Dual Gold-Catalyzed Formal Tetradehydro-Diels–Alder Reactions for the Synthesis of Carbazoles and Indolines

Article abstract of DOI:10.1002/chem.201804529

This work reports a dual gold-catalyzed tetradehydro-Diels–Alder reaction for the synthesis of nitrogen-containing aromatic heterocycles. Under the catalytic system (IPrAuNTf₂/DIPEA), indolines and carbazoles as well as other N-containing aromatic heterocycles were prepared in high yields with good functional group tolerance. Unlike the traditional thermal tetradehydro-Diels–Alder reactions, diluted reaction concentration and radical prohibitors are not required for this protocol. Experimental data support a mechanism involving gold vinylidene species, which undergoes a 6 π electrocyclization, followed with 1,2-hydrogen shift.

Full text of DOI:10.1002/chem.201804529

A Journal of
Accepted Article
Title: Dual Gold-Catalyzed Formal Tetradehydro-Diels-Alder Reactions
for the Synthesis of Carbazoles and Indolines
Authors: Weiwei Zi, Hong-Fa Wang, Shi-Yue Wang, and Tian-Zhu Qin
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To be cited as: Chem. Eur. J. 10.1002/chem.201804529
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Dual Gold-Catalyzed Formal Tetradehydro-Diels-Alder
Reactions for the Synthesis of Carbazoles and Indolines
Hong-Fa Wang, Shi-Yue Wang, Tian-Zhu Qin and Weiwei Zi*[a]
Abstract: We herein report a dual gold-catalyzed tetradehydro-
heterocycles,
such
as
carbazoles,
indolines
and
Diels-Alder reactions for the synthesis of nitrogen-containing
tetrahydroquinolines (Scheme 1c), which represent important
synthetic targets due to their prevalence in bioactive natural
products and pharmaceuticals.[7]
aromatic
heterocycles.
Under
the
catalysts
system
(IPrAuNTf2/DIPEA), indolines and carbazoles as well as other N-
containing aromatic heterocycles were prepared in high yields with
good functional group tolerance. Unlike the traditional thermal
tetradehydro-Diels-Alder reactions, diluted reaction concentration
and radical prohibitors are not required for this protocol.
Experimental data support a mechanism involving gold vinylidene
species, which undergoes a 6π electrocyclization, followed with 1,2-
hydrogen shift.
During the last few years, dual gold catalysis has attracted
intensive study and tremendous success has been achieved in
construction of aromatic compounds through this catalytic
mode.[1] Mechanistic studies, as well as theoretical calculations,
suggest gold vinylidene species from 5-endo-dig cyclization of
dialkynes are incorporated in the mechanism.[1a,b] This
intermediate could undergo facile C-H, N-H or O-H insertion to
give a range of polycyclic arenes with an indene backbone
(Scheme 1a).[1,2] Despite of these pioneering works, developing
new reactions based on gold vinylidene chemistry via dual gold
catalysis is still highly desirable.[1n]
A lot of fundamental studies on Thermal tetradehydro-Diels-
Alder (TDDA) reactions[3] have been reported. These provided a
powerfull strategy to de novo synthesis of benzenoids; however,
the harsh reaction conditions, such as high temperature, diluted
reaction concentrations and requirement of polymerization
inhibitors, make them difficult to be used in practical synthesis
(Scheme 1b).[3] Taking the advantages of the ability of Au
complexes to activate alkynes in catalytic processes,[4] Liu
recently reported a gold-catalyzed TDDA reaction[5] at mild
reaction conditions. Widen substrate scope was achieved
compared to Thermal tetradehydro-Diels-Alder (TDDA) reactions.
Notably, terminal akyne substrate only gave low yield in that
system. Inspired by recent dual gold catalysis, we hypothesized
that if a ynamide tethered terminal enyne[6] was used, the n-
exo-dig (n = 5, 6, 7) type of cyclization would be preferred due to
the stabilization of carbocation by amine group. Then a trialkene
type gold vinylidene would form, which could undergo a rapid
cycloaromatization to afford nitrogen-containing aromatic
Scheme 1. Dual gold-catalyzed tetradehydro-Diels-Alder reaction.
