Room temperature rapid functionalization of E-H bonds (E = O, N, S) via the metal-ligand cooperation mechanism

Article abstract of DOI:10.1021/ic402315a

An arylpalladium PNF-type pincer complex reacts with water and anilines under very mild conditions, providing access to new PNO- and PNN-pincer complexes with concomitant hydrogen transfer to the ligand core. Such a metal-ligand cooperation mode allows for the irreversible double activation of even highly sterically hindered aniline molecules. With thiols, the activation mode depends on the nature of the substituent at the sulfur atom, with thiophenols giving products of C-S elimination.

Full text of DOI:10.1021/ic402315a

Communication
pubs.acs.org/IC
Room Temperature Rapid Functionalization of E−H Bonds (E = O, N,
S) via the Metal−Ligand Cooperation Mechanism
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
Scheme 1. Synthesis of 2 via Iodomethane Elimination
ABSTRACT: An arylpalladium PNF-type pincer complex
reacts with water and anilines under very mild conditions,
providing access to new PNO- and PNN-pincer complexes
with concomitant hydrogen transfer to the ligand core.
Such a metal−ligand cooperation mode allows for the
irreversible double activation of even highly sterically
hindered aniline molecules. With thiols, the activation
mode depends on the nature of the substituent at the
sulfur atom, with thiophenols giving products of C−S
elimination.
the stronger anionic phenoxide ligand did not result in the
expected elongation of the Pd−P distance in the X-ray structure
of 2 [Figure 1a; 2.2344(7) vs 2.2214(7) Å in 1]. It is worth noting
ate-transition-metal-assisted functionalization of E−H
Lbonds (E = O, N, S) is a very active area of research
because of its relevance to a broad spectrum of useful catalytic
processes.1 Although traditionally such functionalization was
associated with the oxidative addition mechanism where the
metal in the low oxidation state inserted into the E−H bond,2
more recent findings, most notably from the Milstein group,
demonstrated that metal−ligand cooperation-based activation
can be a very powerful method of productive cleavage of such
bonds.3 In this mechanism, no change in the metal’s oxidation
states occurs during the bond activation step, with the hydrogen
atom usually migrating to the pincer-type ligand. Still, productive
cleavage of typical E−H bonds, particularly in unactivated amines
and in water, remains a challenge.4 In addition, to the best of our
knowledge, no activation of both E−H bonds has been reported
for water and primary amines.5 Such an activation mode can be
utilized to avert reversibility of the O−H and N−H bond
cleavage in water and primary amines, respectively, which usually
significantly hinders the functionalization efforts. Herein, we
present the first examples of double activation of these bonds that
take place rapidly at room temperature with very high selectivity.
Recently, we reported the first palladium PNF-type pincer
complex 1 and its catalytic properties in the Sonogashira cross-
coupling taking place via the metal−ligand cooperation
mechanism.6 While studying the reactivity of this complex
toward various weakly acidic molecules, we treated 1 with 10
equiv of water in C6H6−THF. To our surprise, the activation of
both O−H bonds was observed within 1 h at room temperature,
resulting in quantitative formation of the PNO-pincer complex 2
(Scheme 1). The newly formed CH2−P group gives rise to a
Figure 1. X-ray structures of complexes 2 (a) and 4a (b). Selected bond
distances (Å) and angles (deg) for 2: Pd1−N11 2.033(2), Pd1−O3
2.0955(19), Pd1−P2 2.2344(7); O3−Pd1−N11 81.28(8), N11−Pd1−
P2 84.20(7). Selected bond distances (Å) and angles (deg) for 4a: Pd1−
N21 2.047(2), Pd1−N22 2.068(2), Pd1−P2 2.2412(7); N22−Pd1−
N21 80.27(8), N21−Pd1−P2 84.08(6).
that complex 2 can be quantitatively obtained by warming the
iodo complex 3 in chloroform or THF. In that case, iodomethane
was obtained as the organic product (Scheme 1), indicating that
metal coordination makes the methoxy group highly susceptible
to a SN2-type attack by a weak nucleophile.
