Synthetic utility of Kabachnik-Fields reaction: A convenient one-pot three-component synthesis of N-phenyl isoquinolone-1-phosphonates

Article abstract of DOI:10.1016/j.tetlet.2012.10.030

A convenient, one-pot three-component synthesis of novel N-phenyl isoquinolone-1-phosphonates (4a-4g) using the Kabachnik-Fields reaction, starting from ethyl 2-(2-formyl-4,5-dimethoxyphenyl) acetate (1) and anilines (2a-2g) is described. The aldehyde (1) on reaction with substituted anilines (2a-2g) and triethyl phosphite in acetonitrile using trifluroacetic acid as catalyst provides N-phenyl isoquinolone-1-phosphonates (4a-4g) in good yields.

Full text of DOI:10.1016/j.tetlet.2012.10.030

Tetrahedron Letters 53 (2012) 6940–6942
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Tetrahedron Letters
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Synthetic utility of Kabachnik-Fields reaction: a convenient one-pot
three-component synthesis of N-phenyl isoquinolone-1-phosphonates
Amulrao U. Borse a, , Nilesh L. Patil a, Mahesh N. Patil a, Raghao S. Mali b
⇑
a School of Chemical Sciences, North Maharashtra University, Jalgaon 425001, M.S., India
b Former Head, Department of Chemistry, University of Pune, Pune 411007, M.S., India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient, one-pot three-component synthesis of novel N-phenyl isoquinolone-1-phosphonates
(4a–4g) using Kabachnik-Fields reaction, starting from ethyl 2-(2-formyl-4,5-dimethoxyphenyl) acetate
(1) and anilines (2a–2g) is described. The aldehyde (1) on reaction with substituted anilines (2a–2g) and
triethyl phosphite in acetonitrile using trifluroacetic acid as catalyst provides N-phenyl isoquinolone-
1-phosphonates (4a–4g) in good yields.
Received 1 September 2012
Revised 5 October 2012
Accepted 7 October 2012
Available online 13 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
One-pot synthesis
Kabachnik-Fields reaction
N-Phenyl isoquinolone-1-phosphonates
a-Aminophosphonates
Recently,
a
-aminophosphonates have attracted the attention of
One of the methods involves molybdenum trioxide catalyzed oxi-
dative cross dehydrogenative coupling (CDC) approach7 for C–H
functionalization of N-aryl or N-phenyl tetrahydroisoquinolines.
The other method makes use of DDQ mediated phosphonation of
N-aryl or N-phenyl tetrahydroisoquinolines. Both these methods
make use of pre-formed tetrahydroisoquinolines. Thus, a few
methods described above are available for the synthesis of simple
organic chemists due to their biological activities, such as antibi-
otic, enzyme inhibitor, HIV protease and as anti-tumor agents.1
The
logues of
hydrolysis.2 In agrochemistry
plant growth regulators, herbicides, insecticides and fungicides.3
Several -aminophosphonates have also been used in organic syn-
a
-aminophosphonates are considered to be structural ana-
-amino acids and transition state mimics of peptide
-aminophosphonates are used as
a
a
a
a-aminophosphonates and for N-aryl or N-phenyl tetrahydroiso-
thesis. For example, phosphorylated allenes are used as versatile
building blocks in organic synthesis.4 Lennoxamine alkaloid
and its analogues have been synthesized using phosphorylated
isoindolinone.5a Couture et al. have used phosphorylated o-aroyl
and heteroaroyl benzamides for the synthesis of 4-aryl and
heteroaryl-1(2H)-isoquinolones.5b In view of this several methods
involving Kabachnik-Fields reaction and Pudovik reactions have
quinoline-1-phosphonates. However, there is not a single method
found in the literature for the synthesis of N-phenyl
isoquinolone-1-phosphonates. Considering the above aspects,
herein we report a convenient, one-pot three-component method
for the synthesis of novel N-phenyl isoquinolone-1-phosphonates
without using pre-formed isoquinolones as starting materials.
Recently one-pot multicomponent reactions have been reviewed
by Singh and Chowdhury.8
been reported for the synthesis of
a
-aminophosphonates.6 In
Kabachnik-Fields reaction carbonyl compounds, amines are reacted
with dialkyl or trialkyl phosphites in presence of catalysts to obtain
Initially it was decided to synthesize the parent N-phenyl
isoquinolone-1-phosphonate (4a) in two steps starting from ethyl
2-(2-formyl-4,5-dimethoxyphenyl) acetate (1) via the intermedi-
a-aminophosphonates (Scheme 1).
