catalytic rearrangement and kinetic resolution of n...
TRANSCRIPT
CATALYTIC REARRANGEMENT AND KINETIC RESOLUTION OF N-ACYL
AZIRIDINES
Allen D. Martin
A Thesis Submitted to the
University of North Carolina Wilmington in Partial Fulfillment
of the Requirements for the Degree of
Masters of Science.
Department of Chemistry and Biochemistry
University of North Carolina Wilmington
2011
Approved by
Advisory Committee
John Tyrell Antje Almeida
Pamela Seaton Jeremy Morgan
Chair
Accepted by
Dean, Graduate School
ii
TABLE OF CONTENTS
ABSTRACT ................................................................................................................................... iv
ACKNOWLEDGMENTS………………………………………………………………………. ..v
DEDICATION…………………………………..………………………………………………..vi
LIST OF TABLES ........................................................................................................................ vii
LIST OF FIGURES ..................................................................................................................... viii
CHAPTER 1: PHOSPHINE-CATALZYED REARRANGMENT OF AZIRIDINES ..................1
INTRODUCTION ...........................................................................................................................2
RESULTS AND DISCUSSION ......................................................................................................8
Reaction Optimization .....................................................................................................................8
Substrate Scope ..............................................................................................................................13
Conclusions ....................................................................................................................................19
EXPERIMENTAL .........................................................................................................................20
Representative Procedure for the Synthesis of 2-Methyl Aziridines .............................................21
Representative Procedure for the Synthesis of Substituted 3,5-Dinitrobezoyl Aziridines ............25
Experimental Conditions for the Phosphine Catalyst Screen ........................................................30
Representative Procedure for the Phosphine-Catalyzed Rearrangement .......................................30
Procedure for the Rearrangement of an Enantioenriched Aziridine ..............................................37
CHAPTER 2: KINETIC RESOLUTION OF N-ACYL AZIRIDINES .......................................38
INTRODUCTION .........................................................................................................................39
RESULTS AND DISCUSSION ....................................................................................................43
Substrate Scope ..............................................................................................................................51
Conclusions ....................................................................................................................................53
iii
EXPERIMENTAL .........................................................................................................................53
HPLC Methodology .......................................................................................................................53
Reaction Optimization ...................................................................................................................54
Experimental Conditions of Isolated Yields ..................................................................................55 54
REFERENCES ..............................................................................................................................57
APPENDIX ....................................................................................................................................60
iv
ABSTRACT
Aziridines are three-membered nitrogen-containing heterocycles that exhibit extensive
reactivity because of the strain inherent in the ring. Aziridines have found uses as intermediates
in the synthesis of bioactive molecules. The aziridine moiety is also found in a number of
naturally occurring compounds. One common transformation of aziridines is to oxazolines via a
nucleophile-catalyzed pathway. Oxazolines, like aziridines, have found a great deal of use in
organic synthesis as well as appearing in natural molecules. The focus of our research is to
develop a novel nucleophile-catalyzed rearrangement of aziridines to oxazolines. Phosphines
were chosen as catalysts for this reaction as it is known that they can open aziridine rings. A
variety of phosphines were explored and standard reaction conditions were generated for this
new synthesis of oxazolines. There has been an increased interest in the synthesis of bio-active
organic compounds that are of a single enantiomer. Many of these compounds contain some
type of carbon–nitrogen bond. Aziridines possess two carbon–nitrogen bonds that are reactive as
well as a chiral carbon. The second focus of our research to explore the kinetic resolution of a
variety of substituted N-acyl aziridines to form useful enantioenriched aziridines.
v
ACKNOWLEDGMENTS
I would like to thank my parents for always encouraging me to chase my dreams and
fostering my love of chemistry with countless chemistry sets. Their relentless support, even
when I thought it was pointless means more to me than they will ever know. I am indebted to
my grandmother, Norma, without her years of love and support this would have never come to
fruition.
I am very appreciative to my advisor, Dr. Jeremy Morgan, for his support and guidance
through this entire process. He was my advisor, my mentor and now I’m proud to call him my
friend.
Finally I would like to thank my committee for their time and guidance through my time
at the university.
vi
DEDICATION
I would like to dedicate this thesis to my wife, Julie. Without her unconditional love and
support this work would have never been possible.
vii
LIST OF TABLES
Table Page Page
1. Phosphine selection .....................................................................................................................9
2. Data from 2-(Di-tert-butylphosphino) biphenyl and X-PHOS .................................................13
3. Exploration of various protecting groups .................................................................................15
4. Substrate scope for the phosphine-catalyzed rearrangement ....................................................17
5. Kinetic resolution initial experimental results ..........................................................................44
6. Experimental results long chain substituted aziridine ..............................................................46
7. Experimental results tert-butyl aziridine ...................................................................................47
8. Experimental results O-benzyl aziridine ...................................................................................48
9. Experimental results isopropyl substituted aziridine ................................................................49
10. Experimental results methyl aziridine ....................................................................................50
11. Experimental results long chain alkene substituted aziridine .................................................51
12. Experimental isolated results for isopropyl substituted aziridine ...........................................51
13. Experimental isolated results for long chain alkene substituted aziridine ..............................52
viii
\
LIST OF FIGURES
Figure Page
1. Various aziridine transformations ...............................................................................................3
2. Biologically active aziridine containing compounds ..................................................................3
3. Oxazolidine, oxazoline and oxazole ...........................................................................................4
4. Ascidiacyclamide structure .........................................................................................................4
5. Privileged ligands........................................................................................................................5
6. Aziridine rearrangement in the presence of iodide ion ...............................................................6
7. Aziridine rearrangement in presence of iodide or thiocyanate ion .............................................6
8. Aziridine opening via phosphine catalysis .................................................................................7
9. Phosphine-catalyzed rearrangement ...........................................................................................7
10. Phosphines resulting in little or no conversion to product ......................................................11
11. Phosphines resulting in highest conversion to product ...........................................................12
12. Rearrangement of enantiopure aziridine .................................................................................18
13. Proposed catalytic cycle for the rearrangement ......................................................................19
14. Kinetic resolution of two enantiomers ....................................................................................39
15. Jacobsen hydrolytic kinetic resolution ....................................................................................40
16. Palladium catalyst ...................................................................................................................41
17. Pd-catalyzed asymmetric alcoholysis .....................................................................................41
18. Aziridine opening by borates ..................................................................................................42
19. Borate synthesis ......................................................................................................................42
20. HPLC of racemic aziridine (left) and enantioenriched (right) ................................................55
21. HPLC of racemic aziridine (left) and enantioenriched (right) ................................................56
CHAPTER 1: PHOSPHINE-CATALZYED REARRANGMENT OF AZIRIDINES
2
INTRODUCTION
Aziridines (1, Figure 1) are three-membered nitrogen-containing heterocyclic rings.
They exhibit high reactivity which is partially due to a high ring strain energy (SE) of 26.7
kcal/mol for an unsubstituted aziridine.1 This large ring strain energy makes them very reactive
towards a host of different nucleophiles resulting in ring cleavage (Figure 1).2 Aziridines are
useful as intermediates for the synthesis of nitrogen-containing pharmaceuticals and bio-active
natural product intermediates. The aziridine group serves as a useful intermediate but it is also
found as a structural fragment in many molecules that are biologically active. The rigidity
aziridines possess as well as their ability to accept protons and undergo ring opening all
contribute to the observed biological activity. Several naturally occurring substances such as
mitomycin C (8), porfiromycin (9), and carzinophilin A (10) contain the aziridine moiety (Figure
2). Mitomycin C and porfiromyin have been used an chemotherapeutic agents while
carzinophilin has been used as an antitumor antibiotic.3
3
Figure 1: Various Aziridine Transformations
Figure 2: Biologically Active Aziridine-Containing Compounds
4
Oxazolines have a variety of uses in organic chemistry. They serve as useful precursors
to a range of other heterocycles. For example, oxazolidine (11) and oxazole (12) are components
of a number of natural products and are usually generated by oxazoline reduction or oxidation,
respectively (Figure 3).4
Oxazolines have been incorporated into peptide-mimics in order to
provide rigidity to compounds that were of pharmacological interest. The oxazoline moiety has
been utilized by nature in the form of many cyclic hepta- and octa-peptides. Many of these
peptides have been shown to be mildly cytotoxic and have exhibited antitumor properties. One
example of these naturally occurring peptides is ascidiacyclamide (14, Figure 4).4
Figure 3: Oxazolidine, Oxazoline and Oxazole
Figure 4: Ascidiacyclamide Structure
Over 20 years ago oxazolines were first being using as recoverable ligands. They were
able to facilitate both ketone reductions as well as nucleophilic additions both in asymmetric
fashion.5
Oxazolines appear in a group of compounds known as privileged catalysts which have
seen much use in asymmetric catalysis. Some examples of which include PHOX (15), BOX (16)
5
and PYBOX (17) (Figure 5). These ligands form superior catalysts with a host of metals
resulting in a variety of transformations. Some of these include aziridinations, copper-catalyzed
cyclopropanations, ruthenium-catalyzed oxidation, and palladium-catalyzed allylations.6
Figure 5: Privileged Ligands
Different aziridine derivatives can possess a variety of groups attached to either of the
carbons in the ring as well as varied protecting groups on the nitrogen. The presence of these
groups has been shown to affect reactivity such that stable compounds can be isolated and
transformed into other new aziridine derivatives.7
Specifically, it is known that aziridines can
undergo rearrangement to oxazolines via a nucleophile-catalyzed pathway first reported in 1959.
This rearrangement is often referred to as the Heine reaction.8,9
Heine describes a reaction in
which 1-p-nitrobenzoylaziridine (18) is regioselectively isomerized in the presence of excess
sodium iodide in acetone (Figure 6). Heine later described a reaction in which 1-(N-
arylbenzimidoyl) aziridines (20) isomerize to 2-arylimidazoline (21) in the presence of iodide or
thiocynate ion (Figure 7).9 This reaction appears to be an efficient synthetic pathway to
nitrogen-containing heterocycles.
6
Figure 6: Aziridine Rearrangement in the Presence of Iodide Ion
Figure 7: Aziridine Rearrangement in Presence of Iodide or Thiocynate Ion
We considered that phosphines might replace iodide as an efficient catalyst for the
rearrangement of aziridines. Phosphines are stronger nucleophiles than amines but are much
weaker bases, and most of their chemistry is dependent on their nucleophilicity.
Organophosphines can act as nucleophiles at saturated or unsaturated carbon centers. It has been
demonstrated that phosphines have the ability to open aziridine rings (Figure 8) to give 2
regioisomers 23, 24. The first step of this reaction involves phosphine attacking the aziridine
and forming a phosphonium salt 26. This phosphonium salt has been isolated as validation for
this mechanism.10
The steric and electronic character of phosphines can be dictated by the
substituents that are added to the phosphorus. Of most importance is the fact that there are
numerous enantiopure phosphines commercially available. These enantiopure phosphines can be
used for the exploration of controlling enantiomer synthesis or separation by kinetic resolution.
