BF3·OEt2-Promoted Propargyl Alcohol Rearrangement/[1,5]-Hydride Transfer/Cyclization Cascade Affording Tetrahydroquinolines

Article abstract of DOI:10.1021/acs.orglett.9b01153

An efficient BF₃·OEt₂-mediated propargyl alcohol rearrangement/[1,5]-hydride transfer/cyclization cascade for the synthesis of tetrahydroquinoline derivatives has been described. The substituents adjacent to triple bonds play an important role in the formation of ketones (via [1,3]-hydroxyl shift) or alkenyl fluorides which are products of formal trans-carbofluorination of internal alkynes. This method provides a rapid access to diverse heterocycles in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.9b01153

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
BF3·OEt2‑Promoted Propargyl Alcohol Rearrangement/[1,5]-Hydride
Transfer/Cyclization Cascade Affording Tetrahydroquinolines
Shuang Zhao,† Xiaoyang Wang,† Pengfei Wang,† Guangwei Wang,*,† Wentao Zhao,†
Xiangyang Tang,*,† and Minjie Guo*,‡
†Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University,
Tianjin 300072, P. R. China
‡Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin
300072, P. R. China
S
* Supporting Information
ABSTRACT: An efficient BF3·OEt2-mediated propargyl alcohol
rearrangement/[1,5]-hydride transfer/cyclization cascade for the
synthesis of tetrahydroquinoline derivatives has been described. The
substituents adjacent to triple bonds play an important role in the
formation of ketones (via [1,3]-hydroxyl shift) or alkenyl fluorides
which are products of formal trans-carbofluorination of internal
alkynes. This method provides a rapid access to diverse heterocycles
in moderate to excellent yields.
s one of the most valuable skeletons and building blocks,
tetrahydroquinoline can be found in many natural
an acetyl and a [1,3]-OAc shift was involved in this process
(Scheme 2b).11 In 2012, Gong et al. reported a transition-
metal-free [1,5]-hydride transfer/cyclization process of termi-
nal alkynes,12 which was promoted by Brønsted acid and
pyridine-N-oxide, to give 2,3-dihydroquinolinones (Scheme
2c). Herein, we will report a propargyl alcohol rearrangement/
[1,5]-hydride transfer/cyclization cascade promoted by Lewis
acid BF3·Et2O (Scheme 2d). The current method provided a
straightforward and convenient one-step synthetic route
toward a variety of tetrahydroquinoline derivatives.
Our study was initiated by examining the [1,5]-hydride
transfer/cyclization with the easily prepared propargyl alcohol
1a being the model substrate in the presence of Lewis acids
(Table 1). To our delight, the desired tetrahydroquinoline
derivative 2a was obtained in 78% yield with 3.0 equiv of BF3·
OEt2 as a Lewis acid in 1,2-dichloroethane (DCE) at 80 °C
(entry 1). In this reaction, 3a was obtained in 7% yield which
probably was formed via Meyers−Schuster rearrangement
reaction13 of propargyl alcohol 1a. When anhydrous Yb(OTf)3
or FeCl3 was employed as a Lewis acid, the reaction was messy
and only a trace amount of 2a was observed (entries 2 and 3).
Other Lewis acids, including AlCl3, ZnCl2, and CuCl2, were
also tested, but no desired product 2a was obtained (entries
4−6). Brønsted acids such as p-toluenesulfonic acid (TsOH),
trifluoroacetic acid (TFA), and camphorsulfonic acid (CSA)
were also screened, however, mainly leading to 3a in modest
yields (entries 7−9). With BF3·OEt2 as the Lewis acid of
choice, different solvents have been investigated, and we found
that nonchlorinated solvents, such as 1,4-dioxane, dimethyl
sulfoxide (DMSO), acetonitrile, tetrahydrofuran, and toluene,
A
products and drugs with strong antibacterial and anti-
inflammatory biological activities.1 Over the past years, [1,5]-
hydride transfer/cyclization cascade reactions proved syntheti-
cally powerful for the construction of structurally diverse
complex molecules, especially tetrahydroquinoline derivatives.2
The hydride transfer process usually requires hydride donors
and hydride acceptors. The typical hydride donor is a C(sp3)−
H moiety adjacent to a tertiary amine or an ethereal oxygen
(Scheme 1).3 In most cases, electron-deficient alkenes were
Scheme 1. [1,5]-Hydride Transfer/Cyclization Cascade
used as hydride acceptors in [1,5]-hydride transfer/cyclization
cascade reactions to construct a tetrahydroquinoline skeleton.4
Besides activated alkenes, aldehydes,5 ketones,6 imines,7
allenes,8 and so on can also serve as different types of hydride
acceptors.