To test our hypothesis, substrate 1a was chosen as the model
substrate for the designed reaction (Table 1). (PhO)3PAuNTf2,
Johnphos(AuNTf2)
and
bisphosphine-gold
catalyst
dppe(AuNTf2)2 were firstly investigated. Although the starting
material 1a was completely consumed in all three cases, only
trace of desired tetradehydro-Diels-Alder cyclization product 2a
was detected, with large amount of unidentified polymers formed
under these catalysts (entries 1-3). Further ligands screening
revealed that strong electron-donating IPr (1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) ligand could largely
improve the yield to 48% (entry 4). Encouraged by this result,
additives were then investigated for the purpose to prohibit the
polymerization side reaction. Lewis acids, Fe(OTf)3 and Zn(OTf)2
have no obvious effect to improve the yields (entries 5, 6) but
pyridine base 2,6-tBu2-Py would decrease the yield to 31%.
Nevertheless, the addition of a catalytic amount of trialkyl amine
could greatly enhance the formation of 2a (entries 8, 9). For
instance, when 10 mol% N,N-diisopropylethylamine (DIPEA)
was adding, the yield of 2a was increasing from 48% to 94%.
Controlled experiments showed DIPEA itself could not catalyze
this transformation (entry 10). In the absence of catalysts and
additives, 1a was recovered in 83% yield after heating for 24
[a]
H.-F Wang, S.-Y. Wang, T.-Z, Qin and Prof. Dr. W. Zi
State Key Laboratory and Institute of Elemento-Organic Chemistry
and college of Chemistry, Nankai University
Tianjin, 300071(China)
E-mail: zi@nankai.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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hours at 80°C in dichloroethane (entry 11), without any
cyclization 2a being detected. This result revealed that no
yields. More importantly, this method could be used as a late-
stage carbazole de Novo synthesis. As demonstrated in Scheme
background thermal tetradehydro-Diels-Alder reaction took place. 2, we successfully constructed a carbazole moiety alongside
natural products Menthone, Estrone, and Camphor, with the
corresponding derivatives being isolated in good yields.
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope
entry
1
LAuX
(PhO)3PAuNTf2
JohnphosAuNTf2
dppe(AuNTf2)2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
--
additives
Convertion (%)
Yield (%)
--
--
100
63
4
4
2
3
--
76
13
4
--
100
100
100
100
100
100
<5%
17%
48
5
Fe(OTf)3
Zn(OTf)3
2,6-tBu2-Py
Et3N
39
6
50
7
31
8
75
9
DIPEA
DIPEA
--
94 (91)b
--
10
11
--
0
[a] Reaction conditions: 0.1 mmol 1a, 10 mol% gold catalyst, 10 mol%
additives, 2 mL solvent, 80°C. Yields and conversions were determined by 1H
NMR spectroscopic analysis using CH2Br2 as the internal standard. [b]
Isolated yield.
Having established the optimized reaction parameters, we
next tested the scope of this dual gold catalyzed tetradehydro-
Diels-Alder reaction for the preparation of indolines (Table 2a).
The R groups on the linker chain were first investigated (2a-2c)
and comparable yields were obtained for methyl, ethyl and H.
However, the yields dropped along with increasing the ring size
of the cyclic olefin (2d-2f). For a twelve membered carbon ring
fused indoline 2f, only 40% yield could be obtained with a
prolonged time (4 days). Substrates with a phenyl ring instead of
the olefin moiety worked as well. Substitution at para- or ortho-
positions with Me, Cl, F, tBu or OMe were well tolerated (2g-2m).
However, regioselective cyclization products were observed for
meta-substituted substrate (2p) with a ratio about 2.7:1. This
reaction was competent to synthesis carbazole scaffolds without
modification of the optimal conditions (Table 2b). In most cases,
the reaction could be finished within 48 hours with the desired
carbazoles being isolated with 52%-99% yields. Extension this
method to access other nitrogen heterocycles was also possible
(Table 2c). Tetrahydroquinoline 4a, tetrahydrobenzoquinoline 4b,
tetrahydrothienoquinoline
4c,
benzazepine
4d
and
dihydrophenanthridine 4e were prepared with good to excellent
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we believe the pathway 1 in Scheme 4 is a more reasonable
process.
Scheme 2. Derivatization of natural products.
To get some insights into the mechanism, deuterium labelling
experiments were conducted (Scheme 3). When deuterium
labelling substrate d-1sa was subjected to the reaction, we
observed the acetylenic-D was not maintained at C1 anymore
after the reaction and 16% D atom was detected at C5 position
in product d-3a (D-H exchange between the d-1sa with residual
water in the solvent might explain the low ratio of D/H at C5).[8]
This result ruled out the thermal tetradehydro-Diels-Alder
mechanism. At the meantime, completely D atom transferring
from benzene ring in d-1g to C1 position of d-2g was observed.
Scheme 3. Deuterium labelling experiments.
