An efficient, expeditious, and diastereoselective one-pot pseudo-five-component reaction for the synthesis of new bis-Betti bases under catalyst-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.04.037

A novel, diastereoselective, one-pot synthesis of new bis-Betti bases via condensation of dihydroxynaphthalene, two equivalents of aryl aldehydes, and two equivalents of 3-amino-5-methylisoxazole is reported. Conversion into the adducts was almost quantitative without the use of solvent or catalyst. The reaction conditions are very simple and enable easy isolation of the product.

Full text of DOI:10.1016/j.tetlet.2012.04.037

Tetrahedron Letters 53 (2012) 3086–3090
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An efficient, expeditious, and diastereoselective one-pot
pseudo-five-component reaction for the synthesis of new bis-Betti bases
under catalyst-free conditions
⇑
⇑
Mehdi Shafiee, Ahmad R. Khosropour , Iraj Mohammadpoor-Baltork , Majid Moghadam,
Shahram Tangestaninejad, Valiollah Mirkhani
Catalysis Division, Department of Chemistry, Faculty of Science, University of Isfahan, Isfahan 81746-7344, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, diastereoselective, one-pot synthesis of new bis-Betti bases via condensation of dihydroxynaph-
thalene, two equivalents of aryl aldehydes, and two equivalents of 3-amino-5-methylisoxazole is
reported. Conversion into the adducts was almost quantitative without the use of solvent or catalyst.
The reaction conditions are very simple and enable easy isolation of the product.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 January 2012
Revised 29 March 2012
Accepted 5 April 2012
Available online 16 April 2012
Keywords:
Bis-Betti base
Condensation
Multi-component reaction
Aldehydes
3-Amino-5-methylisoxazole
Dihydroxynaphthalene
One-pot multi-component reactions are effective processes for
the discovery of new reactions and the synthesis of complex struc-
tures.1 They enable rapid access to large compound libraries with
diverse functionalities, and avoid costly purification processes in
addition to protection and deprotection steps by systematic varia-
tion of the starting material which is either commercially available
or is easily prepared.2
One of the classic multi-component reactions is the synthesis of
Betti bases.3 The typical Betti reaction is a three-component reac-
tion between an aldehyde, ammonia/urea, and b-naphthol.4 Sev-
eral studies have centered on the catalysis of this reaction, using
different bases or metal salts.5 The Betti reaction represents a
useful method to obtain amidoalkyl naphthols.3 These are
very important precursors for the synthesis of bioactive 1-
aminomethyl-2-naphthols, the bradycardiac and hypotensive
effects of which have been evaluated in humans.6 Moreover, they
are attractive compounds as chiral ligands in enantioselective
reactions.7 They can be used as chiral shift reagents for carboxylic
Thus, new hybrid moieties secured by introducing 5-methylis-
oxazole into Betti bases, promise to offer fascinating scaffolds.
In continuation of our work on one-pot multi-component
reactions,10 we embarked on the synthesis of novel bis-Betti bases
possessing 2-amino-5-methylisoxazole, arene, and dihydroxy
naphthalene moieties embedded in a fused molecular framework
via a pseudo-five-component reaction under catalyst-free condi-
tions (Scheme 1).11
Initially, we investigated the one-pot condensation reaction of
2-chlorobenzaldehyde
(2 mmol),
5-amino-3-methylisoxazole
(2 mmol), and 2,3-dihydroxynaphthalene (1 mmol) to give diaste-
reoisomer 3b, as a model system to study the solvent and temper-
ature effects (Table 1).
The stereochemistry of 3b was unambiguously assigned by X-
ray crystallography (CCDC 849432) (Fig. 1). Interestingly, it was
found that this transformation produced ( )-3b selectively.
