A simple one-pot three-component reaction for preparation of secondary amines and amino esters mediated by lithium perchlorate

Article abstract of DOI:10.1016/S0040-4020(01)00636-6

The one-pot synthesis of several secondary amines and secondary amino esters are reported. Treatment of aldehydes (aliphatic or aromatic) with (trimethylsilyl)alkylamines, in the presence of 5 M lithium perchlorate in diethyl ether gives intermediate imines. Reaction of these intermediate imines with different nucleophiles and functionalized organozinc reagents, BrZnCH₂COOR, produce a variety of secondary amines and N-alkyl- or N-arylamino esters in good yields.

Full text of DOI:10.1016/S0040-4020(01)00636-6

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 6829±6832
A simple one-pot three-component reaction for preparation
of secondary amines and amino esters mediated by
lithium perchlorate
p
Mohammad R. Saidi, Najmoddin Azizi and Hasan Zali-Boinee
Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516, Tehran, Iran
Received 26 February2001; revised 21 May2001; accepted 7 June 2001
AbstractÐThe one-pot synthesis of several secondaryamines and secondaryamino esters are reported. Treatment of aldehydes +aliphatic or
aromatic) with +trimethylsilyl)alkylamines, in the presence of 5 M lithium perchlorate in diethyl ether gives intermediate imines. Reaction of
these intermediate imines with different nucleophiles and functionalized organozinc reagents, BrZnCH
secondaryamines and N-alkyl- or N-arylamino esters in good yields. q 2001 Elsevier Science Ltd. All rights reserved.
2
COOR, produce a varietyof
1
±9
The synthesis of secondary amines
N-arylamino esters
and N-alkyl- or
are of great interest due to their
1
0±14
wide use as plant growth regulators and plant growth
promoters as well as other chemical and pharmaceutical
activities. One approach to synthesize these compounds
involves addition of organometallic reagents to imines,
but the low electrophilicityof the imine has frequently
hindered these reactions. The reactivityof the imines has
been improved bycomplexation with Lewis acids, or by
1
5
preparation of `masked' imine derivatives. Recently, it
was reported that lanthanide tri¯ates, tetrabutylammonium
Scheme 1.
¯uoride, and indium trichloride can be used as a catalyst for
addition of nucleophiles to imines.
1
6
reaction of N-alkyl+trimethylsilyl) amines with various
aliphatic or aromatic aldehydes, promoted by 5 M solution
Generallyorganozinc halides are useful organometallic
intermediates and are widelyused for organic s yn thesis.
Their high functional group tolerance associated with their
reactivitytoward electrophiles makes them a unique class of
of LiClO in diethyl ether. Thus, aldehyde, 1 +enolizable or
4
non-enolizable), N-alkyl+trimethylsilyl) amines, 5, in 5 M
ethereal leads to the formation of the intermediate imine
7. The intermediate imine 7 can be detected in solution by
1
7
13
nucleophilic reagents.
C NMR spectroscopy, or can be isolated from the solution
after work-up. BrZnCH COOMe was prepared from the
2
Recentlywe reported a one-pot three component amino-
alkylation of aldehydes with +trimethylsilyl)dialkyl amines
or lithium hexamethyldisilazane and different nucleophiles
such as organolithium, organomagnesium, organosilicon
and functionalized organozinc compounds, in 5 M solution
of lithium perchlorate in diethyl ether +LPDE), for the
corresponding bromoester with Zn±Cu couple in diethyl
ether. Activation of the Zn±Cu couple with trimethylsilyl
chloride enhanced the formation of bromoalkylzinc ester.
1
8
Reaction of bromoalkylzinc esters or other organolithium
and organomagnesium reagents with intermediate 7
afforded the corresponding N-alkyl- or N-arylamino esters
or secondaryamines at room temperature in good yi elds,
Scheme 2. The by-product b-lactam was not formed in this
1
8±22
preparation of various tertiaryand primaryamines,
Scheme 1.