Based on the above results, together with previous studies
from other groups,[1] a proposed mechanism was given in
Scheme 4. Starting from a base-promoted equilibration, gold
acetylide Int A is generated first to enter the catalytic cycle, and
then the second cationic Au ion is coordinated to the alkyne
moiety, forming a balance of σ，π-digold complex Int B and Int
B’. A 5-exo-dig attack affords gold vinylidene Int C, which
immediately undergoes a rapid 6π electrocyclization to give gold
carbenoids Int D.[9] Int D is then transformed to aryl gold Int E
via 1,2-hydrogen shift, and releasing one IPrAu ion at the same
time. The second IPrAu catalyst was leaving the system to enter
the next catalytic cycle by H-Au exchange between acetylenic-H
in starting material 1a and phenyl-Au in Int E.[10] A second
possible pathway, involving Friedel-Crafts alkylation of gold
carbenoid Int C[11] followed by a protodeauration step. We
thought there should not be a big rate difference between the
two phenyl-Au moiety in Int G during the protodeauration. Thus,
the specifically deuterium atom transferring experiments ruled
out this pathway. An alternative pathway 3 is directly Csp2-H
insertion to gold carbenoid Int C,[1l, 12] resulting intermediate Int
E. This pathway is also consistent with deuterium labelling
results. To distinguish these two mechanisms, we designed X (X
= Cl and Me other than H) group migration experiments.[13] As
showed in Scheme 5, when ortho-substituted 5a (X = Cl) was
tested in the reaction, regioselective cyclization products 5aa
and 5ab was formed with 62%, 22% yields respectively.[14]
Similar result was observed for substrate 5b, in which the X
group is methyl. Carbene insertion into Csp2-Cl and Csp2-Csp3
bond were considered unfavourable due to kinetically inert and
thermodynamically stable property of C−Cl and C-C bonds.[15]
Thus, 5ab and 5bb was not likely formed by this way. We
Scheme 4. Proposed mechanism.
rationalized that the intermediate InC undertake
a
6π
electrocyclization to give regioselective dearomative species Int
D and Int D’. The latter followed with 1,2-chloro- or methyl-shift
to furnish 5ab and 5bb respectively. Taken the above together,
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Scheme 5. Regioselective cyclization experiments.
Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2014, 53, 3854-
3858; Angew. Chem. 2014, 126, 3934-3939.
[3]
[4]
For review, see: a) p. Wessig, G. Müller, Chem. Rev. 2008, 108, 2051-
2063; b) W. Li, L. Zhou, J. Zhang, Chem. Eur. J. 2016, 22, 1558-1571.
For reviews on gold(I)-catalyzed alkyne activation: a) R. Dorel, A. M.
Echavarren, Chem. Rev. 2015, 115, 9028-9072; b) A. S. K. Hashmi,
Chem. Rev. 2007, 107, 3180-3211; c) D. J. Gorin, B. D. Sherry, F. D.
Toste, Chem. Rev. 2008, 108, 3351-3378; d) A. M. Asiri, A. S. K.
Hashmi, Chem. Soc. Rev. 2016, 45, 4471-4503; e) A. Fürstner, P. W.
Davies, Angew. Chem. Int. Ed. 2007, 46, 3410-3449; Angew. Chem.
2007, 119, 3478-3519.
In conclusion, we have developed a dual gold-catalyzed
tetradehydro-Diels-Alder reaction. Nitrogen-containing aromatic
heterocycles including indolines and carbazoles are prepared
highly efficiently by catalysts system IPrAuNTf2/DIPEA. This
reaction does not require diluted reaction concentration and
radical prohibitors. Experiments support a mechanism involving
gold vinylidene species, which undergoes a 6π electrocyclization
followed with 1,2-hydrogen shift.
[5]
[6]
For recent work on gold catalyzed Tetradehydro-Diels-Alder reactions
with ynamide: a) W. Xu, G. Wang, X. Xie, Y. Liu, Org. Lett. 2018, 20,
3273-3277. During the preparation of this manuscript, Gagosz and co-
workers reported a closed related work: b) 10.1002/anie.201807136. In
Acknowledgements ((optional))
this work, [(RuPhos)Au]NTf2 was used as the catalyst and
a
mechanism involving Friedel-Craft alkylation of gold vinylidene was
given for that system.
This work was supported by the National “Young Thousand
Talents Plan”, National Natural Science Foundation of China
(Nos. 21871150) and the Fundamental Research Funds for
Central University. We gratefully acknowledge the State Key
Laboratory of Elemento-organic Chemistry and College of
Chemistry of Nankai University for generous financial support.
