Synthesis of novel 1,4 naphthoquinone-based molecules by an Ugi-type four-component reaction

Article abstract of DOI:10.1080/00397911.2018.1551548

In an attempt to further exploit multicomponent reactions in the field of 1,4 naphthoquinone-based compounds, we describe an Ugi-type multicomponent approach for the synthesis of novel 3-substituted 1,4 naphthoquinone molecules. The process relies on the

Full text of DOI:10.1080/00397911.2018.1551548

Synthetic Communications
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Synthesis of novel 1,4 naphthoquinone-based
molecules by an Ugi-type four-component reaction
Waléria F. Rabêlo & Radell Echemendía
To cite this article: Waléria F. Rabêlo & Radell Echemendía (2019) Synthesis of novel
1,4 naphthoquinone-based molecules by an Ugi-type four-component reaction, Synthetic
Communications, 49:4, 515-521, DOI: 10.1080/00397911.2018.1551548
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SYNTHETIC COMMUNICATIONSV
2019, VOL. 49, NO. 4, 515–521
https://doi.org/10.1080/00397911.2018.1551548
Synthesis of novel 1,4 naphthoquinone-based molecules by
an Ugi-type four-component reaction
a
a,b
ꢀ
^
ꢀ
Waleria F. Rabelo and Radell Echemendıa
a
~
~
~
Department of Chemistry, Federal University of Sao Carlos – UFSCar, Sao Carlos, Sao Paulo, Brazil;
bCenter for Natural Products Research, Faculty of Chemistry, University of Havana, La Habana, Cuba
ABSTRACT
ARTICLE HISTORY
Received 30 August 2018
Accepted 19 November 2018
In an attempt to further exploit multicomponent reactions in the
field of 1,4 naphthoquinone-based compounds, we describe an
Ugi-type multicomponent approach for the synthesis of novel 3-sub-
stituted 1,4 naphthoquinone molecules. The process relies on the
execution of an enol-Ugi reaction between an enol-3-nitro-1,4 naph-
thoquinone with different secondary diamines and isocyanides. The
novel methodology showed great chemical efficiency and versatility.
KEYWORDS
Enols; isocyanide chemistry;
multicomponent reac-
tions; quinones
GRAPHICAL ABSTRACT
ꢀ
~
Department of Chemistry, Federal University of Sao Carlos
CONTACT Radell Echemendıa
rechemendia@fq.uh.cu
~
~
– UFSCar, Sao Carlos, Sao Paulo, 13565-905, Brazil
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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W. F. RABELO AND R. ECHEMENDIA
516
Introduction
The 1,4-naphthoquinone scaffolds have received considerable attention because of the
synthetic challenges associated with their interesting biological properties, such as their
[1]
[2]
antifungal,
antiviral,
and anti-inflammatory activities.[3] In this context, the devel-
opment of facile methods to access these new targets with structural diversity is very
desirable and valuable for drug discovery.
Multicomponent reactions (MCRs) enclose an exciting class of chemical transforma-
tions that have been successful in almost all fields of synthetic organic chemistry in the
pursuit of novel bioactive small molecules. Isocyanide based multicomponent reactions
(IMCR) gained significant interest within the scientific community as an efficient, con-
venient, time-saving, and atom-economical approach to rapidly generate chemi-
cal diversity.[4]
The Ugi four-component reaction (U-4CR) is a widely used IMCR for the synthesis
of peptidomimetics.[5] This multicomponent transformation usually refers to the reac-
tion between an amine (usually a primary amine; less often ammonia, or a secondary
amine), a carbonyl compound (aldehyde or ketone), an isocyanide, and a carboxylic
acid. Carboxylic isosteric replacements like carbonic acids,[6] thiocarboxylic acids,[7] iso-
cyanic acids,[8] phenol, thiophenol,[9] allenic acids[10] and N-hydroxyimides[11] were also
successfully used in the Ugi-type reaction. More recently, Marcos and coworkers
reported that enols containing a,b-unsaturated electron-withdrawing groups readily
react as a novel acid surrogate in the U-4CR.[12]
Herein we report the use of 2-hydroxy- 3 nitro-1,4-naphthoquinone as the acid com-
ponent in the Ugi- type for component reaction (UT-4CR). Similarly, we introduce this
multicomponent approach with symmetric secondary diamines which provide a remote
Mumm rearrangement.[13] This allows the straightforward synthesis of N-substituted
naphthoquinone enamines (Figure 1).
Initially, we began our studies by evaluating the reaction between 2-hydroxy-3-nitro-
1,4-naphthoquinone (1), paraformaldehyde as oxocomponent, 1,3-bis(methylamino)pro-
pane and t-butyl isonitrile in methanol as a solvent, which provided the desired product
2a in a 30% yield. Encouraged by this preliminary result, the screening of solvent, time,
as well as the influence of temperature was investigated to establish the optimized reac-
tion conditions (Table 1). Solvent effects were first investigated (Table 1, entries 1–4).
The polar protic solvents provided higher yields than aprotic ones (Table 1, compare
entries 1–4), and the best result was obtained with methanol (entry 1).
Figure 1. Synthesis of 1,4 naphthoquinones derivatives.

