A Gold(I)-Catalyzed Domino Coupling of Alcohols with Allenes Enables the Synthesis of Highly Substituted Indenes

Article abstract of DOI:10.1002/chem.201603154

The reaction of aryl-substituted allenes with alcohols under gold catalysis led to highly substituted indenes in good yields, with low catalyst loading and under mild conditions. During this domino transformation, two C?C bonds are formed with water as the only byproduct.

Full text of DOI:10.1002/chem.201603154

DOI: 10.1002/chem.201603154
Communication
&
Gold Catalysis
A Gold(I)-Catalyzed Domino Coupling of Alcohols with Allenes
Enables the Synthesis of Highly Substituted Indenes
Alexander Preinfalk, Antonio Misale, and Nuno Maulide*[a]
Chem. Eur. J. 2016, 22, 1 – 7
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we present our results on the development of a domino gold-
catalyzed CÀC coupling process.
Abstract: The reaction of aryl-substituted allenes with al-
cohols under gold catalysis led to highly substituted in-
denes in good yields, with low catalyst loading and under
mild conditions. During this domino transformation, two
CÀC bonds are formed with water as the only byproduct.
At the onset of our investigations, allene 1 and allylic alcohol
2 were selected as model substrates. Initial attempts to carry
out the domino cyclization/CÀC coupling focused on using
10 mol% of JohnPhosAu(MeCN)SbF6 (A) and potassium car-
bonate as base. These conditions led to the desired product in
only 4% NMR-yield (Table 1, entry 1). A subsequent screening
Polysubstituted indene derivatives are particularly important
bicyclic scaffolds.[1,2] Many of these form the core of biological-
ly relevant substances, including antitumor, antiallergic, herbi-
cidal, fungicidal, and antimicrobial compounds.[3,4a–j] Besides
that, indenes are also prevalent in materials science and as
ligand precursors in homogeneous catalysis.[1,5a–c]
Table 1. Table 1. Selected examples for the optimization of the reaction
conditions.
Among the many methods reported for the synthesis of
these compounds, one of the most important approaches is
based on intramolecular Friedel–Crafts-type reactions.[2,6,7a–n] In
a recent example,[7h] Toullec and co-workers reported the N-io-
dosuccinimide(NIS)-induced cyclization of allenes leading to
substituted 2-iodoindenes (Scheme 1a), which can then be fur-
ther functionalized.
Entry Catalyst
Solvent Base
T
Conversion Yield
[8C], t
[%][b]
[%][c]
1
2
3
4
A
A
A
A
A
toluene K2CO3 110, 60 h
THF K2CO3 50, 15 h
1,2-DCE K2CO3 50, 15 h
9
4
16
66
71
100
100
100
100
100
100
15
65
58
65
CHCl3
DCM
K2CO3 61, 15 h
K2CO3 40, 15 h
5
[h]
6
A/ AgNTf2 toluene K2CO3 50, 60 h
-
-
7[d]
8[e]
9[e,f]
10[e,g]
11
AgNTf2
A
A
A
DCM
DCM
DCM
DCM
DCM
K2CO3 40, 16 h
[h]
–
–
–
–
23, 5 min
23, 5 min
23, 5 min
100
99
95 (84[i])
9
p-TsOH
23, 10 min 100
[a] Reactions were carried out under anhydrous conditions (1a/2a/cata-
lyst 1:2:0.1). [b] Determined by 1H NMR analysis of the crude reaction
1
mixture. [c] Determined by H NMR analysis of the crude reaction mixture
using 1,3,5-trimethylbenzene as internal standard. [d] Performed in ab-
sence of a gold catalyst. [e] Reaction was carried out under ambient con-
ditions. [f] Reaction was carried out using 1.1 equivalents of alcohol. [g]
Reaction was carried out using 1.1 equivalents of alcohol and 1 mol%
catalyst. [h] Decomposition. [i] Isolated yield after purification. A=John-
PhosAu(MeCN)SbF6.