7
Figure 8: Aziridine Opening via Phosphine Catalysis
We considered designing a phosphine-catalyzed rearrangement of aziridines into 5-
membered heterocycles (29, Figure 9). This reaction would constitute novel reactivity in
phosphine catalysis. It will allow for the synthesis of enantiopure heterocycles from enantiopure
aziridines. Eventually, new reaction pathways for the proposed phosphonium intermediate could
be developed.
Figure 9: Phosphine-Catalyzed Rearrangement
8
RESULTS AND DISCUSSION
Reaction Optimization
The research began with the optimization of conditions for the rearrangement of
aziridines to oxazolines. N-Acyl aziridine 30 was the first protected aziridine to be generated,
since it was readily available by protection of commercially available 2-methylaziridine. A
series of initial experiments were run under constant conditions using this aziridine with varying
phosphine catalysts. Reaction progress was followed by thin layer chromatography (TLC). The
TLC plates were visualized using a ultra-violet (UV) lamp and basic potassium permanganate
stain. During the optimization process, yields were determined by 1H-NMR through the use of
an internal standard. Specifically 1,3,5-trimethoxybenzene was chosen as an internal standard as
it is stable and provides 2 distinctive peaks that exhibit shifts different from any peaks of interest.
The actual formulas used for calculating the % yield from 1H NMR appear as equations 1 and 2.
We anticipated that the electronic nature of the acyl group bound to the aziridine nitrogen
may play a role in reactivity. The p-nitrobenzoyl group, the same group utilized in aziridine 30,
was originally used by Heine. Depending on where aziridine 30 is opened, two possible
oxazoline regioisomers are formed (31 and 32). Several commercially available phosphine
compounds were used under reflux in tetrahydrofuran (THF) (Table 1). It’s worth noting that the
reaction using the original catalyst published by Heine was reproduced under our conditions with
9
successful results (entry 11, Table 1).8 Attempts were made to repeat the original published
procedure and were not successful.
Table 1: Phosphine Selection
Phosphines catalyze the aziridine rearrangement but reactivity varied greatly between the
different phosphines. This experimental data suggests that both sterics and electronics control
the reactivity of the phosphines. Structures of selected phosphine catalysts that resulted in no or
very little conversion have been provided (Figure 10). Additional structures of phosphines that
resulted in the highest percent yields have been provided as well (Figure 11). Interesting trends
10
begin to emerge when one considers the structures of these phosphines. Several of the
phosphines share similar structural properties, but provide very different results. Phosphine 42
resulted in very high yields while phosphine 33 resulted in 0 % yield (entry 1 and 10). The main
difference between the two is the replacement of a benzene ring with a cyclohexyl ring makes 33
less basic than 42. This suggests that electronics are responsible for the high reactivity seen with
42. Compounds 37 and 39 are both similar in structure yet they both exhibit vastly different
yields (entries 5 and 7). Compound 37 has bulky groups attached to the ring ortho to phosphorus
in comparison with compound 39 suggesting steric influence on reactivity. An interesting
comparison can be made between compounds 36 and 40 as well (entry 4 and 8). Both
compounds have similar structure at phosphorus with 40 possessing the more bulky t-butyl
substituents. It appears a balance between sterics and electronics of the phosphine catalyst is
important for optimal reactivity.
11
Figure 10: Phosphines resulting in little or no conversion to product.
12
Figure 11: Phosphines resulting in highest conversion to product.
Efforts were next placed on forcing the reactions to go to 100 % completion. The
strategy to accomplish complete conversion was raising the temperature to 80°C which
necessitated a change of solvent. Toluene, acetonitrile, and dimethoxyethane (DME) were
chosen due to their higher boiling points. The concentration was increased from .2 M to .3 M
and all reactions were allowed to go for 24 hours. The two most productive previously used
catalysts, 2-(Di-tert-butylphosphino)biphenyl and X-PHOS were used under these new
conditions (Table 2). It can be seen from this data that X-PHOS (40) resulted in higher yields
than phosphine 39 in all cases. For this reason X-PHOS was chosen as the primary catalyst for
future experimentation. X-PHOS was also optimal since it is an air stable solid that can be
weighed on the bench top. A thermal rearrangement of N-acylaziridines to allylamides has been
reported.11
We made the observation that 30 undergoes this same rearrangement at 90ºC in
13
DME and 1,4-dioxane. Based on this development, THF was explored as a possible solvent
choice and provided similar values. From this data, THF was chosen as the standard solvent.
Table 2: Data from 2-(Di-tert-butylphosphino) biphenyl and X-PHOS
Substrate Scope
Using the results from this first round of experimentation, the most active catalyst was
used with a variety of protected 2-methyl aziridine compounds. These various aziridine
compounds were synthesized by William Morris, an undergraduate research, according to a
general procedure. A range of aziridines with varying protecting groups were generated for
rearrangement reactions. Once synthesized and checked for purity, each aziridine was reacted
with phosphine 40, one of the most active catalyst (Table 2). Phosphine 42 exhibited the highest
yields of any of the phosphines but results were inconsistent on a larger scale. This necessitated
the use of the second most productive phosphine.
14
With optimized conditions in hand, efforts were then focused on determining actual
isolated yields (Table 3). All aziridines examined showed some rearrangement with the most
productive being the benzoyl groups with electron withdrawing substituents. Compounds 43–45
exhibit low yields due to low conversion of starting material. Heating these aziridines for longer
periods of time did not appreciably increase yields. Starting material was totally consumed for
compounds 46–50. The variation in protecting groups resulted in a noticeable trend. Compound
43 has no additional substituents and resulted in a yield of 21%, one of the lowest yields of all
the protecting groups. Adding an inductive electron withdrawing group to the para position, as
with compound 44, the yield exhibits no change at 21%. Compound 45 suggests that electron
donating groups do not aid the rearrangement. The addition of the electron withdrawing dinitro
group in 46 increased the yield to 77%. Compound 49 suggests that the location of the electron
withdrawing group is important as well. It was decided that the 3,5-dinitrobenzoyl (DNB)
protecting group would be utilized in further substrate exploration since it displayed the best mix
of yield and regioselectivity. The DNB protecting group is crystalline in nature, and there is
precedence for its removal.
15
Table 3: Exploration of various protecting groups.
Since methyl aziridine was the only commercially available aziridine, various other
DNB-protected aziridines were synthesized (see experimental section) and subjected to the
standard X-PHOS-catalyzed rearrangement (Table 4). Two long chain substituted aziridines
were reacted and provided very differing results (entries 1 and 2). The long chained alkane
provided a promising yield of 94% while the corresponding alkene version was more
disappointing at 64%. The only structural difference between the two is the presence of a double
bond. This reduction in yield suggests either an electronic influence on reactivity or a competing
side reaction involving the double bond. The two more sterically hindered aziridines (entry 3
and 4) exhibited high yields. This suggests that the increase in steric bulk did not affect the
16
reactivity negatively. The two oxygen substituted aziridines displayed similar reactivity (entry 5
and 6). Their yields are lower and similar to that of the alkene substituted aziridine (entry 2).
The lower reactivity would again suggest either that electronics are at play. Either electronic
effects are affecting the reactivity of the analyte or resulting in a side reaction which is lowering
the yield. The only disubstituted aziridine (entry 7) showed no reactivity.
17
Table 4: Substrate scope for the phosphine-catalyzed rearrangement.
18
Terminal aziridines possess a chiral center that is maintained in the resulting oxazoline
product. In order to verify this was true for this rearrangement, aziridine 65 was synthesized
with >99% ee and was subjected to the optimized rearrangement conditions. The resulting
oxazoline product (66) was isolated with a 94% yield without any loss of the original
enantiopurity. The fact that the stereocenter is maintained is important for applications in
asymmetric synthesis. It also provides some insight into the mechanistic pathway of the
reaction.
Figure 12: Rearrangement of enantiopure aziridine.
We suggest the rearrangement takes place through a catalytic cycle that is similar to what
was originally suggested by Heine8 (Figure 13). The least hindered carbon of aziridine 67 is
open to attack by a nucleophilic phosphine (70). The catalyst must be small enough that it can
get in and open the aziridine. Any added steric bulk that is present around the phosphine may
stop any decomposition of 68 which would be hindering to the catalytic cycle. Once 68
collapses onto the oxygen the correct oxazoline product (69) is formed.
19
Figure 13: Proposed catalytic cycle for the rearrangement.
Conclusions
Herein we describe a new variation on the Heine reaction using phosphine catalysts.
Based on experimentation, X-PHOS was found to be the most suitable catalyst and general
reaction conditions were developed around this catalyst. These new conditions were used on a
variety of substituted N-acyl aziridines resulting in the synthesis of a variety of oxazoline
counterparts. The aziridines synthesized as well as the oxazolines may find use as starting
materials for a variety of further synthesis.
20
EXPERIMENTAL
General. 1H NMR spectra were recorded on Bruker DRX (400 MHz). Chemical shifts are
reported in ppm from tetramethylsilane with the solvent resonance as the internal standard
(CDCl3: 7.27 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz),
and assignment. 13
C NMR spectra were recorded on a Bruker DRX 400 (100 MHz)
spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent as the internal standard (CDCl3: 77.0 ppm). High resolution
mass spectrometry was acquired with an Agilent DART-TOF at Duke University. Infrared (IR)
spectra were obtained using a Nicolet 6700 FT-IR.
Liquid chromatography was performed using forced flow (flash chromatography) on
EMD Chemicals Geduran® 60 silica gel (SiO2, 40 to 63m) purchased from VWR International.
Thin layer chromatography (TLC) was performed on EMD Chemicals 0.25 mm silica gel 60
plates. Visualization was achieved with UV light or basic potassium permanganate in water
followed by heating.
All reactions were conducted in oven and flame dried glassware under an inert
atmosphere of argon. All solvents were EMD Chemicals anhydrous solvents sold by VWR
International. Each solvent was purged with Argon for a minimum of 15 minutes and stored
over activated 3Å molecular sieves in sure-seal bottles. All phosphine catalysts were purchased
from the Strem Chemical Company, except cyclohexyldiphenylphosphine which was purchased
from Alfa Aesar. All remaining chemicals were purchased from Alfa Aesar, TCI International,
or Aldrich Chemical Company and were used as received.
21
Representative Procedure for the Synthesis of 2-Methylaziridines
A flame-dried round bottom flask was charged with a Teflon-covered stir bar and the
corresponding acyl chloride (1.05 equiv.) under argon. Dry toluene (0.25 M) was added to the
flask via syringe. Triethylamine (2 equiv.) was added to the solution via syringe. Solution was
then cooled with stirring in an ice bath and 2-methylaziridine (1 equiv.) was added to the
solution dropwise. The resulting solution was stirred for 30 minutes in the ice bath and then
allowed to reach room temperature and stirred for another 30 minutes. The resulting suspension
was vacuum filtered to remove solids, and the volatiles were then removed by rotary evaporator.
