The role of acetylides in dual gold catalysis: A mechanistic investigation of the selectivity difference in the naphthalene synthesis from diynes

Article abstract of DOI:10.1002/cctc.201300820

Under the conditions of dual activation catalysis with oxygen nucleophiles, β-substituted naphthalenes were obtained from 1,2-diethinyl arenes. Mechanistic studies, which include isotope labeling experiments, support that dual activation leads to β-substi

Full text of DOI:10.1002/cctc.201300820

CHEMCATCHEM
FULL PAPERS
DOI: 10.1002/cctc.201300820
The Role of Acetylides in Dual Gold Catalysis: A
Mechanistic Investigation of the Selectivity Difference in
the Naphthalene Synthesis from Diynes
Katharina Graf,[a] Philip D. Hindenberg,[a] Yusuke Tokimizu,[b] Saori Naoe,[b]
Matthias Rudolph,[a] Frank Rominger,[a] Hiroaki Ohno,[b] and A. Stephen K. Hashmi*[a, c]
Under the conditions of dual activation catalysis with oxygen
nucleophiles, b-substituted naphthalenes were obtained from
1,2-diethinyl arenes. Mechanistic studies, which include isotope
labeling experiments, support that dual activation leads to b-
substituted naphthalenes, whereas a-naphthalenes are formed
by p activation only, and no gold acetylide or dual activation is
involved in the formation of the a-substituted products. Addi-
tional experiments on substrates that led to dibenzopenta-
lenes support these mechanistic insights.
Introduction
Recently Zhang’s group[1] and
our group[2–6] reported on a new
reactivity pattern for gold-cata-
lyzed reactions in which two
gold fragments are used for sub-
strate activation. One cationic
gold fragment activates one p-
Scheme 1. Selectivity control of the hydroarylating cyclization.
bond of a diyne system, and the
other gold molecule activates
a second terminal alkyne by s-
coordination. This cooperation induces a cyclization that, de-
pendent on the connecting tether of the diyne system, delivers
carbene/vinylidene intermediates. These highly reactive inter-
mediates have already been used for a series of fruitful trans-
formations.[1–6]
tion of a benzene molecule, which was used as the reaction
solvent (Scheme 1).
Based on these findings, we were curious to see if we could
adapt this reaction to other nucleophiles.[7] We envisioned that
if stronger nucleophiles were used, it might be possible to per-
form the reaction in an inert solvent with only a slight excess
of the nucleophile.
In our first contribution on this topic, our group reported on
a gold-catalyzed hydroarylating aromatization reaction.[2] De-
pending on the reaction conditions, either a- or b-naphthalene
derivatives were formed from simple diyne 1 by the incorpora-
Results and Discussion
[a] K. Graf, P. D. Hindenberg, Dr. M. Rudolph, Dr. F. Rominger,+
Prof. Dr. A. S. K. Hashmi
To induce high b-selectivity, we applied s,p-dinuclear propyne
gold acetylides (dual activation catalysts; DACs) for our test re-
actions as these catalysts are ideal for dual activation catalysis
cycles.[8] As the test system, diyne 1 was used in combination
with varying equivalents of methanol as the nucleophile
(Table 1). Indeed it was possible to obtain a high b-selectivity
for all of the applied ratios of nucleophile to substrate. If the
amount of the protic nucleophile was higher than three equiv-
alents, the competing formation of minor amounts of the a-
substituted product was observed (entries 3–5). Next, we
varied the counterions of the DACs (Table 2). Only a minor
effect of the counterion was visible, but the tetrafluoroborate
counterion was the best choice, and a perfect b-selectivity was
observed for this counterion.
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)-6221-54-4205
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
[b] Y. Tokimizu, S. Naoe, Prof. H. Ohno
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
[c] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
[+] Crystallographic investigation
We chose 1,2-dichloroethane (DCE) as the solvent for this re-
action because many other solvents could be ruled out before-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300820.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 199 – 204 199

