1

1Type of the Paper (Article, Review, Communication, etc.)

2Study of the effect of DBU on Michael´s reaction of
3benzylamine to acrylates via solvent-free.

4Leticia Chavelas-Hernández 1, José D. Bahena-Martínez1, Alexa B. Arroyo-Colín1,

5Sinuhe G. Flores-Osorio.1 and Jaime Escalante 1,*
6 1
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad No.
7 1001, Col. Chamilpa, C.P. 62209, Cuernavaca, Mor., México

8 • Tel: +52 (777) 3 29 79 97 ext. 6040.

9 E-mail: jaime@uaem.mx.

10 Received: date; Accepted: date; Published: date

11 Abstract In recent years, the use of solvent-free reactions represents a challenge

12 for organic chemists, since it would optimize procedures and contribute to the
13 development of sustainable chemistry. In this regards, our research group has
14 intensified efforts in the search for reactions that can be carried out in the absence
15 of solvent. In this article we present a protocol for the Michael´s addition of
16 benzylamine to α,β-unsaturated esters for the synthesis of N-benzylated β2- and
17 β3-amino esters in the presence of catalytic amounts of DBU (20% mol) via
18 solvent-free. Depending on the acrylate systems, we observed the decrease
19 reaction times with good to excellent yields for the 1,4 addition reaction.

20 Keywords: Solvent free; β-amino acid esters; Microwave; Michael Addition; DBU.

211. Introduction
22 Currently the development of new procedures in fine chemistry of organic
23compounds, the sustainable points of view must be considered, as well as
24evaluating their viability [1]; reason why now Green Chemistry recommends a
25series of procedures such as the use of new ecological reagents and catalysts, more
26benign solvents with the environment such as water, use of supercritical fluids,
27ionic liquids and, if possible, solvent-free reactions, as well such as the activation of
28reactions with methodologies such as ultrasound, microwaves or
29mechanochemistry [2,3,4]. In this sense, the scope of applications in organic
30synthesis is very extensive and includes, for example, heterocyclic chemistry,
31organometallic chemistry, radio, photo and combinatorial chemistry [5–9].
32 On the other hand, the use of Microwaves allow to reduce reaction times,
33obtain higher yields, avoid collateral products and therefore reduce purification
34processes, as well as carrying out novel transformations, and perform reactions
35which could not take place under conventional thermal conditions [10]. All this has
36encouraged many research groups to apply this technique to optimize the daily
37synthetic process, as well as the synthesis of new compounds. In this way, there is

2Catalysts 2020, 10, x; doi: FOR PEER REVIEW www.mdpi.com/journal/catalysts

 3Catalysts 2020, 10, x FOR PEER REVIEW 2 of 15

38a diverse group of chemical reactions successfully performed through microwave,

39such as Suzuki couplings [11], Claisen rearrangements [12], Mitsunobu reactions
40[13], Michael additions [14,15], and many more [16]. Thus, the Michael reaction is
41one of the most versatile reactions in organic synthesis and one of the most useful
42applications of this process is the synthesis of -amino acids and derivatives
43[17,18], this can also be carried out under asymmetric conditions by of a chiral
44auxiliary [19,20].
45 As reported by our research group, we have developed a methodology for
46Michael´s additions of benzylamine to α,β-unsaturated esters to obtain racemic β-
47amino esters with microwaves [21] and their subsequent enzymatic resolution with
48Cal-B [22,23].
49 On the other hand, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) has excellent
50catalytic activity in Baylis – Hillman reaction as reported by Aggarwal, and was
51found to be far superior to other tertiary amines [24]. In this regard, Kim and
52coworkers examined DBU as a promoter for aza-Michael reaction and a convenient
53and versatile method was developed with a substoichiometric amount of DBU [25],
54although it is noteworthy that they used CH3CN as a solvent.
55 A salient achievement developed in our research group consisted of
56optimizing the decarboxylation reaction by employing Microwaves under solvent-
57free conditions [26]. Taking into account that the use of solvent-free reactions is
58especially important and interesting, in the present research project we decided to
59combine of solvent-free conditions and MW irradiation in the synthesis of N-
60benzylated β2- and β3-amino esters in the presence of catalytic amounts of DBU
61(20% mol), in order to reduction in reaction times, with advantages of the eco-
62friendly approach.

632. Results and Discussion

642.1. 1,4-Addition of benzylamine to methyl acrylate
65 We started our study with the addition of between benzylamine (1) and methyl
66acrylate (2), was carried out without DBU in the solvent-free conditions (scheme 1),
67due to this reaction takes place in short time we decided to perform at room
68temperature, after 2.5 h (Table 1, entry 1), obtaining two products, one
69corresponding to addition 1,4 (3a) and the other one corresponding double
70addition (3b), after purifying by column the ratio was 95:5, and the yield was 41%
71of compound 3a and only 2% of compound 3b was obtained, according to the
72method described by Escalante et al.[21] in which this reaction was carried out
73without DBU, but using MW in open system, for 3 min, at 65 °C in methanol the
74ratio was 90:10, hence observed that a better selectivity for compound 3a was
75obtained under solvent-free conditions. In the second experiment trying to increase
76the yield of compound 3a, DBU was added, although the ratio was slightly better
77that reported by Kim et al. [25], however, the performance dropped to 11%, so in
78the absence of solvent for this reaction it is not necessary to use DBU. To optimize
79the reaction conditions of entry 1, and avoid the possible polymerization of methyl

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 5Catalysts 2020, 10, x FOR PEER REVIEW 3 of 15

80acrylate, for the third experiment we decided to keep at a temperature of 0 °C in a

81time of 2.5 h, as a result the formation of the product of addition 1,4 (2) is favored
82at low temperature in the absence of both solvent and DBU, and after purification
83by column the ratio was 92:8 and yield of 56% of compound 3a and only 5% of
84compound 3b, obtaining very good selectivity and yield for the product 3a.

