Mild transition-metal-free amination of fluoroarenes catalyzed by fluoride ions

Article abstract of DOI:10.1021/jo102063s

Trimethylsilyl-protected heterocycles undergo N-C bond formation with a variety of electron-deficient fluoroarenes catalyzed by fluoride ions. This reaction avoids stoichiometric amounts of base and thus makes N-arylheterocycles accessible in a very mild and transition-metal-free way.

Full text of DOI:10.1021/jo102063s

pubs.acs.org/joc
coupling.6 These methods suffer from several drawbacks
Mild Transition-Metal-Free Amination of
Fluoroarenes Catalyzed by Fluoride Ions
including harsh reaction conditions such as high tempera-
tures, the need for strong bases (K2CO3, K3PO4 ,or NaH), or
the stoichiometric use of copper. During the last two decades,
transition-metal-catalyzed N-arylation has received wide inter-
est. Buchwald7 and Hartwig8 developed broadly applicable
palladium-catalyzed aminations of haloarenes. Following this
breakthrough, numerous publications on the palladium-
catalyzed cross-coupling of aryl halides with amines have
been reported. However, the use of stoichiometric amounts of a
base is still mandatory, and elevated reaction temperatures
are often required.9 Using bidentate ligands, Buchwald10
and Taillefer11 accomplished the copper-catalyzed N-aryla-
tion of heterocycles with bromo- and iodoarenes. Since then,
the Ullmann reaction has seen a resurgence due to the eco-
nomic attractiveness of copper.12 Instead of aryl halides, sev-
eral other types of cross-coupling partners have also been
employed, among them arylboronic acids,13 potassium aryltri-
fluoroborates,14 arylsiloxanes,15 arylstannanes,16 aryllead
triacetates,17 and arylbismuth reagents.18 Quite mild conditions
have been achieved with these substrates; however, these
Daniel Dehe, Isabel Munstein, Andreas Reis, and Werner
R. Thiel*
€
Technische Universitat Kaiserslautern, Fachbereich Chemie,
Erwin-Schrodinger-Strasse, Geb. 54, 67663 Kaiserslautern,
€
Germany
thiel@chemie.uni-kl.de
Received October 18, 2010
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Trimethylsilyl-protected heterocycles undergo N-C bond
formation with a variety of electron-deficient fluoroarenes
catalyzed by fluoride ions. This reaction avoids stoichio-
metric amounts of base and thus makes N-arylhetero-
cycles accessible in a very mild and transition-metal-free
way.
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DOI: 10.1021/jo102063s
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Published on Web 01/18/2011
J. Org. Chem. 2011, 76, 1151–1154 1151
2011 American Chemical Society

Dehe et al.
JOCNote
transformations are limited by the high cost and poor availa-
bility of functionalized substrates.
TABLE 1. Effect of Different EWGs on the N-Arylation of Tri-
methylsilylimidazole with Fluoroarenes at rta
Since most of the common methods utilize at least a
stoichiometric amount of base (K2CO3, K3PO4, or Cs2CO3)
and often apply high temperatures, there is still a demand for
procedures with mild conditions in case substrates are in-
compatible with these requirements. For our approach, we
envisaged the SNAr reaction as a viable alternative. How-
ever, we decided to employ a “masked” nucleophile instead
of generating the nucleophile in situ through deprotonation.
By this method, SNAr reactions under mild conditions can be
achieved. Here, we present N-C bond formations catalyzed
by fluoride ions using fluoroarenes and silylamines as cou-
pling partners.
Trimethylsilyl (TMS) groups are common protecting
groups in organic chemistry.19 Most commonly employed
to protect hydroxyl moieties, they have also proven to be
valuable for amines.20 For example, in the first asymmetric
synthesis of thienamycin, a dibenzyl aspartate was mono-
silylated in order to achieve a Grignard-mediated cyclization.21
Silylamines are easily accessible using trimethylsilyl chloride
or hexamethyldisilazane.22 This class of compounds has
already been used as precursor for the generation of new
N-C bonds. Their addition to aldehydes,23 alkynes,24
thiolesters,25 R,β-unsaturated ketones,26 and a variety of
cumulenes27 is already known. Ring openings of lactones28
and anhydrides29 have also been reported.
