Gold(I)-Catalyzed Formal Intramolecular Dehydro-Diels-Alder Reaction of Ynamide-ynes: Synthesis of Functionalized Benzo[ b]carbazoles

Article abstract of DOI:10.1021/acs.orglett.8b01145

A gold-catalyzed cycloisomerization of ynamide-ynes via a formal dehydro-Diels-Alder reaction has been developed, providing an attractive route to diversely substituted benzo[b]carbazoles. The reaction likely proceeds via regioselective attack of the pendant alkyne moiety to a keteniminium ion intermediate followed by benzannulation. The method offers several advantages such as high efficiency, mild reaction conditions, and wide functional group tolerance and serves as a highly useful complement to the thermal DDA reactions of ynamide-ynes.

Full text of DOI:10.1021/acs.orglett.8b01145

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold(I)-Catalyzed Formal Intramolecular Dehydro-Diels−Alder
Reaction of Ynamide-ynes: Synthesis of Functionalized
Benzo[b]carbazoles
Wei Xu, Gaonan Wang, Xin Xie, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China
S
* Supporting Information
ABSTRACT: A gold-catalyzed cycloisomerization of yna-
mide-ynes via a formal dehydro-Diels−Alder reaction has
been developed, providing an attractive route to diversely
substituted benzo[b]carbazoles. The reaction likely proceeds
via regioselective attack of the pendant alkyne moiety to a
keteniminium ion intermediate followed by benzannulation.
The method offers several advantages such as high efficiency,
mild reaction conditions, and wide functional group tolerance and serves as a highly useful complement to the thermal DDA
reactions of ynamide-ynes.
molecular dehydro-Diels−Alder reaction of ynamides,9a−c
enzo[b]carbazoles, including aryl- and heteroaryl[b]-
Bcarbazoles, are an important class of nitrogen-containing biradical cyclization of N-(2-alkynylphenyl)ketenimines,9d,e
radical cyclization through imidoyl selanide intermediates,4c
heterocyclic compounds, which have been found in a wide
Pd-catalyzed cyclization of 2-alkynylbenzaldehydes with in-
doles,9f iron-catalyzed isomerization/cyclodehydration of 2-
[(indoline-3-ylidene)(methyl)]benzaldehyde derivatives,9g etc.
However, these methods usually have some limitations such as
harsh conditions, being restricted to special substituted
substrates, lack of flexibility, low product yields, etc. Thus,
enhancing the efficiency of the synthetic methods that allow
selective formation of benzo[b]carbazoles with wide substrate
diversity under mild reaction conditions is still highly attractive.
One important result of these previous efforts concerns thermal
intramolecular dehydro-Diels−Alder reactions.10 In 2005, Saa
et al. reported that dehydro-Diels−Alder reactions of ynamide-
tethered alkynes provided benzo[b]carbazoles in generally low
to moderate yields at 150 °C.9a−c However, this method was
incompatible with the substrates bearing substituents (except
for a silyl substituent) on both ends of the alkyne terminals
(three examples, yields <24%). In addition, the regioselectivity
was also difficult to control, since both the arenynamide and
arenyne moieties might undergo a cycloaddition reaction.9a−c
During our study on the gold-catalyzed transformation of
ynamides,11,12 we envisioned that the synthesis of nitrogen
heterocycles might be accessed through cyclization of ynamide-
ynes involving regioselective attack of a nucleophile to
keteniminium ion intermediate I or a gold−alkyne complex.
Such reactions have been reported using furan, indole, alkene,
or a hydride as the nucleophiles;13 however, alkynes have rarely
been utilized15b as the nucleophile in this type of reaction.14,15
variety of biologically active substances and have also received
much attention in the fields of organic functional materials as
fluorescent chemosensors,1 organic light-emitting diodes
(OLEDs),2 and organic field effect transistors (OFETs).3 For
instance, ellipticine A and its analogues have been intensively
studied over the past 50 years because of their anticancer
properties.4 Due to the structural similarity of benzo[b]-
carbazoles to the ellipticines, it is widely concerned whether
such compounds have similar biological activities. In this
context, 5H-benzo[b]carbazole B with an indolyl group at the
C-6 position was found to be an Aβ1−40 aggregation inhibitor
that may be potentially useful for the treatment of progressive
neurodegenerative diseases.5 N-Methyl-substituted benzo[b]-
carbazole C was discovered to have in vitro anticancer activity6
(Figure 1). Although many methods have been developed for
the synthesis of carbazoles, the efficient synthesis of benzo[b]-
carbazoles is quite limited. These compounds have been
commonly prepared from substituted indoles7 or naphtha-
lenes.8 Recently, a number of synthetic approaches to
benzo[b]carbazoles have been reported1,4c,9 such as intra-
́
Received: April 11, 2018
Figure 1. Biologically active benzo[b]carbazole derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01145
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Herein, we describe a highly efficient and regioselective
cyclization of ynamide-ynes to benzo[b]carbazoles under
extremely mild reaction conditions via a formal dehydro-
Diels−Alder reaction (Scheme 1). In this reaction, the
cycloaddition occurs selectively at the arenynamide moiety.