85 Scheme 1. 1,4-Addition of benzylamine to methyl acrylate.

O O
O DBU C6H5 NH O
BnNH2 MeO N OMe
1 OMe Solvent-free OMe
2 C6H5
86 ( ) 3a 3b

87 Table 1. 1,4-Addition of benzylamine (1) to methyl acrylate (2).

Entr 1 2 Temperat DBU Tim ratio

y (mmo (mmo ure (°C) (%mo e 3a:3b
l) l) l) (h) (yield %)
1 1.1 1 rt ------- 2.5 95:51
(41:2)
2 1.1 1 rt 202 2.5 65:35(11:
6)
3 1.1 1 0 ------- 2.5 92:8
(56:5)
881 ratio 90/10 with MW in open vassel without DBU, 3 m at 65 °C in MeOH [21]. 2 ratio 70:30 (75:18) in CH3CN at
89rt, 3 h, and 0.5 eq (20% mol) of DBU according to Kim.[25].
902.2. 1,4-Addition of benzylamine to methyl crotonate
91 Addition of benzylamine to methyl crotonate (scheme 2) as shown in Table 2.
92At first, we tried to carry out at room temperature, but due to the reaction did not
93proceed, we had to use under microwave. Previously our group reported this type
94of reaction [21], which was carried out under microwave conditions but using
95methanol, now solvent-free under conditions at 75 °C, 50 W of power (15 W) for 4
96h, obtained the best yield of 73% of the isolated product 5.

97 Scheme 2. 1,4-Addition of benzylamine to methyl crotonate.

O DBU C6H5 NH O
BnNH2
1 OMe Solvent-free OMe
98 4 ( )5

99 When this reaction despite using DBU (table 2, entry 2), or increasing
100equivalents of benzylamine (entry 3) we found that the reaction proceeds with a
101lower yield in comparison with than obtained in entry 1, and even using solvent
102(entry 4), the lowest yield was obtained, observing that when this reaction was
103carried out without solvent, better results were obtained. Under these conditions
104we can verify that when using solvent, the performance was notably reduced.

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 7Catalysts 2020, 10, x FOR PEER REVIEW 4 of 15

105 Table 2. 1,4-Addition of benzylamine (1) to methyl crotonate (4).

Ent 1 4 Tempera Powe DBU Ti Solve Yiel

ry (mm (mm ture (°C) r (%m me nt d%
ol) ol) (W) ol) (h)
1 1 1 75 50 - 4 - 73
2 1 1 75 50 20 4 - 63
3 4 1 75 50 20 4 - 69
4 1 1 75 50 20 4 3 mL 34
MeO
H
106
1072.3. 1,4-Addition of benzylamine to methyl/tert-butyl cinnamate
108 First, we try adding benzylamine to methyl cinnamate under microwave
109conditions, at 130 °C of temperature and 150 W of power for 1.5 h, solvent-free and
110added DBU, however, as a result, it was observed that our nucleophile added 1,2
111without trace addition 1,4 (compound 9). Thinking that selectivity would be
112improved by using a more bulky ester, decided to used tert-butyl cinnamate as
113Michael acceptor more hindered.
114 When the reaction was carried out with tert-butyl cinnamate and benzylamine,
115solvent-free and without DBU (entry 2, table 3) and after 2 h under microwave
116conditions, at 130 °C of temperature and 150 W of power, but there was no reaction
117(scheme 3); however, in entry 3 with the addition of 20% mmol of DBU during 1.5
118h, interestingly providing 33% yield of compound 8 observing that this reaction
119needed to added DBU. In entry 4 the increased slightly yield, under the above
120reaction conditions, but the reaction time of only 30 minutes. In the next
121experiment (entry 5) we decided to give more reaction time and after 2 h the yield
122increased up to 48%. Thinking that increasing the temperature would improve
123performance, the microwave temperature was programmed at 160 °C, but contrary
124to expectations, performance did not improve (entry 6). The best reaction
125conditions found for this case was under solvent free conditions and to added DBU
126(entry 8), using the microwave at 130 °C 150 W for 6 h, obtaining after purifying
12774% yield of compound 8.

128 Scheme 3. 1,4-Addition of benzylamine (1) to methyl/tert-butyl cinnamate.

BnNH2 O Bn O
DBU NH O
1 Bn
Ph OR Ph N
Ph OR H
Solvent-free
6, R= Me ( ) 8, R= t-Bu 9
129 7, R= t-Bu

130 Table 3. 1,4-Addition of benzylamine (1) to tert-butyl cinnamate (6).

Entry 1 R Temperat Powe DBU Time Yield

(mmo ure (°C) r (W) (%mo (h) (%)

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 9Catalysts 2020, 10, x FOR PEER REVIEW 5 of 15

l) l)
1 4 Me 130 150 20 1.5 321
t
2 4 Bu 130 150 -------- 2 ------
t
3 4 Bu 130 150 20 1.5 332
t
4 4 Bu 130 150 20 0.5 392
t
5 4 Bu 130 150 20 2 482
t
6 4 Bu 160 150 20 2 442
t
7 4 Bu 130 150 20 6 742
1311 Yield between product 9. 2 Yield product 8.

