Gold-Catalyzed Cycloisomerization/1,5-H Migration/Diels-Alder Reaction Cascade: Synthesis of Complex Nitrogen-Containing Heterocycles

Article abstract of DOI:10.1021/acs.orglett.7b00090

An unprecedented gold-catalyzed cycloisomerization/1,5-H migration/Diels-Alder reaction cascade has been developed that enables the rapid construction of complex nitrogen polycyclic compounds. This one-pot, three-step cascade reaction offers good yields o

Full text of DOI:10.1021/acs.orglett.7b00090

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Cycloisomerization/1,5‑H Migration/Diels−Alder
Reaction Cascade: Synthesis of Complex Nitrogen-Containing
Heterocycles
Shuyao Zhang,† Beiming Cheng,† Shen-An Wang,† Ling Zhou,†,§ Chen-Ho Tung,† Jianwu Wang,†
and Zhenghu Xu*,†,‡
†Key Lab for Colloid and Interface Chemistry of Education Ministry, School of Chemistry and Chemical Engineering, Shandong
University, Jinan 250100, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
§Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
S
* Supporting Information
ABSTRACT: An unprecedented gold-catalyzed cycloisomeriza-
tion/1,5-H migration/Diels−Alder reaction cascade has been
developed that enables the rapid construction of complex nitrogen
polycyclic compounds. This one-pot, three-step cascade reaction
offers good yields of the products and is promoted by a single gold
catalyst under very mild conditions.
Scheme 1. Gold-Catalyzed [1,5]-H Migration Reactions
pplications of homogeneous gold catalysis have witnessed
exponential growth in recent years. Gold catalysts serving
A
as π-acids can activate C−C multiple bonds and trigger
subsequent cascade reactions to assemble complex structures.1
Lewis acid promoted [1,5]-H migration has been developed as
an important strategy with which to functionalize sp3 C−H
bonds adjacent to heteroatoms, and it has been widely used in
organic synthesis.2−4 Gold catalyst can also catalyze this
reaction by activating an alkyne moiety to participate as a
hydride acceptor in subsequent cascade reactions (Scheme 1).
In 2010, Gagosz and co-workers reported that C(2)-alkyne-
tethered tetrahydrofurans can undergo [1,5]-hydride migration
to the gold(I)-activated alkyne, followed by the intramolecular
cyclization between the vinylgold species and oxonium
intermediate, generating spirodihydropyran structures (Scheme
1A).5 Gold-catalyzed [1,5]-hydride migration and subsequent
elimination reactions can produce allene products, and this has
been developed as an important method for the synthesis of
chiral allenes (Scheme 1B).6 Recently, the group of Gong
reported a gold-catalyzed [1,5]-hydride shift generating
isoindole intermediate, subsequent Diels−Alder reaction
provided bridged-ring heterocycles in one-pot reaction
(Scheme 1C).7 In this paper, we report an unexpected gold-
catalyzed cycloisomerization/1,5-H migration/Diels−Alder re-
action cascade, generating structurally complex nitrogen
bridged-ring polycyclic compounds in one step from readily
available starting materials (Scheme 1D). This efficient, one-
pot, three-step cascade reaction is promoted by a single gold
catalyst at room temperature in 1 h.
intermediate (M1). This is followed by σ metal Lewis acid
catalyzed [4 + 2] or [3 + 2] cycloaddition reactions giving
complex spiroheterocycles efficiently (Scheme 2).8 During our
continuing studies of this reaction, which combines π-acid and
Recently, we used a gold-catalyzed 5-exo-dig cyclization of an
Received: January 11, 2017
alkynyl amide generating an active exocyclic enamide
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00090
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3). These results prompted us to examine the possible role of
the Lewis acid in this cascade reaction. It was found that this
reaction proceeded equally well in the absence of the Lewis
acid. With only 5 mol % of Ph3PAuNTf2 as catalyst, the
reaction was complete in 1 h at room temperature, and the
target product (3a) was isolated in 93% yield (entry 4). Other
commonly used gold catalysts were screened (entries 5−8), and
it was found that PPh3AuCl/AgOTf gave an acceptable yield
(89%), but other gold catalysts such as AuCl, AuCl3, and
Me2SAuCl gave much lower yields. The solvent effect was also
investigated, and it was found that similar yields were obtained
in THF solution (entry 9) but no reaction was observed in
acetonitrile (entry 10). When the gold catalyst level was
decreased to 1 mol %, the product was obtained in 85% isolated
yield within 2 h, illustrating the efficiency of this gold-catalyzed
cascade reaction.
