Rational design of a gold carbene precursor complex for a catalytic cyclopropanation reaction

Article abstract of DOI:10.1002/anie.201209569

Bridging gas- and solution-phase chemistry: A gold(I) carbene precursor complex has been developed and investigated for catalytic cyclopropanation. Formation of the carbene intermediate was first probed by mass spectrometry, followed by cyclopropanation of p-methoxystyrene in solution. The imidazolylidene leaving group serves as a base generated in situ that is necessary in the putative catalytic cycle. Copyright

Full text of DOI:10.1002/anie.201209569

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Angewandte
Communications
DOI: 10.1002/anie.201209569
Gold Catalysis
Rational Design of a Gold Carbene Precursor Complex for a Catalytic
Cyclopropanation Reaction**
David H. Ringger and Peter Chen*
We report herein the rational design of an isolable gold
carbene precursor complex and its reactivity in stoichiometric
and catalytic cyclopropanation reactions. This work is another
example of combined gas- and solution-phase studies for the
rational discovery of new catalytic transformations.[1]
Cyclopropane motifs play a prominent role in chemistry
and biology, as they are present in natural products and are
found in biologically active compounds, such as pharmaceut-
ical agents.[2] Cyclopropanes are interesting building blocks
owing to their rigid structure and geometric similarities to
olefins.[3] The challenging formation of highly strained cyclo-
alkanes[4] can be accomplished using transition metals,[3,5]
including gold-promoted carbon–carbon bond-forming reac-
tions.[6] Most of these transformations presumably involve
a gold carbene exhibiting carbocationic character.[7]
Our group has recently reported the first example of the
mass spectrometric (ESI-MS/MS) detection of a cationic N-
heterocyclic carbene (NHC) gold(I) benzylidene complex,
generated from a phosphonium ylide.[8] Gas-phase character-
Scheme 1. Design, synthesis, and fragmentation of gold carbene
precursor 2.
ization experiments have shown that these carbenes cyclo-
propanate electron-rich olefins.[8,9] This reactivity was not
observed in solution under thermal conditions. This was
attributed to a too-slow formation of gold benzylidene
compared to other decay products, although the carbon–
phosphorus bond was the first bond to break under collision-
induced dissociation (CID) conditions in the gas phase.
Gai et al. have used sulfone-based compounds in nick-
el(II)-catalyzed cyclopropanation reactions. However, the
procedure requires slow addition of methyllithium to the
refluxing reaction mixture. This complicates the reaction
setup and limits the scope to base-tolerant olefins. Further-
more, the exact mechanism of these transformations and the
nature of the intermediates remain unresolved.[10] Other
Based on these findings, we envisioned that appropriate
modifications on the gold alkyl complex would give access to
an isolable gold(I) carbene precursor complex 2 (Scheme 1),
which would cyclopropanate olefins.[6a,12] The isolation of such
a gold carbene precursor complex would not only allow for
full characterization but also produce insights concerning the
nature of gold carbenes and their cyclopropanation reaction
mechanism.[7,13] Lastly, we sought to eliminate the need for
addition of stoichiometric amounts of a strong base.
We reasoned that an electron-rich NHC ligand[14] and
a methoxy substituent in the para position on the phenyl ring
would stabilize the carbocationic gold carbene 3 and thus
facilitate its formation. The SO2-imidazolium moiety acts as
a leaving group, which can dissociate to give SO2 and
imidazolylidene 6. The latter, produced in situ, serves as
a base to deprotonate another molecule of imidazolium
sulfone salt 1 in the putative catalytic cycle (Scheme 2).
Furthermore, the imidazolium moiety carries a charge,
making it possible to manipulate the gold carbene precursor
2 not only in solution, but also in the gas phase. The presence
of the SO2 moiety is crucial as it: 1) acidifies the a-position in
the imidazolium sulfone salt 1 owing to electronic stabiliza-
tion; and 2) leaves the reaction as a gas that does not interfere
reports have shown that sulfone and structurally similar
I
À
compounds are capable of ligating Ph3P Au to give stable
gold alkyl complexes.[11] The complexes were, however,
unreactive in cyclopropanation.
