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Calcium-catalyzed formal [3 + 2] annulation of

Cite this: Org. Biomol. Chem., 2021,
19, 1060
C,N-diacyliminium ions with nucleophilic phenols:
a diversity oriented synthesis of 3-aminofurans†
Rajesh P.,a Abdulrahman I. Almansour,b Natarajan Arumugamb and
Srinivasarao Yaragorla *a

Received 16th November 2020,
Accepted 22nd December 2020
DOI: 10.1039/d0ob02276d
rsc.li/obc
We have developed a one-pot, three-component, and solvent-free reaction for the synthesis of 3-amino-
furans using a calcium catalyst. In this cascade reaction, the key intermediate, C,N-diacyliminium ion, is
formed in situ from glyoxal and lactam, which further reacted with phenolic nucleophiles to form furan
derivatives in good yields with broad substrate diversity. We also present here the preliminary photo-
physical studies of selected compounds.

Introduction electrophilic carbonyl group by activating it with a suitable

Lewis acid catalyst to obtain 3-amino-naphthofurans as
Furan derivatives such as benzofurans and naphthofurans are depicted in Scheme 1.
well known privileged scaffolds.1 Their natural abundance in
the form of natural products is well recognized (Fig. 1); they
are explicitly used as synthetic building blocks.2 Benzo/
naphthofurans exhibit a broad spectrum of biological
activities3–5 such as antiviral, antifungal, antiparasitic, and
antidiabetic activities; moreover, these structures were used to
design potential anticancer agents,4 and also studied as regu-
lators of nuclear receptors HNF4α.5 Owing to these vital appli-
cations the synthesis of furan derivatives has become more sig-
nificant, and as a result, many synthetic groups have devel-
oped several elegant synthetic protocols.6–9
Having realized the pharmacological importance of furan
derivatives, we also developed novel synthetic strategies for
the construction of furan derivatives from propargyl alcohols,
Fig. 1 Representative examples of natural products having a naphtho/
and the selected compounds were studied to test their anti-
benzofuran moiety.
amyloid activity.9 In a recent study, while we were developing
a simple, multi-component strategy for the synthesis of poly-
substituted pyrroles from C-acylimines, we have incorporated
the naphthol moiety as a C2-substituent (Scheme 1).10 After a
close observation of the intermediate formed in this reaction,
we envisaged that there is a possibility of nucleophilic
addition of the hydroxyl nucleophile (of the naphthol) to the

a
School of Chemistry, University of Hyderabad, 500046 Telangana, India.
E-mail: Srinivas.yaragorla@uohyd.ac.in, ysruoh@gmail.com
b
Department of Chemistry, College of Science, P.O. 2455, King Saud University,
Riyadh 11451, Saudi Arabia
† Electronic supplementary information (ESI) available. CCDC 2035098. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ob02276d Scheme 1 The present and past approaches from acylimines.

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Results and discussion
Recently, we have trapped in situ formed C-acylimines with
naphthols;10 hence we used the same conditions by reacting
phenylglyoxal (1a), aniline and 2-naphthol (3a) using a
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water (entry 5). Surprisingly, no reaction was observed in
water, and other solvents did not yield more than 50% of 4a.
When we switched to solvent-free conditions, gratifyingly, the
reaction yielded 85% of the product 4a in four hours (entry 6).
Neither an increase nor a decrease of the reaction temperature