Scheme 2. Gold-Catalyzed Cycloisomerization/
Cycloaddition Cascade Leading to Molecular Complexity
The scope of this cascade reaction was then investigated by
using the optimal reaction conditions. We first studied the
cascade reaction of N-phenylmaleimide (2a) with various
alkynyl amides. As shown in Scheme 3, a large variety of
σ-acid catalysis, we investigated the reaction of 1a with N-
phenylmaleimide (2a) in the presence of Ph3PAuNTf2 and
La(OTf)3 to determine if it is possible to develop a [2 + 2]
cascade reaction generating a push−pull four-membered ring.
However, the target spirocyclobutane was not detected in this
reaction, but a different nitrogen bridged-ring polycycle (3a)
was isolated in 94% yield (Scheme 2), and its structure was
unambiguously characterized by X-ray crystallography.9 In
contrast with our previous reports, this electron-rich enamide
(M1) isomerizes into an isoindole (M2) and serves as the diene
component in a subsequent Diels−Alder reaction with a
dienophile.10 Interestingly, only the endo isomer of 3a was
observed in this reaction.
a
Scheme 3. Scope of Alkynyl Amides
These findings encouraged us to explore this reaction further
(Table 1). We discovered that various Lewis acids such as
Al(OTf)3, Yb(OTf)3, and La(OTf)3 all undergo very clean
reactions, giving the product (3a) in 91−95% yield (entries 1−
a
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Ph3PAuNTf2 (5
mol %), and dry DCM (2 mL) were stirred at room temperature
under an N2 atmosphere. Isolated yields are reported.
b
entry
[Au]
[LA]
solvent
time (h) yield (%)
1
2
3
4
5
6
7
8
9
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuOTf
Me2SAuCl
AuCl
Al(OTf)3
Yb(OTf)3
La(OTf)3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
1
1
1
1
1
1
1
1
1
1
1
2
91
95
94
93
89
89
57
46
93
0
bridged-ring polycyclic compounds were synthesized as a single
diastereomer and in good to excellent yield by these simple
gold-catalyzed cascade reactions. Substituents at the α position
of nitrogen atom have no effect on the reaction. Substrates with
aliphatic groups such as methyl and benzyl react smoothly to
afford the target products in good yields (3b,c). A tosylamide
bearing a vinyl group was also suitable for this transformation,
giving the product 3d in 56% yield. Substrates with various
aromatic groups as substituents are all amenable to this
transformation, giving the corresponding products (3e−k) in
51−96% yields. Electron-donating groups such as CH3 and
CH3O or electron-withdrawing groups such as CF3 at the para-
or meta-position of the aromatic ring are well tolerated in this
reaction. Unfortunately, when the internal nucleophile NHTs
was replaced with an OH group, the reaction under standard
condition was messy and no major product could be isolated.
AuCl3
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
c
10
MeCN
PhMe
DCM
11
67
85
d
12
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Au] (5 mol %),
solvent (2 mL), N2 atmosphere. Isolated yields were reported. The
reaction mixture was messy, and no 3a was observed. 1 mol % of gold
catalyst.
b
c
d
B
DOI: 10.1021/acs.orglett.7b00090
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Organic Letters
Letter
Various dienophiles were investigated to further explore the
generality of the above reaction (Scheme 4). Maleimides with a
(Scheme 5c). These kinds of multisubstituted naphthalene
compounds are difficult to prepare by other methods.