The reaction was carried out in a range of solvents, including
water, ethanol, PEG-400, acetonitrile, and toluene for a period of
3 h at 80 °C. However, the best result was obtained at 80 °C under
solvent-free conditions (Table 1, entry 6). The results subsequently
showed that the temperature appeared to be crucial as the reaction
did not take place even after stirring for 24 h at room temperature
(Table 1, entry 7). Running the reaction for 3 h at 50–70 °C did not
result in any increase in the yield (Table 1, entries 8–10). Further-
more, no remarkable differences in the diastereoselectivity were
apparent in this temperature range.
acids or as chiral auxiliaries for the synthesis of
a-aminophos-
phonic acids.8 Furthermore, isoxazole derivatives, especially 5-
methylisoxazole represent an interesting class of heterocycles
possessing a wide spectrum of biological activity.9,10
⇑
Corresponding authors. Tel./fax: +98 311 668 9732.
E-mail addresses: khosropour@chem.ui.ac.ir (A.R. Khosropour), imbaltor@sci.
ui.ac.ir (I. Mohammadpoor-Baltork).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.037

M. Shafiee et al. / Tetrahedron Letters 53 (2012) 3086–3090
3087
Figure 1. ORTEP view of compound 3b.
O
N
HO
OH
Ar
O
NH
OH
N
H
N
Ar
OH
H
Ar
N
N
2
O
O
HN
Ar
N
H2N
R3
R2
OH
R1
R2=R3=H
R1= OH
+
N
O
- 4
R1=R3=H
R2= OH
(
)
-
+
(
)-3
-
+
+
2 ArCHO
O
N
2
HO
Ar
1
NH
O
OH
N
N
H
Ar
OH
H
Ar
N
N
O
Ar
3'
HN
OH
N
O
4'
Scheme 1. Synthesis of new bis-Betti bases.
We found that performing the reaction at 80 °C under solvent-
free conditions provided the best result. The reaction was rapid,
and achieved satisfactory conversion without any significant side
reactions.
Next, we considered the introduction of additional diversity to
this new class of Betti bases via the one-pot reaction. We examined
several aryl aldehydes for the synthesis of Betti bases based on 2,6-
or 2,3-dihydroxynaphthalene (Table 2). It is worthwhile to note
that compounds 3 and 4 were obtained as the major products in
racemic form for all the reactions examined in Table 2.
times (Table 2, compare entries 4 and 5). Moreover, this reaction
worked well with heteroaromatic carbaldehydes such as thio-
phene-2-carbaldehyde (Table 2, entry 14). Identification of the
structures of the products was achieved by spectral analysis.12
This simple, straightforward, and atom-economic method rep-
resents an advantageous alternative to the laborious syntheses of
this class of Betti bases. Thus, the reaction developed represents
a short and expedient route to a family of Betti bases for the design
of metal complex catalysts, and building blocks for organic
synthesis.
It was generally observed that high to excellent yields of the
products were obtained with moderate to excellent diastereoselec-
tivity in all cases (Table 2). The stereochemistry of compounds 3a–
e and 4a–i was established by correlation of the spectroscopic data
with those obtained for 3b. Also, it was found that aryl aldehydes
possessing electron-withdrawing groups could be converted into
the desired products in higher isolated yields and shorter reaction
Also, it was found that under the above reaction conditions, 2,7-
dihydroxynaphthalene gave the corresponding mono-Betti base,
exclusively (Table 3), which can be attributed to the steric hin-
drance which would be present in the corresponding bis-Betti
base.
In conclusion, we have described a novel and efficient strategy
for the diastereoselective synthesis of new bis-Betti bases. To our

3088
M. Shafiee et al. / Tetrahedron Letters 53 (2012) 3086–3090
Table 1
The effect of solvent and temperature on the yield of 3ba
O
O
N
N
O
N
2
CH3
HO
OH
HN
NH
H2N
Cl
Cl
OH
OH
CHO
Cl
+
solvent
2
Solventb
Temp (°C)
Yieldc (%)
3b
Entry
1
2
3
4
5
6
7
8
9
H2O
EtOH
PEG-400
CH3CN
80
80
80
80
80
80
25
50
60
70
90
60
13
9
10
50
90
—
17
33
59
91
Toluene
—
—
—
—
—
—
10
11
a
b
c
Reaction conditions: 2-Chlorobenzaldehyde (2 mmol), 5-amino-3-methylisoxazole (2 mmol), 2,3-dihydroxynaphthalene (1 mmol), 2.5 h.
