Non-Bonding Electron Pair versus π-Electrons in Solution Phase Halogen Bond Catalysis: Povarov Reaction of 2-Vinylindoles and Imines

Article abstract of DOI:10.1002/adsc.202000494

The non-bonding electron pair (n-pair) of heteroatoms and π-electrons are both efficient halogen bond (XB) acceptors. In solid and gas phase studies, n-pairs generally prevail over π-bonding orbitals as XB acceptors, whereas few studies have been conducte

Full text of DOI:10.1002/adsc.202000494

Title: Non-bonding Electron Pair versus π-Electrons in Solution Phase
Halogen Bond Catalysis: Povarov Reaction of 2-Vinylindoles and
Imines
Authors: Takumi Suzuki, Satoru Kuwano, and Takayoshi Arai
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000494
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Advanced Synthesis & Catalysis
10.1002/adsc.202000494
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Non-bonding Electron Pair versus π-Electrons in Solution
Phase Halogen Bond Catalysis: Povarov Reaction of 2-
Vinylindoles and Imines
a
a
a
Takumi Suzuki, Satoru Kuwano, and Takayoshi Arai *
a
Soft Molecular Activation Research Center (SMARC), Chiba Iodine Resource Innovation Center (CIRIC), Molecular
Chirality Research Center (MCRC), Department of Chemistry, Graduate School of Science, Chiba University, 1-33
Yayoi, Inage, Chiba 263-8522, Japan
Phone and fax: +81-43-290-2889
E-mail: tarai@faculty.chiba-u.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The non-bonding electron pair (n-pair) of
heteroatoms and π-electrons are both efficient halogen
bond (XB) acceptors. In solid and gas phase studies, n-pairs
generally prevail over π-bonding orbitals as XB acceptors,
whereas few studies have been conducted regarding the
preference in solution phase. Herein, the Povarov reaction
via the C−I···N XB interaction and [4+2] cycloaddition via
the C−I···π XB interaction were evaluated, revealing that
the n-pair was more dominant in the XB catalysis system in
solution. The XB donor-catalyzed Povarov reaction gave
diverse indolyl-tetrahydroquinoline derivatives in good
yields. Synthesis of indolyl-quinolines was also developed.
Keywords: Halogen bond; Povarov reaction;
Tetrahydroquinoline; Quinoline; Indole; Iodine
Halogen bond (XB) is a non-covalent interaction
between a σ-hole of an electron-deficient halogen atom
[1]
(
XB donor) and a Lewis base (XB acceptor). X-ray
crystallographic studies conducted by Hassel in the
950s were crucial in identifying the structural features
1
of these non-covalent interactions, revealing that both
the non-bonding electron pair (n-pair) of a heteroatom
and aromatic π-electrons acted as efficient XB
[2]
acceptors in the solid phase (Figure 1A). When both
an n-pair and π-electrons are present in the XB
acceptor (e.g., 2,2-bipyridine), the n-pair is
[3]
preferentially involved in XB formation.
This
phenomenon is observed in various solid phase studies
where n-pairs generally prevail over π-bonding orbitals
as XB acceptors.
As with the solid phase studies, n-pairs are more
[4]
dominant than π-systems in gas phase studies.
Interestingly, exceptional examples were reported by
Legon for complexes of relatively electron-rich
aromatic compounds such as furan and thiophene with
Figure 1. Halogen bond in solid, gas and solution phases.
[5]
chlorine monofluoride (Figure 1B, left). In those
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000494
aromatic systems, π-electrons dominated over the n- pentafluoroiodobenzene 1d, which is known as a
pairs as XB acceptors. When the XB donor was neutral XB donor, showed negligible catalytic activity.
replaced with hydrogen chloride, a Cl−H···O complex Among the cationic XB donors applied, 2-
was formed through a hydrogen bond (HB), which is a iodoimidazolium salt 1c showed better catalytic
unique difference between XB and HB (Figure 1B, activity to give 5a in 79%. CH
2
Cl
2
was the best solvent
right).[
6]
to give the product, although 1c was not completely
Unlike these solid state and gas phase studies, the solved in the reaction media. An increased amount of
preference for n-pairs and π-electrons as XB acceptors 2a and a shorter reaction time resulted in formation of
in the solution phase has not been extensively 5a in 89% yield, thus these were chosen as the
investigated, despite various applications of XB in optimum reaction conditions (entry 12). When the
molecular recognition and catalysis.[7,8,9] As the first yields of 5a were low in Table 1, unreacted starting
example of the use of C−I···π XB in catalysis, materials were remained and dimerization of 2a was
electrophilic activation of 2-alkenylindoles by cationic not observed.
