Single-Component Phosphinous Acid Ruthenium(II) Catalysts for Versatile C-H Activation by Metal-Ligand Cooperation

Article abstract of DOI:10.1002/chem.201504851

Well-defined ruthenium(II) phosphinous acid (PA) complexes enabled chemo-, site-, and diastereoselective C-H functionalization of arenes and alkenes with ample scope. The outstanding catalytic activity was reflected by catalyst loadings as low as 0.75 mol %, and the most step-economical access reported to date to angiotensin II receptor antagonist blockbuster drugs. Mechanistic studies indicated a kinetically relevant C-X cleavage by a single-electron transfer (SET)-type elementary process, and provided evidence for a PA-assisted C-H ruthenation step. A blockbuster catalyst: Well-defined ruthenium(II) phosphinous acid (PA) complexes were identified as powerful catalysts for highly selective C-H arylations with ample scope, which enabled low catalyst loadings and gave step-economical access to blockbuster drugs. Mechanistic studies were supportive of a PA-assisted C-H activation.

Full text of DOI:10.1002/chem.201504851

DOI: 10.1002/chem.201504851
Communication
&
CÀH Activation
Single-Component Phosphinous Acid Ruthenium(II) Catalysts for
Versatile CÀH Activation by Metal–Ligand Cooperation
Daniel Zell+,[a] Svenja Warratz+,[a] Dmitri Gelman,[b] Simon J. Garden,[c] and Lutz Ackermann*[a]
Abstract: Well-defined ruthenium(II) phosphinous acid
(PA) complexes enabled chemo-, site-, and diastereoselec-
tive CÀH functionalization of arenes and alkenes with
ample scope. The outstanding catalytic activity was re-
flected by catalyst loadings as low as 0.75 mol%, and the
most step-economical access reported to date to angio-
tensin II receptor antagonist blockbuster drugs. Mechanis-
tic studies indicated a kinetically relevant CÀX cleavage by
a single-electron transfer (SET)-type elementary process,
and provided evidence for a PA-assisted CÀH ruthenation
step.
Scheme 1. Single-component ruthenium(II)–PA complexes 3 for CÀH activa-
tion.
The catalytic functionalization of unreactive CÀH bonds avoids
the use of prefunctionalized substrates and thereby prevents
the formation of undesired waste and circumvents lengthy
substrate syntheses.[1] Considerable recent progress in step-
economical CÀH transformations was accomplished by means
of ruthenium(II) catalysis.[2] Particularly, carboxylate assistance[3]
has been recognized as a useful tool for CÀH activations[4]
through metal–ligand cooperation[5] via a six-membered transi-
tion state.[6] In contrast, we have observed a considerable rate
acceleration exerted by pentavalent secondary phosphine
oxide[7] (SPO) preligands 1 (Scheme 1) for in situ-formed ruthe-
nium(II) catalysts.[8] In spite of major advances, the nature of
the in situ-generated ruthenium(II) catalysts continues to be ill-
defined, which significantly hampers a rational design of more
potent catalysts. Within our program on air-stable SPO preli-
gands,[7] we herein present the first use of well-defined air-
and moisture-stable ruthenium(II) complexes 3 of trivalent
phosphinous acid (PA) ligands 2 as catalysts for CÀH function-
alization (Scheme 1). The single-component PA complexes 3
displayed unparalleled catalytic activity and robustness in the
challenging CÀH arylation of arenes and alkenes, as witnessed
by (i) low catalyst loadings (0.75 mol%), and (ii) the most step-
economical access to the blockbuster drug[9] Valsartan
(Scheme 1). Furthermore, experimental and computational
mechanistic studies provide compelling evidence for a kinetical-
ly relevant CÀHal activation to proceed by a single-electron
transfer (SET)-type elementary processes and a PA-assisted CÀ
H metalation.
At the outset of our studies, we prepared various single-
component ruthenium(II)–PA complexes 3 starting from air-
stable SPO preligands 1[10] through P(=O)H!PÀOH tautomeri-
zation.[11] The efficacy of the well-defined catalysts was probed
in a set of representative CÀH chelation-assisted arylations
(Table 1 and Tables S-1–S-4 in the Supporting Information).[12]
Although simple ruthenium precursors failed to provide satis-
factory results (Table 1, entries 1 and 2), the well-defined ruthe-
nium(II)–PA complexes 3 proved to be more powerful (en-
tries 3–8), with catalysts 3d and 3 f giving the best results (en-
tries 6 and 8). Notably, the catalyst loading of the monomeric
ruthenium complexes 3d and 3 f could be significantly re-
duced to only 0.75 mol%, rendering our approach particularly
attractive for applications in industrial settings.
