Preparation and reactivity of versatile α-amino ketones

Article abstract of DOI:10.1021/jo062401o

Many challenges of chemoselectivity arise from the requirement to manipulate incompatible functional groups. Synthetic methods that do not rely on protecting groups are of strategic significance to chemical synthesis. Particularly valuable are molecules w

Full text of DOI:10.1021/jo062401o

Preparation and Reactivity of Versatile r-Amino Ketones
Lily Yu, Akos Kokai, and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, The UniVersity of Toronto,
8
0 St. George Street, Toronto, Canada, M5S 3H6
ayudin@chem.utoronto.ca
ReceiVed NoVember 21, 2006
Many challenges of chemoselectivity arise from the requirement to manipulate incompatible functional
groups. Synthetic methods that do not rely on protecting groups are of strategic significance to chemical
synthesis. Particularly valuable are molecules with reactive functionalities that are kinetically stabilized
against inter- or intramolecular reactions with each other. We have developed a simple access to molecules
that contain both ketone and N-H aziridine functionalities. These compounds were found to undergo
highly selective reduction and carbonyl addition reactions, making them versatile precursors to complex
amines.
Introduction
Nitrogen-containing functional groups are important con-
stituents of many biologically active molecules. The basic
character of the nitrogen lone pair as well as the hydrogen bond-
donating capacity of the NH group can be affected by substitu-
tion. Therefore, specificity of small molecule/biological target
interactions can be modulated in complex nitrogen-containing
FIGURE 1. The relationship between functional groups in R-amino
ketones.
1
molecules. Condensations between amines and carbonyl com-
2
aldehydes. The aziridine aldehydes developed in our lab display
pounds are central to the construction of such molecules. This
chemistry encompasses reductive amination, enamine formation,
aromatic heterocycle synthesis, and many other reactions.
Unveiling the amine functionality in the presence of an aldehyde
or a ketone is typically done when a condensation between them
has to be initiated. Not surprisingly, an unprotected secondary
amine cannot coexist with an aldehyde or a ketone within the
same molecule for a prolonged period of time. Since amine and
carbonyl groups are not orthogonal to each other, protection/
deprotection sequences are essential (Figure 1). Our recent
strategy of kinetic stabilization of amines against condensation
by way of embedding the nitrogen lone pair within a strained
three-membered ring provides a simple solution to the challenge
of making chemically and configurationally stable amino
“
amphoteric” behavior in that they contain functionalities that
are kinetically stabilized against inter- or intramolecular reac-
tions with each other. They exist as dimers in the solid state
and do not exhibit detectable epimerization. This finding has
initiated a search for routes to other molecules that fulfill the
2
basic requirement of amphoterism. In this paper we report a
new route to stable ketone-containing aziridine templates. The
orthogonality between amine and ketone substituents enables
highly diastereoselective transformations of the carbonyl group.
Results and Discussion
Aziridine-2-carboxylate esters were chosen as starting materi-
als. These molecules are either commercially available or easy
(1) Hili, R.; Yudin, A. K. Nature Chem. Biol. 2006, 2, 284.
(2) Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2006, 128, 14772.
1
0.1021/jo062401o CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/26/2007
J. Org. Chem. 2007, 72, 1737-1741
1737

Yu et al.
SCHEME 1. Preparation of Amide 1a
TABLE 1. Preparation of Aziridine Ketones
a
Reagents and conditions: (a) 1.3 equiv of KOH, EtOH; (b) 1.0 equiv
of DCC, 1.0 equiv of HCl‚NH(CH3)OCH3, CH2Cl2, rt; 60% over two steps;
(c) 3.0 equiv of NaN3, 3.0 equiv of NH4Cl, MeOH, reflux; (d) 1.05 equiv
of PPh3, CH3CN, reflux; 71% over two steps.
SCHEME 2. Addition of Organometallic Reagents to
a
N-Methoxy-N-methyl-2-aziridinecarboxamides
a
Reagents and conditions: (a) RLi or RMgX (2.5 eqiv), THF, -78 °C
or 0 °C f room temperature.
to prepare from the corresponding hydroxyl amino esters, azido
3
esters, R-halo-â-amino esters, olefins, imines, or aldehydes.
Grignard additions to aziridine-2-carboxylate esters resulted in
mixtures of alcohols and ketones. We therefore considered
4
converting the ester moiety into the Weinreb amide. Due to
the acid-sensitive nature of aziridines, the ring opening of the
aziridine ring by chloride anion was observed in our first attempt
5
to prepare the corresponding hydroxylamides. Gratifyingly,
simple reversal of the sequence of amide formation and aziridine
ring-closure steps resulted in a clean formation of the aziridine
6
Weinreb amide.
