Synthesis and characterization of catalytically active thiazolium gold(i)-carbenes

Article abstract of DOI:10.1039/c7cc03791k

Thiamin analogs were used to synthesize mono gold(i)-carbene derivatives in a single step under aqueous conditions. The resulting thiazolium gold(i)-carbenes catalyze 5-endo-dig carbocyclization of an acetylenic dicarbonyl compound in organic solvents and hydroalkoxylation of an allene in aqueous buffer.

Full text of DOI:10.1039/c7cc03791k

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Synthesis and characterization of catalytically
active thiazolium gold(I)-carbenes†
Cite this:DOI: 10.1039/c7cc03791k
Clement C. Dince, Roy A. Meoded
´
and Donald Hilvert
*
Received 16th May 2017,
Accepted 15th June 2017
DOI: 10.1039/c7cc03791k
rsc.li/chemcomm
Thiamin analogs were used to synthesize mono gold(I)-carbene
derivatives in a single step under aqueous conditions. The resulting
thiazolium gold(I)-carbenes catalyze 5-endo-dig carbocyclization of
an acetylenic dicarbonyl compound in organic solvents and hydro-
alkoxylation of an allene in aqueous buffer.
The field of gold catalysis has burgeoned over the past several
1
,2
decades. Gold catalysts enable construction of architecturally
complex molecules from simple precursors under conditions that
are unusually mild for metal catalysts. Triphenylphosphines and and benzylthiazolium (4).
Fig. 2 Structures of thiamin diphosphate (1), vitamin B1 (2), oxythiamin (3)
3,4
N-heterocyclic carbenes (NHCs) are frequently used as ligands to
5
control reactivity. Thiamin pyrophosphate (TPP, 1) is a biologically
6
,7
relevant thiazolium salt that shares both chemical and structural
similarities with commonly employed imidazolium-based NHCs solubility in organic solvents. As a result, they are incompatible
Fig. 1). Here we report a one-step route to mono gold(I)-carbenes with standard routes to imidazolium-based gold(I)-carbenes, which
of thiamin derivatives in aqueous buffer, together with their include transmetallation of the corresponding copper or silver NHC
Thiamin derivatives (Fig. 2) are hydrophilic salts with limited
(
8
characterization and catalytic properties.
complex, reaction of the free carbene with a suitable gold
8
precursor, and treatment of imidazolium salts with weak bases
9–11
in the presence of a gold complex
in organic solvents. Instead,
we opted for a one-pot method in aqueous solution. Thiazolium
carbenes were formed by abstraction of the C2 proton from the
thiazolium ring in a range of basic buffers containing a small
2
excess of (SMe )AuCl. In the case of TPP (1), vitamin B1 (2) and
oxythiamin (3), no product was obtained. Instead, decomposition
of the gold reagent to give purple colloidal gold was typically
observed after stirring the reaction mixture for an hour at room
12
2
temperature. Decomposition of (SMe )AuCl might have been
promoted by reactive groups in the ligand. Possibilities include
the carbonyl moiety, the exocyclic amino and heterocyclic nitrogens
of the pyrimidine ring or, alternatively, the pyrophosphate moiety.
Simple N-alkyl- and N-benzylthiazolium derivatives that lack these
functional groups have been shown to be functional TPP mimics.
For example, 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride
Fig. 1 Imidazolium gold(I)-carbenes (top) and analogous thiazolium-
based derivatives (bottom). R = alkyl or aryl, R = H or diphosphate.
0
00
Laboratory of Organic Chemistry, Department of Chemistry and Applied
Biosciences, ETH Z u¨ rich, CH-8093, Switzerland. E-mail: hilvert@org.chem.ethz.ch;
Fax: +41 44 632 3176; Tel: +41 44 632 1486
(benzylthiazolium, 4), which possesses a benzyl group in
place of the pyrimidine ring, catalyzes a range of biomimetic
1
3,14
TPP-dependent reactions.
