Microwave-assisted one-pot synthesis of (aminoalkyl)naphthols and (aminoalkyl)quinolinols by using ammonium carbamate or ammonium hydrogen carbonate as solid ammonia source

Article abstract of DOI:10.1055/s-0028-1083347

Ammonium carbamate and ammonium hydrogen carbonate were used as very effective solid ammonia sources to prepare different (aminoalkyl)naphthols and (aminoalkyl)quinolinols in ethanol and water as solvents under microwave conditions in modified three-compo

Full text of DOI:10.1055/s-0028-1083347

PAPER
775
Microwave-Assisted One-Pot Synthesis of (Aminoalkyl)naphthols and
(Aminoalkyl)quinolinols by Using Ammonium Carbamate or Ammonium
Hydrogen Carbonate as Solid Ammonia Source
M
icrowa
s
ve-Assist
t
e
d
Synt
v
hesis of
(
Am
á
inoalkyl)na
n
phthols and -quino
Slinols zatmári, Ferenc Fülöp*
Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged,
Eötvös u. 6, 6720 Szeged, Hungary
Fax +36(62)545705; E-mail: fulop@pharm.u-szeged.hu
Received 3 September 2008; revised 17 November 2008
naphthoxazine without any workup, and by crystallization
Abstract: Ammonium carbamate and ammonium hydrogen car-
of the final aminonaphthol hydrochloride with ethyl ace-
tate. However, the applications of these methods are still
hampered by one or more disadvantages, such as the use
bonate were used as very effective solid ammonia sources to pre-
pare different (aminoalkyl)naphthols and (aminoalkyl)quinolinols
in ethanol and water as solvents under microwave conditions in
modified three-component Mannich reactions. The products were of methanolic ammonia and unsatisfactory yields.
obtained in excellent yields in one-pot reactions.
Since (aminoalkyl)naphthols have potential pharmaco-
logical activity, our present aim was primarily to improve
the yields of these compounds and to increase the rates of
Key words: amino alcohols, green chemistry, heterocycles,
Mannich bases, multicomponent reactions
the reactions by applying ammonium carbamate or am-
monium hydrogen carbonate (as thermally decomposable
In the past decade, modified three-component Mannich
reactions, based on the aminoalkylation of 2- or 1-naph-
thol as the C–H acid, have become considerably important
for the formation of C–C bonds under mild experimental
conditions.1 The syntheses of the aminonaphthols ob-
tained in this way differ according to the nitrogen starting
material: (a) by use of primary or secondary amines,
secondary or tertiary aminonaphthols have been syn-
thetized;2–9 (b) with ammonia as source, primary amino-
naphthols have been prepared.10–15
solid ammonia sources) and microwave conditions in one-
pot syntheses. Further aims were to extend this method to
the preparation of new (aminoalkyl)naphthols and to use
N-containing naphthol analogues such as quinolinols in-
stead of naphthols.15,17
We began our study with the synthesis of 1-[amino(phe-
nyl)methyl]-2-naphthol (4a) (Table 1). As the first step,
we tested ammonium acetate and formate as solid ammo-
nium sources in comparison to a methanolic ammonia so-
lution. Microwave irradiation is often applied as green
technology to prepare heterocyclic compounds20 and
Mannich-type products.21–23 The discover mode (closed
reaction conditions) of the CEM Discover LabMate mi-
crowave reactor combines the rapidity of the reaction un-
der microwave conditions and the easy handleability of
the reaction even at around 18–19 bar. Accordingly, the
reaction was carried out in a 10-mL pressurized reaction
vial with heating in a microwave reactor. The reactants
were 2-naphthol, two equivalents of benzaldehyde, and
two equivalents of the solid ammonia source. The two am-
monium salts (ammonium acetate and formate) yielded
4a, but the isolation of 3a required aqueous workup,
which defeated the aim of rapidity and one-pot handling
of the reaction. Similar reaction results were obtained
with several equivalents of ammonium carbamate, the
ammonium salt of unstable carbamic acid (Table 1, entry
1). In contrast with other ammonium salts, the excess of
ammonium carbamate or ammonium hydrogen carbonate
formed in the reaction can be simply removed during
evaporation of the reaction mixture above 60 °C.24,25 The
overall yield of 4a could be increased up to 92%. In the
next step, we investigated ammonium hydrogen carbonate
as another inexpensive ammonia source that can be de-
composed by heating of the reaction mixture.
