Selective and Scalable Perfluoroarylation of Nitroalkanes

Article abstract of DOI:10.1021/acs.joc.7b00962

Functionalized per- and polyfluoroarenes are important building blocks, with many industrially and medicinally important molecules containing them. Nucleophilic aromatic substitution can be employed as a quick and straightforward way to synthesize these building blocks. While many methods to derivatize fluoroarenes exist that use heteroatom centered nucleophiles, there are fewer methods that use carbon centered nucleophiles, and of those many are poorly defined. This work presents the SNAr reaction of nucleophiles generated from nitroalkanes with a variety of fluorinated arenes. Given that the products are versatile, accessing polyfluorinated arene building blocks in substantial scale is important. This method is highly regioselective, and produces good to moderate yields on a large scale, sans chromatography, and thus fulfills this need. In addition, the regioselectivity of the addition was probed using both DFT calculations and experimentally via halogen exchange.

Full text of DOI:10.1021/acs.joc.7b00962

Article
pubs.acs.org/joc
Selective and Scalable Perfluoroarylation of Nitroalkanes
Jon I. Day and Jimmie D. Weaver*
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078, United States
S
* Supporting Information
ABSTRACT: Functionalized per- and polyfluoroarenes are
important building blocks, with many industrially and
medicinally important molecules containing them. Nucleo-
philic aromatic substitution can be employed as a quick and
straightforward way to synthesize these building blocks. While
many methods to derivatize fluoroarenes exist that use
heteroatom centered nucleophiles, there are fewer methods
that use carbon centered nucleophiles, and of those many are
poorly defined. This work presents the SNAr reaction of
nucleophiles generated from nitroalkanes with a variety of fluorinated arenes. Given that the products are versatile, accessing
polyfluorinated arene building blocks in substantial scale is important. This method is highly regioselective, and produces good to
moderate yields on a large scale, sans chromatography, and thus fulfills this need. In addition, the regioselectivity of the addition
was probed using both DFT calculations and experimentally via halogen exchange.
INTRODUCTION
■
The bioefficacy of small molecules developed for use in
medicinal and agricultural products has been shown repeatedly
to be significantly augmented by the introduction of a fluorine
substituent, or in many cases multiple fluorines (Figure 1).1−4
While some elegant solutions5−7 to introduce a single fluorine
have recently been published, if a polyfluorinated moiety is
desired, these strategies of installing fluorines one-at-a-time can
become prohibitively unwieldy because the prerequisite starting
materials are a synthetic challenge in their own right. For this
reason, the commercial availability of, or synthetic access to,
polyfluorinated precursors is relatively limited as compared to
that of monofluorinated analogs. This presents the need for a
complementary set of synthetic methodologies that will allow
for the simple, high yielding syntheses of diverse, functionalized
polyfluorinated molecules that will enable rapid incorporation
into larger compounds. Accomplishing this goal will allow for
more complete evaluations of the decisive role fluorine plays
within functional molecules.
While individual replacement of hydrogens on an arene can
be complex, complete replacement of the hydrogen content of
an arene with fluorine is synthetically straightforward,8−10
through methods such as perchlorination followed by
nucleophilic halogen exchange (halex) sequences (Scheme 1).
As a result, many important perfluorinated arene motifs are
commercially available. Congruent with strategies championed
by others,19−21 rather than selectively installing fluorine on each
of the desired carbons, our goal is to develop syntheses that
begin with inexpensive commercially available perfluorinated
starting materials and realize polyfluorination patterns through
selective functionalization13,22−25 or reduction18,26 of the
undesired C−F bonds under mild conditions. As evidenced
by the sophistication of and number of recent C−F
functionalization reactions,11−18 there is an increasing need to
Figure 1. Importance of (poly)fluorinated arenes in medicinal and
agricultural chemicals.
Received: April 21, 2017
© XXXX American Chemical Society
A
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perfluoroarylation of nitromethanate followed by reduction, but
rather produced the bipyridyl species (2f, Figure 2), which
likely arises through a subsequent substitution of the initial
product. While the desired monoarylated product was not
obtained under these conditions, Sandford’s work does provide
strong evidence that the nitronate is sufficiently nucleophilic to
undergo substitution and highlights the complicating chemistry
with which we would need to contend.
In 2012, Vaidyanathaswamy showed that nitromethane could
be used as a nucleophile in the addition to both
pentafluorobenzonitrile and methyl pentafluorobenzoate, also
indicating the feasibility of the reaction.33 In their work, the
addition was accomplished using 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) as the base, diethyl ether as the solvent, and
required a different isolation technique for every product. Given
our intention of scaling the reaction to provide substantial
quantities, we were concerned about the generality of the
reaction, the cost of DBU and its removal from the product, the
ability to use diethyl ether on scale (which is banned in all
Sanofi34 processes), as well as the unique isolation techniques.
We sought to develop a general method with greater scope,
higher yield, lower overall cost, and that was more amenable to
scaling.
A simple analysis of the generally accepted SNAr mechanism
(Figure 2) led us to suspect that it might be possible to favor
the formation of the monoaryl product, 2e.
The addition of the nitromethanate to an aryl group gives
rise to a new pronucleophile (2c), which was expected to be
deprotonated under any conditions capable of deprotonating
nitromethane, given the acidifying effect of the highly
fluorinated aryl group. This was expected to give rise to the
nitronate 2d, which is also able to participate in a subsequent
substitution, leading to 2f. Likely this pathway leads to the
Scheme 1. Strategies To Achieve Aryl Fluorination
functionalize the inchoate highly fluorinated arene cores so that
they may be easily incorporated into more elaborate molecules
with interesting properties.
Uncatalyzed nucleophilic substitution reactions of fluoroar-
enes are well established.8,27 Although the literature predom-
inantly features heteroatom nucleophiles, examples are present
that utilize carbon nucleophiles such as Grignard reagents28 and
carbanions29,30 directly. The advantage of utilizing a nucleo-
phile generated from deprotonation of a nitroalkane (i.e., a
nitronate) in a reaction with polyfluorinated arene motif is that
in one step a highly versatile benzylic nitro group is installed,
which can allow further elaboration. This versatility is due in
part to its acidifying effect as well as the variable oxidation state
of the nitro group. As a synthetic handle, a benzylic nitro group
can be readily employed in the Michael reaction, the nitro-
Henry reaction, the Nef reaction, or reduced to an amine (vide
infra), among many other transfromations.31 We present herein
conditions for the substitution of a C−F bond of polyfluor-
oarenes with nitroalkanes. The method efficiently yields the
monoarylated nitroalkane, is regioselective, is highly scalable,
and can be performed largely without the use of column
chromatography.