The resulting product was purified via silica flash column chromatograph with hexanes and ethyl
acetate.
(2-methylaziridin-1-yl)(4-nitrophenyl)methanone (30). Reaction performed by
representative procedure beginning with 4-nitrobenzoyl chloride (20 mmol, 3.9
g). Purification was performed by silica gel flash column chromatography (80%
hexanes, 20% ethyl acetate) yielding 3.65 g (88%) of aziridine as a pale yellow
solid. HRMS: Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0769 (M+H
+);
1H
NMR (CDCl3, 400 MHz): δ 8.31 (m, 2H), 8.18 (m, 2H), 2.66 (m, 1H), 2.60 (d, J = 5.6 Hz, 1H),
2.23 (d, J = 3.6 Hz), 1.42 (d, J = 5.2 Hz); 13
C NMR (CDCl3, 100 MHz): δ 177.01, 150.28,
138.84, 130.01, 123.63, 35.07, 32.52, 17.61; IR (NaCl Plate): 2971, 1647, 1601, 1345 cm-1
.
22
(2-methylaziridin-1-yl)(phenyl)methanone (entry 1, table 2). Reaction
performed by representative procedure beginning with benzoyl chloride (21
mmol, 3.90 g). Purification was performed by silica gel flash column
chromatography (89% Hexanes, 11% Ethyl Acetate) yielding 2.6 g (76%) of aziridine as a clear
oil. HRMS: Calculated for C10H11NO: 162.0919 (M+H+), found 162.0916 (M+H
+);
1H NMR
(CDCl3, 400 MHz): δ 8.03 (m, 2H), 7.55 (m, 1H), 7.46 (m, 2H), 2.58 (m, 1H), 2.55 (d, J = 5.6
Hz, 1H), 2.15 (d, J = 3.6 Hz, 1H), 1.40 (d, J = 5.6 Hz, 3H); 13
C NMR (CDCl3, 100 MHz): δ
179.32, 133.52, 132.65, 129.04, 128.42, 34.62, 32.14, 17.79; IR (NaCl Plate): 3061, 1658, 1535,
1317 cm-1
.
(4-chlorophenyl)(2-methylaziridin-1-yl)methanone (entry 5, table 2).
Reaction performed by representative procedure beginning with 4-chlorobenzoyl
chloride (10.5 mmol, 1.34 mL). Purification was performed by silica flash column
chromatography (83%: Hexanes, 17% ethyl acetate) yielding 1.59g (81%) of
aziridine as a clear oil. HRMS: Calculated for C10H10ClNO: 196.0529 (M+H+), found 196.0528
(M+H+);
1H NMR (CDCl3, 400 MHz): δ 7.95 (m, 2H), 7.42 (m, 2H), 2.57 (m, 1H), 2.53 (d, J =
5.6 Hz, 1H), 2.14 (d, J = 3.6 Hz, 1H), 1.37 (d, J = 5.2 Hz, 3H); 13
C NMR (CDCl3, 100 MHz): δ
178.21, 138.97, 131.95, 130.40, 128.73, 34.77, 32.23, 17.71; IR (NaCl Plate): 2969, 1672, 1406,
1091 cm-1
.
(4-methoxyphenyl)(2-methylaziridin-1-yl)methanone (entry 3, table 2).
Reaction performed by representative procedure beginning with 4-
methoxybenzoyl chloride (10.5 mmol, 1.79 g). Purification was performed by
23
silica flash column chromatograph (83% hexanes, 17% ethyl acetate) yielding 1.14 g (60%) of
aziridine as a clear oil. HRMS: Calculated for C11H13NO2: 192.1025 (M+H+), found 192.1022
(M+H+);
1H NMR (CDCl3, 400 MHz): δ 8.00 (m, 2H), 6.94 (m, 2H), 3.87 (s, 1H), 2.56(m, 1H),
2.52 (d, J = 5.6 Hz, 1H), 2.11 (d, J = 3.6 Hz, 1H), 1.39 (d, J = 5.2 Hz, 3H); 13
C NMR (CDCl3,
100 MHz): δ 178.87, 163.14, 131.10, 126.11, 113.61, 55.45, 34.60, 32.06, 17.81; IR (NaCl
Plate): 2966, 2258, 1651, 1091 cm-1
.
(3,5-dinitrophenyl)(2-methylaziridin-1-yl)methanone (entry 1, table 4).
Reaction performed by representative procedure beginning with 3,5-
dinitrobenzoyl chloride (21 mmol, 4.84g). Purification was performed by silica
flash column chromatography (75% hexanes, 25% ethyl acetate) yielding 3.97
g (79%) of aziridine as a white solid. HRMS: Calculated for C10H9N3O5: 252.0620 (M+H+),
found 252.0616 (M+H+);
1H NMR (CDCl3, 400 MHz): δ 9.22 (t, J = 4 Hz, 1H), 9.16 (d, J = 2
Hz, 2H), 2.77 (m, 1H), 2.68 (d, J = 4 Hz, 1H), 2.69 (d, J = 6, 1H), 2.34 (d, J = 3.6 Hz, 1H), 1.51
(d, J = 5.2 Hz); 13
C NMR (CDCl3, 100 MHz): δ 174.32, 148.73, 137.00, 128.69, 121.92, 35.77,
32.93, 17.56; IR (NaCl Plate): 3095, 1648, 1541, 1344 cm-1
.
(3,5-bis(trifluoromethyl)phenyl)(2-methylaziridin-1-yl)methanone (entry
6, table 4). Reaction performed by representative procedure beginning with
3,5-bis(trifluoromethyl)benzoyl chloride (10.5 mmol, 1.9 mL). Purification
was performed by silica flash column chromatography (83% hexanes, 17%
ethyl acetate) yielding 2.09 g (70%) of aziridine as a clear oil. HRMS: Calculated for
C12H9F6NO: 298.0667 (M+H+), found 298.0661 (M+H
+);
1H NMR (CDCl3, 400 MHz): δ 8.47
(m, 2H), 8.06 (m, 1H), 2.67 (m, 1H), 2.63 (d, J = 6 Hz, 1H), 2.25 (d, J = 3.6 Hz), 1.44 (d, J = 5.2
24
Hz); 13
C NMR (CDCl3, 100 MHz): 176.18, 135.31, 132.64, 132.30, 131.97, 131.63, 129.09,
129.06, 127.00, 125.96, 125.92, 125.89, 125.85, 124.28, 121.57, 118.86, 35.31, 32.55, 17.54; IR
(NaCl Plate): 3000, 1688, 1280, 1136 cm-1
.
(2-methylaziridin-1-yl)(2-nitrophenyl)methanone (entry 7, table 4). Reaction
performed by representative procedure beginning with 2-nitrobenzoyl chloride
(10.5 mmol, 1.39 mL). Purification was performed by silica flash column
chromatography (75% hexanes, 25% ethyl acetate) yielding 1.57 g (75%) of aziridine as a clear
oil. HRMS: Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0768 (M+H
+);
1H NMR
(CDCl3, 400 MHz): δ 7.94 (dd, J = 8, .8 Hz), 7.71 (m, 2H), 7.59 (m, 1H), 2.80 (m, 1H), 2.63 (d,
J = 6Hz, 1H), 1.32 (d, J = 5.6 Hz, 3H); 13
C NMR (CDCl3, 100 MHz): 177.41, 147.33, 133.41,
132.59, 130.88, 129.33, 124.12, 34.33, 32.83, 17.41; IR (NaCl Plate): 2972, 1733, 1645, 1348
cm-1
.
(2-methylaziridin-1-yl)(perfluorophenyl)methanone (entry 8, table 4).
Reaction performed by representative procedure beginning with
pentafluorobenzoyl chloride (10.5 mmol, 1.5 mL). Purification was performed by
silica gel flash column chromatography (89% hexanes, 11% ethyl acetate)
yielding 2.04 g (81%) of aziridine as a clear oil. HRMS: Calculated for C10H6F5NO: 252.0448
(M+H+), found 252.0446 (M+H
+);
1H NMR (CDCl3, 400 MHz): δ 2.78 (m, 1H), 2.61 (d, J = 6
Hz, 1H), 2.20 (d, J = 3.6 Hz, 1H), 1.35 (d, J = 5.6 Hz, 3H); 13
C NMR (CDCl3, 100 MHz):
168.48, 145.67, 145.62, 143.84, 143.13, 143.09, 143.02, 141.27, 138.94, 136.52, 136.39, 111.65,
35.18, 32.79, 29.72, 17.38; IR (NaCl Plate): 2978, 1689, 1652, 1495 cm-1
.
25
Representative Procedure12
for the Synthesis of Substituted 3,5-Dinitrobezoylaziridines.
A round bottom flask was charged with a Teflon-covered stir bar, the corresponding
epoxide (20 mmol), 30 mL of MeOH, and 10 mL of H2O under argon. Sodium azide (40 mmol)
and ammonium chloride (30 mmol) were added to this solution. The reaction was stirred for 4
hours under argon at 60 °C. Methanol was removed by rotary evaporator and the remaining
solution was extracted 3 x 60 mL with dichloromethane. The organic layers were combined,
washed with 20 mL of brine solution, and dried over anhydrous MgSO4. The mixture was
filtered, and volatiles were then removed by rotary evaporator. The total crude azido alcohol
was dissolved in 50 mL of acetonitrile under argon. Triphenylphosphine (20 mmol) was added,
and the solution was heated for 20 hours at 80 °C. The reaction mixture was cooled to –30 °C
with stirring, and triethylamine (24 mmol) was added via syringe (in some cases a solvent swap
to tetrahydrofuran was beneficial at this point). In a flame dried flask, 3,5-dinitrobenzoyl
chloride (21 mmol) was dissolved in a minimal amount of acetonitrile and then transferred to the
reaction flask dropwise via syringe. The reaction mixture was allowed to stir at –30°C for 50
minutes, 0 °C for 30 minutes, and room temperature for 30 minutes. De-ionized water (20 mL)
was added and the solution was extracted 3 x 60 mL with ethyl acetate. The organic layers were
combined, washed with 20 mL of brine solution, and dried over anhydrous MgSO4. The mixture
was filtered, and volatiles were then removed by rotary evaporator. The crude product was
purified immediately via flash column silica gel chromatography using hexanes and ethyl
acetate.