The areas of application of these aminonaphthols depend
on the nature of the amino group; the enantiomers of sec-
ondary and tertiary aminonaphthols have been successful-
ly applied as chiral catalysts in the enantioselective
alkylation or arylation of benzaldehyde,2–9 while primary
aminonaphthols have been transformed into heterocyclic
compounds,10–12 subsequent condensation with different
aldehydes furnishing interesting model compounds for
examining the ring-chain tautomeric behavior of naph-
thoxazines.13–18 On the other hand, the hypotensive and
bradycardiac effects of 1-(aminomethyl)-2-naphthol de-
rivatives have been evaluated,18 and the syntheses of a
wide variety of this type of compounds have recently been
achieved through the hydrolysis of 1-(amidomethyl)-2-
naphthols.19
The overall yields of the desired aminonaphthols in the
classical Betti reaction (starting from naphthol, methanol-
ic ammonia, and the corresponding aldehyde, followed by
acidic hydrolysis of the intermediate naphthoxazine) have
been slightly improved by means of small modifications
in the synthesis, e.g. by hydrolysis of the intermediate
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Advanced online publication: 02.02.2009
DOI: 10.1055/s-0028-1083347; Art ID: T15508SS
© Georg Thieme Verlag Stuttgart · New York

776
I. Szatmári, F. Fülöp
PAPER
Table 1 Reaction Conditions for the Preparation of (Aminoalkyl)naphthols 4a–d
H
R
N
R
R
NH2⋅HCl
OH
O
OH
solid NH3 source
EtOH
10% aq HCl
+ 2 RCHO
2
1
3a–d
4a–d
Entry
R
3
Conversiona,b (%)
4
Yieldc,d (%)
Ae
97
95
95
92
Bf
Ae
92g
90
Bf
1
2
3
4
Ph
3a
3b
3c
3d
93
91
90
88
4a
4b
4c
85g
88
91
90i
2-thienyl
3-thienyl
i-Pr
88
4dh
87i
a Reagents and conditions: 1, 2 (2 equiv), solid NH3 source, EtOH, MW, 80 °C, 40 min.
b The conversion into 3 was determined from the NMR spectrum of the crude product.
c Reagents and conditions: 3, 10% aq HCl, 100 °C, 90 min.
d The yield of 4 based on the starting naphthol 1.
e Method A: H2NCO2 NH4+ was used as the solid NH3 source.
–
+
f Method B: NH4 HCO3– was used as the solid NH3 source.
g Ref. 13: 56% yield.
h Hydrolysis temperature 80 °C instead of 100 °C.
i Ref. 17: 80% yield.
The pressurized reaction vial proved excellent for follow- hydes (e.g., isobutyraldehyde), which are less reactive
ing the reaction; for example, during the initial heating, than aromatic ones, did not lead to the desired (amino-
the pressure was around 17–19 bar, which fell to 3–4 bar alkyl)quinolinols.
during the reaction, indicating the consumption of the am- In conclusion, ammonium carbamate and ammonium hy-
monia. Ethanol was removed under reduced pressure, the drogen carbonate were applied as solid ammonia sources
temperature being kept at around 60 °C. A 10% hydro- to prepare nine new (aminoalkyl)naphthol and (amino-
chloric acid solution was added to the residue and the sus- alkyl)quinolinol derivatives in ethanol in good yields in
pension was heated. The water was removed under one-pot three-component modified Mannich reactions.
reduced pressure and the residue was crystallized from With this green methodology, three other (amino-
ethyl acetate. The synthesis method was tested for the re- alkyl)naphthols were synthesized. Depending on the solid
action of three other aldehydes with 2-naphthol (Table 1, ammonia source, the 56–80% yields obtained by using
entries 2–4), including isobutyraldehyde to prepare 4d, classical methodology (methanolic ammonia) could be in-
known from the literature.17
creased to 87–92% or to 75–90%, and, simultaneously,
the reaction times could be decreased.
