Water-promoted synthesis of fused bicyclic triazolines and naphthols from oxa(aza)bicyclic alkenes and transformation: Via a novel ring-opening/rearrangement reaction

Article abstract of DOI:10.1039/c7gc03772d

An efficient three-component domino reaction among oxa(aza)bicyclic alkenes, sodium azide, and primary haloalkanes is reported, which offers a mild access to 1,2,3-triazolines in an aqueous medium with excellent diastereoselectivities and yields. Further studies show that, water-promoted isomerization of oxa(aza)bicyclic alkenes can afford 1-naphthol derivatives in good yields. Water not only promotes the reaction, but also provides a recyclable and sustainable approach to the desired product. In addition, a novel metal-free cascade ring-opening/rearrangement reaction of the obtained bicyclic triazolines to form multifunctionalized indenes has been discovered.

Full text of DOI:10.1039/c7gc03772d

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8
substrate (Figure 1). The water-catalysis by solvation of a Figure 2. Selected examples for bioactive triazoline, naphthol and
pharmaceutical containing indene.
leaving group and its dissociation into ions in dehalogenation
9
has been reported in water-solvated environments. Herein,
we describe an alternative strategy that relies on a metal-free
Results and discussion
reaction in aqueous system to functionalize the
oxa(aza)bicyclic alkene through C–X cleavage and C–N
formation. Triazolines are an important class of heterocycles
which in addition to their exceptional biological profiles serve
as versatile precursors to important compounds such as
aziridines, triazoles, and β-amino alcohols. The general
methods for the synthesis of substituted triazolines are
through the 1,3-cycloadditon reaction of azides with activated
In initial experiments, we conducted a three-component
cycloaddition reaction of oxabicyclic alkene (1a), sodium azide
and 1,2-dichloroethane (2a) by employing a series of organic
o
solvents at 65 C without any additive (Table 1, entry 1), and
found that there were no reaction. Adding CuI had no impact
on the reaction (Table 1, entry 2). However, the reaction could
proceed in aqueous system (Table 1, entries 3). When
increasing the temperature, the targeted product was
obtained in moderate yield (Table 1, entries 4). In order to
improve the yield of the reaction, various additives were tried.
1
0
olefins or the 1,3-cycloadditon of Schiff bases with diazo
11
compounds (Scheme 1d). Only a few examples of the
synthesis of the triazoline in the bicyclic alkene have been
1
2
reported . Generally, the organic azides were generally
required to be prepared and isolated prior to use, which may
limit the overall yields and suffer from long reaction time
The optimal result was obtained in water when adding
o
Bu
Bu
4
4
NOAc (5 mol %) at 65 C within 12 h (Table 1, entry 5).
NOAc plays a role of additive to assist water capturing the
1
2a
(about 30 days) . Furthermore, the using of special and toxic
halogen atom in the water surface.
solvents (DMF, DMSO, toluene, etc.) is not avoided in many of
those approaches . On the other hand, reaction efficiency and Table 1. Initial investigations for cycloaddition in water.
substrate scope in aqueous media have so far been limited.
13
a
Thus, new methodologies for the synthesis of triazolines are
still in demand, especially those with economically more
feasible and environmentally friendlier sustainable procedures.
b
Additive
Time
(h)
Yield
We envisioned that the triazolines could be obtained by a
reaction between NaN and haloalkanes in aqueous system,
Entry
Solvent
(mol %)
(%)
3
c-f
1
2
3
solvent
-
24
n.r.
followed by C–N bond formation through 1,3-dipolar
cycloaddition with oxa(aza)bicyclic alkenes (Scheme 1e, Eq. (2)).
To the best of our knowledge, aqueous medium promoted
one-pot synthesis of bicyclic triazolines has not been
demonstrated before. In this way, water as a solvent not only
promotes the reaction by forming H-bonds, but also provides a
recyclable route. When switching the primary haloalkanes to
DCE
CuI (5)
24
24
24
n.r.