2 ml of solvent.
Isolated yield.
Table 2
Synthesis of novel bis-Betti bases via a pseudo-five-component reaction under catalyst-free conditions
Entry
Ar
R1
R2
R3
Product
Time (h)
Yielda (%)
d.r.b
N
O
HO
OH
HN
N
3a
O
NH
1
4-ClC6H4
OH
H
H
2
95
91:9
Cl
Cl
N
+
-
(
)
O
N
O
HO
OH
HN
3b
NH
2
3
2-ClC6H4
OH
OH
H
H
H
H
2.5
2.5
90
89
95:5
94:6
Cl
Cl
O
N
O
N
3c
HO
OH
HN
NH
2-BrC6H4
Br
Br
N
HO
OH
HN
N
O
O
3d
NH
NH
4
5
4-O2NC6H4
OH
OH
H
H
H
H
2
3
95
85
90:10
O2N
N
NO2
N
HO
OH
HN
O
O
3e
4-H3CC6H4
95:5
H3C
CH3
+
-
(
)

M. Shafiee et al. / Tetrahedron Letters 53 (2012) 3086–3090
3089
Table 2 (continued)
Entry
Ar
R1
R2
R3
Product
Time (h)
Yielda (%)
56:34
d.r.b
HO
4a
NH
6
C6H5
H
OH
H
5.5
75
O
N
H
N
O
O
O
N
N
N
OH
OH
OH
+
-
(
)
F
F
HO
4b
4c
7
4-FC6H4
H
OH
H
4
90
67:33
NH
O
N
N
H
+
-
(
)
Cl
Cl
HO
8
4-ClC6H4
H
OH
H
4.5
85
60:40
NH
O
N
H
N
+
-
(
)
Br
Br
HO
4d
4e
9
4-BrC6H4
H
OH
H
4.5
80
67:33
NH
O
N
H
N
O
N
OH
OH
+
-
(
Br
HO
Br
N
10
11
12
3-BrC6H4
H
H
H
OH
OH
OH
H
H
H
4
4
6
83
89
70
68:32
70:30
66:34
NH
O
N
H
O
N
+
-
(
)
NO2
O2N
HO
4f
4-O2NC6H4
NH
O
N
N
H
O
N
OH
+
-
(
)
CH3
H3C
HO
4g
4-H3CC6H4
NH
O
N
H
N
O
N
OH
+
-
(
)
iPr
iPr
HO
4h
13
4-iPrC6H4
H
OH
H
6
72
68:32
NH
O
N
N
H
O
N
OH
+
(
)
-
(continued on next page)

3090
M. Shafiee et al. / Tetrahedron Letters 53 (2012) 3086–3090
Table 2 (continued)
Entry
Ar
R1
R2
R3
Product
Time (h)
Yielda (%)
71:29
d.r.b
HO
S
S
4i
14
2-thienyl
H
OH
H
5
80
NH
O
N
H
N
O
N
OH
+
(
-
a
Isolated yield.
Diastereomeric ratio was determined by 1H NMR and 13C NMR spectroscopy of the crude product.
b
L.; Hu, L. Tetrahedron Lett. 2009, 50, 6393; (e) Hajipour, A. R.; Ghayeb, Y.;
Sheikhan, N.; Ruoho, A. E. Tetrahedron Lett. 2009, 50, 5649; (f) Rashinkar, G.;
Salunkhe, R. J. Mol. Catal. A: Chem. 2010, 316, 146; (g) Luo, J.; Zhang, Q. Monatsh.
Chem. 2011, 142, 923; (h) Karmakar, B.; Banerji, J. Tetrahedron Lett. 2011, 52,
4957; (i) Cimarelli, C.; Fratoni, D.; Mazzanti, A.; Palmieri, G. Eur. J. Org. Chem.
2011, 2094.
