Gold-Catalyzed Intermolecular Oxidative Diyne Cyclizations via 1,6-Carbene Transfer

Article abstract of DOI:10.1002/adsc.201901318

A vinyl/α-oxo carbene is generated via an α-oxo carbene formation and subsequently transferred across the second alkyne. These highly active species can react with nitriles in an intermolecular fashion to provide substituted oxazoles. This methodology goes through 1,6-carbene shift and offers a range of valuable products. (Figure presented.).

Full text of DOI:10.1002/adsc.201901318

Title: Gold-Catalyzed Intermolecular Oxidative Diyne Cyclizations via
1,6-Carbene Transfer
Authors: Qian Wang, Matthias Rudolph, Frank Rominger, and A.
Stephen K. Hashmi
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10.1002/adsc.201901318
Advanced Synthesis & Catalysis
Very Important Publication - VIP COMMUNICATION
DOI: 10.1002/adsc.201901318
Gold-Catalyzed Intermolecular Oxidative Diyne Cyclizations
via 1,6-Carbene Transfer
Qian Wang,a,* Matthias Rudolph,a Frank Rominger,a A. Stephen K. Hashmia,b,*
a
Institute of Organic Chemistry, Heidelberg University, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: (+ 49)-6221-54-4205
E-mail: hashmi@hashmi.de; wangqianlt@163.com
Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi Arabia
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
demonstrated that the final electrophilic vinyl
Abstract. A vinyl/α-oxo carbene is generated via an α-oxo
carbene formation and subsequently transferred across the carbenoids
second alkyne. These highly active species can react with
nitriles in an intermolecular fashion to provide substituted
oxazoles. This methodology goes through 1,6-carbene shift
and offers a range of valuable products.
can be exploited for further
transformations like sp3-C-H insertions[10] or alkyl-
migrations[11] (Scheme 1A). Based on the carbene shift
strategy with N-oxides, we assumed that an
intermolecularly offered reagent could also react with
the final gold carbene which would significantly
expand the applications of diynes in combination with
N-oxides (Scheme 1B).
Keywords: gold catalysis; gold carbene; N-oxides; diyne;
carbene transfer
Homogeneous gold catalysis has attracted great
attention in the field of organic synthesis in the last
nineteen years.[1] Chemists found that gold complexes
as powerful soft Lewis acids are able to activate
alkynes.[A. S. K. Hashmi, Gold Bull. 2003, 36, 3-9.]
If appropriate precursors are used, gold carbenes are
generated, which enable the design of many useful
transformations.[2] Recently, carbene to carbene
transformations to obtain vinyl gold carbenes[3] or
benzyl gold carbenes[4] were reported. Frist, an alkyne
can be activated via π-coordination, then an 1,2-
migration/oxidation generates gold carbenes. This
highly reactive intermediate can be transferred over a
second tethered alkyne that enable a range of fruitful
transformations. This interesting carbene transfer
procedure was founded via Rh catalyzed diazo
substrates[5] and the first gold carbene transfer was
demonstrated by Toste’s group who also used a diazo
compound as carbene precursor.[6]
Scheme 1. 1,6-carbene Transfer.
To test this assumption, we chose diyne substrates
bearing one terminal alkyne and one alkyne
conjugated to a carbonyl group. We assumed that
nitriles could serve as reacting partners finally leading
to oxazole substructures. As initial reaction we
selected diyne 1a in combination with acetonitrile and
various N-oxides. To our delight the desired product
3a was obtained in 13% yield by using IPrAuCl and
Our group has contributed the gold-catalyzed
syntheses of naphthalene derivatives via 1,7-carbene
shifts.[7] That work demonstrated that an tethered
alkyne can capture gold carbenes which were
generated via 1,2-migration. In 2013, we found an
unexpected reaction pathway to obtain gold carbene by
using N-oxides in diyne systems.[8] N-oxides can be
used instead of diazo compounds to access α-oxo gold
AgNTf2
(IPr
=
1,3-bis(2,6-
Tf
diisopropylphenyl)imidazol-2-ylidene,
=
trifluoromethylsulfonyl) in combination with 2,6-
dibromopyridine N-oxide as oxidant. The obtained
structure was additionally confirmed by an X-ray
single crystal structure analysis (Figure 1).[12] The
solid state molecular structure proved that both oxygen
transfer and intermolecular attack occurred during the
reaction.
