Three component aminoalkylation of aldehydes by functionalized organozinc compounds promoted by lithium perchlorate (LiClO4)

Article abstract of DOI:10.1039/a700371d

The one-pot synthesis of several N,N-dialkylamino esters is reported. Treatment of aldehydes 1 (aliphatic and aromatic) with (trimethylsilyl)dialkylamines 2, in the presence of LiClO₄ in diethyl ether presumably gives the intermediates 3. Reaction of these intermediates 3 with functionalized organozinc reagents, RZnBr, produces a variety of N,N-dialkylamino esters in a short time (about 1 h) and in good to moderate yields. The pure products are isolated by extraction with cold hydrochloric acid.

Full text of DOI:10.1039/a700371d

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Three component aminoalkylation of aldehydes by functionalized
organozinc compounds promoted by lithium perchlorate (LiClO4)
Mohammad R. Saidi,a Hamid R. Khalajia and Junes Ipaktschib
a
Department of Chemistry, Sharif University of Technology, PO Box 11365-8693, Tehran,
Iran
b Institut für Organische Chemie, Heinrich-Buff-Ring 58, D-35392 Giessen, Germany
The one-pot synthesis of several N,N-dialkylamino esters is reported. Treatment of aldehydes 1 (aliphatic
and aromatic) with (trimethylsilyl)dialkylamines 2, in the presence of LiClO4 in diethyl ether presumably
gives the intermediates 3. Reaction of these intermediates 3 with functionalized organozinc reagents,
R ZnBr, produces a variety of N,N-dialkylamino esters in a short time (about 1 h) and in good to moderate
yields. The pure products are isolated by extraction with cold hydrochloric acid.
LiClO4
Introduction
R1—CHO
+
Me3SiNR2
R1 CH NR2
OSiMe3
R1 CH=N+R2
–OSiMe3
Et2O
N,N-Dialkylamino esters are widely used for their anti-
spasmodic activity and as topical anaesthetics, amongst other
pharmaceutical uses (such as treatment of hypertension and
heart failure). They are also used as plant growth promoters
(they enhance yields and increase production of useful com-
pounds such as carotene), as plant growth regulators, as anti-
inflammatories and as analgesics.1–4 Usually these compounds
are prepared by reaction of aminal and trimethylsilyl ketene
acetals, by nucleophilic substitution of the corresponding halo
esters, or by palladium catalysed reaction of a Schiff base with
a Reformatsky reagent.4–6 A convenient method for the prepar-
ation of these compounds is the aminoalkylation of aldehydes
in the presence of a (trimethylsilyl)dialkylamine and a func-
tionalized zinc reagent.
Generally alkylzinc reagents are unreactive towards alde-
hydes. For the reaction to proceed, special conditions are
required, involving either highly reactive organozinc reagents
(such as α-zinc esters), or activation in the presence of Lewis
acids or bases (e.g. BF3ؒEt2O, titanium tetrachloride). Thus, α-,
β- or γ-bromozinc esters add to aldehydes in the presence of a
Lewis acid catalyst to produce the corresponding hydroxy
esters.7–11
Recently we reported the LiClO4 mediated one-pot three
component aminoalkylation of aldehydes with (trimethylsilyl)-
dialkylamines, 2 and different nucleophiles, including diethyl-
zinc.12 In this paper we describe an efficient synthesis of amino
esters, as well as functionalized alkylamines, using aldehydes 1
(enolizable or non-enolizable), (trimethylsilyl)dialkylamines 2,
α-, β- or γ-bromo- or iodo-zinc esters, as well as allylzinc
bromide, chlorozinc acetylide and other functionalized organo-
zinc reagents, at room temperature in a concentrated solution
of lithium perchlorate in diethyl ether. The reaction allows
aminoalkylation with good to moderate yields.
Hydroxy compounds are not formed due to the fast reaction
of the aldehyde with the (trimethylsilyl)dialkylamine in con-
centrated lithium perchlorate solution, presumably to form an
iminium salt. This salt is then much more reactive towards
nucleophilic addition compared with the starting aldehyde
(Scheme 1). Bromozinc esters themselves are unreactive
towards benzaldehyde in 5  LiClO4 in diethyl ether.13
room temp.
R1 CH=N+R2
+
Nu–
R1 CH NR2
Nu
LiO
Nu = Et2Zn, R2MgBr, R2Li,
, etc.