To prepare 2-ketoaziridines, we explored the addition of
organometallic reagents to 1. We were able to obtain the ketone
products in up to 91% yields (Scheme 2 and Table 1). Contrary
2
to aziridine aldehydes, dimerization of aziridine ketones did
not take place. The scope of this process was extended to alkyl
and aromatic ketones by employing either the iodine-
7
magnesium exchange protocol described by Knochel or directed
8
ortho-metalation. The high isolated yields of alkyl-substituted
ketones are particularly noteworthy. Prior to our work, the routes
to ketone-containing aziridines have been based on addition/
elimination sequences with NH2-X (X: leaving group) reagents
and R,â-unsaturated ketones. This chemistry is restricted to aryl
3
,9
ketones and does not work with enolizable substrates.
(
3) Zhou, P.; Chen, B.-C.; Davis, F. A. In Aziridines and Epoxides in
Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, Germany,
006; p 73.
4) (a) Singh, J. J. Prakt. Chem. 2000, 342, 340-347. (b) Nahm, S.;
2
(
Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(
5) Yu, L; Yudin, A. K. Unpublished results.
(6) For examples of synthesis of N-protected aziridine Weinreb amides
see: (a) Molander, G. A.; Stengel, P. J. Tetrahedron 1997, 53, 8887-
8
2
1
912. (b) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997, 36,
637-2640. (c) Woydowski, K.; Liebscher, J. Synthesis 2000, 10, 1444-
448. (d) Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J. J.
a
Grignard reagents were prepared by iodine-magnesium exchange with
isopropylmagnesium chloride. b Organolithium reagent was generated by
ortho lithiation.
Org. Chem. 2003, 68, 7675-7680.
7) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
302-4320 and references cited therein.
8) (a) Hoarau, C.; Pettus, T. R. R. Synlett 2003, 1, 127-137. (b)
Snieckus, V. Chem. ReV. 1990, 90, 879-933 and references cited therein.
(
When using unsaturated organometallic reagents such as
allyl-, vinyl-, or ethynylmagnesium halides, we observed
complex mixtures of products (Table 1, entries 11-14). The
4
(
9
1738 J. Org. Chem., Vol. 72, No. 5, 2007

Preparation and ReactiVity of Versatile R-Amino Ketones
SCHEME 3. Reactions between Aziridine 1 and
o-Dihalogenated Aromaticsa
FIGURE 2. Hydrogen bonding in aziridinemethanols.
SCHEME 5. Preparation of Silylated Aziridine Alcohol 4ga
a
Reagents and conditions: (a) NaBH4, methanol:dioxane 2:1, 67%; or
a
i
LiAlH4, THF, 79%; (b) TBDMSCl, DMAP, CH2Cl2, 87%.
Reagents and conditions: (a) o-bromoiodobenzene (2 equiv), PrMgCl
i
(
2 equiv), THF, 0 °C; (b) o-fluoroiodobenzene (2 equiv), PrMgCl (2 equiv),
THF, 0 °C.
of the reduction of N-alkyl-2-ketoaziridines have shown wide
variability in the degree and sense of diastereoselection, and
SCHEME 4. Nucleophilic Aromatic Substitution in the
Presence of an Unprotected Aziridine
13
dependence upon the substrate and reducing agent, which
a
14
mirrors the situation with 2-ketoepoxides.
The molecule 3g contains an interesting array of functional
groups. NMR spectroscopic characterization of 3g in both CDCl3
and DMSO-d6 was complicated by the presence of several broad,
unresolved resonances attributed to the aziridine and alcohol
methine protons. Addition of 1 equiv of pyridine to a sample
1
5
in DMSO-d6 improved resolution. This observation reflects a
dynamic equilibrium between the conformational isomers at-
tributable to the slow (on the NMR time scale) inversion at the
a
Reagents and conditions: (a) 1.5 euiv of methylsulfonylethanol, 4.0
equiv of NaH, DMF; 71%.
1
6
aziridine nitrogen. The effect of heating the alcohol with
pyridine likely comes about by deprotonation, resulting in a rigid
hydrogen-bonded five-membered ring, in which the aziridine
corresponding side reactions, such as intermolecular conjugate
addition of aziridines, may account for the difficulties in
isolation.
When o-bromoiodobenzene was used, the unexpected R,â-
unsaturated ketone 2k was isolated as the main product.