9]
carbene, too.[2a,2d, Our group reported on a 1,6-
carbene shift of a initially formed α-oxo gold carbene
generated by oxygen transfer from N-oxides which
was transferred over a tethered alkyne. We also
1
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10.1002/adsc.201901318
Advanced Synthesis & Catalysis
Table 2. Scope with respect to the substratea,b
Figure 1. Solid-state molecular structure of 3a.
Encouraged by this result, we started to optimize the
reaction conditions (Table 1). Initially, we tested
several N-oxides but no obvious increase in yield was
observed (entries 2 and 3). Without N-oxides we only
detected decomposition of the substrate. After that we
investigated the effect of different ligands (entries 4-
8). Among a series of different phosphane ligands
t
Me4 BuXPhoxAuCl turned out to be the best candidate,
leading to 46% yield (entry 8). The role of the counter
anion was significant and replacing AgNTf2 with
AgOTf led to the best result in combination with the
t
optimized ligand Me4 BuXPhos (entries 9-10). Under
these conditions the desired product 3a was obtained
in 75% yield while with AgOTf alone no product was
formed (entry 11).
Table 1. Optimization of the reaction conditionsa,b
entrya)
catalyst
N-oxide
Yieldb)
(%)
1
2
3
4
5
6
7
8
IPrAuCl
IPrAuCl
IPrAuCl
5a
5b
5c
5c
5c
5c
5c
5c
5c
5c
5c
11
7
17
13
24
18
40
46
65
Ph3PAuCl
SPhosAuCl
JohnPhosAuCl
Mor-DalPhoxAuCl
Me4 BuXPhosAuCl
Me4 BuXPhosAuCl
t
9c
10d
11d
t
t
Me4 BuXPhosAuCl
79(75)e
n.d.
-
a) All reactions were carried out on a 0.2 mmol scale in 1 mL
CH3CN in presence of 1.2 equiv. N-oxide at 60 °C for 1 h.
b) The yield was determined by GC with n-dodecane as
internal standard. c) 5 mol% AgSbF6 was used. d) 5 mol%
AgOTf was used. e) Isolated yield is in the parenthesis.
a)
Reaction conditions: 1 (0.2 mmol), 2a (1 mL)
t
Me4 BuXPhosAuCl (5 mol%), AgOTf (5 mol%) in presence
of 1.2 equiv. 8-Ethylquinoline N-oxide at 60 °C. b) Isolated
yield.
2
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10.1002/adsc.201901318
Advanced Synthesis & Catalysis
With the best reaction conditions in hand, we began to
explore the substrate scope of the reaction (Table 2).
At first, we synthesized a series of substrates
containing differently substituted aromatic backbones
(1b-1j). Electron-donating methyl or methoxy groups
in para- or meta-position to the terminal alkyne at the
arene moiety were tolerated well and the
corresponding products were obtained in 72% and
64%, respectively (entries 2 and 3). Electron-
withdrawing substituents further increased the yield.
Halogen substituents including -F and -Cl afforded the
products in good yields (entries 4 and 5). The same
was the case for a CF3-containing product 3f that was
obtained in 80% yield (entry 6). A decrease of the yield
was observed with dimethoxy substituted 1g that was
obtained in only 44% yield (entries 7). A longer alkyl
chain on the carbonyl group also reacted well (70%,
entry 8). The same was the case for aromatic
substituted keto compound 1i that formed the
corresponding product in 53% yield (entry 9). If an
aldehyde was used instead of the ketone, no product
was formed which might be attributed to the decreased
nucleophilicity of the oxygen atom.
