Regioselective, nucleophilic activation of C&F bonds in o-fluoroanilines

Article abstract of DOI:10.1016/j.jfluchem.2019.03.009

Reactions of ortho-fluorinated anilines with stoichiometric Ti(NMe₂)₄ in mesitylene (typically for 23 h at 120 °C) afforded moderate to high yields of the corresponding N,N-dimethyl-1,2-phenylenediamine derivatives resulting from def

Full text of DOI:10.1016/j.jfluchem.2019.03.009

Accepted Manuscript
Title: Regioselective, Nucleophilic Activation of C-F Bonds in
o-Fluoroanilines
Authors: Sarita E. Hough, Willie R. Hargrove Jr., Paul A. Deck
PII:
S0022-1139(18)30513-X
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2019.03.009
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28 March 2019
28 March 2019
Please cite this article as: Hough SE, Hargrove WR, Deck PA, Regioselective,
Nucleophilic Activation of C-F Bonds in o-Fluoroanilines, Journal of Fluorine
Chemistry (2019), https://doi.org/10.1016/j.jfluchem.2019.03.009
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Regioselective, Nucleophilic Activation of C-F Bonds in o-Fluoroanilines
Sarita E. Hough, Willie R. Hargrove, Jr., and Paul A. Deck*
Department of Chemistry, Virginia Tech, Blacksburg, VA
Graphical Abstract
Highlights
 Fluorinated anilines react with Ti(NMe2)4 to afford products of ortho-
defluoroamination.
 Anilines having two ortho fluorines can undergo one or two defluoroaminations
depending on reaction conditions.
 Reactivity and selectivity patterns are consistent with established ancillary-fluorine
substituent effects.
Abstract. Reactions of ortho-fluorinated anilines with stoichiometric Ti(NMe2)4 in
mesitylene (typically for 15 h at 120 °C) afforded moderate to high yields of the
corresponding
N,N-dimethyl-1,2-phenylenediamine
derivatives
resulting
from
defluoroamination of a fluorine atom vicinal to the NH2 of the starting aniline. Reactivity
increases with additional ring fluorination in general accordance with established
regiochemical (activating and deactivating) trends.
Introduction
Manipulation of C-F bonds in organic compounds has become increasingly important in
areas of organic chemistry where physical properties and bioactivity depend sensitively on the
placement of fluorine substituents.[1–4] Fluorination can afford thermal or photolytic
stability[5] and help tune local molecular polarities.[2,3,5,6] Much has also been written about
the special hydrophobicity and oleophobicity of highly fluorinated aliphatics.[7–9] In
1

fluorinated arenes, conjugation and local polarity effects play key roles in governing reactivity
and properties. Fluorinated aromatic moieties appear in several new drugs and drug candidates
ranging from anti-cancer drugs to antipsychotics.[4,10–15] With that background, new research
to identify additional reaction sequences for the installation, substitution, or removal of aromatic
fluorine substituents seems justified.[16–19]
Aromatic defluorination reactions often involve organometallic species in directing,
activating, or stabilizing roles. Processes include oxidative additions, SNAr-type substitutions,
and radical reactions.[2,19–24] Ideally, aromatic defluorinations would be catalytic with respect
to the metal.[25–34] However, with early transition metals, M—F bonds tend to be strong,
impeding turnover. A common solution employs a co-catalytic main-group compound (for
example, an aluminum hydride like DIBAL) to scavenge fluoride by transmetallation and
regenerate the active catalytic species.[27,34]
We have particular interest in reactions of the general form shown in Scheme 1, where a
Lewis-basic ring substituent coordinates a metal-organic reagent, directing its nucleophilic
ligands toward the ortho ring position.[35–37] Our interest derives from our serendipitous
finding that that pentafluorophenyl-substituted cyclopentadienes and indenes undergo ortho C-F
bond activation upon treatment with Ti(NMe2)4 (Scheme 2).[38]
Schrock and co-workers also reported that polydentate ligands containing 2,6-difluorophenyl
substituents undergo defluoroaminations when treated with either Hf(NMe2)4 or
Mo(NMe2)4.[39,40]. In all of these cases, the intended synthetic objective involved the
installation of new ligands with removal of dimethylamine, but the reactions were accompanied
by exchange of M-NMe2 bonds and aromatic C-F bonds. We therefore wondered whether this
2