Next, we decided to investigate the reactivity of 1 toward even
less acidic unactivated aromatic amines. Unexpectedly, the
addition of 1 equiv of aniline to a benzene solution of 1 resulted
in a very rapid (within seconds!) reaction, giving a new product,
1
4a, in quantitative yield (Scheme 2). H NMR spectrum of 4a
showed a doublet centered at 2.98 ppm (2H), thus confirming
rearomatization of the quinoline core. The X-ray analysis of 4a
revealed formation of the PNN-Pd complex, the product of
double activation of the aniline N−H bonds (Figure 1b). Again,
the strong trans influence of the diarylamido ligand in the 8
position does not lead to elongation of the Pd−P bond
[2.2412(7) Å] compared with that in 1 or 2 [2.2344(7) and
2.2214(7) Å, respectively].
1
doublet at 3.62 ppm (JPH = 8.6 Hz, 2H) in the H NMR
spectrum. Using D2O instead of regular water resulted in transfer
of a deuterium atom at the CH(D)−P position, as confirmed by
1H and 2H NMR spectroscopy. Interestingly, replacement of the
weakly coordinating fluoro substituent at the 8 position in 1 with
Received: September 12, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ic402315a | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Communication
to the metal center. Similarly, ammonia was unreactive under the
reaction conditions.
Scheme 2. Instantaneous Room Temperature Double
Activation of Anilines
Because 1 showed very high reactivity toward the nonacidic
N−H bonds, the activation of more reactive S−H bonds in thiols
should be expected. Yet, because the activation of thiols via the
metal−ligand cooperation mechanism has not been reported, we
were interested in exploring this reaction with 1. Interestingly,
the reaction of 1 with ethylmercaptan in benzene in the presence
of p-IC6H4F led to cleavage of the Pd−C bond and formation of
EtS-C6H4F together with the PNS-Pd pincer complex 6 (Scheme
3). The crystal structure of 6 was also determined and is shown in
Figure 2b. These results suggest that, unlike in the activation of
O−H and N−H bonds, in the case of thiols, there is a
competition between nucleophilic substitution of the 8-F atom
and C−S bond elimination. Theoretically, the latter reaction
leading to 6 can occur after installment of the EtS group in the 8
position. To explore this, we prepared the PNS-pincer complex 7
and treated it with an excess of EtSH (Scheme 4a). Under these
Considering the very low acidity of aniline, such a rapid
cleavage of both N−H bonds is unexpected and unprecedented
in late-transition-metal chemistry.7 Unlike rare monodeproto-
nation of aniline with a rhodium complex via metal−ligand
cooperation,8 the C−F bond cleavage at the 8 position drives the
reaction irreversible. The newly installed amido function at this
position remains basic and can be protonated by acids. For
example, the addition of 1 equiv of trifluoroacetic acid (H-TFA)
to 4a gives the PNN-Pd complex 5, which has a diarylamino
group coordinated to the cationic metal center (Scheme 3 and
Scheme 4. Reactivity of the Dearomatized Palladium Pincer
Complexes toward Thiols
Scheme 3. Reaction of 1 with an Aliphatic Thiol
conditions, no reaction was observed, suggesting that the fluorine
substitution leading to complex 6 takes place after the initial
elimination of EtS−C6H4F. Interestingly, complex 7 reacted with
the more acidic p-thiocresol, giving, in the presence of I−C6H4F,
complex 6 and p-CH3C6H4−S−C6H4F (Scheme 4b). Also,
complex 8, the PNO-pincer analogue of 7,6 reacted with EtSH,
giving 9 (analogous to 6) and EtS−C6H4F (Scheme 4c). These
observations suggest that the selectivity of the reaction between 1
and thiols can be finely tuned. Indeed, using the sterically
hindered 2-Me and 2,6-diMe thiophenols gave exclusively
diarylthioether and complex 8 (Scheme 5).
