1. 1
ABSTRACT
Title of Document: A CATALYTIC METHOD FOR THE
SYNTHESIS OF α-CARBONYLIMINES: NOVEL
ROUTES TO BIOLOGICALLY ACTIVE
MOLECULES
Michael D. Mandler, Bachelor of Science, 2015
Directed By: Professor Michael P. Doyle, Department of
Chemistry and Biochemistry
A dirhodium tetraacetate-catalyzed reaction between α-diazocarbonyl compounds and
organic azides produces imines after overnight reaction times and mild conditions. Imines
containing polar functional groups, such as ketones and α-diesters can be easily
synthesized via this method. Moreover, an unprecedented zinc triflate-catalyzed [4+2]
cycloaddition between an azadiene and aldimines yielded functionalized 1,2,3,4-
tetrahydropyrimidines in good yields. A rhodium-catalyzed Wolff rearrangement of a
phenyldiazoacetoacetate enone followed by a [2+2] cycloaddition yielded novel β-
lactams in high yields and high diastereoselectivities. This methodology, extended to a
one-pot, multicomponent reaction, was developed to convert azide and diazo precursors
directly to β-lactams in almost quantitative yields.
2. 2
A General Method for the Synthesis of α-Carbonylimines: Novel Routes to Biologically
Active Molecules
By
Michael D. Mandler
Thesis submitted to the Department of Chemistry and Biochemistry of the
University of Maryland, College Park, in partial fulfillment
of the requirements for the degree of
Bachelor of Science with Honors
2015
4. 4
ACKNOWLEDGMENTS
First and foremost, I would like to thank my advisor, Professor Michael P. Doyle
for warmly welcoming me into his laboratory after my freshman year at Maryland and
providing me with expert guidance and scholarship. As the chair of the Department of
Chemistry and Biochemistry, Dr. Doyle was very busy with responsibilities, but he
always made time to help us. I will never forget the generous support he provided to his
undergraduates. He is a guru of undergraduate research. The experiences that I acquired
in his lab have strengthened my desire to pursue a Ph.D. in organic chemistry.
I am truly indebted to Dr. Phong M. Truong for taking me under his wing and
teaching me how to work in an organic chemistry laboratory. Phong showed me how to
set up reactions, perform column chromatography (the old-fashioned way), and maximize
my efficiency in the lab. He was always there for me when I needed help creating posters,
reviewing scholarship proposals, performing research, and writing papers.
I am also grateful to Dr. Charles Shanahan, Prof. Dr. Xinfang Xu, Dr. Xichen Xu,
Dr. Maxim Ratnikov, Dr. Dmitry Shabashov, Dr. Xiaochen Wang, Quentin Abrahams,
John Leszczynski, Savannah Mason, Fernando Gama, Huang Qiu, Yifan (Evan) Deng,
Dr. Yongming Deng, Dr. Qiang Sha, Ruby Liu, Prof. Dr. G. Satyanarayana, and Dr. Yu
Qian for being my friends in the laboratory and for teaching me a great deal of synthetic
organic chemistry throughout the years. I wish to thank all of my friends, especially
Steven Klupt, Siddarth Plakkot, Louis Born, and Nate Schreiber. A special thanks goes to
Dr. Darón Freedberg for his support of me inside the lab and out. I thank the members of
my thesis committee Professor Philip DeShong, Dr. Montague-Smith, and David Watts.
Thank you Hannah Lebovics for sticking with me through all my work.
5. 5
TABLE OF CONTENTS
List of Abbreviations ........................................................................................................ 6
Chapter 1: Catalytic Reaction Between Azide and Diazo Compounds: A Portal to
Novel Imines ...................................................................................................................... 7
1.1
Introduction: The Metal-Catalyzed Imine Forming Reaction........................................7
1.2 Overview of Metal Carbenes Derived from Diazo Compounds........................................9
1.3 Azide Trapping of Carbenes ............................................................................................10
1.4 Synthesis of Diazo Compounds.......................................................................................12
1.5 Synthesis of Alkyl and Aryl Azides.................................................................................14
1.6 Reaction and Optimization ..............................................................................................15
1.7 Hydrolysis of Methyl 2-(Benzylimino)-3-oxobutanoate .................................................16
1.8 Aryl Azides Yield More Stable N-Aryl Imines ...............................................................18
1.9 Optimization ....................................................................................................................19
1.10 Donor/Acceptor Carbene Precursors Improve Yield.....................................................20
1.11 The Stereochemistry of Imine Products.........................................................................22
1.12 Substrate Scope..............................................................................................................22
1.13 Experimental..................................................................................................................23
Chapter 2: Synthesis of 1,2,3,4-Tetrahydropyrimidines from Novel [4+2]
Cycloadditions Between an Azadiene and Aldimines.................................................. 33
2.1 Background......................................................................................................................33
2.2 Substrate Scope................................................................................................................34
2.3 Experimental....................................................................................................................35
Chapter 3: Synthesis of β-Lactams by [2+2] Cycloadditions between Ketene and
Imines............................................................................................................................... 43
3.1 Background......................................................................................................................43
3.2 Metal-Catalyzed Wolff Rearrangement...........................................................................43
3.3 Staudinger Synthesis........................................................................................................44
3.4 Structural Assignment of β-Lactams 23 ..........................................................................45
3.5 Substrate Scope................................................................................................................46
3.6 One-Pot Synthesis of β-Lactams......................................................................................47
3.7 Experimental....................................................................................................................49
Chapter 4: NMR Spectra ............................................................................................... 67
References........................................................................................................................ 93
6. 6
List of Abbreviations
Ar aryl
Ac acetyl
Bn benzyl
CDCl3 chloroform-d
Cu(OTf)2 copper(II) triflate
CuPF6 copper(I) hexafluorophosphate
DCE 1,2-dichloroethane
DCM dichloromethane
DMSO dimethyl sulfoxide
dr diastereomeric ratio
ESI electrospray ionization
EtOAc ethyl acetate
equiv equivalents
h hours
HRMS high resolution mass spectrometry
IR infrared spectroscopy
L ligand
Me methyl
MeCN acetonitrile
Mp melting point
m/z mass to charge ratio
NMR nuclear magnetic resonance spectroscopy
NR no reaction
nOe Nuclear Overhauser Effect
OAc acetate
p-ABSA para-acetamidobenzenesulfonyl azide
Ph phenyl
PMP para-methoxyphenyl
Rf retention factor
Rh2(OAc)4 dirhodium(II) tetraacetate
Rh2(cap)4 dirhodium(II) tetracaprolactamate
Rh2(oct)4 dirhodium(II) tetraoctanoate
Rh2(acam)4 dirhodium(II) tetraacetamidate
rt room temperature
TBS t-butyldimethylsilyl
TLC thin-layer chromatography
7. 7
Chapter 1: Catalytic Reaction Between Azide and Diazo Compounds: A
Portal to Novel Imines
1.1 Introduction: The Metal-Catalyzed Imine Forming Reaction
Modern organic chemistry research is focused on the development of novel and
efficient methods for the synthesis of complex molecules. In particular, medicinally
active compounds are important targets because they directly benefit human health. Many
of these products contain complex heterocyclic scaffolds that cannot be easily
synthesized due to the lack of conventional C–C and C–heteroatom bond-forming
methodologies. The latter half of the 20th
century marked the advent of powerful
transition metal complexes that could catalyze the formation of complex C–C and C–
heteroatom bonds under mild conditions. Among these catalysts, dirhodium complexes
(Rh2L4) have been immensely successful. Dirhodium catalysts exist in the +2 oxidation
state with a rhodium-rhodium single bond and four bridging bidentate ligands, arranged
in a paddlewheel structure (Figure 1).1
Figure 1. Examples of dirhodium catalysts
Imines are fundamental building blocks for the construction of nitrogen
containing heterocycles.2-4
Due to the polarity of the carbon-nitrogen double bond, imines
are susceptible to nucleophilic addition reactions on the electrophilic imine carbon (e.g.
the Mannich reaction5
, aza-Baylis-Hillman reaction6
, reductions with hydride sources,
and metal-mediated alkylation reactions). On the other hand, imines are also nucleophilic
8. 8
at the nitrogen atom, allowing for reactions such as the Staudinger synthesis ([2+2]
cycloaddition between ketenes and imines) which has been a major route for the
preparation of β-lactams for over a century.7,8
Imines are versatile intermediates for the
synthesis of biologically relevant molecules, particularly alkaloids. Hence, the installation
of imine functional groups, especially in molecules containing complex functionalities, is
a topic of high importance to chemists.
