Atom-efficient and environment-friendly multicomponent synthesis of amidoalkyl naphthols catalyzed by P2O5

Article abstract of DOI:10.1016/j.tetlet.2009.10.055

An atom-efficient and environment-friendly approach for the synthesis of amidoalkyl naphthols (4a-x) via multicomponent one-pot reaction of 2-naphthol (1), aromatic aldehyde (2) and amide (3) catalyzed by P₂O₅ has been developed. The

Full text of DOI:10.1016/j.tetlet.2009.10.055

Tetrahedron Letters 50 (2009) 7220–7222
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Atom-efficient and environment-friendly multicomponent synthesis
of amidoalkyl naphthols catalyzed by P2O5
*
Ganesh Chandra Nandi, Subhasis Samai, Ram Kumar, M. S. Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An atom-efficient and environment-friendly approach for the synthesis of amidoalkyl naphthols (4a–x)
via multicomponent one-pot reaction of 2-naphthol (1), aromatic aldehyde (2) and amide (3) catalyzed
by P2O5 has been developed. The present approach offers several advantages such as reduced reaction
times, moderate temperature, higher yields, eco-friendly reaction condition, easy purification and eco-
nomic availability of the catalyst.
Received 17 September 2009
Revised 8 October 2009
Accepted 12 October 2009
Available online 29 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Amidoalkyl naphthols
P2O5
Solvent free one-pot synthesis
Moderate temperature
Multicomponent reactions (MCRs) have been proven to be a
very elegant and rapid way to access complex structures in a single
synthetic operation from simple building blocks, and show high
atom-economy, high selectivity and procedural simplicity due to
the formation of carbon–carbon and carbon–heteroatom bonds in
one-pot.1 As a one-pot reaction, MCRs generally afford good yields
and are fundamentally different from the two-component reac-
tions in several aspects2 and permitted rapid access to combinato-
rial libraries of organic molecules for an efficient lead structure
identification and optimization in drug discovery.3 In addition,
the implementation of several transformations in a single manipu-
lation is highly compatible with the goals of sustainable and green
chemistry.4
Compounds having 1,3-amino-oxygenated functional groups are
present in variety of biologically important natural products and
potent drugs including a number of nucleoside antibiotics and HIV
protease inhibitors, such as ritonavir and lipinavir.5 Moreover,
1-amidoalkyl naphthol can be easily hydrolyzed to 1-aminoalkyl
naphthol, which shows biological activities like hypotensive and
bradycardiac effect.6 This1-aminoalkylalcohol-typeligandhasbeen
used for asymmetric synthesis and also as a catalyst.7 Several alter-
native and efficient methods have been developed for the synthesis
of amidoalkyl naphthols by multicomponent reaction of 2-naphthol,
aldehyde and amide in the presence of different acid catalysts such
as montmorillonite K10 clay,8 Ce(SO4)2,9 iodine,10 K5CoW12-
O40Á3H2O,11 p-TSA,12 sulfamic acid,13 HClO4–SiO2,14 molten tetrae-
thylammonium chloride,15 silica sulfuric acid,16 cation-exchanged
resins,17 Al(H2PO4)3,18a Fe(HSO4)3,18b Yb(OTf)3,18c wet cyanuric
chloride,18d,e polymer-supported sulfonic acid18f and FeCl3–SiO2.18g
Hajipour et al.19 have reported the synthesis of amidoalkyl naphthol
in ionic liquid at higher temperature (120 °C). However, some of
these protocols suffer from certain drawbacks such as prolonged
reaction time, use of dichloromethane like carcinogenic solvent,
unsatisfactory yield, high temperature (120–125 °C) and use of
toxic, highly acidic and expensive catalysts. Therefore, introducing
a clean procedure by the use of green and more eco-friendly catalyst
(P2O5) with high catalytic activity, moderate temperature and short
reactiontimeaccompaniedwith excellentyieldfor theproductionof
1-amidoalkyl-2-naphthols is needed. Phosphorous pentoxide has
earlier been widely used for various organic transformations such
as Beckmann rearrangement,20 olefin dimerization,21 tetrahydro-
pyranylation of alcohols22 and formation of 1,1-diacetate.23
Recently we have reported the reaction of 2-naphthol, aldehyde
and active methylene compound such as dimedone or 1,3-dimethyl-
barbituric acid in the presence of catalyst P2O5 or Indium chloride for
the formation of benzoxanthene-11-one or benzoanthracene-9,11-
dione under solvent-free condition.24 The reaction proceeds through
the in situ formation of ortho-quinone methide intermediate,25
a
highly reactive and ephemeral intermediate that has been exten-
sively harnessed by nature. We have now extended our work with
the ortho-quinone methide intermediate (o-QM) using amide as
nucleophile for the synthesis of amidoalkyl naphthols.