In Pudovik reaction the -aminophosphonates are obtained
a
acy of a-aminophosphonate (3a) as shown in Scheme 3. Thus, a
from the aldehyde in two steps (Scheme 2).
Although various methods have been reported for the synthesis
of simple a-aminophosphonates very few efforts have been made
solution of ethyl 2-(2-formyl-4,5-dimethoxyphenyl) acetate (1),
4-fluroaniline (2a), and triethylphosphite in dry acetonitrile was
stirred at room temperature in presence of 4 Å molecular sieves
for the synthesis of N-aryl or N-phenyl tetrahydroisoquinoline-
and catalytic amount of TFA (20 mol %) to obtain a-aminophosph-
1-phosphonates. Recently, some methods have been developed for
onate (3a) in 72% yield. In IR (KBr) spectrum it showed peaks at
3292 and 1712 cmÀ1 for –NH and ester carbonyl group. In 1H
NMR (CDCl3) spectrum it showed absence of aldehyde proton,
present in 1 and appearance of benzylic proton at 4.97 d as doublet
(JH–P = 22.3 Hz). In 1H NMR spectrum it also showed a broad singlet
a-phosphorylation of N-aryl or N-phenyl tetrahydroisoquinolines.
⇑
Corresponding author. Tel.: +91 257 2257427; fax: +91 257 2258403.
E-mail address: amulborse@gmail.com (A.U. Borse).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.030

A. U. Borse et al. / Tetrahedron Letters 53 (2012) 6940–6942
6941
R
NHR1
O
O
R CHO
R1 NH2
H P OR2
OR2
R2O P OR2
OR2
OR
O P OR2
OR2
Scheme 1. Kabachnik-Fields reaction for the synthesis of a-aminophosphonates.
Table 1
O
One-pot synthesis of N-phenyl isoquinolone-1-phosphonates (4a–4g)
H P OR2
OR2
R
NHR1
R
H
Product
R
Time (h)
Yielda (%)
mp (°C)
R1
R1 NH2
R CHO
R2O P O
OR2
N
RT + Reflux
4a
4b
4c
4d
4e
4f
4-F
4-Cl
H
4-Br
3-Cl
4-CH3
4-C2H5
6
6
5
6
7
7
8
17
70
69
74
68
66
71
64
212–214
218–220
206–208
202–204
220–222
216–218
148–150
Scheme 2. Pudovik reaction for the synthesis of
steps.
a-aminophosphonates in two
17
17
16
19
18
19
at 4.60 d for –NH, a multiplet at 4.04–4.15 d for four protons of two
P-OCH2-CH3 and another multiplet at 3.92–3.97 d for –OCH2-CH3.
The methyl protons of two P-OCH2-CH3 groups appeared as multi-
plet at 1.22–1.30 d and the methyl protons of –OCH2-CH3 group ap-
peared as triplet at 1.12 d. In formation of 3a, from 1 and 2a using
triethylphosphite, one-pot three-component Kabachnik-Fields
reaction, occurs. The starting compound (1) was prepared from
the commercially available 3,4-dimethoxyphenyl acetic acid, using
the reported procedure.9
4g
a
Isolated yield.
1H–1H COSY NMR spectrum the two benzylic protons were found
in different environment and observed at 3.58 d and 4.13–4.23 d.
Interestingly, the methylene protons of one of the two P-OCH2-CH3
groups are found in different environments. Thus, one of the
methylene protons is observed at 3.67–3.71 d and the other is
merged in a multiplet at 3.91–3.99 d along with another methylene
protons of P-OCH2-CH3. From HSQC spectrum it is confirmed that
the methylene carbon of one of the P-OCH2-CH3 correlates with
two methylene protons observed at different places. Two benzylic
protons observed at 3.58 d and 4.13–4.23 d on the proton axis
correlates with benzylic carbon at 38.11 d. The carbon at 63.40 d
(JC–P = 153.2 Hz) on the carbon axis correlates with one benzylic
proton at 5.03 d (JH–P = 15.7 Hz).
Though the desired N-phenyl isoquinolone-1-phosphonate (4a)
was obtained in good overall yield in two steps, to improve further,
the yield and efficiency of the approach, a one-pot procedure with-
out isolation of
shown in Scheme 4.