For thermal Tetradehydro-Diels-Alder reactions with ynamide: a) J. R.
Dunetz, R. L. Danheiser, J. Am. Chem. Soc. 2005, 127, 5776-5777; b)
M. F. Martínez-Esperón, D. Rodríguez, L. Castedo, C. Saá, Org. Lett.
2005, 7, 2213-2216; c) M. F. Martínez-Esperón, D. Rodríguez, L.
Castedo, C. Saá, Tetrahedron 2006, 62, 3843-3855; d) M. F. Martínez-
Esperón, D. Rodríguez, L. Castedo, C. Saá, Tetrahedron 2008, 64,
3674-3686.
[7]
[8]
[9]
L. S. Tsutsumi, D. Gündisch, D. Sun, Curr. Top. Med. Chem. 2016, 16,
1290-1313.
Keywords: dual gold catalysis • tetradehydro-Diels-Alder
reactions • gold vinylidene • 6π electrocyclization
Facile H/D exchange of alkyne terminal hydrogen with D2O was
observed: see ref. 1a, 1c.
[1]
a) L. Ye, Y. Wang, D. H. Aue, L. Zhang, J. Am. Chem. Soc. 2012, 134,
31-34; b) A. S. K. Hashmi, I. Braun, M. Rudolph, F. Rominger,
Organometallics 2012, 31, 644-661; c) A. S. K. Hashmi, M. Wieteck, I.
Braun, P. Nçel, L. Jongbloed, M. Rudolph, F. Rominger, Adv. Synth.
Catal. 2012, 354, 555-562; d) A. S. K. Hashmi, I. Braun, P. Nçel, J.
Schulich, M. Wieteck, M. Rudolph, F. Rominger, Angew. Chem. Int. Ed.
2012, 51, 4456-4460; Angew. Chem. 2012, 124, 4532-4536; e) A.
GýmezSu‚rez, S. P. Nolan, Angew. Chem. Int. Ed. 2012, 51, 8156-
8159; Angew. Chem. 2012, 124, 8278-8281; f) A. S. K. Hashmi, M.
Wieteck, I. Braun, M. Rudolph, F. Rominger, Angew. Chem. Int. Ed.
2012, 51, 10633-10637; Angew. Chem. 2012, 124, 10785-10789; g) M.
M. Hansmann, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew.
Chem. Int. Ed. 2013, 52, 2593-2598; Angew. Chem. 2013, 125, 2653-
2659; h) P. Nçel, T. Lauterbach, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Chem. Eur. J. 2013, 19, 8634-8641; i) D. D. Vachhani, M. Galli,
J. Jacobs, L. Van Meervelt, E. V. Van der Eycken, Chem. Commun.
2013, 49, 7171-7173; j) Y. Wang, A. Yepremyan, S. Ghorai, R. Todd, D.
H. Aue, L. Zhang, Angew. Chem. Int. Ed. 2013, 52, 7795-7799; Angew.
Chem. 2013, 125, 7949-7953; k) I. Braun, A. M. Asiri, A. S. K. Hashmi,
ACS Catal. 2013, 3, 1902-1907; l) M. H. Vilhelmsen, A. S. K. Hashmi,
Chem. Eur. J. 2014, 20, 1901-1908; m) M. Wieteck, Y. Tokimizu, M.
Rudolph, F. Rominger, H. Ohno, N. Fujii, A. S. K. Hashmi, Chem. Eur. J.
2014, 20, 16331-16336; n) A. S. K. Hashmi, Acc. Chem. Res. 2014, 47,
864-876; o) J. Bucher, T. Stçßer, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2015, 54, 1666-1670; Angew. Chem.
2015, 127, 1686-1690; p) R. J. Harris, R. A. Widenhoefer, Angew.
Chem. Int. Ed. 2015, 54, 6867-6869; Angew. Chem. 2015, 127, 6971-
6973; (q) M. H. Larsen, K. N. Houk, A. S. K. Hashimi, J. Am. Chem.
Soc. 2015, 137, 10668-10676; (r) Y. Tokimizu, M. Wieteck, M. Rudolph,
S. Oishi, N. Fuji, A. S. K. Hashimi, H. Ohno, Org. Lett. 2015, 17, 604-
607; (s) C. Yu, B. Chen, T. Zhou, Q. Tian, G. Zhang, Angew. Chem. Int.
Ed. 2015, 54, 10903-10907; Angew. Chem. 2015, 127, 11053-11057.
For alternative process involving gold vinylidene species, see: a) P.
Morán-Poladura, E. Rubio, J. M. González, Angew. Chem. Int. Ed.