The cleavage of the TMS group can be achieved by
fluoride ions. Liu and Larock used this approach to generate
arynes from o-silylaryl triflates, which then undergo reaction
with a variety of nucleophiles.30 Lam generated hypervalent
siloxane species with TBAF in order to promote N-
arylation.15 A number of reactions catalyzed by fluoride ions
have been reported, taking advantage of the great affinity
between silicon and fluorine.31 Only a handful of examples
aReaction conditions: fluoroarene (9.7 mmol), trimethylsilylimida-
zole (10.2 mmol), CsF (24 mol % relative to the fluoroarene), DMF (5
mL), rt, N2. bIsolated yields.
have been reported for fluoride-catalyzed SNAr reactions
generally using silyl ethers and silylacetylenes as the nucleo-
phile precursors.32
We recently developed a fluoride-catalyzed method for the
formation of P-C bonds between fluoroarenes and
silylphosphines.33 To the best of our knowledge, there is
only one publication on the usage of silylamines in this type
of reaction: in 1994, Miller and Furin reported the reaction of
bis(trimethylsilyl)amine with perfluorinated arenes yielding a
mixture of arylamines, diarylamines, and triarlyamines.34
For our initial studies on the fluoride-catalyzed N-C
coupling, we used the conditions we had already optimized
for the P-C coupling. Trimethylsilylimidazole was first used
as the nucleophile precursor due to its commercial avail-
ability and the great importance of imidazole arenes.2a All
kinds of fluoroarenes bearing electron-withdrawing groups
can be used as coupling partners, the only exception being
arenes with acidic protons, for example, carboxylic acids.
First tests with three fluoroarenes substituted with electron-
withdrawing groups in the para position showed mixed
results (Table 1).
In case the electron-withdrawing effect is sufficiently
strong, as for the nitro group, the reaction proceeds rap-
idly (Table 1, entry 1). The nitrile and the ester derivative
showed a much lower reactivity (Table 1, entries 2 and 3),
giving the order NO2 > CN . COOMe. This corresponds
well with the Hammett substituent constants σp (NO2:
0.78, CN: 0.66, COOMe: 0.45) for these electron-with-
drawing groups (EWGs),35 which are a measure of the
electron-withdrawing capacity of a substituent. Generally,
the reactivity of fluoroarenes for SNAr reaction increases if
the arene is more electron-deficient. After a brief optimi-
zation, we found that 20 h at 60 °C are sufficient for the
coupling of TMS-imidazole with a series of fluoroarenes
(Table 2).
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F. A. J. Am. Chem. Soc. 1980, 102, 6161–6163. (b) Cabri, W.; Fabio, R. D.
From Bench to Market: The Evolution of Chemical Synthesis; Oxford Uni-
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2809. (b) Bruynes, C. A.; Jurriens, T. K. J. Org. Chem. 1982, 47, 3966–3969.
(c) Roth, C. A. Ind. Eng. Chem. Prod. Res. Dev. 1972, 11, 134–139.
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(24) Chandra, G.; Jenkins, A. D.; Lappert, M. F.; Srivastava, R. C. J.
Chem. Soc., A 1970, 2550.
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K.; Hosomi, A. Chem. Lett. 1994, 23, 719–722.
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Krysina, V. K. J. Organomet. Chem. 1969, 17, 241–262. (b) Yoder, C. H.;
Komoriya, A.; Kochanowski, J. E.; Suydam, F. H. J. Am. Chem. Soc. 1971,
93, 6515–6518. (c) Matsuda, I.; Itoh, K.; Ishii, Y. J. Organomet. Chem. 1974,
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(29) Kricheldorf, H. R.; Greber, G. Chem. Ber. 1971, 104, 3168–3175.
