
Unless otherwise stated, trifluoromethylation reactions were performed in resealable 15 mL test
tubes with PTFE septa. Reactions were monitored by thinꢀlayer chromatography (TLC),
visualizing by quenching of fluorescence or by use of a KMnO4 stain. Flash column
chromatography was performed using an automated system.
Solvents including DMF, PhMe, CH2Cl2, THF, CH3CN, MeOH were used directly from a
solvent purification system in which solvent was dried by passage through two columns of
activated alumina under argon. Anhydrous DMA was purchased from a commercial source, and
used directly from an airꢀfree bottle. The solvents were transferred via syringe from the solvent
purification system to the reaction vial. Tetrabutylammonium fluoride solution 1.0 M in THF
(TBAF) was purchased from in an airꢀfree bottle, and the water content of the solution was
routinely measured to 5–6 mol% using a Karl Fischer coulometer. Unless otherwise noted, all
other commercially available substrates and reagents were used without further purification.
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Infrared spectra were measured using a Fourier transform infrared spectrometer. Melting
points (m.p., uncorrected) were measured on a capillary melting point apparatus. Highꢀresolution
mass data were recorded on a magnetic and electrostatic sector mass analyzer set to electron
impact ionization mode, or a quadrupole and time of flight tandem mass analyzer with an
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1
electrospray ion source, and all samples were prepared in MeOH. H NMR spectra were
recorded on a 400 MHz (at 400 MHz) instrument, and are reported relative to the residual
solvent signal (CHCl3 at 7.27 ppm). 13C NMR spectra were recorded on a 500 MHz (at 125 MHz)
instrument, and are reported relative to the solvent signal (CDCl3 at 77.16 ppm). Fluorine nuclear
magnetic resonance (19F NMR) spectra were recorded on a 400 MHz (at 376 MHz) instrument,
and are reported relative to α,α,αꢀtrifluorotoluene (δ = –63.72 ppm). NMR data are reported as
follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet
of doublets, q = quartet, sept = septet, m = multiplet), and coupling constants (Hz).
Synthesis of New Substrates
3ꢀBenzyloxybenzaldehyde,17 2ꢀbromoꢀ3,4ꢀdimethoxybenzaldehyde,18 dibenzo[b,d]thiophenꢀ
19
eꢀ4ꢀcarbaldehyde,7k 1ꢀPhenylmethylpyrazoleꢀ5ꢀcarboxaldehyde,
5ꢀ(furanꢀ2ꢀyl)ꢀ1ꢀmethylꢀ1Hꢀ
yrazoleꢀ3ꢀcarbaldehyde,6a were prepared according to known procedures.
Butyl 4ꢀformylbenzoate was prepared according to the analogous procedure for the synthesis
of octadecyl 4ꢀformylbenzoate. 20 4ꢀFormylbenzoic acid (3.00 g, 20.0 mmol), 1ꢀbutanol (1.48 g,
20.0 mmol), DMAP (0.240 g, 2.00 mmol) and DCC (4.10 g, 20.0 mmol) were dissolved in
anhydrous CH2Cl2 (0.050 L), and the mixture stirred at rt for 24 h. The suspension was filtered,
and the filtrate was concentrated in vacuo. Chromatography on silica gel (hexane / EtOAc =
1
90:10) produced the desired product (2.80 g, 68% yield). Colorless oil, H NMR (400 MHz,
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CDCl3) δ 10.10 (s, 1H), 8.19 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 4.36 (t, J = 6.6 Hz,
2H), 1.81−1.74 (m, 2H), 1.53−1.44 (m, 2H,), 0.99 (t, J = 7.4 Hz, 3H). Spectroscopic data are
consistent with the previous report.21
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4ꢀFormylꢀN,Nꢀdipropylbenzamide was prepared according to the analogous procedure for the
synthesis of diethyl 2,2'ꢀ(4ꢀformylbenzoylazanediyl)diacetate. 22 SOCl2 (32 mL) was added
dropwise to a cooled solution of 4ꢀformylbenzoic acid (2.00 g, 13.3 mmol) in PhMe (0.030 L) at
0 °C. The solution was refluxed for 1 h, and then cooled to rt. The solvents were removed in
vacuo, and the crude product was used immediately without further purification. A solution of
dipropylamine (2.7 mL, 0.020 mol) and DIEA (9.0 mL, 52 mmol) in CH2Cl2 (15 mL) was added
drop wise to a solution of the above acyl chloride in CH2Cl2 (0.040 L) at 0 °C. The solution was
warmed to rt, and stirred for 4 h. When TLC showed complete consumption of the acyl chloride,
CH2Cl2 (10 mL) was added, and the organic phase was washed with 2 N HCl (2 × 80 mL), and
brine (2 × 80 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude
product was purified by column chromatography over silica gel (hexane / EtOAc = 85:15) to
1
afford the title compound as a colorless oil (2.24 g, 72% yield); H NMR (CDCl3, 400 MHz) δ
10.04 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 3.46 (t, J = 7.6 Hz, 2H), 3.11 (t,
J = 7.6 Hz, 2H), 1.69 (sept, J = 7.5 Hz, 2H), 1.52 (sept, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H),
13
0.73 (t, J = 7.3 Hz, 3H); C{1H} NMR (CDCl3, 125 MHz) δ 191.8, 170.5, 143.2, 136.6, 130.0,
127.2, 50.7, 46.5, 22.0, 20.8, 11.5, 11.1; HRMS (ESI, m/z): calcd. for C14H19NO2Na [M + Na]+
256.1313, found 256.1327; IR (film) υ = 3060, 2964, 2933, 2873, 2837, 2731, 1629, 1608, 1506,
1465, 1427, 1382, 1303, 842, 831 cm–1.
