# Raising the Diversity of Ugi Reactions Through Selective Alkylations and Allylations of Ugi Adducts

Alaa Zidan, Abeer El-Naggar, Nour Abd El-Sattar, Ali Khalil Ali, Laurent El Kaim

► To cite this version:

Alaa Zidan, Abeer El-Naggar, Nour Abd El-Sattar, Ali Khalil Ali, Laurent El Kaim. Raising the Diversity of Ugi Reactions Through Selective Alkylations and Allylations of Ugi Adducts. Frontiers in Chemistry, 2019, 7 (20), 10.3389/fchem.2019.00020. [doi: 10.20968/chemistry.7.20.00020](https://doi.org/10.20968/chemistry.7.20.00020)

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# Raising the Diversity of Ugi Reactions Through Selective Alkylations and Allylations of Ugi Adducts

Alaa Zidan, Abeer El-Naggar, Nour Abd El-Sattar, Ali Khalil Ali, Laurent El Kaim

► To cite this version:

Alaa Zidan, Abeer El-Naggar, Nour Abd El-Sattar, Ali Khalil Ali, Laurent El Kaim. Raising the Diversity of Ugi Reactions Through Selective Alkylations and Allylations of Ugi Adducts. Frontiers in Chemistry, 2019, 7 (20), 10.3389/fchem.2019.00020. [hal-02096847](https://hal-02096847)

HAL Id: hal-02096847

https://polytechnique.hal.science/hal-02096847v1

Submitted on 13 Jan 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
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Distributed under a Creative Commons Attribution 4.0 International License
# Raising the diversity of Ugi reactions through selective alkylations and allylations of Ugi adducts

1 Alaa Zidan¹,², Abeer M. El-Naggar², Nour E. A. Abd El-Sattar², Ali Khalil Ali²*, Laurent El

2 Kaïm¹*

3 ¹Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech, UMR 7652,

4 Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France

5 ²Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, Cairo 11566, Egypt

6 * Correspondence:

7 Corresponding Authors

8 laurent.elkaim@ensta-paristech.fr; alikhalil@sci.asu.edu.eg

9

10 Keywords: Ugi reaction; allylation; palladium; Tsuji-Trost reaction; metathesis; piperidines.

11 Abstract: We report here selective Tsuji-Trost type allylation of Ugi adducts using a strategy

12 based on the enhanced nucleophilicity of amide dianions. Ugi adducts derived from aromatic

13 aldehydes were easily allylated at their peptidyl position with allyl acetate in the presence of

14 palladium catalysts. These substitutions were compared to more classical transition metal free

15 allylations using allyl bromides.

16

17 **1 Introduction**

18 Since its discovery and even more after the 1980's, the Ugi reaction has fascinated chemists with the

19 high diversity brought by its four components nature together with its impressive functional tolerance

20 (Dömling and Ugi, 2000; Hulme and Gore, 2003; Orru and de Greef, 2003; Zhu and Bienaymé,

21 2005; Dömling, 2006; Dömling et al., 2012; Zhu et al., 2014; Boyarskiy et al., 2015; Váradi et al.,

22 2016; Lei et al., 2018). Besides important efforts devoted to the preparation of libraries of

23 heterocycles through cyclization of properly functionalized Ugi adducts (Tempest, 2005; Sunderhaus

24 and Martin, 2009; Ivachtchenko et al., 2010; Orru and Ruijter, 2010; Sadjadi and Heravi, 2011;

25 Eckert, 2012; Sharma et al., 2015), a number of studies have focused on raising the diversity by

26 letting Ugi adducts react in further intermolecular couplings (Elders et al., 2009; Brauch et al., 2010;

27 Zarganes-Tzitzikas et al., 2015; Zarganes-Tzitzikas et al., 2015; Kaur et al., 2016). In contrast with

28 the previous intramolecular couplings, these strategies (such as the combination of MCRs) are much

29 more sensitive to steric hindrance and require more attention in selecting the functionalities required

30 for further couplings. For this reason, most transformations involving the peptidyl position of Ugi

31 adducts are limited to intramolecular reactions (Bossio et al., 1997; Trifilenkov et al., 2007; Salcedo

32 et al., 2008; El Kaïm et al., 2011; Tyagi et al., 2013; Zhang et al., 2013; Ben Abdessalem et al., 2015;

33 Ghandi et al., 2015; Vachhani et al., 2015; Li et al., 2016). We recently proposed a dianionic amide

34 strategy to raise the nucleophilic behaviour of Ugi adducts derived from aromatic aldehydes and

35 demonstrated the interest of this approach using bis-electrophilic derivatives prone to trap the
# Raising the diversity of Ugi reactions through selective alkylations and allylations of Ugi adducts

1 Alaa Zidan¹,², Abeer M. El-Naggar², Nour E. A. Abd El-Sattar², Ali Khalil Ali²*, Laurent El

2 Kaïm¹*

3 ¹Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech, UMR 7652,

4 Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France

5 ²Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, Cairo 11566, Egypt

6 * Correspondence:

7 Corresponding Authors

8 laurent.elkaim@ensta-paristech.fr; alikhalil@sci.asu.edu.eg

9

10 Keywords: Ugi reaction; allylation; palladium; Tsuji-Trost reaction; metathesis; piperidines.

11 Abstract: We report here selective Tsuji-Trost type allylation of Ugi adducts using a strategy

12 based on the enhanced nucleophilicity of amide dianions. Ugi adducts derived from aromatic

13 aldehydes were easily allylated at their peptidyl position with allyl acetate in the presence of

14 palladium catalysts. These substitutions were compared to more classical transition metal free

15 allylations using allyl bromides.

16

17 **1 Introduction**

18 Since its discovery and even more after the 1980's, the Ugi reaction has fascinated chemists with the
19 high diversity brought by its four components nature together with its impressive functional tolerance
20 (Dömling and Ugi, 2000; Hulme and Gore, 2003; Orru and de Greef, 2003; Zhu and Bienaymé,
21 2005; Dömling, 2006; Dömling et al., 2012; Zhu et al., 2014; Boyarskiy et al., 2015; Váradi et al.,
22 2016; Lei et al., 2018). Besides important efforts devoted to the preparation of libraries of
23 heterocycles through cyclization of properly functionalized Ugi adducts (Tempest, 2005; Sunderhaus
24 and Martin, 2009; Ivachtchenko et al., 2010; Orru and Ruijter, 2010; 2010; Sadjadi and Heravi, 2011;
25 Eckert, 2012; Sharma et al., 2015), a number of studies have focused on raising the diversity by
26 letting Ugi adducts react in further intermolecular couplings (Elders et al., 2009; Brauch et al., 2010;
27 Zarganes-Tzitzikas et al., 2015; Zarganes-Tzitzikas et al., 2015; Kaur et al., 2016). In contrast with
28 the previous intramolecular couplings, these strategies (such as the combination of MCRs) are much
29 more sensitive to steric hindrance and require more attention in selecting the functionalities required
30 for further couplings. For this reason, most transformations involving the peptidyl position of Ugi
31 adducts are limited to intramolecular reactions (Bossio et al., 1997; Trifilenkov et al., 2007; Salcedo
32 et al., 2008; El Kaïm et al., 2011; Tyagi et al., 2013; Zhang et al., 2013; Ben Abdessalem et al., 2015;
33 Ghandi et al., 2015; Vachhani et al., 2015; Li et al., 2016). We recently proposed a dianionic amide
34 strategy to raise the nucleophilic behaviour of Ugi adducts derived from aromatic aldehydes and
demonstrated the interest of this approach using bis-electrophilic derivatives prone to trap the
dianions and form heterocycles (scheme 1) (Zidan et al., 2017; Zidan et al., 2018). Following the high yielding cyclizations observed in these studies, we decided to explore more thoroughly the synthetic potential of these dianions (Thompson, 1994; Langer and Freiberg, 2004) towards more simple electrophiles. We now wish to report further applications of this chemistry in Tsuji-Trost reactions as well as metal-free alkylations with bromide derivatives (Scheme 1).

