Metal-ligand bifunctional activation and transfer of N-H bonds

Article abstract of DOI:10.1039/c1cc10999e

The concept of metal-ligand bifunctionality can be employed for an efficient activation of N-H bonds by well-defined ruthenium amido complexes. An enantioselective catalytic aza-Michael reaction was developed on the basis of this process, which gives rise

Full text of DOI:10.1039/c1cc10999e

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COMMUNICATION
Metal–ligand bifunctional activation and transfer of N–H bondsw
Kilian Muniz,*ab Anton Lishchynskyi,a Jan Streuff,c Martin Nieger,d
a
a
´
´
Eduardo C. Escudero-Adan and Marta Martınez Belmonte
Received 20th February 2011, Accepted 10th March 2011
DOI: 10.1039/c1cc10999e
The concept of metal–ligand bifunctionality can be employed for
an efficient activation of N–H bonds by well-defined ruthenium
amido complexes. An enantioselective catalytic aza-Michael
reaction was developed on the basis of this process, which gives
rise to indoline b-amino acids.
The development and improvement of modern transition metal
mediated and catalysed nitrogen transfer reactions represents
an important task in the synthesis of aminated molecules.1,2
Often, the key step requires formation of defined amide
complexes via oxidative insertion of a transition metal into
the N–H bond of an amine or amide, and these transforma-
tions have reached an impressive level of selectivity.3,4 An
alternative activation circumventing oxidation state changes
could be achieved by a novel bifunctional N–H activation
mode, which is cooperatively performed by a metal and a
ligand as established for related activation of small molecules.5
Herein, we report such a direct bifunctional N–H activation of
amides and its subsequent use in a conceptually novel catalytic
aza-Michael reaction.6
Scheme 1 Metal–ligand bifunctional N–H activation of amides
(above) and samples of free dansyl amide and 2f at 360 nm (below).
formation of ruthenium complex 2f accompanied by quenching
of the characteristic fluorescence of the free sulfonamide
(Scheme 1).9 A reaction with deuterated tosylamide TosND2
led to incorporation of two deuterium atoms into the complex,
however, fast deuterium scrambling resulted in a statistical
distribution. This observation suggests related acidity for the
N–H groups in 2b.9
We envisioned that unsaturated transition metal amido
complexes should readily activate N–H bonds. Indeed, treat-
ment of Noyori’s formally unsaturated 16eÀ complex 1a7 with
various amides at room temperature instantaneously led to
irreversible formation of the corresponding complexes 2a–f,
which in all cases were obtained as single stereoisomers.8 In
addition to methanesulfonamide, the corresponding complexes
of tosylamide, benzamide, benzylcarbamate, and trifluoro-
methanesulfonamide were successfully isolated in nearly quanti-
tative yields (Scheme 1). The course of the N–H activation
could also be monitored for the reaction of 1a with one
equivalent of dansyl amide which within seconds results in the
In order to determine the molecular basis of the N–H
activation, products 2a and 2e were analysed by X-ray crystallo-
graphy (Fig. 1).10 The absolute configuration of the ruthenium
atoms is reminiscent of related complexes from formal addition
of other polarised molecules across the polar Ru–N bond in
1.5a–c,7 The newly formed Ru–N bonds are similar in length
indicating that no anion effect is present despite the signifi-
cantly different pKa values of the free amides.11 It is important
to note that while all amide complexes 2 are stable under
neutral conditions under air in solid state and solution, they
readily engage in retrosynthetic loss of amide in the presence
of an alkoxide base. Complex 1a can therefore be assumed as a
chiral transition metal template for the reversible storage of an
amide group through metal–ligand bifunctional N–H activation.
The observed reversibility of this process prompted us to
investigate complex 1a as a catalyst for N–H activation and
subsequent transfer to a prochiral group. To provide the proof
of principle we chose an intramolecular aza-Michael reaction12
of 3a to 4a (Table 1), an indoline analogue of b-homoproline.13
While complex 1a was indeed found to be an efficient catalyst
a Institute of Chemical Research of Catalonia (ICIQ),
Av. Paı¨sos Catalans, 16, E-43007 Tarragona, Spain.
E-mail: kmuniz@iciq.es
b Catalan Institution for Research and Advanced Studies (ICREA),
´
Pg. Lluıs Companys 23, 08010 Barcelona, Spain
¨
c Albert-Ludwigs-Universitat Freiburg, Albertstr. 21, 79104 Freiburg,
Germany
d Department of Chemistry, P.O. Box 55, FI-00014 University of
Helsinki, Finland
w Electronic supplementary information (ESI) available. Experimental
procedures and characterisation and spectral reproduction for new
compounds. CCDC 772672 (2a), 772673 (2e) and 780370. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc10999e
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4911–4913 4911