[a] D. Zell,+ S. Warratz,+ Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de
[b] Prof. Dr. D. Gelman
With the optimized single-component catalysts 3 in hand,
we explored their generality in a representative set of CÀH ary-
lation reactions. Thus, the ruthenium(II) catalyst 3d featuring
the di-n-butyl-substitution pattern allowed for alkenylic CÀH
arylations with broad substrate scope, thereby furnishing aryl-
and even hetereoaryl-substituted alkenes 6 with excellent
levels of diastereocontrol (Scheme 2). Moreover, the well-de-
fined ruthenium(II) complex 3d was not limited to the synthe-
Institute of Chemistry, The Hebrew University
Edmond Safra Campus, 91904 Jerusalem (Israel)
[c] Prof. Dr. S. J. Garden
Department of Organic Chemistry, Instituto de Química
Universidade Federal do Rio de Janeiro, Cidade Universitaria
CT Bloco A, Ilha do Fundao, RJ 21941-909 (Brazil)
[+] D.Z. and S.W. contributed equally.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504851.
Chem. Eur. J. 2016, 22, 1248 – 1252
1248
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
The direct arylations of alkenes (Scheme 2) and arenes
(Scheme 3) were smoothly realized with a variety of organic
electrophiles 5, including aryl bromides, chlorides, and even to-
sylates by challenging CÀH/CÀO cleavages.[13] The chemoselec-
tive nature of the ruthenium(II)–PA complex was reflected by
an excellent functional group tolerance, including halides,
amines, esters, and enolizable ketones. Likewise, an efficient
twofold CÀH arylation proved viable (8i), indicating the poten-
tial of our strategy for the synthesis of functionalized materials
by polycondensation.[14]
Table 1. Optimization of ruthenium(II)–PA catalysts for CÀH arylations.[a]
Entry
Catalyst
3
6a[c] [%]
8a[c] [%]
10a[c] [%]
1
2
3
4
5
6
RuCl3·H2O
<5
9
77
60
92
<5
18
47
48
72
3[d]
n.d.
20
16
18
84[d]
[{RuCl2(p-cymene)}2]
R1 =R2 =Ph
3a
3b
3c
3d
R1 =R2 =pFC6H4
R1 =R2 =iPr
R1 =R2 =nBu
96
98
98[b,d,e]
82[b,d,f]
97[b,d,e]
61[b,d,f]
36
7
8
R1 =Me, R2 =Ph
R1 =Ph, R2 =tBu
3e
3 f
41
51
50
86[d]
63[b,d,e]
48[b,d,f]
[a] Reaction conditions: 4a/7a/9a (0.5 mmol), 5a (0.75 mmol), [RuCl2(p-
cymene)(PA)] 3 (5.0 mol%), K2CO3 (1.0 mmol), PhMe (0.25m), 1208C, 18 h;
Ar=4-MeOC6H4; [b] conversion by 1H NMR or GC with 1,3,5-(MeO)3C6H3
or n-dodecane as the internal standards; [c] yields of isolated product;
[d] T=1408C, c=1.0m; [e] catalyst loading=0.9 mol%; [f] catalyst load-
ing=0.75 mol%.
Scheme 3. CÀH functionalization of arenes 7. [a] With ArCl.
Intriguingly, the well-defined ruthenium(II)–PA complexes 3
also facilitated CÀH arylation of aryl tetrazoles (Scheme 4),
which is of prime importance for the synthesis of blockbuster
drugs such as Losartan, Valsartan, and Candesartan.[9] Here, the
complex 3 f, derived from a sterically hindered PA, gave the
best results, with excellent functional group tolerance, versatili-
ty, and robustness.
These features were illustrated by the unprecedented direct
synthesis of protected Valsartan 11 by a CÀH activation pro-
cess, in high yield and without racemization of the sensitive
amino acid ester moiety. The unprecedented direct use of the
4-bromoaryl amino acid derivative 5j arguably constitutes the
most step-economical approach to the biaryl tetrazole scaffold
of angiotensin II receptor antagonists.[9]
Given the unique catalytic efficacy of the ruthenium(II)–PA
complexes, we performed mechanistic studies to delineate the
catalyst’s mode of action (Scheme 5). First, an in operando
mercury test[15] confirmed the homogeneous nature of the CÀ
H activation. Second, a significant H/D exchange was observed
when using isotopically labeled substrates or co-solvents, re-
vealing the CÀH metalation to be a facile process.[10] Third, the
CÀH arylation reaction was significantly inhibited by typical
radical scavengers, providing strong support for a kinetically-
relevant SET-type CÀHal cleavage. Fourth, a Hammett plot
analysis suggested that CÀBr cleavage was the rate-determin-
ing step for electron-rich substrates 5.