41 Scheme 1

42 **2 Results and discussion**

43 Following our interest in Tsuji-Trost reactions involving isocyanide based MCRs (Dos Santos and El Kaïm, 2014; Cordier et al., 2015; El Mamouni et al., 2016), we decided to explore the behaviour of 45 Ugi adducts dianions towards allyl acetate. Besides the efficiency and regioselectivity issues of the 46 reaction of these dianions with π-allyl palladium complexes, such study might bring interesting 47 pathways for further enantioselective approaches. For this study, Ugi adduct **1a** was selected due to 48 its good behaviour in our previous studies with propargyl bromide and diiodomethane. It was 49 prepared in 89% yield from 4-chloro-benzaldehyde, propylamine, acetic acid and *tert*-50 butylisocyanide. (Table 1). When **1a** was heated with allyl acetate in THF using 2.5 equivalents of 51 potassium *tert*-butoxide together with a Pd(dba)₂/PPh₃ catalytic couple, we were delighted to 52 observe a selective C-allylation of **1a** giving **3a** in 65% isolated yield after 2 hours refluxing (entry 1, 53 Table 1).

54 Table 1.

55 Different bases in various solvents were then evaluated using the same palladium/phosphine couple. 56 The enhanced nucleophilicity of the 1,3-amide dianion towards the π-allyl palladium cationic 57 complex was confirmed experimentally by comparing the use of 2.5 and 1.3 equiv of KHMDS 58 (affording respectively 93% and 37% isolated yields : entries 4 and 5, Table 1). NaH in DMSO, gave 59 the best conditions affording to our delight a nearly quantitative yield of **3a** in only one hour at room 60 temperature (entry 9, Table 1). Further modifications of the catalyst using more complex phosphines 61 led to longer reaction time and lower yields (entries 10-12, Table 1), while in absence of palladium 62 source, no product was observed (entry 13, Table 1).

63 A set of Ugi adducts were then prepared in methanol and submitted to these optimized allylation 64 conditions. The results are gathered in Scheme 2. As observed in our previous studies (Zidan et al., 65 2017; Zidan et al., 2018), an aryl group tethering the peptidyl position is required for efficient 66 allylation. Indeed, Ugi adduct **1j** prepared from isovaleraldehyde failed to form the expected **3j** 67 probably due to the inability to form the dianionic intermediate with this less acidic substrate. 68 Surprisingly, we didn't observe much correlation between yields and the electronic nature of the 69 aldehyde as shown by the similar yields obtained with both 4-nitro or 4-methoxy substituted 70 derivatives **3b** and **3c**. A much stronger effect of the substitution partner of the aromatic moiety was 71 observed with 2-chloro substituted Ugi adduct **1h** which failed to give any adduct under these 72 conditions as observed with **1j**. The same behaviour was observed for the attempted synthesis of the 73 fluoro analogue **3i**. This lack of reactivity can probably be explained by the steric hindrance brought 74 by substituents at the ortho position preventing to reach the planar geometry required for benzylic 75 anion stabilization. Initial trials on enantioselective allylations were rather deceiving. When 76 triphenylphosphine was replaced by BINAP (5mol %) for the reaction of **1a** with **2a**, **3a** could be 77 formed rapidly in good yield (89%) but poor enantioselectivity (5%) whereas the use of Trost ligand 78 (DACH-phenyl) failed to give any allylation reaction. A wider scope of chiral ligands as well as
dianions and form heterocycles (scheme 1) (Zidan et al., 2017; Zidan et al., 2018). Following the high yielding cyclizations observed in these studies, we decided to explore more thoroughly the synthetic potential of these dianions (Thompson, 1994; Langer and Freiberg, 2004) towards more simple electrophiles. We now wish to report further applications of this chemistry in Tsuji-Trost reactions as well as metal-free alkylations with bromide derivatives (Scheme 1).

41 Scheme 1

42 **2 Results and discussion**

43 Following our interest in Tsuji-Trost reactions involving isocyanide based MCRs (Dos Santos and El Kaïm, 2014; Cordier et al., 2015; El Mamouni et al., 2016), we decided to explore the behaviour of 45 Ugi adducts dianions towards allyl acetate. Besides the efficiency and regioselectivity issues of the 46 reaction of these dianions with π-allyl palladium complexes, such study might bring interesting 47 pathways for further enantioselective approaches. For this study, Ugi adduct **1a** was selected due to 48 its good behaviour in our previous studies with propargyl bromide and diiodomethane. It was 49 prepared in 89% yield from 4-chloro-benzaldehyde, propylamine, acetic acid and *tert*-50 butylisocyanide. (Table 1). When **1a** was heated with allyl acetate in THF using 2.5 equivalents of 51 potassium *tert*-butoxide together with a Pd(dba)₂/PPh₃ catalytic couple, we were delighted to 52 observe a selective C-allylation of **1a** giving **3a** in 65% isolated yield after 2 hours refluxing (entry 1, 53 Table 1).

54 Table 1.

55 Different bases in various solvents were then evaluated using the same palladium/phosphine couple. 56 The enhanced nucleophilicity of the 1,3-amide dianion towards the π-allyl palladium cationic 57 complex was confirmed experimentally by comparing the use of 2.5 and 1.3 equiv of KHMDS 58 (affording respectively 93% and 37% isolated yields : entries 4 and 5, Table 1). NaH in DMSO, gave 59 the best conditions affording to our delight a nearly quantitative yield of **3a** in only one hour at room 60 temperature (entry 9, Table 1). Further modifications of the catalyst using more complex phosphines 61 led to longer reaction time and lower yields (entries 10-12, Table 1), while in absence of palladium 62 source, no product was observed (entry 13, Table 1).