26
(3,5-dinitrophenyl)(2-hexylaziridin-1-yl)methanone (51). Reaction
performed by representative procedure beginning with 1,2-
epoxyoctane (20 mmol, 3.09 mL). Purification was performed by
flash column chromatography (89% hexanes, 11% ethyl acetate)
yielding 2.8 g (43%) of aziridine as a white solid. HRMS: Calculated for C15H19N3O5: 322.1403
(M+H+), found 322.1405 (M+H
+);
1H NMR (CDCl3, 400 MHz): δ 9.21 (t, J = 2.4 Hz, 1H), 9.15
(d, J = 2.4 Hz, 2H), 2.72 (m, 1H), 2.63 (d, J = 6 Hz, 1H), 2.38 (d, J = 3.6 Hz, 1H), 1.90 (m, 1H),
1.60-1.26 (m, 9H), 0.90 (t, J = 7.2 Hz, 3H); 13
C NMR (CDCl3, 100 MHz): 174.45, 148.65,
136.96, 128.76, 121.91, 39.87, 32.33, 31.93, 31.65, 28.89, 26.41, 22.53, 14.03; IR (NaCl Plate):
3104, 1646, 1542, 1343 cm-1
.
(3,5-dinitrophenyl)(2-(hex-5-en-1-yl)aziridine-1-yl)methanone (53).
Reaction performed by representative procedure beginning with 1,2-
epoxy-7-octene (20 mmol, 2.96 mL). Purification was performed by
flash column chromatography (83% hexanes, 17% ethyl acetate)
yielding 2.4 g (41%) of aziridine as a pale yellow solid. HRMS: Calculated for C15H17N3O5:
320.1246 (M+H+), found 320.1240 (M+H
+);
1H NMR (CDCl3, 400 MHz): δ 9.20 (t, J = 2 Hz,
1H), 9.14 (d, J = 9.14 Hz), 5.78 (m, 1H), 4.97 (m, 1H), 2.73 (m, 1H), 2.63 (d, J = 6 Hz, 1H), 2.38
(d, J = 2 Hz, 1H), 2.09 (m, 2 H), 1.54 (m, 1H), 1.50 (m, 5H); 13
C NMR (CDCl3, 100 MHz):
174.42, 148.68, 138.36, 136.93, 128.73, 121.90, 114.78, 39.69, 33.50, 32.35, 31.78, 28.40,
25.89; IR (NaCl Plate): 3094, 1645, 1462, 1343 cm-1
.
27
(2-(tert-butyl)aziridine-1-yl)(3,5-dinitrophenyl)methanone (57). Reaction
performed by representative procedure beginning with 3,3-dimethyl-1,2-
epoxybutane (20 mmol, 2.44 mL). Purification was performed by flash
column silica gel chromatography (86% hexanes, 14% ethyl acetate) yielding
2.19 g (48%) of aziridine as a white solid. HRMS: Calculated for C13H15N3O5: 294.1090
(M+H+), found 294.1088 (M+H
+);
1H NMR (CDCl3, 400 MHz): δ 9.21 (t, J = 2 Hz, 1H), 9.16
(d, J = 2 Hz, 2H), 2.63 (dd, J = 6.4, 4 Hz, 1H), 2.55 (d, J = 4 Hz, 1H), 2.43 (d, J = 6.4 Hz, 1H),
1.05 (s, 9H); 13
C NMR (CDCl3, 100 MHz): 175, 148.58, 136.89, 128.84, 121.91, 47.77, 30.86,
30.15, 26.47; IR (NaCl Plate): 3097, 1678, 1543, 1344 cm-1
.
(3,5-dinitrophenyl)(2-(phenoxymethyl)aziridine-1-yl)methanone
(61). Reaction performed by representative procedure beginning with
glycidyl phenyl ether (20 mmol, 2.73 mL). Purification was performed
by flash column silica gel chromatography (50% hexanes, 50% ethyl
acetate) yielding 2.1 g (31%) of aziridine as a pale yellow solid. HRMS: Calculated for
C16H13N3O6: 344.0883 (M+H+), found 344.0881 (M+H
+);
1H NMR (CDCl3, 400 MHz): 9.30 (d,
J = 2 Hz, 2 H) 9.21 (t, J = 2 Hz, 1 H), 7.29 (m, 2H), 6.99 (m, 1H), 6.85 (m, 2 H), 4.38 (dd, J =
10.4, 2.8 Hz, 1 H), 4.06 (dd, J = 10.8, 6.8 Hz, 1 H), 3.22 (m, 1 H), 2.83 (d, J = 6.4 Hz, 1 H) 2.61
(d, J = 3.6 Hz, 1H); 13
C NMR (CDCl3, 100 MHz) 173.95, 157.73, 148.62, 136.37, 129.69,
129.13, 122.14, 121.84, 114.42, 68.00, 38.32, 28.70; IR (NaCl Plate): 3094, 1678, 1543, 1344
cm-1
.
28
(2-((benzyloxy)methyl)aziridine-1-yl)(3,5 dinitrophenyl)methanone
(59).
Reaction performed by representative procedure beginning with
benzyl glycidyl ether (24.1 mmol, 3.96 g). Purification was performed
by flash column silica (50% hexanes, 50% ethyl acetate) yielding 1.82 g (67%) of aziridine as a
pale yellow solid. HRMS: Calculated for C17H15N3O6: 358.1039 (M+H+), found 358.1043
(M+H+);
1H NMR (CDCl3, 400 MHz): δ 9.37 (d, J = 2 Hz, 2 H), 7.39 (m, 3H), 7.26 (m, 2H),
4.60 (m, 2H), 3.88 (dd, J = 10.4, 2.8 Hz, 1 H), 3.40 (dd, J = 10.4, 7.2 Hz, 1 H), 3.00 (m, 1 H),
2.71 (d, J = 6 Hz, 1 H), 2.43 (d, J = 3.6 Hz, 1H); 13
C NMR (CDCl3, 100 MHz) 173.88, 148.50,
137.01, 136.47, 129.31, 128.53, 128.11, 127.94, 121.94, 73.56, 69.81, 39.19, 28.46; IR (NaCl
Plate): 3094, 1652, 1454, 1343 cm-1
.
7-azabicyclo[4.1.0]heptan-7-yl(3,5-dinitrophenyl)methanone12
(63).
Reaction performed by representative procedure beginning with
cyclohexene oxide (20.4 mmol, 2.00 g). Purification was performed
by flash column silica (86% hexanes, 14% ethyl acetate to 77% hexanes, 33% ethyl acetate)
yielding 3.2 g (54%) of aziridine as a white solid. HRMS: Calculated for C13H13N3O5: 292.0933
(M+H+), found 292.0938 (M+H
+);
1H NMR (CDCl3, 400 MHz): 9.20 (t, J = 2 Hz, 1H), 9.11 (d,
J = 2.4 Hz, 2H), 2.92 (m, 2H), 2.13 (m, 2 H), 2.02 (m , 2H), 1.61 (m, 2 H), 1.46 (m, 2 H); 13
C
NMR (CDCl3, 100 MHz): 175.10, 148.65, 137.05, 128.74, 121.78, 38.47, 23.69, 19.79; IR
(NaCl Plate): 3095, 1640, 1540, 1343 cm-1
.
29
(3,5-dinitrophenyl)(2-isopropylaziridin-1-yl)methanone13
(55). DL-
Valinol14
(13.9 mmol, 1.4 g) was dissolved in dry toluene (21 mL), and then
added to a solution of triphenylphosphine (14.57 mmol, 3.82 g) and
diisopropyl azodicarboxylate (14.57 mmol, 2.87 mL) in toluene (32 mL).
This mixture was heated to 100 °C and stirred overnight. After cooling to –30 °C, triethyl amine
(16.66 mmol, 2.32 mL) was added to this solution. 3,5-Dinitrobenzoyl chloride (14.57 mmol,
3.36 g) in THF (4 mL) was added to solution dropwise. Solution was allowed to stir at –30 °C
for 20 minutes and 40 minutes at 0 °C. Water (20 mL) was added dropwise, the mixture was
extracted 3 x 60 mL with ethyl acetate. The combined organics were washed with brine (20 mL),
dried over MgSO4, and filtered. Volatiles were removed by rotary evaporator. The crude
material was purified by flash column silica gel chromatography (86% hexanes, 14% ethyl
acetate) yielding 1.25 g (32%) of aziridine as a white solid. HRMS: Calculated for C12H13N3O5:
280.0933 (M+H+), found 280.0928 (M+H
+);
1H NMR (CDCl3, 400 MHz): δ 9.20 (t, J = 2.4 Hz,
1H) 9.15 (d, J = 2 Hz, 2H), 2.61 (m, 1H), 2.53 (d, J = 6.4 Hz, 1H), 2.50 (d, J = 4 Hz, 1H), 1.87
(m, 1H), 1.12 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H); 13
C NMR (CDCl3, 100 MHz):
174.72, 148.61, 136.89, 128.81, 121.91, 44.97, 31.06, 29.98, 19.85, 18.36; IR (NaCl Plate):
3101, 1647, 1542, 1343 cm-1
.
30
Experimental conditions for the phosphine catalyst screen.
Aziridine 30 (20.6 mg, 0.1 mmol) and 0.01 mmol of a phosphine catalyst were weighed
into an oven-dried reaction vial. Dry tetrahydrofuran (500 L) was added under argon. The
solution was heated at 70 °C under argon for 24 hours. Volatiles were removed by rotary
evaporator. All yields and ratios of regioisomers were determined using 1H NMR following the
addition of 1,3,5-trimethoxybenzene as an internal standard. Since the NMR spectra of 31 have
not been reported, identification of the major regioisomer was possible by extrapolation of know
oxazolines.15,16
Representative procedure for the phosphine-catalyzed rearrangements.
Aziridine (0.3 mmol) and 14.3 mg (0.03 mmol) of X-Phos were weighed into an oven-
dried reaction vial. Dry tetrahydrofuran (1.5 mL) was added under argon. The solution was
heated at 70 °C under argon for 24 hours. Volatiles were removed by rotary evaporator. The
crude reaction mixture was purified via flash column silica gel chromatography using various
hexanes/ethyl acetate solvent systems.
31
4-methyl-2-(4-nitrophenyl)-4,5-dihydrooxazole (31,32). Reaction performed
by representative procedure beginning with 62 mg of the corresponding
aziridine. Purification was performed by flash column chromatography (83%
hexanes, 17% ethyl acetate) yielding 42 mg (71%) of oxazoline. HRMS:
Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0770 (M+H
+);
1H NMR (CDCl3, 400
MHz): δ 8.27 (d, J = 9.2 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 4.59 (5, J = 9.2 Hz, 1H), 4.43 (m,
1H), 4.02 (t, J = 8 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H); 13
C NMR (CDCl3, 100 MHz): 161.69,
149.49, 133.71, 129.25, 123.52, 74.57, 62.46, 21.30; IR (NaCl Plate): 3109, 1737, 1524, 1349
cm-1
.
4-methyl-2-phenyl-4,5-dihydrooxazole15
(entry 1, table 2). Reaction performed
by representative procedure beginning with 48 mg of the corresponding aziridine.