“side-reaction” could be converted and optimized toward a selective, general, and efficient
process in its own right. We now report reactions of ortho-fluorinated anilines with Ti(NMe2)4 to
afford products in which an ortho fluorine atom is replaced with NMe2 to form fluorinated 1,2-
phenylenediamine derivatives. N,N-Dimethyl-1,2-phenylenediamines have found application as
precursors to multidentate ligands for various transition metal catalysts.[41–43]
Results & Discussion
In Scheme 2, cyclopentadiene played a directing role by coordinating the titanium atom
(likely in η5 fashion) and facilitating an intramolecular substitution process.[38] This proposal
neatly rationalized the exclusive ortho selectivity. We surmised that the directing role of the
cyclopentadiene could be shifted to other acidic ligating groups, such as NH2 (Scheme 3).
Our experimental approach used 19F NMR to follow reactions and to estimate conversions
and yields. We chose substrates having at least two ring fluorine substituents so that we could
quantify both the substrate and its defluoroamination product using 19F NMR spectroscopy. The
use of mesitylene as the reaction solvent maintained homogeneity of the reaction mixture.
(Preliminary studies using n-decane led to precipitation of intermediates and very low yields.)
Mildly alkaline aqueous workup conditions minimized water-solubility of the aniline products.
The crude product mixture still contained the mesitylene solvent and the internal NMR standard,
bis(4-fluorophenyl)ether. (We initially chose 3,5-difluoro-1-bromobenzene as the internal
standard, but preliminary control experiments showed this compound to be unstable toward the
titanium reagent at temperatures above 100 °C.) After 19F NMR spectroscopic analysis to
estimate product yields, the mixture was subjected to liquid chromatography to separate the
mesitylene solvent and internal NMR standard and to isolate the products.
3

Product yields are collected in Table 1. Errors of ±5% are conservatively based on the
internal reliability of NMR integration method and are reproducible within those limits in
multiple trials. Yields are mostly high enough to conclude that the method is general and
reasonably efficient. In entries 1, 3, and 4, we still observe some unreacted substrate; likely
these reactions could be driven toward higher conversion by increasing the reaction time or
temperature. In the case of entries 5, 8, and 9, the substrates are sufficiently reactive to give
appreciable yields of products arising from substitution of both ortho fluorine atoms.
Mixtures were separated by liquid chromatography, but not particularly efficiently despite
our efforts to optimize the eluting solvent. Isolated yields from pure chromatographic fractions
were relatively low (ca. 20%) and not particularly reproducible. All new substances were
characterized using NMR spectrometry and exact mass determination (HRMS). We found that
1H and 19F NMR spectra were sufficient for unambiguous identification of all major reaction
13
products, therefore we did not collect C NMR spectra, which would likely be quite complex
1
due to extensive long-range couplings to 19F. The H and 19F spectra show typical chemical
shifts and coupling constants for fluoroaromatic compounds. In the spectra of products having
an NMe2 directly adjacent (vicinal) to a fluorine atom, the methyl groups are split into a doublet
5
with JHF of ca. 2 Hz. This spectral feature was previously documented for N,N-dimethyl-2-
fluoro-aniline and was useful in making signal assignments.[44]
Reactions of Difluoroanilines. As shown in Table 1, difluoroanilines 1a-1d (entries 1–4)
reveal an interesting trend in the relative position of the unreactive (ancillary) fluorine atom.
Conversion of starting material was lowest when the unreactive and departing fluorine atoms had
a para relationship (substrate 1c). Chambers found that fluorines meta and ortho to the departing
fluorine in SNAr reactions tend to be activating, whereas fluorines para to the departing fluorine
4