1
5
process. The results are summarized in Table 1.
Substituted imines are important intermediates in organic
synthesis. Substituted imines can be produced in situ by
In conclusion, we have described a one-pot Mannich-type
reaction of nucleophiles with in situ preformed imines in
5
M ethereal lithium perchlorate solution, which leads to the
Keywords: secondaryamines; aminoesters; lithium perchlorate.
Corresponding author. Tel.: 198-21-6005718; fax: 198-21-6012983;
e-mail: saidi@sharif.edu
p
formation of substituted secondaryamines or N-alkyl- or
N-arylamino esters.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)00636-6

6830
M. R. Saidi et al. / Tetrahedron 57 ꢀ2001) 6829±6832
Scheme 2.
Table 1. Product obtained from the in situ performed reaction of imine with nucleophile
a
Isolated yields.
1
. Experimental
Bruker 500 MHz Ultra Shielde. Mass spectra were
obtained on Fisson 800 Trio, and GC-Mass HP 5973
MSD. All reactions were performed under argon. Most
aldeyhdes were distilled before use. Chemicals were
purchased from Fluka, Merck, and used as received.
1
.1. General
2
LiClO +Fluka) was dried at 1608C and 10 Torr for 48 h.
1
4
Diethyl ether was dried over Na/benzophenone under argon.
IR spectra were taken on Matt Son 1000 Unicam FT-IR, H
1
Caution. Although we did not have anyaccident in using
LiClO , the authors advise that lithium perchlorate is dried
4
1
and C NMR spectra were recorded on Bruker AC 80 or
3

M. R. Saidi et al. / Tetrahedron 57 ꢀ2001) 6829±6832
6831
in a hood using a suitable lab-shield. The etheral solution
should be freshlyprepared and not stored.
+29.4), 207 +8.1), 192 +base peak, 100), 165 +30.1), 148
+16.9), 135 +13.2), 109 +5.8).
2
3
1.2.7. Ethyl 3-!N-butylamino)-3-!4-methylphenyl)pro-
pionate 9i. Known. Yield 60%; yellow oil; IR +thin
2
4
1.2. General procedure for preparation of substituted
secondary amines or N-alkyl- or N-arylamino esters
2
1
1
®lm), nmax 3390 +NH), 1725 +CyO) cm ; H NMR
CDCl ): d 0.60±1.20 +m, 10H, CH CH CH , OCH CH ),
+
3
2
2
3
2
3
The aldehyde +2 mmol) and 3 mL of 5 M LiClO in diethyl
4
2.2 +s, 3H, ArCH ), 2.30±2.60 +m, 4H, CHCH , CH N), 3.55
3 2 2
ether were placed in a 50 mL ¯ask under argon and stirred
for 5 min. +Trimethylsilyl)alkyl amine +3 mmol) was then
added via a syringe. After 30 min the solution of 5±6 mmol
of nucleophile in diethyl ether was added and the mixture
stirred at room temperature for 2 h. The best result was
obtained when 6 mmol of nucleophile was used. Then
water +20 mL) and diethyl ether +20 mL) were added. The
+m, 1H, CHCH ), 4.10 +q, 2H, Jˆ6.7 Hz, OCH CH ), 6.60±
2
2
3
7.19 +m, 5H, Ar±H, NH).
