A competitive and highly selective 7-, 6- And 5-annulation with 1,3-migration through C-H and N-H-alkyne coupling

Article abstract of DOI:10.1039/c9cc07360d

We demonstrated a highly competitive and selective C-C and N-C cross-coupled 7-, 6- and 5-annulation utilizing 2-ethynylanilides to afford functionalized 1H-benzo[b]azepin-2(5H)-ones, 2-quinolinones, and 3-acylindoles in high yield. ZnCl₂ was f

Full text of DOI:10.1039/c9cc07360d

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A competitive and highly selective 7-, 6-
and 5-annulation with 1,3-migration through
C–H and N–H – alkyne coupling†
Cite this: Chem. Commun., 2020,
56, 474
Received 19th September 2019,
Accepted 28th November 2019
Sk Ajarul, Anirban Kayet, Tanmay K. Pati and Dilip K. Maiti
*
DOI: 10.1039/c9cc07360d
rsc.li/chemcomm
We demonstrated a highly competitive and selective C–C and N–C group established Mn(OAc)3 mediated oxidative radical cyclization
cross-coupled 7-, 6- and 5-annulation utilizing 2-ethynylanilides to of a-substituted N-[2-(phenylethynyl)phenyl]acetamides (eqn (vi)).1c
afford functionalized 1H-benzo[b]azepin-2(5H)-ones, 2-quinolinones, However, a catalytic synthesis is preferable over a non-catalytic
and 3-acylindoles in high yield. ZnCl2 was found to be the smart reaction(s). Moreover, the development of smart catalysis is highly
catalyst for 7- and 5-annulation with 1,3-migration through C–H desirable to discard the isomeric by-product(s). Thus, we envisaged
and N–H functionalization, respectively, whereas molecular iodine an expedient cascade catalytic transformation (Scheme 1) of the
performed the C–H functionalized 6-annulation with a nonconven- in situ generated o-ethynylacetoacetanilides using ethyl benzoyl
tional 1,3 H-shift. The mechanism was investigated by intermediate acetate/tert-butyl acetoacetate and o-alkynyl anilines to afford the
trapping, control, and labeling experiments.
aforementioned heterocycles with excellent selectivity. 1H-Benzo[b]-
azepin-2(5H)-one compounds are widely found in numerous natural
The highly selective C–C and C–N coupled annulation reaction products and pharmaceuticals including lennoxamine, 2,3,4,5-
using C–H vs. N–H with unsymmetrical alkyne is attractive and tetrahydro-1H- their syntheses include intramolecular Heck with
challenging because it can deliver a wide range of useful cyclic Pd(II);2 allylic amination with Ir-3a,b Rh-,3c Au(I)3d,f and Fe(III) or Cu(I)-
compounds through the development of cascade cyclization catalysis;3g and the Morita–Baylis–Hillman reaction with phosphine,
processes using simple, inexpensive and easily prepared sub- Pd- and Au-catalyzed ring-expansion approaches.3h 2-Quinolinones
strates. For example, the prime substrate, 2-ethynylanilides are found to be antagonists for respiratory disease, an HBV inhibitor
(3, Scheme 1), can easily be synthesized in situ from the readily for anti-Hepatitis B, and an universal fluorescent marker,4 and
available 2-(phenylethynyl)aniline (1) and ethyl 3-oxo-propionate annulation reactions were employed for their synthesis utilizing
derivatives (2) without employing any catalyst under refluxing Pd(II),5a,f,i Ag(I),5d Au(I),5g Ru(II)–Ag(I),5e and a few other catalysts.5b,c,h
toluene. It can easily undergo dual competitive cyclization among 3-Acyl indoles are bioactive natural products and revealed antibiotic
C–H and CRC to produce valuable azepinones (eqn (i)) and (indiacen A and indiacen B) and antidiabetic (MK-0533) activities,
quinolinones (eqn (ii)) through 7- and 6-annulation, respectively. and used as important pharmaceuticals, key intermediates, and
On the other hand, an N–H and CRC coupled 5-annulation will
furnish important 3-acyl indoles (eqn (iii)) with the possible migra-
tion of the acyl group under catalytic influence. However, selectivity
is a big issue for annulation reactions, which may also be overcome
using suitable catalysts. More than 20 years back, Pace et al. first
reported a C–C coupled 6-annulation through C(sp3)–H and CRC
of anilide (eqn (iv))1a using three equivalents of strong base (NaH or
KOtBu) at 110 1C in DMSO to obtain quinolinones in a low to
moderate yield (30–75%). An electro-chemical approach is reported
to convert 2-ethynylanilides (eqn (v)) to quinolones.1b The Chuang
Department of Chemistry, University of Calcutta, 92 A. P. C. Road, Kolkata-700009,
India. E-mail: dkmchem@caluniv.ac.in
† Electronic supplementary information (ESI) available. CCDC 1911210 and 1911211.
