Environmentally benign regio-and stereoselective synthesis of functionalized tertiary amines

Article abstract of DOI:10.1002/cjoc.201090217

The environmentally benign, regio-and stereoselective synthesis of functionalized tertiary amine 3 from acetates of Baylis-Hillman adducts with the aliphatic primary amines in the absence of any solvent and catalysts was reported.

Full text of DOI:10.1002/cjoc.201090217

FULL PAPER
Environmentally Benign Regio- and Stereoselective Synthesis
of Functionalized Tertiary Amines
Wang, Rendonga(王仁冬)
Li, Dafenga(李大峰)
Li, Jiana(李健)
Li, Chunjua(李春举)
Liu, Juna,b(刘俊)
Jia, Xueshun*,a,b(贾学顺)
Zhai, Hongbin*,b(翟宏斌)
a Department of Chemistry, Shanghai University, Shanghai 200444, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
The environmentally benign, regio- and stereoselective synthesis of functionalized tertiary amine 3 from ace-
tates of Baylis-Hillman adducts with the aliphatic primary amines in the absence of any solvent and catalysts was
reported.
Keywords environmentally benign, regio- and stereoselective synthesis, functionalized tertiary amine, Bay-
lis-Hillman adduct, aliphatic primary amine
Introduction
And many excellent results were also demonstrated.9
Recently, we also focused on searching more “green” or
environmentally friendly chemical processes.10 As a
continuation of our interest in Baylis-Hillman and green
chemistry, herein we wish to report the regio- and
stereoselective synthesis of functionalized tertiary
amines 3 via the reaction of acetates of Baylis-Hillman
adducts 1 with aliphatic primary amines 2 under the
catalyst- and solvent-free conditions (Scheme 1).
Tertiary amines are widely present in a variety of
natural products and drugs.1 Espectially, tertiary amines
are an extremely important class of compounds from the
drug discovery perspective. Indeed no less than a quar-
ter of registered drugs contain tertiary amines.2 They are
particularly common in drugs which are active within
the central nervous system. The allylamine functionality
is found in a wide range of biologically active com-
pounds.3 Allylamines are also valuable synthetic inter-
mediates for the preparation of α- and β-amino acids,
alkaloids, and aza-carbohydrate derivatives.4 In addition,
it is well known that structural and functional diversity
plays an important role in the drug discovery process
because they offer means for the structural derivatiza-
tion. Consequently, the development of simple, conven-
ient, and new methodologies for the synthesis of tertiary
amines, in particular, the highly functionalized tertiary
amines continues to be a challenging endeavor in syn-
thetic organic chemistry.5
The Morita-Baylis-Hillman (MBH) reaction has be-
come one of the powerful carbon-carbon bond forming
methods in organic synthesis.6 The MBH reaction pro-
vides molecules possessing hydroxy, alkenyl, and elec-
tron-withdrawing groups in close proximity, which
makes it valuable in a number of stereoselective trans-
formation processes.7 Furthermore, many strategies/
methodologies have been successfully employed in the
syntheses of biologically active molecules and natural
products.8 In the past several years, we have paid much
attention to the application of Baylis-Hillman adducts.
Scheme 1
Results and discussion
Our initial experiment was carried out with Bay-
lis-Hillman adduct 1a (R1＝phenyl, EWG＝COOMe)
and benzyl amine 2a as model substrates. In a typical
experiment, 3 mmol of 1a was added to 1 mmol of 2a
under solvent- and catalyst-free conditions, and the
mixture was then stirred at 80 ℃. To our delight, this
model reaction finished within 3 h and the corres-
ponding functionalized tertiary amine 3a was afforded
in 92% yield (Table 1, Entry 1). Furthermore, high
1
E,E-selectivity was observed from the H NMR spec-
*
E-mail: xsjia@mail.shu.edu.cn
Received November 11, 2009; revised March 3, 2010; accepted March 30, 2010.
Project supported by the National Natural Science Foundation of China (Nos. 20872087, 20902057), the Key Laboratory of Synthetic Chemistry of
Natural Substances, Chinese Academy of Sciences, Shanghai Leading Academic Discipline (No. J50101) and Innovation Fund of Shanghai Univer-
sity.
Chin. J. Chem. 2010, 28, 1253— 1256
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1253

Wang et al.