Scheme 1
aldehydes, promoted by a 5  solution of LiClO4 in diethyl
ether 12 (Scheme 1). Bromo- or iodo-zinc esters were prepared
from the corresponding bromo esters of iodo esters with a Zn–
Cu couple in THF or diethyl ether. Activation of the Zn–Cu
couple with trimethylsilyl chloride (TMSCl) enhanced the
formation of the bromoalkylzinc esters, BrZn(CH2)nCO2R,
especially when n > 1. These reagents were produced very
slowly (or not at all) from bromo esters without using TMSCl
for activation of the Zn–Cu couple. Reaction of α-, β- or γ-zinc
esters with intermediates 3 in diethyl ether afforded the corre-
sponding dialkylamino esters 4 at room temperature in good to
moderate yields. The yields were higher when BrZnCH2CO2R
compounds were used. Other functionalized organozinc
reagents, RZnBr, were produced in the same manner according
to literature procedures,15–18 and were reacted with intermediate
3, to give the corresponding R-amines, Scheme 2. The results
are shown in Table 1.
Experimental
LiClO4 (Fluka) was dried at 160 ЊC and 10Ϫ1 Torr (1 Torr =
133.322 Pa) for 48 h. Diethyl ether was dried over Na–
benzophenone. IR spectra were taken on Matt Son 1000
1
Unicam FTIR and Beckman IR 4250 spectrometers. H and
13C NMR spectra were recorded on Bruker AC 80, AM 400
and AC 200 spectrometers. Mass spectra were obtained on a
Finnigan MAT model 8430, a Varian MAT 311A or a Varian
MAT 111 spectrometer. J Values are given in Hz. Compounds
4a, 4d, 4e, 4j and 4k were prepared as previously reported.4,5
CAUTION: Although we did not have any accidents using
lithium perchlorate (LiClO4), the authors advise drying lithium
perchlorate in a hood behind a suitable lab-shield.
Results
Iminium salts are important intermediates in organic syn-
thesis.14 These salts may be produced in situ by the reaction of
(trimethylsilyl)dialkylamines with various aliphatic or aromatic
General procedure for the preparation of bromozinc esters
Zinc–copper couple (3.3 mmol, 0.22 g) was placed in a two-
necked flask fitted with a condenser and a stirring bar, under
J. Chem. Soc., Perkin Trans. 1, 1997
1983

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Table 1 Product obtained from the reaction of functionalized zinc reagents via intermediate 3
RZnX
RCHO
+
Amine
3
4
1
2
MeSiN
2a =
1a R =
1b R =
1c R =
N
CH=CH—
2b = Me3SiNEt2
2c = Me3SiNMe2
2d =
Me3SiN
O
S
1d R = Ph
1e R = Pri
Aldehyde 1
Amine 2
RZnX
Product
Yield (%)
N
O
OMe
1a
2a
BrZnCH2CO2Me
71
N
4b
NEt2
O
OMe
Ph
1b
1c
2b
2b
BrZnCH2CO2Me
BrZnCH2CO2Me
67
73
4c
NEt2
O
O
S
OMe
OMe
4d
NEt2
1d
1d
2b
2c
BrZnCH2CO2Me
74
59
4e
NMe2
OEt
BrZn(CH2)2CO2Me
O
4f
NMe2
O
OMe
1d
1d
1e
2c
2c
2b
BrZnCH(Et)CO2Me
69
77
82
4g
NMe2
᎐
ClZnC᎐CSiMe
᎐
SiMe3
4h
NEt2
᎐
ClZnC᎐CSiMe3
᎐
SiMe3
4i
NEt2
O
OEt
1e
2b
BrZnCH2CO2Et
52
4j
O
N
O
1d
1e
2d
2b
BrZn(CH2)3CO2Me
57
62
OMe
4k
NEt2
BrZnCH2CH᎐CH2
᎐
4l
1984
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Table 1 (Continued)
Aldehyde 1
Amine 2
RZnX
Product
Yield (%)
86
NMe2
᎐
1e
2c
ClZnC᎐CPh
᎐
4m
1d
2b
ClZnCH2CN
55
CN
NEt2
4n
CHO
mg (71%); νmax(film)/cmϪ1 1727; δH 7.11–8.72 (m, 4H), 3.91 (s,
3H), 4.06–4.24 (m, 1H), 2.12–2.59 (m, 6H), 1.38–1.79 (m, 4H);
δC 168.94 (CO), 150.00 (CH), 148.60 (CH), 136.18 (CH), 131.74
(C), 122.58 (CH), 82.71 (CH), 52.56 (CH3), 49.07 (CH2), 24.12
(CH2), 23.17 (CH2) (Calc. for C13H18O2N2: C, 66.64; H, 7.74.
