MALONONITRILES AND CYANOACETAMIDES
CONTAINING ISOXAZOLES AND ISOXAZOLINES
A THESIS
SUBMITTED TO THE GRADUATE SCHOOL IN
PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE
MASTERS OF SCIENCE
BY
LEE COURTLAND MOORES
ADVISOR: ROBERT E. SAMMELSON
BALL STATE UNIVERSITY
MUNCIE, INDIANA
JULY 2011
Acknowledgements
I would like to thank all of the members of this department. The knowledge that I have gained
from the faculty, staff, and students will continue to serve me well. There are many memories and
friends I have made here, and will take with me into the future. The opportunity you have given me to
grow as not only a chemist, but a person as well, will aid me as I continue on to PhD studies in
chemistry.
I thank my family members as well. Without the support they have given me throughout my
collegiate career, I most certainly would not be in the position I currently find myself.
I want to thank the members of the graduate committee for admitting me to the program,
when, undoubtedly, I should not have been. They afforded me this challenge, and mandated a level of
effort I was not certain I was capable of.
I would also like to thank the members of my thesis committee for the countless hours they
have put in. You have continually pushed me to become a better chemist, but also taught me many
other life lessons I will try to keep in mind.
Finally I would like to thank my advisor, Dr. Sammelson, for his commitment to my education.
He has been more than understanding and constantly pushing me to succeed in pursuit of my MS
degree, and life.
Sincerely,
Lee Moores
Abstract
Thesis: Malononitriles and Cyanoacetamides Containing Isoxazoles and Isoxazolines
Student: Lee Courtland Moores
Degree: Master of Science
College: Science and Humanities
Date: July 2011
Pages: 130
Isoxazoles and isoxazolines have been shown in the literature to be an important
scaffold for pharmaceuticals and insecticides, as well as a source of synthetic versatility
important to many syntheses. As a substitute for other aromatic rings, isoxazoles are
known to change the efficacy of a given compound. Isoxazolines can be used as a
precursor to many other functional moieties that may be effected during earlier synthetic
steps. There are many routes to the heterocyclic moiety, allowing for their insertion in a
wide range of molecules. Our group has previously reported a condensation of
arylaldehydes with hydroxylamine to first make an aryloxime which can, after generating
the nitrile oxide, then cyclize with an alkene or alkyne in situ and create the isoxazoline
or isoxazole, respectively.
The Knoevenagel Condensation reaction is identified as the addition of an
activated methylene complex, malononitrile or cyanoacetamide, with a carbonyl followed
by dehydration.. Our group has previously reported a facile, one-pot reductive alkylation
of benzyl malononitriles. These compounds have been noted as having many
insecticidal uses, as well as being potent pharmacophores.
The scope of this project is to further explore and optimize the condensation of
aryl aldehydes and methylene complexes. The condensed and reduced methylene
complex will then be alkylated to join the heterocyclic moiety to reach the final
disubstituted methylene product. A second approach will also be explored in which the
monosubstituted malononitrile will first be alkylated with allyl or propargyl bromide, which
can then undergo a 1,3-dipolar cycloaddition with a nitrile oxide. The library of
compounds generated will be sent to collaborators to test the biological activity of the
molecules.
Table of Contents
Page
Number
iii
iv
vi
List of Figures
List of Schemes
List of Tables
Chapter
1
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
Chapter
2
2.1
2.2
2.3
2.4
2.5
2.6
Chapter
3
3.1
3.2
3.3
3.4
3.5
3.6
Introduction and Background
Literature
Introduction to Heterocycles
1
Synthetic Methods for Generating
Nitrile Oxides
Uses for Isoxazole and Isoxazoline
2
5
Introduction to Knoevenagel
Condensation
Synthesis of Monosubstituted
Malononitriles and Other Methylene
Complexes
8
9
Uses of Malononitrile and
Cyanoacetamide
Introduction to Alkylations
References
11
13
14
Reactions of Methylene
Complexes
Introduction to Reductive Alkylation
Installation of Protecting Groups
Results and Discussion
General Experimental
Data
References
17
18
19
24
27
44
Synthesis of Disubstituted
Methylene Complexes
Introduction
Results and Discussion
Biological Testing of Final Products
General Experimental
Data
Referemces
46
48
52
53
54
68
ii
Appendix
69
iii
List of Figures
Page
Number
Chapter
1
Introduction and Background
Literature
Figures
1.1 Reactivity of Dipolarophiles
1.2 Biologically Active Heterocycles
1.3 Malononitriles as Insectides
1.4 Biologically Active Methylene
Complexes
Chapter
2
Reactions of Methylene
Complexes
Chapter
3
Synthesis of Disubstituted
Methylene Complexes
Figures
3.1 Products from Reverse Reaction
Order
2
7
11
12
51
iv
List of Schemes
Page
Number
Chapter
1
Introduction and Background
Literature
Schemes 1.1 General Mechanism of 1,3dipolar Cycloaddition of Nitrile Oxides
1
1.2 Cycloaddition of Nitro Alkanes
with Vinyl Acetate
2
1.3 Magnesium Mediated, Hydroxyl
Directed Cycloaddition
3
1.4 1,3-Dipolar Cycloaddition of
Nitrile Oxides Generated from NaOCl
3
1.5 Generation of Nitrile Oxides from
O-Protected Hydroxamates
4
1.6 DABCO-Br2 Promoted
Aromatization of Isoxazoline
1.7 Reduction of AlkoxycarbonylSubstituted Isoxazoles
1.8 Versatility of Isoxazoline
1.9 Mechanism of the Knoevenagel
Condensation
5
5
6
9
1.10 Sodium Borohydride as the only
Reagent for the Reductive Alkylation
of Malononitrile
10
1.11 Water Catalyzed Knoevenagel
Condensation of Malononitriles and
Subsequent Reduction
10
1.12 Knoevenagel Condensation with
Salicylaldehydes and Subsequent
Cyclizations
11
1.13 Alkylation of Monosubstituted
Malononitrile
13
Chapter
2
Reactions of Methylene
Complexes
Schemes 2.1 One-Pot Water Catalyzed
Knoevenagel Condensation of
Malononitriles and Subsequent
Reduction
17
v
2.2 Reductive Alkylation of Aryl
Aldehydes with Cyanoacetamide
2.3 Acylation of Vanillin
Chapter
3
18
19
Synthesis of Disubstituted
Methylene Complexes
Schemes 3.1 Final Product Scheme for
Isoxazole Derivatives
3.2 Final Product Scheme for
Isoxazoline Derivatives
46
47
vi
List of Tables
Page
Number
Chapter
1
Introduction and Background
Literature
Chapter
2
Reactions of Methylene
Complexes
2.1 Knoevenagel Condensation of
Cyanoacetamide with
Benzaldehydes
19
2.2 Knoevenagel Condensation of
Malononitrile with Benzaldehydes
20
2.3 Reduction of Benzylidene
Methylene Complexes
21
2.4 Reductive Alkylations of
Benzaldehydes with Methylene
Complexes
2.5 Acylations of Phenols
22
23
Tables
Chapter
3
Tables
Synthesis of Disubstituted
Methylene Complexes
3.1 Cycloaddition Products of
Scheme 1
3.2 Alkylation Products of Shceme 1
3.3 Alkylation Products of Scheme 2
48
49
50
3.4 Cycloaddition Products of
Scheme 2
50
Introduction and Background Literature
1.1 Introduction to Heterocycles
The 5 membered aromatic heterocycle, isoxazole, c, and its 4,5-dihydro
counterpart, isoxazoline, e, have proven to be interesting moieties in chemistry and
biology.
As a replacement of other aromatic rings, isoxazoles can greatly alter the
efficacy of biologically active molecules.1,2 Isoxazolines have diverse synthetic utility,
and can be converted to many other functional groups readily via reductive ring
openings.3 Installation of these moieties is very similar differing only in the unsaturation
of the starting material as seen in Scheme 1.1,4 and proceeds via 1,3-dipolar
cycloaddition of nitrile oxides.
Scheme 1.1 General Mechanism of 1,3-dipolar Cylcoaddition of Nitrile Oxides
Generating nitrile oxides, a, may be achieved in a variety of manners, allowing for
insertion of the heterocycle in a range of compounds. In the presence of olefins or
acetylenes the nitrile oxide readily reacts, but in the absence of a suitable dipolarophile
2
the dimerized product, furoxane, f, will be formed as shown in Scheme 1.1. It has been
noted, however, that an alkyne is a much less reactive dipolarophile than a typical
alkene.5
The substitution of the dipolarophile can dramatically increase or decrease the
reaction rate as shown in Figure 1.1. Regiospecificity for the cycloaddition is easily
obtained as well when monosubstituted unsaturated starting materials are used.
Figure 1.1 Reactivity of Dipolarophiles5
1.2 Synthetic Methods for Generating Nitrile Oxides
As shown by Mukaiyama et al. these highly reactive species may be generated
by reacting a primary nitro alkane with phenylisocyanate in the presence of catalytic
amounts of trialkylamines in good yields.6 Due to their high reactivity, intermediates
were not isolable, but only the isoxazoline and the urea side products as shown in
Scheme 1.2.
Scheme 1.2 Cycloaddition of Nitro Alkanes with Vinyl Acetate
3
A
more
widely
used
method
involves
hydroximinoylchlorides to form the nitrile oxide.
the
dehydrohalogenation
of
Hydroximinoylchlorides are easily
obtained from their corresponding oximes through a variety of chlorination reactions, and
in the presence of base will generate the necessary nitrile oxide. Lohse-Fraefel et al.
used tert-butyl hypochlorite as the chlorinating reagent, but also displayed that
magnesium can effectively coordinate with hydroxyl groups on both reactants to obtain
diastereoselective cycloadditions as shown in Scheme 1.3.7
Scheme 1.3 Magnesium Mediated, Hydroxyl Directed Cycloaddition
Also starting from aldoximes, Sammelson et al. were able to generate the nitrile
oxides in situ by slowly adding sodium hypochlorite to the reaction mixture as seen in
Scheme 1.4.4 The oxime is first chlorinated to the hydroximinoyl chloride, which readily
undergoes a dehydrohalogenation due to the basicity of the bleach to yield the nitrile
oxide necessary for the cycloaddition.
Scheme 1.4 1,3-Dipolar Cycloaddition of Nitrile Oxides Generated from
NaOCl
4
As shown in Scheme 1.5,Carreira and coworkers furthered the cycloaddition by
demonstrating that the generation of nitrile oxides can also proceed from O-silylated
hydroxamic acids upon treatment with trifluoromethanesulfonic anhydride and
triethylamine as shown in Scheme 1.5.8 Under these conditions, reagents that undergo
oxidation or halogenation reactions could now yield the cycloadduct product. Although
hydroxamates can undergo a Lössen rearrangement to yield isocyanates under these
conditions, by carefully selecting which protecting group was placed on the oxygen this
undesired product could be averted. Muri et al. determined that silyl protecting groups,
tert-butyldiphenylsilyl in particular, were the most efficient precursors due to their
stability, ease of preparation, and reactivity.
Scheme 1.5 Generation of Nitrile Oxides from O-Protected Hydroxamates
Isoxazoles can also be prepared from isoxazolines through an oxidative
aromatization process.
Using bis-bromo-1,4-diazabicyclo[2.2.2]octane (DABCO-Br2)
Azarifar et al. demonstrated that this reaction will proceed in good yields (78-95%) under
relatively mild conditions represented in Scheme 1.6.9
5
Scheme 1.6 DABCO-Br2 Promoted Aromatization of Isoxazoline
The two moieties were shown to be convertible in the opposite manner as well
via conjugate reduction with sodium borohydride by Lee et al. However, only those
heterocycles substituted in the 4 position exhibited this reactivity as shown in Scheme
1.7.10 This reactivity is exhibited due to the acrylate-type resonance contributor that is
only available to those rings substituted in the 4 position.
Scheme 1.7 Reduction of Alkoxycarbonyl-Substituted Isoxazoles
1.3 Uses for Isoxazole and Isoxazoline
The non-aromatic isoxazoline, as mentioned previously, can be a precursor to
many other synthetically interesting functional groups. Through a variety of reductive
ring cleavage reactions and subsequent dehydrations the moieties depicted in Scheme
1.8 can be generated.3 The conversion to γ-amino alcohols has been shown to be useful
6
-
+
a) 1: DIBAL 2: Resolution; b) 1: OH , H 2: Δ; c) 1: EtONa, EtOH 2: HCl;
d) 1: H2 Raney nickel/acetic acid 2: NahCO3, H2O W-2 Raney nickel, 4
eq Conc. HCl, 5:1methanol-water; e) 1: H2, Raney Ni, AlCl3, MeOH,
H O 2: H IO ; f) 1: H 2: MsCl, Et N; g) 1: H NNHTs, MeOH 2: MeLi
Scheme 1.8 Synthetic Versatility of Isoxazoline
in the synthesis of alkaloids, such as paliclavine, and antibiotics, such as vermiculine, as
the reductive opening and complete saturation leaves the nitrogen intact.