Scheme 2. Ruthenium(II)–PA-catalyzed CÀH arylation on alkenes 4. [a] With
ArCl.
sis of trisubstituted alkenes 6a–o. Indeed, even the first ruthe-
nium-catalyzed assembly of acyclic tetrasubstituted alkenes
(6p) proved feasible in a diastereoselective manner.
Chem. Eur. J. 2016, 22, 1248 – 1252
www.chemeurj.org
1249
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
In line with these observations, a detailed kinetic
analysis[16] by in situ IR and NMR spectroscopy, as
well as by means of gas chromatography, established
a first-order dependence on the concentrations of
substrate [4a] and that of the ruthenium catalyst
[3d], as well as saturation kinetics with electrophile
5a (Figure 1).[10] These findings are in contrast to the
recently reported kinetics for a ruthenium(II)-cata-
lyzed remote functionalization.[17]
Computational studies by DFT calculations[10] using
M06L[18] and the SMD toluene solvent correction[19]
were conducted and provided strong support for the
ruthenium–PA cooperation being of crucial impor-
tance for facilitating the CÀH cleavage step
(Figure 2). Hence, the bifunctional mode of the PA
ligand became apparent through formation of key in-
termediate C, which proved essential for PA-assisted
CÀH metalation via transition state D.
In summary, we have reported the first use of
single-component ruthenium(II)–PA complexes as
powerful catalysts for versatile CÀH arylations of al-
kenes and arenes in a chemo-, site-, and diastereose-
lective fashion. The efficacy of the ruthenium(II)–PA
Scheme 4. Ruthenium(II)–PA-catalyzed CÀH arylation of aryl tetrazoles 9.
Figure 1. Kinetic analysis of the CÀH arylation catalyzed by complex 3d.
Chem. Eur. J. 2016, 22, 1248 – 1252 www.chemeurj.org
1250
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
catalysts was underscored by catalyst loadings as low as
0.75 mol% and demonstrated in the most step-economical
access to the blockbuster drug Valsartan reported to date. De-
tailed mechanistic studies by experimental and computational
means provided convincing evidence for metal–ligand cooper-
ation within a facile CÀH activation, and for a kinetically rele-
vant CÀX cleavage through a SET-type process by a homogene-
ous ruthenium(II) catalyst.
Acknowledgements
Generous support by the European Research Council under
the European Community’s Seventh Framework Program (FP7
2007-2013)/ERC Grant agreement no. 307535, the German–Isra-
eli Science Foundation (GIF), the DFG (SPP 1807), and the
CaSuS PhD program is gratefully acknowledged. S.J.G. thanks
CNPq and FAPERJ for financial assistance.
Keywords: arylation · CÀH activation · kinetics · reaction
mechanisms · ruthenium
[1] For representative recent reviews on CÀH activation, see: a) B. Ye, N.
Cramer, Acc. Chem. Res. 2015, 48, 1308–1318; b) J. Li, L. Ackermann,
Nat. Chem. 2015, 7, 686–687; c) K. Shin, H. Kim, S. Chang, Acc. Chem.
Res. 2015, 48, 1040–1052; d) O. Daugulis, J. Roane, L. D. Tran, Acc.
Chem. Res. 2015, 48, 1053–1064; e) Y. Segawa, T. Maekawa, K. Itami,
Angew. Chem. Int. Ed. 2015, 54, 66–81; Angew. Chem. 2015, 127, 68–83;
f) W. Liu, J. T. Groves, Acc. Chem. Res. 2015, 48, 1727–1735; g) G. Song,
X. Li, Acc. Chem. Res. 2015, 48, 1007–1020; h) N. Kuhl, N. Schroeder, F.
Glorius, Adv. Synth. Catal. 2014, 356, 1443–1460; i) S. A. Girard, T. Knau-
ber, C.-J. Li, Angew. Chem. Int. Ed. 2014, 53, 74–100; Angew. Chem.
