Palladium-assisted room-temperature nucleophilic substitution of an unactivated aryl fluoride

Article abstract of DOI:10.1021/om201175d

An organometallic palladium(II) complex of an 8-fluoroquinoline-based chelating ligand undergoes very facile nucleophilic substitution of the "unactivated" fluorine atom with the methoxy group upon simple stirring of its THF solution with sodium methoxide at room temperature. The final product of this reaction lacks the aromaticity in the heterocyclic ring of the quinoline moiety which might play an important role in the overall reactivity.

Full text of DOI:10.1021/om201175d

Communication
pubs.acs.org/Organometallics
Palladium-Assisted Room-Temperature Nucleophilic Substitution of
an Unactivated Aryl Fluoride
Adam Scharf, Israel Goldberg, and Arkadi Vigalok*
School of Chemistry, The Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel
S
* Supporting Information
ABSTRACT: An organometallic palladium(II) complex of an
8-fluoroquinoline-based chelating ligand undergoes very facile
nucleophilic substitution of the “unactivated” fluorine atom
with the methoxy group upon simple stirring of its THF
solution with sodium methoxide at room temperature. The
final product of this reaction lacks the aromaticity in the
heterocyclic ring of the quinoline moiety which might play an
important role in the overall reactivity.
ctivation of aryl−fluorine bonds by late-transition-metal
Scheme 1
Scheme 2
A
complexes has remained a hot area of research for several
decades.1 For example, cleavage of these bonds can provide
access to defluorinated compounds which are less persistent in
nature than organic fluorides.2 Fluoroaromatic substrates can
also serve as valuable precursors for a variety of catalytic cross-
coupling reactions.3 In all cases, the emphasis of the late-
transition-metal activation of C−F bonds was placed on the
design of electron-rich metal complexes that can cleave these
strong bonds giving new organometallic compounds,4 the
reaction usually requiring harsh reaction conditions.5 Although
polyfluoroaromatic compounds, as well as compounds having
strong electron-withdrawing groups in the position ortho or
para to the fluorine atom, are activated toward the nucleophilic
substitution reaction that proceeds via SNAr mechanism, the
use of late-transition-metal complexes as activating groups in
such reactions has not been reported.6 Herein we present the
first example of extremely facile nucleophilic replacement of
unactivated aryl fluoride that is assisted by a Pd(II) complex.
Pincer ligands play an important role in bond activation
studies and catalysis.7 Heteroatoms, such as P, N, O, and S, are
routinely used as “arms” of various metal pincer complexes.
However, the use of halides as a part of the pincer system
remains unknown. We were interested in exploring the
possibility of using fluorine as a labile arm in pincer complexes.
To facilitate the complexation to the metal center, we chose the
rigid quinoline system, where the metal and fluoro substituents
at the 8-position would be pitched together due to the steric
requirements.8 Toward this end, we prepared the fluorine-
containing ligand 1 via the Doebner−Miller condensation of 2-
fluoroaniline with crotonaldehyde9 followed by a reaction with
lithium diisopropylamide (LDA) and Cl-P(t-Bu)2 (Scheme 1).
The addition of 1 equiv of [Pd(4-FC6H4)I(tmeda)] (tmeda =
tetramethylethylenediamine) to a solution of 1 in acetone
resulted in the formation of complex 2 in 84% yield after 5 days
at room temperature (Scheme 2). The yellow complex is only
sparingly soluble in nonpolar benzene or toluene. The 31P
NMR spectrum of 2 in CDCl3 showed a singlet at 60.7 ppm, 30
ppm downfield from the signal in free 1. Unexpectedly, the 19
F
NMR signal of the 8-fluoro substituent in 2 appears at −102.1
ppm, more than 25 ppm downfield from the fluorine signal in
1. As we attributed such a significant shift in the spectrum to
interactions between the fluorine atom and palladium, we were
eager to determine the crystal structure of 2 (Figure 1;
hydrogens are omitted). Yellow crystals suitable for crystallo-
graphic analysis were obtained upon slow evaporation of its
benzene solution. Surprisingly, the distance between the two
atoms was sufficiently long, 2.991 Å, to rule out bonding
interactions. However, this distance, as well as the I- - -F
distance of 3.301 Å, fall within the sum of the van der Waals
radii of Pd and F (3.1 Å) and of I and F (3.45 Å), respectively.
These factors may explain the significant change in the 19F
chemical shift upon Pd complexation. The steric congestion
also results in the iodo ligand moving out of plane in this
Special Issue: Fluorine in Organometallic Chemistry
Received: November 24, 2011
Published: December 30, 2011
© 2011 American Chemical Society
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dx.doi.org/10.1021/om201175d | Organometallics 2012, 31, 1275−1277