The conventional synthesis of imines involves the condensation of a primary
amine with a carbonyl compound such as an aldehyde or ketone (Scheme 1). The water
formed is often removed by distillation using a Dean-Stark apparatus or by running the
reaction in a solvent containing anhydrous MgSO4 or another suitable drying agent.
Scheme 1. Conventional condensation route to imines
While the condensation methodology is the method of choice for making simple imines,
it is not compatible for producing complex imines; for example, those containing
condensable carbonyl groups such as 1 (Scheme 2). Though the central carbonyl group in
the vicinal tricarbonyl system 2 is the most susceptible to attack by the primary amine 3,
the condensation reaction would be expected to yield multiple products. Hence, another
chemical route is necessary for the efficient synthesis of 1.
Scheme 2. Imine formation complicated by multiple carbonyl groups
9. 9
The major work described in this thesis is focused on a catalytic synthesis of α-
iminoesters. Several novel imines have been prepared by this method, which were
applied in further reactions to form novel heterocyclic compounds, 1,2,3,4-
tetrahydropyrimidines and β-lactams. We highlight novel synthetic routes to imines that
can lead to new, interesting, and potentially biologically active heterocyclic compounds.
1.2 Overview of Metal Carbenes Derived from Diazo Compounds
Novel methods that facilitate the construction of heterocyclic molecular scaffolds
are in high demand by chemists wishing to ameliorate the synthesis of biologically active
molecules. Metal-stabilized carbenes 5 derived from diazo compounds 4 (Figure 2) are
versatile intermediates for a wide variety of complex synthetic transformations,1,9-11
including cyclopropanation,12-14
C–H and C–X insertions,15-17
ylide formation,18-20
among
many others.
Figure 2. Formation of metallocarbene 5 from α-diazocarbonyl precursor 4
Organic azides have been known to form complexes with various transition
metals, such as tantalum,21,22
vanadium,23
iridium,24
zirconium,24
palladium,25
copper,26
and silver,26
to form metal-organo azide complexes.27
Bergman studied the character of
transition metal-imido complexes formed from reactions between metals and organic
azides. Some metals, such as tungsten28
and tantalum,21,22
form these complexes after loss
10. 10
of dinitrogen from the organic azide. However, relatively little is known about the
behavior of organic azides with free and transition metal carbenes.
1.3 Azide Trapping of Carbenes
The trapping of a carbene with an azide was first reported by Szönyi and Cambon
in 1992. Under solid-liquid phase-transfer conditions, dichlorocarbene 7 reacted with
azide 6 to form an isocyanide dihalide product 10 (Scheme 3).
Scheme 3. Reaction between dichlorocarbene and alkyl azides
Four years later, the first RhII
catalyzed reaction between organic azides and diazo
compounds was published by Wee and Slobodian.29
During their investigation of
intramolecular C–H insertion reactions of diazoamides 11, Wee and Slobodian observed
an unexpected intramolecular trapping of the RhII
carbene by an azide (Scheme 4). The
result was imine 12.
Scheme 4. Wee and Slobodian’s unexpected imine product29
Despite this interesting side reaction, there were no further reports about this reaction in
the literature for 15 years––until 2011––when Lecourt and Micouin were experimenting
with the modification of 2-deoxystreptamine surrogates. They reported another
11. 11
intramolecular reaction between an azide functional group and rhodium(II) carbene
generated from 13 (Scheme 5).30
After screening various catalysts, they observed that the
less-electrophilic Rh2(cap)4 and Rh2(acam)4 provided 14 in higher yield (determined by
1
H NMR spectroscopy).
Scheme 5. Lecourt and Micouin’s intramolecular reaction30
The authors proposed a mechanism for this intramolecular transformation (Scheme 6).
First, a dirhodium metal carbene [13a] is generated, which then is attacked by the internal
nitrogen of the azide to form a six-membered ring [13b]. Lastly, a second molecule of
dinitrogen is lost from the azide group to form the endocyclic imine 14.
Scheme 6. Lecourt and Micouin’s proposed mechanism
12. 12
1.4 Synthesis of Diazo Compounds
The installation of the diazo functional group can be accomplished through
several routes.1
The Regitz diazo transfer procedure31
is a simple and effective method
for converting methylene groups to diazo groups using a sulfonyl azide reagent, such as
p-toluenesulfonyl azide (tosyl azide) or p-acetamidobenzenesulfonyl azide (p-ABSA). p-
ABSA is often the diazo transfer reagent of choice because of easier work-up conditions
and less shock sensitivity. It can be synthesized by a substitution reaction of p-
acetamidobenzenesulfonyl chloride and sodium azide32
(Scheme 7).
Scheme 7. Synthesis of p-ABSA
Once p-ABSA had been synthesized, it was used to make diazo compounds 16
using a slight modification of the procedure originally described by Davies et al, using
dichloromethane instead of acetonitrile as the solvent.32
(Scheme 8). In order to confirm
the formation of a diazo compound, a strong characteristic stretching frequency at around
2100 cm-1
could be detected by infrared spectroscopy.
Scheme 8. Synthesis of α-diazocarbonyl compounds 16
13. 13
Dichloromethane (DCM) was used instead of acetonitrile because DCM is easier
to remove during the purification process. However, when the diazo transfer reaction is
performed in DCM instead of MeCN, the reaction rate is slower. Thus, overnight reaction
times were needed. Diazoacetoacetates such as methyl 2-diazoacetoacetate 16a (R1
= Ac)
and dimethyl diazomalonate 16b were synthesized using triethylamine as the base.
Methyl phenyldiazoacetate 16c (R1
= Ph) was made in a similar fashion, except that the
phenylacetic acid ester was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a
stronger base than triethylamine, in order to deprotonate the less acidic α-methylene
protons (Scheme 9).
Scheme 9. Diazo transfer reactions of common α-diazocarbonyl compounds1
Silyl enol diazoacetate 16d was synthesized following a known procedure33
by
treating 16a with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and Et3N
(Scheme 10). The reaction was monitored by 1
H NMR spectroscopy, and then 16d was
purified by aqueous work-up (16d is not silica stable).
14. 14
Scheme 10. Enolization reaction and protection with –OTBS group
1.5 Synthesis of Alkyl and Aryl Azides
Organic azides were synthesized using well-established protocols. Azides are
generally safe if the sum of carbon atoms and oxygen atoms is greater than three times
the number (N) of nitrogen atoms: (NC + NO) ≥ 3NN, and the number of nitrogen atoms is
less than the number of carbon atoms.34
Though we never encountered an explosion
related to azides throughout this research project, we adhered to the motto that all azides
must be treated with care. Alkyl azides were synthesized by nucleophilic substitution
reactions of alkyl halide precursors with sodium azide.35
In this way, benzyl azide was
easily synthesized in 91% isolated yield following an aqueous work-up procedure
(Scheme 11).
Scheme 11. Synthesis of benzyl azide by SN2 reaction35
Aryl azides were synthesized by converting aniline precursors to diazonium salts,
followed by treatment with sodium azide.36
p-Anisyl azide was prepared from p-anisidine
in up to 91% isolated yield after column chromatography. Other aryl azides were
prepared with yields similar to literature values.
15. 15
Scheme 12. Synthesis of p-anisyl azide from diazonium salt
The transformation in Scheme 12 appears similar to that of Sandmeyer-type reactions;
however, no metal catalysts are necessary and the mechanism is thought to occur without
a free radical intermediate.37,38
Furthermore, the carbon–nitrogen bond of the diazonium
salt is not cleaved, but rather, the terminal nitrogen is attacked by the nucleophilic azide
ion.37
1.6 Reaction and Optimization
With methyl 2-diazoacetoacetate 16a and benzyl azide in hand, we attempted to
perform an intermolecular version of the imine forming reactions reported previously. If
successful, such a reaction would be interesting since it allows for the synthesis of α-
imino-β-ketoesters, which are not easy to synthesize by the condensation of a carbonyl
compound and amine.
