A facile synthesis of β-amino carbonyl compounds through an aza-Michael addition reaction under solvent-free conditions

Article abstract of DOI:10.1039/c3ra46789a

An efficient and eco-friendly process for the synthesis of β-amino carbonyl compounds was introduced in this paper. The oxanorbornene β-amino esters and β-enamine esters were successfully prepared from oxabornene and amines by using solvent-free aza-Michael addition reaction in the absence of any catalyst. Oxanorbornene β-amino esters were the major product at room temperature, but higher temperature (e.g. 90 °C) led to the formation of β-enamine esters. In addition, all of the target compounds were characterized by IR, ¹H NMR, ¹³C NMR, and HR-MS. A possible reaction pathway was also proposed.

Full text of DOI:10.1039/c3ra46789a

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A facile synthesis of b-amino carbonyl compounds
through an aza-Michael addition reaction under
solvent-free conditions†
Cite this: RSC Adv., 2014, 4, 10188
ab
Yanqing Yin,a Jiahui Guo,a Jiong Wang,ab Baomin Fanab
*
Chao Huang,
ab
*
and Lijuan Yang
An efficient and eco-friendly process for the synthesis of b-amino carbonyl compounds was introduced in
this paper. The oxanorbornene b-amino esters and b-enamine esters were successfully prepared from
oxabornene and amines by using solvent-free aza-Michael addition reaction in the absence of any
catalyst. Oxanorbornene b-amino esters were the major product at room temperature, but higher
temperature (e.g. 90 ꢀC) led to the formation of b-enamine esters. In addition, all of the target
compounds were characterized by IR, 1H NMR, 13C NMR, and HR-MS. A possible reaction pathway was
also proposed.
Received 19th November 2013
Accepted 27th January 2014
DOI: 10.1039/c3ra46789a
www.rsc.org/advances
Introduction
b-Amino carbonyl structural units exist extensively in natural
products and bioactive compounds.1 They are usually used as
intermediates for the preparation of amino alcohols, diamines,
b-amino acid derivatives and other nitrogen-containing mole-
cules.2 As a result, their synthesis and application have received
a great deal of recent attention in the elds of organic chemistry
and medicinal chemistry.3
The Mannich-type reaction could be a useful and practical
protocol for constructing b-amino carbonyl units.4 Unfortu-
nately, harsh reaction conditions and longer reaction time are
commonly required.5 On the other hand, aza-Michael addition
reaction, addition of an amine to an electron decient alkene,
offers an easy access to b-amino carbonyl compounds.6,7 To
date, a number of synthetic approaches to b-amino carbonyl
compounds have been established through aza-Michael addi-
tion.8 A variety of catalysts, such as acetic acid, boric acid,9 ionic
liquid,10 cyclodextrin, transition metal,11 lanthanide halides,
triates or silica gel, solid salts and quaternary ammonium salt,
have been developed for this purpose.12 However, drawbacks
including use of expensive reagents or organic solvents, or an
excess of catalyst and high temperature still exist.13 Thus, the
development of an efficient and environmentally benign
Scheme 1 Synthesis of b-amino carbonyl compounds 3 and 4.
protocol could be highly desirable for the synthesis of b-amino
carbonyl compounds.
Herein, an efficient and eco-friendly procedure for the
synthesis of b-amino carbonyl compounds from oxabornene
and amine via aza-Michael addition as depicted in Scheme 1
was disclosed without use of any catalyst and solvent. Oxa-
norbornene b-amino esters 3 and (Z)-b-enamine esters 4 were
ꢀ
successfully prepared at r.t. and 90 C, respectively.