2014, 126, 76–103; j) L. Ackermann, J. Org. Chem. 2014, 79, 8948–
8954; k) E. Nakamura, T. Hatakeyama, S. Ito, K. Ishizuka, L. Ilies, M. Naka-
mura, Org. React. 2014, 83, 1–209; l) K. Gao, N. Yoshikai, Acc. Chem. Soc.
2014, 47, 1208–1219; m) G. Rouquet, N. Chatani, Angew. Chem. Int. Ed.
2013, 52, 11726–11743; Angew. Chem. 2013, 125, 11942–11959; n) J.
Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369–375; o) D. J. Schip-
per, K. Fagnou, Chem. Mater. 2011, 23, 1594–1600; p) C. S.
Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–1292; q) T.
Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212–11222; r) R.
Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev.
2009, 38, 3242–3272; s) X. Chen, K. M. Engle, D.-H. Wang, J.-
Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094–5115; Angew.
Chem. 2009, 121, 5196–5217; t) R. G. Bergman, Nature 2007,
446, 391–393, and references therein.
Scheme 5. Key experimental mechanistic findings: a) Mercury test for homo-
geneous catalysis (see the Supporting Information); b) radical scavengers;
c) Hammett plot analysis. Reversible H/D scrambling experiments were also
carried out (not shown; see the Supporting Information). Ar=4-MeOC6H4,
TEMPO=(2,2,6,6-tetramethyl-piperidin-1-yl)oxyl, DPPH=2,2-diphenyl-1-pic-
rylhydrazyl, BHT=butylated hydroxytoluene.
[2] For recent reviews on ruthenium(II)-catalyzed CÀH bond
functionalizations, see: a) C. Bruneau, Top. Organomet.
Chem. 2015, 48, 195–236; b) S. De Sarkar, W. Liu, S. I. Koz-
hushkov, L. Ackermann, Adv. Synth. Catal. 2014, 356, 1461–
1479; c) B. Li, P. H. Dixneuf, Chem. Soc. Rev. 2013, 42, 5744–
5767; d) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev.
2012, 112, 5879–5918; e) L. Ackermann, R. Vicente, Top.
Curr. Chem. 2009, 292, 211 –229, and references therein.
[3] L. Ackermann, Chem. Rev. 2011, 111, 1315–1345.
[4] A review: a) L. Ackermann, Acc. Chem. Res. 2014, 47, 281–
295. Key contributions: b) E. Ferrer Flegeau, C. Bruneau, P. H.
Dixneuf, A. Jutand, J. Am. Chem. Soc. 2011, 133, 10161–
10170; c) P. B. Arockiam, C. Fischmeister, C. Bruneau, P. H.
Dixneuf, Angew. Chem. Int. Ed. 2010, 49, 6629–6632; Angew.
Chem. 2010, 122, 6779–6782; d) L. Ackermann, R. Vicente,
Figure 2. Computed reaction profile for CÀH activation with energies (kcalmolÀ1) com-
puted in PhMe. Computed transition-state structure associated with the CÀH activation
step is shown with key distances in Š and non-participating H atoms omitted for clarity.
H. K. Potukuchi, V. Pirovano, Org. Lett. 2010, 12, 5032–5035;
e) L. Ackermann, R. Vicente, A. Althammer, Org. Lett. 2008,
10, 2299–2302.
Chem. Eur. J. 2016, 22, 1248 – 1252
www.chemeurj.org
1251
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[5] a) J. R. Khusnutdinova, D. Milstein, Angew. Chem. Int. Ed. 2015, 54,
12236–12273; Angew. Chem. 2015, 127, 12406–12445; b) T. Zell, D. Mil-
stein, Acc. Chem. Res. 2015, 48, 1979–1994.
j) N. V. Dubrovina, A. Bçrner, Angew. Chem. Int. Ed. 2004, 43, 5883–
5886; Angew. Chem. 2004, 116, 6007–6010, and references therein.
[9] L. Ackermann, Org. Process Res. Dev. 2015, 19, 260–269.
[10] For detailed information, see the Supporting Information.
[11] L. D. Quin, A Guide to Organophosphorus Chemistry, John Wiley & Sons,
Inc., New York, NY, 2000.
[6] For recent examples of ruthenium-catalyzed direct arylations, see: a) C.
Sollert, K. Devaraj, A. Orthaber, P. J. Gates, L. T. Pilarski, Chem. Eur. J.
2015, 21, 5380–5386; b) M. Seki, Synthesis 2015, 47, 1423–1435; c) S.
Rajkumar, S. Karthik, T. Gandhi, J. Org. Chem. 2015, 80, 5532–5545; d) J.
