Four-component strategy for selective synthesis of azepino[5,4,3-cd]indoles and pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1039/c4cc00740a

A novel four-component strategy for the selective synthesis of fused azepino[5,4,3-cd]indoles and pyrazolo [3,4-b]pyridines has been established. The bond-forming efficiency, accessibility of starting materials and substrate scope provide invaluable access to tetra-, and bis-heterocyclic scaffolds. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00740a

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Four-component strategy for selective
synthesis of azepino[5,4,3-cd]indoles
and pyrazolo[3,4-b]pyridines†
Bo Jiang,*a Qin Ye,a Wei Fan,a Shu-Liang Wang,a Shu-Jiang Tu*a and Guigen Libc
Cite this: Chem. Commun., 2014,
50, 6108
Received 28th January 2014,
Accepted 4th March 2014
DOI: 10.1039/c4cc00740a
www.rsc.org/chemcomm
A novel four-component strategy for the selective synthesis of fused
In recent years, multicomponent domino reactions have played
azepino[5,4,3-cd]indoles and pyrazolo [3,4-b]pyridines has been an important role in synthetic methodologies, and can implement
established. The bond-forming efficiency, accessibility of starting cascade reactions in the total synthesis of natural products.9 Our
materials and substrate scope provide invaluable access to tetra-, groups10 and several others11,12 have developed a series of MDRs for
and bis-heterocyclic scaffolds.
the synthesis of unique heterocycles and natural mimetic com-
pounds of chemical and pharmaceutical importance. To continue
Functionally diverse azepino[5,4,3-cd]indole skeletons com- our efforts on this project, we now discovered a novel ABC2 type
monly exist in natural and unnatural products;1 they are found domino reaction of arylglyoxal monohydrate 1 with electron-rich
in indole alkaloids, such as Aurantioclavine (I),2 Rucaparib (II),3 pyrazol-5-amines 2 and aromatic amines 3, leading to the formation
Hyrtiazepine (III)4 and Hyrtimomines F5 (Fig. 1), which exhibit of pyrazolo[40,30:6,7]azepino[5,4,3-cd]indoles and pyrazolo[3,4-b]-
biological activity as 5-HT1 agonists6 and PARP inhibitors.3 pyridines under microwave (MW) heating (Scheme 1). The former
Aurantioclavines have served as key building blocks during the reaction occurred through (3 + 2)/(3 + 2 + 1 + 1) bis-cyclizations
biosynthesis of complex polycyclic alkaloids of the com- to give tetracyclic pyrazolo[40,30:6,7]azepino[5,4,3-cd]indoles in a
munesin family.7,8 The construction of these compounds and straightforward manner, which are normally difficult to obtain in
their structural analogues has attracted much attention in the a single operation. Both the 2- and 3-positions of p-toluidine 3a
synthetic community.1–5 To the best of our knowledge, an simultaneously served as nucleophilic centers to enable the follow-
efficient construction of the tetracyclic azepino[5,4,3-cd]indole ing domino cyclizations that are rarely encountered in organic
skeleton through sequential cyclizations via a multicomponent reactions. Interestingly, the direct C–C formation between two
domino reaction (MDR) has not yet been documented.
electrophilic centers of arylglyoxal monohydrates can be smoothly
performed through four-component [3 + 2 + 1] heteroannulation
without the use of any metal catalysts.
To optimize the reaction conditions, we began by examining
the reaction of 2,2-dihydroxy-1-phenylethanone (1a), 3-methyl-
1-phenyl-1H-pyrazol-5-amine (2a) and p-toluidine (3a) in DMF at
100 1C (Table S1, entry 1, see ESI.†). When this reaction was
performed in the presence of p-TsOH for 15 min, a 38% yield of
Fig. 1 Several representative natural products.
a Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou, 211116, P. R. China.
E-mail: jiangchem@jsnu.edu.cn, laotu@jsnu.edu.cn; Fax: +86 51683500065;
Tel: +86 51683500065
b Institute of Chemistry & Biomedical Sciences, Nanjing University, Nanjing 210093,
P. R. China
c Department of Chemistry and Biochemistry, Texas Tech University, Lubbock,
TX 79409-1061, USA. E-mail: guigen.li@ttu.edu
† Electronic supplementary information (ESI) available. CCDC 977865 (4a) and
977866 (5g). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4cc00740a
Scheme 1 Multicomponent synthesis of compounds 4 and 5.
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azepino[5,4,3-cd]indole (4a) was obtained. The structure of 4a has
been determined by spectroscopic and X-ray crystallographic analysis
(see ESI†). We next screened different Brønsted acids and Lewis
acids as catalysts (entries 1–5). As shown in Table S1 (see ESI†), the
reaction did not proceed in the presence of Brønsted acids, such as
H2SO4 and CF3COOH. Lewis acids, such as FeCl3 and ZnCl2, also
failed to improve the yield (entries 4 and 5). A variety of both polar
and nonpolar solvents were also examined, and DMF was the most
suitable solvent for this reaction (entry 1). To verify the role of
p-TsOH either as a catalyst or a promoter, we conducted two sets of
reactions by loading p-TsOH at 1.5 equiv. (entry 10) and 30 mol%
(entry 11), respectively. We found that both conditions failed to give
yields greater than 30%. The reaction was then performed in DMF at
different temperatures in a sealed vessel under microwave irradia-
tion for 15 min. The yield of product 4a increased to 46% when the
temperature was increased to 115 1C (entry 13).
