Facile Synthesis of Functionalized Carbene Metal Complexes from Coordinated Isonitriles

Article abstract of DOI:10.1002/asia.201500353

The scope and limitations of the isonitrile-based NHC template synthesis were investigated with a series of precursors containing a nucleophilic amine in combination with tethered electrophiles. In the case of alkynes and phosphonic esters as electrophiles no ring closure was observed and new functionalized NAC gold complexes were obtained. By the use of unsaturated esters and phosphonic esters as Michael acceptors in the amine precursors, ester-modified gold and palladium NHC complexes were accessible in high efficiency.

Full text of DOI:10.1002/asia.201500353

DOI: 10.1002/asia.201500353
Communication
Carbenes
Facile Synthesis of Functionalized Carbene Metal Complexes from
Coordinated Isonitriles
Christian Lothschütz, Thomas Wurm, Anna Zeiler, Alexander Freiherr v. Falkenhausen,
Matthias Rudolph, Frank Rominger, and A. Stephen K. Hashmi*[a]
dination of the metal as the final step. A much shorter route
Abstract: The scope and limitations of the isonitrile-based
was reported in a pioneering work of Fehlhammer, Hahn and
NHC template synthesis were investigated with a series of
co-workers.[11] That route relies on the intramolecular nucleo-
precursors containing a nucleophilic amine in combination
philic attack at the carbon atom of a metal-coordinated isoni-
with tethered electrophiles. In the case of alkynes and
trile as the basic principle (Scheme 1, left). Only the coordina-
phosphonic esters as electrophiles no ring closure was ob-
served and new functionalized NAC gold complexes were
obtained. By the use of unsaturated esters and phosphon-
ic esters as Michael acceptors in the amine precursors,
ester-modified gold and palladium NHC complexes were
accessible in high efficiency.
Scheme 1. Different template strategies towards NHC complexes from isoni-
trile precursors.
Introduction
tion of the functionalized isonitrile activates the carbon atom
In 1915 Chugaev and co-workers[1] conducted a very interest-
ing experiment. By treating a platinum isonitrile compound
with hydrazine, they synthesized the first metal carbene com-
plex. Naturally, at that time they could not assign the correct
structure and thus they assumed a hydrazine bridged dimeric
platinum compound. Interestingly, it took almost 60 years until
Shaw and co-workers[2] were able to correct this misinterpreta-
tion. Today, in modern organometallic chemistry, carbenes play
an intriguing role as ligands in metal complexes spanning
a large part of the periodic table of elements.[3]
for the intramolecular attack by the nucleophile and thus ena-
bles the ring closure in this template synthesis. A drawback is
the limitation that only one nitrogen atom of the NHC in these
metal complexes is substituted, whereas the former isonitrile
nitrogen atom always bears a proton. This restricts the versatil-
ity and the use of this method for the preparation of catalysts.
In addition, an intramolecular mode of cyclization does not
allow a convergent synthesis of the carbenes and combinatori-
al approaches for the installation of screening libraries are not
possible.
The high impact of these ligands is owing to the groups of
Arduengo,[4] Herrmann,[5] Bertrand,[6] Organ,[2h] Nolan,[7]
Grubbs,[8] Glorius[9] and many others, who introduced carbenes,
especially N-heterocyclic carbenes (NHCs), as ligands for cata-
lysts.
A different approach of the groups of Saegusa, Michelin,
Pombeiro and Fehlhammer[12] is based on the nucleophilic ad-
dition of amines with tethered electrophiles/leaving groups
(Scheme 1, right). Thus, after an initial attack onto the isonitrile
carbon atom, the former isonitrile nitrogen can act as a nucleo-
phile and close the cycle to form the heterocyclic carbene. The
advantage of this methodology is the intermolecular process
that enables fast and modular approaches by combining three
components in a template synthesis. Interestingly, despite the
early reports on this simple strategy, no reports on the synthe-
sis of complexes bearing N,N’-disubstituted NHCs were report-
ed and all of the examples delivered protic NHC complexes as
products. This is noteworthy as especially disubstituted com-
plexes are interesting with regard to their potential application
as catalysts.