To test the scope and limitations of the method described
above, we also used 1-naphthol as the C–H acid (Table 2,
entries 1–4). All four aldehydes led to the formation of the
desired (aminoalkyl)naphthols 7a–d in good yields; for
example, the yield of 7a was increased from 57%15 to 80%
(Table 2, entry 1). Due to the relatively low reactivity of
the N-containing naphthol analogues, there are few exam-
ples of their transformations in modified three-component
Mannich reactions.26–30 However, as a result of an inte-
Melting points were determined on a Kofler micro melting appara-
tus and are uncorrected. Elemental analyses were performed with a
Perkin-Elmer 2400 CHNS elemental analyzer. Merck Kieselgel
60F254 plates were used for TLC. The 1H and 13C NMR spectra were
recorded in DMSO-d6 soln in 5-mm tubes, at r.t., on a Bruker
Avance DRX400 spectrometer at 400.13 (1H) and 100.61 (13C)
MHz, with the deuterium signal of the solvent as the lock and TMS
as internal standard. Compounds 4a,13 4d,17 and 7a15 are known
grated, virtual database screening, 7-[anilino(phenyl)meth- from the literature.
yl]-2-methyl-8-quinolinol was found to represent a
Compounds 4b, 4c, and 7b–h; General Procedure
promising new class of non-peptide inhibitors of the
MDM2–p53 interaction.31 Therefore, a further aim was to
study the applicability of N-containing 1-naphthol ana-
logues such as 8-quinolinol and 2-methyl-8-quinolinol in
aminoalkylations with the corresponding aldehyde and
ammonium carbamate as solid ammonia source. The reac-
tion conditions, together with the yields, are listed in
Table 2 (entries 5–8). It was concluded that aliphatic alde-
In a 10-mL pressurized reaction vial, the appropriate compound 1
or 5 (0.7 mmol), aldehyde 2 (2 equiv), and H2NCO2NH4 (0.16 g, 2.1
mmol) were dissolved in EtOH (4 mL), and the reaction mixture
was heated in a CEM Discover LabMate microwave reactor. The re-
action conditions are listed in Tables 1 and 2. The solvent was re-
moved under reduced pressure, the temperature being kept at
around 60 °C. A 10% aq soln of HCl (4 mL) was added to the resi-
due, and the mixture was heated (see Tables 1 and 2 for appropriate
temperature). The H2O was removed under reduced pressure and
Synthesis 2009, No. 5, 775–778 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of (Aminoalkyl)naphthols and -quinolinols
777
Table 2 Reaction Conditions for the Preparation of (Aminoalkyl)naphthols 7a–d and (Aminoalkyl)quinolinols 7e–h
R1
OH
O
NH
R1
OH NH2⋅HCl
R2
X
R2
X
R2
X
R1
solid NH3 source
EtOH
10% aq HCl
+ 2 R1CHO
2
5
6a–h
7a–h
Entry
X
R1
R2
Tempa (°C) Timea (min)
6
Conversiona,b (%) Tempc (°C)
Timec (min)
7
Yieldc,d (%)
Ae Bf
Ae
Bf
1
2
3
4
5
6
7
8
CH
CH
CH
CH
N
H
H
H
H
H
H
Ph
70
40
30
40
40
45
45
45
45
6a 87
6b 80
85
82
87
77
82
75
78
70
80
80
80
80
90
90
90
90
60
30
60
30
60
60
60
60
7a 80g
7b 76
75g
80
70
76
78
73
80
68
2-thienyl
3-thienyl
i-Pr
70
70
6c
85
7c
78
70
6d 82
7d 70
Ph
130
130
130
130
6e
6f
86
82
7e
7f
72
70
N
3-thienyl
N
Me Ph
6g 87
6h 81
7g 75
7h 73
N
Me 3-thienyl
a Reagents and conditions: 5, 2 (2 equiv), solid NH3 source, EtOH, MW, heat.
b The conversion into 6 was determined from the NMR spectrum of the crude product.
c Reagents and conditions: 6, 10% aq HCl, 60 °C, 60 min.
d The yield of 7 based on the starting naphthol/quinolinol 5.
e Method A: H2NCO2 NH4+ was used as the solid NH3 source.