16. 16
Scheme 13. Synthesis of methyl 2-(benzylimino)-3-oxobutanoate
After mixing 16a and benzyl azide together in the presence of 1 mol % Rh2(OAc)4 in
dichloromethane for two hours at room temperature, α-iminoester 17a was observed in
the reaction mixture by NMR spectroscopy (Scheme 13). No difference in the reaction
mixture was observed when the catalyst loading was increased to 2 mol %. A slight
excess of benzyl azide was used to better trap the metal carbene and to avoid other side-
reactions. The purification of imine 17a was attempted by flash column chromatography,
even though 17a appeared to be silica unstable according to TLC (significant streaking
was noted). An emerald-green oil was obtained, which was confirmed to be 17a, albeit in
low yield.
1.7 Hydrolysis of Methyl 2-(Benzylimino)-3-oxobutanoate
Imine 17a appeared to be unstable to acid-catalyzed hydrolysis; after leaving the
purified imine in an NMR tube for several days, its decomposition was monitored (Figure
3).
17. 17
Figure 3. Monitoring the decomposition of 17a by 1
H NMR. The bottom spectrum (red)
is the freshly purified imine. After a few days at room temperature, imine hydrolysis was
observed.
After careful inspection of the NMR spectra of 17a after a few days, a peak at 10.0 ppm
was observed. This was suggestive of the formation of benzaldehyde from
tautomerization of 17a to the benzylideneimine followed by hydrolysis. In CDCl3, the
aldehydic proton of benzaldehyde in CDCl3 appears at 10.0 ppm.39
Scheme 14. Tautomerization of 17a and hydrolysis
H3C OCH3
O O
N
Ph
18. 18
After repeating the purification several times with silica gel as the stationary
phase, irreproducible and low yields were obtained. Basic alumina, neutral alumina, and
Florisil®
(U.S. Silica, Frederick, MD) were used as stationary phases and offered no
improvements in yield. Bulb to bulb distillation of 17a using a Kugelrohr apparatus led to
total decomposition of the imine. After several months of disappointing results with
several purification methods, the best result was 53% isolated yield after purification with
silica gel flash column chromatography (see experimental section). While the yield was
moderate, 17a had never before been synthesized; it was a new compound (according to a
SciFinder search). Fortunately, other diazo and azide compounds provided imines in
much greater yields.
1.8 Aryl Azides Yield More Stable N-Aryl Imines
In order to eliminate the tautomerization-hydrolysis problem, we tested aryl
azides, such as p-anisyl azide 6a. Our hypothesis was that the same process could form
the imine product; however, tautomerization would be impossible due to the N–C(sp2
)
bond. To our initial disappointment, we observed no reaction between 16a and 6a when
the reaction was performed with 2 mol % Rh2(OAc)4 at room temperature. However,
when the temperature was raised to 40 °C (near-refluxing DCM), a reaction occurred to
yield silica stable 17b! Under optimized conditions (see experimental section), imine 17b
was obtained in 68% isolated yield (Scheme 15).
19. 19
Scheme 15. Optimized synthesis of 17b
The nucleophilicity of the azide was observed to play a significant role in
determining the yield of imine product (Scheme 16). p-Anisyl azide 6a, containing the
resonance electron-donating methoxy group, reacted with 16a to form 17b in 68%
isolated yield. Phenyl azide 6b, the electron-neutral aryl azide, offered imine 17c in 50%
yield. Finally, p-nitrophenyl azide 6c provided imine 17d in 31% yield. Imine 17d,
though much more stable than 17a, was labile to significant hydrolysis after prolonged
exposure at room temperature in an NMR tube containing CDCl3 (which produces HCl
that can catalyze hydrolysis).
Scheme 16. Electronic substituent effects on imine yield
1.9 Optimization
The imine formation reaction was optimized using p-anisyl azide 6a in order to
achieve reproducible yields of 17b after purification by silica gel column
20. 20
chromatography. Equimolar amounts of 16a and 6a only yielded 59% of imine 17b with
1 mol % Rh2(OAc)4 at 40 °C in DCM (entry 1). When 1.2 equivalents of diazo
compound were used, the yield improved to 68%, which was the best yield obtained for
these substrates (entry 7). Adding 1.5 equivalents of diazo compound resulted in the same
yield for 17b (entry 8). Other metals such as CuPF6 and Cu(OTf)2 were found to trigger
diazo decomposition, but they did not catalyze the reaction with azide 6a; no product was
formed (entries 2,3). Neither the more hydrophobic Rh2(oct)4 nor the less Lewis acidic
Rh2(cap)4 were able to improve conversion (entries 4,5), and leftover azide was observed.
entry catalyst (mol %) temp (°C) solvent yield (%)
1 Rh2(OAc)4 (1) 40 DCM 59
2 CuPF6 (5) 40 DCM NR
3 Cu(OTf)2 (5) 40 DCM NR
4 Rh2(oct)4 (1) 40 DCM 43
5 Rh2(cap)4 (1) 80 DCE 22
6 Rh2(OAc)4 (1) 80 DCE 45
7 Rh2(OAc)4 (1) 40 DCM 68a
Table 1. Optimization of imine formation reaction; bold font indicates optimized
conditions40
1.10 Donor/Acceptor Carbene Precursors Improve Yield
Acceptor/acceptor carbenes possess two electron-withdrawing substituents
flanking each side of the carbene. Donor/acceptor carbenes possess an electron-donating
substituent and an electron-withdrawing substituent flanking the carbene.41,42
Diazoacetoacetates such as 16a lead to acceptor/acceptor carbenes after dinitrogen
21. 21
extrusion by a suitable metal catalyst. These intermediates are characterized by their high
reactivity and poor selectivity in carbene transformations. In contrast, donor/acceptor
carbenes have longer lifetimes and offer higher selectivities.43
The reaction between
methyl phenyldiazoacetate 16b and 6a, catalyzed by Rh2(OAc)4 under optimized
conditions yielded imine 17e in a remarkable 97% isolated yield as a mixture of
geometric isomers (92:8) (Scheme 17). The reaction was observed to work with only 0.1
mol % of Rh2(OAc)4. Furthermore, 17e was exceptionally stable and could also be
recrystallized.
Scheme 17. Phenyldiazoacetates provide higher yields of imine 17 than
diazoacetoacetates.
The same electronic trends were observed in reactions of aryldiazoacetates with aryl
azides, corroborating the mechanism that proposes nucleophilic attack by the azide
(Scheme 18).
Scheme 18. Similar electronic trends observed with phenyldiazoacetate substrates
22. 22
1.11 The Stereochemistry of Imine Products
1D selective nOe experiments were attempted to determine imine stereochemistry
of 17. However, no conclusive evidence was obtained from these experiments. However,
the Wenhao Hu group had prepared imine 17g previously via another method and
obtained a single-crystal X-ray structure.44
Their X-ray structure revealed that the
stereochemistry of the imine was Z, and because our NMR data for compound 17g were
identical with the literature report, we assigned the major products of the reaction as Z by
analogy. Most imines that were synthesized via this method yielded exclusively one
isomer after chromatography (see experimental section).
1.12 Substrate Scope
After achieving high yields with many other aryldiazoacetates, a full substrate
scope was constructed (Table 2). All aryldiazoacetates provided the corresponding imine
products in greater than 81% isolated yield (entries 5-12). Dimethyl diazomalonate 16b,
with R1
= COOMe, which is less electron-withdrawing than Ac, yielded imine 17m in
60% yield (entry 13). Imine 17n, which would be very difficult to synthesize via
traditional condensation methods, was produced in 65% yield (entry 14). Interestingly,
enoldiazoacetate 17o formed a metal carbene intermediate that reacted with the azide at
the carbene carbon instead of at the vinylogous position45,46
(entry 15).
23. 23
Entry R1
R2
17 yield (%)
1 Ac Bn 17a 53
2 Ac 4-MeOC6H4 17b 68
3 Ac Ph 17c 50
4 Ac 4-NO2C6H4 17d 31
5 Ph 4-MeOC6H4 17e 97
6 Ph Ph 17f 90
7 Ph 4-NO2C6H4 17g 81
8 4-MeOC6H4 17h 86
9 4-MeOC6H4 4-MeOC6H4 17i 90
10 4-ClC6H4 4-MeOC6H4 17j 95
11 4-NO2C6H4 4-MeOC6H4 17k 82
12 2-naphthyl 4-MeOC6H4 17l 96
13 COOMe 4-MeOC6H4 17m 60
14 4-MeOC6H4 17n 65
15 4-MeOC6H4 17o 40
Table 2. Imine formation reaction substrate scope. Reactions were performed under
optimized conditions (see Table 1). Yields are after isolation by column chromatography.