Screening of reaction conditions
†
Electronic supplementary information (ESI) available. CCDC 1470873 and
470874. For ESI and crystallographic data in CIF or other electronic format
with this analogue quickly afforded the desired gold(I)-carbene
1
see DOI: 10.1039/c7cc03791k
5 as a white precipitate.
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Fig. 4 Carbocyclization of acetylenic dicarbonyl 8 (top) and hydroalkoxylation
of allene 10 (bottom) catalyzed by benzylthiazolium gold(I)-carbene 5.
the benzylthiazolium gold(I)-carbene. X-ray crystallography pro-
vided definitive evidence for its structure. Diffraction quality
crystals were obtained by slow diffusion of pentane into an
ethyl acetate solution of 5. As seen in Fig. 3B, the gold carbene
is linear (C2–Au–Cl 178.061) and sits in the plane of the thiazolium
ring (see ESI†). The lengths of the C2–Au (1.980 Å) and the Au–Cl
Fig. 3 (A) Formation of gold(I)-carbenes from benzylthiazolium 4 and
benzylthiazolium pyrophosphate 6. (B) X-ray crystal structure of 5.
(
2.287 Å) bonds are comparable to those observed for other NHC
1
5
gold(I)-carbenes. Although Maldi-TOF analysis gave the mass
of a bis-carbene (663.2 m/z) rather than a mono-gold(I)-carbene
The gold(I) carbene was obtained in 90% yield by mixing (465.0 m/z), the compound presumably rearranged under the
N-benzylthiazolium (4) with 1.1 equivalents of (SMe
)AuCl in a conditions of the measurement.
: 1 mixture of 50 mM Tris–HCl and potassium phosphate
The benzylthiazolium gold(I)-carbene 5 was tested as a catalyst
2
1
buffer (pH 9.0) at 45 1C for 2 h in the dark (Fig. 3A). As expected for two reactions that are efficiently catalyzed by imidazolium
1
for formation of a C2 adduct, the H signal for the C2 proton gold(I)-carbenes (Fig. 4). The first was the 5-endo-dig carbocycliza-
1
3
16
disappeared and the C signal for the C2 carbon shifted from tion of an acetylenic dicarbonyl compound. In the presence of
1
54.91 ppm to 192.17 ppm (see Table 1). For comparison, the silver triflate, compound 5 (1 mol%) promotes transformation of
C resonance of the C2 carbon of analogous NHC derivatives alkyne 8 into the cyclopentene derivative 9 in dichloromethane.
1
3
typically appears around 135 ppm and shifts to ca. 170 ppm for The yield of isolated product was 63%, providing the first evidence
1
5
the corresponding gold(I) carbene.
Elemental analysis of compound 5 confirmed the mass fractions reaction, we examined the gold(I)-catalyzed hydroalkoxylation of
that thiazolium gold(I)-carbenes are active catalysts. As a second
4
,17
of carbon, hydrogen, nitrogen, sulfur and chloride expected for allenes.
Compound 5 (1 mol%) catalyzed the transformation
of 6-methylhepta-4,5-dien-1-ol (10) to 2-(2-methylprop-1-en-1-
yl)tetrahydrofuran (11), again in dichloromethane. The conver-
sion, determined by NMR spectroscopy, was 94% after 24 h
reaction at room temperature.
13
Table 1
C NMR shifts for compounds 4, 5, 6 and 7
Notably, both model reactions were performed under
‘‘open-flask’’ conditions in wet solvents, highlighting the robust-
ness of the catalyst. In their work on entrapped ionic gold catalysts,
Toste et al. showed that the hydroalkoxylation of compound 10,
which had been generated enzymatically by hydrolysis of an acetyl
ester, can also be carried out in phosphate buffer at pH 7 in yields
Compound #
18
ranging from 53 to 100%. When we tested the catalytic activity of
Carbon #
4
5
6
7
carbene 5 with allene 10 in 50 mM potassium phosphate buffer
2
4
5
6
7
8
154.91
142.79
135.64
11.11
29.15
60.33
192.17
140.6
133.91
12.53
30.16
60.86
155.27
143.07
134.9
11.17
27.55
205.05
143.76
135.01
12.17
28.15
65.15
2
(pH = 7) containing 1 mM MgCl and 15 to 30% DMSO, however,
no product was observed by TLC after 24 h at room temperature
or after 5 h at 40 1C, presumably due to the low solubility of the
catalyst under these conditions.