5ꢀ((Benzyloxy)methyl)furanꢀ2ꢀcarbaldehyde.23 A solution of nBuLi (2.5 M, 7.7 mL, 19 mmol)
in hexane was added to a stirred solution of 2ꢀ((benzyloxy)methyl)furan24 (2.41 g, 12.8 mmol) in
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dry THF (0.050 L) at –78 °C. The reaction mixture was warmed to –10 °C, and stirred for 30
min. The mixture was cooled to –78 °C, and DMF (2.0 mL) was added slowly. The mixture was
allowed to warm to rt, and stirred for 6 h. The mixture was poured into a solution of saturated
aqueous ammonium chloride (40 mL), and the aqueous layer was extracted with ethyl acetate (3
x 50 mL). The organic layer was washed sequentially with water and brine (40 mL each), dried
over anhydrous Na2SO4, and concentrated. Chromatography on silica gel (hexane / EtOAc =
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85:15) afforded the desired product (0.390 g, 14% yield) as brown oil. H NMR (CDCl3, 400
MHz) δ 9.63 (s, 1H), 7.38−7.29 (m, 5H), 7.22 (d, J = 3.5 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H), 4.62
(s, 2H), 4.58 (s, 2H). Spectroscopic data are consistent with the previous report.25
tertꢀButyl 5ꢀbromoꢀ3ꢀformylꢀ1Hꢀindoleꢀ1ꢀcarboxylate was prepared according to the
analogous procedure for the synthesis of tertꢀbutyl 5,6ꢀdibromoꢀ3ꢀformylꢀ1Hꢀindoleꢀ1ꢀ
carboxylate.26 5ꢀBromoꢀ1Hꢀindoleꢀ3ꢀcarbaldehyde (2.00 g, 8.90 mmol) was dissolved in THF
(0.050 mL), and the solution cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil,
0.690 g, 17.3 mmol) was added in one portion, and the mixture stirred for 30 min. After this time,
a solution of diꢀtertꢀbutyl dicarbonate (2.34 g, 14.3 mmol) in THF (0.010 mL) was added drop
wise, and the reaction mixture stirred for a further 90 min while warming to rt. When TLC
showed complete consumption of the starting material, the reaction was quenched by the careful
addition of water (6 mL). The mixture was diluted with ethyl acetate (30 mL), and the organic
layer was washed with water (2 x 30 mL), bine (2 x 30 mL), dried over Na2SO4, filtered, and
concentrated. The crude product was purified by column chromatography on silica gel (hexane /
EtOAc = 80:20) to afford the desired product as a white solid (2.70 g, 93% yield); m.p.:
162−163 °C. 1H NMR (CDCl3, 400 MHz) δ 10.06 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H),
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8.02 (d, J = 8.9 Hz, 1H), 7.51 (dd, J = 8.9, 2.0 Hz, 1H), 1.71 (s, 9H). Spectroscopic data are
5
6
27
consistent with the previous report
.
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8
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6ꢀ(4ꢀChlorophenyl)ꢀ2ꢀpyridinecarboxaldehyde.28 Trifluoroacetic acid (0.709 mL, 9.30 mmol)
and 4ꢀchlorophenylboronic acid (2.18 g, 14.0 mmol) were sequentially added to a solution of 2ꢀ
pyridinecarboxaldehyde (1.00 g, 9.30 mmol) in CH2Cl2 (46 mL). Water (28 mL) was added,
followed by a solution of silver(I)nitrate (0.317 g, 1.86 mmol) in water (19 mL). Potassium
persulfate (7.50 g, 27.9 mmol) was added, and the solution was stirred vigorously at rt for 6 h
and monitored by TLC. The reaction was diluted with CH2Cl2 (30 mL) and washed with 5%
sodium bicarbonate (30 mL). The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2 x 20 mL), dried over Na2SO4, filtered, and evaporated. The crude product was
purified by column chromatography on silica gel (hexane / EtOAc = 80:20) to afford the desired
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product in 8% yield in a 1:1.7 ratio (C4:C6) as a pale yellow solid, m.p.: 91−93 °C. H NMR
(CDCl3, 400 MHz) δ 10.15 (s, 1H), 8.06−8.03 (m, 2H), 7.94−7.89 (m, 3H), 7.50−7.47 (m, 2H).