–
f Method B: NH4 HCO3– was used as the solid NH3 source.
+
g Ref. 15: 57% yield.
the residue was treated with EtOAc; this gave 4b, 4c, and 7b–h as
beige or colorless crystals.
1H NMR (400 MHz, DMSO-d6): d = 6.33 (s, 1 H), 7.41–7.61 (m, 6
H), 7.63 (d, J = 8.7 Hz, 1 H), 7.84–7.92 (m, 1 H), 8.34 (t, J = 4.2 Hz,
1 H), 9.06 (br s, 3 H), 10.19 (br s, 1 H).
1-[Amino(2-thienyl)methyl]-2-naphthol Hydrochloride (4b)
Beige crystals; mp 184–187 °C.
13C NMR (100 MHz, DMSO-d6): d = 48.4, 120.0, 120.8, 123.5,
125.5, 126.0, 126.4, 127.5, 127.6, 127.9, 128.6, 130.2, 135.1, 141.9,
150.6.
1H NMR (400 MHz, DMSO-d6): d = 6.11 (s, 1 H), 6.98 (t, J = 4.2
Hz, 1 H), 7.24–7.82 (m, 6 H), 7.81–7.99 (m, 2 H), 7.99 (d, J = 8.6
Hz, 1 H), 8.85 (br s, 3 H), 11.08 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 48.1, 114.7, 119.4, 122.4,
123.9, 127.6, 127.7, 128.2, 128.4, 128.8, 129.6, 131.7, 132.2, 141.0,
154.4.
Anal. Calcd for C15H14ClNOS (291.80): C, 61.74; H, 4.84; N, 4.80.
Found: C, 61.53; H, 4.86; N, 4.81.
2-[Amino(3-thienyl)methyl]-1-naphthol Hydrochloride (7c)
Beige crystals; mp 172–175 °C.
Anal. Calcd for C15H14ClNOS (291.80): C, 61.74; H, 4.84; N, 4.80.
Found: C, 61.85; H, 4.87; N, 4.81.
1H NMR (400 MHz, DMSO-d6): d = 6.14 (s, 1 H), 7.19 (d, J = 4.1
Hz, 1 H), 7.41–7.61 (m, 6 H), 7.82 (d, J = 6.0 Hz, 1 H), 8.29 (d,
J = 6.0 Hz, 1 H), 9.02 (br s, 3 H), 10.09 (br s, 1 H).
1-[Amino(3-thienyl)methyl]-2-naphthol Hydrochloride (4c)
Beige crystals; mp 201–204 °C.
13C NMR (100 MHz, DMSO-d6): d = 49.2, 119.8, 120.9, 123.4,
124.3, 125.7, 126.1, 126.4, 127.6, 127.9, 128.1, 128.6, 130.3, 134.9,
150.6.
1H NMR (400 MHz, DMSO-d6): d = 6.24 (s, 1 H), 7.08–7.17 (m, 2
H), 7.27–7.35 (m, 2 H), 7.43–7.55 (m, 2 H), 7.83 (d, J = 8.6 Hz, 2
H), 8.02 (d, J = 8.8 Hz, 1 H), 8.76 (br s, 3 H), 10.89 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 48.3, 114.6, 119.4, 122.6,
123.8, 124.5, 127.7, 127.9, 128.1, 128.9, 129.6, 131.4, 132.5, 139.1,
154.4.
