UNIVERSITY OF CINCINNATI
Date:______
I, ______, hereby submit this work as part of the requirements for the degree of: in:
It is entitled:
This work and its defense approved by:
Chair: ______
The rate enhancement of multi-component reactions by high speed ball milling
Maxwell Zeb Shumba M.S. Eastern Kentucky University. M.S University of Cincinnati
DISSERTATION
A dissertation submitted the University of Cincinnati
In Partial Fulfillment of
The Requirements of the Degree of
Doctor of Philosophy
In
Chemistry
November 2007
ABSTRACT
Solventless high speed ball milling (HSBM) technique has over the years gained the attention of organic chemists in particular from the viewpoint of green chemistry, because harmful organic solvents are not involved in the reaction process.
Moreover, some novel products can also be obtained only from solvent-free reactions under the HSBM conditions rather than from the liquid-phase reactions. We looked to apply the HSBM technique towards the improvement of multi-component reactions
(MCR). Based on their usefulness in organic synthesis and in pharmaceutical industry, the
Baylis-Hillman reaction, the Gewald, and the Ugi-4-component reaction (U-4CR) were chosen for investigation. For these three reactions we were able to observe a rate enhancement and an increase in the product yields. Herein, we report the utility of HSBM to provide a rate enhancement and increased yields for the following multi-component reactions: The Baylis-
Hillman, the Gewald reactions and the U-4-CR. 2 ACKNOWLEDGEMENTS
First and foremost I would to thank the Lord and vadzimu vekwangu vese for guiding me through the arduous road towards my PhD degree. I would like to thank my wife Kudakwashe for giving me undying support, love and encouragement when the road seemed bleak. Special mention goes to my two daughters; Mia-Karen and
Lisa-Alma who had to endure the pain of growing up without adequate parental attention accorded to other children; ‘Lisa and Mia had to forego sports activities at their respective schools because their dad had commitments in the lab’.
I would like to thank my brother-in-law, Shingirai Mhonda, my mother in law, my brothers Alford and Edmore and my sister Anna (mai Enock) for the moral support and encouragement they offered me. I would like also to take this opportunity to dedicate this work to my late mother and father; Angeline and Callisto, my late brother and sister, Maki and Itai; the two who were tragic victims of the AIDS scourge.
They provided me with the needed spiritual guidance, notably my Great Uncle, the late Francis ‘Franco’ Mutandwa.
I would like to thank my advisor Dr. James Mack who was there for me and my family in the hour of need. His patience with me as I juggled between being a full time graduate student, a father and freedom fighter in the struggle for a free and democratic Zimbabwe; my home country was inspirational. His guidance and advice certainly made this PhD degree a reality. I would like to thank the Chemistry
Departments at the University of Cincinnati and Eastern Kentucky University for providing me with a platform to realize my potential. Noteworthy is Dr. Otieno at
Eastern Kentucky University. I would like to thank the Chemistry Department staff especially Dr. Brooks at the NMR, the now retired Zelda and Betty at the chemistry office, John at the stock room, Cassandra and John at the Chemistry Business Office, all of whom offered me unparralled service.
3 I would like to thank the Mack group members for their support, in particular
Dennis Fulmer, who has over the years come to be a ‘brother’ to me and my ‘sister’
Angela Hurst. I would also want to thank the past and current graduate students in the Department of Chemistry for sharing with me their experiences which helped me a lot on this journey.
I would like to thank my fellow comrades-in-the-struggle for walking with me and providing me with moral support as I trod on this dual road; graduate school and the ‘Struggle’ for Zimbabwe. Special mention goes to Aaron Mhonda, Andrew
Mudzingwa, Oswald ‘Kazie’ Chibanda, Dr. Douglas Magomo, Mr. Cornelius Msimbe,
Dr. Machekano, Modern Makovere, Ronnie Muvirimi, James Charlie, Josphat
Tafirenyika, Paul Shumbayaonda (Shingai Munhamo), Mr. Leonard Chizinga, Ms
Clara Matonhodze, Engineer Elias Mudzuri and MDC President Mr. Morgan
Tsvangirai and others not on this list. To all these dedicated soldiers, I say, your efforts for a Free Zimbabwe are not in vain.
I would like to thank my old friends for giving me unwavering support; Farai
Chaimiti, Musatya Bere, Yamkelani Moyo, Wilson Sangadza, Vincent Aduda, Gitahi
Waiganjo, Justice Dube, John Moto, Cexton Musekiwa, Richard Manungo, Newton
‘Bombeo’ Chihava, Simba Gerald Parumba, and Jane Abey. Special mention goes to the late Tendai Chidemo and Mrs Magreth (Mai Chidemo) Chidemo for bringing me to
Cincinnati.
Lastly, I would like to thank the Department of Chemistry and National
Foundation of Science (NSF) for providing funding for my research projects.
4 CONTENTS
ABSTRACT ...... 1
ACKNOWLEDGEMENTS ...... 3
CONTENTS...... 5
List of Tables ...... 7
List of Figures...... 8
1. Introduction...... 11
1.1 Mechanochemistry: Historical perspective...... 11
1.1 Milling and Grinding...... 12
1.2 Milling and Grinding...... 13
1.3 High Speed Vibrational Milling/High Speed Ball Milling...... 19
1.4 The high speed ball milling technique in organic chemistry...... 20
A. THE BAYLIS-HILLMAN REACTION ...... 34
Background ...... 34
Results and Discussion ...... 37
B. GEWALD MULTI-COMPONENT REACTION...... 62
Background ...... 62
Results and Discussion ...... 67
C. THE UGI-4-COMPONENT REACTION (U-4CR) ...... 73
2.3 Background...... 73
Results and Discussion ...... 76
CONCLUSION ...... 80
EXPERIMENTAL SECTION ...... 81
General Methods...... 81
Materials...... 82
5 (a) Solvents ...... 82 (b) Column Chromatography ...... 83 (c) Reagents...... 84 (d) Instruments and accessories...... 86 (e) Synthesis...... 87 Chapter 1. Baylis-Hillman ...... 98
Chapter2. The Gewald Multi-component Reaction...... 102
Chapter 3. Ugi-4-Component Reaction...... 113
6 List of Tables
Table Page
1. Reaction time against percent yield for Baylis-Hillman reaction 44
2. The Baylis-Hillman reaction using methyl acrylate, p-nitrobenzaldehyde, and the quiniclidine family of catalysts 47
3. Reaction of p-nitrobenzaldehyde, DABCO, and methyl acrylate and various tertiary amine catalysts 48
4. Steric hindrance studies 52
5. Reaction of p-nitrobenzaldehyde, DABCO, and various activated alkenes 60
6. Percent yield obtained from the reaction of para substituted benzaldehyde, DABCO, and methyl acrylate 61
7. The Gewald reaction with cyclic ketones 71
8. The Gewald reaction with aromatic ketones 72
9. Percent yield of the reaction between substituted aniline, trans-cinnamaldehyde, chloroacetic acid and cyclohexyl isocyanide 80
7 List of Figures
Figure Page
1. Mortar and Pestle 13
2. The 8000D Spex Mill. 60 Hz vibrational milling 14
3. Laboratory Planetary Mono mill. Pulverisette 6 15
4. A laboratory attritor mill 16
5. Reformatsky type reaction under solventless conditions 20
6. Mechanism of the Reformatsky reaction 21
7. Dimerization of fullerene s under HSBM 22
8. Two C60 molecules in equilibrium with the C120 dimer 23
9. The Wittig reaction 24
10. The solution based Prato reaction 25
11. The Prato reaction under HSBM 26
12. The Prato reaction without aldehydes under HSBM conditions 26
13. The Bingel reaction under HSMB conditions 28
14. The Bingel reaction using diethyl malonate and a base under HSBM 28
15. The materials used in the HSBM investigations 32
16. The Baylis-Hillman reaction 33
17. The mechanism of the Baylis-Hillman reaction 34
18. 1H NMR of 2-[(4-nitro-phenyl)-hydroxy-methyl]-acryl acid ester 39
19. 13C NMR of 2-[(4-nitro-phenyl)-hydroxy-methyl]-acryl acid ester 40
8 20. Column chromatographic diagram for the reaction involving nitrobenzaldehyde, DABCO, and methyl acrylate 40
21. Plot of reaction time against percent yield for the reaction studies involving DABCO, Methyl acrylate and nitrobenzaldehyde 41
22. A new proposed mechanism for the Baylis-Hillman reaction 42
23. Tertiary amine catalysts used in the study 43
24. Reaction of DABCO, p-nitrobenzaldehyde, and methyl crotonate 46
25. 1H NMR of -[(4-nitro-phenyl)-hydroxy -methyl]-methyl crotonate 47
26. Reaction of DABCO, p-nitrobenzaldehyde, and phenyl crotonate 47
27. 1H NMR of -[(4-nitro-phenyl)-hydroxy -methyl]-phenyl crotonate 48
28. Solution based reaction of p-nitrobenzaldehyde with methyl vinyl ketone 50
29. Non-Baylis-Hillman reaction between aldehyde and acrylamide 51
30. Baylis-Hillman reaction of nitrobenzaldehyde and acrylamide 51
31. Reaction of nitrobenzaldehyde with vinyl sulfone 52
32. Reaction of nitrobenzaldehyde with acrylonitrile 53
33. Reaction of acrylamide, DABCO and nitrobenzaldehyde in the presence of LiCl co-catalyst 53
34. Reaction of p-nitrobenzaldehyde in the presence of DABCO catalyst 54
35. 1H NMR of spectra of 4-nitro-phenyl)-hydroxy -methyl]-acrylonitrile 54
36. Reaction of acrylamide, DABCO and p-nitrobenzaldehyde in the presence of
lithium salt 56
37. (+)-Cinchonine 59
38. Functionalized silica gel 59
39. L-proline 60
40. The Gewald Reaction 62
9 41. The proposed mechanism for the Gewald Reaction 62
42. The 1st Variation of the Gewald Reaction 63
43. The 2nd Variation of the Gewald Reaction 64
44. The 3rd Variation of the Gewald Reaction 64
1 45. H NMR 400MHz 0f C10H13SNO3 67
1 46. H NMR 400MHz 0f C10H14SNO3 69
1 47. H NMR 400MHz 0f C10H14SNO3 70
48. The U-4CR 72
49. The Passerini-3-Component reaction (P-3CR) 72
50. The proposed mechanism for the U-4CR 73
51. The wide variety of products from the U-4CR 74
52. The P-3CR under HSBM 75
53. 1H NMR of the U-4CR product 3a 76
54. The wide variety of products from the U-4CR 77
55. The U-4CR under HSBM conditions 78
56. 1H NMR of the U-4CR product 3a 79
57. Reaction of N-phthaloylgylcine, cyclohexyl isocyanide, formaldehyde and
Benzylamine 79
58. 1H NMR of the U-4CR product 3b 81
10 1. Introduction
1.1 Mechanochemistry: Historical perspective
Mechanically activated processes date back to the early history of humankind, notably, the use of flints to initiate fires.1 Following these early uses, the field of mechanochemistry has continually received attention from chemists, particularly in Europe where the use of ball mills were later developed to process a wide range of materials ranging from minerals to advanced materials.
The majority of review articles dates the beginnings of written history of mechanochemistry to the end of the 19th century, referring to the experimental works of
Matthew Carey Lea or to textbooks of Wilhelm F Ostwald.3 The theoretical considerations concerning the relationship between chemical and mechanical energy could be found in the first and second edition of Oswald’s textbook from 1887 and 1893. The term mechanochemistry was coined by Ostwald in 1919 as an energy source for chemical reactions. Ostwald regarded mechanochemistry as a part of physical chemistry like thermochemistry, electrochemistry or photochemistry. Matthew Carey Lea’s experiments4 are usually considered as the first systematic investigation on the chemical effects of mechanical action. Matthew Carey Lea demonstrated that halides of gold, silver, platinum and mercury decomposed to halogen and metal during fine grinding in a mortar but melt or sublime undecomposed when heated. He pointed out for the first time that mechanical energy initiated chemical reactions and local heating is not the only possible mechanism for initiating chemical reactions by mechanical actions. Matthew Carey Lea is thus credited with establishing mechanochemistry as a separate branch of chemistry. Since then mechanochemistry has generally been used in inorganic chemistry, mostly to grind solids such alloys, ceramics etc.