In this approach10
The next step was the cyclization of
a-aminophosphonates
(3a) to obtain the corresponding N-phenyl isoquinolone-
1-phosphonate (4a). TFA was used as a catalyst in acetonitrile for
cyclization. Under refluxing condition the desired product
N-phenyl isoquinolone-1-phosphonate (4a) was obtained in 61%
yield. The structure of 4a was determined on the basis of analytical
and spectral data. In IR (KBr) spectrum it showed a peak at
1660 cmÀ1 for lactam carbonyl which indicated the cyclization of
3a to 4a. In 1H NMR (CDCl3) spectrum it showed a multiplet at
3.91–3.99 d for two methoxyl, one P-OCH2-CH3 and one methylene
proton of P-OCH2-CH3. The remaining one methylene proton of
P-OCH2-CH3 appeared as multiplet at 3.67–3.71 d. Two triplets
were seen at 1.16 d and 1.13 d for two methyl groups of
P-OCH2-CH3. When the methylene protons were irradiated at
3.91–3.99 d region the two triplets which appeared at 1.16 d and
1.13 d collapsed in to a singlet and triplet, respectively. This
showed that one methylene group of P-OCH2-CH3 has merged in
the multiplet which appeared at 3.91–3.99 d. The structure 4a
was confirmed by 1H–1H COSY and HSQC NMR techniques. In
a-aminophosphonates (3a) was visualized as
a
mixture of ethyl 2-(2-formyl-4,5-
dimethoxyphenyl) acetate (1), 4-fluroaniline (2a) and triethyl
phosphite in dry acetonitrile was stirred at room temperature for
6 h in presence of 4 Å molecular sieves and catalytic amount of TFA
(20 mol %) under nitrogen atmosphere. Additional amount of TFA
COOC2H5
COOC2H5 NH2
H3CO
H3CO
O
TFA (20 mol %)
CH3CN / RT
4Å MS
H3CO
H3CO
H3CO
H3CO
H
TFA / Reflux
CH3CN
N
N
CHO
P(OC2H5)3
C2H5O P O
OC2H5
4a
C2H5O P O
F
F
F
1
2a
OC2H5
3a
Scheme 3. Two-step synthesis of N-phenyl isoquinolone-1-phosphonate (4a).
1) TFA (20 mol %)
4Å MS
COOC2H5
CHO
NH2
H3CO
H3CO
O
H3CO
H3CO
CH3CN / RT
P(OC2H5)3
N
2)
TFA / Reflux
R
C2H5O P O
OC2H5
R
4
2
1
Scheme 4. One-pot synthesis of N-phenyl isoquinolone-1-phosphonates (4a–4g).

6942
A. U. Borse et al. / Tetrahedron Letters 53 (2012) 6940–6942
4. (a) Allenes in Organic Synthesis; Schuster, H. F., Coppola, G. M., Eds.; Wiley: New
York, NY, 1984. pp. 247–252; (b) Patois, C.; Ricard, L.; Savignac, P. J. Chem. Soc.,
Perkin Trans. 1 1990, 1577.
5. (a) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C. Tetrahedron 2000, 56,
1491; (b) Couture, A.; Deniau, E.; Grandclaudon, P.; Woisel, P. Tetrahedron
1996, 52, 4433.
6. (a) Zefirov, S. N.; Matveeva, E. D. Arkivoc 2008, 1–17; (b) Kabachnik, M. I.;
Medved, T. Y. Dokl. Akad. Nauk SSSR 1952, 83, 689; (c) Pudovik, A. N. Dokl. Akad.
Nauk SSSR 1952, 83, 865. Chem. Abstr. 1953, 47, 4300; (d) Pudovik, A. N.;
Konovaloa, I. V. Synthesis 1979, 81.
7. (a) Wang, H.; Li, X.; Wu, F.; Wan, B. Tetrahedron Lett. 2012, 53, 681; (b) Alagiri,
K.; Devadig, P.; Prabhu, K. R. Tetrahedron Lett. 2012, 53, 1456; (c) Rueping, M.;
Zhu, S.; Koenigs, R. M. Chem. Commun. 2011, 47, 8679; (d) Hari, D. P.; Konig, B.
Org. Lett. 2011, 13, 3852; (e) Basle, O.; Li, C.-J. Chem. Commun. 2009, 4124; (f)
Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal. 2010, 352, 1667.