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Table 2 Enantioselective amidation of acrylates via N–H activation
Yielda eeb
Entry Substrate
Product
[%]
[%]
1
80
83
2
3
4
82
89
89
85
80
76
Fig. 1 Crystal structures of complexes 2a and 2e. Except for the NH2
groups, hydrogen atoms are omitted for clarity.
Table 1 Catalyst optimisation for cyclisation of 3a to 4a
5
99
61
6
94
97
94
99
94
94
95
93
96
97
Entry Z6-Arene Ar
Catalyst Ta/1C Yieldb [%] eec [%]
1
2
3
4
5
6
7
8
Cymene Ph
Cymene Ph
1a
1a
1b
1b
1b
25 70
40
25 99
90
À15 69
95
À15 84
À25 82
b
30
43
34
45
53
75
81
80
7
5
C6Me6
C6Me6
C6Me6
C6Me6
C6Me6
C6Me6
Ph
Ph
Ph
5
2,4,6-C6H2Me3 1c
2,4,6-C6H2Me3 1c
2,4,6-C6H2Me3 1c
0
8
a
Temperature of the external cooling bath. Isolated yield after purifi-
c
cation. Determined by chiral analytical HPLC.
9
for this reaction (entries 1 and 2), steric optimisation was
required in order to achieve higher product ee. To this end,
substituting the Z6-coordinated cymene group with hexamethyl
benzene (1b) under concomitant lowering of the temperature
to À15 1C14 allowed for a rise to 53% ee (entries 3–5). The use
of a diamine ligand with sterically more demanding mesityl
substituents (1c) led to a maximum ee of 81% at À15 1C
(entries 6 and 7). Further decrease in temperature had no effect
(entry 8). Cyclization of the corresponding (Z)-alkene led to a
product with the same absolute configuration in 78% ee
suggesting identical alkene face selectivity in the enantioselection.
The ethyl ester derivative of 3a gave 80% yield and 72% ee, while
the sterically more congested tert-butyl ester did not lead to any
conversion.
10
11
94
95
93
À92
12c
a
b
Isolated yield after purification. Determined by analytical HPLC at
c
a chiral stationary phase. Opposite catalyst enantiomer was employed.
with 76 to 85% ee (entries 1–4). Substrate 3f with double meta-
substitution displays high reactivity, but leads to lower enantio-
selection in the formation of 4f (entry 5). Finally, 6-substituted
substrates 3g–k and the naphthalene derivative 4l undergo
cyclisation to 4g–l in excellent yields with enantiomeric excesses
of 93–97% (entries 6–11). For 3l, use of the enantiomeric catalyst
gave the other enantiomer of 4l in 95% yield and 92% ee.
Next, a series of methyl esters was investigated in the metal–
ligand bifunctional catalysis of N–H activation/N–H transfer
chemistry (Table 2). Here, 4-substitued substrates gave the
corresponding indoline derivatives 4b–e in very good yields
c
4912 Chem. Commun., 2011, 47, 4911–4913
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of ammonia: J. I. van der Vlugt, Chem. Soc. Rev., 2010,
39, 2302.
4 Selected examples: (a) A. L. Casalnuovo, J. C. Calabrese and
D. Milstein, J. Am. Chem. Soc., 1988, 110, 6738;
(b) A. L. Casalnuovo, J. C. Calabrese and D. Milstein, Inorg.
Chem., 1987, 26, 971; (c) R. Koelliker and D. Milstein,
Angew. Chem., Int. Ed. Engl., 1991, 30, 707; (d) R. Koelliker and
D. Milstein, J. Am. Chem. Soc., 1991, 113, 8524;
(e) M. A. Salomon, A.-K. Jungton and T. Braun, Dalton Trans.,
2009, 7669; (f) C. M. Fafard, D. Adhikari, B. M. Foxman,
D. J. Mindiola and O. V. Ozerov, J. Am. Chem. Soc., 2007, 129,
10318; (g) G. L. Hillhouse and J. E. Bercaw, J. Am. Chem. Soc.,
1984, 106, 5472; (h) J. Zhao, A. S. Goldman and J. F.
Hartwig, Science, 2005, 307, 1080; (i) E. Sappa and L. Milone,
J. Organomet. Chem., 1973, 61, 383; (j) M. Hirano, K. Onuki,
Y. Kimura and S. Komiya, Inorg. Chim. Acta, 2003, 352, 160;
(k) M. Jimenez-Tenorio, M. C. Puerta and P. Valerga, Eur. J.
´
Inorg. Chem., 2005, 2631; (l) For an example of an N-heterocyclic
carbene mediated N–H activation, see: G. D. Frey, V. Lavallo,
B. Donnadieu, W. W. Schoeller and G. Bertrand, Science, 2007,
316, 439.
Fig. 2 Proposed catalytic cycle.
5 Reviews: (a) R. Noyori, Angew. Chem., Int. Ed., 2002, 41, 2008;
(b) R. Noyori, Adv. Synth. Catal., 2003, 345, 15; (c) R. Noyori and
S. Hachiguchi, Acc. Chem. Res., 1997, 30, 97; (d) S. Kuwata
and T. Ikariya, Dalton Trans., 2010, 39, 2984; (e) T. Ikariya and
A. J. Blacker, Acc. Chem. Res., 2007, 40, 1300; (f) T. Ikariya and
The absolute configuration for product ent-4l was determined
to be R based on the X-ray structure analysis of a derivative.9,10
We tentatively assign an absolute (S)-configuration for all other