1.13 Experimental
General. Diazo compounds 16a-16o were prepared by diazo transfer reactions with p-
ABSA as the diazo transfer agent.1,32
Diazoacetoacetate 16k was prepared by a
Mukaiyama-Michael reaction, reported previously by our group.47
Aromatic azides were
prepared by diazotization of the corresponding anilines, followed by addition of sodium
azide.36
Benzyl azide was prepared by nucleophilic substitution of benzyl bromide with
sodium azide.35
Imines 17 were prepared by condensation reactions between p-anisidine
N
Boc
O
O
OTBS
24. 24
and the corresponding aldehydes. Dichloromethane (DCM) was distilled over calcium
hydride and stored over molecular sieves prior to use. Thin layer chromatography (TLC)
was carried out using EM Science silica gel 60 F254 plates; the developed plate was
analyzed by UV lamp (254 nm) and/or p-anisaldehyde (PAA) stain. Column
chromatography was performed with the Teledyne-Isco CombiFlash Rf200 system using
pre-packed silica gel column cartridges and hexanes/ethyl acetate as the solvent system.
1
H NMR and 13
C NMR spectra were recorded in CDCl3 on a Bruker Avance 400 MHz
spectrometer. Chemical shifts are reported in ppm with the residual CHCl3 signal as the
reference, and coupling constants (J) are given in hertz. The peak information is
described as: br = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, and comp = composite. The molar ratio of isolated imine geometric isomers
was determined by NMR spectroscopy. IR spectra were recorded on a Thermo Nicolet
Nexus 670 FTIR spectrometer. Uncorrected melting points were obtained from Electro
Thermo Mel-Temp DLX 104. High-resolution mass spectra (HRMS) were performed on
a JEOL AccuTOF-ESI mass spectrometer using CsI as the standard.
General Procedure for the Synthesis of Imines 17. To a flame-dried round bottom
flask equipped with a magnetic stirbar was added organic azide 6 (1.0 equiv, 7.1 mmol),
Rh2(OAc)4 (1.0 mol %, 0.071 mmol, 31 mg), and 30 mL of CH2Cl2. The flask was
capped with a rubber septum, and a N2 balloon was attached through a needle into the
septum while the mixture was stirred and heated to reflux. Then, a solution of diazo
compound 16 (1.2 equiv, 8.5 mmol) in 5 mL of CH2Cl2 was slowly added by injection
25. 25
via a syringe pump over the course of 1 h. The reaction mixture was allowed to stir for 24
h at reflux. After cooling, the solvent was removed in vacuo, and the residue was purified
by silica gel column chromatography to provide imines 17. The major imine isomer was
assigned the Z configuration by analogy to a known compound, 17g, whose
stereochemistry was verified by X-ray crystallography in the literature.44
Methyl 2-(Benzylimino)-3-oxobutanoate (17a). Reaction between
diazoacetoacetate 16a and benzyl azide followed by flash chromatographic purification
gave 17a as a single geometric isomer in 53% yield; 17a is not stable on TLC and was
found to decompose on the silica gel column, leaving behind a green streak. Green liquid;
TLC Rf = 0.55 (4:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 7.41 – 7.28 (comp,
5H), 4.74 (s, 2H), 3.92 (s, 3H), 2.46 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 197.0, 164.0,
159.5, 137.0, 128.7, 128.0, 127.6, 59.1, 52.4, 24.6; IR (neat) 1715, 1702 cm-1
; HRMS
(ESI) m/z calculated for C12H14NO3 [M+H]+
220.0974, found: 220.0981.
Methyl 2-(4-Methoxyphenyl)imino-3-oxobutanoate (17b). Reaction between
diazoacetoacetate 16a and p-anisyl azide 6a followed by chromatographic purification
gave 17b as a single geometric isomer in 68% isolated yield. Red liquid; TLC Rf = 0.35
26. 26
(4:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 9.0 Hz, 2H), 6.90 (d, J
= 9.0 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 197.1, 165.3,
159.7, 154.6, 139.6, 123.3, 114.5, 55.5, 52.4, 24.6; IR (neat) 1737, 1695 cm-1
; HRMS
(ESI) m/z calculated for C12H14NO4 [M+H]+
236.0923, found: 236.0941.
Methyl 3-Oxo-2-(phenylimino)butanoate (17c). Reaction between
diazoacetoacetate 16a and phenyl azide 6b followed by chromatographic purification
gave 17c as a single geometric isomer in 50% isolated yield. Yellow liquid; TLC Rf = 0.5
(4:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 7.41 – 7.35 (comp, 2H), 7.28 – 7.22
(m, 1H), 7.05 – 7.00 (comp, 2H), 3.69 (s, 3H), 2.57 (s, 3H); 13
C NMR (100 MHz, CDCl3)
δ 196.8, 164.1, 157.1, 147.2, 129.2, 127.3, 119.9, 52.3, 24.7; IR (neat) 1739, 1701 cm-1
;
HRMS (ESI) m/z calculated for C11H12NO3 [M+H]+
206.0817, found: 206.0819.
Methyl 2-(4-Nitrophenyl)imino-3-oxobutanoate (17d). Reaction between
diazoacetoacetate 16a and p-nitrophenyl azide 6c followed by chromatographic
purification gave 17d as one isomer in 31% yield. Orange solid; TLC Rf = 0.4 (4:1
hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0
Hz, 2H), 3.69 (s, 3H), 2.58 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 195.7, 162.5, 158.6,
27. 27
152.7, 146.0, 124.9, 119.6, 52.7, 24.7; IR (neat) 1733, 1702 cm-1
; HRMS (ESI) m/z
calculated for C11H11N2O5 [M+H]+
251.0668, found: 251.0668.
Methyl 2-(4-Methoxyphenyl)imino-2-phenylacetate (17e). Reaction between
phenyldiazoacetate 16c and p-anisyl azide 6a followed by chromatographic purification
gave 17e as a mixture of geometric isomers (92:8 as measured by 1
H NMR spectrum) in
97% overall yield. 1
H and 13
C NMR spectral data is in accordance with the literature;48
however, we report a different coupling constant for the protons in the p-methoxyphenyl
group. Recrystallization in dichloromethane/hexanes gave yellow needles, mp = 89-91
°C; TLC Rf = 0.5 (4:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) major isomer δ
7.89 – 7.81 (comp, 2H), 7.56 – 7.42 (comp, 3H), 6.97 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0
Hz, 2H), 3.81 (s, 3H), 3.70 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 166.1, 159.1, 157.3,
143.1, 134.1, 131.5, 128.7, 127.8, 121.2, 114.2, 55.4, 52.0; IR (neat) 1735, 1617 cm-1
;
HRMS (ESI) m/z calculated for C16H16NO3 [M+H]+
270.1130, found: 270.1133.
Methyl 2-Phenyl-2-(phenylimino)acetate (17f). Reaction between
phenyldiazoacetate 16c and phenyl azide 6b followed by chromatographic purification
gave 17f as a single geometric isomer in 90% isolated yield. Pale yellow solid, mp = 42-
28. 28
44 °C; TLC Rf = 0.3 (6:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 7.92 – 7.84
(comp, 2H), 7.57 – 7.44 (comp, 3H), 7.38 – 7.31 (comp, 2H), 7.20 – 7.11 (m, 1H), 7.00 –
6.94 (comp, 2H), 3.64 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 165.4, 159.9, 150.0, 133.8,
131.8, 128.9, 128.7, 128.0, 125.0, 119.5, 51.9. IR (neat) 1730, 1622 cm-1
; HRMS (ESI)
m/z calculated for C15H14NO2 [M+H]+
240.1025, found: 240.1033.