Results and discussion
To establish the synthetic process for b-amino carbonyl
compounds from oxabornene 1 and amines 2 through solvent-
free aza-Michael addition reaction, the reaction of oxabornene
1 and 1-phenylpiperazine 2a were initially selected as a model
reaction. As a result, diethyl 2-(4-phenylpiperazin-1-yl)-7-oxa-
bicyclo [2.2.1]hept-5-ene-2,3-dicarboxylate 3a was obtained as
the product. As shown in Table 1, acetone, THF, DCE and
toluene as the solvent, the reaction gave poor results (Table 1,
entries 1–4). To be delighted, the reaction ran well at r.t.
aKey Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Yunnan University of Nationalities, Kunming,
650500, China. E-mail: huang.chao@hotmail.com
bEngineering Research Center of Biopolymer Functional Materials of Yunnan, Yunnan
University of Nationalities, Kunming, 650500, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46789a
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Table 1 Effect of solvent, temperature and role of molar-ratio on the
formation of oxanorbornene b-amino esters 3a
the yield of product 4 was slightly increased (entries 3
and 4). Those results encouraged us to further explore the
reaction in order to develop novel access to b-amino carbonyl
compound 4.
To establish the synthetic process for (Z)-b-enamine esters 4,
a variety of reaction parameters and the results are summarized
in Table 4. THF, toluene, acetone and DMF as the solvent, yields
of diethyl 2-(phenylamino)fumarate 4a were found to be in the
ꢀ
range of 27% to 63% at 90 C for 24 h (Table 4, entries 1–4).
Entry
Solvent
1 : 2a
Temp. (ꢀC)
Time
Yielda (%)
Surprisingly, better yield was achieved for 6 h under solvent-less
conditions (entries 5 vs. 1–4), suggesting solvent-free was
favourable for the reaction. In addition, higher temperature is
benecial for the generation of b-amino ester 4a. The yield of 4a
reached to 77% at 90 ꢀC (entries 5). Further increasing the
1
2
3
4
5
6
7
8
Acetone
THF
DCE
Toluene
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
2 : 1
r.t.
r.t.
r.t.
r.t.
r.t.
30
12 h
12 h
12 h
12 h
30 min
30 min
30 min
30 min
1 min
1 min
1 min
1 min
1 min
60
59
64
62
75
70
63
48
53
51
75
83
68
ꢀ
reaction temperature to 110 C had negative effect on 4a yield
(entries 10). And excellent yield was achieved at 1 : 2 molar ratio
of 1 to 2a (entries 5 vs. 11–14).
50
70
The generality of the reaction was examined and the results
are presented in Table 5. A wide range of amines 2 reacted with
oxabornene 1 to afford (Z)-b-enamine esters 4a–f. The reactions
with alkylamine were easier to perform (Table 4, entries 3–6) in
0.5 h or 1 min. But aromatic amines needed longer time to
react, as the weaker activity (entries 1 and 2 vs. 3–6). Generally,
cyclic amines can produce enamines faster than open-chain
amines (entries 4–6 vs. 3).
9
r.t.
r.t.
r.t.
r.t.
r.t.
10
11
12
13
1 : 1
1 : 1.5
1 : 2
1 : 3
a
Isolated yield by neutral alumina column chromatography.
The plausible mechanism for the formation of oxa-
without solvent under other identical conditions, leading to norbornene b-amino esters 3 and (Z)-b-enamine esters 4 was
75% isolated yield of 3a (entry 5). Accordingly, the solvent-free also proposed on the basis of the experimental results. As
aza-Michael addition reaction was chosen for the further showed in Scheme 2, the reaction of the amine and oxabornene
investigation.
1 generate the oxanorbornene b-amino ester 3 through aza-
The temperature has detrimental effect on the formation of Michael addition reaction. Subsequently, 3 goes at higher
oxanorbornene b-amino ester 3a. The yield decreased from 75% temperature through retro-Diels–Alder reaction to produce
ꢀ
to 48% as the temperature went from r.t. up to 70 C (Table 1, (Z)-b-enamine esters 4. This is understandable that the ther-
entries 5–8), indicating oxanorbornene b-amino ester may have modynamic product 4 forms at higher temperature; while
poor stability at higher temperature. Interestingly, 1 min was oxanorbornene b-amino ester 3 is a major product at room
enough to get better 3a yield (entry 11 vs. 5); on the other hand, temperature.15 Indeed, compound 4a and 5 were obtained from
ꢀ
excellent yield up to 83% was reached at 1 : 2 molar ratio of 1 to thermal degradation of 3h at 90 C, identied by spectroscopy
2a (entries 9–13).