1.2.8. Ethyl 3-!N-phenylamino)-3-phenylpropionate 9j.
Yield 82%; white solid, mp 658C; IR +KBr), n 3246
+NH), 1738 +CyO) cm ; H NMR +CDCl ): d 1.06 +t,
max
2
1
1
3
3H, Jˆ7.1 Hz, OCH CH ), 2.70 +d, 2H, Jˆ6.7 Hz,
2
3
organic phase was separated, dried with MgSO , and the
4
CH CO), 4.12 +q, 2H, Jˆ7.1 Hz, OCH CH ), 4.71 +t, 1H,
2
2
3
solvent was removed in a rotaryevaporator. The crude
product was further puri®ed bycolumn chromatography
on basic alumina. The products are characterized by
Jˆ6.3 Hz, CHCH ), 6.40±7.80 +m, 11H, Ar±H, NH);
2
1
3
CNMR +CDCl ): d 16.8 +CH ), 43.1 +CH ), 56.9 +CH),
3
3
2
61.5 +CH ), 115.1 +CH), 117.8 +CH), 129.1 +CH), 130.1
2
1
13
1
+CH), 139.8 +C), 146.8 +C), 179.9 +C). MS m/e 269 +M ,
comparison of their IR, NMR + H and C) spectra with
those of authentic samples. Yields refer to pure isolated
products.
1
18.8), 270 [+M11) , 3.4], 182 +base peak, 100), 104 +12.3),
77 +13). +Calcd for C H NO : C, 75.81; H, 7.11. Found: C,
1
7
19
2
75.53; H, 6.76%).
1.2.1. Ethyl 3-!N-phenylamino)-3-!pyridin-3-yl)propio-
nate 9a. Yeild 86%; white solid, mp 738C; IR +KBr), n
1.2.9. Methyl 3-!N-butylamino)-3-phenylpropionate 9k.
Yield 74%; viscose oil; IR +thin ®lm), n 3400 +NH), 1738
max
2
KBr) 3246 +NH), 1738 +CyO) cm ; H NMR +CDCl ): d
1 1
+
3
max
2
+CyO) cm ; H NMR +CDCl ): d 0.61±1.30 +m,10H,
1
1
1
.09 +t, 3H, Jˆ7.2 Hz, OCH CH ), 2.72 +d, 2H, Jˆ6.3 Hz,
2
3
3
CH CO), 4.10 +q, 2H, Jˆ7.2 Hz, OCH CH ), 4.80 +t, 1H,
CH CH CH , OCH CH ), 2.34 +t, 2H, Jˆ7.0 Hz, CH N),
2
2
3
2
2
3
2
3
2
1
3
Jˆ6.2 Hz, CHCH ), 6.42±8.60 +m, 10H, Ar±H, NH);
C
NMR +CDCl ): d 18.2 +CH ), 42.0 +CH ), 54.4 +CH), 62.3
2.58 +d, 2H, Jˆ6.8 Hz, CH CO), 3.82 +m, 1H, NCHCH ),
2
2
2
4.08 +q, 2H, Jˆ7.2 Hz, OCH ), 7.20 +braod s, 5H, Ar±H).
3
3
2
2
1
MS m/e 249 +M , 1.4), 206 +17.4), 192 +27.5), 177 +15.9),
162 +base peak, 100), 135 +34.7), 105 +16.9), 91 +8.4).
+
1
1
CH ), 114.8 +CH), 118.1 +CH), 128.0 +CH), 133.8 +C),
2
1
39.8 +C), 147.1 +CH), 171.0 +C); MS m/e 270 +M ,
1
8.3), 271 [+M11) , 2.4], 183 +base peak, 100), 104 +7.0),
9
Found: C, 71.55; H, 7.03%).
3 +5.4), 77 +9.8); +calcd for C H N O : C, 71.09; H, 6.71.
1
1.2.10. Methyl 3-!N-phenylamino)-3-phenylpropionate
9l. Known. Yield 78%; white solid, mp 106±1078C; IR
+
6
18
2
2
2
5
2
KBr), nmax 3384 +NH), 1723 +CyO) cm ; H NMR
1
1
1.2.2. Ethyl 3-!N-phenylamino)-3-!pyridin-4-yl)propio-
nate 9c. Yield 84%; white solid, mp 848C; IR +KBr), n
+CDCl ): d 2.87 +d, 2H, Jˆ6.9 Hz, CH CO), 3.70 +s, 3H,
1
+m, 10H, Ar±H); MS, m/e 255 +M , 21), 256 [+M11) ,
3
2
OCH ), 4.71 +dd, 1H, Jˆ6.9, 5.9 Hz, CHCH ), 6.60±7.30
max
3
2
2
330 +NH), 1732 +CyO) cm ; H NMR +CDCl ): d 1.01 +t,
1
1
1
3
3
3
H, Jˆ7.25 Hz, OCH CH ), 2.71 +d, 2H, Jˆ7.2 Hz,
3.9], 182 +base peak, 100), 121 +13.8), 104 +15.7), 77 +15.6).