FULL PAPER
Table 1 Synthesis of functionalized tertiary aminesa
This procedure represents a very operationally simple
yet powerful method for the construction of two car-
bon-nitrogen bonds and two carbon-carbon double
bonds in one pot. Furthermore, the resulted functional-
ized tertiary amines 3 have reactive ester group, car-
bon-carbon double bond, cyano and tertiary nitrogen
atom, which enable further modifications leading to
molecular diversity. Thus the present method has poten-
tial to be applied in medicinal and synthetic chemistry.
Studies on the broading scope of the reaction are cur-
rently in progress in our laboratory. We believe that our
method will find its use in organic synthesis, especially
in large-scale industrial preparation.
Entry Amine 2
R1
EWG
Yieldb/%
92 (3a)
88 (3b)
96 (3c)
94 (3d)
E,E/E,Zc
1
2
3
4
H
CO2Me
94∶6
4-Me CO2Me
4-Cl CO2Me
91∶9
86∶14
89∶11
H
CN
5
H
CO2Me
97 (3e)
96 (3f)
95 (3g)
92 (3h)
89∶11
89∶11
83∶17
83∶17
6
7
8
4-Me CO2Me
4-Cl CO2Me
H
H
H
CN
Experimental
9
CO2Me
CN
92 (3i)
93 (3j)
83∶17
Unless otherwise stated, all reagents were commer-
cially purchased and used without further purification.
Baylis-Hillman adducts were easily prepared by addi-
tion of aromatic aldehydes with methyl acrylate. The 1H
NMR spectra were recorded on Brucker AC-500 (500
MHz) spectrometer in CDCl3 using TMS as an internal
standard. 13C NMR spectra were measured with Brucker
AC-125 spectrometer. EI-MS were determined with a
HP5989B mass spectrometer. IR spectra were taken as
KBr discs with a Bruck vector 22 spectrometer. Ele-
mental analyses were performed on a Vario EL III ele-
ment analyzer.
General procedure for the synthesis of function-
alized tertiary amines (3) To a stirred solution of 1
mmol aliphatic primary amines 2, 3 mmol of Bay-
lis-Hillman adduct 1 was added. The resulting mixture
was allowed to react at 80 ℃ for 3 h. Then, the reaction
mixture was cooled to room temperature and purified by
column chromatography using ethyl acetate and petro-
leum ether (V∶V＝1∶15) as eluent to afford the cor-
responding product 3a—3l in good to excellent yields.
The products were identified by IR, 1H NMR, 13C NMR,
MS and elemental analyses.
10
84∶16
11
12
H
H
CO2Me
CN
90 (3k)
94 (3l)
80∶20
100∶0
a Reaction conditions: Baylis-Hillman adduct 1 (3 mmol), amine
b
c
2 (1 mmol), 80 ℃; Isolated yields; The ratio was determined
by the 1 H NMR spectrum.
trum of 3a. We have also performed a number of con-
trol experiments: (1) at room temperature, the reaction
proceeded slowly in relatively low yields; (2) when the
ratio of 1a and 2a was 2∶1, 3a was obtained in 87%
yield; (3) when the ratio of 1a and 2a was 1∶2, the
mixture of secondary amine and tertiary amine was ob-
served; (4) when the ratio of 1a and 2a was 1∶3, only
secondary amine was observed; (5) significant solvent
effect was observed in our experiments and solvent-free
case was found to be the best choice. When THF and
DMF were used as solvent in this reaction, the reaction
time was increased and the desired product 3a was iso-
lated in relatively lower yields compared with the neat
condition.
1
Compound 3a: Viscous oil; H NMR (CDCl3, 500
Encouraged by these experimental results, a series of
aliphatic primary amines 2 were treated with Bay-
lis-Hillman adducts 1 at 80 ℃ under catalyst- and sol-
vent-free conditions. As shown in Table 1, various
aliphatic primary amines underwent smooth conversion
to corresponding functionalized tertiary amines 3 in
good to excellent yields. And the good E,E-stereo-
selectivity was demonstrated in all cases and no side
products were observed. In addition, to establish the
generality of the present transformation, a series of
aromatic amines were then tested with Baylis-Hillman
adducts 1. Aromatic amines also underwent smooth
amination under same reaction conditions, however, no
functionalized tertiary amines were observed. Only high
yields of secondary amines were afforded.