of various solvents revealed that dichloromethane allowed an
increase in yield up to 65% (Table 1, entries 2–5). To investigate
the potential role of silver salts in this transformation, AgNTf2
was added to the reaction mixture. This always led to decom-
position (Table 1, entries 6 and 7).[10] Interestingly, in the ab-
sence of the base, the reaction displayed a faster and cleaner
profile, affording the desired product quantitatively within five
minutes at room temperature (Table 1, entry 8). Further at-
tempts to lower the amount of allylic alcohol and catalyst
loading had almost no effect on the reaction outcome (Table 1,
entries 9 and 10).
Scheme 1. a) Electrophilic activation of arylallenes leading to 2-iodoindenes.
b) a-allylation of enals and enones. c) Proposed pathway towards allyl- and
benzhydryl-substituted indenes.
Inspired by a report by Bandini and co-workers[8a] on the
gold-assisted a-allylation of enals and enones using an allen-
amide as precursor (Scheme 1b), we envisioned a synthetic
route in which an aryl-substituted allene reacts with an alcohol
to undergo a domino CÀC coupling sequence.[8b,9a–e] Such a re-
action would form two CÀC bonds in inter- and intramolecular
fashion, and therefore lead to highly substituted indenes in
a single step with water as the only reaction byproduct. Herein
Notably, the use of p-TsOH as catalyst led mainly to decom-
position, while only 9% NMR-yield of desired product was ob-
served (Table 1, entry 11).
[a] A. Preinfalk, Dr. A. Misale, Prof. Dr. N. Maulide
Faculty of Chemistry, Institute of Organic Chemistry, University of Vienna
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
With the optimized conditions in hand, we investigated the
scope of this transformation. The reaction proceeded smoothly
with a variety of different allenes. Notably, all reactions were
run open to air and pre-drying of the solvent was not required.
From Scheme 2 it can be seen how electron-neutral and -rich
E-mail: nuno.maulide@univie.ac.at
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201603154.
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aromatic systems afforded the desired products in good to ex-
cellent yields (3a–3 f). Pleasingly, the reactions of 1e and 1 f
afforded selectively only one regioisomer, 3e and 3 f, respec-
tively. This coupling also tolerates allyl (3g), as well as linear
(3a), branched (3h), and cyclic (3i) aliphatic substituents on
the a-position of the allene. On the g-position, mono- and dis-
ubstituted allenes afforded the corresponding products in ex-
cellent yields (3k and 3l). Terminal allene 1j also led to the de-
sired product 3j in moderate yield and after a slightly longer
reaction time.
Scheme 3. Substrate scope for the domino CÀC coupling of differently sub-
stituted allenes with benzhydrol.
Changing the nature of the substituent at the a-carbon of the
allene (R ’ ’ in Scheme 4) led to longer reaction times, but af-
forded products 6b and 6c in excellent yields. Disubstitution
on the terminal position of the allene showed almost no effect
on the reaction time and indene 6d was obtained in 81%
yield. Importantly, attempts at promoting this transformation
employing Brønsted acid catalysis led to extensive decomposi-
tion of the allene substrate.
Scheme 2. Substrate scope of the CÀC domino coupling reaction.
Furthermore we found that allene 1 can also react with
benzhydrol to deliver the corresponding benzylated products
5 (Scheme 3). The reaction proceeded smoothly with our
model substrate, giving 5a in excellent yield. However, this
transformation appears less facile than the one involving the
allylic alcohol 2a, as reflected by the longer reaction times and
slightly lower yields. The less activated substrates give prod-
ucts 5b and 5 f in good yields. A longer aliphatic chain at the
g-position of the allene leads to a clean reaction and 5d is ob-
tained in 75% yield. Interestingly, more electron-rich allenes
gave the desired products (5c, 5e, and 5g) in moderate yields.
