Gold(i) triazolyls: Organometallic synthesis in air and aqueous media

Article abstract of DOI:10.1039/c3cc43016b

(N-heterocyclic carbene)gold(i) alkynyls and organic azides have undergone cycloadditions in water-t-butanol mixtures with copper metal as the pre-catalyst to give new gold(i) triazolyls in high purity. Substrate tolerability was outlined for organoazides bearing a range of functional groups, and branching alpha to the azide moiety. All products are validated by combustion analysis or high-resolution mass spectrometry; two are also confirmed crystallographically.

Full text of DOI:10.1039/c3cc43016b

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Gold(I) triazolyls: organometallic synthesis in air and
aqueous media†
James E. Heckler,a Nihal Deligonul,a Arnold L. Rheingoldb and Thomas G. Gray*a
Cite this: Chem. Commun., 2013,
49, 5990
Received 23rd April 2013,
Accepted 17th May 2013
DOI: 10.1039/c3cc43016b
www.rsc.org/chemcomm
(N-heterocyclic carbene)gold(I) alkynyls and organic azides have C-5 of the triazole ring, is a functional group in itself. It can act as a
undergone cycloadditions in water–t-butanol mixtures with copper heavy-atom tag,13 a prodrug,14 or a pre-catalyst. Spin–orbit coupling
metal as the pre-catalyst to give new gold(I) triazolyls in high purity. (B5100 cmÀ1 for a 5d-electron in Au15) makes triplet excited
Substrate tolerability was outlined for organoazides bearing a range states accessible,16 and transforms the photophysics of osten-
of functional groups, and branching alpha to the azide moiety. All sibly fluorescent triazoles.17
products are validated by combustion analysis or high-resolution
mass spectrometry; two are also confirmed crystallographically.
Work in this laboratory has evolved a protocol for the synthesis of
5-gold(I)-1,4-triazolyls, beginning from gold alkynyls in the presence
of copper.17 Reaction proceeds on addition of [Cu(MeCN)4]PF6 in
The copper-catalysed [3+2] cycloaddition of terminal alkynes to catalytic amounts. No reaction is observed without added copper.
organic azides has made 1,2,3-triazoles pervasive in materials The reaction broadly tolerates alkynyl functional groups, but high
and bioconjugate chemistry.1 The cycloaddition is specific for the loadings of copper (10 mol%) were employed. Reactions were run in
1,4-isomer,2 is insensitive to reaction conditions, and is high-yielding. anaerobic acetonitrile because the copper source oxidizes and is
The 1,4-disubstituted 1,2,3-triazole is a robust linker in bioconjugation substitutionally labile.
and polymer functionalization.3 Research from this laboratory has
Rougher and readier additives were sought, with attention to
demonstrated [3+2]-cycloaddition of (organophosphine)gold(I) azides cycloaddition reactions in aqueous media. Many copper sources
with terminal alkynes and its inverse, the cycloaddition of hydrolyz- support alkyne–azide coupling, including direct addition of cuprous
able trimethylsilyl azide to gold(I) alkynyls.4 Both reactions yield salts (with or without supporting ligands), in situ reduction of
cycloadducts bearing carbon–gold s-bonds. Thereafter, Veige and Cu(II) salts such as CuSO4Á5H2O, and generation of catalytic
co-workers5 reported a cycloaddition of (triphenylphosphine)gold(I) Cu(I) from metallic copper.
azide to (triphenylphosphine)gold(I) phenylacetylide to produce a
To begin, we assessed several copper sources in the model
mixture of the 1,5-(major) and 1,4-isomers of the di-gold triazolyl. reaction of Scheme 1. The tert-butyl group on the gold alkynyl
None of the three reactions require addition of (pre)catalysts. Several IPrAu(tert-butylethynyl) 1a (IPr = 1,3-bis(2,6-diisopropylphenyl)-
others have sought to add metal centres as a third component to the imidazol-2-ylidene) provided a useful 1H NMR spectroscopic
click cyclization, to produce C-bound triazolyls as intermediates6,7 handle. In the parent alkynyl, the tert-butyl singlet resonates in
or products.8–11 Hashmi and collaborators12 have described benzene-d6 at d 1.18 ppm, between the dual doublet resonances
[3+2]-cycloadditions of azomethine ylides and gold(I) isonitriles that of the carbene isopropyl groups. Upon product formation, this
afford abnormal N-heterocyclic carbene complexes.
singlet shifts downfield to approximately d 1.44 ppm, outside of
Gold(I) triazolyls add a new dimension to the copper-catalyzed the carbene resonances. Table 1 summarizes outcomes of a
azide–alkyne cycloaddition (CuAAC) reaction. The triazole products series of reaction conditions.
carry the functionality of the alkyne and azide precursors; gold is a
third component. The pendant gold(I) fragment, which attaches to
a Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA.