Scheme 2. Control experiments.
According to our previous work and the work of
Zhang,[13,8] a proposed reaction mechanism is shown
in Scheme 3. The first step starts with π-activation of
the terminal alkyne in the presence of the gold
catalysts. An α-oxo gold carbene II is then generated
through oxygen transfer under selective oxidation of
the alkynes by the N-oxides. It is worth noting that N-
oxides do not play the role of base like in the case of
the dual activation reactions.[14] Subsequently, the α-
oxo gold carbene II can undergo an intramolecular
cyclopropenation to form intermediate III.[15] Then a
gold-mediated ring opening takes and a vinyl/α-oxo
carbene V is generated after ring opening of the
cyclopropene. This stablized carbene V can be
captured by the intermoleculary offered nitrile to
obtain a cation intermediate VI. Intramolecular
cyclization then delivers the desired product.
Table 3. Scope with respect to the nitrilea
Scheme 3. Proposed reaction mechanism.
a) All reactions were carried out on a 0.2 mmol scale in 1 mL
nitriles in presence of 1.2 eq N-oxide, at 60 °C.
In conclusion, we demonstrated that gold carbenes
generated by a 1,6-carbene shift can be trapped by an
intermoleculary offered reagent. By following this
strategy highly substituted oxazoles could be
synthesized in good efficiency and broad scope.
Further studies on the intermolecular capture of
rearranged carbenoids are ongoing in our
laboratories.[16]
To further expand the scope, several nitriles were
investigated. Propionitrile and isobutyronitrile proved
to be suitable reaction solvents as well (Table 3, entries
11 and 12). Besides, benzonitrile also reacted with the
diyne leading to 4c in moderate yield (entriy 13). If the
amount of of nitrile was reduced to 10 eq. of
acetonitrile in toluene as solvent after 8h 3a was
obtained in an acceptable yield of 57% yield (eqs 1).
However, 5 eq. of benzonitrile led to a poor yield of
less than 20% (eqs 2) which can be attributed to the
reduced nucleophilicity of the nitrile.
Experimental Section
General procedure for the synthesis of 3-(2,5-
dimethyloxazol-4-yl)-1H-inden-1-one (3a): To a Schlenk
tube were added 4-(2-ethynylphenyl)but-3-yn-2-one(0.2
3
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10.1002/adsc.201901318
Advanced Synthesis & Catalysis
mmol), [Me4 tBuXPhosAuCl]/AgOTf (0.01 mmol), 8-
ethylquinoline N-oxide (0.24 mmol) in CH3CN (1 mL). The
resulting mixture was stirred at 60 °C for 1h. Then the
solvent was removed under vacuum to give a residue, which
was purified by silica gel chromatography (petroleum
ether/ethyl acetate = 8:1) to yield the corresponding product
3a.
differentiated from: c) aurated carbenes: F. F. Mulks, P.
W. Antoni, F. Rominger, A. S. K. Hashmi, Adv. Synth.
Catal. 2018, 360, 1810-1821; d) gold carbenoids: J. M.
Sarria Toro, C. García‐Morales, M. Raducan, E. S.
Smirnova, A. M. Echavarren, Angew. Chem. Int. Ed.
2017, 56, 1859-1863 e) aurated gold carbenes.: F. F.
Mulks, P. W. Antoni, J. H. Gross, J. Graf, F. Rominger,
A. S. K. Hashmi, J. Am. Chem. Soc. 2019, 141, 4687-
4695.
Acknowledgements
[5] a) A. Padwa, Molecules 2001, 6, 1-12; b) A. Padwa, J.
Organomet. Chem. 2000, 610, 88-101; c) S. Jansone-
Popova, J. A. May, J. Am. Chem. Soc. 2012, 134, 17877-
17880.
Q. W is grateful to the CSC (ChinaScholarship Council) for a Ph.D.
fellowship.