(6 mmol) was added to it and refluxed to obtain N-phenyl
isoquinolone-1-phosphonate (4a) in 70% yield. Hence it was
decided to synthesize N-phenyl isoquinolone-1-phosphonates
(4b–4g) using the one-pot method. Under these conditions the
N-phenyl isoquinolone-1-phosphonates (4a–4g) were obtained in
a single step and in good yield (Table 1). It is observed that aniline
and 4-methyl anilines provided the desired products in better
yields as compared to halogenated anilines.
In conclusion a convenient one-pot three-component method
has been developed for the synthesis of novel N-phenyl
isoquinolone-1-phosphonates (4a–4g) from easily available
anilines. Our method does not require pre-formed isoquinolones
and provide the final products with good yields.
8. Singh, M. S.; Chowdhury, S. RSC Adv. 2012, 2, 4547.
9. (a) Stearman, C. J.; Wilson, M.; Padwa, A. J. Org. Chem. 2009, 74, 3491; (b) Kraus,
G. A.; Krolski, M. E. J. Org. Chem. 1986, 51, 3347.
10. General procedure for one-pot synthesis of N-phenyl isoquinolone-1-phosphonates
(4a–4g): To a solution of aldehyde 1 (1.0 mmol), substituted aniline 2a–2g
(1.1 mmol) and triethylphosphite (1.2 mmol) in dry acetonitrile (15 mL) was
added 4Å molecular sieves (1 g) and catalytic amount of TFA (20 mol %) using a
syringe under N2 atmosphere. The yellow reaction mixture was stirred at room
temperature for 5–8 h. TFA (6.0 mmol) was added using a syringe under N2
atmosphere and the reaction was refluxed for the time given against each
compound. Acetonitrile removed at reduced pressure and the reaction mixture
was poured into ice cold water (20 mL). It was extracted using DCM
(3 Â 20 mL).The combined organic layer washed with 20 mL aqueous sodium
bicarbonate solution (10%), water (25 mL) and dried using sodium sulphate.
Evaporation of the solvent gave yellow residue which was chromatographed
over silica gel using hexane/ethyl acetate (7:3) as solvent for elution to obtain
N-phenyl isoquinolone-1-phosphonates (4a–4g) as white amorphous powder.
Data for a representative compound 4a is given below. 4a. Yield 70%; mp. 212–
214 °C; Rf (96% CHCl3:MeOH) 0.25; IR (KBr, cmÀ1): 2983, 2935, 1660, 1517,
1460, 1396, 1307, 1259, 1236, 1213, 1111, 1054, 1022, 962; 1H NMR
(300 MHz, CDCl3): d 7.32–7.36 (dd, 2H, ArH, JH–F = 5 Hz, J = 8.8 Hz), 7.10 (t,
2H, ArH, JH–F = 8.6 Hz, J = 8.5 Hz), 6.84 (s, 1H, ArH), 6.71 (s, 1H, ArH), 5.03 (d, 1H,
JH–P = 15.7 Hz, PCHN), 4.13–4.23 (m, 1H, ArCH), 3.91–3.99 (m, 9H, 2 Â OCH3,
OCH2CH3, OCHCH3), 3.67–3.71 (m, 1H, OCHCH3), 3.58 (d, 1H, ArCH, J = 18.6 Hz),
1.16 &1.13 (t, 3H each, J = 7.0 Hz, 2 Â OCH2CH3); 13C NMR (75 MHz, CDCl3): d
169.26, 161.20 (d, JC–F = 246.4 Hz), 149.40 (d, J = 3.5 Hz), 147.56 (d, J = 2.3 Hz),
137.73, 129.31 (d, J = 8.0 Hz), 125.85 (d, J = 4.6 Hz), 119.84, 115.86, 115.5,
110.11 (d, J = 6.3 Hz), 63.40 (d, JC–P = 153.2 Hz), 63.18 (d, J = 6.9 Hz), 62.53 (d,
J = 6.9 Hz), 56 (d, J = 6.9 Hz), 38.11, 16.23, 16.17; 31P NMR: d 18.28; LCMS (m/z),
438 (M+H); Anal. calcd for C21H25FNO6P: C, 57.66; H, 5.76%; found: C, 57.26; H,
6.03%.
Acknowledgments
This work was supported by the Grant provided to the School of
Chemical Sciences, North Maharashtra University (Jalgaon) by
University Grant Commission (UGC), New Delhi under SAP
programme. One of the authors (NLP) acknowledges UGC, New
Delhi for SAP fellowship under the scheme ‘Research Fellowship
in Sciences for Meritorious Students’. We thank Professor D.D.
Dhavale, University of Pune, for useful discussions.
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