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
Table 1. Screening of the amount of nucleophile.
Table 3. Scope of the reaction.
Entry
Amount of MeOH
[equiv.]
Product yield [%][a]
a-Substituted b-Substituted (4a)
Entry
Product
Yield of b-substituted
product 4 [%][a]
t
1
2
3
4
5
1
3
5
10
50
0
20
44
39
40
29
traces
1
2
3
55
24
44
7 h
3 d
1 d
3
3
7
[a] Yields determined after 3 d by GC–MS with hexamethylbenzene as in-
ternal standard.
Table 2. Catalyst screening.
4
43
24 h
5
41
23
56 h
4 d
Entry
Counterion XÀ
Product yield [%][a]
a-Substituted b-Substituted (4a)
6[b]
À
1
2
3
4
5
6
SbF6
BF4
4
0
0
4
3
2
43
47
29
50
38
43
À
[a] Isolated yields. [b] The diester was used instead of the dimethyl sub-
strate.
OTsÀ
À
NNf2
À
PF6
À
NTf2
[a] Yields determined after 18 h by GC–MS with hexamethylbenzene as
internal standard.
hand. Benzene, acetone, 1,4-dioxane, THF, and even nonpolar
solvents such as cyclohexane and n-hexane reacted with the
substrate under the reaction conditions and were, therefore,
not suitable for this reaction. With the optimized conditions in
hand (three equivalents of the nucleophile in combination
with the tetrafluoroborate counterion), we turned our focus to
the evaluation of the substrate scope (Table 3).
Figure 1. Solid-state structure of 4c.
Based on our previous mechanistic investigation,[2] we pro-
pose the mechanism depicted in Scheme 2. The reaction is ini-
tiated by the transfer of the two gold fragments from the DAC.
The so-formed s,p-activated starting material I can then under-
go either a 5-endo-dig or a 6-endo-dig cyclization. Both of the
pathways are reasonable and depend on the starting material.
Both pathways have already been observed in the dual gold
catalysis of diynes.[6,10] In the case of the 5-endo-dig pathway,
vinylidene II would be formed that, after the attack of metha-
nol, would undergo a ring expansion to form the aurated
naphthyl methyl ether IV, which is in equilibrium with gem-dia-
urated species V. The same species could also be formed
through the 6-endo-dig pathway. In this case, after the initial
cyclization, a fast 1,2-shift of the gold delivers a stabilized car-
bene/cation VII/VIII.[11] The attack of methanol onto this spe-
cies delivers the naphthyl methyl ether intermediate IV. The
last step of the reaction cascade is catalyst transfer, which is
crucial as otherwise the b-selectivity would be lost (no acety-
lide would be formed for the next catalytic cycle).
The isolated yield of b-methoxy naphthalene 4a was only
moderate (entry 1). An even lower yield was obtained by using
phenol as a weaker nucleophile, which was accompanied by
an increased reaction time. Thus we reverted back to other ali-
phatic alcohols that delivered yields in the range of 40% re-
gardless if branched or linear alcohols were applied (entries 3–
5). If we changed the aromatic backbone, lower yields for the
substrate dimethyl 4,5-diethynylphthalate (5), which bears
electron-withdrawing ester moieties, were obtained (entry 6).
Unfortunately, the substrate scope was quite limited, and
amine derivatives (aniline, N-methylaniline, morpholine, and 1-
(p-tolylsulfonyl)pyrrole) and carbon-based nucleophiles (di-
methyl malonate) were not suitable for this transformation (for
details see the Supporting Information). To prove the selectivi-
ty obtained, crystals of 4c were grown that were suitable for
XRD analysis.[9] The molecular structure of the formed b-naph-
thol derivative 4c is depicted in Figure 1.
To support our mechanistic proposal we conducted a deute-
rium labeling experiment by using three equivalents of
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 199 – 204 200

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
Scheme 2. Mechanistic proposal.
um incorporation in the 4-position with respect to
the 1-position can be interpreted as a result of the
competing catalyst transfer step that causes a proto-
deauration by the H atom of the diyne starting mate-
rial.
Scheme 3. Deuterium labeling experiment.
During the preparation of this manuscript, the
group of Ohno reported on a cascade reaction of
diynes that bear one phenyl-substituted alkyne in combination
with a terminal alkyne. In their case, the exclusive formation of
the a-substituted product was observed by using an external
nucleophile (Scheme 4, top right).[12] This is completely in line
with our findings for the related hydroarylating aromatization,
[D4]MeOH as a the nucleophile (Scheme 3). Deuterium incorpo-
ration in the naphthalene backbone was exclusively found in
the 1- (73% D) and 4-positions (36% D). This result strongly
suggests that each or both pathways discussed in Scheme 2
can be involved. Deuterium incorporation in the 1-postion can
be explained by the nucleophilic
attack/protodeauration
step
from carbene/cation VII/VIII to
the aurated naphthyl methyl
ether IV if the reaction proceeds
by the 6-endo-dig pathway. If the
vinylidene pathway is favored,
the deuterium is incorporated
by the [D4]MeOH-induced ring-
expansion step from vinylidene
II to the aurated naphthyl
methyl ether IV. The deuterium
incorporation in the 4-position
results from a [D4]MeOH-mediat-
ed protodeauration of the aurat-
ed naphthyl methyl ether IV to
product 4a. The lower deuteri- Scheme 4. Results of Ohno et al. and Hashmi et al. for the catalytic conversion of 8 and 11.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 199 – 204 201