Purification was performed by flash column chromatography (89% hexanes, 11%
ethyl acetate) yielding 11 mg (21%) of oxazoline. 1H NMR (CDCl3, 400 MHz): δ 7.93 (t, J = 7.2
Hz, 2 H), 7.43 (m, 3H), 4.50 (dd, J = 8 Hz, 9.2, 1H), 4.35 (m, 1H), 3.93 (t, J = 7.6 Hz, 1H), 1.35
(d, J = 6.8 Hz, 3H); 13
C NMR (CDCl3, 100 MHz): 163.42, 131.25, 128.30, 128.19, 127.85,
74.04, 61.99, 21.47; IR (NaCl Plate): 2966, 1449, 1302, 1055 cm-1
.
2-(4-chlorophenyl)-4-methyl-4,5-dihydrooxazole (entry 5, table 2). Reaction
performed by representative procedure beginning with 59 mg of the
corresponding aziridine. Purification was performed by flash column
chromatography (83% hexanes, 17% ethyl acetate) yielding 13 mg (21%) of
oxazoline. HRMS: Calculated for C10H10ClNO: 196.0529 (M+H+), found 196.0530 (M+H
+);
32
1H NMR (CDCl3, 400 MHz): δ 7.88 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.54 (t, J = 9.2
Hz, 1H), 4.39 (m, 1H), 3.97 (t, J = 7.6 Hz, 1H), 1.37 (d, J = 6.8 Hz); 13
C NMR (CDCl3, 100
MHz): 162.62, 137.44, 129.58, 128.63, 126.36, 74.24, 62.11, 21.41; IR (NaCl Plate): 2966,
2258, 1651, 1091 cm-1
.
2-(4-methoxyphenyl)-4-methyl-4,5-dihydrooxazole (entry 3, table 2).
Reaction performed by representative procedure beginning with 57 mg of the
corresponding aziridine. Purification was performed by flash column
chromatography (83% hexanes, 17% ethyl acetate) yielding 3 mg (5%) of
oxazoline. HRMS: 1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz,
2H), 4.49 (dd, J = 8, 9.2 Hz, 1H), 4.35 (m, 1H ), 3.92 (t, 7.6 Hz, 1H), 3.82 (s, 3H), 1.35 (d, J =
6.4 Hz); 13
C NMR (CDCl3, 100 MHz): 163.37, 162.06, 129.98, 120.15, 113.66, 74.03, 61.74,
55.34, 21.49; IR (NaCl Plate): 1648, 1609, 1512, 1254 cm-1
.
2-(3,5-dinitrophenyl)-4-methyl-4,5-dihydrooxazole (entry 5, table 5).
Reaction performed by representative procedure beginning with 75 mg of
the corresponding aziridine. Purification was performed by flash column
chromatography (75% hexanes, 25% ethyl acetate) yielding 58 mg (77%) of
oxazoline. HRMS: Calculated for C10H9N3O5: 252.0620 (M+H+), found 252.0615 (M+H
+);
1H
NMR (CDCl3, 400 MHz): δ 9.12 (t, J = 2 Hz, 1H), 9.07 (d, J = 2 Hz, 2H), 4.66 (dd, J = 9.2, 8
Hz, 1H), 4.49 (m, 1H), 4.10 (t, J = 8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H); 13
C NMR (CDCl3, 100
MHz): 159.73, 148.49, 131.66, 128.17, 120.69, 75.14, 62.69, 21.23; IR (NaCl Plate): 3097,
2970, 1543, 1344 cm-1
.
33
2-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-4,5-dihydrooxazole (entry 6,
table 5). Reaction performed by representative procedure beginning with 90
mg of the corresponding aziridine. Purification was performed by flash
column chromatography (83% hexanes, 17% ethyl acetate) yielding 52 mg (60%) of oxazoline.
HRMS: Calculated for C12H9F6NO: 298.0667 (M+H+), found 298.0668 (M+H
+);
1H NMR
(CDCl3, 400 MHz): δ 8.41 (s, 2 H), 7.97 (s, 1 H), 4.60 (dd, J = 9.2, 8 Hz, 1 H), 4.45 (m, 1 H),
4.03 (t, J = 8.4 Hz, 1 H), 1.40 (d, J = 6.4 Hz, 3 H); 13
C NMR (CDCl3, 100 MHz): 160.98,
132.44, 132.11, 131.77, 131.43, 130.09, 128.40, 128.36, 127.05, 124.65, 124.62, 124.58, 124.54,
124.51, 124.34, 121.62, 118.91, 74.67, 62.41, 21.21; IR (NaCl Plate): 2975, 2931, 1280, 1136
cm-1
.
4-methyl-2-(2-nitrophenyl)-4,5-dihydrooxaole16
(entry 7, table 5). Reaction
performed by representative procedure beginning with 62 mg of the
corresponding aziridine. Purification was performed by flash column
chromatography (83% hexanes, 17% ethyl acetate) yielding 64 mg (92%) of oxazoline. HRMS:
Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0769 (M+H
+);
1H NMR (CDCl3, 400
MHz): δ 7.85 (m, 2H), 7.63 (m, 2H), 4.53 (t, 9.2 Hz, 1H), 4.40 (m, 1H), 3.99 (t, J = 7.6 Hz, 1H),
1.39 (d, J = 6.4 Hz, 3H); 13
C NMR (CDCl3, 100 MHz): 161.00, 149.14, 132.46, 131.36, 131.04,
123.90, 123.54, 75.11, 62.48, 20.99; IR (NaCl Plate): 2917, 1660, 1534, 1356 cm-1
.
4-methyl-2-(perfluorophenyl)-4,5-dihydrooxazole (entry 8, table 5).
Reaction performed by representative procedure beginning with 75 mg of the
34
corresponding aziridine. Purification was performed by flash column chromatography (83%
hexanes, 17% ethyl acetate) yielding 24 mg (34%) of oxazoline. HRMS: Calculated for
C10H6F5NO: 252.0448 (M+H+), found 252.0449 (M+H
+);
1H NMR (CDCl3, 400 MHz): 4.56 (t,
J = 8 Hz, 1H), 4.46 (m, 1H), 4.02 (t, J = 8 Hz, 1 H), 1.40 (d, J = 6.8 Hz, 3H); 13
C NMR (CDCl3,
100 MHz): 153.97, 146.86, 146.81, 146.74, 144.37, 144.30, 144.25, 144.19, 144.14, 144.02,
143.94, 143.89, 143.84, 143.76, 141.45, 141.37, 141.32, 141.27, 141.19, 139.15, 139.11, 139.00,
138.95, 138.88, 138.81, 136.66, 136.59, 136.52, 136.47, 136.39, 136.32, 105.13, 105.08, 104.97,
104.93, 104.81, 104.78, 74.32, 62.54. 21.23; IR (NaCl Plate): 2975, 1625, 1502, 994 cm-1
.
2-(3,5-dinitrophenyl)-4-hexyl-4,5-dihydrooxazole (52).
Reaction performed by representative procedure beginning
with 88 mg of the corresponding aziridine. Purification was
performed by flash column silica gel chromatography (83%
hexanes, 17% ethyl acetate) yielding 85 mg (94%) of oxazoline. HRMS: Calculated for
C15H19N3O5: 322.1403 (M+H+), found 322.1398 (M+H
+);
1H NMR (CDCl3, 400 MHz): 9.13 (t,
J = 2 Hz, 1 H), 9.09 (d, J = 2 Hz, 2 H), 4.62 (dd, J = 9.2, 8.8 Hz, 1 H), 4.39 (m, 1 H), 4.16 (t, J =
8 Hz, 1 H), 1.77 (m, 1 H), 1.53 (m, 9 H), 0.903 (t, J = 6.8 Hz, 3 H); 13
C NMR (CDCl3, 100
MHz): 159.64, 148.52, 131.76, 128.18, 120.64, 73.72, 67.43, 35.78, 31.73, 29.22, 25.86, 22.61,
14.08; IR (NaCl Plate): 3101, 1544, 1466, 1344 cm-1
.
2-(3,5-dinitrophenyl)-4-(hex-5-en-1-yl)-4,5-dihydrooxazole
(54). Reaction performed by representative procedure
beginning with 87 mg of the corresponding aziridine.
35
Purification was performed by flash column silica gel chromatography (83% hexanes, 17% ethyl
acetate) yielding 64 mg (73%) of oxazoline. HRMS: Calculated for C15H17N3O5: 320.1246
(M+H+), found 320.1252 (M+H
+);
1H NMR (CDCl3, 400 MHz): 9.14 (t, J = 2 Hz, 1 H), 9.10 (
d, J = 2 Hz, 2 H), 5.83 (m, 1 H), 5.00 (m, 2 H), 4.63 (dd, J = 9.6, 8.4 Hz, 1H), 4.39 (m, 1 H), 4.16
(t, J = 8 Hz, 1 H), 2.1 (m, 2 H), 1.78 (m, 1 H), 1.54 (m, 5 H); 13
C NMR (CDCl3, 100 MHz):
159.72, 148.52, 138.62, 131.70, 128.21, 120.69, 114.69, 73.71, 67.35, 35.62, 33.60, 28.76,
25.36; IR (NaCl Plate): 3099, 1653, 1544, 1344 cm-1
.
4-(tert-butyl)-2-(3,5-dinitrophenyl)-4,5-dihydrooxazole17
(58).
Reaction performed by representative procedure beginning with 88 mg of
the corresponding aziridine. Purification was performed by flash column
silica gel chromatography (83% hexanes, 17% ethyl acetate) yielding 86
mg (98%) of oxazoline. HRMS: Calculated for C13H15N3O5: 294.1090 (M+H+), found 294.1089
(M+H+);
1H NMR (CDCl3, 400 MHz): 9.14 (t, J = 2 Hz, 1H), 9.10 (d, J = 2 Hz, 2 H), 4.49 (dd,
J = 10.4, 8.8 Hz, 1 H), 4.35 (t, J = 8.4 Hz, 1 H), 4.16 (dd, J = 10, 8.4 Hz, 1 H), .988 (s, 9 H); 13
C
NMR (CDCl3, 100 MHz): 159.00, 148.52, 131.75, 128.19, 120.61, 69.91, 34.10, 25.86; IR
(NaCl Plate): 2956, 1657, 1545, 1343 cm-1
.
2-(3,5-dinitrophenyl)-4-(phenoxymethyl)-4,5-dihydrooxazole
(62). Reaction performed by representative procedure beginning
with 50 mg of the corresponding aziridine. Purification was
performed by flash column silica gel chromatography (75%
hexanes, 25% ethyl acetate) yielding 33 mg (66%) of oxazoline. HRMS: Calculated for
36
C16H13N3O6: 344.0883 (M+H+), found 344.0887 (M+H
+);
1H NMR (CDCl3, 400 MHz): 9.16 (t,
J = 2 Hz, 1 H), 9.12 (d, J = 2 Hz, 2 H), 7.29 (m, 2 H) 6.95 (m, 3 H), 4.83 (m, 1 H), 4.72 (dd, J =
9.6, 8.4 Hz, 1 H), 4.62 (dd, J = 8.4, 7.2 Hz, 1 H) 4.28 (dd, J = 9, 4 Hz, 1 H), 4.13 (dd, J = 9, 6 Hz,
1H); 13
C NMR (CDCl3, 100 MHz): 161.55, 158.39, 148.55, 131.25, 129.58, 128.37, 121.42,
120.99, 114.59, 71.43, 68.93, 66.56; IR (NaCl Plate): 3099, 2925, 1543, 1344 cm-1
.