64.71
1
1
1
1
1
1
2
3–17
4–16
5
56.74
59.84
56.72
59.05
Although thiazolium salts themselves readily dissolve in water,
formation of the corresponding gold(I)-carbene decreases solubility
substantially. The natural TPP cofactor contains a diphosphate
moiety that greatly enhances hydrophilicity and, at the same time,
131.75
129.47
128.23
129.42
133.49
128.88
126.35
128.35
131.73
129.45
128.3
134.22
129.31
126.69
128.63
129.39
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hydroalkoxylation of allenes (Fig. 5). In the case of 7, however,
the reactions were performed in 50 mM phosphate buffer at
neutral pH containing 1 mM magnesium chloride and 15%
DMSO to improve substrate solubility. The conversion of 10 to
11 determined by NMR was 499% after 24 h.
In summary, thiamin analogs were used to prepare novel
mono thiazolium gold(I)-carbenes. The free NHC carbenes, gen-
Fig. 5 Hydroalkoxylation of allene 10 catalyzed by benzylthiazolium erated from the thiazolium salts in aqueous buffer, were found to
pyrophosphate gold(I)-carbene 7.
2
react directly and cleanly with (SMe )AuCl in a single step. The
resulting compounds—both with and without a pyrophosphate
moiety—were active catalysts for carbocyclization and hydro-
alkoxylation reactions. Because the pyrophosphate group of
TPP is essential for supramolecular anchoring of the cofactor
to thiamin-dependent enzymes, complexes between gold(I)-
carbene 7 and suitable host proteins could give rise to novel
gold-enabled biocatalysts.
We are grateful to Dr Nils Trapp and Michael Solar for help with
the X-ray crystal structures. This work was generously supported by
the Schweizerischer Nationalfonds and the ETH Z u¨ rich.
serves as a recognition handle for binding to enzyme active
sites. We anticipated that pyrophosphorylation would similarly
increase the solubility of the thiazolium gold(I)-carbene 5,
enabling homogeneous catalysis in aqueous media. Because
direct attempts to phosphorylate 5 failed, we first transformed
N-benzylthiazolium enzymatically into the corresponding pyro-
phosphate derivative (6) using ATP as the phosphate donor,
and then formed the gold(I)-carbene via a modification of the
procedure described above for 5 (Fig. 3A).
N-Benzylthiazolium (4) is readily accepted as a substrate by
thiamin pyrophosphokinase (TPPK, EC 2.7.6.2), the biosyn- Notes and references
1
9
thetic enzyme that converts vitamin B1 (2) into TPP (1). When
the biocatalytic reaction was performed with 1 mM purified
enzyme in aqueous buffer at 37 1C, product was obtained in
1
2
A. S. K. Hashmi, Angew. Chem., Int. Ed., 2005, 44, 6990–6993.
A. S. K. Hashmi, Gold Bull., 2004, 37, 51–65.
3 N. Marion and S. P. Nolan, Chem. Soc. Rev., 2008, 37, 1776–1782.
4
5
G. L. Hamilton, E. J. Kang, M. Mba and F. D. Toste, Science, 2007,
17, 496–499.
41% yield after purification by preparative HPLC. Precipitation
3
of the enzyme during the 6 h incubation may have limited the
yield of the biocatalytic conversion, so we immobilized the
N-Heterocyclic Carbenes in Transition Metal Catalysis, ed. F. Glorius,
Springer Berlin Heidelberg, 2007, vol. 21.
