A simple and efficient procedure for the synthesis of amidoalkyl naphthols by p-TSA in solution or under solvent-free conditions

Article abstract of DOI:10.1055/s-2006-939034

An efficient and direct procedure for the synthesis of amidoalkyl naphthols has been described that employs a three-component condensation reaction in one pot using aromatic aldehydes, β-naphthol and ureas or amides in the presence of p-toluene sulfonic acid in 1,2-dichloroethane at room temperature or under solvent-free conditions at elevated temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939034

9
16
LETTER
A Simple and Efficient Procedure for the Synthesis of Amidoalkyl Naphthols
by p-TSA in Solution or under Solvent-Free Conditions
S
M
ynthesisof
A
midoalk
o
ylNaphthol sh ammad Mehdi Khodaei,* Ahmad Reza Khosropour,* Hassan Moghanian
Department of Chemistry, Razi University, Kermanshah 67149, Iran
Fax +98(831)4223306; E-mail: mmkhoda@razi.ac.ir; E-mail: arkhosropour@razi.ac.ir
Received 12 September 2005
Abstract: An efficient and direct procedure for the synthesis of
amidoalkyl naphthols has been described that employs a three-com-
OH
CHAr
p-TSA
OH
ponent condensation reaction in one pot using aromatic aldehydes,
b-naphthol and ureas or amides in the presence of p-toluene sulfonic
acid in 1,2-dichloroethane at room temperature or under solvent-
free conditions at elevated temperature.
+ ArCHO
OH
H
O
O
CHAr
Key words: amidoalkyl naphthol, one-pot reaction, condensation,
b-naphthol, aryl aldehyde, solvent-free
OH
CHAr
OH
Ar
O
Multicomponent reactions (MCRs) have attracted consid-
erable attention since they are performed without need to
isolate any intermediate during their processes; this reduc-
Scheme 1
1
es time and saves both energy and raw materials. They
have merits over two-component reactions in several as-
pects including the simplicity of a one-pot procedure, pos-
sible structural variations and bulding up complex
molecules. Bigenilli, Ugi, Passerini and Mannich reac-
tions are some examples of MCRs. Nevertheless, devel-
opment and discovery of new MCRs is still in demand.
p-TSA
RCONH2 +
+ ArCHO
OH
ClCH2CH2Cl, r.t.
or
neat conditions,
125 °C
OH
NHCOR
2
3
4
5
R: NH , CH NH, CH ,
2
3
3
Ar
Ph, CH2=CH
Scheme 2
In this context, ortho-quinone methides (O-QMs) have
6
been used in many tandem processes, but only limited
1
,2-dichloroethane at room temperature (Table 1). The
work has appeared with their reaction with nucleophiles.7
best result was obtained when p-TSA was used (Table 1,
Very recently, we reported a simple and convenient meth- entry 6).
od for the synthesis of dibenzoxanthenes by the condensa-
We then examined the above reaction in different solvents
Table 2). We found that 1,2-dichloroethane was the best
choice. Several aromatic aldehydes with b-naphthol and
urea in 1,2-dichloroethane using p-TSA at room tempera-
ture reacted to afford the corresponding products in good
to excellent yields.
tion of aldehydes with b-naphthol in the presence of p-
(
8
toluene sulfonic acid (p-TSA) as a catalyst. It seems, the
intermediate O-QMs reacted further with another mole-
cule of b-naphthol (molar ratio of b-naphthol to aryl alde-
hyde is 2:1) to afford the corresponding benzoxanthenes
(
Scheme 1).
To expand this type of tandem process that would permit
the condensation of the in situ generated ortho-quninone
methide with nucleophiles other than phenols, we utilized
Table 1 Catalyst Effect on the Reaction of 4-Chlorobenzaldehyde,
b-Naphthol and Urea
ureas and amides to produce novel compounds. The reac- Entry Catalyst
Time (h)
12
Yield (%)
tion of equimolar amounts of b-naphthol, aryl aldehyde
1
2
3
4
5
6
7
BiCl3
–
–
and ureas or amides in 1,2-dichloroethane at room tem-
perature or under solvent-free conditions at 125 °C cata-
lyzed by catalytic amount of p-TSA were examined
Bi(NO ) ·5H O
3 3 2
12
Bi(OTf)3
Zn(OTf)2
12
<30
<30
–
(
Scheme 2).