1322.4. 1,4-Addition of benzylamine to methyl/tert-butyl 2-eno-3-(methoxyphenyl)propanoate.

133 Furthermore, we think that it would happen if the α, β-unsaturated ester had
134an electro donor group, as in the case of OMe. So, we decided to used Methyl 2-
135ene-3-(methoxyphenyl)propanoate 10 (scheme 4), which was reacted with 4 mmol
136of benzylamine due to the poor solubility of compound 10, at a temperature of 130
137°C, 100 W of power and 20% mol of DBU for a time of 2 hours (Table 4, entry 1)
138obtaining as a minority yield of 10% of the addition 1,4 (compound 12a) and 38%
139yield of the product of the addition 1,2 (compound 12b), in addition it was possible
140to recover starting material 15% (compound 10).

141 Scheme 4. 1,4-Addition of benzylamine to methyl/tert-butyl 2-eno-3-(methoxyphenyl)propanoate.

O Bn O
NH O Bn
BnNH2
OR DBU N
OR H
1 MeO Solvent-free MeO
MeO
10, R= Me 12b
( )12a, R= Me
11, R= t-Bu
142 ( )13, R= t-Bu

143 In order to increase the 1,4 addition, we decided to used more bulky Michael
144acceptor, so in entry 2, tert-butyl 2-ene-3- (methoxyphenyl) propanoate was reacted
145under the reaction conditions of the first experiment, and after 2 h of reaction, 39%
146yield of the addition product 1,4 (compound 13) and 56% yield of starting material
147(compound 11) was recovered, with this experiment we found that 1,4 addition
148was favored when using bulky Michael acceptor. In order to consume the starting
149material and increase the yield as shown in entry 3, the reaction time was increased
150to total of 6 h, however, there was still 50% of the starting material and only 22%
151yield of the compound 13 as isolated product, in addition, decomposition products
152began to be observed. To rule out the necessity to used 4 eq of benzylamine, in
153entry 4 we decided to carry out decreasing to 1 mmol of benzylamine the reaction
154and without the presence of DBU at 130 ° C and 150 W, after 1 h there was no
155reaction progress. It was thought that due to the absence of DBU the reaction
156would not occur, but we verified that using the conditions of the previous
157experiment but adding 20% of DBU (entry 5) there was no reaction, so there was
158more reaction time (entry 6), and after 2 h of reaction only 9% yield of 13 was
159obtained.
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 11Catalysts 2020, 10, x FOR PEER REVIEW 6 of 15

160 Table 4. 1,4-Addition of benzylamine (1) to methyl/tert-butyl 2-eno-3-(methoxyphenyl)propanoate.

Entry 1 R Temperatu Powe DBU Time Yield Startin

(mmo re (oC) r (W) (%mo (h) % g
l) l) materia
l
1 4 Me 130 100 20 2 38:103 15%

t
2 4 Bu 130 1001 20 2 394 56%

t
3 4 Bu 130 1001 20 6 224 50%

t
4 1 Bu 130 1501 - 1 05 -

t
5 1 Bu 130 1501 20 1 05 -

t
6 1 Bu 130 1501 20 2 94 83%

1611 Programmed pression. 2 Real pression. 3 Yield between products 12a and 12b. 4 Yield product 13. 5 Addition 2
162mL of MeOH due to the poor solubility of compound 11.
1632.5. 1,4-Addition of benzylamine to methyl 2-eno-3-(nitrophenyl)propanoate.
164 Now, would happen if the α,β-unsaturated ester had an electro withdrawing?,
165so were also carried out using methyl 2-ene-3-(nitrophenyl) propanoate with 4
166equivalents of benzylamine (scheme 5) and it was found that in solvent-fee and
167using 20% mmol of DBU as catalyst (entry 1), and surprisingly with only 10
168minutes of reaction, at 75 °C in an oil bath yield of 30% of the addition product 1,4
169(compound 15a) was obtained, however traces of the product of addition 1,2
170(compound 15b) were obtained, but in addition by-product 15c was obtained.

171 Scheme 5. 1,4-Addition of benzylamine to methyl 2-eno-3-(nitrophenyl)propanoate.

NO2

Bn
O NH O O MeO2C
BnNH2
Bn
OMe 1 OMe N
H
DBU MeO2C
O 2N 14 O 2N O2N
Solvent-free ( ) 15a 15b
15c
172 NO2

173 Due to the poor solubility of compound 14 in entry 2, the α,β-unsaturated ester
174was integrated with the benzylamine using a few drops of dichloromethane to
175integrate everything perfectly, but the performance did not improve. Increasing
176the reaction time (entry 3) yield decreased markedly. In entry 4 the reaction time
177was decreased to 30 minutes, but the yield only increased a little. The reaction
178temperature was increased from 75 to 100 ° C (entry 5), but the performance did
179not improve much. Likewise, in entry 6 we decided to give longer reaction time in
180order to performance increased, but it was not. In entry 7 the α, β-unsaturated ester

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 13Catalysts 2020, 10, x FOR PEER REVIEW 7 of 15

181was treated with only 20% excess benzylamine, and the reaction is affected in its
182performance, because it was necessary to use the 4 eq of benzylamine. In entry 8, it
183was increased to 50% mmol of DBU in order to decrease the reaction time, and
184after 30 minutes of reaction the yield was 22%. Knowing that the best reaction
185conditions were those of entry 1, we was decided to scale the reaction to 7.05
186mmol, however, in entry 9 for the reaction, a larger microwave oven was used, so
187the reaction was carried out in an open system and the yield fell to 19.6%, however
188when this reaction was repeated but in a closed system the temperature increased
189to 36% so it is reaffirmed that the best reaction conditions for the addition of 1,4 the
1902-ene-3- (nitrophenyl) propanoate of methyl with 4 equivalents of benzylamine in
191solvent-free and using 20% mmol DBU as catalyst at 75 ° C for only 10 minutes.