However, with o-fluoroiodobenzene as the starting material, the
desired ketone predominated (Scheme 3). By limiting the
reaction time to 30 min, we were able to selectively obtain 2i
along with recovered starting material (Table 1, entry 9).
When treated with methylsulfonylethanol under basic condi-
1
nitrogen does not undergo inversion (Figure 2). The H NMR
1
0
signals that were broad, but distinctly assignable to the product
methine protons, were observed when using methanol-d4 as the
solvent. Not unexpectedly, the rate of inversion at nitrogen is
increased by the disruption of intramolecular hydrogen bonding
in methanol. Gratifyingly, the O-tert-butyldimethylsilyl deriva-
1
tives (Scheme 5) were found to exhibit well-behaved H NMR
signals.
To further investigate the apparently strong chelation control
in carbonyl additions, aryl ketone 2d was subjected to reactions
with Grignard reagents. As a result, tertiary alcohols 5a-c
1
1
tions, the aryl fluoride 2i underwent chemoselective nucleo-
philic aromatic substitution producing the phenol 2l (Scheme
). This example attests to the stability of N-H aziridine-
4
(Scheme 6, Table 2) were formed. Initial deprotonation of the
containing ketones under basic conditions: the aziridine ring
in 2l resists ring-opening, enabling chemoselective transforma-
tion at the periphery of the molecule.
With the ketoaziridines in hand, their participation in carbonyl
addition chemistry was evaluated. We hypothesized that upon
deprotonation, the NH group may facilitate chelative interactions
with metal-based nucleophiles. In the event, both 2g and 2h
were reduced to the corresponding secondary alcohols with
N-H aziridine moiety can be expected to result in a magnesium
amide intermediate. The ensuing bidentate chelation by the
2
+
aziridine amide and carbonyl oxygen to Mg provides a clear
basis for subsequent highly diasteroselective nucleophilic attack
(Scheme 6). In each case the products were formed as single
diastereomers. X-ray crystallographic structure determination
of 5c revealed that the reaction exclusively followed a stereo-
chemical course consistent with the chelation control model.
We have assigned the structures of 5a and 5b by analogy. These
examples of nucleophilic addition to 2-ketoaziridines stand in
contrast with the analogous transformations of 2-ketoepoxides,
12
sodium borohydride or lithium aluminum hydride (Scheme 5).
Interestingly, the reduction was found to produce a single
diastereomer: the structure of aziridinemethanol 3g was estab-
lished by X-ray crystallography. The product stereochemistry
is consistent with a chelation-control model. Previous examples
(
13) (a) Deyrup. J. A.; Moyer. C. L. J. Org. Chem. 1970, 35, 3424-
3
428. (b) Bartnik, R.; Lesniak, S.; Laurent, A. Tetrahedron Lett. 1981, 22,
(
9) The complications arise from undesired condensation chemistry. For
4811-4812.
a recent example of an amine-promoted aziridination of chalcones, see:
Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew. Chem. Int. Ed. 2006, 45,
(14) (a) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1223. (b)
Buckley, T. F.; Rapoport, H. J. Am. Chem. Soc. 1981, 103, 6157-6163.
(15) The sample was heated in an NMR tube after addition of pyridine
and cooled to room temperature prior to acquiring the spectrum.
(16) Deyrup, J. A. Chemistry of Heterocyclic Compounds; Hassner, A.,
Ed.; Wiley: New York, 1983; Vol. 4, pp 1-214. The barrier to inversion
in N-methylethylene imine is 19 kcal/mol, whereas the barrier to inversion
in trimethylamine is 7.5 kcal/mol. See: Nielsen, I. M. B. J. Phys. Chem. A
1998, 102, 3193.
8
3
3
1
005.
(10) Gomtsyan, A.; Koenig, R. J.; Lee, C.-H. J. Org. Chem. 2001, 66,
613-3616.
(
11) Rogers, J. F.; Green, D. M. Tetrahedron Lett. 2002, 43, 3585-
587.
(12) Sasaki, M.; Yudin, A. K. J. Am. Chem. Soc. 2003, 125, 14242-
4243.
J. Org. Chem, Vol. 72, No. 5, 2007 1739

Yu et al.
TABLE 2. Carbonyl Additions to Ketone 2d
began to form, which was suction-filtered after 20 min, washed
with diethyl ether, and used in the following step without further
purification.