For ESI and crystallographic data in CIF or other electronic format see DOI:
Scheme 1 Diverse 7, 6 and 5-annulation reactions of 2-ethynylanilide.
10.1039/c9cc07360d
474 | Chem. Commun., 2020, 56, 474--477
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synthons.6 Traditional procedures to furnish 3-acyl indoles involved temperature (80 1C). The role of the catalyst was confirmed as the
mainly through acylation of N-protected indoles via Friedel–Crafts,7a reaction did not occur in the absence of ZnCl2 (entry 15). A brief
carbonylative 3-acylation,7b and a few others.7c,d Zinc chloride8 and survey of the solvent (entries 16–20) revealed that the formation of
molecular iodine9 emerged as useful catalysts in organic synthesis the by-product (4a) was enhanced in the case of xylene, dioxane, and
because they are inexpensive, readily available, less toxic, environ- THF (entries 16, 17 and 21). The yield of 5a was reduced (40–60%)
mentally benign, and above all, they have diverse catalytic activities. upon using DMSO, DMF, and MeCN, along with an enhanced yield
We initiated the annulation reaction of in situ generated 3-oxo-3- of the by-product (4a, 20%, entries 18–20). Thus, toluene was found
phenyl-N-(2-(phenylethynyl)phenyl)propanamide (3a) from 2-(phenyl- to be the best reaction medium for the 7-annulation process
ethynyl)aniline (1a) and ethyl benzoyl acetate (2a) under refluxing (entry 11). The viability of our strategy for large scale synthesis of
toluene. The annulation reaction was screened employing 10 mol% azepinone was validated in gram-scale synthesis (86%, entry 22).
of potential catalysts such as FeCl3, RuCl3, and Pd(OAc)2, which
The scope of the new method was explored by utilizing several
could not furnish the 7-annulated product(s), 4a and/or 5a even after in situ prepared o-ethynylacetoacetanilide derivatives (Scheme 2).