products 4a–l assuming an identical mode of enantioselection.
A possible mechanistic scenario starts with bifunctional
N–H activation of the cyclisation precursor 3, in a manner
identical to the N–H activation of tosylamides described for
the stoichiometric reactions (Scheme 1). It is followed by
subsequent transfer of the amidato group onto the prochiral
alkene to give cyclised 4 and regeneration of the active catalyst
(Fig. 2). The transition state should proceed through a cyclic
arrangement including hydrogen bonding15 and is dominated
by steric repulsion between the substituent at the arene ring
of the substrate and the methyl groups at the arene ring of
the ruthenium catalyst. Additional interaction should occur
between the aryl substituent in the diamine backbone and the
ester group, while the remote tosylamido group of the diamine
ligand has no major influence on enantioselection.9
I. D. Gridnev, Chem. Rec., 2009, 9, 106; (g) H. Grutzmacher,
¨
Angew. Chem., Int. Ed., 2008, 47, 1814; (h) J. I. van der Vlugt and
J. N. H. Reek, Angew. Chem., Int. Ed., 2009, 48, 8832;
(i) K. Muniz, Angew. Chem., Int. Ed., 2005, 44, 6622.
6 For a related report on stoichiometric N–H activation of amines:
E. Khaskin, M. A. Iron, L. J. W. Shimon, J. Zhang and
D. Milstein, J. Am. Chem. Soc., 2010, 132, 8542.
7 K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya and R. Noyori,
Angew. Chem., Int. Ed. Engl., 1997, 36, 285.
8 Results on stoichiometric N–H activation are taken from the PhD
Thesis of Jan Streuff, University of Strasbourg, 2008.
9 Please see ESIw for details.
10 CCDC 772672 (2a), CCDC 772673 (2e) and CCDC 7803709.
11 pKa (H2NSO2CH3) = 17.5 (DMSO) and pKa (H2NSO2CF3) = 9.7
(DMSO), F. G. Bordwell and D. Algrim, J. Org. Chem., 1976, 41,
2507.
12 We prefer the denomination as aza-Michael reaction, although the
term hydroamination is usually also encountered for the present
process. (a) For a concise review on hydroamination using
We have developed a new process for transition metal based
bifunctional N–H activation within the coordination sphere of
a defined amido–ruthenium complex, and a first successful
application in enantioselective catalysis was demonstrated.
This work was financially supported by ICREA, ICIQ
Foundation, Deutsche Forschungsgemeinschaft (SFB 624),
Consolider INTECAT 2010 (Project CSD2006-0003) and the
French MESR (fellowship to A.L.).
alternative concepts of transition metal catalysis: T. E. Muller,
¨
K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem. Rev.,
2008, 108, 3795; For recent reviews on aza-Michael additions:
(b) D. Enders, C. Wang and J. X. Liebich, Chem.–Eur. J., 2009,
15, 11058; (c) P. R. Krishna, A. Sreeshailam and R. Srinivas,
Tetrahedron, 2009, 65, 9657; (d) L.-W. Xu and C.-G. Xia, Eur. J.
Org. Chem., 2005, 633.
13 We are not aware of another enantioselective catalytic synthesis of
this class of amino acids, which constitute the indoline analogue
of b-homoprolines. For a recent catalytic approach to chiral
b-homoprolines: (a) A. Farwick and G. Helmchen, Adv. Synth.
Catal., 2010, 352, 1023; For general synthetic approaches to
b-amino acids: (b) Enantioselective Synthesis of b-Amino Acids,
ed. E. Juaristi and V. A. Soloshonok, Wiley-VCH, Weinheim, 2nd
edn, 2005; (c) D. Seebach, A. K. Beck and D. J. Bierbaum, Chem.
Biodiversity, 2004, 1, 1111.
14 For a related temperature effect in the Michael addition of malonates
to nitroalkenes: M. Watanabe, A. Ikagawa, H. Wang, K. Murata and
T. Ikariya, J. Am. Chem. Soc., 2004, 126, 11148.
15 For a related transition state in metal–ligand bifunctional Michael
addition of malonates to enones: M. Watanabe, K. Murata and
T. Ikariya, J. Am. Chem. Soc., 2003, 125, 7508.
Notes and references
1 (a) A. Ricci, Modern Amination Methods, Wiley-VCH, Weinheim,
2000; (b) A. Ricci, Amino Group Chemistry, Wiley-VCH,
Weinheim, 2007; (c) R. Hili and A. K. Yudin, Nat. Chem. Biol.,
2006, 2, 284.
2 Selected reviews: (a) T. E. Muller and M. Beller, Chem. Rev., 1998,
¨
98, 675; (b) A. R. Muci and S. L. Buchwald, Top. Curr. Chem.,
2002, 219, 131; (c) J. F. Hartwig, Synlett, 2006, 1283.
3 For a highlight on N–H activation, see: (a) T. Braun, Angew.
Chem., Int. Ed., 2005, 44, 5012; (b) For a review on N–H activation
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4911–4913 4913