12
First we chose 4-chlorobenzaldehyde and urea as the sub-
strates and examined the reaction with several catalysts in
CuCl ·4H O
12
2
2
CH SO H
12
75
93
3
3
SYNLETT 2006, No. 6, pp 0916–0920
0
4.
0
4.
2
0
0
6
4-CH C H SO H
12
3
6
4
3
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939034; Art ID: D27705ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Amidoalkyl Naphthols
917
Table 2 Solvent Effect on the Reaction of 4-Chlorobenzaldehyde,
b-Naphthol and Urea Catalyzed by p-TSA
In all cases, amido naphthols were the sole products and
no by-product was observed. The results are summarized
in Table 3. Similar results were obtained under the same
reaction conditions when N-methyl urea was used in place
of urea.
Entry
Solvent
Time (h)
12
Yield (%)
1
2
3
4
5
6
7
8
ClCH CH Cl
93
30
2
2
MeCN
12
The reactions of aromatic aldehydes with b-naphthol and
different amides including acetamide, benzamide and pro-
penionamide in 1,2-dichloroethane under similar reaction
conditions also provided the corresponding amido naph-
thols in high yields (Table 3).
MeOH
12
78
C H OH
12
70
2
5
CHCl3
12
85
In all cases, aromatic aldehydes with substituents carrying
either electron-donating or electron-withdrawing groups
reacted successfully and gave the products in high yields.
It was shown that the aromatic aldehydes with electron-
withdrawing groups reacted faster than the aromatic alde-
hyde with electron releasing group as would be expected.
CH Cl2
12
87
2
HCON(CH3)2
1,4-Dioxane
12
<10
80
12
Table 3 Synthesis of Amidoalkyl Naphthols11 in the Presence of Substoichiometric Amounts of p-TSAa
Entry Aldehyde
Urea or amide
Product
Method A9
Time (h)
Method B10
Yield (%) Time (h) Yield (%)
OH
1
H NCONH
12
12
93
95
4
3
91
90
2
2
Cl
CHO
CHO
NHCONH2
Cl
OH
2
H NCONH
2
2
NHCONH2
O2N
NO2
OH
3
H NCONH
15
15
90
89
4
4
88
87
2
2
CHO
NHCONH2
OH
4
5
H NCONH
2
2
Br
CHO
CHO
CHO
NHCONH2
Br
OH
H NCONH
18
10
85
96
6
4
83
93
2
2
CH3
NHCONH2
CH3
OH
NHCONHCH3
6
CH NHCONH
3 2
O2N
NO2
Synlett 2006, No. 6, 916–920 © Thieme Stuttgart · New York

9
18
M. M. Khodaei et al.
LETTER
Table 3 Synthesis of Amidoalkyl Naphthols11 in the Presence of Substoichiometric Amounts of p-TSA (continued)
a
Entry Aldehyde
Urea or amide
Product
Method A9
Time (h)
Method B10
Yield (%) Time (h) Yield (%)
OH
7
CH NHCONH
10
12
15
95
92
90
5
6
6
95
90
89
3
2
Cl
CHO
CHO
NHCONHCH3
Cl
OH
8
9
CH NHCONH
3 2
Br
NHCONHCH3
Br
OH
CH NHCONH
CHO
3
2
NHCONHCH3
OH
1
1
1
0
1
2
CH NHCONH
15
15
18
87
89
83
8
6
8
85
86
80
3
2
CH3
CHO
NHCONHCH3
CH3
OH
PhCONH2
PhCONH2
CHO
NHCOPh
OH
CH3
CHO
NHCOPh
CH3
OH
CHO
1
3
PhCONH2
12
87
5
87
NHCOPh
O2N
NO2
OH
1
1
4
5
PhCONH2
CH CONH
12
12
89
90
6
5
90
88
Cl
CHO
NHCOPh
Cl
OH
3
2
CHO
NHCOCH3
Synlett 2006, No. 6, 916–920 © Thieme Stuttgart · New York

LETTER
Synthesis of Amidoalkyl Naphthols
919
Table 3 Synthesis of Amidoalkyl Naphthols11 in the Presence of Substoichiometric Amounts of p-TSA (continued)
a
Entry Aldehyde
Urea or amide
Product
Method A9
Time (h)
Method B10
Yield (%) Time (h) Yield (%)
OH
CHO
1
1
1
6
7
8
CH CONH
9
10
12
93
91
94
4
4
5
90
90
91
3
2
NHCOCH3
O2N
NO2
OH
CH CONH
3
2
Cl
CHO
NHCOCH3
Cl
OH
CHO
CH =CHCONH
2
2
NHCOCH=CH2
O2N
NO2
OH
1
2
2
9
0
1
CH =CHCONH
12
30
18
90
65
71
6
5
4
89
62
69
2
2
Cl
CHO
NHCOCH=CH2
Cl
CHO
OH
CH CONH