192 Table 5. 1,4-Addition of benzylamine (1) to methyl 2-eno-3-(nitrophenyl)propanoate (14).

Entr 1 14 Temperat DBU Time Yield

y (mmol) (mmo ure (°C) (%) (min) (%)
l)
1 2 0.5 75 20 10 30
21 2 0.5 75 20 10 21
3 2 0.5 75 20 40 10
4 2 0.5 75 20 30 16
5 2 0.5 100 20 10 20
6 2 0.5 100 20 20 16
7 0.6 0.5 60 20 40 12
8 2 0.5 60 50 30 22
92 28.2 7.05 75 20 10 19.6
10 28.2 7.05 75 20 10 36
193 1
Using a few drops of dichloromethane to integrate. 2 The reaction was carried out in an open system.

194 This clearly showed that when the α,β-unsaturated esters has an electro
195withdrawing group in the aromatic ring, addition 1,4 occurs in just 10 minutes,
196irrespective of steric bulkiness, contrary to what had happened to us when using
197methyl cinnamate and Methyl 2- ene-3- (methoxyphenyl) propanoate where the
198product of the additional information 1,2 is obtained mainly.
199
2002.6. 1,4-Addition of benzylamine to tert-butyl 2-eno-3-(nitrophenyl)propanoate.
201 Then methyl in the α,β-unsaturated ester was changed to tert-butyl, and thus,
202having a more bulky Michael acceptor that favors the 1,4 addition, so tert-butyl 2-
203ene-3-(nitrophenyl)propanoate (scheme 6) and reacting it with 4 equivalents of
204benzylamine, at 75 ° C using oil bath for 10 minutes (table 6, entry 1), a yield was
205obtained 44% using 20% DBU as catalyst.

206 Scheme 6. 1,4-Addition of benzylamine to methyl/tert-butyl 2-eno-3-(nitrophenyl)propanoate.

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 15Catalysts 2020, 10, x FOR PEER REVIEW 8 of 15

Bn
O NH O
BnNH2 DBU
1 OtBu OtBu
Solvent-free
O2N O2N
16 ( ) 17
207
208 For the entry 2, proceeded under similar reaction conditions but we decided
209given 30 minutes for reaction time, however the yield was similar of 43%. In the
210entry 3 the reaction time was 50 minutes; the yield was 45%. In the entry 4 was
211carried out under the same conditions as the first one, however he yield was only
21218% the reason the low yield it’s the poor solubility of 16. For the entry 5 the
213temperature was increased to 90 °C, obtaining a yield of 36%. Despite increasing
214the temperature and reaction time, the yield does not increase, so just 10 minutes of
215reaction is sufficient for a 44% yield.

216 Table 6. 1,4-Addition of benzylamine (1) to tert-butyl 2-eno-3-(nitrophenyl)propanoate.

Entry 16 Temperature Time Yield Starting

(mg) (°C) (min) (%) material
(mg)
1 124.6 75 10 44 66
2 124.6 75 30 43 32
3 124.6 75 50 45 23
41 124.6 75 10 18 92
5 124.6 90 10 36 49
217 1
Dichloromethane was used to homogenize the starting material.

2182.7. 1,4-Addition of benzylamine to methyl methacrylate.

219 We also were carried out the Michael´s addition of benzylamine to α,β-
220unsaturated esters substituted in the β-position. Although in our group previously
221this type of addictions had been made [21], in this type or reactions solvent was
222always used, in this work we set out to perform this reaction under solvent-free
223conditions.

224 Scheme 7. 1,4-Addition of benzylamine to methyl methacrylate.

O O
BnNH2 DBU Bn
OMe N OMe
1 H
Solvent-free
18 ( ) 19
225
226 The first reaction between benzyl and methyl acrylate (scheme 7) was carried
227out under the conditions used by Escalante et al.[21], using the microwave at a
228temperature of 130 ° C and 50 W power, but in this case in solvent-free conditions
229and without DBU, after 4 h was obtained a yield 25% product 19 (entry 1). For the
230second reaction we decided to added DBU as the catalyst, in order to increase
231performance, but after 2 h of reaction (entry 2) the yield was 27%, then we
232increased the reaction time and after 4 h of reaction (entry 3) the yield remained
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 17Catalysts 2020, 10, x FOR PEER REVIEW 9 of 15

233the same. In entry 4 we decreased temperature, the microwave was programmed

234at 75 ° C at 50 W power, in solvent-free conditions and without DBU after 4 h of
235reaction only 15% yield of the isolated product 19 was obtained. However, when
23620% mmol of DBU is added (entry 5) and after 2 h 75% yield was obtained. Then
237thought that the longer the reaction time under these conditions the yield
238increases, four hours of reaction were given (entry 6) and indeed the yield
239improved to 83%, however in entry 7, despite increasing the reaction time to 6
240hours, the performance remained at 81%, the reaction proceeds with good yields
241using solvent-free conditions.