13C{1H} NMR (CDCl3, 125 MHz) δ 193.9, 156.8, 152.9, 138.1, 136.6, 136.0, 129.3, 128.4, 124.3,
120.1. HRMS (ESI, m/z): calcd. for C12H8ClNNaO [M + Na]+ 240.0192, found 240.0185. IR
(film) υ = 3058, 2842, 1735, 1708, 1589, 1492, 1450, 1392, 1350, 1298, 1217, 1188, 1163, 1091,
1008, 991, 867, 840, 796, 763, 688, 640, 592 cm–1.
1ꢀ(3ꢀBenzyloxyꢀphenyl)ꢀethanone was prepared according to the analogous procedure for the
synthesis of 1ꢀ(4ꢀBenzyloxyꢀphenyl)ꢀethanone. 29 K2CO3 (3.00 g, 22.0 mmol) and benzyl
bromide (1.44 mL, 12.0 mmol) were added to a solution of 3ꢀhydroxyacetophenone (1.50 g, 11.0
mmol) in acetone (15 mL). The resulting suspension was refluxed for 12 h, and then cooled to rt.
The K2CO3 was removed by filtration, and the acetone was removed in vacuo. The resulting
residue was dissolved in CH2Cl2 (20 mL), and washed with water (3 x 15 mL) and brine (10 mL).
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The organic layer was dried over Na2SO4, and the solvent was removed in vacuo. The crude
product was purified by column chromatography on silica gel (hexane / EtOAc = 90:10) to
afford the desired product as a colorless oil (1.98 g, 79% yield). 1H NMR (CDCl3, 400 MHz) δ
7.61−7.56 (m, 2H), 7.47−7.34 (m, 6H), 7.21−7.19 (m, 1H), 5.13 (s, 2H), 2.60 (s, 3H).
Spectroscopic data are consistent with the previous report.30
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General procedure A: Under an atmosphere of nitrogen, a solution of methylmagnesium
bromide (3.0 M in diethyl ether, 6.0 mL, 18 mmol) was added to a solution of aldehyde (12.0
mmol) in anhydrous THF (0.020 L) at 0 ºC. The ice bath was removed, and the reaction was
stirred for 2 h. The reaction was quenched with a solution of saturated aqueous ammonium
chloride. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x
30 mL). The organic layers were combined and washed with brine (45 mL), dried over Na2SO4,
and filtered. The solvent was removed in vacuo. Column chromatography afforded the
intermediate alcohol.
General procedure B: DMSO (0.030 mol, 2.1 mL) was added dropwise to a solution of
oxalyl chloride (15 mmol, 1.3 mL) in CH2Cl2 (5.0 mL) at −78 °C. After stirring for 30 min, a
solution of the intermediate alcohol (10.9 mmol) was added via syringe at –78 °C, and the
reaction was stirred for an additional 30 min. Triethylamine (50 mmol, 7.0 mL) was added drop
wise, and the reaction was stirred for 20 min at –78 °C. The reaction was quenched with a
solution of saturated ammonium chloride (20 mL), and extracted with CH2Cl2 (3 x 20 mL). The
combined organic layers were washed with water (20 mL) and brine (20 mL), dried over MgSO4,
filtered, and concentrated in vacuo to produce the desired ketone.
1ꢀ(3,5ꢀDimethoxyphenyl)ethanone
was
prepared
by
subjection
of
3,5ꢀ
dimethoxybenzaldehyde to general procedure A to provide the intermediate alcohol (1.83 g, 90%
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yield), followed by subjection of the alcohol to the conditions described in general procedure B
(1.46 g, 81% yield); Brown solid; m.p.: 38–40 °C; 1H NMR (CDCl3, 400 MHz) δ 7.08 (d, J = 2.3
Hz, 2H), 6.64 (t, J = 2.3 Hz, 1H), 3.83 (s, 6H), 2.57 (s, 3H). Spectroscopic data are consistent
with the previous report.31
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1ꢀ(Dibenzo[b,d]thiophenꢀ4ꢀyl)ethanone
was
prepared
by
subjection
of
dibenzo[b,d]thiopheneꢀ4ꢀcarbaldehyde to general procedure A to provide the intermediate
alcohol (1.20 g, 97% yield), followed by subjection of the alcohol to the conditions described in
general procedure B (1.10 g, 96% yield); Pale yellow solid; m.p.: 129–131 °C; 1H NMR (CDCl3,
400 MHz) δ 8.38 (dd, J = 7.8, 1.1 Hz, 1H), 8.20–8.17 (m, 1H), 8.10 (dd, J = 7.6, 1.1 Hz, 1H),
7.96–7.94 (m, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.54–7.47 (m, 2H), 2.79 (s, 3H); C{1H} NMR
13
(CDCl3, 125 MHz) δ 197.6, 142.4, 139.3, 137.5, 133.8, 130.9, 129.2, 127.3, 126.2, 124.7, 124.24,
122.9, 121.5, 26.6; HRMS (ESI, m/z): calcd. for C14H10OSNa [M + Na]+ 249.0350, found
249.0352; IR (film) υ = 3058, 3047, 2995, 1666, 1556, 1454, 1444, 1394, 1355, 1319, 798, 752
cm–1.