11 1.1 Milling and Grinding
The grinding of two solid substances generates a complex series of transformations.
Mechanical energy breaks the order of the crystalline structure to produce cracks, and new
surfaces. At the point of collision of the edges, the solids deform and even melt, forming hot
points where molecules can reach very high vibrational excitation leading to bond breaking.
As a procedure for mechanochemical solid-state reactions, the simplest is grinding
using a mortar and pestle (figure 1). This method promotes the reaction through grinding,
mixing, and triturating.
In a Mechanochemistry Review: an overview5, Jose F. Fernadez-Bertran postulates that the grinding of two solid substances generates a complex series of transformations, the mechanical energy breaking the order of the crystalline structure, producing cracks, and new surfaces. At the point of collision of the edges the solids deform and even melt, forming hot points where the molecules can reach very high vibrational excitation leading to bond breaking. The processes described above occur in a period of 10-7 s in which thermal equilibrium does not exist.6
As the procedure for mechanochemical solid-state reactions, the simplest is grinding using a mortar and pestle (figure 1). This method promotes the reaction through grinding, mixing, and triturating.
12 1.2 Milling and Grinding
The grinding of two solid substances generates a complex series of transformations.
Mechanical energy breaks the order of the crystalline structure to produce cracks, and new
surfaces. At the point of collision of the edges, the solids deform and even melt, forming hot
points where molecules can reach very high vibrational excitation leading to bond breaking.
As a procedure for mechanochemical solid-state reactions, the simplest is grinding
using a mortar and pestle (figure 1). This method promotes the reaction through grinding,
mixing, and triturating.
In a Mechanochemistry Review: an overview5, Jose F. Fernadez-Bertran postulates that the grinding of two solid substances generates a complex series of transformations, the mechanical energy breaking the order of the crystalline structure, producing cracks, and new surfaces. At the point of collision of the edges the solids deform and even melt, forming hot points where the molecules can reach very high vibrational excitation leading to bond breaking. The processes described above occur in a period of 10-7 s in which thermal equilibrium does not exist.6
As the procedure for mechanochemical solid-state reactions, the simplest is grinding using a mortar and pestle (figure 1). This method promotes the reaction through grinding, mixing, and triturating.
13 . Fig 1. The traditional milling and grinding method: mortar and pestle.
Milling and grinding using a mortar and pestle technique can induce a large number of
mechanochemical reactions which do not require surmounting a high energy barrier. The
traditional mortar and pestle is manually operated by hand and an automated version is
available called Mortar Grinder RM 100 is available from Retsch GmbH & Co. KG. The
disadvantage of a mortar and pestle is that it is hand operated and as the operator tires the
energy input becomes uneven and also reactions requiring longer reaction times are ineffective
via this method. The other disadvantage is that the method cannot be used where larger
amounts of energy are necessary. In those situations, ball milling has been used instead.7, 8
There are three types of ball milling devices, namely, shaker/mixer mill, planetary mill, and
attritor mill.
A shaker/mixer mill is a rapidly vibrating mill which generally has been used in laboratories to pulverize KBr pellets into fine powder to be pressed to form a pellet for IR spectral measurement of organic compounds. It is also widely used in geology labs to pulverize rock ores in preparation for mineral assay analysis. The main part of this mixer
14 mill is essentially a stainless steel vial and a milling ball, which is rapidly, vibrated at the speed of 60Hz (for the lab-built mill) 1,700 rpm (for a commercial mill).
Fig. 2. The 8000 D Spex Mill. 60Hz Vibrational Milling.
Shaker mills such as the SPEX mills are the most commonly used for
.laboratory investigations. SPEX mills are manufactured by SPEX CertPrep,
Metuchen, NJ. A SPEX shaker mill can process up to 20g at a time.
15
Figure 3.Laboratory Planetary Mono Mill, Pulverisette 6. Figure courtesy of http://www.lavallab.com/laboratory-mill.
A planetary mill owes its name to the planet-likeness of its vials; the vials are
arranged on a rotating support disk and a special drive mechanism causes them to
rotate around on their own axes. The centrifugal force that is produced by the rotating
support disk both act on the material and grinding balls in the vial. The material in the
vial is ground due to the grinding of the balls. Planetary mills of the Pulverisette type
(Figure 3) are available from Fritsch, GmbH, Germany.
A conventional ball mill consists of a rotating horizontal drum half filled with
small steel balls. In contrast, an attritor mill has a series of impellers inside it (Figure
4).
16 Figure 4. A Laboratory attritor mill. Figure courtesy of http://www.unionprocess.com
A powerful motor rotates the impellers. Set progressively at right angles the impellers energize the steel balls. The material to be ground and the grinding medium are placed in the stationary tank. The mixture is then agitated by a shaft with arms, rotating at a high speed of about 250 rpm. Laboratory attritor mills works up to ten times faster than the conventional mill. Commercial attritors are available from Union Process, Akron,
OH.
To date assessing the capability of a milling process in a shaker/mixer mill has not been accomplished yet (i.e. the possibility of obtaining a given product by suitably choosing the proper milling conditions) however, several attempts have so far been made to understand the fundamentals of the ball milling process and also the main mechanism by which energy is transferred to the powder during a milling process.
17 Maurice and Courtney,9 have modeled ball milling in a planetary mill. The model includes parameters like impact times, areas of the colliding surfaces (derived from
Hertzian collision theory), powder strain rates and pressure peak during collision. Burgio et al10 derived kinematic equations of a ball moving in a planetary mill and the consequent ball-to-powder energy transfer occurring in a single collision event. The fraction of input energy transferred to the powder was subsequently estimated by an analysis of the collision event. Finally an ‘energy map’ was constructed which was the basis for the Burgio collision model.
One of the premises of the Burgio collision model was that it assumed that, in the presence of powder, the collisions are inelastic and that the energy transferred in the hit is represented by the equation:
2 •E = Ka ½ mbvb
Where Ka= 0 for perfect elastic collisions (no energy transfer) and Ka=1 for perfect inelastic collisions. It had been shown that if balls were covered with powder the collisions are almost perfectly inelastic, so that Ka=1. It was also verified that in the early milling stages, the fraction of the kinetic energy transferred to the powder is practically equal to the total energy involved in the collision event.
Experimental data has been found to be in agreement with the Burgio theoretical model.10 However, more research is still needed to accurately determine the activation energy provided by the shaker/mixer mill to enable mechanochemical chemists to accurately determine the activation energy provided under the HSBM conditions.
18 1.3 High Speed Vibrational Milling/High Speed Ball Milling
Milling in a shaker/mixer mill has come to be known as high speed vibrational milling (HSVM), a term proposed by Wang, Komatsu et al.11 Other chemists, including in this report, prefer to call it high speed ball milling (HBSM).
In the HSBM procedure, solid reactants (crystals or powders) are placed inside a steel vessel in the absence of solvent, along with a ball bearing. The vessel is sealed and placed inside the mixer mill apparatus (Fig1) whereby it is agitated.
It has been reported that based on the observed phase transformation of BeF2 and B2O3, pressures as high as 10-20,000 bars are considered to be generated and applied to the particles during the milling process by a ball milling machine.12 It has been shown that the temperature outside of the vial doesn’t reach 60 ºC.13
The action of external activation usually drives the chemical reactions. External activation can be in the form of heat, photo irradiation, microwave, etc. In the case of ball milling, the mechanical energy, such as that caused by stress, friction, and shear deformation, is considered as the important external activator. Solution based organic synthesis uses solvents to break up the crystalline lattice, whereas in ball milling the use of any solvent is eliminated; thus the reacting species are free from solvation. Therefore, two factors, the generation of local high pressure caused by mechanical energy and the absence of solvation, is expected to produce novel reactions, which cannot take place in solution
19 1.4 The high speed ball milling technique in organic chemistry
The pioneering work of Toda and co workers in the early 1990’s 14, 15 in successfully carrying out reactions using a mortar and pestle, broke ground into the use of mechanochemistry in organic synthesis. In 1994, Braun et al16 reported the use of a ball- milling technique to prepare the g-cyclodextrin complex of C60.
However, the first carbon-carbon bond forming organic reaction of C60 under a solventless mechanochemical condition was conducted in 1996 by Komatsu, Wang and
Co-workers.17
In an effort to circumvent the limitations posed by the low solubility of fullerenes in common organic solvent, Komatsu, Wang and Co-Workers turned to a solventless high speed ball milling technique to derivatize fullerenes. The ‘environmentally friendly’ process was applied for the first time to a Reformatsky type derivatization of fullerene which had not been reported before. The Reformatsky type reaction is characterized by the nucleophilic addition of amines, organolithiums and Grignard reagents to C60 (Figure
3).17 This reaction which had not been reported before is characterized by the nucleophilic addition of amines, organolithiums and Grignard reagents to C60.
20 H CH CO Et 2 2 EtO2CH2C CH2CO2Et
HSBM C60 + Zn + BrCH2CO2Et + 6
1 H CO2Et 2
CH2CO2Et EtO2CH2C
+
3 4
Figure 5 Reformatsky Type Reaction by solventless HSBM conditions.
To the researchers’ surprise the HSBM technique, not only gave the expected products (1 and 2), but novel compounds (3 and 4) were formed. A mechanism was proposed to explain the production of the novel compounds. The formation of 3 was attributed to an electrophilic substitution of the Reformatsky reagent BrCH2CO2Et/Zn) and the carbonyl moiety of the stable intermediate 5. Compound 4 is formed by the nucleophilic substitution of ethyl bromoacetate by the intermediate 5.
21 4 BrCH2CO2Et BrCH2CO2Et Zn
_ CH2CO2Et BrZnCH2CO2Et
BrCH CO Et 2 2 H+ 1
BrCH2COCH2CO2Et
Zn 5 C60
BrZnCH2COCH2CO2Et
H CO2Et C C 60 H H+ + H 2
3
Figure 6 Mechanism of the Reformatsky type derivatization of fullerene
The formation of new compounds in the Reformatsky type functionalization of fullerene from the HSBM technique provided the first evidence that solid phase reactions are different from liquid phase. Motivated by these findings, Komatsu, Wang and Co-Workers sought to investigate the scope and utility of this technique with other fullerene reactions. In doing so they studied the cyanation of fullerene using potassium cyanide or sodium cyanide; a reaction known to proceed very well in solution albeit with the use of large volumes of solvents because of the low solubility of fullerene.
22
Figure 7 Dimerization of fullerenes under HSBM conditions
It was noted that the expected cyanation of fullerene did not take place using the
HSBM. Instead a C120 dimer 7 was produced (Figure 5). Dimerization of fullerene until then had been difficulty because of the tendency of the reaction to proceed to give large molecular weight polymers. Controlling the reaction to stop at the C120 dimer product had been a real challenge to fullerene chemists. Therefore, the HSBM method became the first reported viable route for the synthesis of fullerene dimers.
In an effort to explain their findings, further studies were done and it was found
out that in this reaction, the major difference between the solution based synthesis and
solid sate HSBM synthesis was the ability of the HSBM system to reach equilibrium.
Two molecules of fullerene were found to equilibrate with the C120 dimer, a process
which according to the hypothesis would stop the reaction from proceeding to
polymerization
23 HSVM C60
7
Figure 8. Two C60 molecules in equilibrium with the C120 dimer.
The observations made in this reaction were important for two key
reasons:
1. Supported earlier findings that solventless solid state
reactions gave novel compounds.
2. A new method for the synthesis for fullerene dimers had
been developed.
