Gold(I)-catalyzed intramolecular [4 + 2] cycloaddition of ortho-(N-tethered 1,6-diynyl)benzaldehydes to 3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones

Article abstract of DOI:10.1016/j.tetlet.2020.152200

An efficient synthetic method to prepare 3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones through gold(I)-catalyzed intramolecular [4 + 2] benzannulation of o-(N-tethered 1,6-diynyl)benzaldehydes at a low catalyst loading of 2 molpercent is described. The product of 3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones can be easily transformed to benzo[f]isoquinolin-1-ols by simply treating with phenylmagnesium bromide under mild conditions. The structures of compounds 2o and 2w were also ascertained by X-ray crystallographic analysis.

Full text of DOI:10.1016/j.tetlet.2020.152200

Journal Pre-proofs
Gold(I)-Catalyzed Intramolecular [4+2] Cycloaddition of ortho-(N-tethered
1,6-diynyl)benzaldehydes to 3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones
Jiankai Zhong, Rui Hu, Jingjing Sang, Weidong Rao
PII:
S0040-4039(20)30665-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152200
TETL 152200
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 May 2020
27 June 2020
29 June 2020
Please cite this article as: Zhong, J., Hu, R., Sang, J., Rao, W., Gold(I)-Catalyzed Intramolecular [4+2]
Cycloaddition of ortho-(N-tethered 1,6-diynyl)benzaldehydes to 3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152200
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Tetrahedron Letters
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Gold(I)-Catalyzed Intramolecular [4+2] Cycloaddition of ortho-(N-tethered 1,6-
diynyl)benzaldehydes to 3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones
Jiankai Zhonga, Rui Hua, Jingjing Sanga and Weidong Raoa
aJiangsu Co-Innovation Center for Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University,
Nanjing 210037, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author.
E-mail address: weidong@njfu.edu.cn (W. Rao)
Article history:
An efficient synthetic method to prepare 3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones through
Received
gold(I)-catalyzed
intramolecular
[4+2]
benzannulation
of
o-(N-tethered
1,6-
Received in revised form
Accepted
Available online
diynyl)benzaldehydes at a low catalyst loading of 2 mol% is described. The product of 3,4-
dihydrobenzo[f]isoquinolin-1(2H)-ones can be easily transformed to benzo[f]isoquinolin-1-ols
by simply treating with phenylmagnesium bromide under mild conditions. The structures of
compounds 2o and 2w were also ascertained by X-ray crystallographic analysis.
Keywords:
Gold catalysis
2009 Elsevier Ltd. All rights reserved.
o-Alkynylbenzaldehyde
[4+2]-Cycloaddition
Benzopyrilium
3,4-Dihydrobenzo[f]isoquinolin-1(2H)-one
Previous works:[ref 2-15]
Introduction
O
O
O
M
Transition-metal-catalyzed cascade annulation of enynals and
enynones has emerged as a powerful and efficient strategy for the
rapid construction of polycyclic frameworks in a highly step-
economical manner.[1] In particular, transition-metal-catalyzed
transformations of easily accessible ortho-alkynylbenzaldehydes
have received considerable attention and found broad
applications recently.[2-15] It is well recognized that ortho-
alkynylbenzaldehydes can undergo transition-metal-catalyzed
intramolecular 6-endo-dig cyclization to form the metal-bound
benzopyrylium or its resonance form 1,3-dipole metal-carbene
species that allowed further [4+2][3-10] or [3+2][11] cycloadditions
with proper dipolarophiles, thus leading to a diverse array of
products (Scheme 1a). In 2002, Asao and Yamamoto disclosed a
first AuCl3-catalyzed intermolecular [4+2] benzannulation
between ortho-alkynylbenzaldehydes and alkynes via the in situ
generated benzopyrylium key intermediates, providing a novel
synthetic protocol to naphthyl ketones.[3a] Following this seminal
work, a plethora of novel intermolecular [4+2] cycloaddition
reactions have been demonstrated by employing diverse
dipolarophiles, such as benzynes,[4] alkenes,[5] dienes,[6]
cyclopropenes,[7] aldehydes,[8] benzofurans[9] and isoxazoles.[10]
However, the intramolecular version remains less explored,
presumably due to the challenge for the preparation of the
starting materials. In 2005, a novel synthetic approach that relies
on AuX3-catalyzed intramolecular [4+2] cycloaddition of C-
tethered alkynyl enynals has been reported by Asao and
A diversity of
products
(a)
R
6-endo-dig
R
R
[M]
[M]
Metal-bound Benzopyrylium
or 1,3-Dipole Metal-carbene
Asao,Yamamoto and Dyker's works:[ref 12-14]
[4+2]
R
R
O
O
R
[AuX3] or [PtCl2]
X
(b)
-[Au]
X
[Au]
X
O
X = CH2 or O
Oh's Work:[ref 15]
R
[3+2]
R
O
R
O
[AuBr3]
O
-[Au]
(c)
(d)
X
X
X
[Au]
X = CH2(COOEt)2
This work:
O
R
R
R
O
[Au]+
or
[4+2] or [3+2]??
NR'
NR'
NR'
O
Scheme 1. Transition-metal-catalyzed inter- and intramolecular [4+2]
or [3+2] cycloaddition of o-alkynylbenzaldehydes.
Yamamoto group, leading to 2,3-dihydrophenanthrenone
derivatives with excellent efficiency (Scheme 1b, X = CH2).[12]
Later, the group of Dyker reported a similar transformation by
using O-tethered alkynyl enynals (Scheme 1b, X = O).[13] In
addition, this protocol has been successfully applied in the
construction of natural products, such as (+)-rubiginone B2, (+)-
ochromycinon and rac-heliophenanthrone.[14]
On the other hand, the reactivity pattern can be altered greatly
by the nature of the tether in the substrates. For instance, Oh and
co-workers showed that
a
novel intramolecular [3+2]