In many cases the synthesis of NHCs is not trivial,[10] requir-
ing several steps executed as a linear sequence with the coor-
[a] Dr. C. Lothschütz, M. Sc. T. Wurm, Dipl.-Chem. A. Zeiler,
M. Sc. A. Freiherr v. Falkenhausen, Dr. M. Rudolph, Dr. F. Rominger,
Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)06221-54-4205
E-mail: hashmi@hashmi.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201500353.
To address this issue, we recently developed a procedure
which is based on the utilization of b-substituted ethylamines
as starting materials. As mentioned, the initial step is an inter-
molecular nucleophilic addition,[13] and the subsequent ring
This manuscript is part of a special issue on catalysis and transformation
of complex molecules. Click here to see the Table of Contents of the special
issue.
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closure proceeds by an intramolecular nucleophilic substitution
(Scheme 2).[14] This method allows the construction of disubsti-
tuted NHCs in a highly variable way and the modular synthesis
of different metal carbene complexes from coordinated isoni-
triles. In addition, abnormal car-
benes were feasible by following
a
related cycloaddition strat-
egy.[15]
All these reactions are selec-
tive and proceed under mild
conditions without the necessity
of dry or degassed solvents. In
the case of the gold carbene
complexes it is even possible to
start from (tetrahydrothiophe-
ne)AuCl ((tht)AuCl) or (dimethyl
sulfide)AuCl as precursors and to
form the isonitrilegold(I) chloro
complexes in situ in a one-pot
three component procedure. In
this manuscript, we describe our
efforts on the extension of this
short and simple one-pot route
and the scope and limitations of
other potential electrophiles in
the precursors.
Results and Discussion
As mentioned, the methodology
for the carbene synthesis is
based on the combination of an
electrophile and a nucleophile in
the same molecule. Inspired by
this simple concept, we consid-
ered several other potential car-
bene precursors. Scheme 3 sum-
marizes our attempts to synthe-
size new cyclic N,N-carbene
complexes. In addition to the
use of carbon–halogen bonds[14a]
and esters[14b] we considered to
use other electrophiles like al-
kynes and phosphonic acid
esters. The corresponding pre-
cursors 2a–c were synthesized
according to standard proce-
dures (see the Supporting Infor-
mation for synthetic details).
Scheme 2. Summary of our methods for the synthesis of NHC/NHOC metal complexes. NHOC=N-heterocyclic-oxo-
carbene.
Interestingly, we did not ob-
serve the formation of cyclic car-
benes in any of these experi-
ments. To our surprise, in the
case of propargylic amine 1 as
precursor, we observed the for-
mation of bis-NAC-gold(I) com-
plex 3 (Figure 1). Even heating
or the addition of acid did not
initiate ring closure to the NHC
Scheme 3. Syntheses of new non-cyclic metal carbene complexes (isolated yields).
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backbone of the NHC ligand. This is of high importance as for
classical NHC approaches the installation of an additional func-
tional group such as an ester moiety in the backbone of the
ligand is complicated due to the acidic proton in a-position of
the ester. We faced this problem and found a straightforward
solution, which is based on principles from our earlier work.[14]
In order to generate suitable precursors, we used commercially
available methyl 4-bromobut-2-enoate. The reaction with a pri-
mary amine in the presence of Cs2CO3 as a base exclusively
gave a substitution at the g-position, and no products of a Mi-
chael addition or amide formation were observed (Scheme 4).
Next we treated (tht)AuCl with compound 6c in presence of
various isonitriles (Scheme 5). All of the reactions proceeded
cleanly and the corresponding ester-modified NHC (emNHC)
complexes were obtained after a reaction time of 3 days in
CH2Cl2 at room temperature.
1
Monitoring the progress of the reaction by H NMR spectros-
copy indicated a full conversion in each case. The moderate
yields for some of the reactions result from the workup proce-
dure, which was not optimal for a reaction scale of only
100 mmol. To prove this hypothesis, we also performed the
synthesis of 7a on a 2 mmol scale, resulting in a much better
yield of 89% (vs. 60%) of the analytically pure product.
Figure 2 shows the structure of 7a in the solid state.[17] All
bond lengths and other structural parameters are in the typical
range for these compounds.