Found: C, 67.10; H, 8.06%).
+
Me3SiN(C2H5)2
N
1a
2
Et2O
LiClO4
Methyl 3-diethylamino-5-phenylpent-4-enoate 4c. 350 mg
(67%); νmax(film)/cmϪ1 1734; δH 6.92–7.41 (m, 5H), 6.01–6.72
(m, 2H), 4.45–4.73 (m, 1H), 3.51 (s, 3H), 2.66–2.24 (m, 6H),
0.83 (t, 6H, J 7.4) (Calc. for C16H23NO2: C, 73.53; H, 8.87.
Found: C, 73.25; H, 8.60%).
Methyl 3-diethylamino-3-(2-thienyl)propanoate 4d. 355 mg
(73%); νmax(film)/cmϪ1 1724; δH 7.65–7.74 (m, 3H), 4.49 (dd,
1H, J 5.5, 9.8), 3.66 (s, 3H), 2.26–2.77 (m, 6H), 0.98 (t, 6H, J
7.3); δC 171.91 (CO), 148.55 (C), 136.03 (CH), 134.92 (CH),
128.18 (CH), 54.10 (CH), 51.32 (CH3), 47.73 (CH2), 43.75
(CH2), 12.06 (CH3).
Me3SiO
N
N
N
N
3a
–OSiMe3
BrZnCH2CO2CH3
N
O
Methyl 3-diethylamino-3-phenylpropanoate 4e. 345 mg (74%);
νmax(film)/cmϪ1 1741; δH 7.19 (m, 5H), 4.12 (t, 1H, J 8.1), 3.55
(s, 3H), 2.78–2.10 (m, 6H), 0.91 (t, 6H, J 8.1); δC 172.41 (CO),
139.89 (C), 130.30 (CH), 128.09 (CH), 127.82 (CH), 60.37
(CH), 51.32 (CH3), 43.27 (CH2), 37.32 (CH2), 13.36 (CH3).
Ethyl 4-dimethylamino-4-phenylbutanoate 4f. 294 mg (59%);
νmax(film)/cmϪ1 1734; δH 7.28 (m, 5H), 4.09 (q, 2H, J 7.2), 3.23
(dd, 1H, J 9.0, 5.3), 2.20 (s, 6H), 2.14 (m, 2H), 1.26 (m, 2H),
1.21 (t, 3H, J 7.2); δC 173.14 (CO), 137.88 (C), 128.90 (CH),
128.31 (CH), 128.10 (CH), 70.07 (CH2), 60.16 (CH), 42.50
(CH3), 31.04 (CH2), 27.72 (CH2), 14.12 (CH3); m/z 134 (base
OCH3
N
4a
Scheme 2
argon. Dry diethyl ether or dry THF (3 ml) and trimethylsilyl
chloride (0.05 ml) were added and the mixture was stirred for
about 5 min. The appropriate bromo ester (3 mmol) was then
added via syringe. After stirring for an additional 30 to 60 min,
the solvent was removed under reduced pressure and the
BrZn(CH2)nCO2R reagent was ready for the next step. Other
functionalized bromo-, chloro- or iodo-zinc reagents were
prepared according to the literature procedure.16–18
peak, C H CH᎐NϩMe ), 236 (M ϩ 1) (Calc. for C H NO :
᎐
6
5
2
14 21
2
C, 71.46; H, 8.99. Found: C, 71.12; H, 8.63%).
Methyl 3-dimethylamino-2-ethyl-3-phenylpropanoate 4g. 325
mg (69%); νmax(film)/cmϪ1 1730; δH 6.98–7.37 (m, 5H), 3.83 (m,
1H), 3.71 (s, 3H), 2.97 (dt, 1H, J 16.0, 4.5), 2.08 (s, 6H), 1.08–
1.45 (m, 2H), 0.81 (dd, 3H, J 14.0, 6.8) (Calc. for C14H21NO2:
C, 71.59; H, 8.99. Found: C, 72.25; H, 8.62%).
