An improved synthesis of amidoalkyl phenols involving a Ritter-type reaction

Article abstract of DOI:10.1055/s-2007-990923

Three-component condensation of phenols, aromatic aldehydes and alkyl nitriles in the presence of a catalytic amount of triflic acid yielded the corresponding amidoalkyl phenols involving a Ritter-type reaction. The products were formed in high yields and

Full text of DOI:10.1055/s-2007-990923

LETTER
3103
An Improved Synthesis of Amidoalkyl Phenols Involving a Ritter-Type
Reaction1
I
mprove
d
Synthe
i
sis of
A
s
midoalky
w
l
Phenols Involvin
a
g Ritter-Ty
n
pe Reactionath Das,* Keetha Laxminarayana, P. Thirupathi, B. Ramarao
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)7160512; E-mail: biswanathdas@yahoo.com
Received 19 March 2007
Our expectation was fulfilled when a mixture of 2-naph-
thol and 4-chlorobenzaldehyde was heated in MeCN un-
der reflux for 1.5 hours using triflic acid as a catalyst to
form the corresponding amidoalkyl naphthol 4e (Table 1,
entry e). The product was formed in a yield of 91%. 1,3-
Aminooxygenated moieties are frequently found in vari-
ous bioactive natural products and important drug mole-
cules.8 The present method provides a simple route to
such moieties. Initially, we attempted the above reaction
with different catalysts, such as triflic acid, PTSA and io-
dine to prepare 4e but in terms of the reaction times and
yields the first one was found to be the best. Subsequently
this catalyst was used to prepare a series of amidoalkyl
phenols from various phenols, aromatic aldehydes and ac-
etonitrile or acrylonitrile (Table 1). Benzaldehydes con-
taining both electron-donating and electron-withdrawing
groups worked well. 2-Naphthaldehyde (entry i) also un-
derwent the conversion smoothly. Phenol and its deriva-
tives and 2-naphthol were applied for the reaction. 2-
Naphthol required shorter reaction times and the yields
were also comparatively high. Using acetonitrile the reac-
tion was complete within 1.5–5 hours and the yields were
good to excellent (50–91%), while with acrylonitrile the
reaction times were somewhat longer (4.5–6 h) and the
yields were somewhat lower (60–67%). When this work
was ready for submission, a report appeared9 on the prep-
aration of acetamido phenols using Ce(SO4)2 as a catalyst
but the reaction times were long (16–48 h). The catalyst
was used in equivalent amount and the conversion was
studied only with acetonitrile.
Abstract: Three-component condensation of phenols, aromatic al-
dehydes and alkyl nitriles in the presence of a catalytic amount of
triflic acid yielded the corresponding amidoalkyl phenols involving
a Ritter-type reaction. The products were formed in high yields and
in short reaction times.
Keywords: amidoalkyl phenol, three-component condensation,
ortho-quinone methide, Ritter reaction
Multicomponent reactions have gained considerable at-
tention in recent years for generating molecular complex-
ity in a single synthetic operation.2 In this context, ortho-
quinone methides have been utilized in many tandem pro-
cesses.3 The condensation of phenols with aldehydes un-
der acid or base catalysis is believed to proceed via ortho-
quinone methide intermediates.4 Recently the reaction of
2-naphthol and benzaldehydes in the presence of p-tolue-
nesulfonic acid (PTSA)5a or I25b has been employed for the
synthesis of dibenzoxanthenes involving these intermedi-
ates. In these reaction when amides and urea were used as
nucleophiles to react with the in situ generated ortho-
quinone methides the products were found to be ami-
doalkyl naphthols.6 We felt that in the reaction of phenols
and benzaldehydes if alkyl nitriles were used, Ritter-type
reaction7 involving ortho-quinone methide intermediates
and alkyl nitriles might take place to form the correspond-
ing amidoalkyl phenols (Scheme 1).
OH
CHO
R2CN (3)
TfOH (10 mol%)
OH
R
The formation of amidoalkyl phenols possibly takes place
by Ritter-type reaction involving alkyl nitriles and ortho-
quinone methides formed by interaction of phenols and
aromatic aldehydes (Scheme 2).
+
80–85 °C
NHCOR2
R1
R
2
1
4
R1
Scheme 1
In conclusion, we have developed an efficient method for
the synthesis of amidoalkyl phenols utilizing triflic acid
OH
TfOH
+
ArCHO
OH
OH
R
H+
OH
O
CHAr
+
N
Ar
Ar
NHCOR
N
Ar
R
:NCR
OH
H2:O:
Scheme 2
SYNLETT 2007, No. 20, pp 3103–3106
x
x
.x
x
.2
0
0
7
Advanced online publication: 30.11.2007
DOI: 10.1055/s-2007-990923; Art ID: D07807ST
© Georg Thieme Verlag Stuttgart · New York