Table 3
Synthesis of mono-Betti bases from 2,7-dihydroxynaphthalene under catalyst-free
conditionsa
O
N
6. Shen, A. Y.; Tsai, C. T.; Chen, C. L. Eur. J. Med. Chem. 1999, 34, 877.
7. (a) Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org. Chem. 2001, 66,
4759; (b) Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron: Asymmetry 2002,
13, 2417; (c) Cimarelli, C.; Palmieri, G.; Volpini, E. J. Org. Chem. 2003, 68, 1200.
8. Feng, J.; Dastgir, S.; Li, C.-J. Tetrahedron Lett. 2008, 49, 668.
9. (a) Zhang, X.-X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev. 1997, 97, 3313; (b)
Wang, W.; Ma, F.; Shen, X.; Zhang, C. Tetrahedron: Asymmetry 2007, 18, 832; (c)
Pitt, D.; Gonzales, E.; Cross, A. H.; Goldberg, M. P. Brain Res. 2010, 1309, 146; (d)
Maeng, S.; Zarate, C. A.; Du, J.; Schloesser, R. J.; McCammon, J.; Chen, G.; Manji,
H. K. Biol. Psychiatry 2008, 63, 349; (e) Bradley, P. A.; Carroll, R. J.; Lecouturier, Y.
C.; Moore, R.; Noeureuil, P.; Patel, B.; Snow, J.; Wheeler, S. Org. Process Res. Dev.
2010, 14, 1326.
10. (a) Rostami, M.; Khosropour, A. R.; Mirkhani, V.; Mohammadpoor-Baltork, I.;
Moghadam, M.; Tangestaninejad, S. Synlett 2011, 1677; (b) Rostami, M.;
Khosropour, A. R.; Mirkhani, V.; Mohammadpoor-Baltork, I.; Moghadam, M.;
Tangestaninejad, S. Monatsh. Chem. 2011, 142, 1175; (c) Rostami, M.;
Khosropour, A. R.; Mirkhani, V.; Moghadam, M.; Tangestaninejad, S.;
Mohammadpoor-Baltork, I. Appl. Catal., A: Gen. 2011, 397, 27.
OH
H3C
NH
HO
OH
80 o
C
2 ArCHO
+
Ar
HO
1
O
N
CH3
5
H2N
Entry
Ar
4-FC6H5
4-ClC6H5
2-ClC6H5
4-O2NC6H5
4-H3CC6H5
Time (h)
Yieldb (%)
1
2
3
4
5
5a
5b
5c
5d
5e
0.5
0.6
0.6
0.5
0.7
98
95
93
97
89
a
11. General procedure:
A mixture of aryl aldehyde 1 (2 mmol), 5-amino-3-
Reaction conditions: Arylaldehyde (2 mmol), 5-amino-3-methylisoxazole
(2 mmol), 2,7-dihydroxynaphthalene (1 mmol).
methylisoxazole (196 mg, 2 mmol), and dihydroxynaphthalene (1 mmol) was
stirred at 80 °C for 0.5–6 h. After the reaction was completed (monitored by
TLC), the mixture was cooled to room temperature and diluted with H2O. The
precipitated solid was collected by filtration, washed with H2O, and was
purified as appropriate by recrystallisation from acetonitrile.
b
Isolated yield.
12. Selected spectral data for compounds 3b, 4i, and 5d: 1,4-Bis[(2-chlorophenyl)(5-
methylisoxazol-3-ylamino)methyl]naphthalene-2,3-diol (3b): White solid; mp
knowledge, this is the first example of a pseudo-five-component
reaction under solvent-free conditions in the absence of any cata-
lyst for the synthesis of bis-Betti bases under conventional heating.
165–166 °C. FTIR (KBr, solid):3512, 3402, 3073, 1622, 1447, 1039, 752 cmÀ1 1H
.