tertꢀButyl 4ꢀacetylbenzoate was prepared by subjection of tertꢀbutyl 4ꢀformylbenzoate32 to
general procedure A to provide the intermediate alcohol (1.36 g, 91% yield), followed by
subjection of the alcohol to the conditions described in general procedure B (1.20 g, 89% yield);
white solid; m.p.: 56–58 °C; 1H NMR (CDCl3, 400 MHz) δ 8.07 (d, J = 8.4 Hz, 2H), 7.99 (d, J =
8.5 Hz, 2H), 2.65 (s, 3H), 1.62 (s, 9H). Spectroscopic data are consistent with the previous
report.33
General Procedure C: Trifluoromethylation of Aldehydes
A 15 mL screwꢀtop vial was charged with aldehyde (0.400 mmol), Ph3P+CF2CO2 (285 mg,
–
0.800 mmol) and a stir bar, sealed, evacuated and backfilled with N2, DMF (1.6 mL) was added
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via syringe. The vial was placed in a 60 °C heating block, and the reaction mixture was stirred
for the time indicated in Table 2 or 3 (Step 1). A solution of TBAF (1.2 mL, 1.0 M THF) was
added, and the reaction mixture was stirred for the time indicated in Table 2 or 3 (Step 2). The
vial was allowed to cool to rt, and the mixture was diluted with EtOAc (3 mL). α,α,αꢀ
Trifluorotoluene (49 ꢁL, 0.40 mmol) was injected as an internal standard, and an aliquot was
removed for 19F NMR analysis. After determination of the 19F yield, the aliquot was recombined
with the reaction mixture. H2O (6 mL) was added to the vial, and the mixture was extracted with
EtOAc (3 x 10 mL). The combined organic solvents were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by automated flash chromatography to provide
the desired trifluoroethylated products (Note: many of the products are volatile, and special care
was taken not to evaporate lower MW compounds).
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1ꢀNitroꢀ3ꢀ(2,2,2ꢀtrifluoroethyl)benzene (Table 2, entry 1). General procedure C was followed
using butyl 3ꢀnitrobenzaldehyde (60.4 mg, 0.400 mmol) in DMF (5.4 mL); First Step: 60 °C, 40
min; Second Step: 60 °C, 10 min; Workup and chromatographic purification (hexane / EtOAc =
1
95:5) yielded the title compound as a white solid (36.9 mg, 45%); m.p.: 43–44 °C; H NMR
(CDCl3, 400 MHz) δ 8.26–8.23 (m, 1H), 8.21 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8
19
Hz, 1H), 3.51 (q, J = 10.4 Hz, 2H); F NMR (CDCl3, 376 MHz) δ –65.9 (t, J = 10.4 Hz, 3F);
13C{1H} NMR (CDCl3, 125 MHz) δ 148.5, 136.4, 132.1 (q, J = 2.8 Hz), 129.9, 125.3, 125.3 (q, J
= 276.9 Hz), 123.5, 40.0 (q, J = 30.4 Hz); Spectroscopic data are consistent with the previous
report.9a,13a
Butyl 4ꢀ(2,2,2ꢀtrifluoroethyl)benzoate (Table 2, entry 2). General procedure C was followed
using butyl 4ꢀformylbenzoate (82.5 mg, 0.400 mmol) in DMF (5.4 mL); First Step: 60 °C, 60
min; Second Step: 60 °C, 10 min; Workup and chromatographic purification (hexane / EtOAc =
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95:5) yielded the title compound as a colorless oil (52.1 mg, 50%); 1H NMR (CDCl3, 400 MHz)
δ 8.05 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 7.88 Hz, 2H), 4.34 (t, J = 6.6 Hz, 2H), 3.44 (q, J = 10.7
Hz, 2H), 1.80–1.73 (m, 2H), 1.53–1.44 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 19F NMR (CDCl3, 376
MHz) δ –65.6 (t, J = 10.5 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.4, 135.1 (q, J = 2.9
Hz), 130.6, 130.3, 130.0, 125.6 (q, J = 276.9 Hz), 65.1, 40.3 (q, J = 29.9 Hz), 30.9, 19.4, 13.9;
HRMS (ESI, m/z): calcd. for C13H15F3O2Li [M + Li]+ 267.1184, found 267.1168; IR (film) υ =
3043, 2962, 2937, 2875, 1722, 1616, 1579, 1512, 1467, 1433, 14221, 1386, 1361, 1280, 1259,
1207, 1182, 1141, 1108, 1080, 1022, 964, 943, 912, 867, 837, 819, 763, 709, 667, 634 cm–1.