Figure 1. Structures of compounds 3, 4, 5a, and 5b in the solid state and
selected structural parameters. Thermal ellipsoids are shown at 50% proba-
bility. Selected bond distances (pm) and angles (8): 3: AuÀC2, 204.3(2); C2À
N1, 133.9(3); C2ÀN3, 132.8(3); N1-C2-N3, 117.5(2); H1ÀCl, 260. 4: AuÀC2,
199.9(3); C2ÀN1, 133.8(4); C2ÀN3, 134.0(4); N1-C2-N3, 117.3(3); O1ÀH1, 210.
5a’: AuÀC1, 200.2(2); C1ÀN2, 134.0(3); C1ÀN5, 133.4(2); N2-C1-N5,
118.33(18). 5a’’: AuÀC1, 199(2); C1ÀN2, 132(3); C1ÀN5, 136(3); N2-C1-N5,
118(2). 5b: AuÀC1, 199.1(5); C1ÀN2, 134.3(6); C1ÀN5, 134.3(6); N2-C1-N5,
117.5(4).
Noteworthy, an expansion of this methodology towards con-
jugated phophonic esters as Michael acceptors was also possi-
complex.[16] The reactions of gold isonitrile complexes with
substituted phosphonic esters proceeded in high yield to the
non-cyclic amino carbene (NAC) complexes, no matter if two
or one methylene groups were in the tether. These com-
pounds show interesting properties. The solid-state structure
of 4 shows a hydrogen bond between the oxygen atom of the
phosphonic acid group and the carbene moiety, forming
a seven-membered ring (besides the calculated distance of
210 ppm between the oxygen and the hydrogen atom from
1
the X-ray data, the chemical shift of 10.3 ppm in the H NMR
indicates the hydrogen bond). Although this rotamer seems to
be favored, two different rotamers were obtained for all com-
plexes (visible by NMR). In the case of NAC complex 5a the
two rotamers were even obtained as different modifications
(5a’, 5a’’) in the solid-state structures (Figure 1). It should be
mentioned that the incorporation of the phosphorous atom in
the backbone of the ligand
Figure 2. Structure of compound 7a in the solid state. Thermal ellipsoids are
shown at 50% probability. There was one molecule of CH2Cl2 in the elemen-
tary cell, which was omitted for clarity. Bonding distances (pm) and angles
(8): AuÀC1, 197.5(4); AuÀCl, 227.7(11); C1ÀN2, 133.6(4); C1ÀN5, 134.0(4); N2-
C1-N5, 108.7(3).
opens up new possibilities for in
situ NMR studies.
As a next step, we considered
unsaturated esters as electro-
philes. These were supposed to
close the NHC ring via a Michael
reaction which would enable the
simple incorporation of an elec-
tron-withdrawing group in the Scheme 4. Synthesis of the amine precursors 6.
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ble which was demonstrated via
the synthesis of phosphonic
ester substituted NHC complex 8
(Scheme 6).
Next we considered palladium
as central metal for the conju-
gate addition approach. As de-
picted in Scheme 7, the analo-
gous reaction with bis-isonitrile
precurors 9 was highly efficient,
and the target NHC complexes
10a and 10b could be isolated
in excellent yields, but the reac-
tion times were quite long.
Conclusions
We could demonstrate a new
and efficient way for the synthe-
sis of ester- and phosphonic
ester-modified NHC complexes
based on the isonitrile route.
These types of NHC complexes
offer an additional functionality
for further modifications. Due to
the acidic ester protons these
Scheme 5. First examples of the emNHC-AuI complexes. Scale, 100 mmol. The yield in parentheses is that obtained
by a 2 mmol scale.
types of complexes are not easily accessible via classical
routes, which underlines the advantages of the isonitriles ap-
proach. In addition, the modular synthetic access allows the
fast synthesis of catalyst libraries, which is a positive aspect
concerning the potential use in catalyst screenings. Further-
more, the scope and limitations for other electrophiles were
evaluated which led to the synthesis of new types of non-
cyclic carbenes with additional functional groups; a potential
use of these functional groups for anchoring the complexes on
solid support can be envisioned.
Scheme 6. Synthesis of phosphonic ester-modified NHC complex 8.
Acknowledgements
We thank Umicore AG & Co. KG
for the generous donation of
noble metal salts; C.L. is grateful
for financial support by the
Studienstiftung des deutschen
Volkes e.V.