Figure 2. X-ray structures of complexes 5 (a) and 6 (b). Selected bond
distances (Å) and angles (deg) for 5: Pd1−N1 2.045(3), Pd1−N2
2.155(3), Pd1−P1 2.2417(10); N2−Pd1−N1 81.72(11), N1−Pd1−P1
84.61(9). Selected bond distances (Å) and angles (deg) for 6: Pd1−S1
2.3414(13), Pd1−N1 2.072(4), Pd1−P1 2.2741(13); S1−Pd1−N1
84.66(11), N1−Pd1−P1 83.89(11).
Figure 2a). The distance between this group and the palladium
center is significantly longer than that in the parent amido
complex 4a [2.155(3) and 2.184(3) Å (two molecules per unit
cell in 5) vs 2.068(2) Å in 4a], while the distance between the
metal and quinoline nitrogen atom remains unchanged.
Similarly, there were no changes in the Pd−P distance despite
the dramatic change in the nature of the ligand trans to the
phosphine group.
Scheme 5. Exclusive C−S Elimination in the Reaction with
Sterically Hindered Aromatic Thiols
Complex 1 also reacted with the sterically hindered 2,6-
dimethyl- or even 2,6-diisopropylaniline giving products of
double activation of the N−H bonds (4b and 4c) upon stirring in
benzene at room temperature (Scheme 2). Although longer
times were required in those cases, no intermediates could be
observed. Under typical conditions, no N−H bond activation
was observed when 1 was reacted with aliphatic amines or
secondary amines, with reactions resulting in amine coordination
B
dx.doi.org/10.1021/ic402315a | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Communication
As this reactivity mode closes the postulated catalytic cycle, we
explored the possibility of catalytic C−S coupling using 1 as the
catalyst and NaO-t-Bu as the base. With only 1% of 1, the
reaction between 2,6-dimethylthiophenol and p-IC6H4F was
complete within 30 min at room temperature. Although several
systems are known to catalyze the C−S coupling of aromatic
thiols,9,10 the PNF-Pd pincer 1 is unusual because it shows high
selectivity with sterically hindered substrates.
Overall, the results of E−H bond functionalization studies
demonstrate that there are two competing pathways by which
these bonds can be activated in the PNF-pincer system. These
pathways are tentatively presented for the activation of aniline in
Scheme 6. Simultaneous coordination of the nucleophilic
thiol reagent, with bulky aromatic thiols strongly favoring the C−
S coupling pathway. Further studies of bond functionalization via
metal−ligand cooperation in 1 and similar systems are currently
underway.
ASSOCIATED CONTENT
* Supporting Information
Complete experimental details for all new compounds and X-ray
crystallographic data (CIF) for 2, 4a, 5, and 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: avigal@post.tau.ac.il.
■
Scheme 6. Proposed Mechanistic Pathways for the Activation
of N−H Bonds in Aniline
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by U.S.−Israel Binational Science
Foundation Grant 2010119. We thank Dr. Leonid Konstanti-
novsky for help with NMR analysis.
REFERENCES
■
(1) (a) Muller, T. E.; Hultzsch, K.; Yus, C. M.; Foubelo, F.; Tada, M.
̈
Chem. Rev. 2008, 108, 3795−3892. (b) Hintermann, L. Top. Organomet.
Chem. 2010, 31, 123−155. (c) Piers, W. E. Organometallics 2011, 30,
13−16.
(2) For example, see: (a) Ozerov, O. V. Chem. Soc. Rev. 2009, 38, 83−
88. (b) Kanzelberger, M.; Zhang, X.; Emge, T. J.; Goldman, A. S.; Zhao,
J.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 13644−
13645.
(3) (a) Gunanathan, C.; Milstein, D. Top. Organomet. Chem. 2011, 37,
55−84. (b) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007,
317, 790−792. (c) Balaraman, E.; Gunanathan, C.; Zhang, J.; Shimon, L.