4-((benzyloxy)methyl)-2-(3,5-dinitrophenyl)-4,5-
dihydrooxazole (60). Reaction performed by representative
procedure beginning with 107 mg of the corresponding
aziridine. Purification was performed by flash column silica
gel chromatography (75% hexanes, 25% ethyl acetate) yielding 68 mg (67%) of oxazoline.
HRMS: Calculated for C17H15N3O6: 358.1039 (M+H+), found 358.1043 (M+H
+);
1H NMR
(CDCl3, 400 MHz): 9.13 (t, J = 2.4 Hz, 1 H), 9.09 (d, J = 2 Hz, 2H), 7.31 (m, 5 H), 4.61 (m, 4
H), 4.47 (m, 1 H), 3.76 (dd, J = 4.4, 2.4 Hz), 3.64 (dd, J = 10, 5.2 Hz); 13
C NMR (CDCl3, 100
MHz): 161.08, 148.49, 137.76, 131.44, 128.48, 128.30, 127.87, 127.75, 120.82, 77.39, 77.07,
76.76, 73.53, 71.46, 71.26, 67.08; IR (NaCl Plate): 3099, 2919, 1543, 1344 cm-1
.
2-(3,5-dinitrophenyl)-4-isopropyl-4,5-dihydrooxazole17
(56). Reaction
performed by representative procedure beginning with 84 mg of the
corresponding aziridine. Purification was performed by flash column silica
gel chromatography (83% hexanes, 17% ethyl acetate) yielding 67 mg
(80%) of oxazoline. Calculated for C12H13N3O5: 280.0933 (M+H+), found 280.0933 (M+H
+);
1H
NMR (CDCl3, 400 MHz): 9.14 (t, J = 2.4 Hz, 1 H), 9.10 (d, J = 2.4 Hz, 2 H), 4.56 (dd, J = 9.2, 8
37
Hz, 1 H), 4.22 (m, 2 H), 1.90 (m, 1 H), 1.07 (d, J = 6.8 Hz, 3 H), .98 (d, J = 6.8 Hz); 13
C NMR
(CDCl3, 100 MHz): 159.61, 148.51, 131.74, 128.19, 120.63, 73.23, 71.46, 32.86, 18.81, 18.31;
IR (NaCl Plate): 2961, 1656, 1544, 1344 cm-1
.
Procedure for the rearrangement of an enantioenriched aziridine
The enantiopure aziridine 65 (0.2 mmol, 56 mg) and 9.5 mg (0.02 mmol) of X-Phos (40)
were weighed into an oven-dried reaction vial. Dry tetrahydrofuran (1 mL) was added under
argon. The solution was heated at 70 °C under argon for 24 hours. Volatiles were removed by
rotary evaporator. The crude reaction mixture was purified via flash column silica gel
chromatography (83% hexanes, 17% ethyl acetate) to form 53 mg (94%) of the enantiopure
oxazoline 66 as a white solid. The NMR data for enantiopure oxazoline was identical to (56).
Enantiomers of the starting aziridine and oxazoline were separated using a Chiralpak I-B column
(Daicel Chemical Ind.) on HPLC with 85% hexanes, 15% isoproanol as the mobile phase.
2
Chapter 2: KINETIC RESOLUTION OF N-ACYL AZIRIDINES
39
INTRODUCTION
Over the past few decades there has been an increased interest in the generation of bio-
active organic compounds that are single enantiomers. A vast majority of these compounds
contain a carbon–nitrogen bond. Since aziridines possess a chiral carbon and two reactive
carbon–nitrogen bonds, they are key intermediates for the synthesis of chiral bio-active
molecules. Despite their importance in synthesis, methods to produce aziridines as single
enantiomers remains underdeveloped. Progress has been made with aziridine synthesis but
generation in enantiopure form is still a formidable challenge.18-23
There are known synthetic
routes from alkenes to aziridines,24-32
some of which are catalytic enantioselective routes. These
utilize a small range of substrates which thereby decreases the usefulness of the resulting
aziridine. Kinetic resolution of racemic aziridines to form enantiopure aziridines is a viable
solution to the problem.
A kinetic resolution is a process in which one of the two enantiomers of a racemic
mixture is more readily converted to product than the other (Figure 14). In order for a kinetic
resolution to occur kR ≠ kS and the reaction is halted between 0 and 100% conversion. The
desired reaction is one in which only one enantiomer reacts (kS>>kR), in such that 50%
conversion of a mixture yields 50% R enantiomer and 50% product Q. Either a chiral catalyst or
chiral reagent is utilized to effect the difference in rate constants.33
Figure 14: Kinetic resolution of two enantiomers.
40
Efficiency of a kinetic resolution is given by the rate constant ratio krel= k1/k2 = s (s is the
stereoselectivity value). This stereoselectivity value (s) can be calculated by using equation 5 or
6, where c is equivalent to conversion (0≤c≤1), eesm and eeprod (0≤eesm, eeprod ≤ 1) are
enantiomeric excesses of the product and starting material.34
Kinetic resolution has revolutionized asymmetric synthesis for epoxides, the oxygen
containing heterocycle equivalent of aziridines, despite a maximum yield of only 50%. The
Jacobsen hydrolytic kinetic resolution (HKR)35
is an efficient route to enantiopure terminal
epoxides which are useful intermediates for further synthesis (Figure 15). The HKR produces
epoxides with very high krel values (as high as 1000). The racemic epoxides are readily produced
from alkenes in a single step synthetic step.
Figure 15: Jacobsen Hydrolytic Kinetic Resolution
Leung and coworkers have reported a kinetic resolution of racemic N-tosyl aziridines
using a chiral dicationic Pd(II) complexes (74, Figure 16). By treating a racemic N-tosyl
41
aziridine (75) with 0.5 equivalents of alcohol while in the presence of 10 mol % of 74, they were
able to isolate 2-alkoxy tosylamide 76 with a minor product of 2-hydroxy tosylamide 77 (Figure
17).36
The highest observed selectivity value was 8, with a majority of substrates leading to
lower values.
Figure 16: Palladium Catalyst
Figure 17: Pd-Catalyzed Asymmetric Alcoholysis
Even though aziridines and epoxides are analogues of one another their reactivity is
quite different.37
One of the complexities with developing asymmetric reactions of aziridines is
linked to the nitrogen-bound protecting group that is required to facilitate opening of the
aziridine ring. Binding of a Lewis acid to the aziridine is preferred but sites on the protecting
group that are Lewis basic often interfere with this binding. For this reason, the previously
mentioned Jabcobsen’s kinetic resolution has not been successful with aziridines.
Aziridines can be opened in the presence of aryl borates. Aziridine 78 will undergo a
ring opening when in the presence of aryl borates to yield 79 and 80 as a mixture of phenol
42
adducts (Figure 18).38
Using similar reaction conditions39
, aziridines will undergo a reaction to
selectively form a new carbon–carbon bond thereby generating only the ortho-phenol derivative.
Knowing that borates would open aziridines we thought if we could introduce chirality into the
reaction we would be able to effect a resolution.
Figure 18: Aziridine opening by borates.
Chiral borates have been used to aid both Diels–Alder40-45
and Mukiayama aza-aldol
reactions.46-47
Most of these reactions are aryl borates with the source of chirality from BINOL.
Yamamoto and coworkers early work was with borate 82. This was generated by mixing 1
equivalent of BINOL with 1 equivalent of triphenyl borate (B(OPh)3). Further research by
Yamamoto discovered that 1 equivalent of BINOL and 0.5 equivalents of B(OPh)3 generated
borate 83. The structure of 83 has been verified by X-ray crystallography.
43
Figure 19: Borate synthesis.
RESULTS AND DISCUSSION
Research on the resolution of aziridines began with the exploration of reaction conditions
and varying substrates. The resolution chemistry involves the addition of triphenyl borate
(B(OPh)3) to a solution (R)-BINOL and aziridine. Triphenyl borate is extremely air/moisture
sensitive, so a solution is prepared in a glove box. This solution is then added to the
aziridine/BINOL solution slowly as to maintain the reaction temperature. The reaction is
allowed to run at the determined temperature and time and is then quenched with methanol.
Passing the reaction mix through a silica plug is used to remove any residual borate, and the
yield is determined by 1H-NMR and the use of 1,3,5-trimethoxybenzene as an internal standard.
Conversion, which is necessary for the selectivity (s) value calculation, is reported as % yield.
Concentration of the reaction mixture without removal of boron using silica gel lead to higher
conversions. Calculations are exactly the same as shown previously. Enantiomeric excess was
determined by HPLC with the use of a chiral column. HPLC conditions were determined by
44
running a racemic mix of the aziridine and adjusting solvent polarity until the desired resolution
was achieved.
All of the initial work on resolution project was performed by another graduate student
(Mr. Jared Arnette) as seen in Table 6. Research on the resolution of aziridines started with the
addition of a solution of triphenylborate (B(OPh)3) to (R)-BINOL 81 and aziridine 84 in
dichloromethane at -78 °C (Table 5). Early data suggested that the use of polar, aprotic solvents
resulted in very poor reactivity. N-acyl aziridines and N-acyloxy aziridines exhibited a fast ring
opening reaction when reacted with BINOL at -78°C (entries 1–3). Replacing B(OPh)3 with
trimethyl borate (B(OCH)3) generated no consumption of aziridine. The nitrogen protecting
group greatly affects the selectivity. N-Acylaziridines exhibit the best of both conversion and
selectivity (entries 1 and 2). A carbamate exhibited no enantiomer selectivity but had excellent
reactivity (entry 3). Currently it is not apparent if electronics or sterics are responsible for
optimal selectivity.
The substituent that is attached to the carbon backbone may affect the selectivity (s)-
value. Two substrates were synthesized to consider aziridine substitution. It was a delighting
discovery to find that increases the size of R also resulted in an increase in the s-value for N-
acylaziridines (entries 5 and 6). The 3,5-dinitrobenzoyl protecting group was superior to the 3,5-
bis(trifluoromethyl)benzoyl group (entry 7). With this preliminary data in hand, further
experiments were designed for reaction optimization.
45
Table 5: Kinetic resolution initial experimental results.