The
transformation to an α-β-unsaturated carbonyl has been utilized in the production of the
tuberculosis drug sarkomycin. Streptazolin, an antimicrobial and antifungal substance,
can be easily converted from an isoxazoline by first converting to the β-hydroxy ketone. 3
The isoxazole and isoxazoline moieties can also be found in many biologically
active molecules with an array of different modes of action as shown in Figure 1.2.
Valdecoxib was found to be a potent, and selective, COX-2 inhibitor, but has been taken
off of the drug market due to possible cardiac side effects. 2 Muscimol, a potent and
selective agonist of the GABA A receptor, is the chief hallucinogenic aldecoxib was found
7
to be a potent, and selective, COX-2 inhibitor, but has been taken off of the drug market
due to possible cardiac side effects. 2 Muscimol, a potent and selective agonist of the
GABAA receptor, is the chief hallucinogenic compound found in many mushrooms,
Figure 1.2 Biologically Active Heterocycles
but in particularly high concentrations in the Amanita muscaria.11
Soretolide is
susceptible to hydroxylation by CYP1A2 and CYO2C19 isoenzymes, and the metabolite
is twice as potent as the parent drug.12
Isoxaflutole hydrolyzes to the diketonitrile
derivative, which can effectively control grasses and broad-leaf weeds by inhibiting the
enzyme 4-hydroxy-phenylpyruvate dioxygenase can effectively control grasses and
broad-leaf weeds.13 Risperdal is one of the leading drug used in treating psychotic
patients14, and ranks in the top 50 drugs used worldwide. Acivicin is highly specific to
8
glutamine amidotransferases, and can inhibit these enyzmes such that cancerous cells
can no longer make essential metabolites.15 Cyclocerin is used to treat tuberculosis,
when other medications fail to treat the disease.16
1.4 Introduction to Knoevenagel Condensation
Condensation reactions of carbonyl compounds provide a versatile means of
creating carbon-carbon bonds in organic synthesis. The Knoevenagel condensation is
the reaction between a carbonyl, either an aldehyde or ketone, and an activated
methylene complex.17 The pKa of the methylene protons is greatly reduced by the two
electron withdrawing groups attached to the carbon, which help stabilize the
deprotonated carbanion. The general formula for these compounds is Z-CH2-Y, in which
Z and Y may be one of the following: CN, CONH2, COOR, COX, CHO, NO2, SOR,
SO2R. There are two proposed mechanisms for the Knoevenagel condensation which
are dependent on the nature of the base used as a catalyst.17 The mechanism for 2˚
amines is shown in Scheme 1.9.
As a means for creating carbon-carbon bonds, the Knoevenagel Condensation is
synthetically useful. The Sammelson group has worked extensively on the condensation
of malononitrile, and other activated methylene complexes, with aryl ketones and
aldehydes, as well as their subsequent reduction and cycloaddition rearrangements. 18-20
9
O
R2
Z
R1
H
R2NH
Z
Y
R'
R
R2NH
O
R''
Y
P.T.
OH
R'
R''
R'
NHR2
Z
Y
R'
R
NR2
NR2
Z
Y
R'
R
NHR2
P.T.
Z
R'
H
Y
R
NR2
Scheme 1.9 Mechanism of the Knoevenagel Condensation
1.5 Synthesis of Monosubstituted Malononitriles and Other Methylene Complexes
Dunham et al. showed that condensation of malononitrile and aryl or alkyl
carbonyls proceed well in an ethanol solution rather than using a solid state reaction with
the only catalyst being sodium borohydride.18 This condensation/reduction produced the
desired monosubstituted malononitriles, but often resulted in the reduction of the starting
carbonyl. The reduction of ketones by sodium borohydride is much slower than that of
aldehydes, and as such only the primary alcohol side products had to be removed by
purification.
Tayyari et al. further developed this reaction method by showing sodium borohydride
need only be added after the condensation step had run to completion. 19 It was then
surmised that water effectively worked as a catalyst for the reaction in aqueous ethanol.
The addition of the sodium borohydride reduced the chance that the starting aldehyde
10
Scheme 1.10 Sodium Borohydride as the only Reagent for the Reductive
Alkylation of Malononitrile
would be reduced, and thus yields were increased and purification made easier. The
workup of certain products led to unexpected cyclizations that laid the ground work for
future research, as well as expanding the substitution of the methylene complexes to
include ethyl cyanoacetate.
Scheme 1.11 Water Catalyzed Knoevenagel Condensation of Malononitriles and
Subsequent Reduction
McClurg et al. continued to expand upon previous work utilizing the Knoevenagel
Condensation by expanding these methods further.20 When salicyladlehydes were used
in the condensation reaction it was found that the condensation product readily cyclized
with the phenol, and 2-amino-3-cyano-4H-chromenes were produced. Their work also
continued to expand the scope of the methylene complexes used during the
condensation to include malonic esters as well as cyanoacetamides. In these cases the
pKa of the methylene complexes was no longer reduced sufficiently for the reaction to
proceed without the presence of a catalyst.
Unexpectedly, the cyanoacetamide
11
derivatives were found to not exist as the cyclized form like the malononitrile and
malonic esters.
Scheme 1.12 Knoevenagel Condensation with Salicylaldehydes and Subsequent
Cyclizations
1.6 Uses of Malononitriles and Cyanoacetamides
The toxicity of these moieties, in particular malononitrile, has been of particular
interest in controlling pests, as a number of patent references show them to be potent
insecticides, with the general scaffolds shown in Figure 1.3. These are also used to
control aracine and nematode pests.21-23
Figure 1.3 Malononitriles as Insecticides
Cyanoacetamides, although generally less toxic, and malononitriles can also be
found in a range of biologically active compounds shown in Figure 1.4
12
Figure 1.4 Biologically Active Methylene Complexes
Entacapone can be empolyed as a co-drug to allow for transfer of other drugs
through the blood-brain barrier by inhibiting the enzyme, COMT, which would otherwise
destroy the other drugs. Joining entacapone with other drugs allows for their absorption
into the body to occur at identical rates, maximizing the effects of both drugs.24 By
inhibiting dynamin, a large GTPase, endocytosis can be studied. Using small molecules
for this inhibition has advantages over traditional means, particularly in term of fast
action of inhibition and reversibility.25 Prohibition of tubulin polymerization in the G 2/M
phase by (2-phenylindol-3-yl)methylenemalononitrile halts the cell cycle which leads to
the death of breast cancer cells. The inhibitory activity of these derivatives are up to 20
times greater than Docetaxel, a drug currently used to fight cancer.26 The irritant and
lachrymator properties of CS27 named for its discoverers Ben Corson and Roger
13
Stoughton, as well as the antifungal properties of alternatively substituted benylidene
derivatives are well documented.28 Levosimendan has been shown to decrease the
mortality rate more so than other drugs for persons suffering from acute decompensated
heart failure.29
1.7 Introduction to Alkylations
Historically unsymmetrical disubstituted methylene complexes have been difficult
to obtain.
With normal alkylation procedures it was often difficult to obtain the
monoalkylated product in good yields.
Our group has previously reported an efficient
route to these chiral or prochiral compounds. Dunham et al. presented an alkylation
procedure18, which followed the reductive alkylation by Knoevenagel Condensation, that
led to the desired unsymmetric malononitriles (Scheme 3.1).
Scheme 1.13 Alkylation of Monosubstituted Malononitrile
Alkylations of monosubstituted cyanoacetamides, however, have not been explored to
any extent in our lab. To our knowledge, these have not been explored elsewhere in the
literature.
14
1.8 References
1 Armstrong, A.; Bhonoah, Y.; Shanahan, S. E.; J. Org. Cchem. 2007, 72, 8019-8024.
2 Talley, J.J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J.M.;
Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J.
Med. Chem. 2000, 43, 775-777.
3 Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416.
4 Sammelson, R. E., Gurusinghe, C. D.; Kurth, H. M.; Olmstead, M. J. J. Org. Chem.
2002, 67, 876-882.
5
Jaeger, V.; Colinas, P. A. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W.H., Eds.;
Chemistry of Heterocyclic Compounds; Wiley: Hoboken, 2002; Vol. 59, pp 361-472.
6 Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339-5342.
7 Lohse-Fraefel, N.; Carreira, E. M. Org. Let. 2005, 7, 2011-2014.
8 Muri, D; Bode, J. W.; Carreira, E. M. Org. Let. 2000, 2, 539-541.
9 Azarifar, D. ARKIVOC. 2010, ix, 178-184.
10 Lee, C. K. U. J. Org. Chem. 2006, 71, 3221-3231.
11 Loev, B.; Wilson, J. W.; Goodman, M. M. J. Med. Chem. 1970, 13, 738-741.
12 Luszczki, J. J. Pharmacological Reports. 2009, 61, 197-216.
15
13 Beltran, E.; Fenet, H.; Cooper, J. F.; Coste, C. M. J. Agric. Food Chem. 2000, 48,
4399-4403.
14 Mack, D. J.; Brichacek, M.; Plichta, A.; Njardson, J. T. Top 200 Pharmaceutical
Products by Worldwide Sales, 2009.
15 Chittur, S. V.; Klem, T. J.; Shafer, C. M.; Davisson, V. J. Biochemistry, 2001, 40,
876-887.
16 Stammer, C. H.; Wilson, A. N.; Spencer, C. F.; Bachelor, F. W.; Holly, F. W.; Folkers,
K. J. Am. Chem. Soc. 1957, 79, 7236-7240.
17 Kurti, L. Czako, B. Strategic Applications of Named Reactions in Organic Synthesis,
Elsevier Academic Press, 2005.
18 Dunham, J. C.; Richardson, A. D.; Sammelson, R. E. Synthesis, 2006, 4, 680-686.
19 Tayyari, F.; Wood, D.; Fanwick, P.; Sammelson, R. E. Synthesis, 2008, No. 2, 279285.
20 McClurg, R. W. Synthesis of 2-Amino-3-Cyano-4H-Chromenes, Ball State University,
Thesis, 2010.
21 Otaka, K.; Oohira, D.; Okada, S. PCT Int. Appl. WO 02/090320 A3, 2003.
22 Otaka, K.; Oohira, D.; Takaoka, D. PCT Int. Appl. WO 2004/006677 A1, 2004.
23 Pohlmann, M.; Hofmann, M.; Bastiaans, H. M. M.; Rack, M.; Culbertson, D. L.;
Oloumi-Sadeghi, H.; Hokama, T.; Int. Appl. WO 2007/147888 A1, 2007.
24 Leppanen, J.; Huuskonen, J.; Nevalainen, R.; Gynther, J.; Taipale, H.; Jarvinen, T. J.
Med Chem. 2002, 45, 1379-1382.
16
25 Hill, T. A.; Gordon, C. P.; McGeachie, A. B.; Venn-Brown, B.; Odell, L. R.; Chau, N.;
Quan, A.; Mariana, A.; Sakoff, J. A..; Chircop, M.; Robinson, P. J.; McCluskedy, A. J.
Med. Chem, 2009, 52, 3762-3773.
26 Soung, M.; Myung, P.; Sung, N.; J. Korean Soc. Appl. Biol. Chem. 2009, 52, 28-33.
27 Brone, B.; Peeters, P. J.; Marrannes, R.; Mercken, M.; Nuydens, R.; Meert, T.;
Gijsen, H. J. M. Toxicol. Appl. Pharmacol., 2008, 231, 150-156.
28 Sidhu, A.; Sharma, J. R.; Rai, M.; Indian J. Chem. 2010, 49, 247-250.
29 Mebazaa, A.; Nieminen, M. S.; Packer, M.; Cohen-Solal, A.; Kleber, F. X.; Pocock,
S. J.; Thakkar, R.; Padley, R. J.; Poder, P.; Kivikko, M.; J. Am. Med. Assoc., 2007, 297,
1883-1891.