N,NꢀDipropylꢀ4ꢀ(2,2,2ꢀtrifluoroethyl)benzamide (Table 2, entry 3). General procedure C was
followed using 4ꢀformylꢀN,Nꢀdipropylbenzamide (93.4 mg, 0.400 mmol) in DMF (1.6 mL); First
Step: 60 °C, 60 min; Second Step: 60 °C, 10 min; Workup and chromatographic purification
(hexane / EtOAc = 70:30) yielded the title compound as a colorless oil (65.5 mg, 57%); 1H NMR
(CDCl3, 400 MHz) δ 7.37–7.35 (m, 2H), 7.32 (d, J = 8 Hz, 2H), 3.46 (t, J = 8 Hz, 2H), 3.39 (q, J
= 10.7 Hz, 2H), 3.15 (t, J = 6 Hz, 2H), 1.72–1.67 (m, 2H), 1.56–1.51 (m, 2H), 0.99 (t, J = 6 Hz,
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3H), 0.76 (t, J = 6 Hz, 3H); F NMR (CDCl3, 376 MHz) δ –63.1 (t, J = 10.7 Hz, 3F); C{1H}
NMR (CDCl3, 125 MHz) δ 171.3, 137.4, 131.1 (q, J = 3.2 Hz), 130.4, 127.0, 125.7 (q, J = 276.9
Hz), 50.8, 46.4, 40.2 (q, J = 29.8 Hz), 22.0, 20.8, 11.6. 11.1; HRMS (ESI, m/z): calcd. for
C15H20F3NONa [M + Na]+ 310.1389, found 310.1373; IR (film) υ = 3033, 2966, 2937, 2877,
1631, 1466, 1427, 1361, 1259, 1137, 1116, 1099, 1080, 1022, 912, 844, 818 cm–1.
1ꢀ(Benzyloxy)ꢀ3ꢀ(2,2,2ꢀtrifluoroethyl)benzene (Table 2, entry 4). General procedure C was
followed using 3ꢀ(benzyloxy)benzaldehyde (84.8 mg, 0.400 mmol) in DMF (1.6 mL); First Step:
60 °C, 120 min; Second Step: 60 °C, 10 min; Workup and chromatographic purification (hexane)
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yielded the title compound as a colorless oil (59.6 mg, 56%); H NMR (CDCl3, 400 MHz) δ
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7.46–7.29 (m, 6H), 6.98–6.90 (m, 3H), 5.08 (s, 2H), 3.35 (q, J = 10.8 Hz, 2H); 19F NMR (CDCl3,
376 MHz) δ –63.0 (t, J = 10.8 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz) δ 159.1, 136.9, 131.7
(q, J = 2.9 Hz), 129.8, 128.8, 128.2, 127.7, 125.9 (q, J = 276.9 Hz), 122.9, 117.1, 114.4, 70.2,
40.4 (q, J = 29.7 Hz); Spectroscopic data are consistent with the previous report.34
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2ꢀ(2,2,2ꢀTrifluoroethyl)naphthalene (Table 2, entry 5). General procedure C was followed
using 2ꢀnaphthaldehyde (62.4 mg, 0.400 mmol) in DMF (1.6 mL); First Step: 60 °C, 130 min;
Second Step: 60 °C, 10 min; Workup and chromatographic purification (hexane) yielded the title
compound as a white solid (53.0 mg, 63%); m.p.: 53–54 °C; 1H NMR (CDCl3, 400 MHz) δ 7.87–
7.84 (m, 3H), 7.79 (s, 1H), 7.54–7.49 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 3.55 (q, J = 10.8 Hz, 2H);
13
19F NMR (CDCl3, 376 MHz) δ –65.8 (t, J = 10.8 Hz, 3F); C{1H} NMR (CDCl3, 125 MHz) δ
133.4, 133.0, 129.6, 128.5, 127.9, 127.8, 127.7, 127.7, 126.6, 126.5, 126.0 (q, J = 277.0 Hz),
40.5 (q, J = 29.7 Hz); Spectroscopic data are consistent with the previous report.34
4ꢀ(4ꢀ(2,2,2ꢀTrifluoroethyl)phenyl)morpholine (Table 2, entry 6). General procedure C was
followed using 4ꢀmorpholinobenzaldehyde (76.4 mg, 0.400 mmol) in DMF (1.6 mL); First Step:
60 °C, 120 min; Second Step: 90 °C, 120 min; Workup and chromatographic purification
(hexane / EtOAc = 90:10) yielded the title compound as a white solid (74.6 mg, 76%); m.p.: 77–
78 °C; 1H NMR (CDCl3, 400 MHz) δ 7.21 (d, J = 8.5 Hz, 2H), 6.91–6.89 (m, 2H), 3.88–3.86 (m,
19
4H), 3.30 (q, J = 10.9 Hz, 2H), 3.19–3.16 (m, 4H); F NMR (CDCl3, 376 MHz) δ –66.3 (t, J =
11.3 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz) δ 151.1, 131.1, 126.1 (q, J = 276.8 Hz), 121.3 (q,
J = 2.9 Hz), 115.7, 67.0, 49.2, 39.5 (q, J = 29.6 Hz); HRMS (ESI, m/z): calcd. for
C12H14F3NONa [M + Na]+ 268.0925, found 268.0931; IR (film) υ = 2983, 2948, 2925, 2900,
2866, 2837, 1614, 1523, 1450, 1380, 1363, 1336, 1305, 1261, 1234, 1132, 1070, 935, 923, 906,
808 cm–1.