[9x]
XB donors for [4+2] cycloadditions was developed.
To evaluate which is dominant in catalysis in the
solution phase, in this study, C−I···π XB-catalyzed
dimerization was selected as a benchmark reaction. By
adding N-p-methoxyphenyl (PMP) imines to the [4+2]
dimerization system as n-pair type XB acceptors, a
competitive reaction between the dimerization via
C−I···π XB and the Povarov reaction via C−I···N XB
would be investigated (Figure C).
Table 1. Optimization of reaction conditions.
The competitive reaction (Scheme 1, 2a+2a→4a
versus 2a+3a→5a) was performed using XB donor 1a
which was previously found to be the optimum catalyst
for dimerization of 2a.[ The Povarov reaction was
found to be dominant (4a: 0% yield versus 5a: 71%
yield, single diastereomer), suggesting that, in
accordance with previous studies in the solid and gas
phases, C−I···N XB was also preferred in the solution
phase. Several Brønsted acid or Lewis acid catalyzed
9x]
Yield
Povarov reactions of 2-alkenylindoles with N-
Entry
1
Solvent
Time (h)
arylimines have been reported.[10]
a)
(
%)
1
2
3
4
5
6
7
8
9
none
1a
1b
1c
1d
1c
1c
1c
1c
1c
CHCl
CHCl
CHCl
CHCl
CHCl
hexane
toluene
THF
3
3
3
3
3
23
22
21
21
21
21
22
21
22
21
22
13
19
74
78
79
7
65
78
31
50
15
80
89
CH
3
CN
1
1
0
1
MeOH
1c
1c
CH
CH
2
2
Cl
Cl
2
[
b]
1
2
2
a)
Isolated yield. b) 1.3 eq of 2a were used.
We next investigated the substrate scope on the XB-
Scheme 1. Competitive reaction between 2a+2a and 2a+3a
by XB catalysis.
catalyzed Povarov reaction of 2-vinylindole with
imines (Table 2). Neither electron-donating nor
electron-withdrawing substituents at the 5-position of
2
-vinylindole influenced the reaction outcome (5b-d).
N-PMP imines having p-tol, o-tol, 2-naphthyl, p-Br-
This highly selective promotion of the Povarov
reaction by XB catalysis stimulated us to further
optimize the reaction conditions (Table 1). We
evaluated several XB donors (10 mol%), along with
the non-catalyzed reaction, in the presence of 2-
vinylindole (2a, 1.1 eq) and N-PMP imine (3a, 1 eq) in
C
6
H
4
, o-Cl-C
6
H
4
, p-acetyl-C
6
H , 2-furyl, and 2-
4
thiophene groups were all well tolerated to give desired
products (5e-l) in high yields. N-Phenyl, N-1-naphthyl,
and N-p-Br-C
6
H imines were also acceptable to
4
furnish the products in good to moderate yields (5m-
o). When 1-benzyl-2-vinylindole (1-Bn-2a) was used,
tetrahydroquinoline 5p and tetrahydro-γ-carboline 5p’
CHCl
3
(entries 1-5). Cationic XB donors 1a-c
efficiently promoted the reaction, whereas
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000494
were obtained in 23% and 9% yield respectively,
[10b]
together with unidentified byproducts (Scheme 2).
Dimerization of 2-vinylindoles was not observed in all
cases.
In the course of the development of the XB-
catalyzed Povarov reaction, indolyl-quinoline 6a was
[11]
detected as a byproduct (Scheme 3, eq 1).
We
assumed that indolyl-tetrahydroquinoline 5a was
transformed into 6a by dehydrogenation, while the N-
PMP imine functioned as a formal hydrogen
acceptor.[ To verify this hypothesis, a reaction using
12]
1
equivalent of 2a, 3 equivalents of 3a, and 10 mol%
of 1c was performed in CH Cl for 38 hours (Scheme
, eq 2). The yield of indolyl-tetrahydroquinoline 5a
2
2
3
Table 2. Synthesis of indolyl-tetrahydroquinolines
catalyzed by XB donor.