Scheme 3 Domino formation of pyrazolo[3,4-b]pyridines 5a.
With the above conditions in hand, the generality and scope of
the reaction were investigated for a range of arylglyoxal mono-
hydrates 1 and electron-rich pyrazol-5-amines 2 (Scheme 2). A
variety of functional groups of substituted arylglyoxal monohydrates
were found to be well tolerated under the above conditions to give
azepino[5,4,3-cd]indole products (4a–f); even cyclopropyl substitu-
tion at the 3-position of pyrazol-5-amines 2 can be employed for this
reaction. Surprisingly, when the strong electron-donating group
MeO– was placed at the C4 position of the phenyl ring of 1, the
reaction did not give the expected azepino[5,4,3-cd]indoles; instead,
it led to formation of multifunctionalized pyrazolo[3,4-b]pyridines
5a (Scheme 3). When electronically poor 4-chloroaniline (3b) was
utilized to replace p-toluidine (3a) to react with 1 under this system,
pyrazolo[3,4-b]pyridine could still be formed. This interesting obser-
vation of the 1-phenyl-pyrazol-5-amine-based domino reaction indi-
cated that the electronic effect of arylglyoxals and aromatic amines
may control the reaction pathways chemoselectively.
Scheme 4 Domino synthesis of pyrazolo[3,4-b]pyridines 5.
Due to the importance of pyrazolo[3,4-b]pyridines in organic
synthesis and drug design in the pharmaceutical sciences,13 we
then focused on the feasibility of the latter reaction (Scheme 4). We enable the reaction to occur smoothly. Reactions involving methyl-,
found that a variety of functional groups in arylglyoxals 1 can or chloro-substituted phenylglyoxal monohydrate 1 with 2 and 3
all worked efficiently to give the bicyclic pyrazolo[3,4-b]pyridines in
moderate to good yields under microwave irradiation as shown in
Scheme 4. This reaction also tolerated the substrate of arylglyoxal 1
attached by strong electron-withdrawing nitro group and can
smoothly proceed to give pyrazolo[3,4-b]pyridines 5s in 57% yield.
The substituents on the N1 or C3 positions of pyrazole and on
aromatic amines 3 were well tolerated to afford pyrazolo[3,4-b]-
pyridine 5 within short times in good yields. However, ortho-
substituted anilines, such as 2-nitroaniline (3f) or o-toluidine (3g),
failed to give the desired pyrazolo[3,4-b]pyridines 5. The structures
of the resulting products 5 have been unambiguously confirmed by
IR, NMR and HR-MS spectral analysis. In addition, one of them (5g)
has been determined by X-ray diffractional analysis (see ESI†).
To understand the mechanism of reaction, 1-phenyl-2-( p-
tolylimino)ethanone B1 and 2-(4-chlorophenylimino)-1-phenyl-
ethanone B2 were subjected to reaction with 1a and 2a under
the standard conditions. The corresponding azepino[5,4,3-cd]indoles
4a and pyrazolo[3,4-b]pyridines 5b were generated in 47% and 79%
Scheme 2 Domino formation of azepino[5,4,3-cd]indoles 4a–4f.
yields, respectively (Scheme 5). These observations prove that the
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with imines B proceeded to generate enone intermediate G, which
was then transformed into active allene intermediate H. The
following intramolecular 6p-electrocyclization and tautomerism
result in the formation of pyrazolo[3,4-b]pyridines 5 as the final
product (Scheme 7).
In conclusion, we have established novel chemoselective
four-component domino reactions for rapid access to azepino-
[5,4,3-cd]indoles 4 and pyrazolo[3,4-b]pyridines 5. The reactions
are easy to perform under concise conditions under microwave
irradiation. The mechanisms for these two new reactions were
proposed and partially confirmed by control experiments. The
reactions show good substrate scope, particularly the simulta-
neous formations of two C–N and two C–C bonds through a key
6p-electrocyclization in the latter reaction. Further study of
these two new reactions and their applications will be con-
ducted in our laboratories in due course.
We are grateful for financial support from the NSFC
(No. 21232004, 21272095, 21102124 and 21332005), Jiangsu
Science and Technology Support Program (No. SBE2011045),
the Qing Lan Project (12QLG006), Robert A. Welch Foundation
(D-1361, USA) and NIH (R33DA031860, USA).
Scheme 5 Control experiments for mechanistic hypothesis.
electronic effect of aromatic amines plays a key role in controlling
the reaction pathways.
On the basis of this experiment, mechanisms for these two
domino reactions are proposed as shown in Schemes 6 and 7.
In the former, arylglyoxal monohydrates 1 were protonated by
p-TsOH and dehydration occurred, which was followed by an
addition reaction with electron-rich pyrazol-5-amines 2 leading to
intermediate A. The intermolecular CQN addition of intermediate
B and intramolecular cyclization resulted in macrocyclic inter-
mediate D. Ring-opening of D promoted by p-TsOH afforded imine
intermediate E which underwent consecutive intramolecular cycli-
zations and tautomerization to give azepino[5,4,3-cd]indoles 4
(Scheme 6). Similar to the former, the latter reaction occurred to
give the intermediate A at an early stage. Due to the electronic
effect of imines B, the carbonyl addition reaction of intermediate A
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