34
water
water
-
-
g
4
56
5
water
4
Bu NOAc (5)
12
98
a
Reaction conditions: oxabicyclic alkenes (0.2 mmol), NaN (0.4 mmol), DCE (9.7
3
o
b
c
d
e
secondary, tertiary haloalkanes or polyhaloalkanes, an mmol), solvent (2 mL), 65 C. DCE = ClCH
2
CH
2 3
Cl. Isolated yield. CH OH. THF.
f
g
o
toluene. solvent-free. The temperature was 90 C.
isomerization of oxa(aza)bicyclic alkenes takes place even in
1
4
the absence of any strong Brønsted acids and metal catalysts
1
5a
15b
15c
15d
Such as Ru , Cu , Rh , Ag , and Au ), which could just
15e
Encouraged by the preliminary results, we next investigated
the scope of various oxa(aza)bicyclic alkenes (Scheme 2). The
(
1
use H-bonding and water-catalyzed dehalogenation in the
aqueous biphasic system to afford the naphthol derivatives
2
haloalkanes were R Cl except 3j and 3l, which were generated
2
by using R Br. In general, the reaction showed good tolerance
(Scheme 1e, Eq. (1)). These processes may provide high
with respect to the electronic properties of the aryl substituent
diastereoselectivity for the synthesis of heterocyclic triazolines
and naphthols, which are important motifs widely found in
on the oxabicyclic alkenes (3a
–d
). The oxabicyclic alkenes with
could yield the
1
6
electron-withdrawing substituent
natural products and physiologically active molecules , such
as ADD17014 and mollugin (Figure 2). Besides, inspired by the
corresponding triazoline in excellent yield (3d). In addition,
oxabicyclic alkenes with the electron-donating groups could
recent
reports
on
Rh-catalyzed
domino
ring
afford the products in good yields (3b, c). Next, we examined
opening/isomerization of oxabicyclic alkenes with water to
1
7
the scope of azabicyclic alkenes in this transformation. It was
found that azabicyclic alkenes both with electron-rich and
electron-deficient groups on the phenyl ring underwent the
synthesize tetralone (Scheme 1b), we establish a novel
metal-free cascade ring-opening/rearrangement reaction of
bicyclic triazolines to potential bioactive multifunctionalized
1
8
cycloaddition reaction with NaN
3
and primary haloalkane to
). Notably,
indene with denitrogenation (Scheme 1e, Eq. (3)), which has
not been demonstrated before.
produce the desired products in good yields (3e
–
i
the different electronic properties of substituents at 4-position
of arylsulfonyl group on azabicyclic alkenes had great effect on
the multicomponent cycloaddition reaction, and the
azabicyclic alkenes which had electron-withdrawing groups (3g
and 3h) gave higher yields compared with electron-donating
2
| J. Name., 2012, 00, 1-3
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R1 or R2 = H or
group (3e). However, changing the N-protecting group from a
arylsulfonyl group to a butyloxycarbonyl group, the cyclo-
addition reaction was not efficient (3s). Subsequently, various
electron-donating
R2
R2
O
H
R1
R1
H2O
NH
Bu NOAc (5 mol %)
4
R2
65 o
C
haloalkanes were tested with NaN
alkenes, which had proven to be effective (3j
haloalkanes, such as EtBr, n-BuCl, and n-C12 25Br, having a
3
in the presence of bicyclic
R1
R1
NaN3
R1 = R = H, 7a, 48%
2
–q
). Primary
O
+
R1 = Me, R2 = H, 7b, 37%
R1 = H, R2 = OMe, 7c, 44%
Cl
H
R2
2g
R2
R1
R1
steric hindrance, efficiently participated in the cycloaddition
reaction and generated the desired product in 45%, 52% and
H2O
N
O
N
Bu4NOAc (5 mol %)
N
5 o
6
C
R2
R1 = Br, R2 = H, 3t, 72%
9
2% yields (3j
haloalkanes containing electron-donating groups, the product
was formed in a low yield. It was noted that the haloalkanes
containing electron-withdrawing groups (3m and 3p
–
l
and 3o), respectively. In the case of
R1 = electron-withdrawing,
R2 = H
Scheme 3. Synthesis of indines 7a-c and the triazoline 3t
.
