Efficient nucleophilic aromatic substitution between aryl nitrofluorides and alkynes

Article abstract of DOI:10.1021/ol0710818

Equation Presented The nucleophilic aromatic substitution reaction between electron-deficient aryl fluorides and terminal alkynes is shown to be efficiently promoted by sodium bis(trimethylsilyl)amide as a base. Moderate to excellent yields of 2-ethynylnitrobenzene products can be obtained under mild conditions.

Full text of DOI:10.1021/ol0710818

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2741-2743
Efficient Nucleophilic Aromatic
Substitution between Aryl Nitrofluorides
and Alkynes
Patrick L. DeRoy, Simon Surprenant, Megan Bertrand-Laperle, and
Christiane Yoakim*
Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and
DeVelopment, 2100 Cunard Street, LaVal, Quebec, Canada H7S 2G5
cyoakim@laV.boehringer-ingelheim.com
Received May 9, 2007
ABSTRACT
The nucleophilic aromatic substitution reaction between electron-deficient aryl fluorides and terminal alkynes is shown to be efficiently promoted
by sodium bis(trimethylsilyl)amide as a base. Moderate to excellent yields of 2-ethynylnitrobenzene products can be obtained under mild
conditions.
Interest in indole-containing structures arises from their
widespread abundance in natural products and as useful
pharmacophores in medicinal chemistry.1 The synthesis of
the indole core has attracted much attention from the modern
synthetic chemistry community and from medicinal chemists
in particular, leading to the development of new methodolo-
gies.2 We were particularly interested in the design of indole-
based libraries using readily available starting materials. The
indole core can be obtained via intramolecular cyclization
of o-amino alkynyl derivatives, using a diverse set of
catalysts such as indium,3 palladium,4 or gold5 as shown in
Scheme 1. The required o-amino alkynyl intermediates can
nucleophilic aromatic substitution of readily available o-
fluoronitrobenzenes could lead to the key nitro alkynyl
derivatives. These intermediates are easily transformed to
the desired indole precursor.
To date few examples of Sonogashira-type coupling have
been reported in the absence of transition metal catalysis.
Indeed, Leadbeater and co-workers7 published the first
examples using microwave irradiation and sodium hydroxide
in aqueous poly(ethylene glycol). Prajapati et al.8 have shown
that indium trichloride could be efficiently used to catalyze
the Sonogashira coupling in the absence of copper salt,
(1) For recent review of indoles in natural products see: (a) Faulkner,
D. J. Nat. Prod. Rep. 1999, 16, 155. (b) Lounasmaa, M.; Tolvanen, A. Nat.
Prod. Rep. 2000, 17, 175.
(2) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(3) (a) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron Lett. 2006,
47, 631. (b) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett.
2005, 7, 5437.
Scheme 1
(4) Lu, B. Z.; Zhao, W.; Wei, H. X.; Dufour, M.; Farina, V.; Senanayake,
C. Org. Lett. 2006, 8, 3271.
(5) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988, 29,
1799.
(6) Sonogashira, K. In Metal-Catalysed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter
5.
(7) Leadbeater, N. E.; Marco, M.; Tominack, B. J. Org. Lett. 2003, 5,
3919.
be obtained via the Sonogashira reaction6 of the correspond-
ing o-haloanilines. Driven by the need for a general and facile
alternative to the Sonogashira method we envisaged that the
(8) Borah, N. H; Prajati, D.; Boruah, C. R. Synlett 2005, 2823.
10.1021/ol0710818 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/07/2007

activate trimethysilyl phenylacetylene toward nucleophilic
substitution but provided only very low yield of the desired
adduct. We decided to investigate the use of the alkynyl
group in the SNAr11 reaction under anionic conditions. To
our surprise, this transformation although simple had little
precedent in the literature. However, given that lithium
acetylides have previously been incorporated onto arene-
Cr(CO)3 complexes by SNAr displacement12 and the analogy
between nitroarenes and arene-Cr(CO)3, it prompted us to
investigate this process. In this report, we describe the scope
and limitation of this reaction.
Table 1. Optimization Studyc
entry
solvent
T (°C)
time (h)
yield (%)a
1
2
3
4
THF
rt
rt
65
rt
23
23
2
78
52
79
75
toluene
THF
THFb
We began our study by investigating the base and solvent
required for this reaction. To our delight an initial attempt
in which sodium bis(trimethylsilyl)amide (NaHMDS)13 was
added to a mixture of 2-fluoronitrobenzene and 4-ethynyl-
anisole in THF (Table 1, entry 1) provided a good yield of
the desired coupling product. A screen of different solvents
indicated that THF and toluene were the best choices,
although toluene generally provided a lower yield of adduct
at room temperature (Table 1). The reaction in THF was
accelerated 10-fold by increasing the temperature to refluxing
conditions, (entry 3, Table 1). The sequence of addition of
the base did not impact the reaction outcome. Indeed, the
23
a Isolated yields (average of 2 runs). b NaHMDS was first added to a
solution of the alkyne. After 5 min, 2-fluoronitrobenzene was then added.
c Reaction conditions: NaHMDS (1.5 equiv) was added to a mixture of
the starting materials.
phosphine, and palladium. Wang and Pinhua9 have also
reported a novel reaction utilizing silver iodide in the
presence of triphenylphosine and potassium carbonate to
afford the coupling products in high yields. More recently
tetrabutylammonium fluoride10 was used as a catalyst to
Table 2. SNAr of 2-Fluoronitrobenzene with Functionalized Alkynesd
a Isolated yields (average of 2 runs). b 2.0 equiv of NaHMDS was used. c Reaction time was 5 h. d Reaction condition: NaHMDS (1.5 equiv) was added
to a mixture of the starting materials.
2742
Org. Lett., Vol. 9, No. 14, 2007

