Gold-Catalyzed Formal Dehydro-Diels–Alder Reactions of Ene-Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and Mechanistic Studies

Article abstract of DOI:10.1002/anie.201807136

A new protocol for the synthesis of a variety of N-containing aromatic heterocycles by a formal gold-catalyzed dehydro-Diels–Alder reaction of ynamide derivatives has been developed. Deuterium-labeling experiments and kinetic studies support the involvement of a dual gold catalysis mechanism in which a gold acetylide moiety adds onto an aurated keteneiminium.

Full text of DOI:10.1002/anie.201807136

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Accepted Article
Title: Gold-catalyzed Formal Dehydro-Diels-Alder Reactions of Ene-
Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and
Mechanistic Studies
Authors: Qing Zhao, David Fabian León Rayo, Dominic Campeau,
Martin Daenen, and Fabien Gagosz
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807136
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10.1002/anie.201807136
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Gold-catalyzed Formal Dehydro-Diels-Alder Reactions of Ene-
Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and
Mechanistic Studies
Qing Zhao,a David Fabian León Rayo,b Dominic Campeau,b Martin Daenenb and Fabien Gagosz*a,b
Abstract: A new protocol for the synthesis of a variety of N-
containing aromatic heterocycles by formal gold-catalyzed
successful application of this approach, in its intramolecular
version, to the synthesis of various N-containing aromatic
heterocyclic scaffolds 2 from ynamide derivatives 1 (Scheme
1D),[5],[6] as well as mechanistic investigations supporting the
involvement of a dual gold catalysis process.[7]
a
dehydro-Diels-Alder reaction of ynamide derivatives has been
developed. D-labelling experiments and kinetic studies support the
involvement of a dual gold catalysis mechanism in which a gold
acetylide moiety adds onto an aurated keteneiminium.
The thermal enyne-yne dehydro-Diels-Alder (DDA)
reaction represents
a useful synthetic tool for the rapid
construction of polysubstituted aromatic compounds (Scheme
1A).[1] Despite its synthetic potential, this transformation remains
underused probably due to the elevated temperatures it requires
to proceed (generally >150°C) and its highly variable efficiency.
A proper substitution pattern of the substrate is generally
required to obtain the DDA products in an efficient manner.[2]
Recent developments have shown that C-C bond formation
between two alkyne units to produce 1,3-diene motifs could be
achieved under electrophilic gold catalysis (Scheme 1B).[3]
Schematically, this type of transformation can proceed either via
a “vinyl carbocation pathway”[3a-g] or via a “gold-vinylidene
pathway”[3h-v] depending on the nature of substituent R’ in the
nucleophilic alkyne partner. In this way, vinyl carbocation
intermediates I can be accessed and their inherent high
reactivity is tempered by stabilizing R’ groups. Terminal alkynes
(R’=H) can also participate to this type of coupling following a
dual gold catalysis process.[4] In this scenario, the terminal
alkyne is initially converted into
a
gold-acetylide that
subsequently reacts to produce an intermediate vinylidene gold
species II.
In this context, we considered that some enyne-yne DDA
reactions, that would be difficult to achieve under thermal
conditions, could possibly benefit from the use of gold catalysis.
More specifically, we were interested in the possibility to perform
a formal [4+2] DDA reaction between an enyne and a terminal
alkyne (Scheme 1C). In this stepwise transformation,
a
nucleophilic gold acetylide III would initially react with an
electrophilic gold-activated enyne IV to produce an intermediate
vinylidene species V. Its nucleophilic trapping by the alkene
moiety would lead to cyclized species VI that would then
aromatize to deliver the DDA product. We report herein the
Scheme 1. Exploiting dual gold catalysis in dehydro-Diels-Alder processes
Our study started with 1a, a model substrate that was
shown not to convert into the desired tetrahydroquinoline 2a
under thermal conditions (Scheme 2). Various gold(I) complexes
were evaluated as potential catalysts for this transformation (see
the SI for details). Gratifyingly, this screening revealed that 2a
could be produced in an optimum 82% isolated yield by reacting
1a with 5 mol% of [(RuPhos)Au]NTf2 in CHCl3 at 65 °C.[8],[9] We
then investigated the scope of the transformation using these
optimized catalytic conditions.