calcium catalyst. However, all our efforts could not proceed was helpful in obtaining better yield (entries 7 and 8).
beyond the isolation of the intermediate. A thorough literature The reaction yield at the elevated temperature (120 °C) was
search hinted us to use lactams instead of anilines, where a not satisfactory. When we used Ca(NTf2)2 as the catalyst, the
report indicated that the phenylglyoxal, γ-lactam and 4-hydro- reaction yield was only 60% (entry 9). Further attempts to mini-
xycoumarin were refluxed in 1,2-dichloroethane with triflic mize the catalyst loading was unsuccessful (entry 10), and it
acid to obtain furocoumarins.11 Therefore, we replaced aniline was also found that the presence of a catalyst is necessary for
with γ-lactam (2a) and started to develop the reaction con- this transformation (entry 11). The conditions of entries 12
ditions for annulation with 1a and 3a (Table 1). On the other and 13 reiterate that a ligand metathesis takes place between
hand, due to the high abundance, low cost and environmen- the Ca(OTf )2 and Bu4NPF6 to form a more acidic calcium salt
tally benign nature, calcium salts have been explored as poten- and hence it is essential to use them together for a better reac-
tial Lewis acid catalysts in many of the organic transform- tion yield (see the mechanism for details, Scheme 3). Other
ations.12 Therefore, a mixture of 1a (0.64 mmol) and 2a catalysts such as magnesium triflate, para-toluenesulfonic
(0.714 mmol) was refluxed in 1,2-dichloroethane with 10/ acid, ferric chloride and copper triflate moderately catalyzed
10 mol% of Ca(OTf )2/Bu4NPF6 for one hour (until the for- the reaction (entries 14–17). Therefore, the reaction conditions
mation of C,N-diacyliminium ions is monitored by TLC) and of entry 6 (Table 1) are considered as the optimum conditions
3a (0.64 mmol) was added to the reaction mixture and reflux to obtain the maximum reaction yield of 4a.
was continued for 12 h. To our delight, the desired product 1- After establishing the standard reaction conditions for the
(2-phenylnaphtho[2,1-b]furan-1-yl)pyrrolidin-2-one (4a) was in situ preparation of C,N-diacyliminium ions and a sub-
formed in 45% yield (entry 1) along with unreactive C,N-diacy- sequent annulation with 2-naphthol, we were interested in
liminium and the uncyclized intermediate. This prompted us exploring the generality of this protocol. Initially, we studied
to investigate optimum reaction conditions to get the the scope of various arylglyoxals, such as 2-bromophenyl-
maximum reaction yield by studying various factors. One of glyoxal (1b), 4-bromophenylglyoxal (1c), 4-chloro phenylglyoxal
them is a solvent study, where we performed the reaction in (1d), 4-fluoro phenylglyoxal (1e) and 4-methoxyphenylglyoxal
acetonitrile (entry 2), toluene (entry 3), ethanol (entry 4) and (1f ) with γ-lactam (2a) and 2-naphthol (3a) under standard
reaction conditions and obtained the corresponding naphtho-
furans 4b–4f in good yields (Table 2). Next, 6-bromo-2-
Table 1 Optimization of reaction conditions for the annulation of 1a, naphthol (3b) was also treated with various arylglyoxals (1a, 1g,
2a, and 3a a and 1d) to obtain the respective naphtho[2,1-b]furans 4g–4i in
good yields. It is worth noting that not only the arylglyoxals,
but also the alkylglyoxals such as isopropylglyoxal (1h) and
cyclopropylglyoxals (1i) furnished the desired products 4j and
4k with similar reaction yields. We were also successful in uti-
lizing ω-lactam in this three-component, solvent-free annula-
Entry Catalyst (mol%) Reaction conditionsd Yieldb (%) tion reaction to furnish the corresponding naphtho[2,1-b]
1 Ca(OTf)2/Bu4NPF6 (10/10) DCE, 90 °C, 12 h 45 furans 4l–4n in good yields. Furthermore, the structure of 4n
2 Ca(OTf)2/Bu4NPF6 (10/10) CH3CN, 90 °C, 12 h 50 was confirmed unambiguously by obtaining its single crystal
3 Ca(OTf)2/Bu4NPF6 (10/10) Toluene, 100 °C, 12 h 40 X-ray data (CCDC 2035098†).13
4 Ca(OTf)2/Bu4NPF6 (10/10) EtOH, 100 °C, 12 h 40
5 Ca(OTf)2/Bu4NPF6 (10/10) H2O, 100 °C, 12 h nr After studying the general substrate scope of various glyox-
6c Ca(OTf)2/Bu4NPF6 (10/10) Neat, 100 °C, 4 h 85 als, lactams and naphthols, we performed another reaction
7 Ca(OTf)2/Bu4NPF6 (10/10) Neat, 90 °C, 5 h 79 with 1a, 2a and mequinol (5a) under standard reaction con-
8 Ca(OTf)2/Bu4NPF6 (10/10) Neat, 110 °C, 4 h 85
9 Ca(NTf2)2/Bu4NPF6 (5/5) Neat, 100 °C, 12 h 60 ditions and obtained the corresponding benzofuran 6a in 80%
10 Ca(OTf)2/Bu4NPF6 (5/5) Neat, 100 °C, 12 h 71 yield (Scheme 2). In a similar way, glyoxal 1d reacted with 2a
11 — Neat, 100 °C, 12 h 11 and 5a to furnish benzofuran 6b in 76% yield. Later, 4-phenyl
12 Ca(OTf)2 (10) Neat, 100 °C, 12 h 45
13 Bu4NPF6 (10) Neat, 100 °C, 12 h 20 phenol (5b) was also treated with 1a and 2a to obtain 6c in
14 Mg(OTf)2 Neat, 100 °C, 12 h 35 excellent yield (Scheme 2).
15 PTSA (10) Neat, 100 °C, 12 h 53 In a recent study, we have proved that 9,9-diaryl fluorenols
16 FeCl3 (10) Neat, 100 °C, 12 h 30
17 Cu(OTf)2 (10) Neat, 100 °C, 12 h 45 can show similar reactivity to that of naphthols.14 Encouraged
by these facts, we thought to utilize fluorenols in this annula-
a
Reaction conditions: 1a (0.64 mmol) and 2a (0.714 mmol) heated at tion reaction with the in situ formed diacyliminium ions. As
the specified temperature with the catalyst for 1 h, and then 3a
(0.64 mmol) was added. b Isolated yields based on 1. c Optimum con- desired, compounds 1a, 2a, and 1,4-dimethyl-9,9-diphenyl-9H-
ditions. d Oil bath temperature. fluoren-3-ol (7a)15 were heated for six hours under standard

