Generation of Endocyclic Vinyl Carbene Complexes via Gold-Catalyzed Oxidative Cyclization of Terminal Diynes: Toward Naphthoquinones and Carbazolequinones

Article abstract of DOI:10.1021/acscatal.8b04455

Carbene cascade reactions involving carbene/alkyne metathesis have attracted much attention over the past decades because this chemistry offers great potential to build complicated cyclic molecules. However, the formed vinyl metal carbenoids in these reactions are limited to exocyclic carbenes, and the generation of endocyclic vinyl carbene complexes remains unexplored. Here, we report an unprecedented gold-catalyzed oxidative cyclization of terminal diynes. Importantly, the generation of endocyclic vinyl carbene complexes was involved in this oxidative cyclization, which is distinctively different from previous protocols. This method allows the facile synthesis of various valuable naphthoquinones and carbazolequinones from readily available diynes under exceptionally mild reaction conditions and features a broad substrate scope and wide functional group tolerance. Moreover, theoretical calculations provide further evidence on the divergent selectivity of this cyclization reaction.

Full text of DOI:10.1021/acscatal.8b04455

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Article
Generation of Endocyclic Vinyl Carbene Complexes via
Gold-Catalyzed Oxidative Cyclization of Terminal Diynes:
Towards Naphthoquinones and Carbazolequinones
Chao Shu, Chong-Yang Shi, Qing Sun, Bo Zhou, Tian-
You Li, Qiao He, Xin Lu, Rai-Shung Liu, and Long-Wu Ye
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04455 • Publication Date (Web): 24 Dec 2018
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Generation of Endocyclic Vinyl Carbene Complexes via Gold-Catalyzed Oxi-
dative Cyclization of Terminal Diynes: Towards Naphthoquinones and Car-
bazolequinones
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Chao Shu,†,# Chong-Yang Shi,†,# Qing Sun,† Bo Zhou,† Tian-You Li,† Qiao He,† Xin Lu,*,† Rai-Shung
Liu,‡ and Long-Wu Ye*,†,§
†iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces, and Key Laboratory for Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
‡Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan.
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China.
ABSTRACT: Carbene cascade reactions involving carbene/alkyne metathesis have attracted much attention over the past decades
because this chemistry offers great potential to build complicated cyclic molecules. However, the formed vinyl metal carbenoids in
these reactions are limited to exocyclic carbenes, and the generation of endocyclic vinyl carbene complexes remains unexplored.
Here we report an unprecedented gold-catalyzed oxidative cyclization of terminal diynes. Importantly, the generation of endocyclic
vinyl carbene complexes was involved in this oxidative cyclization, which is distinctively different from previous protocols. This
method allows the facile synthesis of various valuable naphthoquinones and carbazolequinones from readily available diynes under
exceptionally mild reaction conditions and features a broad substrate scope and wide functional group tolerance. Moreover, theoret-
ical calculations provide further evidence on the divergent selectivity of this cyclization reaction.
KEYWORDS : gold, oxidation, cyclization, carbenes, diynes
INTRODUCTION
Scheme 1. Non-Diazo Approaches for Carbene Cascade
Catalytic transformations via a metal carbenoid pathway are
considered to be one of the most important aspects of
homogeneous transition-metal catalysis.1 Among those,
carbene cascade reactions involving carbene/alkyne metathesis
have attracted much attention because this chemistry offers
great potential to build complicated cyclic molecules, and
metal-catalyzed decompositions of diazo carbonyls are the
principal and most reliable strategy.2 Unfortunately, this
strategy is hindered by the nature of these diazo substrates,
which are hazardous, not easily accessible, and potentially
explosive. Recently, several non-diazo approaches to such a
carbene cascade reaction have been established.3-5 In 2013,
Gevorgyan and co-workers reported an elegant protocol for
the rhodium-catalyzed transannulation reaction of alkynyl N-
sulfonyl-1,2,3-triazoles, leading to various 5,5-fused pyrroles
Reactions Involving Carbene/Alkyne Metathesis
(Scheme
1a).3
In
addition,
the
gold-catalyzed
cycloisomerization of 1,6-diyne esters via carbene/alkyne
metathesis was also nicely exploited by the research groups of
Chan, Hashmi, and Liu (Scheme 1b).4 In particular, recent