Organometallics
Communication
shortened to 1.359(8) Å from 1.385(11) Å in 2. The change in
the hybridization to sp3 had no effect on the angles around the
nitrogen atoms, which remain close to 120°, likely as a result of
the formation of a rigid planar pincer system. Two five-
membered chelating rings of the new pincer system are clearly
unsymmetrical. The O(22)−Pd(1)−N(21) angle of 76.79(18)°
is significantly smaller than the P(2)−Pd(1)−N(21) angle of
84.26(15)°. Conversely, the C(19)−O(22)−Pd(1) angle is
substantially larger than C(11)−P(2)−Pd(1): 111.8(4)° vs
100.6(2)°, respectively. Due to the enforced planarity of the
chelating rings, the 4-fluorophenyl group is now bent away
from the bulky tert-butyl substituents of the phosphine ligand.
Considering the absence of strong electron-withdrawing
groups directly conjugated with the 8-position, it is very
surprising that the nucleophilic replacement of the fluoro
substituent with OCH3 takes place under very mild conditions.
Heating 1 with excess of sodium methoxide in THF did not
result in the fluorine substitution reaction. In theory, the Pd
center in 2 can be viewed as a Lewis acid that coordinates to
the quinoline nitrogen activating the fluorine atom for the
SNAr-type reaction. To verify this, we prepared the salt N,2-
dimethyl-8-fluoroquinolinium iodide, which possesses a quater-
nary nitrogen center as a very strong electron-withdrawing
group (Scheme 3).10 When this compound was treated with an
Figure 1. X-ray structure of a molecule of 2.
distorted-square-planar Pd(II) complex with an I−Pd−P angle
of 162.73(7)°. At the same time, the quinoline system became
nonplanar near the metal center with an F−C−C−N dihedral
angle of 8.62°.
We then explored the reactivity of 2. Surprisingly, we found
that the addition of 1 equiv of sodium methoxide in THF at
room temperature resulted in an incomplete conversion of 2 to
a new product that has only one signal in its 19F NMR
spectrum. Using a 10-fold excess of NaOCH3 led, within 1 h, to
a very clean formation of a product that exhibits a single
resonance in the 19F NMR spectrum at −120.7 ppm as well as a
singlet at 89.8 ppm in the 31P NMR spectrum (Scheme 2). The
1H NMR spectrum of this new complex, 3, confirmed the
presence of the 4-FC6H4 group at the Pd center as well as a
new OCH3 group (2.87 ppm). The characteristic doublet due
to the CH2−P group (2H) that appeared at 3.84 ppm in 2 has
been replaced by a doublet at 3.35 ppm which integrated as 1H
in comparison with other signals in the system. As the NMR
spectra clearly indicated dramatic changes in the overall
structure of the Pd complex, together with the removal of the
8-fluoro substituent of the quinoline system, we sought to
analyze 3 by X-ray crystallography. Dark orange crystals were
obtained by slow evaporation of its benzene solution, and the
structure is shown in Figure 2 (hydrogens are omitted). The
Scheme 3
excess of NaOCH3 in THF or DMSO, no replacement of the
fluoro atom with OCH3 was observed, even upon moderate
heating. Thus, it seems unlikely that the coordination of a
neutral palladium center to the nitrogen atom is sufficient to
activate the C−F bond toward nucleophilic substitution.
This suggests that the dearomatization of the quinoline
moiety, via the deprotonation of the CH2−P group, triggers the
nucleophilic substitution.11 In order to explore the feasibility of
such a facile deprotonation reaction, we prepared ligand 4,
which already has the 8-CH3O group installed, and reacted it
with [Pd(4-FC6H4)I(tmeda)] (Scheme 4). The complete
formation of the new complex 5 was observed within several
hours at room temperature. Although we presently do not have
the X-ray structure of 5, we believe that the iodo ligand remains
coordinated to the Pd center, similar to the case for 2. In
support, the removal of the iodine with AgBF4, to give 6,
resulted in a significant shift in the 31P NMR spectrum: 92.4 vs
73.0 ppm in 5. The X-ray structure of 6 is shown in Scheme 4.
The structure confirms the pincer-type coordination mode. The
Pd−N coordination bond in the complex 6 is longer than that
in the amide complex 3, 2.056(4) Å vs 2.027(5) Å, while the Pd