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Table 1. Optimization of enol UT-4CR for the synthesis of 2a.
Entrya
Solvent
Temp (ꢀC)
Time(h)
Yield (%)b
1
2
3
4
5
6
7
8
MeOH
EtOH
25
25
25
25
40
50
25
25
36
36
36
36
24
24
72
96
30
20
15
Trace
25
20
65
52
CH2Cl2
Toluene
MeOH
MeOH
MeOH
MeOH
aReaction performed with paraformaldehyde (1.0 equiv) and 1,3-bis(methylamino)propane (1.0 equiv) and, subsequently,
the addition of the enol component 1 (1.0 equiv) and tert-butyl isocyanide (1.0 equiv.). bYield of the isolated product
after column chromatography.
Scheme 1. Reaction scope for the N-substituted naphthoquinone enamines.
The effect of the reaction temperature was investigated; surprisingly, it was observed
that increasing the temperature did not reduce the reaction time and lower yields of
compound 2a were achieved (entries 5 and 6). To improve the yields, we then examined
the reaction time, it was discovered that 72 h of reaction time afforded the best yield
(entry 7); longer reaction times provided complex reaction mixtures. Thus, optimal con-
ditions are the use of methanol as a solvent for 72 h at room temperature.
Under optimal conditions, we widened the scope of the reaction into the achievement
of a novel family of naphthoquinone enamines. The Scheme 1 shows the versatility of
multicomponent reaction, which through the variation of the amino, oxo, and isonitrile
components; made possible the obtention of naphthoquinone derivatives with a wide
structural diversity on position 2 of this ring. In all cases, 2-hydroxy- 3 nitro-1,4-
naphthoquinone (1) was the acid isostere of the Ugi type reaction and reacted with

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W. F. RABELO AND R. ECHEMENDIA
518
Scheme 2. Proposed reaction mechanism.
the preformed imine and the isonitrile to render the Ugi products (2b–2o). Regarding
this, the synthesis was focused on the addition of symmetrical secondary diamines as
well as different isocyanides. Secondary diamines participate in an N-split Ugi type
four-component reaction as a replacement of primary amines.[14] In this transforma-
tion, one nitrogen atom was alkylated and the other was linked to the naphthoquinone
core.
As illustrated in Scheme 1, the methodology is suitable for a wide scope of amines
and isonitriles, including aliphatic (2b–2f), and aromatic (2k and 2l). The incorporation
of saccharidic (2j) and peptidic fragments (2o) was achieved using the corresponding
isocyanides, which were prepared as described previously.[15] Remarkably, the efficiency
of the reactions carried out with these complex isonitriles proved to be as high as those
performed with the simpler, commercially available isocyanides benzyl, cyclohexyl and
t-butyl isocyanides.
On the other hand, good yields were observed (45–62%) with the exceptions 2 h and
2i. Steric hindrance encouraged by the propanone could justify the modest yield in
these cases. All compounds were purified by flash column chromatography (n-hexane/
AcOEt) and were properly characterized by NMR and MS. The racemic mixtures of
compounds 2 m and 2n were also corroborated by chiral stationary phase HPLC (see
the Supporting information).
The possible reaction mechanism is shown in Scheme 2. The reaction commences
with an interaction between one nitrogen of the diamine and the aldehyde to give the
corresponding imine A. An a-addition of the imine and enolate give the primary adduct
B. The resulting primary intermediate may undergo a subsequent conjugate addition of
the second nitrogen atom of the diamine to the naphthoquinone as the first nitrogen
atom has already become a tertiary amine and is unable to receive this group.
In summary, we have implemented a multicomponent approach for the 2-substi-
tuted-1,4-naphthoquinone enamines formation. The process comprises the execution of