J. W.; Milstein, D. Nat. Chem. 2011, 3, 609−614. For recent reviews, see:
(d) Gunanathan, C.; Milstein, D. Science 2013, 341, DOI: 10.1126/
science.1229712. (e) van der Vlugt, J. I. Eur. J. Inorg. Chem. 2012, 363−
375. (f) Gelman, D.; Musa, S. ACS Catal. 2012, 2, 2456−2466.
heteroatom and fluorine “arm” can facilitate the fluorine
substitution, which is followed by a rapid intramolecular
hydrogen transfer to the ligand recovering the aromatic quinoline
core (path A). Alternatively, concerted metal-assisted intermo-
lecular hydrogen transfer to the CH−P group can take place
initially, thus activating the nucleophile toward the C−F
activation reaction (path B). Experimental evidence for the
concerted activation of N−H and O−H bonds by the metal and
CH−P group has been provided in related ruthenium systems
and corroborated by density functional theory studies.7a,11 In any
case, metal coordination seems to be essential in the activation of
E−H bonds by 1 because fairly acidic noncoordinating C−H
acids, such as nitromethane or acetylacetone, did not react under
these conditions. With the softer more acidic thiols, reaction
initially takes place at the metal center, leading to S−aryl
elimination. When sterically encumbered thiols are used, no
fluorine replacement at the 8 position takes place, allowing for
catalytic cross-coupling reactions to occur.6 Although, in the case
of aromatic thiols, such cross-coupling does not necessarily
involve the aromatization−dearomatization mechanism, our
studies suggest that with less acidic E−H bonds it should be
possible to direct cross-coupling chemistry to proceed via such a
pathway when the organic molecule is a poor nucleophile.
In conclusion, we reported the first examples of irreversible
double activation of water and unactivated aromatic amines that
involve the metal−ligand cooperation mechanism, with reactions
taking place under very mild conditions. In addition, the
activation of S−H bonds is dependent on the nature of the
(4) Muniz, K.; Lishchynskyi, A.; Streuff, J.; Nieger, M.; Escudero-Adan
́
,
̃
E. C.; Martínez Belmonte, M. Chem. Commun. 2011, 47, 4911−4913.
(5) Huang, Z.; Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
11458−11460.
(6) Scharf, A.; Goldberg, I.; Vigalok, A. J. Am. Chem. Soc. 2013, 135,
967−970.
(7) For some recent example of single N−H activation via metal−
ligand cooperation mode, see: (a) Khaskin, E.; Iron, M. A.; Shimon, L. J.
W.; Zhang, J.; Milstein, D. J. Am. Chem. Soc. 2010, 132, 8542−8543.
(b) de Boer, S. Y.; Gloaguen, Y.; Reek, J. N. H.; Lutz, M.; van der Vlugt, J.
I. Dalton Trans. 2012, 41, 11276−11520. (c) Chang, Y.-H.; Nakajima,
Y.; Tanaka, H.; Yoshizawa, K.; Ozawa, F. J. Am. Chem. Soc. 2013, 135,
11791−11794. (d) Gutsulyak, D. V.; Piers, W. E.; Borau-Garcia, J.;
Parvez, M. J. Am. Chem. Soc. 2013, 135, 11776−11779.
(8) Feller, M.; Diskin-Posner, Y.; Shimon, L. J. W.; Ben-Ari, E.;
Milstein, D. Organometallics 2012, 31, 4083−4101.
(9) (a) Eichman, C. C.; Stambuli, J. P. Molecules 2011, 16, 590−608.
(b) Bichler, P.; Love, J. A. Top. Organomet. Chem. 2010, 31, 39−64.
(10) The fluorine atom at this position was susceptible to substitution
by the strongly nucleophilic alkoxides: Scharf, A.; Goldberg, I.; Vigalok,
A. Organometallics 2012, 31, 1275−1277.
(11) Yang, X.; Hall, M. B. J. Am. Chem. Soc. 2010, 132, 120−130.
C
dx.doi.org/10.1021/ic402315a | Inorg. Chem. XXXX, XXX, XXX−XXX