Anal. Calcd for C15H14ClNOS (291.80): C, 61.74; H, 4.84; N, 4.80.
Found: C, 61.62; H, 4.82; N, 4.78.
2-(1-Amino-2-methylpropyl)-1-naphthol Hydrochloride (7d)
Colorless crystals; mp 160–163 °C.
Anal. Calcd for C15H14ClNOS (291.80): C, 61.74; H, 4.84; N, 4.80.
Found: C, 61.42; H, 4.81; N, 4.72.
1H NMR (400 MHz, DMSO-d6): d = 0.85 (d, J = 6.7 Hz, 3 H), 1.24
(d, J = 6.6 Hz, 3 H), 2.33–2.47 (m, 1 H), 4.66 (s, 1 H), 7.59–7.68
(m, 4 H), 7.99 (d, J = 6.0 Hz, 1 H), 8.43 (d, J = 6.3 Hz, 1 H), 8.49
(br s, 3 H), 9.97 (br s, 1 H).
2-[Amino(2-thienyl)methyl]-1-naphthol Hydrochloride (7b)
Beige crystals; mp 192–195 °C.
13C NMR (100 MHz, DMSO-d6): d = 19.7, 20.4, 32.7, 55.1, 119.5,
120.7, 123.4, 125.7, 126.0, 126.1, 127.3, 128.5, 134.7, 151.1.
Synthesis 2009, No. 5, 775–778 © Thieme Stuttgart · New York

778
I. Szatmári, F. Fülöp
PAPER
(2) Cardellicchio, C.; Ciccarella, G.; Naso, F.; Schingaro, E.;
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Asymmetry 2002, 13, 2417.
Anal. Calcd for C14H18ClNO (251.75): C, 66.79; H, 7.21; N, 5.56.
Found: C, 66.63; H, 7.28; N, 5.41.
7-[Amino(phenyl)methyl]-8-quinolinol Hydrochloride (7e)
Colorless crystals; mp 208–211 °C.
1H NMR (400 MHz, DMSO-d6): d = 6.05 (q, J = 5.2 Hz, 1 H), 7.25–
7.38 (m, 3 H), 7.47–7.55 (m, 3 H), 7.57–7.64 (m, 1 H), 7.78 (d,
J = 8.7 Hz, 1 H), 8.38 (d, J = 8.2 Hz, 1 H), 8.88 (d, J = 4.0 Hz, 1 H),
9.19 (br s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 52.5, 118.9, 119.2, 121.7,
122.3, 123.4, 126.7, 128.2, 129.1, 129.2, 129.5, 138.1, 138.6, 139.0,
149.3, 150.5.
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Tetrahedron 2003, 59, 2877.
Anal. Calcd for C16H15ClN2O (286.76): C, 67.02; H, 5.27; N, 9.77.
Found: C, 67.25; H, 5.31; N, 9.71.
7-[Amino(3-thienyl)methyl]-8-quinolinol Hydrochloride (7f)
Beige crystals; mp 197–200 °C.
1H NMR (400 MHz, DMSO-d6): d = 6.14 (q, J = 4.9 Hz, 1 H), 7.24
(d, J = 5.0 Hz, 1 H), 7.52–7.58 (m, 2 H), 7.60 (s, 1 H), 7.66–7.72
(m, 1 H), 7.79 (d, J = 8.7 Hz, 1 H), 8.50 (d, J = 8.2 Hz, 1 H), 8.93
(d, J = 4.1 Hz, 1 H), 9.18 (br s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 48.7, 119.2, 122.3, 123.4,
124.6, 127.3, 127.9, 128.2, 129.4, 137.2, 139.2, 139.3, 148.8, 149.9.
(14) Szatmári, I.; Tóth, D.; Koch, A.; Heydenreich, M.;
Kleinpeter, E.; Fülöp, F. Eur. J. Org. Chem. 2006, 4670.
(15) Szatmári, I.; Martinek, T. A.; Lázár, L.; Fülöp, F. Eur. J.
Org. Chem. 2004, 2231.