These key findings stimulated the interest of these (Komatsu, Wang et al) and other researchers to expand their investigations into the utility of HSBM by studying other reactions involving fullerenes and other non fullerene reactions.
Since the publication of Komatsu, Wang and co-workers’ s exploits with functionalization of fullerene, there has been an increased amount of literature publications in the area of HSBM.18 Notable studies reporting the successful use of
HSBM, include the synthesis of methanofullerenes from the reaction of C60 with
19 diethyl bromomalonate in the presence of inorganic bases, [4+2] reactions of C60, with condensed aromatics,20 with phthalazine,21 and with di-(2-pyridyl)-1,2,4,5-
22 23 tetrazine, reactions of C60, organic bromides and alkali metals. The solventless
HSBM technique has also been extended to successfully and efficiently carry out the
Diels-Alder cycloaddition reactions,24 the Wittig reaction25 the Prato reaction26 and the
24 Bingel Reaction18 among others. Some of the reactions and findings made are
discussed below:
Wittig Reaction (2002)
Spurred by the success begotten in the fullerene chemistry, Balema and
Perchasky began to investigate the utility of the new technique with common organic
reactions by using the technique to run the Wittig reaction (figure 9),25
H O
H
CH2B r K2CO3 PhP3 + + Ball-milling no solvent H
Figure 9. The Wittig Reaction
The key observations made in this reaction were:
1. K2CO3, a weak base, was successfully used to carry out this reaction
while in a liquid phase synthesis; a stronger base, such as butyl lithium or phenyl
lithium, is required for this.
2. The stereochemistry of the HSBM product was different from that in the
liquid-phase. Wittig chemistry always give preferably cis stereochemistry in solution
the mechanochemical technique discriminates between Z- and E- substituted products
in favor of the more thermodynamically stable trans isomer.
25 1,3-dipolar cycloaddition of azomethine ylide (The Prato reaction)
(2002) 26
In solution, a typical procedure for this reaction consists of reacting a mixture of C60, N-methylgylicine or other amino acids, and aldehyde or ketone at elevated temperatures (refluxing in toluene or chlorobenzene) to afford fulleropyrrolidine 8.
CH3 N
reflux, toluene
CH3
N
CH 8
O H + N O
OCH3 H
Figure 10. Prato reaction in solution.
The success achieved with the Reformatsky type functionalization of fullerene and the dimerization of fullerene prompted Komatsu and co-workers to investigate whether the solventless HSBM technique could be generalized to include the Prato reaction. In their initial studies which used the same materials (i.e. aldehyde, C60 and
N-methylgylicine) as in solution except the use of a solvent gave the expected fulleropyrrolidine 9 in moderated yields (Figure 11).
26 CH3 CH3
N N R
HSBM + CH3NHCH2CO2H + RCHO +
8 9 Figure 11. The Prato reaction under HSBM conditions.
However, an unexpected monoadduct 10 was isolated as minor product. To explain this finding the same reaction was carried out without the aldehyde and the fulleropyrrolidine was obtained in a yield of 19%. A fullerene C120 dimer was also obtained as a minor product.
10 7
Figure 12. The Prato Reaction without an aldehyde under HSBM conditions.
From this observation, a possible reaction mechanism was proposed for the reaction of C60 with N-alkylglycine to explain the formation of the fulleropyrrolidine and also the fullerene C120 dimer.
Essentially, the difference between the HSBM mechanism and that of the traditional liquid phase Prato reaction is that the solution based reaction undergoes a
1,3-dipolar cycloadition of the azomethine ylide to fullerene, whereas the HSBM goes through a free radical reaction mechanism.
27 The Bingel Reaction (2004)
The Bingel reaction is one of the various known reactions in fullerene chemistry that is employed to give a variety of cyclopropanated fullerenes. In solution, nucleophilic addition of a carbon nucleophile generated by deprotonation of a- halogenated malonic acid esters or •-halogenated b-diketones to C60 and following an intramolecular nucleophilic substitution gives a cyclopropanated fullerene derivative.
These same products have been formed in solution when C60 was reacted with active methylene compounds such as diethyl malonate in the presence of CBr4 and a base
(brominated methylene compounds are formed in situ from active methylene compounds and CBr4 with the aid of a base).
In the Bingel Reaction, 1,8-diazabicyclo [5, 4, 0] undec-7-ene (DBU) is the base of choice used to deprotonate the halogenated active methylene compounds.
However, when DBU was used under the HSBM conditions, no product was formed, only starting material was recovered. Instead the expected cyclopropanated product
11, was produced in higher yields when weaker inorganic bases such Na2CO3,
NaHCO3, NaOAc, Ca(OH)2, and Na2B4O7 were used.. When K2CO3 or triethylamine
(TEA) were used a larger amount was of the cyclopropanated product was produced.
28 CO Et EtO2C 2
base + BrCH(CO2Et)2 HSBM, 60 min
Figure 13. Bingel Reaction under HSBM conditions
In contrast, when the reaction was carried out using diethyl malonate instead of bromomalonate in the presence of Na2CO3 under the HSVM conditions, the expected cyclopropanated product 11, was not obtained, instead a C60 derivative having two bis(ethoxycarbonyl)methyl groups at the 1,4-positions in obtained in 18 % yield. In a previous report it was shown that a reaction of C60 with lithium fluoride gave a similar
1,4-bis(9-fluorenyl) adduct when a small amount of oxygen was present in the reaction system to cause a one-electron oxidation of the initially formed functionalized C60 anion to its radical.27 28
CO Et EtO2C 2
+ base BrCH(CO2Et)2 HSBM, 60 min
11
Figure. 14. The Bingel Reaction using diethyl malonate and a base under HSBM conditions.
A similar radical addition process was proposed for the HSBM conditions which gave 12, since no such product was produced in the absence of air.
The proposed mechanism under the HSBM conditions included the involvement of oxygen in the 3rd step of the reaction mechanism. Nucleophilic addition of carbanion, generated in situ from malonate ester by a base gives fullerene anion which is oxidized by O2 to the corresponding radical. Hydrogen abstraction of
29 malonate ester by previously formed oxygen radical anion affords radical, which couples with intermediate to give the 1,4-bisadduct. The bulky CH (COOR)2 group prohibits the 1,2-bis-additon due to the steric hindrance, thus causing the selective formation of 1,4-bisadducts.
Generally it has been found that derivatization of fullerene under HSBM conditions goes through a mechanism which involves the formation of radicals. The straining of bonds which is produced as result of mechanical stress produces unusual electronic distribution and the formation of the radicals is attributed to the loss of symmetry of the electronic distribution. Strained molecular states can only exist in solid state. Therefore, it cannot be emphasized the importance of the formation of radical under ball milling conditions when making the distinction between solid state and liquid phase reactions.24, 29,
As demonstrated in the examples discussed above (Wittig, Prato, and Bingel) and others discussed elsewhere in literature.30-33 HSBM technique has developed into a genuinely viable alternative to liquid phase synthesis. Mechanochemistry has become the topic of numerous publications and its significance is gradually increasing.
Nowadays it is an integral part of agenda of any international conference on Green
Chemistry.
High speed ball milling has proven to be versatile, very simple, clean and most importantly an alterative technique to give products in higher yields, shorter reaction times and novel products. In continuing to investigate the utility of the HSBM technique we hypothesized that this technique could be useful to run reactions which
30 are difficult to carry out in solution. Therefore, the focus of this dissertation is on the use of HSBM on multi component reactions.
In recent years multi-component reactions (MCRs) have found numerous applications in organic chemistry and combinatorial chemistry. Multicomponent reactions can be defined as those reactions in which two or more reactants combine in an atom economic manner to give important polyfunctionalized products. These reactions are characterized by a series of equilibrium steps culminating in an irreversible final step. In solution based synthesis, the forward reaction is not entropically favored. This aspect renders multicomponent reactions (in neat conditions) to be generally slow, sometimes days to weeks and the yields are generally poor recently there has been great interest in developing a one step synthesis for
MCRs to improve on the amount of reaction time, product yield, and the diversity- oriented synthesis.
The results from other reactions (cited previously) which were run under the
HSBM conditions stimulated our interest into investigating the utility of this technique to carry out multicomponent reactions. Our hypothesis was that:
-since in solution these reactions are slow because of high entropy, then in solventless conditions where entropy is less of an issue, the reactions proceed faster.
In our studies, all efforts were dedicated to designing a one step synthesis for multicomponent reactions. Initially, we investigated the feasibility of doing these reactions by studying the Baylis-Hillman reaction. We then looked at applying the same technique to the Gewald reaction and finally we wanted to generalize this method by running the Ugi reactions.
31 Although the use of HSBM in organic synthesis has been around for almost a decade, there is no general method outlining the type of vials, ball material and ball size to be used to give the best results. In all reports reviewed, the authors consistently ignore this aspect. Therefore, before we began our studies of the utility of
HSBM on multicomponent reactions, we focused on the developing a method which could consistently be used in our lab. The studies included the screening of vials and balls. Vials made out of different materials were included in the study.
Our results showed that screw capped stainless steel vials were the most appropriate. With the vial type selected, we then conducted a ball study. The investigation sought to establish the relationship between ball material, ball size and efficiency. Balls made of different materials and of different sizes were screened.
Our results, which were later collaborated by another independent study done in our lab, found out that 1/8” balls were the most efficient compared to the
1/16” and ¼”. 1/8” balls made out of stainless steel, tungsten carbide, chrome steel, and aluminum oxide were the most efficient ones. Investigations, (including computational calculations) which seek to provide an explanation as to why the 1/8” is the most efficient, are underway in our lab.
With a consistent set of materials for the HSBM technique we then set out to investigate to utility of the HSBM technique in multicomponent reactions.
32 Figure 15. The materials used in the HSBM investigations: holding chamber, vials, balls and an O-ring
Herein we report the results of our extensive study of three multi-component
reactions, namely, the Baylis-Hillman Reaction, the Gewald Reaction, and the Ugi-4-
Component Reaction (U-4-CR).
2. Multi-Component Reactions
In recent years multi component reactions (MCRs) have found numerous applications in organic chemistry and use in the formation of combinatorial libraries.
Multi-component reactions can be defined as those reactions in which two or more reactants combine in an atom economic manner to give polyfunctionalized products. These reactions are characterized by a series of equilibrium steps culminating in an irreversible final step. In solution based synthesis, the forward reaction is not entropically favored. This aspect renders multi-component reactions (in neat conditions) to be generally slow. In recent years there has been a great interest in developing a one step synthesis for MCRs to improve on the amount of reaction time, product yield34-36, and the diversity-oriented synthesis. In our study, all efforts are dedicated to increase the rate of multi-component reactions. Initially, we investigated the feasibility of doing these reactions by studying the Baylis-Hillman reaction
33 A. THE BAYLIS-HILLMAN REACTION
Background
The Baylis-Hillman Reaction (BH) has its origin in the patent given to Baylis and
Hillman in 1972.37 The authors described this reaction as the reaction between b- unsaturated esters, nitriles, amides or ketones with a wide range of aldehydes in the presence of a tertiary amine (figure16)
X EWG R1 XH 3o amine EWG + R R1
X= O, NR2 EWG= electron withdrawing group
Figure 16. The Baylis-Hillman Reaction
The carbon-carbon bond formation is one of the most fundamental reactions in organic chemistry. The reaction can be broadly defined as a condensation between the a-position of activated alkenes with carbon electrophile containing an electron deficient sp2 carbon atom catalyzed by a tertiary amine. The Baylis-Hillman reaction has all the basic properties that an efficient synthetic method should have. It is selective (regio, chemo, enantio and diastereo), atom economic, and provides synthetically useful multi-functional molecules. It also been reported that the BH gives adducts which are biologically active.
All mechanistic studies38-41 are generally agreed that the mechanism for the
Baylis-Hillman reaction involves a series of addition-elimination of steps involving a tertiary amine, an activated alkene and electrophile (Figure17).