(see, ESI†).
The applicability of various amines on solvent-free aza-
Michael addition reaction was further investigated. The results
showed that it is a general method to produce oxanorbornene b-
amino esters 3 as listed in Table 2. Aliphatic amines have higher
Experimental
General method
activity than aromatic counterparts (Table 2, entries 1–7 vs. 8– All compounds were fully characterized by spectroscopic tech-
10), especially cyclic amines, ran much faster (entries 1–4), niques. The NMR spectra were recorded on a Bruker-Avance 400
being in well agreement with the literature results.14 Whereas, MHz spectrometer (1H: 400 MHz, 13C: 100 MHz) with tetrame-
longer reaction time was needed for aromatic amines for thylsilane (TMS) as the internal standard (d 0.0 ppm), chemical
completing the reaction (entries 8–10), probably due to the shis (d) are expressed in ppm, and J values are given in Hz.
electronic and steric effect. The yield of oxanorbornene b-amino Deuterated CDCl3 was used as a solvent. IR spectra were
esters 3 was also affected by the basicity and steric factor of recorded on a FT-IR Thermo Nicolet Avatar 360 using a KBr
the amino group and the nature of the carbonyl group (entries pellet. The reactions were monitored by thin layer chromatog-
3, 5 and 8).
raphy (TLC) using neutral alumina. The melting points were
Unexpectedly, (Z)-b-enamine esters 4 and furan 5 can be determined on an XT-4A melting point apparatus and are
obtained during the solvent-free aza-Michael addition reac- uncorrected. HRMS was performed on an Agilent LC-MSD TOF
tion. When aliphatic amines as the substrates, e.g. 2b and 2e, instrument.
just a trace amount of b-enamine ester 4 was formed and
All chemicals and solvents were used as received without
oxanorbornene b-amino ester 3 became the major product further purication unless otherwise stated. Column chroma-
(Table 3, entries 1 and 2). In the case of aromatic amines, tography was performed on neutral alumina.
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Table 2 Preparation of various oxanorbornene b-amino esters 3 through solvent-free aza-Michael addition reaction at r.t.
Entry
1
Amine 2
Product 3
Time
Isolated yielda (%)
1 min
83
2
3
1 min
1 min
86
89
4
5
6
1 min
0.5 h
1 h
97
76
54
7
8
5 h
93
62
12 h
9
10 h
24 h
78
10
—
Trace
a
The molar ratio of oxabornene 1 to amines 2 was 1 : 2; isolated yield by neutral alumina column chromatography; the progress of the reaction was
monitored by TLC.
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Table 3 Preparation of b-amino carbonyl compounds 3 and 4 through solvent-free aza-Michael addition reaction at r.t.
Entry
1
Amine 2
Time
Product 3
3 Yieldsa (%)
Product 4
4 Yields (%)
1 min
86
—
Trace
2
3
0.5 h
12 h
76
62
—
Trace
12
4
10 h
78
8
a
The molar ratio of oxabornene 1 to amines 2 was 1 : 2; isolated yield by neutral alumina column chromatography; the progress of the reaction was
monitored by TLC.
1127, 1136, 1060, 860, 755, 568 cmꢁ1 1H NMR (400 MHz,
;
Preparation of diethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-
dicarboxylate 1
CDCl3): d 7.23 (2H, m), 6.91–6.83 (3H, m), 6.59–6.57 (1H, m),
6.25–6.23 (1H, m), 5.31 (1H, s), 5.24 (1H, s), 4.23–4.11 (4H, m),
3.42 (1H, s), 3.08–2.93 (8H, m), 1.34–1.31 (3H, t, J ¼ 7.1 Hz),
1.29–1.25 (3H, t, J ¼ 7.1 Hz). 13C NMR (100 MHz, CDCl3): d 171.1,
169.9, 151.3, 140.7, 135.0, 129.2, 120.0, 116.2, 81.2, 80.2, 78.2,
61.2, 61.0, 53.3,50.2, 48.2, 14.6, 14.4; HRMS (TOF ES+): m/z calcd
for C22H28N2O5Na+ [(M + Na)+], 423.1890; found, 423.1885.