In an effort to understand the mechanism of this reaction, we
conducted deuterium-labeling experiments (Scheme 6). When
a
Scheme 4. Substrate Scope of Dienophiles
Scheme 6. Deuterium-Labeling Experiments
a
Reaction conditions: 1b (0.1 mmol), 2 (0.15 mmol), Ph3PAuNTf2 (5
5 equiv of D2O was added to the standard reaction, the newly
formed angular methyl group was 30% deuterated (eq 1). The
reaction of deuterated [D2]-1a under standard conditions led to
product [D2]-3a with a 20% deuterium content at the methyl
group (eq 2). If 5 equiv of D2O was added to this reaction of
[D2]-1a, the methyl group in the product had a deuterium
content of 55% (eq 3). These results clearly indicate a [1,5]-D
migration mechanism. On the other hand, [1.5]-H migration
followed by cyclization can also generate the isoindole
intermediate M2, but the first [1,5]-H migration step breaks
the aromaticity of benzene ring and is therefore unlikely. Gold-
catalyzed 5-exo-dig cyclization and a [1,5]-H migration
sequence are more probable.
In summary, we have developed a highly efficient gold(I)-
catalyzed cascade reaction to build bridged-ring polycyclic
compounds. This approach provides an atom-economical
synthesis of structurally complex polycyclic heterocycles from
readily available starting materials. This cascading cyclo-
isomerization/1,5-H migration/Diels−Alder reaction is trig-
gered by a gold catalyst under mild conditions. This type of
gold(I)-catalyzed cascade reaction to construct complex
structures will find applications in organic synthesis.
mol %), and dry DCM (2 mL) were stirred at room temperature
under an N2 atmosphere. Isolated yields are reported.
methyl group (2b) or a benzyl group (2c) reacted with 1b
efficiently, and the corresponding products (3l,m) were isolated
as the single endo-isomer in 57% and 70% yields, respectively.
The reaction of dimethyl acetylenedicarboxylate (2e) with 1b
provided the unsaturated bridged polycycle (3o) in 86% yield.
Dienophiles 2d and 2f also reacted with 1b, affording the
corresponding products in moderate yields. Notably, methyl-
eneindolinone (2g) was an excellent partner in this reaction,
delivering the corresponding product (3q) as a single
diastereomer in excellent yield.
The reaction of the thiophene-substituted alkyne (1l) gave
the bridged polycyclic 3r, which is unstable and isomerized into
the thienyl naphthalene (4a) in 80% yield (Scheme 5a). Simply
heating product 3a in the presence of 10 mol % of Cu(OTf)2
leads to formation of the polyaromatic compound (4b) in 92%
yield by the elimination of one molecule of TsNH2 (Scheme
5b). Compound 3s can be transformed into the 1-naphthyl-
amine derivative (4c) in 81% yield in the presence of TfOH
Scheme 5. Synthetic Applications
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00090.
Experimental details, crystal structure of 3a, and
characterization data (PDF)
X-ray data for compound 3a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xuzh@sdu.edu.cn.
ORCID
Zhenghu Xu: 0000-0002-3189-0777
C
DOI: 10.1021/acs.orglett.7b00090
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) (a) Wu, X.; Chen, S.-S.; Hu, Y.; Gong, L.-Z. Org. Lett. 2014, 16,
3820.
Notes
The authors declare no competing financial interest.
(8) (a) Wang, X.; Yao, Z.; Dong, S.; Wei, F.; Wang, H.; Xu, Z. Org.
Lett. 2013, 15, 2234. (b) Wang, X.; Dong, S.; Yao, Z.; Feng, L.; Daka,
P.; Wang, H.; Xu, Z. Org. Lett. 2014, 16, 22. (c) Zhang, S.; Xu, Z.; Jia,
J.; Tung, C.-H.; Xu, Z. Chem. Commun. 2014, 50, 12084. (d) Wang, B.;
Chen, Y.; Zhou, L.; Wang, J.; Tung, C.-H.; Xu, Z. J. Org. Chem. 2015,
80, 12718. (e) Wang, B.; Chen, Y.; Zhou, L.; Wang, J.; Xu, Z. Org.
Biomol. Chem. 2016, 14, 826. (f) Wang, B.; Liang, M.; Tang, J.; Deng,
Y.; Zhao, J.; Sun, H.; Tung, C.-H.; Jia, J.; Xu, Z. Org. Lett. 2016, 18,
4614.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Natural Science
Foundation of China and Shandong province (nos. 21572118
and JQ201505), the fundamental subject construction funds
(104.205.2.5), and a Tang Scholar award from Shandong
University.
(9) CCDC 1525500 (3a) contains the supplementary crystallo-
graphic 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.
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DOI: 10.1021/acs.orglett.7b00090
Org. Lett. XXXX, XXX, XXX−XXX