Skeletally Diverse Synthesis of Indole-Fused Diazocine and Diazepine Frameworks by One-Pot, Two-Component Cascade Reaction

Article abstract of DOI:10.1021/acs.orglett.5b03481

An expeditious and novel strategy has been explored for the synthesis of structurally diverse indole-fused diazocine and diazepine derivatives. A substrate-based diversification approach of methyl-3-aminoindole/indoline benzoates coupled with the Pictet-S

Full text of DOI:10.1021/acs.orglett.5b03481

Letter
pubs.acs.org/OrgLett
Skeletally Diverse Synthesis of Indole-Fused Diazocine and
Diazepine Frameworks by One-Pot, Two-Component Cascade
Reaction
†
†
,†,‡
Tushar Ulhas Thikekar, Manikandan Selvaraju, and Chung-Ming Sun*
†
Department of Applied Chemistry, National Chiao-Tung University, 1001 Ta-Hseuh Road, Hsinchu 300-10, Taiwan
‡
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100 Shih-Chuan First Road, Kaohsiung 807-08,
Taiwan
*
S Supporting Information
ABSTRACT: An expeditious and novel strategy has been
explored for the synthesis of structurally diverse indole-fused
diazocine and diazepine derivatives. A substrate-based
diversification approach of methyl-3-aminoindole/indoline
benzoates coupled with the Pictet−Spengler reaction and
three different reaction cascades furnished indolodiazepine and indoloquinoxalines. The formation of indolodiazocines proceeds
through an initial condensation followed by intramolecular alkylation.
ndole represents one of the most versatile and important
classes of heterocycles which occupy a pivotal position in
skeletal rearrangement via aziridine formation. Kuehne et al.
reported the Pictet−Spengler reaction of tryptamine with7
methylchloro pyruvate for the formation of indoloazepine.
Similarly, Flatt and co-workers demonstrated the stepwise
synthesis of azepinoindoles through ring expansion of carbo-
lines obtained by the reaction of tryptamine with bromopyr-
I
medicinal and organic chemistry because of their unique
1
,2
structural and interesting biological properties. In particular,
indoles fused with other heterocycles have shown significant
biological applications. Diazepines and diazocines are seven-and
eight-membered rings of nitrogen-containing heterocycles
found in many natural products. Among those, the indole-
fused diazepines act as kinase inhibitors and antidepressant
8
uvates. Hence, a convenient and novel strategy for an efficient
construction of these scaffolds is highly desirable.
Synthesis of structurally complex and highly functionalized
heterocyclic skeletons is a challenging goal in modern organic
chemistry. Cascade reactions, which are defined as multiple
bond formations in a single step with a sequence of reactions,
3
,4
agents. Over the years, many medicinal chemists synthesized
a variety of compounds by installing various active groups to
the indole/indoline moieties through a new synthetic strategy.
These heterocycles have potential utility in the fields of biology,
9
are one of the most promising approaches. These processes
5
,6
pesticides, and medicinal chemistry.
Some examples of
avoid the isolation and purification of intermediates, max-
imizing the yield of the final product and minimizing solvent
waste with high atom-economy. The attractive features of these
cascade reactions are the formation of several C−C, C−N
bonds for rapid access to fused and complex polycyclic
skeletons. In continuation of our earlier work on the synthesis
biologically important diazepines and diazocines are shown
Figure 1.
10
of indole fused nitrogen heterocycles, we aimed to carry out
an unconventional Pictet−Spengler reaction on 2-(1H-indol-1-
yl)aniline/2-(indolin-1-yl)aniline with α-bromo ketones, as
shown in Scheme 1. In this present work, we were surprised
to find that the reactivity patterns were completely altered by
the reaction conditions and substituents on substrates. The
tunable reactivity of these scaffolds allowed us to design two
different cyclization reactions with α-bromo ketones 2. It is
proposed that indole 6 will undergo cyclization at the C2
position, whereas indoline 1 will cyclize at C7 to create two
different, new molecular entities. 2-(1H-Indol-1-yl)aniline 6
successfully underwent the Pictet−Spengler cyclization which
Figure 1. Biologically important compounds containing fused
indolodiazepine and indolodiazocine.
Their diverse biological activities and synthetic applications
have stimulated substantial interest in the study of these
important heterocycles. Surprisingly, the literature contains
only a few reports describing the synthesis of indole-fused
diazepines. Further, the combination of indoline fused with
diazocine is not yet documented. Typical molecular con-
structions of indole-fused azepine fall into two steps: Pictet−
Spengler reaction of tryptamines with pyruvates, followed by
Received: December 7, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03481
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Organic Letters
Letter
Scheme 1. Synthesis of Skeletally Diverse Indole/Indoline
Fused Diazocines and Diazepines
participation of all starting material in the isolated product and
the absence of −CH Br protons. Similarly, the mass analysis
2
did not show the bromo pattern corresponding to the expected
product 5. Hence, we reasoned that the product 3a is obtained
by stepwise condensation followed by intramolecular C-
alkylation. Under these reaction conditions, a high reaction
selectivity toward aromatic substitution is observed instead of
Pictet−Spengler reaction on imine carbon.