Table 1. Optimization of the Reaction Conditions
Scheme 1. Synthesis of Benzo[b]carbazoles from Ynamide-
Tethered Alkynes
a
entry
catalyst (mol %)
solvent
temp
rt
time
yield (%)
72
1
PPh3AuNTf2 (5)
PPh3AuCl/AgSbF6 (5)
A (5)
DCE
DCE
DCE
DCE
DCE
DCM
THF
toluene
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
2.5 h
2 h
2
rt
75
b
3
rt
5 min
5 min
24 h
5 min
5 min
0.5 h
17 h
1 h
93 (90 )
91
4
B (5)
rt
5
C (5)
rt
31
6
A (5)
rt
91
7
A (5)
rt
91
8
A (5)
rt
85
9
A (5)
rt
75
10
11
12
13
14
15
16
17
18
AgSbF6 (10)
Zn(OTf)2 (10)
ZnCl2 (10)
FeCl3·6H2O (10)
Cu(OTf)2 (10)
TfOH (10)
MsOH (10)
HNTf2 (20)
none
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
80 °C
6
10 h
10 h
7 h
13
15
11
7 h
39
22 h
18 h
3 h
18
22
9
17 h
(62)
a
0.2 mmol scale. NMR yields using 1,3,5-trimethoxybenzene as an
b
internal standard. Isolated yields are shown in parentheses. After
To test our hypothesis, we initially investigated the
cyclization reaction of ynamide 1a bearing two phenyl groups
at the alkyne terminus by using 5 mol % PPh3AuNTf2 as the
catalyst. To our delight, benzo[b]carbazole 2a could be
obtained in 72% NMR yield within 2.5 h at room temperature
in DCE (Table 1, entry 1). Switching the catalyst to PPh3AuCl/
AgSbF6 resulted in a similar yield of 2a (entry 2). Gratifyingly,
it was found that JohnphosAu(MeCN)SbF6 (catalyst A) was
highly efficient for this transformation, leading to 2a in 93%
yield within 5 min (entry 3). The results indicate that the
nature of the ligands played an important role in promoting
catalytic activity. It is worth noting that the isolated product 2a
contained a trace amount of coloring material by direct
separation on a silica gel column. The coloring material could
be removed by treatment of the reaction mixture with H2O2
solution at 80 °C before column chromatography. The use of
treatment with H2O2 solution.
slowly at 80 °C without adding any catalyst, furnishing 2a in
62% yield after 17 h (entry 18).
With the optimized reaction conditions in hand (Table 1,
entry 3), we then focused our attention on the investigation of
the substrate scope of this novel cyclization reaction. The
results are shown in Scheme 2. To begin with, the effects of aryl
substituents on the Ar ring were first studied. Electron-donating
groups such as p-methyl or 3,5-dimethyl on the aryl ring were
well compatible, leading to 2b and 2c in 75% and 85% yields,
respectively. The presence of a p-methoxy substituent on the
aryl ring resulted in a low yield of the desired 2d (18%),
possibly due to undesired side reactions caused by a
methoxyphenyl group.16 Substrates bearing electron-withdraw-
ing aryl groups such as p-Cl, p-CO2Et, and p-NO2 were well
tolerated in the reaction, furnishing 2e−2g17 in 84−90% yields
within 10 min. In addition, a reaction of 1f at 1 mmol scale also
provided a high yield of 2f. It was noted that thermal cyclization
of 1g at 150 °C overnight afforded 2g in only 16% yield.9a−c,18
The results demonstrate the superior advantage of gold
catalysis over thermal reactions for internal alkynes. Cyclization
of 2-pyridyl-containing substrate 1h proceeded slowly, even at
80 °C, and the desired 2h was formed in 29% yield. This is
possibly due to the competing coordination of the pyridyl
moiety with gold, causing deactivation of the catalyst. Next, the
effects of the substituents on the R1 group were evaluated. For
aryl substituents, both the electron-rich and electron-deficient
substituents were compatible, furnishing 2i−2j in 89−93%
t
more crowded BuXphos (catalyst B) also resulted in an
excellent yield of 91% (entry 4). A gold(III) complex of
PicAuCl2 (catalyst C) provided 2a in a low yield with a longer
reaction time (24 h, 31%, entry 5). High product yields could
also be observed when the reactions were carried out in DCM,
THF, and toluene, whereas only 75% of 2a was formed in
MeCN (entries 6−9). Employing Lewis acids such as AgSbF6,
Zn(OTf)2, ZnCl2, FeCl3·6H2O, and Cu(OTf)2 as the catalyst
afforded 2a in yields ranging from 6% to 39% after stirring for
1−10 h at 50 °C (entries 10−14). When Bronsted acids such as
̈
TfOH, MsOH, or HNTf2 were used as the catalyst, 2a was
formed in low yields (entries 15−17). These results indicate
that gold catalysts displayed superior reactivity for this reaction,
compared to that of the other catalysts. The reaction proceeded
B
DOI: 10.1021/acs.orglett.8b01145
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Gold-Catalyzed Cyclization of Ynamide-