General procedure for the three compound aminoalkylation of
aldehydes
The appropriate aldehyde (2.0 mmol) was placed in a two-
necked flask fitted with a stirring bar under argon. LiClO4 solu-
tion in diethyl ether (3–4 ml, 5 ) was added and the mixture
was stirred for about 10 min. Then the (trimethylsilyl)-
dialkylamine (3.5 mmol) was added and the mixture was stirred
for an additional 30 min (or for aliphatic aldehydes, up to 1 h).
The mixture was then added to the prepared BrZn(CH2)nCO2R
reagent via a double needle syringe. After stirring for about 1 h
at room temp., water (20 ml) and diethyl ether (20 ml) were
added and the mixture filtered. The organic layer was separated
and extracted with cold aqueous hydrochloric acid (3 × 20 ml,
0.2 ). Neutralization with a 2.0  solution of KOH, gave the
desired product.19 Further purification, if required, was carried
out by preparative gas chromatography. The structures of the
3-Dimethylamino-3-phenyl-1-trimethylsilylprop-1-yne
4h.
356 mg (77%); νmax(film)/cmϪ1 2162; δH 7.27 (m, 5H), 4.42 (s,
1H), 2.04 (s, 6H), 0.07 (s, 9H); δC 140.61 (C), 128.21 (CH),
127.94 (CH), 127.36 (CH), 100.71 (C), 92.58 (C), 62.11 (CH),
41.15 (CH3), 0.00 (CH3) (Calc. for C14H21NSi, Mϩ 231.1443.
Found: M, 231.1461).
3-Diethylamino-4-methyl-1-trimethylsilylpent-1-yne 4i. 367
mg (82%); νmax(film)/cmϪ1 2159; δH 2.78 (d, 1H, J 9.9), 2.42 (m,
2H), 2.17 (m, 2H), 1.58 (m, 1H), 0.87 (d, 3H, J 6.7), 0.86 (t, 6H,
J 7.3), 0.79 (d, 3H, J 6.5), 0.02 (s, 9H); δC 105.16 (C), 88.72 (C),
60.95 (CH), 44.72 (CH2), 30.98 (CH), 20.62 (CH3), 20.04 (CH3),
13.68 (CH3), 0.30 (CH3); m/z 182 (base peak), 226 (M ϩ 1)
(Calc. for C13H27NSi: C, 69.26; H, 12.07; N, 6.21. Found: C,
69.61; H, 12.41; N, 6.18%).
1
new compounds were determined by H and 13C NMR spec-
troscopy, and by their mass spectra and/or elemental analyses.
Methyl 3-diethylamino-3-(pyridin-3-yl)propanoate 4a. 330 mg
(70%); νmax(film)/cmϪ1 1737; δH 7.05–8.71 (m, 4H), 4.21 (dd, 1H,
J 7.1, 8.4), 3.49 (s, 3H), 2.21–2.77 (m, 6H), 0.88 (t, 6H, J 7.4).
Methyl 3-(pyrrolidin-1-yl)-3-(pyridin-3-yl)propanoate 4b. 330
Ethyl 3-diethylamino-4-methylpentanoate 4j. 224 mg (52%);
νmax(film)/cmϪ1 1734; δH 4.11 (dq, 2H, J 1.0, 7.1), 2.63 (m, 1H),
2.52 (m, 2H), 2.41 (m, 2H), 2.43 (dd, 1H, J 5.9, 14.9), 2.24 (dd,
1H, J 6.6, 14.9), 1.62 (m, 1H), 1.25 (t, 3H, J 7.1), 1.01 (t, 6H, J
7.2), 0.96 (d, 3H, J 6.7), 0.86 (d, 3H, J 6.7); δC 174.09 (CO),
J. Chem. Soc., Perkin Trans. 1, 1997
1985

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63.33 (CH2), 60.11 (CH), 44.18 (CH2), 33.97 (CH2), 31.57 (CH),
Sandberg and S. Aukerman, Chem. Abstr., 114, 121 749g; (e) K.
Yamaguchi and A. Hayashi, Japan Pat., 01 290 606 (Chem. Abstr.,
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262 053 (Chem. Abstr., 110, P232 084y); (g) A. K. L. Fung, J. Jacob,
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P232 882k).
2 M. Kobow, W. D. Sprung and E. Schulz, Ger. Pat., DD262 021
(Chem. Abstr., 110, 232 078z).