In 2012, Sandford and Cobb32 noted the expected
importance of the polyfluorinated heteroaromatic amines and
approached this goal through a strategy similar to that
presented here, speculating that it could be reached through
Figure 2. A hypothetical exploitation of the SNAr mechanism for the formation of the monoarylated SNAr product of pentafluoropyridine in
contrast to Sandford and Cobb’s 2012 work.
B
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diarylated species isolated by Sandford and Cobb. However, the
nitronate 2d was expected to be considerably less nucleophilic35
than 2b, due to not only the difference in pKa of the respective
conjugate acids, but also due to the increased steric demand of
2d. Therefore, we suspected that we could take advantage of
the decreased nucleophilicity to effect the desired selectivity for
the monoarylated product, 2e. Nonetheless, in the presence of
additional fluoroarene, the subsequent arylation was expected
take place (2f, 2g).
We speculated that it might be possible to outcompete the
relatively slow second arylation event of 2d by ensuring that the
starting fluoroarene 2a was completely consumed by reaction
with nitromethanate 2b before a subsequent arylation event
could occur. This could be realized by lowering the amount of
thermal energy present in the system, and through the addition
of another equivalent of base, which would generate a
superstoichiometric amount of the intended nucleophile, 2b.
was found that the use of TMG necessitated a drop in
temperature to avoid the addition of TMG to the
perfluoroarene (entries 3, 5, and 6). The first drop in
temperature from room temperature to 0 °C increased the
selectivity of the reaction toward monoarylation by reducing
the available energy of the system to facilitate the apparently
more sluggish second arylation event, as evidenced by the
decrease in the formation of the biaryl product (2g). Further
decreasing the temperature of the reaction to −25 °C led to
substantially fewer side products, but also a diminishment of
the overall conversion (entry 6). Nonetheless, the majority of
the mass balance was now either the desired product (2e) or
the starting material. The quantity of the nucleophile generated
was then investigated, which showed a steady increase in
conversion that varied directly with the equivalents of TMG
used (entries 6−10). It was not until the equivalents of base,
and therefore nitromethanate 2b, exceeded 2.0 equiv that the
amount of other side products declined sharply in entry 11.
Further increasing the amount of TMG to 2.5 equiv (entry 12)
had a deleterious effect on the reaction, however. Further
decreasing the temperature was found to have completely
suppressed the arylation of the TMG, and gave complete
conversion to the intended product 2e (entry 13).
RESULTS AND DISCUSSION
■
With a hypothesis developed, we began probing the reaction
conditions, starting with the reaction of nitromethanate and
pentafluoropyridine (Table 1). Initial screenings of reaction
Results of an exploration of the scope of fluoroarenes that
were investigated are shown in Figure 3. In reactions in which
Table 1. Optimization of the SNAr Reaction of
Pentafluoropyridine with Nitromethanate
a
equiv conversion to conversion
temp
entry (°C)
of
monoaryl
to biaryl
base
base
product 2e
product 2g conversion
1
2
rt
TEA
1.1
1.0
1.0
1.5
1.0
1.0
1.25
1.5
1.75
2.0
2.1
2.5
2.1
0%
3%
36%
63%
28%
53%
1%
66%
95%
82%
100%
72%
66%
71%
83%
93%
96%
99%
97%
>99%
rt
DBU
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
3
rt
6%
4
rt
21%
18%
57%
63%
79%
79%
84%
98%
92%
>99%
5
0
6
−25
−25
−25
−25
−25
−25
−25
−35
<1%
<1%
<1%
<1%
<1%
0%
7
8
9
10
11
12
13
Figure 3. Scope of the SNAr reaction of nitromethane with
fluoroarenes. Isolated yields: (a) 20 g scale, (b) 1 g scale, and (c)
DBU instead of TMG, rt.
0%
0%
a
All reactions run in excess nitromethane; TEA represents triethyl-
amine; NMR scale; conversion determined by relative integration of
NMR peaks. Products other than 2e and 2g were not characterized
fully.
the perfluoroarene contained a strong electron-withdrawing
group (2e, 3b−3d), it was found that the reactions were
complete in a very short time, that is, less than 5 min after
completion of the addition of the fluoroarene. With less
activated fluoroarenes (3e−3i), nitromethanate underwent
noticeably slower substitution. Consequently, TMG addition
was competitive and only became more problematic as the
reaction temperature was increased. Thus, a change to the more
expensive but less nucleophilic DBU to generate the
nucleophile was required.
conditions produced only the biaryl product when triethyl-
amine was used as the base (entry 1). Some of the intended
product resulted following the use of DBU to generate
nitromethanate 2b (entry 2). Next, 1,1,3,3-tetramethylguani-
dine (TMG) was tried and gave comparable or slightly better
results than DBU (entry 3 vs 2). Given the cost of TMG being
ca. 1/4 the cost of DBU,36 we opted to utilize TMG for further
study (entries 3−13). Increasing the amount of TMG effected
complete conversion of the starting arene, and a substantial
increase in the amount of the intended product (entry 4). It
Initially, workup of the reaction mixtures consisted of
quenching the reaction with aqueous acid to protonate the
anion of the product (2e, Figure 2) and any remaining base. 19
F
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NMR analysis of the aqueous layer revealed that the products
were, to varying degrees, soluble in water. It was also found
that, although it was possible to triturate the materials to purify
them, substantial loss of material resulted.
Scheme 2. Effects of Aryl Hydrogen Substituents on the
Regioselectivity of the SNAr Reaction
a
To mitigate this loss, the crude reaction mixtures were
acidified following the reaction with a sodium chloride
saturated acidic solution. Immediately, better mass recovery
was observed. Presumably, the increase in the ionic strength of
the aqueous layer discouraged dissolution of the product
therein, resulting in improved partitioning of the product into
the ethyl acetate organic layer and increasing the overall
recovery. The resultant mixture was then separated and the
organic layer washed with a small amount of dilute aqueous
acid, which was not saturated with sodium chloride. In the case
of the less activated arenes 3f−3h, which utilized DBU, it was
found that the standard workup conditions did not free the
product completely from the base, and it was necessary to
extract the resultant mixtures with a nonpolar solvent following
the above workup conditions to obtain pure product. These
workup conditions resulted in a simple, chromatography-free,
easily scalable workup that afforded analytically pure product
from the reaction mixture.