Further experimental exploration involved the kinetic resolution of different aziridines
with varying substitutions under a set of standard conditions. Since the dinitro-protected
aziridines provided the most promising results, this group was used with varying substituted
aziridines that were synthesized. Experimental exploration began with a long chain hexyl
substituted aziridine (Table 6).
The initial run with a 2-hexyl aziridine was performed under standard conditions for 3
hours and was quite promising with an enantiomeric excess of 83% (entry 1). The s-value was
encouraging at 28. Considering that solubility may be an issue, several experiments were run
with dichloromethane (DCM) instead of toluene (entries 2–4). All other experimental conditions
were held constant. Employing DCM resulted in a higher conversion, a higher enantiomeric
46
excess, but unfortunately a significantly lower s-value. In light of these results we returned to
toluene as the reaction solvent (entries 5 and 6). In an attempt to increase the enantiomeric
excess, the catalyst amount was increased from 0.1 equivalents to 0.2 equivalents (entries 7–9).
The initial run was promising with an enantiomer excess of 89.9% and a surprising s-value of
47.0. We were skeptical of this result with the large increase in s-value compared to previous
data. The following experiments demonstrated that the enantiomeric excess could be increased
and the s-value maintained.
47
Table 6: Experimental results long chain substituted aziridine.
The next substrate to be explored was a tert-butyl substituted aziridine with the di-nitro
protecting group (Table 7). The initial run was performed at room temperature, instead of the
normal lowered temperature because the substrate had low solubility in toluene. The results of
the first run were disappointing (entry 1). Due to the low conversion, the enantiomeric excess
and s-value were not determined. We considered the low solubility may be hindering reactivity,
so the solvent was switched to DCM in an attempt to get the aziridine to fully dissolve (entry 2).
After 30 minutes at -20 °C only 13.4% conversion was observed. Due to these initial findings
and the availability of other substrates no further effort was spent on this compound.
48
Table 7: Experimental results tert-butyl aziridine.
Further exploration was attempted with a benzyl substituted aziridine containing the di-
nitro protecting group (Table 8). The initial run was performed at room temperature for only 30
minutes resulting in a very high conversion of the aziridine, but with a low selectivity (entry 1).
The temperature was then lowered in an attempt to decrease the amount of conversion (entry 2).
The lower temperature definitely slowed the conversion, but it also negatively impacted the
enantiomeric excess. There was also minimal improvement of the selectivity given by the small
increase in the s-value. We then dropped the temperature to -40 °C and increased the reaction
time to 1 hour (entries 3 and 4). The results of these two runs were not positive. Further
reactions were run at -40 °C under the standard 3 hour reaction time (entries 5–8). The results of
these runs were somewhat inconsistent but none of the resulting were outstanding. One run
looked promising with an enantiomeric excess of 93% and an s-value of 13.3 (entry 5).
However, repeated attempts could not reproduce this result.
49
Table 8: Experimental results O-benzyl aziridine.
The next substrate explored was an isopropyl substituted di-nitro protected aziridine,
(Table 9). The researchers were very excited with the high enantiomeric excess (ee) and s-value
of the first run (entry 1). Based on these high values, the reaction time was reduced to 1 hour
(entry 2). This resulted in a large s-value with a reduced ee. This particular run was repeated in
an attempt to duplicate the results; however, experimental error resulted in a negative s-value
(entry 3).
50
Table 9: Experimental results isopropyl substituted aziridine.
Efforts were then placed on the resolution of a methyl substituted aziridine with the di-
nitro protecting group. The results of these experiments appear in Table 10. This substrate was
challenging in that it was difficult to get reproducible results. Four runs were performed at the
standard 3 hour reaction time (entries 1–4). The values for conversion and ee were inconsistent
and the selectivity is very poor as well. For two of the runs the ee and s-value were not
determined because of the high conversion numbers (entries 3 and 4). In an attempt to lower the
conversion and hopefully increase the selectivity, the reaction time was lowered to one hour
(entry 5 and 6). This effectively lowered the conversion and generated results that seem to be
reproducible. The selectivity was so low that no further experiments were run with this
substrate.
51
Table 10: Experimental results methyl aziridine.
The final substrate for which reaction optimization experiments were performed was a
long chained alkene substituted aziridine with the di-nitro protecting group Table 11. Initial
reactions were run under the normal 3 hour reaction time (entries 1 and 2). Unfortunately, this
resulted in high conversion, with high ee and a very poor selectivity. The reaction time was
lowered to 2 hours to bring the conversion down (entries 3 and 4). This worked in lowering the
conversion. For both runs the ee was high but the s-value could not be determined for entry 3.
52
Table 11: Experimental results long chain terminal alkene substituted aziridine.
Substrate Scope
Once optimized conditions were realized, efforts were placed on determining values
based on isolated yields of compounds. Unfortunately due to time constraints values for only 2
substrates were realized.
Table 12: Experimental isolated results for isopropyl substituted aziridine.
53
Table 13: Experimental isolated results for long chain alkene substituted aziridine.
Conclusions
Here we have demonstrated a new pathway for the resolution of racemic acyl aziridines
to their enantioenriched counterpart, using a borate and (R)-BINOL. A variety of N-acyl
aziridines were explored under these conditions with varying success. The enantioenriched
aziridines may prove to be useful in further asymmetric synthesis of new compounds.
54
EXPERIMENTAL
General. 1H NMR spectra were recorded on Bruker DRX (400 MHz). Chemical shifts are
reported in ppm from tetramethylsilane with the solvent resonance as the internal standard
(CDCl3: 7.27 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz),
and assignment. 13
C NMR spectra were recorded on a Bruker DRX 400 (100 MHz) and a
Bruker DRX 600 (NSF #0821552) spectrometer with complete proton decoupling. Chemical
shifts are reported in ppm from tetramethylsilane with the solvent as the internal standard
(CDCl3: 77.0 ppm). High resolution mass spectrometry was acquired with an Agilent DART-
TOF at Duke University. Infrared (IR) spectra were obtained using a Nicolet 6700 FT-IR.
Liquid chromatography was performed using forced flow (flash chromatography) on
EMD Chemicals Geduran® 60 silica gel (SiO2, 40 to 63m) purchased from VWR International.
Thin layer chromatography (TLC) was performed on EMD Chemicals 0.25 mm silica gel 60
plates. Visualization was achieved with UV light or basic potassium permanganate in water
followed by heating.
All reactions were conducted in oven and flame dried glassware under an inert
atmosphere of nitrogen. All solvents were EMD Chemicals anhydrous solvents sold by VWR
International. Each solvent was purged with Argon for a minimum of 15 minutes and stored
over activated 3Å molecular sieves in sure-seal bottles. All remaining chemicals were purchased
from Alfa Aesar, TCI International, or Aldrich Chemical Company and were used as received.
HPLC Methodology
55
Enantiomers of the starting aziridine and enantioenriched aziridine product were separated using
a Chiralpak I-B column (Daicel Chemical Ind.) on HPLC with varying mobile phases of
hexanes, isopropanol.
Reaction Optimization
An oven dried vial with stir bar was charged with the corresponding aziridine (1 equiv.)
and (R)-BINOL (0.55 equiv.). Dry toluene (0.2 M) was then added via syringe. The solution
was then allowed to cool down to the reaction temperature. A stock solution of B(OPh)3 (0.1
equiv.) in toluene (26 µL) was added to the aziridine solution dropwise over several minutes.
Once all of the borate was added the solution was allowed to stir at temperature for 3 hours. The
reaction was then quenched with methanol (5 equiv.) and diluted with hexanes. The solution
was passed through a small silica plug and eluted with a solution 9:1 hexanes/ethyl acetate.
Percent yields were then determined by 1H-NMR and the use of an internal standard (1,3,5-
trimethoxybenzene). Enantiomeric excess was determined by HPLC and the use of a chiral
column.
Experimental conditions of isolated yields
(3,5-dinitrophenyl)(2-isopropylaziridin-1-yl)methanone (Table 12) The
representative procedure was followed using 111.7 mg of the corresponding
aziridine and 62.9 mg of (R)-BINOL. A solution of B(OPh)3 (93 mg) in toluene
(250 µL, 0.2 M) was prepared in an oven dried vial within a glove box.
Approximately 27 µL of this solution was added to the aziridine solution dropwise over several
minutes. Purification was performed by flash column silica gel chromatography (84% hexanes,
16% ethyl acetate) yielding 58.5 mg (52.3%) of enantiopure aziridine. 1H-NMR data as
56
described in Chapter 1. Enantiomers were separated by HPLC using a IB Chiral column with
85% hexanes and 15% Isopropanol with a flow rate of 1 mL/min.
Figure 20: HPLC of racemic aziridine (left) and enantioenriched (right).
(3,5-dinitrophenyl)(2-(hex-5-en-1-yl)aziridine-1-yl)methanone (Table 13)
The representative procedure was followed using 127.6 mg of the
corresponding aziridine and 62.9 mg of (R)-BINOL. A solution of B(OPh)3
(93 mg) in toluene (250 µL, 0.2 M) was prepared in an oven dried vial within
a glove box. Approximately 27 µL of this solution was added to the aziridine solution dropwise
over several minutes. Purification was performed by flash column silica gel chromatography
(80% hexanes, 20% ethyl acetate) yielding 21.1 mg (16.5%) of enantiopure aziridine. 1H-NMR
data as described in Chapter 1. Enantiomers were separated by HPLC using a IB Chiral column
with 85% hexanes and 15% Isopropanol with a flow rate of 1 mL/min.
57
Figure 21: HPLC of racemic aziridine (left) and enantioenriched (right).
58
REFERENCES
1. Bach, R.D.; Dmitrenko. Effect of Geminal Substitution on the Strain Energy of Dioxiranes.
Origin of the Low Ring Strain of Dimethyldioxirane. O. J. Org. Chem. 2002, 67, 3884 – 3896.
2. Kumar, M., Pandey, S.K., Gandhi, S., Singh, V.K., PPh3/halogenating agents-mediated highly
efficient ring opening of activated and non-activated aziridines, Tetrahedron Lett. (2009), 50,
363 – 365.
3. Fyaz M.D. Ismail; Dmitri O. Levitsky; Valery M. Dembitsky. Aziridine alkaloids as potential
therapeutic agents. European Journal of Medicinal Chemistry. 2009, 44, 3373 – 3387.
4. (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Wein
(b) Hu, X. E. Nucleophilic Ring Opening of Aziridines. Tetrahedron 2004, 60, 2701 – 2743.
5. Gant, Thomas; Meyers, A.I. The Chemistry of 2-Oxazolines (1985-Present). Tetrahedron
1994, 50, 2297 – 2360.
6. (a) Martin Glos; Oliver Reiser. Aza-bis(oxazolines): New Chiral Ligands for Asymmetric
Catalysis. Org. Lett. 2000, 14, 2045 – 2048.
