Three-Component Aminoselenation of Arynes

Article abstract of DOI:10.1021/acs.orglett.9b03789

The three-component coupling of tertiary amines, arynes, and aryl selenium bromide or diaryl diselenide as an electrophilic selenium source allowing the synthesis of 2-selanyl aniline derivatives is reported. This aminoselenation reaction of arynes installs a C-N and C-Se bond under mild conditions, and the products are formed in moderate to good yields. This reaction is compatible with various functional groups, and the preliminary studies on the mechanism of the reaction is also provided.

Full text of DOI:10.1021/acs.orglett.9b03789

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Three-Component Aminoselenation of Arynes
Rahul N. Gaykar, Avishek Guin, Subrata Bhattacharjee, and Akkattu T. Biju*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India
S
* Supporting Information
ABSTRACT: The three-component coupling of tertiary
amines, arynes, and aryl selenium bromide or diaryl diselenide
as an electrophilic selenium source allowing the synthesis of 2-
selanyl aniline derivatives is reported. This aminoselenation
reaction of arynes installs a C−N and C−Se bond under mild
conditions, and the products are formed in moderate to good
yields. This reaction is compatible with various functional
groups, and the preliminary studies on the mechanism of the reaction is also provided.
rganoselenium compounds are important structural
motifs present in a variety of biologically active
Scheme 1. Aryne Three-Component Coupling
O
molecules and pharmaceuticals, and hence this class of
compounds has gained much attention in recent years.1,2
Among these compounds, the diaryl selenides are associated
with interesting biological properties. For instance, the diaryl
selenide A could be used as a human breast cancer cell growth
inhibitor, B is useful as a thioredoxin reductase (TR) and
glutathione reductase (GR) inhibitor,3 and C can serve as an
antitumor agent (Figure 1).4 Moreover, the 2-substituted 1-
CO2,10,11 activated imines,12 and halides13 are known as
electrophilic third components, the use of organoselenium
reagents to intercept the in situ generated aryl anions in aryne
three-component coupling, to the best of our knowledge, is
unknown.14 Herein, we report the three-component coupling
of tertiary amines, arynes, and aryl selenium bromide or diaryl
diselenide as an electrophilic selenium source, the amino-
selenation reaction of arynes resulting in the formation of 2-
selanyl aniline derivatives (eq 2).15
We have recently reported the aryne three-component
coupling triggered by aromatic tertiary amines using aldehydes,
activated ketones, or CO2 as the electrophilic third
component.16,17 Inspired by the aryne three-component
coupling initiated by tertiary amines and given the biological
importance of diaryl selenides, the present study was initiated
by the treatment of aryne generated in situ from the 2-
(trimethylsilyl)aryl triflate 1a18 (using KF and 18-crown-6)
with N,N-dimethylaniline 2a and phenyl selenyl bromide 3a in
THF at 25 °C. To our delight, under these conditions, the 2-
selanyl aniline derivative 4a was formed in 55% yield along
Figure 1. Selected biologically active organoselenium compounds.
naphthol D is a potent 5-lipoxygenase inhibitor,5 the carboxylic
acid E is a retinoic acid receptor (RAR) agonist, which is ∼10
times more powerful than its sulfur analogue,6 and the 4-
substituted quinoline F possesses antioxidant properties.7
Given the biological significance of functionalized diaryl
selenides, synthesis of this class of compounds is highly
desirable.
During the course of our studies on three-component
coupling employing arynes,8,9 we recently envisioned that the
use of organoselenium reagents as the electrophilic third
component could result in the synthesis of functionalized
diaryl selenides. A series of nucleophiles can trigger aryne
three-component reactions (Scheme 1, eq 1).8g,9a Although
various electrophiles such as carbonyl compounds including
Received: October 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03789
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
with the N-arylated product 5a in 18% yield (Table 1, entry
1).19 The desired product 4a and the side product 5a were
Scheme 2. Substrate Scope of Aromatic Tertiary Amines
a
Table 1. Optimization of the Reaction Conditions
b
b
entry
F− source
solvent
yield of 4a (%)
yield of 5a (%)
1
2
3
4
KF/18-crown-6
KF/18-crown-6
CsF
THF
DME
CH3CN
THF
THF
THF
THF
THF
55
48
<5
<5
27
16
51
72
18
16
<5
<5
29
38
<5
<5
TBAF
c
5
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
d
6
7
e
f
8
a
Standard conditions: 1a (0.30 mmol), 2a (0.25 mmol), 3a (0.25
mmol), fluoride source (2.4 equiv), solvent (1.0 mL), 25 °C and 12 h.