242 Table 7. 1,4-Addition of benzylamine (1) to methyl methacrylate (18).

Entry Temperature Power DBU Time Yield

(°C) (W) (% mol) (h) (%)
1 115-130 50 ----- 4 25
2 115-130 50 20 4 27
3 115-130 50 20 2 27
4 75 50 ---- 4 15
5 75 50 20 2 75
6 75 50 20 4 83
7 75 50 20 6 81
243
2442.8. 1,4-Addition of benzylamine to ethyl 2-phenylacrylate.
245 Ethyl 2-phenylacrylate was reacted with benzylamine at room temperature in
246the absence of DBU and solvent-free (Table 8, entry 1), obtaining after 1.5 hr 30%
247yield of compound 21 was obtained (schema 8). But the other hand, better
248performance was obtained when using DBU as catalyst (entry 2), TLC analysis of
249the reaction after only 30 minutes, showed the starting material was consumed,
250after purification 56% yield of compound 21 was obtained, with this it is clearly
251observed that when using DBU the performance increases almost twice and in a
252much shorter reaction time.

253 Scheme 8. 1,4-Addition of benzylamine to ethyl 2-phenylacrylate.

O O
BnNH2 DBU Bn
OEt N OEt
1 H
Ph Solvent-free Ph

254 20 ( ) 21

255 Table 8. 1,4-Addition of benzylamine (1) to ethyl 2-phenylacrylate (20).

Entr 1 20 DBU Tim Yield

y (mmo (mmo (%mo e %
l) l) l) (h)
1 0.43 0.43 - 1.5 30

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 19Catalysts 2020, 10, x FOR PEER REVIEW 10 of 15

2 0.43 0.43 20 0.5 56

256

2574. Materials and Methods

258Materials
259 All chemicals used for the synthesis of β-lactams were obtained commercially
260(Aldrich) and used without further purification. Reactions were monitored by TLC
261on Al plates coated with silica gel with fluorescent indicator (60 F 254). Column
262chromatography (CC) was performed on silica gel (230-400 mesh Merck). Melting
263points were measured in open capillary tubes using a Melt-temp electrothermal
264apparatus, and are uncorrected. The reactions with microwaves were carried out in
265Discover CEM equipment. NMR Spectra: Varian Gemini at 200 ( 1H) and 50 MHz
266(13C), Varian Inova at 400 (1H) and 100 MHz (13C), Bruker AVANCE III HD 500
267MHz (1H) and 125 MHz (13C), spectra were obtained in chloroform-D (99.8%)
268+0.03% V/V TMS of Cambridge Isotope Laboratories, Inc. The chemical shift ( in
269ppm rel. to Me4Si as internal standard, J in Hz. HR-MS: MStation JMS-700 JEOL
270apparatus, in m/z.
271 (rac)-Methyl 3-(benzylamino)propanoate (3a) and bis [Methyl 3-
272(benzylamino)]propanoate (3b). Into a 10 mL flask provided with magnetic stirrer
273were added benzylamine (1, 110 μl) and methyl acrylate (2, 99 μl). The mixture
274was cooled to 0°C during 2.5 h. After completion the reaction, the crude product
275was purified by FC (hexane/ethyl acetate 8:2). Compound 3a Yield: 56 % (Colorless
276oil). 1H RMN (200 MHz, CDCl3), δ (ppm), 1.83 (s, 1 H, NH), 2.53 (t, J3 = 6.0, 2 H,
277CH2), 2.89 (t, J = 3.37, 2 H, CH2), 3.67 (t, J3 = 6.0, 2 H, CH2), 3.80 (s, 2 H, CH2), 7.30 (m,
2785 H, Ar-H). 13C RMN (50 MHz, CDCl3) δ (ppm), 34. 5, 44.4, 51.5, 53.7, 126.9, 128.0,
279128.3, 140.1, 173.1. Compound 3b Yield: 5 %). 1H RMN (200 MHz, CDCl3), δ (ppm),
2802.47 (t, J3 = 6 Hz, 4 H, CH2), 2.80 (t, J3 = 6 Hz, 4 H, CH2-N), 3.58 (s, 2H, CH2Ph), 3.64
281(s, 6 H, OCH3) 7.27 (m, 5 H, Ar-H). 13C RMN (50 MHz, CDCl3) δ (ppm), 32.6, 49.2,
28251.4, 58.3, 127.0, 128.1, 128.6, 138.9, 172.8. Spectroscopic data were compared with
283those reported [21].
284 (rac)-Methyl 3-(benzylamino)butanoate (5). Into a glass microwave reaction vessel
285containing a magnetic stirrer, were addicted methyl crotonate 4 (106 µL, 1 mmol),
286benzylamine 1 (110 µL, 4 mmol). The mixture was placed in a Discover CEM
287equipment at 75°C, 50 W (15 W) for 4 h. After completion the reaction was purified
288by FC (hexane/ethyl acetate 8:2 to 60:40). Yield: 73 %. (yellow oil). 1H RMN (600
289MHz, CDCl3), δ (ppm), 1.15 (d, J3 = 6 Hz, 3 H, CH3), 1.83 (br, 1 H, NH), 2.45 (ddd, J =
29060 Hz, 12 Hz, 6 Hz, 2 H, CH 2CO), 3.15 (m, 1 H, CH), 3.67 (s, 3 H, CH 3O), 3.77 (dd, J
291= 60 Hz, 30 Hz, 2 H, CH2Ph), δ 7.21-7.32 (m, 5H, Ar-H), 13C RMN (150 MHz CDCl3),
292δ (ppm), 20.54, 41.50, 49.74, 51.27, 51.60, 127.02, 128.19, 128.50, 140.43, 172.88.
293Spectroscopic data were compared with those reported [21].
294 (rac)-tert-Butyl 3-(benzylamino)-3-phenylpropanoate (8). Into a glass microwave
295reaction vessel containing a magnetic stirrer, were addicted terbutyl cinnamate 7
296(0.162 g, 1 mmol), benzylamine 1 (436 µL, 4 mmol) and DBU (30 µL, 0.2 mmol).
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 21Catalysts 2020, 10, x FOR PEER REVIEW 11 of 15