[a]
[b]
Dr. Q. Zhao, Prof. F. Gagosz
Département de Chimie, UMR 7652 and 7653 CNRS, Ecole
Polytechnique, 91128 Palaiseau, France.
Dr. D. F. León Rayo, D. Campeau, M. Daenen, Prof. F. Gagosz
Department of Chemistry and Biomolecular Sciences, University of
Ottawa, K1N 6N5, Ottawa, Canada.
E-mail: fgagosz@uottawa.ca
Supporting information for this article is given via a link at the end of
the document.
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kinetic effect was detected as the reaction was found to be twice
faster than in the absence of this additive.[11],[12]
Scheme 2. Optimized conditions for the Au-catalyzed cyclization of model
substrate 1a.
As seen in Scheme 3, various substrates bearing either an
alkenyl (1a,b,d-q, Part A-) or an aryl/heteroaryl substituent on
the ynamide moiety (1r-ae, Part B-) could be converted into the
corresponding DDA products 1a,b,d-ae. The reactions could be
completed in 3-60 h, were generally efficient (40-88%)[10] and led
to the formation of various indoline, tetrahydroquinoline and
azepine derivatives depending on the number of C atoms (2-4)
present in the linker between the N atom and the terminal alkyne
moiety. The process exhibits a high degree of functional group
and substitution compatibility as acyclic and cyclic ethers
(1i,j,m,n,x,y,ad), esters (1z,aa), amides (1k,l), alkyl groups
(1e,f,o), halogen atoms (1t-w,ae) or (hetero)aromatic groups
(1p,q,ab,ac) were tolerated on either the alkenyl- or aryl-
substituted ynamide moiety or on the linker. Notably, the number
of C atoms in the linker had an influence on the relative
efficiency of the process: the formation of a new N-containing 6-
membered cycle was found to be generally more favourable
than that of a 5-membered cycle (compare for example 2a/2b,
2h/2i or 2q/2r). Comparatively, no tetrahydrobenzazepine
product 2c could be formed from the analogous 1c under the
optimized conditions. However, this limitation in reactivity could
be overcome by introducing
a geometrically constraining
aromatic group in the linker as exemplified by the formation of
dibenzoazepine 2q from 1q (40% yield). Interestingly, the yield
could be improved to 81% with a faster reaction rate in the
presence of a basic additive (3,5-dibromopyridine).[11],[12] This
additive was also required for the reaction of heterocyclic
derivatives 1ab and 1ac, and to prevent the decomposition of 2n
which appeared to be somewhat sensitive under acidic
conditions. As for the reactions of aryl/heteroaryl-ynamide
derivatives 1r-1ae, no significant difference in terms of reaction
rate or efficiency (46-81%) could be observed. A variety of
substituents (ether, ester, halogen) were tolerated on the
aromatic moiety.
To get some insight into the mechanism of the reaction, a
series of D-labelling experiments and comparative kinetic
studies were then performed (Scheme 4). With substrate 1a(D3),
a selective and complete transfer of the D atom from the vinylic
position (95% D) to a single position of the newly formed
aromatic ring in 2a(D3) was observed. In contrast, the reaction of
the 1a(D1) (≈ 80% D) led to a selective but largely incomplete
transfer of the D atom to the other position of the aromatic ring
(25% D). No remarkable KIE was observed since the reactions
of 1a(D1) and 1a(D3) exhibit the same kinetic profile than the
non-deuterated substrate 1a.[13] When 0.5 equiv. of 3,5-
dibromopyridine was added to the reaction medium, a significant
Scheme 3. Substrate scope: Dehydro-Diels Alder reaction with ynamides 1.
[a] Reactions were performed on a 0.05-0.2 mmol scale. Isolated yields are
given. [b] The substrate was used as a 8:1 mixture of trans:cis isomers. [c]
The reaction was performed with 0.5 equiv. of 3,5-dibromopyridine. In the
absence of this additive, the reaction was complete after 7 h (yield: 28%). [d]
The reaction was performed with 0.5 equiv. of 3,5-dibromopyridine. [e] p:o is
the ratio of isomers formed (p refers to a cyclization at position para to the R
group, o to a cyclization at position ortho to the R group).