Methyl 2-(4-Nitrophenyl)imino-2-phenylacetate (17g). Reaction between
phenyldiazoacetate 16c and p-nitrophenyl azide 6c followed by chromatographic
purification gave 17g as a single geometric isomer in 81% isolated yield. Pale yellow
solid, mp = 85-88 °C; TLC Rf = 0.4 (4:1 hexanes/EtOAc); 1
H and 13
C NMR spectral data
is in accordance with the literature;44
HRMS (ESI) m/z calculated for C15H13N2O4
[M+H]+
285.0875, found: 285.0865.
tert-Butyl 3-(2-Methoxy-1-(4-methoxyphenyl)imino-2-oxoethyl)-1H-indole-1-
carboxylate (17h). Reaction between 3-(N-Boc-indole)diazoacetate 16e and p-anisyl
azide 6a followed by chromatographic purification gave 17h as a single geometric isomer
in 86% isolated yield. Yellow solid, mp = 98-100 °C; TLC Rf = 0.4 (4:1
29. 29
hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 8.59 – 8.51 (m, 1H), 8.20 – 8.13 (m,
1H), 7.96 (s, 1H), 7.43 – 7.32 (comp, 2H), 6.99 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz,
2H), 3.82 (s, 3H), 3.68 (s, 3H), 1.70 (s, 9H). 13
C NMR (100 MHz, CDCl3) δ 165.4, 157.2,
154.1, 149.2, 143.6, 135.9, 130.5, 127.4, 125.6, 124.0, 123.2, 121.2, 116.7, 115.0, 114.2,
85.0, 55.4, 52.0, 28.1; IR (neat) 1742, 1732, 1607 cm-1
; HRMS (ESI) m/z calculated for
C23H25N2O5 [M+H]+
409.1763, found: 409.1758.
Methyl 2-(4-Methoxyphenyl)-2-[(4-methoxyphenyl)imino]acetate (17i).
Reaction between 4-methoxyphenyldiazoacetate 16f and p-anisyl azide 6a followed by
chromatographic purification gave 17i as a single geometric isomer in 90% isolated yield.
Yellow solid, mp = 93-94 °C; TLC Rf = 0.3 (4:1 hexanes/EtOAc); 1
H and 13
C NMR
spectral data is in accordance with the literature;48
IR (neat) 1729, 1605 cm-1
; HRMS
(ESI) m/z calculated for C17H18NO4 [M+H]+
300.1236, found: 300.1228.
Methyl 2-(4-chlorophenyl)-2-[(4-methoxyphenyl)imino]acetate (17j). Reaction
between 4-chlorophenyldiazoacetate 16g and p-anisyl azide 6a followed by
chromatographic purification gave 17j as a mixture of geometric isomers (93:7) in 95%
31. 31
Methyl 2-(4-Methoxyphenyl)imino-2-(2-naphthyl)acetate (17l). Reaction
between 2-napthyldiazoacetate compound 16i and p-anisyl azide 6a followed by
chromatographic purification gave 17l as a mixture of geometric isomers (94:6) in 96%
overall yield. Yellow solid, mp = 78-81 °C; TLC Rf = 0.4 (4:1 hexanes/EtOAc); 1
H and
13
C NMR spectral data are in accordance with the literature;48
IR (neat) 1734, 1609 cm-1
;
HRMS (ESI) m/z calculated for C20H18NO3 [M+H]+
320.1287, found: 320.1282.
Dimethyl 2-(4-Methoxyphenyl)iminomalonate (17m). Reaction between
diazomalonate ester 16b and p-anisyl azide 6a followed by chromatographic purification
gave 17m in 60% yield. Red oil; TLC Rf = 0.45 (2:1 hexanes/EtOAc); 1
H NMR (400
MHz, CDCl3) δ 7.09 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 3.97 (s, 3H), 3.82 (s,
3H), 3.77 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 163.9, 161.8, 159.5, 148.9, 139.8,
122.8, 114.4, 55.4, 53.5, 52.6; IR (neat) 1739, 1723 cm-1
; HRMS (ESI) m/z calculated for
C12H14NO5 [M+H]+
252.0872, found: 252.0884.
Methyl 2-(4-Methoxyphenyl)imino-3-oxo-4-(3-oxocyclohexyl)butanoate
(17n). Diazoacetoacetate compound 16j was synthesized following a known protocol.47
32. 32
The reaction of 16j with p-anisyl azide 6a followed by chromatographic purification gave
17n as a single geometric isomer in 65% yield. Dark red liquid; TLC Rf = 0.35 (2:1
hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0
Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.02 (qd, J = 16.6, 6.6 Hz, 2H), 2.54 – 2.35 (comp,
3H), 2.34 – 2.21 (m, 1H), 2.21 – 2.11 (m, 1H), 2.11 – 1.93 (comp, 2H), 1.79 – 1.65 (m,
1H), 1.52 – 1.40 (m, 1H); 13
C NMR (100 MHz, CDCl3) δ 210.5, 197.5, 165.1, 159.9,
154.2, 139.3, 123.5, 114.5, 55.5, 52.4, 47.6, 42.7, 41.2, 34.7, 31.0, 24.9; IR (neat) 1735,
1705, 1502 cm-1
; HRMS (ESI) m/z calculated for C18H22NO5 [M+H]+
332.1498, found:
332.1473.
Methyl 3-(tert-Butyldimethylsilyl)oxy-2-[(4-methoxyphenyl)imino]but-3-
enoate (17o). Reaction between silyl enol diazoacetate 16d and p-anisyl azide 6a
followed by chromatographic purification gave 17o as a single geometric isomer in 40%
yield. Yellow solid; TLC Rf = 0.35 (10:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3)
δ 6.89 (d, J = 9.1 Hz, 2H), 6.84 (d, J = 9.1 Hz, 2H), 5.09 (d, J = 1.9 Hz, 1H), 4.90 (d, J =
1.9 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 0.95 (s, 9H), 0.23 (s, 6H); 13
C NMR (100 MHz,
CDCl3) δ 165.5, 157.5, 157.2, 152.3, 142.2, 121.2, 114.1, 101.5, 55.4, 51.9, 25.6, 18.3, -
4.7; IR (neat) 1735, 1609, 1502 cm-1
; HRMS (ESI) m/z calculated for C18H28NO4Si
[M+H]+
350.1788, found: 350.1778.
33. 33
Chapter 2: Synthesis of 1,2,3,4-Tetrahydropyrimidines from Novel
[4+2] Cycloadditions Between an Azadiene and Aldimines
2.1 Background
In the course of preparing several α-iminoesters, we attempted to synthesize
azadiene 17o from silyl enoldiazoacetate 1b (Scheme 19). We envisioned that azadiene
17o could participate in hetero-Diels-Alder reactions with dienophiles. Though the
reaction was successful, azadiene 17o was isolated in only 40% yield.
Scheme 19. Metal-catalyzed synthesis of azadiene 17o from 16d
An alternative synthesis of this compound was accomplished by treating imine 17b with
TBSOTf and EtN3 (Scheme 20). No column chromatography was necessary for this step.
Scheme 20. Alternative synthesis of azadiene 17o from 17b
Now, with an efficient route for the large-scale synthesis of azadiene 17o, we
were delighted to discover a [4+2] cycloaddition reaction between 17o and aldimines 18
to yield highly functionalized 1,2,3,4-tetrahydropyrimidines 19 (Scheme 21). To our
34. 34
knowledge, this Lewis acid catalyzed [4+2] cycloaddition reaction is the first example of
the aza-Diels-Alder reaction49,50
with imines taking the role of both the diene and
dienophile.
2.2 Substrate Scope
Under optimized conditions (see experimental section), the scope of this Lewis
acid-catalyzed [4+2] reaction was examined.
entry Ar 19 yield (%)
1 C6H5 19a 91
2 4-BrC6H5 19b 88
3 4-NO2C6H5 19c 90
4 2-naphthyl 19d 82
5 4-MeC6H5 19e 82
6 2-ClC6H4 19f 75
7 4-MeOC6H4 19g 72
Table 3. Synthesis of 1,2,3,4-tetrahydropyrimidines from novel [4+2] reaction
Hence, this methodology allows for the synthesis of novel functionalized
pyrimidine derivatives, which could be biologically active. Tetrahydropyrimidines are a
class of molecules that exhibit known antimicrobial51
and anti-inflammatory52
properties.
While compounds 19 could be derivatized and investigated for potential bioactivity, we
hope that other research groups will discover the potential of the metal-catalyzed [4+2]
cycloaddition between two imines and produce similar molecules with diverse
35. 35
functionalization patterns. Compounds 19 possess a single stereogenic center; however,
the above synthesis led to a racemic mixture of 19. An asymmetric synthesis of 19 is a
future direction for this reaction.