Dicyclohexylcarbodiimide (2.05 g, 10 mmol) was added to a
solution of potassium 3-phenylglycidate (2.02 g, 10 mmol) in
anhydrous dichloromethane (10 mL) under nitrogen at 0 °C. N,O-
Dimethylhydroxylamine hydrochloride (970 mg, 10 mmol) was
added, and the mixture was warmed to room temperature and stirred
overnight. After 20 h, the solution was filtered and the filtrate was
concentrated in vacuo. The crude product was purified by flash
chromatography eluting with 5% acetone/dichloromethane, afford-
ing (()-N-methoxy-N-methyl-3-phenyloxirane-2-carboxamide as a
white gum (1.2 g, 60% from ethyl 3-phenylglycidate). This step
1
can be performed on the 30 g scale. H NMR (CDCl
3
, 300 MHz)
δ 7.38-7.31 (m, 5H), 4.09 (d, J ) 1.8 Hz, 1H), 3.93 (br s, 1H),
3
1
.72 (s, 3H), 3.28 (s, 3H). 13C NMR (CDCl
35.6, 128.7, 128.6, 125.8, 62.1, 57.6, 55.5, 32.6. HRMS (ESI)
3
, 75 MHz) δ 167.5,
+
3
m/z calcd for C11H14NO (MH ) 208.0968, found 208.0976.
Sodium azide (564.4 mg, 8.68 mmol) and ammonium chloride
(464.3 mg, 8.68 mmol) were added to a solution of (()-N-methoxy-
N-methyl-3-phenyloxirane-2-carboxamide (600 mg, 2.89 mmol) in
methanol (20 mL). The mixture was refluxed for 5 h, concentrated
by evaporation, and poured into a 1:1 mixture of ethyl acetate and
water. The aqueous layer was extracted with ethyl acetate (3 × 20
mL). The combined organic extracts were dried over anhydrous
sodium sulfate, filtered, and concentrated to yield a yellow oil ((()-
a
Reactions were performed with 1.0 equiv of 2d, 10 equiv of Grignard
reagent in THF, -78f0 °C or room temperature.
Addition of Grignard Reagents to Ketone 2da
SCHEME 6.
(2S,3S)-3-azido-2-hydroxy-N-methoxy-N-methyl-3-phenylpropana-
mide), which was carried to the following step without purification.
1
This step can be performed on the 30 g scale. H NMR (CDCl
00 MHz) δ 7.41-7.25 (m, 5H), 3.77 (d, 1H), 3.77 (s, 1H), 3.22
s, 3H), 2.04 (m, 4H, OH + NCH ).
Triphenylphosphine (788 mg, 3.00 mmol) was added in small
3
,
3
(
3
portions to a stirred solution of the azido alcohol intermediate (723.3
mg, 2.89 mmol) in acetonitrile (15 mL). Evolution of nitrogen gas
was observed. The mixture was stirred for 45 min at ambient
temperature before refluxing for 4 h, after which no starting material
a
Reagents and conditions: (a) RMgCl, THF, -78f 0 °C.
f
remained. Product had R 0.27 by TLC eluting with hexanes/ethyl
where chelation control relies upon the neutral epoxide oxygen.14a
In such cases, a balance between chelation control and open-
chain steric factors determines the magnitude and sense of
selectivity. Carbonyl additions to N-protected amino ketones
proceed with moderate stereocontrol.1 The diastereoselectivity
is typically strongly substrate and condition dependent. On the
other hand, Grignard additions to N-H aziridine ketones present
an instance where the diastereoselectivity of nucleophilic
addition is predictable by virtue of reliable chelation control
involving an anion as one of the chelate components. This type
of reaction may therefore have considerable synthetic utility for
the construction of complex nitrogen-containing frameworks.
In conclusion, 2-ketoaziridines can be formed in good yields
from Weinreb amides and organometallic reagents. A straight-
forward synthesis of aziridine-containing ketones has been
developed. The orthogonal relationship between aziridine and
ketone functionalities is maintained during reactions of these
amphoteric compounds. The reactions of 2-ketoaziridines with
hydride reducing agents and Grignard reagents were investi-
gated, and were shown to proceed with remarkably high
diastereoselectivities. The considerable synthetic utility of these
molecules is currently under investigation.
acetate 1:1. The solvent was evaporated in vacuo, the residue was
diluted with 30% ethyl acetate/hexanes, and the precipitate of
triphenylphosphine oxide was filtered. The filtrate was concentrated
in vacuo and the residue purified by flash chromatography, eluting
with 15% acetone/dichloromethane, to yield 1 as a pale yellow
4b
gummy solid (424 mg, 71% over two steps). This step can be
1
performed on the 30 g scale. Mp 37.2-38.0 °C. H NMR (CDCl
3
,
3
00 MHz) δ 7.32-7.25 (m, 5H), 3.69 (s, 3H), 3.28 (s, 3H), 3.11
3 4
(
dd, J ) 7.5 Hz, J ) 1.8 Hz, 1H), 3.00 (d, 1H), 2.04 (t, 1H, NH).