tend to be deactivating, although the exact (quantitative) kinetic effects are system-
dependent.[45] Likewise, the first substitution in 2,6-difluoroaniline is activated by the presence
of another fluorine in a meta position, but after that initial substitution, the remaining fluorine
atom has no activating substitution and remains inert under the reaction conditions described in
Table 1.
Competitive Study of Relative Reaction Rates: All four difluoroanilines were subjected to a
tenfold excess of Ti(NMe2)4 in a competitive experiment at 80 °C. This lower temperature was
chosen to slow down all of the reactions so that we could monitor them conveniently by 19F
NMR spectroscopic analysis of small aliquots. As shown in Figure 1, 2,6-difluoroaniline had the
highest rate of conversion into product, followed closely by 2,4-difluoroaniline. This
observation is consistent with Chambers’s findings; the fluoroanilines substituted meta to the
reactive site are highly activated, while 2,5-difluoroaniline, which has a fluorine atom para to the
reactive site, is highly deactivated in comparison and is the least reactive of the four substrates.
Even though these data were obtained at a lower reaction temperature, we believe they will
reflect relative reactivity trends at 120 °C, at least qualitatively.
Reactions of Highly Fluorinated Anilines. As shown in Table 1 and Scheme 4, aniline 1e
affords a mixture of three products. The major product (2e) arises from substitution of F2,
activated by one ortho and one meta fluorine substituent (F3 and F6, respectively). The minor
product (iso-2e) results from substitution of F6, activated by one meta fluorine (F2) but also
deactivated by one para fluorine (F3). Substitution of both F2 and F6 also afforded 3e.
5

Based on the results with 1e, we were curious to compare the reactivity of 1f and 1g (Scheme 5).
While the observed NMR yield of 2f (104%) is higher than the observed yield of 2g (83%), we
also concede that the estimated error in our NMR yields is probably around ±5%. We wanted a
more direct comparison to minimize sources of experimental error. In a competitive reaction
with both 1f and 1g present in solution at 120 °C for one hour, substrate 1f underwent 67%
conversion to 2f, whereas substrate 1g underwent only 33% conversion to 2g. This result
confirms that an ancillary para fluorine is deactivating compared to an ancillary ortho fluorine.
The reaction of the tetrafluorinated aniline 1h, shown in Scheme 6, also featured a substrate
with two o-fluorines in non-equivalent chemical environments. After 23 h at 120 °C, triamine
3h was the major product, and the remaining product was 2h; all of the substrate (1h) had been
consumed. A separate reaction of substrate 1h at 90 °C for 3 h afforded not only 2h and 3h, but
19
also a third product having three signals in the F spectrum. Because some unreacted 1h was
also still present, chromatographic separation was difficult, and we were not able to obtain a
fraction containing only the third product. Instead we used a fraction containing some 3h, which
was already well characterized, and we used GCMS to provide a nominal assay of the third
product present in that fraction. Following this approach we assigned the structure iso-2h to the
third product. Based on these results, we suggest that both isomers (2h and iso-2h) are produced
early in the reaction, but of the two isomers, the minor component (iso-2h), whose remaining
fluorine has both a meta and ortho fluorine activating the reaction site, undergoes a more facile
defluoroamination, and is thus consumed to form 3h, compared to 2h, which has one meta
fluorine activating and one para fluorine deactivating its remaining substitution site.
6

Pentafluoroaniline (1i), as the most activated substrate, afforded exclusively the disubstituted
product 3i in moderate yield at 120 °C. A separate reaction, conducted at 90 °C for 3 h, afforded
a product with four signals in the 19F NMR spectrum. We were not able to obtain this product in
a pure form, but we assigned the NMR spectrum of the mixture with the aid of simulation
software (please see the Supporting Information), and we found the appropriate exact mass upon
ESI-MS analysis of the mixture, leading to the assignment of 2i. Yields are shown in Scheme 7.
7