With reaction and workup conditions in hand, we attempted
to scale up the reaction. This was accomplished on a 20 g scale
of the reaction of pentafluoropyridine, which proceeded cleanly
to a single product (2e) in a 91% yield. However, upon scaling,
we found that a cosolvent that could help dissipate the heat was
necessary. Initially, diethyl ether was used, which is not an ideal
solvent for industrial processes, so it was additionally run on a 1
g scale using heptane as the solvent, but otherwise the same.
Although the reaction was biphasic, and the nucleophile salt
solidified while cooling, at −35 °C it proceeded to a single
product in 96% yield, although the reaction time had to be
increased to 4 h. It is important to note that care was taken to
slowly add the fluoroarene to the pregenerated nitromethanate,
as the reaction generates significant heat, and increases in
temperature were found to lead to the formation of unintended
side products, that of the substitution of TMG.
The selectivity of the SNAr reaction with 1,2,3-trifluoro-4-
nitrobenzene (F3NB) to produce 3b37−39 is interesting when
compared to pentafluoronitrobenzene40 (PFNB) because it
demonstrates the impact the fluorination pattern has on the
regioselectivity of substitution with a highly reactive, yet
sterically small nucleophile such as nitromethanate (4b and 4c,
Scheme 2). It has been posited27 that in reference to the site of
substitution, ortho- and meta-fluorines facilitate the addition of
nucleophiles inductively, whereas ortho- and para-fluorines
hinder the addition by destabilization of the Meisenheimer
intermediate via resonance. Thus, the major product of addition
to F3NB occurs with excellent selectivity ortho to the nitro
group (eqs 1 and 2, Scheme 2). Attack by the nitromethanate at
the C2 position could potentially maximize both the inductive
and the resonance effects because both the electron-with-
drawing nitro group and the fluorine ortho and meta to the site
of substitution promote it. The directing effect of fluorine is
dramatically observed when this result is compared to the
addition to PFNB, which results in a poorly selective addition
(eqs 3 and 4). In fact, the major product (albeit only slightly)
switches to the para-substituted product. This switch in
selectivity can be rationalized by the aforementioned reasons.
First, para-substitution to the nitro group is favored by two
additional ortho- and meta-fluorines. Second, addition ortho to
the nitro group is retarded by the presence of a fluorine located
a
Percent conversion of arene to products. Relative concentration of
products 4a:4b determined by 19F NMR integrations, with complete
conversion of starting arene.
in the position para to the site of substitution. The net effect is
that both products are produced. It should be noted that that
this selectivity is notably lower than other carbonucleophiles,
which give the para addition in an ca. 86:14 ratio.13,41
Hoping to probe the nuances of this mechanism, the reaction
was the repeated with 1-chloro-2,3,5,6-tetrafluoro-4-nitro-
benzene (1-Cl-F4NB), which recently became accessible.42
Nucleophilic aromatic substitution reactions are generally
thought to have two transition states. The first is the attack
of the nucleophile, which leads to formation of the
Meisenheimer complex, and the second is the breakdown of
that complex. Commonly, formation is the slow step, but the
latter has also been observed to be rate-determining.43 Thus, we
posited that replacing the 4-fluoro substituent would allow us to
probe the reversibility of the first step. If the breakdown of the
Meisenheimer complex was the rate-limiting step following a
reversible addition of the nucleophile, one could expect that the
incorporation of the para-chlorine would lead to exclusive
substitution at the chlorinated position because the fragmenta-
tion of the chloride should be more exothermic. This is not
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Figure 4. (A) LUMO surfaces (upper) and MESP surfaces (lower). (B) Vertical cross section through electron density surface. Incoming nuceophile
added for illustrative purposes.
observed, however. With nitromethanate, the substitution of 1-
Cl-F4NB occurs exclusively at the ortho position (eqs 5 and 6,
4c, Scheme 2), suggesting that attack of the nucleophile on the
arene is not reversible and other forces are responsible for the
observed selectivity.
unselective substitution in which the para position is favored,
albeit only slightly.
In the substitution of 1-Cl-F4NB, the reaction is completely
selective for the position ortho to the nitro group. The MESP
surface for this substrate indicates that the most electropositive
carbon has shifted in relation to that of the PFNB, from the
position para to the nitro group to the ortho position.
An additional factor that may contribute to the change in the
selectivity may be due to the fact that the chlorine is
significantly larger than a fluorine substituent. A side-view of
a cross section of the electron density surface (through C1 and
C4 perpendicular to the molecular plane) indicates that attack
of the nucleophile at C1 may be somewhat occluded by the
To elucidate the factors responsible for the shift in selectivity
(4c vs 4b), DFT calculated molecular electrostatic potential
energy surfaces44,45 (MESPs) were generated for the three
substrates (Figure 4A). While the relative size of the LUMO
does not change appreciably across the substrates, the MESP is
more supportive of the experimentally observed selectivity. For
F3NB, the MESP shows significant partial positive electrostatic
anisotropy at the position ortho to the nitro group, suggesting
that the initial Coulombic attraction of the nucleophile
contributes to the selective formation of the product 3b.
In the reaction of PFNB with nitromethanate, which leads to
products 4a (ortho substitution) and 4b (para substitution) in
44% and 56% conversion, respectively, this hypothesis of
electrostatic attraction of the nucleophile is further supported
by the DFT calculations. The MESP surface illustrates that the
potential energy is more positive at the para position than that
at the ortho position. The observed selectivity can potentially
be rationalized, however, by the fact that because there are two
ortho positions at which substitutions may occur, there is a
greater statistical probability of substitution at these positions as
compared to the para position, leading to an essentially
attached chlorine approaching at the Burgi−Dunitz angle46
̈
(Figure 4B). Curiously, this is in contrast to our previous
observation,41 in which the addition of an oxazolone enolate to
4-chlorotetrafluoropyridine gave substitution at the 4 position
as the major product, which is the same as the fluorinated
analogue. Of all of the factors discussed, they all seem to
support the observed selectivity of the reaction; however, the
relative contribution of each is still unclear.
While we initially focused on the addition of nitromethane,
which generates a highly versatile compound that can be easily
manipulated, there are numerous ways to make nitroalkanes,
and they are versatile building blocks in their own right.
Therefore, we wanted to try our reaction conditions on more
E
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complex nitroalkanes (Figure 5). Vaidyanathaswamy showed
that nitroethane could be used with pentafluorobenzonitrile
aliphatic nitro group to an amine (Table 2). One complicating
factor is that the resultant amine itself could act as a nucleophile
and undergo subsequent addition to the substrate, especially at
the elevated temperatures frequently used in nitro-reductions.