Scheme 3. Product switching controlled by the equivalent of
imine.
drastically decreased to a trace amount, while indolyl-
quinoline 6a was obtained in 74% yield, along with
3
4% yield of amine 7a, which could be generated by
hydrogenation of N-PMP imine 3a. This result
suggests that selective formation of either indolyl-
tetrahydroquinoline 5a or indolyl-quinoline 6a can be
easily controlled by adjusting the amounts of 2-
vinylindole and N-PMP imine. To check whether the
transformation of 5a into 6a is accelerated by XB
donor or not, 1c was added to the mixture of 1 eq of 5a
and 2 eq of 3a (Scheme 3, eq 3). While no reaction
occurred without 1c, indolyl-quinoline 6a was
obtained in 46% yield after 62 h in the presence of 1c,
which indicated that the second step was also promoted
[9a,9d,9p]
by the catalyst.
Additional examples for the synthesis of indolyl-
quinolines were investigated as shown in Table 3.
Table 3. Synthesis of indolyl-quinolines catalyzed by XB
donor.
Scheme 2. Reaction of 1-benzyl-2-vinylindole (1-Bn-2a)
and 3a.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000494
2
To a mixture of 2-vinylindole 2 (0.13 mmol, 1.3 eq) and N-
The introduction of p-tol or p-Br-C
6
H groups at R had
4
2 2
arylimine 3 (0.1 mmol, 1 eq) in CH Cl (0.5 mL) in a round
no effect on the reaction, and the corresponding
indolyl-quinolines 6b and 6c were obtained in 91% and
1% yields, respectively, by conducting the reaction at the mixture was stirred for the appropriate time at room
0 °C for 60 hours. The indolyl-quinolines 6d and 6f
were also obtained from N-phenyl and N-p-Br-C
imines in 20% and 18% yields, but the reaction went chromatography using hexane/acetone = 4/1 as an eluent to
messy when N-1-naphthyl imine was employed.
Several supporting experiments were performed to
confirm that this Povarav reaction was promoted by
XB catalysis (Scheme 4). The addition of DTBP (2,6-
bottom screw vial containing a stir bar was added catalyst 1c
0.01 mmol, 10 mol%). The vial was flushed with argon and
(
8
4
temperature. The solvent was removed under reduced
pressure and the resulting mixture was purified by
preparative thin-layer chromatography or silica gel column
6
H
4
afford the product 5.
General procedure for XB-catalyzed synthesis of indolyl-
quinolines 6.
di-tert-butylpyridine) did not disturb the reaction, To a mixture of 2-vinylindole 2 (0.1 mmol, 1 eq) and N-
arylimine 3 (0.3 mmol, 3 eq) in CH Cl (0.5 mL) in a round
bottom screw vial containing a stir bar was added catalyst 1c
2
2
suggesting that a hidden Brønsted acid, which could
be generated through hydrolysis of the XB donor, was (0.01 mmol, 10 mol%). The vial was flushed with argon and
not the catalyst (Scheme 4a).[13] In the presence of a
chloride anion source, the reaction slowed down to
the mixture was stirred for the appropriate time at room
temperature. After the solvent was removed under reduced
pressure, the resulting mixture was purified by preparative
give 22% of 5a with remaining of the starting materials thin-layer chromatography or silica gel column
Scheme 4b).[ (The similar results are obtained using
9c]
chromatography using hexane/acetone = 4/1 as an eluent to
afford the product 6.
(
1a and 1b. See the details in the supporting
information.) These results indicated that the XB was
important to smoothly catalyze the reaction.
Acknowledgements
This research is supported by JSPS KAKENHI Grant Number
1
9H02709 in Grant-in-Aid for Scientific Research (B), 19K15553
in Grant-in-Aid for Young Scientists, and the Futaba Research
Grant Program of the Futaba Foundation.
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5
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Advanced Synthesis & Catalysis
10.1002/adsc.202000494
UPDATE
Non-bonding Electron Pair versus π-Electrons in
Solution Phase Halogen Bond Catalysis: Povarov
Reaction of 2-Vinylindoles and Imines
Adv. Synth. Catal. Year, Volume, Page – Page
Takumi Suzuki, Satoru Kuwano, Takayoshi Arai*
6
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