Development of building blocks for the synthesis of N-heterocyclic carbene ligands

Article abstract of DOI:10.1021/ol0516521

(Chemical Equation Presented) The synthesis of a series of NHC building blocks that can then be incorporated into more complicated structures by palladium catalysis is reported. This approach is used for the synthesis of three amino acids containing NHC s

Full text of DOI:10.1021/ol0516521

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4605-4608
Development of Building Blocks for the
Synthesis of N-Heterocyclic Carbene
Ligands
Guopin Xu and Scott R. Gilbertson*
Chemical Biology Program, Department of Pharmacology and Toxicology,
UniVersity of Texas Medical Branch, GalVeston, Texas 77555-06309
srgilber@utmb.edu
Received July 13, 2005 (Revised Manuscript Received September 6, 2005)
ABSTRACT
The synthesis of a series of NHC building blocks that can then be incorporated into more complicated structures by palladium catalysis is
reported. This approach is used for the synthesis of three amino acids containing NHC side chains. The ability to use the amino acids in
solid-phase peptide synthesis to make NHC-containing peptides is also demonstrated. Additionally, the NHC side chain can be deprotected
and coordinated to a catalytically active transition metal. Finally, it is illustrated that the building blocks participate in Suzuki coupling to
provide access to substituted NHC ligands.
N-Heterocyclic carbenes (NHCs) have emerged as an
important class of ligands for transition metals and are
beginning to play a role in transition-metal catalysis.1,2 Since
their original disclosure by O¨ fele in 1968,3 a number of
chemists have investigated first their properties as ligands
and later the characteristics of these complexes in a variety
of catalytic reactions. Transition-metal complexes with these
ligands have proven to be effective in the Heck reaction,4
Suzuki and Sonogashira couplings,5,6 aryl amination,7,8 amide
R-arylation,9 hydrosilylation,10 Kumada coupling,11 hydro-
genation,12,13 hydroformylation,14 alkyne coupling,15 olefin
cyclopropanation,16 arylation of aldehydes,17 and of course,
olefin metathesis.18 Thus far, there have been a select number
of examples of their use in asymmetric catalysis.12,13,19-22
In addition to emerging as useful ligands in transition-metal
chemistry, there are numerous examples of NHCs being used
in nucleophilic catalysis.23-32
(12) Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui, X.; Burgess, K. J.
Am. Chem. Soc. 2001, 123, 8878-8879.
(13) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D. R.; Reibenspies, J.
H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113-123.
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265.
(1) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
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(3) O¨ fele, K. J. Organomet. Chem. 1968, 12, P4-P43.
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(5) Herrmann, W. A.; Bohm, V. P. W.; Gstottmayr, C. W. K.; Grosche,
M.; Reisinger, C.-P.; Weskamp, T. J. Organomet. Chem. 2001, 617-618,
616-628.
(6) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell, M. L.;
Nolan, S. P. Organometallics 2002, 21, 2866-2873.
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(8) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F.
Org. Lett. 2000, 2, 1423-1426.
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80.
(15) Barratta, W.; Herrmann, W. A.; Rigo, P.; Schwarz, J. J. Organomet.
Chem. 2000, 593, 489-493.
(16) Cetinkaya, B.; O¨ zdemir, I.; Dixneuf, P. H. J. Organomet. Chem.
1997, 534, 153-158.
(17) Furstner, A.; Krause, H. AdV. Synth. Catal. 2001, 343, 343-350.
(18) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543-6554.
(19) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-
3228.
(20) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka,
O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502-12508.
(21) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A.
H. J. Am. Chem. Soc. 2002, 124, 4954-4955.
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Chem., Int. Ed. 2003, 42, 5871-5874.
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10.1021/ol0516521 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/17/2005