2
Tetrahedron
cycloaddition and subsequent rearrangement can be achieved
we then examined a variety of gold catalysts to improve the yield
of 2a. A similar outcome was observed when the reaction was
conducted with other gold(III) catalysts, such as HAuCl4 and
PicAuCl2 or Ph3PAuNTf2 (Table 1, entries 2-4). Pleasingly, we
found that the reaction mediated by Au(I) complex A led to the
desired product 2a being furnished as the sole product in near
quantitative yield (Table 1, entry 5). Likewise, comparable yields
were observed when the reaction was conducted with the more
sterically crowded Au(I) complex B or NHC-gold(I) (NHC = N-
heterocyclic carbene) complexes C (Table 1, entries 6-7). In
contrast, no reaction was detected in control experiments with
AgSbF6 as the catalyst or at room temperature or switching the
solvent to CH3CN (Table 1, entries 8-10). In addition, slightly
diminished yields of 88-90% were observed upon repeating the
reaction with toluene as solvent or in the absence of 4Å
molecular sieves (Table 1, entries 11-12). Therefore, reaction of
1a in the presence of gold(I) complex A and 4Å MS in 1,2-
dichloroethane at 60 ° C provided the optimum conditions.
by utilizing C(COOEt)2 tethered substrates, providing rapid
access to valuable [6.7.5] tricyclic skeleton (Scheme 1c, X =
C(COOEt)2).[15] Surprisingly, to date, there are no examples of
such
a transformation involving either [4+2] or [3+2]
cycloaddition starting from N-tethered alkynyl enynals. In
conjunction with our continuing efforts to explore the utility of
gold catalysis,[16] we envisioned that a catalytic approach that
made use of o-(N-tethered 1,6-diynyl)benzaldehydes in the
presence of gold catalyst might be feasible to realize [4+2] or
[3+2] cycloaddition selectively for the synthesis of structurally
diverse nitrogen-containing heterocycles such as [6.6.6] or [6.7.5]
tricyclic frameworks (Scheme 1d). Herein, we disclose this
chemistry in details that provides an expedient and
chemoselective approach to potentially usefully 3,4-
dihydrobenzo[f]isoquinolin-1(2H)-ones in good to excellent
yields.
Results and Discussion
With the established conditions in hand, we set out to evaluate
the generality of the present procedure by examining various
functionalized o-(N-tethered 1,6-diynyl)benzaldehydes, and the
results are summarized in Table 2. Overall, the gold(I) complex
A-catalyzed intramolecular [4+2] benzannulation conditions
proved to be broad, providing a variety of
To test the feasibility of this hypothesis, N-(3-(2-
formylphenyl)prop-2-yn-1-yl)-4-methyl-N-(prop-2-yn-1-
yl)benzenesulfonamide (1a) was selected as model substrate to
establish the optimum reaction conditions (Table 1). Initially, we
found that treating 1a with 2 mol% AuBr3 and 4Å molecular
Table 1. Evaluation of Reaction Conditionsa
Table 2. Evaluation of substrate scopea
R3
CHO
R3
[Au] (2 mol%)
R2
R1
R5
[JohnPhosAu(CH3CN)]SbF6
R2
R1
R5
(2 mol%)
solvent, 4Å MS, 60 oC, t
O
NTs
NTs
DCE, 4Å MS, 60 °C, 6-15 h
O
NR4
NR4
1a
2a
O
2
1
SbF6
iPr
tBu tBu
SbF6
Cy Cy
iPr
N
P
Au NCMe
P
Au NCMe
Cl
F
iPr
R2
N
NTs
NBs
NTs
NTs
iPr
R2
iPr
O
2a
O
2b
O
O
Au
iPr
2c
2g
2d
: (97%)
: (98%)
: (79%)
: (96%)
iPr
R2
NTf2
A
B
C
Me
Me
iPr
F
Ph
Cl
MeO
Entry
Catalyst
AuBr3
Solvent
DCE
Time (h)
Yield (%)b
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
O
O
O
O
2e
2f
2j
2h
: (86%)
: (90%)
: (81%)
: (71%)
1
15
15
15
20
12
18
18
24
24
24
12
12
27
29
MeO
MeO
2
3
4
5
6
7
HAuCl4
DCE
NTs
NTs
Ph
O
O
O
O
c
PicAuCl2
DCE
16
2i
2k
2l
: (94%)
: (93%)
: (91%)
: (84%)
Me
O
O
Ph3PAuNTf2
DCE
21
A
B
C
DCE
98
NTs
NTs
O
2n
O
O
O
2m
2o
2s
2p
: (96%)
: (88%)
: (73%)
: (79%)
DCE
95
C8H17
Cy
Me
OR
N
DCE
90
Ts
NTs
NTs
: (67%)
nBu
NTs
NTs
DCE
NR
NR
NR
90
8
AgSbF6
O
O
O
O
2q
2r
2t
: R = Ph (68%)
: (71%)
: (74%)
9d
A
A
A
A
2u
DCE
: R = 4-Ph-C6H4 (67%)
H
Ph
OMe
Me
CH3CN
toluene
DCE
10
11
12e
nBu
NTs
NTs
: (88%)
O
NTs
O
NTs
: (55%)
O
O
2v
b
c
2w
2x
2y
88
: (0%)
: (0%)
aUnless otherwise stated, all reactions were performed with 1a
aUnless otherwise stated, all reactions were performed with 1
(0.2 mmol), 4Å MS (50 mg) and 2 mol% catalyst with solvent (4
(0.2 mmol), 4Å MS (50 mg) and 2 mol% catalyst in DCE (4 mL)
at 60 °C for 12-24 h. Values in parentheses denote isolated
product yields. bDecomposition. cNo reaction based on TLC
analysis and 1H NMR measurements of the crude mixture.
mL)
at
60
°C.
bIsolated
yield.
cDichloro(2-
d
pyridinecarboxylato)gold. Isolated yield.cReaction carried out at
room temperature. eReaction performed in the absence of 4Å MS.
sieves (MS) in 1,2-dichloroethane at 60 °C for 15 h gave 2a in
27% yield, along with some decomposition products (Table 1,
entry 1). The structure of the [6.6.6] tricyclic product was
confirmed by X-ray crystallographic analysis of closely related
analogues (vide infra).[17] Encouraged by this preliminary result,
3,4-dihydrobenzo[f]isoquinolin-1(2H)-ones in 55-98% yields
from the corresponding substrates 1a-y. Changing the link from
NTs to NBs was found to give 2b in a lower yield of 79%.
However, in the case of N-Boc protected substrate, an intractable
complex mixture was generated (this result was not included in