34 Figure 17. The Mechanism for the Baylis-Hillman Reaction
The first step is initiated by the Michael type nucleophilic addition of a tertiary amine to the activated alkene resulting in a transient zwitterionic intermediate A. In the second step the zwitterionic adduct makes a nucleophilic attack on the nucleophile to produce zwitterionic adduct B. The intermediate B gives the final product after a proton migration followed by the elimination of the tertiary amine. The equilibrium in the 1st step, which is the rate determining step, is skewed towards the reactants resulting in an overall slow rate. The mechanism has been supported by computational evidence by Sunoj and Co- worker.42
Generally, in solution, the Baylis-Hillman reaction is very slow (can take several weeks to evolve) when carried out at room temperature and atmospheric pressure under
35 neat conditions.38 Efforts, including the use of using higher proportions of the tertiary amine catalyst, have been made towards achieving a rate enhancement for this reaction.
Other studies towards this goal include, solvent effects and effect of hydrogen bonding,
43-45 substrate structure, pressure,46-48 temperature,49 ultrasound, microwave irradiation50and salt effects51 While these studies have shown some successes at enhancing the rate of the Baylis-Hillman reaction, in neat conditions the reaction is still slow. Our goal was to investigate the utility of solid state High Speed Ball Milling
(HSBM) as an alternate method which can be utilized to enhance the rate of this reaction and improve on the yields. The hypothesis is that the underlying difference between solution based methods and solid state HSBM is entropy. The forward reaction for the 1st step is entropically unfavorable. The hypothesis we put forward is that particles are very close together in solid state (or solvent less conditions). Therefore, entropy in these conditions (solid state or solvent less) is smaller factor.
36 Results and Discussion
Aldehydes are the most used electrophiles. However, aromatic aldehydes are reluctant to serve as substrates for the Baylis-Hillman reaction under the usual relatively mild conditions. Under standard conditions, they give low yields in long reaction periods
(typically 1 to 4 weeks). Due to the synthetic importance of Baylis-Hillman products obtained from aromatic aldehydes,52,53 our investigation focused on finding out whether
HSBM could be a better alternative to the traditional methods in running those reactions which involve aromatic electrophiles. Having these objectives in mind, we describe a complete study on the determination of the scope and limitations of the use of HSBM technique on the Baylis-Hillman reaction with aromatic aldehydes with different activated alkenes and different tertiary amine catalysts. In this study, the main focus was given to aromatic aldehydes because they are difficult to react in the Baylis-Hillman reaction. We also set to determine the best tertiary amine catalyst for the HSBM technique and the generality of the technique to include other activated alkenes besides vinyl esters.
37 Baylis-Hillman reaction under HSBM
In the 1972 German Patent granted to Anthony Baylis and Melvin Hillman, the most
successful catalyst reported was 1, 4-Diazabicyclo (2, 2, 2) Octane (DABCO) which
gave a yield of 75% after one week. 32 years later, in solution based synthesis
DABCO is still the catalyst of choice. This nucleophilic non-hindered base has been
found to be reasonably versatile, working with a range of substrates.54
The starting point of our work was to explore whether the Baylis-Hillman reaction
would go could successfully be carried out using DABCO as a catalyst under HSBM
conditions. We expected that if the reaction was to go successfully under the HSBM
conditions, then both the yield and the reaction rate would be better than under
solvent conditions.
We also hypothesized that entropy effects are significantly different between solvent and solvent-free conditions. Compared to solution based synthesis, under solvent free conditions of HSBM, the reacting molecules are close to each other; in contrast, the addition of solvent molecules increases the negative impact of entropy on the reaction rate. Therefore, under solventless conditions the effect of entropy on the rate of reaction is minimal and it’s expected that DABCO would be more efficient in solventless conditions than it is in solvent based synthesis. The best reported yield for the same reaction in solution is by Johnson Claire et al55 who reported a 96% percent yield for the same reaction but to enhance the reaction rate an ethyltri-n- butylphosphonium tosylate was co-catalyst was used. No report to the best of our
38 knowledge shows the same reaction carried out in neat conditions using DABCO as the only catalyst.
In the Johnson report the enhancement of reaction rate was attributed to the co- catalytic effect of the phosphonium salt and DABCO.
Our initial reactions were carried out using DABCO (with no co-catalyst), methyl acrylate, and nitrobenzaldehyde. The paste-like mixtures were reacted under solvent free conditions in a Spex Mixer/Mill 8000M for 16hours 41min,. An analysis of the products after a flash column chromatograph separation showed a 100 % conversion and a 98 % isolated yield of the Baylis-Hillman adduct which was identified by GC-MS, 1H NMR and 13C NMR (Figure 18 and Table1).
39 The data for his compound is in agreement with the literature: Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J.Org.Chem 2003, 68, 692-700.
Figure 18. 1H NMR.(ppm) 2-[(4-nitro-phenyl)-hydroxy -methyl]-acryl acid methyl ester.
The reaction was complete in 16hours 41min and gave a 71%yield. The same reaction was repeated with p-nitrobenzaldehyde. In the 16hours 41 minutes we got a 100% conversion but there were other things produced which resulted in a product yield of only 71 %
40
Figure 19 13C NMR. [(4-nitro-phenyl)-hydroxy-methyl]-acryl acid methyl ester
Higher molecular Product weight by - products
Figure 20. Column chromatography diagram for the reaction involving nitrobenzaldehyde, DABCO and methyl acrylate.
After column chromatographic separation and GC-MS analysis of all the fractions no
starting materials was left indicating a 100% conversion after 16 hours. Instead, we
identified higher molecular weight and polymeric products which were not fully
characterized
41 We concluded that with p-nitrobenzaldehyde 16hours was probably too long. We
therefore, embarked on an optimum reaction time study for this reaction. The reaction
conditions in the study were not changed. Equimolars of DABCO, nitrobenzaldehyde
and methyl acrylate were ball milled in a screw cap vial using a 1/8" stainless steel
ball for various times as shown.
Table 1 of reaction time vs. percent yield for studies involving DABCO, methyl acrylate and p-nitrobenzaldehyde.
Time % Yield Plot of Yield against Reaction Time
16hrs 71 120 100 4hrs 76 80 60 2hrs 84 40 20 0 1hr 92 0.25 0.5 Time1 (Hrs)2 4 16
30minutes >98 Figure 21. Plot of reaction time vs. % yield for studies involving 15minutes 60.3 DABCO, methyl acrylate, and nitrobenzaldehyde.
In a time range of 15 minutes to a 16 hours study, the results showed that the yield increased from a time of 15minutes and peaked at
30minutes before it began to tail off. The more the time was increased, the less the yield and the more starting material were recovered. (Figure20). As a result, for the rest of the study, we resolved to adopt 0.5 hours as the standard time for the reaction.
In a report by McQuade et al, proposed a different mechanism in which the rate determining step involves the addition of a second equivalent of the aldehyde (Figure 21).
42 O Me O Me O O O H O Ar H OCH NR3 + 3 O Ar
R3N O R3N
Ar H Ar O Ar Ar Me Me Me O O O O O O OH H O O O Ar Ar O R N R3N 3
Figure 22. McQuade proposed mechanism for the Baylis-Hillman.
The new mechanism was supported by rate law studies which showed that the
Baylis-Hillman reaction was second order in aldehyde indicating that 2 equivalents of
aldehyde must be in the rate determining step (RDS) of the BH reaction. The new
mechanism put forward by McQuade has recently been supported by computational
and experimental studies by Aggarwal42 (a,b) whose report put it forward as one of the
two mechanisms which is dominant at the later stage (after 20% conversion to
product) as a result of autocatalysis (involving the alcohol product). The other
mechanism put forward by Aggarwal computational studies has the enolate addition to
the aldehyde in the second step as the rate determining step. This is in agreement with
the generally accepted mechanism38-41 and was also supported by both experimental
computational studies by Sunoj, R and Roy, D42(c) (although there was no evidence of
a second mechanism in their studies), we, however, sought to investigate whether
under HSBM conditions the observations by McQuade could be supported. In accord
with the newly proposed solution based mechanism we conducted our ball milled
reactions with 1 equiv DABCO, 1 equiv methyl acrylate and 2 equiv
43 nitrobenzaldehyde. We did not observe an increase in the reaction rate with increased
aldehyde concentration. Our results support the widely accepted mechanism in which
the rate determining step is the nucleophilic attack on the aldehyde by the ammonium
enolate followed by a proton transfer (Figure 17).
Catalyst Studies
Is the DABCO the best catalyst for the HSBM conditions? To answer this question we looked at a recent study by Aggarwal et al56 which put forward Quiniclidine as the best catalyst. In the study, which sought to investigate the relationship between pKa and catalyst efficiency, Aggarwal et al concluded that in a polar solvent (e.g. methanol), Quiniclidine (pKa= 11.3) was the best catalyst compared to Quiniclidinol
(pKa= 9.9) and DABCO (pKa=8.5).(Figure 23)
Figure 23 Tertiary amine catalysts used in the study.
44 The ability for quiniclidinol and DABCO to produce hydrogen bonds with the solvent was presented as the reason why their efficiency in catalyzing the reaction was limited. In our study we sought to investigate the efficiency of each catalyst in solvent less HSBM conditions. Our results showed that, in agreement with the majority of literature reports,
DABCO was the most efficiency catalyst (Table 2)
Table 2 The Baylis-Hillman reactions using methyl acrylate, nitrobenzaldehyde and the Quiniclidine family of catalysts.
Entry Catalyst Time (hrs) Yield (%)
1 DABCO 0.5 >98
2 Quiniclidinol 0.5 89
3 Quiniclidine 0.5 86
Our study also supports the hypothesis that in a polar solvent, the catalyst which hydrogen bonds more with the solvent will be less efficient. In solvent less conditions hydrogen bonding effects are a non issue, therefore, DABCO, with its ability to form a more stable zwitterionic intermediate, gives a higher yield in shorter time.
Our initial hypothesis in explaining why DABCO is the most efficient catalyst was based on the availability of two basic nitrogen atoms on this catalyst. We argued that
45 the two basic nitrogen atoms would enable DABCO to catalyze the reaction using either one of the nitrogen atoms. To test our hypothesis, we included in our study other tertiary amine catalysts with the number of nitrogen atoms ranging from two to four (Figure 24.)
In tandem with our hypothesis, we expected that hexamethyltetramine (HMT), with four nitrogen atoms would be the most efficient catalysts for the BH reaction, but contrary to our hypothesis, our results showed that was the worst catalyst for the reaction under study. We obtained an 8.2 % yield with HMT in contrast to the >98% yield obtained with DABCO under similar conditions.
Table 3 Reaction of methyl acrylate, p-nitrobenzaldehyde and various tertiary catalysts.
Expt Catalyst Time (hrs) %Yield
4 4-Dimethylpyridine (DMAP) 0.5 80
5 2,8,9-Trimethyl-2,5,8,9- 0.5 69 Tetraaza-1-phospha-bicycli-(3,3)-undecane 6 1,1,3,3-Tetramethylguanidine 0.5 52
7 1,5-Diazabicyclo(4,3)non-5-ene 0.5 45
8 Hexamethylenetetramine (HMT) 0.5 8.2
Our results are in agreement with the experimental finding by Aggarwal group concluded that the efficiency of DABCO as a catalyst is independent of the number of basic nitrogen atom present.
In another report a tertiary amine catalyst with a phosphorous atom, 2, 8, 9-
Trimethyl-2, 5, 8, 9-Tetraaza-1-phospha-bicycli-(3, 3)-undecane was reported to be better than DABCO.57 Our investigations indicated that while 2, 8, 9-Trimethyl-2, 5, 8, 9-
Tetraaza-1-phospha-bicycli-(3, 3)-undecane produced a rate enhancement of the Baylis-
46 Hillman reaction compared to solution based synthesis; it was, however not better than
DABCO.
Activated Alkene Studies
In furthering our studies we sought to investigate whether substituent groups
on the b position of the activated alkene had any effect on the reaction rate and yield.
