A Unique Skeletal Rearrangement of a Bicyclo[33.1]nonanetrione to a Tetrahydroquinolin-2(1 H)-one System

Article abstract of DOI:10.1055/s-0037-1610187

The unexpected formation of a 4-hydroxytetrahydroquinolin-2(1 H)-one from a bicyclo[3.3.1]nonanetrione system and an amino alcohol in the presence of TsOH is reported. The mechanism of this transformation was studied by DFT calculations. The reaction provides an entry to the synthesis of highly functionalized 4-hydroxytetrahydroquinolin-2(1 H)-ones.

Full text of DOI:10.1055/s-0037-1610187

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
Q. Shen et al.
Letter
Synlett
A Unique Skeletal Rearrangement of a Bicyclo[3.3.1]nonanetrione
to a Tetrahydroquinolin-2(1H)-one System
Qi Shena
Fang Liub
OH
O
Yu-Chao Zhanga
Jie Wanga
HO
NH2
N
O
O
Lei Zhanga
Yue Wanga
Hong-Xi Xuc
Zhuzhou Shaob
Yang Caod
HO
HO
• Skeletal rearrangement
• Highly functionalized tetrahydroquinolin-2(1H)-one
• Up to 90% yield
Jing Wu*a
Yong Liang*b
Jian-Xin Li*a
a State Key Laboratory of Analytical Chemistry for Life Science, Collaborative Innovation
Center of Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic
Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210023, P. R. of China
wujnju@nju.edu.cn
lijxnju@nju.edu.cn
b State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210023, P. R. of China
yongliang@nju.edu.cn
c School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P. R. of China
d
Institute of New Energy, Shenzhen 518031, P. R. of China
Received: 06.04.2018
Accepted after revision: 27.05.2018
Bz
O
Published online: 02.07.2018
DOI: 10.1055/s-0037-1610187; Art ID: st-2018-w0213-l
O
O
OH
Abstract The unexpected formation of a 4-hydroxytetrahydroquino-
lin-2(1H)-one from a bicyclo[3.3.1]nonanetrione system and an amino
alcohol in the presence of TsOH is reported. The mechanism of this
transformation was studied by DFT calculations. The reaction provides
an entry to the synthesis of highly functionalized 4-hydroxytetrahydro-
quinolin-2(1H)-ones.
O
OH
Bz
clusianone
nemorosone
iPr
O
O
Key words polyprenylated acylphloroglucinols, skeletal rearrange-
ment, tetrahydroquinolinones, density functional theory, bicyclonona-
netriones, tetrahydroquinolinones
O
HO
Polycyclic polyprenylated acylphloroglucinols (PPAPs)
are a family of natural products isolated from the Guttiferae
(Clusiaceae) family of plants, which feature a variety of
complex structural motifs such as a highly oxygenated and
an unusual bicyclo[3.3.1]nonanetrione skeleton bearing
prenyl or geranyl side chains (Figure 1).1 Well over 150
PPAPs have been isolated, with properties ranging from an-
tiviral to anticancer activities. The diverse biological activi-
ties of PPAPs, as well as their complex and intriguing struc-
tures, make them attractive targets for total synthesis, but a
global model correlating the biological function of PPAPs
with their structural type or substitution pattern is lack-
ing.2 With these challenges in mind, we sought to develop
more analogues of PPAPs so that we might elucidate the
structure−activity relationships of PPAPs.
(–)-hyperforin
Figure 1 Representative PPAP nature products
The tetrahydroquinolin-2(1H)-one ring system is also
important, as it forms the central structural element of
numerous natural products that display a wide range of
biological activities,3 such as camptothecins, drug candi-
dates active against leukemia,4 and others.5 To date, most
protocols for the construction and/or annulation of the tetra-
hydroquinolin-2(1H)-one ring generally involve the conver-
sion of 2-pyrones with ammonia,6 the oxidation of pyri-
dines,7 or the Guareschi–Thorpe condensation of acyclic
precursors such as cyanoacetamide with 1,3-diketones.8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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O
9
7
1
7
H2N
OH
O
O
HO
OH
2
x
4
O
9
TsOH
OH
HO
TsOH
2
4
O
O
NH2
O
O
2
72%
1
3
Scheme 1 Modification of the hydroxy group of bicyclic compound 1
By following the method reported by Spessard and
Stoltz,9 we synthesized bicyclic compound 1 (Scheme 1).