CHO
Table 2, see supporting information). The presence of an
electron-withdrawing (1c-d, 1j-k) or electron-donating (1e-i, 1l-
m) substituent at the R1, R2 position of the phenyl ring were
found to have no appreciable influence on the outcome of the
reaction, producing the corresponding [6.6.6] tricyclic products
2c-m in good to excellent yields. Intriguingly, the reaction of
substrate 1n was also shown to proceed well to afford the
tetracyclic product 2n in 88% yield. Gratifyingly, substrates
possessing various substituents such as acyclic alkyl (1o-q, 1s-u),
cyclohexyl (1r) and vinyl (1v) at the alkyne terminus all reacted
smoothly to deliver the corresponding products 1o-v in 55-79%
yields. Notably, the reaction conditions can be further extended
to ketone substrate (1w), furnishing the target product 2w in 88%
yield. The structure of 2o and 2w were confirmed by X-ray
crystallographic analysis (Figure 1).[17] Unfortunately, reactions
of non-aromatic diynyl enal (2x) and o-(N-tethered 1,6-
diynyl)benzoate (2y) failed to give the desired products. The
former was found to give only decomposition products, while no
reaction for the latter.
A
(1 mol%)
DCE, 4Å MS, 60 oC, 15 h
NTs
2a,
1.307 g, 93% yield
NTs
O
1a,
4 mmol, 1.406 g
PhMgBr (3.0 equiv)
THF, 0 oC, 8 h
NaBH4 (1.0 equiv)
THF-MeOH (1:1), rt, 1 h
N
NTs
NTs
5
(97% yield)
HO
O
HO
6
2a
(88% yield)
Scheme 3. Scale-up Synthesis and Synthetic Applications.
On the basis of the above experimental results and literature
reports,[1-2] a plausible mechanism for the present gold(I)-
catalyzed [4+2] benzannulation reaction is outlined in Scheme 4.
Initially, gold(I) complex selectively coordinates with the alkyne
moiety adjacent to the carbonyl group to give intermediate D.
Subsequent nucleophilic addition of the carbonyl oxygen to
alkyne through 6-endo-dig cyclization would form the gold-
bound benzopyrylium species E. The resulting highly reactive
benzopyrylium species
E undergoes intramolecular [4+2]
cycloaddition with the remaining pendant alkyne moiety to afford
intermediate F. Finally, C-O bond cleavage and rearrangement
would provide the final product 2a and regenerate the gold
catalyst.
1a
[AuL]+
2a
O
O
NTs
NTs
+[LAu]
[Au]
F
D
[4+2]
O
NTs
Figure 1. Crystal structures of 2o (top) and 2w (down) with
thermal ellipsoids drawn at 30% probability.
[Au]
E
It should be noted that the present method can be further
extended for synthesizing 6-6-7 tricyclic heterocycle. Treatment
of one-carbon-prolonged substrate 3 with gold(I) complex A
under the standard conditions resulted in the 6-6-7 tricyclic
adduct 4 being obtained in 76% yield (Scheme 2).
Scheme 4. Proposed mechanism for the gold-catalyzed [4+2]
benzannulation.
In summary, we have developed an efficient synthetic
approach to synthesis 3,4-dihydrobenzo[f]isoquinolin-1(2H)-one
derivatives from gold(I)-catalyzed intramolecular [4+2]
benzannulation of o-(N-tethered 1,6-diynyl)benzaldehydes at a
low catalyst loading of 2 mol%. The practicality and utility of the
present method was exemplified by the gram-scale synthesis of
one example followed by its diversification to a variety of useful
building blocks. Efforts to explore the synthetic applications of
the present reaction are currently underway and will be reported
in due course.
CHO
[JohnPhosAu(CH3CN)]SbF6
(2 mol%)
DCE, 4Å MS, 60 °C, 15 h
NTs
N
O
Ts
3
4
(76% yield)
Scheme 2. Gold(I) complex A-catalyzed intramolecular [4+2]
benzannulation of 3.
To examine the scalability and practicality of the present
method, a gram-scale reaction of 1a (4 mmol, 1.406 g) was
conducted in the presence of only 1 mol% gold catalyst A,
providing 2a in 93% isolated yield (Scheme 3). Accordingly,
Acknowledgments
o
subjecting 2a with NaBH4 in mixed THF-MeOH at 0 C for 1 h
delivered alcohol product 5 in 97% yield. Unexpectedly,
treatment 2a with phenylmagnesium bromide in THF resulted in
deprotection as well as oxidation to the corresponding
benzo[f]isoquinolin-1-ol 6 in 88% yield.
This work was supported by National Natural Science
Foundation of China (21502093) and A Project Fund from the
Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD).