a
General conditions: 1a (1.0 mmol), 2 (0.5 mmol), 3a (0.75 mmol),
b
c
Yield of the isolated product. The reaction was performed from −10
KF (4.0 equiv), 18-crown-6 (4.0 equiv), THF (2.0 mL), 25 °C and 12
h. Yields of isolated products are given. Diphenyl diselenide was used
d
e
b
to 25 °C. The reaction was carried out at 60 °C. 1.5 equiv of 2a was
f
c
used. 2.0 equiv of 1a, 1.5 equiv of 3a, and 4.0 equiv of KF/18-crown-
as the Se source. Reaction was run on a 0.25 mmol scale of 2.
d
e
6 were used.
Reaction was performed at 65 °C for 12 h. 1H NMR yield of the
product is provided.
formed in reduced yield when the reaction was performed in
DME (entry 2). The use of other fluoride sources such as CsF
and tetrabutyl ammonium fluoride (TBAF) provided only
traces of the desired product (entries 3, 4). The optimal
reaction temperature was found to be 25 °C as the reactions
performed at lower and higher temperature afforded a lower
yield of 4a and a better yield of 5a (entries 5, 6). Interestingly,
when the reaction was performed using 1.5 equiv of 3a, the
target product 4a was formed in 51% yield with high selectivity
(entry 7). Performing the reaction with 2.0 equiv of 1a and 1.5
equiv of 3a improved the yield of 4a to 72% while maintaining
high selectivity (entry 8). This set of conditions was chosen for
the substrate scope analysis.20
a
Scheme 3. Substrate Scope of Selenium Source
With the favorable reaction conditions in hand, we then
studied the substrate scope of this three-component coupling.
First, we evaluated the variation on aromatic tertiary amines
(Scheme 2). Several N,N-dimethyl anilines bearing electron-
releasing, -neutral and -withdrawing groups at the 4-position of
the aromatic ring were well tolerated under these conditions
resulting in the formation of the 2-selanyl aniline derivatives in
moderate to good yields (4a−4i). In the case of the 4-bromo-
N,N-dimethylaniline derived o-selanyl aniline derivative 4f, the
structure was confirmed by single crystal X-ray analysis
(CCDC 1953258). Notably, the use of diphenyl diselenide
as the electrophilic selenium source provided comparable
results (4a, 4b, 4c, 4f). Moreover, reactions carried out using
an aromatic tertiary amine having a substituent at the 3-
position, 2-position as well as disubstitution resulted in the
formation of the desired products in moderate to good yields
(4j−4p). It is noteworthy that a tertiary amine with an α,β-
unsaturated ester moiety furnished the product 4q in 50%
yield.
a
General conditions: 1a (0.5 mmol), 6 (0.375 mmol), 2a (0.25
mmol), KF (4.0 equiv), 18-crown-6 (4.0 equiv), THF (1.0 mL), 25
°C and 12 h. Yields of isolated products are given.
(4r−4u). Moreover, diselenide having chlorine at the 3- and 2-
position of the aromatic ring also afforded the aminoselenated
products in moderate yields (4v, 4w). Notably, the insertion of
an aryne to the Se−Se bond of 6 was not observed probably
due to the nucleophilicity of the tertiary amines.15
The tolerance of substituents on the aryne moiety was also
studied (Table 2). 2-Selanyl aniline derivatives 4x−4z are
formed in moderate to good yields when this three-component
reaction was performed using electronically dissimilar 4,5-
disubstituted symmetrical arynes generated from the pre-
cursors (1b−d). Moreover, the unsymmetrical naphthalyne
and tetrahydronaphthalyne generated from precursors 1e and
1f were well tolerated to furnish the single regioisomers 4aa
and 4ab in 48% and 68% yield, respectively.21 In addition, the
unsymmetrical 4-methyl aryne formed from 1g afforded an
inseparable mixture of regioisomers 4ac and 4ac′ in 74% yield
and a 1.4:1 regioisomer ratio. Similarly, inseparable regioiso-
meric products were formed when the reaction was carried out
using unsymmetrical 4-chloro and 4-fluoro arynes.