In recent years, alkynes also served as hydride acceptors in
this cascade reaction.9 For example, Barluenga et al. reported a
Fischer carbene-activated [1,5]-hydride transfer/cyclization
process for the efficient synthesis of 1,2-hydroquinolynyl
carbene complexes (Scheme 2a).10 In addition, Liang et al.
reported a platinum-catalyzed [1,5]-hydride transfer/cycliza-
tion reaction, in which the hydroxyl moiety was protected with
Received: April 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01153
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 2. Alkynes as Hydride Acceptors in [1,5]-Hydride
Transfer/Cyclization Cascade toward the Synthesis of
Tetrahydroquinolines
Table 1. Optimization of Reaction Conditions
b
b
entry
Lewis acid
solvent
temp (°C)
2a (%)
3a (%)
1
2
3
4
5
6
7
8
BF3·OEt2
Yb(OTf)3
FeCl3
AlCl3
ZnCl2
CuCl2
TsOH
TFA
CSA
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
78
<5
<5
<5
<5
<5
<5
<5
<5
34
<5
35
<5
34
69
77
81
72
46
<5
<5
67
7
<5
45
50
45
46
66
64
67
18
<5
8
32
<5
<5
7
<5
8
9
DCE
10
11
12
13
14
15
16
17
18
19
20
21
22
dioxane
DMSO
MeCN
THF
toluene
CHCl3
DCM
DCE
DCE
DCE
DCE
DCE
c
c
c
d
e
f
12
<5
46
21
<5
g
d
d
DCE
DCE
40
60
d
23
91 (83)
a
all led to lower yields compared to DCE (entries 10−14).
Employing dichloromethane and chloroform instead of DCE,
the reaction gave slightly lower yields for the desired product
(entries 15 and 16). The amount of Lewis acid was also
checked, and a slightly higher conversion of 1a was observed
when the Lewis acid was decreased to 2.5 equiv (entry 17).
When 2 equiv of BF3·OEt2 were used, the GC yield of product
2a was 72% (entry 18). However, further decreasing the
amount of BF3·OEt2 to 1.5 equiv resulted in lower selectivity
for the target product (entry 19), while low conversion of 1a
was observed when the amount of BF3·OEt2 was decreased to a
catalytic amount (entry 20). Then, we also screened the
reaction temperature (entries 21−23). When the reaction was
conducted at 60 °C, 2a was obtained in 91% yield (entry 23).
Consequently, 2.5 equiv of BF3·OEt2 as the Lewis acid and 1,2-
dichloroethane as solvent at 60 °C were chosen as the
optimized conditions.
With the optimal reaction conditions in hand, a wide range
of functional groups were then evaluated to investigate their
influence on the overall reactivity and to establish the reaction
scope with respect to the aromatic rings connecting directly to
hydride acceptors (Scheme 3). Excellent yields were obtained
in the reaction including para-alkyl-substituted substrates (2b,
2c) and an electron-donating naphthalene ring (2h, 2i).
Electron-withdrawing substituents such as F (2d), Br (2e), Cl
(2f) in the para position were also well-tolerated, and the
corresponding products were obtained in moderate-to-good
yields. A meta-CH3-substituted product (2g) was smoothly
furnished in 87% yield when the reaction was conducted in 1.5
h. Furthermore, substrates with a larger conjugate structure
proceeded smoothly under the optimized conditions to afford
2j and 2k in 62% and 80% yield, respectively. It was gratifying
to note that substrates with an electron-withdrawing group
Reaction conditions: Unless otherwise noted, all reactions were
performed with 1a (0.5 mmol, 1.0 equiv), Lewis acid (1.5 mmol, 3.0
equiv), in DCE (1 mL) at 80 °C under Ar for 1.5−2 h. Yields were
determined by GC analysis with dodecane as an internal standard.
b
c
The value in parentheses is the isolated yield. The reaction was run in
d
e
sealed reaction tube. BF3·OEt2 (2.5 equiv). BF3·OEt2 (2.0 equiv).
f
g
BF3·OEt2 (1.5 equiv). BF3·OEt2 (30 mol %).