studies on the transition metal-catalyzed diyne oxidations by
an N–O bond oxidant provided an attractive alternative method
for such a carbene/alkyne metathesis, and various synthetic
methods involving a 1,6-carbene transfer were disclosed
(Scheme 1c).5 For example, Hashmi et al. demonstrated that
the α-oxo gold carbenoids generated by gold-catalyzed alkyne
oxidation could be transferred across the second alkyne via a
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presumable 1,6-carbene transfer, which could undergo
entries 1–7). Using 2-bromopyridine N-oxide 3a (3.0 equiv) as
oxidant, trifluoroacetic acid (2.0 equiv) as additive, and the
bulky BrettPhosAuNTf2 (10 mol %) as gold catalyst, we were
pleased to find the corresponding 1,4-naphthoquinone 2a
could be formed in 64% yield (Table 1, entry 6). Of note, oth-
er metal catalysts such as AgNTf2, PtCl2, and Zn(OTf)2 failed
to provide even a trace of the desired 2a (Table 1, entries 8–
10). Further investigation of the oxidants (Table 1, entries 11–
14) revealed that 70% yield was obtained by the use of 8-
ethylquinoline N-oxide 4b as an oxidant (Table 1, entry 13). In
addition, it was found that the reaction efficiency was signifi-
cantly improved by changing the counteranion of the gold
catalyst from Tf2N– to F6Sb–, under which conditions 2a was
furnished in 81% yield (Table 1, entry 15).12 Finally, it should
be mentioned that the reaction gave a slightly decreased yield
in the absence of acid additive.11,7e
subsequent transformations such as Wagner−Meerwein
chemistry, CH insertions and double oxidation.5a Tang et al.
also reported rhodium-catalyzed such a diyne oxidation,
leading to various substituted 2-oxopyrrolidines.5b Very
recently, our group realized the copper-catalyzed oxidation of
azido-diynes, where the generated vinyl copper carbenoid was
eventually trapped by the azido group.5c Moreover, the
relevant gold-catalyzed oxidative cyclization of 1,6-diynes
was further developed by the groups of Zhang5d and Ji,5e
respectively. Despite these findings, the formed vinyl metal
carbenoids in all these carbene cascade reactions are limited to
exocyclic carbenes, and the generation of endocyclic vinyl
carbene complexes has not yet been reported.6
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Inspired by these findings and our study of catalytic alkyne
oxidations,7,8 we envisioned that the gold-catalyzed oxidative
cyclization of terminal diynes might generate endocyclic vinyl
gold carbenoids, which would undergo a subsequent second
oxidation to produce the corresponding 1,4-naphthoquinones.
Table 1. Optimization of Reaction Conditionsa
Herein, we wish to report the realization of such
a
carbene/alkyne metathesis involving the generation of
endocyclic vinyl carbene complexes, which is distinctively
different from the above protocols (Scheme 1d). This method
allowed the facile synthesis of a range of valuable substituted
naphthoquinones9 and carbazolequinones,10 structural motifs
that can be observed frequently in various natural products and
bioactive molecules (Figure 1). Moreover, our proposed
mechanistic rationale for this unique oxidative cyclization,
especially for the distinct selectivity, is well supported by
theoretical calculations. In this paper, we wish to report the
results of our detailed investigations of this gold-catalyzed
oxidative cyclization of terminal diynes involving the
generation of endocyclic vinyl carbene complexes, including
substrate scope, synthetic applications and mechanistic studies.
aReaction conditions: [1a] = 0.05 M, oxidant (3.0 equiv).
1
bMeasured by H NMR using diethyl phthalate as internal stand-
ard. cAr = 2,4-di-tert–butylphenyl. d60 oC, 24 h.
2. Substrate Scope. With the optimized reaction conditions
in hand (Table 1, entry 15), we then investigated the scope of
this oxidative diyne cyclization reaction. As shown in Table 2,
the reaction proceeded smoothly with various diyne substrates
1, and the corresponding 1,4-naphthoquinones 2 were formed
in moderate to good yields. Diynes with electron-donating
groups were first screened, and the reaction furnished the
desired products 2a–2k in 59–83% yields (Table 2, entries 1–
11). It is notable that a range of functional groups such as the
protected hydroxy and amino were well tolerated in this
transformation (Table 2, entries 6–11). In particular, the
reaction could be extended to sterically hindered diyne 1g,
Figure 1. Representative natural products and bioactive mole-
cules with naphthoquinone and carbazolequinone motifs.