(b) Gunter, Helmchen; Adreas Pflatz. Phosphinooxazolines-A New Class of Versitile, Modular
P,N-Ligand for Asymmetric Catalysis. Acc. Chem. Res. 2000, 33, 336 – 345.
(c) Hisao, Nishiyama; et. Al. Chiral and C2-Symmetrical Bis(oxazolinylpyridine)rhodium(III)
Complexes: Effective Catalysts for Asymmetric Hydrosilyation of Ketones. Organometallics
1989, 8, 846 – 848.7. Singh et al., Synthesis and Reactivity of C-Heteroatom-Substituted
Aziridines. Chem. Rev. 2007, 107, 2080 – 2135.
8. Heine, H. W.; Fetter, M. E.; Nicholson, E.M. The Isomerization of Some 1-Aroylaziridines.
J. Am. Chem. Soc. 1959, 81, 2202 – 2204.
9. Heine, H. W.; Bender, H. S. The Isomerization of Some Aziridine Derivatives. 111. A New
Synthesis of 2-Imidazolines. J. Org. Chem. 1960, 25, 461 – 463.
10. (a) Hou, X.-L.; Fan, R.-H.; Dai, L.-X. Tributylphosphine: A Remarkable Promoting Reagent
for the Ring-Opening Reaction of Aziridines. J. Org. Chem. 2002, 67, 5295 – 5300. (b) Fan, R.-
H.; Hou, X.-L.; Dai, L.-X. Formation of P-Ylide under Neutral and Metal-Free Conditions:
Transformation of Aziridines. J. Org. Chem. 2004, 69, 689 – 694.
11. (a) Fanta, P. E.; Walsh, E. N. Aziridines. XIV. 3-Oxa-6-azabicyclo[3.1.0]hexane. J. Org.
Chem. 1966, 31, 59–62. (b) Szeimies,G.;Mannhardt,
K.; Junius, M. On the Electron Donor Ability of the Aziridine Carbon. Chem. Ber. 1977, 110,
1792–1803.
12. Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. De Novo Synthesis of Tamiflu
via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3. J. Am. Chem. Soc.
2006, 128, 6312 – 6313.
13. Xu, J. A new and expeditious asymmetric synthesis of (R)- and (S)-2-aminoalkanesulfonic
acids from chiral amino alcohols. Tetrahedron: Asymmetry 2002, 13, 1129 – 1134.
14. McKennon, M. J.; Meyers, A. I. A Convenient Reduction of Amino Acids and
Their Derivatives. J. Org. Chem. 1993, 58, 3568 – 3571.
15. Chamchaang, W.; Pinhas, A. R. The conversion of an aziridine to a .beta.-lactam. J. Org.
Chem. 1990, 55, 2943 – 2950.
16. Preston, A. J.; Fraenkel, G.; Chow, A.; Gallucci, J. C.; Parquette, J. R. Dynamic Helical
Chirality of an Intramolecularly Hydrogen-Bonded Bisoxazoline. J. Org. Chem. 2003, 68, 22 –
26.
59
17. Wipf, P.; Wang, X. Parallel Synthesis of Oxazolines and Thiazolines by Tandem
Condensation-cyclodehydration of Carboxylic Acids with Amino Alcohols and Aminothiols. J.
Comb. Chem. 2002, 4, 656 – 660.
18. Antilla, J.C.; Wuff, W.D. Catalytic Asymmetric Aziridination with a Chiral VAPOL-Boron
Lewis Acid. J. Am. Chem. Soc. 1999, 121, 5099 – 5100.
19. Kim, S. K.; Jacobsen, E. N. General Catalytic Synthesis of Highly Enantiomerically
Enriched Terminal Aziridines from Racemic Expoxides. Angew. Chem., Int. Ed. 2004, 43, 3952
– 3954.
20. Malkov, A. V.; Stoncius, S.; Kocovsky, P. Enantioselective Synthesis of 1,2-
Diarylaziridines by the Organocatalytic Reductive Amination of a-Chloroketones. Angew Chem.,
Int. Ed. 2007, 46, 3722 – 3724.
21. Vesely, J.; Ibrahem, I.; Zhao, G. L.; Rios, R.; Cordova, A. Organocatalytic Enantioselective
Aziridination of α,β-Unsaturated Aldehydes. Angew Chem., Int. Ed. 2007, 46, 778 – 781.
22. Minakata, S.; Murakami, Y.; Tsuruoka, R.; Kitanaka, S.; Komatsu, M. Catalytic
Aziridination of Electron-Deficient Olefins with an N-Chloro-N-sodio Carbamate and
Application of this Novel Method to Asymmetric Synthesis. Chem. Commun. 2008, 6363 –
6365.
23. Subbarayan, V.; Ruppel, J.V.; Zhu, S.; Perman, J.A.; Zhang, X.P. Highly Asymmetric
Cobalt-Catalyed Aziridination of Alkenes with Trichloroethoxysulfonyl Azide (TcesN3). Chem.
Commun. 2009, 4266 – 4268.
24. Evans, D.A.; Faul, M. M.; Bilodeau, M.T. Copper-Catalyzed Aziridination of Olefins by (N-
(Para-Toluenesulfonyl)Imino)Phenyliodinane. J. Org. Chem. 1991, 56, 6744 – 6746.
25. Jeong, J.U.; Tao, B; Sagasser, I.; Henniges, H.; Sharpless, K.B. Bromine-Catalyzed
Aziridination of Olefins. A Rare Example of Atom-Transfer Redox Catalysis by a Main Group
element. J. Am. Chem. Soc. 1998, 120, 6844 – 6845.
26. Guthikonda, K.; Du Bois, J. A Unique and Highly Efficient Method for Catalytic Olefin
Aziridination. J. Am. Chem. Soc. 2002, 124, 13672 –13673.
27. Cui, Y.; He, C. Efficient Aziridination of Olefins Catalyzed by a Unique Disilver(I)
Compound. J. Am. Chem. Soc. 2003, 125, 16202 – 16203.
28. Catino, A. J.; Nichols, J. M.; Forslund, R.E.; Doyle, M. P. Efficient Aziridination of Olefins
Catalyzed by Mixed-Valent Dirhodium (II, III) Caprolactamate. Org. Lett. 2005, 7, 2787 – 2790.
29. Watson, I. D. G.; Yu, L. L.; Yudin, A. K. Advances in Nitrogen Transfer Reactions
Involving Aziridines. Acc. Chem. Res. 2006, 39, 194 – 206.
30. Lebel, H.; Lectard, S.; Parmentier, M. Copper-Catalyzed Alkene Aziridination With N-
tosyloxycarbamates. Org. Lett. 2007, 9, 4797 – 4800.
31. Fan, R. H.; Pu, D. M.; Gan, J. H.; Wang, B. PhI(OAc)2/I2 Induced Aziridination of Alkenes
with TsNH2 Under Mild Conditions. Tetrahedron Lett. 2008, 49, 4925 – 4928.
32. Varszegi, C.; Ernst, M.; van Laar, F.; Sels, B.F.; Schwab, E.; De Vos, D.E. A Micellar
Iodide-Catalyzed Synthesis of Unprotected Aziridines from Styrenes and Ammonia. Angew
Chem., Int. Ed. 2008, 47, 1477 – 1480.
33. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249 – 330.
34. Timo O. Luukas, Christian Girard, David R. Fenwick, and, Henri B. Kagan. Kinetic
Resolution When the Chiral Auxiliary Is Not Enantiomerically Pure: Normal and Abnormal
Behavior. J. Am. Chem. Soc. 1999, 121, 9299 – 9306.
60
35. Tokunaga, M; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Asymmetric Catalysis with
Water: Efficient Kinetic Resolution of Terminal Epoxides by Mean of Catalytic Hydrolysis.
Science 1997, 277, 936 – 938.
36. Wa-Hung Leung, Wing-Leung Mak, Eddie Y. Y. Chan, Tony C. H. Lam, Wing-Sze Lee,
Hoi-Lun Kwong, Lam-Lung Yeung. Palladium-based Kinetic Resolution of Racemic
Tosylaziridines. Synlett 2002,1688–1690
37. Sweeney, J. B. Aziridines: Epoxides’ Ugly Cousin? Chem. Soc. Rev. 2002, 31, 247 – 258.
38. Pineschi, M; Bertolin, F.; Haak, R. M.; Crotti, P.; Macchia, F. Mild Metal-Free syn-
Stereoselective Ring Opening of Activated Epoxides and Aziridines with Aryl Borates. Chem.
Commun. 2005, 1426 – 1428.
39. Pineschi, M.; Bertolini, F.; Crotti, P.;Macchia, F. Facile Regio- and Stereoselective Carbon-
Carbon Coupling of Phenol Derivatives with Aryl Aziridines. Org. Lett. 2006, 8, 2627 – 2630.
40. Kelly, T. R; Whiting, A.; Chandrakumar, N.S. A Rationally Designed, Chiral Lewis Acid for
the Asymmetric Induction of Some Diels-Alder Reactions. J. Am. Chem. Soc. 1986, 108, 3510 –
3512.
41. Kaufmann, D.; Boese, R. A Borate Propeller Compound as Chiral Catalyst for an
Asymmetrically Induced Diels-Alder Reaction. Angew. Chem., Int. Ed. Engl. 1990, 29, 545 –
546.
42. Hattori, K.; Yamamoto, H. Asymmetric Aza-Diels-Alder Reaction Mediated by Chiral
Boron Reagent. J. Org. Chem. 1992, 57, 3564 – 3265.
43. Ishihara, K.; Yamamoto, H. Bronsted Acid Assisted Chiral Lewis-Acid (BLA) Catalyst for
Asymmetric Diels-Alder Reaction. J. Am. Chem. Soc. 1994, 116, 1561 – 1562.
44. Ishihara, K.; Kurihara, H.; Yamamoto, H. A New Powerful and Practical BLA Catalyst for
Highly Enantioselective Diels-Alder Reaction: An Extreme Acceleration of Reaction Rate by
Bronsted Acid. J. Am. Chem. Soc. 1996, 118, 3049 – 3050.
45. Cros, J. P.; Perex-Fuertes, Y.; Thatcher, M.J.; Arimori, S.; Bull, S.D.; James, T.D. Non-
Linear Effects Operate and Dynamic Ligand Exchange Occurs when Chiral BINOL-Boron
Lewis Acids are Used for Asymmetric Catalysis. Tetrahedron: Asymmetry 2003, 14, 1965 –
1968.
46. Hattori, K.; Miyata, M.; Yamamoto, H. Highly Selective and Operationally Simple
Synthesis of Enantiomerically Pure Beta-Amino Esters Via Double Stereodifferentiation. J. Am.
Chem. Soc. 1993, 115, 1151 – 1152.
47. Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. A New Chiral BLA Promoter
for Asymmetric Aza-Diels-Alder and Aldol-Type Reactions of Imines. J. Am. Chem. Soc. 1994,
116, 10520 – 10524.
61
APPENDIX
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Appendix 4.
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