There are a number of synthetic routes to N-heterocyclic
carbenes available. However, most of these routes are not
compatible with the synthesis of complex molecules contain-
ing diverse and sensitive functionality. These routes involve
the use of strong base, strong acid, or strongly reducing
conditions.2,13 We report here the synthesis of a series of
NHC building blocks that can then be incorporated into more
complicated structures by palladium catalysis. This approach
is used in this paper for the synthesis of three amino acids
containing NHC side chains. We also illustrate that the amino
acids can be used in solid-phase peptide synthesis to make
NHC-containing peptides. Additionally, the NHC side chain
can be deprotected and coordinated to a catalytically active
transition metal. Finally, we show that the building blocks
participate in Suzuki coupling to provide access to substituted
NHC ligands.
aniline provided 2, which could then be reacted with a
p-bromoaniline derivative to give the diamide 3 (Scheme
1). Reaction of 3 with borane dimethyl sulfide complex
gave the desired diamine. Exchange of bromide for io-
dide and reaction with triethylorthoformate provided the salt
5.
Chloride salt 5 was then tested to determine if it could be
used in palladium-catalyzed coupling reactions. Para,
meta, and ortho isomers (5, 6, and 7) were examined to
determine if they would undergo palladium-catalyzed
coupling with metalated amino acid 8 (Scheme 2). In all
Scheme 2
The approach taken toward the synthesis of more complex
NHC ligands was to develop a building block containing a
latent carbene moiety 5 (Scheme 1). If compatible with the
Scheme 1
three cases, these iodides coupled to provided amino acids
9-11 in good yield.
Having found that salts such as 5-7 can be used in
palladium-catalyzed coupling, the next goal was to adjust
the functionality of protected amino acids and determine if
solid-phase peptide chemistry can be used to synthesize more
complex ligands. It is also necessary to be able to convert
molecules such as 9 to the desired carbene in the presence
of the amino acid functionality.
necessary chemistry, chloride salt 5 could then be incor-
porated into larger structures by a variety of different
reactions. Proceeding through salts such as 5 is a common
route to NHC ligands; however, to our knowledge there are
limited examples of chemistry that has been worked out to
use these salts as latent carbenes in other reactions prior to
carbene generation.
Reaction of 9 with the anion of chloroform generated from
KOH and chloroform or by decarboxylation of the sodium
salt of trichloroacetic acid gives the chloroform adduct (12)
(Scheme 3). Grubbs and others have shown that heating
adducts of this type generates the free carbene which can be
trapped with a metal.33 This approach provided a route to
the amino acid NHC ruthenium complexes but was not
compatible with additional chemistry such as conversion of
the ester to the free acid or removal of the Boc group. It
seems rather unlikely that the chloroform adducts would be
sufficiently stable to allow multiple reaction steps while
attached to a solid support.
The desired approach required an unsymmetrical diamine.
Reaction of oxalyl chloride with 1 equiv of 2,4,6-trimethyl-
(24) Nair, V.; Menon, R. S.; Sreekumar, V. Pure Appl. Chem. 2005, 77,
1191-1198.
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(28) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J. J. Am. Chem.
Soc. 2005, 127, 1654-1655.
Another method for the conversion of salts such as 9 to a
NHC is by reaction with silver(I) oxide. Stirring the salt 9
with Ag2O provided the silver carbene complex (14) (Scheme
(29) Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem. Soc. ReV.
2004, 33, 619-636.
(30) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004,
43, 5130-5135.
(31) Hachisu, Y.; Bode, J. W.; Suzuki, K. AdV. Synth. Catal. 2004, 346,
1097-1100.
(33) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl,
M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 2546-2558.
(32) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541.
4606
Org. Lett., Vol. 7, No. 21, 2005

desirable to protect the amino acid as the FMOC carbamate.
Hydrolysis with lithium hydroxide followed by treatment
with hydrochloric acid in dioxane gave the free amino acid,
which was treated without isolation with FMOC-OSu to
provide the FMOC-protected amino acid (16) (Scheme 4).
To determine the ability to use such amino acids in standard
peptide couplings, this amino acid was coupled into a four-
residue peptide. Reaction of FMOC acid 16 on the supported
dipeptide proceeded smoothly using DIC as the coupling
agent. Removal of the FMOC protecting group followed by
coupling of FMOC-alanine gave a tetrapeptide (19) that was
removed from the support with TFA. Chloride salt (20) was
fully characterized.
Scheme 3
Reaction of the tetrapeptide with silver carbonate provided
the silver NHC complex, which was then exchanged with
Grubbs (I) catalyst to provide the ruthenium complex (21)
(Scheme 5). This complex was identified by the characteristic
Scheme 5
3). Silver NHC complexes are very labile and readily undergo
exchange with metals such as rhodium or ruthenium.34
Reaction with Grubbs bisphosphine catalyst provided the
ruthenium NHC phosphine complex (13). Reaction with
rhodium cyclooctadiene chloride dimer afforded the rhodium
complex 15.
proton resonance for the proton on the benzylidene carbon
(19.07 vs 20.01 in CD2Cl2 for the Grubbs (I) precursor). This
complex was also found to be a competent metathesis catalyst
catalyzing the polymerization of norbornadiene at room
temperature.
Scheme 4
In addition to providing a route to amino acid containing
NHC ligands, salts such as 7 can be used to synthesize a
variety of different NHC ligands. Compound 7 was substi-
tuted using the Suzuki reaction. Reaction of the iodide with
both boronic acids and boronic esters provides the substituted
salt. Thus far, we have used this reaction in the synthesis of
salts substituted with benzene (23) and pyrazole (25) groups
(Scheme 6).
Scheme 6
We are currently using this reaction in the synthesis of
catalyst systems that have not been accessible prior to this
methodology. Specifically compounds 5-7 will be of value
Before they can be used in solid-phase peptide synthesis,
the NHC-containing amino esters must be converted to amino
acids by hydrolysis of the methyl ester. Additionally, it was
(34) Chianese, A. R.; Li, X.; Janzen, M. C.; Faller, J. W.; Crabtree, R.
H. Organometallics 2003, 22, 1663-1667.
Org. Lett., Vol. 7, No. 21, 2005
4607

for the synthesis of a variety of different NHC ligands
systems. The general approach reported here should prove
useful in the synthesis of novel chiral and achiral NHC
ligands.
Supporting Information Available: Experimental pro-
cedures, spectra, and characterization of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the
Robert A Welch Foundation.
OL0516521
4608
Org. Lett., Vol. 7, No. 21, 2005