RESULTS AND DISCUSSION
1. Catalyst Evaluation. At the outset, dialkyne 1a was em-
ployed as the model substrate to examine the oxidative cy-
clization, and some of the results are listed in Table 1.11 The
influence of various gold catalysts was first screened (Table 1,
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leading to the desired 2g in 60% yield (Table 2, entry 7).
We next considered the possibility of extending the reaction
to other heterocycle-tethered diynes. Gratifyingly, this
oxidative cyclization of indole-linked diynes 5 also occurred
readily, leading to the desired carbazole-1,4-quinones 6 in
moderate yields (Table 3). Diynes bearing different N-
protecting groups, even the labile N-Ac group (Table 3, entry
5), were suitable substrates for such an oxidative cyclization to
afford the corresponding products 6a–6e in 59–65% yields
(Table 3, entries 1–5). Substrates with both electron-donating
and electron-withdrawing substituents on the indole ring also
worked (Table 3, entries 6–9), but the reaction proceeded less
efficiently in the latter case (Table 3, entries 8 and 9). The
molecular structure of 6a was further confirmed by X-ray dif-
fraction (Figure 2).15 Thus, this protocol provides a facile and
general way for the synthesis of valuable carbazolequinones,
which are not readily accessible by known methods.16
Electron-deficient aryl substrates were also suitable substrates
for this oxidative cyclization to produce the corresponding
naphthoquinones 2m–2o in serviceable yields, and similar
decreased efficiency was also observed in Zhang’s13a and
Gagosz’s13b protocols on the oxidative cyclization (Table 2,
entries 13–15). Moreover, it was found that the naphthalene-
linked diyne 1p also proceeded well (Table 2, entry 16). Nota-
bly, attempts to extend the reaction to the cyclohexene-linked
diyne 1q and internal diynes such as 1r and 1s gave only a
complex mixture of products, and the oxidative cyclization of
unsymmetrical diyne 1t only led to the formation of the exo-
cyclic product 2t as the main product.11,14 A gram-scale reac-
tion of 1a (1.08 g) was carried out in the presence of 5 mol %
of gold catalyst, and the desired 2a was formed in 75% yield,
highlighting the synthetic utility of this chemistry (Table 2,
entry 1).
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Table 3. Reaction Scope for the Formation of Carbazole-
1,4-quinones 6a
Table 2. Reaction Scope for the Formation of 1,4-
Naphthoquinones 2a
aReactions run in vials; [5] = 0.05 M; isolated yields are reported.
Figure 2. Structure of compound 6a in its crystal.
aReactions run in vials; [1] = 0.05 M; isolated yields are reported.
In addition, this oxidative cyclization also proceeded effi-
ciently with pyrrole-linked diynes 7, and the desired
indolequinones 8a–8b were formed in good yields (eq. 1).
b7.0 mmol scale with 5 mol % of BrettPhosAuCl/AgSbF6.
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Notably, this heterocyclic motif is found in a variety of bioac-
4. Mechanistic Study. To gain further mechanistic insights
into this process, several control experiments were performed.