MHz) δ: 7.79 (s, 2H), 7.52 (d, J＝7.5 Hz, 4H), 7.26—
7.17 (m, 11H), 3.70 (s, 6H), 3.54 (s, 4H), 3.50 (s, 2H);
IR －(KBr) ν: 3059, 3026, 2948, ＋2843, 1707, 1622, 1576
cm 1; MS (EI) m/z: 456 (M ＋1). Anal. calcd for
C29H29NO4: C 76.46, H 6.42, N 3.07; found C 76.71, H
6.38, N 2.96.
Compound 3b: Viscous oil; 1H NMR (CDCl3, 500
MHz) δ: 7.77 (s, 2H), 7.44 (d, J＝8.0 Hz, 4H), 7.25—
7.21 (m, 5H), 6.98 (d, J＝8.0 Hz, 4H), 3.69 (s, 6H),
3.55 (s, 4H), 3.52 (s, 2H), 2.30 (s, 6H－); IR (KBr) ν:
1
3026, 2949, 2850, 1707, 1609, 1511 cm . Anal. calcd
for C31H33NO4: C 76.99, H 6.88, N 2.90; found C 77.16,
H 6.79, N 2.83.
Compound 3c: Viscous oil; 1H NMR (CDCl3, 500
MHz) δ: 7.72 (s, 2H), 7.44 (d, J＝8.5 Hz, 4H), 7.31—
7.15 (m, 5H), 7.12 (d, J＝8.5 Hz, 4H), 3.71 (s, 6H),
3.50 (s, 4H), 3.49 (s, 2H－); IR (KBr) ν: 3061, 2949, 2845,
1708, 1623, 1590 cm 1; MS (EI) m/z: 523 (M＋).
Anal. calcd for C29H27Cl2NO4: C 66.42, H 5.19, N 2.67;
In summary, we have developed an environmentally
benign, facile, regio- and stereoselective synthesis of the
functionalized tertiary amines 3 in excellent yields from
acetates of Baylis-Hillman adducts with aliphatic pri-
mary amines in the absence of any solvent and catalyst.
1254
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1253— 1256

Regio- and Stereoselective Synthesis of Functionalized Tertiary Amines
found C 66.53, H 5.32, N 2.59.
1.15 (s, 9H); IR (KBr) ν: 3057, 3024, 2970, 2839, 1717,
1639 cm . Anal. calcd for C26H31NO4: C 74.08, H 7.41,
－1
Compound 3d: Viscous oil; 1H NMR (CDCl3, 500
MHz) δ: 7.78 (d, J＝8.0 Hz, 4H), 7.46—7.23 (m, 11H),
7.23 (s, 2H), 3.80 (s, 2H), 3.52 (s, 4H); 13C NMR
(CDCl3, 125 MHz) δ: 147.1, 137.3, 133.0, 130.5, 129.8,
129.0, 128.8, 127.50, 124.70, 118.7, 108.1, 57.3, 48.9;
IR (KBr)－ν: 3053, 3025, 2920, 2828＋, 2212, 1622, 1573,
N 3.32; found C 73.84, H 7.53, N 3.47.
1
Compound 3l: Viscous oil; H NMR (CDCl3, 500
MHz) δ: 7.70 (s, 2H), 7.69 (d, J＝1.0 Hz, 2H), 7.35—
7.34 (m, 8H), 3.55 (s, 4H), 1.23 (s, 9H－); IR (KBr) ν:
1
3059, 3026, 2970, 2823, 2211, 1623 cm . Anal. calcd
1
1492 cm ; MS (EI) m/z: 389 (M ). Anal. calcd for
for C24H25N3: C 81.09, H 7.09, N 11.82; found C 80.76,
H 7.13, N 11.72.
C27H23N3: C 83.26, H 5.95, N 10.79; found C 83.51, H
5.82, N 10.64.
Compound 3e: Viscous oil; 1H NMR (CDCl3, 500
MHz) δ: 7.78 (s, 2H), 7.42 (d, J＝7.5 Hz, 4H), 7.25—
7.27 (m, 11H), 3.97 (q, J＝7.0 Hz, 1H), 3.68 (s, 6H),
3.54 (s, 2H), 3.41 (s, 2H), 1.27 (d, J＝7.0 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) δ: 169.4, 142.0, 141.9, 141.8,
141.5, 135.1, 131.2, 130.1, 128.7, 126.7, 78.8, 57.3,
54.5, 51.9, 10.1; IR (KBr) ν: 3058, 3026, 2948, 1714,
References
1
(a) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.;
Venkatateswaelu, Y.; Rosser, R. M.; Faulkner, D. J.; Chen,
M. H. M.; Clary, J. J. Am. Chem. Soc. 1984, 106, 7983.
(b) Daranas, A. H.; Fernandez, J. J.; Gavln, J. A.; Norte, M.