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pattern observed in product 2a(D1) is consistent with
a
demetallation proceeding on 10 or by catalyst transfer from 9.
The observed reduced D-%age in 2a(D1) might be due to the
presence of residual water in the reaction medium,[16] which
could lead to a H/D exchange in 1a and consequently to a
competitive H incorporation in the final product.
Scheme 4. Deuterium labelling experiment and comparative kinetic studies.
[a] The reactions were performed in parallel in screw-cap NMR tubes under
the same experimental conditions (0.07 mmol of substrate and 5 mol% of
[(RuPhos)Au]NTf2 in dry CDCl3 (0.1 M) at 65°C) and monitored by 1H NMR
spectroscopy. Conversion and yields were determined by 1H NMR
spectroscopy using mesitylene as an internal standard. See the Supporting
Information for more details.
Scheme 5. Mechanistic proposal.
To probe that aurated species 3, 4, 9 and 10 could be
involved as reactive intermediates in this process, a series of
additional experiments were performed (Scheme 6). Gold
acetylide 3[17] was first treated with 1 equiv. of [(RuPhos)Au]NTf2
at 20°C in CD2Cl2 (Scheme 6, Part A-). 1H and 31P NMR
spectroscopy analysis showed the instantaneous and
quantitative formation of complex 4 ((31P)=44.52 ppm)[19] thus
demonstrating that the additional LAu+ fragment has a higher
affinity for the gold acetylide moiety than for the ynamide. 4 was
found to be relatively stable in solution at 20°C but rapidly and
predominantly rearranged at 65°C into a new aurated species
whose spectroscopic data were in agreement with the structure
of the postulated intermediate 9 ((31P)=58.50 ppm). In parallel,
On the basis of our experimental observations and by
analogy with previous studies by the Hashmi group,[3h,j,k,m,q,r,t]
a
mechanism that features a dual gold catalysis cycle is proposed
for the formation of 2a from 1a (Scheme 5). The reaction is
believed to start with the formation of the gold acetylide 3 which
is in equilibrium with 1a and LAu+. The favourable kinetic effect
observed in the presence of a basic additive might be related to
the shifting of this equilibrium towards the formation of 3. A
second LAu+ moiety can then interact with 3 to produce the ,-
digold complex 4.[14] This one could be in equilibrium with
species 5 by intramolecular transfer of LAu+. The cyclization
event could then proceed by addition of the gold-acetylide onto
the keteneiminium followed by a trapping of the resulting
vinylidene-gold species 6[3k] by the pendent alkene.[15]
Intermediate 7 would then be converted into 8 by a 1,2-H shift,[3r]
a step that is supported by the D-labelling pattern observed in
product 2a(D3) (see Scheme 4). Species 8 could subsequently
evolve into the gem-diaurated complex 9, a type of intermediate
previously proposed in dual catalysis processes.[3h] A catalyst
transfer step between 9 and 1a would complete the cycle by
delivering 2a and regenerating 4.[3t] Alternatively, 2a could be
directly produced by protodemetallation of 10 in the presence of
H+ released during the initial formation of 4. The D-labelling
10 could be accessed by reacting
[(RuPhos)Au]NTf2 in CD2Cl2 at 65°C. This catalytic
transformation represents truncated version of that
3 with 5 mol% of
a
represented in Scheme 5 with the regeneration of gold-acetylide
3 from 1a being passed over. NMR spectroscopy monitoring of
the reaction showed this transformation to be of zero order with
respect to 3, and 4 was detected as the resting state species. 10
could also be isolated and characterized ((31P)=49.38 ppm). Its
treatment with 1 equiv. of [(RuPhos)Au]NTf2 at 20°C in CD2Cl2
led to the instantaneous formation of 9, thus confirming its initial
structural assignment. We then focused our attention on probing
the viability of the catalyst transfer step (Scheme 6, Part B-).