[6] C. A. Witham, P. Mauleon, N. D. Shapiro, B. D. Sherry,
F. D. Toste, J. Am. Chem. Soc. 2007, 129, 5838-5839.
[7] a) T. Lauterbach, S. Arndt, M. Rudolph, F. Rominger, A.
S. K. Hashmi, Adv. Synth. Catal. 2013, 355, 1755-1761;
b) T. Lauterbach, S. Gatzweiler, P. Nösel, M. Rudolph,
F. Rominger, A. S. K. Hashmi, Adv. Synth. Catal. 2013,
355, 2481-2487; c) T. Lauterbach, M. Ganschow, M. W.
Hussong, M. Rudolph, F. Rominger, A. S. K. Hashmi,
Adv. Synth. Catal. 2014, 356, 680-686.
References
[1] a) Z. Li, C. Brouwer, C. He, Chem. Rev. 2008, 108,
3239-3265; b) A. Arcadi, Chem. Rev. 2008, 108, 3266-
3325; c) A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev.
2008, 37, 1766-1775; d) A. Corma, A. Leyva-Pérez, M.
J. Sabater, Chem. Rev. 2011, 111, 1657-1712; e) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180-3211; f) A. S. K.
Hashmi, G. Hutchings, Angew. Chem. 2006, 118, 8064-
8105; Angew. Chem. Int. Ed. 2006, 45, 7896-7936.
[2] a) L. Zhang, Acc. Chem. Res. 2014, 47, 877-888; b) J.
Xiao, X. Li, Angew. Chem. 2011, 123, 7364-7375;
Angew. Chem. Int. Ed. 2011, 50, 7226-7236; c) A.
Fürstner, P. W. Davies, Angew. Chem. 2007, 119, 3478-
3519; Angew. Chem. Int. Ed. 2007, 46, 3410-3449; d) C.
W. Li, K. Pati, G. Y. Lin, S. M. A. Sohel, H. H. Hung, R.
S. Liu, Angew. Chem. 2010, 122, 10087-10090; Angew.
Chem. Int. Ed. 2010, 49, 9891-9894; e) N. D. Shapiro, F.
D. Toste, J. Am. Chem. Soc. 2007, 129, 4160-4161; f) H.
S. Yeom, J. E. Lee, S. Shin, Angew. Chem. 2008, 120,
7148-7151; Angew. Chem., Int. Ed. 2008, 47, 7040-7043;
g) G. Henrion, T. E. J. Chavas, X. Le Goff, F. Gagosz,
Angew. Chem. 2013, 125, 6397-6402; Angew. Chem., Int.
Ed. 2013, 52, 6277-6282; h) L. Wang, X. Xie, Y. Liu,
Angew. Chem. 2013, 125, 13544-13548; Angew. Chem.
Int. Ed. 2013, 52, 13302-13306; i) E. L. Noey, Y. Luo, L.
Zhang, K. N. Houk, J. Am. Chem. Soc. 2012, 134, 1078-
1084; j) X. Tian, L. Song, M. Rudolph, F. Rominger, T.
Oeser, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2019, 58,
3589-3593 ; k) X. Tian, L. Song, M. Rudolph, Q. Wang,
X. Song, F. Rominger, A. S. K. Hashmi, Org. Lett. 2019,
21, 1598-1601; l) X. Tian, L. Song, C. Han, C. Zhang, Y.
Wu, M. Rudolph, F. Rominger, A. S. K. Hashmi, Org.
Lett. 2019, 21, 2937-2940; m) X. Tian, L. Song, M.
Rudolph, F. Rominger, A. S. K. Hashmi, Org. Lett. 2019,
21, 4327-4330; n) L. Song, X. Tian, M. Rudolph, F.
Rominger, A. S. K. Hashmi, Chem. Commun. 2019, 55,
9007-9010.
[8] P. Nösel, L. N. dos Santos Comprido, T. Lauterbach, M.