ynes
Scheme 3. Transformation of 1r and Detosylation Reaction
a
intermediate, and also demonstrate its further utility through
functionalization of the C−Au bond, Au/Sn transmetalation
reactions using 2-tributylstannylfuran as the tin reagent were
performed.20 To our delight, treatment of 1a with 3 equiv of 2-
tributylstannylfuran and 10 mol % JohnphosAu(MeCN)SbF6 at
65 °C in DCE for 1 h formed stannylated benzo[b]carbazole 4a
in 64% yield, along with 18% of nonstannylated product 2a
(Scheme 4). This result represents an important extension of
Scheme 4. Gold-Catalyzed Stannyl Transfer Reaction
a
a
b
Isolated yields. The yields of nonstannylated products 2 are shown in
0.2 mmol scale. Isolated yields. After treatment with H2O2 solution.
c
d
e
parentheses after treatment with H2O2.
Reaction was run at 1 mmol scale. 50 °C. 80 °C.
our previous work in which β-stannyl naphthalenes were
synthesized.20a The scope of the reaction was briefly
investigated, and the yields ranged from 29 to 35% for
stannylated products in the cases of 4b−4d. These products
might be further functionalized through a Stille coupling
reaction. The C-6 position of the Bu3Sn group on the
benzo[b]carbazole was confirmed by a deuterium-labeling
experiment through the reaction of 4a with DCl in a mixed
solvent of MeOD/CDCl3 (Scheme 5).
yields. Alkyl substituents were also well suited for this reaction.
For example, employing methyl-substituted substrate 1k led to
the formation of 2k in 60% yield. The reaction of a phenethyl-
substituted alkyne took place readily and efficiently to give 2l in
75% yield. A substrate with a cyclopropyl group as R2 was
transformed into the corresponding product 2m in 83% yield.
Cyclization of 1n bearing a bottom terminal alkyne moiety
proceeded less efficiently to give 2n in 28% yield at 50 °C,
possibly due to the reduced stability of the resulting vinyl
cationic species involved in the reaction. It was noted that when
R1 was a TMS group, the desilylated product 2n was formed in
a high yield of 87%.19 Thus, the TMS group can be used as a
hydrogen equivalent in this reaction. N-Mesyl-substituted
substrate 1p afforded 2p in a good yield of 85%, indicating
that the protecting group has little effect on this reaction. In
addition, the reactivity of a linear substrate 1q was also
examined, and the corresponding cyclized product 2q was
formed in a high yield of 84%.
Scheme 5. Deuterium Labeling Experiment
Interestingly, when substrate 1r bearing a cyclobutanol
moiety was employed as the substrate, the desired product 2r
was obtained only in 21% yield, along with benzo[b]carbazole
2n in 40% yield. The results indicate that a C−C bond cleavage
reaction occurred during the reaction. In addition, the
protecting group on the nitrogen can be facilely removed
though base-promoted detosylation (Scheme 3).
We propose the following reaction mechanism for this
reaction (Scheme 6). Initially, the alkyne moiety attacks the
gold-coordinated ynamide 5 or keteniminium ion intermediate
5′ regioselectively due to the polarity of the ynamide to afford
vinylcation species 6. Subsequent nucleophilic attack of the
phenyl ring on the vinyl cation followed by aromatization leads
to the formation of aryl gold intermediate 8, which undergoes
protodeauration to give the product 2. To account for the
formation of 2n in the case of cyclobutanol-substituted aryl
Our original mechanistic proposal suggested that an aryl-gold
intermediate might be formed during the process. To verify this
C
DOI: 10.1021/acs.orglett.8b01145
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Possible Reaction Mechanism
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development
Program (2016YFA0202900), the National Natural Science
Foundation of China (21572256), the Science and Technology
Commission of Shanghai Municipality (18XD1405000), the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20000000), and the Shanghai Institute of
Organic Chemistry (sioczz201807) for financial support.
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Accession Codes
CCDC 1836362 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhliu@sioc.ac.cn.
ORCID
Yuanhong Liu: 0000-0003-1153-5695
Notes
(14) For related gold-catalyzed cyclization of diynes without an
The authors declare no competing financial interest.
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Letter
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