To reduce the aliphatic nitro group, a variety of catalytic
reductions of 2e were carried out under acidic conditions
(Table 2). We hoped the presence of an acid would protonate
the product amine immediately upon formation, thus
preventing further nucleophilic substitution. Refluxing of 2e
with iron dust and concentrated HCl yielded some of the
intended product, albeit very slowly (entry 1). We then focused
on a catalytic palladium reduction with a hydrogen atmosphere.
The reaction did not reduce the nitro group under an
atmosphere of hydrogen (balloon pressure, entry 2), but
upon increasing the H2 pressure in a pressure reactor in the
presence of formic acid (entries 3 and 4) slowly gave the
desired product. The same reaction conditions but with acetic,
instead of formic, acid did not result in a detectable amount of
the intended product (entry 5). We next focused on Raney
nickel reductions. Reaction with off-the-shelf activated Raney
Ni in water resulted in none of the intended amine (entry 6).
Questioning the activity of the preactivated Raney Ni, W6
Raney Ni was prepared according to literature.47 Screening the
activity of the W6 Raney Ni with 3 equiv of acetic acid for only
1 h at room temperature, 50 °C, and 100 °C resulted in 0%,
7%, and 8% of the intended amine (entries 7−9, respectively).
Increasing the pressure of hydrogen gas resulted in better
yields, with 13% in entry 10. At this point, increasing the
temperature to 150 °C led to a substantial increase in the yield
to 56% (entry 11). Increasing the acetic acid to 6 equiv further
improved the yield to 78% (entry 12). However, further
increases (9 equiv) proved slightly detrimental to the yield
(entry 13). Returning to the conditions in entry 19 but
extending the reaction time to 3 h resulted in 98% conversion
(entry 14).
Figure 5. Investigation of the scope of the nucleophile. Isolated yields:
(a) reacted at −25 °C, and (b) reacted at 0 °C.
and methyl pentafluorobenzoate, and we found it to work
similarly under our conditions with pentafluoropyridine (5a).
Reactions with other, more complex nitroalkanes were also
found to take place (5b and 5c), albeit with modest to poor
yields. The majority of the mass balance was presumed to be
addition of the base, although the other products were not fully
characterized. It should be noted that no further optimization
was performed, which may have increased yields. Nonetheless,
these reactions do indicate that the reaction can work with
other enolizable nitroalkanes and can rapidly give rise to highly
elaborated polyfluorinated arenes.
Polyfluorinated benzylic amines are a useful and biologically
important moiety, as can be seen in Figure 1. The structures of
cabotegravir and pimavanserin are particularly interesting
because, after reduction of the nitro group, the products of
Figure 3 could conceivably serve as uninvestigated, fluorinated
analogues with improved properties. For this to happen, we first
had to find conditions that would facilitate the reduction of the
We wanted to avoid the use of a column to isolate the
product and to be able to isolate it in such a way that it would
a
Table 2. Reduction of Nitromethyl Arenes to Amines
b
entry reductant
catalyst
time (h) solvent
acid (equiv)
temp (°C) pressure (atm) SM remaining conversion to intended product
1
2
HCl
H2
H2
H2
H2
H2
H2
H2
H2
H2
H2
H2
H2
H2
Fe
144
42
72
72
72
72
1
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
HCl
100
80
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
28%
0%
Pd/C
AcOH (4.4)
CHOOH (2)
CHOOH (2)
AcOH (10)
3
Pd/C
60
5.5
6.8
6.8
6.8
6.8
6.8
6.8
5%
4
Pd/C
100
100
40
5%
5
Pd/C
trace
0%
6
Raney Ni
7
RaneyNi (W6)
Raney Ni (W6)
Raney Ni (W6)
Raney Ni (W6)
Raney Ni (W6)
Raney Ni (W6)
Raney Ni (W6)
Raney Ni (W6)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (6)
AcOH (9)
AcOH (6)
rt
0%
8
1
50
7%
9
1
100
100
150
150
150
150
8%
10
11
12
13
14
1
21
13%
56%
78%
72%
98%
1
21
21
21
21
1
1
3
a
b
Isolated yield, ca. 500 mg scale; isolated as the hydrochloride salt. Conversion to intended product determined by relative integration of 19F peaks.
F
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solvent in vacuo. The product was extracted from the resultant oily
material (5 × ∼20 mL hexanes) and carefully decanted, leaving the
denser, colored layer behind each time. The combined hexanes layer
was stripped of solvent in vacuo. General purity was sufficient so as to
negate the need for further purifiaction. Variations are noted per
substrate.
be stable. The following workup allowed us to both isolate it
and safely store it as the HCl salt. After filtration and
evaporation of the solvent, the heterogeneous mixture showed a
greenish discoloration and the NMR signals were degraded,
potentially due to the presence of nickel salts. Both the
discoloration and the NMR signal degradation resolved upon
extraction with acidic water and washing with ether. Increasing
the pH of the aqueous layer followed by extraction into ether
led to the isolation of the amine, which was subsequently
precipitated as the hydrochloride salt by addition of anhydrous
ethereal hydrogen chloride.
2e: 2,3,5,6-Tetrafluoro-4-(nitromethyl)pyridine. General proce-
dure A was followed in a 500 mL RB, pentafluoropyridine (95.2
mmol, 10.45 mL), TMG (200.0 mmol, 25.10 mL), MeNO2 (1142.4
mmol, 61.10 mL), NaCl saturated-1 M HCl (210 mL). Deviation from
standard reaction conditions: diethyl ether (100 mL) was used as a
cosolvent, added to the reaction mixture prior to degassing. After the
reaction, the crude material was ground by mortar and pestle and
washed with approximately 800 mL of 0.1 M HCl over vacuum
filtration until no further lightening of coloration was observed. This
resulted in a pale yellow-orange crystalline solid, mass 18.197 g, 91%
yield. Mp 69−71 °C. 19F NMR (376 MHz, chloroform-d): δ −87.79
CONCLUSION
■
We have demonstrated a highly scalable method to quickly and
easily functionalize and replace a C−F bond in a variety of
perfluorinated and polyfluorinated arenes utilizing inexpensive
reagents and mild reaction conditions. This will successively
help facilitate C−F functionalization as a viable strategy for the
synthesis of multifluorinated arenes. Furthermore, we were able
to demonstrate for the first time the elusive monoarylation of
nitromethane with pentafluoropyridine and provided con-
ditions for its reduction to the benzylic amine. Thus, by
using this method, we have shown that more complex
molecules can be produced in short order from commercially
available poly- and perfluorinated arenes, adding to the
collective knowledge for the synthesis of versatile building
blocks, which will enable the synthesis of many useful highly
fluorinated arenes.