17
Reactions of Methylene Complexes
2.1 Introduction to Reductive Alkylation
The uncatalyzed condensation of malononitrile with benzaldehydes proceeded
as described by our group’s previous works with comparable yields. Some of these
intermediates were isolated to confirm complete condensation, but as these molecules
are known to be potent insecticides as well as other biologically active compounds many
were reduced in the one pot procedure as shown in Scheme 2.1.1-5
Scheme 2.1 One-Pot Water Catalyzed Knoevenagel Condensation of
Malononitriles and Subsequent Reduction
Cyanoacetamide condensations were run under similar conditions, but the
general procedure required some modification. Cyanoacetamide did not seem to be as
soluble in aqueous ethanol as malononitrile, so small portions of additional solvent were
added until all of the reactant was dissolved into solution. Due to the increased pKa of
cyanoacetamide (13.45)6 as opposed to malononitrile (11) a base was required for the
18
condensation to occur. Following the procedure set forth by McClurg,7 piperidine
was added to catalyze the reaction shown in Scheme 2.2.
Scheme 2.2 Reductive Alkylation of Aryl Aldehydes with Cyanoacetamide
2.2 Installation of Protecting Groups
During the synthesis of the propanamide derivatives it was found that, unlike the
malononitrile derivatives, when substituted with a phenol the alkylation step preferentially
alkylated on the oxygen. In an effort to eliminate these undesired side reactions, the
phenol must be protected.
Trimethylsilyl protecting groups were believed to be too
easily hydrolyzed so other groups were investigated.
Gries et al.8 have reported that vanillin can be easily acylated by first
deprotonating the hydroxybenzaldehyde in an aqueous sodium hydroxide solution to
first deprotonate the phenol.
After the deprotonation a solution of ether and acetic
anhydride is added to the cooled reaction mixture to allow the acylation to occur
(Scheme 4.1)
Vanillin was one of the starting benzaldehydes used in this multi-step synthesis
and multiple derivatives of hydroxybenzaldehydes were made.
19
Scheme 2.3 Acylation of Vanillin
Section 2.3 Results and Discussion
Reaction times for the condensation of cyanoacetamide were much greater than
that of the malononitrile derivatives. No side products were ever isolated from allowing
Product
#
R1
R2
R3
Time (h)
% Yield
1
OMe
H
H
over night
89
2
NMe2
H
H
over night
65
3
OMe
OH
H
over night
68
4
Cl
H
H
over night
73
5
OH
OMe
H
23:10
78
6
NO2
H
H
69:35:00
80
7
H
Cl
H
23:50
65
8
OAc
OMe
H
over night
14
9
OH
H
H
118:50:00
70
10
OH
H
OH
69:35:00
71
Table 2.1 Knoevenagel Condensation of Cyanoacetamide with Benzaldehydes
20
the reaction to stir for extended periods of time, and thus many of these reactions were
allowed to stir for multiple days often over a weekend.
As with the malononitrile
intermediates, the cyanoacetamide intermediates were not often isolated prior to
reduction.
Those intermediates that were isolated after the condensation step was
arose from the poor quality of the reducing agent after exposure to atmospheric
moistrure. The products from the condensation with cyanoacetamide can be found in
Table 2.1, and those from the condensation with malononitrile are shown in Table 2.2.
Product
#
R1
R2
Time (h)
% Yield
11
OMe
OH
24
80
12
OMe
H
overnight
93
Table 2.2 Knoevenagel Condensation of Malononitrile with Benzaldehydes
Reduction of the malononitrile condensation products proved much easier than
those containing cyanoacetamides.
These reductions of both methylene complexes
often proceeded to completion within 30 minutes, but were periodically monitored by
TLC.
The reduced malononitrile products precipitated from solution after carefully
quenching excess hydride and dilution with DI water. The mixture was cooled before a
vacuum filtration was employed to isolate the product. The yields of these reactions are
shown in Table 2.3.
21
Product #
R1
R2
R3
Time
(min)
% Yield
13
CONH2
OMe
H
35
86
14
CONH2
OH
OMe
35
77
15
CONH2
H
Cl
25
92
16
CONH2
OH
H
240
67
17
CN
OMe
OH
15
98
Table 2.3 Reduction of Benzylidene Methylene Complexes
Cyanoacetamide intermediates were more difficult to reduce than malononitriles,
in particular those intermediates containing activated benzene rings. This may be a
result of the conjugation of the intermediate. Reductions often ran longer, and at times a
greater excess of sodium borohydride needed to be employed. After investigating the
differences between the two reduction steps it was determined that for the
cyanoacetamide reduction to take place a fresh bottle of the reductant was needed to
obtain good yields.
Although many reductions can proceed to completion in the
presence of .25 molar equivalent of borohydride, the first hydride to be donated by the
reductant is the most reactive which, in the case of older bottles of reagent, had already
been quenched by atmospheric moisture.
22
Many of the intermediates were not isolated, but the benzylidene bond reduced
in a two-step, one-pot method. The yields of this reductive alkylation can be found in
Table 2.4.
Product
#
R1
R2
R3
Time (h)
Condensation
Time
(min)
Reduction
% Yield
18
CONH2
Cl
H
98:40:00
40
99
14
CONH2
OH
OMe
16
15
98
19
CONH2
OMe
OH
75
60
69
20
CONH2
H
OH
15
60
79
21
CONH2
NMe2
H
98
60
81
17
CN
OMe
OH
24
10
92
Table 2.4 Reductive Alkylations of Benzaldehydes with Methylene Complexes
In general the acylations ran well with often 100% conversion to the acylated
product were observed. After some experimentation it was found that to increase overall
yield the best approach had these phenols protected after the condensation/reduction
step with cyanoacetamide shown in Table 2.5, but each intermediate was able to
undergo the acylation in good yields.
23
Product
#
R1
R2
Time
(min)
% Yield
22
H
OH
30
67
23
OH
OMe
35
72
24
OMe
OH
30
78
Table 2.5 Acylations of Phenols
It was also discovered that the reaction worked well when ether was not
employed as the organic layer/solvent.
The product gelled from the basic aqueous
layer, and could be isolated via vacuum filtration. The precipitate was often found to not
be crystalline due to the acetic acid that is resultant from this reaction. When using the
filtration method multiple washings with water were required, but isolating a crystalline
solid remained difficult. Although the reaction goes forward without the ethereal layer,
this method was avoided to allow for complete reaction of all phenolic substituents. In
using this bi-layered reaction mixture, the product could easily be isolated by extraction.
Gries’ procedure called for an extraction with ether, but it was found that those
derivatives that had already undergone the reductive alkylation were not readily soluble
in ether so ethyl acetate was used instead.
For the same reasons as the filtration
method work up, when the extraction method was used many washings with DI water
were required to remove impurities from the desired product as well as allowing the
mixture to dry completely under high vacuum.
24
It also must be noted that most of the compounds generated were not soluble
enough in chloroform-d, and acetone-d6 needed to be used instead. Those derivatives
that contain phenolic substituents were often not observed by NMR due to the deuterium
exchange with the solvent.
2.4 General Experimental
Infrared Spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR
spectrometer using an ATR accessory with a diamond element.
Proton nuclear
magnetic resonance spectra (1H NMR) and carbon-13 nuclear magnetic resonance
spectra (13C NMR) were recorded on a JEOL Eclipse spectrometer at 400 MHz or 300
MHz and 100 MHz or 75 MHz, respectively. Chemical shifts were reported downfield
from referenced values for Acetone-d6 (1H: 2.05 ppm;
13
C: 29.84 ppm). Analytical thin-
layer chromatography was performed using Baker-Flex silica gel IB-F plates.
Visualization of TLC plates was aided by a UV lamp and basic KMnO 4 (15 g K2CO3, 1.9
mL 2.5M NaOH in 300 mL DI H2O). Column chromatography was performed using silica
gel (35-70mm, 6nm pore) from Acros. All chemicals purchased from Sigma-Aldrich were
used without further purification.
Synthesized materials were purified by column
chromatography or recrystallization prior to use.
Representative Procedure for the Knoevenagel Condensation of Benzaldehydes
with Cyanoacetamide
The corresponding
benzaldehyde (1.00 equiv.) and
cyanoacetamide (1.05 equiv.) were dissolved in 95% aqueous ethanol (0.25M solution).
After complete dissolution piperidine (0.20 equiv.) was added. The mixture was allowed
to stir overnight, or often longer, until the reaction had run to completion by monitoring
with TLC or by precipitation. DI H2O (5 mL) was added to the reaction flask and the
mixture cooled to complete precipitation. The crude product was isolated via vacuum
25
filtration, and when necessary recrystallized from a mixture of hexanes and ethyl
acetate.
Representative Procedure for the Knoevenagel Condensation of Benzaldehydes
with Malononitrile
The corresponding benzaldehyde (1 equiv.) and of malononitrile (1.05 equiv.)
were dissolved in 95% aqueous ethanol (0.50M solution). The mixture was allowed to
stir until the reaction had run to completion by monitoring with TLC or by precipitation.
DI H2O (5 mL) was added to the reaction flask and the mixture cooled to complete
precipitation. The crude product was isolated via vacuum filtration.
Representative Reductive Alkylation of Benzaldehydes with Malononitrile
The corresponding benzaldehyde (1 equiv.) and malononitrile (1.05 equiv.) were
dissolved in 95% aqueous ethanol (0.50M solution). The flask was allowed to stir at
room temperature until precipitation of the intermediate was complete or overnight. The
flask was then diluted with additional absolute ethanol (0.17M solution) and cooled to 0
˚C in an ice bath. Sodium borohydride (1 mol. equiv.) was then added to the stirring
mixture. After the reduction of the benzylidene intermediate was complete by monitoring
with TLC or after 1 hour the excess hydride was carefully quenched with 1M HCl. DI
H2O (5 mL) was added to the flask to precipitate the monosubstituted malononitrile. If a
precipitate formed, the crystals were isolated via vacuum filtration. In cases where no
precipitate formed the product was isolated via extraction with ethyl acetate (3 times with
10 mL). The combined organic layers were dried over MgSO4, filtered through a pad of
celite or cotton wool, and solvent removed in vacuo.
26
Representative Procedure for Reductive Alkylation with Cyanoacetamide
The corresponding benzaldehyde (1 equiv.) and cyanoacetamide (1.05 equiv.)
were dissolved in 95% aqueous ethanol (0.25M solution). After complete dissolution
piperidine (0.20 equiv) was added. The mixture was allowed to stir overnight, or often
longer, until the reaction had run to completion by monitoring with TLC or by
precipitation. Additional absolute ethanol (0.125M solution) was added to the mixture,
which was then cooled to 0 ˚C in an ice bath. Sodium borohydride (1-2 mol. equiv.)was
then added to the reaction mixture. After the reduction of the benzylidene intermediate
was complete by TLC or after 1 hour the excess hydride was carefully quenched with 1M
HCl.
DI H2O (5 mL) was added to the mixture to precipitate the monosubstituted
cyanoacetamide. If a precipitate formed, the crystals were isolated via vacuum filtration.
In cases where no precipitate formed the product was isolated via extraction with ethyl
acetate (3 times with 10 mL). The combined organic layers were dried over MgSO 4,
filtered through a pad of celite or cotton wool, and solvent removed in vacuo.
Representative Procedure for Reduction of Benzylidene Malononitriles and
Cyanoacetamides
The corresponding benzylidene condensation product (1.00 equiv) was dissolved in of
absolute ethanol (0.33M solution) and chilled to 0 ˚C in an ice bath. Sodium borohydride
(1 mol. equiv.) was added to the solution. The reaction was allowed to stir for 1 hour or
until completed by TLC. The excess hydride was carefully quenched with 1M HCl prior
to dilution with DI H2O (5 mL). If a precipitate formed upon dilution the flask was cooled
further and then the solid vacuum filtered. In cases where no such precipitate formed an
extraction with ethyl acetate was performed (3 times with 10 mL). The combined organic
27
layers were dried over MgSO4, filtered through a pad of celite or cotton wool, and solvent
removed in vacuo.
Representative Procedure for Acylation of Phenols
The corresponding phenol (1.00 equiv.) was dissolved in 1M NaOH (1.00 equiv.).
The solution was cooled to 0 ˚C.
Acetic anhydride (1.10 equiv.) was then added
suspended in diethyl ether (1.00 equiv.). The reaction stirred for 30 minutes prior to
extraction with ethyl acetate (3 times with 10 mL). The combined organic layers were
washed with DI H2O, dried over MgSO4, filtered through cotton wool or a pad of celite,
and solvent removed in vacuo.