Experiments where run with methyl acrylate (a vinyl ester with no substituent groups),
DABCO, and p-nitrobenzaldehyde. Parallel experiments were run with acrylates
bearing methyl and phenyl ring on the b position of the vinyl ester (Table 4).
O
OCH3
OH OCH3
O
O O2N DABCO H
O2N CH3
Figure 24 Reaction of DABCO, p-nitrobenzaldehyde, and methyl crotonate
47 1 Figure 25. H NMR (400MHz, CDCl3) for 4-nitro-phenyl)-hydroxy-methyl]- methyl crotonate.
O
OCH3 OH O
O
OCH3 O2 N DABCO H
O2N
Figure 26. Reaction of DABCO, p-nitrobenzaldehyde and phenyl crotonate
48 Figure 27. 1H NMR for 4-nitro-phenyl)-hydroxy-methyl]-phenyl crotonate.
49 Table 4. Steric hindrance studies
O O OH O
DABCO H OCH3 + OCH3 HSBM
O2N Y O2N
Y %Yield Time
H 71 16hrs 40min
Ph 8 16hrs 40min
CH3 6 16hrs 40min
Our results showed that methyl acrylate (no substituent group on the b position of the acrylate) with gave the highest yield and very low yields were realized from the acrylates bearing a bulky substituent group had the lowest % yield indicating a slow down on the reaction rate. The reduction in the percent yield was attributed to the negative influence of the steric hindrance. The alkene moiety (in the activated alkene bearing a substituent group) was not easily accessible to the attack by the tertiary amine in the first step of the reaction mechanism. On a side note, a report by Isaacs et al47 indicates that for the sterically hindered •-substituted alkenes require high pressure.
Therefore the low yields obtained from the methyl and phenyl •-substituted crotonates as an indicator of the low pressure generated inside the reaction steel vial.
With the good results obtained from using vinyl esters we decided to focus our attention to the generality of HSBM to include other activated alkenes. Reactions were run using DABCO and p-nitrobenzaldehyde and various activated alkenes.
50 Min Shi and co-workers58 observed that the Baylis-Hillman reaction of aryl aldehydes with phenyl vinyl ketone lead to the exclusive formation of di-adducts (figure
24)
O OH CH3
O O CH3 DABCO + DMF Me O N O2N 2
O CH3
Figure 28. Solution based reaction of p-nitrobenzaldehyde with methyl vinyl ketone.
Our results with vinyl ketone did not yield the expected results neither did we observe the formation of the diadduct reported by Min Shi and Co-workers. Only starting material was recovered. A possible explanation is that the methyl group decreases the electron-withdrawing capability of the carbonyl group, making the ketone a weak
Michael acceptor.
Hu Longqin and Yu Chengzhi 59 reported a % yield of 61-99% with acryl amide and aromatic aldehydes over a period of 12-48 hours in a solvent mixture of dioxane and water. In our solvent less HSBM conditions, we obtained very low yields in a reaction involving acryl amide, nitrobenzaldehyde, and DABCO (Table…). Hu et al reported the existence of a competing non Baylis-Hillman reaction involving the nucleophilic addition of the acrylamide nitrogen to the aldehyde (Figure 29)
51 O O O O R N NH 3 + 2 R H R N
Figure 29. Non-Baylis-Hillman reaction between aldehydes and acrylamide in the presence of DABCO to give an N-acylhemiaminal.
In the reaction carried out with nitrobenzaldehyde, acrylamide and DABCO under HSBM conditions (Figure 25) gave a poor yield of only 15%. Our results were in agreement with our hypothesis that the nitrogen of the amide moiety would decrease the electron-withdrawing effect of the carbonyl carbon rendering it a weak Michael acceptor.
We did not, however notice, any formation of the expected N-acylhemiaminal. We only recovered the normal Baylis-Hillman product and starting material.
O OH O O + DABCO NH H 2 HSBM NH2
O N O2N 2 15% yield
Figure 30. Reaction of nitrobenzaldehyde and acrylamide in the presence of a DABCO catalyst.
52 Figure 31. 4-nitro-phenyl)-hydroxy -methyl]-acryl amide. The data for this compound is in agreement with the literature: Hu, L.; Chengzhi,Y. J. Org. Chem. 2002 67,219-223).
To the best our knowledge no attempt has been done to use sulfones as the
activated alkene in the Baylis-Hillman reaction in neat conditions. We carried out
reactions with vinyl sulfones, nitrobenzaldehyde and DABCO (Figure 26). We
expected vinyl sulfones to be more reactive than the ketone but not as much as the
vinyl esters. This is because of the positive effect of electron-withdrawing ability of
the sulfone group which makes it a good Michael acceptor but the methyl group has a
negative effect on the electron-withdrawing effect of the sulfonyl group.
53 O O O OH O DABCO + S CH3 S H HSBM CH3 O
O2N O2N 60% yield
Figure 32. Reaction of p-nitrobenzaldehyde and methyl vinyl sulfone in the presence of a DABCO catalyst.
Figure 33. 4-nitro-phenyl)-hydroxy -methyl]-acryl –methyl sulfone.
Our results showed that vinyl sulfones give moderate yields of the expected
Baylis-Hillman product. We also noted the presence of higher molecular weight by-
products which did not fully characterize. We repeated the same experiment using
vinyl nitrile (acrylonitrile) in place vinyl sulfone (Figure 34.) and we obtained a
moderate yield of 48%.
54 O OH + DABCO CN CN H HSBM
O N O2N 2 48 % yield Figure 34. Reaction of p-nitrobenzaldehyde with acrylonitrile in the presence of DABCO catalyst
Figure 35. 1NMR spectra of 4-nitro-phenyl)-hydroxy -methyl]-acrylonitrile. The data for this compound is in agreement with the literature: Imagawa, T.; Uemura, K.; Nagai, Z.; Kawanisi, M. Commun. 1984.
A report by Shi Min60 et al shows a 70% yield in a reaction time of 120 hours for the same reaction in a DMF solvent system. We could not find in literature of any report of this reaction being carried out in neat.
55 Effect of salt on rate of reaction
A report by Kumar Anil and Pawar Sanjay 61indicated that the use of a LiCl salt as a co- catalyst together with DABCO accelerates the rate of the Baylis-Hillman reaction. Other researchers have also used salts to accelerate the Baylis-Hillman reaction. According to these researchers, salts enhance the Baylis-Hillman reaction because of a ‘salting-out’ phenomena as a result of interactions between the salt molecules and solvent molecules.62
The relevant theory of the salting phenomena is described elsewhere.63-65 Our rational of using LiCl salt to enhance the Baylis-Hillman reaction was based on an entirely different argument.
Mechanistically the rate of the Baylis-Hillman reaction depends on three
factors which are the stability of the ammonium enolate formed in the first step, the
reactivity of the electrophile, and the reactivity of the activated alkene. Therefore, the
coordination of the Li+ ion to the carbonyl oxygen (Figure 29), should activate the
electrophile making it more reactive. We decided to test this theory under or HSBM
conditions using the substrates that had given very poor yields; acrylamide,
acrylonitrile and vinyl sulfone.
Reactions were carried out with an activated alkene, p-nitrobenzaldehyde and
DABCO in the presence of a lithium chloride salt (Figure 29 and Table
56 O
H
LiCl Li Cl O
d H Li O O O O
R N NH2 + 3 NH2 NH2
R3N R3N
OH O
NH2 + NR3 + LiCl
Figure 36. Reaction of acrylamide, tertiary amine, and aldehyde in the presence of a lithium salt co catalyst.
We noted a decrease in the yield. The decrease in the yield was attributed to a phenomenon called ‘compacting’. We noted that the addition of the salt increased the volume of the materials inside the vial creating a vial overload. The ball milling technique is based on the ability of the ball to pulverize the crystalline substrates until they are amorphous. To achieve this, the ball should be able to reach all parts of the reacting vessel. If the reaction vial is overloaded, then the material at the bottom of the vial becomes inaccessible and the pounding by the ball on the material produces what we termed ‘compacting’ of the material. The compacted material was observed to be constituted of the starting material. As a result the low product yield is obtained.
57 Table 5. Reaction of 0.5mmol p-nitrobenzaldehyde, 0.5mmol activated alkene and 20% DABCO in the presence of a 0.1mmol LiCl salt.
O OH + DABCO EWG EWG H LiCl HSBM
O2N O2N
EWG % Yield %Yield (No Salt (With LiCl) SO2CH3 60 28
Sulfone
CONH2 15 4
Amide
CN 48 32
Nitrile
When a large reaction vials was used for the same amount it was noted that the use of LiCl also resulted in reduced yields (Table 5). A possible explanation is that the salt molecules occupy the spaces between the reactant molecules resulting in less space for the reactants. Therefore the expected enhancement of the reaction rate due to coordination of the Li+ to the carbonyl oxygen is rendered less dominant.
58 Electrophile Studies: Substituted Aryl Aldehyde.
As indicated elsewhere in this paper, aliphatic aldehydes give faster rates and high yields for the Baylis-Hillman reaction but aryl aldehydes are not good electrophiles for this reaction; they give very low yields and slow reaction times (usually 1 to 4 weeks).
Table 6. Percent yield obtained from the reaction of para substituted benzaldehydes, methyl acrylate and DABCO O OH O O + DABCO
OCH3 OCH3 H HSBM
Y Y
Entry Y Time Yield (%)
(hrs)
1 NO2 0.5 >98
2 Br 9 97
3 H 39 96
4 Cl 21 54
5 OCH3 45 28
In our earlier studies we managed to show that aryl aldehydes with electron withdrawing groups (nitro and bromo) give high yields in a very short period of time (30 minutes). We extended our investigation to include aryl aldehydes with electron donating groups (Table
6)
59 The results showed that the more the electron withdrawing the group on the ring is, the less efficient it is as an electrophile. Clearly, nitrobenzaldehyde which has the strongest electron withdrawing group (of all the electron withdrawing groups studied), gave the best results and the benzaldehydes with the methoxy group (a very strong electron donating group) gave lowest results.
Asymmetric Baylis-Hillman Reaction
We refocused our attention to the asymmetric synthesis of the Baylis-Hillman products.
To achieve this we first investigated the efficiency of chiral tertiary amines (fig…)
H2C
N H Si N N
H HN N
Fig 37 (+)-Cinchonine Figure 38. Functionalized silica gel: 3-(1, 3, 4,6,7,8,-Hexahydro-2H-pyrimido- [1,2- a]pyrimidino)propyl, functionalized silica gel
None of the catalysts gave product; only starting material was recovered. We concluded that the bulkiness of the catalyst was impeding on its efficiency. We tested this theory by using a less bulky chiral catalyst, L-proline.
60 OH
N O H
Figure 39. L-Proline
Just like in the previous case only starting material was recovered. The inability of L- proline to catalyze the Baylis-Hillman reaction was probably due to the presence of a carboxylic functional group which interferes with.
In published reported it was observed that the use of chiral 3-quiniclidinol, gave
Baylis-Hillman products with a high percent ee. To determine the percent ee of the products obtained with 3-quiniclidinol, we did a 1NMR analysis with a chiral shift reagent Eu(Fod)3, of the products from the reaction of p-nitrobenzaldehyde, methyl acrylate and 3-quiniclidinol.
We performed separate 1NMR analysis of the products obtained using DABCO and Quiniclidine but we were unable to establish the percent ee of our products.