2
3
CH CO), 3.98 +q, 2H, Jˆ7.25 Hz, OCH CH ), 4.70 +t, 1H,
2
2
3
Jˆ7.2 Hz, CHCH ), 6.40±8.60 +m, 10H, Ar±H, NH); MS
1.2.11. Ethyl 3-!N-butylamino)-4-methylpentanoate 9m.
Known. Yield 45%; pale yellow oil.
2
1
1
m/e 270 +M , 22.8), 271 [+M11) , 4.3], 183 +base peak,
25
1
00), 104 +76.4), 93 +5.7), 77 +8.6).
1.2.12. Ethyl 3-!N-phenylamino)-3-!4-cyanophenyl)pro-
pionate 9n. Known. Yield 86%; white solid, mp 1128C;
2
6
1.2.3. Ethyl 3-!N-phenylamino)-3-!4-chlorophenyl)pro-
pionate 9e. Known. Yield 80%; pale yellow solid; mp
2
3
21
1
IR +KBr), nmax 3390 +NH), 1735 +CyO) cm ; H NMR
+CDCl ): d 1.10 +t, 3H, Jˆ7.1 Hz, OCH CH ), 2.72 +d,
9
28C.
3
2
3
2
H, Jˆ6.9 Hz, CH CO), 4.10 +q, 2H, Jˆ7.1 Hz,
2
1
.2.4. Ethyl 3-!N-butylamino)-3-!4-chlorophenyl)propio-
nate 9f. Known. Yield 70%; brownish oil.
OCH CH ), 4.68 +t, 1H, Jˆ6.9 Hz, CHCH CO) 6.40±7.80
2
3
2
2
3
+m, 10H, Ar±H, NH).
1.2.5. Ethyl 3-!N-butylamino)-2-!4-chlorophenyl)propio-
nate 9g. Known. Yield 80%, Yellowish solid; mp 788C.
1.2.13. !N-Phenyl)-1,2-dimethylpropanamine 8a. Known,
yield 74%; pale yellow oil.
2
3
28
2
7,30
1.2.6. Ethyl 3-!N-butylamino)-3-!3-methoxyphenyl)pro-
pionate 9h. Yield 78%; pale yellow oil; IR +thin ®lm),
1.2.14. !N-Phenyl)-1-phenylethanamine 8b. Known.
Yield 76%; yellow oil; IR +thin ®lm), n 3361 +NH),
3030, 1607 cm ; H NMR +CDCl ): d 1.40 +d, 3H,
max
2
1
nmax 3330 +NH), 1730 +CyO) cm ; H NMR +CDCl ): d
1
21
1
3
3
0
.60±1.31 +m, 10H, CH CH CH , OCH CH ), 1.62 +s, 1H,
2
Jˆ7.9 Hz, NCHCH ), 3.55 +br. s, 1H, NH), 4.38 +q, 1H,
2
3
2
3
3
NH), 2.28 +t, 2H, Jˆ6.8 Hz, CH N), 2.30±2.60 +m, 2H,
Jˆ7.9 Hz, NCHCH ), 6.50±7.27 +m, 10H, Ar±H).
2
3
CHCH ), 3.70 +s, 3H, CH O), 3.86 +m, 1H, CHCH ), 4.05
2
3
2
+
MS m/e 279 +M , 3.7), 280 [+M11) , 0.7], 236 +9.6), 222
q, 2H, Jˆ7.2 Hz, OCH CH ), 6.60±7.30 +m, 4H, Ar±H);
1.2.15. !N-Butyl)-1-phenylethanamine 8c. Known. Yield
71%; pale brown oil.