2.5 Data
Knoevenagel Condensation of Benzaldehyde with Cyanoacetamide
2-cyano-3-(4-methoxyphenyl)propenamide9 (1)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using anisaldehyde (0.0727 g, 0.59 mmol) and
cyanoacetamide (0.0516 g, 0.61 mmol) and 10 µL of piperidine. Filtration method work
up. The reaction yielded a white crystalline solid (0.0962 g, 89%). 1H NMR (400 MHz,
CDCl3) δ 3.90 (s, 3H), 5.68 (bs, 1H), 6.30 (bs, 1H), 7.00 (d, J = 8.8 Hz, 2H), 7.96 (d, J =
8.8 Hz, 2H), 8.27 (s, 1H).
28
2-cyano-3-(4-dimethylaminophenyl)propenamide10 (2)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using 4-dimethylaminobenzaldehyde (0.0744 g,
0.50 mmol), cyanoacetamide (0.0452 g, 0.53 mmol) of and 10 µL of piperidine. Filtration
method work up. The reaction yielded a pale yellow-orange crystalline solid (0.0699 g,
65%). 1H NMR (400 MHz, CDCl 3) δ 3.11 (s, 6H), 5.52 (bs, 1H), 6.18 (bs, 1H), 6.70 (d, J
= 9.2 Hz, 2H), 7.90 (d, J = 9.2 Hz, 2H), 8.16 (s, 1H).
2-cyano-3-(3-hydroxy-4-methoxyphenyl)propenamide11 (3)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using of 3-hydroxy-4-methoxybenzaldehyde
(0.0812 g, 0.53 mmol), cyanoacetamide (0.0471 g, 0.56 mmol) and 10 µL of piperidine.
Filtration method work up. The reaction yielded a pale yellow crystalline solid (0.800 g,
68%). 1H NMR (300 MHz, CDCl 3) δ 3.98 (s, 3H), 5.67 (bs, 1H), 6.29 (bs, 1H), 6.94 (d, J
= 8.5 Hz, 1H), 7.41-7.43 (m, 1H), 7.62 (s, 1H), 8.21 (s, 1H).
29
2-cyano-3-(4-chlorophenyl)propenamide9 (4)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using 4-chlorobenzaldehyde (0.0710 g, 0.51
mmol), cyanoacetamide (0.0461 g, 5.4 mmol), and 10 µL of piperidine. Filtration method
work up. The reaction yielded a white crystalline solid (0.0760 g, 73%).
1
H NMR (400
MHz, Acetone-d6) δ 3.17 (dd, J = 13.7 Hz, 8.3 Hz, 1H), 3.28 (dd, J = 13.7 Hz, 6.8 Hz,
1H), 3.94 (dd, J = 8.4 Hz, 6.6 Hz, 1H), 6.84 (bs, 1H), 7.26 (bs, 1H), 7.37 (m, 4H).
2-cyano-3-(4-hydroxy-3-methoxyphenyl)propenamide11 (5)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using vanillin (0.0786 g, 0.52 mmol),
cyanoacetamide (0.0470 g, 0.55 mmol), and 10 µL of piperidine. Filtration method work
up. The reaction yielded a pale yellow crystalline solid (0.0881 g, 77%).
1
H NMR (400
MHz, Acetone-d6) δ 3.92 (s, 3H), 6.99 (d, J = 8.0 Hz, 1H), 6.99 (bs, 1H), 7.09 (bs, 1H),
7.56 (dd, J = 8.0 Hz, 2.2 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 8.14 (s, 1H).
30
2-cyano-3-(4nitrophenyl)propenamide12 (6)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using 4-nitrobenzaldehyde (0.0770 g, 0.51mmol),
cyanoacetamide (0.0445 g, 0.52 mmol), and 10 µL of piperidine. Filtration method work
up. The reaction yielded a pale yellow crystalline solid (0.0899 g, 80%). 1H NMR (300
MHz, Acetone-d6) δ 7.26 (bs, 1H), 7.39 (bs, 1H), 8.24 (d, J = 8.8 Hz, 2H), 8.37 (s, 1H),
8.43 (d, J = 8.8 Hz, 2H).
13
C NMR (75 MHz, Acetone-d6) 110.8, 116.5, 125.0, 132.1,
139.1, 149.9, 150.3, 162.0 ppm.
2-cyano-3-(3-chlorophenyl)propenamide13 (7)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using 3-chlorobenzaldehyde (0.0730 g, 0.52
mmol), cyanoacetamide (0.0450 g, 0.53 mmol), and 10 µL of piperidine.
Filtration
method work up. The reaction yielded a white crystalline solid (0.0700 g, 65%).
1
H
NMR (400 MHz, CDCl3) 5.67 (bs, 1H), 6.29 (bs, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.16 (d, J
= 8.4 Hz, 1H), 7.40-7.42 (m, 1H), 8.28 (s, 1H).
31
2-cyano-3-(4-acetoxy-3-methoxyphenyl)propenamide (8)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using 4-acetoxy-3-methoxybenzaldehyde (0.185
g, 0.95 mmol), cyanoacetamide (0.0845 g, 1.00 mmol), and 20 µL of piperidine.
Filtration method work up. The reaction yielded an off white crystalline solid (0.0339 g,
14%). M.P. 160.5-161.5 ˚C. IR (ATR) 3429, 3350, 3301, 3159, 3010, 2948, 2797, 2226,
1729, 1672, 1622 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.91 (s, 3H), 5.80 (bs,
1H), 6.32 (bs, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 8.3 Hz, 1.9 Hz, 1H), 7.70 (d, J
= 1.9 Hz, 1H), 8.29 (s, 1H).
13
C NMR (100 MHz, Acetone-d6) 20.5, 56.5, 106.4, 114.9,
117.4, 124.5, 124.6, 131.8, 144.1, 151.9, 152.7, 165.6, 168.7 ppm.
2-cyano-3-(4-hydroxyphenyl)propenamide11 (9)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using 4-hydroxybenzaldehyde (0.0614 g, 0.50
mmol), cyanoacetamide (0.0443 g, 0.53 mmol), and 10 µL of piperidine.
Filtration
method work up. The reaction yielded a white crystalline solid (0.0669 g, 70%).
1
H
32
NMR (300 MHz, Acetone-d6) δ 7.00-7.04 (m, 3H), 7.09 (bs, 1H), 7.97 (d, J = 8.8 Hz, 2H),
8.14 (s, 1H), 9.40 (bs, 1H).
7-hydroxy-2-imino-2H-chromene-3-carboxamide (10)
The general procedure for the Knoevenagel condensation of benzaldehydes with
cyanoacetamide was followed to scale using 2,4-dihydroxybenzaldehyde (0.0720 g, 0.52
mmol), cyanoacetamide (0.0474 g, 0.56 mmol), and 10 µL of piperidine. No precipitate
formed upon dilution with DI H2O, and was, therefore, isolated via extraction with ethyl
acetate followed by rotary evaporation. Filtration method work up. The reaction yielded
a yellow crystalline solid (0.0812 g, 71%).
1
H NMR (300 MHz, Acetone-d6) δ 3.58 (s,
1H), 6.35 (d, J = 2.2 Hz, 1H), 6.55 (dd, J = 8.8 Hz, 2.2 Hz, 1H), 6.72 (bs, 1H), 7.15 (bs,
1H), 7.59 (d, J = 8.8 Hz, 1H), 9.76 (s, 1H).
Knoevenagel Condensation of Benzaldehydes with Malononitrile
2-(3-hydroxy-4-methoxybenylidene)malononitrile11 (11)
The general procedure for the Knoevenagel condensation of benzaldehydes with
malononitrile was followed to scale using 4-methoxy-3-hydroxybenzaldehyde (0.762 g,
5.00 mmol), and malononitrile (0.403 g, 6.10 mmol). Filtration method work up. The
33
reaction yielded a yellow crystalline solid (1.001 g, 80%). 1H NMR (400 MHz, DMSO-d6)
δ 3.89 (s, 3H), 7.16 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.53 (d, J = 2.2
Hz, 1H), 8.29 (s, 1H), 9.84 (s, 1H).
2-(4-methoxybenzylidene)malononitrile14 (12)
The general procedure for the Knoevenagel condensation of benzaldehydes with
malononitrile was followed to scale using 4-hydroxybenzaldehyde (3.7330 g, 27.4 mmol)
and malononitrile (1.8198 g, 27.5 mmol).
Filtration method work up.
The reaction
yielded an off white crystalline solid (4.6932 g, 93%). 1H NMR (400 MHz, CDCl3) δ 3.92
(s, 3H), 7.01 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H).
Reduction of Benzylidene Malononitriles and Cyanoacetamides
2-cyano-3-(4-methoxyphenyl)propanamide15 (13)
The general procedure for the
cyanoacetamides
was
reduction of
followed
to
benzylidene
scale
malononitriles and
using
2-cyano-3-(4-
methoxyphenyl)propenamide (0.2463 g, 1.22 mmol) and sodium borohydride (0.0462 g,
1.22 mmol) were stirred together for 35 minutes.
Filtration method work up.
The
34
reaction yielded a white crystalline solid (0.2128 g, 86%).
1
H NMR (400 MHz, CDCl3) δ
3.17 (dd, J = 13.9 Hz, 7.68 Hz, 1H), 3.24 (dd, J = 13.9 Hz, 5.5 Hz, 1H), 3.59 (dd, J = 7.9
Hz, 5.3 Hz, 1H), 3.80 (s, 3H), 5.61 (bs, 1H), 6.04 (bs, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.21,
(d, J = 8.4 Hz, 2H).
2-cyano-3-(4-hydroxy-3-methoxyphenyl)propanamide (14)
The general procedure for the
cyanoacetamides
was
followed
reduction of
to
scale
benzylidene
using
malononitriles and
2-cyano-3-(4-hydroxy-3-
methoxyphenyl)propenamide (0.1061 g, 0.49 mmol) and sodium borohydride (0.0190 g,
0.50 mmol) were stirred together for 35 minutes. Extraction method work up.
The
product yielded a pale yellow crystalline solid (0.0825 g, 77%). M.P. 167-168 ˚C. IR
(ATR): 3413, 3352, 2926, 2255, 1669, 1517, 1232, 799 cm -1.
1
H NMR (400 MHz,
Acetone-d6) δ 3.05 (dd, J = 13.7 Hz, 8.6 Hz, 1H), 3.19 (dd, J = 13.9 Hz, 6.6 Hz, 1H), 3.83
(s, 3H), 3.86 (dd, J = 8.8 Hz, 6.6 Hz, 1H), 6.77-6.80 (m, 2H), 6.96 (s, 1H), 7.18 (bs, 1H),
7.51, (bs, 1H).
13
C NMR (100 MHz, Acetone-d6) δ 36.5, 41.1, 56.2, 113.5, 115.8, 118.8,
122.6, 129.1, 146.7, 148.3, 167.2.
35
2-cyano-3-(3-chlorophenyl)propanamide (15)
The general procedure for the
reduction of
benzylidene
malononitriles and
cyanoacetamides was followed to scale using 2-cyano-3-(3-chlorophenyl)propenamide
(0.0690 g, 0.33 mmol) and sodium borohydride (0.015 g, 0.40 mmol) were stirred
together for 25 minutes. Extraction method work up. The product yielded a pale yellow
crystalline solid (0.0643 g, 92%). IR (ATR): 3392, 3311, 3188, 3086, 2982, 2244, 1697,
1683, 1492, 919, 755.
1
H NMR (400 MHz, CDCl3) δ 3.20 (dd, J = 13.9 Hz, 8.0 Hz, 1H),
3.28 (dd, J = 13.9 Hz, 5.1 Hz, 1H), 3.54 (dd, J = 8.1 Hz, 5.1 Hz, 1H), 5.57 (bs, 1H), 6.03
(bs, 1H), 7.18-7.22 (m, 1H), 7.29-7.30 (m, 3H).
13
C NMR (100 MHz, Acetone-d6) δ 41.8,
41.9, 52.0, 120.4, 120.7, 129.2, 132.5, 132.8, 133.8, 135.3, 168.8.
2-cyano-3-(4-hydroxyphenyl)propanamide16 (16)
The general procedure for the
reduction of
benzylidene
malononitriles and
cyanoacetamides was followed to scale using 2-cyano-3-(-hydroxyphenyl)propenamide
(0.2396 g, 1.27 mmol)
and sodium borohydride (0.050 g, 1.32 mmol) were stirred
together for 4 hours. Filtration method work up. The reaction yielded a white crystalline
36
solid (.0420 g, 17%). The filtrate was then extracted with ethyl acetate to recover more
product. The reaction yielded a pale yellow crystalline solid (0.1620 g, 67%) (0.2040 g,
84%). 1H NMR (300 MHz, Acetone-d6) δ 3.0 (dd, J = 13.7 Hz, 8.8 Hz, 1H), 3.19 (dd, J =
13.7 Hz, 6.6 Hz, 1H), 3.83 (dd, J = 8.3 Hz, 6.6 Hz, 1H), 6.78 (d, J = 8.3 Hz, 2H), 7.16 (d,
J = 8.3 Hz, 2H), 8.28 (bs, 1H).
