Indium(iii) catalyzed reactions of vinyl azides and indoles

Article abstract of DOI:10.1021/acs.orglett.0c00919

Indium trichloride catalyzes the reaction of vinyl azides with unfunctionalized indoles to give vinyl indoles. This is the first example of displacement of the azide group by a carbon nucleophile while preserving the vinyl function. The protocol employs very mild reaction conditions and offers excellent yields of diverse 3-vinyl indoles. It is amenable to gram scale. Access to a library of 3,3′-bis(indolyl)methanes through condensation of vinyl azides with 2 equiv of an indole is demonstrated.

Full text of DOI:10.1021/acs.orglett.0c00919

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Letter
Indium(III) Catalyzed Reactions of Vinyl Azides and Indoles
Atul A. More and Alex M. Szpilman*
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ABSTRACT: Indium trichloride catalyzes the reaction of vinyl azides with unfunctionalized indoles to give vinyl indoles. This is the
first example of displacement of the azide group by a carbon nucleophile while preserving the vinyl function. The protocol employs
very mild reaction conditions and offers excellent yields of diverse 3-vinyl indoles. It is amenable to gram scale. Access to a library of
3,3′-bis(indolyl)methanes through condensation of vinyl azides with 2 equiv of an indole is demonstrated.
azide anion 7 would lead to formation of the charged species 6
and close the catalytic cycle. This step would likely be
irreversible.
Finally, azide anion would abstract a proton from 6 to give
the product vinyl indole 9 and hydrazoic acid 8. Formally this
would constitute a substitution reaction on a vinyl (sp2)
carbon with azide as the leaving group. In contrast to reactions
with other electrophiles, the reaction would be driven by an
electrophilic catalyst, thereby uniquely preserving the double
bond.
Challenging this proposal was that Brønsted acid activation
of vinyl azides has been shown by Hassner et al.8 to lead
predominantly to Schmidt type 1,2-rearrangements to furnish
amides, or hydrolysis to give ketones in the presence of water.
Chiba and co-workers9 and Bi et al.10 have shown the same to
occur using superstoichiometric amounts of boron-trifluoride
etherate or substoichiometric Tf2NH11 and elegantly trapped
the intermediates with different electrophiles. These reactions
possibly take place through intermediates like 3 (with a proton
or boron in lieu of Indium).8−11 Notably, an intermediate,
analogous to 3, in Scheme 1b has been proposed in a
mechanistic study on the InBr3 catalyzed reaction of enol
ethers with silyl ketene imines.12
inyl azides are chemical chameleons. The unique
Vproperties of the azide function renders vinyl azides
able to serve as a source of electrons for reaction with an
electrophile1 or a radical2 as well as able to let nitrogen serve as
a leaving group in reactions with a nucleophile1e,3 (Scheme
1a).4 This first step typically leads to different imine type
species that may undergo further reactions.4 Thus, the first step
in the chemistry of vinyl azides is typically at the α-position of
the azide moiety.4 In addition, vinyl azides have a rich
chemistry in cycloaddition reactions and are able to form
nitrenes and azirines.4 The recent upsurge in studies on vinyl
azides is probably due to their ready availability in high yields
from feedstock alkenes2b,5 and alkynes.6
Surprisingly, substitution of the azide group on the sp2
carbon with preservation of the alkene system (Scheme 1b) is
unknown yet would be an attractive type of reactivity and open
up many new possibilities in chemistry. Combined with the
multitude of methods for alkene functionalization,7 such a
reaction would not only provide a metaphorical novel color to
the vinyl azide chameleonic properties, but also allow novel
access to functionality of value in, e.g., materials and medicinal
chemistry. We proposed attaining this goal using catalysis. In
such a process, it would of course be necessary to reversibly
attach an electrophilic catalyst, e.g., a Lewis acid, exemplified in
Scheme 1b by indium trichloride (2), at the α-position of vinyl
azide 1, giving rise to an electrophilic diazo-imine species 3
(Scheme 1b). Attack at the α-position is dictated by the
reactivity of vinyl azides with electrophiles.1,4
Received: March 11, 2020
This initial step would allow a nucleophile such as, e.g.,
indole 4 to attack at the azide bearing carbon in 3 with
formation of 5. E2 type elimination of indium-trichloride and
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© XXXX American Chemical Society
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A

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a
Scheme 1. This Work in Perspective and Mechanistic
Hypothesis
Table 1. Optimization of Reaction Conditions
b
c
entry
Lewis acid
mol % acid T/°C t/h conv (%) yield (%)
de
,
1
2
3
4
5
6
7
8
AcCl/MeOH
BF3·OEt2
Zn(OTf)2
Cu(OTf)2
Mg(OTf)2
Ca(OTf)2
B(C6F5)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
In(OTf)3
InCl3
150
100
5
5
5
5
10
5
5
5
0
6
6
100
100
100
0
0
0
100
70
100
50
100
100
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
84
d
d
rt
rt
rt
rt
rt
rt
rt
60
rt
rt
rt
24
24
24
24
3
24
24
24
8
66
78
f
9
10
11
12
43
89
96
5
5
6
a
Unless otherwise specified, all reactions were performed with 1.0
mmol of 10, 1.0 mmol of 11, and CH2Cl2 as the solvent in 4−5 mL.
