2021, D0ob02276d
2021, D0ob02276d
Biomolecular Chemistry
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We have developed a one-pot, three-component, and solvent-free reaction for the synthesis of 3-amino-
Received 16th November 2020, furans using a calcium catalyst. In this cascade reaction, the key intermediate, C,N-diacyliminium ion, is
Accepted 22nd December 2020
formed in situ from glyoxal and lactam, which further reacted with phenolic nucleophiles to form furan
DOI: 10.1039/d0ob02276d derivatives in good yields with broad substrate diversity. We also present here the preliminary photo-
rsc.li/obc physical studies of selected compounds.
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 water (entry 5). Surprisingly, no reaction was observed in
water, and other solvents did not yield more than 50% of 4a.
Recently, we have trapped in situ formed C-acylimines with When we switched to solvent-free conditions, gratifyingly, the
naphthols;10 hence we used the same conditions by reacting reaction yielded 85% of the product 4a in four hours (entry 6).
phenylglyoxal (1a), aniline and 2-naphthol (3a) using a Neither an increase nor a decrease of the reaction temperature
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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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Scheme 2 Annulation of 1 and 2a with phenol 5. Scheme 3 Annulation of C,N-diacyliminium with 4-hydroxycoumarin.
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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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as phenols, naphthols, fluorenols, and 4-hydroxycoumarin, 3 (a) M. W. Khan, M. J. Alam, M. A. Rashid and
were successfully subjected to annulation with in situ formed R. Chowdhury, Bioorg. Med. Chem., 2005, 13, 4796;
C,N-diacyliminium ions. We also demonstrated that not only (b) N. Zanatta, S. H. Alves, H. S. Coelho, D. M. Borchhardt,
the arylgylyoxals but also the alkylglyoxal could participate in P. Machado, K. M. Flores, F. M. Silva, T. B. Spader,
this reaction. The substrate scope and high reaction yields are J. M. Santurio, H. G. Bonacorso and M. A. P. Martins,
Published on 08 January 2021. Downloaded by Insytut Chemii Organicznej Pan Bibilioteka on 9/19/2023 10:11:34 AM.
demonstrated and the preliminary photophysical properties of Bioorg. Med. Chem., 2007, 15, 1947.
selected compounds are studied. 4 (a) D. J. Kerr, E. Hamel, M. K. Jung and B. L. Flynn, Bioorg.
Med. Chem., 2007, 15, 3290; (b) R. R. Rao, V. Chaturvedi,
K. S. Babu, P. P. Reddy, V. R. S. Rao, P. Sreekanth,
Conflicts of interest A. S. Sreedhar and J. M. Rao, Med. Chem. Res., 2012, 21,
634.
There are no conflicts to declare. 5 R. L. Guevel, F. Oger, A. Lecorgne, Z. Dudasova,
S. Chevance, A. Bondon, P. Barath, G. Simonneaux and
G. Salbert, Bioorg. Med. Chem., 2009, 17, 7021.
Acknowledgements 6 (a) X. L. Hou, H. Y. Cheung, T. Y. Hon, P. L. Kwan,
PR is thankful to the CSIR for the fellowship; AIA and NA T. H. Lo, S. Y. Tong and H. N. C. Wong, Tetrahedron,
acknowledge the Researchers Supporting Project number 1998, 54, 1955; (b) B. A. Keay, Chem. Soc. Rev., 1999, 28,
(RSP-2020/231), King Saud University, Riyadh, Saudi Arabia; 209; (c) A. Jeevanandam, A. Ghule and Y.-C. Ling, Curr.
and SY is thankful to the School of Chemistry, University of Org. Chem., 2002, 6, 841; (d) X. L. Hou, Z. Yang and
Hyderabad for facilities. H. N. C. Wong, Progress in Heterocyclic Chemistry, ed.
G. W. Gribble and T. L. Gilchrist, Pergamon Press,
Oxford, 2003, vol. 15, p. 167; (e) R. C. D. Brown, Angew.
Notes and references Chem., Int. Ed., 2005, 44, 850; (f ) S. F. Kirsch, Org.
Biomol. Chem., 2006, 4, 2076; (g) S. F. Kirsch, Org. Biomol.
1 (a) B. H. Lipshutz, Chem. Rev., 1986, 86, 795; (b) H. Heaney Chem., 2006, 4, 2076; (h) D. M. D′Souza and
and J. S. Ahn, Comprehensive Heterocyclic Chemistry II, ed. T. J. J. Mueller, Chem. Soc. Rev., 2007, 36, 1095;
A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Elsevier, (i) N. T. Patil and Y. Yamamoto, ARKIVOC, 2007, x, 121;
Oxford, 1996, vol. 2, p. 297; (c) W. Friedrichsen, ( j) G. Balme, D. Bouyssi and N. Monteiro, Heterocycles,
Comprehensive Heterocyclic Chemistry II, ed. A. R. Katritzky, 2007, 73, 87.