Next, we examined the scope of electrophilic selenium
source in this reaction (Scheme 3). The substituted diaryl
diselenides were used as the selenium source due to their ease
of preparation. Differently substituted diaryl diselenides having
a substituent at the 4-position of the ring are well tolerated,
and the corresponding products are formed in good yields
B
DOI: 10.1021/acs.orglett.9b03789
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Organic Letters
Letter
a
were unreacted, which explains the moderate yield of products
formed. Moreover, the reaction of aryne generated from 1a
and 3a with N-methyl tetrahydroquinoline 7c under the
present conditions afforded the aminoselenated product 4ag in
44% yield with 32% recovery of 7c (eq 4). Furthermore, the
present three-component reaction is not limited to amino-
selenation, but the method can be extended to aminothiolation
using 8 as the thiolating reagent and the corresponding
product 9a was formed in 40% yield (eq 5).22
Table 2. Variation of the Aryne Moiety
Mechanistically, the reaction proceeds via the nucleophilic
addition of tertiary amine 2 to the in situ generated aryne
(formed by the fluoride induced 1,2-elimination from 1)
resulting in the formation of the 1,3-zwitterionic intermediate
10 (Scheme 5). This aryl anion intermediate adds to the
Scheme 5. Proposed Mechanism of the Reaction
electrophilic selenium source to form the ammonium salt 11.
The rapid demethylation of the salt 11 most likely by the
nucleophile X− results in the formation of the desired product
4.
Direct evidence for the suggested mechanism and the role of
the nucleophile in the dealkylation step was obtained when the
three-component reaction was performed using N-phenyl
pyrrolidine 7d. Treatment of the triflate 1a with bromide 3a
and amine 7d under the optimized conditions resulted in the
formation of the product 13 in 35% yield (Scheme 6). The
a
General conditions: 1 (1.0 mmol), 2a (0.5 mmol), 3a (0.75 mmol),
KF (4.0 equiv), 18-crown-6 (4.0 equiv), THF (2.0 mL), 25 °C and 12
b
h. Yields of isolated products are given. Reaction was performed on
0.25 mmol scale of 2a. Regioisomer ratio was determined by H
NMR analysis.
c
1
Interestingly, when the present three-component reaction
was carried out using an aliphatic tertiary amine 7a, the
aminoselenated product 4af was formed in 46% yield via a
selective debenzylation instead of a demethylation (Scheme 4,
eq 3). A similar reaction course via the debenzylation was
observed when the reaction was performed using N-benzyl-N-
methyl aniline 7b, and the product 4a was formed in 46%
yield. In both cases, considerable amounts of tertiary amine
Scheme 6. Reaction Using Cyclic Tertiary Amine
Scheme 4. Aminoselenation and Aminothiolation of Arynes
structure of 13 was confirmed by single crystal X-ray analysis
(CCDC 1961216). A similar result was obtained using 6a as
the selenium source, and the corresponding product 14 was
formed in 34% yield.23 The initially formed 1,3-zwitterionic
intermediate 12 from 7d and aryne could add to the selenium
source, and the eliminated X− could open the cyclic quaternary
ammonium salt to form the desired products 13 and 14.
In conclusion, we have developed the three-component
coupling of arynes, tertiary amines, and electrophilic selenium
reagents for the synthesis of 2-selanyl aniline derivatives in
C
DOI: 10.1021/acs.orglett.9b03789
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03789.
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■
S
Details on experimental procedures, characterization,
and NMR spectra of functionalized 2-selanyl aniline
derivatives (PDF)
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CCDC 1953258 and 1961216 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: atbiju@iisc.ac.in.
ORCID
Akkattu T. Biju: 0000-0002-0645-8261
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Generous financial support by the Science and Engineering
Research Board (SERB), Government of India in the form of a
Distinguished Investigator Award to A.T.B. is gratefully
acknowledged (File Number: DIA/2018/000018). R.N.G.
thanks IISc, and A.G. and S.B. thank CSIR for a research
fellowship. We thank Dr. M. Venkateswarulu and Dr. Prodip
Howlader (both IPC, IISc) for the X-ray data and Dr. Tony
Roy (CSIR-NCL) for helpful discussions.
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E
DOI: 10.1021/acs.orglett.9b03789
Org. Lett. XXXX, XXX, XXX−XXX