See the Supporting Information for details. N.D. indicates that 12 was
b
c
not detected. Conversion of 10. Isolated yields of 12.
d
e
f
Acetophenone was formed. Solvent was THF (2 mL) Solvent
was dichloroethane
conversion within 24 h (entry 9), but the yield is inferior to
that of B(C6F5)3 (entry 7). Remarkably, indium(III) triflate
affords 89% yield of 12 in only 8 h (entry 11). Finally, the best
result is achieved by carrying the reaction out in the presence
of 5 mol % InCl3 in CH2Cl2 at room temperature. Under these
conditions, complete conversion is achieved in 6 h to give the
3-vinyl indole 12 as a single regioisomer in 96% isolated yield
(Table 1, entry 12).
As outlined in Scheme 1b, we pursued proof of concept in
the form of a direct C(sp2)-C(sp2) bond forming reaction
between vinyl azides with indoles to give vinyl indoles. To the
best of our knowledge, there are no examples of such a
transformation. Vinyl indoles are attractive intermediates for
the synthesis of alkaloids. Previously vinyl indoles have been
prepared from nitrimines and indoles.13 However, nitrimines
are not attractive starting materials as their preparation is very
low yielding (nitrimines were prepared in 12−42% yield, but
typically yields were less than 20%).13 Vinyl indoles have also
been prepared from ketones, but the conditions require strong
acid and high temperature, incompatible with many function-
alities.14
In order to identify an effective Lewis acid catalyst, (1-
azidovinyl)benzene 10 and 2-methyl-1H-indole 11 were
selected as suitable reactants for optimizing the reaction
conditions (Table 1). As expected, treatment of the 1:1
mixture of 10 and 11 with the Lewis acid BF3·OEt2 (Table 1,
entry 2) or a Brønsted acid (stoichiometric HCl formed in situ
from acetyl chloride and methanol, Table 1, entry 1) at 0 °C to
room temperature does not afford the desired 3-vinyl-indoles
12. However, acetophenone can be observed by TLC and
isolated after water workup.8a
A number of metal salt Lewis acids such as zinc(II) triflate,
copper(II) triflate, as well as magnesium(II) triflate and
calcium(II) triflate also fail to give any desired product (Table
1, entries 3−6). In contrast, even substoichiometric (10 mol
%) amounts of B(C6F5)3 leads to formation of vinyl indole
product 12 in 84% isolated yield (entry 7). The use of
lanthanide Lewis acids was also investigated. Scandium(III)
triflate catalyzes the reaction, but the reaction only reaches
70% conversion after 24 h (entry 8). In dichloroethane, the
reaction is even slower (entry 10). At an increased temperature
of 60 °C, scandium(III) triflate catalyzes the reaction to 100%
It was important to investigate whether the reaction
proceeds via hydrolysis of the (1-azidovinyl)benzene (10) to
the acetophenone observed in the early experiments (Table 1,
entries 1−3). Accordingly, a series of reactions of 10 with
varying stoichiometry of 2-methyl indole (11) were carried
out, and the reactions were monitored. Reaction in the absence
of catalyst returned the unreacted starting materials. Reaction
in the complete absence of 11 also affords no product, and the
vinyl azide 10 is recovered unchanged (Scheme 2a). Neither
acetophenone nor 1-phenyl-vinyl chloride was observed by IR
or NMR of the reaction mixture. Thus, the observed
acetophenone (Table 1, entries 1−3) is likely formed upon
addition of water at the end of the reaction. When the reaction
is carried out with 0.5 equiv of 11, the product 12 is isolated in
42% yield along with unreacted 10 (46%, Scheme 2b). Again,
no acetophenone is detected. Notably, acetophenone fails to
react with indole 10 under the standard reaction conditions
(Scheme 2c) and no product is observed. This makes the
possibility of the mechanism going through a ketone as an
intermediate highly unlikely.14 Additionally, signals attributable
to azide are observed by IR spectroscopy in the reaction
mixture after completion (see Supporting Information). These
experiments support the mechanism outlined in Scheme 1b.