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an enol UT-4CR for the decoration of naphthoquinone ring. Also, the present method-
ology offers a versatile way for introducing higher molecular complexity on naphthoqui-
none ring.
Experimental
General methods
Reagents and materials were used as received from commercial sources without further
purification. Flash column chromatography was carried out using silica gel 60 (230–400
mesh) and analytical thin layer chromatography (TLC) was performed using Merck
silica gel 60 F254 aluminum sheets. Visualization of the compounds was achieved by
1
1
UV or KMnO4. H NMR and 13C NMR spectra were recorded at 400 MHz for H and
100 MHz for 13C, respectively. Chemical shifts (d) are reported in parts per million rela-
tives to the residual solvent signals, and coupling constants (J) are reported in Hertz.
High-resolution mass spectra (HRMS) were recorded using electron spray ionization
(ESI) (Hybrid linear ion trap-orbitrap FT-MS/MS – and QqTOF Microtof –
QII models).
2-Hydroxy-3-nitro-1,4-naphthoquinone (1)
To a suspension of 2-hydroxy-l,4-naphthoquinone (0.17 g, 1.00 mol) in dry acetonitrile
(15 mL) nitronium tetrafluoroborate (0.15 g, 1.15 mmol) was added under nitrogen
atmosphere. The resulting reaction mixture was stirred for 30 min during which the
light yellow suspension turned into a transparent yellow solution. The solvent was
evaporated followed by the addition of HCl (4 M, 50 mL). The resulting aqueous sus-
pension was extracted with ethyl ether (2 ꢁ 50 mL). The combined organic layers were
dried over MgSO4, filtered off, and evaporated to yield 1 (0.201 g, 92%) as a yellow
1
solid. H NMR (400 MHz, DMSO-d6) d ¼ 8.68 (brs, 1 H); 8.25–8.18 (m, 2 H); 7.95–7.82
(m, 2H). 13C NMR (100 MHz, DMSO-d6) d ¼ 184.2, 178.4, 161.9, 136.7, 135.4, 135.1,
134.2, 132.0, 131.1, 15.8.
General procedure for the multicomponent conjugation
A suspension of the diamine (0.50 mmol, 1 equiv.) and the carbonyl compound
(0.50 mmol, 1 equiv.) in MeOH (1 mL) was stirred for 8 h at room temperature. The 2-
hydroxy-3-nitro-1,4-naphthoquinone (0.50 mmol,
1
equiv.) and the isocyanide
(0.6 mmol, 1.2 equiv.) are then added and the reaction mixture is stirred at room tem-
perature for 72 h. The volatiles are concentrated under reduced pressure and the result-
ing crude product is dissolved in 30 mL of CHCl3. The organic phase is washed
sequentially with an aqueous saturated solution of citric acid (3 ꢁ 10 mL), aqueous 10%
NaHCO3 (3 ꢁ 10 mL), and brine (30 mL), and then dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product is purified by flash column
chromatography (n-hex/AcOEt) on silica to afford the corresponding compound.
Compound 2a: A suspension of 1,3-bis(methylamino)propane (63 lL, 0.5 mmol) par-
aformaldehyde (15 mg, 0.5 mmol) 2-hydroxy-3-nitro-1,4-naphthoquinone 1 (110 mg,

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W. F. RABELO AND R. ECHEMENDIA
520
0.5 mmol) and tert-butyl isocyanide (56 lL, 0.5 mmol) in MeOH (1 mL) were reacted
according to the general procedure A. Flash column chromatography purification (n-
hex/AcOEt 1:1) afforded compound 1a (135 mg, 65%) as an amorphous yellow solid;;
1H NMR (400 MHz, CDCl3) d ¼ 8.28–8.12 (m, 2 H); 7.89–7.67 (m, 2H); 6.08 (s, 1H);
4.01 (s, 2H); 3.38 (t, J ¼ 6.9 Hz, 2H); 2.90 (s, 3H); 2.51 (t, J ¼ 7.0 Hz, 2H); 2.39 (s, 3H);
2.04–1.92 (m, 2H); 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3) d ¼ 187.2, 183.4, 171.6,
147.8, 135.9, 135.0, 134.1, 133.2, 129.5, 127.2, 124.8, 59.6, 55.8, 52.9, 51.7, 42.4, 41.1,
29.1, 24.8. HRMS (ESI-FT-QQTOF) m/z: 417.2142 [M þ H]þ; calcd. for
C21H29N4O5: 417.2138.
Acknowledgments
~
We are grateful to the Federal University of Sao Carlos (UFSCar).
Funding
This work was supported by the CNPq under [Grant 141770/2015-5].
ORCID
ꢀ
Radell Echemendıa
http://orcid.org/0000-0001-5310-2068
References
ꢀ
ꢀ
[1] Leyva, E.; Lopez, L.; Cruz, R.; Espinosa-Gonzalez, C. G. Synthesis and Studies of the
Antifungal Activity of 2-Anilino-/2,3-Dianilino-/2-Phenoxy- and 2,3-Diphenoxy-1,4-
Naphthoquinones. Res. Chem. Intermediat. 2016, 43, 1813–1827. doi:10.1007/s11164-016-
2732-3
[2] Jin, Y. R.; Ryu, C. K.; Moon, C. K.; Cho, M. R.; Yun, Y. P. Inhibitory Effects of J78, a
Newly Synthesized 1,4-naphthoquinone Derivative, on Experimental Thrombosis and
Platelet Aggregation. Pharmacology. 2004, 70, 195–200. doi:10.1159/000075548.
[3] Sasaki, K.; Abe, H.; Yoshizaki, F. In Vitro Antifungal Activity of Naphthoquinone
Derivatives. Biol. Pharm. Bull. 2002, 25, 669–670. doi:10.1248/bpb.25.669.
[4] (a) Domling, A.; Ugi, I. Multicomponent Reactions with Isocyanides. Angew. Chem., Int.
Ed 2000, 39, 3168–3210. (b) Zhu, J. Recent Developments in the Isonitrile-based
Multicomponent Synthesis of Heterocycles. Eur. J. Org. Chem. 2003, 2003, 1133–1144. (c)
Domling, A. Recent Developments in Isocyanide Based Multicomponent Reactions in
Applied Chemistry. Chem. Rev 2006, 106, 17–89. (d) Akritopoulou-Zanze, I. Isocyanide-
based Multicomponent Reactions in Drug Discovery. Curr. Opin.Chem. Biol. 2008, 12,
324–331. doi:10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U
[5] Ugi, I.; Werner, B.; Domling, A. The Chemistry of Isocyanides, their Multicomponent
Reactions and Their Libraries. Molecules 2003, 8, 53–66. doi:10.3390/80100053.
€
[6] Ugi, I.; Steinbru€ckner, C. a-Addition Von Immonium-ionen Und Carbonsaure-anionen
an Isonitrile. Chem. Ber. 1961, 94, 2802. doi:10.1002/cber.19610941032.
€
[7] Heck, S.; Domling, A. A Versatile Multi-component One-pot Thiazole Synthesis. Synlett.
2000, 3, 424–426. doi:10.1055/s-2000-6517
€
[8] Ugi, I.; Rosendahl, F. K.; Bodesheim, F. Kondensation Von Primaren Aminen Und
€
Ketonen Mit Isonitrilen Und Rhodanwasserstoffsaure. Justus Liebigs Ann. Chem. 1963,
666, 54–61. doi:10.1002/jlac.19636660107.