13C NMR (CDCl , 75 MHz) δ 170.4, 138.4, 128.4, 127.5, 126.1,
3
61.9, 40.0, 37.5, 32.8. HRMS (ESI) m/z calcd for C H N O
2
1
1
15
2
+
(MH ) 207.1128, found 207.1129.
General Procedure for Addition of Organometallic Reagents
to Amide 1. In a flame-dried Schlenk flask under a nitrogen
atmosphere, the aryl iodide (2.8 equiv, 1.34 mmol) was dissolved
in 3 mL of anhydrous tetrahydrofuran at -15 °C. Isopropylmag-
nesium chloride (2.8 equiv, 1.34 mmol) was added dropwise and
the solution was stirred for 30 min at -15 °C. The amide (1 equiv,
0.48 mmol) was added dropwise as a solution in 0.5 mL of
anhydrous tetrahydrofuran, and the reaction was allowed to warm
to room temperature. After 45 min, the reaction was cooled to 0
°C, quenched with 5 mL of water, and diluted with 5 mL of ethyl
acetate. The aqueous layer was extracted with ethyl acetate. The
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated. The crude products were purified by flash
chromatography over silica gel, eluting with 20% ethyl acetate/
hexanes.
Experimental Section
(
()-trans-N-Methoxy-N-methyl-3-phenylaziridine-2-carboxa-
(()-(2-Hydroxyphenyl)((2S,3R)-3-phenylaziridin-2-yl)metha-
none (2l). To a stirred solution of aryl fluoride 2i (0.124 mmol) in
1.5 mL of dry N,N-dimethylformamide was added 2-(methylsul-
fonyl)ethanol (0.186 mmol), and the solution was cooled to 0 °C.
Sodium hydride (0.498 mmol) was added, and the reaction mixture
mide (1). Ethyl 3-phenylglycidate (1.0 equiv, 30 g) was sonicated
in ethanol (400 mL). The mixture was cooled in an ice bath and a
solution of KOH (1.3 equiv, 7.54 g) in ethanol (100 mL) was added
slowly. A white solid precipitate (potassium 3-phenylglycidate)
1740 J. Org. Chem., Vol. 72, No. 5, 2007

Preparation and ReactiVity of Versatile R-Amino Ketones
was warmed to room temperature. The reaction was quenched with
water and extracted with ethyl acetate and brine. The organic layer
was concentrated to dryness and the crude organics purified by
phase was decanted and filtered, and the remaining solids were
washed with diethyl ether. The organic phase was dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue
was purified by flash chromatography.
flash column chromatography. Yield 22.1 mg (73%). Mp 59.7 °C.
1
H NMR (CDCl , 400 MHz) δ 11.92 (s, 1H), 7.83-6.89 (m, 9H),
3
3
4
3
4
3
.51 (dd, J ) 8.0 Hz, J ) 2.4 Hz, 1H), 3.22 (dd, J ) 9.2 Hz, J
2.4 Hz, 1H), 2.70 (br s, 1H). 1 C NMR (CDCl
99.7, 162.2, 162.2, 137.9, 137.0, 137.0, 129.7, 128.6, 128.0, 126.2,
19.4, 118.5, 44.0, 43.2. HRMS (ESI) m/z calcd for C15
3
Acknowledgment. We thank NSERC, Canada Foundation
for Innovation, ORDCF, Amgen, and University of Toronto for
financial support. X-ray crystallographic analysis was performed
by Dr. Alan Lough.
)
1
1
3
, 75 MHz) δ
H14NO
2
+
(
MH ) 240.1019, found 240.1030.
General Procedure for the Addition of Grignard Reagents
to 2d. A solution of 2d (0.2 mmol) in anhydrous tetrahydrofuran
20 mL) at -78 °C was treated with Grignard reagent (in
Supporting Information Available: Full experimental proce-
dures, characterization data, NMR spectra, and crystallographic
information files. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
tetrahydrofuran, 2 mmol). The reaction was warmed to 0 °C and
monitored by TLC (eluent: 3:2 hexanes/ethyl acetate). The reaction
was quenched with ice (1 mL) and several drops of saturated
aqueous sodium bicarbonate, under vigorous stirring. The liquid
JO062401O
J. Org. Chem, Vol. 72, No. 5, 2007 1741