formation of the alkynyl anion prior to addition of 2-fluoro-
nitrobenzene afforded the desired compound in a comparable
yield (entry 4 vs entry 1). Replacement of the 2-fluoro-
nitrobenzene by the analogous chloro, bromo, or iodo
compound unfortunately did not provide the desired coupling
product under different reaction conditions.14 The observed
chemoselectivity limits the scope of this methodology but
provides complementarity with the Sonogashira reaction.
Encouraged by the ease of this reaction, we next focused
on expanding the scope of the methodology. Table 2
highlights the broad range of the various alkynes that can
be used in the SNAr reaction. Phenylacetylene provided the
desired adduct in excellent yield (Table 2, entry 1). The
addition of electron-withdrawing or electron-donating groups
on the phenylalkyne did not alter the course of the reaction
(entries 2-6). A notable exception was observed with the
presence of a cyano group (entry 5); only a modest 53%
yield of the coupled product was obtained, along with a
number of undefined byproducts. In addition, the presence
of an ortho substituent gave slightly lower yields (entries 7
and 8). On the other hand, the presence of a bromine atom
at the meta position (entry 9) did not interfere with the
reaction conditions, and provided an extra handle for further
elaboration, using for instance palladium-catalyzed processes.
It is of particular interest that a coupling under Sonogashira
reaction conditions between 2-fluoronitrobenzene and 4-bromo-
1-fluoro-2-nitrobenzene gave a 12 to 1 mixture in favor of
the bromo displacement product. This result further substan-
tiates the complementarity of these methodologies. It was
also gratifying to observe the tolerance of this reaction to
aromatic heterocycles. Indeed, the use of 3-ethynylpyridine
and 2-ethynylthiophene gave the desired adducts in 77% and
60% yield, respectively (entries 10 and 11). The reaction
could also be performed with nonaromatic alkynyl derivatives
in moderate to almost quantitative yields (entries 13-16).
Finally, we probed the SNAr reaction of 4-ethynylanisole
with sterically hindered 2-fluoronitrobenzene derivatives. As
illustrated in Table 3, the presence of a substituent ortho to
the fluorine atom did not negatively impact the reaction and
afforded excellent yields of the alkynyl derivatives (entries
1 and 2). It is worth noting that the presence of a
trifluoromethyl group or a bromine atom para to the fluorine
did not greatly influence reactivity (entries 3 and 4). In
addition, chemoselective reaction was observed with 2-chloro-
6-fluoronitrobenzene; substitution took place exclusively at
the most electrophilic carbon and generated the desired
adduct (entry 5).
Table 3. SNAr of Functionalized 2-Fluoronitrobenzenes with
4-Ethynylanisoleb
a Isolated yields (average of 2 runs). b Reaction conditions: NaHMDS
(1.5 equiv) was added to a mixture of the starting materials.
In summary, we have successfully demonstrated that the
nucleophilic aromatic substitution reaction between electron-
deficient 2-fluoronitrobenzene derivatives and terminal alkynes
can be efficiently performed via deprotonation using sodium
bis(trimethylsilyl)amide as a base. This novel C-C bond
formation reaction provides moderate to excellent yields of
the corresponding 2-ethynylnitrobenzene adducts under facile
conditions and short reaction times. The versatility of this
reaction allowed us to efficiently prepare indole-containing
compounds which are subsequently evaluated as novel
xenobiotics. Results from these studies will be reported in
due course.
Acknowledgment. We are grateful to S. Bordeleau and
N. Aubry for analytical support and to Pierre R. Bonneau,
Jeff A. O’Meara, and Martin Tremblay for their help during
the preparation of this paper.
(9) Li, P.; Wang, L. Synlett 2006, 2261.
(10) Ueno, M.; Hori, C.; Suzawa, K.; Ebisawa, M.; Kondo, Y. Eur. J.
Org. Chem. 2005, 1965.
(11) Zoltewicz, A. J. Top. Curr. Chem. 1975, 59, 33.
(12) Rossillo, M.; Dominguez, G.; Casarrubios, L.; Pe´rez-Catells, J. J.
Org. Chem. 2005, 70, 10611.
(13) Other bases were evaluated: sodium hydride only returned starting
materials; in general LiHMDS and KHMDS gave lower yields and had a
more limited scope.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) The 2-chloro derivative gave only recuperated starting material, and
decomposition was observed with 2- iodo and 2-bromo derivatives.
OL0710818
Org. Lett., Vol. 9, No. 14, 2007
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