Herein, we are reporting the multicomponent reaction of
2-naphthol, aldehyde and amide using P2O5 as catalyst at 60 °C
for the preparation of amidoalkyl naphthols in excellent yield
* Corresponding author. Tel.: +91 542 6702502; fax: +91 542 2368127/9951.
E-mail address: mssinghbhu@yahoo.co.in (M.S. Singh).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.055

G. C. Nandi et al. / Tetrahedron Letters 50 (2009) 7220–7222
R1
7221
version time. So, 10 mol % of catalyst was found to be the optimal
quantity and sufficient to push the reaction forward. To explore the
generality of the reaction, we extended our study using P2O5
(10 mol %) as catalyst under solvent-free condition at 60 °C with
different aromatic aldehydes to prepare a series of amidoalkyl
naphthols26 (4a–x, Table 2). It was found that the use of 1.2 equiv of
amide, instead of 1.0 equiv provides a better yield. Various aromatic
aldehydes containing electron-withdrawing and electron-donating
substituent at ortho, meta or para-positions show equal ease towards
the product formation in high yields. The scope of the reaction was
CHO
O
OH
P2O5
O
H2N
R2
+
+
N
H
OH
R2
Solvent-free
60 oC
R1
1
3
2
4a-x
Scheme 1. Synthesis of amidoalkyl naphthols.
also investigated with aliphatic aldehydes and
aldehydes.Allourattemptswithaliphaticaldehydessuchasacetalde-
hyde, butyraldehyde, isobutyraldehyde and ,b-unsaturated alde-
a,b-unsaturated
Table 1
Comparison of P2O5 with other catalysts for the synthesis of N- [(2-hydroxynaphth-
alen-1-yl) (3-nitrophenyl)-methyl]acetamide
a
hydes such as cinnamaldehyde and crotonaldehyde failed to yield
the corresponding amidoalkyl naphthols.
Entry
Catalyst
Time
Yield (%)
Temp (°C)
Ref
1
2
3
4
5
6
7
8
9
Fe(HSO4)3
25 min
30 min
3 h
97
96
78
81
95
93
92
63
76
55
97
92
85
125
125
125
125
125
110
40
50
60
60
60
18b
8
In order to show the accessibility of the present work we have
summarized some of the literature results for the preparation of N-
[(2-hydroxynaphthalen-1-yl)(3-nitro-phenyl)-methyl]acetamide in
Table 1, which shows that P2O5 is the better catalyst with respect to
reaction time and temperature than the reported ones. Encouraged
by the successful reaction of aldehydes, 2-naphthol and acetamide
under solvent-free condition to give amidoalkyl naphthols (Scheme
1), next we replaced acetamide with benzamide and 2-chloroacet-
amidewherethe results weresatisfactory. The mainadvantage ofthis
procedure is the simple work-up, that is, the catalyst and the excess
amide were simply washed away with hot water and the residue
was crystallized from ethanol to give the pure product.
Montmorillonite K10
K5CoW12O40Á3H2O
Iodine
HClO4.SiO2
Al(H2PO4)3
Cation exchange resin
P2O5 (10 mol %)
P2O5 (10 mol %)
P2O5 (5 mol %)
P2O5 (10 mol %)
P2O5 (15 mol %)
11
10
14
18a
17
—
—
—
—
—
5 h
30 min
17 min
15 min
8 h
20 min
55 min
5 min
7 min
10
11
12
(Scheme 1). There are no reports on the use of P2O5 as catalyst in
the synthesis of 1-amidoalkyl-2-naphthols. It has various advanta-
ges due to its low toxicity, low price, ease of handling and experi-
mental simplicity.
A mechanistic rationale portraying the probable sequence of
events is given in Scheme 2. We supposed that the reaction may
proceed via the ortho-quinone methides intermediate,25 which
was formed by the nucleophilic addition of 2-naphthol to aldehyde
catalyzed by P2O5. Subsequent Michael addition of the o-QM with
the amide afforded the expected amidoalkyl naphthol. The P2O5 is
supposed to act as water scavenger, which assists the reaction.