3n
,
q)
N
N
N
N
worked well in the reaction as well. Furthermore, we tried to
use the 1-methyl-1,4-dihydro-1,4-epoxynaphthalene as the
unsymmetric oxabicyclic alkene and studied the selectivity of
NaN3
Cl
Cl
NaN3
H2O
3u, 42%
+
+
(a)
Cl Bu4NOAc (5 mol %)
+
Cl
Cl
65 o
Cl
N
N
1ab
C
1ab'
the reaction for the formation of C–N
three-component cycloaddition. According to yield of the 3r
and 3r’ (37% / 55%), the C–N was preferred to form in the less
1 3
and C–N bond in the
3
u', 42%
N
N
H2O
O
+
NaN3
Cl
O
N
1
(b)
Bu4NOAc (5 mol %)
70 o
steric hindrance side of the substrate. When using the benzyl
chloride as the haloalkane, the cycloadduct was obtained in
only a trace amount, and the product azidomethylbenzene
was found in the reaction system. Unfortunately, the
cycloaddition reaction could not occur with alkyl polyhalides
1ac
C
3v, 38%
Scheme 4. Exploration of the substrate scope.
To make this reaction a general approach, cyclopentadiene
ab had been used to conduct the reaction. Fortunately, a
1
(
such as CH
2
Cl
2
3
, CHCl ) or the aromatic halides as the
multicomponent reaction to synthesize the fused carbo-
bicyclic triazoline have been achieved and lead to 3u and 3u’ in
moderate yield (Scheme 4, eq a). Furthermore, an oxabicyclic
alkene 1ac with a pre-functionalized alkyl halide for an
intramolecular substitution reaction followed by cycloaddition
reaction to generate fused cyclic compound had been
conducted. And then, intramolecular cycloadduct could been
obtained in 38% yield (Scheme 4, eq b).
haloalkanes.
R1
X
R2 halide
H2O
N
N
+
NaN3
+
R1
X
N
Bu4NOAc (5 mol %)
X = O, N-Ts,
N-Fs, N-Bs, N-Boc
2
6
5 o
C
R2
1
3a-r
OMe
N
N
MeO
MeO
N
Br
N
N
N
N
O
O
N
O
N
O
N
N
N
Br
Cl
Cl
Cl
Cl
3
a
OMe 3b
3c
3d
9
8%,12h
77%,12h
54%,12h
99%,12h
As we switched the primary haloalkanes to the secondary,
tertiary or ClF COOC H , the reaction proceeded differently,
N
MeO
MeO
N
Ts
N
N
N
N
Ts N
N
N
N
N
Fs N
N
N
Bs N
2
2 5
N
Cl
Cl
Cl
Cl
Cl
3g
3h
92%,12h
which a ring-opening/isomerization reaction taking place
under the same condition.
3
e
3f
4
4%,12h
63%,12h
87%,12h
F
F
N
Bs
N
N
N
N
R = CH2CH3, 3j, 45%, 24h
R = (CH2)3CH3, 3k, 52%, 24h
R = (CH2)11CH , 3l, 92%, 24h
O
N
N
N
O
N
N
Initially, synthesis of naphthol (4a) from oxabicyclic alkene (1a)
Cl
Cl
3
3
i
R
3m
93%,12h
3
was tried in different solvent systems. Unfortunately, with
either water or various haloalkane as the solvent, the
isomerization reaction did not occur (Table 2, entries 1, 2). It
was found that the desired product was obtained in good yield
in the biphasic water-haloalkane solvent system (Table 2,
entries 3–5); when the haloalkanes were chlorocyclohexane
and ClF CCOOCH CH , the optimal result was obtained.
7
2%,12h
OMe
O
N
N
N
N
N
O
N
N
N
Ts
N
N
Fs N
N
N
N
OMe
Cl
3n
OMe
3o
3
3p
3
3q
67%,12h
3
2
2%, 24h
42%, 24h
66%,12h
Cl
N3
N1
N
N3
N
BocN
N
O
N
N1
O
N
+
Cl
Cl
3
r
3r'
3s
2
2
3
trace, 12h
3
r : 3r' = 37% : 55%
Moreover, the isomerization of 1a could also carry out in an
excellent yield in 99% by decreasing the amount of chlorinated
solvent (rate of ClF COOC H and Water = 0.025 : 1 v/v, 2.05
Scheme 2. Substrate scope for the synthesis of triazolines.