The reaction is readily scaled to gram scale. Thus, reaction
of (1-azidovinyl)benzene gives 12 in 96% yield at 100 mg scale
and a similar 91% yield at 2 g scale (Scheme 3). The scope of
the reaction is fairly wide (Scheme 3). Reaction of (1-
azidovinyl)benzene 13 (R1 = H) with 2-phenyl-indole leads to
B
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Scheme 2. Control Experiments
Scheme 3. Scope of the 3-Vinyl Indole Synthesis from
a
Indoles and Vinyl Azides
a
b
No reaction observed in the absence of indole. Conversion is
c
function of equivalents of indole. Acetophenone is not an
intermediate. Azide signal does not fade during the reaction (see
d
IR in the Supporting Information; see structure 33 in Scheme 3).
compound 17 in 94% yield. This indicates a low steric and
electronic influence with regard to the 2-substituent on the
indole. A para-methyl or even tert-butyl group on the 1-phenyl-
vinyl-1-azide is also well tolerated (see compounds 19−21 in
Scheme 3). These results similarly confirm the low importance
of the nature of the 2-indole substituent. A naphthyl-
substituent as the aromatic group of the vinyl azide 13 is
also well tolerated (22 and 23 in Scheme 3).
The substitution pattern on the vinyl azide has a significant
influence on reaction rate albeit not on the yield. Both 1-
phenyl-vinyl azides with two or even three methoxy groups on
the phenyl ring work well in the reaction giving products 24
and 25 in 89% and 87% yield, respectively, in only 12 h. Thus,
the effect of an ortho substituent as is present in 1-(1-
azidovinyl)-2,4-dimethoxybenzene used to prepare 24 does not
appear to make any significant difference in the yield or rate.
Vinyl azides with electron withdrawing substituents such as 12
(R1 = H, R2 = F, Cl, or Br) give the products 26−32 in similar
yields, but at a lower rate (Scheme 3). Methyl 4-(1-
azidovinyl)benzoate 12 (R1 = H, R2 = −CO2Me) reacts
even slower with a variety of indoles to give products 33−36 in
88% to 95% yield over 18 h. Importantly, the reaction is not
limited to terminal vinyl azides. While (Z)-(1-azidoprop-1-en-
1-yl)benzene 13 (R1 = Me) reacts sluggishly at room
temperature, at 65 °C complete conversion is achieved in 18
h to give 16 in 61% isolated yield.