2015, 54, 3052-3055; Angew. Chem. 2015, 127, 3095-3098; b) Y.
Wang, M. Zarca, L.-Z. Gong, L. Zhang, J. Am. Chem. Soc. 2016, 138,
7516-7519; c) J. Bucher, T. Wurm, K. S. Nalivela, M. Rudolph, F.
For metal vinylidene in 6π electrocyclization: a) C. A. Merlic, M. E.
Pauly, J. Am. Chem. Soc. 1996, 118, 11319-11320; b) K. Maeyama, N.
Iwasawa, J. Org. Chem. 1999, 64, 1344-1346; c) J. W. Dankwardt,
Tetrahedron Lett. 2001, 42, 5809-5812; d) T. Miura, N. Iwasawa, J. Am.
Chem. Soc. 2002, 124, 518-519; e) H.-C. Shen, S. Pal, J.-J. Lian, R.-S.
Liu, J. Am. Chem. Soc. 2003, 125, 15762-15763; f) J.-J. Lian, A.
Odedra, C.-J. Wu, R.-S. Liu, J. Am. Chem. Soc. 2005, 127, 4186-4187.
[10] An off-cycle gem-diaurated species might be involved: a) D. Weber, T.
D. Jones, L. L. Adduci, M .R. Gagné, Angew. Chem. Int. Ed. 2012, 51,
2452-2456; Angew. Chem. 2012, 124, 2502-2506; b) D. Weber, M. R.
Gagné, Chem. Sci. 2013, 4, 335-338; and Ref 1c.
[11] For Friedel-Craft alkylation of gold carbenoid: a) N. D. Shapiro, F. D.
Toste, J. Am. Chem. Soc. 2007, 129, 4160-4167; b) B. Yu, Y. Li, Y.
Wang, D. H. Aue, Y. Luo, L. Zhang, J. Am. Chem. Soc. 2013, 135,
8512-8512; c) Y. Wang, K. Ji, S. Lan, L. Zhang, Angew. Chem. Int. Ed.
2012, 51, 1915-1918; Angew. Chem. 2012, 124, 1951-1954; d) Z. Yu, B.
Ma, M. Chen. H.-H. Wu, L. Liu, J. Zhang, J. Am. Chem. Soc. 2014, 136,
6904-6907; e) Z. Yu, B. Ma, M. Chen, H.-H. Wu, L. Liu, J. Zhang,
Angew. Chem. Int. Ed. 2017, 56, 2749-2753; Angew. Chem. 2017, 129,
2793-2797.
[12]
For C-H insertion into gold carbenoid: a) Y. Horino, T. Yamamoto, K.
Ueda, S. Kuroda, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 2809-
2811; b) Y. Wang, Z. Zhang, L. Zhang, J. Am. Chem. Soc. 2015, 137,
5316-5319.
[13] The corresponding indoline type product 2m was formed exclusively,
without any Cl-migration product being detected.
[14] CCDC-1864280
(5aa),
CCDC-1864281
(5ab)
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
[15] So far, only formal carbene insertion to Csp2-Csp3 and C-X bonds were
reported, which were enabled by transition metal oxidative addition of
Csp2-Csp3 and C-X bonds. For examples, see: a) Y. Xia, Z. Lin, Z. Liu, R.
Ge, F. Ye, M. Hossain, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2014,
136, 3013-3015; b) K. L. Greenman, D. L. V. Vranken, Tetrahedron,
2005, 61, 6438-6441; c) Y. Gao, G. Wu, Q. Zhou, J. Wang, Angew.
Chem. Int. Ed. 2018, 57, 2716-2720; Angew. Chem. 2018, 130, 2746-
[2]
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2750; for review for carbene migratory insertion: d) Y. Xia, D. Qiu, J.
Wang, Chem. Rev. 2017, 117, 13810-13889.
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Entry for the Table of Contents (Please choose one layout)
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Dual gold-catalyzed tetradehydro-
Diels-Alder reaction was achieved.
Hong-Fa Wang, Shi-Yue Wang, Tian-
Zhu Qin and Weiwei Zi*
Nitrogen-containing
aromatic
Page No. – Page No.
heterocycles including indolines and
carbazoles are prepared with high
Dual Gold-Catalyzed Tetradehydro-
Diels-Alder Reactions for the
Synthesis of Carbazoles and
Indolines
yields
Experiments support
under
mild
conditions.
mechanism
a
involving gold vinylidene species,
which undergoes 6π
a
electrocyclization followed with 1,2-
hydrogen shift.
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