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Table 2 Substrate scope reaction conditions and the product 8a was obtained in 84%
yield (Table 3). Prompted by this result, we planned to verify
the generality of this protocol, and hence we treated arylglyox-
als 1c and 1g with lactam 2a and fluorenol 7a to obtain the
corresponding fluorenofurans 8b and 8c in excellent yields.
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Using the same conditions, we also synthesized fluorenofurans

8d, 8e and 8f in excellent yields.
Further experiments were performed by using 4-hydroxy-
coumarin as the nucleophilic partner for the annulation with
1a and 2a. However, the solvent-free approach could not work
efficiently in this case. After performing a set of reactions, we
observed that the use of 1,2-dichloroethane as the solvent was
beneficial. Accordingly, 1a, 2a and 4-hydroxycoumarin (9) were
refluxed in DCE along with the calcium catalyst to furnish the
desired furocoumarin 10a in 56% yield after 12 h. Similarly,
4-chlorophenylglyoxal (1d) gave 10b in 50% yield (Scheme 3).
The detailed reaction mechanism for this annulation reac-
tion is described in Scheme 4. Ligand metathesis between Ca

Table 3 Annulation of C,N-diacyliminiums with fluorenols

Scheme 2 Annulation of 1 and 2a with phenol 5. Scheme 3 Annulation of C,N-diacyliminium with 4-hydroxycoumarin.

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hydroxyl group can add to it to form intermediate Z.