24 h (entries 1–3, Table 1). To our delight, the construction of A number of substrates bearing electron-donating substituents
isomeric 3-benzoyl-4-phenyl-1H-benzo[b]azepin-2(5H)-one (5a) was (R2 = Me, Et, and OMe) and electron-withdrawing substituents
detected (5–15%) with catalysts CuCl and Cu(OTf)2 (entries 4 and 5). (R2 = F, Cl, Br, NO2, and CF3) worked well in this cascade reaction
The yield was moderately improved (40%, entry 6) by the use of under the developed conditions to obtain the corresponding azepi-
Zn(OAc)2. Screening of Zn(II)-salts such as Zn(OTf)2, ZnI2, ZnBr2, and nones (5a–l) in excellent yields (82–95%). Interestingly, in the case of
ZnCl2 led to a significant improvement in the yield (40–70%, entries electron withdrawing substituents at the aromatic residue of the
7–10) along with the formation of 4a (10–15%). Gratifyingly, an alkyne moiety, the reaction led to a comparatively higher yield than
excellent yield (5a, 90%, entry 11) was obtained upon enhancing the that bearing electron donating substituents. Again, the o-ethynyl-
catalyst loading of ZnCl2 from 10 to 20 mol% with the subsidized anilides (3m, n) obtained from tert-butyl acetoacetate and ethyl
by-product 4a (3%). However, no further improvement in the propionylacetate, respectively, furnished the corresponding azepi-
yield (5a) was observed upon using more amount of the catalyst nones 5m and 5n in 85–86% yield without changing the reaction
(entry 12). The 7-annulation reaction did not occur at room conditions. However, the outcomes of the 7-annulation reactions
temperature (entry 13), and the desired product (5a) was formed led us to conclude that the cascade cyclization is independent of
only in 60% yield along with 20% of 4a (entry 14) at moderate electronic influence exerted by the carbonyl residue. The structure of
all the new azepinones (5a–o) was unambiguously established with
NMR, FTIR and ESI-MS spectroscopy and also single crystal XRD
Table 1 Development of the 7-annulation reactiona
analyses of compound 5e.10a
Yieldb (%)
Entry Catalyst (mol%) Solvent Temp (1C) Time (h) 4a 5a
1
2
3
4
5
6
7
8
FeCl3(10)
RuCl3(10)
Pd(OAc)2(10)
CuCl(10)
Cu(OTf)2(10)
Zn(OAc)2(10)
Zn(OTf)2(10)
ZnI2(10)
ZnBr2(10)
ZnCl2(10)
ZnCl2(20)
ZnCl2(30)
ZnCl2(20)
ZnCl2(20)
—
ZnCl2(20)
ZnCl2(20)
ZnCl2(20)
ZnCl2(20)
ZnCl2(20)
ZnCl2(20)
ZnCl2(20)
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene Reflux
Toluene rt
24
24
24
24
24
8
—
—
—
—
—
NRc
NRc
NDd
5
15
40
8
—
40
12
12
10
6
5
24
6
15 50
15 50
10 70
3
2
ND ND
20 60
ND ND
30 60
35 50
20 55
20 50
20 40
30 60
9
10
11
12
13
14
15
16
17
18
19
20
21
22e
90
90
Toluene 80
Toluene Reflux
12
8
Xylene
120
Dioxane 120
12
12
20
18
12
8
DMSO
DMF
120
120
CH3CN Reflux
THF Reflux
Toluene Reflux
5
88
a
Reactions were carried out using 1 mmol of 3a in the presence of
b
10 mol% of catalysts. Yields of 4a and 5a after purification by column
chromatography. No reaction. Not detected. Gram scale synthesis
c
d
e
Scheme 2 Synthesis of functionalized azepinones.
of 1a (5.5 mol%, 1 g), 2a (5 mol%, 0.96 g), 20 mol% ZnCl2.
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Table 2 Evaluation of the 6-annulation reactiona
toluene (entry 1, Table 2). On the other hand, HI could not
transform 3a into 6a or 7a at all (entry 2) via activation of the
alkyne moiety. To our delight, IPy2BF4 facilitated the formation of
the quinolinone derivative (6a) in a moderate yield (57%) along
with a trace of 7a (entry 3), and the existence of 7a (X = I)
was detected by recording mass spectrometry of the product
mixture (ESI†). Attempts were made to generate nascent iodine
using PhI(OAc)2 in combination with NaI, or TBAI formation of the
desired product was not detected (entries 4 and 5). Gratifyingly,
treatment of 3a with inexpensive molecular iodine (10 mol%)
at ambient temperature led the reaction to completion within
5 h to furnish the desired 2-quinolinone (6a) in a high yield
(90%, entry 6). The yield was further improved to 95% upon
enhancement of the catalyst loading to 20 mol% (entry 7). However,
a further increase of molecular iodine (40 mol%) showed a
detrimental effect on the yield of the product 6a from 95% to
77% (entry 8) along with the generation of the by-product 7a, which
was not detected in the previous two experiments (entries 6 and 7).