63 A set of Ugi adducts were then prepared in methanol and submitted to these optimized allylation 64 conditions. The results are gathered in Scheme 2. As observed in our previous studies (Zidan et al., 65 2017; Zidan et al., 2018), an aryl group tethering the peptidyl position is required for efficient 66 allylation. Indeed, Ugi adduct **1j** prepared from isovaleraldehyde failed to form the expected **3j** 67 probably due to the inability to form the dianionic intermediate with this less acidic substrate. 68 Surprisingly, we didn't observe much correlation between yields and the electronic nature of the 69 aldehyde as shown by the similar yields obtained with both 4-nitro or 4-methoxy substituted 70 derivatives **3b** and **3c**. A much stronger effect of the substitution partner of the aromatic moiety was 71 observed with 2-chloro substituted Ugi adduct **1h** which failed to give any adduct under these 72 conditions as observed with **1j**. The same behaviour was observed for the attempted synthesis of the 73 fluoro analogue **3i**. This lack of reactivity can probably be explained by the steric hindrance brought 74 by substituents at the ortho position preventing to reach the planar geometry required for benzylic 75 anion stabilization. Initial trials on enantioselective allylations were rather deceiving. When 76 triphenylphosphine was replaced by BINAP (5mol %) for the reaction of **1a** with **2a**, **3a** could be 77 formed rapidly in good yield (89%) but poor enantioselectivity (5%) whereas the use of Trost ligand 78 (DACH-phenyl) failed to give any allylation reaction. A wider scope of chiral ligands as well as
79

80

81

82

alternative solvents allowing lower temperatures will have to be evaluated to reach an enantioselective version. The reaction could not be extended to more substituted allylic acetate derivatives such as cinnamyl acetate. The latter failed to react with Ugi adduct **1a** even under prolonged heating, leading only to saponification of the ester and isolation of cinnamyl alcohol.

83

Scheme 2.

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

Submitting propargylamine-derived Ugi adduct **1s** to the same reaction conditions didn't afford any allylated product but resulted in the clean formation of 2,3-dihydropyrrole **4** (Scheme 3), a reaction already reported by Miranda *et al*. in 2012 (Polindara-García and Miranda, 2012). They could isolate the same dihydropyrrole **4** in 36% yield treating **1s** with *t*-BuOK (2.5 equiv) in THF, while we could obtain 79% yield with our conditions. This selectivity was not very surprising when considering the respective intra and intermolecular properties of the two pathways. However, the ability to form enyne derivatives from Ugi adducts together with the interest of reversing a preferred selectivity were challenging enough to explore different set of conditions. Indeed, the dihydropyrrole formation probably involves a first isomerization into allene followed by further 5-endo-trig cyclization. This could leave some space for a previous intermolecular allylation if the lifetime of the dianion could be reduced by increasing the kinetic of the allylation step. Introducing the allyl acetate together with the palladium catalyst and the Ugi adduct in DMSO followed by the addition of the base resulted in a lower 54% yield of **4** together with a complex mixture of allylated products. We next explored the use of allyl bromide as a potential electrophilic species in the absence of palladium. When adding the latter to Ugi adduct **1s** followed by NaH, we were delighted to observe the expected enyne **3s** obtained in 58% isolated yield without any trace of dihydropyrrole (Scheme 3). This interesting control of the selectivity offers an attractive access to enyne derivatives for further cyclization studies.

102

Scheme 3.

103

104

105

106

107

108

109

110

111

112

113

These conditions settled with allyl bromide proved useful as well for the reaction of other alkyl bromides and iodides as shown in Scheme 4. The lowest 30% yield of **6c** obtained using 3-bromocyclohex-1-ene may be explained by the use of secondary halides together with the high steric hindrance around the peptidyl position of the Ugi adduct. In order to confirm further the importance of forming dianionic intermediates, the formation of **3a** was attempted using allyl bromide in excess (1.5 equiv) but reducing the amount of sodium hydride to 0.9 equiv. In this case, only traces of allylated compound could be identified after 2h at rt whereas the reaction was completed after the same time when using 2.5 equiv of sodium hydride. Interestingly, whereas under Tsuji-Trost type conditions we couldn't observe any allylation of both 2-chloro and 2-fluoro substituted derivatives **1h** and **1i**, the latter gave us a moderate 40% isolated yields of **3i** when using just sodium hydride with allyl bromide.

114

Scheme 4.

115

116

117

118

A further interest of the use of palladium free conditions may be found in the ability to carry the reaction *starting directly from* the four Ugi components. Indeed remaining isocyanides after the Ugi reaction are potentially inhibitor for most classical palladium catalyzed processes making thus one-pot processes difficult to achieve (El Kaim *et al.*, 2008).<fnref n="1" /> After completion of the Ugi adduct, the

<footnote n="1">¹ However, one-pot processes may be envisioned if the remaining isocyanide is destroyed by an acidic hydrolysis prior palladium addition.</footnote>
alternative solvents allowing lower temperatures will have to be evaluated to reach an enantioselective version. The reaction could not be extended to more substituted allylic acetate derivatives such as cinnamyl acetate. The latter failed to react with Ugi adduct **1a** even under prolonged heating, leading only to saponification of the ester and isolation of cinnamyl alcohol.

Scheme 2.

Submitting propargylamine-derived Ugi adduct **1s** to the same reaction conditions didn't afford any allylated product but resulted in the clean formation of 2,3-dihydropyrrole **4** (Scheme 3), a reaction already reported by Miranda *et al*. in 2012 (Polindara-García and Miranda, 2012). They could isolate the same dihydropyrrole **4** in 36% yield treating **1s** with *t*-BuOK (2.5 equiv) in THF, while we could obtain 79% yield with our conditions. This selectivity was not very surprising when considering the respective intra and intermolecular properties of the two pathways. However, the ability to form enyne derivatives from Ugi adducts together with the interest of reversing a preferred selectivity were challenging enough to explore different set of conditions. Indeed, the dihydropyrrole formation probably involves a first isomerization into allene followed by further 5-endo-trig cyclization. This could leave some space for a previous intermolecular allylation if the lifetime of the dianion could be reduced by increasing the kinetic of the allylation step. Introducing the allyl acetate together with the palladium catalyst and the Ugi adduct in DMSO followed by the addition of the base resulted in a lower 54% yield of **4** together with a complex mixture of allylated products. We next explored the use of allyl bromide as a potential electrophilic species in the absence of palladium. When adding the latter to Ugi adduct **1s** followed by NaH, we were delighted to observe the expected enyne **3s** obtained in 58% isolated yield without any trace of dihydropyrrole (Scheme 3). This interesting control of the selectivity offers an attractive access to enyne derivatives for further cyclization studies.

Scheme 3.

These conditions settled with allyl bromide proved useful as well for the reaction of other alkyl bromides and iodides as shown in Scheme 4. The lowest 30% yield of **6c** obtained using 3-bromocyclohex-1-ene may be explained by the use of secondary halides together with the high steric hindrance around the peptidyl position of the Ugi adduct. In order to confirm further the importance of forming dianionic intermediates, the formation of **3a** was attempted using allyl bromide in excess (1.5 equiv) but reducing the amount of sodium hydride to 0.9 equiv. In this case, only traces of allylated compound could be identified after 2h at rt whereas the reaction was completed after the same time when using 2.5 equiv of sodium hydride. Interestingly, whereas under Tsuji-Trost type conditions we couldn't observe any allylation of both 2-chloro and 2-fluoro substituted derivatives **1h** and **1i**, the latter gave us a moderate 40% isolated yields of **3i** when using just sodium hydride with allyl bromide.

Scheme 4.