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Lett., 1983, 841; (b) S. Toki, S. Hida, S. Takamuku and H. Sakurai,
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310.
5 P. Aube, I. Christot, J. C. Combert and J. L. Klein, Bull. Soc. Chem.
Fr., 1988, 1009.
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1988, 53, 1343.
12 M. R. Saidi, A. Heydari and J. Ipaktschi, Chem. Ber., 1994, 127,
1761.
13 M. R. Saidi, unpublished work.
14 (a) M. E. Jung, in Comprehensive Organic Synthesis, eds., B. Trost
and I. Fleming, Pergamon Press, Oxford, 1991, vol. 2, p. 893;
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220.
18 A. Devasagayaraj, L. Schwink and P. Knochel, J. Org. Chem., 1995,
60, 3311.
21.05 (CH3), 20.06 (CH3), 14.66 (CH3), 14.10 (CH3); m/z 216
(M ϩ 1), 128 (base peak, Me CH᎐CH᎐NϩEt ).
᎐
2
2
Methyl 5-morpholino-5-phenylpentanoate 4k. (57%); νmax
-
(film)/cmϪ1 1739; δH 7.32 (m, 5H), 4.10–4.28 (m, 1H), 3.58
(s, 3H), 3.57–3.8 (m, 4H), 2.14–2.79 (m, 6H), 0.78–1.28 (m, 4H).
4-Diethylamino-5-methylhex-1-ene 4l. 210 mg (62%);
νmax(film)/cmϪ1 1641; δH 5.90 (m, 1H), 4.96 (m, 2H), 2.60 (m,
1H), 2.55 (m, 2H), 2.47 (m, 2H), 2.33 (m, 1H), 2.31 (m, 1H),
1.70 (m, 1H), 0.99 (t, 6H, J 7.3), 0.92 (d, 3H, J 6.9), 0.90 (d, 3H,
J 6.9); δC 139.36 (CH), 114.67 (CH2), 65.95 (CH), 44.62 (CH2),
33.04 (CH), 31.07 (CH2), 20.95 (CH3), 20.76 (CH3), 14.96
(CH ); m/z 128 (base peak), Me CH᎐CH᎐NϩEt ), 170 (M ϩ 1)
᎐
3
2
2
(Calc. for C11H23N, Mϩ, 169.1830. Found M, 169.1808).
3-Dimethylamino-4-methyl-1-phenylpent-1-yne 4m. (86%);
νmax(film)/cmϪ1 1946 (weak), 1598; δH 7.44 (m, 2H), 7.29 (m,
3H), 3.03 (d, 1H, J 9.8), 2.32 (s, 6H), 1.85 (m, 1H), 1.11 (d, 3H,
J 6.6), 1.02 (d, 3H, J 6.6); δC 131.72 (CH), 128.22 (CH), 127.75
(CH), 123.67 (C), 86.75 (C), 86.41 (C), 65.58 (CH), 41.76
(CH3), 31.03 (CH), 20.60 (CH3), 19.83 (CH3) (Calc. for
C14H19N: C, 83.53; H, 9.51; N, 6.69. Found: C, 83.23; H, 9.94;
N, 7.36%).
3-Diethylamino-3-phenylpropanenitrile 4n. (55%); νmax(film)/
cmϪ1 2192; δH 7.21 (m, 5H), 4.15 (dd, 1H, J 7.44, 5.68), 2.50–
2.79 (m, 6H), 1.10 (t, 6H, J 7.05) (Calc. for C13H18N2: C, 77.18;
H, 8.97. Found: C, 77.42; H, 8.62%).
Acknowledgements
M. R. Saidi gratefully acknowledges receipt of a grant for a
two months study visit from Deutscher Akademischer Aus-
tauschienst, DAAD and the staff of Justus-Liebig-Universität.
We thank ‘Volkswagen-Stiftung, Federal Republic of Germany’
for financial support towards the purchase of laboratory
equipment. We also thank the Research Council of Sharif
University of Technology for its partial financial support of
this work and the Chemistry & Chemical Engineering Research
Center of Iran for the use of some of their research facilities.
19 J. O. Karlsson, A. Svensson and S. Gronowitz, J. Org. Chem., 1984,
49, 2018.
References
Paper 7/00371D
Received 15th January 1997
Accepted 27th March 1997
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