C. W. Rees and E. F. V. Scriven, Elsevier, Oxford, 1996, vol. 7 (a) A. A. A. Hashem, H. A. R. Hussein, A. S. Aly and
2, p. 351; (d) H. N. C. Wong, P. Yu and C.-Y. Yick, Pure Appl. M. A. Gouda, Synth. Commun., 2014, 44, 2285; (b) A. Blanc,
Chem., 1999, 71, 1041; (e) H.-K. Lee, K. F. Chan, C.-W. Hui, V. Bénéteau, J. M. Weibel and P. Pale, Org. Biomol. Chem.,
H.-K. Yim, X.-W. Wu and H. N. C. Wong, Pure Appl. Chem., 2016, 14, 9184; (c) D. X. Duc, Mini-Rev. Org. Chem., 2019,
2005, 77, 1393; (f) V. Cadierno, J. Dıez, J. Gimeno and 16, 422.
N. Nebra, J. Org. Chem., 2008, 73, 5852; (g) M. E. Welsch, 8 (a) T. Kumar, S. M. Mobin and I. N. N. Namboothiri,
S. A. Snydar and B. R. Stockwell, Curr. Opin. Chem. Biol., Tetrahedron, 2013, 69, 4964; (b) M. L. N. Rao and
2010, 14, 347; (h) H. Khanam and Shamsuzzaman, V. N. Murty, Eur. J. Org. Chem., 2016, 2177.
Eur. J. Med. Chem., 2015, 97, 483. 9 (a) S. Yaragorla, R. Dada, A. Pareek and G. Singh, RSC Adv.,
2 (a) G. Schulte, P. J. Schener and O. McConnel, Helv. Chim. 2016, 6, 28865; (b) A. Pareek, R. Dada, M. Rana,
Acta, 1980, 63, 2159; (b) H. Wagner and B. Fessler, Planta A. K. Sharma and S. Yaragorla, RSC Adv., 2016, 6, 89732;
Med., 1986, 52, 374; (c) R. J. Salmon, J. P. Buisson, (c) S. Yaragorla, R. Dada, G. Singh, A. Pareek, M. Rana and
B. Zafrani, L. Aussepe and R. Royer, Carcinogenesis, 1986, 7, A. K. Sharma, ChemistrySelect, 2016, 1, 6902;
1447; (d) P. A. Jacobi and H. G. Selnick, J. Org. Chem., 1990, (d) S. Yaragorla and P. Rajesh, Org. Biomol. Chem., 2019, 17,
55, 202; (e) J. Lee, J.-H. Li, S. Oya and J. K. Snyder, J. Org. 1924.
Chem., 1992, 57, 5301; (f ) K. Kobayashi, H. Shimizu, 10 J. Vannada, M. Sulthan, D. Arun, R. Dada and S. Yaragorla,
A. Sasaki and H. Suginome, J. Org. Chem., 1992, 57, 1170; J. Org. Chem., 2020, 85, 6697.
(g) A. F. Furstner and H. Weintritt, J. Am. Chem. Soc., 1998, 11 V. N. Babu, A. Murugan, N. Katta, S. Devatha and
120, 2817; (h) P. P. Gupta, R. C. Srimal, N. Verma and D. S. Sharada, J. Org. Chem., 2019, 84, 6631.
J. S. Tandon, Pharm. Biol., 1999, 37, 46; (i) J. Ito, Y. Takaya, 12 See for reviews on calcium-catalysis. (a) S. Harder, Chem.
Y. Oshima and M. Niwa, Tetrahedron, 1999, 55, 2529; Rev., 2010, 110, 3852; (b) S. Kobayashi and Y. Yamashita,
( j) A. F. Furstner, K. Reinecke and H. H. Waldmann, Acc. Chem. Res., 2011, 44, 58; (c) J. M. Begouin and
ChemBioChem, 2004, 5, 1575; (k) L. Chiummiento, M. Niggemann, Chem. – Eur. J., 2013, 19, 8030;
M. Funicello, M. T. Lopardo, P. Lupattelli, S. Choppin and (d) D. Leboeuf and V. Gandon, Synthesis, 2017, 49, 1500;
F. Colobert, Eur. J. Org. Chem., 2012, 188; (l) M. M. Heravi, (e) Y. Sun, M. Hu, S. Fu and B. Liu, Org. Biomol. Chem.,
V. Zadsirjan, H. Hamidi and P. H. T. Amiri, RSC Adv., 2017, 2020, 18, 6443.
7, 24470. 13 See the ESI† for details.
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14 (a) S. Yaragorla, P. Rajesh, A. Pareek and A. Kumar, Adv. 15 (a) L. F. Yao, D. Tan, Xi. Miao and K. W. Huang, RSC Adv.,
Synth. Catal., 2018, 360, 4422; (b) S. Yaragorla and 2012, 2, 7594; (b) S. Yaragorla and P. Rajesh, Eur. J. Org.
P. Rajesh, Eur. J. Org. Chem., 2020, 7243. Chem., 2019, 5740.
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