1
(dq, J = 28.2, 13.1 Hz, 2F), −141.45 to −141.72 (m, 2F). H NMR
(400 MHz, chloroform-d): δ 5.70 (s, 2H). 13C{1H} NMR (101 MHz,
chloroform-d): δ 143.4 (app. dddd, J = 251.3, 15.5, 12.2, 3.3 Hz, 2C),
140.7 (app. dd, J = 264.6, 35.5 Hz, 2C), 121.3 (tt, J = 15.6, 3.0 Hz,
1C), 65.4 (s, 1C). 19F DOSY mass: calcd 210; found 216. HRMS (m/
z): [M − H]− calcd for [C6HF4N2O2]−, 208.9979; found, 208.9966.
2e: 2,3,5,6-Tetrafluoro-4-(nitromethyl)pyridine (in Heptane). This
was done as in the above procedure, except on a 1 g scale with 10 mL
of heptane instead of diethyl ether, and the reaction time was increased
to 4 h. The initial temperature was −35 °C and was allowed to slowly
increase to 0 °C over the course of the reaction. Workup was the same
as the standard conditions, but the solidified material was ground in a
mortar and pestle and washed with ∼50 mL of aq HCl (0.1 M) over
vacuum filtration. 0.9551 g, 96% yield. 19F and 1H NMR spectra
agreed with characterization above.
3b: 1,2-Difluoro-4-nitro-3-(nitromethyl)benzene. General proce-
dure A was followed on a 1 g scale, using 4-nitro-1,2,3-
trifluorobenzene (4.58 mmol, 0.53 mL) with TMG (9.63 mmol,
1.21 mL) and nitromethane (55.02 mmol, 2.98 mL), except the
resultant material had to be successively washed with 0.1 M aq HCl to
remove the base. 0.753 g pale yellowish crystalline solid, 75% yield. Mp
86−91 °C. 19F NMR (376 MHz, chloroform-d): δ −123.28 (m, 2F),
EXPERIMENTAL SECTION
■
NMR spectra were obtained on a Bruker A400 instrument. High-
resolution mass spectra were obtained on a ThermoFisher LTQ-
OrbitrapXL using electrospray ionization. Chemicals were obtained
from commercial sources and used as received, except as noted. 19F
DOSY was performed according to Sibi and Jasperse’s technique.48 1 g
scale means that the general procedures were scaled ad valorem 1 g of
the intended product with 100% theoretical yield.
1
−133.39 (m, 2F). H NMR (400 MHz, chloroform-d): δ 8.16 (ddd, J
= 9.3, 4.4, 2.1 Hz, 1H), 7.52 (dt, J = 9.3, 8.1 Hz, 1H), 5.94 (d, J = 1.8
Hz, 2H). 13C{1H} NMR (101 MHz, chloroform-d): δ 154.0 (dd, J =
262.4, 13.8 Hz), 149.8 (dd, J = 256.8, 14.3 Hz), 143.9, 122.6 (dd, J =
7.9, 3.9 Hz), 119.2 (dd, J = 18.7, 1.8 Hz), 115.9 (dd, J = 14.0, 1.4 Hz),
67.6 (dd, J = 5.9, 1.7 Hz). HRMS (m/z): [M − H]− calcd for
[C7H3F2N2O4]−, 217.0066; found, 217.0053.
3c: 2,3,5,6-Tetrafluoro-4-(nitromethyl)benzonitrile. General pro-
cedure A was followed on a 1 g scale, with pentafluorobenzonitrile
(4.27 mmol, 0.54 mL), TMG (8.97 mmol, 1.13 mL), and
nitromethane (51.26 mmol, 2.78 mL) in a 100 mL RBF, except
with 10 mL of diethyl ether. The organic layer was washed with 3 mL
of 0.1 M HCl total, resulting in a peach colored crystalline solid. 0.852
g, 85% yield. Mp 67−71 °C (lit. 65−65.5 °C).33 19F NMR (376 MHz,
chloroform-d): δ −87.80 (dq, J = 27.9, 13.1 Hz, 2F), −141.47 to
−141.70 (m, 2F). 1H NMR (400 MHz, chloroform-d): δ 5.70 (s, 2H).
13C{1H} NMR (101 MHz, chloroform-d): δ 143.6 (dddd, J = 248.1,
17.0, 12.4, 3.3 Hz, 2C), 140.9 (d, J = 264.7 Hz, 2C), 121.5 (tt, J = 15.3,
2.9 Hz, 1C), 65.6 (s, 1C). HRMS (m/z): [M − H]− calcd for
[C8HF4N2O2]−, 232.9979; found, 232.9965.
3d: Methyl 2,3,5,6-Tetrafluoro-4-(nitromethyl)benzoate. General
procedure A was followed on a 1 g scale, with methyl
pentafluorobenzoate (3.74 mmol, 0.55 mL), TMG (7.86 mmol, 0.99
mL), and nitromethane (44.92 mmol, 2.43 mL) except instead of
washing the organic layers with 0.1 M HCl, crude material was
dissolved in methanol and triturated by dripping the solution into DI
water, resulting in an amber colored crystalline solid. 0.746 g, 75%
yield. Mp 35−36 °C (lit. mp 30−31 °C).33 19F NMR (376 MHz,
chloroform-d): δ −137.85 to −138.07 (m, 2F), −139.64 to −139.84
(m, 2F). 1H NMR (400 MHz, chloroform-d): δ 5.58 (s, 2H), 3.95 (s,
3H). 13C{1H} NMR (101 MHz, chloroform-d): δ 159.4 (s, 1C), 145.4
General Procedures for the SNAr−F Arylation of Nitro-
methanes. General Procedure A. To a clean, dry round-bottom flask
was added 12 equiv of nitromethane. The round-bottom flask was
fitted with a magnetic stir bar, rubber septum, internal thermometer,
and a ventiliation needle. The solution was degassed with with
bubbling argon for 10 min. While under continuous argon flow, 2.1
equiv of TMG was added, and the solution was stirred for an
additional 20 min. The solution and the arene to be added were then
cooled to −35 °C. Next, the chilled fluoroarene was added dropwise.
The addition of the fluoroarene was done such that the reaction
temperature did not rise more than 5 °C. The reaction was complete
in less than 5 min following the completion of the addition, and was
then quenched with a solution of 1 M HCl (2.3 equiv) that had been
saturated with NaCl. The resultant crude mixture was extracted with
ethyl acetate (3 × 5 reaction volumes), and the combined organic layer
was washed with successive small amounts (∼0.5 reaction volumes) of
HCl (0.1 M), separated, and the organic layer was stripped of solvent,
in vacuo. Generally purity was sufficient so as to negate the need for
further purifiaction. Variations are noted per substrate.