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1,2,3ꢀTrimethoxyꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)benzene (Table 2, entry 8). General procedure C was
followed using 3,4,5ꢀtrimethoxybenzaldehyde (78.4 mg, 0.400 mmol) in DMF (1.6 mL); First
Step: 60 °C, 120 min; Second Step: 60 °C, 60 min; Workup and chromatographic purification
(hexane / EtOAc = 90:10) yielded the title compound as a colorless oil (68.1 mg, 68%); 1H NMR
(CDCl3, 400 MHz) δ 6.50 (s, 2H), 3.87 (s, 6H), 3.86 (s, 3H), 3.31 (q, J = 10.7 Hz, 2H); 19F NMR
(CDCl3, 376 MHz) δ –64.9 (t, J = 9.4 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz) δ 153.4, 138.0,
125.9 (q, J = 276.8 Hz), 125.7 (q, J = 2.9 Hz), 107.4, 61.0, 56.3, 40.6 (q, J = 29.8 Hz); HRMS
(ESI, m/z): calcd. for C11H13F3NaO3 [M + Na]+ 273.0714, found 273.0728; IR (film) υ = 3072,
2999, 2943, 2842, 1593, 1510, 1463, 1427, 1367, 1328, 1294, 1259, 1244, 1157, 1128, 1085,
1006, 981, 937, 902, 852, 819, 784, 709 cm–1.
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1ꢀ(Benzyloxy)ꢀ2ꢀmethoxyꢀ4ꢀ(2,2,2ꢀtrifluoroethyl)benzene (Table 2, entry 9). General
procedure C was followed using 4ꢀ(benzyloxy)ꢀ3ꢀmethoxybenzaldehyde (97.0 mg, 0.400 mmol)
in DMF (1.6 mL); First Step: 60 °C, 120 min; Second Step: 68 °C, 120 min; Workup and
chromatographic purification (hexane / EtOAc = 95:5) yielded the title compound as a white
1
solid (85.3 mg, 72%); m.p.: 59–60 °C; H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 8.2 Hz, 2H),
7.40–7.36 (m, 2H), 7.34–7.30 (m, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.78 (d, J = 8 Hz,
1H), 5.17 (s, 2H), 3.91 (s, 3H), 3.30 (q, J = 10.8 Hz, 2H); 19F NMR (CDCl3, 376 MHz) δ –63.4 (t,
13
J = 10.8 Hz, 3F); C{1H} NMR (CDCl3, 125 MHz) δ 149.7, 148.2, 137.1, 128.7, 128.0, 127.4,
126.0 (q, J = 276.8 Hz), 123.1 (q, J = 3.0 Hz), 122.67, 113.9, 113.8, 71.0, 56.2, 39.9 (q, J = 29.7
Hz); HRMS (ESI, m/z): calcd. for C16H15F3O2Na [M + Na]+ 319.0922, found 319.0900; IR (film)
υ = 3035, 2966, 2931, 2869, 1608, 1593, 1519, 1465, 1456, 1421, 1379, 1367, 1338, 1263, 1234,
1161, 1134, 1083, 1031, 1006, 918, 864, 833, 800, 792, 746, 698 cm–1.
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2ꢀBromoꢀ3,4ꢀdimethoxyꢀ1ꢀ(2,2,2ꢀtrifluoroethyl)benzene (Table 2, entry 10). General
procedure C was followed using 2ꢀbromoꢀ3,4ꢀdimethoxybenzaldehyde (98.0 mg, 0.400 mmol) in
DMF (0.80 mL); First Step: 80 °C, 100 min; Second Step: 60 °C, 10 min; Workup and
chromatographic purification (hexane / EtOAc = 95:5) yielded the title compound as a colorless
oil (81.4 mg, 68%); 1H NMR (CDCl3, 400 MHz) δ 7.11 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 8.5 Hz,
1H), 3.88 (d, J = 9.1 Hz, 6H), 3.6 (q, J = 10.5 Hz, 2H). 19F NMR (CDCl3, 376 MHz) δ –65.5 (t, J
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= 10.5 Hz, 3F); C{1H} NMR (CDCl3, 125 MHz) δ 153.6, 146.9, 126.98, 125.8 (q, J = 277.6
Hz), 123.1 (q, J = 2.7 Hz), 121.7, 111.3, 60.6, 56.2, 39.3 (q, J = 30.2 Hz); HRMS (ESI, m/z):
calcd. for C10H10BrF3O2Li [M + Li]+ 304.9976, found 304.9990; IR (film) υ = 3002, 2966, 2943,
2912, 2840, 1595, 1488, 1450, 1438, 1407, 1359, 1305, 1284, 1269, 1249, 1211, 1137, 1091,
1035, 946, 900, 817, 806, 781, 765, 680 cm–1.