Interestingly, the proton NMR spectra of 3g shows two
conformers which are non-interconverting on the NMR time
scale at ambient temperature. This conformational behavior is
further supported by varying temperature studies as shown in
Figures 3 and 4 (Supporting Information). Although the
anticipated product was not obtained, this unprecedented
formation of indolo-fused diazocine 3 might be more
rewarding, as there are no previous reports on such a
convenient one-pot synthesis of new molecules from these
readily available starting materials. Hence, we aimed to
generalize this outcome by carrying out optimization studies
with various acid catalysts and solvents as shown in Table 1. No
reaction was observed when TCT (trichlorotriazine) or p-TSA
was employed as an acid catalyst. A survey of various solvents
such as DMSO, DMF, and acetonitrile showed the same results
with very little conversion to the desired product. Increasing
the amount of TFA (3equiv) in refluxing chloroform improved
the reaction yield up to 38%.
However, a higher yield of 88% was obtained when the
reaction was carried out in a sealed vessel at 80 °C in
chloroform for 4 h (entry 11). Further increase in TFA or
temperature did not improve the reaction yield. Thus, we
concluded that the optimum conditions for this cyclization is
the employment of 3 equiv of TFA in chloroform in a sealed
tube at 80 °C for 4 h.
The scope and limitation of the reaction were next studied to
understand, in particular, the influence of the substituents
presenting on α-bromo acetophenones (Scheme 2). We found
that the final outcome of the reaction is significantly dependent
on further reaction to furnish three novel heterocycles under
three different reaction conditions. To our surprise, 2-(indolin-
1
-yl)aniline 1 performed condensation followed by intra-
molecular C-alkylation to deliver compounds 3 or 4 instead
the expected Pictet−Spengler reaction.
The key aspect of our new approach is the construction of
3
quaternary sp carbon atoms in fused ring systems, which
disrupts the one-dimensional planarity of the scaffolds.
Increasing the saturation may create several conformations
which can act as a suitable substrate in drug discovery to design
several high affinity ligands by creation of diverse chemical
1
1
space.
Our studies began with the preparation of a key substrate,
methyl 3-amino-4-(indolin-1-yl)benzoate 1a, from 4-fluoro-3-
nitrobenzoic acid by sequential reactions such as esterification,
10c
nucleophilic substitution with indoline, and nitro reduction.
Then, we carried out an unconventional Pictet−Spengler
reaction on compound 1a with α-bromo acetophenone 2a in
the presence of TFA (1 equiv) in refluxing chloroform (Table
1
, entry 1). To our surprise, the possible Pictet−Spengler
product 5 was not observed, and a serendipitous formation of
a was isolated in 20% yield with the remaining of starting
3
material 1a. Careful analysis of the proton NMR reveals the
Scheme 2. Synthesis of Indolo-Fused Diazocines 3 or 4
Table 1. Effect of Different Reaction Parameters on the
a
Preparation of Indolodiazocines 3a
b
entry
acid (equiv)
solvent
temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
TFA (1)
TCT (1)
TCT (1)
PTSA (1)
PTSA (1)
TFA (3)
TFA (3)
PTSA (1)
TFA (3)
TFA (6)
TFA (3)
CHCl3
DMSO
CHCl3
CHCl3
DMF
reflux
80
24
24
24
24
24
24
24
24
24
12
4
20
c
NR
reflux
reflux
80
NR
NR
NR
10
DMF
80
CH CN
reflux
reflux
reflux
reflux
80
20
3
CH CN
NR
38
3
CHCl3
CHCl3
CHCl3
10
45
d
1
1
88
a
The reaction was performed in the presence of 1a (0.25 mmol) and
b
2
a (0.25 mmol) and acid catalyst in solvent (2 mL). Isolated yield.
c
d
NR = no reaction. Reaction performed in sealed tube.
B
DOI: 10.1021/acs.orglett.5b03481
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Letter
on the electronic nature of substituents attached directly on the
aromatic rings of α-bromo acetophenones. Two different types
of product formation were observed under these conditions.
Scheme 4. Synthesis of Indole-Fused Azirinoquinoxalines 8
and Diazepines 9 or 10
3
Aryl rings bearing R electron-donating groups furnished
compounds 3a−k, whereas products 4a−d were obtained
3
when the R groups are electron-withdrawing. For example,
electron-donating substituents as well as thiophene 3k, an
electron-rich heterocycle, favor the formation of enamines 3,
whereas the electron-deficient cyano and nitro groups favor the
formation of 4. However, α-bromo ketone possessing a nitro
substituent at the ortho position did not deliver the product 4d
due to steric effects. In general, all of the substituents are well-
tolerated under the same conditions and delivered the products
with satisfactory yields. As shown in Scheme 2, the structure of
one of the representative compounds 4a is elucidated by X-ray
single-crystal analysis. On the basis of experimental observation,
a plausible mechanism is depicted in Scheme 3.
