Dual gold catalysis: Synthesis of polycyclic compounds via C-H insertion of gold vinylidenes

Article abstract of DOI:10.1002/chem.201404987

New and interesting polycyclic compounds have been synthesized from non-conjugated diyne systems by dual gold catalysis. A quaternary carbon center in the backbone and the accompanying Thorpe-Ingold effect enabled the unprecedented insertion of sp³ and sp² C-H bonds that for the first time were incorporated within the backbone of the diyne system and allowed the construction of complex polycyclic carbon scaffolds inaccessible by previous approaches in which the C-H bonds for the insertion were situated at the other end of the alkyne.

Full text of DOI:10.1002/chem.201404987

DOI: 10.1002/chem.201404987
Full Paper
&
Gold Catalysis
Dual Gold Catalysis: Synthesis of Polycyclic Compounds via CÀH
Insertion of Gold Vinylidenes
Marcel Wieteck,[a] Yusuke Tokimizu,[b] Matthias Rudolph,[a] Frank Rominger,[a]
Hiroaki Ohno,*[b] Nobutaka Fujii,*[b] and A. Stephen K. Hashmi*[a, c]
Abstract: New and interesting polycyclic compounds have
been synthesized from non-conjugated diyne systems by
dual gold catalysis. A quaternary carbon center in the back-
bone and the accompanying Thorpe–Ingold effect enabled
the unprecedented insertion of sp3 and sp2 CÀH bonds that
for the first time were incorporated within the backbone of
the diyne system and allowed the construction of complex
polycyclic carbon scaffolds inaccessible by previous ap-
proaches in which the CÀH bonds for the insertion were sit-
uated at the other end of the alkyne.
Introduction
In the field of gold catalysis,[1] the principle of dual activation[2]
has of late attracted much interest. Intra- and intermolecular
CÀH activation of substrates with 1,5-diyne substructures ren-
ders possible the synthesis of dibenzopentalenes, benzocyclo-
butenes, and thiophene-based annelated compounds.
Due to the highly electrophilic nature of carbene and vinyli-
dene intermediates that are accessible from these diyne sys-
tems in the presence of a gold catalyst,[2b] C(sp2)ÀH and even
C(sp3)ÀH activations of unactivated CÀH bonds are possible in
an intra- or intermolecular fashion, which presents a perfectly
atom-economical and fast access to polycyclic frameworks.[3] In
the case of intramolecular CÀH insertions, all of the substrates
used so far have reacted at a CÀH unit of the substituent at
the distal terminus of one of the alkynes (Scheme 1a). We now
considered that it also might be possible to apply starting ma-
terials incorporating CÀH units within the tether of the diyne
system (Scheme 1b),[4] which would allow the construction of
completely different organic frameworks by gold-catalyzed
CÀH activation.
Scheme 1. Diyne cyclization by dual catalysis: a) Known CÀH insertions
through substituents at the terminus; b) envisioned CÀH insertions through
substituents in the tether.
Results and Discussion
The work of Lin et al. on a gold-catalyzed cyclization of Ru–
acetylide 1 to form Ru–vinylidene 2 (Scheme 2a) inspired our
choice of test substrates. In the aforementioned case, a stable
ruthenium vinylidene could be isolated and be characterized
by X-ray crystal structure analysis, but with this stable type of
ruthenium vinylidene species, no further cyclization took
place.[5]
[a] M. Wieteck, Dr. M. Rudolph, Dr. F. Rominger,+ Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut, Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-54-4205
The high reactivity of gold vinylidenes should allow the de-
sired CÀH activation process. We therefore started with diyne
3 (Scheme 2b), which was already known to undergo the initial
cyclization step under the bimetallic conditions. Indeed with
s,p-propyne gold acetylide complex DAC-NTf2 (DAC=dual ac-
tivation catalyst),[6] a complete but unselective consumption of
the starting material 3 was detected (Scheme 2b). This result
can be explained by the presence of two non-equivalent termi-
nal alkynes with similar acidity, causing the formation of two
different gold acetylides. To solve this problem, substrate 4a,
in which one of the alkyne groups is blocked by an additional
methyl group, was used. Under the same reaction conditions,
the polycyclic product 5a was selectively formed in a good
E-mail: hashmi@hashmi.de
[b] Y. Tokimizu, Prof. Dr. H. Ohno, Prof. Dr. N. Fujii
Graduate School of Pharmaceutical Sciences, Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: hohno@pharm.kyoto-u.ac.jp
nfujii@pharm.kyoto-u.ac.jp
[c] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University, Jeddah 21589 (Saudi Arabia)
[+] Crystallographic investigation
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404987.