2.3 Experimental
General. Imines 18 were prepared by condensation reactions between p-anisidine and the
corresponding aldehydes. Dichloromethane (DCM) was distilled over calcium hydride
and stored over molecular sieves prior to use. Thin layer chromatography (TLC) was
carried out using EM Science silica gel 60 F254 plates; the developed plate was analyzed
by UV lamp (254 nm) and/or p-anisaldehyde (PAA) stain. Column chromatography was
performed with the Teledyne-Isco CombiFlash Rf200 system using pre-packed silica gel
column cartridges and hexanes/ethyl acetate as the solvent system. 1
H NMR and 13
C
NMR spectra were recorded in CDCl3 on a Bruker Avance 400 MHz spectrometer.
Chemical shifts are reported in ppm with the residual CHCl3 signal as the reference, and
coupling constants (J) are given in hertz. The peak information is described as: br = broad
singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and comp =
composite. The molar ratio of isolated imine geometric isomers was determined by NMR
spectroscopy. IR spectra were recorded on a Thermo Nicolet Nexus 670 FTIR
spectrometer. Uncorrected melting points were obtained from Electro Thermo Mel-Temp
DLX 104. High-resolution mass spectra (HRMS) were performed on a JEOL AccuTOF-
ESI mass spectrometer using CsI as the standard.
36. 36
Procedure for the Conversion of 17b to 17o. To a solution of 17b (1.2 g, 5.0
mmol, 1 equiv) in 25 mL of DCM at 0 °C under nitrogen was added Et3N (1.4 mL, 10
mmol, 2.0 equiv). Then TBSOTf (1.3 mL, 5.5 mmol, 1.1 equiv) was added via syringe
over 5 min and stirred at room temperature for an additional 8 h. The reaction mixture
was diluted with 100 mL of hexanes and then washed with 30 mL of saturated NaHCO3
three times. The organic layer was dried over anhydrous Na2SO4, filtered, and
evaporated. The yellow solid product 17o (1.64 g, 94% yield) was used without further
purification.
General Procedure for the Synthesis of 1,2,3,4-Tetrahydropyrimidines 19. To
a flame dried vial equipped with a magnetic stirbar was added 17o (0.20 mmol, 1.0
equiv), imine 18 (0.24 mmol, 1.2 equiv), and 1 mL of DCM under nitrogen atmosphere.
After stirring at 0 °C for ten minutes, Zn(OTf)2 (10 mol %) was added, and the reaction
mixture was stirred for an additional 36-48 h at 0 °C. The product was purified by
column chromatography (hexanes/ethyl acetate) to afford 1,2,3,4-tetrahydropyrimidines
19.
43. 43
Chapter 3: Synthesis of β-Lactams by [2+2] Cycloadditions between
Ketene and Imines
3.1 Background
During our investigation of the substrate scope of the RhII
-catalyzed conversion of
diazo compounds to imines, we noticed that diazoacetoacetate enone 16k failed to form
the corresponding imine product 21. TLC analysis of the reaction mixture was messy,
and a significant amount of 6a was present on the plate, indicating that 6a had failed to
react with 16k (Scheme 21). Furthermore, 1
H NMR of the reaction mixture revealed a
significant amount of p-anisyl azide left over, corroborating the same hypothesis.
Scheme 21. Diazoacetoacetate enone 16k fails to react with 6a to form imine 21
3.2 Metal-Catalyzed Wolff Rearrangement
While the failure of 16k was an initial disappointment for us, we quickly
discovered the problem. When ~10 mg compound 16k was dissolved in an NMR tube
containing CDCl3 and a few milligrams of Rh2(OAc)4, and the NMR tube was heated at
60 °C for 1 hour, bubbles evolved from the bottom of the tube. Immediately, we
performed TLC analysis on this solution and observed a large streak. However, after
taking a 1
H NMR of the unpurified mixture, we noticed only one major compound in
solution, which we identified to be ketene 22 (Scheme 22). The methoxy, vinyl, and
44. 44
phenyl protons of the ketene were clearly observed in the NMR spectrum, with little
impurities present and no 16k visible. Hence, a transition metal-catalyzed Wolff
rearrangement53-56
had occurred to generate ketene 22 in vitro.
Scheme 22. Diazoacetoacetate enone 16k undergoes Wolff Rearrangement
In order to verify our hypothesis that a true ketene was being formed within the
NMR tube, we added crystals of imine 17e to the NMR tube. Immediately afterwards, we
retook a 1
H NMR spectrum. The ketene 22 had completely disappeared and was replaced
by new signals. After purification of the mixture, β-lactam 23a was isolated and
characterized (Scheme 23).
Scheme 23. A [2+2] cycloaddition between ketene 22 and imine 17e formed a β-
lactam product with high diastereoselectivity
3.3 Staudinger Synthesis
We were impressed by the high diastereomeric ratio of compound 23a formed in
Scheme 23, which led us to develop an optimized method for the synthesis of the β-
45. 45
lactam from diazoacetoacetate enone 16k and imine 17e (Scheme 24). The optimal
stoichiometry was found to be 1.2 equivalents of 16k to 1.0 equivalents of imine 17e. 1
mol % Rh2(OAc)4 was found to be a sufficient catalyst loading to catalyze the
transformation in one hour at 40 °C in dichloromethane (Scheme 24).
Scheme 24. Catalytic synthesis of β-lactam 23a from diazoacetoacetate enone
16k and imine 17e. dr was measured by NMR analysis of vinyl protons in the unpurified
reaction mixture.
3.4 Structural Assignment of β-Lactams 23
We performed a 1D selective nOe experiment on β-lactam 23a and observed no
through-space correlations between the ester groups (Figure 4).
Figure 4. 1D selective nOe experiment to determine relative stereochemistry of
ester groups in 23a.
While these results suggested that the stereochemistry of β-lactam 23a might be
trans, they were negative results. We believed that if the ester groups were sufficiently
far away from each other in the cis stereoisomer, the nOe correlations may not be
46. 46
observed. We performed a single crystal X-ray analysis of the product in order to
eliminate these doubts (Figure 5). This experiment found that the ester groups in 23a
were positioned in trans.
Figure 5. X-ray crystal structure of 23a reveals trans stereochemistry
3.5 Substrate Scope
The scope of this transformation was examined by varying the groups on imine
17. Compound 23a was obtained in 97% isolated yield and > 20:1 dr with R1
= Ph and R2
= 4-MeOC6H4 (Entry 1). A similar yield (95%) and diastereoselectivity was observed for
R1
= Ph and R2
= 4-NO2C6H4 (Entry 2). The yield of the reaction dropped when R1
and R2
= 4-MeOC6H4 to 81%, but the diastereoselectivity remained the same (Entry 3). With R1
= 4-NO2C6H4, the yield was high, but the diastereoselectivity decreased to 15:1 (Entry 4).
An acetyl group as R1
provided product that had the lowest dr of 1.4:1, but the product
yield was excellent (Entry 5). Finally, a silyl enol ether as R1
provided greater than 20:1
diastereoselectivity (Entry 6), which may be the result of the bulky t-butyldimethylsilyl
group providing steric hindrance.
47. 47
entry R1
R2
23 yield (%)
dr
(anti:syn)
1 Ph 4-MeOC6H4 23a 97 > 20:1
2 Ph 4-NO2C6H5 23b 95 > 20:1
3 4-MeOC6H4 4-MeOC6H4 23c 81 > 20:1
4 4-NO2C6H5 4-MeOC6H4 23d 89 15:1
5 Ac 4-MeOC6H4 23f 93 1.4:1
6 4-MeOC6H4 23g 85 > 20:1
Table 4. Substrate scope for the formation of β-lactams 23
3.6 One-Pot Synthesis of β-Lactams
We were excited by the possibility of forming β-lactams directly from diazoester
and azide precursors. If this reaction could be accomplished (Scheme 25), it would
remove the step requiring purification of the intermediate imine 17.
Scheme 25. One pot synthesis of β-lactams from diazo and azide precursors
We combined 1.2 equivalents of phenyl diazoacetoacetate enone 16k, 1.2
equivalents of aryldiazoacetate 16, and 1.0 equivalents of azide 6a in a 4 dram vial
containing DCM and 1 mol % Rh2(OAc)4 (see experimental section for details). After 3
OTBS
48. 48
hours of stirring at either room temperature or 40 °C, the β-lactam products were cleanly
generated in near-quantitative yields (Table 5).
entry R 23 yield (%)
dr
(anti:syn)
1 H 23a 99 > 20:1
2 OCH3 23c 99 > 20:1
3 Cl 23g 99 > 20:1
Table 5. Substrate scope for the one-pot synthesis of β-lactams 23
To our knowledge, this reaction represents the first case of a mixture of two diazo
compounds being simultaneously added to a solution containing a dirhodium catalyst.