Rudolph, F. Rominger, A. S. Hashmi, J. Am. Chem. Soc.
2013, 135, 15662-15666.
[9] a) H. S. Yeom,; Y. Lee, J. Jeong, E. So, S. Hwang, J. E.
Lee, S. S. Lee, S. Shin, Angew. Chem. 2010, 122, 1655-
1658; Angew. Chem., Int. Ed. 2010, 49, 1611-1614; b) S.
N. Karad, R. S. Liu, Angew. Chem. 2014, 126, 5548-
5552; Angew. Chem. Int. Ed. 2014, 53, 5444-5448.
[10] a) B. Lu, C. Li, L. Zhang, J. Am. Chem. Soc. 2010, 132,
14070-14072; b) D. Y. Li, W. Fang, Y. Wei, M. Shi,
Chem. Eur. J. 2016, 22, 18080-18084; c) Y. Horino, T.
Yamamoto, K. Ueda, S. Kuroda, F. D. Toste, J. Am.
Chem. Soc. 2009, 131, 2809-2811; d) M. R. Fructos, T.
R. Belderrain, P. de Fremont, N. M. Scott, S. P. Nolan,
M. M. Diaz-Requejo, P. J. Perez, Angew. Chem. 2005,
117, 5418-5422; Angew. Chem., Int. Ed. 2005, 44, 5284-
5288; e) Y. Wang, Z. Zheng, L. Zhang, J. Am. Chem. Soc.
2015, 137, 5316-5319.
[11] a) A. S. Hashmi, T. Wang, S. Shi, M. Rudolph, J. Org.
Chem. 2012, 77, 7761-7767; b) P. Calleja, O. Pablo, B.
Ranieri, M. Gaydou, A. Pitaval, M. Moreno, M. Raducan,
A. M. Echavarren, Chem. Eur. J. 2016, 22, 13613-13618;
c) K. Ji, B. D' Souza, J. Nelson, L. Zhang, J. Organomet.
Chem. 2014, 770, 142-145.
[12] CCDC 1843822 (3a) contains the supplementary
crystallographic data for this paper, which can be
obtained free of charge from the Cambridge
Crystallographic Data Centre.
[13] W. He, C. Li, L. Zhang, J. Am. Chem. Soc. 2011, 133,
8482-8485.
[14] Y. Wang, A. Yepremyan, S. Ghorai, R. Todd, D. H.
Aue, L. Zhang, Angew. Chem. 2005, 125, 7949-7953;
Angew. Chem. Int. Ed. 2013, 52, 7795-7799.
[15] C. Pei, C. Zhang, Y. Qian, X. Xu, Org. Biomol. Chem.
2018, 16, 8677-8685.
[3] a) S. B. Wagh, R.-S. Liu, Chem. Commun. 2015, 51,
15462-15464; b) H. Chen, L. Zhang, Angew. Chem. 2015,
127, 11941-11945; Angew. Chem. Int .Ed. 2015, 54,
11775-11779; c) K. Ji, X. Liu, B. Du, F. Yang, J. Gao,
Chem. Commun. 2015, 51, 10318-10321.
[4] a) W. Rao, M. J. Koh, D. Li, H. Hirao, P. W. H. Chan, J.
Am. Chem. Soc. 2013, 135, 7926-7932; b) C. H. Oh, J. H.
Kim, L. Piao, J. Yu, S. Y. Kim, Chem. Eur. J. 2013, 19,
10501-10505; such species clearly have to be
[16] For related work, see: H. Su, M. Bao, C. Pei, W. Hu, L.
Qiu, X. Xu, Org. Chem. Front. 2019, 6, 2404-2409.
4
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Gold-catalyzed Intermolecular Oxidative Diyne
Cyclizations via 1,6-carbene Transfer
Adv. Synth. Catal. Year, Volume, Page – Page
Qian Wang,* Matthias Rudolph, Frank Rominger,
A. Stephen K. Hashmi*
5
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