(bromo) and electron-donating group (methyl) in the meta or
para position to the nitrogen atom also give rise to the desired
products in typically excellent yields (2l−2n). Unfortunately,
substrates with a para methoxy group and thiophene group led
to only an α,β-unsaturated ketone. Various heterocycles
derived from different cyclic or acyclic amines were also
investigated to demonstrate the substrates scope of this
methodology. Substrates containing aza-cycle scaffolds with
different ring sizes, (1o−1q) and 5,6,7,8-tetrahydroisoquino-
line (1r), successfully give rise to the desired fused products in
moderate to good yields, generally with the anti-products being
preferred. Although the two diastereomers can be isolated by
column chromatography, they can convert to each other under
the reaction conditions (see Supporting Information (SI) for
the detailed discussion). When ethereal oxygen containing
substrates, with N,N-dimethyl group in 2a being substituted by
methoxy or allyloxy, were subjected to the standard conditions,
the reactions were messy resulting in a complicated inseparable
mixture (see SI for the details).
Subsequently, a variety of substrates with aliphatic
substitution on the alkyne moiety were subjected to the
above reaction conditions (Scheme 4). Unexpectedly,
exoalkenyl fluoride 4 resulted as a major product, which is a
formal trans-carbofluorination product of the internal alkyne.
Substrate with TMS-substitution (1s) afforded 77% 4s with
B
DOI: 10.1021/acs.orglett.9b01153
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Letter
high selectivity. Propargylic alcohols 1t−1w led to similar
outcomes for the formation of an alkenyl fluoride 4 product
with moderate results, along with a minor amount of 2 being
isolated in these reactions. The stereochemistry of alkenyl
fluoride was determined by NOE measurement of compound
4w.
Scheme 3. BF3·OEt2-Promoted [1,3]-Hydroxyl Shift/[1,5]-
a b
,
Hydride Transfer/Cycloaddition
Based on previous studies,11,14 a plausible reaction pathway
is postulated in Scheme 5 (Path I), which involves a Lewis acid
Scheme 5. Control Experiment and Proposed Mechanism
induced 1,3-hydroxyl shift (Meyer−Schuster rearrangement)
leading to an α,β-unsaturated ketone (3). Then, coordination
of a Lewis acid to the carbonyl oxygen forms a complex which
undergoes a [1,5]-hydride shift to afford the zwitterionic
intermediate A. Finally, Mannich cyclization afforded the
desired tetrahydroquinoline (2). However, when α,β-unsatu-
rated ketone (3a) was subjected under standard conditions (eq
1), only a 21% yield of 2a was obtained, which indicates the
presence of other possible reaction pathways. Moreover, the
formation of 4 cannot be explained through this pathway.
Therefore, an alternative pathway is proposed (Path II) in
which the Meyer−Schuster rearrangement product is bypassed.
First, reaction of propargyl alcohols with Lewis acid may lead
to propargyl cation intermediate B, which undergoes an SN1′
nucleophilic attack leading to allenyl-boron complex C.15 Then
the hydrogen on the methyl group adjacent to the nitrogen
atom migrates in a [1,5]-fashion to the most electrophilic
carbon of allene, affording zwitterionic intermediate D.
Afterward, intermediate D undergoes Mannich cyclization
affording the intermediate E. The formation of product 2 or 4
as major products is dependent on the substituted group on
the alkyne. When the alkyne is substituted by an aromatic
group, the nucleophilic SN1′ attack of OH− is favored due to
its higher nucleophilicity compared with fluoride. Accordingly,
the intermediate E will be hydrolyzed to give the keto product
2. However, when the alkyne is substituted by the alkyl group,
the nucleophilic SN1′ attack of F− is favored due to the higher
steric demand of alkyl substitution and the alkenyl fluoride 4
will be the dominant product.16 For the highly steric hindered
a
Reaction conditions: Unless otherwise noted, all reactions were
performed with 1 (0.5 mmol, 1.0 equiv), BF3·OEt2 (1.25 mmol, 2.5
b
equiv), in DCE (1 mL) at 60 °C under Ar for 1.5−2 h. All yields
were the isolated yields.
Scheme 4. BF3·OEt2-Promoted [1,5]-Hydride Transfer/
Cycloaddition
a b
,
a
Reaction conditions: Unless otherwise noted, all reactions were
performed with 1 (0.5 mmol, 1.0 equiv), BF3·OEt2 (1.25 mmol, 2.5
b
equiv), in DCE (1 mL) at 60 °C under Ar for 1.5−2 h. All yields
were the isolated yields of alkene-form and keto-form products.
C
DOI: 10.1021/acs.orglett.9b01153
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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Experimental procedures, spectral and analytical data,
copies of 1H, 19F, and 13C NMR spectra for new
compounds (PDF)
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Guangwei Wang: 0000-0003-4466-9809
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors are grateful for the financial support from Major
National Science and Technology Projects (2017ZX07-
402003). We also thank the Natural Science Foundation of
Tianjin (No. 16JCYBJC20100) and Tianjin University for
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