Diethyl- 2-(4-methylpiperazin-1-yl)-7-oxabicyclo[2.2.1]hept-5-
Diethyl acetylenedicarboxylate 12 mmol and furan 60 mmol
were placed in a sealed tube, which was heated at 100 ꢀC for 20
hours. The reaction mixture was distilled under vacuum. The
endoxide was obtained as a light yellow oil.16
General procedure for the synthesis of oxanorbornene b-
amino esters 3 through solvent-free aza-Michael addition
reaction
ene-2,3-dicarboxylate (3b). Yield 86%; yellow oil; IR (KBr) (nmax
,
cmꢁ1) 3447, 3136, 2838, 2345, 1733, 1455, 1378, 1266, 1127,
1
1056, 859, 808, 558 cmꢁ1; H NMR (400 MHz, CDCl3): d 6.53–
A Schlenk was charged with 1 (0.4 mmol, 95.3 mg), amine 2 (0.8
mmol), and the solution was stirred for 1 minute to 6 days at
room temperature until the 1 was completely consumed. The
mixture was puried by ash column chromatography. The
desired compounds (3a–j) were formed from 1 in yields: 54–97%.
6.51 (1H, m), 6.17–6.16 (1H, m), 5.23–5.17 (2H, m), 4.20–4.09
(4H, m), 3.35–3.34 (1H, m), 2.82 (4H, m), 2.20–2.19 (7H, m),
1.30–1.23 (6H, m); 13C NMR (100 MHz, CDCl3): d 170.1, 169.8,
140.5, 134.8, 81.0, 79.9, 77.9, 60.9, 60.7, 55.8, 53.0, 46.0, 14.3,
14.2; HRMS (TOF ES+): m/z calcd for C22H28N2O5Na+ [(M + Na)+],
423.1890; found, 423.1885.
The data of the oxanorbornene b-amino esters 3
Diethyl 2-(piperidin-1-yl)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
Diethyl- 2-(4-phenylpiperazin-1-yl)-7-oxabicyclo[2.2.1]hept-5- dicarboxylate (3c). Yield 89%; white solid; mp: 81–82 ꢀC; IR
ene-2,3-dicarboxylate (3a). Yield 83%; white solid; mp: 114– (KBr) (nmax, cmꢁ1) 3448, 3134, 2332, 1728, 1452, 1265, 1126,
1
115 ꢀC; IR (KBr) (nmax, cmꢁ1) 3447, 2333, 1731, 1597, 1452, 1263, 1061, 860, 568 cmꢁ1; H NMR (400 MHz, CDCl3): d 6.54–6.53
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Table 4 Effect of solvent reagent, temperature and molar ratio of
materials on preparation of 4a
NMR (400 MHz, CDCl3): d 6.73–6.71 (1H, dd, J ¼ 5.8, 1.6 Hz),
6.36–6.34 (1H, dd, J ¼ 5.8, 1.8 Hz), 5.08–5.06 (1H, m), 4.79 (1H,
m), 4.14–4.09 (4H, m), 3.06–3.05 (1H, d, J ¼ 4.3 Hz), 2.80–2.73
(1H, m), 2.58–2.52 (1H, m), 1.84 (1H, s), 1.53–1.46 (2H, m), 1.38–
1.33 (2H, m) 1.26–1.22 (6H, m), 0.90 (3H, t, J ¼ 7.28 Hz); 13C
NMR (100 MHz, CDCl3): d 170.8, 170.6, 137.8, 133.0, 85.6, 80.4,
75.7, 61.3, 60.9, 60.0, 45.3, 32.5, 20.5, 14.3, 14.1, 14.0; HRMS
(TOF ES+): m/z calcd for C16H25NO5Na+[(M + Na)+], 334.1624;
found, 334.1625.