2
0,21
6 R. Kluger and K. Tittmann, Chem. Rev., 2008, 108, 1797–1833.
M. Pohl, G. A. Sprenger and M. M u¨ ller, Curr. Opin. Biotechnol., 2004,
5, 335–342.
biocatalyst in a silica sol–gel matrix.
Although the overall
7
yields did not improve, the immobilized pyrophosphokinase
could be reused multiple times, increasing overall efficiency. The
identity of the pyrophosphorylated product 6 was confirmed by
1
8 For a comprehensive review, see: J. C. Y. Lin, R. T. W. Huang,
C. S. Lee, A. Bhattacharyya, W. S. Hwang and I. J. B. Lin, Chem. Rev.,
2009, 109, 3561–3598.
1
13
31
LCMS, H-, C- and P-NMR spectroscopy, and X-ray crystallo-
graphy (see ESI,† Table S2).
9
R. Visbal, A. Laguna and M. C. Gimeno, Chem. Commun., 2013, 49,
5642–5644.
1
0 A. Collado, A. G o´ mez-Su ´a rez, A. R. Martin, A. M. Z. Slawin and
S. P. Nolan, Chem. Commun., 2013, 49, 5541–5543.
As observed for TPP, purple colloidal gold nanoparticles were
formed when we simply mixed compound 6 with (SMe )AuCl
2
11 A. Johnson and M. C. Gimeno, Chem. Commun., 2016, 52, 9664–9667.
under the conditions used to prepare 5. We therefore compensated 12 G. A. Fern ´a ndez, A. S. Picco, M. R. Ceol ´ı n, A. B. Chopa and
G. F. Silbestri, Organometallics, 2013, 32, 6315–6323.
3 H. Stetter, R. Y. R ¨a msch and H. Kuhlmann, Synthesis, 1976, 733–735.
4 H. Stetter and H. Kuhlmann, Org. React., 1991, 40, 407–496.
2
for the loss of (SMe )AuCl by supplementing the reaction with an
additional equivalent. When the transformation was complete as
1
1
judged by reversed-phase TLC and LCMS, the sample was purified 15 P. de Fr ´e mont, N. M. Scott, E. D. Stevens and S. P. Nolan, Organo-
metallics, 2005, 24, 2411–2418.
6 S. T. Staben, J. J. Kennedy-Smith and F. D. Toste, Angew. Chem., Int.
Ed., 2004, 43, 5350–5352.
by preparative HPLC. Under the HPLC conditions, three species
were obtained, one of which was the desired thiazolium gold(I)-
1
carbene chloride 7 (21% yield), the second, the more activated and 17 T. J. Brown, D. Weber, M. R. Gagn ´e and R. A. Widenhoefer, J. Am.
Chem. Soc., 2012, 134, 9134–9137.
8 Z. J. Wang, K. N. Clary, R. G. Bergman, K. N. Raymond and
F. D. Toste, Nat. Chem., 2013, 5, 100–103.
19 A. I. Voskoboyev and Y. M. Ostrovsky, Ann. N. Y. Acad. Sci., 1982, 161–176.
less stable gold(I)-carbene acetonitrile derivative (8%), and the
1
1
13
third, the bis-carbene (16%). The H- and C-NMR spectra of 7
resembled those of 5, including the absence of a signal for the C
proton on the thiazolium ring and a 50 ppm downfield shift of
2
2
0 D. T. Nguyen, M. Smit, B. Dunn and I. J. Zink, Chem. Mater., 2002,
4, 4300–4306.
1
13
the C signal from 155.27 ppm to 205.05 ppm for the carbene
2
1 H. Frenkel-Mullerad and D. Avnir, J. Am. Chem. Soc., 2005, 127,
carbon (Table 1). Like 5, compound 7 catalyzes the intramolecular
8077–8081.
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