Mechanism and Scope. All of the reactions shown in Table 1 involve substitution of fluorine
atoms exclusively ortho to the NH2 group. This observation supports a pathway (Scheme 8) in
which the dimethylamino group is delivered to the ortho position of the aromatic ring by means
of prior attachment of the aniline nitrogen to titanium, forming the Meisenheimer intermediate 4
in a process resembling intramolecular SNAr. We stress, however, that the pathway shown in
Scheme 7 is largely speculative. Even though there is strong precedent for such pathways in the
published literature,[3,39,40,46] none of the putative intermediates (4, 5, and 6) were observed
spectroscopically. A solution of 2,6-difluoroaniline (1d) and Ti(NMe2)4 prepared in C6D6 at
25°C (at which temperature the rate of defluoroamination should be negligible) showed a
complex 19F NMR spectrum that we could not assign. At least three prominent intermediates are
present. In none of our spectra could we identify any Ti-F species, but we did tentatively assign
1
free dimethylamine in the H NMR spectrum. Spectra are provided in the supporting
information.
8

The overall success of the foregoing synthetic method prompted a preliminary investigation
of its scope and generality. As shown in Scheme 9, we subjected N-ethyl-2,6-difluoroaniline
[47,48] (8) to the same reaction conditions as the other compounds in this study (Table 1) and
obtained a 42 percent yield of the defluoroamination product (8). This result supports the
proposal of putative reaction intermediate 4 which arises from metathesis of one aniline N—H
bond with one Ti—NMe2 bond. In particular, the reactivity of 7 argues against the intermediacy
of arylimidotitanium species, e.g., ArN=Ti(NMe2)2.
Attempting to cast a wider net, we found that 2,6-dichloroaniline (Scheme 10) is unreactive
toward Ti(NMe2)4 even at 150 °C, and that the reaction of 2,6-difluoroaniline with titanium(IV)
isopropoxide under the same conditions returned only the starting aniline. Treatment of 2,6-
difluorophenol (9) with Ti(NMe2)4 at 120 °C gave a low conversion to the corresponding
monosubstitution product (10), and the reaction produced additional byproducts that we were not
able to identify.
Conclusions
o-Fluoroanilines undergo defluorodimethylamination when treated with Ti(NMe2)4.
Reactivity increases with added fluorine substituents ortho or meta to the departing fluorine
atom. Trifluoro-, tetra-, and pentafluoroaniline compounds having fluorines in both the 2- and 6-
positions undergo substitution at both positions after extended reaction intervals. Preliminary
experiments show poor generalization to ortho-fluorinated phenols.
Experimental
9

Materials and Methods. Ti(NMe2)4 (Alfa Aesar), bis(4-fluorophenyl)ether (Oakwood),
mesitylene (Acros Organics), and fluoroanilines (various suppliers) were used as received. NMR
spectrometry was performed using an Agilent U4-DD2 (proton at 400 MHz) or Varian MR4
instrument (proton at 400 MHz). Exact masses of new substances were determined using an
Agilent 6220 ESI-TOF instrument.
General Reaction Procedure. In nitrogen glovebox, a flame-dried Schlenk tube was charged
with Ti(NMe2)4 (0.300 g, 1.30 mmol). Under a nitrogen counterstream, 0.15 g of bis(4-
fluorophenyl)ether internal standard, 1.15 mmol of the aniline reactant, and 3.0 mL of mesitylene
were added. The tube was then sealed (PTFE valve) and heated at 120 °C in an oil bath for 18-
24 hours. After cooling, the mixture was diluted with dichloromethane (ca. 50 mL) and
quenched with aqueous 10% sodium bicarbonate solution. The layers were separated, and the
aqueous portion was extracted with additional dichloromethane (10 mL). The combined organic
portions were dried over anhydrous magnesium sulfate, filtered, and evaporated to afford mostly
19
yellow oils. Yields of products (and unreacted starting aniline, if any) were estimated using F
NMR spectroscopy. A characteristic signal from each fluorinated aniline was integrated against
the bis(4-fluorophenyl)ether internal standard, after correcting for concentration and symmetry
factors. Products were isolated using liquid chromatography on silica gel, eluting with
dichloromethane or ethyl acetate.
N-Ethyl-2,6-difluoroaniline [47,48] was synthesized by N-acylation and LAH-reduction of
the acyl as follows. First, a mixture of 2,6-difluoroaniline (2.23 g), acetic anhydride (1.9 mL),
and 4 mL of glacial acetic acid reacted at 25 °C for 15 h and then diluted with dichloromethane.
The solution was washed with 0.75 M aqueous sodium hydroxide solution, dried over anhydrous
magnesium sulfate, filtered, and solvent was evaporated to afford a white solid, which was
10