A further interest of the use of palladium free conditions may be found in the ability to carry the reaction *starting directly from* the four Ugi components. Indeed remaining isocyanides after the Ugi reaction are potentially inhibitor for most classical palladium catalyzed processes making thus one-pot processes difficult to achieve (El Kaim *et al.*, 2008).<fnref n="1" /> After completion of the Ugi adduct, the

<footnote n="1">¹ However, one-pot processes may be envisioned if the remaining isocyanide is destroyed by an acidic hydrolysis prior palladium addition.</footnote>
119 methanol was evaporated under reduced pressure. The solvent was then replaced by DMSO. Addition
120 of sodium hydride followed by allyl bromide afforded the final allylated Ugi adducts in good overall
121 yields (Scheme 5).

122 Scheme 5.

123 With this easy allylation of Ugi adducts in hand, we decided to take advantage of the diversity
124 offered by the latter coupling to explore Ugi/allylation/Ring Closure Methathesis (RCM) strategies
125 towards various nitrogen based heterocycles. The use of RCM as Ugi post-condensation has already
126 demonstrated its power for the formation of 5, 6-membered heterocycles as well as macrocyclic
127 derivatives (Banfi et al., 2003; Beck et al., 2003; Hebach and Kazmaier, 2003; Ribelin et al., 2007;
128 Ku et al., 2011). However the synthetic potential of these strategies is in a way limited by the need of
129 introducing the two allylated moieties at an early stage which reduces the diversity offered by the
130 two-step process. The late stage allylation we propose is highly versatile allowing to settle the
131 strategy with a single alkenyl moiety in the starting components. Thus using allyl amine, we could
132 easily prepare a library of piperidines with five points of diversity (Scheme 6).

133 Scheme 6.

134 This access to 3,4-dehydropiperidine derivatives **7** could be further enriched by a potential
135 isomerisation into cyclic enamines as demonstrated by the ruthenium hydride catalysed conversion of
136 **7a** into **8** (Scheme 6). The versatility of the method can be pictured by the alternative choice of the
137 alkenyl moiety on the acidic component such as in cinnamic acid offering now a very simple access
138 to 3,4-dehydropiperidine-2-one **9** (Scheme 7).

139 Scheme 7.

140 **3 Conclusion**

141 In summary, we have extended the potential of the Ugi reaction using 1,3-amide dianionic species as
142 intermediates for efficient allylations at the peptidyl moiety of Ugi adducts. The procedure raises the
143 diversity of Ugi adducts and offers unique opportunities for the preparation of nitrogen based
144 heterocycles through association with ring closure metathesis. The power of the latter strategy has
145 been demonstrated by the preparation of various piperidines which are important scaffolds for
146 medicinal applications.

147

148

149 **Scheme 1.** Reaction of Ugi amide dianion with mono and biselectrophiles.

150 **Scheme 2.** Scope of the Ugi/Tsuji-Trost cascade

151 **Scheme 3.** Allylation of Ugi propargyl adduct.

152 **Scheme 4.** Scope of alkylating agents

153 **Scheme 5.** Cascade one pot reaction

154 **Scheme 6.** Ugi/allylation/RCM strategy
119 methanol was evaporated under reduced pressure. The solvent was then replaced by DMSO. Addition
120 of sodium hydride followed by allyl bromide afforded the final allylated Ugi adducts in good overall
121 yields (Scheme 5).

122 Scheme 5.

123 With this easy allylation of Ugi adducts in hand, we decided to take advantage of the diversity
124 offered by the latter coupling to explore Ugi/allylation/Ring Closure Methathesis (RCM) strategies
125 towards various nitrogen based heterocycles. The use of RCM as Ugi post-condensation has already
126 demonstrated its power for the formation of 5, 6-membered heterocycles as well as macrocyclic
127 derivatives (Banfi et al., 2003; Beck et al., 2003; Hebach and Kazmaier, 2003; Ribelin et al., 2007;
128 Ku et al., 2011). However the synthetic potential of these strategies is in a way limited by the need of
129 introducing the two allylated moieties at an early stage which reduces the diversity offered by the
130 two-step process. The late stage allylation we propose is highly versatile allowing to settle the
131 strategy with a single alkenyl moiety in the starting components. Thus using allyl amine, we could
132 easily prepare a library of piperidines with five points of diversity (Scheme 6).

133 Scheme 6.

134 This access to 3,4-dehydropiperidine derivatives **7** could be further enriched by a potential
135 isomerisation into cyclic enamines as demonstrated by the ruthenium hydride catalysed conversion of
136 **7a** into **8** (Scheme 6). The versatility of the method can be pictured by the alternative choice of the
137 alkenyl moiety on the acidic component such as in cinnamic acid offering now a very simple access
138 to 3,4-dehydropiperidine-2-one **9** (Scheme 7).

139 Scheme 7.

140 **3 Conclusion**

141 In summary, we have extended the potential of the Ugi reaction using 1,3-amide dianionic species as
142 intermediates for efficient allylations at the peptidyl moiety of Ugi adducts. The procedure raises the
143 diversity of Ugi adducts and offers unique opportunities for the preparation of nitrogen based
144 heterocycles through association with ring closure metathesis. The power of the latter strategy has
145 been demonstrated by the preparation of various piperidines which are important scaffolds for
146 medicinal applications.

147

148

149 **Scheme 1.** Reaction of Ugi amide dianion with mono and biselectrophiles.

150 **Scheme 2.** Scope of the Ugi/Tsuji-Trost cascade

151 **Scheme 3.** Allylation of Ugi propargyl adduct.

152 **Scheme 4.** Scope of alkylating agents

153 **Scheme 5.** Cascade one pot reaction

154 **Scheme 6.** Ugi/allylation/RCM strategy
155 **Scheme 7.** Ugi/allylation/MCR towards piperidones

156 **3.1 Tables**

<figure><img src="image_2.png" /><figcaption>157 **Table 1. Screening of various conditions<sup>a</sup>**</figcaption></figure>

158

<table><thead><tr><th>Entry</th><th>Base (equiv)</th><th>Solvent</th><th>Temp (°C)</th><th>Time (h)</th><th>Yield (%)</th></tr></thead><tbody><tr><td>1</td><td>t-BuOK(2.5)</td><td>THF</td><td>reflux</td><td>2</td><td>65</td></tr><tr><td>2</td><td>t-BuOK(2.5)</td><td>DMF</td><td>70</td><td>12</td><td>70</td></tr><tr><td>3</td><td>KHMDS (2.5)</td><td>THF</td><td>reflux</td><td>1</td><td>95</td></tr><tr><td>4</td><td>KHMDS (2.5)</td><td>THF</td><td>50</td><td>1</td><td>93</td></tr><tr><td>5</td><td>KHMDS (1.3)</td><td>THF</td><td>50</td><td>1</td><td>37</td></tr><tr><td>6</td><td>KHMDS (2.5)</td><td>THF</td><td>rt</td><td>1</td><td>88</td></tr><tr><td>7</td><td>NaH (2.5)</td><td>THF</td><td>reflux</td><td>12</td><td>45</td></tr><tr><td>8</td><td>NaH (2.5)</td><td>DMF</td><td>70</td><td>12</td><td>50</td></tr><tr><td>9</td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>1</td><td>96</td></tr><tr><td>10<sup>b</sup></td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>12</td><td>Traces</td></tr><tr><td>11<sup>c</sup></td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>12</td><td>80</td></tr><tr><td>12<sup>d</sup></td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>1</td><td>94</td></tr><tr><td>13<sup>e</sup></td><td>KHMDS (2.5)</td><td>THF</td><td>rt</td><td>12</td><td>-</td></tr></tbody></table>