3104
B. Das et al.
LETTER
catalyzed one-pot three-component condensation of phe- high yields and short reaction times are the notable advan-
nols, aromatic aldehydes and alkyl nitriles involving a tages of the protocol.
Ritter-type reaction. The simple experimental procedure,
Table 1 Synthesis of Amidoalkyl Phenolsa,10
Entry Phenol
Aldehyde
Nitrile
MeCN
Time (h) Product
4.5
Isolated yields (%)
56
a
PhOH
CHO
OH
NHCOMe
Cl
Cl
b
4-HOC6H4OH
MeCN
MeCN
5
50
58
CHO
HO
OH
NHCOMe
Cl
Cl
Cl
c
4-ClC6H4OH
5
CHO
Cl
OH
NHCOMe
Cl
d
e
2-naphthol
2-naphthol
MeCN
MeCN
2
90
91
CHO
OH
NHCOMe
1.5
CHO
OH
NHCOMe
Cl
Cl
f
2-naphthol
MeCN
2.25
89
CHO
OH
NHCOMe
NO2
NO2
g
2-naphthol
2-naphthol
MeCN
MeCN
2.5
2.5
86
82
CHO
Cl
OH
NHCOMe
Cl
Cl
Cl
h
CHO
Br
OH
NHCOMe
Br
Synlett 2007, No. 20, 3103–3106 © Thieme Stuttgart · New York

LETTER
Improved Synthesis of Amidoalkyl Phenols Involving Ritter-Type Reaction
3105
Table 1 Synthesis of Amidoalkyl Phenolsa,10 (continued)
Entry Phenol
Aldehyde
Nitrile
MeCN
Time (h) Product
3
Isolated yields (%)
i
2-naphthol
89
CHO
OH
NHCOMe
j
2-naphthol
2-naphthol
2-naphthol
2-naphthol
2-naphthol
2-naphthol
MeCN
MeCN
MeCN
CN
2.25
86
CHO
OH
NHCOMe
NO2
O2N
k
3.25
81
75
63
60
67
CHO
OH
NHCOMe
OMe
CHO
MeO
l
3.5
OH
NHCOMe
OH
HO
m
n
o
4.5
CHO
OH
NHCOCH=CH2
Cl
Cl
5
CHO
CN
Cl
OH
NHCOCH=CH2
Cl
Cl
Cl
6
CN
CHO
OH
NHCOCH=CH2
NO2
NO2
a The structures of the products were determined from their spectral (IR, 1H and 13C NMR and MS) data.
(3) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367.
Acknowledgment
The authors thank CSIR, New Delhi for financial assistance.
(4) (a) Wolff, A.; Boechmer, V.; Vogt, W.; Ugozzoli, F.;
Andreetti, G. D. J. Org. Chem. 1990, 55, 5665. (b) No, K.
W.; Kim, J. E.; Kwon, K. M. Tetrahedron Lett. 1995, 36,
8453. (c) Mashraqui, S. H.; Patil, M. B.; Mistry, H. D.;
Ghadigaonkar, S.; Meetsma, A. Chem. Lett. 2004, 33, 1058.
(5) (a) Khosropour, A. R.; Khodaei, M. M.; Moghanian, H.
Synlett 2005, 955. (b) Das, B.; Ravikanth, B.; Ramu, R.;
Laxminarayana, K.; Rao, B. V. J. Mol. Catal. A: Chem.
2006, 255, 74.
References and Notes
(1) Part 118 in the series ‘Studies on novel synthetic
methodologies’.
(2) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1993,
32, 563. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995,
34, 259. (c) Ugi, I. Pure Appl. Chem. 2000, 77, 187.
Synlett 2007, No. 20, 3103–3106 © Thieme Stuttgart · New York