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Complex 9, generated in situ from 10, was treated with 2 equiv.
of 1a at 20°C and the reaction was monitored by 1H NMR
spectroscopy. Species 9 and 1a were observed to be gradually
consumed while 2a and 4 were concomitantly produced.
65°C). Interestingly, while 9 was quantitatively converted into 2a,
only 0.65 equiv. of 4 was formed while more than 1 equiv. of 1a
was consumed and no other products could be detected.[20] This
tends to show that the demetallation of 9 might competitively
proceed via different pathways, possibly by protodeauration via
10. Heating the reaction mixture to 65°C, after the complete
consumption of 9, led to the rapid and gradual production of 2a
and the concomitant disappearance of 1a. The amount of 4
slowly decreased while 9 progressively accumulated as the
catalyst transfer to 1a became less favourable. This reactivity
profile seems to fit with the mechanistic proposal shown in
Scheme 5. However, when 1a was reacted with 10 mol% of
[(RuPhos)Au]NTf2 (instead of 5 mol%, as shown Scheme 4), the
initial reaction rate was observed to only double, which is not in
agreement with the cyclization event being the rate determining
step in the case of a dual gold catalysis cycle involving a catalyst
transfer from 9 to 1a to regenerate 4. This tends to prove that
this transfer, while feasible, is actually rather inefficient under
catalytic conditions and that the deauration of 9 should proceed
mainly via 10 by reaction with a protic source. This is consistent
with the D-labelling pattern observed in product 2a(D1). A key
process in this Au-mediated DDA reaction should be the
equilibrated sequence leading to 4 from 1a via 2, an assumption
that is supported by the rate enhancement observed when a
base additive was employed (Scheme 5).[3j]
In conclusion, we have developed a new method to access
a variety of N-containing aromatic heterocycles by a gold-
catalyzed formal dehydro-Diels-Alder reaction of ynamide
derivatives. A series of D-labelling experiments and kinetic
studies support the involvement of a dual gold catalysis
mechanism. Further computational studies dedicated to
elucidate the complete mechanism of this transformation are
currently under way.
Acknowledgements
This work was supported by the Ecole Polytechnique, the
University of Ottawa and the Natural Sciences and Engineering
Research Council. The authors thank Solvay (Dr. F. Metz) for a
generous gift of HNTf2, D. Dong for his work on the synthesis of
compound 2u and, Prof. D. Pratt (uOttawa) and Prof. D. Tantillo
(UCDavis) for helpful discussions.
Keywords: Gold catalysis • Dual catalysis • Gold acetylide •
Dehydro-Diels-Alder reactions • Mechanism • Kinetic studies
[1]
[2]
For a review, see: P. Wessig, G. Müller, Chem Rev. 2008, 108, 2051.
Efficient thermal DDA reactions generally involve substrates with a) a
matching in the electronic properties of the enyne and yne reacting
partners, b) a tether that is geometrically restricted in order to bring
closer the enyne and the yne moieties.
Scheme 6. Mechanistic investigations on the dual-Au catalysis process. [a]
The reactions were performed in screw-cap NMR tubes. 1H and 31P NMR
spectroscopies were employed to monitor the reaction and characterize the
species. See the Supporting Information for more details.
[3]
For reports on Au-catalyzed alkyne-alkyne coupling via vinyl
carbocation intermediates, see: a) T. Shibata, R. Fujiwara, D. Takano,
Synlett 2005, 2062; b) Y. Odabachian, X. F. Le Goff, F. Gagosz, Chem.
Eur. J. 2009,15, 8966; c) S. Kramer, Y. Odabachian, J. Overgaard, M.
Rottländer, F. Gagosz, T. Skrydstrup, Angew. Chem. Int. Ed. 2011, 50,
5090; Angew. Chem. 2011, 123, 5196.d) J. Schädlich, T. Lauterbach,
M. Rudolph, F. Rominger, A. S. K. Hashmi, J. Organomet. Chem. 2015,
This supports our mechanistic hypothesis and demonstrates that
the catalyst transfer from 9 to 1a is a thermodynamically more
favourable process than the cyclization event (20°C versus
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795, 71; e) T. Wurm, J. Bucher, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Adv. Synth. Catal. 2017, 359, 1637; f) T. Wurm, J. Bucher, S.