159 <sup>a</sup>Reaction conditions: **1a** (0.5 mmol), **2** (0.75 mmol), Pd(dba)₂ (0.025 mmol) and PPh₃ (0.05 mmol)

160 in solvent (0.5 M).<sup>b</sup>Using Xantphos (5 mol%) instead of PPh₃.<sup>c</sup>Using Johnphos (10 mol%) instead of

161 PPh₃.<sup>d</sup>Using Pd(PPh₃)₄ (5 mol%) instead of Pd(dba)₂/PPh₃.<sup>e</sup>Reaction without Pd(dba)₂ and PPh₃.

162

163 **4 Conflict of Interest**
155 **Scheme 7. Ugi/allylation/MCR towards piperidones**

156 **3.1 Tables**

<figure><img src="image_2.png" /><figcaption>157 **Table 1. Screening of various conditions<sup>a</sup>**</figcaption></figure>

158

<table><thead><tr><th>Entry</th><th>Base (equiv)</th><th>Solvent</th><th>Temp (°C)</th><th>Time (h)</th><th>Yield (%)</th></tr></thead><tbody><tr><td>1</td><td>t-BuOK(2.5)</td><td>THF</td><td>reflux</td><td>2</td><td>65</td></tr><tr><td>2</td><td>t-BuOK(2.5)</td><td>DMF</td><td>70</td><td>12</td><td>70</td></tr><tr><td>3</td><td>KHMDS (2.5)</td><td>THF</td><td>reflux</td><td>1</td><td>95</td></tr><tr><td>4</td><td>KHMDS (2.5)</td><td>THF</td><td>50</td><td>1</td><td>93</td></tr><tr><td>5</td><td>KHMDS (1.3)</td><td>THF</td><td>50</td><td>1</td><td>37</td></tr><tr><td>6</td><td>KHMDS (2.5)</td><td>THF</td><td>rt</td><td>1</td><td>88</td></tr><tr><td>7</td><td>NaH (2.5)</td><td>THF</td><td>reflux</td><td>12</td><td>45</td></tr><tr><td>8</td><td>NaH (2.5)</td><td>DMF</td><td>70</td><td>12</td><td>50</td></tr><tr><td>9</td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>1</td><td>96</td></tr><tr><td>10<sup>b</sup></td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>12</td><td>Traces</td></tr><tr><td>11<sup>c</sup></td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>12</td><td>80</td></tr><tr><td>12<sup>d</sup></td><td>NaH (2.5)</td><td>DMSO</td><td>rt</td><td>1</td><td>94</td></tr><tr><td>13<sup>e</sup></td><td>KHMDS (2.5)</td><td>THF</td><td>rt</td><td>12</td><td>-</td></tr></tbody></table>

159 <sup>a</sup>Reaction conditions: **1a** (0.5 mmol), **2** (0.75 mmol), Pd(dba)<sub>2</sub> (0.025 mmol) and PPh<sub>3</sub> (0.05 mmol)

160 in solvent (0.5 M).<sup>b</sup>Using Xantphos (5 mol%) instead of PPh<sub>3</sub>.<sup>c</sup>Using Johnphos (10 mol%) instead of

161 PPh<sub>3</sub>.<sup>d</sup>Using Pd(PPh<sub>3</sub>)<sub>4</sub> (5 mol%) instead of Pd(dba)<sub>2</sub>/PPh<sub>3</sub>.<sup>e</sup>Reaction without Pd(dba)<sub>2</sub> and PPh<sub>3</sub>.

162

163 **4 Conflict of Interest**
164 *The authors declare that the research was conducted in the absence of any commercial or financial*
165 relationships that could be construed as a potential conflict of interest.

166 **5 Author Contributions**

167 AZ was responsible for designing and performing the experiments. AZ, AMLN, NEAAES, AKA and
168 LEK discussed the evolution of the project and revised the manuscript together, LEK and AKA
169 directed the project and wrote the publication.

170 **6 Acknowledgment and dedication**

171 We dedicate this work to our colleague Mohamed Ali Hassan who passed away few months before
172 the end of this study. We gratefully acknowledge a Scholarship from the Egyptian Government,
173 which was awarded to A. Zidan.

174 **7 References**

175 Banfi, L., Basso, A., Guanti, G., and Riva, R. (2003). Application of tandem Ugi reaction/ring-closing metathesis in multicomponent synthesis of unsaturated nine-membered lactams. *Tetrahedron Lett.* **44**, 7655-7658. doi: **10.1016/j.tetlet.2003.08.027**.

178 Beck, B., Larbig, G., Mejat, B., Magnin-Lachaux, M., Picard, A., Herdtweck, E., and Dömling, A. (2003). Short and Diverse Route Toward Complex Natural Product-Like Macrocycles. *Org. Lett.* **5**, 1047-1050. doi: **10.1021/ol034077e**.

181 Ben Abdessalem, A., Abderrahim, R., Agrebie, A., Dos Santos, A., El Kaïm, L., and Komesky, A. (2015). Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines. *Chem. Commun.* **51**, 1116-1119. doi: **10.1039/C4CC08282F**.

184 Bossio, R., Marcos, C.F., Marcaccini, S., and Pepino, R. (1997). Studies on Isocyanides and Related Compounds. An Unusual Synthesis of Functionalized Succinimides. *Synthesis*, **1389-1390**. doi: **10.1055/s-1997-1367**.

187 Boyarskiy, V., Bokach, N., Luzyanin, K.V., and Kukushkin, V. (2015). Metal-mediated and Metal-catalyzed reactions of isocyanides. *Chem. Rev.* **115**, 2698-2779. doi: **10.1021/cr500380d**.

189 Brauch, S., Gabriel, L., and Westermann, B. (2010). Seven-component reactions by sequential chemoselective Ugi–Mumm/Ugi–Smiles reactions. *Chem. Commun.* **46**, 3387-3389. doi: **10.1039/B927388C**.

192 Cordier, M., Dos Santos, A., El Kaïm, L., and Narboni, N. (2015). Passerini/Tsuji–Trost strategies towards achieving lactams and cyclopentane derivatives. *Chem. Commun.* **51**, 6411-6414. doi: **10.1039/C5CC00584A**.

195 Dömling, A. (2006). Recent developments in isocyanide based multicomponent reactions in applied chemistry. *Chem. Rev.* **106**, 17-89. doi: **10.1021/cr0505728**.

197 Dömling, A., and Ugi, I. (2000). Multicomponent reactions with isocyanides. *Angew. Chem. Int. Ed.* **39**, 3168-3210. doi: **10.1002/1521-3773(20000915)39:18<3168:: AID-ANIE3168>3.0.CO;2-U**.

200 Dömling, A., Wang, K., and Wang, W. (2012). Chemistry and Biology of multicomponent reactions. *Chem. Rev.* **112**, 3083-3135. doi: **10.1021/cr100233r**.
164 *The authors declare that the research was conducted in the absence of any commercial or financial*
165 relationships that could be construed as a potential conflict of interest.

166 **5 Author Contributions**

167 AZ was responsible for designing and performing the experiments. AZ, AMLN, NEAAES, AKA and
168 LEK discussed the evolution of the project and revised the manuscript together, LEK and AKA
169 directed the project and wrote the publication.