Anal. Calcd for C14H13ClN2OS (292.78): C, 57.43; H, 4.48; N, 9.57.
Found: C, 57.61; H, 4.41; N, 9.62.
(16) Turgut, Z.; Pelit, E.; Köycü, A. Molecules 2007, 12, 345.
(17) Tóth, D.; Szatmári, I.; Fülöp, F. Eur. J. Org. Chem. 2006,
4664.
(18) Shen, A. Y.; Tsai, C. T.; Chen, C. L. Eur. J. Med. Chem.
1999, 34, 877.
(19) Shaterian, H. R.; Yarahmadi, H.; Ghashang, M. Bioorg.
Med. Chem. Lett. 2008, 18, 788.
(20) Bryson, T. A.; Stewart, J. J.; Gibson, J. M.; Thomas, P. S.;
Berch, J. K. Green Chem. 2003, 5, 174.
7-[Amino(phenyl)methyl]-2-methyl-8-quinolinol Hydro-
chloride (7g)
Colorless crystals; mp 150–153 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.76 (s, 3 H), 6.09 (s, 1 H),
7.27–7.42 (m, 4 H), 7.48–7.79 (m, 4 H), 8.42 (d, J = 6.3 Hz, 1 H),
9.17 (br s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 23.7, 51.9, 117.8, 118.9,
121.8, 123.3, 123.8, 124.5, 125.8, 125.9, 127.6, 127.8, 129.0, 130.1,
142.8, 146.5, 158.6.
(21) El Kaim, L.; Gautier, L.; Grimaud, L.; Harwood, L. M.;
Michaut, V. Green Chem. 2003, 5, 477.
(22) Shimizu, S.; Shimada, N.; Sasaki, Y. Green Chem. 2006, 8,
Anal. Calcd for C17H17ClN2O (300.78): C, 67.88; H, 5.70; N, 9.31.
Found: C, 67.92; H, 5.74; N, 9.33.
608.
(23) Zhang, J.; Cui, Z.; Wang, F.; Wang, Y.; Miao, Z.; Chen, R.
Green Chem. 2007, 9, 1341.
(24) Litvić, M.; Filipan, M.; Pogorelić, I.; Cepanec, I. Green
7-[Amino(3-thienyl)methyl]-2-methyl-8-quinolinol Hydro-
chloride (7h)
Beige crystals; mp 210–212 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.81 (s, 3 H), 6.19 (s, 1 H), 7.23
(d, J = 5.1 Hz, 1 H), 7.52–7.62 (m, 3 H), 7.66 (d, J = 8.6 Hz, 1 H),
7.78 (d, J = 8.6 Hz, 1 H), 8.52 (d, J = 8.2 Hz, 1 H), 9.19 (br s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 23.8, 48.8, 113.8, 119.1,
121.0, 124.1, 124.2, 126.4, 126.5, 127.4, 127.8, 133.0, 139.1, 140.5,
158.8.
Chem. 2005, 7, 771.
(25) Ammonium carbamate is not stable above 60 °C, and
decomposes, affording gaseous ammonia and carbon
dioxide; see: The Merck Index, 12th ed.; Merck Research
Laboratories: Whitehouse Station NJ, 1996.
(26) Phillips, J. P.; Keown, R.; Fernando, Q. J. Am. Chem. Soc.
1953, 75, 4306.
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Lett. 2001, 42, 8111.
Anal. Calcd for C15H15ClN2OS (306.81): C, 58.72; H, 4.93; N, 9.13.
Found: C, 58.63; H, 4.95; N, 9.11.
(29) Robin, Y.; Godard, A.; Queguiner, G. J. Heterocycl. Chem.
Acknowledgment
1987, 24, 1487.
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The authors’ thanks are due to the Hungarian Research Foundation
(OTKA No. K 75433) for financial support.
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Shangary, S.; Qiu, S.; Qin, D.; Wang, S. J. Med. Chem.
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Synthesis 2009, No. 5, 775–778 © Thieme Stuttgart · New York