We employed several alcohols in an attempt to etherify the
hydroxy group on the bicyclic skeleton. In the presence of
TsOH, the expected ether 2 was formed when propane-1,3-
diol was used (Scheme 1). However, to our surprise, 3-amino-
propan-1-ol gave an unexpected product that displayed
quite different NMR spectra to ether 2, whereas the expect-
ed product 3 was not detected.
To elucidate the structure of this unknown compound,
we attempted to prepared a single crystal, but with no suc-
cess. We therefore derivatized the compound and found
that, fortunately, the corresponding (4-bromobenzene)sul-
fonyl derivative could be crystallized. A subsequent X-ray
analysis indicated that the derivative had structure 5a, with
a highly substituted tetrahydroquinolin-2(1H)-one skeleton
(Scheme 2). This showed that a unique skeletal rearrange-
ment of the bicyclo[3.3.1]nonane core in 1 had occurred in
the presence of the amino alcohol and TsOH. A skeletal rear-
rangement of a bicyclo[3.3.1]nonane framework had been
reported by Couladouros and co-workers,10 but our result
was totally different from theirs. During our work on PPAPs
analogues, we explored an impressive skeletal rearrange-
ment of a bicyclo[3.3.1]nonane core that provided a simple
alternative route to the synthesis of highly functionalized
tetrahydroquinolin-2(1H)-ones.
To make this unexpected discovery synthetically useful,
we optimized the conditions for the reaction of 1 with 3-
aminopropan-1-ol.11 Initially, we varied the catalyst, the
solvent, and the temperature from the original conditions
(Table 1, entry 1). A control experiment confirmed that the
reaction did not proceed in the absence of the TsOH catalyst
(entry 2). Other acids, such as acetic acid, sulfuric acid, or
the Lewis acid CuCl2 were tested (entries 3–5). Acetic acid
gave a slightly better yield than TsOH (entry 3), whereas the
other acids gave complex mixtures. The bases TMEDA and
TEA also gave complex mixtures (entries 6 and 7), suggest-
ing that an appropriate acid was necessary for the re-
arrangement. Among the reaction solvents screened, DMSO
and DMF (entries 9 and 10) did not give the desired prod-
uct. Benzene was a superior solvent to toluene, affording
better yield of the desired product (entry 8), but owing to
the toxicity and environmentally unfriendly nature of ben-
zene, we continued to use toluene for further screening.
The temperature was also crucial in this reaction, as the
yield improved greatly at the reflux (entries 11–13). The re-
action was almost completed within four hours with a yield
of 90% (entry 16). A short reaction time gave insufficient
reaction, whereas extending the reaction time resulted in
an increase in byproduct formation and lower yields of the
required product (entries 13–15). The optimum reaction
conditions therefore include the use of 20 mol% of TsOH rel-
ative to 1 and two equivalents of 3-aminopropan-1-ol with
toluene as the solvent at 120 °C for four hours.
With the optimized conditions in hand, we investigated
the substrate scope of the reaction (Scheme 3). When 2-
aminoethanol was used, product 4a was isolated in 78%
yield. For amino alcohols with longer alkyl chains (n = 4 or
5), the corresponding products 4b and 4c were obtained in
moderate yields. Ethane-1,2-diamine and N-methylethane-
1,2-diamine similarly gave the corresponding products 4d
and 4e. However, when propylamine was used, the desired
product 4f was not be detected; instead the product in
which the C-4 carbonyl group was replaced by an imine was
obtained exclusively. This showed that the additional OH or
NH group attached to the aliphatic amine plays a crucial
Scheme 2 Preparation of derivative 5a and its crystal structure
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Table 1 Optimization of the Reaction Conditionsa
R2
O
OH
R2
R1
n
H2N
OH
N
N
O
toluene, 120 °C, 4 h
TsOH (cat.)
