A novel one-pot conversion of amines to homologated esters in poly(ethylene glycol)

Article abstract of DOI:10.1016/j.tetlet.2006.12.035

The first deaminative homologation of amines (-CH₂NH₂) to esters (-CH₂CH₂COOEt) in one-pot is reported. The reaction proceeds through, formation of an aldehyde from an amine in the presence of Pd/C as catalyst followed by Wittig reaction and catalytic hydrogenation using poly(ethylene glycol) as the solvent in one-pot.

Full text of DOI:10.1016/j.tetlet.2006.12.035

Tetrahedron Letters 48 (2007) 1269–1271
A novel one-pot conversion of amines to homologated
esters in poly(ethylene glycol)I
S. Chandrasekhar,* G. Pavan Kumar Reddy, Ch. Nagesh and Ch. Raji Reddy
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 October 2006; revised 29 November 2006; accepted 8 December 2006
Abstract—The first deaminative homologation of amines (–CH2NH2) to esters (–CH2CH2COOEt) in one-pot is reported. The
reaction proceeds through, formation of an aldehyde from an amine in the presence of Pd/C as catalyst followed by Wittig reaction
and catalytic hydrogenation using poly(ethylene glycol) as the solvent in one-pot.
Ó 2007 Elsevier Ltd. All rights reserved.
The importance of one-pot reactions was recognized
early in the history of organic synthesis.1 Useful chemi-
cal products can be produced in one-pot with less waste
and greater economic benefits by avoiding lengthy sepa-
ration and purification of the intermediate compounds.2
Creating one-pot synthetic routes is a challenge and the
most important factors are the choice of solvent and
selection of a reagent/reaction which enables the desired
conversion efficiently. Poly(ethylene glycol) (PEG) has
recently received considerable attention as an inexpen-
sive, non-toxic, thermally stable reusable solvent by
us3 and others.4 Also, Pd/C is a stable catalyst which tol-
erates a reasonable environment. Taking advantage of
this combination and also to add a new dimension in
one-pot reactions, we designed a transformation where-
in the initially added catalyst (in this instance Pd/C
required for conversion of the amine to an imine) will
also act as a catalyst for the hydrogenation of the olefin
generated upon Wittig reaction. This procedure would
allow one to convert an amine to a two-carbon homo-
logated ester in one-pot involving three chemical
transformations.
cess is also available, where an amine was converted to
an imine using a strong base such as n-BuLi or DBU
with subsequent hydrolysis to obtain ketones.11 How-
ever, these methods suffer from disadvantages such
as the requirement of larger amounts of reagents,
anhydrous reaction conditions and low yields of
the products. Recently, Miyazawa et al. reported the
conversion of an amine to a ketone using water as the
solvent (oxygen source) albeit with limited substrates.12
However, this reaction strongly depends on the structure
of the reactant, especially the number of hydrogens on
the carbon adjacent to the nitrogen and also affords
unwanted by-products. Herein we report a novel trans-
formation of amines to homlogated esters in one-pot
using poly(ethylene glycol) as the solvent (Scheme 1).
Initially, benzylamine, 5% Pd/C and poly(ethylene gly-
col)-400 were taken in a pressure resistant glass ampoule
and the mixture was subjected to microwave irradiation
at 170 °C for 3 h. After cooling to room temperature, a
68% yield of benzaldehyde was obtained after workup
by ether extraction (Table 1, entry 1). The same reaction
was carried out by conventional heating at 170 °C and a
similar result was obtained after 9 h (Table 1, entry 2).
Based on the above observations, we conducted further
The conversion of an amine to a carbonyl compound
has been reported with various metal oxidizing reagents
8
such as KMnO4,5 K2FeO4,6 Pb(OAc)4,7 NiO2 and
HgO– I29 and as a biological process.10 A two-step pro-
i) 5% Pd/C, MW, H2O
ii) Ph3P=CHCOOEt, rt
iii) H2 (gas), rt
Keywords: Palladium; One-pot reaction; Poly(ethylene glycol); Amines;
COOEt
R
NH2
R= aryl or alkyl
Scheme 1.
R
Esters.
PEG-400
q IICT Communication No. 060810.
*
Corresponding author. Tel.: +91 40 27193210; fax: +91 40
27160512; e-mail: srivaric@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.035