Entry
Solvent
1 : 2a
Temp. (ꢀC)
Time
Yielda/%
Diethyl
2-(allylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
1
2
3
4
5
6
7
8
THF
Toluene
Acetone
DMF
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
2 : 1
1 : 1
1 : 1.5
1 : 3
90
90
90
90
90
r.t.
30
50
70
110
90
90
90
90
24 h
24 h
24 h
24 h
6 h
5 d
4 d
3 d
17 h
6 h
63
41
27
27
77
62
65
70
72
65
13
44
59
72
dicarboxylate (3g). Yield 93%; colorless oil; IR (KBr) (nmax, cmꢁ1
)
3323, 2985, 1734, 1659, 1606, 1459, 1376, 1254, 1170, 1062, 914,
859, 786, 710, 554 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 6.75–6.74
(1H, dd, J ¼ 5.8, 1.7 Hz), 6.35–6.33 (1H, dd, J ¼ 5.8, 1.8 Hz), 5.98–
5.88 (1H, m), 5.23–5.18 (1H, m), 5.11–5.07 (2H, m), 4.80–4.79
(1H, m), 4.16–4.08 (4H, m), 3.46–3.41(1H, m), 3.24–3.19 (1H, m),
3.08 (1H, d, 4.3 Hz), 2.00 (1H, s), 1.26–1.22 (6H, m); 13C NMR
(100 MHz, CDCl3): d 170.5, 170.4, 137.9, 136.0, 132.8, 116.7,
85.8, 80.4, 75.5, 61.3, 60.9, 55.9, 48.5, 14.2, 14.1; HRMS (TOF
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
9
10
11
12
13
14
38 h
36 h
19 h
5 h
+
ES+): m/z calcd for C15H22NO5 [(M + H)+], 296.1498; found,
296.1501.
Diethyl 2-(phenylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
a
Isolated yield by alumina column chromatography; the progress of the
reaction was monitored by TLC.
ꢀ
dicarboxylate (3h). Yield 62%; white solid; mp: 107–108 C; IR
(KBr) (nmax, cmꢁ1) 3385, 2974, 2331, 1735, 1604, 1511, 1449,
1377, 1321, 1254, 1062, 1011, 859, 749, 689, 551 cmꢁ1; 1H NMR
(400 MHz, CDCl3): d 7.26–7.16 (2H, m), 6.84–6.80 (4H, m), 6.47–
(1H, m), 6.20–6.18(1H, m), 5.29 (1H, s), 5.18 (1H, s), 4.25–4.11 6.46 (1H, dd, J ¼ 5.8, 1.9 Hz), 5.15–5.14 (1H, m), 5.06–5.05 (1H,
(4H, m), 3.36 (1H, s), 2.72–2.67 (4H, m), 1.46–1.36 (6H, m), 1.32– m), 4.41 (1H, s), 4.20–4.09 (4H, m), 3.19 (1H, d, J ¼ 4.4 Hz), 1.30
1.26 (6H, m); 13C NMR (100 MHz, CDCl3): d 171.3, 170.3, 140.6, (3H, t, J ¼ 7.2 Hz), 1.15 (3H, t, J ¼ 7.1 Hz); 13C NMR (100 MHz,
135.2, 81.3, 80.2, 80.1, 79.1, 60.0, 60.9, 60.8, 53.0, 50.6, 49.3, CDCl3): d 170.6, 169.8, 144.9, 138.3, 132.3, 129.1, 119.5, 115.8,
27.0, 24.6, 14.6, 14.3; HRMS (TOF ES+): m/z calcd for 86.5, 80.6, 72.4, 61.9, 61.2, 58.2, 14.1, 14.0. HRMS (TOF ES+): m/z
C
17H25NO5Na+ [(M + Na)+], 346.1624; found, 346.1622.
Diethyl 2-morpholino-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
dicarboxylate (3d). Yield 97%; yellow oil; IR (KBr) (nmax, cmꢁ1
3447, 3134, 2332, 1730, 1453, 1262, 1122, 1061, 860, 553 cmꢁ1
calcd for C18H22NO5+ [(M + H)+], 332.1492; found, 332.1483.