H2N
OH
R1
n
O
1
HO
O
O
TsOH, toluene
OH
N
HO
O
4a, n = 2, 78%
4, n = 3, 90%
4b, n = 4, 56%
4c, n = 5, 42%
OH
4
O
Entry Catalyst
Solvent
Temp (°C )
Time (h)
Yieldb (%)
n
OH
1
2
TsOH
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
DMF
80
80
8
8
8
8
8
8
8
8
8
8
8
8
8
1
2
4
44
ndc
45
OH
4d, R1 = NH2, 62%
3
HOAc
H2SO4
CuCl2
TMEDAe
TEAe
80
4e, R1 = NHMe, 60%
4f, R1 = Me, nd
N
O
d
4
80
–
d
5
80
–
R1
d
6
80
–
HO
O
N
d
7
80
–
4g, R2 = geranyl, 70%
4h, R2 = allyl, 80%
OH
8
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
80
61
9
80
ndc
4i, R2 = CH2-4-FC6H4, 84%
d
10
11
12
13
14
15
16
DMSO
80
–
R2
toluene
toluene
toluene
toluene
toluene
toluene
90
52
68
80
86
89
90
Scheme 3 Substrate scope of the rearrangement reaction.
100
reflux
reflux
reflux
reflux
a Reaction conditions: 1 (0.5 mmol), 3-aminopropan-1-ol (1 mmol),
TsOH (20 mol%).
H2N
OH
O
O
b Isolated yield.
X
4
c Not detected.
TsOH, toluene
Rearrangement
d Complex mixture of products.
e Two equivalents of the base were used.
O
O
HO
N
OH
1a
1aa
role in the rearrangement of the bicyclo[3.3.1]nonane
skeleton. To promote the rearrangement, a molecule must
possess at least one OH or NH group and one NH2 group;
both functional groups are necessary to drive the re-
arrangement. Moreover, geranyl, allyl, and 4-fluorobenzyl
side chains on the bicyclo[3.3.1]nonane were well tolerated,
and the corresponding products 4g–i were obtained in
good yields.
We also found that the C-4 hydroxy-group-protected
compound 1a, gave product 1aa under the optimized reac-
tion conditions (Scheme 4), and that this could not be con-
verted into 4, even with a prolonged reaction time. This re-
sult suggests that the rearrangement does not start with
substitution of the C-4 hydroxy group of 1, because 1aa
does not transform into the rearrangement product. Thus,
1aa cannot be an intermediate in the reaction. In addition,
the C-4 hydroxy group of 1 must play some other important
role in the rearrangement.
Scheme 4 Control experiment.
On the basis of the above findings, a possible mecha-
nism including several transformations is proposed
(Scheme 5). Although we made considerable efforts to cap-
ture the rearrangement intermediates, we unfortunately
failed to do so. Consequently, we conducted a detailed com-
putational study by density functional theory (DFT; M06-
2X with solvation) calculations to explore the mechanism
of the unique reaction.12 The computed free energies for the
skeletal rearrangement of bicyclic compound A (in which
the 3-methylbut-2-enyl side chain of the bicyclic com-
pound 1 was replaced by a hydrogen atom to simplify the
calculation ) with 3-aminopropan-1-ol in the presence of
TsOH are summarized in Scheme 5(B) (blue). To reveal why
the rearrangement does not occur when a diol or simple
amine is employed, the free energies for the reactions of bi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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cyclic compound A with propane-1,3-diol (pink) or propyl-
amine (green) were also computed and are shown in
Scheme 5(B).
The reaction with propane-1,3-diol [Scheme 5(B); pink
lines] has a high activation-energy barrier of 37.6 kcal/mol
(via TS2_O), and therefore the rearrangement is not likely to
occur under the current reaction conditions (an etherifica-
tion occurred experimentally; see Scheme 1). Compared
with the reaction with 3-aminopropan-1-ol, the difference
in the overall energy barrier (37.6 versus 28.9 kcal/mol)
arises mainly from the difference in the thermodynamic
stability of the intermolecular Michael addition products
C_O and C (18.8 versus 5.3 kcal/mol), although the retro-
aldol step from intermediate C_O has a barrier of only 18.8
kcal/mol. The superior nucleophilicity of an amine
compared with an alcohol makes the intermolecular
Michael addition step more favorable both kinetically and
For the skeletal rearrangement reaction of bicyclic com-
pound A with 3-aminopropan-1-ol [blue lines, Scheme
5(B)], the DFT calculations indicate that the overall process
involves an intermolecular Michael addition (via TS1), a
retro-aza-aldol reaction (via TS2),13 and an intramolecular
Michael addition (via TS3), followed by dehydration to give
the final product. Various isomers were considered for each
intermediate and transition-state structure, and the lowest-
energy ones are presented in Scheme 5(B). The rate-deter-
mining step is the retro-aza-aldol reaction, which has an
overall energy barrier of 28.9 kcal/mol in toluene.