In conclusion we have developed an atom-efficient and envi-
ronment-friendly multicomponent protocol for the synthesis of
amidoalkyl naphthols.26 The remarkable catalytic activity of P2O5
is superior to the other reported catalytic methods with respect
to shorter reaction times, moderate temperature (60 °C), and the
pure products were obtained by simple crystallization from etha-
nol. The higher yields, mild reaction condition, easy purification
A test reaction using 2-naphthol, 3-nitrobenzaldehyde and acet-
amide at 60 °C without catalyst was performed in order to establish
the real effectiveness of the catalyst. It was found that no conversion
to product was obtained even after 2.5 h of heating. In order to
evaluate the appropriate catalyst loading, a model reaction using
2-naphthol, 3-nitrobenzaldehyde and acetamide was carried out
using 5 mol %, 10 mol % and 15 mol % of P2O5 at 60 °C without solvent
(Table 1, entries 10–12). It was found that 10 mol % of catalyst shows
maximum yield in minimum time. Higher percentage of loading of
the catalyst (15 mol %) neither increases the yield nor lowers the con-
Table 2
P2O5-catalyzed synthesis of amidoalkyl naphthols
Entry
R1
R2
Product
Time (min)
Yield (%)
Mp (lit. mp)[ref]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-NO2
3-NO2
2- NO2
4-Cl
–CH3
–CH3
–CH3
–CH3
–CH3
-CH3
–CH3
–CH3
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–CH2Cl
–CH2Cl
–CH2Cl
–CH2Cl
–CH2Cl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
5
5
7
5
6
5
7
5
10
8
15
10
15
10
15
10
15
10
10
10
10
10
10
10
96
97
95
96
94
95
94
92
88
89
85
90
84
88
86
85
88
85
84
85
85
80
81
84
237–238 (248–250)14a
256–258 (241–242)14a
218–219 (180–182)14a
237–238 (230–231)14b
206–207 (213–215)18b
163–164 (183–185)18b
241–242 —
2-Cl
4-OMe
2-OMe
4-Me
4-NO2
3-NO2
2-NO2
4-Cl
224–225 (222–223)14a
228–229 —
242–243 (240–242)18e
266–267 —
168–170 (168–170)14b
284–285 —
2-Cl
4-OMe
2-OMe
H
2,4-Cl2
4-NMe2
4-Me
4-NO2
4-Cl
206–208 —
266–267 —
238–240 (233–235)18a
262–263 —
220–221 —
4s
4t
4u
4v
4w
4x
214–215 (215–216)18e
217–218 —
198–199 —
174–175 —
173–174 —
206–207 —
4-Me
4-OMe
H

7222
G. C. Nandi et al. / Tetrahedron Letters 50 (2009) 7220–7222
O
R1
O
H2N
R2
R1
R1
OH
H
H
R1
O
O
OH
O
P2O5
R2
N
H
OH
o-QMs
Scheme 2. Tentative mechanism showing the formation of amidoalkyl naphthol.
7. Hulst, R.; Heres, H.; Peper, N. C. M. W.; Kellogg, R. M. Tetrahedron: Asymmetry
1996, 7, 1373; (b) Li, X.; Yeung, C.-H.; Chan, A. S. C.; Yang, T.-K. Tetrahedron:
Asymmetry 1999, 10, 759.
8. Kantevari, S.; Vuppalapati, S. V. N.; Nagarapu, L. Catal. Commun. 2007, 8, 1857.
9. Selvam, N. P.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 7481.
10. (a) Das, B.; Laxminarayana, K.; Ravikanth, B.; Rao, B. R. J. Mol. Catal. A: Chem.
2007, 261, 180; (b) Nagawade, R. R.; Shinde, D. B. Mendeleev Commun. 2007, 17,
299.
and economic availability of the catalyst make the eco-friendly
procedure an attractive alternative to the existing methods for
the synthesis of amidoalkyl naphthols. Further applications of
P2O5 and o-QM intermediate on the extension of this protocol
are ongoing in our group.
11. Nagarapu, L.; Baseeruddin, M.; Apuri, S.; Kantevari, S. Catal. Commun. 2007, 8,
1729.
Acknowledgement
12. Khodaei, M. M.; Khosropour, A. R.; Moghanian, H. Synlett 2006, 916.
13. Patil, S. B.; Singh, P. R.; Surpur, M. P.; Samant, S. D. Ultrason. Sonochem. 2007, 14,
515.
14. (a) Shaterion, H. R.; Yarahmadi, H.; Ghashang, M. Tetrahedron 2008, 64, 1263;
(b) Mahdavinia, G. H.; Bigdeli, M. A.; Heravi, M. M. Chin. Chem. Lett. 2008, 19,
1171.
15. Dorehgiraee, A.; Khabazzadeh, H.; Saidi, K. Arkivoc 2009, 303.
16. Srihari, G.; Nagaraju, M.; Murthy, M. M. Helv. Chim. Acta 2007, 90, 1497.
17. Patil, S. B.; Singh, P. R.; Surpur, M. P.; Samant, S. D. Synth. Commun. 2007, 37,
1659.
18. (a) Shaterian, H. R.; Amirzadeh, A.; Khorami, F.; Ghashang, M. Synth. Commun.
2008, 38, 2983; (b) Shaterian, H. R.; Yarahmadi, H.; Ghashang, M. Bioorg. Med.