Given the latter observation, we were naturally drawn to
briefly examine the gold-catalyzed cyclization leading to
simple indenes 6. Interestingly, this transformation needed
slightly different conditions and careful control of reaction
time to avoid isomerization of the double bond towards the
exocyclic isomer.[11] To our delight (Scheme 4), subjecting
model-allene 1a to the optimized conditions resulted in a very
clean reaction and gave indene 6a in 90% isolated yield.
Scheme 4. Gold-catalyzed cyclization of allenes to indenes.
Further experiments to investigate the mechanism of the re-
action were carried out employing the allenes in the presence
of activated alcohols. Firstly, as also observed by the Bandini
group,[8a,b] we wanted to clarify the role of allylic ether I, which
is a typical byproduct of the gold-catalyzed allylation reaction.
Premixing of allylic alcohol 2a and gold catalyst A in CD2Cl2 re-
sulted in an equilibrium ratio of alcohol 2a : ether I of 1:6.7.
Adding allene 1a to this mixture gave the corresponding prod-
uct 3a in the same yield as the original reaction (vide supra),
but with a significantly longer reaction time (Scheme 5a). This
strongly suggests that ether I is not an intermediate of the cat-
alytic cycle, but rather a byproduct reversibly formed during
the reaction.
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Scheme 5. Preliminary mechanistic investigations.
We then prepared allylic alcohols 2b and 2c. Upon reaction
with allene 1a both led to the same product 3m, as confirmed
by NMR analysis (see the Supporting Information, NOESY ex-
periment) (Scheme 5b). Since the CÀC bond formation occurs
selectively at the position where benzylic stabilization is high-
est, this result is suggestive of a cationic pathway via activation
of the allylic alcohol by the gold catalyst.
nied by allene activation which, upon cyclization, forms an in-
termediate vinyl gold species. Combination of the latter spe-
cies with the carbocationic intermediate then forms the prod-
uct (Scheme 6, Pathway b).[12,13] At this point it is not possible
to rule out any of the two pathways. However, the failure of
simple Brønsted acids to efficiently promote the reaction
would appear to favor pathway b.
We can rationalize these observations according to two pos-
sible pathways, both relying on the formation of an allylic car-
bocation. One possible pathway is the direct capture of the
carbocation by the allene, which, in this case, would act as the
nucleophile, forming another allylic carbocation. Friedel–Crafts
cyclization then leads to the final product (Scheme 6, Pathway
a). The second possibility would be a synergistic catalytic trans-
formation with two cycles. Gold-catalyzed activation of the al-
lylic alcohol to form the carbocation intermediate is accompa-
In summary, we have presented an atom-economical, gold-
catalyzed domino CÀC coupling of aryl-substituted allenes and
activated alcohols. The corresponding substituted indenes
were obtained in good yields, with low catalyst loadings and
under mild conditions. Notably, these reactions proceed with-
out a need for exclusion of air or pre-drying of the solvent.
The cyclization of aryl-substituted allenes using gold catalysis
was also achieved, and preliminary mechanistic evidence in
favor of carbocationic intermediates was obtained.
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Scheme 6. Plausible mechanistic scenarios.
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gam, P. Rajasingh, Chem. Lett. 2005, 34, 1494–1495; d) D. H. Dethe, G.
Murhade, Org. Lett. 2013, 15, 429–431; e) S. Ma, Acc. Chem. Res. 2009,
42, 1679–1688; f) X. Zhang, W. T. Teo, W. Rao, D.-L. Ma, C.-H. Leung,
P. W. H. Chan, Tetrahedron Lett. 2014, 55, 3881–3884; g) S. Yamazaki, Y.
Yamamoto, Y. Fukushima, M. Takebayashi, T. Ukai, Y. Mikata, J. Org.