(30) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198–3209.
(31) (a) Uneyama, K. J. Fluorine Chem. 2007, 128, 1087–1090. (b) Amii,
H.; Uneyama, K. Chem. Rev. 2009, 109, 2119–2183.
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Kirchmeier, R. L.; Shreeve, J. M. Inorg. Chem. 1994, 33, 5463–5470. (c) Zhang,
Y.; Kirchmeier, R. L.; Shreeve, J. M. J. Fluorine Chem. 1994, 68, 287–292. (d)
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1152 J. Org. Chem. Vol. 76, No. 4, 2011

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TABLE 2. N-Arylation of Trimethylsilylimidazole with Fluoroarenesa
SCHEME 1. Fluoride-Catalyzed N-C Coupling
Table 3. First, we investigated the reaction between fluoro-
benzene and trimethylsilylimidazole. The functionalization
of the fluoroarene with an EWG is an absolute necessity.
Without an EWG present, not even traces of product can be
detected (Table 3, entry 1). The fluoride source also plays an
important role. From our studies on the P-C coupling it can
be concluded that CsF is superior compared to KF or TBAF.
We also noticed that different batches of CsF showed
different reactivity. A huge increase in reactivity could be
achieved by dissolving CsF in deionized water followed by
removal of the solvent and drying under vacuum at 150 °C
for several days. A possible reason for the increased reactiv-
ity may be a change in the morphology of the treated CsF.
When the reaction was carried out in the absence of CsF no
reaction occurred (Table 3, entry 2). Instead of CsF, catalytic
amounts of bases, for example, K2CO3, are also able to start
the reaction; however, the yields are lower in this case. We
suppose that under these basic conditions traces of water in
the solvent will initially cleave the TMS group from the
imidazole, which then will liberate the catalyst fluoride by
N-C coupling. There have been several reports on the usage
of CsF as a base in transition-metal-catalyzed N-C bond
formations.9a,36 We therefore wanted to rule out this role for
CsF. If 1H-imidazole is applied instead of trimethylsilylimi-
dazole only traces of product are formed at rt (Table 3, entry
3), compared to 94% at rt with the silylated reagent (Table 3,
entry 4). Even at 60 °C, just 9% of the product are formed
(Table 3, entry 5), proving that the noncatalyzed SNAr
reaction with CsF acting as base only has a minor impact
on the overall rate. With potassium acetate as base, which is
comparable to CsF in terms of its basicity,37 only traces of
the product were detected (Table 3, entry 6); with K2CO3, a
much stronger base, only 1 equiv of product according to the
amount of base is generated (Table 3, entry 7). These results
clearly prove that the reaction takes place due to the special
capability of fluoride ions to cleave TMS groups and not
because of their basicity.
aReaction conditions: fluoroarene (9.7 mmol), trimethylsilylimida-
zole (10.2 mmol), CsF (24 mol % relative to the fluoroarene), DMF (5
mL), 60 °C, 20 h, N2. bIsolated yields.
The nitro and nitrile derivatives gave excellent yields, the
only exception being the meta-functionalized arene which
still gave a satisfactory result (Table 2, entry 3). This differ-
ence in reactivity is explained by the fact that a substituent in
the meta position will not stabilize the intermediate in the
addition-elimination mechanism by a resonance effect. Due
to steric reasons, the reactivity of ortho-functionalized arenes
is slightly lower than that of the para derivatives (Table 2,
entries 2 and 4). This is consistent with the general order of
reactivity in SNAr reactions being para>ortho . meta. Since
a fluoro substituent accelerates the addition step to the ipso
position in SNAr reactions by its enormous inductive effect,
the halide-substituted fluoroarenes (Table 2, entries 6 and 7)
showed exclusive displacement of fluoride, which was con-
firmed by NMR and high-resolution mass spectroscopy.
Only traces of product could be isolated when 1-bromo-4-
fluorobenzene was used as the coupling partner (Table 2,
entry 7). This shows that activation of the arene by one
bromine group is not sufficient, whereas two chloro groups
in the ortho and para positions are activating enough to
achieve a acceptable yield (Table 2, entry 6).