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
which was a-selective if no additive (a base or an organogold
species) was present.[2] However, there was a contradiction be-
tween the mechanistic proposal that was discussed for the for-
mation of the a-substituted product and other preceding
mechanistic insights. The authors speculate that for the forma-
tion of the a-substituted product an acetylide complex can be
the key intermediate. This assumption is based on an experi-
ment with gold acetylide 11 that was reported to deliver quan-
titative amounts of the a-substituted product 9a if catalytic
amounts of a cationic gold source were present (Scheme 4,
bottom right).[13] In addition, if Ohno et al. used a deuterated
alkyne and 10 equivalents of EtOH as the nucleophile, almost
a complete loss of deuterium was observed after the transfor-
mation, which was explained by an exchange process in which
the intermediate gold acetylide was reprotonated. The involve-
ment of an acetylide in the formation of the a-isomers is con-
tradictory to our observation as exclusively b-substituted prod-
ucts are formed if additives for acetylide formation are present
or if stoichiometric reactions that start from the preformed
acetylides are performed. Furthermore, with exactly the same
starting material in the absence of a nucleophile, our group
was able to obtain benzopentalenes 7 (Scheme 4, top left). In
addition, we could show that in this reaction gem-diaurated
benzopentalenes were formed if an acetylide was used as the
starting material in a stoichiometric experiment. For us it was
not understandable that the same acetylide could give the a-
substituted product in high yield. It seems clear that upon
dual activation, intramolecular trapping should be favored,
and, furthermore, in the case of an acetylide as the starting
material, we would expect a b-substituted product to be
formed if an external nucleophile could trap the intermediate.
With this in mind, we performed the reaction with acetylide
11 and N-methylaniline under exactly the same conditions as
those used by the Ohno group. In our experiment, we were
able to detect 65% of monoaurated benzopentalene 12 ac-
companied by only traces of the a-substituted product 9a (<
7%; even <3% if the reaction was performed in CH2Cl2 that
was saturated with water; Scheme 4). The fact that only traces
matization and the products are not derived from acetylides as
starting materials. Both the cyclization by the free acetylene
followed by a nucleophilic attack onto the so-formed aryl
cation or the formation of an enamine/enol ether intermediate
and a subsequent attack of the nucleophilic double bond onto
the second alkyne are reasonable. Nevertheless, still no precise
mechanistic picture exists for the formation of the a-substitut-
ed products.
As Ohno et al. used ethanol as the nucleophile for both their
screening reaction and most of their mechanistic investiga-
tions, we performed test reactions with this nucleophile too.
All their reported transformations were performed under an
Ar atmosphere, therefore, we assumed that dry conditions
(inert gas atmosphere, dry solvents, molecular sieves) were cru-
cial. At first we encountered problems in trying to reproduce
this reaction, but by variation of several parameters we found
that trace amounts of water in the reaction mixture are essen-
tial for this reaction mode. The next reactions were, therefore,
performed under air and without molecular sieves. First we re-
acted acetylide 11 with 2 mol% of IPrAuCl/AgOTf in the pres-
ence of 10 equivalents of ethanol. This gave monoaurated ben-
zopentalene species 12, the product also obtained with N-
methylaniline as the nucleophile (Scheme 4). The isolation of
12 in 58% yield was possible despite the fact that the product
was fairly unstable during column chromatography
(Scheme 5).
1
Scheme 5. Gold(I)-catalyzed conversion of 8 and 11.
of the a-substituted product can be seen in the H NMR spec-
trum of the crude material is clear evidence that gold acety-
lides are not involved in the formation of the a-substituted
product. Instead, if a gold acetylide is formed, direct trapping
of the intermediate vinylidene occurs and the outcome is the
expected benzopentalene product.
With the purified product in hand, single crystals suitable for
XRD analysis were obtained, which gave unambiguous proof
of the formation of the monoaurated benzopentalene
system.[9] Interestingly, two different modifications were ob-
tained in the solid state.[9] Both solid-state molecular structures
are depicted in Figure 3. In addition to the expected conformer
with an orthogonal alignment of the two ligands, a conformer
with all of the residues in one plane can be found in the other
modification. The superimposed structures document this phe-
nomenon well.
Indeed, only the a-substituted
product 9a can be obtained if the
reaction is performed in the ab-
sence of an acetylide and by using
N-methylaniline as the nucleophile.
When we reproduced the reaction,
we were able to obtain crystals
Next, both groups together re-investigated the assumption
of the Ohno group that the D/H exchange of the starting ma-
terial (which can be monitored during the course of the reac-
tion) and the accompanying loss of deuterium labeling in the
product allows us to conclude that a gold acetylide is involved
in the catalytic cycle. To evaluate if the acetylide can be proto-
demetalated, which would be crucial for H/D exchange, we
suitable for XRD analysis, and the
results deliver the final proof for
the a-substitution (Figure 2).[9] We
assume that in this case, the reac-
tion pathway is related to the a-
Figure 2. Solid-state structure
of 9a.
pathway of the hydroarylating aro-
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 199 – 204 202