It was found that when diyne 1a was treated with 2 equiv of
N-oxide 4b in 1,2-dichloroethane (DCE) as solvent under the
standard conditions, the formation of chlorinated naphthalen-
1-ol 2ae was observed in 18% yield, and the yield could be
further improved to 35% by employing (ArO)3PAuNTf2 as a
catalyst (eq. 2). Moreover, the oxidative cyclization of 1a in
1,2-dibromoethane (EDB) also led to the significant formation
of the corresponding brominated naphthalen-1-ol 2af. These
results are consistent with the involvement of a highly reactive
gold carbene intermediate in this tandem sequence.21
tive molecules.17
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3. Synthetic Applications. The substituted naphthoqui-
nones, which are not readily prepared by typical ways for
naphthoquinone synthesis, are potentially useful in organic
synthesis and medicinal chemistry. Moreover, these naphtho-
quinones could be converted to an array of valuable naphtho-
quinone derivatives.18 For example, naphthoquinone 2a un-
derwent selective bromination to deliver the desired 2aa and
2ab in 85 and 80% yield,18a respectively, and both could be
further converted to bioactive molecules.19 In addition, 2a
could be transformed into the desired epoxide compound 2ac
in 75% yield.18b In particular, the direct arylation of 2a with
phenyl boronic acid via palladium-catalyzed C–C coupling led
to the formation of aryl-substituted naphthoquinone 2ad in
79% yield,18c which is a beneficial supplement to the reaction
scope of this protocol. Furthermore, naphthoquinone 2g, a
BoNT/A inhibitor,20 could be readily transformed into juglone
2ga9e by removal of the Me group. Of note, selective palladi-
um-catalyzed arylation of 2ga by the addition of boronic acids
afforded the corresponding BACE1 inhibitors9g 2gb and 2gc,
respectively, according to the known procedures.18c
On the basis of the above experimental observations and
density functional theory (DFT) computations, plausible
mechanisms to rationalize the formation of naphthoquinone 2l
using bulky model ligand L = BrettPhos and simplified model
ligand L= PH3, respectively, are illustrated (Scheme 3).11,22,23
Initially, nucleophilic attack by N-oxide on the Au(I)-ligated
diyne A forms a vinyl gold intermediate B. Notably, cleavage
of the N-O bond in intermediate B gives directly the cyclopro-
penic intermediate C1, by
-oxo gold-
carbene intermediate C. This step follows the so-called two-
step no-intermediate mechanism.24 The absence of the pre-
sumed gold-carbene intermediate C accounts for the absence
of 1,2-diketone byproduct which otherwise can be readily
formed by nucleophilic attack of a second N-oxide to the gold-
carbene intermediate. The intermediate C1 readily isomerizes
into another cyclopropenic intermediate D with Au(I)L coor-
dinated to the C=C bond, which further transforms into the
endocyclic vinyl gold carbenoid intermediate E. Nucleophilic
attack by another N-oxide on the carbenoid carbon atom of E
is barrierless and exothermic, forming intermediate F. Cleav-
age of the N-O bond in F affords the Au(I)-ligated naphtho-
quinone G, which releases the final product 2l upon migration
of Au(I)L to diyne 1l. The whole process is highly exothermic
with free energy release amounting to 152.1 kcal/mol. Note
that the use of bulky ligand has little effect on the activation
free energies of the rate limiting step (the first O-transfer step
around the transition state TSC by N-O bond cleavage), 13.4
kcal/mol for L=PH3 vs. for 12.1 kcal/mol for L=BrettPhos.
This justifies the use of the simplified model ligand instead of
the large BrettPhos for efficient computational exploration of
the reaction mechanism. Furthermore, a more detailed mecha-
nistic research and the mechanistic difference between termi-
nal diynes and internal diynes using the simplified model lig-
and PH3 are provided in the supporting materials.11 Thus,
based on these results and previous studies,6 exo vs endo selec-
Scheme 2. Synthetic Applications
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We are grateful for the financial support from the National Natu-
tivity might be dependent on the nature of the substituent at-
tached to the alkyne tether, and the generation of stable vinyl
cation is the key for the regioselectivity of cyclization.
ral Science Foundation of China (21572186, 21622204, 21772161
and 91545105), PCSIRT, NFFTBS (J1310024) and Science &
Technology Cooperation Program of Xiamen (3502Z20183015).
Scheme 3. Plausible Reaction Mechanism. Relative Free
Energies (ΔGDCM) of Key Intermediates and Transition
States Were Computed at the SMD-M06/6-31+G(d)/SDD
Level for Model Reaction in DCM at 298 K. Data for the
Case of L=PH3 Were Given in Parentheses.
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CONCLUSIONS
In summary, we have developed a novel gold-catalyzed oxida-
tive cyclization of terminal diynes. Importantly, the generation
of endocyclic vinyl carbene complexes was involved in this
oxidative cyclization, which is distinctively different from
previous protocols. The new method leads to the facile and
straightforward synthesis of various valuable naphthoquinones,
carbazolequinones and indolequinones from readily available
diynes under exceptionally mild reaction conditions and fea-
tures a broad substrate scope and wide functional group toler-
ance. Furthermore, a computational study provides further
evidence for the feasibility of the proposed mechanism, espe-
cially for the distinct selectivity.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Experimental procedures, compound characterization data,
computational details, and copies of 1H and 13C NMR
spectra (PDF)
Crystallographic data of 6a (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: longwuye@xmu.edu.cn
*E-mail: xinlu@xmu.edu.cn
Author Contributions
C.S. and C.-Y.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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