Tetrahedron 1999, 55, 5539.
－1
(c) Bleicher, L. S.; Cosford, N. D. P. J. Org. Chem. 1999,
64, 5299.
(d) Agosti, A.; Britto, S.; Renaud, P. Org. Lett. 2008, 10,
1417.
1625, 1576 cm . Anal. calcd for C30H31NO4: C 76.73,
H 6.65, N 2.98; found C 76.59, H 6.71, N 3.02.
1
Compound 3f: Viscous oil; H NMR (CDCl3, 500
MHz) δ: 7.72 (s, 2H), 7.29 (d, J＝8.0 Hz, 4H), 7.22—
6.99 (m, 9H), 3.94 (q, J＝7.0 Hz, 1H), 3.72 (s, 1H),
3.62 (s, 6H), 3.49 (s, 1H), 3.38 (d, J＝12.5 Hz, 2H),
2.31 (s, 6H), 1.28 (d, J＝7.0 Hz, 3H); IR (KBr) ν: 3026,
2
3
4
This estimate was obtained by searching the World Drugs
Index (Derwent Information Ltd.) for compounds with a
tradename which also contain a tertiary amine group.
(a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103,
2921.
(b) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1.
(a) Burgess, K.; Liu, L.; Pal, B. J. Org. Chem. 1993, 58,
4758.
－1
2948, 2843, 1712, 1608, 1511 cm . Anal. calcd for
C32H35NO4: C 77.24, H 7.09, N 2.81; found C 77.41, H
6.87, N 2.93.
1
Compound 3g: Viscous oil; H NMR (CDCl3, 500
MHz) δ: 7.68 (s, 2H), 7.32—7.14 (m, 13H), 3.94 (q, J＝
7.0 Hz, 1H), 3.74 (s, 1H), 3.65 (s, 6H), 3.47 (s, 1H),
3.33 (d, J＝12.5 Hz, 2H), 1.28 (d, J＝6.5 Hz, 3H); IR
(KBr) ν: 3061, 3027, 2949, 2845, 1713, 1625, 1591
(b) Ito, K.; Akashi, S.; Saito, B.; Katsuki, T. Synlett 2003,
1809.
(c) Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999, 121,
8126.
(d) Liu, H.; Liang, X.; Sohoel, H.; Buelow, A.; Bols, M. J.
Am. Chem. Soc. 2001, 123, 5116.
－1
cm . Anal. calcd for C30H29Cl2NO4: C 66.92, H 5.43,
N 2.60; found C 66.73, H 5.61, N 2.64.
1
Compound 3h: Viscous oil; H NMR (CDCl3, 500
5
(a) Sreedhar, B.; Reddy, P. S.; Prakash, B. V.; Ravindra, A.
Tetrahedron Lett. 2005, 46, 7019.
MHz) δ: 7.77 (d, J＝8.0 Hz, 4H), 7.47—7.38 (m, 11H),
7.29 (s, 2H), 4.13 (q, J＝7.0 Hz, 1H), 3.52 (d, J＝1.0
Hz, 2H), 3.43 (d, J＝1.0 Hz, 2H), 1.50 (d, J＝7.0 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ: 145.1, 141.6,
137.3, 133.0, 130.5, 129.8, 129.0, 128.8, 127.50, 124.70,
118.7, 58.7, 49.1, 11.2; IR (KBr) ν: 3059, 2930, 2839,
(b) Watson, I. D. G.; Styler, S. A.; Yudin, A. K. J. Am.
Chem. Soc. 2004, 126, 5086.
(c) Wei, C.; Li, C. J. Am. Chem. Soc. 2003, 125, 9584.
(d) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763.
(e) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron 2006, 62,
6312.
(f) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am.
Chem. Soc. 1989, 111, 2588.
(g) Yang, S.; Hsu, Y.; Gan, K. Tetrahedron 2006, 62, 3949.
(h) Kuwano, R.; Takahashi, M.; Ito, Y. Tetrahedron Lett.
1998, 39, 1017.
(i) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323.
(j) Akamatsu, H.; Kusumoto, S.; Fukase, K. Tetrahedron
Lett. 2002, 43, 8867.