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
Scheme 6. Reaction of 11 with ethanol.
tion with free active catalyst) in the presence of a strong nucle-
ophile that can deliver the a-substituted product through the
non-acetylide pathway. In the presence of EtOH as a weaker
nucleophile, hardly any a-substituted 9b was obtained
(Scheme 7c), although 30% of 13 was formed. Furthermore,
we subjected s,p-gem-diaurated phenylacetylene 14 (11 can
cyclize through activation of the second alkyne) to stoichio-
metric amounts of acid at 508C (Scheme 8). It is not unexpect-
ed that no protodeauration takes place in this case as there
are reports by Brown and Widenhofer who used exactly the re-
verse reaction for the preparation of s,p-gold complexes.[14]
No exchange could be monitored even at elevated tempera-
tures. This shows that in contrast to 11 no protodemetalation
is possible with s,p-gem-diaurated complexes. The reason for
the H/D exchange process reported by the Ohno group re-
mains unclear. Two options are reasonable. One could be the
direct H/D exchange via a gold p-coordinated alkyne, which in-
creases the acidity of the proton at the alkyne. On the other
hand, it is possible that an equilibrium between the free
Figure 3. Solid-state structure of 12.
heated acetylide 11 for 31 h at 508C but no traces of proto-
deauration were visible (Scheme 6). To exclude the involve-
ment of a terminal alkyne in the exchange process, the same
reaction was conducted in the presence of equimolar amounts
of phenylacetylene but again no exchange was observed.
As one might speculate that
a second Au atom or a strong
acid (which is indeed released
during acetylide formation if no
base is present) might be neces-
sary for an exchange process, we
subjected 11 to stoichiometric
amounts of acid (both in normal
CD2Cl2 and in CD2Cl2 that was sa-
turated with water; Scheme 7).
Indeed in all three cases the
formation of the digold species
13 was observed in yields up to
84% (referring to gold; yield de-
1
termined by H NMR spectrosco-
py), whereas free diyne 8 was
1
not seen in the H NMR spectra.
This indicated that the protode-
metalation of 11 is possible and
then in a subsequent reaction
13 is formed by the dual activa-
tion pathway. If the same reac-
Scheme 7. Reaction of 11 with HBF4 etherate.
tion was conducted in the pres-
ence of N-methylaniline as a po-
tential nucleophile, the forma-
tion of significant amounts of
the a-substituted product 9a
was observed (Scheme 7b). This
can be explained by the genera-
tion of free alkyne (in combina- Scheme 8. s,p-gem-Diaurated phenylacetylene 14 does not react with acid.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 199 – 204 203