recrystallized from ethyl acetate/hexanes (3:1) mixture to afford intermediate N-acyl-2,6-
difluoroaniline as a colorless crystalline solid. This solid was dissolved in dry THF and cooled
using a dry ice bath and then lithium aluminum hydride (1.44 g) was added. The reaction was
stirred for 20 h while warming to room temperature and then diluted with dichloromethane. The
mixture was washed with aqueous sodium bicarbonate, then with water, dried over magnesium
sulfate, filtered, and evaporated to form a pale solid, which was found to be impure by NMR
spectroscopic analysis. The crude product was purified by silica gel chromatography, eluting
with dichloromethane. After evaporation, 0.67 g of a pale oil was obtained. This procedure was
not optimized. Analytical data are provided in the Supporting Information.
Acknowledgments
We thank the Virginia Tech Graduate Student Assembly for a Travel Grant for SEH. We thank
the National Science Foundation for Grant No. CHE-0722638 for the purchase of the Agilent
6220 ESI-TOF-MS. We thank Ken Knott for help with NMR measurements.
11

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18

Figure captions
Figure 1: Concentrations of products over time in a competitive reaction of four
difluoroanilines with a tenfold excess of Ti(NMe2)4 in mesitylene at 80 °C.
19

Scheme captions
Scheme 1: Aromatic C-F activation using a metal-organic reagent (M−Nu) directed by a
ring substituent (G).
Scheme 2: C-F activation of (pentafluorophenyl)cyclopentadiene with Ti(NMe2)4.
Scheme 3: Defluoroamination of ortho-fluoroanilines using Ti(NMe2)4.
Scheme 4: Reaction of 2,3,6-trifluoroaniline 1e with Ti(NMe2)4.
20

Scheme 5: Reactions of anilines 1f and 1g with Ti(NMe2)4.
Scheme 6: Temperature-dependent defluoroamination of 2,3,4,6-tetrafluoroaniline.
Scheme 7: Temperature-dependent defluoroamination of 2,3,4,5,6-pentafluoroaniline.
Scheme 8: Possible pathway for reactions of o-fluoroanilines with Ti(NMe2)4.
21

Scheme 9: Reaction of N-ethyl-2,6-difluoroaniline with Ti(NMe2)4.
Scheme 10: Reaction of 2,6-difluorophenol with Ti(NMe2)4.
22

Table
Table 1. NMR yields of defluoroamination products resulting from the reaction shown. Yields
(±5%) were estimated by NMR analysis of crude product mixtures.
Yields by 19F NMR, ±5%
Entry Substrate
time
20 h
23 h
23 h
23 h
23 h
23 h
18 h
23 h
18 h
1
8
2
86
92
60
3
2,3-difluoroaniline (1a)
2,4-difluoroaniline (1b)
2,5-difluoroaniline (1c)
2,6-difluoroaniline (1d)
2,3,6-trifluoroaniline (1e)
2,3,4- trifluoroaniline (1f)
2,4,5- trifluoroaniline (1g)
2,3,4,6- tetrafluoroaniline (1h)
2,3,4,5,6-pentafluoroanline (1i)
1
2
3
4
5
6
7
8
9
31
3
96
83a
104
83
13
14b
88
68
a Product 2e is a 7:1 mixture of 2-dimethylamino-3,6-difluoroaniline (2e) and 2,3-difluoro-6-
dimethylaminoaniline (iso-2e), respectively. See Scheme 5 below.
b Product 2h is 2-dimethylamino-3,4,6-trifluoroaniline.
23