61 B. GEWALD MULTI-COMPONENT REACTION
Background
Poly substituted 2-aminothiophenes, the products of Gewald reaction, provide important poly-functional synthetic starting materials. They have found use as starting materials for the synthesis of agrochemicals66, dyes, 67 and conducting polymers.68Their core heterocycle forms an internal part of numerous natural products.69 The pharmacological importance of 2- aminothipohenes arises from their wide range of biological activities, notably, their application as selective site-directed inhibitors of various biological targets. 70
The chemistry of 2-aminothiophenes has received much attention and many synthetic methods have since been published. The various preparative methods were summarized in a review by Sabnis et67 al as follows: reduction of the nitro group,71 nucleophilic displacement of hydroxy,72 mercapto,73,74 halo,75,76 methoxy, 77,78 p-nitrophenoxy,79,80 benzenesulfonyl groups,81the Beckmann rearrangement,82 the Hoffmann reaction,83 the Schmidt reaction,84 the Curtis rearrangement85, 86 and the cyclization of thioamides and their S-alkylates.887-90All of the methods listed above and others which were subsequently reported in literature involve difficult preparation of starting materials and multi-step synthesis. The key intermediates for the synthesis of 2-aminothiophenes by these methods are generally expensive.
The most convenient method for preparing 2-aminothiophenes with a high degree of substitution is via the Gewald Reaction (figure 33).91, 92
62 O N R1 S8 EWG R 2 + C EWG R1 amine base
R2 S NH2
Figure 40. The Gewald reaction
The Gewald method, described by Gewald in 1960, involves the reaction of ketones or aldehydes or 1, 3-dicarbonyl with activated nitriles and elemental sulfur in the presence of an amine base. This method offers a lot of improvements over all the other existing synthetic methods for the synthesis of 2-aminothiophenes.
The proposed mechanism for the Gewald reaction (figure 34) involves a
Knovaenegel-Cope condensation in the 1st step followed by the thiolation of the
condensation product.
O O O N N -H2O C R2 + C OR3 R1 OR3 R3 R1
S8
O S+ O R1 OR3 C R3O NH
H R2 S NH2 R2
R1
Figure 41. The proposed reaction mechanism for the Gewald reaction.
In the original version of the Gewald synthesis, a-carbonylthiols reacted with nitriles possessing an active a-methylene group, in the presence of catalytic amounts of base.92 A range of electron withdrawing substituents can be introduced into the 3-
63 position, but the choice of substituents in the 4- and 5- positions is limited by the accessibility of the required a-carbonylthiols.
There are three different methods to prepare 2-aminothiophene products proposed by Gewald.
In the first variation, a-mercaptoaldehyde or a-mercaptoketone is treated with an activated nitrile bearing an electron withdrawing groups such as methyl cyanoacetate, malononitrile, benzoylacetonitrile in solvents polar such as ethanol, dimethylformamide, dioxane, or water in the presence of a basic catalyst such as triethylamine or piperidine at
50º.
R O 1 EWG
SH R1 + NC EWG R2 S NH2 R2
Figure 42. Variation 1 of the Gewald Reaction
The major drawback of this route is that a-mercaptoaldehydes or a-mercaptoketones are unstable and difficult top prepare. The other limitation is that it is limited only to aliphatic a-mercapto derivatives.
The 2º version of the Gewald reaction, which consists of a one-pot-procedure, is the most elegant and simpler.
64 NC EWG R 1 EWG
S8 amine R1 R2 S NH2 R2
Figure 43 The 2• Variation of the Gewald reaction.
This is an improvement over the 1st variation in that it replaces the a-mercaptoaldehyde or a-mercaptoketone with simpler starting materials. However, with this method, literature reports indicate the less reactive ketone such as aryl ketones are unreactive in this direct one one-pot Gewald synthesis. Therefore, the normal method by which 4-aryl- substituted 2-aminothiophene-3-carboxylates are prepared, with limited success, though, involves a two step technique which is the 3º variation of the Gewald reaction.
CN o X CN R S X S8 1 R1 - NH2 B- B
R2 R1 R2 X R2 Figure 44. The 3• variation the Gewald Reaction
In the 3º variation, a two-step procedure is preferred a a,b-unsaturated nitrile is first prepared by a Knovaenegel-Cope condensation and then treated with sulfur and amine.
This version generally gives higher yields of the thiophenes product and is known to give acceptable yields with alky aryl ketones. The two step synthesis of 4-phenyl-2- aminothiophene-3-carboxylic acid ethyl ester with acetophenone as the starting material was reported to occur in yields not higher than 43% over two steps.
Generally, Gewald-thiophene synthetic procedures require long reaction times for the condensation step and the resulting products require laborious purification. Recently many modifications to this reaction have been developed and these include using solid support,93microwave irradiation combined with insoluble polymer support.94 Some of
65 these methods, however, are limited by low loading capacity; difficulty of monitoring the reaction progress and configuration of polymer-bound products; use of large excess of reagents, expensive catalysts, or toxic volatile organic solvent; tedious work-up; and sometimes low yields. The need for facile and efficient methods for the Gewald reaction is still an area of immense research interest.
Generally, aliphatic ketones have successfully been used in the Gewald synthesis.
However, the preparative synthesis 2-aminothiophenes from alkyl aryl ketones still prove to be challenging and have only been achieved with low yields through the two step synthesis.
In a recent paper Tormyshev et al,95 reported a modified one-pot synthesis
version of the Gewald reaction. In this version, sulfur is added in portions, with the
first portion being added after 3 hours and continued over a period of 8-12hours. The
overall reaction time in this procedure is between 36-40hours (with isolated yields of
5—70%).
The success we had with the Baylis-Hillman coupled with our desire to obtain
the polyfunctionalized Gewald product in shorter reaction times stimulated our interest
towards the use of HSBM technique. In continuing our studies we first investigated
the utility of HSBM with acyclic and cyclic aliphatic ketones. We then continued our
studies to include alkyl aryl ketones.
66 Results and Discussion
Several different organic and inorganic bases have been used for the Gewald reaction.
In our effort to develop an environmentally friendly synthetic method, we focused our investigation on screen inorganic bases. The bases investigated were: NaHCO3,
Na2CO3, NH4Cl and K2CO3. Unfortunately none of these bases gave the expected 2- aminothiophene product. In an effort to find out why the bases were unsuitable for the
Gewald reaction, we ran a two step synthesis.
The first step involved reacting ethyl acetoacetate, in the presence of a K2CO3. After a reaction period of 60 minutes the mixtures was purified to give the intermediate. In
nd the 2 step the intermediate was reacted with K2CO3 and elemental sulfur. This step did not yield the expected product. The same reaction was repeated with the other inorganic bases but the expected product was not produced. We then investigated with the amine bases which are generally the bases of choice in the solution based synthesis. Of the bases screened, DMAP, DABCO, and morpholine, we got our best results with morpholine. As a result in all of our subsequent investigations we used morpholine as the base.
Aliphatic ketones in solution provide the 2-aminothiophene-3- carboxylate Gewald product more readily. Based on this knowledge we began our investigations by carrying out one-pot synthesis of the Gewald reaction using an aliphatic ketone, methyl keto ester.
67 O O O O H C N 3 S8 OET + C H3C OCH3 OET amine base 15 minutes O NH EtO S 2 2a. 60%
O NH S 2 H3C
O H3C O
1 Figure 45 H NMR 400MHz of C10H13SNO3 (2a)
Our results were in tandem with those obtained in solution. However, we were
able to obtain the Gewald product (2a) in 60% yield in as little as 15 minutes
compared to the reported 24 hours solution phase reaction time; clearly a significant
rate enhancement yet to be reported.
In continuation of our studies of the Gewald reaction we investigated with cyclic ketones (Table 7). Literature reports indicate that cyclic ketones give good to moderate yields of the Gewald product.
68 Table 7. The Gewald reaction with cyclic ketones
O O N S C + O N OEt NH2 S8 R HSBM 1/8" ss ball R OEt
R Time %Yield
(2b) CH3 15 56 (2c) H 15 72
69 NH2
O S
O
1 Figure 46 H NMR 400MHz, of C11H14SNO2 (2c )
Investigations with aliphatic cyclic ketones also showed a rate enhancement of the
Gewald Reaction (Table 7). The % yield reported for the product obtained from 3-
methylpentanone was a mixture of the isomers. Attempts made in an effort to separate
the individual isomers were unsuccessful.
To establish the scope of this reaction in our investigation, we included a variety of para-substituted acetophenone. To our surprise we were able not only to carry out this reaction in a one-pot synthesis, but also in a very short time (20 minutes) (Table 8 and
Figure 40).
70 Table 8. The Gewald Reaction with aromatic ketones
O O
O S N H C N + NH OEt S8 2 Y HSBM 1/8" ss ball OEt Y
Y Time % Yield
(2d) NO2 20min 70 (2e) Br 6 hrs 55
H2N O
S O
O2N
1 Figure 47. H NMR 400 MHz of C13H12SN2O2 (2e)
In the short time of 20 minutes we were able to obtain the Gewald aryl product in yields ranging from 55% (2e) and 70% (2d) (Table 8). When the reaction time was increased it was noted that the yield did not increase any further. There was formation of secondary products which, however were not characterized. The formation of
71 secondary products was confirmed by the decrease of the amount of unreacted starting material.
72 C. THE UGI-4-COMPONENT REACTION (U-4CR)
2.3 Background
For a whole century, the chemistry of isocyanides was a rather empty part of chemistry. Only 12 isocyanides were known and their chemistry was not well developed. In 1958, a new era of isocyanides chemistry became available and in 1959 the four component reaction of the amines, carbonyl compounds, acid components and isocyanides was introduced by Ivar Ugi et al (figure
48). 96 Since 1962 various authors began to quote this reaction as the Ugi 4-component reaction and along with the Passerini reaction97 (figure 49), it is classified as an isocyanide-based multicomponent reaction. The prototype reaction results in the formation of a a-N-acylamino amide.
R4 O + + R CHO R2 NH2 + R3 NC R4 CO2H 1 O NH
N R3
R2 R1
Figure 48. The Ugi-4-Component Reaction (U-4CR)
O
O
O R4 + R3 NC + R4COOH R1 R1 R2 N R3 R2 O
Figure 49. The Passerine-3-component reaction (P-3CR)
In the proposed mechanism for the U-4CR, the interaction of an amine with an
aldehyde produces an iminium ion, an isocyanide, and a carboxylic acid relies on the
formation of an iminium ion in the first step. The iminium then suffers a nucleophilic attack
by the isocyanide in the key step of the reaction (Figure 43)
73 H
R4CO2H 1 1 + 1 R R R N 4 - R CHO + R CO2 R2 R2
R3NC
R3 NH R3
3 1 R N R N R1 O
4 4 2 R N R O2C HN R R1 R2 HN R2 O
Figure 50. The proposed mechanism for the U-4CR
The mechanism is believed to involve a prior formation of an imine by condensation of the amine with the aldehyde, followed by addition of the carboxylic acid oxygen and the imine carbon across the isocyanide carbon; the resulting acylated isoamide rearranges by acyl transfer to generate the final product. The carboxylic acid plays a dual role of; it serves as a Bronsted acid in the formation of the iminium ion intermediates and as a donor of an acyl group, which finally migrates to the a-amino group in the products. Because the acyl migration is involved in the key step, the typical U-4CR requires a primary amine of which the nitrogen atoms are able to accept the acyl group through amide formation. The mechanism-based requirements makes it difficult to use secondary amines as the amine component in the U-4CR. Secondary amines, however have partly been used Therefore in general, secondary amines have rarely been achieved by the use of secondary amines that carry additional functional groups , such as OH and NHR, which serve as intramolecular acyl group acceptor. In this study we initially focused on the typical U-4CR which uses a primary amine and then we investigated the utility of the HSBM technique with secondary amines.
The Ugi-type processes are the most powerful and versatile multicomponent reactions
(MCRs) developed to date and have been massively exploited in chemistry and biosciences. Since
74 1995, the U-4CR has become increasingly popular, particularly as libraries and its chemistry has become one of the most often used methods of finding new desirable products (Figure 44).