2
2 5
o
mL, see Table 2, entry 6) in 80 C. In addition, when the
haloalkane was tert-butyl chloride, the reaction generated
some by-products after 3 h. Subsequently, the reactions were
tested in ClF CCOOCH CH with different organic solvents
In particular, when oxabicyclic alkene (1a), 3-chloroprop-1-yne
2g) and NaN were subjected to the three-component domino
reaction under the optimized condition, a distinctive product
7a) was isolated in a reasonable yield (Scheme 3). Moreover,
(
3
2
2
3
(
(Table 2, entry 7), but the isomerization could not proceed.
the reaction also could proceed with the oxabicyclic alkenes
containing electron-donating groups on the aromatic ring and
There was also no reaction using biphasic solvent of water and
CH COOCH CH (Table 2, entry 8). These results suggested the
3
2
3
give the products of the indene (7b, c). However, when the
both haloalkane and water were necessary for the formation
of naphthol through isomerization of oxa(aza)bicyclic alkene.
substituent on the aromatic ring in oxabicyclic alkene was
electron-withdrawing group, there was fused bicyclic triazoline
(
3t) in 72% yield.
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The deuterium-labeling experiments had been carried out in
the investigation (Figure 5, and more details in Scheme S1).
a
Table 2. Initial investigations for Ring-Opening in water.
Temp.
o
Entry
Solvent
Yield (%)
(
C)
Scheme 5. Substrate scope for the synthesis of naphthols.
1
2
3
water
85
85
85
65
65
80
65
65
65
65
65
n.r.
n.r.
b
84(n.r. )
chlorocyclohexane
Water/chlorocyclohexane
Water/tert-butyl chloride
c
4
77
99
5
Water/ClF
Water/ClF
2
2
CCOOCH
CCOOCH
2
2
CH
CH
3
d
6
3
99
e-h
7
8
9
ClF
Water/CH
Water/CF
Water/CCl
Water/CF
2
CCOOCH
2
CH
COOCH
COOCH
COOCH
CH OH
3
/solvent
n.r.
n.r.
94
3
2
CH
3
3
2
CH
3
1
0
1
3
2
CH
3
92
1
3
2
n.r.
Figure 3. The pH of the aqueous layer in different haloalkane/Water system.
a
The reaction was carried out using oxabicyclic alkenes (0.1 mmol) in
b
solvent (rate of various solvent = 1 : 1 v/v, 2 mL) for 12 h. The reaction
o
c
d
To explore the haloalkane/Water system in the different
was performed at 65 C.
Water/ClF CCOOCH CH = 1 : 0.025v/v, 2.05 mL. CH
toluene. 1,4-dioxane.
The reaction was performed for 3h.
e
f
2
h
2
3
3
CH
2
OH. isopropanol. reactions, we measured the pH of the aqueous layer in the
mixture system respectively (Figure 3). And we found the pH of
the Water in the DCE/Water system had no obvious change,
g
With these optimized condition in hand, we then explored the
scope of various oxa(aza)bicyclic alkenes. It was found that
different substituted oxabicyclic alkenes were compatible in
this reaction and afforded structurally diverse naphthols in 34–
which was in favour of producing fused bicyclic triazolines in
this environment. When using the propargyl chloride to
replace DCE in the haloalkane/Water system, the pH had been
+
dropped obviously, which confirmed that H had been
9
9% yields (Scheme 5). The reaction proceeded well with
oxabicyclic alkenes containing electron-donating groups on the
aromatic ring (4c and 4g). However, substituted halogens
Br and F) impaired the reactivity to some extent, giving lower
yields compared with electron-donating groups (4e ). The
generated in that reaction. A one pot approach to the
synthesis of indines in the propargyl chloride/Water system
could be initiated by the acid catalyzed rearrangement of the
,
d
(
triazolines. There was
ClF CCOOCH CH /water
a
same trend of the
like the propargyl
,
f
2
2
3
system
reactivity for the ring-opening reaction of brominated
oxabicyclic alkene was relatively low, that could also explain
the reason why the brominated oxabicyclic alkene could not
take place the ring-opening/rearrangement reaction in the
chloride/Water system. Differently, the pH was lower than the
tow system which mentioned above. The more acidic
environment would be better to produce the naphthols from
the oxabicyclic alkenes.
NaN
Scheme 3). Moreover, the bulkier substrate was also tolerated
under the same condition, affording desired product 4h in 73%
yield, but the amount of the ClF CCOOCH CH need to be
3
and 3-chloroprop-1-yne system to synthesize the indene
To further demonstrate the synthetic application of the
developed protocol, the gram-scale reactions were tested and
could proceed smoothly, delivering the oxa(aza)bicyclic
triazoline and naphthalene-1-ol in good yield (Scheme 6, eq a).