170 **6 Acknowledgment and dedication**

171 We dedicate this work to our colleague Mohamed Ali Hassan who passed away few months before
172 the end of this study. We gratefully acknowledge a Scholarship from the Egyptian Government,
173 which was awarded to A. Zidan.

174 **7 References**

175 Banfi, L., Basso, A., Guanti, G., and Riva, R. (2003). Application of tandem Ugi reaction/ring-closing metathesis in multicomponent synthesis of unsaturated nine-membered lactams. *Tetrahedron Lett.* **44**, 7655-7658. doi: **10.1016/j.tetlet.2003.08.027**.

178 Beck, B., Larbig, G., Mejat, B., Magnin-Lachaux, M., Picard, A., Herdtweck, E., and Dömling, A. (2003). Short and Diverse Route Toward Complex Natural Product-Like Macrocycles. *Org. Lett.* **5**, 1047-1050. doi: **10.1021/ol034077e**.

181 Ben Abdessalem, A., Abderrahim, R., Agrebie, A., Dos Santos, A., El Kaïm, L., and Komesky, A. (2015). Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines. *Chem. Commun.* **51**, 1116-1119. doi: **10.1039/C4CC08282F**.

184 Bossio, R., Marcos, C.F., Marcaccini, S., and Pepino, R. (1997). Studies on Isocyanides and Related Compounds. An Unusual Synthesis of Functionalized Succinimides. *Synthesis*, **1389-1390**. doi: **10.1055/s-1997-1367**.

187 Boyarskiy, V., Bokach, N., Luzyanin, K.V., and Kukushkin, V. (2015). Metal-mediated and Metal-catalyzed reactions of isocyanides. *Chem. Rev.* **115**, 2698-2779. doi: **10.1021/cr500380d**.

189 Brauch, S., Gabriel, L., and Westermann, B. (2010). Seven-component reactions by sequential chemoselective Ugi–Mumm/Ugi–Smiles reactions. *Chem. Commun.* **46**, 3387-3389. doi: **10.1039/B927388C**.

192 Cordier, M., Dos Santos, A., El Kaïm, L., and Narboni, N. (2015). Passerini/Tsuji–Trost strategies towards achieving lactams and cyclopentane derivatives. *Chem. Commun.* **51**, 6411-6414. doi: **10.1039/C5CC00584A**.

195 Dömling, A. (2006). Recent developments in isocyanide based multicomponent reactions in applied chemistry. *Chem. Rev.* **106**, 17-89. doi: **10.1021/cr0505728**.

197 Dömling, A., and Ugi, I. (2000). Multicomponent reactions with isocyanides. *Angew. Chem. Int. Ed.* **39**, 3168-3210. doi: **10.1002/1521-3773(20000915)39:18<3168:: AID-ANIE3168>3.0.CO;2-U**.

200 Dömling, A., Wang, K., and Wang, W. (2012). Chemistry and Biology of multicomponent reactions. *Chem. Rev.* **112**, 3083-3135. doi: **10.1021/cr100233r**.
202 Dos Santos, A., and El Kaïm, L. (2014). Reductive Passerini/Tsuji-Trost Strategy towards β,γ-
203 Unsaturated Amides. *Synlett* 25, 1901-1903. doi: 10.1055/s-0033-1340187.

204 Eckert, H. (2012). Diversity Oriented Syntheses of Conventional Heterocycles by Smart Multi
205 Component Reactions (MCRs) of the Last Decade. *Molecules* 17, 1074. doi:
206 10.3390/molecules17011074.

207 El Kaim, L., Gizzi, M., and Grimaud, L. (2008). New MCR-Heck-Isomerization Cascade toward
208 Indoles. *Org. Lett.* 10, 3417-3419. doi: 10.1021/ol801217a.

209 El Kaïm, L., Grimaud, L., Le Goff, X.-F., Menes-Arzate, M., and Miranda, L.D. (2011).
210 Straightforward four-component access to spiroindolines. *Chem. Commun.* 47, 8145-8147.
211 doi: 10.1039/C1CC12236C.

212 El Mamouni, E.H., Cattoen, M., Cordier, M., Cossy, J., Arseniyadis, S., Ilitki, H., and El Kaïm, L.
213 (2016). Selective Tsuji-Trost type C-allylation of hydrazones: a straightforward entry into
214 4,5-dihydropyrazoles. *Chem. Commun.* 52, 14490-14493. doi: 10.1039/C6CC08171A.

215 Elders, N., Van Der Born, D., Hendrickx, L.J.D., Timmer, B.J.J., Krause, A., Janssen, E., De Kanter,
216 F.J.J., Ruijter, E., and Orru, R.V.A. (2009). The efficient One-Pot reaction of up to eight
217 components by the union of Multicomponent reactions. *Angew. Chem. Int. Ed.* 48, 5856-
218 5859. doi: 10.1002/anie.200902683.

219 Ghandi, M., Zarezadeh, N., and Abbasi, A. (2015). One-pot synthesis of spiropyrroloquinoline-
220 isoindolinone and their aza-analogs via the Ugi-4CR/metal-free intramolecular bis-annulation
221 process. *Org. Biomol. Chem.* 13, 8211-8220. doi: 10.1039/C5OB01095K.

222 Hebach, C., and Kazmaier, U. (2003). Via Ugi reactions to conformationally fixed cyclic peptides.
223 *Chem. Commun.* 0, 596-597. doi: 10.1039/B210952B.

224 Hulme, C., and Gore, V. (2003). Multi-component reactions: emerging chemistry in drug discovery
225 from xylocain to crixivan. *Curr. Med. Chem.* 10, 51-80. doi: 10.2174/0929867033368600.

226 Ivachtchenko, A.V., Ivanenkov, Y.A., Kysil, V.M., Krasavin, M.Y., and Ilyin, A.P. (2010).
227 Multicomponent reactions of isocyanides in the synthesis of heterocycles. *Russ. Chem. Rev.*
228 79, 787-817. doi: 10.1070/RC2010v079n09ABEH004086.

229 Kaur, T., Gautam, R.N., and Sharma, A. (2016). Assembly of New Heterocycles through an Effective
230 Use of Bisaldehydes by Using a Sequential GBB/Ugi Reaction. *Chem. Asian J.* 11, 2938-
231 2945. doi: 10.1002/asia.201601009.

232 Ku, I.W., Kang, S.B., Keum, G., and Kim, Y. (2011). Synthesis of α,β-Unsaturated 2-
233 Oxopyrrolidinyl Acetamide derivatives by Application of the Ugi/RCM Reaction Sequence.
234 *Bull. Kor. Chem. Soc.* 32, 3167-3170. doi: 10.5012/bkcs.2011.32.8.3167.

235 Langer, P., and Freiberg, W. (2004). Cyclization Reactions of Dianions in Organic Synthesis. *Chem.*
236 *Rev.* 104, 4125-4150. doi: 10.1021/cr0102031.

237 Lei, J., Meng, J.P., Tang, D.Y., Frett, B., Chen, Z.Z., and Xu, Z.G. (2018). Recent advances in the
238 development of polycyclic skeletons via Ugi reaction cascades. *Mol. Divers.* 22, 503-516.
239 doi: 10.1007/s11030-017-9811-2.