Diethyl 2-(p-tolylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
)
;
dicarboxylate (3i). Yield 78%; yellow oil; IR (KBr) (nmax, cmꢁ1
)
3386, 2356, 1730, 1519, 1454, 1257, 1126, 1061, 858, 814, 567
1H NMR (400 MHz, CDCl3): d 6.58–6.57 (1H, dd, J ¼ 5.8, 1.6 Hz), cmꢁ1; 1H NMR (400 MHz, CDCl3): d 7.00 (2H, d, J ¼ 8.4 Hz), 6.79
6.23–6.21 (1H, dd, J ¼ 5, 1.7 Hz), 5.26–5.23 (2H, d, J ¼ 9.5 Hz), (1H, dd, J ¼ 5.8, 1.6 Hz), 6.74–6.71 (2H, m), 6.46 (1H, dd, J ¼ 5.8,
4.28–4.11 (4H, m), 3.61–3.59 (4H, t, J ¼ 4.5 Hz), 3.38 (1H, s), 1.8 Hz), 5.13–5.12 (1H, m), 5.04 (1H, s), 4.26 (1H, s), 4.19–4.09
2.86–2.82 (2H, m), 2.74–2.73 (2H, m), 1.60 (1H, s), 1.35–1.25 (7H, (4H, m), 3.18 (1H, d, J ¼ 4.4 Hz), 2.25 (3H, s), 1.29 (3H, t, J ¼ 7.13
m); 13C NMR (100 MHz, CDCl3): d 171.1, 169.8, 140.8, 134.9, Hz), 1.17 (6H, t, J ¼ 7.13 Hz); 13C NMR (100 MHz, CDCl3): d
81.2, 79.8, 78.3, 67.8, 61.2, 60.9, 53.3, 49.7, 48.7, 14.6, 14.4; 170.7, 170.40, 142.5, 138.1, 132.5, 129.6, 129.1, 116.4, 86.3, 72.8,
HRMS (TOF ES+): m/z calcd for C16H23NO6Na+ [(M + Na)+], 61.9, 61.2, 58.1, 20.6, 14.2, 14.1; HRMS (TOF ES+): m/z calcd for
+
348.1417; found, 348.31407.
C
19H24NO5 [(M + H)+], 346.1468; found, 346.1649.
Diethyl
2-(ethylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
dicarboxylate (3e). Yield 76%; yellow oil; IR (KBr) (nmax, cmꢁ1
)
General procedure for the synthesis of (Z)-b-enamine esters 4
3447, 2980, 2357, 1733, 1457, 1377, 1257, 1126, 1061, 859, 709,
558 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 6.73–6.71 (1H, dd, J ¼
5.8, 1.7 Hz), 6.36–6.34 (1H, dd, J ¼ 5.8, 1.8 Hz), 5.07–5.06 (1H,
m), 4.79 (1H, m), 4.14–4.09 (4H, m), 3.07–3.05 (1H, d, J ¼ 4.3
Hz), 2.81–2.78 (1H, m), 2.65–2.60 (1H, m), 1.78 (1H, s), 1.26–1.22
(6H, t, J ¼ 7.1 Hz), 1.17–1.13 (3H, t, J ¼ 7.1 Hz); 13C NMR (100
MHz, CDCl3): d 170.6, 170.4, 137.7, 132.8, 85.5, 80.3, 75.6, 61.1,
60.8, 55.9, 39.8, 15.6, 14.2, 14.0. HRMS (TOF ES+): m/z calcd for
A Schlenk was charged with diethyl 7-oxabicyclo[2.2.1]hepta-2,5-
diene-2,3-dicarboxylate 1 (0.4 mmol, 95.3 mg), amine 2 (0.8
mmol), and the solution was stirred for 1 minute to 6 days at
90 ꢀC until 1 was completely consumed. The mixture was
puried by ash column chromatography. The desired
compounds 4 were formed from 1 in yields 42–77%.