Scheme 3. Plausible Mechanism for the Unexpected
Formation 3 or 4
This domino transformation begins with the condensation of
-(indolin-1-yl)aniline 1 with α-halo ketone 2 to give
2
intermediate A, which will undergo intramolecular alkylation
at electron-rich C7 to deliver the unexpected indolo-fused
diazocine analogues 3 or 4 with respect to the substituents.
Creation of diverse libraries with various molecular scaffolds
is an ideal goal in drug discovery research. Hence, the indoline
moiety present in compound 1 gave ample opportunity for
further diversification. The oxidation of indoline to its
corresponding indole 6 was achieved with DDQ as shown in
Scheme 4. The obtained 2-(1H-indol-1-yl)aniline 6 could act as
a suitable substrate for modified Pictet−Spengler reaction with
α-bromo ketones under acid conditions to furnish indolo
quinoxaline 7 (Scheme 4). The obtained indolo quinoxaline 7
was further treated with potassium iodide and cesium carbonate
in acetonitrile under reflux conditions for 3 h. Interestingly, this
reaction furnished a new kind of heterocycle 9 possessing
Figure 2. ORTEP diagram of compound 9a.
3
nature of R plays a crucial role on the stability of the aziridine
intermediate. We were able to isolate the aziridines 8a−d only
3
when the R is an electron-withdrawing substituent. As shown
in Scheme 4, the structure of aziridine 8c is elucidated by X-ray
single-crystal analysis. All efforts to isolate compound 8
possessing electron-donating R3 groups were unsuccessful,
and they furnished only compound 9 directly.
3
hydroxyl group at quaternary carbon (when R = H). The
structure of representative compound 9a is unequivocally
confirmed by X-ray crystallography as shown in Figure 2. The
compound exhibit attractive 3D-shapes due to the obvious sp3
character in the skeleton. The indole-fused seven membered
diazepine ring is twisted and hence makes the molecule
nonplanar.
The formation of 9 can be rationalized by the initial
formation of aziridine 8 which undergoes ring-opening reaction
on aqueous workup to give indole-fused diazepine 9. However,
addition of water as a cosolvent did not deliver the observed
product 9. In a further study, we tried to isolate the aziridine
intermediate 8 to understand the original source of hydroxyl
group in compound 9. Herein, we observed that the electronic
In addition, the reaction of isolated aziridine 8a with water as
a cosolvent under the optimized conditions did not proceed to
the expected product 9. Hence, the driving force for the
formation of hydroxyl-substituted product could be the
substituent-aided stability of the aziridine ring. The presence
of an electron-withdrawing group at the para position of the
aromatic ring stabilized the highly strained aziridine ring,
whereas ring-opening of aziridine was observed during the
aqueous workup if there is an electron-donating group at the
para position. Treatment of the isolated aziridines 8 in pyridine
at 140 °C in a sealed tube for 2 h underwent skeletal
C
DOI: 10.1021/acs.orglett.5b03481
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Organic Letters
Letter
rearrangement to indole-fused diazepines 10. Delighted with
this observation, we evaluated the possibility of performing the
whole transformation in a one-pot, two-step domino fashion
without isolation of the aziridine intermediate 8. To our delight,
treatment of Pictet− Spengler product 7 with pyridine at 140
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03481.
°
C in a sealed tube for 3 h furnished compound 10 directly. In
Experimental details plus spectroscopic and other data
for compounds (PDF)
X-ray data for 4a (CIF)
X-ray data for 8c (CIF)
X-ray data for 9a (CIF)
this transformation, the reaction condition plays a crucial role
as both the electron-donating and -withdrawing substituents
3
(
R ) deliver the seven-membered products with satisfactory
yields. Hence, three different unique heterocycles were formed
exclusively depending on the electronic nature of the
substituents and the reaction conditions as depicted in Scheme
4
. On the basis of experimental observation, a plausible
AUTHOR INFORMATION
Corresponding Author
■
mechanism is depicted in Scheme 5. To gain insight into the
*
E-mail: cmsun@mail.nctu.edu.tw.
Scheme 5. Plausible Mechanism for the Formation of Indole
Fused Azirinoquinoxalines 8 and Diazepines 9 or 10
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Council of Taiwan for financial
support and the authorities of the National Chiao Tung
University for providing laboratory facilities. This study was
particularly supported by the “Centre for bioinformatics
research of aiming for the Top University Plan” of the National
Chiao Tung University and Ministry of Education, Taiwan.
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