Elimination or the aromatization of Z leads to the formation of
the naphthofuran 4.
After the development of a novel, green synthetic protocol,
we were curious to explore the possible applications of these
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products. Hence, as a preliminary investigation, we have

studied the photophysical properties such as UV-Visible and
fluorescence characteristics of the selected five compounds,
two of them were naphthofurans (4a and 4f ), one benzofuran
(6a), one fluorenofuran (8a), and one furocoumarin (10a). The
UV-Visible spectra of these compounds in ethanol exhibited
the maximum absorption wavelength (λmax) at 337 nm, as
shown in Table 4 and Fig. 2. It is interesting to note that all
the poly-fused-furans showed a λmax above 330 nm, whereas a
simple benzofuran has a λmax at 303 nm, which indicate that,
with the increase in the number of rings fused, the λmax also
increased. The fluorescence spectrum of naphthofuran 4a
Scheme 4 Possible reaction mechanism.
showed the emission maxima (λem) at 369 nm, and that of 4f is
377 nm, which indicates the role of the electron-donating
group on the phenyl ring of 4f. Though compound 6a is a ben-
Table 4 The absorbance, extinction coefficients (ε), and emission zofuran, it showed the emission maxima λem at 371 nm, which
wavelengths of selected compounds
is close to 4a, probably due to the presence of a methoxy sub-
λmax a Absorbance ε λem b
stituent on it. Compound 8a, which has more number of rings
Entry Compound (nm) at λmax (1 × 104 M−1 cm−1) (nm) fused with furan, showed the emission maxima (λem at 383).
Among all the five compounds, 10a showed the highest emis-
1 4a 330 1.337 1.337 369
2 4f 335 1.719 1.719 377 sion maxima (λem) at 417 nm; this is because of the coumarin
3 6a 303 0.319 0.319 371 group attached. The absorption peak wavelengths (λabs), calcu-
4 8a 337 1.460 1.460 383 lated molar extinction coefficient (ε), and emission peak wave-
5 10a 330 0.634 0.634 417
lengths in EtOH are summarised in Table 4. Based on these
a
Absorption wavelengths. b Emission wavelengths at room temperature observations, these compounds may be suitable for appropri-
(25 °C) in EtOH at a concentration of 1 × 10−4 M.
ate modifications so that they can be used as fluorescent
probes for plausible organic light-emitting diodes and biologi-
cal labelling applications.
(OTf )2 and Bu4NPF6 takes place to furnish a more acidic
calcium catalyst. In the presence of this catalyst, the formation
of the key intermediate, C,N-diacyliminium, takes place from Conclusions
glyoxal 1 and lactam 2. In the next step, calcium facilitates the
nucleophilic addition of naphthol (3) by chelating with the In conclusion, we have developed a facile calcium-catalyzed
diacyliminium to furnish the intermediate Y. Furthermore, the one-pot, three-component, and solvent-free strategy for the
Lewis acidic catalyst continues to activate the carbonyl group synthesis of a diverse range of fused-furans from readily avail-
and thus increases the electrophilicity so that the phenolic able compounds. In this approach, various nucleophiles, such

Fig. 2 Absorbance (left) and fluorescence emission (right) spectra of compounds 4a, 4f, 6a, 8a and 10a in EtOH recorded at a concentration of 1 ×
10−4 M at room temperature (25 °C).

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Paper
as phenols, naphthols, fluorenols, and 4-hydroxycoumarin,
were successfully subjected to annulation with in situ formed
C,N-diacyliminium ions. We also demonstrated that not only
the arylgylyoxals but also the alkylglyoxal could participate in
this reaction. The substrate scope and high reaction yields are
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demonstrated and the preliminary photophysical properties of
selected compounds are studied.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
PR is thankful to the CSIR for the fellowship; AIA and NA
acknowledge the Researchers Supporting Project number
(RSP-2020/231), King Saud University, Riyadh, Saudi Arabia;
and SY is thankful to the School of Chemistry, University of
Hyderabad for facilities.
Notes and references
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