a
Unless otherwise specified, all reactions were performed at room
temperature. Yields are unoptimized isolated yields after flash
b
chromatography. Reaction was conducted at 65 °C
Due to the importance of fluorinated compounds in
pharma,15 we also investigated the applicability of the reaction
to fluorinated indoles and vinyl azides. Accordingly, reaction of
5-fluoro substituted 2-methyl-indole with (1-azidovinyl)-
benzene (10) gives product 18 in 91% yield, while reaction
(1-azidovinyl)benzene (37, R1=H)is carried out using 1 equiv
of simple, i.e. 2,3-unsubstituted, indole, the bis(indolyl)-
methane 40 is formed as the only observable product together
with unreacted starting material. When the amount of indole is
increased to 2 equiv the product 40 is formed in 92% isolated
yield. (Scheme 4). Clearly the initially formed vinyl-indole is so
reactive it rapidly reacts a second time. This is likely due to the
steric requirements of a 2-substitution forcing the indole to
adopt a confirmation with no coplanarity with the vinyl system
(as drawn in Scheme 3). This would reduce the ability of the
indole substituent to stabilize carbocationic species. In the
absence of a 2-substituent, however, such stabilization is lower
in energy, allowing these vinyl indoles to react faster under
acidic conditions.
with methyl 4-(1-azidovinyl)benzoate (12, R1 = H, R2
=
−CO2Me) gives product 34 in 88% yield. Reaction of 1-(1-
azidovinyl)-4-fluorobenzene (12, R1 = H, R2 = F) with 2-
methyl-indole, 2-phenyl-indole, 5-methoxy-2-methyl-indole,
and 5-fluoro-2-methyl-indole gives product 26 in 97% yield,
27 in 86% yield, 28 in 92% yield, and 29 in 86% yield. This
showcases the applicability of the method to make fluorinated
products and also the negligible influence of electron-donating
and electron-withdrawing groups on the indole for the reaction
outcome.
Interestingly, a C(2)-substituent on the indole is necessary if
the vinyl-indole is the desired product. When the reaction of
Indeed, slow addition of indole or performing the reaction at
0 or −15 °C does not lead to isolation of the vinyl indole but
C
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reacts with indole to give 58 in 96% yield. As already observed,
electron-withdrawing groups somewhat retard the rate.
With respect to the indole, alkyl, methoxy, ester, and halide
substituents are all tolerated. Interestingly both fluorine in
indole and the vinyl azide may be present. See, e.g., compound
53 which is isolated in 79% yield (Scheme 4). Fluorine may
also be present as a CF3 group as may be seen for product 42
which was isolated in 66% yield (Scheme 4). In products 45
and 54, an iodine is present, and in 44, 56, and 57 a bromide is
present (Scheme 4). Bromide is also found in vinyl indole 32
(Scheme 3). These functionalities are completely compatible
with the reaction conditions and may be used as a handle for
classical transition metal catalyzed coupling chemistry. These
reactions (Schemes 3 and 4) are therefore completely
orthogonal to classical coupling reactions.
Scheme 4. Scope of the Synthesis of Bis(indolyl) Methanes
Synthesis from Indoles and Vinyl Azide
a
To further demonstrate the utility of the BIM preparation
method, we prepared the synthesis of bis(indolyl)methane 60,
a molecule that inhibits growth and induces apoptosis in
human prostate cancer cells (Scheme 5).17 Mariangela et al.
Scheme 5. Synthesis of Apoptosis Agonist
Bis(indolyl)methane 60
reported the synthesis of compound 60 using condensation of
indole with 3,4,5-trimethoxyacetophenone (59) in the
presence of catalytic amounts of hydrochloric acid as well as
by a second method involving the use of oxalic acid and N-
cetyl-N,N,N-trimethylammonium bromide in water in moder-
ate yields (26% and 62%, respectively).17 For comparison,
reaction of vinyl azide 61 and indole (2 equiv) afforded the
desired BIM 6o in a single step in 88% yield (Scheme 5).
In conclusion, indium trichloride acts as a catalyst that
brings about formal substitution of the azide by a carbon
nucleophile. This is in contrast to the classical reactivity of
vinyl azides that usually react at the α-position. Proof of
concept has been achieved in the form of a C(sp2)−N3/
C(sp2)−H cross coupling reaction of vinyl azides with indoles.