B. Duckworth, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew.
Chem. Int. Ed. 2017, 56, 3364; Angew. Chem. 2017, 129, 3413; g) V.
Weingand, T. Wurm, V. Vethacke, M. C. Dietl, D. Ehjeij, M. Rudolph, F.
Rominger, J. Xie, A. S. K. Hashmi, Chem. Eur.J. 2018, 24,3725. For
reports on Au-catalyzed alkyne-alkyne coupling via vinylidene-gold
intermediates, see: h) A. S. K. Hashmi, I. Braun, P. Nösel, J. Schädlich,
M. Wieteck, M. Rudolph, F. Rominger, Angew. Chem. Int. Ed. 2012, 51,
4456; Angew. Chem. 2012, 124, 4532; i) A. S. K. Hashmi, M. Wieteck, I.
Braun, M. Rudolph, F. Rominger, Angew. Chem. Int. Ed. 2012, 51,
10633; Angew. Chem. 2012, 124, 10785; j) A. S. K. Hashmi, I. Braun,
M. Rudolph, F. Rominger, Organometallics 2012, 31, 644; k) A. S. K.
Hashmi, M. Wieteck, I. Braun, P. Nösel, L. Jongbloed, M. Rudolph, F.
Rominger, Adv. Synth. Catal. 2012, 354, 555; l) L. Ye, Y. Wang, D. H.
Aue, L. Zhang, J. Am. Chem. Soc. 2012, 134, 31; m) M. M. Hansmann,
M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed.
2013, 52, 2593; Angew. Chem. 2013, 125, 2653; n) P. Nösel, T.
Lauterbach, M. Rudolph, F. Rominger, A. S. K. Hashmi, Chem. Eur. J.
2013, 19, 8634; o) D. D. Vachhani, M. Galli, J. Jacobs, L. Van Meervelt,
E. V. Van der Eycken, Chem. Commun. 2013, 49, 7171; p) K. Graf, P.
D. Hindenberg, Y. Tokimizu, S. Naoe, M. Rudolph, F. Rominger, H.
Ohno, A. S. K. Hashmi, ChemCatChem 2014, 6, 199; q) M. M.
Hansmann, S. Tšupova, M. Rudolph, F. Rominger, A. S. K. Hashmi,
Chem. Eur. J. 2014, 20, 2215; r) M. H. Vilhelmsen, A. S. K. Hashmi,
Chem. Eur. J. 2014, 20, 1901; s) M. Wieteck, Y. Tokimizu, M. Rudolph,
F. Rominger, H. Ohno, N. Fujii, A. S. K. Hashmi, Chem. Eur. J. 2014,
20, 16331; t) M. H. Larsen, K. N. Houk, A. S. K. Hashmi, J. Am. Chem.
Soc. 2015, 137, 10668; u) Y. Tokimizu, M. Wieteck, M. Rudolph, S.
Oishi, N. Fujii, A. S. K. Hashmi, H. Ohno, Org. Lett. 2015, 17, 604; v) C.
Yu, B. Chen, T. Zhou, Q. Tian, G. Zhang, Angew. Chem. Int. Ed. 2015,
54, 10903; Angew. Chem. 2015, 127, 11053. For other processes,
involving vinylidene-gold species as intermediates, see: w) Y. Wang, M.
Zarca, L.-Z. Gong, L. Zhang, J. Am. Chem. Soc. 2016, 138, 7516; x) J.
Bucher, T. Wurm, K. S. Nalivela, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2014, 53, 3854; Angew. Chem. 2014,
126, 3934.
Tetrahedron 2006, 62, 3843; d) M. F. Martínez-Esperꢀn, D. Rodríguez,
L. Castedo, C. Saꢁ, Tetrahedron 2008, 64, 3674.
[6]
[7]
For a review on the cyclization of π-Tethered Ynamides, see: B.