240 Li, Z., Kumar, A., Peshkov, A., and Van Der Eycken, E.V. (2016). A domino Ugi/Michael approach
241 for the synthesis of α,β-un saturated γ-lactams. *Tetrahedron Lett.* 57, 754-756. doi:
242 10.1016/j.tetlet.2016.01.014.
202 Dos Santos, A., and El Kaïm, L. (2014). Reductive Passerini/Tsuji-Trost Strategy towards β,γ-
203 Unsaturated Amides. *Synlett* 25, 1901-1903. doi: 10.1055/s-0033-1340187.

204 Eckert, H. (2012). Diversity Oriented Syntheses of Conventional Heterocycles by Smart Multi
205 Component Reactions (MCRs) of the Last Decade. *Molecules* 17, 1074. doi:
206 10.3390/molecules17011074.

207 El Kaim, L., Gizzi, M., and Grimaud, L. (2008). New MCR-Heck-Isomerization Cascade toward
208 Indoles. *Org. Lett.* 10, 3417-3419. doi: 10.1021/ol801217a.

209 El Kaïm, L., Grimaud, L., Le Goff, X.-F., Menes-Arzate, M., and Miranda, L.D. (2011).
210 Straightforward four-component access to spiroindolines. *Chem. Commun.* 47, 8145-8147.
211 doi: 10.1039/C1CC12236C.

212 El Mamouni, E.H., Cattoen, M., Cordier, M., Cossy, J., Arseniyadis, S., Ilitki, H., and El Kaïm, L.
213 (2016). Selective Tsuji-Trost type C-allylation of hydrazones: a straightforward entry into
214 4,5-dihydropyrazoles. *Chem. Commun.* 52, 14490-14493. doi: 10.1039/C6CC08171A.

215 Elders, N., Van Der Born, D., Hendrickx, L.J.D., Timmer, B.J.J., Krause, A., Janssen, E., De Kanter,
216 F.J.J., Ruijter, E., and Orru, R.V.A. (2009). The efficient One-Pot reaction of up to eight
217 components by the union of Multicomponent reactions. *Angew. Chem. Int. Ed.* 48, 5856-
218 5859. doi: 10.1002/anie.200902683.

219 Ghandi, M., Zarezadeh, N., and Abbasi, A. (2015). One-pot synthesis of spiropyrroloquinoline-
220 isoindolinone and their aza-analogs via the Ugi-4CR/metal-free intramolecular bis-annulation
221 process. *Org. Biomol. Chem.* 13, 8211-8220. doi: 10.1039/C5OB01095K.

222 Hebach, C., and Kazmaier, U. (2003). Via Ugi reactions to conformationally fixed cyclic peptides.
223 *Chem. Commun.* 0, 596-597. doi: 10.1039/B210952B.

224 Hulme, C., and Gore, V. (2003). Multi-component reactions: emerging chemistry in drug discovery
225 from xylocain to crixivan. *Curr. Med. Chem.* 10, 51-80. doi: 10.2174/0929867033368600.

226 Ivachtchenko, A.V., Ivanenkov, Y.A., Kysil, V.M., Krasavin, M.Y., and Ilyin, A.P. (2010).
227 Multicomponent reactions of isocyanides in the synthesis of heterocycles. *Russ. Chem. Rev.*
228 79, 787-817. doi: 10.1070/RC2010v079n09ABEH004086.

229 Kaur, T., Gautam, R.N., and Sharma, A. (2016). Assembly of New Heterocycles through an Effective
230 Use of Bisaldehydes by Using a Sequential GBB/Ugi Reaction. *Chem. Asian J.* 11, 2938-
231 2945. doi: 10.1002/asia.201601009.

232 Ku, I.W., Kang, S.B., Keum, G., and Kim, Y. (2011). Synthesis of α,β-Unsaturated 2-
233 Oxopyrrolidinyl Acetamide derivatives by Application of the Ugi/RCM Reaction Sequence.
234 *Bull. Kor. Chem. Soc.* 32, 3167-3170. doi: 10.5012/bkcs.2011.32.8.3167.

235 Langer, P., and Freiberg, W. (2004). Cyclization Reactions of Dianions in Organic Synthesis. *Chem.*
236 *Rev.* 104, 4125-4150. doi: 10.1021/cr010203l.

237 Lei, J., Meng, J.P., Tang, D.Y., Frett, B., Chen, Z.Z., and Xu, Z.G. (2018). Recent advances in the
238 development of polycyclic skeletons via Ugi reaction cascades. *Mol. Divers.* 22, 503-516.
239 doi: 10.1007/s11030-017-9811-2.

240 Li, Z., Kumar, A., Peshkov, A., and Van Der Eycken, E.V. (2016). A domino Ugi/Michael approach
241 for the synthesis of α,β-un saturated γ-lactams. *Tetrahedron Lett.* 57, 754-756. doi:
242 10.1016/j.tetlet.2016.01.014.
243 Orru, R., and De Greef, M. (2003). Recent advances in Solution-Phase multicomponent methodology for the synthesis of heterocyclic compounds. *Synthesis* 10, 1471-1499. doi: 10.1055/s-2003-40507.

246 Orru, R.V.A., and Ruijter, E. (2010). *Synthesis of Heterocycles via Multicomponent Reactions I.* Berlin, Heidelberg: Springer Verlag.

248 Orru, R.V.A., and Ruijter, E. (2010). *Synthesis of Heterocycles via Multicomponent Reactions II.* Berlin Heidelberg: Springer Verlag.

250 Polindara-García, L.A., and Miranda, L.D. (2012). Two-Step Synthesis of 2,3-Dihydropyrroles via a Formal 5-endo Cycloisomerization of Ugi 4-CR/Propargyl Adducts. *Org. Lett.* 14, 5408-5411. doi: 10.1021/ol3024727.

253 Ribelin, T.P., Judd, A.S., Akritopoulou-Zanze, I., Henry, R.F., Cross, J.L., Whittern, D.N., and Djuric, S.W. (2007). Concise Construction of Novel Bridged Bicyclic Lactams by Sequenced Ugi/RCM/Heck Reactions. *Org. Lett.* 9, 5119-5122. doi: 10.1021/ol7023373.

256 Sadjadi, S., and Heravi, M.M. (2011). Recent application of isocyanides in synthesis of heterocycles. *Tetrahedron* 67, 2707-2752. doi: 10.1016/j.tet.2011.01.086.

258 Salcedo, A., Neuville, L., and Zhu, J. (2008). Palladium-Catalyzed Intramolecular C-Arylation of Benzylic Carbon: Synthesis of 3-Benzoxazolylisoindolinones by a Sequence of Ugi-4CR/Postfunctionalization. *J. Org. Chem.* 73, 3600-3603. doi: 10.1021/jo800266y.

261 Sharma, U.K., Sharma, N., Vachhani, D.D., and Van Der Eycken, E.V. (2015). Metal-mediated post-Ugi transformations for the construction of diverse heterocyclic scaffolds. *Chem. Soc. Rev.* 44, 1836-1860. doi: 10.1039/C4CS00253A.