Chem. 2010, 75, 5216–5222; h) C. Grandclaudon, V. Michelet, P. Y. Toul-
lec, Org. Lett. 2016, 18, 676–679; i) B. V. S. Reddy, B. B. Reddy, K. V. R.
Rao, J. S. Yadav, Tetrahedron Lett. 2010, 51, 5697–5700; j) C. M. Sousa, J.
Berthet, S. Delbaere, P. J. Coelho, J. Org. Chem. 2014, 79, 5781–5786;
k) M. Egi, K. Shimizu, M. Kamiya, Y. Ota, S. Akai, Chem. Commun. 2015,
51, 380–383; l) D. Eom, S. Park, Y. Park, T. Ryu, P. H. Lee, Org. Lett. 2012,
14, 5392–5395; m) X. Sun, K.-J. Izumi, C.-Q. Hu, G.-Q. Lin, Chin. J. Chem.
2006, 24, 430–434; n) N. Marion, S. Dꢄez-Gonzꢅlez, P. de Frꢆmont, A. R.
Noble, S. P. Nolan, Angew. Chem. Int. Ed. 2006, 45, 3647–3650; Angew.
Chem. 2006, 118, 3729–3732.
Acknowledgements
We are grateful to the University of Vienna and the European
Research Council (ERC StG 278872) for generous financial sup-
port. Ing. E. Macoratti and Dr. H. Kꢁhlig (University of Vienna)
are gratefully acknowledged for expert assistance with chroma-
tographic purification and NMR analysis.
Keywords: alcohols
catalysis · indenes
· allenes · domino coupling · gold
[1] T. D. Lash, Acc. Chem. Res. 2016, 49, 471–482.
[8] a) M. M. Mastandrea, N. Mellonie, P. Giacinto, A. Collado, S. P. Nolan, G. P.
Miscione, A. Bottoni, M. Bandini, Angew. Chem. Int. Ed. 2015, 54, 14885–
14889; Angew. Chem. 2015, 127, 15098–15102; b) E. Manoni, M. Daka,
M. M. Mastandrea, A. De Nisi, M. Monari, M. Bandini, Adv. Synth. Catal.
2016, 358, 1404–1409.
[9] a) P. H. S. Paioti, A. Aponick, in Homogeneous Gold Catalysis (Ed.: M. L.
Slaughter), Springer International Publishing, Cham, 2015, pp. 63–94;
b) J. Muzart, Tetrahedron 2008, 64, 5815–5849; c) B. Biannic, A. Aponick,
Eur. J. Org. Chem. 2011, 6605–6617; d) M. Bandini, Chem. Soc. Rev. 2011,
40, 1358–1367; e) A. Quintavalla, M. Bandini, ChemCatChem 2016, 8,
1437–1453.
[10] The use of silver alone as promoter did not lead to cyclization. See the
Supporting Information for details.
[11] For optimization of the reaction conditions, see the Supporting Infor-
mation.
[12] For the reactivity of NHC-Au-OH complexes, see: a) S. Gaillard, A. M. Z.
Slawin, S. P. Nolan, Chem. Commun. 2010, 46, 2742–2744; b) R. S.
Ramon, N. Marion, S. P. Nolan, Tetrahedron 2009, 65, 1767–1773; c) N.
Marion, P. Carlqvist, R. Gealageas, P. de Fremont, F. Maseras, S. P. Nolan,
Chem. Eur. J. 2007, 13, 6437–6451.
[2] B. Gabriele, R. Mancuso, L. Veltri, Chem. Eur. J. 2016, 22, 5056–5094.
[3] J. W. Huffman, L. W. Padgett, Curr. Med. Chem. 2005, 12, 1395–1411.
[4] For selected, more recent examples, see: a) J. Banothu, S. Basavoju, R.