Prabagar, N. Ghosh, A. K. Sahoo, Synlett 2017, 28, 2539.
While this manuscript was in preparation, a report by Liu and co-
workers on the formation of benzo[b]carbazoles by a gold-catalyzed
DDA reaction was published: W. Xu, G. Wang, X. Xie, Y. Liu, Org. Lett.
2018, 20, 3273. This work involved substrates bearing substituted
alkyne reacting with aryl-substituted ynamides following
a vinyl
carbocation pathway. A single low yielding (28%) example involving a
terminal alkyne was reported.
[8]
[9]
Brønsted acids, Ag or Cu salts were shown to be ineffective in
promoting this transformation. See the SI for more details.
For similar substrates evolving into different structurally different
products under gold catalysis, see : a) X. Chen, J. T. Merrett, P. Wai
Hong Chan, Org. Lett. 2018, 20, 1542; b) N. Ghosh, S. Nayak, A. K.
Sahoo, Chem. Eur. J. 2013, 19, 9428.
[10] While some isolated yields were moderate, no other by-products could
be observed by 1H NMR of the crude reaction mixture. Polymerization
of the ynamide substrates under acidic conditions might be the reason
behind this observation.
[11] Base additives are known to accelerate dual gold catalysis processes.
See for instance ref. 3j.
[12]
A
series of base additives were tested among which 3,5-
dibromopyridine gave the best results. See the SI for more details.
[13] Surprisingly, NMR yields of deuterated products 2a(D1) and 2a(D3)
were however found to be lower than that obtained starting from 1a.
[14] a) T. N. Hooper, M. Green, C. A. Russell, Chem. Commun. 2010, 46,
2313; b) T. J. Brown, R; A. Widenhoefer, Organometallics 2011, 30,
6003.
[15] An alternative [4+2] concerted process leading directly to 7 from 5
cannot be ruled out in the case of alkene substituted ynamides.
[16] Similar observation and hypothesis were made by Hashmi and co-
workers, see ref. 3k.
[17] 3 could be conveniently accessed from 1a, isolated and characterized. .
See the SI for more details.
[18] 31P NMR monitoring of the reaction under catalytic conditions only
shows the presence of the free [(RuPhos)Au]NTf2 complex.
[4]
[5]
For highlights on dual gold catalysis, see : a) A. Gómez-Suárez, S. P.
Nolan, Angew. Chem. Int. Ed. 2012, 51, 8156; Angew. Chem. 2012,
124, 8278; b) I. Braun, A. M. Asiri, A. S. K. Hashmi, ACS Catal. 2013, 3,
1902; c) A. S. K. Hashmi, Acc. Chem. Res. 2014, 47, 864.
[19]
A
single signal was observed as the result of
a rapid σ,π-
interconversion of the two AuL groups, see ref. 12b.
[20] No other by-product could be observed by 1H NMR spectroscopy. This
inaccurate material balance might be due to partial polymerization of
the ynamide substrate 1a.
For thermal DDA reactions with ynamide derivatives, see: a) J. R.
Dunetz, R. L. Danheiser, J. Am. Chem. Soc. 2005, 127, 5776; b) M. F.
Martínez- Esperꢀn, D. Rodríguez, L.Castedo, C Saꢁ, Org. Lett. 2005, 7,
2213; c) M. F. Martínez- Esperꢀn, D. Rodríguez, L. Castedo, C. Saꢁ,
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Qing Zhao, David Fabian León Rayo,
Dominic Campeau, Martin Daenen and
Fabien Gagosz*
Page No. – Page No.
Gold-catalyzed
Diels-Alder
Formal
Reactions
Dehydro-
of
Ene-
Ynamide
Derivatives
Bearing
Terminal Alkyne Chains: Scope and
Mechanistic Studies
A new protocol for the synthesis of a variety of N-containing aromatic heterocycles
by a formal gold-catalyzed dehydro-Diels-Alder reaction of ynamide derivatives has
been developed. D-labelling experiments and kinetic studies support the
involvement of a dual gold catalysis mechanism in which a gold acetylide moiety
adds onto an aurated keteneiminium.
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