E-mail: tgray@cwru.edu
b Department of Chemistry and Biochemistry, University of California San Diego,
San Diego, California, USA
† Electronic supplementary information (ESI) available: Experimental details,
optical spectra of 6a–b, and crystallographic data. CCDC 935201 and 935202.
Scheme 1 Model reaction for optimization of cycloaddition of organic azides
(R2 = benzyl) and gold alkynyls (R1 = t-butyl).
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3cc43016b
c
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Table 1 Screening of copper catalysts for the cycloaddition of 1a with benzyl azide
Table 2 Results of the cycloadditions of 1a (R1 = tert-butyl) or 1b (R1
=
1-naphthyl) with various azides under copper catalysisa
Loading
(mol%)
Time
(h)
Conv.a
(%)
Entry R1
R2-N3
Product Yieldb (%) Yieldc (%)
Entry
Cu source
Solvent
1
2
3
4
5
6
7
8
None
0
11
10
12
10
10
10
10
10/10
5
5/5
2.5d
2.5e
Excess
CH3CN
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
H2O–t-BuOH
24
14
48
14
72
24
24
3
0
0
IPrCuCl
IPrCuCl/KPF6
(IPr)2CuBF4
(IPr)2CuBF4
IPrCuOAc
CuI
1
2
t-Bu
2a
68
67
76
82
0b
0
t-Bu
t-Bu
t-Bu
CH3(CH2)6CH2N3 3a
0b
0
100
100
32
100
62
0
3
4
4a
5a
51
88
65
CuI
9
CuI/TBTAc
CuI
1
6
3
N/Ad
10
11
12
13
14
CuI/TBTAc
CuI
14b
14b
8
CuI
Cu metal
0
100
5
t-Bu
6a
80
89
a
b
Determined by 1H NMR integration comparisons. Reaction done at
c
d
45 1C. TBTA = tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine. Catalyst
concentration approximately 0.3 mM. Catalyst concentration approxi-
e
6
7
1-Naphthyl
6b
7a
82
97
92
89
mately 0.01 mM.
t-Bu
Copper sources stabilized by the N-heterocyclic carbene
ligand IPr were first tested. All attempts at performing the
model reaction of Scheme 1 using IPr-ligated copper(I) led to
complete recovery of starting material, regardless of catalyst
loading, solvent choice, or temperature. These results contrast
sharply with observations that these compounds catalyse
azide–alkyne cycloadditions at low loadings.18
Reactions were then carried out in the presence of copper(I)
iodide. This copper source was investigated for its higher
formula weight and air stability relative to other binary copper
compounds. We had earlier reported one example of a cyclo-
addition at high loadings (15 mol%) of copper iodide.17
After several trials, it emerged that a catalyst loading of
5 mol% with stirring for 6 h produced a variety of gold triazolyls.
Higher loadings afford faster conversion, but the lower loading
is preferred as it permits isolation of purer product.19
8
9
t-Bu
8a
N/Ad
64
t-Bu
t-Bu
N/A
N/A
0
0
0
0
10
a
b
Isolated yields are of non-crystallized products. Method A, CuI
c
(5 mol%), 6 h stir in CH3CN. Method B, copper metal (excess),
4–24 h stir in H2O–tBuOH (2: 1 v/v), see ESI for reaction times. Reaction
not run using method A.