Figure 51.The wide variety of products from the U-4CR
Other notable reactions carried using the U-CR was carried out by Merck Company who produced the HIV protease inhibitor Crixivan. The first synthesis of this compound, by a conventional multi-step sequence of procedures was too ineffective and too expensive. However the introduction of a U-4CR as a key step, Crixivan could be prepared in fewer steps, much easier and in better yields. It is the importance of the U-4CR demonstrated over the years which made us focus our attention to this reaction as we continued to investigate the utility of the HSBM technique in running multi-component reactions. It has been reported that the U-4CR usually proceeds particularly well, if the amines and carbonyl compounds are precondensed before the other compounds are added.98, 99 Under the HSBM conditions the precondensation step is not needed because all the starting materials will be put in the vials at once. We, therefore, sought to
75 provide a HSBM as a cheaper, benign and simpler alternative technique to carry out the U-4CR reaction.
Results and Discussion
To test the utility of the HSBM technique with theU-4-CR we ran a series of
reactions which were reported by under HSBM conditions with primary amines. In
doing so we carried out a reaction with aniline, trans-cinnamaldehyde, 2-chloro-
ethanoic acid and cyclohexyl isocyanide.100 In the literature report by Ricardo Bossio,
the reaction was carried out in a methanol solvent system in reaction time of 24 hours.
NH2 O H NH NC O
O N Cl 3a Cl OH O 3 Hrs HSBM % Yield Quantitative 1/8" ss ball
Figure 52. U-4CR under HSBM
In reaction time of 15 minutes we obtained a quantitative yield. The 1NMR
spectra (figure 46) of product from this reaction under HSBM conditions matched the
literature report.
76 NH O
N Cl O
99
1 Figure 53. H NMR in CD2Cl2 of (E)-2-[(N-chloroacetyl-Nsubstituted) amino]-4-phenyl-but-3-enoic acid N-cyclohexylamides After a reaction period of 15 minutes we were able to obtain a quantitative yield of the polyfunctional U-4CR product. We then decided to investigate the utility of the technique with some para-substituted aniline.
77 Table 9. Percent yield of the reactions between p-substituted aniline, trans- cinnamaldehyde, chloro acetic acid and cyclohexyl isocyanide.
NH2 X O H X NH NC O
O N Cl
Cl OH O
Compound X Time % Yield
3b NO2 15 >98
3c Br 15 >98
3d OCH3 15 80
We carried out another reaction with N-phthalylgylcine, benzylamine, cyclohexyl isocyanide and formaldehyde (Figure 54)
Figure 54. Reaction of N-phthaloylgylcine, benzylamine, cyclohexylisocyanide, and paraformaldehyde
78 Figure 55. 1H NMR 400 MHz (N-phthaloylgylcyl-Nsubstituted)- 4-phenyl-but-3-enoic acid N-cyclohexylamides
For compound 3e we got a yield of 35% in a reaction time of 16 hours 40 minutes. Our result was in tandem with the literature.101 The low yield is attributed to the presence of an electron donating nitrogen atom in the phthaloyl moiety which
79 reduces its ability to serve as a Bronstead acid in the formation of the iminium ion intermediates and as a donor of an acyl group.
CONCLUSION
HSBM gives higher yields at faster reaction rates because in solid state particles are close to each other resulting in lower entropy. For the Baylis-Hillman reaction; aryl aldehydes, with an electron withdrawing group on the ring, give faster rates because they produce a larger positive charge on the carbonyl oxygen atom, thus making the carbonyl moiety more reactive. DABCO, quiniclidine and quiniclidine and DMAP were the most efficient of the catalysts studied. DABCO was found to be the best catalyst for the HSBM system because it is the best nucleophile under HSBM conditions. For the Gewald Reaction, our results show that HSBM gives higher yields in a short amount of time for the one-pot synthesis of aryl heterocyclic thiophenes.
The best results were obtained using p-nitroacetophenone and the lowest yield was obtained using p-hydroxyacetophenone. These results compare very well with the 2 step synthesis developed earlier by Victor Tormyshevs group95. The advantage in using HSBM lies in the non use of a solvent, one pot synthesis and an opportunity to obtain increased yields in faster times. The HSBM technique was extended to the U-
4CR reaction. We obtained a rate enhancement of the U-4CR using chloroacetic acid though our results with N-phthalylyglycine were lower than the literature. Studies to determine the methods to enhance the rate with phthalylglycine and other less reactive acids under HSBM can be an attractive area of study.
80 EXPERIMENTAL SECTION
General Methods
1HNMR Spectra (1H NMR) were obtained on a Bruker AM 400 FT-NMR
spectrometer operating 400 MHz. All chemical shifts are reported in parts per million
(ppm) relative to Me4Si (TMS) unless otherwise noted.
13C NMR Spectra (13C NMR), were obtained on a Bruker AM 400 FT-NMR spectrometer operating 400 MHz Carbon nuclei spin at 100 MHz). All chemical shifts are reported in parts per million (ppm) relative to Me4Si (TMS) unless otherwise noted.
GC-MS were performed on an Agilent 7890 A GC System.
Automatic Column Chromatography Separation was performed on Teledyne Isco
Combiflash
Silica gel flash columns were obtained from Teledyne Isco.
High Speed Ball Milling Reactions were carried out using an 8000m Spex mill obtained from SPEX CertPrep, Inc.
81 Materials
(a) Solvents
Note: All solvents were used without further purification.
Acetone (reagent grade) was obtained from Acros.
Chloroform (CHCl3) was obtained from Acros.
Ethyl Acetate (CH3CO2C2H5) was obtained from Acros.
Methylene Chloride (CH2Cl2) was obtained from Acros.
Cyclohexane (C6H12) was obtained from Acros.
95% Ethanol (C2H5OH) was obtained from Acros.
Hexane was obtained from Acros
82 (b) Column Chromatography
Combiflash instrument the automatic column chromatographic instrument) was obtained from Teledyne Isco.
Column Cartridges were obtained from Teledyne Isco.
Silica Gel Packed Columns (4g, 12 g and 40g Flash Column Chromatography Packing).
83 (c) Reagents
Note: All reagents were used without further purification.
Methyl Acrylate (C4H6O2) was obtained from Acros. p-Nitrobenzaldehyde (C7H5NO3) was obtained from Acros. p-Bromobenzaldehyde (C7H5OBr) was obtained from Acros. p-Chlorobenzaldehyde (C7H5OCl) was obtained from Acros.
Anisaldehyde (C8H8O2) was obtained from Acros
DABCO (C8H12N2) was obtained from Acros.
Quiniclidine (C8H13N) was obtained from Acros
3-Quiniclidinol (C8H14NO) was obtained from Acros
DMAP (C7H10N2) was obtained from Acros.
Trans-cinnamaldehyde was obtained from Acros
P-nitroacetophenone was obtained from Acros
P-hydroxy-acetophenone was obtained from Acros.
P-methoxy-acetophenone was obtained from Acros.
P-bromo-acetophenone was obtained from Acros.
Ethyl cyanoacetate was obtained from Acros.
Morpholine was obtained from Acros.
Elemental sulfur was obtained from Acros.
Methyl ethyl acetoacetate was obtained from Acros.
3-methyl pentanone was obtained from Acros.
Pentanone was obtained from Acros. p-nitroaniline was obtained from Acros
84 p-methoxy-aniline was obtained from Acros
Aniline was obtained from Acros
L-Proline was obtained from Sigma Aldrich
Eu(FOD3) was obtained from Sigma Aldrich
(+)-cinchonine was obtained from Sigma Aldrich
Functionalized silica gel was obtained from Sigma Aldrich
N-phthalylglycine was obtained from Sigma Adrich
Choroacetatic acid was obtained from Acros
Paraformaldehyde was obtained from Acros
85 (d) Instruments and accessories
Spex Mill 800M was purchased from Spex CertPrep, Inc.
Milling balls were purchased from Small Parts.com
Steel Vials (non screw cap) were purchased from Spex Certiprep
Steel Vials (screw cap) custom made by the University of Cincinnati Department of
Chemistry machine shop
86 (e) Synthesis.
(i) Baylis-Hillman
Baylis-Hillman under HSBM
Typical procedure for the Baylis-Hillman reaction under HSBM: 20% DABCO, 0.5mmol p-nitrobenzaldehyde, and 0.5mmolmethyl acrylate. The mixture was put in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an
8000 M Spex mill and ball milled for various times.
Optimum Reaction Time Studies
Typical procedure for the optimum reaction time studies: 20% DABCO, (0.112 g),
0.5mmol (0.755g) p-nitrobenzaldehyde, 0.5mmol activated Alkene (Table 2). The mixture was put in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 8000 M Spex mill and ball milled for various times (15 min, 30 min, 1 hr, 2hrs, 4 hrs, and 16 hrs (Table 1). Need grams and moles
Catalyst Studies
Typical procedure for the catalyst studies: 20% tertiary amine catalyst (Table 2),
0.5mmol p-nitrobenzaldehyde, and 0.5mmolmethyl acrylate. The mixture was put in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 8000 M Spex mill and ball milled for various times.
Activated Alkene Studies
Typical procedure for the activated Alkene studies: 20% DABCO, 0.5mmol p- nitrobenzaldehyde, 0.5mmol activated Alkene (Table 5). The mixture was put in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 800M Spex mill and ball milled for various times (Table 5)
87 Electron Withdrawing Group Studies
Typical procedure for the activated Alkene studies: 20% DABCO, 0.5mmol p- nitrobenzaldehyde, 0.5mmol activated Alkene (Table 5). The mixture was put in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 800M Spex mill and ball milled for various times (Table 5)
NO2C6H4CH(OH) C (CH2)SO2CH3 (4-nitro-phenyl)-hydroxy -methyl]-acryl –methyl sulfone).
1 H NMR (400MHz; CDCl3)-1.544 (s, CH3); 5.645 (s, CH (OH)); 5.667(s, CH=C); 6.402 (s, CH); 7.597 (d, Ar). NO2C6H4CH(OH) C (CH2)SO2C6H5 (4-nitro-phenyl)-hydroxy -methyl]-acryl –phenyl sulfone).
1 H NMR (400MHz; CDCl3)- 5.645 (s, CH (OH)); 5.667(s, CH); 6.402 (s, CH); 7.597 (d, Ar); 8.233 (Ar). 4-nitro-phenyl)-hydroxy -methyl]-acrylonitrile
1 H NMR (400MHz; CDCl3)- 4.289 (s, OH), 5.451( s, CH(OH)); 6.074 (s, CH=C); 6.175 (s, CH=C); 8.043-8.352(Ar) Steric hindrance Studies
Typical procedure for the Electrophile studies: 20% DABCO, 0.5mmol methyl acrylate,
0.5mmol electrophile (Table 4). The mixture was placed in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 800M Spex Mill and ball milled for various times (Table 4) nitro-phenyl)-hydroxy-methyl]-methyl crotonate. 1 H NMR (400MHz; CDCl3) 1.931(s, CH3); 3.987 (s, O CH3); 5.825 (s, CH (OH)); 5.887 (s, CH=C); 7.046-7.203 (Ar)
4-nitro-phenyl)-hydroxy-methyl]-phenyl crotonate 1 H NMR (400MHz; CDCl3) 3.812 (s, OCH3); 6.414 (s, CH(OCH3); 6.478 (s, CH=C), 7.263- 7.535 (Ar); 8.063-8.421 (Ar).
88 Effect of salt on rate of Baylis-Hillman reaction
Typical procedure for the Electrophile studies: 20% DABCO, 0.5mmol methyl acrylate,
0.5mmol electrophile (Table 5). The mixture was placed in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 800M Spex Mill and ball milled for various times (Table 5)
Electrophile Studies
Typical procedure for the Electrophile studies: 20% DABCO, 0.5mmol methyl acrylate,
0.5mmol electrophile (Table 6). The mixture was placed in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 800M Spex Mill and ball milled for various times (Table 6)
Aryl Aldehydes Studies
Typical procedure for the electrophile studies: 20% DABCO, 0.5mmol methyl acrylate,
0.5mmol electrophile (Table 6). The mixture was placed in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 800M Spex Mill and ball milled for various times (Table 6).