NMR (400 MHz, DMSO-d6): d = 9.59 (s, 2H), 7.80–7.83 (m, 2H), 7.51–7.53 (m,
2H), 7.39–7.41 (m, 2H), 7.25–7.32 (m, 4H), 7.15–7.18 (m, 2H), 7.07 (d,
J = 5.6 Hz, 2H), 6.67 (d, J = 5.6 Hz, 2H), 5.77 (s, 2H), 2.22 (s, 6H). 13C NMR
(125 MHz, DMSO-d6): d = 167.9, 163.5, 145.3, 138.9, 132.7, 129.5, 128.7, 127.0,
126.7, 123.0, 117.8, 94.03, 53.2, 11.9. CHN: Anal. Calcd for C32H26N4O4Cl2: C,
63.90; H, 4.36; N, 9.31. Found: C, 64.10; H, 4.53; N, 9.09. 1,5-Bis[(5-
Acknowledgements
The authors are grateful to the Center of Excellence of
Chemistry and the Research Council of the University of Isfahan
for financial support of this work.
methylisoxazol-3-ylamino)(thiophen-2-yl)methyl]naphthalene-2,6-diol
White solid, mp 224–226 °C. FTIR (KBr, solid):3346, 3085, 2713, 1611, 1518,
1295, 701 cmÀ1 1H NMR (400 MHz, DMSO-d6): d = 9.84 (s, 2H), 7.93 (s, 2H),
(4i):
.
7.28–7.30 (m, 2H), 7.09–7.11 (m, 2H), 6.86–6.88 (m, 4H), 6.78–6.80 (m, 2H),
6.73–6.74 (m, 2H), 5.85 (s, 2H), 2.20 (s, 6H). 13C NMR (125 MHz, DMSO-d6):
d = 167.51, 164.08, 150.00, 148.03, 127.08, 126.43, 124.13, 123.77, 119.94,
118.38, 93.92, 52.21, 12.02. CHN: Anal. Calcd for C28H24N4O4S2: C, 61.75; H,
4.44; N, 10.29; S, 11.77. Found: C, 61.29; H, 4.51; N, 10.48, S, 11,61. 1-[(5-
References and notes
1. (a) Mueller, T. J. J. Beilstein J. Org. Chem. 2011, 7, 960; (b) Choudhury, L. H.;
Parvin, T. Tetrahedron Lett. 2011, 67, 8213; (c) De Moliner, F.; Crosignani, S.;
Galatini, A.; Riva, R.; Basso, A. ACS Comb. Sci. 2011, 13, 453; (d) Isambert, N.;
Duque, M. D. S.; Plaquevent, J. C.; Genisson, Y.; Rodriguez, J.; Constantieux, T.
Chem. Soc. Rev. 2011, 40, 1347.
2. Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234.
3. Cardellicchio, C.; Capozzi, M. A. M.; Naso, F. Tetrahedron: Asymmetry 2010, 21,
507.
Methylisoxazol-3-ylamino)(4-nitrophenyl)methyl]naphthalene-2,7-diol
Yellow solid, mp 190 °C. FTIR (KBr, solid):3488, 3396, 1626, 1514, 1342,
1189, 845 cmÀ1 1H NMR (400 MHz, DMSO-d6): d = 10.02 (s, 1H), 9.65 (s, 1H),
(5d):
.
8.15 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.50 (d,
J = 8.8 Hz, 2H), 7.18 (s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.82–6.86 (m, 2H), 6.62 (d,
J = 6 Hz, 1H), 5.86 (s, 1H), 2.23 (s, 3H).13
C NMR (100 M Hz, DMSO-d6):
d = 167.42, 164.33, 155.89, 153.06, 151.90, 145.72, 133.61, 130.19, 129.50,
127.27, 123.17, 123.09, 117.33, 114.93, 114.74, 94.05, 52.56, 12.01. CHN: Anal.
Calcd for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.29; H, 4.51; N,
10.65.
4. Betti, M. Org. Synth. Coll. 1941, 1, 381.
5. (a) Khodaei, M. M.; Khosropour, A. R.; Moghanian, H. Synlett 2006, 916; (b)
Shaterian, H. R.; Yarahmadi, H.; Ghashang, M. Bioorg. Med. Chem. Lett. 2008, 18,
788; (c) Zhang, P.; Zhang, Z. H. Monatsh. Chem. 2009, 140, 199; (d) Lei, M.; Ma,