2-cyano-3-(3-hydroxy-4-methoxybenzyl)malononitrile (17)
The general procedure for the
cyanoacetamides
was
followed
reduction of
to
scale
benzylidene
using
malononitriles and
2-cyano-3-(3-hydroxy-4-
methoxybenzylidene)malononitrile (0.0775 g, 0.35mmol) and sodium borohydride
(0.0148 g, 0.39 mmol) were stirred together for 30 minutes. Extraction method work up.
The product yielded a pale yellow crystalline solid (0.0763 g, 98%). M.P. 166-167 ˚C.
IR (ATR): 3413, 3018, 2330, 2259, 1592.
1
H NMR (400 MHz, CDCl3) δ 3.20 (d, J = 7.0
Hz, 2H), 3.85 (t J = 7.0 Hz, 1H), 3.90 (s, 3H), 6.80-6.88 (m, 3H).
13
C NMR (75 MHz,
Acetone-d6) δ 25.6, 36.1, 56.2, 112.5, 114.5, 116.9, 121.5, 128.2, 147.6, 148.4.
Reductive Alkylation of Benzaldehydes with Cyanoacetamide
2-cyano-3-4’chlorophenylpropanamide17 (18)
37
The
general
procedure
for
the
reductive
alkylation
of
benzaldehydes
with
cyanoacetamide was followed to scale using 4-chlorobenzaldehyde (0.0816 g, 0.58
mmol), cyanoacetamide (0.0531 g, 0.63 mmol), and piperidine (0.0108 g, 0.13 mmol)
were stirred together for 98:40 hours. An additional portion of absolute ethanol was
added to the mixture which was then cooled in an ice bath. Sodium borohydride (0.025
g, 0.66 mmol) of was then added to the flask. The reductant stirred for 40 minutes
before quenching with 1M HCl, and diluting with DI H2O. Filtration method work up. The
reaction yielded a white crystalline solid (0.1197 g, 99%). 1H NMR (400 MHz, Acetoned6) δ 3.17 (dd, J = 13.7 Hz, 8.3 Hz, 1H), 3.28 (dd, J = 13.7 Hz, 6.8 Hz, 1H), 3.95 (dd, J =
8.4 Hz, 6.6 Hz, 1H), 6.84 (bs, 1H), 7.26 (bs, 1H), 7.37 (m, 4H).
2-cyano-3-(4-hydroxy-3-methoxyphenyl)propanamide (14)
The
general
procedure
for
the
reductive
alkylation
of
benzaldehydes
with
cyanoacetamide was followed to scale using vanillin (0.1600 g, 1.05 mmol),
cyanoacetamide (0.0957 g, 1.14 mmol), and piperidine( 0.0108 g, 0.13 mmol) were
stirred together for 16 hours. An additional portion of absolute ethanol was added to the
mixture which was then cooled in an ice bath. Sodium borohydride (0.038 g, 1.00 mmol)
38
was then added to the flask. The reductant stirred for 15 minutes before quenching with
1M HCl.
The solution was diluted with DI H 2O.
Extraction method work up.
The
reaction yielded a pale yellow crystalline solid (0.2254 g, 97%). M.P. 167-168 ˚C. IR
(ATR): 3413, 3352, 2926, 2255, 1669, 1517, 1232, 799 cm -1.
1
H NMR (400 MHz,
Acetone-d6) δ 3.05 (dd, J = 13.7 Hz, 8.6 Hz, 1H), 3.19 (dd, J = 13.9 Hz, 6.6 Hz, 1H), 3.83
(s, 3H), 3.86 (dd, J = 8.8 Hz, 6.6 Hz, 1H), 6.77-6.80 (m, 2H), 6.96 (s, 1H), 7.18 (bs, 1H),
7.51, (bs, 1H). 13C NMR (100 MHz, Acetone-d6) δ 36.5, 41.1, 56.2, 113.5, 115.8, 118.9,
122.6, 146.7, 148.3, 167.2.
2-cyano-3-(3-hydroxy-4-methoxyphenyl)propanamide (19)
The
general
procedure
for
the
reductive
alkylation
of
benzaldehydes
with
cyanoacetamide was followed to scale using 4-hydroxy-3-methoxybenzaldehyde (0.8546
g, 5.62 mmol), cyanoacetamide (0.5208 g, 6.19 mmol), and piperidine (0.098 g, 1.15
mmol) were stirred together for 75 hours. An additional portion of absolute ethanol was
added to the mixture which was then cooled in an ice bath. Sodium borohydride .
(0.218 g, 5.76 mmol) was then added to the flask. The reductant stirred for 60 minutes
before quenching with 1M HCl.
The solution was diluted with DI H2O.
Extraction
method work up. The reaction yielded a pale yellow crystalline solid (0.855 g, 69%).
M.P. 166-167 ˚C. IR (ATR): 3445, 3351, 3175, 2951, 2255, 1664, 1518, 1233, 799.
1
H
NMR (400 MHz, Acetone-d6) δ 3.05 (dd, J = 13.9 Hz, 8.4 Hz, 1H), 3.19 (dd, J = 13.9 Hz,
6.6 Hz, 1H), 3.83 (s, 3H), 3.86 (dd, J = 8.8 Hz, 7.0 Hz, 1H), 6.75-6.79 (m, 3H), 6.96 (s,
39
1H), 7.18 (bs, 1H), 7.52, (bs, 1H).
13
C NMR (100 MHz, Acetone-d6) δ 36.5, 41.1, 56.2,
113.5, 115.8, 118.8, 122.6, 129.1, 146.7, 148.3, 167.3.
2-cyano-3-(3-hydroxyphenyl)propanamide (20)
The
general
procedure
for
the
reductive
alkylation
of
benzaldehydes
with
cyanoacetamide was followed to scale using 3-hydroxybenzaldehyde (0.270 g, 2.21
mmol), cyanoacetamide (0.2043 g, 2.43 mmol), and 45µL of piperidine were stirred
together for 15 hours.
An additional portion of absolute ethanol was added to the
mixture which was then cooled in an ice bath. Sodium borohydride (0.085 g, 2.25 mmol)
was then added to the flask. The reductant stirred for 60 minutes before quenching with
1M HCl.
The solution was diluted with DI H 2O.
Extraction method work up.
The
reaction yielded a pale yellow crystalline solid (0.3302 g, 79%). M.P. 170-171 ˚C. IR
(ATR): 3381, 3319, 3206, 3044, 2919, 2270, 1682, 1590, 788. 1H NMR (400 MHz,
Acetone-d6) δ 3.06 (dd, J = 13.6 Hz, 8.8 Hz, 1H), 3.20 (dd, J = 13.6 Hz, 6.6 Hz, 1H),
3.89 (dd, J = 8.4 Hz, 6.6 Hz, 1H), 6.73-6.81 (m, 4H), 7.14 (t, J = 7.7 Hz, 1H), 7.24 (bs,
1H), 8.34 (bs, 1H).
13
C NMR (100 MHz, Acetone-d6) δ 36.6, 40.6, 115.0, 116.8, 116.9,
119.7, 121.0, 130.4, 139.4, 158.41, 167.1.
40
2-cyano-3-(4-dimethyaminophenyl)propanamide18 (21)
The
general
procedure
for
the
reductive
alkylation
of
benzaldehydes
with
cyanoacetamide was followed to scale using 4-dimethylaminobenzaldehyde (0.1496 g,
1.00 mmol), cyanoacetamide (0.0926 g, 1.10 mmol), and piperidine (0.021 g, 0.24 mmol)
were stirred together for 98 hours. An additional portion of absolute ethanol was added
to the mixture which was then cooled in an ice bath. Sodium borohydride (0.040 g, 1.06
mmol) was then added to the flask.
The reductant stirred for 60 minutes before
quenching with 1M HCl. The solution was diluted with DI H 2O. Extraction method work
up. The reaction yielded a pale yellow crystalline solid (0.2379 g, 81%). . 1H NMR (400
MHz, Acetone-d6) δ 2.90 (s, 6H), 3.02 (dd, J = 13.9 Hz, 8. Hz 8, 1H), 3.15 (dd, J = 13.6
Hz, 6.2 Hz, 1H), 3.81 (dd, J = 8.4 Hz, 6.6 Hz, 1H), 6.69 (d, J = 8.8 Hz, 4H), 6.78 (bs,
1H), 7.15 (d, J = 8.4 Hz, 2H), 7.21 (bs, 1H).
Reductive Alkylation of Benzaldehydes with Malononitrile
3-hydroxy-4-methoxybenzylmalononitrile (17)
41
The general procedure for reductive alkylation of benzaldehydes with malononitrile was
followed to scaled using 3-hydroxy-4-methoxybenzaldehyde (0.798 g, 5.12 mmol) and
malononitrile (0.424 g, 5.04 mmol) were dissolved in 10 mL of 95% aqueous ethanol.
The reaction mixture was stirred for 24 hours. An additional portion of absolute ethanol
was added to the mixture which was then cooled in an ice bath. Sodium borohydride
(0.092 g, 2.43 mmol) was then added to the flask. The reductant stirred for 10 minutes
before quenching with 1M HCl. The solution was diluted with DI H 2O. Filtration method
work up. The reaction yielded a pale yellow crystalline solid (1.019 g, 92%). IR (ATR):
3413, 3018, 2330, 2259, 1592.
1
H NMR (400 MHz, CDCl3) δ 3.20 (d, J = 7.0 Hz, 2H),
3.85 (t J = 7.0 Hz, 1H), 3.90 (s, 3H), 6.80-6.88 (m, 3H).
13
C NMR (75 MHz, Acetone-d6)
δ 25.6, 36.1, 56.2, 112.5, 114.5, 116.9, 121.5, 128.2, 147.6, 148.4.
Acylations of Phenols
3-(3-amido-2-cyanopropyl)phenyl acetate (22)
The general procedure for the acylation of phenols was followed to scale using 2-cyano3-(3-hydroxyphenyl)propanamide (0.0721 g, 0.38 mmol) and acetic anhydride (0.048 g,
0.47 mmol). The reaction yielded a white crystalline solid (0.0588 g, 67%). M.P. 111112 ˚C. IR (ATR): 3424, 3329, 3289, 3217, 2945, 2254, 1739, 1679, 1623, 1185, 1141,
915. 1H NMR (400 MHz, Acetone-d6) δ 2.25 (s, 3H), 3.17 (dd, J = 13.9 Hz, 8.8 Hz, 1H),
3.30 (dd, J = 13.9 Hz, 6.6 Hz, 1H), 3.81 (dd, J = 8.8 Hz, 6.6 Hz, 1H), 6.82 (bs, 1H), 7.04
42
(d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 7.22-7.27 (m, 2H), 7.36 (t, J = 7.9 Hz, 1H).
13
C NMR
(100 MHz, Acetone-d6) δ 20.9, 36.2, 40.3, 118.6, 121.5, 123.3, 127.3, 130.2, 139.5,
152.1, 166.8, 139.5.
4-(3-amido-2-cyanopropyl)-2-methoxyphenyl acetate (23)
The general procedure for the acylation of phenols was followed to scale using 2-cyano3-(4-hydroxy-3-methoxyphenyl)propanamide
(0.0238
g,
0.11
mmol)
and
acetic
anhydride (0.014 g 0.13 mmol). The reaction yielded a white crystalline solid (0.0210 g,
72%). M.P. 87-88 ˚C. IR (ATR) 3374, 3198, 2973, 2932, 2842, 2254, 2051, 1771, 1665,
1514.
1
H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 3.21 (dd, J = 13.9 Hz, 8.0 Hz, 1H),
3.29 (dd, J = 13.9 Hz, 5.0 Hz, 1H), 3.62 (dd, J = 7.9 Hz, 5.0 Hz, 1H), 5.52 (bs, 1H), 6.03
(bs, 1H), 6.88 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 7.00 (d, J = 8.1 Hz,
1H).
13
C NMR (100 MHz, Acetone-d6) δ 20.5, 35.7, 40.7, 56.2, 113.4, 118.7, 124.4,
128.3, 130.2, 140.8, 151.5, 167.0, 168.9.