Other Electrophiles
Typical procedure for the other electrophiles (ketone, sulfone, amide and carboxylic acid). 20%DABCO, 0.5mmol methyl acrylate, and 0.5mmol electrophile. The mixture was placed in screw cap stainless steel vial together with a 1/8inch stainless steel ball.
The mixture was put in an 800M Spex Mill and ball milled for 16 hours 40 minutes.
Asymmetric Baylis-Hillman Reaction
Typical procedure for the asymmetric studies: 20% chiral tertiary amine catalyst (+)-
Cinchonine, L-proline, 3-(1,3,4,6,7,8,-Hexahydro-2H-pyrimido-[1,2-]pyrimidino)propyl,
89 functionalized silica gel ), 0.5mmol p-nitrobenzaldehyde, 0.5mmol methylacrylate and L-
Proline. The mixture was put in screw cap stainless steel vial together with a 1/8inch stainless steel ball. The mixture was put in an 800M Spex mill and ball milled for 30 minutes. The same procedure was repeated using 0.1mmol DABCO/ 0.1mmol L-proline a co-catalytic system.
Purification (Typical for all the Baylis-Hillman reactions in this study)
Mixture was transferred from the vial into a separatory funnel with 30mL CH2Cl2 and
30mL H2O. The organic layer was separated and filtered through a short plug of anhydrous magnesium sulfate. The Baylis-Hillman adduct was isolated by
Chromatography (silica gel), using a CH2Cl2/ethyl acetate solvent system and concentrated in vacuo.
(ii) Gewald
Typical procedure: To a stainless steel screw cap vial 0.5mmol of the ketone, 0.5mmol ethyl cyanoacetate 0.010.5mmol, elemental sulfur and 0.01mmol morpholine were added to a stainless steel screw cap vial together with an 1/8• stainless steel ball. The contents were ball milled in an 8000M Spex mill machine for 20 minutes.
Purification
Mixture was transferred from the vial into a separatory funnel with 30mL CH2Cl2 and
30mL H2O. The organic layer was separated and filtered through a short plug of anhydrous magnesium sulfate. The 2-aminothiophene-3-carboxylate product was isolated by a Chromatography (silica gel), using a CH2Cl2/Cyclohexane solvent system and concentrated in vacuo to give:
90 2a. C10H13SNO3
1 H NMR (400MHz, CH2Cl2), 1.33 (t, 3H); 1,375 (s, 3H); 2.703 (s,3H); 6.488 (d, NH2)
NMR solvent is CDCl3.
13 C NMR (400MHz, CDCl3.
), 14.361 (CH3, t); 14.621 (CH3t);16.168 (CH3, t); 60.428 (CH2d); 103.457 (CHs); 107.502(CH3);
148.066 (CH), 166.247 (CO).
2b. C10H10SNO2
1 H NMR (400MHz, CDCl3), 2.20 (t, 3H); 2,401 (t, 2H); 3.148 (q, 2H); 2.925 (t, 2H);
5.947 (d, 2H, NH2).
13 C NMR (400MHz CDCl3.), 11.884 (CH3,), 14.61 (CH3,); 26.926 (CH3,); 59.433
(CH2), 105.555 (CH); 113.541 (CH), 136.717 (CH), 165.877 (CO)
2c C11H14SNO2
1 H NMR (400MHz, CDCl3), 2.20 (t, 3H); 2.30 (3H); 2,401 (t, 2H); 3.148 (q, 2H);
2.925 (t, 2H); 5.947 (d, 2H, NH2).
13 C NMR (400MHz, CDCl3), 11.884 (CH3,), 26.926 (CH2,); 59.433 CH2), 105.555 (CH);
113.541 (CH), 136.717 (CH), 165.877 (CO)
2d C13H13SNO2
1 H NMR (400MHz, CDCl3 2.203 (t, 3H); 2.343 (3H); 2,401 (t, 2H); 3.148 (q, 2H); 2.925 (t,
2H); 5.947 (d, 2H, NH2).
13 C NMR (400MHz, CDCl3), 13.762(CH3) 59.433 (CH2), 105.563 (CH); 127.299
(CH); 128.993 (CH, Ar) 138.517 (CH, Ar); 141.613 (CH, Ar); 165.807 (CO)
2e. C11H12SN2O
1 H NMR (400MHz, CDCl3), 1.004 (t, 3H); 4.094 (q, 2H); 6.182 (s, 2H, NH2); 6.2
81(CH), 8.182 (dd, ArH), 8.344 (dd, ArH)
91 13 C NMR (400MHz, CH2Cl22), 13.968; (CH3,); 59.77 (CH2), 105.555 (CH); 107.099
(CH), 122.587 (CH); 123.870 (CH,); 129.330 (CH, Ar); 141.398 (CH, Ar); 145.267 (Ar, Ar);
165.131 (CO).
1 2f. H NMR (400MHz, CH2Cl22), 1.004 (t, 3H);4.094 (q, 2H); 6.182 (s, 2H, NH2); 6.281
(CH), 8.182 (dd, ArH), 8.344 (dd, ArH).
13 C NMR (400MHz, CH2Cl22), 13.968 (CH3,); 59.777 (CH2),105.555 (CH); 107.099
(CH), 122.587 (CH); 123.870 (CH,); 129.330 (CH, Ar); 129.540 (CH, Ar); 129.473.153 (Ar, Ar)
2g. C13H13SNO3
1 H NMR (400MHz, CH2Cl2), 1.0 (t, 3H); 4.0 (q, 2H); 6.2 (CH), 6.1 (s, 2H, NH2); 7.180
(dd, ArH), 7.449 (dd, ArH)
13 C NMR (400MHz, CH2Cl2), 13.968 (CH3,); 59.777 (CH2), 105.555 (CH); 107.099
(CH), 122.587 (CH); 123.870 (CH,); 129.330 (CH, Ar); 141.398 (CH, Ar); 145.267 (Ar,).
2h. C14H15SNO2
1 H NMR (400MHz, CDCl3), 1.330 (t, 3H); 2.327 (s,3H); 4.194 (q, 2H); 6.182 (s,2h,
1 NH2,), 6.261 (s, H, NH2); 8.163 (dd, ArH), 8.344 (dd, ArH)
13 C NMR (400MHz, CDCl3), 13.866 (CH3,); 26.566 (CH3); 59.777 (CH2), 107.1832
(CH), 122.587 (CH); 123.552 (CH,); 129.373(C, Ar) 129.776 (CH, Ar); 141.405 (CH, Ar);
151.352 (Ar,), 165.394 (CH, Ar).
92 (iii) Ugi-4CR (compounds 3a-d)
Typical procedure: To a stainless steel screw cap vial 0.5mmol (…g) of the trans- cinnamaldehyde, 0.5mmol chloroethanoic acid 1-cyclohexenyl isocyanide 0.010.5mmol, and p-substituted aniline were added to a stainless steel screw cap vial together with an
1/8• stainless steel ball. The contents were ball milled in an 8000M Spex mill machine for 20 minutes.
iv. Ugi-4CR (Compounds 3e-f)
Typical procedure: To a stainless steel screw cap vial 0.5mmol (…g) of the trans- benzaldehyde, 0.5mmol N-Phthalylglycine, 1-cyclohexenyl isocyanide 0.010.5mmol, and benzylamine were added to a stainless steel screw cap vial together with an 1/8• stainless steel ball. The contents were ball milled in an 8000M Spex mill machine for 3 hours.
Purification (compounds 3a-3f)
Mixture was transferred from the vial into a separatory funnel with 30mL CH2Cl2 and 30mL H2O. The organic layer was separated and filtered through a short plug of anhydrous magnesium sulfate. The organic layer was dried under reduced pressure. The solid Ugi crude product was recrystallized in 95% ethanol.
3a. (E)-2-[(N-chloroacetyl-Nsubstituted) amino]-4-phenyl-but-3-enoic acid N- cyclohexylamides 1 H NMR (400 MHz, CDCl3); 0.491-1.940 (m, 10H cyclohexyl); 3.97 (s, CH2Cl); 5.581 (s, NH); 6.126 (s, PhCH=CH); 6.666 (s, PhCH=CH); 6.876-8.243 (ArH 10H)
3b. (E)-2-[(N-chloroacetyl-Nsubstituted) amino]-4-(4-bromochlorophenyl)-but-3-enoic acid N-cyclohexylamides 1 H NMR (400 MHz, CDCl3); 0.491-1.940 (m, 10H cyclohexyl); 3.97 (s, CH2Cl); 5.581 (s, NH); 6.126 (s, PhCH=CH); 6.666 (s, PhCH=CH); 6.876-8.234 (ArH 10H)
93 3d. (E)-2-[(N-chloroacetyl-Nsubstituted) amino]-4-(4-methoxyphenyl)-but-3-enoic acid N- cyclohexylamides 1 H NMR (400 MHz, CDCl3); 0.491-1.940 (m, 10H cyclohexyl); 3.97 (s, CH2Cl); 5.581 (s, NH); 6.126 (s, PhCH=CH); 6.666 (s, PhCH=CH); 6.876-8.334 (ArH 10H
3e. (N-phthaloylgylcyl-Nsubstituted)- 4-phenyl-but-3-enoic acid N-cyclohexylamides 1H NMR (400MHz, CDCl3); 1.039-1.229 (m, 10H, cyclohexyl); 4.463-4.674 (m, 4H, CH2); 5.073 (NH); 7.039-7.889 (m, 9H, ArH)
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97 Appendix
Chapter 1. Baylis-Hillman
O OH
OCH3
The data for his compound is in agreement with the literature: Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J.Org.Chem 2003, 68, 692-700.
ppm (
98 Benzaldehyde BH
The data for his compound is in agreement with the literature: Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J.Org.Chem 2003, 68, 692-700.
99 O OH
OCH3
H3CO The data for his compound is in agreement with the literature: Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J.Org.Chem 2003, 68, 692-700.
100 O OH OCH3 H
H H
Br
The data for his compound is in agreement with the literature: Hong, Wang Pyo; Lee, Kee-Jung; Synthesis. 2005. 1. 33-38
101 Chapter2. The Gewald Multi-component Reaction
O NH S 2 H3C
O H3C O
2a C10H13SNO3
102 1 H NMR 400MHz of C10H13SNO3
O NH S 2 H3C
O H3C O
2a C10H13SNO3
13 C 400 MHz of C10H13SNO3
103
NH2
O S
O
2b
104 1 H NMR 400MHz,of C10H10SNO2 in CDCl3.
NH2
O S
O
2b
13 C NMR 400 MHz, of C10H10SNO2
105 NH2
O S
O
2c
1 Fig…. H NMR 400MHz, of C11H14SNO2
106 NH2
O S
O
2c
13 Fig…. C NMR 400 MHz of C11H14SNO2
107 H2N O
S O
2d
13 C 400 MHz of C13H13NO2 in CDCl3
108 H2N O
S O
O2N
2e C13H12SN2O2
1 H NMR 400 MHz of C13H12SN2O2 in CDCl3
109 H2N O
S O
O2N
2e C13H12SN2O2
13 C NMR 400 MHz of C13H12SN2O2 in CDCl3
110 H2N O
S O
Br
2f C13H12BrSNO2
1 H NMR 400 MHz of C13H12BrSNO2 in CDCl3
111 H2N O
S O
Br
2f C13H12BrSNO2
13 C NMR 400 MHz of C13H12BrSNO2 in CDCl3
112 Chapter 3. Ugi-4-Component Reaction
1 H NMR 400 MHz in CDCl3 . U-4CR product 3b. Data for this compound is in agreement with the literature: Bossio, R et al. J. Chem. Ed. 2000, 77,3, 382-384
113 1 H NMR 400 MHz in CDCl3. U-4CR product 3c. Data for this compound is in agreement with the literature: Bossio, R et al. J. Chem. Ed. 2000, 77,3, 382-384
114 1 H NMR 400 MHz in CDCl3 . U-4CR product 3d.
115