Experimental Procedures for Compounds in Table 3
2ꢀ((Benzyloxy)methyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)furan (Table 3, entry 1). General procedure C
was followed using 5ꢀ((benzyloxy)methyl)furanꢀ2ꢀcarbaldehyde (86.4 mg, 0.400 mmol) in DMF
(1.6 mL); First Step: 80 °C, 40 min; Second Step: 60 °C, 15 min; Workup and chromatographic
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purification (hexane) yielded the title compound as a colorless oil (62.7 mg, 58%); H NMR
(CDCl3, 400 MHz) δ 7.39–7.28 (m, 5H), 6.31 (d, J = 3.2 Hz, 1H), 6.29 (d, J = 3.3 Hz, 1H), 4.56
(s, 2H), 4.47 (s, 2H), 3.47 (q, J = 10.2 Hz, 2H); 19F NMR (CDCl3, 376 MHz) δ –65.8 (t, J = 10.2
13
Hz, 3F); C{1H} NMR (CDCl3, 125 MHz) δ 152.3, 144.7 (q, J = 3.7 Hz), 137.9, 128.6, 128.1,
127.9, 124.7 (q, J = 277.0 Hz), 110.7, 110.6, 72.1, 63.9, 33.7 (q, J = 32.1 Hz); HRMS (ESI, m/z):
calcd. for C14H17F3NO2 [M + NH4]+ 288.1211, found 288.1197; IR (film) υ = 3089, 3066, 3033,
2927, 2864, 1774, 1720, 1701, 1602, 1560, 1496, 1454, 1417, 1369, 1263, 1220, 1139, 1083,
1026, 973, 892, 800, 742, 698 cm–1.
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4ꢀ(2,2,2ꢀTrifluoroethyl)dibenzo[b,d]thiophene (Table 3, entry 2). General procedure C was
followed using dibenzo[b,d]thiopheneꢀ4ꢀcarbaldehyde (85.0 mg, 0.400 mmol) in DMF (1.6 mL);
First Step: 80 °C, 110 min; Second Step: 60 °C, 40 min; Workup and chromatographic
purification (hexane) yielded the title compound as a white solid (56.5 mg, 53%); m.p.: 100–
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102 °C; H NMR (CDCl3, 400 MHz) δ 8.19–8.15 (m, 2H), 7.91–7.87 (m, 1H), 7.52–7.47 (m,
3H), 7.45 (d, J = 7.4 Hz, 1H), 3.69 (q, J = 10.6 Hz, 2H); 19F NMR (CDCl3, 376 MHz) δ –64.7 (t,
J = 10.6 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz) δ 141.0, 138.9, 136.40, 135.9, 128.8, 127.2,
126.0 (q, J = 277.8 Hz), 125.0, 124.9, 124.8, 122.9, 122.0, 121.6, 39.5 (q, J = 30.6 Hz); HRMS
(ESI, m/z): calcd. for C14H9F3NaS [M + Na]+ 289.0275, found 289.0271; Spectroscopic data are
consistent with the previous report.7k
1ꢀBenzylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ1Hꢀpyrazole (Table 3, entry 3). General procedure C was
followed using 1ꢀbenzylꢀ1Hꢀpyrazoleꢀ5ꢀcarbaldehyde (74.4 mg, 0.400 mmol) in DMF (1.6 mL);
First Step: 60 °C, 40 min; Second Step: 60 °C, 60 min; Workup and chromatographic
purification (hexane / EtOAc = 70:30) yielded the title compound as a colorless oil (58.6 mg,
61%); 1H NMR (CDCl3, 400 MHz) δ 7.57 (d, J = 2.1 Hz, 1H), 7.36–7.29 (m, 3H), 7.08–7.06 (m,
2H), 6.36 (s, 1H), 5.40 (s, 2H), 3.37 (q, J = 10.1 Hz, 2H); 19F NMR (CDCl3, 376 MHz) δ –65.4 (t,
J = 10.2 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz) δ 139.2, 136.5, 131.4 (q, J = 3.2 Hz), 129.1,
128.1, 126.7, 124.7 (q, J = 276.7 Hz), 108.4, 53.7, 31.1 (q, J = 32.2 Hz); HRMS (ESI, m/z):
calcd. for C12H11F3N2 [M + H]+ 241.0953, found 241.0944; IR (film) υ = 3066, 3033, 2983, 2948,
1606, 1541, 1496, 1479, 1456, 1407, 1363, 1282, 1257, 1199, 1141, 1116, 1064, 933, 902, 838,
783, 719 cm–1.
tertꢀButyl 5ꢀbromoꢀ3ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate (Table 3, entry 4).
General procedure C was followed using tertꢀbutyl 5ꢀbromoꢀ3ꢀformylꢀ1Hꢀindoleꢀ1ꢀcarboxylate
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(129.6 mg, 0.400 mmol) in DMF (1.6 mL); First Step: 60 °C, 60 min; Second Step: 60 °C, 10
min; Workup and chromatographic purification (hexane) yielded the title compound as a white
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solid (107.4 mg, 71%); m.p.: 89–91°C; H NMR (CDCl3, 400 MHz) δ 8.05 (d, J = 7.9 Hz, 1H),
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7.68 (s, 1H), 7.60 (s, 1H), 7.45 (dd, J = 8.7 Hz, 2.2 Hz, 1H), 3.46 (q, J = 10.5 Hz, 2H), 1.68 (s,
9H); 19F NMR (CDCl3, 376 MHz) δ –65.6 (t, J = 10.4 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz)
δ 149.2, 134.2, 131.7, 127.8, 127.0, 125.7 (q, J = 276.8 Hz), 121.8, 116.9, 116.5, 108.8 (q, J =
3.3 Hz), 84.7, 30.4 (q, J = 31.9 Hz), 28.3; HRMS (ESI, m/z): calcd. for C15H15BrF3NNaO2 [M +
H]+ 400.0136, found 400.0145; IR (film) υ = 2981, 2935, 1737, 1450, 1379, 1280, 1259, 1141,
1105, 1080, 1014, 916, 856, 842, 806, 796 cm–1.