Keywords: amines
·
gold
·
isonitriles · Michael acceptors ·
phosphonates
[1] a) L. Chugaev, M. Skanavy-Grigori-
zeva, J. Russ. Chem. Soc. 1915, 47,
776; b) L. Chugaev, M. Skanavy-Gri-
gorizeva, A. Posnjak, Z. Anorg.
Chem. 1925, 148, 37.
[2] G. Rouschias, B. L. Shaw, J. Chem.
Soc. D 1970, 183–183.
Scheme 7. Synthetic scheme and examples of the synthesis of emNHC-PdII-complexes.
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[3] For selected representative reviews, see: a) W. A. Herrmann, Angew.
Chem. Int. Ed. 2002, 41, 1290–1309; Angew. Chem. 2002, 114, 1342–
1363; b) E. Peris, R. H. Crabtree, Coord. Chem. Rev. 2004, 248, 2239–
2246; c) E. Colacino, J. Martinez, F. Lamaty, Coord. Chem. Rev. 2007, 251,
726–764; d) E. A. B. Kantchev, C. J. O’Brien, M. G. Organ, Angew. Chem.
Int. Ed. 2007, 46, 2768–2813; Angew. Chem. 2007, 119, 2824–2870;
e) N. Marion, S. P. Nolan, Acc. Chem. Res. 2008, 41, 1440–1449; f) N.
Marion, S. P. Nolan, Chem. Soc. Rev. 2008, 37, 1776–1782; g) G. C. Fort-
man, S. P. Nolan, Chem. Soc. Rev. 2011, 40, 5151–5169; h) C. Valente, S.
C¸alimsiz, K. H. Hoi, D. Mallik, M. Sayah, M. G. Organ, Angew. Chem. Int.
Ed. 2012, 51, 3314–3332; Angew. Chem. 2012, 124, 3370–3388; i) M. J.
Ingleson, R. A. Layfield, Chem. Commun. 2012, 48, 3579–3589.
[4] A. J. Arduengo, R. L. Harlow, M. Kline, J. Am. Chem. Soc. 1991, 113, 361–
363.
[5] For representative articles, see: a) C. S. Linninger, E. Herdtweck, S. D.
Hoffmann, W. A. Herrmann, J. Mol. Struct. 2008, 890, 192–197; b) S. K.
Schneider, W. A. Herrmann, E. Herdtweck, J. Mol. Catal. A 2006, 245,
248–254; c) C. W. K. Gstçttmayr, V. P. W. Bçhm, E. Herdtweck, M. Gro-
sche, W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41, 1363–1365;
Angew. Chem. 2002, 114, 1421–1423; d) V. P. W. Bçhm, C. W. K. Gstçtt-
mayr, T. Weskamp, W. A. Herrmann, J. Organomet. Chem. 2000, 595,
186–190.
[6] For representative articles, see: a) V. Lavallo, Y. Canac, C. Präsang, B.
Donnadieu, G. Bertrand, Angew. Chem. Int. Ed. 2005, 44, 5705–5709;
Angew. Chem. 2005, 117, 5851–5855; b) V. Lavallo, G. D. Frey, B. Donna-
dieu, M. Soleilhavoup, G. Bertrand, Angew. Chem. Int. Ed. 2008, 47,
5224–5228; Angew. Chem. 2008, 120, 5302–5306; c) V. Lavallo, G. D.
Frey, S. Kousar, B. Donnadieu, G. Bertrand, Proc. Natl. Acad. Sci. USA
2007, 104, 13569–13573.
[7] For representative articles, see: a) J. Huang, E. D. Stevens, S. P. Nolan,
J. L. Petersen, J. Am. Chem. Soc. 1999, 121, 2674–2678; b) C. Zhang, J.
Huang, M. L. Trudell, S. P. Nolan, J. Org. Chem. 1999, 64, 3804–3805;
c) O. Navarro, R. A. Kelly, S. P. Nolan, J. Am. Chem. Soc. 2003, 125,
16194–16195; d) N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M.
Scott, S. P. Nolan, J. Am. Chem. Soc. 2006, 128, 4101–4111.
Tamm, F. E. Hahn, Coord. Chem. Rev. 1999, 182, 175–209; c) F. E. Hahn, V.
Langenhahn, N. Meier, T. Lügger, W. P. Fehlhammer, Chem. Eur. J. 2003,
9, 704–712; d) K. Bartel, W. P. Fehlhammer, Angew. Chem. Int. Ed. Engl.