Further transformations for the substrates (3a and 3e) were
performed with oxa(aza)bicyclic triazolines in the presence of 2
(
2
2
3
increased for the poor water-solubility of the bulkier substrate.
In addition, neutral group in the aromatic ring of oxabicyclic
alkene were well tolerated (4a and 4i). The reactions could
also proceed with azabicyclic alkene and generate the product
2 3 3 2
equiv of Cs CO in CH CH OH to give elimination (Scheme 6, eq
b), which afforded the corresponding products
excellent yields.
5 and 6 in
4
b
in good yield. Specially, when the water/CF
was used, the yield of naphthol was 94%, and the
water/CCl COOCH CH system gave a 92% yield (Table 2, 9 and
0). And using trifluoroethanol to replace CF COOCH CH , the
reaction could not carry out.
3 2 3
COOCH CH
3
2
3
1
3
2
3
4
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Scheme 6. Gram reaction and transformation.
We performed
a recycling experiment under aqueous
conditions (Figure 4). The experimental details were provided
in Scheme S2. Five cycles provided a conversion of the
reactants into the desired adduct 3a without significant loss of
yield. Both NaN
phase.
3
and Bu
4
NOAc could be recovered in aqueous
Figure 5. H/D exchange experiments and control experiment for the
cycloaddition.
a
Figure 4. A simple isolation and recycling of the aqueous phase.
A plausible mechanism was proposed for the three-component
cycloaddition and isomerization of oxa(aza)bicyclic alkenes in
water (Figure 6). Hydrogen bond formation between water
and the halogen atom of haloalkane compound increases the
electrophilic character at the halocarbon. Intramolecular
nucleophilic attack at halocarbon by oxygen atom of water
Figure 6. Plausible reaction mechanism for the cycloaddition (Path a) and
isomerization of bicyclic alkenes in water (Path b).
+
2
produces the aliphatic alcohols and H , while using the R –X
path b, see the control experiment, Figure 5 and Scheme S3).
(
Table 3. Synthesis of indene 7d–f via BF
3
-induced cascade ring-opening/rearrangement
a
In addition, the reaction could be further promoted via the reaction of oxabicyclic triazolines.
transition state
3 2 3
A while using the X CCOOCH CH (X = F or Cl)
7
e
which contain C=O . Furthermore, chlorinated ester would
generate haloacetic acid after hydrolysis, and the acid also
promoted the reaction. Subsequently, the cleavage of C–O
bond occurs concomitantly to give the allyic cation
B
by the
protonation of bridging oxygen with H . Simultaneously,
compound is formed from species with the H group
migrating. The isomerization of generates the final product
To obtain further insight into the reaction mechanism, the
isomerization reaction was performed in D O and monitored
NMR spectroscopy (Scheme S1). Switching the
+
C
B
C
4.
b
Time
h)
Yield
Entry
Cat. (eq)
-
solvent
Prod.
2
(
(%)
1
by
haloalkane to the primary haloalkane (R –X) with Bu
NaN promotes the dehalogenation to undergo a different
reaction way, probably because the nucleophilicity of N
H
1
2
3
4
5
6
7
8
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
24
24
7d
7d
7d
7d
7d
7d
7e
7f
n.r.
1
4
NOAc and
FeCl
3
(0.1)
(0.3)
2
n.r.
34
3
.
3
BF
OEt
2
2
0.2
0.2
0.2
0.2
0.2
0.2
-
3
is
TfOH (1.0)
2
n.r.
52
more than that of oxygen atom of water in this way (path a,
.
3
BF
BF
BF
BF
OEt
OEt
OEt
OEt
2
2
2
2
(0.3)
(0.3)
(0.3)
(0.3)
toluene
see the control experiment, Figure 5 and Scheme S3). The
.
3
1
to R –
C
C
C
6
6
6
H
5
Br
Br
Br
70
azides were obtained by the nucleophilic attack of NaN
X with Bu
transition state
3
.
3
H
5
74
4
NOAc. Afterward, concerted cycloaddition of
toward C–N bond formation occurs
.