d
Primary, secondary, and aryl azides were added to 1a with full
conversion. Reactions with the tertiary azide 1-azidoadamantane did
Interestingly, loadings lower than 5 mol% failed to yield any not proceed. To determine if steric clashes between the adamantyl
product, even when reactions were performed at 45 1C at any group and the IPrAu fragment impeded reaction, the IPr ligand was
concentration. The addition of polytriazole ligands20 for copper substituted with the smaller Cl2IMe22 ligand to produce gold alkynyl
produced no discernible acceleration as monitored by 1H NMR. (Cl2IMe)Au(tert-butylethynyl). No reaction was found with 1-azidoada-
The production of copper(I) by reduction in situ obviates the mantane. A less encumbering tertiary azide, 2-azido-2-(4-biphenyl)-
need for air- and moisture-free measures. However, when using propane, was mixed with 1a, but with no discernible reaction. Lastly,
1 mol% of CuSO4 and 5 mol% sodium ascorbate, only trace an activated gold alkynyl, IPrAu(carboxymethylethynyl), was mixed with
amounts of aurated triazole were obtained. Instead, the majority both tertiary azides. In neither case was reaction observed, leading us to
of the gold alkynyl was reduced, as evidenced by a violet colour conclude that tertiary azides do not readily undergo [3+2] cycloadditions
observed during the workup, the signature of colloidal gold.
However, when reactants were stirred in a 2 : 1 mixture of alkynes do cyclize with tertiary azides under copper catalysis.1b
water and tert-butanol using an excess of copper(0) turnings,21
A reaction of IPrAu(carboxymethylethynyl) and benzyl azide
with gold(I) alkynyls under these conditions. In contrast, organic
gold(I) triazolyls resulted after 4–24 h in comparable or higher yield run in the presence of one equiv. (IPr)AuNTf2 (NTf2 = triflimi-
than when using copper iodide. This result affirms the hydrolytic date) yielded a di-gold cation metalated at C-1 and N-3 in the
stability of the gold–carbon s-bond of the triazole, and precludes solid state. This species is only isolated if a second equivalent
the need for most precautions in carrying out the reaction.
of (IPr)Au+ is supplied to the reaction mixture. A thermal
Table 2 sets out reaction conditions and organogold products. ellipsoid depiction appears as Fig. S1, ESI.† Cycloaddition of
Isolated yields are moderate to high and compare favourably to methyl propiolate with benzyl azide in the presence of copper
those from previous reports of gold triazolyl syntheses. In general, turnings and (IPr)AuNTf2 or (IPr)AuCl yielded the unmetalated
cycloadditions performed in water led to higher isolated yields, and triazole, without evidence of copper-to-gold transmetalation.
products usually precipitated in sufficient purity to pass combus-
tion analysis after vacuum-drying.
Vapour diffusion of hexanes into a saturated benzene solution
of 6a produced single crystals suitable for X-ray diffraction.
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relevant substituents. Further investigations of the method’s
scope, with attention to ambiphilic ligands, are ongoing.
This research was supported by the U.S. National Science
Foundation, Grant CHE-1057659 to T. G. G.; N. D. thanks the
Republic of Turkey for a fellowship.
Notes and references
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2 In contrast, the ruthenium-catalysed variant affords primarily the
1,5-regioisomer. See: (a) S. Grecian and V. V. Fokin, Angew. Chem., Int.
Ed., 2008, 47, 8285–8287; (b) B. C. Boren, S. Narayan, L. K. Rasmussen,
L. Zhang, H. Zhao, Z. Lin, G. Jia and V. V. Fokin, J. Am. Chem. Soc.,
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¨
3 R. K. Iha, K. L. Wooley, A. M. Nystrom, D. J. Burke, M. J. Kade and
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4 D. V. Partyka, J. B. Updegraff III, M. Zeller, A. D. Hunter and
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5 T. J. D. Castillo, S. Sarkar, K. A. Abboud and A. S. Veige, Dalton
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Fig. 1 Structure of 6a shown with 50% probability ellipsoids and partial atom
6 Y. Zhou, T. Lecourt and L. Micouin, Angew. Chem., Int. Ed., 2010, 49,
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labelling schemes. Hydrogen atoms are omitted; unlabelled atoms are carbon.
7 P. N. Liu, J. Li, F.-H. Su, K. D. Ju, L. Zhang, C. Shi, H. H. Y. Sung,
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A thermal ellipsoid projection appears as Fig. 1. Intermolecular
aurophilic interactions are absent. A single gold complex inhabits
the asymmetric unit along with 1.5 benzene molecules of
crystallization. The structure exhibits a linear, two-coordinate,
geometry about the Ctriazole–Au–CNHC bond with an angle of 10 M. C. Clough, P. Zeits, N. Bhuvanesh and J. A. Gladysz, Organo-
metallics, 2012, 31, 5231–5234.