(k) Singh, V.; Pathak, R.; Kanojiya, S.; Batra, S. Synlett
2005, 2465.
(l) Klemarczyk, P. Polymer 2001, 42, 2837.
(m) Akssira, M.; Guemmout, F. E.; Bauchat, P.; Foucaud, A.
Can. J. Chem. 1994, 72, 1357.
－1
2212, 1623 cm . Anal. calcd for C28H25N3: C 83.34, H
6.24, N 10.41; found C 83.52, H 6.19, N 10.33.
1
Compound 3i: viscous oil; H NMR (CDCl3, 500
MHz) δ: 7.73 (s, 2H), 7.47 (d, J＝1.5 Hz, 4H), 7.32—
7.30 (m, 6H), 3.70 (s, 6H), 3.53 (s, 4H), 2.37 (m, 1H),
1.66—0.97 (m, 10H);－ IR (KBr) ν: 3058, 3025, 2927,
1
2852, 1714, 1624 cm . Anal. calcd for C28H33NO4: C
75.14, H 7.43, N 3.13; found C 75.33, H 7.59, N 2.92.
1
Compound 3j: Viscous oil; H NMR (CDCl3, 500
MHz) δ: 7.77 (d, J＝8.0 Hz, 4H), 7.75 (s, 2H), 7.41—
7.39 (m, 6H), 3.51 (s, 4H), 2.63 (m, 1H), 1.94—1.25 (m,
10H); IR (KBr) ν: 3058, 3025, 2927, 2852, 1714, 1624
－1
cm . Anal. calcd for C26H27N3: C 81.85, H 7.13, N
11.01; found C 81.73, H 7.35, N 10.87.
1
Compound 3k: Viscous oil; H NMR (CDCl3, 500
MHz) δ: 7.72 (s, 1H), 7.50—7.14 (m, 10H), 6.84 (s, 1H),
6
(a) Ciganek, E. Org. Reactions 1997, 51, 201.
3.76 (s, 3H), 3.70 (s, 2H), 3.46 (s, 3H), 3.30 (s, 2H),
Chin. J. Chem. 2010, 28, 1253— 1256
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1255

Wang et al.
FULL PAPER
(b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001.
(c) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653.
(c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
(d) Brzezinski, L. J.; Rafel, S.; Leahy, J. M. J. Am. Chem.
Soc. 1997, 119, 4317.
7
(a) Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.;
Reddy, M. V. R.; O’Donnel, M. J. J. Am. Chem. Soc. 2005,
127, 13450.
(b) Kabalka, G. W.; Venkataiah, B.; Dong, G. Or-
ganometallics 2005, 24, 762.
(c) Chung, Y. M.; Gong, J. H.; Kim, T. H.; Kim, J. N. Tet-
rahedron Lett. 2001, 42, 9023.
(d) Singh, V.; Saxena, R.; Batra, S. J. Org. Chem. 2005, 70,
353.
(e) Wori, M.; Kuroda, S.; Dekura, F. J. Am. Chem. Soc.
1999, 121, 5591.
(f) Trost, B. M.; Thiel, O. R.; Tsui, H. C. J. Am. Chem. Soc.
2003, 125, 13155.
(a) Li, S. Y.; Li, J.; Jia, X. Synlett 2007, 1115.
(b) Zhao, P.; Li, J.; Jia, X. Synlett 2008, 932.
(c) Li, J.; Wang, X. X.; Zhang, Y. M. Tetrahedron Lett.
2005, 46, 5233.
(d) Li, J.; Wang, X. X.; Zhang, Y. M. Synlett 2005, 1039.
(e) Li, J.; Qian, W. X.; Zhang, Y. M. Tetrahedron 2004, 60,
5793.
9
(e) Patra, A.; Roy, A. K.; Batra, S.; Bhaduri, A. P. Synlett
2002, 1819.
8
(a) Radha Krishna, P.; Nasingam, M.; Kannan, V. Tetrahe-
dron Lett. 2004, 45, 4773.
10 (a) Jia, X.; Huang, Q.; Li, J.; Li, S.; Yang, Q. Synlett 2007,
806.
(b) Rodgen, S. A.; Schaus, S. E. Angew. Chem., Int. Ed.
2006, 45, 3913.
(b) Wang, G.; Li, C.; Li, J.; Jia, X. Tetrahedron Lett. 2009,
50, 1438.
(E0911112 Sun, H.; Dong, H.)
1256
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1253— 1256