3ꢀ(2,2,2ꢀTrifluoroethyl)quinolone (Table 3, entry 6). General procedure C was followed
using quinolineꢀ3ꢀcarbaldehyde (62.8 mg, 0.400 mmol) in DMF (1.6 mL); First Step: 90 °C, 50
min; Second Step: 60 °C, 10 min; Workup and chromatographic purification (hexane / EtOAc =
1
80:20) yielded the title compound as a white solid (33.8 mg, 40%); m.p.: 64–66°C. H NMR
(CDCl3, 400 MHz) δ 8.85 (d, J = 2.4 Hz, 1H), 8.15–8.12 (m, 2H), 7.84 (dd, J = 8.2, 1.5 Hz, 1H),
7.78–7.74 (m, 1H), 7.62–7.58 (m, 1H), 3.59 (q, J = 10.5 Hz, 2H); 19F NMR (CDCl3, 376 MHz) δ
–65.7 (t, J = 10.7 Hz, 3F); 13C{1H} NMR (CDCl3, 125 MHz) δ 151.7, 147.9, 137.4, 130.1, 129.5,
127.8, 127.8, 127.3, 125.6 (q, J = 276.9 Hz), 123.3 (q, J = 2.6 Hz), 38.0 (q, J = 30.4 Hz); HRMS
(ESI, m/z): calcd. for C11H9F3N [M + H]+ 212.0687, found 212.0674; Spectroscopic data are
consistent with the previous report.34
2ꢀ(4ꢀChlorophenyl)ꢀ6ꢀ(2,2,2ꢀtrifluoroethyl)pyridine (Table 3, entry 7). General procedure C was
followed using 6ꢀ(4ꢀchlorophenyl)ꢀ2ꢀpyridinecarboxaldehyde (87.1 mg, 0.400 mmol) in DMF
(1.6 mL); First Step: 60 °C, 60 min; Second Step: 60 °C, 10 min; Workup and chromatographic
purification (hexane / EtOAc = 85:15) yielded the title compound as a pale white solid (51.1 mg,
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The Journal of Organic Chemistry
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47%); m.p.: 64–66 °C; 1H NMR (CDCl3, 400 MHz) δ 7.99–7.96 (m, 2H), 7.77 (m, 1H), 7.68 (dd,
J = 7.8, 1.1 Hz, 1H), 7.47–7.44 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 3.69 (q, J = 10.8 Hz, 2H); 19F
NMR (CDCl3, 376 MHz) δ –61.7 (t, J = 10.7 Hz, 3F). 13C{1H} NMR (CDCl3, 125 MHz) δ 156.3,
151.0 (q, J = 3.3 Hz), 137.7, 137.5, 135.5, 129.1, 128.4, 125.8 (q, J = 282.6 Hz), 122.9, 119.5,
43.0 (q, J = 29.2 Hz); HRMS (ESI, m/z): calcd. for C13H10ClF3N [M + H]+ 272.0454, found
272.0421; IR (film) υ = 3074, 2954, 2927, 1593, 1494, 1456, 1429, 1390, 1355, 1301, 1284,
1255, 1236, 1224, 1132, 1085, 1058, 1012, 993, 883, 852, 831, 796, 757, 717, 690, 657, 611 cm–
3
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.
General Procedure D: Trifluoromethylation of Ketones
In an N2 filled glove box, a 15 mL screwꢀtop vial equipped with a stir bar was charged with
ketone (0.400 mmol) and (Me2N)3P+CF2CO2 (206 mg, 0.800 mmol). The vial was sealed with a
–
PTFEꢀlined cap, and transferred outside the glove box. A solution composed of PhMe / DMA
(vol./vol. = 3:1) was added via syringe. The vial was placed in a 100 °C heating block and the
reaction mixture was stirred for the time indicated in Table 4 (Step 1). A solution of TBAF (1.2
mL, 1.0 M THF) was added, and the reaction was stirred for the time indicated in Table 4 (Step
2). The vial was allowed to cool to rt, and the mixture was diluted with EtOAc (3 mL). α,α,αꢀ
Trifluorotoluene (49 ꢁL, 0.40 mmol) was injected as an internal standard, and an aliquot was
removed for 19F NMR analysis. After determination of the 19F yield, the aliquot was recombined
with the reaction mixture. H2O (6 mL) was added to the vial, and the mixture was extracted with
EtOAc (3 x 10 mL). The combined organic solvents were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by automated flash chromatography, to provide
the desired trifluoroethylated products (Note: many of the products are volatile, and special care
was taken not to evaporate lower MW compounds).
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