179.04(13)1. Gold–carbon bond lengths of AuÁ Á ÁCNHC and
11 S. A. Knott, J. N. Templeton, J. L. Durham, A. M. Howard,
AuÁ Á ÁCtriazolyl are 2.021(3) and 2.022(3) Å, respectively, and are
R. McDonald and L. F. Szczepura, Dalton Trans., 2013, 42, 8132–8139.
typical of gold(I)–carbon single bonds.23,24 The triazolyl and 12 (a) A. S. K. Hashmi, D. Riedel, M. Rudolph, F. Rominger and T. Oeser,
Chem.–Eur. J., 2012, 18, 3827–3830; (b) R. Manzano, F. Rominger and
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13 D. J. Gorin and F. D. Toste, Nature, 2007, 446, 395–403.
coumarin ring systems are nearly orthogonal; the dihedral angle
between their (non-hydrogen-atom) mean planes is 84.061; that
of the N-heterocyclic carbene and triazolyl mean planes is 26.471. 14 J. L. Hickey, R. A. Ruhayel, P. J. Barnard, M. V Baker, S. J. Berners-
Price and A. Filipovska, J. Am. Chem. Soc., 2008, 130, 12570–12571.
15 J. S. Griffith, Theory of Transition Metal Ions, Cambridge University
The former contrasts with structures where the triazolyl and
substituent ring systems are nearly coplanar.17
Press, Cambridge, 1964.
´
Coumarins are blue-light emitting fluorophores; they pos- 16 R. A. Vogt, T. G. Gray and C. E. Crespo-Hernandez, J. Am. Chem. Soc.,
sess anti-inflammatory25 and anti-proliferative26 properties.
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17 D. V. Partyka, L. Gao, T. S. Teets, J. B. Updegraff III, N. Deligonul and
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in search of heavy-atom induced phosphorescence.16 Triazolyl 18 (a) S. Dıez-Gonzalez, E. D. Stevens and S. P. Nolan, Chem. Commun.,
´
´
´
´
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complexes bearing coumarin fragments luminesce in fluid
solvents at room temperature. Absorption and emission pro-
files of coumarins 6a and 6b appear respectively in Fig. S2 and
S3, ESI.† Absorption sets in near 360 nm; maxima occur at 333
and 318 nm, with an absorption shoulder near 300 nm. Emis-
Int. Ed., 2008, 47, 8881–8884.
19 Cuprous bromide, acetate and triflate were also determined to be
effective at similar loadings, but were rejected for their higher
sensitivity to air and moisture.
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structure in the emission spectrum. The luminescence is
unquenched in air. That and the small Stokes shift suggest
210–216.
22 Cl2IMe
=
4,5-dichloro-1,3-dimethylimidazol-2-ylidene. Ph3P
=
singlet-state emission. Spectra of 6a (ESI†) are similar.
In conclusion, (N-heterocyclic carbene)gold(I) alkynyls and a
variety of organic azides have undergone [3+2] cycloadditions in
triphenylphosphine. (a) See ESI† for the synthesis of (Cl2IMe)AuCl;
(b) E. Schuh, C. Pflu¨ger, A. Citta, A. Folda, M. P. Rigobello,
A. Bindoli, A. Casini and F. Mohr, J. Med. Chem., 2012, 55,
5518–5528.
˜
´
both acetonitrile (using copper(I) iodide as the pre-catalyst) and 23 M. Fananas-Mastral and F. Aznar, Organometallics, 2009, 28,
666–668.
water–alcohol mixtures (using copper metal). While the methods
are complementary, that with copper metal is milder, does not
24 Y. Shi, S. D. Ramgren and S. A. Blum, Organometallics, 2009, 28,
1275–1277.
require dry or anaerobic conditions, and generally affords higher 25 K. C. Fylaktakidou, D. J. Hadjipavlou-Litina, K. E. Litinas and
D. N. Nicolaides, Curr. Pharm. Des., 2004, 10, 3813–3833.
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yields and greater purity. Gold(I) triazolyls have earlier been shown
to be cytotoxic toward 3T3 mouse fibroblasts in vitro.27 The
present work allows for high-purity syntheses with biologically
Trans., 2011, 40, 8083–8085.
c
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5992 Chem. Commun., 2013, 49, 5990--5992