Hubrich, T. Himmler, L. Rodefeld, L. Ackermann, ACS Catal. 2015, 5,
4089–4093; e) Y. Zhao, V. Snieckus, Adv. Synth. Catal. 2014, 356, 1527–
1532; f) M. Seki, ACS Catal. 2014, 4, 4047–4050; g) R. K. Chinnagolla, M.
Jeganmohan, Chem. Commun. 2014, 50, 2442–2444; h) B. Li, C. Darcel,
P. H. Dixneuf, ChemCatChem 2014, 6, 127–130; i) A. Tlili, J. Schranck, J.
Pospech, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2013, 52, 6293–
6297; Angew. Chem. 2013, 125, 6413–6417, and references therein.
[7] L. Ackermann, Isr. J. Chem. 2010, 50, 652–663.
[12] The connectivity of catalyst 3d was unambiguously established by
means of X-ray diffraction analysis.
[13] For recent reviews on CÀO functionalizations, see: a) J. Cornella, C.
Zarate, R. Martin, Chem. Soc. Rev. 2015, 44, 8081–8097; b) M. Tobisu, N.
Chatani, Acc. Chem. Res. 2015, 48, 1717–1726; c) S. I. Kozhushkov, H. K.
Potukuchi, L. Ackermann, Catal. Sci. Technol. 2013, 3, 562–571.
[14] a) S. Kowalski, S. Allard, K. Zilberberg, T. Riedl, U. Scherf, Prog. Polym. Sci.
2013, 38, 1805–1814; b) L. G. Mercier, M. Leclerc, Acc. Chem. Res. 2013,
46, 1597–1605.
[15] a) J. F. Sonnenberg, R. H. Morris, Catal. Sci. Technol. 2014, 4, 3426–3438;
b) R. H. Crabtree, Chem. Rev. 2012, 112, 1536–1554; c) L. N. Lewis, Chem.
Rev. 1993, 93, 2693–2730.
[16] a) E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry, Uni-
versity Science Books, Sausalito, CA, 2006; for a recent kinetic study on
oxidative rhodium(III) catalysis, see: b) M. Brasse, J. Cµmpora, J. A.
Ellman, R. G. Bergman, J. Am. Chem. Soc. 2013, 135, 6427–6430.
[17] J. Li, S. Warratz, D. Zell, S. D. Sarkar, E. E. Ishikawa, L. Ackermann, J. Am.
Chem. Soc. 2015, 137, 13894–13901.
[8] a) L. Ackermann, A. Althammer, R. Born, Angew. Chem. Int. Ed. 2006, 45,
2619–2622; Angew. Chem. 2006, 118, 2681–2685; b) L. Ackermann,
Org. Lett. 2005, 7, 3123–3125. For reviews and recent contributions on
SPO preligands in catalysis, see: c) I. Cano, M. A. Huertos, A. M. Chap-
man, G. Buntkowsky, T. Gutmann, P. B. Groszewicz, P. W. N. M. van Leeu-
wen, J. Am. Chem. Soc. 2015, 137, 7718–7727; d) E. Tomµs-Mendivil, V.
Cadierno, M. I. MenØndez, R. López, Chem. Eur. J. 2015, 21, 16874–
16886; e) E. Tomµs-Mendivil, L. MenØndez-Rodríguez, J. Francos, P. Cro-
chet, V. Cadierno, RSC Adv. 2014, 4, 63466–63474; f) F. Schrçder, C.
Tugny, E. Salanouve, H. Clavier, L. Giordano, D. Moraleda, Y. Gimbert, V.
Mouries-Mansuy, J.-P. Goddard, L. Fensterbank, Organometallics 2014,
33, 4051–4056; g) I. Cano, A. M. Chapman, A. Urakawa, P. W. N. M. van
Leeuwen, J. Am. Chem. Soc. 2014, 136, 2520–2528; h) A. Christiansen,
C. Li, M. Garland, D. Selent, R. Ludwig, R. Franke, A. Bçrner, ChemCat-
Chem 2010, 2, 1278–1285; i) L. Ackermann, Synthesis 2006, 1557–1571;
[18] Y. Zhao, D. G. Truhlar, J. Chem. Phys. 2006, 125, 194101.
[19] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Chem. Phys. 2009, 113,
6378–6396.
Received: December 3, 2015
Published online on December 22, 2015
Chem. Eur. J. 2016, 22, 1248 – 1252
www.chemeurj.org
1252
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim