Construction of indeno[1,2-b]pyrrolesviachemoselectiveN-acylation/cyclization/Wittig reaction sequence

Article abstract of DOI:10.1039/d0cc08184a

An efficient protocol for the chemoselective construction of the indeno[1,2-b]pyrroles and rearranged indeno[1,2-b]pyrrole derivatives is reportedviaanN-acylation/cyclization/Wittig reaction. Extensive mechanistic investigations revealed that the initially formed crucial spiro-indene-1,2′-[1,3,4]oxadiazol intermediate further reacts with phosphine to generate betaine, thus predominately resulting in the aforementioned heteroarenes proceeding by a Wittig reaction.

Full text of DOI:10.1039/d0cc08184a

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Construction of indeno[1,2-b]pyrroles via
chemoselective N-acylation/cyclization/Wittig
reaction sequence†
Cite this: Chem. Commun., 2021,
57, 2045
Received 17th December 2020,
Accepted 12th January 2021
Athukuri Edukondalu, ‡ Sandip Sambhaji Vagh,‡ Ting-Han Lin and
Wenwei Lin
*
DOI: 10.1039/d0cc08184a
rsc.li/chemcomm
An efficient protocol for the chemoselective construction of the Owing to their significant pharmaceutical importance in the
indeno[1,2-b]pyrroles and rearranged indeno[1,2-b]pyrrole derivatives area of drug discovery, great efforts are being focused on the
is reported via an N-acylation/cyclization/Wittig reaction. Extensive development of diverse methods for the efficient construction
mechanistic investigations revealed that the initially formed crucial of indeno[1,2-b]pyrroles.
spiro-indene-1,20-[1,3,4]oxadiazol intermediate further reacts with
Earlier, the first method for direct b-acylation of 2-arylidene-
phosphine to generate betaine, thus predominately resulting in the 1,3-indandiones with acyl chlorides catalyzed by organopho-
aforementioned heteroarenes proceeding by a Wittig reaction.
sphanes has been reported from our laboratory.8 The discovery
of this reaction guided us to conduct several experiments and it
Phosphine-mediated transformations have enormous synthetic was successfully extended to other cyclic and acyclic a,b-
potential and are ubiquitous in organic synthesis due to the unsaturated carbonyl compounds to install the carbonyl func-
construction of a wide range of biologically active and medicinally tionality at the b-position.9 In continuation of our pursuit of the
important molecules.1 Despite all of these transformations, the exploration of organophosphane chemistry,10 we were keen on
Wittig reaction has predominantly been explored to generate the applications of indane-1,3-dione hydrazones toward the
olefins in achieving a variety of high yielding and stereoselective construction of multifarious heteroarenes. Herein, we wish to
reactions.2 Consequently, it has witnessed its efficacy in multi- report an efficient synthesis of indeno[1,2-b]pyrroles and their
faceted applications toward the preparation of vast libraries of rearranged adducts from the corresponding zwitterions with
heteroarenes and heterocyclic compounds with diverse skeletons.3 acyl chlorides and a base (Scheme 1). It is worth noting that the
Considering the prominence of this transformation, the develop- reaction of phosphorus zwitterions and acyl chlorides in the
ment of various methods for providing multifarious privileged presence of a base exclusively resulted in the Wittig products
heterocyclic compounds is highly desirable.
instead of b-acylated adducts.
On the other hand, indenopyrroles with a 6/5/5 framework
Initially, we started our investigation to prepare phosphorus
containing a pyrrole core have shown remarkable biological zwitterions from the indane-1,3-dione hydrazones 1, PBu3, and
activities,4 and their derivatives have also been employed as various aldehydes 2 via a tandem three-component reaction.10f
antitumor activators, potent human protein kinase CK2 inhi- To our delight, the desired zwitterions 3a–3h were obtained in
bitors, and breast cancer resistance protein ABCG2 inhibitors.5 high yields, irrespective of the nature and position of the
Methods for the synthesis of different types of indenopyrroles
are well-explored,6 but only a few synthetic methods regarding
the preparation of indeno[1,2-b]pyrroles have been reported.7
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4,
Tingchow Road, Taipei 11677, Taiwan, Republic of China.
E-mail: wenweilin@ntnu.edu.tw; Fax: +886 2 2932 4249
† Electronic supplementary information (ESI) available: Synthetic procedures,
characterisation data and copies of the spectra of all compounds. CCDC 2009731
(3a), 2016707 (6aa), 2009642 (6ae), 2009644 (6ai), 2009643 (6aj), 2009645 (7ak),
2009646 (7ik), 2009650 (8aa) and 2019535 (8ak). For ESI and crystallographic data
Scheme 1 Chemoselective Wittig approach towards the indeno[1,2-
b]pyrroles 6/7.
in CIF or other electronic format see DOI: 10.1039/d0cc08184a
‡ These authors contributed equally.
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Table 1 Synthesis of functional zwitterions 3ab
Table 3 Substrate scope for the indeno[1,2-b]pyrroles 6ab
a
The reactions were carried out with 1 (1.0 mmol), 2 (1.1 equiv.),
PhCO2H (10 mol%), PBu3 (1.2 equiv.), and pyrrolidine (10 mol%) in dry
b
THF (10 mL) under argon at 30 1C. Isolated yield.
a
The reactions were carried out with 3 (0.3 mmol), 5 (1.1 equiv.), and
b
Et3N (1.5 equiv.) in dry THF (3 mL) under argon at 50 1C. Isolated
yield. Performed a gram-scale reaction (3a: 2 mmol, 1.267 g).
substitution on the aryl ring (R1) (Table 1). The substitution on
different hydrazones 1 (R2) also furnished the corresponding
zwitterions 3i and 3j in good yields. The chemoselectivity of the
reaction was realized with zwitterion 3 bearing a charge on the
nitrogen atom rather than another possible zwitterion with
charge on an oxygen atom. Further X-ray diffraction analysis
unambiguously demonstrated the structure of the zwitterion 3a
with the charge on the nitrogen atom which is adjacent to the
benzoyl group presumably; due to the electron-withdrawing
capacity of the carbonyl group the charge will be delocalised
over both the nitrogen and oxygen atoms of the amide like
anion.11a
c
12 h (Table 2, entry 1). To find the optimal conditions, screen-
ing of different bases was carried out, and the product 6aa was
furnished in 51–84% yields in THF (entries 2–5). Next, various
solvents were screened by using Et3N as a base. The reaction in
CH2Cl2 showed poor reactivity, providing the desired product
6aa in only 25% yield even after 24 h (entry 6). Whereas other
solvents like CH3CN, toluene, and Et2O afforded the product
6aa in moderate yields, albeit requiring longer reaction times
(entries 7–9). Interestingly, when the reactions were screened at
40 1C and 50 1C, the desired product 6aa was obtained in 85%
and 90% yields within 4 h, respectively (entries 10 and 11).
Furthermore, a different addition sequence was also tested,
but the results were not as efficient as previous conditions
(entry 12). Finally, the optimal result was found by treating 3a
with 5a in the presence of Et3N in anhydrous THF at 50 1C as
shown in entry 11.
At first, we examined a reaction with phosphorus zwitterion
3a and benzoyl chloride (5a) as model substrates in the
presence of Et3N in THF at 30 1C. Delightfully, the indeno
[1,2-b]pyrrole derivative 6aa was obtained in 85% yield in
Table 2 Optimization of the reaction conditionsa
Having found the optimal conditions, the substrate scope
was further investigated (Table 3). First, the zwitterions bearing
different R1, and R2 substitutions were subjected to PhCOCl
(5a) under the standard conditions. Substrates with an
electron-withdrawing group (R1) at the para-position reacted
with 5a smoothly, furnishing the desired indeno[1,2-b]pyrroles
6aa–6ca in up to 94% yields. It was found that the steric and
electronic properties of the substituents have a significant
effect on the reaction outcome. When the substrates 3d (R1 =
4-OMeC6H4) and 3e (R1 = Ph) participated in the reaction, the
corresponding products 6da and 6ea were obtained in up to
64% yields. The substrate with Cl at the meta-position of R1 (3f)
was also tested to provide the desired product 6fa in only
moderate yield. The zwitterions bearing an ortho-substituted
R1, such as 3g and 3h, did not react with 5a even when
prolonging the reaction time up to 24 h, presumably due to
the steric hindrance. Delightfully, zwitterions with different R2
substitutions were well-tolerated, affording the corresponding
Entry
Base
Solvent
t (h)
6aab
1
2
3
4
5
6
7
8
Et3N
DIPEA
DBU
TMG
TBD
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
THF
THF
THF
THF
12
18
10
10
12
24
24
48
24
4
85
60
75
51
84
25
50
47
65
85
90
76
THF
CH2Cl2
CH3CN
Toluene
Et2O
THF
THF
9
10c
11d
12de
4
4
THF
a
The reactions were carried out with 3a (0.1 mmol), 5a (1.1 equiv.), and
base (1.5 equiv.) in dry solvent (1 mL) under argon at 30 1C. Yield of products 6ia–6ja in up to 83% yields.11b
the product 6aa was determined by NMR analysis of the crude reaction
b
Furthermore, various acyl chlorides 5 were tested in the
reaction with zwitterion 3a. Acyl chlorides bearing electron-
withdrawing and electron-donating groups afforded the desired
c
mixture using 1,3,5-trimethoxybenzene as an internal standard. At
40 1C. At 50 1C. Addition sequence: 3a (0.1 mmol), Et3N (1.5 equiv.),
and 5a (1.1 equiv.).
d
e
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Table 4 Altering the reactivity of zwitterions by using PPh2Me for the
synthesis of 8ab
Scheme 2 Synthesis of rearranged indeno[1,2-b]pyrroles 7.
products 6ab–6ai in up to 85% yields, irrespective of the nature
and position of the substituents.11b Interestingly, the acyl
chloride (5j) containing a heteroaryl group (2-furyl) was also
well-tolerated, and the corresponding product 6aj was obtained
in 72% yield. In addition, to test the preparative utility of this
chemoselective Wittig reaction, we performed a 2 mmol scale-up
reaction using zwitterion 3a and PhCOCl (5a). The desired
indeno[1,2-b]pyrrole 6aa was obtained in 87% yield with sub-
stantial quantity.
Accordingly, we also examined a reaction of aliphatic acyl
chloride such as pivaloyl chloride (5k) with zwitterion 3a under
the optimal conditions. It was found that the rearranged
indeno[1,2-b]pyrrole 7ak was obtained in 60% yield instead of
6ak (Scheme 2).11a Surprised by the results, the other zwitterions
3i and 3j were examined with 5k under the same conditions. To
our delight, zwitterions 3i and 3j also participated, albeit providing
only moderate yields of the desired rearranged products 7ik and
7jk. Due to the low reactivity of pivaloyl chloride 5k, the corres-
ponding unreacted zwitterion 3 has also been recovered along
with the rearranged indeno[1,2-b]pyrroles 7. Notably, the acetyl
chloride was also tested with 3a, but the reaction did not furnish
the desired products. It could be understood that when less
reactive and hindered pivaloyl chloride 5k was utilized as an
acylating agent, rearranged products were realized via an intra-
molecular acyl group exchange/Wittig reaction sequence.11b This
new approach of pivaloyl chloride utilized as an acyl group
exchange precursor in the presence of a more reactive acyl group
on hydrazones, can become a powerful tool to access diverse
rearranged heteroarenes.
Next, we turned our attention to preparing the other phosphorus
zwitterions 4 from the indane-1,3-dione hydrazones 1, less nucleo-
philic PPh2Me, and aldehydes 2 via a tandem three-component
reaction.10f Unfortunately, we could not isolate the desired zwitter-
ions 4 using column chromatography or even crystallization.11c To
test the reactivity of zwitterions bearing PPh2Me under our protocol,
we have in situ generated the zwitterion 4a and further reacted it
with 5a in the presence of Et3N (Table 4). To our surprise, the
spiro-indene-1,20-[1,3,4]oxadiazol derivative 8aa was obtained
in 45% yield within 3 h, instead of indeno[1,2-b]pyrroles 6aa/
7aa. Furthermore, we have tested the different aldehydes 2 and
acyl chlorides 5 with 1a under the reaction conditions. All the
tested substrates furnished the desired products in low to
moderate yields in a one-pot manner. Probably, the instability
of in situ generated zwitterion 4 could be the reason for the
formation of the corresponding spiro products 8 in lower yields.
Two different types of products were found in our protocol by
using the zwitterion bearing different phosphines. At an instance,
we have assumed that the spiro-indene-1,20-[1,3,4]oxadiazol
a
The reactions were carried out with 1 (0.5 mmol), 2 (1.1 equiv.),
PhCO2H (10 mol%), PPh2Me (1.2 equiv.), and pyrrolidine (10 mol%) in
dry THF (5 mL) under argon at 30 1C for 12 h. Afterwards, 5 (1.5 equiv.),
and Et3N (2.0 equiv.) were sequentially added, and the reaction was
performed under argon at 50 1C. Isolated yield. Performed a gram-
scale reaction (1a: 4 mmol, 1.057 g).
b
c
8 could be a possible intermediate for formation of the indeno
[1,2-b]pyrrole. To test our hypothesis, we have examined the
reactions of different spiro-indene-1,20-[1,3,4]oxadiazols 8aa, 8ac,
and 8ai with PBu3 in the presence of Et3N. To our delight, the
desired indeno[1,2-b]pyrroles 6aa, 6ac, and 6ai were obtained
in up to 75% yields within 4–7 h (Scheme 3).11b Furthermore,
the acyl transfer reaction has been investigated in the case of
spiro compound 8ak with PBu3. Remarkably, the rearranged
indeno[1,2-b]pyrrole 7ak was also found in the reaction with 50%
yield.11b This clearly indicates that PBu3 with higher nucleophili-
city could further react with 8 to result in the indeno[1,2-b]pyrrole
6 or 7, depending on the relative reactivities of acylating agents.
Based on the above results, a plausible mechanism is
depicted in Scheme 4. Initially, a chemoselective tandem
three-component reaction of indane-1,3-dione hydrazone 1,
aldehyde 2, and phosphine furnished the phosphorus zwitter-
ion 3/4 which could be interchangeable with another possible
zwitterion I. The chemoselective N-acylation of the zwitterion I
with acyl chloride 5 would generate phosphonium salt II that
can easily cyclize to give the spiro compound 8 via allylic
substitution with elimination of PR3. When the eliminated
PR3 has less nucleophilic nature such as PPh2Me, only the
spiro compound 8 would be provided. Instead, a more nucleo-
philic PR3, such as PBu3, would further react with 8 to generate
the phosphonium salt IIa. The deprotonation of IIa by
Et3N generates ylide III, and subsequent chemoselective
intramolecular Wittig reaction upon III would lead to the
indeno[1,2-b]pyrrole
6 via the formation of a crucial
betaine IV. On the other hand, the less reactive and hindered
pivaloyl group present on the spiro compound 8 would facil-
itate the intramolecular acyl group exchange to generate the
Scheme 3 Control experiments for the conversion of 8 to 6/7.
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phosphonium salt IIb, and that would provide ylide V in the
presence of Et3N. Furthermore,
a chemoselective intra-
molecular Wittig reaction upon ylide V would result in the
rearranged indeno[1,2-b]pyrrole 7. Although the exact factors
leading to acyl group exchange are not clear, it was presumed
on the basis of our results and control experiments (see Table 4,
and Scheme 3).11d It is worth noting that the rearrangement
reaction was not efficient to furnish the b-acylated products in
both cases, which was probably due to the lower C–N than C–O
bond lability of the corresponding betaines.
In summary, we have demonstrated a novel method for the
synthesis of indeno[1,2-b]pyrroles via a chemoselective zwitter-
ion formation/N-acylation/cyclization/Wittig reaction sequence.
A series of phosphorus zwitterions were prepared and could be
utilized for the synthesis of multifarious heteroarenes in moderate
to high yields. Furthermore, an unprecedented intramolecular
acyl group exchange/chemoselective Wittig reaction was realized
for synthesis of the rearranged indeno[1,2-b]pyrroles. In addition,
we have found a spiro-indene-1,20-[1,3,4]oxadiazol as a crucial
intermediate by choosing an appropriate zwitterion with PPh2Me,
and it could easily be transformed into indeno[1,2-b]pyrroles 6/7.
The authors thank the Ministry of Science and Technology
of the Republic of China (MOST 107-2628-M-003-001-MY3) for
financial support.
Conflicts of interest
There are no conflicts to declare.
11 See the ESI† for(a) the detailed characterization of the products
including X-ray diffraction analysis; (b) the compounds in Table 3
(6ia, 6ja, and 6ab–6aj), Scheme 2 (7ik, and 7jk), and Scheme 3 (6aa,
6ac, 6ai, and 7ak) further confirmed by the EIMS analysis; (c) the
formation of zwitterion 4a confirmed by 31P NMR and HRMS
analysis of the crude reaction mixture; (d) the detailed intra-
molecular acyl group exchange reaction mechanism.
Notes and references
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