General Procedure B. To a clean, dry round-bottom flask was
added 12 equiv of nitromethane. The round-bottom flask was fitted
with a magnetic stir bar. Next, 2.1 equiv of DBU was added, and the
solution was stirred for an additional 10 min. Next, the fluoroarene was
added dropwise and allowed to stir for 1 h. The reaction was then
quenched with a solution of 1 M HCl (2.3 equiv) that had been
saturated with NaCl. The resultant crude mixture was extracted twice
with ethyl acetate (2 × 5 reaction volumes), the combined organic
layer was washed with a small amount (∼0.5 reaction volume) of HCl
(0.1 M), separated, and the combined organic layer was stripped of
G
DOI: 10.1021/acs.joc.7b00962
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ddt, J = 254.0, 14.8, 4.7 Hz, 2C), 144.4 (ddt, J = 258.3, 14.9, 4.7 Hz,
2C), 115.2 (td, J = 16.3, 4.1 Hz, 1C), 111.2 (t, J = 17.6 Hz, 1C), 65.6
(s, 1C), 53.7 (d, J = 2.3 Hz, 1C). HRMS (m/z): [M − H]− calcd for
[C9H4F4NO4]−, 266.0082; found, 266.0071.
110.9 (t, J = 16.7 Hz, 2C), 109.3 (s, 2C), 65.8 (s, 2C). HRMS (m/z):
[M − H]− calcd for [C14H3F8N2O4]−, 414.9970; found, 414.9944
4a: 1,2,3,4-Tetrafluoro-5-nitro-6-(nitromethyl)benzene and 3b:
1,2,4,5-Tetrafluoro-3-nitro-6-(nitromethyl)benzene. General proce-
dure A was followed, resulting in both. Relative integrations were 44%
and 56%, respectively, by 19F NMR, with complete consumption of
starting material. They were separated by normal phase liquid
chromatography on silica gel, ethyl acetate/hexanes with 2e eluting
at 5% ethyl acetate, retention time 15 min. The concentration of ethyl
acetate was then increased, and 3b eluted at 10% ethyl acetate after 25
min. Both 4a and 4b were somewhat viscous liquids.
3e: 1,2,3,4,5,6,8-Heptafluoro-7-(nitromethyl)naphthalene. Gen-
eral procedure B was followed on a 250 mg scale, with
octafluoronaphthalene (0.80 mmol, 217.24 mg), DBU (1.68 mmol,
0.25 mL), and nitromethane (9.58 mmol, 0.52 mL), except the
reaction time was increased to 3 h. The product was separated by
normal phase liquid chromatography with the product eluting at 5%
EtOAc in hexanes. 0.1688 g of off-white crystalline solid, 68% yield.
Mp 96−98 °C. 19F NMR (376 MHz, chloroform-d): δ −118.32 (ddt, J
= 67.7, 19.4, 3.9 Hz, 1F), −138.15 (ddq, J = 16.7, 8.1, 4.1 Hz, 1F),
−142.39 (dtt, J = 67.8, 16.8, 4.6 Hz, 1F), −144.72 (dddt, J = 58.1,
19.1, 14.9, 2.4 Hz, 1F), −147.07 (dtt, J = 58.1, 18.1, 4.7 Hz, 1F),
−149.98 (dddt, J = 20.2, 17.6, 8.4, 4.2 Hz, 1F), −153.57 (ddtd, J =
4a: 1,2,3,4-Tetrafluoro-5-nitro-6-(nitromethyl)benzene. 19F NMR
(376 MHz, chloroform-d): δ −135.53 (dddt, J = 21.4, 10.0, 6.2, 1.8
Hz, 1F), −141.91 (ddd, J = 21.8, 10.2, 8.3 Hz, 1F), −144.97 (ddd, J =
1
21.5, 20.1, 8.3 Hz, 1F), −145.77 (ddd, J = 21.6, 20.0, 6.2 Hz, 1F). H
NMR (400 MHz, chloroform-d): δ 5.67 (t, J = 2.2 Hz, 2H). 13C{1H}
NMR (101 MHz, chloroform-d): δ 146.6 (dddd, J = 256.4, 11.5, 4.3,
2.5 Hz, 1C), 143.2 (dddd, J = 264.9, 17.1, 11.9, 3.2 Hz, 1C), 142.6 (d,
J = 263.5 Hz, 1C), 135.0 (s, 1C), 129.3−126.8 (m, 1C), 109.3 (ddd, J
= 16.3, 4.6, 2.0 Hz, 1C), 66.8 (s, 1C). HRMS (m/z): [M − H]− calcd
for [C7HF4N2O4]−, 252.9878; found, 252.9869.
1
19.5, 17.1, 7.4, 4.0 Hz, 1F). H NMR (400 MHz, chloroform-d): δ
5.75 (s, 1H). 13C{1H} NMR (101 MHz, chloroform-d): δ 151.9 (d, J =
263.7 Hz), 145.6 (dd, J = 254.5, 14.3 Hz), 141.8 (d, J = 261.1 Hz),
141.4 (d, J = 255.3 Hz), 140.8 (dt, J = 258.9, 15.1 Hz), 140.6 (d, J =
259.7 Hz), 139.1 (dt, J = 256.3, 14.9 Hz), 112.8, 107.7 (t, J = 13.5 Hz),
107.2 (t, J = 19.2 Hz), 65.9 (p, J = 2.1 Hz). Structure assigned by 13C:
1H HMBC. HRMS (m/z): [M − H]− calcd for [C11HF7NO2]−,
4b: 1,2,4,5-Tetrafluoro-3-nitro-6-(nitromethyl)benzene. 19F NMR
(376 MHz, chloroform-d): δ −136.27 to −136.45 (m, 2F), −144.49 to
1
−144.88 (m, 2F). H NMR (400 MHz, chloroform-d): δ 5.69 (t, J =
311.9901; found, 311.9893.
1.5 Hz, 2H). 13C{1H} NMR (101 MHz, chloroform-d): δ 145.7 (dd, J
= 257.4, 23.0 Hz), 140.2 (dd, J = 265.0, 22.1 Hz), 132.0, 112.5 (t, J =
16.9 Hz), 65.4 (p, J = 2.1 Hz). HRMS (m/z): [M − H]− calcd for
[C7HF4N2O4]−, 252.9878; found, 252.9869.