Scheme 5 (A) Proposed mechanism. (B) DFT-computed free energies for the reactions of bicyclic compound A with 3-aminopropan-1-ol (blue lines),
propane-1,3-diol (pink lines), and propylamine (green lines) in the presence of TsOH. Key transition structures are shown at the bottom.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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thermodynamically, leading to a lower overall barrier for
the skeletal rearrangement reaction. This explains why the
diol is not suitable for this reaction.
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using propylamine [Scheme 5(B); green lines] is also very
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the reaction.
In conclusion, the bicyclo[3.3.1]nonanetrione skeleton
of PPAPs can be transformed into a 4-hydroxytetrahydro-
quinolin-2(1H)-one through a unique rearrangement reac-
tion. The reaction mechanism was rationalized by DFT
calculations. The method provides a simple route for the
synthesis of derivatives of 4-hydroxytetrahydroquinolin-
2(1H)-one.
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Funding Information
This work was supported by National Natural Science Foundation of
China (21702101, 21778029, and 21761142001) and the Fundamen-
tal Research Funds for the Central Universities in China. Y.L. thanks
the National Thousand Young Talents Program, Jiangsu Specially-
Appointed Professor Plan, and the NSF of Jiangsu Province
(BK20170631) in China for financial support. Y.C. acknowledges the
support from the Shenzhen Peacock Plan (No.1208040050847074).
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Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610187.
S
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p
p
ortioInfgrmoaitn
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p
ortiInfogrmoaitn
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A 250 mL round-bottomed flask was charged with bicyclic com-
pound 1 (1.3 g, 5.0 mmol, 1.0 equiv) in toluene (100 mL).
TsOH·H2O (20 mol%) was added, followed by 3-aminopropan-1-
ol (0.8 mL, 10.0 mmol, 2.0 equiv). The flask was fitted with a
References and Notes
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Dean–Stark head and a condenser, and the mixture was heated
at 120 °C for 4 h. The mixture was then concentrated to a brown
oil that was purified by chromatography (silica gel, 1–3%
MeOH–CH2Cl2) to give a white foam; yield: 1.4 g (90%); Rf = 0.40
(10% MeOH–CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 6.10 (s,
1 H), 5.15 (t, J = 7.0 Hz, 1 H), 4.32–4.19 (m, 1 H), 4.16–4.02 (m,
1 H), 3.54 (s, 2 H), 2.68 (dd, J = 17.7, 5.5 Hz, 1 H), 2.44 (s, 2 H),
2.32–2.20 (m, 1 H), 2.08 (dd, J = 17.6, 9.6 Hz, 1 H), 1.88–1.79 (m,
2 H), 1.79–1.71 (m, 1 H), 1.70 (s, 3 H), 1.59 (d, J = 1.2 Hz, 3 H),
1.40 (m, 1 H), 1.07 (s, 3 H), 0.87 (s, 3 H). 13C NMR (101 MHz,
CDCl3): δ = 166.63, 165.31, 142.97, 132.54, 123.08, 110.76,
96.93, 58.16, 41.85, 41.45, 39.45, 32.77, 32.23, 28.85, 27.90,
25.86, 24.77, 21.35, 17.81. HRMS (ESI): m/z [M + H]+ calcd for
optimized structures by using the CPCM model at the M06–
2X/6–311+G(d,p) level. For details, see the Supporting Informa-
tion.
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C19H30NO3: 320.2225; found: 320.2211.
(12) Geometries of minima and transition structures were opti-
mized at the level of M06–2X with the 6–31G (d) basis set.
Solvent effects in toluene were evaluated on the gas-phase
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F