1270
S. Chandrasekhar et al. / Tetrahedron Letters 48 (2007) 1269–1271
Table 2. One-pot conversion of an amine to a homologated estera
Table 1. Conversion of amines to carbonyl compoundsa
Entry Amine
1
Carbonyl compound Yieldb (%)
Entry Amine
Esterb
Yieldc
(%)
O
NH2
NH2
68
CO2Et
CO2Et
NH2
NH2
H
H
1
2
3
65
60
O
2c
70
70
CO2Et
NH2
O
61
NH2
3
H
CO2Et
NH2
MeO
4
62d
60
MeO
Cl
O
CO2Et
NHMe
NH2
NH2
4
74
66
69
H
5
MeO
MeO
CO2Et
CO2Et
O
NHMe
NHBn
6
7
64
57
5
H
N
N
NH2
O
H
6
7
CO2Et
NH2
8
50
CO2Et
O
NH2
NH2
9
54
21
18
26
N
N
NH2
O
10
Ph
CO2Et
Ph
NH2
Ph
8
Ph
H
a For reaction conditions see Ref. 13.
b All the products were characterized by 1H NMR and mass spectro-
O
scopy.
NH2
9d
66
c Isolated yields.
d Dechlorination occurred.
H
a Reaction conditions: 5% Pd/C, PEG-400, MW, 3 h.
b Determined by GC and GC–MS.
c Conventional heating at 170 °C for 9 h.
yield (Table 2, entry 1). After successful one-pot conver-
sion of an amine to an unsaturated homologated ester,
we next attempted the reduction of the double bond
using hydrogen gas in the same vessel and obtained
the desired saturated ester in 60% yield (Table 2, entry
2).13 The initially added 5% Pd/C was still active enough
for further reduction of the olefin. Encouraged by this
interesting result, our attention was transferred to the
other amines and the results are summarized in Table
2.14
d The reaction was performed over three runs in the same pot without
substantial loss of activity.
reactions using various benzylamines including N-
methyl benzylamine and 2-aminophenyl ethane (Table
1, entries 3–6) in the presence of 5% Pd/C in poly(ethyl-
ene glycol) under microwave irradiation. Satisfactory
results were obtained and are summarized in Table 1.
However, aliphatic amines (Table 1, entries 7 and 8)
gave low yields of the desired products. Recycling of
the reagent system (Pd/C in PEG) was also successfully
achieved (Table 1, entry 9).
When a variety of substituted benzylamines bearing dif-
ferent groups were employed, the reactions proceeded
smoothly to give the desired homologated esters in rea-
sonably good yields (Table 2, entries 3–5). N-Substi-
tuted benzylamines and 2-naphthyl methylamine also
proved to be good substrates in the reaction, giving
the corresponding esters in good yields (Table 2, entries
6–8). The Wittig products of entries 9 and 10 (Table 2)
on hydrogenation gave a complex mixture of products.
However, the pure a,b-unsaturated esters could be
obtained on work-up.
With these positive results in hand, we next investigated
the Wittig reaction of the aldehyde in the same vessel.
Accordingly, benzylamine was subjected to the above
mentioned reaction conditions under microwave irradia-
tion for 3 h and then cooled to room temperature, after
which water was added. After stirring for 30 min, the
two-carbon stable ylide (ethoxycarbomethylene)tri-phen-
ylphosphorane was added to the same reaction vessel
and the mixture stirred at room temperature for 12 h
to afford the expected a,b-unsaturated ester in a 65%
In summary, we have successfully demonstrated the one-
pot conversion of amines to homologated esters using