R
SYNTHETIC COMMUNICATIONSV
521
[9] (a) Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R.; Polo, C. Studies on Isocyanides and
Related Compounds. Synthesis of Benzofuran Derivatives. Synthesis. 1991, 1991, 999–1000.
(b) El Kaim, L.; Grimaud, L. Beyond the Ugi Reaction: Less Conventional Interactions
between Isocyanides and Iminium Species. Tetrahedron. 2009, 65, 2153–2171. doi:10.1016/
j.tet.2008.12.002.
[10] Cheng, G.; He, X.; Tian, L.; Chen, J.; Li, C.; Jia, X.; Li, J. Ugi/Himbert Arene/Allene
Diels ꢂ Alder Cycloaddition to Synthesize Strained Polycyclic Skeleton. J. Org. Chem.
2015, 80, 11100–11107. doi:10.1021/acs.joc.5b01724
€
[11] Chandgude, A. L.; Domling, A. N-Hydroxyimide Ugi Reaction toward a-Hydrazino
Amides. Org. Lett. 2017, 19, 1228–1231. doi:10.1021/acs.orglett.7b00205
[12] (a) Neo, A. G.; Castellano, T. G.; Marcos, C. F. Enol-Ugi Reaction of Hydroxycoumarins:
straightforward Synthesis of Amino Acid Derived Coumarin Enamines. Synthesis. 2015,
47, 2431–2438. (b) Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Enols as
Feasible Acid Components in the Ugi Condensation. Org. Lett. 2012, 14, 6218–6221. (c).
Neo, A. G.; Marcos, C. F. Selective Synthesis of 3-substituted Pyrrolidinones by enol-
Passerini and Anomalous enol-Passerini Condensations. Org. Lett. 2018, 20, 3875–3878.
doi:10.1055/s-0034-1380436
[13] Tron, G. C. Off the Beaten Track: The Use of Secondary Amines in the Ugi Reaction.
Eur. J. Org. Chem. 2013, 2013, 1849–1859. doi:10.1002/ejoc.201201660
[14] Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I.; Pirali, T. A Mimicry of
Primary Amines by Bis-secondary Diamines as Components in the Ugi Four Component
Reaction. Angew. Chem. Int. Ed. 2006, 45, 1099–1102. doi:10.1002/anie.200503095.
ꢀ
^
[15] Echemendıa, R.; de la Torre, A. F.; Monteiro, J. L.; Pila, M.; Correa, A. G.; Westermann,
~
B.; Rivera, D. G.; Paixao, M. W. Highly Stereoselective Synthesis of Natural-product-like
Hybrids by an Organocatalytic/multicomponent Reaction Sequence. Angew. Chem. Int. Ed.
2015, 54, 7621–7625. doi:10.1002/anie.201412074.