3
H
5
68
D
successfully to finally generate the product 3.
a
b
The reaction was performed at room temperature. Isolated yield.
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Subsequently, an investigation regarding the transformation of enrich the exploration for the oxa(aza)bicyclic alkenes and
.
oxabicyclic triazoline revealed that the Lewis acid BF
able to induce a domino ring-opening reaction into the well.
corresponding indene (Table 3, entry 3). The reaction was
not carried out without catalyst or adding the metal catalysis
like the FeCl
(Table 3, entries 1, 2). However, when using the Acknowledgements
TfOH to replace the BF , the ring-opening rearranged product
3 2
OEt was provide new scaffolds to constitute bioactive compounds as
7
3
3
We gratefully thank the National Natural Science Foundation
of China (21172081, 21372090), the Natural Science
Foundation of Guangdong Province (S2013020013091) and the
City of Guangzhou Science and Technology Plan Projects
(201510010054).
could not be found in the reaction system at room
temperature. According to a one pot approach to the synthesis
of indines (see Scheme 3), the initiation of the ring-opening
rearrangement needed to be heated on suit temperature and
+
added in H environment to generate the ring-opening
rearranged product. It was possible to obtain the indene (7d
)
.
in 70% yield by addition of 30 mol % of BF
of the oxabicyclic triazoline (3k) in bromobenzene (Table 3,
entry 6). The substrates possessing bulkier substituted
3 2
OEt to a solution
Conflicts of interest
n
-
There are no conflicts to declare.
dodecyl (3l) or OMe substituents at the aryl ring also produced
the corresponding indene 7e and 7f in moderate yield (Table 3,
entries 7,8). This reaction process represents the first example
of denitrogenative and ring-opening of bicyclic triazolines to
Notes and references
synthesize indenes. The reaction possibly starts with the BF
coordinating to oxygen atom and the cleavage of C–O bond
occurs concomitantly to form intermediate (Scheme 7), that
could explain the reason why the BF could catalyze the ring-
opening rearrangement but the TfOH could not catalyze in the
room temperature. Then, a 1,2-H shift occurs and another BF
3
1
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A
3
3
1
9
coordinates to the N
intermediate from
out with the cleavage of the N
induction of BF followed by a new C=N bond formation from
the intermediate to . Afterward, the hydroxyl group acts as
1
atom to generate the more stabilizing
. A denitrogenative reaction is carried
–N and C–N bonds under the
C
B
Fagnou, M. Taylor, T. Rovis, J. Organomet. Chem., 2001, 624
,
1
2
3
2
3
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the electron supplier supplying both electrons for the
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bond migrated onto the leaving diazonium species to give the
2
3
3
6, 48; (b) D. K. Rayabarapu, C. H. Cheng, Acc. Chem. Res.
intermediate
E. The product 7 is obtained with the 1,3-H shift
2
007, 40, 971; (c) C. Bournaud, F. Chung, A. Luna, P. M.
from the E successfully.
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Scheme 7. Plausible mechanism.
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In summary, we report herein the reagent-controlled water-
promoted three-component domino reaction and the
isomerization of oxa(aza)bicyclic alkenes, which affords highly
functionalized bicyclic triazolines and naphthols in excellent
yields. Water is used as a recyclable and sustainable medium in
the synthesis of the desired product, providing a green route.
,
2
Wu, H. P. Zeng, Y. Chen, J. Org. Chem., 2010, 75, 7291; (e) D.
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3
We also investigate the first BF -induced denitrogenative ring-
5
Y. Miki, K. Hirano, T. Satoh, M. Miura, Org. Lett., 2014, 16
,
opening/rearrangement of bicyclic triazolines to give the
multifunctionalized indenes. The protocol and transformation
1
498.
6
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DOI: 10.1039/C7GC03772D
TOC
O
H
H O
N
.
2
BF Et O
3 2
R1 = 1 haloalkane
o
R3
X
N
R3
1
NH
R
R -halide
N
R1
1
R3
X
NaN3
XH
XH
X = O, NR
2
R -halide
R2 = 2 , 3o haloalkane
o
R3
R3
or ClF2CCOOCH2CH3
H O
2
1
3
5
. Metal-free
. Water-promote 4. Gram-scale synthesis
. Reaction in water 6. Recycling is OK
2. Good selectivity and highly yield