[*] D. H. Ringger, Prof. Dr. P. Chen
Laboratorium fꢀr Organische Chemie
Eidgençssische Technische Hochschule (ETH)
Zꢀrich (Switzerland)
E-mail: peter.chen@org.chem.ethz.ch
Homepage: http://www.chen.ethz.ch
[**] The support from ETH Zꢀrich and Swiss Nationalfonds is gratefully
acknowledged. We thank: Dr. Bernd Schweizer for the crystal
structure determination, Dr. Daniel Serra and Dr. Tim den Hartog
for useful discussions, and Armin Limacher and Dino Wu for
synthetic support.
with further steps.[15] The exact order of the C1 S1 and C2 S1
bond cleavage (Figure 1) is still unclear and could not be
determined through gas- or solution-phase experiments.
However, preliminary theoretical density functional theory
(DFT) calculations suggest that either both bonds are cleaved
À
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209569.
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mass spectrometry (ESI-MS/MS) on a Thermo-Finnigan TSQ
Quantum instrument.[17] CID of 2 gave two signals, the first
corresponding to gold carbene 3 (m/z 706),[8] generated by the
loss of imidazolylidene 6 and SO2. The second signal at m/z
906 appears to have been generated through the extrusion of
SO2 to give gold complex 4 (Table 1).[18] Such a rearrangement
was not observed in solution but has previously been
observed in the gas phase for organic sulfonamide com-
pounds.[19]
Table 1: Chemical behavior of gold carbene precursor 2 in the gas and
the solution phase.[a]
solvent
t [h]
T [8C]
7
yield [%][b]
cis/trans
Scheme 2. Proposed catalytic cycle of gold carbene precursor 2 in the
presence of imidazolium sulfone salt 1 and p-methoxystyrene. Triflate
ions are omitted for clarity. R=4-MeOC6H4, NHC=1,3-bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene.
1
2
3
4
5
6
7
8
MeCN
THF
3
3
3
120
120
120
120
100
80
99
96
99
99
87
79
88
63
5:1
14:1
14:1
14:1
12:1
11:1
19:1
9:1
C6H5Cl
CH2Cl2
CH2Cl2
CH2Cl2
toluene
hexane
3
16
16
3
120
120
3
[a] Reactions were conducted in pressurizable glassware and in the
presence of excess p-methoxystyrene. [b] Yields (by GC) relative to an
internal standard.
Heating gold carbene precursor 2 to 1208C in the
presence of p-methoxystyrene gave the expected cyclopro-
pane 7[6a,12] in up to 99% yield (Table 1). The reaction did not
exhibit strong solvent dependence and proceeded equally
well in a range of solvents at 1208C. The influence of the
observed 5:1 to 19:1 cis/trans selectivity in cyclopropane
formation warrants further studies, especially since a recently
published article shows an opposite trend of selectivity.[6a]
When a solution of 2 in the absence of p-methoxystyrene was
heated to 1208C, p-methoxybenzaldehyde along with other
products was detected but no homocoupling product (stil-
bene) was observed.
The formation of cyclopropane 7 in solution is an
indication that the desired gold carbene 3 was in fact
generated. We then turned our attention to the development
of a catalytic reaction (Scheme 2). The addition of gold
carbene precursor 2 to a solution of imidazolium sulfone salt
1 and p-methoxystyrene gives the desired cyclopropanation
product with up to 4.3 turnovers (Table 2), which is limited by
a side reaction (see below).
Figure 1. Structure of gold(I) carbene precursor 2 in the solid state.
Ellipsoids are set at 50% probability for all heavy atoms except for Au
(94% probability); hydrogen atoms (except H1) and the triflate ion are
omitted for clarity.[16]
À
simultaneously or the C1 S1 bond dissociates first, followed
À
by the dissociation of S1 C2.
The syntheses of imidazolium sulfone salt 1 and air-stable
gold carbene precursor 2 (93% yield) were facile. The X-ray
crystallographic structure of 2 (Figure 1) is consistent with
reported structures of related complexes.[11]
For further characterization and confirmation of the
formation of gold carbene 3, precursor 2 was analyzed in
the gas phase by means of electrospray ionization tandem
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Table 2: Gold-catalyzed cyclopropanation reaction and competitive
decay of imidazolium sulfone salt 1.[a]
imidazolium sulfone salt 1 allows for a catalytic cyclopropa-
nation reaction, which renders the addition of external base
unnecessary, albeit with only modest turnover at present. The
individual steps within the catalytic cycle were first probed in
the gas phase, and then incorporated into the solution phase
design. Further investigations concerning kinetics (to opti-
mize turnover), as well as DFT calculations of the reaction,
are underway.