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Scheme 2. Initial explorative experiments.
yield (Scheme 2c). The tricyclic structure of the product was
confirmed by X-ray crystal structure analysis of 5a.[7]
To avoid competing insertions from the blocking substituent
on the alkyne, we focused on internal alkynes bearing methyl
groups. Firstly, one of the aryl groups at the quaternary center
was replaced by a proton (Scheme 2d, 6a) or by a methyl
group (6b). Neither group should be able to reach the vinyli-
dene center, so selective reactions were expected. However,
even after variation of the reaction conditions, decomposition
of the starting material was the only reaction observed. A plau-
sible explanation for the decomposition of the two diyne sub-
strates could be the low tendency to undergo the first cycliza-
tion step due to the reduced Thorpe–Ingold effect when com-
pared to 4a.
With substrate 7, bearing an additional ethyl group, an in-
separable 1:1 mixture of two compounds was isolated
(Scheme 3a). In addition to the expected product 8 resulting
from an attack of the vinylidene at the aryl group, the product
9 of a CÀH insertion at the ethyl group was also obtained
(total yield 46%). This CÀH insertion of the unactivated
C(sp3)ÀH bond of the ethyl moiety strongly indicates a pathway
including a vinylidene species as a high-energy intermediate,
which is known to be able to insert into C(sp3)ÀH bonds.[6]
Blocking the two aromatic ortho positions with fluorine sub-
stituents (10) enabled selective insertion at the ethyl moiety
and led to the formation of 11 albeit still in low yield
(Scheme 3b).
Scheme 3. Selectivity in unsymmetrical substrates.
aryl group. A selective C(sp3)ÀH activation took place and the
bicyclic product 13 was isolated in an excellent yield as
a single diastereomer (Scheme 3c). Neither a product contain-
ing a six-membered ring (derived from C(sp3)ÀH activation of
the methyl group in the propyl chain) nor the product of
a C(sp2)ÀH activation of the aromatic system was detected.
Next, we evaluated the selective generation of six-mem-
bered rings to extend the scope of this new gold-catalyzed
transformation. With a benzylic moiety in the backbone, a se-
lective attack of the vinylidene center at the arene of the
benzyl group took place, which created the desired fused six-
membered central ring in the polycycle 15 in high selectivity
(even though the competing aryl group bears an activating
methoxy group) and a short reaction time of only 15 min
(Scheme 3d). The connectivity of the tricyclic moiety could be
verified by an X-ray single crystal structure analysis.[7] This
result can be explained by the increased flexibility of the
benzyl group which facilitates the attack of the electrophilic
vinylidene carbon.
With test substrate 14, we carried out a screening of the re-
action conditions (Table 1). A solvent screening revealed that
only toluene and 1,2-dichloroethane are suitable solvents for
the catalysis, both showing comparable reaction rates. Howev-
A completely selective transformation occurred in the reac-
tion with diyne 12, bearing a propyl group and an activated
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Table 1. Catalyst screening.
Table 2. Substrate scope for the synthesis of compounds 17.