The yield (6a) was reduced (48–61%) upon screening the
Yield (%)
Solvent Temp. (1C) Time (h) 6ab 7a
Entry Catalyst (mol%)
1
2
3
NICc (10)
HI (10)
IPy2BF4 (10)
Toluene Reflux
Toluene Reflux
Toluene Reflux
12
12
6
8
8
5
3
2
12
12
NRd,e
NRd
57
NR Trace
ND Trace
90
95
77
61
48
—
—
Trace f
4
5
NaI, PhI(OAc)2 (10) Toluene Reflux
TBAI, PhI(OAc)2 (10) Toluene Reflux
6
7
8
9
I2 (10)
I2 (20)
I2 (40)
I2 (15)
I2 (15)
Toluene Reflux
Toluene Reflux
Toluene Reflux
NDg
ND
Trace
Trace
Trace
THF
Reflux
10
DMSO Reflux
a
Reaction developed using 1 mmol of 3a in the presence of 0.15 mmol
of catalysts taken in toluene at ambient temperature. b Yield after purifica-
c
d
tion by column chromatography. N-Iodosuccinimide. No reaction.
e
f
g
Complete recovery of 3a. X = I. Not detected.
Next, we hypothesized the catalytic C–C coupled selective
6-annulation (Table 2) of the same substrate (3a) and the cyclization
reaction was examined to furnish quinolinone (6a) and/or the
isomeric product (7a) tactfully to restrict 7-annulation. To suppress
the 7-annulation reaction, our initial experiments for 3a began with
iodine-based nonmetallic catalysts (10 mol%, Table 2). No reaction
occurred with N-iodosuccinimide (10 mol%) even in refluxing
Scheme 4 Synthesis of indoles through 5-annulation.
Scheme 3 Scope for direct synthesis of functionalized 2-quinolinones.
476 | Chem. Commun., 2020, 56, 474--477
Scheme 5 Plausible mechanistic pathways.
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Scheme 6 Control experiments.
6-annulation reaction with polar solvents such as THF and DMSO
(entries 9 and 10).
On the basis of the developed reaction conditions, we scrutinized
the validation of the reaction employing a wide variety of in situ
generated o-ethynylanilides (3, Scheme 3), and it was observed that
electronically rich and poor substrates worked well in this reaction
to obtain quinolinone derivatives 6a–o in a high yield (84–95%). The
quinolinone derivatives were characterized by FTIR, NMR and ESI
MS spectroscopy, and also the structural elucidation of 6a through
single-crystal XRD analyses.10b
To understand the role of C–H, relatively less acidic C–H was
employed by changing the substrate to N-acetyl-2-phenylethynyl
anilines (10a, Scheme 4) instead of 3, and a 5-annulation reaction
occurred through N–C coupling using the ZnCl2 catalyst under the
same reaction conditions. Valuable 3-acyl-2-aryl indoles (12a) were
easily produced in a high yield (84%). The substrate scope of
the rapid (2–4 h) reaction was also verified to obtain 3-acyl indoles
(12a–i) in a good yield (72–88%). Interestingly, 1,3-acyl and
1,3-benzoyl group migration was observed,11 and the other possible
products (11) were found in traces only when R1 = Ph (12e and 12i).
The plausible mechanism (ESI†) for ZnCl2 catalysed 7- and
5-annulation with 1,3-migration and I2 tuned 6-annulation with
nonconvensional 1,3 H-shift are displayed in Scheme 5 along with
intermediate trapping, control, and labeling experiments (Scheme 6).
In conclusion, we discovered diverse catalytic 5-, 6- and
7-cyclization processes with a concerted 1,3-migration to achieve
three valuable heterocycles from 2-ethynyl anilides with excellent
selectivity, yield and operational simplicity, which will find
considerable application in synthetic chemistry and the allied
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Notes and references
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