5-(3-amido-2-cyanopropyl)-2-methoxyphenyl acetate (24)
43
The general procedure for the acylation of phenols was followed to scale using 2-cyano3-(3-hydroxy-4-methoxyphenyl)propanamide (0.855 g, 3.88 mmol) and acetic anhydride
(0.447 g, 4.38 mmol). The reaction yielded a white crystalline solid (0.7964 g, 78%).
M.P. 108-109 ˚C. IR (ATR) 33.49, 31.73, 29.52, 29.24, 28.14, 22.54, 2098, 1768, 1668,
1515.
1
H NMR (400 MHz, Acetone-d6) δ 2.23 (s, 3H), 3.08 (dd, J = 13.8 Hz, 8.6 Hz,
1H), 3.29 (dd, J = 13.9 Hz, 6.6 Hz, 1H), 3.80 (s, 3H), 3.89 (dd, J = 8.4 Hz, 6.6 Hz, 1H),
6.80 (bs, 1H), , 7.04-7.06 (m, 2H), 7.19 (dd, J = 8.1 Hz, 2.2 Hz, 1H), 7.22 (bs, 1H).
13
C
NMR (100 MHz, Acetone-d6) δ 20.5, 36.5, 40.5, 56.2, 114.4, 118.7, 122.0, 123.6, 136.7,
14.1, 152.2, 167.0, 169.0.
44
2.6 References
1 Otaka, K.; Oohira, D.; Okada, S. PCT Int. Appl. WO 02/090320 A3, 2003.
2 Otaka, K.; Oohira, D.; Takaoka, D. PCT Int. Appl. WO 2004/006677 A1, 2004.
3
Pohlmann, M.; Hofmann, M.; Bastiaans, H. M. M.; Rack, M.; Culbertson, D. L.;
Oloumi-Sadeghi, H.; Hokama, T.; Int. Appl. WO 2007/147888 A1, 2007.
4 Brone, B.; Peeters, P. J.; Marrannes, R.; Mercken, M.; Nuydens, R.; Meert, T.; Gijsen,
H. J. M. Toxicol. Appl. Pharmacol. 2008, 231, 150-156.
5 Sidhu, A.; Sharma, J. R.; Rai, M.; Indian J. of Chem. 2010, 49, 247-250.
6 Eberlin, A.; William, D. L. H. J. Chem. Soc., Perkin Trans 2, 2002, 1316-1319.
7 McClurg, R. W. Synthesis of 2-Amino-3-Cyano-4H-Chromenes, Ball State University,
Thesis, 2010.
8 Gries, G.; Gries, R.; Nair, R.; Paduraru, P.M.; Plettner, E.; Popoff, R. T. W.; J. Comb.
Chem. 2008, 10, 123-134.
9 Oh, H. K.; Ku, M. H., Lee, H. W. Bull. Korean Chem. Soc. 2005, 26, 935-938.
10 Bhattacharyya, S. P.; De, A. J. Chem. Soc. Perkin Trans II. 1985, 473.
11 Wells, G.; Seaton, A.; Stevens, M. F. G. J. Med. Chem. 2000, 43, 1550-1562.
12 Balalaie, S.; Barajanian, M.; Hekman, S.; Salehi, P. Synth. Comm., 2006, 36, 25492557.
13 Karras, J. W.; Lindquist, N. A.; Camenisch, D. R.; Elam, L.; Hope, N.; Jancius, M.;
Kaim, M.; Kharas, G. B.; Watson, K. Journal of Macromolecular Science, Pure
and Applied Chemistry, 1998, A35 (2), 395-400.
14 Brillon, D.; Sauvé, G. J. Org. Chem. 1992, 57, 1838-1842.
15 Westfahl, J. C.; Gresham, T. L. J. Am. Chem. Soc. 1954, 76, 1076-1080.
16 Gardner, P. D.; Brandon, R. L.; J. Org. Chem. 1957, 22, 1704-1705.
45
17 Schular, C. L.; Pitta, I. d. R.; Anais da Associacao Brasileira de Quemica, 1979, 30
(3-4), 117-122.
18 Fuentes, L.; Lorente, A.; Soto, J. L.; J. Heterocyclic Chem. 1979, 16, 273.
Synthesis of Disubstituted Methylene Complexes
3.1 Introduction
Two schemes were developed to generate the desired disubstituted, heterocycle
containing methylene complexes. The schemes differ in the order of alkylation versus
1,3-dipolar cycloaddition. Scheme 3.1 depicts the reaction sequence for insertion of the
aromatic isoxazole to create the desired products. The already reduced reactivity of
Scheme 3.1 Final Product Scheme for Isoxazole Derivative
47
alkynes toward dipolar cycloadditions is exacerbated by having sterically larger groups
attached.1 It was also noted that when alkylating with the cycloadduct, the nucleophilic
methylene complex will be attacking a “benzylic” carbon.
The stabilization of the
aromatic ring through conjugation aided in the alkylation process 2
Alternatively the reaction order for insertion of the isoxazoline derivatives are
shown in Scheme 3.2. Alkylation with the isoxazoline ring already in place does not
have the same aromatic stabilization as with the isoxazole ring. The reactivity of olefins
also decreases as substitution increases, but not to the extent of acetylenes.1
Scheme 3.2 Final Product Scheme for Isoxazoline Derivatives
These reaction orders were chosen in an effort to increase overall yield
48
3.2 Results and Discussion
Scheme 3.1 was chosen to generate the disubstituted methylene complexes which
contain the aromatic isoxazole ring. The products of this cyclization are listed in Table
3.1, and the products of the alkylation are shown in Table 3.2.
Product
#
R
Dipolarophile
Time (h)
% Yield
25
H
propargyl bromide
16
69
26
OMe
propargyl bromide
3
85
27
Me
propargyl bromide
over night
66
28
OMe
allyl bromide
16
99
Table 3.1 Cycloaddition Products from Scheme 1
49
Product
#
R1
R2
R3
R4
Time (h)
% Yield
29
CONH2
H
Cl
Me
18
83
30
CN
OMe
OH
Me
12
36
31
CN
H
H
Me
24
63
32
CN
OMe
OH
H
20
62
33
CN
NO2
H
Me
25
68
34
CN
Br
H
Me
48
70
Table 3.2 Alkylation Products from Scheme 1
Scheme 3.2 was selected to generate the disubstituted methylene complexes that
contain the non-aromatic heterocycles. The products of the alkylation and cycloaddition
steps are shown in Tables 3.3 and 3.4, respectively.
50
Product
#
R1
R2
Alkylating
Agent
Time (h)
%
Yield
35
CN
OMe
allyl bromide
12
92
36
CN
H
allyl bromide
44
94
37
CN
Br
propargyl
bromide
14
89
38
CONH2
Cl
allyl bromide
18
94
Table 3.3 Alkylation Products from Scheme 2
Product
#
R1
R2
R3
R4
Time (h)
% Yield
39
CN
H
H
Me
16
87
40
CN
H
H
OMe
68
84
41
CONH2
Cl
H
Me
22
83
42
CONH2
Cl
H
H
24
83
43
CONH2
Cl
H
OMe
3
97
Table 3.4 Cycloaddition Products from Scheme 2
51
To confirm the reasoning behind the two different reaction orders reactions were
carried out contrary to the expected reactivities. Although the cycloaddition with allyl
bromide was able to be done in excellent yields, the alkylation with the cycloadduct
could not be carried out in acceptable yields. Alkylating first with propargyll bromide, like
with allyl bromide, was completed in good yield, but due to the lowered reactivity of the
sterically hindered acetylene the cycloaddition could not be completed in acceptable
yields. These two products are represented in Figure 3.1.
Figure 3.1 Products from Reverse Reaction Order
The alkylations performed on the methylene complexes proved to be far easier
for malononitrile than cyanoacetamide. This can be related to the reduced acidity of the
methylene protons when the less electron withdrawing substituent, CONH 2, is in place
as well as the steric bulk of the moiety. Many of these reactions were not complete after
stirring for over 24 hours. After first encountering these difficulties a new procedure for
alkylating monosubstituted cyanoacetamides was searched for, but the literature
provided no results.
52
Alkylating phenol substituted cyanoacetamides was shown to preferentially
alkylate at the phenolic oxygen rather than the carbon of the methylene complex. This
was not observed when attempting to alkylate similarly substituted malononitriles. In an
effort to eliminate this side reaction, and undesired products, acyl protecting groups were
added to these products. Alkylation of the acylated phenols proved difficult as well
without any clear indication that alkylation was occurring at the desired carbon by crude
1
H NMR.
Later attempts at alkylating cyanoacetamides that were substituted with activated
benzyl groups would not occur, and only starting materials could be isolated from these
trials. This again was not the case in malononitriles that were similarly substituted. In
this instance, the lower acidity of the cyanoacetamide moieties does not explain this
phenomenon, and further investigation into the matter is needed to shed light on the
lowered reactivity.
Attempts were made to alkylate these derivatives in N,N-
dimethylformamide, with heating, but again no product could be seen via crude 1H NMR.
It also must be noted that most of the compounds generated were not soluble
enough in chloroform-d, and acetone-d6 needed to be used instead. Those derivatives
that contain phenolic substituents were often not observed by NMR due to the deuterium
exchange with the solvent.
3.3 Biological Testing of Final Products
Some of the products generated were sent to Eli Lilly through the PD2 program to
be tested for biological activity3, but little to no activity was detected.
53
3.4 General Experimental
Infrared Spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR
spectrometer using an ATR accessory with a diamond element.
Proton nuclear
magnetic resonance spectra (1H NMR) and carbon-13 nuclear magnetic resonance
spectra (13C NMR) were recorded on a JEOL Eclipse spectrometer at 400 MHz or 300
MHz and 100 MHz or 75 MHz, respectively. Chemical shifts were reported downfield
from referenced values for Acetone-d6 (1H: 2.05 ppm;
13
C: 29.84 ppm). Analytical thin-
layer chromatography was performed using Baker-Flex silica gel IB-F plates.
Visualization of TLC plates was aided by a UV lamp and basic KMnO 4 (15 g K2CO3, 1.9
mL 2.5M NaOH in 300 mL DI H2O). Column chromatography was performed using
silica gel (35-70mm, 6nm pore) from Acros.
All chemicals purchased from Sigma-
Aldrich were used without further purification. Synthesized materials were purified by
column chromatography or recrystallization before use.
Representative
Procedure
for
Alkylation
of
Monosubstituted
Methylene
Complexes
The corresponding methylene complex (1 equiv.) and appropriate alkylating
agent (1-2 equiv.) were dissolved in acetone (0.2M solution). Anhydrous K2CO3 (2.5
equiv.) was then added and the flask capped to stir until completed by TLC or overnight.
DI H2O (5 mL) was added to the mixture to precipitate the product. The product could
then be isolated via vacuum filtration.
In cases where no precipitate formed an
extraction with ethyl acetate was performed (3 times with 10mL). The combined organic
layers were dried over MgSO4, filtered through a pad of celite or cotton wool, and solvent
removed in vacuo. Products were purified by recrystallization in a mixture of hexanes
and ethyl acetate or by column chromatography.
54
Representative Procedure for 1,3-Dipolar Cycloaddition
The corresponding olefin or acetylene (1 equiv.) and the appropriate oxime (1
equiv.) were dissolved in dichloromethane. The flask was chilled in an ice bath. Sodium
hypochlorite (3 equiv.) was then slowly added via addition funnel over a period of 20-30
minutes. The addition funnel was capped and the reaction mixture allowed to stir until
complete by TLC or overnight. The product was isolated via extraction with ethyl acetate
(3 times with 10 mL). The combined organic layers were dried over MgSO4, filtered
through a pad of celite or cotton wool, and solvent removed in vacuo.
3.5 Data from Scheme 3.1
5-(bromomethyl)-3-phenylisoxazole4 (25)
The general procedure for 1,3-dipolar cycloaddition was followed to scale using
propargyl bromide (1.33 g of 80% w/w in toluene, 8.94 mmol propargyl bromide),
benzaldoxime (1.0182 g, 8.41 mmol), and NaOCl (69.84 g of 3% w/w NaOCl(aq)
solution, 28.15 mmol). The reaction stirred for 16 hours. The reaction yielded a pale
yellow oily solid (1.373 g, 69%). 1H NMR (400 MHz, CDCl3) δ 4.52 (s, 2H), 6.63 (s, 1H),
7.45-7.48 (m, 3H), 7.78-7.81 (m, 2H).