1974, 13, 599–600; Angew. Chem. 1974, 86, 588–589; e) F. E. Hahn,
M. C. Jahnke, Angew. Chem. Int. Ed. 2008, 47, 3122–3172; Angew. Chem.
2008, 120, 3166–3216.
[12] a) R. A. Michelin, A. J. L. Pombeiro, M. F. C. Guedes da Silva, Coord. Chem.
Rev. 2001, 218, 75–112; b) A. J. L. Pombeiro, M. F. C. Guedes da Silva,
R. A. Michelin, Coord. Chem. Rev. 2001, 218, 43–74; c) R. A. Michelin, L.
Zanotto, D. Braga, P. Sabatino, R. J. Angelici, Inorg. Chem. 1988, 27, 93–
99; d) R. Bertani, M. Mozzon, R. A. Michelin, Inorg. Chem. 1988, 27,
2809–2815; e) R. Bertani, M. Mozzon, R. A. Michelin, F. Benetollo, G.
Bombieri, T. J. Castilho, A. J. L. Pombeiro, Inorg. Chim. Acta 1991, 189,
175–187; f) Y. Ito, T. Hirao, K. Tsubata, T. Saegusa, Tetrahedron Lett.
1978, 19, 1535–1538; g) W. P. Fehlhammer, T. Bliß, J. Fuchs, G. Holz-
mann, Z. Naturforsch. B 1992, 47, 79–89.
[13] A. S. K. Hashmi, T. Hengst, C. Lothschütz, F. Rominger, Adv. Synth. Catal.
2010, 352, 1315–1337.
[14] a) A. S. K. Hashmi, C. Lothschütz, C. Bçhling, T. Hengst, C. Hubbert, F. Ro-
minger, Adv. Synth. Catal. 2010, 352, 3001–3012; b) A. S. K. Hashmi, C.
Lothschütz, K. Graf, T. Häffner, A. Schuster, F. Rominger, Adv. Synth.
Catal. 2011, 353, 1407–1412; c) D. Riedel, T. Wurm, K. Graf, M. Rudolph,
F. Rominger, A. S. K. Hashmi, Adv. Synth. Catal. 2015, 357, 1515–1523.
[15] a) A. S. K. Hashmi, D. Riedel, M. Rudolph, F. Rominger, T. Oeser, Chem.
Eur. J. 2012, 18, 3827–3830; b) R. Manzano, F. Rominger, A. S. K.
Hashmi, Organometallics 2013, 32, 2199–2203; c) R. Manzano, T. Wurm,
F. Rominger, A. S. K. Hashmi, Chem. Eur. J. 2014, 20, 6844–6848.
[16] A ring closure of an unsubstituted propargylamine on a manganese iso-
nitrile template to form the NHC was reported by: J. Ruiz, B. F. Peran-
dones, G. García, M. E. G. Mosquera, Organometallics 2007, 26, 5687–
5695.
[17] CCDC 1059433 (3), CCDC 1059434 (4), CCDC 1059435 (5a’),
CCDC 1059436 (5a’’) and CCDC 1059437 (5b) contain the supplementa-
ry crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[8] For representative articles, see: a) M. Scholl, S. Ding, C. W. Lee, R. H.
Grubbs, Org. Lett. 1999, 1, 953–956; b) M. Scholl, T. M. Trnka, J. P.
Morgan, R. H. Grubbs, Tetrahedron Lett. 1999, 40, 2247–2250.
[9] G. Altenhoff, R. Goddard, C. W. Lehmann, F. Glorius, Angew. Chem. Int.
Ed. 2003, 42, 3690–3693; Angew. Chem. 2003, 115, 3818–3821.
[10] L. Benhamou, E. Chardon, G. Lavigne, S. Bellemin-Laponnaz, V. CØsar,
Chem. Rev. 2011, 111, 2705–2733.
Manuscript received: April 5, 2015
Revised: May 15, 2015
Accepted Article published: May 28, 2015
Final Article published: July 3, 2015
[11] For representative contributions, see: a) F. E. Hahn in Advances in Organ-
ometallic Chemistry and Catalysis, Wiley, 2013, pp. 111 –132; b) M.
Chem. Asian J. 2016, 11, 342 – 346
www.chemasianj.org
346
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