297The mixture was placed in a Discover CEM equipment at 130 °C, 150 W and 1 psi,
298for 6 h. After completion the reaction was concentrated to dryness and purified on
299column, hexane/ethyl acetate 95:5 to 80:20 was used for separation. Yield: 74.34 %
300(Yellow oil), 1H-RMN (200 MHz, CDCl3), δ (ppm), 1.36 (s, 9 H, tert-Bu), 2.10 (br, 1
301H, NH), 2.57 (m, 2 H, CH2), 3.56 (m, 2 H,CH2), 4.08 (m, 1 H, CH), 7.11-7.43 (m, 10 H,
302Ar-H); 13C RMN (50 MHz, CDCl3), δ (ppm), 28.0, 44.3, 51.4, 59.2, 80.6, 126.8, 127.2,
303127.3, 128.1, 128.3, 128.4, 140.4, 142.7, 171.04.
304 N-benzylcinnamamide (9). Into a glass microwave reaction vessel containing a
305magnetic stirrer, were addicted methyl cinnamate 6 (0.162 g, 1 mmol), benzylamine
3061 (436 µL, 4 mmol) and DBU (30 µL, 0.2 mmol). The mixture was placed in a
307Discover CEM equipment at 130 °C, 150 W and 1 psi, for 1.5 h. After completion the
308reaction was concentrated to dryness and purified on column, hexane/ethyl acetate
30995:5 to 80:20 was used for separation. Yield: 32.48% (Yellow oil), 1H-RMN (200
310MHz, CDCl3), δ (ppm), 4.60 (d, J=8 2 H, CH2), 5.58 (br, 1 H, NH),
3116.47(d,J=15.16Hz,1H,CH), 7.30(m,10H,H-Ph), 7.60(d, J=15.20 Hz,1H,CH); 13C RMN
312(50 MHz, CDCl3), δ (ppm),
313 (rac)-Methyl 3-(benzylamino)-3-(4-methoxyphenyl)propanoate (12a) and N-benzyl-3-
314(4-methoxyphenyl)acrylamide (12b). Into a glass microwave reaction vessel
315containing a magnetic stirrer, were addicted methyl 2-eno-3-
316(methoxyphenyl)propanoate 10 (0.192 g, 1 mmol), benzylamine 1 (440 µL, 4 mmol)
317and DBU (30 µL, 0.2 mmol). The mixture was placed in a Discover CEM equipment
318at 130 °C, 100 W (20 W) and 1 psi, during 2 h. After completion the reaction was
319concentrated to dryness and purified on column, hexane/ethyl acetate 95:5 to 80:20
320was used for separation. Compound 12a Yield: 38 %. (yellow oil) 1H RMN (200
321MHz, CDCl3), δ (ppm), 1.92 (s, 1 H, NH), 2.66 (m, 2 H, CH2CO), 3.63 (s, 3 H, CH3O),
3223.42-3.73 (m, 2 H, CH2Ph), 3.81 (s, 3 H, CH 3O), 4.07 (m, 1 H, CH), 6.79-7.43(m, 9 H,
323Ar-H); 13C RMN (50MHz, CDCl3), δ (ppm) 42.9, 51.2, 51.5, 55.2, 58.1, 113.9, 126.8,
324128.1, 134.4, 140.3, 158.9, 172.2. Elemental analysis for C18H21NO3: Observed: %C=
32574.0614, %H= 7.7957, %N= 4.0996, Calculate: %C= 73.8730, %H= 7.9700, %N=4.1015.
326Compound 12b, Yield: 10%. 1H RMN (200 MHz, CDCl3), δ (ppm), 3.81 (s, 3 H,
327CH3O), 4.52 (d, J3 = 6, 2 MHz, 2 H, CH 2Ph), 6.16 (br, 1 H, NH), 6.27 (d, J3 = 6, 1 H,
328CH), 6.74-7.54 (m, 9 H, Ar-H), 7.58 (d, J3 = 8 Hz, 1H, CHPh) . 13C RMN (50 MHz,
329CDCl3), δ (ppm), 43.7, 55.3, 104.9, 114.2, 118.1, 112.4, 127.8, 128.6, 129.3, 138.3, 140.9,
330160.8, 166.2.
331 (rac)-tert-Butyl 3-(benzylamino)-3-(4-methoxyphenyl)propanoate (13). Into a glass
332microwave reaction vessel containing a magnetic stirrer, were addicted tert-butyl
3332-eno-3-(p-methoxyphenyl)propanoate 11 (0.234 g, 1 mmol), benzylamine 1 (440
334µL, 4 mmol) and DBU (30 µL, 0.2 mmol). The mixture was placed in a Discover
335CEM equipment at 130 °C, 100 W (20 W) and 1 psi, during 2 h. After completion
336the reaction was concentrated to dryness and purified on column, hexane/ethyl
337acetate 95:5 to 80:20 was used for separation. Yield: 39 %. (yellow oil). 1H RMN
338(200 MHz CDCl3), δ (ppm), 1.39 (s, 9 H, tert-Bu), 2.06 (br, 1 H, NH), 2.42-2.79 (m, 2
339H, CH2CO), 3.44-3.68 (m, 2 H, CH2Ph), 3.82 (s, 3 H, CH3O), 4.05 (m, 1 H, CH), 6.67-