3f: 1,2,4,5-Tetrafluoro-3-(nitromethyl)-6-(trifluoromethyl)-
benzene. General procedure B was followed on a 1 g scale, with
octafluorotoluene (3.61 mmol, 0.51 mL), DBU (7.58 mmol, 1.13 mL),
and nitromethane (43.31 mmol, 2.35 mL) resulting in a colorless
crystalline solid. 0.9362 g, 98% yield. Mp 46−51 °C. 19F NMR (376
MHz, chloroform-d): δ −56.16 to −56.95 (m), −138.25 to −139.03
4c: 1-Chloro-2,3,6-trifluoro-4-nitro-5-(nitromethyl)benzene. Be-
ginning with starting materials prepared as in the literature,42 general
procedure A was followed on a 0.218 mmol scale, with 1-chloro-
2,3,5,6-tetrafluoro-4-nitrobenzene (0.218 mmol, 50 mg), TMG (0.46
mmol, 60 μL), and nitromethane (2.62 mmol, 140 μL) with reaction
time extended to 3 h, resulting in a light brown oil, 31 mg, 53% yield.
19F NMR (376 MHz, chloroform-d): δ −114.00 to −114.19 (m, 1F),
−123.57 to −124.11 (m, 1F), −142.87 to −143.54 (m, 1F). 1H NMR
(400 MHz, chloroform-d): δ 5.68 (s, 2H). 13C{1H} NMR (101 MHz,
chloroform-d): δ 152.5 (d, J = 255.5 Hz, 1C), 148.6 (ddd, J = 262.2,
14.5, 4.3 Hz, 1C), 140.9 (ddd, J = 266.4, 15.7, 4.6 Hz, 1C), 136.7 (m,
1C), 116.4 (dd, J = 23.5, 17.8 Hz, 1C), 107.6 (d, J = 19.5 Hz, 1C),
66.1 (s, 1C). HRMS (m/z): [M − H]− calcd for [C7HClF3N2O4]−,
268.9582; found, 268.9564.
1
(m). H NMR (400 MHz, chloroform-d): δ 5.67 (s, 2H). 13C{1H}
NMR (101 MHz, chloroform-d): δ 145.7 (d, J = 257.2 Hz, 2C), 144.1
(d, J = 264.6 Hz, 2C), 120.4 (q, J = 275.3 Hz, 1C), 113.0−112.3 (m,
2C), 65.4 (t, J = 2.5 Hz, 1C). HRMS (m/z): [M − H]− calcd for
[C8HF7NO2]−, 275.9901; found, 275.9881.
3g: 1,2,3,4,5-Pentafluoro-6-(nitromethyl)benzene. General proce-
dure B was followed on a 1 g scale, with hexafluorobenzene (4.40
mmol, 0.508 mL), DBU (9.25 mmol, 1.38 mL), and nitromethane
(52.84 mmol, 2.86 mL), except with reaction time extended to 4 h.
This resulted in a light tan liquid. 0.833 g, 83% yield. 19F NMR (376
MHz, chloroform-d): δ −140.82 to −140.95 (m, 2F), −149.28 (tt, J =
20.8, 3.3 Hz, 1F), −160.56 to −160.89 (m, 2F). 1H NMR (400 MHz,
chloroform-d): δ 5.51 (t, J = 1.50, 2H). 13C{1H} NMR (101 MHz,
chloroform-d): δ 146.1 (dddt, J = 252.7, 11.4, 7.6, 4.1 Hz), 143.2 (dtt,
J = 258.8, 13.3, 5.3 Hz, 1C), 137.9 (d, J = 253.2, Hz, 2C), 104.1 (td, J
= 17.3, 4.2 Hz, 2C), 65.5 (s, 1C). HRMS (m/z): [M − H]− calcd for
[C7HF5NO2]−, 225.9933; found, 225.9916.
3h: 1,2,4,5-Tetrafluoro-3-(nitromethyl)benzene. General proce-
dure B was followed on a 2 g scale, with pentafluorobenzene (9.56
mmol, 1.06 mL), DBU (20.09 mmol, 3.00 mL), and nitromethane
(114.78 mmol, 6.22 mL), but the reaction time was lengthened to 18
h, resulting in a light tan liquid. 1.852 g, 93% yield. 19F NMR (400
MHz, chloroform-d): δ −140.87 (m, 2F), −149.28 (tt, J = 20.85 Hz,
3.33 Hz 1F), −160.73 (m, 2F). 1H NMR (400 MHz, chloroform-d) δ
5.51 (t, J = 1.50, 2H). 13C{1H} proton decoupled NMR (101 MHz,
CDCl3): δ 146.1 (dddt, J = 252.73 Hz, 11.35 Hz, 7.62 Hz, 4.10 Hz,
2C), δ 143.7 (m, 1C), δ 137.9 (m, 2C), δ 104.1 (td, J = 17.26 Hz, 4.18
Hz, 1C), δ 65.5 (s, 1C). HRMS (m/z): [M − H]− calcd for
[C7H2F4NO2]−, 208.0027; found, 208.0022.
5a: 2,3,5,6-Tetrafluoro-4-(1-nitroethyl)pyridine. General proce-
dure A was followed on a 1 g scale, with pentafluoropyridine (4.76
mmol, 0.52 mL), TMG (10.00 mmol, 1.25 mL), and nitroethane
(57.12 mmol, 4.08 mL), with the crude reaction mixture separated by
normal phase liquid chromatography over silica gel, eluting at 5%
DCM in hexanes, yielding 0.6652 g of pale golden liquid, 66% yield.
19F NMR (376 MHz, chloroform-d): δ −88.23 to −88.66 (m, 2F),
1
−142.21 to −142.44 (m, 2F). H NMR (400 MHz, chloroform-d): δ
5.88 (q, J = 7.2 Hz, 1H), 2.04 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101
MHz, chloroform-d): δ 143.7 (dddd, J = 247.5, 16.5, 12.6, 3.1 Hz, 2C),
140.1 (d, J = 263.0 Hz, 2C), 128.1 (tt, J = 13.9, 2.7 Hz, 1C), 74.8, 17.5
(t, J = 2.4 Hz, 1C). HRMS (m/z): [M − H]− calcd for
[C7H3F4N2O2]−, 223.0136; found, 223.0142.