The catalytic reaction of diazo compounds 16 with azide 6a occurs before the Wolff
rearrangement to form intermediate imines 17 in a fast step. Then, ketene 22 is generated
in situ, which undergoes a [2+2] cycloaddition with 17 to form β-lactams 23. Hence, the
reagents react in a tightly orchestrated manner.
49. 49
3.7 Experimental
General. Diazoacetoacetate enone 16k was prepared by a Wittig olefination, followed by
diazo transfer, reported previously by our group.57
Dichloromethane (DCM) was distilled
over calcium hydride and stored over molecular sieves prior to use. Thin layer
chromatography (TLC) was carried out using EM Science silica gel 60 F254 plates; the
developed plate was analyzed by UV lamp (254 nm) and/or p-anisaldehyde (PAA) stain.
Column chromatography was performed with the Teledyne-Isco CombiFlash Rf200
system using pre-packed silica gel column cartridges and hexanes/ethyl acetate as the
solvent system. 1
H NMR and 13
C NMR spectra were recorded in CDCl3 on a Bruker
Avance 400 MHz spectrometer. Chemical shifts are reported in ppm with the residual
CHCl3 signal as the reference, and coupling constants (J) are given in hertz. The peak
information is described as: br = broad singlet, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, and comp = composite. The molar ratio of isolated imine
geometric isomers was determined by NMR spectroscopy. IR spectra were recorded on a
Thermo Nicolet Nexus 670 FTIR spectrometer. Uncorrected melting points were
obtained from Electro Thermo Mel-Temp DLX 104. High-resolution mass spectra
(HRMS) were performed on a JEOL AccuTOF-ESI mass spectrometer using CsI as the
standard.
50. 50
General Procedure for the Synthesis of β-Lactams 23. To a flame dried 4-dram
vial equipped with a magnetic stirbar was added phenyl diazoacetoacetate enone 16k
(0.43 mmol, 1.2 equiv), imine 17 (0.36 mmol, 1.0 equiv), and 2 mL of DCM. After
dissolution, Rh2(OAc)4 (1.0 mol %) was added and the solution was sealed with a septum
and N2 balloon. The reaction mixture was stirred for 1 h at 40 °C. Upon completion of the
reaction, the unpurified mixture was analyzed by 1
H NMR spectroscopy for
diastereoselectivity, and then chromatographed to afford β-lactams 23.
Dimethyl 1-(4-Methoxyphenyl)-4-oxo-2-phenyl-3-[(E)-styryl]azetidine-2,3-di-
carboxylate (23a). Reaction between phenyldiazoacetoacetate enone 16k and diaryl
imine 17e followed by chromatographic purification gave 23a in 97% yield, with > 20:1
dr. Recrystallized from DCM/hexanes as colorless crystals, mp = 170-174 °C; TLC Rf =
0.3 (4:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 7.75 – 7.68 (m, 2H), 7.47 – 7.38
(comp, 4H), 7.38 – 7.24 (comp, 6H), 6.97 (d, J = 16.4 Hz, 1H), 6.84 (d, J = 9.1 Hz, 2H),
6.56 (d, J = 16.4 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 3.18 (s, 3H); 13
C NMR (100 MHz,
CDCl3) δ 167.8, 166.3, 160.4, 156.3, 135.8, 135.1, 131.0, 130.6, 129.0, 128.7, 128.5,
128.2, 128.0, 126.8, 119.7, 119.0, 113.9, 76.3, 75.0, 55.4, 52.9, 52.3; IR (neat) 1764,
51. 51
1737, 1510 cm-1
; HRMS (ESI) m/z calculated for C28H26NO6 [M+H]+
472.1760, found:
472.1768.
Dimethyl 1-(4-Nitrophenyl)-4-oxo-2-phenyl-3-[(E)-styryl]azetidine-2,3-
dicarboxylate (23b). Reaction between phenyldiazoacetoacetate enone 16k and imine
17g followed by chromatographic purification gave 23b in 95% yield, with > 20:1 dr.
Recrystallized from DCM/hexanes as pale yellow solid, mp = 143-144 °C; TLC Rf = 0.3
(4:1 hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 9.4 Hz, 2H), 7.71 –
7.64 (comp, 2H), 7.60 (d, J = 9.4 Hz, 2H), 7.46 – 7.27 (comp, 8H), 6.93 (d, J = 16.4 Hz,
1H), 6.55 (d, J = 16.4 Hz, 1H), 3.66 (s, 3H), 3.21 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ
167.0, 165.6, 161.4, 143.8, 142.1, 135.4, 135.3, 129.9, 129.6, 128.8, 128.8, 128.5, 127.8,
126.9, 124.7, 118.6, 118.4, 75.8, 53.3, 52.5. IR (neat) 1776, 1740 cm-1
; HRMS (ESI) m/z
calculated for C27H23N2O7 [M+H]+
487.1505, found: 487.1518.
Dimethyl 1,2-bis(4-Methoxyphenyl)-4-oxo-3-[(E)-styryl]azetidine-2,3-
dicarboxylate (23c). Reaction between phenyldiazoacetoacetate enone 16k and diaryl
53. 53
Dimethyl (E)-2-Acetyl-1-(4-Methoxyphenyl)-4-oxo-3-styrylazetidine-2,3-di-
carboxylate (23e). Reaction between phenyldiazoacetoacetate enone 16k and imine 17b
followed by chromatographic purification gave 23e in 93% yield, with 1.38:1 dr. White
solid, mp not determined due to presence of both diastereomers; TLC Rf = 0.2 (3:1
hexanes/EtOAc); 1
H NMR (400 MHz, CDCl3) δ values for major isomer: 6.18 (d, J =
16.2 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 2.43 (s, 3H) (aromatic resonances
of both stereoisomers are obscured by overlap; vinyl resonance of major isomer obscured
by overlap with other aromatic signals); δ values for minor isomer: 6.95 (d, J = 16.3 Hz,
1H), 6.36 (d, J = 16.3 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.68 (s, 3H), 2.47 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ values for both stereoisomers: 198.9, 198.6, 167.3, 167.0,
166.8, 166.2, 159.9, 159.7, 157.0, 157.0, 137.9, 136.5, 135.3, 135.0, 130.1, 129.8, 129.1,
128.9, 128.7, 128.7, 127.0, 126.9, 120.5, 119.9, 118.0, 117.4, 114.2, 114.1, 78.4, 77.9,
74.2, 73.0, 55.5, 55.4, 53.5, 53.5, 53.4, 53.3, 29.4, 28.9; IR (neat) 1767, 1739, 1728, 1511
cm-1
; HRMS (ESI) m/z calculated for C24H24NO7 [M+H]+
438.1553, found: 438.1558.
Dimethyl 2-(1-(tert-Butyldimethylsilyl)oxyvinyl)-1-(4-Methoxyphenyl)-4-oxo-
3-[(E)-styryl]azetidine-2,3-dicarboxylate (23f). Reaction between
54. 54
phenyldiazoacetoacetate enone 16k and imine 17o followed by chromatographic
purification gave 23f in 85% yield, with >20:1 dr. Recrystallized from DCM/hexanes as
colorless crystals, mp = 145-150 °C; TLC Rf = 0.3 (4:1 hexanes/EtOAc); 1
H NMR (400
MHz, CDCl3) δ 7.54 (d, J = 9.1 Hz, 2H), 7.39 – 7.34 (m, 2H), 7.33 – 7.23 (m, 3H), 6.93
(d, J = 16.2 Hz, 1H), 6.83 (d, J = 9.1 Hz, 2H), 6.28 (d, J = 16.2 Hz, 1H), 4.93 (d, J = 3.1
Hz, 1H), 4.61 (d, J = 3.1 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.69 (s, 3H), 0.74 (s, 9H),
0.09 (s, 3H), -0.08 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 167.2, 166.4, 160.4, 156.3,
149.6, 135.6, 135.1, 131.0, 128.6, 128.5, 126.8, 120.5, 119.4, 113.7, 96.3, 75.7, 71.6,
55.5, 52.7, 52.7, 25.3, 17.9, -5.0, -5.7; IR (neat) 1764, 1739, 1509 cm-1
; HRMS (ESI) m/z
calculated for C30H38NO7Si [M+H]+
552.2418, found: 552.2405.