Received: November 29, 2012
Revised: January 18, 2013
Published online: March 25, 2013
solvent t [h] 2/1
conversion into 7
TON[b,c] conv. [%][d] cis/trans [%]
8[e]
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
1.7
1.7
3.0
1.7
1.7
1.7
2.7
1:6
1:14
1:22
2.7
4.0
4.3
29
22
16
1
6
6
8:1
7:1
7:1
6:1
9:1
6:1
13:1
37
36
50
49
27
5
Keywords: carbenes · cyclopropanation · gas-phase reactions ·
gold · sulfones
.
1:112 2.6
1:15
1:12
1:7
1.8
1.6
1.7
MeCN
C6H5Cl
9
40
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presence of excess p-methoxystyrene. [b] Yields that form the basis of the
TON (by GC-FID) using internal standard. [c] TON: Turnover with
respect to 2. [d] Conversion of 1 into cyclopropane 7. [e] Yields (by GC) of
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The catalytic cycle only tolerated a narrow range of
solvents, CH2Cl2 being the solvent of choice (Table 2,
entries 1–4). MeCN and THF are less suitable owing to the
I
À
Lewis acidity of NHC Au , which might lead to the deacti-
vation of the gold cation. Nolan et al. have observed that
gold(I) activates THF towards a cationic ring opening and
subsequent polymerization.[20] Subjecting a reaction mixture
after 1.7 h to ESI-MS/MS revealed complete consumption of
1 and precursor 2 along with nearly exclusive formation of 9
and 10. This observation indicates that the rate-determining
step is likely to be formation of gold carbene 3, as complex
11[11b] was not observed, while deprotonation of 1 followed by
complexation to gold cation 5 is assumed to be rapid.
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I
À
absence of NHC Au , is the competitive decay of imidazo-
lium sulfone salt 1 to form olefin 8 thereby limiting the
turnover number. This reaction presumably proceeds by the
heterolytic formation of an oxonium species, which is trapped
by p-methoxystyrene, followed by deprotonation to form 8.[21]
Increasing the amount of 1 relative to gold carbene precursor
2 only increased the number of turnovers to a certain degree.
This is most likely due to an irreversible trapping of
imidazolylidene 6 by 5, which removes the base needed for
deprotonation in the catalytic cycle, as well as non-productive
deprotonation of the carbocation leading to 8, which we noted
above. Control experiments indicate that cyclopropane 7 and
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olefin 8 do not undergo rearrangement in the presence of
[13] D. Wang, R. Cai, S. Sharma, J. Jirak, S. K. Thummanapelli, N. G.
Akhmedov, H. Zhang, X. Liu, J. L. Petersen, X. Shi, J. Am.
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I
À
NHC Au at 1208C for 16 h. Under these conditions,
I
À
a solution of NHC Au in the presence of p-methoxystyrene
and 1 gave only the olefin product 8.
In conclusion, we have rationally designed a robust,
isolable, and well-defined gold carbene precursor 2, which is
capable of effecting cyclopropanation of p-methoxystyrene in
a range of different solvents at 1208C. The addition of
[15] Denk et al. have reported that some NHCs are capable of
À
forming a stable NHC SO2 adduct. However, we reasoned that
such an adduct is very unlikely to be stable at 1208C, namely the
temperature at which the cyclopropanation reactions in the
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present study are conducted (see: M. K. Denk, K. Hatano, A. J.
Lough, Eur. J. Inorg. Chem. 2003, 224 – 231).
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[20] S. P. Nolan, P. De Frꢁmont, Vol. US 7767841(B1), C01F1/00;
C07F1/12 ed., USA, 2008.
[21] A reaction vessel charged with 1 and p-methoxystyrene in
CH2Cl2 at 1208C for 2 h yields olefin 8 in 36–48% along with
[16] For a summary of crystallographic data, see the Supporting
Information. CCDC 928355 contains the supplementary crystal-
lographic 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.
[17] For instrument setup and spectra, see the Supporting Informa-
tion.
other polymerization products.
mechanism is provided in the Supporting Information.
A more detailed reaction
[18] For a more detailed discussion of the species at m/z 906, see the
Supporting Information.
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