5b: 2,3,5,6-Tetrafluoro-4-(1-nitro-2-phenylethyl)pyridine. General
procedure B was followed on a 0.95 g scale, but 2.2 equiv of (2-
nitroethyl)benzene (6.93 mmol, 1.047 g), prepared according to the
literature, was added to DBU (7.62 mmol, 1.14 mL) in 20 mL of
diethyl ether, vigorously stirred, followed by 250 mg of silica gel. The
reaction mixture was cooled to 0 °C, and pentafluoropyridine (3.15
mmol, 0.346 mL) in 5 mL of diethyl ether (chilled) was added
dropwise. Workup was the same as the general procedure. The
resultant mixture was separated from the nitroalkene by reverse phase
liquid chromatogaphy, C-18 column, eluting at 45−55% acetonitrile in
water after 40 min. Fractions were stripped of organic solvent,
extracted with DCM, dry loaded onto silica gel, and further purified by
normal phase liquid chromatography on a silica gel column, with the
product eluting at 5% DCM in hexanes. 0.2001 g of viscous yellowish
liquid, 21% yield. 19F NMR (376 MHz, methylene chloride-d2): δ
3i: 2,2′,3,3′,5,5′,6,6′-Octafluoro-4,4′-bis(nitromethyl)-1,1′-bi-
phenyl. General procedure B was followed on a 50 mg scale, with
decafluorobiphenyl (0.12 mmol, 40.1 mg), DBU (0.25 mmol, 40 μL),
and nitromethane (1.44 mmol, 80 μL), except the reaction was
conducted at 60 °C. Following concentration, the material was purified
by normal phase flash chromatography, with the product eluting at
25% ethyl acetate in hexanes. 36 mg yield, 72%. Mp 171−173 °C. 19F
NMR (376 MHz, chloroform-d): δ −135.81 to −136.38 (m, 4F),
1
−139.33 to −139.58 (m, 4F). H NMR (400 MHz, chloroform-d): δ
5.65 (t, J = 1.4 Hz, 4H). 13C{1H} NMR (101 MHz, chloroform-d): δ
145.5 (dd, J = 254.8, 11.7 Hz, 4C), 144.0 (dd, J = 254.9, 15.3 Hz, 4C),
H
DOI: 10.1021/acs.joc.7b00962
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The Journal of Organic Chemistry
Article
1
−89.31 to −89.57 (m, 2F), −141.47 to −141.71 (m, 2F). H NMR
(400 MHz, methylene chloride-d2): δ 7.36−7.11 (m, 5H), 6.11 (dd, J
= 10.0, 6.4 Hz, 1H), 4.11 (dd, J = 13.9, 6.4 Hz, 1H), 3.56 (dd, J = 13.9,
10.0 Hz, 1H). 13C{1H} NMR (101 MHz, methylene chloride-d2): δ
144.1 (dddd, J = 246.4, 16.7, 12.8, 3.0 Hz, 2C), 140.9 (d, J = 262.7 Hz,
2C), 133.9 (s, 1C), 129.7 (s, 2C), 129.4 (s, 2C), 128.6 (s, 1C), 127.0
(tt, J = 13.9, 2.8 Hz, 1C), 80.8 (t, J = 2.0 Hz, 1C), 37.7 (t, J = 2.2 Hz,
1C). HRMS (m/z): [M − H]− calcd for [C13H7F4N2O2]−, 299.0449;
found, 299.0429.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jimmie.weaver@okstate.edu.
ORCID
Jimmie D. Weaver: 0000-0003-4427-2799
Notes
The authors declare no competing financial interest.
■
5c: 2,3,5,6-Tetrafluoro-4-(2-nitropropan-2-yl)pyridine. General
procedure B was followed on a 4.60 mmol scale, but 2.2 equiv of 2-
nitropropane (10.12 mmol, 0.92 mL) was used instead of nitro-
methane, with pentafluoropyridine (4.60 mmol, 0.51 mL) and DBU
(9.66 mmol, 1.44 mL). The reaction mixture was cooled to 0 °C.
Workup was the same as the general procedure. Crude material was
purified by normal phase liquid chromatography over silica gel, with
the indended product eluting at 10% EtOAc in hexanes, 17−20 min
retention. Evaporation yielded 31.4 mg (3% yield) of brownish
crystalline solid. Mp 124−129 °C. 19F NMR (376 MHz, chloroform-
ACKNOWLEDGMENTS
■
We would like to thank Dr. Anuradha Singh for an initial
experimental result, and Dr. Chris Fennell for his computa-
tional assistance. This work was funded through the generous
support of the NIH NIGMS award R01GM115697. High-
resolution mass spectrometry analyses were performed in the
Genomics and Proteomics Center at Oklahoma State
University, using resources supported by the NSF MRI and
EPSCoR programs (award DBI/0722494). Molecular graphics
and analyses were performed with the UCSF Chimera 1.11.2
package, Inkscape 0.92.0 r15299, FreeCAD 0.16, and GIMP
2.8.20. Chimera is developed by the Resource for Biocomput-
ing, Visualization, and Informatics at the University of
California, San Francisco (supported by NIGMS P41-
GM103311). Inkscape and GIMP are available under GNU
General Public License. FreeCad is available under the GNU
Lesser General Public License.
1
d): δ −90.16 to −90.46 (m, 2F), −162.99 to −163.40 (m, 2F). H
NMR (400 MHz, chloroform-d): δ 1.80−1.69 (m, 6H). 13C{1H}
NMR (101 MHz, chloroform-d): δ 145.4−145.1 (m, 1C), 143.7 (d, J
= 241.5 Hz, 2C), 132.7 (d, J = 254.1 Hz, 2C), 91.6 (s, 1C), 23.1 (s,
2C). HRMS (m/z): [M − H]− calcd for [C8H5F4N2O2]−, 237.02926;
found, 237.0278.
Procedure for the Reduction of 2e to 6a: (Perfluoropyridin-4-
yl)methanamine. W6 Raney Ni was prepared according to the
literature.47 To a 450 mL glass jacketed stirring pressure reactor were
added 100 mL of anhydrous ethanol, 1 equiv of 1a, 6 equiv of acetic
acid, and 40% m/m Raney Ni. The reactor was then sealed, stirring
commenced, and the atmosphere filled and vented with 21 ATM
hydrogen gas 5×. The reactor was again filled to 21 ATM and heated
to 150 °C. The reaction was stirred at 150 °C for 3 h. The reactor was
then cooled in an ice bath to room temperature, vented, and then
opened. The resultant solution was vacuum filtered through Celite and
stripped of solvent in vacuo. The solids that formed were dissolved in a
1 M aqueous HCl and washed with diethyl ether, the organic phase
then being discarded. The aqueous layer was made basic with 2 M
aqueous NaOH, at which time a visible white precipitate formed. The
aqueous layer was then extracted with diethyl ether. The organic layer
was dried with MgSO4, and made acidic with anhydrous ethereal HCl.
White solids precipitated and were separated by vacuum filtration,
washed with additional anhydrous diethyl ether, and dried over
vacuum.
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COMPUTATIONAL METHODS
■
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00962.
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Spectral and computational data (PDF)
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