The method offers excellent yields of structurally diverse 3-
vinyl indoles. The vinyl azide starting materials are readily
available from alkenes or alkynes. Additionally, the reaction has
been extended to direct formation of bis(indolyl)methanes
with potential pharmaceutical importance. Further application
of this concept and its scope will be reported in due course.
a
Yields are unoptimized isolated yields after flash chromatography
always leads to the bis(indolyl)-methane product. Rather than
perceiving this as a limitation, we saw this as an opportunity to
prepare 3,3′-bis(indolyl)methanes (BIMs) in a single synthetic
step (Scheme 4). BIMs are known to have various medicinal
properties and are a common structure found in natural
products and compounds with pharmaceutical properties.16,17
The scope of this reaction is quite wide. Similar to what was
found in the synthesis of vinyl indoles, a wide range of
substituents may be present in both the vinyl azide 37 and the
indole 38 (Scheme 4). In the vinyl azide, both electron
donating groups such as methyl, tert-butyl, and methoxy may
be present on the phenyl group. Thus, BIMs 40−50 are all
produced and isolated in yields ranging from 66% to 94% yield.
Again an ortho substituent on the vinyl azide seems to have
little effect, and product 50 is formed 88% isolated yield within
only 8 h. A fluorine, chlorine, or bromine substituent on the
phenyl of 37 leads to products 51−57 that are isolated in 79−
94% yield. A ester functionalized vinyl azide 37 (R1 = CO2Me)
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00919.
Procedures, characterization data, and spectroscopic
studies of the reaction and the resulting data (PDF)
D
https://dx.doi.org/10.1021/acs.orglett.0c00919
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Letter
113−166. (b) Hayashi, H.; Kaga, A.; Chiba, S. Application of Vinyl
Azides in Chemical Synthesis: A Recent Update. J. Org. Chem. 2017,
82, 11981−11989. (c) Hu, B.; DiMagno, S. G. Reactivities of vinyl
azides and their recent applications in nitrogen heterocycle synthesis.
Org. Biomol. Chem. 2015, 13, 3844−3855. (d) Fu, J.; Zanoni, G.;
Anderson, E. A.; Bi, X. α-Substituted vinyl azides: an emerging
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(5) Hassner, A.; Levy, L. A. Additions of Iodine Azide to Olefins.
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AUTHOR INFORMATION
Corresponding Author
■
Alex M. Szpilman − Department of Chemical Sciences, Faculty
of Natural Science, Ariel University, Ariel 4070000, Israel;
orcid.org/0000-0001-7790-4129; Email: amszpilman@
gmail.com
Author
Atul A. More − Department of Chemical Sciences, Faculty of
Natural Science, Ariel University, Ariel 4070000, Israel;
orcid.org/0000-0003-4604-5354
(6) Liu, Z.; Liao, P.; Bi, X. General Silver-Catalyzed Hydroazidation
of Terminal Alkynes by Combining TMS-N3 and H2O: Synthesis of
Vinyl Azides. Org. Lett. 2014, 16 (14), 3668−3671.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00919
(7) (a) The Chemistry of Alkenes; Wiley Interscience; Vol. 1, 2010.
(b) The Chemistry of Alkenes; Wiley Interscience; Vol. 2, 2010.
(8) (a) Hassner, A.; Ferdinandi, E. S.; Isbister, R. J. Stereochemistry.
XLVII. Hydrolysis of vinyl azides. Comparison with the Schmidt
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Author Contributions
The manuscript was written through contributions of both
authors.
Notes
(9) (a) Zhang, F.-L.; Wang, Y.-F.; Lonca, G. H.; Zhu, X.; Chiba, S.
Amide Synthesis by Nucleophilic Attack of Vinyl Azides. Angew.
Chem., Int. Ed. 2014, 53, 4390−4394. (b) Zhu, X.; Chiba, S.
Construction of 1-pyrroline skeletons by Lewis acid-mediated
conjugate addition of vinyl azides. Chem. Commun. 2016, 52,
2473−2476.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by an Israel Science Foundation
Individual Research Grant (Grant No. 870/19) to A.M.S.
■
(10) Zhang, Z.; Kumar, R. K.; Li, G.; Wu, D.; Bi, X. Synthesis of 4-
Ynamides and Cyclization by the Vilsmeier Reagent to Dihydrofuran-
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