2
3
1
1
30

6832
M. R. Saidi et al. / Tetrahedron 57 ꢀ2001) 6829±6832
1.2.16. !N-Phenyl)-1-!2-thienyl)ethanamine 8d. Known.
Yield 76%; pale brown oil.
12. Yamaguchi, K.; Hayashi, A. Jpn Patent 01,290,606; Chem.
2
9
Abstr., 1990, 112, P193797c. Kobow, M.; Sprung, W. D.;
Schulz, E. Ger. Patent DD262,021; Chem. Abstr., 1989, 110,
232078z.
1
.2.17. !N-Phenyl)-a-2-propenyl-p-chlorobenzomethan-
amine 8e. Known. Yield 44%; yellow oil.
1
6b
13. Ogumi, N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem.
Lett. 1983, 841±842.
1
8
+
.2.18. !N-Phenyl)-1-!pyridin-3-yl)ethanamine 8f. Yield
6%; pale orange solid, mp 688C; IR +KBr), n 3384
NH), 3030, 1607 cm ; H NMR +CDCl ): d 1.48 +d, 3H,
14. Schulz, E.; Sprung, W. D.; Kroening, G. Pharmazie 1983, 38,
310±315.
max
2
1 1
3
15. +a) Kleinman, E. F. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, B. M., Eds.; Pergamon: Oxford, 1991; Vol. 2,
pp. 915±935. +b) Manabe, K.; Mori, Y.; Kobayashi, S. Synlett
1999, 1401. +c) Akiyama, T.; Takaya, J.; Kogashima, H. Synlett
1999, 1428±1429. +d) Hart, D. J.; Kanai, K.; Thomas, D. G.;
Yang, T.-K. J. Org. Chem. 1983, 48, 289±294.
Jˆ7.2 Hz, NCHCH ), 3.71 +br. s, 1H, NH), 4.46 +q, 1H,
3
1
3
Jˆ7.9 Hz, NCHCH ), 6.40±7.70 +m, 9H); C NMR
3
+
CDCl ): d 24.5 +CH ), 51.0 CH), 113.1 +CH), 114.8
3 3
+
1
CH), 126.3 +CH), 128.9 +CH), 133.2 +CH), 134.6 +CH),
51.2 +C), 151.7 +CH), 156.9 +C); +calcd for C H N : C,
13 14 2
7
8.76; H, 7.12. Found: C, 71.98; H, 7.28%).
16. +a) Dudot, B.; Chiaroni, A.; Royer, J. Tetrahedron Lett. 2000,
1, 6355±6359. +b) Wang, D.-K.; Zhou, Y.-G.; Tang, Y.; Hou,
4
1
.2.19. !N-Phenyl)-a-!n-butyl)-o-hydroxybenzomethan-
amine 8g. Yield 63%; yellow oil.
X.-L.; Dai, L. X. J. Org. Chem. 1999, 64, 4233±4237. +c) Loh,
T.-P.; Liung, S. B. K. W.; Tan, K.-L.; Wei, L.-L. Tetrahedron
2
8
2
000, 56, 3227±3237.
7. +a) Knochel, P.; Singer, R. Chem. Rev. 1993, 93, 2117±2188.
b) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
1
Acknowledgements
+
Chem., Int. Ed. 2000, 39, 4414±4435.
8. Saidi, M. R.; Khalaji, H. R.; Ipaktschi, J. J. Chem. Soc., Perkin
We thank `Volkswagen-Stiftung, Federal Republic of
Germany' for ®nancial support towards the purchase chemi-
cals and equipment. M. R. Saidi thanks the Iranian National
Research Council for partial ®nancial support.
1
1
2
2
Trans. 1 1997, 1983±1986.
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Lett. 1997, 38, 8071±8072.
0. Saidi, M. R.; Javanshir, S.; Mojtahedi, M. M. J. Chem. Res. ꢀS)
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