22
 23Catalysts 2020, 10, x FOR PEER REVIEW 12 of 15

3407.46 (m, 9 H, Ar-H); 13C RMN (50MHz CDCl3), , δ (ppm) 28.0, 44.3, 51.3, 55.2, 58.5,
34180.5, 113.8, 126.8, 128.3, 134.7, 140.4, 158.8, 171.1.
342 (rac)-Methyl 3-(benzylamino)-3-(4-nitrophenyl)propanoate (15a), methyl 3-
343(benzylamine)-3-(4-nitrophenyl)propanoate (15b) and dimethyl (1S,2S,3R,4R)-3,4-bis(4-
344nitrophenyl)cyclobutane-1,2-dicarboxylate (15c). Into a glass microwave reaction
345vessel a 5 mL flask provided with magnetic stirrer were added methyl 2-eno-3-
346(nitrophenyl)propanoate 14 (0.5 mmol), benzylamine 1 (2 mmol) and DBU (30 µL,
3470.02 mmol). The reaction was heating at 75 °C (oil bath) for 10 min. After
348completion the reaction was purified on column, hexane/ethyl acetate 80:20 was
349used for separation. Compound 15a: Yield: 36%. 1H RMN (200 MHz, CDCl3) δ
350(ppm) 2.08 (s, 1 H, NH), 2.67 (m, 2 H, CH 2), 3.56 (m, 2 H, CH2), 3.64 (s, 3 H, CH3),
3514.24 (m, 1 H, CH), 7.29-8.22 (m, 9 H, Ar-H).13C RMN (50 MHz, CDCl3) δ (ppm) 42.4,
35251.5, 51.9, 58.4, 124.0, 127.3, 128.1, 128.2, 128.6, 139.7, 147.5, 150.4, 171.6. Compound
35315b. 1H RMN (200 MHz, CDCl3), δ (ppm), 4.48-4.61 (dd, J3 = 6 Hz, J3 = 6 Hz, 2 H,
354CH2Ph), 6.51 (d, J3 = 6 Hz, 1 H, CH2), 7.66 (m, 1 H, CH-C6H4NO2), 7.27-8.22 (m, 9 H,
355Ar-H). 13C RMN (50 MHz, CDCl3) δ (ppm). Compound 15c. 1H RMN (600 MHz,
356CDCl3), δ (ppm), 3.37 (s, 3 H, OCH3), 3.41 (dd, J3 = 12 Hz, J = 8.4 Hz, 1 H, CH-CO),
3573.74 (s, 3 H, OCH3), 3.97 (t, J = 9 Hz, 1H, CH-CO), 4.07 (t, J = 9.6 Hz, 1 H, CH-
358C6H4NO2), 4.80 (t, J = 10.8 Hz, 1 H, CH), 7.39 (d, J = 8.4 Hz, 1 H, CH-C), 7.50 (d, J =
3598.4 Hz, 1 H, CH-C), 8.18 (m, 2 H) . 13C RMN (150 MHz, CDCl3) δ (ppm), 43.4, 43.7,
36044.3, 46.5, 52.0, 52.3, 123.9, 123.9, 124.1,126.5,127.5,128.2,144.9, 148.3, 171.0, 171.6.
361(FAB-MS y HR-FAB-MS resultados pendientes)
362 (rac)-tert-Butyl 3-(benzylamino)-3-(4-nitrophenyl)propanoate (17). Into a glass
363microwave reaction vessel a 5 mL flask provided with magnetic stirrer were added
364tert-butyl 2-eno-3-(nitrophenyl)propanoate 16 (0.5 mmol) benzylamine 1 (2 mmol)
365and DBU (30 µL, 0.02 mmol). The reaction was heating at 75°C (oil bath) for 10
366min. After completion the reaction was purified on column, hexane/ethyl acetate
36780:20 was used for separation. Yield: 44%. 1H RMN (200 MHz, CDCl3) δ (ppm) 1.38
368(s, 9 H, tert-Bu), 1.99 (br, 1 H, NH), 2.48-2.71 (m, 2 H, CH 2), 3.46-3.66 (t, 2 H, CH 2),
3694.10-4.23 (m, 1 H, CH), 7.12-8.28 (m, 9 H, Ar-H). 13C RMN (50 MHz, CDCl3) δ
370(ppm) 28.0, 43.7, 51.54, 58.6, 81.2, 123.7, 127.1, 128.0, 128.1, 128.4, 139.6, 150.5, 170.2.
371FAB-MS: 357 ([M + H]+). HR-FAB-MS: 357.18 ([M + H]+, C7H14NO+; calc. 356.42)
372 (rac)-Methyl 3-(benzylamino)-2-methylpropanoate (19). A mixture of methyl
373methacrylate 18 (0.1g, 0.1mL, 1.0 mmol), benzylamine 1 (0.1g, 0.1 mL, 1 mmol) and
374DBU (0.02 mmol, 30µL, 0.030 g.) was placed into a microwave reaction vial
375provided with a magnetic stirrer. The capped vial was placed in a microwave
376synthesis equipment at 75 ° C and 50 W for 4 h. The crude product was purified by
377FC (hexane/ethyl acetate 98:2 to 90:10) to produce (±)-19. Yield: 87 % (Colorless oil).
3781H RMN (200 MHz CDCl3), δ (ppm), 1.18 (d, J = 4 Hz, 3 H, CH3); 1.61 (br, 1 H, NH),
3792.54-2.76 (m, 1 H, CH-NH), 2.78-2.98 (m, 2 H, CH), 3.68 (s, 3 H, CH 3O), 3.79 (s, 2 H,
380CH2Ph), 7.09-7.49 (m, 5 H, Ar-H). 13C RMN (50 MHz CDCl3), δ (ppm)
381 (rac)-Ethyl 3-(benzylamino)-2-phenylpropanoate (21). Into a 10 mL flask provided
382with magnetic stirrer were added ethyl 2-phenylacrylate 20 (0.43 mmol, 75 mg ),
383benzylamine 1 (0.43 mmol, 0.046g, 47 μl) and DBU (0.02 mmol, 1.31mg, 1.3 µL).
24
 25Catalysts 2020, 10, x FOR PEER REVIEW 13 of 15