3
2
NHCOCH3
Cl
Cl
Cl
CHO
OH
NHCONHCH3
Cl
CH NHCONH
3
2
Cl
Cl
OH
2
2
2
3
CH CONH
24
24
20
<5
10
10
0
0
3
2
CHO
O
NHCOCH3
O
NH CONH
OH
2
2
S
CHO
NHCONH2
S
2
2
4
5
CH CH(CH )CH CHO NH CONH
24
24
<5
<5
10
10
<10
<10
3
3
2
2
2
OH
CH3CH(CH3)CH2
NHCOCH3
CH CH CHO
NH CONH
OH
NHCOCH3
3
2
2
2
CH3CH2
Synlett 2006, No. 6, 916–920 © Thieme Stuttgart · New York

9
20
M. M. Khodaei et al.
LETTER
To demonstrate the scope and limitations of the proce-
dure, the reactions of ortho-substituted aromatic alde-
hydes such as 2-chlorobenzaldehyde and 2,4-di-
chlorobenzaldehyde, and heteroaromatic aldehydes in-
cluding furfural and thiophene-2-carbaldehyde were stud-
ied and the results were collected in Table 3. Aliphatic
aldehydes like isovaleraldehyde and propionaldehyde
were also examined but their yields were not satisfactory
at all, even after 24 hours at room temperature or 10 min-
utes at 125 °C (Table 3). On the other hand, the reactions
with thiourea were considered, but no corresponding
products were produced. Also, amines such as ethylamine
and aniline were utilized and no aminoalkyl naphthol was
obtained.
(5) (a) Akiyama, T.; Matsuda, K.; Fuchibe, K. Synlett 2005,
22. (b) Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.;
3
Sun, D. Green Chem. 2004, 6, 75. (c) Chowdari, N. S.;
Ramachary, D. B.; Barbas, C. F. III Synlett 2003, 1906.
(d) Akiyama, T.; Takaya, J.; Kagoshima, H. Tetrahedron
Lett. 1999, 40, 7831. (e) Arend, M.; Westermann, B.; Risch,
N. Angew. Chem. Int. Ed. 1998, 37, 1045.
(6) (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002,
58, 5367. (b) Wan, P.; Backer, B.; Diao, L.; Fischer, M.; Shi,
Y.; Yang, C. Can. J. Chem. 1996, 74, 465. (c) Desimon, G.;
Tacconi, G. Chem. Rev. 1975, 75, 65.
(7) (a) Angle, S. R.; Rainer, J. D.; Woytowiez, Z. J. Org. Chem.
1997, 62, 5884. (b) Merijan, A.; Gardner, P. D. J. Org.
Chem. 1965, 30, 3965. (c) Gardner, P. D. J. Am. Chem. Soc.
1959, 51, 3364.
(8) Khosropour, A. R.; Khodaei, M. M.; Moghanian, H. Synlett
005, 955.
2
The reactions carried out under solvent-free conditions
were examined and the corresponding products obtained
in high yields with very much lower reaction times
(
9) General Experimental Procedure (Method A).
A mixture of aromatic aldehyde (1 mmol), b-naphthol
(1 mmol), urea or amide (1.1 mmol) and p-TSA (0.1 mmol)
(
Table 3). No reaction occurred at room temperature un-
in 1,2-dichloroethane (2 mL) at r.t. was stirred for the time
as shown in Table 3. The progress of the reaction was
monitored by TLC. On completion, the reaction mixture was
der neat conditions and thus the reactions were followed
at 125 °C.
filtered and the precipitate washed with H O. The crude
2
In conclusion, a novel and highly efficient methodology
for the synthesis of amidoalkyl naphthols by the straight-
forward three-component condensation in one pot using
aromatic aldehyde, b-naphthol and ureas or amides in or-
ganic solvent (method A) and neat conditions (method B)
is reported. The simplicity, low cost and the speed of the
reactions under solvent-free conditions and mildness of
the reactions under organic solvent conditions are other
merits.
products were purified by recrystallization from EtOH–H O
(1:3) and the pure products were obtained in 83–96% yields.