5-(bromomethyl)-3-(4-methoxyphenyl)isoxazole4 (26)
55
The general procedure for 1,3-dipolar cycloaddition was followed to scale using
propargyl bromide (0.782 g of 80% w/w in toluene, 5.26 mmol propargyl bromide), 4methoxybenzaldoxime (0.586 g, 3.88 mmol), and NaOCl (32.68 g of 3% w/w aqueous
solution, 13.17 mmol). The reaction stirred for 3 hours. The reaction yielded a pale
yellow oily solid (0.8405 g, 85%). 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 4.50 (s, 2H),
6.58 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H).
5-(bromomethyl)-3-4-methylphenylisoxazole5 (27)
The general procedure for 1,3-dipolar cycloaddition was followed to scale using
propargyl bromide (0.534 g of 80% w/w in toluene, 3.59 mmol propargyl bromide), 4methlybenzaldoxime (0.369 g, 2.73 mmol), and NaOCl (22.33 g of 3% w/w aqueous
solution, 9.00 mmol). The reaction stirred over night. The reaction yielded a pale yellow
oily solid (0.459 g, 66%).
1
H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 4.51 (s, 2H), 6.61
(s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H).
5-(bromomethyl)-3-(4-methoxyphenyl)-isoxazoline8 (28)
The general procedure for 1,3-dipolar cycloaddition was followed to scale using allyl
bromide (0.2421 g, 2.00 mmol), 4-methoxybenzaldoxime (0.304 g, 2.02 mmol), and
NaOCl (16.66 g of 3% w/w aqueous solution 6.71 mmol). The reaction stirred for 16.5
56
hours. The reaction yielded a pale yellow oily solid (0.5132 g, 99%). 1H NMR (400 MHz,
CDCl3) δ 3.30 (dd, J = 16.9 Hz, 6.2 Hz, 1H), 3.39 (dd, J = 10.3 Hz, 8.4 Hz, 1H), 3.49 (dd,
J = 16.8, 10.6, 1H), 3.58 (dd, J = 10.3 Hz, 7.0 Hz, 1H), 3.84 (s, 3H), 4.94-5.01 (m, 1H),
6.92 (d, J = 9.2, 2H), 7.61 (d, J = 8.8, 2H).
2-(3-chlorobenzyl)-2-cyano-3-(3-4-methylphenylisoxazol-5-yl)propanamide (29)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 3-(3-chlorophenyl)-2-cyanopropanamide (0.0600 g, 0.29 mmol),
5-(bromomethyl)-3-4-methylphenylisoxazole (0.0727 g, 0.29 mmol), and K2CO3 (0.0790
g, 0.57 mmol) were stirred together for 18 hours. Upon dilution with DI H 2O a white
precipitate formed. Filtration method work up. The crude product was recrystallized in
hexanes/ethyl acetate to yield a white crystalline solid (0.0914 g, 83%). M.P. 123-124
˚C. IR (ATR): 34.27, 33.18, 31.86, 29.37, 22.43, 1693, 1671, 1093, 815.
1
H NMR (400
MHz, Acetone-d6): δ 2.38 (s, 3H), 3.25 (d, J = 13.56, 1H), 3.55 (m, 2H), 3.66 (d, J =
14.46, 1H), 6.80 (s, 1H), 7.05 (bs, 1H), 7.09 (bs, 1H), 7.30-7.42 (m, 6H), 7.76 (d, J =
8.04, 2H).
13
C NMR (100 MHz, Acetone-d6): δ 21.3, 34.4, 42.4, 51.0, 102.6, 119.8,
127.2, 127.2, 127.4, 128.7, 129.8, 130.5, 131.1, 141.0, 163.1, 168.0, 168.7.
57
2-(3-hydroxy-4-methoxybenzyl)-2-((3-4-methylphenylisoxazol-5yl)methyl)malononitrile (30)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 3-hydroxy-4-methoxybenzylmalononitrile (0.0997 g, 0.49 mmol),
5-(bromomethyl)-3-4-methylphenylisoxazole (0.1243 g, 0.49 mmol), and K2CO3 (0.173 g,
1.25 mmol) were stirred together for 12 hours. Extraction method work up. The reaction
yielded a yellow oily solid (0.177 g, 48%) which upon recrystallization yielded an off
white crystalline solid (0.132 g, 36%). M.P. 171-172 ˚C. IR (ATR): 3462, 3138, 2952,
2850, 2253, 2040, 1710, 1606 cm-1.
1
H NMR (400 MHz, Acetone-d6): δ 2.38 (s, 3H),
3.49 (s, 2H), 3.85 (s, 2H), 3.87 (s, 3H), 6.94 (dd, J = 8.2 Hz, 2.0, 2H), 6.99 (s, 1H), 7.017.02 (m, 2H), 7.33 (d, J = 8.1, 2H), 7.81 (d, J = 8.0, 2H).
13
C NMR (100 MHz, Acetone-
d6) δ 21.4, 34.4, 39.9, 42.4, 56.2, 103.7, 112.5, 115.8, 118.0, 122.7, 126.3, 126.9, 127.5,
130.5, 141.3, 147.6, 148.8, 163.4, 166.8.
2-benzyl-2-((3-4-methylphenylisoxazol-5-yl)methyl)malononitrile (31)
58
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using benzylmalononitrile (0.0776 g, 0.50 mmol), 5-(bromomethyl)-3(4-methylphenyl)isoxazole
(0.1258 g, 0.50 mmol), and K2CO3 (0.138 g, 1.00 mmol)
were stirred together for 24 hours. Upon dilution with DI H2O a precipitate formed.
Filtration method work up. The reaction yielded a white crystalline solid (0.1227 g, 76%)
which was recrystallized in hexanes/ethyl acetate to yield a pure white crystalline solid
(0.102 g, 63%). M.P. 147-148 ˚C. IR (ATR): 3121, 3031, 2996, 2258, 1609, 1426, 811
cm-1. 1H NMR (400 MHz, Acetone-d6): δ 2.38 (s, 3H), 3.62 (s, 2H), 3.90 (s, 2H), 7.04 (s,
1H), 7.33 (d, J = 8.1 Hz, 2H), 7.40-7.48 (m, 3H), 7.51-7.54 (m, 2H), 7.81 (d, J = 8.1, 2H).
13
C NMR (100 MHz, Acetone-d6) δ 21.4, 34.5, 39.8, 42.8, 103.8, 115.6, 126.9, 127.5,
129.5, 129.7, 130.5, 131.4, 133.8, 141.3, 163.4, 166.7.
2-(3-hydroxy-4-methoxybenzyl)-2-((3-phenylisoxazol-5-yl)methyl)malononitrile (32)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 3-hydroxy-4-methoxybenzylmalononitrile (0.0946 g, 0.47 mmol),
5-(bromomethyl)-3-phenylisoxazole (0.1179 g, 0.50 mmol), and K2CO3 (0.139 g, 1.00
mmol) were stirred together for 20 hours. Upon dilution with DI H 2O an oil formed.
Extraction method work up. The reaction yielded a pale yellow crystalline solid (0.1046
g, 62%) which was recrystallized in hexanes/ethyl acetate to yield a white crystalline
solid (0.0892 g, 53%). M.P. 165-166 ˚C. IR (ATR): 3483, 3128, 2948, 2852, 2578, 2250,
59
1595, 1511 cm-1. 1H NMR (400 MHz, Acetone-d6): δ 3.50 (s, 2H), 3.86 (m, 5H), 6.95 (dd,
J = 8.2 Hz, 2.0 Hz, 1H), 6.98 (s, 1H), 7.01-7.02 (m, 1H), 7.06 (s, 1H), 7.50-7.55 (m, 3H),
7.81 (bs, 1H), 7.91-7.95 (m, 2H).
13
C NMR (100 MHz, Acetone-d6) δ 21.4, 34.5, 39.8,
42.8, 103.8, 115.6, 126.9, 127.5, 129.5, 129.7, 130.5, 131.4, 133.8, 141.3, 163.4, 166.7.
2-(3-nitrobenzyl)-2-(3-phenylisoxazol-5-yl)methyl)malononitrile (33)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 3-nitrobenzylmalononitrile (0.1004 g, 0.50 mmol), 5(bromomethyl)-3-phenylisoxazole (0.1179 g, 0.50 mmol), and K2CO3 (0.136 g, 0.98
mmol) were stirred together for 25 hours.
Upon dilution with DI H 2O a precipitate
formed. Filtration method work up. The reaction yielded a white crystalline solid (0.1431
g, 80%) which was recrystallized in hexanes/ethyl acetate to give a white crystalline solid
(0.1219 g, 68%). IR (ATR): 3122, 3098, 3077, 2257, 1988, 1729, 1611, 1532, 1344 cm1
. 1H NMR (300 MHz, Acetone-d6): δ 3.89 (s, 2H), 4.01 (s, 2H), 7.10 (s, 1H), 7.52-7.53
(m, 3H), 7.81 (dd, J = 7.90, 1H), 7.91-7.95 (m, 3H), 8.01 (d, J = 7.68, 1H), 8.34 (d, J =
8.22, 1H), 8.47 (s, 1H).
13
C (75 MHz, Acetone-d6): δ 34.4, 39.6, 41.8, 104.0, 115.3,
124.5, 126.3, 127.6, 129.7, 130.0, 131.2, 136.0, 137.8, 149.4, 163.5, 166.6.
60
2-(4-bromobenzyl)-2-((3-4-methylphenylisoxazol-5-yl)methyl)malononitrile (34)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using of 4-bromobenzylmalononitrile (0.1008 g, 0.43 mmol), 5(bromomethyl)-3-4-methylphenylisoxazole (0.1086 g, 0.43 mmol), and K2CO3 (0.160 g,
1.16 mmol) were stirred together for 48 hours. Upon dilution with DI H 2O no precipitate
formed. Extraction method work up. The reaction yielded a yellow-orange oily solid
(0.1957 g, 113%) which when recrystallized in hexanes/ethyl acetate yielded a white
crystalline solid (0.1213 g, 70%). M.P. 135-136. IR (ATR): 2992, 2256, 1926, 1607,
1490, 1432, 1072, 803.
1
H NMR (300 MHz, Acetone-d6) δ 2.39 (s, 3H), 3.64 (s, 2H),
3.91 (s, 2H), 7.03 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.65 (dd, J =
8.3 Hz, 1.1 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H).
13
C NMR (75 MHz, Acetone-d6) δ 21.3,
34.4, 42.0, 103.8, 115.4, 123.3, 126.8, 127.5, 132.8, 133.2, 133.4, 141.3, 163.4, 166.5.
2-(4-methoxybenzyl)-2-((2-phenyl-isoxazolin-5-yl)methyl)malononitrile (35)
61
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 4-methoxybenzylmalononitrile (0.1572 g, 0.84 mmol), 5(bromomethyl)-3-phenylisoxazoline (0.2000 g, 0.83 mmol), and K2CO3 (0.288 g, 2.08
mmol) were stirred together for 80 hours.
Upon dilution with DI H 2O no precipitate
formed. Extraction method work up. The reaction yielded a yellow-orange oil (19%
conversion by 1H NMR). 1H NMR (400 MHz, CDCl3) δ 2.24 (dd, J = 14.5 Hz, 4.9 Hz,
1H), 2.47 (dd, J = 14.3 Hz, 7.7 Hz, 1H), 3.17 (dd, J = 16.5 Hz, 7.7, 1H), 3.27 (d, J = 13.9
Hz, 1H), 3.40 (d, J = 13.9 Hz, 1H), 3.67 (dd, J = 16.9 Hz, 10.2 Hz, 1H), 3.82 (s, 3H),
5.10-5.17 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.42-7.44 (m, 2H),
7.66-7.69 (m, 3H).
3.6 Data from Scheme 3.2
2-allyl-2-(4-methoxybenzyl)malononitrile6 (36)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 4-methoxybenzylmalononitrile (0.185 g, 1.00mmol), allyl bromide
(0.168 g, 1.40 mmol), and K2CO3 (0.346 g, 2.50 mmol) were stirred together for 12
hours. Upon dilution with DI H2O no precipitate formed. Extraction method work up.
The reaction yielded a white crystalline solid (0.2092 g, 92%).