distance to the 4-FC6H4 group trans to it is now slightly
shorter, 2.001(5) Å vs 2.013(6) Å, indicating a weaker trans
influence of the aromatic nitrogen atom compared with that of
the amide. The addition of 10 equiv of NaOCH3 to a THF
solution of 5 resulted in the quantitative formation of 3. The
reaction is reversible, and the addition of HI rapidly converts 3
to 5. Thus, it is likely that the addition of the methoxide leads
to the dearomatization of the quinoline ring in 2, followed by
the nucleophilic replacement of the 8-fluoro substituent via a
Pd-assisted pathway.12
Figure 2. X-ray structure of a molecule of 3.
structure of 3 shows that the 8-fluorine atom was replaced by a
methoxy group which now coordinates to the metal center. In
addition, dearomatization of the quinoline system took place
due to the deprotonation of the CH2−P group and formation
of the CC double bond. The latter is clearly observed in the
structure, the distance C(11)−C(12) being 1.374(9) Å
compared with 1.488(12) Å in 2. The now covalent Pd(1)−
N(21) bond is noticeably shorter (2.027(5) Å) than in 2
(2.178(7) Å), although this can be attributed to the enforced
elongation due to steric repulsions in the latter. The C(12)−
N(21) bond distance is significantly longer than that in 2
(1.376(8) Å vs 1.348(11) Å), while the C(20)−N(21) distance
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Organometallics
Communication
Scheme 4
Angew. Chem., Int. Ed. 2005, 44, 7216. (b) Yoshikai, N.; Mashima, H.;
Nakamura, E. J. Am. Chem. Soc. 2005, 127, 17978.
In summary, we have presented the first example of a mild
and selective nucleophilic substitution of an unactivated
aromatic fluoride that is assisted by a late-transition-metal
center. Although the detailed mechanism of the metal
activation mode is presently under investigation, the facile
base-promoted dearomatization of the quinoline system seems
to play a role in the overall process. We are now exploring the
scope of this and similar nucleophilic substitution reactions.
(6) For an example of Ar−Factivation via Cr η6 complexation see:
Widdowson, D. A.; Wilhelm, R. Chem. Commun. 1999, 2211.
(7) For early work see: (a) Moulton, C. J.; Shaw, B. L. J. Chem. Soc.,
Dalton Trans. 1976, 1020. For recent reviews see: (b) Selander, N.;
Szabo, K. J. Chem. Rev. 2011, 111, 2048. (c) Niu, J.-L.; Hao, X.-Q.;
Gong, J.-F.; Song, M.-P. Dalton Trans. 2011, 40, 5135. (d) Serrano-
Becerra, J. M.; Morales-Morales, D. Curr. Org. Synth. 2009, 6, 169.
(e) Leis, W.; Mayer, H. A.; Kaska, W. C. Coord. Chem. Rev. 2008, 252,
1787. (f) Benito-Garagorri, D.; Kirchner, K. Acc. Chem. Res. 2008, 41,
201. (g) Albrecht, M.; van Koten, G. Angew. Chem., Int. Ed. 2001, 40,
3750. (h) van der Boom, M. E.; Milstein, D. Chem. Rev. 2003, 103,
1759.
ASSOCIATED CONTENT
■
S
* Supporting Information
Text giving complete experimental details and CIF files giving
X-ray crystal data for complexes 2, 3, and 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) Complexes of chelating 8-substituted quinoline P,N-ligands are
very rare: (a) Deeming, A. J.; Rothwell, I. P.; Hursthouse, M. B; Abdul
Malik, K. M. J. Chem. Soc., Dalton Trans. 1980, 1974. (b) Grotjahn, D.
B.; Joubran, C. Organometallics 1995, 14, 5171.
(9) For the improvedprotocolsee: Reynolds, K. A.; Young, D. J.;
Loughlin, W. A. Synthesis 2010, 21, 3645.
(10) For the synthesisof a similar salt see: Barfield, M.; Walter, S. R.;
Clark, K. A.; Gribble, G. A.; Kelly, W. J.; Le Houllier, C. S. Org. Mag.
Res. 1982, 20, 92.
(11) The deprotonationof the CH2−P group in pyridine-based
complexes canbe very facile and lead to unusual metal−ligand
cooperationin catalysis: Gunanathan, C.; Milstein, D. Acc. Chem.
Res. 2011, 44, 588.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: avigal@post.tau.ac.il.
ACKNOWLEDGMENTS
■
We thank the US−Israel Binational Science Foundation for
supporting this research.
(12) The reaction mightinvolve initial OCH3 attack at the Pd center,
giving theanionic Pd(II) center. An anionic dearomatized pyridinium
Pt(II) complexhas been reported: Vuzman, D.; Poverenov, E.;
Shimon, L. J. W.; Diskin-Posner, Y.; Milstein, D. Organometallics 2008,
27, 2627.
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