Bavantula, J. Heterocycl. Chem. 2015, 52, 853–860; b) H. S. El-Sheshtawy,
A. M. Abou Baker, J. Mol. Struct. 2014, 1067, 225–232; c) A. K. Kahlon,
A. S. Negi, R. Kumari, K. K. Srivastava, S. Kumar, M. P. Darokar, A. Sharma,
Appl. Microbiol. Biotechnol. 2014, 98, 2041–2051; d) M. A. Norrgꢂrd, B.
Mannervik, J. Mol. Biol. 2011, 412, 111–120; e) D. Chanda, D. Saikia, J. K.
Kumar, J. P. Thakur, J. Agarwal, C. S. Chanotiya, K. Shanker, A. S. Negi,
Bioorg. Med. Chem. Lett. 2011, 21, 3966–3969; f) C. Huang, W. J. Moree,
S. Zamani-Kord, B.-F. Li, F. C. Tucci, S. Malany, J. Wen, H. Wang, S. R. J.
Hoare, C. Yang, A. Madan, P. D. Crowe, G. Beaton, Bioorg. Med. Chem.
Lett. 2011, 21, 947–951; g) S. Tu, L.-H. Xu, L.-Y. Ye, X. Wang, Y. Sha, Z.-Y.
Xiao, J. Agric. Food Chem. 2008, 56, 5247–5253; h) E. Alcalde, N. Mes-
quida, J. Frigola, S. Lopez-Perez, R. Merce, Org. Biomol. Chem. 2008, 6,
3795–3810; i) J. H. Ahn, M. S. Shin, S. H. Jung, J. A. Kim, H. M. Kim, S. H.
Kim, S. K. Kang, K. R. Kim, S. D. Rhee, S. D. Park, J. M. Lee, J. H. Lee, H. G.
Cheon, S. S. Kim, Bioorg. Med. Chem. Lett. 2007, 17, 5239–5244; j) M.
Voets, I. Antes, C. Scherer, U. Mꢃller-Vieira, K. Biemel, S. Marchais-Ober-
winkler, R. W. Hartmann, J. Med. Chem. 2006, 49, 2222–2231.
[13] The reaction of isolated indene 6a with allylic alcohol 2a was carried
out under the conditions of Table 1, entry 5 and did not lead to product
formation.
[5] a) Y. Li, Acc. Chem. Res. 2012, 45, 723–733; b) M. Stradiotto, M. J.
McGlinchey, Coord. Chem. Rev. 2001, 219–221, 311–378; c) J. M.
O’Connor, C. P. Casey, Chem. Rev. 1987, 87, 307–318.
[6] E. Markus, W. B. Robert, Curr. Org. Chem. 2006, 10, 937–953.
[7] For selected examples on the synthesis of indenes, see: a) S. Guo, Y. Liu,
Org. Biomol. Chem. 2008, 6, 2064–2070; b) J. Wang, L. Zhang, Y. Jing, W.
Huang, X. Zhou, Tetrahedron Lett. 2009, 50, 4978–4982; c) P. Shanmu-
Received: July 1, 2016
Published online on && &&, 0000
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COMMUNICATION
&
Gold Catalysis
A. Preinfalk, A. Misale, N. Maulide*
&& – &&
A Gold(I)-Catalyzed Domino Coupling
of Alcohols with Allenes Enables the
Synthesis of Highly Substituted
Indenes
Highly substituted indenes were ob-
tained in good yields, with low catalyst
loading and under mild conditions from
the reaction of aryl-substituted allenes
with alcohols under gold catalysis.
During this domino transformation, two
CÀC bonds are formed with water as
the only byproduct.
Gold Catalysis
The domino coupling of alcohols with allenes is reported by
N. Maulide et al. in their Communication in page &&. In
this transformation, a gold catalyst orchestrates the
sequential cyclisation and CÀC coupling of aromatic allenes
and benzylic alcohols to generate indene products in high
yields. This reaction cascade proceeds with water as the
only byproduct and does not need strict exclusion of
moisture or oxygen.”
Chem. Eur. J. 2016, 22, 1 – 7
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