Procedure for the One-Pot, Multicomponent Synthesis of β-Lactams 23. To a
flame dried 4 dram vial equipped with a magnetic stirbar was added p-anisyl azide 6a
(54.0 mg, 0.362 mmol, 1.0 equiv), 1 mL of DCM, and Rh2(OAc)4 (1.8 mg, 1.0 mol %,
0.0036 mmol). The solution was then sealed with a septum and N2 balloon and stirred at
40 °C for 23a and 23c, or at room temperature for 23g. A mixture of 16(c,g, or f) (0.434
mmol, 1.2 equiv) and phenyl diazoacetoacetate enone 16k (100.0 mg, 0.434 mmol, 1.2
equiv) in 2 mL of DCM was injected into the vial over the course of 2 h. The reaction
mixture was stirred for an additional 1 h at the given temperature. Upon completion of
the reaction, the unpurified mixture was chromatographed to afford β-lactam 23.
56. 56
A colorless prism-like specimen of C28H25NO6, approximate dimensions 0.16 mm ×
0.20 mm × 0.47 mm, was used for the X-ray crystallographic analysis. The X-ray
intensity data were measured. Data collection temperature was 150 K. The total exposure
time was 12.63 hours. The frames were integrated with the Bruker SAINT software
package using a narrow-frame algorithm. The integration of the data using
a monoclinic unit cell yielded a total of 38583 reflections to a maximum θ angle
of 30.00° (0.71 Å resolution), of which 6952 were independent (average
redundancy 5.550, completeness = 100.0%, Rint = 2.15%) and 5952 (85.62%) were
greater than 2σ(F2). The final cell constants of a =
8.3217(7) Å, b = 14.4515(12) Å, c = 20.1226(17) Å, β
= 100.2680(13)°, V = 2381.2(3) Å3, are based upon the refinement of the XYZ-centroids
of 9954 reflections above 20 σ(I) with 4.974° < 2θ < 63.47°. The calculated minimum
and maximum transmission coefficients (based on crystal size) are 0.9150 and 0.9850.
The structure was solved and refined using the Bruker SHELXTL Software Package,
using the space group P21/c, with Z = 4 for the formula unit,C28H25NO6. The final
anisotropic full-matrix least-squares refinement on F2 with 425 variables converged at
R1 =3.99%, for the observed data and wR2 = 8.63% for all data. The goodness-of-fit
was 1.000. The largest peak in the final difference electron density synthesis was 0.342 e-
/Å3 and the largest hole was -0.175 e-/Å3 with an RMS deviation of0.039 e-/Å3. On the
basis of the final model, the calculated density was 1.315 g/cm3 and F(000), 992 e-.
APEX2 Version 2010.11-3 (Bruker AXS Inc.)
SAINT Version 7.68A (Bruker AXS Inc., 2009)
SADABS Version 2008/1 (G. M. Sheldrick, Bruker AXS Inc.)
XPREP Version 2008/2 (G. M. Sheldrick, Bruker AXS Inc.)
XS Version 2008/1 (G. M. Sheldrick, Acta Cryst. (2008). A64, 112-122)
XL Version 2012/4 (G. M. Sheldrick, (2012) University of Gottingen, Germany)
Platon (A. L. Spek, Acta Cryst. (1990). A46, C-34)
Table 1. Sample and crystal data for UM2489.
Identification code 2489
Chemical formula C28H25NO6
Formula weight 471.49
Temperature 150(2) K
Wavelength 0.71073 Å
57. 57
Crystal size 0.16 × 0.20 × 0.47 mm
Crystal habit colorless prism
Crystal system monoclinic
Space group P21/c
Unit cell dimensions a = 8.3217(7) Å α = 90°
b = 14.4515(12) Å β = 100.2680(13)°
c = 20.1226(17) Å γ = 90°
Volume 2381.2(3) Å3
Z 4
Density (calculated) 1.315 Mg/cm3
Absorption coefficient 0.093 mm-1
F(000) 992
Table 2. Data collection and structure refinement for
UM2489.
Theta range for
data collection
1.75 to 30.00°
Index ranges
-11 ≤ h ≤ 11, -20 ≤ k
≤ 20, -28 ≤ l ≤ 28
Reflections
collected
38583
Independent
reflections
6952 [R(int) = 0.0215]
Coverage of
independent
reflections
100.0%
Max. and min.
transmission
0.9850 and 0.9150
Structure solution
technique
direct methods
Structure solution
program
ShelXS-97 (Sheldrick, 2008)
Refinement
method
Full-matrix least-squares on F2
Refinement
program
ShelXL-2012 (Sheldrick, 2012)
Function
minimized
Σ w(Fo
2
- Fc
2
)2
Data / restraints / 6952 / 11 / 425
58. 58
parameters
Goodness-of-fit on
F2 1.000
Δ/σmax 0.001
Final R indices 5952 data; I>2σ(I)
R1 = 0.0399, wR2 =
0.0817
all data
R1 = 0.0476, wR2 =
0.0863
Weighting scheme
w=1/[σ2
(Fo
2
)+(0.0200P)2
+1.2330P] ,
P=(Fo
2
+2Fc
2
)/3
Largest diff. peak
and hole
0.342 and -0.175 eÅ-3
R.M.S. deviation
from mean
0.039 eÅ-3
Table 3. Atomic coordinates and equivalent isotropic
atomic displacement parameters (Å2
) for UM2489.
U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x/a y/b z/c U(eq)
N1 0.13814(10) 0.73320(6) 0.00380(4) 0.02147(16)
C2 0.15288(12) 0.73633(7) 0.07795(5) 0.02098(18)
C3 0.34134(12) 0.70184(7) 0.08011(5) 0.02111(18)
C4 0.29521(12) 0.70643(7) 0.00270(5) 0.02192(19)
O4 0.36773(9) 0.69322(6) 0.95663(4) 0.02904(17)
C11 0.00108(12) 0.74475(7) 0.95163(5) 0.02146(18)
C12 0.85646(13) 0.78202(8) 0.96512(5) 0.0270(2)
C13 0.72002(13) 0.78936(8) 0.91399(6) 0.0284(2)
C14 0.72836(13) 0.75931(8) 0.84911(5) 0.0255(2)
C15 0.87450(13) 0.72314(8) 0.83547(5) 0.0258(2)
C16 0.01023(12) 0.71563(7) 0.88614(5) 0.02367(19)
O17 0.60044(10) 0.76080(7) 0.79586(4) 0.03414(19)
C17 0.44929(15) 0.79866(12) 0.80844(7) 0.0402(3)
C21 0.03266(12) 0.67290(7) 0.10457(5) 0.02186(19)
C22 0.96399(15) 0.69402(9) 0.16097(6) 0.0328(2)
C23 0.84858(16) 0.63542(10) 0.18087(7) 0.0386(3)
C24 0.80127(14) 0.55534(9) 0.14562(6) 0.0343(3)
C25 0.86878(15) 0.53331(9) 0.08961(6) 0.0328(2)
93. 93
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![1
ABSTRACT
Title of Document: A CATALYTIC METHOD FOR THE
SYNTHESIS OF α-CARBONYLIMINES: NOVEL
ROUTES TO BIOLOGICALLY ACTIVE
MOLECULES
Michael D. Mandler, Bachelor of Science, 2015
Directed By: Professor Michael P. Doyle, Department of
Chemistry and Biochemistry
A dirhodium tetraacetate-catalyzed reaction between α-diazocarbonyl compounds and
organic azides produces imines after overnight reaction times and mild conditions. Imines
containing polar functional groups, such as ketones and α-diesters can be easily
synthesized via this method. Moreover, an unprecedented zinc triflate-catalyzed [4+2]
cycloaddition between an azadiene and aldimines yielded functionalized 1,2,3,4-
tetrahydropyrimidines in good yields. A rhodium-catalyzed Wolff rearrangement of a
phenyldiazoacetoacetate enone followed by a [2+2] cycloaddition yielded novel β-
lactams in high yields and high diastereoselectivities. This methodology, extended to a
one-pot, multicomponent reaction, was developed to convert azide and diazo precursors
directly to β-lactams in almost quantitative yields.](https://image.slidesharecdn.com/d567c9e3-cc90-4b6c-9d1c-c8feb97c62a3-151109005808-lva1-app6892/85/mandlerthesis2015draft4-1-320.jpg)