Entry
Catalyst
Yield [%]
Time [h]
1
2
3
4
5
6
7
8
DAC-NTf2
[IPrAuNTf2]
80
79
1
12
48
48
24
2
5
4
3
1
[Ph3PAuNTf2]
[PhXPhosAuNTf2]
[(Cy)3PAuNTf2]
[SPhosAuNTf2]
[XPhosAuNTf2]
[MorDalPhosAuNTf2]
[PhDavePhosAuNTf2]
DAC-SbF6
incomplete
incomplete
70
65
65
78
79
87[a]
86
79
87
Entry
R
R1
R2
Product (Yield [%])
9
10
11
12
13
1
2
3
4
5
6
7
8
9
OMe
Me
F
OMe
Me
F
OMe
Me
F
H
H
H
Me
Me
Me
H
H
H
H
H
H
17a (87)
17b (89)
17c (75)
17d (88)
17e (83)
17f (85)
17g (83)
17h (60)
17i (99)
DAC-BF4
DAC-OTs
DAC-PF6
1
1
0.25
All reactions were carried at 808C using 200 mm concentration of the
substrate and 5 mol% of DAC catalysts or 10 mol% of the monomeric
gold catalysts in anhydrous toluene. The products were isolated and puri-
fied by flash column chromatography. [a] The product contained traces of
H
Me
Me
Me
H
H
impurities.
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl,
MorDal-
XPhos=2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl,
Phos=di(1-adamantyl)-2-morpholinophenylphosphine, PhDavePhos=2-
dicyclohexylphosphino-2’-(N,N-dimethylamino)biphenyl
Table 3. Substrate scope for the synthesis of compounds 5.
er, toluene furnished slightly higher yields. As expected, com-
pared to the corresponding monomeric gold catalyst
[IPrAuNTf2], the dual activation catalyst DAC-NTf2 shortened
the reaction time from overnight to one hour (Table 1, en-
tries 1 and 2). A test series with different phosphine ligands at
the gold center showed that selected Buchwald-type ligands
also provide suitable catalysts (Table 1, entries 5–9). Acceptable
yields were obtained for all of the phosphine ligands except
for complexes [Ph3PAuNTf2] (entry 3) and [PhXPhosAuNTf2]
(entry 4), both of which gave incomplete conversions. As faster
reaction times were observed for the DAC-NTf2, an additional
screening of the counterions was conducted with this catalyst
type in combination with the IPr ligand (as the synthesis of the
DAC is more efficient with this ligand than with Buchwald-type
ligands). The effect of the counterion of the DACs on the yield
was low (Table 1, entries 10–13), but the reaction rate was
faster for the hexafluorophosphate counterion than those of
others (entry 13); therefore DAC-PF6 was selected as the opti-
mal catalyst for the subsequent reactions.
Entry
R
Product (Yield [%])
1
2
3
4
5
H
Me
tBu
OMe
F
5a (73)
5b (78)
5c (62)
5d (68)
5e (20)
6
5f (40)
Next, the conversion of several diynes leading to six-mem-
bered products was investigated (Table 2). All of the reactions
ran to completion within 15 min, with yields up to 99%. At the
additional benzene moiety that was introduced in order to in-
crease the Thorpe–Ingold effect, a broad variation of substitu-
tion patterns was tolerated. For all substrates the yields were
high, no matter whether a methoxy, alkyl, or fluoro substituent
was attached (Table 2, entries 1–6). An additional methyl group
in the benzyl position had no influence on the catalysis and no
competing C(sp3)ÀH insertion took place (Table 2, entries 7–9).
NOE-experiments and an X-ray structure analysis (17i)[7] were
carried out to confirm the relative configurations of the stereo-
centers in the molecule.
tion conditions (Table 3). In general, yields were lower and re-
action rates were slower than those for the catalysis providing
the six-membered ring systems. An additional methyl group in
para-position of the benzene system gave a slightly higher
yield than the unsubstituted analogue (Table 3, entries 1 and
2). A tert-butyl group in the same position led to a slightly
lower yield (Table 3, entry 3) and the same was the case for
a methoxy group in the para-position of the aromatic moiety,
despite its electron-donating properties (entry 4). Not unex-
pectedly, a drop in yield was observed with substrate 4e bear-
ing the electron-withdrawing fluorine substituents on the
phenyl groups (Table 3, entry 5). Substrate 4 f, bearing hetero-
aromatic thiophenyl groups, could also be converted, albeit in
a moderate yield (Table 3, entry 6).
As a next step, we converted several symmetric diynes to
the corresponding tricyclic products under the optimized reac-
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formation of gold vinylidene IV, nucleophilic attack by one of
the phenyl groups delivers the final product.