Fluorotrimethylsilane, the byproduct of the synthesis,
has a boiling point of 16 °C and evaporates through a bub-
bler during the reaction. This offers an additional driv-
ing force to shift the equilibrium to the products. Monitoring
the progress of the reaction is therefore quite simple: as soon
as the evolution of fluorotrimethylsilane ceases, the reaction
is finished. Typical workup consists of removing the sol-
vent under reduced pressure and extraction with dichloro-
methane and washing with water. According to NMR and
elemental analysis data the products are usually clean with-
out further purification.
The proposed catalytic cycle can be explained as follows: a
fluoride ion cleaves the TMS group from the amine generat-
ing a nucleophile. This nucleophile undergoes SNAr with a
fluoroarene yielding the product and regenerates the fluoride
ion (Scheme 1).
(36) Phillips, D. P.; Zhu, X. F.; Lau, T. L.; He, X.; Yang, K.; Liu, H.
Tetrahedron Lett. 2009, 50, 7293–7296.
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To gain a deeper insight into the coupling reaction, we set
up a series of control experiments which are summarized in
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Dehe et al.
JOCNote
TABLE 3. Control Experimentsa
aReaction conditions: fluoroarene (9.7 mmol), nucleophile (10.2 mmol), DMF (5 mL), 20 h, N2. bIsolated yields. cKOAc (24 mol % relative to the
fluoroarene); dK2CO3 (24 mol % relative to the fluoroarene).
TABLE 4. Reaction of Fluoroarenes with Trimethylsilylpyrrolidinea
Experimental Section
All reactions were performed under nitrogen by using stan-
dard Schlenk techniques unless otherwise specified. CsF was
obtained from Sigma-Aldrich and activated by dissolving in
deionized water followed by removal of the solvent and drying
under vacuum at 150 °C for several days. Trimethylsilylpyrro-
lidine was prepared according to ref 22a. All other reagents were
purchased from commercial sources and used without further
purification.
General Procedure for the Coupling Reactions. An oven-dried
Schlenk tube was charged with CsF (2.3 mmol) and flame-dried
under vacuum. After the tube had cooled to rt, dry DMF (5
mL) and a magnetic stirring bar were added under nitrogen.
After the resulting suspension was stirred for 30 min, the
fluoroarene (9.7 mmol) was added, and the mixture was stirred
for 10 min followed by the addition of the nucleophile (10.2
mmol). The cap of the Schlenk tube was replaced by a bubbler,
and the mixture was heated to the required temperature for the
aReaction conditions: fluoroarene (9.7 mmol), trimethylsilylpyrroli-
indicated time. For the workup, most of the solvent was
dine (10.2 mmol), CsF (24 mol % relative to the fluoroarene), DMF (5
removed under vacuum. Dichloromethane (20 mL) and water
(20 mL) were added to the residue, and the layers were
mL), 60 °C, N2. bIsolated yields.
separated. The aqueous layer was extracted with dichloro-
methane (2 Â 20 mL). The combined organic layers were
washed with water (15 mL) and a saturated NH4Cl aqueous
solution (15 mL). After drying over MgSO4, the solvent was
removed under reduced pressure.
For extension of this method to aliphatic amines, trimeth-
ylsilylpyrrolidine was investigated. Satisfactory results could be
obtained (Table 4); however, the general reactivity is lower
compared to imidazole since pyrrolidine lacks to stabilize the
negative charge generated by the cleavage of the TMS group.
To summarize: fluoride-catalyzed N-C bond formation
allows a mild and general access to N-arylated amines, which
opens up new opportunities for the synthesis of pharmaceu-
ticals and other valuable fine chemicals.
Supporting Information Available: Compound character-
ization data. This material is available free of charge via the
Internet at http://pubs.acs.org.”
1154 J. Org. Chem. Vol. 76, No. 4, 2011