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
Acknowledgements
The authors thank Umicore
AG&Co. KG for the generous don-
ation of gold salts.
Keywords: alcohols · alkynes ·
isotopic labeling · gold · reaction
mechanisms
[1] L. Ye, Y. Wang, D. H. Aue, L. Zhang,
J. Am. Chem. Soc. 2012, 134, 31–
34.
[2] A. S. K. Hashmi, I. Braun, M. Ru-
Scheme 9. Two possible pathways.
dolph, F. Rominger, Organometal-
lics 2012, 31, 644–661.
alkyne and the gold acetylide exists. This process is induced by
the acid that is generated if no additive is present. This indi-
cates that under the reaction conditions traces of acetylides
might be formed, but for the formation of the a-substituted
product the reverse reaction of the equilibrium must take
place, which releases the free alkyne that then undergoes cycli-
zation. In the presence of a dual catalyst or if one starts with
an acetylide and catalytic amounts of a gold catalyst no acid is
released and, therefore, the a-pathway is suppressed
(Scheme 9).
[3] A. S. K. Hashmi, M. Wieteck, I. Braun, P. Nçsel, L. Jongbloed, M. Rudolph,
F. Rominger, Adv. Synth. Catal. 2012, 354, 555–562.
[4] A. S. K. Hashmi, I. Braun, P. Nçsel, J. Schꢁdlich, M. Wieteck, M. Rudolph,
F. Rominger, Angew. Chem. 2012, 124, 4532–4536; Angew. Chem. Int. Ed.
2012, 51, 4456–4460.
[5] A. S. K. Hashmi, M. Wieteck, I. Braun, M. Rudolph, F. Rominger, Angew.
Chem. 2012, 124, 10785–10789; Angew. Chem. Int. Ed. 2012, 51, 10633–
10637.
[6] M. M. Hansmann, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew.
Chem. 2013, 125, 2653–2659; Angew. Chem. Int. Ed. 2013, 52, 2593–
2598.
[7] For Ru-catalyzed naphthalene syntheses from endiynes see: A. Odedra,
C.-J. Wu, T. B. Pratap, C.-W. Huang, Y.-F. Ran, R.-S. Lui, J. Am. Chem. Soc.
2005, 127, 3406–3412.
[8] A. S. K. Hashmi, T. Lauterbach, P. Nçsel, M. H. Vilhelmsen, M. Rudolph, F.
Rominger, Chem. Eur. J. 2013, 19, 1058–1065.
Conclusions
[9] CCDC 962802 (4c), CCDC 962803 (9a), CCDC 962804 (12, modification
1) and CCDC 962805 (12, modification 2) contain the supplementary
crystallographic 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.
[10] I. Braun, A. M. Asiri, A. S. K. Hashmi, ACS Catal. 2013, 3, 1902–1907.
[11] For the generation of carbenoid species from enediynes with Pt cata-
lysts see: B. P. Taduri, Y.-F. Ran, C.-W. Huang, R.-S. Liu, Org. Lett. 2006, 8,
883–886.
[12] S. Naoe, Y. Suzuki, K. Hirano, Y. Inabe, S. Oishi, N. Fujii, H. Ohno, J. Org.
Chem. 2012, 77, 4907–4916.
[13] Reinvestigation of the reaction (Scheme 4, bottom right) by the Ohno
group has now revealed that the reported yield (quantitative) should
be corrected to 10%. This correction will be reported in the near future.
[14] T. J. Brown, R. A. Widenhoefer, Organometallics 2011, 30, 6003–6009.
We have shown that b-substituted naphthalene systems can
be generated by a dual catalyzed gold reaction. The scope of
the reaction is limited and only oxygen nucleophiles were suit-
able. Although for this kind of transformation acetylides are as-
sumed to be key intermediates, we have shown that in the
gold(I)-catalyzed formation of a-substituted naphthalene deriv-
atives, which was previously reported by the Ohno group,
gold(I) acetylenes 11 as true intermediate structures are unlike-
ly. If 11 is formed, it follows the reaction mechanism to form
benzopentalenes as reported by the Hashmi group in previous
contributions. For the formation of the a-substituted product
9, free alkyne 8 is necessary in combination with free catalyst.
Even if acetylides are present in the reaction, the equilibrium
between free alkyne/cationic gold and acetylide/acid enables
an a-pathway if a strong nucleophile is present.
Received: September 26, 2013
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 199 – 204 204

Copyright of ChemCatChem is the property of Wiley-Blackwell and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.