4
Tetrahedron
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Declaration of interests
6.
7.
8.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
influence the work reported in this paper.
Supplementary Material
Supplementary data (detailed experimental procedures,
characterization data, 1H and 13C NMR spectra for all new
compounds as well as X-ray data for 2o and 2w) can be found
material that may be helpful in the review process should be
found online at https://doi.org/xxxxx.
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Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
Graphical Abstract
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:

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Gold(I)-Catalyzed Intramolecular [4+2]
Cycloaddition of ortho-(N-tethered 1,6-
diynyl) benzaldehydes to 3,4-
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dihydrobenzo[f]isoquinolin-1(2H)-ones
Jiankai Zhonga, Rui Hua, Jingjing Sanga and Weidong Raoa,
R3
R3
R2
R1
R5
[JohnPhosAu(CH3CN)]SbF6
(2 mol%)
R2
R1
R5
O
DCE, 4Å MS, 60 °C, 6-15 h
NR4
NR4
O
23 examples
up to 98% yield
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Highlights
 3,4-Dihydrobenzo[f]isoquinolin-1(2H)-ones were
synthesized efficiently.
 An atom-economic approach using readily
accessible materials.
 Low catalyst loading of 2 mol% and mild
reaction conditions.
 The reaction can be scaled-up to gram scale.