The data of the (Z)-b-enamine esters 4
C
14H21NNaO5+ [(M + Na)+], 306.1312; found, 306.1316.
Diethyl 2-(butylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
Diethyl 2-(phenylamino)fumarate (4a). Yield 77%; yellow
oil; IR (KBr) (nmax, cmꢁ1) 3279, 2984, 2344, 1735, 1668, 1607,
dicarboxylate (3f). Yield 54%; yellow oil; IR (KBr) (nmax, cmꢁ1
)
3381, 2357, 1734, 1664, 1460, 1259, 1127, 860, 550 cmꢁ1
;
1H 1498, 1382, 1274, 1208, 1137, 1039, 861, 755, 693, 553 cmꢁ1; 1H
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Table 5 Synthesis of (Z)-b-enamine esters 4 under solvent-free condition at 90 ꢀ
C
Entry
1
Amine 2
Product 4
Time
6 h
Isolated yielda (%)
PhNH2
4a
4b
77
2
3
p-MePhNH2
4 h
54
42
4c
0.5 h
4
5
4d
1 min
70
4e
4f
1 min
1 min
61
73
6
a
The molar ratio of oxabornene 1 to amines 2 was 1 : 2; isolated yield by neutral alumina column chromatography; the progress of the reaction was
monitored by TLC.
Scheme 2 Plausible mechanism for solvent-free aza-Michael addition reaction.
NMR (400 MHz, CDCl3): d 9.68 (1H, s), 7.30–7.25 (2H, m), 7.11–
7.07 (1H, m), 6.92 (2H, d, J ¼ 7.7 Hz), 5.38 (1H, s), 4.22–4,13
(4H, m), 1.30 (3H, t, J ¼ 7.1 Hz), 1.09 (3H, t, J ¼ 7.1 Hz); 13C
NMR (100 MHz, CDCl3): d 169.7, 164.5, 148.5, 140.5, 129.2,
124.3, 121.1, 93.9, 62.2, 60.1, 14.5, 13.7. HRMS (TOF ES+): m/z
Diethyl 2-(p-tolylamino)fumarate (4b). Yield 54%; yellow oil;
IR (KBr) (nmax, cmꢁ1) 3448, 2331, 1735, 1666, 1613, 1519, 1457,
1274, 1207, 1071, 859, 811, 551; 1H NMR (400 MHz, CDCl3): d
9.62 (1H, s), 7.07–7.05 (2H, m), 6.83–6.81 (2H, m), 5.32 (1H, s),
4.21–4.12 (4H, m), 2.29 (3H, s), 1.29 (3H, t, J ¼ 7.1 Hz), 1.10 (3H,
t, J ¼ 7.1 Hz); 13C NMR (100 MHz, CDCl3): d 168.8, 163.5, 147.9,
136.9, 133.1, 128.7, 120.3, 91.8, 61.1, 58.9, 19.9, 13.4, 12.8.
calcd for
286.1055.
C +
14H17NO4Na+ [(M Na)+], 286.1050; found,
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Foundation of Key Laboratory of Chemistry in Ethnic-medicine
Resources (Yunnan Nationalities University), Ministry of
Education (MZY1115).
Diethyl 2-((1-phenylethyl)amino)fumarate (4c). Yield 42%;
yellow oil; IR (KBr) (nmax, cmꢁ1) 3449, 3134, 2981, 2356, 1733,
1662, 1605, 1453, 1372, 1264, 1209, 1132, 1045, 861, 779, 698,
564 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 8.43 (1H, d, J ¼ 6.7 Hz),
7.32–7.28 (2H, m), 7.23–7.19 (3H, m), 5.09 (1H, s), 5.07–5.00
(1H, m), 4.19–4.14 (2H, m), 4.08–4.03 (2H, m), 1.51 (3H, d, J ¼
6.9 Hz), 1.28 (3H, t, J ¼ 7.1 Hz), 1.12 (3H, t, J ¼ 7.1 Hz). 13C
NMR (100 MHz, CDCl3): d 170.4, 163.8, 151.7, 145.0, 128.8,
127.3, 126.1, 88.5, 61.8, 59.5, 53.8, 24.9, 14.6, 14.0; HRMS (TOF
ES+): m/z calcd for C16H21NO4Na+[(M + Na)+], 314.1362; found,
314.1364.