Chem. Lett. 2008, 18, 788; (c) Kumar, A.; Rao, M. S.; Ahmad, I.; Khungar, B. Can. J.
Chem. 2009, 87, 714; (d) Mahdavinia, G. H.; Bigdeli, M. A. Chin. Chem. Lett. 2009,
20, 383; (e) Zhang, P.; Zhan-Hui Zhang, Z.-H. Monatsh. Chem. 2009, 140, 199; (f)
An, L.-T.; Lu, X.-H.; Ding, X.-Q.; Jiang, W.-Q.; Zou, J.-P. Chin. J. Chem. 2008, 26,
2117; (g) Shaterian, H. R.; Yarahmadi, H. Tetrahedron Lett. 2008, 49, 1297.
19. Hajipour, A. R.; Ghayeb, Y.; Sheikhan, N.; Ruoho, A. E. Tetrahedron Lett. 2009, 50,
5649.
20. Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron Lett. 2001, 42, 8441.
21. Hamamatsu, T.; Kimura, N.; Takashima, T.; Morikita, T. Patent USPTO Appln.
No. 20090099400—Class: 585529.
22. Eshghi, H.; Shafieyoon, P. Phosphorous, Sulfur Silicon Relat. Elem. 2004, 179,
2149.
23. Eshghi, H.; Gordi, Z. Phosphorous, Sulfur Silicon Relat. Elem. 2004, 179, 1341.
24. Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron 2009, 34, 7129.
25. Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367.
26. General procedure for the synthesis of amidoalkylnaphthol: To a nicely ground
mixture of 2-naphthol (1.0 mmol), aldehyde (1.0 mmol) and amide (1.2 mmol),
the catalyst P2O5 (10 mol %) was added and the reaction mixture was heated at
60 °C for the stipulated period of time. Completion of the reaction was checked
by TLC. Hot water was added to the reaction mixture to remove the unreacted
amide and catalyst. The crude product obtained was crystallized from ethanol
to give the pure compound.
S.S. and G.C.N. are thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for senior research
fellowship.
References and notes
1. (a) Ugi, I. Pure Appl. Chem. 2001, 73, 187. and references cited therein; (b) Devi, I.;
Bhuyan, P. J. Tetrahedron Lett. 2004, 45, 8625; (c)For a monograph, see: Zhu, J.,
Bienayme, H., Eds.Multicomponent Reactions; Wiley-VCH,: Weinheim,
Germany, 2005; (d) Domling, A. Chem. Rev. 2006, 106, 17–89; (e) D’Souza, D.
M.; Mueller, T. J. J. Chem. Soc. Rev. 2007, 36, 3169; (f) Cariou, C. C. A.; Clarkson, G. J.;
Shipman, M. J. Org. Chem. 2008, 73, 9762; (g) Alizadeh, A.; Mobahedi, F.; Esmaili,
A. Tetrahedron Lett. 2006, 47, 4469; (h) Umkeherer, M.; Kalinski, C.; Kolb, J.;
Burdack, C. Tetrahedron Lett. 2006, 47, 2391; (i) Domling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168; (j) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602; (k) Tejedor, D.; Garcia-Tellado, F. Chem. Soc. Rev. 2007, 36, 484.
2. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123; (b) Tietze, L. F. Chem. Rev. 1996, 96, 115; (c)
Weber, L.; Illegen, K.; Almstetter, M. Synlett 1999, 366.
3. (a) Weber, L. Drug Discovery Today 2002, 7, 143; (b) Hulme, C.; Gore, V. Curr.
Med. Chem. 2003, 10, 51; (c) Tempest, P. A. Curr. Opin. Drug Discovery Dev. 2005,
8, 776; (d) Kalinski, C.; Lemoine, H.; Schmidt, J.; Burdack, C.; Kolb, J.; Umkehrer,
M.; Ross, G. Synlett 2008, 4007.
4. For reviews see: (a) Trost, B. M. Science 1991, 254, 1471; (b) Sheldon, R. A. Pure
Appl. Chem. 2000, 72, 1233.
5. (a) Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem. Commun. 1997, 2015; (b)
Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104,
6465; (c) Knapp, S. Chem. Rev. 1995, 95, 1859; (d) Juaristi, E. In Enantioselective
Synthesis of b-Aminoacids; John Wiley & Sons: New York, 1997.
6. (a) Dingermann, T.; Steinhilber, D.; Folkers, G. In Molecular Biology in Medicinal
Chemistry; Wiley-VCH, 2004; (b) Shen, A. Y.; Tsai, C. T.; Chen, C. L. Eur. J. Med.
Chem. 1999, 34, 877;(c) Shen, A. Y.; Chen, C. L.; Lin, C. I. Chin. J. Physiol. 1992, 35, 45.