S. Chandrasekhar et al. / Tetrahedron Letters 48 (2007) 1269–1271
1271
8. Nakagawa, K.; Onoue, H.; Sugita, J. Chem. Pharm. Bull.
1964, 12, 1135.
poly(ethylene glycol) as the solvent. Further investiga-
tions aimed at improving the yields and applications
are in progress.
9. Orito, K.; Hatakeyama, T.; Takeo, M.; Uchiito, S.;
Tokuda, M.; Suginhome, H. Tetrahedron 1998, 54, 8403.
10. (a) Metzler, D. E. Adv. Enzymol. Relat. Areas Mol. Biol.
1979, 50, 1; (b) Davis, L.; Metzler, D. E. In The Enzymes,
3rd ed.; Academic Press: New York, 1972; Vol. 7.
11. (a) Chen, H. G.; Knochel, P. Tetrahedron Lett. 1988, 29,
6701; (b) Buckley, T. F.; Rapport, H. J. Am. Chem. Soc.
1982, 104, 4446.
Acknowledgement
G.P.K.R. is thankful to the UGC and C.N. is grateful to
the CSIR, New Delhi, for a fellowship. S.C. thanks the
DST for funding the project.
12. Miyazawa, A.; Tanaka, K.; Sakakura, T.; Tashiro, M.;
Tashiro, H.; Surya Prakash, G. K.; Olah, G. A. Chem.
Commun. 2005, 2104.
13. Representative experimental procedure:
A mixture of
Supplementary data
benzylamine (0.25 g, 2.33 mmol), 5% Pd/C (125 mg) and
ploy(ethylene glycol)-400 (5 ml) in a pressure resistant
glass ampoule was subjected to microwave irradiation
(100 W, CEM Discover, 2.45 GHz, CEM Corporation,
NC, USA) at 170 °C. After 3 h, the reaction mixture was
cooled to room temperature; water was added and the
reaction stirred at room temperature for 30 min. To the
same reaction vessel, (ethoxycarbomethylene)triphenyl-
phosphorane (1.2 g, 3.5 mmol) was added and stirring
was continued at room temperature. After 12 h, the
reaction mixture was subjected to hydrogenation (hydro-
gen gas balloon) at room temperature. After completion of
the reaction (8 h), the mixture was extracted with diethyl
ether, the combined organics dried (Na2SO4) and evapo-
rated in vacuo to give a crude residue which was purified
by column chromatography (Table 2, entry 2).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.12.035.
References and notes
1. (a) Strecker, A. Liebigs Ann. Chem. 1850, 75, 27; (b)
Tietze, L. F. Chem. Rev. 1996, 96, 115.
2. Broadwater, S. J.; Roth, S. L.; Price, K. E.; Kobasˇliza, M.;
McQuade, D. T. Org. Biomol. Chem. 2005, 3, 2899.
3. (a) Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.;
Reddy, N. R. Org. Lett. 2002, 4, 4399; (b) Chandrasekhar,
S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy, N. R. Chem.
Commun. 2003, 1716; (c) Chandrasekhar, S.; Narsihmulu,
Ch.; Saritha, B.; Sultana, S. S. Tetrahedron Lett. 2004, 45,
5865; (d) Chandrasekhar, S.; Narsihmulu, Ch.; Chandra-
sekhar, G.; Shyamsundar, T. Tetrahedron Lett. 2004, 45,
2421; (e) Chandrasekhar, S.; Reddy, N. R.; Sultana, S. S.;
Narsihmulu, Ch.; Reddy, K. V. Tetrahedron 2006, 62,
338.
14. Spectroscopic data for selected products: (Table 2, entry
1
1): H NMR (CDCl3, 300 MHz): d 7.69 (d, J = 15.8 Hz,
1H), 7.53–7.52 (m, 2H), 7.39–7.38 (m, 3H), 6.44 (d,
J = 5.8 Hz, 1H), 4.27 (q, J = 6.8 Hz, 2H), 1.34 (t,
J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 166.2,
143.9, 133.9, 129.5, 128.2, 127.4, 117.7, 59.8, 13.6; EIMS
(m/z): 199.1 (M+Na)+. (Table 2, entry 2): 1H NMR
(CDCl3, 300 MHz):
d 7.30–7.09 (m, 5H), 4.10 (q,
J = 7.1 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.58 (t,
J = 7.5 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 172.3, 140.0, 127.9, 127.7, 125.7, 59.8,
35.4, 30.4, 13.6; EIMS (m/z): 201.1 (M+Na)+. (Table 2,
4. (a) Li, J.-H.; Zhu, Q.-M.; Liang, Y.; Yang, D. J. Org.
Chem. 2005, 70, 5347; (b) Li, J.-H.; Liu, W.-J.; Xie, Y.-X.
J. Org. Chem. 2005, 70, 5409; (c) Huaxing, Z.; Yuhong, Z.;
Leifang, L.; Hailiang, X.; Yangguang, W. Synthesis 2005,
2129.
1
entry 10): H NMR (CDCl3, 200 MHz): d 7.42–7.00 (m,
6H), 5.81 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H),
3.52 (d, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3, 50 MHz): d 166.4, 147.2, 137.6, 128.7,
5. (a) Rawalay, S. S.; Schechter, H. J. Org. Chem. 1967, 32,
3129; (b) Noureldin, N. A.; Bellegarde, J. W. Synthesis
1999, 939.
128.6, 126.6, 122.3, 60.2, 38.4, 14.2; EIMS (m/z): 213.2
6. Audette, R. J.; Quail, J. W.; Smith, P. J. Tetrahedron Lett.
1971, 279.
1
(M+Na)+. See Supplementary data for H NMR and 13
C
NMR spectra of the products.
7. Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971.