Table 4. Substrate scope for the synthesis of compounds 19.
The first experiment that suggested the vinylidene pathway
involved the use of stoichiometric amounts of gold. After treat-
ment of gold acetylide 20 with one equivalent of [IPrAuNTf2],
the gem-diaurated[8] compound 21 was isolated (Scheme 6a;
the product was also characterized by X-ray crystal structure
analysis).[7] Next we carried out labeling experiments, which led
to the same conclusion (Scheme 6b). In the first labeling ex-
periment, the deuterated terminal alkyne 4a-(d1) was convert-
ed with 5 mol% of DAC-NTf2 and the deuterium ended up in
the same position the gold catalyst was located after the
second cyclization step. Addition of D2O increased the level of
deuteration up to 100%. This result is in complete accordance
with the previously reported dual catalysis via gold vinyli-
Entry
R
R’
Product (Yield [%])
1
2
3
4
5
OMe
Me
F
OMe
F
Me
Me
Me
nHex
nHex
19a (92)
19b (92)
19c (74)
19d (95)
19e (85)
Table 4 summarizes the expan-
sion of the substrate scope for
alkyl-substituted diynes leading
to five-membered bicycles. In all
cases, the yields were good to
excellent (up to 95%). Both elec-
tron-donating and electron-with-
drawing groups in the arene
moiety were tolerated (Table 4,
entries 1–3). Although the con-
version of diynes containing
a propyl moiety was highly se-
lective, traces of a byproduct
could be detected for the cycli-
zation of the analogous sub-
strates bearing an octyl moiety
(Table 4, entries 4 and 5). In the
Scheme 5. Mechanistic considerations.
case of 18 f, bearing the neopentyl group, only an attack of
a CH3 group is possible, which led to the six-membered prod-
uct 19 f in good yield (Scheme 4).
Mechanistic Studies
Next we studied the mechanism of the reaction (Scheme 5).
Two pathways are plausible for the formation of the polycyclic
compound 5a. Pathway A includes a gold-catalyzed 5-endo-dig
hydroarylation followed by a subsequent 5-endo-dig cyclization
step. Pathway B describes a dual-catalyzed process. After the
Scheme 4. CÀH insertion at the g-position to the quaternary center for neo-
pentyl substrate 18 f.
Scheme 6. Mechanistic experiments.
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Scheme 7. Catalytic cycle for the formation of XII.
Acknowledgements
denes; the deuterium can be found in the same position as
the gold fragment prior to the catalyst transfer step. These ex-
periments can rule out the non-vinylidene pathway A, as in
this case the deuterium would be positioned at the other
double bond. However, not even trace amounts of deuterium
could be detected at this position by NMR spectroscopy. The
conversion of diyne 4a-(d10), with two fully deuterated phenyl
groups, led to the expected deuterium distribution in which
the labeling was located at the former vinylidene carbon
(Scheme 6c).
The authors thank Umicore AG & Co. KG for the generous
donation of gold salts. Y.T. is grateful to the Strategic Young
Researcher Overseas Visits Program for Accelerating Brain Cir-
culation as well as Research Fellowships for Young Scientists
from the Japan Society for the Promotion of Science (JSPS).
Keywords: alkynes · CÀH insertion · gold · vinylidene ligands ·
polycycles
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The above results suggest a detailed mechanism that fully cor-
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Published online on && &&, 0000
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FULL PAPER
&
Gold Catalysis
M. Wieteck, Y. Tokimizu, M. Rudolph,
F. Rominger, H. Ohno,* N. Fujii,*
A. S. K. Hashmi*
&& – &&
Dual Gold Catalysis: Synthesis of
Polycyclic Compounds via CÀH
Insertion of Gold Vinylidenes
In dual activation gold catalysis, intra-
molecular competition experiments
show a clear selectivity, with alkyl CÀH
activation preferred to aryl CÀH activa-
tion. This principle can be used for re-
gioselective annelation reactions utiliz-
ing even normal, unactivated alkyl side-
chains as “reactive” groups for synthesis
of polycyclic compounds from non-con-
jugated diynes.
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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