264 Sunderhaus, J.D., and Martin, S.F. (2009). Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds. *Chem. Eur. J.* 15, 1300-1308. doi: 10.1002/chem.200802140.

267 Tempest, P.A. (2005). Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction. *Curr. Opin. Drug Discov.* 8, 776-788. doi: 10.1080/17518253.2012.691183.

270 Thompson, C.M. (1994). *Dianion Chemistry in Organic Synthesis*. Boca Raton: CRC press.

271 Trifilenkov, A.S., Ilyin, A.P., Kysil, V.M., Sandulenko, Y.B., and Ivachtchenko, A.V. (2007). One-pot tandem complexity-generating reaction based on Ugi four component condensation and intramolecular cyclization. *Tetrahedron Lett.* 48, 2563-2567. doi: 10.1016/j.tetlet.2007.02.015.

275 Tyagi, V., Khan, S., and Chauhan, P.M.S. (2013). Facile synthesis of diverse isoindolinone derivatives via Ugi-4CR followed by Cu-catalyzed deamidative C(sp2)-C(sp3) coupling. *Tetrahedron Lett.* 54, 1279-1284. doi: 10.1016/j.tetlet.2012.12.091.

278 Vachhani, D.D., Butani, H.H., Sharma, N., Bhoya, U.C., Shah, A.K., and Van Der Eycken, E.V. (2015). Domino Heck/borylation sequence towards indolinone-3-methyl boronic esters: trapping of the σ-alkylpalladium intermediate with boron. *Chem. Commun.* 51, 14862-14865. doi: 10.1039/C5CC05193B.

282 Váradi, A., Palmer, T., Dardashti, R., and Majumdar, S. (2016). Isocyanide-based multicomponent reactions for the synthesis of heterocycles. *Molecules* 19. doi: 10.3390/molecules21010019.
243 Orru, R., and De Greef, M. (2003). Recent advances in Solution-Phase multicomponent methodology for the synthesis of heterocyclic compounds. *Synthesis* 10, 1471-1499. doi: 10.1055/s-2003-40507.

246 Orru, R.V.A., and Ruijter, E. (2010). *Synthesis of Heterocycles via Multicomponent Reactions I.* Berlin, Heidelberg: Springer Verlag.

248 Orru, R.V.A., and Ruijter, E. (2010). *Synthesis of Heterocycles via Multicomponent Reactions II.* Berlin Heidelberg: Springer Verlag.

250 Polindara-García, L.A., and Miranda, L.D. (2012). Two-Step Synthesis of 2,3-Dihydropyrroles via a Formal 5-endo Cycloisomerization of Ugi 4-CR/Propargyl Adducts. *Org. Lett.* 14, 5408-5411. doi: 10.1021/ol3024727.

253 Ribelin, T.P., Judd, A.S., Akritopoulou-Zanze, I., Henry, R.F., Cross, J.L., Whittern, D.N., and Djuric, S.W. (2007). Concise Construction of Novel Bridged Bicyclic Lactams by Sequenced Ugi/RCM/Heck Reactions. *Org. Lett.* 9, 5119-5122. doi: 10.1021/ol7023373.

256 Sadjadi, S., and Heravi, M.M. (2011). Recent application of isocyanides in synthesis of heterocycles. *Tetrahedron* 67, 2707-2752. doi: 10.1016/j.tet.2011.01.086.

258 Salcedo, A., Neuville, L., and Zhu, J. (2008). Palladium-Catalyzed Intramolecular C-Arylation of Benzylic Carbon: Synthesis of 3-Benzoxazolylisoindolinones by a Sequence of Ugi-4CR/Postfunctionalization. *J. Org. Chem.* 73, 3600-3603. doi: 10.1021/jo800266y.

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287 Zarganes-Tzitzikas, T., Chandgude, A.L., and Dömling, A. (2015). Multicomponent reactions, union of MCRs and beyond. *Chem. Rec.* 15, 981-996. doi: 10.1002/tcr.201500201.

289 Zhang, L., Zhao, F., Zheng, M., Zhai, Y., and Liu, H. (2013). Rapid and selective access to three distinct sets of indole-based heterocycles from a single set of Ugi-adducts under microwave heating. *Chem. Commun.* 49, 2894-2896. doi: 10.1039/C3CC00111C.

292 Zhu, J., and Bienaymé, H. (2005). *Multicomponent reactions*. Weinheim: Wiley-VCH.

293 Zhu, J., Wang, Q., and Wang, M.-X. (2014). *Multicomponent reactions in organic synthesis*. Weinheim: Wiley-VCH.

295 Zidan, A., Cordier, M., El-Naggar, A.M., Abd El-Sattar, N.E.A., Hassan, M.A., Ali, A.K., and El Kaïm, L. (2018). Propargylation of Ugi Amide Dianion: An Entry into Pyrrolidinone and Benzoindolizidine Alkaloid Analogues. *Org. Lett.* 20, 2568-2571. doi: 10.1021/acs.orglett.8b00687.

299 Zidan, A., Garrec, J., Cordier, M., El-Naggar, A.M., Abd El-Sattar, N.E.A., Ali, A.K., Hassan, M.A., and El Kaim, L. (2017). β-Lactam Synthesis through Diodomethane Addition to Amide Dianions. *Angew. Chem. Int. Ed.* 56, 12179-12183. doi: 10.1002/anie.201706315.

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284 Zarganes-Tzitzikas, T., Patil, P., Khoury, K., Herdtweck, E., and Dömling, A. (2015). Concise Synthesis of Tetrazole-keto-piperazines by Two Consecutive Ugi Reactions. *Eur. J. Org. Chem.* 1, 51-55. doi: 10.1002/ejoc.201403401.

287 Zarganes-Tzitzikas, T., Chandgude, A.L., and Dömling, A. (2015). Multicomponent reactions, union of MCRs and beyond. *Chem. Rec.* 15, 981-996. doi: 10.1002/tcr.201500201.

289 Zhang, L., Zhao, F., Zheng, M., Zhai, Y., and Liu, H. (2013). Rapid and selective access to three distinct sets of indole-based heterocycles from a single set of Ugi-adducts under microwave heating. *Chem. Commun.* 49, 2894-2896. doi: 10.1039/C3CC00111C.

292 Zhu, J., and Bienaymé, H. (2005). *Multicomponent reactions*. Weinheim: Wiley-VCH.

293 Zhu, J., Wang, Q., and Wang, M.-X. (2014). *Multicomponent reactions in organic synthesis*. Weinheim: Wiley-VCH.

295 Zidan, A., Cordier, M., El-Naggar, A.M., Abd El-Sattar, N.E.A., Hassan, M.A., Ali, A.K., and El Kaïm, L. (2018). Propargylation of Ugi Amide Dianion: An Entry into Pyrrolidinone and Benzoindolizidine Alkaloid Analogues. *Org. Lett.* 20, 2568-2571. doi: 10.1021/acs.orglett.8b00687.

299 Zidan, A., Garrec, J., Cordier, M., El-Naggar, A.M., Abd El-Sattar, N.E.A., Ali, A.K., Hassan, M.A., and El Kaim, L. (2017). β-Lactam Synthesis through Diodomethane Addition to Amide Dianions. *Angew. Chem. Int. Ed.* 56, 12179-12183. doi: 10.1002/anie.201706315.

302