3106
B. Das et al.
LETTER
115.8, 121.8, 122.3, 129.3, 130.4, 132.2, 134.4, 146.1,
(6) (a) Khodaei, M. M.; Khosropour, A. R.; Moghanian, H.
Synlett 2006, 916. (b) Das, B.; Laxminarayana, K.;
Ravikanth, B.; Rao, B. R. J. Mol. Catal. A: Chem. 2007, 261,
180.
(7) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70,
4045. (b) Benson, F. R.; Ritter, J. J. J. Am. Chem. Soc. 1949,
71, 4128. (c) Bishop, R. In Comprehensive Organic
Synthesis, Vol. 6; Fleming, I.; Trost, B. M., Eds.; Pergamon
Press: New York, 1991, 261–300.
(8) (a) Knapp, S. Chem. Rev. 1995, 95, 1859. (b) Seebach, D.;
Matthews, J. L. Chem. Commun. 1997, 2015.
(9) Selvam, N. V.; Perumal, P. T. Tetrahedron Lett. 2006, 47,
7481.
(10) General Experimental Procedure: To a mixture of a
phenol (1 mmol) and aromatic aldehyde (1 mmol) in MeCN
or acrylonitrile (5 mL), triflic acid (10 mol%) was added.
The mixture was heated under reflux and the reaction was
monitored by TLC. After completion of the reaction, H2O
(10 mL) was added and the mixture was extracted with
EtOAc (3 × 10 mL). The extract was dried and concentrated.
The residue was subjected to column chromatography (silica
gel; eluent: hexane–EtOAc, 4:1) to obtain the pure amido-
alkyl phenol.
148.2, 157.1, 169.3. MS (FAB): m/z (%) = 278 (2), 276 (6)
[M + H]+·, 184 (33), 182 (100).
Compound 4i: IR (KBr): 3409, 1644, 1537, 1370, 1330,
1272 cm–1. 1H NMR (200 MHz, CDCl3 + DMSO-d6): d =
9.82 (br s, 1 H), 8.26 (m, 1 H), 8.02 (m, 1 H), 6.62–7.76 (m,
6 H), 7.32–7.41 (m, 3 H), 7.18–7.25 (m, 4 H), 2.06 (s, 3 H).
13C NMR (50 MHz, DMSO-d6): d = 22.9, 48.0, 118.4, 119.1,
122.5, 123.3, 123.4, 123.9, 125.1, 125.3, 126.4, 126.7,
127.2, 127.9, 128.7, 128.8, 128.9, 131.3, 132.2, 132.9,
140.6, 153.2, 169.1. MS (FAB): m/z (%) = 342 (2) [M + H]+·,
198 (100).
Compound 4k: IR (KBr): 3425, 1647, 1513, 1462, 1274
cm–1. 1H NMR (200 MHz, CDCl3 + DMSO-d6): d = 9.65 (br
s, 1 H), 9.12 (d, J = 8.0 Hz, 1 H), 8.00 (m, 1 H), 7.68 (d, J =
8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.36 (m, 1 H), 7.06–
7.22 (m, 5 H), 6.64 (d, J = 8.0 Hz, 2 H), 3.64 (s, 3 H), 2.02
(s, 3 H). 13C NMR (50 MHz, DMSO-d6): d = 23.2, 48.2, 55.5,
113.9, 119.0, 119.5, 122.9, 126.8, 127.8, 129.0, 129.6,
132.8, 134.9, 153.6, 158.2, 169.6. MS (FAB): m/z (%) = 322
(3) [M + H]+·, 178 (100).
Compound 4m: IR (KBr): 3446, 1657, 1622, 1514, 1337,
1276 cm–1. 1H NMR (200 MHz, CDCl3 + DMSO-d6): d =
9.61 (br s, 1 H), 8.22 (m, 1 H), 8.00 (m, 1 H), 7.76 (d, J = 8.0
Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.41 (m, 1 H), 7.10–7.28
(m, 7 H), 6.21–6.38 (m, 2 H), 5.61 (m, 1 H). 13C NMR (50
MHz, DMSO-d6): d = 47.5, 117.5, 118.0, 121.8, 122.2,
125.0, 125.8, 127.0, 127.2, 127.5, 128.5, 128.7, 130.6,
130.9, 131.9, 140.1, 152.4, 164.0. MS (FAB): m/z (%) = 340
(2), 338 (6) [M + H]+·, 196 (33), 194 (100).
The spectral (IR, 1H and 13C NMR and MS) data of some
representative products are given below.
Compound 4a: IR (KBr): 3422, 1654, 1511, 1460, 1376,
1269 cm–1. 1H NMR (200 MHz, CDCl3 + DMSO-d6): d =
8.99 (br s, 1 H), 8.01 (m, 1 H), 7.90 (br s, 1 H), 7.44–7.52 (m,
2 H), 6.84 (d, J = 8.0 Hz, 3 H), 6.68 (d, J = 8.0 Hz, 3 H), 1.92
(s, 3 H). 13C NMR (50 MHz, DMSO-d6): d = 23.0, 55.4,
Synlett 2007, No. 20, 3103–3106 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.