2
(10) General Experimental Procedure (Method B).
A mixture of aromatic aldehyde (1 mmol), b-naphthol
(1 mmol), urea or amide (1.1 mmol) and p-TSA (0.1 mmol)
was magnetically stirred at 125 °C for the appropriate time
as indicated in Table 3. The reaction was followed by TLC.
After completion, the reaction mixture was washed with
H O. The pure products were obtained by recrystallization
2
using EtOH–H O (1:3) in 80–95% yields.
2
(
11) Selected Characterization Data.
Table 3, entry 1: IR (neat): nmax = 3456, 3360, 3200–2240,
–
1 1
Acknowledgment
1
632, 1580, 1513, 1430, 1370, 1238, 816 cm . H NMR
(
200 MHz, DMSO-d ): d = 10.30 (s, 1 H), 7.88–7.71 (m, 3
6
13
We are thankful to the Razi University Research Council for partial
support of this work.
H), 7.45–7.10 (m, 7 H), 6.90 (s, 2 H), 5.85 (s, 2 H). C NMR
(
1
50 MHz, DMSO-d ): d = 159.4, 153.7, 144.4, 132.9, 131.2,
6
30.1, 129.5, 129.2, 129.0, 128.7, 128.5, 127.5, 123.4,
1
20.5, 119.3, 48.5. MS (EI): m/z (%) = 266 (6), 231 (14), 202
References and Notes
(
10), 172 (18), 144 (100), 115 (57), 60 (52), 44 (70).
(
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1580, 1535, 1430, 1360, 1240, 815 cm . H NMR (200
MHz, DMSO-d ): d = 10.16 (s, 1 H), 8.07–6.96 (m, 12 H),
6.43 (s, 1 H), 2.61 (d, J = 3.72 Hz, 3 H). C NMR (50 MHz,
–1 1
(
6
1
3
(
Tetrahedron Lett. 2004, 45, 2649. (d) Wang, L. M.; Xia, J.;
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DMSO-d ): d = 159.4, 153.8, 148.5, 148.0, 133.5, 132.9,
6
130.5, 130.4, 129.6, 129.2, 127.8, 123.5, 123.3, 122.0,
121.0, 120.1, 119.3, 49.0, 27.2. MS (EI): m/z (%) = 260 (4),
229 (17), 207 (100), 144 (23), 115 (33), 77 (40), 58 (70).
Table 3, entry 19: IR (neat): nmax = 3390, 3300–2800, 1648,
(
(
(
b) Prajapati, D.; Sandhu, J. S. Synlett 2004, 235.
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–1 1
1620, 1517, 1418, 1322, 1262, 1062, 970, 820 cm . H
6
NMR (200 MHz, DMSO-d ): d = 10.16 (s, 1 H), 8.80 (d,
6
Soc. 1995, 117, 7842. (c) Groger, H.; Hatam, M.; Martens,
J. Tetrahedron 1995, 51, 7173. (d) Yamada, T.; Omote, Y.;
Yamanaka, Y.; Miyazawa, T.; Kuwata, S. Synthesis 1998,
J = 7.91 Hz, 1 H), 7.91–7.78 (m, 3 H), 7.44–7.18 (m, 8 H),
6.75–6.60 (m, 1 H), 6.10 (d, J = 16.99 Hz, 1 H), 5.60 (d,
1
3
J = 10.40 Hz, 1 H). C NMR (50 MHz, DMSO-d ): d =
6
991.
165.0, 154.2, 142.3, 133.1, 132.5, 131.7, 130.5, 129.5,
129.3, 128.9, 128.8, 127.4, 126.8, 124.0, 123.4, 119.3,
119.0, 48.5. MS (EI): m/z (%) = 339 (2) [M + 2], 337 (7) [M],
266 (40), 231 (64), 202 (54), 144 (64), 115 (54), 101 (63), 71
(25), 55 (100).
(
4) (a) Kobayashi, K.; Matoba, T.; Susumu, I.; Takashi, M.;
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Synlett 2006, No. 6, 916–920 © Thieme Stuttgart · New York