1
H NMR (400 MHz,
Acetone-d6) δ 2.78-2.82 (m, 1H), 2.89 (d, J = 7.4, 1H), 3.36 (s, 2H), 3.81 (s, 3H), 5.415.47 (m, 2H), 5.94-6.04 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H),
62
2-benzyl-2-allylmalononitrile7 (37)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using benzylmalononitrile (0.1566 g, 1.00 mmol), allyl bromide (0.16 g,
1.32 mmol), and K2CO3 (0.346 g, 2.50 mmol) were stirred together for 44 hours. Upon
dilution with DI H2O no precipitate formed. Extraction method work up. The reaction
yielded a white crystalline solid (0.1841g, 94%). 1H NMR (300 MHz, Acetone-d6) δ 2.70
(d, 7.4 Hz, 2H), 3.20 (s, 2H), 5.40-5.48 (m, 2H), 5.88-6.02 (m, 2H), 7.31-7.45 (m, 5H).
2-(4-chlorobenzyl)-2-cyanopent-4-enamide (38)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 2-cyano-3-(4-chlorophenyl)propanamide (0.402 g, 1.93 mmol),
allyl bromide (0.242 g, 2.00 mmol), and K2CO3 (0.671 g, 4.85 mmol) were stirred
together for 14 hours. Upon dilution with DI H2O no precipitate formed. Extraction
method work up. The reaction yielded a white crystalline solid (0.4514g, 94%). IR
(ATR): 3391, 3188, 3086, 2244, 1698, 1683, 1492, 919, 755 cm-1. 1H NMR (400 MHz,
Acetone-d6) δ 2.55 (dd, J = 13.5 Hz, 7.7 Hz, 1H), 2.76-2.83 (m, 1H), 3.05 (d, J = 13.5 Hz,
1H), 3.27 (d, J = 13.6, 1H), 5.19-5.29 (m, 2H), 5.80-5.90 (m, 1H), 6.91 (bs, 2H), 7.32-
63
7.37 (m, 4H).
13
C NMR (100 MHz, Acetone-d6) δ 41.8, 42.0, 52.0, 120.4, 120.7, 129.2,
132.5, 132.8, 133.8, 135.3, 168.8.
2-(4-bromobenzyl)-2-propargyllmalononitrile (39)
The general procedure for alkylation of monosubstituted methylene complexes was
followed to scale using 4-bromobenzylmalononitrile (0.1152 g, 0.49 mmol), propargyll
bromide (0.076 g, 0.51 mmol), and K 2CO3 (0.173 g, 1.25 mmol) were stirred together for
18 hours. Upon dilution with DI H2O no precipitate formed. Extraction method work up.
The reaction yielded a white crystalline solid (0.1193 g, 89%). M.P. 83-84 ˚C. IR (ATR):
3309, 2975, 2256, 1596, 1490, 1070, 838 cm-1. 1H NMR (400 MHz, Acetone-d6) δ 2.482.50 (m, 1H), 2.89 (d, J = 2.5, 2H), 3.32 (s, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5
Hz, 2H).
13
C NMR (75 MHz, Acetone-d6) δ 28.1, 39.9, 41.2, 76.4, 76.7, 115.5, 123.3,
132.8, 133.2, 133.3.
2-benzyl-2-((3-4-methylphenylisoxazolin-5-yl)methyl)malononitrile (40)
64
The general procedure for 1,3-dipolar cycloaddition was followed to scale using 2-allyl-2benzylmalononitrile (0.1050 g, 0.53 mmol), 4-methylbenzaldoxime (0.0726 g, 0.54
mmol), and NaOCl (3.79 g of 3% w/w aqueous solution, 1.53 mmol). The reaction
stirred for 16 hours before extracting with dichloromethane. The reaction yielded a white
crystalline solid (0.1533 g, 87%). M.P. 125.5-126.5 ˚C. IR (ATR) 3032, 2930, 2256,
1886, 1609 cm-1.
1
H NMR (300 MHz, CDCl3) δ 2.25 (dd, J = 14.3 Hz, 5.0 Hz, 1H), 2.39
(s, 3H), 2.49 (dd, J = 14.3 Hz, 7.7 Hz, 1H), 3.15 (dd, J = 16.6 Hz, 4.8 Hz, 1H), 3.31 (d, J
= 13.6 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 3.66 (dd, J = 16.7 Hz, 10.2, 1H), 5.07-5.17 (m,
1H), 7.21-7.30 (m, 5H), 7.40-7.41 (m, 3H), 7.56 (d, J = 8.0 Hz, 1H)
2-benzyl-2-((3-(4-methoxyphenyl)isoxazolin-5-yl)methyl)malononitrile (41)
The general procedure for 1,3-dipolar cycloaddition was followed to scale using 2-allyl-2benzylmalononitrile (0.1028 g, 0.52 mmol), 4-methoxybenzaldoxime (0.0795 g,
0.53mmol), and NaOCl (3.90 g of 3% w/w aqueous solution, 1.57 mmol). The reaction
stirred for 68 hours before extracting with dichloromethane. The reaction yielded a white
crystalline solid (0.1519 g, 84%). M.P. 174-175 ˚C. IR (ATR): 3060, 2936, 2251, 1607,
1513. 1H NMR (300 MHz, Acetone-d6) δ 2.55 (dd, J = 14.6 Hz, 4.7 Hz, 1H), 2.61 (dd, J =
14.6 Hz, 8.5 Hz, 1H), 3.30 (dd, J = 17.0 Hz, 7.4 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 3.57
(d, J = 13.7 Hz, 1H), 3.75 (dd, J = 16.7 Hz, 10.2, 1H), 3.85 (s, 3H), 7.01 (d, J = 9.1 Hz,
2H), 7.37-7.52 (m, 5H), 7.66 (d, J = 9.1 Hz, 2H).
13
C NMR (75 MHz, Acetone-d6) δ 38.2,
65
41.8, 42.2, 43.6, 55.8, 78.1, 115.0, 116.2, 122.9, 129.2, 129.3, 129.5, 131.5, 134.1,
157.1, 162.2.
2-(4-chlorobenzyl)-2-cyano-3-(3-4-methylphenylisoxazolin-5-yl)propanamide (42)
The general procedure for 1,3-dipolar cycloaddition was followed to scale using 2-allyl-2cyano-3-(4-chlorophenyl)propanamide (0.0593 g, 0.24 mmol), 4-methylbenzaldoxime
(0.0322 g, 0.24 mmol), and NaOCl (1.92 g of 3% w/w aqueous solution, 0.77 mmol).
The reaction stirred for 22 hours before extracting with dichloromethane. The reaction
yielded a white crystalline solid (0.0756 g, 83%). IR (ATR): 3427, 3320, 3184, 2243,
1671, 1493, 917, 814.
1
H NMR (300 MHz, Acetone-d6) δ 2.20 (dd, J = 14.0 Hz, 5.5 Hz,
1H), 2.36 (s, 3H), 2.59 (dd, J = 14.3 Hz, 8.0 Hz, 1H), 3.10-3.26 (m, 2H), 3.33 (d, J = 13.4
Hz, 1H), 3.59-3.69 (m, 1H), 6.92 (bs, 1H), 7.04 (bs, 1H), 7.26 (d, J = 7.7 Hz, 2H), 7.377.39 (m, 4H), 7.58 (d, J = 8.0 Hz, 2H).
2-(4-chlorobenzyl)-2-cyano-3-(3-phenylisoxazolin-5-yl)propanamide (43)
66
The general procedure for 1,3-dipolar cycloaddition was followed to scale using 2-allyl-2cyano-3-(4-chlorophenyl)propanamide (0.0630 g, 0.25 mmol), benzaldoxime (0.0353 g,
0.29 mmol), and NaOCl (2.15 g of 3% w/w aqueous solution, 0.86 mmol). The reaction
stirred for 24 hours before extracting with dichloromethane. The reaction yielded a white
crystalline solid (0.0775 g, 83%). M.P. 177-178 ˚C (dec). IR (ATR): 3421, 3312, 3192,
2928, 2244, 1669, 1359, 918 cm-1. 1H NMR (300 MHz, Acetone-d6) δ 2.21 (dd, J = 14.3
Hz, 5.5 Hz, 1H), 2.33 (dd, J = 14.3 Hz, 7.7 Hz, 1H), 2.38 (dd, J = 14.3 Hz, 5.2 Hz, 1H),
3.11-3.36 (m, 3H), 3.63-3.72 (m, 1H), 4.89-5.00 (m, 1H), 6.93 (bs, 1H), 7.05 (bs, 1H),
7.33-7.46 (m, 7H), 7.69-7.71(m, 2H).
2-(4-chlorobenzyl)-2-cyano-3-(3-(4-methoxyphenyl)isoxazolin-5-yl)propanamide
(44)
The general procedure for 1,3-dipolar cycloaddition was followed to scale using 2-allyl-2cyano-3-(4-chlorophenyl)propanamide (0.0965 g, 0.39 mmol), 4-methoxybenzaldoxime
(0.0600 g, 0.39 mmol), and NaOCl (3.41 g of 3% w/w aqueous solution, 1.37 mmol).
The reaction stirred for 3 hours before extracting with dichloromethane. The reaction
yielded a white crystalline solid (0.1437 g, 97%). M.P. 181-182 ˚C. IR (ATR): 3402,
3314, 3187, 2919, 2247, 1707, 1672, 1251, 1013, 836 cm -1.
1
H NMR (400 MHz,
Acetone-d6) δ 2.16-2.21 (m, 1H), 2.30 (dd, J = 14.6 Hz, 7.7 Hz, 1H), 2.36 (dd, J = 14.3
67
Hz, 5.1 Hz, 1H), 2.58 (dd, J = 14.3 Hz, 7.7 Hz, 1H), 3.11-3.23 (m, 2H), 3.33(d, J = 13.2
Hz, 1H), 3.58-3.67 (m, 1H), 3.84 (s, 3H), 4.84-4.92 (m, 1H), 6.90 (bs, 1H), 6.99 (d, J =
8.8 Hz, 2H), 7.04 (bs, 1H), 7.34-7.39 (m, 4H), 7.63 (d, J = 9.2, 2H).
2-(4-bromobenzyl)2-((3-phenylisoxazol-5-yl)methylmalononitrile (45)
The general procedure for 1,3-dipolar cycloaddition was followed to scale using 2-(4bromobenzyl)-2-propargyllmalononitrile (0.129 g, 0.47 mmol), 4-methoxybenzaldoxime
(0.0719 g, 0.48 mmol), and NaOCl (3.51 g of 3% w/w aqueous solution, 1.41 mmol).
The reaction stirred for 65 hours before extracting with dichloromethane. The reaction
yielded a white crystalline solid (0.1933 g recovered, 99% recovery,10% Conversion by
1
H NMR). M.P. 135-136. IR (ATR): 2992, 2256, 1926, 1607, 1490, 1432, 1072, 803. 1H
NMR (300 MHz, Acetone-d6) δ 2.39 (s, 3H), 3.64 (s, 2H), 3.91 (s, 2H), 7.03 (s, 1H), 7.33
(d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.65 (dd, J = 8.3 Hz, 1.1 Hz, 2H), 7.80 (d, J
= 8.3 Hz, 2H).
13
C NMR (75 MHz, Acetone-d6) δ 21.3, 34.4, 42.0, 103.8, 115.4, 123.3,
126.8, 127.5, 132.8, 133.2, 133.4, 141.3, 163.4, 166.5.
68
3.7 References
1 Jaeger, V.; Colinas, P. A. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W.H., Eds.;
Chemistry of Heterocyclic Compounds; Wiley: Hoboken, 2002; Vol. 59, pp 361-472.
2 Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry Part A: Structure and
Mechanism. 4th ed., 2004, Springer Science + Business Media, LLC.
3 https://pd2.lilly.com/pd2Web/
4 Liu, Y.; Ciu, Z.; Liu, B.; Cai, B.; Li, Y.; Wang, Q. J. Agri. Food Chem. 2010, 58, 26852689.
5 Hatta, R.; Kawano, M.; Maeda, H.; Tsuge, O. J. Heterocyclic Chem. 1997, 34, 579583.
6 Otaka, K.; Suziki, M.; Oohira, D. PCT Int. Appl. WO 02/089579 A1, 2002.
7 Shim, J.; Park, J. C.; Cho, C. S.; Shim, S. C.; Yamamoto, Y. Chem. Comm. 2002,
852-853.
8 Moser, M. D.; Norman, A. L.; Shurrush, K. A. Tet. Let., 2009, 50, 5647-5648.
Apendix
O
O
N
8
O
NH2
70
O
O
O
N
8
O
NH2
71
O
O
O
N
8
O
NH2
72
O
73
74
75
76
77
O
OH
N
17
N
78
O
OH
N
17
N
79
O
OH
N
NH2
19
O
80
O
OH
N
NH2
19
O
81
O
OH
N
NH2
19
O
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130