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yellow oil; IR (KBr) (nmax, cmꢁ1) 3449, 2331, 1738, 1691, 1586,
1498, 1447, 1382, 1277, 1154, 1063, 858, 803, 755, 689, 548; H
1
NMR (400 MHz, CDCl3): d 7.30–7.26 (2H, m), 6.92–6.89 (3H, m),
4.83 (1H, s), 4.40–4.39 (2H, m), 4.14–4.09 (2H, m), 3.34–3.32 (4H,
m), 3.24–3.22 (4H, m), 1.39 (3H, t, J ¼ 7.2 Hz), 1.24 (3H, t, J ¼ 7.1
Hz); 13C NMR (100 MHz, CDCl3): d 167.4, 165.6, 154.5, 150.7,
129.4, 120.8, 116.7, 87.5, 62.3, 59.6, 48.8, 47.1, 14.5, 14.0; HRMS
(TOF ES+): m/z calcd for C18H25N2 O4Na+[(M + Na)+], 333.1808;
found, 333.1807.
Diethyl 2-(4-methylpiperazin-1-yl)fumarate (4e). Yield 61%;
yellow oil; IR (KBr) (nmax, cmꢁ1) 3450, 2980, 2801, 2331,
1739, 1693, 1582, 1450, 1379, 1285, 1201, 1159, 1049, 1007,
801, 750, 552; 1H NMR (400 MHz, CDCl3): d 4.68 (1H, s), 4.32–
4.27 (2H, m), 4.03–3.98 (2H, m), 3.09 (3H, t, J ¼ 5.1 Hz), 2.37–
2.35 (4H, m), 2.21 (3H, s), 1.27 (3H, t, J ¼ 7.2 Hz), 1.13 (3H, t,
J ¼ 7.1 Hz); 13C NMR (100 MHz, CDCl3): d 166.3, 164.4, 153.4,
85.8, 61.0, 58.2, 52.9, 45.8, 44.9, 13.3, 12.8; HRMS (TOF ES+):
m/z calcd for C13H22N2O4Na+[(M + Na)+], 2 931 471; found,
293.1477.
Diethyl 2-morpholinofumarate (4f). Yield 73%; yellow oil; IR
(KBr) (nmax, cmꢁ1) 3451, 2980, 2330, 1739, 1694, 1585, 1444,
1
1380, 1276, 1158, 1113, 1041, 917, 861, 802, 748, 552; H NMR
(400 MHz, CDCl3): d 4.73 (1H, s), 4.34–4.29 (2H, m), 4.06–4.01
(2H, m), 3.69–3.66 (4H, m), 3.08 (4H, t, J ¼ 4.9 Hz), 1.32–1.29
(3H, m), 1.19–1.15 (3H, m); 13C NMR (100 MHz, CDCl3): d 166.2,
164.4, 153.7, 86.7, 64.9, 61.2, 58.5, 46.1, 13.4, 12.9; HRMS (TOF
ES+): m/z calcd for C12H19NO5Na+[(M + Na)+], 280.1155; found,
280.1161.
Conclusions
In summary, an efficient and eco-friendly protocol for the
synthesis of b-amino carbonyl compounds through solvent-free
aza-Michael addition reaction was disclosed. Meanwhile, two
kinds of b-amino carbonyl compounds were obtained by tuning
the reaction temperature. We believe these results stimulate
further research efforts to develop b-amino carbonyl
compounds and extend solvent-free aza-Michael addition
reaction to pharmaceutical synthesis.
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Acknowledgements
The work was supported by the National Natural Science
Foundation of China (Nos. 21202142, 21162042), the Key Project
of Chinese Ministry of Education (No. 212161) and the Opening
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