384The reaction was kept a room temperature for 30 min. After was purified on
385column, hexane/ethyl acetate 8: 2 was used for separation. Yield: 56% (colorless
386oil). 1H RMN (200 MHz, CDCl3), δ (ppm), 1H-RMN (500 MHz) CDCl3, δ (ppm), 1.06
387(t, J3 = 2, 3 H, CH3), 1.63 (br, 1 H, NH), 2.92 (dd, J3 = 5, J3 = 5, 1 H, CH) , 3.28 (dd, J3 = 5
388Hz, J3 = 5 Hz, 2 H, CH 2), 3.80 (s, 1 H, CH 2Ph), ), 3.82 (dd, J3 = 4 Hz, J3 = 4 Hz, 1 H,
389CH), 4.08-4.19 (m, 2 H, CH2CH3), 7.21-7.33 (10 H, Ar-H). 13C RMN (75 MHz CDCl3),
390δ (ppm), 14.3, 52.3, 53.8, 61,0, 127.1, 127.6, 128.2, 128.2, 128.6, 128.9, 137.6, 140.3,
391173.3 Spectroscopic data were compared with those reported [27].

3925. Conclusions
393 In summary, a solvent-free method has been applied for the Michael addition
394of benzylamines to α,β-unsaturated esters, when the esters with less steric hindered
395were used, the nucleophile was added 1,2, on the other hand when using an ester
396with greater hindered, the addition 1,4 was carried out. Furthermore, when the
397aromatic system has an electro withdrawing group such as NO 2, addition 1,4 is
398favored in very short times even without using the microwave. Finally, α, β-
399unsaturated esters with substituents in the β-position were used, obtaining yields
400of almost double compared with those obtained by not using the DBU and in short
401reaction periods from 10 minutes.
402
403
404

4056. Patents
406 This section is not mandatory, but may be added if there are patents resulting
407from the work reported in this manuscript.

408Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, Figure S1: title, Table
409S1: title, Video S1: title.
410Author Contributions: For research articles with several authors, a short paragraph specifying their individual
411contributions must be provided. The following statements should be used “Conceptualization, X.X. and Y.Y.;
412methodology, X.X.; software, X.X.; validation, X.X., Y.Y. and Z.Z.; formal analysis, X.X.; investigation, X.X.;
413resources, X.X.; data curation, X.X.; writing—original draft preparation, X.X.; writing—review and editing,
414X.X.; visualization, X.X.; supervision, X.X.; project administration, X.X.; funding acquisition, Y.Y. All authors
415have read and agreed to the published version of the manuscript.”, please turn to the CRediT taxonomy for the
416term explanation. Authorship must be limited to those who have contributed substantially to the work
417reported.
418Funding: Please add: “This research received no external funding” or “This research was funded by NAME
419OF FUNDER, grant number XXX” and “The APC was funded by XXX”. Check carefully that the details given
420are accurate and use the standard spelling of funding agency names at https://search.crossref.org/funding, any
421errors may affect your future funding.
422Acknowledgments: In this section you can acknowledge any support given which is not covered by the author
423contribution or funding sections. This may include administrative and technical support, or donations in kind
424(e.g., materials used for experiments).
425Conflicts of Interest: Declare conflicts of interest or state “The authors declare no conflict of interest.” Authors
426must identify and declare any personal circumstances or interest that may be perceived as inappropriately
427influencing the representation or interpretation of reported research results. Any role of the funders in the
428design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in
26
 27Catalysts 2020, 10, x FOR PEER REVIEW 14 of 15

429the decision to publish the results must be declared in this section. If there is no role, please state “The funders
430had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the
431manuscript, or in the decision to publish the results”.

432Appendix A
433 The appendix is an optional section that can contain details and data
434supplemental to the main text. For example, explanations of experimental details
435that would disrupt the flow of the main text, but nonetheless remain crucial to
436understanding and reproducing the research shown; figures of replicates for
437experiments of which representative data is shown in the main text can be added
438here if brief, or as Supplementary data. Mathematical proofs of results not central
439to the paper can be added as an appendix.

440Appendix B
441 All appendix sections must be cited in the main text. In the appendixes,
442Figures, Tables, etc. should be labeled starting with ‘A’, e.g., Figure A1, Figure A2,
443etc.

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© 2020 by the authors. Submitted for possible open access publication under the terms
and conditions of the Creative Commons Attribution (CC BY) license
(http://creativecommons.org/licenses/by/4.0/).
514

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